Evaluation of women with possible appendicitis using technetium-99m leukocyte scan, The authors evaluated the use of technetium-99m albumin colloid white blood cell (TAC-WBC) scan in women with possible appendicitis. One hundred and nine women underwent 110 TAC-WBC scans. One woman had a second scan on a separate admission and was considered two individual patients in the analysis. Twenty-six women had appendicitis. 10 of whom had a perforated appendix at surgery. The TAC-WBC scan was indeterminate (abnormal but nondiagnostic for appendicitis) in 52 women (47%). nine of whom had appendicitis. Fifty-eight scans were read as positive or negative for appendiceal pathology. There were 16 true positives. 5 false positives. 36 true negatives. and 1 false negative. The predictive value of a positive scan was 76%. and the predictive value of a negative scan was 97%. The TAC-WBC scan was positive in 62% of patients with appendicitis and negative in 43% of the patients without appendicitis resulting in an overall accuracy of 47% in the 109 women. The main value of TAC-WBC scan in women with possible appendicitis is its high negative predictive value and the main problem with the TAC-WBC scan is its high indeterminate rate.
Cause of death in an emergency department, A retrospective review was done of 601 consecutive emergency department deaths. Nontrauma causes accounted for 77% of the deaths and this group had an average age of 64 years and a male to female ratio of 1.9:1. Trauma caused 23% of the fatalities and this group had a younger average age of 29 years and a male to female ratio of 4.6:1. The most common causes of nontrauma death were sudden death of uncertain cause (34%). coronary artery disease (34%). cancer (5%). other heart disease (4%). chronic obstructive lung disease (3%). drug overdose (3%). and sudden infant death syndrome (2%). The most common causes of trauma death were motor vehicle accidents (61%) and gunshot wounds (16%). The overall autopsy rate was 40%. Death certificates were often in error.
Intermittent obstruction of an incarcerated hiatal hernia with a total thoracic stomach, A case of intermittent obstruction of a sliding hiatal hernia is presented. The obstruction occurred when the patient's stomach was totally above the diaphragm. The anatomy of sliding hiatal hernias is discussed. as well as the presenting signs and symptoms of obstruction in sliding hiatal hernias.
Excitatory amino acids in the developing brain: ontogeny, plasticity, and excitotoxicity, Besides their role as neurotransmitters. excitatory amino acids (EAAs) in the developing brain are crucially involved in plasticity and excitotoxicity which are modified by their distinct ontogeny. Along with incomplete neuritogenesis and synaptogenesis. presynaptic markers of the EAA system are immature in the developing brain; however. postsynaptic EAA system activities. particularly of the N-methyl-D-aspartate and quisqualate receptors. are transiently enhanced early in life. This transient enhancement is presumably beneficial to the immature brain because physiologic activation of the EAA system plays a critical role in plasticity of early learning and morphogenesis. At the same time. this transient hypersensitivity renders the immature brain vulnerable to pathologic excitation of the EAA system (excitotoxicity) as observed during neonatal hypoxia-ischemia.
Anencephaly: clinical determination of brain death and neuropathologic studies, Twelve liveborn anencephalic infants were serially examined to determine if they would meet our clinical criteria for whole brain death within a 7-day period: Protocol 1 infants (6) received intensive care including intubation from birth; and Protocol 2 infants (6) received intensive care during the period in which death was imminent. Brain death was determined by absence of brainstem function. including loss of all cranial nerve responses and sustained apnea (PCO2 greater than 60 torr) for 48 hours with confirmation of findings by an outside consulting child neurologist. The initial examinations of these 12 infants revealed spontaneous movements and startle myoclonus (12). suck. root. and gag responses (7). increased tone (8). deep tendon reflexes (9). absent pupillary responses (9). absent oculocephalic and corneal responses (6). absent auditory/Moro responses (7). and nonvisualization of the optic nerve (8). Mild depression of neurologic function occurred during the first several days of life; subsequently. the infants' responses were easier to elicit and more sustained. Only 2 infants met the clinical criteria for brain death. Neuropathologic findings indicated that observed complex motor responses were not based upon cortical activity because no infant had a normally-formed cerebrum. Brainstem neuronal activity may have accounted for these motor responses in some patients but even at this level neurons were scanty or absent. Our findings suggest that. although rare. clinical brain death can be determined in liveborn anencephalic infants; ophthalmologic and otologic developmental abnormalities may confound examination of cranial nerve function; and absence of cortical neurons supports the widely held opinion that these infants do not experience sensation.
ACTH therapy in infantile spasms: relationship between dose of ACTH and initial effect or long-term prognosis, The relationship between the dose of ACTH and the initial effect was investigated in 41 children with infantile spasms. More than 0.015 mg (0.6 IU)/kg/day of ACTH was needed for a good initial response of seizures and electroencephalographic abnormalities. The relationship between the dose of ACTH and long-term prognosis was investigated in 29 patients. There was no relationship between the daily or total ACTH dosage. provided the dose was greater than 0.015 mg (0.6 IU)/kg/day. and the outcome of seizures and electroencephalographic abnormalities; however. ACTH 0.04-0.06 mg (1.6-2.4 IU)/kg/day and a total ACTH dose of 1.1-1.5 mg (44-60 IU)/kg resulted in better mental development than smaller doses of ACTH. Side effects of ACTH increased with dosage. Too small or too large a dose of ACTH does not lead to better mental development. The proper dose of ACTH should be used with careful attention to potential side effects.
Gross motor patterns in children with cerebral palsy and spastic diplegia, Rolling. sitting. and crawling patterns were motoscopically analyzed in 72 children with cerebral palsy and spastic diplegia; the relation between these patterns and the severity of the locomotive disability was studied. In rolling. trunk rotation and elbow support were difficult for the most severely diplegic children. When sitting. most patients had a between-heel sitting pattern in which the thighs were adducted and the knees were flexed. When crawling. the reciprocal thigh movements were insufficient and accompanied by lateral bending of the trunk in many patients. In the more impaired patients. the thighs supported the weight in flexion and did not move reciprocally. Creeping on the elbows without reciprocal leg movements was demonstrated in the most severely affected children after 2 years of age.
Dystrophin analysis in the differential diagnosis of autosomal recessive muscular dystrophy of childhood and Duchenne muscular dystrophy, We report 2 patients with childhood autosomal recessive muscular dystrophy. Both patients had slight muscle weakness without enlargement of the calf muscles or involvement of the facial muscles. Their clinical courses are static. Muscle histology revealed characteristic features of muscular dystrophy. Dystrophin was identifiable in the sarcolemma of both patients by immunocytochemical staining with an antidystrophin antibody. At an early age. immunocytochemical analysis with antidystrophin antibody was useful in distinguishing between childhood autosomal recessive and Duchenne muscular dystrophies.
Cerebellopontine angle lipoma in a teenager, Lipomas of the cerebellopontine angle are very rare lesions. To date. 18 patients have been reported. 17 of whom were adults. A second child is described with cerebellopontine angle lipoma.
The role of bacterial adherence in otitis media with effusion, Adherence of nontypable Haemophilus influenzae and Streptococcus pneumoniae to nasopharyngeal epithelial cells was investigated in vitro. Both strains had higher affinity to the epithelial cells of children than to those of adults. In children. the adherence was significantly greater in patients with otitis media with effusion than in normal subjects. Secretory IgA in nasopharyngeal secretions was found to have antibody activity against the bacteria. Adherence of both bacteria was significantly smaller in the group having secretory IgA antibody activity than in the group having no activity. These results suggest that bacterial adherence to the nasopharynx may play an important role in the pathogenesis of otitis media with effusion in children. and that secretory IgA in nasopharyngeal secretions may be related to the decrease of adherence.
Tissue expansion of the head and neck. Indications, technique, and complications, Tissue expansion is indicated in the reconstruction of various defects of the head and neck in instances where there is inadequate adjacent tissue to allow either primary closure of the defect or repair with a local flap. It may also be indicated in instances where repair of a defect by an alternative method such as a local. regional. or distant flap will result in an unacceptable donor or recipient site deformity. Although tissue expansion is simplistic in concept. it does require judgment and indepth preoperative planning to ensure optimal results. The complication rate is high for tissue expansion in the head and neck. particularly in the cheek and neck area. Despite the frequency of complications. in the vast majority of cases the intended reconstruction is successful.
Salivary gland cancer. A case-control investigation of risk factors, Unlike most upper aerodigestive tract cancers. salivary gland cancers are relatively infrequent. are characterized by a diversity of histologic subtypes. and have never been etiologically associated with tobacco exposure. We present the results of a case-control study of risk factors for these cancers. with risk estimates derived from self-administered comprehensive risk-factor questionnaires distributed to patients at The University of Texas M. D. Anderson Cancer Center. Houston. Cases were 64 patients with histologically confirmed salivary gland cancer. Control subjects. randomly selected from the same patient population excluding patients with cancer of the head and neck or nonmelanoma skin cancer. were frequency-matched to the cases by age. sex. and ethnicity to achieve a 2:1 control subjects/cases ratio. On multivariate analysis. prior radiotherapy was a significant risk factor for both men (odds ratio [OR] = 2.1) and women (OR = 2.3). Among women. higher educational attainment (OR = 2.4). alcohol use (OR = 2.0). and hairdye use (OR = 2.5) were also significantly associated with risk. There were no significant differences between cases and control subjects with respect to tobacco exposure or specific occupational or leisure-time exposures. There is biological plausibility for associations with hairdye use and alcohol exposure.
Cisplatin-fluorouracil interaction in a squamous cell carcinoma xenograft, Patients with squamous cell carcinoma of the head and neck are treated with cisplatin and fluorouracil according to a schedule based on the findings of clinical studies. A similar schedule showed a supra-additive effect in the treatment of xenografted human squamous cell carcinoma of the head and neck. We sought to ascertain whether this schedule was optimal. A single intraperitoneal injection of cisplatin (7.5 mg/kg) was combined with three injections of fluorouracil given during a 24-hour period (total dose. 150 or 80 mg/kg) before. during. or after cisplatin administration. The combined effect of cisplatin and fluorouracil on tumor growth and toxic effects was schedule dependent. Consideration of both toxic effects and tumor growth inhibition. as assessed by reduction of the area under the growth curve. the optimal administration interval was found to be fluorouracil given 3 days after cisplatin administration.
HLA class I and class II antigen expression on squamous cell carcinoma of the head and neck, We compared human major histocompatibility (HLA) class I and class II antigen expression on squamous cell carcinoma of the head and neck with that on normal mucosa. Frozen sections of a consecutive series of 30 squamous cell carcinomas were stained with the monoclonal antibodies W6/32 (class I) and anti-DR (class II) using an immunoperoxidase technique. Normal mucosa showed class I and class II expression in the basal layers only. Class I expression on tumors was diffuse in 87%. patchy in 10%. and scattered in 3%. Class II expression on tumors was diffuse in 20%. patchy in 53%. scattered in 20%. and absent in 7%. Patterns of expression did not correlate significantly with clinical parameters. including survival. except that class II diffuse and patchy patterns were found to correlate with more poorly differentiated tumors.
Transtympanic endoscopic findings in patients with otitis media with effusion, Using a fine. rigid endoscope (Olympus. SES-1711K). we examined the middle ear. including the tympanic orifice of the eustachian tube. of children with otitis media with effusion (OME) in its active stage (26 ears). in the convalescent stage (13 ears). and during treatment with ventilation tubes for 10 days to 6 months (five ears) through myringotomy with the patients under general anesthesia. Several color photographs of representative ears are shown. In the active stage of OME. edema (73.1%) and hyperemia (23.1%) were characteristic features of the middle ear mucosa. and normal mucosa was seen in only one ear (3.1%). The tympanic orifice of the eustachian tube. which could be examined in 12 ears. were stenosed with edema in four ears (33.3%) or plugged with effusion in three ears (25.0%) in this group. In the convalescent stage of OME. dilated vessels were most often seen (69.2%). but the rest of the patients had normal mucosa (30.8%) in the middle ear. and none of them had edema nor hyperemia. The tympanic orifice of the eustachian tube. which could be examined in five ears. was clearly patent in all the patients in this group. One ear that was treated with a ventilation tube for 1 month showed dilated vessels and less severe inflammation than did ears that were in the active stage of OME. and three ears that were treated for more than 3 months showed almost normal middle ear mucosa.
Computed tomography of metastatic cervical lymph nodes. A clinical, computed tomographic, pathologic correlative study, A retrospective comparative study of 63 neck dissections was undertaken to evaluate further the accuracy of high-resolution computed tomography (CT) in the detection of nodal metastases. as previous studies have indicated a trend toward the superiority of CT scanning over palpation. The respective values of neck examination. CT scanning. and histopathologic examination were assessed in 51 patients with head and neck cancer who underwent a total of 63 neck dissections. The overall agreement between clinical examination findings and histopathologic findings was 92% vs 81% for CT scanning. A retrospective analysis of the CT findings failed to reveal greater accuracy. We found nodes measuring 10 mm or more with central low density always to be malignant. Because CT scanning seems to offer little advantage over palpation in the nonirradiated neck. it should not be regarded as an essential tool in the staging of nodal disease. After radiation therapy. as neck dissection is only performed because of clinical or radiologic suspicion. CT scanning is of utmost importance.
Ultrasonic integrated backscatter two-dimensional imaging: evaluation of M-mode guided acquisition and immediate analysis in 55 consecutive patients, We have shown previously that cardiac cycle-dependent integrated backscatter characterizes the physical state of myocardium in patients with ischemic heart disease and cardiomyopathy. In the present study the clinical applicability of M-mode guided two-dimensional integrated backscatter imaging was defined in evaluation of 55 nonselected patients. The mean amplitude of cyclic variation of integrated backscatter in normal segments (long-axis view) was as follows: basal septum. 4.2 +/- 1.3 dB (mean +/- SD; n = 27). mid-septum. 4.5 +/- 1.0 dB (n = 26). basal posterior. 4.8 +/- 1.0 dB (n = 30). and mid-posterior. 4.8 +/- 1.2 decibels (n = 27). The respective mean delay values (R wave to nadir) were as follows: 0.89 +/- 0.09. 0.84 +/- 0.09. 0.86 +/- 0.09. and 0.85 +/- 0.12. At least one cardiac cycle could be analyzed fully in 62% of patients. Limitations included technically difficult two-dimensional echocardiography. inadequate M-line orientation. technically remediable errors. or poor quality integrated backscatter images. In abnormal segments (n = 13) cyclic variation was reduced and delay was prolonged (1.2 +/- 1.1 dB and 1.21 +/- 1.1. respectively). Intraobserver and interobserver variability for amplitude measurements were modest. with respective correlation coefficients of r = 0.93; r = 0.72. The findings demonstrate that M-mode--assisted integrated backscatter is a practical approach for characterization of regional myocardial properties promptly and at the bedside in a large portion of patients with cardiac disease.
Left and right ventricular flows by Doppler echocardiography: serial measurements in patients with aortic regurgitation during exercise, cold pressor stimulation, and vasodilation, To test the practicality of Doppler echocardiography to measure serial change. biventricular outputs were measured in 15 patients with aortic regurgitation during control periods and during interventions of bicycle exercise. cold pressor stimulation. and vasodilation. Biventricular stroke volumes were measured in 10 normal subjects for validation of methods and differed by 2.8%. Reading errors were 3.7%. Signal quality improved between the first and last observation (p less than 0.05). Velocity signals were corrected for intercept angles. which averaged 12 and 19 degrees for right heart flows and 31 and 32 degrees for the left side of the heart in all subjects. Negative correlations occurred between intercept angles and the chronologic order in which the patients were studied for left (p = 0.02) and right (p = 0.05) flows. Mean flow areas varied 9% in the left ventricle and 20% in the right ventricle. Total variability for measuring flow determined from control values was 11% to 13%. When twice the variability was used as the detectable level of change. only exercise provoked real increases in biventricular flows in the majority of patients. We conclude that serial measurements of flow by Doppler echocardiographic methods had to exceed 20% to 25% to achieve significant change. Measuring intercept angle. resolving flow area. and learning are variables that need greater emphasis.
Flow patterns in dilated cardiomyopathy: a pulsed-wave and color flow Doppler study, In 48 patients with dilated cardiomyopathy. pulsed-wave and color Doppler examination were performed. In addition. 14 normal patients served as control subjects. Peak inflow velocity at the level of the mitral valve. middle left ventricle. and apex and outflow velocity at the level of the apex. middle left ventricle. and subaortic area were measured. In normal patients there was brisk propagation of inflow velocity to the apex. Patients with dilated cardiomyopathy demonstrated delayed propagation and prolongation of the duration of inflow compared with control subjects (p less than 0.04). Continuous apical flow was visualized in 25% of dilated cardiomyopathies and in no normal patients. Apical velocities were significantly increased in cardiomyopathies with significant mitral regurgitation. Outflow velocities were decreased in dilated cardiomyopathy. In patients with dilated cardiomyopathy and apical dyskinesis. flow directed toward the base was measured in the middle left ventricle during isovolumic relaxation secondary to dyskinetic rebound. Patterns of abnormal flow in dilated cardiomyopathies are readily apparent by color M-mode and two-dimensional color Doppler.
Prevalence of aortic regurgitation by color flow Doppler in relation to aortic root size, To determine whether there is a correlation between aortic root size and the prevalence of aortic regurgitation. we performed color flow Doppler echocardiographic studies on 1015 consecutive patients during a 3-month period. Patients were grouped according to their M-mode aortic root diameter as measured in the left parasternal position. The measured groups ranged from 2.0 to 4.5 cm. grouped at 0.1 cm intervals. As the aortic root size enlarged. the prevalence of aortic regurgitation increased linearly (p less than 0.001; correlation coefficient. r = 0.75). At an aortic root size in the "small normal" range of 2.0 to 2.4 cm. the prevalence of aortic regurgitation was 0% to 15%. In the "intermediate" and "top normal" ranges of 2.9 to 3.7 cm. the prevalence of aortic regurgitation increased linearly from 15% to 47%. With aortic root dilation. the prevalence of aortic root regurgitation was generally more than 50%. The severity of aortic regurgitation was semiquantified. Aortic root size was not a good indicator for the severity of aortic regurgitation. Patients with moderate and severe aortic regurgitation had variable aortic root sizes. Throughout the range of aortic root sizes. mild aortic regurgitation predominated. We conclude that aortic regurgitation is a common finding in patients with aortic roots that are dilated or are in the "top normal" size range. that the prevalence of aortic regurgitation increases linearly with aortic root size. and that aortic root size does not correlate with the severity of aortic regurgitation.
Two-dimensional echocardiographic features of double outlet left ventricle, In a cyanotic newborn infant. the diagnosis of double outlet left ventricle was made from the two-dimensional echocardiographic examination. The diagnosis was later confirmed at cardiac catheterization and surgery. The parasternal and subcostal views were especially useful for identification of the origin of both great arteries from the morphologic left ventricle. A review of the medical literature since 1967 revealed 77 cases of double outlet left ventricle. most of which were diagnosed only at surgery or postmortem examination. The anatomic features demonstrated with two-dimensional echocardiography in this case are representative of the findings cited most often in the cases reported in the medical literature.
Evolution of the continuity equation in the Doppler echocardiographic assessment of the severity of valvular aortic stenosis, The use of Doppler techniques has greatly enhanced the noninvasive ultrasound technique for evaluation of valvular aortic stenosis. M-mode and two-dimensional echocardiography could not reliably distinguish patients with severe aortic stenosis from those with milder obstructions. The hemodynamic information offered by Doppler complemented echocardiographic imaging and provided an alternative modality for evaluation of patients with aortic stenosis. By application of the modified Bernoulli equation. the pressure gradient across the stenotic aortic valve could be estimated by Doppler echocardiography. Though helpful and widely used. the information provided by the pressure gradient across the valve about the severity of the obstruction was not complete. The assessment of valvular aortic stenosis therefore includes an estimation of the valve area by application of the continuity equation. This review examines the maturation of the continuity equation by Doppler techniques and discusses the implications of the procedure.
The determination of aortic valve area by the Gorlin formula: what the cardiac sonographer should know, The application of the Gorlin formula in the cardiac catheterization laboratory is the standard of reference for the determination of aortic valve area. The continuity equation now enables the cardiac sonographer to determine aortic valve area noninvasively in the echocardiography laboratory. The comparison of the results obtained by the two methods is inevitable. The cardiac sonographer should have a basic understanding of the theory and pitfalls of the Gorlin formula so that when conflicting results are obtained. the possible reasons why will be clear.
The evaluation of the abdominal aorta: a "how-to" for cardiac sonographers, A thorough evaluation of the abdominal aorta can be readily achieved by use of the standard views of the echocardiographic examination. The ultrasound evaluation of the abdominal aorta represents a logical extension of the standard echocardiographic examination of the adult patient. This article provides the information needed to carry out a complete ultrasound examination of the abdominal aorta including the anatomy. the vascular disease. and the steps involved in accomplishing the ultrasound examination of the abdominal aorta.
Multivariate analysis in the prediction of death in hospital after acute myocardial infarction, Prognostic factors in patients with acute myocardial infarction based on clinical and investigative data on admission were evaluated prospectively in 111 consecutive patients. Seventeen patients (15.3%) died during hospital stay. Age. a previous infarct. high Killip class. cardiomegaly. high serum concentrations of cardiac enzymes. a low ejection fraction. and a high wall motion score index correlated significantly with in-hospital mortality; whereas sex. risk factors. and pericardial effusion did not. Multivariate analysis showed that age and the wall motion score index were the best predictors of death in hospital. Wall motion detected by cross sectional echocardiography may reflect the extent of myocardial involvement. Age and wall motion score index predicted in-hospital mortality with a sensitivity of 76.5%. a specificity of 91.5%. and a predictive accuracy of 89.2%. Age and the wall motion score index can be determined on admission and are useful for identifying patients at high risk of cardiac death who might benefit from early intervention.
Ischaemic left ventricular failure: evidence of sustained benefit after 18 months' treatment with xamoterol, The long term effects of treatment with xamoterol in 14 patients aged 44-73 with mild to moderate heart failure as a result of ischaemic heart disease are reported. After 18 months' treatment with xamoterol. patients were assessed in a randomised double blind crossover comparison of xamoterol (200 mg twice a day) and placebo. each given for one month. Compared with placebo. xamoterol significantly increased exercise duration and work done on a bicycle ergometer and reduced the maximum exercise heart rate. Assessment of symptoms and activities at 12 months by visual analogue and Likert scales showed a trend towards the relief of symptoms of breathlessness and tiredness and an improvement in activity. There was an improvement in the clinical signs of heart failure and no haemodynamic deterioration over a 12 month period as assessed by ejection fraction. The improvement in exercise tolerance. symptoms. and activities was sustained for 18 months without side effects or development of tolerance.
Geographical clustering of risk factors and lifestyle for coronary heart disease in the Scottish Heart Health Study, A large cross sectional study. the Scottish Heart Health Study. of 10.359 men and women from 22 districts of Scotland was undertaken to try to explain the geographical variation of coronary heart disease mortality. Analysis by district showed that of the classic risk factors only cigarette smoking was strongly associated with heart disease mortality among both men and women. Mean diastolic blood pressure was weakly associated with rates among men and high density lipoprotein cholesterol showed a strong negative association among women. Total cholesterol showed a weak negative association with heart disease mortality. but. because the serum concentrations of cholesterol were uniformly high in all districts. a strong association with mortality would not be expected. In both men and women many dietary factors showed moderate or strong associations with mortality from coronary heart disease in a district--of these a low consumption of vitamin C was most notable. Other factors associated with heart disease included alcohol consumption and serum triglycerides among men. and obesity. physical activity. and serum triglycerides among women. Many factors associated with heart disease showed strong intercorrelations. Clustering of risk factors (including smoking. alcohol. and diet among men. and smoking. diet. and obesity among women) was associated with much of the regional variation in heart disease mortality in Scotland.
Cardiac catheterisation with 5 French catheters, From the beginning of November 1987 to the end of January 1989. 526 coronary arteriograms and left ventricular angiograms were performed with 5 French coronary catheters. In 448 (85%) patients diagnostic pictures were obtained with three standard types of 5 French catheters (No 4 Judkins): that is. left coronary. right coronary. and pigtail catheters. In 60 patients (11.4%) various other 5 French catheters were required to complete the study. In nine patients (1.7%). a 7 or 8 French catheter was used. Major complications causing cardiac arrest or requiring urgent operation developed in five patients. Sixty two patients (11.77%) had minor complications that required sublingual nitrates or a single bolus of atropine. or developed a haematoma that did not need intervention or had a mild reaction to the contrast material. Complications of moderate severity developed in 17 patients (3.2%): severe chest pain. arrhythmia requiring a temporary pacemaker. contrast reaction associated with hypotension. haematoma requiring blood transfusion. or a transient ischaemic episode. There were no deaths. 5 French catheters were used for routine coronary angiography and left ventriculography in 98.3% of patients. There were no major complications related to femoral artery puncture. The routine use of 5 French coronary catheters should increase the feasibility of safe coronary angiography in outpatients and should reduce the cost of this investigation.
Discrepancies in the measurement of isovolumic relaxation time: a study comparing M mode and Doppler echocardiography, Mitral valve cusp separation on M mode echogram. the mitral valve opening artefact. and the onset of forward transmitral flow recorded by Doppler echocardiography have all been taken to mark the end of isovolumic relaxation. while its onset has been taken either as the aortic closure sound (A2) recorded phonocardiographically or the aortic closure artefact determined by Doppler technique. Possible differences in the measurement of the isovolumic relaxation time were studied when these landmarks were used in 44 healthy people. 14 patients with mitral stenosis. 21 patients with left ventricular hypertrophy. and 24 patients with dilated cardiomyopathy by recording M mode echograms of the mitral valve. and pulsed and continuous wave Doppler spectra of transmitral flow. with simultaneous electrocardiograms and phonocardiograms. A2 was effectively synchronous with the aortic artefact. However. when the onset of Doppler flow was regarded as the end of isovolumic relaxation. the interval was significantly longer than when mitral cusp separation on M mode echograms was used: by 25 (10) ms in healthy individuals. by 25 (15) ms in patients with left ventricular hypertrophy. and by 50 (35) ms in patients with dilated cardiomyopathy. In patients with mitral stenosis the interval was only 5 (5) ms longer. The mitral valve opening artefact consistently followed the onset of flow and corresponded much more closely to the E point on the M mode echogram. This shows that it occurred during the rapid filling period and well beyond isovolumic relaxation by any definition. Thus isovolumic relaxation time measured from A2 to the onset of transmitral flow or the mitral valve opening artefact differs from that derived from A2 to mitral valve cusp separation. These intervals cannot be used interchangeably to measure "isovolumic relaxation time".
DNA content and Ks8.12 binding of the psoriatic lesion during treatment with the vitamin D3 analogue MC903 and betamethasone, Twenty patients with psoriasis were treated with the vitamin D3 analogue MC903 and betamethasone ointment in a double-blind trial with a left-right comparison. In addition to the clinical severity scores. Ks8.12 binding which detects keratin 16 expression and the DNA synthesis were quantified using flow cytometry. Both markers decreased significantly with treatment. but remained above the normal range even in those who had total clearance of the lesions. Treatment with MC903 with regard to Ks8.12 binding was significantly better than with betamethasone.
Invasive migration of epidemic Kaposi's sarcoma cells in vitro, Kaposi's sarcoma (KS) is a low grade malignant neoplasm which shows invasive growth and often occurs in immunosuppressed patients with the Acquired Immune Deficiency Syndrome (AIDS; epidemic KS). It is also found in elderly men where it is usually limited to the skin (classic KS). The present study investigated the chemotaxis and invasive migration of epidemic KS cells in vitro and compared them to cells grown from classic KS lesions and to fibroblasts. Epidemic KS cells demonstrated invasive migration through reconstituted basement membrane (Matrigel) as well as through interstitial connective tissue (collagen I) in early passages. whereas fibroblasts did not invade either barrier. Epidemic KS cells in late passages did not show any invasive migration. Following pretreatment with tumour necrosis factor alpha (TNF-alpha) there was no enhanced migration through the Matrigel and collagen I for epidemic KS cells. whereas classic KS cells showed an increased migration through the type I collagen barrier.
Neutrophil zinc levels in psoriasis and seborrhoeic dermatitis, The median zinc content of neutrophils was significantly reduced in 16 patients with psoriasis in comparison to both normal controls and six patients with seborrhoeic dermatitis (P less than 0.05). This reduction was unrelated to the extent of skin involvement. Plasma and erythrocyte zinc levels were unchanged.
Autologous mixed lymphocyte reaction is reduced in patients with psoriasis, The autologous mixed lymphocyte reaction (auto-MLR) was studied to test the interactions between immunocompetent cells in patients with psoriasis. The auto-MLR in 20 patients with psoriasis was significantly lower than in 16 normal controls. Lower values were found in untreated psoriatic patients than in those in remission following treatment. The values in the latter group were significantly lower than in controls and in six patients with atopic dermatitis in remission. The tendency for an increase in the auto-MLR with a decrease in disease activity was further confirmed in five patients studied before and after treatment. In contrast. the allogeneic lymphocyte reaction (allo-MLR) in psoriatics was similar to that in normal controls.
Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin, Pentoxifylline. an analogue of the methylxanthine theobromine. inhibits the proliferation and certain biosynthetic activities of fibroblasts derived from normal human skin. Fibroblasts from the skin of patients with keloids. scleroderma and morphoea were cultured in vitro in the presence and absence of pentoxifylline (100-1000 micrograms/ml) to determine whether it inhibits fibroblast proliferation and the production of collagen. glycosaminoglycans (GAG). fibronectin and collagenase activity. The exposure of subconfluent fibroblast cultures to pentoxifylline resulted in non-lethal. dose-dependent reductions in serum-driven fibroblast proliferation. with 1000 micrograms/ml pentoxifylline virtually negating the proliferative effect of serum on the cells. The fibroblasts assayed as confluent cultures produced reduced amounts. by up to 95%. of collagen and GAG. dependent on the concentration of pentoxifylline. both in the presence and absence of serum. Pentoxifylline similarly inhibited the fibronectin production by keloid and scleroderma fibroblasts. but had no effect on collagenase activity.
Effects of haem arginate on variegate porphyria, Four patients with variegate porphyria (VP) were treated with repeated haem arginate infusions daily for 4 days and then weekly for 4 weeks. After the initial four daily doses of haem arginate (haem 3 mg/kg). the excretion of faecal protoporphyrin (mean 579 nmol/g dry wt) fell to an almost normal level (mean 123 nmol/g dry wt). and that of coproporphyrin (mean 162 nmol/g dry wt) to the normal level (mean 21 nmol/g dry wt) in all patients. However. during the period of the four weekly infusions of haem the excretion of porphyrins increased almost to the pretreatment level. Phototesting showed no changes in the photoreactivity of the skin. and no improvement in skin lesions was seen during the treatment. Except for one case of thrombophlebitis no side-effects occurred. In a child with homozygous VP. four daily infusions of haem arginate (2 mg/kg) normalized the faecal protoporphyrin content. but had no effect on the increased erythrocyte protoporphyrin concentration.
Effects of recombinant human interleukin-3 in aplastic anemia, In a phase I/II study. nine patients with aplastic anemia were treated with recombinant human interleukin-3 (rhIL-3) to assess the toxicity and biologic effects of this multipotential hematopoietic growth factor. Doses ranging from 250 micrograms/m2 to 500 micrograms/m2 were administered as subcutaneous bolus injections daily for 15 days. An increase in platelet counts from 1.000/microL to 31.000/microL was induced by rhIL-3 in one patient. and an increase in reticulocyte counts by more than 10.000/microL in four patients. The blood leukocyte counts temporarily increased in eight patients 1.5- to 3.3-fold (median. 1.8-fold). mainly due to an increase in the number of neutrophils. eosinophils. lymphocytes. and monocytes. In two patients. bone marrow cellularity increased from 7% to 33% and from 10% to 80%. respectively. but without resulting in a substantial improvement of peripheral blood counts. Mild side effects (headache and flushing) were observed in some patients. while low-grade fever occurred in all patients. Transient thrombocytopenia necessitating discontinuation of rhIL-3 treatment occurred in one patient. In conclusion. rhIL-3 can stimulate hematopoiesis in patients with aplastic anemia; however. no lasting effects were obtained.
Impact of marrow cytogenetics and morphology on in vitro hematopoiesis in the myelodysplastic syndromes: comparison between recombinant human granulocyte colony-stimulating factor (CSF) and granulocyte-monocyte CSF, Marrow cells from 36 patients with myelodysplastic syndromes (MDS) (13 refractory anemia [RA]. 14 refractory anemia with excess of blasts [RAEB]. 9 RAEB in transformation [RAEB-T]) were evaluated for their in vitro proliferative and differentiative responsiveness to recombinant human granulocyte colony-stimulating factor (G-CSF) or granulocyte-monocyte CSF (GM-CSF). GM-CSF exerted a stronger proliferative stimulus than G-CSF for marrow myeloid clonal growth (CFU-GM) in these patients (44 v 12 colonies per 10(5) nonadherent buoyant bone marrow cells [NAB]. respectively. P less than .025). GM-CSF stimulated increased CFU-GM growth in the 16 patients with abnormal marrow cytogenetics in comparison with the 20 patients who had normal cytogenetics (52 and 30 colonies per 10(5) NAB. respectively. P less than .05). whereas no such difference could be demonstrated with G-CSF (11 and 16 colonies per 10(5) NAB. respectively). In contrast. granulocytic differentiation of marrow cells was induced in liquid culture by G-CSF in 15 of 32 (47% patients). while GM-CSF did so in only 4 of 18 (22%) patients (P less than .025) including. for RAEB/RAEB-T patients: 9 of 18 versus 0 of 9. respectively (P less than .025). For MDS patients with normal cytogenetics. G-CSF- and GM-CSF-induced marrow cell granulocytic differentiation in 12 of 18 (67%) versus 3 of 11 (27%). respectively (P less than .025). contrasted with granulocytic induction in only 3 of 14 (21%) and 1 of 7 (14%) patients with abnormal cytogenetics. respectively. We conclude that G-CSF has greater granulocytic differentiative and less proliferative activity for MDS marrow cells than GM-CSF in vitro. particularly for RAEB/RAEB-T patients and those with normal cytogenetics.
Selective regulation of the activity of different hematopoietic regulatory proteins by transforming growth factor beta 1 in normal and leukemic myeloid cells, The viability of normal bone marrow myeloid precursor cells induced by interleukin-6 (IL-6) or IL-1 alpha and the ability of IL-6 and IL-1 alpha to induce the formation of colonies of granulocytes. macrophages. or megakaryocytes in densely seeded bone marrow cultures was suppressed by transforming growth factor-beta 1 (TGF-beta 1). Induction of normal bone marrow colony formation by IL-3 was much less sensitive to TGF-beta 1. and there was little or no effect of TGF-beta 1 on colony formation induced by macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage CSF (GM-CSF). In different clones of myeloid leukemic cells. TGF-beta 1 suppressed differentiation induced with IL-6. IL-1 alpha. or lipopolysaccharide (LPS). but did not suppress differentiation induced with IL-3 or GM-CSF. The effect of TGF-beta 1 on differentiation of the leukemic cells can be dissociated from its effect on cell growth. TGF-beta 1 suppressed the production of IL-6 in normal bone marrow cells cultured with IL-1 alpha and the production of IL-6 and GM-CSF in leukemic cells cultured with IL-1 alpha or LPS. The suppression of IL-6 production can explain the suppression by TGF-beta 1 of the effects of IL-1 alpha and LPS that are mediated by IL-6. TGF-beta 1 also suppressed differentiation in clones of myeloid leukemic cells induced with differentiation factor/leukemia inhibitory factor and tumor necrosis factor. In different leukemic clones TGF-beta 1 suppressed or enhanced induction of differentiation with dexamethasone. The results show that TGF-beta 1 can selectively control the activity of different molecular regulators of normal and leukemic hematopoiesis.
A specific in vitro bioassay for measuring erythropoietin levels in human serum and plasma, The accurate measurement of biologically active erythropoietin (Ep) in human serum and plasma using present in vivo and in vitro bioassays is difficult because of the presence of both inhibitors and non-Ep stimulators of erythropoiesis. We have developed a simple procedure to quantitatively purify Ep from serum and plasma for subsequent testing in the phenylhydrazine-treated mouse spleen cell assay. The method involves absorption of Ep to an immobilized high-affinity anti-Ep monoclonal antibody and acid elution of the antibody-bound material. After neutralization. the eluted EP is then tested directly in the in vitro bioassay without interference by other serum proteins. By using magnetic beads as a solid support for the antibody. washing and elution steps can be performed rapidly and efficiently. Recoveries of Ep after this procedure show very little sample-to-sample variation and are consistently between 45% and 55%. which is close to the maximum binding expected for the anti-Ep antibody. Coupled with the 7.4-fold concentration that this procedure affords. there is an overall increase in sensitivity of three- to fourfold. which makes this assay suitable for accurately measuring Ep levels in patients with below-average titers. Results with this magnetic bead assay indicate that accurate and reproducible estimates for Ep levels in the serum and plasma from healthy donors as well as from patients with hematologic disorders can be obtained. Titers of biologically active Ep in the sera from a group of patients with either leukemia or lymphoma were found to be elevated. and the values correlated well with titers of immunoreactive Ep measured in the Ep radioimmunoassay. Because of its specificity and high sensitivity. the magnetic bead assay is a valuable alternative to immunoassays for the measurement of elevated. normal. and even subnormal Ep levels in human serum and plasma.
Induction of mixed erythroid-megakaryocyte colonies and bipotential blast cell colonies by recombinant human erythropoietin in serum-free culture, The effects of recombinant human erythropoietin (rEp) on murine hematopoietic progenitors were studied using a serum-free culture. A high concentration of rEp stimulated the formation of mixed erythroid-megakaryocyte colonies (EM colonies) and blast cell colonies. as well as erythroid colonies. erythroid bursts. and megakaryocyte colonies from normal mouse bone marrow cells. Direct effects of rEp on EM colony. megakaryocyte colony. and erythroid burst formation were confirmed by depletion of accessory cells such as T cells. B cells. and macrophages from crude bone marrow cells. and inhibition of the colonies by the addition of rabbit anti-rEp antibody to the culture in a dose-dependent fashion. Replating experiments were performed to confirm the differentiating ability of blast cell colonies grown in the presence of rEp. Most of the blast cell colonies yielded not only secondary erythroid colonies but also megakaryocyte colonies in the presence of 2 IU/mL rEp. Some of the blast cell colonies produced secondary EM colonies in the presence of 16 IU/ml rEp of 2 IU/mL rEp plus interleukin-3. although no granulocyte-macrophage colonies were found in the secondary culture. These results suggest that Ep acts not only as a late-acting factor that is specific for erythroid progenitors. but also as a bipotential EM-stimulating factor for murine hematopoietic cells.
Uremic platelets have a functional defect affecting the interaction of von Willebrand factor with glycoprotein IIb-IIIa, Uremic patients have an impaired platelet function that has been related to membrane glycoprotein (GP) abnormalities. Using a perfusion system. we have studied the interaction of normal and uremic platelets with vessel subendothelium (SE) under flow conditions. Reconstituted blood containing washed platelets. purified von Willebrand factor (vWF) (1 U/mL). and normal washed red blood cells was exposed to de-endothelialized rabbit segments for 10 minutes at two different shear rates (800 and 1.600 seconds-1). In some experiments a monoclonal antibody to the GPIIb-IIIa complex (EDU3) was added to the perfusates. With normal platelets. the percentage of the vessel covered by platelets (%CS) was 23.1% +/- 3.7% at 800 seconds-1 and 30% +/- 4.3% at 1.600 seconds-1. Platelets were observed in contact or forming monolayers on vessel SE. EDU3 inhibited the spreading of normal platelets. The %CS (11.1% +/- 3.3%) was statistically decreased (P less than .01) and most of the platelets were observed in contact with the vessel surface. These data indicate that. under flow conditions. the interaction of vWF with GPIIb-IIIa can support the spreading of normal platelets in the absence of exogenous fibrinogen. Under the same experimental conditions. the interaction of uremic platelets with SE was markedly impaired at both shear rates studied (P less than .01 v normal platelets). The presence of EDU3 did not modify the interaction of uremic platelets. These results confirm the impairment of the platelet adhesion observed in uremic patients. Furthermore. they indicate the presence of a functional defect in the interaction of vWF with GPIIb-IIIa. The fact that perfusions with normal and uremic platelets in the presence of an antibody to the GPIIb-IIIa complex did not show any differences gives indirect evidence on a functionally normal interaction vWF/GPIb in uremic patients.
Distinct characteristics of lymphokine-activated killer (LAK) cells derived from patients with B-cell chronic lymphocytic leukemia (B-CLL). A factor in B-CLL serum promotes natural killer cell-like LAK cell growth, We show that lymphokine-activated killer (LAK) cell precursors derived from patients with B-cell chronic lymphocytic leukemia (B-CLL) and cultured in the presence of recombinant interleukin-2 and normal human serum (NHS). develop into primarily NK cell-like (CD 57+) LAK cells. whereas identically prepared LAK cell precursors from normal subjects develop into mainly T cell-like (CD 3+. CD 8+) LAK cells. B-CLL LAK cells exhibited greater proliferative capacity than did normal LAK cells. When normal LAK cells were grown in B-CLL serum instead of NHS. their proliferation increased; NK cell levels also increased to those found in B-CLL LAK cells. suggesting that B-CLL serum contains a factor that promotes NK cell-like growth. LAK cells derived from normal or B-CLL patients demonstrated similar lytic activity toward K562 and Raji cells. Growth in B-CLL serum did not reduce their lytic potential. Thus. the altered phenotype and growth exhibited by B-CLL LAK cells and normal LAK cells grown in B-CLL serum does not lead to abnormalities in their cytolytic functions. We propose instead that the predominance of NK-like cells in B-CLL LAK cell populations and the presence of an NK cell-like growth factor in B-CLL serum reflect abnormalities related to NK cell-mediated B-cell regulation; ie. either inhibition of normal B-cell growth and/or growth stimulation of the leukemic clone in B-CLL.
Genotypic characterization of centrocytic lymphoma: frequent rearrangement of the chromosome 11 bcl-1 locus, Centrocytic lymphomas are defined in the Kiel classification as B-cell lymphomas composed exclusively of cells resembling cleaved follicular center cells (FCC). These lymphomas have been shown to be histologically. immunophenotypically. and clinically distinct from other cleaved FCC lymphomas. DNA from 18 centrocytic lymphomas (14 patients) was analyzed using Southern blotting and probes for immunoglobulin heavy (JH) and kappa light chain (JK) joining gene. T-cell receptor beta chain constant gene (CB). bcl-1. bcl-2. and c-myc gene rearrangements. All of the lymphomas had JH and JK rearrangements. confirming their B-cell origin. None of the specimens had detectable CB. bcl-2. or c-myc rearrangements. However. 4 of 14 patients (28.6%) had rearrangement of the chromosome 11 bcl-1 locus. Therefore. centrocytic lymphomas are genotypically distinguishable from the majority of other small cleaved FCC lymphomas by their lack of demonstrable bcl-2 rearrangements. This supports the distinct nature of centrocytic lymphomas and suggests the lack of importance for the putative oncogene bcl-2 in these cases. Furthermore. the frequent rearrangement of bcl-1 suggests a possible role for this locus in the pathogenesis of at least some centrocytic lymphomas.
Transfusion and alloimmunization in sickle cell disease. The Cooperative Study of Sickle Cell Disease, In 1.814 patients with sickle cell disease who had been transfused. the overall rate of alloimmunization to erythrocyte antigens was 18.6%. The rate of alloimmunization in this group appears to be an explicit function of the number of transfusions received because it increases exponentially with increasing numbers of transfusions. Alloimmunization usually occurred with less than 15 transfusions. although the rate of alloimmunization continued to increase when more transfusions were given. The rate of alloimmunization was less in patients with hemoglobin SC disease and sickle-beta+ thalassemia because these patients had received fewer transfusions. Children less than 10 years old had a slightly lower rate of alloimmunization than patients in other age groups even after correction for the number of transfusions given. Women were more frequently alloimmunized than men; this was largely due to the fact that women received more transfusions than men. but in the age group 16 to 20 years the increase may have been due in part to alloimmunization owing to pregnancy. Forty-five percent of those alloimmunized made antibodies of only one specificity; 17% made four or more antibodies reacting with different antigens. Antibodies to the C and E antigens of the Rh group. the Kell antigen. and the Lewis antigens were most commonly made. These findings may be important in formulating a rational transfusion policy in sickle cell disease.
Coordinate secretion of interleukin-1 beta and granulocyte-macrophage colony-stimulating factor by the blast cells of acute myeloblastic leukemia: role of interleukin-1 as an endogenous inducer, Acute myeloblastic leukemia (AML) blasts have been shown to produce a variety of cytokines in culture such as interleukin-1 (IL-1). IL-6. granulocyte-. macrophage-. and granulocyte-macrophage colony-stimulating factor (GM-CSF). and tumor necrosis factor-alpha (TNF alpha). Using two sensitive and specific enzyme-linked immunosorbent assays for IL-1 beta and GM-CSF. we document in the present study that the production of the two cytokines by AML blasts in culture is coordinated. First. we observe a striking correlation between the levels of GM-CSF and IL-1 beta released by the cells. Thus. a high production of IL-1 beta is always concordant with a high production of GM-CSF and. conversely. low production of IL-1 beta is concordant with low levels of GM-CSF. Second. neutralization of intrinsic IL-1 using antibodies that are specific for IL-1 alpha and -1 beta suppresses the release of GM-CSF by the cells. Third. neutralization of the endogenous source of IL-1 also results in an abrogation of GM-CSF mRNA. Fourth. the production of both IL-1 beta and GM-CSF is up-regulated by exposing AML blasts to an exogenous source of IL-1. suggesting a positive regulation of autocrine growth factor production. Taken together. our results indicate that GM-CSF production by AML blasts is mediated by endogenously produced IL-1. Both IL-1 beta and -1 alpha are produced by AML blasts. although IL-1 beta appears to be more abundant. Spontaneous colony formation by AML blasts is abrogated by the addition of neutralizing antibodies against IL-1 beta and GM-CSF. whereas each antibody alone has little effect on blast proliferation. Taken together. our results are consistent with the view that the production of IL-1 beta by AML blasts supports autocrine growth in culture. through induction of CSFs or other cytokines that stimulate blast proliferation.
The pharmacokinetics of plasminogen activator inhibitor-1 in the rabbit, The pharmacokinetics of the activated and latent forms of plasminogen activator inhibitor-1 (PAI-1) isolated from HT1080 fibrosarcoma cells (HT1080 PAI-1) and a nonglycosylated form of human PAI-1 isolated from a yeast expression system (rPAI-1) were followed in the rabbit. As assessed by an immunologic assay specific for human PAI-1. guanidine HCI activated HT1080 PAI-1 and rPAI-1 entered the total plasma volume following intravenous bolus administration and exhibited a biphasic clearance pattern. The t1/2s of HT1080 PAI-1 for the initial and beta phases equalled 6.0 and 24.8 minutes. respectively. The t1/2s of rPAI-1 for the initial and beta phases equalled 8.8 and 34.0 minutes. respectively. Similar results were obtained by measuring PAI-1 activity in plasma and with trace amounts of 125I-rPAI-1. suggesting that the above pharmacokinetic behavior could also apply to endogenous PAI-1. The liver was the main site of rPAI-1 clearance. Unactivated. latent PAI-1 exhibited a very different pharmacokinetic profile. Over 80% of latent rPAI-1 cleared from the circulation within 10 minutes (t1/2 = 1.7 minutes). The difference in clearance behavior between activated and latent PAI-1 may be related to the ability of activated PAI-1. but not latent PAI-1. to rapidly form high-molecular-weight complexes with plasma binding factors which were observed in vitro and in vivo. Because PAI-1 could potentially tilt the fibrinolytic balance toward a prothrombotic state. its rapid clearance may represent an important control mechanism governing the circulating levels of this key component of the fibrinolytic pathway.
Recombinant lipoprotein-associated coagulation inhibitor inhibits tissue thromboplastin-induced intravascular coagulation in the rabbit, Lipoprotein-associated coagulation inhibitor produces feed-back inhibition of tissue factor (tissue thromboplastin)-induced coagulation in the presence of factor Xa Recombinant lipoprotein-associated coagulation inhibitor (rLACI) was tested for its ability to modify thromboplastin-induced intravascular coagulation in a rabbit model that allows monitoring of iodine-125 fibrin accumulation/disappearance in the lung and sampling of blood for the measurement of coagulation parameters. Infusion of thromboplastin into the rabbit caused a rapid increase of radioactivity over the lungs. possibly due to the accumulation of 125I fibrin in the lungs. followed by a rapid decline of radioactivity. suggestive of removal of fibrin from the lungs. Thromboplastin also caused a rapid decrease of systemic fibrinogen that was accompanied by a lengthening of the activated partial thromboplastin time and prothrombin time. The effect of coinfusion of rLACI with thromboplastin or bolus injection of rLACI before thromboplastin infusion was studied. At a high dose of rLACI (800 micrograms/kg body weight). the thromboplastin-induced radioactivity increase in the lungs and the systemic fibrinogen decrease were completely suppressed. The activated partial thromboplastin time and prothrombin time of the plasma samples lengthened. possibly due to the presence of thromboplastin in circulation. The thromboplastin-induced radioactivity increase over the lungs was not completely suppressed by lower doses of rLACI (135 to 270 micrograms/kg body weight). but these doses of rLACI prevented systemic fibrinogen decrease. At a bolus dose of 23 micrograms/kg body weight. rLACI provided 50% protection of the fibrinogen consumption (fibrinogen decreased to 82% compared with 65% in rabbits treated with thromboplastin alone). These results show that rLACI is effective in the inhibition of thromboplastin-induced coagulation in vivo.
Effect of recombinant human granulocyte-macrophage colony-stimulating factor administration on the lymphocyte subsets of patients with refractory aplastic anemia, Human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was administered to 14 patients with refractory aplastic anemia (AA). The effect of rhGM-CSF therapy on the lymphocyte phenotype; on the proliferative responses to the mitogen phytohemagglutinin. Candida albicans. and tetanus toxoid antigens; and on the natural killer (NK) activity of the circulating lymphocytes was studied. Samples were collected before (baseline) and twice during the rhGM-CSF administration. The absolute number of circulating lymphocytes remained relatively constant during the first period. but experienced a significant increase (P less than .001) during the second period. The increase was most prominent in the B cells (P less than .001). but the T cells (P less than .016) also increased. Detailed investigation of lymphocyte subsets showed an increase of the markers CD38 (Leu17). HLA-DR. and the transferrin receptor throughout the treatment course giving evidence of lymphoid cell activation. The NK cell activity was suppressed (P less than .008) throughout the treatment. However. proliferative responses to phytohemagglutinin. Candida antigen. and tetanus toxoid were unaffected. Although the mechanism is not yet defined. GM-CSF does induce activation and increase in absolute lymphoid cell number. especially B cells. together with a decrease in NK cytotoxicity. The implication of these immune cell changes in relation to host resistance to microorganisms remains to be established.
The role of cellular maturation in neutrophil heterogeneity, Previous studies have shown that many neutrophil (PMN) characteristics are heterogeneous but the origin of PMN heterogeneity is unknown. It is unclear if PMN functional heterogeneity is secondary to maturational differences or due to distinct subpopulations of cells that possess different functional capacities. The PMN 31D8 antigen is a useful probe for evaluation of PMN subpopulations. The majority of PMNs (approximately 85%) exhibit a high intensity fluorescence after 31D8 monoclonal antibody (MoAb) labeling (31D8 enriched or "bright" PMNs) as determined by flow cytometric analysis. These cells are more functional than cells with low intensity fluorescence (31D8 diminished or "dull" PMNs). Various immunologic. clonogenic and functional techniques were used to study the expression of the 31D8 antigen in HL-60 cells and myeloid cells in order to evaluate antigenic and functional heterogeneity during morphologic maturation. The results of this study indicate that the percentage of 31D8 antigen positive (31D8 antigen enriched and diminished) bone marrow cells increases from 20 +/- 11% in myeloblast cells to 68 +/- 10% in promyelocytes. 93 +/- 2% in myelocytes and 99 +/- 1% in bands and PMNs. 31D8 antigen enriched cells first appear at the myelocyte stage (32 +/- 10%) and increase in bands (52 +/- 13%). marrow PMNs (62 +/- 13%) and peripheral blood PMNs (88 +/- 4%). These data indicate that the heterogeneous expression of 31D8 antigen in PMNs is due. at least in part. to maturational differences within the PMN population and raise the possibility that other heterogeneously expressed PMN characteristics are also maturationally derived. They also suggest that 31D8 antigenic expression may be a more precise indicator of myeloid functional maturation than maturation as identified by cellular morphology.
B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny, The circulating lymphocytes of 88 consecutive patients following autologous. conventional. or T-cell depleted bone marrow transplantation were serially analyzed for B-cell surface antigen expression and function. In the majority of patients. except for those who developed chronic graft-versus-host disease. the number of circulating CD20+ B cell normalized by the fourth posttransplant month. The earliest detectable B cells normally expressed HLA-DR. CD19. surface immunoglobulin (slg). CD21. Leu-8. and lacked expression of CD10 (CALLA). In addition. the circulating B cells expressed CD1c. CD38. CD5. and CD23 for the first year following transplant. antigens that are normally expressed on a small percentage of circulating B cells in normal adults. but highly expressed on cord blood B cells. Similar to cord blood B cells. patient B cells isolated during the first year following transplant. proliferated normally to Staphylococcus aureus Cowan strain I (SAC). and produced IgM. but minimal or no IgG when stimulated with pokeweed mitogen and SAC. unlike normal adult B cells that produce both. The similar phenotype and function of posttransplant and cord blood B cells. and their similar rate of decline in patients and normal children adds further evidence to support the hypothesis that B-cell differentiation posttransplant is recapitulating normal B-cell ontogeny.
Transmission of HTLV-I by blood transfusion and its prevention by passive immunization in rabbits, To determine the minimum volume of blood required to transmit human T-cell leukemia virus type I (HTLV-I). heparinized blood was collected from a virus-infected female rabbit and aliquots of 10. 5. 1. 0.5. 0.1. and 0.01 mL were transfused into groups of two male rabbits each. All 10 rabbits transfused with 10 to 0.1 mL and 1 of 2 rabbits transfused with 0.01 mL seroconverted for HTLV-I after 2 to 4 weeks. HTLV-I-producing lymphoid cell lines of recipient origin were established from one seroconverted rabbit of each aliquot group. To determine the ability of passive immunization to protect against HTLV-I infection. two groups of three rabbits were first transfused with 5 mL of blood from the same virus-infected rabbit and then infused after 24 or 48 hours with 10 mL of HTLV-I immune globulin (77 mg/mL of IgG) prepared from seropositive healthy persons. None of the 24-hour immunization group seroconverted for HTLV-I during the observation period of six months; however. all of the 48-hour immunization group became seropositive after 2 to 4 weeks. These results indicate that HTLV-I can be transmitted with as little as 0.01 mL of virus-infected blood. and that passive immunization is effective in preventing cell-to-cell infection of HTLV-I when given within 24 hours of transfusion of virus-infected blood.
Adrenaline and nocturnal asthma, OBJECTIVE--To determine whether the nocturnal fall in plasma adrenaline is a cause of nocturnal asthma. DESIGN--Double blind placebo controlled cross-over study. In the first experiment the nocturnal fall in plasma adrenaline at 4 am was corrected in 10 asthmatic subjects with an infusion of adrenaline after parasympathetic blockade with 30 micrograms/kg intravenous atropine. In the second experiment 11 asthmatic subjects showing similar variations in peak expiratory flow rate had the nocturnal fall in plasma adrenaline corrected by infusion before atropine was given. PATIENTS--Asthmatic subjects with a diurnal variation in home peak expiratory flow rate of greater than 20% for at least 75% of the time in the two weeks before the study. MAIN OUTCOME MEASURES--Peak expiratory flow rate and plasma adrenaline. RESULTS--Correction of the nocturnal fall in plasma adrenaline at 4 am to resting 4 pm levels did not alter peak expiratory flow rate either before or after parasympathetic blockade with atropine. CONCLUSION--A nighttime fall in plasma adrenaline is not a cause of nocturnal asthma.
Rectal examination in general practice, OBJECTIVE--To investigate factors influencing a general practitioner's decision to do a rectal examination in patients with anorectal or urinary symptoms. DESIGN--Postal questionnaire survey. SETTING--General practices in inner London and Devon. SUBJECTS--859 General practitioners. 609 (71%) of whom returned the questionnaire. MAIN OUTCOME MEASURES--Number of rectal examinations done each month; the indication score. derived from answers to a question asking whether the respondent would do a rectal examination for various symptoms; and the confidence score. which indicated the respondent's confidence in the diagnosis made on rectal examination. RESULTS--279 General practitioners did five or fewer rectal examinations each month and 96 did more than 10 each month. Factors significantly associated with doing fewer rectal examinations were a small partnership and being a female general practitioner. and the expectation that the examination would be repeated. Lack of time in the surgery. and a waiting time of less than two weeks for an urgent outpatient appointment were also important. General practitioners were deterred from doing rectal examinations by reluctance of the patient (278). the expectation that the examination would be repeated (141). and lack of time (123) or a chaperone (39). Confidence in diagnosis was significantly associated with doing more rectal examinations. the perception of having been well taught to do a rectal examination at medical school. and being a male general practitioner. CONCLUSIONS--Factors other than clinical judgment influence the frequency of rectal examination in general practice. Rectal examination may become commoner with the trend towards larger group practices and if diagnostic confidence is increased and greater emphasis put on rectal examination in undergraduate and postgraduate teaching.
Menstrual state and exercise as determinants of spinal trabecular bone density in female athletes, OBJECTIVE--To study the effects of amenorrhoea and intensive back exercise on the bone mineral density of the lumbar spine in female athletes. DESIGN--Cross sectional study comparing amenorrhoeic with eumenorrhoeic athletes and rowers with non-rowers. SETTING--The British Olympic Medical Centre. Northwick Park Hospital. PATIENTS--46 Elite female athletes comprising 19 rowers. 18 runners. and nine dancers. of whom 25 were amenorrhoeic and 21 eumenorrhoeic. MAIN OUTCOME MEASURE--Trabecular bone mineral density of the lumbar spine measured by computed tomography. RESULTS--Mean trabecular bone mineral density was 42 mg/cm3 (95% confidence interval 22 to 62 mg/cm3) lower in the amenorrhoeic than the eumenorrhoeic athletes; this difference was highly significant (p = 0.0002). Mean trabecular bone mineral density was 21 mg/cm3 (1 to 41 mg/cm3) lower in the non-rowers than the rowers; this was also significant (p = 0.05). There was no interaction between these two effects (p = 0.28). CONCLUSION--The effect of intensive exercise on the lumbar spine partially compensates for the adverse effect of amenorrhoea on spinal trabecular bone density.
Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study, OBJECTIVE--To evaluate the antihypertensive activity of potassium given alone or in combination with magnesium in patients with mild hypertension. DESIGN--A double blind. randomised. placebo controlled. crossover trial of 32 weeks' duration. SETTINGS--Cardiology outpatient department. Sassoon General Hospitals. Pune. India. PATIENTS--37 Adults with mild hypertension (diastolic blood pressure less than 110 mm Hg). INTERVENTION--Patients received either placebo or potassium 60 mmol/day alone or in combination with magnesium 20 mmol/day in a crossover design. No other drug treatment was allowed. MEASUREMENTS--Blood pressure and heart rate assessed at weekly intervals and biochemical parameters at monthly intervals. RESULTS--Potassium alone or in combination with magnesium produced a significant reduction in systolic and diastolic blood pressures (p less than 0.001) and a significant reduction in serum cholesterol concentration (p less than 0.05); other biochemical variables did not change. Magnesium did not have an additional effect. Urinary potassium excretion increased significantly in the groups who received potassium alone or in combination with magnesium. The drug was well tolerated and compliance was satisfactory. CONCLUSION--Potassium 60 mmol/day lowers arterial blood pressure in patients with mild hypertension. Giving magnesium as well has no added advantage.
Nuclear techniques for the analysis of urinary calculi, Sections of urinary calculi were prepared and point-by-point analyses along a line-scan were carried out using the techniques of proton-induced X-ray emission (PIXE) and nuclear reaction analysis (NRA). Correlations between several pairs of elements (including trace elements) were noted and it was also clear that the composition of a stone varied markedly at different stages of development.
Flexible cystoscopy as an adjunct to extracorporeal shockwave lithotripsy, Ancillary procedures associated with extracorporeal shockwave lithotripsy (ESWL) include placement and subsequent removal of double pigtail ureteric stents. A simple new technique has been developed for the insertion of these stents. Using the flexible cystoscope. the procedure is performed on an out-patient basis under local anaesthesia. Placement of the stents was successful in 30/34 patients and removal was successful in 14/14 patients.
Use of the double pigtail stent in stone retrieval following unsuccessful ureteroscopy, Insertion of a double pigtail stent is known to cause ureteric dilatation. We analysed the effect of an indwelling double pigtail stent on the success rate of calculus extraction by second ureteroscopy when the initial ureteroscopy fails. Over a 12-month period. a first ureteroscopy failed in 42 patients; 30 were then treated by ureteroscopy combined with a ureteric stent and 12 were treated without a ureteric stent. The group with an indwelling stent had a successful second ureteroscopy or spontaneously passed the calculus in 24 cases (84%) compared with 5 unstented cases (45%). Ureterolithotomy was necessary in 2 patients with a stent and 3 with no stent. It was concluded that following failed ureteroscopic manipulation of calculi. insertion of a double pigtail stent was associated with a higher subsequent success rate for removal of stone by ureteroscopy and a consequent lower rate of ureterolithotomy.
Immunofluorescent and histochemical staining confirm the identification of the many diseases called interstitial cystitis, Interstitial cystitis comprises a complex of diseases typified by symptoms of pelvic pain. Functional complaints do not aid the clinician in determining loss of anatomical capacity. Histochemical staining with PAS-colloidal iron/Van Geison's counterstain offers improved diagnostic ability for the pathologist and correlates well with immunofluorescent findings. Four distinct diseases can be identified through immunofluorescent staining. indicating that each is the result of different responses of the urothelium and endothelium to injury. Loss of bladder capacity associated with these diseases can be expected with age. but immunofluorescent staining for IgM within the capillaries of the interstitium is a more sensitive predictor.
Do women with idiopathic sensory urgency have early interstitial cystitis, Interstitial cystitis is rarely considered as a cause of urinary symptoms in referrals to gynaecology clinics. Recent concepts in the diagnosis of this condition mean that it is emerging as a much more common entity. with both early and late forms of the disease being described. Mast cell density in the detrusor muscle has been reported to be useful as a disease marker to substantiate the diagnosis of interstitial cystitis where no classical diagnostic features exist. We assessed mast cell counts in bladder biopsies from 27 women with idiopathic sensory urgency and 10 control patients about to undergo a colposuspension procedure for pure genuine stress incontinence; 30% of the study group had a clear increase in the detrusor muscle mast cell population (detrusor mastocytosis). No control patient showed such an increase. Early interstitial cystitis should be considered as a possible cause of lower urinary tract symptoms in patients with apparently idiopathic sensory urgency.
Symptoms versus flow rates versus urodynamics in the selection of patients for prostatectomy, Many prostatectomies are performed on the basis of symptoms alone; 39% of patients referred by their family doctors and 23% of patients who were on waiting lists for prostatectomy of other hospitals. but who had not undergone any urodynamic investigations. were found to be unobstructed on urodynamic criteria. A screening peak urinary flow rate of 12 ml/s or less was associated with urodynamic evidence of obstruction in 95% of cases; 35% of patients with symptoms of outflow obstruction and a flow rate greater than 12 ml/s were also found to be obstructed. One year post-operatively. 84% of patients who were selected for surgery on combined symptomatic and urodynamic criteria were pleased symptomatically with their result. The failure of detrusor instability to resolve following prostatectomy was associated with symptomatic failure of treatment. Residual obstruction was demonstrated in 5 patients who had undergone prostatectomy and were asymptomatic at this time. This study illustrates that objective measures are necessary in the assessment of patients prior to prostatectomy in order to select only patients who are obstructed. The importance of a screening flow rate is emphasised. All patients who underwent surgery had cystometric evidence of obstruction but the symptomatic results of surgery were no better than the results in patients who had been assessed according to non-urodynamic selection criteria. We have thus failed to identify a need for routine cystometry in the pre-operative assessment of these patients. Cystometry does. however. have a role in assessing patients with pre-operative flow rates greater than 12 ml/s and in those who remain symptomatic following prostatectomy.
Ritual circumcision (Umkhwetha) amongst the Xhosa of the Ciskei, The Umkhwetha is an ancient custom of ritual circumcision still practised by the Xhosa people of Southern Africa. In 45 consecutive youths who required hospital admission the mortality rate was 9%. The complication seen over the years are reviewed and their management discussed.
Papillary cystic neoplasm of the pancreas: radiological and pathological characteristics in 11 cases, Clinical charts. radiological features. macroscopic and microscopic findings. and clinical follow-up data were retrospectively reviewed in 11 patients with papillary cystic neoplasm of the pancreas (PCNP). The patients were nine women and two men. aged from 13 to 51 years with a mean age of 25 years. The greatest diameter of the PCNPs ranged from 2.5 cm to 14.0 cm with a mean size of 7.5 cm. Six tumours were located in the tail of the pancreas. two in the body and three in the head. Most patients complained of abdominal pain or a mass. Ultrasonographic and/or computed tomography findings showed five solid. four mixed (solid and cystic) and two cystic types of tumour. Angiographically. PCNP was either a hypovascular or mild hypervascular mass with a displacement of the surrounding vessels. No vascular encasement was seen. Macroscopically all 11 tumours consisted of a well defined solid mass with degenerative change of various widths. including haemorrhage. necrosis or dystrophic calcification. and were represented by three radiological types of PCNP. The 11 patients with PCNP survived for from 3 to 253 months after curative resection without any signs of local recurrence or remote metastasis. PCNP usually affects the distal portion of the pancreas of young women. Despite its huge size. PCNP should be explored with aggressive surgical intent because of the inherently good prognosis.
CA72-4: a new tumour marker for gastric cancer, To date. tumour markers for gastric cancer have proved unreliable. In this study the value of a new serum marker. CA72-4. was compared with the serum activities of carcinoembryonic antigen (CEA) and CA19-9 in a consecutive series of patients with gastric cancer. The results show that the CA72-4 assay is significantly better at separating stage I and II disease from normal controls (P less than 0.01) than CEA (n.s.) or CA19-9 (n.s.). CA72-4 also gave better differentiation between patients with positive and negative nodes (P less than 0.01) and between those who were serosa positive and negative (P less than 0.01). CEA differentiated between patients with positive and negative nodes (P less than 0.05) but CA19-9 could not. CA19-9 and CEA could not discriminate between patients who were serosa positive and negative. In this study. at a specificity of 95 per cent. the sensitivities of CEA. CA19-9 and CA72-4 were 0.25. 0.41 and 0.94 respectively. These preliminary findings indicate that CA72-4 is a reliable tumour marker of disease stage and activity in gastric cancer. Further longitudinal studies are required for full evaluation of its clinical utility.
Treatment of adenocarcinoma of the cardia with synchronous chemotherapy and radiotherapy, Twenty-nine evaluable patients with adenocarcinoma of the cardia were treated with synchronously administered chemotherapy (two cycles of 5-fluouracil and cisplatin and 30-36 Gy of radiation to determine whether these tumours are responsive to such treatment. Complete regression of tumour was observed endoscopically in 19 patients. and partial regression in four. Fourteen patients had their tumours resected and in six no microscopic tumour was found in the specimen. Nine patients received additional radiotherapy to a total dose of 54-60 Gy instead of surgery. Tumour response was associated with rapid reversal of dysphagia. Only one patient required subsequent intervention for relief of dysphagia due to fibrous stricture. Enhanced survival was associated with a complete endoscopic response to initial chemotherapy and radiotherapy. and a tumour of less than 5 cm in length. The median survival of responding patients was 15 months. Synchronous chemotherapy and radiotherapy was of major palliative benefit in this series and merits further evaluation.
Manometric evaluation of jejunal limb after total gastrectomy and Roux-Orr anastomosis for gastric cancer, Total gastrectomy with Roux-Orr anastomosis is frequently performed for gastric cancer. Since intestinal motility of the Roux limb has never been evaluated after this operation. pressure activity was investigated in the Roux limb of ten patients (aged 51-77 years) who had undergone total gastrectomy and Roux-Orr reconstruction. Investigations were carried out during a 6-h fast and 3 h after a 605 kcal mixed meal. During fasting only two patients had activity fronts and these were abnormal. All ten patients displayed non-propagating bursts of contractions and three had discrete clustered contractions and high amplitude jejunal contractions. The fed state was characterized by a severely reduced motor activity pattern and other abnormalities. Total gastrectomy with Roux-Orr anastomoses provokes a relatively severe disturbance in intestinal activity.
Single lumen ileum with myectomy: a possible alternative to the pelvic reservoir in restorative proctocolectomy, An alternative procedure to construction of a pelvic ileal reservoir was assessed which avoids the need for a pouch. while providing an adequate rectal substitute and good continence. Thirty-six female adult beagles were allotted randomly to undergo total colectomy with (a) ileo-anal anastomosis alone. (b) ileo-anal anastomosis with two 15 cm myectomies. (c) ileo-anal anastomosis and myectomy with an ileo-ileal valve. or (d) ileo-anal anastomosis with a duplicated J pouch. The animals were studied before operation and at 4-weekly intervals for 20 weeks after operation. Mortality rates were similar. Ileal compliance was increased significantly by myectomy from 0.64 ml/mmHg (median. interquartile range 0.49-0.78) after ileo-anal anastomosis alone to 1.65 mmHg (1.16-1.93). P less than 0.01. an increase which was maintained. Ileal capacity was also increased both by myectomy and by the J pouch: ileo-anal anastomosis = 85 ml (75-100 ml). ileo-anal anastomosis and myectomy = 139 ml (116-156 ml). ileo-anal anastomosis and myectomy and ileo-ileal valve = 125 ml (range 85-145 ml). ileo-anal anastomosis and J pouch = 130 ml (range 75-165 ml) (P less than 0.01). Bowel function in the other three groups was markedly superior to ileo-anal anastomosis alone. Mean transit time was significantly less after ileo-anal anastomosis. 5.2 h (2.6-8.2 h) than after both ileo-anal anastomosis and myectomy. 10.5 h (9.6-13.9 h). P less than 0.05 and ileo-anal anastomosis and J pouch. 11.0 h (8.4-13.0 h). P less than 0.05. but addition of an ileo-ileal valve did not produce a further increase in transit time. 12.9 h (range 10.5-14.5 h). P = n.s. Myectomy of single lumen ileum may be a useful alternative to a pelvic ileal reservoir in restorative proctocolectomy.
Gracilis muscle transposition for faecal incontinence, Transposition of the gracilis muscle for faecal incontinence was performed in 13 patients. Six gained satisfactory continence. four were improved. two did not benefit from the operation and one patient died from intercurrent disease before closure of a pre-existing colostomy. Anal manometry compared with a control group showed no alteration in resting and pressure at a median of 35 mmHg (range 5-63 mmHg). whereas maximum squeeze pressure increased from a median of 38 mmHg (range 5-79 mmHg) to 59 mmHg (range 10-143 mmHg) (P = 0.041) which was. however. significantly lower than 130 mmHg (range 81-236 mmHg) in the control group. All patients who benefited from the operation had an increase in maximum squeeze pressure. The ability to retain a viscous fluid in the rectum was measured in seven patients. four of whom had gained satisfactory continence and three of whom had improved continence. They were able to retain a median volume of 200 ml (range 50-225 ml) without leakage compared with 325 ml (range 250-400 ml) in the control group. These patients could retain the maximum amount of viscous fluid for 5-8 min. whereas all control subjects could do so for more than 15 min. It is concluded that. although gracilis transposition never results in normal continence. acceptable continence may be achieved in selected patients provided careful attention is paid to the technical details of the procedure and provided that systematic postoperative exercises are performed.
Resympathectomy of the upper extremity, Resympathectomy was performed in 27 patients (eight bilaterally) with ischaemic hand phenomena. An extended operative technique. resecting parts of the second and third intercostal nerves and their surrounding tissue. was used. In all 35 procedures the posterior extrapleural approach was used. Follow-up was from 3 to 12 years. Only the sympathetic ganglia had been removed during the previous surgery by the axillary approach (67 per cent of these patients had had a transient response for between 6 months and 2 years; 33 per cent had had no response at all). A direct subjective improvement was seen after 27 of the 35 reoperations (77 per cent). In 14 patients continuous wave Doppler ultrasound studies were available and showed a significant increase in peak forward frequency after operation (P less than 0.001). From these data it may be concluded that it is possible to obtain a resympathectomy effect. but reoperation should be reserved for special cases for whom survival of digits is essential.
Intraoperative ultrasonography and the detection of liver metastases in patients with colorectal cancer, A total of 213 patients with carcinoma of the colon and rectum were examined to detect liver metastases. The study compared preoperative ultrasonography and inspection and palpation of the liver during surgery with intraoperative ultrasonography. Preoperative ultrasonography. inspection and palpation identified 238 metastases in 42 patients. Intraoperative ultrasonography detected 116 previously unrecognized metastatic tumours during 40 surgical procedures (P less than 0.01). High resolution intraoperative ultrasonography is safe and more accurate than preoperative imaging and surgical exploratory methods. The examination is simple to perform and success appears to be related to careful attention to detail.
Changing indications for penetrating keratoplasty in Vancouver, 1978-87, Indications for penetrating keratoplasty (PK) were assessed by clinicopathological review of 659 corneal buttons submitted from 1978 to 1987 to the Ophthalmic Pathology Service in Vancouver. Leading indications for PK were bullous keratopathy (22.2%). keratoconus (17.1%). scarring with or without chronic inflammation (13.5%). graft failure (12.1%). scarring or active keratitis secondary to virus (9.0%) and Fuchs' dystrophy (8.3%). The principal factors responsible for graft failure were also judged by clinicopathological correlation. The authors compare their findings with those in other series.
The management of chalazion: a survey of Ontario ophthalmologists, Owing to the variability and lack of standardization of chalazion management. a survey of Ontario ophthalmologists was undertaken. The results highlight what ophthalmologists consider to be problems in chalazion management and suggest that a chalazion operation should be treated with the same respect given any other operation.
Acanthamoeba keratitis with two species of Acanthamoeba, We describe a case of Acanthamoeba keratitis related to soft contact lens wear. The patient presented with a 3-week history of severe uniocular pain. radial stromal infiltrates and subepithelial infiltrates with no epithelial defect. Acanthamoeba was cultured from the corneal biopsy specimen. contact lens and lens case. The corneal biopsy culture grew both A. castellani and A. polyphaga as well as Escherichia coli. The patient was treated with topical dibromopropamidine isethionate (Brolene) drops. neomycin and polymyxin B drops and fortified gentamicin drops. Gradual clinical improvement ensued.
The effect of the gastrin receptor antagonist proglumide on survival in gastric carcinoma, Gastric cancer remains a disease with a very poor prognosis. and there is no safe and effective form of therapy for advanced disease. Evidence is now abundant to show that gastrin stimulates the growth of both gastric and colorectal cancer cells in vitro and in vivo. and that blockade of gastrin receptors can prolong survival in xenografted nude mice. We have thus performed a randomized. controlled study of the gastrin/cholecystokinin receptor antagonist proglumide as therapy in 110 patients with gastric carcinoma. Proglumide had no overall effect on survival (Mantel-Cox statistic = 0.5. P = 0.48). The 95% confidence interval for the proglumide treated group was 260 to 474 days compared to 230 to 372 days for the control group. No significant difference was seen with proglumide. which has a relatively low affinity with the gastrin receptor and also has partial agonist activity. Drugs that are far more specific and potent gastrin receptor antagonists are becoming available. which may have a greater effect on survival. and further clinical trials of such compounds are clearly indicated to determine the efficacy of hormonal control of gastrointestinal malignancy.
Autopsy-documented cure of multiple myeloma 14 years after M2 chemotherapy, Multiple myeloma was diagnosed in a 65-year-old woman in 1974 who thereafter received five-drug M2 chemotherapy. All protein abnormalities subsequently returned to normal and serial bone marrow studies documented complete bone marrow remission. Destructive bone lesions persisted radiographically. but did not progress. In 1987. a localized sigmoid adenocarcinoma was resected. In 1988. the patient presented with multiple brain metastases associated with a primary pulmonary adenocarcinoma that proved rapidly fatal. At autopsy. no evidence of multiple myeloma was found. This report describes the first tissue-documented cure of multiple myeloma 14 years after diagnosis and initiation of M2 chemotherapy. The possible association of multiple myeloma with other malignancies is also discussed.
Prospective evaluation of radiologically directed fine-needle aspiration biopsy of nonpalpable breast lesions, The application of fine-needle aspiration biopsy (FNAB) to the diagnosis of nonpalpable breast lesions was evaluated with a new method which uses standard needle localization under mammographic guidance to assure accurate sampling by FNAB. This method was prospectively applied to 100 mammographically detected breast lesions in 100 women (mean age. 53 years). All 100 patients underwent surgical excision of these nonpalpable lesions after cytologic aspiration. Sufficient aspirated material was obtained for cytologic diagnosis from 91 patients (91%). The histologic and cytologic interpretations were then compared. Twenty malignancies were ultimately diagnosed by histology (12 invasive ductal carcinoma. six ductal carcinoma in situ. and two lobular carcinoma in situ). of which 17 had been cytologically diagnosed. There were no false-positive diagnoses of malignancy by FNAB. False-negative readings (3.3%) included two cases of lobular carcinoma in situ and one case of ductal carcinoma in situ. This technique thus demonstrated a sensitivity of 85%. specificity of 100%. and overall diagnostic accuracy of 96.7% for the nonsurgical detection of malignancy in nonpalpable breast lesions. These results suggest that the established safety. reliability. and cost-effectiveness of FNAB can be maintained in this clinical setting. This procedure may obviate the need for open surgical biopsy in those patients with an unequivocal diagnosis of malignancy. It can also be done using standard techniques and equipment available in many community hospitals.
In vitro natural killer and lymphokine-activated killer activity in patients with bronchogenic carcinoma, The authors examined peripheral blood mononuclear cells from 45 patients with bronchogenic carcinoma to determine natural killer (NK) and lymphokine-activated killer (LAK) activity after in vitro incubation with media alone or media plus interferon gamma (IFN. 200 U/ml) and/or interleukin-2 (IL-2. 100 U/ml). Our results show that lymphocytes from patients with bronchogenic carcinoma can acquire LAK activity. but the level of activity acquired was significantly lower compared with lymphocytes from 25 control subjects when IL-2 cultures were supplemented with 10% autologous human serum (AHS) (15.6% +/- 2.1% specific release versus 26.0% +/- 2.9% specific release. P = 0.004). The LAK activity. defined as cytotoxicity of an NK-resistant cell line. of the patients' lymphocytes was augmented when cells were cultured with both IL-2 and IFN compared with IL-2 alone (P = 0.0001. paired t-test). Control subjects were unchanged (P = 0.09). There was no significant difference between groups of patients with different histologic types of tumor or different stages of disease. The NK activity. defined as killing of NK-sensitive K-562 target cells. of the patients' lymphocytes was not significantly different from that of the controls' lymphocytes (42.8% +/- 3.0% specific release versus 49.3% +/- 3.3% specific release. P = 0.16). These studies indicate the feasibility of IL-2 and IFN therapy in patients with bronchogenic carcinoma.
Acute T-cell leukemia/lymphoma mimicking Hodgkin's disease with secondary HTLV I seroconversion, The authors observed a pleiomorphic lymphoma mimicking Hodgkin's lymphoma in a French Guyana black woman lacking antibodies for human T-cell lymphoma/leukemia virus type I (HTLV I). After two courses of chemotherapy with either mechlorethamine. vincristine. procarbazine. and prednisone (MOPP) or doxorubicin. bleomycin. vincaleukoblastine. and dacarbazine (ABVD). a typical acute T-cell leukemia/lymphoma developed with HTLV I seroconversion. Specific HTLV I DNA sequences were detected using the polymerase chain reaction (PCR) on a lymph node biopsy obtained before chemotherapy. The mechanisms of the seroconversion are discussed.
Immunohistochemical studies on the main entrance-route of CA19-9 into the peripheral venous blood of gastric cancer patients. Correlation with CA19-9 levels in peripheral and portal blood, The correlation between CA19-9 levels of portal and peripheral venous blood. and immunohistochemical variables of cancer lesions was examined in 53 gastric cancer patients and eight patients with benign diseases. Immunohistochemically. CA19-9 was found in 33 (62.5%) of 53 primary lesions. The antigen was found in the cancer cells of invasive lymphatics and node metastases of every CA19-9 localized cancer. although the cancer cells in veins showed little or no CA19-9. There was little or no antigen in the cancer cells in veins. lymphatics. or metastases of 20 CA19-9 nonlocalized primary lesions. Patients with CA19-9 nonlocalized cancer or with benign diseases showed no elevation of the antigen levels in peripheral or portal blood. CA19-9 levels of portal blood (mean. 76.4 U/ml; positive rate. 33.3%) were not different from those of peripheral blood (mean. 91.5 U/ml; positive rate. 33.3%). Additionally. the antigen levels of the blood in patients with lymphatic invasion or node metastases were significantly higher than those in patients without the invasion or the metastases. and every patient without the invasion showed no elevation of the antigen. These results suggest that production of the antigen in cancer cells may be a premise of CA19-9 elevation in peripheral blood and that CA19-9 may be drained by the thoracic duct of the lymphatic system via node metastases or invasive lymphatics. but not by the hematogenous portal system.
Establishment of an erythroid cell line (JK-1) that spontaneously differentiates to red cells, The authors established a new hemopoietic cell line (JK-1) from a patient with chronic myelogenous leukemia in erythroid crisis. This JK-1 line predominantly consists of immature cells. but a small number of mature erythroblasts and red cells can be consistently seen without any specific differentiation inducer. The JK-1 cells grow in suspension culture supplemented with human plasma and carry double Philadelphia chromosomes. Hemoglobin staining with benzidine was positive for about 20% of cells and the type of the hemoglobin was for the most part HbF. Surface-marker analysis revealed JK-1 cells positive for glycophorin A. EP-1. and HAE9. The proportion of mature cells was elevated by the addition of delta-aminolevulinic acid. Erythropoietin (EPO) enhanced the growth of JK-1 cells either in the suspension or in methylcellulose semisolid culture. The total number of EPO receptors was 940 per cell. of which 220 sites had an affinity higher than the other 720 sites. This is the first report of an established human erythroid cell line which spontaneously undergoes terminal differentiation.
Pathologic delineation of the papillonodular type of cystic partially differentiated nephroblastoma. A review of 11 cases, Eleven cases of a previously unrecognized papillonodular variant of cystic partially differentiated nephroblastoma (CPDN) are described. This type of CPDN has all the features of the conventional type of CPDN; however. in addition. there are grossly demonstrable papillonodular projections extending from the septa into the cyst lumina. The septa do not show any expansile tumor masses. Like most cases of the conventional type. this new type of CPDN was usually diagnosed in infants. Nephrectomy (total in 10 and partial in 1) was done in these cases. Additional chemotherapy with or without radiation therapy was given in seven cases. No recurrence was noted during the period extending from 21 months to 8 years in the eight cases in which follow-up data are available. Nephrectomy with regular follow-up visits for possible recurrence may be the management of choice. Pathologists should be aware of this variant of CPDN so that overtreatment can be avoided. The revised criteria for CPDN can be summarized as follows: (1) The discrete entirely cystic tumor contains luminal papillonodules in some cases. (2) Septa and the papillonodules. when present. are the only solid portion of the tumor and contain blastemal cells admixed with their normal and aberrant derivatives. (3) The tumor without and with papillonodules is classified as a conventional and papillonodular type of CPDN. respectively.
Mammographic screening of women with increased risk of breast cancer, Five hundred one women from Dallas County. Texas who participated in the American Cancer Society 1987 Texas Breast Screening Project were selected because of a self-reported family history of breast cancer (cases). They were matched with 501 randomly selected women from the same county with no family history (controls). Although there was a statistically significant trend with age for an increasing proportion of women to report having undergone mammography. there was no significant difference when comparing mammographic histories of cases with controls after controlling for age (31.5% versus 35.1%. P = 0.33). Significantly more cases (79%) perceived their risk for breast cancer to be moderate or greater compared with controls (54%. P less than 0.0001). but mammographic histories were not different when controlling for perceived risk. Both cases and controls cited lack of physician referral and cost as their reasons for not having undergone mammography. Women at increased risk for breast cancer (because of their family history) are not undergoing regular mammographic screening despite their self-awareness of the increase in their risk.
The scapegoat effect on food aversions after chemotherapy, The effects of consuming a novel food (halva) versus a familiar food (cookies) before gastrointestinal (GI) toxic chemotherapy on patients' preference for familiar foods consumed after chemotherapy treatment were compared. The development of aversions to the novel and familiar foods was also assessed. Patients with a history of posttreatment nausea consumed either a novel or a familiar food before chemotherapy and were asked to keep a food record through the next breakfast and to rate their preference for these foods. Patients who consumed halva before treatment were significantly more likely to increase their ratings for foods consumed after chemotherapy than patients who consumed familiar cookies. Aversions to the novel food were significantly more frequent than aversions to the familiar food. These findings provide evidence that a novel but not a familiar food consumed before chemotherapy can act as a scapegoat to prevent items in the regular diet consumed after chemotherapy from decreasing in preference. Providing patients with a novel food before chemotherapy is a useful clinical intervention to reduce the likelihood of forming aversions to familiar foods consumed after chemotherapy.
Cancer mortality in a higher-income black population in New York State. Comparison with rates in the United States as a whole, In the 1980 Census the median family income among blacks in Suffolk County. New York (i.e.. $19.604) was much higher than that for American blacks as a whole (i.e.. $12.618) and 94.1% of that for American whites (i.e.. $20.840). but the proportion below the poverty level was still higher for Suffolk County blacks than for American whites. Observed numbers of deaths from 1979 to 1985 for total cancers and most cancer sites in Suffolk County black men and women were not lower than expected on the basis of age-specific and gender-specific death rates for blacks in the US. Although numbers of deaths from cervical cancer and prostate cancer were slightly lower than expected in Suffolk County blacks versus American blacks. these numbers were still significantly greater than expected on the basis of death rates among American whites. Age-specific death rates for age groups 25 to 44 years to 55 to 64 years tended to be lower in Suffolk County for lung cancers in black men but not for breast cancer in black women. Specific cancer sites. which differ in the direction of the association between incidence and socioeconomic status. age. and gender must be considered in comparisons of cancer mortality by race and socioeconomic level. Implications of the comparisons were discussed with regard to the goal of reducing racial differences in cancer death rates.
Immunocytochemical estrogen and progestin receptor assays in breast cancer with monoclonal antibodies. Histopathologic, demographic, and biochemical correlations and relationship to endocrine response and survival, Breast cancer specimens from 600 women were assayed for estrogen receptors (ER) using an immunocytochemical assay (ICA) employing the monoclonal antiestrophilin antibody H222 Sp gamma. Results showed significant correlation with biochemical ER determinations as well as with tumor grade and menopausal status. In 449 cases. results of progesterone receptor assay by ICA using the monoclonal anti-PgR antibody KD 68. also correlated significantly with biochemical PgR measurements. The ERICA/PgRICA positivity was significantly more frequent in postmenopausal white women. Colloid carcinomas were most likely to be ERICA positive and PgRICA positive whereas medullary carcinomas were most often negative. In 47 patients with advanced mammary carcinoma. results of ERICA and PgRICA were more closely related to endocrine response than those of ER and PgR by dextran-coated charcoal assay (DCC). In 339 women with Stage I or Stage II breast cancer. ERICA was significantly associated with disease-free survival. Analysis by Cox's proportional hazard model. however. showed PgRICA to be the best predictor of survival and disease-free survival in 197 women at the same stages of disease. These data indicate that ICA is more predictive of prognosis than biochemical ER and PgR. The ease of ICA performance coupled with these results indicate that the method is an acceptable substitute for DCC in analyzing breast cancers for ER/PgR.
Teniposide (VM-26) and continuous infusion cytosine arabinoside for initial induction failure in childhood acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study, Twenty-six evaluable children with newly diagnosed acute lymphoblastic leukemia (ALL) who failed to achieve initial remission after receiving two to seven drugs for at least a 4-week period were given teniposide (VM-26) and continuous infusion cytosine arabinoside (Ara-C). Twenty-two received 150 mg/m2 of VM-26 on days 1 and 2 with 100 mg/2 of Ara-C as a continuous infusion on days 1 through 5; a second shortened course was given on day 14 to eight patients who had evidence of some antileukemic effect or were clinically judged able to tolerate a second course. The last four patients received three daily doses of VM-26 and a 7-day infusion of Ara-C at the same daily dosages. Twelve (48%) achieved complete remission (CR) of ALL. There was a trend toward decreasing response rates with an increasing number of drugs used in the initial induction regimen. i.e.. five CR among seven patients with a prior two-drug induction attempt. six CR among 14 patients with a prior three- to four-drug induction attempt. and one CR among four patients with a prior five- to seven-drug induction attempt (P = 0.14). Ten of 17 non-T-cell patients and two of nine T-cell patients achieved remission (P = 0.10). The median time required to achieve a complete remission from the initiation of treatment was 26 days (range. 14-72 days). This period was shorter in those who required one course compared with those who required two induction courses. i.e.. 25 days median vs. 44 days median. Toxicity was significant and due mainly to marrow aplasia and infection; one patient had severe prolonged VM-26-induced hypotension. Of the 12 patients entering remission. two were removed for marrow transplant and one was removed due to parental request. In the remaining nine patients. median remission duration was only 2 months (range. 1-18 months). All nine patients relapsed in the marrow. Among the entire group of 26 patients. only one patient is alive and a long-term event-free survivor (after allogeneic marrow transplant). Due to the current use of more aggressive initial induction regimens and the extremely poor prognosis in children who fail to achieve initial remission. more intensive regimens of continuation therapy or alternative therapies. such as bone marrow transplant. should be considered.
Association of disease-free survival and percent of ideal dose in adjuvant breast chemotherapy, The relationship between percent of ideal dose and disease-free survival was examined in 256 Stage II and III patients who participated in a 2-year breast adjuvant chemotherapy trial consisting of cyclophosphamide. methotrexate. and 5-fluorouracil (CMF) given postoperatively. When analyzed analogously to previous work. the results confirmed a dose-response relationship: that is. there appeared to be an improved disease-free survival for patients receiving higher doses of adjuvant chemotherapy. The major criticism of such an analysis is its bias. This bias was addressed by considering only patients who were still receiving therapy at 6. 12. and 24 months; then. the dose-response relationship was no longer seen. Although causality cannot be inferred. the apparent differences in disease-free survival among the dose groups can be attributed to recurrences in the first 2 years among patients receiving lower doses of chemotherapy.
Doxorubicin for unresectable hepatocellular carcinoma. A prospective study on the addition of verapamil, A prospective study was conducted to assess the safety and efficacy of the addition of oral verapamil to intravenous Adriamycin (doxorubicin) for the management of patients with unresectable hepatocellular carcinoma (HCC). All 28 patients studied had histologically verified disease. and cirrhosis was present in 20 of the 21 patients with adequate tissue sampling. The overall median survival was 57 days. Chemotherapy was terminated in seven patients after one course of treatment. Partial response and complete response were noted in four patients (19%) and one patient (4.8%). respectively. among the 21 patients evaluated. Side effects related to the chemotherapy were present in all patients studied. Death from fulminating sepsis occurred in three of the 13 patients with leukopenia. Symptomatic myocardial dysfunction developed in one patient. The addition of verapamil apparently did not potentiate the tumoricidal effect of systemic Adriamycin on HCC but probably did increase its complications.
A phase I trial of cisplatin in hypertonic saline and escalating doses of 5-fluorouracil by continuous intravenous infusion in patients with advanced malignancies, Thirty-four patients with incurable solid tumors were treated in a Phase I trial with a fixed dose of high-dose cisplatin (CDDP) administered in hypertonic saline and escalating doses of infusional 5-fluorouracil (5-FU). Five treatment levels of 5-FU. ranging from 500 to 900 mg/m2/day for 5 days. were studied. Leukopenia. thrombocytopenia. and oral mucositis were the dose-limiting toxicities encountered. Nephrotoxicity was minimal. Ototoxicity and peripheral neuropathies were rare and mild in this patient group. but most patients received only a small number of treatment cycles. Diarrhea was not dose-limiting. Two complete responses (one non-small cell lung cancer and one sweat gland carcinoma) were observed. No other major responses were noted. With the dose of CDDP set at 35 mg/m2/day for 5 consecutive days. the maximum tolerated dose (MTD) of a concurrent 5-day 5-FU infusion was found to be 900 mg/m2/day. The recommended dosages for Phase II trials are 35 mg/m2/day CDDP and 800 mg/m2/day 5-FU for 5 consecutive days. Cancers of the lung. breast. gastrointestinal tract. and genitourinary tract would be reasonable targets for Phase II studies.
Treatment of advanced squamous cell carcinoma of the skin with cisplatin, 5-fluorouracil, and bleomycin, The authors treated 14 patients with advanced squamous cell carcinoma (SCC) of the skin or lip with one to four cycles of combination chemotherapy consisting of cisplatin by bolus injection. and 5-fluorouracil (5-FU) and bleomycin by continuous 5-day infusion. Objective responses were seen in 11 of the 13 evaluable patients (84%). Four patients had a complete remission (30%) and seven patients. a partial remission (54%). Local control after definitive complementary radiation and/or surgical treatment was achieved in seven patients. Toxic side effects was acceptable; they consisted of nausea and vomiting in all patients. transient skin changes. hematologic (Grade 3/4) abnormalities in four patients. and pulmonary fibrosis in one elderly patient. These results show that this chemotherapy combination could play a role in reducing the tumor mass and in facilitating definitive treatment to obtain better functional and cosmetic results in advanced SCC of the skin.
Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (study COSS-86), In osteosarcoma. intraarterial (IA) administration of systemic treatment has been advocated to improve local tumor response preparing for. or even obviating. definitive surgery. Because data from the literature did not unequivocally support the local superiority of IA infusion. a comparative study was started in 1986. Preoperative chemotherapy consisted of 45 mg/m2 of doxorubicin on days 1 and 2; 12 g/m2 of high-dose methotrexate on days 15 and 22; and 3 g/m2 of ifosfamide on days 29. 30. 50. and 51 followed on days 31 and 52 by intravenous (IV) versus IA tourniquet infusion of cisplatin (DDP). A strict randomization of patients was not feasible. A balanced distribution of risk factors was strived for by stratifying and allocating the appropriate patients centrally. The infusion time was prolonged from 1 to 5 hours in the IV group. and the DDP dose was reduced from 150 to 120 mg/m2 in both arms when intolerable ototoxicity became apparent. A multivariate analysis was performed to exclude a bias on the response rates from risk factor distribution and from modifications of DDP infusion time and dosage. The overall fraction of histologic good responders (greater than 90% necrosis) was not found to be different after IA versus IV treatment (34/50 [68%] vs. 41/59 [69%]). Intraarterial instead of IV use of DDP within an aggressive systemic treatment does not seem to improve the local tumor response.
Long-term follow-up of 24 patients undergoing radical resection for ampullary carcinoma, 1953 to 1988, Potentially curative radical pancreaticoduodenectomy for ampullary adenocarcinoma was performed in 24 patients over a 35-year period. The overall operative mortality was 12.5%. Actuarial survival rate at 5 years was 61% +/- 13.4 standard error of the mean (SEM) and subsequently remained unchanged. In the same time period. 21 patients underwent potentially curative radical pancreaticoduodenectomy for periampullary tumors of pancreatic origin. Similar analysis showed an overall operative mortality of 23.8% and a survival rate at 5 years of 27% +/- 12.5 SEM. The results of radical pancreaticoduodenectomy for ampullary carcinoma in the most recent years (1976 to 1988) were compared with those of former years (1953 to 1975). There were no statistically significant differences in the 5-year survival rate; however. the operative mortality decreased from 25% in the former period to 6.3% in the recent period. Survival was dependent on nodal status. The 5-year survival rate was 78% +/- 11.5 SEM in the absence of nodal metastasis versus 50% +/- 25 SEM in the presence of regional nodal metastasis. These findings support the concept that radical pancreaticoduodenectomy offers a realistic probability for cure in a selected group of patients with carcinomas of the ampulla of Vater.
Expression of Ki-1 antigen (CD30) in mesenchymal tumors, Expression of CD30(Ki-1) antigen has long been considered to be restricted to activated lymphocytes and related tumors. However. expression of this antigen has also been detected in embryonal carcinomas. in nonembryonal carcinomas. in malignant melanomas. and even in some myeloid cell lines and macrophages at late stages of differentiation. In this study. using monoclonal antibody Ki-1. expression of CD30 antigen was immunohistochemically examined in frozen sections of 28 benign and 63 malignant mesenchymal tumors. The authors found CD30 expressed in two of four leiomyomas. seven of 11 leiomysarcomas. one of six rhabdomyosarcomas. two of two aggressive fibromatoses. one of three fibrosarcomas. two of four synovial sarcomas. one giant cell tumors of tendon sheaths. all five malignant fibrous histiocytomas. all three osteosarcomas. one of three Ewing's sarcomas. in a tumor cell subpopulation of two of ten malignant schwannomas. and in the Schwann cell compartment of one of two ganglioneuromas tested. Furthermore. CD30 was consistently expressed in the myoepithelial compartment of 13 fibroadenomas. However. all five lipomas. all seven liposarcomas. all three neuroblastomas. both ganglioneuroblastomas. both chondrosarcomas. and tumors of disputed origin tested were consistently CD30 negative. These findings indicate that. outside the lymphatic system. CD30 antigen is not restricted to epithelial neoplasms but may also be present in tumors of mesenchymal origin. The authors conclude that CD30 antigen. although having limited utility in the differential diagnosis of tumors of questionable histogenesis. may eventually define relevant subgroups within the main tumor categories.
Immunophenotypes in "classical" B-cell chronic lymphocytic leukemia. Correlation with normal cellular counterpart and clinical findings, This study evaluates the expression of a series of membrane antigens. normally expressed by B-lymphocytes of the lymphocytic mantle and marginal zone. in 90 selected cases of "classical" (mouse red blood cell-receptor+. CD20+. CD5+. surface immunoglobulin +/-) B-chronic lymphocytic leukemia (B-CLL) with the aim of contributing toward identifying the normal counterpart of B-CLL and any correlations between surface antigen pattern and certain clinical characteristics. Clustered (CD23. 25. 39. 40. 27. 1c. w75) and unclustered (NuB1. 7F7. KiB3) monoclonal antibodies (MoAb) were tested. Almost all cases showed high reactivity to CD23. 27. w75. 39. 40. and NuB1: expression of CD1c was very low and that of 7F7. KiB3. and CD25 was variable. The reactivity of 7F7 and KiB3 was strictly correlated. and they correlated individually with CD25. Results show that the most frequent B-CLL phenotype (CD19+. 5+. 23+. 27+. 39+. NuB1+. KiB3 +/-. 7F7 +/-. and CD25 +/-) corresponds to one or more cellular subsets in the mantle zone. No correlation was found between MoAb expression. surface immunoglobulin (SIg) class or type. clinical stage. disease activity. or age at diagnosis. The only difference (statistically borderline) was the expression of 7F7 and KiB3 (in young versus old patients). This suggests that modulations in the expression of surface antigens do not affect the clinical behavior of the disease.
Rearrangement of immunoglobulin, T-cell receptor, and bcl-2 genes in malignant lymphomas in Hong Kong, The pattern of malignant lymphomas in the Hong Kong Chinese population is characterized by a low incidence of Hodgkin's disease and follicular lymphomas. The authors studied the immunoglobulin (Ig). T-cell receptor (TCR). and bcl-2 gene rearrangement in 62 cases of malignant lymphoma in this population by Southern blot hybridization. Two cases of Hodgkin's disease showed no rearrangement of the Ig and TCR genes. All 42 cases of B-cell lymphoma had Ig heavy chain (JH) rearrangement with or without additional rearrangement of the light chains (C kappa and C lambda). One case of diffuse B-cell lymphoma had additional T-cell receptor beta-chain (C beta) rearrangement. Sixteen of 18 cases of T-cell lymphoma had C beta rearrangement. and one case of T-lymphoblastic lymphoma had additional JH rearrangement. Two of eight (25%) cases of follicular lymphoma but only one of the 34 (2.9%) cases of diffuse B-cell lymphoma had bcl-2 rearrangement that was detected by pFL-1 probe. None of the 62 cases showed bcl-2 rearrangement using the pFL-2 probe. In conclusion. the Ig and TCR gene rearrangement pattern of the lymphomas found in Hong Kong correlates well with the T-cell and B-cell lineage. which is similar to reports in the white population. However. the incidence of bcl-2 gene rearrangement in follicular B-cell lymphoma is lower than that reported in the US but comparable with that in Japan.
Prognostic implication of ecto-5'-nucleotidase activity in acute lymphoblastic leukemia, Ecto-5'-nucleotidase (5'-N) activity was determined in 191 patients (71 children and 120 adults) with acute leukemia. Elevated values for 5'-N were registered in common acute lymphoblastic leukemia (ALL). but blast cells of T-cell ALL (T-ALL) and common ALL antigen-negative non-T-ALL had low enzyme activity comparable with the values of acute non-lymphocytic leukemia. Dependence of remission duration on 5'-N activity was analyzed in 74 adults with ALL. treated similarly in a prospective multicenter trial. The remission curves for ALL patients with 5'-N activity lower than 10 nmol/h x 10(6) cells were substantially and significantly better than those of patients with high activity (greater than 10 nmol/h x 10(6) cells). This difference was also evident in the immunologic subclass common ALL. Statistical evaluation showed that an interaction between immunologic subtype of the blast cells and their 5'-N activity had prognostic significance for remission duration. In addition to the independent factor. initial age. this interaction was also prognostic for survival.
Lewis system alterations in gastric carcinogenesis, Alterations in the expression of type 1 blood group-related antigens (Lewis a and b) were examined immunohistochemically in 371 consecutives gastric biopsy and 80 surgical specimens from patients of gastric carcinoma. The ABH and Lewis phenotype and secretor status of the patients were correlated with histologic findings. An anomalous expression of Lewis a antigen was found in 88 of 249 gastric biopsy specimens of Lewis (a-b+) phenotype patients. The prevalence of this anomaly increased with the evolution of the premalignant process. in agreement with the commonly accepted model of gastric carcinogenesis. Thus. anomalous Lewis a antigen appeared in 66.6% of gastric dysplasia cases. in 64.6% of intestinal metaplasia. in 15.4% of atrophic gastritis. and in 7.4% of superficial gastritis. No alterations were found in subjects with normal gastric mucosa. Forty-seven of the 49 Lewis (a-b+) phenotype gastric carcinoma patients showed antigenic alterations in tumor cells (anomalous Lewis a antigen in 36 and loss of Lewis antigens in 11). In 26 of these gastric specimens an anomalous Lewis a antigen was present in areas of intestinal metaplasia and/or dysplasia away from the area of neoplastic transformation. The expression of Lewis a antigen in Lewis (a-b+) phenotype patients is a frequent phenomenon in gastric neoplastic cells and could result from the blocked synthesis of Lewis b antigen with accumulation of its precursors. These findings suggest that. during gastric carcinogenesis. antigenic alterations may precede neoplastic transformation. An anomalous Lewis a antigen could constitute a significant index of severity of the histologic lesion and contribute to identifying high-risk individuals.
Comparison of DNA content in gastric cancer cells between primary lesions and lymph node metastases, Cytophotomtric DNA contents of tumor cells in primary lesions and the corresponding metastatic lymph nodes were compared in 61 cases of gastric cancer to determine whether the DNA content remains stable during lymph node metastasis. The DNA distribution patterns were grouped into three types. according to the proportion of aneuploid cell population. Changes in DNA patterns between primary and metastatic lesions were evident in 36 of 61 patients (59.0%); in the remaining 25 (41.0%). the same DNA distribution patterns were noted for both lesions. In 33 of these 36. DNA pattern in the primary carcinoma was transformed into a more narrowly scattered one in the metastatic lesion of the lymph node. Mean and modal values and the frequency of cells over tetraploid (4c) or hexaploid (6c) were significantly higher in the primary lesion compared with findings in the metastatic lesions. This reduction in DNA content in the metastatic lesions was a more frequent occurrence in differentiated (18 of 23) than in undifferentiated adenocarcinoma (15 of 35) (P less than 0.01). Therefore. in primary lesions with a widely scattered DNA ploidy. the tumor cells with a smaller DNA ploidy frequently metastasized to lymph nodes. particularly in cases of a differentiated carcinoma. Such observations may be pertinent in future designing of treatment protocols.
Angiotropic (intravascular) large cell lymphoma. A clinicopathologic study of seven cases with unique clinical presentations, The authors recently reported the antigenic phenotypes of three cases of so-called "malignant angioendotheliomatosis" and suggested that angiotropic large cell lymphoma (ALCL) is a more appropriate designation for this disease. The authors now report an additional seven cases of ALCL with unique clinical presentations. One patient presented with prostate enlargement. the second with lytic bone lesions and thickened nasal sinus mucosa. the third had diffuse myalgia. the fourth had dyspnea and pulmonary infiltrates. the fifth had gangrene of the lower extremities. total-body skin involvement. and pancytopenia. the sixth had a lesion of the foreskin mimicking squamous cell carcinoma. and the seventh had a mediastinal mass. In all cases histologic features were characteristic of ALCL with. in two cases. extravascular spread into soft tissue. Immunohistologic studies showed a B-cell phenotype in five cases and a T-cell phenotype in one case. Two patients received combination chemotherapy using established treatment protocol for large cell lymphoma. and remain in complete clinical remission and two patients are responding clinically to combination chemotherapy. Two patients died shortly after receiving combination chemotherapy. One patient has only recently been diagnosed as having ALCL and no long-term follow-up is available. These data indicate that. although ALCL affects predominantly the central nervous system and skin. unusual clinical presentations may occur. and patients with ALCL may respond to combination chemotherapy for large cell lymphoma.
Mucinous adenocarcinoma of the submandibular gland, A rare tumor not easily classifiable among published histologic categories for salivary gland tumors is reported. The neoplasm developed within the submandibular gland of a 78-year-old woman with invasion of the mandible and metastasis to regional lymph nodes. Histopathologically. cuboidal cells possessing clear cytoplasm and displaced round nuclei proliferated and exhibited an adenomatous pattern. Many cystic spaces surrounded by tumor cell strands were seen. mucus substance filled in the cystic spaces. and the tumor cells seemed mucus-secreting. but neither epidermoid cells nor papillary appearance could be observed. Electromicroscopically. numerous mucous droplets of low electron density were prominent in the cytoplasm. and the tumor cells had sparse irregular microvilli on the luminal surface. Mucin histochemistry. including paradoxical concanavalin A staining. revealed that the tumor cells contained neutral and acid mucins. and these were identified as class II and III mucosubstances. No other neoplastic lesion. except recurrent metastatic neck nodes. has been detected 6 years after the first examination. and it seems that the tumor is a rare primary mucinous adenocarcinoma of the submandibular gland.
The use of flow cytometry for the prognosis of stage II adjuvant treated breast cancer patients, Characterization of breast cancer cells by histology. flow cytometry. and steroid receptors was performed on 197 Stage II breast node positive cancer patients given adjuvant chemotherapy. plus tamoxifen for patients with positive hormone receptors. Histologic and steroid receptor assays were performed using standard techniques; flow cytometric analysis was performed from paraffin-embedded blocks obtained from the primary tumor. Quality control studies on reproducibility. tissue heterogeneity. and analysis procedures have been included. Of the 197 patients studied. aneuploidy was found in 102 (52%); the median %S value was 8% with a range of 0.4% to 38%. Our results demonstrated that number of positive nodes. receptor status. and grade were of prognostic value. Cell cycle kinetic data were not of independent prognostic value in this series. However. ploidy could differentiate in prognosis in the receptor-negative subgroup. Patients with receptor-negative tumors had a significantly better overall survival if the tumor was diploid in nature. Cell kinetics was not significantly prognostic for either receptor subgroup. although patients with higher %S tended to have better relapse-free and overall survival. This is in disagreement with other studies and may demonstrate that treatment has confounded our results and diminished the ability of flow cytometry data to help predict outcome.
Comparison of the conventional method of lymph node staging with a comprehensive fat-clearing method for gastric adenocarcinoma, Discrepant results in long-term survival between United States and Japanese patients with resectable gastric adenocarcinoma may result from more accurate staging in the Japanese series. The authors compared a comprehensive fat-clearing method with the conventional pathology method of lymph node sampling in 11 patients undergoing curative gastrectomy and extended lymphadenectomy at their institution. Comprehensive fat-clearing doubled total lymph node counts (P less than 0.01). identified smaller lymph nodes (P less than 0.001). and identified more histologically involved nodes of significantly smaller size (P less than 0.001). Comprehensive fat-clearing pathologically upstaged 29% of the authors' eligible specimens. Accurate pathologic staging is necessary when comparing Japanese and United States survival data for resectable gastric adenocarcinomas.
Neuropeptide Y and neuron-specific enolase levels in benign and malignant pheochromocytomas, Neuron-specific enolase (NSE) is the isoform of enolase. a glycolytic enzyme found in the neuroendocrine system. Neuropeptide Y (NPY) is a peptide recently discovered in the peripheral and central nervous systems. Serum NSE and plasma NPY levels have been reported to be increased in some patients with pheochromocytoma. The authors evaluated whether the measurement of these molecules could help to discriminate between benign and malignant forms of pheochromocytoma. The NSE levels were normal in all patients with benign pheochromocytoma (n = 13) and elevated in one half of those with malignant pheochromocytoma (n = 13). Plasma NPY levels were on the average significantly higher in the malignant (177.1 +/- 38.9 pmol/l. n = 16) than in the benign forms of the disease (15.7 +/- 389 pmol/l. n = 24). However. there was no difference in the percentage of patients with elevated NPY levels. These results show that determination of serum NSE may be useful for distinguishing between malignant and benign pheochromocytoma; the measurement of plasma NPY is not useful for differentiating the two kinds of tumors.
Myxoid malignant fibrous histiocytoma of the bladder, Although the most common soft tissue sarcoma of adulthood. malignant fibrous histiocytoma (MFH) is an extremely rare tumor of the urinary bladder. Only three well-documented cases have been reported in the world literature. The patient presented in this report represents the first case of the myxoid variant to develop in the urinary bladder. Whereas all previous patients with MFH of the bladder had intermittent hematuria. this patient's chief complaint was bladder outlet obstruction due to extension of the tumor into the prostate. He was managed with radical cystoprostatectomy. postoperative radiation therapy to the tumor bed. and adjuvant chemotherapy using doxorubicin. The patient tolerated the therapy well and was disease-free at the 3-year follow-up visit. The histogenesis. clinical features. pathologic characteristics. and treatment considerations of this rare bladder tumor are discussed in detail.
Retrograde recanalization of an occluded posterior tibial artery by using a posterior tibial cutdown: two case reports, Recanalization of two occluded posterior tibial arteries was successfully achieved by utilizing a retrograde approach via a posterior tibial artery cutdown at the level of the ankle. Both cases were previously unsuccessfully attempted by using an antegrade approach. Thus. the choice of access vessel (arterial entry site) becomes a crucial determinant of angioplasty success.
Simplified method for estimating true aortic valve mean gradient from simultaneous left ventricular and peripheral arterial pressure recordings, Estimation of the aortic valve gradient by simultaneous recording of left ventricular and peripheral arterial pressures is subject to error due to delay and modulation of the arterial pressure contour as it propagates from the ascending aorta. This error can be corrected by averaging the mean gradients derived from unaltered and temporally aligned simultaneous left ventricular-peripheral arterial pressure tracings. In 26 patients with aortic stenosis and simultaneous recordings of ascending aortic and femoral arterial pressure we compared this method with a simplified approach in which the peripheral arterial pressure is partially aligned by advancing it against the left ventricular pressure by 50% of the time delay of the simultaneously recorded upstrokes. Gradients measured this way predicted the true aortic valve gradients (left ventricular-ascending aortic) with a mean difference of +1.1 mm Hg (range = +10 to -5 mm Hg). We recommend use of this simplified method of correction because it predicts true aortic valve gradient equally well as the averaging technique (r = 0.977 vs. 0.979) and requires half the time and effort.
Experience with the use of coronary autoperfusion catheter during complicated angioplasty, Between February and July of 1989. 22 patients underwent the use of the Stack autoperfusion catheter following acute occlusion or obstructive dissection during coronary angioplasty; in 20 cases conventional balloon was used in an attempt to correct the angiographic appearance followed by the use of Stack catheter when results were sub-optimal. Only 1 patient (4.5%) required surgical revascularization. Although our study is not prospective or randomized. our observations suggest a significant impact in decreasing the need for emergency surgical revascularization after complicated coronary angioplasty with the use of this approach.
Use of a guiding catheter for contralateral femoral artery angioplasty, We describe a unique method employing a transseptal sheath as a "guiding catheter" that allows contralateral retrograde femoral artery access to perform balloon angioplasty of proximal superficial femoral artery lesions. This technique simplifies arterial access. provides support for crossing lesions. and allows angiographic visualization of target lesions during the procedure.
Percutaneous valvuloplasty in a patient with mitral stenosis following surgical annuloplasty, A case is described in which a patient with a Carpentier-Edwards annuloplasty ring developed mitral stenosis and was treated with percutaneous mitral valvuloplasty. Possible mechanisms for the development of mitral stenosis are briefly discussed.
Left main percutaneous transluminal coronary angioplasty with the autoperfusion catheter in an animal model, Left main coronary angioplasty is associated with high risk because of interruption of blood flow to much of the left ventricle during balloon inflation. An "autoperfusion" balloon angioplasty catheter that allows blood to flow passively distal to an inflated balloon was tested in dogs and compared with inflations with standard balloon catheters. During 3 min occlusions of the left main coronary artery with the autoperfusion catheter. regional myocardial blood flow was preserved at 0.60 +/- 0.14 ml/min/g. compared with 0.07 +/- 0.03 ml/min/g during inflation with standard balloon catheters (P less than 0.01). Similarly. at the end of 3 min of inflation. left ventricular systolic pressure and dP/dt were maintained with autoperfusion catheter inflation. but they were severely depressed after standard angioplasty balloon inflation. All seven dogs survived autoperfusion balloon inflation. whereas five of seven developed sustained ventricular tachycardia and/or ventricular fibrillation during or after standard balloon inflation. Thus. distal blood flow. hemodynamics. and survival were preserved during autoperfusion balloon inflation in the left main coronary artery.
A rapid, effective technique for retrograde crossing of valvular aortic stenosis using standard coronary catheters, Retrograde crossing of valvular aortic stenosis can be challenging even to experienced angiographers. In 446 of 447 consecutive patients with aortic stenosis catheterized during the past 3 years. a technique using a standard Judkins right coronary catheter and a floppy straight tipped guide wire was successful in rapidly and efficiently crossing these pathologically distorted valves in retrograde fashion. Once the valve was crossed. the coronary catheter was replaced with a pigtail catheter for pressure and ventriculography. The majority of these valves required less than 2 min to cross using this technique. This method is valuable in limiting the time required for catheterization. thus helping to reduce procedure related morbidity in these oftimes critically ill patients.
Nitrous oxide does not exacerbate pulmonary hypertension or ventricular dysfunction in patients with mitral valvular disease, Using the rapid-response thermistor pulmonary artery catheter and transoesophageal echocardiography. this study examined the effects of 100 per cent oxygen. 70 per cent nitrous oxide/30 per cent oxygen. and 70 per cent nitrogen/30 per cent oxygen on the pulmonary circulation and ventricular function in ten patients with pulmonary hypertension. In comparison with baseline measurements. nitrous oxide administration resulted in small but statistically significant (P less than 0.05) changes in mean arterial pressure (76 +/- 14 to 67 +/- 12). mean pulmonary arterial pressure (37 +/- 14 to 33 +/- 13 mmHg). and cardiac output (3.7 +/- 1.4 to 3.2 +/- 1.1 L.min-1). Seventy per cent nitrogen resulted in no significant changes from baseline. The repeat 100 per cent oxygen measurements were nearly identical to the nitrous oxide measurements. It is concluded that nitrous oxide does not exacerbate pulmonary hypertension or ventricular dysfunction during high-dose fentanyl anaesthesia in patients with mitral valvular disease.
Ethyl chloride and venepuncture pain: a comparison with intradermal lidocaine, One hundred and twenty unpremedicated patients undergoing gynaecological surgery were randomly allocated to one of three equal treatment groups to assess the effectiveness of ethyl chloride in producing instant skin anaesthesia to prevent the pain of venepuncture from a 20 G cannula. They received either no anaesthetic. 0.2 ml one per cent lidocaine plain intradermally or a ten-second spray of ethyl chloride at the cannulation site. Ethyl chloride produced skin anaesthesia that significantly reduced the pain of venepuncture. However. it was not as effective as intradermal lidocaine. It had no effect on vein visualisation or ease of cannulation. Ethyl chloride can be recommended as a method of producing instant skin anaesthesia.
Brain protection: physiological and pharmacological considerations. Part I: The physiology of brain injury, Ischaemia. whether focal or global in nature. produces a sequence of intracellular events leading to increased cell permeability to water and ions including Ca++. There is a loss of cellular integrity and function. with increased production of prostaglandins. free radicals. and acidosis with lactate accumulation. These events may be exacerbated by glucose administration. Pharmacological agents aimed at alleviating ischaemic injury could be directed at decreasing cerebral metabolic requirements for oxygen. improving flow to ischaemic areas. preventing Ca+(+)-induced injury. inhibition of free radical formation. lactate removal. inhibition of prostaglandin synthesis. and prevention of complement-mediated leukocyte aggregation. Part I of this paper describes some of the pathophysiological events leading to ischaemic brain injury. Part 2 of this paper will consider the current agents available for brain protection.
Epidural analgesia for a parturient with herpes gestationis, A 23-yr-old parturient with herpes gestationis spontaneously delivered a normal healthy infant under epidural analgesia. She received five injections of bupivacaine 0.5 per cent over a ten-hour period. There was no infection at the lumbar region. even though her body was covered with vesicles and bullae including the face and neck. Eight months after delivery the patient still has a vesicular eruption which occurs mainly during her menses.
Regulation of fibrillar collagen types I and III and basement membrane type IV collagen gene expression in pressure overloaded rat myocardium, Left ventricular hypertrophy is based on cardiac myocyte growth. The hypertrophic process can be considered heterogeneous based on whether it also includes a remodeling and accumulation of fibrillar types I and III collagens that are responsible for impaired myocardial stiffness. In the heart. the messenger RNA (mRNA) for fibrillar collagen types I and III has been detected only in cardiac fibroblasts. whereas mRNA for basement membrane collagen type IV is present in both fibroblasts and myocytes. We studied the early and long-term expression of these collagenous proteins in rat myocardium after abdominal aortic banding with renal ischemia. Complementary DNA probes for rat pro-alpha 2 (I). mouse type III and mouse type IV collagens. and chicken beta-actin were used. Northern and dot blot analysis on total RNA extracted from left ventricular tissue indicated a sixfold increase in steady-state levels of mRNA for collagen type I on day 3 of abdominal aortic banding. which had declined to control levels by day 7 where it remained rather constant at 4 and 8 weeks. Type III collagen showed a similar pattern of gene expression after banding. mRNA levels for type IV collagen. on the other hand. were elevated on day 1 after banding. returning to control at day 7 and remaining constant. Actin mRNA levels also increased on day 1 of banding. followed by a rapid return to control levels. Monospecific antibody to types I and III collagens and immunofluorescent light microscopy on frozen sections of the myocardium revealed that at 1 week after banding. the distribution and density of these collagens were similar to those of control animals.
Pulmonary edema induced by phagocytosing neutrophils. Protective effect of monoclonal antibody against phagocyte CD18 integrin, We studied the changes in pulmonary hemodynamics and lung wet weight induced with opsonized zymosan (OZ) in isolated guinea pig lungs perfused with Ringer-albumin solution containing neutrophils (PMNs). Addition of OZ to the PMN-perfused lungs caused pulmonary vasoconstriction and weight gain; neither OZ nor PMNs added individually to the perfusate altered pulmonary vasomotor tone or wet weight. The steady gain in lung weight by 1.588 +/- 464 mg over the 45-minute study period was associated with pulmonary capillary hypertension and an increase in the capillary filtration coefficient. indicative of increased lung vascular permeability. These responses may not be due to generation of oxygen radicals. because the alterations in pulmonary hemodynamics and lung weight were not reduced by addition of superoxide dismutase. catalase. or superoxide dismutase plus catalase. We examined the basis of the PMN-mediated effects by layering PMNs on bovine pulmonary artery endothelial monolayers. Challenge with OZ resulted in increased endothelial permeability to 125I-albumin. The monoclonal antibody IB4 (directed against CD18. the common beta-subunit of structurally related adhesion receptors on phagocytes. LFA-1. Mac-1. and P150.95) prevented the OZ-mediated increase in PMN adherence to endothelial cells and the increase in endothelial permeability to 125I-albumin. IB4 also inhibited the lung weight gain mediated by the OZ-stimulated PMNs in intact lungs. The protective effect of IB4 could be ascribed neither to inhibition of uptake of OZ by PMNs nor to inhibition of release of oxygen radicals. myeloperoxidase. and elastase.
Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart, To determine the effects of age on the myocardium. the functional and structural characteristics of the heart were studied in rats at 4. 12. 20. and 29 months of age. Mean arterial pressure. left ventricular pressure and its first derivative (dP/dt). and heart rate were comparable in rat groups up to 20 months. During the interval from 20 to 29 months. elevated left ventricular end-diastolic pressure and decreased dP/dt indicated that a significant impairment of ventricular function occurred with senescence. In the period between 4 and 12 months. a reduction of nearly 19% in the total number of myocytes was measured in both ventricles. In the subsequent ages. similar decreases in myocyte cell number were found in the left ventricle. whereas in the right ventricle. the initial loss was fully reversed by 20 months. Moreover. from 20 to 29 months. a 59% increase in the aggregate number of myocytes occurred in the right ventricular myocardium. In the left ventricle. a 3% increment was also seen. but this small change was not statistically significant. These estimations of myocyte cellular hyperplasia. however. were complicated by the fact that cell loss continued to take place with age. The volume fraction of collagen in the tissue. in fact. progressively increased from 8% and 7% at 4 months to 16% and 22% at 29 months in the left and right ventricles. respectively. In conclusion. myocyte cellular hyperplasia tends to regenerate the ventricular mass being lost with age in the adult mammalian rat heart.
Is fibrillation chaos, Ventricular fibrillation is examined to determine whether it is an instance of deterministic chaos. Surface ECGs from dogs in fibrillation were used to generate a state space representation of fibrillation. Our analysis failed to identify a low-dimensional attractor that could be associated with fibrillation. The results suggest that fibrillation is similar to a nonchaotic random signal. We note. however. that such random-looking but nonchaotic behavior can also be generated by a nonlinear deterministic system.
Intertrochanteric corrective osteotomy in slipped capital femoral epiphysis. A long-term follow-up study of 26 patients, The results of intertrochanteric corrective osteotomy in a series of 26 hips with moderate to severe chronic slipped capital femoral epiphysis are reported from follow-up studies in 1976 and 1986. In hips with a slippage of less than 40 degrees (ten hips). arthrosis was present in one hip. In the remaining 16 cases in which slippage exceeded 40 degrees. osteoarthrosis was present in 15. even though correction was adequate. From these observations it can be concluded that intertrochanteric corrective osteotomy does not prevent degeneration in cases with the most severe slip. On the basis of the present observations on treated and untreated cases. the authors advocate treatment by fixation without realignment. accepting the deformity in moderate and severe chronic slips. Rotational osteotomy may be considered in the event of hip joint contracture.
Genetic aspects of juvenile chronic arthritis, Immunogenetic studies in the past decade have confirmed the theory of an association between one's immunogenetic background and the manifestation of several forms of juvenile chronic arthritis (JCA). in particular pauciarticular-onset JCA. Considerable work has been done at the serologic level to demonstrate disease association with the major histocompatibility Class II antigens in pauciarticular-onset JCA. The polygenic nature of JCA is best illustrated by the findings in this particularly well-defined clinical subgroup. Evidence is now emerging that analysis of the DNA sequence. the derived protein sequence. and the structure of Class II molecules will yield significant insight into the genetic predisposition to JCA.
Subtrochanteric fractures. A retrospective analysis, In a retrospective review of 107 patients treated during an eight-year period for subtrochanteric fractures. the average follow-up period was 25.5 months (range. six to 96 months). Comparisons of fracture patterns. fixation devices. and complications of osteosynthesis were made in an attempt to identify fixation devices that are best suited for the treatment of this difficult orthopedic problem. The Seinsheimer system of classification was used. and the fracture at risk was identified. Long spiral fractures with associated butterfly fragments in the osteopenic bone of elderly patients occurred most frequently. with complications of osteosynthesis and inherent instability. Despite the theoretic biomechanical advantages offered by the intramedullary systems. follow-up observations showed better results in patients with treatment by extramedullary devices.
The influence of joint line position on knee stability after condylar knee arthroplasty, Using a special knee-testing device. ten knees obtained at autopsy were subjected to varus-valgus. anterior-posterior. and flexion-rotation analysis in the intact state and after total knee arthroplasty. The ten knees showed no significant change in stability after knee replacement when the joint line was maintained in its natural position. When the femoral component was repositioned 5 mm proximally and 5 mm anteriorly. a significant increase in laxity occurred during midflexion. When the joint line was shifted 5 mm distal and 5 mm posterior to its anatomic location. significant tightening occurred in midrange of motion. Coupled rotation of the tibia with knee flexion was decreased after surgery in all knees with no specific relationship to joint line position. Coupled rotation with varus-valgus testing. however. remained within the normal range through the first 30 degrees of flexion only when the joint line was restored to its normal anatomic position. Stability in condylar knee arthroplasty is in part dependent on position of the joint line. Surgical techniques that rely on restoring the flexion and extension gap without regard to joint line position may result in alteration of varus-valgus or anterior-posterior displacement in midrange flexion.
Effects of screws and a sleeve on initial fixation in uncemented total knee tibial components, Aseptic loosening of tibial components remains a serious problem in uncemented total knee arthroplasties. Achieving rigid initial fixation of porous-coated components is one of the most important factors in promoting bone ingrowth. The results of a biomechanical study for micromovement of the tibial component under posteroanterior shear and axial compressive loading are presented. Forty anatomic specimen tibiae were stress tested on a servohydraulic mechanical test machine to evaluate the effects of screws and a sleeve on initial fixation of the uncemented total knee tibial component. Twenty specimens were used for posteroanterior shear loading and 20 for anterolateral axial compressive loading. Four cancellous screws were inserted through holes of the tibial tray to pierce the cortex of the proximal tibia. The methylmethacrylate sleeve was applied to the central stem. Rigidity of fixation was significantly improved by the combination of screws and a sleeve. Bone strength was also an important factor affecting the quality of fixation.
The effect of screws and pegs on the initial fixation stability of an uncemented unicondylar knee replacement, Two uncemented unicompartmental tibial components were examined for initial fixation stability. A conventional design that employed a single posteriorly angled peg was compared with a new design that was held in place by cancellous bone screws. The components were implanted into the medial condyles of 12 preserved human tibiae. and a cyclic load was first applied anteromedially and then posteromedially. The screwed implants failed at significantly higher loads (1634.8 +/- 121.6 N. mean +/- standard error of the mean) than the pegged implants (1103.3 +/- 152.0 N). On application of a 19.6-N preload. the screwed implants moved significantly less than the pegged implants. Although the differences in micromotion and subsidence were not always significant. there were definite trends. The screwed implants had much lower levels of temporary and permanent displacement compared with the pegged implants for all load levels from the initial load of 245.2 N up to and including the failure load. When the motion that resulted from moving the load from the anterior position to the posterior position was examined. the screwed implant's average total motion was less than 10 microns compared with almost 135 microns for the pegged implant after the 245.2-N load cycle. For the cycle before failure. the screwed implant's average motion increased to less than 29 microns. whereas the pegged implant's average total motion was almost 354 microns. From this information it appears clear that screws provide better initial fixation stability than angled pegs for uncemented unicondylar tibial components.
Pediatric spondyloarthropathies, Seronegative spondyloarthropathies in childhood are often misdiagnosed as juvenile rheumatoid arthritis. but recognition of their distinct clinical manifestations and unique underlying pathophysiologies can aid in making a proper diagnosis. Ankylosing spondylitis. Reiter's syndrome. psoriatic arthritis. and the arthritis associated with inflammatory bowel disease are arthritides most often found in young adults. but they may also be present in children. Extraarticular manifestations include inflammation of the eyes. skin. gastrointestinal tract. and genitourinary tract associated with inflammation of the entheses. The proper diagnosis will allow for treatment regimens that differ from those usually used for juvenile rheumatoid arthritis. Early diagnosis and treatment often lead to an early recovery and a return to normal daily activities.
Paradoxes in the history of the anterior cruciate ligament, A historic review of anterior cruciate ligament (ACL) investigation reveals two important paradoxes. (1) Ideas and concepts recently proposed were first put forth much earlier. (2) Controversy regarding this ligament continues despite the increased amount of information available. Much of the recent ACL literature. although regarded as newly discovered. has its roots in far older. and apparently forgotten or overlooked. work. Examples include: (1) ACL intactness is best tested at full extension; (2) hemarthrosis and ACL rupture are closely associated; and (3) ACL rupture sometimes masquerades as a minor injury. Additionally. early investigators achieved notable advances in surgical techniques. These contributions disappeared from the literature for two major reasons. First. early investigators observed few patients. with typical practitioners rarely seeing ACL injuries. and consequently. little data existed to support their observations. Second. observations could not be confirmed until the advent of widespread. successful surgery. Undoubtedly. orthopedists now know much more about the ACL. yet many issues remain controversial. Does the ACL perform a vital function? What is the efficacy of operative versus nonoperative treatment? What are the relative merits of direct repair. intraarticular substitutes. and extraarticular nonanatomic procedures? The origins and continued existence of controversy stem from several sources. including the less than rigorous study design and the scarcity of natural history. long-term follow-up studies. and basic science studies. The perception of the ACL as a simple structural unit has also perpetuated this controversy.
The outcome of nonoperatively treated complete tears of the anterior cruciate ligament in active young adults, The results of nonoperative treatment of 72 patients with complete anterior cruciate ligament (ACL) tears. documented by examination under anesthesia and arthroscopy. were evaluated. All patients had an acute injury with hemarthrosis in a previously normal knee. Patients having meniscal repair were excluded as were those with collateral or posterior cruciate ligament tears or associated fractures. Treatment in all cases consisted of a standard protocol of early rehabilitation and bracing. A detailed rating of symptoms and function was performed at an average of 38 months postinjury (range. eight to 84 months). Overall results were 11% excellent. 20% good. 15% fair. and 54% poor. Thirty-five percent had ACL reconstruction during the follow-up period. Results indicate that young adults who return to a vocation requiring strenuous physical activity frequently can expect unsatisfactory results after nonoperative treatment of an acute complete tear of the ACL.
Isolated avulsion of the biceps femoris insertion. A case report, The clinical. roentgenographic. and operative findings of an isolated biceps femoris avulsion in a 21-year-old man demonstrated the significance of the static stabilizers about the knee. menisci. and articular cartilage. Examination of the dynamic structures about the knee. however. may present a diagnostic problem. A systematic examination of the musculature (hamstrings. quadriceps. and patellofemoral mechanism) should be included in the evaluation of every acute knee injury. Special attention should be given to the surface anatomy as well as function of the knee.
A ten-year review of treatment of delayed union and nonunion with an implanted bone growth stimulator, A ten-year clinical and roentgenographic review was conducted on the patients in the original Australian multicenter trial that evaluated use of an implantable bone growth stimulator for delayed union and nonunion. Of the original 81 patients. 38 patients were located. seven patients had died from unrelated causes. and 36 were unlocatable. Of the 38 patients located. 37 patients (representing 38 fractures) participated in a detailed clinical review and had a roentgenographic assessment. All fractures had remained united. and normal bone remodeling had occurred. There were no adverse effects of the generator or cathode wire. Six patients initially reported as failures had healed after further surgical intervention. Thus. normal osteogenesis occurs in association with electrical stimulation using an implantable bone growth stimulator. This ten-year review supports the long-term safety and effectiveness of this technique in treating nonuniting fractures.
Influence of postmortem time and temperature on osteoinductive activity of demineralized microperforated ethylene oxide-sterilized syngeneic bone implant in the rat, Bone morphogenetic protein is labile and easily inactivated by many extracorporeal factors. It is crucial to establish whether delay in retrieval of donor bone and ambient holding temperature of the donor body influence osteoinductivity of bone left in situ. Of ten adult rats that were killed. five were kept at 4 degrees and five at room temperature. Femurs were harvested at 24. 36. 48. 72. and 168 hours. After processing. segments were implanted in 20 four-week-old syngeneic rats for 14 days. The level of osteoinduction was evaluated histologically. It was excellent in the 4 degrees group in the 24-. 36-. and 48-hour specimens but less advanced at 72 hours. Bone taken from the room temperature group showed findings identical to those kept at 4 degrees through 36 hours. but osteoinduction was less advanced at 48 hours and absent at 72 hours. No bone formed at 168 hours in either temperature group. The following observations were made. (1) Osteoinductivity of demineralized bone left in situ after death was unexpectedly stable. (2) Retrieval time was extended by donor cooling. (3) Microperforated demineralized bone actively induced new bone formation. (4) Ethylene oxide does not inhibit osteoinduction when correctly applied for sterilization. If confirmed in humans. retrieval of bone to be used for osteoinduction could be delayed for some hours. particularly if the donor was immediately refrigerated. This would increase the effective number of bone tissue donors and utilize an undeveloped resource.
The influence of growth hormone on the reversibility of articular cartilage degeneration in rabbits, Growth hormone has chondrogenic affects on normal as well as on damaged articular cartilage. In this study. the influence of growth hormone is investigated on early degenerative changes in the articular cartilage in 72 New Zealand white rabbits. Cartilage lesions were created in femoral condyles using an immobilization model. Cartilage damage was assessed using biochemical. histologic. and biomechanical criteria. Growth hormone had no influence on prevention of immobilization abnormalities but had a significant affect on healing of established lesions.
A newly established human osteosarcoma cell line with osteoblastic properties, A human osteosarcoma cell line. HuO9. was established from a tumor that was heterotransplanted into athymic nude mice. Antiserum against nude mouse spleen cells was added to the early passage cultures to eliminate the host fibroblastic cells. The cell line retained a high activity of liver/bone/kidney-type alkaline phosphatase (ALP) and secreted osteocalcin. i.e.. bone gamma-carboxyglutamic acid-containing protein (BGP). into the medium. The addition of 1.25-dihydroxyvitamin D3 (1.25(OH)2D3) increased the ALP activity as well as the level of BGP secreted into the medium. The ALP of 1.25(OH)2D3-treated cells has the same inhibition characteristics to heat and amino acids as that of untreated cells. Synthetic human parathyroid hormone stimulated the production of intracellular adenosine 3'.5'-cyclic monophosphate (cAMP) approximately 100-fold within five minutes. However. the stimulation was not observed with a synthetic human thyrocalcitonin. When HuO9 cells were transplanted into the back of a nude mouse. a tumor with an abundant osteoid formation and mineralization was produced. The results indicate that the HuO9 cell line expresses well-differentiated osteoblastic phenotypes. HuO9 is the first established human cell line to produce BGP. and it provides a useful model for the studies of osteoblasts and the regulatory mechanisms of BGP production.
Biomechanical comparison of single- and double-pin fixation for acute slipped capital femoral epiphysis, Biomechanics of pin fixation for acute slipped capital femoral epiphysis (SCFE) was studied in an in vitro immature canine model. Acute SCFE were created in 24 paired femurs. The paired specimens were pinned with either one or two pins and loaded to failure. Strength and stiffness of the paired limbs were expressed as percentages of the loads necessary to create the initial SCFE in the intact specimen. Strength and stiffness were equivalent statistically for the intact physis and the fractured physis fixed with two pins. Single pinning was only 83% as strong and 78% as stiff as the intact physeal plate. Double-pin fixation is recommended over single-pin fixation for acute SCFE. These data. however. should not be extrapolated to the clinical situation of fixation for chronic SCFE.
Soluble mediators of articular cartilage degradation in juvenile rheumatoid arthritis, Juvenile rheumatoid arthritis (JRA) involves a wide range of joint tissues. Tissue changes include proliferation of synovial cells. alterations in synovial fluid. and degradation of articular cartilage. Synovial cell proliferation results in increased numbers of fibroblasts and lymphocytes. Changes in the synovial fluid include increased content of antibodies. altered complement ratios. increased levels of factors stimulating cartilage-mediated proteoglycan degradation. and decreased levels of insulinlike growth factor I. Levels of cytokine such as interleukin-1 and interleukin-2 vary with cell culture and assay technique. Cartilage degradation is apparent from increased quantities of proteoglycan and glycosaminoglycan in serum and synovial fluid. Type II collagen peptide antibodies are also prevalent in JRA patients. Cartilage degradation appears linked to factors in JRA synovial fluid. Conditioned medium of peripheral blood mononuclear cells from patients with JRA also stimulates increased release of cartilage proteoglycan. Thus. the outcome in JRA likely reflects activities of interacting soluble factors that directly influence cartilage homeostasis.
Medical treatment of juvenile arthritis, The range of medications available to treat juvenile arthritis has markedly expanded over the past 15 years. Multiple new nonsteroidal antiinflammatory drugs (NSAIDs) are available in the United States. although only a few are approved for use in children. and none have been proven to be significantly better than aspirin in suppressing inflammation. The average time before significant improvement is noticed is over 30 days in the 50% of the children who respond to any NSAID within three months. The percentage of responders progressively increases with the length of therapy. so treatment should be continued until one is reasonably certain that improvement will not occur before changing medication. In the more severely involved child. gold and other disease-modifying medications are used. However. it has been difficult to prove the value of these medications in controlled studies because of the high rate of significant improvement in the control group treated with NSAIDs. In preliminary studies. methotrexate appears to have significant benefit in children who have failed other treatments. Other newer therapies. such as intravenous gammaglobulin. have only been used in a small number of patients and have not as yet been proven beneficial.
The surgery of juvenile chronic arthritis. An overview, Surgery now has a well-established place in the management of childhood arthritis. However. satisfactory results can only be achieved by a team of medical experts composed of a pediatric rheumatologist. an orthopedic surgeon. an anesthetist. a physiotherapist. and others who are knowledgeable about the particular problems of juvenile chronic arthritis. An aggressive team approach offers the best available help.
Total hip and knee arthroplasty in juvenile rheumatoid arthritis, Total hip or knee arthroplasty is indicated in patients with juvenile rheumatoid arthritis when there is marked functional impairment and/or severe disabling pain from advanced structural hip or knee joint involvement. Relief of pain and dramatic improvement in function can be achieved in most patients. When both the hip and knee are involved. hip arthroplasty should probably be done first. Regional anesthesia is preferable. Careful preoperative planning is essential because custom prostheses are often required. Small bone size. osteoporosis. and soft-tissue contractures make the surgery technically demanding. Skeletal immaturity is not an absolute contraindication to surgery. Component loosening is the most frequent late complication in hip arthroplasty. It is less common in condylar metal-to-plastic knee arthroplasty in which patellar complications predominate. Cementless arthroplasty has an evolving role in the patient with juvenile rheumatoid arthritis and. to date. is more often used in the hip than in the knee.
Wiskott-Aldrich syndrome. A case report, This paper presents a report on a child with Wiskott-Aldrich syndrome. The clinical picture and laboratory findings are characteristic of this disease. The prevailing symptoms have included recurrent respiratory and alimentary tract infections. seborrhic dermatitis-type skin lesions. and thrombocytopenia. Humoral and cellular immunological disturbances have been noted. and the pedigree pattern is very characteristic.
Superficial cultures in neonatal sepsis evaluations. Impact on antibiotic decision making, The authors performed a retrospective analysis of neonatal superficial cultures and their effect on antimicrobial decision making during a nine-month period at Nashville General Hospital. They obtained and reviewed charts of infants (n = 66) having paired superficial (skin and/or gastric aspirate) and deep (blood and cerebrospinal fluid) cultures for the evaluation of early-onset sepsis. Superficial cultures were positive for pathogens (any streptococcus or enteric gram-negative) in 15% (10/66) of cases. Antimicrobial decision making was affected in only one of these cases. and in a seemingly inappropriate manner. In summary. there was no evidence or review that superficial cultures used in sepsis evaluation influenced physician antimicrobial decision making; in one case they may have led to unnecessary antibiotic exposure.
Toxic psychosis due to chloroquine--not uncommon in children, Toxic psychosis due to Chloroquine is a relatively uncommon occurrence in childhood. This entity must be kept in differential diagnosis in a case of unexplained psychosis. before resorting to a sophisticated array of detailed investigations. The purpose of this is to familiarize pediatricians with this relatively uncommon entity. The authors encountered four cases of psychosis with a wide variety of symptomatology over a period of the past 18 months.
Underlying illness associated with failure to thrive in breastfed infants, Over a four-year period in a suburban pediatric practice. 38 infants aged six months or less were identified with failure to thrive (FTT) while breast-feeding. In seven cases (18.4%). an associated organic illness was diagnosed. Only 2 of 28 breast-fed neonates (8%) were found to have FTT associated with another illness. as compared to 5 of 10 older infants (50%). Breast-fed infants with FTT. particularly those presenting after the first month of life. should be considered high risk for having other disease. Their clinical evaluation should include an appropriate search for organic illnesses.
Gastrointestinal bleeding in a 15 month old male. A presentation of Munchausen's syndrome by proxy, Munchausen's syndrome by Proxy is a well-described entity that may not always be immediately considered in a complicated case. We describe this syndrome being portrayed through the guise of gastrointestinal bleeding in a 15 month old male and discuss not only the difficulty involved in solidifying this diagnosis but also the consequences that may occur should this diagnosis not be entertained. Failure to diagnose Munchausen's syndrome by proxy often results from failure to consider the diagnosis. These cases frequently have specific characteristics that allow seasoned clinicians to suspect the diagnosis. Once the diagnosis is considered. it is crucial to take steps to protect not only the index patient but also siblings who not infrequently are also recipients of this life threatening form of child abuse.
Tests of thyroid function: update in the diagnosis and management of thyroid disease, Current thyroid function tests give the clinician powerful tools for the accurate assessment of thyroid status in the majority of patients encountered. There are. however. a small number of clinical situations in which there appear to be inconsistencies in the interrelationship of the thyroid function tests and/or in which they are apparently inappropriate to the clinical status of the patient. In most instances. there is a rational explanation for these observed alterations. The application of this information should allow clinicians to further refine their diagnostic accuracy and thereby enable them to proceed with an appropriate therapeutic or management program.
Management of primary hypothyroidism, Primary hypothyroidism is a common condition requiring lifelong treatment and monitoring. The type and amount of thyroid hormone replacement. selection of laboratory tests. and timing of office visits are all important for optimizing patient well-being and reducing the costs of medical care. The aim of treatment is to bring the patient to the euthyroid state. Currently this is defined as a normal serum concentration of TSH by recently developed sensitive and specific immunometric assays. and is accomplished by titrating the dose of levothyroxine and changing it not more often than at 4- to 6-week intervals. As an indicator of euthyroidism. the sensitive TSH assay has advantages over tests of serum T4. FT4I. T3. FT4. and TSH by RIA because it is independent of TBG changes that result from pregnancy. birth-control pills. and estrogen replacement. is not spuriously elevated by the levothyroxine treatment itself. and is the only test that detects both subclinical hypothyroidism and subclinical hyperthyroidism. Additional serum tests are not usually necessary but have advantages under special circumstances. Once the optimal replacement dose is determined. monitoring can be done yearly or even bi-yearly. depending on the adequacy of patient education and patient compliance.
Inflammatory nodular reactions after hepatitis B vaccination due to aluminium sensitization, In 2 patients. pruritic nodules appeared after revaccination against hepatitis B. Aluminium was found to be responsible for this side effect: contact allergy to aluminium was present in both patients. whereas controls were negative.
Prevalence and sources of sensitization to emulsifiers: a clinical study, 737 patients with suspected cosmetic- or medicament-related contact dermatitis were patch tested with 6 emulsifier agents: triethanolamine. cetyl stearyl alcohol. sorbitan sesquioleate. polyoxyethylene sorbitan monopalmitate. polyoxyethylene sorbitan monooleate. and Amerchol L 101. 39 patients (5.3%) gave 1 or more positive patch tests to emulsifiers. A total of 54 positive reactions were found. 23 of which were clinically relevant. triethanolamine being the most frequent sensitizer. Patients with emulsifier sensitivity generally give a high prevalence of positive patch tests to other common ingredients of topical preparations. such as preservatives or active ingredients. Cosmetics and topical medicaments were detected as the source of sensitization in an equal number of patients. Patch tests with patients' own causative preparations were frequently negative. To avoid overlooking emulsifier sensitivity. it is advisable to test these compounds in patients with contact dermatitis that is possibly due to topical preparations. regardless of whether they have other clinically relevant positive reactions or whether patch tests with their own products are negative.
Olive oil as a cause of contact allergy in patients with venous eczema, and occupationally, From 1985 to 1989. 13 cases of contact allergy to olive oil have been identified in the Departments of Dermatology of Kristianstad and Ostersund Hospitals. Known components of olive oil could not be proved to be the cause of the allergy. This high number of patients with contact allergy to olive oil and possible explanations are discussed.
Contact allergy due to colophony (VI). The sensitizing capacity of minor resin acids and 7 commercial modified-colophony products, 3 minor resin acids and 7 commercial modified-colophony products of different origins were studied by experimental sensitization by means of a modified FCA method. All 3 resin acids were almost negative. The commercial products gave different results. While the maleic-modified product of Greek origin showed a strong sensitizing power. the fumaric-modified. terpene-phenol-modified and a disproportioned rosin were only moderate. A remarkable difference was obtained with the Swedish and Finnish tall oil rosins. which. in contrast to the previously studied French product. exhibited only a weak sensitizing capacity.
Contact dermatitis from acrylate and methacrylate compounds in Lowicryl embedding media for electron microscopy, This report is about occupational contact dermatitis found in 3 out of 6 workers of a chemistry laboratory using Lowicryl embedding media. which contain (meth)acrylate monomer mixtures of known composition. The notation (meth)acrylates is used to refer to both acrylates and methacrylates. (Meth)acrylate monomers will polymerize in the absence of oxygen when induced by metal ions. peroxides. heat or ultraviolet light. The monomers are of low viscosity and remain in the liquid state at temperatures far below 0 degree C. The volatile compounds. some of which exhibit a most pungent odour. have a tendency to penetrate all tissue and to permeate into the finest fissures. a property which makes them suitable as sealants. glues. embedding material. etc. This and their toxicity may represent a danger to the health of individuals who need to work with them. especially if no precautions are taken. We show with patch testing that one patient reacted strongly to the compound 2-hydroxyethyl acrylate at the dilutions tested (0.5 and 1% v/v). but not at all to 10 other (meth)acrylates. In the same test. 3 volunteer controls were negative to 2-hydroxyethyl acrylate. We demonstrate that at maximum working concentration. 2-hydroxyethyl acrylate penetrates both latex and vinyl gloves and elicits irritant/allergic reactions on the patient and irritant reactions on a control. Finally. we discuss the necessary protective measures.
Catheter-related sepsis: prospective, randomized study of three methods of long-term catheter maintenance, We studied the infectious risk of different methods of managing vascular catheters during long-term use. Consecutive surgical ICU patients requiring triple lumen catheters. pulmonary artery catheters. or arterial catheters for greater than 7 days were prospectively randomized to one of three management groups: a) percutaneous (PERC) puncture with every 7-day catheter change at a new site. b) no weekly change (NWC) with a new site when changed. or c) guidewire exchange (GWX) with every 7-day catheter change at the same site. In all groups. a catheter change was mandatory for a positive blood culture. skin site infection. or sepsis without a likely source. Cultures were obtained when clinically indicated and at the time of every catheter change. Catheter-related sepsis (CRS) was defined as a positive blood culture and catheter culture with the same organism. A total of 112 patients met evaluation criteria. There were no intergroup differences in age. primary diagnosis. severity of injury or illness. number of study days. number of protocol violations. route of catheterization. number of catheters present/patient day. catheter sepsis rate. or bacteremia rate. The NWC group demonstrated an increased number of days/catheter. fewer catheter/subcutaneous tract segment cultures/patient. and a reduced incidence of catheter tip colonization. These results occurred in a setting where the number of CRS episodes/patient was 0.17 for GWX. 0.22 for PERC. and 0.16 for NWC. We conclude that there is no difference in infectious risk between these three methods of long-term catheter management. The method with the least complications and expense should be used.
Flow and volume dependence of respiratory system mechanics during constant flow ventilation in normal subjects and in adult respiratory distress syndrome, Seven control subjects and seven patients with adult respiratory distress syndrome (ARDS) were artificially ventilated and flow. volume. and tracheal pressure were monitored. Respiratory system resistance (Rrs.max) was partitioned into its homogeneous (Rrs.min) and uneven (Rrs.u) components. Respiratory system elastance (Ers) was also measured. In both groups Ers did not vary with different inspiratory flows and volumes. but was significantly higher in ARDS. With increasing volume (isoflow maneuvers). Rrs.max and Rrs.u increased but Rrs.min remained unaltered in ARDS. In control patients. however. resistances did not vary but Rrs.max and Rrs.u were smaller and Rrs.min equaled their corresponding values in ARDS. Hence. stress relaxation seems to be increased in ARDS. During isovolume maneuvers Rrs.max and Rrs.u decreased with increasing flows (both groups). although they were significantly higher in ARDS. Rrs.min was not modified by different flows and was similar in both groups. Thus. pendelluft is also increased in ARDS. In conclusion. the mechanical profile of ARDS is characterized by increased Ers and Rrs.max. the latter being secondary to augmented mechanical unevenness within the system.
Effect of blood transfusion on oxygen consumption in pediatric septic shock, Treatment plans for pediatric septic shock advocate increasing oxygen consumption (VO2). Recent studies in septic shock indicate that improving oxygen delivery (DO2) by increasing blood flow will increase VO2. We prospectively examined the effect on VO2 of improving DO2 by increasing oxygen content (CO2) with blood transfusion in eight hemodynamically stable septic shock patients. Transfusion consisted of 8 to 10 ml/kg of packed RBC over 1 to 2 h. Hemodynamic and oxygen transport measurements were obtained before and after blood transfusion. Transfusion significantly (p less than .05) increased Hgb and Hct from 10.2 +/- 0.8 g/dl and 30 +/- 2% to 13.2 +/- 1.4 g/dl and 39 +/- 4%. respectively (mean +/- SD). DO2 significantly (p less than .05) increased after transfusion (599 +/- 65 to 818 +/- 189 ml/min.m2). but VO2 did not change (166 +/- 68 to 176 +/- 74 ml/min.m2; NS). In pediatric septic shock patients. increasing CO2 by blood transfusion may not increase VO2.
Prospective trial comparing a combination pH probe-nasogastric tube with aspirated gastric pH in intensive care unit patients, Upper GI bleeding related to stress ulcer syndrome is estimated to affect as much as 15% of patients in an ICU. Since the occurrence of bleeding after ICU admission may be associated with increased morbidity and mortality. many efforts have been directed at defining optimal therapy for stress ulcer prophylaxis. Titration of intragastric pH with antacids or iv doses of H2-receptor antagonists may prevent stress ulcer bleeding in high-risk ICU patients. We evaluated a recently developed pH probe incorporated into an NG tube and compared it with aspiration of gastric contents using pH paper as a means to monitor pH in 22 surgical ICU patients. Regression analysis comparing the intragastric probe pH values with the aspirated pH values showed a good correlation between the two methods (r = .71). This new technique for intragastric pH measurement appears technically simple and clinically applicable for use on patients at risk for stress ulcer bleeding. It may be more accurate than pH paper in patients receiving antacids.
Hemodynamic and metabolic effects of dobutamine in 18 patients after open heart surgery, Low cardiac output syndrome frequently follows cardiopulmonary bypass (CPB) surgery. In the present study. we used dobutamine to increase cardiac index (CI) and oxygen delivery (DO2) in 18 patients after open heart surgery. Using increasing doses of dobutamine up to 10 micrograms/kg.min-1. we observed statistically significant (p less than .01) increases in mean CI (2.50 +/- 0.10 to 3.56 +/- 0.18 L/min.m2) and in mean heart rate (HR) (83 +/- 3 to 105 +/- 3 beat/min). Mean systemic vascular resistance index decreased significantly (p less than .01) in all patients (2271 +/- 101 to 1648 +/- 83 dyne.sec/cm5.m2). Pulmonary vascular resistance index did not change in the ten coronary artery bypass graft patients. but decreased significantly (p less than .01) in the eight valve replacement patients (561 +/- 98 to 421 +/- 79 dyne.sec/cm5.m2). Mean DO2 increased in all patients. although there was no concomitant increase in oxygen consumption (VO2) in four patients. We observed a significant (p less than .01) increase in mean VO2 in the remaining 14 patients (110 +/- 6 to 148 +/- 12 ml/min.m2). in spite of significant decreases in PaO2 and increases in right-to-left intrapulmonary shunting. Although increases in HR and ventricular arrhythmias may limit its use. dobutamine increases CI and DO2 in patients after CPB. In the present study. dobutamine's varying metabolic effect exemplifies the need for close monitoring of hemodynamic and metabolic variables when using vasoactive drugs in the postoperative period.
Critical care for clonidine poisoning in toddlers, Clonidine may be a source of serious toxicity when ingested by toddlers. We describe 11 cases of clonidine ingestion by toddlers (mean dose 0.15 mg/kg; range 0.01 to 0.57). The source of the clonidine was a grand-parent in six of 11 cases. Symptoms included altered level of consciousness (n = 11). miosis (n = 5). bradycardia (n = 8). hypotension (n = 5). apnea and respiratory depression (n = 6). hypothermia (n = 5) and hypertension (n = 3). Therapeutic interventions included naloxone (n = 8) and atropine (n = 4). dopamine (n = 1). fluid resuscitation (n = 4). and endotracheal intubation (n = 1). There were no deaths. Symptoms of clonidine ingestion were typically mild if the dose ingested was less than 0.01 mg/kg. while bradycardia and hypotension occurred usually with doses of greater than 0.01 mg/kg. Apnea and respiratory depression were common when the dose exceeded 0.02 mg/kg. More effective measures are needed to prevent these potentially serious intoxications.
Plasma epinephrine levels in resuscitation with cardiopulmonary bypass, Since the highest plasma epinephrine levels have been recorded during resuscitation. we evaluated the isolated effect of cardiac arrest upon adrenomedullary secretion. We determined plasma epinephrine in dogs resuscitated with cardiopulmonary bypass (CPB) after cardiac arrest periods of 12 (CPB-12; n = 4) or 16 min (CPB-16; n = 5). Through 2 h of CPB and the following 6 h of critical care. there was no difference between CPB-12 and CPB-16 regarding most cardiopulmonary functional variables. Plasma epinephrine was markedly elevated immediately after initiation of CPB (p less than .01 at 1 min CPB vs. basal) and returned rapidly to basal concentrations. Comparison of plasma epinephrine levels between CPB and standard CPR groups showed that responses to cardiac arrest were similar (p greater than .05 at 1 min CPB vs. 11.5 min CPR). We conclude that cardiac arrest is the main or sole determinant of the plasma epinephrine elevation of resuscitation.
Rapid admixture blood warming: technical advances, The technique of rapid admixture blood warming of cold erythrocyte units is designed to warm erythrocyte units rapidly (less than 30 sec) while simultaneously providing saline for dilution. However. questions have been raised about the recommended use of a standard 250-ml bolus of 70 degrees C admixture saline. the uniformity and speed of blood unit warming. the difficulties inherent in keeping saline bags at 70 degrees C. and the safety of the methodology. To answer these questions. a series of tests were performed and modifications of the technique were introduced. The mean weight of 1000 successive units of erythrocytes for adult infusion was 305 g (range 220 to 410). The maximum temperature was 44 degrees C. using an internal temperature probe (1-cm temperature gradations; 2-sec recording intervals) when the smallest unit was admixed with a 250 ml 70 degrees C saline bolus; the largest unit had a minimum temperature of 30 degrees C. Plasma Hgb. osmotic fragility. and K of the minimum size erythrocyte unit showed no significant deviation from its control. Both thermographic photographs and the internal temperature recordings of the erythrocyte units demonstrated that solely due to fluid turbulence. uniform mixing occurs within approximately 30 sec of beginning the admixture process. Inverting the blood units caused a thermal layering of fluids and an unacceptable maximum blood temperature of 50 degrees C. There was no difference between the mixing time or efficacy in the presence of standard or large-bore iv tubing or additional in-line filters. Volumes of the 250-ml saline bags for admixture decreased markedly with deviations in electrolyte composition after greater than 2 wk at 70 degrees C.
Effect of hemodilution on capillary and arteriolovenous shunt flow in organs after cardiac arrest in dogs, The purpose of this study was to observe the changes in capillary and arteriolovenous shunting blood flow after cardiac arrest and subsequent resuscitation by venous return occlusion produced by inflation of an intra-atrial balloon and cross-clamping of the ascending aorta. and to determine how hemodilution might modify such changes. Organ capillary blood flow and the fractional distribution of cardiac output were measured by the microsphere (9-microns diameter) trapping method in dogs. Simultaneously. the arteriolovenous shunt rate was measured by continuous collection of venous blood drained at 4.8 ml.min-1 for 2 min from the brain. kidney. liver. splanchnic organs. skeletal muscle of the pelvic limb. and all of the systemic circulatory organs. The capillary blood flow of the brain. thyroid gland. pancreas. and stomach decreased after circulatory arrest in five nonhemodiluted dogs (group C); arteriolovenous shunt rate was unchanged after circulatory arrest in this group. However. with hemodilution. which was induced either before (pre group. n = 5) or after (post group. n = 5) circulatory arrest. no change occurred in the shunt rate in any of the organs. with the exception of an increase in the systemic arteriolovenous shunt rate in the pre group. Capillary blood flow was maintained at almost the same level as before circulatory arrest in the pre group. but increased significantly in several organs of the post group. The data indicated that hemodilution might be effective for prevention of organ ischemia after cardiac arrest.
Bronchial blood flow reduction with positive end-expiratory pressure after acute lung injury in sheep, Smoke inhalation increases bronchial blood flow (Qbr) and produces edema of the airway system. This study investigates whether the increased Qbr seen 24 h after inhalation injury can be affected by mechanical ventilation with PEEP (5. 10. 15 cm H2O). Sheep (n = 8) previously prepared with cardiopulmonary catheters and ultrasonic transit time flow probes mounted around their bronchial arteries were insufflated with four sets of 12 breaths each of cotton smoke. Different levels of PEEP were added to the mechanical ventilation 24 h after injury; each PEEP level was applied for 45 min. There were significant increases in Qbr and lung lymph flow (QL) associated with a marked decrease in bronchial vascular resistance (BVR) 24 h after injury. However. no change was observed in mean arterial pressure (MAP) or cardiac index (CI). There was a substantial reduction in PaO2/FIO2 (P/F). which indicated a deterioration in arterial oxygenation. The application of varying levels of PEEP decreased Qbr (p less than .05) while BVR increased (p less than .05). but QL and P/F did not. CI and MAP were recorded. After removal of PEEP. none of the cardiopulmonary variables were significantly different from their postsmoke control values. These findings suggest that mechanical ventilation with PEEP markedly decreases the smoke-induced hyperemia edema frequently seen after inhalation injury without any significant alterations in MAP or CI.
Noninvasive determination of pulmonary artery wedge pressure: comparative analysis of pulsed Doppler echocardiography and right heart catheterization, To compare left ventricular filling variables as derived by transmitral pulsed Doppler echocardiography (tpDE) and hemodynamic variables as assessed at right heart catheterization (RHC). 104 ICU patients (64 male. 40 female) aged 26 to 73 yr (mean 54.6 +/- 10.3) without valvular heart disease were examined. Simultaneously with RHC. transmitral flow velocity profiles were obtained by tpDE. and the ratio of the velocity-time integrals of late diastolic active (A wave) and early diastolic passive inflow into the left ventricle (E wave) was calculated (A/E ratio). Invasively determined pulmonary capillary wedge pressure (WP) ranged from 3 to 36 mm Hg (median 13.35. 5%/95% 6/31 mm Hg). Linear regression analysis showed a highly significant correlation between the A/E ratio and WP (r = .98. p less than .001. standard error of the estimate [SEE] = 0.10). The A/E ratio also correlated with other hemodynamic variables such as cardiac output (r = -.68. p less than .001. SEE = 0.33). cardiac index (r = -.74. p less than .001. SEE = 0.31). and stroke volume index (r = -.68. p less than .001. SEE = 0.34). The interobserver agreement (derived by intraclass correlation analysis between two examiners) on the A/E ratio was high (r = .95. p less than .001. n = 26). We conclude that WP can be accurately determined noninvasively by tpDE. For the assessment of systolic ventricular function. tpDE is of limited diagnostic value.
Nutritional assessment and requirements, Nutrition plays an important role in health and disease. both in prevention and treatment. Increasing emphasis is being placed upon nutrition as a therapeutic tool to decrease the morbidity and mortality associated with obesity. hypertension. coronary artery disease. and cancer. Adequate nutrition should be a concern for all health care workers because of its impact on the overall health of patients. Health care professionals should be familiar with the essentials of nutritional assessment and basic nutritional requirements and be able to improve their patients' care in the face of nutritional deficiencies or excesses.
Nature, nurture, nutrition: interdisciplinary programs to address the prevention of malnutrition and dehydration, Malnutrition and dehydration are common problems in nursing home patients. One explanation for this may be the large number of patients requiring feeding assistance. The Dysphagia Team at the Department of Veterans Affairs Medical Center in Miami. Florida served as the primary source in the expansion of a nutritionally supportive environment to assist in the prevention of malnutrition and dehydration in patients with feeding/swallowing disorders. "Silver Spoons." a program in which volunteers provide supervised feeding. "Happy Hour." a time each day during which an atmosphere is provided that encourages socialization and hydration. and "Second Seating." during which lunch is provided for patients who require modification of eating style. food texture. or timing are described. Analysis of the program's outcomes show it to be timely. pleasing to patients. and cost-effective.
Traumatic rupture of aorta. Diagnosis by Doppler echocardiography, Traumatic rupture of aorta is a serious complication in accidents. mainly road accidents. with a high mortality unless an immediate diagnosis and surgical correction is made. A case of traumatic rupture of the aorta shown in the acute phase by Doppler-echocardiography is reported. This technique can be of great value in the study of patients with thoracic trauma who do not show clear signs of aortic rupture which require urgent aortography.
The effect of prolonged hypothermia on cardiac function in a young patient with accidental hypothermia, A 20-year-old man had accidental. prolonged. and severe hypothermia. Serial radionuclide ventriculography disclosed reduced myocardial contractility during hypothermia that resolved after warming. The effects of hypothermia on cardiac function are discussed.
Oncocytic glomus tumor of the trachea, An oncocytic variant of glomus tumor of the trachea occurred in a 47-year-old woman. She experienced intermittent cough and hemoptysis for about three years. Bronchoscopy and chest CT scan showed a small reddish polypoid tumor on the lower end of the trachea. Bronchoscopic biopsy was carefully done and was diagnosed as oncocytoma. A wedge resection of the tumor was done. Tumor cells were characterized by strongly eosinophilic granular cytoplasm on light microscopy and by numerous closely packed round or ovoid mitochondria with prominent tubular cristae on electron microscopy. They were arranged in a sheet around small vessels. as a result of which the biopsy diagnosis of oncocytoma was changed to oncocytic glomus tumor. To our knowledge. this is the first report of an oncocytic glomus tumor arising from the trachea.
Confluence of pulmonary veins simulating a pulmonary mass, Confluence of the pulmonary veins commonly appears on the frontal view of the chest and generally is easily recognized as such. On plain film tomography. computerized tomography. and pulmonary angiography. the anatomy of convergence of pulmonary veins prior to common entry into the left atrium is clearly displayed. In this report. attention is called to the occasional appearance of confluence of the pulmonary veins on the lateral view of the chest as a clearly circumscribed round opacity mimicking a lung or mediastinal mass.
Orthostatic hypotension following right ventricular myocardial infarction corrected with mineralocorticoid therapy, Severe hypotension while standing became a problem in a patient after discharge from the hospital following right ventricular myocardial infarction. Hemodynamic studies showed that right ventricular systolic function did not maintain adequate left ventricular preload and that the patient did not compensate for cardiac dysfunction by increasing blood volume. Volume expansion by mineralocorticoid therapy corrected the orthostatic hypotension and ameliorated symptoms. Hypotension eventually resolved and therapy was stopped four months after the myocardial infarction.
Cytomegalovirus pneumonia in allogeneic bone marrow transplantation. An immunopathologic process, Recent literature suggests that CMV pneumonia is an immunopathologic process. This case report summarizes the clinical course of a patient which supports this hypothesis. The patient is the recipient of an allogeneic BMT who recovered from an episode of CMV pneumonia that occurred about two months after the transplant. Despite recovery from the viral infection. follow-up BALs revealed persistent lymphocytosis in an apparent asymptomatic patient. He subsequently developed BOOP about four months after the initial CMV infection. These observations suggest that the viral infection may have resulted in the activation of the host's cell-mediated response and provides evidence to support the hypothesis that CMV pneumonia is an immune-mediated process.
Florid pulmonary veno-occlusive disease, A young woman presented with rapidly progressive dyspnea and clinical findings strongly suggestive of primary pulmonary hypertension or possible pulmonary embolism (or both). She died of acute right-sided heart failure. A diagnosis of pulmonary veno-occlusive disease was made at autopsy. Approximately 100 cases of this disease have been reported previously in the literature. We describe a patient with a particularly florid progression of this unusual disease. Death occurred within six weeks of the onset of symptoms.
Hypokalemic and ECG sequelae of combined beta-agonist/diuretic therapy. Protection by conventional doses of spironolactone but not triamterene, Salbutamol (Albuterol) and diuretics are commonly prescribed together in patients with airflow obstruction and are associated with electrocardiographic effects. We have now investigated whether the use of potassium-sparing drugs might prevent the ECG sequelae of such combined therapy. Ten healthy subjects received seven days of randomized treatments with: placebo. bendrofluazide (5 mg). bendrofluazide plus triamterene 50 mg (conventional dose). or triamterene 200 mg (high dose). and bendrofluazide plus spironolactone (100 mg). Potassium and ECG responses to inhaled salbutamol. 2 mg. were measured after each treatment period. The T-wave flattening in response to bendrofluazide and salbutamol (0.24[CI. 0.19 to 0.29]mV) was attenuated by the addition of triamterene. 200 mg (0.33[CI. 0.28 to 0.37]mV; p less than 0.05) and spironolactone 100 mg (0.42[CI. 0.37 to 0.47]mV; p less than 0.01). but not by triamterene 50 mg (0.25[CI. 0.20 to 0.30]mV). Spironolactone and high dose triamterene also diminished the frequency of U waves and ST depression. The ECG effects mirrored hypokalemic responses which were also blunted by high dose (p less than 0.01) but not low dose triamterene. as well as by spironolactone (p less than 0.001). Thus. the use of high dose triamterene and spironolactone protected against the hypokalemic and ECG sequelae of combined beta-agonist/diuretic therapy. whereas a conventional dose of triamterene had no effect. These findings may be important in the prevention of a potentially dangerous interaction in susceptible patients taking this combination of drugs.
Ventilatory and diffusion abnormalities in potential heart transplant recipients, Few data are available concerning pulmonary function in patients with severe chronic congestive heart failure. Of 315 patients evaluated for potential cardiac transplantation at UCLA. 132 underwent pulmonary function tests. The latter patients had severe heart failure with a mean left ventricular ejection fraction of 19 percent and mean cardiac index of 2.1 L/min/m2. Diffusion impairment either alone or combined with restrictive and/or obstructive ventilatory defects occurred in 67 percent of the patients evaluated. Diffusion impairment occurred as the sole abnormality in 31 percent of the patients and in combination with a restrictive ventilatory defect in 21 percent. A reduction in diffusing capacity has not been previously described as a frequent finding in patients with chronic congestive heart failure. In contrast to other studies involving patients with acute heart failure. obstructive ventilatory defects were uncommon. None of the lung function abnormalities was associated with smoking status. prior drug use. chest roentgenographic changes. hemodynamic findings. or clinical features. including duration of congestive heart failure. The mechanism for the diffusion impairment is unclear but could be due to chronic passive congestion with pulmonary fibrosis and/or recurrent pulmonary emboli. Recognition of diffusion impairment as a common finding in patients with severe chronic congestive heart failure who are candidates for heart transplantation is important for proper interpretation of possible post-transplant changes in diffusing capacity due to other causes.
Characteristics and correlates of asthma in a university clinic population, To contribute more comprehensive information about the characteristics of asthma. this article analyzed patients served by the University of Alabama at Birmingham Comprehensive Asthma Program. Their physicians rated one fifth of these patients as having "severe" asthma with the remainder about equally divided between "moderate" and "mild". One in two first received a diagnosis of asthma ten or more years previously. Common comorbidities were hypertension. obesity. rhinitis. bronchitis. sinusitis. and arthritis. One half had visited an emergency room or been hospitalized for asthma in the past year. Inhaled bronchodilators and continuous theophylline were the most commonly prescribed medications. Side effects. especially tachycardia and insomnia. were common and almost exclusively associated with theophylline or corticosteroid therapy. Spirometric assessment showed chronic airflow obstruction in those with more severe asthma. Prevalence of respiratory symptoms. intensity of medication regimen. incidence of side effects. and health care utilization increased as asthma severity increased.
Diagnostic value of nonfluoroscopic percutaneous lung needle aspiration in patients with pneumonia, In forty-one patients (mean [+/- SD] age 51 +/- 19 years; range. 11 to 88 years; seven female and 34 male) with clinical signs and symptoms of pneumonia. we performed a nonfluoroscopic percutaneous lung needle (22 gauges) aspiration (PLNA) to investigate the diagnostic yield of this technique. All the patients were receiving antibiotics at the time of the study. and PLNA was performed either because of a lack of response to empiric antibiotic treatment or because of the severity of the pneumonia or the underlying condition of the patient. Eight patients were mechanically ventilated (MV) due to acute respiratory failure. The PLNA was performed at bedside and without fluoroscopic guidance. Twenty-two microorganisms were identified by means of stains and/or cultures of PLNA samples. Sensitivity of PLNA was 43 percent (18/41). We detected three false-positive cultures probably due to contamination from the skin area punctured. In the eight MV patients studied. the sensitivity of PLNA was 37.5 percent. and the microbiologic findings turned out to be crucial for the outcome of the patients. Pneumothorax developed in three patients (7 percent) after PLNA. None of these three patients developed a pleural infection but two of them required thoracostomy drainage. None of the MV patients presented complications. Our results showed that nonfluoroscopic PLNA is a technique with moderately good sensitivity and with a low rate of false-positive cultures (8 percent) to diagnose pulmonary infections in patients with unresponsiveness to empiric antibiotic treatment or with severe pneumonia. Further evaluation of its diagnostic value and complications in MV patients is needed. although our preliminary results suggest that PLNA can be an alternative technique to other methods for diagnosing pulmonary infections in patients receiving artificial ventilatory support.
Formoterol in the treatment of nocturnal asthma, Formoterol fumarate is a new beta 2-adrenergic agonist with a long lasting effect. The bronchospasmolytic effect of 12 micrograms of formoterol was compared with that of 200 micrograms of albuterol (salbutamol) in a single-center. double-blind. randomized within-patient study. The drugs were given as aerosols by MDI to 16 patients with nocturnal asthma in a stable phase. The inhalations were given at 10 PM and the FEV1 values as parameter were measured before and at 1. 2. 6. 8. 10. and 12 hours afterwards. The FEV1 6 hours after administration of formoterol was significantly higher than that after albuterol (ANCOVA: p = 0.008). and this was still the case 12 hours after the test dose at 10 AM the following morning (ANCOVA: p = 0.009). At 4 AM. the FEV1 fell below the basic starting value after albuterol. whereas it remained at least 10 percent above the formoterol inhalation. Five patients required rescue therapy after albuterol and two after formoterol. We conclude that formoterol in a dose of 12 micrograms via MDI confers good protection against nocturnal asthma; this was only insufficient for some patients with severe asthma. and further studies with higher dosages in these patients are clearly indicated.
Severe aortic regurgitation as a late complication of temporal arteritis, Two patients with a remote history of pathologically documented giant cell arteritis developed severe regurgitation. The first patient developed severe aortic regurgitation five years after the pathologic documentation of giant cell arteritis of the temporal arteries. Giant cell arteritis involvement of the aortic root was confirmed. The second patient developed aortic regurgitation seven years after pathologic documentation of giant cell arteries of the temporal arteries. Although pathologic confirmation of the aortic root process was not obtained. this case strengthens the clinical association between giant cell arteritis of the temporal arteries and subsequent aortic root dilatation and severe aortic regurgitation. Observation for signs of de novo severe aortic regurgitation is indicated in follow-up of patients with temporal arteritis.
Lung sound nomenclature survey, We report the terms used by 223 pulmonary physicians and 54 physicians in other specialties to describe eight recorded examples of lung sounds. The participants listened to the lung sounds at the 1988 American College of Chest Physicians annual convention and wrote "free form" answers. Pulmonary physicians used the terms "crackles" and "rales" with equal frequency to describe discontinuous adventitious lung sounds (ALS) and not at all to describe continuous ALS. Other physicians preferred the term "rales" in describing discontinuous ALS. The terms "wheeze" and "stridor" were used only in describing continuous ALS; however. the term "rhonchi" was frequently used to describe continuous and discontinuous ALS. The majority of participants recognized the normal breath sounds but not the pleural friction rub. Most did not use a qualifying adjective to describe ALS. and there was little agreement among those who did. The lung sound terminology used by physicians is not well standardized and the recommendations of the ATS/ACCP nomenclature subcommittee are not widely accepted.
Acute pulmonary effects of aerosolized pentamidine. A randomized controlled study. Toronto Aerosolized Pentamidine Study (TAPS) Group, From June 1988 to February 1989. we enrolled 36 patients with human immunodeficiency virus into a randomized double-blind placebo-controlled trial assessing the efficacy and toxicity of aerosolized pentamidine (AP) as secondary prophylaxis for Pneumocystis carinii pneumonia. Each patient underwent spirometric evaluations before and after aerosolized treatment. There was no significant difference in the results of baseline pulmonary function tests between the two groups. Eleven patients (65 percent) in the AP group developed cough but only four demonstrated significant reduction in the forced expiratory flow rates after AP; four patients (21 percent) in the placebo group developed cough. but no significant change in the expiratory flow rates was noted. All bronchospastic episodes were self-limited and symptomatically responded to remedial inhaled albuterol (salbutamol) treatment. We conclude that AP treatment is frequently associated with coughing attacks (65 percent). but the actual incidence of bronchospasm on spirometry is much lower (24 percent) and is generally quite mild.
Neutrophilia in bronchoalveolar lavage fluid of diffuse panbronchiolitis, The clinical and pathologic features of diffuse panbronchiolitis (DPB) have been well reported to date. although its pathogenesis remains unknown. In the present study. we performed bronchoalveolar lavage (BAL) on three patients with biopsy specimen-proven DPB and eight patients with highly probable DPB (six women and five men; one smoker and ten nonsmokers). nine patients with chronic bronchitis (all men. five smokers and four nonsmokers). and nine normal control subjects (six women and three men. all nonsmokers) to clarify the cell populations in the lower respiratory tract. Neutrophils comprised 55.3 +/- 24.4 percent of recovered cells by BAL in DPB patients but only 6.6 +/- 6.4 percent in chronic bronchitis patients. and 1.8 +/- 1.5 percent in normal control subjects (p less than 0.001. all comparisons). The DPB patients also exhibited a decreased percentage of alveolar macrophages (34.9 +/- 23.5 percent) compared with chronic bronchitis patients and normal control subjects (p less than 0.001. all comparisons). The percentage of lymphocytes of the recovered lavage cells in DPB patients did not differ from that in chronic bronchitis patients and normal control subjects. These results indicate that neutrophils play an important role in the pathogenesis of DPB. They also suggest that neutrophilia of BAL-recovered fluid is a common finding in diseases associated with bronchiolar inflammation despite some clinical and pathophysiologic differences.
Reactive airway dysfunction syndrome in three police officers following a roadside chemical spill, The reactive airway dysfunction syndrome (RADS) is a recently described syndrome in which bronchial hyperreactivity and asthmatic symptoms develop in previously healthy individuals after a single large exposure to an irritating gas. fume. or vapor. We report a cluster of three Philadelphia police officers who developed RADS after a common exposure to toxic fumes from a roadside truck accident. Results of initial pulmonary function testing were normal in all three. and methacholine challenge was required for diagnosis in two out of the three. This syndrome needs to be recognized by physicians dealing with environmental or industrial medicine as a potential cause of loss of work or inability to perform on the job. Also. there is a potential for multiple individuals to develop this syndrome from a single incident.
Pulmonary lipid peroxidation in cigarette smokers and lung cancer patients, Lipid peroxidation (LPO) was studied in lung tissues of patients with lung cancer (LC. n = 37) or nonlung cancer (NLC. n = 13) and its relationships with the smoking habits and the degree of airway obstruction were investigated. Specimens of peripheral lung parenchyma. free of tumor tissue. were taken and the malondialdehyde (MDA) content was measured in the S-12 fractions. Airway obstruction was assessed by flow-volume curves. and data were expressed as percentage of the predicted values. Cigarettes smoked were expressed as pack-years. The patients with LC and NLC did not differ by MDA content. age. and number of pack-years. On the contrary. FEF75-85 and MEF75 were significantly lower in LC than in NLC patients (p less than 0.05). The MDA content was inversely correlated to number of days patients had refrained from smoking (r = -0.66. p less than 0.001). The MDA content was higher in recent smokers (ie. people smoking during the last 30 days before surgery) than in the other patients (0.136 +/- 0.007 vs 0.116 +/- 0.007 mumol/g of tissue. p less than 0.05) and. by considering only recent smokers. MDA content was higher in LC patients (0.144 +/- 0.008 mumol/g of tissue) than in NLC patients (0.113 +/- 0.014 mmol/g tissue. p = 0.059). When patients were divided into "high MDA" and "low MDA" groups. MEF75 was much lower in the high MDA group (35.1 +/- 3.4 percent) than in the low MDA group (55.1 +/- 8.1 percent) (p less than 0.01). These results suggest the following: (1) enhanced level of prooxidant state in the lungs is associated with recent cigarette smoking; (2) LC patients may be more prone than respective NLC patients to oxidative stress; (3) MDA level and degree of small airway obstruction were associated and differed between LC and NLC patients even though these groups did not differ in the percentage of recent smokers; and (4) a common free-radical mediated pathway may be active for both LC and small airway obstruction.
Effect of PAF-acether inhalation on nonspecific bronchial reactivity and adrenergic response in normal and asthmatic subjects, Bronchial hyperreactivity. although recognized as a hallmark of asthma. is not totally understood. Mast cell-derived mediators. including histamine. have been shown to cause immediate bronchoconstriction. but until recently. no single mediator has been shown to induce prolonged changes in airway reactivity. Recent reports indicate PAF-acether (PAF) can induce increased nonspecific bronchial reactivity in normal subjects but not in asthmatics. We sought to elucidate the role of PAF in airway hyperreactivity by comparing the effect of inhaled PAF on methacholine and isoproterenol airway responsiveness in six nonasthmatic and six asthmatic subjects. Neither nonspecific airway reactivity nor isoproterenol responsiveness was changed following PAF inhalation in the nonasthmatic subjects in the six days following PAF. Asthmatics had increased airway responsiveness to methacholine at two hours post-PAF. which did not persist. Responsiveness to isoproterenol did not change in the asthmatic subjects. Additional evaluation of the role of PAF in causing changes in airway reactivity is warranted.
Laryngomalacia in children, Two hundred three (68 percent) of 297 children with laryngomalacia had associated respiratory disorders by flexible fiberoptic bronchoscopy (FFB). Associated disorders included congenital respiratory anomalies. a variety of anatomic obstructions of the upper and lower airways. and aspiration disorders. Mean age for isolated laryngomalacia (type 1) was 11.5 weeks (range. 5 weeks to 4 months) while children with laryngomalacia and associated respiratory disorders (type 2) had a mean age of 9.06 years (range. 6 weeks to 18 years). We conclude the following: (1) complete evaluation of the pediatric airways (bronchoscopy) is recommended in every symptomatic child with diagnosis of laryngomalacia confirmed by laryngoscopy; (2) type 1 laryngomalacia was more common in early infancy while type 2 laryngomalacia was associated with older age; (3) although type 2 laryngomalacia is the most common endoscopic diagnosis in our experience. the majority of cases were associated with lower airway dysfunction.
Multicentric endobronchial granular cell myoblastoma, Granular cell myoblastoma (GCM) is a rare benign neoplasm involving the tracheobronchial tree. It is believed to arise from the Schwann cell. Four cases of tracheobronchial GCM. all of which were multicentric. are presented and a conservative therapeutic approach is suggested.
Effects of epinephrine on hemodynamics and oxygen metabolism in dopamine-resistant septic shock, The hemodynamic effects of epinephrine were prospectively studied in 13 patients with septic shock who remained hypotensive after both fluid loading and dopamine. Hemodynamic measurements were performed before and one hour after the start of epinephrine infusion. Systolic. diastolic. and mean arterial pressure increased in all patients (p less than 0.01). Cardiac index and systemic vascular resistance increased by 34 and 32 percent. respectively (p less than 0.05). but heart rate and pulmonary vascular resistance remained unchanged. There was a concomitant increase in oxygen delivery (p less than 0.01) and oxygen consumption (p less than 0.05). the magnitude of the latter being related to baseline lactacidemia (p less than 0.01). In view of the generally recognized physiologic goals of septic shock management. we conclude that epinephrine could be an appropriate alternative where fluid loading and dopamine have failed.
Lactate levels as predictors of the relationship between oxygen delivery and consumption in ARDS, We reviewed the changes in Do2 and Vo2 in 58 patients with ARDS after interventions which included fluid loading. blood transfusion. and PEEP. After a significant change in Do2. patients with lactic acidosis (lactate level greater than 2.4 mmol/L) exhibited significant corresponding changes in Vo2 (p less than 0.001); however. no change in Vo2 was observed in patients without lactic acidosis (1-beta greater than 0.8). We conclude that a biphasic pattern of oxygen utilization in patients with ARDS emerges when subsets of patients with and without lactic acidosis are compared. Lactic acidosis. a marker of anaerobic metabolism. may be a characteristic of patients with ARDS who exhibit changes in Vo2 that are dependent on changes in Do2.
Pulmonary functional impairment associated with pleural asbestos disease. Circumscribed and diffuse thickening, To define the pulmonary functional impairment associated with pleural asbestos signs (PAS). we compared 738 men with only circumscribed (plaques) or diffuse pleural thickening on chest roentgenograms but no irregular opacities by ILO pneumoconiosis criteria (1980) with 738 age-matched asbestos-exposed men without any roentgenographic signs and with 228 men unexposed to asbestos. All men were white. Spirometry and total thoracic gas volumes (TGV) were measured and expressed as percentage of predicted of white Michigan men who have been modeled for spirometric values thereby adjusting for height. age. and in current and ex-smokers for duration of smoking. Asbestos-exposed men who never smoked had reduced FEF75-85 (p less than 0.01) and increased TGV (p less than .0001) as compared with unexposed men. The 155 men with PAS who had never smoked had reduced flows (p less than .0001). FVC (p less than 0.0056). and TGV (p less than .0001) when compared with 155 age-matched asbestos-exposed men. The 325 asbestos-exposed current smokers with normal chest roentgenograms compared with unexposed smokers had reduced expiratory airflows (p less than 0.0001). reduced FEV1 (p less than 0.004). and increased TGV (p less than 0.0001). The 325 current smokers with PAS had additional air trapping that further reduced vital capacity. Thus. PAS were associated with significant pulmonary dysfunction in men who never smoked. and current and ex-smokers had additional dysfunction even after adjustment for duration of smoking.
Mechanical disruption of pulmonary emboli in dogs with a flexible rotating-tip catheter (Kensey catheter), Pulmonary embolism was induced in 11 dogs by the injection of three- to four-day-old allogeneic blood clots. The clots were made radiopaque by soaking them in contrast material. The resulting clots were firm. 3 to 4 cm long. and 1 cm in diameter. Injection of the clots into the external jugular vein consistently produced occlusion of at least one of the lobar pulmonary arteries. In every instance in which the tip of the catheter could be positioned at the clot embolus (six dogs). the clots were readily fragmented with a number 8 French (2.67 mm OD) flexible rotating tip catheter (Kensey catheter) activated at 80.000 rpm. Overall perfusion was shown by posttreatment angiograms to be markedly improved. These studies show that catheter-tip fragmentation of pulmonary emboli with a Kensey catheter has excellent potential for therapeutic application in patients with pulmonary embolism.
The effects of methoxamine and epinephrine on survival and regional distribution of cardiac output in dogs with prolonged ventricular fibrillation, This study compares the effects of methoxamine. a pure alpha 1-agonist. and epinephrine on cerebral and myocardial blood flow. central hemodynamics. and survival in a randomized placebo-controlled fashion during prolonged ventricular fibrillation (VF) in a canine model. Twenty-four anesthetized and ventilated adult mongrel dogs were instrumented for regional blood flow determinations using radio-labeled microspheres. The dogs were randomized to receive either 20 mg of methoxamine as a single intravenous bolus or repeated boluses of 0.02 mg/kg of epinephrine. 0.2 mg/kg of epinephrine. or normal saline solution placebo beginning at three minutes following induction of VF and initiation of closed chest cardiac massage (CCCM). Organ blood flow measurements were determined during normal sinus rhythm and after five and 20 minutes of VF. All six dogs receiving methoxamine were successfully resuscitated in contrast to only one in each of the epinephrine-treated groups and none of the dogs receiving placebo (p less than .01). Although epinephrine was associated with significantly higher blood pressures than placebo during cardiopulmonary resuscitation (CPR). blood pressures achieved with methoxamine were significantly higher than those observed in the other three treatment groups (p less than .001). Cerebral blood flow was significantly higher with both methoxamine and high-dose epinephrine (p less than .05). Mean left and right ventricular myocardial flows were highest with methoxamine but this did not achieve statistical significance. In contrast. organ flows measured in the animals receiving the lowest dose of epinephrine were not significantly higher than those associated with placebo. Cardiac output after 20 minutes of CPR was significantly lower with high-dose epinephrine than with methoxamine or placebo (p less than .05). Our results suggest that methoxamine significantly improves regional cerebral blood flow and survival during CPR and although high-dose epinephrine is associated with comparable improvements in regional cerebral blood flow. this treatment is associated with deterioration in central hemodynamics during prolonged VF and does not enhance survival.
Absorption and motility of the bypassed human ileum, The authors assessed absorption and motility of the human ileum after a prolonged period of disuse. In eight patients with ulcerative colitis. a manometric-catheter assembly was placed via the ileostomy into the unused portion of distal ileum two months after ileal pouch-anal anastomosis and temporary diverting loop ileostomy. The distal ileum was perfused at 5 ml/min with an isosmotic solution of either sodium chloride or ileal chyme diluted with sodium chloride for three hours before and three hours after a meal on two consecutive days. Absorption was measured. single and clustered pressure waves were identified and quantitated with the aid of a computer program. and a motility index was calculated. Mean absorption +/- S.E.M. of both perfusates was poor on day 1 (-10 +/- 2 ml/25 cm x 30 min). and the meal induced no ileal motor response. By day 2. however. absorption of both perfusates was much improved (-1 +/- 2 ml/25 cm x 30 min; P less than 0.05). and the number of discrete clustered contractions and the motility index now clearly increased after the meal (2.6 +/- 0.6 vs. 7.2 +/- 1.0 clustered waves/hr; 7.5 +/- 0.5 vs. 9.7 +/- 0.2 motility units/30 min; P less than 0.05). The conclusion was that absorption and motility of the human ileum were impaired after two months of disuse. but that ileal absorption and motility improved one day after the introduction of isosmotic ileal perfusates.
The freckle sign--an endoscopic feature of the cecum, Mucosal spots. or "freckles." surrounding the appendiceal orifice are an endoscopic feature of the cecum. These are clusters of 1 to 2 mm round or oval slightly raised spots. each with a pale center and an erythematous border. They correlate microscopically with subepithelial and submucosal lymphoid follicles. The freckling pattern. identified in about one third of colonoscopies. was seen best with the videoendoscope and was identified more commonly in patients with systemic illness. Recognition of mucosal freckling around the appendiceal orifice helps identify the cecum and may be useful in the evaluation of cecal and appendiceal pathology.
Endosonography of pararectal lymph nodes. In vitro and in vivo evaluation, One hundred thirteen patients with carcinoma of the rectum were evaluated for lymph node metastases by endorectal ultrasound. With the use of 7.5 MHz and based on different echo patterns. two main groups of lymph nodes can be differentiated: hypoechoic and hyperechoic lymph nodes. Compared with pathologic findings. hypoechoic lymph nodes represent metastases. whereas hyperechoic lymph nodes are visualized due to unspecific inflammation. Lymph node metastases can be predicted with a sensitivity of 72 percent and inflammatory lymph nodes with a specificity of 83 percent. The physical basis of the differentiation of lymph nodes was assessed in vitro by the determination of ultrasound parameters (speed of sound. acoustic impedance. attenuation. and backscattered amplitude). The attenuation coefficient of benign lymph nodes [2.5 dB/(MHz x cm)] is significantly higher than the mean value of lymph node metastases [1.3 db/(MHz x cm)]. The results demonstrate that involved nodes can principally be differentiated from not involved nodes. Micrometastases. mixed lymph nodes. and changing echo patterns within inflammatory nodes explain the accuracy rate of 78 percent.
Healing of experimental intestinal anastomoses. Parameters for repair, Anastomotic dehiscence remains a major complication in surgery of the large bowel. and studies on the healing sequence of experimental anastomoses are necessary to define underlying mechanisms and find ways to improve surgical outcome. particularly in high-risk situations. For the quantitative description of anastomotic repair. both mechanical and biochemical parameters are employed. each with their own limitations. Mechanical parameters. either bursting pressure or breaking strength. only reflect growing anastomotic strength as long as disruption occurs within the anastomotic area. which is less than one week after surgery for the bursting pressure and probably up to two weeks for the breaking strength. The biochemical description of anastomotic repair has been limited to behavior of collagen. as represented by its rather unique constituent amino acid hydroxyproline. Conclusions based on collagen concentrations--per unit weight--should be considered with caution since they may change as a consequence of changes in noncollagenous substances. In this respect. collagen content. per unit length. is probably a better parameter to describe anastomotic collagen levels. Few investigations have addressed the quality of collagen (e.g.. crosslinking or type). Since. at this time. no distinct correlations have been demonstrated between development of mechanical strength or occurrence of leakage and collagen levels in the healing anastomosis. attention should not be restricted to a description of the quantity of collagen present: the quality of anastomotic collagen should be investigated. perhaps even more so.
Foreign body removal through an appendicostomy, The removal of button cell batteries or small coins impacted in the terminal ileum or right colon through an appendicostomy is described. This technique was used effectively in three patients.
Effects of milk, prostaglandin, and antacid on experimentally induced duodenitis in the rat. Use of myeloperoxidase as an index of inflammation, Ulcerogenesis of the duodenal mucosa frequently involves an inflammatory reaction with infiltration of leukocytes. Measurement of neutrophil myeloperoxidase activity might thus be a sensitive indicator of damage. before visible lesions occur. To test this possibility. a rat model for duodenal injury was used where fasted animals were treated with indomethacin and histamine-diHCl. Twenty-four hours after indomethacin treatment. duodenal tissues were collected for histochemical staining and biochemical assay for myeloperoxidase activity. Indomethacin- and histamine-challenged rats had significantly elevated myeloperoxidase activity compared to unchallenged controls (P less than 0.05) for both histochemistry and biochemistry. There was also a significant correlation between these two parameters (r = 0.68. P less than 0.001). The duodenal injury model then was used to test the effectiveness of known gastric protective agents. Results indicated that milk and buttermilk did not aggravate or protect against duodenal injury. while antacid and prostaglandin did significantly protect against inflammation (P less than 0.02). We concluded that measurement of myeloperoxidase activity is a sensitive and potentially useful estimate of duodenal injury that can be valuable in assessing ulcerogenesis and healing.
Sterol-dependence of gastric protective activity of unsaturated phospholipids, The major aim of this study was to investigate the gastric protective effect of unsaturated phospholipids and to determine the ability of neutral lipids to enhance this activity. We found that although a liposomal suspension of unsaturated phosphatidylcholine (PC) administered intragastrically failed to protect rats from acid-induced gastric ulcer formation. addition of cholesterol to unsaturated PC induced a dose-dependent protective response with the maximally effective dose. reducing lesion score greater than 70%. This effect also was seen with the plant sterol. beta-sitosterol (reducing lesion score by 81.6 +/- 36%) but was blocked if cholesterol was esterified to fatty acids of varying chain length. Addition of sterols to liposomes of saturated dipalmitoylphosphatidylcholine. in contrast. attenuated the gastric protective action of the saturated PC. It appears that the protective mechanism elicited by sterols and unsaturated PC is not mediated by alterations in gastric emptying rate or prostaglandin biosynthesis. although maintenance of surface hydrophobicity may be involved. These results suggest that the sterol may promote the packing of adjacent unsaturated phospholipid molecules of either the cell membrane or a putative extracellular hydrophobic lining of the gastric epithelium to provide the mucosa with protection against luminal acid.
Gastric lesions secondary to long-distance running, Gastrointestinal disorders have been reported during long-distance running. The purpose of this study was to evaluate the effects of prolonged exercise on the upper digestive tract. Seven subjects were submitted to a standard endoscopic examination of the upper digestive tract before and after long-distance running (range 18-50 km). Mucosal biopsy specimens were taken during all endoscopies. After running. all runners had histologically pathological features in the stomach. Vascular lesions were present in the chorion in six subjects after running. with the intensity of the lesions ranging from congestion to hemorrhage. Postexercise histological examination also showed a decrease in mucosal secretion. These lesions secondary to prolonged exercise indicate the presence of hemodynamic perturbations in the upper digestive tract.
Behavioral modification of colonic function. Can constipation be learned, We challenged the two hypotheses: first. that defecation can be suppressed for an extended time. and second. if so. that this has an effect on upper colonic motility. Thus we studied 12 male volunteers with conditions of identical nutrition and patterns of physical activity over a two-week period. where one week with normal defecation and one week with voluntary prolonged suppression of defecation followed each other in randomized order. Frequencies of defecation. stool weights. total and segmental colonic transit times (using radiopaque markers) were compared. Frequency of defecations and stool weights were lower during suppressed defecation [8.9 +/- 0.66 vs 3.7 +/- 0.41 (mean +/- SE) bowel movements per week. P = 0.003. and 1.30 +/- 0.09 vs 0.98 +/- 0.13 kg/week. P = 0.01]. Total transit times were increased from 28.8 +/- 4.4 to 53.1 +/- 4.3 hr. P = 0.004. Segmental transit times were increased in the rectosigmoid (from 8.83 +/- 3.6 to 32.1 +/- 5.6 hr. P = 0.04) and right hemicolon (from 14.5 +/- 0.9 hr to 19.7 +/- 1.5 hr. P = 0.02) by suppression of defecation. We conclude that defecation habits may induce changes in colonic function such as those seen in constipation and that functional anorectal outlet obstruction may. probably by reflex mediation. affect the right colon.
Outpatient health care utilization of patients with inflammatory bowel disease, On the basis of the normal life expectancy of inflammatory bowel disease patients. the early onset of their disease. and the variety of symptoms. inflammatory bowel disease patients were anticipated to be frequent users of outpatients services. This study assesses (1) the characteristics. (2) outpatient health care utilization. and (3) the degree of satisfaction with health care of inflammatory bowel disease patients compared to patients with other gastrointestinal disease. The study method was a secondary analysis of data collected on 395 patients attending the University of Calgary Gastroenterology Outpatient Clinic in 1988. Inflammatory bowel disease patients were significantly younger (P less than 0.001) and better educated (P less than 0.05) than other patients. During the past year inflammatory bowel disease patients consulted significantly more often with their gastroenterologist (P less than 0.001) and spent more time in hospital (P less than 0.05) than other patients. Inflammatory bowel disease patients also consulted more frequently with herbalists and naturopaths. Lastly. inflammatory bowel disease patients were as satisfied with the health care they received as other patients. These results provide information useful for health care planners as well as for those dealing directly with inflammatory bowel disease patients.
Investigation of mode of action of biofeedback in treatment of fecal incontinence, A study was carried out in 25 incontinent patients to evaluate some of the factors thought to be responsible for the success of retraining for fecal incontinence. Subjects were initially allocated to one of two groups; one group was trained to perceive small rectal volumes (active retraining). the other group carried out the same maneuvers but were not given any information or instruction. Active sensory retraining reduced the sensory threshold from 32 +/- 8 to 7 +/- 2 ml (P less than 0.001). corrected any sensory delay that was present (P less than 0.004). and reduced the frequency of incontinence from 5 +/- 1 to 1 +/- 1 episodes per week (P less than 0.01). Sham retraining caused a modest reduction in the sensory threshold (from 29 +/- 9 to 20 +/- 8; P less than 0.05) but did not significantly reduce the frequency of incontinence. Subsequent strength and coordination training did not significantly improve continence. although at the end of the study. 50% of patients had no incontinent episodes at all and 76% of patients had reduced the frequency of incontinence episodes by more than 75%. This improvement in continence was not associated with any change in sphincter pressures or in the continence to rectally infused saline but was associated with significant improvements in rectal sensation. The functional improvement was sustained over a period of two years in 16 of the 22 patients available for follow-up. In conclusion. the results support the use of retraining in the management of fecal incontinence and suggest that retraining may work by enhancing rectal sensitivity and instilling confidence.
Is menarche associated with diabetic retinopathy, The goal of this study was to evaluate the association between menarchal status and diabetic retinopathy. Diabetic retinopathy was present in 51 of 129 females; 7 were premenarchal. and 44 were postmenarchal. The range of severity of retinopathy was greater in the postmenarchal group. In multivariate analyses. duration of diabetes. menarchal status. and diastolic blood pressure were associated with the prevalence of diabetic retinopathy. After partitioning the duration of diabetes into years before and years after menarche. both were significant. but the number of years of diabetes after menarche was more strongly associated. At a 4-yr follow-up examination. more postmenarchal than premenarchal females had progression of their retinopathy (P = 0.06). These data suggest that stage of sexual development. as reflected by menarchal status. is associated with the presence and possibly the risk of progression of diabetic retinopathy.
Randomized crossover study of effect of resistance training on glycemic control, muscular strength, and cholesterol in type I diabetic men, The goal of this study was to evaluate a program of resistance weight training on cardiovascular risk factors. blood glucose management. and overall strength in diabetic subjects. A randomized crossover design was performed on eight male type I (insulin-dependent) diabetic subjects (mean +/- SD age 31 +/- 3.5 yr. height 176 +/- 5.6 cm. body wt 80 +/- 15 kg. duration of diabetes 12.3 +/- 9.8 yr. and insulin dose 24 U NPH/day and 21 U regular/day). The program consisted of heavy-resistance weight training 3 days/wk for 10 wk. concentrating on the strengthening of major muscle groups through progressive resistance. Blood tests included total cholesterol. triglycerides. very-low-density lipoprotein and high-density lipoprotein cholesterol. and HbA1c. These tests were repeated at three time points during the program. Field-strength testing was performed before and after training. An improvement was seen in the squat (93.6% increase. P less than 0.0001) and bench press (58% increase. P less than 0.005). HbA1c and triglyceride levels showed no change during the resting portion of the experiment but showed a significant change with the training program: HbA1c 6.9 +/- 1.4 vs 5.8 +/- 0.9% (P = 0.05) and triglyceride 5.044 +/- 1.06 vs. 4.628 +/- 0.88 mM (P = 0.01). Self-monitored glucose (taken pre- and postexercise) showed a decrease from 7.85 +/- 3.13 to 7.05 +/- 2.91 mM (P = 0.0001). Very-low-density lipoprotein cholesterol and triglycerides did not change after training. Analysis of variance showed no significant differences over time from the three time points with regard to reductions in cardiovascular risk factors or HbA1c.
Impact of glucose self-monitoring on non-insulin-treated patients with type II diabetes mellitus. Randomized controlled trial comparing blood and urine testing, The goal of this study was to compare the relative efficacy and cost of self-monitoring of blood glucose (SMBG) with routine urine testing in the management of patients with type II (non-insulin-dependent) diabetes mellitus not treated with insulin. Fifty-four patients with type II diabetes mellitus. not treated with insulin. who had inadequate glucose control on diet alone or diet and oral hypoglycemic agents were studied. Patients performed SMBG or urine glucose testing as part of a standardized treatment program that also included diet and exercise counseling. During the 6-mo study. both the urine-testing and SMBG groups showed similar improvement in glycemic control; within each group. there were significant improvements in fasting plasma glucose (reduction of 1.4 +/- 3.2 mM. P less than 0.03) and glycosylated hemoglobin (reduction of 2.0 +/- 3.4%. P less than 0.01) levels. Seventeen (31%) of 54 patients actually normalized their glycosylated hemoglobin values. 9 in the urine-testing group and 8 in the SMBG group. Comparisons between the urine-testing and SMBG groups showed no significant differences in mean fasting plasma glucose (P greater than 0.86). glycosylated hemoglobin (P greater than 0.95). or weight (P greater than 0.19). In patients with type II diabetes mellitus not treated with insulin. SMBG is no more effective. but is 8-12 times more expensive. than urine testing in facilitating improved glycemic control. Our results do not support widespread use of SMBG in diabetic patients not treated with insulin.
Incidence of IDDM during 1984-1986 in population aged less than 30 yr. Residents of Turin, Italy, The goal of this study was to measure the incidence of insulin-dependent diabetes mellitus (IDDM) during 1984-1986 in residents of Turin. Italy. aged less than 30 yr. The primary data source was the list of all subjects diagnosed with IDDM who attended diabetes clinics in Turin. Other data sources were the general register of death certificates. the list of hospital discharges. and the computerized data base of insulin prescriptions. Eighty incident cases of IDDM were identified during the study in 1.130.284 person-yr for those less than 30 yr of age. Age-adjusted (world standard) incidence rates were 8.05. 8.10. and 6.96/100.000 in the age-groups 0-14. 0-19. and 0-29 yr. respectively. Estimated completeness of the primary data source compared with all other data sources was 91%. whereas the estimated completeness of ascertainment of the registry was 99%. Incidence rates of IDDM in northern Italy compare with those of European countries with low-medium incidence. A population-based register is being established for the province of Turin (951.445 inhabitants aged 0-29 yr) for the collection of incident cases since 1984.
WHO Multinational Project for Childhood Diabetes. WHO Diamond Project Group, Insulin-dependent diabetes mellitus (IDDM) is one of the most important chronic diseases of children worldwide. IDDM leads to an 8- to 10-fold excess risk of mortality in developed countries. whereas in developing countries. most cases die within a few years. A 60-fold international gradient in IDDM incidence has been reported. and epidemic periods have been identified. A new World Health Organization program. Multinational Project for Childhood Diabetes (Diabetes Mondiale or DIAMOND). has been developed to investigate and characterize global incidence. mortality. and health care. Over 10 yr (1990-1999). this study will collect population-based data concerning IDDM in greater than 90 centers in 50 countries worldwide. The goals of DIAMOND are to collect standard information on incidence. risk factors. and mortality associated with IDDM; evaluate the efficiency and effectiveness of health care and the economics of diabetes; and establish national and international training programs in diabetes epidemiology. It is hoped that the DIAMOND project will be instrumental for the prevention of this serious disease and its sequelae.
Evaluation of new rapid office test for microalbuminuria and its comparison to fully quantitative radioimmunoassay, A novel enzyme-linked immunosorbent assay (ELISA [Dialbumin]) for rapid office measurement of microalbuminuria was evaluated and its performance compared with that of a commercially available radioimmunoassay (double-antibody albumin). Urine samples containing between 0.75 and 1800 micrograms/ml of albumin were obtained from 31 diabetic patients and assayed by both methods. A comparison of the paired values obtained from the two methods gave a correlation coefficient of greater than 0.99. The Dialbumin assay. which used detachable eight-well strips (1 strip/sample). 10-min incubation. tap water wash. and a 2-min color development step. was read on both an ELISA reader and a hand-held analytical device (Acc-U-Dial) designed specifically for this test. The findings of this study indicate that the Dialbumin assay. used in conjunction with the Acc-U-Dial device. affords a rapid. convenient. and sensitive method for quantitative determination of a broad range (0.3-1280 micrograms/ml) of urinary albumin levels in the office setting.
Controlled study in diabetic children comparing insulin-dosage adjustment by manual and computer algorithms, A controlled trial of a new microprocessor device for insulin-dosage adjustment was undertaken in two matched groups of a priori well-controlled diabetic children. A prospective study design with three equal 8-wk periods was used. In the first period. both groups used manual methods for insulin-dosage adjustment after manual criteria. In the second period. one group of children adjusted insulin dosage by computer algorithms. whereas the other continued to use manual methods. In the third period. both groups again adjusted insulin by traditional methods. Mean premeal glycemia and glycosylated hemoglobin levels did not change in either group throughout the study. During the second period. episodes of hypoglycemia were more frequent in children without the computer than in those who used the device. In keeping with the latter outcome. the group that used the microprocessor device was given less insulin in the second period than the first (0.88 +/- 0.02 vs. 0.94 +/- 0.02 U.kg-1.day-1. P less than 0.0001) and in comparison to the control group of patients who concurrently were given an increased insulin dose in the second period compared with the first. This study showed that insulin treatment through specific computer-mediated dosage-adjusting algorithms was safe and minimized hypoglycemia by effectively accommodating seasonally changing insulin requirements. We recommend the device to help diabetic children and their families in the care of insulin-dependent diabetes.
Complement-fixing antibodies to sympathetic and parasympathetic tissues in IDDM. Autonomic brake index and heart-rate variation, We describe herein complement-fixing anti-adrenal medullary (CF-ADM) and anti-sympathetic ganglia (CF-SG) antibodies in insulin-dependent diabetes mellitus (IDDM). This study describes complement-fixing anti-vagus (CF-V) nerve antibodies and their relationship to the cardiovascular autonomic brake index (a measure of transient decrease in heart rate during the 1st min after a tilt). and R-R interval variation with deep breathing. CF-V was detectable in 7 of 83 (8.4%) subjects with IDDM aged 1.5-65.5 yr (mean +/- SE 28.7 +/- 1.8 yr) and duration of diabetes 0-47 yr (11.8 +/- 1.4 yr). Seventy-six nondiabetic subjects (aged 10-65 yr) all had negative CF-V scores. CF-V scores correlated with CF-ADM (0-16 yr of IDDM. r = 0.61. P less than 0.0001) and CF-SG (r = 0.39. P less than 0.05). Seventy IDDM subjects (aged 28 +/- 5 yr. duration of diabetes 17 +/- 3 yr) without proteinuria or proliferative retinopathy were screened for CF-ADM. CF-SG. and CF-V antibodies. Five of 70 (7.1%) had CF-SG only (negative for CF-ADM and CF-V). Brake indices ranged from 14.7 to 51.3 (37.3 +/- 6.9). Three of 70 (4.2%) had CF-ADM only. with brake indices from 26.9 to 45.1 (32.9 +/- 6.1). Four of 70 (5.7%) had CF-V antibodies only. with brake indices of 12.7-17.3 (15.1 +/- 1.1). Subjects with CF-SG or CF-ADM (anti-sympathetic) had higher brake indices than subjects with CF-V (anti-parasympathetic) antibodies (P less than 0.03).
Impact of intensive educational approach to dietary change in NIDDM, The aim of this study was to compare the effects of an intensive educational approach incorporating longer time. greater simplicity. repetition. and cognitive motivational techniques with a conventional one in subjects with established non-insulin-dependent diabetes mellitus (NIDDM) whose weight. glycemic control. and diet were not optimal. Subjects were randomly allocated to intensive or conventional education. Of 350 subjects. 70 met the study criteria. which included established NIDDM (greater than or equal to 3 mo). suboptimal recent glycemic control. dietary fat intake greater than or equal to 35% of total energy intake. and body mass index greater than or equal to 25 kg/m2. The intensive approach was associated with significantly greater improvements in dietary compliance. dietary intake (complex carbohydrate. [P = 0.013]. legumes [P less than 0.0001]. fiber [P less than 0.0001]. total fat [P less than 0.004]. saturated fat [P less than 0.004]). and total cholesterol level (P = 0.007). The transient improvement in glycemic control was similar in both groups. An intensive education program can improve dietary compliance in established NIDDM subjects more than a conventional one. These recommended dietary improvements achieve better improvement in total cholesterol but do not necessarily improve glycemic control.
Effects of childbearing on glucose tolerance and NIDDM prevalence [published erratum appears in Diabetes Care 1990 Nov;13(11):1138, The goal of this study was to estimate the effects of childbearing on subsequent glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM) prevalence. A sample of subjects from 64 different locations in the United States were recruited for inclusion in the Second National Health and Nutrition Examination Survey. A complex survey design was used to select a probability sample of subjects from each location. A total of 4577 women were recruited. of whom 3057 underwent clinical and laboratory evaluation for the presence of diabetes mellitus. Women were classified as to their glucose tolerance based on the results of an oral glucose tolerance test or previous physician diagnosis of diabetes mellitus combined with current use of hypoglycemic medication. Childbearing was defined as number of live births experienced by each woman at the time of the interview. Fasting plasma glucose increased linearly with increasing number of live births (coefficient 0.009. 95% confidence interval [CI] 0.006-0.012). as did the 2-h value (coefficient 0.015. 95% CI 0.009-0.021). Adjustment for age. body mass index (BMI). education. and income substantially reduced the magnitude of the association between childbearing and either plasma glucose measurement. When the prevalence of NIDDM in relation to childbearing was examined with logistic regression analysis. a significant linear increase in diabetes prevalence was seen with increasing number of live births (relative prevalence of NIDDM. 1 birth vs. 0 = 1.73. 95% CI 1.39-2.15). but adjustment for age. BMI. education. and income greatly reduced the magnitude of this association (relative prevalence of NIDDM. 1 birth vs. 0 = 1.07. 95% CI 0.98-1.17).
Lowering of plasma glucose concentrations with bezafibrate in patients with moderately controlled NIDDM, The goal of this study was to investigate whether treatment with bezafibrate improves glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM). The study included 37 NIDDM patients with HbA1 concentrations greater than 8.5% and normal kidney and liver function who were being treated with diet alone or diet together with a sulfonylurea drug. One patient withdrew because of constipation. At randomization and after 3 mo of treatment. patients were given a standard mixed-test-meal tolerance test (MTT; 500 cal) after an overnight fast. and plasma glucose. insulin. C-peptide. metabolite. nonesterified fatty acid (NEFA). and triglyceride concentrations were measured at 15- to 30-min intervals. Serum lipid. HbA1. and fructosamine concentrations were measured at monthly intervals. Glucose. NEFA. and triglyceride concentrations were significantly lower throughout the second MTT in bezafibrate patients (P less than 0.01-0.001) but not in the placebo group. Fasting serum insulin and C-peptide levels. but not postprandial concentrations. were reduced only in bezafibrate patients (P less than 0.05). After 3 mo. mean fasting serum triglyceride concentrations fell from 2.2 to 1.4 mM (P less than 0.001). total serum cholesterol concentrations from 6.3 to 5.5 mM (P less than 0.001). and low-density lipoprotein cholesterol concentrations from 4.2 to 3.5 mM (P less than 0.001) in bezafibrate patients. There were no changes in serum lipid concentrations in the placebo group. Treatment of patients with moderately controlled NIDDM with bezafibrate improves glucose tolerance and the serum lipid profile. Bezafibrate treatment may be a useful adjunct to hypoglycemic therapy in patients with NIDDM.
Comparison of albumin excretion rate obtained with different times of collection, This study was undertaken to assess the usefulness of different techniques for determination of albumin excretion rate (AER). Ninety patients with type I (insulin-dependent) diabetes mellitus and 45 with type II (non-insulin-dependent) diabetes mellitus. with AER/24 h of less than 200 micrograms/min. were included. All patients were free of major systemic complications of diabetes and overt kidney disease (mean serum creatinine 1.1 +/- 0.1 mg/dl. range 0.4-1.2 mg/dl). We compared timed day. night. and 24-h specimens. as well as timed spot specimens during water-induced diuresis. Most patients with type I (75 of 90) and type II (30 of 45) diabetes had AER less than 20 micrograms/min and showed significant differences in AER that were dependent on the collection time. Differences were diminished or absent with AER less than 20 micrograms/min. Sensitivity. specificity. and prediction rates of AER in different specimens were evaluated against 24-h AER. Use of albumin concentrations and albumin-creatinine ratios did not improve test performance in comparison with AER. Sampling time and the overall rate of AER influenced measurement of urinary albumin excretion. Day or 24-h AER is most useful to determine the presence of abnormal AER. AER and albumin concentration in spot samples are of limited use for initial screening and frequently require day or 24-h specimens of AER for confirmation. Day or 24-h AER should be used for long-term follow-up of the diabetic patient.
Total serum glycosylated proteins in detection and monitoring of gestational diabetes, The goal of this study was to determine whether serum glycosylated protein levels (i.e.. fructosamine) can reliably screen for gestational diabetes and whether these levels are valid markers of short-term glycemic control in the third trimester of pregnancy. Ninety-seven pregnant women at 26-28 wk gestation were evaluated over 9 mo. HbA1c and serum glycosylated protein (serum fructosamine) were determined at the baseline venipuncture of the 100-g oral glucose tolerance test performed to detect gestational diabetes. Of the 97 women studied. 13 tested positive for gestational diabetes (National Diabetes Data Group criteria). There were significant differences in the fasting and 1-. 2-. and 3-h glucose values between nondiabetic and diabetic patients (P less than 0.005 at each time point). No difference was noted in the baseline serum glycosylated protein level (2.02 +/- 0.08 vs. 1.98 +/- 0.02 mM. NS) or HbA1c level (4.42 +/- 0.2 vs. 4.6 +/- 0.3%. NS) between gestational and nondiabetic patients. Diabetic patients were followed at 2-wk intervals. with serum glycosylated protein analysis. HbA1c. fasting glucose. and mean glucose determined by outpatient monitoring. Serum glycosylated protein correlated significantly to fasting blood glucose (r = 0.81. P less than 0.001) and mean outpatient glucose (r = 0.62. P less than 0.001) at the 2-wk follow-up visits. No correlation was found between HbA1c and fasting blood glucose (r = 0.11. NS) or mean outpatient glucose (r = -0.12. NS) during the follow-up period. The serum glycosylated protein level (serum fructosamine) is not a useful screening test for gestational diabetes. However. this assay shows potential as an objective marker of short-term control in evaluating the maternal glycemic state.
Development of IDDM after donating kidney to diabetic sibling, The goal of this study was to describe a patient who developed insulin-dependent diabetes mellitus (IDDM) after donating a kidney to his sibling and to suggest a possible solution to prevent such an occurrence. A 42-yr-old man was found to have islet cell autoantibodies (ICAs) as part of a screening program of first-degree relatives with IDDM. Two years previously. he had donated his kidney to his HLA-identical sibling with long-standing IDDM. Both oral and intravenous glucose tolerance tests demonstrated a gradual loss of insulin secretion and increasing glucose intolerance until the patient developed IDDM 6 yr after the nephrectomy. Whether the presence of ICA is an absolute contraindication to being a kidney donor could be debated. Nonetheless. ICA should be used as a screening test to identify individuals at risk for subsequent IDDM. For those found to be positive. counseling should be provided.
Effect of isocaloric substitution of chocolate cake for potato in type I diabetic patients, Traditional dietary advice given to people with diabetes includes eliminating simple sugars (primarily sucrose) from the diet. Many people have difficulty following this recommendation. Because patients with type I (insulin-dependent) diabetes do not need overall calorie restriction. there is no caloric reason to restrict sucrose. In this study. we looked at the effect of the isocaloric substitution of a piece of chocolate cake for a baked potato in a mixed meal to determine whether this would increase the blood glucose in patients with type I diabetes. The glucose response to a cake-added meal was significantly greater than to a standard meal. The glucose response was no different between a cake-substitution meal and a standard meal. The reproducibility studies showed no difference between repeated standard meals. The urinary glucose excretion was significantly greater after a cake-added meal but was no different with the other pairs. There were no significant differences in the counterregulatory hormone responses at baseline between any of the paired studies. In conclusion. patients with type I diabetes may substitute a sucrose-containing dessert for another carbohydrate in their diet without compromising their postprandial glucose response. These data suggest that a dessert exchange may be helpful and not harmful in the management of diabetic patients. There is an inherent variability (at least 16%) in an insulin-requiring patient's response to a meal. making self-monitoring of blood glucose and adjustment of insulin doses necessary to achieve near euglycemia.
Comparison of HbA1 and fructosamine in diagnosis of glucose-tolerance abnormalities, Total glycosylated hemoglobin (HbA1) and fructosamine were evaluated as screening tools for detection of glucose-tolerance abnormalities in 144 asymptomatic subjects undergoing a 75-g oral glucose tolerance test. Subjects were classified according to World Health Organization criteria as having normal (n = 78). impaired (n = 40). or diabetic (n = 26) glucose tolerance. We found good specificity for HbA1 and fructosamine (100 and 97%. respectively) but low sensitivity (15 and 19%. respectively). At the intersection of the curves of sensitivity and specificity drawn from various thresholds of normality. both sensitivity and specificity were 75% for HbA1 and 55% for fructosamine. Thus. neither HbA1 nor fructosamine seems to be suitable for the diagnosis of mild abnormalities in glucose tolerance.
Sulfonylureas. Why, which, and how, Although controversies remain as to the usefulness of sulfonylureas. most evidence is in favor of their use in many if not patients with non-insulin-dependent diabetes mellitus. When used properly. sulfonylureas improve insulin secretion and action. and these effects may be maintained for years. If combined with hypocaloric dietary regulation. rapid- and short-acting sulfonylureas may help patients reach and maintain euglycemia without provoking chronic hyperinsulinemia or weight increase. There is no evidence that sulfonylurea treatment causes beta-cell exhaustion; instead. the antihyperglycemic effect helps improve beta-cell function. Sulfonylurea "failures" are often dietary failures or may be due to late introduction of these drugs. i.e.. when beta-cell function is already attenuated. Desensitization of the insulinotropic effect of sulfonylureas may occur but might be avoided by discontinuous (less than 24 h/day) sulfonylurea exposure. i.e.. once-daily administration of a short-acting sulfonylurea in a moderate dose. The most important adverse effect of sulfonylureas is long-lasting hypoglycemia. which may lead to permanent neurological damage and even death. This is mainly seen in elderly subjects who are exposed to some intercurrent event. e.g.. acute energy deprivation or a drug interaction. i.e.. aspirin. Long-acting sulfonylureas may be more likely to promote long-lasting hypoglycemia. The dose-response relationships of sulfonylureas have been poorly investigated. and sulfonylurea therapy should always be initiated and maintained at the lowest possible dose.
Characterization and significance of sulfonylurea receptors, This study describes and characterizes a putative sulfonylurea receptor. The radioligand used was [3H]glipizide (9 Ci/mmol). The beta-cell plasma membranes were derived from a transplantable rat insulinoma generated by subcutaneous injection of RINm5F cells and purified by ultracentrifugation on a 15-55% sucrose gradient. Specific binding of [3H]glipizide to purified beta-cell plasma membranes was determined to be maximal at temperatures of 4-23 degrees C. pH 7.3. and an incubation of 2 h. Scatchard analysis indicated a single binding site with Kd = 7 nM and sulfonylurea binding of 0.93 pmol/mg membrane protein. Displacement of [3H]glipizide from the purified beta-cell plasma membranes by various sulfonylureas and their analogues correlated well with their known hypoglycemic and insulin-releasing activities. Various agents. including nutrients. agents affecting Ca2+ flux. gastrointestinal hormones. and pancreatic hormones. had no effect on [3H]glipizide binding to the beta-cell plasma membranes. Putative sulfonylurea receptors on beta-cell and brain cell plasma membranes have been reported by several groups of investigators. Sulfonylurea binding to the beta-cell is hypothesized to close an ATP-sensitive K+ channel. which leads to depolarization of the membrane and activation of a voltage-dependent Ca2+ channel.
Effect of acarbose on carbohydrate and lipid metabolism in NIDDM patients poorly controlled by sulfonylureas, The ability of acarbose to lower plasma glucose concentration was studied in 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) who were poorly controlled by diet plus sulfonylurea drugs. Patients were studied before and 3 mo after the addition of acarbose to their treatment program. and a significant improvement in glycemic control was noted. Although the decrease in fasting plasma glucose concentration was modest (12.0 +/- 0.8 to 10.8 +/- 0.3 mM). average postprandial plasma glucose concentration decreased by 3.4 mM. When acarbose therapy was discontinued in 5 patients. plasma glucose levels rapidly returned toward pretreatment levels. In addition to the improvement in glycemia. acarbose treatment also led to a significant reduction in HbA1c (7.4 +/- 0.2 to 6.4 +/- 0.2%. P less than 0.01) and triglyceride (2.4 +/- 0.1 to 2.1 +/- 0.1 mM. P less than 0.01) concentrations. Neither the plasma insulin response to meals nor insulin-stimulated glucose uptake improved with acarbose therapy. consistent with the view that acarbose improves glycemic control by delaying glucose absorption. Considerable individual variation was noted in the response to acarbose. and the results in 4 patients were dramatic. with striking reductions in both fasting and postprandial glucose concentrations. The addition of acarbose to patients with NIDDM not well controlled by sulfonylureas appears to have significant clinical benefit.
Biguanides and sulfonylureas as combination therapy in NIDDM, Oral combination therapy with biguanides (metformin) and sulfonylureas is discussed. The rationale for the use of this combination is based on the different sites of action of the two kinds of drugs and the possibility for obtaining additive or potentiating effects and reduced side effects. The clinical usefulness of chlorpropamide and glyburide in combination with metformin has been demonstrated in some clinical trials. The combination may provide satisfactory glycemic control for several years. and possibly insulin therapy can be postponed or even avoided. No special safety problems are encountered with the use of the combination other than those attributed to the use of metformin or sulfonylurea alone. i.e.. lactic acidosis and hypoglycemia. respectively. The lethality risks of these associated conditions are comparable. It is concluded that more data are needed to evaluate the full clinical potential and the mechanism of action of oral combination therapy.
Metabolic effects of combination glipizide and human proinsulin treatment in NIDDM, The effects of 3 mo of treatment with a combination of glipizide and human proinsulin were studied in a small group of closely monitored patients. The patients had non-insulin-dependent diabetes mellitus (NIDDM) and poor glucose regulation. despite maximal sulfonylurea therapy. This was a randomized double-blind placebo-controlled trial in which there were three treatment groups who received either 20 mg glipizide given 30 min before breakfast and dinner and human proinsulin given subcutaneously at bedtime (n = 5). glipizide and human proinsulin placebo (n = 5). or glipizide placebo and human proinsulin (n = 5). Glycemic regulation was assessed by measurements of 24-h plasma glucose profiles and glycosylated hemoglobin. Our observations demonstrate that the combination of glipizide plus human proinsulin was more effective than either agent alone in controlling overall glycemia in patients with NIDDM. The data support the concept of use of an agent during the day that has its major effects postprandially and another agent at bedtime that is relatively hepatospecific.
Combined insulin-sulfonylurea therapy in treatment of NIDDM, For the past few years. interest has focused on the combination of insulin and sulfonylurea in the search for effective treatments for non-insulin-dependent diabetes mellitus (NIDDM) patients who fail on oral hypoglycemic agents. Although several studies have demonstrated beneficial effects of such therapy in NIDDM patients. the average effect is small and is observed in only about half of the patients. However. there are several problems with most previous studies. including small sample size. selection of patients. and simultaneous use of several end points. First. residual beta-cell function has been considered to be a prerequisite for a beneficial effect of combination therapy. Therefore. most studies have failed to demonstrate improved glycemic control after adding sulfonylurea to insulin therapy in patients with insulin-dependent diabetes mellitus. Inclusion of patients with impaired beta-cell function will therefore attenuate the effect of combination therapy. Second. most studies have used glycemic control as an end point. Nevertheless. the insulin dose has been reduced by 20-30% to avoid hypoglycemia after adding sulfonylurea to insulin. Thus. the comparison has been made between treatments with a smaller insulin dose with sulfonylurea and a larger insulin dose without sulfonylurea. The patient most likely to benefit from combination therapy is slightly obese. has had NIDDM for a relatively short period. and has preserved beta-cell function. In such a patient. combined insulin-sulfonylurea therapy predominantly stimulates basal insulin secretion. resulting in more effective suppression of hepatic glucose production and lower fasting plasma glucose. The side effects are few. most notably more frequent but mild hypoglycemic reactions.
Will sulfonylurea treatment of impaired glucose tolerance delay development and complications of NIDDM, The chronic hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) evolves gradually and is usually preceded by more transient hyperglycemia. classified as impaired glucose tolerance (IGT). Already in this phase. there is an increased risk of cardiovascular complications. and many IGT subjects. like NIDDM patients. often display several of the metabolic and circulatory disturbances that are associated with hyperglycemia. e.g.. insulin resistance. hyperinsulinemia and/or hyperproinsulinemia. delayed insulin release. dyslipidemia. and hypertension. Therefore. and because untreated hyperglycemia is a self-perpetuating condition. early detection and early intervention may be necessary to prevent the progression and complications of NIDDM. This in turn would necessitate screening procedures. and the therapeutic goal should include both euglycemia and normalization of plasma insulin. plasma lipids. and blood pressure. A study in the German Democratic Republic indicated that the mortality in screening-detected NIDDM patients did not differ from that in patients detected in routine care. In a Swedish study on screening-detected NIDDM subjects. only those who had IGT rather than manifest NIDDM could maintain fasting blood glucose less than or equal to 6 mM for 5 yr by hypocaloric dietary regulation alone. In those with screening-detected NIDDM. the delayed acute insulin release and net postprandial hyperglycemia were improved by addition of glipizide. and most managed to attain and maintain fasting blood glucose less than or equal to 6 mM for approximately 2 yr after such addition. However. after 4 yr. there was an increase in blood glucose. suggesting that preventive intervention either may not be possible or may have to start in the IGT phase.
Myasthenia gravis, Myasthenia Gravis is a disorder of neuromuscular function resulting from an immunologically based premature destruction of acetylcholine receptors. The disease is characterized clinically by variable weakness accentuated by repetitive muscular activity and usually responding to the administration of acetylcholinesterase inhibitors. Myasthenia Gravis is a complex disease and requires understanding of the many facets of its natural history and immunological basis to ensure optimal individual patient management. The long-term goal is control of the immunological imbalance; treatment regimens include thymectomy. corticosteroids. azathioprine. and plasmapheresis. The common use of acetylcholinesterase inhibitors provides symptomatic relief during variable daily muscular activity. Disability due to myasthenia gravis is to a large extent reversible and death is preventable. Early recognition of myasthenia gravis and appropriate treatment are often rewarded by remission that may be permanent.
Treatment of tubal pregnancy by local injection of methotrexate after adrenaline injection into the mesosalpinx: a report of 25 patients, Twenty-five patients with a tubal pregnancy were treated by an injection of methotrexate (MTX) into the tubal swelling after vasoconstriction of the mesosalpinx with adrenaline. Twenty-four of the 25 patients had an uneventful clinical course. In one case. the tube ruptured despite falling serum human chorionic gonadotropin (hCG) concentrations. In 17 of 24 patients. the dose of 100 mg that was locally injected was sufficient. Seven patients were given additional systemic injections. In 3 of the 4 patients with high initial serum hCG levels (greater than 10.000 mIU/mL). the clinical course was uneventful. The side effects of MTX and adrenaline were minimal. Whether this way of treatment guarantees better chances of fertility in the future is unknown. Therefore a prospective. case-controlled study comparing the fertility rates in different ways of treatment is needed.
The effect of metoclopramide on ovarian responsiveness to gonadotropin administration in patients with severe polycystic ovarian syndrome, Six patients with poor ovarian response to menotropin after pretreatment with a gonadotropin-releasing hormone analog exhibited improved ovarian responsiveness when metoclopramide was added on days 3. 5. and 7 of the cycle. This was evidenced by a higher number of leading follicles (4.4 versus 0.6). a higher mean of maximal serum 17 beta-estradiol levels (560 versus 178 pg/mL). a shorter duration of menotropin treatment (7 versus 11 days). and fewer ampules of menotropin used (20 versus 37 ampules/cycle) in metoclopramide-treated cycles as compared with control cycles. respectively. Serum prolactin levels reached a maximum of 172 ng/mL within 1 hour after metoclopramide administration and declined to normal range within 6 hours. These results suggest that intermittent increased prolactin secretion may augment ovarian response to gonadotropins.
Aromatase activity of human granulosa cells in patients with polycystic ovaries treated with dexamethasone, The effect of dexamethasone (DEX) (9 alpha-Fluro-16 alpha-methyl prednisolone) on secretion of steroids by human granulosa luteinized cells was studied by culturing cells from mature follicles of women with polycystic ovarian disease and treated for infertility in the in vitro fertilization program. Patients were treated with DEX 0.5 mg/d until the day of human chorionic gonadotropin administration. The cells were cultured for 24 hours in the presence of androstenedione (10(-7)M). After incubating for 24 hours. the medium was replaced and the cells were incubated for an additional 24 hours. The medium was then harvested and assayed for estradiol (E2) and progesterone (P). Results were compared with those of a control group who was not treated with DEX. Estradiol production by cells was significantly lower in the study group treated with DEX. Progesterone production was not influenced by DEX. Follicular fluid levels. E2. and androgens did not vary with DEX treatment. whereas cortisol levels markedly decreased and P levels increased with the treatment. These findings suggest that glucocorticosteroids can directly influence granulosa luteinized cell function.
Serum levels of anticardiolipin antibodies are pathologically increased after active immunization of patients with recurrent spontaneous abortion, Although the pathophysiological mechanisms leading to recurrent spontaneous abortion are still not fully understood. treatment schemes based on immunological principles have been advocated in recent years claiming that the production of the so-called blocking factor is being specifically stimulated. We investigated. retrospectively. whether active immunization can affect the production of immunoglobulin (Ig)G and IgM anticardiolipin antibodies. In a group of untreated recurrent spontaneous abortion patients (n = 9). the range of variation of cardiolipin antibodies. during consecutive controls taken at the same time interval as after immunization. was not statistically significant. In contrast to this. significant increases of both IgG and IgM antibodies occurred after active immunization with paternal leucocytes in 10 of 15. and in 6 of 15 cases. respectively. The mean basal and posttransfusion levels were: 7.26 +/- 2.53 and 30.15 +/- 23 U/mL for IgG and 2.26 +/- 1.2 and 6.82 +/- 5.6 U/mL for IgM. respectively. We conclude that active immunization with human lymphocytes leads to the production of antibodies against cardiolipin. This effect is exerted on both IgM and IgG antibodies.
High dietary fiber and low saturated fat intake among oligomenorrheic undergraduates, Numerous functional risk factors are associated with the occurrence of secondary amenorrhea in young women. Less is known regarding factors associated with the more prevalent problem of oligomenorrhea. We have evaluated nutrient intake. body composition. perceived psychological stress. 24-hour urinary cortisol. and urinary C peptide (UCP) in 35 eumenorrheic. 11 mildly oligomenorrheic. and 10 oligomenorrheic nonathletic undergraduate women. Nutrient intake was evaluated by a validated food frequency questionnaire. Oligomenorrheic women were found to consume significantly more dietary fiber. crude fiber. and polyunsaturated fat. and significantly less saturated fat than their eumenorrheic classmates. Oligomenorrheic women had significantly lower 24-hour UCP excretion than mildly oligomenorrheic women. The groups did not differ in any aspect of body composition. body weight. age of menarche. perceived psychological stress. or urinary cortisol excretion. The data suggest that higher intake of fiber and lower intake of saturated fat may be associated with oligomenorrhea among otherwise healthy undergraduate nonathletic women.
A serial section study of visually normal pelvic peritoneum in patients with endometriosis, Defined criteria were used to select small samples of visually normal study peritoneum for serial section light microscopy in 45 patients with biopsy-proven endometriosis and 10 patients without endometriosis. A glandular element compatible with possible endometriosis was found in only 1 patient. Visually normal peritoneum does not harbor a high prevalence of invisible microscopic endometriosis.
Treatment of idiopathic testicular failure with high-dose testosterone undecanoate: a double-blind pilot study, The effect of high-dose (240 mg/d) intake of testosterone (T) undecanoate was studied for sperm characteristics. function of the accessory sex glands. and hormonal parameters of men with idiopathic oligozoospermia. asthenozoospermia. or teratozoospermia using a two-phase protocol including a 3-month double-blind period followed by a 3-month open phase. Increased sperm viability and semen content of adenosine triphosphate were either not reproducible after patients on placebo were switched over to T undecanoate or did not reach statistical significance. whereas no changes were detected in other sperm characteristics and the accessory sex glands. Intake of T undecanoate significantly increased the concentration of 5-alpha-dihydrotestosterone (DHT) and the ratio of DHT over T in peripheral blood. suppressed the luteinizing hormone concentration. and tended to decrease serum follicle-stimulating hormone concentration. It is concluded that high-dose T undecanoate is not effective in the treatment of men with infertility with idiopathic testicular failure.
A portable digital data recorder for long-term monitoring of scrotal temperatures, The application of a new. miniaturized portable digital data recorder "Thermoport" (Institute for Reproductive Medicine. Munster. West Germany) for continuous determination of scrotal temperatures revealed great variations of scrotal temperature during 24 hours in normal men. Maximum temperatures approached body core temperatures. Mean scrotal temperatures of 10 normal men rose during sauna from 32.72 +/- 0.23 degrees C to 37.53 +/- 0.38 degrees C. During treadmill running. scrotal temperatures increased by more than 2.5 degrees C. Minimal scrotal temperatures were increased in some men with varicocele compared with normal fertile men indicating impaired cooling mechanisms. The continuous temperature measurements facilitate assessment of temperature dynamics. The miniaturized design of the Thermoport makes it suitable for routine use in outpatients of infertility clinics. in occupational medicine for evaluation of heat hazards. and for investigations of body temperatures under various experimental conditions.
Analysis of sperm function in globozoospermia: implications for the mechanism of sperm-zona interaction, The globozoospermic condition has provided a unique opportunity to determine how the abnormal mitochondrial organization and acrosomal loss associated with this syndrome. influence sperm function. Despite the abnormal midpiece architecture. the movement characteristics of the spermatozoa. in terms of the curvilinear. path. and progressive velocities. amplitude of head displacement. and hyperactivation were all within the normal range. Similarly. the behavior of the spermatozoa on Percoll gradients was normal. although the capacity of the isolated fractions to generate reactive oxygen species was negligible. Of particular significance was the fact that the globozoospermic spermatozoa were incapable of sperm-oocyte fusion or binding the human zona pellucida. even after an intracellular calcium signal had been generated with the ionophore A23187. The sudden induction of sperm-zona interaction could. however. be achieved by the use of a ferrous ion promoter system to induce limited lipoperoxidation. This result demonstrates that the enhancing effect of peroxidation on sperm-zona adhesion involves a direct action on the properties of the sperm-plasma membrane. rather than an indirect consequence of acrosomal damage and acrosin leakage. Such findings emphasize the value of specific teratozoospermic conditions. such as globozoospermia. in dissecting the mechanisms that regulate human sperm function.
Heterologous transplantation of activated murine peritoneal macrophages inhibits gamete interaction in vivo: a paradigm for endometriosis-associated subfertility, Macrophage hyperactivation has been postulated to be the pathologic aberration in patients suffering from endometriosis-associated subfertility. In this report an in vivo model for macrophage-mediated infertility is described. Populations of macrophages were obtained from an inbred strain of mice (Balb/C) as follows: (1) in vivo hyperactivated macrophages (harvested from donor mice treated with intraperitoneal thioglycolate); (2) hyperactivated macrophages deactivated ex vivo with the protein synthesis inhibitor emetine; and (3) basal state (nonactivated) macrophages obtained from untreated mice. Recipient mice underwent ovarian hyperstimulation with pregnant mare serum gonadotropins; 2 x 10(6) macrophages were transferred on the afternoon of stimulation day 3 before injection of human chorionic gonadotropin (hCG) and mating. Unfertilized oocytes and 4-cell embryos were counted on day hCG +2 as a reflection of reproductive performance. Heterologous transfer of in vivo hyperactivated macrophages. but not basal state macrophages. significantly inhibited fertilization. This effect was largely reversed by pretreatment with emetine. These experiments confirm the relevance of macrophage-mediated interference with early reproductive performance and provide a model for the development of alternative therapies (e.g.. immunomodulation of the peritoneal fluid environment) for endometriosis-associated subfertility.
Insulin-mimetic effects of vanadate. Possible implications for future treatment of diabetes, Vanadate ions. low-molecular-weight phosphate analogues. mimic most of the rapid actions of insulin in various cell types. When administered orally to diabetic hyperglycemic rats. vanadate reaches the circulation. mimics insulin stimulation of glucose uptake and metabolism. and leads to normoglycemic and partial anabolic states. In addition. vanadate restores tissue responsiveness to insulin and hepatic glycogen levels and activates new synthesis of key enzymes for carbohydrate metabolism. This suggests that correcting hyperglycemia is sufficient to correct the typical metabolic alterations found in streptozocin-induced diabetic rats. Several weeks of oral administration of vanadate to diabetic rats has not produced detectable liver or kidney toxicity. The mechanism by which vanadate mimics the actions of insulin is still obscure. Unlike insulin. vanadate does not seem to stimulate the autophosphorylation and endogenous tyrosine phosphorylation of insulin-receptor kinase or other intracellular proteins either directly or by virtue of its known inhibitory effect on protein phosphotyrosine phosphatase. Results from many studies support a model in which vanadate activates glucose metabolism by either utilizing an alternative (insulin-independent) cascade or bypassing the early events of the insulin-dependent cascade. Either of these possibilities is of clinical importance. because early insulin events may become defective. as a result of severe hyperinsulinemia. and may contribute to insulin resistance. Alternative pathways by which vanadate may stimulate glucose metabolism. e.g.. by increasing intracellular Ca2+ levels and/or regulating intracellular and intravesicular pH. are discussed. From a clinical perspective. studies should be continued in evaluating the level of vanadate toxicity after prolonged treatment and searching for agents that potentiate its insulin mimetic actions in vitro and in vivo.
Association of elevated fasting C-peptide level and increased intra-abdominal fat distribution with development of NIDDM in Japanese-American men, The Japanese-American population of King County. Washington. is known to have a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). As part of a community-based study. we reexamined 146 second-generation Japanese-American men who had been initially classified as nondiabetic. At a mean follow-up period of 30 mo. 15 men had developed NIDDM. and 131 remained nondiabetic. The variables measured at the initial visit that distinguished the 15 diabetic men from the 131 nondiabetic men were older age. higher serum glucose level at 2 h after 75 g oral glucose. higher fasting plasma C-peptide level. and increased cross-sectional intra-abdominal fat area as determined by computed tomography. Both older age and higher 2-h glucose levels are variables that have been associated with the development of NIDDM. but the association of higher fasting C-peptide level and greater intra-abdominal fat area with subsequent development of NIDDM were new observations. The elevated fasting C-peptide level persisted after adjustment for fasting serum glucose. The elevated C-peptide level represents hypersecretion of insulin and was interpreted to reflect a compensatory response to an underlying insulin-resistant state that antedates the development of NIDDM. The fasting C-peptide level was correlated with the intra-abdominal fat area. suggesting that the intra-abdominal fat area may be associated with insulin resistance. Thus. in individuals who develop NIDDM. insulin resistance. increased insulin secretion. and increased intra-abdominal fat are present before diabetic glucose tolerance can be demonstrated.
Absence of angiogenesis-inhibitory activity in aqueous humor of diabetic rabbits, We studied inhibitory activity of angiogenesis in the eye to explore the formation of new blood vessels in diabetic microvascular diseases. When we examined the effects of extracts from various ocular tissues of nondiabetic rabbits on the proliferation of bovine aortic endothelial cells. potent inhibitory activity was found in lens and aqueous humor. Aqueous humor inhibited both angiogenesis on chorioallantoic membrane in vivo and promotion of endothelial cell growth in vitro. which were induced by retinal extracts. However. in diabetic rabbits. aqueous humor lost the ability to inhibit the growth of endothelial cells. The loss of activity became evident 1 mo after the alloxan injection and lasted while the animals were hyperglycemic. In addition. diabetic aqueous humor failed to suppress retinal extract-induced angiogenesis promotion and endothelial cell growth. The absence of the inhibitory activity of angiogenesis in diabetic aqueous humor might be involved in promotion of neovascularization in diabetic ocular disease.
Occurrence of type VI collagen in extracellular matrix of renal glomeruli and its increase in diabetes, Human and bovine glomerular basement membrane (GBM) preparations. representing the extracellular matrix of the renal filtration units. were found to contain type VI collagen. This protein was solubilized by guanidine and guanidine-dithiothreitol extractions and characterized after polyacrylamide gel electrophoretic resolution by immunoblotting with an antiserum directed against the alpha 1(VI) and alpha 2(VI) polypeptide chains and by its insensitivity to collagenase digestion in the nonreduced state. In contrast to GBM. which is the product of three distinct cells. type VI collagen could not be detected in extracts from calf lens capsule. an epithelial cell-derived basement membrane. Quantitation by radioimmunoassay of the type VI collagen content of GBM from 17 diabetic and 15 nondiabetic human subjects indicated a 2.8-fold higher level (P less than 0.001) in the diabetic preparations. Because in the glomerulus type VI collagen is considered on the basis of immunohistochemistry to be localized to the mesangium. we believe that measurement of this protein in GBM preparations can provide a valuable index of mesangial expansion in diabetic and other glomerulopathies.
Leucine metabolism in IDDM. Role of insulin and substrate availability, The effect of insulin on plasma amino acid concentrations and leucine metabolism was examined in 18 healthy nondiabetic young volunteers and in 7 subjects with insulin-dependent diabetes mellitus (IDDM) with the euglycemic insulin-clamp technique (40 mU.m-2.min-1) in combination with [1-14C]leucine. All diabetic subjects were studied while in poor metabolic control (fasting glucose 13.3 +/- 1.1 mM; HbA1c 10.8 +/- 0.2%) and again after 2 mo of intensified insulin therapy (fasting glucose 7.2 +/- 0.5 mM; HbA1c 8.0 +/- 0.2%). Insulin-mediated total-body glucose uptake in poorly controlled diabetic subjects (3.6 +/- 0.5 mg.kg-1.min-1) was significantly reduced compared with control subjects (7.5 +/- 0.2 mg.kg-1.min-1; P less than .001) and improved slightly after insulin therapy (4.8 +/- 0.3 mg.kg-1.min-1; P less than .05). although it still remained significantly lower than in control subjects (P less than .01). During the insulin-clamp study performed in subjects with poorly controlled IDDM. endogenous leucine flux (ELF). leucine oxidation (LO). and nonoxidative leucine disposal (NOLD) all decreased (50.1 +/- 2.0 to 26.4 +/- 0.4; 9.2 +/- 0.4 to 6.0 +/- 0.3; 40.9 +/- 2.0 to 20.4 +/- 2.0 mumol.m-2.min-1. respectively) to the same extent as in control subjects. After 2 mo of intensified insulin therapy. the effect of acute hyperinsulinemia on ELF. LO. and NOLD was comparable to that of control subjects. whereas insulin-stimulated glucose metabolism was still impaired. To examine the effect of substrate availability on leucine turnover. well-regulated IDDM and control subjects underwent a repeat insulin-clamp study combined with a balanced amino acid infusion designed to increase circulating plasma amino acid levels approximately twofold. Under these conditions. NOLD was equally enhanced above baseline in both control and IDDM subjects (P less than .01). whereas ELF was inhibited to a greater extent (P less than .01) than during the insulin clamp performed without amino acid infusion (control vs. diabetic subjects. NS). In conclusion. insulin-mediated glucose metabolism is severely impaired in subjects with both poorly controlled and well-controlled IDDM. whereas the effect of acute insulin infusion on leucine turnover is normal. and combined hyperaminoacidemia/hyperinsulinemia stimulated NOLD to a similar extent in both IDDM and control subjects.
Polymorphisms of HepG2/erythrocyte glucose-transporter gene. Linkage relationships and implications for genetic analysis of NIDDM, To assess the contribution of the HepG2/erythrocyte glucose-transporter (HepG2 GT) gene to the inherited susceptibility to non-insulin-dependent diabetes mellitus (NIDDM). cDNA and genomic probes were used to search for restriction-endonuclease polymorphisms at this locus. Analysis of DNA from 16 unrelated Black American individuals with 19 enzymes and as many as six different probes. defined four polymorphisms over a 45-kilobase region. Nucleotide diversity (pi = 0.006) was low relative to that at other loci. with an average of 1 in 1700 base pairs different between two chromosomes at this locus. The observed combined heterozygosity for these four sites was 0.69. which indicates that the markers at this locus could be useful for linkage analysis in families. Linkage-disequilibrium values between the four polymorphisms were evaluated by pairwise analysis and extended haplotypes. Calculating pairwise associations by the disequilibrium statistic delta or by another measure of disequilibrium. D' (the maximum likelihood of disequilibrium. which is less dependent on frequency). significant linkage disequilibrium could not be demonstrated. However. the frequencies of the observed extended haplotypes were shown to differ (chi 2 = 9.1. df = 2. P less than 0.025) from predicted frequencies if the sites were in linkage equilibrium in Blacks. The frequencies of these four polymorphisms were determined in Black nondiabetic (n = 44) and NIDDM (n = 63) subjects. Neither the allelic nor genotypic frequencies of the polymorphisms differed between the two groups.
Absence of brown product FFI in nondiabetic and diabetic rat collagen, Accumulation of brown products in long-lived proteins might be an important factor in determining long-term diabetic complications. Fluorescent chromophore 2-(2-furoyl)-4-(5)-(2-furanyl)-1H-imidazole (FFI). isolated from hydrolyzed brown products synthesized in vitro. was proposed as a specific brown product responsible for functional and structural changes in long-lived proteins. In this study. an attempt was made to demonstrate by means of collision spectroscopy the presence of FFI in collagen samples taken from diabetic rats. Diabetic rat collagen samples showed mean values of absorbance per milligram of 4-hydroxy-L-proline significantly higher than those observed in nondiabetic rats. suggesting higher FFI levels. Surprisingly. all collagen samples from diabetic and nondiabetic rats gave collision spectra in which no peak diagnostic of FFI presence was observed. These data suggest that the absorbance level observed in diabetic rats is not due to the presence of FFI but to structurally related compounds. which are being investigated by means of mass spectrometry.
Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes, Glucose transport by facilitated diffusion is mediated by a family of tissue-specific membrane glycoproteins. At least four members of this gene family have been identified by cDNA cloning. The HepG2-type transporter is the most widely distributed of these proteins. It provides many cells with their basal glucose requirement for ATP production and the biosynthesis of sugar-containing macromolecules. The liver-type transporter is expressed in tissues from which a net release of glucose can occur and in beta-cells of pancreatic islets. A genetic defect resulting in reduced activity of this transporter could hypothetically lead to the two principal features of non-insulin-dependent diabetes mellitus. insulin resistance and relative hypoinsulinemia. The adipocyte/muscle transporter is expressed exclusively in tissues that are insulin sensitive with respect to glucose uptake. This protein is an excellent candidate for a highly specific genetic defect predisposing to insulin resistance.
Effects of converting-enzyme inhibition on barrier function in diabetic glomerulopathy, Differential solute clearances were used to examine the effects of a 90-day course of enalapril on glomerular barrier function in 16 proteinuric patients with diabetic glomerulopathy. By day 90. plasma renin and prorenin became elevated. and arterial pressure declined. Transglomerular passage of dextrans of broad size distribution (radii 28-60 A) was lowered significantly. In a subset of 8 patients. withdrawal of enalapril was followed after an additional 30 days by a return of renin levels and arterial pressure to pretreatment levels. The dextran-sieving profile also returned to baseline. becoming uniformly elevated above treated day-90 levels. A theoretical analysis of the serial dextran-sieving profiles indicated that enalapril shifted glomerular pore size distribution to smaller size. These changes in barrier size selectivity were associated with a reduction in fractional albumin and IgG clearances during enalapril therapy and a subsequent rise in these quantities after its withdrawal; urinary protein excretion rate tended to vary in parallel. We conclude that inhibition of converting enzyme in humans with established diabetic glomerulopathy diminishes glomerular permeability to proteins by enhancing barrier size selectivity. Because neither enalapril therapy nor its withdrawal influenced the glomerular filtration or renal plasma flow rates significantly. we propose that the primary action of enalapril may be to modulate the intrinsic membrane properties of the glomerular barrier.
Interaction between insulin and glucose-delivery route in regulation of net hepatic glucose uptake in conscious dogs, In the presence of fixed basal levels of insulin. the route of intravenous glucose delivery (protal vs. peripheral) determines whether net hepatic glucose uptake (NHGU) occurs. Our aims were to determine if the route of intravenous glucose delivery also plays a role in regulating NHGU in the presence of hyperinsulinemia and to determine if length of fast (18 vs. 36 h) influences regulation of NHGU. Five conscious dogs fasted 18 h were given somatostatin and replacement insulin (245 +/- 34 microU.kg-1.min-1) and glucagon (0.65 ng.kg-1.min-1) infusions intraportally. After a 40-min control period. the insulin infusion rate was increased fourfold. and glucose was infused for 3 h. Glucose was given either through a peripheral vein or the portal vein for 90 min to double the glucose load reaching the liver. The order of infusions was randomized. NHGU was measured with the arterial - venous difference technique. Insulin and glucagon levels were 12 +/- 2. 35 +/- 6. and 36 +/- 5 microU/ml and 55 +/- 12. 61 +/- 13. and 59 +/- 7 pg/ml during the control. peripheral. and portal infusions. respectively. The glucose infusion rate. the load of glucose reaching the liver. and the arterial-portal plasma glucose gradient were 0. 9.58 +/- 2.28. and 10.44 +/- 2.94 mg.kg-1.min-1; 29.4 +/- 3.6. 56.8 +/- 3.4. and 56.8 +/- 2.8 mg.kg-1.min-1; and 2 +/- 1. 5 +/- 1. and -51 +/- 15 mg/dl during the same periods.
Differences in lipoprotein subfraction composition and distribution between type I diabetic men and control subjects, Subfractions of very-low-density and low-density lipoproteins were examined in 10 male normolipidemic type I (insulin-dependent) diabetic patients before and after improvement of metabolic control and were compared with subfractions from male control subjects matched to the diabetic patients at entry for age. body mass index. plasma cholesterol. and plasma triglycerides. Two consistent differences in subfraction composition were noted between the diabetic patients at entry and the control subjects. First. subfractions from diabetic patients tended to be cholesterol-ester poor and triglyceride rich; this was particularly marked for the low-density lipoprotein subfractions. Second. the subfractions from pretreatment diabetic patients contained higher proportions of non-apolipoprotein B apolipoproteins. This compositional anomaly. but not the lipid modifications. responded to but was not completely normalized by improved glycemic control. which was also accompanied by reductions in the plasma concentrations of all subfractions. Treatment modified subfraction distribution so that the lipoprotein profile of posttreatment diabetic patients more closely resembled the profile observed in the control subjects. These changes were achieved without significant modification of daily insulin dose. In the context of blood lipid risk factors. the results argue for the need to maintain optimal insulinization even in apparently normolipidemic diabetic patients to avoid modifications of the lipoprotein pattern toward a potentially more atherogenic profile.
Increased preproinsulin mRNA in pancreatic islets incubated with islet cell-stimulating antibodies from serums of type I diabetic patients, We recently described autoantibodies that stimulate the release of insulin from pancreatic beta-cells both in vitro and in vivo. The aim of this study was to establish whether islet cell-stimulating antibodies (ICSTAs) also increase islet cell preproinsulin mRNA content. Wistar rat islets. isolated by collagenase digestion. were exposed to 2.7 and 11.1 mM glucose. Insulin release increased 10-fold in response to the higher glucose concentration. and dot-blot analysis of islet mRNA with a rat preproinsulin cDNA probe showed a concomitant increase in mRNA levels. The globulin fractions of four test serums. three from patients with type I (insulin-dependent) diabetes and one from a patient with the insulin autoimmune syndrome. showed clear (5- to 8-fold) stimulation of insulin release. The nonglobulin fractions of these serums and both fractions of three control serums failed to stimulate secretion of insulin. The insulin mRNA content of islets incubated with the ICSTA globulin fractions was greatly increased compared with levels observed in islets treated with control serum globulin fractions. We conclude that ICSTAs not only can stimulate the release of insulin but also increase the preproinsulin mRNA content of islet cells.
Fasting and postprandial concentrations of somatostatin-28 and somatostatin-14 in type II diabetes in men, Recent evidence suggests that somatostatin-28 (SRIF-28). cleaved from prosomatostatin by cells of the upper intestine. acts as a nutrient-stimulated inhibitor of insulin secretion in healthy men. A role for SRIF-28 in the pathophysiology of diabetes has not been previously explored. although several groups have measured circulating somatostatinlike immunoreactivity (SLI) in diabetic subjects. To investigate the possible mediation of abnormal insulin secretion in diabetes by SRIF-28. plasma levels were measured in 10 non-insulin-dependent diabetic men and 9 age- and weight-matched control subjects. Concentrations of SRIF-14 and SLI were also obtained. Subjects were admitted for study after an overnight fast. blood was collected before and at 30-min intervals for 4 h after a fat meal. and plasma samples were analyzed for SRIF-28 and SRIF-14 by specific methods. Basal glucose levels in the diabetic men were significantly higher than in control subjects (10.2 +/- 1 vs. 5.8 +/- 0.2 mM). but insulin levels were similar (79 +/- 14.2 vs. 93.3 +/- 14.2 pM). The diabetic men had significantly lower basal SRIF-28 levels than the control subjects (11.4 +/- 0.6 vs. 14.6 +/- 1.0 pM. P = 0.017). After fat intake. SRIF-28 levels throughout the 4 h of study were indistinguishable in the two groups (270 vs. 292% of basal). Basal SRIF-14 and SLI levels were not significantly different in the two groups. and SRIF-14 and SLI concentrations rose similarly after the meal. There were no correlations between basal SRIF-28 and glucose or insulin levels.
Increased transcapillary escape rate of albumin in nondiabetic men in response to hyperinsulinemia, Diabetic patients manifest increased vascular permeability. To determine whether insulin per se might increase vascular permeability. five nondiabetic men were studied by the hyperinsulinemic-euglycemic clamp technique. Each subject received a 0.72-nmol/kg body wt i.v. insulin bolus. followed by a 72-pmol.kg-1.min-1 insulin infusion for 4 h. Euglycemia was maintained by the Biostator glucose controller. At 7 h of study. 10 microCi i.v. 125I-labeled albumin was injected as bolus dose. Frequent blood samples were drawn during the next 70 min for determination of the transcapillary escape rate (TER) of albumin. Subjects returned 1-2 wk later for a control study. during which 0.45% saline was infused at a rate identical to the dextrose and insulin infusion rates during the hyperinsulinemic clamp. The mean +/- SE serum insulin levels during the hyperinsulinemic clamp and saline infusion were 9786 +/- 126 and 46 +/- 4 pM. respectively. whereas serum glucose during the two sessions was similar (5.0 +/- 0.2 vs. 4.8 +/- 0.1 mM. NS). Identical fluid volumes were infused during the two sessions (1767 +/- 197 ml/7 h). and urine outputs did not differ significantly (1615 +/- 309 vs. 1035 +/- 248 ml/7 h). The TER of albumin was greater in all five men after hyperinsulinemia than after saline infusion (18.3 +/- 2.7 vs. -2.8 +/- 2.3%/h. P = 0.01).
Physiological and pharmacological stimulation of pancreatic islet hormone secretion in type I diabetic pancreas allograft recipients, Successful heterotopic and denervated pancreas allograft transplantation (PAT) often results in normoglycemia and peripheral hyperinsulinemia in insulin-dependent (type I) diabetic recipients. The contribution of altered hepatic insulin extraction (HIE) to the resulting hyperinsulinemia in such patients remains uncertain. Furthermore. whether the denervated pancreas allografts exhibit beta-cell hyperresponsiveness to physiological and pharmacological stimulation is controversial. We evaluated beta-cell function and HIE after successful whole cadaveric PAT with systemic venous drainage in 13 type I diabetic patients before and after mixed-meal and intravenous glucose and glucagon administration. The results were compared with those of 5 nondiabetic patients with kidney transplantation only. who had native innervated pancreases with portal insulin delivery and were receiving an equivalent triple immunosuppressive therapy (cyclosporin. azathioprine. and prednisone). and 7 healthy control subjects with no family history of diabetes. After PAT. fasting and poststimulation serum glucose concentrations were normalized. PAT was associated with marked basal hyperinsulinemia (3- to 8-fold) as assessed by immunoreactive insulin (IRI) levels in type I diabetic patients (mean +/- SE 345 +/- 43 pM) compared with control subjects (43 +/- 14 pM) and nondiabetic kidney-transplantation patients (129 +/- 38 pM). After mixed-meal ingestion. the mean incremental integrated insulin area was similar in PAT patients (18 +/- 3 nM.min) compared with kidney-transplantation patients (20 +/- 4 nM.min) and healthy control subjects (21 +/- 3 nM.min). Basal serum C-peptide levels were significantly greater in PAT (1.72 +/- 0.13 nM) and kidney-transplantation (2.15 +/- 0.33 nM) patients than in healthy control subjects (0.50 +/- 0.10 nM; P less than 0.01).
Insulinomimetic properties of trace elements and characterization of their in vivo mode of action, Lithium and vanadate have insulinomimetic actions in vitro. In this study. we examined the in vivo effects of lithium and vanadate on glucose metabolism in diabetic (90% partial pancreatectomy) rats. Four groups of chronically catheterized rats were studied: control. diabetic. diabetic treated with lithium (plasma concn 1.0 +/- 0.1 meq/L) and vanadate (0.05 mg/ml in drinking water). and diabetic treated with lithium. vanadate. zinc. and magnesium. Postmeal plasma glucose was increased in diabetic versus control rats (18.7 vs. 7.7 mM. P less than 0.01) and was normalized by addition of lithium and vanadate (8 mM) or lithium. vanadate. zinc. and magnesium (7.4 mM). Euglycemic insulin-clamp studies were performed 2 wk posttreatment; insulin-mediated glucose uptake was reduced in diabetic compared with control rats (142 +/- 4 vs. 200 +/- 5 mumol.kg-1.min-1. P less than 0.01). returned to normal with lithium and vanadate (206 +/- 6 mumol.kg-1.min-1). or increased to supranormal levels with lithium. vanadate. zinc. and magnesium (238 +/- 6 mumol.kg-1.min-1). During the insulin clamp. muscle glycogenic rate was severely impaired in diabetic versus control rats (18 vs. 70 mumol.kg-1.min-1) and was normalized by lithium and vanadate (91 mumol.kg-1.min-1) or lithium. vanadate. zinc. and magnesium (93 mumol.kg-1.min-1).
Limited duration of remission of insulin dependency in children with recent overt type I diabetes treated with low-dose cyclosporin, Preliminary data from our group indicated that cyclosporin A induced frequent remissions of insulin dependency in a group of 40 insulin-dependent (type I) diabetic children if given at the onset of clinical manifestations of diabetes. We report a 2-yr analysis of the response to cyclosporin A in the group of 81 patients included in the initial study. As observed before. a remission could be obtained in most of the patients (65%) in association with a shorter duration of symptoms. less severe hyperglycemia. lower incidence of ketoacidosis. and higher plasma C-peptide concentrations. All remissions ended during the follow-up period after a mean +/- SE duration of 316 +/- 21 days (range 31-850 days). Two parameters were linked to the duration of remissions: the mean circulating level of cyclosporin during the first 3 mo and the duration of prediagnostic polyuria. We were unable to relate the end of a remission to variations in the cyclosporin regimen. titer of autoantibodies. or progression of beta-cell failure. The euglycemic clamp technique revealed that insulin sensitivity decreases with time in patients not taking insulin. At 24 mo. the patients who had a remission of insulin dependency had better glycemic control. lower insulin dosages. and C-peptide levels two- to threefold higher than the nonremission patients and four- to sixfold higher than the historical control subjects. The cyclosporin regimen was well tolerated over the observed period: more specifically. serum creatinine remained unchanged. and kidney biopsies performed at 18-24 mo of treatment were within normal limits.
Biochemical studies of RT6 alloantigens in BB/Wor and normal rats. Evidence for intact unexpressed RT6a structural gene in diabetes-prone BB rats, Lymphocytes bearing the T-lymphocyte differentiation antigen RT6 play an important immunoregulatory role in the development of autoimmune diabetes in BB rats. Immunofluorescence studies suggest that diabetes-prone (DP)- but not diabetes-resistant (DR)-BB rat lymphocytes fail to express RT6 antigen during ontogeny. Two alloantigenic forms of the molecule exist. i.e.. RT6.1 and RT6.2; both are linked to cell membranes by a phosphatidylinositol (PI) linkage. In these studies. PI-phospholipase C (PLC) treatment of lymphocytes from BB and normal rats followed by immunoabsorption and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of released proteins with anti-RT6 allotype-specific monoclonal antibodies was performed. RT6.1 in several nondiabetic rat strains was found to consist of a family of nonglycosylated and variably glycosylated molecules: an N-Glycanase-resistant 24.000- to 26.000-Mr peptide and four N-Glycanase-sensitive peptides of 29.000. 31.000. 33.000. and 34.000 Mr. In contrast. RT6.2 was found to be a 24.000- to 26.000-Mr nonglycosylated polypeptide. The electrophoretic pattern of RT6.1 was observed to be the same when the antigen was extracted from W3/25+ (CD4+) versus W3/25- T lymphocytes or from resting versus mitogen-activated cells. A pattern of bands characteristic of the RT6.1 antigen found in normal rat strains was detected after PLC treatment or detergent solubilization of lymphocytes obtained from DR rats. In contrast. no evidence of either RT6 species was found after PLC or detergent treatment of comparable numbers of T lymphocytes from DP-BB rats. Interestingly. T lymphocytes from Wistar-Furth (RT6.2+) x DP (RT6-) F1 crosses were observed to coexpress both RT6.2 and RT6.1 molecules. with the electrophoretic pattern of RT6.1 being similar to that obtained in DR and other rat strains. This study provides biochemical evidence that DP rats may have an intact RT6a structural gene.
Diabetes and the myo-inositol paradox, To test the general applicability of the hypothesis that diabetes mellitus causes increased polyol pathway activity. decreased tissue free myo-inositol. and resultant pathological changes in tissues susceptible to the ravages of diabetes. we measured glucose. sorbitol. and myo-inositol with quantitative histochemical techniques in layers of the cornea. the aortic myointima. the cardiac left ventricle and atrioventricular node (AVN). and retina and kidney after 19 days or 2 mo (mildly diabetic non-insulin-treated [MD] and severely diabetic insulin-treated [SD] groups) in the alloxan-induced diabetes model. In the aqueous humor. glucose rose linearly with increased serum glucose. sorbitol was markedly increased in the MD and SD groups. and myo-inositol did not change in any diabetic group. There was no change in glucose or sorbitol in aortic myointima in any group. but myoinositol was decreased in 19-day diabetic rabbits by 26%. unchanged in MD rabbits but paradoxically increased by 60% in SD rabbits. Glucose. sorbitol. and myo-inositol increased in all three corneal layers in SD rabbits but only in epithelium and stroma in 19-day and MD rabbits. AVN glucose and sorbitol did not change in 19-day diabetic. MD. or SD diabetic rabbits. AVN myo-inositol was three times higher than ventricular myo-inositol and did not appear to change in SD rabbits. Retinal pigmented epithelium myo-inositol was decreased 30% in SD rabbits. Glomerular myo-inositol was also decreased. but not significantly. in SD rabbits. We conclude that the paradoxical increase in corneal and aortal myo-inositol raises fundamental questions about the general applicability of the myo-inositol-depletion hypothesis.
Phospholipids from rat, human, and canine gastric mucosa. Composition and metabolism of molecular classes of phosphatidylcholine, To validate a recent proposal that a phospholipid lining with a high content of dipalmitoylphosphatidylcholine may protect gastric mucosa against luminal acid. it was decided to study composition and metabolism of phospholipids in the gastric mucosa. Phospholipids were analyzed in rat. human. and dog gastric mucosal surface tissue and in a chloroform/methanol-lavage of rat and canine stomach. Phosphatidylcholine and phosphatidylethanolamine were the main components. Saturated fatty acids were almost exclusively esterified at the sn-1 position of the glycerol moiety of phosphatidylcholine. and unsaturated fatty acids mainly at the sn-2 position. The disaturated class of phosphatidylcholine comprised 2%-6% of total phosphatidylcholine. Precursors of phosphatidylcholine. i.e.. [32P]orthophosphate and [methyl-14C]choline. were preferentially incorporated into the disaturated molecular class 0.5-6 hours after IV administration. It can be speculated that disaturated phosphatidylcholine. although quantitatively a minor component. is specifically triggered in mucosal renewal processes.
Alpha 1-antitrypsin excretion in stool in normal subjects and in patients with gastrointestinal disorders, Fecal clearance of plasma alpha 1-antitrypsin is used as a measure of protein leakage into the intestinal tract. In this study. the alpha 1-antitrypsin concentration in stool and the plasma clearance of alpha 1-antitrypsin in normal subjects and in a consecutive series of patients with chronic diarrhea. malabsorption. or unexplained hypoalbuminemia was determined. The normal subjects were studied in their usual state and also when they had diarrhea secondary to ingestion of lactulose. sorbitol. sodium sulfate. or phenolphthalein. The study first concluded that induced diarrhea can cause an increase in alpha 1-antitrypsin clearance; if this is not considered in establishing normal values. there may be an overdiagnosis of excess protein leakage in patients with diarrhea. Second. there is a highly significant statistical correlation (P less than 0.001) between alpha 1-antitrypsin clearance and serum albumin concentration. On average. the serum albumin falls below 3.0 g/dL (30 g/L) when the alpha 1-antitrypsin clearance exceeds 180 mL/day. a value that is about threefold higher than the upper limit of normal. Third. three of nine patients with microscopic/collagenous colitis had elevated clearance of alpha 1-antitrypsin; by contrast. abnormal alpha 1-antitrypsin clearance was not found in 23 patients with idiopathic secretory diarrhea. Fourth. fecal alpha 1-antitrypsin concentration is not a reliable index of abnormal alpha 1-antitrypsin clearance.
Piezoelectric lithotripsy: stone disintegration and follow-up results in patients with symptomatic gallbladder stones, One hundred symptomatic patients with radiolucent gallbladder stones were treated with a new piezoelectric lithotripter and oral chemolitholytic agents. Stone disintegration was achieved in 99 of these patients (99%) with a mean (+/- SD) maximum fragment size of 5.1 +/- 4.1 mm. Significant differences were found when the mean (+/- SD) fragment sizes of single stones less than or equal to 20 mm (4.2 +/- 2.5 mm) were compared with those of single stones greater than 20 mm (5.8 +/- 3.4 mm; P less than 0.05) and multiple stones (6.2 +/- 3.8 mm; P less than 0.05). respectively. None of the patients required anesthesia. analgesics. or sedatives before or during the treatment. The stone-free rates for all patients followed up for up to 4-12 months (mean +/- SD. 10.7 +/- 2.9 months) were 18% (1 month). 25% (2 months). 38% (4 months). 52% (8 months). and 67% (12 months). Partly significant differences were obtained in stone-free rates for single stones (less than or equal to 20 mm) compared with larger stones (greater than 20 mm) and multiple stones (P less than 0.05). respectively. Serious adverse reactions (i.e.. cholestasis and pancreatitis) were observed in only 3 patients (3%). These conditions were induced by fragment impaction in the common bile duct. In 2 of these patients. endoscopic retrograde cholangiopancreatography with endoscopic sphincterotomy was required. It is concluded that piezoelectrically generated shock waves are suitable for the effective and safe disintegration of gallbladder stones in humans. The anesthesia-free and analgesia-free shock-wave application opens up the possibility to perform biliary lithotripsy as an outpatient procedure. The stone-free rate achieved in combination with oral bile acids is most promising for single stones (less than or equal to 20 mm).
The effects of synthetic human secretin on calcium carbonate solubility in human bile, This study sought to determine the effects of synthetic human secretin on ionized calcium and carbonate concentrations in human hepatic bile. Five patients with a nasobiliary drain in the right hepatic duct were studied. Three basal samples of bile were collected. each over a 15-minute period. Synthetic human secretin was then infused IV at 0.05 micrograms.kg-1.h-1 for 45 minutes followed by 0.5 micrograms.kg-1.h-1 for 45 minutes. Bile was sampled over 15-minute periods. To document return to baseline conditions. two further samples of bile were obtained over 15-minute periods 2 hours after the infusion was terminated. Bile acid concentration was determined by an enzymatic method; pH and PCO2 were measured with an automated analyzer. Total calcium was determined by inductively coupled plasma emission spectrometry and ionized calcium by an ion-specific electrode. Bicarbonate and carbonate concentrations were calculated using Henry's law and the Henderson-Hasselbalch equation. The fraction of bile sampled by the catheter was determined by Indocyanin Green recovery at the end of the experiment. Secretin caused an increase in bile flow and bicarbonate output. Bicarbonate concentrations increased from 26 +/- 3 mmol/L to 41 +/- 3 mmol/L (P less than 0.05). and chloride concentrations decreased. Mean bile acid concentrations declined significantly from 14.6 +/- 2 mmol/L to 4.7 +/- 1 mmol/L (P less than 0.05). Ionized calcium concentrations decreased from 0.7 +/- 0.005 mmol/L to 0.5 +/- 0.02 mmol/L (P less than 0.05) while pH increased significantly from 7.44 +/- 0.06 to 7.6 +/- 0.04 (P less than 0.05). Carbonate concentrations increased significantly from 0.15 +/- 0.02 mmol/L to 0.26 +/- 0.03 mmol/L. and the ion product for calcium carbonate increased significantly from 0.099 +/- 0.002 (mmol/L)2 to 0.135 +/- 0.015 (mmol/L)2 (P less than 0.05). Synthetic human secretin augments the ion product of calcium and carbonate in human hepatic bile. increasing the tendency for calcium carbonate precipitation.
Bile duct emptying in response to fat: a validation study, Fatty meal sonography has been suggested to assess patients with biliary pain after cholecystectomy. but the effects of gallbladder removal on biliary dynamics has not been studied prospectively. Before elective cholecystectomy. 25 patients had their common hepatic ducts' diameter measured by ultrasonography before and after a fat stimulus. In 23. tests were repeated 1 month. 1 year. and 5 years after surgery. In preoperative studies. 5 patients showed dilatation after fat and 2 of these had stones in the common bile duct. However. another 4 patients with stones or sludge in the duct did not show dilatation. so that the response to fat was a poor indicator of patients requiring common bile duct exploration. No patient had major symptoms after surgery. At 1 month and 12 months. the response to fat was variable with more than half of those tested showing no decrease in duct size. A more consistent pattern emerged at 5 years. when 14 of 18 patients tested showed a decrease in common hepatic duct after fat; 3 were unchanged and 1 increased by 1 mm. The response to fat was less consistent and more difficult to measure in the common bile duct. even 5 years after operation. It was concluded that not all patients with indications for exploration of the common bile duct on operative cholangiography show a dilatation response to fat on preoperative testing. Also. fatty meal sonography should be used with caution because the response to fat in asymptomatic patients soon after operation is unpredictable. with occasional patients showing dilation without apparent obstruction. Measurement of common hepatic duct is preferred to common bile duct and increases in diameter of 1 mm are probably not significant.
The uncoupling of biliary lipid from bile acid secretion by organic anions in the rat, A number of organic anions has been shown to inhibit biliary phospholipid and cholesterol secretion without affecting bile acid secretion. However. the mechanism of this uncoupling phenomenon is still unclear. This study shows a comparison of the effects of ampicillin (18 mumol/100g body wt). sulfated taurolithocholic acid (0.2 and 1.0 mumol/100 g body wt). and indocyanine green (0.6 mumol/100 g body wt) in control and Groningen Yellow-Wistar rats with chronic (8 days) biliary drainage. Groningen Yellow rats have a hereditary defect in hepatobiliary transport of various organic anions. Bile secretion. but not hepatic uptake. of the three organic anions was strongly impaired in Groningen Yellow rats compared with controls. Ampicillin and sulfated taurolithocholic acid caused a strong uncoupling in control rats but had no effect or a much smaller effect on lipid secretion in Groningen Yellow rats. Indocyanine green did not affect lipid secretion. in either control or in Groningen Yellow rats. Gel-filtration chromatography of bile showed a specific coelution of ampicillin and sulfated taurolithocholic acid with the bile acid fraction. whereas indocyanine green coeluted with the phospholipid/cholesterol fraction. This study concludes that the uncoupling by ampicillin and sulfated taurolithocholic acid occurs after their secretion into bile and is caused by interaction of these compounds with bile acids. It is hypothesized that this interaction inhibits the capacity of bile acids to induce secretion of phospholipids and cholesterol into the bile.
Caliber-persistent artery of the stomach (Dieulafoy's vascular malformation), Caliber-persistent artery of the stomach (also known as cirsoid aneurysm. Dieulafoy's lesion. and submucosal arterial malformation) is clinically manifested as recurrent. massive. often fatal hematemesis. The lesion often is not seen endoscopically. Left gastric angiography in one patient with hematemesis showed a convoluted and ectatic artery in the gastric fundus. which proved to be caliber-persistent artery of the stomach on pathological examination. The tortuosity of the abnormal vessel in this condition has been attributed to artefactual contraction of the stomach following excision and formalin fixation. This is the first reported case in which a pathologically proven lesion has been clearly visualized by angiography. This demonstrates that the submucosal vessel is truly and not artifactually sinuous. It is proposed that angiographic demonstration of a nontapering. convoluted artery in the territory of the left gastric artery is highly suggestive of caliber-persistent artery of the stomach.
Pemoline-associated hepatic injury, Among 100 cases of hepatic injury attributed to the administration of pemoline. 43 had sufficient accompanying information to permit analysis. All but two patients were less than 20 years old. and 80% were less than 12 years old. Males predominated the study. Injury appeared as early as 1 week or as late as greater than 1 year of taking the drug. The injury was uniformly hepatocellular as judged by the high values for aminotransferases and by death in massive necrosis in one patient. Mechanism was judged to be idiosyncratic. and the idiosyncrasy was probably metabolic rather than immunologic.
Endoscopic ultrasonography for the evaluation of smooth muscle tumors in the upper gastrointestinal tract: an experience with 42 cases, Before surgery. 12 patients with suspected leiomyoma and 12 patients with suspected leiomyosarcoma were studied by endoscopic ultrasonography (EUS). computed tomography (CT). endoscopy. and barium swallow. The results were correlated with surgery and histology. Ten leiomyomas. one benign gastric ulcer. one carcinoid metastasis. eight leiomyosarcomas. two leiomyoblastomas. one mucus secreting adenocarcinoma. and one bronchial carcinoma were diagnosed. Eighteen additional patients suspected to have benign submucosal lesions by endoscopy and barium meal were treated non-surgically. and studied by EUS and CT. EUS was superior to other imaging techniques in the detection. staging. and follow-up of submucosal smooth muscle tumors because of clear imaging of the intramural abnormality and adjacent lymph nodes.
Mechanical lithotripsy of common duct stones, Over the past 8 years we have utilized various types of mechanical lithotriptors to crush common bile duct stones. The procedure was performed in 93 patients with an overall success rate of 94%. However. because many accessories were in a developmental stage. entrapment of stones was not always possible on the first attempt. and the procedure was repeated in some patients a second or third time. During the interim. while awaiting another attempt at lithotripsy. cholangitis was prevented by leaving a prosthesis in place. A variety of lithotriptor models from different manufacturers have proven effective. We recommend that endoscopists use these devices to rid the bile duct of retained stones.
The role of ERCP in children and adolescents, The diagnostic and therapeutic role of ERCP in 42 patients ranging from 1 to 19 years of age is discussed. ERCP provided useful additional information in 15 patients with biliary tract disease. 15 patients with pancreatic disease. and 9 patients with abdominal pain. The appropriate duct was cannulated in 95% of cases. Mild pancreatitis occurred in two patients after ERCP. Endoscopic papillotomy was successful in five patients. ERCP plays an important part in the investigation of unexplained biliary tract and pancreatic disease. It rarely demonstrates abnormal pathology in patients with otherwise unexplained abdominal pain.
Can clinicians accurately assess esophageal dilation without fluoroscopy, This study questioned whether clinicians could determine the success of esophageal dilation accurately without the aid of fluoroscopy. Twenty patients were enrolled with the diagnosis of distal esophageal stenosis. including benign peptic stricture (17). Schatski's ring (2). and squamous cell carcinoma of the esophagus (1). Dilation attempts using only Maloney dilators were monitored fluoroscopically by the principle investigator. the physician and patient being unaware of the findings. Physicians then predicted whether or not their dilations were successful. and they examined various features to determine their usefulness in predicting successful dilation. They were able to predict successful dilation accurately in 97% of the cases studied; however. their predictions of unsuccessful dilation were correct only 60% of the time. Features helpful in predicting passage included easy passage of the dilator (98%) and the patient feeling the dilator in the stomach (95%). Excessive resistance suggesting unsuccessful passage was an unreliable feature and was often due to the dilator curling in the stomach. When Maloney dilators are used to dilate simple distal strictures. if the physician predicts successful passage. he is reliably accurate without the use of fluoroscopy; however. if unsuccessful passage is suspected. fluoroscopy must be used for confirmation.
Endoscopic appearance and significance of functional lymphangiectasia of the duodenal mucosa, Intestinal lymphangiectasia is found in a wide variety of pathologic conditions. Functional lymphangiectasia has not been well characterized. We report 20 patients followed for 9 to 55 months (mean 30 months) after incidental detection at endoscopy of lymphangiectasia. Our study indicates that functional lymphangiectasia is not pathologic and does not warrant repeat endoscopy in the absence of other clinical indications.
Practical nutritional advice for the elderly, Part I: Evaluation, supplements, RDAs. A geriatrics panel discussion, By the time someone reaches old age. he or she thinks they know everything they want. or need. to know about nutrition. Yet malnutrition and its many effects are a rising danger. In this first of two installments of a panel discussion. nutritional experts review practical concerns for the treating physician. including assessment. interpretation of weight loss. use of supplements. and the relevance of RDAs to the elderly.
Dementia, depression, or grief? The differential diagnosis, Depression. grief. and dementia are conditions frequently encountered among the community-living elderly. This review offers a primary care perspective of the distinguishing features for each and discusses the special issues of managing the elderly. Major depression in the elderly usually responds to antidepressant medication. whether the depression occurs alone (endogenous) or as a response to another condition (reactive).
Pneumonia syndromes: a clinical approach in the elderly, Important in the pathogenesis of pneumonia in the elderly patient are chronic diseases. including diabetes mellitus. coronary artery disease. congestive heart failure. chronic obstructive pulmonary disease. and cerebrovascular disease. Also vital are the changes that take place in the immune system and mucociliary clearance mechanisms of the lung. The clinician should be aware of these risk factors. especially since the mortality rate of lower respiratory infections approaches 40% in these elderly patients. Treatment guidelines are included.
Aging and the skin: recognizing and managing common disorders, Senescent changes in structure and function of the skin and chronic solar radiation damage predispose the skin of the elderly to certain inflammatory and infectious diseases. In this context. the diagnosis and treatment of senile xerosis and pruritus are discussed. as are the common types of dermatitides. infections. and infestations.
Semantic deterioration in Alzheimer's: the patterns to expect, Differentiating language changes between the normal aged and those in the early stages of dementia is never simple. Knowing the differences and what to expect can aid in making this diagnosis.
Acute hypervolaemia increases gastroduodenal resistance to the flow of liquid in the rat, The effect of volume expansion of extracellular fluid on gastroduodenal resistance to the flow of isotonic saline was assessed in three groups of rats using intravenous infusions of isotonic. isotonic-isoncotic. and isotonic-isoncotic-isohaemic solutions. The gastroduodenal segment of 29 male Wistar rats was barostatically perfused at a constant pressure gradient of 4 cm H2O and changes in flow (ml/minute) were taken as a reflection of changes in gastroduodenal resistance. Isotonic expansion led to a 33% drop in gastroduodenal flow compared with the normovolaemic period in the same animals (p less than 0.01). Extracellular fluid expansion with isotonic-isoncotic and isotonic-isoncotic-isohaemic solutions was associated with reductions in gastroduodenal flow of 29% (p less than 0.05) and 31% (p less than 0.01) respectively. The increase in gastroduodenal resistance is due to hypervolaemia per se and not to haemodilution. decreases in plasma oncotic pressure. or electrolyte imbalance. The effect of hypervolaemia on gastroduodenal resistance. which was reversed by small haemorrhages (0.5-1.0 ml per 100 g body weight). may be due to changes in tonus or phasic motor activity. or both. and may be part of the homeostatic processes that help the organism minimise liquid volume excess.
Circulating antibodies against human colonic extract enriched with a 40 kDa protein in patients with ulcerative colitis, We have previously described a 40 kDa colonic protein(s) which is specifically recognised by tissue-bound immunoglobulin G obtained from the colon of patients with ulcerative colitis. We now report the presence of circulating antibodies against this antigen using an enzyme-linked immunosorbent assay with a highly enriched preparation of the 40 kDa protein from normal colon extracts. Serum was collected from 79 patients with ulcerative colitis. 36 with Crohn's disease. 16 with specific diarrhoeal syndromes. and from 19 normal subjects. Twenty nine of 79 patients with ulcerative colitis. 21 of 36 with Crohn's disease. and all patients with diarrhoea were symptomatic during the collection of sera. The difference in optical density values between patients with symptomatic ulcerative colitis and each of the other groups. including patients with ulcerative colitis in remission. was highly significant (p less than 0.01). Seventy nine per cent of patients with symptomatic ulcerative colitis had optical density values above the means for all other groups. Fifty five per cent of sera from patients with symptomatic ulcerative colitis had optical densities beyond two SDs of the values for all other groups and only two of 71 sera from non-ulcerative colitis patients (one Crohn's disease and one normal subject) had values in this range. These results show the presence of anti-colon antibodies against the 40 kDa protein(s) in the sera of many patients with symptomatic ulcerative colitis.
Effect of ulcerative colitis and smoking on rectal blood flow, Rectal blood flow was measured by laser doppler flowmetry over 60 minutes in eight patients with colitis in remission and eight healthy male non-smokers. Ten smokers were also examined on two occasions. one of which included smoking a cigarette. Plasma nicotine concentrations were measured in smokers. All subjects showed a pronounced fall in rectal blood flow in the first 30 minutes and patients with colitis had significantly higher values compared with smokers (p less than 0.002; p less than 0.04) and non-smokers (p less than 0.007; p less than 0.002) during the first and second 30 minutes respectively. Values in smokers and non-smokers were similar. but smoking a cigarette was associated with a significant fall in blood flow (p less than 0.04) and this change was inversely related to the rise in plasma nicotine concentration (r = -0.63; p less than 0.05). The findings may be relevant to the association between colitis and the smoking history.
Inhibition of cell mediated cytotoxicity by sulphasalazine: effect of in vivo treatment with 5-aminosalicylic acid and sulphasalazine on in vitro natural killer cell activity, Decreased cell mediated cytotoxicity occurs frequently in inflammatory bowel disease. particularly in patients with active disease. It is not clear. however. whether this decrease is caused by the disease or is a consequence of the medical treatment. In this study we evaluated the effect of in vivo treatment with 5-aminosalicylic acid and sulphasalazine on the in vitro natural killer cell activity in five patients with inflammatory bowel disease in remission and in four healthy control subjects in a double blind randomised crossover trial preceded and separated by four weeks of treatment with placebo. The natural killer cell activity was significantly impaired in 67% (six of nine subjects) after four weeks' sulphasalazine treatment and tended to be related to subjects with a slow acetylator phenotype. In contrast. 5-aminosalicylic acid treatment caused only a marginal reaction in the natural killer cell activity in 22% (two of nine subjects). The inhibitory effects were found to be reversible since the decreased natural killer cell activity was completely restored after placebo treatment in all subjects. In conclusion. in vivo treatment with sulphasalazine inhibits the in vitro natural killer cell activity and this seems to be mediated by the sulphapyridine moiety. This phenomenon may contribute to the low natural killer cell activity found in patients with active inflammatory bowel disease.
Soluble interleukin-2 receptor in Crohn's disease: relation of serum concentrations to disease activity, Serum concentrations of soluble interleukin-2 receptor (sIL-2R) were measured as a marker of immune activation in a group of 30 patients with Crohn's disease. sIL-2R concentrations were determined by enzyme linked immunosorbent assay during periods of active and inactive disease and correlated with standard parameters of disease activity. Serum concentrations of sIL-2R were significantly raised in patients with active Crohn's disease compared with patients with inactive disease (p less than 0.001) and control subjects. There was a significant correlation between serum sIL-2R concentrations and disease activity as assessed by the Harvey-Bradshaw index (r = 0.42. p less than 0.01). platelet numbers (r = 0.49. p less than 0.01). and orosomucoid (r = 0.47. p less than 0.01). alpha 1 antitrypsin (r = 0.44. p less than 0.01). and C reactive protein concentrations (r = 0.48. p less than 0.001) but not with the erythrocyte sedimentation rate. Measurement of serum sIL-2R concentration is a simple and useful laboratory means of assessing disease activity. Raised concentrations in patients with active Crohn's disease is further evidence for in vivo immune activation occurring in this disease.
Characteristics of cholinergic neuroeffector transmission of ganglionic and aganglionic colon in Hirschsprung's disease, Differences in the release and content of acetylcholine and the alpha 2 adrenoceptor mediated interaction between noradrenergic and cholinergic neurons were investigated by neurochemical and pharmacological methods in aganglionic and ganglionic segments of isolated human colon taken from children suffering from Hirschsprung's disease. Both at rest and during transmural stimulation the release of acetylcholine was significantly higher in the spastic (aganglionic) segment than in the proximal dilated bowel. Significant differences were found in the tissue concentration of acetylcholine between ganglionic and aganglionic specimens. The pattern of response to transmural stimulation was also different in the spastic and dilated bowel. Transmural stimulation induced relaxation and contraction in ganglionic specimens but only contractions in aganglionic specimens. The sensitivity of the smooth muscle in the aganglionic portion to exogenous acetylcholine and to field stimulation was found to be higher than in the ganglionic portion. While noradrenaline added to the organ bath reduced the stimulation-evoked release of acetylcholine from spastic segments. via an alpha 2 adrenoceptor mediated process. yohimbine did not enhance the release. It is suggested that in Hirschsprung's disease the increased acetylcholine release. the enhanced sensitivity of smooth muscle cells to acetylcholine. and the lack of alpha 2 adrenoceptor mediated noradrenergic modulation of acetylcholine release from cholinergic interneurons might be responsible for the spasm of aganglionic segments.
Use of the pudendo-anal reflex in the treatment of neurogenic faecal incontinence, An electrical stimulator has been devised to treat neurogenic faecal incontinence caused by pudendal nerve neuropathy and works on the basis of repeated stimulation of the pudendo-anal reflex arc. Although conduction in the pudendo-anal reflex arc may be prolonged. and is so in neurogenic faecal incontinence. it must be shown to be present before the method can be used. This stimulation results in an immediate rise in the pressure in the anal canal and a significant increase in the electromyographic activity of the external anal sphincter. Maintenance of the stimulus over a two month period raised the mean resting pressure significantly in the anal canal and increased the reflex and voluntary responses of the external anal sphincter to coughing and squeezing actions respectively. The length of the sphincter was not affected. There was widening of the mean motor unit potential duration. though this was not significant. The resting electromyogram was enhanced after the course of treatment. indicating greater spontaneous activity in the external sphincter. The changes led to seven of the eight patients studied becoming continent at the end of the treatment.
Relation between rectal sensation and anal function in normal subjects and patients with faecal incontinence, The relation between sensory perception of rapid balloon distension of the rectum and the motor responses of the rectum and external and internal anal sphincters in 27 normal subjects and 16 patients with faecal incontinence who had impaired rectal sensation but normal sphincter pressures was studied. In both patients and normal subjects. the onset and duration of rectal sensation correlated closely with the external anal sphincter electrical activity (r = 0.8. p less than 0.0001) and with rectal contraction (r = 0.51. p less than 0.001). but not with internal sphincter relaxation. All normal subjects perceived a rectal sensation within one second of rapid inflation of a rectal balloon with volumes of 20 ml or less air. Six patients did not perceive any rectal sensation until 60 ml had been introduced. while in the remaining nine patients the sensation was delayed by at least two seconds. Internal sphincter relaxation occurred before the sensation was perceived in three of 27 normal subjects and 11 of 16 patients (p less than 0.001). and could be associated with anal leakage. which stopped as soon as sensation was perceived. The lowest rectal volumes required to induce anal relaxation. to cause sustained relaxation. or to elicit sensations of a desire to defecate or pain were similar in patients and normal subjects. In conclusion. these results show the close association between rectal sensation and external anal sphincter contraction. and show that faecal incontinence may occur as a result of delayed or absent external anal sphincter contraction when the internal anal sphincter is relaxed.
Inter- and intraindividual variation in pressure-volume relations of the rectum in normal subjects and patients with the irritable bowel syndrome, The relation between intrarectal volume and pressure during increasing rectal distension by a latex balloon were studied on repeated occasions in 10 healthy adult volunteers to define variations within and between individuals. A wide intersubject variation in the maximum tolerable volume (58-908 ml) and pressure (12.2-108.8 cm H2O) at this end point was seen. and these two values were correlated (r = 0.78). Intrasubject variation in maximum tolerable volume also occurred which was related to study order and progressively reduced with repeated study. In 26 unselected patients with pain predominant irritable bowel syndrome similar intersubject variation was noted and virtually all patients data fell within the calculated 95% confidence limits of the normal individuals. Differentiation between patients and normal subjects was not possible from knowledge of rectal responses. These noticeable inter- and intrasubject variations in rectal responses to distension need to be considered whenever similar techniques are proposed for use in the study of rectal disease or of rectal response to treatment.
Pancreatic function in Crohn's disease, We investigated exocrine pancreatic function in a population of patients with Crohn's disease in order to correlate the pancreatic function with clinical and laboratory variables. A total of 143 patients affected by Crohn's disease and 115 control subjects were studied. All had a Lundh meal test. As a group patients with Crohn's disease had significantly decreased activity of both amylase (p less than 0.02) and lipase (p less than 0.001) in duodenal aspirates. In patients with Crohn's disease enzyme activities were not correlated to duration of disease or to extent or localisation of previous bowel resection. The lowest enzyme values were found in patients with the most extensive bowel involvement. and they were significantly lower (p less than 0.05) than in patients with disease confined to the terminal ileum. The differences between enzyme values in other subgroups of patients were not significant. For the patient group as a whole no correlation was found between disease activity and enzyme values. but for the most uniform group of patients. those with terminal ileitis. pancreatic function was significantly lower (p less than 0.05) in patients with moderate and severe disease compared with patients with mild disease. Thus at least two factors seem to be responsible for impaired pancreatic function in Crohn's disease: firstly disease activity and secondly localisation or extent of disease.
Loss of duodenal folds allows diagnosis of unsuspected coeliac disease, We report three patients with coeliac disease who presented without the classic features of malabsorption and who underwent biopsy and were diagnosed only because of the endoscopic finding of the disappearance of Kerckring's folds in the descending duodenum. This sign constitutes a new and valid aid for the identification of patients with otherwise unsuspected coeliac disease.
Comparison of omeprazole and cimetidine in reflux oesophagitis: symptomatic, endoscopic, and histological evaluations, Symptomatic patients with endoscopically verified reflux oesophagitis were randomised to a double blind trial in which they received either omeprazole (20 mg once daily) or cimetidine (400 mg four times daily) for four. and if necessary. eight weeks. In an 'intention to treat' analysis. oesophagitis was found to have healed after four weeks in 77 of 137 (56%) in the omeprazole group and in 34 of 133 (26%) in the cimetidine group (p less than 0.001). By eight weeks these values were 71% and 35% respectively; p less than 0.001. Histological assessments were available for 73% of the patients. At entry. 63% (66 of 104) in the omeprazole group and 60% (56 of 94) in the cimetidine group (ns) had abnormal histology. After the study. the proportions of patients who initially had had abnormal histology but who then progressed to normal were 67% (44 of 66: omeprazole) and 48% (27 of 56: cimetidine) respectively (p less than 0.001). All patients had reflux symptoms at entry. After four weeks. 46% in the omeprazole group and 22% (p less than 0.001) in the cimetidine group were asymptomatic. Diary cards completed for the first two weeks showed that patients treated with omeprazole experienced fewer reflux symptoms by day and night and used fewer antacids. Omeprazole. 20 mg once a day for four to eight weeks. healed a greater proportion of patients with reflux oesophagitis than cimetidine. 1.6 g per day. assessed endoscopically and histologically. and relieved more patients' symptoms.
Towards a true prevalence of peptic ulcer: the Sorreisa gastrointestinal disorder study, This study. designed to overcome methodological problems inherent in earlier prevalence studies of peptic ulcer. was carried out in a municipality in northern Norway. It included the total population of 2027. aged 20-69 years. and comprised a questionnaire and search for previously diagnosed peptic ulcers in the local medical records for all subjects. and additional endoscopy of all subjects with dyspepsia and their matched healthy controls (n = 619). The overall prevalence was 10.5% in men and 9.5% in women. a sex ratio close to one and a higher duodenal:gastric ratio than previously reported from this region. A substantial 1% prevalence of asymptomatic ulcers was also observed.
Duodenal ulcer and refined carbohydrate intake: a case-control study assessing dietary fibre and refined sugar intake, An association between duodenal ulceration and a low fibre intake and a high refined carbohydrate diet has been reported. We therefore compared the current diet. smoking habits. social class. and possible other risk factors of 78 patients with duodenal ulcer and a community control group matched for age and sex. Logistic regression for matched sets was used to calculate the relative risks for successive quintiles of dietary fibre and sugar intake before and after adjustment for total calorie intake and for the possible confounding effect of other known risk factors. Relative risks did not differ materially or consistently for total dietary fibre or for the cereal moiety whether adjusted or not for calorie intake. By contrast. relative risks tended to be reduced with high vegetable fibre intake and with low refined sugar intake. After controlling for smoking and social class. both of which were associated with ulcer disease. and for relative weight (Quetelet's index). the relation between ulcer disease and low refined sugar intake persisted. while that with high vegetable fibre intake was reduced. The results of this study indicate that a lack of cereal or total fibre intake plays no part in duodenal ulcer development but that a low refined sugar intake may be a protective factor.
Duodenal ulcer is associated with low dietary linoleic acid intake, It has been suggested that the falling incidence and virulence of duodenal ulcer is related to increased dietary polyunsaturated essential fatty acid intake. The adipose fatty acid profile. which closely reflects dietary intake. was measured in 35 men with chronic duodenal ulcer and 35 matched control men. The mean percentage of linoleic acid in adipose tissue was significantly lower in the ulcer group (10.0 (0.7) v 12.3 (0.7)%. p less than 0.01) and this difference was found in both smokers and non-smokers. This finding suggests that the diets of duodenal ulcer patients are deficient in linoleic acid and this could be of aetiological importance.
Biliary cholesterol transport and precipitation: introduction and overview of conference, Cholesterol is secreted into bile as cholesterol-phospholipid vesicles. The cholesterol and phospholipid are subsequently exposed to the bile salts contained in the bile. which leads to the process of micellation. Two situations may arise depending on whether there is enough bile salt in proportion to cholesterol to complete this "maturation" process. If the cholesterol saturation is low. at equilibrium the bile salts will have completely micellized the vesicles. On the other hand. if bile is saturated with cholesterol. the micellation process is incomplete and vesicles and micelles will be present at equilibrium. The residual vesicle in this latter situation may have a higher cholesterol/phospholipid ratio because of the greater propensity of phospholipid to be micellized. This situation may result in cholesterol nucleation. The mechanism of nucleation from vesicles and the possible role of nucleating and antinucleating proteins in this process have been discussed.
Bile sampling, processing and analysis in clinical studies, Obtaining a proper bile sample for investigative purposes is of utmost importance to obtain valid results. Bile can be collected by direct aspiration of the gallbladder. by duodenal intubation or by T-tube drainage. The optimal method of collection depends on the investigative question. as well as on the resources available to the investigator. The procedures for obtaining. processing and analyzing human bile (gallbladder and hepatic) are summarized. pointing out the disadvantages and pitfalls that may occur.
Gallbladder mucin as a pronucleating agent for cholesterol monohydrate crystals in bile, Mucin is a densely glycosylated macromolecule secreted by the gallbladder epithelium as the principal constituent of gallbladder mucus. Hypersecretion of gallbladder mucus occurs in response to a lithogenic diet in experimental animals. and mucus accumulates as a viscous gel within the gallbladder lumen before gallstone formation. In both animals and man. the initial stage of cholesterol gallstone formation. the nucleation of cholesterol monohydrate crystals. occurs within the mucus gel. Inhibition of mucus secretion with aspirin prevents gallstone formation in the cholesterol-fed prairie dog. indicating the importance of mucus in gallstone formation. Mucin contains domains that bind cholesterol and lecithin transported as vesicles in supersaturated bile. Furthermore. mucin accelerates the nucleation of cholesterol crystals in both supersaturated model and native biles. Binding of cholesterol-enriched vesicles to hydrophobic domains on the mucin protein core appears to be critical for the acceleration of cholesterol crystal nucleation by mucin. Further study of the structure and function of gallbladder mucin should help to elucidate the pathogenesis of cholesterol cholelithiasis.
Nonmucous glycoproteins as pronucleating agents, Cholesterol crystallization-promoting factors probably play an important role in the pathogenesis of gallstone disease. We have isolated one of the factors involved by using lectin-affinity chromatography. A potent promoting activity binds to concanavalin A-Sepharose. The activity is heat labile and sensitive to digestion by glycosidase but remarkably insensitive to proteases. The concanavalin A-binding pronucleator affects cholesterol solubilization in model bile in two ways. It induces a shift of cholesterol and phospholipid from the micellar to the vesicular phase but also interacts directly with cholesterol-phospholipid vesicles. The concanavalin A-binding protein fraction contains at least two different promoting factors with gel permeation molecular weights of about 150 kD and 5 kD. respectively. The higher molecular weight activity could be assigned to a protein with an apparent molecular weight of 130 kD. Concanavalin A-binding-promoting activity was present in bile from both patients with and without stones. indicating that it is a normal constituent of bile. However. the activity was strongly increased in bile from patients with multiple cholesterol gallstones. suggesting that it could play a key role in gallstone formation in these patients.
Pathogenesis of biliary sludge, The increasing application of ultrasonography in biliary tract disease had led to more frequent recognition of an old disorder--"biliary sludge." Sludge is detected on ultrasound as low-amplitude echoes without acoustic shadowing. It layers in the most dependent part of the gallbladder and shifts with positioning. Particulate matter in bile. such as cholesterol monohydrate crystals. has been shown to be echogenic. Agglomeration of these crystals in biles with high mucus content accounts for the layering and the characteristic appearance of the movement of sludge with alteration in patient position. Within the gallbladder. the stability of the vesicular form of cholesterol and protein-lipid interactions are important determinants of cholesterol precipitation. In mixed and pigment gallstones. the equilibrium between ionized and unionized calcium and the hydrolysis of conjugated bilirubin are also important factors. Although the risk factors contributing to the formation of gallbladder sludge have not been critically examined. it is now known that in some instances sludge can produce biliary pain and can be associated with acalculous cholecystitis. recurrent pancreatitis and. ultimately. the formation of gallstones. A better appreciation of the pathogenesis of sludge formation can help in the understanding of the genesis of gallstones and also perhaps in understanding other documented but poorly understood biliary and pancreatic disorders.
Unconjugated bilirubin and cholesterol gallstone formation, Cholesterol gallstones usually have small amounts of pigment at their centers and often have diffuse pigmentation or pigmented layers alternating with cholesterol layers and/or pigmented rims associated with calcium carbonate (eggshell calcification). The pigments are primarily monomeric calcium salts of unconjugated bilirubin anions and/or an insoluble. black. network polymer of tetrapyrroles. Bilirubin presumably can precipitate only if bile is supersaturated with calcium bilirubinates. Among various in vitro model systems. the aqueous solubilities and pK'a values for unconjugated bilirubin differ greatly. It is therefore not known whether normal bile is saturated with unconjugated bilirubin. However. all systems indicate that unconjugated bilirubin is solubilized by binding to bile salt monomers and oligomers. as well as micelles; marked metastable supersaturation of unconjugated bilirubin can occur in the presence of bile salt micelles. and both pK'a values of unconjugated bilirubin are greater than 6.0. probably because of internal hydrogen-bonding of the--COOH groups. Lecithin decreases equilibrium solubilization of unconjugated bilirubin crystals but enhances metastable supersaturation of unconjugated bilirubin. Calcium ions form insoluble salts with unconjugated bilirubin monoanions and dianions but soluble complexes with bilirubin conjugates. The solubility products of the calcium bilirubinate salts suggest that normal hepatic bile is not saturated with CaB or Ca(HB)2 but that gallbladder bile may be supersaturated with Ca(HB)2.
Current concepts of cholesterol transport and crystal formation in human bile, The presence of vesicles in human bile probably accounts almost entirely for the frequently observed. but hitherto unexplained. phenomenon of metastable cholesterol supersaturation. This. in turn. largely explains the prolonged stability of cholesterol solubilized in supersaturated human bile. Under certain overall compositional conditions for a supersaturated native bile. the vesicular phase in its contribution to total cholesterol transport also becomes supersaturated in cholesterol. Because of this. the vesicles also become unstable. leading to formation of cholesterol crystals. A simple but common example of one factor affecting composition in this way is concentration of total solutes. especially the biliary lipids. Conversely. dilution of bile (e.g.. hepatic bile) markedly reduces the cholesterol saturation level in biliary vesicles. The result is that such vesicles become much more stable. Under these conditions. cholesterol crystal formation becomes unlikely and rarely. if ever. occurs.
Fluorescence assays to monitor membrane fusion: potential application in biliary lipid secretion and vesicle interactions, Membrane fusion constitutes an essential. intermediate step in numerous cell biological processes. occurring for example during endocytosis. membrane recycling and exocytosis. Also less desirable events such as the infection of cells by animal viruses are mediated by membrane fusion during which the viral envelope merges with a cellular membrane. causing the expulsion of the viral nucleocapsid into the cytoplasm of the cell as an initial step in virus replication. Much of our current knowledge concerning the mechanism of membrane fusion has been derived from studies using simple artificial membranes. such as liposomes or phospholipid vesicles. as model systems. A most essential feature of these studies has been the development of membrane fusion assays that register in a sensitive and continuous fashion the mixing of membranes or the aqueous volumes initially enclosed by these membranes. Not only do these assays allow one to readily detect and quantify fusion. but they also provide the possibility to relate the kinetics of fusion to the rate by which certain molecular changes in membranes take place. Obviously. this insight is of relevance for understanding the mechanism of membrane fusion. The principles and applications of some representative assays that rely on the use of fluorescence spectroscopy will be discussed. Assays that monitor membrane mixing are commonly based on the detection of changes in resonance energy transfer efficiency or the relief of fluorescence self-quenching of appropriate fluorescent lipid analogs. Contents mixing assays rely on either the formation of a (aqueous-soluble) fluorescent complex or quenching of a fluorophore. encapsulated in one vesicle population. by a suitable quencher. entrapped in a second population.
Growth of group A rotaviruses in a human liver cell line, Recent observations in children with rotavirus gastroenteritis and in infant mice given rotavirus vaccine by oral administration suggest that this well-known gastrointestinal pathogen may infect the liver. To examine this possibility. the susceptibility of Hep G2 cells to infection with a variety of rotavirus strains was tested. These cells were used because they are considered to be well differentiated and exhibit many liver-specific functions. The Hep G2 cells supported the growth of the simian strain rhesus rotavirus (MMU 18006). a strain currently being used in vaccine trails. but did not support the growth of any human strain (D. DS1. Price or ST3). The rhesus rotavirus infection was cytopathic and resulted in release of lactate dehydrogenase. Rhesus rotavirus growth in Hep G2 cells displayed trypsin-enhanced infectivity and was inhibited by pretreatment of cells with Arthrobacter ureafaciens neuraminidase but not with neuraminidase from Clostridium perfringens. Hep G2 cells were also permissive for another simian strain (SA11). a bovine strain (UK) and single gene substitution reassortants containing VP7 (the major outer capsid neutralization protein) from a human rotavirus strain and the remaining 10 genes from either rhesus rotavirus or UK. In general. UK and its reassortants produced lower levels of antigen than did rhesus rotavirus and its reassortants. Hep G2 cells and other hepatic cell lines may prove to be useful tools to explore the hepatotropic potential of wild-type rotaviruses and candidate vaccine strains.
Hepatocyte plasma membrane glycosphingolipid reactive with sera from patients with autoimmune chronic active hepatitis: its identification as sulfatide, Sera from patients with autoimmune chronic active hepatitis were found to contain IgG-class antibody to the acidic glycosphingolipid fraction from rabbit hepatocyte plasma membrane by solid-phase enzyme-linked immunosorbent assay. Using serum positive for the antibody as a probe. we isolated the target antigen by Iatrobeads column chromatography. Analysis by thin-layer chromatography and negative ion fast atom-bombardment mass spectrometry revealed that the antigen was sulfatide. The presence of antisulfatide antibody was also confirmed by immunoblotting. The reactivity of the serum with sulfatide was diminished by preincubation of the serum with galactosylceramide-6-sulfate and sulfatide. indicating that the antibody reacted with sulfated galactosylceramide regardless of the position of the sulfate residue. The antibody was found in 92.3%. 42.9%. 15.8%. 14.2%. 0% and 0%. respectively. of patients with autoimmune chronic active hepatitis. primary biliary cirrhosis. cirrhosis. systemic lupus erythematosus. chronic active hepatitis and chronic persistent hepatitis. Thus antisulfatide antibody was characteristic of autoimmune-type chronic liver diseases. Antisulfatide antibody was absorbed by rabbit hepatocyte plasma membrane. Preincubation of sera with sulfatide immobilized on Sepharose decreased their reactivities with not only sulfatide but also rabbit plasma membrane and rat hepatocytes. Therefore sulfatide may be a target antigen of the antibody to hepatocyte surface membrane.
HBV-DNA sequences in tumor and nontumor tissue in a patient with the fibrolamellar variant of hepatocellular carcinoma, One patient with the fibrolamellar variant of hepatocellular carcinoma was found to be seropositive for HBsAg and anti-HBe. DNA from tumor and nontumor areas of the liver was examined by molecular hybridization for hepatitis B virus DNA sequences. Undigested DNA from the tumor gave a high-molecular-weight smear. and restriction-enzyme analysis indicated a single instance of integration. Nontumor liver tissue was analyzed from three separate areas. Hepatitis B virus DNA was detected in two of these; restriction-enzyme digestion suggested they contained different sites of viral integration. As with the typical hepatitis B virus-related hepatocellular carcinoma. analysis of hepatitis B virus DNA from nontumorous liver yielded a different pattern of high-molecular-weight bands. indicating that the virus genome had integrated at different chromosomal locations than that seen in the tumor. The finding of integrated hepatitis B virus DNA. especially in tumorous but also in nontumorous liver. would be consistent with an oncogenic role for hepatitis B virus in certain instances of fibrolamellar tumors and in the more typical hepatitis B virus-related hepatocellular carcinoma.
Increased serotoninergic and noradrenergic activity in hepatic encephalopathy in rats with thioacetamide-induced acute liver failure, Functional changes of various neurotransmitter systems have been implicated in the pathogenesis of hepatic encephalopathy. In this study the role of brain monoaminergic neurotransmitter systems in hepatic encephalopathy was investigated in rats with thioacetamide-induced acute liver failure. Concentrations of serotonin. dopamine. noradrenaline and of their metabolites 5-hydroxyindoleacetic acid. dihydroxyphenylalanine (following inhibition of dihydroxyphenylalanine-decarboxylase). dihydroxyphenylacetic acid. homovanillic acid and 3-methoxy-4-hydroxyphenyl-glycol. were measured in the cerebral cortex. striatum and hippocampus by high performance liquid chromatography with electrochemical detection. In hepatic encephalopathy concentrations of 5-hydroxyindoleacetic acid were increased in all three brain areas (196%. 204% and 264% of saline-treated controls. p less than 0.01). and concentrations of serotonin were increased in the frontal cortex (121%. p less than 0.01). In the frontal cortex and hippocampus of encephalopathic rats dopamine levels were increased (157% and 289%. p less than 0.05). and levels of noradrenaline (53% and 46%. p less than 0.05) were decreased associated with increased 3-methoxy-4-hydroxyphenylglycol levels (173% and 206%. p less than 0.05). The extent of these changes correlated with the stage of hepatic encephalopathy. In hepatic encephalopathy dihydroxyphenylalanine accumulation was increased in the hippocampus and unchanged in the cerebral cortex. Dopamine. noradrenaline. dihydroxyphenylacetic acid and homovanillic acid concentrations were unchanged in the striatum. The results of this study indicate that hepatic encephalopathy in thioacetamide-induced acute liver failure in rats is associated with neurochemical changes. suggesting an increased activity of the noradrenergic and serotoninergic neurotransmitter systems.
Relative frequencies of portosystemic pathways and renal shunt formation through the "posterior" gastric vein: portographic study in 460 patients, Percutaneous transhepatic portography was carried out in 460 patients with portal hypertension to study various collateral routes. Besides the left gastric vein. which was the most frequent collateral route and feeder of esophageal varices. a distinct vein located between the left gastric vein and the short gastric vein constituted a major collateral route in 191 patients (42%). In terms of frequency. this vein was more significant than the short gastric (34%) and the paraumbilical vein (24%) as a collateral route. We propose that this previously anonymous vein be called the "posterior gastric" vein because it runs posterior to the stomach. This vein also formed a renal shunt. a common cause of encephalopathy. in 43 (23%) of the 191 patients; the relative frequency of renal shunt formation by this vein was significantly greater than that by the left gastric vein (12%) and the short gastric vein (18%).
Albumin absorption and protein secretion by the gallbladder in man and in the pig, To study albumin absorption by the gallbladder in man. an in vitro model was first established in the pig and compared with in vivo function in the same species. Water and electrolyte transport and 125I-albumin absorption and protein secretion in vivo and in vitro were compared. Then similar in vitro studies were performed on human gallbladders obtained at surgery. The in vivo study in the pig was performed without disturbing the gallbladder except to tie a cannula in the cystic duct end. The in vitro model was identical in the pig and human gallbladders. Gallbladders were excised using a technique causing minimal injury and anoxia. They were oxygenated on both mucosal and serosal surfaces in a temperature-controlled environment. Luminal and external bath test solutions consisted of modified Ringers bicarbonate with added glucose; luminal solutions also contained 125I-albumin from different species. depending on the study. Active absorption of sodium and water occurred in both types of studies in the pig but in vivo absorption rates were considerably greater than in vitro rates. Albumin absorption in vivo was substantial; although present in vitro. the absorption of albumin was diminished relatively more than electrolyte transport rates. Protein secretion rates into the gallbladder were similar in vitro and in vivo. The results of studies in the human gallbladders in vitro were similar to the pig. except albumin absorption was greater. Some human gallbladders were obtained from control patients and some from patients with cholesterol gallstones. There were no significant differences between the two groups for any of the variables studied; however. the numbers were small and some control gallbladders were not normal gallbladders.
Amyloid deposition in intrahepatic large bile ducts and peribiliary glands in systemic amyloidosis, Amyloid deposition in the hepatic parenchyma and portal tracts in the liver is well known in systemic amyloidosis. We recently experienced an autopsy case of systemic amyloidosis presenting the amyloid deposits in the intrahepatic biliary tree. This experience prompted us to survey 19 autopsy cases of systemic amyloidosis. Amyloid deposition was found just under the lining epithelium of the intrahepatic large bile duct in 10 of 19 cases and around the peribiliary glandular acini in 7 of the 19 cases. respectively. Amyloid deposition in the intrahepatic large bile duct and peribiliary glands was positively correlated with the degree of amyloid deposition in the liver but not with type of amyloid protein. Double-staining of amyloid and vascular endothelium disclosed that amyloid deposition was more closely related to the inner part of the peribiliary vascular plexus and to the vascular plexus encircling the peribiliary glands than the lining biliary epithelium and peribiliary glandular acinar cells themselves. The exact pathogenesis of amyloid deposition in these anatomical components. however. remains unclear. Although our cases failed to show any overt clinical symptomatologies related to amyloid deposition in these biliary components. it seems conceivable that more massive amyloid deposition in these anatomical components could give rise to some clinical symptoms.
Prognostic factors of hepatocellular carcinoma in the west: a multivariate analysis in 206 patients, To investigate the prognostic factors in Western patients with hepatocellular carcinoma. 206 patients with confirmed diagnoses of hepatocellular carcinoma were studied in terms of survival. All patients were diagnosed between 1983 and 1987. A multivariate survival analysis (Cox regression model) using clinical. biochemical. ultrasonographical and pathological data obtained at diagnosis disclosed that bilirubin (p = 0.0001). ascites (p = 0.0001). toxic syndrome (defined by the presence of weight loss greater than 10% premorbid weight. malaise and anorexia) (p = 0.009). blood urea nitrogen (p = 0.025). tumor size (p = 0.001). gamma-glutamyltranspeptidase (p = 0.0006). age (p = 0.0005). serum sodium (p = 0.003) and presence of metastases (p = 0.002) were independent predictors of survival. According to the contribution of each of these factors to the final model. a prognostic index was constructed allowing division of patients in different groups according to their relative risk of death: RRD = EXP (Age x 0.03 + Ascites x 0.8281 + BUN x 0.0137 + Serum sodium x (-0.0538) + gamma-Glutamyltranspeptidase x 0.0019 + Bilirubin x 0.0734 + Tumor size x 0.33 + Toxic syndrome x 0.4965 + Metastases x 0.55). These results facilitate the stratification of hepatocellular carcinoma patients to design and evaluate future controlled trials.
Time course of hemodynamic responses to sodium in elderly hypertensive patients, Thirty-one patients with essential hypertension (81.6 +/- 6.9 years old) were studied during two different regimens of sodium intake: 120 meq/day for 8 weeks and 344 meq/day for 2 weeks. Systemic hemodynamic data were measured with Doppler echocardiography from which the mitral flow velocity integral. cardiac index. and total peripheral resistance were calculated. The salt-sensitive patients in whom the increase in total peripheral resistance was greater than the increase in cardiac index with salt loading were termed SST. In the salt-sensitive patients termed SSC. the increase in cardiac index was greater than the increase in total peripheral resistance with increased sodium intake. All SST patients on day 7 of the high sodium diet remained in the SST group on day 14. Nine of 13 patients in the SSC group on day 7 remained in the SSC group on day 14. and the remaining four patients in the SSC group on day 7 fell into the SST group on day 14. Four of eight non-salt-sensitive (NSS) patients on day 7 of the high salt regimen remained in the NSS group on day 14. whereas the remaining four patients in the NSS group on day 7 fell into the SSC group on day 14. Our data suggest a changing pattern with sodium loading of initially high cardiac index followed by a persistently raised total peripheral resistance. The celiac. superior mesenteric. and renal arteries vasoconstricted with sodium repletion in both SST and SSC patients. With salt loading. the terminal aortic vascular bed vasodilated in the SSC patients and vasoconstricted in the SST patients.
Two-way factorial study of alcohol and salt restriction in treated hypertensive men, The aim of this study was to determine whether moderate restriction of dietary salt intake leads to an additional fall in blood pressure in treated hypertensive men who are asked to simultaneously reduce their usual alcohol intake. Sixty-three subjects entered an initial 2-week familiarization period during which they continued their usual alcohol intake and commenced a "low sodium" diet (less than 60 mmol/day) supplemented with 100 mmol sodium chloride per day as enteric-coated tablets. Subjects were then randomly assigned to either drink a low alcohol beer alone for a 4-week period (reducing their self-reported alcohol consumption from 537 to 57 ml/week) or to continue their usual alcohol intake (543 versus 557 ml/week). Within the low and normal alcohol intake groups. subjects were assigned to either a low or normal sodium intake. The low sodium groups continued the sodium-restricted diet but were switched to placebo sodium chloride tablets for the 4 weeks. This resulted in a fall in the 24-hour urinary sodium excretion from 144 to 69 mmol/day. The normal sodium groups continued the low sodium diet but kept taking 100 mmol/day of the sodium chloride tablets. and their urinary sodium excretion remained unchanged (125 versus 142 mmol/day). Regular antihypertensive therapy was continued throughout. Fifty-nine subjects completed the trial. In those who reduced their alcohol intake there was a fall in both systolic blood pressure (-5.4 mm Hg supine. p less than 0.01) and diastolic blood pressure (-3.2 mm Hg supine. p less than 0.01).
Diurnal cardiovascular patterns in spontaneously hypertensive and Wistar-Kyoto rats, This study was designed to determine whether diurnal patterns of blood pressure. heart rate. or locomotor activity differed among two substrains of Wistar-Kyoto rats. derived originally from Charles River or Taconic Farms stock. or the spontaneously hypertensive rat. Cardiovascular parameters were continuously monitored over 24 hours. Resting systolic and diastolic blood pressure values were statistically different among the three groups both during the lights-on (rest) and lights-off (active) phases of the cycle with blood pressure of spontaneously hypertensive rats greater than that of Wistar-Kyoto rats from Taconic Farms. which was greater than that of Wistar-Kyoto rats from Charles River. The largest difference in arterial pressure between Wistar-Kyoto/Taconic Farms and Wistar-Kyoto/Charles River was during the lights-on period. Heart rates of all rats decreased during the lights-on period; Wistar-Kyoto/Charles River had the largest decrease (-70 +/- 5 beats/min). Wistar-Kyoto/Taconic Farms had the least (-17 +/- 2 beats/min). and in spontaneously hypertensive rats the decrease was intermediate (-29 +/- 3 beats/min). The pronounced diurnal variation in pressure and heart rate exhibited by Wistar-Kyoto/Charles River was not present in either Wistar-Kyoto/Taconic Farms or spontaneously hypertensive rats. Blood pressure magnitude correlated with locomotor activity during both periods. although all groups showed minimal activity during the rest period. Observed differences between Wistar-Kyoto/Charles River and Wistar-Kyoto/Taconic Farms were not due to a lack of or an abnormality in baroreceptor reflex function.
A kallikrein-like enzyme in blood vessels of one-kidney, one clip hypertensive rats, Active and inactive kallikrein or a kallikrein-like enzyme are found in the aorta. vena cava. and tail artery and veins of the rat. We studied the concentration of vascular kininogenase in rats with one-kidney. one clip renovascular hypertension and in unilaterally nephrectomized normotensive rats. Six weeks after surgery. active and total vascular kininogenase activity (active plus trypsin-activated) was measured. Blood pressure was 212 +/- 4 mm Hg in the hypertensive rats (n = 33) and 120 +/- 1 mm Hg in the normotensive rats (n = 32) (p less than 0.001). Active kininogenase was lower in the hypertensive rats; although the difference was not significant in the thoracic aorta (56 +/- 8 versus 77 +/- 15). it was highly significant in the abdominal aorta (63 +/- 13 versus 167 +/- 17. p less than 0.001) and tail artery (48 +/- 8 versus 197 +/- 31. p less than 0.003). Total vascular kininogenase activity (active plus trypsin-activated) was lower in the hypertensive rats in all arteries examined: thoracic aorta (183 +/- 16 versus 380 +/- 38. p less than 0.003). abdominal aorta (565 +/- 61 versus 1.093 +/- 74. p less than 0.001). and tail artery (532 +/- 112 versus 1.243 +/- 135. p less than 0.003). Active kininogenase in the vena cava was higher in the hypertensive rats (213 +/- 56 versus 131 +/- 31); however. this difference was not statistically significant. whereas in the tail veins it was highly significant (1.803 +/- 221 versus 771 +/- 79. p less than 0.003).
Development of hypertension from unilateral renal artery stenosis in conscious dogs, The renal and systemic changes after stenosis of the left renal artery (n = 5) or sham stenosis (n = 6) in conscious dogs were studied sequentially over 25 days. Stenosis produced a prompt rise in arterial pressure. which was at all times due to reduced peripheral vascular conductance. with no increase in cardiac output despite initial evidence of mild fluid retention. The decrease in peripheral conductance was attributable to 1) the stenotic kidney (25% of the total and due to the mechanical effect of the stenosis itself). 2) the nonstenotic kidney (about 15% of the total and not caused by angiotensin II). and 3) the nonrenal vasculature (60%). The decrease in conductance in the nonrenal vasculature was due partly to angiotensin II. but there was also a gradually developing non-angiotensin II component. Acute administration of captopril caused significantly greater changes in arterial pressure and peripheral conductance throughout the period of stenosis than before stenosis (and greater than in sham-stenosis dogs). indicating that angiotensin II was constricting the peripheral vasculature even when plasma renin levels were no longer elevated. In the stenotic kidneys. captopril produced a fall in renal vascular resistance. but renal blood flow did not rise because there was an approximately equal rise in the resistance of the stenosis. There was no evidence for a role for the autonomic nervous system in the hypertension. as ganglion blockade (pentolinium) had similar hemodynamic effects before and after stenosis. Thus. the hypertension was due at all times to reduced peripheral conductance. with the two kidneys responsible for 40% of this reduced conductance.
Interleukin-2 does not attenuate hypertension in spontaneously hypertensive rats, It was recently reported that interleukin-2. when administered as a single bolus injection (5.000 units/kg). could prevent the development of hypertension in young spontaneously hypertensive rats and lower blood pressure to normotensive levels in spontaneously hypertensive rats with established hypertension. Consequently. efforts were made to duplicate this finding. Male spontaneously hypertensive rats (35 days old) were injected subcutaneously with 50.000 units/kg (3.500 units/rat) of recombinant interleukin-2 (Amgen) and had systolic blood pressure measured twice weekly by the tail-cuff technique. Systolic blood pressure in the interleukin-2-treated group was not significantly different from the vehicle-treated control group at any time point over 32 days of follow-up. A second injection of recombinant interleukin-2 (5.000 units/kg) was administered 32 days after the first injection. Again. no reduction in blood pressure was observed in the interleukin-2-treated group over an additional 38 days. Mean arterial pressure (+/- SEM) measured via intra-arterial cannula in conscious rats at age 105 days (38 days after the second treatment) was 168.5 +/- 3.5 mm Hg in interleukin-2-treated spontaneously hypertensive rats and 170.3 +/- 3.6 mm Hg in vehicle-treated controls. Both recombinant interleukin-2 preparations conformed to their respective manufacturer's indicated specific activity as determined by the ability of the interleukin-2 to induce proliferation of the interleukin-2-dependent cell line HT-2. Thus. this study demonstrated that interleukin-2 was ineffective in preventing or attenuating hypertension in spontaneously hypertensive rats.
Changes in self-concept during pulmonary rehabilitation, Part 1, The purpose of this two-part study was to describe changes in self-concept during and after a formal pulmonary rehabilitation program. A 20-item semantic meaning differential scale was administered to 37 patients with severe chronic obstructive pulmonary disease who were participating in a multidisciplinary pulmonary rehabilitation program. Patients were asked to evaluate their past. present. and future selves on program admission. on program discharge. and 2 to 6 months after home discharge. Mean total self-concept score for the present self significantly increased between program admission and home discharge 3 weeks later (mean change 31.32 +/- 22.04. p less than 0.0001). No significant declines in self-concept were found 2 to 6 months after home discharge (p = 0.39). Men showed a significantly higher change in total self-concept score than women during the 3-week program (p = 0.03). However. the men's change score dropped significantly after home discharge (p = 0.02). suggesting a need for more intensive follow-up care than with women. The self-concept tool in this study provided an easy way to monitor subjective changes in psychologic status.
Changes in self-concept during pulmonary rehabilitation, Part 2, This two-part study describes changes in self-concept during pulmonary rehabilitation. A 20-item semantic meaning differential scale was administered to 37 patients with severe chronic obstructive pulmonary disease who were participating in a multidisciplinary pulmonary rehabilitation program. Patients were asked to evaluate their past. present. and future self-concepts on program admission. on program discharge. and 2 to 6 months after home discharge. In this part of the study item-level quantitative data as well as qualitative data from the counseling session at program discharge are reported. The quantitative data documented detailed changes in self-concept at various stages of pulmonary rehabilitation. Counseling session results indicated that patient involvement in item-level analysis greatly facilitates psychosocial intervention. Findings from this study establish clinical indications for use of the Self-concept Evaluation tool in adult patients with chronic obstructive pulmonary disease. Use of this tool is recommended early in the rehabilitation process.
Effects of differential touch on nervous system arousal of patients recovering from cardiac disease, Previous research suggests that the neural properties of certain types of touch as well as their perceived significance to the disease state may be related to heightened activation of the nervous system. In this study the effects of different types of touch on nervous system arousal were examined in 59 adult patients who were receiving treatment for coronary artery disease. They were exposed to a standardized protocol that systematically varied the neural properties and procedural nature of the touch received. Measures of cardiovascular reactivity (heart rate and rhythm data as well as blood pressure measurements) and state anxiety were used as indexes of arousal. The results indicated that all types of touch evoked heart rate deceleration in contrast to both baseline and verbal conditions. However. there were no differential effects related to either the neural properties or procedural nature of touch. Diastolic blood pressure and state anxiety were also lower as a result of the touch. No changes were observed for systolic blood pressure or heart rhythm. In general. findings suggested that touch served to reduce arousal rather than to produce negative psychophysiologic consequences for recovery.
Family recovery after vascular surgery, Twenty-one families were observed in a 3-month study to assess family coping with major vascular surgery and recovery. Analysis of family measures data (the Family APGAR. the Family Inventory of Resource for Management. and the Family Crisis Oriented Personal Evaluation Scales) was combined with grounded theory method to assess family responses over time and recovery outcomes. Containment emerged as the major conceptual category of the grounded theory. Containment refers to a constellation of constructed meanings for events and behavioral responses used by families to regulate the impact of the surgical crisis and reduce family disruption. This "contained" coping pattern was manifested in families' avoidant behaviors and narrow definitions of the problem: that is. they defined their situation in terms of the surgical repair as cure rather than palliative intervention for a chronic. progressive disease. Situational factors such as the insidious development of the illness and the primary focus of care providers in the hospital on surgical care (allowing families' narrow definitions of their situation to remain unchallenged) also contributed to containment. Containment resulted in poor risk factor management as a major recovery outcome. Isolation and family conflict were evident throughout the recovery period. Concerns generated by continued evidence of morbidity during recovery contributed to a developing awareness of underlying disease. and diminishing containment when this growing awareness was openly shared within the family. Significant findings of the family measures analysis were compared with the grounded theory of the qualitative data. Each corroborated the other in key dimensions.
Nurse-monitored cardiac recovery: a description of the first 8 weeks, Health problems and related patient management during early recovery after cardiac surgery are not well documented. As part of a larger study of recovery from cardiac surgery 75 patient-care giver pairs received telephone calls from nurses at 1. 2. 3. 4. 6. and 8 weeks after discharge for the purpose of intervening to facilitate early recovery at home. After each call. nurses recorded detailed notes on the patients' progress and concerns. Content analysis of detailed nurses' recordings revealed the following predominant nursing actions: assessment. provision of support. reinforcement of predischarge teaching. referrals. and teaching. The five nursing diagnoses that occurred most frequently across the 8-week recovery period were altered comfort: pain; ineffective coping. individual; activity intolerance; sleep pattern disturbance; and altered nutrition. In response to these problems. patients managed and prevented health-related problems and engaged in health promotional and normalizing activities. By anticipating common problems in recovery. patients and care givers can be better prepared for going home. Similarly nurses can be better prepared to anticipate and respond to common recovery problems.
Torsade de pointes: a critical care nurse's dilemma, Torsade de pointes is a polymorphous ventricular tachycardia characterized by a gradual change in the direction of the QRS complex. Because critical care nurses are the first to recognize arrhythmias. they require the knowledge and skill to intervene appropriately. This case report focuses on identification of the characteristics. contributing factors. therapeutic modalities. and relevant nursing diagnoses for the patient with torsade de pointes.
Role of angiotensin-converting enzyme inhibitors in congestive heart failure, Conventional therapy for congestive heart failure (CHF) includes sodium-restricted diet. diuretics. digitalis. vasodilators. and short-term intravenous administration of beta-adrenergic agonists during episodes of decompensation. A specific class of vasodilators. the angiotensin-converting enzyme inhibitors. has recently gained predominance in the treatment of congestive heart failure. The primary mechanism of action is to reduce production of angiotensin II by competitive inhibition of the enzyme that converts angiotensin I into angiotensin II. Reduced levels of angiotensin II. in turn. promote vasodilation and lower aldosterone production. The benefits of angiotensin-converting enzyme inhibitor therapy in chronic congestive heart failure have been demonstrated by improvement in left ventricular performance. exercise capacity. functional status (using New York Heart Association classification). and survival.
Effects of endotracheal suctioning on mixed venous oxygen saturation and heart rate in critically ill adults, The purpose of this multisite study was to determine the effects of endotracheal suctioning on mixed venous oxygen saturation (SvO2) and heart rate in 189 critically ill adults. One-pass. intermittent suction was applied for 10 or fewer seconds. with three prehyperoxygenation and three posthyperoxygenation breaths of 100% oxygen. Subjects at three hospitals (n = 127) underwent suctioning using hyperoxygenation with anesthesia bags and traditional suction catheters (open suction method). Subjects at one hospital (n = 62) underwent suctioning with hyperoxygenation by ventilator and in-line suction catheters (closed suction method). For subjects from all hospital sites combined. the SvO2 decreased from 67% to 64% (p = 0.001). a 4% change from baseline. and returned to baseline within 2 minutes. However. in subjects receiving the open method of suction. SvO2 dropped from 66% to 62% immediately after suctioning and returned to baseline within 4 minutes. In contrast. when the closed suction method was used. SvO2 rose from 67.7% to 67.86% immediately after suctioning. drifting upward to 71% for the next 2 minutes before dropping toward the baseline after 4 minutes. Mean heart rate increased from a baseline of 99 beats/min to 104 beats/min immediately after suctioning (p = 0.001). a 5% change from baseline. and gradually returned to baseline over the next 4 minutes. No significant differences were seen in heart rate between subjects having the open versus closed suction method. In conclusion. the closed suction method showed a higher SvO2 after endotracheal suctioning compared with the open suction method (p = 0.0001). Some form of hyperoxygenation before and after endotracheal suctioning is recommended.
Blood loss reduced during hip arthroplasty by lumbar plexus block, We measured the blood loss during and after hip replacement in two groups of women. each consisting of 10 patients. In one group the lumbar plexus was infiltrated with bupivacaine. in the other it was not. The group in whom the plexus was blocked had significantly less blood loss.
Secondary total hip replacement after fractures of the femoral neck, We studied the rate of revision in 84 consecutive total hip replacements performed for failed osteosynthesis of femoral neck fractures and compared it with that for primary arthroplasty for osteoarthritis. The age and sex adjusted risk of prosthetic failure was 2.5 times higher after failure of fixation. but all the excess risk was in patients over 70 years of age. There were radiographic signs of loosening of the femoral component at five to 12 years after secondary arthroplasty in six of 33 survivors. In general. the results of secondary replacement were no worse than those obtained after primary arthroplasty for femoral neck fracture. We consider that internal fixation should be the primary procedure: total hip replacement is a safe secondary procedure when osteosynthesis fails.
The AO dynamic hip screw and the Pugh sliding nail in femoral head fixation, We compared. under laboratory conditions. the resistance to cutting out of the AO dynamic hip screw and the Pugh sliding nail. The mean load at cut out. adjusted for bone strength. was 70% greater for the Pugh sliding nail. The reasons for this difference are discussed.
Femoral neck fracture fixation. Comparison of a sliding screw with lag screws, The rigidity of a sliding compression screw and three cannulated lag screws in the treatment of subcapital fractures was compared in five pairs of female cadaver femora. There were no significant differences between the compressive strength. bone density. cortical thickness or Singh index of the bones in each pair. A subcapital fracture was standardised using a perpendicular saw cut across the femoral neck. A uniaxial 'load test system' with force and length measurement facilities was used to mimic cyclical stressing applied in vivo at a frequency of 0.5 Hz from 0 to 3 times body-weight. There was no significant difference between the fixation afforded by the sliding compression screw and three lag screws. Bone quality was the single most important factor in the stability of the bone implant unit.
Locked intramedullary nailing for displaced tibial shaft fractures [published erratum appears in J Bone Joint Surg [Br] 1991 Jan;73(1):181, We analysed the results of 93 tibial shaft fractures treated with the Grosse-Kempf locked nail. Twenty-six fractures were comminuted. 19 were open grade I to II. and 54 were located outside the middle third of the tibia. The deep infection rate was 3.2%. There were only two poor results. The use of this method is recommended and discussed.
Mechanism of the pivot shift, The mechanism of the pivot shift was investigated by analysing movements under valgus torque in 29 fresh cadaveric knees. The movements were measured in three dimensions. using biplanar photography. when all the ligaments were intact. and then after the ligaments were sequentially divided. When only the anterior cruciate ligament was sectioned. the pivot shift occurred in seven out of 20 knees examined. In the other 13. though the pivot shift was not observed. an abnormal internal rotation occurred at between 10 degrees and 50 degrees of flexion. Division of the iliotibial tract in addition to division of the anterior cruciate ligament stopped the pivot shift. as the tibia remained internally rotated throughout the range of flexion. The axis of rotation of the pivot shift was located at the medial collateral ligament. which was kept tight by the applied valgus torque. The sudden movement in the pivot shift was caused by a complex interaction between the geometry of the knee and the valgus torque applied.
Healing of non-vascularised diaphyseal bone transplants. An experimental study, Four different experiments were performed to study the healing of a large. non-vascularised. diaphyseal. bone segment in adult cats. In the first experiment. a 4 cm segment of tibia with its periosteum was excised and replaced in its bed. The other experiments were similar. except that in the second. the periosteum of the segment was removed. in the third its medullary canal was blocked with a Silastic rod. and in the last group the segment was isolated from its muscle bed by a Silastic sheet. The reparative processes were quantified by estimating the resorption index. the cortical new bone formation index. the callus encasement index. and the osteocyte count. Bone resorption and apposition occurred in the segment even when the periosteum was absent or the medullary canal was blocked. with osseous union at both ends by eight to 12 weeks. provided the segment was not isolated from its muscle bed. Thus. the muscle bed played a significant role in these reparative processes.
Corticocancellous grafting and an AO/ASIF lag screw for nonunion of the scaphoid. A retrospective analysis, We report our experience in 42 patients. using corticocancellous bone grafts and lag screw fixation for un-united scaphoid fractures. Using a grading system. we analysed the suitability of the method for three types of nonunion. We recommend the operation for the treatment of scaphoid nonunion. except where there is avascular necrosis of the proximal pole.
Denatured muscle grafts for nerve repair. An experimental model of nerve damage in leprosy, About 20% of patients with leprosy develop localised granulomatous lesions in peripheral nerves. We report experiments in guinea-pigs in which freeze-thawed autogenous muscle grafts were used for the treatment of such mycobacterial granulomas. Granulomas were induced in guinea-pig tibial nerves and the animals were left for 7 to 100 days in order to assess maximal damage. The local area of nerve damage was then excised and the gap filled with denatured muscle grafts. Clinical assessment after periods up to 150 days showed good sensory and motor recovery which correlated well with the histological findings. The muscle graft technique may be of value for the treatment of chronic nerve lesions in selected cases of leprosy.
Extensor indicis proprius transfer for rupture of the extensor pollicis longus tendon, We reviewed 21 patients with 22 ruptures of the extensor pollicis longus at a mean of 5.3 years after transfer of the extensor indicis proprius tendon. Of these. 19 with 21 transfers described the result as good. and two as fair. The mean deficit of extension between the operated and unoperated thumbs was 1.4 cm. and the mean flexion deficit 0.6 cm. Pressure gauge measurements showed that the strength of the transfer was 51% of that of the uninjured extensor. The two fair results had an extensor lag of over 1.5 cm. Independent extension of the index was maintained in all patients. none having a discernible lag. but the strength of index extension was reduced to 49% of that of the normal finger. There was no evidence of functional loss. Extensor indicis proprius transfer for rupture of the extensor pollicis longus tendon is a simple and reliable procedure with few complications. It gives satisfactory long-term extension of the thumb.
Open transpedicular biopsy of the vertebral body, We describe a method of obtaining a biopsy from the body of a vertebra by an open transpedicular route. This minimises the danger of contamination of tissue planes and spaces.
Long-term prognosis of soft-tissue injuries of the neck, We reviewed 43 patients who had sustained soft-tissue injuries of the neck after a mean 10.8 years. Of these. only 12% had recovered completely. Residual symptoms were intrusive in 28% and severe in 12%. Pain in the neck and lower back was the commonest complaint and older patients had a worse prognosis. After two years. symptoms did not alter with further passage of time.
Radiographic appearances in lumbar disc prolapse, The pre-operative lumbar spine radiographs of 200 consecutive patients who had undergone discectomy for prolapsed intervertebral disc were reviewed. Prolapse was recognized as bulging or sequestration of the disc with consequent root compromise. Measurement of the lumbar level of the interiliac line was shown to correlate with the level of disc prolapse and the incidence of transitional vertebrae at the lumbosacral junction was significantly higher than normal. A pathological value for the lumbosacral angle could not be identified.
Current results of elective aortic reconstruction for aneurysmal and occlusive disease, Decisions to resect small aortic aneurysms or employ non-operative treatment for aorto-iliac occlusive disease must depend on current rather than historical surgical results. To assess current morbidity and mortality. we reviewed 200 consecutive aortic resections in two groups of patients treated from 1981 to 1989: those undergoing elective aortofemoral bypass for occlusive disease (AFB. no. 100) or resection of infrarenal abdominal aortic aneurysms (AAA. no. 100). Indications for AFB included claudication (54%). rest pain (32%). and gangrene (13%). AAA size ranged from 3 to 14 cm (mean 6.5 +/- 2.4 cm); 45% presented with abdominal or back pain. Patients undergoing AFB were younger (AFB 61.5 +/- 10 years vs AAA 68.7 +/- 8.9 years) with a higher incidence of some atherosclerotic risk factors. diabetes mellitus 30% vs 10%. tobacco use 77% vs 49%. hyperlipidemia 21% vs 7%; p less than 0.001). Coronary artery disease (CAD) was more prevalent in AAA patients (49% vs 34%; p less than 0.001). Postoperative mortality was not different in occlusive or aneurysmal disease (3% AFB vs 2% AAA). nor was the occurrence of serious complications such as myocardial infarction (2% vs 1%) or pulmonary embolism (2% vs 3%). Improvements in patient selection. perioperative care and surgical technique have lowered the mortality of elective aortic surgery. Given the current standard of care. an aggressive approach to AAA even in high risk patients is appropriate. The low morbidity of AFB for occlusive disease mandates a critical appraisal of less effective nonoperative therapies.
Synchronous reconstruction for combined aortoiliac and femoropopliteal occlusive lesions. The role of proximal bypass, Between January 1984 and December 1986. 31 patients underwent synchronous revascularization (SR) because of the serious clinical condition of a lower limb and presence of arteriographically visible lesions. Average follow-up was 30 months. Operative mortality was 10%. Two patient populations were identified: Group I (N = 13): patients who underwent ilio-femoral or aorto-femoral proximal revascularization (PR); Group II (N = 18): patients who had axillo-femoral PR. Group I patients were younger than those in Group II (64 yr versus 72 yr; p less than 0.01). An association of pre-operative risk factors (arterial hypertension; coronary. renal or respiratory insufficiency) was twice as frequent in Group II as in Group I (p less than 0.02). The rate of SR compared to PR alone was 15%. However. there was no statistically significant difference between Groups I and II. Comparison of the actuarial survival curves for patients ahd the patency rates of SR in Groups I and II failed to reveal any statistically significant differences. Axillo-femoral bypass can be used for PR when SR is necessary in high risk patients.
Selection of antibiotic coverage in vascular patients undergoing cystoscopy, Bacteremic seeding of prosthetic vascular grafts represents a cause for graft infection; transurethral procedures account for one source of bacteremia. Therefore. a prospective study of 200 patients undergoing cystoscopy was conducted to identify the incidence of bacteruria and factors associated with it. organisms involved and their antibiotic sensitivities. Positive cultures were found in 21%. The incidence was 64% in in-patients and 8% in out-patients. Positive cultures were found in 12% of patients who received antibiotics and 29% who did not. Four percent showed signs of bacteremia. The cultures identified both Gram positive and negative organisms; multiple organisms grew in 22%. Gram negative organisms were more common in in-patients. Candida grew in 8%. The Gram positive organisms were sensitive to ampicillin (92%). sulfatrimethoprim (75%) and cefazolin (60%); Gram negative to aminoglycosides (100%) and cefazolin (92%). In view of the unpredictable and multiple organisms. it is recommended that pre-cystoscopy cultures be performed and specific antibiotic coverage be based on the sensitivities.
Primary repair for complete atrioventricular canal: recommendation for early primary repair, Forty patients with complete atrioventricular canal (CAVC) underwent primary repair at Fukuoka Children's Hospital in Fukuoka. Japan. between August 1. 1981 and July 31. 1989. The age at repair ranged from 2 months to 6 years (mean 19 months); weight ranged from 2.3 to 22 kg. The surgical mortality was 2.5%. Justification for early primary repair was examined. Eleven patients underwent repair before 6 months of age (Group 1). 12 patients. between 7 and 11 months of age (Group 2). and 17 patients. after 12 months of age (Group 3). Degenerative changes in the atrioventricular valve increased significantly as age at repair increased (p less than 0.05 Group 1 versus Group 3). The incidence of residual mitral regurgitation tended to increase in the order of Group 1. 2 and 3. though the degree ranged from trivial to mild. Study of the left atrium/aorta ratio by echocardiography revealed that stable values of around 1.1 in Groups 1 and 2 and around 1.3 in Group 3 continued during the follow-up period of 3 years. Assessment of the diameter of the repaired mitral valve in the mean interval of 26 months in groups 1 and 2 revealed normal growth of the mitral valve annulus. The angle between the repaired mitral valve and ventricular septum. which can be affected by the growth of the ventricular septum. converged to normal range in the mean interval of 26 months. Postoperative pulmonary vascular resistance in Groups 2 and 3 was higher at 4.4 +/- 2.3 and 6.3 +/- 2.2. respectively. than in Group 1 at 3.3 +/- 2.2 (p less than 0.01 versus Group 3).
Perioperative myocardial injury in patients undergoing aortic valve replacement, In cases of myocardial hypertrophy myocardial protection may be insufficient. In order to determine the factors responsible for myocardial injury we assessed myocardial injury in 54 patients undergoing isolated aortic valve replacement. In all cases hypothermic cardioplegic arrest was induced. At 13 different times we measured the serum level of creatine-kinase (CK). myocardial bound creatine-kinase (CKmb). lactic dehydrogenase (LDH). alpha-hydroxybutyrate dehydrogenase (alpha-HBDH). glutamic oxaloacetic transferase (GOT) and myoglobin. The mean duration of ischemia was 52.6 +/- 16.2 minutes and the mean time of extracorporeal circulation was 85.85 +/- 20.25 minutes. By performance of a multiple regression analysis a significant correlation between ischemia and LDH and alpha-HBDH was found; CK. GOT. LDH and alpha-HBDH correlated with duration of extracorporeal circulation. In none of the patients was a low cardiac output syndrome observed. From our results we conclude that in our study myocardial protection was sufficient and therefore the detrimental effects of extracorporeal circulation were the determining factors of enzyme release.
Blunt traumatic pericardial rupture. A ten-year experience 1979 to 1989, Blunt traumatic pericardial rupture is rarely diagnosed preoperatively and is associated with high mortality. During a ten-year period from 1979 to 1989 over 20.000 patients were admitted to a major trauma center and 22 were found to have blunt traumatic pericardial rupture. Sixteen of the 22 (72.7%) were injured in vehicle accidents. 3 (13.6%) in motorcycle crashes. and 2 (9.1%) in falls; 1 (4.5%) was crushed. Eighteen (81.8%) were diagnosed intraoperatively during resuscitation or surgery for associated injuries. and four (18.1%) were diagnosed preoperatively with pericardial window. Eighteen were males and four were females. The median age was 40.14 years (range. 17 to 68). The tears were found at the following sites: left pleuropericardial (14/22 [64%]). diaphragmatic (4/22 [18%]). right pleuropericardial (2/22 [9%]). and superior mediastinal (2/22 [9%]). Associated cardiac injuries were found in only 5 of the 22 (22.7%); all of those patients died. The overall mortality rate was 63.6% (14/22). A high index of suspicion should alert the trauma surgeon to make the diagnosis intraoperatively during emergency surgical resuscitation in the hemodynamically unstable patient and by pericardial window in the stable patient.
Right coronary artery injury during tricuspid valve annuloplasty, An unusual complication after tricuspid valve annuloplasty is described where a ring suture ligated right coronary artery and precipitated myocardial infarct and patient death. The need for caution to prevent this complication with such surgery is emphasized.
Left ventricular fibroma: echocardiographic diagnosis and successful surgical excision in three cases, The management of three patients with left ventricular fibromas is outlined. All were asymptomatic children. Routine chest radiography suggested cardiac masses. M-mode and two-dimensional echocardiography were valuable adjuncts to conventional angiography in assessing these children. Electrocardiographic changes. present in all cases. were shown to regress postoperatively. We stress the importance of these noninvasive aids in the initial investigation and outline our operative methods of reconstruction.
Amyloidosis in saphenous vein aortocoronary bypass grafts, A patient in whom idiopathic amyloidosis of aortocoronary saphenous vein grafts was found at autopsy two years after myocardial revascularization due to coronary atherosclerosis is reported. Idiopathic generalized immunocyte derived amyloidosis extensively studied at autopsy was obviously present at the time of surgery although it remained unnoticed macroscopically in the inserted graft. It appears that simultaneously with arterialization further deposition and also significant redistribution of amyloid within the walls of the vein grafts additionally took place after their insertion. It seems interesting that in spite of the amyloidosis the grafts functioned well and were found patent two years after surgery.
Hyponatremia in rats induces downregulation of vasopressin synthesis, Hyponatremia due to inappropriate secretion of vasopressin is a common disorder in human pathophysiology. but vasopressin synthesis during hypoosmolality has not been investigated. We used a new method to quantitate synthesis of vasopressin in rats after 3. 7. and 14 d of hyponatremia induced by administering dDAVP (a vasopressin agonist) and a liquid diet. Vasopressin synthesis was completely turned off by 7 d. Vasopressin mRNA levels in the hypothalamus paralleled the reduction in synthesis and were reduced to levels of only 10-15% of the content in control rats. When hyponatremia was corrected by withdrawal of dDAVP. vasopressin mRNA slowly returned to normal over 7 d. The observation that vasopressin synthesis can be so completely turned off leads to several conclusions: under normal physiological conditions the neurohypophysis is chronically upregulated; there must be an osmotic threshold for initiation of vasopressin synthesis (and release); the large store of hormone in the posterior pituitary is essential for vasopressin to be available during times of decreased synthesis; and. finally. some nonosmolar stimulus for synthesis must be present during clinical disorders when vasopressin is secreted (and synthesized) despite hypoosmolality.
Possible role of bacterial siderophores in inflammation. Iron bound to the Pseudomonas siderophore pyochelin can function as a hydroxyl radical catalyst, Tissue injury has been linked to neutrophil associated hydroxyl radical (.OH) generation. a process that requires an exogenous transition metal catalyst such as iron. In vivo most iron is bound in a noncatalytic form. To obtain iron required for growth. many bacteria secrete iron chelators (siderophores). Since Pseudomonas aeruginosa infections are associated with considerable tissue destruction. we examined whether iron bound to the Pseudomonas siderophores pyochelin (PCH) and pyoverdin (PVD) could act as .OH catalysts. Purified PCH and PVD were iron loaded (Fe-PCH. Fe-PVD) and added to a hypoxanthine/xanthine oxidase superoxide- (.O2-) and hydrogen peroxide (H2O2)-generating system. Evidence for .OH generation was then sought using two different spin-trapping agents (5.5 dimethyl-pyrroline-1-oxide or N-t-butyl-alpha-phenylnitrone). as well as the deoxyribose oxidation assay. Regardless of methodology. .OH generation was detected in the presence of Fe-PCH but not Fe-PVD. Inhibition of the process by catalase and/or SOD suggested .OH formation with Fe-PCH occurred via the Haber-Weiss reaction. Similar results were obtained when stimulated neutrophils were used as the source of .O2- and H2O2. Addition of Fe-PCH but not Fe-PVD to stimulated neutrophils yielded .OH as detected by the above assay systems. Since PCH and PVD bind ferric (Fe3+) but not ferrous (Fe2+) iron. .OH catalysis with Fe-PCH would likely involve .O2(-)-mediated reduction of Fe3+ to Fe2+ with subsequent release of "free" Fe2+. This was confirmed by measuring formation of the Fe2(+)-ferrozine complex after exposure of Fe-PCH. but not Fe-PVD. to enzymatically generated .O2-. These data show that Fe-PCH. but not Fe-PVD. is capable of catalyzing generation of .OH. Such a process could represent as yet another mechanism of tissue injury at sites of infection with P. aeruginosa.
Synergism between hepatic injuries and a nonhepatotropic reovirus in mice. Enhanced hepatic infection and death, Reovirus type 1. after intravenous inoculation in the adult mouse. is secreted via bile into the intestine in an infectious form. Although reovirus type 1 is rapidly removed from systemic circulation by the liver and the lung. very few hepatocytes express reovirus antigen during infection. In intestinal cells. reovirus replicates selectively in the crypts. This site preference may be due to active cell proliferation in the crypts. We hypothesized that the state of the cell may affect virus replication and tested this hypothesis by using chemical and surgical means to increase hepatic mitotic activity. Adult mice were treated with carbon tetrachloride or surgical trauma. inoculated with reovirus type 1 intravenously. and subsequently killed. Virus antigen was identified using a highly specific immunohistochemical technique. Liver sections were stained using immunoperoxidase with specific rabbit antireovirus antibody. Hepatotoxin and surgical trauma increase reovirus antigen detection in both Kupffer cells and hepatocytes. Only the sequential administration of CCl4 and virus caused mortality at doses sublethal for each alone. These data demonstrate a synergism between hepatic injury and reovirus which results in a significant increase in the magnitude of viral infection and contributes to mortality. Such synergism may be important in idiopathic liver disease.
Relationship between the content of lysyl oxidase-dependent cross-links in skin collagen, nonenzymatic glycosylation, and long-term complications in type I diabetes mellitus, Many abnormalities in collagen have been reported in insulin-dependent diabetes mellitus. some or all of which have been attributed to increased cross-linking. Although recent work has focused on the role of glucose-derived collagen cross-links in the pathogenesis of diabetic complications. relatively few studies have investigated the role of lysyl oxidase-dependent (LOX) cross-links. In the present study. LOX cross-links and nonenzymatic glycosylation were quantified in skin collagen from diabetic subjects. There was an increase in the difunctional cross-link dihydroxylysinonorleucine (DHLNL) as well as in one of its trifunctional maturation products. hydroxypyridinium. All other LOX crosslinks were normal. Nonenzymatic glycosylation was increased in diabetic skin collagen. and this increase was correlated with increases in DHLNL (P less than 0.001). The biochemical results were examined for correlations with clinical data from the same subjects. Increases in DHLNL content were associated with duration of diabetes (P less than 0.003). glycohemoglobin levels (P less than 0.001). hand contractures (P less than 0.05). skin changes (P less than 0.005). and microalbuminuria (P less than 0.01). In nondiabetic subjects age was not correlated with collagen cross-link content with the exception that his-HLNL increased with age (r = 0.79. P less than 0.02). In diabetic subjects. PA levels decreased with age (r = 0.51. P less than 0.02). With increased duration of diabetes. DHLNL content was increased (r = 0.55. P less than 0.003) and OHP was increased (r = 0.59. P less than 0.01). whereas PA levels were decreased (r = -0.48. P less than 0.04). Nonenzymatic glycosylation of collagen was also increased with increased duration of diabetes (hex-lys. r = 0.47. P less than 0.02; hex-hyl. r = 0.39. P less than 0.05). We conclude that: (a) lysyl oxidase-dependent cross-linking is increased in skin collagen in diabetes and (b) that these changes in skin collagen are correlated with duration of diabetes. glycemic control. and long-term complications.
Platelet-derived growth factor in idiopathic pulmonary fibrosis, Fibrosis is a complex process involving an inflammatory reaction. fibroblast proliferation. and abnormal accumulation of interstitial collagens. Mononuclear cells are usually present in lung fibrosis. Activated monocytes and macrophages in culture have been shown to produce several growth factors including platelet-derived growth factor (PDGF). PDGF is a potent mitogen and chemoattractant for fibroblasts and smooth muscle cells and a stimulator of collagen synthesis. We have studied the expression of c-sis/PDGF-2 mRNA in lung tissues derived from five patients with idiopathic pulmonary fibrosis (IPF) and from four control individuals without IPF. Northern blot analysis of specimens obtained from four patients with IPF revealed the expression of the c-sis/PDGF-2 protooncogene. A control lung tissue without IPF did not express the c-sis protooncogene. In situ hybridization extended these studies demonstrating the expression of the c-sis mRNA in the five specimens with IPF but not in the four control specimens without IPF. The expression of c-sis mRNA was localized primarily in the epithelial cells. Invading alveolar macrophages also expressed c-sis mRNA. The expression of c-sis mRNA was accompanied by the expression of PDGF-like proteins in lung specimens with IPF but not in control lung specimens. These findings demonstrate the in vivo expression of the c-sis/PDGF-2 protooncogene and the production of PDGF-like proteins in the epithelial cells and macrophages of the fibrotic tissue. This localized and sustained production of PDGF-like mitogen may constitute an important contributing factor in the abnormal fibroblast proliferation and collagen production. events associated with pulmonary fibrosis.
Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism, Preproparathyroid hormone (preproPTH) gene mutation has been proposed as a cause of familial isolated hypoparathyroidism (FIH). We cloned the preproPTH alleles of a patient with autosomal dominant FIH and sequenced the coding regions. 5' flanking regions. and splice junctions. The putatively abnormal (based on previous linkage studies) allele differed from the other allele's normal sequence at only one nucleotide. This T to C point mutation changes the codon for position 18 of the 31 amino acid prepro sequence from cysteine to arginine. disrupting the hydrophobic core of the signal sequence. Because the hydrophobic core is required by secreted proteins for efficient translocation across the endoplasmic reticulum. the mutant protein is likely to be inefficiently processed. Indeed. in vitro studies demonstrated dramatically impaired processing of the mutant preproPTH to proPTH. In summary. we observed a point mutation in the signal peptide-encoding region of a preproPTH gene in one FIH kindred and demonstrated a functional defect caused by the mutation. Mutation of the signal sequence constitutes a novel pathophysiologic mechanism in man. and further study may yield important insights both into this form of hormone deficiency and into the role of signal sequences in human physiology.
Modulation of interleukin-1 beta RNA in monocytic cells infected with human immunodeficiency virus-1, The effect of HIV-1 infection on cytokine levels was studied in monocytic cells by using Northern blotting analysis. Monoblasts (THP-1. U937) did not express IL-1 beta RNA even if the cells were infected with HIV-1. After exposure to LPS (10 micrograms/ml) and 12-O-tetradecanoylphorbol-13-acetate (TPA. 100 nM) for 12 h. these HIV-1-infected monoblasts accumulated 8-15-fold greater levels of IL-1 beta RNA as compared with their HIV-1-uninfected counterparts that were similarly stimulated. In contrast. levels of RNAs coding for monocyte-colony-stimulating factor (M-CSF) and tumor necrosis factor-alpha (TNF alpha) were elevated less than twofold in the HIV-1-infected cells as compared with HIV-1-uninfected cells after their stimulation with LPS and TPA. Inhibition of new protein synthesis did not block the marked accumulation of IL-1 beta RNA produced by exposure to LPS and TPA in the HIV-1-infected cells. Time-course experiments showed that the maximal levels of IL-1 beta RNA occurred at 12 and 24 h after LPS and TPA stimulation of the HIV-1-infected and uninfected U937 cells. respectively. Studies of stability of RNA using actinomycin D showed that IL-1 beta RNA was equally stable in infected and uninfected U937 cells after their stimulation with TPA and LPS. Taken together. our data show that HIV-1 infection markedly augments IL-1 beta RNA accumulation in stimulated monocytic cells. probably through increasing rate of transcription of IL-1 beta.
Activation pathways of synovial T lymphocytes. Expression and function of the UM4D4/CDw60 antigen, Accumulating evidence implicates a central role for synovial T cells in the pathogenesis of rheumatoid arthritis. but the activation pathways that drive proliferation and effector function of these cells are not known. We have recently generated a novel monoclonal antibody against a rheumatoid synovial T cell line that recognizes an antigen termed UM4D4 (CDw60). This antigen is expressed on a minority of peripheral blood T cells. and represents the surface component of a distinct pathway of human T cell activation. The current studies were performed to examine the expression and function of UM4D4 on T cells obtained from synovial fluid and synovial membranes of patients with rheumatoid arthritis and other forms of inflammatory joint disease. The UM4D4 antigen is expressed at high surface density on about three-fourths of synovial fluid T cells and on a small subset of synovial fluid natural killer cells; in synovial tissue it is present on more than 90% of T cells in lymphoid aggregates. and on approximately 50% of T cells in stromal infiltrates In addition. UM4D4 is expressed in synovial tissue on a previously undescribed population of HLA-DR/DP-negative non-T cells with a dendritic morphology. Anti-UM4D4 was co-mitogenic for both RA and non-RA synovial fluid mononuclear cells. and induced IL-2 receptor expression. The UM4D4/CDw60 antigen may represent a functional activation pathway for synovial compartment T cells. which could play an important role in the pathogenesis of inflammatory arthritis.
Polyclonal B cell activation in lupus-prone mice precedes and predicts the development of autoimmune disease, Polyclonal B cell activation is an early feature of autoimmune disease in humans and mice with systemic lupus erythematosus. The contribution of polyclonal activation to the progression of autoimmunity is unclear. however. since it precedes the development of end-organ damage by months or years. To examine this issue. 109 autoimmune-prone (NZB X NZW)F1 X NZB backcross mice were hemi-splenectomized at 10 wk and the number and antigenic specificity of their Ig-secreting B cells quantitated by ELISA spot assay. Of the 61 mice that had polyclonally increased numbers of Ig-secreting cells/spleen. 31 died by 6 mo. In contrast. 0/48 backcross mice with normal numbers of Ig-secreting B cells at 10 wk died over the same period (P less than 0.001). Polyclonally activated mice also developed proteinuria earlier and more frequently than littermates with normal numbers of Ig-secreting cells (P less than 0.001). As adults. backcross mice with proteinuria expressed repertoires skewed towards the production of anti-DNA antibodies. At 10 wk these same mice expressed repertoires marked by polyclonal activation rather than preferential anti-DNA production. These findings indicate that autoimmune disease in SLE is accompanied by the autoantigen-driven production of autoantibodies but is preceded and predicted by polyclonal B cell activation.
Chylomicron remnant clearance from the plasma is normal in familial hypercholesterolemic homozygotes with defined receptor defects, The retinyl palmitate fat tolerance test was used to measure chylomicron remnant clearance in 10 normal subjects (apolipoprotein E [apo E] isotypes 3 or 4 only). 6 normolipidemic apo E2/2 homozygotes and 5 familial hypercholesterolemic homozygotes. Skin fibroblasts with fully upregulated LDL receptors from the latter subjects degraded rabbit 125I-beta VLDL in vitro at rates ranging from less than 10-48% of normal. Experiments in vivo revealed no significant differences between the normal and homozygous familial hypercholesterolemic (FHH) subjects in chylomicron remnant clearance assessed on the basis of "areas under the curves" for retinyl palmitate levels present in post-prandial serum. chylomicron remnants (Sf. less than 1.000). or chylomicrons (Sf. greater than 1.000). Remnant clearance was greatly decreased at all times in the apo E2/2 homozygotes. indicative of an important degree of flux control exerted by a receptor-mediated step involving apo E as ligand. The absence of any excess remnant accumulation in FHH subjects with varying "impairment" of LDL receptor-mediated degradation of apo E-containing lipoproteins. permits the conclusion that chylomicron remnants are initially cleared from the plasma by apo E-recognizing receptors which are genetically distinct from LDL receptors.
Regulation of parathyroid hormone gene expression by hypocalcemia, hypercalcemia, and vitamin D in the rat, In vivo in the rat 1.25(OH)2D3 decreases and a low calcium increases PTH mRNA levels. We now report the effect of 3 and 8 wk of changes in dietary vitamin D and calcium on PTH mRNA levels. PTH mRNA levels were increased by 3 wk of calcium deficiency (five times). a vitamin D-deficient diet (two times). and combined deficiency (10 times). but not changed by high calcium. Vitamin D-deficient-diet rats' PTH mRNA did not decrease after a single large dose of 1.25(OH)2D3. but did decrease partially after repeated daily doses of 1.25(OH)2D3. Rats after a vitamin D-. calcium-deficient (-D-Ca) diet did not respond to changes in serum calcium at 1 h. Flow cytometry of isolated cells from parathyroid-thyroid tissue separated the smaller parathyroid from the larger thyroid cells and allowed an analysis of parathyroid cell number. In normal vitamin D/normal calcium (NDNCa) rats the parathyroid cells were 24.7 +/- 3.4% (n = 6) of the total cell number. whereas in -D-Ca rats they were 41.8 +/- 6.6% (n = 6) (P less than 0.05). That is. -D-Ca rats had 1.7 times the number of cells. whereas they had 10 times the amount of PTH mRNA. indicating the major contribution (6 times) of increased PTH gene expression per cell. Moreover. a calcium-deficient. more so than a vitamin D-deficient diet. amplifies the expression of the PTH gene. and vitamin D is necessary for an intact response of PTH mRNA to 1.25(OH)2D3 or calcium.
An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels, A polymorphism consisting of the presence or absence of a 250-bp DNA fragment was detected within the angiotensin I-converting enzyme gene (ACE) using the endothelial ACE cDNA probe. This polymorphism was used as a marker genotype in a study involving 80 healthy subjects. whose serum ACE levels were concomitantly measured. Allele frequencies were 0.6 for the shorter allele and 0.4 for the longer allele. A marked difference in serum ACE levels was observed between subjects in each of the three ACE genotype classes. Serum immunoreactive ACE concentrations were. respectively. 299.3 +/- 49. 392.6 +/- 66.8. and 494.1 +/- 88.3 micrograms/liter. for homozygotes with the longer allele (n = 14). and heterozygotes (n = 37) and homozygotes (n = 29) with the shorter allele. The insertion/deletion polymorphism accounted for 47% of the total phenotypic variance of serum ACE. showing that the ACE gene locus is the major locus that determines serum ACE concentration. Concomitant determination of the ACE genotype will improve discrimination between normal and abnormal serum ACE values by allowing comparison with a more appropriate reference interval.
Failure of T cell receptor-anti-CD3 monoclonal antibody interaction in T cells from marrow recipients to induce increases in intracellular ionized calcium, There are multiple immune defects in T cells from recipients after bone marrow transplantation (BMT). This study examines recipient T cells for increases in intracellular ionized calcium concentration [( Ca2+]i) after binding the T cell receptor-CD3 complex with anti-CD3 MAb. PBL from 10 of 23 short-term recipients (less than 1 yr after BMT) responded poorly (less than 35% of control) to anti-CD3 stimulation and PBL from 9 of 23 had blunted calcium flux responses (35-70% of control). Purified CD2+. CD56- cells from seven additional short-term recipients including three autologous marrow recipients were closely examined. and a sizable proportion of CD3+ cells from six of seven recipients did not increase [Ca2+]i after anti-CD3 stimulation. The decreased magnitude of the responses was due to decreased numbers of responding cells and not to a decrease in mean CD3 fluorescent intensity or in calcium flux responses on a single cell basis. Five of seven long-term recipients (greater than 1 yr after BMT) had PBL that responded normally and two of seven had PBL with blunted calcium flux responses. The data show that the signal transduction response mediated by the CD3-antigen receptor as measured by calcium flux is defective early after autologus or allogeneic BMT.
Upper gastrointestinal pathology in familial adenomatous polyposis: results from a prospective study of 102 patients, Multiple gastric and duodenal biopsy specimens from 102 asymptomatic patients with familial adenomatous polyposis. taken during a prospective endoscopic screening programme were examined. One hundred patients had microscopic gastroduodenal pathology. often in the absence of macroscopic lesions. Adenomas were found in 94 patients in the duodenum. in the second and third parts. Hyperplasia of villous and crypt epithelium was also seen. sometimes in the absence of adenomas: this may be a precursor of neoplastic change. In the stomach fundic gland polyps were the commonest abnormality. seen microscopically in 44 patients. Chronic antral gastritis was common in patients without fundic polyps. Gastric adenomas were present in six patients. all of whom also had duodenal adenomas. If duodenal adenomas in familial adenomatous polyposis have a similar malignant potential to those in the colorectum sequential endoscopy and biopsy are necessary to detect cancer in these patients.
Immunohistochemical detection of abnormal cell proliferation in colonic mucosa of subjects with polyps, Previous studies have shown the presence of increased proliferation in the large bowel epithelium of those at high risk of developing colon cancer. An in vitro technique for labelling large bowel mucosa with the thymidine analogue bromodeoxyuridine (Brdu) was therefore developed and its ability to distinguish differences in mucosal proliferation between subjects with colorectal adenomas and normal controls was assessed. Sigmoid biopsy specimens from 15 subjects with polyps and 15 age and sex matched controls were labelled and the incorporated Brdu visualised with an immunohistochemical technique. Mean labelling index (LI) was significantly higher in those with polyps than in controls. Differences in the pattern of labelling in colonic crypts were compared by the generation of cumulative labelling distributions. Analysis showed a significant expansion of the proliferative compartment in the colon crypts of those with polyps. It is concluded that in vitro labelling with Brdu provides a useful method for the assessment of mucosal proliferation in subjects at high risk of developing colon cancer.
Multiple breakpoint method for measuring effect of antibiotics on endocarditis strains of streptococci, The activity of penicillin alone and combined with aminoglycoside on endocarditis strains of streptococci was examined. Good assay reproducibility was obtained by the use of logarithmic phase cultures standardised by opacity. careful inoculation of well-plates. removal of antibiotic by membrane transfer and incubating survival counts in hydrogen plus carbon dioxide. The use of 10-fold intervals for penicillin concentration simplified assay design without loss of efficiency.
Cultured epidermal autografts and allografts: a study of differentiation and allograft survival, Cultured epidermal sheets were examined before and at various times after grafting on skin ulcer beds. Before grafting. the sheet consisted of four to five layers of keratinocytes with incomplete differentiation. Ten days after grafting. graft recipient sites showed compact hyperkeratosis. a normal-appearing epidermis. and a flat dermoepidermal junction. At 6 months. the stratum corneum had a basket-weave appearance but the dermoepidermal junction remained flat. Monoclonal antibodies to keratins 14 and 10 showed normal basal and suprabasal localization. respectively. Electron microscopy showed a normal basement membrane with anchoring fibrils. LH7:2. a monoclonal antibody that binds to the type VII collagen molecule. stained the dermoepidermal junction in all biopsy specimens. AE-1. an antibody that stains suprabasal cells in hyperproliferative skin. was expressed suprabasally for up to 12 weeks after healing (16 weeks after grafting). but expression was confined to the basal layer at 18 weeks after healing (6 months after grafting). Anti-involucrin staining was found in the deeper layers of the epidermis up to 12 weeks after healing (16 weeks after grafting) but had receded to a normal distribution in upper spinous and granular layers at 18 weeks (6 months after grafting). Overall. the histologic patterns observed in recipient sites during the first 4 months after grafting resembled those observed for 10 to 14 days in newly healed epidermis and in hyperproliferative states such as psoriasis. In four sex-mismatched graft sites. specimens were reacted with a biotinylated probe to the Y chromosome by in situ hybridization. Lack of Y chromosome-positive cells suggested that host keratinocytes had replaced the allografts. Multilocus DNA analysis in one patient confirmed this observation. Our data suggest that an altered state of epithelial maturation persists for several months after culture grafting. with restoration of the normal pattern by 6 months. No differences were detected between autografted and allografted sites.
Condylomata acuminata in children: frequent association with human papillomaviruses responsible for cutaneous warts, To identify the papillomavirus types associated with condylomata acuminata in children and to evaluate their mode of transmission. we studied 32 children with anogenital warts. External condylomata were found in 12 of their mothers and in 10 of their fathers. Ten mothers. including two without external lesions. had cervical condylomata. Blot hybridization studies disclosed a genital human papillomavirus (HPV) in 14 of 27 children (HPV-6 in 12 and HPV-11 in two) and in 8 of 14 patients (HPV-6 in all). HPV-6 was found in another child by the polymerase chain reaction technique. Infection occurred most likely at birth or from nonsexual contact. but sexual abuse could not be excluded in one 11-year-old girl. Cutaneous HPV-2 was found in seven children and as yet uncharacterized papillomaviruses were found in two children. Three mothers of HPV-2-infected children had common hand warts. and two children had subungual warts. This study shows the frequent nonsexual transmission of genital papillomaviruses in children and the unexpectedly high association of children's condylomata with papillomaviruses responsible for skin warts. possibly transmitted by heteroinoculation or autoinoculation.
Activation and inducer subset phenotype of the lymphocytic infiltrate around epidermally derived tumors, An in situ analysis of the mononuclear cell infiltrate found in association with a range of benign. premalignant. and malignant epidermal tumors is described. The predominant cell phenotype was that of the recently described immunoregulatory helper/inducer T lymphocyte. A large number of lymphocytes expressed antigens associated with cellular activation. suggesting an ongoing immunologic response by the host against the tumor. although evidence of in situ proliferation of these cells was lacking. These findings suggest that the infiltrate found in association with cutaneous tumors does not represent passive accumulation of lymphocytes from the circulation but rather an active antitumor response.
Benign lymphangioendothelioma, We have studied eight cases of an acquired lymphatic endothelial lesion for which we propose the name "benign lymphangioendothelioma." The lesions developed as solitary. slowly extending. erythematous macules and plaques. usually occurring on the extremities or the shoulders in adolescents or adults. The characteristic histopathologic feature is permeation of the dermal collagen by flattened. endothelium-lined channels and spaces. Hemorrhage. iron deposition. and inflammation were not part of the lesion. Ulex europaeus agglutinin I labeled the lesional endothelial cells consistently. but factor VIII-related antigen labeling was negative. This histologic pattern and the special studies suggested a lymphatic lesion. Surgical excision. performed in six patients. was not followed by recurrence.
Localized hyperhidrosis in pretibial myxedema, Two cases of spontaneous hyperhidrosis limited to pretibial myxedema lesions were studied. Quantitative measurements of stimulated eccrine sweat were made after the intradermal injection of methacholine. The sweat rate was two to four times greater in the lesional skin than in perilesional skin. Eccrine secretory glands in excisional biopsy specimens from the pretibial lesions were significantly larger than those in perilesional skin. To our knowledge. hyperhidrosis localized to areas of pretibial myxedema has not been reported.
Chilblains (perniosis), Unfamiliarity of physicians with chilblains (perniosis) gives rise to unnecessary hospital admissions with expensive laboratory and radiologic evaluations and. at times. hazardous therapy. Seven cases of chilblains were seen in San Francisco from November 1986 through January 1987. The patients presented with pruritic. at times painful. purple acral patches or plaques on the fingers. toes. and nose after exposure to a cool or a cold. damp environment. Histologic examination in two cases revealed a perivascular lymphocytic infiltrate with endothelial swelling of the subcutaneous fat and of the upper and lower dermal plexus.
Platelet activating factor-induced clinical and histopathologic responses in atopic skin and their modification by the platelet activating factor antagonist BN52063, The clinical and histopathologic responses to intradermal platelet-activating factor (PAF-acether) in atopic subjects. without evidence of atopic dermatitis are documented. An immediate acute wheal and flare reaction was observed in all volunteers. Histopathologically. the reaction was characterized by a predominantly neutrophilic response. which was seen at 30 minutes and was maximal at 4 hours. Eosinophils were observed in the infiltrate as early as 30 minutes after injection. and were maximal by 12 hours. The specific PAF-acether antagonist BN52063 antagonized the acute flare response to intradermal PAF-acether but had little effect on cellular recruitment at the site of injection.
Cutaneous surgery and the pregnant patient, Cutaneous surgery in 34 pregnant women is described. The main indication for surgery was the diagnosis and/or treatment of malignancy. Surgery during the period of organogenesis (15 to 56 days) should be avoided when possible. Patients should be positioned on the left side during the procedure to avoid the supine hypotensive syndrome. Monitoring of the fetal heartbeat is desirable. Local anesthetics. penicillin. and erythromycin are safe if used carefully. Acetaminophen is the analgesic of choice. Exposure to the sun should be avoided during the perioperative period.
Comparison of methods for checking surgical margins, Surgical margins of a cutaneous neoplasm can be evaluated by various combinations of three major types of sections: vertical (perpendicular). horizontal (parallel). and oblique (Mohs method). Vertical sections may run transversely through tumor (breadloaf method). longitudinally through tumor (breadloaf-cross method). or peripheral to the tumor. The peripheral (perimeter) sectioning methods are the only methods that can evaluate almost 100% of the margin. but they have the disadvantage of not showing the relationship of the tumor to its margin. which can be seen clearly with the vertical transverse sections. Seven methods of checking surgical margins are compared and contrasted. None of these is judged to be perfect or best.
Years of potential life lost: another indicator of the impact of cutaneous malignant melanoma on society, Years of potential life lost (YPLL) is an indicator of premature mortality that complements traditional incidence and mortality rates and that facilitates comparisons among different cancers. We calculated YPLL from cutaneous melanoma and 11 other cancers routinely recorded and tracked by Surveillance. Epidemiology and End Results (SEER). YPLL from cutaneous melanoma ranked eighth for persons younger than 65 years of age and fourth for those 20 to 49 years of age. An average of 17.1 YPLL per death were due to melanoma. one of the highest rates for adult-onset cancers. The results of our study. the first to apply YPLL to cutaneous melanoma. emphasize the disproportionate impact of this cancer on young and middle-aged adults and reemphasize the importance of this cancer as a public health priority.
Trends in basal cell carcinoma, squamous cell carcinoma, and melanoma of the skin from 1973 through 1987, Major increases have occurred in the incidence of basal cell carcinoma and squamous cell carcinoma of the skin. as well as in cutaneous malignant melanoma during the period 1973 through 1987 in British Columbia. The greatest increases in basal and squamous cell carcinomas are on the head and neck. This indicates that exposure to sunlight is the major causative factor. The greatest increase in melanoma is on the trunk in men and on the lower limbs in women. The dramatic increases in nonmelanoma skin cancers in British Columbia. a relatively low sunlight area. suggest that major prevention programs are needed in areas that are not considered "sunspots.".
A method for the determination of UVA protection for normal skin, Although the UVB portion of the electromagnetic spectrum (290 to 320 nm) is responsible for most of the harmful effects of sunlight on the skin. wavelengths in the UVA region also contribute to photodamage. A simple and rapid clinical test. the sun protection factor determination. is available to assess the sunburn protective effect of a sunscreen. primarily a UVB effect. However. no practical test has been proposed to measure a sunscreen's UVA protection. We described a method for the calculation of UVA protection in normal subjects. The determination of UVA protection involves three steps: (1) the UV absorbance spectrum of the sunscreen on skin is determined spectrophotometrically; (2) a convolution spectrum is calculated by multiplying the solar spectrum with the Commission Internationale de l'Eclairage UV Hazard Spectrum; and (3) the sunscreen transmission spectrum is then incorporated into the convolution spectrum to obtain the UVA effectiveness ratio. which can be expressed as the UVA protection percentage. Because the UVA protection percentage value is based both on normal erythemic risk and on standard sunlight. the protection for any product can be easily measured. The procedure is simple. and values generated can be reproduced in other laboratories.
Treatment of hirsutism with the pure antiandrogen flutamide, The effectiveness of the antiandrogen flutamide in combination with an oral contraceptive was studied in 20 patients with moderate to severe hirsutism. Eight patients had no previous therapy. whereas 12 had failed to respond to oral contraceptives. spironolactone. or dexamethasone therapy. Treatment with the antiandrogen flutamide (250 mg twice daily) and an oral contraceptive (Ortho 1/35) resulted in a particularly rapid and marked decrease in the total hirsutism score. which reached the normal range at 7 months. Seborrhea. acne. and hair loss score were also rapidly corrected. Treatment was associated with a decrease in plasma luteinizing hormone. progesterone. and estradiol levels. Plasma sex hormone-binding globulin levels were initially low in 18 to 20 patients but increased significantly during therapy. No clinically significant side effects were observed.
Transdermal viprostol in the treatment of male pattern baldness, Fifty-seven men were randomly assigned for treatment of androgenetic alopecia with viprostol. vehicle. or placebo twice daily for 24 weeks. Nonvellus hair growth was assessed subjectively by both patient and investigator and objectively through hair counts from macrophotographs of the target area. Nonvellus target area hair counts declined in all three treatment groups at the end of the 6-month study. Viprostol is not an effective hair growth promoter in androgenetic alopecia.
Piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid, A photocontact dermatitis developed in three patients after the application of gel containing 0.5% piroxicam. Patch tests were positive to thiomersal and thiosalicylic acid. Photopatch tests with piroxicam at several concentrations were positive in the three patients but negative in 62 normal volunteer subjects. Patch tests performed on 14 patients with proved systemic photosensitivity to piroxicam were positive for thiomersal and thiosalicylic acid. Nine of 12 patients previously sensitized to thiosalicylic acid and with no history of exposure to piroxicam showed positive photopatch test reactions to this chemical. These results support a relation between piroxicam-induced photosensitivity and contact sensitivity to thiosalicylic acid. Contact allergic sensitivity to the latter is a marker for patients with a high risk of developing photosensitivity reactions to piroxicam. These reactions may be due to photoproducts of the drug rather than metabolites.
Treatment of fungal skin infections: state of the art, The number of cases of mycotic infections are increasing. presenting physicians today with an unprecedented challenge in handling the treatment and prophylactic control of these disorders. The increase in mycotic disorders is due to many factors. such as longer life span. organ transplantation. and the acquired immunodeficiency syndrome. The pharmaceutical industry is providing physicians with newer. more potent drugs to manage mycoses. An overview of current practice in the use of topical and oral agents. especially ketoconazole. are given in the following specific mycoses: tinea capitis. pityriasis versicolor. seborrheic dermatitis. Trichophyton rubrum infections. vaginal candidiasis. and moist intertriginous tineas. The efficacy of ketoconazole in various vehicles and dosage schedules and of traditional agents such as griseofulvin are discussed with relation to each of the mycoses.
Itraconazole in tinea versicolor: a review, Itraconazole. a new orally active triazole antifungal. has been tested in patients with pityriasis versicolor. A number of studies have shown that itraconazole is effective for this mild fungal skin disease. The total dose required for effective treatment is 1000 mg. and it has been given as 200 mg for 5 days or 7 days. The organisms disappear slowly from the skin. even when dead. and the results should be assessed clinically and mycologically at around 3 to 4 weeks after treatment. Numerous studies have shown that itraconazole is superior to placebo and as effective as selenium sulfide. clotrimazole. and ciclopirox olamine. It is also better tolerated by patients than selenium sulfide.
Itraconazole in common dermatophyte infections of the skin: fixed treatment schedules, Itraconazole is an effective medication against the most common dermatophytoses. It has been shown to be more active than griseofulvin and ketoconazole. Ease of use. affinity for keratinized tissues. lack of toxicity. continued activity after discontinuation. and the possibility of using fixed schedules are advantages of itraconazole. The fixed schedules indicated by pharmacokinetics and clinical studies are one 100 mg capsule daily for 15 days in cases of tinea corporis and tinea cruris and the same dosage for 30 days in cases of tinea pedis and tinea manuum. These fixed treatments have some limitations. and they are not recommended for treating tinea capitis and tinea unguium. The drug is well tolerated.
Itraconazole in the treatment of tinea capitis, Fifty patients with tinea capitis were treated with itraconazole. 25 to 100 mg/day. for 20 to 73 days in six countries. Forty-seven patients (94%) responded clinically (healed or markedly improved) to therapy. of which 38 patients (76%) completely healed and 9 patients (18%) markedly improved. Three patients (6%) failed therapy. Forty-two patients were assessable for mycologic examination; 38 patients (93%) converted mycologically to negative and 4 patients (7%) remained positive for organisms. In one group of 20 patients treated for 30 days. 6 patients were clinically and mycologically healed. By the 2-week follow-up visit 9 additional patients were healed. and 4 weeks after treatment all 20 patients were both clinically and mycologically healed. The primary organisms reported were Microsporum canis and Trichophyton tonsurans. Only one patient reported a possible side effect (tired legs). Laboratory values were all within normal limits. except for one patient who had a transient and slight increase in serum transaminase level. Low-dose itraconazole appears to be safe and effective in the treatment of tinea capitis.
Treatment of oral candidosis with itraconazole: a review, Oral candidosis is a common infection in infants. elderly persons. patients receiving immunosuppressive therapy. and patients with acquired immunodeficiency syndrome (AIDS). The orally active antifungal agent itraconazole has been evaluated in a number of different patient populations with oral and oropharyngeal candidosis. Initial studies have shown that itraconazole. 100 or 200 mg/day for 14 days. is more active than placebo in treating oral candidosis. A comparative study between itraconazole capsules (200 mg once daily) and clotrimazole troches (10 mg five times daily) showed equivalent results at the end of therapy but a significantly faster response to itraconazole and a faster relapse rate with clotrimazole. A study in AIDS patients with oropharyngeal candidosis demonstrated that itraconazole. 200 mg/day. and ketoconazole. 400 mg day. for 4 weeks give equivalent clinical cure rates and similar relapse rates. A pilot study with an oral solution of itraconazole has given an impressive 100% clinical and mycological response rate within 1 week of treatment. In conclusion. itraconazole in capsule or in solution form may constitute a major addition to the armamentarium of drugs against oropharyngeal candidosis.
Individualizing treatment of vaginal candidiasis, Clinicians have a vast array of effective antimycotics for the treatment of vaginal candidiasis. Multiple topical formulations are available. yet there is little evidence to suggest that formulation per se influences outcome. A growing number of highly effective oral systemic antimycotic agents provide the practitioner with additional options. Treatment regimens have also changed with the introduction of shorter. often single-day/single-dose courses of therapy. Not all therapeutic agents have the same activity against vaginal fungal pathogens in that topical azoles tend to be more active than nystatin. Differences in patient characteristics. however. are more important than the differences between antimycotic agents and therapeutic regimens in determining selection of the appropriate antimycotic. Patients with vaginal candidiasis vary with regard to duration and severity of symptoms and past frequency of attacks. distribution of inflammation. and pregnancy status. The clinician should consider all these variables both in selecting the appropriate antimycotic agent and the route of administration and in planning the duration of therapy. Individualized therapy offers additional benefits to patients. who may then enjoy the maximum advantages of antimycotics now available.
Itraconazole treatment of phaeohyphomycosis, Nineteen patients with phaeohyphomycosis were treated with itraconazole. Of these. 17 were assessable for clinical outcome. Of these. two had received no prior therapy. five had failed amphotericin B therapy. four had failed ketoconazole or miconazole therapy. and five had failed both amphotericin B and azole therapy. One patient had received only prior surgical intervention. Fungi of seven different genera caused disease of the skin in nine patients. soft tissue in nine. sinuses in eight. bone in five. joints in two. and lungs in two. Itraconazole was given in dosages ranging from 50 to 600 mg/day for 1 to 48 months. Clinical improvement or remission occurred in nine patients. Two patients have had stabilization of disease. Six patients failed treatment. one had a relapse after initially successful treatment. Itraconazole appears to be highly effective in some patients with phaeohyphomycosis. including patients refractory to other antifungal agents.
Problem solving in implant dentistry, Dental implants have become an accepted form of dental care. with reported functional 5-year success rates of 90% and higher. These impressive statistics include. but do not identify. the problems that may have been created by clinical ineptitude. Diagnostic acumen and preventive measures at each stage of the implant treatment can avoid many problems. Also. appropriate measures of timely recognition. rescue. and repair can often restore ailing implants and their prosthetic appliances to full function.
The restorative and surgical technique for the full maxillary subperiosteal implant, The edentulous atrophic maxilla represents one of the most challenging implant restorative opportunities. When prescribed within the appropriate diagnostic range and performed by a highly skilled and experienced practitioner. the full maxillary subperiosteal implant is a predictable solution for the patient with an edentulous atrophic maxilla.
Diagnosing periodontal diseases, At present. the diagnosis of periodontal disease requires a clinical evaluation of the patient including visual findings. the use of the periodontal probe. and radiographs. No test is available to evaluate disease activity. In specific cases. adjunctive procedures may also be useful. The identification of pathogenic microorganisms may aid in evaluating the periodontal status of special patients. However. these are not required for an adequate diagnosis of the common adult form of chronic periodontitis.
Reviewing nonsurgical periodontal therapy, Selection of the appropriate case and clinical competency in treatment modalities results in success in nonsurgical periodontal therapy. The patient with early periodontitis with significant local factors in the form of professionally accessible plaque and calculus is the most receptive to nonsurgical periodontal treatment. The clinician must make decisions centering around the important question. "Can the patient. or moreover. can the therapist delivering the debridement. gain access to the microbial subgingival plaque on a frequent basis below the host defense threshold of the respective patient?" If the answer is "yes." nonsurgical periodontal therapy will be rewarding. If the answer is "no." other modalities such as periodontal surgery must be instituted.
Surgical pocket reduction, It is not possible within the scope of this paper to describe in any detail each of the aforementioned procedures. These can be found in the various textbooks and journals on clinical periodontology. Instead. the objectives of treatment. the spectrum of techniques available. and the rationale for their use have been described. Periodontal surgery should be performed only under certain conditions: the patient must be physically and mentally competent to undergo any type of surgery. and should understand and agree to the procedure and to postoperative management. Finally. periodontal surgery should only be considered when nonsurgical therapy will not accomplish the desired result. When periodontal surgery for pocket elimination is performed for selected defects that have been properly evaluated after a debridement and healing period. and is executed with technical competence and proper postoperative care. it can preserve the dentition affected by periodontal disease.
Using periodontal plastic surgery techniques, In the 1980s. mucogingival surgery evolved into periodontal plastic surgery with various techniques designed to produce root coverage in areas of marginal tissue recession. to augment deficient ridges. and to lengthen crowns in cases of excessive gingival display. Periodontal plastic surgery not only enables the dentist to reconstruct but also to regenerate lost tissues.
Maintaining periodontal treatment, Dental maintenance. or supportive periodontal treatment (SPT). can keep the periodontium and peri-implant tissues healthy after active therapy. Patients who comply to suggested SPT fare better periodontally and keep their teeth longer. Data should be gathered by examinations. talking with patients. and reviewing personal oral hygiene. Then sub- and supra-gingival deposits should be removed. The average SPT visit should last 1 hour and should be scheduled every 3 months. Supportive periodontal treatment for patients with more advanced periodontal or peri-implant destruction should be the responsibility of the periodontist.
Dental implants used for periodontal patients, For those performing implant treatment. continued research and reports of long-term successful results are essential to evaluating the validity of implants. especially when variables such as design and surface treatment are introduced. The dental profession has enthusiastically embraced the clinical results of implant treatment and its benefits to the patient. However. just as patients who undergo periodontal and restorative treatment must continue a regular long-term routine of maintenance therapy to ensure their dental health. so must those patients who receive dental implants. Both the periodontist who places the implants and the dentist who fabricates the prosthetic replacement must work cooperatively to deliver a healthy restoration that will function for many years.
Premolarization of a fractured maxillary first molar: a multidisciplinary treatment, The diagnosis and treatment of a fractured maxillary first molar are described in this case report of a 28-year-old male. Successful treatment of the retained palatal root of the fractured molar. referred to as premolarization. ensued from integration of endodontic. orthodontic. periodontic. and fixed prosthodontic care.
An esthetic approach to vertical root extrusion in a patient with an anterior open bite: report of case, A previous attempt to locate the root canal system in the maxillary left central incisor with a bur created a perforating root defect at the level of the alveolar crest. The patient received root canal therapy. Next. vertical root extrusion was chosen to expose sound tooth structure apical to the defect so that a crown could be constructed. With an anterior open bite. the natural crown was left intact and it was possible to position the anchor bar in an incisal and lingual position. maintaining esthetics for the patient during both the extrusive and stabilization phases of treatment.
Incidence of lingual nerve trauma and postinjection complications in conventional mandibular block anesthesia, Trauma to the lingual nerve is potential risk factor for patients receiving mandibular block anesthesia. This paper describes the results of a patient survey of 9.587 conventional mandibular blocks received by 2.289 adults. The incidence of lingual nerve trauma and postinjection complications is reported along with an associated analysis of the duration of complications. procedures at the time of incident. the side of occurrence (right or left). and gender ratios. In addition. recommendations for patient evaluation. treatment. and follow-up care are discussed.
Improved morphologic characterization of atrial septal aneurysm by transesophageal echocardiography: relation to cerebrovascular events, Transthoracic and transesophageal echocardiography was performed in 23 consecutive adult patients with an atrial septal aneurysm. In three patients with a cerebrovascular event the diagnosis was established by the transesophageal approach only. Interatrial shunting on transthoracic imaging with use of echocardiographic contrast imaging or Doppler color mapping. or both. was detected in 7 (41%) of 17 patients. On performing contrast imaging in combination with color flow mapping during transesophageal echocardiography. positive shunting was demonstrated in 15 (83%) of 18 patients. Echocardiographic identification of multiple fenestrations (n = 4) and thrombus within the aneurysm (n = 2) could be achieved for the first time by transesophageal ultrasound application. Cerebrovascular events occurred in 12 (52%) of 23 patients and were regarded as being definitely thromboembolic in 10 (43%); 8 (67%) of the 12 patients had repeated cerebral events. Except for mitral valve prolapse in one patient. no other potential cardiac source of embolism could be identified despite the use of transesophageal echocardiography. A thickening of the aneurysmal membrane greater than or equal to 5 mm was found in 9 (75%) of 12 patients with versus 3 (27%) of 11 patients without a cerebrovascular event (p less than 0.05); this proved to be the only significant difference between the two patient groups. The mechanism of embolization may be both primary thrombus formation within the aneurysm and paradoxic embolization through an interatrial communication as demonstrated by the findings in two patients. It is concluded that atrial septal aneurysm is a cardiac abnormality with thromboembolic potential. In patients with this lesion and a history of an embolic event. long-term anticoagulant therapy is indicated.
Transesophageal Doppler color flow mapping assessment of atrial septal defect, Transesophageal Doppler color flow imaging was performed in 19 adult patients (mean age 35 years) with an atrial septal defect demonstrated by cardiac catheterization or at surgery. or both. The transesophageal study correctly identified and classified 19 of 19 shunts in contrast to 16 of 18 shunts identified by the transthoracic approach. The area of the atrial septal defect was calculated by assuming it to be circular and taking the maximal Doppler color flow jet width at the defect site as its diameter. The pulsed Doppler sample volume was placed parallel to the shunt flow direction at the defect site to obtain the mean velocity and flow duration. From these values. the shunt volume was calculated as a product of the defect area. mean velocity. flow duration and heart rate. The calculated shunt flow volume obtained by transesophageal study showed a good correlation with shunt flow volume (r = 0.91. p less than 0.001) and pulmonary to systemic blood flow ratio (r = 0.84. p less than 0.001) obtained at cardiac catheterization. The size of the defect by transesophageal Doppler color flow mapping correlated fairly well with the size estimated at surgery (r = 0.73. p = 0.004). It is concluded that transesophageal Doppler color flow imaging is useful in the detection and classification of atrial septal defects and in the assessment of shunt volumes.
Outlook after acute myocardial infarction in the very elderly compared with that in patients aged 65 to 75 years, Little is known concerning late outcome and prognostic factors after acute myocardial infarction in the very elderly (greater than 75 years of age). Accordingly. this study compared the clinical course and mortality rate for up to 1 year in a large multicenter data base that included 702 patients greater than 75 years of age (mean +/- SD 81 +/- 4 years). with a less elderly subset of 1.321 patients between 65 and 75 years of age (mean 70 +/- 3 years). The postdischarge 1 year cardiac mortality rate was 17.6% for those greater than 75 years of age compared with 12.0% for patients between 65 and 75 years of age (p less than 0.01). There were differences in the prevalence of several factors. including female gender. history of angina pectoris. history of congestive heart failure. smoking habits and incidence of congestive heart failure during hospitalization. Multivariate analyses of predictors of cardiac death in hospital survivors selected different factors as important in the two age subgroups; age was selected in the 65 to 75 year age group but was not an independent predictor in the very elderly. The survival curves beginning at day 10 for patients 65 to 75 and in those greater than 75 years old were similar for up to 90 days but diverged later. In the very elderly. 63% of late cardiac deaths were sudden or due to new myocardial infarction. similar to the causes of 67% of deaths in the younger age group.
Changes in left ventricular diastolic performance after aortic balloon valvuloplasty: acute and late effects, To evaluate acute and follow-up changes in left ventricular diastolic performance. simultaneous digital left ventriculography and micromanometry were performed in 49 patients undergoing aortic balloon valvuloplasty. All patients improved symptomatically after valvuloplasty. and 26 returned 6.3 +/- 1.5 months later for follow-up catheterization. Immediately after valvuloplasty. aortic valve area increased (before 0.5 +/- 0.2 versus after 0.8 +/- 0.2 cm2. p less than 0.01). cardiac output (before 4.3 +/- 1.2 versus after 4.4 +/- 1.3 liters/min) and ejection fraction (before 51 +/- 18% versus after 52 +/- 17%) did not change and diastolic indexes worsened. signified by a decrease in peak filling rate (before 247 +/- 80 versus after 226 +/- 78 ml/s. p less than 0.01) and increase in the time constant of isovolumetric relaxation (tau) (before 78 +/- 29 versus after 96 +/- 40 ms. p less than 0.01) and the modulus of chamber stiffness (before 0.107 +/- 0.071 versus after 0.141 +/- 0.083. p less than 0.01). At follow-up catheterization. 16 patients continued to have symptomatic improvement (group 1) and 10 had recurrence of symptoms (group 2). Aortic valve area. cardiac output and ejection fraction at follow-up catheterization in both groups were similar and unchanged from values before valvuloplasty.
Coronary angioplasty in patients with severe left ventricular dysfunction, The applications for coronary angioplasty have greatly expanded and the procedure is now increasingly used in complex and potentially high risk conditions. This report describes the short- and long-term effects of coronary angioplasty in 61 patients with severely depressed left ventricular function (ejection fraction less than or equal to 35%) with unstable or refractory anginal symptoms. or both. in whom revascularization was necessary despite increased risk. In a retrospective analysis of 1.260 patients undergoing angioplasty between January 1985 through December 1987. 61 had an ejection fraction less than or equal to 35%. The common clinical presentation was unstable angina (70%) with or without recent myocardial infarction. Mean left ventricular ejection fraction was 27 +/- 6%. Forty-five patients (74%) had multivessel disease. Clinical success after angioplasty was achieved in 55 patients (90%). Major complications (death. infarction and emergency bypass surgery) occurred in five patients (8.2%). with death in two (3.2%). During long-term (mean 21 +/- 11 months) follow-up study of the 55 patients with successful angioplasty. 13 (23%) died. including 3 of noncardiac causes. and 11 (20%) had clinically symptomatic recurrence. Continued clinical success was present in 39 patients (71%). of whom 28 (51%) were event-free patients and 11 (20%) had clinical recurrence; a successful second angioplasty procedure was performed in 9 because of restenosis. Thus. in patients with depressed left ventricular function. coronary angioplasty can be performed with a short-term success rate comparable to that of routine angioplasty or surgical procedures. However. acute complications are more frequent and the late mortality rate is higher than in patients with less depressed function.
Natural history of hypertrophic cardiomyopathy in the elderly, The prognosis of patients diagnosed as having hypertrophic cardiomyopathy at advanced age has not been well defined. This study details follow-up information obtained for 95 patients initially diagnosed as having hypertrophic cardiomyopathy at age greater than or equal to 65 years. Seventy-five percent of patients were symptomatic. as defined by the presence of chest pain. dyspnea or syncope. and the mean ventricular septal thickness was 20 mm. The median duration of follow-up study was 4.2 years. The survival rate at 1 and 5 years was 95% and 76%. respectively. which was not significantly different from that an age- and gender-matched control group. Of patients presenting with New York Heart Association functional class I or II dyspnea. only 18% progressed to class III or IV during the follow-up period. However. patients presenting with class III dyspnea had a 1 year mortality rate of 36%. significantly higher than that of control subjects (p less than 0.003). Of the echocardiographic variables. indexed left atrial size was most strongly associated with reduced survival (p less than 0.008). These results suggest that the prognosis of elderly patients with hypertrophic cardiomyopathy is generally favorable. Certain clinical and echocardiographic variables appear to be of use in identifying patients with a less favorable prognosis.
Prognostic importance of the serum magnesium concentration in patients with congestive heart failure, Magnesium abnormalities are common in patients with congestive heart failure but the clinical and prognostic significance of an abnormal serum magnesium concentration in this disorder has not been investigated. Therefore. the relation between serum magnesium concentration and the clinical characteristics and long-term outcome of 199 patients with chronic heart failure was evaluated. The serum magnesium concentration was less than 1.6 mEq/liter in 38 patients (19%). within the normal range in 134 patients (67%) and greater than 2.1 mEq/liter in 27 patients (14%). Patients with hypomagnesemia had more frequent ventricular premature complexes and episodes of ventricular tachycardia than did patients with a normal serum magnesium concentration (p less than 0.05). Even though the two groups were similar with respect to severity of heart failure and neurohormonal variables. patients with a low serum magnesium concentration had a significantly worse prognosis during long-term follow-up (45% versus 71% 1 year survival. p less than 0.05). Patients with hypermagnesemia had more severe symptoms. greater neurohormonal activation and worse renal function than did patients with a normal serum magnesium concentration but tended to have fewer ventricular arrhythmias. Hypermagnesemic patients had a worse prognosis than did those with a normal magnesium concentration (37% versus 71% 1 year survival. p less than 0.05). In conclusion. the measurement of serum magnesium concentration provides important clinical and prognostic information in patients with chronic heart failure.
Cardiac rhythm disturbances early after orthotopic heart transplantation: prevalence and clinical importance of the observed abnormalities, To precisely define the incidence. type and consequences of cardiac arrhythmias early after heart transplantation. 25 cardiac transplant recipients were monitored continuously for 728 days from the day of surgery to discharge or death. A subset of 15 patients had sinus node function studies with overdrive suppression performed weekly at the time of endomyocardial biopsy. Results revealed sinus bradycardia in 10 patients (40%) and junctional bradycardia in 6 (24%). Supraventricular tachycardia in the form of atrial tachycardia. atrial fibrillation and atrial flutter occurred in 11 patients (44%). Ventricular tachycardia occurred in 15 patients (60%) and was nonsustained in all. Cardiac pacing for 1.403 h was used in nine patients with a pulse rate less than 50 beats/min; seven recovered and permanent pacing was instituted in two. In the subgroup that had sinus node function studies. seven patients were identified with clinical bradyarrhythmia; each had abnormal sinus node recovery time (greater than 1.400 ms) and abnormal corrected sinus node recovery time (greater than 525 ms) in at least one study. These seven patients also had a significantly prolonged ischemic time (236 +/- 26 versus 159 +/- 68 min. p less than 0.01). In conclusion. cardiac arrhythmias. particularly ventricular tachycardia and bradyarrhythmia. occur more commonly early after orthotopic heart transplantation than has previously been reported. Sinus node dysfunction due to prolonged organ ischemic time. antiarrhythmic drug use or surgical trauma. alone or in combination. may contribute to these arrhythmias.
A new single catheter technique for simultaneous measurement of action potential duration and refractory period in vivo, In vivo correlations of action potential duration measured by a monophasic action potential catheter and effective refractory period measured by a separate pacing catheter have been poor. probably because of the known variability of both action potential duration and effective refractory period between different ventricular sites. In this study. a new quadripolar contact electrode catheter designed for simultaneous pacing and monophasic action potential recording at closely adjacent sites (2 mm separation between recording electrodes and pacing electrodes) was tested in five closed chest dogs and four patients. Dog studies: Pacing thresholds were extremely low. ranging from 0.02 to 0.25 mA (mean +/- SD 0.099 +/- 0.051. n = 36) and were stable over time (less than 20% increase during 1 h of continuous pacing). Because of the close proximity of pacing and recording electrodes. the pacing artifact nearly coincided with the monophasic action potential upstroke. Because of the low pacing threshold. however. pacing artifacts were small (33 +/- 17% of the monophasic action potential amplitude at twice diastolic threshold strength) and did not affect the duration or configuration of the simultaneously recorded monophasic action potential. The short stimulus response time and the undisturbed monophasic action potential signal fidelity during pacing allowed precise simultaneous measurements of action potential duration and effective refractory period at the same endocardial site.
An effective and adaptable transvenous defibrillation system using the coronary sinus in humans, With use of a coronary sinus catheter electrode. a right ventricular catheter electrode and a chest wall patch electrode system. defibrillation threshold voltage. current and energy were measured with four distinct transvenous defibrillation techniques delivered in random sequence in each of 12 survivors of cardiac arrest immediately before implantation of a standard epicardial patch defibrillation system. The four transvenous defibrillation techniques were 1) single pathway monophasic pulsing. 2) single pathway biphasic pulsing. 3) dual pathway sequential pulsing. and 4) dual pathway simultaneous pulsing. A transvenous defibrillation method was considered to be potentially useful only if the defibrillation threshold was less than or equal to 500 V (less than or equal to 15 J delivered energy). The 500 V value would allow a 2:1 defibrillation safety margin for a device with a maximal output of 30 J. No single transvenous pulsing technique was uniformly superior in efficacy. However. by choosing the best pulsing technique for each patient. it was possible to obtain an average defibrillation threshold of 410 +/- 135 V leading edge voltage. 7.2 +/- 2.5 A leading edge current and 11.3 +/- 7.4 J delivered energy for the group of 12 patients. With the ability to vary defibrillation technique. transvenous antiarrhythmic device implantation would have been possible in 10 (83%) of the 12 patients at or below a 15 J defibrillation threshold cutoff point. In contrast. if only one transvenous defibrillation method had been used. as few as 5 and at most 8 of the 12 patients would have been candidates for a transvenous defibrillation system given a 15 J defibrillation threshold cutoff point for insertion.
The daylong pattern of the antianginal effect of long-term three times daily administered isosorbide dinitrate, Three times daily administration of isosorbide dinitrate may avoid much of the tolerance seen with more frequent dosing. To determine the daylong pattern of the antianginal effect of three times daily isosorbide dinitrate. eight men with stable exertional angina and a positive exercise test were studied. The subjects had demonstrated increased exercise duration in response to oral isosorbide dinitrate therapy and absence of complete tolerance to long-term three times daily isosorbide dinitrate. Treadmill exercise to onset of angina was performed over 2 days at 8 AM. 9 AM. 11 AM. 1 PM. 2 PM. 4 PM. 6 PM and 7 PM. On one day each patient received isosorbide dinitrate at 8 AM. 1 PM and 6 PM in a previously titrated dose (mean 27.5 mg). which had been taken three times daily for at least 2 weeks. On the other day at the same hours each patient received double blind a placebo identical in appearance to isosorbide dinitrate. One hour after the 8 AM dose of isosorbide dinitrate. mean systolic blood pressure at rest had fallen by 19 mm Hg and mean exercise time to angina increased by 200 s. However. by 11 AM exercise time had returned to control level. One hour after the 1 PM dose of isosorbide dinitrate. exercise time increased by a mean of 150 s but was again at control level 2 h later.
Myocardial amiodarone and desethylamiodarone concentrations in patients undergoing cardiac transplantation, Myocardial amiodarone and desethylamiodarone concentrations were measured at multiple sites in the explanted heart in four patients who underwent cardiac transplantation. Patients were taking amiodarone. 200 to 400 mg/day (mean 300 +/- 115). for 88 to 428 days (mean 229 +/- 148). The mean cumulative dose was 58 +/- 21.3 g. Plasma amiodarone concentration in three subjects was 204. 312 and 419 ng/ml and desethylamiodarone concentration was 268. 513 and 880 ng/ml. respectively. Significant interindividual variability in myocardial concentrations of amiodarone and desethylamiodarone was observed (p less than 0.05). Mean myocardial amiodarone concentration ranged from 4 +/- 1.0 to 29 +/- 17.2 micrograms/g (p less than 0.05); mean desethylamiodarone concentration ranged from 22 +/- 8.8 to 141 +/- 102.5 micrograms/g (p less than 0.05). At each site. save for fat. myocardial desethylamiodarone concentration was higher than amiodarone concentration. Greater intraindividual variability was observed in myocardial desethylamiodarone compared with amiodarone concentration particularly in septal and scar tissue (p = NS). No significant relation was found between myocardial concentration and duration of treatment. In patients with significant ventricular disease. usefulness of plasma amiodarone and desethylamiodarone concentration to estimate myocardial concentration is limited by intra- and interindividual variability.
Effects of benazepril and metoprolol OROS alone and in combination on myocardial ischemia in patients with chronic stable angina, The efficacy of benazepril. metoprolol OROS and their combination was evaluated in 29 patients (42 to 74 years of age) with chronic stable angina and documented coronary artery disease in a placebo-controlled. double-blind. crossover trial using serial quantitated exercise testing and ambulatory electrocardiographic (ECG) monitoring. The mean (+/- SEM) exercise time was 8.5 +/- 0.7 min with placebo. 8.3 +/- 0.6 min (95% confidence interval [CI]-1.06 to 0.54) with benazepril. 9.4 +/- 0.5 min (95% CI -0.32 to 2.14) with metoprolol OROS and 9.6 +/- 0.5 min (95% CI -0.25 to 2.47) with the combination of benazepril and metoprolol OROS. The mean exercise time to the development of 1 mm ST segment depression was prolonged from 6.0 +/- 0.6 min with placebo to 6.3 +/- 0.6 min (95% CI -0.93 to 1.45) with benazepril. 7.9 +/- 0.5 min (95% CI 0.83 to 3.0) with metoprolol OROS and 8.1 +/- 0.6 min (95% CI 0.88 to 3.29) with the combination of benazepril and metoprolol OROS. Benazepril did not alter the rest or maximal heart rate. whereas metoprolol OROS alone and in combination significantly lowered the heart rate at rest and during maximal exercise. Systolic blood pressure at rest was nonsignificantly reduced. whereas diastolic blood pressure was lowered significantly by all treatments in comparison with placebo. At maximal exercise. only metoprolol OROS. whether given alone or in combination with benazepril. was able to blunt significantly systolic blood pressure and rate-pressure product.
Does intracoronary infusion of Fluosol-DA 20% prevent left ventricular diastolic dysfunction during coronary balloon angioplasty, Distal intracoronary infusion of the perfluorochemical Fluosol-DA 20% has been shown to prevent systolic dysfunction during coronary artery balloon occlusion in coronary angioplasty. To assess its effect on global diastolic dysfunction. a randomized. single-blind. crossover protocol comparing intracoronary infusion of Fluosol or no infusion (control) was performed during 60 s balloon inflations in 10 patients (mean age 67 years) undergoing coronary angioplasty. Assessment of global systolic and diastolic function was obtained with high fidelity micromanometer measurements of left ventricular pressure. Eighteen pairs of balloon inflations (Fluosol versus control) were analyzed. Patients reported significantly less severe chest pain during inflations accompanied by Fluosol compared with control. However. during coronary balloon occlusion. no significant differences in the changes from baseline values were observed between Fluosol and control with regard to ventricular relaxation. including the time constant of early ventricular relaxation (tau) and maximal rate of fall in left ventricular pressure (maximal negative dP/dt). No differences between Fluosol and control were observed in terms of the increase in end-diastolic pressure or minimal diastolic pressure during balloon inflation. Mean systolic pressure decrease from baseline values was greater during control than during Fluosol inflations (-9.0 +/- 3.3 mm Hg. p = 0.013). but no significant difference was observed in the change in maximal rate of rise in left ventricular pressure (maximal positive dP/dt). These results suggest that Fluosol does not preserve global left ventricular diastolic function during coronary balloon occlusion. possibly because of its limited oxygen delivery capability relative to arterial blood.
Early and late effects of captopril treatment after large myocardial infarction in rats, The early (after 21 days) and late (after 4 months) effects of continuous treatment with captopril on left ventricular performance. weight and volumes were studied in rats with myocardial infarction. Early effects were examined in rats subjected to coronary ligation and randomized to either immediate treatment with captopril (2 g/liter drinking water) starting 2 h after surgery or no treatment. After 21 days. the treated group showed reductions in mean arterial. left ventricular systolic and left ventricular end-diastolic pressures compared with untreated rats. Right and left ventricular weight and left ventricular volumes were decreased and the ejection fraction index was increased by captopril treatment. To study the late effects of captopril. a second group of rats was randomized to immediate captopril treatment (starting 2 h after surgery). delayed captopril treatment (starting 21 days after surgery) or no treatment. When studied after 4 months of treatment. rats started on captopril treatment 2 h after infarction showed no differences compared with rats started on treatment 21 days after infarction. Treatment with captopril for 4 months produced changes that were similar to those in rats treated for 21 days. Captopril treatment improved hemodynamic function after myocardial infarction in rats examined after either 21 days or 4 months of treatment. The extent of the benefit was similar in the two treatment periods. Initiation of captopril therapy immediately after infarction did not appear to produce a greater effect than treatment started at 21 days after infarction in rats studied after the drug had been administered for 4 months.
Echocardiographic definition of the left ventricular centroid. II. Determination of the optimal centroid during systole in normal and infarcted hearts, Although two-dimensional echocardiography is widely used in both clinical and experimental evaluations of regional cardiac wall motion. there is no established clinical method for quantitative analysis of the wall motion. not even for the normal radial motion observed in short-axis images. Measurement of radial wall motion requires determination of a centroid from which the radii emanate. Depending on its definition. the centroid is variously affected throughout systole by cardiac translation. regional wall motion and any shift of the subject position or transducer. A floating centroid is defined relative to the ventricular walls frame by frame. whereas a fixed centroid never moves with respect to the transducer. Evaluation of the best approach to definition of a centroid was previously presented (part I. this issue). The next question is how to use the centroid. This study examines which of four centroid applications provides the best reference for quantifying regional wall motion during systole. Method 1 is a floating centroid (defined separately for every image frame). method 2 uses the end-diastolic centroid as a fixed reference for all image frames. method 3 uses the end-systolic centroid as a fixed reference and method 4 uses the average as a fixed reference. Wall motion was measured with respect to each of these centroids by determining radial wall motion from end-diastole to end-systole and correlating radial motion throughout the cardiac cycle with that in normal control hearts.
Anaphylaxis during induction of general anesthesia: subsequent evaluation and management, Twenty-seven patients were referred for evaluation of anaphylaxis after induction of general anesthesia (GA) in which thiobarbiturates. muscle relaxants. or antibiotics were administered intravenously. Skin testing by the prick and intracutaneous methods was performed with dilutions of the thiobarbiturates and muscle relaxants; beta-lactam reagents were used in patients who had also received these drugs. No skin test reactivity was noted in 16 normal subjects. Skin tests were positive in 13 patients (thiobarbiturates in five. muscle relaxants in six. and antibiotics in two patients). Two patients were dermatographic and yielded indeterminate skin test results. Eleven of the 27 patients subsequently had GA; all patients received a premedication regimen of prednisone and diphenhydramine. Of three patients with negative skin tests. one experienced an arrhythmia. but no other signs attributable to anaphylaxis were noted. One patient with dermatographism had GA without a reaction. Positive skin tests implicated an agent that was avoided in seven patients; one of these patients experienced delayed urticaria/angioedema after the completion of GA. Thus. no patients developed anaphylaxis during subsequent GA for which agents producing positive skin tests were avoided. and a premedication regimen was used.
Determinants of in vivo histamine release in cutaneous allergic reactions in humans, To determine host factors influencing the magnitude of mediator release during ongoing cutaneous allergic reactions in humans. we compared. in 22 subjects. the first-hour. second- to fifth-hour. and total (0 to 5 hours) skin chamber histamine release to (1) the in vitro reactivity and sensitivity of basophils to antigen for histamine release and (2) skin test sensitivity and reactivity to antigen. histamine. and codeine. There was no significant correlation between the first-hour and second- to fifth-hour histamine release. With a combination of basophil. antigen. histamine. and codeine skin sensitivity and reactivity. 64% to 75% of the magnitude of the first-hour. second- to fifth-hour. and total (0 to 5 hours) skin chamber histamine release could be accounted for. We conclude that antigen-induced in vivo allergic responses are a complex phenomenon dependent. in part. on antigen sensitivity. basophil and mast cell reactivity. and end organ responsiveness to mediators.
Aqueous beclomethasone diproprionate nasal spray: regular versus "as required" use in the treatment of seasonal allergic rhinitis, OBJECTIVE: to determine the effect of alternative regimens of nasal steroid administration on symptoms and quality of life. DESIGN: randomized. double-blind. parallel-group comparison. SUBJECTS: sixty ragweed-sensitive adults recruited from participants of previous studies and through media advertising. INTERVENTIONS: 200 micrograms of aqueous beclomethasone diproprionate nasal spray. twice daily. from 1 week before until 1 week after the ragweed-pollen season (regular) or 100 micrograms of the spray. taken as required. up to 400 micrograms daily; troublesome nasal symptoms were treated. in both groups. by increasing the daily dose to 800 micrograms until symptoms were controlled. If this treatment was insufficient. 120 mg of terfenadine. daily. was added. RESULTS: One subject in the "as required"-treated group withdrew with uncontrolled nasal symptoms. In the remaining subjects. sneezing. stuffy nose. and rhinorrhea. measured by a daily diary. were significantly better controlled in the regular-treated group (p less than 0.025). Impairment of quality of life. including sleep disturbance. nonhay fever symptoms. practical problems. and uncomfortable emotions were greater in the as required-treated group (p less than 0.001). Subjects in the regular-treated group required less additional terfenadine (0.27 tablets per subject versus 1.40; p = 0.022). Eye symptoms and eye-drop use were similar in the two treated groups. CONCLUSION: In patients with seasonal allergic rhinitis. regular use of inhaled steroids results in fewer symptoms and better quality of life than when the spray is taken only as required.
The relationships among shrimp-specific IgG subclass antibodies and immediate adverse reactions to shrimp challenge, High levels of shrimp-specific IgE. in association with a positive prick test. are not always predictive of a positive. immediate response to double-blind. placebo-controlled. food challenge (DBPCFC) with shrimp. The observation that shrimp-sensitive individuals in general have increased levels of circulating shrimp-specific IgG is of interest because antigen/allergen-specific IgG subclasses have been associated with adverse reactions to foods. Therefore. this current study measured shrimp-specific IgG subclass and IgE antibodies in 31 individuals with histories of immediate. adverse reactions to shrimp immediately before DBPCFC and 20 shrimp-tolerant subjects. Individuals with a history of shrimp sensitivity had significantly raised shrimp-specific IgG2 and IgG4 compared to shrimp-tolerant individuals. Challenge-positive subjects were distinguished from subjects with negative or equivocal responses by an increased IgG2 (p less than or equal to 0.001). Specific IgG4 was not raised (p less than or equal to 0.065). These studies indicate that some shrimp-specific IgG subclass levels are increased in shrimp-sensitive subjects. However. none of the subclass responses were significantly predictive of a positive response to DBPCFC and therefore were not diagnostic of shrimp intolerance.
Increased serum IgE and increased prevalence of eosinophilia in 9-year-old children of smoking parents, We studied the relationship of serum IgE levels and eosinophil counts with passive smoking in 9-year-old. nonselected children from three Italian towns near Rome. Male children of smoking parents had a significantly higher total count and percentage of eosinophils (p = 0.008) and higher IgE levels (p = 0.01) than male children of nonsmoking parents. Prevalence of eosinophilia (defined as greater than or equal to 4% of total white blood cell count) was significantly correlated with the number of cigarettes smoked by parents among boys (p = 0.003) but not among girls (p = 0.20). There was a significant trend (p = 0.008) for prevalence of eosinophilia to increase with increasing levels of serum IgE. For any given level of serum IgE. the frequency of eosinophilia was higher among children of smoking parents than among children of nonsmoking parents. When parental smoking was studied in a multivariable analysis and after controlling for the other variable. it was still significantly associated with eosinophilia in the children of these smoking parents but not with serum IgE levels. We conclude that parental smoking is associated with a significant enhancement of the expression of the most important markers of allergic sensitization in the children of smoking parents. This is particularly evident for boys and may explain. at least in part. the increased frequency of respiratory symptoms in children of smoking parents.
Promoting adherence to low-fat, low-cholesterol diets: review and recommendations, Evidence that lowering blood cholesterol levels reduces risk of coronary heart disease has prompted widespread recommendations that hyperlipidemic individuals undergo dietary therapy. However. the extent to which people can adopt and maintain diets to lower lipids is unclear. In our article. we review what is currently known regarding adherence to low-fat diets and present an approach to dietary counseling for lowering cholesterol that incorporates elements of behavioral self-management and social learning theory. We discuss specific recommendations for counseling hyperlipidemic patients based on the Dietary Alternatives Study. Recommendations include providing patients with an adequate knowledge base to make dietary changes. using goal setting and self-monitoring to help patients initiate dietary changes. enlisting support from the patient's family. and enhancing self-efficacy to promote long-term dietary maintenance.
Prevalence and characteristics of multiple analgesic drug use in an elderly study group, With few exceptions. use of multiple analgesic drugs achieves dubious increases in analgesia while placing elders at increased risk of the many potential adverse effects of analgesic drugs. The potential for duplication of analgesic therapy among the elderly is great due to prevalent painful chronic conditions and the variety of prescription and nonprescription analgesic remedies available. The prevalence of multiple analgesic product use and patterns of concurrent use of different analgesic categories was investigated in a geographically defined population of persons 65 years of age and older. The demographic characteristics of users of multiple analgesic drug products were examined. as were their smoking status. alcohol use. lifetime history rates of major illnesses. physical functioning. pain experiences. memory performance. and depressive symptoms. A substantial proportion of analgesic users reported taking multiple products in the preceding 2 weeks (14.4% of female and 10.5% of male analgesic users). Men who reported pain in the preceding year were more likely to use multiple analgesic products. Women who experienced pain or limited physical functioning. or who had higher depressive symptom scores or a life-time history of ulcers were most likely to use multiple analgesic products. Thus. although some users of multiple analgesic products reported significant pain. several other factors were shown to be related to the phenomenon of multiple use.
Dietary preference for sweet foods in patients with dementia, Using a telephone survey. patients with probable Alzheimer's disease (n = 31) and vascular dementia (n = 14) were compared with elderly normal controls (n = 43) in preferences for different foods. Patients with Alzheimer's disease had a greater preference than normal controls for relatively high-fat. sweet foods and for high-sugar. low-fat foods. but did not significantly differ in preference for other foods. including those high in complex carbohydrates and protein. Vascular dementia patients showed a similar pattern. not significantly different from that for Alzheimer's patients. Results did not consistently support a hypothesis that increased sweet preference is a nonspecific form of disinhibited behavior related to declining mental status. nor was a hypothesis relating sweet preference to serotonin activity within the brain consistently supported. Results provide preliminary evidence that craving for sweet food may be a significant part of the clinical syndrome of dementia. but further research is needed to delineate the psychological and biological mechanisms accounting for it.
Generation of ammonia and mucosal lesion formation following hydrolysis of urea by urease in the rat stomach, We examined the morphological changes in gastric mucosa and the generation of ammonia after exposure of the rat stomach to urea in the presence of urease. in attempts to investigate a pathophysiological role of urea. urease. and ammonia system in gastric ulcer diseases. Exposure of the stomach for 20 min to 2 ml urea (0.025-0.2%) together with urease (100 IU) induced histological damages in a concentration-related manner. Either urea or urease alone did not induce any histological change in the mucosa. Instillation of urea into the stomach generated ammonia in the presence of urease; the amount of ammonia was increased depending on the concentration of urea. and was closely associated with the severity of histological damage. The exposure of the stomach to ammonia (NH4OH: 0.01-0.1%) also produced histological damages in the gastric mucosa in a concentration-related manner. The characteristics of injury induced by 0.5-1.0% ammonia were stasis of microcirculation. disruption of the surface epithelial cells. and necrosis of the mucosa. These results demonstrated that ammonia generated from the hydrolysis of urea by urease in the stomach causes damages in the gastric mucosa.
Effect of gastric mucus on the uptake of the carcinogen MNNG by gastric mucosal DNA, In prostaglandin E2 (PGE2)-. pirenzepine-. and indomethacin-administered rats. the incorporation of N-[methyl-3H]-N'-nitro-N-nitrosoguanidine ([methyl-3H]MNNG) into gastric mucosal DNA was measured quantitatively by liquid scintillation counting after intragastric instillation of [methyl-3H]MNNG. The amount of incorporation was 25.4 +/- 5.9 pmol/mg DNA in control rats. 11.7 +/- 3.8 pmol/mg DNA in PGE2-administered rats. 6.2 +/- 5.6 pmol/mg DNA in pirenzepine-administered rats. and 42.9 +/- 14.4 pmol/mg DNA in indomethacin-administered rats. PGE2 and pirenzepine significantly decreased the incorporation as compared with the control group. In contrast. indomethacin increased the incorporation. In addition. gastric mucosa of these drug-treated rats was studied histochemically. PGE2 and pirenzepine increased secretion of gastric mucus whereas indomethacin decreased it. It is possible that gastric mucus has a protective effect not only against ulcerogenic agents but also against carcinogens. It is considered that gastric mucus plays an important role in the defense mechanism against carcinogenesis.
"Healed" experimental gastric ulcers remain histologically and ultrastructurally abnormal, The present study was designed to assess histologic and ultrastructural features of gastric mucosa in the areas of grossly healed ulcers (acetic acid-induced gastric ulcers) in rats. The specific question we studied was whether the structure and cellular composition of the gastric mucosa in an area of grossly healed ulcer were fully restored. Eighty Sprague-Dawley rats underwent laparotomy; 100% acetic acid was applied to the lower gastric corpus serosa for 30 s and the abdomen was closed. The stomachs were reopened after 2 weeks or after 2. 3. or 4 months. Standardized gastric wall specimens from the area of grossly healed ulcers were obtained. processed. and evaluated by light microscopy and by transmission electron microscopy. The gastric mucosa of grossly healed ulcers demonstrated re-epithelialization at each study time but the mucosa beneath the surface epithelium displayed prominent histologic and ultrastructural abnormalities. Two different patterns of scar could be distinguished: (a) the mucosa in the area of healed ulcer was thinner (25-45% reduction vs. normal). with increased connective tissue and poor differentiation and/or degenerative changes in the glandular cells; or (b) the mucosa displayed ballooning dilatation of gastric glands. reduction in the microvascular network. and poor differentiation of glandular cells. We conclude that (i) the subepithelial mucosa of grossly healed gastric ulcer displays disorganized restoration of glandular and vascular structures and remains histologically and ultrastructurally abnormal; (ii) these abnormalities may interfere with oxygenation. nutrient supply. and with mucosal resistance and defense. and therefore could be the basis for ulcer recurrence.
Vascular and microvascular changes--key factors in the development of acetic acid-induced gastric ulcers in rats, The present study examined the time sequence and histologic and ultrastructural features of the formation and evolution of experimental. acetic acid-induced gastric ulcerations in rats. One hundred percent acetic acid was applied to the gastric serosa of 140 fasted male Sprague-Dawley rats through a polyethylene tube for 30 s. Gastric mucosal changes were evaluated at 1. 5. 15. and 30 min. 1 and 3 h. and 1. 2. 3. 5. 8. and 11 days after acetic acid application by visual inspection. by quantitative and qualitative light microscopy. and by transmission electron microscopy. Following exposure to acetic acid. the earliest morphologic changes occurred at 1 min and consisted of dilatation of large submucosal veins and arteries and mucosal collecting venules. Five to 15 minutes after injury. thrombi developed in submucosal veins and collecting venules. leading to microvascular stasis and mucosal necrosis. By 3 h. necrotic masses started to detach. By 24-48 h. necrotic changes penetrated the submucosa. By 72 h. most ulcers underwent transition into a "chronic" stage characterized histologically by the presence of granulation tissue at the bottom. and the appearance of a transitional healing zone at the margins. By 5 days. an increased amount of granulation tissue was observed and the gastric glands in transitional zones at the ulcer margin displayed cystic dilatation. Based on this study. we conclude that a key feature of acetic acid-induced ulcer formation is the early vascular and microvascular injury. which precedes glandular cell necrosis.
Further study of mucosal repair by sofalcone in experimental gastritis, The effect of sofalcone on the glandular structure and cell proliferation in the gastric mucosa of rats with gastritis induced by the administration of sodium taurocholate (TCA) for 6 months was examined by histoquantitative analysis and [3H]thymidine autoradiography. Morphometric observation revealed that. with TCA treatment. mucosal thickness. parietal cell mass. and the ratios of the length of the glandular portion/total length of the gastric gland were decreased in both the fundic and pyloric glands. Inflammatory cell infiltration and collagenous fiber proliferation were present in the gastric mucosa following TCA and indicated the presence of atrophic gastritis. These atrophic changes and inflammatory cell infiltration were reversed by a 3 week administration of sofalcone. Cellular proliferative activity assessed by the labeling indices of the gastric mucosa increased in TCA-induced gastritis in rats. The administration of sofalcone to rats with TCA-induced gastritis significantly increased labeling indices. particularly in the pyloric glands. From these results. it appears that sofalcone stimulates the compensatory increase in proliferative activity of generative cells. which then may become available to heal the gastritis.
Effect of epidermal growth factor in combination with sucralfate or omeprazole on the healing of chronic gastric ulcers in the rat, Epidermal growth factor (EGF) has been shown to enhance healing of experimental gastric ulcers when given subcutaneously or orally in the drinking water. This effect of EGF occurs without reducing gastric acid secretion. On the other hand. EGF reportedly is excreted rapidly from gastric lumen when administered by intragastric bolus. This suggests that further stimulation of ulcer healing may be expected if EGF is given with an acid-suppressive agent or with an agent allowing EGF to remain in rat gastric lumen at high concentrations. In the present study. EGF administered by gastric intubation at a dose of 10 micrograms/kg. which is three times smaller than reported in previous studies. was evaluated for its effect on acetic acid-induced rat gastric ulcers in combination with sucralfate or omeprazole. Sucralfate is well known selectively to bind proteins covering the ulcer base. and omeprazole is a potent acid-suppressive agent. Prior to the study of combined EGF and sucralfate. oral sucralfate was confirmed to allow endogenous gastric EGF and mouse EGF given exogenously to remain at high concentrations in gastric contents and tissues. EGF and sucralfate (2 g/kg/day) given alone failed to stimulate ulcer healing in submandibularectomized rats (SMR rat) whose endogenous gastric EGF was depleted. However. the combination of both drugs administered at the same doses significantly accelerated ulcer healing in the SMR rat. Omeprazole (200 mg/kg/day) significantly enhanced ulcer healing regardless of removal of the submandibular glands. The combination of EGF and omeprazole further stimulated ulcer healing in the SMR rat.
Effects of stress on gastric mucosal prostaglandin generation in intact, adrenalectomized, and sham-operated rats, To study the effects of (a) cold restraint stress and (b) adrenalectomy in association with cold restraint stress on gastric mucosal ulceration and prostaglandin generation. we performed two experiments. In the first. 40 rats were divided into four groups of 10 rats each: (a) unstressed and (b) stressed for 0.5 h. (c) stressed for 2 h. and (d) stressed for 4 h. In the second experiment. another 80 rats were divided into four groups of 20 rats each: (a) adrenalectomy plus cold restraint stress for 2 h. (b) adrenalectomy plus no stress. (c) sham operated plus 2 h of stress. and (d) sham operated plus no stress. In both experiments we recorded an ulcer index and measured mucosal generation of prostaglandin E2 (PGE2) and prostaglandin I2 (6-keto-PGF1a). In conclusion: (a) Cold restraint stress is associated with a time-dependent decrease in gastric mucosal PGE2 generation. but no change in 6-keto-PGF1a generation. and an increase in mucosal injury that is maximal by 2 h. (b) Adrenalectomy augments the effects of stress on mucosal injury but has no effect on prostaglandin generation; thus. the ulcerogenic effect of adrenalectomy appears to be independent of an effect on prostaglandin generation.
Fibronectin-related substance located in the chief cells of human and rat gastric mucosa, A novel substance located in the chief cells of human and rat gastric mucosa. which was detected immunologically by either polyclonal or monoclonal antihuman fibronectin (FN) antibodies. is reported. All three polyclonal antihuman FN antibodies used in this study reacted immunohistologically exclusively with the chief cells. Monoclonal antibody against C-terminal peptide or cell binding peptide reacted clearly with the human chief cells. but monoclonal antibodies against FN N-terminal and midmolecule failed to react with the cells. Western blot analysis of the rat gastric mucosal extract with polyclonal antihuman FN antibody showed that this substance has a molecular weight of about 70.000 Da. Therefore. this substance appears to be a fragment containing the C-terminal peptide of whole molecule FN and thus in the present study is named FN-related substance (FNRS). In a further study with ethanol-induced ulcer model of the rat. the physiological significance of FNRS was examined. The FNRS decreased remarkably. in a dose-dependent manner. in the fundic mucosa of the rats that ingested ethanol. The FNRS appeared to be associated with development of mucosal damage and repair. subsequently playing. in part. an important role in the gastric mucosal protection mechanism.
Campylobacter pylori interactions with gastric cell tissue culture, Many investigators have reported that gastric mucosal biopsies of patients with chronic gastritis and peptic ulcer disease show the presence of Campylobacter pylori in a large majority of cases. Histologic examinations of such tissues indicate a close approximation of C. pylori with gastric surface epithelial cells. A recent report has described both adherence and cell invasion of gastric cells by C. pylori. Using a transmission electron microscope. we have examined the interaction between C. pylori. C. jejuni. and E. coli in vitro with a gastric cancer cell line. Kato III. Our results indicate marked toxicity of E. coli and moderate toxicity of C. jejuni for Kato III cells. C. pylori had only a minor effect on tissue culture viability. C. pylori was found to have a strong association with the Kato III cell membranes and evidence of occasional cell invasion. Both C. jejuni and E. coli showed no attachment or association with the Kato III cells. We interpret these findings as indicating that C. pylori may have a specific adhesion for gastric cells.
Neuropsychological outcome of survivors of out-of-hospital cardiac arrest, Thirty patients resuscitated from out-of-hospital cardiac arrest (15 with and 15 without postanoxic coma on admission) underwent a clinical examination and neuropsychological testing. In order to assess quality of life. they were compared to two matched control groups; 15 patients with previous myocardial infarction and 15 healthy subjects. None of the survivors showed severe neurologic impairment. and all had returned to self-sufficient physical activity. However. the behavior rating scale scores were significantly worse in patients with postanoxic coma. The processing ability linked to memory was significantly worse in the postanoxic coma group. Mood disorders were also observed in this group. but they did not have pathological significance. The remarkably low incidence of neurologic and psychological sequelae in these resuscitated patients. particularly in those with early clinical evidence of severe cerebral damage. is an encouraging result that supports the therapeutic systems development and efforts in the management of out-of-hospital cardiac arrest.
An aid to the management of pediatric trauma in peripheral centers--a proposal for a pediatric trauma board, In 1986. 630.000 children under the age of 15 were living in Queensland. This accounted for 17% of Australia's pediatric population. That year there were 39 pediatric deaths in Queensland resulting from road traffic incidents. Another 408 injured children were admitted to hospital. Less than 20% of these children were treated in an accident and emergency (A&E) department staffed by a qualified pediatrician. Only 35% of the A&E departments were staffed by a qualified emergency physician. A Pediatric Trauma Board is proposed. which will lead to improvement in the care of injured or critically ill pediatric patients. This board is made of pre-marked whiteboard and includes normal pediatric values and replacement fluid flow charts; it is approximately three feet in height and six feet in width. The Board is aimed primarily at nonpediatric clinicians who may or may not be specifically trained or interested in emergency medicine. It provides quick. easy access to the normal values of vital signs for children of different ages and sizes. It enables accurate calculation of the fluid requirements for resuscitation and provides a means for following the response to this therapy. Drug doses per weight are provided. A copy of the board can be made on size A4 photostats for inclusion in the hospital chart as part of the admission notes.
Scroto-abdominal impalement injury in a skateboard rider, The injuries sustained by skateboard riders vary from minor cuts and abrasions to fractures. This report describes a unique injury sustained by a young skateboard rider who was impaled on a metal rod. Literature review of over 1.254 skateboard injuries did not reveal any other instances of penetrating abdominal trauma.
Traumatic rupture of the thoracic aorta presenting as transient paraplegia, A patient involved in a high-speed motor vehicle accident presented paraplegic to the emergency department. He was noted to have an abnormal chest x-ray and. subsequently. underwent aortography which revealed aortic transection. The patient's paraplegia resolved spontaneously prior to definitive aortic repair hours later. Aortic rupture presenting as paraplegia is a rare association. but one an emergency physician should be cognizant of. especially in the case of blunt or decelerating trauma.
Pneumatic firearm injuries: trivial trauma or perilous pitfalls, This report describes an injury due to a pneumatic firearm. Though powder firearm injuries are generally considered serious. pneumatic weapon injuries are often viewed as minor or insignificant trauma. Children and adolescents primarily wield these weapons contributing to their "harmless" aura. However. dramatic increases in muzzle and impact velocities have transformed the newer generation of pneumatic firearms into formidable weapons. Consequently. the literature is replete with increasing incidences of serious injury due to pneumatic weapons.
Tricyclic antidepressant overdose: conservative management in a community hospital with cost-saving implications, Reports of late-onset cardiovascular complications following tricyclic antidepressant (TCA) overdose have led to a very conservative approach to these patients. Many patients have been hospitalized for continuous cardiac monitoring. regardless of the clinical presentation. Management algorithms based on clinical predictors of outcome have recently been proposed. We used the algorithm developed by Tokarski and Young to retrospectively evaluate the care of 33 TCA overdose patients admitted to our hospital over a 3-year period. We then identified 11 patients who could have been treated on an outpatient basis had the algorithm been employed. Ten were admitted to a monitored unit and spent a mean of 31.6 +/- 15.64 hours on the unit. None of the 11 patients developed complications during their hospital stay. Use of the algorithm would have resulted in an estimated cost savings of 13 hospital days and $14.000.
Effects of 4-methylpyrazole, methanol/ethylene glycol antidote, in healthy humans, 4-Methylpyrazole (4-MP). an inhibitor of alcohol dehydrogenase. may be useful for the treatment of methanol and ethylene glycol intoxications. A placebo-controlled. double blind. multiple dose. sequential. ascending-dose study has been performed to determine the tolerance of 4-MP in healthy volunteers. Oral loading doses of 4-MP were followed by supplemental doses every 12 h through 5 days. producing plasma levels in the therapeutic range. A slight. transient elevation in one or both serum transaminase values was observed in 6 of the 15 subjects treated with 4-MP. This effect was not dose related nor apparently mediated through a hypersensitivity reaction. Serum triglyceride levels were increased in 30% of 4-MP treated subjects. but also in 25% of the placebo subjects. 4-MP treatment did not produce any other significant changes in objective clinical parameters nor in subjective side effects. The results suggest that a mild. transient increase in liver function tests might be observed in some subjects treated with multiple doses of 4-MP. Nevertheless. the slower elimination rate and lesser degree of toxicity of 4-MP would make it preferable to ethanol in therapy of these poisonings.
Musculoskeletal infection, microbial adhesion, and antibiotic resistance, Osteomyelitis and intra-articular infection are septic diseases that present pathogenic features characteristic of molecular mechanisms involving adhesion to substrata. In this review. mechanisms of microbial adhesion to bone and cartilage as substrata are presented and related to host tissue response and to antibiotic treatment.
Diagnostic imaging of osteomyelitis, There are many imaging procedures for diagnosing osteomyelitis. each with unique strengths and weaknesses. Plain radiographs are inexpensive and can be very accurate but may provide a delayed diagnosis. Computed tomography and magnetic resonance imaging are both excellent at differentiating soft tissue infection from osteomyelitis. Computed tomography. magnetic resonance imaging. and bone scans are accurate diagnostic tools for use when the bone has not be violated by surgery. trauma. or other structural alterations. When such changes are present. an Indium-111 leukocyte or Indium-111 polyclonal antibody study may be necessary for accurate diagnosis.
Infection in total joint replacement, Although a small number of infections in total joint replacements are blood borne from distant sources. most infections appear to have been derived at operation. Strenuous attempts to reduce this risk by cleaning the air in the wound environment. coupled with prophylactic antibiotics. have reduced infection rates by an order of magnitude in a decade. During that time the potential for exchange arthroplasty in established infection has been shown. and the results are encouraging. Rigorous infection control is the key to containing this difficult and expensive problem.
Antibiotic therapy for osteomyelitis, Antibiotic therapy for osteomyelitis has dramatically changed within the past twenty years. The diagnostic criteria for osteomyelitis remain confusing to practicing physicians. Bone biopsy culture is now the standard for determining specific antimicrobial therapy. Many of the newest and most potent antimicrobials are now used to treat the increasingly broad bacterial spectrum of etiologies of osteomyelitis. There are tremendous economic incentives for outpatient and/or oral therapy. The third-generation cephalosporins and the new fluoroquinolones have replaced older. more toxic regimens. especially those containing aminoglycoside used to treat gram-negative osteomyelitis due to susceptible organisms.
Surgical approaches in osteomyelitis. Use of laser Doppler flowmetry to determine nonviable bone, The surgical management of osteomyelitis includes radical debridement on nonviable bone. Laser Doppler flowmetry is a method for directly assessing the functional microcirculation in bone. The early results of the use of this technique as a surgical adjunct in the management of osteomyelitis are promising.
Infectious arthritis, Any patient who presents with an acute monarticular arthritis. especially a new asymmetric effusion with underlying joint disease. should be suspected of having a bacterial process. Because synovial fluid findings (leukocyte counts and glucose) may not be predictive of infection. bacteriologic analysis by smear and culture is necessary in the evaluation of any new synovial effusion. A chronic monarticular process is highly likely to be infectious also. but mycobacterial or fungal etiologies frequently require appropriate culture of synovial tissue in addition to processing fluid. Acute polyarticular syndromes are seen as manifestations of disseminated gonococcal infections (DGI) and certain viral infections in adults. Diagnostic clues include historic and physical findings (exposure history and type of rash). The major pathogen in adults remains Staphylococcus aureus. so initial therapy is directed at this organism unless urinary tract infection is present also. Proper recommended therapy for DGI is ceftriaxone because penicillin-resistant strains are present in many urban centers. Early recognition and treatment of bacterial arthritis may prevent poor outcome. particularly in elderly patients or those with underlying joint diseases. For chronic mycobacterial or fungal infections. surgery may need to be combined with medical management.
Vertebral osteomyelitis, Vertebral osteomyelitis can be caused by a variety of microorganisms. The hematogenous pyogenic form is characteristically a disease of people over age 50. predominantly in the male population. and most frequently caused by S. aureus. In IVDAs. however. younger patients and a heavier predominance of males are seen. and P. aeruginosa is one of the most commonly seen pathogens. The disease is generally monomicrobial. unless it is secondary to a contiguous process such as a pressure sore. in which polymicrobial infection with participation of anaerobes is the general rule. Lumbar. greater than thoracic. greater than cervical involvement is the rule in the general population. but cervical spine involvement is frequently seen more often than thoracic involvement in IVDAs. Diabetic patients are over-represented among patients with vertebral osteomyelitis. and they also have a tendency for higher morbidity and mortality. Simultaneous involvement of adjacent vertebral end plates and the intervening disk is the general rule. The vertebrae are generally involved. and the posterior elements of the spine are involved infrequently. Posterior element involvement is seen more commonly in actinomycosis. coccidioidomycosis. and neoplasms. Newer diagnostic modalities. such as CT. MRI. and radionuclide scans. may detect the disease earlier than conventional radiographs. Immunobilization by bed rest and appropriate antimicrobial therapy are generally sufficient in the therapy of pyogenic. as well as tuberculous. vertebral osteomyelitis. In selected circumstances. such as in the presence of marked instability of the spine. the presence of new neurologic deficits. or with progression of previous neurologic deficits. surgical intervention may be necessary. With prompt diagnosis and proper management. the prognosis should generally be good.
Augmentation of monocyte chemotaxis by 1 alpha,25-dihydroxyvitamin D3. Stimulation of defective migration of AIDS patients, Preincubation for 20 h with 1 alpha.25-dihydroxyvitamin D3 (1.25(OH)2D3) markedly augmented the chemotactic responsiveness of human blood monocytes to the classical chemoattractant. FMLP. A modest enhancement of monocyte spontaneous locomotion in the absence of chemoattractants was also observed. Maximal increase of monocyte migration was observed after pretreatment with 10(-9) M 1.25(OH)2D3 and was detectable at FMLP concentrations ranging from 10(-10) to 10(-7) M. Pretreatment with 1.25(OH)2D3 augmented the number of monocyte high affinity FMLP receptors (1500 +/- 220 and 3800 +/- 300 sites per cell for untreated and 1.25(OH)2D3-pretreated cells. respectively) with no significant changes in Kd values (2 +/- 0.5 nM and 4 +/- 1 nM. for untreated and 1.25(OH)2D3-pretreated monocytes). Enhanced chemotaxis was not restricted to FMLP. because 1.25(OH)2D3-treated monocytes showed enhanced migration also in response to activated C components and chemotactic cytokines. In agreement with previous observations. monocytes from AIDS patients showed defective migration capacity. In vitro exposure to 1.25(OH)2D3 stimulated monocyte migration in all 10 patients examined with considerable quantitative differences among individuals. Regulating the responsiveness of mature monocytes to chemo-attractants. 1.25(OH)2D3. produced systemically or in situ by immunocompetent cells. could play a role in the regulation of the recruitment of monocytes at sites of inflammation. cell-mediated immunity. or bone resorption. The potential of 1.25(OH)2D3 as a restorative agent under conditions of defective phagocyte recruitment deserves further exploration.
In vivo effects of anti-IL-4 monoclonal antibody on neonatal induction of tolerance and on an associated autoimmune syndrome, The role of IL-4 in the cellular interactions leading to the induction of CTL tolerance to H-2b alloantigens and to the development of a lupus-like autoimmune disease in BALB/c mice after neonatal injection with (C57BL/6 x BALB/c)F1 cells was investigated in vivo by using an anti-IL-4 mAb. Treatment of F1 cell-injected BALB/c mice with 15 mg of anti-IL-4 mAb was shown to interfere with tolerance induction. as assessed by the high percentages of H-2b target cell lysis and the very low or undetectable levels of B cell chimerism markers observed in these mice. Treatment with 4.5 mg of anti-IL-4 mAb interfered with tolerance induction only in one-third of F1 cell-injected BALB/c mice. but that dose induces specific modulations of the autoimmune manifestations in all mice. leading to the nearly complete prevention of the disease. In particular. the production of anti-ssDNA IgG1 and of total IgG1 and IgE antibodies was seriously affected by the treatment. as well as the proliferation and membrane Ia and K expression of F1 donor splenic cells and thymic APC. Treatment of F1 cell-injected BALB/c mice between 24 and 48 h of life with 0.5 mg of anti-IL-4 mAb did not interfere with tolerance induction. but had similar effects on the autoimmune syndrome as treatment with 4.5 mg. These results suggest that. after F1 cell injection of newborn mice. IL-4 plays an important role in the cellular interactions leading to the induction of tolerance to the corresponding alloantigens and to the development of the associated autoimmune syndrome.
Loss of epidermal integrity by T cell-mediated attack induces long term local resistance to subsequent attack. II. Thymus dependency in the induction of the resistance, Our previous study showed that in cutaneous graft-vs-host disease (GVHD) induced by intradermal injection of autoreactive T cells the epidermal structures spontaneously recovered from the destruction became resistant to the subsequent attempts to induce the cutaneous GVHD and that the resistance correlated well with a 30-fold increase in the number of Thy-1+ epidermal cells (Thy-1+EC). We show that the resistance to the cutaneous GVHD was never induced in athymic nude mice and adult thymectomy lethal radiation and bone marrow reconstitution (ATXBM) mice under the same conditions. indicating that the induction of the resistance is dependent on the presence of thymus. A great increase in the number of Thy-1+EC was similarly observed in the epidermis of the athymic nude and ATXBM mice that spontaneously recovered from the cutaneous GVHD and that remained susceptible to the induction of the cutaneous GVHD. However. the results with B10Thy-1.1----B6 radiation chimeras clearly demonstrate that the vast majority of the increased Thy-1+EC found in the "susceptible" epidermis of the ATXBM mice were of donor bone marrow origin and there was no increase in the number of host-derived Thy-1+EC. whereas in the "resistant" epidermis of the XBM mice both Thy-1+EC populations were equally increased. The overall results indicate that the expansion of Thy-1+EC that mature in the thymus is crucial to the induction of the resistance. although the migration of bone marrow-derived Thy-1+EC precursors to the epidermis occurs quite independently of the presence of thymus.
Antagonistic and agonistic effects of transforming growth factor-beta and IL-1 in rheumatoid synovium, We investigated potential mechanisms by which lymphocytes infiltrating rheumatoid synovium become immunosuppressed. In 20 of 22 synovial fluids and 12 of 13 synovial tissue culture supernatants. no IL-1 bioactivity could be detected in the thymocyte proliferation assay. These same preparations could. however. support proliferation of fibroblast monolayers. consistent with the presence of IL-1 and/or other fibroblast growth factors. Addition of either rheumatoid synovial fluids or synovial culture supernatants to exogenous IL-1 in the IL-1 bioassay caused marked inhibition of the assay indicative of an IL-1 inhibitor. This inhibition of IL-1 could be reversed by treating the effusions or supernatants with a neutralizing antibody to transforming growth factor-beta (TGF-beta). Furthermore. monocyte-macrophages isolated from rheumatoid synovial fluid constitutively released both latent and active TGF-beta in culture at levels sufficient to completely block the biologic activity of 100 U/ml IL-1. The production of substantial levels of TGF-beta by synovial macrophages. as well as the apparent ability of these inflammatory macrophages to activate latent TGF-beta. implicates TGF-beta not only as an important inhibitor of IL-1-induced lymphocyte proliferation. but also as a key cytokine in promoting synovial fibroblast hyperplasia and pathology.
Evidence that a receptor-operated event on the neutrophil mediates neutrophil accumulation in vivo. Pretreatment of 111In-neutrophils with pertussis toxin in vitro inhibits their accumulation in vivo, The role of neutrophil chemoattractant receptors in neutrophil stimulation in vitro is well established. however. the precise mechanisms underlying local neutrophil accumulation at inflammatory sites in vivo have not been defined. A fundamental question that remains open is whether chemoattractants act on the endothelial cell or the neutrophil to initiate the process of neutrophil migration in vivo. To address this question we have investigated whether neutrophil accumulation in vivo can occur if chemoattractant receptor occupancy is uncoupled from neutrophil stimulation. For this purpose we have used pertussis toxin (PT) as the pharmacologic tool. We have investigated the effect of in vitro pretreatment of rabbit neutrophils with PT on their responses in vitro and on their accumulation in vivo. Pretreatment of rabbit neutrophils with PT inhibited FMLP- and C5a-. but not PMA- induced increases in CD18 expression. neutrophil adherence. and degranulation in vitro. This pretreatment procedure with PT inhibited the accumulation of radiolabeled neutrophils in vivo in response to intradermally injected FMLP. C5a. C5a des Arg. leukotriene B4. IL-8. and zymosan in rabbit skin. Further. in contrast to the in vitro results. PT inhibited the PMA-induced 111In-neutrophil accumulation in vivo. Interestingly. pretreatment of neutrophils with PT also inhibited accumulation in response to intradermally injected IL-1. despite the reports that IL-1 lacks neutrophil chemoattractant activity in vitro. Although the experimental techniques used cannot distinguish the different stages of neutrophil migration involved. these results suggest that the accumulation of neutrophils induced by local extravascular chemoattractants in vivo depends on a pertussis toxin-sensitive receptor operated event on the neutrophil itself. Further. PMA and IL-1 may release secondary chemoattractants in vivo.
Inhibition of neutrophil migration by tumor necrosis factor. Ex vivo and in vivo studies in comparison with in vitro effect, Coincubation of neutrophils with TNF inhibited the chemoattractant-directed migration of neutrophils under agarose and enhanced their migration in the multiwell chemotaxis chamber. To assess the physiological significance of these differing in vitro TNF effects. ex vivo and in vivo investigations were performed using animal models. Neutrophils from the peripheral blood of rabbits preadministered systemic TNF showed impaired ability to migrate toward chemoattractants in vitro. In addition. systemic TNF administration suppressed zymosan-activated plasma-induced local accumulation of leukocytes in mouse skin. The results indicate that circulating TNF may act as a suppressor for local inflammatory reaction.
Expression and characterization of TCA3: a murine inflammatory protein, TCA3 is a cDNA originally isolated from activated T cells. Transcription of this gene has been shown to correlate with Ag-induced cellular activation of both T cells and mast cells. Based on the predicted amino acid sequence encoded by the cDNA. we previously proposed that TCA3 represents a cytokine. In this report we have used rDNA technology to express TCA3 in two mammalian cell lines. In both cases. TCA3 was expressed as a secreted molecule with an apparent molecular mass of 16 kDa. Digestion of the (rTCA3) with the enzyme N-glycanase revealed that approximately 8 kDa is caused by N-linked glycosylation. Intradermal injection of rTCA3 into mouse footpads resulted in a rapid swelling response. The sites of injection were characterized histologically by a local accumulation of neutrophils. These findings are discussed with particular attention to a family of related proteins. some of whose members also have inflammatory properties.
Murine monoclonal anti-idiotype antibody as a potential network antigen for human carcinoembryonic antigen, Carcinomas of the gastrointestinal tract are not curable by standard therapies. Thus. new therapeutic approaches for this disease are needed. This study proposes the use of anti-Id mAb as Ag substitutes to induce anti-tumor immunity in gastrointestinal cancer patients. Recently. we have generated and characterized one monoclonal anti-Id antibody. designated 3H1 (Ab2). which mimics biologically and antigenically a distinct and specific epitope of the 180.000 m.w. carcinoembryonic antigen (CEA) primarily expressed in high density by human pancreatic and colonic tumor cells. This epitope is unique to CEA and not present on other CEA-related lower m.w. members of the Ag family also found on normal tissues. The antigenic determinant as defined by the mAb 8019 (Ab1) against which the Ab2. 3H1 was raised. is absent on normal adult tissues by immunoperoxidase staining and haematopoietic cells including granulocytes by flow cytometry analysis. Anti-Id (Ab2) 3H1 induced CEA-specific antibodies in mice and rabbits. The immune sera from both mice and rabbits competed with Ab1 for binding to the colon carcinoma cell line LS174T and inhibited the binding of radioiodinated Ab1 to Ab2. This indicates that anti-anti-Id (Ab3) in mice and rabbits share idiotopes with Ab1 (8019). Furthermore. monoclonal Ab3 that bind to CEA have been generated from mice immunized with 3H1. The Ab3 (both polyclonal as well as monoclonal) immunoprecipitated the same 180.000 m.w. CEA as Ab1 (8019) by Western blotting analysis and showed almost identical immuno-staining patterns as Ab1 on colonic adenocarcinoma tissue sections from several patients. Collectively these data suggest that Ab2 3H1 could potentially be used clinically as a network Ag for immunotherapy of patients with CEA positive tumors.
Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization, These studies address the hypothesis that Ag-bearing epidermal Langerhans cells migrate to the regional lymph node during contact sensitization and function as APC. Skin from C3H mice was grafted onto BALB/c nude mice. and 7 or 14 days later. the recipients were sensitized with FITC through the grafts. APC from lymph nodes draining the site of sensitization were capable of sensitizing C3H recipients to FITC. Because sensitization is MHC restricted. only cells reaching the lymph node from the grafted skin could have induced contact hypersensitivity in C3H mice. Examination of the FITC+ draining lymph node cells by immunofluorescence and immunoelectron microscopy demonstrated that all were Ia+. most were F4/80+. and some contained Birbeck granules. These studies demonstrate that Ia+. FITC+ cells from the skin. at least some of which are Langerhans cells. leave the skin after epicutaneous sensitization with FITC and participate in the initiation of the contact hypersensitivity response within the regional lymph node.
Intact antigen receptor-mediated generation of inositol phosphates and increased intracellular calcium in CD4 CD8 T lymphocytes from MRL lpr mice, The predominant T lymphocytes that accumulate in the peripheral lymphoid tissues of mice homozygous for the lpr gene bear the phenotype CD3+CD4-CD8-. By certain functional criteria these cells would appear to have impaired CD3-mediated signal transduction. in that they do not respond to alloantigen and produce little if any detectable IL-2 or other lymphokines. However. the signal pathway appears adequate for achieving other T cell functions. including induction of high affinity IL-2R. and thymic deletion. To clarify the basis of this seeming discrepancy. we examined transmembrane signal transduction in T cell subsets of lpr/lpr (lpr) and +/+ mice. as defined by increased [Ca2+]i and the generation of inositol phosphates (InsPs). Stimulation of lpr CD4-CD8- cells with anti-CD3 antibody produced prompt and sustained increases in the concentration of [C2+]i and in InsPs. Similar responses occurred in mature T cells from lpr and +/+ mice. except for the somewhat slower kinetics of their increased [Ca2+]i. In marked distinction to the anti-CD2-mediated response. Con A. even in high doses. could not stimulate any increase of [Ca2+]i in lpr CD4-CD8- cells. and only modest increases in InsPs. Mature T cells. whether of lpr or +/+ origin. yielded normal increased [Ca2+]i with Con A. The reason for the differences in signal transduction between anti-CD3 and Con A stimulation of lpr CD4-CD8- cells may relate to the absence of surface structures on these immature T cells that are required for activation by Con A but not by anti-CD3. The data demonstrate that the CD3 complex in lpr CD4-CD8- T cells can couple to phospholipase C to hydrolyze phosphoinositides. These activation properties of lpr CD4-CD8- T cells have interesting functional parallels to thymocytes at the time of thymic selection. as well as tolerance induction of mature T lymphocytes.
Human severe combined immunodeficiency disease: phenotypic and functional characteristics of peripheral B lymphocytes, Human severe combined immunodeficiency disease (SCID) includes an X-chromosome-linked type characterized by a complete absence of mature T cells. hypogammaglobulinemia but normal or elevated number of B cells. suggesting that the disease results from a block in early T cell differentiation. It has been shown that B cells from obligate carrier women of this disorder exhibit the preferential use of the nonmutant X chromosome as the active X (as shown for T cells). suggesting that the SCID gene product has a direct effect on B cells as well as on T cells. To examine this question. we analyzed the phenotypic and functional characteristics of peripheral B cells from nine infants with SCID. We found a constant absence of spontaneously expressed activation Ag on B cell membrane from all SCID patients tested which contrasts with the phenotypic pattern exhibited by age-matched infants whom all cells bearing surface Ig express the 4F2 Ag and to a lesser extent the transferrin receptor. Concurrently. B cells from SCID patients have a profound impairment in their responses to stimuli that induce in vitro B cell proliferation and differentiation. Although rIL-2 and low-Mr B cell growth factor are potent inducers of proliferation on age-matched infants' B cells. they are poorly efficient in inducing proliferation of anti-mu-activated SCID B cells. This impairment is not related to the resting B cell phenotype of SCID B cells as shown by comparison with normal resting B cells. Furthermore. we observed an apparent block in B cell differentiation inasmuch as neither rIL-2 nor rIL-6 could support SAC-activated SCID B cell differentiation. both lymphokines being very efficient in inducing SAC-activated age-matched infants' B cell or purified resting B cell differentiation. These results suggest that the SCID gene defect has a direct effect on B cells and is required during B cell maturation.
Cytokine regulation of IL-1 beta gene expression in the human polymorphonuclear leukocyte, Although recently polymorphonuclear leukocytes (PMN) have been identified as producers of IL-1 beta in response to LPS and granulocyte/monocyte colony stimulating factor. little is known regarding the ability of other cytokines to induce the production of IL-1 beta in the PMN. Inasmuch as IL-1 and TNF have been shown to be important priming agents. as well as agents that induce migration of PMN. we investigated their effect on IL-1 beta gene expression in human peripheral blood PMN. In the present study. we demonstrate that human peripheral blood PMN produce IL-1 beta in response to IL-1 alpha. IL-1 beta. and TNF-alpha. Control (unstimulated) human PMN had virtually undetectable levels of IL-1 beta mRNA. Either IL-1 beta or TNF. induced PMN to transiently express IL-1 beta mRNA with peak expression at 1 h. returning to untreated levels by 2 h. A dose response indicated that as little as 0.05 ng/ml of IL-1 beta or TNF resulted in IL-1 beta induction. with maximal effects at 1 ng/ml of IL-1 beta and 5 ng/ml of TNF. IL-1 alpha or IL-1 beta exhibited similar dose responses in IL-1 beta mRNA induction. Inasmuch as cytokines have been shown to have synergistic effects in cell function studies. we induced PMN with a combination of maximally effective doses of TNF plus IL-1 beta. They demonstrated a cooperative effect on IL-1 beta gene expression. in that mRNA levels were sustained for three hours. IL-1 beta Ag expression. as measured by ELISA. paralleled IL-1 beta mRNA expression with cell associated peak levels at 2 to 4 h. IL-1 beta Ag levels in PMN lysates and supernatants correlated with IL-1 beta mRNA levels. i.e.. TNF + IL-1 greater than TNF greater than IL-1. Thus. these studies represent the first demonstration of IL-1 and TNF induction of IL-1 beta gene expression in the PMN. Furthermore. the time course of induction is unique to the PMN. with peak induction of mRNA at 1 h. which is consistent with the short lived nature of these cells in inflammatory lesions.
Analysis of the immune response to lipopolysaccharide. Existence of an interspecies cross-reactive idiotype associated with anti-lipid A antibodies, LPS is the major surface glycolipid on gram-negative bacteria. In this work. we have idiotypically characterized the antibody response against LPS in different species. To do this. we have produced mAb against LPS. Binding of many of these antibodies to LPS could be inhibited by LPS and lipid A. indicating that the monoclonals are specific for lipid A. the toxic moiety of the LPS molecule. One anti-lipid A antibody. IC9. proved protective against gram-negative bacteremia and endotoxic shock in murine protection models. We generated anti-idiotypic antibodies against IC9. The binding of several of these anti-Id to IC9 was specifically inhibited by lipid A. We used these anti-Id to characterize the anti-LPS response. and the results revealed that the IC9 Id is conserved in different species. The importance of an interspecies cross-reactive Id in the response to endotoxin and its relevance in vaccine development for septic shock are discussed.
Regulation of HLA class II molecule expressions by IFN-gamma. The signal transduction mechanism in glioblastoma cell lines, We examined the signal transduction mechanism responsible for the IFN-gamma-induced HLA class II molecule expressions on glioblastoma cell lines. T98G and A172. A series of experiments demonstrated that the activation of protein kinase C (PKC) is involved in the DR and DP molecule expressions on T98G cells. In addition to the activation of PKC. calcium influx appeared to be involved in the DR and DP molecule expressions on T98G. Northern blot analyses with actinomycin D or cycloheximide revealed that these second messengers induce the transcription of DRA and B and DPA and B genes without de novo protein synthesis. Furthermore. we examined the region of the DPB gene that is responsible for IFN-gamma-induced gene transcription by gene transfer of a series of 5' and 3' deletion mutants in which the upstream region of the DPB was linked to a reporter gene. chloramphenicol acetyltransferase. By using these deletion mutants. it appeared that the region between -152 and -126 bp contains a critical IFN-gamma-responsive element. Taken together. these results suggest that IFN-gamma activates PKC and stimulates calcium influx. resulting in the induction of transcription of DRA and B and DPA and B genes without de novo protein synthesis. In DPB gene. we speculate that preexiting protein(s) phosphorylated by PKC in the presence of Ca2+ might directly bind or indirectly interact with the region between -152 and -126 bp of the upstream sequence. leading to the induction of the transcription (possibly in concert with other nuclear protein(s) bound to the promoter sequences).
Low doses of IL-4 injected perilymphatically in tumor-bearing mice inhibit the growth of poorly and apparently nonimmunogenic tumors and induce a tumor-specific immune memory, The ability of rIL-4 to trigger host reactivity against both a chemically induced fibrosarcoma (CE-2) and a spontaneous adenocarcinoma (TS/A) of BALB/c mice was studied. Daily local s.c. administration around tumor draining lymph nodes of 10 injections of progressive amounts (0.00001 to 1000 pg/day) of rIL-4 induced appreciable inhibition of the growth of both tumors after a dose-response survival curve peaking at 0.1 pg/day. Inasmuch as rIL-4 has no direct antitumor activity. as shown by in vitro tests. host immune reactivity plays a fundamental role in this lymphokine activated tumor inhibition (LATI). LATI. in fact. is abolished when recipient mice are sublethally irradiated or treated with cyclosporin A. or when the reactivity of CD4+ lymphocytes is suppressed. whereas it is not affected by anti-asialo GM1 antibody. The morphologic data show that rIL-4 LATI rests on the recruitment of several cell reaction mechanisms. among which those that are nonspecific seem to predominate. rIL-4 LATI also leads to a state of long lasting and specific immune memory: the growth of a second contralateral tumor challenge is significantly impaired after LATI. This immune memory takes place after LATI of both the poorly immunogenic CE-2 fibrosarcoma and the TS/A adenocarcinoma. previously classed as nonimmunogenic on the basis of immunization-protection tests. In the latter case. adoptive transfer experiments show that Thy-1+ lymphocytes and. in particular. the CD4 cell-depleted T lymphocyte subpopulation. are responsible for the immune memory. Finally. the ability of rIL-4 to trigger LATI is greater than that of the most effective doses of rIL-2. rIL-1 beta. and IFN-gamma. whereas its association with rIL-1 beta induces a more effective immune memory.
Retroviral expression of transforming growth factor-alpha does not transform fibroblasts or keratinocytes, Transforming growth factor alpha (TGF alpha) is a peptide so named because it helps to impart anchorage-independent growth to normal rat kidney (NRK) cells in vitro and is secreted by many rodent and human tumor cells. To directly investigate the transforming properties of this factor. we constructed a replication-defective murine retrovirus that expresses the human sequence coding for TGF alpha. Infection of NIH/3T3 cells with the TGF alpha retrovirus led to the integration of a transcriptionally active provirus and overexpression of biologically active TGF alpha. but failed to induce morphologic transformation. Similarly. the TGF alpha retrovirus failed to induce morphologic transformation of five other types of rodent fibroblasts. We also investigated the effect of TGF alpha expression on the growth of BALB/MK mouse keratinocytes. which require epidermal growth factor (EGF) for proliferation. We show that exogenously added TGF alpha is an extremely potent mitogen for BALB/MK cells. However. retroviral expression of TGF alpha in BALB/MK cells failed to relieve dependence on exogenously added EGF (or TGF alpha) for cell growth. These results suggest that overexpression of TGF alpha does not. by itself. transform rodent fibroblasts or keratinocytes.
Aberrant proliferation of lumen-forming cells in stratified epithelium of porokeratosis skin, The present investigation was based on the postulate. first proposed by Reed and Leone in 1970. that porokeratosis lesions represent clonal growth of epidermal cells. Comparative studies using immunocytochemical staining. epidermal cell culture. and non-equilibrium pH gradient (NEpHG) gel electrophoresis analysis of the keratins extracted were carried out on five patients with various types of porokeratosis. Positive type IV collagen staining on the stratum corneum was found in lesional skin specimens of all patients. but not in normal controls. A search for connections between type IV collagen in the basement membrane of epidermis and the skin surface disclosed infrequent intra-epidermal streaking of type IV collagen and one positively stained trans-epidermal acrosyringium. Positive intra-epidermal laminin staining in porokeratosis lesions confirmed the trans-epidermal passage of basement-membrane materials. Epidermal cells cultured from lesional skin showed low plating efficiency. and all colonies exhibited intracytoplasmic vacuole formation and excessive top cell shedding. NEpHG gel electrophoresis of keratins extracted showed that lesional profiles not only contained keratins normally present in glabrous skin. but also possibly K9 and some additional proteins. K9 had been immunolocalized to periductal cells in previous studies. Our findings. taken together. strongly suggest that porokeratosis epidermis consists of epithelial cells with lumen-forming ability.
The innermost cell layer of the outer root sheath is positive with Ki-67, The expression of a cell proliferation-associated human nuclear antigen was immunohistochemically studied in human anagen hair and hair follicles using the monoclonal antibody Ki-67. The reaction of Ki-67 in mature anagen hair follicles was observed in the hair matrix cells and outer root sheath (ORS) cells. Nuclear staining was seen in a small number of matrix cells and in some ORS cells; this finding corresponded to the thymidine or bromodeoxyuridine labeling studies previously reported. In addition. there were two different patterns of cytoplasmic staining in the ORS: strong staining of the innermost cells (IMC) and weaker staining of the other ORS cells in the isthmus. Ki-67 reactivity of the IMC layer was observed at each stage of anagen and was regularly seen from the upper bulb to the isthmus. Ki-67 is a commercially available antibody that detects cycling cells. However. the IMCs in anagen hair follicles showed cytoplasmic labeling by Ki-67 from the matrix cells in the upper bulb to the distal portion of the isthmus.
Recruitment of mononuclear cells by endothelial cell binding into wounded skin is a selective, time-dependent process with defined molecular interactions, Wound healing involves a complex series of interactions between cells in the dermis and epidermis. and important relationships exist between keratinocytes and resident dermal cells. Monocytes and lymphocytes secrete cytokines that are capable of stimulating dermal repair and influencing keratinocyte and fibroblast migration and proliferation. although the mechanism by which mononuclear cells are recruited into the wound is unknown. We have tested the hypothesis that in wounded skin specialized endothelial cells are induced to mediate peripheral blood mononuclear cell (PBMC) emigration from the vasculature into the dermis. For this purpose. partial-thickness wounds made with a keratome on the backs of domestic pigs were excised 0 to 9. 12. 15. and 21 d after wounding. The biopsies were then tested for the capacity to adhere selectively to PBMC. The results indicated that PBMC overlaid onto sections of wounds from day 4 to 15 adhered selectively to dermal endothelium. with two distinct peaks of adherence observed on day 7 and day 12. In contrast. PBMC did not adhere to the tissue sections when overlaid onto frozen sections of normal skin or 0-. 1-. 2-. 3-. and 21-d-old wounded skin. Additional studies on the binding properties of PBMC subsets revealed that monocytes adhered maximally at day 7. whereas T cells adhered optimally at day 12 post-wounding. Furthermore. the adhesion process was energy and magnesium dependent but not calcium dependent and involved surface protein and carbohydrate moieties on PBMC surface. Pre-treatment of PBMC with monoclonal antibodies against the LFA-1 adhesive receptors inhibited the binding by greater than 80%. suggesting that LFA-1 adhesive receptors play an important role in the binding process. These studies provide evidence that the recruitment of monocytes and lymphocytes into wounds is an active. dynamic. and regulated process mediated at least in part by specific adhesive interactions between mononuclear leukocytes and dermal endothelial cells.
Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia, We studied 10 cutaneous telangiectatic lesions of hereditary hemorrhagic telangiectasia (HHT). ranging in size from pinpoint to 2 mm. by light and electron microscopy. Four representative lesions were reconstructed by computer from serial 1- or 2-mm plastic embedded sections. The earliest clinically detectable lesion of HHT is a focal dilatation of postcapillary venules. which continue to enlarge and eventually connect with dilated arterioles through capillaries. As the vascular lesion increases in size. the capillary segments disappear and a direct arterio-venous communication is formed. This entire sequence of morphologic events is associated with a perivascular mononuclear cell infiltrate in which the majority of cells are lymphocytes and the minority are monocytes/macrophages by ultrastructure. Comparison of these findings with the telangiectatic mats of scleroderma and cherry angiomas revealed that the former. previously shown to be composed of dilated postcapillary venules. are also associated with perivascular infiltrates. but the latter. which are produced by capillary loop aneurysms. are not.
Increased phospholipase C-catalyzed hydrolysis of phosphatidylinositol-4,5-bisphosphate and 1,2-sn-diacylglycerol content in psoriatic involved compared to uninvolved and normal epidermis, Evidence suggests that the phospholipase C/protein kinase C signal transduction system participates in the regulation of epidermal cell growth and differentiation. Psoriatic epidermis is characterized by hyperproliferation. defective differentiation. and inflammation. In this report. we have determined the activity of phospholipase C-catalyzed hydrolysis of phosphatidylinositol-4.5-bisphosphate (PIP2) and 1.2-diacylglycerol content in normal and psoriatic involved and uninvolved epidermis. 1.2-diacylglycerol is formed from phospholipase C-catalyzed hydrolysis of PIP2 and is the physiologic activator of protein kinase C. PIP2 hydrolysis was assayed in soluble and particulate fractions prepared from keratome biopsies of normal and psoriatic skin. Total lipids were extracted from normal and psoriatic epidermis and 1.2-diradylglycerol (a mixture of 1.2-diacylglycerol and 1-ether. 2-acyl-glycerol) quantitated by enzyme assay. Because 1.2-diacylglycerol is a more potent activator of protein kinase C. the relative proportions of 1.2-diacyl and 1-ether. 2-acylglycerol in uninvolved and involved psoriatic epidermis were determined. This was accomplished by separation of acetate derivatives of 1.2-diacylglycerol and 1-ether. 2-acyl-glycerol by thin layer chromatography. Soluble and membrane-associated phospholipase C-catalyzed PIP2 hydrolysis were increased 3.7 times (p less than 0.001) and 3 times (p less than 0.004). respectively. in psoriatic involved compared to uninvolved and normal epidermis. 1.2-diradylglycerol content was also significantly elevated (3 times. p less than 0.01) in psoriatic involved versus uninvolved and normal epidermis. Analysis of the acetate derivatives of 1.2-diradylglycerol in psoriatic uninvolved and involved epidermis revealed that 1.2-diacylglycerol was the major species (86% and 95%. respectively). There were no significant differences in either phospholipase C-catalyzed PIP2 hydrolysis or 1.2-diacylglycerol content between uninvolved and normal epidermis. 1.2-diacylglycerol purified from normal and involved psoriatic epidermis was capable of activating protein kinase C from normal epidermis in vitro. In epidermal slices. activation of protein kinase C by addition of 12-0-tetradecanoylphorbol-13-acetate and 1.2-diacylglycerol (1.2-dioctanoylglycerol) resulted in subsequently decreased protein kinase C activity. a process termed down-regulation. These data are consistent with the possibility that the elevation in lesional 1.2-diacylglycerol content may account. in part. for the previously reported reduction of protein kinase C activity in psoriasis (Horn. Marks. Fisher. et al: J Invest Dermatol 88:220-222. 1987).
Successful culture of adult human melanocytes obtained from normal and vitiligo donors, The development of growth conditions for human melanocytes from uninvolved skin from vitiligo patients and age-matched normal adults is a prerequisite to understanding the etiology of this pigmentary disorder. By using new growth conditions. pure melanocyte cultures were prepared from normal adults and the pigmented skin of vitiligo donors. Both cell types grew without a lag period and were maintained for more than six months (4-8 passages). The cultures could be expanded from several thousand melanocytes in the original cell suspension to several million cells (2-7 x 10(6] in pure culture. To obtain these results. the current standard conditions for the culture of fetal melanocytes were substantially modified. MEM-S medium was less satisfactory than MCDB-153. Adult normal and vitiligo cells also required the presence of exogenous catalase (20 micrograms/ml) during isolation and primary seeding. Thereafter. this enzyme was not necessary. Melanocytes grew best and gave the highest yields if the concentrations of both calcium (200 microM) and the phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) were low (4-8 nM). Other growth factors included in the MCDB-153 media were bFGF. crude bovine pituitary extract. insulin. transferrin. hydrocortisone. 5% FCS. and the antioxidant alpha-tocopherol. Cholera toxin and isobutylmethylxanthine (IBMX) were omitted from the MCDB-153 growth medium because they slowed down growth even at very low concentrations. The results indicate adult and vitiligo melanocytes can be cultured. Preliminary studies of the normal and vitiligo cells indicate that vitiligo melanocytes retain some of the ultrastructural abnormalities observed in skin even when grown in culture.
Isolation and quantitation of human erythrocyte deformability classes, A new technique is described that fractionates erythrocytes according to their deformability. The method is a modification of the method of Beutler et al. (J Lab Clin Med 1976;88:328-33). in which small cellulose columns are used to remove white cells from blood samples. We find that when the length-to-width ratio of the columns is increased. the mixed cellulose bed also fractionates the red cells. Measurement of mean cell volume. mean corpuscular hemoglobin concentration. hemoglobin level. deformability index. and cell density showed that deformability is the physical property of the erythrocyte that forms the basis for the fractionation. This is a separation modality that complements the numerous density gradient techniques for red cells. The following experimental results can be obtained by using the technique: (1) The number of cells with a defined degree of rigidity can be quantitated in an erythrocyte population. (2) Large numbers of cells that differ with respect to their deformability can be isolated. (3) Application of the method to sickle cells has quantitated the remarkable heterogeneity of these cells with regard to their deformability.
Acute effects of captopril and ibuprofen on proteinuria in patients with nephrosis, Captopril decreases protein excretion in patients with nephrosis. To evaluate whether captopril has an acute antiproteinuric effect and to evaluate the role of changes in renal hemodynamics or glomerular permselectivity on this effect. renal clearance studies were performed in patients without diabetes but with nephrosis. Protein excretion and renal hemodynamics were measured at baseline and after the administration of captopril. To measure the contribution of renal prostaglandins. patients were restudied on a separate day. after the combined administration of captopril and the prostaglandin synthetase inhibitor ibuprofen. Both treatments significantly reduced mean protein excretion. but the change was greater with combined therapy than with captopril alone (40.6% vs 20.0%). Mean glomerular filtration rate (GFR) decreased by 4.8% (not significant) and 16.5% (p less than 0.001). and filtration fraction (FF) decreased by 13.6% (p less than 0.001) and 14.9% (p less than 0.001) after captopril alone and combined therapy. respectively. No significant correlation was found between changes in proteinuria and changes in GFR or FF after treatment with captopril alone. In contrast. the decrease in proteinuria correlated with the change in GFR after combined drug administration (r = 0.68. p = 0.06). The ratio of immunoglobulin G to albumin clearance. an index of glomerular permselectivity. was unaffected by captopril but decreased significantly (by 43%) after combined drug administration. The results suggest that the acute antiproteinuric effect of captopril is not due to changes in FF. GFR. or glomerular perselectivity. The addition of ibuprofen enhances the antiproteinuric effect of captopril by decreasing the GFR as well as by enhancing the permselectivity of the glomerular capillary membrane.
Assessment of platelet antibody by flow cytometric and ELISA techniques: a comparison study, Two different methods for evaluating platelet antibody were used to study 12 normal subjects and 24 patients consisting primarily of intravenous drug users (IVDUs) who were positive for human immunodeficiency virus (HIV). Total platelet-associated immunoglobulin G (IgG) and immunoglobulin M (IgM) were measured by enzyme-lined immunosorbent assay on platelet lysate. and platelet surface-associated IgG and IgM were measured by semiquantitative flow cytometry. IgG and IgM values showed significant correlations between the two measurement methods. Mean platelet surface IgG and total IgG were 3.6 and 4.3 times greater. respectively. in IVDUs than in controls. and platelet IgM was also significantly higher in IVDUs than in controls as measured by both techniques. Although mean platelet immunoglobulin levels were higher in the IVDUs with thrombocytopenia than in IVDUs with normal platelet counts. these differences did not achieve significance. These data show that platelet IgG and IgM levels are increased in IVDU-associated HIV infection and suggest that these increases are not confined to patients manifesting thrombocytopenia. The herein described platelet surface antibody and total platelet antibody measurements appear to be equally useful in studying this patient population. Specific details for generating platelet-associated immunofluorescence units are discussed.
DNA sequence analysis of three inhibitor-positive hemophilia B patients without gross gene deletion: identification of four novel mutations in factor IX gene, Three hemophilia B patients with anti-factor IX antibodies who had no detectable gross deletion of the factor IX gene by Southern blotting analysis were investigated at the molecular level. All eight exons. accompanied by their splicing junction sites and presumptive promoter regions of the factor IX gene in these patients (total 5.5 kb in length) were amplified with the use of the polymerase chain reaction. followed by complete nucleotide sequence analysis. Three different types of novel single base substitutions and a 2 base-pair nucleotide deletion were identified. Patient HB-5 had two point mutations in his factor IX gene. One was located at the promoter region at nucleotide -793 and the other (C-to-T transition) was found in exon VI of the gene changing Gln-191 to a stop codon. Patient HB-6 had a point mutation (G-to-A) in the splice acceptor site. which interrupted the normal splicing of the last intron G. A small two-nucleotide deletion in exon III was detected in patient HB-7 and yielded frameshifted amino acids and terminated by a stop codon. These resuslts suggest that not only the gross gene deletion of factor IX gene but also the point mutations or small nucleotide deletion that may cause the interruption of coding informations for mature protein synthesis is predisposed to development of anti-factor IX inhibitors in patients with hemophilia B.
Immune activation is associated with phenylhydrazine-induced anemia in the rat, Long-term phenylhydrazine (PHZ) treatment caused pronounced anemia and a concomitant increase in the numbers of circulating leukocytes in Long-Evans rats. The leukocytosis was caused mainly by an elevation in mononuclear cells. most notably in the lymphocyte population. PHZ has been reported to cause the direct lysis of erythrocytes by nonimmune mechanisms. However. recent reports indicate that PHZ can cross-link red cell band 3 protein (senescent antigen). resulting in the binding of autologous immunoglobulin G (IgG). Recognition of this complex by macrophage Fc receptor mechanisms triggers rapid erythrophagocytosis-in the spleen and possibly the liver as well. In our study. analysis of the blood. bone marrow. and spleen cells of long-term (1 to 6 weeks) PHZ-treated rats was performed by using flow cytometry. Total serum IgG levels were determined by radial immunodiffusion. and antibodies reactive with red cells that were sensitized to PHZ either in vivo or in vitro were titered by using the indirect Coombs' method. Serum prostaglandin E2 titers also were determined at different time intervals after PHZ administration. The results indicate that PHZ induces an increase in circulating antibody and prostaglandin E2 titers that correlates with the onset of anemia and that the serum of PHZ-treated rats can induce anemia in normal recipients after passive transfer. Cytofluorographic studies revealed a marked increase in the B-cell population of the peripheral blood and spleen and an altered ratio T-helper to T-suppressor cells at certain time intervals after PHZ injection. The results indicate that in addition to inducing senescence-like alterations in erythrocyte membrane proteins. PHZ stimulates the production of the autologous IgG that recognizes these sites and promotes lymphoid blastogenesis. most notably in the B-cell lineage.
Use of ektacytometry to determine red cell susceptibility to oxidative stress, To define a more sensitive and reliable method to determine changes in the overall cellular characteristics of erythrocytes after oxidative damage. we used a viscodiffractometric method (ektacytometry) to measure the effect of oxidative stress. Erythrocytes were incubated in the presence of hydrogen peroxide. t-butyl hydroperoxide. or cumene hydroperoxide in phosphate buffer. This treatment resulted in decreased cellular deformability of the intact erythrocytes. In addition. deformability and fragility measurements of the erythrocyte ghost membranes indicated an increased membrane dynamic rigidity and altered-mechanical stability as a consequence of oxidant stress. These changes were observed before the onset of hemolysis. The observed decrease in deformability was accompanied by oxidation of hemoglobin. alterations of membrane proteins. and lipid peroxidation. To continuously measure the time course of the decrease in deformability in intact erythrocytes under oxidative stress. a new ektacytometric method was developed. Erythrocytes were oxidatively challenged within the viscometer at a constant osmolality and shear stress. The change in deformability was monitored and a typical range was defined for erythrocytes from normal individuals. Comparison of erythrocytes from patients with sickle cell disease with those from normal individuals demonstrated a higher susceptibility of sickle red cells toward oxidative stress.
Abnormal processing of pro-IGF-II in patients with hepatoma and in some hepatitis B virus antibody-positive asymptomatic individuals, Hepatomas are a common malignancy in countries with a high prevalence of hepatitis B virus infections. These tumors may present with severe persistent hypoglycemia. We have studied the possible relationship of production of insulin-like growth factor II (IGF-II) by these tumors and the development of hypoglycemia. Mean IGF-II concentration was not significantly higher in 23 patients with hypoglycemia than in nine patients with euglycemia (542 +/- 61 [SE] micrograms/L vs 382 +/- 52 micrograms/L). Serum IGF-I was more suppressed in patients with hypoglycemia (16 +/- 3 micrograms/L) than in patients with euglycemia (57 +/- 18 micrograms/L). Because an increased percentage of IGF-II in serum of patients with hypoglycemia who have other tumors is present as partially processed pro-IGF-II ("big" IGF-II). we passed sera of patients with hypoglycemia and patients with euglycemia with hepatomas through acidic Bio-Gel P-60 columns. We found that 57% +/- 4.6% of the IGF-II in sera from patients with hypoglycemia was present as big IGF-II compared with 22% +/- 3% in patients with euglycemia with hepatomas (not significantly different from that in normal controls). Four of 11 apparently healthy control subjects who were hepatitis B virus positive also had increased percentages of big IGF-II. suggesting that abnormal processing of pro-IGF-II may result from subtle changes in liver function with this infection. It remains to be determined whether these subjects with increased big IGF-II are at increased risk for the development of hepatomas. In conclusion. we have confirmed marked suppression of IGF-I in the sera of patients with hepatoma and hypoglycemia.
Community screening for hypercholesterolemia, This study focused on a cholesterol screening and education program conducted in Scottsdale. Arizona. to determine the prevalence of hypercholesterolemia among the volunteer participants. and whether such a program motivates lifestyle changes and physician follow-up. The study also examined whether participants used the program to monitor known hypercholesterolemia. During the 6-month program. 1228 individuals were screened. Of these. 29% had a previous history of elevated cholesterol and 5% were on cholesterol-lowering medication. Of the group with no previous history of hypercholesterolemia. 41% had cholesterol levels higher than 5.17 mmol/L (200 mg/dL) and 10% had levels higher than 6.21 mmol/L (240 mg/dL). A subgroup of 120 persons with levels higher than 6.21 mmol/L (240 mg/dL) were contacted 4 to 6 months after the screening. Most of this group reported improvement in diet and exercise patterns. and 58% had consulted a physician. These results suggest that people with known hypercholesterolemia are using community screening programs to monitor their own cholesterol levels. and that such programs identity new high-risk individuals. Program participants appear to change diet and exercise patterns and to seek physician follow-up.
Oscillometric finger blood pressure versus brachial auscultative blood pressure recording, In this study. a recently marketed proprietary finger blood pressure monitor. the Marshall. Astro F-88. was compared with the standard auscultative brachial mercury sphygmomanometer on 125 subjects. Measurements were undertaken according to the standards set by the American Heart Association. Sensitivity of the finger blood pressure measurement was 76% for systolic and 75% for diastolic blood pressure in diagnosis of high blood pressure (systolic greater than 140 mm Hg and diastolic greater than 90 mm Hg). Specificity was 86% for systolic and 82% for diastolic blood pressure. Positive predictive values were 58% for systolic and 38% for diastolic blood pressure in the study population in which prevalence of hypertension was 12%. The correlation coefficient (Pearson) for systolic values between devices was 0.76 (P less than .0001) and 0.57 (P less than .0001) for diastolic pressure. Values obtained by the finger monitor were found to be higher than those obtained by the mercury sphygmomanometer. Mean differences and standard deviations (paired t test) for systolic and diastolic pressures between the two devices were 2.3 +/- 14.9 mm Hg (P less than .08) and 2.9 +/- 14.5 mm Hg (P less than .02). respectively. These values are not in accordance with the proposed national standards because only 48% of the systolic and 37% of the diastolic blood pressure measurements were within 5 mm Hg of the mercury sphygmomanometer measurements. Therefore. although these differences may well be due to different techniques of monitoring employed by the devices. this device is not recommended for evaluation of blood pressure.
Botulinum toxin treatment in spasmodic torticollis, Botulinum toxin A was administered to 19 patients in a double-blind placebo controlled trial. Toxin was more effective than placebo for improving both head position and pain which was measured by an objective rating scale and videofilm assessments. Following the controlled trial. treatment with botulinum toxin was continued in an open fashion. A total of 60 patients with torticollis received toxin in a total of 117 treatment periods. The mean follow up period was 8.4 months. In 39 patients with pain there was benefit in 77% of treatment periods. Some improvement in neck posture occurred in 83% of the treatment periods with a mean duration of 12 weeks. Side effects were frequent with dysphagia being the most common (28% of treatment periods). Botulinum toxin is an effective treatment for toticollis but treatment should be initiated with doses at the lower end of the range used in this study (400-600 mouse units).
Bimanual simultaneous motor performance and impaired ability to shift attention in Parkinson's disease, The ability to share time and to shift attention between bimanual simultaneous motor tasks were studied in 18 patients with Parkinson's disease (PD) and 19 age- and intelligence-matched controls. The task consisted of drawing triangles with the dominant hand and squeezing a rubber bulb with the nondominant hand. Motor performance was measured using the variables: amplitude of squeezing. frequency of squeezing and velocity of drawing triangles. After eliminating variance due to baseline differences in single-handed performance. the bimanual simultaneous performance of PD and controls turned out to be similar to the frequency of squeezing and the velocity of drawing triangles. The amplitude of squeezing. however. differed between the two groups: it was significantly reduced in PD. Arguably the disturbance in the bimanual performance of PD patients was not due to a disorder of time sharing. but to a decreased ability to shift attention from the visually cued task to the non visually cued task. The results agree with current evidence that PD patients are more impaired when they have to rely upon internal control for the regulation of shifting attention than when external cues are available.
Misperceptions of comprehension difficulties of stroke patients by doctors, nurses and relatives, Doctors. nurses and relatives involved with 30 recently aphasic stroke patients were asked to predict how the patient would perform on a comprehension test. Results show that not only do doctors. nurses and relatives underestimate the receptive disability of these patients. but they also illustrate a lack of agreement between health professionals. Implications for management are considered.
Practice effects on the preprogramming of discrete movements in Parkinson's disease, The effects of practice on the simple and choice reaction times (RTs) of Parkinson's disease (PD) and control subjects in a discrete aiming task were analysed. For controls. practice led to a selective decrease in choice RTs. as has been reported previously. An opposite effect was seen in the PD group. with little change in choice RTs and substantial reduction in simple RTs. The results suggest that PD subjects can use advance information to initiate discrete movements more rapidly. but that this ability to "preprogramme" movements requires practice. Reconciliation of these results with studies reporting an inability to preprogramme in PD are made in a discussion of task characteristics which may allow or preclude preprogramming.
Spirometric findings and mortality in never-smokers, The relation of ventilatory function to overall mortality has been studied in 662 male and 2048 female never-smokers who during the period 1976-1978 participated in the Copenhagen City Heart Study. a prospective community study of more than 14.000 men and women randomly selected from the general population of the City of Copenhagen. Until the end of 1986. 195 subjects who said they were never-smokers died. Mortality was analyzed using the proportional hazards model of Cox. In addition to measures of ventilatory function. the mortality analysis included age. sex. body-mass index. alcohol consumption. school education. diabetes mellitus. heart disease and bronchial asthma as confounding factors. Forced expiratory volume in 1 second (FEV1) as a percentage of that predicted. forced vital capacity (FVC) as a percentage of that predicted and the ratio of FEV1 to FVC were significant risk factors for mortality among both sexes. The relative risk of death associated with a 50% decrease in FEV1 and FVC as a percentage of a predicted value was 1.65 and 1.81. respectively. This study confirms that lowered ventilatory function is a strong risk factor for mortality among never-smokers of both sexes.
Hospitalization experience of Navajo subjects with type II diabetes and matched controls: an historical cohort study, Using an historical cohort study design with a 12 year follow-up. we found that 77 Navajo adults with type II diabetes mellitus were hospitalized at a rate of 335 hospitalizations per 1000 patient years compared to a rate of 167 hospitalizations per 1000 patient years for 77 age. sex. and residence matched non-diabetic controls. yielding a risk ratio of 2.0. Using matched pairs analysis (sign test). the observed difference in number of hospital admissions is statistically significant (z = 2.30. p less than 0.05). The average duration of hospitalization. however. was not statistically different in matched pairs analysis (z = 0.95. p greater than 0.05). The 136 excess hospitalizations of the diabetic subjects included 45 admissions for poor metabolic control of diabetes. 50 excess admissions for infectious disease. and 26 excess admissions for conditions of the heart. eye. kidney. or non-traumatic amputation. In multivariate analyses. variables found to be associated with greater hospitalization experience among the 77 diabetic subjects in the 12 years follow-up period included older age at entry to the study. poorer metabolic control early in the study period. and presence of diabetic complications.
Assessing the clinical effectiveness of preventive maneuvers: analytic principles and systematic methods in reviewing evidence and developing clinical practice recommendations. A report by the Canadian Task Force on the Periodic Health Examination, This paper examines a process for evaluating clinical effectiveness and developing recommendations in which systematic methods are used to review evidence from published clinical research and to reach sound conclusions about appropriate medical policy. The methodology addresses four important components of the analytic process: (1) the criteria that must be satisfied for a clinical practice to be considered effective; (2) proper methods for reviewing evidence from published clinical research to determine whether a clinical practice meets these criteria (including methods for performing comprehensive literature reviews. for judging the quality of individual studies. and for synthesizing or pooling the results of multiple studies); (3) theoretical and practical concerns in translating the results of the scientific review into sound clinical practice recommendations; and (4) the importance of documentation. guidelines. and other safeguards to minimize the effect the reviewers themselves have on the objectivity and consistency of the analytic methods.
The leukocyte count: a predictor of hypertension, In an exploratory study of 1031 persons observed to progress from normotension to essential hypertension and 1031 matched subjects who remained normotensive. the initial leukocyte count (WBC) was found to be related to the development of hypertension. with risk increased 40% (95% confidence interval 12-82%) in persons in the highest as compared to the lowest quartile of WBC. This relationship proved to be largely independent of body mass index. body fat distribution. alcohol and tobacco consumption. and parental history of hypertension. An increased WBC may reflect greater sympathetic tone or may directly increase peripheral vascular resistance by impeding circulation through small blood vessels. If confirmed. this study adds another condition to the growing list for which the WBC is predictive. This simple. cheap test should be considered for inclusion in prospective epidemiological studies of many different diseases.
Plasma fibrinogen and coronary risk factors: the Scottish Heart Health Study, Plasma fibrinogen was measured in a sample of 8824 men and women aged 40-59 years participating in the Scottish Heart Health Study. and related to cardiovascular risk factors. Women had higher fibrinogen levels than men. In both sexes. multivariate analysis showed that fibrinogen was positively associated with age. smoking. total cholesterol and body mass index and negatively associated with alcohol consumption. Among women. early menopause and systolic blood pressure were also associated with fibrinogen levels. Univariate analyses showed weak positive associations with fish consumption for both sexes although only male white fish consumption entered the final model. Women with a history of contraceptive pill usage had significantly lower fibrinogen levels. The relationship between fibrinogen and physical activity was complex. and could largely be explained by smoking. These findings support the hypothesis that raised fibrinogen is one mechanism by which several major risk factors may promote coronary heart disease. However. known risk factors explained. at most. 10% of the total variance in fibrinogen levels among the general population.
The effects of generation and gender on the joint distributions of lipid and apolipoprotein phenotypes in the population at large, The generation and gender effects on the joint distributions of total plasma cholesterol (Total-C). ln triglycerides (lnTrig). HDL-cholesterol (HDL-C). LDL-cholesterol (LDL-C). apolipoproteins AI (Apo AI). AII (Apo AII). and E (lnApo E) were studied in 184 male grandparents (MGP). 242 female grandparents (FGP). 237 male parents (MP). 235 female parents (FP). 202 male children (MC). and 200 female children (FC). Homogeneity of variance tests revealed that lipid variances were gender and/or generation specific while apolipoprotein variances were homogeneous across strata. In the absence of heterogeneity of variance. significant heterogeneity in LDL:lnTrig and lnTrig:Apo AII covariation was found between genders in the parental generation. In the presence of heterogeneity of variance. significant heterogeneity of correlation between genders and/or across generations was found for the HDL-C:LDL-C. Total-C:LDL-C. Total-C:lnTrig. lnTrig:LDL-C. Total-C:lnApo E and HDL-C:lnApo E bivariate distributions. Analyses of principal components revealed that the generation and gender specific cohorts have similar eigenvalues but distinct eigenvectors for the first two principal components underlying the seven dimensional lipid and apolipoprotein distribution. We conclude that the amount of variability explained by the first two principal components is the same across cohorts but how the interindividual variability is distributed among the lipid and apolipoprotein traits is generation and gender specific. This study documents the role that variance and covariance might play in determining risk of disease for special subgroups of the population at large. It also demonstrates how variances and covariances between risk factors traits characterize life processes of aging and sexual dimorphism. This study argues that future biometrical genetic and epidemiological studies of coronary artery disease must take into account age and gender effects on interindividual variability and covariability of risk factors.
Body mass index and 15-year mortality in a cohort of black men and women, The association between body mass index (BMI) and mortality was investigated in 2453 black male (aged 30-79 years) and 2731 black female (aged 40-79 years) members of the Kaiser Foundation Health Plan. During a 15-year follow-up 393 male and 283 female deaths were identified. Analyses were conducted separately in a lower and an upper range of BMI (as well as over the entire range). to isolate separate effects of low weight and high weight on mortality. Particular attention was also paid to potential bias from cigarette smoking and antecedent illness. Cox regression analyses showed that over the entire range of BMI the adjusted BMI-mortality association was significantly J-shaped for the men and essentially flat for the women. The inverse association between BMI and mortality in the lower range of BMI was statistically significant for the men; the adjusted relative hazard increasing from the 10th to the 50th percentile of BMI was 0.76 (95% confidence interval [CI] 0.59-0.98). The positive association between BMI and mortality in the upper range of BMI was highly statistically significant for the men; the adjusted relative hazard increasing from the 50th to the 90th percentile of BMI was 1.37 (95% CI 1.14-1.63). Whether controlled by multivariate analysis. by excluding the first 5 years of follow-up from the analyses. or by analyzing the BMI-mortality association in smoking-specific and/or illness-specific subgroups. smoking and antecedent illness did not have much impact on the BMI-mortality association. in either sex. The general observations on the BMI-mortality association are similar to findings in some white cohorts.
Risk ratios and risk differences in estimating the effect of risk factors for cardiovascular disease in the elderly, This article reviews the nature of the effects of hypertension. smoking and cholesterol on the incidence of cardiovascular disease and emphasizes how these effects vary by age. In the Methods section. we discuss briefly the concepts of additive and multiplicative statistical models as tools for summarizing data. In the results section. we summarize available data on the association between incident stroke and coronary heart disease in the elderly and each of these major risk factors. The traditional multiplicative model parsimoniously characterizes the individual and joint effects of age and high blood pressure in terms of risk ratios; but. for smoking and cholesterol. an additive model appears to be the most parsimonious. We discuss the consequences of these observations for the study and prevention of cardiovascular disease in the elderly.
Changes in surgical treatments: the example of hysterectomy versus conization for cervical carcinoma in situ, From 1969 through 1985. 4584 women in the state of New Mexico were diagnosed with carcinoma in situ of the cervix. Of these women. 65.5% underwent hysterectomy while 31.1% had a conservative therapy (primarily conization). Over the 17-year period. there was a steady increase in the percentage of women receiving conservative therapies. from 11.8% in 1969 to 50.3% in 1985. Younger women. unmarried women and American Indian women were more likely to receive conservative therapy. This marked shift in therapeutic approach occurred during a time of apparent controversy as to the optimal treatment for cervical carcinoma in situ. and illustrates a rapid change in surgical practice in the absence of any controlled trials comparing the two major treatment modalities.
Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study, Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer. although it has been used most frequently in patients with far-advanced. refractory disease. To evaluate the effects of chemotherapy given earlier in the course of the disease. the Southwest Oncology Group (SWOG) performed a randomized trial between September 1982 and October 1986 comparing endocrine therapy (diethylstilbestrol [DES] or orchiectomy) alone followed by cyclophosphamide-Adriamycin (doxorubicin; Adria Laboratories. Columbus. OH) chemotherapy at progression versus initial combined chemo-endocrine therapy. One hundred forty-three patients were registered. and only six were declared ineligible. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared with endocrine therapy alone (48%). A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm (P = .059). Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy. while two others had stable disease. Despite the difference in initial response rate. time to treatment failure and survival were identical in the two treatment arms. Seventy-seven percent of patients on the initial endocrine therapy alone arm have died (median survival. 25.6 months) compared with 78% on the chemo-endocrine therapy arm (median survival. 22.0 months). No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model. Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy. Eighty-six percent of patients treated by orchiectomy have died compared with only 65% of those treated with DES. These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer.
Response of oral leukoplakia to beta-carotene, Leukoplakia is associated with increased risk of oral cancer and is considered a premalignant lesion. Retinoids. particularly 13-cis retinoic acid. can frequently reverse leukoplakia. However. these drugs have considerable toxicity and are not suitable for large-scale use in the prevention of oral cancer. Beta-carotene is a naturally occurring. nontoxic carotenoid with biologic properties that suggest that it might be efficacious against oral leukoplakia. In 1986. we began a randomized study of 13-cis retinoic acid (1 mg/kg/d) versus beta-carotene (30 mg/d) in leukoplakia. However. owing to the marked differences in toxicity between the two compounds outlined in the consent form. 11 of the initial 16 eligible patients refused to participate unless they were "guaranteed" beta-carotene. Therefore. the study design was changed to a phase II trial of beta-carotene in which the compound was given daily for 3 months. Responding patients were continued for another 3 months of treatment. All lesions were examined histologically at entry. Responses were monitored by bidimensional measurements and photography done at entry. then monthly while on treatment and at study completion. Twenty-four evaluable patients were treated. and 17 had major responses (two complete. 15 partial). a response rate of 71% (95% confidence limits. 53% to 89%). There was no significant toxicity requiring drug discontinuation or dose reduction. These results indicate that beta-carotene has substantial activity in oral premalignancy. Because of its lack of toxicity. it is an excellent candidate for a preventive agent for oral cancer.
Pharmacodynamics in cancer therapy, Our understanding of anticancer pharmacodynamics. and the relationships between pharmacologic measurements and clinical effects. has grown markedly in recent years due to advances in analytical and computational technology. Although methotrexate plasma levels have been empirically used to guide leucovorin dosing during high-dose methotrexate therapy. there has been no other standard use of therapeutic drug monitoring in oncology. More recently. investigators have attempted to titrate precisely the dose of antineoplastic agents based on previously derived models and real-time analysis of plasma drug or tissue concentrations. Studies have been completed or are in progress using hexamethylene bisacetamide. etoposide. teniposide. fluorouracil (FUra). and cytarabine (ara-C). Future studies will focus on optimal sampling strategies. analysis of intermediate biochemical end points. combination chemotherapy. modulation by colony-stimulating factors. and more sophisticated pharmacodynamic models.
A surgeon's risk of AIDS, A probabilistic model is used to estimate the cumulative risk to surgeons from human immunodeficiency virus (HIV). Recent data suggest that the probability of infection following percutaneous inoculation is about 1 in 250 cases. Several studies suggest that the frequency of percutaneous injury in surgery is at least 1 in 40 cases. for some as high as 1 in 20 cases. Assuming that on the average a surgeon will perform 350 operations per year and will practice for 30 years. the cumulative risk of HIV infection will depend on the prevalence of HIV infection in the surgical population. For HIV prevalences of 1 in 100 to 1 in 10. the cumulative risk per surgeon ranges from 1 in 100 to 1 in 5. respectively. Based on these risk estimates. it is crucial to decrease the frequency of percutaneous injury. The case is made for substantial improvements in barrier protection and modification of surgical technique.
Surgical management of exophytic chiasmatic-hypothalamic tumors of childhood, Sixteen children underwent 18 operations for radical resection of chiasmatic-hypothalamic tumors. The clinical presentation correlated with age: infants under 1 year of age presented with macrocephaly. failure to thrive. and severe visual failure; children aged 1 to 5 years predominantly had precocious puberty with mild visual deficits; and older children (greater than 5 years old) had slowly progressive loss of vision. All three infants had biologically aggressive tumors in spite of low-grade histology. and died from progressive tumor growth. Eleven of the 13 children aged 1 year or over are alive and well. without clinical or radiographic evidence of disease progression. 4 months to 4 1/2 years following surgery. Six of these patients. with a follow-up period of 10 months to 4 1/2 years (mean 27 months). have had no adjuvant therapy following radical surgical resection. The authors conclude that: 1) radical surgical resection of chiasmatic-hypothalamic tumors can be performed with minimal morbidity; 2) radical resection may delay the time to disease progression in older children and postpone the need for irradiation; 3) resection of postirradiation recurrent tumors may provide neurological improvement and long-lasting clinical remission; and 4) chiasmatic-hypothalamic tumors of infancy are aggressive neoplasms that require multimodality therapy.
Zygomatic approach to skull-base lesions, A modification of the preauricular skull-base approach is described. After sectioning and downward displacement of the zygomatic arch. the coronoid process of the mandible is dissected and sectioned at its base. The temporal muscle. with its coronoid insertion. is then retracted upward. This approach provides direct and unobstructed access to the temporal and infratemporal fossae. Adequate vascularity of the temporal muscle is maintained. The exposure encompasses the internal carotid artery in the neck for vascular control. Extensive reconstruction is eliminated. The described technique was used in seven patients with lesions of the skull base. There was no operative mortality. and morbidity consisted of temporary restriction of mandibular opening in two patients.
Long-term follow-up review of 31 children with severe closed head trauma, Thirty-one children aged 3 to 15 years were followed for 5 to 11 years after suffering severe closed head trauma which caused coma for 1 week or more (median duration of coma 3 weeks). One patient remained in a persistent vegetative state until his death 9 years later. The other 30 recovered consciousness and were discharged. All suffered diminution of their abilities. and 24 of them had major permanent disability. The most common motor disabilities were pure spastic hemiparesis (seven cases). basal ganglia syndromes (four cases). ataxia (three cases). and a combination of hemiparesis and ataxia (five cases). Of the 30 patients. 26 regained independent ambulation. seven were epileptic. and 14 were dysarthric in various degrees. Only 10 had the cognitive ability to profit from the normal educational system. and none had attempted postsecondary education. Social problems were common. The worst outcomes were associated with intracranial bleeding and/or brain contusion seen on computerized tomography (CT) scans at the acute stage; the best were associated with normal CT scans. The degree of residual disability in these children seems no less than that of adults with trauma of similar severity.
Neurobehavioral outcome 1 year after severe head injury. Experience of the Traumatic Coma Data Bank, The outcome 1 year after they had sustained a severe head injury was investigated in patients who were admitted to the neurosurgery service at one of four centers participating in the Traumatic Coma Data Bank (TCDB). Of 300 eligible survivors. the quality of recovery 1 year after injury was assessed by at least the Glasgow Outcome Scale (GOS) in 263 patients (87%). whereas complete neuropsychological assessment was performed in 127 (42%) of the eligible survivors. The capacity of the patients to undergo neuropsychological testing 1 year after injury was a criterion of recovery as reflected by a significant relationship to neurological indices of acute injury and the GOS score at the time of hospital discharge. The neurobehavioral data at 1 year after injury were generally comparable across the four samples of patients and characterized by impairment of memory and slowed information processing. In contrast. language and visuospatial ability recovered to within the normal range. The lowest postresuscitation Glasgow Coma Scale (GCS) score and pupillary reactivity were predictive of the 1-year GOS score and neuropsychological performance. The lowest GCS score was especially predictive of neuropsychological performance 1 year postinjury in patients who had at least one nonreactive pupil following resuscitation. Notwithstanding limitations related to the scope of the TCDB and attrition in follow-up material. the results indicate a characteristic pattern of neurobehavioral recovery from severe head injury and encourage the use of neurobehavioral outcome measurements in clinical trials to evaluate interventions for head-injured patients.
Characteristics and biological role of steroid hormone receptors in neuroepithelial tumors, Tissue samples from 57 patients with neuroepithelial tumors (25 glioblastomas. 18 anaplastic astrocytomas. and 14 astrocytomas) were analyzed in order to evaluate the presence of estrogen. progesterone. glucocorticoid. and androgen receptors. Glucocorticoid- and androgen-specific binding proteins were present in 38.6% and 21.6% of the cases. respectively. Only a few tumors showed estrogen or progesterone receptors. A correlation was found between grade of anaplasia. patient's sex and age. and presence of glucocorticoid and androgen receptors. The biological role of these two receptors was investigated in 10 primary cell cultures derived from neuroepithelial tumors. For this purpose. dexamethasone and testosterone were added to culture medium at different concentrations (from 50 to 0.016 micrograms/ml). A significant stimulation of the cell growth was observed in four of five glucocorticoid receptor-positive cultures when dexamethasone in doses ranging from 2 to 0.016 microgram/ml was added to the culture. No modulation of the growth was observed in glucocorticoid receptor-negative cultures at the same doses. Higher dexamethasone doses induced a significant decrease of the growth index independently from the glucocorticoid receptor status. All of the cultures tested for testosterone activity were negative for androgen receptors. This hormone induced an inhibition of the growth index at doses ranging from 50 to 0.4 micrograms/ml. The data suggest that neuroepithelial tumors contain specific glucocorticoid and androgen binding proteins. Glucocorticoid receptors modulate the growth of cultured neuroepithelial tumors in the presence of different concentrations of dexamethasone.
Intracarotid hydroxyethyl methacrylate solution causing stroke in dogs, Hydroxyethyl methacrylate (HEMA) has been advocated as a polymerizing solution with which to prevent deflation of detachable balloons in interventional neuroradiology. It is pertinent to know if unpolymerized HEMA would have untoward effects if accidentally released into the carotid artery by balloon rupture or deflation. Seven mongrel dogs underwent transfemoral catheterization of the common carotid artery and subsequent injection of HEMA solution in volumes of 1 cc in five dogs. 2 cc in one. and 4 cc in one. Angiography performed at the time of injection revealed evidence of intravascular thrombosis as well as possible spasm. Three surviving animals were sacrificed at 48 hours; the brains were fixed and examined histopathologically. One brain was normal and one was autolyzed and could not be examined. Five of the seven animals had histopathologically documented cerebral infarctions of varying size. No foreign substance was seen within the blood vessels to suggest intravascular polymerization. The animals injected with 2 or 4 cc HEMA solution did not survive 48 hours. Literature review reveals little documentation of the toxicology of intravascular HEMA. With its increasing popularity as a compound for polymerization in detachable balloons introduced into the brain. further investigations are warranted to understand the physical properties of the compound and potential risks of its use.
Hemiparkinsonism as a complication of an Ommaya reservoir. Case report, The authors describe the case of a 28-year-old woman who developed the following symptoms in her right hand: a lasting resting tremor. transient focal rigidity. and paresthesia. These deficits occurred following treatment with intrathecal methotrexate via an Ommaya reservoir which was placed too deeply. resulting in trauma to the contralateral mesencephalon.
Stereotactic investigation of limbic epilepsy using a multimodal image analysis system. Technical note, A methodology has been developed for stereotactic investigation of limbic epilepsy using an image-analysis system that simultaneously displays different structural and functional images of the brain. The validity and accuracy of this system were established with phantom studies. Surgical planning and electrode implantation are guided by stereotactic magnetic resonance imaging. digital subtraction angiography. and position emission tomography. This methodology provides the spatiotemporal relationship of cerebral structure and function necessary to identify seizure onset and propagation in human limbic system epilepsy.
A simple technique of posterior wiring in traumatic instability of the mid to lower cervical spine. Technical note, Wiring without bone fusion in the treatment of traumatic cervical instability is an uncommon procedure. The authors describe a semirigid wiring technique for stabilizing the acute injured movement segment in the mid and lower cervical spine. Results are briefly discussed.
Significance of fill-in after thallium-201 reinjection following delayed imaging: comparison with regional wall motion and angiographic findings, To identify reversible defects. reinjection of a small amount of thallium-201 (201Tl) following 3-hr delayed imaging was performed in 60 patients with coronary artery disease who had perfusion abnormalities on their post-exercise 201Tl images. Thallium-201 uptake was visually scored and judged as normal (Group 1). reversible defect (Group II). new fill-in after reinjection (Group IIIa) and no fill-in even after reinjection (Group IIIb). New fill-in after reinjection was observed in 27 segments of the 85 segments (32%). showing persistent defect on the stress and delayed images. The wall motion in Group IIIa was worse than Group II but better than Group IIIb. Group IIIa showed Q-wave on ECG more often (69%) than Group II (27%) (p less than 0.01). but less often than Group IIIb (85%) (p less than 0.05). These data indicate that the reinjection 201Tl imaging often identifies new fill-in in the areas of no redistribution on the delayed images and it may hold promise for assessing tissue viability which the conventional imaging may underestimate.
Lymphocele: the spectrum of scintigraphic findings in lymphoceles associated with renal transplant, Lymphocele is a well recognized complication of renal transplant surgery. We performed a retrospective review of 305 renal transplant patients with over 2.500 scintigraphic exams to describe the pattern of activity on technetium-99m-DTPA blood flow and dynamic imaging. and iodine-131-OIH studies. Diagnostic criteria for a lymphocele were ultrasonic evidence of a perirenal fluid collection and analysis of that fluid that demonstrated BUN. creatinine. and electrolytes similar to the patient's plasma. Scintigraphic findings were attributed to a lymphocele if abnormalities were in the same area as the ultrasound fluid collection. Scintigraphic findings attributable to lymphocele resolved in all patients following surgical drainage or peritoneal window placement. Six of the 11 documented lymphoceles demonstrated a cold defect on initial dynamic images that "filled in" to equal background activity and another exceeded background. Three cases showed a rim of increased activity surrounding the lymphocele ("rim sign").
Scintigraphic evaluation of aggressive fibromatosis, Despite its benign microscopic appearance. aggressive fibromatosis has potential to recur and infiltrate neighboring tissues. Therefore. it is necessary to determine the exact extent before therapy. In the present study. 11 cases of aggressive fibromatosis were examined scintigraphically using [99mTc(V)]dimercaptosuccinic acid (11 cases) and 67Ga-citrate (7 cases). Technetium-99m-(V)-dimercaptosuccinic acid demonstrated all lesions. while 67Ga-citrate detected 57% of the cases.
N-[18F]fluoroacetyl-D-glucosamine: a potential agent for cancer diagnosis, Positron labeled substrates such as sugars. amino acids. and nucleosides have been investigated for the in-vivo evaluation of biochemical processes in cancerous tissue. Hexosamines are obligatory structural components of many biologically important macromolecules. including membrane glycoproteins and mucopolysaccharide. We evaluated a new synthesized pharmaceutical. N-[18F]fluoroacetyl-D-glucosamine (18F-FAG). which is a structural analog of N-acetyl-D-glucosamine. C3H/HeMsNRS mice bearing spontaneous hepatomas were used for the tissue distribution study. At 60 min after injection. high uptakes were found in tumor (5.16. mean value of %dose/g). liver (3.71). and kidney (3.27). The tumor uptake of 18F-FAG showed the highest value in all tissue. In the PET study. VX-2 carcinoma of the rabbit was clearly visualized. Our preliminary results suggest that 18F-FAG has potential as a new agent for tumor imaging.
Effects of excess dietary tyrosine on cholesterol, bile acid metabolism and mixed-function oxidase system in rats, Excess dietary tyrosine (12%) caused hypercholesterolemia in male Wistar rats and significantly increased cytochrome P-450 and b5 contents. Bile flow and biliary output of total bile acids were significantly increased in rats fed this diet. Biliary output of cholesterol was not significantly altered. whereas that of taurocholic acid was significantly increased. Excess dietary tyrosine significantly decreased the fecal excretion of neutral steroids. whereas total steroid excretion was not significantly changed. The present results indicate that excess dietary tyrosine causes hypercholesterolemia without modifying the fecal total steroid excretion. thus supporting our previous hypothesis that stimulated synthesis of cholesterol is a main reason why excess dietary tyrosine leads to hypercholesterolemia.
Effect of vitamin C depletion on serum cholesterol and lipoprotein levels in ODS (od/od) rats unable to synthesize ascorbic acid, The effect of ascorbic acid deficiency on serum and liver cholesterol. phospholipid and triglyceride levels. serum lipoprotein levels and serum lipoprotein cholesterol levels were examined in male rats with a hereditary defect in ascorbic acid synthesis (ODS rats). Male homozygotes (od/od) and male rats of their parent strain (+/+) were each divided into four treatment groups and were fed vitamin C-deficient or vitamin C-replete diets containing either 0 or 0.5% cholesterol. During the 3-wk feeding-period the ODS (od/od) rats fed the vitamin C-deficient diet gradually decreased food intake. resulting in a lower body weight than that of od/od rats given ascorbic acid. The serum cholesterol level was significantly higher in the vitamin C-deficient od/od rats fed the cholesterol diet. and it tended to be higher in those fed the control (0% cholesterol) diet. whereas the liver lipid levels remained unchanged relative to those in od/od rats fed the vitamin C-replete diet. The serum very low density lipoprotein and high density lipoprotein (HDL) cholesterol levels were lower in od/od rats fed the vitamin C-deficient diet without cholesterol. but intermediate density lipoprotein and low density lipoprotein cholesterol levels were markedly higher in the vitamin C-deficient od/od rats than in od/od rats given ascorbic acid. regardless of dietary cholesterol level. The ratio of HDL2 cholesterol to HDL3 cholesterol was also higher in the vitamin C-deficient od/od rats. The parent strain of the od/od rats (+/+) showed no change due to vitamin C deficiency. These results suggest that vitamin C deficiency delays low density lipoprotein metabolism and produces hypercholesterolemia in male od/od rats.
Ascorbic acid effects on vitamin D hormone metabolism and binding in guinea pigs, Ascorbic acid deficiency in guinea pigs fed a vitamin D-replete diet caused a moderate reduction of Ca level in serum and bone; 25-hydroxy-cholecalciferol or 25-hydroxyergocalciferol (25-OHD) serum concentration tended to decline; renal 25-hydroxycholecalciferol-1-hydroxylase (1-OHase) activity decreased 50%; and 25-hydroxycholecalciferol-24-hydroxylase activity increased 1.6-fold. Chromatin 1.25-dihydroxycholecalciferol [1.25-(OH)2D3] receptor concentration in the intestinal mucosa decreased 20-30%. and the percentage of occupied receptors decreased from 12-15% to 6-8%. Receptor affinity for 1.25-(OH)2D3 did not change (Kd = 0.24-0.26 nmol/L. Kd2 = 0.06-0.10 nmol/L). but the cooperativity coefficient decreased from 1.7 to 1.4. Vitamin C deficiency potentiated effects of vitamin D deprivation and impaired a restorative action of vitamin D. It was accompanied by a marked delay in the elevation of 25-OHD concentration in serum as well as decreased 1-OHase activity in kidneys and a lower concentration of occupied 1.25-(OH)2D3 receptors in the intestinal mucosa. The data demonstrate a critical role for ascorbic acid in vitamin D metabolism and binding.
Effects of inflammation and copper intake on rat liver and erythrocyte Cu-Zn superoxide dismutase activity levels, Stress such as inflammation produces an acute phase response that includes elevated levels of ceruloplasmin. the main copper component of plasma. Inflammatory effects on cellular copper enzyme activity levels are largely unknown. Cu-Zn superoxide dismutase (SOD) activities in liver. the main site of ceruloplasmin secretion. decreased with turpentine-induced inflammation (0.1 mL. intramuscular. leg) in rats fed any of three copper levels (adequate = 6 mg/kg. marginal = 2.5 mg/kg and deficient less than 0.5 mg/kg). Ceruloplasmin activities rose significantly with inflammation in the adequate and marginal groups but not in the deficient animals. Hepatic Cu-Zn SOD immunoreactive protein levels were unaffected by copper status or inflammatory state. Erythrocyte Cu-Zn SOD activities were influenced by dietary copper but not inflammation. An additional group of rats fed 15 mg copper/kg did not show a turpentine-induced decrease in liver Cu-Zn activity levels. Inflammatory effects on other copper enzyme activities did occur as evidenced by increases in ceruloplasmin and decreases in serum extracellular SOD. In conclusion. an acute phase response in rats increased the amount of dietary copper required to maintain hepatic Cu-Zn SOD activity at levels equal to those of nonstressed. copper-adequate rats. Rat erythrocyte Cu-Zn SOD activities provided a blood measurement reflective of copper intake with or without stress. but these values did not reflect decreases in liver Cu-Zn SOD activities after 3 d of inflammation.
Vitamin A deficiency decreases natural killer cell activity and interferon production in rats, We examined the effect of vitamin A deficiency on natural killer (NK) cell activity and interferon (IFN) production. Rats were weaned at 16 or 21 d of age onto semisynthetic diets containing either 0 or 4 micrograms retinol/g diet. At the time of study. retinol-depleted rats had serum vitamin A concentrations less than 7% of those of pair-fed controls. In two studies. rats exhibited no external signs of retinol deficiency. but with further depletion some symptoms were observed. Splenic NK cell activity against chromium-51-labeled YAC-1 cells was significantly decreased in vitamin A-depleted rats (22-80% of values for control rats. depending on the degree of retinol deficiency). regardless of the ratio of effector to target cells used. When vitamin A-depleted rats were repleted orally with retinol. NK cell activity was consistently normalized. To understand the possible mechanisms involved in decreasing NK cell activity. we investigated IFN production by concanavalin A-stimulated spleen cells from vitamin A-depleted. from repleted and from control animals. IFN titers were significantly decreased (22-33% of values for control rats) in supernatants of spleen cell cultures of the vitamin A-depleted rats. Repletion with vitamin A resulted in IFN activities ranging from 80 to 130% of controls. Adding alpha/beta IFN in vitro to the spleen cells of vitamin A-depleted animals increased their NK cell activity. The number of spleen cells reacting with a monoclonal antibody specific for rat NK cells was slightly lower in retinol-depleted rats. but not enough to account for the differences in NK cell and IFN activities. These data suggest that vitamin A deficiency affect the nonspecific arm of the immune system. possibly by altering the functional capacity of cells to produce lymphokines needed for the generation of an appropriate cytolytic response.
A prospective evaluation of the effectiveness of temporomandibular joint arthroscopy, This is a prospective study to evaluate therapeutic arthroscopy for internal derangement of the temporomandibular joint (TMJ). Fifty-nine patients with 76 abnormal joints were evaluated preoperatively for pain. noise. maximal incisal opening (MIO). and deviation on opening. Preoperative and postoperative magnetic resonance imaging (MRI) scans were obtained for 29 joints. Patients were treated by superior joint arthroscopy. lysis of adhesions. lavage. and steroid injection. along with preoperative and postoperative splint and physiotherapy. Pain. noise. and motion were evaluated at three time periods: 1) early (10 to 30 days); 2) intermediate (1 to 6 months); and 3) late (greater than 6 months). At early. intermediate. and late follow-up. increase in MIO was statistically significant (P less than .05). Noise did not return in the majority of patients. Disc position. evaluated by MRI. did not appear to change in 25 of 29 joints and did not correlate with clinical outcome. The results of this study indicate that TMJ arthroscopy is effective in reducing pain and increasing motion in patients with TMJ internal derangement.
Management of delayed union and nonunion of maxillary osteotomies, Delayed union and nonunion of maxillary osteotomies are unusual. but have been seen with a variety of surgical moves. Management of these problems can be divided into early and late therapy. Four cases are presented illustrating some of these methods of treatment.
Composite temporalis pedicle flap as an interpositional graft in temporomandibular joint arthroplasty: a preliminary report, Fifteen temporomandibular joint patients were evaluated preoperatively and postoperatively to evaluate the effectiveness of a composite (fascia. muscle and periosteum) temporalis pedicle flap as an interpositional disc replacement. A modified Craniomandibular Index (CMI) and Symptom Severity Index (SSI) were used to assess clinical and subjective symptoms. Eighteen months postoperatively there was a significant reduction in the CM and SS indices (P less than .001). with significant clinical improvement of the mandibular range of motion (P less than .05). However. a significant reduction of translation (P less than .01) was evident indicating that the increased mandibular opening was owing to a compensatory rotational movement. This study indicates that the composite temporalis pedicle flap is a good autogenous tissue for the reconstruction of the temporomandibular joint.
An evaluation of sensory changes and pain relief in trigeminal neuralgia following intracranial microvascular decompression and/or trigeminal glycerol rhizotomy, Nineteen patients with trigeminal neuralgia were treated with either trigeminal ganglion glycerolysis or glycerolysis and intracranial microvascular decompression. All had a good degree of pain relief. Of those receiving glycerol alone (group A). 50% subjectively reported a mild reduction of fine tactile sensation. A similar response was reported by those treated with both glycerol and decompression (group B). The degree of sensory loss was so mild that thermal testing was useless as a discriminatory tool. The degree of sensory loss was not greater when both surgical procedures were performed than when the less-invasive trigeminal ganglion glycerolysis alone was used.
An animal model for human masseter muscle: histochemical characterization of mouse, rat, rabbit, cat, dog, pig, and cow masseter muscle, The masseter muscle of several animal species was investigated by use of a histochemical method for the demonstration of acid-stable and alkali-stable myosin adenosine triphosphatase (ATPase). The following subdivisions of fiber types were used: Type I fibers show weak ATPase activity at pH 9.4. type IM fibers react moderately. and type II fibers react strongly. Rat and mouse masseter muscles contained type II fibers only. as did some rabbit masseter muscles. whereas other rabbit masseter muscles possessed equal amounts of type I and II fibers. Cat and dog masseter muscles possessed both type II and I fibers. with type II predominating. Cow masseter muscle consisted mainly of type I fibers. although some cow masseter muscles contained a very small number of type II fibers. Pig masseter muscle had both type I. II. and IM fibers. One of the characteristics of human masseter muscle is type IM fibers. which are rarely seen in muscles other than the masticatory muscles. Therefore. pig masseter muscle might be a suitable animal model for experimental studies. such as an investigation of the distribution and diameter of fiber types in the masticatory muscles before and after orthognathic surgery.
Tissue response to composite ceramic hydroxyapatite/demineralized bone implants, This study evaluated the tissue reactions to two materials: ceramic hydroxyapatite (CHA). and a composite material of demineralized bone powder (DBP) and CHA (ratio of 4:1) in a collagen vehicle. The materials were tested in a subcutaneous pocket. a mandibular onlay. and in a calvarial onlay model. Specimens were evaluated histologically at 7. 10. 14. and 21 days postimplantation. Ceramic hydroxyapatite. implanted subcutaneously. elicited a fibrous response with minimal inflammation. but did not induce bone formation. In specimens of subcutaneously implanted composite material. induced bone was evident in association with the DBP. In CHA onlay specimens. there was a small amount of reactive bone extending from the host bone into the implant. In composite onlays. bone filled the entire body of the implant. The results of this study indicate that CHA particles were not osteoinductive in heterotopic sites and that osteoconductive ingrowth was minimal in onlays. Bone was induced by DBP even when mixed with CHA particles and implanted in subcutaneous and intraosseous sites. It was concluded that composite implants may provide a means of combining the osteoinductive properties of DBP with the bulk and structural support of osteoconductive CHA particles.
Bone response to hydroxyapatite particles of different shapes in rabbit tibia, Four holes drilled in rabbit tibia were filled with different commercial hydroxyapatite products. All particles caused a mild inflammatory reaction. which disappeared in 2 months. The line between the new and original bone was visible even after 6 months. No differences in healing pattern were discovered for the various products. When bone cavities are filled with hydroxyapatite particles. the shape of the particles does not seem to affect the healing process.
A protocol for management of temporomandibular joint ankylosis, A management protocol for temporomandibular joint (TMJ) ankylosis consisting of 1) aggressive resection. 2) ipsilateral coronoidectomy. 3) contralateral coronoidectomy when necessary. 4) lining of the TMJ with temporalis fascia or cartilage. 5) reconstruction of the ramus with a costochondral graft. 6) rigid fixation. and 7) early mobilization and aggressive physiotherapy is presented. The protocol was retrospectively evaluated in the first 14 patients (18 involved TMJs) treated and followed postoperatively for at least 1 year. The facial asymmetries present in all unilateral cases remained corrected. The mean maximum postoperative interincisal opening at 1 year was 37.5 mm (292.36% mean increase). lateral excursions were present in 16 of 18 joints (vs 0 of 18 joints preoperatively). and pain was present in 2 of 18 joints (vs 13 of 18 preoperatively). The results of this study indicate that this protocol is effective for treatment of TMJ ankylosis.
An improved technique for development of the pectoralis major myocutaneous flap, The pectoralis major myocutaneous flap is the most commonly employed muscle skin transfer used in soft-tissue reconstruction of defects of the upper neck and jaw region. This article presents conceptual and technical changes in the development of the pectoralis major myocutaneous flap that preserve a greater vascular pedicle and enhance the flap's arc of rotation. Data from 54 consecutive cases using this modified approach show a reduction in complications. a greater range of use. and consistent healing in radiated and nonradiated tissues without requiring sectioning or removing the clavicle or causing significant chest deformities. These modifications have produced a more predictable transfer compared with other reported techniques.
Comparison of functional recovery after nonsurgical and surgical treatment of condylar fractures, This article evaluates 16 cases of condylar fracture treated surgically. comparing them with the 20 cases treated nonsurgically. with a 2-year follow-up. Although severely displaced and luxated fractures were involved in the surgical group with rigid internal fixation. satisfactory postoperative function and occlusion were achieved at the same level as in the nonsurgical group. without severe complications.
Desmoplastic variant of ameloblastoma: report of a case and review of the literature, A case of desmoplastic variant of ameloblastoma is reported. The lesion. in a 36-year-old Japanese woman. was successfully treated by partial maxillectomy. Reconstruction was carried out with a block of hydroxyapatite about 7 years and 6 months later. Six cases. including our case. reported up to the present are summarized and reviewed.
Magnetic resonance imaging appearance of the muscles in childhood dermatomyositis, Documentation of muscle involvement in a child thought to have dermatomyositis may require the performance of invasive procedures such as electromyography and/or muscle biopsy. We describe four patients with dermatomyositis in whom magnetic resonance imaging (MRI) demonstrated the muscle involvement. The involved muscles had increased signal intensity on the T2-weighted images (SE 2500/80) and normal appearance on the T1-weighted images (SE 600/20). The involvement of the muscles was not uniform. There was good correlation between the distribution of muscle involvement by MRI and functional testing. Follow-up MRI scans in patients with favorable outcome demonstrated that the affected muscles had returned to normal signal intensity. Although the MRI findings are not specific. in the proper clinical context they may be helpful in establishing the diagnosis of dermatomyositis. MRI may also be used in establishing an appropriate muscle biopsy site. In addition. MRI may be used for monitoring the progress of the disease.
Benefits and risks of anemia correction with recombinant human erythropoietin in children maintained by hemodialysis, Ten children with renal failure (age range 2 years 6 months to 18 years 9 months; median 11 years 10 months). maintained by long-term hemodialysis. had successful correction of their anemia after intravenous administration of recombinant human erythropoietin in a dosage escalating every 2 weeks (75 to 150 to 300 to 450 IU/kg/wk). Mean hemoglobin concentration increased from 6.4 +/- 0.9 to 11.5 +/- 1.0 gm/dl. Blood cell counts used to evaluate the correction of anemia were done after dialysis; this was especially important for children less compliant with water restriction. The higher hemoglobin concentration resulted in improvement of the quality of life. a greater tolerance for physical effort (exercise tolerance doubled and the ventilatory anaerobic threshold increased significantly). correction of some subclinical central nervous system abnormalities detected by evoked potentials testing. and reduction of bleeding time. Few side effects were noted; severe hypertension developed in one patient when postdialysis hematocrit was only 28%. and there were two episodes of hypertransaminasemia with no other evidence of liver dysfunction. We conclude that in children with renal failure the use of recombinant human erythropoietin to correct anemia is safe and strongly advisable. because of the resolution of many of the symptoms correlated with anemia.
Patterns of food hypersensitivity during sixteen years of double-blind, placebo-controlled food challenges, For 16 years the double-blind. placebo-controlled food challenge (DBPCFC) has been used at the National Jewish Center for Immunology and Respiratory Medicine to determine whether adverse reactions to foods do occur in children. The objective of these studies was to explore these reproducible adverse reactions and to characterize them. Although skin testing was performed on all subjects. a history of an adverse reaction to food and to subsequent DBPCFC were the only criteria for entry into this study. Of 480 children studied. 185 (39%) have had positive DBPCFC results. In these 480 children. 245 (24%) of 1014 DBPCFCs showed positive results. Egg. peanut. and cow milk accounted for 73% of the positive DBPCFC reactions. but many foods produced reactions. Skin test results were positive in most children with a positive DBPCFC reaction. but the large number of patients with asymptomatic hypersensitivity limited the accuracy of a positive skin test result alone as a predictor of clinical symptoms during food ingestion. Evaluation of results in this large number of children for a prolonged period revealed reproducible patterns of symptoms. timing. and incriminated foods. Placebo reactions were rare. The procedure was safe. Twelve youngsters with a negative DBPCFC result subsequently had positive reactions to open challenges when large amounts of the challenge food were used. In each of these cases the reactions were limited to areas of direct contact with the food or could be explained by the larger amount of food ingested during the open challenge. Multiple food hypersensitivity has been a rare finding. The DBPCFC should be the "gold standard" for both research and clinical diagnostic evaluations until it is superseded by methods that have yet to be developed.
Ibuprofen suspension in the treatment of juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group, Ninety-two children with juvenile rheumatoid arthritis were randomly assigned to treatment in a multicenter. double-blind. 12-week trial designed to compare the efficacy and safety of a liquid formulation of ibuprofen at a dosage of 30 to 40 mg/kg/day versus those of aspirin at a dosage of 60 to 80 mg/kg/day. No significant intergroup differences in response rates or in the amount of improvement in articular indexes of disease activity were observed. More children treated with aspirin discontinued treatment early because of adverse reactions. After this trial. 84 additional patients with juvenile rheumatoid arthritis entered a 24-week. multidose (30. 40. and 50 mg/kg/day). open trial of ibuprofen suspension. Favorable response rates for the three groups were similar. and continued improvement was observed throughout the 24-week period. A dose-response relationship was observed with respect to adverse reactions of the upper gastrointestinal tract. We conclude that ibuprofen suspension is an effective nonsteroidal antiinflammatory drug and that its tolerability in children is acceptable.
Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis, Twenty-nine children with juvenile rheumatoid arthritis were studied to determine the safety and efficacy of methotrexate therapy. The initial dose of methotrexate averaged 7.1 mg/m2/wk and was given as a single. oral weekly dose or as three divided doses. each separated by 12 hours. Current antiinflammatory medications were continued; 25 of 29 children had had lack of efficacy. and 8 of 29 had toxic effects. with one or more prior drugs such as intramuscularly or orally administered gold. hydroxychloroquine. or D-penicillamine. Intolerable corticosteroid dependency or toxic effects were present in 18 of 29 cases. Methotrexate-treated patients were examined monthly; minimum treatment duration required to assess efficacy and toxicity was 6 months. The range of treatment duration was 8 to 39 months (mean 18.5 months). Efficacy was assessed by comparing pretreatment versus posttreatment fever and rash. swollen-joint counts. articular indexes. duration of morning stiffness. functional class. hemoglobin levels. and platelet counts. Treatment with methotrexate effectively controlled fever and rash in 83% of children with systemic juvenile rheumatoid arthritis. reduced morning stiffness by 63%. eliminated recalcitrant joint restriction in 48%. and reduced numbers of swollen joints and swelling indexes by 46% and 52%. respectively. No significant toxic effects were observed. Juvenile rheumatoid arthritis of long duration. or with major erosions. was more likely to be refractory to methotrexate therapy. We recommend earlier consideration of methotrexate in place of other slow-acting antirheumatic drugs for juvenile rheumatoid arthritis not responding well to usual therapy. Future studies should address potential methotrexate toxic effects in the lungs and reproductive system. as well as outcome after discontinuation of methotrexate treatment.
On the use of laboratory markers as surrogates for clinical endpoints in the evaluation of treatment for HIV infection, There are strong ethical and practical reasons for hastening decision-making about the efficacy of new treatments for human immunodeficiency virus (HIV) infection. One strategy is to use early markers of disease progression. such as CD4+ lymphocyte levels. as surrogates for ultimate clinical endpoints. such as the development of acquired immune deficiency syndrome (AIDS) or death. in the evaluation of new therapies. We used a simple model of transitions among three health states (well; alive but with an adverse marker; and having experienced a definitive clinical endpoint) to examine the extent to which treatment comparisons based on the surrogate endpoint predict ultimate clinical benefits. With parameters chosen to model the treatment of HIV infection. computer simulations of clinical trials demonstrated substantial time savings by use of the surrogate endpoint. However. reliance on the surrogate led to serious overestimates of ultimate clinical benefit if treatment entailed delayed toxicity or had only transient beneficial effects. Likewise. reliance on the surrogate led to serious underestimates of ultimate clinical benefit when the treatment had no effect on the transition from well to the marker state but did reduce the rates of transition from the marker state to the ultimate clinical endpoint and directly from the well state to the ultimate clinical endpoint.
A report of eight HIV-seropositive patients with major depression responding to fluoxetine, This pilot study examined the effectiveness of fluoxetine in depressed human immunodeficiency virus (HIV)-seropositive asymptomatic patients. Eight patients. participating in an AZT trial who met criteria for major depression syndrome (DSM-III-R). were treated with fluoxetine (20 or 40 mg/day) for 4 weeks. Initially. mean Hamilton Depression scores were 23.8 (range of 17-31). and improved to 6.4 (range of 3-10). All subjects maintained their remission over a 2-month follow-up. Fluoxetine treatment may be effective in treating major depression in HIV-seropositive asymptomatic patients.
Effects of long-term administration of haloperidol on electrophysiologic properties of rat mesencephalic neurons, Haloperidol (1.5-1.7 mg/kg/day) was administered to rats via their drinking water for periods of either 4 weeks or 13 to 14 months. after which the animals were withdrawn from the neuroleptic for 1 or 2 weeks. respectively. Rats given haloperidol for 13 to 14 months exhibited significantly more perioral dyskinesias than controls. Single-unit extracellular recordings were obtained from the substantia nigra and ventral tegmental area in subjects under urethane anesthesia. After 1 month and after 1 year of treatment. a significant decrease in the mean firing rate of substantia nigra pars reticulata neurons was found. Subtle changes in the response of pars reticulata neurons to striatal stimulation were seen after extended haloperidol intake. No consistent effects of haloperidol administration for 4 weeks or 13 to 14 months were found for either the number of spontaneously active dopamine neurons or their firing rates. Histopathologic assessment of tissue from dorsomedial. dorsolateral and ventrolateral sectors of the striatum revealed no significant effect of long-term haloperidol treatment on neuronal cell counts. The results are discussed with reference to neuroleptic-induced tardive dyskinesias.
The effect of sulindac on the abnormal cough reflex associated with dry cough, In order to determine the possible role of prostaglandins in the abnormal cough reflex in patients with dry cough. the effects of a cyclooxygenase inhibitor on cough symptoms were examined. This was measured by a cough symptom score and by the cough reflex sensitivity to inhaled capsaicin in a double blind. randomized. cross-over study comparing the effects of placebo with sulindac. 200 mg daily for 1 week. We studied six hypertensive patients with angiotensin converting enzyme inhibitor-associated cough and six patients with an idiopathic. dry. unproductive cough. all of whom had an increase in the sensitivity of the cough reflex. There was no change in blood pressure control in the hypertensive patients during sulindac therapy. The patients with the angiotensin converting enzyme-associated cough had a significant reduction in the cough symptom score and also a significant increase in the dose of capsaicin causing two or more coughs (threshold sensitivity) and that causing five or more coughs (near maximum response) during sulindac therapy as compared to placebo. In those patients with idiopathic. dry. unproductive cough. sulindac did not alter the symptom of cough or the cough reflex response to capsaicin. These results suggest that prostaglandins may be involved in cough associated with angiotensin converting enzyme inhibitor therapy. but are less likely to be important in the pathogenesis of more common dry coughs of unknown cause.
Thromboxane A2-mimetics are potent microvascular permeability factors in the conjunctiva, These studies demonstrate that the thromboxane (Tx) A2 mimetics U-46619. U-44069 and carbocyclic-TxA2 elicit a microvascular permeability response in the conjunctiva. U-46619 and U-44069 are among the most potent microvascular permeability factors described to date for the conjunctiva; their potency is exceeded only by that reported for leukotrienes D4 and E4. The conjunctival microvascular permeability response to U-46619 was inhibited by the TxA2-antagonists daltroban (BM 13505) and SQ 29548. Prostaglandin (PG) D2 also increased conjunctival microvascular permeability. but was less potent than U-46619 and far less susceptible to pretreatment with daltroban or SQ 29548. PGE2. PGF2 alpha and the prostacyclin analog carbocyclin did not increase conjunctival microvascular permeability. It appears that the conjunctiva exhibits a unique microvascular permeability response to TxA2-mimetics: this view is experimentally supported by the absence of a cutaneous microvascular permeability response to U-46619. U-44069 and carbocyclic-TxA2.
Platelet activating factor (PAF) and tumor necrosis factor-alpha (TNF alpha) interactions in endotoxemic shock: studies with BN 50739, a novel PAF antagonist, BN 50739. a new PAF receptor antagonist. was tested in vitro and in vivo for its capacity to block PAF. endotoxin and recombinant human tumor necrosis factor-alpha (rTNF)-mediated effects. In vitro. BN 50739 blocked PAF-induced platelet aggregation by 60 to 100% at 0.2-1 x 10(-7) M (P less than .002). respectively. In the conscious rat. pretreatment (30 min) with BN 50739 (n = 5-13) dose-dependently attenuated PAF-induced hypotension (-5 +/- 5 vs. - 43 +/- 2 mm Hg. P less than .01) and shortened the recovery time of mean arterial pressure (22 +/- 13 vs. 325 +/- 46 sec. P less than .01). BN 50739 (10 mg/kg i.p.. n = 5-11) prevented endotoxin (14.4 mg/kg) induced-hemoconcentration (54 +/- 1 vs. 46 +/- 1%. P less than .01) and reduced 24-hr mortality (100 vs. 60%. P less than .05). Only partial protection was conveyed by BN 50739 against the hypotensive response to endotoxin (115 +/- 3 vs. 91 +/- 4 mm Hg. P less than .03). Also. BN 50739 attenuated the lipopolysaccharide-induced elevation of plasma thromboxane B2 (21.2 +/- 0.8 vs. 46.7 +/- 11.8 pg/100 microliters. P less than .01) and tumor necrosis factor-alpha (7523 +/- 3983 vs. 26.430 +/- 3541 U/ml. P less than .05). whereas leukopenia and thrombocytopenia remained unchanged.
Effects of long-term coenzyme Q10 and captopril treatment on survival and functional capacity in rats with experimentally induced heart infarction, The effects of coenzyme Q10 (CoQ) and captopril on functional capacity. hemodynamics and survival were studied in 154 rats that recovered after experimental myocardial infarction. Rats were randomized into four groups receiving either CoQ. captopril. a combination of the two drugs or 1 ml of tap water once daily for 12 weeks from the day of coronary artery ligation. CoQ as well as captopril and the combined treatment significantly improved exercise capacity as evaluated by lactate production during a standardized treadmill exercise test. No significant changes in heart rate or mean blood pressure were observed during the study in the captopril-treated group. CoQ treatment increased the maximum heart rate significantly. whereas no effect on mean blood pressure was observed. Both captopril and CoQ decreased pulmonary congestion. Furthermore. the data may suggest that captopril prevents right ventricular hypertrophy seen in placebo-treated rats with large infarcts. This was not observed after CoQ treatment. Captopril treatment improved 3-month probability of survival (93%) as compared with placebo (74%) (P less than .05). CoQ and the combined treatment tended to improve survival. but this was. however. not statistically significant.
Characterization of the effect of two 4-methyl piperidine derivatives of hemicholinium-3, A-4 and A-5, on choline transport, A-4 and A-5 are tertiary and N-methyl quaternary 4-methylpiperidine analogs of hemicholinium-3 (HC-3). Previous work in this laboratory has shown A-4 and A-5 to be inhibitors of the sodium-dependent. high affinity choline uptake system (SDHACU). Their effects on choline transport were characterized further using neuroblastoma 41A3 cells. These cells rapidly take up choline through two separate mechanisms: a SDHACU system and a sodium-independent. low affinity uptake system (SILACU). A-4. A-5 and HC-3 decreased 5 microM choline transport in a dose-dependent fashion. The compounds were unable to decrease choline transport at 250 microM choline suggesting that they are inactive with respect to SILACU. All three compounds significantly increased the Km but not the Vmax for the SDHACU system. suggesting a competitive mechanism of inhibition. Ki values ranged from 18 to 25 microM for A-4. 20 to 26 microM for A-5 and 68 to 75 microM for HC-3. Dose-response curves for inhibition of choline transport by A-5 and HC-3 were not changed by a 24-hr pre-exposure of the cells to each inhibitor. However. after a 24-hr pre-exposure to A-4. a significantly different dose-response curve was obtained compared to the dose-response curve for A-4 in untreated cells. After a 24-hr pre-exposure. a 4-hr recovery period was sufficient to remove the effect of each compound. These data suggest that A-4 and A-5. like HC-3. inhibit the SDHACU. competitively and reversibly.
Cardiovascular effects of microinjection of angiotensin II in the brainstem of renal hypertensive rats, The cardiovascular effects of microinjection of angiotensin II (AII) into the area postrema (AP). nucleus of the solitary tract (NTS) and rostroventrolateral medulla were studied in urethane anesthetized sham-normotensive (NT) and two-kidney. one-clip renal hypertensive rats. Microinjection of AII (2-2000 ng) in the AP of renal hypertensive rats elicited a dose-dependent decrease in blood pressure. heart rate and renal sympathetic nerve activity. Similar effects were observed in the NTS. In the NT rats. low doses of AII (2 and 20 ng). either in the AP or NTS. were also depressor. High doses of AII (200-2000 ng) were needed to observe a modest pressor effect in the NT animals. A decrease in heart rate and renal sympathetic activity was observed with the pressor effect. The AII-antagonist. [Sar1.Val5.Ala8]-AII. into the NTS or AP increased blood pressure and heart rate and inhibited the cardiovascular effects of low doses of AII in both group of rats. In contrast. [Sar1.Val5.Ala8]AII did not affect the pressor action of high doses of AII in the NT group. While the microinjection of AII into the rostroventrolateral medulla did not produce any significant cardiovascular effect in the renal hypertensive group. it resulted in a modest pressor effect in the NT rats. These results indicate that acute activation of AII receptors in the AP or NTS does not contribute to the pressor effect of AII in renal hypertensive rats.
Problems in the clinical diagnosis of stress incontinence, A significant number of women suffer from urinary incontinence. which often requires surgical intervention. Prior to proceeding with surgery. it is essential that all women undergo a thorough preoperative assessment to detect nonsurgical causes of their urinary leakage. This paper reviews the reliability of the initial history and basic clinical tests in the evaluation of women with lower urinary tract abnormalities.
Nonsurgical treatment of detrusor overactivity in postmenopausal women, Detrusor overactivity with subsequent urge incontinence becomes increasingly more prevalent as women age. Because of that. most women treated for detrusor instability and hyperreflexia are postmenopausal and are not always good candidates for the same treatments given to their younger counterparts. Nonsurgical treatments of detrusor overactivity are available to postmenopausal women.
Histology of the connection between the vagina and levator ani muscles. Implications for urinary tract function, The proximal urethra is a mobile structure. and voluntary control of its position is an integral part of the initiation of urination and continence. This paper describes the histology of the vagina's attachment to the medial portion of the levator ani muscles. which. because of the intimate attachment of the vagina and urethra. is responsible. in part. for control of the urethral position. A histologic examination of 1.500 serial microscopic slides from eight women. dissection of four bodies and study of whole pelvis cross-sections from two cadavers were performed. Smooth muscle. collagen and elastin fibers of the vaginal wall and paraurethral tissues directly interdigitate with the muscle fibers of the most medial portion of the levator ani. in the region of the proximal urethra. This strong connection lies at a level just below the entry of the urethra into the bladder and extends downward to the level of the perineal membrane (urogenital diaphragm) in an area corresponding to the mobile portion of the urethra. The inseparable nature of the vagina and urethra in this region makes it possible for the connection of the levator ani to the vagina to control the proximal urethral position. These observations suggest a specific role of the medial levator ani muscle in controlling vesical neck position and open the question of the specific part played by this arrangement in voiding and continence relative to other factors known to influence lower urinary tract function.
Urethral mobility and its relationship to stress incontinence in women, Multiple physiologic factors. only one of which is urethral support. make up the female continence mechanism. Abnormal urethral support leads to deficient transmission of abdominal pressure to the urethra. which results in genuine stress incontinence in some women. Many techniques are available for measuring urethral mobility. The determination of urethral mobility is not useful in the diagnosis of urinary incontinence. However. it provides some information about which surgical procedure is most appropriate for the correction of genuine stress incontinence.
Stripping the fetal membranes at term. Is the procedure safe and efficacious, A prospective. randomized investigation was undertaken in a low-risk group of pregnant women at term (38-42 weeks' gestation) to determine if stripping the fetal membranes would safely result in earlier delivery. Ninety-nine patients entered the study; 51 underwent stripping of the membranes. and 48 controls did not. Fifty-nine percent of the patients in the stripped group delivered within one week as compared to 21% in the nonstripped group (P less than .0003). Two pregnancies in the stripped group advanced beyond 42 weeks' gestation as compared to six pregnancies in the control group (P = .12). A single gravida in the control group developed chorioamnionitis during labor. There were no other infections or other complications. Stripping the membranes was associated with earlier delivery and was not associated with any complications.
Coexistence of an intrauterine pregnancy with both an ectopic pregnancy and salpingitis in the right fallopian tube. A case report, The current epidemic of pelvic inflammatory disease and recent advances in gynecologic techniques have resulted in a marked increase in the incidence of combined pregnancy. In the case reported on here the coexistence of an intrauterine pregnancy with acute salpingitis and an ectopic gestation in the same fallopian tube led to early diagnostic errors.
The clinical significance of immune reactions with some streptococcal antigens in rheumatoid arthritis, The level of antibodies and delayed-type hypersensitivity to the group specific polysaccharides and cell wall proteins of groups A. B. C and G streptococci was determined in 247 patients with rheumatoid arthritis (RA) as well as in healthy persons and in patients with other articular disorders by means of an enzyme linked immunosorbent assay. passive hemaglutination and leukocyte migration inhibition tests. An increase of the immune response to antigens of group B streptococcus was found in patients with RA. The greatest sensitization against these antigens was typical for high disease activity of short duration. and a rapidly progressive course of RA. High titers of antibodies to polysaccharide of group B streptococcus appeared in the synovial fluid in the early stages of the clinical development of RA. Values of immune response to streptococcal antigens correlated well with the titer of rheumatoid factor and the concentration of immunoglobulins and immune complexes. The presence of group B streptococcus in the urogenital tract appeared more often in patients with RA than in healthy persons. The possibility of a triggering role for immune reactions with antigens of group B streptococcus in the immunopathological process of RA is discussed. as well as the diagnostic significance of our results.
Antibodies to denatured type II collagen in rheumatoid arthritis: negative association with IgM rheumatoid factor, Serum samples from 129 patients with definite or classic rheumatoid arthritis (RA) were assayed by ELISA for antibodies to denatured bovine type II collagen (dII). All patients had active disease at the time of serum sampling. Anti-dII antibodies were found in 18 (14%) of 129 patients (95% confidence intervals: 8-20%). The only clinical or laboratory feature associated with the presence of anti-dII antibodies was seronegativity for IgM rheumatoid factor (IgM RF): 6 (37.5%) of 16 seronegative patients had anti-dII antibodies vs 12 (10.6%) of the 113 seropositive patients (OR = 5. p less than 0.01). There were no associations of anti-dII antibodies with age. sex. race. disease activity. disease duration. functional class. or the presence of HLA-DR1. DR4. or DQw3 in these patients. Antibodies to type II collagen may have a pathophysiologic role in RA. especially in patients seronegative for RF.
Pulsed suppressive treatment in rheumatoid arthritis: intravenous methylprednisolone and nitrogen mustard, Persistent polyarticular rheumatoid arthritis (RA) and aggressive disease flares resistant to conventional therapy can effectively be controlled by intravenous pulse methylprednisolone (IVMP) or nitrogen mustard (HN2). The efficacy. toxicity and immunologic effects of each agent are reviewed. Clinical response is evident within days of the start of therapy for both; persisting up to 6 weeks for IVMP and at least 59 days for HN2. Morbidity from both agents is minimal when appropriate precautions are taken. No mortalities directly related to either modality have been reported in RA.
Immunoadsorbent plasma perfusion in patients with systemic lupus erythematosus, Extracorporeal treatment of acute systemic lupus erythematous (SLE) by plasmapheresis has been reported for more than 10 years. Risks of plasmapheresis include unselective procedure. an immunoadsorbent plasma perfusion by IM-P column. Eight of 10 patients evaluated improved through 3 treatments of a 2-liter perfusion. Analysis of proteins removed during plasma perfusion showed a semiselectivity of the IM-P column for circulating immune complexes and anti-dsDNA antibodies. After perfusion of 2 liters of plasma. these substances were reduced by about 35-40%. whereas whole protein was lowered by less than 10% and immunoglobulins by about 18%. Our results in severe SLE indicate that immunoadsorption having the advantage of lowering side effects by dispensing wih foreign protein substitution.
Elevated serum levels of soluble interleukin 2 receptor, interleukin 2 and neopterin in diffuse and limited scleroderma: effects of chlorambucil, In a study of 48 patients with systemic sclerosis (SSc). elevated serum levels of soluble interleukin 2 receptor (IL-2R). interleukin 2 (IL-2) and neopterin (indicators of lymphocyte/monocyte activation) were noted in 100. 44 and 40% of early untreated patients with SSc (11 diffuse. 5 Limited). Levels of IL-2R. but not IL-2 or neopterin. were lower in patients with longer duration of disease and possibly with chlorambucil therapy. Pharmacologic alterations of markers of humoral or cell mediated immunity may not be an accurate reflection of clinical efficacy of chlorambucil.
How ancient is temporal arteritis, Realism is one of the characteristics of Amarnian art; some details of The Harpist represented in the tomb of Pa-Aton-Em-Heb (1350 BC. 18th Dynasty) might gives clues to a diagnosis: the eyes are closed with swollen lids. and the harpist appears to stare into space; he is round shouldered with a very wasted face. his temporal ara is heightened and hollowed by a broken line joining the extremity of the eyebrow with the corner of the eye. These details are not found elsewhere. Did the harpist's blindness result from temporal arteritis associated to polymyalgia rheumatica?.
Prevalence and concentration of IgM rheumatoid factor in polyarticular onset disease as compared to systemic or pauciarticular onset disease in active juvenile rheumatoid arthritis as measured by ELISA, The prevalence and concentration of IgM rheumatoid factor (RF) in children with juvenile rheumatoid arthritis (JRA) and its major disease onset groups remains uncertain. In our study enzyme linked immunoabsorbent assay (ELISA) of 68 children with active JRA showed IgM RF in the area of 67% (16/24) of those with polyarticular onset disease. 26% (7/27) of those with systemic onset disease. and 6% (1/17) of those with pauciarticular onset disease. The median IgM RF concentration was 50-fold higher in polyarticular disease compared to systemic disease. The prevalence of IgM RF in polyarticular disease was greater in those with severe disease (functional classes and 3 and 4). with 90% (9/10) seropositive. By agglutination assay. the prevalence of IgM RF in JRA was significantly less than by ELISA. with 33% of the polyarticular group positive for IgM RF. and none of the systemic group positive. Relatively low concentration IgM RF similar to that seen in systemic JRA was also found in high prevalence in the area of children with non-JRA. systemic rheumatic disease (n = 8). In summary. our study shows by ELISA that high concentrations of IgM RF are found essentially only in the sera of children with polyarticular onset JRA and especially in those with severe disease.
A modification of the Health Assessment Questionnaire for the spondyloarthropathies [published erratum appears in J Rheumatol 1991 Feb;18(2):305, A functional status measure was developed by adding 5 items to the Health Assessment Questionnaire (HAQ-S). and compared to anthropometric measures of spinal mobility. Forty-four patients with spondylitis were evaluated by the HAQ-S and measures of spine flexibility (finger-to-floor. Smythe test. neck rotation. and chest expansion). Modification of the HAQ raised the mean difficulty score by 29% from 0.38 (SD = 0.49) to 0.49 (SD = 0.51). indicating increased ability to capture functional limitations. Neck rotation correlated most strongly with the HAQ-S score (r = -0.57). which suggests an important role for this measure in clinical management and followup of spondylitis.
A double blind placebo controlled trial of low dose clotrimazole in rheumatoid arthritis, Seventy-three patients with rheumatoid arthritis were randomized in a double blind study to receive either clotrimazole (20 mg/kg/day) 2 days a week for 12 weeks or matching placebo. Patients receiving clotrimazole had significant improvements (p less than 0.05) from baseline in measurements of grip strength. joint count. and patient assessment of pain. but did not show significant improvement over patients treated with placebo. More adverse experiences. predominantly gastrointestinal complaints. occurred in patients taking clotrimazole resulting in 9 patients discontinuing therapy.
Lack of significant interaction between low dose methotrexate and ibuprofen or flurbiprofen in patients with arthritis, Low dose methotrexate (MTX) is widely used in the treatment of rheumatoid arthritis. Current product recommendations accompanying MTX preparations advise against concurrent usage of nonsteroidal antiinflammatory drugs (NSAID). and adverse pharmacokinetic interactions have been reported with this combination. Six patients who were receiving MTX were studied with both oral and parenteral MTX. 10-25 mg/dose. without NSAID and with ibuprofen (2400 mg/day) and flurbiprofen (300 mg/day) for 6 weekly doses. Serum MTX levels were obtained at frequent intervals. Serum was separated and MTX analyzed using a radioimmunoassay (RIA). There was no observable interaction between MTX and either ibuprofen or flurbiprofen. with respect to the area under the curve per unit dose. Cmax. Cmax/dose. Tmax. and serum half-life. The pharmacokinetic indices were not significantly influenced by the route of administration.
Psychological screening in rheumatoid arthritis, Our objective was to examine the utility of the Symptom Checklist-90-R (SCL-90-R) as a psychological screening instrument for patients with rheumatoid arthritis (RA). Subjects were 81 male and 3 female patients with classic or definite RA who were categorized into 3 anatomic stage groups based on roentgenograms. Erythrocyte sedimentation rates. joint counts. and the SCL-90-R were obtained on all subjects. In addition. rheumatologists were surveyed. and items were analyzed to identify potential disease related items on the SCL-90-R. Both the survey and the item analyses supported the utility of the SCL-90-R as a psychological screening instrument in a population with RA.
Reliability of pain scales in the assessment of literate and illiterate patients with rheumatoid arthritis, The assessment of a measure of chronic pain. should be reliable. valid and sensitive to change. Our study evaluated the reliability of 3 pain scales. visual analogue scale (VAS). numerical rating scale (NRS) and verbal rating scale (VRS) in literate and illiterate patients with rheumatoid arthritis (RA). Patients with RA attending an outpatient rheumatology clinic were interviewed and asked to score their pain levels on the 3 pain scales. The scales were presented in random order. twice. before and just after a regular medical consultation. Ninety-one patients were studied (25 illiterate and 66 literate). The Pearson product moment correlation between first and second assessment was 0.937 for VAS. 0.963 for NRS and 0.901 for VRS in the literate patient group and 0.712 for VAS. 0.947 for NRS and 0.820 for VRS in the illiterate patient group. These results indicate that the NRS has the higher reliability in both groups of patients.
Decreased number of peripheral blood CD4 + CD29+ lymphocytes and increased in vitro spontaneous production of anti-DNA antibodies in patients with active systemic lupus erythematosus, Flow cytometric 2-color analysis of peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE) showed a reduction of relative and absolute number of CD4+ CD29+ cells compared to matched healthy individuals. This abnormality was more marked in patients with active/very active disease. Absolute number of CD4+ CD29+ cells was negatively correlated with spontaneous anti-DNA Ig production that we demonstrated to be a laboratory index strongly correlated with a clinical disease activity score. A decrease of the percentage of CD8+ CD29+ lymphocytes in patients with active disease was also observed.
Adult Still's disease: a multicenter survey of Japanese patients, A comprehensive survey of Japanese patients with adult Still's disease was made by questionnaire which was sent to major institutions with rheumatology units in Japan. Of 146 cases from 32 institutions. 90 were judged to be definitely diagnosed as adult Still's disease. The major clinical features in these 90 patients consisted of high fever. polyarthralgia. rash. increased erythrocyte sedimentation rate. negative autoantibodies. leukocytosis. liver dysfunction. and hyperferritinemia. The incidence of several features showed significant differences between these cases and previous nonJapanese cases.
Growth and differentiation of B lymphocytes of patients with juvenile rheumatoid arthritis, We studied growth and differentiation of B lymphocytes of patients with juvenile rheumatoid arthritis (JRA) using B cell enriched populations. Mitogen stimulation led to similar proportionate increases in proliferation and immunoglobulin (Ig) secretion in cultures of patient and control lymphocytes. While there was no increase in proliferation. IgG secretion was increased in the absence of mitogen. Nonmitogen activated Ig synthesis could be reduced by replacing culture medium with fresh medium after 16-20 h in culture. It was partly reconstituted by addition of recombinant cytokines. interleukin (IL). IL-2. IL-4. or IL-6. Our results suggest there may be a population of B circulating B cells in patients with JRA and other rheumatic diseases which is sufficiently mature to differentiate and secrete Ig in response to cytokines alone.
Clonal analysis of joint fluid T lymphocytes in patients with juvenile rheumatoid arthritis, Synovial fluid (SF) lymphocytes from 4 patients with pauciarticular juvenile rheumatoid arthritis (JRA) and 4 patients with polyarticular JRA were examined for their phenotypic and functional characteristics. In all 8 patients there was a high proportion of activated SF T cells. together with an increased proportion of CD2+CD3- and the presence of CD3+CD4-CD8-WT31- lymphocytes. The functional analysis at the clonal level in 5 patients (427 clones) showed a relevant proportion of cytotoxic T cell clones. which were not confined to typically cytolytic phenotypes. but were also present among CD3+CD4+CD8- cultures. Compared to those with pauciarticular JRA. patients with polyarticular disease had a significantly higher proportion of T cell clones with cytotoxic activity. Although derived from a limited number of patients. our data suggest a direct involvement of T cells in the pathogenetic mechanisms that originate and maintain the articular damage. and the possibility of different or more pronounced T cell reactivities in the clinically more diffuse JRA types.
Estimating the incidence and prevalence of rare rheumatologic diseases: a review of methodology and available data sources [editorial, Where the need for descriptive epidemiology is great. population based registries can be established. at considerable cost. to provide the desired data. In many instances. however. there may be existing data and information systems that provide morbidity information on sufficiently large. well defined populations to allow reasonable estimates of the incidence and prevalence of rare rheumatologic diseases.
Increasing annual incidence of primary malignant brain tumors in the elderly, Between 1973 and 1985. total age-adjusted cancer incidence in the United States (all races. men and women) rose by 10.7%. with an average annual percentage change of +0.9%. Analysis of reported age-specific incidence of primary malignant brain tumors over the same years demonstrates that incidence rates increased dramatically between 1973/1974 and 1985. In 1985. incidence rates for persons aged 75-79. 80-84. and 85 years of age and over were 187%. 394%. and 501%. respectively. of rates in 1973/1974. Similar increases were found in both men and women. analyzed separately and combined. Average annual percentage changes in primary brain tumor incidence were +7.0%. +20.4%. and +23.4% in these age ranges. respectively. Reported incidence in younger persons varied little over the same period of time. The most common histologic type of primary brain tumor in the elderly was of glial origin. predominantly the glioblastoma multiforme and astrocytoma. These tumors are highly malignant and invariably fatal. Two possible causes may explain the increased incidence in the elderly: the introduction and extensive use of x-ray computed tomography since 1973 and/or a true increase in incidence occurring independently of diagnostic advances.
Rise in prostatic cancer incidence associated with increased use of transurethral resection, We examined the association between prostatic cancer incidence rates and the rates of transurethral prostatectomy to explore reasons for the nationally reported dramatic increases in incidence rates of prostatic cancer from 1973 through 1986. There was a strong correlation between both incidence of all stages of prostatic cancer combined and of localized disease and the increasing use of transurethral resection. a common surgical procedure usually performed to relieve urinary obstruction due to benign enlargement of the prostate. Our analyses suggest that increased detection of existing tumors via transurethral resection was the primary reason for the observed increase in incidence rates of prostatic cancer. However. analyses of mortality trends. particularly among nonwhites. and laboratory studies of the histologic nature of clinically asymptomatic tumors suggest that part of the increase may reflect changes in the real risk of prostatic cancer.
Unexplained excess risk of bladder cancer in men, In nearly all populations studied. the risk of bladder cancer is two to four times as great in men as in women. We estimated what the gender-specific incidence rates would be in the absence of exposure to known carcinogenic factors. The data used were obtained from interviews with 2.806 white individuals with bladder cancer and 5.258 white controls in the National Bladder Cancer Study and from incidence data for 1978 from the National Cancer Institute Surveillance. Epidemiology. and End Results Program. The total age-adjusted incidence of bladder cancer was 27.5 cases per 100.000 person-years for men and 7.0 for women. yielding a ratio of 3.9. Even in the absence of exposure to cigarettes. occupational hazards. or urinary tract infection. the gender-related risk persisted; the incidence of bladder cancer was 11.0 in men and 4.1 in women. yielding a ratio of 2.7. Possible explanations for the excessive risk in men include environmental and dietary exposures not yet identified and innate sexual characteristics such as anatomic differences. urination habits. or hormonal factors.
Progress in characterizing anatomic injury, A three-valued description of anatomic injury is presented. Anatomic profile (AP) components A. B. and C summarize serious injuries (greater than AIS 2) to the head/brain or spinal cord; to the thorax or front of the neck; and all remaining serious injuries. Relationships between AP components and survival rate reaffirm the seriousness of head injury. Logistic function models relating AP components and the Injury Severity Score (ISS) to survival probability were based on 20.946 Major Trauma Outcome Study (MTOS) patients (9.2% mortality rate) submitted through 1986. Model performance comparisons were based on 5.939 MTOS patients (7.8% mortality rate) submitted during 1987. The AP better discriminated survivors from nonsurvivors and provided a 31% increase in sensitivity when compared with the ISS. Neither the ISS nor the AP alone reliably predict patient outcome. The predictive power of methods for estimating patient survival probability which include physiologic indices or profiles. patient age. and an anatomic profile should be compared with current methods. The AP. which is based on the severity and location of all serious injuries. provides a more rational basis for comparing patient samples than the ISS.
Injured drivers and alcohol use: culpability, convictions, and pre- and post-crash driving history, The culpability. crash-related traffic convictions. and pre- and post-crash driving records of a group of injured impaired (blood alcohol level greater than 80 mg/dl) drivers (N = 58) who were admitted to a Level I trauma center were compared with a group of admitted unimpaired drivers (N = 92). Both groups of drivers were 21 years of age or older. sustained moderate injuries (defined as having no injury of the brain. spinal column or cord. extremity. or pelvis with an Abbreviated Injury Score of greater than 2). and were discharged home. In the 140 crashes in which culpability was clearly defined. the impaired drivers caused a significantly greater percentage of their crashes (92.7%) compared to unimpaired (64.7%) drivers (p less than 0.001). Of the 55 unimpaired drivers who were considered culpable of causing their crashes. 12.7% received a traffic conviction compared with 39.2% of the 51 culpable impaired drivers. The mean number of total pre-crash traffic violations was higher for impaired drivers than for unimpaired drivers (p less than 0.01). While the mean number of total post-crash convictions for unimpaired and impaired was not significantly different. the mean number of pre- and post-crash alcohol convictions was significantly higher for impaired drivers compared to unimpaired drivers (p less than 0.02). The data suggest that injury protects from legal prosecution and does not alter impaired driving practices.
The effect of prehospital fluids on survival in trauma patients, The effect of prehospital intravenous fluids upon survival was studied in 6.855 trauma patients. Mean prehospital time was 36 minutes in both the group of patients who received fluids and the group that did not. The volume of fluid administered was not significantly different in the group who survived compared to those who died. Eighty-five per cent of the patients had an Injury Severity Score (ISS) less than 25 and the mortality rate in the 56% of patients in this group who received fluids was similar to that of the patients who did not receive fluids (0.7% vs. 0.5%). Twelve per cent of the patients had an ISS between 25 and 50. Sixty per cent of these patients received fluids and the mortality rates were similar to the patients who received fluids compared to those who did not (23% vs. 22%). Three per cent of patients had an ISS of greater than 50 and the mortality rate was highest in this group but was not influenced by the administration of fluids (90% vs. 86%). Comparison of groups with similar probability of survival according to the TRISS methodology also failed to show an influence of fluid administration on survival. The mortality rate in patients with an initial systolic blood pressure (BP) of 90 torr or greater was compared to the rate in patients with an admission BP less than 90 torr. Although hypotension was associated with a significantly higher mortality rate. the administration of fluids had no influence on this rate.
Blunt trauma in adults and children: a comparative analysis, Trauma remains the major cause of death in children and young adults. Adult and pediatric patients differ significantly in both mechanism of and physiologic response to injury. We reviewed the records of all consecutive adult and pediatric blunt trauma patients admitted to a major metropolitan trauma center for a 10-year period. An extensive computerized database has been maintained for all patients since 1977. A comparative statistical analysis of mechanism of injury. specific organ injury. and clinical outcome was performed. Altogether. 1.722 adults and 289 children were treated during the study period. Blunt trauma accounted for 82.8% of adult and 94.3% of pediatric injury (p = 0.00005). and only these patients were considered for analysis. Diagnostic peritoneal lavage was performed in 249 children and 1.464 adults. with a respective accuracy of 99.6% and 97.2%. Mechanism of injury was comparable for both groups. although children were far more likely to be injured by falls. bicycle accidents. or struck by an automobile. Comparative analysis of specific injuries demonstrated significantly fewer pediatric chest (p = 0.001). spine (p = 0.03). and pelvic (p = 0.003) injuries. Central nervous system (CNS) injury in children was a strong determinant of outcome: serious pediatric CNS trauma was associated with a tenfold increase in mortality. Mortality for children in the absence of CNS injury was less than 3%. Spinal injury also appeared to be a predictor of poor outcome in the pediatric population. with an associated mortality of greater than 50%. Overall. survival was age independent (82.5% of adults and 85.8% of children were survivors.
Alcohol intoxication, injuries, and dangerous behaviors--and the revolving emergency department door, Suicides. homicides. motor vehicle crashes. and other violent deaths and injuries are linked inextricably to alcoholism. The association of injury and alcoholism should be particularly obvious to Emergency Department (ED) physicians. We sought to determine the extent to which intoxicated patients in an ED were properly diagnosed. counselled. and referred for substance abuse care. We reviewed the charts of 153 consecutive patients seen in a teaching hospital ED who had blood alcohol levels above 100 mg%. Most were male (70%). white (62%). young (mean age. 34 years) and severely intoxicated (mean BAL. 245; range. 109-558 mg%). Forty-six per cent of visits were for trauma; half of the patients were victims of violent assaults. The intoxicated patients received extensive medical and surgical management: an average of five tests or X-rays were performed per patient; 75% received at least one medication; at discharge 48% were referred for followup to medical or surgical clinics. In contrast. few patients were evaluated for dangerous behaviors or referred for treatment of alcoholism: only 19 patients (12.5%) were asked about depression. suicide. or homicide; 15% were advised to stop drinking; 13% received a referral to a psychiatrist. mental health worker. or alcohol rehabilitation facility. Forty-seven per cent of patients received "stat" intravenous thiamine (although the Wernicke-Korsakoff syndrome is rare). In contrast. only 16% received a stat on-site psychiatric consultation (although dangerous behaviors are common in alcoholics). There was a strong. statistically significant negative association between the occurrence of an injury and the decision to initiate treatment and referrals for alcoholism.
Oxygen delivery and consumption in head-injured and multiple trauma patients, Critically ill patients often demonstrate that whole body oxygen consumption (VO2) is dependent on oxygen delivery (DO2). In this retrospective study. the relationship of VO2 to DO2 in patients with isolated head injury (HI. n = 18) was compared to that in patients with multiple trauma (MT. n = 60) without serious head injury. Mean pulmonary capillary wedge pressure. central venous pressure. arterial PCO2. cardiac index. and oxygen delivery were significantly lower in HI. but oxygen consumption was not different in the groups. In both groups. changes in DO2 (delta DO2) within each patient were significantly correlated with changes in VO2 (delta VO2) in that same patient. This relationship was not different between the HI patients. (delta VO2 = (0.20 +/- 0.02) delta DO2). and the MT patients (delta VO2 = (0.17 +/- 0.01) delta DO2). When these groups were further divided into those with high hematocrit (greater than 32%) and low hematocrit (less than 32%). HI patients with a low hematocrit demonstrated a steeper regression slope. with 26 +/- 3% of the DO2 change being reflected in the VO2 change. This was significantly greater than the slope in HI patients with high hematocrit (13 +/- 3%) and the MT patients at high (19 +/- 2%) or low (16 +/- 2%) hematocrits. These data show a correlation between changes in oxygen delivery and consumption that is similar in both head-injury patients and multiple trauma patients without serious head injury. This relationship was greatest in head-injured patients at low hematocrit. This relationship of VO2 and DO2 in both groups suggests an influence of neurohumoral factors rather than local tissue phenomena.
Skeletal transfixation in treatment of comminuted fractures of the distal end of the radius in the elderly, Ninety-five patients (71 females and 24 males). average age. 69 years (35-92 years). with comminuted distal radial fractures were treated with transfixation wires (Kirschner wires) through the bases of metacarpals II-V and an above-elbow plaster cast. Two cases of early infections and four of Sudeck's dystrophy (4.2%) were encountered. Followup studies which lasted an average of 24 months (9-50 months) could be conducted on 77 patients. Using Sarmiento's ratings 27 patients fell into the very good category. 44. good. eight. fair. and two. poor. Although most of the cases were of the comminuted intra-articular fracture types. good results were achieved with this simple and quite straightforward method.
Serum phospholipase A2 in patients with multiple injuries, Catalytic phospholipase A2 activity (CA-PLA2) and the concentration of immunoreactive pancreatic PLA2 (IR-PLA2) were measured in serum samples from 12 patients with multiple injuries (median Injury Severity Score: 41). CA-PLA2 was increased in all patients and positive correlations were found between the extent of the increase of CA-PLA2. mortality. and impairment of pulmonary function. IR-PLA2 values were slightly increased in the serum of nine patients with multiple injuries. Of these nine patients. eight had an additional blunt abdominal trauma. On the other hand. no relationship was found between IR-PLA2 and CA-PLA2 values. This finding was confirmed by immunoadsorption experiments with an antiserum to human pancreatic PLA2. which demonstrated that the increased serum levels of IR-PLA2 were not responsible for the increased CA-PLA2 values. The results suggest the existence of at least two immunologically different phospholipase A2 enzymes in sera of patients with multiple injuries.
A reassessment of the peritoneal lavage leukocyte count in blunt abdominal trauma, Nine hundred and three patients undergoing diagnostic peritoneal lavage (DPL) over a 6-year period were retrospectively reviewed to evaluate the utility of the white blood cell (WBC) count in the lavage fluid. Eleven patients (1.2%) had dialysate WBC counts greater than 500/mm3. with erythrocyte counts less than 10(5)/mm3. Nine of these patients who were lavaged within 4 hours of injury had no intra-abdominal pathology. Two patients. lavaged after 4 hours. demonstrated intra-abdominal injury. Two hundred twenty-three patients (24.7%) had grossly clear dialysate which was not sent for laboratory analysis. None of these patients required laparotomy. We conclude that the WBC count in DPL fluid is of no diagnostic value in victims of blunt abdominal trauma who are lavaged within 4 hours of injury. In addition. laboratory analysis of clear dialysate is not required in these patients.
Analysis of 46 intra-abdominal aortic injuries from blunt trauma: case reports and literature review, Blunt trauma causing aortic injury is infrequent and primarily involves the thoracic aorta. Abdominal aortic injury after blunt trauma is much less frequent and has a varied presentation. Within a 3-month period. our trauma unit diagnosed and treated two cases of abdominal aortic injury secondary to blunt trauma. One was a belted passenger in a motor vehicle accident. and one was secondary to a crush injury. The addition of these two cases brings the number found in the literature to 46. Reviewing these cases has emphasized the need for prompt recognition and treatment of this vascular catastrophe.
Reduced dependency on arteriography for penetrating extremity trauma: influence of wound location and noninvasive vascular studies, Indications for arteriography in penetrating extremity trauma remain controversial. We reviewed our clinical experience in 454 patients (514 extremities) with penetrating trauma admitted during a prior 3 1/2-year period. Injuries were caused by stab wounds in 60 (11.7%) extremities and by gunshot wounds in 454 (88.3%) extremities. Thirty-three of the 60 stab wounds (55%) required urgent exploration. and 27 underwent arteriography. No arteriograms were positive for unsuspected arterial injury in this group. Forty-two of 454 gunshot wounds (9.3%) underwent mandatory exploration; arteriograms were performed on 412 extremities. Forty-four arteriograms (10.7%) demonstrated evidence of unsuspected arterial injuries. During the last year. randomly selected extremities (n = 23) have been studied with B-mode ultrasonography and segmental Doppler pressure measurements. Using the subsequent arteriography as the "gold" standard. sensitivity was 83% and specificity was 100%. Gunshot wounds were categorized according to location and positive arteriograms. Injuries to the lateral thigh and arm resulted in no positive arteriograms. while positive studies were observed in 11% of medial and posterior arm. 14% of antecubital fossa. 25% of forearm. 7.5% of medial and posterior thigh. 8% of popliteal fossa. and 26% of calf injuries. We recommend arteriography for gunshot injuries to identified high-risk areas. while clinical evaluation alone is accurate in all stab wounds to the extremities and gunshot wounds to the lateral thigh and outer arm. Preliminary data suggest expanded use of B-mode ultrasonography may further reduce our dependency on arteriography in these cases.
The impact of volume on outcome in seriously injured trauma patients: two years' experience of the Chicago Trauma System, The American College of Surgeons has stated that in considering the development of trauma systems it is important to ensure an appropriate volume of seriously injured patients be seen by each trauma center in order to achieve acceptable mortality rates. Clinical data supporting this recommendation are lacking. An analysis was performed on 1.643 seriously injured trauma patients to determine the relationship between volume and mortality rates. Three separate statistical methods were used: Pearson correlation coefficients. mortality odds ratios. and direct pairwise mortality comparisons. In addition. Tobit analysis was introduced as a method to analyze the relationship between volume and mortality. Mortality rates were adjusted for the confounding variable of serious head injury. Pearson correlation coefficients for volume vs. adjusted mortality was -0.65. Mortality odds ratios comparing the low-volume (less than 140 pts) trauma centers vs. the high-volume (greater than 200 pts) trauma centers was 1.3 for adjusted mortality rates (95% CI = 1.01-1.66; p = 0.04). Categorical analysis showed significantly different mortality rates in the centers before and after adjusting for patient mix. Tobit analysis showed the relationship between volume and mortality to be significant. accounting for 30-40% of the observed variation in mortality rates. In addition. Tobit analysis allowed construction of a model to predict mortality rates. given specific volumes of patients. Our data suggest that an inverse relationship exists between volume and mortality. and support the necessity of configuring trauma systems in a manner that will ensure designated trauma centers will see a high volume of seriously injured patients.
Acute hospital costs of trauma in the United States: implications for regionalized systems of care, As part of a larger effort to determine total direct and indirect costs of injury in the United States. national estimates of the numbers and expenditures associated with acute hospitalization due to traumatic injury were derived using data from the 1984. 1985. and 1986 National Hospital Discharge Surveys (NHDS). Estimates of the numbers of hospital episodes and total expenditures are reported in this paper for subgroups of patients defined by age. sex. and body region and AIS severity of the injuries sustained. In 1985 2.1 million individuals sustained a traumatic injury which resulted in hospitalization. Hospital expenditures totaled $11.4 billion inclusive of professional fees. Adolescents and young adults aged 15-44 years accounted for nearly one half of all discharges and total hospital costs. The elderly. who represent only 12% of the population. accounted for an additional one quarter of total discharges and hospital costs. Nearly three quarters of the hospitalizations and one half of total expenditures were for minor (ICD/AIS = 1. 2) injuries. Moderate (ICD/AIS = 3) and severe (ICD/AIS = 4. 5). injuries respectively accounted for 23% and 3% of total episodes and 37% and 11% of total expenditures. Only 12% of patients and 25% of trauma care dollars involved injuries sufficiently severe to require treatment at a trauma center.
Differential effects of alpha and beta adrenergic blockade on glucose and lactate metabolism during acute stress, In this study we examined the role of alpha and beta blockade on glucose and lactate metabolism during the acute stress of insulin-induced hypoglycemia. Three groups of conscious dogs with chronically fitted catheters in the femoral artery and in the femoral. portal. and hepatic veins were studied after an 18-hr fast. After a 1-hr basal period. hypoglycemia was induced with insulin infusion at 5 mU/kg.min for 3 hr. Group 1 received no other treatment. Groups 2 and 3 received. respectively. phentolamine (8 micrograms/kg.min) and propranolol (4 micrograms/kg.min) beginning 30 minutes before and throughout the experimental period. Despite similar hyperinsulinemia. plasma glucose dropped in Group 1 (from 115 +/- 10 to 40 +/- 3 mg/dl) and in Group 2 (from 110 +/- 4 to 60 +/- 3 mg/dl) but in Group 3 it was maintained at 45 +/- 4 mg/dl by exogenous glucose infusion at a rate of 2.2 +/- 0.4 mg/kg.min. Hepatic glucose production increased 50 +/- 13%. 127 +/- 30%. and 55 +/- 30% in Groups 1. 2. and 3. respectively. within 60 minutes and was 56 +/- 19%. 55 +/- 17%. and -0.04 +/- 12% during the last hour of the experiment. Glucose utilization did not change in Groups 1 and 2 but it increased in Group 3. Plasma lactate increased in Group 1 (from 850 +/- 190 to 1.980 +/- 450 mumol/L) and in Group 2 (985 +/- 180 to 4.785 +/- 500 mumol/L). while in Group 3 there was an early rise (to 695 +/- 120 mumol/L) within 30 minutes that gradually dropped to near basal.
Geographic patterns of urban trauma according to mechanism and severity of injury, The purpose of this study was to investigate the distribution of various mechanisms of injury and the relative severity of such injury cases throughout the different geographic zones of a large urban area using a computerized emergency medical services (EMS) dispatch/patient record database. The study city (population. 2 million residents) was divided into 156 geographic grids (each 4.5 by 3 miles) and the incidence and relative severity of various injury mechanisms were determined for each zone. Results: In one year (1988). there were more than 115.000 separate EMS incidents involving more than 150.000 patients. 26.000 of whom were transported for injuries incurred in 10.064 motor vehicle accidents. 4.587 falls. 4.015 lacerations/stabwounds. 1.796 beatings. 1.270 gunshots. and 952 auto-pedestrian accidents. Analysis of the 156 zones showed a disproportionate number of EMS responses in the city center with two centralmost grids accounting for about 25% of all responses. Call volume then progressively diminished toward the periphery of the city. However. with some very minor exceptions. the relative incidence and severity of the various injury mechanisms remained proportionally uniform within each zone. regardless of geographic location. Therefore. contrary to popular notoriety. the incidence and associated severity of any given injury type generally was not necessarily predicted by any particular neighborhood predilection for it. but rather by the overall demand for EMS in that zone of the city.
Management of complex perineal soft-tissue injuries, Debridement. fecal diversion. and rectal washout have been proposed as the primary therapy for complex perineal lacerations. but. in most series. survivors have a pelvic sepsis rate of 40-80%. In a retrospective study. six of 18 patients sustaining severe perineal lacerations died within the first few hours of injury due to exsanguination from pelvic injuries. The remaining 12 patients underwent sigmoidoscopy. diversion of the fecal stream with irrigation of the distal rectal stump. and radical initial debridement of necrotic soft tissue. Enteral access was obtained in two patients. In the patients with mandatory daily debridement and pulsatile irrigation. no pelvic sepsis occurred. In three patients without daily debridement. pelvic sepsis complicated recovery. The ability of patients to resume oral nutrition was significantly delayed. necessitating total parenteral nutrition in three patients. We conclude that sigmoidoscopy. total diversion of the fecal stream with irrigation of the distal rectal stump. enteral access for feeding. radical initial debridement of necrotic soft tissue. and mandatory daily debridement with pulsatile irrigation optimize recovery from this devastating injury.
Intra-abdominal and retroperitoneal organ injuries diagnosed on dynamic computed tomograms obtained for assessment of renal trauma, The efficacy of dynamic computed tomography in assessment of renal. intra-abdominal. and retroperitoneal organ injuries is analyzed in some 444 patients. This technique contributed most valuable information toward the diagnosis of such coexistent injuries in patients who sustained blunt trauma. CT identified associated abdominal or retroperitoneal organ injuries in 85% of the patients (277 of 324). clinical examination in only 26%. CT proved invaluable for assessment of injury to bowel and mesentery. pancreas. and retroperitoneal vascular structures. giving rise to hematomas. CT diagnosed all such injuries. clinical examination from 0% (pancreas) to 11% (retroperitoneal hematomas). In patients with penetrating injury. dynamic CTs added valuable information on the status of viability of the injured organs. A relatively high number of false positive diagnoses resulted in only four unnecessary explorations. In all other patients. the erroneous diagnosis was revealed on repeat CTs undertaken because of inconsistency of the clinical course and clinical findings with the initially suggested CT diagnosis or at time of exploration undertaken for correction of other confirmed injuries. Discovery of associated intra- or retroperitoneal organ injuries. particularly in patients who sustained blunt trauma. has resulted in modification of treatment which prevented late sequelae and complications and thereby substantially reduced hospitalization time.
The importance of routine surveillance of distal bypass grafts with duplex scanning: a study of 379 reversed vein grafts, To assess the utility of routine duplex surveillance. 379 infrainguinal reversed vein grafts performed at two independent teaching hospitals were prospectively entered into a surveillance protocol from March 1986 through August 1989. An average of 3.2 postoperative duplex graft flow velocity (GFV) measurements per graft was obtained during a mean follow-up interval of 21 1/2 months. Only 2.1% of 280 grafts with GFV measurements greater than 45 cm/sec failed within 6 months of a normal surveillance examination. GFV measurements less than 45 cm/sec in 99 grafts led to arteriography in 75 grafts. identifying 50 stenotic lesions in 48 bypasses (12.6% of series). Inflow lesions were present in 5%. outflow stenoses in 2%. and intrinsic graft stenoses in only 6% of bypasses. Only 29% of grafts identified as failing by duplex scan were associated with a reduction in ankle-brachial index of greater than 0.15. Secondary reconstructions were performed in 48 grafts based on detection of a reduced GFV measurement; all such reconstructions are patent after a mean follow-up of 5 months. Duplex surveillance is more reliable in identification of failing vein grafts than is determination of ankle-brachial index.
Surgical procedures in the management of Takayasu's arteritis, Takayasu's arteritis is an inflammatory arteriopathy that often progresses to obliteration of multiple large arteries. Variable results have been reported after medical and surgical management. Twenty female patients with Takayasu's arteritis were treated from 1973 to 1989. Eleven (55%) patients had hypertension. Upper or lower extremity ischemia was present in 12 (60%) patients and cerebrovascular insufficiency in seven (35%). Nine patients initially managed with corticosteroids had no improvement in signs or symptoms of arterial insufficiency. Eleven patients had 16 vascular procedures for the following indications: renovascular hypertension (6). extremity ischemia (5). cerebrovascular insufficiency (2). dilation ascending aorta with aortic insufficiency (1). thoracic aortic aneurysm (1). abdominal aortic aneurysm (1). Procedures included aortorenal bypass (5). carotid-subclavian. axillary. or brachial bypass (4). aorto-carotid bypass (2). aneurysm resection (2). supra-celiac aorto-femoral bypass (1). ascending aorta/aortic valve replacement (1). and nephrectomy (1). Clinical improvement occurred in all patients. There were no operative deaths. All are alive at a mean follow-up of 5.75 years (6 months to 16 years). Revision of the initial reconstruction has been required for recurrent renovascular hypertension in one patient and extremity ischemia in another. The other nine patients remain symptomatically improved. Symptomatic Takayasu's arteritis frequently requires arterial reconstruction. Symptomatic improvement and excellent long-term graft patency can be expected after arterial reconstruction.
Propagation of deep venous thrombosis identified by duplex ultrasonography, To investigate the efficacy of anticoagulation in preventing continuing thrombosis. we prospectively evaluated 24 patients with acute deep venous thrombosis using duplex ultrasonography. All patients were hospitalized with conclusive ultrasonic evidence of deep venous thrombosis identified in one of four levels: I. calf only; II. calf-popliteal; III. calf-popliteal-femoral; or IV. calf-popliteal-femoral-iliac. Duplex scans were obtained on admission and on three subsequent occasions during therapy. Progression of thrombosis was defined as advancement of thrombus to the more proximal venous level. Demographic data. symptoms. risk factors for deep venous thrombosis. physical findings. anticoagulation regimens. and hematologic variables were ascertained. Adequacy of anticoagulation was defined as elevation of baseline activated partial thromboplastin time by 150%. Nine patients (38%) had progression of thrombosis. and 15 (62%) had stable or improving duplex scans. Progression occurred as follows: I----II (2). I----III (2). II----III (1). and III----IV (4). Of the demographic and clinical variables examined. only smoking correlated with progression of thrombus (p = 0.04). Average heparin dose in the stable group was 1214 +/- 294 units/hr and 1122 +/- 248 units/hr in the group that progressed (p = 0.8): activated partial thromboplastin time was 45.6 +/- 7 seconds in the stable group and 49.8 +/- 9 seconds in the progression group (p = 0.7). Nine patients in the stable group had consistently adequate anticoagulation. whereas six did not; six in the progression group were consistently anticoagulated. and three were not. Two patients (one with stable thrombus and one with progressive thrombus) suffered nonfatal pulmonary emboli. Clot progression as determined by duplex scanning did not predict acute complications of deep venous thrombosis.
Clinical spectrum of symptomatic external iliac fibromuscular dysplasia, External iliac fibromuscular dysplasia is a rare and usually asymptomatic disorder. We report eight symptomatic patients seen over a 15-year period and review pathophysiologic mechanisms accounting for the three following distinct lower extremity ischemic sequelae: (1) Emboli--episodic focal digital ischemia (blue toe) was seen in three patients. Resection and primary anastomosis of focal iliac ulcerative fibromuscular dysplasia (one patient) or resection and replacement (two patients) removed the embolic source and relieved the symptoms. (2) Chronic ischemia--gradual onset of full leg claudication in four patients was treated by operative graduated intraluminal dilation in three patients and prosthetic bypass in one. Arteriography subsequently showed a remodeled lumen in the three patients who underwent dilation. (3) Dissection--acute onset leg ischemia resulted from presumed dissection of the external iliac segment. After 4 months of conservative management of antiplatelet agents and exercise. symptoms resolved completely. and arteriogram showed spontaneous restoration of a normal lumen in the dissected segment. The clinical presentation of fibromuscular dysplasia may mimic other arterial processes such as atherosclerosis. Diagnosis is made only by arteriography with specific magnification views of the external iliac arteries and careful surveillance of the renal arteries. Appropriate treatment should be tailored to the clinical presenting symptom. For microembolic disease. resection and replacement are required. For chronic ischemia. intraluminal dilation is generally sufficient and durable and has proved to be a simpler and acceptable alternative to replacement or bypass. In acute dissection. surgical intervention may be deferred if the limb is viable to allow spontaneous healing and remodeling. Persistent symptoms may be the only indication for intervention in this ischemic manifestation of external iliac fibromuscular dysplasia.
Initial clinical evaluation of carotid artery laser endarterectomy, Clinical study of carotid artery laser endarterectomy began April 15. 1988. This report describes the first 10 cases that were performed in nine patients (five men and four women. mean age 70 years). Indications were asymptomatic stenosis (5). transient ischemic attacks (4). and stroke in evolution (1). There were two emergency cases and eight elective cases (including one reoperative case). Surgical exposure. systemic heparinization. vascular control. and a longitudinal arteriotomy were used. The cleavage plane between atheromas and media was developed with argon ion laser radiation (488 and 514.5 nm) directed through a 300 microns quartz fiber at power 1.0 W. Laser radiation was used to cut the atheromas out of the arteries and weld the end points. Residual atheromatous debris were vaporized with individual laser exposures. Arteriotomies were closed with sutures. and blood flow was restored. The endarterectomies were 3.9 +/- 1.1 cm long and required 330 +/- 97 joules. Mean clamp time was 22.5 +/- 7.9 minutes. Shunts were used in two cases. There were no arterial perforations or injuries as a result of laser light. Complications were hematoma (1). respiratory arrest (1). and transient neurologic deficit (1). Carotid endarterectomy is technically feasible with argon ion laser radiation. In the present series. postoperative observations. averaging 12 months and ranging from 5 to 19 months. have shown satisfactory results. No angiographic follow-up examinations were carried out.
Transcervical balloon tuboplasty. A multicenter study, Transcervical balloon tuboplasty represents a noninvasive technique to treat proximal tubal occlusion. In a multicenter study. 77 women with confirmed bilateral proximal tubal occlusion underwent the procedure. In 71 patients (92%). at least one proximally obstructed fallopian tube was recanalized. Concomitant distal bilateral tubal occlusions were diagnosed after successful proximal tubal balloon recanalizations in 13 patients (17%). In the remaining 64 patients. 22 clinical pregnancies (34%) have been confirmed during a median follow-up period of 12 months. Among those. 17 (77%) resulted in normal deliveries and five (23%) resulted in a first-trimester miscarriage. One patient was diagnosed with an ectopic pregnancy. Among 25 patients who had not conceived within 6 months of the procedure. 17 (68%) demonstrated continuing tubal patency on repeated hysterosalpingogram. We conclude that transcervical balloon tuboplasty is a safe outpatient technique that may represent an alternative to in vitro fertilization or microsurgical reanastomosis of fallopian tubes.
The direct costs of universal precautions in a teaching hospital, An analysis of the increase in expenditures for barrier isolation materials before and after the institution of universal precautions at our 900-bed university hospital was used to generate a national estimate of the cost of implementation of the new Centers for Disease Control guidelines. Following the institution of universal precautions. use of rubber gloves at our hospital increased from 1.64 million pairs of 2.81 million pairs annually. A 5-year review of hospital purchasing and supply records in both inpatient and outpatient areas indicated that the total annual costs for isolation materials increased by $350.900. This represented an increase from $13.70 to $22.89 per admission (60%) after adjustment for inflation. The cost of isolation materials increased from $98 to $215 per 1000 outpatient visits. an adjusted increase of 92%. Two thirds of the increase (64%) was due to rubber gloves and an additional 25% was due to disposable isolation gowns. Universal precautions are estimated to have cost at least $336 million in the United States in fiscal year 1989 after adjustment for inflation. If expenditures for isolation materials at our medical center are representative. previous estimates may have significantly underestimated costs nationwide.
Epidemiologic, clinical, and laboratory findings of human ehrlichiosis in the United States, 1988, In 1988. the Centers for Disease Control and the Oklahoma State Department of Health identified 40 patients who had a fourfold or greater change in antibody titer in response to Ehrlichia canis. The median age of these patients was 42 years. 83% were male. 76% became ill between May and July. and 92% reported recent exposures to ticks. Patients resided in or were exposed to ticks in 14 states. including five where ehrlichiosis had not been reported before 1988. Thirty-four patients (85%) were hospitalized. and many had serious complications. including acute respiratory failure (seven patients). encephalopathy (six patients). and acute renal failure (four patients). Pulmonary infiltrates were demonstrated in 14 patients. cerebrospinal fluid pleocytosis was seen in 10 patients. and elevated levels of serum creatinine were demonstrated in eight patients. Two patients. both of whom had preexisting medical problems. died. Nonhospitalized patients received tetracycline therapy earlier in the course of their illness than hospitalized patients. There was no significant difference in the interval from initiation of antibiotic therapy to the first day of defervescence between patients treated with tetracyclines and those treated with chloramphenicol.
Vitamin D and bone, Recent studies of the effects of vitamin D on bone include characterization of the receptors for 1.25-(OH)2D3 in bone and bone derived cells. The receptors show similar affinities in the different tissues. The receptor concentration is affected by the stage of the cell cycle. Glucocorticoid treatment affects the number of receptor sites. The most extensively studied effects of 1.25-(OH)2D3 on macromolecular synthesis in bone have been on collagen. where both anabolic and antianabolic effects are found. Differences in the response may reflect the state of differentiation of the cells. Significant effects are seen on osteocalcin synthesis. although the role of this protein in vitamin D action on bone is still unclear. 1.25-(OH)2D3 influences the activity of alkaline phosphatase and 25-OH-D3 24-hydroxylase in bone. Receptors for growth factors. and production of cytokines may be influenced by 1.25-(OH)2D3 treatment. Although some of these findings would be consistent with direct anabolic effects of vitamin D or its metabolites on bone. such a process has yet to be integrated into the complete picture of vitamin D action at physiological and pharmacological levels in vivo. Recent studies are consistent with earlier results that indicate that hypercalcemic effects of 1.25-(OH)2D3 are mediated by a direct effect on bone. Studies with analogs of 1.25-(OH)2D3 suggest that the stimulation of bone resorption can be dissociated from effects on differentiation of cells of the monocyte lineage.
Immune reactivity in bronchogenic carcinoma and its relation to 5-year survival rate, We performed a prospective study on the correlation of various parameters of the immune response with the 5-year survival rate in patients with bronchogenic carcinoma. Parameters were initially examined before starting treatment. Delayed hypersensitivity skin tests. lymphoblastogenesis. natural killer (NK) cell activity. and interleukin-2 (IL-2) production were employed to assess immune competence. Each reaction was classified into four or five grades in accordance with intensity; the 5-year survival rate of the patients showing each grade of the immune response was calculated. A correlation between response before treatment and the survival rate was most clearly noted for lymphoblastogenesis. The skin tests and the NK cell activity showed poorer correlations. and no exact correlation was noted between the IL-2 production and the immune response.
Effect of prostaglandin E in multiple experimental models: V. Effect on tumor/host interaction, Prostaglandin E (PGE) has long been incriminated as a cause of the immunosuppression seen in cancer patients and for the increased rates of tumor growth due to the impairment of the immunologic response to the tumor. We have investigated the effect of PGE on tumor-host interaction by utilizing a parenterally administered long-acting PGE derivative. 16.16-dimethyl-prostaglandin E (dPGE). Administration of dPGE was found to decrease the rate of tumor growth but at a cost of decreasing tumor-free body mass. The dPGE did not alter resting metabolic rates but did alter some parts of brain dopamine metabolism and significantly decreased the serum level of multiple amino acids. In conclusion. elevated PGE levels may significantly alter metabolism in tumor patients.
Malignant melanoma occurring during pregnancy: a report of the Northern Israel Oncology Center (1968-1988), Medical records of seven patients treated within a 20 year period for malignant melanoma during pregnancy were reviewed. No significant detrimental prognostic effects could be attributed to pregnancy. The current literature on melanoma and pregnancy is discussed. Based on this. pregnancy seems not to be contraindicated in melanoma patients.
Renal vein leiomyosarcoma, The 11th case of primary leiomyosarcoma of the renal vein is reported. Unique features of this case included concomitant resection of an isolated hepatic metastasis. intraoperative radiation therapy. and the use of electron microscopy and immunohistochemical stains in confirming the diagnosis. A review of the previously reported cases shows a tendency toward slow tumor growth and infrequent recurrence (18%). Metastases are common (82%). primarily to the lung and liver. Aggressive surgical resection and adjuvant radiation therapy. including intraoperative radiation therapy. are recommended. Adjuvant chemotherapy should be considered. although its benefits at present are unclear.
Adrenal carcinosarcoma, The clinical and pathologic features of a case of adrenal carcinosarcoma are reported. Although synchronous malignancy of the adrenal gland has been described. no case of an adrenal tumor combining both carcinomatous and sarcomatous elements has been previously documented. This neoplasm is extremely aggressive with distant metastasis arising from the sarcomatous component. and rapid progression despite multimodal therapy.
Utility of surgical margins in the radiotherapeutic management of soft tissue sarcomas, Seventy-four adult patients with localized soft tissue sarcomas were treated with radiation therapy following surgery between 1965 and 1988. Fifty-three were treated after the first excision of their tumor with 6 (11.3%) local recurrences. Twenty-one received radiation after excision of recurrent disease with 11 (52.4%) local failures (P less than .0005). Metastatic disease occurred in 14 (26.4%) of the primary tumors and 8 (38.1%) with multiple previous excisions (P less than .48). Of those patients treated for primary sarcoma. there were no local failures with pathologically wide margins or if a single margin was microscopically positive. Local failure occurred in 4 of 26 (15.4%) if the tumor was merely enucleated and in 2 of 11 (18.2%) who had grossly positive surgical margins (P not significant). Local failure was also more common in truncal locations (33.3%) as compared with extremity locations (8.7%. P = .1359). Additional factors analyzed which adversely affected prognosis included tumor grade. stage. and inadequate radiation dose.
Acral melanoma: a review of 185 patients with identification of prognostic variables, One hundred eight-five patients with acral melanoma treated since 1972 were reviewed. These included 53 subungual lesions. 123 plantar lesions. and 9 palmar lesions. Eighty percent presented with stage I disease. Mean age was 57 years. Males outnumbered females 1.1:1. Seventeen percent (17%) were blacks. Actuarial 10-year survival was 58% for stage I patients and 35% for stage II patients. Univariate Cox regression analyses identified 5 prognostic variables affecting survival: stage at diagnosis (P less than 0.001). race (P less than 0.001). ulceration (P = 0.012). Clark's level (P = 0.014). and thickness of the primary lesion (P = 0.013). Factors unrelated to survival included sex of the patient. site (volar vs. subungual). histology. and treatment with amputation. Multivariate analysis for patients with stage I lesions identified race (P = 0.001) and ulceration (P = 0.018) as significant variables. with thickness approaching significance (P = 0.094). In an additional series of 71 patients with melanomas arising from extremity sites near the junction of glabrous and non-glabrous skin. survival was significantly poorer for those arising from glabrous skin (P = 0.024). and reflects a higher incidence of metastatic disease at diagnosis. Specific active immunotherapy was the principal adjuvant used for these patients. and survival was comparable to that reported with regional perfusion therapy. Acral melanoma a) has a strong racial predilection. b) carries a grave prognosis. and c) arises from glabrous skin. It is a clinical entity distinct from other extremity melanomas. Surgical management with either wide excision or amputation is appropriate for the primary lesion.
Long-term experience with a totally implanted catheter system in cancer patients, Long-term experience with totally implanted catheter systems (TICS) is limited. We retrospectively evaluated the performance and long-term complications of TICS for intravenous infusion in cancer patients; 134 systems were implanted in 128 patients. The median duration of implantation was 144 weeks with 49 systems implanted for more than one year. Complications related to surgical factors included malposition of reservoir (2%). skin perforation or wound dehiscence (1.5%) and pneumothorax (less than 1%). Complications not related to surgical factors included: drug extravasation (1.5%). mechanical malfunction (1.5%). vein thrombosis (less than 1%). clotting of the reservoir or catheter (2%). skin infection (1.5%). and sepsis (less than 1%). The total complication rate was 13%. Most complications resolved spontaneously or with medical treatment and only 6 patients (4.6%) required re-implantation of a second system. We conclude that with long-term usage of TICS. the complication rate remains low. making it a safe and viable alternative for patients requiring long-term intravenous therapy.
The influence of extracorporeal circulation on erythrocytes and flow properties of blood, The influence of extracorporeal circulation on red blood cells and flow properties of blood was studied in 10 patients undergoing aorta-coronary bypass grafting. Blood samples were drawn on admission. under general anesthesia before the operation. during extracorporeal circulation. immediately after extracorporeal circulation. and 24 hours after extracorporeal circulation. Echinocytes were found during and shortly after extracorporeal circulation. but disappeared within 24 hours. Washing the cells in buffer restored the normal discocytic shape. which indicated that a plasma factor was responsible. Red cell membrane lipids were not affected. Analysis of the membrane proteins revealed a decrease of ankyrin after extracorporeal circulation. which was prevented by protease inhibitors during preparation. This suggests an increased proteolytic activity of the plasma after extracorporeal circulation. Red cell deformability was not altered. Plasma viscosity and hematocrit were markedly reduced by hemodilution with the priming solution. Their low levels resulted in a low blood viscosity during extracorporeal circulation. which was even lower at 26 degrees C than before or after the operation at 37 degrees C. We conclude that the red cell is affected by extracorporeal circulation. The flow properties of blood. however. are not impaired. but are improved by hemodilution.
Prostacyclin and prostaglandin E2 mediate reduction of increased mean arterial pressure during cardiopulmonary bypass by aspiration of shed pulmonary venous blood, Increased mean arterial pressure during the aortic crossclamp period while on cardiopulmonary bypass was usually treated by us with hypotensive drugs. We noticed. however. that aspirating shed excess pulmonary venous blood from the open pleural cavities causes an immediate reduction in mean arterial pressure. obviating the need for any further pharmaceutical intervention. In this study we investigated the relationship between the reduction in mean arterial pressure and the levels of prostacyclin and prostaglandin E2 in the peripheral and pulmonary venous blood. Ten men undergoing coronary bypass operations had 21 episodes of increased mean arterial pressure (106.9 +/- 11.4 mm Hg) during aortic crossclamping. which was reduced to 67.4 +/- 11.4 mm Hg (p less than 0.001) only by aspirating a mean of 490 ml (range 150 to 1100 ml) of pulmonary venous blood from the pleurae back into the circulation. Mean peripheral prostacyclin level. measured as 6-keto-prostaglandin F1 alpha. and prostaglandin E2 level. both measured by radioimmunoassay technique. were significantly lower at peak mean arterial pressure (419 +/- 180 and 59.5 +/- 21.2 pg/ml) than at lowest mean arterial pressure (632 +/- 271 and 96.7 +/- 52.4 pg/ml for 6-keto-prostaglandin F1 alpha and prostaglandin E2. respectively; p less than 0.001). Prostaglandin F1 alpha and prostaglandin E2 levels in the aspirated pulmonary venous blood were 2309 +/- 3098 pg/ml and 749 +/- 909 pg/ml. respectively. The hypotensive effect of shed pulmonary venous blood that is aspirated back from the pleurae into the circulation seems to be mediated by the high levels of prostacyclin and prostaglandin E2. both powerful vasodilators.
Myocardial temperature during cardiac operations: influence on right ventricular function, Maintenance of right heart integrity is frequently neglected during coronary operations. Right ventricular dysfunction sometimes limits the success of the surgical procedure. however. In addition to the use of cardioplegic solutions. myocardial hypothermia during ischemic cardiac arrest seems to be an important factor for guaranteeing right ventricular performance thereafter. This study was designed to measure myocardial temperature in patients with coronary artery disease who have significant stenosis of the right coronary artery in comparison with those who do not have stenosis of the right coronary artery and to evaluate the influence of myocardial temperature on right ventricular hemodynamics after cardiopulmonary bypass. Right ventricular function was assessed by thermodilution technique. which allows measurement of right ventricular ejection fraction. right ventricular end-diastolic volume. and right ventricular end-systolic volume. Right ventricular temperature differed significantly between the two groups. with the lowest value of 15.1 degrees +/- 1.8 degrees C in the group without stenosis of the right coronary artery and a value of 22.2 degrees +/- 2.1 degrees C in the group with stenosis of the right coronary artery. Left ventricular and septal temperatures were without group differences within the investigation period. Right ventricular hemodynamics were impaired only in the group with stenosis of the right coronary artery with a decrease in right ventricular ejection fraction from 44.2% to 34.1% immediately after termination of bypass and an increase in right ventricular end-diastolic volume index (+38%) and right ventricular end-systolic volume index (+70%). Cardiac index decreased only in this group. too (-22.5%). Analysis of covariance revealed a significant correlation only between changes in right ventricular ejection fraction. right ventricular end-diastolic volume. and right ventricular end-systolic volume and the course of right myocardial temperature. It is concluded that right ventricular hypothermia is more difficult to achieve in patients with a diseased right coronary artery. Constant myocardial hypothermia. however. seems to be important in guaranteeing right ventricular function. which easily can be evaluated by the thermodilution technique.
Prediction of risk in noncardiac operations after cardiac operations, To determine the preoperative variables affecting the mortality rate and the development of severe complications in patients who have had myocardial revascularization or a valve replacement and who then undergo a noncardiac operation. we retrospectively studied data from 120 such patients over the 5 years from 1982 through 1986. Thirty-six percent of patients had a noncardiac operation during the first month after the cardiac operation. The mortality rate was 11%. and the morbidity rate was 56%. The statistical comparison of the predictive accuracy of postoperative complications of three simple. widely used classifications (American Society of Anesthesiologists physical status. New York Heart Association classification. Massachusetts General Hospital cardiac risk index) demonstrated the superiority of the simplified three-class cardiac risk index (Massachusetts General Hospital-cardiac risk index; predictive accuracy of 84%). In a multivariate discriminant analysis of 21 variables in this population. five variables (myocardial infarction in previous 6 months. S3 gallop or jugular vein distention. arrhythmia on last preoperative electrocardiogram. emergency operation. delay between cardiac and noncardiac operation) were identified as being the most predictive of a postoperative complication. When these variables were used in the function (DF3) obtained by linear discriminant analysis. the prediction accuracy of a postoperative complication reached 83%. Performance of the new models in a prospective validation population remained satisfactory (75% for Massachusetts General Hospital-cardiac risk index three-class index and 72% for DF3). Extensive statistical analysis of our data tested by a validation study provided simple predictive models based on clinical variables easily available even in emergency situations.
Intraoperative coronary artery endarterectomy with excimer laser, Compared with continuous-wave lasers. excimer lasers exhibit several in vitro advantages: nonthermal ablation process and linear relation between the number of pulses and the depth of the crater. A 308 nm. 20 nsec pulse duration. 1 to 5 repetition rate laser was specifically designed for clinical application. At the time of cardiopulmonary bypass in 10 symptomatic patients. before bypass grafting. a 1 mm diameter core specifically ultraviolet-tipped fiberoptic scope was introduced via the coronary arteriotomy and placed upstream (seven patients) and downstream (three patients) in contact with the stenosis. Laser power was increasingly delivered up to the clearing of the stenosis or occlusion. Quality of angioplasty was controlled by calibration of the neolumen. cardioplegic solution output through the laser-treated segment. and an eighth day or sixth month coronary arteriogram. In the first three patients studied on the eighth day. all laser-treated coronary artery segments showed an early parallel-linked patent neolumen despite competitive bypass graft flow. In the patients studied after 6 months. all recanalized segments were patent except one; in one patient the venous graft was occluded. but the upstream laser angioplasty was patent. The main limitation of the method lies in the fact that laser coronary recanalization is confined to the fiber core diameter. We conclude that (1) excimer laser angioplasty may be safe and efficient during surgical procedure and (2) as catheter flexibility remains the most critical problem. we are now assuming an appropriate tool with a multifiber system that is suitable for intraoperative as well as percutaneous routes.
Cutaneous malignant melanoma in Rochester, Minnesota: trends in incidence and survivorship, 1950 through 1985, In Rochester. Minnesota. 107 incidence cases of cutaneous malignant melanoma (in 46 male and 61 female patients) were diagnosed during the years 1950 through 1985. Overall crude incidence rates were 6.0 and 6.6 per 100.000 males and females. respectively. Evaluation of trends in 9-year periods showed that the rates increased from 3.2 to 8.9 for males (P = 0.015) and from 4.4 to 11.7 for females (P less than 0.001). Age-specific rates suggested that the highest incidence occurs in the age-groups 50 to 59 years and 70 years or older for males and 40 to 49 years and 70 years or older for females. Lesions were most common in the head and neck area among males (P = 0.044) and on the lower extremities among females (P = 0.018). The most frequent histologic type was superficial spreading melanoma (61%). Five-year survival was diminished overall for patients with cutaneous malignant melanoma--0.72 in comparison with 0.88 expected for the general population. Statistically significant risk factors for survival were depth of invasion of the lesion (Clark level). thickness of the lesion. histologic type. and age of the patient.
Diagnosis of corticotropin-producing bronchial carcinoid tumors causing Cushing's syndrome, Cushing's syndrome due to ectopic production of adrenocorticotropic hormone (corticotropin) has been recognized for many years. Traditionally. clinicians have thought that most cases were due to lung carcinomas and that the clinical manifestations differed from those for pituitary-dependent Cushing's syndrome. We report two cases of corticotropin-producing bronchial carcinoid tumors that were clinically and biochemically indistinguishable from pituitary-dependent Cushing's syndrome. Review of the literature revealed that bronchial carcinoid tumors are the most common cause of Cushing's syndrome due to ectopic secretion of corticotropin. On biochemical and anatomic studies. they are frequently indistinguishable from pituitary-dependent Cushing's syndrome and thus may be difficult to diagnose. Inferior petrosal sinus sampling for corticotropin and computerized imaging of the chest may be the best aids in making the diagnosis.
Rehabilitative techniques for athletes after reconstruction of the anterior cruciate ligament [published erratum appears in Mayo Clin Proc 1991 Jan;66(1):114, A wide spectrum of protocols is available for rehabilitation after anterior cruciate ligament reconstruction. and little agreement exists on the specifics of strengthening exercises or the sequence of activities. In this article. we discuss the current rehabilitative techniques used at the Mayo Clinic for athletes who have undergone anterior cruciate ligament reconstruction. These techniques are based on established principles of rehabilitation. clinical experience. and new information about the related biomechanics of the knee. An illustrative case reflects the benefits of this rehabilitation program. which lasts up to 1 year and is divided into five stages. The early stages focus on protected mobilization and a strengthening program that emphasizes closed rather than open kinetic chain exercises. Later. neuromuscular-proprioceptive training and sport-specific agility training redevelop the reaction time and the "coordination engrams" necessary for athletic competition. High-quality surgical care and a closely supervised rehabilitation program. based on kinesiologic and biomechanical factors as they pertain to the anterior cruciate ligament. are necessary for a successful outcome.
Transcranial Doppler ultrasonography: clinical applications in cerebrovascular disease, Transcranial Doppler ultrasonography was introduced in 1982 as a noninvasive procedure for assessment of the intracranial cerebral circulation. The lightweight and portable equipment used for transcranial Doppler examination facilitates its use in the bedside assessment of critically ill hospitalized patients and outpatients. Clinical applications include the diagnosis of vasospasm in patients with subarachnoid hemorrhage. assessment of intracranial collateral flow in patients with extracranial arterial occlusive disease. detection of intracranial arterial stenosis. identification of the feeding arteries of arteriovenous malformations and monitoring the hemodynamic effects of their treatment. confirmation of the clinical diagnosis of brain death. intensive-care unit monitoring of brain-injured patients. and intraoperative and postoperative monitoring of neurosurgical patients. Transcranial Doppler technology is also providing new insights into the pathophysiologic mechanisms of a variety of cerebrovascular conditions. Clinicians will find transcranial Doppler technology most helpful if they have a specific question about the status of the intracranial circulation. Further investigations may expand the clinical and research utility of this technology.
Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. The RISC Group, 796 men with unstable coronary artery disease (unstable angina or non-Q-wave myocardial infarction [MI] ). were randomised to double-blind placebo-controlled treatment with oral aspirin 75 mg/day and/or 5 days of intermittent intravenous heparin. The risk of MI and death was reduced by aspirin. After 5 days the risk ratio was 0.43 (confidence intervals. 0.21-0.91). at 1 month 0.31 (0.18-0.53). and at 3 months 0.36 (0.23-0.57). Aspirin reduced event rate in non-Q-wave MI and unstable angina. independently of electrocardiographic abnormalities or concurrent drug therapy. Heparin had no significant influence on event rate. although the group treated with aspirin and heparin had the lowest number of events during the initial 5 days. Treatment had few side-effects and high patient compliance.
Rapid detection and prenatal diagnosis of beta-thalassaemia: studies in Indian and Cypriot populations in the UK, The application of the amplification refractory mutation system (ARMS) to the detection of individual beta-thalassaemia mutations in heterozygous parents and "at risk" fetuses has been assessed in Indian and Cypriot immigrant populations in the UK. 100 first trimester prenatal diagnoses have been done. entailing the detection of 17 different mutations. The method. which allows the determination of the mutations in both parental and fetal DNA on the same day. should have wide application to the carrier detection and prenatal diagnosis of monogenic diseases with heterogeneous molecular defects.
Arterial responses during migraine headache, The superficial temporal artery has been thought to be the main focus of pain during migraine attacks. but its diameter has never been measured directly. The use of a new. high-resolution ultrasound machine to measure arterial size in 25 migraine patients with unilateral head pain showed that the lumen was wider on the painful than on the non-painful side during a migraine attack. The diameters of both radial arteries and the temporal artery on the non-painful side were smaller during than between attacks. The generalised vasoconstriction was not shared by the temporal artery on the affected side. which suggests a local vasodilatory response. The findings suggest that cephalic arteries may play a role in migraine pathogenesis.
European experience of bone-marrow transplantation for severe combined immunodeficiency, The outcome of bone-marrow transplantations (BMT) carried out between 1968 and March 1. 1989. in 183 patients with severe combined immunodeficiency (SCID) was analysed. Recipients of HLA-identical BMTs (70) had a 76% probability of survival (median follow-up 73 months). Of the 32 treated since 1983. 97% have been cured (median follow-up 41 months). This good prognosis was associated with rapid development of T and B cell function. HLA-non-identical. T-cell-depleted. BMT (n = 100) gave significantly lower survival (52%; median follow-up 47 months). Factors associated with poor prognosis were the presence of a lung infection before BMT. absence of a protected environment. and use of female donors for male recipients. Use of a conditioning regimen significantly increased the frequency of sustained engraftment (86% vs 50% for non-conditioned BMT) and resulted in more frequent engraftment of donor B lymphocytes and myeloid cells. Donor B-cell chimerism was strongly associated with the development of normal B-cell function.
Measurement of airborne mite antigen in homes of asthmatic children, The airborne concentration of major house dust mite antigen Der p1 was measured by low volume sampling (2 litres/min) in the homes of 68 allergic. asthmatic children. The presence of detectable airborne antigen was strongly associated with sensitivity to the mite. whereas there was no significant relation between sensitivity and the previously recommended threshold level of 2 micrograms Der p1 per g carpet dust. There was a significant association with lower threshold levels in carpet dust (0.5 microgram/g) but at no level was the association as strong as that with air measurements. Concentrations of airborne antigen were higher in rooms with wool carpets than in those with synthetic carpets or hard floors. but there was no significant difference between the dust levels of Der p1 in the two carpet types. Air sampling is a more appropriate method of assessing antigen exposure than dust sampling for asthmatic patients.
Specialist versus general practitioner treatment of problem drinkers, The efficacy of specialist versus general practitioner (GP) treatment of problem drinkers was assessed in a randomised controlled trial. 40 problem drinkers referred consecutively to a specialist alcohol clinic by their GP were. after assessment. randomly allocated to either GP or specialist clinic treatment groups. All subjects received initial advice and counselling in the clinic about their drinking. The specialist clinic group received continued care from the clinic including. if necessary. admission to hospital. Patients in the GP group were returned to the care of the GP who was contacted and supported by the specialist. After 6 months of follow-up. there were significant reductions in alcohol consumption and alcohol-related problems in both groups. No significant difference was found between the two groups with respect to the main outcome measures. No differential treatment effect was found with the more severely dependent drinkers. The findings show that after an initial detailed assessment and advice session. the treatment provided by GPs is at least as effective as that from a specialist clinic with respect to improvements in drinking behaviour and alcohol-related problems. After initial assessment and advice. specialist clinics should encourage GPs to become more involved in the subsequent care of problem drinkers. Such a practice should be based on the individual patient's needs and the adequacy of support offered to GPs.
Ecology, life cycle, and infectious propagule of Cryptococcus neoformans, Cryptococcus neoformans is a biotrophic smut-like fungus. and the epidemiology of cryptococcosis can mainly be explained by exposure to an infective aerosolised inoculum. For C neoformans var gattii it is postulated that the principal infectious propagule is the basidiospore and that exposure to Eucalyptus camaldulensis. the host tree. is required to initiate infection in man and animals. C neoformans var gattii may have been exported from Australia by infected seeds of E camaldulensis containing dormant dikaryotic mycelium of the fungus. For C neoformans var neoformans both the basidiospore and desiccated encapsulated yeast cells are postulated to act as infectious propagules. the basidiospores showing a seasonal distribution in association with an as yet unidentified host plant. and the encapsulated yeast cells dispersed from accumulations of dried bird (mainly pigeon) droppings which act as a year-round vector.
Contraceptive efficacy of testosterone-induced azoospermia in normal men. World Health Organization Task Force on methods for the regulation of male fertility, A multicentre study (ten centres) in seven countries was done to assess the contraceptive efficacy of hormonally-induced azoospermia in 271 healthy fertile men. Each subject received 200 mg testosterone enanthate weekly by intramuscular injection. 157 men (cumulative rate at 6 months 65%) became azoospermic in three consecutive semen samples. These men entered a 12-month efficacy phase during which continuing testosterone injections were the only form of contraception. There was 1 pregnancy during 1486 months of the efficacy phase (0.8 conceptions [95% confidence interval 0.02-4.5] per 100 person-years). Discontinuations from the study were mainly because azoospermia was not achieved within 6 months and because of dislike of the injection schedule. The mean time to become azoospermic was 120 days (SD 40); reappearance of spermatozoa was detected in 11 men and in no case led to discontinuation from the study or to pregnancy. After the testosterone injections had been stopped. the estimated median time from azoospermia to recovery (sperm concentration of at least 20 million/ml) was 3.7 months (3.6-3.9) and to the subject's mean baseline sperm concentration was 6.7 months (6.2-8.7). Hormonal regimens that induce azoospermia can provide highly effective. sustained. and reversible male contraception with minimum side-effects.
Evoked potentials in assessment and follow-up of patients with Wilson's disease, Treatment of 9 patients with Wilson's disease was prospectively studied with evoked potentials and magnetic resonance imaging (MRI). Oral penicillamine therapy led to a decrease in auditory brainstem (ABP) and somatosensory (SEP) conduction times in 6 and 4 neurologically symptomatic patients. respectively. ABP and SEP were normal in 3 other symptom-free patients. MRI showed cerebral lesions in 4 of 7 patients. Quantified indices of brain atrophy were unaffected by treatment. ABP and SEP may reveal a reversible component of the disease that cannot be detected by MRI. and may be a more sensitive measure of treatment efficacy.
Laryngeal mask airway and tracheal tube insertion by unskilled personnel, After a short training programme 11 naval medical trainees inserted a laryngeal mask airway (LMA) and a tracheal tube (ETT) in random order in a total of 110 anaesthetised patients. They were allowed 40 s for each attempt. Success was defined as the detection of expired carbon dioxide within 40 s of Guedel airway removal which subsequently rose to an end-tidal value of at least 4 kPa. together with satisfactory lung expansion and ventilation. without other airway intervention by the anaesthetist. 104 LMA insertions were successful compared with 56 of ETTs (p less than 0.01). All first attempts at LMA insertion were successful. whereas satisfactory ETT placement was progressive. Insertion was also quicker with the LMA (20 s) than with the ETT (35 s) (p less than 0.01). Further studies are indicated to assess the value of the LMA in emergencies.
Adult T-cell leukaemia/lymphoma in Brazil and its relation to HTLV-I, In a series of fourteen patients with adult T-cell lymphoma-leukaemia (ATLL) in Brazil the main features were lymphadenopathy. hepatosplenomegaly. hypercalcaemia. and high leucocyte counts. with abnormal lymphoid cells which had irregular nuclei. The series included the youngest patient with ATLL so far (18 months). Analysis with monoclonal antibodies showed a mature T-cell phenotype (CD4+. CD8-). Antibodies to HTLV-I and/or integration of HTLV-I proviral DNA were found in eleven patients. In the other three HTLV-I DNA could not be demonstrated even by means of the polymerase chain reaction; they therefore had HTLV-I-negative ATLL. This report of ATLL in Brazil corroborates serological reports that HTLV-I may be endemic in some parts of that country. Follow-up studies are required to identify precisely the main route of transmission of HTLV-I in South America and the risk factors for the development of ATLL in carriers.
Hypothesis: inhibition of endothelium-derived relaxing factor by haemoglobin in the pathogenesis of pre-eclampsia, Although the aetiology of pre-eclampsia is unknown. haemodynamic studies suggest that many of the clinical findings may be explained by a generalised vasoconstrictive disorder and abnormal endothelial cell function. Vasoconstriction may be attributed to the increased concentrations of haemoglobin found in pre-eclampsia compared with normal pregnancy. Free haemoglobin may be derived from haemolysis and placental haemorrhage and. at concentrations known to be present in pre-eclampsia. vasodilatation mediated by endothelium-derived relaxing factor is inhibited. Infusion of oxyhaemoglobin into human coronary arteries inhibits acetylcholine-induced vasodilatation. We suggest that an increased free haemoglobin concentration is the cause of vasoconstriction in pre-eclampsia.
Antibody persistence in Gambian children after high-dose Edmonston-Zagreb measles vaccine, Measles antibody concentrations in Gambian children immunised at 4 months of age with a high-dose Edmonston-Zagreb (EZ) measles vaccine or at 9 months with conventional Schwarz vaccine were measured 5 months after vaccination. and at 18 and 36 months of age. Schwarz vaccinees produced. on average. a 2.4-fold higher concentration of measles haemagglutinin inhibiting (HAI) antibody than EZ vaccinees. but at 36 months of age 82 of 93 (88%) EZ vaccinees and 83 of 87 (95%) Schwarz vaccinees had measles plaque-neutralising antibody concentrations above the assumed protective level of 200 mIU/ml (p greater than 0.1). HAI antibody concentrations 5 months after vaccination were inversely related to the presence of maternal antibody at vaccination. but above protective levels; at 18 and 36 months of age there was no relation to antibody concentration at vaccination. and decay of HAI antibody between 18 and 36 months of age was similar for EZ and Schwarz vaccinees.
The location of the maxillary os and its importance to the endoscopic sinus surgeon, As functional endoscopic sinus surgery continues to gain popularity and support. the necessity for a clear and accurate understanding of the anatomy of the ostiomeatal complex becomes essential. To clarify this anatomy. serial cadaver dissections were performed and the anatomy of the ostiomeatal complex was detailed in three dimensions. with an emphasis on precise localization of the internal os of the maxillary sinus as it relates to the orbit. natural antronasal canal. and ethmoid infundibulum. Measurements of the position of the internal os relative to the position of the anterior and posterior walls of the maxillary sinus and the position of the orbit were taken. The dimensions and configuration of the antronasal canal and its relationship to the infundibulum were also detailed. These measurements and relationships must be understood for an endoscopic sinus surgeon to locate the natural ostia without injuring the orbit.
Local control of auricular, periauricular, and external canal cutaneous malignancies with Mohs surgery, Three hundred ninety-seven patients with 407 cutaneous malignancies of the auricle. periauricular region. and cartilaginous external ear canal were reviewed. Tumors were most commonly located in the preauricular and postauricular regions. followed by the helix. concha. antihelix. and ear canal. All lesions were excised with Mohs microscopic control of margins. For lesions requiring lateral temporal bone resection. an adaptation of fresh-tissue microscopic control was used to analyze deep and anterior margins suspected of harboring residual tumor. Two-year minimum follow-up of 229 patients with periauricular and auricular tumors (N = 231 tumors) and 14 patients with cartilaginous ear canal tumors (N = 14 tumors) revealed recurrence rates of 6.9% and 14.3%. respectively. Recurrences were most common in cases of large tumors (greater than 2.5 cm). basal cell carcinomas with morphea elements. and multiply recurrent lesions. We conclude that Mohs surgery is comparatively effective. though not uniformly curative. and can be adapted to supplement excision of large tumors in these regions.
Lidocaine in the middle ear, Anesthesia of the ear canal is produced by injection of lidocaine hydrochloride into the skin of the lateral external ear canal. Ear canal. tympanic membrane. and middle ear surgeries are performed with this injection. The fluid found in the middle ear during tympanotomy was collected and analyzed. The percentage of lidocaine in the fluid was calculated by an enzyme immunoassay technique. Fifteen surgical cases were undertaken in which perilymphatic fluid in the middle ear would not be suspected. such as tympanotomy for otosclerosis. Lidocaine was found in all middle ears in which there was sufficient fluid to collect. The authors question the validity of using the presence of clear fluid in the middle ear. even with reaccumulation. as the sole criterion for identifying perilymph and cerebrospinal fluid.
Managing segmental facial nerve injuries by surgical repair, This report describes our experiences and evolving philosophy with regard to managing segmental facial nerve injuries. We present the results of 13 facial nerve repairs of traumatic injury to a segment of the facial nerve. All peripheral facial nerve branches contribute essential elements to normal mimetic facial movement; therefore. we recommend early. appropriate repair of the nerve segment. This recommendation is based on principles established for managing disruptions of the main trunk of the facial nerve. It offers the patient the chance for complete recovery of facial function.
Effects of uvulopalatopharyngoplasty on sleep architecture and patterns of obstructed breathing, In this retrospective study. 72 obstructive sleep apnea patients with polysomnograms taken before and after uvulopalatopharyngoplasty were evaluated. Postoperatively. there was a significant improvement of sleep architecture and respiratory indices. In addition. a second group of 17 patients also had position recordings with their polysomnograms. Time spent in supine and lateral sleep positions changed postoperatively. There was significant decrease of the apnea plus hypopnea index in the lateral position. This study indicates that there is significant improvement of sleep architecture and respiratory indices in the majority of patients after uvulopalatopharyngoplasty. particularly in the lateral sleep position.
The role of the facial nerve latency test in the prognosis of Bell's palsy, Eighty patients with idiopathic facial nerve palsy were evaluated by the facial nerve latency test. Depending on the latency time. the patients were classified into the following four groups: group A patients had normal latency times (3.25 msec); group B patients had slightly extended latency times (4 to 7 msec) and a mean of 5.6 msec; group C patients had extended latency times (10 to 14 msec) and a mean of 10.2 msec; and group D patients displayed complete disappearance of evoked compound muscle action potential (no responses). Under the same therapeutic regimen. it was determined that. when the latency time was normal or close to normal. the functional recovery of the nerve was complete or almost complete. and the recovery time was short. When the latency time was extended or there was no response. the functional recovery of the nerve was either incomplete or absent.
Stapedotomy technique and results: ten years' experience and comparative study with stapedectomy, Fifty of the 810 patients who underwent stapedotomy for otosclerosis from 1969 through 1988 were randomly chosen for follow-up of at least 5 years. Most of the patients (65%) had follow-up of 10 years after stapedotomy. but another 50 patients who underwent stapedectomy had follow-ups of longer than 10 years. In 50 patients. stapedectomy under local anesthesia was performed by removal of the footplate of the stapes. using an endaural incision. and covering the oval window with Gelfoam. In the other 50 patients. stapedotomy was performed under general anesthesia. using an endopreauricular incision. making a small hole in the footplate. and covering the hole only with blood from the surgical area. Although both groups showed improvement in hearing after the operation. the air-bone gap in the stapedotomy group was significantly better than that in the stapedectomy group. The use of the endopreauricular incision under general anesthesia was preferable to endaural incision under local anesthesia because the operative field was wider. more convenient for the surgeon. and conducive to patient safety. There were no significant complications in either group.
Clinical classification and staging for primary malignancies of the maxillary antrum, A study of 51 patients with primary malignant maxillary sinus neoplasms was conducted. None of the patients had neck nodes and/or metastases. and each had 5-year follow-up. The tumors were staged according to the 1983 and 1988 American Joint Committee on Cancer staging systems for maxillary sinus cancers. There were 13 early stage (T1. T2) and 38 advanced (T3. T4) tumors in both systems. Cox regression analyses of survival curves showed increasingly worse prognoses for advanced tumors in both T-staging systems. Further analyses showed a significant difference in survival between T3 and T4 in the 1988. but not in the 1983 system. There were no significant differences in survival according to treatment modality or histological type of malignancy. We conclude that the 1988 system prognosticates successfully for T-stage (1 to 4) and demonstrates significant improvement in detecting T3 versus T4 differences compared to the 1983 system. The 1988 system applies equally for epidermoid cancer and other malignancies of the antrum.
A new method of needle-electrode placement in the posterior cricoarytenoid muscle for electromyography, In 1979 the authors developed a new method of needle-electrode placement in the posterior cricoarytenoid muscle (PCA) for electromyography. The PCA muscle is easily reached by inserting a needle electrode through the cricothyroid membrane at the midline and penetrating the lamina of the cricoid cartilage in the subglottic cavity. Access to the PCA muscle for electrode insertion was best afforded by a percartilaginous approach. This report details the new technique used at our laboratory. To our knowledge. this is the first report of needle-electrode placement in the PCA muscle by a percartilaginous approach. This new electrode insertion technique has been applied to more than 100 dogs for research purposes and to 1200 patients with laryngeal motor disorders for clinical diagnosis. This is a simple technique requiring the usual skills. Reliable electromyographic recordings have been obtained by this new method. No untoward effects. such as hematoma or infection from repeated placements were observed in approximately 3200 examinations performed to date. It is reasonable to assume that the percartilaginous route for electrode insertion in the PCA muscle is feasible in man. Techniques of electrode placement in the intrinsic laryngeal muscles are reviewed and compared.
An improved stent method for choanal atresia repair, Short intranasal stents secured sublabially have a number of advantages. They provide secure fixation without an external ligature across the columella. The short length of the stents allows them to sit only in the operative area where the atretic plate had been removed. This lessens the chance of intranasal syechiae formation and eliminates the possibility of erosion in the anterior septal and nasal alar region from pressure exerted by a stent. Since the stents do not protrude from the nose. they cannot be grasped by infants or young children and are not visible externally. School-aged children who have undergone repair of a unilateral choanal atresia can attend school without having to suffer the embarrassment of being teased about a tube protruding from the nose. When compared with other stenting methods. the posterior stent is more secure and less likely to become dislodged.
Non-ossicle homograft bone prostheses in the middle ear, This thesis proposes the use of human cadaver non-ossicle temporal homograft bone as middle ear reconstructive material. Bone obtained from the otic capsule histologically resembles that of the ossicles more so than any other bone in the body. The otic capsule. due to its proximity to the middle ear. can be harvested with the middle ear structures when bone cores are obtained. making it easily accessible. These prostheses are cost effective because multiple prostheses can be sculptured from one temporal bone core. This paper further proposes the use and introduction of non-ossicle homografts in primary stapedectomy. as well as in selected cases to bypass the incus and the superstructure of the stapes. Audiological data is provided. Some of the grafts have been in the middle ear for up to 5 years. There have been no extrusions and no complications. The method of harvesting. preservation. and sterilization is presented. as well as a pictorial illustration of the finished product and its relation to the natural ossicles. One histological specimen is presented. On the basis of the audiologic results. as well as the fact that no ossicles have extruded and none have been resorbed. it is proposed that non-ossicle temporal bone homografts have a place in transplantation surgery.
The molecular biology of occlusive stroke in childhood, It is very likely that many of the same factors involved in occlusive disease in the adult are operative in the child. The major difference may be in the factors that damage endothelium in these two age groups and thereby initiate this catastrophe (atherosclerosis versus "other" causes of endothelial changes). Our task in this next decade is the rational exploration of the effects of endothelium-mediated kinins. endothelial secretory products. angiospasm. platelet aggregration. prostaglandins. and lipoproteins on pediatric stroke.
AIDS and pediatric neurology, Human immunodeficiency virus type 1 (HIV-1). the etiologic agent of AIDS. causes a wide spectrum of disease in children owing to its selective tropism for the immune system. nervous system. and perhaps other organs. By 1991. there may be as many as 10.000 to 15.000 children with symptomatic HIV-1 infection in the United States. This article reviews the current knowledge of the clinical. neuroradiologic. and neuropathologic features of HIV-1-related central nervous system involvement in infants and children with symptomatic HIV infection.
Infantile spasms, Infantile spasms are a seizure disorder in young infants with diverse etiologies. suggesting that they arise from any disturbance of central nervous system function during susceptible periods of development. The prognosis for normal intellectual and neurologic development parallels that of the underlying etiology. Early and appropriate treatment with ACTH may lead to seizure control in a majority of patients. The treating physician must anticipate the side effects of this modality.
Rett syndrome and the autistic disorders, Rett syndrome is a disorder noted to date only in females and characterized by a pervasive developmental disability following apparently normal early infancy. In addition to gait difficulties. stereotypic hand movements. and loss of communication and purposeful hand skills. autistic-like behavior is an early sign that often results in misdiagnosis. Despite these significant clinical abnormalities. neuropathologic features are modest. and no consistent laboratory abnormality or diagnostic marker has been identified. The current status of research in RS is considered within the context of autism and other disorders in which autistic features may occur. such as the fragile X syndrome. The concept of autism as neurobiologically based behavior is developed. As such. autism is regarded as an umbrella category containing an ever-expanding list of specific disorders.
Pediatric behavioral neurology: an update on the neurologic aspects of depression, hyperactivity, and learning disabilities [published erratum appears in Neurol Clin 1991 Feb;9(1):viii, The high incidence of poor social adjustment in long-term follow-up studies of depressed children seems to relate to the inadequacy of the pharmacotherapy necessary to sustain long-lasting remission or possibly to repetitive inappropriate stresses. Insufficient antidepressant therapy with resultant intermittent depression-induced dysfunction of the socialization functions performed by the right cerebral hemisphere would not permit the child to develop appropriate interpersonal skills (causing failure in most social situations). and associated cognitive difficulties would complicate academic performance. Repeated school failure and chronic social ineptitude preclude development of the skills necessary for successful independent living in society. Thus. if symptoms of depression are found. it is imperative that the learning-disabled or behaviorally disturbed child or adolescent receive adequate antidepressant therapy to ensure complete long-term remission of the depression. In addition. learning-disabled individuals. even without apparent diagnosable depressive illness. must be offered appropriate methods for learning and communication which reduce stress. When such appropriate educational strategies are offered and poor performance still ensues (or continues). a trial of antidepressant therapy should be considered. Recognition of the depressive nature of symptoms may not be possible until treatment-induced improvement has occurred and depression-associated learning disability has resolved. Improvement in academic performance associated with improved cognitive function after treatment-induced remission of a depressive episode can be dramatic. with resolution of apparent learning disability. Poor educational achievement associated with chronic learning difficulties ultimately affects adult social functioning. and untreated or improperly treated chronic depression may result in the development of later personality disturbances. Therefore. before attributing school problems in children to untreatable conditions. depressive disorder must be excluded. and appropriate antidepressant therapy (along with removal of all apparent inappropriate stress. including inappropriate demands on brain function) should be provided to children and adolescents with evidence of depression.
Tourette syndrome: recent advances, Clinical and genetic studies have allowed the limits of Tourette syndrome to be broadened. There is now strong evidence that chronic motor tics and Tourette syndrome are different manifestations of an autosomal dominant gene with high penetrance. A genetic link with obsessive-compulsive disorder also appears to have been established. Up to 10% of cases of Tourette syndrome may be nongenetic phenocopies. however. There is also an association between Tourette syndrome and attention deficit hyperactivity disorder. This complicates therapy. as psychostimulant drugs may precipitate or exacerbate tics in some individuals. A high proportion of patients with Tourette syndrome also has neuropsychological deficits and learning disabilities. The pathophysiology is incompletely understood. The best supported hypothesis is that there is dopamine receptor supersensitivity. although there are strong suggestions of abnormalities in serotonin metabolism. The possibility of abnormalities in neuropeptide systems is being explored. Treatment of tics relies primarily on neuroleptics with dopamine receptor blocking activity. Clonidine may be useful in some patients. especially those with behavior problems. Obsessive-compulsive symptoms can be treated using appropriate pharmacologic agents. The treatment of attention deficit disorder in patients with tics should begin with behavioral strategies. Clonidine can be tried as the first-line drug. and psychostimulants should be used only if necessary and with great caution. In rare instances it may be necessary to combine a psychostimulant and a neuroleptic.
The floppy infant: recent advances in the understanding of disorders affecting the neuromuscular junction, The clinician is often asked to evaluate the floppy infant. Numerous conditions that cause hypotonia in infancy are briefly outlined in this article. These conditions may affect the brain. spinal cord. or motor unit. Several disorders of neuromuscular transmission. including four distinct and recently described congenital myasthenic syndromes and infant botulism. are discussed thereafter.
Rehabilitation of the pediatric patient with a neuromuscular disease, A rehabilitation program for a patient with a neuromuscular disease can be developed only after an accurate diagnosis has been established. The diagnosis and its ramifications should suggest a natural course of disease which. it is hoped. can be improved upon with a rational and realistic program. The program is best developed by an interdisciplinary team. including a pediatric neurologist. who should have the greatest understanding of the patient's problem and should ultimately be responsible for the implementation and monitoring of the program. A child with cerebral palsy commonly requires the services of physical and occupational therapists as well as knowledgeable orthopedists. Is the program appropriate? Does it consider the child's potential as well as his limitations? A child with a traumatic brain injury requires. in addition to the above. psychological intervention and an intensive educational program. Will the child and family need help from mental health professionals? A child with a motor unit disease such as Duchenne's muscular dystrophy requires. in addition to the above services. a "philosophy" of care. Will the child ever ambulate independently? If so. at what cost? What will be necessary for the child to reach this potential. including items such as orthoses and adaptive equipment? Will respirator care become necessary? What issues must be addressed for this form of care to be established? There is no one program for all children. The programs must be individualized to meet the needs of the patient and the family. This point cannot be overemphasized.
The use of ultrasound in evaluating neurologic diseases of childhood, Real-time cranial sonography. intracranial Doppler. and neuromuscular sonography are the sonographic techniques that are applicable to the neurologic evaluation of infants and children. Although limited by age. specificity. and operator skill and experience. the advantages of real-time cranial and intracranial Doppler sonography make them useful techniques in the evaluation of the young infant. particularly in the serial assessment of ventricular size and in the study of the critically ill infant. The use of neuromuscular sonography in the assessment of the floppy infant and in the guidance of biopsy makes this an increasingly valuable tool.
Effect of long-term monitoring of glycosylated hemoglobin levels in insulin-dependent diabetes mellitus, BACKGROUND. The value of routine measurements of glycosylated hemoglobin (hemoglobin A1c) in the care of patients with diabetes mellitus is uncertain. We undertook this study to determine whether knowledge of hemoglobin A1c values would result in improved metabolic control in a group of patients with insulin-dependent diabetes mellitus (IDDM). METHODS. We randomly assigned 240 patients with IDDM to one of two groups that were comparable in age. sex. duration of diabetes. and initial hemoglobin A1c levels. The patients were followed for a year. and the hemoglobin A1c concentration was measured at three-month intervals. The hemoglobin A1c values were used in assessing glycemic control and modifying therapy in one of the two groups. In the other. care givers were not aware of the hemoglobin A1c levels and relied on blood or urine glucose measurements to monitor treatment. RESULTS. Among the 222 patients still being followed after one year. the mean hemoglobin A1c value decreased significantly--from 10.1 to 9.5 percent (P less than 0.005)--in the group whose hemoglobin A1c level was monitored (n = 115). whereas the initial and one-year values in the control group (n = 107) were 10.0 and 10.1 percent. respectively. The proportion of patients with poor control. defined as those having a hemoglobin A1c value above 10.0 percent. decreased from 46 to 30 percent (P less than 0.01) in the group whose hemoglobin A1c level was monitored but did not change significantly (45 to 50 percent) in the control group. The patients in the group whose hemoglobin A1c level was monitored were seen and their insulin regimens changed more often. but they were hospitalized for acute care of their diabetes less often than those in the control group. A similar decrease in hemoglobin A1c values occurred in the control group in the following year. when their care givers knew their hemoglobin A1c values. CONCLUSIONS. Regular measurements of hemoglobin A1c lead to changes in diabetes treatment and improvement of metabolic control. indicated by a lowering of hemoglobin A1c values.
The renin-angiotensin-aldosterone system and autosomal dominant polycystic kidney disease, BACKGROUND. A high incidence of hypertension (50 to 75 percent) occurs early in the course of autosomal dominant polycystic kidney disease. Cyst enlargement. causing bilateral renal ischemia and subsequent release of renin. is proposed as the cause of this form of hypertension. METHODS. To investigate this hypothesis. we measured plasma renin activity and aldosterone concentrations during short-term and long-term converting-enzyme inhibition in 14 patients with hypertension due to polycystic kidney disease. 9 patients with essential hypertension. 11 normotensive patients with polycystic kidney disease. and 13 normal subjects. The groups were comparable with respect to age. sex. body-surface area. degree of hypertension. sodium excretion. and renal function. RESULTS. During the short-term study. the mean (+/- SE) plasma renin activity was significantly higher in the hypertensive patients with polycystic kidney disease than in the patients with essential hypertension. in the supine (0.36 +/- 0.06 vs. 0.22 +/- 0.06 ng per liter.second. P = 0.05) and upright positions (1.03 +/- 0.14 vs. 0.61 +/- 0.08 ng per liter.second. P less than 0.03) and after converting-enzyme inhibition (1.97 +/- 0.28 vs. 0.67 +/- 0.17 ng per liter.second. P less than 0.0006). The mean arterial pressures measured in the supine and upright positions and the plasma aldosterone concentrations measured in the upright position were significantly higher in the normotensive patients with polycystic kidney disease than in the normal subjects. After six weeks of converting-enzyme inhibition. renal plasma flow increased (P less than 0.005). and both renal vascular resistance (P less than 0.007) and the filtration fraction (P less than 0.02) decreased significantly in the hypertensive patients with polycystic kidney disease but not in the patients with essential hypertension. CONCLUSIONS. The renin-angiotensin-aldosterone system is stimulated significantly more in hypertensive patients with polycystic kidney disease than in comparable patients with essential hypertension. The increased renin release. perhaps due to renal ischemia caused by cyst expansion. probably contributes to the early development of hypertension in polycystic kidney disease.
A preliminary report on oocyte donation extending reproductive potential to women over 40, BACKGROUND. Fertility in women 40 years of age or older is decreased. and in those with ovarian failure it is thought to be irrevocably lost. The donation of oocytes to young (less than 35 years old) women with ovarian failure has allowed many considered infertile a chance to become pregnant. In these women gonadal hormone replacement results in an endometrium receptive to implantation. It is not known whether the endometrial response to such replacement is decreased in women over the age of 40. METHODS. To test the efficacy of oocyte donation to older women. we enrolled seven women 40 to 44 years old with ovarian failure in a trial of hormone replacement and embryo transfer. using oocytes obtained from women undergoing ovarian hyperstimulation solely for gamete donation. RESULTS. Seven stimulated cycles in the donors that were synchronized with nine cycles in the recipients resulted in eight embryo transfers. Five viable pregnancies were established. one with twins. A sixth pregnancy ended in miscarriage. Five normal infants were delivered by cesarean section. and one stillborn infant was delivered vaginally. The outcomes were compared with those in women under the age of 40 with ovarian failure who were also participating in our donor-oocyte program and in infertile ovulating women 40 or older who were undergoing standard in vitro fertilization. No significant differences in rates of implantation or ongoing pregnancy were noted in older women as compared with younger women receiving donated embryos. These rates. however. were higher than the rates in the infertile ovulating women of similar age who were undergoing standard in vitro fertilization. CONCLUSIONS. These preliminary results suggest that the endometrium retains its ability to respond to gonadal steroids and provides a receptive environment for embryo implantation and gestation even in older women.
The epidemiology and clinical aspects of the hemolytic uremic syndrome in Minnesota, BACKGROUND. The frequency of the hemolytic uremic syndrome. characterized by microangiopathic hemolytic anemia. thrombocytopenia. and renal failure. is increasing. Although Escherichia coli serotype 0157:H7 has been implicated as a causative agent. more information is needed about the basic epidemiology and clinical aspects of this syndrome. METHODS. We conducted a retrospective population-based study of hemolytic uremic syndrome in Minnesota residents less than 18 years of age from 1979 through 1988 to assess trends in disease occurrence. describe the clinical illness. and identify predictors of disease severity and outcome. We also conducted a case-control study of patients with onsets of illness from 1986 through 1988 to examine risk factors. RESULTS. One hundred seventeen patients were identified. The mean annual incidence increased from 0.5 case per 100.000 child-years among children less than 18 in 1979 (6 cases) to 2.0 cases per 100.000 in 1988 (26 cases) (P = 0.000004). E. coli 0157:H7 was isolated from 13 of 28 patients (46 percent) who had stool specimens submitted for testing. For those who presented with typical hemolytic uremic syndrome. an elevated polymorphonuclear-leukocyte count on hospital admission. a shorter duration of prodrome. and the presence of bloody diarrhea were predictive of severe disease. In the case-control study. the patients were more likely to attend large daycare centers (more than 50 children) than were the controls (odds ratio. 10.2; P = 0.03). suggesting that day-care attendance may be a risk factor. On the basis of the population-attributable risk. however. this factor could account for no more than 16 percent of the cases. CONCLUSIONS. This study provides evidence for an increase in the incidence of hemolytic uremic syndrome. which is probably related to an increased incidence of E. coli 0157:H7 infections. Hemolytic uremic syndrome has become an important pediatric and public health problem.
A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes, BACKGROUND. The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM). but the magnitude of the risk is unknown. as is the influence of other factors. such as age. sex. and race. METHODS. From 1979 through 1989. we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies. as well as other factors. RESULTS. Of the 4015 nondiabetic relatives. 125 (3.1 percent) had islet-cell antibodies in their initial serum samples. and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001). membership in a multiplex pedigree (P = 0.02). and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM. giving a relative risk of IDDM of 68 (95 percent confidence interval. 34 to 134) for antibody-positive relatives. Islet-cell-antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes. CONCLUSIONS. Nondiabetic relatives of probands with IDDM who are in the first two decades of life. are members of multiplex pedigrees. and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves.
Predicting the appropriate use of carotid endarterectomy, upper gastrointestinal endoscopy, and coronary angiography, BACKGROUND AND METHODS. In a nationally representative population 65 years of age or older. we have demonstrated that about one quarter of coronary angiographies and upper gastrointestinal endoscopies and two thirds of carotid endarterectomies were performed for reasons that were less than medically appropriate. In this paper we examine whether specific characteristics of patients (age. sex. and race). physicians (age. board-certification status. and experience with the procedure). or hospitals (teaching status. profit-making status. and size) predict whether a procedure will be performed appropriately. RESULTS. In general. we found that little of the variability in the appropriateness of care (4 percent or less) could be explained on the basis of standard. easily obtainable data about the patient. the physician. or the hospital. For all three procedures. however. performance in a teaching hospital increased the likelihood that the reasons would be medically appropriate (P = 0.09 for angiography. P = 0.30 for endoscopy. and P less than 0.01 for endarterectomy). In addition. angiographies were more often performed for appropriate reasons in older or more affluent patients (P less than 0.01 for both). Being treated by a surgeon who performed a high rather than a low number of procedures decreased the likelihood of an appropriate endarterectomy by one third. from 40 to 28 percent (P less than 0.01). CONCLUSIONS. Appropriateness of care cannot be closely predicted from many easily determined characteristics of patients. physicians. or hospitals. Thus. for the present. if appropriateness is to be improved it will have to be assessed directly at the level of each patient. hospital. and physician.
Spinal bone loss and ovulatory disturbances, BACKGROUND. Osteoporosis develops in women with estrogen deficiency and amenorrhea who lose bone at an accelerated rate. It is not known to what extent bone loss differs between ovulatory women with regular menstrual cycles who are training intensely and those who are sedentary. METHODS. We measured the density of cancellous spinal bone from the 12th thoracic vertebra to the 3rd lumbar vertebra by quantitative computed tomography on two occasions one year apart in 66 premenopausal women 21 to 42 years of age. All the women had two consecutive ovulatory cycles immediately before entering the study. Twenty-one women were training for a marathon. 22 ran regularly but less intensively. and 23 had normal levels of activity. The lengths of the women's menstrual cycles and luteal phases. diet. exercise levels. and hormonal levels were also determined. We defined ovulatory disturbances as anovulatory cycles and cycles with short luteal phases. RESULTS. The mean (+/- SD) spinal bone density in the 66 women decreased 3.0 +/- 4.8 mg per cubic centimeter per year (2.0 percent per year) (P less than 0.001). Amenorrhea did not develop in any woman during the year of observation (only 2.7 percent of the cycles were greater than 36 days long). Ovulatory disturbances occurred in 29 percent of all cycles. however. Bone loss was strongly associated with these disturbances (r = 0.54. 24 percent of the variance). The 13 women who had anovulatory cycles lost bone mineral at a rate of 6.4 +/- 3.8 mg per cubic centimeter per year (4.2 percent per year). The women training for a marathon had menstrual cycles similar to those of the women in the other two groups. CONCLUSION. Decreases in spinal bone density among women with differing exercise habits correlated with asymptomatic disturbances of ovulation (without amenorrhea) and not with physical activity.
Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation, BACKGROUND AND METHODS. The plasma cholesteryl-ester transfer protein (CETP) catalyzes the transfer of cholesteryl esters from high-density lipoprotein (HDL) to other lipoproteins. We recently described a Japanese family with increased HDL levels and CETP deficiency due to a splicing defect of the CETP gene. To assess the frequency and phenotype of this condition. we screened 11 additional families with high HDL levels by means of a radioimmunoassay for CETP and DNA analysis. RESULTS. We found the same CETP gene mutation in four families from three different regions of Japan. Analysis of restriction-fragment-length polymorphisms of the mutant CETP allele showed that all probands were homozygous for the identical haplotype. Family members homozygous for CETP deficiency (n = 10) had moderate hypercholesterolemia (mean total cholesterol level [+/- SD]. 7.01 +/- 0.83 mmol per liter). markedly increased levels of HDL cholesterol (4.24 +/- 1.01 mmol per liter) and apolipoprotein A-I. and decreased levels of low-density lipoprotein cholesterol (1.99 +/- 0.80 mmol per liter) and apolipoprotein B. Members heterozygous for the deficiency (n = 20). whose CETP levels were in the lower part of the normal range. had moderately increased levels of HDL cholesterol and apolipoprotein A-I and an increased ratio of HDL subclass 2 to HDL subclass 3. as compared with unaffected family members (1.5 +/- 0.8 vs. 0.7 +/- 0.4). CETP deficiency was not found in six unrelated subjects with elevated HDL cholesterol levels who were from different parts of the United States. CONCLUSIONS. CETP deficiency appears to be a frequent cause of increased HDL levels in the population of Japan. possibly because of a founder effect. The results that we observed in heterozygotes suggest that CETP normally plays a part in the regulation of levels of HDL subclass 2. There was no evidence of premature atherosclerosis in the families with CETP deficiency. In fact. the lipoprotein profile of persons with CETP deficiency is potentially antiatherogenic and may be associated with an increased life span.
Somatostatin-receptor imaging in the localization of endocrine tumors, BACKGROUND AND METHODS. A number of different tumors have receptors for somatostatin. We evaluated the efficacy of scanning with 123I-labeled Tyr3-octreotide. a somatostatin analogue. for tumor localization in 42 patients with carcinoid tumors. pancreatic endocrine tumors. or paragangliomas. We then evaluated the response to octreotide therapy in some of these patients. RESULTS. Primary tumors or metastases. often previously unrecognized. were visualized in 12 of 13 patients with carcinoid tumors and in 7 of 9 patients with pancreatic endocrine tumors. The endocrine symptoms of these patients responded well to therapy with octreotide. Among 20 patients with paragangliomas. 8 of whom had more than one tumor. 10 temporal (tympanic or jugular). 9 carotid. and 10 vagal tumors could be visualized. One small tympanic tumor and one small carotid tumor were not seen on the scan. CONCLUSIONS. The 123I-labeled Tyr3-octreotide scanning technique is a rapid and safe procedure for the visualization of some tumors with somatostatin receptors. A positive scan may predict the ability of octreotide therapy to control symptoms of hormonal hypersecretion.
Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B, BACKGROUND AND METHODS. The effect of intensive lipid-lowering therapy on coronary atherosclerosis among men at high risk for cardiovascular events was assessed by quantitative arteriography. Of 146 men no more than 62 years of age who had apolipoprotein B levels greater than or equal to 125 mg per deciliter. documented coronary artery disease. and a family history of vascular disease. 120 completed the 2 1/2-year double-blind study. which included arteriography at base line and after treatment. Patients were given dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice a day) and colestipol (10 g three times a day); niacin (1 g four times a day) and colestipol (10 g three times a day); or conventional therapy with placebo (or colestipol if the low-density lipoprotein [LDL] cholesterol level was elevated). RESULTS. The levels of LDL and high-density lipoprotein (HDL) cholesterol changed only slightly in the conventional-therapy group (mean changes. -7 and +5 percent. respectively). but more substantially among patients treated with lovastatin and colestipol (-46 and +15 percent) or niacin and colestipol (-32 and +43 percent). In the conventional-therapy group. 46 percent of the patients had definite lesion progression (and no regression) in at least one of nine proximal coronary segments; regression was the only change in 11 percent. By comparison. progression (as the only change) was less frequent among patients who received lovastatin and colestipol (21 percent) and those who received niacin and colestipol (25 percent). and regression was more frequent (lovastatin and colestipol. 32 percent; niacin and colestipol. 39 percent; P less than 0.005). Multivariate analysis indicated that a reduction in the level of apolipoprotein B (or LDL cholesterol) and in systolic blood pressure. and an increase in HDL cholesterol correlated independently with regression of coronary lesions. Clinical events (death. myocardial infarction. or revascularization for worsening symptoms) occurred in 10 of 52 patients assigned to conventional therapy. as compared with 3 of 46 assigned to receive lovastatin and colestipol and 2 of 48 assigned to receive niacin and colestipol (relative risk of an event during intensive treatment. 0.27; 95 percent confidence interval. 0.10 to 0.77). CONCLUSIONS. In men with coronary artery disease who were at high risk for cardiovascular events. intensive lipid-lowering therapy reduced the frequency of progression of coronary lesions. increased the frequency of regression. and reduced the incidence of cardiovascular events.
Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa, BACKGROUND. Night blindness is an early symptom of retinitis pigmentosa. The rod photoreceptors are responsible for night vision and use rhodopsin as the photosensitive pigment. METHODS AND RESULTS. We found three mutations in the human rhodopsin gene; each occurred exclusively in the affected members of some families with autosomal dominant retinitis pigmentosa. Two mutations were C-to-T transitions involving separate nucleotides of codon 347; the third was a C-to-G transversion in codon 58. Each mutation corresponded to a change in one amino acid residue in the rhodopsin molecule. None of these mutations were found in 106 unrelated normal subjects who served as controls. When the incidence of these three mutations was added to that of a previously reported mutation involving codon 23. 27 of 150 unrelated patients with autosomal dominant retinitis pigmentosa (18 percent) were found to carry one of these four defects in the rhodopsin gene. All 27 patients had abnormal rod function on monitoring of their electroretinograms. It appears that patients with the mutation involving codon 23 probably descend from a single ancestor. CONCLUSIONS. In some patients with autosomal dominant retinitis pigmentosa. the disease is caused by one of a variety of mutations of the rhodopsin gene.
Receptor autoimmunity in endocrine disorders, The discovery in 1956 of the long-acting thyroid stimulator of Graves' disease. now known as thyroid-stimulating antibodies. was seminal. A new mechanism for disease was revealed that appears applicable to virtually all endocrine systems. involving the growth as well as the function of endocrine cells. An endocrine gland may fail through at least three autoimmune mechanisms: destruction. atrophy. and inhibition of function. Destruction is probably irreversible but is not usually distinguishable clinically from receptor blockade causing atrophy or from metabolic unresponsiveness. The contribution made by receptor autoimmunity to endocrine diseases other than thyroid disease is at present unclear. but with immunologic manipulation it is potentially reversible. improving the replicative capacity of the gland. its metabolic responsiveness. or both.
Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells, The cystic fibrosis transmembrane conductance regulator (CFTR) was expressed in cultured cystic fibrosis airway epithelial cells and Cl- channel activation assessed in single cells using a fluorescence microscopic assay and the patch-clamp technique. Expression of CFTR. but not of a mutant form of CFTR (delta F508). corrected the Cl- channel defect. Correction of the phenotypic defect demonstrates a causal relationship between mutations in the CFTR gene and defective Cl- transport which is the hallmark of the disease.
Expression and characterization of the cystic fibrosis transmembrane conductance regulator, Cystic fibrosis (CF) is a common lethal genetic disease that manifests itself in airway and other epithelial cells as defective chloride ion absorption and secretion. resulting at least in part from a defect in a cyclic AMP-regulated. outwardly-rectifying Cl- channel in the apical surface. The gene responsible for CF has been identified and predicted to encode a membrane protein termed the CF transmembrane conductance regulator (CFTR). Identification of a cryptic bacterial promoter within the CFTR coding sequence led us to construct a complementary DNA in a low-copy-number plasmid. thereby avoiding the deleterious effects of CFTR expression on Escherischia coli. We have used this cDNA to express CFTR in vitro and in vivo. Here we demonstrate that CFTR is a membrane-associated glycoprotein that can be phosporylated in vitro by cAMP-dependent protein kinase. Polyclonal and monoclonal antibodies directed against distinct domains of the protein immunoprecipitated recombinant CFTR as well as the endogenous CFTR in nonrecombinant T84 cells. Partial proteolysis fingerprinting showed that the recombinant and non-recombinant proteins are indistinguishable. These data. which establish several characteristics of the protein responsible for CF. will now enable CFTR function to be studied and will provide a basis for diagnosis and therapy.
The scid mutation in mice causes a general defect in DNA repair, Mice homozygous for the scid mutation on chromosome 16 have a severe combined immune deficiency as a result of their inability to correctly rearrange their immunoglobulin and T-cell receptor genes. In scid mice. when precursors for B and T lymphocytes reach the stage of development requiring expression of these surface receptors. a defective recombinase system aberrantly cuts and rejoins the receptor gene segments greatly reducing the efficiency of producing functional receptors. As a result. most scid mice have no detectable B or T lymphocytes. We have demonstrated that the scid defect is not specific to lymphocyte development. Myeloid cells and fibroblasts from scid mice show a marked increase in sensitivity to ionizing radiation. indicating that the scid mutation leads to an inability to repair DNA damage induced by ionizing radiation as well as interfering with rearrangement of the immunoglobulin and T-cell receptor genes.
Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1, Mutations at the mouse dwarf locus (dw) interrupt the normal development of the anterior pituitary gland. resulting in the loss of expression of growth hormone. prolactin and thyroid-stimulating hormone. and hypoplasia of their respective cell types. Disruptions in the gene encoding the POU-domain transcription factor. Pit-1. occur in both characterized alleles of the dwarf locus. The data indicate that Pit-1 is necessary for the specification of the phenotype of three cell types in the anterior pituitary. and directly link a transcription factor to commitment and progression events in mammalian organogenesis.
Retinal degeneration in the rd mouse is caused by a defect in the beta subunit of rod cGMP-phosphodiesterase, Mice homozygous for the rd mutation display hereditary retinal degeneration and the classic rd lines serve as a model for human retinitis pigmentosa. In affected animals the retinal rod photoreceptor cells begin degenerating at about postnatal day 8. and by four weeks no photoreceptors are left. Degeneration is preceded by accumulation of cyclic GMP in the retina and is correlated with deficient activity of the rod photoreceptor cGMP-phosphodiesterase. We have recently isolated a candidate complementary DNA for the rd gene from a mouse retinal library and completed the characterization of cDNAs encoding all subunits of bovine photoreceptor phosphodiesterase. The candidate cDNA shows strong homology with a cDNA encoding the bovine phosphodiesterase beta subunit. Here we present evidence that the candidate cDNA is the murine homologue of bovine phosphodiesterase beta cDNA. We conclude that the mouse rd locus encodes the rod photoreceptor cGMP-phosphodiesterase beta subunit.
Tonic contraversive ocular tilt reaction due to unilateral meso-diencephalic lesion, We studied 4 patients with tonic contraversive ocular tilt reactions due to unilateral. paramedian. mesodiencephalic lesions. This is in contrast to the only 2 previously reported patients with ocular tilt reactions due to unilateral mesodiencephalic lesions. each of whom had a paroxysmal ipsiversive ocular tilt reaction. This new finding is considered in the context of previous clinical and experimental data on the various types of ocular tilt reactions that follow stimulation or destruction of the peripheral and central vestibular system. Otolithic inputs to the interstitial nucleus of Cajal from the contralateral vestibular nucleus and motor outputs from the interstitial nucleus of Cajal to cervical and ocular motoneurons could be involved in the ocular tilt reaction. We propose that in patients with unilateral meso-diencephalic lesions. a tonic contraversive ocular tilt reaction could be due to persistently decreased resting activity of ipsilateral interstitial nucleus neurons. whereas a paroxysmal ipsiversive ocular tilt reaction could be due to transiently increased activity of the same interstitial nucleus neurons. Cases of ocular tilt reaction due to unilateral meso-diencephalic lesion point to the existence of a crossed graviceptive pathway between the vestibular nucleus and the contralateral interstitial nucleus of Cajal.
An estimate of the incidence of dementia in idiopathic Parkinson's disease, The proportion of patients with idiopathic Parkinson's disease (PD) who are considered demented ranges from 10% to 15%. Because dementia may affect survival in PD. the incidence rate of dementia. rather than proportion. would be a more accurate measure of disease frequency. We previously estimated the proportion of patients with PD and dementia to be 10.9% from the records of a cohort with the idiopathic form of PD in a major medical center. We reviewed the clinical records of this cohort after 4 years and 9 months to estimate the incidence rate of dementia. We identified 65 new cases of dementia from the 249 patient-records available. Using the number of person-years of follow-up for each case as the denominator. we estimated the overall incidence rate to be 69 per 1.000 person-years of observation. The mean age of this cohort was 71.4 years. The cumulative incidence of dementia increased with age. By 85 years of age. over 65% of the surviving members of the cohort were demented. The age-specific incidence rates for dementia in this cohort of PD were significantly greater than for a similarly aged cohort of healthy elderly people. The age-specific standard morbidity ratios indicated that. compared with people of similar ages. patients with PD have the highest increase in risk for dementia between ages 65 and 75.
Antemortem diagnosis of diffuse Lewy body disease, Using the presence of widespread cortical Lewy bodies (LB) as the pathologic criteria of diffuse Lewy body disease (DLBD). we describe serial neurologic and mental status examinations in 6 patients with DLBD. 3 patients with Alzheimer's disease (AD). and 1 patient with Parkinson's disease (PD). The 6 patients with DLBD included 3 with neocortical neurofibrillary tangles (NFT) consistent with coincident AD. Most patients with DLBD had gait impairment concurrent with mild to moderate dementia. Abnormalities of tone or resting tremor were also prominent early symptoms in the subjects with DLBD. but not AD. Patients with DLBD frequently had abnormal EEGs with background posterior slowing and a frontally dominant burst pattern at the time of mild to moderate dementia. Agitation. hallucinations. and delusions were frequent early symptoms in DLBD patients. Patients with DLBD without concomitant AD had numerous Alz-50 negative cortical plaques. Patients with DLBD have a distinct clinical syndrome that can be differentiated from AD. Pathologic features. including the absence of Alz-50 immunoreactivity. also differentiate DLBD from AD.
Borrelia burgdorferi infection of the brain: characterization of the organism and response to antibiotics and immune sera in the mouse model, To learn more about the neurologic involvement in Lyme disease. we inoculated inbred mice with the causative agent of Lyme disease. Borrelia burgdorferi. We cultured brains and other organs. and measured anti-B burgdorferi antibody titers. We further studied a brain isolate for its plasmid DNA content and its response in vitro to immune sera and antibiotics. One strain of B burgdorferi. N40. was consistently infective for mice. and resulted in chronic infection of the bladder and spleen. SJL mice developed fewer culture-positive organs and had lower antibody titers than Balb/c and C57Bl/6 mice. Organism was cultured from the brain early in the course of infection. and this isolate. named N40Br. was further studied in vitro. The plasmid content of N40Br was different from that of the infecting strain. implying either a highly selective process during infection or DNA rearrangement in the organism in vivo. N40Br was very sensitive to antibiotics. but only after prolonged incubation. Immune sera from both mice and humans infected with B burgdorferi were unable to completely kill the organism by complement-mediated cytotoxicity. These data demonstrate that B burgdorferi infects the brain of experimental animals. and is resistant to immune sera in vitro but sensitive to prolonged treatment with antibiotics.
Multiple sclerosis sibling pairs: clustered onset and familial predisposition, We evaluated 48 relapsing-remitting multiple sclerosis (R/R MS) sibling pairs derived from 44 families for age and date of onset of MS symptoms. clinical course. and family history of MS. Age- and sex-matched R/R MS clinic patients provided a statistical comparison group. The age of onset tended to cluster within multiplex families. The initial symptom of MS occurred within 5 years of age in 30/48 sibling pairs compared with 16/48 controls. A positive family history of MS (other than siblings) was present in 43% of the multiplex families compared with 20% among simplex controls. In 1st-. 2nd-. and 3rd-degree relatives who had lived into the age at risk. 22/1.134 family members of multiplex sibling pairs had probable or definite MS compared with 10/1.215 control family members. Age of onset clustering in siblings concordant for R/R MS and an increased risk of MS in other family members suggest that factors influencing disease onset may be in part inherited in these kindreds.
Abnormal pulsatile secretion of luteinizing hormone in men with epilepsy: relationship to laterality and nature of paroxysmal discharges, We compared the pulsatile secretion of luteinizing hormone (LH) between 13 men with clinically and electrographically documented temporal lobe seizures and 8 age-matched controls. Serum for LH measurement was drawn every 15 minutes during 8 hours of EEG telemetry in both groups. The 2 groups did not differ significantly in average mean baseline LH secretion. total LH secretion. or average pulse amplitude. The group with seizures. however. showed a significantly greater (p less than 0.05) variability of baseline LH secretion and pulse frequency. Among the men with unilateral paroxysmal EEG findings. pulse frequency was significantly greater (p = 0.05) with right epileptiform discharges or left slowing (6.4 +/- 0.4) than with left epileptiform discharges or right slowing (3.0 +/- 1.3). The relationship of pulse frequency to the nature and laterality of paroxysmal discharges makes it unlikely that endocrine abnormalities can be attributed to medication alone and strengthens the notion that temporal lobe epileptiform discharges may disrupt hypothalamic regulation of pituitary secretion.
Cortical tremor: a variant of cortical reflex myoclonus, Two patients with action tremor that was thought to originate in the cerebral cortex showed fine shivering-like finger twitching provoked mainly by action and posture. Surface EMG showed relatively rhythmic discharge at a rate of about 9 Hz. which resembled essential tremor. However. electrophysiologic studies revealed giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex and premovement cortical spike by the jerk-locked averaging method. Treatment with beta-blocker showed no effect. but anticonvulsants such as clonazepam. valproate. and primidone were effective to suppress the tremor and the amplitude of SEPs. We call this involuntary movement "cortical tremor." which is in fact a variant of cortical reflex myoclonus.
Topographic mapping of electrophysiologic measures in patients with homonymous hemianopia, We analyzed electroencephalographic (EEG) activity and spatial distribution of the pattern-reversal visual evoked potential (PVEP) in 20 patients with unilateral lesions in the retrochiasmal visual pathways. Focal abnormalities that were consistent with lesion location were present in the topographically analyzed EEG or VEP of 85% of the patients. compared with a 70% detection rate for conventional analysis techniques. Quantitative analysis of spectrally analyzed EEG revealed focal abnormality in 7 patients whose conventional EEG was interpreted as either normal or diffusely slow. However. focal paroxysmal spikes present in the EEG of 1 patient were missed by EEG mapping. and a false localization of quantitative EEG abnormality contralateral to the lesion occurred in 1 patient. Topographic analysis of the PVEP was no more sensitive to retrochiasmatic lesions than conventional analysis of 2 lateral occipital electrodes. We conclude that topographic mapping is a valid technique in the detection of localized cerebral lesions.
Neuroexcitatory plasma amino acids are elevated in migraine, To investigate the role of glutamic (Glu) and aspartic acid (Asp) in migraine. we measured the plasma amino acids in migraine patients with and without aura. between and during attacks. and compared the profiles with the plasma amino acid profiles of tension headache patients and healthy controls. Between attacks. migraineurs (notably with aura) had substantially higher plasma Glu and Asp levels than did controls and tension headache patients. In addition. patients with migraine without aura showed low plasma histidine levels. During migraine attacks. Glu (and to a lesser extent Asp) levels were even further increased. The results suggest a defective cellular reuptake mechanism for Glu and Asp in migraineurs. and we hypothesize a similar defect at the neuronal/glial cell level. predisposing the brain of migraineurs to develop spreading depression.
Borderzone hemodynamics in cerebrovascular disease, To investigate the possible existence of chronic selective hemodynamic impairment in the arterial borderzone regions of the brain. we used positron emission tomography (PET) to measure regional mean vascular transit time (rt. equal to the ratio of regional cerebral blood volume to cerebral blood flow) and regional oxygen extraction fraction (rOEF) in 32 patients with either severe internal carotid artery stenosis or occlusion and 11 normal controls. Twenty-four of the patients had had TIAs or amaurosis fugax from 1 to 60 days before PET; all had normal brain CT. We used a stereotactic localization method to locate the anterior and posterior borderzone regions of the middle cerebral artery (MCA) territory. We then calculated ratios of each borderzone to the ipsilateral MCA territory for both rt and rOEF. There was no significant difference from control ratios in any patient subgroup including those with greater than or equal to 75% stenosis or occlusion. those with or without contralateral greater than or equal to 50% stenosis. or those with abnormal hemodynamics in the MCA territory. We therefore found no evidence for selective borderzone hemodynamic impairment in this group of patients with severe carotid artery disease.
Diffuse CNS involvement in systemic lupus erythematosus: intrathecal synthesis of the 4th component of complement, In extracerebral systemic lupus erythematosus (SLE). the complement system plays a prominent pathogenic role. and decreased serum concentration of the 4th component (C4) is a reliable indicator of systemic disease activity. In diffuse CNS-SLE. however. the pathogenic role of complement is less clear. In 12 patients with active diffuse CNS-SLE presenting with delirium (4). organic personality syndrome (3). or generalized seizures (5). we determined the CSF indexes of the complement components C3. C4. and factor B. and of IgG. IgA. and IgM. There was a significant increase of the C4 index in these patients compared with controls and a significantly higher CSF C4 index in patients with an increased IgM index. We conclude that intrathecal C4 is being produced in diffuse CNS-SLE.
Comparison of algorithms of testing for use in automated evaluation of sensation, Estimates of vibratory detection threshold may be used to detect. characterize. and follow the course of sensory abnormality in neurologic disease. The approach is especially useful in epidemiologic and controlled clinical trials. We studied which algorithm of testing and finding threshold should be used in automatic systems by comparing among algorithms and stimulus conditions for the index finger of healthy subjects and for the great toe of patients with mild neuropathy. Appearance thresholds obtained by linear ramps increasing at a rate less than 4.15 microns/sec provided accurate and repeatable thresholds compared with thresholds obtained by forced-choice testing. These rates would be acceptable if only sensitive sites were studied. but they were too slow for use in automatic testing of insensitive parts. Appearance thresholds obtained by fast linear rates (4.15 or 16.6 microns/sec) overestimated threshold. especially for sensitive parts. Use of the mean of appearance and disappearance thresholds. with the stimulus increasing exponentially at rates of 0.5 or 1.0 just noticeable difference (JND) units per second. and interspersion of null stimuli. Bekesy with null stimuli. provided accurate. repeatable. and fast estimates of threshold for sensitive parts. Despite the good performance of Bekesy testing. we prefer forced choice for evaluation of the sensation of patients with neuropathy.
Right-left disorientation in dementia of the Alzheimer type, We demonstrated that right-left orientation (R/L-O) on a confronting subject is more impaired in patients with dementia of the Alzheimer type than in patients with multi-infarct dementia of comparable degree of dementia. The impairment in R/L-O is independent of aphasia and spatial disorientation.
Dopamine beta-hydroxylase activity in cerebrospinal fluid of idiopathic torsion dystonia, Since a postmortem biochemical study and a genetic linkage study of idiopathic torsion dystonia suggested possible involvement of dopamine beta-hydroxylase (DBH). we determined CSF DBH activities of Jewish and non-Jewish patients with childhood-onset idiopathic torsion dystonia and found no differences from a control population.
Inconsistent response to divalproex sodium in hemichorea/hemiballism, We report 6 patients with hemichorea/hemiballism of vascular origin who were treated with divalproex sodium (Depakote). Four of 6 responded initially. Marked improvement was seen in 2 patients only and in 1 of these hemiballism recurred despite continuing therapy. Divalproex sodium is not uniformly effective in the treatment of hemichorea/hemiballism.
Oxidation reactions in Parkinson's disease, Free radicals generated from oxidation reactions may contribute to the pathogenesis of Parkinson's disease (PD). Free radicals are capable of reacting almost instantaneously with membrane lipids and causing lipid peroxidation. membrane injury. and cell death. Dopamine is metabolized by oxidation reactions capable of generating free radicals. Recent evidence indicates that the substantia nigra of patients with PD contains increased iron. which enhances oxidation. and decreased glutathione. which protects against the formation of free radicals. Further. the end products of lipid peroxidation are increased in the substantia nigra of patients with PD. supporting the notions that free radicals are being generated and may contribute to dopamine neuronal death. This hypothesis suggests that antioxidant therapies may slow the rate of progression of PD and raises concern that metabolites of levodopa therapy may accelerate the rate of neuronal degeneration.
Effect of estrone sulfate on postmenopausal bone loss, Estrogen replacement therapy confers many beneficial effects to postmenopausal women. such as slowing the rate of bone loss and decreasing the risk of coronary artery disease. This multicenter. placebo-controlled study evaluated the lowest effective daily dose of estrone sulfate (0.3. 0.625. or 1.25 mg) combined with 1000 mg elemental calcium supplementation for preventing bone loss in the immediate supplementation for preventing bone loss in the immediate postmenopausal period. Spinal bone mineral density was measured using quantitative computed tomography. Compared with baseline. bone mineral density increased significantly (P less than .05) after 12 months of 0.625 mg daily (+ 1.9%) or 1.25 mg daily (+ 2.5%). The difference between the 0.625-mg and 1.25-mg doses was not statistically significant. Estrone sulfate administration (0.625 and 1.25 mg) produced significant changes in various lipid measurements at both the 6- and 12-month observation points. The prevalence rates for adverse events were comparable among the estrone sulfate groups and the placebo group. Estrone sulfate 0.625 mg daily. combined with 1000 mg elemental calcium supplementation. was the minimum effective dosage to prevent loss of spinal bone mineral density in postmenopausal women over a 12-month period.
Cefazolin for hysterectomy prophylaxis, Efficacy data for single-dose cefazolin prophylaxis at hysterectomy are meager. and there are none evaluating the impact of route of administration on efficacy. For these reasons. 772 women undergoing elective abdominal or vaginal hysterectomy for benign diseases were given 1 g cefazolin either intramuscularly or intravenously in a randomized clinical trial. Preoperative diagnoses and clinical. surgical. and outcome variables were similar by route of administration for each surgical approach. Risk factors for infection after abdominal hysterectomy included younger age. lower postoperative hemoglobin concentration. and pelvic hematoma; women who developed infection after vaginal hysterectomy were heavier than those who remained uninfected and were more likely to have a pelvic hematoma. The overall incidence of major operative site infection requiring parenteral antimicrobial therapy in evaluable women was 7.2%: 7.6% for 539 women undergoing abdominal hysterectomy and 6.3% for 207 women undergoing vaginal hysterectomy. Postoperative infection was unrelated to route of cefazolin administration.
Intraoperative radioimmunodetection of ovarian cancer using monoclonal antibody B72.3 and a portable gamma-detecting probe, To assess the value of radioimmunoguided surgery in the intraoperative detection of ovarian cancer. we used monoclonal antibody B72.3. radiolabeled with 125I. and a hand-held gamma-detecting probe in 13 women with ovarian cancer undergoing exploratory laparotomy. B72.3. which recognizes a tumor-associated glycoprotein. TAG 72. was injected 12-29 days preoperatively (intraperitoneally in four cases. intravenously in nine. and by both routes in one). Intraoperatively. the abdomen was surveyed with the probe and probe counts were correlated with biopsies and excised specimens studied by routine histologic stains. Probe counts were positive in four of seven evaluable patients with histologically confirmed disease. In three of these four patients. the probe detected cancer in specimens interpreted as normal on frozen histologic sections. The probe also identified microscopic cancer in the one patient who had no gross disease. The specificity of the probe was 70%. Preoperative computed tomography was normal in all patients. including those with tumors as large as 3 cm. This pilot study shows the ability of radioimmunoguided surgery to detect occult ovarian cancer.
Prognostic factors for outcome of and survival after second-look laparotomy in patients with advanced ovarian carcinoma, In ovarian cancer stages IIB-IV. pre-treatment variables and variables obtained intraoperatively at second-look laparotomy were investigated for their prognostic influence on the outcome of 109 patients and survival after second-look laparotomy in 131 patients. The subjects came from a randomized trial of sequential versus alternating combination chemotherapy. The overall median survival after second-look laparotomy was 62 months. Logistic regression analysis identified stage and hysterectomy plus bilateral salpingo-oophorectomy and omentectomy as significant prognostic covariates for second-look laparotomy outcome. Based on a Cox multivariate stepwise analysis. independent prognostic factors for survival after second-look laparotomy were secondary residual tumor size. pre-treatment histologic differentiation grade. and performance status. A high differentiation grade and a good performance status at the start of therapy thus still had a prolonging effect on survival after second-look laparotomy. The prognostic power of these pre-treatment variables was increased substantially by the addition of the secondary residual tumor size variable. The 3-year survival rate after second-look laparotomy for high- and low-risk patients was 15 and 87%. respectively. Second-look laparotomy thus provides prognostic information in patients with advanced ovarian carcinoma. but the benefit in terms of survival is still unclear.
Ovarian metastases are rare in stage I adenocarcinoma of the cervix, Over a 32-year period at the University of California. Los Angeles Medical Center. all cases of adenocarcinoma and adenosquamous carcinoma of the uterine cervix were reviewed to determine the incidence of ovarian metastases in stage I disease. One of 25 patients (4.0%) who underwent an exploratory laparotomy and radical hysterectomy had a microscopic ovarian metastasis. A literature review identified nine additional patients who had ovarian metastases and stage I adenocarcinoma of the cervix. Including our series. the overall reported rate of ovarian metastases is 1.8%. All ten patients had at least one of the following additional characteristics: They were postmenopausal. they had adnexal pathology. or they had positive pelvic lymph nodes. Thus. ovarian preservation is warranted in premenopausal patients who do not have ovarian pathology or evidence of other metastatic disease at surgery. Bilateral oophorectomy may be performed if frozen-section examination of enlarged or suspicious nodes documents metastases. If the ovaries are left in the pelvis at the completion of the surgical procedure and microscopic spread to other pelvic tissues is documented. pelvic irradiation can be administered.
The fallacy of the screening interval for cervical smears, One hundred seventy-four women with invasive cervical carcinoma were interviewed about their cervical smear histories to assess the accuracy of self-reporting and to relate the smear history with patient and tumor characteristics. Patients reported significantly more frequent. more recent. and more normal smears than were documented in medical records. The interval between onset of cancer symptoms and previous smear correlated directly with advanced stage. Sixteen women with normal smears within 36 months had significantly more advanced cancers than did 25 women with recent abnormal smears. Women with recent normal and abnormal smears had similar sociodemographic and behavioral characteristics. Because of inaccuracies in patients' self-reported smear histories and cancers developing in women with recent normal smears. we conclude that a specific screening interval should not be relied upon.
Cold-knife and laser conization for cervical intraepithelial neoplasia, In a 5-year study. 425 women had conization performed for cervical intraepithelial neoplasia (CIN) I. II or III. Conization was performed only in cases of positive endocervical curettage or when colposcopy was inconclusive. In all other cases. local destruction was the operation of choice. In the early years of the study. conization was done by the cold-knife method (N = 201). whereas CO2 laser was used in the latter part of the study (N = 224). Success and complication rates were the same for the two methods. Abnormal cytology after conization was found in a total of 53 cases (12.5%). but a histologic confirmation of residual or recurrent CIN was made in only 27 women (6.4%). This corresponds to a success rate of 92% after cold-knife and 95% after laser conization. The CIN grading of the residual or recurrent CIN was similar to or less than the CIN diagnosis of the cone. Because our success rate was comparable to that of other series with much less strict referral criteria. our policy seems adequate.
Primary invasive carcinoma of the vagina, A retrospective review was conducted of 53 women with invasive carcinoma of the vagina and without documented exposure to diethylstilbestrol who were seen at the University of California Irvine Medical Center. Long Beach Memorial Medical Center. and Saddleback Memorial Medical Center from 1976-1988. Forty-seven (89%) had squamous cell carcinoma and six (11%) adenocarcinoma. Thirty-seven (70%) were treated with whole-pelvis irradiation and brachytherapy. nine with surgery alone. and the other seven with a combination of treatments. The crude and corrected 2-year survival rates for the entire group were 47 and 69%. respectively. Those with previous pelvic surgery were more likely to develop serious treatment-related complications. There was a statistically significant correlation between previous hysterectomy and the diagnosis of primary invasive carcinoma of the vagina after the onset of symptoms. Women diagnosed during routine examination. before symptom onset. tended to have a survival advantage. All women. including those who have had hysterectomy. should be counseled to continue gynecologic cancer surveillance regardless of age.
Premature rupture of membranes at term in nulliparous women: a hazard, One hundred five consecutive women with premature rupture of the membranes (PROM) at term were managed expectantly for at least 24 hours. Seventy-six went into spontaneous labor. of whom 38 were augmented with oxytocin. Twenty-nine had labor induced. Subjects who delivered during the same study interval after artificial rupture of the membranes served as controls. There were no statistically significant differences in the frequency of amnionitis. endometritis. cystitis. neonatal infection. low Apgar score. low cord arterial blood pH. instrumental delivery. or cesarean delivery. Morbidity was seen most often in induced labor whether or not the membranes were ruptured for a long time. It is concluded that expectant management of PROM at term does not increase perinatal morbidity.
Zinc status in women with premature rupture of membranes at term, Zinc concentrations were measured by atomic absorption spectrometry in whole blood. scalp hair. pubic hair. and colostrum from patients at term with and without premature rupture of membranes (PROM). A maternal zinc index was established for each patient. expressed as an average ranking of the four determinations. The mean +/- SD value of the maternal zinc index in patients with PROM was significantly lower than in patients without this complication (4.33 +/- 1.18 versus 5.97 +/- 1.39. respectively; P = .0002). The inverse relationship between maternal zinc index and parity was statistically significant (r = -0.61; P = .04). These results suggest that the subnormal tissue zinc content in pregnancy may play a role as a causative factor in PROM at term.
Evaluation of a perinatal autopsy protocol: influence of the Prenatal Diagnosis Conference Team, This study was designed to evaluate changes in the perinatal autopsy following the adoption of a new autopsy protocol. The University of Utah Medical Center has a Prenatal Diagnosis Conference Team composed of obstetricians. pediatricians. geneticists. and other health care professionals. These individuals are involved in the care of patients whose pregnancies are at risk for congenital malformations. An autopsy protocol was designed to increase the interaction of the pathologist with the Prenatal Diagnosis Conference Team in the evaluation of perinatal death. Two years. 1982 and 1987. before and after the protocol was implemented. were selected for retrospective review. The autopsies in 1987 made more specific diagnoses compared with those in 1982. Additional congenital anomalies were diagnosed. and increased numbers of patients were found to have well-described congenital disorders. The number of attempted postnatal autopsy chromosome studies increased and more chromosomal abnormalities were detected. The final autopsy diagnoses made in 1987 have provided more information to the physician for genetic or other patient counseling. After the protocol was adopted. increased numbers of cases were referred to the Medical Center for evaluation at autopsy. More of those who came to autopsy had been evaluated during life by members of the Prenatal Diagnosis Conference Team. Premortem sonograms had been done at an earlier gestational age and a greater number of anomalies were detected. Fewer of the fetuses had intrauterine death and more had pregnancy terminated by induction of labor. The gestational age at delivery declined.
Correlation between first- and early third-trimester glucose screening test results, One hundred twenty-four normal gravidas had paired first- and early third-trimester (26-32 weeks) 1-hour oral glucose screening tests performed. First-trimester oral glucose screening test values correlated significantly with third-trimester glucose screening test results for the entire population. for whites and non-whites. and for normal-weight and obese patients. First-trimester oral glucose screening test values at or below 110 mg/dL were seldom associated with third-trimester oral glucose screening test results at or above 135 mg/dL and were not associated with abnormal 3-hour glucose tolerance test (GTT) results. Nine of the gravidas (7.3%) were diagnosed with gestational diabetes mellitus during the third trimester. all of whom had first-trimester glucose screening test results above 110 mg/dL. The difference in incidence of gestational diabetes mellitus between gravidas having first-trimester glucose screening test results at or below 110 mg/dL (0%) and those having values above 110 mg/dL (16.4%) was highly significant (P less than .0001). For patients with first-trimester glucose screening test values at or below 110 mg/dL. third-trimester glucose screening may be unnecessary. In contrast. for gravidas having first-trimester glucose screening test results at or above 135 mg/dL. there is a high positive predictive value for elevated repeat glucose screening test results during the early third trimester. Patients having elevated first-trimester glucose screening values at or above 140 mg/dL are at particularly high risk for elevated glucose screening test results later in pregnancy and should forego repeat 1-hour third-trimester glucose screening in favor of a direct third-trimester 3-hour GTT.
The twin-twin transfusion syndrome, Twin-twin transfusion syndrome is a complication of monozygotic-monochorionic twinning with serious perinatal implications. An extensive literature review revealed that our current understanding of the anatomy and pathogenesis of the syndrome has not changed over the last 3 decades. However. modern diagnostic modalities. such as sonography and Doppler studies. allow antenatal diagnosis and therefore may change the current definition of the syndrome. Based on these data. a new composite definition of the syndrome is suggested. This definition includes the following criteria: 1) sonographic signs (inter-twin differences in abdominal circumference greater than 18 mm. polyhydramnios-oligohydramnios. and signs of monozygosity). 2) Doppler velocimetry of the umbilical arteries (inter-twin difference in systolic/diastolic ratios above 0.4). 3) demonstration of a transplacental vascular shunt. 4) inter-twin birth weight difference of 15% or more. and 5) inter-twin hemoglobin difference of 5 g/dL or more. In addition. prenatal diagnosis may help in the management of this complication. and it seems that intrauterine treatment of the placental vascular anomalies may be more effective than other antenatal therapeutic options.
Carbon dioxide laser vaporization of diaphragmatic metastases for cytoreduction of ovarian epithelial cancer, Three patients with International Federation of Gynecology and Obstetrics state IIIC ovarian adenocarcinoma underwent CO2 laser vaporization of large-volume (5-6 cm) and miliary right hemidiaphragmatic metastases at the conclusion of standard debulking surgery to effect optimal cytoreduction. Destruction of diaphragmatic metastases was accomplished rapidly with no added morbidity or blood loss. The hand-held CO2 laser is a useful modality for removal of isolated large- and small-volume diaphragmatic disease. particularly if only the peritoneum is involved. and avoids the morbidity that may accompany entry into the pleural space.
Vaginal birth after cesarean delivery: results of a 5-year multicenter collaborative study, Cesarean delivery has become the most frequently performed major operation in the United States. Widespread use of vaginal birth after previous cesarean delivery could potentially eliminate up to one-third of cesareans. However. many physicians have been reluctant to adopt this policy without large studies conclusively demonstrating its safety. This study evaluated the maternal and perinatal outcomes of over 5000 cases of labor after previous cesarean delivery. This multicenter study began in 1984 and initially included nine California hospitals. During the first 2 years. there were 1776 trials of labor resulting in 1314 vaginal births. In January 1986 two additional hospitals joined the collaborative project. Over the next 3 years. there were 3957 trials of labor resulting in 2977 vaginal births at the 11 participating hospitals. During the entire study period. 5733 patients opted for a trial of labor and 4291 (75%) delivered vaginally. There were no maternal deaths in the trial-of-labor group. and perinatal mortality was not significantly different from that of the general obstetric population. These results support the findings of numerous smaller studies that have concluded that the policy of routine repeat cesarean delivery should be abandoned.
Real-time microcomputer-based analysis of spontaneous and augmented labor, In an attempt to develop a reproducible. objective measure of adequate uterine activity in labor. real-time measurements of intrauterine pressure amplitude and contraction frequency. interval. duration. and integral were made in 54 patients. 11 of whom received oxytocin augmentation. We determined the active pressure integral required per centimeter of cervical dilatation. expressed in kPa seconds. and the mean active pressure. expressed in kPa. The augmented group had a significantly higher mean active pressure integral per centimeter than those in normal labor (P less than .01). There was a trend. which did not reach statistical significance. for subjects who required oxytocin augmentation of labor to develop a higher mean active pressure than those in normal labor. However. the correlation of any uterine contractility index (Montevideo units. Alexandria units. mean active pressure) with progress in labor was poor. We conclude that women with dysfunctional labor require more uterine activity for progress in labor than women with normally progressing labor. and that the computer-derived "area under the curve" is not a better predictor of labor progress than Montevideo units.
Accuracy and safety of transvaginal sonographic placental localization, Transvaginal sonographic localization of the placenta was performed in 100 patients suspected of having placenta previa. Except in one patient. the diagnosis was confirmed at cesarean delivery in all cases of placenta previa found by sonography before delivery. resulting in a 93.3% predictive value of a positive test. The predictive value of a negative test was 97.6%; in two patients a low-insertion placenta diagnosed by sonography was found to be a placenta previa at delivery. The sensitivity and specificity of the technique were 87.5 and 98.8%. respectively. Although in some instances transvaginal sonography was performed during vaginal hemorrhage. aggravation of bleeding was never observed. Transvaginal sonographic localization of the placenta proved to be an accurate and safe diagnostic procedure.
Prenatal diagnosis of congenital toxoplasmosis, Prenatal diagnosis of congenital toxoplasmosis was attempted in 50 pregnant women at risk for giving birth to an affected child. Fifteen of these patients seroconverted during pregnancy and 35 had a high initial antibody level in their first serum sample. Prenatal diagnosis consisted of a combination of ultrasound screening. amniocentesis. and funipuncture at about 20 weeks' gestation. Diagnosis of congenital toxoplasmosis was based on a positive toxoplasma culture of amniotic fluid or fetal blood and on the presence of specific immunoglobulin M antibodies in fetal blood. In addition. alterations in fetal hematology. cellular immunology. and fetal liver tests were indicative of infection. Fetal infection was detected in six fetuses; two died in utero as a consequence of the infection and four were born after 37 weeks' gestation. Despite antibiotic treatment with pyrimethamine and sulfadiazine. one child has internal hydrocephalus and chorioretinitis and another has unilateral chorioretinitis. In the two other children. the disease is still subclinical. Of the 44 children born after a negative prenatal diagnosis. 35 have reached the age of 1 year; toxoplasma antibodies have disappeared in all of them. Investigation of the remaining nine children showed a decrease in toxoplasma antibodies. suggesting that none of them are affected. Prenatal diagnosis was never associated with fetal loss. and premature delivery occurred in only two cases. We conclude that prenatal diagnosis of congenital toxoplasmosis is safe and reliable.
Fructosamine compared with a glucose load as a screening test for gestational diabetes, Five hundred seven women were screened for gestational diabetes between 20-36 weeks' gestation. All received a 100-g glucose (polycose) load at 28 weeks with measurement of plasma glucose 1 hour later. Fructosamine levels were measured at 4-week intervals from 20-36 weeks. At 36 weeks. a full 100-g 3-hour glucose tolerance test was performed on all subjects. Eighteen women were diagnosed as having gestational diabetes. The glucose load had a sensitivity of 81% in detection of gestational diabetes. compared with 50% for fructosamine at 36 weeks. Fructosamine is not useful as a screening test for gestational diabetes as currently defined.
Effect of peritoneal fluid from endometriosis patients on endometrial stromal cell proliferation in vitro, Late proliferative phase endometrial stromal cells grown in short-term culture were used as a model for the stromal component of endometriotic implants. Cells were grown in medium alone and in medium supplemented by 5. 10. and 20% concentrations of the cell-free fractions of peritoneal fluid obtained from patients with and without endometriosis. Nine fluid-sample pairs were matched based on the presence or absence of endometriosis at laparoscopy and the similarity of peritoneal fluid estradiol concentrations. Stromal cell proliferation as reflected by 3H-thymidine incorporation during sequential cell harvests over 72 hours was greater for cells exposed to endometriosis peritoneal fluid than for those exposed to non-endometriosis peritoneal fluid. This reached statistical significance with exposure to peritoneal fluid concentrations of 10 and 20% (P less than .05). A linear dose-response relationship between 3H-thymidine incorporation and peritoneal fluid concentration could be derived only for stromal cells exposed to fluid samples obtained from endometriosis patients (r = 0.51; P less than .001). In addition. proliferation over 72 hours was significantly greater for cells grown in 20% endometriosis peritoneal fluid than for those grown in nutrient medium alone (P less than .001). These data imply that factor(s) secreted into the peritoneal fluid of endometriosis patients may play a role in the proliferation or maintenance of disease implants.
Control of immediate postoperative pain with topical bupivacaine hydrochloride for laparoscopic Falope ring tubal ligation, Conflicting reports exist in the literature on the effectiveness of topical local anesthetic applied to the serosal surface of the fallopian tubes for the control of immediate postoperative pain after mechanical (band or clip) tubal ligation. Sixty-four patients were studied prospectively during outpatient laparoscopic Falope ring tubal ligation using the modified McGill Present Pain Intensity Scale. Patients randomly assigned to four groups received topical bupivacaine hydrochloride on both fallopian tubes. the right tube only. or the left tube only. or received none (controls). A unique study design was incorporated which allowed the untreated fallopian tube to serve as a within-subject control for each patient receiving unilateral treatment. Statistical analysis confirmed significant benefit when both fallopian tubes were treated as compared with no treatment (P less than .05). There was also consistent evidence of decreased immediate postoperative pain perception on the treated side for patients receiving unilateral treatment. The value of topical bupivacaine was demonstrated by both subjective patient response (McGill Pain Scale) and reduced need for pain medication before outpatient discharge. Our data support the value of topical bupivacaine applied to the serosal surface of the fallopian tubes for the reduction of postoperative pain after outpatient laparoscopic mechanical (band or clip) tubal ligation.
"Macrosomic" twinning: a study of growth-promoted twins, We evaluated 56 twin pregnancies representing the tenth decile of the mean twin birth weight distribution to investigate whether larger twins face the same increased perinatal risk as do macrosomic singletons. Compared with pregnancies in the ninth decile. no significant difference was found between the means of maternal age. parity. and gestational age; between the rates of presentation combinations and cesareans; or between the neonatal sex ratios. However. the incidence of growth-discordant pairs was significantly higher in the heavier group (P = .034). Compared with the general twin population. the tenth-decile group contained significantly fewer primiparas (P = .0023). Maternal obesity and diabetes were infrequent and could not explain the increased birth weight. The neonatal outcome was excellent. Although the comparison revealed insignificant differences. it is possible that the combination of higher parity. malpresentation rate. and male-to-female ratio may be operative in the genesis of large twins.
Antepartum and intrapartum events in women exposed in utero to diethylstilbestrol, Using a retrospective cohort design. we analyzed the effects of intrauterine diethylstilbestrol (DES) exposure on various antepartum and intrapartum events. Gravidas exposed to DES had a higher likelihood of being delivered abdominally. undergoing manual removal of the placenta. and hemorrhaging in the postpartum period. The increased risk for these events remained after controlling for age. race. and parity. We also constructed labor curves in DES-exposed women by plotting cervical dilation against time. The curves were similar for nulliparous DES-exposed women and nulliparous controls. but DES-exposed parous women experienced prolonged labors. These findings suggest that. in addition to the well-known adverse effects of intrauterine DES exposure. the interaction between the uterus and placenta is altered in some DES-exposed patients.
Quality assurance indicators and short-term outcome of hysterectomy, Fifteen gynecologic quality assurance indicators recently published by The American College of Obstetricians and Gynecologists were applied to a previously reported hysterectomy data base. Chart reviews were performed for the most recent 257 cases in the data base. representing an 18-month interval. The indicators were divided into two groups: those intended to identify morbidity and mortality and those intended to screen for appropriateness of care. Rates of actual morbidity and cases that failed to meet published criteria sets for hysterectomy were determined by chart review regardless of the presence of a quality assurance indicator. A total of 135 indicators were identified in 114 (44%) of the 257 cases. including 64 patients (25%) with morbidity indicators and 50 (19%) with appropriateness indicators. Actual morbidity was correctly identified in all 64 cases in which morbidity indicators were present. Three cases with significant morbidity were identified by chart review but not identified by the indicators. yielding positive and negative predictive values of 100 and 98%. respectively. and an overall accuracy of 99% for morbidity indicators. By contrast. 14 of the 50 cases in which appropriateness indicators were present actually failed to meet published criteria sets. An additional seven cases failing to meet criteria sets were identified by chart review and not identified by the indicators. yielding a positive predictive value of 28%. a negative predictive value of 97%. and an overall accuracy of 83% for appropriateness indicators.
Anatomy of anal sphincters and related structures in continent women studied with magnetic resonance imaging, Five anally continent nulliparas of reproductive age were studied with magnetic resonance imaging. The internal and external anal sphincters could be easily delineated. as could the intervening longitudinal musculature. puborectalis muscle. anococcygeal raphe. anorectal lumen. vagina. uterus. bladder. urethra. coccyx. and pubis. The shape of the sphincters was nearly cylindrical. with an anterior component averaging 18.3 mm thick and 28.0 mm long. Fifty-four percent of this anterior thickness was attributable to the internal sphincter. The anorectal angle varied considerably. with a mean of 86.8 +/- 19.1 degrees (range 60-112). The angle between the portion of the rectal lumen supported by the anococcygeal raphe. or levator plate. and the plane of the puborectalis muscle was consistent at 149.0 +/- 6.3 degrees (138-154). The finding of anterior anal sphincters with substantial thickness and length contrasts markedly with a view often pictured in the literature of a female anal sphincter that narrows anteriorly to half its posterior length and forms a small bundle of muscle rather than a broad band. Knowledge of these relationships is important in primary repair of obstetric sphincter lacerations as well as in surgical correction of anal incontinence.
Detection, prevalence, and prognosis of asymptomatic carcinoma of the cervix, Between 1979-1986. 82 of 407 patients (20%) treated for infiltrative carcinoma of the cervix were asymptomatic at the time of diagnosis. Sixteen (20%) of these 82 patients had stage IA. 60 (73%) had stage IB. and six (7%) had stage IIA disease. Asymptomatic patients represented 16 of 23 (70%) of stage IA. 60 of 196 (31%) of stage IB. and six of 77 (8%) of stage IIA. In the Netherlands. population screening for cervical carcinoma is conducted on women aged 35-55 years. To examine the prevalence of asymptomatic cervical carcinoma and the way in which it was detected in different age groups. we studied the patients referred to our department. Among the patients younger than 35 years with cervical carcinoma. 20 of 70 (29%) were asymptomatic with disease detected by incidental screening. whereas eight of 177 (5%) in the group 55 years or older had been detected by incidental screening. In the age category 35-55 years. 54 of 160 (34%) were asymptomatic. Patients aged 35-55 years had undergone population screening or incidental screening. In the patients 55 years or older. asymptomatic disease was significantly less prevalent than in younger patients. Only one of the 66 asymptomatic patients in stage IB or higher suffered tumor recurrence. Among symptomatic patients. 25 of 136 (18%) with stage IB and 17 of 71 (24%) with stage IIA had tumor recurrence. Despite the favorable prognosis of patients with asymptomatic carcinoma. asymptomatic presentation could not be shown to be a significant prognostic factor. as were tumor diameter and lymph node status.
Primary mass closure of midline incisions with a continuous polyglyconate monofilament absorbable suture, Mass closure of midline incisions with a running large-bore permanent monofilament polypropylene suture has been used in general surgery and gynecology patients with a reported small incidence of fascial dehiscence. Late-occurring wound sinus formation is one problem reported with the use of this permanent suture material. Over a 22-month period. 285 patients had midline incisions closed with a continuous. running no. 1 polyglyconate monofilament delayed absorbable suture. Closely spaced bites (about 1.5 cm apart) were taken and placed 2 cm lateral to the fascial edge. Over 60% of the patients had surgery because of gynecologic cancer. Other high-risk factors included obesity in 62%. diabetes in 19%. and previous irradiation or chemotherapy in 22%. An ovarian cancer staging procedure was done in 16% of the patients. Of the remaining patients. almost half had extensive operative procedures that ranged from exenterations to hysterectomies with lymph node dissection. Wound complications were noted in nine patients (3.2%). Seven had superficial infections. one had an evisceration. and one developed a ventral hernia. Wound sinuses did not occur. The closure technique is safe and expedient and distributes tension equally over a continuous line. It has the additional advantage of eventual absorption of the suture material. thereby avoiding the wound sinus problems occasionally reported with large-bore permanent sutures.
Experimental and clinical studies with radiofrequency-induced thermal endometrial ablation for functional menorrhagia, A method of ablating the endometrium has been introduced into clinical practice that uses radiofrequency electromagnetic energy to heat the endometrium. using a probe inserted through the cervix. Preliminary studies suggest that over 80% of patients treated will develop either amenorrhea or a significant reduction in flow. The advantages of radiofrequency endometrial ablation over laser ablation or resection are the avoidance of intravascular fluid absorption. simplicity (no special operative hysteroscopic skills are required). speed of operation. and reduced cost compared with the Nd:YAG laser. In this paper. we describe the experimental studies performed during development of this new technique.
Clomiphene citrate stimulation as an adjunct in locating ovarian tissue in ovarian remnant syndrome, Ovarian remnant syndrome results from residual ovarian tissue after bilateral oophorectomy. The syndrome is associated with chronic pelvic pain and is suspected when premenopausal levels of FSH and LH are present in a patient with documented bilateral oophorectomy. Histologic demonstration of ovarian tissue at operation confirms the diagnosis. We treated a patient with ovarian remnant syndrome with a 10-day course of clomiphene citrate. 100 mg daily. to stimulate the residual ovarian tissue and facilitate localization. Preoperative ultrasound revealed a 5.0 x 3.5 x 6.2-cm cystic mass in the right adnexal region. Exploratory laparotomy easily localized the mass. and it was removed intact. Histologic slides demonstrated normal ovarian tissue with multiple follicles in various stages of development and a corpus luteum cyst. Clomiphene citrate is capable of stimulating an ovarian remnant. producing an enlarged. cystic structure easily localized by ultrasound. The increased size and preoperative knowledge of the location facilitated surgical removal.
Preoperative angiographic uterine artery embolization in the management of cervical pregnancy, The diagnosis of a cervical ectopic pregnancy is often made intraoperatively in the presence of extensive hemorrhage during attempted evacuation. In some cases. hysterectomy has been the necessary treatment to control bleeding. We report two cases of cervical pregnancy detected by ultrasound. Before pregnancy termination. the uterine arteries were successfully embolized using angiographic techniques. As a result. surgical evacuation was performed with minimal hemorrhage; hysterectomy was not required and the patients' potential fertility was retained.
Successful treatment of cervical pregnancy with oral etoposide, Cervical ectopic pregnancy is an uncommon entity associated with significant morbidity and devastating effects on future fertility. A woman with a cervical gestation with quantitative serum beta-hCG levels higher than 46.000 mIU/mL and fetal cardiac activity on ultrasound was treated successfully with one course of oral etoposide. a fetocidal agent. which avoided operative intervention and preserved the patient's fertility.
Pregnancy associated with Friedreich ataxia, The pregnancy of a woman with Friedreich ataxia was complicated by the onset of preterm labor and preeclampsia. Administration of magnesium sulfate (MgSO4.7H2O) in the usual intravenous dosage resulted in the dramatic development of profound motor weakness and respiratory distress. Magnesium acts to antagonize the action of acetylcholine at the motor end plate of the neuromuscular junction and may operate synergistically with underlying neuromuscular disorders. Therefore. the use of magnesium sulfate in patients with Friedreich ataxia and other similar neurodegenerative diseases is contraindicated.
Successful pregnancy outcome in association with lipoatrophic diabetes mellitus, Lipoatrophic diabetes mellitus is a rare syndrome characterized by lipoatrophy and insulin-resistant diabetes mellitus. Partial lipodystrophy without clinical diabetes mellitus has been associated with intrauterine growth retardation and fetal death. We report successful pregnancy outcomes in two women with lipoatrophic diabetes mellitus.
Fetal levels of tobramycin following maternal administration, A single dose of tobramycin 2 mg/kg was given intravenously to a woman who presented a 22-week heterotopic pregnancy with both intrauterine and ovarian gestations and two living fetuses. After excision of the adnexum. tobramycin levels were measured in the maternal serum and in the fetal fluids and tissues. Antibiotic levels were especially high in the fetal spleen and kidney.
Umbilical cord hematoma following diagnostic funipuncture, Major complications associated with funipuncture have been reported but are rare. This is a report of a diagnostic funipuncture performed on a 29-week fetus with a single umbilical artery and multiple malformations. Immediately after the procedure. a voluminous hematoma developed at the site of needle insertion in association with a severe fetal bradycardia. Fetal death was confirmed within 5 minutes of needle insertion. It is hypothesized that the risk of complications of funipuncture may vary according to the clinical indication for the procedure and may be increased in the presence of certain fetal malformations. The rapid evolution of complications. as occurred in the present case. underlines the importance of having a clear plan of management in the event of mishap and discussing this plan with the parents before undertaking diagnostic funipuncture.
The modified superior based pharyngeal flap technique. Part II. An anatomic study, There is little in the literature on the topographic and/or applied surgical anatomy related to superior based pharyngeal flap surgery. Herein we report on the applied surgical anatomy of pharyngeal flap surgery. especially as it applies to critical anatomic relationships to vessels. muscles. and nerves.
Oral and pharyngeal herpes simplex virus infection after allogeneic bone marrow transplantation: analysis of factors associated with infection, This study analyzed factors associated with acute oropharyngeal herpes simplex virus (HSV) infection in 627 patients who had undergone allogeneic bone marrow transplantation for leukemia. lymphoma. or aplastic anemia. HSV infection developed in 233 (37%) of the patients; all but two were seropositive for HSV before transplant. Sixty-two percent of the seropositive patients had at least one episode of HSV reactivation during the first 100 days after transplant. Other factors that placed patients at increased risk for HSV infection were a pretransplant diagnosis of leukemia. being in remission at the time of transplant. and/or having been conditioned for transplant with chemoradiotherapy. Recognition of factors that may predispose patients to HSV infection helps determine those transplant recipients who might benefit most from antiviral prophylaxis or other approaches to prevention of HSV reactivation.
Bone trabecular pattern analysis in Down syndrome with the use of computed panoramic radiography. Part II: Visual pattern analysis with the frequency and gradational enhancement, Visual pattern analysis of mandibular bone trabeculation of 51 patients with Down syndrome and 78 normal persons was performed by using rotational panoramic radiography with a laser scan system. The findings for patients with Down syndrome were consistent with geromorphism. one of the somatic characteristics of Down syndrome.
Silicone rubber fossa implant removal via partial arthrotomy followed by arthroscopic examination of the internal surface of the fibrous capsule, Thirteen temporomandibular joints were examined arthroscopically for evaluation for fibrous encapsulation of silicone elastomer disk replacement implants. Partial arthrotomies were performed with removal of silicone rubber implants. followed by arthroscopic examination of the internal surfaces of the fibrous capsule as a pseudodisk and to verify the continuity of the fibrous barrier between the condyle and the fossa.
A comparative study of temporomandibular symptoms following mandibular advancement by bilateral sagittal split osteotomies: rigid versus nonrigid fixation, Rigid fixation to attach proximal and distal segments during bony healing of osteotomy sites has become increasingly popular. The effects of rigid fixation on the temporomandibular joints have been questioned. The purpose of this study was to evaluate the effects of rigid fixation after bilateral sagittal split osteotomies on temporomandibular dysfunction symptoms. Forty patients who had mandibular advancement surgery were evaluated for temporomandibular joint dysfunction. Twenty had received rigid fixation. and twenty had received nonrigid fixation. It was determined that there was no statistically significant difference in temporomandibular signs or symptoms between patients who were treated with rigid internal fixation for bilateral sagittal split osteotomies for mandibular advancement and those patients who were treated with nonrigid wire fixation.
A retrospective evaluation of 301 TMJ Proplast-Teflon implants, A retrospective review of 301 meniscectomies with Proplast-Teflon implants was performed. Factors such as interincisal opening. occlusion. joint sounds. joint degeneration. and patient satisfaction were examined. The overall surgical success rate was 88.7%. with an average follow-up period of 33 months. Although many patients demonstrated significant condylar degeneration at 1-year follow-up. such change did not necessarily result in symptomatology or joint dysfunction. Only 10% of implants resulted in removal. Surgical and postoperative procedures are contrasted with those of other clinicians experiencing lower success rates.
Triple bone labeling of canine mandibles, Fluorescence microscopy was used for evaluation of new bone formation in 16 canine mandibles augmented with hydroxylapatite (HA) granules. Three fluorochromes were injected at different time intervals during therapeutic radiation treatment. Oxytetracycline. DCAF. and alizarin-complexone were given intravenously to mark the bone level at these times. respectively. Oxytetracycline. which defined the baseline of bone at implantation of HA. was detectable in 42% of animals that were irradiated and in no animal of the nonirradiated control group. The marker DCAF. designating levels of bone at the start of radiation. was demonstrated in 92% of irradiated animals. and in 75% of animals in the control group. The uptake of alizarin-complexone determined the level of bone found at the end of irradiation. This marker was demonstrated in 50% of the dogs irradiated and in 75% of the control dogs. Bony trabeculae were found between and at the surface of the HA granules. New generation of bone directly on the HA granule and in the surrounding haversian systems as part of normal bone turnover was demonstrated to take place more than 5 months after implantation of HA.
Dental patient reaction to electrocardiogram screening, Ninety-one patients receiving routine dental treatment at the University of Minnesota School of Dentistry participated in an electrocardiogram screening study. The purpose of the study was to evaluate patient reaction to electrocardiogram screening in a dental school clinic. The vast majority of patients indicated the test was easy and did not intrude on the dental appointment. Most of the patients reported that the test was a valuable service and should be available in the dental office. None of the patients indicated that the tests should not be performed in the dental office. Few patients expressed any significant concern or anxiety about the test either before or after it was completed. Twenty-six percent (24/91) of the patients were found to have a cardiac arrhythmia; however. most of these were nonserious arrhythmias (18/24) and would not have had an impact on planned dental procedures. Six patients were identified with arrhythmias that required medical referral before dental treatment was started.
Peripheral giant cell granuloma: evidence for osteoclastic differentiation, Nine cases of peripheral giant cell granuloma of the oral cavity have been immunohistochemically analyzed to assess the nature of the giant cells. Giant cells were unreactive when tested with antibodies recognizing myelomonocytic and macrophage markers (lysozyme. MAC 387. HAM 56) but showed strong immunoreactivity with MB1. an antibody reactive with osteoclasts. It is concluded that giant cells characterizing giant cell granuloma exhibit a phenotype distinct from other giant cells found in sites of chronic inflammation and may be true osteoclasts.
Microleakage associated with retrofilling of the apical two thirds with amalgam, In this investigation the effect of increasing the thickness of amalgam retrofilling on its sealing ability was studied and compared with the sealing ability of the laterally condensed gutta-percha with a sealer. The apical two thirds of the canals of 118 upper central incisors. filled with laterally condensed gutta-percha. were sealed with amalgam. Amalgam retrofills were also used to seal the apices of the roots of six teeth that had no other filling in their canals. The effectiveness of both techniques was determined by their ability to inhibit the penetration of methylene blue dye for the periods of 24 hours. 1 week. and 1. 3. and 6 months. At 24 hours both materials showed comparable sealing ability. However. the sealing ability of laterally condensed gutta-percha was significantly better than that of amalgam from the 1-week period until the end of the study. The depth of marginal penetration around both materials increased with time. The amount of the dye penetration increased acutely around amalgam. whereas its increase around gutta-percha was more uniform. At the end of the study. specimens retrofilled with amalgam exhibited total dye penetration that exceeded the full thickness of amalgam (6 mm) and spread into the root canal space. On the other hand. the mean value for marginal penetration of the dye around the laterally condensed gutta-percha was 2.6 mm at the end of the study. The present investigation proved beyond doubt that the use of any thickness of retrograde amalgam to seal the apex. with no other filling within the canal. invites failure.
Prevalence of shovel-shaped incisors in Saudi Arabian dental patients, The prevalence of maxillary incisor shoveling was studied radiographically in 990 Saudi patients. According to the radiomorphologic characteristics. a new classification was developed and shovel teeth were categorized. The findings of this study showed 9% shovel-shaped incisors; among those. 4% were central incisors and 5% were lateral incisors. Frequency of dens invaginatus occurrence with the shovel-shaped incisors was also investigated. Eight percent of shovel-shaped incisors showed presence of dens invaginatus. Prevalence was found to be 4% in central shovel-shaped incisors. whereas that in lateral shovel-shaped incisors was 11%.
Tibial defects. Reconstruction using the method of Ilizarov as an alternative, Although used in the USSR since the 1950s. the method of Ilizarov has only recently been employed in North America to manage bone defects. Seven cases of patients with tibial bone defects are presented (five with deep infection) that were treated by gradual compression at the defect with one or two transported tibial segments that not only filled the tibial defect but preserved or regained the original bone length. Six of the seven patients had their defect obliterated while leg length was maintained. The method is minimally invasive. allows immediate weight-bearing and permits modifications in strategy while treating the bone defects but requires close attention to detail and has a steep learning curve.
Preoperative planning for the treatment of nonunions and the correction of malunions of the long bones, A detailed analysis of the steps of preoperative planning as employed in our clinic has been presented. We have found these techniques to be of great value in anticipating the requirements that must be fulfilled to correct malalignments and obtain healing when the malalignments occur alone or are associated with nonunion. Besides helping one to decide where a malalignment is best corrected to anatomically match the normal extremity. tracings aid in allowing the surgeon to appreciate the kinetics of the operative procedure. as well as to define the best methods of stabilizing the resulting correction.
Treatment of tibial malunions and nonunions with reamed intramedullary nails, Reamed intramedullary nailing is an effective. relatively low-risk technique for the management of delayed union. nonunion. and malunion of the tibia. Closed technique should be used where possible and open realignment. when necessary. should be executed with minimal dissection. Bone grafting is rarely indicated. The use of interlocking nails provides an added degree of security in the control of rotation.
The treatment of nonunions and pseudarthroses of the humeral shaft, In summary. if one follows the AO/ASIF principles of open reduction and stable internal fixation of nonunions and pseudarthroses of the humerus. mostly with plate fixation supplemented by shingling or petaling. cement for loose screws when necessary. and bone grafting of defects or atrophic nonunions. then successful healing with one operative procedure can be achieved in over 95%. with almost full correction of preoperative deformity. Return of useful function and range of motion can also be achieved in 75% to 90% by early active exercises. physiotherapy. and occasional continuous passive motion. supported by hinged braces or cast braces in the postoperative period until union occurs. Union was achieved in an average of 6.6 months after the operative procedure.
Intraarticular malunions and nonunions, The principles of intraarticular fracture care and stable internal fixation. when applied to intra-articular nonunions and malunions. can result in the restoration of an amazing function to joints that seem almost totally doomed to either an arthrodesis or an arthroplasty. The high degree of success achieved in almost all cases illustrates the amazing recuperative powers of human joints once articular cartilage congruence and stability is re-established together with correction of axial deformities and the mobilization of joints.
Diagnosis and treatment of nonunions and malunions of acetabular fractures, The surgical treatment of nonunions and malunions of acetabular fractures is often a challenge. The diagnosis of a nonunion or malunion rests on clinical and radiologic examination. Apart from the union troubles involving only one column. all other cases justify the use of the extensile approach.
Heat illness. Fluid and electrolyte issues for pediatric and adolescent athletes, The primary mechanism for maintaining normal body temperature during physical exercise in the heat is the evaporation of sweat. With profuse sweating. water loss far exceeds electrolyte loss. Rigorous exercise in the heat places the athlete at risk for thermoregulatory dysfunction from dehydration. Because children are inherently less efficient thermoregulators than adults. they are at even greater risk for heat illness. The three primary syndromes of heat illness are heat cramps. heat exhaustion. and heat stroke. Treatment of heat illness is based on reduction of body temperature and rehydration. Heat stroke is a true medical emergency with a high mortality rate; immediate reduction of body temperature is critical to the survival of these patients. Prevention of heat illness is based on reducing known risk factors. Physical activity should be modified in the face of high ambient temperature and humidity. The athlete should begin exercise well hydrated; frequent consumption of cold water during exercise decreases likelihood of significant dehydration. After exercise. the athlete should continue drinking to replace fluid losses. Clothing should be lightweight; the more skin exposed. the greater the available evaporative surface. A preseason conditioning program. when combined with an 8- to 14-day period of acclimatization. further reduces the risk of heat injury. Although athletes engaged in endurance sports may benefit from drinking carbohydrate/electrolyte-containing solutions. for the majority of young athletes. cold water remains the preferred choice for fluid replacement during exercise. The relatively greater body surface area of young athletes also places them at risk for hypothermia. Special attention should be given when these athletes are competing under cold environmental conditions.
Iron deficiency in the young athlete, Although overt anemia is uncommon. depletion of body iron stores is common among adolescent female athletes. Poor dietary iron intake. menstruation. and increased iron losses associated with physical training all appear to be important factors. Whether nonanemic iron deficiency can impair exercise performance is uncertain. Nonetheless. athletes with low ferritin levels are at risk for impaired erythropoiesis and should receive therapeutic iron supplementation.
A review of the use of prophylactic knee braces in football, A review of nine studies of prophylactic knee braces worn by players in American tackle football lends some support for the use of double-hinged braces at the high-school level. Evidence for their use at the college level seems less persuasive. Caution should be exercised in interpreting these studies owing to the probable presence of bias and confounding variables and to difficulty in generalizing results beyond the study populations. The two studies that assigned braces randomly found lower injury rates for knees and knee ligaments among high-school and high-school size players. Conversely. a large. multiteam collegiate study found a significantly higher rate of knee injuries among brace users. a difference that remained when controlled for position. skill. and previous injury.
Strength training in children and adolescents, Strength is the ability to exert muscular force against resistance. It is a fundamental requirement of most daily physical activities of children and of adults. Strength training is the use of progressive resistance exercise methods specifically to increase strength. Strength training for children and adolescents is not without risk. Proven medical concerns relate to back. shoulder. and other joint injuries and to hypertension and related diseases. However. the rate of injury is probably rather low. comparable to many youthful activities that are considered safe. Also. the incidence and severity of injury can probably be minimized by adherence to the guidelines presented. Children may be expected to become stronger with appropriate training. Increased strength can enhance their performance in those athletic activities in which strength. power. or speed are required. It may reduce the incidence and severity of overuse injury in sport. However. it cannot reasonably be expected to protect against serious. acute injury in sport.
IgG subclass concentrations in absolute, partial and transient IgA deficiency in childhood, Sixty-seven children with symptomatic IgA deficiency were studied on two separate occasions. Eighteen had aIgAd at presentation. and 49 had pIgAd. IgA concentrations had risen to the normal range for age in 22.2% of children presenting with aIgAd and 77.6% presenting with pIgAd when restudied at a median interval of 3.2 and 3.0 years. respectively. IgG subclass concentrations were measured by enzyme immunoassay in serum samples collected at enrollment from 12 children with aIgAd and 22 children with pIgAd. IgG2 and IgG4 concentrations for these 34 children were below the 5th centile for age and sex more frequently than expected (IgG2: chi square 5.8. P less than 0.025; IgG 4: chi square 18.4. P less than 0.0005). The prevalence of IgG2 deficiency or IgG4 deficiency did not differ significantly between those with aIgAd and those with pIgAd. IgG2 concentrations remained below the 5th centile more frequently than expected when retested in 31 children whose pIgAd had resolved (chi square 4.6. P less than 0.05). Children with aIgAd at presentation had IgG1 and IgG2 concentrations above the 95th centile more frequently than expected (IgG1: chi square 19.7. P less than 0.0005; IgG2: chi square 13.5. P less than 0.001) but this was not seen for IgG3 and IgG4 concentrations. Children with pIgAd did not have elevated IgG1 or IgG2 concentrations at presentation. High IgG1 and IgG2 concentrations in aIgAd may be a compensatory mechanism to afford protection from infection or could be part of a selective secondary response to repeated episodes of infection.
Nebulized albuterol in acute childhood asthma: comparison of two doses, Thirty-three children and adolescents from 5 to 17 years of age with moderate to severe acute asthma were given nebulized albuterol therapy in either a high (0.30 mg/kg body weight) or standard (0.15 mg/kg) dose administered at three hourly intervals in a randomized double-blind study. The high-dose hourly regimen resulted in significantly greater improvement in the forced expiratory volume in 1 second (FEV1). Furthermore. patients receiving the high dose showed a steady improvement in the FEV1 from the start to the end of the study. whereas FEV1 plateaued after the second dose in the standard-dose group. Although a rise in heart rate and a fall in serum potassium level occurred. neither of these changes nor other side effects were different in the two groups. The high-dose therapy resulted in much higher serum albuterol levels than the standard dose. There was no correlation between the drug levels and side effects or initial and subsequent FEV1. It is concluded that occasional hourly high-dose albuterol therapy should be considered for some pediatric patients with acute asthma of moderate severity. especially those who relapse between doses.
The UCLA-University of Utah epidemiologic survey of autism: prenatal, perinatal, and postnatal factors, In a recent epidemiologic survey conducted in Utah. 241 autistic patients (DSM-III criteria) were found. Medical records of 233 autistics were surveyed for the presence of 36 potentially pathologic prenatal. perinatal. and postnatal factors. These results were compared with those of an identical survey of 62 of their nonautistic siblings. with the results of four previously published surveys. and with normative data. No potentially pathologic factor or group of factors occurred significantly more frequently among the autistic patients. Also. previous observations of significant differences in the occurrence of certain factors in the histories single vs multiple siblings with autism were not confirmed. with the exception of increased viral-type illness during gestation in single-incidence cases. Thus. the etiology of the brain pathology that characteristically disrupts normal development and produces the syndrome of autism remains obscure. Other data from the epidemiologic survey. however. suggest that the role of genetic factors needs to be explored further.
Safety and immunogenicity of Haemophilus influenzae type b oligosaccharide-CRM197 conjugate vaccine in infants aged 15 to 23 months, A total of 268 infants aged 15 to 23 months received one dose of a vaccine composed of Haemophilus influenzae type b oligosaccharides covalently linked to the nontoxic diphtheria toxin variant CRM197 (HbOC; HibTITER). Side effects associated with vaccination were infrequent. transient. and mild. One month after a single vaccination. the anti-H influenzae type b capsular polysaccharide antibody concentration rose from a geometric mean prevaccination level of 0.20 microgram/mL to 13.77 micrograms/mL. Of these infants. 99% had a postvaccination level greater than or equal to 1.00 microgram/mL. a level associated with long-term protection. The immune response was long-lived: all of the children who were monitored 17 to 27 months after vaccination had concentrations greater than or equal to 1.00 microgram/mL. The anti-H influenzae type b capsular polysaccharide antibody generated was predominantly of the IgG isotype and IgG1 subclass. The immune sera had bactericidal activity in vitro and conferred passive protection in the infant rat meningitis model.
Substance abuse education in pediatrics, Historically. physicians have received little formal education related to alcohol or other drug abuse and dependence. A survey of all pediatric programs in the United States was conducted to assess the current status of alcohol/drug education in pediatrics. At the medical student and residency training levels. only 44% and 40% of programs. respectively. required any formal instruction. and only 27% and 34%. respectively. offered an elective for medical students or residents. Although most respondents endorsed the inclusion of both required and elective alcohol and drug education in the curriculum. few programs that did not include it already had a future plan for it. Major impediments identified were curriculum time constraints (86% medical student level. 68% resident level) and the lack of a qualified instructor (55% medical student level. 50% resident level). The survey results suggest a strong need for development of faculty and structured alcohol and drug abuse educational plans specific to pediatrics.
Single- versus multiple-dose surfactant replacement therapy in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome, To assess the efficacy of a multiple-dose protocol of surfactant replacement therapy in neonates of 30 to 36 weeks' gestation. 75 neonates were randomly assigned to control. single-dose surfactant. or multiple-dose surfactant groups. Neonates at less than 6 hours of age with a diagnosis of respiratory distress syndrome were eligible. Subjects were randomly assigned to receive either 100 mg/kg of bovine surfactant or air placebo. Neonates in the multiple-dose group were eligible to receive up to three additional doses as indicated. Neonates in both surfactant groups showed a positive response to treatment. with marked improvement in oxygenation by 10 minutes postinstillation (P less than .0001). Both surfactant groups had better oxygenation than control subjects at lower ventilatory parameters over the first 24 hours. A deterioration in oxygenation and ventilatory requirements was seen in both treatment groups starting 6 to 12 hours after the first dose. The deterioration in oxygenation could be minimized by the use of multiple doses; however. extra doses had no effect on diminishing ventilatory requirements or time to extubation. It is concluded that surfactant therapy at less than 6 hours of age is effective in acutely reducing oxygen and ventilatory requirements in neonates of 30 to 36 weeks' gestation with respiratory distress syndrome. It appears that multiple doses of surfactant have a greater effect on sustaining improvements in oxygenation than on ventilatory requirements. Further study is required to determine optimal dosage and retreatment strategy.
Vancomycin-induced red man syndrome, A total of 11 cases of red man syndrome collected among 650 children who had received vancomycin in our hospital between 1986 and 1988 (estimated prevalence 1.6%) were retrospectively analyzed. These 11 children were compared with 11 age-matched children who received vancomycin in whom red man syndrome did not develop. Of the patients with red man syndrome. 73%. and of the patients with no reaction. 45.4% received vancomycin for penicillin-resistant Staphylococcus epidermidis-positive cultures. or because of history of penicillin allergy. No difference was observed in the dose per kilogram given to both groups (12.9 +/- 3.5 mg/kg per dose in those with red man syndrome vs 12.3 +/- 6.9 mg/kg per dose in control children. The duration (mean +/- standard deviation) of vancomycin infusion was 45.9 +/- 16.7 minutes (range 10 to 90 minutes) in patients with red man syndrome and 54.5 +/- 7.6 minutes (range 45 to 65 minutes) in the control group (P = .07). In the 5 children with red man syndrome rechallenged with vancomycin. slower infusion rates prevented or reduced the syndrome. which emphasized the fact that the rate of administration is the important determinant of red man syndrome in susceptible cases. Clinically. the syndrome developed at the end of the infusion in most patients. but appeared as early as 15 minutes after initiation of the infusion. It was mostly manifested as a flushed. erythematous rash on the face. neck. and around the ears. Less frequently. the rash was distributed all over the body. Pruritus was usually localized to the upper trunk but was also generalized (2 of 11 children).
Serial Munchausen syndrome by proxy, Five cases of Munchausen syndrome by proxy (MSBP) are presented in which more than one child in the family was victimized. There was a high incidence of maternal psychiatric histories. marital difficulties. and Munchhausen syndrome in the mothers themselves. Seventy-one percent of the children in the families were known to be victims of MSBP; four of these children (31%) died. Multiple-child MSBP may reflect more significant maternal psychopathology than found in other cases of MSBP. or it may indicate the deteriorating consequences to the mother and other children in the family if this syndrome is not identified with the first child and effective interventions made.
Outcome and predictors of outcome in pediatric submersion victims receiving prehospital care in King County, Washington, Predictors of outcome in pediatric submersion victims treated by Seattle and King County's prehospital emergency services were studied. Victims less than 20 years old were identified from hospital admissions and paramedic and medical examiners' reports. The proportion of fatal or severe outcomes in patients were compared with various risk factors. Of 135 patients. 45 died and 5 had severe neurologic impairment. A subset of 38 victims found in cardiopulmonary arrest had a 32% survival rate. with 67% of survivors unimpaired or only mildly impaired. The two risk factors that occurred most commonly in victims who died or were severely impaired were submersion duration greater than 9 minutes (28 patients) and cardiopulmonary resuscitation duration longer than 25 minutes (20 patients). Both factors were ascertained in the prehospital phase of care. Submersion duration was associated with a steadily increasing risk of severe or fatal outcomes: 10% risk (7/67) for 0 to 5 minutes. 56% risk (5/9) for 6 to 9 minutes. 88% risk (21/25) for 10 to 25 minutes. 100% risk (4/4) for greater than 25 minutes. None of 20 children receiving greater than 25 minutes of cardiopulmonary resuscitation escaped death or severe neurologic impairment. Our rates for saving all victims. particularly victims in cardiopulmonary arrest. are considerably higher than has been reported before the children. Prompt prehospital advanced cardiac life support is the most effective means of medical intervention for the pediatric submersion victim. Prehospital information provided the most valuable predictors of outcome.
Successful renal transplantation accelerates development in young uremic children, To examine the impact of renal transplantation on subsequent development of children with chronic renal failure. 37 children undergoing primary renal transplantation at or before 30 months of age whose allograft functioned for at least 1 year were prospectively studied. Psychometric tests were performed an average of 4 months before transplantation; reevaluation was done an average of 14 months after surgery. Comparison of individual pretransplantation and posttransplantation mental development scores in 33 patients. assessed by either Bayley Mental Development Index or Stanford-Binet Intelligence Quotient. revealed an average increase of 12.6 (P less than .001). After transplantation. there was a significant improvement in mental performance in 12 of 18 patients (P less than .02) from the range of mild delay (Mental Development Index or Stanford-Binet IQ score = 50 to 69) to the range of normal mental development (greater than or equal to 70). The Bayley Psychomotor Development Index scores were frequently lower than Mental Development Index scores and also increased an average of 14.4 (P less than .01) after transplantation in all 12 patients with paired data. Significant individual improvement in occipital-frontal circumference standard deviation score (P less than .001) was noted in 24 children after transplantation. It is concluded that successful renal transplantation in young children with chronic renal failure is often associated with significant improvements in cognitive and psychomotor function. as well as improved cephalic growth.
Predictive value of visible lesions (cheeks, lips, oropharynx) in suspected caustic ingestion: may endoscopy reasonably be omitted in completely negative pediatric patients?, The relationship between absence or presence of grossly visible lesions in the cheeks. lips. and oropharynx (C.L.O. burns) and the incidence. site. and degree of visceral burns was evaluated in all children referred to our hospital for a suspected caustic ingestion during a 10-year period. All children underwent eso-gastro-duodenoscopy within 24 hours. Of the 156 children. 96 (61.6%) showed no visible signs of contact with the caustic substance; however. in 36/96 (37.5%). endoscopy revealed burns in one or more visceral sites. Eight of 36 children (22.2%) sustained potentially dangerous lesions (second to third degree). Sixty of 156 children (38.4%) showed visible lesions; in 30/60 (50%). endoscopy revealed other burns in one or more visceral sites. Fourteen of 30 patients (46.6%) sustained potentially dangerous lesions (second to third degree). A total of 50 esophageal burns have been recorded: first degree (E1). 32; second degree (E2). 12; third degree (E3). 6. Two of 12 patients with E2 lesions and 6/6 with E3 lesions developed esophageal stenosis. One patient in this latter group died because of complications related to a tracheostomy. A total of 31 gastric burns have been recorded: G1 (22). G2 (6). G3 (3). One gastric perforation was observed in the G3 group. whereas the remaining two lesions healed with residual asymptomatic scarring. Minimal scarring was observed in two of six patients with G2 burns. A total of eight lesions have been recorded in the larynx [L1 (3). L3 (1)] and in the duodenum [D1 (2). D2 (2)].
Acute respiratory infections during the first three months of life: clinical, radiologic and physiologic predictors of etiology, The usefulness of clinical. radiologic. and physiologic characteristics to identify pathogens was assessed in 90 infants aged two through 12 weeks. presenting to an outpatient clinic with an acute respiratory infection. Eighty-four cases had cultures or rapid diagnostic tests for RSV. of which 25 were positive. Eighty-two infants had cultures or rapid diagnostic tests for Chlamydia. of which 16 were positive. Additional respiratory pathogens identified included parainfluenza (6 cases). rhinovirus (3 cases). pertussis (2 cases). and CMV (1 case). Multiple pathogens were identified in four cases: Chlamydia and RSV (2 cases). Chlamydia and parainfluenza (1 case). and Chlamydia and CMV (1 case). Clinical characteristics other than the need for hospitalization were not useful predictors of specific pathogens. X-rays were obtained in 20 (80%) of the RSV infections. 13 (81%) of the Chlamydia infections. six of the parainfluenza infections. two pertussis infections. and 25 cases without identification of the pathogen. X-ray findings could not distinguish between patients with or without a pathogen or between the pathogens. Severe findings were present in 28% (11/40) of cases with a pathogen identified. compared to 12% (3/26) of cases without a pathogen identified (NS). Moderate findings were present in 58% (23/40) of cases with a pathogen identified compared to 62% (16/26) of cases without a pathogen identified. Slight/negative findings were present in 15% (6/40) of cases with a pathogen identified. compared to 27% (7/26) of cases without a pathogen identified. Pulse oximetry was done in 30 cases. 22 of which had a pathogen identified (RSV 14. Chlamydia 7. pertussis 1).
Poor compliance with universal precautions: a universal phenomenon, An anonymous survey was conducted in order to examine compliance with universal precautions in the Department of Pediatrics at Loyola University Medical Center in Maywood. Illinois. Completed questionnaires were returned by 23 faculty members. 29 residents. and 22 medical students. Gloves were worn consistently during venipuncture or intravenous catheterization by 13. 7. and 18% of attending physicians. residents. and students. respectively. Most physicians wear gloves only occasionally and cite presence of high-risk factors as their selection criterion. Interference with the performance of procedures is the most common cause of noncompliance. In view of poor compliance with universal precautions. further efforts are needed in order to decrease the incidence of preventable exposure to blood-borne infections.
Rapid sequence anesthesia induction for emergency intubation, Emergency intubations are done for a variety of reasons in the emergency department (ED). In some patients. a rapid. controlled induction of anesthesia is useful to facilitate intubation and to reduce the complications of intubation. This is referred to a rapid sequence induction (RSI) in the anesthesia literature. Atropine. thiopental. fentanyl. diazepam. ketamine. vecuronium. succinylcholine. other drugs and their applications for RSI are described. The purpose of this article is to describe the use of RSI in the airway management of ED patients. Nineteen pediatric patients requiring emergency intubation were intubated using RSI with vecuronium and thiopental. Actual intubation difficulty using RSI was significantly less than the anticipated intubation difficulty without RSI. There were no complications caused by intubation or RSI that had a significant impact on patient outcome. We feel that a sedative in combination with vecuronium represents the most optimal means of achieving RSI in the ED setting. Although the induction of general anesthesia is best done by anesthesiologists. emergency physicians are often the most experienced physicians immediately available to manage an airway in a critical emergency. An objective protocol such as that described will make it easier for emergency physicians to perform this procedure when needed.
Bell's palsy. Ensuring the best possible outcome, Bell's palsy is thought to be an idiopathic polyneuritis and must be distinguished from other disorders that cause facial weakness. In most cases. differentiation can be accomplished on the basis of the history. physical examination. and clinical course. Routine follow-up care ensures that recovery is occurring. Electrodiagnostic testing often helps to assess prognosis. Eye care and corticosteroid therapy are recommended.
Reactions to iodinated radiographic contrast agents. How to identify and manage patients at risk, Systemic adverse reactions to iodinated radiographic contrast material are infrequent but can be dramatic. The number of patients experiencing such reactions can be minimized by selecting the most appropriate diagnostic study for each patient and by identifying patients at increased risk. Pretreatment with corticosteroids and use of low-osmolality contrast materials can minimize the number of severe reactions in high-risk patients.
The infant with a reddish diaper, The infant with a reddish diaper presents a diagnostic challenge to the primary care physician. As described by Dr Baumgardner. the cause may be benign. but more ominous disorders must be ruled out.
New findings in treatment of colon cancer, Patients with colon cancer involving regional lymph nodes (stage C disease) have a 5-year survival rate of only 30% to 40%. and the majority die of recurrent disease. Recent trials have shown increased survival rates with postoperative use of fluorouracil plus levamisole. The authors discuss these findings and the implications on treatment recommendations for stage C colon cancer.
Initial management of trauma. The next 60 minutes, If and when hemodynamic stability has been achieved in a trauma patient. a detailed physical examination and appropriate diagnostic studies are performed. The successful management of trauma demands that immediately life-threatening problems receive top priority and that patients be continuously reexamined and problems reprioritized as conditions change. Finally. it is imperative that appropriate surgical evaluation and treatment be undertaken as soon as possible. Trauma patients should not be allowed to languish or undergo extensive examination in a hospital lacking surgical or other specialists trained to treat the problems identified. Transfer to another facility. whether for specialized diagnostic tests or for evaluation and treatment by surgical specialists. should be accomplished as quickly as possible.
Down-regulation of a calmodulin-related gene during transformation of human mammary epithelial cells, A human cDNA library obtained from cultured normal mammary epithelial cells (HMECs) was searched by subtractive hybridization for genes whose decrease in expression might be relevant to epithelial transformation. One clone identified by this procedure corresponded to a 1.4-kilobase mRNA. designated NB-1. whose expression was decreased greater than 50-fold in HMECs tumorigenically transformed in vitro after exposure to benzo[a]pyrene and Kirsten sarcoma virus. Sequence analysis of NB-1 cDNA revealed an open reading frame with a high degree of homology to calmodulin. NB-1 expression could be demonstrated by polymerase chain reaction amplification in normal breast. prostate. cervix. and epidermal tissues. The presence of NB-1 transcripts was variable in primary breast carcinoma tissues and undetectable in tumor-derived cell lines of breast. prostate. or other origins. NB-1 mRNA expression could be down-regulated in cultured HMECs by exposure to reconstituted extracellular matrix material. while exposure to transforming growth factor type beta increased its relative abundance. The protein encoded by NB-1 may have Ca2+ binding properties and perform functions similar to those of authentic calmodulin. Its possible roles in differentiation and/or suppression of tumorigenicity in epithelial tissues remain to be examined.
Worldwide differences in the incidence of type I diabetes are associated with amino acid variation at position 57 of the HLA-DQ beta chain, The presence of an amino acid other than aspartic acid at position 57 of the HLA-DQ beta chain (non-Asp-57) is highly associated with susceptibility to insulin-dependent diabetes mellitus (IDDM). whereas an aspartic acid at this position (Asp-57) appears to confer resistance to the disease. We hypothesize that the 30-fold difference in IDDM incidence across racial groups and countries is related to variability in the frequency of these alleles. Diabetic and nondiabetic individuals were evaluated in five populations. including those at low. moderate. and high risk. HLA-DQ beta genotype distributions among the IDDM case groups were markedly different (P less than 0.001). as were those among nondiabetic controls (P less than 0.001). Non-Asp-57 alleles were significantly associated with IDDM in all areas; population-specific odds ratios for non-Asp-57 homozygotes relative to Asp-57 homozygotes ranged from 14 to 111. Relative risk information from the case-control study and population incidence data were combined to estimate genotype-specific incidence rates for the Allegheny County. PA. Caucasians. These rates were used to predict the overall incidence rates in the remaining populations. which were within the 95% confidence intervals of the actual rates established from incidence registries. These results are consistent with the hypothesis that population variation in the distribution of non-Asp-57 alleles may explain much of the geographic variation in IDDM incidence.
Tumorigenic 3T3 cells maintain an alkaline intracellular pH under physiological conditions, One of the earliest events in the response of mammalian cells to mitogens is activation of Na+/H+ exchange. which increases intracellular pH (pHin) in the absence of HCO3- or at external pH values below 7.2. The proliferative response can be blocked by preventing the pHin increase; yet. the proliferative response cannot be stimulated by artificially raising pHin with weak bases or high medium pH. These observations support the hypothesis that optimal pHin is a necessary. but not sufficient. component of the proliferative-response sequence. This hypothesis has recently been challenged by the observation that transfection of NIH 3T3 cells with yeast H(+)-ATPase renders them tumorigenic. Although previous measurements indicated that these transfected cells maintain a higher pHin in the absence of HCO3-. whether H(+)-ATPase transfection raised the pHin under physiologically relevant conditions was not known. The current report shows that these transfected cells do maintain a higher pHin than control cells in the presence of HCO3-. supporting the possibility that elevated pHin is a proliferative trigger in situ. We also show that these cells are serum-independent for growth and that they glycolyze much more rapidly than phenotypically normal cells.
Incomplete synthesis of N-glycans in congenital dyserythropoietic anemia type II caused by a defect in the gene encoding alpha-mannosidase II, Congenital dyserythropoietic anemia type II. or hereditary erythroblastic multinuclearity with a positive acidified-serum-lysis test (HEMPAS). is a genetic anemia in humans inherited by an autosomally recessive mode. The enzyme defect in most HEMPAS patients has previously been proposed as a lowered activity of N-acetylglucosaminyltransferase II. resulting in a lack of polylactosamine on proteins and leading to the accumulation of polylactosaminyl lipids. A recent HEMPAS case. G.C.. has now been analyzed by cell-surface labeling. fast-atom-bombardment mass spectrometry of glycopeptides. and activity assay of glycosylation enzymes. Significantly decreased glycosylation of polylactosaminoglycan proteins and incompletely processed asparagine-linked oligosaccharides were detected in the erythrocyte membranes of G.C. In contrast to the earlier studied HEMPAS cases. G.C. cells are normal in N-acetylglucosaminyltransferase II activity but are low in alpha-mannosidase II (alpha-ManII) activity. Northern (RNA) analysis of poly(A)+ mRNA from normal. G.C.. and other unrelated HEMPAS cells all showed double bands at the 7.6-kilobase position. detected by an alpha-ManII cDNA probe. but expression of these bands in G.C. cells was substantially reduced (less than 10% of normal). In Southern analysis of G.C. and normal genomic DNA. the restriction fragment patterns detected by the alpha-ManII cDNA probe were indistinguishable. These results suggest that G.C. cells contain a mutation in alpha-ManII-encoding gene that results in inefficient expression of alpha-ManII mRNA. either through reduced transcription or message instability. This report demonstrates that HEMPAS is caused by a defective gene encoding an enzyme necessary for the synthesis of asparagine-linked oligosaccharides.
Simian virus 40 small tumor antigen and an amino-terminal domain of large tumor antigen share a common transforming function, The 82-residue amino-terminal sequences of simian virus 40 large tumor antigen (TAg) and small tumor antigen (tAg) are identical. Genetic analysis of TAg lacking amino acids 1-82 revealed that it was transformation-defective. as revealed by the agar growth assay. except when introduced in the presence of tAg. Since the latter. alone. lacks overt transforming activity. it would appear that the function of the sequence common to TAg and tAg is necessary. but not sufficient. for TAg transforming activity and that tAg can provide that function or its equivalent in trans. Thus. tAg may. in part. be viewed as a "portable" copy of a TAg functional domain.
Cloning of the cDNA for human 12-lipoxygenase, A full-length cDNA clone encoding 12-lipoxygenase (arachidonate:oxygen 12-oxidoreductase. EC 1.13.11.31) was isolated from a human platelet cDNA library by using a cDNA for human reticulocyte 15-lipoxygenase as probe for the initial screening. The cDNA had an open reading frame encoding 662 amino acid residues with a calculated molecular weight of 75.590. Three independent clones revealed minor heterogeneities in their DNA sequences. Thus. in three positions of the deduced amino acid sequence. there is a choice between two different amino acids. The deduced sequence from the clone plT3 showed 65% identity with human reticulocyte 15-lipoxygenase and 42% identity with human leukocyte 5-lipoxygenase. The 12-lipoxygenase cDNA recognized a 3.0-kilobase mRNA species in platelets and human erythroleukemia cells (HEL cells). Phorbol 12-tetradecanoyl 13-acetate induced megakaryocytic differentiation of HEL cells and 12-lipoxygenase activity and increased mRNA for 12-lipoxygenase. The identity of the cloned 12-lipoxygenase was assured by expression in a mammalian cell line (COS cells). Human platelet 12-lipoxygenase has been difficult to purify to homogeneity. The cloning of this cDNA will increase the possibilities to elucidate the structure and function of this enzyme.
Identification and characterization of a regulated promoter element in the epidermal growth factor receptor gene, We have identified a 36-base-pair proximal element (-112 to -77 relative to the AUG translation initiation codon) in the epidermal growth factor receptor 5' region that functions as a promoter; mediates inductive responses to epidermal growth factor. phorbol 12-myristate 13-acetate. and cyclic AMP; and acts in an orientation-independent manner. This region functions as an enhancer when transferred to a heterologous promoter containing a TATA box. Mutations within the 36-base-pair region alter function as assayed by reporter gene expression in recipient cells. A protein has been identified that demonstrates appropriate binding specificity to mutant DNA sequences that correlates with promoter activity observed in vivo. On the basis of DNA binding characteristics and size. the identified protein appears distinct from several previously identified transcription factors known to bind to G+C-rich regions.
Identification and preliminary characterization of protein-cysteine farnesyltransferase, Ras proteins must be isoprenylated at a conserved cysteine residue near the carboxyl terminus (Cys-186 in mammalian Ras p21 proteins) in order to exert their biological activity. Previous studies indicate that an intermediate in the mevalonate pathway. most likely farnesyl pyrophosphate. is the donor of this isoprenyl group. Inhibition of mevalonate synthesis reverts the abnormal phenotypes induced by the mutant RAS2Val-19 gene in Saccharomyces cerevisiae and blocks the maturation of Xenopus oocytes induced by an oncogenic Ras p21 protein of human origin. These results have raised the possibility of using inhibitors of the mevalonate pathway to block the transforming properties of ras oncogenes. Unfortunately. mevalonate is a precursor of various end products essential to mammalian cells. such as dolichols. ubiquinones. heme A. and cholesterol. In this study. we describe an enzymatic activity(ies) capable of catalyzing the farnesylation of unprocessed Ras p21 proteins in vitro at the correct (Cys-186) residue. This farnesylating activity is heat-labile. requires Mg2+ or Mn2+ ions. is linear with time and with enzyme concentration. and is present in all mammalian cell lines and tissues tested. Gel filtration analysis of a partially purified preparation of protein farnesyltransferase revealed two peaks of activity at 250-350 kDa and 80-130 kDa. Availability of an in vitro protein farnesyltransferase assay should be useful in screening for potential inhibitors of ras oncogene function that will not interfere with other aspects of the mevalonate pathway.
p53 mutations in colorectal cancer, Immunohistological staining of primary colorectal carcinomas with antibodies specific to p53 demonstrated gross overexpression of the protein in approximately 50% of the malignant tumors examined. Benign adenomas were all negative for p53 overexpression. To determine the molecular basis for this overexpression we examined p53 protein expression in 10 colorectal cancer cell lines. Six of the cell lines expressed high levels of p53 in ELISA. cell-staining. and immunoprecipitation studies. Direct sequencing and chemical-mismatch-cleavage analysis of p53 cDNA by using the polymerase chain reaction in these cell lines showed that all cell lines that expressed high levels of p53 were synthesizing mRNAs that encoded mutant p53 proteins. In two of those four cell lines where p53 expression was lower. point mutations were still detected. Thus. we conclude that overexpression of p53 is synonymous with mutation. but some mutations would not be detected by a simple immunohistochemical analysis. Mutation of the p53 gene is one of the commonest genetic changes in the development of human colorectal cancer.
U1 small nuclear RNA plays a direct role in the formation of a rev-regulated human immunodeficiency virus env mRNA that remains unspliced, rev-regulated expression of HIV-1 envelope proteins from a simian virus 40 late replacement vector was found to be dependent on the presence of a 5' splice site in the env mRNA in spite of the fact that this mRNA remains unspliced. When the 5' splice site upstream of the env open reading frame was deleted or mutated. expression of envelope protein was lost. RNA analysis of cells transfected with 5' splice-site mutants showed a dramatic reduction in the steady-state levels of env mRNA whether or not rev was present. Envelope expression could be restored in one of the 5' splice-site mutants by cotransfection with a plasmid expressing a suppressor U1 small nuclear RNA containing a compensatory mutation. These experiments show that U1 small nuclear RNA plays a direct and essential role in the formation of an unspliced RNA that is subject to regulation by rev.
Levels of mRNA for a putative kainate receptor are affected by seizures, In situ hybridization and RNA blot-hybridization techniques were used (i) to examine the regional distribution of mRNA for a putative kainate receptor in adult rat brain and ii) to test the possibility that seizures affect expression of the receptor gene. The highest densities of hybridization were distributed within hippocampal pyramidal and granule cells. medial habenula. Purkinje cells and the molecular layer of cerebellum. and olfactory bulb. Recurrent limbic seizures caused a massive. delayed. and reversible reduction in levels of the kainate receptor mRNA in dentate gyrus; lesser decreases were found in pyramidal cell fields of hippocampus and superficial cortex. These findings provide evidence that unusual patterns of physiological activity can alter genomic expression for a subclass of glutamate receptors in brain.
Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris, Of 26 Ashkenazi Jewish patients with pemphigus vulgaris. 24 (92.3%) carried the major histocompatibility complex (MHC) class II alleles HLA-DR4. DQw3. of which all were of the subtype DR4. DQw8. From studies of the patients and their families. haplotypes were defined. It was found that. of the patients who carried HLA-DR4. DQw8. 75% carried one or the other (and in one case. both) of two haplotypes [HLA-B38. SC21. DR4] or HLA-B35. SC31. DR4. The former is a known extended haplotype among normal Jews. with a frequency of 0.102. and the latter may also be an extended haplotype in this ethnic group. with a frequency of 0.017 among normal haplotypes from Jews. Of the remaining DR4-positive patients. all but one had a presumed D-region segment (defined as SC21. DR4. DQw8 or SC31. DR4. DQw8 with variable HLA-B) of these haplotypes. Only one patient had DR4. DQw8 without any other markers of the extended haplotypes. The number of homozygotes and heterozygotes for DR4. DQw8 was consistent with dominant but not recessive (P less than 0.01) inheritance of a class II or a class II-linked susceptibility gene for the disease. Since the disease is entirely attributable to the presence of an antibody to an intraepidermal intercellular cement substance. it is likely that the class II susceptibility gene (on [HLA-B38. SC21. DR4. DQw8]. HLA-B35. SC31. DR4. DQw8. or their segments. in Jewish patients) controls the production of the antibody as a dominantly expressed immune response gene.
Evidence for susceptibility of intrathymic T-cell precursors and their progeny carrying T-cell antigen receptor phenotypes TCR alpha beta + and TCR gamma delta + to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion, Individuals infected by the human immunodeficiency virus type 1 (HIV-1) demonstrate progressive depletion and qualitative dysfunction of the helper T4 (CD4+) cell population. Mechanisms proposed for attrition of CD4+ T cells include direct cytopathicity of these mature cells following infection as well as infection of early T-lymphocyte progenitors. The latter mechanism could lead to failure to regenerate mature functioning CD4+ T cells. The present study determines the susceptibility of thymocytes at various stages of maturity to infection with HIV-1. Various normal thymocyte populations were inoculated with HIV-1. including unfractionated (UF). CD3- CD4- CD8- ["triple negative" (TN)]. CD4+ CD8+ ["double positive" (DP)] thymocytes. and thymocyte populations obtained by limited dilution cloning. Cultures were studied for the presence of HIV-1 DNA by polymerase chain reaction in addition to examination for reverse transcriptase activity. We determined that transformed T-cell and thymocyte cell lines completely lacking CD4 were not susceptible to infection by HIV-1. whereas all of the following lines were: UF thymocytes (70-90% CD4hi+); DP thymocytes (99% CD4hi+); TN thymocytes (0% CD4hi+); and TCR alpha beta +. TCR gamma delta +. or CD16+ CD3- (natural killer) thymocyte clones expressing variable levels of CD4 and representing the progeny of TN thymocytes. [TCR alpha beta + and TCR gamma delta + refer to the chains of the T-cell antigen receptor (TCR). and CD4hi refers to a strong rightward shift (greater than 30 linear channels) of the CD4 curve on flow cytometric analysis compared with control.] Monoclonal antibodies (mAbs) to CD4 (T4a epitope) but not to CD3 (T3) were capable of blocking infection of mature and immature CD4hi+ thymocytes. Moreover. anti-CD4(T4a) mAbs also inhibited infection of CD4hi- TN thymocytes. indicating that these T-cell precursors--despite their apparent "triple negativity" (CD3- CD4hi- CD8-)--expressed sufficient CD4 molecules to become infected. Cell sorter analysis with a panel of CD4 mAbs demonstrated a mean shift of the mean fluorescence channel (MFC) with CD4 mAbs on TN thymocytes of 6 +/- 4 MFC units. Thus. intrathymic T-cell precursors and their progeny representing many stages of T-cell ontogeny are susceptible to infection by HIV-1. including early TN thymocytes. which express very low levels of CD4. Infection of multiple stages and multiple subsets of the T-cell lineage in man. mediated via the CD4 molecule. may explain the inability of the T-cell pool to regenerate in the setting of progressive HIV infection.
Identification of three related human GRO genes encoding cytokine functions, The product of the human GRO gene is a cytokine with inflammatory and growth-regulatory properties; GRO is also called MGSA for melanoma growth-stimulatory activity. We have identified two additional genes. GRO beta and GRO gamma. that share 90% and 86% identity at the deduced amino acid level with the original GRO alpha isolate. One amino acid substitution of proline in GRO alpha by leucine in GRO beta and GRO gamma leads to a large predicted change in protein conformation. Significant differences also exist in the 3' untranslated region. including different numbers of ATTTA repeats associated with mRNA instability. A 122-base-pair region in the 3' region is conserved among the three GRO genes. and a part of it is also conserved in the Chinese hamster genome. suggesting a role in regulation. DNA hybridization with oligonucleotide probes and partial sequence analysis of the genomic clones confirm that the three forms are derived from related but different genes. Only one chromosomal locus has been identified. at 4q21. by using a GRO alpha cDNA clone that hybridized to all three genes. Expression studies reveal tissue-specific regulation as well as regulation by specific inducing agents. including interleukin 1. tumor necrosis factor. phorbol 12-myristate 13-acetate. and lipopolysaccharide.
Chemical carcinogenesis: too many rodent carcinogens, The administration of chemicals at the maximum tolerated dose (MTD) in standard animal cancer tests is postulated to increase cell division (mitogenesis). which in turn increases rates of mutagenesis and thus carcinogenesis. The animal data are consistent with this mechanism. because a high proportion--about half--of all chemicals tested (whether natural or synthetic) are indeed rodent carcinogens. We conclude that at the low doses of most human exposures. where cell killing does not occur. the hazards to humans of rodent carcinogens may be much lower than is commonly assumed.
Immunodominant regions for T helper-cell sensitization on the human nicotinic receptor alpha subunit in myasthenia gravis, In myasthenia gravis an autoimmune response against the nicotinic acetylcholine receptor (AChR) occurs. The alpha subunit of the AChR contains both the epitope(s) that dominates the antibody response (main immunogenic region) and epitopes involved in T helper cell sensitization. In this study. overlapping synthetic peptides corresponding to the complete AChR alpha-subunit sequence were used to propagate polyclonal AChR-specific T helper cell lines from four myasthenic patients of different HLA types. Response of the T helper lines to the individual peptides was studied. Four immunodominant sequence segments were identified--i.e.. residues 48-67. 101-120. 304-322. and 419-437. These regions did not include residues known to form the main immunogenic region or the cholinergic binding site. and they frequently contained sequence motifs that have been proposed to be related to T-epitope formation.
Conditioning of the spinal stretch reflex: implications for rehabilitation, The purpose of this article is to describe a new technique that can potentially be applied to patients with hyperactive spinal stretch reflexes (SSRs). The progression of clinical research from conditioning of individual muscles or muscle groups (electromyographic biofeedback) to conditioning SSRs is explained. Research data from subhuman primates in addition to the first human experiments are reviewed. Potential applications of SSR conditioning are discussed. as are the issues requiring further delineation and research before the specificity of a training effect can be ascertained.
The Le Fort III advancement osteotomy in the child under 7 years of age, This is a longitudinal study of 12 patients with craniofacial synostosis syndromes (Crouzon's. Apert's. Pfeiffer's) who underwent Le Fort III advancement under the age of 7 years (average age 5.1 years. range 4.0 to 6.7 years). The average follow-up was 5.0 years and included clinical. dental. and cephalometric examinations according to a prescribed protocol. The study demonstrated that the procedure could be safely performed in the younger child with an acceptable level of morbidity. There was a remarkable degree of postoperative stability of the maxillary segment. However. although vertical (inferior) growth or movement of the midfacial segment was demonstrated. there was minimal. if any. anterior or horizontal growth. Any occlusal disharmony developing during the period of follow-up could be attributed to anticipated mandibular development and could be corrected by orthognathic surgery. The roles of surgical overcorrection and anterior-pull headgear therapy after release of intermaxillary fixation are also discussed. The Le Fort III osteotomy is justifiably indicated during early childhood for psychological and physiologic reasons.
Histologic investigation of vascular malformations of the face after transarterial embolization with ethibloc and other agents, Twenty-one vascular malformations located in the facial area. 11 high-flow arteriovenous malformations and 10 slow-flow malformations. underwent combined treatment by embolization and later surgery. Embolization was performed simultaneously with superselective angiography of the branches of the external carotid artery. The new biodegradable fibrosing agent Ethibloc was used in 16 cases. Histologic examination of the surgical specimens confirmed the good target orientation by the transarterial injection of Ethibloc. Limitations of this technique are discussed. The agent proved to have thrombogenic and fibrogenic properties. Some of the vascular walls degenerated and ruptured following the embolization. but there were no instances of necrosis of interstitial tissue or skin. Embolization treatment of vascular malformations of the face was not curative. but it facilitated subsequent surgery in all examined cases.
One-stage closure of the entire primary palate, Timing of the closure of the anterior palate and alveolus is a subject of debate. Late repair of this defect is complicated by high fistula formation and subjects the patient to the problems of palate fistula for extended periods of time. We have utilized a single procedure performed when the child is 3 months of age that completely closes the anterior hard palate and alveolus along with the cleft lip. Our series consisted of 61 consecutive patients with unilateral clefts of the primary and secondary palate. Mucosal turnover flaps from the vomer along with lateral nasal mucosal flaps provide the nasal lining. A buccal sulcus flap with a Veau flap completes the oral repair. Ninety-five percent (58 of 61) of the patients had complete and stable closure of their anterior palate and alveolus after 1 year. The incidence of fistula formation in our series (3 of 61) is much lower than that reported with the utilization of other protocols. Excellent exposure of the anterior palate and alveolar defect during lip repair. early restoration of anatomic relationships. establishment of a good nostril floor and sill. and very low fistula formation are among the benefits of this procedure. The increase in operative time is considered minimal in light of aforementioned advantages.
Retro-orbicularis oculus fat (ROOF) resection in aesthetic blepharoplasty: a 6-year study in 63 patients, Sixty-three nonconsecutive patients have undergone resection of the retro-orbicularis oculus fat (ROOF) in conjunction with aesthetic blepharoplasty. In these patients. a consistent and useful ability to soften and flatten heaviness and bulkiness in the lateral upper orbital region was seen. Two patients developed postoperative hematoma. and two different patients had transient dry-eye symptoms following blepharoplasty. Twenty percent of patients had a transient degree of numbness in the lateral supraorbital nerve region. and all patients noted some transient numbness over the lateral upper brow region. No patient demonstrated significant paralysis of the orbicularis oculus or corrugator muscle. From this experience. retro-orbicularis oculus fat resection would appear to be a useful adjunct to standard blepharoplasty techniques in selected patients.
Augmentation mammaplasty by means of the transrectus route, A new operative technique has been developed for augmentation mammaplasty. Through an inframammary incision. the anterior rectus sheath is entered. and the pocket is dissected in an entirely submuscular plane. We have performed this procedure in 112 patients to date. Complications have been few. The capsular contracture rate in 90 patients followed for greater than 1 year is 7 percent. The inframammary crease can be lowered using this technique. making mastopexy unnecessary in most patients with moderate ptosis.
Polyurethane foam-covered implants and capsular contracture: a laboratory investigation, Experiments were conducted in rabbits comparing polyurethane foam-covered implants with otherwise identical smooth silicone gel implants. Using five objective methods of measurement of capsular contracture. no significant difference could be identified. The foam-covered implants consistently developed capsular contracture. although in most cases this was of mild degree and would not have been clinically significant. In the two foam-covered implants with hard contractures. there was no evidence of hematoma or separation of the foam.
Surgical augmentation of skin blood flow and viability in a pig musculocutaneous flap model, A porcine rectus abdominis musculocutaneous (TRAM) flap model was designed and validated in nine pigs. This TRAM flap was based on the deep inferior epigastric (DIE) vessels with an 8 x 18 cm transverse skin paddle at the superior end of the rectus abdominis muscle. The model was subsequently used to test our hypothesis of surgical augmentation of flap viability by vascular territory expansion. Specifically. we observed that ligation of the superior epigastric (SE) vessels at 4. 7. 14. and 28 days (N = 6 to 8) prior to raising the TRAM flaps significantly increased (p less than 0.05) the length and area of the viable skin in the transverse skin paddles of the treatment flaps compared with the contralateral shammanipulated control flaps. This significant increase in skin viability was seen to be accompanied by a significant increase (p less than 0.05) in skin and muscle capillary blood flow in the treatment TRAM flaps compared with the controls (N = 9). The mechanism of vascular territory expansion is unclear. We postulate that hypoxia resulting from the ligation of the superior epigastric vessels prior to the flap surgery may play a role in the triggering of the deep inferior epigastric artery to take over some of the territory previously perfused by the superior epigastric artery. This would then increase the skin and muscle capillary blood flow in the transverse paddle when the TRAM flap was raised on the deep inferior epigastric vascular pedicle.
Critical ischemia times and survival patterns of experimental pig flaps, Previous work on critical ischemia time suggested (1) a greater susceptibility of myocutaneous flaps over skin flaps to the ischemia reperfusion injury and (2) that duration of ischemia may affect the survival area of a flap. Using a pig model. 55 animals were operated on and the critical ischemia times and survival patterns of the buttock skin (n = 85) and latissimus dorsi myocutaneous (n = 88) island flaps were determined after being submitted to 0. 2. 4. 6. 8. 10. 12. 14. and 16 hours of normothermic ischemia. The average critical ischemia times (CIT50) were determined to be 9 and 10 hours for the buttock skin and latissimus dorsi myocutaneous flaps. respectively. Percentage of total area surviving (%TAS) in those flaps which did survive was adversely affected by increases in the ischemic interval in both flap models. A statistically significant decrease in percentage of total area surviving was found after 6 and 8 hours of ischemia for the buttock skin and latissimus dorsi myocutaneous flaps. respectively.
Comparison of lymphatic and venous interpositional autografts in experimental microsurgery of the canine lymphatics, In mongrel dogs. 56 autologous lymphatic and vein grafts were interpositioned to bridge a defect in the femoral collecting lymphatics. In one group. 26 lymphatic autografts were interpositioned with good results. No obstruction was observed over 6 months. In another group. 20 venous autografts were interpositioned after irrigation with heparinized saline and another 10 autografts were interpositioned without irrigation. After 1 week. four irrigated grafts were partially occluded with a red thrombus; after 6 months. all grafts were totally occluded. In a third group. 15 lymphaticolymphatic anastomoses were enveloped by a silicone sheet to provoke prolonged devascularization. None of the vessels was patent. Anastomotic patency was inspected in vivo postoperatively. The specimens were studied with light microscopy and scanning and transmission electron microscopy. Prolonged devascularization damaged the endothelial cells. The results show that the lymphatic vessel autograft is the best choice for an interpositional autografting to bridge a defect in lymphatic vessels.
Intracerebral hematoma complicating split calvarial bone-graft harvesting, A case is reported of an intracerebral hematoma following the harvest of split calvarial bone. Full recovery by the patient occurred. Complications following calvarial bone graft harvest are reviewed. Potential devastating complications warrant serious consideration of alternative sources of bone. especially in the purely elective surgical candidate.
Congenital lateral cleft palate: a new anomaly, A case of atypical cleft palate abnormality that had not been identified before in a 9-year-old girl is presented. The cleft was localized laterally and in an oblique position at the soft palate. The patient had cleft palate repair. Finally. she had acceptable soft palate movements and speech.
New treatment for frontal sinus hypertrophy, A new treatment of frontal sinus hypertrophy is described. The anterior wall is removed. inverted. and attached again. The resulting depression is filled with bone dust. Details are discussed. and a case is presented.
A trilaminar skin coverage technique for treatment of severe degloving injuries of the extremities and torso, A 60 percent degloving injury involving the torso and lower extremities of an 8-year-old boy is described. Successful management employed the use of a new trilaminar skin coverage technique. With the avulsed flap still attached to its bed. a 0.14-inch split-thickness graft of epithelium and superficial dermis is raised with a power-driven dermatome. From the same harvest site. one level deeper. a second layer consisting of split-thickness dermis (0.14 inch) is taken. Both the first and second layers are meshed and expanded. The remaining degloved flap is excised and. on a sterile bench. defatted to produce a third layer of deep dermis. In our case. this third layer was ultimately lost. but it functioned well as a temporary biologic dressing. Depending on donor-site morbidity. other potential applications of this method (i.e.. major burn injuries) may be feasible.
An angiographic technique for three-dimensional determination of arterial supply patterns in cadaver soft tissue, A method for arterial tree mapping that can be used in cadaver soft tissue is presented. In situ angiograms and photographs are supplemented with profile angiograms of relatively narrow bands of tissue from the removed specimen. The described method was better suited for mapping the course and supply patterns of a soft-tissue arterial network than either in situ angiograms or dissection. While practical problems were encountered with most of the solutions used for providing radiopacity or structural support to the vessels. pure barium sulfate was found to be suitable because it filled the vascular tree to the capillary level without leakage during excision of the specimen.
Haemopoietic growth factors, The availability of recombinant haemopoietic growth factors has permitted more precise in vitro experiments and human in vivo studies to be performed. In general. the results have been in accord with expectations from previous in vitro studies. The clinical exploitation of the haemopoietic growth factors offers great promise but careful studies are required to define their value. The effects of some growth factors are multiple and complex. and it cannot be assumed that improvements in blood cell counts are per se beneficial to the patient under all circumstances. Randomized controlled trials with clinical end-points are now essential. In the situation of chemotherapy-induced neutropenia. large studies would be required to show an improvement in mortality although lesser morbidity would be easier to demonstrate. In the field of cancer therapy the major benefit of the haemopoietic growth factors will be if they permit dosage escalation and there is a consequent improvement in response rate and long-term survival. This will require careful patient selection and large. probably multicentre. trials. It is also likely that such studies will be limited by the development of severe thrombocytopenia and an effective means to ameliorate this (perhaps the elusive thrombopoietin) will be required. The possibility of using haemopoietic growth factors as an adjunct to the treatment of severe infections is enticing. but designing a trial to evaluate this possibility is fraught with difficulties. Finally. it must be noted that all the studies reported to date use single factors. This is just the beginning and the use of other factors and synergistic combinations may give greater efficacy without increased toxicity.
Wilson's disease: 35 years' experience, Thirty-seven Chinese patients fulfilling the criteria for Wilson's disease seen during a 35-year period were reviewed. Males and females were equally affected. Twenty-two patients were symptomatic and 15 asymptomatic; most of them presented before the third decade. Thirty-one per cent of the relatives screened showed evidence of disease. and parents were rarely affected (13 per cent). Half of the adult symptomatic females presented with primary amenorrhoea. Liver laboratory tests were abnormal in only 50 per cent of patients. with gamma-glutamyltranspeptidase being the most sensitive index. Renal disease was infrequent. Serum caeruloplasmin level was the single biochemical parameter of prognostic significance (p = 0.0001). Seventy per cent of the symptomatic patients showed an improvement after treatment with penicillamine.
Clinical, autonomic and therapeutic observations in two siblings with postural hypotension and sympathetic failure due to an inability to synthesize noradrenaline from dopamine because of a deficiency of dopamine beta hydroxylase, A brother and sister with long-standing symptoms of postural hypotension are described. They were considerably worse in the morning. after exercise and in warm weather. In the male. erection was unaffected but ejaculation was prolonged or absent. Both had nocturia. but there were no urinary bladder. bowel or sweating abnormalities. Autonomic function tests confirmed sympathetic adrenergic failure with spared sympathetic cholinergic and intact parasympathetic function. There were no other neurological abnormalities. Noradrenaline and adrenaline were undetectable in the plasma. but plasma dopamine was elevated. Urinary levels of noradrenaline and adrenaline metabolites were below detection limits. but dopamine metabolites were normal or elevated. Dopamine beta-hydroxylase activity was undetectable in the plasma. Immunohistochemical studies of perivascular cutaneous tissue confirmed normal peptidergic and tyrosine hydroxylase immunoreactivity. with absent dopamine beta-hydroxylase immunoreactivity. The findings were consistent with an enzymatic deficit in the conversion of dopamine to noradrenaline. The parents were clinically and biochemically normal. Treatment of both patients with the synthetic amino acid. d-l-threo-dihydroxyphenylserine. which contains a hydroxyl group and is converted to noradrenaline by dopa-decarboxylase. reduced symptoms and signs of postural hypotension and increased levels of plasma noradrenaline and its urinary metabolites. In the male. ejaculation became possible. Behavioural changes included a feeling of confidence and optimism. with a tendency to be argumentative. The laevo isomer also raised blood pressure and plasma noradrenaline levels. The drug had no direct pressor effects. as its actions were prevented by the dopa-decarboxylase inhibitor. carbidopa.
A study to assess the efficacy of chemoprophylaxis in the prevention of endoscopy-related bacteraemia in patients aged 60 and over, Five hundred and fifteen patients aged 60 and over (mean age 74.7; 278 men and 237 women) underwent routine endoscopic procedures (gastroscopy. bronchoscopy and cystoscopy). Alternate patients were given antibiotics before the procedure. as currently recommended. and blood was taken for culture from all patients within five minutes of completion of the procedure. Of 74 patients who underwent bronchoscopy. only one culture. from one of 37 controls was positive. Of 262 who underwent gastroscopy. cultures were negative in the 130 who received antibiotics but positive in 13 of the 132 controls (9.8 per cent p less than 0.001). Cystoscopy was performed in 179; one culture was positive in the 88 given antibiotics (1.1 per cent) compared to 25 in the 91 controls (27.5 per cent; p less than 0.001). Bacteraemia rates appear to be low following bronchoscopy (less than 5 per cent) but higher with gastroscopy (10 per cent) and cystoscopy (28 per cent). Chemoprophylaxis was effective in reducing these rates in this patient group.
Final outcome of ursodeoxycholic acid treatment in 126 patients with radiolucent gallstones, One hundred and twenty-six patients with radiolucent gallstones in 'functioning' gallbladders were treated with 8-10 mg ursodeoxycholic acid (UDCA) kg/day and followed to a treatment conclusion. Complete or partial gallstone dissolution was achieved in 74 (59 per cent). However. only 22 achieved complete gallstone dissolution. as judged by two normal oral cholecystograms; ultrasonograms were performed in 16 of these patients. and all were normal. UDCA was stopped in 76 patients: because of cystic duct obstruction (n = 12). severe biliary pain (n = 13). non-response (n = 25) or partial stone dissolution with arrested progress (n = 26). Life-table analysis showed that complete gallstone dissolution rates at four years were 25-30 per cent (two normal oral cholecystograms) and 17-19 per cent (two normal oral cholecystograms plus one ultrasonogram). All patients with complete gallstone dissolution had shown partial stone dissolution at 6-12 months; of those with partial stone dissolution at six months. only 25 per cent went on to complete gallstone dissolution. and then always within two years. Efficacy correlated inversely with stone size but not with age. sex. obesity or on-treatment saturation indices. Acquired surface gallstone calcification developed in 13 patients (life-table analysis 22 +/- 7 per cent at four years); none of these patients achieved complete gallstone dissolution and only five achieved partial stone dissolution. Thus. despite relatively high partial gallstone dissolution rates. the ultimate efficacy of UDCA in achieving complete gallstone dissolution is low.
Clinical diagnosis of tamponade in Malawi, A consecutive series of 25 Malawian patients with tamponade secondary to tuberculosis were compared to 25 patients with congestive cardiac failure. without pericardial effusion in a retrospective study. More patients with tamponade had an impalpable apex beat (21/1). pulsus paradoxus (13/0). soft heart sounds (13/2). paradoxical rise in jugular venous pressure (6/0). and fewer had a murmur (1/14). All these results are significant (p less than 0.05) by the chi 2 test with Yates' correction. The presence of two or more of these discriminating physical signs has a positive predictive value of 75 per cent. and a negative predictive value of 99.5 per cent for the diagnosis of tamponade. Clinical diagnosis of tamponade by primary health care personnel in Malawi should be possible. and lead to earlier treatment.
Double-blind randomized study of prolonged higher-dose oral amoxycillin in purulent bronchiectasis, Thirty-eight patients with bronchiectasis and daily expectoration of purulent sputum despite conventional antibiotic courses were randomly allocated to receive a sachet of amoxycillin (3 g) or matched placebo twice daily for 32 weeks in a double-blind study. Nine patients (four amoxycillin. five placebo) were withdrawn from the study treatment; the response of the two patients (both on amoxycillin) withdrawn within the first six weeks was not assessed. The pretreatment characteristics of the two groups were similar. Independent assessment of overall response based on patients' diary cards showed that a higher proportion improved in the amoxycillin group (11 of 17) than in the placebo group (four of 19; p = 0.02). Patients in the amoxycillin group spent significantly less time confined to bed and away from work during treatment. The frequency of exacerbations during the study treatment phase was similar in the two groups but they were less severe than before study treatment in the amoxycillin group. There was a greater reduction in purulent sputum volume between exacerbations during the study treatment in the amoxycillin group to 20 per cent of pretreatment volume than in the placebo group (88 per cent of pretreatment volume. p = 0.008). although the concentrations of Haemophilus spp. in sputum between exacerbations was similar in the two groups. Adverse effects experienced were minor except in one patient (amoxycillin) withdrawn after developing a rash and in six patients (three amoxycillin. three placebo) who had diarrhoea lasting more than one week necessitating withdrawal of two patients (one amoxycillin. one placebo) from study treatment. Sputum and stool cultures collected regularly during the study showed no important changes in the bacterial flora in either group. Prolonged higher-dose antibiotic therapy in these patients with severe purulent bronchiectasis significantly reduced the host (patient) inflammatory response to colonizing microorganisms and reduced morbidity.
Defect in thermoregulation in malnutrition reversed by weight gain. Physiological mechanisms and clinical importance, Previous studies in infants and in the elderly have shown that a low body weight is associated with a defect in thermoregulation and an increased risk of hypothermia. In the present study. thermoregulatory responses to a cooling stimulus were measured in 10 young and middle-aged patients who lost at least 10 per cent of their body weight during illness. Investigations were performed before and after restoration of body weight (mean weight gain 7.2 kg. SE 1.2 kg. p less than 0.001). The cooling stimulus was provided by a special suit perfused with water at 28 degrees C and then at 23 degrees C. Before weight gain. there was no increase in metabolic rate in response to cooling. despite a fall in core temperature. Following weight gain. the thermogenic response to cooling was restored towards normal. Peripheral vasoconstriction. the principal mechanism for heat conservation. was similar before and after weight gain. The thermogenic response to an infusion of adrenaline (25 ng/kg/min) was not abolished by weight loss. suggesting that the defect in cold-induced thermogenesis following weight loss is due to a change in central control mechanisms of thermoregulation. and not to tissue unresponsiveness. The phenomenon of abnormal thermoregulation following weight loss and the return to normal with subsequent weight gain may be clinically important. particularly in the elderly. since quite small falls in core temperature may impair both neuromuscular coordination and cerebral function.
Subacute sclerosing panencephalitis in black children--a review of 18 cases, Despite the fact that measles is severe and presents in very young Black children in Natal. South Africa. no case of subacute sclerosing panencephalitis was reported from this region prior to 1982. A retrospective study was therefore made over the six-year period 1982-1987 of 18 patients who presented to the King Edward VIII teaching hospital. Durban. with clinical and laboratory features of subacute sclerosing panencephalitis. The majority of patients (66 per cent) were between 8 and 12 years of age. The mean age of onset was 9.3 years. the youngest patient being four years nine months and the oldest 14 years. The male to female ratio was 1.25:1. A previous history of primary measles infection was obtained in 44.4 per cent of cases; 62.5 per cent occurred before the second birthday. The commonest mode of presentation was personality. intellectual and behaviour disorders (83 per cent) followed by myoclonic seizures (61 per cent) and choreiform movements (28 per cent). Measles antibody was present in the CSF in all cases. The EEG was abnormal in all recorded cases with pathognomonic periodic complexes being found in 56.2 per cent. Confirmation of the diagnosis was provided by brain biopsy in two cases and by necropsy in one case. The findings of this study suggest that subacute sclerosing panencephalitis may not be as uncommon in Black children as has hitherto been thought.
The source and significance of raised serum enzymes in rheumatoid arthritis, Hepatobiliary dysfunction in rheumatoid arthritis has been suggested on the basis of raised serum activity of alkaline phosphatase. 5-nucleotidase. lactic dehydrogenase and gamma-glutamyl transferase. but a specific pathological lesion has not been demonstrated and serum transaminases and bilirubin are almost invariably normal. This paper reports a series of studies designed to determine the tissues of origin of the enzymes and offers an alternative interpretation of the enzymological findings. The results suggest that only alkaline phosphatase originates from the liver. while lactic dehydrogenase and 5-nucleotidase originate from synovial fluid polymorphs and synovial lining cells. respectively. Serum alkaline phosphatase may be induced by inflammatory mediators such as interleukin-1 because it correlates with the acute phase response. Serum lactic dehydrogenase is an integrated measure of polymorph lysis in all joints and offers a marker of joint inflammation more specific than measures such as the ESR. Levels of serum 5-nucleotidase provide information about the activity of the synovium. Finally. because hepatic necrosis does not normally occur. the transaminases may be used to monitor drug toxicity.
Pinch-off syndrome: a complication of implantable subclavian venous access devices, Implantable central venous access devices placed via the subclavian vein may become obstructed by thrombosis. impingement against a vein wall. or compression between the clavicle and first rib. The latter has been termed pinch-off syndrome (POS). Eleven patients with POS were studied. including one whose catheter had fractured and one whose catheter had fragmented. They were compared with 22 matched control patients and 100 consecutive routine clinic patients. Each catheter was graded: 0 = normal. 1 = abrupt change in course with no luminal narrowing. 2 = luminal narrowing. and 3 = complete catheter fracture. POS was present in most (eight of 11) cases within 3 weeks after placement. A grade 1 catheter was common (33%) among control subjects. but grades 2 and 3 were uncommon (1%). Catheter fracture or fragmentation was seen in two of five cases with long-term (greater than 3 weeks) pinching (grade 2 catheter). The following conclusions were reached: Grade 2 represents significant catheter compression and the potential for serious complications. Grade 1 is of uncertain clinical significance. due to its high prevalence in control subjects.
Hemoptysis: CT-bronchoscopic correlations in 58 cases, Computed tomographic (CT) and chest radiographic findings were retrospectively correlated with those found at fiberoptic bronchoscopy (FOB) in 58 patients presenting with hemoptysis. Abnormalities involving the airways were depicted by CT in a total of 28 cases (48%). In 18 of these (31% of the total group of 58). focal abnormalities involving the central airways were identified (17 were subsequently proved to be malignant) and in 10 (17% of the total). CT showed bronchiectasis. Focal airway abnormality was shown by FOB in 18 cases (31%); all of these were depicted with CT. Malignancy was diagnosed in 24 patients. including three in whom results of FOB were normal but malignant cells were identified at transbronchial biopsy. CT abnormalities were identified in all cases of malignancy. In 10 of 21 cases (48%) of non-small cell lung cancer. CT allowed definitive staging by documenting either direct mediastinal invasion and/or metastatic disease. while FOB allowed definitive staging in only three cases. CT studies provided no false-negative results. It is concluded that when carefully performed. CT may be an effective modality for evaluating patients presenting with hemoptysis.
Coal worker's pneumoconiosis: CT assessment in exposed workers and correlation with radiographic findings, To study the signs of coal worker's pneumoconiosis (CWP) at computed tomography (CT). the authors obtained thoracic CT scans in 170 coal-dust-exposed workers who were concomitantly evaluated with conventional posteroanterior and lateral radiography. The profusion and extent of disease was assessed by means of CT in two groups of miners: group 1 (n = 86). miners with worker's compensation and radiographic evidence of CWP. and group 2(n = 84). miners who had applied for compensation without radiographic evidence of CWP. The CT signs of CWP consisted of micronodules. nodules. and progressive massive fibrosis. The comparative analysis demonstrates the superiority of an optimal CT technique over chest radiography in the evaluation of simple silicosis. with improved sensitivity in the detection of small parenchymal opacities. CT provides additional information on the stage of the disease but also clarifies some ambiguities of the ILO classification of small opacities. CT was equivalent to radiography for complicated silicosis. except in the identification of necrosis. CT evaluations are complementary to plain radiography in the assessment of CWP. and the addition of high-resolution CT is useful in achieving a more accurate evaluation of the small parenchymal opacities.
Gd-HP-DO3A in clinical MR imaging of the brain, As part of a phase II clinical trial. 14 patients with presumed intracranial neoplastic disease underwent magnetic resonance (MR) imaging before and after intravenous injection of gadolinium 1.4.7-tris(carboxymethyl)-10-(2'-hydroxypropyl)-1.4.7.10-tetraazacycl ododecane (HP-DO3A). This neutral (nonionic) gadolinium chelate has lower osmolality. when formulated at equimolar concentrations. and superior in vitro stability compared with gadopentetate dimeglumine. The safety profile of Gd-HP-DO3A permitted administration of doses up to 0.3 mmol/kg. three times the dose of gadopentetate dimeglumine approved by the U.S. Food and Drug Administration. In this limited clinical trial. Gd-HP-DO3A proved to be a safe and efficacious agent in MR imaging of the head. The only change documented in patient monitoring was that of slight skin redness at the injection site immediately after administration in two patients. No statistically significant changes due to administration of the agent were noted in laboratory evaluations. These results differ from those obtained with gadopentetate. which induces a transient rise in serum iron and bilirubin levels in up to 26% of patients. Administration of higher doses of Gd-HP-DO3A. either 0.2 or 0.3 mmol/kg. appeared to provide improved enhancement. No decrease in efficacy at these high doses was noted.
The cloacal malformation: radiologic findings and imaging recommendations, The imaging studies and records of 65 patients with the cloacal malformation seen from 1969 to 1989 were reviewed. The malformations were described according to cloacal configuration (urethral. vaginal). type of urinary-cloacal communication (urethral. vesical). and level of rectal communication (vaginal. cloacal. vesical. other). Lower urinary tract abnormalities were frequent (reflux. ureteral ectopia. bladder diverticula. bladder duplication. urachal remnants. urethral duplication). as were genital abnormalities (uterine duplication. vaginal duplication. uterine atresia. vaginal atresia). abnormalities of the bony pelvis (partial sacral agenesis. pubic diastasis). and renal abnormalities (agenesis. obstruction. horseshoe kidney). Contrast material studies of the cloaca and the distal limb of the colostomy with fluoroscopy in various projections were essential for diagnosis. Voiding cystourethrography was important for detecting vesicoureteric reflux. Sonography was of limited value for evaluation of the malformation but was valuable for imaging the kidneys. MR imaging revealed that spinal cord abnormalities cannot be predicted based on the appearance of the lumbosacral spine and are more common than previously thought.
Primary Ewing sarcoma: follow-up with Ga-67 scintigraphy, While avid accumulation of gallium-67 citrate and technetium-99m methylene diphosphonate (MDP) occurs initially in most cases of primary Ewing sarcoma. uptake after therapy is less well defined. Thirty patients with Ewing sarcoma who underwent Ga-67 and bone scintigraphy at diagnosis. at completion of therapy. and at relapse from 1978 to 1988 were evaluated. All 30 patients showed less primary site Ga-67 activity following therapy. Twenty-three of 28 patients who underwent corresponding bone scintigraphy showed less uptake. but residual activity was usually more intense than with Ga-67. Avid reaccumulation of Ga-67 occurred in four of five patients with primary site relapse. while patients who underwent bone scintigraphy showed less change. It was concluded that a greater decrease in Ga-67 than in Tc-99m MDP uptake often occurs in patients successfully treated for primary Ewing sarcoma. Information obtained at Ga-67 scintigraphy is most likely to be helpful if results of bone scintigraphy remain abnormal or if occult relapse is suspected.
Dermatomyositis: correlative MR imaging and P-31 MR spectroscopy for quantitative characterization of inflammatory disease, Magnetic resonance (MR) imaging and phosphorus-31 MR spectroscopy were used to examine four patients with dermatomyositis and five control subjects. T2-weighted images of the thigh muscles of patients showed increased signal intensity. with focal and inhomogeneous involvement predominantly in the vastus lateralis and secondarily in the vastus intermedius and vastus medialis. T1 and T2 values of the vastus lateralis in patients were significantly higher than those of the control subjects. T1 values of the rectus femoris and biceps femoris with more generalized inflammation were moderately elevated but still significantly higher than those of the control subjects. P-31 MR spectra of the quadriceps muscles were obtained during rest. during exercise at two graded levels. and in recovery. Concentrations of adenosine triphosphate and phosphocreatine (PCr) in the diseased muscles were 30% below normal values. and the inorganic phosphate/PCr ratios were increased in the patients' muscles at rest and throughout exercise. The T1 and T2 values as well as the P-31 metabolite data correlated with symptoms and clinical assessment.
Experimental treatment of benign prostatic hyperplasia with transurethral balloon dilation of the prostate: preliminary study in 73 humans, A prospective noncontrolled study of the safety and potential efficacy of transurethral balloon catheter dilation of the prostate (TUDP) in the treatment of benign prostatic hyperplasia (BPH) was performed in 73 subjects with moderate to severe symptoms and signs of prostatism who were selected on the basis of a quantitative symptom score (SS). uroflowmetry measurements. and residual urine volume. Seven patients had urinary retention. Mean age was 69.6 years (range. 59-95 years). TUDP was successfully accomplished in 70 patients (96%). There were no significant complications. Mean follow-up was 16.2 months (range. 6-36 months). Forty-six patients (66%) showed improved SS at the most recent follow-up. In 24 patients (34%) SS was unimproved. necessitating prostatectomy in 17 subjects (24%). Reduction in mean residual urine volume was not statistically significant. Only 38% of patients with median lobe enlargement showed improvement in SS. compared with 74% for the others. The authors conclude that TUDP is safe and shows promising effectiveness and that the ultimate demonstration of effectiveness requires a controlled clinical trial.
Intrauterine growth retardation: diagnosis based on multiple parameters--a prospective study, A scoring system has previously been developed to diagnose intrauterine growth retardation (IUGR) based on three parameters: estimated fetal weight. amniotic fluid volume. and maternal blood pressure status. To test the IUGR score prospectively. the authors computed the score in 356 third-trimester fetuses. 39 growth retarded and 317 normal. scanned within 2 weeks prior to delivery. The IUGR score identified three groups. each with a distinct probability of IUGR: A score below 50 virtually excludes IUGR (3% probability). a score above 60 allows confident diagnosis (74% probability). and score of 50-60 is indeterminate (13% probability). The IUGR score performed best in patients with accurate dating by early ultrasound (US). but even among patients lacking accurate dating. the performance of the IUGR score was superior to that previously reported for any single sonographic parameter. The IUGR score can be used in any US facility to diagnose or exclude third-trimester IUGR.
Lower extremity venography with iohexol: results and complications, The frequency of side effects of a nonionic contrast agent (iohexol) was studied in 463 consecutive patients who underwent venography for clinically suspected deep-vein thrombosis (DVT) and compared with the frequency of adverse reactions of another series in which patients received either the same contrast material or a high-osmolar ionic compound. Minor side effects. including local pain and discomfort. nausea and vomiting. dizziness. skin reactions. superficial phlebitis. and edema. occurred in 83 patients (17.9%; 95% confidence interval [CI]. 15%-22%). The only serious adverse reaction (bronchospasm) was seen in two patients (0.4%; 95% CI. 0.1%-1.4%). Postvenographic thrombosis confirmed by means of repeat venography occurred in one of 41 consecutive patients with a previous normal venogram (incidence. 2%; 95% CI. 0%-13%). The frequency of side effects appears to be significantly less than when conventional high-osmolar contrast agents are used. Use of iohexol for venography is associated with minor side effects in approximately one-fifth of patients. and serious adverse reactions necessitating therapy are rare.
Biliary lithotripsy: in vitro analysis of gallstone fragmentation for equivalent stone volumes, The relationship between gallstone fragmentation during extracorporeal shock wave lithotripsy (ESWL) and gallstone volume is poorly understood. Clinical results of ESWL show that the highest stone-free rate at 6 months occurs with radiolucent single gallstones 20 mm or less in diameter. In an in vitro study. individual gallstones from cholecystectomy specimens were divided by size and composition into nine single- and nine multiple-stone groups; the stones were then paired on the basis of similar volume. ESWL was performed in a phantom and the size of the largest fragment was measured at 500. 1.000. and 1.500 shock waves. At 1.500 shock waves. sandlike particles were present in six of nine single stones versus two of nine multiple stone groups; the mean size of the largest fragment at 1.500 shock waves was 2.1 mm (single) and 4.4 mm (multiple) in diameter. When corrected for volume. the authors' data suggest that single stones are more easily broken into fragments smaller than 5 mm in diameter than multiple gallstones. The implication. especially when spark-gap technology is used. is that more shock wave energy (ie. an increased number of shock waves at a higher kilovoltage) will be necessary to achieve the same results when treating patients with multiple stones versus a single gallstone with a similar stone volume.
Rectal carcinoma: CT staging with water as contrast medium, Computed tomography (CT) was used to study 42 patients with rectal carcinoma. Water was used as a contrast medium for studying the local extent of tumor in all patients. Scans were read prospectively without knowledge of the histologic staging and then compared with pathologic specimens. CT depicted the tumor in all patients. Comparison of CT and histologic results (following the Dukes classification) showed that disease was correctly staged as A in three of four patients. as B in eight of 12. as C in 15 of 17. and as D in nine of nine. Overall. carcinoma was correctly staged with CT in 35 of 42 patients (diagnostic accuracy. 83.3%). The accuracy in the assessment of local invasion was 97.6% (41 of 42). In the detection of lymph node involvement. the accuracy was 78.6% (sensitivity. 88%; specificity. 64.7%). CT is recommended in the preoperative staging of rectal carcinoma and as an aid in choosing the appropriate therapy. The use of water enema and complete distention of the rectum are reliable techniques for improving the accuracy of CT in the assessment of local invasion by cancer.
Mitral stenosis: evaluation with MR imaging after percutaneous balloon valvuloplasty, To evaluate the pathoanatomic findings of mitral valve stenosis and changes after percutaneous balloon valvuloplasty (PBV). magnetic resonance (MR) imaging was performed in 23 patients. The patients were imaged with a 2.0-T system within 1 week before and 3-10 days after PBV. The angle of the interatrial septum was measured on the transverse image to facilitate a successful transseptal puncture. On MR images. the mean transverse and anteroposterior diameters of the left atrium at the level of the aortic root in the ventricular diastolic phase decreased significantly after PBV. Areas of flow-related intraluminal signal intensity detected in the left atrial cavity of 17 patients (74%) before the procedure disappeared in 15 patients after the procedure. Other MR imaging findings after PBV were the disappearance of intraluminal signal intensity in the pulmonary artery. normal curvature of the interatrial and interventricular septa. and pericardial effusion as a complication. MR imaging was thought to provide useful information before and after PBV in patients with mitral stenosis.
Vena caval flow: assessment with cine MR velocity mapping, The authors used cine magnetic resonance (MR) velocity mapping to study flow in the superior vena cava (SVC) and inferior vena cava (IVC) of 13 healthy control subjects and 13 patients with right-sided cardiac disease. In the control subjects. peaks of flow in systole and diastole were observed. and mean SVC flow was 35% of the cardiac output. Respiratory gating was used in six control subjects to acquire images at end inspiration and end expiration. and although the systolic peak was reduced at end expiration. total flow was unchanged. A reduced systolic peak and retrograde flow in the IVC were observed in patients with tricuspid regurgitation. A reduced diastolic peak was seen in patients with pulmonary hypertension. pericardial constriction. and right ventricular dysplasia. reflecting reduced diastolic compliance of the right ventricle. In the patient with obstruction of the SVC. absence of flow was confirmed. and retrograde flow was seen in the azygos vein. The authors believe that cine MR velocity mapping is a reliable method of studying vena caval flow noninvasively and that it has important potential applications for the investigation of disorders of the right side of the heart.
Evolution of deep venous thrombosis: a prospective evaluation with US, Forty-six patients with a diagnosis of acute deep venous thrombosis (DVT) established by means of duplex ultrasound (US) were prospectively followed up with serial duplex US examinations during a 6-month period to assess the persistence of venous abnormalities. All patients were asymptomatic. Isolated popliteal DVT was found to be more likely to revert to normal at duplex compression US than thrombosis involving both the femoral and popliteal systems (P less than .05). Increased venous diameter was a sign of acute clot (P less than .005). Clot echogenicity did not help to enable distinction of acute DVT and chronic DVT. At compression US. 10 of 21 patients (48%) who initially had occlusive thrombosis had persistent abnormalities that mimicked findings consistent with acute DVT. Chronic venous changes that persisted after 6 months consisted of either lumen recanalization (with resultant intimal thickening) or persistent venous occlusion. Both of these conditions can result in incomplete compression. the major US indication of acute DVT. This appearance should not be confused with that of acute DVT. Follow-up examinations to establish a baseline appearance can be obtained as early as 6 months after an acute episode of DVT.
Effect of somatostatin analogue (octreotide) on blood flow to endocrine tumors metastatic to the liver: angiographic evaluation, The effect of an octapeptide analogue of somatostatin. octreotide. on tumor blood flow was evaluated with angiography in eight patients with hepatic endocrine tumors; one patient had primary intrahepatic gastrinoma. two patients had hepatic metastases from gastrinomas. two patients had VIPomas (vasoactive intestinal polypeptide-secreting tumor). and three patients had carcinoid tumors. Octreotide caused a marked decrease in tumor blood flow in two patients with gastrinomas and two with VIPomas. One patient could not be evaluated due to the lack of a tumor blush on a control angiogram. In patients with carcinoid tumors. octreotide caused a slight reduction in blood flow through the tumors in two patients. while there was no change in one patient. Octreotide markedly decreased gastrin and gastric acid secretion in two of three patients with gastrinomas. lowered VIP and stopped the diarrhea in patients with VIPomas. and controlled symptoms in two of three patients with carcinoid tumors. The vasoactive effect of octreotide on hepatic endocrine tumors may be a direct action on tumor blood supply or secondary to inhibition of the endocrine tumor cell secretion and consequent decreased blood flow.
Fate of patients undergoing transluminal angioplasty for lower-limb ischemia, A prospective study of 370 patients who underwent 500 percutaneous transluminal angioplasties (PTAs) for lower-limb ischemia over a 7-year period was performed. A 97% follow-up rate was achieved. The first PTA was successful in 188 patients (51%). Of the failures. 31% were failed attempts at dilation and 73% occurred within 1 month of intervention. Of the patients with failed PTA. 39% underwent bypass surgery and 24% underwent amputation. The 30-day mortality rate was 3%. with 1% of the deaths attributed to PTA. The survival rate at 5 years for the successes was double that for the failures (P less than .0005). The best results were in femoropopliteal stenoses with two or three patent calf vessels (cumulative patency rate. 78% at 3 years) and the worst in femoropopliteal occlusions with one or no patent calf vessels (cumulative patency rate. 25% at 3 years). Log rank tests on the life-table data were used to show factors favoring a good outcome. It is concluded that PTA is the treatment of first choice in suitable patients and. although the failure of intervention in critical ischemia has a significant risk. it is a valuable addition to the therapeutic options in patients with little chance of surgical treatment.
Percutaneous transluminal angioplasty of crural arteries, The authors dilated 103 stenosed crural arteries in 71 patients. Primary success was defined as traversing and reducing the lesion to a residual stenosis of less than 30%. This was achieved in 96% of cases. Complications included one vessel rupture and one occluding intimal flap. which were treated by the vascular surgeon with bypass and venous patch. respectively. One hematoma at the puncture site was treated surgically because of its size. With modern materials such as steerable guide wires and low-profile balloon catheters. dilation of crural arteries has become safe. Until now. the indications for percutaneous transluminal angioplasty (PTA) of crural arteries have been limited to Fontaine stages III and IV disease. The authors believe that the indications for PTA in Fontaine stage IIb disease are justified. especially if intervention improves outflow after a more proximal recanalizing procedure is performed.
Angioplasty from the contralateral approach: use of a guiding catheter and coaxial angioplasty balloons, An 8-F guiding catheter has been developed for use with coaxial angioplasty balloon catheters in angioplasty of the femoral artery from the contralateral approach when antegrade puncture of the ipsilateral femoral artery is not possible. The catheter may be used for angioplasty of the femoral artery bifurcation and the superficial femoral artery and for arterial stenoses in patients with renal transplants.
MR imaging of the bird's nest filter, The appearance of the Bird's Nest inferior vena cava filter on magnetic resonance (MR) images of 11 patients is described. No complication or symptomatic filter displacement was encountered as a result of MR imaging performed at 1.5 T. The filters created significant local artifact and distortion on MR images. However. diagnostic MR images of the pelvis. spine. and brain may still be obtained.
Irrigation device for neuroangiographic procedures, A simple irrigation device for use in diagnostic and interventional neuroangiographic procedures is described. The device is used to flush bubbles and blood clots from catheter hubs. The authors also describe a technique in which this device can be used to prevent filling a catheter with air when a guide wire is removed.
Molecular targets for AIDS therapy, The development of antiretroviral therapy against acquired immunodeficiency syndrome (AIDS) has been an intense research effort since the discovery of the causative agent. human immunodeficiency virus (HIV). A large array of drugs and biologic substances can inhibit HIV replication in vitro. Nucleoside analogs--particularly those belonging to the dideoxynucleoside family--can inhibit reverse transcriptase after anabolic phosphorylation. 3'-Azido-2'.3'-dideoxythymidine (AZT) was the first such drug tested in individuals with AIDS. and considerable knowledge of structure-activity relations has emerged for this class of drugs. However. virtually every step in the replication of HIV could serve as a target for a new therapeutic intervention. In the future. non-nucleoside-type drugs will likely become more important in the experimental therapy of AIDS. and antiretroviral therapy will exert major effects against the morbidity and mortality caused by HIV.
Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2, The erbB2 oncogene encodes a 185-kilodalton transmembrane protein whose sequence is similar to the epidermal growth factor receptor (EGFR). A 30-kilodalton factor (gp30) secreted from MDA-MB-231 human breast cancer cells was shown to be a ligand for p185erbB2. An antibody to EGFR abolished the tyrosine phosphorylation induced by EGF and transforming growth factor-alpha (TGF-alpha) but only partially blocked that produced by gp30 in SK-BR-3 breast cancer cells. In two cell lines that overexpress erbB2 but do not expresss EGFR (MDA-MB-453 breast cancer cells and a Chinese hamster ovary cell line that had been transfected with erbB2). phosphorylation of p185erbB2 was induced only by gp30. The gp30 specifically inhibited the growth of cells that overexpressed p185erbB2. An antibody to EGFR had no effect on the inhibition of SK-BR-3 cell colony formation obtained with gp30. Thus. it appeared that gp30 interacted directly with the EGFR and erbB2. Direct binding of gp30 to p185erbB2 was confirmed by binding competition experiments. where gp30 was found to displace the p185erbB2 binding of a specific antibody to p185erbB2. The evidence described here suggests that gp30 is a ligand for p185erbB2.
Different tumor-derived p53 mutants exhibit distinct biological activities, In its wild-type form. the protein p53 can interfere with neoplastic processes. Tumor-derived cells often express mutant p53. Full-length mutant forms of p53 isolated so far from transformed mouse cells exhibit three common properties in vitro: loss of transformation-suppressing activity. gain of pronounced transforming potential. and ability to bind the heat shock protein cognate hsc70. A tumor-derived mouse p53 variant is now described. whose site of mutation corresponds to a hot spot for p53 in human tumors. While absolutely nonsuppressing. it is only weakly transforming and exhibits no detectable hsc70 binding. The data suggest that the ability of a p53 mutant to bind endogenous p53 is not the sole determinant of its oncogenic potential. The data also support the existence of gain-of-function p53 mutants.
Impact of mass treatment of onchocerciasis with ivermectin on the transmission of infection, Onchocerciasis is a major blinding disease that. until recently. has been essentially untreatable. Ivermectin is a safe and effective drug for the mass treatment of onchocerciasis and when used on an individual basis. it reduces the ability of the treated person to transmit Onchocerca volvulus infection. In the present study. the effect of community-based ivermectin treatment on the degree of transmission within the community was assessed by determining the incidence of new infection in children. Ivermectin was distributed annually on three occasions to the eligible members of a population of approximately 14.000 people living on a rubber plantation in a forest area endemic for onchocerciasis. After 2 years. the prevalence of infection in 5-year-old children decreased by 21%. The annual incidence in an uninfected cohort of children decreased by 35% and. after age-specific adjustment. the reduction in incidence in 7- to 12-year-old children was 45%. Thus. community-based distribution of ivermectin led to a significant reduction in incidence of new infection. These findings suggest that ivermectin can be important in reducing the transmission of onchocerciasis.
Rhodopsin mutants that bind but fail to activate transducin, Rhodopsin is a member of a family of receptors that contain seven transmembrane helices and are coupled to G proteins. The nature of the interactions between rhodopsin mutants and the G protein. transduction (Gt). was investigated by flash photolysis in order to monitor directly Gt binding and dissociation. Three mutant opsins with alterations in their cytoplasmic loops bound 11-cis-retinal to yield pigments with native rhodopsin absorption spectra. but they failed to stimulate the guanosine triphosphatase activity of Gt. The opsin mutations included reversal of a charged pair conserved in all G protein-coupled receptors at the cytoplasmic border of the third transmembrane helix (mutant CD1). replacement of 13 amino acids in the second cytoplasmic loop (mutant CD2). and deletion of 13 amino acids from the third cytoplasmic loop (mutant EF1). Whereas mutant CD1 failed to bind Gt. mutants CD2 and EF1 showed normal Gt binding but failed to release Gt in the presence of guanosine triphosphate. Therefore. it appears that at least the second and third cytoplasmic loops of rhodopsin are required for activation of bound Gt.
Chromosomal region of the cystic fibrosis gene in yeast artificial chromosomes: a model for human genome mapping, A general strategy for cloning and mapping large regions of human DNA with yeast artificial chromosomes (YAC's) is described. It relies on the use of the polymerase chain reaction to detect DNA landmarks called sequence-tagged sites (STS's) within YAC clones. The method was applied to the region of human chromosome 7 containing the cystic fibrosis (CF) gene. Thirty YAC clones from this region were analyzed. and a contig map that spans more than 1.500.000 base pairs was assembled. Individual YAC's as large as 790 kilobase pairs and containing the entire CF gene were constructed in vivo by meiotic recombination in yeast between pairs of overlapping YAC's.
Surgical management of palmar hyperhidrosis, Hyperhidrosis is an idiopathic pathologic condition characterized by excessive sweating beyond that required to cool the body. Disturbance of the central nervous system. endocrine system. or obesity has been associated with this condition. Patients have a history of several years of occupational or social embarrassment. Individuals of Japanese ancestry and Jews of Northern African. Yemeni. or Balkan descent are predisposed to the condition. Nonoperative therapy is merely temporizing and unacceptable because of lack of efficacy or side effects. Surgical intervention provides effective and permanent control. The key to surgical correction appears to be the division of the sympathetic chain above the T-2 ganglion and below the T-3 ganglion of the involved side with removal of the entire T2-3 segment with its corresponding spinal nerves. This paper presents our experience with the dorsal thoracic approach for interruption of sympathetic innervation for severe palmar hyperhidrosis. We also review surgical efficacy of various approaches to the sympathetic chain. as well as possible side effects of operative intervention.
Nephrotoxicity associated with concomitant ACE inhibitor and NSAID therapy, Angiotensin-I converting enzyme (ACE) inhibitors and nonsteroidal anti-inflammatory drugs (NSAIDs) can be nephrotoxic and may synergistically compromise renal function. A computer-assisted study was done to asses the prevalence of compromised renal function and the clinical importance of this drug interaction. A search of the records of all patients seen in the University of Nebraska Medical Center Internal Medicine Clinic was conducted to identify cases involving renal insufficiency. therapy with ACE inhibitors. or therapy with NSAIDs. Records of cases meeting these criteria were reviewed for clinical correlation and revealed 2278 patients treated with NSAIDs. 328 with ACE inhibitors. and 162 with both. No nephrotoxicity was found in conjunction with monotherapy. but three cases of reversible renal failure were found in conjunction with combination therapy. Significant nephrotoxicity during the concomitant use of ACE inhibitors and NSAIDs is not uncommon. and attention should be drawn to this potentially important interaction.
The absence of nephrotoxicity and differential nephrotoxicity between tobramycin and gentamicin, We conducted a prospective. double-blind. randomized trial of gentamicin and tobramycin to evaluate differences in nephrotoxicity. We evaluated levels of creatinine. creatinine clearance. beta 2-microglobulin. and N-acetyl-beta-D-glucosaminidase (NAG) as indicators of nephrotoxicity. and attempted to correlate them. Forty patients met the criteria for evaluation; 14 were given tobramycin and the remaining 26 received gentamicin. Significant nephrotoxicity. as defined by an increase in creatinine of 0.5 mg/dL. did not occur in either group. Increases in beta 2-microglobulin values were seen in 67% of the patients in the tobramycin group. and 52% of those in the gentamicin group. Elevations in NAG levels occurred in 54% of those in the tobramycin group and 52% of those in the gentamicin group. Elevation of NAG and beta 2-microglobulin levels was congruent in only 40% of the cases. We conclude that there was no significant difference in nephrotoxicity between gentamicin and tobramycin. Elevations of NAG and beta 2-microglobulin occurred at rates similar to those reported in the literature. but they did not correlate with significant nephrotoxicity.
Carcinoma of the male breast: a review of 41 cases, We reviewed the cases of 41 consecutive men treated for breast carcinoma from 1950 through 1987 at Vanderbilt University Affiliated Hospitals to examine controversies in and methods of therapy for this disease. Twenty-two patients (52%) had stage I or II lesions potentially curable by operative therapy. The overall 5-year survival rates were 100% for stage I. 65% for stage II. 56% for stage III. and 0% for stage IV. Radical mastectomy offered no advantage over modified radical mastectomy in terms of survival or rate of recurrence. Diagnosis at an early clinical stage and no finding of disease in axillary lymph nodes were important factors in survival in this series of patients. All tumors evaluated for hormone receptors were positive. Although experience was limited. encouraging results were obtained with the use of tamoxifen citrate in adjuvant as well as palliative roles. With the exception of a predominance of centrally located lesions and a uniquely high frequency of positive hormone receptor status. carcinoma of the male breast appears biologically similar to the disease in women. and treatment should be guided by similar principles.
Dementia: what to do, Dementia is a syndrome of acquired intellectual deterioration that interferes with personal or social functioning. Diagnosis requires historical information from the family and the mental status evaluation of orientation. recent memory. comprehension. calculation. and abstraction. Most dementias create permanent. even progressive cognitive deterioration. yet there are some presentations for which remission exists. Common reversible conditions include depression. drug toxicity. normal-pressure hydrocephalus. hypothyroidism. subdural hematoma. and neoplasm. Screening laboratory studies consist of urinalysis. chemistry profile. blood count. thyroid survey. vitamin B12 and folate measurements. serology. chest roentgenogram. computerized tomographic scan of the head. electroencephalogram. and electrocardiogram. Treatment focuses on potential reversibility. psychosocial issues. restoring deficits. and specific symptoms.
Malignant melanoma and pigmented lesions: a diagnostic and management dilemma, We document two cases of malignancy occurring at the site of partially removed benign nevi. Because of the difficulty in clinical diagnosis and the uncertainty in its behavior. we propose that any recurring melanocytic nevus expanding beyond the original surgical scar be re-excised and the specimen carefully analyzed to ensure complete removal.
Sagittal plane analysis in idiopathic scoliosis patients treated with Cotrel-Dubousset instrumentation, One hundred sixty patients with idiopathic scoliosis treated with Cotrel-Dubousset instrumentation (CDI) underwent preoperative and postoperative sagittal plane analysis of the thoracic spine. thoracolumbar junction. and lumbar spine. The data suggest that mild to moderate improvements in thoracic hypokyphosis are possible. When crossing the thoracolumbar junction. reversal of rod bend and reversal of hooks on the derotation rod appear to provide the most physiologic sagittal contour. Cotrel-Dubousset instrumentation to the mid and distal lumbar spine can preserve and. at times. enhance lumbar lordosis.
Long scoliosis fusion to the sacrum in adults with nonparalytic scoliosis. An improved method, The first 17 adults with nonparalytic scoliosis having long fusion to the sacrum treated with the Luque-Galveston technique were reviewed. There were 3 men and 14 women. Their average age at the time of surgery was 47 years and the mean follow-up period was 42 months. There were no neurologic complications and no patient developed significant loss of lumbar lordosis. Fusion occurred in 88% of patients. Two patients developed pseudarthrosis. neither of whom had anterior fusion at the level of pseudarthrosis. The best results occurred in patients who had two-stage procedures. with initial anterior lumbar fusion to the sacrum without instrumentation followed by posterior segmental instrumentation with the Galveston technique of fixation to the pelvis.
Orthotic stabilization of thoracolumbar injuries. A biomechanical analysis of the Jewett hyperextension orthosis, Spinal orthoses have been traditionally used in the management of thoracolumbar injuries treated with or without surgical stabilization. However. the orthotic treatment modality in the management of spinal fractures remains subjective since few objective data are available on the effectiveness of orthoses in stabilizing injured segments. This study used a finite element model of the spine to evaluate the effectiveness of a hyperextension orthosis in controlling the progression of deformities at the injury site under gravitational and flexion loads. Two types of injuries were simulated: a single-level injury at T12-L1 and a two-level injury at T11-T12-L1 segments. An injury of increasing severity was simulated by progressively reducing the bending stiffness of the affected segments relative to the normal values in flexion-extension mode. The interaction of a three-point hyperextension orthosis with the spine was simulated using experimentally measured stiffness properties of the orthosis. The authors' results suggest that in single-level injuries that cause up to 50% loss of segmental stiffness. the orthosis can restore normal resistance to deformity at the injured segments. under gravitational as well as large flexion loads. In loss of stiffness between 50% and 85% of normal. such as severe two-column disruptions. the orthosis can restore resistance to deformity under restricted patient activity level in the brace (low-flexion moment). Beyond 85% loss of segmental stiffness. such as three-column injuries. the orthosis alone appears to be ineffective in preventing progression of deformity.
Evaluation of surgical treatment for burst fractures, The authors instituted a prospective. randomized study of patients presenting with acute burst fractures of the thoracolumbar and lumbar spine. Patients were alternately treated by posterior distraction using pedicle instrumentation (AO fixateur interne) or anterior decompression and instrumentation (Kostuik-Harrington device). Forty patients are presented with a mean follow-up of 20 months. Preoperatively. there was significant canal compromise in 39 patients. This measured 44.5% in those patients undergoing posterior surgery and 58% in those patients undergoing anterior surgery. Postoperatively. this was reduced to 16.5% and 4%. respectively. There is a statistically significant difference between these two groups (P less than 0.0001). The mean preoperative kyphotic deformity was 18.7 degrees in those patients treated by anterior surgery and 18.2 degrees in the group treated by posterior surgery. At last follow-up. the mean improvement in kyphotic deformity was 9.3 degrees in the anterior group and 11.3 degrees in the posterior group. There is no statistically significant difference between these two groups. There were two implant failures of the anterior Kostuik-Harrington construct and two implant failures of the AO fixateur interne. Blood loss was significantly higher in the patients undergoing anterior surgery. but there were no complications from thoracotomy and anterior decompression of the dural sac. This study supports the hypothesis that posterior distraction instrumentation can effectively decompress the canal and correct kyphosis in patients sustaining burst-type injuries. Anterior surgery. however. results in a more complete and reliable decompression of the canal.
High levels of inflammatory phospholipase A2 activity in lumbar disc herniations, Inflammation of neural elements is frequently mentioned clinically in association with lumbar radiculopathy. Mechanical embarrassment of neural elements by definable structural abnormalities is inadequate as a sole explanation of nerve injury in this condition. The purpose of this study was to demonstrate whether an enzymatic marker for inflammation (phospholipase A2) could be identified in human disc samples removed at surgery for radiculopathy due to lumbar disc disease. Samples were assayed for phospholipase A2 activity. The level of activity in the disc samples was compared with values obtained from other human tissues using the same assay. Specific activity (percent hydrolysis radiolabelled substrate) ranged from 238 to 1.014.5 nmol/min/mg. Mean activity for the human disc material was 568.7 nmol/min/mg. compared with 0.006 nmol/min/mg for human PMN. and 12.1 nmol/min/mg for inflammatory human synovial effusion. The pH and cation-related activity were identical to those demonstrated for phospholipase A2 inflammatory conditions. Human lumbar disc phospholipase A2 activity is from 20- to 100.000-fold more active than any other phospholipase A2 that has been described. As the enzyme responsible for the liberation of arachidonic acid from cell membranes. phospholipase A2 is the rate-limiting step in the production of prostaglandins and leukotrienes. These data establish biochemical evidence of inflammation at the site of lumbar disc herniations.
High lumbar disc degeneration. Incidence and etiology, Three hundred seventy-nine consecutive magnetic resonance images (MRIs) with dual-echo images of the entire lumbar spine were reviewed by the authors. All 379 patients presented with back pain and/or leg pain; they were interviewed and examined. Pain drawings were completed by all. There were 42 patients (11.1%) with disc pathologies involving T12-L1. L1-2. and/or L2-3 levels. Six patients (1.6%) had isolated disc degeneration and/or herniations limited only to these high lumbar segments. The remaining 36 patients had degenerative changes of the higher discs with variable involvement of the lower lumbar discs. Out of 12 spondylolistheses of L5 on S1. 7 had high disc pathologies at one or more levels presenting as skipped lesions; more severe high disc lesions were noted in Grade II slips. Isolated high disc degeneration is often associated with pre-existing abnormalities such as end-plate defects. Scheuermann's disease. limbus vertebra. and so forth. and stressful cumulative work activities such as in construction workers. airplane mechanics. and so forth. High disc degeneration was noted above or below previous fractures. High disc involvement with diffuse changes in lower lumbar spine was more commonly found in ascending fashion in older age groups. and in patients who have had previous lower lumbar spine surgeries. prior fusions in particular. Our findings suggest that altered mechanics are associated with the high lumbar disc pathologies.
Lumbar discography followed by computed tomography. Refining the diagnosis of low-back pain, Two hundred fifty patients with low-back pain who underwent lumbar discography followed by computed tomography (CT) are the subject of this prospective study. In 93% of the patients. these combined imaging techniques provided additional useful diagnostic information that affected patient management and the selection of treatment alternatives. Lumbar discography followed by CT proved valuable in determining the significance of equivocal or multiple level abnormalities. determining the type of disc herniation. defining surgical options. and evaluating the previously operated spine. In 94% of patients who had surgery. CT-discography correctly predicted the type of disc herniation as protruded. extruded. sequestrated. or internally disrupted. Computed tomography-discography may be more sensitive that magnetic resonance imaging (MRI) in the early stages of disc degeneration because 18 of 177 discs with a normal T2-weighted image were discographically abnormal and the CT-discogram revealed annular tears or radial fissuring. The radiographic morphology of the normal herniated and degenerative lumbar discs shown by CT-discography gives unique insight into the pathogenesis of disc degeneration. The complications that followed the 750 discograms were one case of urticaria and one disc space infection. Even with the availability of high resolution CT and MRI. lumbar discography remains the only pain provocation challenge to the lumbar disc.
A multicenter analysis of percutaneous discectomy, This study was performed to evaluate a group of patients undergoing percutaneous discectomy. All patients had a single level unilateral L4-5 or L5-S1 disc herniation documented on either computer tomographic (CT) scan. myelogram. and/or magnetic resonance imaging (MRI). Average follow-up after percutaneous discectomy was 16.8 months (range. 2-46 months). The average hospitalization time was 1.7 days (range. 1-5 days). Only 21 patients (55%) were able to return to work after the procedure. Thirteen patients ultimately underwent surgical discectomy for continued symptoms after the procedure. The additional 4 patients did not undergo surgical discectomy and never returned to work. Of those 25 percutaneous discectomy patients who did not undergo surgical discectomy. there was significantly more pain. residual weakness. and numbness compared with the patients undergoing surgical discectomy. The results of this study clearly indicate that percutaneous discectomy does not appear to be as predictable or successful a treatment modality as surgical discectomy.
Results of conservative surgery and radiation therapy for breast cancer, For stage I or II breast cancer. conservative surgery and radiation therapy are as effective as modified radical or radical mastectomy. In most cases. cosmetic considerations and the availability of therapy are the primary concerns. The extent of a surgical resection less than a mastectomy has not been a subject of a randomized trial and is controversial. It appears that removal of a quadrant of the breast for small lesions is safe but excessive. Using histologic findings in the biopsy as a guide. it may be possible to limit the breast resection to gross tumor removal for most patients while using wider resections for patients with an extensive intraductal component or for invasive lobular carcinoma. It also appears that excluding patients from breast conservation on the basis of positive margins on the first attempt at tumor excision may be unnecessarily restrictive. Although patients with an extensive intraductal component or invasive lobular carcinoma should have negative margins. it appears that a patient with predominantly invasive ductal carcinoma can be treated without re-excision if all gross tumor has been resected and there is no reason to suspect extensive microscopic disease. Patients with indeterminate margins should have a re-excision. Axillary dissection provides prognostic information and prevents progression of the disease within the axilla. Axillary dissections limited to level I will accurately identify a substantial number of patients who have pathologically positive but clinically negative nodes. When combined with radiation therapy to the axilla. a level I dissection results in a limited number of patients with progressive axillary disease. Patients with pathologically positive axillas and patients at particularly high risk for systemic disease because of the extent of axillary node involvement can be identified by dissections of levels I and II. Radiation therapy can be avoided safely in patients who have pathologically negative axillas by level I and II dissection. There appears to be no advantage to routine dissection of level III lymph nodes. Lymphedema of the arm and breast increases with more extensive dissections and with radiation therapy.
Role of mastectomy in breast cancer, The surgical management of breast cancer continues to evolve in an attempt to define the ideal line between therapeutic efficacy and morbidity. It is clear that breast cancer is a biologically heterogeneous group of diseases. and no single hypothesis explains its behavior. The surgical options proposed to the individual patient must draw from the experience of retrospective clinical studies and prospective randomized trials in an attempt to optimize the treatment plan. Most patients without distant disease are eligible to consider mastectomy. which can accomplish excellent local control and significantly improve survival for earlier stages of disease. However. breast conservation remains an appropriate alternative for a carefully defined subset of patients. Today. with early-stage disease. no patient need leave the operating room without a breast. Recent advances in reconstructive surgery make mastectomy with immediate reconstruction or limited resection plus axillary dissection with postoperative radiation therapy the two principal treatment choices available. Future studies will focus on the integration of other treatment modalities. Clinical research into the use of preoperative chemotherapy to downstage the disease to permit less extensive surgery is of interest. Recent application of molecular biologic techniques such as oncogene analysis. cytogenetic studies. proliferative indices. and the highly sensitive detection of distant micrometastases using monoclonal antibodies may assist in the design of innovative approaches to surgery. radiation therapy. and systemic drug treatment. These advances show great promise for improving the quality of life and the cure rate for patients with breast cancer. Today. surgical treatment options have evolved that fulfill some of the objectives outlined by Dr. James Ewing of Memorial Hospital some 50 years ago. His concerns about breast cancer remain as relevant today as they were half a century ago: "I have drawn the impression that in dealing with mammary cancer. surgery meets with more peculiar difficulties and uncertainties than with almost any other form of the disease. The anatomical types are so numerous. the variations in clinical course so wide. the paths of dissemination so free and diverse. the difficulties of determining the actual conditions so complex. and the sacrifice of tissues so great. as to render impossible in the majority of cases a reasonably accurate adjustment of a means to an end.".
Selection of breast-preservation therapy for primary invasive breast carcinoma, Breast-preservation treatment for primary breast cancer should not be used for all women. Women frequently excluded from consideration for such treatment or who choose not to have it may be elderly and not concerned about cosmetic appearance or live at a distance so that 6 weeks of daily trips to radiotherapy would be inconvenient or even impossible. Also. if radiotherapeutic expertise or facilities are not available. a breast-preservation program is difficult. In Massachusetts. a full course of just over 6000 cGy (4500 cGy to the whole breast and a 1600-cGy local boost) costs roughly $6000. Thus. breast preservation is more expensive than mastectomy even with reconstruction. as patients still frequently require a hospital admission with general anesthesia for an axillary dissection. Although insurance policies cover such expenses. patients who do not have insurance or have inadequate coverage may find the extra expense of the breast-preservation technique burdensome or impossible. Women with a small breast and a proportionately large cancer may have an unsatisfactory cosmetic outcome after appropriate lumpectomy. The cosmetic result in such patients frequently cannot be predicted beforehand; this fact adds emphasis to the need for a two-step process of lumpectomy and then re-evaluation of the cosmetic outcome as well as pathologic features for decisions regarding breast preservation. Finally. women may have strikingly different attitudes toward breast preservation than expected by the surgeon. For some women. the urge to preserve the breast is so strong that they will accept virtually any risk to achieve this option. whereas for other women. the constant anxiety about a recurrence or undergoing radiation therapy is traumatic enough that they readily accept mastectomy. In our referral surgical oncology practice. roughly 60% of patients are currently treated with breast-preservation techniques; the remainder undergo mastectomy. with immediate reconstruction in approximately three fourths of the cases. The proportion of patients who elect to have breast preservation depends greatly on local medical customs and attitudes; the radiotherapeutic skills available; women's attitudes. which frequently are dependent on the local press and publicity; and the surgeon's interest and enthusiasm for such a program. There is no appropriate proportion of patients who should be treated by breast-preservation techniques. but clearly. the proportion of patients so treated increases with experience. acceptability. publicity. and availability. Thus. the selection of breast-preserving therapy for individual patients is a result of an extraordinary array of factors that need to be considered in each patient.(ABSTRACT TRUNCATED AT 400 WORDS).
Selection of therapy for stage III breast cancer, Locally advanced breast cancer is a heterogenous group including both operable and inoperable lesions. Local surgery or radiation alone produces poor survival rates. indicating micrometastases at diagnosis. Systemic chemotherapy as part of multimodality regimens has increased the length and rate of disease-free survival.
Adjuvant chemotherapy of breast cancer, Many women will not be cured of breast cancer by even the best early detection and surgical techniques because of micrometastases present at diagnosis. Adjuvant therapy has extended the disease-free interval for most patients and lengthens overall survival for many. Combination chemotherapy has become the standard form of adjuvant treatment for premenopausal women with breast cancer and positive lymph nodes after primary therapy. With minimal toxicity. disease-free and overall survival are improved. Results are less impressive or less clear-cut for postmenopausal women or any woman with negative lymph nodes. Long-term toxicities of adjuvant chemotherapy may include second malignancies and cardiac dysfunction. Although these complications probably are rare. they must be considered seriously when weighing chemotherapy for patients in whom its benefits may be slight. Innovations likely to become standard in adjuvant therapy decision making include risk assessment with new prognostic indicators (growth fraction. oncogene expression) and investigation of dose intensification using bone marrow growth factors and autologous stem-cell support.
Adjuvant antiestrogen therapy for breast cancer. Past, present, and future, Laboratory investigations using animal models of breast cancer growth have indicated that the antiestrogenic compound tamoxifen is a tumoristatic agent. It is therefore effective in suppressing. rather than destroying. the breast tumor. Its use as an adjuvant in breast cancer management has been successful. with a proportion of women benefiting from long periods of tamoxifen treatment. All the initial studies recruited postmenopausal women. but tamoxifen is now proposed for the treatment of premenopausal women for an extended time. Naturally. there are many aspects of the toxicology of tamoxifen to consider; however. careful monitoring of clinical trials will determine the safety of the drug for the general patient population.
Management of local and regional recurrence after mastectomy or breast-conserving treatment, Locoregional failures after primary treatment for breast cancer include a diverse group of lesions that represent different categories of failures with various prognoses. Although patients with chest wall recurrences and regional nodal failures after traditional radical surgery have a poor prognosis. many patients can still achieve a significant degree of palliation and even long-term survival or cure with carefully orchestrated multimodal treatment. In patients who have breast failures after breast-conservation surgery and radiation. long-term salvage and cure can be achieved for the majority with prompt detection and appropriate treatment. which. like treatment for primary breast cancer. includes a consideration not only of local control but also of the risk of subsequent systemic failure and its need for treatment.
Reconstruction after mastectomy, Advances in materials and techniques. especially those involving transposition of muscle and skin flaps. have made breast reconstruction possible for most women who undergo mastectomy for breast cancer. The availability of this option can alleviate the breast and chest wall deformity that results from virtually all local treatment of breast cancer. It is essential that the reconstruction surgeon be part of the breast cancer management team from the beginning of treatment planning and that this surgeon work closely with the general surgeon. medical oncologist. and radiation therapist as well as the adjunctive treatment team members. The patient's clinical status and the type of local treatment will be significant determinants of the reconstructive options. For women with stage I breast cancer. these decisions may be based largely on the oncologist's local and adjunctive therapy procedures and the woman's desire to proceed or delay. For women with systemic disease. all members of the breast management team may need to agree on the advisability and timing of reconstruction. Central to all of the numerous decisions described in this paper regarding the timing. type. and extent of breast reconstruction is the primary goal of the entire team: the best possible management of the breast cancer itself. The promise of attractive. symmetric. and natural appearing breasts. complete with a symmetric nipple-areolar complex. has eased somewhat the diminishment of self-esteem and the threat to femininity that can accompany the loss of a breast. By lowering fear. the widely recognized availability of breast reconstruction may encourage more women to monitor their breasts and seek diagnosis of changes and may influence selection of the type of local treatment if cancer is detected. Because of the psychological and cultural significance of the breast. the reconstructive surgeon must be particularly sensitive to the psychological and aesthetic expectations of the patient. Even in those patients with metastases and limited life expectancy. breast reconstruction can enhance the quality of life.
Bilateral breast cancer, A second primary breast cancer in the opposite breast can be either synchronous or metachronous. The majority are metachronous. A woman who has had breast cancer has a fivefold increase in risk for a second breast cancer. Additional risk factors include multifocal cancer. lobular carcinoma in situ. and an original cancer at an early age with long survival. Lobular carcinoma in situ is predominantly a marker for the subsequent development of a second primary breast cancer. The incidence of synchronous bilateral cancer is approximately 1% to 2% and that of metachronous cancer 5% to 6%. The cancer can be invasive or noninvasive. Mammography has increased the number of synchronous cancers found but not the overall incidence. The incidence of invasive cancer detected by random biopsy of the opposite breast is not high enough to justify routine adoption of this procedure. The remaining breast must be followed for the remainder of the patient's life by physical examination and annual mammography. The treatment of the secondary primary breast cancer should be that appropriate for the stage of the disease. The prognosis for the woman with a second primary breast cancer is quite favorable and is dependent on the stage of both the first and the second cancer.
Breast cancer during pregnancy and lactation, Breast cancer is the most frequently seen cancer in pregnancy and lactation. but the incidence is low. the disease being seen in approximately 0.03% of pregnancies. Only 1% to 2% of breast cancer overall is diagnosed during pregnancy or lactation. There is no evidence to implicate pregnancy or lactation in either the etiology or the progression of breast cancer. Careful breast examination early in the pregnancy is very important to find solid masses that require biopsy before breast engorgement hides them. Therapeutic options vary. depending on the stage of disease and the stage of the pregnancy. Operable disease in the first 6 to 7 months of the pregnancy should be treated by mastectomy. as irradiation is contraindicated. Late in the pregnancy. a lumpectomy and axillary dissection can be done. with irradiation being delayed until after delivery. General anesthesia is safe if the usual precautions are taken to compensate for the physiologic changes induced by pregnancy. Unfortunately. delay in diagnosis is common. and 70% to 89% of patients with operable primary lesions have positive axillary lymph nodes. Late stage appears to be the only reason for the generally worse prognosis in these patients. as stage for stage. they have a course similar to that of nonpregnant patients. Adjuvant chemotherapy can be considered late in the pregnancy but should usually be delayed until after delivery. In patients with locally advanced or metastatic cancer diagnosed early in the pregnancy. for whom both chemotherapy and radiation therapy would normally be recommended. consideration must be given to termination of the pregnancy. There is no evidence that termination of pregnancy improves the outlook for the patients. but it does permit standard aggressive therapy in advanced disease.
Male breast cancer, Male breast cancer is uncommon but important. The diagnosis is easily made by breast biopsy. and patients are presenting earlier in the course of the disease than in the past. Despite this. patients are often first seen with tumors that have metastasized to the axillary nodes. which markedly decreases the survival rate. Therapy of localized disease includes simple excision. modified radical mastectomy. and radical mastectomy. but there is no consensus for which operation is appropriate. Radiation therapy should be strongly considered in patients with metastases to the axillary nodes. but the role of adjuvant hormonal therapy or chemotherapy is unclear. For treatment of disseminated disease. tamoxifen seems to be replacing orchiectomy. The favorable response rate. especially in patients with estrogen-receptor-positive tumors. the lack of side effects. and the high level of patient acceptability make it an attractive therapeutic choice.
Clinical problems in follow-up of patients after conservative surgery and radiotherapy, Patients treated with conservative surgery and radiotherapy for early-stage breast carcinoma are at risk of developing an ipsilateral breast recurrence for a long period. Fortunately. few such patients present with an inoperable recurrence or simultaneous distant metastases. Salvage rates are high and may be improved by early detection. Although usually unambiguous. physical examination of the treated breast may reveal changes attributable to surgery and radiotherapy that can mimic a recurrent cancer. There also is substantial overlap in radiologic appearance between benign and malignant lesions. It may be necessary to perform a biopsy when there is a question of recurrence. Careful life-long follow-up of patients thus is a critical part of their care.
Trends in primary breast cancer management. Where are we going, The treatment of cancer during any period has been based not on the whim of a clinician but on the therapeutic consequences of the dominant biologic model of the disease. Until the 1960s. the dominant model of breast cancer was of a disease that spread centrifugally along anatomic pathways. with time being the only determinant of prognosis. An alternative model. that of biologic determinism. posits that the outcomes of treatment are determined by the extent of microscopic dissemination that occurred before the tumor became detectable. This model. too. has flaws. and the author suggests that it is time for a Kuhnian paradigm shift. Breast cancer exhibits a heterogeneity of phenotypes resulting from one or perhaps two mutations. The multiple prognostic variables may be epiphenomena. expressing different degrees of amplification of a limited domain of the genome.
Prognostic indicators in invasive breast cancer, Tumor size and axillary lymph node involvement are the primary determinants of clinical course for most patients. Receptors for estrogen and progesterone are important additional prognostic factors for disease-free survival. overall survival. survival time after initial disease recurrence. and the likelihood of response to hormonal therapy. Histologic grading has merit as a prognostic factor. although poor reproducibility limits its broad application. Promising data have been emerging from the use of flow cytometry to analyze DNA content and proliferative rate. Patients with aneuploid tumors are more likely to have a shorter survival time than patients with diploid tumors. A high S-phase fraction also identifies a subset of patients at increased risk for early relapse. A combined index of ploidy and S-phase may be a more useful guide; together. diploidy and low S-phase identify a subgroup of node-negative patients at very low risk for disease recurrence. A number of oncogenes have been identified in breast cancer; amplification of the HER-2/neu gene or overexpression of the gene product may be an important prognostic indicator for node-positive patients.
A comparison of hospital costs and morbidity between octogenarians and other patients undergoing general surgical operations, The hospital costs and clinical results of 304 patients who were more than 80 years old and who underwent general surgical procedures were evaluated. The over-all mortality rate was 14 per cent; 19.9 per cent occurred in patients admitted under emergency conditions as compared with 8.9 per cent that occurred in patients undergoing elective procedures (p less than 0.001). Seventy-nine per cent of the patients were discharged and 7 per cent required care in a skilled nursing facility. Survival rates were as good or better than standard life table survival rates for 80 year old patients. Costs were higher in those who were admitted under emergent conditions or who died in the hospital. Deaths were a result of complications of the primary disease rather than associated disease in most groups. Neither costs nor length of stay could accurately predict survival of individual patients. We concluded that health resources should be directed at treating problems. such as cholelithiasis. hernia or carcinoma. early before complications develop.
Carcinoma of the thyroglossal duct, A review of 39 instances of excision of a cyst of the thyroglossal duct performed at St. Paul Medical Center. Dallas. Texas. revealed two patients with carcinoma of the thyroglossal duct. A review of the English literature yielded 146 instances of this uncommon tumor. Eighty-four per cent were papillary adenocarcinoma of thyroid type and 5 per cent were squamous cell carcinoma. The patients were from six to 81 years old with a 2:1 female to male ratio. Metastatic disease to lymph nodes was noted in 11 per cent and invasion of overlying strap muscles was found in 4 per cent. Carcinoma of the thyroid gland occurred in 14 per cent. Preoperative diagnosis was rare. The Sistrunk procedure is recommended for initial surgical therapy with further surgical or adjuvant therapy dependent on associated clinical findings. Prognosis for carcinoma of the thyroglossal duct of thyroid type parallels that of carcinoma of the thyroid gland.
Response of spinal cord blood flow and motor and sensory evoked potentials to aortic ligation, To produce spinal cord ischemia in the lamb. ligation of the thoracic aorta was performed for 15. 30. and 45 minutes in three animals each. Spinal cord blood flow and motor and sensory evoked potentials were measured before. during. and after aortic ligation. Ischemia with a blood flow of zero during ligation was encountered in the thoracic and lumbar cords. followed by hyperemia upon release of the ligature. Both somatosensory and motor evoked potentials were obliterated during aortic ligation and gradually recovered following resumption of flow. Motor and sensory evoked potentials behaved similarly to high aortic ligation.
Effects of medical and surgical treatment on cerebral perfusion and cognition in patients with chronic cerebral ischemia, The effects of medical treatment with and without cerebral revascularization procedures on cognition and cerebral blood flow were compared among 36 patients with extracranial occlusive cerebrovascular disease and cognitive impairments. Three comparable groups were studied. The first group (N = 18) received only medical treatment by control of risk factors for stroke (including hypertension. diabetes. and hyperlipidemia) and antiplatelet aggregant medication. The second group (N = 10) had the same medical treatment plus superficial temporal-to-middle cerebral artery bypass. and the third group had the same medical treatment plus carotid endarterectomy. Regional cerebral blood flow and cognition were monitored in all three treatment groups over a 3-year interval. All groups showed stabilization without expected rates of decline for both cerebral blood flow and cognition. but no statistically significant differences emerged among the treatment groups.
An unusual epidural, vascular spinal lipoma in a 3-year-old child: a case report and review of the literature, Epidural lipomas are usually benign tumors affecting the spinal cord. We report the unusual presentation of a cervicothoracic spinal lipoma associated with a cervical dysraphism in a young boy. Diagnostic options using magnetic resonance imaging and gadolinium-diethylenetriaminepentaacetic acid are discussed as a pathway to early diagnosis of these and other occult spinal lesions.
Neonatal intracranial teratomas, Two neonates with intracranial teratomas presented with cranial enlargements a few weeks after birth. Both cases underwent surgery: one died intraoperatively; the other is the longest known survivor. alive 7 years and 9 months after subtotal excision of a mature teratoma of the left sylvian fissure. Previous operations have been relatively few and nearly all have been unsuccessful. Size and favorable location may be the most important prognostic features regardless of the histologic classification as mature or immature. One of our cases demonstrates that even subtotal excision of a mature teratoma can result in long-term survival.
Prospective evaluation of clinical and pathologic detection of axillary metastases in patients with carcinoma of the breast, Complete axillary dissection was performed in 287 patients undergoing modified radical mastectomy between 1984 and 1987 to identify patterns of axillary node metastases. as well as discontinuous axillary node ("skip") metastases. Positive pathologic findings were compared with preoperative clinical examinations in 266 patients and showed only 60 cases (22.6%) clinically suspicious for tumor. in contrast to 131 (45.6%) with pathologically confirmed positive lymph nodes. Axillary contents were classified level I. II. or III based on their relationship to the pectoralis minor muscle. An average of 24.2 nodes was resected per patient (level I. 10; level II. 8.1; and level III. 5.3). Tumors ranged in size from 0.5 to 12.0 cm (mean. 2.6 cm). and increasing tumor size was associated with an increased likelihood of positive nodes. The data on 204 patients with complete clinical and pathologic data show that of 119 patients with negative level I nodes a limited axillary dissection (level I only) would fail to identify 6 with positive level II and 2 with positive level III nodes. whereas of 85 patients with positive level I nodes limited axillary dissection would fail to identify 17 with positive level II nodes. 7 with positive level III nodes. and 27 with positive levels II and III nodes. Complete axillary dissection (levels I. II. and III) should be performed to stage patients accurately. as well as to remove tumor-involved nodes and diminish local axillary recurrences. Clinical examination of the axilla appears to be a poor means of identifying axillary metastatic cancer.
Short-term tamoxifen plus chemotherapy: superior results in node-positive breast cancer, Three hundred eleven patients with node-positive breast cancer were randomized to one of three adjuvant treatments: cyclophosphamide (Cytoxan). methotrexate. and 5-fluorouracil; all of the above with tamoxifen citrate; or all of the above with tamoxifen and bacillus Calmette-Guerin vaccination. Local therapy for all patients was a modified radical mastectomy. Estrogen receptors were measured on all primary tumors. Patients were stratified by the number of positive nodes (one to three nodes and more than three nodes) and estrogen-receptor value (less than 3 femtomole/mg and greater than or equal to 3 femtomole/mg). Follow-up is available. with a mean of 9.1 and maximum of 14.2 years. In this study the efficacy of short-term tamoxifen is apparent over that of chemoimmunotherapy alone and continues to be significant with prolonged follow-up. The addition of tamoxifen to chemoimmunotherapy significantly prolonged disease-free survival among patients with estrogen receptor-positive tumors who were postmenopausal. who had larger tumors (greater than 3 cm). or who had more extensive axillary node involvement (more than three nodes). Tamoxifen improved overall survival for patients with estrogen receptor-positive tumors larger than 3 cm. The addition of bacillus Calmette-Guerin Cytoxan. methotrexate. 5-fluorouracil. and tamoxifen did not significantly alter disease-free or overall survival.
Pancreatogastrostomy: a safe drainage procedure after pancreatoduodenectomy, The purpose of this study was to evaluate the role of pancreaticogastrostomy as an alternative method of restoring pancreaticointestinal continuity after pancreaticoduodenectomy. Since 1975. 45 patients have undergone pancreaticogastrostomy after pancreaticoduodenectomy at our institution. Pancreaticoduodenectomy was performed for pancreatic carcinoma (24 patients). ampullary carcinoma (8 patients). duodenal carcinoma (4 patients). common bile duct carcinoma (4 patients). pancreatic islet cell carcinoma (1 patient). trauma (1 patient). extensive colon carcinoma (1 patient). chronic pancreatitis (1 patient). and gastroduodenal artery aneurysm (1 patient). There was one operative death. for an overall operative mortality rate of 2%. and seven patients had major postoperative complications. for an overall morbidity rate of 15%. No pancreatic anastomotic leaks or other complications related to the pancreaticogastrostomy occurred. Twenty-four patients have died of recurrent carcinoma. with a mean survival of 25 months (range. 5 to 66 months). and 20 patients are alive and well. with a mean follow-up of 27 months (range. 2 to 106 months). Eight of these patients are alive 2 or more years after operation and four do not have exocrine pancreatic insufficiency. This experience confirms that pancreaticogastrostomy is a safe method of pancreatic drainage after pancreaticoduodenectomy and suggests that it may have technical advantages and therefore merits more widespread application.
Early results of combined electrohydraulic shock-wave lithotripsy and oral litholytic therapy of gallbladder stones at the University of Iowa, One hundred thirty-three patients were entered into a randomized. double-blind. placebo-controlled trial of extracorporeal shock-wave lithotripsy for symptomatic gallstones versus extracorporeal shock-wave lithotripsy plus adjuvant litholytic therapy with ursodeoxycholic acid (UDCA). Six months after lithotripsy. patients receiving placebo were crossed over to UDCA therapy without unblinding the study. One hundred sixteen patients have completed 6 months of follow-up. Five patients were dropped from the study. Nine percent have required cholecystectomy (11 patients with biliary colic and 1 with acute cholecystitis). Ninety-one patients had a solitary stone (64 patients had stones less than or equal to 20 mm and 27 patients had stones greater than 20 mm in diameter). and 25 patients had two to three stones. Fifty percent were retreated. Cumulative stone-free rates at 6. 12. and 18 months were 26%. 39%. and 41%. respectively. At 6 months there was a significant advantage for patients treated with UDCA versus placebo (36% vs 17% were stone free) that had disappeared by 12 months (placebo-treated patients had received 6 months of UDCA). Patients with solitary stones equal to or less than 20 mm in diameter treated with UDCA had stone-free rates at 6. 12. and 18 months of 58%. 58%. and 62%. respectively. versus 27%. 56%. and 50%. The difference was significant only at the 6- month follow-up. Stone-free rates for patients with large solitary stones and multiple stones were very low. Extracorporeal shock-wave lithotripsy is both safe and effective therapy for treatment of symptomatic gallstones in patients with a solitary stone equal to or less than 20 mm in diameter. UDCA markedly improves the efficiency of the procedure and results in a stone-free gallbladder sooner.
Inadequate granulopoiesis after major torso trauma: a hematopoietic regulatory paradox, Late postinjury sepsis is largely the result of defective host defense including failure to maintain an adequate number of functioning phagocytic cells. In this study we used stem cell culture techniques to measure colony-stimulating activity and have quantitated the number of circulating myeloid stem cells to see if defects in granulopoiesis occur after major torso trauma. Forty-two acutely injured patients (13 blunt and 29 penetrating injuries; mean age. 29.7 years) undergoing laparotomy with an abdominal trauma index of 15 to 40 were studied prospectively. Blood samples were obtained on days 1. 5. and 10. Patients were segregated by injury severity: abdominal trauma index less than 25 (n = 25) versus abdominal trauma index greater than or equal to 25 (n = 17). The more severely injured (abdominal trauma index greater than or equal to 25) patients had fewer circulating granulocytes and monocytes. Colony-stimulating activity was below normal control levels in all patients and was decreased further with increased injury severity. The more severely injured patients had a blunted bone marrow response (significantly fewer circulating myeloid stem cells) and suffered more major septic complications (24% vs 8%). In conclusion. major trauma to the torso causes a paradoxic depression in granulopoiesis that worsens with increased injury severity and may contribute to late septic morbidity. This colony-stimulating activity deficiency state is similar to that seen after major burns and may be amenable to future modulation.
Subxiphoid pericardiotomy versus echocardiography: a prospective evaluation of the diagnosis of occult penetrating cardiac injury, Diagnostic subxiphoid pericardiotomy (SP) is presently advocated for the diagnosis of occult cardiac injuries in patients with stable vital signs with juxta-cardiac-penetrating chest wounds. This approach. however. results in a reported 80% negative pericardial exploration rate. To investigate the reliability of bedside two-dimension echocardiography (2-D echo) in predicting cardiac injury as compared to SP. a prospective study was undertaken of patients with stable vital signs who were admitted with penetrating chest wounds that were located within the space bounded by the manubrium. nipples. and subcostal line. Initial evaluation of the patients with bedside 2-D echo was found to have a 96% accuracy. 97% specificity. and 90% sensitivity in predicting cardiac injury. The only false-negative findings were in a patient who consented to SP 18 hours after bedside 2-D echo was performed. The reliability of bedside 2-D echo compared to SP was not significantly different according to the kappa measure of reliability. These data suggest that bedside 2-D echo is an expeditious and reliable method to diagnose occult cardiac injuries during the initial assessment of a patient with stable vital signs who had penetrating chest trauma. This approach may allow for the selective use of SP on patients with positive bedside 2-D echo and could eliminate unnecessary surgical procedures.
The use of the Jarvik-7 total artificial heart and the Symbion ventricular assist device as a bridge to transplantation, The proliferation of transplantation programs has not been paralleled by a similar increase in the availability of organ donors. Between 1984 and 1987. 104 orthotopic heart transplantations were performed at Loyola University Medical Center. During the same period. 25 patients died while awaiting a donor organ. To reduce the mortality. we began using the total artificial heart (TAH) and a ventricular assist device (VAD) as a bridge to transplantation in 1988. Of 29 patients who underwent transplantation. 15 patients required a TAH and three patients required a VAD as a bridge. The underlying heart conditions were ischemic cardiomyopathy (11 patients). dilated cardiomyopathy (5 patients). giant cell myocarditis (1 patient). and allograft failure (1 patient). The average duration of mechanical support was 10 days (range. 1 to 35 days). Of the 17 patients who successfully underwent transplantation. 1 patient died at 17 days because of acute rejection of the transplanted heart. and another patient died at 14 days because of a cerebral vascular event. Fifteen patients (83%) were long-term survivors. Nine patients required reoperation for bleeding. While the mechanical device was in place. the activated clotting time was maintained between 170 and 200 seconds with heparin. Dipyridamole was given. We conclude that the TAH and VAD are excellent mechanical bridges to transplantation.
Is DNA ploidy of prognostic significance in stage I cutaneous melanoma, Recent studies have suggested that the presence of DNA aneuploidy in stage I cutaneous melanoma carries a poor prognosis. To see if our experience correlated with these reports. we used DNA analysis by flow cytometry of propidium iodide-stained nuclei disaggregated from formalin-fixed paraffin-embedded tissue of biopsy specimens to retrospectively study 55 patients who had cutaneous stage I melanomas. The patients had been treated from 1977 to 1987 with a mean follow-up of 5.4 years. Thirty-nine (71%) of the 55 histograms were diploid. and 16 (29%) of the histograms were aneuploid. DNA content was significantly associated with other conventional prognostic factors. including growth pattern. ulceration. pathologic stage. tumor thickness. and Clark's level. DNA aneuploidy was significantly related to disease-free survival and predicted a poorer prognosis (p less than 0.05). but when stratified for tumor thickness it lost significance. A multivariate discriminant function analysis of 12 factors in melanoma showed six factors to be independently significant in determining prognosis. DNA content (p = 0.034) ranked fifth in importance behind growth pattern (p less than 0.001). ulceration (p less than 0.001). thickness (p = 0.001). and pathologic stage (p less than 0.005). DNA content. although significantly associated with conventional prognostic factors and disease-free survival. is not the best indicator of biologic behavior of melanomas in this study. Further investigation into its usefulness is necessary before DNA content can become a routine diagnostic modality in the work-up of stage I cutaneous melanomas.
Kidney transplantation in patients aged sixty years and older, Outcomes of renal transplantation were reviewed for 26 transplants performed in 25 patients 60 years of age or older between 1985 and 1989. Three grafts were from family donors and 23 were from cadaver donors. Twenty-one were first transplants and five were retransplants. Cyclosporine was used as primary immunosuppression and azathioprine and prednisone were administered to most patients. Overall patient and graft actuarial survival rates were 79% and 71%. respectively. at both 1 and 3 years. Patients (n = 14) free of both diabetes and cardiac disease (low risk) had 1- and 3-year patient and graft survival rates of 91% and 84%. respectively. Conversely. high-risk patients (n = 12) had patient and graft survival rates at 1 and 3 years of 67% and 58%. respectively. Early deaths (less than or equal to 6 months) were caused by sepsis (two patients) or cardiac events (three patients). and four of the five were in high-risk patients. Irreversible rejections and serious infectious complications were not as common as steroid-induced diabetes. which occurred in five patients. This experience suggests that kidney transplantation can be done safely and successfully in patients older than 60 years of age and should be the treatment of choice for low-risk patients in this category.
Beneficial effects of fetal liver tissue on fetal pancreatic transplantation, Recently. composite grafts of hepatocytes and islets have been shown to improve the survival of hepatocytes. The possibility of a reciprocal effect of hepatocytes on islet function was investigated. Diabetic Lewis rats were isografted with (1) fetal pancreas and fetal liver (FP/FL). (2) fetal pancreas alone (FP). and (3) fetal pancreas and fetal spleen (FP/FS). Grafts were transplanted to the small bowel subserosa. All (6/6) FP/FL recipients were cured (glucose less than 250 mg/dl for greater than 30 days). whereas only 72% (13/18) of FP alone and 60% (3/5) of FP/FS recipients were cured. The amount of time to normoglycemia for FP/FS recipients was less (26 +/- 15 days) compared with FP (50 +/- 29 days) or FP/FS recipients (71 +/- 40 days). Mean glucose levels at 6 weeks were 166 +/- 78 mg/dl. 237 +/- 97 mg/dl. and 355 +/- 81 mg/dl in cured FP/FL. FP. and FP/FS recipients. respectively. Glucose tolerance test results were not significantly different from those of nondiabetic control rats. In contrast to FP alone. FP/FL recipients had well-granulated hyperplastic islets and hepatocytes on histologic examination. When new isograft recipients were treated with cyclosporine. all FP recipients remained hyperglycemic; however. 75% (6/8) of FP/FL recipients were cured. In conclusion. FL in a composite graft with FP resulted in better engraftment. earlier isograft function. and protection from cyclosporine islet toxicity.
Lower extremity percutaneous transluminal angioplasty: multifactorial analysis of morbidity and mortality, We analyzed the outcome of 202 percutaneous transluminal angioplasty (PTA) procedures performed between 1983 and 1989 to quantitate procedural risks and define factors associated with suboptimal results or immediate clinical failure. Premorbid factors studied included age. sex. treatment of single versus multiple lesions. stenoses versus occlusions. premorbid status of the limb (claudication vs limb threat). and most distal level of PTA. Adverse outcomes included complications (hematoma. acute occlusion. or thrombosis of PTA site. distal embolization. failure to dilate or cross. arterial dissection. rupture. and significant systemic derangement). major amputations (below knee and above knee). and deaths. There were 66 complications (32.7%). 22 amputations (10.9%). and 12 deaths (5.9%) in our series. Logistic regression analysis revealed that the major predictive variable for the occurrence of a complication (p = 0.002). and the only predictive variable for the outcomes of amputation and death (p = 0.0001 and p = 0.0139. respectively). was the premorbid clinical status of the limb. Lower extremity PTA is not an intrinsically benign procedure and is associated with a significant risk of complication. amputation. and procedure-associated death. These adverse outcomes cluster in patients with limb threat. Therefore it may be reasonable to restrict the use of PTA to patients with claudication and strictly selected cases of limb threat.
Circadian esophageal motor function in patients with gastroesophageal reflux disease, Effective esophageal peristalsis is a major determinant of esophageal clearance function and may contribute to the development of complications in gastroesophageal reflux disease. Using 24-hour ambulatory esophageal manometry. we compared the circadian esophageal motor activity of normal volunteers to that of patients with increased esophageal exposure to gastric juice and various grades of mucosal injury (no mucosal injury. esophagitis. stricture. or Barrett's esophagus). The prevalence of a mechanically defective lower esophageal sphincter. esophageal acid exposure time. and the frequency of nonperistaltic esophageal contractions during the supine. upright. and meal periods increased with increasing severity of mucosal injury. The median amplitude of esophageal contractions was compromised only in patients with a mechanically defective sphincter. This was particularly so in patients with stricture or Barrett's esophagus and was associated with an increased frequency of ineffective contractions (less than 30 mm Hg). These data show that esophageal motor function deteriorates with increasing severity of mucosal injury. This appears to be caused by persistent reflux of gastric juice across a mechanically defective lower esophageal sphincter. The need for surgical correction of a mechanically defective sphincter before the loss of esophageal body function is implicated.
Local recurrence after curative resection of colorectal adenocarcinoma, A total of 853 patients with 861 colorectal adenocarcinomas were operated on at our institution between 1965 and 1981. Complete follow-up information was obtained in all but six patients (99.4%). and all available histologic slides were reviewed to determine pathologic stage and characteristics. Six hundred fifty-one patients (76.3%) underwent a potentially curative procedure. and their operative mortality rate was 2.8%. Of the 627 patients available for analysis. 50 (8%) had a local recurrence. The median time to local recurrence was 18 months. and only 16% of local recurrences were diagnosed 5 years after the original resection. Median survival of patients with a local recurrence was 3 1/2 years from the original resection. and 16 patients (32%) survived 5 years or longer. A multivariate logistic regression analysis was conducted to examine the influence of several clinical and pathologic characteristics on local recurrence among Dukes' stages B and C adenocarcinomas (n = 539) after exclusion of patients with synchronous tumors (n = 8). postoperative deaths (n = 18). loss to follow-up (n = 6). or incomplete data (n = 11). This analysis revealed that the local recurrence rate was significantly related to depth of invasion (B1 + C1 = 0%; B2 + C1 = 10%; p less than 0.01). site of origin (right plus transverse colon = 6%; left plus rectosigmoid colon = 10%; rectum = 12%; p less than 0.05). and lymphatic or capillary microinvasion (absent. 6%; present. 14%; p less than 0.05). This analysis attempts to identify patients at high risk for development of local recurrent disease to select candidates for postoperative adjuvant therapy.
Intraoperative parathormone level measurement in the management of hyperparathyroidism, To investigate the potential use of intraoperative intact parathormone measurements to predict curative parathyroidectomy. we measured ionized calcium (Cai) levels and parathormone levels in 33 patients with hyperparathyroidism who underwent exploratory bilateral neck surgery. Nineteen patients each had a solitary adenoma. 13 patients had hyperplasia. and one patient had four normal parathyroid glands. These results were compared to the results for 37 patients who underwent either thyroid lobectomy (TL) (n = 10) or near-total thyroidectomy (NTT) (n = 27) and of 14 control patients who underwent miscellaneous operations. Parathormone decline after curative parathyroidectomy was 86.4 +/- 1.2% (mean +/- SE). which was significantly greater than a decline of 25.7% +/- 9.8% in three patients with persistent postoperative hyperparathyroidism (p less than 0.01). Declines were 38.5% +/- 8.7% after TL (p less than 0.01). 52.2% +/- 5.9% after NTT (p less than 0.01). and 8.3% +/- 4.3% (p less than 0.01). in the control patients. An intraoperative Cai decline of 4.0% +/- 0.6% after curative parathyroidectomy did not differ significantly from the results after TL. NTT. or miscellaneous operations in the control patients. Patients with persistent postoperative hyperparathyroidism had the greatest decline in Cai levels (7.1% +/- 2.3%; p less than 0.05). From these data we conclude that (1) a decline in parathormone level of 70% or more 20 minutes after parathyroidectomy is predictive of cure. (2) thyroidectomy. even unilaterally. produces a significant decline in parathormone level that affects interpretation of intraoperative parathormone level changes. (3) Cai level because of its slow decline is not useful in predicting effective parathyroidectomy. and (4) measurement of intraoperative parathormone level changes should not be used as a substitute for exploratory bilateral neck surgery.
Assessment of cardiac function in patients who were morbidly obese, Cardiac function of 30 patients who were morbidly obese was studied before bariatric surgery. Twelve patients were studied 13 +/- 4 months after surgery. These patients had a mean age of 37.1 +/- 2.9 years and a body mass index of 50.0 +/- 1.4 kg/m2. Cardiac function was measured by echocardiography. radionuclide angiography scanning. and right heart catheterization. To determine the degree of cardiac dysfunction. the patients were studied with exercise and intravenous fluid challenges. Ultrasonography produced evidence of myocardial thickening with an increased interventricular septum in eight patients (32%) and increased left ventricular mass in 17 patients (53%). The radionuclide scan suggested that morbid obesity was associated with a significantly (p less than 0.05) increased end-diastolic volume and decreased left ventricular ejection fraction as compared with patients who were of normal weight. With exercise the patient who was of normal weight had an increase in the end-diastolic volume. stroke volume. and heart rate. but the patient who was morbidly obese only increased heart rate to produce the necessary increase in cardiac output. Right heart catheterization indicated that the relationship of the pulmonary wedge pressure and the left ventricular stroke work index was abnormal in 14 of 29 patients (48.3%) and depressed in six of 29 patients (20.7%) with exercise. One liter of fluid caused an abnormal relationship of the pulmonary wedge pressure and the left ventricular stroke work index in 12 of 30 patients (40%) and a depressed response in 10 of 30 patients (33.3%). Cardiac studies were repeated in 12 patients after a 54.8 +/- 1.9 kg weight loss. Echocardiography indicated a decrease in dilatation (27.3% to 9.1%) and a significant (p less than 0.05) decrease in hypertrophy (45.5% to 0%). After the weight loss. radionuclide and right heart catheterization studies indicated improved cardiac function with reduced filling pressures and increased left ventricular work during fluid and exercise challenges. These results support the presence of obesity-related cardiomyopathy with ventricular dysfunction. which appears to be caused by a noncompliant ventricle. Significant weight loss achieved with gastroplasty results in increased ventricular compliance and improved cardiac function.
Trends in lung cancer, chronic obstructive lung disease, and emphysema death rates for England and Wales 1941-85 and their relation to trends in cigarette smoking, Trends in smoking associated respiratory diseases in England and Wales during 1941-85 have been studied. with careful attention to problems caused by changes in classification of cause of death. Three diseases were selected for analysis: lung cancer. emphysema. and chronic obstructive lung disease. During 1971-85 deaths that would previously have been certified under chronic bronchitis have increasingly tended to be classified under chronic airways obstruction. The definition of chronic obstructive lung disease that was used includes both terms to avoid the artificial decline caused by consideration of chronic bronchitis in isolation. Age specific rates for all three diseases show a pronounced cohort (period of birth) pattern. rates for men rising up to the rates for those born shortly after the turn of the century and then declining. and rates for women peaking in the cohort born 20-25 years later. For chronic obstructive lung disease. but not for lung cancer and emphysema. the cohort peak is superimposed on a sharply declining downward trend. In both sexes cohort patterns of cumulative cigarette consumption peak at a time broadly similar to those seen for the three diseases. Trends in cigarette consumption. however. cannot explain the underlying steeply declining rate of chronic obstructive lung disease. Nor can they fully explain the declining trends in lung cancer and emphysema rates in younger men and women.
Use of biological glue to control pulmonary air leaks, Biological glue is a natural adhesive generated by the interaction between fibrinogen (pre-glue) and thrombin to produce fibrin. The pre-glue is prepared from a single donor (to avoid the problems of pooled plasma) and stored as cryoprecipitate. Before being used it is thawed. dissolved in saline. and activated into an adhesive by the addition of topical thrombin. Biological glue was used prophylactically to prevent air leaks from bronchial suture lines and raw lung surfaces after pulmonary resections in six patients. In addition two new methods of using biological glue have been developed for the control of persisting air leaks. In selective intrabronchial tamponade the glue is instilled into the bronchial tree through a flexible bronchoscope. and in therapeutic pleurodesis it is instilled into the pleural cavity through a chest drainage tube. The air leaks were resolved in all cases. Seven procedures using selective intrabronchial tamponade were carried out in six patients. Four were immediately successful but three were not and required further interventions. Therapeutic pleurodesis alone was successfully carried out in one patient and as an adjunct to selective intrabronchial tamponade on two occasions. A thoracotomy was eventually needed in one of the seven patients.
Appropriate and inappropriate neuroendocrine products in pulmonary tumourlets, Pulmonary tumourlets are focal aggregates of neuroendocrine cells that occur in the periphery of the lung and may be associated with chronic inflammation and scarring. Six such lesions were seen in five lungs from a series of 35 pairs of lungs studied at necropsy. All were immunoreactive for neurone-specific enolase. protein gene product 9.5. and a range of neuroendocrine products. Of the peptides found in neuroendocrine cells in normal human lungs. gastrin releasing peptide was present in all tumourlets and calcitonin in all but one; none contained leucineenkephalin. Of a series of peptide and protein hormones not present in the neuroendocrine cells of healthy human lungs. growth hormone was present in all six tumourlets and adrenocorticotrophin in two. Identical patterns of peptide expression were displayed by neuroendocrine cells in the airway associated with the tumourlets in two cases. Such cells were increased in number and abnormally clustered. Aberrant expression of peptides might accompany the morphological changes in the pulmonary neuroendocrine cells seen in diseased lungs. their florid focal proliferation occasionally resulting in the formation of a tumourlet.
Plasma cross linked fibrin degradation products in pulmonary embolism, Plasma concentrations of cross linked fibrin degradation products. a marker of intravascular thrombosis and fibrinolysis. were measured in 495 patients with suspected pulmonary embolism referred for ventilation-perfusion lung scanning to determine whether concentrations are increased in pulmonary embolism and their potential use in diagnosis. Lung scans were described as normal (n = 66) or as showing a low (n = 292). indeterminate (n = 58). or high probability (n = 79) of pulmonary embolism. There was a difference between the mean levels of cross linked fibrin degradation products in each scan category: normal scans. 142 ng/ml; low probability scans. 295 ng/ml; indeterminate probability scans. 510 ng/ml; high probability scans. 952 ng/ml (p less than 0.001). Of the patients with high probability scans. 96% had raised concentrations. Explanations for discrepant low results include incorrect scan diagnosis. delay in blood sampling. and anticoagulation. Of the patients with a low or indeterminate probability of pulmonary embolism. 43% had increased concentrations of cross linked fibrin degradation products that could be attributed in most cases to another illness. Owing to the wide range of values in each lung scan diagnostic category. raised concentrations of these fibrin degradation products cannot be used without reference to the patient's clinical state as a discriminatory test for pulmonary embolism. Further evaluation of the significance of normal concentrations in excluding a diagnosis of pulmonary embolism appears to be warranted.
External detection of pulmonary accumulation of indium-113m labelled transferrin in the guinea pig, Accumulation of radioisotope labelled transferrin in the lungs of guinea pigs was determined with an external detection system. The method is based on the intravascular and extravascular distribution of indium-113m labelled transferrin compared with the intravascular distribution of technetium-99m labelled red blood cells. Guinea pigs were given iloprost. a prostacyclin analogue and potent pulmonary vasodilator. and noradrenaline. a pulmonary vasoconstrictor. in an attempt to increase and decrease respectively the blood volume in the lungs. Neither agent altered transferrin accumulation in the lung by comparison with a saline infusion. Iloprost infused before and after oleic acid infusion reduced macro-molecular leakage when compared with oleic acid alone. These data suggest that the double isotope method can distinguish between hydrostatic and injury induced pulmonary oedema.
Prostaglandin F2 alpha enhancement of capsaicin induced cough in man: modulation by beta 2 adrenergic and anticholinergic drugs, The effect of inhaled prostaglandin (PG) F2 alpha on the response to the inhaled tussive agent capsaicin was investigated in normal subjects. Seven subjects inhaled three breaths of four doses of capsaicin (0.3. 0.6. 1.2. and 2.4 nmol) before and immediately after inhaling PGF2 alpha (0.1 mumol) or placebo (0.15M NaCl) on separate days. The numbers of capsaicin induced coughs were greater after PGF2 alpha (mean 42.3 coughs) than after 0.15M sodium chloride (30.1). Visual analogue scores (0-10 on a 10 cm continuous scale) showed that capsaicin was more irritant after PGF2 alpha than after saline. Total respiratory resistance (Rrs). measured by the forced oscillation technique. was unaltered throughout the study. A double blind. placebo controlled study of the effects of inhaled salbutamol (200 micrograms. 0.6 mumol) and ipratropium bromide (40 micrograms. 0.1 mumol) on cough induced by capsaicin (2.4 nmol) and by PGF2 alpha (0.1 mumol) and on PGF2 alpha augmented. capsaicin induced coughing was performed in seven subjects. Neither drug had any effect on capsaicin induced coughing. Salbutamol reduced coughing due to PGF2 alpha (mean 7.7 coughs after salbutamol. 9.3 after placebo) but ipratropium bromide did not (mean 6.9 coughs after ipratropium bromide. 6.6 after placebo). Salbutamol also inhibited the augmentation of the capsaicin induced cough that followed inhalation of PGF2 alpha (mean augmentation 1.9 coughs after salbutamol. 4.1 after placebo). whereas ipratropium bromide did not (augmentation 1.7 coughs after ipratropium bromide. 2.7 after placebo). No changes in Rrs were seen after PGF2 alpha or either drug. Thus salbutamol reduces PGF2 alpha induced cough and the augmentation of capsaicin induced cough that follows PGF2 alpha.
Use of a fenestrated silicone drain to stent a malignant tracheobronchial stenosis, An innovative use of a fenestrated silicone drainage tube as an endobronchial stent is reported. The patient had respiratory obstruction due to a carinal tumour and laser photoresection had failed to restore airway patency.
Effort rupture of the diaphragm, Effort rupture of the diaphragm is rare and accounts for only 1% of all diaphragmatic injuries. A 23 year old patient with bilateral rupture that followed sudden movement is described.
Hemodynamics in internal carotid artery occlusion examined by positron emission tomography, Using positron emission tomography in nine patients with minor strokes. unilateral internal carotid artery occlusion. and good collateral circulation through the anterior portion of the circle of Willis. we analyzed regional cerebral blood flow. cerebral metabolic rate of oxygen. oxygen extraction fraction. and cerebral blood volume. These studies allowed quantification of the regional hemodynamic status. especially in relation to watershed areas. Compared with eight normal controls. the patients had significantly (p less than 0.01) decreased regional cerebral blood flow in the middle cerebral artery territory and the surrounding watershed areas of the occluded hemisphere. The oxygen extraction fraction rose with the distance from the anterior portion of the circle of Willis. attaining the highest value in the superior parietal and posterior temporo-occipital watershed area. A concomitant decrease in the cerebral blood flow/cerebral blood volume ratio suggested reduction in the mean blood flow velocity. whereby elevated blood viscosity would be more liable to reduce cerebral blood flow. These findings suggest hemodynamic vulnerability of the watershed areas after internal carotid artery occlusion in persons with good collateral circulation through the anterior portion of the circle of Willis. Our results also emphasize the importance of systemic hemodynamic factors such as blood pressure and circulating blood volume in the genesis of watershed infarction.
Acute and long-term changes in serum lipids after acute stroke, We studied serum lipid profiles in 171 patients less than or equal to 48 hours after the onset of acute stroke and 3 months later. The 83 patients suffering cerebral infarction had significantly higher serum concentrations of total cholesterol. low density lipoprotein-cholesterol. and apolipoprotein B and significantly lower serum concentrations of triglycerides and lipoprotein (a) less than or equal to 48 hours after ictus than 3 months later. The lipid profiles of the 53 patients suffering lacunar infarction were similar on both occasions. the only significant differences being higher total cholesterol and low density lipoprotein-cholesterol concentrations less than or equal to 48 hours after ictus. No significant changes were observed among the 35 patients suffering cerebral hemorrhage apart from a significantly higher concentration of high density lipoprotein3-cholesterol less than or equal to 48 hours after ictus. Our study. with many patients classified according to stroke subtype. gives results different from those of previous studies with much fewer patients. We conclude that in studies of serum lipid and lipoprotein concentrations as risk factors for cerebral infarction. comparing values obtained less than or equal to 48 hours after admission with control values may incorrectly identify certain lipid fractions as risk factors.
Beneficial effect of 1,3-butanediol on cerebral energy metabolism and edema following brain embolization in rats, We assessed the effect of 1.3-butanediol on cerebral energy metabolism and edema after inducing multifocal brain infarcts in 108 rats by the intracarotid injection of 50-microns carbonized microspheres. An ethanol dimer that induces systemic ketosis. 25 mmol/kg i.p. butanediol was injected every 3 hours to produce a sustained increase in the plasma level of beta-hydroxybutyrate. Treatment significantly attenuated ischemia-induced metabolic changes by increasing the concentrations of phosphocreatine. adenosine triphosphate. and glycogen and by reducing the concentrations of pyruvate and lactate. Lactate concentration 2. 6. and 12 hours after embolization decreased by 13%. 44%. and 46%. respectively. Brain water content increased from 78.63% in six unembolized rats to 80.93% in 12 saline-treated and 79.57% in seven butanediol-treated rats 12 hours after embolization. (p less than 0.05). The decrease in water content was associated with significant decreases in the concentrations of sodium and chloride. The antiedema effect of butanediol could not be explained by an osmotic mechanism since equimolar doses of urea or ethanol were ineffective. Our results support the hypothesis that the beneficial effect of butanediol is mediated through cerebral utilization of ketone bodies arising from butanediol metabolism. reducing the rate of glycolysis and the deleterious accumulation of lactic acid during ischemia.
Pharmacologic irreversible narrowing in chronic cerebrovasospasm in rabbits is associated with functional damage, We studied isolated basilar artery segments from a rabbit model of chronic cerebrovasospasm. Autologous blood placed around the basilar artery of rabbits killed 1. 2. 3. 4. 5. 6. 7. or 9 days later caused narrowing of the segments with a biphasic time course. The first (immediate) phase was reversed by intra-arterial papaverine; the second phase exhibited an increasing component of narrowing that was papaverine-insensitive. Based on the passive force/length curves. basilar artery segments became increasingly stiff over 9 days. By contrast. the segments' contractility decreased. Responses of the basilar artery segments were greater over the first few days. but then became less than that of saline-injected controls. Contractions in response to norepinephrine and potassium were reduced. Endothelium-based acetylcholine-induced vasodilation progressively diminished. as did the response to sympathetic nerve stimulation. There was a negative correlation between artery wall stiffness and contractility. The papaverine-insensitive component of angiographic narrowing correlated directly with loss of contractility and with artery wall stiffness. These results are consistent with the conclusion that increased artery wall stiffness is a primary determining factor in the arterial narrowing of chronic cerebrovasospasm.
Etiologic importance of the intimal flap of the external carotid artery in the development of postcarotid endarterectomy stroke, A technically unsatisfactory end point (transition from the removed diseased plaque to normal distal intima) leading to an intimal flap of the external carotid artery has been identified as a source of perioperative stroke. The mechanism involves thrombus formation with retrograde propagation of the thrombus and subsequent embolization of the internal carotid artery. This report describes three cases illustrating this mechanism and methods of identification and correction. This mechanism of postoperative stroke adds further justification for the routine use of intraoperative surveillance studies to document the technical result of endarterectomy involving the internal and external carotid arteries. When an unsatisfactory end point is identified in the external carotid artery. it should be corrected with the same sense of concern as a similar finding in the internal carotid artery.
Two cases of spontaneous internal carotid artery occlusion due to giant intracranial carotid artery aneurysm, Although spontaneous thrombosis of a giant intracranial aneurysm is relatively common. occlusion of its parent artery is rare. We describe two recent patients in whom the parent artery spontaneously occluded. One patient had severe stenosis of the left internal carotid artery. with delayed appearance of a faint shadow of vascular widening near the posterior clinoid process. One month later. complete occlusion of the left internal carotid artery was shown angiographically. The second patient had dysarthria and left hemiparesis. resulting in the diagnosis of a left internal carotid artery giant aneurysm. He had suffered an episode of visual disturbance of the right eye 5 years before. Angiography showed the right cervical internal carotid artery to be occluded. We believe the mechanism of parent artery occlusion in our two patients to be due first to stretching of the internal carotid artery by the enlarged aneurysm. followed by compression of the internal carotid artery by the aneurysm itself. Next. the anterior clinoid process and the optic nerve are involved. and. finally. thrombosis of the aneurysmal cavity extends into the internal carotid artery itself.
Effective ultraviolet irradiation of platelet concentrates in teflon bags, Several plastic materials used in blood storage were evaluated for their ability to transmit ultraviolet B (UVB) light. A plastic bag manufactured from sheets of transparent Teflon efficiently (78-86%) transmitted UVB light and was employed in subsequent functional studies of lymphocytes and platelets exposed to UVB light while contained in these bags. In vitro experiments showed a UVB dose-dependent abrogation of lymphocyte responder and stimulator functions. with concurrent preservation of platelet aggregation responses. In a phase I pilot study. UVB-treated platelet concentrates were administered to four bone marrow transplant recipients. Adverse effects attributable to the transfusions were not observed. and patients showed clinically effective transfusion responses. No patient developed lymphocytotoxic HLA or platelet antibodies. These studies suggest that platelets can be effectively irradiated with UVB light in a closed system. However. numerous variables. including container material. volume and composition of contents. steady exposure versus agitation. and exact UV wavelength. must be considered.
Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia, Reported here are studies of Fanconi anemia fetal cells that led to the first use of umbilical cord blood for hematopoietic reconstitution in a clinical trial. Prenatal diagnosis and HLA typing were performed in fetuses at risk for Fanconi anemia (FA) to identify. prior to birth. those that were unaffected with the syndrome and were HLA-identical to affected siblings. Umbilical cord blood was harvested at the delivery of these infants; assays of progenitor cells indicated the presence of colony-forming units-granulocyte-macrophage (CFU-GM) in numbers similar to those of bone marrow CFU-GM that are associated with successful engraftment in HLA-matched allogeneic bone marrow transplantation. The possibility that umbilical cord blood from a single individual can be used as an alternative to bone marrow for hematopoietic reconstitution has now been demonstrated by the successful engraftment of two patients with FA. Progenitor cell assays of umbilical cord blood collected at the birth of a child affected with FA. who had been misdiagnosed on the basis of chorionic villus sampling (CVS) studies. indicated a profound deficiency in colony formation. consistent with previously reported abnormalities in the growth of FA cells in vitro. These results suggest that the hematopoietic disorder in FA is related to an underlying problem with cell proliferation.
The differentiation of delayed serologic and delayed hemolytic transfusion reactions: incidence, long-term serologic findings, and clinical significance, Delayed serologic transfusion reactions (DSTRs) and delayed hemolytic transfusion reactions (DHTRs) were studied in a large tertiary-care hospital. A DSTR was defined by the posttransfusion finding of a positive direct antiglobulin test (DAT) and a newly developed alloantibody specificity. A DHTR was defined as a DSTR case that showed clinical and/or laboratory evidence of hemolysis. Thirty-four cases of DSTR. 70 percent of which were due to anti-E and/or -Jka. were documented prospectively over a 20-month period. Retrospective review of the medical records found clinical evidence of hemolysis in only 6 (18%) of the 34. Thus. the incidence of DSTR was 1 (0.66%) of 151 recipients with posttransfusion samples available for testing. whereas the incidence of DHTR was only 1 (0.12%) of 854 patients tested. Fifteen of the 34 patients were followed for up to 174 days after reaction. Twelve of the 15 still demonstrated a positive DAT with anti-IgG only. Eluate studies indicated that the persistence of a positive DAT after DSTR or DHTR may involve several immunologic mechanisms. including the development of posttransfusion autoantibodies. This study indicates 1) that DSTRs are a frequent finding in multiply transfused patients. although most cases are benign and fail to meet rigid criteria for DHTR. and 2) that the persistence of a positive DAT after DSTR or DHTR is common.
Detection of drug-dependent, platelet-reactive antibodies by antigen-capture ELISA and flow cytometry, The effectiveness of flow cytometry in the detection of drug-dependent. platelet-reactive antibodies was investigated. In studies of seven sera known to contain quinine- or quinidine-dependent. platelet-reactive antibodies. flow cytometry was 5 to 10 times more sensitive in detecting drug-dependent antibodies (DDAbs) than the 51Cr release assay. antigen-capture enzyme-linked immunosorbent assay (ELISA). and indirect immunofluorescence microscopic assay. With flow cytometry. DDAbs could be detected at drug concentrations as low as 0.1 microM. or less than one-tenth the level required with other methods. Antigen-capture ELISA was not as sensitive as flow cytometry in DDAb detection. but it did allow identification of the DDAbs' target molecules. With this assay. five of the seven DDAbs recognized both the glycoprotein Ib/IX (GPIb/IX) and glycoprotein IIb/IIIa (GPIIb/IIIa) complexes. while the remaining two sera reacted only with GPIb/IX. Of 44 consecutive patients who developed thrombocytopenia while taking quinidine. DDAbs were detected by flow cytometry in 11 (25%). more than twice the number detected by other methods. In one patient who developed thrombocytopenia while taking trimethoprim/sulfamethoxazole. DDAbs could be detected only by flow cytometry. It can be concluded that flow cytometry is highly sensitive in detecting DDAbs and allows their detection at pharmacologic concentrations of the drug. Most quinidine-dependent antibodies recognize at least two different glycoprotein complexes in the platelet membrane.
Incubation of platelet concentrates before transfusion does not improve posttransfusion recovery, Incubation of stored platelet concentrates (PCs) at 37 degrees C for 1 hour has been reported to result in a better morphology score and improved platelet recovery. A study was conducted in adult patients with leukemia to determine whether incubation of stored PCs results in an improved platelet recovery as measured by 10-minute posttransfusion corrected count increments (CCI). Eligible patients had platelet counts of less than 30.000 per microL and were clinically stable. Patients were transfused with 6 to 10 units of PC stored for 3 days (15 studies) or 4 days (5 studies). Platelets were pooled and then split in two equal volumes so that each patient received two sequential half-transfusions. one incubated at 37 degrees C for 1 hour and the other kept at 22 degrees C for 1 hour. Patients were randomized as to which half-transfusion was received first. The mean CCI of the incubated half-transfusions was 13.6 x 10(3) when they were given first and 14.5 x 10(3) when given second; this was not significantly different from the mean CCI of the nonincubated half-transfusions: 13.8 x 10(3) when they were given first and 13.8 x 10(3) when given second. In contrast to earlier reports. it can be concluded that incubation of pooled PCs does not improve platelet recovery.
Red cell autoantibodies, multiple immunoglobulin classes, and autoimmune hemolysis, The effects and interrelationships of multiple immunoglobulin coating (i.e.. increased red cell [RBC]-bound IgM and/or IgA in addition to IgG) were investigated in 404 patients with warm-reactive RBC autoantibodies on 590 occasions. Multiple immunoglobulins were detected by enzyme-linked direct antiglobulin tests in 218 samples (37%). but in only 87 (15%) by agglutination methods. Differences in populations were examined by chi-square. with p less than 0.005 being required for significance because of the multiple tests. Compared with IgG coating alone. multiple immunoglobulins were significantly associated with larger quantities (greater than 800 molecules/RBC) of IgG. multiple IgG subclasses. IgG3 and C3d bound to the cells. and with serum haptoglobin levels of less than 0.1 g per L. The latter association was still significant when higher levels of RBC-bound IgG and subclass pattern were taken into account. In samples with multiple immunoglobulin coating. there was no significant relationship (p greater than 0.05) between haptoglobins of less than 0.1 g per L and either C3d or multiple IgG subclasses. It was concluded that multiple immunoglobulin coating. even when undetected by agglutination methods. is a major cause of hemolysis: it is part of a more generalized autoimmune response and acts with other factors such as the quantity of bound IgG. the IgG subclass pattern. and complement; it also has an important hemolytic effect in its own right.
Clinical significance of white cell antibodies in febrile nonhemolytic transfusion reactions, Febrile nonhemolytic transfusion reactions (FNHTRs) are associated with white cell (WBC) antibodies. The purposes of this study were to determine the frequency of WBC antibodies. to associate the severity of reactions with antibody specificity. and to distinguish FNHTRs from infection and postoperative fever. By using the granulocyte indirect immunofluorescence test in conjunction with lymphocytotoxicity testing. it was found that 70 percent of FNHTRs in 24 patients involved WBC antibodies. The remaining 30 percent of apparent FNHTRs were associated with infections and postoperative fever. Granulocyte-specific antibodies were as prevalent as HLA antibodies and were associated with the severest reactions. Because FNHTRs occur with granulocyte-specific antibodies. HLA antibodies. and possible monocyte-specific antibodies (untested in this and other studies). these reactions could be grouped together as WBC-associated reactions.
Autoimmune hemolytic anemia in Kawasaki disease: a case report, A 3-year-old boy presented with the fever. conjunctivitis. rash. and lymphadenopathy diagnostic of Kawasaki disease. Treatment with antibiotics. aspirin. and intravenous immunoglobulin was instituted. The hematocrit decreased from 35 percent on admission to 11 percent by hospital Day 10. and the white cell count had increased from 13.7 to 42 x 10(3) per microL. and the patient had a leukoerythroblastic blood smear. The direct antiglobulin test demonstrated IgG but not complement on the red cell (RBC) surface. An acid eluate reacted (titer of 4) with all panel cells in the antiglobulin phase. Intravenous immunoglobulin from the same lot used for treatment did not contain antibody that reacted with the patient's group O RBCs or a panel of group O RBCs. but did contain IgG anti-A and -B (titer of 4). The patient received a transfusion and was given methylprednisone. The direct antiglobulin test and acid eluate were negative 4 days later. The patient had an uneventful recovery. The distinction between antibody-mediated hemolytic anemia and autoimmune hemolytic anemia is important in the treatment of this disease.
Use of somatostatin for complications occurring after liver transplantation, Somatostatin can be helpful after liver transplantation in some well-defined indications. In uncontrolled digestive haemorrhage. a short course of somatostatin therapy can be of great help in controlling the acute bleeding and to avoid emergency laparotomy. Somatostatin could also be helpful in bilio-pancreato-intestinal fistula. but in this case its advantage over elective surgical treatment remains to be confirmed.
Natural history of low-stage prostatic cancer and the impact of early detection, An expanding and increasingly older population. a rising incidence of prostate cancer. and uncertainties regarding treatment effectiveness have made this disease a target of special concern. The natural history of the cancer must be a consequence of host-tumor interactions. but little is known for sure about this subject. The growth rate of the tumor is determined by many factors. including genetic instability. At present. tumor grade. volume. and ploidy are the most useful techniques for judging the growth rate and metastatic potential. Stage A1 tumors generally are indolent. whereas stage A2 tumors are more aggressive. The natural history of stage B lesions is not well documented. The author asks two questions (Is cure necessary in those in whom it may be possible? Is cure possible in those in whom it may be necessary?) and reviews the problems inherent in screening for prostate cancer at this time.
Epidemiology of prostate cancer, Available epidemiologic data do not allow targeting of specific populations for prostate cancer screening or early detection programs. Although certain strong factors have been identified (age. race. location). none sufficiently defines high-risk groups in whom recommendations should differ from those of other age-matched patients. Certainly. a strong familial tendency has been identified. but the relative contribution of genetic and environmental factors in these patients remains unclear. Some hypotheses on the pathogenesis of prostate cancer are possible based on the available data. Genetic factors appear to be permissive. as are hormonal influences. which are partially regulated by genetics. Environmental factors appear to be promotional in genetically susceptible men. Dietary fat may also be an important promotional factor in genetically susceptible men. Dietary factors appear to exert some influence by modulating sex hormone concentration. Several factors demand more investigation and understanding of the epidemiology of prostate cancer. The relative frequency of the disease and the increasing death rate from prostate cancer are of concern. The similarities in the incidence of latent prostate cancer among various groups with strong differences in the rate of clinically apparent disease raise significant issues regarding potential lifestyle or environmental promotional factors. Further understanding of the pathogenesis of prostate cancer may allow a refinement and definition of programs for prevention and early detection of the disease.
Economics of screening for carcinoma of the prostate, The proposition of whether to adopt a system of mass screening for carcinoma of the prostate in the U.S. is well suited to the clinical decision analysis approach. The authors demonstrate this by using available data. which suggest that offering a screening program to all men ages 50 to 70 would be prohibitively expensive. The method also permits calculation of the eventual morbidity of screening and its costs. This analysis demonstrates the importance of attempting to predict ultimate patient outcomes before implementing any health care strategy as standard.
Digital rectal examination in the early detection of prostate cancer, Screening using digital rectal examination improves the clinical stage distribution of prostate cancer and prolongs survival. Unfortunately. digital rectal examination may not be sensitive enough to detect the small-volume tumors that are most amenable to cure. In several studies. approximately 50 per cent of cancers detected through screening had already spread beyond the prostate. Regardless. the key to demonstrating overall benefit from screening is a diminished disease-specific mortality rate. To date. this has not been shown. Lower mortality rates from prostate cancer can be demonstrated only through a randomized study comparing screened and unscreened populations. Such a study. which has recently been approved and funded by the National Institutes of Health. will require 10 to 15 years to complete. Until that time. the value of screening for prostate cancer by digital rectal examination or any other method will be unknown. Beyond a lack of proved benefit. screening for prostate cancer may be harmful because of the variable natural history of the disease and the morbidity and mortality rates associated with treatment. There exists a large population of patients with pathologically detectable prostate cancer who will never have clinical disease. The detection of some of these tumors may expose those patients to the risks of unnecessary treatment. Large-scale prostate cancer screening studies may ultimately be shown to be advantageous. The sooner this occurs. the earlier aggressive screening can be advocated. similar to screening for breast cancer. However. the temptation to embark on such screening programs without first demonstrating clear benefit should be resisted.
Transrectal ultrasonography for the early detection and staging of prostate cancer, Relatively recent changes and improvements in equipment have vastly increased image resolution for transrectal ultrasonography of the prostate. The expanded use of transrectal ultrasonography has greatly furthered knowledge of prostate zonal anatomy and permitted clinical evaluation of internal prostate architecture. The technique is operator dependent. as the quality of the results is related directly to that person's knowledge and experience. The significant majority of prostate cancers originate from the peripheral zone. Palpable stage B nodules characteristically have a hypoechoic appearance. There is disagreement about the tumor characteristics that cause hypoechogenicity. but large tumors may obscure the normal prostate anatomy and appear isoechoic because of the lack of contrast with surrounding prostate tissue. The transition zone of the prostate is the origin of benign prostatic hyperplasia and almost 20 per cent of prostate cancers. These tumors probably correspond to most stage A lesions. Transrectal ultrasonography is less accurate in identifying transition zone tumors because of the mixed echogenicity of the transition zone. interference from prostatic calculi or calcified corpora amylacea. and poorer image resolution in this area. Studies evaluating the use of transrectal ultrasonography for early detection of prostate cancer generally have shown a twofold increase in the detection rate compared with digital rectal examination. However. the decreased morbidity and expense of transrectal prostate biopsy using an automatic gun device have increased the frequency of biopsy in ultrasound-examined patients compared with those historically evaluated by digital rectal examination. The increased detection rate may in part be a function of the increased use of biopsies. independent of other factors. Transrectal ultrasonography rarely detects cancer in patient with normal digital rectal examination and a normal serum prostate-specific antigen level. Transrectal ultrasonography may be capable of identifying early capsular penetration or seminal vesicle invasion in some patients with known prostate cancer. However. its superiority to digital rectal examination for this purpose has not been demonstrated unequivocally. Ultrasonography does allow directed biopsies of the seminal vesicles or other suspect areas. and this may be helpful in staging the disease. The use of transrectal ultrasonography in prostate cancer has evolved rapidly. and changes in technology antiquate reports within a few years.(ABSTRACT TRUNCATED AT 400 WORDS).
Laboratory studies for the detection of carcinoma of the prostate, Acid phosphatase and prostate-specific antigen are extremely useful markers for the management of patients with prostatic carcinoma. Prostatic acid phosphatase. because of its relatively low sensitivity and specificity. as well as analyte instability and diurnal variability. is unsuitable for prostate cancer screening. Improved performance characteristics. stability. the lesser diurnal variation. and the association of elevated prostate-specific antigen with prostatic intraepithelial neoplasia make prostate-specific antigen possibly a better candidate for early detection of this common malignancy. Further investigations in this area are clearly indicated before we can recommend screening with prostate-specific antigen.
Radiation therapy for localized prostate cancer. Justification by long-term follow-up, In the series presented here. survival patterns at 15 years after radiotherapy for patients with clinical stage A carcinoma of the prostate did not deviate significantly from those of an age-matched peer group. For patients with clinical stage B disease (nodular disease that did not exceed involvement of one lateral lobe). survival was only 5% less at 15 years than for the age-matched group of California men. This was in spite of the fact that the lymph node status and the true incidence of capsular penetration were unknown. Moreover. the patients were not stratified by histopathologic grade or by either acid phosphatase or prostate-specific antigen values. If one were to restrict the patients to those with intermediate and low Gleason scores. normal acid phosphatase. and low prostate-specific antigen values. it is likely that there would have been no difference between the survival of those with prostatic cancer and their age-matched peers. As one deviates from these conservative selection criteria and includes patients with more advanced stages. the likelihood of achieving 15-year survival diminishes. With radiation treatment. however. patients whose disease. by clinical examination. extends beyond the prostate and who seem too advanced for radical prostatectomy still may have a 20 per cent to 30 per cent chance of 15-year survival.
Patient selection for, results of, and impact on tumor resection of potency-sparing radical prostatectomy, Our results show that by using the nerve-sparing radical retropubic prostatectomy. potency can be preserved in the majority of appropriately selected patients without compromising the adequacy of tumor excision. However. proper patient selection is important. Patients with focal. well-differentiated tumors. especially young patients with stage A or B1 tumors. are ideal candidates. In patients with more extensive and less well-differentiated tumors. there is a higher risk of incomplete tumor excision. Although we suspect that the adequacy of tumor excision is determined more by the extent of the tumor than by the technique of radical prostatectomy used. we believe that nerve-sparing surgery should be used with great caution. if at all. in patients with extensive or high-grade tumors. In these patients. microscopic extracapsular tumor extension is extremely common. can be impossible to detect at the time of operation. and is less likely to be adequately encompassed by nerve-sparing techniques. On the other hand. our current data provide little evidence that excision of the neurovascular bundles is beneficial. It is possible that more extensive resections will not materially alter the incidence of positive margins or cure rates. Finally. it might be argued that all forms of radical prostatectomy are inappropriate for patients with poorly differentiated clinical stage B2 prostate cancer for whom there are no really effective treatment options. We continue to recommend radical prostatectomy for these patients based on the finding that patients with clinical stage B2 disease who have organ-confined tumors can be expected to have excellent long-term disease-free survival rates similar to those of clinical stage B1 patients. In the remaining patients who are clinically understaged. the prospects for the minimal microscopic tumor remaining being controlled with adjunctive radiation therapy may be better than those of controlling the bulky primary tumor with radiation therapy alone. This hypothesis will need to be tested in a randomized clinical trial.
The case for no initial treatment of localized prostate cancer, This contribution summarizes the evidence from the natural history and pathology of this disease that. given the high incidence of latent cancer. a policy of radical treatment at diagnosis will represent over-treatment in the majority of cases. As yet. neither radical prostatectomy nor radical radiotherapy has been shown to be effective in managing the poorly differentiated tumor in the patient with "localized" disease. For the patient with well-differentiated disease. there is little evidence that early treatment is mandatory. because the majority of these patients will not die of prostatic cancer. The adoption of a policy of diagnosis followed by active surveillance would spare many patients the hazard and discomfort of a major operation or of a course of radiotherapy. would minimize expenditure. and would ensure that treatment was given only to those patients in whom progression had been demonstrated. Such an approach is almost certain to be as effective as treatment at diagnosis. Confirmation of this view is likely to be obtained from the existing studies of immediate versus delayed orchiectomy or LHRH therapy currently being undertaken by the Urological Working Party of the Medical Research Council in the United Kingdom and the Urological Group of the EORTC within Europe.
Current options in the management of clinical stage C prostatic carcinoma, The evaluation of clinical stage C prostatic cancer has been enhanced by advances in staging modalities over the past 15 years. Better staging of the local lesion is possible with transrectal ultrasound-guided multiple biopsies of the prostate and its vicinity. Biopsies of suspect pelvic lymph nodes guided by CT (or lymphangiography) may obviate pelvic lymphadenectomy. particularly in patients with high-grade stage C lesions. Advances in the understanding of serum markers have supplemented other staging information. No single therapeutic modality is appropriate for all cases of clinical stage C cancer. In C1 lesions. radical prostatectomy with adjunctive radiation or hormonal therapy seems to produce the best 5- and 10-year survival rates. External-beam radiation alone. or in combination with interstitial radiation. may have equivalent success. In clinical stage C2 disease. external-beam radiotherapy seems at present to be the best therapeutic modality. Interstitial radiation as a sole method of management in stage C disease carries a high local recurrence rate and a significant risk of metastatic progression. Transurethral prostatectomy and hormonal treatment continue to have a place in the management of selected poor-risk patients. The current results with surgery or radiation therapy alone are less than ideal. It is recommended that aggressive combination treatment be compared with monotherapy in randomized clinical trials monitored jointly by radiation and urologic oncologists.
Flow cytometry in carcinoma of the prostate, Flow cytometry is a quantitative cytologic technique with demonstrated utility in the assessment of prostate cancer as well as other tumors. The authors summarize current data on its use in disease detection and diagnosis. prognostic evaluation. and monitoring of response to therapy. They also project future developments.
Squamous cell carcinoma antigen (TA-4) in penile carcinoma, TA-4 antigen. originally isolated from women with squamous cell carcinoma of the cervix. is elevated in the sera of patients with squamous cell carcinomas of several sites. including esophagus. lungs. and head and neck. In this study. we compared the serum levels of TA-4 in normal volunteers. patients with resected penile squamous cell carcinoma. and patients with metastatic penile squamous cell carcinoma. TA-4 values were elevated in 5 of 11 patients (45%) who had metastatic disease. In 2. TA-4 was normal the first time metastasis was clinically detected but rose as the disease progressed. Moreover. in 3 patients in whom serial determinations were made. serum TA-4 values correlated well with disease progression and response to treatment. We conclude that TA-4 values are elevated in some patients with metastatic squamous cell carcinoma of the penis and may become a useful marker for monitoring response to therapy.
Treatment of primary nocturnal enuresis by oral androgen mesterolone. A clinical and cystometric study, A double-blind clinical study of 30 boys. six to ten years of age. with primary nocturnal enuresis was undertaken to assess the role of androgens in treating enuresis. The oral synthetic androgen mesterolone was selected because of its minimal potential toxic effects. Twenty boys were treated with mesterolone and 10 received placebo. Fourteen boys (70%) became dry during treatment (20 mg daily for 14 days). and 5 (25%) remained dry for a follow-up period of four months. Increased cystometric bladder capacity and disappearance of uninhibited detrusor contractions were noticed in a significant number of cases after treatment. No side effects were recorded. Mesterolone has probably modulated the autonomic innervation of the vesical musculature with correction of the defective neural mechanism which is believed to be implicated in the pathogenesis of nocturnal enuresis.
Urothelial grafts in mice, Mouse bladder epithelium has been successfully transplanted to the bladders of syngeneic mice and has survived for at least twenty weeks. The fate of the transplanted tissue was followed using a fluorescein label. The recipient bladders were prepared by stripping the urothelium either by a surgical or a chemical method. The possibility of adopting a comparable technique for the treatment of early bladder cancer in man is discussed.
Uneventful delivery following series of successive treatments for virilized Cushing syndrome due to adrenocortical carcinoma, A twenty-one-year-old virilized woman with Cushing syndrome due to a huge adrenocortical carcinoma was successively treated with trilostane (3 beta-hydroxysteroid dehydrogenase inhibitor). subsequent adrenalectomy. and postoperative cis-platinum. Clinical or biochemical abnormalities peculiar to Cushing syndrome gradually subsided. and three and one-half years after the adrenal surgery. the patient delivered a normal female infant. This study points out some of the clinical and biochemical responses of each treatment.
The changing epidemiology of diabetes mellitus among Navajo Indians, Although early descriptions of diabetes mellitus among Navajo Indians characterized the disease as an infrequent and "benign chemical abnormality." the prevalence of diabetes and its complications among Navajos appears to have increased substantially in this century. We reviewed recent Indian Health Service inpatient and ambulatory care data and compared these data with previous reports. Of the estimated Navajo population aged 45 years or older. 4.331 (16.9%) had an ambulatory care visit for diabetes between October 1. 1986. and September 30. 1987. Diabetes was coded for 1.041 (7.0%) of hospital admissions of persons aged 20 and older. Of 377 lower-extremity amputations done from 1978 to 1987. diabetes was involved in 245 (66%). The 1986 age-adjusted mortality rate from diabetes was 30.3 per 100.000. approximately twice that for the general US population. The explanation for the increased prevalence of diabetes mellitus among Navajos probably relates to an increasing prevalence of obesity.
Alcohol and trauma. An endemic syndrome, Injuries are a pervasive and costly problem. and alcohol use appears to be an important risk factor for injury. We examined the blood alcohol levels and selected demographic and epidemiologic variables recorded on trauma patients by 1 trauma center for a 28-month period. A total of 2.262 trauma patients were admitted to the trauma center during this period. of whom 75% were male and 72% were injured in vehicle-related incidents. Blood alcohol levels of 2.095 patients (93%) were measured. and alcohol was present in the blood of 855 (41%). Of those patients with a blood alcohol level done. 32% had a level higher than 100 mg per dl. We conclude that the level of alcohol involvement in trauma is high and that this involvement must be addressed by the medical community and the health care system.
From Leningrad to the day-care center. The ubiquitous Giardia lamblia, Giardiasis is recognized as a worldwide public health problem. Seroprevalence data from both the developing and developed world show high rates of carriage in populations at risk for fecal-oral transmission. such as children in day-care centers. Outbreak investigation has expanded our understanding of reservoirs for Giardia lamblia and of the routes of transmission. Various host factors have been associated with infection. The pathogenesis of giardial infections is being elucidated. in particular the role of lectin activation in producing disease. Three standard chemotherapeutic agents are available in the United States. The institution of community-wide prevention measures is equally important. Current areas of investigation including antigenic composition and enzymatic variants should result in effective forms of immunotherapy. while more effective forms of chemoprophylaxis could assist in eradicating the pathogen from institutional settings.
Selenium. Nutritional, toxicologic, and clinical aspects, Despite the recent findings of environmental contamination. selenium toxicosis in humans is exceedingly rare in the United States. with the few known cases resulting from industrial accidents and an episode involving the ingestion of superpotent selenium supplements. Chronic selenosis is essentially unheard of in this country because of the typical diversity of the American diet. Nonetheless. because of the growing public interest in selenium as a dietary supplement and the occurrence of environmental selenium contamination. medical practitioners should be familiar with the nutritional. toxicologic. and clinical aspects of this trace element.
Prostaglandins, the kidney, and hypertension, Prostaglandins are part of the family of oxygenated metabolites of arachidonic acid known collectively as eicosanoids. While they are formed. act. and are inactivated locally and rarely circulate in plasma. they can affect blood flow in some tissues and so might contribute to the control of peripheral vascular resistance. Few studies have shown any derangement of total body prostaglandin synthesis or metabolism in hypertension. but increased renal synthesis of one prostanoid. thromboxane A2. has been noted in spontaneously hypertensive rats and some hypertensive humans. This potent vasoconstrictor may account for the increased renal vascular resistance and suppressed plasma renin activity seen in many patients with hypertension. Increased renal vascular resistance could increase the blood pressure directly as a component of total peripheral resistance or indirectly by increasing glomerular filtration fraction and tubular sodium reabsorption. Specific thromboxane synthesis inhibitors not only decrease renal thromboxane production but also increase renal vasodilator prostaglandin synthesis when prostaglandin synthesis is stimulated. This redirection of renal prostaglandin synthesis toward prostacyclin might be of benefit in correcting a fundamental renal defect in patients with hypertension.
Overview of hemochromatosis, Hemochromatosis is an autosomal recessive genetic disorder that occurs with high prevalence in populations of European origin. The gene that is abnormal in hemochromatosis is found on the short arm of chromosome 6 in close proximity (approximately 1 centimorgan) to HLA-A. but the product coded for by that gene is unknown. The pathogenetic mechanism in hemochromatosis is that of continued. excessive absorption of dietary iron with loss of normal control mechanisms. leading to a gradual but vast expansion of storage iron as ferritin and especially as hemosiderin. Through mechanisms that probably include peroxidation of lipid membranes. the excess iron injures hepatocytes. islet B cells. gonadotropes in the anterior pituitary. myocardium. synovial cells. and chondrocytes. and probably other cells and tissues as well. Most patients with hemochromatosis remain undiagnosed throughout life. Removal of the excess iron by phlebotomy will prevent all of the complications of hemochromatosis when begun early and will significantly improve survival in virtually all patients. It is important. therefore. that the diagnosis of hemochromatosis be considered much more frequently in clinical medicine in order that this effective therapy be utilized.
Inhaler and spacer use in obstructive airway diseases, The role of inhaled aerosols in the treatment of obstructive airway diseases is increasing for both immediate bronchodilation and prophylactic anti-inflammatory effects. Inhaled aerosol agents are available in metered-dose inhaler and nebulizer forms. Maximum therapeutic benefit from metered-dose inhalers is assured when the correct inhaler technique is used. Spacer devices may be helpful in some patients.
Puffer fish poisoning, Regarded by many as a delicacy. puffer fish can be the source of lethal food poisoning in humans. The syndrome is caused by tetrodotoxin. one of the most potent poisons known. Intoxication produces a constellation of symptoms. with paresthesias and generalized muscle weakness being common complaints. Treatment is symptomatic and often needs to be aggressive. Life support may be required. In some series. the mortality rate has approached 60 percent.
HIV disease: a review for the family physician. Part I. Evaluation and conventional therapy, Family physicians will be challenged with caring for increasing numbers of patients infected with human immunodeficiency virus. After confirming the presence of the infection. the physician must follow a logical sequence of evaluation. counseling and treatment. The current Centers for Disease Control classification and a series of evaluation and treatment protocols form the basis for prescribing zidovudine to delay or mitigate involvement of T lymphocytes and neuronal cells.
Ascariasis, Ascaris lumbricoides is the most common helminth to infect humans. Infection occurs when contaminated soil containing mature eggs is swallowed. Clinically. infection ranges from the asymptomatic carrier state to life-threatening pulmonary disease or intestinal obstruction. Diagnosis is most frequently established by identification of the eggs in stool specimens. Treatment with antiparasitic drugs is effective in preventing serious complications and eradicating the parasite from all members of the household.
Time delays in the diagnosis and treatment of acute myocardial infarction: a tale of eight cities. Report from the Pre-hospital Study Group and the Cincinnati Heart Project, To establish the magnitude of prehospital and hospital delays in initiating thrombolytic therapy for acute myocardial infarction. the time from telephone 911 emergency medical system (EMS) activation to treatment and its components were analyzed from eight separate ongoing trials. This included estimates of ambulance response time. prehospital evaluation and treatment time. and time from admission to the hospital to initiation of thrombolytic therapy. The average time from EMS activation to patient arrival at the hospital was prospectively determined to be 46.1 +/- 8.2 minutes in 3715 patients from eight centers. The time from admission to the hospital to initiation of thrombolytic therapy was retrospectively determined to be 83.8 +/- 55.0 minutes in a separate group of 730 patients from six centers. Both the prehospital and hospital time delays were much longer than those perceived by paramedics and emergency department directors. Shorter hospital time delays were observed in patients in whom a prehospital ECG was obtained as part of a protocol-driven prehospital diagnostic strategy and a diagnosis of acute infarction made before arrival at the hospital (36.3 +/- 11.3 minutes in 13 patients). These results show that the magnitude of time required to evaluate. transport. and initiate thrombolytic therapy will preclude initiation of treatment to most patients within the first hour of symptoms. Implementation of a protocol-driven prehospital diagnostic strategy may be associated with a reduction in time to thrombolytic therapy.
Intracoronary adenosine administration during reperfusion following 3 hours of ischemia: effects on infarct size, ventricular function, and regional myocardial blood flow, Previous studies have demonstrated that adenosine significantly enhances myocardial salvage after 90 minutes of regional ischemia. To determine its effect after prolonged ischemia. closed-chest dogs underwent 3 hours of left anterior descending artery occlusion followed by 72 hours of reperfusion. Intracoronary adenosine (3.75 mg/min; at 1.5 ml/min:total volume = 90 ml; n = 10) or an equivalent volume of saline (1.5 ml/min: total volume = 90 ml; n = 9) was infused into the left main coronary artery during the first 60 minutes of reperfusion. Regional myocardial blood flow was assessed serially with microspheres and regional ventricular function was assessed by contrast ventriculography. Infarct size was determined histologically. Light and electron microscopy were utilized to assess neutrophil infiltration and microvascular injury. Adenosine failed to reduce infarct size expressed as a percentage of the area at risk (38.0 +/- 4.9% versus 34.8 +/- 4.6%; p = NS) or to improve regional ventricular function as measured by the radial shortening method (3.2 +/- 1.8% versus 2.2 +/- 3.1%; p = NS) at 72 hours after reperfusion. Vasodilatory effects were not observed in the endo- and midmyocardial regions of the ischemic zone during adenosine administration. This was associated with a similar extent of capillary endothelial changes and neutrophil infiltration in both adenosine-treated and saline control groups. These results suggest that severe functional abnormalities are present in the vasculature after 3 hours of ischemia and that adenosine therapy is ineffective in enhancing myocardial salvage.
Clinical significance of plasminogen activator inhibitor activity in patients with exercise-induced ischemia, To assess the fibrinolytic system in patients with exercise-induced ischemia and its relation to ischemia and severity of coronary artery disease (CAD). 47 patients with CAD confirmed by results of coronary angiography underwent symptom-limited multistage exercise thallium-201 emission computed tomography. All patients with CAD had exercise-induced ischemia as assessed from thallium-201 images. Pre- and peak exercise blood samples from each patient and preexercise blood samples from control subjects were assayed for several fibrinolytic components and were also assayed for plasma adrenaline. The extent of ischemia was defined as delta visual uptake score (total visual uptake score in delayed images minus total visual uptake score in initial images) and the severity of CAD as the number of diseased vessels. In the basal condition. plasminogen activator inhibitor (PAI) activity was significantly higher in patients with exercise-induced ischemia as compared to control subjects (p less than 0.01). although there were no significant differences in other fibrinolytic variables between the two groups. Moreover. PAI activity in the basal condition displayed a significantly positive correlation with the extent of ischemia (r = 0.47. p less than 0.01). Patients with exercise-induced ischemia were divided into two groups (24 with single-vessel disease and 23 with multivessel disease). There were no significant differences in coronary risk factors. hemodynamics. or plasma adrenaline levels during exercise between single-vessel and multivessel disease except that delta visual uptake score was significantly higher in multivessel disease (p less than 0.01).
Comparison of coronary angiography and early oral dipyridamole thallium-201 scintigraphy in patients receiving thrombolytic therapy for acute myocardial infarction, We evaluated 50 consecutive patients who received thrombolytic therapy for acute myocardial infarction using thallium-201 single photon emission computed tomography in combination with oral dipyridamole (300 mg) to assess the frequency of residual myocardial ischemia. Thallium studies were performed early after myocardial infarction at a mean of 4.6 days (range 3 to 11) in 50 patients. The time from the onset of chest pain to the administration of thrombolytic therapy was 2.6 hours (range 0.5 to 5.5). Q wave myocardial infarction was evident in 46 patients; four patients had a non-Q wave infarction (anterior infarction in 31 patients and inferior infarction in 19 patients). The serum mean peak creatinine kinase was 1503 IU/L (range 127 to 6500). Coronary angiography was performed in all patients at a mean of 3.1 days (range 2 to 10) and revealed the infarct-related vessel to be patent in 36 patients (72%). The ejection fraction was 48% (range 26% to 67%). After dipyridamole administration. 13 patients (26%) developed angina that was easily reversed with the administration of intravenous aminophylline. Systolic blood pressure decreased from 122 to 115 mm Hg (p less than 0.05) and the heart rate increased from 76 to 85 beats/min (p less than 0.05). None of the patients had significant hypotension. arrhythmias. or evidence of infarct extension. Perfusion abnormalities were present on the initial thallium images in 48 patients. Redistribution suggestive of ischemia was present in 36 patients (72%). Ischemia confined to the vascular distribution of the infarct vessel was evident in 22 patients. Seven patients had ischemia in the infarct zone as well as in a remote myocardial segment. Thus 29 patients (58%) had ischemia in the distribution of the infarct vessel. Ischemia in the infarct zone was evident in 19 of 36 patients (53%) with open infarct vessels and in 10 of 14 patients (71%) with occluded infarct vessels. In conclusion. thallium-201 single photon emission computed tomography using oral dipyridamole was safely performed in patients with recent myocardial infarctions who receive thrombolytic therapy.
Prolongation of ventricular refractoriness by class Ia antiarrhythmic drugs in the prevention of ventricular tachycardia induction, The effects of class la antiarrhythmic drugs (procainamide. quinidine) on the right ventricular effective refractory period (VERP) and intraventricular conduction time were assessed during serial invasive electrophysiologic studies for sustained monomorphic ventricular tachycardia (VT). In 47 patients with remote myocardial infarction. sustained VT was inducible by up to two extrastimuli after the basic drive at one of two basic cycle lengths at the right ventricular apex. With oral drug administration. sustained VT was no longer inducible (group I) in 27 patients but remained inducible (group II) in 20 with the same protocol. Class la drugs prolonged the VERP in both groups. but there was greater lengthening when drugs were effective (e.g.. +32 +/- 14 msec in group I vs +12 +/- 19 msec in group II; p less than 0.005. basic cycle length 600 to 700 msec). Prolongation of the VERP by greater than 30 msec had an 88% positive predictive value for prevention of sustained VT induction. In all except one patient in group I. drugs prolonged the VERP such that the coupling intervals that had resulted in sustained VT induction under control conditions were no longer attainable. In contrast. conduction time through the ventricle (surface QRS duration) in sinus rhythm and during right ventricular pacing was prolonged similarly regardless of efficacy (e.g.. +33 +/- 21 msec vs +27 +/- 27 msec at a cycle length of 400 msec). The presence of similar plasma levels of drug did not imply equivalent prolongation of the VERP in the two groups. These results suggest that greater prolongation of the VERP by oral procainamide or quinidine correlates with drug efficacy against VT induction and is a better predictor of drug effect than achievement of a "therapeutic plasma level.".
Lesions in side branches of arteries having undergone percutaneous transluminal coronary angioplasty: a histopathologic study, Percutaneous transluminal coronary angioplasty (PTCA) may cause occlusion in side branches. No histologic studies. however. have been made on side branches of the arteries in which PTCA has been performed. A histologic study was therefore made to explain the effect of PTCA on side branches. Histologic specimens were prepared by serial step sectioning from 15 side branches of 10 autopsied cases that had undergone PTCA. The results of examination by light microscope were as follows: (1) Stenoses due to PTCA were seen in seven branches (46.7%). (2) The stenoses were classified into three types: (a) stenosis due to blocking of the orifice of a side branch by the disrupted portion of the intima of the main artery (one branch); (b) stenosis due to medial dissection of the main artery or further dissection occurring even in the side branches (three branches); and (c) stenosis due to fragmentation of the internal elastic lamina of the main artery accompanied by proliferation of smooth muscle cells even in the side branch (three branches). It is now clear that stenosis is caused in side branches long after PTCA. Extra care is required when major side branches exist in the portion where this procedure is to be performed.
Left ventricular end-systolic stress-volume index ratio in aortic and mitral regurgitation with normal ejection fraction, To evaluate the left ventricular contractile state in regurgitant valvular disease with normal ejection fraction. we analyzed the end-systolic stress-volume index relationship (ESSVR) by means of cineangiography in 15 normal subjects. 11 patients with aortic regurgitation (AR). and 10 patients with mitral regurgitation (MR) whose ejection fraction (EF) was 60% or more. The end-systolic stress-volume index ratio in normal subjects was 5.57 +/- 0.60 kdyne/cm5/m2 (mean +/- standard deviation). and we defined the range including +/- 2 standard deviations of the ratio as the normal ESSVR range. Six patients with AR and five patients with MR placed inside the normal ESSVR range. termed AR IN and MR IN. but the remaining five patients with AR and MR placed to the right of the normal range. termed AR OUT and MR OUT. EF did not differ between patients with AR IN and AR OUT (69.4 +/- 5.4 verus 70.7 +/- 6.1%) and between MR IN and MR OUT (71.6 +/- 3.6 versus 71.1 +/- 7.9%). The EF of the subdivided groups with AR and MR also did not differ from that of normal subjects (70.7 +/- 7.3%). This finding showed that the left ventricular contractile state was depressed in patients with AR OUT and MR OUT despite a normal EF. In AR and MR the end-systolic stress and end-systolic volume index of OUT did not differ from those of IN. but the end-diastolic volume index of OUT was larger than that of IN (AR OUT 156.8 +/- 27.9 versus AR IN 110.8 +/- 24.1 ml/m2. MR OUT 160.5 +/- 44.7 versus MR IN 101.0 +/ 16.6 ml/m2; both p less than 0.05). and the regurgitant fraction of OUT was higher than that of IN (AR OUT 52.6 +/- 13.6 versus AR IN 29.7 +/- 13.3%. MR OUT 52.9 +/- 10.2 versus MR IN 30.2 +/- 11.4%; both p less than 0.05). In addition. there was a linear inverse correlation between the end-systolic stress-volume index ratio and the end-diastolic volume index in all subjects (r = -0.82. n = 36). In normal subjects there was a linear inverse correlation between end-systolic stress and the EF (r = -0.91. n = 15). but this relationship failed to separate patients with OUT from those with IN. Results of the present study suggest that some patients with AR and MR whose EF was normal had a depressed contractile state. and these patients had a large end-diastolic volume index and a high regurgitant fraction.(ABSTRACT TRUNCATED AT 400 WORDS).
Maximal oxygen uptake in severe aortic regurgitation: a different view of left ventricular function, Respiratory gas exchange was used to assess left ventricular (LV) function in 22 patients with severe aortic regurgitation (19 men and three women. aged 18 and 70 years. mean 49 years). Anaerobic threshold and symptom-limited maximal oxygen consumption (VO2 max) were measured during treadmill exercise. and the results were compared with conventional echocardiographic and radionuclide indices of LV systolic function. The results were considered with respect to the patients' New York Heart Association functional class. Both rest and exercise LV ejection fractions were variable. but the mean results were similar in all classes. The echocardiographic indices of LV cavity dimensions. fractional shortening. radius/thickness ratio. and systolic wall stress also showed a wide range but with similar mean results in each class. In contrast. VO2 max and anaerobic threshold showed a relationship to functional class. VO2 max was 32.4 +/- 3.4 ml/kg/min in age-matched control subjects; in the patients it was 27.9 +/- 4.7 in class I. 24.7 +/- 5.7 in class II. and 14.2 +/- 2 in the combined class III/IV. Results in patients in classes I and II were similar. but both groups were significantly different from control subjects (p less than 0.05) and from patients in class III/IV (p less than 0.01). About half of the patients with moderate LV dysfunction (judged by reduced VO2 max) were asymptomatic. and LV function was impaired in 4 of 10 patients in class I. Thus. unlike conventional indices of LV function. VO2 max appeared capable of distinguishing patients with moderate-to-severe LV dysfunction from those with little or no LV dysfunction. Measurement of respiratory gas exchange appears to be a valid and useful supplementary means of assessing LV function in severe aortic regurgitation. Further long-term evaluation is required.
Contribution of transesophageal echocardiography to patient diagnosis and treatment: a prospective analysis, The capability of transesophageal (TEE) versus transthoracic (TTE) echocardiography as a diagnostic tool in clinical practice was prospectively examined in 86 consecutive cases. A conclusive diagnosis was possible in 95% with TEE. whereas the same result was achieved in 48% by TTE. Specifically. TEE provided a conclusive diagnosis in 14 of 16 cases of infective endocarditis. while TTE gave this result in 4 of the 16 cases (p less than 0.001). Similarly. TEE allowed a conclusive diagnosis in 11 of 11 instances of aortic dissection. while TTE gave this indication in two cases (p less than 0.001). TEE was similarly effective in eight of eight cases of atrial thrombi. whereas TTE gave the diagnosis in three of eight cases (p less than 0.01). In five subjects with intracardiac masses. TEE gave a conclusive diagnosis in all five. whereas TTE was able to diagnose conclusively in one subject (p less than 0.02). In seven patients with mitral regurgitation. TEE gave the conclusive diagnosis in all seven and TTE was able to provide this information in four (p = NS). TEE was able to provide a conclusive diagnosis in four patients with aortic insufficiency. and TTE gave the same information in two of the four (p = NS). In 14 patients with prosthetic valve dysfunction. TEE gave the diagnosis in 12 and TTE gave it in eight patients (p = NS). Both methods gave a conclusive diagnosis in 13 out of 13 cases of mitral stenosis (p = NS). Also. TEE provided a conclusive diagnosis in eight of eight patients with adult congenital heart disease and TTE gave this information in four (p = NS).
Left ventricular mass regression after aortic valve replacement measured by ultrafast computed tomography, Left ventricular mass and function were measured using ultrafast computed tomography. and were correlated with clinical status in 17 patients with aortic stenosis and/or insufficiency undergoing aortic valve replacement or balloon valvuloplasty. Wall mass was 159 +/- 38 gm/m2 initially. decreased 25% to 116 +/- 29 gm/m2 at 4 month (p less than 0.001). and decreased a total of 34% to 105 +/- 33 gm/m2 at 8 months after valve repair. By 8 months not only was the mean wall mass within the normal range. but only three patients retained abnormal hypertrophy. Ejection fraction increased 8% (p = 0.06). Clinical function improved in all patients. with only three patients remaining outside of New York Heart Association functional class 1 at 8 months. Regression of ventricular mass into the normal range correlated with attainment of class 1 functional status (p less than 0.02). despite a lack of increase of ejection fraction. The single patient followed for 8 months after valvuloplasty had minor wall mass regression and minor clinical improvement.
Hypertensive heart disease: relationship of silent ischemia to coronary artery disease and left ventricular hypertrophy, ECG evidence of silent ischemia occurs commonly in patients with systemic hypertension. but its relationship to left ventricular hypertrophy (LVH). large-vessel coronary artery disease (CAD). and neurohumoral factors remains unclear. Accordingly we validated the results of the echocardiographic method used to measure left ventricular (LV) mass in the Soviet Union by comparison with necropsy measurements in 30 patients. and we examined the relationships in 46 men with essential hypertension among ST segment depression during ambulatory monitoring. exercise stress and transesophageal pacing (n = 38). and LV mass. catheterization evidence of CAD (n = 25). and neurohumoral factors (plasma catecholamines and platelet aggregability). Echocardiographic measurements of LV mass by both the Soviet and Penn methods were closely correlated with necropsy values (r = 0.78 and 90. respectively; both p less than 0.001). During ambulatory monitoring from 1 to 17 episodes of greater than or equal to 1 mm ST depression occurred in 26 of 46 (65%) patients with hypertension; ischemia was also provoked by exercise or pacing stress in most but not all of these patients (65% and 80%. respectively). Neither ST depression nor the occurrence of additional episodes of symptomatic angina was related to the presence of coronary obstruction at catheterization; patients with and without ST depression did not differ in age. blood pressure. or LV mass.
Marfan syndrome in China: a collective review of 564 cases among 98 families, This is a collective review of 564 patients with Marfan syndrome among 98 pedigrees reported from 18 provinces and cities in China over a 37-year period from 1951 to 1987. A positive family history of Marfan syndrome was found in 74.3% of the patients: the mode of inheritance was dominant in 73.8% and recessive in 0.5%. Sporadic cases occurred in 25.7%. A screening of 29.067 children found five children with Marfan syndrome. giving a prevalence of 17.2 per 100.000 of the population. a gene frequency of 8.61 per 100.000 genes. and a penetrance of 71.69%. Pleiotropy was clear in these cases: arachnodactyly in 77%. ectopia lentis in 86.8%. and dilated aortic root in 80.1%. Chromosome examination showed no regular aberrations except in a family of five in whom a giant-satellited chromosome 14 was found in three afflicted members but not in the two unaffected relatives. The high prevalence of aortic root dilation in Marfan syndrome makes echocardiography the most useful and practical means of diagnosis. Close follow-up and regular echocardiographic evaluation are indicated not only in patients with Marfan syndrome but also in their families. for both diagnostic and therapeutic purposes.
Parental history is an independent risk factor for coronary artery disease: the Framingham Study, Family history of CAD. defined as parental death by CAD. was found to be a significant independent predictor of CAD in a logistic regression model controlling for standard risk factors and length of follow-up among the 5209 participants in the Framingham Study. Persons with a positive parental history have a 29% increased risk of CAD. and the strength of the association between parental history and CAD is similar to that found for other standard risk factors such as systolic blood pressure. cholesterol level. and cigarette smoking. No evidence was found that persons with a family history of CAD have a decreased capacity to cope with the deleterious effects of known risk factors; that is. no significant interaction was found between any of the risk factors and parental history of CAD. Among men with low risk for CAD by risk-factor profile (i.e.. nonsmoking. thin. nonhypertensive persons). more than two thirds of those who experience CAD have a positive parental history. This study suggests that CAD among persons who are predicted to be at low risk by standard risk factors may have a substantial genetic component and that the risk associated with parental history may not be reduced by modification of these factors. Nevertheless. among persons with a positive family history. those with a favorable risk profile are at substantially less risk for CAD than those with an unfavorable risk profile.
Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II--DAVIT II), The effect of verapamil on death and major events (i.e.. death or reinfarction) after an acute myocardial infarction was studied in a double-blind. randomized. placebo-controlled multicenter trial. Eight hundred seventy-eight patients started treatment with verapamil. 360 mg/day. and 897 patients with placebo. Treatment started in the second week after admission and continued for up to 18 months (mean 16 months). Ninety-five deaths and 146 major events occurred in the verapamil group and 119 deaths and 180 major events in the placebo group. The 18-month mortality rates were 11.1 and 13.8% (p = 0.11. hazard ratio. 0.80; 95% confidence limits. 0.61 to 1.05). and major event rates 18.0 and 21.6% (p = 0.03. hazard ratio. 0.80; 95% confidence limits. 0.64 to 0.99) in the verapamil and placebo groups. respectively. In patients without heart failure in the coronary care unit the mortality rates were 7.7% in the verapamil group and 11.8% in the placebo group (p = 0.02. hazard ratio. 0.64; 95% confidence limits. 0.44 to 0.94). and major event rates 14.6 and 19.7% (p = 0.01. hazard ratio 0.70; 95% confidence limits (0.52 to 0.93). In patients with heart failure the mortality rates were 17.9 and 17.5% (p = 0.79. hazard ratio. 1.05; 95% confidence limits. 0.72 to 1.54). and major event rates 24.9 and 24.9% (p = 1.0. hazard ratio 0.98; 95% confidence limits 0.72 to 1.39). Long-term treatment with verapamil after an acute myocardial infarction caused a significant reduction in major events. and the positive effect was found in patients without heart failure.
Impact of field-transmitted electrocardiography on time to in-hospital thrombolytic therapy in acute myocardial infarction, To assess the impact of a field-transmitted electrocardiogram (ECG) on patients with possible acute myocardial infarction. randomized and open trials were performed with a portable electrocardiographic system coupled with a cellular phone programmed to automatically transmit ECGs to the base hospital. Consecutive patients served by the 6 units of the Salt Lake City Emergency Rescue System were studied; 71 patients were randomized to in-field ECG (n = 34) versus no ECG (n = 37). Time on scene was 16.4 +/- 9.7 minutes for the ECG group versus 16.1 +/- 7.0 minutes for the non ECG group (difference not significant). Time of transport averaged 18.2 +/- 9.9 and 17.6 +/- 13.1 minutes. respectively (difference not significant). Six of 34 patients with in-field ECG showed acute myocardial infarction. qualified for and received thrombolytic therapy at 48 +/- 12 minutes after hospital arrival (range 30 to 60) compared with 103 +/- 44 minutes (p less than 0.01) for 51 historical control patients and 68 +/- 29 minutes for 6 concurrent control patients without in-field ECG. Thus. in-field ECG causes negligible delays in paramedic time. leads to significant decreases in time to in-hospital thrombolysis and may make in-field therapy feasible. In-field ECG may be an important addition to reperfusion strategies.
Sensitivity of a set of myocardial infarction screening criteria in patients with anatomically documented single and multiple infarcts, A subset of 3 screening criteria (Q wave greater than or equal to 30 ms in lead aVF. any Q or R wave less than or equal to 10 ms and less than or equal to 0.1 mV in lead V2. and R wave greater than or equal to 40 ms in V1) has been proposed to identify single nonacute myocardial infarcts. Cumulatively. these 3 criteria achieved 95% specificity. and 84 and 77% sensitivities for inferior and anterior myocardial infarcts. respectively. among patients identified by coronary angiography and left ventriculography. This study establishes the true sensitivities of the set of screening criteria in 71 patients with anatomically proven single myocardial infarcts and 32 patients with multiple myocardial infarcts. In the single inferior infarct group. the aVF criterion was 90% sensitive. The V2 criterion (any Q or R wave less than or equal to 10 ms and less than or equal to 0.1 mV) was 67% sensitive in the single anterior infarct group. No single criterion proved sensitive in identifying a posterolateral infarct. The set of screening criteria performed just as well for multiple infarcts as it did for single infarcts. with a cumulative sensitivity of 72%. The overall sensitivity of the screening set in the 103 patients in all groups was 71%.
Two-year outcome after angiographically documented myocardial reperfusion for acute coronary occlusion. Thrombolysis and Angioplasty Study Group, Reperfusion therapy has been clearly shown to decrease the early mortality after acute myocardial infarction. but the impact of this therapy on long-term survival has been less extensively evaluated. This study reports the extended follow-up of a large cohort of 810 patients treated with intravenous thrombolytic therapy combined. when considered necessary to maintain or augment infarct vessel patency. with mechanical reperfusion therapies. Each patient underwent coronary angiography within 2 hours of the initiation of the thrombolytic infusion. Coronary angioplasty was performed in 62% of the patients before hospital discharge and 21% underwent coronary artery bypass graft surgery. Follow-up was obtained in 96% to a mean of 18.8 months (range. 1.5 to 48 months). All-cause mortality over this period was 3.3%; 2.1% died from cardiac causes. Nonfatal reinfarction occurred in 5.1%. Although the low event rate limits the validity of statistical comparisons. the patients who survived the follow-up period tended to be younger (56 +/- 10 vs 65 +/- 7 years). to have better predischarge left ventricular function (left ventricular ejection fraction. 52 +/- 11 vs 46 +/- 13%) and to have a lower prevalence of multivessel coronary artery disease (45 vs 67%). This excellent long-term survival may. in part. reflect the exclusion of high-risk patients from enrollment in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) studies. It may also be attributable. however. to the frequent use of combined thrombolysis and mechanical revascularization in this population.
Functional significance of myocardial perfusion defects induced by dipyridamole using thallium-201 single-photon emission computed tomography and two-dimensional echocardiography, The mechanisms responsible for inhomogeneous myocardial blood flow after oral administration of a large dose (300 mg) of dipyridamole were assessed in 27 patients with serial thallium-201 single-photon emission computed tomography (SPECT) and simultaneous 2-dimensional echocardiograms. Myocardial tomographic images were obtained 50 minutes and 3 to 4 hours after administration of dipyridamole. Two-dimensional echocardiograms were recorded at baseline and then every 15 minutes for 60 minutes. Dipyridamole caused only a mild reduction in blood pressure (from 129 +/- 18 to 126 +/- 16 mm Hg) and a mild increase in heart rate (from 69 +/- 15 to 73 +/- 4 beats/min). Sixteen patients had perfusion defects after dipyridamole by SPECT. which underwent partial or total filling-in. Fourteen of these patients (87.5%) had either a new abnormality or further deterioration of a preexisting wall motion abnormality by 2-dimensional echocardiography. and thus were considered to have developed transient ischemia during dipyridamole administration. Ten of 11 patients (91%) with normal perfusion or fixed defects by SPECT had no further deterioration in wall motion after oral dipyridamole. and were thus considered to have no evidence of myocardial ischemia. In conclusion. most patients with transient thallium-201 defects after dipyridamole develop transient worsening of resting wall motion by 2-dimensional echocardiography. suggestive of true myocardial ischemia. Because myocardial oxygen demand. as indicated by the heart rate-blood pressure product. did not change significantly. the mechanism of myocardial ischemia in these patients is likely to be diminished regional blood flow related to a "subendocardial steal" induced by dipyridamole.
Left ventricular dilatation and pulmonary thallium uptake after single-photon emission computer tomography using thallium-201 during adenosine-induced coronary hyperemia, This study examined the implications of left ventricular (LV) dilatation and increased pulmonary thallium uptake during adenosine-induced coronary hyperemia. The lung-to-heart thallium ratio in the initial images was significantly higher in patients with coronary artery disease (CAD) than normal subjects; 0.48 +/- 0.16 in 3-vessel disease (n = 16). 0.43 +/- 0.10 in 2-vessel disease (n = 20). 0.43 +/- 0.08 in 1-vessel disease (n = 16) and 0.36 +/- 0.05 in normal subjects (n = 7) (p less than 0.001. 0.09 and 0.06. respectively). There was a significant correlation between the severity and the extent of the perfusion abnormality (determined from the polar maps) and the lung-to-heart thallium ratio (r = 0.51 and 0.52. respectively. p less than 0.0002). There was also a significant correlation between lung thallium washout and lung-to-heart thallium ratio (r = 0.42. p = 0.0009) and peak heart rate (r = -0.49. p less than 0.0001). The LV dilatation was mostly due to an increase in cavity dimension (30% increase) and to a lesser extent (6% increase) due to increase in LV size. (The cavity dimensions were measured from the short-axis slices at the midventricular level in the initial and delayed images). The dilation was seen in patients with CAD but not in the normal subjects. These changes correlated with the extent and severity of the thallium perfusion abnormality. Thus. adenosine-induced coronary hyperemia may cause LV dilation and increased lung thallium uptake on the basis of subendocardial ischemia.
Effects of bepridil and diltiazem on ventricular repolarization in angina pectoris, To examine the time-course and potential predictors of prolongation of ventricular repolarization with the calcium antagonist bepridil. the effects of bepridil (300 to 500 mg/day; n = 45) and diltiazem (180 to 300 mg/day; n = 42) on QT and QTc interval duration were analyzed in a randomized double-blind study in patients with angina pectoris. Electrocardiograms were recorded before and 14. 28. 70 and 112 days after treatment was begun. After 14 days. bepridil prolonged QT interval by 26 +/- 35 ms (range. -60 to 120 ms) and QTc (Bazett's formula) by 17 +/- 33 ms (range. -73 to 107 ms) compared to baseline (both p less than 0.05). QT or QTc did not significantly increase thereafter. However. among the 30 patients who had less than 40 ms QTc prolongation at day 14 compared with baseline. 13 (43%) exceeded this limit on at least 1 of the following visits. Diltiazem did not significantly alter QT or QTc intervals. The absolute change in QTc interval from baseline observed after 14 days of bepridil therapy was inversely proportional to the baseline QTc interval (r = -0.68; n = 42; p less than 0.001). The degree of bepridil-induced QTc prolongation on day 14 correlated with pretreatment RR interval (r = 0.36; n = 42; p less than 0.02). In conclusion. chronic administration of bepridil but not of diltiazem prolongs ventricular repolarization in patients with angina pectoris. The overall effects of bepridil therapy on QT and QTc intervals can be assessed by an electrocardiogram recorded after 14 days of treatment but subsequent measurements may be required in individual patients. A short baseline QTc interval and a slow initial heart rate may be potentially useful predictors of a greater QTc prolongation with bepridil.
Effects of intravenous verapamil on left ventricular relaxation and filling in stable angina pectoris, Left ventricular (LV) diastolic function is often impaired in coronary artery disease (CAD). To assess whether verapamil could improve LV diastolic properties. 12 patients with CAD undergoing right- and left-sided cardiac catheterization. as well as simultaneous radionuclide angiography. were studied before and during intravenous administration of verapamil (0.1 mg/kg as a bolus followed by 0.007 mg/kg/min). The heart rate was kept constant by atrial pacing in both studies. LV pressure-volume relations were obtained. Verapamil decreased LV systolic pressure (130 +/- 22 to 117 +/- 16 mm Hg. p less than 0.01) and the end-systolic pressure/volume ratio (2.4 +/- 1.3 to 1.6 +/- 0.5 mm Hg/ml. p less than 0.05). and increased LV end-diastolic (13 +/- 4 to 16 +/- 4 mm Hg. p less than 0.02) and pulmonary capillary pressures (10 +/- 5 to 12 +/- 5 mm Hg. p less than 0.005). Despite such negative inotropic effects. cardiac index increased (3.4 +/- 0.7 to 3.9 +/- 0.6 liters/min/m2. p less than 0.02). The time constant of isovolumic relaxation shortened (63 +/- 14 to 47 +/- 9 ms. p less than 0.02); peak filling rate increased (370 +/- 155 to 519 +/- 184 ml/s. p less than 0.001; 2.6 +/- 1.1 to 3.3 +/- 0.9 end-diastolic counts/s. p less than 0.02; and 4.1 +/- 1.6 to 5.5 +/- 1.5 stroke counts/s. p less than 0.001).
Long-term follow-up in patients with incessant ventricular tachycardia, Seventeen patients with coronary artery disease. idiopathic dilated cardiomyopathy or no organic heart disease who presented with incessant ventricular tachycardia (VT) were studied and followed for a mean period of 51 +/- 35 months. In these patients the incessant VT included greater than or equal to 3 episodes of sustained VT at a rate of greater than or equal to 120 beats/min and frequent episodes of nonsustained VT over a 24-hour period. No patient had electrolyte disorder. prolonged QT interval. drug-induced arrhythmia or myocardial infarction less than 2 weeks old. Six patients died within 27 months of follow-up; 4 from sudden death and 2 from acute myocardial infarction. Three of the 11 surviving patients had remission of their VT within 1 week after the diagnosis of incessant VT. In 3 other patients in whom antiarrhythmic drugs were discontinued during follow-up because of adverse effects of the drugs or other medical reasons. 2 were found in remission. In the remaining 5 alive patients. deliberate attempts were made to discontinue the antiarrhythmic drugs; 4 of these patients were found in remission when the drugs were discontinued. Thus. 9 of these patients (53%) with incessant VT had remission over a mean follow-up of 55 +/- 34 months after discontinuation of the antiarrhythmic drugs. The probability of remission in patients surviving incessant VT warrants trials of discontinuation of antiarrhythmic drugs in these patients.
The nuclear pacemaker: is renewed interest warranted, From 1973 through 1987. 155 radioisotope-powered "nuclear" pacemakers were implanted in 132 patients at the Newark Beth Israel Medical Center. The longevity of the first 15 devices. all of which were fixed-rate (VOO) pacemakers. was significantly better than that of 15 lithium-chemistry demand (VVI) pacemakers used as control devices (p = 0.0002). Of the entire cohort of 155 nuclear pacemakers. 136 were VVI devices and 19 were VOO units. The patients with VOO pacemakers needed reoperations more often than did those with VVI pacemakers. chiefly for mode change (p less than 0.001). Power-source failure was observed in only 1 case. but 47 nuclear pacemakers were removed for other reasons. including component malfunction (15 units). mode change (12 units). high pacing thresholds (8 units) and lead or connector problems (5 units). The actuarial survival at 15 years was 99% for power sources and 82% for the entire pacing systems (pulse generators plus leads). The frequency of malignancy was similar to that of the population at large and primary tumor sites were randomly distributed. Deaths most commonly were due to cardiac causes (68%). Thus. nuclear pacemakers are safe and reliable and their greater initial cost appears to be offset by their longevity and the resulting decrease in the frequency of reoperations. It is reasonable to suggest that further use be made of long-lasting nuclear power sources for modern pacemakers and other implantable rhythm-management devices.
Mechanisms in heart failure and the role of angiotensin-converting enzyme inhibition, The four major diagnostic criteria for the syndrome of congestive heart failure are left ventricular dysfunction. exercise intolerance. pulmonary congestion or edema and ventricular arrhythmias. Activation of norepinephrine. angiotensin II. vasopressin and atrial natriuretic peptide may be a key factor in the vasoconstriction and increased impedance to left ventricular ejection in heart failure. Interventions that interfere with these vasoconstrictor mechanisms should have a salutary effect on left ventricular performance. Treatment with angiotensin-converting enzyme (ACE) inhibitors. alpha-adrenoceptor blockers and vasopressin antagonists has resulted in hemodynamic benefits. but it has been more difficult to demonstrate long-term clinical effectiveness. Reductions in mortality have been demonstrated in patients with heart failure treated with vasodilators and ACE inhibitors. Improvement in the quality of life and prolongation of life are the only two appropriate goals in the management of heart failure. Further understanding of the role of angiotensin II and its interference by ACE inhibition in the tissue processes of heart failure is needed.
Potential role of the tissue renin-angiotensin system in the pathophysiology of congestive heart failure, The circulating renin-angiotensin system (RAS) plays an important role in the maintenance of cardiovascular homeostasis. It has recently been demonstrated that endogenous RAS exist in target tissues that are important in cardiovascular regulation. This article reviews the multiple effects of angiotensin II in target tissues. the evidence for the presence of functional tissue RAS and the data that suggest a role for these tissue RAS in the pathophysiology of heart failure. Activation of circulating neurohormones is predictive of worsened survival in heart failure; however. cardiac and renal tissue RAS activities are also increased in the compensated stage of heart failure. when plasma renin-angiotensin activity is normal. It is hypothesized that the plasma RAS maintains circulatory homeostasis during acute cardiac decompensation. while changes in tissue RAS contribute to homeostatic responses during chronic sustained cardiac impairment. This concept of different functions of circulating and tissue RAS in the pathophysiology of heart failure may have important pharmacologic implications.
Neuroendocrine activity in congestive heart failure, The increased neuroendocrine activity in patients with congestive heart failure appears to be a generalized attempt to maintain blood pressure at the expense of reduced cardiac performance and salt and water retention. It is likely that baroreceptor dysfunction contributes to increased sympathetic nervous system activity in patients with congestive heart failure. The usual tonic inhibitory messages emanating from baro- and mechanoreceptors in the great vessels and heart fail to adjust sympathetic traffic from the brain to the periphery. leading to uninhibited sympathetic tone. Arginine vasopressin and plasma renin activity may be increased secondarily; however. plasma renin activity activation could also be induced by a low-salt diet and diuretic use. Preliminary baseline data indicate that patients with left ventricular dysfunction (ejection fraction less than or equal to 35%) but no or very mild symptoms of heart failure have increased plasma levels of norepinephrine. atrial natriuretic factor and arginine vasopressin. while plasma renin activity is normal. suggesting that neuroendocrine activity contributes to the pathogenesis of congestive heart failure. Neurohormones such as angiotensin II may alter gene expression. leading to changes in the shape and size of the cell. Remodeling of the heart and blood vessels is associated with both heart failure and hypertension. Angiotensin-converting enzyme inhibitors have been demonstrated to retard or reverse the remodeling process under certain experimental conditions. Studies are currently under way to test this possibility in patients.
Effects of enalapril and neuroendocrine activation on prognosis in severe congestive heart failure (follow-up of the CONSENSUS trial). CONSENSUS Trial Study Group, This study enrolled 253 patients with severe heart failure (New York Heart Association functional class IV) from 35 centers in Scandinavia. randomly assigned to treatment with placebo or enalapril. in addition to their usual treatment for heart failure. After an initial titration period. the daily doses of enalapril ranged from 2.5 to 40 mg. At the end of the trial. 46% of the placebo-treated patients and 61% of the enalapril-treated patients were alive (p = 0.003); the survival figures at 8 months after completion of the trial were 32 and 48%. respectively (p = 0.001); and 21 and 30%. respectively (p = 0.006) at the 2-year follow-up. In the placebo group. there was a significant positive association between mortality and baseline levels of norepinephrine. epinephrine. angiotensin II. aldosterone and atrial natriuretic peptide; no such association was found in the enalapril-treated patients. The results suggest that the effects of enalapril on mortality are related to a counteraction of the neuroendocrine activation in general and to the renin-angiotensin system in particular.
Pharmacology of angiotensin-converting enzyme inhibitors as a guide to their use in congestive heart failure, The pharmacokinetics of the angiotensin-converting enzyme (ACE) inhibitors are difficult to assess for several reasons. First. these compounds exert their influence by inhibiting an intermediary enzyme of a cascade of enzymatic events. whose rate-limiting enzyme (renin) is not directly affected by ACE inhibition. Second. renin and angiotensin I accumulate during ACE inhibition and a change in the dose of an ACE inhibitor could produce sudden shifts of angiotensin I to angiotensin II. Third. components of the circulating renin system require the interaction of several organ systems and effector sites. Fourth. the kinetics of ACE inhibitors can be influenced by the organ systems responsible for drug absorption. metabolism and excretion. and the functional status of these systems can be affected by the heart failure process. Fifth. at least some portion of the cardiovascular effects of ACE inhibitors is influenced by the contributions of other systems whose physiologic effects may be of importance in some patients with congestive heart failure. Sixth. the potential impact of tissue-bound ACE is not yet fully understood. Finally. for appropriate drug dosing. the effects of aging on the heart failure process. the extent of renin system activity. and the disposition of ACE inhibitors need to be considered. Because of their complex pharmacokinetics. treatment with ACE inhibitors has been guided by their pharmacodynamic and clinical characteristics.
Clinical and hemodynamic assessment of the hepatojugular reflux, The hepatojugular reflux (HJR) test was studied to assess the ability to clinically predict response during cardiac catheterization and to determine its significance in patients without heart failure and correlate it to their baseline hemodynamic parameters. Sixty-five patients considered to be free of heart failure undergoing routine cardiac catheterization were enrolled. The HJR test. defined as the venous pressure response to sustained abdominal compression. was performed in a standardized manner at the bedside assessing change in internal jugular venous pressure and during right-sided cardiac catheterization measuring change in right atrial pressure. For comparison a sustained increase greater than or equal to 1 cm was considered positive. In 62 of 65 patients the HJR test stabilized by 15 seconds. The results during examination at the bedside agreed with those at catheterization (K = 0.74. p less than 0.001). The HJR test result correlated best with baseline mean right atrial pressure (r = 0.59) and right ventricular end-diastolic pressure (r = 0.51). and in bivariate regression analysis predicted right atrial (F(1.63) = 32.8. R2 = 0.34. p less than 0.0001) and right ventricular end-diastolic (F(1.63) = 22. R2 = 0.26. p less than 0.0001) pressures. A positive test had high sensitivity and specificity for predicting right atrial pressure greater than 9 mm Hg (1.0. 0.85) and right ventricular end-diastolic pressure greater than 12 mm Hg (0.90. 0.89). It is concluded that 15 seconds is adequate for interpretation. and bedside observation predicts the response during right-sided cardiac catheterization.
Anatomic correlations of the long-axis views in biplane transesophageal echocardiography, The number of views obtainable during transesophageal echocardiography (TE) has been limited by the fixed position of the transducer at the end of the probe. This has confined standard TE studies to short-axis tomography of the heart and aorta. Recently. a biplane TE probe has become available that is capable of both long- and short-axis imaging. This study prospectively assessed the application of the long-axis plane of the biplane probe in providing complementary long-axis views in ambulatory patients. Six standard long-axis views could be obtained and were compared with corresponding anatomic sections to illustrate anatomic relations and facilitate structure identification. The long-axis views provide a better appreciation of the 3-dimensional nature of cardiac anatomy and function. especially in demonstrating the relation of vertically aligned structures.
Transient left ventricular filling abnormalities (diastolic stunning) after acute myocardial infarction, A variety of experimental studies suggest that diastolic left ventricular (LV) function changes after acute myocardial infarction (AMI). but limited data exist on these changes in humans. To assess diastolic filling after AMI. 60 patients underwent Doppler echocardiographic examination within 24 hours of AMI. Of 54 patients who also underwent catheterization. 45 (83%) were successfully reperfused. A subgroup of 17 patients underwent a follow-up Doppler examination at 7 days after infarction. whereas 15 patients with stable exertional angina served as control subjects. There was no significant difference in age. gender. incidence of systemic hypertension or diabetes mellitus. heart rate. mean arterial pressure or severity of coronary artery disease between the infarct and control groups. The infarct group had a lower velocity time integral total (9.9 +/- 0.4 cm vs 12.0 +/- 0.9 cm. p less than 0.001). a lower velocity time integral E (5.8 +/- 0.3 cm vs 6.8 +/- 0.5 cm. p less than 0.01) and a lower velocity time integral 0.333 (3.5 +/- 0.4 cm vs 6.1 +/- 0.5 cm. p less than 0.01) than the control group. In addition. velocity time integral A/total was significantly greater in the infarction group (0.44 +/- 0.03 vs 0.35 +/- 0.04. p less than 0.01) compared to the control group. The follow-up subgroup showed an increase in velocity time integral total (p less than 0.01). velocity time integral E (p less than 0.05) and velocity time integral 0.333/total (p less than 0.05) over the first 7 days after infarction. The final recovery values at 7 days were not significantly different from those of the coronary artery disease group.
Functional status after coronary artery bypass grafting and percutaneous transluminal coronary angioplasty, Two cohorts of consecutive patients of comparable age with similar preprocedure cardiac function who underwent either coronary artery bypass grafting (CABG; n = 106) or percutaneous transluminal coronary angioplasty (PTCA; n = 64) were entered into a prospective comparison study examining functional status and return to work during the first year of recovery. Patients were evaluated using standardized functional status instruments for activities of daily living. work performance. social activity. mental health and quality of social interaction at 1. 6 and 12 months after the procedure. Within the CABG group. statistically significant improvements of functional status on every subscale were noted over the 1-year follow-up. Patients undergoing PTCA demonstrated significant improvement in all dimensions except for the quality of interaction at 1 year as compared with baseline. When the 2 groups were compared. the PTCA group demonstrated greater participation than the CABG group in routine daily physical and social activities at 1 and 6 months. but this apparent advantage disappeared by 1 year. Measures of psychological functioning were better after CABG than after PTCA. A reduction in the number of those with employment occurred in both the CABG and PTCA groups. independent of physical functional status measures. which improved in both groups after the procedures. For those with employment. the CABG group reported the greatest improvement in work performance.
Early postoperative balloon coronary angioplasty for failed coronary artery bypass grafting, In a small number of patients. coronary artery bypass grafting (CABG) fails to relieve anginal symptoms. The usefulness of coronary angioplasty for the treatment of early (less than or equal to 90 days) recurrent ischemia after CABG was examined. Forty-five patients were treated from 2 to 90 days after CABG. including 8 patients studied emergently for prolonged ischemic symptoms. One-. 2- and 3-vessel native disease was found in 4. 10 and 31 patients. respectively. At the time of postoperative angiography. the major anatomic mechanism of recurrent ischemia was complete vein graft occlusion in 12 patients (27%). internal mammary artery occlusion in 3 (7%). vein graft stenoses in 13 (29%). internal mammary artery stenoses in 10 (22%). unbypassed disease in 4 (8%) and disease distal to the graft insertion site in 3 (7%). Angioplasty was successful at 91 of 98 sites (93%). including 95% of 41 lesions in native arteries. 89% of 46 lesions in vein grafts and 100% of 11 internal mammary artery lesions attempted. Complete revascularization was achieved in 84% of patients. There were 2 in-hospital deaths and 2 myocardial infarctions. Two additional patients underwent repeat CABG before discharge after uncomplicated but unsuccessful angioplasty. At late follow-up of the 43 survivors (mean 44 months). there were 4 deaths. 2 of which were noncardiac. Repeat CABG was required in only 3 patients and repeat angioplasty was performed in 10. Angina was absent or minimal in 35 patients; 17 patients were employed full time. Thus. percutaneous transluminal coronary angioplasty can relieve myocardial ischemia after unsuccessful CABG in the majority of patients.
Circadian rhythmicity of rate-normalized QT interval in hypothyroidism and its significance for development of class III antiarrhythmic agents, Lengthening of repolarization and refractoriness occurs in hypothyroidism; it is associated with a reduced probability of arrhythmias. with the converse occurring in hyperthyroidism. Because the QT interval and its circadian rhythmicity relative to heart rate is poorly defined in man. we used our new computer-assisted technique to measure QT interval in our analysis of 24-hour Holter tapes before and after (8 to 12 weeks) thyroxine (T4) replacement in 10 patients with hypothyroidism; the findings were compared to those in 6 normal control subjects. QTc interval was prolonged (p less than 0.02) and heart rate decreased (p less than 0.005) during the hypothyroid state. Data were analyzed for circadian rhythmicity by repeated-measures analysis. Circadian variation in QTc and heart rate was statistically significant during hypothyroid and euthyroid states (p less than 0.001) as well as in control subjects. but the circadian rhythmicity of QTc interval and heart rate were out of phase; the maximum prolongation of QTc occurred between midnight and 6 A.M.. at a time when heart was at its lowest. QTc interval remained significantly prolonged after 8 to 12 weeks of T4 replacement. when biochemical indexes of hypothyroidism had returned to normal values. The computer-assisted QTc interval determination technique that we used. and our data on the circadian rhythmicity of QTc and heart rate. have significant implications for the development of new class III antiarrhythmic agents.
Comparison of the antihypertensive efficiency of nitrendipine, metoprolol, mepindolol and enalapril using ambulatory 24-hour blood pressure monitoring, In a randomized 6-month study of 201 patients. the antihypertensive efficiency of the calcium antagonist nitrendipine. the beta 1-selective blocker metoprolol. mepindolol. the beta blocker with intrinsic activity and the angiotensin-converting enzyme inhibitor enalapril were compared as monitored by 24-hour ambulatory blood pressure (BP) measurements. The study was designed so that a comparable decrease in casual BP values was obtained with all 4 drugs. If normotension was not achieved with monotherapy. a diuretic also was administered. Pretreatment casual BP and mean 24-hour ambulatory BP values did not differ between the 4 groups. Normotension as assessed by casual BP measurements was observed in all 4 groups after 6 months of therapy. there being no significant differences between the groups. However. significantly more diuretics were required in the mepindolol (n = 14) and in the enalapril (n = 20) groups compared to the nitrendipine (n = 5) and metoprolol (n = 7) groups. Despite comparable casual BP control. the 4 groups differed significantly in their mean 24-hour measurements. The greatest systolic and diastolic BP decreases were seen in the metoprolol group. Metoprolol was also the most effective drug in decreasing the frequency of systolic pressure peaks greater than 180 mm Hg. Both beta blockers and enalapril significantly decreased the morning BP increase compared to the values before treatment. while nitrendipine did not. These data show that casual BP measurement is not a good predictor of 24-hour BP in patients taking hypertensive therapy. Despite an equal degree of "office" BP control. different antihypertensive regimens do not confer the same degree of "nonoffice" BP control.
Usefulness of verapamil for congestive heart failure associated with abnormal left ventricular diastolic filling and normal left ventricular systolic performance, Normal left ventricular systolic performance with impaired left ventricular diastolic filling may be present in a substantial number of patients with congestive heart failure (CHF). To evaluate the effect of oral verapamil in this subset. 20 men (mean age 68 +/- 5 years) with CHF. intact left ventricular function (ejection fraction greater than 45%) and abnormal diastolic filling (peak filling rate less than 2.5 end-diastolic volumes per second [edv/s]) were studied in a placebo-controlled. double-blind 5-week crossover trial. All patients underwent echocardiography to rule out significant valvular disease. and thallium-201 stress scintigraphy to exclude major active ischemia. Compared to baseline values. verapamil significantly improved exercise capacity by 33% (13.9 +/- 4.3 vs 10.7 +/- 3.4 minutes at baseline) and peak filling rate by 30% (2.29 +/- 0.54 vs 1.85 +/- 0.45 edv/s at baseline) (all p less than 0.05). Placebo values were 12.3 +/- 4.0 minutes and 2.16 +/- 0.48 edv/s. respectively (difference not significant for both). Improvement from baseline in an objective clinico-radiographic heart failure score (scale 0 to 13) was significantly greater with verapamil compared to placebo (median improvement in score: 3 vs 1. p less than 0.01). Mean ejection fraction and systolic blood pressure were unchanged from baseline; diastolic blood pressure and heart rate decreased to a small degree. Verapamil may have therapeutic efficacy in patients with CHF. preserved systolic function and impaired diastolic filling.
Detection and location of myocardial infarction using technetium-99m sestamibi imaging at rest, Technetium-99m (Tc-99m) sestamibi imaging at rest has been used to detect and localize myocardial infarction. The largest study to date is a cooperative study of 146 patients in 17 institutions. There were 24 normal subjects and 122 patients with documented myocardial infarction based on clinical. enzymatic or electrocardiographic criteria. The presence of segmental myocardial perfusion defects was compared to the presence of a Q wave on the electrocardiogram or wall motion abnormality on gated blood pool scans. performed within 48 hours of the Tc-99m sestamibi study. Of the 122 infarct patients. 118 (97%) showed perfusion abnormalities by Tc-99m sestamibi imaging. A perfusion defect was found in 110 (99%) of 111 patients with a Q wave and a wall motion abnormality. 113 (99%) of 114 patients with a wall motion abnormality and 113 (98%) of 115 patients with a Q wave. Of the 24 normal subjects. 22 (92%) had normal Tc-99m sestamibi images. In 75% of 1.986 segments. both a Tc-99m sestamibi defect and a regional wall motion abnormality on gated blood scans were present. In 11% of segments. wall motion was normal but Tc-99m sestamibi imaging was abnormal; in 14% of segments. wall motion was abnormal and Tc-99m sestamibi images were normal. In the 24 control subjects. 99% of the segments were normal. Thirty-eight patients had coronary angiography. A close relation existed between the coronary anatomy and myocardial Tc-99m sestamibi uptake. All 9 territories supplied by an occluded vessel and poor collaterals had grade 0 uptake (scale 0 to 2: 0 = markedly reduced; 2 = normal).
Detection and assessment of unstable angina using myocardial perfusion imaging: comparison between technetium-99m sestamibi SPECT and 12-lead electrocardiogram, Forty-five studies using technetium-99m (Tc-99m) sestamibi single photon emission computed tomography (SPECT) were performed on patients hospitalized for spontaneous chest pain suggestive of myocardial ischemia. The studies were done after an injection during an episode of chest pain and a repeated injection when the patients were free of pain. All patients were hospitalized with a presumed diagnosis of unstable angina. and none had evidence of a previous myocardial infarction. The presence of a perfusion defect observed with Tc-99m sestamibi injected during chest pain had a 96% sensitivity and a 79% specificity for the detection of significant coronary artery disease (stenosis greater than or equal to 50%) on subsequent angiography. When the criterion of a larger perfusion defect during pain compared to absence of pain was used. the sensitivity was 81% and the specificity was 84%. In contrast. transient electrocardiographic ischemic changes during pain had a sensitivity of 35% and a specificity of 68%; electrocardiographic changes during or outside episodes of chest pain had a sensitivity of 65% and a specificity of 63% for the diagnosis. Tc-99m sestamibi SPECT represents a reliable noninvasive diagnostic tool that could aid in the diagnosis of myocardial ischemia in patients with spontaneous chest pain and provide additional information to that provided by the electrocardiogram.
Planar imaging techniques used with technetium-99m sestamibi to evaluate chronic myocardial ischemia, The results of published and some unpublished studies comparing planar imaging performed with 2 radionuclides. thallium-201 (T1-201) and technetium-99m (Tc-99m) sestamibi. are reviewed. The average sensitivity for the detection of coronary artery disease (CAD) in studies involving 594 patients was 85% (range 73 to 96%). The average sensitivity for individual vessels was 65% (range 60 to 70%). The average segmental concordance between T1-201 and Tc-99m sestamibi was 89%. End-diastolic gated perfusion images improved the concordance between Tc-99m sestamibi and angiography in 22 patients from 83.4 to 87%. Semiquantitative analysis increased the concordance between T1-201 and Tc-99m sestamibi from 89 to 91%. Ventricular function derived from gated Tc-99m sestamibi perfusion images showed a significant correlation with echocardiography (n = 62. r = 0.85); with angiography (n = 70. r = 0.91); and with equilibrium radionuclide ventriculography (n = 18. r = 0.86). The ratio of lung to left ventricle uptake and the ratio of right ventricle to left ventricle uptake was assessed. Eight of 52 patients had an abnormally elevated lung index (greater than 42%) and these patients had the most severe CAD. Six of the 52 patients had an abnormally elevated right ventricular index (greater than 56%) and these patients had more severe CAD.
Experimental studies of the physiologic properties of technetium-99m isonitriles, Recently. efforts have been directed at the development of technetium-99m (Tc-99m)-labeled isonitrile compounds for assessment of regional perfusion and viability after experimental myocardial infarction or ischemia. One of the most promising of these agents. Tc-99m sestamibi. has undergone rather extensive laboratory investigation. Like thallium-201 (Tl-201). the uptake of Tc-99m sestamibi in myocardial tissue is proportional to myocardial blood flow after intravenous injection. Similar to other diffusible indicators. Tc-99m sestamibi underestimates blood flow at high flow rates. In low flow regions. the myocardial uptake of this agent is higher relative to nonischemic uptake than is microsphere-determined blood flow. This is attributed to increased extraction at low flows. This first-pass myocardial extraction fraction for Tc-99m sestamibi is less than that for Tl-201. However. Tc-99m sestamibi has a higher parenchymal cell permeability and higher volume of distribution than T;-201. Tc-99m sestamibi shows minimal "delayed redistribution" after initial intravenous administration. Uptake of Tc-99m sestamibi is not altered by myocardial "stunning" or with ischemic dysfunction produced by sustained low coronary flow. The uptake of the isonitrile is still proportional to blood flow in these situations. In intact animal models. myocardial uptake of Tc-99m sestamibi during coronary occlusion delineates the in vivo area at risk. When Tc-99m sestamibi is administered after reperfusion following variable periods of preceding coronary occlusion. Tc-99m sestamibi uptake delineates the area of viable myocardium that is salvaged and not simply the degree of reflow. This suggests that serial Tc-99m sestamibi imaging might be useful in assessing the efficacy of coronary reperfusion after thrombolytic therapy.
Myocardial perfusion imaging with technetium-99m sestamibi SPECT in the evaluation of coronary artery disease, Technetium-99m (Tc-99m) sestamibi is a new myocardial perfusion imaging agent that offers significant advantages over thallium-201 (Tl-201) for myocardial perfusion imaging. The results of the current clinical trials using acquisition and processing parameters similar to those for Tl-201 and a separate (2-day) injection protocol suggest that Tc-99m sestamibi and Tl-201 single photon emission computed tomography (SPECT) provide similar information with respect to detection of myocardial perfusion defects. assessment of the pattern of defect reversibility. overall detection of coronary artery disease (CAD) and detection of disease in individual coronary arteries. Tc-99m sestamibi SPECT appears to be superior to Tc-99m sestamibi planar imaging because the former provides a higher defect contrast and is more accurate for detection of disease in individual coronary arteries. Research is currently under way addressing optimization of acquisition and processing of Tc-99m sestamibi studies and development of quantitative algorithms for detection and localization of CAD and sizing of transmural and nontransmural myocardial perfusion defects. It is expected that with the implementation of the final results of these new developments. further significant improvement in image quality will be attained. which in turn will further increase the confidence in image interpretation. Development of algorithms for analysis of end-diastolic myocardial images may allow better evaluation of small and nontransmural myocardial defects. Furthermore. gated studies may provide valuable information with respect to regional myocardial wall motion and wall thickening. With the implementation of algorithms for attenuation and scatter correction. the overall specificity of Tc-99m sestamibi SPECT should improve significantly because of a substantial decrease in the occurrence of attenuation-related image artifacts.
Clinical experience with technetium-99m teboroxime, a neutral, lipophilic myocardial perfusion imaging agent, Technetium-99m (Tc-99m) teboroxime is a new technetium-based myocardial perfusion imaging agent (investigational code = SQ30217 [Cardiotec. Squibb Diagnostics]). A member of a class of neutral. lipophilic. technetium-containing complexes known as boronic acid adducts of technetium dioxime (BATO) complexes. this agent is chemically very different from the cationic tracer thallium-201 (Tl-201) and from the cationic technetium complex Tc-99m sestamibi (Cardiolite. Du Pont Imaging Agents). Tc-99m teboroxime has high myocardial extraction. rapid blood clearance. little lung uptake and rapid myocardial washout. A biexponential pattern of myocardial washout is demonstrated in animals and in man. Effective half-lives of the 2 washout components in man are 5.2 minutes and 3.8 hours and represent approximately 66 and 33% of the myocardial activity. respectively. The first half-life for the myocardium is approximately 11 minutes. As the agent washes out of the heart. hepatic uptake occurs. peaking at about 5 minutes after injection. The liver is the major organ of excretion and receives. along with the large bowel. the largest radiation dose. Rapid imaging protocols using standard cameras have achieved good myocardial counts from 3 planar views acquired over a 4- to 5-minute period or for single photon emission computed tomography (SPECT) images acquired over a 10-minute period. An entire stress/rest procedure can be completed in 1 hour. Analysis of data from 155 patients from 4 centers using planar or SPECT imaging showed a sensitivity and specificity for blinded readings of 82 and 91%. respectively. when compared against overall clinical impression.
Simultaneous measurement of myocardial perfusion and ventricular function during exercise from a single injection of technetium-99m sestamibi in coronary artery disease, New radiopharmaceuticals permit simultaneous assessment of myocardial perfusion and left ventricular function using a single tracer injection. The purpose of this study was to quantitate the relation between myocardial perfusion and function at rest and during exercise in patients with documented coronary artery disease (CAD). A rest first-pass radionuclide angiocardiogram (RNA) was recorded in 51 patients with CAD during injection of 10 mCi of technetium-99m (Tc-99m) sestamibi. and tomographic perfusion images were obtained 60 minutes later. A treadmill test was then performed. and on attainment of an exercise end point a second first-pass RNA was recorded with 30 mCi of Tc-99m sestamibi. Tomographic images reflecting myocardial perfusion during exercise were obtained 1 hour later. Tomographic perfusion defect size. quantified using modifications of the Cedars-Sinai program. correlated directly with end-systolic volume and inversely with ejection fraction at rest and during exercise. However. perfusion defect size often varied widely in patients with similar left ventricular function. This independence between measurements of perfusion and function suggests that simultaneous assessment of the 2 physiologic variables could improve the diagnostic and prognostic information of radionuclide tests.
Comparison of SPECT using technetium-99m agents and thallium-201 and PET for the assessment of myocardial perfusion and viability, This report reviews the applications of tomographic imaging with current and new tracers in assessing myocardial perfusion and viability. Multiple studies with thallium-201 (TI-201) single photon emission computed tomography (SPECT) imaging for the detection of coronary artery disease (CAD) have demonstrated high sensitivity. high rates of normalcy and high reproducibility. In assessing viability. fixed defects are frequently detected in viable zones in 4-hour studies with TI-201 imaging. Redistribution imaging performed 18 to 72 hours after injection or reinjection of TI-201 before 4-hour redistribution imaging has been shown to improve accuracy of viability assessment. TI-201 SPECT studies are limited by the suboptimal physical properties of TI-201. which result in variable image quality. The 2 new technetium-99m (Tc-99m) - labeled myocardial perfusion tracers offer the ability to inject much higher amounts of radioactivity. making it possible to assess ventricular function as well as myocardial perfusion from the same injection of radiotracer. Tc-99m sestamibi has very slow myocardial clearance. which allows for prolonged imaging time and results in image quality superior to that obtained with TI-201 and Tc-99m teboroxime. The combination of minimal redistribution of Tc-99m sestamibi and high count rates makes gated SPECT imaging feasible. and also permits assessment of patients with acute ischemic syndromes by uncoupling the time of injection from the time of imaging. The combination of high image quality and first-pass exercise capabilities may lead to a choice of this agent over TI-201 for assessment of chronic CAD.
Technetium-99m sestamibi myocardial imaging: same-day rest-stress studies and dipyridamole, Unlike thallium-201. technetium-99m (Tc-99m) sestamibi does not redistribute in the myocardium after injection. Thus. 2 separate injections. 1 at rest and the other at stress (or after dipyridamole). are required to differentiate ischemia from scar. From a physical viewpoint. a 24-hour interval between the 2 injections is preferable for detection of coronary artery disease (CAD) with Tc-99m sestamibi imaging. However. same-day studies are more convenient in clinical practice. Results of studies using different Tc-99m sestamibi injection protocols are presented with emphasis on the advantages of a rest-stress injection sequence with a low dose at rest (7 mCi) followed 2 hours later by a higher dose at stress (25 mCi). A prospective study was conducted in a patient population with proven CAD using same-day studies to compare a rest-stress (7 and 25 mCi. respectively) to a stress-rest (7 and 25 mCi) Tc-99m sestamibi injection sequence. There was an agreement in 87.3% of the analyzed segments between the 2 protocols. However. the largest discordance for type of defect applied to 7.4% of the segments judged ischemic in the rest-stress protocol. which were called scars on stress-rest. This study showed that a rest-stress sequence is preferable when using a same-day protocol with a short time interval (less than 2 hours) between the 2 Tc-99m sestamibi injections because the rest image performed initially represents a "true" rest study. which is not necessarily the case with the stress-rest sequence. Preliminary studies were performed to evaluate dipyridamole with Tc-99m sestamibi imaging in normal subjects and in patients with CAD. These studies showed that treadmill and dipyridamole Tc-99m sestamibi imaging are comparable and the results are similar to those obtained with thallium-201.
Use of technetium-99m sestamibi to determine the size of the myocardial area perfused by a coronary artery, The value of the new radionuclide tracer. technetium-99m (Tc-99m) sestamibi. to demonstrate myocardial perfusion in areas supplied by specific coronary arteries was evaluated in patients injected with the agent during cardiac catheterization. Tc-99m sestamibi differs from thallium-201 in its physical characteristics (photon energy 140 keV). half-life (6 hours) and lack of significant redistribution. allowing its administration during an episode of chest pain or ischemia occurring outside the nuclear medicine laboratory with later imaging to visualize the distribution. In 13 patients Tc-99m sestamibi was administered intravenously during balloon-occlusion angioplasty. In 11 of 13 patients. defects of the single photon emission computed tomography images corresponded to the area made ischemic during angioplasty. In the remaining 2 patients. abundant collateral flow was present and no defects were seen. In a second study. 15 patients had Tc-99m sestamibi selectively injected into a coronary artery during angiography. Later imaging identified the area supplied by the artery injected. Tc-99m sestamibi imaging can detect perfusion defects associated with short episodes of ischemia. and the area supplied by the different coronary arteries.
Technetium-99m sestamibi in chronic coronary artery disease: the European experience, Since the introduction of technetium-99m methoxy-isobutyl isonitrile (Tc-99m sestamibi) in Europe. there has been a growing interest in its use. Several European multicenter trials have been conducted to evaluate this new agent in relation to the traditional perfusion marker thallium-201. and other studies are in progress to understand the use of this perfusion marker for the diagnosis of coronary disease. for use in conjunction with pharmacologic vasodilation. for use in the assessment of ventricular function and wall motion and for the assessment of interventions.
Percutaneous excimer laser coronary angioplasty, To determine the efficacy of percutaneous excimer laser coronary angioplasty as an adjunct or alternative to conventional balloon angioplasty. 55 patients were studied in a multicenter trial. These patients underwent the procedure using a modification of conventional balloon angioplasty technique. A first-generation. 1.6-mm diameter catheter constructed of 12 individual silica fibers concentrically arranged around a guidewire lumen was used. Catheter tip energy density varied from 35 to 50 mJ/mm2. The mean number of pulses delivered at 20 Hz was 1.272 +/- 1.345. Acute success was defined as a greater than or equal to 20% increase in stenotic diameter and a lumen of greater than or equal to 1 mm in diameter after laser treatment. Acute success was achieved in 46 of 55 (84%) patients. Adjunctive balloon angioplasty was performed on 41 patients (75%). The percent diameter stenosis as determined by quantitative angiography decreased from a baseline of 83 +/- 14 to 49 +/- 11% after laser treatment and to 38 +/- 12% in patients undergoing adjunctive balloon angioplasty. The mean minimal stenotic diameter increased from a baseline of 0.5 +/- 0.4 to 1.6 +/- 0.5 mm after laser treatment and to 2.1 +/- 0.5 mm after balloon angioplasty. There were no deaths and no vascular perforations. One patient (1.8%) required emergency coronary bypass surgery. These data suggest that excimer laser energy delivered percutaneously by specially constructed catheters can safely ablate atheroma and reduce coronary stenoses.
Results of percutaneous transluminal coronary angioplasty in patients greater than or equal to 65 years of age (from the 1985 to 1986 National Heart, Lung, and Blood Institute's Coronary Angioplasty Registry), The 1985 to 1986 National Heart. Lung. and Blood Institute Percutaneous Transluminal Coronary Angioplasty (PTCA) Registry series of 1.801 initial procedures included 486 patients age greater than or equal to 65 years (elderly). In comparison to younger patients. a greater proportion of elderly patients were women and had unstable angina. Elderly patients had more history of hypertension and more history of congestive heart failure. Although the elderly had more extensive vessel disease. the numbers of lesions and vessels attempted with PTCA were similar in the older and younger cohorts. Angiographic success rates were similar for all age groups. Although complication rates in the catheterization laboratory did not differ. patients greater than or equal to 65 years were much more likely to require emergency coronary artery bypass graft surgery (CABG) (5.4 vs 2.8%. p less than 0.05) or elective CABG (3.9 vs 1.6%. p less than 0.01). The in-hospital death rate was considerably higher among the elderly (3.1 vs 0.2%. p less than 0.01). At 2-year follow-up. symptomatic status and cumulative rates of myocardial infarction. CABG and repeat PTCA were similar for elderly and younger patients. The death rate after 2 years was higher among elderly patients (8.8% of patients greater than or equal to 65 years vs 2.9% of patients less than 65 years. p less than 0.01). When the relative risk of death for the elderly was adjusted for factors more prevalent among those greater than or equal to 65 years (history of congestive heart failure. multivessel disease. unstable angina. history of hypertension and female gender). the relative risk remained significant but was substantially reduced (from 3.3 to 2.4).
Timing and mechanism of in-hospital and late death after primary coronary angioplasty during acute myocardial infarction, The effect of early myocardial reperfusion on patterns of death after acute myocardial infarction (AMI) is unknown. Thus. the mechanism and timing of in-hospital and late deaths among a group of 614 patients treated with coronary angioplasty without antecedent thrombolytic therapy for AMI were determined. Death occurred in 49 patients (8%) before hospital discharge. Four patients died in the catheterization laboratory. Death was due to cardiogenic shock in 22 patients. acute vessel reclosure in 5 patients. was sudden in 8 patients and followed elective coronary artery bypass surgery in 8 patients. Cardiac rupture was observed in only 2 patients after failed infarct angioplasty. and did not occur among the 574 patients with successful infarct reperfusion. Intracranial hemorrhage did not occur. Multivariate predictors of in-hospital death included failed infarct angioplasty. cardiogenic shock. 3-vessel coronary artery disease and age greater than or equal to 70 years. During a follow-up period of 32 +/- 21 months (range 1 to 87). 55 patients died. The cause of death was cardiac in 36 patients. including an arrhythmic death in 23 patients and was due to circulatory failure in 13 others. One patient died of reinfarction due to late reclosure of the infarct artery. Actuarial survival curves demonstrated overall survival after hospital discharge of 95 and 87% at 1 and 4 years. respectively. Freedom from cardiac death at 1 and 4 years was 96 and 92%. Multivariate predictors of late death included 3-vessel disease. a baseline ejection fraction of less than or equal to 40%. age greater than 70 years and female gender.
Circadian rhythm of heart rate variability after acute myocardial infarction and its influence on the prognostic value of heart rate variability, This study examined heart rate (HR) variability in patients surviving acute myocardial infarction (AMI) to find the optimum time and duration of recording of the ambulatory electrocardiogram for the prediction of the risk of sudden cardiac death. or serious arrhythmic events. or both. Twenty patients (group I) who initially survived an AMI but later experienced serious events (death or symptomatic sustained ventricular tachycardia) during a 6-month follow-up were compared with 20 patients (group II) who remained free of complications for greater than 6 months after discharge. Groups I and II were matched with regard to age. gender. infarct site. ejection fraction. and beta-blocker treatment. HR variability was assessed in the 24-hour electrocardiograms recorded during the first 2 weeks after an AMI and in various portions of the complete 24-hour recording. with both the beginning and the length of the analyzed portion varied by 20 minutes (a total of 5.113 possibilities). The maximum reduction of HR variability in group I patients was systematically found when assessing HR variability in recordings starting approximately at 6 A.M. and lasting for approximately 8 hours. In the low-risk patient. the diurnal rhythm of HR variability is more marked than in the high-risk patient and the long-term components of HR variability due to the diurnal variation must be included in the measurement of HR variability when using it as a long-term predictor of risk from arrhythmic events after an AMI.
Doppler assessment of left ventricular filling pattern in silent ischemia in patients with Prinzmetal's angina, Spontaneous angina is an ideal condition in which to study left ventricular (LV) dysfunction induced by acute myocardial ischemia. In 6 patients with Prinzmetal's angina. LV diastolic function during 16 episodes of spontaneous angina was studied by simultaneous recordings of electrocardiographic (ECG). echocardiographic and hemodynamic parameters. In particular. pulsed Doppler echocardiography measured peak velocity of early (E) and late (A) transmitral flow and E/A ratio. as indexes of relative early versus late LV filling. During the ischemic attacks. the time sequence of pulsed Doppler echocardiographic and ECG changes showed 3 distinct phases: (1) "waxing phase: transmitral flow changes with minimal ECG modifications (E/A = 0.85 +/- 0.1); (2) "steady" phase: maximal ECG changes (E/A = 0.9 +/- 0.1); and (3) "waning" phase: regression of the ECG changes (E/A = 1.26 +/- 0.15). In each phase. E/A ratio showed a significant difference from the baseline value (E/A = 1.17 +/- 0.2) as a result of changes in E. suggesting that myocardial ischemia affects mainly the early phase of diastole. In the waxing phase. LV diastolic dysfunction preceded systolic abnormalities. as documented by a significant reduction of E/A ratio in the absence of alterations in LV ejection fraction. as well as in systemic arterial and pulmonary wedge pressures. Finally. all the recorded parameters were consistent with LV "contractile rebound" occurring in the waning phase and affecting both diastole and systole.
Comparison of direct and indirect measures of systemic arterial pressure during weightlifting in coronary artery disease, Based on auscultation measurements after exercise. circuit weight training in cardiac patients has been reported to provoke minimal increases in systolic pressure. Direct (brachial artery catheter) and indirect (sphygmomanometry) measures of blood pressure were compared at rest. during lifting with the legs (approximately the fourth. ninth and fourteenth repetition) and during 2 minutes of recovery after lifting with the arms and legs. Subjects performed 15 repetitions of single-arm curl. single-arm military press and single- and double-leg press exercises at 40 and 60% of the maximum load that could be lifted once on a multistation weightlifting apparatus. Indirect measures of systolic pressure at rest were 13% less than those recorded directly (130 +/- 7 vs 149 +/- 8 torr; p less than 0.01); diastolic pressures were similar using either method. This pattern was maintained during lifting with the legs at both intensities. and after exercise with both the legs and the arms. The mean systolic pressure recorded indirectly immediately after exercise was 63 torr (31%) and 76 torr (34%) less than the average peak intraarterial value recorded during leg and arm exercises. respectively. The highest intraarterial pressures were generated during the final repetitions of the set; immediately after the last repetition. both systolic and diastolic pressures rapidly decreased. It is concluded that indirect estimates of systolic pressure are significantly less than true arterial values at rest. and during and after lifting. Moreover. indirect measurements after lifting do not allow accurate conclusions to be drawn about the arterial pressures generated during lifting because of the rapid decrease in pressure that occurs after exercise.
Response of angiographically normal and atherosclerotic left anterior descending coronary arteries to acetylcholine, Acetylcholine-induced constriction of human coronary arteries in vivo is commonly attributed to endothelial dysfunction. To examine the effects of 2 other important determinants of vascular responses--namely. agonist concentration and the segment of circulation under study--the diameters of proximal. middle and distal segments of the left anterior descending artery (LAD) and coronary sinus oxygen saturation were measured in 10 patients with angiographically normal coronary arteries (group 1) and in 7 patients with coronary atherosclerosis (group 2) after intracoronary acetylcholine was infused at concentrations from 10(-7)M to between 10(-4)M and 10(-2)M. In group 1. acetylcholine caused minor (less than or equal to 6%) but progressive dilatation of the LAD up to 10(-4)M. but constriction. particularly of the distal segments and tertiary branches. occurred at higher concentrations. Over the same concentration range. coronary sinus oxygen saturation rose progressively from a basal level of 36 +/- 3% to a maximum of 72 +/- 3% in the absence of changes in heart rate and blood pressure. suggesting marked progressive dilatation of resistance vessels. Concentrations greater than or equal to 10(-3)M caused intense constriction of distal epicardial vessels and. in some cases. anginal pain and objective signs of ischemia. Conversely. in group 2. acetylcholine (infused only up to 10(-4)M for ethical reasons) failed to cause significant changes in LAD diameter. These data suggest that the local acetylcholine concentration and coronary vascular segment under study may determine the observed response to at least an equivalent extent as does the presence or absence of coronary atherosclerosis. raising the question of whether a constrictor response to intracoronary acetylcholine reliably indicates the presence of coronary atherosclerosis.
Clinical and electrophysiologic characteristics of patients with antidromic circus movement tachycardia in the Wolff-Parkinson-White syndrome, Antidromic circus movement tachycardia was documented in 36 of 345 consecutive patients with Wolff-Parkinson-White syndrome undergoing detailed electrophysiologic evaluation. Twenty-six patients were men and 10 were women (mean age +/- standard deviation 26 +/- 12 years [range 12 to 45]). Multiple accessory pathways were identified in 12 of these 36 patients (33%). Ten of the patients (67%) with clinically documented antidromic tachycardia had multiple accessory pathways. Dizziness and syncope occurred in 61 and 50% of patients with antidromic circus movement tachycardia. Six patients had clinical documentation of atrial fibrillation. and 4 patients (11%) were resuscitated from ventricular fibrillation. In the 36 patients. 56 distinct antidromic tachycardias were recorded and several different pathways were observed. Orthodromic tachycardia was the most frequently associated arrhythmia (72%). Dual atrioventricular nodal pathways were present in 12 patients (33%); however. atrioventricular nodal tachycardia could be initiated in only 2 of them. Interruption of the accessory pathway was successfully performed in all 20 patients undergoing surgery.
Persistence of arrhythmia exercise response in healthy young men, This study assesses the persistence of arrhythmia at rest or during exercise tests. or both. after a mean follow-up period of 6.7 years in 76 young men (mean age 21.5 years) without evidence of organic heart disease. The exercise test was performed using a near-maximal protocol based on progressively increasing intermittent work loads. each of 5 minutes' duration. The initial work load was 50 W. The electrocardiogram was continuously registered throughout all stages of the examination. Arrhythmia was defined as the occurrence of greater than or equal to 1 supraventricular or 1 ventricular premature beat at any stage of the examination. At the follow-up examination. the rate of persistence of arrhythmia did not differ significantly among the subgroups. irrespective of follow-up interval. type of arrhythmia. or arrhythmia patterns of response to exercise. Two-dimensional echocardiography did not show any structural abnormalities and Doppler examination did not demonstrate significant abnormal flow patterns. Our data show that almost all patients continued to present arrhythmia after the follow-up period. without any evidence of development of organic heart disease. Moreover. the arrhythmia pattern of response to exercise remained constant throughout the years. At this time. arrhythmia without underlying heart disease seems to be of a benign natural course in these young men.
Electrocardiographic signal-averaging during atrial pacing and effect of cycle length on the terminal QRS in patients with and without inducible ventricular tachycardia, Electrocardiographic signal-averaging during sinus rhythm (61 to 99 beats/min) and atrial pacing (100 to 171 beats/min) were performed to determine the effect of heart rate on late potentials in 15 patients without (group 1) and 7 patients with (group 2) inducible sustained ventricular tachycardia (VT). In sinus rhythm (79 +/- 12 vs 77 +/- 12 beats/min. difference not significant). the duration of the low-amplitude signal less than 40 microV was longer in group 2 than group 1 (43 +/- 21 vs 26 +/- 8 ms. p = 0.034) and more patients had late potentials (57 vs 7%. p = 0.021). but QRS duration (121 +/- 32 vs 98 +/- 19 ms) and terminal voltage (33 +/- 33 vs 50 +/- 26 ms) were not significantly different. With atrial pacing in group 1 (128 +/- 16 beats/min). 3 patients developed a simultaneous decrease in terminal voltage and an increase in terminal QRS duration consistent with a late potential. but mean total and terminal durations were unchanged. Terminal voltage increased (50 +/- 26 to 59 +/- 40) but not significantly. With atrial pacing in group 2 (119 +/- 12 beats/min) all patients either had a late potential or developed a simultaneous decrease in terminal voltage and an increase in terminal QRS duration (p = 0.001 vs group 1). Root mean square (p = 0.001 vs group 1). Root mean square voltage decreased (33 +/- 23 to 22 +/- 23) and became significantly different from group 1 (p = 0.017). Mean QRS duration. root mean square terminal voltage and low-amplitude terminal QRS duration. however. were unchanged.
Comparison of intravenous amrinone and dobutamine in congestive heart failure due to idiopathic dilated cardiomyopathy, A prospective randomized study was performed in 46 consecutive patients with refractory congestive heart failure (CHF) due to idiopathic dilated cardiomyopathy to compare the hemodynamic responses to 48-hour infusions of amrinone and dobutamine. Both drugs substantially reduced pulmonary arterial wedge pressure. right atrial pressure and systemic vascular resistance and increased cardiac index. Amrinone caused a greater decrease in right atrial pressure than dobutamine (p less than 0.02) and had a positive chronotropic effect not observed with dobutamine (p less than 0.01). The increase in heart rate produced by amrinone correlated inversely with the changes in right atrial and pulmonary arterial wedge pressures. suggesting a baroreceptor response to reduced preload. Dobutamine produced a larger increase in stroke volume index than amrinone (p less than 0.01). Ninety-one percent of patients receiving amrinone and only 65% receiving dobutamine had reduction of greater than or equal to 30% in pulmonary arterial wedge pressure (p less than 0.05). Cardiac index increased greater than or equal to 30% in similar numbers of patients given amrinone (74%) and dobutamine (65%). Negative fluid balance was recorded in all patients receiving amrinone and in 78% of patients receiving dobutamine (p less than 0.05). Target hemodynamic criteria were achieved in 83% of patients receiving 10 micrograms/kg/min of amrinone. The effective maintenance dose of dobutamine was extremely variable. No clinically important adverse effects were observed with either drug regimen. Both amrinone and dobutamine are effective and safe agents for short-term parenteral therapy of patients with dilated cardiomyopathy in severe CHF that is unresponsive to oral medication.
Value of carvedilol in congestive heart failure secondary to coronary artery disease, Despite considerable interest in the use of beta-blocking agents in congestive heart failure (CHF). their clinical application is limited because of their negative inotropic effects. Beta blockers with vasodilating properties may have the advantage of overcoming this. however. Carvedilol. a beta-blocking agent with vasodilating properties. was evaluated in 17 patients with chronic CHF secondary to ischemic heart disease with a resting left ventricular ejection fraction less than or equal to 45%. who were being maintained on diuretics. Exercise testing. radionuclide ventriculography. and right-sided cardiac catheterization were performed and intraarterial blood pressure measured before and after 8 weeks of carvedilol therapy in a dosage of 12.5 to 50.0 mg twice a day. Twelve patients completed the study and 5 withdrew. Symptomatic and hemodynamic improvement was demonstrated in 11 of the 12 patients. Heart rate and intraarterial blood pressure were both reduced by chronic therapy. Mean +/- standard deviation exercise time improved from 4.3 +/- 1.6 to 7.1 +/- 2.7 minutes (p less than 0.0001). as did resting left ventricular ejection fraction. from 27 +/- 9 to 31 +/- 11% (p less than 0.02). Pulmonary arterial wedge pressure fell from 19 +/- 7 mm Hg to 12 +/- 5 mm Hg (p less than 0.001) and total systemic vascular resistance from 1.752 +/- 403 to 1.497 +/- 310 dynes/s/cm-5/m2 (p less than 0.02). Stroke volume index improved also. from 31 +/- 6 ml to 40 +/- 6 ml (p less than 0.0005). These hemodynamic changes were mediated partly by vasodilation. diminished myocardial oxygen demand and reduction of sympathetic overactivity in the failing heart. These data suggest that carvedilol may have beneficial effects in patients with chronic CHF secondary to coronary artery disease.
Improvement in early diastolic filling dynamics after aortic valve replacement, With use of ultrafast computed tomography. 13 patients undergoing aortic valve replacement for aortic stenosis were prospectively followed to evaluate the relation between left ventricular mass and diastolic function. Studies were done before intervention. and then at 4 and 8 months later. Mass decreased from 161 +/- 11 g/m2 (+/- standard error of the mean) at baseline to 106 +/- 5 g/m2. and then to 97 +/- 7 g/m2 at 4 and 8 months. respectively. in 12 patients who demonstrated significant (greater than 20%) mass regression after operation. One patient failed to show significant changes in mass. Diastolic function. as defined by the peak filling rate of early diastole. improved (p less than 0.02) in the group with mass regression. from 2.11 +/- 0.17 s-1 at baseline to 2.12 +/- 0.23 s-1. and then to 2.62 +/- 0.26 s-1 at 4 and 8 months. respectively. Improvement in the time to peak filling rate was also noted. Heart rates were unchanged. whereas end-diastolic volumes decreased and ejection fractions increased slightly. Postoperative increase in peak filling rate correlated with regression of ventricular mass to within normal range (+/- 2 standard deviations) and attainment of New York Heart Association class I status by 8 months (p less than 0.02). Thus. improvement in diastolic function can be seen after aortic valve surgery and is associated with improved functional class. Diastolic function improves later than the regression in wall mass and may imply a delayed remodeling of the ventricle.
Serial evaluation of lipid profiles and risk factors for development of hyperlipidemia after cardiac transplantation, To determine the prevalence. time course and factors responsible for hyperlipidemia after heart transplantation. 83 consecutive 1-year survivors were studied. By 1 year. 83% of patients had serum total cholesterol levels greater than 5.2 mmol/liter (200 mg/dl) and 28% of the patients had serum total cholesterol higher than the age- and sex-matched ninety-fifth percentile. At the end of 1-year follow-up. serum total cholesterol correlated with the recipient age (p less than 0.0001). the preoperative cholesterol level (p less than 0.001). the actual dose of maintenance prednisone at 1 year (p less than 0.02) and the cumulative 1-year steroid dose (p less than 0.03). Similarly. the serum triglyceride level at 1 year correlated with the pretransplant level of serum triglycerides (p less than 0.0001). recipient age (p less than 0.03) and cumulative 1-year steroid dose (p less than 0.03). Patients with a pretransplant diagnosis of coronary artery disease had a significantly higher level of serum total cholesterol and triglyceride levels at 1 year (p less than 0.02 and p less than 0.03. respectively). Heart transplant recipients with body mass index greater than or equal to 25 kg/m2 also presented with significantly elevated serum total cholesterol and triglyceride levels at 1 year compared with nonobese patients (p less than 0.01 and p less than 0.002. respectively). Hyperlipidemia occurs frequently and is detected within the first month after heart transplantation. Optimal management of this problem requires further study.
Relevance of intrinsic sympathomimetic activity for beta blockers, Intrinsic sympathomimetic activity (ISA) characterizes a group of beta blockers that are able to stimulate beta-adrenergic receptors (agonist effect) and to oppose the stimulating effects of catecholamines (antagonist effect) in a competitive way. Partial agonists are ligands that elicit a submaximal response when bound to beta receptors at maximal occupancy. In the isolated rat atrium. acebutolol produces a maximal stimulatory effect that is only 17 +/- 8% of the maximal effect induced by the full beta agonist isoproterenol. The presence of ISA results in less resting bradycardia and less of a reduction in cardiac output than is observed with beta blockers without ISA. In the long term. partial beta agonists may produce arterial vasodilation and increase arterial compliance. possibly leading to additional beneficial effects in the treatment of hypertension. beta blockers with ISA do not have adverse effects on plasma lipoproteins during long-term treatment; in addition. the presence of ISA could counteract the up-regulation of beta adrenoceptors often observed with beta blockers without ISA. Finally. the presence of ISA has been a conflicting issue for the use of such beta blockers in secondary prevention after myocardial infarction. However. the impressive results of the Acebutolol Prevention of Secondary Infarction trial in high-risk patients after myocardial infarction show that acebutolol. a beta blocker with moderate partial agonist activity. can be effective in decreasing the postinfarction mortality rate. By exhibiting a strikingly different hemodynamic profile from that of beta blockers without ISA. the partial beta agonists form an intriguing pharmacologic class of drugs for which prospective clinical trials should be extensively pursued.
Efficacy of acebutolol after acute myocardial infarction (the APSI trial). The APSI Investigators, A randomized. placebo-controlled trial was carried out to determine the effectiveness of acebutolol in preventing late death in high-risk patients surviving an acute myocardial infarction (MI). The average 1-year mortality rate in placebo groups of 9 trials of beta blockers in post-MI patients was 7.2% compared with 17% in a nonselected cohort of patients who had survived at least 7 days after an MI. The mandate for this trial was based on the fact that high-risk patients whose mortality rate exceeds 20% have not been enrolled in significant numbers in previous trials. It remains to be proved whether beta-blocking therapy in this patient population is beneficial. Selection of high-risk patients for inclusion in the trial was based on an algorithm set up from the Essai de Prevention Secondaire de l'Infarctus du Myocarde Registry. At the time of the second interim analysis. the mortality rate in the placebo group was 12%. lower than expected (greater than or equal to 20%). The trial was stopped; at that time. 309 patients had been allocated to placebo and 298 patients to acebutolol therapy. After 318 days. there were 17 deaths in the acebutolol-treated group and 34 in the placebo group. a reduction in total mortality of 48% (p = 0.019). There were 30 vascular deaths in the placebo group and 12 in the acebutolol group. Thus. cardiovascular mortality with acebutolol was reduced by 58% (p = 0.006). The incidence of all cardiovascular-related deaths was lower in the acebutolol-treated group. The total reduction in mortality did not appear to be correlated with secondary risk factors.
Secondary prevention of acute myocardial infarction with beta-blocking agents and calcium antagonists, The discovery that beta blockers possess clinically useful hypotensive. antianginal and antiarrhythmic properties has attracted the interest of clinicians. researchers and the pharmaceutical community alike. In addition. minor differences in a variety of ancillary properties have led to speculation that specific classes of drugs might have advantages over other classes. The enthusiasm that greeted reports from the first small trials. which showed that beta blockers reduced the postmyocardial infarction mortality rate. attracted the commercial support necessary to evaluate different beta blockers in this clinical setting. The plethora of beta blockers that subsequently became available for study led to considerable improvement in both the design and implementation of large clinical trials. Despite apparent discrepancies in the results of various trials. meta-analysis indicates that most. if not all. beta blockers reduce postinfarction mortality. However. because meta-analysis cannot recommend a particular drug or specific dose for use in an individual patient. clinical practice must be based on the results of individual trials. not on the conclusions of meta-analysis. The clinical utility of beta blockers in the secondary prevention of myocardial infarction. coupled with experimental evidence that calcium antagonists reduce infarct size. led to a series of large studies designed to establish whether calcium antagonists have any effect on reducing mortality in patients with myocardial infarction. Lessons learned from the beta-blocker trials permitted a more rapid evaluation of the efficacy of calcium antagonists in this setting. It is clear that. unlike beta blockers. calcium antagonists are not effective in the secondary prevention of myocardial infarction.
Characteristics of participants at baseline in the Treatment of Mild Hypertension Study (TOMHS), The Treatment of Mild Hypertension Study (TOMHS) is a randomized. double-blind clinical trial currently being conducted to compare the effects of nonpharmacologic therapy alone with those of 1 of 5 active drug regimens combined with nonpharmacologic therapy. for long-term management of patients with mild hypertension. Six classes of drugs were studied: (1) acebutolol (beta blocker). (2) amlodipine (calcium antagonist). (3) chlorthalidone (diuretic). (4) doxazosin (alpha 1 antagonist). (5) enalapril (angiotensin-converting enzyme inhibitor) and (6) placebo. All participants received nutritional-hygienic advice to reduce weight and sodium and alcohol intakes and to increase physical activity. End points include blood pressure change. side effects and quality-of-life indices; incidence of electrocardiographic and echocardiographic abnormalities; and incidence of cardiovascular clinical events. including death. among participants receiving drugs as first-step treatment as well as nonpharmacologic treatment compared with incidence among those participants randomized to nonpharmacologic treatment only as the initial step.
Mechanical factors in large artery disease and antihypertensive drugs, Hypertension may induce early alterations in large arteries by 2 mechanical stresses: one related to intravascular pressure. the other to blood flow dynamics. Distending pressure force acts in a circumferential direction. inducing decreased arterial distensibility. Arterial distensibility can be evaluated in humans by measurement of arterial compliance and pulse-wave velocity. It is well established that in chronic hypertension age and elevated pressure act together to increase arterial rigidity. Blood flow dynamics induce frictional forces in the endothelial surfaces of arteries. These forces. expressed by shear stress. are proportional to the viscosity of the blood and to the velocity gradient at the arterial wall. Measurement of blood viscosity and evaluation of velocity profile in the brachial arteries of hypertensive subjects have shown a reduction in wall shear rate and stress despite the elevation in blood viscosity. Several studies have shown that drug therapy that successfully reduces blood pressure does not necessarily improve arterial compliance. In contrast. few data are available on the effects of antihypertensive medication on arterial wall shear in humans. Arterial compliance and wall shear stress are 2 main therapeutic targets of potential importance in the physiopharmacologic approach to the effects of hypertension on atherogenesis.
Documentation of the effective length of action of antihypertensive treatment, The technique of automated ambulatory blood pressure (BP) monitoring offers an innovative means for measuring BP throughout the 24-hour period. Recently available compact monitoring instruments have been shown to be accurate and to provide reproducible measurements of the circadian BP pattern. The monitoring procedure is advantageous in that it minimizes or avoids placebo effects during therapeutic trials. Moreover. its power makes it possible to draw statistically valid conclusions regarding efficacy in fewer patients than would be required if conventional methods were used. This procedure also enhances the diagnosis of hypertension by identifying patients with "office" or "white coat" hypertension. and thereby facilitates assessment of treatment effects in those patients who are truly hypertensive. Automated monitoring measures BP at critical times of the day. including the preawakening and early morning hours. and it enables peak and trough antihypertensive drug effects to be carefully quantified. Since patient compliance appears to be enhanced with once- or twice-daily dosing. antihypertensive agents with long durations of action (24 hours) are of considerable interest. This report reviews some recent studies in which the monitoring technique has been used to measure the efficacy and duration of action of differing antihypertensive drugs.
Acebutolol effects on lipid profile [published erratum appears in Am J Cardiol 1990 Dec 1;66(19):A8, The relation between lipid profile and the incidence of coronary artery disease has been confirmed by the results of epidemiologic and intervention studies. Among antihypertensive agents. beta blockers. particularly those without intrinsic sympathomimetic activity (ISA). are generally reported to have negative effects on lipids. which may increase the risk of coronary artery disease. The ongoing Treatment of Mild Hypertension Study. now in its third year. has evaluated 847 patients to date with regard to lipid profile. Additional end points measured in this multicenter. randomized. controlled. double-blind study include blood pressure reduction and target organ deterioration. During the trial. all patients received nutritional and behavioral counselling to modify their diet. exercise habits and alcohol and sodium consumption to control their hypertension by nonpharmacologic means. In addition. some patients were randomized to receive low doses of 1 of the 5 classes of antihypertensive medication: acebutolol. a beta blocker with ISA (n = 124); amlodipine. a calcium channel blocker (n = 122); chlorthalidone. a diuretic (n = 125); doxazosin. an alpha blocker (n = 128); enalapril. an angiotensin-converting enzyme inhibitor (n = 127) or placebo (n = 221). At 1 year. acebutolol showed a statistically significant (p less than 0.001) decrease in total cholesterol (-12.7 mg/dl) compared with placebo (-5.2 mg/dl) and with chlorthalidone (1.0 mg/dl); a significant (p less than 0.001) decrease in low-density lipoprotein cholesterol (-6.0 mg/dl) compared with placebo (+0.7 mg/dl) and with chlorthalidone (+8.0 mg/dl) and no change in high-density lipoprotein cholesterol (-0.4 mg/dl).
Apocrine mammary carcinoma. A clinicopathologic study of 72 cases, Apocrine carcinoma (AC) is an uncommon. poorly characterized type of breast tumor. In this review. 55 patients with intraductal (ID) AC and 17 patients with infiltrating (IF) AC were analyzed retrospectively to define the histologic features and clinical course of this neoplasm. Recurrences in the breast occurred in 3 of 20 ID-AC patients treated by biopsy alone. but not in the 2 patients who received local radiation therapy after biopsy. One patient with ID-AC had axillary metastases at the time of treatment by mastectomy and died of disease five years later. The remaining patients with ID-AC treated by mastectomy have remained disease free. One of the three patients with IF-AC treated by biopsy alone died of disease. and one of two patients with IF-AC treated by biopsy and radiotherapy was alive with carcinoma. Twelve patients with IF-AC were treated by mastectomy. Ten of them were recurrence free at the time of last observation. More than one-third of the cases of ID-AC and IF-AC were detected by mammography alone. Survival analysis of IF-AC cases compared with nonapocrine duct carcinoma cases matched for stage revealed no statistical difference in estimated recurrence-free survival or estimated survival probability. AC is a distinct morphologic entity with a natural history similar to that of nonapocrine ductal carcinoma.
Bcr/abl recombinant DNA analysis versus karyotype in the diagnosis and therapeutic monitoring of chronic myeloid leukemia, Karyotype and bcr/abl recombinant DNA analyses are two means of detecting the chromosomal aberration in chronic myeloid leukemia. The authors compared these two methods in a retrospective study of 36 patients with CML in which they found the bcr/abl DNA recombinant event in 100% (29 of 29) of those patients who had the Philadelphia chromosome. To achieve this sensitivity. a battery of two bcr probes and three restriction enzymes is necessary. The authors propose a sequential algorithm for efficient use of these probes and enzymes. In 76% of the patients. bcr/abl rearrangement can be detected with a Bgl II digest and a 3' commercial probe. An additional 21% of patients can be detected by a second assay in which the same membrane is rehybridized to a 3' and 5' combination bcr probe. One patient (3%) required an additional restriction enzyme digest with BamH I to detect the recombinant event by the same 3' probe. Karyotype analysis is used to determine cytogenetic remission in patients with CML under therapy. The authors studied the use of DNA analysis by the Southern blot technique to detect a decrease in the relative number of leukemic cells. By dilution studies and densitometric scanning of autoradiographs. the authors were able to detect a 15% decrease in the relative number of cells having the bcr/abl recombinant event. The authors report the preliminary results of three patients in whom they compared the karyotype and recombinant DNA analysis at multiple time points in their clinical course. In conclusion. the bcr/abl recombinant DNA analysis is superior to karyotype for the diagnosis of CML and can be used for monitoring treated patients.
Clostridium difficile invasion and toxin circulation in fatal pediatric pseudomembranous colitis, The direct involvement of Clostridium difficile in the lesional tissue of pseudomembranous colitis has not been demonstrated; the organism's effects have been assumed to be strictly toxin mediated. Because C. difficile cytotoxin may be found incidentally in the intestinal lumina of asymptomatic infants. the role of the organism in a variety of pediatric intestinal diseases is uncertain. The authors studied seven cases of fatal pediatric pseudomembranous colitis in which the presence of C. difficile was uniformly demonstrable in lesional tissues with the use of both an intestinal spore stain and a specific immunostain. The patients had either underlying Hirschsprung's disease or hematologic malignancy; the striking pathologic features peculiar to these patients were altered mucosal mucin and immunologic barriers in the former group and neutropenia in the latter. Two patients had demonstrable circulating cytotoxin in serum or ascitic fluid. and C. difficile was identified invading colonic mucosa or submucosa. Such phenomena did not occur in control pediatric patients with multiple other intestinal lesions. Altered host factors may be responsible for the intestinal invasion of C. difficile and its systemic toxin circulation in cases of fatal pediatric pseudomembranous colitis.
Isolation of human immunodeficiency virus (HIV) at autopsy one to six days postmortem, Blood and tissue were studied for potential infectivity at autopsy of ten patients with human immunodeficiency virus (HIV) infection. Special attention was paid to the possibility of detecting HIV in bone at craniotomy. Postmortem intervals were one to six days. Specimens for HIV isolation included skull bone. brain. blood. bone marrow. spleen. and lymph node. and cerebrospinal fluid in one case. HIV grew in culture from at least one specimen from eight autopsies. one of which was performed six days postmortem. HIV was recovered from the blood of five patients and the tissue of five patients. including three with negative blood cultures. Skull bone contained HIV in two cases. HIV also grew from native spleen specimens stored for up to 14 days postmortem at 20 degrees C. Recommended precautions. including those for bone. are indicated at autopsy of HIV-infected patients even after long postmortem intervals.
Cerebrospinal fluid changes after 48 hours of effective therapy for Hemophilus influenzae type B meningitis, Interval cerebrospinal fluid (CSF) analysis is often performed to assess efficacy of treatment for bacterial meningitis. The authors reviewed 101 cases of pediatric bacterial meningitis resulting from Hemophilus influenzae type b in which analysis of CSF occurred on admission and between 48 and 72 hours after initiation of parenteral antibiotic therapy; of these. only one patient had a positive repeat CSF culture. Of the 100 cases with sterile CSF on repeat culture. there was no instance of recrudescence of infection during hospitalization. The following characterized the interval changes in CSF profile of this group: 100 (100%) with persistence of pleocytosis; 14 (14%) with differential cell count conversion from polymorphonuclear neutrophil leukocyte (PMN) predominance to relative lymphocytosis; 96 of 98 (98%) with initial positive Gram-stained smear with negative results for organisms; 53 of 75 (71%) with normalization of initial hypoglycorrhachia; and 10 of 94 (11%) with normalization of initial abnormally elevated protein levels. The differences in mean values of CSF total white blood cell counts. percentage PMNs. and glucose and protein concentrations on presentation and between 48-72 hours of therapy were highly significant (P less than 0.0001). After 48 hours of effective antibiotic therapy for H. influenzae type b meningitis. CSF pleocytosis and abnormally elevated protein concentration are usually preserved. whereas hypoglycorrhachia usually resolves; it is not uncommon for the differential cell count to convert from a PMN predominance to a relative lymphocytosis. Significant alteration in all CSF parameters associated with H. influenzae type b meningitis can occur after 48 hours of effective parenteral antibiotic therapy.
The use of molecular probes to distinguish new primary tumors from recurrent tumors in gynecologic malignancies, This is the first report using DNA molecular probe technology to distinguish between recurrent tumor and a second primary malignancy in a patient. Tumor DNA was extracted from squamous cell carcinoma of the cervix at the time of radical hysterectomy. Eighteen months later a squamous cell cancer was found in a vaginal apex biopsy from which DNA was extracted. Tumor DNA from both lesions was subjected to restriction enzyme digestion and DNA molecular hybridization with human papillomavirus (HPV) probes. Although both lesions were positive for HPV 16. their respective restriction enzyme patterns had different HPV genetic arrangements. thereby demonstrating their distinctness.
Small cell neuroendocrine carcinoma of Bartholin's gland, A small cell neuroendocrine carcinoma that arose in Bartholin's gland in a 30-year-old woman is reported. The tumor had light. electron microscopic. and immunohistochemical features typical of pulmonary small cell carcinoma and was metastatic to inguinal lymph nodes at presentation. This is the first reported example of this tumor occurring in Bartholin's gland.
Thyroid carcinoma with mixed tall-cell and columnar-cell features, Tall-cell and columnar-cell carcinomas have been regarded as aggressive variants of papillary thyroid carcinoma. In the present case report the authors describe a composite tumor where these forms of differentiation coexisted. with transitional changes occurring within single follicular structures. This finding indicates that the two variants are closely related. In local recurrences. one or the other feature appeared in separate lesions. Lung metastases developed. and the patient died 5 1/2 years after diagnosis and primary treatment.
Primary splenic lymphocyte-depletion Hodgkin's disease, A case of lymphocyte-depletion Hodgkin's disease is described for the purpose of reviewing the criteria currently used to distinguish this disease from other pleomorphic large-cell malignancies. A 76-year-old man with a 3-month history of daily fevers underwent extensive evaluation and exploratory laparotomy. which revealed only two large. separate splenic tumor nodules. Postoperatively. the patient remained asymptomatic. Histologically. the tumor was composed of giant cells. including both typical Reed-Sternberg forms and mononuclear variants with inflammatory stromal response along its borders. Immunoperoxidase showed tumor cells to be strongly reactive for Leu-M1 (CD15). BER-H2 (CD30). Leu-3 (CD4). and T11 (CD2) and weakly reactive for Leu-4 (CD3) but nonreactive for EMA. LCA. lysozyme. Leu-9. Leu-M3. Leu-M5. and immunoglobulin light chains. Southern blot analysis revealed an isolated clonal band for kappa light chain only. Included in the discussion of this case of primary splenic lymphocyte-depletion Hodgkin's disease is a review of clinical. histologic. immunohistochemical. and gene-rearrangement characteristics of what can be defined as lymphocyte-depletion Hodgkin's disease.
Confronting cisternae presenting as intracytoplasmic inclusions in monocytes, Small gray-blue intracytoplasmic inclusions were noted in the peripheral monocytes and neutrophils from a patient with renal failure. Ultrastructural analysis revealed confronting cisternae within the cytoplasm. The authors submit a case report to introduce a previously undescribed morphologic feature of leukocytes that may be mistaken at the light microscopic level for Dohle bodies or other inclusions.
A diagnostic expert system for colonic lesions, The diagnostic expert system for colonic lesions (DESCL) was designed to discriminate colonic adenoma and adenocarcinoma from normal colonic tissue. Although it was originally developed for use in conjunction with a machine vision analytic system. the DESCL has evolved into a teaching tool and a model for conceptual machine learning. The expert system is table driven and consists of a shell and a knowledge base. The latter comprises a series of architectural and cytologic observations and a quantitative estimate of diagnostic importance relating these observations to diagnostic outcome. In a validation study of 100 colonic lesions. the expert system achieved a success rate of 98%. It has the flexibility to allow individual pathologists to "customize" the knowledge base to suit their diagnostic criteria.
Estimation of PR and ER by immunocytochemistry in breast cancer. Comparison with radioligand binding methods, Immunocytochemical assays for progesterone receptor (PR) using monoclonal antirabbit PR antibodies (PR-ICA) and for estrogen receptor (ER) (ER-ICA) were compared with radioligand binding (dextran-coated charcoal [DCC]) methods for receptor determination in patients with breast cancer. Immunocytochemical staining for PR was exclusively nuclear in localization. In this regard. PR staining is similar to previous findings for ER; PR-ICA showed a sensitivity of 89% and specificity of 100%. ER-ICA was also 89% sensitive and similarly specific. There was good correlation between the degree and intensity of staining and quantitative binding of radioligand. Receptor-positive tumors. however. show considerable variation of immunocytochemical staining. suggesting heterogeneity of cellular PR content. The availability of an immunocytochemical assay for PR increases the discriminatory potential for these methods of receptor determination.
Wounding effects of the AK-47 rifle used by Patrick Purdy in the Stockton, California, schoolyard shooting of January 17, 1989, The limited disruption produced in tissue simulant by the rifle and bullets used in the Stockton. California. schoolyard shooting is entirely consistent with the autopsy reports on the five children who died of their wounds. It is also entirely consistent with well-documented battlefield studies and with previous tissue-simulant studies from many laboratories. It is inconsistent with many exaggerated accounts of assault-rifle wounding effects described by the media in the aftermath of this incident. This information should be documented for the historical record. However. the critical reason for correcting the misconceptions produced by media reaction to this incident is to prevent inappropriate gunshot-wound treatment.
Identification of the driver in two-rider motorcycle accidents. Inguinal contusion-laceration as an indication of the driver, In motorcycle accidents involving two riders. medicolegal identification of the driver is necessary when one or both riders die. It is particularly important in the latter case. because the survivor almost always insists that he or she was not driving. One characteristic injury that distinguishes the driver from the passenger is inguinal contusion-laceration (accompanied internally by pelvic fracture). This injury. caused by collision of the pelvis with the fuel tank. identifies the driver.
Sudden unexpected nocturnal death syndrome in the Mariana Islands, Sudden unexpected nocturnal death syndrome (SUNDS) is a distinct clinical entity in previously healthy. young. Southeast Asian males. It is well known in the Philippines and more recently recognized in the U.S. by nonspecific autopsy findings. with no evidence of underlying disease and absence of toxic drug or alcohol levels. In 1973-89. 14 cases of apparent SUNDS came to coroner's autopsy in the Commonwealth of the Northern Marianas (CNMI) and Guam. All 14 cases. with the exception of one Yapese. were previously healthy. male Filipinos. aged 23 to 55. who were either found dead in bed. or described by their colleagues as having nocturnal seizure activity consisting of gurgling. frothing. and tongue biting immediately prior to death. Autopsy findings showed no anatomic findings to account for death. Comprehensive serum and urine drug analyses were negative. All decedents showed absence of significant atherosclerosis or grossly detectable structural cardiac anomaly. while four showed cardiomegaly. Migrants from Southeast Asia carry with them a pre-disposition to this syndrome. which appears to decline with longer residence in the new country. The mechanism of death in SUNDS is believed to be ventricular fibrillation. possibly precipitated by sudden sympathetic discharge. Studies suggest at least some deaths may be associated with an abnormal cardiac conduction system. Acute pancreatitis has been a finding in some series. but not our cases. Why the condition is virtually limited to males and seemingly sleep-triggered. has not been adequately explained. Stress and depression are believed to be predisposing factors.
Fatal big cat attacks, Two cases of fatal attacks by large cats are presented. In the first case. a 30-year-old female zoo worker was attacked by a jaguar that had escaped its cage. In the second case. a 2-year-old girl was fatally injured by her father's pet leopard. The pattern of injuries in these cases is nearly identical to those of these cats' prey in the wild.
Carbon monoxide poisoning. Five-years' experience in a defined population, A review is presented of 302 cases in East Denmark in 1982-1986 in which the manner of death was fatal carbon monoxide (CO) poisoning. The incidence of this far too frequent single-substance poisoning has as yet not decreased over the years despite preventive measures. The number of fatal CO poisoning cases may diminish as a result of a natural gas project in progress. The purpose of this survey. therefore. is to contribute to the evaluation of the actual causes of these fatal poisonings in East Denmark. and to discuss existing measures that prevent gas poisonings. in the expectation of a decline both in gas suicides and in accidental gas poisonings within the next few years.
Path of bullet and injuries determined by radiography, Radiography is commonly used to find bullet pathways in forensic pathology. In the case presented here. a man had sustained multiple gunshot wounds and one bullet could not be traced. A radiograph was used to find the bullet and showed an interesting bullet pathway. By observing the bullet pathway on a radiograph. sometimes we can surmise the victim's body posture at the time of an incident.
Identification of the driver in an automobile collision, We report on a three-occupant automobile collision in which one of the two survivors claimed that the deceased had operated the vehicle. We attempted to identify the driver. The left face and neck of the deceased appeared to have struck the vehicle's interior. The survivors were slightly injured on the right side of their faces. In Japan. the passenger side is on the left. and in this case. the right side of the vehicle had been damaged. By comparing the injuries of the deceased and the survivors in relation to the vehicle damages. we concluded that the deceased occupant had probably been a passenger. not the driver.
Fatal high cervical spinal cord injury in an automobile accident complicating os odontoideum, We report a case where spinal instability from incomplete fusion of the dens of C2 (os odontoideum) allowed anterior displacement of the skull and first cervical vertebra following right frontal impact against the A pillar in an automobile accident. Resultant crushing and laceration of the spinal cord occurred at the level of C1 and C2. Without either radiographic investigation or detailed examination of the spine. the fatal injury might have been overlooked and death attributed to acute alcoholic poisoning because the blood alcohol level was .613%.
Clinical significance of colonic fermentation, Recent evidence of the potential benefits of short chain fatty acids has prompted renewed interest in the area of human colonic fermentation. This paper reviews the clinical and metabolic consequences of colonic fermentation.
Prospective randomized comparison of Brown-McHardy and microvasive balloon dilators in treatment of achalasia, We report the results of a randomized prospective study comparing a standard bougie rubber balloon dilator [Brown-McHardy (BMH)] and a newer polyethylene dilator passed over a guide wire [Microvasive Rigiflex (MVR)]. Twenty achalasia patients (15M. 5F. mean age 45.4 yr) considered candidates for either dilator were randomized. Symptom assessment. body weight. and upright radionuclide solid esophageal emptying study were measured before and 6 months after pneumatic dilatation. All dilatations were performed by one of three experienced gastroenterologists under fluoroscopic guidance. Overall success occurred with 10/10 BMH and 7/10 MVR. One patient not improved with MVR had myotomy; the other two were successfully treated by BMH. No complications occurred with either dilator.
Healing or amelioration of esophagitis does not result in increased lower esophageal sphincter or esophageal contractile pressure [published erratum appears in Am J Gastroenterol 1991 Feb;86(2):253, There is conflicting evidence regarding whether lower esophageal sphincter and esophageal contractile pressures are affected by changes in the severity of gastroesophageal reflux disease. We compared the manometric and endoscopic findings from 30 patients before and after treatment for esophagitis. Before treatment. the grade of esophagitis (I-III) was significantly correlated (r = -0.37; p less than 0.05) with lower esophageal sphincter pressure. but not with esophageal contractile pressure. After treatment. the grade of esophagitis did not change or became worse in 15 patients. and became better in 15 patients. Of these. seven healed. The group that showed no endoscopic improvement demonstrated no change in lower esophageal sphincter or esophageal contractile pressures. The group that did show endoscopic improvement also demonstrated no increase in lower esophageal sphincter or esophageal contractile pressures. and this was particularly evident in those whose esophagitis healed. These data suggest that healing of esophagitis does not result in improvement of esophageal motor function.
Sucralfate used as adjunctive therapy in patients with severe erosive peptic esophagitis resulting from gastroesophageal reflux, A total of 36 patients with grade 2 or greater erosive esophagitis and an abnormal 24-h pH monitor study. were treated in a randomized. double-blind fashion to assess the efficacy of sucralfate suspension as adjunctive therapy to cimetidine for severe esophagitis secondary to gastroesophageal reflux. Treatment consisted of cimetidine. 300 mg qid and either sucralfate suspension (1 g/10 ml) or an identical placebo suspension. 10 ml after meals and 20 ml hs. Patients were treated for 12 wk unless endoscopic healing occurred earlier. Initial evaluation and monthly follow-up consisted of symptom monitoring. endoscopic evaluation and pre- and post-therapy esophageal manometry. Bernstein test. and 24-h pH monitoring. The combination of cimetidine and sucralfate suspension was superior to cimetidine alone in improving daytime heartburn symptoms (p less than 0.05) but not nighttime heartburn. dysphagia. or regurgitation. Sucralfate plus cimetidine improved the overall endoscopic outcome of esophagitis more than cimetidine alone (p less than 0.05). More patients exhibited endoscopic healing in the adjunctive sucralfate group than in the cimetidine-only group. Endoscopic healing. however. was not statistically different between groups. We conclude that sucralfate used as adjunctive therapy to cimetidine resulted in improvement of some of the symptoms of reflux. and probably increases the likelihood of complete healing of esophagitis. compared with cimetidine alone.
Endoscopic ultrasonography in staging rectal cancer, Endoscopic ultrasonography (EUS) was used to stage rectal cancer by assessing depth of invasion through bowel wall layers and/or involvement of lymph nodes. EUS findings were correlated with histopathologic findings to discern the usefulness of this modality in predicting which patients could be candidates for sphinctersaving procedures and the avoidance of abdominoperineal resection. The Olympus EU-M3 endoscopic ultrasound system was used to assess depth of penetration through rectal wall layers and to identify lymph nodes. Comparison of EUS findings to histopathologic findings was possible in 13 patients. EUS agreed with histopathology in 9 of 13 cases (69.3%) ( p = 0.07. kappa statistic). EUS agreed with histopathology as the presence or absence of lymph nodes in 9 of 13 cases (69.3%) (p = 0.07). However. the presence of lymph nodes could not necessarily predict metastatic involvement of these nodes. In one patient. invasion of vaginal cuff was correctly predicted. In nine cases. computed tomographic analysis (CT) was available for comparison to EUS in detection of penetration beyond the bowel wall. CT agreed with histopathology in 3 of 9 (33%). whereas EUS agreed with histopathology in 7 of 9 (78%).
Exacerbation of chronic active hepatitis type B after short-term corticosteroid therapy resulting in fatal liver failure, The case of a 36-yr-old male with chronic active type B hepatitis in whom 4-wk prednisone therapy resulted in prolonged and fatal exacerbation of liver disease is described. Thus. short-term corticosteroid therapy may in some patients have disastrous effects on the course of chronic active hepatitis B.
Overview: renal physiology and pathophysiology of aging, Cross-sectional studies in humans have suggested that there is a progressive decline of renal function with age after 40 years. The decline in various functions (eg. tubular maximums. concentrating and diluting abilities. and acidification) tend to parallel the decreases in glomerular filtration rate (GFR) and renal blood (plasma) flow (RPF). Recent observations from the Baltimore Longitudinal Study of Aging suggest that not all individuals follow this pattern. and that. indeed. many show no decline and some even an increase in their renal function over time. Whether the observed decreases in renal function with aging are the results of intervening pathologic processes. eg. immunologic. infectious. and toxic injury and ischemia. or can be related to hyperperfusion and hyperfiltration with resultant glomerulosclerosis. or to some other relentless involutional process. remains unclear. The purpose of this report is to review the descriptive studies documenting the changes in renal morphology and physiology with age and to discuss what is known about mechanisms involved in these losses of renal substance and function.
Geriatric pharmacokinetics and the kidney, The general population is aging and. as a result. drugs are increasingly prescribed for a variety of medical conditions in a group of patients with multiple physiologic and pharmacokinetic abnormalities. The present report summarizes principles of prescribing for the elderly. especially those related to the decline in renal function that frequently occurs.
Nutritional causes of renal impairment in old age, The occurrence of renal insufficiency tends to increase in late adulthood. This common complication of old age is associated with increased physical dependency. morbidity. and mortality. and a lowered quality of life. In this review. the authors will develop the thesis that dietary practices during early and middle adulthood importantly influence the risk of renal insufficiency in the elderly.
Basic evaluation of female urinary incontinence, Urinary incontinence is a common disorder that is frequently underreported because of its social implications. Although several types of urinary incontinence are recognized. they can be generally classified as failure of the bladder to store or failure of the urethral mechanism. A systematic approach for the evaluation of incontinence that includes history. physical examination. basic laboratory tests. and often urodynamic evaluation. offers the most comprehensive assessment of the etiology of incontinence.
Treatment of renal calculi in the elderly, The management of renal calculi in the geriatric patient population poses some unique problems that include anesthetic risks. underlying medical disease. and general risk/benefit concerns. A variety of relatively noninvasive procedures are available. including extracorporeal shock wave lithotripsy (ESWL) and percutaneous nephrostolithotomy (PCNL). A practical management plan is presented that is based primarily on stone size and takes into consideration problems unique to the elderly patient.
Systolic hypertension in the elderly: reasons not to treat, Isolated systolic hypertension in the elderly is associated with increased morbidity and mortality. Accurate measurement of blood pressure in older patients is difficult. Therapy can be associated with various complications. and the special problems of the elderly. such as orthostatic hypotension and hyperkalemia. should be carefully considered. Drugs should be used in low doses and changes in dosage should be made infrequently. Patients should be monitored frequently for untoward effects of therapy. The benefits of blood pressure reduction and the optimal degree of blood pressure reduction remain unknown.
Hemodialysis and the elderly patient: potential advantages as to quality of life, urea generation, serum creatinine, and less interdialytic weight gain, A total of 204 patients treated by maintenance hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) were studied to ascertain how advancing age influences adaptation to uremia therapy. No difference in Karnofsky score was noted among patients over 70 years of age and two groups of patients. 16 to 59. and 60 to 69 years of age. respectively. In a subset of 33 hemodialysis patients studied midweek. it was noted that increasing age is associated with a lower serum creatinine concentration. lower interdialytic weight gain. and a lower urea generation rate. These three findings contribute to a relative ease in treating older uremia patients with hemodialysis or CAPD. as they tend to be stable and compliant relative to younger patients.
The elderly on dialysis: some considerations in compliance, Compliance with scheduled treatments. dietary and fluid restrictions. and multiple medications is an important component in the care and well-being of end-stage renal disease (ESRD) patients. Given the rigorus and complex demands of dialysis. it is important to examine the issue of compliance. focusing on a large and ever-increasing segment of our patient population. the elderly. The ESRD literature reflects efforts to define and measure levels of compliance. identify factors that influence and predict compliance. and develop intervention strategies to improve adherence to treatment regimens. While limited attention has been focused specifically on the elderly. there are studies suggesting that age may be a factor associated with improved adherence and that social support may be a significant contributor to compliance in this patient group. In an effort to examine the current status and needs of the dialysis elderly. research is in progress at Chromalloy American Kidney Center. Washington University. which replicates a study of 5 years ago. Eighty-four patients age 60 and over. on dialysis for a minimum of 6 months. were identified. Sociodemographic. treatment. compliance. and functional capacity data were collected; additional mental and psychological testing was completed on patients willing and able to participate. Preliminary data suggest the current elderly population is larger and significantly older than that of 5 years ago. Other sociodemographic data indicate the population is increasingly female. black. and more socioeconomically disadvantaged. In regard to compliance. the vast majority of elderly demonstrate good compliance as measured by serum potassium. fair to good compliance with phosphorus. and fair to poor compliance with fluid restrictions.
Strategies for enhancing compliance in the dialysis elderly, Noncompliance must be viewed as a symptom of another problem or problems. Treatment plans should be developed based on an individualized assessment of the patient's physiologic functioning and psychosocial situation. It must be determined whether the patient is intentionally or unintentionally not complying. Staff must also be aware of how they impact compliance. While staff have a responsibility to maximize the individual's efforts to comply. it must be realized that the ultimate decision and responsibility rests with the patient.
Ethical issues in geriatric nephrology: overview, Developments in medical care over the past five to six decades have provided remarkable life-sustaining technologies (LST) that have contributed to prolongation of the life span of patients. as well as to a general increase in health and well-being. End-stage renal disease (ESRD) treatment is a prototype of these LST treatments and of the issues surrounding provision of chronic/catastrophic care. This remarkable progress has been accompanied by ethical dilemmas that include allocation of scarce resources. and initiation and termination of care with LST. Consideration of these ethical dilemmas are especially poignant for the elderly. because they raise "hard choices" and there are no easy answers to these ethical dilemmas.
Ethical principles in geriatric nephrology, Seven principles are suggested to resolve ethical issues raised by medical developments affecting an aging society. First. there must be clear identification of the goals of medical treatment. Second. treatments must consider the whole person. Third. physiological concerns are more important than chronological age. Fourth. a patient's choice must be respected when choice is the result of an informed decision-making process. Fifth. access has to be equitable while respecting the sixth principle which requires allocation of resources. Finally. society must more clearly identify the appropriate principles to guide the care of the dying person.
Ethical and legal issues in geriatric nephrology, Ethical and legal issues affecting geriatric nephrology are conditioned more by individuals' status as elderly. sick people than by the distinctive characteristics of kidney disease or failure. Key ethical issues are the obligation to respect persons. in particular by recognizing competent persons' autonomy of medical choice and affording due protection to dependent or vulnerable individuals. by beneficence or doing good. and by acting with justice. treating like cases alike and avoiding unjust discrimination. The law reinforces ethical obligations through such legal concepts as informed consent and the duty to maintain appropriate confidentiality. which have special applications concerning medication and management of the elderly. Additional legal issues concern advanced care directives and terminal care decisions.
Rationing of health care and the end-stage renal disease program, The potential impact of rationing health care on the end-stage renal disease (ESRD) program is considered. The possible implications of the recommendations emanating from the study being conducted by the Institute of Medicine of the National Academy of Sciences are also mentioned. Particular emphasis is given to the potential consequences of rationing health care on the elderly and on certain socioeconomic groups with ESRD.
Effects of calcium antagonists on renal hemodynamics, Recent attention has been focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney. calcium antagonists exhibit consistent actions permitting characterization of actions permitting characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney. but they do markedly alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine. calcium antagonists markedly augment the glomerular filtration rate but produce only a modest improvement in renal perfusion. Studies using the isolated perfused hydronephrotic rat kidney model. which permits direct visualization of afferent and efferent arterioles. have demonstrated that the augmentation of the glomerular filtration rate is attributable to a preferential vasodilation of preglomerular vessels. Although the clinical implications of such observations are not fully delineated. preliminary studies in experimental animal models indicate that calcium antagonists might exert salutary effects on renal function in clinical settings characterized by an acute impairment of renal hemodynamics. It is apparent. however. that the renal hemodynamic effects of calcium antagonists commend their use in the management of essential hypertension.
Cardiac contractility and conduction: a comparison of antihypertensives, The four classes of first-line antihypertensive agents recommended in the 1988 report of the Joint National Committee on Detection. Evaluation. and Treatment of High Blood Pressure are reviewed here. Particular consideration is given to the effects of these agents on heart rate. atrioventricular nodal conduction. and myocardial contractility in patients with other cardiovascular diseases. Diuretics and angiotensin-converting enzyme inhibitors have no significant direct effects on cardiac function. beta-Blockers inhibit catecholamine stimulation of the heart and may be particularly beneficial in treating patients with a history of myocardial infarction. Calcium channel blockers reduce blood pressure by dilating arterial resistance vessels. They are structurally heterogeneous and highly selective in their sites of action. As a consequence. cardiac effects can be minimized by selecting a calcium channel blocker with more potent peripheral vasodilatory effects. A new calcium channel blocker. isradipine. currently undergoing clinical trials. is highly selective for arterial smooth muscle and appears to be a safe and effective antihypertensive agent.
Hypertension: racial differences, Racial differences in the prevalence. course. and pathophysiologic characteristics of hypertension in black and white populations are reviewed. Accumulated epidemiologic data indicate that the prevalence of hypertension among blacks is greater than that among whites in almost all age- and sex-matched groups. Hypertensive blacks have a higher incidence of left ventricular dysfunction. stroke. and renal damage. but a lower incidence of ischemic heart disease. than do hypertensive whites. A significant pathophysiologic difference between blacks and whites is salt sensitivity; normotensive. as well as hypertensive. blacks tend to be salt sensitive. Blacks also tend to have lower renin levels than do whites. while dopamine response to a salt load is diminished among blacks as compared with whites. These differences and others lead to the recommendation that hypertension among blacks should be managed initially with salt restriction; if dietary control is insufficient. administration of an antihypertensive agent with 24-hour efficacy. which lowers vascular peripheral resistance. promotes sodium excretion. and potentially improves renal hemodynamics. is recommended. A calcium channel blocker may satisfy these requirements.
Diet, smoking, and alcohol: influence on coronary heart disease risk, The Framingham study on coronary heart disease (CHD) has shown that life-style. particularly diet. smoking. and alcohol consumption. has a great impact on the incidence of CHD. Blood lipoproteins. rather than total blood cholesterol. have been found to be more accurate predictors of CHD risk. Blood triglyceride. previously considered to have little bearing on CHD risk. was found to have a negative impact in many cases. A population subgroup with high triglyceride greater than or equal to 1.7 mmol/L (greater than or equal to 150 mg/dL). low high-density lipoprotein less than or equal to 1.04 mmol/L (less than or equal to 40 mg/dL). increased insulin resistance. and a higher incidence of diabetes mellitus has been found to be at increased risk for CHD. Diet intervention trials have shown that a reduction in total cholesterol and saturated fat consumption produced reduction in CHD incidence proportionate to the fall in cholesterol. Cigarette smoking increased CHD risk moderately; those who smoked one pack per day had twice the risk of nonsmokers. Alcohol consumption actually lowered CHD incidence in the Framingham study; however. when alcohol consumption was greater than two drinks per day. a rise in mortality from cancer and stroke was observed.
Cytogenetic analysis of 750 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage, Altogether. 750 cases of spontaneous abortion between the fifth and 25th week of gestation were analyzed cytogenetically by the direct-preparation method using chorionic villi. The majority of cases (68%) were derived from early abortions before the 12th week of gestation. The frequency of abnormal karyotypes was 50.1%; trisomy was predominant (62.1%). followed by triploidy (12.4%). monosomy X (10.5%). tetraploidy (9.2%). and structural chromosome anomalies (4.7%). Among trisomies. chromosomes 16 (21.8%). 22 (17.9%). and 21 (10.0%) were prevalent. The frequency of chromosomally abnormal abortions increased with maternal age but only because of an increase of trisomy. Polyploidy and monosomy X. however. decreased. Mean maternal age was significantly increased for trisomies 16. 21. and 22 and was highest for trisomies 18 and 20. The results obtained are within the range of variability reported earlier from tissue culture-type studies. A consistent feature during our study is the excess of females in chromosomally normal abortions (male:female sex ratio 0.71). According to the methodology applied. maternal cell contamination and undetected 46.XX molar samples cannot have influenced the sex ratio. However. a bias introduced by social status or maternal age cannot be excluded. With the more rapid and convenient direct preparation of chorionic villi. reliable cytogenetic data on causes of spontaneous abortions can be obtained.
Frequency of three Hex A mutant alleles among Jewish and non-Jewish carriers identified in a Tay-Sachs screening program, Mutations in the HEX A gene. encoding the alpha-subunit of beta-hexosaminidase A (Hex A). are the cause of Tay-Sachs disease as well as of juvenile. chronic. and adult GM2 gangliosidoses. We have examined the distribution of three mutations--a 4-nucleotide insertion in exon 11. a G----C transversion at a 5' splice site in intron 12. and a 269Gly----Ser amino acid substitution in exon 7--among individuals enzymatically diagnosed as carriers of Hex A deficiency. Mutation analysis included polymerase chain reaction (PCR) amplification of the relevant regions of genomic DNA. followed by allele-specific oligonucleotide hybridization; another test for heterozygosity of the exon 11 insertion was based on the formation of heteroduplex PCR fragments of low electrophoretic mobility. The percentage distribution of the exon 11. intron 12. exon 7. and unidentified mutant alleles was 73:15:4:8 among 156 Jewish carriers of Hex A deficiency and 16:0:3:81 among 51 non-Jewish carriers. Regardless of the mutation. the ancestral origin of the Jewish carriers was primarily eastern and (somewhat less often) central Europe. whereas for the non-Jewish carriers it was western Europe. Because a twelfth of the Jewish carriers and four-fifths of the non-Jewish carriers of Hex A deficiency had mutant alleles other than the three common ones tested. enzyme-based tests cannot be replaced by DNA-based tests at the present time. However. DNA-based tests for two-carrier couples could identify those at risk for the chronic/adult GM2 gangliosidoses rather than for infantile Tay-Sachs disease.
Haplotype analysis of the human apolipoprotein B mutation associated with familial defective apolipoprotein B100, Haplotype analysis was conducted on the mutant allele of 14 unrelated subjects heterozygous for a mutation in the codon for amino acid 3500 of human apolipoprotein B100. This mutation is associated with defective binding of low-density lipoprotein to the low-density lipoprotein receptor and with moderate hypercholesterolemia. Ten markers were used for haplotyping: eight diallelic markers within the structural gene and two hypervariable loci flanking the gene. Seven of eight unequivocally deduced haplotypes were identical. and one revealed only a minor difference at one of the hypervariable loci. The genotypes of the six other affected subjects were consistent with this same assigned haplotype. These data are consistent with a common ancestral chromosome and provide no evidence for a recurrent mutation at this potentially hypermutable CG dinucleotide. despite the fact that this mutation is not rare.
Thyroid antibodies as a risk factor for Down syndrome and other trisomies, To test whether the presence of thyroid antibodies in a parent is a risk factor for meiotic nondisjunction. we measured the levels of thyroid antibodies in serum samples drawn during early pregnancy from 101 gravidas who delivered a child with a trisomy. from 11 gravidas who had had a trisomic child in a previous pregnancy. and from 44 of their husbands. For each case mother. three controls were randomly selected from the same population and matched for age. race. sex of the child. and hospital of birth. Cases and controls came from two longitudinal populations. the Child Health and Development Studies (CHDS) and the national Collaborative Perinatal Project (CPP). together comprising more than 70.000 live births. All cases with both a definite diagnosis of trisomy-Down syndrome (DS) or other-and available serum were included. Overall. there was no association between the presence of thyroid antibodies in a mother and a trisomy in her offspring (odds ratio [OR] = .98. confidence interval [CI] = .54-1.85). The lack of association was seen in all three subgroups (DS only. other trisomies. and DS in a previous pregnancy). in all ethnic groups. and in the age groups of white mothers either less than 30 years of age (OR = .80. CI = .40-1.6) or greater than or equal to 30 years of age (OR = 1.26. CI = .82-1.9). In the CHDS population. case fathers. as compared with control fathers. did not have a higher prevalence of thyroid antibodies.
Definitive prenatal diagnosis for type III glycogen storage disease, Prenatal diagnosis for type III glycogen storage disease was performed by using (1) immunoblot analysis with a polyclonal antibody prepared against purified porcine-muscle debranching enzyme and (2) a qualitative assay for debranching-enzyme activity. Cultured amniotic fluid cells from three pregnancies (three families in which the proband had absence of debrancher protein) were subjected to immunoblot analysis. Two unaffected and one affected fetus were predicted. In addition. cultured amniotic fluid cells from nine pregnancies (eight families) were screened with a qualitative assay based on the persistence of a polysaccharide that has a structure approaching that of a phosphorylase limit dextrin when the cells were exposed to a glucose-free medium. This qualitative assay predicted six unaffected and three affected fetuses. All predictions by either method were confirmed postnatally except for one spontaneously aborted fetus. Our data indicate that a definitive diagnosis of type III glycogen storage disease can be made prenatally by these methods.
Alkaline phosphatase (tissue-nonspecific isoenzyme) is a phosphoethanolamine and pyridoxal-5'-phosphate ectophosphatase: normal and hypophosphatasia fibroblast study, To clarify its physiologic role. alkaline phosphatase (ALP) was examined in normal skin fibroblasts and was shown to be the tissue-nonspecific (TNS) isoenzyme type (as evidenced by heat and inhibition profiles) and to be active toward millimolar concentrations of the putative natural substrates phosphoethanolamine (PEA) and pyridoxal-5'-phosphate (PLP). Fibroblast ALP has a low-affinity activity. with a distinctly alkaline pH optimum (9.3). toward 4-methylumbelliferyl phosphate (4-MUP). PEA. and PLP but a more physiologic pH optimum (8.3) toward physiologic concentrations (micromolar) of PEA and PLP. Normal fibroblast ALP is linked to the outside of the plasma membrane. since in intact cell monolayers (1) dephosphorylation rates of the membrane-impermeable substrates PEA and PLP in the medium at physiologic pH were similar to those observed with disrupted cell monolayers. (2) brief exposure to acidic medium resulted in greater than 90% inactivation of the total ALP activity. and (3) digestion with phosphatidylinositol-specific phospholipase C (PI-PLC) released about 80% of the ALP activity. Hypophosphatasia fibroblasts were markedly deficient (2%-5% control values) in alkaline and physiologic ALP activity when 4-MUP. PLP. and PEA were used as substrate. The majority of the detectable ALP activity. however. appeared to be properly lipid anchored in ecto-orientation. Thus. our findings of genetic deficiency of PEA- and PLP-phosphatase activity in hypophosphatasia fibroblasts. as well as our biochemical findings. indicate that TNS-ALP acts physiologically as a lipid-anchored PEA and PLP ectophosphatase.
Pseudohypophosphatasia: aberrant localization and substrate specificity of alkaline phosphatase in cultured skin fibroblasts, We explored the biochemical basis for the disorder pseudohypophosphatasia (PsHYPT) in one patient by examining the substrate specificity and localization of alkaline phosphatase (ALP) in cultured dermal fibroblasts. Despite substantial ALP activity. in cell homogenates. toward the artificial substrate 4-methyl-umbelliferyl phosphate (4-MUP). there was a marked deficiency in ALP activity toward the natural substrates pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA). indicating altered substrate specificity. Furthermore. although 4-MUP phosphatase (4-MUP-P'tase) activity was predominantly localized as an ecto-enzyme. the small amount of PLP phosphatase (PLP-P'tase) activity was intracellular. This differential localization was apparent in intact cells. since (1) brief acidification of the medium at 4 degrees C inactivated a majority of the 4-MUP-P'tase activity but only 15% of the PLP-P'tase activity (in contrast to greater than 85% inactivation of both in homogenates). (2) greater than 70% of the 4-MUP-P'tase activity but only 30% of the PLP-P'tase activity was released by phosphatidylinositol-specific phospholipase C (PI-PLC) digestion. and (3) degradation of extracellular PLP was less than 35% of that of disrupted cells. Both 4-MUP- and PLP-P'tase activities were predominantly in a lipid-anchored form that could be converted to a soluble. lipid-free form by PI-PLC digestion. Our findings suggest that the clinical and biochemical presentation of this PSHPT patient results from the production of two aberrant ALP species. One form of ALP has appropriate ectoorientation but is preferentially deficient in activity toward natural substrates; the other ALP species has appropriate substrate specificity but is sequestered from substrates by its intracellular location.
More than one mutant allele causes infantile Tay-Sachs disease in French-Canadians, Two Tay-Sachs disease (TSD) patients of French-Canadian origin were shown by Myerowitz and Hogikyan to be homozygous for a 7.6-kb deletion mutation at the 5' end of the hexosaminidase A alpha-subunit gene. In order to determine whether all French-Canadian TSD patients were homozygotes for the deletion allele and to assess the geographic origins of TSD in this population. we ascertained 12 TSD families of French-Canadian origin and screened for occurrence of mutations associated with infantile TSD. DNA samples were obtained from 12 French-Canadian TSD families. Samples were analyzed using polymerase-chain-reaction (PCR) amplification followed by hybridization to allele-specific oligonucleotides (ASO) or by restriction analysis of PCR products. In some cases Southern analysis of genomic DNA was performed. Eighteen of the 22 independently segregating mutant chromosomes in this sample carried the 7.6-kb deletion mutation at the 5' end of the gene. One chromosome carried the 4-nucleotide insertion in exon 11 (a "Jewish" mutation). In this population no individuals were detected who had the substitution at the splice junction of exon 12 previously identified in Ashkenazi Jews. One chromosome carried an undescribed B1 mutation; this allele came from a parent of non-French-Canadian origin. Patients in three families carried TSD alleles different from any of the above mutations. The 5' deletion mutation clusters in persons originating in southeastern Quebec (Gaspe) and adjacent counties of northern New Brunswick.
Equal parental origin of chromosome 22 losses in human sporadic meningioma: no evidence for genomic imprinting, Inactivation of tumor suppressor genes can occur either by mutation at the gene locus or by loss of part or all of the chromosome region containing the gene. The latter is most frequently detected by DNA markers as loss of heterozygosity in the tumor tissue. In several reports. the paternal homologue was preferentially retained in embryonal tumors associated with loss of particular chromosomal regions. suggesting genomic imprinting of the corresponding tumor suppressor loci. To explore the generality of these findings and the possible role of genomic imprinting in adult tumors of the nervous system. we have determined the parental origin of chromosome 22 loss in sporadic meningioma. Of nine cases studied. five tumors retained the maternally derived chromosome 22 homologue while four retained the paternally derived chromosome 22. Thus. in contrast to the embryonal tumors. the meningioma locus on chromosome 22 is inactivated by random mutation in sporadic adult meningiomas.
Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region, We recently mapped the gene for ataxia-telangiectasia group A (ATA) to chromosome 11q22-23 by linkage analysis. using the genetic markers THY1 and pYNB3.12 (D11S144). The most likely order was cent-AT-S144-THY1. The present paper describes further mapping of the AT locus by means of a panel of 10 markers that span approximately 60 cM in the 11q22-23 region centered around S144 and THY1. Location scores indicate that three contiguous subsegments within the [S144-THY1] segment. as well as three contiguous segments telomeric to THY1. are each unlikely to contain the AT locus. while the more centromeric [STMY-S144] segment is most likely to contain the AT locus. These data. together with recent refinements in the linkage and physical maps of 11q22-23. place the AT locus at 11q23.
Digitalis-like activity in human plasma: relation to blood pressure and sodium balance, PURPOSE: On the assumption that renal tubular cells are more important as the target cells for a natriuretic factor than blood cells. we used a well-characterized cultured renal tubular cell line. Madin-Darby canine kidney (MDCK). cells to monitor the circulating digitalis-like factor in human plasma and examine its role in the regulation of blood pressure and sodium balance. SUBJECTS AND METHODS: We investigated the effects of plasma on binding of radioactive ouabain to monolayered MDCK cells in order to determine the level of a circulating digitalis-like factor. First. we measured specific 3H-ouabain binding to MDCK cells in the presence of plasma from 71 outpatients (34 normotensive subjects and 37 hypertensive patients) after incubation for 4 hours. Second. we measured specific 3H-ouabain binding after incubation of cells with plasma from 16 hospitalized subjects (eight normotensive subjects and eight hypertensive patients) receiving low and high sodium diets. RESULTS: In Study 1. ouabain binding was lower by 30% with plasma from hypertensive patients than with plasma from normotensive subjects (p less than 0.01). There was a significant negative correlation between individual subject's systolic or mean blood pressure and ouabain binding (r = -0.34. p less than 0.01 or r = -0.29. p less than 0.01). In Study 2. ouabain binding was also significantly reduced by 25% in the presence of plasma from hypertensive subjects as compared with plasma from normotensive subjects irrespective of sodium intake (p less than 0.01). A significant negative correlation was also found for all subjects between either systolic. diastolic. or mean blood pressure and ouabain binding (r = -0.58. p less than 0.01. r = -0.51. p less than 0.01. or r = -0.55. p less than 0.01. respectively). With the changes from low to high sodium intake. there was a corresponding decrease in ouabain binding (p less than 0.01) and an increase in sodium excretion (p less than 0.01). A significant negative correlation was observed between these two parameters (r = -0.47. p less than 0.05). CONCLUSIONS: These findings suggest that a circulating digitalis-like factor. which may act on renal tubular cells as the ouabain-displacing compound. is increased in patients with essential hypertension and also demonstrate that plasma levels may be influenced by changes in dietary sodium intake.
Streptococcus mitis sepsis in bone marrow transplant patients receiving oral antimicrobial prophylaxis, PURPOSE: Streptococcal infection has increasingly become a problem in neutropenic patients. We report on an outbreak of Streptococcus mitis sepsis in six bone marrow transplant patients receiving oral antimicrobial prophylaxis. PATIENTS AND METHODS: We performed an epidemiologic study of all patients in our bone marrow transplant program from 1986 to 1988. The hospital and microbiology records for all patients were reviewed. All bone marrow patients were treated according to specified protocols. including an oral prophylactic antimicrobial regimen that was changed in late 1987 from vancomycin/polymyxin/tobramycin to norfloxacin. Identification. susceptibility testing. and whole cell protein analysis of streptococcal isolates were performed at the Reference and Antimicrobial Investigations Laboratories at the Centers for Disease Control. RESULTS: We detected six cases of S. mitis sepsis among 21 patients undergoing bone marrow transplantation. No other concurrent pathogen was isolated from any patient at the time of the S. mitis bacteremia. Bacteremia developed within 72 hours of transplant in five of six patients and was associated with severe mucositis in four patients. An environmental study failed to reveal any common source for the outbreak. and whole cell protein analysis of all six S. mitis isolates revealed each to be distinct. Of 12 patients receiving oral vancomycin/polymyxin/tobramycin. one developed S. mitis bacteremia. versus five of nine patients receiving norfloxacin (p less than 0.03). CONCLUSION: We believe S. mitis bacteremia is a potential complication of bone marrow transplantation and is associated with antimicrobial prophylaxis with norfloxacin. especially in the setting of mucositis.
Immunoproliferative small intestinal disease: portrait of a potentially preventable cancer from the Third World, PURPOSE: To review the recent progress in the understanding of clinical and laboratory characterization as well as management of immunoproliferative small intestinal disease (IPSID). DATA IDENTIFICATION: A literature search was conducted using Index Medicus. MEDLINE (1962 to 1989). and bibliographies of identified relevant articles. STUDY SELECTION: All international comprehensive reviews. reported epidemiologic or immunologic studies. and prospective clinical trials published or abstracted in English were selected. RESULTS OF DATA SYNTHESIS: A high incidence of lymphoma primarily in the gastro-intestinal tract in Third World countries has stimulated enormous epidemiologic and pathogenetic interests globally. IPSID. with a distinctive biologic marker (alpha heavy chain para-protein). affects the young underprivileged population of those countries. The initially benign-appearing antibiotic-responsive immunoproliferative lesions often evolve to fatal high-grade lymphomas. Roles of environmental and host factors in this evolutionary course are emerging. Recently demonstrated malignant potentials form the early onset of pathogenesis have given a new dimension to the traditional management strategy of IPSID. CONCLUSIONS: Epidemiologic. immunologic. and pathogenetic data that have emerged over the last 25-year study of IPSID have improved our understanding about the complexity of infection-immunity-cancer interrelationships. comparable to those that have arisen from the study of the acquired immunodeficiency syndrome. Early detection and institution of antimicrobial-based treatment regimens with judicious and consistent follow-up can save the lives of many young patients whose manpower is badly needed in Third World countries.
Contraception and ectopic pregnancy risk, Studies of the association of ectopic pregnancy with contraception have generated a conflicting array of results because of methodologic differences between studies. We estimated the absolute incidence rates of ectopic pregnancy for various contraceptives by multiplying the pregnancy rate by the proportion of pregnancies with ectopic implantation for each method. Our results indicated a more than 500-fold difference in ectopic pregnancy incidence. from a low of 0.005 ectopic pregnancies per 1000 women years of oral contraception or vasectomy to a high of 2.6 per 1000 women years of no contraception. These estimated incidence rates should be useful for clinicians and patients seeking to better understand the risks and benefits of contraceptives.
Calcium supplementation during pregnancy may reduce preterm delivery in high-risk populations, Results are presented of a randomized. double-blinded controlled clinical trial of calcium supplementation (2.0 gm of elemental calcium as calcium carbonate) and a placebo. All participants were 17 years of age or less and clinically healthy. Patients were enrolled by the twenty third week of gestation. The mean duration of calcium supplementation or placebo was approximately 14 weeks. Treatment consisted of 2.8 (+/- 1.5) tablets per day in the placebo group (N = 95) and 3.0 (+/- 1.4) tablets per day in the calcium group (N = 94). Dietary calcium intake was similar in both groups at about 1200 mg/day. The calcium group had a lower incidence of preterm delivery (less than 37 weeks; 7.4% vs 21.1%; p = 0.007); spontaneous labor and preterm delivery (6.4% vs 17.9%; p = 0.01); and low birth weight (9.6% vs 21.1%; p = 0.03). This effect was also present after stratified analysis by level of treatment compliance. urinary tract infection. and chlamydial infection. Life-table analysis demonstrated an overall shift to a higher gestational age in the calcium group compared with the placebo group (log-rank test. p = 0.02). As suggested previously. the observed effect could be mediated by a reduction in uterine smooth muscle contractibility. If confirmed by future research. these results could represent an important preventive intervention for prematurity in high-risk populations.
The association of intrapartum asphyxia in the mature fetus with newborn behavior, A matched cohort study of mature newborns with biochemically determined intrapartum fetal asphyxia and mature newborns with normal blood gas and acid-base assessments at delivery were studied to demonstrate the effect of fetal asphyxia on newborn behavior as expressed by the Brazelton newborn behavioral assessment scale. The newborn behavioral assessment scale was administered 3 days after delivery and again 2 weeks after delivery. The Lester newborn behavioral assessment scale summary scores for the group with asphyxia were of the same order as those in the control group. This was also true of the group of newborns with asphyxia with the more severe metabolic acidosis and those with low Apgar scores. These findings support the contention that many newborns who have undergone an intrapartum asphyxial insult will not have evidence of central nervous system injury and that the threshold of central nervous system injury is at the severe end of the spectrum of asphyxia as expressed by a metabolic acidosis.
The prognostic significance of CA 125 half-life in patients with ovarian cancer who have received primary chemotherapy after surgical cytoreduction, Fifty-four patients with advanced epithelial ovarian cancer were monitored with serial serum CA 125 levels after surgical cytoreduction and during multi-agent chemotherapy with cisplatin-containing regimens. CA 125 half-life of less than 20 days was associated with prolonged overall survival (p less than 0.015). In those patients who eventually were found to be disease-free at surgical surveillance procedures. normalization of serum CA 125 levels to less than 35 U/ml within 65 days of primary operation also suggested an improved survival (p less than 0.059).
Ovarian pregnancy: a report of twenty cases in one institution, A series of 20 cases of primary ovarian pregnancy that were diagnosed and treated in one institution is reported. The prevalence rate of 1:3600 deliveries seems to be increasing in past years and comprises 3.3% of all extrauterine pregnancies. Clinical presentation. possible pathogenesis. diagnostic steps. preferred management. and future fertility are detailed. Inasmuch as all our 18 fertile patients used an intrauterine contraceptive device before the operation. special emphasis is made on the controversial relationship between use of intrauterine contraceptive devices and ovarian pregnancy.
Preoperative evaluation of serum CA 125, TAG 72, and CA 15-3 in patients with endometrial carcinoma, We evaluated 109 women with endometrial carcinoma to determine the accuracy of preoperative tumor-associated antigen levels (CA 125. CA 72. CA 15-3) for prediction of extrauterine disease and whether TAG 72. CA 15-3. or both would improve the predictive value of CA 125 alone. Eleven (12%) of 80 patients with disease confined to the uterus or positive cytologic findings had CA 125 values greater than 35 U/ml versus 12 (65%) of 20 patients with extrauterine metastasis. Therefore CA 125 values had sensitivity of 65% and specificity of 88%. The TAG 72 level was elevated (greater than 6 U/ml) in 4% of patients with localized disease and 30% with metastasis. CA 15-3 was elevated (greater than 30 U/ml) in 17% and 65% in these categories. respectively. TAG 72 or CA 15-3 levels did not improve the combination of sensitivity and specificity of CA 125 alone. In addition. only one of 10 patients with microscopic metastasis (three cases) or positive peritoneal cytology (seven) had elevation of any of these tumor-associated antigen levels. Failure to detect occult metastasis and a high false-positive rate limit the role of these tumor-associated antigen assays in the preoperative evaluation of patients with endometrial carcinoma.
The effect of race on the relationship between fetal death and altered fetal growth, This population study examines racial differences in the relationship between birth weight and fetal death. An earlier report showed that a birth weight that results in a fourfold increased risk of stillbirth is not a constant birth weight percentile (2nd percentile at 25 weeks. 17th percentile at 42 weeks). This analysis was applied to 782.430 white and black births in Illinois from 1980 to 1984. Mean and 10th percentile growth for white and black infants is identical before 34 weeks' gestation and growth diverges by 250 gm at term. with white infants being larger. Race-specific birth weights resulting in quadrupling of the stillbirth rate were determined with an exponential regression analysis of the relationship between birth weight and fetal death rate for each gestational age. The data indicate (1) that the birth weights resulting in quadrupling the stillbirth rate are substantially above the Denver 10th percentile and the previously unpublished race-specific Illinois 10th percentiles and (2) that at term white infants demonstrate this constant risk at the 12th percentile. whereas black infants exhibit the risk at the 18th percentile. From these data we conclude that black fetuses are more sensitive than white fetuses to factors that adversely affect growth and that continued use of "race-neutral" data for clinical management in racially heterogenous populations will not accurately predict the risk of stillbirth.
Effects of intravascular fetal blood transfusion on fetal intracardiac Doppler velocity waveforms, In 12 fetuses from pregnancies with red blood cell isoimmunization Doppler velocity waveforms were recorded at the level of atrioventricular valves immediately before and at 15-minute intervals for 2 hours after the intravascular transfusion. The left and right cardiac outputs. the ratio between the peak velocities during early passive ventricular filling and active atrial filling at the level of both ventricles as well as the heart rate were calculated. Before transfusion. the left and right cardiac outputs were significantly higher than reference ranges for gestation that were constructed from the cross-sectional study of 187 normal pregnancies. After transfusion there was a significant temporary fall in right and left outputs associated with increased ratios between the peak velocities during early passive ventricular filling and active atrial filling. Within 2 hours after transfusion both parameters returned toward the normal range. In addition. no significant changes were found for fetal heart rate values before and after transfusion. The fall of cardiac output was significantly related to the amount of expansion of the feto-placental volume.
Suppression of serum insulin level by diazoxide does not alter serum testosterone or sex hormone-binding globulin levels in healthy, nonobese women, Suppression of serum insulin levels with diazoxide is associated with a decrease in serum testosterone and an increase in serum sex hormone-binding globulin in obese women with the polycystic ovary syndrome. To determine whether physiologic insulin levels play a regulatory role in the androgen status of nonobese women with normal menses. the androgen status of five nonobese normal women was assessed on two occasions: during a control study and after 10 days of oral diazoxide (100 mg. three times daily) administration. Insulin release in response to 100 gm oral glucose administration decreased from 108.0 +/- 28.2 to 49.3 +/- 5.2 nmol.min/L (p = 0.05) after diazoxide administration. However. despite suppression of insulin release. diazoxide administration did not affect serum total testosterone (diazoxide. 0.73 +/- 0.10; control. 0.69 +/- 0.11 nmol/L; p = NS) or sex hormone-binding globulin (diazoxide. 79.7 +/- 16.6; control. 70.2 +/- 12.6 nmol/L; p = NS) concentrations. These observations suggest that physiologic insulin levels in nonobese healthy women do not regulate testosterone metabolism and that diazoxide does not exert a direct or independent effect on serum testosterone or sex hormone-binding globulin levels.
Prenatal diagnosis of congenital cytomegalovirus infection by virus isolation from amniotic fluid, Cytomegalovirus was isolated antenatally from the amniotic fluid of two pregnant women. In both cases prenatal diagnosis of the fetal virus infection aided the subsequent management of the mother and newborn infant.
Intraamniotic infection in the very early phase of the second trimester, A total of 157 consecutive patients were studied in an effort to examine prospectively the incidence of asymptomatic intraamniotic infection in the early phase of the second trimester. All patients were referred for amniotic fluid karyotyping. In addition. the amniotic fluids were examined for Gram stain and were directly cultured on blood agar and MacConkey agar as well as in thioglycollate broth. We found positive amniotic fluid cultures in eight cases (5.09%); however. results of Gram stain examinations were negative in all amniotic fluid samples. The data indicate that there is no correlation between white blood cells in the amniotic fluid and positive amniotic fluid culture results. Only one pregnancy with positive amniotic fluid culture resulted in a septic abortion. Therefore we can suggest that intraamniotic infection can exist early in pregnancy. even with intact membranes. and in most cases without any clinical symptoms.
Placental histology in fetuses between 18 and 23 weeks' gestation with abnormal karyotype, Placentas from karyotypically abnormal fetuses (18 to 23 weeks' gestation) were analyzed prospectively at the light microscopic level. Group I consisted of 14 control placentas. Group II consisted of 14 placentas from fetuses with an abnormal karyotype. Secondary and tertiary stem villi counts. small muscular artery counts. and total vessel counts were determined per 100 x field. There were no differences in secondary and tertiary stem villi counts between groups. A significant decrease in small muscular artery counts (p less than 0.01) and total vessel counts (p less than 0.01) was noted in group II. Placental and fetal weights were comparable between groups. This undervascularization may represent placental immaturity as a result of arrested or delayed angiopoiesis. It appears that this abnormality is established before the third trimester and may be enhanced by late vascular obliteration as reported by others. These data substantiate the concept that the structure and function of the placenta is determined to a great degree by fetal karyotype and may help explain the morbidity and mortality seen in these fetuses.
Autologous antibodies eluted from membrane fragments in human ovarian epithelial neoplastic effusions. III. Cytotoxic potential in vitro and characterization of antigen(s), Cyst and ascites fluids from patients with ovarian epithelial neoplasms contain immunoglobulins with antitumor activity. Autologous antibodies bound to the cellular membrane fragments obtained from human ovarian neoplastic effusions react with cell-surface antigens on different human ovarian cell lines. surgical specimens of human ovarian adenocarcinoma. and human ovarian tumors grown in athymic Balb/c mice. The antibodies do not react with tissue preparations from normal human ovaries. other nonovarian normal or neoplastic tissues. and nonovarian human cell lines. These studies indicate that these antibodies are capable of complement-mediated lysis of human ovarian tumor cell lines in vitro. Preliminary characterization of the autologous ovarian tumor-associated antigen(s) indicates that it may be composed of three large-molecular-weight proteins of 182.000. 164.000. and 122.000 d.
A progesterone-induced blocking factor corrects high resorption rates in mice treated with antiprogesterone, Earlier we showed that because of the presence of functional progesterone receptors. lymphocytes of healthy pregnant women produced an immunomodulatory protein in the presence of progesterone. whereas those of nonpregnant persons did not. Progesterone-treated murine pregnancy lymphocytes release a similar factor. The present study reveals the biologic significance of this finding. Treatment of BALB/c mice that were 8 days pregnant with a progesterone receptor blocker (RU 486) resulted in 100% resorption of the fetuses. Simultaneous administration of the supernatant from progesterone-treated murine pregnancy spleen cells restored the resorption rate to the original 6% observed in untreated control animals. These data suggest that functional lymphocytic progesterone binding sites are needed for the maintenance of normal pregnancy. Because of the blockage of progesterone receptors and the consequent inability of the lymphocytes to produce the progesterone-induced blocking factor. abortion is initiated by immune factors. The fact that administration of the preformed blocking factor counteracted the effect of antiprogesterone treatment suggests that progesterone-mediated immunosuppression is needed for the maintenance of normal gestation.
Long-term maternal-fetal exposure to high-low insulin concentrations alter liver but not brain insulin receptors, We investigated the effects of long-term (5 to 6 days) in vivo exposure to hyperinsulinemia and hypoinsulinemia on maternal and fetal rat (18 to 20 days' gestation; term approximately 21 days) brain and liver insulin receptors. Further we studied the in vitro effects of long-term insulin exposure on cultured rabbit neuronal cell insulin receptors. Long-term glucose infusions to maternal rats resulted in maternal and fetal hyperglycemia and mild hyperinsulinemia. which decreases the liver insulin receptor abundance of the mother but increased that of the fetus. Streptozotocin-induced maternal diabetes resulted in maternal and fetal hyperglycemia with hypoinsulinemia (or near-normal insulin levels) and increased maternal and fetal liver insulin receptors. The maternal and fetal brain insulin receptor abundance failed to change at high or low insulin concentrations. Similarly long-term insulin (5 micrograms/ml) exposure failed to alter cultured neuronal cell insulin receptors as well. We conclude that perturbations in maternal and fetal circulating insulin concentrations fail to affect the brain insulin receptors. This protective phenomenon may be critical in maintaining the normal neuronal energy balance and functioning during certain disease states such as diabetes mellitus and hyperinsulinism.
Oral contraceptives and breast cancer, Among women in general the risk of breast cancer through 59 years of age does not appear to be affected appreciably by the use of oral contraceptives. Nonetheless. concern continues to be expressed about the effects of early age at first use. long-term duration of use. formulation. and a variety of other factors thought to influence breast cancer risk in the presence of oral contraception. A number of recent studies restricted to young women suggest that long-term use may increase the risk of disease occurring very early. but the present lack of consistent findings in well-conducted epidemiologic studies prevents any certain conclusion with regard to cause-and-effect. However. if an increased risk were indeed present. the most plausible interpretation is that long-term oral contraception promotes earlier clinical manifestation of breast cancer in some women while having no net impact on their lifetime risk of the disease.
Oral contraceptives, lipoproteins, and atherosclerosis, A nonhuman primate model was developed to study the effects of oral contraceptives on lipoproteins and atherosclerosis. Cynomolgus macaques were selected because of their susceptibility to diet-induced atherosclerosis and because their reproductive physiology. menstrual cycle. and circulating sex hormone patterns are similar to those of human females. The first study compared a vaginal ring containing levonorgestrel and estradiol with an oral contraceptive containing norgestrel and ethinyl estradiol. A second study compared two oral combinations: norgestrel-ethinyl estradiol and ethynodiol diacetate-ethinyl estradiol. As predicted. use of all the contraceptives led to lowering of high-density lipoprotein cholesterol levels. However. contrary to what might be expected. use of the ethinyl estradiol-containing oral contraceptives did not lead to an increase in the prevalence or extent of atherosclerosis. We concluded that ethinyl estradiol neutralized the atherogenic influence of the progestin component of oral contraceptives.
Magnetic resonance imaging in the evaluation of vitreoretinal disease in eyes with intraocular silicone oil, Media opacification in eyes filled with silicone oil makes the evaluation of recurrent retinal detachment difficult. Ultrasonography through silicone oil is subject to significant imaging artifacts. We performed magnetic resonance imaging on six patients with unilateral intravitreal silicone oil to determine if the technique would detect detached retina and subretinal oil. All patients had undergone pars plana vitrectomy with silicone oil injection for proliferative vitreoretinopathy; five patients had encircling solid silicone scleral buckles. In five patients the media were clear. and ophthalmoscopic findings were correlated with magnetic resonance findings. Four patients had recurrence of inferior retinal detachment; magnetic resonance imaging demonstrated subretinal oil in three of these patients. One patient had a concentric. shallow. anterior retinal detachment; magnetic resonance scanning demonstrated a globular hyperintensity suggestive of subretinal oil. In the sixth patient. who had an opaque cornea. magnetic resonance imaging suggested that the retina was attached preoperatively; this was confirmed at subsequent surgery. A chemical shift artifact was helpful in defining the contour of retinal detachments and the presence of subretinal oil by outlining the silicone oil within the eye.
Histopathologic study of the Molteno glaucoma implant in three patients, Three eyes with the Molteno glaucoma implant (one eye with epithelial downgrowth. one eye with iridocorneal endothelial syndrome. and one eye with aphakia and glaucoma) were enucleated two to six years after implantation. Histopathologic examinations disclosed no evidence of erosion of sclera or conjunctiva of the eye by the glaucoma implant device. In the outer layers of the bleb wall. few and mostly degenerated inflammatory cells were present. which represented a minimal inflammatory reaction. Scanning electron microscopy of the tubes in these three patients showed that the tube was intact. patent. and without signs of degradation. The tube entering into the anterior chamber caused no appreciable inflammation and maintained its patency even when downgrowth epithelial cells lined the anterior chamber. The Molteno plate induced little or no inflammatory reaction. Therefore. the Molteno glaucoma implant is a useful device for patients with high risk for failure after surgery for glaucoma.
Limbal autograft reconstruction after conjunctival squamous cell carcinoma, Two patients who had squamous cell carcinoma with extensive limbal and corneal involvement were treated with surgery and cryotherapy. Rarely large areas of the cornea are involved by this tumor. Visual prognosis in such patients is poor. In these two patients. autologous limbal transplants were effective in restoring an excellent corneal surface and good visual function. This technique may be useful in the reconstruction of eyes with extensive neoplastic involvement of the corneoscleral limbus and cornea.
Response of Bitot's spots in preschool children to vitamin A treatment, In a double-masked. placebo-controlled. clinical trial in Indonesia. 88 preschool children between the ages of 36 and 72 months with Bitot's spots were randomly assigned to 200.000 IU of oral vitamin A or placebo and followed up for five weeks. Baseline and follow-up serum vitamin A levels were obtained. Of the 45 children receiving vitamin A. 33 (73.3%) showed complete cure and disappearance of Bitot's spots. six (13.3%) had disappearance of some but not all Bitot's spots. and six (13.3%) were unresponsive to treatment. The nonresponsive children were older. all male. and had higher initial mean serum vitamin A levels. 23.0 micrograms/dl. compared to 15.9 micrograms/dl in the cured group (P = .017). These data suggest that normal vitamin A status may be found in approximately 13% of children with Bitot's spots before vitamin A intervention and that one fourth of those who had Bitot's spots originally will not be cured of all Bitot's spots after intervention. These are important factors to consider when using Bitot's spots in prevalence surveys as a clinical sign of vitamin A deficiency.
Facial nerve injury and hemifacial spasm, We studied evidence of facial nerve damage in patients with hemifacial spasm. Three types of evidence of nerve damage were analyzed: objectively measured weakness in eyelid protractor strength. clinically evident weakness of muscles innervated by the seventh nerve. and clinically evident aberrant seventh nerve regeneration. Of the 60 patients in the study. 54 (90%) had at least one of these features of seventh nerve damage. Objectively measured eyelid protractor weakness was noted in 27 of 58 patients (47%) who were tested. Clinically apparent weakness of at least one of four facial muscle groups was noted in 42 of 60 patients (70%). Aberrant seventh nerve regeneration was documented in 25 of 60 patients (42%). These findings indicate that facial nerve damage is common in patients with hemifacial spasm.
Reversal of colchicine-induced mitotic arrest in Chinese hamster cells with a colchicine-specific monoclonal antibody, The ability of a high-affinity colchicine-binding monoclonal antibody to reverse the effects of colchicine on Chinese hamster ovary cells was investigated. Using flow cytometry. a complete mitotic blockade was demonstrated after 16 hours with 2.5 x 10(-7) mol/l (molar) colchicine. Colchicine-induced changes were reversible when equimolar antibody was added simultaneously with or up to 6 hours after colchicine. With further delay in addition of antibody. a progressive irreversible increase in mitotic blockade and increase in mean cell size was observed. Prolonged colchicine exposure. without antibody reversal. led to polyploidy and structural chromosome breakage. Early antibody reversal restored cells to the diploid state. whereas delayed reversal resulted in a time-dependent increase in polyploidy. Colchicine-induced polyploidy and chromosomal aberrations may be the basis for both colchicine toxicity and the time-dependent increase in irreversibility of colchicine effects.
Immunohistochemical study of fibronectin in experimental myocardial infarction, Light microscopic immunohistochemical studies were performed to evaluate the distribution of fibronectin in paraffin sections of p-formaldehyde-fixed normal rat hearts and the hearts of rats that had undergone ligation of the left coronary artery. A peroxidase-labeled antibody technique was used. together with appropriate immunohistochemical control procedures. for the localization of fibronectin in normal hearts and in the hearts of sham-operated animals. Fibronectin was localized in the interstitial space between myocytes. and beneath arterial. venous. and capillary endothelium. At 4 hours after coronary ligation. fibronectin was localized in a patchy fashion in the cytoplasm and interstitial space of some of the myocytes in the area supplied by the ligated vessel. At 24 hours. there was more intense. homogeneous staining in necrotic myocytes in the infarcted area and in the capillary endothelium in the border zone. At 48 hours. the intensity of staining for fibronectin was maximal in and between the necrotic myocytes in the center of the infarct and in proliferating and migrating capillaries and fibroblasts in the border zone. Similar patterns of localization were observed at 3 and 7 days after coronary ligation. but with progressive decreases in the intensity of staining. Two sources of fibronectin appeared to have contributed to these changes: plasma fibronectin diffusing through damaged blood vessels would account for the early staining observed in necrotic myocytes in the center of the infarct. whereas de novo synthesis of fibronectin by connective tissue cells and endothelial cells in sprouting capillaries would be responsible for the subsequent staining observed in viable capillaries in the border zone of the infarct. Known properties of fibronectin in vitro. combined with these in vivo observations. indicate that fibronectin may influence the thrombotic. inflammatory. angiogenic. and fibrotic processes involved in infarct healing.
An immunohistochemical study of pi class glutathione S-transferase expression in normal human tissue, Glutathione S-transferases (GSTs). a family of isoenzymes that play an important role in protecting cells from cytotoxic and carcinogenic agents. can be separated by biochemical and immunologic characteristics into three distinct classes named alpha. mu. and pi. Previous studies have indicated that there is marked heterogeneity in the expression of different GST isoenzymes in different normal and malignant tissues. To better understand the regulation of the human pi class glutathione S-transferase isoenzyme (GST-pi). the tissue distribution of this protein wa studied by an immunohistochemical technique using an anti-GST-pi polyclonal antibody in normal paraffin-embedded human tissues. These studies indicate that there is a broad distribution of GST-pi in normal human tissues and establish a precise localization within the different organs studied. GST-pi was expressed predominantly in normal epithelial cells of the urinary. digestive. and respiratory tracts. suggesting a possible role for GST-pi in detoxication and elimination of toxic substances. Previous studies have indicated that GST-pi and the putative drug efflux pump P-glycoprotein are both overexpressed in multidrug-resistant human breast cancer cells and in xenobiotic resistant preneoplastic rat hyperplastic liver nodules. Results from this study indicate that there are also similarities between the normal tissue distribution GST-pi and that previously reported for mammalian P-glycoprotein. particularly in secretory epithelia. This finding suggests that these two gene products. which have been implicated in the development of resistance to cytotoxic drugs. may be coregulated in normal and malignant cells.
Decreased expression of integrin adhesive protein receptors in adenocarcinoma of the breast, The integrin superfamily represents a major class of receptors mediating cell-substrate adhesion. Our recent study of the tissue distribution of the alpha 2 beta 1 integrin. a cell-surface collagen receptor. revealed that high levels of receptor expression were associated with orderly. regulated epithelial cell proliferation. Those observations prompted the present investigation of alpha 2 beta 1 and other integrins in adenocarcinoma of the breast. The alpha 2 beta 1 integrin was highly expressed on the epithelium of the ducts and ductules of normal breast tissue. Normal or nearly normal levels of the receptor were expressed in fibroadenomas. In contrast. markedly decreased or undetectable alpha 2 beta 1 expression was typical of poorly differentiated adenocarcinomas. Well-differentiated lesions exhibited intermediate levels of expression. Similar. but less extensive. decreases in expression were observed for the alpha 5 beta 1 (fibronectin receptor) and alpha v beta 3 (vitronectin receptor). Significant expression of the beta 1 subunit on even poorly differentiated tumors suggests that the expression of other undefined members of the beta 1 family is not reduced to the same low level as alpha 2 beta 1 and alpha 5 beta 1. Expression of the alpha 2 beta 1 integrin was highly correlated with estrogen-receptor expression. Decreased expression of alpha 2 beta 1 and other integrin adhesive protein receptors probably contributes to the altered adhesive properties of tumor cells characteristic of the malignant phenotype.
Accelerated arteriosclerosis in heart transplant recipients is associated with a T-lymphocyte-mediated endothelialitis, Accelerated arteriosclerosis has emerged as a major life-threatening complication in long-term survivors of heart transplantation. It has been proposed that accelerated arteriosclerosis is an immune-mediated complication of rejection. We observed a striking endothelialitis in the coronary arteries of two explanted hearts obtained from patients with severe transplant-related accelerated arteriosclerosis. This finding prompted us to review the pathologic changes in the coronary arteries of 23 autopsied patients who had received heart transplants. The infiltrate in these vessels was characterized using immunohistochemical stains for lymphocytes (CD45). macrophages (MAC-387). T lymphocytes (CD45RO). B lymphocytes (L-26). and smooth muscle cells (actin). In addition. a full panel of monoclonal antibodies was used on the fresh-frozen tissue available from one of the two explanted hearts. Ten of the eleven recipients with accelerated arteriosclerosis had a moderate to marked lymphocytic endothelialitis compared to 3 of 14 without transplant-related arteriosclerosis (P less than 0.005). Immunohistochemical staining of the paraffin-embedded material demonstrated that most of the lymphocytes in the subendothelial space of these vessels were T lymphocytes and that this infiltrate was associated with an accumulation of macrophages and a proliferation of smooth muscle cells in the intima. In the explanted heart from which fresh-frozen tissue was available for more detailed cell typing. the T cells marked predominantly as cytotoxic T lymphocytes (CD8+. CD2+). These results suggest that accelerated arteriosclerosis may be mediated. in part. by a cytotoxic T-lymphocyte-directed endothelialitis.
Morphometric analysis of follicular center cell lymphomas, The Lukes/Collins classification of non-Hodgkin's lymphomas subdivides follicular center cell (FCC) lymphomas into four categories based on nuclear size. shape. and state of transformation. Because of the well-recognized difficulty in making these subdivisions in routine histologic sections. a morphometric analysis of typical small cleaved (SC). large cleaved (LC). small noncleaved (SNC). and large noncleaved (LNC) FCCs was performed to describe and compare these four categories using objective parameters. The following features. which had been previously tested on normal follicles. were measured and calculated: nuclear area (NA). nuclear contour index of ellipticity (NCIe). nuclear contour index of nuclear irregularity (NCIni). and a relative chromatin dispersal index (CDI). The presence of nucleoli also was recorded. Mean values for the NA. NCIe. NCIni. and CDI were significantly different among all four FCC lymphoma subtypes. except that the CDI. which reflects transformation. was similar for the SC and LC cell groups. Comparison using the proportion of cells with nucleoli in each case revealed significant differences between all but the SNC and LNC groups. The LC group had the highest mean nuclear ellipticity and nuclear irregularity values. Mean nuclear area was smallest for the SC group followed by the LC. SNC. and LNC groups. Despite these many differences. all parameters showed a broad spectrum of values when either mean values for individual cases of each FCC subtype or distribution curves for all cells within a certain subtype were compared. This morphometric data demonstrates that the four histologically recognized types of FCC lymphomas are distinctive using a more analytic technique. This study also provides further insight into the differences among them. Evidence of nuclear transformation (nuclear size. chromatin dispersal. and frequent nucleoli) is a more important criterion than nuclear contours in distinguishing LNC from LC lymphomas. Although LC lymphomas have some features intermediate between SC and the noncleaved FCC lymphomas. they more closely resemble SC lymphomas. Finally morphometric analyses such as these provide an objective morphologic foundation for future prospective investigations of transformation-related phenomena; these studies may facilitate comparison of morphologic data with immunophenotype and genotype in non-Hodgkin's lymphomas and comparison of various other B-cell neoplasms with follicular center cell neoplasms.
Bacterial lipopolysaccharide transforms mesangial into proliferative lupus nephritis without interfering with processing of pathogenic immune complexes in NZB/W mice, Systemic lupus erythematosus is a multifactorial systemic disease in which genetic. immunologic. hormonal. and environmental factors may contribute to disease pathogenesis. Bacterial products (eg. bacterial lipopolysaccharide [LPS]) induce a lupuslike disease in normal mice and trigger an early and accelerated form of lupus nephritis in NZB/W mice. To investigate whether the mechanism by which LPS accelerates nephritis in the NZB/W mice involves interference with processing of immune complexes (IC). we administered LPS to NZB/W mice for 5 weeks and probed the kinetics of removal. liver uptake. and organ localization of a subsaturating dose of radiolabeled IC (2.5 mg of bovine serum albumin-antibovine serum albumin). Control NZB/W mice received vehicle (saline) alone. In NZB/W exposed to LPS. features of polyclonal B-cell activation (PBA) were enhanced. anti-DNA antibodies were raised. and a proliferative glomerulonephritis developed that was associated with renal insufficiency and substantial proteinuria. This LPS-accelerated nephritis could not be attributed to altered complement concentration. to altered blood cell carrier function. to delayed removal of pathogenic (large-sized) ICs from the circulation. to impaired liver uptake of ICs. or to enhanced localization of ICs in kidney. The findings indicate that transformation of nephritis is probably the result of LPS-induced PBA. that defective processing of pathogenic IC is not a contributory factor to nephritis. and that mechanisms other than passive renal localization of circulating ICs must be operative.
Auditory hallucinations and smaller superior temporal gyral volume in schizophrenia, Recent neuropathologic investigations in schizophrenia report smaller volume of medial temporal lobe structures. These findings are confirmed by preliminary magnetic resonance imaging (MRI) studies. Direct stimulation of lateral temporal lobe structures in the region of the superior temporal gyrus provokes hallucinations. The authors' MRI study of young schizophrenic patients demonstrates smaller volume of the superior temporal gyrus (an auditory association area) and of the left amygdala. Smaller size of the left superior temporal gyrus and left amygdala is not accounted for by smaller size of the overall brain or temporal lobe. Shrinkage of the left superior temporal gyrus is strongly and selectively correlated with severity of auditory hallucinations.
A discriminant validity study of negative symptoms with a special focus on depression and antipsychotic medication, If the construct validity of the negative symptom syndrome is to be established. the conceptual and operational overlap between negative symptoms and other syndromes such as depression and the effects of medication must be explained. The author assessed 26 patients with schizophrenia and 21 patients without schizophrenia. most of whom had depression. at the end of an average 2-week drug washout period and after approximately 2 months of psychotropic medication administration. Negative symptoms were remarkably consistent in patients with schizophrenia despite pharmacological intervention. In contrast. the patients without schizophrenia manifested significant decreases in negative symptoms.
Plasma norepinephrine in chronic schizophrenia, Several lines of evidence indicate altered noradrenergic function in schizophrenia. The authors examined resting. standing. and change (standing minus resting) in plasma norepinephrine levels in 14 drug-free patients with chronic schizophrenia or schizoaffective disorder and in 33 age- and sex-matched healthy volunteers. Schizophrenic patients had significantly higher resting and standing plasma norepinephrine levels and significantly greater change. Resting and standing levels were significantly related to positive and negative symptoms. There was a significant positive correlation between resting plasma and CSF norepinephrine levels and a significant negative correlation between CSF homovanillic acid and resting. standing. and change in plasma norepinephrine levels.
Depression in dementia of the Alzheimer type and in multi-infarct dementia, The authors used the Hamilton Rating Scale for Depression and a rating of depressed mood to investigate the prevalence of depression in 55 patients with Alzheimer's disease. 37 patients with multi-infarct dementia. and 30 nondemented comparison subjects. The prevalence of depressed mood depended on the severity of dementia as measured by the Mini-Mental State examination and was significantly lower among patients in more severe stages of Alzheimer's disease but not among patients with severe multi-infarct dementia.
Antidepressant pharmacotherapy of depression associated with multiple sclerosis, In a double-blind clinical trial involving 28 patients with multiple sclerosis and major depressive disorder. 14 patients were randomly assigned to a 5-week trial of desipramine and individual psychotherapy and 14 to placebo plus psychotherapy. Clinical judgments indicated that patients treated with desipramine improved significantly more than the placebo group. This was confirmed by scores on the Hamilton Rating Scale for Depression but not by Beck Depression Inventory scores. Side effects limited desipramine dosage in half of the treated patients. The authors conclude that desipramine has a modest beneficial effect in serious depression associated with multiple sclerosis but that side effects may be more of a limiting factor than in patients without medical or neurologic disease.
Update on the epidemiology of anorexia nervosa in a defined region of Switzerland, In this follow-up investigation. the authors studied all Swiss women in the canton of Zurich who developed anorexia nervosa between ages 12 and 25 years and who were hospitalized for the first time with this diagnosis between 1983 and 1985. Data were compared with those from an earlier study. which focused on the periods 1956-1958. 1963-1965. and 1973-1975. The incidence of anorexia nervosa did not increase significantly during 1983-1985 compared to 1973-1975. in contrast to the constant increase found between 1956 and 1975. However. the more frequent use of vomiting and abuse of laxatives in 1983-1985 may indicate an increase in cases with mixed features of anorexia nervosa and bulimia.
The natural history of alcohol abuse: implications for definitions of alcohol use disorders, Is the DSM-III-R category of alcohol abuse validly differentiated from the DSM-III-R category of alcohol dependence. or is abuse primarily a mild. prodromal condition that typically deteriorates into dependence? A 4-year longitudinal epidemiologic study of male drinkers provided data to answer this question. The study used identical questions at baseline and follow-up. At follow-up. 70% of the subjects who were initially classified as alcohol abusers were still abusers or were classified as remitted. This contrasted significantly with outcome in the subjects who initially reported alcohol dependence. Although additional research is needed. these results indicate that alcohol abuse often has a course distinct from that of alcohol dependence.
Humoral and cell-mediated immune responses to the Plasmodium falciparum antigens PF155/RESA and CS protein: seasonal variations in a population recently reexposed to endemic malaria, Resurgence of falciparum malaria occurred in the Central Highlands of Madagascar in the 1980s and the disease is currently hyperendemic. We determined the humoral and cellular responses to synthetic peptides reproducing the repeat sequences of 2 major Plasmodium falciparum antigens: the Pf155/RESA and the circumsporozoite (CS) protein. Blood samples from 83 subjects living in a rural community near Antananarivo were obtained at the beginning and the end of the transmission season. At enrollment. 40 subjects presenting with and 43 without blood parasites had similar T cell proliferative response and antibody level to all antigens tested. However. P. falciparum-infected individuals exhibited a decrease in the absolute number of T lymphocytes. due to a diminished number of CD8+ and natural killer lymphocytes. The number of CD4+ cells was similar in both groups. In the overall population. 45% of subjects had a T cell response to at least 1 RESA peptide (29-35% responding to a given peptide) and 35% to the CS protein peptide. Thirty-two percent of the donors presented with RESA antibodies and 23% had CS protein antibodies. After 20 weeks. at the end of the transmission season. cellular proliferative responses to all antigens markedly decreased as evidenced by a decrease of both the number of responders and mean stimulation indexes. Humoral response to RESA. as detected by erythrocyte membrane immunofluorescence (number of responders and mean antibody titers) markedly increased. Humoral responses to the CS protein and RESA peptides were similar.
In vitro growth inhibition of Plasmodium falciparum by sera from different regions of the Philippines, Sera from different malaria endemic regions of the Republic of the Philippines were compared for their ability to inhibit growth of Plasmodium falciparum in vitro. Dialyzed serum was added to synchronous cultures containing schizonts for either the total 48 hr test period or only the last 24 hr in order to analyze the effects on erythrocytic invasion and intraerythrocytic growth. respectively. Reduction in 3H-hypoxanthine uptake was used to determine the percent of inhibition compared to nonimmune serum. One hundred seventy sera from Mindanao and Palawan in the South. the centrally located island of Mindoro. and Luzon in the North. were tested against 4 P. falciparum strains from the Philippines and 1 from Africa. Indirect fluorescent antibody titers were not predictive of inhibition. Inhibition of merozoite invasion rather than intraerythrocytic parasite growth is suggested by this study. Generally. sera were more inhibitory to parasite strains from the same geographical area than to those from more remote areas.
Comparison of active and passive case detection of cutaneous leishmaniasis in Guatemala, To estimate the degree to which passive case detection underestimates the true incidence of cutaneous leishmaniasis in Guatemala. we compared data from the passive surveillance system of the Guatemalan Ministry of Health with a cross-sectional population-based survey of cutaneous leishmaniasis in Guatemala. Of the 2.938 persons interviewed. 143 (5%) reported having had cutaneous leishmaniasis at some time in the past. 37 (1.3%) reported the onset of infection in the 12 months before the survey. 31 (1.1%) had active infections. and 16 (0.5%) had parasitologically confirmed infections. Calculated on the basis of these reports and the estimated population of the endemic area. the total number of new cases in the leishmaniasis-endemic area in the 12 months before the survey was approximately 2.574; during the same 12 month period. Ministry of Health data based on passive surveillance listed 64 cases of cutaneous leishmaniasis. In Guatemala. incidence estimates based on passive surveillance may underestimate the occurrence of cutaneous leishmaniasis by as much as a factor of 40.
Diffuse cutaneous leishmaniasis acquired in Peru, A case of diffuse cutaneous leishmaniasis (DCL) acquired in Peru is described. The causative agent was Leishmania mexicana amazonensis as determined by isoenzyme analysis and species-specific monoclonal antibody binding characteristics. Histological examination of biopsy material showed a large number of intracellular and extracellular amastigotes and few lymphocytes. Treatment with meglumine antimoniate (Glucantime) administered iv at a dosage of 20 mg antimony/kg body weight/day for 60 days resulted in visible improvement of the lesions. but not in clinical or parasitological cure.
Transmission indices of Loa loa in the Chaillu Mountains, Congo, A longitudinal entomological survey of the vectors of loiasis was conducted in the Missama area (Lekoumou region) in the Congo from September 1987 to August 1989. The principal catching site was a palm grove surrounded by forest 3 km from the village. Landing/biting densities of Chrysops were measured by standardized fly catches lasting 11 hr carried out twice a month. Vector landing densities were also assessed in the Bantu and Pygmy villages and in the fields. Populations of Chrysops from the palm grove were examined 6 times a month for infection with the infective stage of Loa loa. Chrysops silacea was the predominate vector except at the beginning of the rainy season. when C. dimidiata was the prevailing species. Chrysops were caught throughout rainy season. from October to June. The host-seeking activity of C. silacea was greatest in the middle of this season (February). but occurred sooner (October) for C. dimidiata. The following variables associated with transmission were calculated from our observations in the palm grove (the first figure corresponds to the first year of the study and the figure in parentheses corresponds to the second year). It was calculated that 2.658 (2.185) C. silacea and 1.412 (1.182) C. dimidiata could bite a person in the palm grove per year. including an average of 14.4 (12.7) infective C. silacea and 9.8 (7.2) infective C. dimidiata. The percentage of all dissected flies with third stage larvae in the head and the mean number of larvae in the head/infective fly were 0.57% and 10.1 +/- 6.8 for C. silacea and 0.66% and 11.2 +/- 6.5 for C. dimidiata. respectively. The estimated annual transmission potentials were 171.1 (102.9) for C. silacea and 116.1 (73.8) for C. dimidiata. In the palm grove. transmission was ensured by 2 effective vectors during the rainy season (October to May). Although the annual biting rate for both species was twice as low in the village as in the forest. our data suggest that effective transmission occurs there also.
Isolation of Tete serogroup bunyaviruses from Ceratopogonidae collected in Colorado, Two viruses were isolated from ceratopogonid midges collected in northern Colorado. Electron microscopy indicated that both isolates were bunyavirus-like. Indirect fluorescent antibody and serum dilution-plaque reduction neutralization tests showed that these isolates were members of the Tete serogroup. most closely related antigenically to Tete and Batama viruses but distinguishable from both and from each other. We suggest the name Weldona virus for these isolates. Antibody in both waterfowl and passerine birds in northern Colorado indicates the enzootic presence of these viruses in northern Colorado and raises unanswered questions about the introduction and establishment of Tete serogroup viruses in the Americas.
Lymph node metastasis from papillary-follicular thyroid carcinoma in young patients, A total of 117 patients under 20 years of age with papillary and/or follicular thyroid cancer presented to the M. D. Anderson Cancer Center between 1949 and 1987. The most common presenting symptom was a cervical mass. Twenty percent of the patients had a history of prior irradiation. Sixty percent initially had palpable lymph nodes. while 26% who had clinically negative examinations had pathologically positive lymph nodes. Recurrence was highest in regional lymph nodes at 24%. with only a 4% recurrence rate at the primary site and a 3% recurrence rate at distant sites. There were no deaths due to the thyroid cancer. To maintain a low rate of recurrence. near-total thyroidectomy with neck dissection followed by iodine 131 treatment should be considered in these young patients.
Survival discriminants for differentiated thyroid cancer, Since 1975. the American Cancer Society. Illinois Division. has published end results of major cancer sites drawn from patient data contributed voluntarily by hospital cancer registries throughout the state. The current study was undertaken. in part. to apprehend information regarding contested areas in the management of patients having differentiated (papillary/follicular) thyroid cancer. A total of 2.282 patients with either papillary or follicular carcinoma of the thyroid from 76 different Illinois hospitals and providing 10 years of follow-up information (life-table analysis) were retrospectively analyzed for demographic. disease. and treatment-related predictors of survival. Multivariate analysis using the Cox proportional hazards method was made for stage. age. race. sex. morphology. history of radiation exposure. presence of positive lymph nodes. initial surgical treatment. postoperative iodine 131 therapy. and replacement/suppressive thyroid hormone treatment. Statistically significant (p less than or equal to 0.05) predictors of favorable survival after thyroid cancer were low stage (I and II). young age (less than 50 years). white race. female sex. and the administration. postoperatively. of either thyroid hormone or radioactive iodine. Factors that had no influence on survival were lymph node status. choice of initial surgical treatment. and a history of prior irradiation. We suggest that where a prospective clinical trial is impracticable. a retrospective analysis of a large and detailed database. such as that available from cooperating hospital-based tumor registries. may yet provide useful insights to solutions of cancer management problems.
Soft tissue sarcomas of the head and neck in adults, We reviewed the clinical records and pathologic material of 176 adults with primary soft tissue sarcomas treated at Memorial Sloan-Kettering Cancer Center between 1950 and 1985. Seventy-two patients (41%) had low-grade sarcomas and 104 (59%) had high-grade sarcomas. All but 18 patients underwent some form of excision as initial therapy. Adjuvant radiotherapy and chemotherapy combined with surgical excision showed no significant effect. A significantly increased risk of treatment failure was associated with large tumor size. positive surgical margins. bone involvement. local recurrence. metastatic spread. and high histologic grade. Except for recurrence. the p value by univariate analysis in the log-rank test for comparison of survival according to these clinical and pathologic characteristics was p less than 0.0001. Although the overall survival was 75% at 2 years. 55% at 5 years. and 46% at 10 years. only 20% of the patients with high-grade sarcomas were alive 10 years after treatment. Most patients with rhabdomyosarcoma. high-grade peripheral nerve tumor. and high-grade fibrous histiocytoma and all patients with high-grade angiosarcoma died of disease less than 5 years after diagnosis. New therapeutic strategies are needed to improve the survival of adult patients with high-grade soft tissue sarcomas of the head and neck.
Multimodality preoperative treatment for advanced stage IV (MO) cancer of the head and neck, Sixty-three patients with advanced unresectable squamous cell carcinoma of the head and neck were treated with a combination of chemotherapy. radiation. and surgery. We observed a 75% response to neoadjuvant chemotherapy. The 5-year survival rate for all 63 patients was 20%. and only 3 patients were alive at 8 years. The 5-year survival rate for patients who completed the treatment plan and received chemotherapy. radiation. and surgery was 43% compared with 20% for those who had chemotherapy and radiation but refused surgery. Development of a second primary cancer was the cause of death in 62% of the patients who survived more than 24 months.
Needle aspiration biopsy in salivary gland lesions, The value of needle aspiration biopsy in the evaluation and management of salivary gland pathology is controversial. The major reasons for this controversy are the difficulty in cytologic evaluation and the fact that the extent of surgery can be easily defined based on clinical judgement. However. a preoperative diagnosis is helpful in discussions with patients regarding the extent and type of surgery. Apart from the fact that needle biopsy can distinguish benign from malignant conditions. it is also very useful in distinguishing between salivary and other nonsalivary pathology. Over the past 7 1/2 years. we have performed 160 needle aspirations of parotid. submandibular. and submucosal lesions. Adequate specimens for cytologic evaluation were obtained in 155 patients (97%). A total of 84 parotid lesions. 70 submandibular lumps. and 6 submucosal abnormalities were detected. A cytologic diagnosis of benign pathology was made in 120 patients. Twelve patients had lymphoma and the diagnosis was suspected based on needle aspiration. There were 10 patients with tuberculosis and 30 patients with hyperplastic lymph nodes or benign lymphoepithelial disease of the parotid. There were three false-positive and two false-negative reports. No complications such as hematoma. nerve injury. or infection developed. The major difficulty was in distinguishing between malignancy and obstructive sialadenitis in the submandibular region. Needle aspiration was helpful in evaluating lesions in the tail of the parotid and submandibular area. The cytologic distinction between salivary and nonsalivary pathology was useful in planning the appropriate surgery and the extent of surgical resection. From a clinical standpoint. the distinction between benign and malignant salivary and nonsalivary pathology was very helpful. Preoperative diagnosis of Warthin's tumor. lymphoma. or benign lymphoepithelial disease was essential to the correct management of these patients.
Whole organ sectioning of mixed parotid tumors, A pathologic study involving 15 standard formal parotidectomy specimens was carried out using the whole organ sectioning technique. Histopathologic characteristics noted included the presence of exposed capsule. breaks of the capsule. capsular incompleteness. tumor ingrowth and thickness. cellularity. and lymphocytic infiltration. Tracings of histopathology slides were used to reconstruct the three-dimensional configuration of each tumor as viewed from different angles. No tumor had a smooth surface. At the extreme. two tumor lumps were connected by just a narrow waist. Separated tumors were not seen. In only one specimen did a lymph node contain an additional tumor in the form of an adenolymphoma. All tumors showed some exposed capsule or "bare area" to a degree affected mainly by the position of the tumor. Capsular damage was occasionally seen and was usually minor. Capsular incompleteness and tumor ingrowth make global capsular dissection unsafe. It is concluded that formal parotidectomy remains the operation of choice for pleomorphic adenoma of the parotid gland. although capsular dissection (otherwise termed enucleation) cannot be entirely avoided during the procedure.
Long-term fate of the vascularized iliac crest bone graft for mandibular reconstruction, Vascularized bone grafts. such as the iliac crest. have become a major tool for mandibular reconstruction. Due to the growing trend toward immediate bone replacement followed by implant osseointegration and dental rehabilitation. further understanding of the long-term characteristics of these grafts is essential. Early postoperative bone scans demonstrate increased activity within the vascularized graft relative to surrounding bone. This study addressed the use of bone SPECT (single photon emission computed tomography) scintigraphy as a long-term method of evaluating the integrity of vascularized bone grafts.
Significance of positive margins in oral cavity squamous carcinoma, Three hundred ninety-eight consecutive. previously untreated patients undergoing surgery for epidermoid carcinoma of the oral cavity from 1979 to 1983 were reviewed. One hundred twenty-nine patients were classified as having positive surgical margins. Of these. 83 patients had tumor within 0.5 mm of the surgical margin. 9 had premalignant changes at the margin. 9 had in situ carcinoma at the margin. and 28 had invasive cancer at the margin. The remaining 269 patients had uninvolved margins. The significance of positive margins relating to survival. subsequent clinical course. local recurrence. and patterns of treatment failure was examined. along with the impact of adjuvant postoperative radiotherapy on positive margins. The percentage of patients having positive margins progressively increased with increasing T stage: 21% in T1 versus 55% in T4 primary cancer. The overall 5-year survival for patients with negative margins was 60%. For patients with positive margins. 5-year survival was 52%. This difference was statistically significant. The incidence of local recurrence in patients having positive surgical margins was twice as much as in those with negative margins (36% versus 18%). Metastasis rates in the neck and at distant sites were not significantly influenced by the status of the surgical margin. Of the 129 patients with positive margins. 49 received postoperative radiotherapy. In those patients so treated. a trend toward lower recurrence rates was noted. Differences were not statistically significant. This retrospective review confirms the importance of adequate resection of the primary tumor as well as the relative ineffectiveness of adjuvant postoperative radiotherapy in the improvement of local control in patients with positive surgical margins.
Flow cytometric evaluation of chemosensitive and chemoresistant head and neck tumors, For patients with head and neck squamous carcinoma. a clinical response to induction chemotherapy has correlated with a survival advantage. Similarly. patients with diploid tumors have displayed a survival advantage when compared with patients with aneuploid tumors. This study examined DNA content in 33 patients who had undergone induction chemotherapy as part of two clinical protocols to determine if there was a correlation between the patients with diploid tumors and the patients with a clinical response to chemotherapy. Although patients with stage III tumors had a longer disease-free survival than stage IV patients (p less than 0.0002). the addition of DNA content information did not improve the ability to predict response. Specifically. there was no correlation between DNA content and the response to chemotherapy. In addition. for this group of patients. a diploid DNA content was not correlated with a survival advantage. We conclude that DNA content information did not add significantly to the prediction of clinical outcome in these patients who received induction chemotherapy.
Serologic determinants of survival in patients with squamous cell carcinoma of the head and neck, Specific circulating serum proteins may reflect unique properties governing the growth and progression of head and neck cancers. One hundred three previously untreated patients with squamous cell carcinoma of the head and neck were prospectively evaluated for serum IgA. IgG. and IgM and C1q-binding macromolecules. Immunoglobulins were assessed by the immunoturbidimetric technique. C1q-binding macromolecules (C1qBM) were measured utilizing the iodine-125 assay of Zubler et al (J Immunol 1976; 116: 232-5). Neither the level of serum immunoglobulins nor C1qBM values were correlated with the primary site. AJC (American Joint Committee on Cancer) stage of disease. or size of primary lesion. Likewise. comparison of serum IgA with C1qBM values demonstrated that these laboratory parameters were independent variables (r = 0.15 by Pearson linear regression). Univariate statistical analysis. utilizing the Cox proportional hazard model. showed serum IgA and C1qBM values to each contribute significantly to the ability to predict survival in patients with advanced squamous cell carcinoma of the head and neck (p = 0.01 and 0.003. respectively). Furthermore. multivariate analysis reveals that both C1qBM and serum IgA levels contribute significantly to the hazards model beyond staging in predicting survival (p less than 0.001). Predictive results were most apparent in patients with stage IV disease and related to the probability of both regional and distant metastatic recurrences. Conversely. serologic analysis provided no information in patients who were staged early. These results support pretreatment multiparametric serologic analysis of patients with squamous cell carcinoma of the head and neck.
Delayed reconstruction following Mohs' chemosurgery for skin cancers of the head and neck, The case records of 52 patients with 55 cutaneous neoplasms treated by Mohs' chemosurgery and subsequently reconstructed by plastic surgeons were reviewed to determine if delay between resection and reconstruction adversely affected the outcome of reconstruction. Reconstruction was performed from 5 to 61 days after Mohs' chemosurgery for 45 basal cell carcinomas and 10 other cutaneous neoplasms. There were no complications during the interval between resection and reconstruction. Following reconstruction. minor wound complications occurred in 6% of patients; there were no major complications. Microscopic examination of the re-excised wound revealed residual disease in 2 of 45 cases of basal cell carcinoma and 0 of 10 other cutaneous malignancies. Both patients with residual basal cell carcinomas (i.e.. false-negative margins after Mohs' surgery) had presented to the Mohs' surgeon with recurrent tumors. During a follow-up period of 3 months to 3 years after complete resection. recurrent tumor developed in 2 of 45 cases of basal cell carcinoma and 3 of 8 cases of squamous cell carcinoma. Delayed reconstruction. usually 5 to 20 days after Mohs' chemosurgery. can be performed without significant morbidity. Re-excision of the Mohs' chemosurgical wound for pathologic examination can detect residual disease and may be especially indicated for large recurrent wounds.
Plasma noradrenaline, platelet alpha 2-adrenoceptors, and functional scores during ethanol withdrawal, Plasma noradrenaline and platelet alpha 2-adrenoceptor density (sites/cell using 3H-rauwolscine with and without phentolamine) were correlated with withdrawal score in 23 hospitalized patients undergoing ethanol withdrawal. Control groups for plasma noradrenaline were 25 patients admitted to hospital for elective gastroscopy and 12 laboratory workers accustomed to venipuncture. Controls for platelet alpha 2-adrenoceptor measurements were a separate group of 31 normal subjects with a mean age close to that of the patients' withdrawing from ethanol. Plasma noradrenaline was significantly higher in the patients undergoing ethanol withdrawal than in patients admitted to hospital for elective endoscopy. Twelve laboratory controls had plasma noradrenaline levels significantly lower than either patient group. A significant though poor statistical correlation existed between ethanol withdrawal score and simultaneously determined plasma noradrenaline level. Platelet alpha 2-adrenoceptor sites/cell were reduced in ethanol withdrawal compared with the normal controls. Platelet alpha 2-adrenoceptor sites/cell increased over the first 24 hr of ethanol withdrawal but remained significantly lower than control values. The change in platelet adrenoceptors was accompanied by a fall in mean plasma noradrenaline. Thus. the stress of hospital admission itself is associated with an increase in plasma noradrenaline. but ethanol withdrawal enhances this increase. which is accompanied by and probably causes a reduction in platelet alpha 2-adrenoceptor numbers. These changes begin to return towards normal within 24 hr as the withdrawal reaction subsides.
Application of the Tridimensional Personality Questionnaire to a population of alcoholics and other substance abusers, To assess its construct validity and application. Cloninger's Tridimensional Personality Questionnaire (TPQ) was administered to 267 inpatient substance abusers. One hundred seventy-two of the patients were alcoholic. 47 abused stimulants. and 48 abused other drugs. primarily benzodiazepines. marijuana. or were polysubstance abusers. Of the sample 33.8% were female. Analyses were conducted to (1) determine whether TPQ scores could be used to classify alcoholics as either Cloninger Type I or Type II; (2) examine the intercorrelations of TPQ scales and identify differences in these patterns due to drug of choice; (3) replicate previously obtained gender differences on the TPQ. The results indicate that (1) TPQ scores did not classify the alcoholics into the expected frequencies for Type I and Type II; (2) the scales were not independent and did not give rise to any differences among drug user groups. but (3) did confirm previously reported gender differences. These results indicate that Cloninger's model and the TPQ must be subjected to careful empirical study prior to their widespread acceptance.
Isoenzymes of aldehyde dehydrogenase in human lymphocytes, The types of isozymes of aldehyde dehydrogenase (ALDH) present in human lymphocytes has been investigated using isoelectric focusing of polyacrylamide gels followed by substrate-specific staining. Lymphocytes obtained from most individuals were found to contain both types I and II ALDH. This group of 'typical' individuals reported that they did not develop marked facial flushing or rapid heart rate after drinking alcohol nor did they develop an erythema to cutaneously applied ethanol. Lymphocytes obtained from 'atypical' individuals who do suffer from alcohol-induced flushing and rapid heart rate and who developed erythema to cutaneous ethanol displayed type II. but not type I. ALDH. Lymphocytes thus appear to be an easily accessible and suitable tissue for determining type I ALDH phenotype.
Maternal genetic effects on ethanol teratogenesis and dominance of relative embryonic resistance to malformations, Maternal genetic factors and/or fetal genetic factors contribute to variations in response to prenatal alcohol exposure. To assess the contribution of maternal genotype to ethanol teratogenesis. a reciprocal cross study was conducted in an animal model using C57BL/6J (B6) and long-sleep (LS) mice. B6 mice are more susceptible than LS mice to prenatal ethanol-induced malformations but both mouse stocks are susceptible to fetal weight deficits following in utero alcohol exposure. B6 and LS dams were reciprocally mated to B6 or LS males producing four embryonic genotype groups: the true-bred B6B6 and LSLS genotypes. and the genetically similar B6LS and LSB6 genotypes (the F1 genotype). Dams were intubated with either 5.8 g/kg ethanol (E) or an isocaloric amount of sucrose (S) on day 9 of pregnancy. Fetuses were removed on gestation day 18. weighed. and assessed for soft tissue or skeletal malformations. Results showed a greater litter weight deficit and increased total malformation rate in ethanol-exposed F1 litters carried by B6 mothers compared to ethanol-exposed F1 litters carried by LS mothers. This result would be expected only if maternal genetic factors contribute significantly towards susceptibility to ethanol teratogenesis. The influence of the LS mother was to decrease susceptibility to ethanol teratogenesis compared to the B6 mother while the influence of the B6 mother was to increase susceptibility to ethanol teratogenesis compared to the LS mother. The average malformation rate for F1 litters was significantly less than the predicted midparental value. This shows that the F1 genotype exhibited dominance towards resistance to prenatal alcohol effects.
Murine model of ethanol-induced immunosuppression, Alcohol abuse has been associated with an increased susceptibility to infectious diseases and certain tumors. On the basis of these observations. an effect of ethanol on the immune system has been suggested. We have used a mouse model system in which male C57Bl/6 mice were fed either Lieber-DeCarli liquid diet containing ethanol sufficient to supply 37% of the total calories or isocaloric control diet in a pair-feeding design to examine the effect of ethanol on the immune system. The group consuming the ethanol-containing diet maintained relatively stable levels of blood ethanol for the 8 days of feeding. Consumption of ethanol for 8 days resulted in a profound loss of thymus and spleen cells. and the recovery of thymus cellularity was delayed relative to the recovery of spleen cell numbers after ethanol feeding was discontinued. Proliferation of spleen lymphocytes to T-cell stimuli (concanavalin A and alloantigens) was diminished; however. B-cell proliferation to lipopolysaccharide was relatively unchanged in mice fed ethanol-containing diet. Also in ethanol-fed mice a significant decrease in the primary antibody response to sheep red blood cells but not to the T-independent antigen trinitrophenol-ficoll occurred. These data establish the murine model system as a means to define further the effect of ethanol on the immune system and host defense mechanisms.
Deranged vitamin D metabolism but normal bone mineral density in Finnish noncirrhotic male alcoholics, To study the effect of prolonged ethanol consumption on calcium metabolism and on the prevalence of osteoporosis we examined 38 Finnish noncirrhotic male alcoholics (30-55 years of age) with dietary interviews and biochemical measurements and by measuring the bone mineral content of the forearm using single photon absorptiometry (SPA) and the bone mineral density of the spine. humerus and proximal femur using nonquantified computer tomography (CT) and dual-energy x-ray absorptiometry (DEXA). In comparison two groups of healthy controls were studied. The mean daily dietary intake of calcium was 1.3 g in the patients and 1.2 g in the controls. The dietary intake of vitamin D was equal in the study groups. too. The serum levels of calcium. phosphate and parathyroid hormone did not show any difference between the patients and controls but in the alcoholics the urinary excretion of calcium was reduced by 42% (p less than 0.0001) as compared to the controls. The serum levels of 25-hydroxyvitamin D3. 1.25-dihydroxyvitamin D3. and 24.25-dihydroxyvitamin D3 were reduced in the alcoholics by 40% (p less than 0.0001). 23% (p less than 0.01). and 48% (p less than 0.0001). respectively. as compared to the controls. The alcoholic men had normal levels of serum testosterone and they did not have hypercortisolism. The bone mineral content of the dominant forearm measured by SPA was similar in the study groups as were the bone mineral densities (BMD) of the lumbar and humeral areas measured by CT. The BMD at the lumbar. femoral neck. Ward's triangle and trochanter sites measured by DEXA did not differ. either.
The detection of alcoholism in hospitalized schizophrenics: a comparison of the MAST and the MAC, The Michigan Alcoholism Screening Test (MAST) and the MacAndrew Alcoholism Scale (MAC) were administered to forty-one schizophrenic inpatients also meeting DSM-III criteria for either alcohol abuse or alcohol dependence and 29 schizophrenic inpatients who did not qualify for an additional substance abuse diagnosis other than marijuana abuse/dependence. The MAC failed to differentiate between the alcoholic and nonalcoholic groups and both groups scored above the recommended cutting score. The MAST significantly differentiated the alcoholic and nonalcoholic schizophrenic patients and was as sensitive to a history of alcohol abuse as to alcohol dependence. Neither the MAST nor MAC was sensitive to recent versus more remote drinking. The overall classificatory accuracy of the MAST was found to be 80% and that of the MAC was 56%. A logistic regression analysis revealed that the use of just four MAST items can yield a group classificatory rate of 83%. It was concluded that the MAST exhibited sufficient sensitivity and specificity to be used as an initial screening instrument for alcoholism in schizophrenic patients.
Alcohol protects the diaphragm during dietary restriction, We recently reported that alcoholic rat diaphragm develops greater contractile force than diaphragm of pair-fed control animals. The present experiment examines whether alcohol or dietary restriction is the more likely cause of this surprising finding. We conditioned 10 rats using a liquid diet containing ethanol as 36% of calories. Ten pair-fed control animals received an equal amount of isocaloric. ethanol-free liquid diet. Ten ad libitum control animals had unrestricted access to lab chow and water. Rats were killed after 30 weeks. Left costal diaphragm strips were studied in vitro at optimal length using direct stimulation at supramaximal voltage. Isometric force was measured and divided by muscle cross-section to compute stress. Maximal tetanic stresses developed by muscle from pair-fed controls were systematically less than alcoholic and ad libitum control values (p less than 0.0001); this did not depend on temperature (25 degrees vs. 37 degrees; p greater than 0.50). Pair-feeding increased twitch half-relaxation times (p less than 0.03) and shifted the tetanic stress-stimulation frequency relationship leftward by 10 Hz (p less than 0.01). Diaphragm of pair-fed rats continued to generate lower stresses during the fatigue caused by repeated contractions (p less than 0.01). We conclude that dietary restriction associated with pair-feeding compromises diaphragm performance in rats. Chronic alcohol consumption prevents or reverses these changes. since diaphragm function of alcoholic and ad libitum control animals was not different.
Late versus early onset problem drinking in older men, Age at onset of problem drinking was studied in 132 older men (age 60 years and older) admitted to a VA geriatric alcoholism outpatient treatment program. Demographics. alcohol history. self reported psychological status. special treatment. and treatment compliance variables were tested for association with onset age. Late onset (defined as onset of the first alcohol problem at or after age 60) was not uncommon. occurring in 15% of the sample (29% of patients age 65 or older). Compared to earlier onset cases. late onset alcohol problems were milder and more circumscribed. and were associated with less family alcoholism and greater psychological stability. Late onset patients were also more compliant with outpatient treatment requirements; however. treatment program variables were better predictors of compliance than onset age.
Inpatient treatment of employed alcoholics: a randomized clinical trial on Hazelden-type and traditional treatment, The first randomized clinical trial on the Hazelden-type of treatment showed that this AA-oriented treatment for alcoholism can result in significant improvement in drinking behavior as compared to a more traditional form of treatment. One hundred forty-one employed alcoholics were randomized to either Hazelden-type treatment (N = 74) or to traditional-type treatment (N = 67). The treatment groups were highly comparable. The bimonthly follow-up lasted one year. According to the COPES-questionnaire (short form). the treatment at the Hazelden-type institute was significantly more involving. supportive. encouraging to spontaneity and oriented to personal problems than at the traditional-type institute. In accordance the treatment drop-out rate was 7.9% at Hazelden-type institute and 25.9% at traditional-type institute (p less than 0.02). The participation in outpatient treatment was significantly better after the Hazelden-type treatment. The proportion of those abstinent (admitted ethanol consumption. 0 g/day; gammaglutamyl transferase. and mean cell volume were normal) was higher at Hazelden-type institute during the last (8-12 months) follow-up period (26.3% vs. 9.8%. p = 0.05). Fourteen percent of the Hazeldon-type institute patients and 1.9% of the traditional-type institute patients stayed abstinent during the whole 1-year follow-up period (p less than 0.05). The differences for the corresponding rates for controlled drinking (admitted ethanol consumption less than 40 g/day. GGT. and MCV normal) were in the same direction but did not reach statistical significance. Thus the Hazelden-type treatment obtained better results in 1-year abstinence rate than a more traditional-type treatment.
Ethanol-inducible cytochrome P-450: assessment of substrates' specific chemical probes in rat liver microsomes, The capacity of liver microsomes to oxidize various substrates known to be specific of alcohol-inducible cytochrome P-450 was studied in rats treated with different xenobiotics such as 3-methylcholanthrene. phenobarbital. acetone. and ethanol. Analysis of results showed a significantly marked increase following ethanol and acetone treatments of the p-nitrophenol hydroxylation (283 +/- 19% and 304 +/- 21%). N-nitrosodimethylamine (NDMA) demethylation (280 +/- 105% and 228 +/- 95%). benzene hydroxylation (258 +/- 60% and 236 +/- 61%). butanol oxidation (173 +/- 34% and 154 +/- 32%). aniline hydroxylation (147 +/- 22% and 95 +/- 8%). and ether de-ethylation (95 +/- 17% and 83 +/- 17%) and a not significant increase of N-nitrosodiethylamine (NDEA) de-ethylation (34 +/- 11% and 9 +/- 8%) in rat microsomes. respectively. versus control animals (mean +/- SD. values expressed as nmol/min/nmole P-450). All of these activities significantly decreased after 3-MC treatment. except for the p-nitrophenol hydroxylation. PB treatment markedly enhanced NDEA de-ethylation. p-nitrophenol. and benzene hydroxylations (106 +/- 38%. 109 +/- 14%. and 153 +/- 62%. respectively) versus controls. These results suggest that NDMA and especially 1-butanol are the most specific and useful probes of alcohol-inducible cytochrome P-450 in crude liver microsomes.
Effects of alcohol on the import of aldehyde dehydrogenase precursor into rat liver mitochondria, We previously showed that incubation of rat liver mitochondria with alcohols resulted in the inhibition of the import of aldehyde dehydrogenase precursor but not that of ornithine transcarbamylase precursor (Wang TTY. Farres J. and Weiner H: Arch Biochem Biophys 272:440-449. 1989). The time required for inhibition of import to occur was now measured with ethanol (200 mM) and butanol (100 mM) at 0 degree and 30 degrees C. It required approximately 30 min to achieve 50% inhibition with butanol and 50 min with ethanol. To further substantiate the membrane perturbing effects of alcohols. we also examined the effect of oleic acid on import. We found that incubation of mitochondria with oleic acid (0-100 microM) resulted in inhibition of aldehyde dehydrogenase precursor import in a dose response fashion. In addition to in vitro effects of alcohols on import. we conducted a preliminary study on import of protein into liver mitochondria isolated from rats fed ethanol. We found that the rate of aldehyde dehydrogenase precursor import into liver mitochondria isolated from ethanol fed rats was identical to that from control. The results are consistent with finding that the activity and amount of aldehyde dehydrogenase was the same in mitochondria isolated from the alcohol-fed or control animals.
Alterations in splanchnic blood flow following chronic ethanol exposure, The purpose of these experiments was to determine whether or not tolerance develops to the effect of 3.0 g/kg ethanol on total and regional splanchnic blood flow in male Wistar rats. The animals were given the Lieber-DeCarli liquid diet containing ethanol for 10 days; ethanol-fed animals were withdrawn 24 hr prior to experiments. Regional blood flow and cardiac output (CO) were measured by the reference microsphere technique after an intraperitoneal injection of 3.0 g/kg of ethanol. Acute ethanol administration produced early nonsustained increases in portal vein blood flow in animals fed ethanol for 10 days and withdrawn for 24 hr and in control animals. However. after chronic exposure to ethanol. the pattern of increase in blood flow in response to ethanol in the splanchnic organs was different between the ethanol-fed and control groups. Increases in portal vein flow in control groups were due to concomitant increases in small intestinal. colonic. and cecal blood flow while the increase in the ethanol-fed group was due to a rise in small intestinal and stomach blood flow. The increase in stomach blood flow that occurred in the animals treated chronically with ethanol may be viewed as a conditioned response to ethanol. since this was not found in the control group. These results. demonstrate that the pattern of increase in blood flow in the splanchnic organs produced by an acute dose of ethanol depends on the animal's previous exposure to ethanol.
Examination of Cloninger's type I and type II alcoholism with a sample of men alcoholics in treatment, Cloninger's clinical method of classifying alcoholics into two groups (Types I and II) was examined with data obtained from 360 VA hospitalized male alcoholic patients. For operational criteria. the Cloninger clinical method of subtyping alcoholics employs age-of-onset of problem drinking and symptom-clusters supposedly associated with each subtype. Marked overlap was found between the symptom-clusters used to define the two subtypes. Ninety-one percent of the entire sample satisfied criteria for both symptom-clusters. Dividing the sample by early-onset (Type II. less than or equal to 25 years) and late-onset (Type I. greater than 26 years) alcoholism did not substantially reduce the overlap between symptom-clusters; i.e.. 96% of the early-onset and 83% of the late-onset subgroups were positive for both symptom-clusters. Only 21 men (6%) could be classified when both age-of-onset and the type-appropriate symptom-cluster were used to separate patients. In hospital settings. at least. these findings suggest that the two-group clinical alcoholism typology proposed by Cloninger basically reflects the age-of-onset of problem drinking.
Does isoflurane lead to a higher incidence of myocardial infarction and perioperative death than enflurane in coronary artery surgery? A clinical study of 1178 patients, To examine if the choice of volatile agents influences cardiac outcome in coronary artery surgery. 1178 patients undergoing elective coronary artery bypass grafting without additional operations received enflurane (608) or isoflurane (570) as their primary anesthetics. The inspired concentration of volatile agent (administered with 50% nitrous oxide) was adjusted depending on the level of blood pressure at the discretion of the anesthesiologist. In addition to the volatile agent assigned. each patient received small doses of fentanyl at induction and before sternotomy (total 0.006-0.008 mg/kg). The groups did not differ in preoperative and surgical characteristics except for a more frequent history of renal dysfunction in patients given isoflurane. The rates of postoperative myocardial infarction. administration of positive inotropic agents at the time of weaning from cardiopulmonary bypass. and in-hospital deaths in the enflurane and isoflurane groups were 1.8% and 4.0% (P less than 0.05). 4.9% and 8.1% (P less than 0.05%). and 0.3% and 2.1% (P less than 0.01). respectively. Although the mechanism of the adverse effects of isoflurane could not be clarified in this study. these results demonstrate that the use of isoflurane could be inappropriate in patients undergoing coronary artery bypass grafting.
Low-dose almitrine bismesylate enhances hypoxic pulmonary vasoconstriction in closed-chest dogs, The effect of almitrine bismesylate on the hypoxic pulmonary vasoconstrictor response was studied in six closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2; the left lung was ventilated either with 100% O2 ("hyperoxia") or with an hypoxic gas mixture ("hypoxia": end-tidal oxygen tension = 60.3 +/- 0.6 mm Hg). On two consecutive days. each dog received either almitrine (Vectarion. Servier Lab) or malic acid. Consecutive almitrine doses of 0.003. 0.03. 0.3. and 3.0 micrograms.kg-1.min-1. or the equivalent volumes of malic acid without almitrine. were administered intravenously as a constant peripheral infusion for 15 min. Percent blood flow to each lung was calculated based on a variation of the traditional shunt equation. The change in percent left lung blood flow (delta %QL-VA) increased significantly between the hypoxia-no drug and the hypoxia-almitrine (3.0 micrograms.kg-1.min-1) phase. No significant changes occurred during the other almitrine doses or the respective malic acid control phases. The change in arterial oxygen tension (delta PaO2) also increased significantly between the hypoxia-no drug and the hypoxia-almitrine (3.0 micrograms.kg-1.min-1) phase. No significant changes occurred during the other almitrine doses or the respective malic acid control phases. It is concluded that in dogs low-dose almitrine enhances hypoxic pulmonary vasoconstriction and that this enhancement is dose-related.
Hemodynamic effects of diltiazem during vasoconstrictor pulmonary hypertension in sheep, Calcium channel blockers have been effective as pulmonary vasodilators in patients with pulmonary hypertension. The current study therefore compared the effects of prostaglandin E1. an effective pulmonary vasodilator. with the effects of the water-soluble calcium channel blocker diltiazem during pulmonary hypertension in sheep. Pulmonary hypertension was produced by continuous intravenous administration of U46619 to halothane-anesthetized sheep. Prostaglandin E1 decreased pulmonary artery pressure 29%. decreased pulmonary vascular resistance (Rp) 57%. and did not affect the ratio of pulmonary to systemic vascular resistance (Rp/Rs). Diltiazem decreased pulmonary artery pressure 15%. decreased Rp 50%. and did not affect Rp/Rs. When 0.33 mL/kg polyethylene glycol-ethanol vehicle (the vehicle used for nifedipine administration in a prior study) was administered during diltiazem infusion. pulmonary artery pressure increased 19%. Rp increased 72%. and Rp/Rs increased 29%. These results indicate that diltiazem is an effective pulmonary vasodilator and suggest that the previously reported unfavorable results of nifedipine may have been due to the vehicle used for nifedipine administration.
Changes in cerebral blood flow velocity after release of intraoperative tourniquets in humans: a transcranial Doppler study, The effect of release of intraoperative thigh tourniquets on velocity of blood flow in the middle cerebral artery was examined in five patients given general anesthesia with controlled ventilation for lower extremity orthopedic procedures using transcranial Doppler sonography. Middle cerebral artery blood flow velocity increased significantly from 52 +/- 6 (SEM) to 82 +/- 24 cm/s (an increase of 58% +/- 13%) within 4 +/- 1 min after tourniquet release and remained significantly elevated for 7 min. A positive linear correlation was found between middle cerebral artery blood flow velocity and PETCO2 on each occasion (0.97 greater than or equal to r greater than or equal to 0.84. 0.001 greater than P greater than 0.0001) after tourniquet deflation. Assuming a linear relationship between flow velocity and flow. these findings suggest that significant increase in cerebral blood flow can occur after intraoperative tourniquet release and that this increase appears to be mostly CO2-dependent.
Comparison of propofol and thiopental/halothane for short-duration ENT surgical procedures in children, Experiences with propofol in pediatric anesthesia are limited. We undertook a study to evaluate the quality of induction and recovery from anesthesia with propofol compared to thiopental/halothane. Twenty children received 3 mg.kg-1.min-1 of propofol as a loading dose followed by a maintenance dose of 0.1 mg.kg-1.min-1 (+/- 10%). Twenty children received 5-7 mg/kg of thiopental. and maintenance was provided with halothane (0.5%-1.5%). The interval between the end of the administration of propofol or thiopental/halothane and extubation. as well to discharge to the ward. was significantly shorter with propofol (4.4 versus 13.5 min and 7.22 versus 30.4 min. respectively). Spontaneous movements and pain on injection were seen significantly more frequently with propofol. whereas laryngospasm and hiccup were only observed with thiopental. During the first 6 h after the surgical procedure. analgesics were needed significantly more often in the thiopental group. Nausea and vomiting also were observed more frequently in the thiopental group. In conclusion. propofol used as a single anesthetic is a satisfactory technique for ENT surgery of short duration in children.
Cardioprotective effects of carnitine in extensive aortocoronary bypass grafting: a double-blind, randomized, placebo-controlled clinical trial, The cardioprotective effects of carnitine were tested in patients undergoing multiple aortocoronary bypass grafting. Intermittent aortic cross-clamping at 28 degrees C was used. Mean total cross-clamping time was 30 +/- 11 min. Patients were randomized into three groups: a control group receiving placebo (group 1). a group pretreated with 3 g carnitine intravenously before cardiopulmonary bypass (CPB) (group 2). and a group pretreated with 6 g carnitine intravenously (group 3). The markers of myocardial ischemia included levels of adenosine triphosphate. its catabolites. and creatine phosphate in transmural left ventricular biopsy specimens taken at the beginning and end of CPB. as well as hemodynamic recovery during weaning from CPB and for the next 24 h. The intravenous infusion of carnitine (3 or 6 g) had no hemodynamic effect. At the end of CPB myocardial tissue levels of adenosine triphosphate and creatine phosphate did not differ significantly among the groups (P greater than 0.05). Recovery of cardiac function during weaning from CPB and for the following 24 h was similar in all three groups (P greater than 0.05). It is concluded that pretreatment with carnitine neither facilitates weaning from cardiopulmonary bypass in patients undergoing aortocoronary bypass surgery nor favorably affects hemodynamic function during the next 24 h.
Anterior fontanel pressure and visual evoked potentials in neonates and infants undergoing profound hypothermic circulatory arrest, To determine the effects of cardiopulmonary bypass with profound hypothermic circulatory arrest (PHCA) on anterior fontanel pressure (AFP) and visual evoked potentials (VEPs). 21 neonates and infants undergoing cardiopulmonary bypass (CPB) with PHCA for surgical correction of congenital heart defects were studied. Mean (+/- SD) minimum nasopharyngeal. esophageal. and rectal temperatures of 16.4 +/- 2.2. 11.2 +/- 2.7. and 17.7 +/- 1.9 degrees C. respectively. were achieved for a mean duration of PHCA of 51.6 +/- 18.7 min. AFP increased significantly above pre-CPB values for the first 21.7 +/- 8.1 min of rewarming. The duration of this increase in AFP was related logarithmically and directly to the product of the nasopharyngeal temperature (NPT) at the end of PHCA and the duration of PHCA (r2 = 0.82. P less than 0.0001). Nineteen of these patients had simultaneous monitoring of VEPs. The latency of both the N70 and P100 components of the VEPs increased as temperature decreased. The cerebral perfusion pressure was linearly and inversely related to the AFP (r2 = 0.72. P less than 0.01). The VEPs disappeared as a nasopharyngeal temperature (NPT) of 18.9 +/- 2.8 degrees C and reappeared after 21.9 +/- 8.8 min post-PHCA at an NPT of 32.8 +/- 1.4 degrees C. There was no significant difference between duration of increased AFP (20.9 +/- 8.1 min) and the duration of absence of VEPs during the post-PHCA period. The duration of increased AFP correlated linearly and directly with the duration of absence of VEPs (r2 = 0.84. P less than 0.005). These data demonstrate that transient neurophysiologic dysfunction occurs after PHCA. This dysfunction is related to the duration of elevation of the AFP and cannot be explained solely by a temperature effect.
hemofiltration reverses left ventricular dysfunction during sepsis in dogs, Depressed left ventricular (LV) contractility in sepsis has been ascribed to the presence of circulating cardiodepressant substance (filterable cardiodepressant factor in sepsis [FCS]); however. this finding is controversial. The authors hypothesized that if a decrease in LV contractility indeed occurred due to a circulating depressant substance. then removal of this substance by hemofiltration would reverse by dysfunction. In this study. LV mechanics were examined before and after hemofiltration in anesthetized dogs during continuous intravenous infusion of live Escherichia coli. Left ventricular anterior-posterior and apex-base dimensions were measured by subendocardial ultrasonic crystal transducers implanted 4 weeks before the experiments. Left ventricular contractility was determined from the end-systolic pressure-dimension relationship. The slope of this relationship (Emax) is an index of contractility. After 4 h of sepsis. Emax was reduced by one half. Hemofiltration resulted in a return of Emax to control values. The FCS activity in the plasma was also assessed by the percent reduction in isometric contraction of electrically stimulated. isolated right ventricular trabeculae obtained from nonseptic dogs. The FCS activity reached a peak 4 h after sepsis and was reduced after 2 h of hemofiltration. The results show that during experimental sepsis. a circulating substance of less than 30.000 d produces a decrease in LV contractility and that this LV dysfunction may be improved by hemofiltration.
Endogenous vasopressin supports blood pressure and prevents severe hypotension during epidural anesthesia in conscious dogs, To evaluate whether. and to what extent. release of endogenous vasopressin supports blood pressure when efferent sympathetic drive is blocked by epidural anesthesia. the authors studied the effects of high epidural anesthesia alone and when vasopressin was prevented from acting at its vascular (V1)-receptor in six awake. trained. unsedated dogs. On different days. the same dose of 0.5% bupivacaine (8-13 ml) was injected epidurally in a randomized fashion either in the presence or absence of (V1)-vasopressin receptor blockade. and the effects were evaluated on cardiovascular (arterial blood pressure. heart rate) and respiratory (blood gases. oxygen consumption) variables. and on plasma concentrations of vasopressin and renin. Results were also contrasted to those obtained after epidural injection of saline alone (placebo) in the same dogs. When endogenous vasopressin was prevented from acting by intravenous pretreatment with a specific V1-receptor antagonist (beta-mercapto-beta. beta-cyclopenta-methylene-propionyl-O-Me-Tyr-Arg-Vasopressin). epidural anesthesia resulted in a rapid and sustained 35% decrease in mean arterial blood pressure from 92 mmHg +/- 5 SE to 60 mmHg +/- 4. In contrast. only a 14% decrease in mean blood pressure from 92 mmHg +/- 5 to 79 mm Hg +/- 6 was noted after epidural anesthesia alone. This difference between groups was statistically significant (P = 0.0001). The V1-receptor blockade alone had no detectable effect. Vasopressin plasma concentrations significantly increased from 3.4 +/- 0.3 pg.ml-1 to 16.2 +/- 3.2 pg.ml-1 after epidural anesthesia but did not change after epidural saline.
Resistance to d-tubocurarine in lower motor neuron injury is related to increased acetylcholine receptors at the neuromuscular junction, The hypothesis that lower motor neuron injury. with its associated proliferation of acetylcholine receptors (AChR). induces resistance to the neuromuscular effects of d-tubocurarine (dTC) was tested in the rat. The left gastrocnemius was denervated by a 75-80% lesion of the sciatic nerve. The effective dose for 95% twitch depression (ED95) was studied in the denervated gastrocnemius and compared to the contralateral undenervated and sham-injured (control) gastrocnemius muscles approximately 2 weeks after injury. The AChR number was quantitated by the specific ligand 125I-alpha-bungarotoxin (125I-alpha-BT). Plasma dTC concentrations. measured by high-performance liquid chromatography (HPLC). were correlated to twitch tension during spontaneous recovery from neuromuscular blockade in the denervated animal. The ED95 (mean +/- SE) of dTC for the denervated leg was significantly (P less than 0.05) higher (0.26 +/- 0.06 mg.kg-1) than contralateral (0.16 +/- 0.03) and sham-operated left (0.13 +/- 0.03) legs. The twitch tension recovered to 50% of control twitch height at significantly (P less than 0.05) higher plasma dTC concentrations in the denervated (0.78 micrograms.ml-1) compared to contralateral (0.24 micrograms.ml-1) limb. The AChR number was significantly increased in the denervated limb (1041 +/- 96 fmol.mg protein-1) compared to contralateral right (109 +/- 4) and control left limb (113 +/- 11). There was a significant (P less than 0.05) positive correlation (R2 = 0.73) between ED95 and AChR number; that is. 73% of the variability in ED95 could be explained by changes in AChR. This study. therefore. confirms the hypothesis that proliferation of AChR after nerve denervation results in resistance to the neuromuscular effects of dTC.
Experimental and clinical percutaneous angioscopy experience with dynamic angioplasty, The authors have used ultrathin angioscopes with high optical resolution to assess the effects of dynamic angioplasty in vitro and in vivo. Experimentally. angioscopy was used to study the effects of the 5F "Kensey" catheter in "normal" porcine coronary arteries (NPCA) and postmortem human coronary arteries (PMHCA). In NPCA. the catheter keeps a coaxial position. Intimal flaps (IFs) were seen in 21/23 NPCAs. They occurred with all cam rotation speeds and were usually single and small (less than 25% of lumen). Perforations in patent arteries were rare (1/23). However. when the catheter was forced against the wall by passing through a narrowing of 5F diameter (made by a band ligature). perforations were more common at higher cam speeds. The epicardium remained intact in two thirds of perforations. Angioscopy visualized perforations in only 10% of cases (1/10). the common sign being that of large and multiple intimal flaps. which were often obstructive (5/10). In PMHCAs. angioscopy was more sensitive than angiography in detecting atheromatous lesions. The authors were able to give a better assessment of the effect of dynamic angioplasty on treated lesions. including the demonstration of intimal flaps that were not visible on angiography. In vivo. they have performed percutaneous angioscopy before and after dynamic angioplasty using 8 French Kensey catheters. Angioscopy revealed features that were not shown angiographically.
Optimizing heparin utilization in angiographic flush solutions, Various concentrations of heparin in angiographic flush solutions are employed during angiography. In an effort to determine whether differences in outcome are seen when either high or low concentrations of heparin in angiographic flush solutions are utilized. two groups of patients were evaluated. There was no difference in outcome and a small systemic effect from heparin was seen in both groups. Use of a low concentration of heparin is suggested for routine angiography.
Hindbrain ischemia produced by bilateral vertebral artery occlusion and moderate hypotension in spontaneously hypertensive rats, Hindbrain ischemia was induced by bilateral vertebral artery occlusion and moderate hypotension in spontaneously hypertensive rats (SHRs). Mean arterial blood pressure was lowered to 80 mmHg in SHRs and to 50 mmHg in Wistar-Kyoto rats (WKYs) by a controlled hemorrhage. and then the vertebral artery was bilaterally occluded through alar foramina of the first cervical vertebra. Following vertebral occlusion. blood flow of the cerebellum was significantly decreased to 9.4 +/- 2.0 mL/100g/min (+/- SEM) while flow of the cerebrum remained at 32.1 +/- 5.4 in SHRs. In contrast. cerebellar blood flow in WKYs was preserved at 24.2 +/- 2.9 mL/100g/min. Brain lactate. pyruvate. and adenosine triphosphate (ATP) were determined in SHRs after sixty minutes of hypotension with or without vertebral occlusion. Although infratentorial metabolites were actually unaltered in rats with hypotension alone. infratentorial lactate and lactate/pyruvate ratio significantly increased to 14.38 +/- 3.61 mmol/kg and 67.7 +/- 12.1. respectively. with a concomitant decrease in ATP in SHRs with hypotension and vertebral occlusion. Bilateral vertebral artery occlusion. together with moderate hypotension. was shown to produce a marked reduction of cerebellar blood flow and to induce ischemic metabolic changes in the infratentorial brain in SHRs.
Comparison of standard one-minute treadmill exercise and strandness test (absolute walking distance) in relation to site of lesion, walking distance, and diastolic blood flow velocity (Doppler curves), In 215 outpatients suffering from occlusive arterial disease of the lower limbs the authors compared the decrease in the ratio of ankle systolic pressure to brachial systolic pressure according to whether the treadmill exercise was limited to one minute or extended until pain forced the patient to stop. After a one-minute walk the pressure index always decreased significantly. especially when walking was restricted. The decrease in the pressure index was generally greater when the exercise was continued until the absolute walking distance. and the recovery time was usually twice as long. The fall in the pressure index was significantly greater for patients with single and multiple iliac stenoses than for those with stenoses at lower levels. In patients having a diastolic blood flow velocity on Doppler curves at rest. not modified by walking. a maximum drop in peripheral pressure was recorded after walking for one minute. In this instance there was no intensification of the decrease in peripheral pressure. unlike in patients without a diastolic blood flow velocity at rest. This one-minute test is not a maximal hemodynamic response. but it is sufficient for the appreciation of ischemia during exercise. according to the different parameters measured.
Use of Doppler flow velocity waveform analysis in detection of initial diabetic microangiopathy, Doppler flow velocity waveform analysis (FVWFA). recorded from the dorsalis pedis artery (DPA) and the radial artery (RA). was performed on 36 women in attempting to detect an initial diabetic microangiopathy (DM). The study comprised two groups of women affected by non-insulin-dependent diabetes mellitus. 6 patients (pts) of reproductive age (1). 12 pts in menopause (II). and two groups of age-matched healthy controls (C) (III and IV). Clinical signs of initial DM were present in group I. All the examined pts were nonsmokers and normotensive and without cardiopathy. signs of diabetic macroangiopathy. collagen vascular disease and/or Raynaud's phenomenon. and renal failure. Four waveform dimensions capable of separating different degrees of peripheral obstructive arteriolar disease were determined on velocity tracing and the results used in a single best discriminant equation. The resultant discriminant score (DS). derived by FVWFA on DPA. showed a highly accurate rate of separating the young pts with DM from both C and the pts in menopause without DM. Furthermore. the resultant DS was statistically not different in groups II. III. and IV. In conclusion. FVWFA on DPA. in this experience. has proved to be an accurate and sensitive method in the detection of initial DM.
Coronary artery dissection--a case report, Coronary artery dissection. both spontaneous and catheter-induced. is associated with a significant morbidity and mortality. The authors present a case of a middle-aged woman with spontaneous right coronary artery dissection causing inferior wall myocardial infarction and left coronary artery dissection at the time of coronary arteriography. It is suggested that emergency aortocoronary bypass surgery be performed preceded by insertion of an intra-aortic balloon in acute evolving cases where coronary anatomy is favorable to limit infarction and avert loss of life.
Underestimation of treatment effect in crossover trials, In crossover trials each subject serves as his own control. For the study of cardiovascular diseases such as hypertension and angina pectoria. properly designed crossover studies are preferred to parallel studies. There is a considerable between-subject variability of symptoms in some of these conditions. Bias due to this is eliminated by the use of a crossover design. However. a problem is the so-called treatment-by-period interaction. The present study analyzes the potential influences of this on the outcome of the trial. Physical carryover effect. defined as a physical effect of the first treatment period carrying on into the second. tends to minimize differences between two consecutive treatment periods. So does the frustrating experience of an inactive agent in the first treatment period. Outside influences such as the change of the seasons may affect lengthy crossover trials in a similar way. The author concludes that the treatment effect in a crossover trial tends to be underestimated. The current concept that reports of clinical trials are generally biased toward an exaggeration of treatment effects does not seem to apply to crossover trials.
Electrocardiographic abnormalities in cerebrovascular accidents, The electrocardiographic abnormalities found in 100 patients with acute cerebrovascular disease and previously normal hearts are described. The abnormalities were more often seen in patients with intracerebral and subarachnoid hemorrhages. The most common changes were Q-Tc Prolongation and ST segment and T wave abnormalities. The mechanisms of these electrocardiographic abnormalities appear to be multiple.
Hemodynamic effects of nebivolol at rest and on exertion in patients with heart failure, Nebivolol is a novel B-1-adrenoceptor-blocking drug with an unusual hemodynamic profile unlike classical B-blockers. In dogs and in healthy volunteers it decreases blood pressure and heart rate but improves left ventricular function. The authors studied 10 male patients with coronary artery disease and heart failure (ejection fraction mean = 46%). A Swan-Ganz catheter was placed into the pulmonary artery. and the mean blood pressure. the heart rate. the pulmonary artery pressure. the pulmonary wedge pressure. the right atrial pressure. the cardiac output. and the stroke volume were measured at rest and on exertion before and after seven days' treatment with oral nebivolol (5 mg/day). While the blood pressure and the heart rate decreased significantly. the pulmonary artery and wedge pressures. as well as the right atrial pressure and the cardiac output. did not change during treatment. The stroke volume increased significantly. The maintained cardiac output cannot be explained by any changes in preload or afterload; instead a positive inotropic mechanism must be assumed. Unlike other B-blockers it seems to be possible to treat patients with heart failure with nebivolol without causing the hemodynamic situation to deteriorate.
Effects of diltiazem on the functional recovery of the myocardium at organ and cellular level during prolonged hypothermic ischemic cardiac arrest, The effectiveness of diltiazem on the functional recovery of the heart. calcium (Ca++) uptake and binding. Ca++ ATPase of cardiac sarcoplasmic reticulum (SR). and MB fraction of creatine kinase (MBCK) of coronary sinus blood was investigated after one and a half hours of reperfusion following three hours of ischemic cardiac arrest. The dogs were divided into three groups: group I. sham bypass; group II. cold crystalloid cardioplegia; and group III. cold crystalloid cardioplegia with diltiazem. There was a decrease in aortic pressures left ventricular pressure development (dp/dt). left ventricular work index (LVWI). total systemic vascular resistance (TSVR). and left ventricular systolic pressure (LVSP) in the sham bypass group. There was a decrease in cardiac index (CI). LVWI. and mean right atrial pressure (mRAP) and an increase in TSVR and pulmonary vascular resistance (PVR) in group II as compared with group I. Although there was a tendency for a decrease in the indices of myocardial contractility in group II. they were not significantly different from those in group I. The indices of myocardial contractility. CI. and LVWI in group III were slightly higher than in group II. but they were not significantly different from each other. The values for calcium uptake by SR in groups II and III were similar but significantly lower than those in group I. Calcium binding in group III was significantly lower than that in group I. Calcium ATPase of SR in the three groups were similar. Although MBCK increased in all the groups. the increases were not significantly different among the three groups. The results of this study indicate that cold crystalloid cardioplegia with diltiazem was not better than cold crystalloid alone in preserving the cardiac contractility and cellular function during prolonged ischemic cardiac arrest. However. the cardiac function in terms of cardiac index was better preserved with diltiazem.
Successful direct PTCA on LAD after first episode of acute myocardial infarction: does it improve cardiac function, Patients who received direct percutaneous transluminal coronary angioplasty (PTCA) after acute mycardial infarction and maintained potency but with unimproved cardiac function were studied. In 15 patients. the first episode of acute myocardial infarction was caused by a left anterior descending branch lesion; 11 had an ejection fraction of 50% or more in the left ventriculogram in the follow-up period (improved group). and 4 patients had ejection fraction of less than 50% (unimproved group). There was so significant difference between the groups in the mean time between the onset of infarction and revascularization (improved group. 259.3 +/- 76.9 min; unimproved group. 168.0 +/- 101.6 min) or in the sigma Q. which was the sum of the Q wave depth of V2. V3. and V4 at the time of admission (improved group. 12.1 +/- 15.6 mm; unimproved group 29.8 +/- 13.4 mm). The maximum creatine kinase concentration was significantly higher in the unimproved group (improved group 2670 +/- 893 IU/L; unimproved group. 7243 +/- 1928 IU/L. p less than 0.05). and the time taken from the onset to reach its peak was significantly shorter in the unimproved group (improved group. 13.0 +/- 5.1 hr; unimproved group. 6.8 +/- 1.3 hr. p less than 0.05.) These results suggest the probability of sudden deterioration of myocardium. and factors other than microcirculatory thromboembolism should be considered as the cause of unimproved cardiac function after successful direct PTCA.
Separation of a ruptured angioplasty balloon with successful percutaneous retrieval--a case report, A case of ruptured angioplasty balloon with complete separation from the catheter is presented. Successful percutaneous retrieval of the balloon with endoscopic biopsy forceps was performed.
Effects of a 2.15-micron laser on human atherosclerotic xenografts in vivo, The thulium-holmium-chromium:yttrium-aluminum-garnet (THC:YAG) laser has a tissue effect similar to that of the CO2 laser. with the advantage of transmissibility through flexible fibers. The authors used a human-rabbit xenograft model to evaluate the thrombotic and healing responses of atherosclerotic vessels subjected to laser energy. Occluded atherosclerotic human coronary artery segments were recanalized in vitro by use of the THC:YAG laser. Destruction of plaque by the laser was achieved with minimal collateral thermal damage. These vascular segments were then transplanted into the rabbit abdominal aorta. The authors observed that the luminal surface of the lased vessels was more thrombogenic than that of the nonlased control vessels. However. occlusion of the lased vessels did not occur. Repair of laser-treated tissue progressed until a mature. nonthrombogenic fibrin-platelet aggregate was adherent to the luminal wall. Overall. the lased vessels behaved in a fashion similar to the nonlased control vessels. On the basis of these results. the authors believe that the THC:YAG laser may have use in human angioplasty.
Intraoperative coronary excimer laser angioplasty: preliminary clinical experience, Diffuse coronary artery atherosclerosis is generally recognized as a deterrent to successful revascularization if it cannot be adequately treated. Mechanical endarterectomy can be useful. but it is not the optimal solution owing to the associated higher incidences of perioperative infarction and mortality. The use of laser energy as an endarterectomy tool appears promising. To investigate the application of excimer laser radiation to intraoperative coronary artery endarterectomy. 15 stenotic lesions in 13 patients were treated with excimer irradiation during coronary artery bypass grafting. Eleven (73%) of the lesions were enlarged by the excimer probe (6 of the successes were in calcified lesions). The 4 arteries not enlarged by the excimer laser all demonstrated calcified lesions. There were 3 perforations and 2 dissections. all but 1 in heavily calcified arteries. The results of this phase 1 safety and efficacy study indicate that excimer irradiation can recanalize most arteries. including total and subtotal occlusions and some calcified lesions. Further evaluation with better delivery systems is needed to determine whether the perforation rate can be reduced.
Intravascular ultrasound: a new potential modality for angioplasty guidance, Current angioplasty devices are limited by significant rates of arterial perforation and dissection. due to inadequate techniques of guidance. and by restenosis. which may be partly attributed to inadequate debulking of lesions. This paper describes the authors' initial experience in-vitro and in-vivo with intravascular ultrasound as a possible method of enhancing the three-dimensional guidance of devices through atherosclerotic obstructions. Using an in-vitro model they correlated the dimensions and histologic morphology of animal and human arteries with ultrasound images of the specimens. Additional in-vivo evaluations of this technology in canine arteriosclerotic and human atherosclerotic arteries preliminarily support the hypothesis that intravascular ultrasound defines the transmural arterial morphology and may enhance the accuracy of angioplasty procedures. Simultaneous imaging with angioscopy and intravascular ultrasound is demonstrated as a potential method of accurately defining both intraluminal and transmural arterial wall characteristics.
Additive effect of albuterol and ipratropium bromide in the treatment of bronchospasm in children, Inhaled albuterol (A) (salbutamol) alone and albuterol plus ipratropium bromide (IB) were administered to 12 asthmatic children. Following administration of A alone or in combination with IB. there was a significant increase in FEV1 and FEF. Significant statistical difference in favor of the association A plus IB was observed at 120 and 240 minutes for FEV1 and in the period 120. 180. and 240 minutes for FEF. The additive effect was present both in the large and small airways. The short-lived additive effect of A plus IB suggests the opportunity to increase the frequency of drug administration in patients with severe bronchial obstruction.
Effects of albuterol and procaterol on exercise-induced asthma, Procaterol and albuterol. beta agonists. were studied using a placebo-controlled. repeated exercise challenge design in order to assess their duration of effectiveness in both bronchodilation and in modifying exercise-induced asthma (EIA). Fifty-three subjects aged 12 to 50 years who had at least a 20% drop in FEV1 during a screening exercise tolerance test were entered. Subjects took two inhalations of procaterol (10 micrograms/inhalation). albuterol (90 micrograms/inhalation). or placebo. Thirty minutes later they exercised on a treadmill at a workload sufficient to induce greater than or equal to 80% aerobic O2 consumption for six minutes. Pulmonary function was measured before and serially for 30 minutes after exercise. The same exercise challenge was repeated three. six. and nine hours after drug administration. Both procaterol and albuterol bronchodilated and modified EIA at 30 minutes and three hours. mean drops in FEV1 being 8.2 and 9.7% respectively at 30 minutes and 16.8 and 16.3% at three hours. This was compared with placebo falls of 30% and 26%. At six hours the subjects' response was similar after both procaterol and albuterol. and fewer subjects had a 20% fall in FEV1 than with placebo. although protection afforded by both beta agonists was substantially less than at three hours. Both drugs were tolerated well.
Basophil histamine release and airway response to mite allergen in atopic dermatitis, Twelve patients with atopic dermatitis (AD) were subjected to in vitro histamine release from peripheral blood leukocytes (basophils) and in vivo bronchial inhalation challenge using house dust mite (Dermatophagoides farinae) allergen. Not only seven patients with asthmatic history but also five patients without asthma responded to both the in vitro and the in vivo challenges. A significant correlation was observed between HR30 (a mite concentration producing a 30% release of total cellular histamine) and PC20 allergen (a mite concentration producing a 20% fall in FEV1). There was also a significant correlation between MHR (maximal histamine release) and the maximal fall in FEV1. The relationship held for both AD patients with asthma and without asthma. These results suggest that histamine release induced by the house dust mite allergen is a good in vitro test for predicting the bronchial response to this allergen. They also suggest that these tests are not disease specific. but are valuable in evaluating the degree of atopic state in a subject.
Exercise-induced biphasic responses and methacholine reactivity in asthma, Biphasic (early and late) asthmatic responses to exercise occurred in seven of 43 children with reproducible exercise-induced asthma. As biphasic allergen-induced asthma is associated with a prolonged increase in nonspecific bronchial hyperreactivity. this effect was not sought in the 43 asthmatic children. There was no significant change in methacholine PD20 FEV1 before and after exercise challenge. either in children who had early. or early and late. exercise responses. Late reactions after allergen exposure are likely to be of considerable clinical significance in relation to the enhancement of bronchial responsiveness. It is reassuring that this is not the case for exercise challenge. as it would have major implications in relation to the recommendations that asthmatics should participate in normal activities and even in training programs. Furthermore. it suggests that there are differences between the pathophysiology of asthma induced by exercise and that produced by allergens.
Dust mite assays in clinical allergy practice: mite antigen exposures among skin test positive patients in Kansas, We have attempted to determine whether sensitive monoclonal antibody assays for Dermatophagoides mite antigens Der p I and Der f I can be carried out in a private clinical allergy practice laboratory. to ascertain incidence of significant home mite exposure in dust samples from patient homes in Kansas. and to consider whether such information impacts on patient management. We analyzed 152 dust samples from 62 patient homes. All patients were skin prick test positive for one or both common mite species available for skin testing. and had potentially relevant histories. Der p I and Der f I antigen levels were added together. and levels above 2 micrograms/g of dust were considered "positive." By this definition. elevated levels were found in at least one sample from 48 of 62 homes tested (77%); however. 61% of mattress samples tested. 41% of carpet samples. and 54.5% of furniture samples had levels below those considered likely to cause symptoms. Only 13 of 152 samples yielded Der p I levels above 2 micrograms/g. We conclude that monoclonal antibody assays for Der p I and Der f I antigens can be performed in a well-equipped office laboratory staffed by trained medical technologists. that Der f I is the predominant mite species in Kansas. and that data derived from mite assays may be important in treatment planning for patients suspected of having mite-related allergy symptoms.
A controlled, double-blind study of the effect of quazolast on nasal challenge with ragweed antigen, Quazolast is a potent mediator release inhibitor as determined by in vitro and in vivo testing. A placebo-controlled. double-blind. two-way crossover study compared the safety and efficacy of Quazolast. 400 mg bid orally. with placebo in 23 subjects with ragweed (RW) allergy. out of season. Subjects were assigned to two 7-day treatments in a random sequence with an 8-day washout. Subjects were challenged on days 1 and 7 of each trial with serial dilutions (10. 100. 1000. 1350. and 2700 PNU/0.135 mL) of RW. using metered pump spray bottles. (two sprays delivered 0.135 mL). preceded by saline control. Efficacy evaluation consisted of nasal flow rates measured by rhinomanometry. sneeze counts. nasal itchiness scores. and weight of nasal secretions during challenges. During Quazolast treatment. subjects had significantly lower (P less than .05) mean percent decreases in nasal flow rate at 1350 and 2700 PNU. Nasal itchiness scores were significantly lower (P less than .05) during Quazolast treatment than at placebo at 1000. 1350. and 2700 PNU. Although sneeze counts were lower during treatment with Quazolast than with placebo. the results did not reach statistical significance. No significant improvement was seen in the weight of nasal secretions. Adverse experiences. clinical laboratory results. and physical examinations were unremarkable. posttreatment. Quazolast was superior to placebo in protecting against nasal congestion and nasal itchiness after ragweed nasal challenge.
Effect of exercise on complement activity, Complement measurements of C1. C1q. C2. C3. C4. C5; the anaphylatoxins. C3a. C4a. and C5a; and total hemolytic activity of the classical and alternative pathways were made in 26 experienced adult runners before and after shortterm aerobic exercise. The baseline results were compared with those of nonexercising age-matched controls. In most subjects tested. running resulted in nanogram increases in C3a and C4a with corresponding decreases in the hemolytic activity of C4 (C4H). Baseline values of C3 and C4H were decreased significantly in runners when compared with nonexercising controls. Preliminary studies measuring the effect of exercise on C3a levels were also done in three asthmatic runners. Mean resting and postexercise levels. and exercise-induced increases in C3a anaphylatoxin in the asthmatic subjects were significantly higher than in the nonasthmatic subjects. The findings indicate that short-term exercise results in the activation of C3 and C4 and subsequent generation of C3a and C4a anaphylatoxins. and suggest that both activation of the classical pathway of complement and a selective downregulation of C3 production may occur in persons regularly engaged in aerobic exercise. The exaggerated generation of C3a by asthmatic subjects during exercise raises the possibility that anaphylatoxins play an etiologic role in exercise-induced asthma.
Effect of vitamin C on histamine bronchial responsiveness of patients with allergic rhinitis, The effect of acute oral administration of 2 g vitamin C on bronchial responsiveness to inhaled histamine in 16 patients with allergic rhinitis was compared with placebo on two consecutive days in a double-blind. crossover design. The PC15FEV1 was significantly increased one hour after treatment with vitamin C but not after placebo.
Bronchoconstriction induced by spirometric maneuvers in patients with bronchial asthma, We analyzed forced expiration maneuver-induced bronchoconstriction in 14 asthmatic patients and in seven normal subjects by breaking down the forced expiration maneuver of spirometry (the FVC maneuver) into two phases: a slow. deep inspiration to the total lung capacity (TLC) (the DI maneuver) and a forced expiration to the residual volume (RV) (the PFV maneuver). Specific airway conductance (sGaw) was measured at functional residual capacity (FRC) after each of the three maneuvers. All of the maneuvers caused the greatest bronchoconstriction immediately after completion of the maneuver. The mean decreases in the sGaw immediately after the FVC. DI. and PFV maneuvers were 45.0 +/- 6.6 (SD)% (P less than .001). 29.6 +/- 5.3% (P less than .001). and 16.7 +/- 5.3% (P less than .03). respectively. The decrease in sGaw by the FVC maneuver was very close to the combined algebraic sum of the DI maneuver and the PFV maneuver. The normal subjects did not show any changes in the sGaw by any of the maneuvers. The inhalation of albuterol almost abolished the response of bronchoconstriction to any of the three maneuvers. but inhalation of an anticholinergic agent. ipratropium bromide. did blunt the response. This study suggests that forced expiration maneuver-induced bronchoconstriction in asthmatics can be caused not only by deep inspiration to the TLC but also by forced expiration to the RV. and that the bronchoconstriction may be brought about mainly by an increase in parasympathetic activity.
A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department, STUDY OBJECTIVE: To determine the effectiveness of IV metoclopramide as sole therapy for relieving the pain of acute migraine in the emergency department. DESIGN: Prospective study. Fifty patients were divided randomly into subjects and placebo controls with blinding of the treating physician and the patient. PARTICIPANTS: Patients presenting to the ED with migraine requiring parenteral treatment. INTERVENTIONS: Subjects received 10 mg IV metoclopramide and controls received IV normal saline; patient assessment of relief was followed by means of a numerical scale. MEASUREMENTS AND MAIN RESULTS: Sixty-seven percent of subjects compared with 19% of controls had effective pain relief within one hour (P less than .001). Subjects achieved mean relief scores of 2.46 compared with 1.69 for controls (P less than .02). No significant side effects were observed. CONCLUSION: IV metoclopramide as a single agent is effective and safe therapy for migraine in the ED.
Improved survival and reduced myocardial necrosis with cardiopulmonary bypass reperfusion in a canine model of coronary occlusion and cardiac arrest, STUDY QUESTION: Does cardiopulmonary bypass (CPB) improve resuscitation rates and limit infarct size after cardiac arrest and acute myocardial infarction? DESIGN: Controlled randomized trial with all animals undergoing left anterior descending coronary artery occlusion and subsequent ventricular fibrillation and resuscitation. All animals were supported for four hours after resuscitation in an intensive care setting. INTERVENTION: Group 1 (eight) was resuscitated with standard external CPR and advanced life support. Group 2 (eight) was resuscitated with CPB. MEASUREMENTS AND MAIN RESULTS: Group hemodynamic. resuscitation variables. number resuscitated. and number of four-hour survivors were compared. Ischemic and necrotic myocardial weights were determined with histochemical staining techniques in four-hour survivors. Infarct size was measured as the ratio of necrotic weight to ischemic weight. Significantly fewer dogs were resuscitated in group 1 (four of eight) than in group 2 (eight of eight) (P less than .05). Group 2 survivors required significantly less epinephrine and lidocaine than group 1 survivors (P less than .05) and higher aortic diastolic and coronary perfusion pressures after CPB (P less than .001). The ratio of myocardial necrotic weight to ischemic weight at four hours was 0.82 +/- 0.25 in group 1 and 0.22 +/- 0.25 in group 2 (P less than .05). However. collateral blood flow was not measured in this study. CONCLUSION: This pilot study further substantiates the improvement in resuscitation rates obtainable with CPB. CPB may also limit infarct size during the postresuscitation period and requires further study.
Interaction between whole-bowel irrigation solution and activated charcoal: implications for the treatment of toxic ingestions, STUDY OBJECTIVES: The purpose of this study was to address the issues of safety and efficacy of combining whole-bowel irrigation and activated charcoal administration for the treatment of toxic ingestions. STUDY DESIGN: Two in-vitro studies were performed. In the first. serial ratios of polyethylene glycol (PEG) and activated charcoal (AC) powders were added to water and the solutions were analyzed for PEG concentration and osmolality. In the second. serial ratios of a pharmaceutical bowel irrigation solution and an AC preparation were combined with a constant amount of salicylic acid. Solution osmolalities. PEG. and salicylic acid concentrations were then quantified. RESULTS: Adsorption of PEG powder by AC was demonstrated; however. changes in solution osmolality were negligible. Thus. concurrent administration of these therapies appears safe. However. combining bowel irrigation solution with AC resulted in decreased salicylic acid adsorption. This was especially so with smaller amounts of AC that would pertain more to the smaller doses of AC used for multiple-dose charcoal therapy. CONCLUSION: If these in-vitro data are applicable to overdose patients. the administration of a routine initial charcoal dose to those who will be treated with whole-bowel irrigation would be appropriate. However. it is unlikely that the addition of multiple-dose charcoal therapy to whole-bowel irrigation would provide additional benefit for the patient.
Whole-bowel irrigation as treatment for zinc sulfate overdose, A 16-year-old boy ingested approximately 50 zinc sulfate tablets (ZnSO4; 500-mg tablets). After spontaneous emesis. ipecac-induced emesis. and orogastric lavage. an abdominal radiograph performed four hours after ingestion still demonstrated approximately 50 ZnSO4 tablets within the stomach and three pills within the colon. Whole-bowel irrigation was begun with a polyethylene glycol lavage solution (PEG; Golytely) that was administered through a nasogastric tube; within one hour. the patient began producing a rectal effluent that contained pills. The patient remained asymptomatic throughout whole-bowel irrigation. Stool guaiac tests were negative. The serum chloride. however. increased from 105 to 127 mEq/L. Follow-up kidney. ureter. and bladder studies demonstrated the clearance of the zinc tablets from the gastrointestinal tract during the next 24 hours.
Effect of recombinant hirudin, a specific inhibitor of thrombin, on endotoxin-induced intravascular coagulation and acute lung injury in pigs, We hypothesized that thrombin activation may play a prominent role in endotoxin-induced secondary organ failure. such as acute lung injury. To test this hypothesis. we administered a thrombin-specific inhibitor. recombinant hirudin. in endotoxemic pigs. The pigs were anesthetized. mechanically ventilated. and prepared with Swan-Ganz and extravascular lung water (EVLW) catheters. A total of 18 randomly selected animals received a pretreatment of 1.000 U/kg of hirudin. followed by a continuous infusion over 6 h of 500 U/kg/h given simultaneously with the infusion of 10 micrograms/kg/h of Salmonella abortus equi endotoxin. Another 18 animals received a continuous infusion over 6 h of endotoxin but did not receive hirudin. All animals were fluid resuscitated with 17 ml/kg/h of saline for the duration of the experiment. Data are expressed as the mean (95% confidence interval). Hirudin reduced the endotoxin-induced consumption of plasma fibrinogen from -110 (-138 to -82) mg/100 ml to -39 (-67 to -12) mg/100 ml (p = 0.0001) and endotoxin-induced increases in the soluble fibrin in plasma from 434 (369 to 499) ng/ml to 236 (171 to 300) ng/ml (p = 0.0002). These data suggest an effective inhibition of the endotoxin-generated thrombin by hirudin. Furthermore. hirudin significantly reduced endotoxin-induced increases in pulmonary vascular resistance from 32 (27 to 37) kdyn x s x cm-5 x kg to 20 (15 to 25) kdyn x s x cm-5 x kg (p = 0.0015) and increases in EVLW from 15.4 (13.2 to 17.6) ml/kg to 12.2 (10.0 to 14.4) ml/kg (p = 0.0299).
Effects of deep inhalation during early and late asthmatic reactions to allergen [published erratum appears in Am Rev Respir Dis 1991 Feb;143(2):451, Eighteen asthmatic patients with a biphasic asthmatic reaction to house dust mite were studied. The effect of deep inhalation (DI) was quantitated by comparing the maximal expiratory flow at 40% (MEF40) of vital capacity from partial (P) and maximal (M) flow-volume curves. and specific airway conductance (SGaw) before and after DI (SGawDI). At baseline. the ratio MEF40M/P was significantly larger than unity (1.45 +/- 0.26 SD). whereas the ratio SGawDI/SGaw was not significantly different from unity (0.92 +/- 0.24). During early phase reaction. both MEF40M/P and SGawDI/SGaw were significantly increased to 2.66 +/- 0.97 and 1.96 +/- 0.47. respectively. During late phase reaction. when the FEV1 values were similar to those observed during early phase reaction. MEF40M/P and SGawDI/SGaw were 1.86 +/- 0.46 and 1.43 +/- 0.29. respectively. significantly higher than the values at baseline but significantly lower than those during early phase reaction. Similar results were obtained in a subgroup of nine patients when SGaw values during the late phase reaction were similar to those during the early phase reaction. We conclude that DI has a different effect during early and late asthmatic reactions. suggesting a different ratio of airway to parenchymal hysteresis. This may result from an increased parenchymal hysteresis (more peripherally located bronchial obstruction) or a decreased airway hysteresis (prominent airway inflammation) during the late phase reaction.
The effect of repetitive exercise on airway temperatures, To determine if a relationship exists between intra-airway thermal events and the reduction in pulmonary mechanics that occur in asthmatics when they perform repetitive exercise. we recorded intrathoracic airstream temperatures in seven subjects during and after two identical bouts of cycle ergometry performed 30 min apart. From these data. global and regional thermal energy exchanges were calculated. Inspired air conditions. work loads. and minute ventilations were held constant for both trials. Pulmonary mechanics were measured prior to and serially after each challenge. As expected. the second provocation produced a smaller response than did the first. In association with these mechanical changes. the second challenge also produced less airway cooling and slower rewarming in the central airways. Hence. repetitive exercise trials performed over short intervals attenuate the essential thermal gradients necessary to produce obstruction. To the extent that these differences in intra-airway temperature reflect changes in perfusion. our data raise the possibility that the responsivity of the bronchial microcirculation of asthmatics may be altered by repetitive exercise.
Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics, Several short-term studies have shown that inhaled steroids can reduce airway hyper-responsiveness in asthma. To evaluate whether prolonged treatment can bring about full recovery. this double-blind. randomized. controlled trial examined the effect of budesonide. 400 micrograms daily for 1 yr. on airway hyperresponsiveness. The time course and characteristics of improvements and associated changes in clinical asthma severity were also evaluated. Thirty-two stable adult asthmatics. requiring bronchodilators alone. were selected. Before and monthly throughout the study. airway responsiveness to methacholine was measured and clinical asthma severity assessed by questionnaire. daily bronchodilator use. and number of asthma exacerbations. Patients receiving budesonide showed a fourfold mean improvement in airway responsiveness compared with those receiving placebo (p less than 0.0005). whose responsiveness remained very stable. Fifteen of the 16 budesonide subjects improved and 5 returned to the normal range. Largest improvements occurred during the first 3 months but. in some. were still progressing slowly at 1 yr. Improvements in responsiveness were accompanied by significant improvements in asthma symptoms. bronchodilator use. and number of asthma exacerbations. The results show that regular. prolonged use of inhaled steroid can produce marked improvements in airway hyperresponsiveness. sometimes with full resolution. and these improvements are accompanied by clinically significant improvements in clinical asthma.
Asbestos content of lung tissue, lymph nodes, and pleural plaques from former shipyard workers, Autopsy samples from eight former shipyard workers were collected from lung parenchyma. tracheal lymph nodes. and pleural plaques. The tissue from each respective area was prepared by a modified bleach digestion technique. and the residue was collected on a 0.2-micron pore polycarbonate or 0.22-micron mixed cellulose ester filter. Quantitation of ferruginous bodies and uncoated fibers was done by light and transmission electron microscopy. respectively. Differences in the asbestos burden were noted for each site. Ferruginous bodies were observed in both parenchyma and nodes but not in plaques. Three subjects were found to have more ferruginous bodies per gram dry weight in their lymph nodes than in their lung parenchyma. Likewise. all subjects were found to have more uncoated fibers per gram in the nodes than in the parenchyma. Amphibole and chrysotile fibers were noted in the lung and extrapulmonary sites. with chrysotile being the predominant asbestiform in plaques. The majority of the uncoated fibers in both the nodes and the plaques were less than or equal to 5 microns in length. However. some fibers with dimensions conforming to the "Stanton hypothesis" reached both areas. These residual patterns most likely reflect the impact of clearance on lung burden as opposed to the eventual accumulation and stasis in the extrapulmonary areas.
Selective IgG subclass deficiencies and antibody responses to pneumococcal capsular polysaccharide antigen in adult community-acquired pneumonia, We measured the serum concentrations of IgG subclasses in healthy subjects (n = 26) and in patients with community-acquired pneumonia (CAP) on admission (n = 38). at recovery (n = 21). and 9 months after admission (n = 19). Then. in 8 of the control subjects and 15 of the patients. we measured IgG subclasses and mean serum antibody concentrations of pneumococcal capsular polysaccharides before and 3 wk after immunization with a pneumococcal vaccine. Compared to the control subjects. the serum concentration of the IgG2 subclass was lower at admission in patients with CAP of bacterial or unknown cause (p less than 0.005). Concentrations of IgG subclasses in patients did not differ between admission and recovery. or between admission and 9 months later. After vaccination. in both control subjects and patients. there was an increase in the concentrations of IgG2 subclasses (p = 0.01) and antipneumococcal antibodies (p less than 10(-4)). We show that serum IgG2 concentration in patients with CAP of bacterial or unknown cause is lower than in healthy subjects and remains lower for several months. After immunization with a pneumococcal vaccine. the increase in serum concentrations of IgG subclasses and antipneumococcal antibodies in patients does not differ from those in control subjects.
Quantitation of mast cells and eosinophils in the bronchial mucosa of symptomatic atopic asthmatics and healthy control subjects using immunohistochemistry, We have used fiberoptic bronchoscopy to obtain endobronchial biopsies in which mast cells and eosinophils were enumerated using monoclonal antibodies directed against mast cell tryptase (AA1) and the eosinophil cationic protein (EG2). Eleven symptomatic atopic asthmatics treated with beta 2-agonists alone and six normal subjects were studied. Over a period of 2 wk prior to bronchoscopy. patients recorded asthma symptom scores. bronchodilator usage. and twice-daily peak expiratory flow. Five days before bronchoscopy. methacholine responsiveness was assessed. Two biopsies were taken from the subcarinae. one of which was processed into araldite for immunostaining by the streptavidin biotin immunoperoxidase method and the other into Spurr resin for electron microscopy. The number of AA1 staining mast cells present in the bronchial mucosa was not significantly different in the epithelium or submucosa between the asthmatic and the normal subjects. However. in the biopsies from asthmatics. there were significantly greater numbers of EG2-staining eosinophils in the epithelium (median. 1.2/mm versus zero; p less than 0.005) and in the submucosa (median. 50/mm2 versus 1/mm2; p less than 0.001). Electron microscopy showed morphologic features of mast cell and eosinophil degranulation in the asthmatics. No correlation could be established between mast cell or eosinophil numbers and indices of disease activity of PC20 methacholine. which points to the complexity of mechanisms responsible for the symptoms and the airway hyperresponsiveness of asthma.
Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression, In summary. these findings indicate the importance of designing future experiments that delineate between opioid and nonopioid forms of respiratory disease and dysfunction. and the need to identify means of diagnosing them in order to achieve successful recovery. Apparently there is great diversity between animal species in terms of contributions of endogenous opioids to tonic control of ventilation. and future work should strive to identify which species is most appropriate as a model of human ventilatory control and disease. Certain opioid receptor types appear to be linked to independent respiratory functions. For instance. mu receptors in the brain stem produce strong inhibitory actions on respiratory parameters. including RR. VT. VE. and CO2 sensitivity. These effects have been observed in vivo and by electrophysiologic recordings in vitro. Delta receptors may also exert some inhibitory effect on respiration. especially in the NTS. In the CNS. the ventral surfaces of the medulla and pons. especially the NTS and NA. seem to be important sites for opioid-induced inhibition of respiration. whereas the spinal cord probably is not involved in opioid-mediated ventilatory depression. Kappa receptors appear to be devoid of respiratory depressant activity. whereas sigma receptors may stimulate some ventilatory parameters. Morphine and similar pure mu agonists. such as fentanyl and oxymorphine. probably produce their analgesic and respiratory depressant effects through stimulation of mu receptors. Mixed agonists/antagonists that have mu antagonist (or partial agonist) activity plus kappa agonist and/or sigma agonist activity show a ceiling effect for respiratory depression. Future tests need to determine which opioid receptor may be responsible for the ceiling effect. In addition. the effects of mu. delta. kappa. and sigma selective agonists on hypoxic drive should also be determined. as a drug that stimulates hypoxic sensitivity in the face of hypercapnic depression may produce less overall respiratory depression due to counteractive effects. In the future. clinically optimal opiates should have more specificity of action than those available now. This may be achieved by creating drugs selective for single receptors or by creating drugs with desirable combinations of receptor selectivities. The combinations of mixed agonists/antagonists with pure mu agonists currently in use today are promising. as they provide analgesia with reduced respiratory depression. In the early days of opiate research and development. combination drug regimens were thoroughly tested to determine the "ideal ratios" that would retain analgesic properties but not the other undesirable effects such as respiratory depression (196).(ABSTRACT TRUNCATED AT 400 WORDS).
Management of the acute abdomen complicating oral anticoagulation therapy, Acute abdominal pain in the patient receiving oral anticoagulants poses a difficult diagnostic and therapeutic challenge. We describe two cases of peritonitis requiring laparotomy in anticoagulated patients. and review 49 similar case reports from the world literature. These patients were usually explored for signs of bowel obstruction. At operation. the intestine often appeared infarcted. but pathologic examination commonly revealed intramural hematomata. In contrast. we present microscopic evidence of hemorrhagic cecal infarction complicating oral anticoagulation therapy in one patient. Intramural intestinal hemorrhage is the most common cause of acute abdominal pain in the anticoagulated patient who undergoes laparotomy. In addition to intramural hemorrhage. 14 per cent of patients had coexistent volvulus. appendicitis. intestinal wall disruption or intestinal infarction. We conclude that anticoagulated patients with suspected intramural intestinal hemorrhage may have severe intraabdominal pathology requiring operation. Therefore. operation is mandatory for patients who fail to improve after a short course of expectant management.
Nonoperative management of small-bowel obstruction with endoscopic long intestinal tube placement, Intestinal obstruction remains a major cause of morbidity and mortality in surgical patients. We reviewed the records of 77 patients with mechanical small-bowel obstruction who were treated with endoscopically and fluoroscopically placed Leonard long intestinal tube decompression. Most patients (59%) had failed a trial of nasogastric tube or Miller-Abbott tube decompression. Overall. 29 per cent of patients were able to resolve their obstruction with Leonard tube decompression alone. Subdivision of patients on the basis of the etiology of their obstruction demonstrated a much higher rate of success for tube decompression in adhesive obstruction (37%) versus malignant obstruction (12%) or inflammatory obstruction (no successes). Patients with radiographic and clinical evidence of complete intestinal obstruction were significantly less likely to respond to long intestinal tube treatment (13%). The long intestinal tube was easily passed in all patients. There were no complications of the intubation procedure in our series. and the incidence of tube-related complications was four per cent. We conclude that an initial period of long intestinal tube decompression allows a significant percentage of patients with mechanical small-bowel obstruction to be treated nonoperatively. particularly if a partial obstruction from postoperative adhesions is present. Patients who have failed a trial of nasogastric tube decompression and are poor operative risks should also be considered for long intestinal tube placement.
The influence of sclerotherapy on gastric mucosal blood flow distribution, Hemodynamic events and structural vascular changes of the gastric mucosa in cirrhotics have caught the attention of investigators in the recent past. but as yet it is not known whether therapeutic interruption of variceal blood flow at gastroesophageal level alters such portal hypertensive mucosal features. The newly developed endoscopic laser-Doppler technique was used to assess whether variceal eradication by means of endoscopic sclerotherapy influences the gastric mucosal congestion in portal hypertension patients. Gastric mucosal blood flow was determined at ten defined sites of the stomach. before the first session of sclerotherapy and after complete variceal eradication had been achieved in 15 patients. A statistically significant decrease (P less than 0.01 to 0.05) in microcirculation was found at the gastric antrum and corpus. an increase at the pylorus (P less than 0.05). but no change in the fundic area. An important question following these findings is: What are the consequences of such aggravation of gastric congestion on the integrity of the gastric mucosa?.
Ceftazidime/clindamycin versus tobramycin/clindamycin in the treatment of intra-abdominal infections, In order to assess the efficacy and toxicity of ceftazidime as a substitute for aminoglycosides in the treatment of intra-abdominal sepsis. a prospective randomized trial was conducted. Ninety-four patients (49% trauma) were randomized to receive ceftazidime/clindamycin (CAZ/C) (n = 47) or tobramycin/clindamycin (T/C) (n = 47). CAZ (2.0 gm) and C (0.9 gm) were administered intravenously every 8 hours while T dosage was adjusted to maintain peak (5-8 mg/L) and trough (less than 2 mg/L) concentrations. Age. sex. baseline serum creatinine. and etiology of infection were comparable in the two groups. Clinical cure was similar in culture-positive and culture-negative patients who received CAZ/C (94% vs 88%). The clinical cure rate however was significantly lower in the T/C culture positive (73%) than in the culture negative patients (100%) (P = 0.016). Pathogenic organisms were eradicated in 100% (30/30) and 76% (13/17) of CAZ/C and T/C patients. respectively (P = 0.0006). Nephrotoxicity Nephrotoxicity or ototoxicity was observed in none of the CAZ/C patients and in one and two T/C patients. respectively. CAZ/C more effectively eradicated the bacteria isolated from these patients and no significant difference in clinical response was observed in culture-positive patients. These findings plus the lack of toxicity suggest that CAZ/C is an effective alternative for treatment of IAI.
A comparison of parallel versus perpendicular placement of retention sutures in abdominal wound closure, A new technique for placement of retention sutures is described. Twenty-five rats underwent midline laparotomy incision. The control group was closed with traditional placement of through-and-through retention sutures placed in a perpendicular direction to the wound. The experimental group was closed with retention sutures placed in a parallel direction to the wound as described below. Wound bursting strength was significantly (P less than 0.001) greater at one to five days in the experimental group compared with the control animals. In addition. inflammatory reaction and pressure necrosis were greater in the control group. It appears that parallel placement of sutures has less of a tendency to cut through tissue when subjected to the distracting forces on a midline wound.
CT diagnosis of acquired small bowel volvulus, Small-bowel volvulus is an uncommon but important cause of small-bowel obstruction and often results in ischemia or infarction. Clinical examination and plain film radiography may be nondiagnostic. leading to delay in surgical intervention with subsequent increase in morbidity and mortality. We present two patients in whom the diagnosis of strangulating small-bowel volvulus was made by computed tomography (CT). allowing rapid surgical correction of this potentially life-threatening condition.
Effects of method of hemostasis on wound-infection rate, Adequate hemostasis is important in preventing postoperative wound infection. This study compared four methods of hemostasis: specific pinpoint vessel electrocautery (SPC). specific vessel ligation with 4-0 vicryl (SVL). nonspecific electrocautery of vessel plus excessive surrounding tissue (NSC). and nonspecific ligation of vessel and excessive surrounding tissue with 4-0 vicryl (NSL). on the rate of wound infection in rabbits that were contaminated with 10(6) Staphylococcus aureus. There was no statistical significant increase in the rate of wound sepsis when electrocautery was used in a fashion producing minimal nonviable tissue compared to specific vessel ligation. Electrocautery use for specific vessel hemostasis does not result in a higher wound infection rate in contaminated wounds.
Penetrating injuries of the abdominal aorta, The charts of 56 consecutive patients with penetrating injuries to the abdominal aorta were reviewed in an attempt to identify prognostic factors. Mechanism of injury was gunshot wound (GSW). 82 per cent (.22 cal: 15.2%; greater than .38 cal: 84.8%); shotgun wound (SGW). 5 per cent; and stab wound (SW). 13 per cent. Overall mortality was 73 per cent. with GSW 78 per cent (.22 cal: 0%; greater than .38 cal: 92%). 67 per cent with SGW. and 43 per cent with SW. Average initial systolic blood pressure (ISBP) was 53 (0-130); 87 (0-120) in survivors; and 40 (0-130) in nonsurvivors (NS). Eighteen patients (32%) had no ISBP. with one survivor. Thirty (54%) patients had ISBP less than 70. with three survivors. Six Emergency Department (ED) thoracotomies were performed. with five patients surviving to reach the operating room (OR). and none surviving long-term. Ten patients died in the ED. 18 during surgical intervention. six within 24 hr. and seven greater than 24 hr postop. Average time from injury to OR was 75 minutes. with 122 minutes in survivors. and 53 minutes in nonsurvivors (P less than 0.05); 49 minutes in those dying in the OR; and 58 minutes in those surviving the OR but dying postop (NS). At surgery. six patients had thoracotomy before celiotomy for control of the thoracic aorta. with three surviving the OR and two surviving long-term. Survivors had 2.53 associated injuries; nonsurvivors had 2.89 (NS). No significant difference was noted in number or location of associated injuries between survivors and nonsurvivors.
Exercise thallium-201 scintigraphy in the diagnosis and prognosis of coronary artery disease, OBJECTIVE: To determine the discriminant accuracy of exercise thallium-201 myocardial perfusion scintigraphy for the diagnosis and prognosis of patients with known or suspected coronary artery disease. DATA IDENTIFICATION: A survey of the National Library of Medicine MEDLINE database. STUDY SELECTION: The key medical subject headings used were coronary disease. myocardial infarction. radionuclide imaging. and thallium. A total of 122 retrieved studies were considered relevant and were reviewed in depth. DATA EXTRACTION: Only studies reporting both the sensitivity and specificity of thallium scintigraphy were analyzed. RESULTS: Discriminant accuracy for diagnosis and prognosis was summarized in terms of pooled sensitivity and specificity. CONCLUSIONS: Exercise thallium scintigraphy is useful in the noninvasive diagnosis of coronary artery disease. especially in patients with abnormal resting electrocardiograms. restricted exercise tolerance. and intermediate probability of having disease at the time of testing as well as of defining the prognosis of patients with known or suspected coronary artery disease. especially in those with previous myocardial infarction. Because of various shortcomings in the published record. however. the marginal discriminant accuracy and cost effectiveness of thallium scintigraphy compared with conventional clinical assessment and exercise electrocardiography remain controversial.
Spectral electroretinography in thioridazine toxicity, In three patients with thioridazine toxicity. the electroretinogram (ERG) to red light was found to be below the average normal range. A significant increase in its amplitude appeared with cessation of therapy in two cases. A further deterioration of the ERG amplitude to all stimulus conditions (white. blue. and red lights) occurred when the dose of the medication was increased in the third patient.
Congenital insensitivity to pain with neuroparalytic keratitis, Congenital insensitivity to pain is a well-defined entity in the group of sensory deficiency syndromes. To the best of our knowledge. unilateral neuroparalytic keratitis associated with congenital insensitivity to pain has not been reported. We report such a case to alert clinicians to this potentially blinding problem.
Laryngeal framework reconstruction with miniplates, Defects of the laryngeal framework after trauma. cancer. and thyroplasty have been reconstructed with mini-reconstruction plates. Six patients had miniplates used to repair the thyroid cartilage defect after type I thyroplasty to prevent lateralization of the Silastic implant; three patients had miniplates used after hemilaryngectomy to bridge the thyroid cartilage remnants. resulting in better deglutition after hemilaryngectomy; and three patients had miniplates used to repair laryngeal fractures. The plates were tolerated well by the patients; there were no major complications. Rigid fixation using miniplates for laryngeal reconstruction has unique advantages over the use of wires. It offers the advantages of rigid and immediate stabilization with the ability to bridge large defects. It can be an alternative to existing techniques of laryngeal reconstruction.
Auditory brain stem implant: effect of tumor size and preoperative hearing level on function, The auditory brain stem implant is an investigational device designed to provide hearing sensations to patients without functioning auditory nerves. We analyzed results from 17 implants in 15 patients to determine if tumor size or preoperative hearing level might be related to proper device function. We found no significant correlation between preoperative hearing level or tumor size and device function. We also found no significant correlation between preoperative hearing level and tumor size in these 15 patients.
Cochlear implant flap complications, In a series of 52 patients who received cochlear implants. 4 patients suffered flap complications (7.7%). The problems encountered involved the postauricular flap and were usually minor in nature. None required explantation as a direct result of these complications. Flap ischemia in a patient with Cogan's syndrome and vasculitis. two cases of suture extrusion with one having exposure of the implant. and a case of receiver unit magnet extrusion repaired with a vascularized pericranial flap based upon temporalis muscle are presented. Flap design in patients who have had postauricular incisions demands special consideration. Principles useful for avoiding complications as well as their management are discussed.
Percutaneous pedestal in cochlear implantation, Direct electrical connection between an external sound-processing device and intracochlear electrodes is accomplished via a percutaneous pedestal. Patient pedestal complaints and experience have been recorded. Pedestal problems have been classified into six classes. with class 0 indicating no problems and the severity of problem increasing in classes 1 through 4. Class 5 indicates pedestal trauma. No class 5 problems were encountered. At 48 months of experience. 53% of patients were class 0 and 26% were class 1. The pedestal experience is detailed in the paper. The percutaneous pedestal has been found to be a well-tolerated. efficient system for information transfer in cochlear implant patients.
Vestibular recruitment in Meniere's disease, The aim of this study was to search for vestibular recruitment in a sample of patients with Meniere's disease. Recruitment was defined as an abnormal growth of response with increasing stimulus intensity. Twenty-nine patients were tested with sinusoidal rotation of three different magnitudes at four different frequencies. We also searched for auditory recruitment in each patient via tests of auditory brain stem responses. acoustic reflexes. and loudness balance and discomfort level. Analysis of vestibular responses indicated. on average. a linear relationship between stimulus magnitude and response magnitude. ie. doubling the stimulus magnitude resulted in twice the response magnitude. Meniere's patients did not yield results significantly different (although they were more variable) from those of the normal subjects. The vestibular responses of patients with auditory recruitment did not differ systematically from those of patients without auditory recruitment. We conclude that vestibular recruitment. if it exists in patients with Meniere's disease. is not demonstrated by sinusoidal rotational testing.
Identification and characterization of middle ear vascular leakage sites in experimental otitis media, The site of leakage in middle ear vessels was determined and characterized in experimental otitis media in rats. Middle ear effusion was induced by intravenous administration or local application in the tympanic bulla of substance P (SP). acetylcholine. and histamine. In another experiment. a 14 degrees C airstream was blown into the external auditory canal. Colloidal carbon was used to trace leakage sites at the light and electron microscopic levels. All mediators tested and the 14 degrees C airstream resulted in an increased number of leaking vessels in the pars flaccida and the middle ear mucosa. The leakage sites were restricted to capillaries and postcapillary venules. Increased numbers of degranulated pars flaccida mast cells were observed for SP only. Interendothelial gaps formed in leakage vessels after administration of mediators and stimulation of the external auditory canal with a 14 degrees C airstream. Also. cytoplasmic vesicle-like structures within the endothelial cells increased in number following SP and histamine treatment. suggesting that an increased permeability in experimental otitis media does not occur exclusively through interendothelial gaps.
Cholinergic deficiency and frontal dysfunction in Parkinson's disease, To investigate the influence of central cholinergic deficit on cognitive function in Parkinson's disease (PD). we compared the neuropsychological performance of a group of 20 patients who were treated with anticholinergic drugs (mean daily dose. 10.2 mg) with that of a group of 20 patients who received no anticholinergics. The two groups were matched for all the variables of parkinsonism and levodopa therapy. At the dose used. there was no significant difference between the two groups of patients for intellectual. visuospatial. instrumental. and memory function. In contrast. in the group that received anticholinergics severe impairment was observed on tests believed to assess frontal lobe function. These results suggest that the lesion of the ascending cholinergic neurons. which has been demonstrated post mortem in PD. may play a role in the subcorticofrontal behavioral impairment of this disease.
Ubiquitin immunoreactivity in kuru plaques in Creutzfeldt-Jakob disease, Cerebellar kuru plaques in 2 cases of Creutzfeldt-Jakob disease were studied immunohistochemically. Similar to cerebellar senile plaques in Alzheimer's disease. many kuru plaques contained ubiquitin-positive. tau-negative small granular elements. presumably representing dystrophic neurites. Our results suggest that similar mechanisms are involved in neuritic changes in cerebellar plaques in Creutzfeldt-Jakob and Alzheimer's diseases despite differences of amyloid proteins in the plaques.
Multiple sclerosis is prevalent in the Zoroastrians (Parsis) of India, Using Schumacher's classification. we determined the prevalence rate of clinically definite multiple sclerosis (MS) in the distinct but tiny Zoroastrian (largely Parsi) community in the adjacent cities of Bombay (latitude. 18.55 degrees) and Poona (Pune). On prevalence day. 16 clinically definite cases of MS were counted. 14 in Bombay and 2 in Poona. from a total Zoroastrian population of 50.053 and 3.399. respectively. The crude prevalence ratio was 26 per 100.000 for Bombay and 58 per 100.000 for Poona. The age-adjusted prevalence ratio for Bombay was 24 per 100.000. with 95% confidence limits of 13.1 to 40.3. These are much higher than the low rates believed to be prevalent in India. and are comparable with those found in parts of Europe and the United States.
Vasoactive peptide release in the extracerebral circulation of humans during migraine headache, The innervation of the cranial vessels by the trigeminal nerve. the trigeminovascular system. has recently been the subject of study in view of its possible role in the mediation of some aspects of migraine. Since stimulation of the trigeminal ganglion in humans leads to facial pain and flushing and associated release of powerful neuropeptide vasodilator substances. their local release into the extracerebral circulation of humans was determined in patients who had either common or classic migraine. Venous blood was sampled from both the external jugular and cubital fossa ipsilateral to the side of headache. Plasma levels of neuropeptide Y. vasoactive intestinal polypeptide. substance P. and calcitonin gene-related peptide were determined using sensitive radioimmunoassays for each peptide. and values for the cubital fossa and external jugular and a control population were compared. A substantial elevation of the calcitonin gene-related peptide level in the external jugular but not the cubital fossa blood was seen in both classic and common migraine. The increase seen in classic migraine was greater than that seen with common migraine. The other peptides measured were unaltered. This finding may have importance in the pathophysiology of migraine.
In vivo assessment of antimicrobial agents against Toxoplasma gondii by quantification of parasites in the blood, lungs, and brain of infected mice, The in vivo effects of antimicrobial agents against Toxoplasma gondii were evaluated in mice that were infected intraperitoneally with 10(4) tachyzoites of the RH strain by determination of survival rates and study of the kinetics of growth of T. gondii in infected mice. At various intervals after infection. subcultures of serial dilutions of blood. lung. and brain homogenates were performed in fibroblast tissue cultures for determination of parasitic loads. Pyrimethamine (18.5 mg/kg per day). sulfadiazine (375 mg/kg per day). and clindamycin (300 mg/kg per day) were administered for 10 days from day 1 or day 4 after infection. Untreated control mice died within 9 days and showed early and predominant lung involvement. All mice treated with sulfadiazine administered from day 1 survived and were apparently healthy; parasitic loads decreased early after treatment. but a relapse was observed 5 days after the cessation of therapy. When pyrimethamine was administered from day 1. 7 of 11 mice died within 25 days; by determination of parasitic loads. the effect of pyrimethamine was only demonstrable from day 6. and a relapse was constantly observed after the cessation of therapy. When pyrimethamine and sulfadiazine were administered in combination. 100% of mice survived; when therapy was started at day 1. parasites remained undetectable; in mice treated from day 4. parasites were eradicated by day 8 but infection relapsed 8 days after the cessation of therapy. All mice treated with clindamycin from day 1 or day 4 died within 10 days. but parasitemia was always undetectable.
In vitro evaluation of nicotinamide riboside analogs against Haemophilus influenzae, Exogenous NAD. nicotinamide mononucleotide. or nicotinamide riboside is required for the growth of Haemophilus influenzae. These compounds have been defined as the V-factor growth requirement. We have previously shown that the internalization of nicotinamide riboside is energy dependent and carrier mediated with saturation kinetics. Thionicotinamide riboside. 3-pyridinealdehyde riboside. 3-acetylpyridine riboside. and 3-aminopyridine riboside were prepared from their corresponding NAD analogs. These compounds and several other nicotinamide riboside analogs were evaluated for their ability to support the growth of H. influenzae and for their ability to block the uptake of [carbonyl-14C]nicotinamide riboside by H. influenzae. 3-Aminopyridine riboside blocked the uptake of [carbonyl-14C]nicotinamide riboside and inhibited the growth of H. influenzae when NAD. nicotinamide mononucleotide. or nicotinamide riboside served as the V factor. The antibacterial activity of 3-aminopyridine riboside was found to be specific for H. influenzae but had no effect on the growth of Staphylococcus aureus or Escherichia coli. In additional experiments by reversed-phase high-performance liquid chromatography. it was determined that whole cells of H. influenzae degrade 3-aminopyridine adenine dinucleotide to 3-aminopyridine riboside. which is then internalized. Inside the cell. 3-aminopyridine riboside has the ability to interfere with the growth of H. influenzae by an undetermined mechanism.
Pharmacokinetics of enoxacin and its oxometabolite following intravenous administration to patients with different degrees of renal impairment, Enoxacin is a fluorinated quinolone with potential clinical use in the treatment of serious infections. Twenty-three patients (age. 19 to 87 years) with different degrees of renal function. including a group undergoing chronic hemodialysis. received enoxacin (400 mg) by intravenous infusion (1 h). Blood samples were collected before infusion; at the end of infusion; and at 5. 10. 20. 30. 45. 60. 90. and 120 min and 3. 4. 6. 12. 18. 24. 48. and 72 h after infusion. Enoxacin and oxoenoxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters (mean +/- standard deviation) were calculated by using a noncompartmental PK model according to creatinine clearances (in milliliters per minute). Total clearance of enoxacin decreased from 4.95 +/- 1.16 ml/min per kg in the group with normal creatinine clearance to 0.76 +/- 0.21 ml/min per kg in the patients with severe renal failure (creatinine clearance. less than 15 ml/min). whereas the elimination half-life increased from 4.5 +/- 1.0 to 20 +/- 5 h. respectively. The elimination of oxoenoxacin (the main metabolite of enoxacin) in urine was markedly decreased when creatinine clearance was less than 15 ml/min. Hemodialysis removed an insignificant amount of enoxacin and oxoenoxacin. These data indicate that as creatinine clearance falls below 30 ml/min. the daily enoxacin dose should be reduced by half. During prolonged administration of enoxacin to patients with creatinine clearances of less than 30 ml/min. the accumulation of oxoenoxacin might lead to unexpected side effects.
Bactericidal effect of doxycycline associated with lysosomotropic agents on Coxiella burnetii in P388D1 cells, There is no consistently reliable treatment for endocarditis resulting from chronic Coxiella burnetii infection. the causative agent of Q fever. Although certain antibiotics are recommended on the basis of their in vitro bactericidal activities. results of therapy with these antibiotics are often disappointing. To evaluate whether the currently recommended antibiotic susceptibility tests for C. burnetii give misleading results because of continued division of uninfected cells. thereby resulting in the dilution of infected cells and. hence. a false picture of antibiotic efficacy. we blocked cell division during antibiotic susceptibility testing with cycloheximide. Using this new method. we found that the currently recommended antibiotics for the treatment of Q fever. doxycycline. pefloxacin. and rifampin. did not reduce the ratio of infected to noninfected cells (either L929 or P388D1) by 9 days postinfection. To test the hypothesis that this lack of antibacterial activity is due to antibiotic inactivation by the low pH of the phagolysosomes in which C. burnetii is found. we used alkalinizing lysosomotropic agents (chloroquine or amantadine) concurrently with doxycycline. This resulted in the sterilization of C. burnetii infection in P388D1 cells. This finding seems to confirm our suspicion that the acidic conditions of the phagolysosomes in which C. burnetii is located inhibit antibiotic activity. This inhibition can be reversed in vitro when lysosomotropic alkalinizing agents are used.
Meropenem pharmacokinetics and penetration into an inflammatory exudate, The pharmacokinetics and penetration into a cantharidine-induced inflammatory exudate of meropenem was studied in six volunteers following a single 1-g intravenous dose. Concentrations in plasma. urine. and the inflammatory exudate were determined by a microbiological assay. The mean elimination half-life of meropenem in plasma was 1.1 h. with the concentration in plasma declining from a mean of 23.6 micrograms/ml at 1 h to 0.7 micrograms/ml at 6 h. The inflammatory fluid penetration was rapid (time to maximum concentration of drug in serum. 0.75 h). and the penetration was 111%. The recovery of meropenem in urine at 24 h was 65.4% of the administered dose.
Beta-lactamase production and susceptibilities to amoxicillin, amoxicillin-clavulanate, ticarcillin, ticarcillin-clavulanate, cefoxitin, imipenem, and metronidazole of 320 non-Bacteroides fragilis Bacteroides isolates and 129 fusobacteria from 28 U.S. centers, beta-Lactamase production (nitrocefin disk method) and agar dilution susceptibility of amoxicillin. amoxicillin-clavulanate. ticarcillin. ticarcillin-clavulanate. cefoxitin. imipenem. and metronidazole were determined for 320 Bacteroides species (not Bacteroides fragilis group) and 129 fusobacteria from 28 U.S. centers. Overall. 64.7% of Bacteroides species and 41.1% of fusobacteria were beta-lactamase positive. Among the Bacteroides species. positivity rates were highest for B. bivius (85.0%). followed by B. splanchnicus (83.3%). B. eggerthii (77.8%). and B. oralis (77.1%); 54.5% of black-pigmented Bacteroides species were beta-lactamase positive. Among the fusobacteria. Fusobacterium mortiferum showed the highest rate of beta-lactamase positivity (76.9%). MICs of amoxicillin (128 micrograms/ml) and ticarcillin (64 micrograms/ml) for 90% of all beta-lactamase-positive strains were reduced to 4 and 2 micrograms/ml. respectively. with the addition of clavulanate. MICs of amoxicillin and ticarcillin for 90% of all beta-lactamase-negative strains were 1 and 4 micrograms/ml. respectively. and greater than or equal to 98.4% of the strains were susceptible to the beta-lactams tested. Of the beta-lactamase-producing strains. 45.9% were susceptible to amoxicillin at less than or equal to 4 micrograms/ml and 93.4% were susceptible to ticarcillin at less than or equal to 64 micrograms/ml; the addition of clavulanate raised the rates to 90.4 and 100%. respectively. All strains were susceptible to cefoxitin. imipenem. and metronidazole. The activity of amoxicillin against 29 beta-lactamase-producing strains (10 Bacteroides species and 19 fusobacteria) was not enhanced by the addition of clavulanate; however. 82.7% of these strains were susceptible to amoxicillin. and all were susceptible to ticarcillin.
Suppression of herpes simplex virus type 1 reactivation from latency by (+-)-9-([(Z)-2-(hydroxymethyl)cyclohexyl]methyl) guanine (L-653,180) in vitro, Latent herpes simplex virus type 1 (HSV-1) infection was induced in human embryonic lung cells in vitro by using a combination of viral replication inhibitors and elevated temperature. Under reactivating conditions (superinfection by human cytomegalovirus or temperature manipulation). a nonantiviral thymidine kinase inhibitor (L-653.180) was found to suppress or delay reactivation of HSV-1 from latently infected human embryonic lung cells. L-653.180 alone or in combination with interferon was ineffective as a primary or acute viral replication inhibitor and was unable to induce latent HSV-1 infection in cell culture. These data suggest that initial or acute virus replication and replication resulting from reactivation from latency are separate events.
Activity of compound G2 isolated from alfalfa roots in experimental dermatophyte infection, Compound G2 isolated from alfalfa roots was applied topically to skin lesions of guinea pigs experimentally infected with the dermatophyte Trichophyton mentagrophytes var. granulare. After 12 to 15 applications. 80% of the infected lesions were cured. as judged by clinical and microbial criteria. compared with 20% of the untreated lesions which healed spontaneously (P less than 0.01).
In vitro susceptibility of Xanthomonas (Pseudomonas) maltophilia to newer antimicrobial agents, The susceptibilities of 45 clinical and 3 environmental isolates of Xanthomonas maltophilia to 14 antimicrobial agents was determined by broth microdilution. The newer quinolones PD117596. PD117558. PD127391. A-56620. amifloxacin. and fleroxacin were the most active agents tested. with 70 to 99% of isolates being susceptible to these agents. All isolates were resistant to trospectomycin. The new aminoglycosides SCH24120 and SCH22591 were active against 12 and 1% of isolates. respectively.
Comparison of cilofungin and amphotericin B for therapy of murine candidiasis, We compared the efficacies of cilofungin and amphotericin B treatment in a murine model of disseminated candidiasis. Three different dosages of each drug plus controls were evaluated. Statistically improved survival was noted only among mice treated with 1 mg of amphotericin B per kg of body weight (P less than 0.05). While all amphotericin B regimens and the two lower-dosage cilofungin regimens significantly reduced yeast cell counts in kidneys compared with the controls. the amphotericin B-treated mice had a significantly higher percentage of sterile kidneys following therapy compared with those treated with cilofungin (P = 0.0001).
Abnormal essential fatty acid metabolism in Darier's disease, Fatty acid levels in plasma and erythrocyte cell membranes were determined in 13 Danish patients with Darier's disease and 21 Danish controls. Concentrations of the main dietary essential fatty acids. linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3). were consistently modestly above normal; concentrations of the delta 6-desaturase metabolites of both linoleic and alpha-linolenic acids. however. were consistently and often significantly below normal. These results suggest that the capacity of the enzyme delta 6-desaturase activity is inadequate in patients with Darier's disease.
Histopathologic spectrum of clinically atypical melanocytic nevi. II. Studies of nonfamilial melanoma [published erratum appears in Arch Dermatol 1990 Dec;126(12):1616, We studied the clinically most atypical pigmented lesion removed from each of 142 patients with newly diagnosed sporadic melanoma. The specimens were categorized as to the type of nevus. ie. junctional or compound. presence of congenital features. and degree of nuclear atypicality--presence of nuclear enlargement. nuclear pleomorphism. hyperchromatism. and prominent nucleoli--of intraepidermal nevomelanocytes. The frequency of nuclear abnormality was graded as 1 (rare cells). 2 (10% to 50% of cells). or 3 (greater than 50% of cells) for each nuclear parameter. Among all lesions. 42 (29.6%) were junctional nevi. 74 (52.1%) were compound nevi. and 14 (9.9%) were dermal nevi. Eighteen percent of the total were either dysplastic nevi (23 cases) or malignant melanoma in situ (three cases). Fourteen nevi (9.9%) had congenital features. There were 12 junctional and 39 compound nevi and one dermal nevus that exhibited nuclear abnormality. but only four junctional nevi compared with 19 compound nevi had sufficient atypia for a designation of dysplastic nevus. Only two nevi with congenital features demonstrated any nuclear abnormality. and these were clearly nondysplastic. Thus. among nevi surgically removed as the clinically most atypical lesion in this study. compound nevi were much more likely to demonstrate nuclear atypia (and dysplasia) than were other nevi. ie. junctional or dermal nevi. or nevi with congenital features.
Ionizing radiation-induced pemphigus. Case presentations and literature review, Reports of pemphigus following ionizing radiation exposure are rare. We report two cases and review the literature regarding this association. Characteristics common to these cases include a prodromal persistent nonspecific dermatitic eruption that is often interpreted as radiation dermatitis. and latency of variable duration before the onset of a vesiculobullous eruption that begins at the portal of irradiation. Direct immunofluorescence is positive for intercellular IgG. while indirect immunofluorescence is commonly positive only at low titers; HLA correlations have not been studied. Documentation of clinical course and laboratory confirmation of the diagnosis. including hematoxylin-eosin. direct and indirect immunofluorescence. and HLA determinations (if available). should be recorded to enable further clarification of this entity.
Compound blue nevus: a variant of blue nevus with an additional junctional dendritic component. A clinical, histopathologic, and immunohistochemical study of six cases, We studied six cases of heavily pigmented melanocytic lesions with features of blue nevi within the dermis. but with an additional junctional dendritic component. This compound variant of blue nevus is an uncommon lesion that has not been previously identified as a distinct histologic entity. Immunoperoxidase staining for S100 protein and counterstaining with azure B distinguished the presence of melanocytes among numerous melanophages within the dermis. The compound variant of blue nevus can be distinguished histologically from combined blue nevus. pigmented spindle cell nevus. malignant melanoma. and melanosis due to a regressed malignant melanoma. The six lesions were from three men and three women whose ages ranged from 11 to 51 years (mean. 31 years). Three lesions were located on the trunk. two on the extremities. and one on the head. After a mean follow-up period of 47 months (range. 38 to 58 months). there was no evidence of recurrence.
Severe phototoxic burn following celery ingestion, A 65-year-old woman developed a severe. generalized phototoxic reaction following a visit to a suntan parlor. History taking revealed that she had consumed a large quantity of celery root (Apium graveolens) 1 hour earlier. With the use of thin-layer chromatography. methoxsalen (8-methoxypsoralen) and 5-methoxypsoralen were identified in the extract from a similar celery root. The biologic activity of this extract. as evaluated with the semiquantitative Candida albicans inhibition technique. indicated a total psoralen dose of approximately 45 mg. Substantial amounts of psoralen may be absorbed from vegetables. such as celery. and under unusual circumstances. this may constitute a health hazard.
Autoantibodies from patients with localized and generalized bullous pemphigoid immunoprecipitate the same 230-kd keratinocyte antigen, Two patients demonstrating the typical clinical. histologic. and immunopathologic features of nonscarring localized bullous pemphigoid are described. These patients possess circulating IgG autoantibodies that bind the epidermal side of 1.0-mol/L sodium chloride-split human skin in indirect immunofluorescence microscopy. Immunnoprecipitation studies demonstrate that these patients have circulating autoantibodies that immunoprecipitate the same 230-kd bullous pemphigoid antigen that is precipitated by autoantibodies from patients with generalized bullous pemphigoid. These findings indicate that localized bullous pemphigoid is a true clinical variant of generalized pemphigoid rather than a separate nosologic entity.
Slow release carbamazepine in treatment of poorly controlled seizures, Thirty three children with poorly controlled epilepsy. and six new patients. were treated with slow release carbamazepine. Twelve of the former had a reduction in the number of seizures of more than half. and 10 had fewer side effects. Three of the new patients stopped having seizures. Variations in plasma concentrations between doses was significantly less when patients took the slow release preparation (22%) compared with the standard preparation (41%). Slow release carbamazepine may improve the conditions of children whose seizures are poorly controlled.
Prognosis of chronic granulomatous disease, The records of 28 patients with chronic granulomatous disease born over a 32 year period were reviewed. The characteristics of the group. and the frequency with which various clinical and laboratory features had been recorded. was assessed. Nine patients were known to have died. in most cases of progressive suppurative infection. Actuarial analysis showed 50% survival through the third decade of life. The long term survival of patients developing symptoms after the end of the first year of life was significantly better than that of patients whose illness started in infancy. Our data confirm that the severity of chronic granulomatous disease is not uniform. and that the prognosis for long term survival is better than that suggested in earlier reports. Early onset may be a poor prognostic sign and invasive aspergillosis is a life threatening complication. In the absence of curative treatment. trials to assess the effectiveness of interferon gamma are necessary and early antenatal diagnosis should be offered to as many affected families as possible.
Recurrent cyanotic episodes with severe arterial hypoxaemia and intrapulmonary shunting: a mechanism for sudden death, The pathophysiology of recurrent cyanotic episodes has been investigated in 51 infants and children. Episodes began at a median age of 7 weeks (range 1 day to 22 months. 39 at less than 4 months). They were characterised by the rapidity of onset and progression of severe hypoxaemia with early loss of consciousness from cerebral hypoxia. The most common precipitating factor was a sudden naturally occurring stimulus from pain. fear. or anger. In uncontrolled trials. cyanotic episodes were reduced in frequency and severity by tetrabenazine (n = 15) and additional inspired oxygen (n = 10). Eight patients died suddenly and unexpectedly (four during cyanotic episodes). Twenty eight patients underwent physiological studies during cyanotic episodes. There was no evidence of seizure activity at the onset and although prolonged absence of inspiratory effort with continued expiratory efforts was common. breathing sometimes continued. Episodes were not caused by upper airway obstruction and sometimes occurred during positive airway pressure ventilation. The rapidity of fall in arterial oxygen pressure and continued breathing suggested a right to left shunt of sudden onset. The results of contrast echocardiography and lung imaging studies confirmed that this was occurring within the lungs. These cyanotic episodes included both intrapulmonary shunting and prolonged expiratory apnoea. They are best explained by interactions between central sympathetic activity. brainstem control of respiration and vasomotor activity. reflexes arising from around and within the respiratory tract. and the matching of ventilation to perfusion in the lungs. They are a cause of sudden unexpected death in infancy and early childhood.
Natural and modified history of complete atrioventricular septal defect--a 17 year study, We reviewed 103 cases of isolated complete atrioventricular septal defect. These cases represented 4.4% of the cases of congenital heart disease diagnosed in our hospital by catheterisation and angiography during 1971-88. Most children (n = 76) had Down's syndrome. Banding of the pulmonary artery was performed in seven cases and complete repair in 67 cases. In the period 1971-82 the complete correction was performed at a mean age of 23 months with a surgical mortality of 88.8%. In the period 1983-8 the mean age at complete correction was 13 months. the mortality 43.2%. and the five year actuarial survival was 46.8%. The 22 patients that survived after complete correction were in functional classes I and II of the New York Heart Association classification. After a mean follow up of 10 years only eight (36%) of the 22 who were followed up and treated medically survived; all had developed pulmonary vascular obstructive disease and were in functional classes III or IV. Our findings stress the importance of early complete surgical repair.
Pharmacokinetics of paracetamol after cardiac surgery, Plasma concentration was measured after rectal and nasogastric administration of paracetamol 15 mg/kg to 28 febrile children aged between 9 days to 7 years who had undergone cardiac surgery. After equivalent doses. rectal administration in neonates and children on the first postoperative day was found to produce plasma concentrations below the therapeutic range with higher concentrations after nasogastric paracetamol on the second postoperative day. There was less variance in plasma paracetamol concentrations in neonates. Both plasma elimination half life and area under the plasma concentration time curve were significantly increased in neonates after suppository dosing compared with older children. There was no difference in antipyretic effect between the two routes of administration. but this was much lower than that previously reported in febrile children.
Social integration of the older thalassaemic patient, Because social policy favours the fullest possible social integration of chronically ill patients. we have evaluated the facilities that are needed to achieve this for patients with beta thalassaemia major in the light of the therapeutic advances that now permit them to survive into adulthood. We have investigated the social integration of adolescent and young adult thalassaemic patients. 171 from Greece and 112 from Ferrara in Italy. Patients in both areas show a good level of social integration and favourable self image. indicating what may be achieved by providing psychosocial support as part of a comprehensive approach to treatment.
Spontaneous resolution of congenital nephrotic syndrome in a neonate, An infant with congenital nephrotic syndrome recovered spontaneously and completely by the age of 11 days and had remained well at the age of 1 year. This reinforces the view that reversible congenital nephrotic syndrome does occur and that it is not a single disease with a universally dismal prognosis.
Urinary tract re-functionalization after long-term diversion. A 20-year experience with 177 patients, From 1969 to 1990. previously diverted urinary tracts were 'undiverted' in 177 patients whose ages ranged from 1 to 31 years. Fifty-six of the patients (32%) had been diverted for 10 years or longer. There were 67 female and 110 male patients. Forty-four patients had only one kidney and in two of those patients it was a previous renal transplant. One patient was anephric at the time of reconstruction. having had two unsuccessful transplants. Most of the diversions had been considered permanent. Types of diversions that were reversed include ileal loop. colon conduit. loop ureterostomy or pyelostomy. end ureterostomy. cystostomy or vesicostomy. long-term nephrostomy. and ureterosigmoidostomy.
Tumor necrosis factor-alpha mediates acid aspiration-induced systemic organ injury, Acid aspiration-induced systemic organ injury is mediated by the sequestration of activated neutrophils (PMN). In other settings cytokines have been shown to increase neutrophil-endothelial adhesion. a requisite for injury. This study tests whether the systemic leukosequestration and permeability following localized aspiration is mediated by tumor necrosis factor (TNF)-alpha-induced synthesis of an adhesion protein. Anesthetized rats underwent tracheostomy and insertion of a fine-bore cannula into the anterior segment of the left lung. This was followed by the instillation of either 0.1 mL 0.1 N HCI (n = 18) or 0.1 mL saline in control rats (n = 18). Localized aspiration induced generalized pulmonary leukosequestration with 95 PMN/10 high-power fields (HPF) in the aspirated lung and 46 PMN/10 HPF in the nonaspirated lung. higher than control values of 7 PMN/10 HPF and 5 PMN/10 HPF in saline- and nonsaline-aspirated sides. respectively (p less than 0.05). The leukosequestration was associated with permeability edema shown by increased protein concentrations in bronchoalveolar lavage (BAL) of 3900 micrograms/mL in the aspirated and 2680 micrograms/mL in the nonaspirated side. higher than saline with 482 micrograms/mL and 411 micrograms/mL. respectively (p less than 0.05). There was generalized pulmonary edema following aspiration measured by increase in wet-to-dry weight ratios (w/d) of 6.6 in the aspirated and 5.1 in the nonaspirated lung. higher than control values of 3.5 and 3.4. respectively (p less than 0.05). Localized aspiration led to systemic leukosequestration documented by increases in myeloperoxidase activity (units/g tissue) of 2.2 and 1.7 in heart and kidney. higher than control values of 0.3 and 0.4. respectively (p less than 0.05). This event was associated with edema of these organs with w/d ratios of 4.6 and 4.3. relative to control values of 3.0 and 3.4 (p less than 0.05). Treatment of animals (n = 18) 20 minutes after aspiration with anti-TNF-alpha antiserum (rabbit anti-murine) but not normal rabbit serum (n = 18) reduced lung leukosequestration in the aspirated and nonaspirated segments (61 and 32 PMN/10HPF). BAL protein concentration (1490 and 840 micrograms/mL). and w/d ratio (4.3 and 3.7) (all p less than 0.05). In the heart and kidney there were reductions in myeloperoxidase activity (0.7 and 0.6) and w/d ratio (3.5 and 3.6) (both p less than 0.05). Treatment of rabbits (n = 18) with the protein synthesis inhibitor cycloheximide. 0.2 mg/kg/hr was as effective as TNF-alpha antiserum in modifying aspiration injury.(ABSTRACT TRUNCATED AT 400 WORDS).
Upper GI bleeding in an urban hospital. Etiology, recurrence, and prognosis, Acute upper gastrointestinal bleeding (UGIB) continues to be a common cause of hospital admission and morbidity and mortality. This study reviews 469 patients admitted to a surgical service of an urban hospital. There were 562 total admissions because 53 patients were readmitted 93 times (recurrence rate. 20%). The most common causes of bleeding. all endoscopically diagnosed. included acute gastric mucosal lesion (AGML) (135 patients. 24%). esophageal varices (EV) (121 patients. 22%). gastric ulcer (108 patients. 19%). duodenal ulcer (78 patients. 14%). Mallory-Weiss tear (61 patients. 11%). and esophagitis (15 patients. 3%). Nonoperative therapy was sufficient in 504 cases (89.5%). Endoscopic treatment was used in 144 cases. Operations were performed in 58 cases (10.5%). including 29% of ulcers. Emergency operations to control hemorrhage were required in only 2.5% of all cases. The rate of major surgical complications was 11% and the mortality rate was 5.2%. There were 58 deaths (12.6%). with 36 deaths directly attributable to UGIB. Factors correlating with death include shock at admission (systolic blood pressure less than 80). transfusion requirement of more than five units. and presence of EV (all p less than 0.001). Most cases of UGIB can be treated without operation. including endoscopic treatment. when diagnostic endoscopy establishes the source. Subsequent operation in selected patients can be done with low morbidity and mortality rates.
Ionized calcium, parathormone, and mortality in critically ill surgical patients, A prospective study measured ionized calcium and parathormone sequentially at 48- to 72-hour intervals in 25 surgical intensive care unit patients. Twelve patients (48%) died at mean day 40 and median day 26. Levels of ionized calcium. parathormone. blood urea nitrogen. creatinine. albumin. magnesium. and phosphate for patients who lived were compared with levels for patients who died. The incidence of hypotension. renal failure (creatinine greater than or equal to 3.0). and bacteremia. as well as the amount of red cell. crystalloid. and colloid administration for the two groups was compared. Hypotension. bacteremia. red cells. crystalloid. and colloid were no different. On days 1 and 2 ionized calcium levels were significantly lower and parathormone levels significantly higher in nonsurviving patients; this difference persisted through days 3 and 4. Blood urea nitrogen and creatinine levels increased early in nonsurviving patients but renal failure. which occurred in nine nonsurviving patients. did not develop until mean day 14. median day 18. The phosphate level was slightly higher but still within normal range in nonsurviving patients. By days 5 and 6 ionized calcium and parathormone levels were no different in nonsurviving patients. despite there being no improvement in renal function. Magnesium and albumin levels were no different between groups. Ionized calcium levels are lower and parathormone levels higher early in nonsurviving patients. This difference is not readily explained by associated clinical conditions. including renal dysfunction. Although etiology remains unclear. low ionized calcium and elevated parathormone are early predictors of mortality in critically ill surgical patients.
Surgical aspects of sclerosing cholangitis. Results in 178 patients, Of 178 patients with sclerosing cholangitis treated since 1950. 88 patients had associated inflammatory bowel disease. 72 had no such history. and 18 had iatrogenic injury or stone disease. A total of 233 biliary operations were performed. with a 75% rate of temporary improvement after initial operation. Subsequent operations resulted in a lower success rate and a higher mortality rate. Radiologic findings included predominant extrahepatic. intrahepatic. and diffuse disease in 29%. 28%. and 43% of patients. respectively; no survival differences were noted. Seventy-five of one hundred three deaths (73%) were related to liver failure. bleeding. or sepsis. Of 14 patients undergoing portosystemic shunt. 13 died of surgical complications or related disease. Orthotopic liver transplantation was performed in 16 patients and resulted in eight deaths. mainly in patients who had previously undergone extensive surgical treatment. No survival differences were seen between the patients with inflammatory bowel disease. those without the condition. or those who had colectomy. Surgical treatment in patients with sclerosing cholangitis should be minimized. Orthotopic liver transplantation should be offered as the treatment of choice for patients with portal hypertension. refractory cholangitis. advanced cirrhosis. or progressive liver failure.
Selective monitoring of patients with suspected blunt cardiac injury, Blunt chest trauma can result in cardiac injury with consequent dysrhythmias. valve malfunction. or frank rupture. Typically. patients with blunt chest trauma and suspected cardiac injury have required cardiac monitoring for 48 to 72 hours. Predicting which patients with blunt chest trauma are not at risk for cardiac complications would obviate many patient-hours of monitoring in the intensive care unit. This series examines the sensitivity of two-dimensional surface echocardiography in predicting cardiac complications. Over a 24-month period. 115 patients were admitted with blunt chest trauma and prospectively evaluated for cardiac injury with admission electrocardiograms. serial creatine kinase isoenzyme studies. and two-dimensional echocardiography. Thirty-one patients (27%) had abnormal two-dimensional echocardiograms. In 8 (25.8%) of these patients. cardiac complications requiring treatment developed. Eighty-four patients (73%) had normal two-dimensional echocardiograms. and a cardiac complication requiring treatment developed in only 1 (1.2%) of them. Of the 9 patients who required treatment of cardiac complications. 3 had normal admission electrocardiograms and only 1 had elevated levels of the myocardial-specific isoenzymes of creatine kinase. We believe two-dimensional echocardiography is a sensitive test for evaluating cardiac injury resulting from blunt chest trauma and is helpful in selecting those patients who require monitoring in the intensive care unit.
Combined internal mammary artery graft for coronary artery revascularization, Five patients with multiple-vessel coronary artery disease underwent isolated coronary artery bypass grafting with a technique involving both internal mammary arteries and a small piece of interposed saphenous vein. The combined internal mammary artery grafts were used for sequential grafting. A total of 20 anastomoses were performed (average number. 4 anastomoses per patient). There were no operative deaths. Postoperative complications included reoperation for bleeding in 1 patient and diaphragmatic dysfunction in another. Postoperative coronary angiography 2 days before discharge (mean time. 10 days postoperatively) revealed that all the sequential anastomoses with the combined IMA graft were patent. Exercise tolerance tests performed 3 and 11 months postoperatively indicated excellent results and no ischemia. Based on this experience. we conclude that this method appears promising for multivessel coronary artery bypass grafting.
Surgical treatment of cardiac myxomas: long-term results, Between 1965 and 1988. 22 patients underwent 24 operations for cardiac myxomas. Two patients had the complex myxoma syndrome. Mitral valve replacement was required at initial operation in 2 patients. One patient died perioperatively. and 5 others died subsequently. The 16 surviving patients recently underwent evaluation at a mean duration of 9 years after operation. Ten are asymptomatic and 6 have New York Heart Association class II symptoms. Nine patients continue to be employed. Eleven are in sinus rhythm. 3 have permanent pacemakers. and 2 have chronic atrial arrhythmias. Echocardiography showed atrioventricular valve insufficiency in 3 patients and reduced contractility in 4. but no new tumor recurrences. The long-term prognosis of this relatively large group of patients with cardiac myxomas has been good. Patients without the complex myxoma syndrome had no recurrence. whereas 2 patients did require reoperation for mitral valve replacement. Long-term disability and chronic arrhythmias have been infrequent. and functional status and employability of these patients have been very good.
Long-term amiodarone administration protects against global myocardial ischemia, Reports on the effects of amiodarone on cardiac function have been variable. This study addresses the effect of long-term amiodarone administration on recovery of cardiac function after a period of global ischemia. Normotensive and spontaneously hypertensive rats were used. Normotensive rats (n = 6) received 240 mg/kg amiodarone for 4 weeks. for a total of 72 +/- 3 mg. Hypertensive rats (n = 6) received 500 mg/kg amiodarone for 4 weeks. for a total of 116 +/- 5 mg. Final myocardial concentrations of amiodarone and desethylamiodarone were 1.85 +/- 1.75 and 0.50 +/- 0.61 micrograms/g wet weight for the normotensive rats and 1.30 +/- 0.58 and 0.31 +/- 0.17 micrograms/g for the hypertensive rats (p = nonsignificant). Equal numbers of controls received sterile saline solution for 4 weeks. The hearts were excised and perfused in a Langendorff apparatus. The results indicate that. after 15 minutes of normothermic ischemia. hearts treated with this relatively low dose of amiodarone recovered a greater percentage of preischemic work (97% +/- 13%) as compared with the controls (76% +/- 17%) (p less than 0.005).
Subaortic obstruction: intraoperative echocardiography as an adjunct to operation, Fourteen patients undergoing operation for subaortic obstruction (membranous obstruction in 11 patients. tunnel obstruction in 2 patients. obstruction due to reduplicated mitral valve tissue in 1 patient) were evaluated by intraoperative epicardial echocardiography. In all 9 patients with "discrete" obstruction who underwent prebypass epicardial echocardiography. the septal and lateral attachments of the lesion were correctly demonstrated. The precise extent of tunnel stenosis was seen in both patients. The lateral attachment of the membrane in 4 patients and multiple extensions in another 2 were identified by the epicardial study (having been missed on precordial echocardiography). The discrete membrane was enucleated in 10 of the 11 patients and was partially resected in 1. One tunnel obstruction was completely relieved; the other was partially relieved. Reduplicated mitral valve tissue in the remaining patient was completely resected. Epicardial imaging after bypass showed remnants of the membrane in 2 patients. Intraoperative Doppler echocardiography and color flow imaging confirmed the absence of clinically significant residual gradients (less than 20 mm Hg) in all but 1 patient with tunnel obstruction. Epicardial imaging provided excellent morphological information about obstructive lesions of the left ventricular outflow tract and enabled immediate assessment of surgical repair.
Reoperations on heart valve prostheses: an analysis of operative risks and late results, To evaluate risks and complications of reoperations on heart valve prostheses. we reviewed data on 183 patients who underwent reoperation because of prosthetic valve malfunction. The incremental effect of the redo procedure on hospital mortality and morbidity was studied by comparing primary and reoperative procedures and analyzing a series of possible predisposing factors. Late survival after first and second reoperations was computed. and possible determinants of late mortality were examined. Overall operative mortality was 8.7%; emergency operation (p = 0.0001). previous thromboembolism (p = 0.05). and advanced New York Heart Association functional class (p = 0.031) were the independent determinants. In a series of 1.355 patients having primary or secondary isolated valve replacement. the redo procedure was a significant risk factor in the univariate analysis (p = 0.025) but not in the multivariate analysis except for the subset of patients having mitral valve replacement (p = 0.052). The postoperative course was quite complicated. as evidenced by the long mean stay in the intensive care unit (mean stay. 3.8 days; longer than 2 days for 26% of the survivors). Nevertheless. postoperative complications were not significantly greater after a redo procedure than after a primary operation. Actuarial survival at 7 years was 57.3% +/- 8%. A comparison with a nonhomogeneous series from our institution did not demonstrate significant differences. In the subset of 16 patients having a second reoperation. late survival was 37.8% +/- 16% at 2 years. Advanced New York Heart Association class (p = 0.0001). double prosthetic valve dysfunction (p = 0.003). and any indication other than primary tissue failure (p = 0.06) were determinants of late mortality.
Results in 104 patients undergoing bronchoplastic procedures for bronchial lesions, Bronchoplastic procedures were used in 104 patients with various bronchial disorders. Ten had benign lesions and 94. malignant tumors. The principal operative procedures were sleeve lobectomy and sleeve pneumonectomy for bronchogenic carcinoma. but 11 limited bronchial resections were performed in patients with benign lesions. minute bronchogenic carcinomas. and low-grade malignant tumors. Of the 94 patients with malignant tumors. 79 underwent a bronchoplastic procedure without carinal resection (sleeve lobectomy in 75 and limited bronchial resection in 4). and there was one operative death (1.3%). The overall 5-year survival rate for the patients with bronchogenic carcinoma in this group was 45% and that for patients undergoing curative resection. 57% (survival of patients in stages I. II. and IIIA was 79%. 55%. and 30%. respectively). A bronchoplastic procedure with carinal resection was performed in 15 patients. Twelve in this group underwent sleeve pneumonectomy. There were two operative deaths. and 1 patient has survived for longer than 4 years. Two patients with low-grade malignant tumors underwent carinal resection without lung resection and are still alive. We believe that bronchoplasty is a safe and valuable procedure and that limited bronchial resection appears to be the procedure of choice for localized bronchial lesions.
Use of the variable-length intraluminal sutureless graft, From August 1987 to May 1988 we treated 4 patients with acute ascending aortic dissections with a variable-length intraluminal aortic prosthesis. This operation uses profound hypothermic circulatory arrest and represents a refinement of existing techniques. There was no mortality. and morbidity was minimal. Modifications of this technique can be used in performing proximal aortic root reconstruction with a composite valved conduit. The use of a variable-length intraluminal prosthesis and hypothermic circulatory arrest is illustrated. This is a safe and useful technique in select cases of acute ascending aortic dissection.
Value of transesophageal echocardiography during repair of congenital heart defects, Two-dimensional transesophageal color Doppler echocardiography was employed intraoperatively in 30 children undergoing repair of a variety of simple and complex cardiac malformations. There were 16 female and 14 male patients. with a mean age of 9 +/- 3 years (range. 4 to 13 years) and a mean weight of 31 +/- 9 kg (range. 16 to 50 kg). 16 children weighing less than 30 kg. A standard. commercially available transesophageal echocardiography probe (5 MHz. 64 elements) was used in all patients without complications. Transesophageal echocardiography proved helpful in selecting the surgical approach. in assessing the adequacy of surgical repair. in detecting residual intracardiac shunts. and in allowing uninterrupted monitoring of ventricular performance throughout the procedure. Our initial experience suggests that transesophageal echocardiography is a valuable tool to be used in children with congenital cardiac malformations. particularly in those requiring complex intracardiac procedures. The amount of information obtained by the surgeon should favor the routine use of transesophageal echocardiography during open heart procedures and stimulate the development of probes to be safely used even in infants and newborns.
Left superior vena cava: a pitfall in computed tomographic diagnosis with surgical implications, We report 2 cases in which computed tomography of the mediastinum demonstrated an abnormality originally misinterpreted as lymphadenopathy but subsequently shown to represent a left superior vena cava. Misinterpretation may result in errors in optimum treatment and may complicate surgical exploration of the mediastinum. These 2 cases are presented to remind radiologists and surgeons of the possibility of this unusual anatomy.
Liver transplantation with atrioatrial anastomosis for Budd-Chiari syndrome, We report the case of a young woman with Budd-Chiari syndrome in whom mesentericoval shunt was first performed. followed by transcaval liver resection and hepatoatrial anatomosis 3 years later. Liver transplantation became necessary 5 years later because of deterioarating liver function with portal hypertension and bleeding. Successful transplantation was performed with atrioatrial anastomosis with help of cardiopulmonary bypass. simplifying considerably the technical procedure and reducing dramatically blood loss.
Polytetrafluoroethylene graft for spontaneous coronary dissection: 7-year follow-up, Spontaneous coronary artery dissection remains an exceedingly rare cause of myocardial ischemia. The patients are usually young and female. and the dissection is frequently fatal. The use of polytetrafluoroethylene as an aortocoronary conduit is generally followed by early occlusion. We report a case of spontaneous right coronary dissection in which a polytetrafluoroethylene graft was placed that was observed to remain patent by angiography at least 72 months after operation.
Improved cannulation method for extracorporeal membrane oxygenation, Extracorporeal membrane oxygenation has been shown to be useful for patients in reversible cardiogenic shock. Effective arterial cannulation techniques for infants have been developed that are simple to use and require minimal subsequent vascular repair or reconstruction after removal. Groin cannulation in adults frequently requires bidirectional arterial cannulation to ensure adequate distal perfusion as well as frequent complex arterial repairs after discontinuation. We describe a simple arterial cannulation technique using a single right-angle. high-flow arterial cannula. With this technique adequate bidirectional arterial perfusion is maintained with a single arterial cannula while the need for vascular repairs or reconstruction is minimized.
Guidelines for transfusion support in patients undergoing coronary artery bypass grafting. Transfusion Practices Committee of the American Association of Blood Banks, We have reviewed the impact of evolving issues in coronary artery bypass grafting (CABG) on transfusion support for these patients. Issues include increased awareness of transfusion risks. reappraisal of traditional indicators triggering transfusion. and evolving alternatives to homologous blood transfusion such as autologous blood and pharmacologic therapy. These issues have been prompted by programs. such as the National Institutes of Health Consensus Conferences. to provide physicians with guidelines for appropriate use of blood components. However. evidence suggests that transfusion practice in coronary artery bypass grafting procedures remains variable and does not take into account the results of recently published clinical studies. We have therefore developed guidelines and recommendations for transfusion support in patients undergoing coronary artery bypass grafting. In summary. they are the following. 1. Institutions with coronary artery bypass grafting programs should establish a multidisciplinary approach to use a combination of interventions designed to minimize homologous blood exposure. 2. Prophylactic transfusion of plasma and platelets are of no benefit and therefore carry an unnecessary risk to the patient. 3. Special request products such as designated blood donation from first-degree relatives should not be used because of the risk of transfusion-associated graft versus host disease. 4. For support of intravascular volume. crystalloids or colloids should be used because they do not have the potential to transmit infection.
Electroencephalography should not be routine in the evaluation of syncope in adults, We reviewed the reports of all electroencephalograms obtained at the Nashville (Tenn) Veterans Administration Hospital from September 1987 to August 1989. Seventy-three patients were referred for evaluation of syncope or near syncope. Of these 73 patients. 10 (13.7%) had abnormal findings. Twenty-six patients were referred for other complaints similar to syncope (ie. blackouts. loss of consciousness. falling out. passing out. and fainting). Of these 26 patients. five (19.2%) had abnormal findings. We reviewed the medical records of the patients with abnormal findings and found that the final diagnosis or treatment of the syncope was affected by electroencephalogram in only one patient. These findings suggest that routine electroencephalography is not of significant value in the evaluation of syncope in adults.
Treatment of adult chickenpox with oral acyclovir, Thirty-one late adolescents and adults with varicella were studied. Patients identified within 72 hours of varicella exanthem were offered open treatment with acyclovir (4 g/d). and those patients identified after 72 hours of exanthem were followed up but not treated. Twenty-two patients were treated with acyclovir. Nine patients were not treated. No severe complications occurred in any of the 31 patients. Minor complications. including prolonged fever. localized secondary infections. persistent cough. and prolonged fatigue were more frequent in the untreated group. If the acyclovir therapy was begun within the first 24 hours of varicella exanthem. then the rash and clinical illness were dramatically lessened. Treatment with oral acyclovir should be considered for varicella in adults who are identified within the first 24 hours of exanthem.
Lipoprotein and apolipoprotein levels in subclinical hypothyroidism. Effect of levothyroxine therapy, To assess whether subclinical hypothyroidism is associated with changes in lipoprotein fractions. 13 patients maintained in a stable state of subclinical hypothyroidism for at least 3 months were studied prior to and 2 and 4 months following restoration of a euthyroid state with incremental levothyroxine sodium therapy. Thyrotropin levels ( +/- SEM) had decreased from 16.6 +/- 3.2 mU/L to 3.1 +/- 0.7 mU/L and 3.2 +/- 0.7 mU/L at 2 months and 4 months. At 2 months. levothyroxine treatment led to a decrease in levels of total cholesterol from 5.5 +/- 0.3 mmol/L (213 +/- 12 mg/dL) to 4.8 +/- 0.3 mmol/L (186 +/- 12 mg/dL). in low-density lipoprotein cholesterol (LDL-C) from 3.7 +/- 0.3 mmol/L (143 +/- 12 mg/dL) to 2.9 +/- 0.3 mmol/L (112 +/- 12 mg/dL). and in apolipoprotein B from 91 +/- 8 mg/dL to 74 +/- 7 mg/dL. At 4 months. levels of LDL-C and apolipoprotein B remained significantly lower than pretreatment values (2.9 +/- 0.2 mmol/L [112 +/- 8 mg/dL] and 75 +/- 6 mg/dL. respectively). While high-density lipoprotein cholesterol (HDL-C). HDL3-C. and apolipoprotein A-I were not significantly affected by levothyroxine therapy. there was a slight trend of increase in HDL2-C during levothyroxine substitution. There was also a tendency for a decrease in triglyceride levels from 1.3 +/- 0.2 mmol/L (115 +/- 18 mg/dL) to 0.9 +/- 0.1 mmol/L (80 +/- 9 mg/dL) at 4 months of levothyroxine therapy. Levels of HDL-C tended to decrease from 4.8 +/- 0.4 mmol/L (186 +/- 15 mg/dL) to 4.5 +/- 0.5 mmol/L (174 +/- 19 mg/dL) at 2 months and to 3.9 +/- 0.4 mmol/L (151 +/- 15 mg/dL) at 4 months. The LDL-C/HDL-C ratio also decreased from 3.3 +/- 0.3 mmol/L (128 +/- 12 mg/dL) to 2.9 +/- 0.5 mmol/L (112 +/- 19 mg/dL) and 2.5 +/- 0.3 mmol/L (97 +/- 12 mg/dL) at 2 months and 4 months. respectively. These results suggest that long-term levothyroxine therapy in patients with subclinical hypothyroidism is associated with a decrease in LDL-C and apolipoprotein B levels that are reflected in a trend of decreases in cholesterol/HDL-C and LDL-C/HDL-C ratios known to have a relationship with coronary artery disease.
Mortality following hip fracture before and after implementation of the prospective payment system, Recent studies of patients with hip fractures from two hospitals have suggested that the marked reduction in length of stay that occurred following implementation of the Medicare prospective payment system (PPS) resulted in decreased quality of care for these patients. To assess whether this change influenced mortality. we studied patients with hip fractures aged 65 years or older from a 20% sample of Michigan Medicare enrollees. There were 2130 such patients in the 2 years preceding (October 1981 through September 1983) and 2238 in the 2 years following (October 1984 through September 1986) implementation of PPS. Although the demographic characteristics of patients with hip fractures did not change after PPS. the mean length of stay (95% confidence interval) decreased by 4.4 (4.1 to 4.7) days. However. mortality in the year following the fracture did not change: 23.2% before PPS. 23.7% after PPS; rate difference of 0.5% (-2.0 to 3.0). This finding was consistently present within subgroups defined by patient demographic characteristics. Furthermore. when the analysis was restricted to patients treated in those hospitals with the greatest reduction in average length of stay following PPS (7.5 days. or 35%). there was no significant change in 1-year mortality. For those patients who were enrolled in Medicaid and not in a nursing home at the time of the fracture. there was no increase in the rate of nursing home residence 1 year after the fracture. Thus. the findings of this population-based study suggest that the key outcomes of postfracture mortality and nursing home residence were not affected by the implementation of PPS.
Emergence of ciprofloxacin resistance in nosocomial methicillin-resistant Staphylococcus aureus isolates. Resistance during ciprofloxacin plus rifampin therapy for methicillin-resistant S aureus colonization, We initiated a randomized. single-blinded trial of ciprofloxacin plus rifampin vs sulfamethoxazole and trimethoprim plus rifampin in the therapy for patients who underwent colonization with methicillin-resistant Staphylococcus aureus (MRSA). Patients who were colonized with MRSA received 2 weeks of either regimen. The study was terminated after the enrollment of 21 subjects due to the recognition of ciprofloxacin resistance in 10 of 21 new MRSA isolates during the last 2 months of the study. Five of the 10 patients with ciprofloxacin-resistant MRSA isolates had never received ciprofloxacin. Long-term (6-month) eradication had been achieved in only three of 11 ciprofloxacin plus rifampin and four of 10 sulfamethoxazole and trimethoprim plus rifampin recipients. The use of this new fluoroquinolone for the eradication of MRSA colonization is usually not effective and may risk the development of ciprofloxacin resistance in MRSA within the hospital environment.
Vision screening in a primary care setting. A missed opportunity, To determine the effectiveness of vision screening in a primary care setting. we administered a questionnaire and a vision test to 458 patients from a general medical clinic. Subjects were referred for complete ophthalmologic evaluation if they failed the vision test or met other "high-risk" criteria based on information contained in the questionnaire. Patient-initiated requests for eye examinations were also honored. A total of 169 patients were scheduled for eye examinations. and 148 actually underwent ophthalmologic evaluation. One hundred one of those examined were referred on the basis of the study criteria. "Serious eye disease" (cataract. glaucoma. diabetic retinopathy. or age-related macular degeneration) was diagnosed in 96 (95%) of these patients. Prompt surgical intervention was recommended in 27 (27%). and medical treatment was begun in 21 (21%). Of those with serious eye disease. 59% met the criteria by failing the vision test. while 69% met the high-risk criteria determined by the questionnaire. Of the 148 subjects who received ophthalmologic evaluations. 47 requested them. Serious eye disease was diagnosed in 23 (50%) of the 47 patients. None of these individuals required immediate surgery. and medical treatment for glaucoma was begun in eight (17%). These data suggest that screening for serious eye disease in a primary care setting is an efficient mechanism to use for the identification of patients with undetected ocular disorders that require follow-up or treatment.
Long-term therapeutic use of benzodiazepines. I. Effects of abrupt discontinuation [published erratum appears in Arch Gen Psychiatry 1991 Jan;48(1):51, We compared the effect of abrupt discontinuation of therapeutic doses of short half-life and long half-life benzodiazepines in 57 benzodiazepine-dependent patients (daily use. greater than 1 year). Despite the use of a mean daily dose of 14.1 mg of diazepam equivalents. there were notable residual symptoms of anxiety and depression present at intake (Hamilton Rating Scale for Anxiety score. 17.0; Hamilton Rating Scale for Depression score. 14.0). Benzodiazepine intake was stabilized for 3 weeks before double-blind assignment to placebo (n = 47). or continued benzodiazepine use (n = 10). Clinical assessments were performed daily. including benzodiazepine plasma levels. Depending on the outcome criteria used. anywhere from 58% to 100% of patients were judged to have experienced a withdrawal reaction. with a peak severity at 2 days for short half-life and 4 to 7 days for long half-life benzodiazepines. Relapse onto benzodiazepines occurred in 27% of patients who were receiving long half-life benzodiazepines and in 57% of patients who were receiving short half-life benzodiazepines. Baseline predictors of relapse were nonpanic diagnoses. a higher benzodiazepine dose. and a higher Eysenck neuroticism score. A short half-life and higher daily doses were associated with greater withdrawal severity. as were personality traits. such as dependency and neuroticism. less education and higher baseline levels of anxious and depressive symptoms. Patients who were able to remain free of benzodiazepines for at least 5 weeks obtained lower levels of anxiety than before benzodiazepine discontinuation. These results provide a detailed picture of the symptoms. time course. and multidimensional determinants of the benzodiazepine withdrawal syndrome.
Long-term therapeutic use of benzodiazepines. II. Effects of gradual taper, We compared the effect on withdrawal severity and acute outcome of a 25% per week taper of short half-life vs long half-life benzodiazepines in 63 benzodiazepine-dependent patients. Patients unable to tolerate taper were permitted to slow the taper rate. Ninety percent of patients experienced a withdrawal reaction. but it was rarely more than mild to moderate. Nonetheless. 32% of long half-life and 42% of short half-life benzodiazepine-treated patients were unable to achieve a drug-free state. The most difficulty was experienced in the last half of taper. Baseline personality. high Eysenck neuroticism. female sex. and mild-to-moderate alcohol use were found to be more significant predictors of withdrawal severity than the daily benzodiazepine dose or benzodiazepine half-life. These findings suggest that personality factors contribute significantly to the patient's difficulties with gradual benzodiazepine discontinuation of therapeutic doses of benzodiazepines.
HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia, Agranulocytosis develops in approximately 1% of patients with chronic schizophrenia treated with the atypical neuroleptic drug clozapine. Previous studies have not identified the mechanism or risk factors for this adverse reaction. Because of an observed association between Jewish ethnic background and the development of agranulocytosis in our patient sample treated with clozapine for refractory symptoms. HLA typing was performed in 31 patients (19.4% of whom had developed agranulocytosis). The HLA-B38 phenotype was found in 83% of patients who developed agranulocytosis and in 20% of clozapine-treated patients who did not develop agranulocytosis. Because B38 is part of a haplotype known to occur frequently in the Ashkenazi Jewish population. the frequencies of the combined alleles HLA-B38. DR4. and DQw3 were examined. The incidence of HLA-B38. DR4. DQw3 was significantly increased in patients with agranulocytosis (five of five patients) compared with control patients of Ashkenazi Jewish ancestry (two of 17 patients). These findings indicate that genetic factors marked by major histocompatibility complex haplotypes may be associated with the susceptibility of Jewish schizophrenic patients treated with clozapine to develop agranulocytosis. We postulate that gene products contained in the haplotype may be involved in mediating drug toxicity.
Financial impact of a rapid CK-MB-specific immunoassay on the diagnosis of myocardial infarction, The purpose of this study was twofold. First. we evaluated the financial impact of a rapid. monoclonal antibody-based CK-MB mass assay (Stratus. Dade Division. Baxter Laboratories. Miami. Fla) for the direct measurement of CK-MB in serum samples from 65 patients admitted to the coronary care unit with the possible diagnosis of acute myocardial infarction. Second. we evaluated retrospectively the Stratus assay and an activity assay (electrophoresis) for CK-MB in the following patient categories: acute myocardial infarction treated with and without thrombolytic therapy. angina. congestive heart failure. skeletal muscle trauma. and the acutely ill without acute myocardial infarction. The advantageous features of the Stratus mass assay were as follows. First. the laboratory was able to perform the assay more frequently because of the short assay time per specimen (less than 10 minutes) without additional personnel. This had a substantial impact on the clinician's ability to diagnose acute myocardial infarction and to move patients out of an intensive care unit at substantial financial savings to the patient. the hospital. or the third-party payer. Second. the Stratus assay was able to detect low levels of CK-MB (1 to 2 micrograms/L) in the presence of low total creatine kinase activity (less than 100 U/L). Third. the Stratus assay showed no interference due to very-high-total creatine kinase activities (greater than 100.000 U/L). CK-BB. macro-creatine kinase. and mitochondrial creatine kinase.
The technicon H6000 analyzer discriminates chronic lymphocytic leukemia from other B-cell leukemias through automatic assessment of large unstained cells, The separation of chronic lymphocytic leukemia of B-cell origin from other chronic B-cell leukemias is subjective. being largely based on the morphologic features of the lymphoid cells in the peripheral blood. The percentage of large unstained cells determined with a Technicon H6000 analyzer (an automated blood cell differential analyzer. Technicon Instruments Corp. Tarrytown. NY) was used as a cell volume variable in an investigation of 70 cases of chronic lymphocytic leukemia of B-cell origin and of other chronic B-cell leukemias. The significant degree of correlation between the percentage of large unstained cells and morphoimmunophenotypic diagnosis. although obtained for a relatively small number of cases. suggests that this method of cell volume analysis can be used to improve diagnostic reproducibility in chronic B-cell leukemia.
Persistence of mucosal gastric carcinomas for 8 and 6 years in two patients, A small gastric carcinoma was detected in a man. but he refused surgery. Eight years later. he was readmitted for a check-up. and a partial gastrectomy was performed. Pathologic examination revealed a well-differentiated adenocarcinoma restricted within the mucosa. In another man. an irregularly shaped. grossly depressed lesion indicating a malignancy was present at the gastric angle. and 6 years later he agreed to a partial gastrectomy. The lesion proved to be a well-differentiated adenocarcinoma confined to the mucosa. Retrospective examination of the original biopsy specimen revealed a small area of adenocarcinoma. presumably overlooked at the initial examination. Thus. some gastric carcinomas of the well-differentiated type can grow at an extremely slow rate. without extensive spread or invasion. Findings in these cases contribute to knowledge of the biological behavior of gastric carcinomas.
Tumor of the atrioventricular nodal region. A clinical and immunohistochemical study, Autopsy specimens of 17 tumors of the atrioventricular nodal region were studied. Sudden death occurred in 14 children and adults; seven of these patients had a history of atrioventricular block or syncope. Three tumors were incidental findings in infants with other congenital anomalies; diaphragmatic agenesis. pulmonary hypoplasia. and Meckel's diverticulum in one patient; mitral atresia in one; and congenital hydrocephalus. ventricular septal defect. patent ductus arteriosus. coarctation of the aorta. and patent omphalovitelline duct in the third. Immunohistochemical stains demonstrated strong positivity for carcinoembryonic antigen in 13 of 13 cases. B72.3 antigen in 5 of 7 cases. and cytokeratin in 11 of 11 cases. Twenty control cases of mesothelioma and mesothelial hyperplasia were all negative for B72.3; one showed focal carcinoembryonic antigen staining. Ultrastructural analysis of one case demonstrated short rudimentary microvilli not characteristic of mesothelial cells. We conclude that so-called mesotheliomas of the atrioventricular nodal region are not of mesothelial origin. because of strong carcinoembryonic antigen positivity and occasional positivity with B72.3. as these antibodies react with glycoproteins found in endodermally derived tissue and generally not with mesothelial tissue. Conduction system tumors are most likely congenital rests of endodermal origin. can be associated with other congenital anomalies. and often cause symptoms of heart block and sudden death.
A signet-ring cell carcinoma of the ampulla of Vater, We describe a variant of carcinoma of the ampulla of Vater. which. to our knowledge. has not been previously described. Classic signet-ring cells represented the predominant cell type. and were admixed with more poorly differentiated tumor cells that were chromogranin positive. These findings raise the possibility of an amphicrine tumor of the ampulla.
Acalculus lymphoeosinophilic cholecystitis associated with interleukin-2 and lymphokine-activated killer cell therapy, A case of unusual cholecystitis that developed on completion of interleukin-2 and lymphokine-activated killer cell therapy is described. A 62-year-old man was treated with interleukin-2 and lymphokine-activated killer cells for disseminated renal cell carcinoma. During the course of the immunotherapy. his serum alkaline phosphatase level increased. as did the peripheral eosinophil count (0.31). Subsequently. clinical and radiologic evidence of acute cholecystitis was noted. The removed gallbladder showed acalculus cholecystitis with extensive diffuse infiltrates of numerous eosinophils and T lymphocytes. but sparse polymorphonuclear leukocytes. The authors name this unusual cholecystitis acalculus lymphoeosinophilic cholecystitis and believe it to be associated with interleukin-2 and lymphokine-activated killer cell therapy. The pathogenic relationship is discussed.
Functional assessment scales: a study of persons with multiple sclerosis, The purpose of this study was to investigate disability in persons with multiple sclerosis (MS) by using combinations of functional assessment scales and subscales to predict (1) the burden of care measured in minutes of assistance provided per day by another person in the home. and (2) the subject's level of satisfaction with life in general. The Functional Independence Measure (FIM). Incapacity Status Scale. Environmental Status Scale. and the Barthel Index had high intercorrelations with each other. Although each was predictive of the MS subject's physical care needs. the FIM was the most useful. A change in total FIM score of one point was equivalent to an average of 3.38 minutes of help from another person per day. With the Brief Symptom Inventory and the Environmental Status Scale. the FIM contributed to predicting the patient's general satisfaction as well. We propose that burden of care and subjective satisfaction with life be the standards by which functional assessment instruments are compared to reflect. in pragmatic terms. the impact of disability on the lives of individuals and on the human and economic resources of the community.
Rehabilitation of chronic stroke patients: changes in functional performance, Forty stroke patients who were at least one year post-onset completed a one-month intensive rehabilitation program. The month before the program served as a control period. During the program. patients received individual sessions in occupational and physical therapy four days a week. and they participated in group activities on the fifth day. Therapy emphasized instruction in motor planning. balance and weight shift. and the use of adaptive equipment; these motor abilities were then practiced within real life situations. The patients demonstrated significant improvement in the outcome measures of weight shift. balance. and ADL scores after the one-month rehabilitation program (weight shift: F = 16.1. p = .0001; balance: F = 6.26. p = .0007; ADL: F = 13.8. p = .0001). They retained these new skills during a three-month follow-up period.
Childhood stroke after minor neck trauma: case report, Cerebral infarction after minor trauma to the neck has rarely been reported. A case is presented of a child with trauma to the vertebrobasilar artery resulting in stroke. Computerized tomography scan and angiography results are presented. Despite two subsequent. separate transient episodes of vertigo. the child had good functional recovery with complete restoration of language and cognitive function. After 28 months. residual impairments identified were a mild right-sided ataxia and hemiparesis.
Is arterial proximity a valid indication for arteriography in penetrating extremity trauma? A prospective analysis, Three hundred seventy-three patients with a penetrating extremity injury were studied to assess the yield of arteriography. Patients underwent arteriography if any of the following was present: bruit. history of hemorrhage or hypotension. fracture. hematoma. decreased capillary refill. major soft-tissue injury. or nerve or pulse deficit. In the absence of these findings. arteriography was performed if the injury was in "proximity" to a major neurovascular bundle. In 216 patients. arteriography was performed when an abnormal finding was noted. Sixty-five injuries were identified. 19 requiring intervention. Proximity was the indication for arteriography in 157 patients. Seventeen injuries were identified. of which one required repair. In penetrating extremity trauma. the need for arteriography is based on clinical findings. The use of arteriography to screen for an arterial injury when proximity alone is the indication rarely identifies a significant injury and should be abandoned.
The impact of microinvasion on axillary node metastases and survival in patients with intraductal breast cancer, A rational approach to the local treatment of intraductal breast cancer continues to generate considerable debate. However. the finding of an invasive component in intraductal breast cancer is widely regarded as an appropriate indication for axillary node dissection as part of the local treatment and staging of this disease. Despite this view. the natural history of patients with intraductal breast cancer with foci of microinvasion is poorly defined. Between 1965 and 1988. 41 patients with this pathologic finding of intraductal carcinoma with foci of microinvasion were seen at the UCLA Medical Center. Twenty-three patients presented with mammographic abnormalities. while 17 patients presented with a palpable mass. One patient presented with Paget's disease of the nipple. Thirty-three patients underwent axillary node dissection as part of their local treatment. No lymph node metastases were identified. The median follow-up in 37 patients was 47 months. There have been no local recurrences and no deaths from recurrent breast cancer. Intraductal breast cancer associated with microinvasion appears to be an extremely favorable lesion with minimal risk of nodal metastases.
Analysis of potential risks associated with 7.5% sodium chloride resuscitation of traumatic shock [published erratum appears in Arch Surg 1991 Jan;126(1):43, We evaluated the potential side effects of rapidly infusing 250 mL of either 7.5% sodium chloride or 7.5% sodium chloride per 6% dextran 70. using lactated Ringer's as the control. to 106 critically injured patients in two prospective double-blinded emergency department trials. Eight patients had a significant hyperchloremic acidemia in association with infusion of the hypertonic solutions. but all eight were moribund before infusion and many factors other than hyperchloremia could have contributed to their acidemia. Other blood chemistry changes that might have been associated with the hypertonic solutions. such as hyperosmolality or hypernatremia. were made insignificant by other factors. such as high blood alcohol levels or concomitant administration of sodium bicarbonate. There were no cases of central pontine myelinolysis; bleeding was not potentiated. There was no difficulty with crossmatching of blood. No anaphylactoid reactions occurred. In a setting of limited volume resuscitation. the solutions are likely to have a favorable risk-to-benefit ratio.
The efficacy of central venous and pulmonary artery catheters and therapy based upon them in reducing mortality and morbidity, The purpose of this study was to (1) evaluate the relative cost effectiveness of the central venous pressure and flow-directed pulmonary artery catheters used to maintain normal hemodynamic values as therapeutic goals in the control groups vs supranormal values empirically observed in critically ill postoperative survivors in the protocol groups. and (2) to evaluate tissue perfusion and oxygenation in relationship to organ failure and mortality. In two prospective clinical trials there were no significant differences in outcome between the central venous pressure and pulmonary artery control groups that used normal values as therapeutic goals. However. there were marked and significant reductions in morbidity and mortality of the protocol groups using the supranormal cardiac index. oxygen delivery. and oxygen consumption values as goals. The cumulative oxygen debt was less and organ failures were fewer and less severe in the protocol groups than in the control groups.
Angioscopy for intraoperative management of thromboembolectomy, Our experience with angioscopy suggests that direct visualization of the arterial lumen during thromboembolectomy procedures would provide a more reliable method of assessing luminal morphologic characteristics than angiography alone. We inspected 32 grafts (seven aortobifemoral. 18 infrainguinal bypass. and seven dialysis access fistula grafts) in 32 patients. Thirty-one patients had thrombotic events and one patient had an acute embolus. Angioscopy following standard catheter thrombectomy revealed significant amounts of retained thrombus or neointima in all thrombectomies. Angioscopic information from 18 patients with an infrainguinal bypass graft led to graft revision in six cases and placement of a new graft in 10 cases. One graft limb was replaced in seven aortobifemoral grafts. and multiple repeated thrombectomies were employed to extract debris in the remaining six cases. Repeated graft thrombectomy was also beneficial in dialysis access fistulas. Angioscopy allowed us to omit the completion angiogram and led to an improved technical result. We conclude that angioscopy is useful during thromboembolectomy procedures.
Massive splenomegaly. Superior results with a combined endovascular and operative approach, Splenectomy for massive splenomegaly (drained splenic weight. greater than 1000 g) has an uncommonly high morbidity and mortality because of technical challenges and problems of hemostasis. In a group of 10 patients with massive splenomegaly due to myeloproliferative disorders (average splenic weight. 4193 g). we developed a management algorithm based on preoperative angiographic embolization of the splenic artery. Average operating time was 1.7 hours (range. 1 to 2.5 hours). Average blood loss was 528 mL; six of the 10 patients had blood loss less than 250 mL. There were four minor complications and one major complication (gastric ulcer requiring reoperation). There were no deaths in the perioperative period. and no patients required reoperation for hemorrhage.
Selection factors resulting in improved survival after surgical resection of tumors metastatic to the lungs, From 1973 through 1987. a total of 140 patients underwent 184 operations for removal of metastatic tumors to the lungs. The number of lesions removed ranged form one to 30. Of the patients. 44% had solitary lesions. Overall 3-year survival was 62.6%. and 5-year survival was 48.2%. In all primary tumors except melanoma and breast cancer. 3-year survival was greater than 50% and 5-year survival was greater than 40%. With rare exceptions. the operation of choice for unilateral lesions was ipsilateral thoracotomy. and for bilateral lesions it was median sternotomy. Adequate conservative resection was the rule. There were three pneumonectomies. 25 lobectomies. 71 single wedge resections. 38 multiple unilateral wedge resections. and 47 bilateral wedge resections. There were no postoperative hospital deaths. Cox covariate analysis demonstrated improved survival in patients whose largest lesion was less than 1.5 cm in diameter and with disease-free interval longer than 1 year. but survival was not related to number of lesions or age of patient. An aggressive surgical approach is justified in patients with most primary tumors and a limited number of lung metastases less than 1.5 cm in diameter. Resection of metastases from melanoma and breast cancer should be accomplished after other sites of metastatic disease have been ruled out by the most stringent criteria.
Apneic oxygenation in apnea tests for brain death. A controlled trial, We performed a prospective controlled study of apneic oxygenation on 15 patients undergoing apnea tests for brain death. All patients were preoxygenated with 100% oxygen at existing respirator settings. During the 10-minute apnea tests. nine patients were given continuous apneic oxygenation by tracheal cannula. The other six patients had tracheal tubes open to room air. The patients given apneic oxygenation had little or no hypoxia by the end of the test. The patients given room air during the test became hypoxic. Many neurologists perform apnea tests with no oxygenation or with preoxygenation alone. This is the first prospective controlled study (to our knowledge) of apneic oxygenation; it shows that preoxygenation alone does not prevent hypoxia during apnea tests for brain death. We recommend that all apnea tests be performed with apneic oxygenation.
Geographic patterns of parkinsonism-dementia complex on Guam. 1956 through 1985, Average annual age-adjusted incidence rates of parkinsonism-dementia complex were obtained for the 19 election districts of Guam from 1956 through 1985. The highest rates were found in the southern and central districts. and the lowest rates were found in the northern and western districts. Geographic and temporal patterns of incidence were associated with socioeconomic status but not with geochemical factors. The risk of parkinsonism-dementia complex in susceptible sibships was much higher than that in the general population--even in districts with the highest incidence rates. but especially in districts with the lowest incidence rates. Our evidence tends to support the hypothesis that multiple factors linked to cycad use play an important role in the cause of PDC. Hypotheses related to metal exposure and simple genetic factors were unsatisfactory explanations for the epidemiologic patterns observed.
Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors, The entry characteristics of 1367 patients enrolled into the Extracranial/Intracranial Bypass Study were examined to determine if site differences in intracranial and extracranial arterial lesions among racial groups could be explained by differences in risk factors. Blacks were more often hypertensive. diabetic. or cigarette smokers. while whites had higher systolic blood pressure and hemoglobin values. Orientals had the lowest prevalence of vascular risk factors. Despite these differences in risk factors. multivariate analysis showed race to be an independent and strong predictor of the location of cerebrovascular lesions. To our knowledge. this study is unique in documenting risk factors prospectively and systematically in three racial groups simultaneously. Although generalization is limited by possible biases related to patient selection. the results affirm previous tentative conclusions about the role of race in determining the location of cerebrovascular disease.
The large striatocapsular infarct. A clinical and pathophysiological entity, We examined 29 patients with strictly subcortical large striatocapsular infarctions. Eight of them had aphasia or neglect. All patients underwent transcranial Doppler ultrasonography or selective carotid angiography. magnetic resonance imaging. and single photon emission tomography for assessment of cerebral blood flow. blood volume. and cerebral perfusion reserve. The signs were compatible with cortical territorial infarctions rather than lacunes. On both magnetic resonance imaging and computed tomographic scans. the lesions corresponded to the territories of the medial and lateral group of the lenticulostriate arteries. Heubner's artery. or the anterior choroidal artery. The infarctions were either due to cerebral embolization into the M1 segment of the middle cerebral artery or due to stenosis at the same site. ie. lesions that acutely and simultaneously occluded the orifices of the lenticulostriate or neighboring arteries. Persistent occlusion of the middle cerebral arteries and a decrease of cortical regional cerebral blood flow were only found in patients with aphasia or neglect. All patients without aphasia or neglect showed a rapid recanalization of the middle cerebral artery occlusion or a stenosis of the M1 segment and no cortical regional cerebral blood flow decrease. Large striatocapsular infarctions occur due to occlusive disease of the middle cerebral artery (large-vessel disease) and not due to a disseminated in situ occlusion of the long penetrating arteries (small-vessel disease). as in lacunes. Neuropsychological deficits can be explained by decreased cortical blood flow due to a persistent occlusive lesion of the middle cerebral artery.
Brain imaging abnormalities in mental disorders of late life, Psychiatric inpatients with dementia (N = 61) or depression (N = 67) in late life were 2.6 times more likely to manifest magnetic resonance imaging abnormalities of the brain than were elderly controls (N = 44). Controlling for the effects of age and gender. demented patients were distinguishable from controls by an increased prevalence of cortical atrophy and infarction. while depressed patients exhibited an increased prevalence of cortical infarctions and leukoencephalopathy. Patients with dementia were distinguishable from those with major depression by an increased prevalence of cortical atrophy. These results indicate that major depression in late life. like dementia. is associated with a remarkable increase in overt pathologic changes in the brain.
Adjuvant chemotherapy for primary lymphoma of the central nervous system, Ten immunocompetent patients with primary non-Hodgkin's lymphoma of the central nervous system were treated by the neuro-oncology service at the University of California at San Francisco (UCSF). After undergoing surgery for biopsy or removal of their tumors. these patients (group 1) received irradiation with hydroxyurea followed by adjuvant chemotherapy with the combination of procarbazine. lomustine (CCNU). and vincristine. The outcome of treatment in this group was compared with that in three other groups of patients with primary CNS lymphoma: patients treated at the UCSF Cancer Research Institute who underwent surgery and radiation therapy (RT) (group 2); patients described in the literature who had surgery and RT (group 3); or patients described in the literature who had surgery. RT. and chemotherapy (group 4). Median and quartile survival times were greater in patients who received adjuvant chemotherapy (group 1. 30 and 50 months; group 4. 20 and 25 months) than in patients who did not receive chemotherapy after RT (group 2. 13 and 20 months; group 3. 15 and 24 months). These results suggest that adjuvant chemotherapy is useful in the treatment of primary CNS lymphoma.
Multicenter trial of cryotherapy for retinopathy of prematurity. One-year outcome--structure and function. Cryotherapy for Retinopathy of Prematurity Cooperative Group, This study of the safety and efficacy of cryotherapy in treating severe retinopathy of prematurity registered 9751 infants with birth weights less than 1251 g at 23 study centers. Two hundred ninety-one infants developed a defined threshold retinopathy of prematurity. and cryotherapy was performed in approximately half of the eyes through a randomization protocol. Twelve months after randomization. results of masked grading of fundus photographs of the posterior pole were similar to results obtained 3 months after randomization. and indicated an unfavorable outcome in 25.7% of the eyes that received cryotherapy compared with 47.4% of the control eyes (P less than .0001). For the first time. masked Teller Acuity Card assessment of grating acuity was performed in this study group and indicated an unfavorable functional outcome in 35.0% of the treated eyes compared with 56.3% of the control eyes (P less than .0001). These results indicate that cryotherapy reduces the risk of unfavorable retinal and functional outcome from threshold retinopathy of prematurity.
Clinical and morphometric results of penetrating keratoplasty with one-piece anterior-chamber or suture-fixated posterior-chamber lenses in the absence of lens capsule, The clinical records and serial corneal endothelial images of 25 acapsular. pseudophakic eyes with Kelman-style. one-piece. anterior-chamber intraocular lenses and 24 acapsular. pseudophakic eyes with suture-fixated. posterior-chamber intraocular lenses following penetrating keratoplasty were reviewed to determine clinical success and endothelial survival after 1 year. Twenty-two (88%) of 25 grafts in the anterior-chamber intraocular lens group and 23 (96%) of 24 grafts in the sutured posterior-chamber intraocular lens group were clear after 1 year; best corrected visual acuity of 20/40 or better was noted in 25% of the eyes in the anterior-chamber intraocular lens group and 29% of the eyes in the sutured posterior-chamber intraocular lens group. The mean intraocular pressure for the anterior-chamber intraocular lens group was significantly lower than for the sutured posterior-chamber intraocular lens group at 3 months (17 +/- 4 vs 21 +/- 7 mm Hg) and at 6 months (17 +/- 3 vs 20 +/- 5 mm Hg); but did not differ at 1 year. The mean percent of endothelial cell loss after 1 year did not differ between the anterior-chamber intraocular lens group (32% +/- 26%) and the sutured posterior-chamber intraocular lens group (27% +/- 26%). No clinical or endothelial morphometric advantages were noted after 1 year for the suture-fixated. posterior-chamber intraocular lens over the Kelman-style. one-piece anterior chamber. intraocular lens following pseudophakic penetrating keratoplasty; however. a long-term. prospective. randomized study of these two intraocular lens types is recommended.
Assessment of vitamin A status by a disk applicator for conjunctival impression cytology, Conjunctival impression cytology was performed on 236 Indonesian preschool children. half of whom had mild xerophthalmia and half of whom were age-matched controls. We devised an applicator that applies a paper disk of fixed area to the conjunctiva with even pressure. The disk applicator was used to collect impression cytology specimens from the temporal bulbar conjunctiva of one eye while the original strip technique was used on the other eye. Mean (+/- SD) serum retinol values for children with normal and abnormal discs were 22.0 +/- 8.6 micrograms/dL and 18.0 +/- 7.2 micrograms/dL P less than .0001). Mean serum values for normal and abnormal strips were 21.7 +/- 8.6 micrograms/dL and 19.0 +/- 7.7 micrograms/dL (P less than .03). Specimens obtained with the new disk applicator corresponded more closely with serum vitamin A levels and therefore vitamin A status than those obtained with the traditional strip technique.
S-antigen. Identification of human T-cell lymphocyte proliferation sites, Immune responses to normal retinal proteins. including S-antigen. have been demonstrated in patients with a variety of retinal disorders. as well as in those who have received panretinal laser photocoagulation. T-cell lymphocytes (T cells) have been implicated in the pathogenesis of several ocular inflammatory diseases of possible autoimmune etiology. We used synthetic peptides that correspond to the amino acid sequence of S-antigen in lymphocyte proliferation assays to identify specific sites in the molecule recognized by human T cells. Ten patients with type II diabetes were studied before and after initial panretinal laser photocoagulation for proliferative diabetic retinopathy. T-cell responses. expressed as a stimulation index. to S-antigen and peptides were negative in all patients before treatment. Three weeks after panretinal laser photocoagulation. eight of 10 assays were positive (stimulation index greater than 2; P less than .01) when lymphocytes were stimulated with peptide BSA(273-292); six of nine were positive (P less than .01) with peptide BSA(303-332); and six of six were positive (P less than .001) with peptide BSA(343-362). Our study identifies several specific sites in S-antigen that elicit human immune responses. The implications of these findings with regard to the pathogenesis and treatment of autoimmune uveitis are discussed.
Systemic amiloride inhibits experimentally induced neovascularization, Amiloride is an inhibitor of urokinase-type plasminogen activator. and might therefore have an inhibitory effect on neovascularization. Neovascularization was induced in rabbit corneas via local implantation of prostaglandin E1 pellets prepared in a slow-release polymer. Animals received daily intraperitoneal injections of 30 mg of amiloride. or an equivalent volume of saline solution for 5 days; both were well tolerated without severe untoward effect. Neovascular response. as documented by corneal photographs. was evaluated after 5 days of injections. The area of induced corneal neovascularization was decreased by 55% in animals receiving amiloride when compared with controls. Thus. amiloride and similar compounds may prove useful in the study and management of neovascularization.
The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses, We performed 2 metaanalyses of placebo-controlled and comparative clinical trials to examine the relative efficacy and toxicity of methotrexate (MTX). injectable gold. D-penicillamine (DP). sulfasalazine (SSZ). auranofin (AUR). and antimalarial drugs. the second-line drugs most commonly used to treat rheumatoid arthritis (RA). For the efficacy study. we applied a set of inclusion criteria and focused on trials which provided information on tender joint count. erythrocyte sedimentation rate. or grip strength. We found 66 clinical trials that contained 117 treatment groups of interest. and for each drug. we combined the treatment groups. For each outcome. results showed that AUR tended to be weaker than other second-line drugs. The results of the 3 outcome measures were synthesized into a composite measure of outcomes. and AUR was significantly weaker than MTX (P = 0.006). injectable gold (P less than 0.0001). DP (P less than 0.0001). and SSZ (P = 0.009) and was slightly. but not significantly. weaker than antimalarial agents (P = 0.11). We also found heterogeneity among antimalarial agents. in that patients treated with chloroquine did better than those treated with hydroxychloroquine. We found little difference in efficacy between MTX. injectable gold. DP. and SSZ. A power analysis showed that a trial should contain at least 170 patients per treatment group to successfully differentiate between more effective and less effective (e.g.. AUR) second-line drugs. None of the reported interdrug comparative trials we reviewed were this large. For the toxicity study. our inclusion criteria captured RA trials which reported the proportion of patients who discontinued therapy because of drug toxicity and the total proportion who dropped out. We found 71 clinical trials that contained 129 treatment groups. The average proportion who dropped out and the average proportion who dropped out because of drug toxicity were computed for each drug. Overall. 30.2% of the patients in these trials dropped out; 50% of them did so because of drug toxicity. Injectable gold had higher toxicity rates (P less than 0.05) and higher total dropout rates (P less than 0.01) than any other drug; 30% of gold-treated patients dropped out because of side effects versus 15% of all trial patients. Antimalarial drugs and AUR had relatively low rates of toxicity; the rate for MTX was imprecise because of discrepancies between trials. Thus. of the commonly used second-line drugs. AUR is the weakest. and injectable gold is the most toxic. Agents introduced in the future will be compared with these drugs.(ABSTRACT TRUNCATED AT 400 WORDS).
Diminished incidence of severe rheumatoid arthritis associated with oral contraceptive use, It has been suggested that the negative association between rheumatoid arthritis (RA) and oral contraceptive (OC) use might be limited to the more severe forms of RA. To investigate this further. we studied 121 consecutive female patients with definite RA. 52 female patients with probable RA. and 378 female controls. All patients had RA symptoms of recent onset. After a mean followup period of 6 years. patients with definite RA were classified as having either a severe disease course (n = 76) or a mild disease course (n = 45). The negative association between OC use prior to the onset of RA symptoms and the development of RA was limited to those patients with definite RA who had a severe disease course. We therefore conclude that OC use prior to the onset of RA symptoms is only associated with a reduction in the incidence of severe RA. This may explain the divergent results of previous studies.
Relationship of glucocorticoid dosage to serum bone Gla-protein concentration in patients with rheumatologic disorders, Serum bone Gla-protein (BGP) measurements in 50 rheumatic disease patients receiving long-term prednisone therapy revealed an inverse relationship (r = -0.71. P less than 0.001) between serum BGP levels and prednisone dosage. Multiple regression analysis demonstrated significant relationships (R2 = 0.72. P less than 0.001) between serum BGP1/2 and prednisone dosage. dosage2. serum creatinine. age. and an age-creatinine interaction. This model predicts the suppression of serum BGP with low dosages of steroids and 50% suppression with dosages of 20-25 mg/day.
Use of molecular cloning methods to map the distribution of epitopes on topoisomerase I (Scl-70) recognized by sera of scleroderma patients, We report the initial molecular characterization of the autoimmune response against DNA topoisomerase I (topo I; Scl-70). Sera from 36 patients with scleroderma and 4 healthy control subjects were studied using 6 subcloned portions of topo I. Twenty-three sera recognized at least 2 independent epitopes on the molecule. Therefore. anti-topo I. like other non-organ-specific autoantibodies characterized to date. is polyclonal and multifocal. The cloned protein should prove suitable for sensitive early detection of anti-topo I in the clinical setting.
Alteration of the cellular fatty acid profile and the production of eicosanoids in human monocytes by gamma-linolenic acid, We administered borage seed oil (9 capsules/day) for 12 weeks to 7 normal controls and to 7 patients with active rheumatoid arthritis. The therapy provided 1.1 gm/day of gamma-linolenic acid (GLA). GLA administration resulted in increased proportions of its first metabolite. dihomo-gamma-linolenic acid (DGLA). in circulating mononuclear cells. The ratios of DGLA to arachidonic acid and DGLA to stearic acid increased significantly in these cells. Significant reductions in prostaglandin E2. leukotriene B4. and leukotriene C4 produced by stimulated monocytes were seen after 12 weeks of GLA supplementation. The antiinflammatory effects of GLA administration observed in animal models. and the apparent clinical improvement experienced by 6 or 7 rheumatoid arthritis patients given borage seed oil in this open. uncontrolled study may be due in part to reduced generation of arachidonic acid oxygenation products.
Increased expression of platelet-derived growth factor type B receptors in the skin of patients with systemic sclerosis, The expression of B-type receptors for platelet-derived growth factor (PDGF) was investigated in skin biopsy samples from patients with systemic sclerosis (SSc). by immunohistochemical staining using monoclonal antibodies specific for the receptor. Whereas skin from healthy individuals lacked expression of PDGF-B receptors. receptor expression was seen in sclerodermatous skin lesions from 13 of 14 patients. Increased receptor expression was observed in dermal vessels. as well as on many stromal fibroblast-like cells close to these vessels. PDGF-B receptor expression was most pronounced within and around dermal vessels in which perivascular infiltrates of Leu-4-positive T lymphocytes and HLA-DR-positive. RFD7-positive activated macrophages were present. Both perivascular inflammatory cell infiltrates and PDGF-B receptor expression were generally also seen in macroscopically normal areas of the skin of the SSc patients. indicating that the observed phenotypic alterations may precede the macroscopically observable features of scleroderma in the skin. The observed induction of PDGF-B receptors. together with indirect indications of increased synthesis and release of PDGF. would be compatible with altered PDGF-mediated control of connective tissue cell growth as part of the molecular basis for development of the skin lesions in SSc.
D-penicillamine-induced lupus erythematosus, We describe a patient who presented with polyarthritis. pleurisy. rash. and a positive antinuclear antibody result after 5 years of D-penicillamine therapy. D-penicillamine-induced antinuclear antibodies were mainly high-titer IgG directed against the (H2A-H2B)-DNA complex. Weak IgM activity with H1 and H2B was also observed. Withdrawal of D-penicillamine therapy resulted in improvement in clinical symptoms and gradual resolution of serologic abnormalities.
Laboratory tests in the follow-up of treated alcoholics: how often should testing be repeated, The study group consisted of 60 male and 13 female alcohol-dependent employed patients who participated in inpatient treatment for alcoholism. They were followed up bimonthly for eight months after the treatment period. The results with GGT. ASAT. ALAT. MCV and the combination of GGT and MCV were studied with respect to the effect of taking the tests once (at eight months). twice (once every four months) or four times (bimonthly). According to our definition. the treatment outcome was good when the laboratory test values were within the normal range during the whole follow-up period. The differences in observed outcome (at eight months after treatment) were small whether one took the tests once at the end of the follow-up period or up to four (i.e. bimonthly) times. Nevertheless. there were some differences between the laboratory markers. To get the most accurate picture of drinking during the follow-up period one should repeat the test bimonthly with ASAT or ALAT. once every four months with GGT (or combined GGT and MCV). and once after eight months with MCV. When the time course of relapses is important for the study the more frequent test taking is also indicated.
Serum and urinary beta-hexosaminidase as markers of heavy drinking, Serum and urinary beta-hexosaminidase (SHEX and UHEX) were determined in 32 alcoholic men admitted to inpatient detoxification treatment for seven days. and in 27 teetotallers. On the admission SHEX was increased in 68.8% and UHEX in 81.3% and after seven days of abstinence the corresponding percentages were 37.5 (SHEX) and 71.9 (UHEX). During the treatment SHEX decreased significantly while UHEX did not. On the admission to the treatment UHEX correlated positively with SHEX (r = 0.54; P less than 0.01). The results suggest that UHEX may be a more sensitive marker of heavy drinking than SHEX. Furthermore UHEX stays longer elevated than SHEX.
Estimation of the amount of alcohol ingested from a single blood alcohol concentration, Capillary blood alcohol concentrations (BAL) measured in 22 young adult male volunteers each of whom received three different treatments of alcohol (total N = 66) have been related quantitatively to the dose of alcohol ingested. Linear regression with reasonably homogeneous variances have been found when the BAL at 2. 2.5 and 3 hr are divided by the person's body weight and plotted versus the g/kg (D/W) dose. Error analysis indicated that the least error in the predicted dose (D/W) was obtained for BAL measured at 2 hr post dosing. In the latter case the mean absolute error was 6.23%. 59% of the errors were within +/- 5% and 88% of the errors were within +/- 10%.
Ethanol-inducible cytochrome P-450 activity and increase in acetaldehyde bound to microsomes after chronic administration of acetaldehyde or ethanol, Chronic ethanol consumption results in acetaldehyde adduct formation with proteins such as haemoglobin and liver proteins in vivo. Our purpose was to study the binding of acetaldehyde to liver microsomal proteins. a site of ethanol oxidation via cytochrome P-450 (especially P-450 II E1). after chronic administration of ethanol or acetaldehyde for 21 days to rats. The liver microsomal oxidation of 1-butanol by the ethanol-inducible P-450 also was examined. Acetaldehyde bound to liver microsomal proteins was higher in ethanol-fed rats compared with acetaldehyde-treated rats (0.735 vs 0.413 nmol/mg of protein respectively). The biotransformation of n-butanol to butyraldehyde by liver microsomes was increased (by 136%) in ethanol-fed rats vs controls. whereas in acetaldehyde-treated rats this increase was much lower (only 27%). However. in this last group. a significant negative relationship between the quantity of acetaldehyde bound to microsomal proteins and the monooxygenase-catalyzed transformation of butanol by liver microsomes was demonstrated (r = -0.79. P less than 0.01). These results suggest that proteins of liver microsomes are a target for acetaldehyde binding during ethanol oxidation and such adduct formation could impair the oxidative properties of the alcohol-inducible cytochrome P-450.
The effect of maternal ethanol infusion on placental blood flow and fetal glucose metabolism in sheep, Intravenous infusion of 1 g ethanol/min over 1 hr to seven catheterised pregnant ewes decreased blood flow on both sides of the placenta. The reductions in blood flow were maintained for at least 2 hr after the infusion of ethanol had ceased. Although blood flow was reduced. fetal blood gases were unchanged. Plasma glucose concentrations were unchanged by ethanol. but fetal glucose supply and consumption were both decreased following maternal ethanol infusions. If maintained by chronic alcohol consumption these changes could contribute to the growth retardation seen in the Fetal Alcohol Syndrome.
Alcohol use and depressive symptoms among Mexican Americans and non-Hispanic Whites, Alcohol use is associated with depressive symptoms in several studies. Using data from a community survey. this study examined whether this relationship (a) can be accounted for by ethnic or sociodemographic differences among persons who engage in various levels of alcohol use; and (b) differs for Mexican Americans (N = 1244) and non-Hispanic Whites (N = 1149). Using large quantities of alcohol. and. among men. daily drinking. were associated with depressed mood. These associations were similar for Mexican Americans and non-Hispanic Whites. and associations of quantity and frequency with depression were independent of each other. Among women. the cultural and demographic characteristics of high-quantity drinkers and abstainers (both of whom tended to be Mexican Americans) accounted for the association of alcohol use with depression. Among men. there was some suggestion that unemployment and unmarried status mediated the association of alcohol quantity with depression. People who drank greater quantities of alcohol per occasion reported more somatic depressive symptoms. and more frequent male drinkers reported more of most types of depressive symptoms.
Prospective evaluation of gastric emptying in the self-poisoned patient, The authors prospectively studied the effect of gastric emptying (GE) and activated charcoal (AC) upon clinical outcome in acutely self-poisoned patients. Presumed overdose patients (n = 808) were treated using an alternate day protocol based on a 10-question cognitive function examination and presenting vital sign parameters. Asymptomatic patients (n = 451) did not receive GE. AC was administered to asymptomatic patients only on even days. GE in the remaining symptomatic patients (n = 357) was performed only on even days. On emptying days. alert patients had ipecac-induced emesis while obtunded patients received gastric lavage. AC therapy followed gastric emptying. On nonemptying days. symptomatic patients were treated only with AC. No clinical deterioration occurred in the asymptomatic patients treated without GE. AC use did not alter outcome measures in asymptomatic patients. GE procedures in symptomatic patients did not significantly alter the length of stay in the emergency department. mean length of time intubated. or mean length of stay in the intensive care unit. Gastric lavage was associated with a higher prevalence of medical intensive care unit admissions (P = .0001) and aspiration pneumonia (P = .0001). The data support the management of selected acute overdose patients without GE and fail to show a benefit from AC in asymptomatic overdose patients.
Controlling for the severity of injuries in emergency medicine research, The injury severity score (ISS) and age have been used retrospectively to control for trauma severity. Other control variables such as the revised trauma score (RTS) and the TRISS method (which estimates the probability of survival for each patient) additionally require that values of blood pressure. Glasgow coma scale. and respiratory rate. be recorded in the emergency department. The authors question when the RTS. ISS. the ISS and age. or the probability of survival calculated using the TRISS method should be used to control for severity of injuries in trauma research. Relations between predictor variables and (1) survival to hospital discharge. (2) hospital length of stay for survivors. and (3) length of ICU stay were compared by cause of injury: penetrating. motor vehicle accident. low fall. or other blunt. Data were collected over 12 months for 2.914 consecutive adult patients who died or stayed in five nontrauma and three trauma centers for 48 hours or more. For survival. the false-negative rates of probability of survival calculated using the TRISS method were approximately half that of the ISS and age; no variable adequately explained survival among those with low falls. Combinations of ISS. RTS. and age explained the most variation in lengths of hospital stay among survivors. while ISS explained the most variation in lengths of intensive care unit (ICU) stay. Researchers should consider the ISS with RTS and age to control for severity when lengths of hospital or ICU stay are studied. The TRISS method should be used in studies of survival. In both cases. the RTS which requires data collection in the emergency department must be calculated.
Urgent care center pediatric telephone advice, Pediatric telephone advice is sought frequently by members of the community. This study was undertaken to evaluate the quality and accuracy of pediatric telephone advice given by free-standing urgent care centers. One hundred such facilities were telephoned and advice was requested by a research assistant. A case was presented that could have represented a pediatric medical emergency. Overall only 17 centers gave adequate advice. The data suggest that under some circumstances free-standing urgent care center pediatric telephone advice may be inaccurate and inappropriate. Workable policies and protocols for pediatric telephone advice should be instituted by these facilities.
Ectopic pregnancy: ten common pitfalls in diagnosis, Ectopic pregnancy (EP) is a common. life-threatening complication of pregnancy. Modern technology (ultrasonography and improved pregnancy tests) should facilitate the diagnosis of EP. However. in a retrospective review of 65 cases of confirmed EP managed over 18 months at an urban teaching hospital. only 37 of 65 patients (57%. Cl95 = 44%. 69%) received prompt diagnosis and treatment; delays occurred in 28 patients (43%). In 10 of the 27 delayed cases. the diagnosis of EP was not even considered at the time of the first visit. In patients with a delayed diagnosis. morbidity (transfusions. cardiovascular instability. progression of illness) did occur. Diagnostic pitfalls that resulted in delayed care were reviewed. delays most commonly occurred in patients with a benign examination or "atypical" pain. Risk factors for EP were missed (7 patients. 25%). subtle clues to blood loss were often ignored (10 patients. 36%). and passage of tissue was thought to exclude EP (2 patients). Ultrasound was only helpful for half of the diagnoses and was misinterpreted in 27%. A dry or serous culdocentesis occurred frequently. In five patients. a falling or low quantitative human chorionic gonadotropin level was believed to indicate a completed abortion. The authors conclude that almost half of EPs are still missed on the first physician visit; errors and pitfalls in diagnosis are still common in the 1980s.
Whole bowel irrigation and the cocaine body-packer: a new approach to a common problem, Gastrointestinal drug smuggling is a common problem in many major cities. Though the majority of cases never require medical attention. the "body-packer" frequently presents with life-threatening symptoms of intoxication. including seizures and cardiorespiratory collapse. as well as mechanical obstruction from the ingested drug packets. The risk to asymptomatic smugglers may vary with packaging materials. and remains unknown. Lack of controlled studies. and variations in packaging materials and clinical outcomes have prevented formulation of a consistent management strategy. Current recommendations for asymptomatic body-packers vary from immediate surgical removal. to use of laxatives. to observation. The authors present the first reported case of an asymptomatic cocaine body-packer treated with whole bowel irrigation with polyethylene glycol electrolyte lavage solution. This strategy was safe. well tolerated. resulted in the rapid elimination of drug packets from the gastrointestinal tract. and facilitated assessment by contrast radiography. The potential benefits and limitations for the use of whole bowel irrigation in this difficult problem are discussed.
The spectrum of emergency care of agricultural trauma in central Wisconsin, Agriculture is among the most dangerous occupations in the United States. When injuries do occur. the emergency department (ED) is the primary source of care. Over a 2-year period. the emergency medicine section of the Marshfield Clinic/St Joseph's Hospital. cared for 913 victims of agricultural trauma. Although 11% were initially admitted and 4% were later treated. the remainder received their care solely in the ED. Unlike most occupational injuries. people of any age may be involved in agricultural injuries; 27% in this series were less than 18 years of age and 5% were 65 years or older. Just over half of all injuries were from mechanical devices. including tractor and farm machinery. The remainder were from animals. falls. or exposure. Although several different types of injuries occurred. the most common diagnoses were soft tissue injuries and fractures and the most common procedure was diagnostic radiography followed by wound and fracture care. An ED in a rural setting should be prepared to deal with agricultural trauma.
Methylene chloride: report of five exposures and two deaths, Five patients presented to the emergency department (ED) following exposure in an enclosed space to methylene chloride (dichloromethane). used for removing paint. Two workers and three rescuers were involved. Two rescuers complained only of dizziness and mild nausea. and were subsequently discharged from the ED. One rescuer was asymptomatic. Worker no. 1 arrived in cardiac arrest and eventually died in the ED despite resuscitation efforts. Worker no. 2 also presented to the ED in cardiac arrest. and was successfully resuscitated to pulse and blood pressure. However. he never regained consciousness or spontaneous respirations. and died on the fourth day. Of interest is that worker no. 2's carboxyhemoglobin level increased from 2% to 8% over the 9 hours following admission. despite administration of 40% to 50% oxygen by endotracheal tube. Among the conclusions that can be drawn are (1) the cause of death in these patients was not carbon monoxide poisoning. but solvent-induced narcosis; (2) carboxyhemoglobin levels may continue to rise following cessation of exposure. despite administration of high flow oxygen; (3) rescuers can easily become victims if proper protective clothing and respirators are not worn.
Epidural hematoma: an unusual presentation, The authors present a patient with a traumatic epidural hematoma who complained only of headache and presented to the emergency department 48 hours after a fall. Mental status and neurological examination were normal. This delayed presentation is more commonly seen when a subdural hematoma is present but may result from epidural bleeding. Delayed formation of a traumatic epidural hematoma may occur when the following are present: elevated intracranial pressure. hypovolemic shock. a concomitant mass lesion. coagulopathy. bleeding from dural or diploic veins. a dural sinus laceration. a traumatic pseudoaneurysm. or an arteriovenous fistula. Although criteria for computed tomography of patients with head injuries remain variable in the literature. delayed presentation of epidural bleeding must be considered in the differential diagnosis of posttraumatic headache irregardless of the time interval or neurological presentation.
Buccal cellulitis, Buccal cellulitis (BC) is an innocuous appearing infection of the cheek that is found in children and has a high incidence of concomitant bacteremia. Typically. the child is younger than 12 months and has a 2 to 8 hour prodrome of coryza and fever before developing the cellulitis on the cheek. A purplish hue on the cellulitic region is highly suggestive of Hemophilus influenzae bacteremia. The differential diagnosis is reviewed. A complete blood count. blood culture. and cellulitis aspirate culture. should be obtained on all patients with BC. Meningitis may be present despite the lack of meningeal signs. A lumbar puncture should be performed on all children at risk for bacteremic BC. The vast majority of these children are bacteremic and require parenteral antibiotics. A typical case of BC is presented and its management is reviewed.
Critical care transportation medicine: new concepts in pretransport stabilization of the critically ill patient, Regionalization of health care for trauma has become commonplace. and the same concept for critically ill medical/surgical patients is developing. Recent evidence suggests that current stabilization measures used by transport teams can be inadequate for this critically ill patient population. In trauma. speed has been considered a necessity to get the patient to a facility which cannot be carried out to the field. eg. an operating room. For acute medical illnesses. critical care transport teams can bring intensive care technology to the patient. Accumulating evidence supports the premise that speed of transport is not as important as stabilization before transport. knowledge of hemodynamics during transport. and early use of critical care monitoring systems. Other reports identify the need for initial evaluation and stabilization of critically ill patients by physicians at the critical care level of expertise. Accordingly. critical care transportation teams have evolved. creating new notions of pretransport stabilization not applicable to previous transport systems.
Ventricular arrhythmias in hypertensive left ventricular hypertrophy. Relationship to coronary artery disease, left ventricular dysfunction, and myocardial fibrosis, Ventricular arrhythmias occur with increased frequency in hypertensive patients with left ventricular hypertrophy (LVH). The relationships. however. between ventricular arrhythmias and coexistent coronary artery disease. left ventricular dysfunction and left ventricular fibrosis have not been examined in hypertensive LVH. We carried out coronary arteriography on fifteen hypertensive patients with LVH and nonsustained ventricular tachycardia (greater than or equal to 3 consecutive ventricular complexes) of whom nine (60%) were free of significant (greater than 50% stenosis) coronary disease. To identify other possible correlates of left ventricular arrhythmias. 28 patients with LVH. comprising 17 with ventricular tachycardia and 11 without ventricular arrhythmias. underwent quantitative assessment of left ventricular function (angiographic ejection fraction). left ventricular mass (echocardiography). and left ventricular fibrosis (endomyocardial biopsy). Ejection fraction was not significantly different between the two groups (53 +/- 8% v 62 +/- 2%. P = NS). However. left ventricular mass was significantly greater (442 +/- 28 g v 339 +/- 34 g. P less than .05) and percentage fibrosis significantly higher (19 +/- 4% v 3 +/- 1%. P less than .001) in those patients with ventricular tachycardia. Thus ventricular arrhythmias in hypertensive patients with LVH cannot be entirely attributed to coexistent coronary disease. nor to left ventricular dysfunction. but are related to the degree of cardiac hypertrophy and subendocardial fibrosis.
Effects of n-3 fatty acids in essential hypertension, We examined the effects on blood pressure. plasma lipoproteins. and platelet function when marine oil supplements (rich in n-3 fatty acids) or vegetable oil supplements (rich in n-6 fatty acids) were added to the usual diets of patients with mild essential hypertension. In a randomized. double-blind. parallel-group study. patients received 50 g of either marine oil (n = 8) or vegetable oil (n = 8) daily for 6 weeks following a baseline observation period. Diastolic blood pressure declined during treatment with fish oil (mean +/- SEM. 96 +/- 2 v 89 +/- 2 mm Hg. P = .02). but did not change with vegetable oil (92 +/- 1 v 94 +/- 1 mm Hg). Systolic blood pressure did not change significantly during either treatment. Serum triglycerides declined (by approximately 30%) in patients receiving only marine oil. but total cholesterol. LDL-. HDL-. HDL2-. and HDL3-cholesterol-subfractions and apolipoproteins A-I and B were unchanged in both treatment groups. Bleeding time increased by 33% during treatment with marine oil but did not change with vegetable oil supplements. Marine oil did not alter in vitro platelet aggregation thresholds. The lack of a significant correlation between blood pressure changes and platelet membrane fluidity. plasma renin activity. aldosterone. norepinephrine. or epinephrine suggests that these variables did not mediate the antihypertensive effect of the marine oil. We conclude that large doses of marine oil reduce diastolic blood pressure. lower triglycerides. and increase bleeding time in patients with mild hypertension.
Effect of captopril injection in patients with moderate to severe hypertension, The effect of intravenous captopril was studied in 24 white patients who had moderate to severe hypertension. Patients received incremental doses of 1 to 10 mg delivered at 10 min intervals over 50 to 80 min. Blood pressure (BP) was lowered within 5 to 10 min after the initial dose was administered and continued to decline. reaching a maximum response after 20 min (2 to 4 mg). At this time group mean BP fell from 175 +/- 3/111 +/- 1 to 166 +/- 3/97 +/- 2 mm Hg (P less than 0.01). Additional dose increments to an average cumulative dose of 40 mg did not increase the initial effect. No adverse side effects or symptomatic hypotension occurred in any subject. There was a significant correlation between diastolic BP decreases observed in response to intravenous captopril and subsequent long-term oral captopril therapy. The addition of hydrochlorothiazide increased the proportion of patients reaching normotension. We conclude that small intravenous bolus injections of captopril appear to be effective rapidly and are well tolerated in moderate to severe essential hypertension. Short-term intravenous administration seems to predict the response to chronic oral captopril therapy.
Amiloride blocks the onset of ACTH-induced hypertension in the sheep, This study investigated the ability of two diuretics. amiloride and frusemide. to prevent the development of ACTH induced hypertension in conscious sheep. Infusion of amiloride (20 mg/day) or frusemide (50 mg/day) for three days into normotensive sheep did not have any significant effects on blood pressure. Amiloride blocked ACTH-induced hypertension and the sodium retention and hypokalemia which is usually associated with ACTH administration. Frusemide failed to completely block the hypertension and potassium loss. however it blocked the transient initial urinary sodium retention associated with ACTH-induced hypertension. As frusemide failed to completely block the hypertension it is unlikely that the amiloride effect is due primarily to effects on urinary Na excretion. It is possible that amiloride is exerting its antihypertensive effects by blocking sodium channels.
Randomized trials in the study of antihypertensive drugs, Heterogeneity in response to antihypertensive drugs can be addressed by randomized trials in individual subjects. In such a trial a patient receives pairs of treatment periods (one period of each pair active drug. one matched placebo. in random order); patient and clinician are blinded to allocation. and treatment targets are monitored. These trials can optimize antihypertensive therapy in clinical practice and facilitate the investigation of new drugs and the study of pathophysiology. Such trials also have potential in helping decide whether common. nonspecific symptoms reported by patients are really drug related.
From the parallel group design to the crossover design, and from the group approach to the individual approach, The consequences of heterogeneity in response to antihypertensive drugs for the clinical development programs of new antihypertensive drugs and for the care of the individual hypertensive patient have not previously been sufficiently recognized. They play a role in the inappropriate choice of too-high daily doses of some antihypertensive drugs at the end of extensive international development programs. They are also implicated in the insufficient control of blood pressure observed in the long-term multicenter trials in hypertension. where some patients have been treated for several years with drugs that were not the most appropriate for their disease and which did not adequately control their blood pressure. In addition to the parallel group studies. the use of double-blind two-period or multiple period crossover designs can provide valid data for the dose-finding of new antihypertensive drugs and their comparative evaluation. At the end of the trial. these designs also offer each patient the opportunity to be treated with the right dose of the drug most appropriate for his or her disease.
Humoral factors determining the blood pressure response to converting enzyme inhibition and calcium channel blockade, Renin and catecholamine levels were determined in patients with mild to moderate hypertension before and after treatment with sustained release diltiazem or captopril and were correlated with the blood pressure response to these antihypertensives. Eight weeks of treatment with either agent led to equal decreases in both systolic and diastolic blood pressure. Pretreatment plasma renin activity (PRA) and plasma norepinephrine did not predict the blood pressure response to either agent. Diltiazem significantly increased both PRA and supine norepinephrine levels. However. in the diltiazem treated patients. there was no correlation between the change in plasma norepinephrine and the change in systolic or diastolic blood pressure. In contrast. there was a negative correlation (P less than .05) between the reactive rise in PRA and the decrease in systolic blood pressure. Thus. the antihypertensive response to a calcium channel blocker may be determined. in part. by the reactive response of pressor systems.
Alarm reaction and serum K+ in hypertensive patients, The effect of serum K+ of the alarm reaction induced by the participation to an experimental noninvasive study was evaluated in 35 subjects with borderline hypertension and in 18 essential hypertensives. A group of 44 inpatients undergoing routine blood sampling served as a control. Serum K+. blood pressure and heart rate were measured before (casual) and after (baseline) 20 min of rest in the recumbent position. Baseline serum K+ values were significantly higher than casual values in patients participating to the experimental protocol while no change was observed in inpatients undergoing routine blood sampling. The increase in serum K+ induced by relaxation was significantly related to heart rate decrease (r = 0.73). After relaxation 75% of patients had an increase in serum K+ with a change greater than 10% in about 35% of patients. In a subgroup of patients who repeated the same test three times. the alarm reaction was still evident and not reproducible within each patient. These data suggest that when potassium levels are measured in outpatients undergoing diagnostic or experimental procedures falsely reduced levels can be found in a large proportion of subjects.
Studies of salt intake in hypertension. What can epidemiology teach us, It has been suggested that small changes in population blood pressure will have a major impact upon the incidence of cardiovascular disease caused by blood pressure elevation. Early reports indicated a close correlation between intercultural differences in salt intake and blood pressure. Before such epidemiological associations can be translated into population advice. certain conditions have to be met. The association has to be validated scientifically. and persuasive evidence has to be produced that the relationship is causal and reversible by changes in salt intake. Further. risk-benefit analysis should indicate that net harm is unlikely. Finally it has to be demonstrated that the population measures being advocated will produce an adequate change in dietary salt intake. The small individual effects upon blood pressure being examined. and the prevailing changes in blood pressure and cardiovascular mortality suggest that data will always fall short of the ideal and therefore that extrapolation will always be necessary. Nevertheless. a review of the present evidence indicates the inadequacies of the available data as a basis for population advice.
Calcium and blood pressure. An epidemiologic perspective, We reviewed the research literature on the epidemiologic relationship between blood pressure levels and calcium. with an emphasis on dietary intake. A conceptual framework for causal inference is summarized; then the designs and results of observational and intervention studies are presented. Of 25 reports of observational studies relating intake of calcium or calcium-rich foods to blood pressure. the majority found some evidence of an inverse association. However. many analyses did not support this relationship. and only two studies have confirmed the inverse association with a prospective design. Nineteen randomized controlled clinical trials of calcium supplementation have been reported. excluding those exclusively in pregnant women. Eleven of these showed no significant effects on blood pressure; in two trials. both systolic and diastolic pressure were significantly reduced; and in the remainder results were equivocal. Pooled analyses yielded estimates of a small (1.8 mm Hg). significant reduction in systolic blood pressure. but no effect on diastolic pressure. Epidemiologic relationships with serum and urinary calcium. and the possible mechanisms of these effects. are also discussed. We conclude that the evidence from studies in humans is suggestive. but not conclusive. regarding a role for calcium in hypertension. Recommendations for further epidemiologic studies are presented.
Blood pressure response to dietary calcium intervention in humans, Epidemiological and experimental studies have suggested that dietary calcium deficiency may lead to the development of hypertension. This article reviews findings in human trials on calcium intervention with special reference to the responses of blood pressure and biochemical variables. Calcium supplementation consistently resulted in decreased blood pressure in a subset of hypertensive and normotensive subjects. but led to increased blood pressure in some hypertensive patients. The variable blood pressure responses to calcium supplementation could not be predicted on the basis of routine biochemical parameters and appeared to be due to differences in the backgrounds of the subjects and/or the design and size of the trials. It is concluded that further studies are required on the hypotensive effect of calcium supplementation.
Sodium-calcium interactions and salt-sensitive hypertension, In humans with essential hypertension. salt-induced increases in blood pressure have been reported to correlate directly with salt-induced increases in intracellular free calcium [( Ca2+]i) in circulating mononuclear cells. These findings are consistent with the hypothesis that salt-induced increases in [Ca2+]i mediate the phenomenon of salt sensitivity. Circumstantial evidence suggests that salt-induced increases in intracellular sodium or in plasma levels of 1.25-dihydroxy vitamin D might mediate salt-induced increases in [Ca2+]i and blood pressure. However. in humans with salt-sensitive hypertension. it remains to be determined: (1) whether salt-induced increases in white blood cell [Ca2+]i reflect corresponding increases in vascular smooth muscle [Ca2+]i; (2) whether salt-induced increases in [Ca2+]i are a cause or consequence of salt-induced increases in blood pressure; and (3) whether salt-induced increases in 1.25-dihydroxy vitamin D or intracellular sodium precede salt-induced increases in [Ca2+]i.
Putative mechanism of blood pressure reduction induced by increases in dietary calcium intake, An increase in dietary calcium intake lowers blood pressure in spontaneously hypertensive rats and in some patients with arterial hypertension. The mechanisms by which this decrease come about are not clear. A membrane-stabilizing effect wrought by an increase in extracellular calcium would appear unlikely. since the increases in extracellular calcium concentration with increased dietary intake are minimal. Calcium regulatory hormones may be the mediators. and a cybernetic framework has been suggested. Striking defects have been reported in the calcium handling and hormonal household of the spontaneously hypertensive rat. However. a clear cut relationship in terms of a hormonal "template" has not yet been identified in prospective experiments. Data have been presented to show that increased calcium intake has a direct effect on regulatory areas in the brain. However. the mechanisms by which such a response would be mediated are entirely unknown. Increased calcium intake may induce natriuresis. It has been suggested that increased calcium intake helps the "salt sensitive"; however. prospective studies to this effect have not been presented. Increased calcium intake may induce phosphaturia. However. the evidence that blood pressure lowering effects are mediated by phosphate depletion are unconvincing. Some evidence suggests that increased calcium intake may influence local regulatory processes which in turn influences cell integrity and growth. At this point. a unifying hypothesis is not available. However. the clues to various possibilities are intriguing.
Calcium regulating hormones in essential hypertension. Importance of gender, Alterations of calcium metabolism have been described in human essential hypertension and experimental hypertension. We investigated the interrelationship of parathyroid hormone (PTH) and 1.25(OH)2-vitamin D (1.25(OH)2D) in patients with untreated essential hypertension as compared to normotensive controls. The hypertensive subjects (n = 75; 43 men. 32 women) had a mean blood pressure of 138 +/- 8/95 +/- 5 mm Hg as compared with 120 +/- 11/80 +/- 8 in the normotensive group (n = 40; 22 men. 18 women). Serum PTH was measured with an intact molecule immunochemiluminometric assay and 1.25(OH)2D was measured with radioimmunoassay after HPLC separation. Hypertensive men had PTH levels that were 36% higher than normotensive men (5.3 +/- 2.9 v 3.9 +/- 0.8 pmol/L. P = .005). When blood pressure was analyzed as a continuous variable. there was a direct correlation between it and serum PTH in men (r = .31. P = .004). In women. by contrast. there was no difference in serum PTH between hypertensive and normotensive subjects and no relationship between blood pressure and the serum PTH concentration. Blood pressure was inversely correlated with serum phosphorus levels in both sexes (r = -0.20. P = .04). In men. the elevated serum PTH levels and depressed serum phosphorus levels would have predicted that serum 1.25(OH)2D would be higher in the hypertensive subjects. However. that was not observed. as serum 1.25(OH)2D was slightly lower in hypertensive (38.3 +/- 15.2 pg/mL) than normotensive men (42.7 +/- 11.3. P = .21).
Calciotropic hormones in human and experimental hypertension, Although altered cellular calcium handling plays a critical role in the pathophysiology of hypertension. little attention has been focused on the impact of calcium regulating hormones on this process. Recent research provides evidence that parathyroid hormone. calcitonin. 1.25-dihydroxyvitamin D. as well as newly described factors such as calcitonin gene-related peptide (CGRP). exert target-organ-specific actions in cardiac and peripheral vascular tissues. are linked to the renin-aldosterone system. and thus to the control of sodium metabolism. and may directly participate in the hypertensive process. especially in low renin and salt sensitive forms of hypertensive disease. The metabolic set-point of these linked renin and calcium hormone systems. which serve to transduce environmental dietary mineral signals at the cellular level. determines the blood pressure consequences of sodium and calcium loading and/or restriction. and helps to explain the heterogeneous and seemingly inconsistent effects of these dietary maneuvers on blood pressure. Measurement of renin and calcium factors in hypertension thus provides a physiological basis for individualized therapeutic recommendations in human hypertension.
Dietary Ca2+ prevents NaCl-sensitive hypertension in spontaneously hypertensive rats by a sympatholytic mechanism, The current study tested the hypothesis that dietary Ca2+ supplementation reverses the NaCl-sensitive component of hypertension and the associated neurochemical abnormalities in the NaCl-sensitive spontaneously hypertensive rat (SHR-S). Male SHR-S were begun on one of four diets at 8 weeks of age: control (0.75% NaCl/0.68% Ca2+); high NaCl (8.00% NaCl/0.68% Ca2+); high Ca2+ (0.75% NaCl/2.00% Ca2+); and high NaCl/high Ca2+ (8.00% NaCl/2.00% Ca2+). High NaCl SHR-S (X2 weeks) had higher mean arterial pressure (MAP) (161 +/- 4 mm Hg) than controls (149 +/- 3 mm Hg; P less than .05). Supplementation with Ca2+ prevented the rise in MAP in high NaCl rats. but did not alter MAP in controls. The 8% NaCl diet elevated plasma norepinephrine and reduced anterior hypothalamic (AHA) norepinephrine stores and turnover; concomitant Ca2+ supplementation restored both plasma norepinephrine and AHA norepinephrine turnover to normal. Clonidine was microinjected into the AHA of rats maintained on the four diets for 2 weeks to test the hypothesis that dietary Ca2+ supplementation prevents the previously observed NaCl-induced upregulation of alpha 2-adrenoceptors in AHA. Clonidine caused dose-dependent decreases in MAP that were greater in high NaCl rats than in controls. The Ca2+ supplementation prevented the exaggerated depressor response to clonidine in the high NaCl group. but not in the controls. The Ca2+ supplementation had no effect on pretreatment MAP or on MAP responses to clonidine in control NaCl-resistant SHR (SHR-R) or Wistar-Kyoto (WKY) rats. Thus. dietary Ca2+ supplementation prevents the NaCl-induced exacerbation of hypertension and augmented depressor response to clonidine in SHR-S by increasing noradrenergic input to AHA. thereby preventing the upregulation of AHA alpha 2-adrenoceptors.
Vascular and calcemic effects of plasma of spontaneously hypertensive rats, Circulating substances that increase intracellular calcium. and other circulating substances that increase blood pressure. have been described in hypertensive animals and humans. In this study. we report the existence of a factor of the plasma of spontaneously hypertensive rats that does both. These effects were dose-dependent. and the time course for such effects was correlated with the time course for potentiation of pressor agents by the plasma. In addition. the plasma of spontaneously hypertensive rats was found to inhibit the depressor effects of parathyroid hormone. Our results confirm the presence of a circulating hypertensive factor in the plasma of spontaneously hypertensive rats. which may act by increasing calcium uptake in vascular smooth muscle. These findings may also help explain the secondary increase in parathyroid hormone noted in some forms of human and experimental hypertension.
Epithelial abnormalities in intestine and kidney of the spontaneously hypertensive rat, A variety of perturbations of calcium metabolism are reported to occur in the spontaneously hypertensive rat (SHR) compared to its genetic control the Wistar-Kyoto rat (WKY). including significant dysfunction of calcium handling by the proximal renal tubule of the SHR. resulting in impaired active calcium transport in the gut and an apparent renal calcium leak. We explored the intestinal and renal epithelia of 12- to 14-week-old SHR and WKY using electron microscopy. Biochemical comparisons of these transport epithelia included measurements of three vitamin D dependent cellular proteins and one structural protein: alkaline phosphatase. intestinal CaBP9K. renal CaBP28K. and villin expression. Electron microscopy demonstrated a patchy loss in microvilli in the SHR. accounting for approximately 10 to 15% of the total microvillar surface. In the kidney. morphological abnormalities were observed only in the proximal renal tubule. Again. there was patchy loss of microvilli from the brush border membrane. In SHR duodenal alkaline phosphatase activity was significantly reduced compared to the WKY (0.145 +/- 0.002 v 0.186 +/- 0.002 integrated extinction/min/micron 3 X 10(3) brush border (P less than .001). Duodenal CaBP9K and renal CaBP28K were significantly reduced in SHR compared to WKY. There were no differences in villin expression. These data are consistent with the previously characterized disturbances of active calcium transport in the intestine and inappropriate renal calcium leak in the SHR. While a possible link between these disturbances and hypertension remains to be determined. this study provides supportive evidence for a primary disturbance in cell calcium handling and transporting epithelia in this form of genetic hypertension.
Possible mechanisms of abnormal norepinephrine sensitivity and reactivity of resistance vessels and the development of hypertension in spontaneously hypertensive rats. A hypothesis, This study examined structural and functional changes of mesenteric resistance vessels in early. developing. and established stages of hypertension development in spontaneously hypertensive rats in an attempt to identify possible mechanisms of the development and maintenance of hypertension. Our results suggest that the development of hypertension in spontaneously hypertensive rats may be caused by genetic structural and functional abnormalities of resistance vessels. Both abnormalities may be caused by hyperreactivity to norepinephrine through an altered signal transduction process. including the regulation of protein kinase C in smooth muscle cells of resistance vessels in spontaneously hypertensive rats.
Contribution of calmodulin and protein kinase C to renin release in spontaneously hypertensive rats, This study was designed to evaluate the contribution of calmodulin and protein kinase C to renin release from isolated glomeruli of spontaneously hypertensive rats (SHR. Okamoto and Aoki). Male 7-week-old SHR and age-matched control Wistar-Kyoto rats (WKY) were used in this study. Isolated glomeruli were sealed in the superfusion chamber and perfused with Krebs-Ringer solution at a constant flow of 0.3 mL/min. Renin release was increased by calmodulin inhibitor. W-7. and protein kinase C inhibitor. H-7. in both SHR and WKY. SHR showed higher maximal levels of renin release by W-7 and lower maximal levels by H-7 compared to WKY. These results indicate that calmodulin and protein kinase C play inhibitory roles in renin release from juxtaglomerular cells. The calmodulin-mediated suppression mechanism in renin release appears to be augmented in the SHR. whereas the protein kinase C-mediated system is attenuated.
Increase of calmodulin activator in hypertension. Modulation by dietary sodium and calcium, The aim of this study was to investigate the effects of dietary calcium and sodium on blood pressure (BP) in normotensive rats (Wistar. WKY). spontaneously hypertensive rats (SHR) and Dahl rats and on calmodulin (CaM) activator. a newly-discovered hydrophobic compound that increases CaM activity in SHR and spontaneously hypertensive mice (SHM) tissues (J Clin Invest 82:276. 1988). The CaM activator was assessed by its capacity to stimulate a CaM-dependent phosphodiesterase (CaM-PDE). In Wistar rats. which were fed a high sodium diet (3.5%). BP significantly increased (P less than .01) from 106 +/- 4 to 128 +/- 8 mm Hg in parallel to an elevation of the CaM activator from 1.57 +/- 0.14 to 2.80 +/- 0.18 U. WKY. SHR. and Dahl salt-sensitive (DS/JR) and salt-resistant (DR/JR) rats were given low (0.15%) or high (2.5%) Ca diets. both with 1% sodium. In rats receiving high dietary Ca the progression of hypertension diminished and BP was lower in SHR (156 +/- 4 mm Hg) and young DS/JR rats (125 +/- 3 mm Hg) than in those receiving low dietary Ca (192 +/- 10 and 183 +/- 2 mm Hg). There was a concomitant decrease of CaM activator in these animals to levels indistinguishable from those of WKY or DR/JR rats. The activator was also found in the heart. kidneys and erythrocytes from SHM. In the presence of exogenously added CaM. lipidic extracts from the SHM heart showed augmented CaM-PDE activity relative to normotensive preparations. This difference was eliminated by trifluoperazine.
Responses of cytosolic free calcium to ADP in platelets of spontaneously hypertensive rats, Abnormalities of Ca2+ handling have been reported in patients with essential hypertension and in spontaneously hypertensive rats (SHR). In this study. responses of cytosolic Ca2+ to ADP in platelets of SHR were examined. Four- and seven-week-old male SHR and age- and sex-matched Wistar-Kyoto rats (WKY) were used. Basal levels of the intracellular Ca2+ concentration in platelets and responses to ADP were estimated using fluorescent indicator fura-2 in the medium containing 1 mmol/L CaCl2 and Ca2(+)-free buffer with 1 mmol/L EGTA. Basal levels of platelet cytosolic Ca2+ of SHR were significantly higher than those of WKY at 4 and 7 weeks of age in the presence of external Ca2+. However. no significant difference was observed in basal levels of platelet cytosolic Ca2+ in the Ca2(+)-free EGTA-containing buffer between SHR and WKY. The peak cytosolic Ca2+ concentration evoked by ADP was significantly diminished in SHR compared with WKY in the absence of external Ca2+. whereas the responses of platelet cytosolic Ca2+ to ADP were similar in SHR and WKY in the presence of external Ca2+. These results suggest that release from intracellular Ca2+ store is reduced in SHR and that the regulation of cytosolic Ca2+ in SHR is more dependent on extracellular Ca2+ compared with WKY.
Calcium and contractile responses to phorbol esters and the calcium channel agonist, Bay K 8644, in arteries from hypertensive rats, This study examined the calcium dependency of contractions in arteries from rats made hypertensive by aortic coarctation and in rats with genetic hypertensive (stroke-prone spontaneously hypertensive rats). Mesenteric artery and aortic strips were suspended in tissue baths for isometric force recording and contractions to two drugs were characterized: 1) a phorbol ester. TPA (12-O-tetrade-canoylphorbol-13-acetate). and 2) the calcium channel agonist. Bay K 8644. Thoracic aortae and mesenteric arteries from hypertensive rats were more sensitive to the contractile properties of the protein kinase C activator TPA than comparable arteries from normotensive rats. In thoracic aortae from coarcted rats. the contractile activity of Bay K 8644 was potentiated compared to normotensive values. In the presence of 19.2 mmol/L KCl. responses to Bay K 8644 in thoracic aortae from normotensive rats were potentiated and did not differ from coarcted values. In contrast. contractions to Bay K 8644 and TPA in abdominal aortae obtained below the coarctation were not different from normotensive values. Upon exposure to 26.2 mmol/L KCl. contractions to Bay K 8644 in abdominal aortae were potentiated and those in aortae from coarcted rats did not differ from sham values. Contractile responses to both drugs were blocked by nifedipine and verapamil and responses were attenuated in calcium-free solution. We conclude that calcium channel function and its regulation by protein kinase C contribute to altered vascular reactivity in hypertension. Further. these abnormalities have a pressure dependency. because they did not occur in abdominal aortae from coarcted rats.
Age-related changes in membrane fluidity of erythrocytes in essential hypertension, In the present study. age- and calcium-related changes in the membrane fluidity of erythrocytes were examined in patients with essential hypertension by use of electron spin resonance method (ESR). The erythrocytes were obtained from patients with essential hypertension. We examined the ESR spectra for a fatty acid spin label agent (5-nitroxy stearate) incorporated into the erythrocyte membranes. The values of outer hyperfine splitting and order parameter (S) were significantly higher in subjects with essential hypertension than in the normotensive subjects. This finding indicates that the membrane fluidity of erythrocytes was lower in essential hypertension. Calcium-loading of erythrocytes with the Ca-ionophore A23187 decreased the membrane fluidity (S value was increased) more strongly in essential hypertension than in the normotensive subjects. Furthermore. this Ca-induced change in membrane fluidity was significantly correlated with age in essential hypertension. These results demonstrate that the membrane fluidity of erythrocytes is markedly decreased by calcium. especially in essential hypertension in older patients. This suggests an increased calcium-sensitivity of cell membranes in the aged hypertensive patient.
Post-transplant hypertension, Post-transplant hypertension remains an important risk factor for cardiovascular mortality and graft function. There are multiple mechanisms responsible for post-transplant hypertension. The details of these mechanisms are poorly understood. Steroids. acute and chronic rejection. recurrent renal disease. native kidney disease. and renal artery stenosis have all been implicated in causing post-transplant hypertension. With the addition of cyclosporine. a known hypertensive agent. to the immunosuppressive armamentarium. the evaluation of post-transplantation hypertension has become difficult. Presently. medical therapy is initially directed toward the complications of cyclosporine nephrotoxicity. Empirically. converting enzyme inhibitors are added to the antihypertensive regimen. Further management is aimed at identification of specific causes of post-transplant hypertension. Unfortunately. because of the multifactorial etiology of post-transplant hypertension and a lack of detailed information about the mechanisms. medical and surgical therapy are often unrewarding. Further study is needed to clarify the mechanisms involved in post-transplant hypertension. and thus direct therapy.
The alien hand sign. Localization, lateralization and recovery, The alien hand sign was first described by Brion and Jedynak as a "feeling of estrangement between the patient and one of his hands." The affected hand frequently shows a grasp reflex and an instinctive grasp reaction as well as elements of what Denny-Brown referred to as a "magnetic apraxia" associated with frontal lobe damage. Most notably. however. the affected hand is observed to perform apparently purposive behaviors that are perceived as being outside the volitional control of the patient. The patients interpret the behavior of their own affected limb as being controlled by an external agent. They do not feel that they are initiating or controlling the behavior of the hand and often express dismay at the hand's "extravolitional" activity. The patients attempt to control behavior of the alien hand with the unimpaired hand by forcibly restraining the affected limb. an act that may be termed "self-restriction." In this paper. we report an additional four cases of alien hand sign in right-handed subjects: two involving the right hand and two involving the left hand. In each case. the clinical findings were associated with extensive unilateral damage of the medial frontal cortex of the hemisphere contralateral to the affected hand. Furthermore. the alien movement gradually disappears over the course of 6-12 months after the stroke. These clinical case studies are presented and discussed in the context of the "dual premotoer systems hypothesis." an anatomicophysiological model that proposes that action is organized by two separate but interactive premotor brain systems corresponding to evolutionarily defined medial and lateral cortical moieties. It is hypothesized that the alien mode behavior results from unconstrained activity of the lateral premotor system in the damaged hemisphere. The residual volitional control in the limb occurs through the activity of the intact medial premotor system of the ipsilateral hemisphere. Recovery may occur through extension of these ipsilateral control mechanisms by compensatory changes in subcortical systems controlling hemispheric activation associated with adaptive behavior. This observation may be important in understanding mechanisms involved in motor recovery after stroke.
The effect of local deep microwave hyperthermia on experimental zymosan-induced arthritis in rabbits, The effect of local deep microwave hyperthermia (LDMWH) on normal and Zymosan-induced arthritis has been evaluated in 12 rabbits (24 joints). LDMWH. four treatments to each joint (twice weekly for a period of 2 wk). was generated by an antenna operating at 915 MHz for 60 min. reaching an intraarticular temperature of 42.5 +/- 0.5 degrees C. A surface cooling system was used with the microwave apparatus. Two weeks after the last treatment. all animals were sacrificed. The application of LDMWH on normal joints induced a limited proliferation of the synovial lining cells with a minimal perivascular infiltration of mononuclear and neutrophil cells. However. no histologic damage to the skin. muscles. bone. cartilage or bone marrow adjacent to the heated joints could be noted. Induction of Zymosan arthritis (2 wk before LDMWH) was characterized by pannus formation and granulomatous reaction accompanied by fibrinoid deposits and disseminated necrotic foci in the synovial intima. The LDMWH treatment on the examined arthritic joints brought about a reduction in the degree of granulomatous reaction concomitant with the appearance of some fibrocytes and fine collagen fibrils. These findings suggest that LDMWH can be safely applied. even repeatedly. without morphologic evidence of damage to any normal mesenchymal tissue. Moreover. it reduces the inflammatory process in experimentally induced synovitis.
The influence of prophylactic orthoses on abdominal strength and low back injury in the workplace, This study was designed to determine the effect of multimodal intervention and the prevention of back injury. and to evaluate the adverse side effects of using a lumbosacral corset in the workplace. Subjects were 90 male warehouse workers randomly selected from over 800 employees at a grocery distribution center. Subjects were assigned to three groups: true controls. no back school. no brace orthoses; back school only; and back school plus wearing a custom molded lumbosacral orthosis. Comparisons of pre-testing and 6-month follow-up post-testing for abdominal strength. cognitive data. work injury incidence and productivity and use of health care services were evaluated. Controls and training-only group showed no changes in strength productivity or lost time. Orthoses and training-group showed no changes in strength productivity or accident rate; however. they showed substantially less lost time. This study supports the concept of using education and prophylactic bracing to prevent back injury and reduce time loss. It appears that the use of intermittent prophylactic bracing has no adverse affects on abdominal muscle strength and may contribute to decreased lost time from work injuries.
Cytotoxic activity against HIV-infected monocytes by recombinant interleukin 2-activated natural killer cells, Natural killer (NK) cells have long been known to aid in the control of viral infections by killing virus-infected cells. including those infected with human immunodeficiency virus (HIV). Among the possible NK-susceptible target cells in an infected individual. the monocyte/macrophages are of special significance since they may serve as both a reservoir of HIV and aid in dissemination of the virus throughout the body. A new technique for the enrichment and cultivation of large numbers of recombinant interleukin 2 (rIL-2)-stimulated NK cells has been developed which provides cells with high cytotoxic activity. These IL-2-activated NK cells. adherent lymphokine-activated killer cells (A-LAK). can kill monocytes infected with HIV for 24 h to 7 days. with optimal target sensitivity between 3 and 7 days. Recognition and killing of the infected monocytes did not appear to be restricted by the major histocompatibility complex (MHC) antigens and could be cold-target inhibited by tumor cell lines. A-LAK cells may be useful in newer therapeutic approaches to treatment of HIV infection.
Macrophage tropism of HIV-1, Both in vivo and in vitro studies clearly demonstrate that cells of the mononuclear phagocyte lineage are major hosts for human immunodeficiency virus type 1 (HIV-1) replication. Presumably these cells play a key role in the pathogenesis of acquired immunodeficiency syndrome (AIDS). To further delineate the interactions between HIV-1 and host cells. the susceptibility and permissivity of normal human peripheral blood-derived monocyte/macrophages (M/M) and T lymphocytes. and neoplastic monocytoid and lymphoid cell lines to various HIV-1 isolates was assessed. The results suggest: (1) "fresh" isolates recovered from patients and propagated only in normal host cells exhibit a dual tropism for both M/M and T cells. regardless of their tissue of origin or the cell type from which they were isolated; (2) the repeated passage of an HIV-1 isolate through normal M/M does not generally result in the loss of the ability to infect normal T cells nor vice versa; (3) the majority of fresh HIV-1 isolates do not infect neoplastic cells of either origin. and those that do show no preference for monocytoid or lymphoid targets. regardless of their cell origin.
Full-length recombinant CD4 and recombinant gp120 inhibit fusion between HIV infected macrophages and uninfected CD4-expressing T-lymphoblastoid cells, Human immunodeficiency virus-(HIV) infected monocyte-macrophages may contribute to the pathogenesis of HIV-associated immune deficiency and dysfunction by acting as a target and potential reservoir for the virus in vivo. and by functioning abnormally following infection. We have shown that HIV-infected macrophages fuse with uninfected CD4-expressing lymphoid cells in vitro; this may provide an additional mechanism for CD4 lymphocyte depletion in vivo. We report here the inhibition of syncytium formation between HIV-infected macrophages and uninfected CD4-expressing T-lymphoid cells by monoclonal antibody S3.5. directed against an epitope of CD4 involved in binding HIV gp120. by a recombinant protein that comprises the full-length extracellular domain of the CD4 molecule. and by recombinant full-length HIV envelope glycoprotein. gp120. These results indicate that both molecules (gp120 and CD4) are critical to the fusion process. and suggest that gp120 is expressed on the surface of HIV-infected monocyte-macrophages.
Effects of GLQ223 on HIV replication in human monocyte/macrophages chronically infected in vitro with HIV, GLQ223 is a formulated version of tricosanthin. a single-chain ribosome-inactivating protein that was shown in earlier studies to inhibit human immunodeficiency virus (HIV) replication in T-lymphoblastoid cells and to decrease HIV p24 levels in HIV-infected monocyte-derived macrophages as measured by flow cytometry. The current studies were performed to test the selectivity of the observed inhibitory effects on HIV replication in chronically infected macrophages infected in vitro. Peripheral blood-derived monocyte/macrophages were infected in vitro and cultivated in suspension for at least two weeks prior to GLQ223 treatment. Anti-HIV effects were quantitated by measurement of cytoplasmic HIV p24. by both enzyme-linked immunosorbent assay (ELISA) and flow cytometry and HIV RNA levels were measured by slot blot analysis. Incorporation of [3H]leucine into trichloroacetic acid- (TCA) precipitable protein was also evaluated as an index of nonspecific inhibitory effects mediated by the compound in infected and uninfected cultures. Five days after a single 3-h treatment with GLQ223 there was a concentration-dependent decrease in all measurable HIV parameters within infected cultures. The anti-HIV effects persisted at least 28 days without evidence for increasing HIV expression. GLQ223 treatment of parallel uninfected macrophage cultures showed no significant inhibition of tritiated leucine uptake. These experiments demonstrate that a single pulsed exposure with GLQ223 of macrophages infected with HIV in vitro caused a sustained. concentration-dependent decrease in both HIV p24 antigen levels as well as HIV RNA without causing measurable toxicity in uninfected cultures.
Ability of anti-HIV agents to inhibit HIV replication in monocyte/macrophages or U937 monocytoid cells under conditions of enhancement by GM-CSF or anti-HIV antibody, Monocyte/macrophages (M/M) are an important target cell for human immunodeficiency virus (HIV) infection in the body. The study of HIV infection in these cells. however. is rather complicated because they represent a variable population. and because HIV entry and replication in M/M may be markedly influenced by a number of factors. These must be considered in therapeutic approaches to HIV infection. In the present set of experiments. we studied the interaction between certain agents which increase the infection of monocyte/macrophages (M/M) by HIV and two groups of anti-HIV agents: dideoxynucleosides and specific inhibitors of gp120-CD4 binding. We found that the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). which markedly enhances HIV replication in M/M. does not affect the activity of recombinant soluble CD4 (sCD4) or OKT4A. two agents which block gp120-CD4 binding. However. it had varying effects on different dideoxynucleosides: GM-CSF increased the net anti-HIV activity of 3'-azido2'.3'-dideoxythymidine (AZT). while at the same time it reduced the activity of 2'.3'-dideoxycytidine (ddC) and 2'.3'-dideoxyinosine (ddI). These effects probably represent an interplay between varying effects of GM-CSF on drug entry and phosphorylation. In additional experiments. we showed that very low concentrations of anti-HIV antibodies could enhance HIV infection of the U937 monocytoid cell line. Interestingly. while this effect has been hypothesized to occur through a CD4-independent mechanism. we found that the anti-HIV activities of both sCD4 and OKT4A were unchanged under conditions of enhancement.
The effect of interleukin 4 (BSF-1) on infection of peripheral blood monocyte-derived macrophages with HIV-1, The effects of various cytokines were examined in an in vitro model of human immunodeficiency virus type 1 (HIV-1) infection of human peripheral blood monocyte-derived macrophages (MDM). Monocytes were obtained from blood of normal donors by Ficoll/hypaque gradient centrifugation and adherence. These cells were allowed to mature in the presence of varying concentrations of cytokines. After five days in culture. cells were harvested. counted. and inoculated with S5G7. an HTLV-IIIB subclone. The cells were replated in the presence of the same concentrations of cytokines. Culture supernatants were sampled over 28 days for p24 antigen (Ag) as measured by Ag capture assay. In repeat experiments. the following observations were made: 1. MDM from some donors could be infected only in the presence of tumor necrosis factor-alpha (TNF-alpha). granulocyte/macrophage colony-stimulating factor (GM-CSF) or interleukin 4 (IL-4); 2. The effect of GM-CSF was variable; TNF alpha also enhanced HIV replication above controls; 3. IL-4 was the most potent enhancer of HIV-1 replication in MDM of the cytokines tested. inducing p24 Ag levels 75-230 times those seen in control cultures run simultaneously. This effect was dose dependent. Ag production was not observed until Day 14 postinfection in most experiments. Multinucleated giant cell formation was observed only in the presence of IL-4.
FcR-mediated enhancement of HIV-1 infection by antibody, Although CD4 is a major receptor for human immunodeficiency virus (HIV) infection of cells. studied by ourselves and others clearly show that the Fc receptor (FcR) also plays a role in infection. perhaps in conjunction with other surface receptors. IgG antibodies to HIV-1 will enhance infectivity in cells (such as monocyte-macrophages) that have surface Fc receptors; F(ab')2 fragments of antibodies did not enhance. and blocking of FcR inhibited enhancement. The high-affinity FcR for IgG (Fc gamma RI) appeared to be functional. Sera from HIV-1-infected patients had neutralizing activity at high concentrations. but enhanced infection at low concentrations (i.e.. high dilutions). Our studies show that the CD4 receptor is required for antibody-mediated enhancement of infection. as enhancement can be blocked by recombinant soluble CD4 and by Leu3 antibody. Although enhancement can be demonstrated in vitro. the in vivo importance of enhancing antibodies remains to be defined in HIV-1 infection.
Systemic pattern of free radical generation during coronary bypass surgery, Diffuse impairment of ventricular function after cardiac surgery may be related to the generation during reperfusion of the myocardium of free radicals derived from oxygen. Fifteen patients undergoing elective coronary bypass surgery were studied by previously described assays for peroxidised lipids and for isomerised lipids which were used as indices of free radical activity. Serial blood samples were obtained from systemic arterial. mixed venous. and coronary sinus catheters before. during. and after the ischaemic period. The patients underwent coronary artery surgery on cardiopulmonary bypass with a membrane oxygenator. relative hypothermia 30-34 degrees C. and intermittent cross-clamping of the aorta. During the ischaemic periods there were no significant changes in the indices of free radical activity. During the reperfusion phase there was a significant increase in free radical indices in arterial and mixed venous blood. A small rise in free radical indices in coronary venous blood was not statistically significant. These data indicate that free radical activity is increased in patients shortly after the cessation of cardiopulmonary bypass. The pattern of distribution between the different sampling sites suggests that much of the observed increase in isomerised and peroxidised lipids originates from tissues other than the myocardium.
Does blood rheology revert to normal after myocardial infarction, After myocardial infarction there is an acute deterioration of the flow properties of blood. The present study was designed to test whether the abnormality persists. Blood and plasma viscosity. red cell aggregation and deformability. haematocrit. erythrocyte sedimentation rate. white cell count. cholesterol. and triglycerides were measured in 51 patients who had had a myocardial infarction 5.4 (mean) years before. Results in patients and controls were compared and matched pairs with identical cardiovascular risk factors were also selected. Blood viscosity and red cell aggregation were increased and red cell deformability was decreased in the 51 patients. The abnormalities were independent of the interval since infarction and persisted for years. The rheological abnormalities present after myocardial infarction are at least partly independent of the acute event and acute phase reactions. They contribute to the reduced perfusion of the microcirculation of the heart.
Prospective evaluation of a protocol for induction of sustained ventricular tachycardia in patients referred to a tertiary centre, All eight stages of a stimulation protocol that used one then two extrastimuli from the right ventricular apex in sinus rhythm and three ventricular drive rates (100. 120. and 140 beats/min) were performed in 24 patients with recurrent spontaneous sustained ventricular tachycardia despite drug treatment. Twenty two of the patients had sustained a previous myocardial infarct and 18 were on long term treatment with amiodarone. Sustained (greater than 30 s) ventricular tachycardia was induced in all patients. Two extrastimuli were significantly more likely to induce sustained ventricular tachycardia than one extrastimulus. both overall and individually for the three ventricular drive rates. A ventricular drive rate of 140 beats/min was significantly more likely to induce ventricular tachycardia than ventricular drive rates of 100 and 120 beats/min which were significantly more effective than sinus rhythm. A ventricular drive rate of 140 beats/min with one or two extrastimuli induced ventricular tachycardia in 23/24 (95%) of the patients in this study. The full eight stage protocol was progressive separately for both extrastimuli and ventricular drive rate but the last two stages (ventricular drive rate of 140 beats/min with one or two extrastimuli) were as effective as the entire protocol in inducing ventricular tachycardia.
Use of computed tomographic scanning and aortography in the diagnosis of acute dissection of the thoracic aorta, Before the introduction of computed tomographic (CT) scanning. aortography was the investigation of choice for acute aortic dissection. Between 1978 and 1982. 24 patients were referred to the Brompton Hospital with suspected acute thoracic aortic dissection; all had aortography with diagnosis confirmed at surgery (n = 12) or necropsy (n = 2) or supported by clinical outcome (n = 8). One patient in whom aortography was negative had type B dissection at necropsy and another patient was lost to follow up. CT scanning became available in this unit in 1983 and between 1983 and 1987 was used as the only imaging investigation in 32 patients with suspected acute dissection of the thoracic aorta while in a further 22 patients aortography was used alone. Results were confirmed at surgery (n = 18). necropsy (n = 3). or supported by clinical outcome (n = 31). Two patients were lost to follow up. In an additional 16 patients both aortography and CT scanning were performed with concordant findings in 10. In six in whom the results were discordant. aortography was normal in three in whom subsequent CT scanning showed type B dissection and CT scanning was normal in three patients in whom aortography showed type A dissection. Both CT scanning and aortography are reliable techniques for assessment of suspected acute dissection of the thoracic aorta. Both techniques misdiagnose occasionally and the frequency of misdiagnosis will be minimised by performing both investigations in patients where the level of clinical suspicion is high and the initial investigation negative. CT scanning tends to miss type A dissection and in view of the success of surgery in this condition this failing has the more serious clinical consequences.
Transoesophageal echocardiography in the longitudinal axis: correlation between anatomy and images and its clinical implications, Transoesophageal echocardiographic imaging in the longitudinal axis is a recent addition to the non-invasive evaluation of congenital and acquired heart disease. The technique provides unique images of intracardiac anatomy but their interpretation remains difficult. A heart specimen was therefore cut according to the echocardiographic imaging planes to elucidate the morphological details. The results suggested that longitudinal transoesophageal imaging complements the transverse axis approach. It gave new imaging information on the right ventricular outflow tract and the pulmonary trunk. the atrioventricular valves. the interventricular septum. the cardiac apex. and the thoracic aorta. In particular. it showed the entire length of the right ventricular outflow tract. When longitudinal imaging was used in combination with transverse imaging almost all the thoracic aorta could be examined. Imaging in the longitudinal axis may also allow better assessment of the mechanisms of atrioventricular valve regurgitation.
Pharmacokinetics of propofol infusions in patients with cirrhosis, We have compared the pharmacokinetics of propofol as an infusion in 10 control and 10 patients with cirrhosis. Anaesthesia was induced within 3-4 min during administration of an infusion of propofol 21 mg kg-1 h-1. After 5 min. the infusion was decreased in a stepwise manner to 12 mg kg-1 h-1 and subsequently 6 mg kg-1 h-1. The mean recovery time after discontinuation of the infusion was significantly longer in the cirrhotic group; however. when patients opened their eyes. blood concentrations of propofol were similar in both groups (1 micrograms ml-1). Pharmacokinetic analysis was performed from the beginning of infusion to 8 h after termination. Total body clearance was not reduced significantly in cirrhotic (1.56 (SD 0.48) litre min-1) compared with control (1.75 (0.32) litre min-1) patients. The volume of distribution at steady state was significantly greater in patients with cirrhosis than in control patients (202 (82) litre vs 121 (49) litre). However. this difference did not change terminal elimination half-life. The pharmacokinetics of propofol given by infusion to maintain general anaesthesia were not affected markedly by moderate cirrhosis.
Effect of flumazenil on midazolam-induced amnesia, We have studied the effect of i.v. flumazenil 0.01 mg kg-1 on the amnesia and sedation caused by midazolam 2 mg and 5 mg i.v. in volunteers in order to determine the relationship between the actions of the antagonist on these two effects. Midazolam caused dose-dependent central neural depression as assessed by critical flicker fusion frequency. and dose-dependent amnesia for word cards. In subjects given flumazenil 5 min after administration of midazolam. fusion frequency readings and memory were restored to levels comparable to those before midazolam administration. These two effects of flumazenil were similar in time course and extent. suggesting that they share the same mechanism of action. Flumazenil given alone had no effect on memory. The study has demonstrated anterograde amnesia following benzodiazepine administration and antagonism by flumazenil. There was neither retrograde amnesia nor retrograde antagonism of amnesia.
Plasma concentrations of methadone during postoperative patient-controlled extradural analgesia, Plasma concentrations of methadone were measured by gas chromatography in 16 patients receiving extradural methadone by continuous infusion for relief of postoperative pain. Venous blood samples were taken after a loading dose of extradural methadone 2 mg and during infusion of 0.46 mg h-1 plus patient-controlled increments of 0.2-1 mg. Mean (SD) plasma concentration of methadone was 9.8 (2.1) ng ml-1 at 15 min; this did not change significantly during the first 2 h. after which it increased gradually to 32.2 (4.6) ng ml-1 (P less than 0.001) at the end of 24 h. The mean quantity of extradural methadone required to produce effective analgesia was 10.3 (1.8) mg during the first 12 h after operation and 6 (1.0) mg for the subsequent 12 h. The mean amount of methadone for effective analgesia on the second day was 7.6 (1.1) mg. No adverse effects were detected during the 2-3 days of methadone therapy. Plasma concentration of methadone increased significantly during patient-controlled infusion of extradural methadone in the first 24 h after operation. suggesting rapid vascular uptake. Systemic activity of the drug contributes to the analgesic effect of extradural methadone.
Double-blind comparison of topical lignocaine-prilocaine cream (EMLA) and lignocaine infiltration for arterial cannulation in adults, In a double-blind. double-dummy study. the efficacy of topical 5% EMLA cream was compared with that of lignocaine infiltration in alleviating the pain of arterial cannulation. Forty unpremedicated adults were allocated randomly to four groups to receive EMLA cream alone. EMLA and 0.9% saline infiltration. EMLA and 1% lignocaine infiltration or placebo cream and 1% lignocaine infiltration. Following arterial cannulation. pain was assessed by the patient using a visual analogue score and by an independent observer using a four-category verbal rating score. Significantly lower pain scores were observed in all patients receiving EMLA compared with those receiving placebo cream and lignocaine infiltration by both patient (P less than 0.01) and observer (P less than 0.001) assessments. There were no significant differences between the three EMLA groups.
Comparison of four pulse oximeters: effects of venous occlusion and cold-induced peripheral vasoconstriction, The ability of four pulse oximeters (the Ohmeda 3700. Nellcor N100 and N200 and the Datex Oscar) to detect hypoxaemia was determined in the presence of venous obstruction and cold-induced peripheral vasoconstriction. Significant increases in detection time for hypoxaemia were found in both cases. There were no significant differences in detection time between the instruments. although the Ohmeda 3700 displayed smaller values of SaO2 under certain conditions. Peripheral vasoconstriction was induced using three differing methods which gave differing results. thus emphasizing the importance of methodology in assessments of pulse oximetry.
Anaesthetic management of systemic mastocytosis, Systemic mastocytosis is an uncommon disorder of mast cell proliferation in connective tissues. Mast cell degranulation may occur on exposure to various stimuli and drugs. The release of histamine. heparin and vasoactive substances such as prostaglandin D2 may cause severe hypotension and other anaphylactoid manifestations. Anaesthetic management should include perioperative stabilization of mast cells and avoidance of the use of histamine-releasing drugs. Intradermal skin testing is useful in predicting the sensitivity to drugs that may be used during anaesthesia. We present a patient with systemic mastocytosis who underwent uneventful cholecystectomy.
Effect of different rates of infusion of propofol for induction of anaesthesia in elderly patients, The effect of changing the rate of infusion of propofol for induction of anaesthesia was studied in 60 elderly patients. Propofol was administered at 300. 600 or 1200 ml h-1 until loss of consciousness (as judged by loss of verbal contact with the patient) had been achieved. The duration of induction was significantly longer (P less than 0.001) with the slower infusion rates (104. 68 and 51 s). but the total dose used was significantly less (P less than 0.001) in these patients (1.2. 1.6 and 2.5 mg kg-1. respectively). The decrease in systolic and diastolic arterial pressure was significantly less in the 300-ml h-1 group at the end of induction and immediately after induction (P less than 0.01). The incidence of apnoea was also significantly less in the slower infusion group.
Cerebral effects of sevoflurane in the dog: comparison with isoflurane and enflurane, The cerebral effects of sevoflurane were compared in dogs with those of enflurane and isoflurane. Initially. the minimum alveolar concentrations (MAC) of sevoflurane and enflurane were determined and the electroencephalographic (EEG) responses to increasing doses of sevoflurane (1.5. 2.0 and 2.5 MAC) or enflurane (1.5 and 2.0 MAC) in unparalysed animals were examined. Administration of sevoflurane was not associated with seizure activity at any concentration either during normocapnia (PaCO2 5.3 kPa) or hypocapnia (PaCO2 2.7 kPa). even in the presence of intense auditory stimuli. All dogs anaesthetized with enflurane demonstrated sustained EEG and motor evidence of seizure activity induced by auditory stimuli at concentrations of enflurane greater than 1 MAC. particularly during hypocapnia. In a separate group of dogs. the effects of increasing concentrations of sevoflurane and isoflurane (0.5. 1.5 and 2.15 MAC) were compared directly on arterial pressure. cardiac output and heart rate. cerebral blood flow and the cerebral metabolic rate for oxygen (CMRO2) using the venous outflow technique. Sevoflurane. in common with isoflurane. had minimal effects on cerebral blood flow at the concentrations studied. but significantly reduced the CMRO2 at end-tidal concentrations sufficient to produce a burst suppression pattern on the EEG (approximately 2.15 MAC). Both sevoflurane and isoflurane significantly decreased arterial pressure in a dose-dependent manner. but neither drug significantly altered cardiac output.
Serum acute phase proteins after orthotopic liver transplantation, Acute phase proteins were measured in six patients before liver transplantation and for 72 h after orthotopic liver transplantation. The ability of the donor liver to mount an acute phase response was demonstrated. although the response was less than that seen in other groups of patients in whom this has been studied. Because of the reduced response to stress. the value of these measurements as indicators of liver function in this group of patients is limited.
Muscle relaxation rates in individuals susceptible to malignant hyperthermia, Muscle relaxation rate following a tetanic stimulus of adductor pollicis muscle was measured prospectively in 26 patients potentially susceptible to malignant hyperthermia (MH) the day before a muscle biopsy was obtained for MH in vitro screening. Eleven subjects were found to be MH susceptible (MHS) and 15 subjects MH-negative (MHN). In all patients. relaxation rate was recorded at three different temperatures of the skin overlying adductor pollicis (30. 34 and 38 degrees C) achieved by a small surface heating unit placed over the thenar eminence. The MHS group exhibited slightly higher relaxation rate at 34 and 38 degrees C compared with the MHN group and this difference was accentuated with increasing temperature. but was not statistically different. The results of the present study suggest that relaxation rates are normal in MHS individuals under physiological conditions and cannot be used diagnostically for MH screening.
Prolonged paralysis following suxamethonium and the use of neostigmine, A case of prolonged neuromuscular block following the administration of suxamethonium is reported. Three hours after administration of suxamethonium. a well defined. recovering phase II block was demonstrated with a T4:T1 ratio of 0.25. and neostigmine was administered. Although the T4:T1 ratio was improved to 0.9. T1 remained at 25% of control. and significant paralysis persisted which responded to administration of cholinesterase. It is concluded that neuromuscular monitoring cannot reliably predict reversibility in such cases and that. even after 3 h. antagonism of prolonged suxamethonium block should commence with cholinesterase. followed by neostigmine if necessary.
Foam cuffed tracheal tubes: clinical and laboratory assessment, The efficiency of a foam cuffed tracheal tube has been studied in protecting the pulmonary tree from aspiration of oropharyngeal and gastric contents. Following instillation of methylene blue dye above the cuff. subsequent fibreoptic bronchoscopy revealed no instance of dye staining of the tracheal mucosa. A "bench" study was undertaken subsequently to estimate the likely pressure that the cuff would exert on the tracheal mucosa as a result of elastic recoil properties of the foam. The results suggested that. under normal clinical conditions. the pressure is not likely to exceed a value at which impairment of the mucosal blood supply would occur.
Failure to prevent preterm labour and delivery in twin pregnancy using prophylactic oral salbutamol, A double blind. controlled study was performed to see whether the use of prophylactic oral salbutamol would reduce the incidence of preterm labour in twin pregnancy. Of the 144 women studied. 74 took salbutamol and 70 placebo. No difference was found in the length of gestation. birthweight or fetal outcome. although fewer babies suffered from respiratory distress syndrome in the salbutamol group. Women did not experience troublesome side-effects from salbutamol.
The relative risks of caesarean section (intrapartum and elective) and vaginal delivery: a detailed analysis to exclude the effects of medical disorders and other acute pre-existing physiological disturbances, OBJECTIVE--To compare maternal mortalities attributable to vaginal delivery. elective caesarean section (CS) and intrapartum CS. DESIGN--The number of deaths associated with each method of delivery was ascertained among unselected and among low-risk women by detailed retrospective review of the case-notes of women who died after delivery. The frequency of each method of delivery throughout the study period was ascertained from the computer database and enhanced by analysis of the case-notes of unselected groups of women. SETTING--The Peninsula Maternity Services (Cape Town) during the years 1975-1986 inclusive. SUBJECTS--A total of 108 maternal deaths arising from 263.075 maternities provided accurate information. The relative frequency of vaginal and abdominal delivery was determined from the computer database. The ratio of elective CS to emergency prepartum CS to intrapartum CS was obtained by review of the first 200 operations in the years 1975. 1977. 1979. 1982 and 1984. MAIN OUTCOME MEASURES--(i) Mortality rates associated with the different methods of delivery in unselected women and in women who were healthy before surgery; (ii) mortality rates apparently attributable to the method of delivery. RESULTS--The overall relative risk of mortality associated with caesarean section compared with vaginal delivery was 7 decreasing to 5 after the exclusion of women with medical or life-threatening antenatal complications (eg. haemorrhage. hypertension). The relative risk associated with intrapartum compared with elective sections was 2.3 decreasing to 1.4 after the exclusion of women with medical disorders or life-threatening complications. The relative risk of maternal mortality which was apparently attributable to intrapartum compared with elective sections was 1.7. However. the 95% confidence intervals of these values. even from this large data-set. are wide. Nevertheless. these rates are in broad agreement with an approximation derived from the British confidential enquiries into maternal deaths. CONCLUSION--The attributable relative mortalities of caesarean section compared with vaginal delivery and intrapartum compared with elective caesarean section are lower than the overall relative mortalities of these modes of delivery and are approximately 5:1 and 1.5:1 respectively. These data are crucially important in the decision to recommend elective caesarean section compared with trial of labour.
Diagnosis of ectopic pregnancy by vaginal ultrasonography in combination with a discriminatory serum hCG level of 1000 IU/l (IRP), The diagnostic value of vaginal sonography in combination with a discriminatory serum hCG level of 1000 iu/l (International Reference Preparation) was tested prospectively in 200 pregnant women suspected of having an ectopic pregnancy. An ectopic pregnancy was diagnosed in 68 women (34%). a miscarriage in 56 (28%) and a normal pregnancy in 76 (38%). On admission. an intrauterine sac was seen in 89% of the intrauterine pregnancies. but in none of the ectopic pregnancies. Detection of an adnexal mass separate from the ovaries was diagnostic of ectopic pregnancy with a sensitivity of 93%. a specificity of 99%. a positive predictive value of 98% and a negative predictive value of 96%. In 19 patients (9%) the initial sonogram was non-diagnostic and the final diagnosis was obtained after a repeated scan within 6 days. Five of these women had an ectopic pregnancy. 12 a miscarriage and two a normal pregnancy. On admission the hCG level exceeded 1000 iu/l in 77% of all patients and in 67% of those with ectopic pregnancies. In patients with an initial level exceeding 100 iu/l. an intrauterine sac was found in all the intrauterine pregnancies but in none of the ectopic pregnancies. The use of this threshold in combination with sonographic detection of an adnexal mass was diagnostic of ectopic pregnancy with a sensitivity of 97%. a specificity of 99%. a positive predictive value of 98% and a negative predictive value of 98%.
Hormone implants and tachyphylaxis, The serum oestradiol levels of 1388 women treated with hormone implants at a menopause clinic were reviewed in 1988. Thirty-eight (3%) were found to be above 1750 pmol/l. Of these 38 women with supraphysiological oestradiol levels 23 had started therapy for menopausal symptoms and 15 for the premenstrual syndrome (PMS). Of the 23 women treated for menopausal symptoms 11 had a history of psychiatric referral for depression and nine had undergone a surgical menopause. Nine of the 15 women with PMS had a history of psychiatric referral for depressive symptoms. We conclude that the women who attain supraphysiological levels of oestradiol on implant therapy have a high frequency of psychopathology or surgical menopause and may require higher oestradiol levels for adequate control of symptoms.
Haemostatic changes during continuous oestradiol-progestogen treatment of postmenopausal women, To identify changes in haemostatic balance during continuous oestradiol-progestogen treatment. 60 postmenopausal women with climacteric complaints. mean age 55.4 years (range 44-68) were randomly allocated to receive one of four hormone replacement regimens for one year. All four formulations were administered daily and continuously. each contained 2 mg of 17 beta-oestradiol in combination with either norethisterone acetate. 1 mg (group A) or 0.5 mg (group B) or megestrol acetate. 5 mg (group C) or 2.5 mg (group D). No significant changes occurred during treatment within or between the groups in platelet count. fibrinogen and 2-antiplasmin. Activated partial thromboplastin time was shortened (P less than 0.05) in group D and a decline in factor VII activity and antigen (P less than 0.001) and in ATIII activity (P less than 0.05) was noted in group A. Protein C tended to decline in all treatment groups but statistically significant changes were noted only in groups A and C. Two women developed crural thrombosis during the observation period.
Intraocular pressure changes and postural changes of intraocular pressure in experimentally induced Hansen's disease of rhesus, mangabey, and African green monkeys, In our long term evaluation of patients with Hansen's disease we have frequently found reduction of their intraocular pressure. Furthermore. we noted changes in their intraocular pressure on change of posture. To determine if these changes have any significance we measured the intraocular pressures of 24 experimentally infected and 39 control monkeys in both sitting and reclining positions. We found significant reduction of intraocular pressure in 66.7% compared with controls in the sitting position. and a significant increase in intraocular pressure in 79% when checked first in the sitting then in the reclining position. We offer a possible pathophysiological explanation as to why the changes occur.
A survey of the initial referral of children to an ophthalmology department, We report on a survey of the referral of 525 children making their first visit to an ophthalmology department. Information was gathered by interviewing the parents and reviewing the case notes. Parents and relatives initiated the referrals in 223 cases (42%) and health visitors initiated a further 123 cases (23%). General practitioners were rarely the first to notice a condition. though they played a major part in the subsequent referral process. Of 556 reasons for referral squint was the most important (319 cases. 57%). followed by poor vision (106 cases. 19%). There were 44 confirmed cases of amblyopia. of which 15 (34%) were not detected until the child was aged 5 years or over. The overall accuracy of referral was 66% (367 reasons for referral confirmed). In 109 cases (21%) the child was found to be normal. Parents and relatives first noticed 54% of cases of confirmed squint but only 15% of the cases of poor vision. Health professionals. especially health visitors. were of great importance in first detecting poor vision.
Biometry of the crystalline lens in early-onset diabetes, Lenticular biometry on non-cataractous lenses has been studied by means of Scheimpflug photography and digital image analysis in 153 patients with early-onset insulin-dependent diabetes and 153 non-diabetic controls. Anteroposterior axial lens thickness. cortical thickness. nuclear thickness. anterior and posterior lenticular curvatures. and anterior chamber depth were assessed. Highly significant differences between the lenses of the diabetic subjects and non-diabetic controls were found. After the effect of age had been accounted for within the diabetic subgroup. diabetic duration was found to be a highly significant determinant of lens dimensions. such that age-related dimensional changes for various biometric parameters were accelerated by between 52% and 121% after the onset of diabetes. Because the diabetic duration of the early-onset diabetic subjects studied in this work was accurately known. this report is the first in which a precise assessment of the effect of 'true' diabetic duration on lens biometry has been possible.
Aqueous humour and serum zinc and copper concentrations of patients with glaucoma and cataract, Serum and aqueous humour zinc and copper concentrations of 44 patients with glaucoma and cataract were determined. Serum values were found within normal ranges. The highest mean copper concentration was seen in the glaucoma group. In addition there was a significant negative correlation between the aqueous humour levels of zinc and copper in patients with glaucoma. It was concluded that an increased copper value together with a low zinc value might be of importance in patients with glaucoma.
Topical timolol and serum lipoproteins, Oral timolol taken for the treatment of systemic hypertension has been shown to affect adversely serum lipoprotein levels. In a 15-week study on 19 patients topical timolol therapy for raised intraocular pressure was found to have no significant adverse effect on serum lipoprotein levels. This is reassuring in view of the large number of patients on this form of long term therapy. and selection of the type of beta blocker to use should not be influenced by lipid changes associated with the oral form of the drug.
Haemorheological changes in patients with retinal vein occlusion after isovolaemic haemodilution, In 83 patients with central retinal vein occlusion and branch vein occlusion we measured the haematocrit (HCT). plasma viscosity (PV). red cell aggregation (RCA). red cell filterability (RCF) and apparent whole blood viscosity (WBV). A control group (n = 41) was matched for sex. age. and cardiovascular risk factors. Measurements were performed before and after treatment with isovolaemic haemodilution (IHD). We found no significant differences between patients with retinal vein occlusion (RVO) and control subjects in haematocrit. plasma viscosity. red cell aggregation. and red cell filterability and no increased whole blood viscosity in the patient group. Patients with ischaemic retinal vein occlusion and non-ischaemic retinal vein occlusion did not show different haemorheological parameters either. After treatment with haemodilution. only the haematocrit and whole blood viscosity were significantly decreased. and there were no changes in plasma viscosity. red cell aggregation or red cell filterability.
Cytopathology of adenovirus keratitis by replica technique, Corneal replicas were made from the severely affected eyes of 12 patients presenting with typical signs and symptoms of epidemic keratoconjunctivitis. Adenovirus was isolated from the eyes. Histopathological study of the replicas and cytology of diseased cells removed with the replica showed diffuse mild oedema of the epithelium. with scattered moderately swollen and deformed cells. The clinically observed punctate lesions histologically consisted of markedly swollen cells that had become oval or rounded. Fusion of these cells led to small syncytial formations. and the development of pseudopodia-like processes was occasionally observed. Loss of cell contents resulted in the formation of plicae on the surface of many cells. Two types of inclusion bodies were detected in the epithelial cells. The first type. intranuclear vacuolar inclusions. contained homogeneous material. The second type of inclusions were round. dense bodies. that developed in the homogeneous material of intranuclear vacuolar inclusions. The dense bodies contained the replicating and maturing virus particles. After cell degeneration the dense bodies become extracellular. Making a corneal replica had a beneficial effect on the clinical course of adenovirus keratitis.
Pupillary responses in amblyopia, Relative afferent pupillary defects (RAPD) were detected in 32.3% of patients with amblyopia by a modification of the swinging flashlight test and the synoptophore. After consideration of various clinical investigations the significant factors identified in patients showing a RAPD were: anisometropia. early age of onset where strabismus was present. level of visual acuity following treatment. longer period of occlusion therapy. These points bear similarities to the results of pattern electroretinograms (PERG) in amblyopes. and the possibility of the causative defect being at ganglion cell level is discussed. The effect of occlusion treatment cannot be predicted from the presence or absence of a RAPD.
The electroretinogram in minimal diabetic retinopathy, The pattern and diffuse flash electroretinograms were measured in 20 normal subjects and 40 diabetic patients who had either normal fundi or microaneurysms only. The amplitudes of the pattern electroretinogram were found to be similar in both normals and diabetics. In the case of the flash electroretinogram the diabetic patients showed a division into two main groups. One group was not dissimilar to the group of normal subjects. while the second group showed hypernormal amplitudes. No explanation could be given. from the data collected. for this subdivision. though it is suggested it might reflect the degree of metabolic disturbance.
Multifocal posterior uveitis: clinical and pathological findings, A pathological study was performed on the necropsy eyes of a 59-year old-woman who had suffered for nine years from multifocal posterior uveitis. The disease had been controlled by steroid therapy with good preservation of visual function. Extensive investigation did not reveal the aetiology. On macroscopic examination numerous focal lesions with various degrees of pigmentation were observed scattered across the fundi. These lesions were studied by light and electron microscopy and immunohistochemistry. There was ongoing chorioretinal inflammation in the foci. producing destruction of Bruch's membrane. the retinal pigment epithelium (RPE). and the outer retina. The focal scars showed migration of RPE and glial cells and neovascularisation. Capillary and venule endothelial cells were swollen at the inflammatory sites. Attempts to establish a cause for this condition were unsuccessful.
Bleeding complications associated with cardiopulmonary bypass, Bleeding after CPB has been difficult to characterize and its treatment equally difficult to standardize. The complexity of this problem is related to the hemostatic process. the technical variations in the operative procedures. and the many uncontrolled variables associated with CPB. including the effects of anesthetic or pharmacologic agents. the nature of the priming solution. hemodilution. hypothermia. the type of oxygenator. and the use of transfused blood products. Although there are multiple and generally predictable complex changes in the hemostatic mechanism during CPB. the temporary loss of platelet function is the most common and clinically relevant. This transient platelet dysfunction occurs in all patients undergoing CPB; however. it only causes excessive bleeding in a small percentage of patients. Unfortunately. it has not yet been possible to predict which patients will develop hemorrhagic complications. although prolonged pump times are a contributing risk factor. Over the past decade there has been extensive investigation into the management of bleeding associated with CPB. provoked primarily by the increased awareness of transfusion-transmitted viral diseases and the inappropriately excessive use of homologous blood products. Several approaches to autotransfusion of shed blood and autologus blood donation have been developed to minimize perioperative homologous blood transfusion. Pharmacologic agents such as desmopressin. aprotinin. and topical fibrin glues have also been introduced to improve hemostasis during CPB. The protease inhibitor aprotinin is particularly promising in the reduction of bleeding associated with CPB when given prophylactically. Aprotinin may provide new insights into the mechanism of CPB-induced platelet dysfunction. Desmopressin is indicated only for the treatment of bleeding after CPB. The management of bleeding associated with CPB will undoubtedly.
Autologous bone marrow transplantation in high-risk remission T-lineage acute lymphoblastic leukemia using immunotoxins plus 4-hydroperoxycyclophosphamide for marrow purging, Fourteen patients with high-risk T-lineage acute lymphoblastic leukemia (ALL) in complete remission underwent autologous bone marrow transplantation (BMT) in an attempt to eradicate their residual disease burden. A combined immunochemotherapy protocol using a cocktail of two immunotoxins directed against CD5/Tp67 and CD7/Tp41 T-lineage differentiation antigens in combination with the in vitro active cyclophosphamide congener 4-hydroperoxy-cyclophosphamide (4-HC) was used to purge autografts. Despite high dose pretransplant radiochemotherapy and effective purging of autografts. 9 of 14 patients relapsed at a median of 2.5 months (range. 1.2 to 16.8 months) post BMT. Two patients remain alive and disease free at 26 and 28 months post BMT. We used a novel quantitative minimal residual disease (MRD) detection assay. which combines fluorescence activated multiparameter flow cytometry and cell sorting with leukemic progenitor cell (LPC) assays. to analyze remission bone marrow (BM) samples from T-lineage ALL patients for the presence of residual LPCs. Notably. high numbers of residual LPC detected in remission BM before BMT constituted a poor prognostic indicator. providing the first evidence for the biologic significance and clinical value of in vitro T-lineage ALL LPC assays. The median value for the residual leukemia burden before BMT. was approximately 8.6 x 10(3) LPC/10(8) mononuclear cells (MNC) (approximately 0.0086% LPC). Patients with a residual leukemia burden less than this median value appeared to have a better outlook for remaining free of relapse after autologous BMT than patients with a greater leukemia burden (53 +/- 25% v 14 +/- 13%. P = .006. Mantel-Cox). By comparison. the log kill efficacy of purging. the remaining numbers of LPC in purged autografts. or the estimated numbers of reinfused LPC. did not correlate with the probability of disease-free survival (DFS). These results indicate that the primary reason for the recurrence of leukemia was inefficient pretransplant radiochemotherapy rather than inefficient purging of autografts.
Human basophils express interleukin-4 receptors, Interleukin-4 (IL-4). a multipotential lymphokine reputed to play an important role in the regulation of immune responses. interacts with a variety of hemopoietic target cells through specific cell surface membrane receptors. The present study was designed to investigate whether human basophils express IL-4 binding sites. For this purpose. basophils were enriched to homogeneity (93% and 98% purity. respectively) from the peripheral blood of two chronic granulocytic leukemia (CGL) donors using a cocktail of monoclonal antibodies (MoAbs) and complement. Purified basophils bound 125I-radiolabeled recombinant human (rh) IL-4 in a specific manner. Quantitative binding studies and Scatchard plot analysis revealed the presence of a single class of high affinity IL-4 binding sites (280 +/- 40 sites per cell in donor 1 and 640 +/- 45 sites per cell in donor 2) with an apparent dissociation constant. kd. of 7.12 x 10(-11) +/- 2.29 x 10(-11) and 9.55 +/- 3.5 x 10(-11) mol/L. respectively. KU812-F. a human basophil precursor cell line. was found to express a single class of 810 to 1.500 high affinity IL-4 binding sites with a kd of 2.63 to 5.54 x 10(-10) mol/L. No change in the numbers or binding constants of IL-4 receptors was found after exposure of KU812-F cells to rhIL-3 (a potent activator of basophils) for 60 minutes. No effect of rhIL-4 on 3H-thymidine uptake. release or synthesis of histamine. or expression of basophil differentiation antigens (Bsp-1. CD11b. CD25. CD40. CD54) on primary human CGL basophils or KU812-F cells was observed.
The hematopoietic defect in aplastic anemia assessed by long-term marrow culture, Thirty-two patients with aplastic anemia (AA) have been studied using the long-term bone marrow culture (LTBMC) system. Of these patients. 26 had been treated with immunosuppressive therapy including antilymphocyte globulin (ALG) with or without androgens or high-dose methyl prednisolone. The remaining six patients either required no treatment or were studied before therapy was begun. Thirty-one of 32 patients (96%) had defective hematopoiesis in LTBMC with little or no evidence for the generation of primitive progenitor cells. The only exception was a patient with spontaneous recovery of aplasia in whom the defect was less marked. Crossover LTBMC experiments were performed in 23 cases by inoculating (1) patient marrow hematopoietic cells that had been depleted of adherent cells onto preformed. irradiated. normal stromas to assess the proliferative capacity of the hematopoietic cells. and (2) normal marrow hematopoietic cells that were depleted of adherent cells onto preformed. irradiated stromas from patients with AA to assess stromal function. Results of these experiments demonstrated a hematopoietic defect in all patients that was independent of the degree of hematologic recovery after ALG therapy. Only one patient had a probable stromal defect and this coexisted with a defect in the regenerative capacity of hematopoietic cells. We conclude that LTBMC is a sensitive method for detecting and defining the hematopoietic failure in AA. We suggest that the defective hematopoiesis present in all patients studied may be important in the pathogenesis of clonal evolution in AA.
Developmental regulation of granulocytic cell binding to hemonectin, Hemonectin (HN). a component of the bone marrow (BM) extracellular matrix which promotes adhesion of cells in the granulocytic lineage. was purified to near homogeneity and tested for its ability to mediate attachment of normal and leukemic cells of granulocytic lineage. Purified HN immobilized on plastic substrates promoted serum-free attachment of normal granulocyte/macrophage progenitor cells (CFC-GM). using an in situ attachment assay in which cell attachment is inhibited by specific polyclonal antisera. When unfractionated BM cells were allowed to attach to purified HN and stained in situ. HN preferentially bound cells at earlier stages of granulocytic differentiation. These observations were confirmed using cells of the HL-60 progranulocytic cell line which mirrored this differentiation-stage specific binding to HN. HN promoted attachment of 60% of uninduced HL-60 cells which were arrested at the progranulocyte stage. whereas only 15% of uninduced HL-60 cells attached to uncoated plastic and 4% to attached plastic coated with equal microgram quantities of bovine serum albumin (BSA). When HL-60 cells were induced to differentiate along the granulocytic pathway by incubation with dimethylsulfoxide (DMSO). attachment to hemonectin was reduced. Thus. both primary BM granulocytic cells and a granulocytic cell line show preferential attachment of those cells at earlier stages of differentiation. This developmentally regulated binding suggests a mechanism for release of maturing BM into the peripheral circulation.
Enhanced endogenous leukotriene biosynthesis in patients treated with granulocyte-macrophage colony-stimulating factor, The hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is being used in clinical trials for its potential in the treatment of hematopoietic insufficiency due to various causes. Involvement of leukotrienes in the effects of GM-CSF is suggested by analytical and pharmacologic evidence obtained in vitro. However. until now no data in support of a role of leukotrienes in GM-CSF action in vivo have been presented. In the present investigation this question was approached by measurement of endogenous cysteinyl leukotriene formation in patients treated with the cytokine for cytopenia induced by cytostatic drugs or for refractory anemia with excess of blasts (RAEB). Endogenous cysteinyl leukotriene formation was assessed by determination of urinary leukotriene metabolites using combined high-performance liquid chromatography and radioimmunoassay analysis. After GM-CSF administration a distinct increase in urinary cysteinyl leukotrienes was found in the cytopenic and the RAEB patients that ranged from 2.3- to 57-fold and 2.4- to 333-fold. respectively. In the cytopenic patients the increase in leukotriene production was correlated to an expansion of peripheral blood leukocytes; RAEB patients responded to GM-CSF with enhanced leukotriene biosynthesis even if the peripheral leukocytes decreased. possibly due to an abnormal number and/or irritability of leukotriene-producing cells. The increase in endogenous leukotriene production during therapy with GM-CSF may indicate that leukotrienes play a role in GM-CSF action in vivo.
Human macrophage colony-stimulating factor induces macrophage colonies after L-phenylalanine methylester treatment of human marrow, Macrophage-colony stimulating factor (M-CSF) has well-known effects on murine bone marrow. but its colony stimulating activity for human bone marrow is controversial. After treatment of human bone marrow with L-phenylalanine methylester (PME). macrophage-colonies (CFU-M) were induced by M-CSF in a dose-dependent fashion. The optimal concentration of recombinant human-macrophage colony stimulating factor (rhM-CSF) was 1.000 U/mL. Purified human urine M-CSF had colony stimulating activity similar to rhM-CSF. Further studies were performed to determine the factors responsible for the enhanced CFU-M formation from PME treated marrow. Compared with nylon wool and carbonyl iron monocyte depletion methods. PME eliminated significantly more monocytes and myeloid cells. This observation suggested that these cells may release hematopoietic inhibitory factors for CFU-M. Low concentrations (1%) but not normal (10%) concentrations of blood monocytes were inhibitory (mean inhibition. 48%) to CFU-M. High concentrations of monocytes (50%) augmented CFU-M colonies. HL-60 conditioned media was used to simulate secretory products of early myeloid cells. HL-60 conditioned media (1%) inhibited CFU-M formation but not granulocyte macrophage or granulocyte colonies. We conclude that M-CSF has colony stimulating activity for human marrow that can be recognized after removal of inhibitory cells by PME treatment.
Seven-day administration of recombinant human granulocyte colony-stimulating factor to newborn rats: modulation of neonatal neutrophilia, myelopoiesis, and group B Streptococcus sepsis, Single-pulse administration of rhG-colony-stimulating factor (CSF) to neonatal rats was previously demonstrated to induce peripheral neutrophilia and modulate bone marrow (BM) neutrophil storage and proliferative pools (NSP + NPP). In this study. we investigated the prolonged effects of 7 days of rhG-CSF therapy (5 micrograms/kg/per day). Sprague-Dawley newborn rats (less than or equal to 24 hours) were injected intraperitoneally (IP) (daily for 7 days) with rhG-CSF or phosphate-buffered saline/human serum albumin (PBS/HSA). RhG-CSF induced a significant early and late peripheral neutrophilia: 6.905 +/- 1.625 (day 1) and 9.223 +/- 515 microL (day 7) v 1.275 +/- 90/microL (P less than or equal to .0001). In addition. 7 days of rhG-CSF resulted in a significant increase in the BM NSP: 3.247 +/- 190/microL v 1.677 +/- 339/microL (P less than or equal to .001). There was. however. no depletion or significant change in the BM NPP. Seven days of rhG-CSF also induced a mild increase in BM CFU-GM colony formation (P less than or equal to .01). There was. however. no significant change in liver/spleen CFU-GM colonies or in the CFU-GM proliferative rate in either the BM or liver/spleen cultures. Finally. 7 days of prophylactic rhG-CSF therapy resulted in a synergistic response with antibiotic therapy and significantly modulated the mortality rate during experimental group B streptococcal sepsis (GBS) (100% v 50%) (GvsC) (P less than or equal to .001). Pulse rhG-CSF administered at 6 hours or 18 hours after GBS inoculation. however. failed to act synergistically with antibiotics to improve survival or prevent peripheral neutropenia. This study suggests that 7 days of prophylactic rhG-CSF therapy induces peripheral neutrophilia. myeloid maturation. increases neutrophil BM reserves and also may provide immunologic enhancement of neonatal host defense during experimental GBS in term neonatal rats.
New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia, A new and rare type of Bcr/Abl junction between exon C3 of the 3' portion of the Bcr gene and Abl exon 2 has been identified in the leukemic cells of two Ph1-positive chronic myelogenous leukemia patients in chronic phase. This is the fourth type of Bcr/Abl junction so far identified in Ph1-positive hematologic malignancies and is a consequence of an unusual breakpoint position on chromosome 22 that falls approximately 20 kb downstream of the major breakpoint cluster region (bcr) of the Bcr gene. The new hybrid mRNA is 540 base pairs (bp) longer than that expressed by the K562 cell line and could codify for a Bcr/Abl protein carrying 180 additional aminoacids with respect to the larger P210 protein so far identified. The hematologic phenotype expressed by the two patients carrying this unusual type of Bcr/Abl rearrangement does not significantly differ from that commonly seen in chronic myelogenous leukemia.
Deficiency of glycosyl-phosphatidylinositol-linked membrane glycoproteins of leukocytes in paroxysmal nocturnal hemoglobinuria, description of a new diagnostic cytofluorometric assay, Paroxysmal nocturnal hemoglobinuria (PNH) is a disease that affects not only red cells. but other blood cells as well. The common defect is supposed to be an acquired deficiency of glycosyl-phosphatidylinositol (GPI)-anchored membrane proteins. which may be present already at the hematopoietic stem cell level. Recently. a panel of monoclonal antibodies (MoAbs) has become available directed against various GPI-linked membrane proteins. This makes it possible to study various cell lineages for the deficiency of such proteins in PNH in more detail. Using cytofluorography. we could show that the granulocytes of 20 different PNH patients miss not only GPI-linked FcRIII (CD16 antigen). but also three other GPI-linked proteins. ie. CD24 antigen. CD67 antigen and a granulocyte-specific 50 to 80 Kd antigen. The affected granulocytes were not only neutrophils but also eosinophils. as was found in a more detailed analysis of three patients. Moreover. in all 10 PNH patients tested. the monocytes were found to be deficient for the GPI-linked CD14 antigen. and we found with CD24 and CD55 (DAF) antibodies that lymphocytes may be involved as well. However. abnormal B and T lymphocytes were detected only in a subset of patients (2 of 10 tested). The uniform deficiency of GPI-linked proteins of granulocytes allows the introduction of a new diagnostic cytofluorometric assay for PNH with MoAbs against GPI-linked granulocytic antigens. This test was positive in all PNH patients studied and not in a group of 40 control patients or 50 normal donors. with the exception of three of 16 aplastic anemia (AA) patients. In the three AA patients. subpopulations (10% to 20%) of PNH granulocytes could be detected. whereas these patients had a negative acidified serum (Ham) test. This indicates that the new test is more sensitive than the Ham test and allows the early diagnosis of PNH in AA. An advantage of the neutrophil assay is that. in contrast to the Ham test. it is not influenced by recent red-cell transfusions. Moreover. it is possible to quantify the number of affected cells by single cell analysis.
Autologous bone marrow transplantation in multiple myeloma: identification of prognostic factors, Multiple myeloma remains a universally fatal malignancy with a median survival time not exceeding 3 years. A clinical trial was undertaken to determine feasibility and efficacy of marrow-ablative chemoradiotherapy supported by unpurged autologous bone marrow (ABMT) and to define prognostic variables. Total body irradiation and either melphalan or thiotepa were administered to 55 patients (median age 53 years; range 20 to 66 years). The group of 21 patients with resistance to standard melphalan-prednisone and to continuous infusions of vincristine and Adriamycin with high dose dexamethasone (VAD) included 7 with primary unresponsive disease and 14 with resistant relapse; among the 34 patients achieving remission with the VAD regimen. 14 were in first and 20 in a subsequent remission. Marked cytoreduction by greater than or equal to 75% was observed among all 21 patients with refractory myeloma. whereas further cytoreduction of this magnitude was noted in only 56% of the 34 patients already in remission after VAD. Five of the 6 early deaths among all 55 patients occurred in the 14 patients with resistant relapse. none of whom achieved complete remission and who. as a group. had median durations of relapse-free and overall survival of only 8 and 7 months. respectively. Among the 41 remaining patients. there was only one early death. and 27% achieved complete remission including a 36% incidence among the 14 patients treated in first remission; their projected 4-year survival rate was 82% regardless of their disease status (first or later remission or primary resistance). When information about sensitivity to prior therapy is unavailable. the presence before ABMT of both high beta-2-microglobulin levels (greater than 3 mg/L) and non-IgG isotype helped identify 9 among the 55 patients with a very poor prognosis: all 8 responders relapsed within 9 months. and 8 patients died within 15 months. By contrast. a 4-year projected survival rate of over 70% for the other patients (about 80% of this series) justifies further investigation of this novel treatment approach in comparison with standard dose regimens. Our results indicate that marrow-ablative therapy cannot be recommended for myeloma patients with resistant relapse or those with a combination of risk factors (advanced tumor burden. absence of IgG isotype). The apparent lack of an adverse effect of even marked plasmacytosis in autografts (up to 30%) emphasizes the need for better cytoreduction rather than bone marrow purging.
Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens, A randomized trial of 12.0 Gy versus 15.75 Gy of total body irradiation (TBI) was performed in patients with acute myeloid leukemia undergoing allogeneic marrow transplantation while in first complete remission. All patients received 120 mg/kg cyclophosphamide followed by TBI and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease (GVHD). Thirty-four patients received 2.0-Gy fractions of irradiation daily for 6 days and 37 received 2.25-Gy fractions daily for 7 days. The 3-year actuarial probabilities for relapse-free survival were 0.58 for the patients who received 12.0 Gy and 0.59 for those who received 15.75 Gy. The 3-year probabilities of relapse were 0.35 for the 12.0 Gy group and 0.12 for the 15.75 Gy group (P = .06). The 3-year probabilities of transplant-related mortality were 0.12 and 0.32. respectively (P = .04). The probability of moderate to severe acute GVHD was 0.21 for the 12.0 Gy group and 0.48 for the 15.75 Gy group (P = .02). Patients exposed to the higher irradiation dose received less immunoprophylaxis against. and had a higher incidence of. acute GVHD. The increased dose of TBI significantly reduced the probability of relapse but did not improve survival because of increased mortality from causes other than relapse.
Induction of donor-type chimerism in murine recipients of bone marrow allografts by different radiation regimens currently used in treatment of leukemia patients, Three radiation protocols currently used in treatment of leukemia patients before bone marrow transplantation (BMT) were investigated in a murine model (C57BL/6----C3H/HeJ) for BM allograft rejection. These include (a) a single dose of total body irradiation (8.5 Gy TBI delivered at a dose rate of 0.2 Gy/min). (b) fractionated TBI (12 Gy administered in six fractions. 2 Gy twice a day in 3 days. delivered at a dose rate of 0.1 Gy/min. and (c) hyperfractionated TBI (14.4 Gy administered in 12 fractions. 1.2 Gy three times a day in 3 days. delivered at a dose rate of 0.1 Gy/min). Donor-type chimerism 6 to 8 weeks after BMT and hematologic reconstitution on day 12 after BMT found in these groups were compared with results obtained in mice conditioned with 8 Gy TBI delivered at a dose rate of 0.67 Gy/min. routinely used in this murine model. The results in both parameters showed a marked advantage for the single dose 8.5 Gy TBI over all the other treatments. This advantage was found to be equivalent to three- to fourfold increment in the BM inoculum when compared with hyperfractionated radiation. which afforded the least favorable conditions for development of donor-type chimerism. The fractionated radiation protocol was equivalent in its efficacy to results obtained in mice irradiated by single-dose 8 Gy TBI. both of which afforded a smaller but not significant advantage over the hyperfractionated protocol. This model was also used to test the effect of radiation dose rate on the development of donor-type chimerism. A significant enhancement was found after an increase in dose rate from 0.1 to 0.7 Gy/min. Further enhancement could be achieved when the dose rate was increased to 1.3 Gy/min. but survival at this high dose rate was reduced. These results demonstrated indirectly that dose rate affects the expression of host-type pluripotent stem cells. the progeny of which appear 3 to 6 weeks after treatment with 8 Gy TBI delivered at a dose rate of 0.1 Gy/min. but which are eradicated if radiation is delivered at a dose rate of 1.3 Gy/min.
Contamination of peripheral blood stem cell harvests by circulating neuroblastoma cells, Peripheral blood stem cells (PBSC) are being used as one alternative to autologous marrow rescue for patients with neuroblastoma and other solid malignancies. Some physicians prefer use of PBSC because less risk of tumor contamination is believed to exist. This hypothesis was evaluated by immunocytologic analysis of blood samples and concurrently drawn bone marrow (BM) samples and of PBSC harvests obtained from 31 patients with disseminated neuroblastoma. We found circulating neoplastic cells in 75% of specimens analyzed at diagnosis. in 36% during therapy. and in 14% of PBSC harvests. Tumor cells in blood obtained during therapy did not appear until 3 months after the time of diagnosis. Clearance of circulating neuroblastoma cells was documented after two courses of induction chemotherapy. Six of 13 patients with minimal or no BM disease had positive blood specimens. We conclude that substantial risk of tumor contamination of PB harvests exists and recommend that induction chemotherapy be administered before hematopoietic progenitor cells are collected from blood.
A clinical epidemiological study in low back pain. Description of two clinical syndromes, In 100 patients with mainly chronic low back pain (LBP) signs and symptoms were evaluated prospectively and without preconceived expectation of particular findings. Two clinical syndromes were distinguished. both characterized by 'typical local tenderness' and associated with specific clinical features; these syndromes. described previously in the literature but receiving scant attention. were named the greater trochanteric pain syndrome (trochanteric bursitis) and the iliac crest pain syndrome (iliolumbar syndrome). and occurred in 35% and 43% of the patients. respectively. The recognition of these syndromes may enable us to study aetiology. prognosis. and therapy of LBP in more homogeneous groups of patients.
The inhibition of NK cell function by azathioprine during the treatment of patients with rheumatoid arthritis, Treatment with azathioprine of patients with rheumatoid arthritis leads to a dramatic reduction in the 4 h NK cytotoxicity against K562 cells. The 24 h cytotoxicity against K562 and U937 cells. however. remains intact. The generation of cell-free supernatant cytotoxic factor(s) after incubating non-adherent mononuclear cells with U937 cells for 24 h is similar in the azathioprine patients and the controls. A large part of this supernatant cytotoxicity is due to tumour necrosis factor alpha which can be inhibited by a specific monoclonal antibody. The mechanism of the reduced 4 h NK cytotoxicity remains unknown but is probably not related to the anti-inflammatory properties of azathioprine.
Does primary fibromyalgia exist?, Twenty-one of 25 consecutive primary fibromyalgia or fibrositis patients. identified during a 5-year period in a tertiary care day-ward for pain syndromes. were re-examined. Fifteen fulfilled criteria for fibromyalgia but unexpectedly. all cases had either psychiatric disturbance or thyroid dysfunction. Of the four patients not seen at follow-up. two had developed neurological diseases. another rheumatoid arthritis and one other hypothyroidism. Thus. after 5 years no patient fulfilled the criteria for primary fibromyalgia. Women occupied as manual workers were over-represented. Most patients reported beneficial effects of physiotherapy. None of the patients has been able to return to full time work.
Sedoanalgesia in urology: a safe, cost-effective alternative to general anaesthesia. A review of 1020 cases, Sedoanalgesia is a technique developed to provide safe and satisfactory operating conditions for a wide range of patients independent of age and overall level of fitness (although its use in children remains to be established). It is suitable for both endoscopic and open procedures. day-cases and in-patients. When used in day-case surgery it significantly improves overall efficiency. It is recognised that day-case surgery is an important and cost-effective element in surgical care. With increasing restraints being imposed upon hospital finances. patient beds and staffing levels. any strategies designed to improve efficiency in this sphere of surgical activity are to be welcomed. That 93% of patients prefer sedoanalgesia to conventional general anaesthesia attests to its high degree of acceptability. The technique of sedoanalgesia. its applications and potential impact for urology are detailed.
Ureteric substitution with Boari bladder flap, Between 1986 and 1989. 12 patients underwent ureteric substitution with a Boari bladder flap at this Institute. The indications were ureteric injury following hysterectomy. difficult forceps delivery. difficult ureterolithotomy. ureteric strictures caused by a Dormia basket and previous ureteric surgery. tuberculosis. retroperitoneal fibrosis and a post-ureteric reimplantation fistula. There were 2 patients with a solitary kidney and 2 in acute renal failure. Double J stenting was carried out in 11 patients and the stent was removed 3 to 6 weeks post-operatively. Good results. with no morbidity or mortality. were achieved in all but 1 patient where a simple Silastic stent had migrated to the pelvis and required open surgery to remove it. We attribute our success to the tension-free anastomosis. a wide based posterior flap with preservation of its vascular supply. the use of a double J stent and vicryl suture material.
Variations in urethral and bladder pressure during stress episodes in healthy women, Pressure variations in the urethra and bladder during stress episodes and their time separations were investigated in 30 healthy female volunteers. The pressure was measured by means of a double microtip transducer catheter with the distal sensor in the bladder and the proximal sensor at the bladder neck. the mid-urethra and the distal urethra. In advance of the pressure spike during cough a pressure rise was demonstrated in the bladder and at all 3 sites of measurement in the urethra. The urethral pressure increments preceding and following the pressure spike were statistically significantly higher in the mid-urethra than the corresponding bladder pressures. This active urethral pressure generation in the mid-urethra and distal urethra was initiated 200 ms before the bladder pressure began to rise. The pressure in the urethral high pressure zone was higher than the bladder pressure in all cases. Passive pressure transmission to the urethral high pressure zone can take place only insignificantly due to a continuous higher pressure inside the urethra than in the bladder and due to the location of the high pressure zone in the demarcation of the abdominal cavity. It was concluded that the urethral pressure rise in the high pressure zone during stress episodes is mainly generated actively by intra- and/or peri-urethral structures.
In vitro evaluation of the pollen extract, cernitin T-60, in the regulation of prostate cell growth, Nine human-derived cancer and non-cancer continuous cell lines were employed to evaluate the relative in vitro activity of the pollen extract. Cernitin T-60. Responses of the cell lines to the drug were assessed by measuring growth and cell survival as determined by cell count. The results demonstrated that of the 9 continuous cell lines tested. only those derived from the human prostate were growth inhibited by the pollen extract. whereas the non-prostate derived cells exhibited variable degrees of resistance to the T-60. The selectivity of the drug for the prostate cell lines was even more pronounced in the hormone-independent models. suggesting that there might be a place for the pollen extract in the control of abnormal growth in hormone-insensitive cells.
Treatment of outflow tract obstruction due to benign prostatic hyperplasia with the pollen extract, cernilton. A double-blind, placebo-controlled study, Whilst prostatectomy remains the "gold standard" for the treatment of outflow tract obstruction due to benign prostatic hyperplasia. medical treatment--if only for symptomatic relief--appears to be an attractive alternative. Most of the pharmacological agents in use block the hormonal or the sympathetic neurological pathways that influence prostate growth and function. All of these drugs are known to have side effects. Sixty patients with outflow obstruction due to benign prostatic hyperplasia (BPH) were entered into a double-blind. placebo-controlled study to evaluate the effect of a 6-month course of the pollen extract. Cernilton. There was a statistically significant subjective improvement with Cernilton (69% of the patients) compared with placebo (30%). There was a significant decrease in residual urine in the patients treated with Cernilton and in the antero-posterior (A-P) diameter of the prostate on ultrasound. However. differences in respect of flow rate and voided volume were not statistically significant. It is concluded that Cernilton has a beneficial effect in BPH and may have a place in the treatment of patients with mild or moderate symptoms of outflow obstruction.
Prostatic carcinoma: histological and immunohistological factors affecting prognosis, Neuro-endocrine or paracrine cells of the human prostate and urethra have been identified by various methods. predominantly silver stains and immunocytochemistry. The incidence of neuro-endocrine differentiation in prostatic carcinoma has varied considerably from 10 to 100%. but has not been studied previously as an independent factor affecting prognosis. Nucleolar organiser regions (NORs) are loops of ribosomal RNA occurring in the nucleoli of cells which ultimately process RNA genes. NORs have been demonstrated by silver (Ag) staining techniques and have been studied in numerous malignant tumours. A pilot study from this laboratory has shown a distinct and significant difference in AgNOR staining between prostatic carcinoma and benign prostatic epithelial hyperplasia. A retrospective study was performed with at least 6 years' follow-up. This confirmed the presence of neuro-endocrine cells in more than half of the patients under investigation. A significant correlation between survival and the absence of neuro-endocrine cells was demonstrated. AgNOR staining was shown to be of no prognostic value.
Intraoperative air testing of colorectal anastomoses: a prospective, randomized trial, A total of 145 consecutive patients receiving a colorectal anastomosis were randomized to 'test' or 'no test' once the anastomosis had been completed. Anastomotic testing was performed with the pelvis filled with saline and the rectum distended by sigmoidoscopic insufflation of air. Any leaks demonstrated were oversewn. A water-soluble contrast enema was performed on the tenth postoperative day. Seventy-four patients were randomized to 'test' and 71 to 'no test' but one patient was withdrawn from each group leaving a total of 143 for analysis. The two groups were well matched for age. sex. diagnosis and operative details. Eighteen (25 per cent) air leaks were detected and repaired in the 'test' group. After operation there were three (4 per cent) clinical leaks in the 'test' group and ten (14 per cent) in the 'no test' group (Fisher's exact test. P = 0.043). There were eight (11 per cent) radiological leaks in the 'test' group and 20 (29 per cent) in the 'no test' group (P = 0.006). Intraoperative air testing and repair of colorectal anastomoses significantly reduces the risk of postoperative clinical and radiological leaks.
Pulse oximetry: a new non-invasive assessment of peripheral arterial occlusive disease, Peripheral skin perfusion reflects the level of vascularity and viability of a limb and may help in planning the site of amputation or bypass surgery in patients with vascular disease. This study used peripheral pulse oximetry in 20 healthy volunteers and in 20 patients with limb ischaemia. Pulse oximetry saturation levels (Psa.O2) were compared with ankle artery Doppler pressures and transcutaneous oxygen measurements (Ptc.O2). Recordings were taken at two standard sites distally and referenced to finger and forearm to calculate an index. A significant correlation was found between Ptc.O2 and Psa.O2 in patients with ischaemia (r = 0.68. P less than 0.01). A further group of 12 patients with acute limb ischaemia was similarly assessed before and after revascularization. After revascularization mean(s.d.) Ptc.O2 increased from 38(13) to 44(1) mmHg (P greater than 0.05) and mean(s.d.) Psa.O2 increased from 86(3) to 90(4) per cent (P less than 0.01). These data suggest that pulse oximetry is a more sensitive index of peripheral perfusion than Ptc.O2 or ankle artery Doppler pressure and that. because of its accuracy and simplicity. it merits further use.
Graft stenosis: justification for 1-year surveillance, In all. 412 femorodistal grafts (femoropopliteal and femorocrural). performed between 1984 and 1988. have been prospectively studied at 6 weeks and 3. 6. 9 and 12 months after operation and at intervals of 6 months thereafter by duplex scanning and intravenous digital subtraction angiography. The overall incidence of stenoses was 16 per cent (femorocrural 20 per cent. femoropopliteal 15 per cent). All stenoses were detected in the first year after operation and none occurred after this. Twenty-four non-haemodynamically significant stenoses were not treated but were followed at intervals of 3 months. Forty-two haemodynamically significant stenoses were detected and secondary procedures were performed in 30 grafts at a mean of 8 months after surgery. Thirteen had percutaneous balloon dilatation and six (46 per cent) remain patent at a mean follow-up of 22 months. Two grafts which occluded within 30 days and three which restenosed at a mean of 8 months had tertiary procedures. Seventeen grafts were surgically revised. nine with patch grafts and eight with bypass grafts. Eleven of these remain patent at a mean follow-up of 30 months. One occluded immediately and three occluded late. Two grafts which restenosed at a mean of 19 months had successful tertiary procedures. In total. seven grafts had tertiary procedures (two had balloon dilatation and five had surgery) and six of these remain patent at a mean follow-up of 13.5 months. In conclusion. 37 procedures have been performed on 30 grafts. of which 23 (77 per cent) remain patent at a mean follow-up of 12 months. Approximately one-quarter of femorodistal grafts will develop graft-related stenoses and graft surveillance is worthwhile. but only for the first year after operation.
Recent changes in the treatment of aortoiliac occlusive disease by the Oxford Regional Vascular Service, Over the four years from 1 January 1985 to 31 December 1988. 192 patients were treated for aortoiliac occlusive disease by the Oxford Regional Vascular Service. The number of patients treated by percutaneous transluminal angioplasty increased from two in the first year of the study to 34 in the third year of the study. This increase was accompanied by a decrease in the proportion of patients treated by aortobifemoral bypass but the proportion of patients treated by extra-anatomic bypass remained constant at around 30 per cent. Twice as many patients were treated in the fourth year as in the first year of the study so that the number of surgical operations increased despite many patients being treated exclusively by percutaneous transluminal angioplasty. The number of patients requiring mandatory treatment for limb salvage increased by 109 per cent and optional treatment for intermittent claudication by 85 per cent. The introduction of percutaneous transluminal angioplasty in Oxford has coincided with an increase in the number of patients presenting with symptomatic aortoiliac occlusive disease and has allowed twice as many people to be treated while the number of aortobifemoral bypass operations has remained unchanged. It is concluded that the introduction of percutaneous transluminal angioplasty has not only generated its own workload but has also led to an increased demand for surgical reconstruction for aortoiliac occlusive disease.
Conservative management of asymptomatic popliteal aneurysm, Historical review shows that the treatment of popliteal aneurysm has developed by trial and error and there is disagreement about the proper management of the symptomless patient. In 1981 a policy of conservative management for asymptomatic popliteal aneurysm was adopted in this unit. Since that time we have also managed nine patients with thrombosed popliteal aneurysms by arteriography and low-dose intra-arterial streptokinase. Six patients treated within 72 h of occlusion achieved significant (70-100 per cent) lysis. but streptokinase was ineffective in those treated 10 or more days after the thrombosis. Of the six patients with significant lysis. three were treated by elective reconstruction and two by anticoagulation. One patient who had significant lysis died. Vascular patency of all five successfully treated limbs was maintained and no limb loss occurred in those who presented late and failed to achieve significant lysis. These results reinforce the view that thrombolysis is the treatment of choice for thrombosed popliteal aneurysms. The low complication rate for asymptomatic popliteal aneurysms and the advent of safe. effective thrombolysis indicate that operation for symptomless popliteal aneurysm is no longer required.
Stress in surgeons, A sample of 1000 members of the Association of Surgeons of Great Britain and Ireland was circulated with a postal questionnaire relating to their occupational stressors. their type A coronary-prone behaviour and their mental health. Six hundred and seventy-two (67 per cent) useable forms were returned anonymously. The major individual stressors were: (1) the interference of the job with personal life. (2) general administration. and (3) the number of patients in clinics. Type A behaviour was similar to that of other professional groups. Surgeons showed mean scores significantly higher than the general population on two subscales of the mental health index (free-floating anxiety and hysterical anxiety). The findings for the few female surgeons (2 per cent) were similar to those in men but they did not exhibit raised free-floating anxiety levels.
Premorphological metabolic changes in human breast carcinogenesis, Malignant breast tissue is characterized by morphological and metabolic changes when compared with normal breast tissue. In this study. the cytochemical measurement of glucose-6-phosphate dehydrogenase (G6PD) activity was used to detect abnormal metabolism in breast tissue and to determine whether abnormal metabolic activity precedes morphological change during human breast carcinogenesis. Normal and benign breast tissue. morphologically normal tissue from cancer-containing breasts. and malignant breast tissue were studied. In malignant tissue. mean(s.e.m.) G6PD activity was significantly increased when compared with normal and benign tissue (9.69(2.3) versus 27.02(1.7) mean integrated extinction (MIE) x 100. P less than 0.01). G6PD activity was increased in morphologically normal tissue from cancer-containing breasts when compared with normal and benign breast tissue from breasts with no known cancer (27.02(1.7) versus 18.42(2.6) MIE x 100. P less than 0.05). These findings suggest that metabolic abnormalities precede morphological changes in breast carcinogenesis. Abnormal metabolism can be detected widely within a cancer-containing breast. The detection of such abnormality may prove helpful in identifying patients at high risk of developing breast cancer.
The physician's role, Physicians can play an important role in society's response to alcohol problems. In diagnosis. alcohol problems among patients are frequently overlooked. Physicians should routinely ask patients about alcohol intake. In light of evidence on the effectiveness of brief interventions. especially with heavy-drinking but nondependent patients. physicians' treatment efforts should be focused in this direction. Patients who are alcohol dependent might best be treated by nonphysicians. Research contributions of physicians should be concentrated on topics for which physician input is needed: longitudinal studies of health consequences. factors contributing to mortality and health service costs. biochemical markers of alcohol use and basic pharmacology. Strong evidence links population alcohol consumption levels to overall harm. Therefore. prevention efforts should be aimed at the population as well as at people who may be at risk. Physicians can contribute to these efforts by influencing public policy and by setting healthy examples in their own alcohol use.
The role of medical schools in the prevention of alcohol-related problems, There is agreement that physicians can play a major role in the prevention of alcohol problems among their patients and that medical schools should prepare physicians for this role by teaching three major subject areas: knowledge. attitudes and clinical skills. Despite this agreement and the acknowledged high prevalence of alcohol problems in clinical populations. medical school coverage of these problems is not proportional to their importance. Barriers to adequate coverage of alcohol problems are traditional attitudes. confusion as to whether such problems are "medical" and lack of adequate faculty role models. These problems could be remedied by encouragement and training of interested faculty members. establishment of substance abuse centres in university medical schools. integration of alcohol-related material with relevant topics in all departments and inclusion of alcohol-related questions on medical qualifying exams.
Spectrum of drinkers and intervention opportunities, Most adults in North America are either light drinkers or abstainers. so alcohol does not cause them problems. However. a small but often highly visible minority--approximately 5% of the adult population--show major symptoms of alcohol dependence. Between these extremes. there is a sizable group of about 20% of the population. particularly young men. who are drinking at risk levels and have encountered some problems related to their alcohol use. Traditionally. physicians' efforts have focused on diagnosing and treating patients with a substantial history of alcohol dependence. and relatively little attention has been given to early intervention with nondependent problem drinkers. such as identifying patients who present in primary care settings with alcohol-related morbidity or an accidental injury. Recent evidence indicates that early intervention by primary care physicians is an effective strategy for reducing alcohol problems among patients.
Early identification of alcohol problems, A high proportion of patients seen in clinical practice have an underlying alcohol problem. This is often difficult to detect. but failure to make the diagnosis may result in unnecessary investigations and inappropriate treatment. Furthermore. there is now good evidence of the effectiveness of brief intervention for problem drinking when it is still at an early stage. Several questionnaires and procedures based on clinical examination findings and laboratory tests are available to help in early diagnosis. They can be incorporated into the standard medical assessment and form the basis for screening programs for health risk factors.
Brief intervention strategies for harmful drinkers: new directions for medical education, Recent advances in the technology of behavioural interventions for harmful drinkers have created a new role for clinical practice and new challenges for medical education. Several reports from expert committees have recommended new initiatives in the secondary prevention of alcohol problems through physician-based interventions at the primary care level. The conceptual and scientific bases for these recommendations are discussed in terms of recent studies of harmful and hazardous drinkers. The behavioural principles thought to account for the effectiveness of brief interventions are explained. Despite these promising developments. difficulties are inherent in the introduction of new technologies. especially behavioural technologies. into medical practice. A major challenge to medical education will be the development of academic programs that not only teach skills and competencies in secondary prevention but also deal with the socialization of physicians as behavioural practitioners.
Preventing alcohol problems: survey of Canadian medical schools, In preparation for a national conference on medical education in the prevention of alcohol problems. a survey of conference participants was conducted. Participants were undergraduate and postgraduate representatives from each Canadian medical school and representatives from 11 provincial and territorial alcohol and other drug agencies. There was agreement that physicians and medical schools have important roles in prevention and treatment of alcohol problems. with "traditional" medical roles seen as the most important. Current training is variable and was seen as inadequate. with more time devoted to treatment than prevention. To correct this situation. renewed priorities and faculty leadership are needed. Respondents felt that there should be uniform standards for assessing undergraduate students' skills in dealing with alcohol problems. Provincial alcohol and other drug agencies are underused in medical education in the prevention and treatment of alcohol problems.
The development of medical education on alcohol- and drug-related problems at the University of Toronto, Medical education on alcohol- and drug-related problems at the University of Toronto covers undergraduate. residency and graduate programs. a result of collaboration since 1959 between the university and the Addiction Research Foundation of Ontario. An undergraduate core curriculum. developed in the early 1970s. is offered in year 2; it has been supplemented by electives. selectives and comprehensive clinics. The undergraduate program is rated highly by students; since 1978. 3024 have completed the core program. Residency training started in 1974 and is available through electives lasting from 1 to 12 months in internal medicine. psychiatry. and family and community medicine. To date. 370 residents have completed one of these electives; 129 have completed graduate programs in which their theses concerned alcohol- and drug-related topics. and there have been an additional 13 research and postdoctoral fellows. Despite the progress. there is still a need to improve and expand the undergraduate and residency programs and to develop an effective program of continuing medical education. The goals should be to ensure that. as far as possible. all medical graduates from the University of Toronto have the knowledge. attitudes. skills and behaviours needed to contribute effectively to the prevention and treatment of alcohol- and drug-related problems in their chosen field of practice and to avoid problems from their personal use of alcohol and other drugs.
Medical education for alcohol and other drug abuse in the United States, Initiatives by individuals. private foundations and government have led to improvements in the United States in medical education dealing with alcohol and drug-related problems. Progress has been made. particularly in the past 5 years. in developing new medical school curricula and in faculty development. Greater activity by national professional organizations has helped raise the priority of training in alcohol- and drug-related areas for undergraduate and postgraduate medical education. As an example. Project ADEPT (Alcohol and Drug Education for Physician Training in primary care) at Brown University in Providence. Rhode Island. is described. The importance of positive and motivated faculty role models and of skills training is emphasized.
Zidovudine (Retrovir) update, Zidovudine (AZT) is the first antiretroviral agent to be licensed for the treatment of human immunodeficiency virus (HIV) infection. Since the initial placebo-controlled trial showing improved survival among patients with acquired immunodeficiency syndrome (AIDS) or symptomatic HIV infection (AIDS-related complex [ARC]) zidovudine has been evaluated in other stages of HIV infection. This review offers physicians who treat patients with HIV infection a comprehensive analysis of the current data on the clinical efficacy of zidovudine in various stages of HIV infection and on zidovudine's adverse effects. After a search of MEDLINE for pertinent articles published since 1985. controlled studies and studies of long-term zidovudine therapy. of zidovudine therapy for HIV-related conditions and of the incidence and management of adverse reactions were evaluated. In addition. abstracts from international meetings were reviewed. No significant difference in clinical outcome was found between high-dose and low-dose zidovudine therapy. but there were significantly fewer toxic effects in the low-dose group. In two other studies zidovudine was found to delay disease progression in patients with asymptomatic or mildly symptomatic HIV infection who had an absolute CD4 count of less than 0.5 x 10(9)/L; the low incidence of adverse reactions may have been due to either the early stage of the infection or the low dose used. The demonstration of zidovudine-resistant isolates after at least 6 months of therapy has yet to be correlated with clinical deterioration. When to begin zidovudine therapy among asymptomatic patients with a CD4 count of less than 0.5 x 10(9)/L remains unclear. Zidovudine can be used safely to delay progression to AIDS or ARC in certain patients with asymptomatic or mildly symptomatic HIV infection and can prolong survival in those with more severe infection. Further studies are necessary to identify indicators that could better define when to start treatment and how to alleviate toxic effects. Combination therapy with such agents as interferon alpha may become the preferred choice of therapy to prevent toxic effects and zidovudine resistance. Zidovudine prophylaxis has been used after HIV exposure. Although studies with animal models have had encouraging results infection has occurred despite immediate prophylaxis and thus further investigation is required.
HIV infection among Quebec women giving birth to live infants, This is the first anonymous unlinked seroprevalence study in Canada to use serum samples from newborns to determine the seroprevalence rate of human immunodeficiency virus (HIV) infection among childbearing women. Of the 68.808 samples tested 42 were confirmed as positive. for an overall crude seroprevalence rate of 6.1 per 10.000 live births (95% confidence interval [CI] 4.4 to 8.3). or 1 woman in 1638. Women who lived on Montreal island had an overall rate of 17.9 per 10.000 live births (95% CI 12.2 to 25.4). or 1 woman in 559. We observed a significant association between revenue index and seroprevalence; the rates were as high as 46.4 per 10.000 live births (95% CI 18.7 to 95.3). or 1 woman in 216. for Montreal island postal code areas with revenue indexes 20% or more below the provincial median. Extrapolation of the data suggested that 56 women with HIV infection gave birth to a live infant during 1989 in Quebec. Even though attempts to generalize the data from childbearing women to women of childbearing age have an inherent conservative bias. the results of our study suggest that 988 women (95% CI 713 to 1336) aged 15 to 44 years in Quebec had HIV infection in 1989. The actual number is likely substantially higher. The need for well-designed. creative interventions to prevent further HIV transmission to women is evident. Planning for the provision of medical and psychosocial services sensitive to specific needs of women who are already infected should start immediately.
Heterogenous amplification of myc family oncogenes in small cell lung carcinoma, One hundred forty-two foci of small cell lung carcinoma (SCLC) from 47 patients were examined for amplification of myc family oncogenes (c-myc. N-myc. and L-myc). by dot blot hybridization using formalin-fixed and paraffin-embedded materials which were resected surgically or obtained at autopsy. Some selected patients were also examined by in situ hybridization. Amplification of myc family genes was detected in 11 patients (23.4%) (c-myc in one. N-myc in five. and L-myc in five). Two of the 11 patients (one with N-myc and one with L-myc) had heterogenously amplified clones. In the patient with N-myc amplification. amplification was detected in metastatic tumors in the pancreas. lung. and pleura. but not in the liver and lymph node metastases. In the primary tumor. areas with and without N-myc amplification were seen. In the patient with L-myc amplification. although amplification was not detected in the surgically resected primary lesion. mediastinal lymph node metastatic lesions obtained at autopsy showed L-myc gene amplification. These two cases. together with previously reported evidence. suggest that myc gene amplification plays an important role in malignant progression. rather than development. of SCLC. In Stage III and IV groups. patients with over ten-fold myc gene amplification were suggested to survive for a shorter time than patients without such amplification (P = 0.06).
Endoscopic screening of early esophageal cancer with the Lugol dye method in patients with head and neck cancers, The poor prognosis for esophageal cancer could be improved if lesions were detected at an early stage. To detect early esophageal cancer. endoscopic screening of the esophagus with the Lugol dye method was performed in patients with head and neck cancers who were asymptomatic but regarded as being at high risk for synchronous or metachronous esophageal cancer. Of 178 patients screened. 9 had esophageal cancer (5.1%). Eight of these patients (89%) were at early stages with no lymph node metastasis. Most of the lesions (9 of 13 lesions) were not detectable by barium studies or ordinary endoscopic study. The epidemiologic statistical analysis of the patients confirmed that they had a significantly high observed and expected number (O/E) ratio (39.7; P less than 0.001). These results demonstrate the value of endoscopic screening of the esophagus with the Lugol dye method in patients with head and neck cancers and imply that endoscopic screening with the Lugol dye method may be useful for detecting early esophageal cancer in individuals at risk for other causes.
Surgical treatment of brain metastases in malignant melanoma, The authors report the results of a retrospective review of 13 patients who underwent 19 craniotomies for resection of metastatic malignant melanoma at the University of Colorado (Denver. CO) between 1983 and 1989. There was preoperative evidence of extracranial disease in 11 patients. Eight patients had more than one intracranial metastasis at operation. Intraoperative ultrasound was used in 18 of the 19 craniotomies to minimize surgical trauma to the brain. The 30-day mortality was zero. The 30-day morbidity was minimal. No patient acquired a new neurologic deficit as a result of surgery. All patients regained at least their preoperative level of functioning. Six of the patients who were living at the time of review have been followed for 4 to 25 months (median. 7.5 months). The seven patients who were dead at the time of review survived 4 to 18 months (median. 10 months). These results compare favorably with the survival of untreated patients with metastatic melanoma to the brain (median. 1 month). patients treated with radiation therapy alone (median. 2-4 months). and those treated with chemotherapy alone (median. 2-4 months). The excision of metastatic melanoma from the brain. although not curative. may increase survival in patients with this problem with little morbidity and mortality even in the presence of other metastases.
Loss of expression of blood group antigen H is associated with cellular invasion and spread of oral squamous cell carcinomas, Membrane-bound carbohydrates may influence the metastatic behavior of cancer cells. Forty-two squamous cell carcinomas (SCC) of the buccal and maxillary alveolar mucosa were studied retrospectively using a monoclonal antibody (BE2) that reacts with blood group H (type 2 chain) structure and an immunoperoxidase (avidin-biotin peroxidase complex) staining technique. H-antigen staining within the entire tumor did not correlate with the stage of the tumor. i.e.. tumor spread. However. loss of staining within the most invasive sites of the tumors correlated significantly with the stage of tumor development and histologic grade of malignancy. These findings support the view that features regarding the cells of deeper parts of the carcinomas are very important for the clinical behavior of the tumors and that loss of H-antigen expression is related to the stage of the tumor and invasion of carcinoma cells.
Occurrence of beta-hexachlorocyclohexane in breast cancer patients, The residues of polycyclic aromatic hydrocarbon (PAH) and neutral organochlorine compounds in breast fat of 44 breast cancer patients and 33 women free of cancer were determined. No statistically significant differences appeared between the two comparison groups with regard to occurrence of PAH compounds. Of the neutral organochlorine compounds. residues of beta-hexachlorocyclohexane (HCH) were found more frequently in breast cancer patients. After adjusting for age and parity by stepwise logistic regression. beta-HCH remained a significant risk factor of breast cancer. Using a cutoff point for the residue level of beta-HCH in breast adipose tissue of more than 0.1 mg/kg fat. the odds ratio was 10.51 (95% CI. 2.00-55.26).
Identification of somatostatin receptors in human small cell lung carcinoma, Biopsy specimens obtained from eight patients with lung cancer were tested for content of somatostatin receptors by autoradiography. Somatostatin receptors were detected in two of three patients with small cell lung cancer (SCLC) but in none of five patients with non-small cell lung cancer (NSCLC) including adenocarcinoma (two). squamous cell carcinoma (two). and bronchoalveolar carcinoma (one). In those with SCLC. specific somatostatin receptor binding was evidenced only in tumor foci and not in surrounding stroma or normal lung parenchyma. Further tissue characterization by immunoperoxidase staining with the pancytokeratin monoclonal antibody. mAB-lu-5. revealed labeling to all of the NSCLC but to none of the SCLC specimen. Selective immunoreactivity was detected in both the SCLC and the NSCLC specimen to chromogranin and neuron-specific enolase (NSE) whereas none of the specimen had detectable immunostaining to somatostatin. bombesin. serotonin. adrenocorticotropic hormone. neurofilament. calcitonin. and synaptophysin. The identification of somatostatin receptors in primary human lung cancer may have a bearing on the biology of this disease and perhaps on the clinical application of somatostatin analogues in patients with SCLC.
Cell lineage markers in human pancreatic cancer, The normal pancreas consists of three major cell types or lineages that share a common embryologic origin from pluripotent endodermal precursors. The type of cell that undergoes neoplastic transformation to form a pancreatic carcinoma is controversial and may influence the phenotype and biologic behavior of the tumor. In this study. immunohistologic techniques were used to determine the cell lineage differentiation expressed in 29 primary exocrine pancreatic adenocarcinomas. five metastatic exocrine pancreatic adenocarcinomas. and five islet cell neoplasma. Specimens of normal pancreas and chronic pancreatitis were used for comparison. The cell lineage markers consisted of monoclonal and polyclonal antibodies against trypsin and lipase (acinar cells); secretory component. carbonic anhydrase II. and pancreatic cancer mucin SPan-1 (ductal cells); and chromogranin-A and somatostatin (islet cells). The expression of carcinoembryonic antigen (CEA) and lysozyme were also determined. This collection of markers allowed the differentiation between acinar. ductal. and islet cells of normal pancreas and chronic pancreatitis specimens. The expression of cell lineage markers in islet cell tumors was homogeneous and restricted to chromogranin-A. In contrast. the expression of these markers in primary and metastatic exocrine pancreatic adenocarcinomas was variable. Reactivity with monoclonal anti-CEA was absent in normal pancreas. and was present in 83% of chronic pancreatitis specimens as well as 90% of exocrine pancreatic adenocarcinomas. In addition. lysozyme reactivity was absent in normal pancreas; however. lysozyme was expressed in one case of chronic pancreatitis. 17 cases of primary carcinoma. and three cases of metastatic carcinoma. These findings support the concept that the original transformed cell type in many pancreatic exocrine carcinomas resemble endodermal "stem cells" that retain the capability of differentiation along more than one cell lineage pathway.
Expression of pancreatic secretory trypsin inhibitor gene in human colorectal tumor, Expression of pancreatic secretory trypsin inhibitor (PSTI) gene was examined by Northern blotting analyses in 31 human colorectal tumors that included two benign adenomas and 26 adenocarcinomas. Among the total of 28 cases which proved to be adequate for mRNA analyses. all but one showed the expression of PSTI at various levels. In contrast. PSTI expression was not detected in two malignant lymphomas of the rectum. The level of PSTI expression was not correlated with the patient's age. sex. tumor location or size. stage of differentiation. lymph node metastasis. or progression stage. Some colorectal adenocarcinomas were also shown to express genes that can hybridize with human trypsinogen cDNA probe. It looks as though in these tumors. a protease(s) and its inhibitor are produced simultaneously as part of a cellular self-defense mechanism.
The physical state of human papillomavirus 16 DNA in cervical carcinoma and cervical intraepithelial neoplasia, Cervical carcinomas and cervical intraepithelial neoplasias (CIN) were analyzed for the presence of human papillomavirus (HPV) DNA using Southern blot hybridization. Of the five HPV types examined (HPV types 6. 11. 16. 18. and 33). HPV 16 DNA was detected most frequently. In most HPV 16-positive carcinomas examined. HPV 16 DNA was present in an integrated state in cellular DNA with or without the coexistence of episomal species. In one case. however. only episomal species were detected. Among seven cases of HPV 16-positive CIN. four contained HPV 16 DNA only in the episomal state and the rest contained HPV 16 DNA only in the integrated state. but the coexistence of both states was not found. These results suggest that the integration of HPV 16 DNA is not necessary for cells to become malignant. although it is frequently associated with malignant cells.
Distribution of immunoglobulins and secretory component in gastric cancer of the aged, The secretory immune system plays an important role in the local humoral immunity of the gastrointestinal tract. In order to evaluate humoral immunity in gastric cancer. distribution of immunoglobulins (Ig) and secretory component was immunohistochemically studied in 74 early and 15 advanced primary gastric cancers. In non-cancerous gastric mucosa. IgA and IgM. and secretory component were mainly identified in the cytoplasm of the intestinal metaplasia. In early gastric cancer of well-differentiated type. the localization of IgA and IgM. and secretory component was similar to that of intestinal metaplasia. In advanced gastric cancer. they were faintly observed and showed low positivity. The number of Ig-containing cells infiltrating cancerous stroma was enumerated. Immunoglobulin A-containing cells were dominant in the stroma of early gastric cancer. On the other hand. there were few Ig-containing cells in the stroma of advanced gastric cancer. and the number of IgA-containing and IgM-containing cells was also decreased. These results suggest that local humoral immunity is suppressed in gastric cancer. especially in advanced gastric cancer.
Giant cell tumor of bone. A clinicopathologic and DNA flow cytometric analysis, Flow cytometric DNA analysis was performed on 60 cases of giant cell tumor of bone and the results were correlated with the clinicopathologic features. Tumors studied were from 31 men and 29 women whose ages ranged from 18 to 62 years (median. 29 years). The most common sites were the distal end of the femur and proximal end of the tibia. accounting for 75% of the lesions. Treatment consisted of resection in 29 patients (48%). curettage with bone chip packing in 15 patients (25%). or curettage with cement packing in 16 patients (27%). Ten patients (17%) had local relapse within 1 to 3 years. and two had lung metastases. Forty-two patients (70%) exhibited tumors with a diploid DNA content. 16 aneuploid (27%). and two tetraploid (3%). Six (37.5%) of the aneuploid patients had relapses: one of those had been treated by resection of the tumor and five by curettage. Of the remaining ten (62.5%) unrelapsed aneuploid patients. nine had been treated by resection of the tumor and one by curettage. Four of the 42 diploid patients (9.5%) had relapses; all had been treated by curettage of the tumor. The two tetraploid tumors were treated by resection and none relapsed. Histologic parameters did not correlate with relapse rate or DNA pattern. Although relapse was more common among aneuploid tumors. our study shows that this appears to be influenced by the treatment modality rather than the ploidy status. Based on this study the DNA analysis of giant cell tumor of bone has a limited utility for predicting the tumor's biologic behavior.
Hyperthermia alone in the treatment of recurrences of malignant tumors. Experience with 60 lesions, Localized hyperthermia alone has been used for the treatment of cancer recurrences in which previous conventional therapies have failed. Since 1983 and 1988. 57 patients with 60 lesions have been heated by means of a microwave and radiofrequency system. Treatment protocol provided 45 minutes of heating at the intratumor temperature of at least 42 degrees C. twice a week. for a total number of six. eight. or ten heating sessions. Invasive intratumor thermometry was performed for all lesions. Complete response (CR) was obtained in ten cases (16.6%) and partial response (PR) in 14 (23.4%). Higher rates of CR were observed in the chest wall (38.5%) compared with the head and neck area (11.4%). trunk (10%). and limbs (none). Adenocarcinoma was the most responsive histologic type (40%). Squamous cells carcinoma had 7.7% CR. The only case of undifferentiated carcinoma showed CR; there were none on five sarcomas. Long-term local control (24 months) was approximately 7%. The multivariate analysis showed the statistical significance of the histologic variety (adenocarcinoma versus others. P less than 0.0001). Side effects and complications of the treatment were minimal.
Clear cell adenocarcinoma of the lower genital tract. Correlation of mother's recall of diethylstilbestrol history with obstetrical records, The written obstetric records of maternal exposure to diethylstilbestrol (DES) were used as a criterion standard and compared with the DES exposure history recalled by mothers of women with vaginal. cervical. or indeterminable vaginal/exocervical clear cell adenocarcinoma. Among cervical cases. the sensitivity of maternal recall was 50% (N = 2). and its specificity was 100%. Among vaginal and vaginal/exocervical cases. this sensitivity was 72%; specificity was 60%; and the majority of these mothers who said they did not take DES were DES positive by written records. Thus investigators should avoid using maternal recall alone to measure DES exposure. Among subjects for whom written maternal obstetric records were available. 88% of vaginal cases and 46% of cervical cases were DES positive. The authors conclude that few cases of vaginal clear cell adenocarcinoma should occur in young women as the cohort of women exposed in utero to DES continues to age. whereas cases of cervical origin may continue to occur.
Multiple spinal metastases from paraganglioma, Isolated vertebral body metastases from paraganglioma are exceedingly rare. They have been reported to occur in the presence of active primary tumor in the neck. local recurrence. or widespread metastases. A unique case of carotid body tumor (paraganglioma) is reported with the following features: (1) multiple vertebral body metastases (C6. T9. and L3) presenting with spinal cord compression. and no evidence of local recurrence or other metastatic disease; (2) absence of mitoses on the original specimen or the metastatic deposit; and (3) a prolonged interval (9 years) to the development of symptomatic metastases.
Cancer in the families of children with soft tissue sarcoma, The cancer experience among 754 first-degree relatives (mothers. fathers. and siblings) of a population-based series of 177 children with soft tissue sarcoma is reported. The current study represents an extension of our earlier work in which the authors found an excess of breast cancer in the mothers of 143 of these children. There were 40 cancers among all first-degree relatives. compared with 24.82 expected (relative risk [RR] 1.61. P = 0.006). There was no excess in fathers. but an excess of borderline significance was seen in mothers (RR 1.67. P = 0.0545). and a significant excess in siblings (RR 4.55. P = 0.0002). mainly due to carcinoma of the breast and pediatric tumors. Results of a step forward Cox multivariate analysis identified three variables in the index child which were independently associated with high cancer risk in relatives. as follows: age younger than 24 months at diagnosis; histologic type. embryonal rhabdomyosarcoma or other and unspecified soft tissue sarcoma; and male sex. It was possible. therefore. to identify a subgroup of children whose relatives are at high risk of early onset cancer (RR in this group 10.14). The pattern of cancers is consistent with the Li-Fraumeni syndrome. The authors conclude that a marked proportion of childhood soft tissue sarcoma has a genetic basis.
Cholecystectomy and right colon cancer in Puerto Rico, A case-control study was undertaken to evaluate the possible relationship between cholecystectomy and right colon cancer. Two hundred patients with adenocarcinoma of the cecum or ascending colon (diagnosed between 1984 and 1989) were compared with 200 matched neighborhood controls. Cholecystectomy history was obtained through interviews using structured questionnaires and subsequently validated from hospital records. A statistically significant association (odds ratio = 2.14) was found between right colon cancer and a history of prior cholecystectomy. The altered bile metabolism which occurs after removal of the gallbladder may have a carcinogenic effect on the right colon. Dietary habits of the colon cancer patients in our study were consistent with prior reports in the literature. showing that this group has a lower intake of vegetables and cereal fiber than the control population.
Concomitant cisplatin chemotherapy and radiotherapy in advanced mucosal squamous cell carcinoma of the head and neck. Long-term results of the Radiation Therapy Oncology Group study 81-17, One hundred twenty-four eligible patients with advanced mucosal squamous cell carcinoma of the head and neck were entered into a pilot study of concomitant cisplatin (100 mg/m2 given every 3 weeks for three doses) and standard irradiation. The initial complete response (CR) was 71% with an additional two cases salvaged by surgery for an overall 73% CR. When no keratin was identified in the histologic specimen (41 patients) the CR was 90%. The nasopharynx showed the best CR (89%) among the sites. At 4 years after treatment. the estimated locoregional tumor control rate was 43% and the survival. 34%. When no keratin was present in the specimen. the estimated locoregional control of tumor was superior (56% versus 38% with keratin identified. P = 0.02) and the estimated survival was also superior (48% versus 26%. P = 0.008). Acute treatment-related toxicities included one death due to renal damage and two patients with life-threatening renal damage. The delivery of radiotherapy was not altered. Late toxicity included necrosis -3%. fibrosis -4%. and one fistula. The results of this study justify a randomized trial for the comparison of this combination of cisplatin and radiotherapy versus radiotherapy alone in advanced mucosal carcinomas of the head and neck.
Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases, One hundred sixty-nine patients with histologic evidence of disseminated malignant melanoma. including patients with cerebral metastases. were entered into a Phase II study of the nitrosourea fotemustine. The treatment regimen consisted of a 100 mg/m2 1 hour IV infusion every week for 3 consecutive weeks. followed by a 4- to 5-week rest period (induction therapy). In responding or stabilized patients. maintenance therapy consisted of 100 mg/m2 every 3 weeks until the disease progressed. One hundred fifty-three patients were evaluable for response. Three complete responses and 34 partial responses were observed (according to the World Health Organization criteria). leading to an objective response rate of 24.2% (95% confidence interval: 17.4% to 31.0%). Responses were also documented on cerebral (25.0%). visceral (19.2%). or nonvisceral (31.8%) metastatic sites. The median duration of response was 22 weeks (range. 7 to 80 weeks). The objective response rate in previously untreated patients was 30.7% (19 of 62 patients). The main toxicity was hematologic with delayed and reversible leukopenia and/or thrombopenia. The objective response rate observed (especially in untreated patients). the activity on cerebral metastases. and the small amount of extra-hematologic toxicity encountered suggest that fotemustine is an effective drug in disseminated malignant melanoma.
Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the Study Group of Japan, One hundred nine newly treated patients with advanced neuroblastoma were entered in this study between January 1985 and May 1989. The eligible patients included infants younger than 12 months of age with Stage IVA disease (bone cortex. distant lymph node. and/or remote organ metastases) and patients aged 12 months or older with Stage III or IV disease (IVA plus IVB with tumor crossing the mid-line and with metastases confined to bone marrow. liver. and skin). The patients first received six cyclic course of intensive chemotherapy (regimen A1). consisting of cyclophosphamide (1200 mg/m2). vincristine (1.5 mg/m2). tetrahydropyranyl adriamycin (pyrarubicin; 40 mg/m2). and cisplatin (90 mg/m2). Original tumors and the regional lymph node metastases were removed some time during these first six cycles of chemotherapy. The patients were further divided into three groups. Patients in course 1 received alternating treatment by regimen B (cyclophosphamide and ACNU) and intensified regimen A1. and those in course 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in course 3 were treated with bone marrow transplantation (BMT) preceded by high-dose preconditioning chemotherapy. Survival rates were 77% in Stage III and 54% in Stage IV at 2 years. and 70% in Stage III and 45% in Stage IV at 3 years. The major toxicities encountered were bone marrow suppression with leukocyte counts down to 100/mm3. mild cystitis. and hearing impairment. The 2-year survival rate was 78% in 21 patients who underwent BMT when complete remission was achieved. We concluded that our intensive induction chemotherapy is of significant value in increasing the rate of complete response. and in widening the indications for and achieving improved results of treatment with BMT.
A randomized comparison of methotrexate dose and the addition of bleomycin to CHOP therapy for diffuse large cell lymphoma and other non-Hodgkin's lymphomas. Cancer and Leukemia Group B study 7851, In 1978. Cancer and Leukemia Group B initiated a randomized study to determine the usefulness of the addition of bleomycin and/or high-dose methotrexate to standard therapy for the treatment of certain adult non-Hodgkin's lymphomas. Between 1978 and 1985. 177 patients with diffuse large cell lymphoma (DLCL) and 97 patients with other intermediate-grade non-Hodgkin's lymphoma were randomized to receive therapy with three courses of cyclophosphamide. adriamycin. vincristine. and prednisone (CHOP) every 3 weeks with or without low-dose bleomycin by continuous IV infusion. Responders after three courses were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 gm/m2/week intravenously with leucovorin rescue) or standard-dose methotrexate (30 mg/m2/week orally without rescue). Therapy was concluded with three additional courses of CHOP. Neither the addition of low-dose infusion bleomycin nor the use of high-dose rather than low-dose methotrexate had significant effects on response for patients with DLCL; complete response rates for the four treatment programs ranged from 47% to 51%. Median failure-free survival (FFS) for the entire group of DLCL patients was 12 months; 5-year FFS was 27%. There was no significant effect on FFS from the addition of either low-dose bleomycin to CHOP (5-year FFS: CHOP. 28%; CHOP-B. 26%. P = 0.81). or from the use of different doses of methotrexate (5-year FFS: high-dose. 34%; standard-dose. 33%. P = 0.51). Patients with follicular large cell lymphoma. with or without diffuse areas. had a better FFS (5-year FFS. 47%) than patients with DLCL (5-year FFS. 27%). while the patients with the other histopathologic subtypes of diffuse lymphomas had the poorest FFS (5-year FFS. 16%).
Immune deficiency in family members of patients with Hodgkin's disease, Indirect data supporting a preexisting immunologic impairment in patients with Hodgkin's disease (HD) have been presented in recent years. These immunologic defects are supposed to be related to genetic and/or environmental factors. In this study. 65 first-degree relatives and 12 spouses of 21 consecutive patients with HD were studied immunologically. Furthermore. seven twin pairs in which one partner had HD and four additional nonmatched healthy co-twins were also included in the study. A decreased lymphocyte DNA synthesis induced by Concanavalin A. a high spontaneous DNA synthesis. or a low CD4+/8+ ratio was found in 21 (32%) consanguineous. two (17%) nonconsanguineous relatives. and five (50%) healthy co-twins. The corresponding figures for the untreated patients with HD and the control series were 14 of 21 (65%) and 21 of 127 (16%). respectively. Total lymphocyte counts or lymphocyte subpopulations did not differ between HD relatives and controls. The increased frequency of blood lymphocyte defects among consanguineous first-degree relatives favors the existence of a genetically determined immune deficiency in at least a proportion of apparently healthy relatives of patients with HD. However. nongenetic factors such as age and environment may add to the defect.
Impaired production of tumor necrosis factor in breast cancer, Spontaneous and lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF) by peripheral blood macrophages was investigated in breast cancer. Whereas spontaneous TNF production by macrophages derived from patients with breast cancer was comparable with the one found in healthy controls (P greater than 0.1). LPS-stimulated macrophages derived from patients in the disease-free interval as well as with metastatic breast cancer were found to produce significantly lower amounts of TNF. as compared with macrophages derived from healthy control individuals (P less than 0.0005). However. the production of TNF did not significantly differ between the two patient populations (P greater than 0.05). The impairment of LPS-induced TNF production did not depend upon such characteristics of the primary tumor as size. axillary lymph node and estrogen receptor status. or upon the fact of administration of adjuvant chemotherapy and. in patients with metastatic disease. hormone treatment. To further investigate cytokine production by macrophages. spontaneous and LPS-induced interleukin-1 (IL-1) production was investigated also. However. no difference was found between patients and controls concerning IL-1 generation. The authors thus conclude that LPS-induced TNF production was impaired in breast cancer independent of the presence of detectable metastatic disease. whereas IL-1 production remained unimpaired.
Medroxyprogesterone acetate lowers plasma corticotropin and cortisol but does not suppress anterior pituitary responsiveness to human corticotropin releasing factor, The endocrine action of medroxyprogesterone acetate (MPA) has been claimed to be of a glucocorticoid-like nature. Upon clinical observation. MPA has been shown to improve life quality and overall well-being in patients with advanced breast cancer. renal carcinoma. prostatic carcinoma. and uterine adenocarcinoma. The authors have evaluated MPA endocrine action by the administration of human corticotropin releasing factor (hCRF) in a 90-minute assay in 15 patients with advanced breast cancer or renal cell carcinoma both. before the initiation of oral high-dose MPA treatment (1000 mg MPA) as well as after at least 10 days of therapy. The curves for corticotropin. beta-endorphin. and cortisol responses to hCRF of tumor patients who were tested before the initiation of MPA treatment were parallel to the curves of a healthy control group of probands tested under equal conditions. although at significantly higher respective hormone levels. In patients with malignant disorders assayed after MPA administration. both basal and peak hormone levels were found to be comparable with values obtained in healthy controls. In conclusion. MPA appeared to act at a suprapituitary level since pituitary responsiveness to hCRF was preserved under MPA treatment. Moreover. it appeared that MPA brought the hormonal stress state found in patients with malignant tumors back to normal.
Sialosyl-Tn. A novel mucin antigen associated with prognosis in colorectal cancer patients, Colon cancers typically produce mucin. However. it is not known whether tumor mucin plays a biological role in cancer cell behavior. To address this issue. the expression of a mucin-associated antigen. sialosyl-Tn. was examined by immunohistochemical study in 128 primary colorectal carcinoma specimens from 137 patients who underwent curative surgical resection. Antigen expression was correlated with disease-free and overall 5-year survival. Sialosyl-Tn antigen expression occurred in 112 (87.5%) tumors. and was independent of age. gender. tumor location. Dukes' stage. depth of invasion. degree of differentiation. and ploidy status. Survival at 5 years for patients with sialosyl-Tn-negative versus sialosyl-Tn-positive tumors was 100% versus 73% (P less than 0.05) and disease-free survival was 94% versus 73%. respectively (P = 0.12). Although more advanced Dukes' stage. deeper invasion. and aneuploidy were all associated with poorer overall 5-year survival. antigen-negative tumors within each of these groups had much better prognoses than antigen-positive tumors. Multivariate regression analysis revealed that tumor ploidy (P less than 0.001) and sialosyl-Tn expression (P less than 0.05) were the two variables of most importance for predicting both disease-free and overall survival. The authors conclude that sialosyl-Tn expression is an independent predictor of poor prognosis in colon cancer. and therefore suggest that qualitative mucin alterations may reflect important differences in the biological behavior of these neoplasms.
Increased expression of the multidrug-resistance gene in undifferentiated sarcoma, We analyzed multidrug-resistance gene (mdr1 gene) expression in a patient with undifferentiated sarcoma of the liver using the cloned cDNA for the mdr1 gene. Tissue samples were available at the time of initial diagnosis and of two intracranial relapses after chemotherapy with a regimen including doxorubicin and teniposide. The level of mdr1 gene expression was increased sevenfold in the intracranial tumor at the time of first relapse and 11-fold at the second relapse. This case may be an example of acquired multidrug resistance associated with overexpression of the mdr1 gene.
Non-Hodgkin's lymphoma in the elderly. I. Pathologic features at presentation, The pathologic findings of 118 patients aged 70 years or older with non-Hodgkin's lymphoma (NHL) are reported. These patients formed 27.2% of 433 consecutive cases of NHL seen in a single institution over a 5-year period. Thirty-one of 433 NHL cases were histologically not classified. whereas the remaining 402 could be classified according to the International Working Formulation (WF) of NHL for clinical usage. Immunophenotypic analyses were carried out in 112 NHL cases; of this group 28 were NHL in elderly patients. Of the 95 elderly NHL that could be classified in the histologic categories of the WF 28 cases were in the low-grade. 41 in the intermediate-grade. and 26 in the high-grade categories. Eighty-one cases had diffuse histologic types and 14 had follicular/nodular histologic types. Thirty-five cases were of the G (diffuse large cell) + H (large cell. immunoblastic) categories. No significant differences in the prevalence of the different subtypes were observed among patients younger or older than 70 years. Immunohistologically. most NHL cases in the elderly expressed B-cell phenotype. Sixty-two NHL in the elderly were extranodal at presentation. The results of this study indicate that elderly patients form a relevant proportion of patients developing NHL and thereby present a very difficult management problem. The pathologic features of NHL in the elderly does not differ significantly from those of their younger counterparts. although an increase in diffuse versus follicular histologic patterns. and in extranodal versus nodal disease was observed with advancing age.
Intraoperative pathologic diagnosis of thyroid neoplasms. Report on experience with 504 specimens, Intraoperative pathologic examination with frozen section (FS) was performed on 504 specimens of thyroid tissue obtained from 457 patients over a period of 9 years. After examination of permanent sections (PS) a malignant neoplasm was diagnosed in 57 specimens (11.3%); 50 (87%) of these were primary thyroid carcinoma. four (8%) metastatic carcinoma. and three (5%) malignant lymphoma. The FS diagnosis was "benign" in 448 (88.9%). "malignant" in (30) 5.9%. and "deferred" in 26 (5.2%). The sensitivity of FS diagnosis of malignancy was 53% and the specificity and positive predictive value 100%. The negative predictive value was 97.8% and overall accuracy 97.9%. The PS disclosed a malignant neoplasm in 62% of specimens in which FS diagnosis was "deferred." Sixty-eight percent of papillary carcinomas. 87% of undifferentiated carcinomas. and a single case of medullary carcinoma were diagnosed with FS examination. A FS diagnosis of malignancy was not made in any of the ten specimens containing follicular carcinoma; in all ten the neoplasms were well-differentiated and eight were encapsulated and minimally invasive. The inability to diagnose follicular carcinoma intraoperatively with FS is the most significant factor accounting for the relatively low sensitivity of FS diagnosis of malignant thyroid neoplasms.
Cerebral tumor staging in patients with bronchial carcinoma by computed tomography, Computerized tomographic (CT) scans of 271 patients with histologically proven bronchial carcinoma accomplished for initial tumor staging were retrospectively evaluated for signs of cerebral metastasis. The results for the histologic subtypes were quite different. In 13.8% of patients with small cell carcinoma and limited disease the authors found signs of brain metastasis. However. routine cerebral staging in these patients did not seem to be useful because of lack of therapeutic consequences. On the other hand. no patient with non-small cell carcinoma (N-SCC) and tumor Stage I or II had brain metastases. All patients with brain metastasis from N-SCC had been classified as tumor Stage III before cerebral imaging. Among these patients. however. the authors found brain metastasis in 17.5% of those without known distant metastatic disease (III/M0). especially in large cell carcinoma and in adenocarcinoma. Stage III/M0 patients should undergo routine cerebral imaging if their tumor is surgically resectable and thoracotomy is planned.
Infiltration of dendritic cells in relation to tumor invasion and lymph node metastasis in human gastric cancer, The infiltration of dendritic cells determined in 210 patients with gastric carcinoma was investigated from the standpoint of tumor invasion. lymph node metastasis. and prognosis. Dendritic cell infiltration was graded as "slight" and "marked." The 39% frequency in the marked infiltration group at the mucosal stage did not change in proportion to invasion into the deeper layers. The 5-year survival rate was 60.4% in patients with marked infiltration and 38.8% in those with slight infiltration. which was statistically different (P less than 0.01). The difference in survival rates was only statistically significant in those with cancer emerging from the serosa (P less than 0.001). There was a similar incidence of lymph node metastasis between the marked and slight infiltration groups in each grade of tumor invasion. However. marked infiltration of dendritic cells prevented widespread nodal involvement beyond the primary node in cases of advanced carcinoma (P less than 0.05). These findings indicate that infiltrating dendritic cells do not prevent the spread of tumor invasion but do prevent nodal involvement; therefore. for patients with a gastric cancer emerging from the serosa. the prognosis will be good.
Familial testicular cancer in five members of a cancer-prone kindred, Of a family of 13 siblings. four brothers have developed testicular neoplasms. one embryonal cell carcinoma and three testicular seminomas. A first cousin once removed on their mother's side of the family (fourth-degree relative) has developed an embryonal carcinoma. After treatment they are all alive and well. Their mother is a dizygous twin and one of ten siblings. Multiple other cancers have been diagnosed among her siblings and their offspring including breast carcinoma at age 30 years in monozygous twin nieces. Associated urogenital abnormalities. concordance of age. and discordance of pathology in the five males with testicular cancer is discussed. Further identification and reporting of this risk factor is encouraged.
Familial occurrence of gastric cancer in the 2-year experience of a population-based registry, The authors studied the familial occurrence of tumors in 154 individuals with gastric cancer by reviewing the clinical data and the genealogical tree of all patients registered in 1986 through 1987 in the Local Health Care District of Modena. Italy. for cancer of the stomach. Crude and age-adjusted (world population) incidence rates of gastric cancer were 34.0 and 21.4 new cases/100.000/year. respectively. in men. and 24.5 and 10.9 in women. respectively. Among first-degree relatives of the registered patients there were 30 cases of gastric carcinoma versus 15 cases in a control group matched for age and sex (Mantel-Haenszel odds ratio [M-H OR] 3.14. P less than 0.01). This excess of gastric neoplasms was observed in siblings (17 versus 7. M-H OR 4.33. P less than 0.02) but not in parents (13 versus 8. not significant). Besides gastric cancer. there was no significant excess of other type of tumors in case families. The familial occurrence of gastric cancer tended to be more frequent in patients with "diffuse" carcinoma (52%) than in subjects with "intestinal" cancer (33%). although the difference was not statistically significant. In conclusion. the current investigation suggests that a "family history" for gastric neoplasms is usually observed in approximately 10% to 15% of the registered cases. As already described for other common malignancies. therefore. the familial occurrence of gastric carcinoma suggests the existence of a genetic susceptibility to cancer of the stomach. at least in a fraction of these patients.
Angioplasty of occluded coronary arteries: use of thin shaft balloon over-the-wire system without pre-dilatation, A retrospective review was done on 13 consecutive patients who underwent PTCA of totally occluded coronary arteries using a recently released thin shaft balloon over-the-wire angioplasty system. Balloon size was determined by the closest fit to the arterial size and used without predilatation techniques. This technique was initially successful in 12 patients with only 2 clinically insignificant episodes of distal embolization and one probable early reclosure. Using thin shaft angioplasty systems. balloon dilatation of totally occluded coronary arteries can be done safely with a single balloon in many cases resulting in simplified procedures and economic benefits.
Probe angioplasty of total coronary occlusion using the Probing Catheter technique, Coronary angioplasty (PTCA) of total coronary occlusion is limited by the inability of guidewires and conventional dilating catheters to cross all such lesions. A new technique was therefore prospectively evaluated for PTCA of these lesions using the ultra-low-profile Probe "balloon on a wire" device. An intracoronary Probing Catheter was used to facilitate crossing the stenosis with a guidewire and then to deliver a Probe into the obstruction for balloon dilatation. This technique was utilized in 64 consecutive patients with "absolute" coronary occlusions demonstrating no angiographically detectable antegrade coronary flow. Successful dilatation was achieved in 47 (73%). Among 33 occlusions of less than 3 mo duration 31 (94%) were successfully dilated whereas only 16 of 31 more chronic occlusions were dilated (P less than .01). Chronic occlusions with a tapered morphology and those located more than 1 cm from a branch point were more frequently dilatable. There were no serious complications including no vessel perforations with this technique. The Probing Catheter technique offers a safe and effective method for the dilatation of recent coronary occlusions by using balloon on a wire technology.
Regression of infundibular pulmonary stenosis after successful balloon pulmonary valvuloplasty in adults, Between July 1985 and March 1988. 22 adult patients with congenital pulmonary stenosis underwent balloon pulmonary valvuloplasty. There were 10 males and 12 females aged 16-45 (average 25 +/- 9.9) years. All patients had additional mild to severe infundibular stenosis; 16 were restudied 6-36 (mean 12.6) months later by repeat catheterization. Student's t-test was used for comparison of data. Right ventricular (RV) systolic pressure before dilatation was 84-196 (mean 129 +/- 32.3) mm Hg. and the peak pulmonary gradient (PPG) was 60-176 (mean 111 +/- 33.2) mm Hg immediately after dilatation. The RV systolic pressure dropped to 32-140 (mean 59.2 +/- 27) (P less than 0.001); and PPG dropped to 10-113 (mean 37.8 +/- 26.4) (P less than 0.001). and the infundibular gradient ranged from 8 to 113 (mean 35.1 +/- 25.8) mm Hg. The infundibular diameter. before dilatation. ranged from 2 to 15 (mean 9.5 +/- 4) mm Hg. At repeat catheterization. the RV systolic pressure dropped further to 33-66 (mean 42.8 +/- 9.7) mm Hg and the PPG was reduced to 0-48 (mean 18.4 +/- 10.9) mm Hg (P less than 0.001). The infundibular gradient regressed to 0-34 (mean 15 +/- 8.8) mm Hg (P less than 0.001). The infundibular diameter increased to 8-25 (mean 15.8 +/- 5.4) (P less than 0.001). It is concluded that moderate to severe infundibular stenosis. in adults. can regress after successful pulmonary valvuloplasty.
Diagnosis of left atrial thrombi in mitral valve disease by coronary arteriography, Arteriographic findings of neovascularity and fistula formation between coronary arteries and left atrium have occasionally been described in association with left atrial thrombosis in patients with mitral valve disease. The validity of these coronary arteriographic findings in diagnosis of atrial thrombi has been evaluated in 112 patients with mitral valve disease. Comparison was made with surgery. The study furnished these diagnostic values: sensitivity 70%. specificity 85%. positive predictive value 72%. Even if this angiographic finding is complementary in diagnosis of atrial thrombosis. its identification during coronary arteriography in patients with mitral valve disease is useful. Its detection could improve diagnostic prediction of thrombosis. especially in patients without previous embolic events or where echocardiography failed to reveal thrombi.
Balloon rupture due to lesion morphology during coronary angioplasty, We report a case of coronary angioplasty of a left anterior descending artery lesion that was complicated by the rupture of three successive balloon catheters. Each rupture occurred as a pinhole jet of contrast into a diagonal side branch. causing subintimal staining. This case demonstrates that balloon rupture may result from lesion morphology.
Severe mitral insufficiency post-balloon valvuloplasty: the late changes found in a disrupted mitral valve, The case of a 45-yr-old woman who had balloon valvuloplasty for rheumatic mitral stenosis is presented. An anterior mitral leaflet tear occurred as a complication of the procedure. Both partial healing of the anterior mitral leaflet and gradual dilatation of the left atrium occurred which allowed the damaged valve to remain in situ for several months. Some of the late changes which occur after such a complicated valvuloplasty are illustrated here. as this patient eventually required surgery and valve excision for definitive repair.
Inflation pressure requirements during coronary angioplasty, To examine the balloon inflation pressures required for successful percutaneous transluminal coronary angioplasty (PTCA). the maximal inflation pressure required for 477 coronary lesions in 200 consecutive patients was determined retrospectively. When graded balloon inflations just sufficient to achieve full expansion were used. the maximal inflation pressure used was less than or equal to 8 atm in 412 stenoses (86%) and was less than or equal to 10 atm in 463 stenoses (97%). Successful PTCA was achieved in 98% of lesions with a 3.5% major procedural complication rate. In a second group of 100 patients studied prospectively. the inflation pressure required to achieve full balloon expansion was less than or equal to 8 atm in 214 of 232 stenoses (92%) and less than or equal to 10 atm in 228 stenoses (98%). Thus. PTCA of coronary stenoses can be achieved with high success rates and low complication rates when graded inflations to pressures just sufficient to achieve full balloon expansion are performed. Most coronary stenoses will respond to pressures less than or equal to 8-10 atm.
Percutaneous popliteal approach for angioplasty of superficial femoral artery occlusions, Angioplasty using the percutaneous popliteal approach was utilized in 50 patients (PTS) to recanalize 59 occluded superficial femoral arteries which had been unsuccessfully canalized by using the antegrade approach because of either a flush origin occlusion or inability to maintain the guide wire in the true lumen. All PTS had claudication; 8 had rest pain; 3 had non-healing ulcers. The laser Probe was used in 17 cases and the Rotablator in 3 cases. Occlusion length varied between 1 and 40 cm: 7 lesions were less than 10 cm (group 1); 9 were between 10 and 20 cm (group 2); and 43 were greater than 20 cm (group 3). An angiographic success was obtained in 48/59 lesions (81%): 14/16 (87%) in groups 1 and 2 and 34/43 (79%) in group 3. Three PTS needed complementary common femoral endarterectomy and one required percutaneous aspiration of a thromboembolus. Complications included: arterial perforation and/or dissection (without clinical sequelae) in 11 and a popliteal hematoma in 1 PT. One patient with a severely ischemic leg underwent successful emergency vascular surgery. while another limb salvage patient required below-knee amputation. There was no worsening of limb ischemia from any popliteal approach attempt. At discharge. 39 patients (78%) whose outcome would have been unsuccessful with the traditional antegrade approach were clinically improved after utilizing the popliteal approach to achieve a successful angioplasty procedure.
Percutaneous puncture of a nondeflatable coronary artery angioplasty balloon, We report a case in which a balloon catheter became permanently inflated in a coronary artery saphenous vein bypass graft. While still inflated. the balloon was forcibly withdrawn from the graft into the external iliac artery and successfully deflated via percutaneous puncture using a CHIBA needle.
Percutaneous transluminal coronary angioplasty of gastroepiploic artery graft, The right gastroepiploic artery is being used as a third arterial conduit for coronary artery bypass surgery. Presented here is a case demonstrating successful percutaneous transluminal coronary angioplasty of the gastroepiploic artery graft. This successful accomplishment may avoid repeat surgical revascularization in case of failure of the gastroepiploic artery graft. hence may encourage people to use it more often.
Usefulness of digital angiography in the assessment of left ventricular ejection fraction, With modern digital cardiac systems the image data are digitized on-line and in real-time. allowing the replay and subsequent interpretation and analysis during or directly after the cardiac catheterization procedure. In this study we have evaluated the advantages and limitations of a manual tracing technique for left ventricular digital angiograms on the Phillips DCI system. Thirty-three patients who were catheterized for suspected coronary artery disease were studied. The manual tracings were performed by a senior cardiologist and an experienced function-analyst. It was found that the short- and long-term intraobserver variabilities in the assessment of the global ejection fraction were very small; short-term mean difference +/- standard deviation (correlation coefficient): 0.5 +/- 2.7 (r = 0.97) global EF%-units; long term; 0.7 +/- 2.7 (r = 0.96) EF%-units. The interobserver variabilities (5.1 +/- 4.8 (r = 0.93) EF%-units) were slightly higher than the intraobserver variabilities. A decrease by 25% in the amount of contrast medium administered did not significantly influence the variabilities in the contour tracings. which would suggest the use of smaller doses. At the average. the cardiologist and the function-analyst required 6 and 11 min of analysis time for a left ventricular study. respectively. emphasizing the need for further developments towards automated contour detection. Finally. an excellent correlation was found with a standard off-line cinefilm analysis procedure. Thus. it may be concluded that quantitative digital left ventricular angiography based on manual tracing of the outlines performed immediately following the cardiac catheterization (post-processing) is feasible as a routine procedure for the assessment of left ventricular function.
Temporary cardiac pacing using a new, steerable, balloon-tipped pacing catheter, A new balloon-tipped. flow-directed. steerable pacing catheter for unipolar temporary ventricular pacing is presented. It was successfully and uneventfully tested in 25 patients with acute myocardial infarction in the coronary care unit. The main advantage of the new catheter is the ease with which a stable contact may be achieved between the pacing electrode and the endocardium.
Reduction of postoperative morbidity following patient-controlled morphine, The present study examined the impact of two methods of pain management on recovery in 38 women undergoing hysterectomy. One group received IV morphine in the recovery room and IM morphine on the ward on a PRN basis (PRN group). In the other group. a loading dose of morphine 8 mg IV was given when the patient first complained of pain and patient-controlled IV morphine (PCA) was initiated and continued for 48 h (PCA group). Both groups received similar amounts of morphine overall. differently distributed over time. The PCA patients received 8 mg.h-1 in the recovery room (approximately 2.5 hrs) and less thereafter. The PRN patients received approximately 2 mg.h-1 for the entire 48-hr period. Pain control was better throughout convalescence and less variable across time with PCA management. Minute ventilation also recovered faster and by day four was 25 per cent above the preoperative baseline in the PCA group. In addition. oral temperature became normal one day earlier. ambulation recovered more rapidly and patients were discharged from hospital earlier. The data suggest that early treatment with relatively high. self-titrated morphine doses may alter the course of the metabolic response to surgery.
Brachial plexus block with a new local anaesthetic: 0.5 per cent ropivacaine, A new local anaesthetic. ropivacaine hydrochloride. was used in a concentration of 0.5 per cent in 32 patients receiving a subclavian perivascular block for upper extremity surgery. One group (n = 15) received 0.5 per cent ropivacaine without epinephrine and a second group (n = 17) received 0.5 per cent ropivacaine with epinephrine in a concentration of 1:200.000. Anaesthesia was achieved in 87 per cent of the patients in both groups in all of the C5 through T1 brachial plexus dermatomes. Motor block was profound with 100 per cent of patients in both groups developing paresis at both the shoulder and hand and 100 per cent developing paralysis at the shoulder. There was a rapid initial onset of sensory block (a mean of less than four minutes for analgesia) with a prolonged duration (a mean of greater than 13 hr of analgesia). The addition of epinephrine did not significantly affect the quality or onset of sensory or motor block. The duration of sensory block was reduced by epinephrine at T1 for analgesia and at C7. C8. and T1 for anaesthesia. The duration of sensory block in the remaining brachial plexus dermatomes as well as the duration of motor block was not effected by epinephrine. There was no evidence of cardiovascular or central nervous system toxicity in either group with a mean dose of 2.5-2.6 mg.kg-1 ropivacaine.
Neurological phenomena during emergence from enflurane or isoflurane anaesthesia, During emergence from anaesthesia. transient neurological signs that would usually be considered pathological may appear. The objective of this randomized. patient (n = 30) and observer-blinded study was to compare prospectively the incidence and duration of post-anaesthetic neurological abnormalities in healthy patients undergoing minor elective procedures following thiopentone and succinylcholine induction. and enflurane-N2O or isoflurane-N2O anaesthesia. Patients were studied for 60 min after anaesthesia. Arousal state. muscle tone. deep tendon reflexes. plantar reflex. sustained clonus. shivering. intense muscular spasticity and temperature were assessed. Results of neurological examination were correlated with the patient's state of arousal. Transient emergent neurological abnormalities occurred more frequently following enflurane-N2O anaesthesia than isoflurane N2O anaesthesia. This was statistically significant (P less than 0.05) for quadriceps hyperreflexia. upgoing toes (positive Babinski reflex) and intense muscular spasticity. Neurological abnormalities occurred most commonly 5-20 min after anaesthesia and all abnormalities resolved within 60 min. Following enflurane anaesthesia. as patients became more alert the incidence of abnormalities declined. while the arousal state did not affect the incidence of abnormalities after isoflurane. There was no significant difference between axillary temperatures of those patients who shivered and those who did not. In conclusion. temporary emergent neurological abnormalities occurred more often following enflurane-N2O than after isoflurane-N2O anaesthesia.
Continuous suprascapular nerve block for analgesia of scapular fracture, Fracture of the scapular is uncommon but painful. A case is described in which a comminuted scapular fracture was treated with a continuous suprascapular nerve block. With the patient lying supine an epidural needle was directed towards the scapular notch via a superior approach and an epidural catheter was placed when the notch was believed to have been identified. Repeat injections of 10 ml bupivacaine 0.25 per cent with 1/200.000 epinephrine provided analgesia within minutes and a duration of 8-10 hr. Injection of 10 ml radio-opaque dye demonstrated the catheter to be lateral to the scapular notch. However. dye dispersed throughout the supraspinous fossa including the scapular notch thus blocking the suprascapular nerve. This case demonstrates that continuous suprascapular nerve block can be performed for five days and that location of the scapular notch is less important than previously thought.
Vertigo after epidural morphine, Severe complications from the use of epidural morphine for analgesia after Caesarean section are rare. A case is reported of extreme prostrating vertigo several hours after epidural morphine injection. where the time of onset of the symptom coincided with the expected time of arrival of the morphine within intra-cerebral cerebro-spinal fluid.
Electrotonic influences on action potentials from isolated ventricular cells, This work combines a theoretical study of electrical interactions between two excitable heart cells. using a variable coupling resistance. with experimental studies on isolated rabbit ventricular cells coupled with a variable coupling resistance to a passive resistance and capacitance circuit. The theoretical results show that the response of an isolated cell to an increased frequency of stimulation is strongly altered by the presence of a coupling resistance to another cell. As the coupling resistance gradually is decreased. the stimulated cell becomes able to respond successfully to more rapid stimulation. and then. at levels of coupling resistance that allow conduction between the two cells. the coupled pair of cells exhibits arrhythmic interactions not predicted by the intrinsic properties of either cell. The experimental results show that the isolated rabbit ventricular cell is extremely sensitive to even a very small electrical load. with shortening of the action potential by 50% with electrical coupling to a model cell (of similar input resistance and capacitance to the ventricular cell) as high as 1.000 M omega. even though the action potential amplitude and current threshold are very insensitive to the electrical load.
Nonuniform regional deformation of the pericardium during the cardiac cycle in dogs, We hypothesized that local contact forces between the pericardium and the heart cause regional variation in pericardial deformation during the cardiac cycle. reflecting volume changes of the underlying cardiac chambers. To test this. we measured regional pericardial area over the right atrium (RA) and right ventricle (RV) with orthogonal pairs of sonomicrometers in six open-chest dogs. At a left ventricular end-diastolic pressure of 5 mm Hg. RV pericardial area paralleled RV volume. that is. shrinkage during ejection by 10 +/- 8% and expansion during filling. RA pericardial area was reciprocally related to RV pericardial area. with average expansion during ventricular ejection of 2 +/- 2%. thus paralleling RA volume during RV ejection. With volume loading. RV pericardial shrinkage during ejection increased to 14 +/- 6%. but the RA pericardial area change was no longer reciprocal (0 +/- 3% change during RV ejection). Elimination of contact forces by cardiac tamponade resulted in both marked attenuation of RV pericardial area changes and synchronization of the RV and RA pericardial area pattern; that is. both shrank during RV ejection. In two additional dogs. measurement of pericardial area over left ventricle and atrium showed similar results. We conclude that dynamic pericardial contact forces cause regional variation in pericardial deformation. which reflects volume changes of the underlying chambers. These findings imply that the influence of the pericardium on filling and ejection may be more complex than previously recognized. varying both by chamber and dynamically over the course of the cardiac cycle.
Role of calcium and the calcium channel in the initiation and maintenance of ventricular fibrillation, The cellular events during the initiation and maintenance of ventricular fibrillation (VF) are poorly understood. We developed a nonischemic. isolated. perfused rabbit Langendorff preparation in which sustained VF could be induced by alternating current (AC) and which allowed changes in perfusate composition. We also used Na(+)-K+ pump inhibition (10 microM ouabain or K(+)-free perfusate) to induce VF. AC stimulation or Na(+)-K+ pump inhibition always initiated VF. Calcium channel blockade by verapamil or nitrendipine uniformly inhibited the initiation of VF in both models. During Na(+)-K+ pump inhibition. 1) VF was prevented by calcium channel blockade. despite evidence of Ca2+ overload. and 2) abolition of spontaneous sarcoplasmic reticulum-generated cytosolic Ca2+ oscillations by ryanodine or Na+ channel blockade with tetrodotoxin did not prevent VF initiation. Lowering extracellular [Ca2+] to 80 microM uniformly prevented the initiation of VF due to Na(+)-K+ pump inhibition but not that due to AC stimulation. VF maintenance also was studied using 1) reduction in perfusate [Ca2+]. 2) blockade of Ca2+ channels. or 3) electrical defibrillation. Decreasing the perfusate [Ca2+] to 80 microM resulted in defibrillation during VF whether induced by AC or Na(+)-K+ pump inhibition. Verapamil or nitrendipine also resulted in defibrillation regardless of the initiation method. Electrical defibrillation was successful only in AC-induced VF. The results demonstrate that VF can be initiated and maintained in a nonischemic rabbit Langendorff preparation. The data suggest that increases in slow channel Ca2+ flux. as opposed to increases in cytosolic Ca2+ per se. were necessary for the initiation and maintenance of VF. The data. however. do not exclude an important role for cytosolic Ca2+ in the modulation of VF.
Vagal modulation of the rate-dependent properties of the atrioventricular node, Vagal effects on atrioventricular (AV) nodal conduction are accentuated by increases in heart rate. To establish the mechanism of these rate-dependent negative dromotropic actions. we studied the properties governing AV nodal adaptation to changes in heart rate in chloralose-anesthetized dogs in the absence and presence of bilateral cervical vagal nerve stimulation (20 Hz. 0.2 msec). Stimulation protocols were applied to evaluate the contributions of changes in AV nodal recovery. facilitation. and fatigue independently of each other. Vagal stimulation slowed AV nodal recovery in a voltage-dependent way. increasing the time constant of recovery (tau r) from 80 +/- 7 to 194 +/- 16 msec (mean +/- SEM. p less than 0.01) at the highest voltage studied. The facilitating effect of a premature (A2) beat was manifested by a leftward shift of the recovery curve (A3H3 versus H2A3) of a subsequent A3 beat. The magnitude of shift depended on the A1A2 coupling interval and was reduced by vagal stimulation at all A1A2 intervals (maximum shift: control. 63 +/- 12 msec; vagus. 24 +/- 11 msec; p less than 0.01). When recovery and facilitation were kept constant. abrupt increases in AV nodal activation rate caused a slow (tau = 75 beats) increase in AH interval (fatigue). Vagal stimulation increased the magnitude of this process (maximum: control. 11 +/- 2 msec; vagus. 27 +/- 3 msec; p less than 0.001). without altering its time course. At activation rates comparable to sinus rhythm in humans. vagal stimulation at an intermediate voltage increased the AH interval by 25 msec. As heart rate increased. vagally induced changes in dynamic processes amplified AH prolongation up to fivefold at maximum rate. The role of vagal changes in individual functional properties depended on heart rate. but slowing of recovery was the single most important factor. constituting over 50% of overall vagal action at rapid rates. We conclude that vagal stimulation alters the ways in which the AV node responds to changes in activation rate and that at rapid rates most of the negative dromotropic action of the vagus is due to changes in the AV nodal response to tachycardia. Alterations in rate-dependent AV nodal properties are a novel and potentially important mechanism through which interventions may affect AV nodal conduction.
Biphasic effects of doxorubicin on the calcium release channel from sarcoplasmic reticulum of cardiac muscle, To define the mechanism of doxorubicin cardiotoxicity. the effects of doxorubicin and caffeine were examined on calcium release channels from cardiac sarcoplasmic reticulum. We found that calcium release from cardiac sarcoplasmic reticulum vesicles was induced by both compounds. When sarcoplasmic reticulum vesicles were incorporated into planar lipid bilayers. calcium-permeable channels were observed. Addition of caffeine (2.5-10 mM) increased channel open probability from less than 0.1% to 40%. and this effect persisted for a mean of 44 minutes. In contrast. doxorubicin (2.5-10 microM) had a biphasic effect; initially. doxorubicin activated the channel. whereas after a mean of 8 minutes. the channel became irreversibly inhibited. Although the degree of channel activation by doxorubicin was concentration dependent. the time needed to inactivate the channel was concentration independent. Pretreatment with dithiothreitol (0.2 mM) prevented doxorubicin-induced channel inactivation. and channel activity persisted for an average of 58 minutes. Dithiothreitol alone did not alter channel open probability. Our results support the hypotheses that 1) the integrity of sulfhydryl groups is important for some aspects of calcium release channel function and 2) activation and inactivation of the channel are separable processes. The biphasic effect of doxorubicin on channel function may also correspond to the clinically observed adverse effects of doxorubicin. a widely used chemotherapeutic agent that. after prolonged usage. causes a dilated cardiomyopathy.
Enhanced alpha 1-adrenergic responsiveness in cardiomyopathic hamster cardiac myocytes. Relation to the expression of pertussis toxin-sensitive G protein and alpha 1-adrenergic receptors, The pathogenesis of the myopathy occurring in the heart of the cardiomyopathic strain of the Syrian hamster is not well understood but is believed to be associated with abnormal calcium handling by myopathic cells. The purpose of this study was to determine whether the cardiomyopathy occurring in strain BIO 14.6 animals is associated with an enhanced alpha 1-adrenergic receptor-mediated rise in cytosolic calcium. whether a pertussis toxin-sensitive G protein is involved in coupling the alpha 1-adrenergic receptor to changes in intracellular calcium and whether enhanced alpha 1 responsiveness is associated with an increase in the level of expression of the alpha 1-adrenergic receptor or in the pertussis toxin-sensitive G protein or proteins. To test the hypothesis that the cardiomyopathic state is associated with a greater alpha 1-receptor-mediated rise in cytosolic calcium. we studied the effect of phenylephrine (in the presence of propranolol) on time-averaged cytosolic calcium concentration ([Ca2+]i) in isolated cardiac myocytes from cardiomyopathic and age-matched control hamsters. Phenylephrine caused a greater increase both in time-averaged [Ca2+]i (an increase of 48 +/- 8% versus 12 +/- 3%. p less than 0.01) and in contractility (+181 +/- 22% versus +35 +/- 9%. p less than 0.01) in cardiomyopathic than in normal cardiac myocytes. Exposure to pertussis toxin (200 ng/ml for 3 hours) attenuated the alpha 1-adrenergic receptor-mediated increase in contractility and time-averaged [Ca2+]i in both cardiomyopathic and normal cells. The level of pertussis toxin-sensitive G protein. as determined by pertussis toxin-mediated [32P]ADP-ribosylation. was 1.6-fold higher in cardiomyopathic versus normal hamster hearts. The density of alpha 1-adrenergic receptors. as measured by the antagonist radioligand [3H]prazosin and the affinity of the receptor for agonist and antagonist were similar in myopathic and normal heart membranes. Thus. in cardiac myocytes from hamsters. the alpha 1-adrenergic receptor-mediated effects on [Ca2+]i and contractility appear to be mediated by a pertussis toxin-sensitive G protein or proteins. In myocytes from cardiomyopathic hamsters. these alpha 1-adrenergic effects were increased in magnitude. as was the level of pertussis toxin-sensitive G protein. but there was no measurable alteration in the density or ligand binding properties of alpha 1-adrenergic receptors.
Evidence for decreased coronary flow reserve in viable postischemic myocardium, To try to unravel the complexity and heterogeneity of the "no-reflow" phenomenon and its underlying mechanisms. we studied tissue perfusion in reperfused heart muscle by using tracer microspheres in an anesthetized dog model of 90-minute coronary occlusion followed by reperfusion for 2 1/2 hours. 24 hours. or 1 week. Regional myocardial blood flow was determined both in basal flow conditions and during reactive hyperemia. The effect of intracoronary adenosine administration was examined. and the ultrastructure of postischemic myocardium was analyzed. In viable reperfused tissue (as delineated by triphenyltetrazolium chloride staining). reflow in basal conditions is unimpaired. Coronary flow reserve (as approximated by peak reactive hyperemic flow) is intact at the start of reperfusion. decreases by more than half after 2 1/2 hours. and recovers completely within 1 week. This impairment of coronary reserve can be relieved by intracoronary adenosine administration. On ultrastructural examination. the capillaries are patent. On the other hand. in irreversibly damaged myocardium. both the basal reflow impairment and the decrease in coronary flow reserve are severe and permanent. Coronary flow reserve is already decreased at the start of reperfusion. and the pharmacological intervention has no beneficial effect. Ultrastructurally. extracellular and intracellular edema invariably are present. whereas the vascular endothelium is damaged and the capillaries are packed with red blood cells. We conclude that the no-reflow phenomenon (i.e.. mechanical obstruction to blood flow) is limited to infarcted tissue. In viable myocardium. however. coronary flow reserve is transiently diminished. probably because of washout and subsequent insufficient availability of the chemical mediator adenosine after breakdown and slow recovery of the precursor ATP pool.
Time course of cellular enzyme release in dog heart injury, The transport time of enzyme from heart to plasma was studied in two experimental models. First. the enzyme alanine aminotransferase was slowly infused into the left ventricular wall in open-chest dogs. The half-life for the washout of alanine aminotransferase activity into plasma was 20 +/- 4 minutes (mean +/- SEM. n = 8) and was not different in ischemic and normally perfused tissue. From measurements of arteriovenous differences in alanine aminotransferase activity and left ventricular blood flow. it was concluded that 77 +/- 14% of total enzyme washout from ischemic tissue occurred by direct entry into the bloodstream. The corresponding value for the vascular permeability-surface area product was 264 +/- 55 ml.kg-1.hr-1. For a second model. we studied myocardial enzyme release into plasma after abrupt heart injury induced by 10 minutes of calcium-free coronary perfusion followed by reintroduction of calcium (calcium-paradox mechanism). The half-life for the release into plasma was 1.9 +/- 0.2 hours (mean +/- SEM. n = 6) and was again not influenced by sustained ischemia. Slower washout. as observed for this second model. is consistent with increased interstitial protein space and corresponds to a permeability--surface area product between 135 and 285 ml.kg-1.hr-1. These results were used to calculate the time course of cellular enzyme leakage from the rate of enzyme release into plasma in various forms of heart injury. Significant shifts between the time curves of evolving cellular injury and enzyme release into plasma are observed after 2 hours of ischemia followed by coronary reperfusion. but not after permanent ischemia.
Recent progress in understanding apolipoprotein B, For the past 5 years. investigators from many different laboratories have contributed to a greatly increased understanding of two very important lipid-carrying proteins in plasma--apo B-100 and apo B-48. Apo B-100. an extremely large protein composed of 4.536 amino acids. is synthesized by the liver and is crucial for the assembly of triglyceride-rich VLDL particles. Apo B-100 is virtually the only protein of LDL. a cholesteryl ester-enriched class of lipoproteins that are metabolic products of VLDL. The apo B-100 of LDL serves as a ligand for the LDL receptor-mediated uptake of LDL particles by the liver and extrahepatic tissues. The LDL receptor-binding region of apo B-100 is located in the carboxyterminal portion of the molecule. whereas its lipid-binding regions appear to be broadly dispersed throughout its length. Apo B-48 contains the amino-terminal 2.152 amino acids of apo B-100 and is produced by the intestine as a result of editing of a single nucleotide of the apo B mRNA. which changes the codon specifying apo B-100 amino acid 2.153 to a premature stop codon. Apo B-48 has an obligatory structural role in the formation of chylomicrons; therefore. its synthesis is essential for absorption of dietary fats and fat-soluble vitamins. Both apo B-48 and apo B-100 are encoded on chromosome 2 by a single gene that contains 29 exons and 28 introns. An elevated level of apo B-100 in the plasma is a potent risk factor for developing premature atherosclerotic disease. In the past 3 years. many different apo B gene mutations that affect the concentrations of both apo B and cholesterol in the plasma have been characterized. A missense mutation in the codon for apo B-100 amino aid 3.500 is associated with hypercholesterolemia. This mutation results in poor binding of apo B-100 to the LDL receptor. thereby causing the cholesteryl ester-enriched LDL particles to accumulate in the plasma. This disorder is called familial defective apo B-100. and it is probably a cause of premature atherosclerotic disease. Familial hypobetalipoproteinemia is a condition associated with abnormally low levels of apo B and cholesterol; affected individuals may actually have a reduced risk of atherosclerotic disease.(ABSTRACT TRUNCATED AT 400 WORDS).
Effects of adenosine on human coronary arterial circulation, Adenosine is a potent vasodilator used extensively to study the coronary circulation of animals. Its use in humans. however. has been hampered by lack of knowledge about its effects on the human coronary circulation and by concern about its safety. We investigated in humans the effects of adenosine. administered by intracoronary bolus (2-16 micrograms). intracoronary infusion (10-240 micrograms/min). or intravenous infusion (35-140 micrograms/kg/min) on coronary and systemic hemodynamics and the electrocardiogram. Coronary blood flow velocity (CBFV) was measured with a 3F coronary Doppler catheter. The maximal CBFV was determined with intracoronary papaverine (4.5 +/- 0.2.resting CBFV). In normal left coronary arteries (n = 20). 16-micrograms boluses of adenosine caused coronary hyperemia similar to that caused by papaverine (4.6 +/- 0.7.resting CBFV). In the right coronary artery (n = 5). 12-micrograms boluses caused maximal hyperemia (4.4 +/- 1.0.resting CBFV). Intracoronary boluses caused a small. brief decrease in arterial pressure (similar to that caused by papaverine) and no changes in heart rate or in the electrocardiogram. The duration of hyperemia was much shorter after adenosine than after papaverine administration. Intracoronary infusions of 80 micrograms/min or more into the left coronary artery (n = 6) also caused maximal hyperemia (4.4 +/- 0.1.resting CBFV). and doses up to 240 micrograms/min caused a minimal decrease in arterial pressure (-6 +/- 2 mm Hg) and no significant change in heart rate or in electrocardiographic variables. Intravenous infusions in normal patients (n = 25) at 140 micrograms/kg/min caused coronary vasodilation similar to that caused by papaverine in 84% of patients (4.4 +/- 0.9.resting CBFV). At submaximal infusion rates. however. CBFV often fluctuated widely. During the 140-micrograms/kg/min infusion. arterial pressure decreased 6 +/- 7 mm Hg. and heart rate increased 24 +/- 14 beats/min. One patient developed 1 cycle of 2:1 atrioventricular block. but otherwise. the electrocardiogram did not change. In eight patients with microvascular vasodilator dysfunction (delta CBFV. less than 3.5 peak/resting velocity after a maximally vasodilating dose of intracoronary papaverine). the dose-response characteristics to intracoronary boluses and intravenous infusions of adenosine were similar to those found in normal patients.(ABSTRACT TRUNCATED AT 400 WORDS).
Sex differences in control of cutaneous blood flow, Women are far more likely than men to suffer from Raynaud's disease. The purpose of this study was to determine whether there are gender differences in local or central control of cutaneous blood flow that could account for the increased incidence of Raynaud's disease in women. To assess cutaneous blood flow. hand blood flow (HBF). finger blood flow (FBF). or skin perfusion (SP) was measured by fluid plethysmography. mercury strain-gauge plethysmography. or laser Doppler spectroscopy. respectively. in 47 volunteers. Basal HBF in men exceeded that of women (12.1 +/- 2.0 versus 6.2 +/- 1.5 ml/100 ml/min). Likewise. FBF in men surpassed that of women (19.5 +/- 4.1 versus 7.7 +/- 1.8 ml/100 ml/min). Similarly. SP in men was greater than that of women (270 +/- 42 versus 81 +/- 16 perfusion units). However. after total body warming (to induce a thermal sympatholysis). HBF in women exceeded that of men. suggesting that the lower basal HBF in women was due to increased sympathetic outflow to the extremities. Mental stress and deep inspiration reduced HBF and SP in men. Paradoxically. both of these maneuvers increased HBF and SP in women. To determine whether these paradoxical responses in women were due to the women's elevated basal sympathetic tone. these experiments were repeated after total body cooling in men to increase sympathetic tone and after total body warming in women to reduce sympathetic tone. Total body cooling reduced HBF and SP in men. Under these conditions. mental stress and deep inspiration induced vasodilation. In women. total body warming for 10 minutes increased HBF.
Mortality after 10 1/2 years for hypertensive participants in the Multiple Risk Factor Intervention Trial, The Multiple Risk Factor Intervention Trial (MRFIT) is a randomized primary prevention trial that tested the effect of a multifactor intervention program on coronary heart disease (CHD) mortality in 12.866 high-risk men aged 35-57 years. Men were randomly assigned to either a special intervention (SI) program. which consisted of dietary advice for lowering blood cholesterol levels. counseling aimed at cessation for cigarette smokers. and stepped-care treatment for hypertension for those with elevated blood pressure. or to their usual sources of health care within the community (UC). Among the 12.866 randomized men. 8.012 (62%) were hypertensive at baseline. For this subgroup. mortality rates with 10.5 years of follow-up were lower for the SI than for the UC group by 15% (p = 0.19) for CHD and 11% (p = 0.13) for all causes. These results reflected more favorable outcomes for SI compared with UC hypertensive men during the 3.8 posttrial years (March 1982 through December 1985) than during the preceding 6-8 years (through February 1982). During the posttrial years. death rates were lower for SI than for UC men by 26% (p = 0.09) for CHD and 23% (p = 0.02) for all causes. For those with diastolic blood pressure equal to or more than 100 mm Hg. this posttrial trend was a continuation of a trend during the trial; therefore. with 10.5 years of follow-up. death rates were markedly lower for SI than for UC by 36% (p = 0.07) for CHD and 50% (p = 0.0001) for all causes. Similarly. for those without baseline resting electrocardiographic abnormalities. the favorable posttrial outcome for the SI group was a continuation of a trend during the trial. In contrast. for those with baseline diastolic blood pressure of 90-99 mm Hg and for those with baseline resting electrocardiographic abnormalities. the favorable posttrial mortality findings for the SI group were a reversal of unfavorable trends recorded during the trial. Two factors appear to have contributed to this more favorable mortality trend for the SI group: 1) a change in the diuretic treatment protocol for SI men about 5 years after randomization. which involved replacement of hydrochlorothiazide with chlorthalidone at a daily maximum dose of 50 mg; and 2) a favorable effect of intervention on nonfatal cardiovascular events during the trial years. In addition. delay until the full impact of beneficial effects on mortality end points from smoking cessation and cholesterol lowering could have contributed.(ABSTRACT TRUNCATED AT 400 WORDS).
Ten-year follow-up of survival and myocardial infarction in the randomized Coronary Artery Surgery Study, The Coronary Artery Surgery Study (CASS) randomized 780 patients to an initial strategy of coronary surgery or medical therapy. Of medically randomized patients. 6% had surgery within 6 months and a total of 40% had surgery by 10 years. At 10 years. there was no difference in cumulative survival (medical. 79% vs. surgical. 82%; NS) and no difference in percentage free of death and nonfatal myocardial infarction (medical. 69% vs. surgical. 66%; NS). Patients with an ejection fraction of less than 0.50 exhibited a better survival with initial surgery treatment (medical. 61% vs. surgical. 79%; p = 0.01). Conversely. patients with an ejection fraction greater than or equal to 0.50 exhibited a higher proportion free of death and myocardial infarction with initial medical therapy (medical. 75% vs. surgical. 68%; p = 0.04) although long-term survival remained unaffected (medical. 84% vs. surgical. 83%; p = 0.75). There were no significant differences either in survival and freedom from nonfatal myocardial infarction. whether stratified on presence of heart failure. age. hypertension. or number of vessels diseased. Thus. 10-year follow-up results confirm earlier reports from CASS that patients with left ventricular dysfunction exhibit long-term benefit from an initial strategy of surgical treatment. Patients with mild stable angina and normal left ventricular function randomized to initial medical treatment (with an option for later surgery if symptoms progress) have survival equivalent to those patients randomized to initial surgery.
Ten-year follow-up of quality of life in patients randomized to receive medical therapy or coronary artery bypass graft surgery. The Coronary Artery Surgery Study (CASS), Quality of life indexes were assessed in 780 patients 10 years after randomization to medical therapy (n = 390) or coronary artery bypass graft surgery (n = 390) in the Coronary Artery Surgery Study. At 10 years. mortality was 21.8% in the medical group and 19.2% in the surgical group (p = NS). and 144 (37%) of the medical group had undergone surgery because of increasing chest pain. At study entry. 22% of medical and surgical patients were angina free; at 1 and 5 years after entry. the frequency of asymptomatic patients was 66% and 63% in the surgical group and 30% and 38% in the medical group. However. by 10 years after entry. the proportion of patients free of angina had fallen to 47% in the surgical group and to 42% in the medical group. Activity limitation and use of beta-blockers and long-acting nitrates were less in the surgical than the medical group at 1 and 5 years after entry but little different from the medical group at 10 years after entry. Throughout follow-up. recreational status. employment status. frequency of heart failure. use of other medications. and hospitalization frequency were similar between the two groups. Thus. indexes of quality of life such as angina relief. increased activity. and reduction in use of antianginal medications initially appear superior in patients with stable manifestations of ischemic heart disease assigned to surgery. but by 10 years after entry. these advantages are much less apparent. Although the observed similarities of the medically and surgically assigned groups at 10 years reflect return of symptoms in the surgical group to some extent. a more important explanation is the performance of late surgery in a large proportion of the medically assigned patients. rendering them asymptomatic.
Blood pressure level, trend, and variability in Dunedin children. An 8-year study of a single birth cohort, In a birth cohort of children in the Dunedin Multidisciplinary Health and Development Study in New Zealand. resting blood pressures were recorded biennially five times from age 7 to 15 years. Using previously described methods. we examined the level. trend. and variability of blood pressures in those children with at least three readings. The level. trend. and variability of height. weight. and body mass index were compared among six separate groups of children. Two groups were categorized on the basis of high systolic pressure levels. one with low variability and the other with high variability. which was thought to resemble adult labile hypertension. Two additional groups were categorized on the basis of increasing and decreasing blood pressure trends; the fifth group had consistently low blood pressures. and the sixth group consisted of the remaining children. There were significant differences among the groups for the level of all the physical measurements and for the trend of body mass index. No significant differences were found among the groups for gender or socioeconomic status. A parental history of high blood pressure. stroke. or heart attack was significantly more common in the first two groups.
Prognostic value of radionuclide angiography in medically treated patients with coronary artery disease. A comparison with clinical and catheterization variables, To evaluate the usefulness of multiple measures from rest and exercise radionuclide angiography (RNA) in predicting cardiovascular death and cardiovascular events (death or nonfatal myocardial infarction) and to assess the prognostic usefulness of the RNA relative to clinical and catheterization data. we studied 571 stable patients with symptomatic coronary artery disease who had upright rest/exercise first-pass RNA within 3 months of catheterization and were medically treated. With a median follow-up of 5.4 years. 90 patients have died from cardiovascular causes. and 147 patients have either died or suffered a nonfatal myocardial infarction. Using the Cox regression model and a preselected group of RNA variables. the most important RNA predictor of mortality was exercise ejection fraction (chi 2 = 81. p less than 0.00001). Neither rest ejection fraction nor the change in ejection fraction from rest to exercise contributed additional predictive information. Two other RNA study variables. the change in heart rate from rest to exercise and rest end-diastolic volume index. did contribute additional prognostic information to the exercise ejection fraction (chi 2 = 23. p less than 0.0001). Compared with noninvasive clinical data (history. physical examination. electrocardiogram. and chest radiograph). RNA variables were considerably more predictive of mortality (chi 2 = 71 [clinical variables] versus chi 2 = 104 [RNA]). Remarkably. the strength of the relation of RNA variables with mortality was equivalent to that of the set of catheterization variables previously demonstrated in our large angiographic population to be prognostically important (chi 2 = 104 [RNA] versus chi 2 = 102 [catheterization variables]). The RNA contained 84% of the information provided by clinical and catheterization descriptors combined. Furthermore. the RNA contributed significant additional prognostic information to the clinical and catheterization data (chi 2 = 13.6. p = 0.0035). For cardiovascular events. the relative prognostic usefulness of the RNA was similar. although relations with this outcome were generally weaker. Descriptors from the rest/exercise RNA exhibit a powerful relation with long-term outcomes and can be useful in defining risk. even when clinical and catheterization data are available.
Prognostic value of electrophysiology testing in asymptomatic patients with Wolff-Parkinson-White pattern [published erratum appears in Circulation 1991 Mar;83(3):1124], The prognostic value of electrophysiology testing was studied in 75 asymptomatic patients with the Wolff-Parkinson-White electrocardiographic pattern. All patients underwent electrophysiology testing at entry to the study and were followed up annually for a total of 348 patient-years (median. 4.3 years). There were 44 male and 31 female patients. and age at enrollment ranged from 7 to 77 years (mean. 34 +/- 14 years). The median effective refractory period of the accessory pathway was 293 msec (interquartile range. 280-310 msec). and the median shortest RR interval between preexcited beats during atrial fibrillation (SRR) [corrected] was 274 msec (240-320 msec). Twenty-three patients had an SRR of 250 msec or less and eight patients had a median shortest SRR interval of 200 msec or less. Twelve patients had inducible sustained reciprocating tachycardia. 10 patients had inducible nonsustained reciprocating tachycardia. and 23 patients had inducible sustained atrial fibrillation. Twenty patients (27%) lacked retrograde conduction over the accessory pathway. No patient died suddenly during a median follow-up of 4.3 years. Six patients (8%) became symptomatic with documented supraventricular tachycardia. of whom two underwent operative ablation of their accessory pathways. No patient with absent retrograde accessory pathway conduction during the electrophysiology study became symptomatic. Inducible sustained or nonsustained reciprocating tachycardia at electrophysiology study did not predict the development of subsequent symptomatic supraventricular tachycardia. Nine patients lost preexcitation during follow-up. Age at enrollment (relative risk/decade. 1.4; 95% confidence interval. 1.0-1.8) and anterograde accessory pathway refractory period (relative risk. 1.06/10 msec; 95% confidence interval. 1.0-1.12) were independent predictors of loss of preexcitation.
Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group, There is a varying hormonal activation in heart failure. To be able to evaluate this activation and relate it to prognosis. we took blood samples at baseline and after 6 weeks from 239 patients with severe heart failure (all in New York Heart Association class IV) randomized to additional treatment with enalapril or placebo. In this study (CONSENSUS). which has previously been reported. there was a significant reduction in mortality among patients treated with enalapril. The present data show in the placebo group a significant positive relation between mortality and levels of angiotensin II (p less than 0.05). aldosterone (p = 0.003). noradrenaline (p less than 0.001). adrenaline (p = 0.001). and atrial natriuretic factor (p = 0.003). A similar relation was not observed among the patients treated with enalapril. Significant reductions in mortality in the groups of patients treated with enalapril were consistently found among patients with baseline hormone levels above median values. There were significant reductions in hormone levels from baseline to 6 weeks in the group of patients treated with enalapril for all hormones except adrenaline. There were no correlations between these changes in hormone levels. Summarily. there is a pronounced but variable neurohormonal activation in heart failure even in patients with similar clinical findings. This activation is reduced by enalapril therapy. The results suggest that the effect of enalapril on mortality is related to hormonal activation in general and the renin-angiotensin system in particular.
Excretion of thromboxane A2 and prostacyclin metabolites before and after exercise testing in patients with and without signs of ischemic heart disease, We addressed the hypothesis that platelets are not activated in association with effort-induced myocardial ischemia in stable coronary disease. Seventy-two patients undergoing a diagnostic bicycle exercise test were stratified according to the development of chest pain (yes/no. 33/39) and of exercise-induced ST-segment depression of at least 200 microV in the electrocardiogram (yes/no. 12/60). Noninvasive indexes of platelet activation and of platelet/vessel wall interaction (urinary excretion of the 2.3-dinor-metabolites of thromboxane A2 [Tx-M] and prostacyclin [PGI-M]. respectively) were analyzed in samples collected in the basal state and after the test. Basal Tx-M and PGI-M did not differ in patients with (236 +/- 35 and 131 +/- 22 pg/mg creatinine. respectively) and without (185 +/- 16 and 101 +/- 13 pg/mg creatinine. respectively) chest pain. or in those with (178 +/- 45 and 162 +/- 41 pg/mg. respectively) and without (216 +/- 22 and 104 +/- 11 pg/mg. respectively) ST-segment depression during the test. Patients without chest pain or without ST-segment depression moderately increased (p less than 0.05) their urinary Tx-M (by 21% and 13%. respectively) and PGI-M (by 28% and 23%. respectively) after exercise. No significant increases were observed in those developing chest pain or ST depression during exercise. These data indicate that effort-induced myocardial ischemia is not associated with an increase in platelet activation or platelet/vessel wall interaction in patients with stable coronary disease.
Effect of long-term exercise on regional myocardial function and coronary collateral development after gradual coronary artery occlusion in pigs, The effect of myocardial ischemia. induced by long-term exercise. on regional myocardial function and coronary collateral development was examined in pigs after gradual occlusion of the left circumflex coronary artery (LCx) with an ameroid occluder. Thirty days after surgery. regional myocardial function and blood flow were assessed during exercise in 22 pigs separated into exercise (n = 12) and sedentary groups (n = 10). The exercise group trained on a treadmill for 25 +/- 1 days. 30-50 min/day. at heart rates of 210-220 beats/min. After 5 weeks. another exercise test was performed. In the exercise group. after training. we observed an improvement in systolic wall thickening. expressed as a percentage of rest. in the collateral-dependent LCx region from 64 +/- 8% to 87 +/- 6% (p less than 0.01) at moderate exercise levels (220 beats/min) and from 45 +/- 7% to 73 +/- 7% (p less than 0.01) at severe exercise levels (265 beats/min). Transmural myocardial blood flow in the LCx region expressed as a ratio of flow in the nonoccluded region of the left ventricle also increased significantly (p less than 0.01) during severe exercise after 5 weeks. The sedentary group showed an improvement in systolic wall thickening in the LCx region during moderate exercise compared with the initial exercise test (p less than 0.05) but no significant change in systolic wall thickening or myocardial blood flow ratios during severe exercise after 5 weeks. We conclude that long-term exercise after gradual LCx coronary artery occlusion in pigs improves myocardial function and coronary collateral reserve in collateral-dependent myocardium during exercise.
Effect of tachycardia on regional function and transmural myocardial perfusion during graded coronary pressure reduction in conscious dogs, The purpose of the present study was to examine subendocardial flow and function during graded coronary pressure reduction to determine the effect of tachycardia on the lower autoregulatory pressure limit (critical coronary pressure) in unanesthetized dogs. During atrial pacing at a rate of 200 beats/min. subendocardial flow measured by radioactive microspheres averaged 1.55 +/- 0.34 ml/min/g and remained unchanged as pressure was reduced over the autoregulatory plateau from 84 +/- 10 to 59 +/- 7 mm Hg. Further reductions in coronary pressure to below a critical coronary pressure of approximately 60 mm Hg were associated with concomitant reductions in subendocardial flow and the endocardial-epicardial flow ratio during tachycardia. Although regional function remained constant over the autoregulatory plateau. there was a rightward shift of the coronary pressure-function relation during ischemia in response to a steady-state increase in rate from 100 to 200 beats/min. Reductions in regional wall thickening began when coronary pressures reached 38 +/- 7 mm Hg at a heart rate of 100 beats/min and 61 +/- 6 mm Hg at a heart rate of 200 beats/min (p less than 0.005). Similar critical coronary pressure values were obtained for subendocardial segment shortening. Relations between subendocardial flow and myocardial function measured by both transmural wall thickening and subendocardial segment shortening were linear during pacing at a heart rate of 200 beats/min with relative reductions in wall thickening related to reductions in subendocardial flow on a nearly one-to-one basis. The results of this study demonstrate that there is a shift in the lower limit of subendocardial autoregulation during tachycardia as manifest by the onset of subendocardial ischemia at a higher distal coronary artery pressure. The shift in critical coronary pressure relates to an increase in resting flow requirements due to increased demand and diminished subendocardial vasodilator reserve at any given coronary pressure secondary to a reduction in the time available for diastolic subendocardial perfusion during tachycardia.
Optimizing the exercise test for pharmacological investigations, Exercise trials in cardiology are often hindered by inconsistent approaches to exercise testing. These inconsistencies include the choice of exercise protocol. exercise end points. points of analysis. and absence or misuse of gas exchange data. Gas exchange techniques greatly enhance the accuracy with which cardiopulmonary function is assessed by exercise. Commonly used protocols are not always appropriate for all patients or all studies. Both cardiovascular disease and the exercise protocol can have an important impact on the relation between changes in work rate and oxygen uptake. Ramp protocols appear to offer the greatest promise for assessing cardiopulmonary function. Analyzing hemodynamic and gas exchange responses at several points submaximally. in addition to those at peak exercise. can add important information concerning the efficacy of a drug. A great deal of confusion continues to hinder the application of the gas exchange anaerobic threshold. and many of the commonly used testing end points are not reliable.
Clinical and Doppler echocardiographic evaluation of bioprosthetic valve failure after 10 years, Four hundred thirteen consecutive patients underwent valve replacement with a bioprosthesis between 1976 and 1982. Aortic valve replacement was performed in 240 patients. mitral valve replacement in 132 patients. and multiple valve replacement in 41. The Carpentier-Edwards porcine (n = 336). Angell-Shiley porcine (n = 23). Hancock porcine (n = 11). and the Ionescu-Shiley pericardial valves (n = 43) were inserted. Follow-up between 5 and 12 years postoperatively was 98% complete. Freedom from structural valve deterioration was 72 +/- 7%. 59 +/- 9%. and 59 +/- 9%. respectively. after aortic. mitral. and double valve replacement. The risk of structural valve deterioration and reoperation for valve-related complications was significantly increased with the Ionescu-Shiley pericardial prosthesis. The risk for reoperation was inversely related to patient age. Postoperative Doppler echocardiographic studies in 87% of available patients revealed a subgroup of asymptomatic patients with evidence of structural valve deterioration. These patients (n = 61) had significantly reduced prosthetic valve areas (aortic less than 1 cm2. mitral less than 1.7 cm2). elevated resting transvalvular gradients (aortic greater than 40 mm Hg). or moderate-to-severe regurgitation. In summary. postoperative Doppler echocardiographic examination identified asymptomatic patients with structural valve dysfunction. These patients must be followed up carefully to determine the optimal timing of reoperation.
William Glenn lecture. The cavopulmonary shunt. Evolution of a concept, A bold and imaginative development. the cavopulmonary anastomosis. appeared to originate in several centers almost simultaneously. After extensive research on right heart bypass. Glenn was the first in North America to perform a successful experimental cavopulmonary shunt. and it became known by his name. In properly selected patients. palliation success was excellent. and mortality rates were low. From 1961 through 1988. we used a cavopulmonary anastomosis for palliation in 139 infants and children. There were eight hospital deaths. and most occurred early in the series. Palliation generally lasted 6-8 years-until the child outgrew the blood supply to the contralateral lung. Palliation could be restored by increased flow to that lung with another shunt. Six otherwise inoperable patients received benefit from the addition of an axillary arteriovenous fistula. Late pulmonary arteriovenous fistulas were identified in 11% of our patients by angiography. but with more sensitive testing. the incidence rate may be as high as 21%. The occurrence of pulmonary arteriovenous fistulas caused general concern and less frequent use of the shunt. Recent application of an end-to-side anastomosis. creating a bidirectional shunt. has restored interest. A major legacy of the cavopulmonary anastomosis was demonstration of the feasibility of partial right heart bypass. which paved the way for the Fontan operation. and it is frequently constructed as part of that operation. Currently. the Glenn shunt is most often used as a temporary or permanent alternative to a Fontan repair if there appears to be significant risk. The risk factors usually encountered include small pulmonary arteries. young age. poor ventricular function. atrioventricular valve incompetence. and myocardial hypertrophy-sometimes alone but often in combination.
Longitudinal results after first-stage palliation for hypoplastic left heart syndrome, To evaluate the results of palliative surgery for hypoplastic left heart syndrome. we reviewed the records of 57 infants who underwent first-stage reconstruction at our institution between July 1983 and April 1989. Of the 57 infants. 12 (21%) are long-term survivors and 45 (79%) have died. Thirty-one infants died within the first 30 days after surgery. Twenty-six of the 31 early deaths occurred within the first 24 hours after surgery. Causes of early mortality were low cardiac output (23). sepsis (two). sudden death (two). pulmonary vein atresia (three). and cardiac transplant (one). Late death occurred in 14 infants due to sepsis (three). sudden death (four). and death at reoperation (seven - three after Fontan procedure. three after shunt replacement. and one after transplant). Of the 31 patients who survived more than 24 hours. the complications noted by echocardiography and confirmed by catheterization when reoperation was indicated were significant arch obstruction (13%). branch pulmonary artery stenosis (23%). small atrial septal defect (16%). inadequate shunt (26%). neoaortic regurgitation (13%). tricuspid regurgitation (13%). ventricular dysfunction (29%). thrombus (6%). and superior vena cava obstruction (3%). Of the 31 patients who survived more than 24 hours. 16 additional palliative surgical procedures were performed in eight patients. These procedures included arch reconstruction (four). additional shunt (four). Glenn shunt (three). atrial septectomy (two). coarctation balloon angioplasty (two). and pulmonary artery reconstruction and reshunting (one). Of the 12 long-term survivors. four have had a successful Fontan procedure. one has had a transplant. and seven are awaiting a second-stage procedure. Thus. 69% of all deaths occurred within the first 30 days of surgery. and 58% of all deaths occurred within the first 24 hours due to cardiovascular collapse.
Right ventricular growth after transventricular pulmonary valvotomy and central aortopulmonary shunt for pulmonary atresia and intact ventricular septum, We performed transventricular pulmonary valvotomy as initial surgery in 22 consecutive patients with pulmonary atresia and intact ventricular septum who had a patent infundibulum. Nineteen patients also had placement of a central aortopulmonary shunt. All patients survived surgery. and 16 patients have had preoperative and later postoperative catheterizations. The purpose of this study was to determine the response of the right ventricle to transventricular pulmonary valvotomy with regard to relief of right ventricular hypertension and growth of the entire right ventricle. including tricuspid valve. right ventricular volume. and right ventricular outflow tract. Right ventricular systolic pressure decreased from 111.3 +/- 31.7 mm Hg before initial surgery to 65.6 +/- 26.2 mm Hg. Right ventricular end-diastolic volume increased from 59.1 +/- 39.3% of predicted normal before initial surgery to 114.6 +/- 63.2% at late follow-up catheterization. Tricuspid valve anulus circumference also increased in size from 73.2 +/- 21.3% of predicted normal before initial surgery to 90.4 +/- 22.8% at late follow-up catheterization. Only one patient (6%) required a transanular right ventricular outflow tract patch at the time of biventricular repair. Twenty of 22 patients (91%) either have had or are awaiting biventricular repair. We conclude that transventricular pulmonary valvotomy and central aortopulmonary shunt can be performed safely in newborn infants with pulmonary atresia and intact ventricular septum who have a patent infundibulum. Effective valvotomy relieves right ventricular hypertension. allows for excellent right ventricular and tricuspid valve growth. and optimizes potential for biventricular repair.
Fontan operation in 176 patients with tricuspid atresia. Results and a proposed new index for patient selection, Between 1973 and March 1989. 176 patients with tricuspid atresia had the Fontan procedure performed at the Mayo Clinic. Age range at the time of surgery was 7 months to 42 years. with 43 patients (24%) 16 years old or older. Hospital mortality rates were 17% (nine of 54) from 1973 through 1980 and 8% (10 of 122) from 1981 through 1989. There have been 10 late cardiovascular deaths. Postoperative follow-up of 139 survivors (range. 6 months to 14 years; mean. 5.5 years) revealed 91% to be in excellent or good condition and 9% to be in fair or poor condition. Patients in fair or poor condition had poor stamina and/or fluid retention with intermittent pleural effusion. ascites. and so on. Two factors that clearly influence operative and late results are preoperative pulmonary arteriolar resistance (Rpa) and left ventricular diastolic function. A preoperative catheterization index devised by adding Rpa to left ventricular end-diastolic pressure divided by QpI plus QsI may be helpful in selecting candidates most likely to survive and benefit from the Fontan operation. In our experience. if this index is less than 4.0. then the postoperative right atrial mean pressure will be 20 mm Hg or less. a circumstance associated with 95% early and 89% overall survival rates.
Atrial cardiomyoplasty after Fontan-type procedures, The purpose of right atrial cardiomyoplasty is to increase atrial-pulmonary flow in patients undergoing Fontan-type procedures. We developed two surgical techniques to bypass the right ventricle. followed by right atrial cardiomyoplasty with a stimulated latissimus dorsi muscle flap (LDMF). In 10 goats. the left LDMF was transferred into the chest by removal of the second rib. After sternotomy. the right atrial appendages of five goats (group 1) were connected to the distal main pulmonary artery with polytetrafluoroethylene tubing and the proximal pulmonary trunks were ligated. In the other five goats (group 2). under cardiopulmonary bypass. bioprosthetic valves were implanted into the inferior venae cavae. The tricuspid orifice was closed. and the atriopulmonary connection was performed. The left LDMF was sutured over the right atrium and stimulated using synchronous 30-Hz bursts of impulses delivered by a Medtronic Cardiomyostimulator. Hemodynamic studies were performed in the acute phase. Right atrial. pulmonary arterial. and aortic pressures were assessed. Cardiac output was measured using ultrasonic flow studies. LDMF stimulation restored pulsatile pressure patterns in the pulmonary artery and increased the cardiac output. These observations were more evident in the model with caval valvular implant. This functional "ventricularization" of the right atrium could improve long-term results after Fontan-type procedures and extend operative indications. Chronic experimental studies are necessary to evaluate the diastolic and systolic functions of the neo-right ventricle.
Partial anomalous pulmonary venous return, Anomalous pulmonary venous return from the left lung is an extremely rare condition that is reported sporadically and in general in case reports. From 1964 through 1988. we identified 13 patients with this condition. all of whom underwent surgical correction. This represents the single largest reported institutional experience with this anomaly. The patients ranged in age from 15 months to 40 years. Seven were asymptomatic. and six had symptoms ranging from recurrent pulmonary infection to moderate congestive heart failure. Six had anomalous venous return from the entire left lung. and seven had anomalous return from the upper lobe only. Eight of the patients had associated cardiovascular anomalies. Four of the patients underwent surgical correction via a sternotomy approach with cardiopulmonary bypass to allow correction of coexisting intracardiac anomalies. The remaining patients underwent surgical repair through a left thoracotomy. The technique included high ligation and division of a persistent left superior vena cava with anastomosis to the left atrium at the site of partial excision of the atrial appendage. There were no deaths and only one complication in our series.
Hypoplastic left heart syndrome. Outcome after initial reconstruction and before modified Fontan procedure, The outcome and clinical course before modified Fontan procedure were reviewed for 200 patients with hypoplastic left heart syndrome who underwent initial reconstructive surgery between August 1985 and March 1989. The median age at the time of initial reconstruction was 6 days (range. 1 day to 7.2 months). In 28 patients. a right modified Blalock-Taussig shunt was used; in 172 patients. a central shunt was placed. Additional procedures (n = 41) performed in 38 patients (median age. 5 months; range. 6 days to 17.5 months) were revision of systemic-to-pulmonary shunt (n = 15). arch reconstruction (n = 8). balloon angioplasty of arch obstruction (n = 7). atrial septectomy (n = 4). pulmonary artery angioplasty (n = 2). tricuspid valve annuloplasty or replacement (n = 4). and modified Glenn shunt (n = 1). There was no significant difference in the frequency of additional procedures performed more than 30 postoperative days in the survivors compared with the nonsurvivors. Actuarial survival rates were 0.66 (1 month). 0.48 (12 months). and 0.44 (18 months). Seventy percent of all deaths occurred during the initial admission. with 32% resulting from acute cardiovascular collapse during the first postoperative day. There was no statistical difference in actuarial survival when assessed by the type of shunt used or by anatomical subtype or when the influence of additional interventions was considered. Substantial improvement in outcome may be possible if immediate perioperative mortality can be reduced. We speculate that some of the intermediate mortality (30 days to 1 year) may be related to the effects of chronic exposure of the right ventricle to volume overload at systemic pressure.
Clinical evaluation of single versus multiple mammary artery bypass, The superior patency and clinical advantages of internal mammary artery (IMA) grafting are well established. However. the relative benefits of routine multiple IMA grafting remain uncertain. To determine whether routine multiple compared with single IMA utilization improved survival of patients undergoing coronary bypass procedures. 1.063 patients were prospectively allocated. beginning in 1984. to divergent management strategies of single (group 1. n = 420) versus multiple IMA grafting (group 2. n = 643). Subsequent analysis of anatomical extent of disease and preoperative baseline risk factors showed no differences (p = NS) between the two groups. All variables reflecting operative technique were similar (p = NS) for the two groups. except 74% of group 1 patients with multivessel disease received a single IMA graft. whereas 71% of group 2 patients with multivessel disease received multiple IMAs (p less than 0.05). By multivariate analysis. impairment of left ventricular ejection fraction. acute evolving myocardial infarction. advanced age. and unstable angina were incremental risk factors for mortality (all p less than 0.03). but group assignment (p = 0.4) and ultimate therapy were not (p = 0.6). Survival probabilities (expressed as 30-day group 1/group 2; 4-year group 1/group 2) were overall (0.97/0.98; 0.93/0.90). elective (0.98/0.99; 0.97/0.92). acute (0.95/0.97; 0.89/0.88). age of less than 65 years (0.98/0.99; 0.97/0.93). age of 65 years or older (0.93/0.97; 0.84/0.89). ejection fraction of 0.40 or more (0.97/0.99; 0.95/0.94). ejection fraction of less than 0.40 (0.95/0.96; 0.87/0.82). nondiabetic (0.98/0.98; 0.94/0.91). and diabetic (0.92/0.97; 0.88/0.87). No differences in survival were significant (p = NS).
Early and late results after isolated coronary artery bypass surgery in 159 patients aged 80 years and older, We have studied 159 patients 80 years of age or older who have had isolated coronary artery bypass grafting (CABG) since 1977. Eighty-seven percent have had surgery since 1984. Two thirds of the patients were male. and the mean age was 82 years. Most patients (97%) were in New York Heart Association (NYHA) functional class III or IV. 89% had unstable/postinfarction angina pectoris. and 67% had rest pain. Almost half (47%) required preoperative admission to the coronary care unit. 6% required preoperative use of an intra-aortic balloon pump. and 20% were operated on emergently. Significant left main coronary artery disease (greater than or equal to 50% stenosis) was present in 41%. Ten patients (6.3%) died within 30 days of surgery. with seven more patients dying during the same hospital admission or soon after transfer to another institution. This resulted in an overall hospital mortality of 10.7%. The median hospital stay was 10 days. On univariate analysis. the significant predictors of hospital mortality were NYHA IV. angina at rest. preoperative admission to the coronary care unit. emergency operation. ejection fraction less than 0.50. and the presence of mitral regurgitation. On multivariate analysis. ejection fraction less than 0.50 was the only significant risk factor (p less than 0.01). Of hospital survivors. 98% have been followed for a mean of 29 months. The estimated 5-year survival (+/- SEM) of all patients was 71 +/- 4.5%. and for hospital survivors. 80 +/- 4.5%. The most important predictor of adverse survival was an ejection fraction less than 0.50. Seventy-nine percent are angina-free. and 89% are in NYHA classes I and II. The majority of patients felt that they were improved by surgery. We conclude that CABG in patients 80 years or older. although associated with increased operative risk. gives excellent relief of symptoms and good 5-year survival. Patients should not be denied CABG because of age alone.
Internal mammary artery and saphenous vein graft patency. Effects of aspirin, As part of two Department of Veterans Affairs Cooperative Trials. we obtained angiographic patency data for internal mammary artery (IMA) and saphenous vein grafts to the left anterior descending (LAD) coronary artery at 1 year after coronary artery bypass surgery. Patients received either aspirin 325 mg q.d.. aspirin 325 mg t.i.d.. aspirin 325 mg and dipyridamole 75 mg t.i.d.. or placebo. Aspirin was initiated either 12 hours before or 6 hours after operation. Patients were stratified preoperatively for extent of disease and randomized to the therapies outlined above. There was no randomization to IMA versus saphenous vein grafts to the LAD. When the patients taking placebo were compared with those taking aspirin. there were no differences in the IMA (100.0% versus 92.1%. p = 0.385) or vein graft (88.8% versus 90.4%. p = 0.675) patency rates. The patency rate. irrespective of treatment. for all IMA grafts was 92.8% (220 of 237) versus 90.1% (345 of 383) for all vein grafts to the LAD (p = 0.309). Thus. both the IMA and vein grafts had excellent patency rates at 1 year. Aspirin did not alter this at 1 year. and there were no differences between IMA and vein graft patency to the LAD.
Surgical repair of postinfarction ventricular septal defect, Thirty-one patients underwent repair of postinfarction ventricular septal defect (VSD) from 1980 to 1989. All patients were in New York Heart Association functional class IV. and 15 of them were in cardiogenic shock when operated on. Coronary arteriography was performed in all patients before surgery: nine had one-vessel. 11 had two-vessel. and 11 had three-vessel disease. The VSD was anterior in 15 patients and posterior in 16. The operative technique evolved over the years from a fairly extensive infarctectomy and reconstruction of the septum and right and left ventricular walls with a double Dacron patch. to minimal or no infarctectomy and closure of the VSD by excluding the infarcted muscle from the left ventricular cavity. This is accomplished by suturing a single patch of bovine pericardium to healthy endocardium surrounding the infarcted muscle. The right ventricle is left intact. Overall mortality was 10%. with three operative deaths. All deaths occurred in patients in cardiogenic shock who had three-vessel coronary artery disease. Thus. the mortality for patients in shock was 20%. and the mortality for patients with three-vessel disease was 27%. The operative mortality for patients with posterior VSD was twice as high as in patients with anterior VSD. However. univariate analysis of various clinical. hemodynamic. and operative variables indicated that only three-vessel disease was predictive of operative mortality. Because the number of patients was small and the overall operative mortality relatively low. the results of this analysis may not be valid.
Relative risks of left ventricular aneurysmectomy in patients with akinetic scars versus true dyskinetic aneurysms, From 1971 to 1988. 303 patients underwent left ventricular aneurysm resection. We analyzed preoperative and procedure-related variables to ascertain risk factors for surgery. A distinction was made between akinetic and dyskinetic aneurysms to assess potential relation with postoperative outcome. Indications for surgery were arrhythmia in 20 patients. congestive heart failure in 81. angina in 133. congestive heart failure and angina in 42. and other combinations in the remaining 27 patients. The left ventricular aneurysm was dyskinetic in 180 patients and akinetic in 121. Risk factors and surgical procedures were similar in both groups. Left ventricular ejection fraction was less than or equal to 30% in 98 patients. Coronary bypass grafting was performed in 269 patients. with an average of 2.3 grafts per patient. Mitral valve replacement. the most common concomitant procedure. was performed in 16 patients. Intra-aortic balloon assist was required postoperatively in 47 patients. Overall operative mortality was 13% (38 patients) and was due to low cardiac output in 23 patients and arrhythmia in 12 patients. Univariate and multivariate analyses related early mortality to New York Heart Association functional classification of heart failure. the predominant indications of arrhythmia or congestive heart failure. left ventricular ejection fraction less than or equal to 30%. the need for intra-aortic balloon support. and the excision of an akinetic (18%) rather than dyskinetic (8%) left ventricular aneurysm. Over a follow-up period averaging nearly 5 years. the actuarial survival at 5 years was 63% in the dyskinetic group and 51% in the akinetic group.
Latissimus dorsi cardiomyoplasty in the treatment of patients with dilated cardiomyopathy, Stimulated skeletal muscle grafts have been proposed as a means to reinforce ventricular wall in the treatment of severe myocardial failure. Latissimus dorsi cardiomyoplasty was performed in 11 patients with advanced heart failure due to cardiomyopathy who were in New York Heart Association (NYHA) class III or IV despite maximal medical therapy. There were no operative deaths. Eight patients were followed for a mean of 10.8 months. Two patients remain in muscle conditioning protocol. One patient died with latissimus dorsi ischemia and congestive heart failure. Four of the eight patients in long-term follow-up are in NYHA class I. three in class II. and one in class III. At 3 months of follow-up. rest radioisotopic left ventricular ejection fraction increased from 20.5 +/- 3.6% to 26.8 +/- 8.1% (p less than 0.01). Doppler-echocardiography demonstrated that left ventricular segmental wall shortening improved from 11.3 +/- 2.5% to 16.5 +/- 3.9% (p less than 0.01) and left ventricular stroke volume from 22.9 +/- 4.6 to 33.1 +/- 10 ml (p less than 0.01). Cardiopulmonary exercise test showed that maximal oxygen consumption during treadmill test increased from 14.8 +/- 3.7 to 18.2 +/- 3.3 ml/kg.min (p less than 0.05). At 6 months of follow-up. all the above values remained essentially unchanged. Furthermore. nonsustained ventricular tachycardia was abolished without specific medical therapy in four patients. Thus. cardiomyoplasty improves left ventricular function. reverses congestive heart failure. and may improve long-term survival in severe cardiomyopathies.
Five-year experience with triple-drug immunosuppressive therapy in cardiac transplantation, Although triple-drug immunosuppression with a combination of cyclosporine. prednisone. and azathioprine has been shown to improve short-term survival after cardiac transplantation. its long-term effects still are unknown. From December 1983 through December 1988. all patients (N = 139) who underwent orthotopic cardiac transplant at our institution received triple-drug immunosuppressant therapy. Follow-up averaged 32.2 +/- 15.8 months. Twenty-one patients died; 134 survived more than 30 days. Actuarial survival was 92% at 1 year. 85% at 3 years. and 78% at 5 years. Twenty-five episodes of acute graft rejection were diagnosed in 21 of the 139 recipients (0.18 episode per patient). In patients. the incidence of infection was 0.82 episode; 72% of infections were viral. with 10% due to cytomegalovirus. The incidence of coronary artery disease was 10% at 1 year. 25% at 3 years. and 36% at 5 years. Coronary artery disease was responsible for 60% of late deaths. Arterial hypertension developed in 81% of patients. despite relatively well-maintained renal function (serum creatinine. 1.7 +/- 0.3 mg/dl). Skeletal complications occurred in 15.8% and lymphoma in 1.4% of recipients. Complete long-term rehabilitation was achieved in all but two of the surviving patients. These data support the short- and long-term effectiveness of triple-drug therapy. This regimen reduces the incidence of rejection. infection. and lymphoma. as well as the degree of renal failure. However. the incidence of posttransplant coronary artery disease has not been reduced. and graft atherosclerosis represents the major cause of late graft failure and death.
Low-dose lovastatin safely lowers cholesterol after cardiac transplantation, Hypercholesterolemia occurs in many cardiac transplant patients and may aggravate graft coronary arteriopathy as well as contributing to peripheral vascular disease. Lovastatin. which inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase. in doses of 40-80 mg/day effectively lowers cholesterol in the general cardiac population but has been associated with rhabdomyolysis in cardiac transplant recipients. To determine whether lower doses of lovastatin would be effective and safe for lowering cholesterol after cardiac transplantation. 44 patients with blood cholesterol greater than 200 mg/dl at least 6 months after cardiac transplantation received 10-20 mg lovastatin daily. In addition. lovastatin enzyme inhibitor level was assayed in six patients to determine whether metabolism of the drug was abnormal. Lovastatin decreased total cholesterol by 28% from 282 +/- 54 to 208 +/- 62 mg/dl (p less than 0.005). primarily because of reduction in the low-density lipoprotein fractions. and was well-tolerated without any symptoms or abnormal creatine phosphokinase levels in 43 of 44 patients. One patient developed rhabdomyolysis and reversible renal failure when lovastatin was increased to 40 mg daily. Enzyme inhibitor levels in the six transplant patients were 4.2-7.8 times higher than those measured in normal volunteers. Low-dose lovastatin effectively lowers cholesterol in patients after transplantation. but metabolism is altered. perhaps by cyclosporine. Monitoring of enzyme inhibitor levels may be required to allow safe administration of this drug to cardiac transplant recipients.
Mechanical myocardial actuation during ventricular fibrillation improves tolerance to ischemia compared with cardiopulmonary bypass, Direct mechanical ventricular actuation (DMVA) is a unique non-blood-contacting biventricular assist device that provides circulatory support during ventricular fibrillation without demonstrating adverse effects on the myocardium. The purpose of this study was to assess the preservation of myocardial energy stores and myocardial responses to ischemia after circulatory support during ventricular fibrillation with direct mechanical ventricular actuation versus cardiopulmonary bypass. Twenty adult mongrel dogs were randomized to receive circulatory support with either cardiopulmonary bypass or direct mechanical ventricular actuation. After 4 hours of ventricular fibrillation. hearts were defibrillated and left ventricular transmural biopsies were obtained. Hearts were then excised and subjected to 90 minutes of normothermic total ischemia. Serial biopsies were obtained at 15-minute intervals to determine regional depletion of high energy phosphates. The time-to-peak ischemic contracture was recorded by using needle-tipped Millar catheters placed in the left ventricular endocardium. epicardium. septum. and right ventricle. Time-to-peak ischemic contracture of the endocardium (62.6 +/- 1.4 vs. 58.8 +/- 1.0 minutes. p less than 0.05) and septum (61.1 +/- 6.9 vs. 46.9 +/- 6.2 minutes. p less than 0.004) were significantly prolonged after direct mechanical ventricular actuation versus cardiopulmonary bypass. respectively. Similar trends were noted in the epicardium and right ventricular regions; however. these differences were not statistically significant. Left ventricular adenosine triphosphate (ATP) levels were better preserved after direct mechanical ventricular actuation (22 +/- 1.5 mumols/g dry wt) compared with cardiopulmonary bypass (17 +/- 1.9 mumols/g dry wt). The depletion of left ventricular endocardium ATP during normothermic ischemia was significantly delayed after direct mechanical ventricular actuation compared with cardiopulmonary bypass.
The changing clinical spectrum of thromboangiitis obliterans (Buerger's disease), Between 1970 and 1987. 112 patients were diagnosed as having thromboangiitis obliterans (TAO). The age was 42 +/- 11 years (mean +/- SD; range. 20-75 years); 23% were women. and 7% were more than 60 years old when they were first diagnosed. Ischemic ulcerations were present in 85 (76%) patients: 24 (28%) patients with upper-extremity. 39 (46%) patients with lower-extremity. and 22 (26%) patients with both upper- and lower-extremity lesions. Ninety-one (81%) patients had rest pain. 49 (44%) patients had Raynaud's phenomenon. and 43 (38%) patients had superficial thrombophlebitis. We were able to follow up 89 of the 112 (79%) patients for 1-460 months (mean follow-up time. 91.6 +/- 84 months). Sixty-five (73%) patients had no amputations. while 24 (27%) had one or more of the following amputations: finger. six (15%) patients; toe. 13 (33%) patients; transmetatarsal. four (10%) patients; below knee. 14 (36%) patients; and above knee. two (5%) patients. Forty-three (48%) patients stopped smoking for a mean of 80 +/- 105 months (median. 46.5 months; range. 1-420 months). and only two (5%) patients had amputations after they stopped smoking. while 22 (42%) patients had amputations while continuing to smoke (p less than 0.0001). The spectrum of patients with TAO is changing in that the male-to-female ratio is decreasing (3:1). more older patients are being diagnosed. and upper-extremity involvement is commonly present. In the 48% of patients who stopped smoking. amputations and continued disease activity were uncommon.
High-risk reparative surgery. A neglected alternative to heart transplantation, The selection of patients for either high-risk reparative operations on the heart or for transplantation has become increasingly difficult as a result of improved results with both modalities. A retrospective review was done of patients referred for heart transplantation who were not considered candidates for conventional cardiac surgery. yet instead underwent reparative procedures rather than transplantation. Of 23 adult patients referred during a 7-year period. 18 had coronary artery disease. and five had valvular heart disease. All had New York Heart Association class IV symptoms. Preoperative left ventricular ejection fractions were in the range 0.08-0.63 (mean. 0.28). Ten of 18 patients with coronary artery disease required insertion of an intra-aortic balloon pump for hemodynamic support perioperatively. Seven patients had primary coronary artery bypass grafts. and 10 had reoperative coronary bypass procedures. One patient had a left ventricular aneurysmectomy. and one had endocardial stripping in addition to myocardial revascularization procedures. Of the patients with valvular disease. three had aortic valve replacement. of which two were reoperations. and two others had mitral valve replacements with tricuspid annuloplasties. With a mean follow-up of 25 months. 1-. 3-. 12-. and 24-month actuarial survival rates were 91%. 87%. 82%. and 76%. respectively. One patient who underwent aortic valve replacement in this study successfully received heart transplantation 19 months postoperatively. These results compare favorably with the current results for patients undergoing first-graft heart transplantation. All survivors enjoy New York Heart Association class I or II functional capacity.
Bradyarrhythmia after heart transplantation. Incidence, time course, and outcome, From June 1980 to April 1989. 72 of 401 (18%) adult recipients of orthotopic heart transplantation developed prolonged (greater than 24 hours) bradyarrhythmias (less than 60 beats/min) within 5 days after transplantation. Junctional bradycardia occurred in 50 (69%) recipients. sinus bradycardia in 18 (25%). and slow ventricular response during atrial fibrillation in four (6%). Fifty-five of 72 (76%) patients had bradyarrhythmias of less than 20 days' duration (less than 7 days. 50 patients; 7-20 days. five patients). Fifty patients returned to sinus rhythm (greater than 60 beats/min) by the time of discharge. Five patients expired within 20 days. Seventeen of 72 (24%) patients had bradyarrhythmia for more than 20 days. which was symptomatic in 11. All 17 patients (junctional bradycardia. 13 patients; sinus bradycardia. four patients) received a permanent pacemaker within 40 days after transplantation. Between 1 and 12 months (mean. 4 +/- 3 months) after pacemaker implantation. 12 patients recovered sinus rhythm (greater than 70 beats/min). The other five patients had intrinsic rates of 32-57 beats/min (mean. 48 +/- 10 beats/min) during 1-9 months (mean. 4 +/- 3 months) of follow-up. The donor ischemic time in bradyarrhythmia patients was 202 +/- 34 minutes. which was significantly longer (p less than 0.01) than the 173 +/- 43 minutes for those patients without bradyarrhythmia. Conclusively. the incidence of posttransplantation bradyarrhythmia is relatively high. It is usually temporary. however. even in patients with a prolonged duration of bradyarrhythmia. A relation appears to exist between donor ischemic time and the incidence of bradyarrhythmia.
Factors affecting survival in total artificial heart recipients before transplantation, To identify factors affecting the successful bridge to transplantation. experience with 32 recipients of the Jarvik-7 artificial heart was reviewed. Between patients with and without a successful bridge. there were no significant differences in preoperative hepatorenal function or postoperative hemodynamics. but there were significant differences in body size. When recipients were divided according to body surface areas of less than or greater than 1.8 m2. the smaller patients more frequently developed respirator dependence (73% vs. 18%. p less than 0.01). renal failure (53% vs. 18%. p less than 0.05). and hepatic failure and sepsis. resulting in less frequent qualification for transplantation (20% vs. 65%. p less than 0.05). There were no successful bridge operations in seven patients with body surface areas of less than 1.7 m2. and only one success in nine patients who were less than 170 cm in height. despite use of a smaller stroke volume model. The smaller patients had poorer ventricular filling. which was largely compensated for by the drive controls set for significantly longer diastole and higher vacuum. resulting in similar hemodynamics between the groups. The results suggest that device fitting as manifested by body size is an important factor affecting major organ recovery and subsequent transplantation in recipients of the Jarvik-7 artificial heart. A paracorporeal device may be advisable for patients with body surface areas of less than 1.8 m2 or who were less than 175 cm in height until an even smaller model with a better fit in the thorax becomes available.
Deferoxamine fails to improve postischemic cardiac function in hypertrophied hearts, Myocardial hypertrophy is a well-recognized risk factor in congenital cardiac surgery. Hypertrophied hearts have been demonstrated to have an increased vulnerability to ischemia/reperfusion injury. We studied the effects of the iron chelator and hydroxyl radical scavenger deferoxamine given during early reperfusion in a model of isolated retroperfused rabbit hearts made hypertrophic by aortic banding early in life (1 week of age). The rabbits were studied at 6-8 weeks of age. and the hearts were subjected to 30 minutes of 37 degrees C ischemia followed by 30 minutes of reperfusion. Postischemic recovery of isovolumic developed pressure was measured by using an intracavitary balloon in both the untreated (n = 6) and the deferoxamine-treated (n = 6) groups and compared with normal age-matched controls. Deferoxamine (50 mumol/kg) was given to one group with the hypertrophied hearts during the first 10 minutes of reperfusion. The left ventricular weight/body weight ratio in the hypertrophied hearts was 2.9 +/- 0.4 x 10(-3) (n = 14) versus 2.0 +/- 0.1 x 10(-3) in the age-matched controls (p less than 0.05). Postischemic peak developed pressure recovered to 102 +/- 6% of the preischemic value in the normal hearts after 30 minutes of reperfusion compared with 75 +/- 5% for the untreated and 71 +/- 4% for the deferoxamine-treated hearts (p less than 0.05 vs. control). We conclude that chronic hypertrophy from early in life leads to increased susceptibility to ischemia and that the iron chelator deferoxamine is not effective in preventing the injury of reperfusion in hypertrophied hearts.
Right ventricular function and metabolism, Right ventricular protection may be limited with current methods of cardioplegic delivery. Sensitive measurements of right and left ventricular function and metabolism were made in 30 patients undergoing elective coronary artery bypass surgery with cold cardioplegic arrest. Myocardial adenine nucleotide concentrations decreased with cardioplegia and reperfusion in both the right and left ventricles despite adequate levels of precursors. suggesting perioperative mitochondrial dysfunction. Postoperatively. right and left ventricular pressures were measured with micromanometer catheters and volumes were measured by nuclear ventriculography. Right and left ventricular systolic elastance was calculated by the isochronic method and by the end-systolic method. Both methods provided sensitive indexes of end-systolic elastance. This study demonstrated that right ventricular function and metabolism can be evaluated by methods analogous to methods used in the left ventricle. These results suggest that right ventricular functional and metabolic recovery are delayed despite apparently adequate myocardial protection. Sensitive measurements may permit improved assessment of alternative methods of right ventricular protection.
Is adenosine 5'-triphosphate derangement or free-radical-mediated injury the major cause of ventricular dysfunction during reperfusion? Role of adenine nucleoside transport in myocardial reperfusion injury, The aim of this study was to determine the dual role of ATP as an energy substrate and as a major source of oxygen-derived free-radical-mediated reperfusion injury by using adenine nucleoside blocker. p-nitrobenzylthioinosine (NBMPR). and adenosine deaminase inhibitor. erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). In a randomized study. 16 dogs were instrumented with minor-axis LTZ-piezoelectric crystals and intraventricular pressure transducers to monitor. off bypass. left ventricular performance by using a sensitive and load-independent index of contractility (slope of the stroke work-end-diastolic length relation). Hearts were subjected to 60 minutes of normothermic global ischemia and 120 minutes of reperfusion. Normal saline without (Group 1. n = 8) or with (Group 2. n = 8) NBMPR and EHNA was infused in three boluses into the cardiopulmonary bypass reservoir before ischemia and reperfusion. Transmural serial biopsies were obtained before and during ischemia and reperfusion and analyzed for myocardial adenine nucleotide pool intermediates by using high-performance liquid chromatography. In the control group. three hearts developed ischemic contracture and another three hearts exhibited cardiogenic shock during reperfusion. In the EHNA/NBMPR-treated group. left ventricular performance recovered within 30 minutes of reperfusion (p less than 0.05 vs. control). Myocardial ATP was depleted to 20% of normal in both groups by the end of ischemia (p less than 0.05). Intramyocardial adenosine in the EHNA/NBMPR-treated group was 12-fold greater (15.09 +/- 1.6 nmol/mg protein) than the control group at the end of the ischemic period (p less than 0.05). Inosine was about fourfold higher in the control group (19.07 +/- 1.50 nmol/mg protein) compared with the drug-treated group (p less than 0.05). During reperfusion. myocardial ATP levels increased to approximately 50% of normal in the EHNA/NBMPR group while remaining depressed (20% of normal) in the control group. Thus. despite the dramatic loss of myocardial ATP during ischemia. complete recovery of ventricular performance and significant repletion of ATP during reperfusion were observed when adenosine transport and deamination were modulated during ischemia and reperfusion. These results suggest that 1) the myocardium may have more ATP than is needed for basic cardiac functions and 2) washout of ATP diffusible catabolites is detrimental to ventricular performance during reperfusion. Specific blockade of nucleoside transport resulted in complete functional recovery despite low but critical ATP levels.(ABSTRACT TRUNCATED AT 400 WORDS).
Prolonged cardiac preservation. Evaluation of the University of Wisconsin preservation solution by comparison with the St. Thomas' Hospital cardioplegic solutions in the rat, The University of Wisconsin solution differs from other types of solutions used for organ preservation because it contains high-energy phosphate precursors (adenosine and phosphate). impermeants (lactobionate and raffinose). an oncotic agent (pentafraction). and antioxidants (allopurinol and glutathione). These components have the potential to enhance the preservation of ATP. reduce intracellular and extracellular edema. and attenuate free-radical-mediated injury. The University of Wisconsin solution has been demonstrated to enhance and extend the preservation of the liver. pancreas. and kidney. but its potential role in the heart remains unproven. We have evaluated the University of Wisconsin solution (Du Pont) by comparing it with the St. Thomas' Hospital cardioplegic solutions No. 1 and No. 2 (Plegisol). which are used in Europe and the United States for routine cardiac surgery and transplantation. For each solution. 10 isolated working rat hearts were arrested by 10 ml of the solution (at 4 degrees C) and then maintained immersed in the same solution for 4 hours at 4 degrees C. Mean recovery of functional indexes (expressed as a percentage of their preischemic control values) after use of the University of Wisconsin solution were as follows: peak aortic pressure. 90.6 +/- 1.0; dP/dt. 71.5 +/- 5.5; aortic flow. 81.6 +/- 4.7; coronary flow. 87.5 +/- 3.5; and cardiac output. 82.6 +/- 3.5. In contrast. the mean recoveries after St. Thomas' Hospital solution No. 1 were as follows: peak aortic pressure. 82.8 +/- 1.3; dP/dt. 49.7 +/- 3.0; aortic flow. 58.4 +/- 5.3; coronary flow. 79.6 +/- 5.9; and cardiac output. 63.0 +/- 4.9. In contrast still. mean recoveries after St. Thomas' Hospital solution No. 2 were as follows: peak aortic pressure. 83.1 +/- 1.2; dP/dt. 40.7 +/- 6.1; aortic flow. 37.0 +/- 5.1; coronary flow. 65.8 +/- 3.6; and cardiac output. 43.1 +/- 5.6. The recovery of all indexes were significantly superior (p less than 0.005) after preservation with University of Wisconsin solution compared with either of the St. Thomas' Hospital solutions.
Efficacy of recombinant-derived human superoxide dismutase on porcine left ventricular contractility after normothermic global myocardial ischemia and hypothermic cardioplegic arrest, A porcine model of normothermic global ischemia (40 minutes) followed by systemic cooling to 25 degrees C with 4 degrees C crystalloid cardioplegic arrest (90 minutes) was used to assess the efficacy of recombinant-derived human superoxide dismutase (r-HSOD) on postreperfusion left ventricular function while on cardiopulmonary bypass. Isovolumic hemodynamic function was monitored. and adenine nucleotide pool was measured in myocardial biopsy specimens and coronary sinus effluent. The treatment group of pigs (n = 7) received 15 mg/kg r-HSOD immediately before warm reperfusion. both left ventricular peak systolic pressure and developed pressure were significantly better in the r-HSOD group of pigs (p less than 0.05 vs. placebo). This improvement persisted at 60 minutes of reperfusion (p less than 0.05 vs. placebo). Myocardial ATP and total adenine nucleotides did not differ. nor did adenine nucleotide catabolites in the coronary sinus effluent differ between treatment groups of pigs. The exception to this was the nucleotide catabolite inosine. which was significantly elevated in coronary sinus effluent of pigs treated with r-HSOD at 30 minutes of reperfusion (p less than 0.05 vs. placebo). In this model of global ischemia and reperfusion. a recombinant-derived human free-radical scavenger provides significant protection of systolic but not diastolic function. Values for myocardial ATP and total adenine nucleotide content suggest that the improvement in mechanical function during reperfusion is not due to enhanced preservation of myocardial bioenergetics.
Effects of low perfusate Ca2+ concentration on newborn myocardial function after ischemia, A greater dependence on transsarcolemmal Ca2+ flux and immaturity of Ca2+ sequestration capacity may potentiate Ca2(+)-mediated reperfusion injury in the newborn myocardium. The effect of serum ionized Ca2+ concentration on left ventricular systolic and diastolic function after ischemia was studied in 5-7-day-old piglets undergoing a 90-minute period of cold-blood cardioplegic arrest. In the control group. Ca2+ was maintained at 1.2 mM (Group A [n = 6]). The cardioplegic solution and bypass perfusate were modified to achieve a low Ca2+ concentration. 0.25 mM. in Group B (n = 6). Left ventricular pressure-volume loops were acquired by using high-fidelity pressure-sensor-tipped and volume-conductance catheters. Ventricular function was assessed from the slope of end-systolic (Ees) and end-diastolic (k) pressure-volume relations during transient caval occlusion. Both groups showed a significant reduction in Ees after ischemia (p less than 0.05). Intergroup comparison of Ees after ischemia demonstrated a better recovery of the systolic function in the low Ca2+ group. 64 +/- 7% versus 49 +/- 6% in the normal Ca2+ group (p = 0.05). There was a significant increase in chamber stiffness index in group A (k. 0.48 +/- 0.06 to 0.65 +/- 0.05 ml-1. p less than 0.01) versus no significant change in group B. This study shows 1) the feasibility of acquiring continuous pressure-volume data in neonatal hearts by using a conductance catheter system. and 2) better preservation of systolic function and diastolic compliance in normal newborn myocardium by low Ca2+ concentration in the peri-ischemic period.
Identification of patients at greatest risk for developing major complications at cardiac surgery [published erratum appears in Circulation 1991 Jul;84(1):446, As part of a prospective program to use risk-adjusted outcome (operative mortality and morbidity) as a measure of quality of care. we have analyzed perioperative complication data in 10.634 patients representing 73% of all patients undergoing cardiac surgery requiring cardiopulmonary bypass at Veterans Administration medical centers between April 1. 1987. and March 31. 1989. One or more complications occurred in 15% of patients undergoing coronary artery bypass grafting. and in 24% of patients undergoing valve and other cardiac surgery. Patients experiencing one or more complications had an eightfold to 10-fold increase in operative mortality compared with patients with no perioperative complications. The most frequent complication was requirement for mechanical ventilation for at least 48 hours occurring in 8% of patients undergoing coronary artery bypass and in 15% of patients undergoing valve and other cardiac surgery; 24-25% of these patients died within 30 days of surgery or as a direct result of a surgical complication. Previous heart surgery was a strong predictor of development of one or more complications in both groups of patients. being associated with an adjusted relative risk of 1.6-2.0. Other important predictors in both surgical groups were surgical priority. older age. peripheral vascular disease. and higher serum creatinine. Although a number of preoperative risk factors could be identified for the development of renal failure. low cardiac output. and requirement for prolonged mechanical support. few risk factors could be identified for the development of mediastinitis and reoperation for bleeding. This observation suggests that mediastinitis and reoperation for bleeding are more likely the result of technical factors rather than patient-related risk factors.
Comparison of medical and surgical therapy for uncomplicated descending aortic dissection, To guide the choice of medical versus surgical therapy for patients with descending (type B) aortic dissection (tear in the descending aorta without involvement of the ascending aorta). multivariate survival analysis was applied to 136 patients admitted to two medical centers between 1975 and 1988 with acute (n = 89) or chronic (n = 47) descending dissection: group 1. all 136 patients; group 2. 106 patients without rupture. pulse loss. or visceral organ compromise; and group 3. 56 patients from group 2 without major cardiac or renal disease (23 surgical and 33 medical). Group 3 medical and surgical subgroups were well matched for baseline characteristics and were potential candidates for either mode of therapy. By Cox model analysis. significant predictors of mortality were pleural rupture. other dissection complications. increasing age. and cardiac disease (all p less than 0.01). Surgical versus medical therapy was not an independent determinant of survival in any of the three groups for acute or chronic dissection. Survival probabilities for all group 3 patients at 1. 5. and 10 years were 0.94. 0.87. and 0.32 (medical) and 0.90. 0.80. and 0.50 (surgical). Despite the limitations of this retrospective study (including the possibility of undefined treatment selection biases). these data suggest that medical or early surgical therapy is associated with equivalent outcome in selected patients with uncomplicated acute or chronic descending aortic dissection.
Iron chelation by deferoxamine inhibits lipid peroxidation during cardiopulmonary bypass in humans, Iron catalysis is involved in oxygen-derived free radical generation and subsequent lipid peroxidation. which have been reported to occur during cardiopulmonary bypass in humans. We assessed the effects of the iron chelator deferoxamine on the susceptibility of circulating low density lipoproteins (LDLs) to induced peroxidation in 20 adult patients (10 controls and 10 treated) undergoing cardiopulmonary bypass for coronary or valve procedures. Deferoxamine was given both intravenously (30 mg/kg body wt. starting 30 minutes before bypass and extending for the next 4 hours) and as an additive to the cardioplegic solution (250 mg/l). Blood samples were taken from both atria before and immediately after the end of cardiopulmonary bypass. Plasma lipid peroxidation was assessed by measuring spectrophotometrically the thiobarbituric acid reactive substances (TBARS) content of selectively isolated LDLs after their exposure to a peroxidizing agent. Before cardiopulmonary bypass. the right and left atrial blood values of LDL-TBARS were not significantly different between the two groups. Cardiopulmonary bypass resulted in a lipid peroxidation of significantly greater magnitude in control than in treated patients. Postbypass right atrial values for LDL-TBARS (expressed in mumol/mmol LDL-phospholipids) were 45.7 +/- 17.2 (mean +/- SEM) in control patients and 6.9 +/- 2.9 in treated patients (p less than 0.02). whereas in the left atrial blood. LDL-TBARS yielded values of 62.7 +/- 20.5 and 10.3 +/- 3.9. respectively (p less than 0.01).
Diabetic patients have abnormal cerebral autoregulation during cardiopulmonary bypass, We tested the hypothesis that insulin-dependent diabetic patients with coronary artery bypass graft surgery experience altered coupling of cerebral blood flow and oxygen consumption. In a study of 23 patients (11 diabetics and 12 age-matched controls). cerebral blood flow was measured using 133Xe clearance during nonpulsatile. alpha-stat blood gas managed cardiopulmonary bypass at the conditions of hypothermia and normothermia. In diabetic patients. the cerebral blood flow at 26.6 +/- 2.42 degrees C was 25.3 +/- 14.34 ml/100 g/min and at 36.9 +/- 0.58 degrees C it was 27.3 +/- 7.40 ml/100 g/min (p = NS). The control patients increased cerebral blood flow from 20.7 +/- 6.78 ml/100 g/min at 28.4 +/- 2.81 degrees C to 37.6 +/- 8.81 ml/100 g/min at 36.5 +/- 0.45 degrees C (p less than or equal to 0.005). The oxygen consumption was calculated from jugular bulb effluent and increased from hypothermic values of 0.52 +/- 0.20 ml/100 g/min in diabetics to 1.26 +/- 0.28 ml/100 g/min (p = 0.001) at normothermia and rose from 0.60 +/- 0.27 to 1.49 +/- 0.35 ml/100 g/min (p = 0.0005) in the controls. Thus. despite temperature-mediated changes in oxygen consumption. diabetic patients did not increase cerebral blood flow as metabolism increased. Arteriovenous oxygen saturation gradients and oxygen extraction across the brain were calculated from arterial and jugular bulb blood samples. The increase in arteriovenous oxygen difference between temperature conditions in diabetic patients and controls was significantly different (p = 0.01). These data reveal that diabetic patients lose cerebral autoregulation during cardiopulmonary bypass and compensate for an imbalance in adequate oxygen delivery by increasing oxygen extraction.
Treatment with desmopressin acetate in routine coronary artery bypass surgery to improve postoperative hemostasis, Desmopressin acetate (DDAVP) has been shown to decrease blood loss and transfusions in complex cardiac operations with long extracorporeal times. Its use in routine cardiac valve operations has been shown not to be beneficial. but its role in routine coronary artery bypass grafting operations has not been defined. We examined the effect of DDAVP in a prospective study of 60 patients undergoing uncomplicated primary coronary artery bypass grafting operations. Thirty consecutive patients received DDAVP (0.3 micrograms/kg) after cardiopulmonary bypass and were compared with 30 consecutive patients who did not receive DDAVP. No significant differences were seen in 12-hour mediastinal blood loss (465 +/- 207 ml with DDAVP versus 511 +/- 221 ml without DDAVP) or 12-24-hour mediastinal blood loss (236 +/- 127 ml with DDAVP versus 260 +/- 112 ml without DDAVP). Transfusion of blood products were similar for both groups. Platelet aggregometry at intraoperative and postoperative time points using ADP. collagen. and ristocetin was not significantly different from baseline values in either group. In a subgroup of patients with poor initial ristocetin-induced platelet aggregometry. a significant increase (p less than 0.05) in ristocetin-induced platelet aggregometry was seen postoperatively only in those patients who had received DDAVP. A decrease in blood loss and transfusions. however. was not demonstrable. In those patients who had been on aspirin or nonsteroidal anti-inflammatory drugs preoperatively. DDAVP did not improve mediastinal blood loss or transfusion needs.
Late results with Carpentier-Edwards porcine bioprosthesis, From 1977 to 1984. 429 patients underwent aortic valve replacement (AVR). and 339 underwent mitral valve replacement (MVR) with a Carpentier-Edwards bioprosthesis. Early mortality for AVR was 4.6% (isolated AVR. 1.9%) and for MVR was 5.3% (isolated MVR. 4.1%). Follow-up was 99.3% complete at a mean of 5.9 years. Actuarial event-free rates at 10 years for AVR and MVR were. respectively. 1) for structural valve deterioration. 91.4 +/- 3.2% versus 75.1 +/- 4.0% (p less than 0.01); 2) for nonstructural dysfunction. 100% versus 97.8 +/- 1.6% (p = NS); 3) for thromboembolism. 90.6 +/- 2.3% versus 87.3 +/- 2.6% (p = NS); 4) for anticoagulant-related bleeding. 95.3 +/- 1.1% versus 88.6 +/- 2.4% (p = 0.05); 5) for endocarditis. 87.8 +/- 5.7% versus 90.6 +/- 2.4% (p = NS); 6) for reoperation. 91.0 +/- 2.5% versus 74.4 +/- 3.7% (p less than 0.01); 7) for valve-related mortality. 76.1 +/- 6.9% versus 71.4 +/- 5.2% (p = 0.01); 8) for permanent physical impairment. 85.0 +/- 3.0% versus 71.5 +/- 3.6% (p less than 0.01); and 9) for combined operative mortality. valve-related mortality. and reoperation. 68.7 +/- 6.4% versus 51.5 +/- 4.9% (p = 0.01). No structural valve dysfunction was observed in any AVR patient whose valve was inserted after age 70. Age at operation was the only factor that predicted structural valve deterioration (p less than 0.01).
The reversibility of canine vein-graft arterialization, We assessed the reversibility of functional and morphological changes of arterialized vein segments by returning them to the venous circulation. Thirteen dogs underwent right carotid and femoral veno-arterial grafting. After 12 weeks. veno-arterial grafts were removed for contractility (norepinephrine [NE] and 5-hydroxytryptamine [5-HT]). luminal prostacyclin (PGI2). and morphometric analyses; the remaining segments were used as left jugular and femoral veno-venous grafts. After another 12 weeks. the veno-venous grafts were harvested. To NE. veno-arterial grafts (ED50. 5.4 +/- 0.1 [-log M]) were less sensitive than control veins (ED50. 6.0 +/- 0.2) or veno-venous grafts (ED50. 6.4 +/- 0.2) but were more sensitive than control arteries (ED50. 4.0 +/- 0.1); the maximum tension of veno-arterial grafts (6.2 +/- 0.6 g) was greater than that of veins. less than that of arteries (9.8 +/- 1.0 g). and comparable with that of veno-venous grafts (5.1 +/- 1.1 g). To 5-HT. veno-arterial (ED50. 7.5 +/- 0.1) and veno-venous (ED50. 7.3 +/- 0.2) grafts were more sensitive than arteries (ED50. 6.0 +/- 0.3). while the vein was unresponsive; the maximum tension of veno-arterial grafts (5.0 +/- 0.7 g) was less than that of arteries (6.9 +/- 0.9 g) and greater than that of veno-venous grafts (1.4 +/- 0.3 g). PGI2 production in veins (3.6 +/- 0.8 ng/ml). veno-arterial grafts (3.9 +/- 0.8 ng/ml). and veno-venous grafts (3.3 +/- 0.9 ng/ml) was comparable and less than that of arteries (6.4 +/- 0.9 ng/ml). Veno-arterial graft intimal thickness (127 +/- 8 microns) and intimal area (15.6 +/- 1.8 x 10(3) microns 2) tended to be greater than that in the veno-venous graft (113 +/- 9 microns and 12.4 +/- 1.8 x 10(3) microns 2); also. the veno-arterial graft medial area (103.0 +/- 7.3 x 10(3) microns 2) was greater than that of the veno-venous graft (80.3 +/- 6.9 x 10(3) microns 2). thereby resulting in a similar relative intimal area (13 +/- 1%). Therefore. some changes associated with arterialization. for example. adrenergic sensitivity. maximum tension to 5-HT. medial thickening. and perhaps intimal hyperplasia. reverted toward venous values when replaced in the venous environment. possibly due to variations in pressure. flow. shear stress. and/or graft preparation techniques. Luminal PGI2 was unchanged in the grafts. implying that graft contractility was not modulated by luminal PGI2.
Informed consent in head and neck surgery, Informed consent is the fastest growing problem in the medical negligence debate. It was highlighted recently in the United Kingdom in the Sidaway case. Informed consent comprises the advice you would give the patient. the consequences of not taking your advice. the specific risks of the surgery or treatment you have in mind. and the risks of surgery in general. In an attempt to identify what the present practice in otolaryngology was. a postal survey was carried out of the members of the Scottish and North of England Otolaryngological Societies.
Repair of salivary fistulae after laryngectomy, A new surgical technique is described for the repair of salivary fistulae. It has been used in three patients. The fistulae occurred after laryngectomy and had been unsuccessfully treated with local and regional flaps. The principle of the technique is to use a bipedicled jejunal patch as a free microvascular transfer. One patch is used for reconstruction of the pharynx and after excising the mucosa the skin defect is closed with the other patch. The mucosa is excised to expose the muscle and to create a recipient site for a split skin graft.
The influence of calcium alginate haemostatic swabs upon operative blood loss in adenotonsillectomy, Although adenotonsillectomy is regarded as a minor procedure. it has been shown that 18% of patients may experience an operative blood loss of 10-20% of the total blood volume. The aim of this study was to determine whether calcium alginate haemostatic swabs reduce operative blood loss in adenotonsillectomy. Seventy-two patients (ages 2-12 years) entered a prospective trial in which the operation was performed either with normal gauze swabs or calcium alginate swabs. Thirty-six children were randomized to each group. The mean blood loss was found to be 34.9 ml (2.07% of total blood volume) and 47.8 ml (2.97% of total blood volume) respectively. Although there was no significant reduction in operative blood loss using calcium alginate. in both groups the blood loss was much smaller than that stated by the majority of previous workers.
Hearing aids for high-frequency hearing loss, This cross-over study compares the relative benefits of a standard NHS contracted hearing aid with a high-frequency emphasis commercial aid in subjects with high-frequency hearing loss. Disability questionnaires and free-field speech-in-noise (FAAF II) tests were used to assess subjects unaided and after 6 weeks of wearing each aid. Total FAAF II test scores showed no significant difference with either aid. but analysis of frequency-specific subscores demonstrated less use of low-frequency information when using the high-frequency emphasis aid. Overall questionnaire responses relating to conversation showed more benefit with the high-frequency emphasis aid. Subjects generally preferred this aid. possibly due to less low-tone gain than the standard NHS aid.
Peak flow nasal patency indices and self-assessment in septoplasty, The present study evaluates the results of septoplasty monitored by the objective peak flow nasal patency indices and the subjective patient self-assessment scores of nasal obstruction. Mini-Wright peak flow meters were used. The peak flow nasal patency index was defined as the ratio between nasal and oral peak flow rates. Uni and bi-lateral. as well as ex and in-spiratory. indices were calculated. Both peak ex and in-spiratory flow nasal patency indices were significantly increased 1 and 6 months post-operatively. indicating improved nasal patency. The most marked post-operative increase of the nasal patency indices was seen for the preoperatively worst airway and the total airway. A weak significant positive correlation was found between the peak flow nasal patency indices and the patient mean self-assessment scores of the uni and bi-lateral nasal obstruction. The change of the peak flow nasal patency indices measured 6 months post-operatively correlated well with the patient overall assessment of the operative changes of the total nasal patency. The method was found quick and easy to handle in monitoring the effect of functional septoplasty and is recommended as an alternative to rhinomanometry.
Analgesia and removal of nasal packing, We present a prospective controlled trial. comparing methods of analgesia for the relief of discomfort on removing nasal packing. including a general discussion on the considerations for. and methods of. nasal tamponade. On the basis that nasal packing is likely to continue to be used frequently. nitrous oxide (as Entonox) is advocated as a safe and relatively cheap means of pain relief with a statistically significant advantage over papaveretum.
A randomized comparison of manipulation of the fractured nose under local and general anaesthesia, Reduction of simple nasal fractures may be performed under local or general anaesthesia: the latter is by far the most popular method in Britain. though why is hard to define. We have attempted to compare the 2 approaches by means of a randomized. prospective trial. Fifty consecutive. adult patients with radiologically proved fractures of the nasal bones were randomized to a local or general anaesthesia group and underwent manipulation with Asch's and Walsham's forceps between 7 and 15 days post-injury. Analysis of results at 4 h and 8 weeks post-operatively showed no significant benefit conferred by fracture reduction under general anaesthesia as opposed to local anaesthesia with respect to post-operative airway patency or cosmesis. It is suggested that significant benefits can be obtained in terms of patient convenience and cost effectiveness if nasal fractures are reduced under local anaesthesia as an outpatient procedure.
Trimming of the inferior turbinates: a prospective long-term study, The aim of this study was to determine whether the initial benefits of radical trimming and anterior trimming of the inferior turbinates on nasal airflow persisted in the long term. Radical trimming significantly reduced nasal resistance at 2 months following operation (n = 12) (P less than 0.005). There was no significant change in nasal resistance over the next 20 months. Symptom scores for nasal obstruction also showed a significant reduction (n = 16) (P less than 0.005). at 2 months. and did not change significantly over the next 20 months. Radical trimming of the inferior turbinates is a highly effective operation in patients with hypertrophy of the inferior turbinates with few initial complications. However. further analysis of the data revealed that up to 20% of patients lose the initial subjective benefit of relief of nasal obstruction within 2 years of follow-up. Late onset crusting occurs in some patients though this is not directly attributable to an increase in nasal airflow. This study also concludes that anterior trimming of the inferior turbinates cannot be recommended as a form of treatment.
Sensorineural hearing loss in bullous myringitis. A prospective study of eighteen patients, Eighteen patients were seen over a period of 3 years. Twenty of their ears were diagnosed as having bullous myringitis. Pure tone audiograms and stapedial reflexes were performed within 48 h of referral. Six ears demonstrated sensorineural hearing loss. 7 ears mixed loss and 4 conductive loss. Recovery of sensorineural hearing loss complete in 8 out of 13 ears. Stapedial reflexes were elicited in 5 patients and all showed recruitment. The findings of this study confirms the fact that sensorineural hearing loss is more common in bullous myringitis than previously thought and that it is temporary in many cases. The stapedial reflex results suggest that the site of the lesion is in the cochlea.
Comparison of pathological lesions on repeated renal biopsies in 73 patients with primary IgA glomerulonephritis: value of quantitative scoring and approach to final prognosis, In order to improve our possibility of establishing a long-term prognosis in IgA nephritis. 73 patients out of a cohort of 282. followed over a mean period of 12 years at the same institution for an IgA nephritis. had a prospective second renal biopsy 5 years later. For all biopsies (RB1 and RB2). we developed a quantitative scoring for all elementary lesions with a glomerular. an interstitial. a tubular and a vascular index. The sum of these 4 indexes gave a global optical score (GOS). Pathological improvement on light microscopy (delta GOS less than or equal to -2) was noticed only in 3 patients (4%). stability (-2 less than delta GOS less than +2) in 30 patients (41%). mild deterioration (+2 less than or equal to GOS less than 5) in 23 patients (32%) and major progression (delta GOS greater than or equal to 5) in 17 patients (23%). We observed no pathological remission. even in the 14 patients with complete clinical remission. The pathological progression was characterized by an increase in all elementary lesions. mainly the tubulo-interstitial and vascular ones. By immunofluorescence mesangial IgA deposits remained stable with no disappearance; however. the number and intensity of vascular C3 deposits were significantly greater on RB2. Chronic renal failure (serum creatinine greater than 1.5 mg/dl) correlated best with major pathological progression and mainly with the progression of extraglomerular lesions. IgA nephritis is a slowly progressive disease with no pathological remission. and its evolution is characterized by progression of extraglomerular lesions. mainly vascular. which might play a major role in the ultimate development of chronic renal failure.
The treatment of mesangial IgA nephropathy with cyclophosphamide, dipyridamole and warfarin: a two-year prospective trial, Of 52 patients with mesangial IgA nephropathy. 25 were allocated to treatment with cyclophosphamide (6 months). and dipyridamole and warfarin (2 years) and 27 to no treatment in a randomized prospective 2-year study. At entry. the treated and untreated groups of patients did not differ in mean serum creatinines. urinary protein excretions. quantitative urinary erythrocyte counts or blood pressure readings. At the end of the trial mean (+/- SEM) serum creatinine values had gone from 0.12 +/- 0.01 to 0.13 +/- 0.01 mmol/l (p less than 0.05) in untreated patients and from 0.10 +/- 0.01 to 0.12 +/- 0.01 mmol/l (p less than 0.05) in treated patients. Mean (+/- SEM) log values of urinary erythrocyte (rbc) counts had not changed significantly from 5.47 +/- 0.09 to 5.21 +/- 0.14 log rbc/ml in untreated patients. from 5.45 +/- 0.11 to 5.49 +/- 0.19 log rbc/ml in treated patients. However. in treated patients. mean (+/- SEM) urinary protein excretions decreased from 1.67 +/- 0.35 to 1.15 +/- 0.31 g/24 h (p less than 0.01) whereas in untreated patients urinary protein was unchanged between initial values of 1.76 +/- 0.34 and follow-up at 1.89 +/- 0.45 g/24 h. No significant changes in blood pressure occurred in either group. This study supports the observation that treatment of IgA nephropathy with cyclophosphamide. dipyridamole and warfarin is associated with a reduction of urinary protein excretion but a significant effect on preservation of renal function. at least as determined by serum creatinine values. could not be confirmed over this two-year study.
Is preliminary binephrectomy necessary in patients with autosomal dominant polycystic kidney disease undergoing renal transplantation, Patients with end-stage chronic renal failure due to autosomal dominant polycystic kidney disease who underwent renal transplantation with or without preliminary binephrectomy were retrospectively studied to determine the effect of binephrectomy on outcome. Nineteen patients were identified. Thirteen patients had no surgery prior to transplantation and six underwent preliminary binephrectomy. One patient died as a result of the nephrectomy. Twenty-one renal allografts were performed on 18 patients of whom seven have died of sepsis; 10 have functioning grafts and one has returned to dialysis. Patients not undergoing preliminary binephrectomy had a statistically significant (p less than 0.05) increase in mortality and morbidity due to septic complications related to polycystic kidney disease. Indications for bilateral nephrectomy should be reconsidered.
Hypophosphatemia in infants on continuous ambulatory peritoneal dialysis, Three infants with irreversible renal failure and treated with continuous ambulatory peritoneal dialysis (CAPD) developed hypophosphatemia. In one of them rachitic lesions were observed on X-ray and bone biopsy showed osteomalacic osteodystrophy. Different mechanisms may have been at the origin of the hypophosphatemia: high doses of phosphate binders. low phosphorus intake. phosphate loss with the dialysate and possibly nutritional repletion. Dietary phosphorus restriction and use of phosphate binders should be applied with caution and serum phosphate should be monitored regularly in infants treated with CAPD.
SLE nephritis: an ultrastructural immunogold study to evaluate the relationship between immune complexes and the basement membrane components type IV collagen, fibronectin and heparan sulphate proteoglycans, The nature of immune complexes and their relationship to the normal glomerular basement membrane (GBM) components type IV collagen. fibronectin. and heparan sulphate proteoglycans (HSPG) have been examined in the glomeruli of 7 cases of systemic lupus erythematosus (SLE) glomerulonephritis using an ultrastructural immunogold technique. In paraformaldehyde-fixed. Lowicryl resin-embedded tissue. the electron-dense deposits contained IgG. IgM. IgA. and C3 whether they were subepithelial. intramembranous. subendothelial. or mesangial and there was no particular relationship between the class of immunoglobulin and site of immune complex localization within the glomerulus. The normal GBM components type IV collagen. fibronectin. and HSPG were found within all the glomeruli. but did not have the same distribution. Type IV collagen and fibronectin were found predominantly on the inner aspect of the GBM and diffusely throughout the more central regions of the mesangial matrix. By contrast the HSPG was seen mainly on the outer aspect of the GBM and at the periphery of the mesangial matrix. In none of the cases were GBM antigens localized within the electron-dense deposits. results which suggest that autoantibodies to these GBM components may not play a role in the development of the glomerulonephritis.
Treatment of juxtaarticular nonunion fractures at the knee with long-stem total knee arthroplasty, A retrospective study of ten patients with juxtaarticular nonunions at the knee treated with long stem total knee arthroplasty was performed. The average age of the patients was 76 years old. with an average follow-up of 36 months. The nonunions were present for an average of 36 months. There were six patients in the series with prior total knee arthroplasty. Clinical union was achieved in all ten patients. All patients improved their ambulatory status. Range of motion improved from an average preoperative range of 40 degrees to an average postoperative range of 85 degrees. Complications occurred in three of ten patients. with one being a postoperative infection. Surgical techniques are described to aid in treatment of difficult juxtaarticular nonunion fragments.
Patellar resurfacing in total knee arthroplasty, Technical errors in patellar resurfacing at the time of total knee arthroplasty (TKA) are responsible for many of the complications that affect the patellofemoral joint. Instability. patellar fracture. and wear of metal-backed patellar implants are significantly affected by errors of patellar resurfacing. A review of 50 TKAs using a condylar prosthesis and a standardized technique for patellar resurfacing was performed to evaluate the accuracy of the technique. The patients were evaluated at a mean of 2.5 years (range. two to five years) after surgery. The Hospital for Special Surgery Knee Score improved from a preoperative mean of 56 to 92 at the last evaluation. The Hospital for Special Surgery Knee Scores were excellent in 92% and good in 8%. The Knee Society Knee Score improved from a preoperative mean of 28 for pain and 49 for function to a last evaluation mean of 96 for pain and 85 for function. None of the patients had symptoms referable to the patellofemoral joint. There were no patellar fractures. dislocations. or instances of implant loosening of the patella. Roentgenograms revealed nine asymmetrically resurfaced patellae and five tilted patellae. There were no patellar subluxations. Patellar thickness was maintained at the preoperative level of 21 mm. Joint-line height was elevated 1 mm. The patellar height was decreased 2 mm from the preoperative height. Using a standard technique. satisfactory clinical results can be achieved. but minor errors in resurfacing and alignment will still occur.
Radionuclide imaging of asymptomatic versus symptomatic total knee arthroplasties, Ninety-eight total knee prostheses were evaluated by roentgenograms and bone scans. Fifty-three were asymptomatic. and 45 were symptomatic. Thirteen prostheses required revision surgery. At a mean of 54 months. asymptomatic knee replacements generally showed only mild uptake in one or more zones. Only one knee had uptake equal to surrounding bone. However. symptomatic knee replacements showed significantly greater uptake in the patella. femur. and medial and lateral tibial plateau regions (Mann-Whitney two-sample rank test). Bone scans in the symptomatic group were obtained at a mean of 44 months. Excluding those patients who had revision surgery. the differences remained significant. Furthermore. symptomatic knee replacements with normal roentgenograms also had significantly greater uptake. Radiolucent lines were noted in 30% of asymptomatic patients. whereas 29% of symptomatic knees had radiolucencies. Radiolucencies were not generally associated with significantly greater uptake. Lateral release had no effect on the patellar score.
Bone loss in the distal anterior femur after total knee arthroplasty, Bone loss in the distal anterior femur in asymptomatic total knee arthroplasty (TKA) patients has been noted roentgenographically and during revision surgery. A retrospective roentgenographic review of 147 TKA cases was carried out to document bone loss. The influence that the mode of fixation (porous coated and cemented) and the implant design have on bone loss was examined. The time of onset and the progression of bone loss were studied. Bone loss occurred in the distal anterior femur in the majority of cases reviewed (68%). The prevalence of bone loss was independent of the mode of fixation and the implant design. By qualitative observation. roentgenographically detectable bone loss occurred within the first postoperative year and did not progress further. Previously three-dimensional finite element analysis demonstrated that the replacement of the bearing surface of the femur with a stiff metallic implant reduces the stress in the distal anterior femur by at least one order of magnitude. It is therefore speculated that the observed bone loss results from stress shielding. The apparent lack of progression may reflect the development of a new remodeling equilibrium under the altered stress conditions. The bone loss in the distal anterior femur described has not been implicated as a source of failure. However. since the bone strength in the femoral region is compromised as it becomes osteopenic. bone failure may occur with longer periods of cyclic loading. Furthermore. as a result of bone loss. revision arthroplasty may be more difficult.
Massive allografts in salvage revisions of failed total knee arthroplasties, Ten patients with failed total knee arthroplasties and severe bone loss were treated with massive whole distal femur and proximal tibial allografts in combination with prosthetic implants. Fourteen allografts were inserted either as invaginated or segmental grafts and were rigidly fixed to the host bone. Clinically and roentgenographically. 12 of 14 grafts (86%) seemed to have united to the host bone. The average range of motion was 92 degrees. Five patients developed complications; two of these involved the allograft (nonunion and fracture) and two were caused by inadequate healing at the ligament-allograft junction. One patient had a late infection. With careful planning and improved surgical techniques. these complications can be avoided. The massive allograft-prosthesis composite techniques is a viable reconstructive alternative worthy of further clinical trials.
Reconstruction of patellar tendon rupture after total knee arthroplasty with an extensor mechanism allograft, Although patellar tendon rupture after total knee arthroplasty (TKA) is a rare complication. the consistently poor outcome of conventional tendon repair has convinced some to abandon such reconstruction in favor of a prospective protocol using an allograft distal extensor mechanism. The graft consists of a quadriceps tendon. a patella with a cemented prosthesis. a patellar tendon. and a tibial tubercle. Since December 1985. 13 knees in 12 patients were reconstructed using this method. Ten knees were followed for six to 51 months; five of these knees were followed for more than 24 months. Knee extension power and improved function were ultimately attained in all cases. although minimal extensor lags were present in three cases. Preoperative motion returned in all but one knee. Healing of the allograft to the host tissue was attained primarily at all of the tibial junctions. Two graft complications occurred. both in the first three months after surgery: one quadriceps junction treated by resuture failed at the one-month mark. and the other graft had to be revised for extensor weakness from rupture of the graft at the patella-patellar tendon junction. which was attributed to surgical damage to the tendon. After completion of healing to the host and rehabilitation of the knee joint. no grafts in the series failed during the course of normal daily activities. One patient fractured the allograft patella in a severe fall. The long-term durability of this construct needs to be studied further.
A sequential three-step lateral release for correcting fixed valgus knee deformities during total knee arthroplasty, An approach to mild. moderate. and severe fixed valgus deformities of the knee is described. The sequential approach to soft-tissue releases in the fixed valgus knee allows the surgeon to regain a neutral alignment in valgus deformities of up to 90 degrees. An additional benefit of the approach is spontaneous correction of fixed external tibial rotation deformities. Using this approach. early and late stability allows the use of unconstrained knee implants. including those with mobile-bearing elements.
Anaphylactic shock associated with chymopapain skin test. A case report and review of the literature, The allergic response to chymopapain intradiscal therapy has been well documented. The most serious of these reactions is anaphylactic shock. which may result in death. Various screening methods. including skin tests. have been proposed to identify susceptible patients. Anaphylactic shock occurred in a 40-year-old woman from application of the screening skin test. Appropriate therapeutic intervention should be readily accessible when this test is performed.
The latissimus dorsi musculocutaneous flap for extremity reconstruction in orthopedic surgery, The latissimus dorsi was transferred as a pedicle flap in ten patients and as a free vascular flap in ten others for extremity reconstruction. Group I comprised ten patients in whom the transfer was used solely to cover a skin or soft-tissue defect. Although there was partial necrosis of the transferred skin in one patient. the remaining nine patients obtained complete coverage without further reconstructive surgery. Group II comprised five patients in whom transfer of the latissimus dorsi was performed for active flexion or extension of the elbow or for abduction of the shoulder. Postoperatively. muscle strength obtained was classified from Grades 0 to 5 according to the muscle testing method. Three patients obtained muscle strength of Grade 3. while two obtained Grade 2. Group III comprised five patients who had brachial plexus palsy after high-dose irradiation. Coverage of the skin and soft tissue was performed after neurolysis of the brachial plexus palsy to free the tissue bed of scarred tissue. Postoperatively. sensory and motor disturbances were alleviated in four of five patients.
Complications associated with limb salvage for extremity sarcomas and their management, A retrospective clinical review of 100 consecutive patients with extremity sarcomas managed by limb salvage operations was performed to evaluate local tumor control and morbidity. The mean follow-up period was 45.1 months. Overall survival was 86%. There were local recurrences in 3% of patients. and 26 complications in 22 patients. Wound necrosis was the most frequent complication. Failure of allogeneic bone graft operations occurred in 25 patients. Most of the complications were salvageable without loss of limb. Limb salvage is an acceptable surgical treatment of extremity sarcomas based on adequate local control and minimal morbidity.
Giant-cell reparative granuloma of the hand and foot bones, Giant-cell reparative granuloma (GCRG) is an uncommon benign reactive intraosseous lesion. It occurs in the skull. jaw. hand. foot. and facial bones and rarely in other skeletal sites. It is a solitary. lytic. expanded lesion and infrequently may extend into the surrounding soft tissue. Histologically. it is composed of fibrous stroma with spindle-shaped fibroblasts. multinucleated giant cells. and inflammatory mononuclear cells. Areas of hemorrhage are uniformly present. It may be difficult to distinguish this entity from an aneurysmal bone cyst. giant-cell tumor. or brown tumor of hyperparathyroidism because of roentgenographic and histologic similarities. Accurate diagnosis is essential for appropriate treatment; serum calcium. phosphorus. and parathyroid hormone levels should be measured. Curettage and bone graft are effective treatments for both primary lesions and recurrences. Second recurrences are rare.
Leiomyoma of a digital artery, Benign. soft-tissue masses of the hand are common. A vascular leiomyoma is an unusual tumor of smooth-muscle origin. In a 62-year-old man. the tumor arose from within a digital artery. Persistent symptoms prompted an excisional biopsy. requiring resection of a portion of the artery. Adequate collateral circulation preempted the need for a vascular graft. Vascular repair or grafting may be necessary if collateral circulation is not adequate.
Immune responses to allogeneic and xenogeneic implants of collagen and collagen derivatives, Whereas xenogeneic collagen has provided a safe and effective biomaterial for numerous medical applications. there are few instances in which data permit the correlation of the immunologic profile of well-defined devices with their clinical sequelae. A major exception is the use of injectable bovine dermal collagen for soft-tissue contour correction. The low incidence of hypersensitivity has been studied in the context of clinical efficacy and safety with several devices. The findings indicate that such immunity usually results in the manifestation of local symptoms of dermal inflammation at sites of treatment that resolve as the implant is resorbed by the host. In contrast. more immunogenic hemostatic agents may elicit a more frequent or vigorous immune response that is not clinically visible or relevant in that application. Recent experiences with collagen-based devices for the repair and regeneration of bone have also demonstrated that the presence of immunity to their collagenous or non-collagenous components does not necessarily predict adverse clinical sequelae. Indeed. numerous specific data indicate that this immunity can exist as an epiphenomenon with no effect on osteogenesis. To get a true composite picture of biocompatibility. significant steps must be taken to characterize biomaterials properly and to ensure that immunologic. clinical. histologic. and other pertinent laboratory data are viewed in relation to one another and not in isolation.
The effect of continuous epidural analgesia on postoperative pain, rehabilitation, and duration of hospitalization in total knee arthroplasty, Efficacies of three alternate methods of postoperative analgesia were studied in 156 patients who had total knee arthroplasty (TKA). Forty-two of these patients received parenteral meperidine hydrochloride or morphine (Group 1). 58 patients received periodic epidural injections of morphine (Group 2). and 56 patients received continuous epidural infusions of bupivacaine hydrochloride and Duramorph (Group 3). The postoperative course of all patients was documented in terms of the incidence and severity of pain. range of joint motion. duration of hospitalization. and occurrence of complications. Although epidural analgesia increased the cost and duration of the operation. good-to-excellent pain relief was attained in 86% (Group 2) and 88% (Group 3) of cases with epidural analgesia compared with 61% of patients (Group 1) receiving conventional analgesia. Moreover. 67% of patients in Group 1 experienced frequent episodes of moderate-to-severe postoperative pain in contrast to 40% of patients in Group 2 and only 10% of patients in Group 3. As a result of diminished pain. greater joint motion was obtained within the first 72 hours in Groups 2 and 3. They also had shorter hospitalization (9.6 days versus 11.2 days for Group 1 and 10.8 days for Group 2). However. the use of epidural analgesia did not reduce the incidence of complications. including nausea. Continuous infusion of epidural bupivacaine and Duramorph provided good-to-excellent control of postoperative pain after TKA. However. better analgesics are needed to reduce the high incidence of side effects associated with various treatment methods.
The inwardly pointing knee. An unrecognized problem of external rotational malalignment, Twelve patients with inwardly pointing knees had chronic knee pain and disability suggestive of patellofemoral subluxation. None had responded well to conservative measures or surgical correction at the level of the soft tissues. Their pattern of limb alignment was studied roentgenographically and was found to differ significantly from the control group of 49 healthy young adults. The deformities primarily related to the tibia were external tibial torsion. excess varus angulation of the tibial plateau. and varus knees. Angulation of the femoral condyles was normal and femoral anteversion did not appear to contribute significantly to the deformity. Surgery in seven cases (nine knees) was by derotation valgus Maquet osteotomy of the tibia and lateral release realignment of the patellae. Outcome assessments after a three-year follow-up period (five knees) were excellent. Early results on the remaining cases were satisfactory.
Total knee arthroplasty fixation. Comparison of the early results of paired cemented versus uncemented porous coated anatomic knee prostheses, The results of 18 matched pairs of Porous Coated Anatomic knee prostheses were studied to compare the early clinical and functional performance of cemented versus uncemented fixation with an average five-year follow-up period for both. The knee score improved from a preoperative average of 35 points to a postoperative average of 90 points in the cemented group. and from 38 points to 93 points in the uncemented group. In particular. the individual pain scores and the range-of-motion values were well matched at the three-. six-. and 12-month follow-up visits and showed a steady improvement. Subjectively. all patients were pleased with the results of surgery; one-third preferred the cemented side. one-third preferred the uncemented side. and one-third found no difference in the performance of either knee. The clinical and functional performance of knee prostheses in patients who had one cemented knee and one uncemented knee were comparable and possibly unrelated to the type of fixation method.
Cemented and ingrowth fixation of the Miller-Galante prosthesis. Clinical and roentgenographic comparison after three- to six-year follow-up studies, One hundred thirty-nine cemented and 132 cementless Miller-Galante total knee prostheses were followed between three and six years (average. 43-44 months). The fixation technique was based on patient age. bone quality. and ability to delay full-weight bearing. Clinical follow-up studies were possible on 116 cemented knees. Fifteen knees were lost because of death before the three-year follow-up study. and eight knees required component removal. One hundred twenty-three cementless knees were available for clinical follow-up studies; there were three deaths. and six failures required component removal. No cemented failure was due to fixation. and three cementless failures were due to lack of tibial ingrowth in two and pain of undetermined etiology in one. Preoperative knee scores were slightly significant with cemented knees averaging 48 points and cementless knees averaging 52 points. A similar significant difference was maintained at the final follow-up study. No significant differences were noted for pain. limp. or support scores. Average range of motion was similar in the two groups. Radiolucent lines about the femoral component were rare. Cementless tibial radiolucencies were partial in up to 20% of examined zones. and complete tibial tray radiolucency was seen in only three patients. No correlation between radiolucency and knee scores was seen.
Review of the all-polyethylene tibial component in total knee arthroplasty. A minimum seven-year follow-up period, A retrospective analysis of 144 total knee arthroplasties was performed between 1975 and 1981 with a minimum follow-up period of seven years. A posterior cruciate condylar prosthesis was used in each procedure. Patients were followed clinically and roentgenographically. and a set of statistical variables was established based on elevation in joint line. tibial component angular alignment. overall limb alignment. and position of the tibial component on anteroposterior and lateral roentgenograms. Review of the study group found that the Hospital for Special Surgery knee scores improved from a preoperative score of 55 to a postoperative score of 88. with 94.5% having good or excellent results. The mean postoperative range of motion was 106 degrees with a mean extension of -0.3 degrees. Radiolucencies developed in 41% of the knees with 5% of the knees having progressive radiolucencies. Eight knees were considered failures based on clinical and roentgenographic evaluations. Factors found to significantly affect the formation of radiolucent lines included a shift of the tibial component medially by greater than 4 mm. a varus tilt of the tibial component greater than 2 degrees. and the diagnosis of rheumatoid arthritis. The only variable associated with aseptic loosening was an elevation of the joint line by greater than 8 mm.
An all-polyethylene cementless tibial component. A five- to nine-year follow-up study, An all-polyethylene cementless tibial component was used in 221 total knee arthroplasties. With one exception. failures did not occur before three years. Failure was characterized by medial subsidence of the tibial component. There was abrasion of the polyethylene on the undersurface of all components that failed. Survivorship was seven to nine years (87.1%). This study demonstrated that a flexible cementless component can function well when used with any type of bone. However. abrasion of the polyethylene that occurs from shearing forces is a concern. Polyethylene components need adequate provisions to prevent shearing or need surface treatment to prevent abrasion.
Clinical approach to prenatal detection of human structural defects, Tremendous advances in prenatal diagnosis have allowed clinicians to recognize a variety of structural defects in the developing fetus. Guidelines for fetal ultrasonography and an approach to fetal evaluation are outlined. The developmental morphologic approach is emphasized as a way of categorizing congenital anomalies whether they are detected during prenatal or postnatal life. The use of this approach for diagnosing and managing fetal malformation syndromes is illustrated.
Teratogenically induced fetal anomalies, A variety of infectious and physical agents. maternal diseases and altered metabolic states. and drugs and chemicals have been shown to cause postnatal structural or functional disabilities when embryonic or fetal exposure occurs during human pregnancy. These disabilities are potentially preventable through public education and awareness. Health-care providers must be equipped to collect relevant data regarding exposures of concern from their pregnant patients. locate and evaluate pertinent current teratology information resources. and sensitively counsel these women regarding the associated potential teratogenic risks. Comprehensive care of the patient exposed to a human teratogen may also include discussion of prenatal diagnostic procedures and other pregnancy management options.
Aberrant morphogenesis of the central nervous system, This overview of congenital defects of the CNS has emphasized pathogenesis. As developmental pathways continue to be elucidated. this approach remains to an extent hypothetical. When. however. an understanding of the features of morphogenesis and dysmorphogenesis helps to indicate time of onset or to elucidate causal factors. important steps toward the prevention of birth defects are taken.
A protocol for the investigation of pregnancy loss, A protocol for the evaluation of pregnancy loss should include a maternal history. dysmorphic examination of the fetus or abortus. photographs. autopsy. chromosome studies (in most cases). and radiographic or xeroradiographic studies. Selected cases with suspected ascending or transplacental infection may require microbiologic investigation. Increasing specialized laboratory techniques may help in the diagnosis of inborn errors of metabolism or storage disorders. Coordination of studies requires the interaction of OB/GYN. pathology. genetics. cytogenetics. and nursing in order to assure delivery of this clinical service. Knowledge of the causes of pregnancy loss and their typical time and mode of presentation can facilitate a focused evaluation. with a high chance of achieving an accurate diagnosis. The goal of all investigations is to provide families with recurrence risk data on which to base future childbearing decisions. as well as information on potential prenatal monitoring.
Monitoring glucocorticoid therapy: a pharmacokinetic approach, Although glucocorticoid therapy is essential for the treatment of severe inflammatory disorders. there is no systematic approach to patient variables that may affect availability of a steroid dose. After the development of a data base of pharmacokinetic parameters. we examined glucocorticoid pharmacokinetics in 54 patients between 2 and 70 years of age using 70 pharmacokinetic studies after administration of intravenous methylprednisolone (n = 25). oral methylprednisolone (n = 15). intravenous prednisolone (n = 18). and oral prednisone (n = 12). Eleven patients had unusually rapid methylprednisolone elimination (clearance. 565 to 837 ml/min/1.73 m2; population mean. [+/- SD] 380 +/- 100 ml/min/1.73 m2) without an identifiable cause. Incomplete absorption of methylprednisolone and prednisone was observed in three patients and one patient. respectively. Evaluation of glucocorticoid pharmacokinetics in children aged 1 year 8 months to 18 years demonstrated a significant inverse correlation (r = 0.88; p less than 0.001) between prednisolone clearance and age. It is therefore important to consider age in the interpretation of pharmacokinetic data. To simplify measurement of prednisolone clearance. a single-dose single-point method was developed. This was based on a highly significant relationship between the 6-hour postdose prednisolone concentration and prednisolone clearance (log prednisolone clearance = 2.66 + [6-hour postdose concentration] [-0.00167]; r2 = 0.96; p less than 0.0001). Evaluation of glucocorticoid pharmacokinetics in the clinical setting can be used to identify abnormalities in absorption. elimination. and patient compliance. This technique can be used to individualize glucocorticoid dosing regimens.
The antihypertensive efficacy of hydrochlorothiazide is not prostacyclin dependent, We tested the hypothesis that vascular prostacyclin synthesis is stimulated by hydrochlorothiazide and could account for some of the drug's antihypertensive effect. We studied 13 patients with mild essential hypertension in a randomized. double-blind design to assess the effects of indomethacin on hydrochlorothiazide's ability to lower blood pressure. alter body weight. stimulate plasma renin activity. and modulate vascular prostacyclin biosynthesis as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin. 2.3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha). measured by GC/MS. Administration of hydrochlorothiazide. 50 mg daily for 2 weeks. was associated with a significant decrease in both systolic and diastolic blood pressure in both supine (systolic. 148 +/- 3 to 136 +/- 3 mm Hg; diastolic. 97 +/- 2 to 94 +/- 3 mm Hg) and upright (systolic. 151 +/- 4 to 131 +/- 2 mm Hg; diastolic. 103 +/- 2 to 97 +/- 3 mm Hg) positions. Hydrochlorothiazide administration resulted in a 1 kg weight loss and stimulation of plasma renin activity from 1.7 +/- 0.4 to 5.3 +/- 1.1 ng angiotensin I/ml/hr. However. the urinary excretion of 2.3-dinor-6-keto-PGF1 alpha was unchanged after administration of hydrochlorothiazide (86 +/- 13/ng/gm creatinine during placebo. 74 +/- 13 ng/gm during week 1 of hydrochlorothiazide. and 70 +/- 9 ng/gm during week 2 of the drug). Administration of indomethacin. 50 mg twice a day. resulted in greater than 60% inhibition of 2.3-dinor-6-keto-PGF1 alpha excretion but did not affect the antihypertensive response to hydrochlorothiazide. Indomethacin did not oppose the diuretic effect of hydrochlorothiazide as assessed by weight loss but did attenuate the rise in plasma renin activity. Our data demonstrate that the blood pressure-lowering effect of a thiazide diuretic does not require enhanced prostacyclin synthesis and the cyclooxygenase inhibitor indomethacin does not antagonize the antihypertensive efficacy of hydrochlorothiazide.
Quality of life among hypertensive patients with a diuretic background who are taking atenolol and enalapril, The cardioselective beta-blocker atenolol and the angiotensin-converting enzyme inhibitor enalapril were compared for efficacy. safety. and quality-of-life factors in 30 patients with hypertension whose hypertension was inadequately controlled with diuretic alone. Atenolol (50 to 100 mg once a day) and enalapril (2.5 to 40 mg once a day). combined with hydrochlorothiazide (25 mg once a day). had similar levels of efficacy and safety. A comprehensive battery of psychologic assessments for quality of life was administered. including measures of anxiety. depression. psychiatric symptoms. memory. and psychomotor function. These five conceptually based clusters were first analyzed by multivariate analysis of variance procedures. followed by univariate analyses of the individual variables composing each domain. In general. neither atenolol nor enalapril was associated with major changes in psychologic functioning. The only data cluster with a statistically significant change was memory function. primarily as a result of lower scores of the digit span (backward) test. for atenolol relative to enalapril. These preliminary findings suggest that atenolol and enalapril have comparable degrees of efficacy and safety. with no major disparities in quality-of-life effects. for hypertensive patients with a history of taking diuretics and this sort of quality-of-life assessment can be performed during trials of antihypertensive drugs.
Effects of lovastatin in diabetic patients treated with chlorpropamide, Patients with non-insulin dependent diabetes mellitus (NIDDM) have a higher risk of atherosclerotic cardiovascular disease than nondiabetic subjects. In seven patients with both hypercholesterolemia and NIDDM controlled by chlorpropamide. lovastatin (20 mg b.i.d. for 6 weeks) lowered low-density lipoprotein cholesterol by 28%. total cholesterol by 24%. and apolipoprotein B by 24%. Lovastatin levels for a 4-hour period (measured as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitory activity) were similar to those measured previously in nondiabetic patients. Lovastatin did not alter chlorpropamide kinetics or glycemic profiles. No patient had an elevation in serum transaminases or creatinine phosphokinase. and no patient had any other laboratory or clinical drug-related adverse experience during the study. Lovastatin was as effective in reducing low-density lipoprotein cholesterol in patients with NIDDM as in nondiabetic subjects. Diabetic control was unaltered. and no evidence of alteration in lovastatin or chlorpropamide blood levels was noted.
Validity of creatinine clearance estimates in the assessment of renal function, In clinical practice. estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous-infusion inulin clearance (CLIN). 4-hour creatinine clearance (CLCR.m). and 24-hour creatinine clearance (CLCR.a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN. 6 to 209 ml/min) and compared with CLCR values as predicted by five equations on the basis of plasma creatinine concentrations. age. weight. and/or height. The CLCR.m was positively correlated with CLIN (r = 0.92; p less than 0.0001) but exceeded CLIN by 15% between the range of 30 and 209 ml/min (CLIN). Similarly. CLCR.a correlated well with both CLCR.m (r = 0.84; p less than 0.0005) and CLIN (r = 0.84; p less than 0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLIN and exceeded 40% when CLIN was below 30 ml/min. CLCR estimated by the Cockcroft-Gault and Mawer methods did not significantly differ from either CLCR.m or CLCR.m. whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations. CLCR as estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN (CLIN = 1.05CLRCR - 18.38 or CLIN = 1.12CLCR - 20.60. respectively; r = 0.81; p less than 0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting.
Effect of facial cooling on mucosal blood flow in the mouth in humans, 1. To determine the effects of facial cooling on intraoral thermal events. we placed a thermal conductivity sensor on the buccal surface of the left cheek in six normal and six asthmatic subjects. Room temperature and cold stimuli were then applied to the integument surface of both sides of the face while mucosal surface temperature and thermal conductivity. as an index of blood flow. were recorded. 2. The room temperature challenge had no effect. Application of the cold stimulus to the exterior of the left cheek caused a monotonic decrease in temperature in the mouth in all subjects and was associated with a change in thermal conductivity in which blood flow increased and then fell to baseline despite a continued drop in temperature. These responses were purely local in that cooling of the right side of the face did not change the temperature or blood flow on the left side. No differences were noted between the asthmatic and normal subjects. 3. The data indicate that lowering the temperature of the skin of the face produces significant alterations in the thermal environment within the mouth. With facial cooling. buccal temperature falls and mucosal blood supply transiently rises. This effect appears to be a purely local thermally mediated event. Facial pressure and cutaneous reflexes do not play a role. The above changes may contribute to the conditioning of inspired air during oral breathing.
Increased erythrocyte sodium-lithium countertransport activity in essential hypertension is due to an increased affinity for extracellular sodium, 1. Sodium-lithium countertransport activity in a standard assay. its sodium affinity constant and maximum velocity were measured in erythrocytes from normal subjects and from essential hypertensive patients with and without a family history of hypertension. 2. In normal subjects the sodium concentration used in the standard assay was similar to the sodium affinity constant so that the activity measured in this assay was less than the maximum velocity. 3. In patients with essential hypertension and a positive family history. 33% had a sodium-lithium countertransport activity greater than the upper limit of the normal control range (0.4 mmol of Li+ h-1 l-1 of cells). 4. The reason for the raised sodium-lithium countertransport activity was an increased sodium affinity (lower sodium affinity constant) at the outside ion-binding site. 5. Of the patients with essential hypertension and a positive family history but sodium-lithium countertransport activity within the normal range in the standard assay. 30% also had a low sodium affinity constant. 6. A low sodium affinity constant at the outside site of the sodium-lithium countertransporter may be a more specific indicator for a group of patients with inherited hypertension than the standard sodium-lithium countertransport activity assay.
Effect of amiodarone on erythrocyte shape and membrane properties, 1. Amiodarone is a potent anti-arrhythmic drug with lipophilic properties. The intercalation of such a drug into the membrane of erythrocytes may alter their shape and have an impact on the flow properties of blood. We therefore studied the influence of amiodarone on erythrocyte shape and deformability in vitro and in vivo. 2. Incubation in vitro with increasing amiodarone concentrations led to a progressive stomatocytic shape transformation and a decreased deformability of the erythrocytes. 3. Amiodarone treatment in eight patients did not affect erythrocyte morphology and deformability. However. an increase in the membrane cholesterol/phospholipid ratio was found. 4. The stomatocytic shape transformation of erythrocytes in vitro indicates that amiodarone intercalates in the inner hemileaflet of the lipid bilayer leading to membrane internalization. These results shed light on the interaction of amiodarone with biomembranes.
Studies of the porcine intestinal calcitriol receptor in pseudo-vitamin D deficiency rickets type I, 1. Calcitriol (1.25-dihydroxyvitamin D3) concentrations in plasma of humans and pigs with pseudo-vitamin D deficiency rickets type I (PVDRI) have been reported to be significantly lower than in normal subjects and animals. Sometimes. however. calcitriol concentrations are relatively high in these subjects and animals (50-80 pmol/l) and nevertheless clinical symptoms of rickets develop. We have studied whether or not the development of rachitic lesions in piglets with PVDRI is due to altered binding properties of the intestinal calcitriol receptor in addition to the defective renal production of calcitriol. PVDRI piglets with clinical and biochemical symptoms of rickets (hypocalcaemia. increased activity of alkaline phosphatase) and with calcitriol concentrations in plasma of 83.7 +/- 4.2 pmol/l (n = 7) were used. They were compared with unaffected piglets with normal calcitriol concentrations (178.0 +/- 17.7 pmol/l. n = 9). 2. The equilibrium dissociation constant (Kd) of the receptor in the PVDRI piglets (0.31 +/- 0.05 nmol/l) and in control piglets (0.33 +/- 0.05 nmol/l) and the maximum binding capacity (Bmax.) (674 +/- 103 and 719 +/- 122 fmol/mg of protein. respectively) were not different (n = 9). 3. The association rate constant (kass) at 4 degrees C [0.15 x 10(7) and 0.24 x 10(7) (mol/l)-1 min-1] and the dissociation rate constant (kdiss) (0.40 x 10(-3) and 0.48 x 10(-3) min-1; half-life of dissociation = 24.1 and 28.9 h. respectively) were also not different between diseased and control piglets.
Depression and recovery of right ventricular function after cardiopulmonary bypass, Transient left ventricular dysfunction is commonly described in association with cardiopulmonary bypass (CPB). We evaluated changes in right ventricular (RV) function after elective cardiac surgery in 24 patients with normal preoperative cardiac function. In all. irrespective of distribution of coronary artery disease or use of pharmacologic support. a transient depression of RV systolic function with respect to both preinduction and initial postoperative (Postop) values occurred 262 +/- 116 min post-CPB as represented by a decrease in RV stroke volume index (25.0 +/- 1.7 vs. 33.4 +/- 1.9 ml/m2 Postop) and RV ejection fraction (31.0 +/- 2.2 vs. 45.6 +/- 2.5% Postop). and an increase in RV end-systolic and end-diastolic volume indices. This depression responded readily to pharmacologic therapy within 2 h. resolved within 24 h. and had no adverse consequences in these otherwise healthy patients. Further studies are needed to identify the cause of this phenomenon and its importance in patients with preexisting cardiac dysfunction.
Community-acquired pneumonia: evidence of functional inactivation of alpha 1 proteinase inhibitor, Quantitative and qualitative elastase inhibitory capacity (EIC) alpha 1 proteinase inhibitor (alpha 1 PI) was measured in pulmonary arterial and systemic arterial blood of patients with community-acquired pneumonia (CAP). Eleven patients with uncomplicated CAP were compared with 16 patients with fulminating pneumonia requiring intensive care management. An appropriate increase in quantitative alpha 1 PI was demonstrated in all patients. A significant functional inactivation of alpha 1 PI was demonstrated in the ICU-treated patients that was not apparent in the uncomplicated CAP patients (p less than .01). This low EIC returned to normal 4 wk after hospital discharge in all survivors. A significant (p less than .02) difference in EIC between the pulmonary arterial and systemic arterial blood was found in the nonsurvivors on admission. which suggests that alpha 1 PI is inactivated in the lungs of patients with fulminating CAP. The present data demonstrate that alpha 1 PI is functionally inactivated in patients with fulminating CAP. This low serum functional alpha 1 PI may result in proteolytic lung damage and an unfavorable outcome.
Hypophosphatemia--incidence, etiology, and prevention in the trauma patient, Hypophosphatemia is associated with a number of undesirable physiologic consequences and has been reported to occur frequently in trauma patients. We studied patients in the immediate posttraumatic period to document a) the decrease in serum P. b) renal P excretion. and c) the response to prophylactic PO4 administration. In both group 1 (n = 12) and group 2 (n = 10) patients. we measured serum P. creatinine. ionized Ca. urinary P excretion. and creatinine clearance daily for the first 3 to 4 days postinjury. Patients in group 2 also received 0.5 mmol/kg.day of PO4 for the first 48 h after admission. Group 1 patients exhibited a significant (p less than .05) decrease in serum P over the first 24 h (1.00 +/- 0.30 to 0.75 +/- 0.23 mmol/L). In contrast. group 2 patients did not demonstrate a decrease in serum P. Urinary P excretion in group 1 accounts for the observed decrease in serum P. The results of our study show that the immediate posttraumatic period is associated with a decrease in serum P and massive urinary P excretion. We also showed that prophylactic administration of 0.5 mmol PO4/kg.day prevents serum P decrease.
Fluosol DA-20 in the treatment of severe anemia: randomized, controlled study of 46 patients, We evaluated the safety and efficacy of Fluosol DA-20% (FDA) as a blood substitute in the treatment of severe anemia. Thirty-six patients received either FDA (n = 21) or crystalloid/hydroxyethyl starch (CHS) (n = 15) as part of a randomized. controlled trial. Ten patients received FDA as part of a humanitarian protocol. All were Jehovah's Witnesses who refused transfusion. had bled recently. and had average Hgb levels of 4.3 g/dl. After pulmonary artery catheter insertion. each patient was infused with CHS to attain a pulmonary artery wedge pressure (WP) of 10 to 18 mm Hg. FDA was given as a one-time dose of 30 ml/kg. Data were collected at baseline. 12. 24. and 48 h. None of the patients with negative reactions to a 0.5-ml test dose of FDA had adverse reactions to the subsequent infusion. The plasma or dissolved component of oxygen content was significantly higher in the FDA group at 12 h (FDA group 1.58 +/- 0.47 ml/dl. control group 1.01 +/- 0.31 ml/dl. p less than .02. t-test). Nineteen patients died: 12 (37.5%) FDA. seven (46.6%) control. The difference was not significant. We conclude the following: a) FDA can be given safely to severely anemic patients in doses of 30 ml/kg; b) FDA significantly increased the dissolved component of oxygen content after 12 h but the effect did not persist; c) severely anemic patients can survive without transfusion although mortality is high. In this study. inability of FDA to sustain increased oxygen content was due in part to the rapid elimination of FDA and also to the limited amount given.
Tracheostomy in children with Guillain Barre syndrome, During the 10-yr period beginning January 1979. 59 infants and children with Guillain Barre syndrome (GBS) were admitted to our hospital. Tracheostomies were performed in 15 patients and their records were reviewed. Fourteen patients were recalled for assessment of pulmonary function and respiratory muscle strength (RMS). The median duration of assisted ventilation (including endotracheal [ET] intubation) was 21 days and the median duration of tracheostomy was 39 days. Only two patients were discharged with the tracheostomy in situ. All patients were successfully decannulated at the first attempt. No tracheostomy-related complications or symptoms were reported apart from croup in two patients. On review. lung volumes and maximal inspiratory and expiratory flows were normal. There was no evidence of tracheal stenosis or significant tracheomalacia. RMS tests were normal. In this hospital. tracheostomy is a safe. well-tolerated procedure in the management of infants and children with GBS who need long-term ventilation. There were no deaths and all patients returned to their normal school or were gainfully employed after their illness. although 12 patients had mild persistent weakness of at least foot dorsiflexion.
Effects of intravenous immunoglobulin on hemorrhage-induced alterations in plasma cell repertoires, Hemorrhage produces decreases in serum immunoglobulin (Ig) levels and alterations in the number and frequency of B cells producing antibodies against bacterial antigens. These abnormalities in immune response may contribute to the increased susceptibility to infection after injury and hemorrhage. To examine the relationship between serum Ig levels and bacterial antigen-specific plasma cell numbers and frequencies after blood loss. we treated hemorrhaged mice with intravenous Ig (IVIG). Hemorrhaged mice given IVIG had increased total numbers of splenic plasma cells compared with normal or hemorrhaged. untreated mice. Immunization with the bacterial polysaccharide antigen levan immediately after hemorrhage resulted in approximately 60% fewer levan-specific splenic plasma cells than those seen in normal unhemorrhaged mice. Treatment of hemorrhaged mice with IVIG did not correct the decrease in levan-specific plasma cells. These results demonstrate that hemorrhage-induced alterations in the numbers and frequencies of bacterial antigen-specific B cells are not related to changes in serum Ig levels and cannot be corrected through administration of IVIG.
High-frequency oscillation during simulated altitude exposure, Ventilatory requirements using high-frequency oscillation (HFO) during simulated altitude exposure were investigated in control dogs and animals with oleic acid-induced lung injury. FIO2 values of 0.21 and 1.0 were supplied by bias flow to the normal and injured dogs. respectively. After a control period. animals were exposed to a simulated altitude of 8.000 ft (barometric pressure 564 torr). followed by a second control period at ground level. Both experimental groups had similar values of PaCO2 at ground level and during exposure to reduced barometric pressure. The tidal volume necessary to maintain eucapnia was higher in oleic acid-injured animals compared with the control group; cardiac output and functional residual capacity were lower. The alveolar-arterial oxygen difference was substantially larger in the oleic acid group. Adequate gas exchange can be maintained with HFO during exposure to altitude provided that ventilation and inspired PO2 are not reduced below normobaric levels.
Ringer's acetate and dextran-70 with or without hypertonic saline in endotoxin-induced shock in pigs, The effects of Ringer's acetate. 6% dextran-70. 7.5% NaCl. and the combination of 7.5% NaCl and dextran-70 were tested in resuscitation from endotoxin shock induced by continuous iv infusion of Escherichia coli endotoxin in pigs. After about 3 h. a reproducible shock state was achieved and treatment was started. governed by the left atrial pressure. The hypertonic solutions (7.5% NaCl and 7.5% NaCl in dextran-70) did not show any overall advantages over the isotonic solutions (Ringer's acetate and dextran-70). Only transient beneficial hemodynamic effects lasting less than 30 min after infusion were seen. When dextran-70 was administered. cardiovascular function was markedly improved and oxygen delivery (DO2) and survival were significantly higher compared with the crystalloid groups (Ringer's acetate and 7.5% NaCl). Administration of large amounts of Ringer's acetate resulted in an immediate deterioration of pulmonary function. It was difficult to elevate left atrial pressure or even to keep it at baseline level. and cardiac index was only transiently increased. The overall result was a deterioration of DO2 and poor survival compared with the dextran-70 treated pigs. We conclude that dextran-70 is superior to Ringer's acetate in resuscitation from endotoxin-induced shock in pigs. Furthermore. we found no role for the use of hypertonic saline. alone or in combination with dextran. in the treatment of this type of prolonged endotoxin shock.
Use of a palatal stabilizing device in prevention of palatal grooves in premature infants, A prospective. randomized study using an acrylic palatal stabilizing device (PSD) was conducted to evaluate the effectiveness of this device in preventing disruptions in palatal architecture. A total of 26 premature infants with birth weights of 540 to 1740 g. and intubated orally for a period varying from 7 to 109 days were randomized to control and experimental groups. All neonates in the control group developed palatal grooving ranging from 2 to 5 mm in depth. whereas those in the experimental group (with a PSD) showed no evidence of palatal grooving. We conclude that a PSD is an effective preventive device in premature orally intubated infants.
Mortality from pulmonary embolism in the United States: 1962 to 1984, To examine the effect of advances in the prevention of and therapy for PE. we reviewed mortality for PE in the United States from 1962 to 1984. Age-adjusted PE mortality increased by 67 to 100 percent between 1962 and 1974 for white and non-white men and women. From 1975 to 1984. these rates declined by 20 to 28 percent. Non-white PE mortality was greater than white PE mortality; men had a greater risk of PE death than women. Age-specific patterns (more than 40 years of age) of PE mortality followed those of the age-adjusted death rates. with increases noted in all groups between 1962 and 1974 and declines during the 1975-1984 period. These patterns might reflect improved ascertainment of cases and better prevention of disease. The magnitude of the rates suggests that the list of indications for prophylactic anticoagulation should be re-examined for possible expansion.
Computed tomography in patients with esophageal perforation, Contrast esophagram is the diagnostic procedure of choice in patients with clinically suspected perforation of the esophagus. In patients in whom the usual clinical signs or symptoms are unrecognized and in whom the diagnosis is obscure. the diagnosis of a perforated esophagus may be suggested by the finding of mediastinal fluid and air on CT. Three patients are reviewed. The perforations included one spontaneous. one from erosion of an esophageal carcinoma. and one iatrogenic. In two of the three patients. the diagnosis of perforated esophagus had not been made initially and in one patient the initial esophagram was interpreted as normal. Computed tomography of the chest in each patient led to the suspected diagnosis of perforated esophagus. Prompt appropriate surgical intervention followed. The findings of mediastinal fluid and more importantly mediastinal air on CT of the chest are strongly suggestive of esophageal perforation.
Bronchial hyperreactivity in patients with mitral valve disease, To elicit the mechanism of bronchial hyperreactivity (BHR) in chronic heart failure (CHF). a methacholine inhalation test. pulmonary function test. and cardiac catheterization were performed in 19 patients with mitral valve disease (MVD). and the change of severity of BHR before and after mitral valve replacement (MVR) was also examined in seven of 19 patients with MVD. Sixteen of 19 patients with MVD showed significant increase in respiratory resistance in methacholine inhalation test. while all normal subjects did not. The maximal expiratory flow at 25 percent of vital capacity (Vmax25). a parameter of small airway disease. correlated significantly with log cumulative dose producing a 35 percent decrease in respiratory conductance (PD35Grs) (r = 0.536) and the duration of symptoms (r = -0.682). There was a significant correlation between log PD35Grs and mean pulmonary artery wedge pressure (r = -0.466). After MVR. log PD35Grs was significantly improved in all seven operated-on patients. although six patients retained BHR. We conclude that patients with long-term MVD have marked BHR and that BHR in long-term MVD is related to peripheral airway narrowing with organic remodeling. which was not ameliorated with MVR procedure. in addition to pulmonary congestion.
Respiratory muscle strength in congestive heart failure, In experimental animals. conditions which drastically decrease cardiac output may reduce the strength and endurance of respiratory muscles leading to hypercapnic respiratory failure. Because patients with chronic CHF have reduced cardiac output and vital capacity (FVC). we measured PImax and PEmax and maximal handgrip force in 16 patients with CHF and 18 AMNs. The patients with CHF had a mean left ventricular ejection fraction of 26 +/- 7 percent. Maximal respiratory pressures were significantly reduced; group mean values (+/- SD) for PImax at FRC were 41.4 +/- 5.6 cm H2O (CHF) and 102.1 +/- 27.4 cm H2O (AMN) (p less than 0.001). with PImax values in five patients with CHF as low as 20 to 30 cm H2O. In most patients. PEmax was comparably reduced. Handgrip force was less dramatically reduced. suggesting selective respiratory muscle weakness. Possible explanations include reduction in respiratory muscle blood flow or generalized muscular atrophy and weakness related to cardiac cachexia.
Comparison of aerosolized glycopyrrolate and metaproterenol in acute asthma, The efficacy of nebulized glycopyrrolate compared with metaproterenol was evaluated in 46 patients with acute asthma. In a double-blinded. randomized fashion. patients received. as sole therapy. either 2 mg of glycopyrrolate or 15 mg of metaproterenol every 2 h over a 6-h study period. Of the 35 patients completing the study. analysis of variance demonstrated no difference in percentage of change in FEV1 between glycopyrrolate and metaproterenol. Two hours after the initial dose. there was a 30 percent increase in FEV1 for glycopyrrolate compared with a 25 percent increase for metaproterenol (p greater than 0.05. NS). In contrast to the comparable bronchodilator activity. the side effects profile of the two agents were markedly dissimilar. Not only were subjective complaints of tremor. palpitations. and paresthesias increased for metaproterenol. but the heart rate response was significantly elevated (p less than 0.05) compared with glycopyrrolate. Based on these data. administration of the aerosolized anticholinergic agent. glycopyrrolate. is a reasonable therapeutic alternative for acute asthma.
Myocardial revascularization for the third time. Clinical characteristics and follow-up, Twenty-five patients presenting for a third revascularization procedure were retrospectively reviewed at Loyola University Medical Center. Maywood. IL. This represents 0.5 percent of the total revascularization cases over a five-year period extending from 1985 through 1989. Perioperative mortality was none. and seven complications occurred in six patients. Internal mammary arteries were used for revascularization in 60 percent of this group. Follow-up reveals that only one patient has died secondary to an arrhythmia. All patients except one are symptomatically improved. and 18 patients remain angina free at a mean follow-up of 22.3 months. It is therefore concluded that patients are clinically improved with a third revascularization. and this procedure should be offered as an effective means of treatment.
The effects of phenylephrine on right ventricular performance in patients with pulmonary hypertension, Pulmonary hypertension causes right ventricular ischemia and failure as a result of increased afterload combined with reduced coronary blood flow. Increasing coronary driving pressure by raising aortic pressure with phenylephrine has been shown to reverse right ventricular ischemia from pulmonary hypertension in animals. Since vasodilators often fail to reduce afterload. we tested whether raising the coronary driving pressure would improve right ventricular function in man. Ten patients with pulmonary hypertension had hemodynamics and right ventricular coronary driving pressure measured before and 10 minutes after a steady state was reached with a phenylephrine infusion titrated to raise aortic pressure by 25 percent. Phenylephrine caused a significant (p less than .01) increase in mean aortic pressure (84 to 108 mm Hg) and right ventricular coronary driving pressure (46 to 69 mm Hg). In response. there was a significant (p less than .01) rise in mean pulmonary artery pressure (58 to 67 mm Hg). right ventricular end-diastolic pressure (10 to 16 mm Hg) and wedge pressure (5 to 9 mm Hg). and an insignificant fall in cardiac output (3.26 to 3.09 L/min) and pulmonary artery O2 saturation (57 to 49 percent). Although phenylephrine increased right ventricular coronary driving pressure. it worsened right ventricular function as manifest by a rise in end-diastolic pressure and fall in cardiac output. Any benefit of raising right ventricular coronary driving pressure may have been offset by alpha vasoconstriction of right ventricular coronary blood flow and/or pulmonary arterial vasoconstriction. Phenylephrine does not appear to be a useful therapy of right ventricular failure from pulmonary hypertension in patients who fail vasodilators.
Single lung transplantation for primary pulmonary hypertension, Single lung transplantation has become a therapeutic option for end-stage interstitial lung disease and obstructive lung disease. Our group recently extended this treatment to three patients with primary pulmonary hypertension. All patients had marked decreases in pulmonary artery pressures and pulmonary vascular resistance and increases in cardiac output following single lung transplantation. Spirometry. lung volumes. and diffusion capacity were not different in comparison to preoperative studies. Quantitative ventilation-perfusion scans revealed the majority of perfusion distributed to the transplanted lung. with ventilation approximately equally divided between the native and the transplanted lung. Despite ventilation-perfusion imbalance. there was no resting hypoxemia and there was no arterial oxygen desaturation with exercise. One patient expired on the 30th postoperative day due to cytomegalovirus infection of the lungs. In the remaining two patients. maximum exercise capacity following transplantation was near normal in one recipient and reduced in the second recipient. Of note. there was no evidence of ventilatory limitation or impaired oxygenation during exercise in these two recipients. Although an exaggerated exercise ventilatory response was present. this did not limit exercise performance. This report supports the use of single lung transplantation for the treatment of primary pulmonary hypertension.
Bronchial cartilage alterations in lung transplantation, Changes in the hyaline cartilage of the proximal bronchial tree were investigated in a group of combined heart-lung and double-lung recipients with and without OB. Ossification. calcification and fibrovascular ingrowth into the normally avascular hyaline bronchial cartilage were observed in almost all patients and were independent of small or large airway inflammation. Alterations in the integrity of hyaline cartilage have been produced by others in animals by ligation of the blood supply. Finding similar changes in airway cartilage of all transplanted lungs argues that there is relatively poor perfusion to the proximal air-conducting passage. Such a mechanism may contribute to the development of OB. bronchiectasis and a predilection for infections following pulmonary transplantation.
Serum concentration of soluble interleukin-2 receptor as a sensitive parameter of disease activity in sarcoidosis, We investigated the clinical value of measuring serum concentrations of soluble IL-2R in monitoring sarcoidosis. Serum concentrations of soluble IL-2R were measured in 70 patients with sarcoidosis. The mean value for active untreated sarcoidosis was 1.143 +/- 509 U/ml. while the normal range in 97 healthy control subjects was 80 to 300 U/ml. The mean value for active untreated sarcoidosis was significantly higher than that for dormant disease (353 +/- 183 U/ml) or that for corticosteroid-treated patients (380 +/- 151 U/ml). Serial changes in serum soluble IL-2R level were studied in cases of spontaneous remission or in corticosteroid-treated patients; a good correlation was noted between the changes in serum level of soluble IL-2R and clinical status. A positive correlation was noted between serum concentration of soluble IL-2R and serum ACE activity. These data confirmed that measurement of serum concentration of soluble IL-2R could be used in monitoring the disease activity in sarcoidosis.
Bronchoalveolar lavage in liquid paraffin pneumonitis, We evaluated cells and lipids recovered in the bronchoalveolar lavage fluid from seven patients with liquid paraffin pneumonitis. For each patient. the BALF was whitish with oil droplets on the surface. Alveolar macrophages contained numerous. large vacuoles that did not react with May-Grunwald-Giemsa. Papanicolaou. or periodic acid-Schiff but were stained in black with Sudan B. orange with Sudan III and red with oil Red O. Liquid paraffin was identified on thin layer chromatography of BALF-extracted lipids as a very hydrophobic compound migrating on the solvent front as control liquid paraffin. This abnormal spot was definitely identified as liquid paraffin by infrared spectroscopy and gas liquid chromatography for the first patient. The number and percentage of AMs were largely decreased in the BALF of each patient. whereas the number of neutrophils. eosinophils and lymphocytes was increased. These findings suggest that this cell-mediated inflammatory response plays a role in the development of interstitial fibrosis at late stages of liquid paraffin pneumonitis.
Progressive functional deterioration of bioprostheses assessed by Doppler ultrasonography, Doppler echocardiography was used to study the function of bioprosthetic heart valves by noninvasive means in 32 patients aged 29 to 72 years at various postoperative intervals. There were 24 Ionescu-Shiley. four Hancock. and four Carpentier-Edwards prostheses. 19 in the aortic and 13 in the mitral position. Initial studies were performed at a mean of 2.3 years after implantation and were repeated one. two. and three years thereafter. Flow velocities in the mitral orifice. left ventricular outflow tract. and ascending aorta. as well as mitral pressure half-time. were measured from pulsed-wave or continuous-wave Doppler recordings. Mitral and aortic valve areas and aortic pressure gradients were calculated. In aortic prostheses the valve area decreased and pressure gradient increased progressively in relation to the time from implantation. The mean value (+/- SD) of the aortic valve area was 67 +/- 17 percent of the manufacturer's nominal value at the first examination and 57 +/- 20 percent one year later. 51 +/- 14 percent two years later. and 46 +/- 11 percent three years later (overall differences. p less than 0.01). In mitral prostheses. reduction of the valve area was not related to the time from implantation. The mean mitral valve area was 45 +/- 12 percent of the nominal value at rest and increased to 68 +/- 18 percent during exercise at a mean of 45 months after implantation. There was no change in these values at the one-year repeat study. It is concluded that in a population with predominantly pericardial bioprostheses. (1) aortic tissue prostheses showed a progressive functional deterioration demonstrable by Doppler echocardiography. most probably due to degenerative changes; and (2) in mitral tissue prostheses. there was no significant reduction of orifice area in relation to time from implantation. Reduction of mitral valve areas may. to some extent. reflect a less than full opening at rest.
Cardiac abnormalities in children with sickle cell anemia, The cardiac status of 64 children (ages 0.2 to 18 yr) with sickle cell anemia documented by hemoglobin electrophoresis was evaluated by echocardiography. Left atrial. left ventricular and aortic root dimensions were significantly increased in over 60 percent of these children at all ages compared to values for 99 normal black (non-SCA) control subjects. Left ventricular wall thickness was increased in only 20 percent of older children with sickle cell anemia. Estimated LV mass/m2 and left ventricular cardiac index were increased compared to control subjects (p less than 0.001). Left heart abnormalities expressed as a single composite function. derived from multivariate regression analysis. correlated well with severity of anemia expressed as grams of hemoglobin (r = -0.52. p = less than 0.001) and with percentage of hemoglobin S (r = 0.51. p less than 0.001). but not to the same extent with age. Echocardiographically assessed left ventricular function at rest was comparable to that of control subjects. These data suggest that the major cardiac abnormalities in children are related to the volume overload effects of chronic anemia. and that in this age group. there is no evidence for a distinct "sickle cell cardiomyopathy" or cardiac dysfunction.
Abnormal hemodynamic response to Valsalva maneuver in patients with atrial septal defect evaluated by Doppler echocardiography, Hemodynamic responses to the Valsalva maneuver were studied in eight healthy subjects (group 1) and eight patients with ASD (group 2) using Doppler echocardiography. The acute changes of aortic blood flow profiles during the Valsalva maneuver were investigated on a basis of beat-to-beat estimation. During the active strain phase (phase 2). group 1 showed a significant decrease in systolic blood pressure. SV and CO with reflex tachycardia; in group 2. there was a significant decrease in SV and CO with reflex tachycardia. but not systolic blood pressure. The percentage decreases in SV and CO in group 2 were significantly less than those in group 1 (23 +/- 16 percent vs 48 +/- 10 percent for SV. p less than 0.01; 17 +/- 12 percent vs 40 +/- 13 percent for CO. p less than 0.05). After release of strain phase (phase 4). group 1 showed significant reversed changes in systolic blood pressure. SV and heart rate. indicating an overshoot effect which was. however. not observed in group 2. Thus. patients with ASD presented abnormal Valsalva response which was characterized by the absence of phase 4 overshoot and a less marked phase 2 change. The findings suggest that the decremental effect of impaired venous return on stroke output during active strain may be attenuated by the increased pulmonary blood volume due to left-to-right shunt. In patients with ASD. the lesser decrement of CO during phase 2 may not provoke sufficient sympathetic activity to induce overshoot response in phase 4.
Real and pseudo late asthmatic reactions after submaximal exercise challenge in patients with bronchial asthma. A new definition for late asthmatic responses after exercise challenge, The late asthmatic reaction after exercise challenge remains a controversial issue. In this study. 21 patients recorded peak expiratory flow rate (PEFR) on two control days without performing exercise. There was no difference between both control days when PEFR at 1 h was compared with baseline PEFR and when PEFR at 4 to 13 hours was compared with baseline PEFR. After analyzing variation coefficients of baseline PEFR on a control day and exercise day. PEFR was not allowed to differ more than 15.3 percent in the same patient when comparing exercise day and control day for the late fall in PEFR in the study. In 17 of 81 patients. a late asthmatic reaction after exercise challenge was present when PEFR fall was greater than or equal to 20 percent compared with baseline PEFR value. In eight of the 17 patients. a real late asthmatic reaction to exercise challenge was present with a PEFR fall greater than or equal to 20 percent on at least three successive time points and who had a PEFR fall greater than or equal to 20 percent compared with corresponding clocktime on a control day. The late asthmatic reaction to exercise challenge is characterized not as a nonspecific epiphenomenon. but as a fall in PEFR of greater than or equal to 20 percent compared with baseline PEFR value and with corresponding clocktime on a control day on at least three successive time points. Graphic illustration of airway responses following exercises may facilitate the detection of a late asthmatic response.
Hemodynamic status in critically ill patients with and without acute heart disease, Physicians have been urged to reduce the use of the pulmonary artery catheter. However. there are no guidelines to help the clinician make the decision to use or withhold invasive monitoring in the individual patient. This study was designed to examine the accuracy of physician estimates of cardiac function in a spectrum of patients with hemodynamic instability to determine whether differences in accuracy among subgroups would suggest subgroups of patients who could be managed without invasive measurements. Physician estimates of cardiac index were found to be sufficiently accurate in patients without acute heart disease that initial management without invasive monitoring may be appropriate in selected cases. However. due to the general inaccuracy of physician estimates. efforts to improve the accuracy of clinical judgments of cardiac function and hemodynamic status should be pursued with vigor in patients both with and without acute cardiac dysfunction.
Systemic hemodynamic and cardiac function changes in patients undergoing orthotopic liver transplantation, The objective of this study was to determine the changes in systemic hemodynamics (systemic vascular resistance [SVR]. cardiac output [CO]. systemic blood pressure [SBP]) and cardiac function (pulmonary artery pressure [PAP] and pulmonary wedge pressure [PWP]) during the 96 hours following orthotopic liver transplantation (OLT) and correlate these with changes in hepatic and renal function and patient outcome. The study took place in a 12-bed medical respiratory intensive care unit in a large teaching hospital. Twenty-one patients had OLT performed over a 21.5-month period (January 1988 to October 15. 1989) for end stage liver disease (ESLD) from a variety of causes. A flow-directed right heart catheter and an indwelling arterial cannula were inserted for hemodynamic monitoring over a 96-hour postoperative period. Liver and renal function studies. total serum calcium. serum albumin. and fluid balance were determined daily. The SVR increased significantly to 12.8 +/- 0.6 U at 48 hours compared with immediate (less than 8 hours) postoperative levels (p less than 0.05) and remained elevated for 96 hours. The CO fell progressively and was significantly lower than baseline values from 64 to 96 hours. There was significant inverse correlation between the increase in SVR and the fall in CO (r = .85. p less than 0.01). The SBP was stable except for a small. but significant fall at 16 and 24 hours postoperatively. The PWP increased significantly from a baseline value of 12.5 +/- 0.9 mm Hg to 15 +/- 0.9 mm Hg at 32 hours and remained elevated through 96 hours (p less than 0.05). The serum bilirubin level fell progressively postoperatively and the prothrombin time and partial thromboplastin time (PTT) shortened significantly. Bile flow increased progressively from 107 +/- 120 ml/24 hours at the end of the first 24 hours to 188 +/- 125 ml/24 hours by 96 hours postoperatively. Five patients died from nine to 43 days postoperatively. These patients' hemodynamic parameters were not significantly different from the patients who survived. Successful OLT is associated with a rapid increase in SVR and a fall in CO without changes in SBP. These findings tend to parallel the improvement found in results of liver function tests. However. there is no correlation between the improvement in the hemodynamic state and long-term survival.
Permeability pulmonary edema following lung resection, The etiology of edema associated with pulmonary resection was investigated in five patients during the immediate postoperative period. Three patients received pneumonectomy while two patients had one lobe resected. All patients suffered from severe respiratory distress and had x-ray evidence of diffuse interstitial pulmonary edema within 12 hours of surgery. Hemodynamic data were obtained with radial and pulmonary artery catheters. Edema fluid was obtained along with blood samples for simultaneous determination of protein and albumin content. All patients studied had normal or high cardiac output. normal cardiac filling pressures. and edema fluid protein to serum protein ratio of 0.6 or greater suggestive of permeability changes contributing to edema fluid accumulation. Calculated shunt fraction exceeded 25 percent in all patients. Pulmonary edema has been noted in patients following pulmonary resection in the early postoperative period. In patients reviewed here. two factors appeared to be significant. First is an increase in pulmonary capillary pressure associated with passage of a normal to high cardiac output in a reduced volume pulmonary vascular bed. The second factor. as demonstrated by protein content in the edema fluid. is injury to the alveolar capillary membrane.
Measuring crackles, Crackles heard on auscultation can be represented graphically as a time-amplitude plot of the associated waveform. To assess the relative merits of several measures which might be considered for machine implementation in diagnostic instruments. we compared the reproducibility of those based on the initial voltage deflection which begins a crackle with those based on the largest deflection. The latter group showed less interobserver and less intraobserver variability when the same crackles were measured twice by each of two observers. Crackles from a teaching tape. categorized as fine and coarse. were used in this study. The ability of the various measures tested to distinguish between fine and coarse crackles on an individual basis was assessed and found to favor the measures based on the largest deflection. They showed an average of 9.96 percent incorrectly classified crackles. as opposed to 19.53 percent for the two measures based on the initial deflection.
Pulse oximetry. Uses and abuses, Pulse oximetry has made a significant contribution to noninvasive monitoring in a wide variety of clinical situations. It allows for continuous reliable measurements of oxygen saturation while avoiding the discomfort and risks of arterial puncture. As the extent of hypoxic episodes during various procedures and clinical settings is better appreciated. the role of continuous noninvasive monitoring will undoubtedly expand. An understanding of the principles and technology of pulse oximetry will allow physicians to obtain maximal clinical benefit from its use.
Rapid percutaneous tracheostomy, We describe a new method of performing percutaneous tracheostomy rapidly and safely using a specialized instrument kit. The technique permits the safe insertion of a full-sized 7.0 (ID) or 7.5 mm (ID) cuffed cannula into the trachea within 1-2 min. through the membranous second intercartilagenous space. Animal studies have demonstrated a superior healing process compared to that seen after conventional tracheostomy techniques.
A randomized trial comparing direct current therapy and bipolar diathermy in the outpatient treatment of third-degree hemorrhoids, Fifty patients with third-degree hemorrhoids were randomized to receive outpatient treatment with either bipolar diathermy or direct current therapy. Direct current therapy was used to treat 26 patients and bipolar diathermy was used to treat 24 patients. Twenty patients in each group were successfully treated as judged by resolution of symptoms and shrinkage of hemorrhoidal tissue. Both treatments are effective in the outpatient management of large. prolapsing hemorrhoids. Bipolar diathermy is less time consuming and better tolerated.
Survival in patients with large-bowel cancer. A population-based investigation from the Melbourne Colorectal Cancer Study, Five-year survival data were obtained in 97 percent or 1105 of 1140 new patients with histologically confirmed colorectal adenocarcinoma during a 12-month period in 1981 and 1982. as part of a large comprehensive population-based study of colorectal cancer incidence. etiology. and survival. The Melbourne Colorectal Cancer Study. Fifteen percent of patients were Dukes' A stage. 32 percent were Dukes' B. 25 percent were Dukes' C. and 29 percent were Dukes' D. At five years after diagnosis. the observed survival rate was 36 percent and the adjusted rate was 42 percent. Dukes' staging was a highly discriminating factor in survival (P less than 0.001). Survival rates were better in women than in men and better for patients with colon cancer than for patients with rectal cancer. Survival by Dukes' staging was not affected by colon subsite or by the tumor being the first and single tumor. metachronous tumor. or synchronous tumor. The survival of younger patients was better for Dukes' stages A. B. and C. and worse for Dukes' D. Survival was worse in the presence of bowel perforation in Dukes' C and D stages. Within Dukes' D (incurable cases). survival was best in the absence of hepatic metastases. slightly worse when only hepatic metastases were present. and poorest in the presence of both hepatic and extrahepatic metastases. Statistical modeling of survival determinants other than staging indicated that cell differentiation had the largest effect (survival decreasing with poor cell differentiation). followed by site (survival worse for rectal cancer than colon cancer). then age (survival better for younger patients). while bowel perforation had the smallest effect on survival.
Enteroglucagon and peptide Y-Y response after construction of a pelvic reservoir in humans, The results of an investigation of plasma levels of gastrointestinal hormones in patients after the construction of a pelvic reservoir are reported. Enteroglucagon (EG) and peptide tyrosine-tyrosine (PYY). two hormones believed to play a relevant role in the adaptive response to bowel resection. were investigated using a specific radioimmunoassay in basal conditions and after a standard meal. Pouch patients showed a statistically significant increase in basal levels of both enteroglucagon and PYY compared with control subjects (P less than 0.02 and P less than 0.001. respectively). The response of enteroglucagon to food ingestion. evaluated by means of the total integrated response. was similar in patients and controls. Conversely. the response of PYY was significantly increased in pouch patients compared with control cases (P less than 0.02). Results of this investigation suggest that gut hormones may be involved in mediating the adaptive response of the intestine to pouch construction. Changes of gut peptides may explain. at least in part. the functional results observed after pouch construction.
Association of anterior ectopic anus and partial absence of levator musculature in a woman with impaired defecation. Report of a case, A 25-year-old nulliparous woman with adult onset constipation and slight anterior displacement of the anus underwent pelvic magnetic resonance imaging and was diagnosed with congenital hemiabsence of the levator ani sling. Impaired defecation was confirmed by anorectal function studies and defecography demonstrated an anterior rectocele. perineal descent at the upper limit of normal. and partial obstruction of defecation. which appeared related to the levator sling abnormality. To our knowledge. this combination of findings has not been previously described as a cause of adult onset constipation.
Early gastric cancer. Endoscopic diagnosis of depth of invasion, In order to decide on a treatment strategy against gastric cancers. an accurate preoperative evaluation of the depth of cancer invasion is essential. Preoperative endoscopic diagnosis of the depth of invasion was compared with pathological results of the resected specimen in 206 early gastric cancers and 32 early-like advanced gastric cancers. The endoscopic distinction between early and early-like advanced cancers was correctly made in 83.6% of the cases. Among the early gastric cancers. mucosal and submucosal invasion was correctly presumed in 71.9% of the cases. When the tumor was an elevated type. or located in the antrum. the endoscopic diagnosis tended to be deeper than the true depth. The size of tumor contributed little to the depth diagnosis. Pathomorphological changes on the tips of converging folds were the important clue for diagnosing depth.
Evaluation of antral mast cells in nonulcer dyspepsia, Two hundred twenty-five patients with the symptoms of nonulcer dyspepsia underwent clinical and endoscopic evaluation including histologic assessment of endoscopic biopsies. Mast cells were counted after special staining with low pH Alcian blue. Of 225 patients. 31 (13%) were found to have 11 or greater mast cells per high-power field. Endoscopic and routine histologic findings were similar between the subset of 31 patients with 11 or more mast cells and the entire group of 225. The 31 patients with increased antral mast cells had failed treatment with standard drug used for peptic ulcer disease. H1-antagonists improved symptoms in the majority of patients (79%) in whom we had adequate follow-up. Patients with increased mast cells on antral biopsy appear to be subset of patients with nonulcer dyspepsia amenable specific treatment with H1-antagonists.
Morphological and biochemical changes in gastric mucosa of aging rats, Although previous data from this laboratory have indicated that aging is associated with increased gastric mucosal proliferative activity. no direct assessment of proliferative potential of the tissue has been made during aging. In order to assess this. and to determine whether changes in mucosal proliferative potential would be reflected in growth of the tissue. we have examined the labeling index (LI). height and morphology of the gastric mucosa in young (4-month-old) and aged (24-month-old) Fischer-344 rats. In addition. tyrosine kinase (Tyr-k) activity and the levels of phosphotyrosine proteins were determined to evaluate their relationship to mucosal proliferative activity. Histologic evaluation revealed a marked atrophy of the mucosal glandular component with 32% reduction in height in aged rats when compared with young animals. In aged rats. there was also a decrease in gland density. resulting in a reduction in the number of epithelial cells of all types with evidence of decreased secretory activity. Despite the occurrence of mucosal atrophy in aged rats. LI in these animals was significantly increased by 28%. This was associated with a parallel rise in mucosal Tyr-k activity. and a two- to threefold increase in the relative concentrations of seven phosphotyrosine membrane proteins with Mr of 120. 105. 90. 60. 55. 48 and 32 kDa. We conclude that (1) although aging is associated with increased gastric mucosal proliferative activity. this does not result in mucosal growth and that (2) Tyr-k and tyrosine phosphorylation of certain proteins play a role in the regulation of gastric mucosal cell proliferation during aging.
Cholecystokinin stimulates growth of human pancreatic adenocarcinoma SW-1990, The effect of a synthetic analogue of CCK (Thr4.Nle7CCK-9) on growth of SW-1990 human pancreatic cancer was examined in two experimental models. Nude mice bearing SW-1990 pancreatic cancer xenografts were injected with CCK (5. 15. or 25 micrograms/kg) or vehicle twice daily for 20 days. Animals were then sacrificed and tumor volume. weight. protein. and deoxyribonucleic acid (DNA) content were evaluated. SW-1990 cells were grown in vitro and the effects of CCK. secretin. vasoactive intestinal peptide (VIP). and proglumide (a CCK-receptor antagonist) on cell number and DNA synthesis were determined. The highest dose of CCK. 25 micrograms/kg. significantly increased tumor weight. protein content. and DNA content (P less than 0.005). In vitro. CCK caused significant increases in cell counts of up to 47% at six days and 66% at 12 days compared to control. Graded concentrations of CCK had a biphasic effect on DNA synthesis with significant increases of up to 65% (P less than 0.005). CCK-induced cell proliferation was inhibited by proglumide. Secretin slightly increased cancer cell growth. although not as potently as CCK. VIP or secretin in combination with CCK did not show potentiation. These results indicate that growth of some human pancreatic cancers may be influenced by gastrointestinal peptides. of which CCK is the most potent.
Effect of race upon organ donation and recipient survival in liver transplantation, The effect of the race of the donor on organ donation and on the outcome of clinical liver transplantation has not been addressed previously. The aims of this study were to determine: (1) the number of organs donated by each of the major racial groups of the United States. (2) the outcome of transplantation of these organs across racial groups. and (3) the pattern of liver disease that required transplantation in each of these racial groups. A significantly higher proportion of organs were donated by white non-Hispanic Americans than either black or Hispanic Americans. There was no significant difference in survival when an organ was transplanted between black and white Americans and vice versa. Postnecrotic cirrhosis from a variety of causes was the most common indicator affecting black and white recipients. while primary biliary cirrhosis and primary sclerosing cholangitis were uncommon in the black population. While the number of organs donated by blacks was low. it was. however. proportional to the number of black recipients in this study. Reasons for the low rate of donation by the black and white Hispanic population are discussed. It is concluded that race is not a criteria to be used in selection of donors for liver transplantation. Educational programs addressing issues of organ donation and transplantation directed towards the black and Hispanic populations are recommended.
Short-term effect of hepatic arterial versus portal venous reperfusion on energy levels of liver tissue, The hepatic artery and the portal vein blood vary in flow. oxygenation. and hormonal content. It was uncertain which blood supply has a greater effect on the recuperative process of the hepatocytes in the ischemic liver during the initial reperfusion. The ability of the liver cells to restore its energy phosphates is related to the viability of the liver. This study was designed to determine the differences of the high energy phosphate in the liver predicated upon whether reflow was first provided by either the hepatic artery or the portal vein followed by subsequent reperfusion from both vessels. The recovery of ATP upon 10 min of only hepatic arterial reperfusion after 15 min of total ischemia was much slower compared to the portal venous reperfusion only. It may be undesirable. therefore. to reperfuse the liver with hepatic arterial blood first immediately after warm liver ischemia.
Cirrhosis of the liver. A risk factor for development of cholelithiasis in males, An ultrasonographic study about the prevalence of cholelithiasis was performed in 410 cirrhotic patients and in 414 controls matched for age and sex. Gallstone disease was found more often in cirrhotic patients (31.9%) than in controls (20.7%) (P less than 0.001). The female-to-male ratio of gallstones prevalence in cirrhotic patients approached to 1:1. Gallstone disease in cirrhotic patients vs controls was significantly higher (30.2% vs 16.5%) (P less than 0.001) in males only. No difference was found. for gallstone disease prevalence in cirrhosis of different etiology. The prevalence of cholelithiasis increased from Child's A to Child's C with a significant trend (P less than 0.001); this difference was significant in males (12.3% vs 40.5%) (P less than 0.001) but not in females. This study shows that cirrhosis represents a risk factor for the development of cholelithiasis in males. We suggest that high levels of estrogens could play a role in these patients. by an impairment of gallbladder emptying similar to that observed in pregnant women.
Corticosteroid treatment reduces mast cell numbers in inflammatory bowel disease, Mast cell degranulation in the gut causes mucus secretion. mucosal edema. and increased gut permeability and may be responsible for some of the symptoms and signs of inflammatory bowel disease. We have used a novel monoclonal antibody (AAI) against tryptase expressed exclusively in the granules of mast cells to enumerate mast cells in rectal biopsies in order to study the effect of inflammatory bowel disease and drug treatment upon rectal mast cell numbers. Rectal mast cell numbers are significantly reduced in inflammatory bowel disease patients taking corticosteroids (mean 4.95 cells/mm2) when compared with control patients (10.1. P less than 0.001) and inflammatory bowel disease patients not taking corticosteroids (9.7. P less than 0.001 Wilcoxon rank sum test). The reduction in mast cell counts was independent of the degree of inflammation or architectural distortion. There was a negative correlation between the dose of corticosteroids and mast cell count (r = 0.53. P less than 0.05 Spearman rank correlation). and the mast cell count was reduced within a few days of treatment and remained low throughout steroid therapy. Mucosal mast cell depletion may be an important mechanism of action of corticosteroids in inflammatory bowel disease.
Prospective study of alcohol intake and large bowel cancer, The alcohol intake of a cohort of Japanese men in Hawaii is directly and significantly related to the risk of developing rectal cancer. whether assessed on the basis of amount consumed or as a percent of total calories. Wine and whiskey are directly related to rectal cancer. but beer is the only alcoholic beverage that displays a statistically significant dose-response (P = 0.008). Colon cancer risk also is related directly to alcohol intake. but the association is statistically significant only when measured as a percent of energy intake. This suggests that alcohol might displace cancer inhibitors from the diet. Calcium. vitamin C. and dietary fiber are inversely related to colon cancer risk in this cohort. and each of these micronutrients displays statistically significant negative correlation with alcohol intake. A possible positive association between alcohol and lung cancer was ruled out after adjusting for cigarette smoking. Cancers of the prostate and stomach were unrelated to alcohol intake. but the risk of acquiring cancer at all other sites combined was strongly related to alcohol intake.
Diagnosis of metastatic lesions to the stomach by salvage cytology. A report of three cases, Secondary neoplasms of the stomach are rare and are often clinical and diagnostic problems. Three patients with bleeding "volcano-like" ulcers were diagnosed by combined endoscopic "salvage" cytology and surgical biopsy as having metastatic submucosal lesions from hematologic spread. The combination of endoscopic appearance. clinical findings. and tissue and cytologic examination can lead to the correct diagnosis. The results from these cases support the utility of this cytologic technique in combination with biopsy in this clinical setting.
Primary non-Hodgkin's T-cell lymphoma of the esophagus. A case with peculiar endoscopic ultrasonographic pattern, We report a case of primary esophageal non-Hodgkin's T-cell lymphoma in a young white female. At admission. endoscopy revealed large. irregularly shaped. esophageal ulcerations with super imposed candidiasis. Endoscopic ultrasonography to assess submucosal alterations and periesophageal involvement revealed a diffuse hypoechogenic thickening (up to 5 mm) of the esophageal wall. a pattern consistent with lymphomatous infiltration. Definitive diagnosis was made with the aid of histology and immunohistochemistry.
Insulin use in NIDDM. Rationale based on pathophysiology of disease, Because basal hyperglycemia is a major feature in non-insulin-dependent diabetes mellitus. diabetes control can be monitored by the fasting blood glucose concentration. A hierarchical sequence of therapies is proposed in which the major aim is to maintain near-normal fasting blood glucose concentrations. in the expectation that this will help prevent development of long-term complications. When diet and tablet therapy are no longer effective in keeping the fasting blood glucose level less than 6 mM. a basal insulin supplement from a long-acting insulin such as ultralente can be added. When monitored by fasting blood glucose concentration. there is little risk of hypoglycemia. and the patient can continue a normal life-style without restrictions concerning exercise or the size of individual meals. A basal insulin supplement does not induce marked weight gain. The dose of insulin required can be predicted from the level of the fasting blood glucose and the degree of obesity. which provides an index of the accompanying insulin resistance. Based on current evidence. insulin therapy is equally appropriate in patients with insulin deficiency and insulin resistance. because the benefit from maintaining near-normal glucose concentrations probably outweighs a putative risk of hyperinsulinemia. In more severely affected patients. additional regular insulin to cover meals is needed. Lowering fasting blood glucose to normal with a basal insulin supplement reduces endogenous insulin production. and this may be advantageous if accompanying production of islet amyloid polypeptide and islet amyloid formation are also reduced.
Insulin administration via liposomes, Liposomes have been used in insulin therapy as a means to selectively target insulin to the liver. enhance oral absorption of insulin. and prolong insulin action. Liposomes are an effective means of delivering insulin specifically to hepatocytes. The usefulness of hepatically targeted liposomes in the treatment of diabetes is restricted due to the requirement that they be given intravenously. the dilute concentration of insulin present in liposomal preparations. and the cost associated with liposome production. Encapsulating insulin in liposomes results in enhanced oral absorption of insulin. The high doses of liposome-entrapped insulin required perorally. coupled with extreme variability in the glycemic response to peroral liposomes. limits the value of peroral liposomal insulin as a viable diabetic therapy. Insulin action can be sustained via encapsulation of insulin in liposomes given subcutaneously. Most insulin appears to remain at the injection site. and the presence of a lipid matrix for subcutaneous insulin delivery raises concerns over enhanced antigenicity of liposomal insulin given subcutaneously. Viewed in the light of the limitations outlined above. the contribution of liposomal insulin to understanding and treatment of diabetes mellitus will probably be via use of hepatically targeted liposomes as a pharmacological probe to decipher the role of the liver in the metabolic complications associated with diabetes mellitus.
Monomeric insulins and their experimental and clinical implications, Due to the inherent pharmacokinetic properties of available insulins. normoglycemia is rarely. if ever. achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors. among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that. because of more rapid absorption. are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay). ranging from 0.05 to 600% relative to human insulin. were strongly correlated (r = 0.97). In vivo. most of the analogues exhibited approximately 100% activity. explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus. an analogue with reduced binding and clearance gives higher circulating concentrations. counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects. rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly. a more rapid rise in plasma insulin concentration and an earlier hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast. two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results. the effects of insulin concentration. injected volume. temperature. and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS).
Devices for insulin administration, There is a significant need for revised. safe. and more effective insulin-delivery methods than subcutaneous injections in the treatment of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes. The aim of this review is to describe the rationale and methods for better use of injection and infusion devices for intensive insulin therapy and to describe results of animal and human research that will lead to an implantable artificial pancreas. Injection devices. e.g.. jet injectors. insulin pens. and access ports. cannot be considered as a major breakthrough in the quest for improved control. although they may improve the patient's comfort. External pumps have benefits over multiple injections and conventional insulin therapy only in specific subgroups of patients. e.g.. those with recurrent severe hypoglycemia. but only when used by experienced personnel. The external artificial pancreas (Biostator) is also to be used by experienced personnel for limited clinical and research applications. e.g.. surgery of the diabetic patient. The development of an implantable version of the artificial pancreas is linked to progress in the field of reliable long-duration glucose sensors. Finally. programmable implantable insulin pumps. used as an open-loop delivery system. are the most promising alternative to intensive subcutaneous insulin strategies in the short term. although clear evidence of improved safety and efficacy remains to be documented.
Role of insulin in management of surgical patients with diabetes mellitus, Because surgery is a likely event during the lifetime of patients with diabetes. health-care team members need to be aware of the metabolic problems that may occur during the perioperative period. Surgery. especially in the presence of general anesthesia. will produce a diabetogenic response. This is generally due to an elevation of counterregulatory hormones. although endogenous insulin is also suppressed. The excessive lipolysis and ketogenesis that can occur during surgery can have particularly deleterious effects for patients with diabetes. Thus. sufficient insulin must be provided during this period to suppress these catabolic processes. The major controversy regarding surgery and diabetes concerns the route of insulin administration. This article reviews the various treatment options for patients with insulin-dependent and non-insulin-dependent diabetes mellitus. with particular emphasis on the role of insulin. Special situations. e.g.. outpatient surgery. coronary artery bypass. and emergency surgery. are also discussed.
Natural history of beta-cell dysfunction in NIDDM, Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance and beta-cell dysfunction. This review focuses on the beta-cell. what defects occur when and why. Two major anatomic observations have been made in NIDDM. The beta-cell mass is mildly reduced. especially when obesity is taken into account. Also. amyloid deposits are frequently observed in the islets. It is unclear whether these changes are genetically mediated or result secondary to the loss of glucose homeostasis. Many studies have looked at some aspect of insulin secretion in NIDDM. and two types of distinct abnormalities have been described. Early on. there is a marked disruption in pulsatile insulin delivery. which is potentially an important contributor to the insulin resistance. It is unclear whether the loss of pulsatile delivery is acquired or genetically induced. Later. after glucose intolerance has started. several other secretory abnormalities develop coincident with loss of beta-cell glucorecognition. The net result is further deterioration in timing of insulin delivery and postprandial hyperglycemia. A second important consequence of the glucose blindness is that the inherent compensatory beta-cell mechanisms that guard against hyperglycemia are bypassed. We propose that the loss of glucose responsiveness is a direct result of an elevated glucose concentration (so-called glucotoxicity) and have generated substantial data in rat models that support this idea. The logical conclusion is that beta-cell function in NIDDM can be maximized by achieving the best metabolic control possible.
Acute intoxication, Acute alcohol intoxication is a commonly encountered clinical presentation in Emergency Medicine. Its role should be considered in many Emergency Department presentations. specifically in major and minor trauma. and in gastrointestinal. metabolic. neurologic. and psychiatric disorders. The differential diagnosis of change in mental status must be considered in all intoxicated patients. Management of intoxicated patients is generally supportive although complications of chronic alcoholism should be considered. Management should consist of correction of complications resultant from intoxication. as well as observation and the provision of a safe environment for the patient during the recovery phase of acute intoxication.
Alcohol withdrawal syndromes, Current studies have begun to elucidate the pathophysiology of alcoholism and its withdrawal syndrome. Newer benzodiazepines. beta-blockers. alpha-agonists. butyrophenones and calcium channel blocking agents. alone and in combination. have been studied recently in alcohol withdrawal. This article discusses evaluation and therapy for delirium tremens. major alcohol withdrawal. mild alcohol withdrawal. adjunct therapy. and admission criteria.
Pancreatitis, Pancreatitis is a common but rather poorly understood entity most often associated with alcohol abuse or biliary tract disease. Despite the availability of a variety of diagnostic tests and imaging techniques. the diagnosis of pancreatitis continues to be primarily a clinical one. Of major concern to the emergency physician is distinguishing pancreatitis from other. potentially lethal. causes of abdominal pain. and identifying those patients with severe pancreatitis who are at risk for a complicated course secondary to the remote systemic effects of the disease.
Alcoholic liver disease, Alcoholic liver disease presents a wide spectrum of clinical manifestations ranging from mild asymptomatic fatty liver to alcoholic hepatitis and severe life-threatening liver failure with ascites. hemorrhaging esophageal varices. and encephalopathy. Although still poorly understood. the mechanism of this injury is probably the result of numerous direct toxic and metabolic effects of alcohol on the hepatocyte. Therapy consists primarily of abstinence and supportive care. However. several newer treatments are actively being studied. These include prednisolone. anabolic steroids. glucagon and insulin. propylthiouracil. and cyanidanol. Colchicine is promising as an agent to inhibit fibrosis. Complications of cirrhosis. including ascites and variceal hemorrhage. are the result of end stage disease. A return to old techniques of ascitic fluid management suggests that therapeutic large-volume paracentesis with albumin infusion is a safe and effective form of therapy. Variceal hemorrhage is best treated with sclerotherapy. vasoconstrictors. and balloon tamponade. Little has been done to alter the ultimately dismal prognosis and long-term survival of alcoholic liver disease.
Alcoholism and society, The problems of alcohol abuse are rampant in society and permeate the Emergency Department experience. The cost to society as measured by social. medical. occupational. and legal effects is exceedingly high and probably underestimated. Emergency physicians have the opportunity to intervene in this vicious cycle and must learn their role in the process.
The other alcohols. Methanol, ethylene glycol, and isopropanol, The alcoholic patient. in an attempt to maintain an altered mental status. may ingest ethanol substitutes containing methanol. ethylene glycol. or isopropanol. The subsequent clinical presentation in the Emergency Department is highly variable and depends on the ethanol substitute ingested. the time since ingestion. and concomitant ethanol abuse. This article describes the clinical features of intoxication by the ethanol substitutes. Early diagnosis and therapeutic intervention may prevent irreversible sequelae. The rationale for treatment interventions is discussed.
Alcohol and trauma, Countermeasures to alcohol-related trauma are essential. The public perception that there is low risk of detection and punishment for alcohol-precipitated violence is being addressed. Current legislation is aimed at decreasing the availability of alcohol (e.g.. adjusting legal drinking age. decreasing the serum alcohol intoxication limit. restricting the sale of alcoholic beverages at public events). increasing detection (e.g.. greater driver surveillance. increased number of dedicated personnel). strengthening legal penalties for alcohol-related offenses. and mandating rehabilitative therapy. Physicians can intervene in the alcohol-trauma cycle. Unfortunately. they are notably poor in detecting the patient with alcohol-related injury. Moreover. physicians infrequently refer these patients to facilities and personnel that are expert in alcohol detoxification and rehabilitation. Recidivism can be positively impacted by physicians who are sensitive to and versed in the medical and social patterns of alcohol abuse.
Anionic complex-carbohydrate units of human thyroglobulin, Human thyroglobulin (hTG) contains sulfate in chondroitin 6-sulfate chains and in complex carbohydrates. In this study the sulfate-containing complex carbohydrates were characterized by the number of sulfate and sialic acid residues that they contain. Samples of normal and nodular thyroid tissue were incubated for 16 h in [35S]sulfate-containing medium. and hTG was purified from the tissues and the media. Complex carbohydrates were enzymatically removed from hTG. Subsequent analysis on an HPLC anion exchange column at pH 2.2 separated the carbohydrate units according to their number of negative charges. Sulfate-containing peaks were monitored by radioactivity. and sialic acid-containing peaks were identified by their shift to lower charge after treatment with neuraminidase. Peaks corresponding to sialic acid-free carbohydrate units with one to four sulfates were identified. Also. carbohydrate units with two and three negative charges containing both sulfate and sialic acid were present. In the nodular tissue of one patient there were more sulfated units with higher charge. especially units containing sialic acid. In this patient the proportion of sulfated polyvalent units with sialic acid was 22.4% for normal and 64.6% for nodular tissue. No difference in the composition of the charged units between the tissues and their corresponding media was seen. making it unlikely that the sulfate-containing carbohydrates play a role in hTG release. It is concluded that hTG contains complex carbohydrate units with up to four sulfate groups and units with both sulfate and sialic acid. In some patients. the sulfate-containing anionic carbohydrate units of hTG from normal and nodular thyroid tissue are different.
Intercellular propagation of individually programmed growth bursts in FRTL-5 cells. Implications for interpreting growth factor actions, Five methods are commonly used to quantify FRTL-5 cells' and other thyrocytes' growth in vitro and the impact of growth inhibiting or stimulating maneuvers: Total cell count. mitotic index. DNA measurement. total [3H]thymidine incorporation. and the fraction of [3H]thymidine labeled cells. All of them assess cell growth as though all cells were homogeneous with an identical response to growth factors. We demonstrate here that this assumption is not valid. Rather. some intrinsically growth-prone cells appear to pass a growth signal to neighboring cells so that variably sized colonies of synchronized cells within each cluster growing from monodispersed cells are formed. This is true for FRTL-5 cells growing in vitro in monolayers and in three-dimensional. collagen embedded spheroids. The pattern is the same when cell suspensions or collagen-embedded spheroids are implanted onto nude mice. Patches with alternating high and low growth become particularly prominent in the large tumor-like organoids grown from monodispersed cells in nude mice. The pattern much reminds of similar observations in growing intact thyroids. Since there is no significant correlation between the fraction of [3H]thymidine labeled cells and the size of two- or three-dimensional clusters in any experiment. growth of signal-spreading cells is assumed to occur in leaps and bounds. Growth velocity in each subclone of a cell population depends on the mean interval between bursts of replications and on the number of cells synchronized by cell-to-cell diffusion of the growth signal emanating from one dividing cell. Thus. growth-promoting and growth-inhibiting factors may not only act on the mean interval between successive growth bursts. but they may also change cell-to-cell spreading of growth signals.
Alterations in phospholipase A2 activity during luteal regression in pseudopregnant and pregnant rats, The activity of phospholipase A2 was measured in microsomes prepared from ovaries of superovulated pseudopregnant rats during spontaneous and prostaglandin F2 alpha-induced regression and during regression in pregnant rats. Microsome samples were incubated at 40 C for 90 min in Tris buffer (pH 8.3) with 1.0 mM CaCl2 added. The substrate. radiolabeled phosphatidylcholine. was incorporated into liposomes. During spontaneous regression. there was a significant 2- to 4-fold increase in phospholipase A2 activity. when compared with levels at mid-pseudopregnancy (days 8-9). This elevation was correlated with a significant decrease in plasma progesterone concentration. On day 6 or 7 of pseudopregnancy. treatment of rats with luteolytic doses of prostaglandin F2 alpha also caused a significant increase in phospholipase A2 activity. which remained elevated throughout the 72-h sampling period. In pregnant rats there was a small but significant rise in phospholipase A2 activity after parturition. These results indicate that the activity of phospholipase A2 increases during luteal regression in pregnant and pseudopregnant rats and that it could be involved in the mechanism that causes the loss in progesterone secretion.
Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse, The op/op variant of murine osteopetrosis is a recessive mutation characterized by impaired bone resorption due to lack of osteoclasts. Cultured osteoblasts and fibroblasts from this mutant do not secrete M-CSF activity and resident macrophages are absent in bone marrow. This failure has been related to a mutation within the M-CSF coding region. We report now that the administration of recombinant human M-CSF (rhM-CSF) corrects in vivo the impaired bone resorption in this animal. The treatment restores the bone marrow cavity virtually absent in the op/op animal and induces the appearance of resorbing osteoclasts and of resident bone marrow macrophages. This proves that the deficiency of M-CSF is the cause of the op/op bone disorder and that this cytokine is directly or indirectly necessary for physiological osteoclastogenesis. the resulting bone resorption and for the establishment of bone marrow hemopoiesis.
Anatomical, physiological, and theoretical basis for the antiepileptic effect of vagus nerve stimulation, The vagus is a mixed nerve carrying somatic and visceral afferents and efferents. The majority of vagal nerve fibers are visceral afferents and have a wide distribution throughout the central nervous system (CNS) either monosynaptically or via the nucleus of the solitary tract. Besides activation of well-defined reflexes. vagal stimulation produces evoked potentials recorded from the cerebral cortex. the hippocampus. the thalamus. and the cerebellum. Activation of vagal afferents can depress monosynaptic reflexes. decrease the activity of spinothalamic neurons. and increase pain threshold. Depending on the stimulation parameters. vagal afferent stimulation in experimental animals can produce electroencephalographic (EEG) synchronization or desynchronization and has been shown to affect sleep states. The desychronization of the EEG appears to depend on activation of afferent fibers that have conduction velocities of less than or equal to 15 m/s. Vagal afferent stimulation can also influence the activity of interictal cortical spikes produced by topical strychnine application. and either attenuate or stop seizures produced by pentylenetetrazol. 3-mercaptoproprionic acid. maximal electroshock. and topical alumina gel. The mechanisms for the antiepileptic effects of vagal stimulation are not fully understood but probably relate to effects on the reticular activating system. The vagus provides an easily accessible. peripheral route to modulate CNS function.
Feasibility and safety of vagal stimulation in monkey model, The feasibility. safety. and preliminary effects of chronic vagal stimulation were studied in an aluminagel monkey model. Pilot studies to perfect the equipment. determine stimulation thresholds. and insure the comfort and safety of the animals preceded this study. Four monkeys were equipped with an indwelling. 2-electrode cuff (titanium bands spaced 7 mm apart; silicone encased; 1.5 cm total length) in contact around the right vagus nerve; avoidance of the cardiac branch was confirmed by electrocardiograms. After postsurgical recovery. the intact and awake animals received constant-current stimulation (5 mA; 83 Hz. 143 Hz. or 50-250 Hz randomly; 0.5-ms pulse width) at the onset of every spontaneous seizure for the duration of the seizure or every 3 h for 40 s if stimulation had not occurred in the preceding hour. Stimulation periods of 2-6 weeks. with differing levels of stimulation. were preceded and followed by at least a 2-week baseline period of no stimulation. During the stimulation periods. the seizure rate decreased to zero in two monkeys and the interseizure intervals became invariable in the remaining two monkeys. These effects carried over temporarily into the poststimulation baseline periods. Vagal stimulation had no consistent effects on seizure severity or EEG interictal spikes. Histological studies of six vagus nerves were unable to separate electrode cuff damage from any direct effects stimulation may have had on the nerves. Although it appears that chronic vagal stimulation is feasible and that epileptogenic processes are influenced. the safety and efficacy of the procedure are still in question.
An implantable neurocybernetic prosthesis system, The neurocybernetic prosthesis (Cyberonics. Inc.) is an implantable. multiprogrammable pulse generator that delivers constant current electrical signals to the vagus nerve for the purpose of reducing the frequency and/or severity of epileptic seizures. The device is implanted in a subcutaneous chest pocket just below the clavicle. similar to cardiac pacemaker placement. The stimulation signal is transmitted from the prosthesis to the vagus nerve through a stimulation lead. The prosthesis can be programmed using any IBM-compatible personal computer with programming software and a programming wand. The electrodes used in the first group of patients were found to break at an unacceptable rate. Design modifications appear to have resolved this problem.
Surgical technique for implantation of the neurocybernetic prosthesis, The surgical technique for the implantation of the neurocybernetic prosthesis is described in detail. This procedure is straightforward and is easily carried out by surgeons familiar with carotid surgery.
Efficacy and safety of vagus nerve stimulation in patients with complex partial seizures, A clinical trial of chronic intermittent vagal stimulation in five patients suggests that the procedure may be safe and effective as adjunctive treatment of medically intractable seizures of partial onset. Patients tolerated well the implantation of the neurocybernetic prosthesis and the vagal stimulation without serious physiological or lifestyle changes. Stimulation of the vagus nerve either reduced the seizure frequency or decreased the duration or intensity of seizures. Adverse side effects were limited to a tingling sensation in the throat and hoarseness during stimulation. A major complication was mechanical interruption of the wire-electrode circuitry. with consequent cessation of stimulation. The small number of patients and the relatively short follow-up period make this a pilot study. but the results are promising.
Vagus nerve stimulation in humans: neurophysiological studies and electrophysiological monitoring, Evidence from studies of experimental animals indicates that electrical stimulation of the vagus nerve alters behavioral and electrographic seizure activity. We report on effects of electrical stimulation of the vagus nerve in five patients with medically intractable seizures as part of a clinical trial of chronic vagal stimulation for control of epilepsy. The mechanism of action of the vagal antiepileptic effect is unknown. and it is hoped that analysis of electrophysiological effects of vagal nerve stimulation will help elucidate which brain areas are affected. Stimulation of the left vagus nerve in the neck was accomplished with a programmable implanted stimulator. Effects of stimulus amplitude. duration. and rate were studied. Noncephalic reference recording of the vagus-nerve-evoked potential showed some unusual properties: a scalp negative component occurred with latency of 12 ms. very high amplitude (up to 60 microV). and widespread scalp distribution. Field distribution studies indicate that this potential is generated in the neck. in the region of the stimulating electrodes. Muscle paralysis confirms this observation. Stimulation at various frequencies had no noticeable effect on electroencephalographic (EEG) activity regardless of whether the patient was under general anesthesia. awake. or asleep.
Effects of vagal stimulation on experimentally induced seizures in rats, Repetitive stimulation of the vagus nerve inhibits chemically induced seizures in dogs. We report here the results and conclusions from studies designed to answer some of the immediate questions raised by this finding. (1) Maximal stimulation of vagal C fibers at frequencies greater than 4 Hz prevents or reduces chemically and electrically induced seizures in young male rats. (2) Antiepileptic potency is directly related to the fraction of vagal C fibers stimulated. (3) Vagal stimulation shortens but does not shut down a chemical seizure once it has begun. (4) In rats. optimal stimulus frequency is approximately 10-20 Hz; duration of stimulus. 0.5-1 ms; and stimulus strength. 0.2-0.5 mA/mm2 of nerve cross-section. These results. when taken together with similar results obtained from dogs. monkeys. and humans. strongly suggest that periodic stimulation of the vagus nerve using appropriate stimulation parameters is a powerful method for preventing seizures. The data from the literature suggest that the antiepileptic actions of vagal stimulation are largely mediated by widespread release of GABA and glycine in the brainstem and cerebral cortex. The probable pathway is via projections from the nucleus of the solitary tract to the reticular formation and thence by diffuse projections to the cortex and other areas. Intermittent vagal stimulation has the potentiality of reducing the number and/or the intensity of seizures in patients with intractable epilepsy. These results indicate that feasibility studies in humans should be continued and expanded.
The epilepsies: clinical implications of the international classification, From the earliest days of neurology. the classification of epileptic seizures into those generalized from the beginning and those with a definable localization in the cortex from the onset has added to knowledge about the function of the nervous system. Further elaboration of the classification of seizures into those localized to the six-layered isocortex and those whose elaboration involves regions of the brain involved with consciousness and memory has provided the basic focus for the burgeoning subspecialty of epilepsy surgery. It is increasingly apparent that the etiology of a seizure disorder is of at least equal or of greater significance than the nature of the seizures it spawns and is the product not only of localization in the nervous system but also of causative factors with implications reaching into areas of genetics. higher cortical function. and intelligence. The prognosis concerning the outcome of the epilepsy under consideration is based on all of these facets. This pathophysiological substratum. of which the seizure is only the presenting symptom. constitutes the epilepsy or epileptic syndrome on which the formulation of a rational treatment plan is based.
Current concepts of beta-endorphin physiology in female reproductive dysfunction, beta-Endorphin has a role in the regulation of the normal menstrual cycle and possibly in the onset of puberty. We have reviewed the evidence pointing to an alteration in this neuropeptide that may contribute to the pathogenesis of various reproductive dysfunctions. Elevated or high levels of beta-endorphin have been associated with exercise-associated amenorrhea. stress-associated amenorrhea. and polycystic ovarian syndrome. Depressed or low levels of beta-endorphin have been associated with PMS and menopause. Alterations in the levels of beta-endorphin may change the pulsatile release of GnRH via noradrenergic and/or dopaminergic pathways. We have primarily focused on beta-endorphin as representative of the endogenous opioid peptides. but other opioid peptides may also contribute to the pathogenesis of various types of reproductive dysfunction. Perhaps it will become possible to characterize and hone our understanding of the function of beta-endorphin and the other substances composing the endogenous opioid peptides. A better understanding of their role in physiological as well as pathophysiological processes may allow for the development of rational approaches to the treatment of specific disorders pertaining to reproduction. Many questions remain unanswered. Among the most relevant are: what is the precise mechanism of action by which beta-endorphin exerts its influence on pulsatile GnRH release? Is there a functional relationship between CNS and peripheral (serum) levels of beta-endorphin? Are the detected changes in beta-endorphin levels merely associated. or are they a cause of a particular disorder? Since it took almost 40 years between the time prostaglandins were first discovered and eventual realization of their clinical application. it may take some time before the beta-endorphin story is complete.
Further observations on the doubling time of human chorionic gonadotropin in early asymptomatic pregnancies, The doubling time (DT) of human chorionic gonadotropin (hCG) in serum was investigated retrospectively using serial serum hCG values that had been obtained from asymptomatic pregnant women with a prior history of infertility. The DT of hCG did not increase significantly as pregnancy advanced during the period in gestation when the serum hCG concentration was less than 10.000 mIU/mL (International Reference Preparation). Serum hCG concentrations increased subnormally in 2 of 60 women with normal intrauterine pregnancies. 5 of 8 women with asymptomatic ectopic pregnancies (EPs). and in 2 of 8 asymptomatic women who subsequently aborted their pregnancies. Neither the sensitivity nor the specificity of serial hCG testing for EP was enhanced by adopting different test criteria at different serum hCG concentrations.
Oocyte retention after follicle luteinization, Indirect evidence supports the existence of the luteinized unruptured follicle syndrome in infertile women. To seek direct evidence of oocyte retention. infertile and normal women were studied in the early and midluteal phase by visual documentation of ovulation stigma. needle aspiration of ovarian follicles. and peritoneal fluid collection for estradiol and progesterone assay. Luteal phase was confirmed by endometrial biopsy (postovulation day 2 to 8). In normal control subjects (n = 16). 25% of test cycles were stigma-negative and no oocytes were recovered. In infertile group (n = 23). 43% of test cycles were stigma-negative. Five oocytes were recovered including one from a stigma-bearing follicle. Peritoneal fluid steroid levels failed to discriminate stigma-positive from stigma-negative cycles in either group. Oocyte retention after luteinization occurs in infertile women.
Endocervical chlamydial deoxyribonucleic acid in infertile women, The presence of chlamydial deoxyribonucleic acid (DNA) was evaluated by DNA hybridization in endocervical cells of infertile and normal fertile women. Chlamydial DNA was detected in 49 of 186 (26.3%) infertile patients. which is significantly more common than in fertile control individuals (12.5%. or 8 of 64 individuals). Among infertile patients. 49.3% (33 of 67) of those with tubal factors as cause of infertility and 13.4% (16 of 119) of those with nontubal factors were found to contain chlamydial DNA in their endocervical cells. The results show that chlamydial DNA could be found significantly more frequently in endocervical cells of infertile patients with tubal factor than those without tubal factors or in normal controls.
Late onset adrenal hyperplasia: mutation at codon 282 of the functional 21-hydroxylase gene is not ubiquitous, Ten patients affected with 21-hydroxylase (21-OH) deficient late-onset adrenal hyperplasia were studied to determine the prevalence of a mutation at codon 281 of the functional 21-OH gene (CYP21B) that results in a valine to leucine amino acid shift. This mutation has been reported in eight unrelated late-onset adrenal hyperplasia patients of Ashkenazi Jewish descent possessing the human leukocyte antigen-B14.DR1 haplotype. Normally. there are two 21-OH genes; a pseudogene (CYP21A) and a functional gene (CYP21B). The aberrant codon 281 sequence is normally present only in CYP21A. In all of our late-onset adrenal hyperplasia patients. hybridization of an oligonucleotide probe specific for this mutation was demonstrated to CYP21A but not to CYP21B. The mutation at codon 281 of CYP21B does not appear to be a ubiquitous genetic marker for 21-OH deficient late-onset adrenal hyperplasia. suggesting that this disorder may demonstrate the same molecular heterogeneity as congenital adrenal hyperplasia.
The interaction of parameters of male and female fertility in couples with previously unexplained infertility, A prospective study was undertaken of the relationship between semen variables. serial endocrine and follicular ultrasound measurements in one complete menstrual cycle. and the treatment-independent chance of conception for couples who were referred with unexplained infertility. For the 91 couples studied. the mean length of infertility was 70 months. A 100% follow-up rate was achieved. When a stepwise analysis was performed examining semen variables and ultrasonographic and endocrine variables. the mean ratio of salivary progesterone/plasma estradiol between days +1 and +3. with respect to the luteinizing hormone surge and the Grade 2 motile sperm density. were the only variables that achieved the 5% level of significance. There was a highly significant relationship between the product of these two variables and the chance of conception. This study clearly demonstrates an interaction between parameters of male and female fertility.
Subzonal insemination for the alleviation of infertility, Methods were developed to facilitate the use of subzonal insemination to achieve fertilization in vitro. A clinical trial was undertaken in those patients having previously failed to achieve fertilization by in vitro fertilization. and in those presenting with severe oligospermia/oligoasthenospermia. From 85 patients. 585 oocytes were obtained. Of these. 0.3% had been "activated" parthenogenetically in vivo. 369 (72%) at metaphase II underwent subzonal insemination. 15% were fertilized. and 0.5% had three pronuclei. Thirty-eight percent of the patients had fertilization with 36% having a replacement. One conceptus was replaced in 19 patients. two conceptus in 8 patients. and three in 4 patients. A twin and two singleton pregnancies were established.
The role of tubal pathology and other parameters in ectopic pregnancies occurring in in vitro fertilization and embryo transfer, Contradictory findings were reported concerning the role of tubal disease in the genesis of ectopic pregnancy in in vitro fertilization and embryo transfer (IVF-ET). We report on six ectopics that occurred in 141 IVF-ET pregnancies (4.3%). All of the six cases were among 84 patients with tubal disease. and none occurred in the remaining 57 patients with other etiological factors. No correlation was found in other parameters including: ovulation induction. number of embryos transferred. and luteal support. A comparison between the ectopics and six matched controls demonstrated similar estradiol levels. but beta-hCG levels on day 15 to 17 after ET were lower. Homolateral salpingectomy was performed in all six cases. but a contralateral resection was carried out in three of them. More comprehensive studies are needed to clarify whether tubal pathology really increases the risk for ectopic gestation in IVF-ET.
Psychological assessment and follow-up after in vitro fertilization: assessing the impact of failure, The present study was conducted to assess the immediate psychological impact of failed in vitro fertilization (IVF). Emotional status and marital functioning were also examined pre-IVF. and both demographic information and psychological test scores were evaluated as predictors of reaction to treatment failure. After a failed first cycle. both males and females showed significant increases in anxiety and depressive symptoms. Although group means were not clinically elevated and most participants were coping adequately. the prevalence of both mild and moderate depression increased substantially. particularly among women. In addition. women without children were a subgroup particularly vulnerable to the stress of failure. Predisposition towards anxiety. pre-IVF depressive symptoms. and fertility history were the most important predictors of emotional response. Treatment implications of these findings were discussed.
A reverse (antibody capture) enzyme-linked immunosorbent assay for detection of antisperm antibodies in sera and genital tract secretions, A reverse (antibody capture) enzyme-linked immunosorbent assay (ELISA) for detection of antisperm antibodies has been developed. The assay enables detection of immunoglobulin (Ig) M. IgG. IgA. or IgM. IgG. and IgA--antisperm antibodies in serum. cervical mucus. and seminal plasma samples. The reverse ELISA is more specific and sensitive than conventional ELISA in detecting human antisperm antibodies of different isotypes. Using this assay. statistically significant differences in levels of antibodies between infertile and fertile individuals were demonstrated in sera and in genital tract secretions. Studies with 143 infertile couples revealed that the presence of antibodies in sera was not necessarily reflected in individual's genital tract secretion and vice versa. These data emphasize the importance of detecting antisperm antibodies in sera as well as in genital tract secretions for correct evaluation of sperm immunity.
Protein differences between normal and oligospermic human sperm demonstrated by two-dimensional gel electrophoresis, Protein expression by sperm obtained from men with normal semen analysis and men with oligospermia were evaluated by two-dimensional gel electrophoresis. Proteins were solubilized in a 9.5 M urea/2% Nonidet-P40 (LKB. Bromma. Sweden) lysis buffer and underwent second dimension separation on 10 to 16% polyacrylamide gradient gels. A set of 36 invariant proteins was identified in all normospermic samples. whereas 8 of 10 evaluable oligospermic samples lacked 1 or more of the invariant proteins. Proteins absent in oligospermic samples may be critical to normal sperm function and may serve as markers for infertility.
Pooled sequential ejaculates: a way to increase the total number of motile sperm from oligozoospermic men, We investigated the yield of total number of motile spermatozoa from oligozoospermic men by pooling two closely spaced sequential ejaculates. Semen characteristics were compared between sequential ejaculates (within a period of 1 to 4 hours) of 18 oligozoospermic males (sperm concentration less than 20 X 10(6)/mL and total sperm count less than 40 X 10(6) in the ejaculate) and a control group of 16 normozoospermic men. Whereas the median total number of motile sperm of normozoospermic males significantly decreased from 70 X 10(6) in the first ejaculate to 23 X 10(6) in the second sequential ejaculate. such a decrease was not detected in oligozoospermic males. 3.6 X 10(6) and 3.1 X 10(6). respectively. The percent of normozoospermic and oligozoospermic men who demonstrated a decreased (less than 50%). a comparable (50% to 150%). or an increased (greater than 150%) total motile sperm count in the second ejaculate in comparison with the first ejaculate were 69%. 31%. and 0 versus 39%. 28%. and 33%. respectively. Consequently. pooling of two sequential ejaculates significantly increased the median total number of motile sperm from normozoospermic males by 144% and from oligozoospermic males by 329%. (to 10.2 X 10(6]. We suggest that pooling of two sequential ejaculates from oligozoospermic males is a simple and cost effective method to increase significantly the total number of motile sperm for intrauterine insemination. in vitro fertilization. gamete intrafallopian transfer. or semen cryopreservation.
Studies on requirements for trackpoints in CellSoft automated semen analysis, The CellSoft (CRYO Resources. Ltd.. New York. NY) system for computer-assisted sperm analysis was evaluated as to the appropriate settings for trackpoints. Fifty-eight human spermatozoa exhibiting complex swimming modes were chosen for analysis at room temperature. The accumulated measures for curvilinear velocity. linearity. mean and maximum amplitude of lateral head displacement. and beat cross frequency were determined over a range of trackpoints from 2 to 37. Stable measures (within the 95% confidence interval at 37 frames) were observed at 4 frames for curvilinear velocity and at 20 frames for linearity. The corresponding figure for mean amplitude of lateral head displacement and beat cross frequency was 8 frames. We conclude that the frame requirements concerning measures for curvilinear velocity/linearity and mean amplitude of lateral head displacement/beat cross frequency should be 20 and 8. respectively. Thus. 20 consecutive frames to analyze will suffice.
Effect of serum from patients with minimal to mild endometriosis on mouse embryo development in vitro, Two-cell mouse embryos were cultured at 37 degrees C in 5% CO2. 95% air with a 7.5% serum supplement from patients with minimal to mild endometriosis. (group I. n = 31). tubal factor (group II. n = 33). male factor (group III. n = 17). fetal cord samples (group IV. n = 37). and Ham's F-10 medium (Gibco. Grand Island. NY) without a serum supplement (group V. n = 30). The progression to blastocyst stage (mean percent +/- SE) at 96 hours in groups I. II. III. IV. and V was 29.9% +/- 3.7%. 60.6% +/- 4.9%. 56.2% +/- 5.2%. 61.7% +/- 5.8%. and 63.2% +/- 6.9%. respectively. Serum factors appear to be associated with an inhibition of early embryogenesis. which may explain the decreased fertility rates observed in patients with minimal to mild endometriosis.
Peritoneal fluid fractions from patients with endometriosis do not promote two-cell mouse embryo growth, Peritoneal fluid (PF) from 10 infertile patients with endometriosis. obtained during the follicular phase of the cycle during laparoscopy. did not promote two-cell mouse embryo growth to the extent observed by fluid obtained from seven normal controls. Five molecular weight (MW) fractions were obtained by ultrafiltration. and each was used as media supplement in the assay and compared with PF fractions from normal controls. All fractions of PF from patients with endometriosis inhibited mouse embryo growth to a greater extent than did normal controls. However. the MW fractions greater than 100.000 daltons showed greater inhibition of embryo development than did fractions less than 100.000 daltons. This study of cell-free PF suggests the presence of a humoral factor greater than 100.000 daltons that is inhibitory on mouse embryo growth.
Retroperitoneal mobilization of the vas deferens in the complex vasovasostomy, Anatomic distances along retroperitoneal. inguinal. and infrainguinal segments of the vas deferens were measured in 14 formalin fixed cadavers and in 15 recently postmortem males. There were no significant differences in segment lengths between the two groups nor between the right and left vasa. Data from the recent postmortem group reveals a mean length of 5.83 +/- .65 cm to be gained from retroperitoneal mobilization of the vas deferens. This information is important to surgical decisions in cases of microsurgical repair of obstructive azoospermia resulting from damage to the inguinal segment of the vas deferens. Data on other vasal segment lengths is beneficial for planning repair in other complex cases of obstructive azoospermia as well.
Triplet tubal pregnancy treated by outpatient laparoscopic salpingostomy, To our knowledge. this represents the first case of a laparoscopically treated triplet EP and the first time that a double EP in the same tube was treated conservatively (with preservation of the tube). Multiple EPs may be more common than currently thought. and our report offers an alternative explanation for at least some cases of persistent EP after conservative surgical therapy. Finally. given the substantial cost savings and reduced postoperative recovery time associated with operative laparoscopy. when the patient is stable and the surgeon experienced. the laparoscopic approach should be tried. regardless of the number of EPs or their size.
Transient hyperprolactinemia is associated with a midcycle luteinizing hormone surge, This study demonstrates that LH surge cycles in IVF patients were associated with significantly higher serum PRL concentrations than cycles in which a spontaneous LH surge did not occur. Our findings support the hypothesis of concomitant LH and PRL release at the time of the midcycle gonadotropin surge. as well as that of estrogen sensitization of pituitary lactotropes. and suggest a possible mechanism for transient midcycle hyperprolactinemia.
Reduced insulinotropic effects of glucagonlike peptide I-(7-36)-amide and gastric inhibitory polypeptide in isolated perfused diabetic rat pancreas, The pathophysiological role of incretin in diabetes mellitus has not been established. We therefore examined the effects of glucagonlike peptide I-(7-36)-amide (truncated GLP-I) and gastric inhibitory polypeptide (GIP) on insulin and glucagon release from isolated perfused pancreases of diabetic rats (12-14 wk of age. mean +/- SE fasting plasma glucose 8.9 +/- 0.6 mM. n = 25) after an injection of 90 mg/kg streptozocin on the 2nd day after birth and compared the results with those of nondiabetic control rats. In diabetic rats. the infusion of 1 nM GLP-I or GIP in perfusates with varying glucose concentrations (2.8. 5.6. 8.3. 11.1. or 22.2 mM) caused a nearly equal degree of insulin stimulation from a similar basal insulin level. Meanwhile. basal and GLP-I- or GIP-stimulated insulin release increased in correlation with the ambient glucose concentration in nondiabetic rats. The degree of stimulation of insulin release at glucose concentrations of 5.6 mM in diabetic rats was approximately 33% that of nondiabetic rats. The stimulation potency was the same between GLP-I and GIP. The insulin treatment for diabetic rats (5 U/kg NPH insulin at 0900 and 2100 for 6 days) brought only a slight improvement in the glucose dependency of GLP-I-stimulated insulin release. The effects of GLP-I and GIP on glucagon release were completely opposite. GLP-I suppressed release; GIP stimulated it. In diabetic rats. the degree of suppression by GLP-I and stimulation by GIP were almost the same with similar basal glucagon levels in the perfusate with varying glucose concentrations.
Characteristics of learning and memory in streptozocin-induced diabetic mice, We demonstrated that mice with streptozocin-induced diabetes mellitus have normal acquisition for relatively simple tasks but show problems in learning more complex tasks such as shuttle box avoidance. Enhanced learning previously reported in simple passive avoidance tasks appears to be due to increased foot shock sensitivity. Diabetic mice show a marked memory retention deficit after learning an active avoidance T-maze task. This retention deficit was reversed by a single injection of insulin. suggesting that it may be related to hyperglycemia per se. Diabetic mice have a shift to the left in the inverted U-shaped dose-response curve for memory retention produced by the acetylcholine agonist arecoline. Based on a preliminary screening. responses to several other pharmacological memory enhancers are probably altered in diabetic mice. These studies suggest that this mouse model of diabetes mellitus demonstrates a deficit in memory retention and retrieval similar to that seen in humans with diabetes mellitus.
Insulinlike activity of new antidiabetic agent CP 68722 in 3T3-L1 adipocytes, We examined the in vitro effects of CP 68722. a novel antidiabetic agent. in 3T3-L1 adipocytes. CP 68722 stimulated 2-deoxyglucose uptake in the absence of insulin. At least 30 min of incubation were required for stimulation of uptake. This effect increased over 5 h and was sustained up to 72 h. The stimulation of 2-deoxyglucose uptake by CP 68722 could be inhibited approximately 60% by inhibition of protein synthesis with cycloheximide. Half-maximal and maximal responses to CP 68722 at 72 h of incubation were observed at 10 and 100 microM of drug. respectively. with a threefold stimulation of uptake at 100 microM approximating the maximal response of these cells to acute insulin stimulation. CP 68722 was able to overcome insulin resistance induced by dexamethasone in 3T3-L1 cells. The effect of drug. like that of insulin. was primarily to increase the Vmax of 2-deoxyglucose uptake. The stimulation of uptake by CP 68722 or insulin could be prevented by incubating the cells at 10 degrees C. a temperature that impedes translocation of glucose transporters to the plasma membrane. Therefore. it appears that CP 68722. like insulin. stimulates glucose uptake by a mechanism that involves translocation of intracellular glucose transporters to the plasma membrane and de novo protein synthesis. We compared the effect of CP 68722 with the sulfonylureas. the primary drugs used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). CP 68722 was a more potent and effective stimulator of 2-deoxyglucose uptake in 3T3-L1 cells than either first- or second-generation sulfonylureas.
Autoxidative glycosylation and possible involvement of peroxides and free radicals in LDL modification by glucose, It has been postulated that the etiology of the complications of diabetes involves oxidative stress. perhaps as a result of hyperglycemia. Consistent with this hypothesis. it has been shown that glucose. under physiological conditions. produces oxidants that possess reactivity similar to the hydroxyl free radical. These oxidants hydroxylate benzoic acid. fragment protein. and induce peroxidation in phosphatidylcholine liposomes and low-density lipoprotein (LDL) when LDL is incubated with hyperglycemic levels of glucose in vitro. These reactions are accelerated by transition metals and inhibited by a metal-chelating agent. The atherosclerotic potential of LDL in diabetes mellitus is often discussed in terms of protein glycosylation. which may affect cellular interactions. Our studies demonstrate. however. that peroxidative reactions also accompany LDL glycosylation in vitro. Peroxidative modification of LDL has also been implicated in LDL atherogenicity. Our studies indicate that glycosylation and peroxidation occur concomitantly in LDL modified by glucose in vitro and may both contribute to the behavioral changes of this lipoprotein.
Multiple alterations in insulin responses to glucose in islets from 48-h glucose-infused nondiabetic rats, To examine the biochemical mechanisms by which hyperglycemia produces insulin secretory abnormalities. we studied isolated islets from control rats and rats infused for 48 h with a 50% glucose solution. To preserve the effects of in vivo hyperglycemia during in vitro handling for islet isolation. our standard isolation procedure utilized buffers containing 16.8 mM glucose. Islets from infused rats released similar amounts of insulin in low or high glucose during first incubations at 37 degrees C (92.4 +/- 7.0 ng.10 islets-1.45 min-1 at 2.8 mM. 84.4 +/- 4.1 ng.10 islets-1.45 min-1 at 16.8 mM) in contrast with control (uninfused) islets (18.6 +/- 2.8 ng.10 islets-1.45 min-1 at 2.8 mM and 109.8 +/- 8.0 ng.10 islets-1.45 min-1 at 16.8 mM glucose) (P less than 0.01). Secretion by islets of glucose-infused rats was lower during 60-min second incubations at 28 mM glucose than in first incubations of the same islets in low glucose (P less than 0.01). This phenomenon is comparable to the paradoxical hypersecretion observed during the first 10-15 min of exposure of glucose-infused pancreas to low-glucose perfusions. Paradoxical secretion in low glucose waned rapidly. so that during second incubations at 37 degrees C. little immunoreactive insulin release occurred at 2.8 mM glucose. despite the persistence of two additional lesions. The glucose-insulin dose-response curves in second incubations showed a leftward shift for glucose-infused islets. with two- to threefold higher secretion at 5.6-8.4 mM glucose than control islets. This is termed sensitization to glucose.
Structural abnormality in LDL from diabetic patients as revealed by resonance Raman spectroscopy, Resonance Raman spectra of low-density lipoprotein (LDL) isolated from the plasma of diabetic patients (age range 13-77 yr. mean age 37 yr) and age- and sex-matched control subjects were recorded in the 1000- to 1600-cm-1 region as a function of temperature (0-50 degrees C). Both nondiabetic and diabetic LDL yield spectra characterized by two major bands near 1160 and 1530 cm-1 due to the carotenoid component of lipoproteins. The relative intensity of 1530- and 1160-cm-1 bands. assigned to -C = C- and = C-C = stretchings. respectively. i.e.. I1530-I1160 ratio. was plotted against temperature. For nondiabetic control subjects. the plots showed an inflection in the temperature range of 30-39 degrees C. which corresponded to the thermal transition of LDL. This transition was abolished in the LDL of diabetic patients (P less than 0.001). suggesting an altered lipid structure. The transition (30-39 degrees C) was also abolished in the in vitro glycosylated nondiabetic LDL. Lipid analysis did not show any appreciable change between nondiabetic control subjects and diabetic patients. The change in the thermal transition properties of diabetic LDL has been attributed to the organizational change in the LDL protein.
Defective free-fatty acid and oxidative glucose metabolism in IDDM during hypoglycemia. Influence of glycemic control, To examine the impact of diabetes and its treatment on plasma free-fatty acid (FFA) and oxidative fuel metabolism during hypoglycemia. we combined indirect calorimetry with [3-3H]glucose during a 4-h low-dose insulin infusion (plasma insulin approximately 2-fold above basal) in six poorly controlled and nine well-controlled insulin-dependent diabetes mellitus (IDDM) patients and in six healthy subjects. Diabetic subjects received insulin overnight to maintain euglycemia before study. Although free-insulin levels and counterregulatory hormone responses were similar. the plasma glucose fall was more pronounced in well-controlled diabetic subjects. In well-controlled diabetic and healthy subjects. the small increment in insulin rapidly suppressed plasma FFA and fat oxidation by approximately 50% and stimulated carbohydrate oxidation by approximately 80%. In contrast. plasma FFA levels did not fall in poorly controlled diabetic subjects. and glucose oxidation was not stimulated. To determine whether this resistance to the antilipolytic effect of insulin occurs in the absence of hypoglycemic counterregulation. we used a sequential low-dose euglycemic insulin clamp (0.2. 0.3. and 0.5 mU.kg-1.min-1). In healthy subjects. plasma FFA was nearly maximally suppressed at the lowest insulin dose. In contrast. plasma FFA remained persistently elevated in poorly controlled diabetic subjects at each insulin dose. However. the insulin dose-response curve for suppression of plasma FFA was near normal in well-controlled subjects. We conclude that poorly controlled IDDM diabetic patients are resistant to the antilipolytic effects of insulin and show impaired stimulation of glucose oxidation during insulin-induced hypoglycemia. Amelioration of these defects in well-controlled patients may be another factor contributing to the higher risk of hypoglycemia during intensified insulin therapy.
Calcitonin gene-related peptide and induction of hyperglycemia in conscious rats in vivo, The effect of calcitonin gene-related peptide (CGRP) on glucose metabolism was investigated in conscious and unrestrained rats in vivo. Intravenous injection of rat CGRP (5.67 and 0.567 nmol/kg) caused a significant. dose-dependent increase in plasma glucose concentration and a simultaneous dose-dependent increase in plasma insulin level. In contrast. plasma glucagon level was not changed. On the other hand. intravenous infusion of CGRP (46.6 pmol.kg-1.min-1) decreased tolerance to intragastric administration of glucose (IGGTT). Plasma insulin response to IGGTT. however. was not affected by CGRP infusion. Moreover. although intravenous injection of CGRP (5.67 nmol/kg) elicited a significant increase in plasma epinephrine and norepinephrine concentrations. concomitant administration of epinephrine and norepinephrine. inducing a more prominent rise in plasma catecholamines than those induced by CGRP. affected neither plasma glucose nor insulin levels. Finally. plasma insulin levels obtained by simulating CGRP-induced changes in plasma glucose or glucose plus catecholamine levels by infusion of glucose or glucose plus catecholamines were not different from those induced by CGRP injection. These results suggest that CGRP has a hyperglycemic action that is not mediated by sympathetic outflow in conscious rats. and inhibition of insulin secretion. if any. does not play a major role in this hyperglycemic action of CGRP. We have demonstrated specific CGRP receptors linked to adenylate cyclase activation in rat liver plasma membranes; this hyperglycemic effect of CGRP in vivo may be partly due to its direct action on the liver.
Change in hexose distribution volume and fractional utilization of [18F]-2-deoxy-2-fluoro-D-glucose in brain during acute hypoglycemia in humans, We used positron emission tomography (PET) to study the effects of mild hypoglycemia on cerebral glucose uptake and metabolism. Nine healthy men were studied under basal saline-infusion conditions. and during euglycemic and hypoglycemic clamp studies. Insulin was infused at the same rate (1 mU.kg-1.min-1) in both clamp studies. In euglycemic clamp studies. glucose was infused at a rate sufficient to maintain the basal plasma glucose concentration. whereas in hypoglycemic clamp studies. the glucose infusion rate was reduced to maintain the plasma glucose at 3.1 mM. Each study lasted 3 h and included a 30-min baseline period and a subsequent 150-min period in which insulin or glucose was administered. Blood samples for measurement of insulin. glucose. cortisol. growth hormone. and glucagon were obtained at 20- to 30-min intervals. A bolus injection of 5-10 mCi [18F]-2-deoxy-2-fluoro-D-glucose (2-DFG) was administered 120 min after initiation of the study. and plasma radioactivity and dynamic PET scans were obtained at frequent intervals for the remaining 40-60 min of the study. Cerebral regions of interest were defined. and concentrations of radioactivity were calculated and used in the three-compartment model of 2-DFG distribution described by Sokoloff. Glucose levels were similar during saline-infusion (4.9 +/- 0.1 mM) and euglycemic clamp (4.8 +/- 0.1 mM) studies. whereas the desired degree of mild hypoglycemia was achieved during the hypoglycemic clamp study (3.1 +/- 0.1 mM. P less than 0.05). The insulin level during saline infusion was 41 +/- 7 pM.
Altered steady-state mRNA levels of basement membrane proteins in diabetic mouse kidneys and thromboxane synthase inhibition, We examined steady-state levels of mRNA encoding type IV collagen. B1 chain of laminin. and the basement membrane heparan sulfate proteoglycan in the kidney cortex of a mouse model (KKAy) of non-insulin-dependent diabetes. mRNAs encoding laminin B1 and the proteoglycan were unchanged in kidneys taken from diabetic mice with demonstrable basement membrane thickening. mRNA levels for type IV collagen. in contrast. were significantly elevated (2-fold) in diabetic mice concurrent with but not preceding morphologically thickened basement membranes. There was a negative correlation between a ratio of proteoglycan/type IV collagen and levels of albuminuria in the diabetic mice. No correlation was noted with laminin. We also examined the effects of inhibiting the synthesis of thromboxane. a potent vasoconstrictor. on the steady-state levels of type IV collagen in the diabetic mice. Inhibition of thromboxane stopped the progression of albuminuria and prevented an increase in type IV collagen mRNA levels. We conclude that basement membrane thickening in diabetes. a hallmark of diabetic nephropathy. is partly a consequence of an unbalanced increase in the production of type IV collagen. The relative decrease in proteoglycan production may contribute to chronic albuminuria.
Lack of predictive value of islet cell antibodies, insulin antibodies, and HLA-DR phenotype for remission in cyclosporin-treated IDDM patients. The Canadian-European Randomized Control Trial Group, The effect of immunosuppression on the humoral immune response to islet autoantigens and exogenously administered insulin and the predictive value of islet cell cytoplasmic antibodies (ICAs). insulin antibodies (IAs). and HLA-DR phenotype for remission during immunosuppression were studied in a prospective randomized double-blind trial of cyclosporin administration in 98 newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients. HLA-DR phenotype and glycosylated hemoglobin were determined at study entry. and insulin requirement. glucagon-stimulated C-peptide. ICAs. and IAs were measured at entry and after 1. 3. 6. 9. and 12 mo of follow-up. Cyclosporin therapy caused significant suppression of the prevalence and serum concentrations of ICAs and IAs. Cyclosporin-treated IDDM patients ICA+ at study entry had higher levels of stimulated C-peptide after 1 mo of study. but the increased beta-cell function was not associated with a higher frequency of insulin-free remission at 1 mo. ICA and IA status at entry did not predict cyclosporin-insulin-free remission as assessed by the prevalence of insulin-free remission or beta-cell function at 3-12 mo of study. and significant decrements in the titers or total disappearance of ICAs were not associated with an increased prevalence or duration of non-insulin-requiring remission or higher stimulated C-peptide values. There was no correlation between the serum levels of ICAs and IAs at entry and beta-cell function at 12 mo of follow-up.
Contribution of impaired muscle glucose clearance to reduced postabsorptive systemic glucose clearance in NIDDM, The reduced postabsorptive rates of systemic glucose clearance in non-insulin-dependent diabetes mellitus (NIDDM) are thought to be the consequence of insulin resistance in peripheral tissues. Although the peripheral tissues involved have not been identified. it is generally assumed to be primarily muscle. the major site of insulin-mediated glucose disposal. To test this hypothesis. we measured postabsorptive systemic and forearm glucose utilization and clearance in 15 volunteers with NIDDM and 15 age- and weight-matched nondiabetic volunteers. Although systemic glucose utilization was increased in NIDDM subjects (14.5 +/- 0.5 vs. 11.2 +/- 0.2 mumol.kg-1.min-1. P less than 0.001). systemic glucose clearance was reduced 1.40 +/- 0.06 vs. 2.13 +/- 0.05 ml.kg-1.min-1. P less than 0.01). Although forearm glucose utilization was increased in NIDDM subjects (0.663 +/- 0.058 vs. 0.411 +/- 0.019 mumol.dl-1.min-1. P less than 0.001). forearm glucose dl-1 clearance was reduced (0.628 +/- 0.044 vs. 0.774 +/- 0.037 ml.L-1.min-1. P less than 0.01). However. extrapolation of forearm data to total-body muscle indicated that impaired clearance reduced muscle glucose disposal by only 61 +/- 21 mumol/min. whereas impaired systemic clearance reduced systemic glucose disposal by 662 +/- 82 mumol/min. Thus. impaired muscle glucose clearance accounted for less than 10% of the reduced systemic glucose clearance in NIDDM subjects. Therefore. we conclude that muscle insulin resistance plays only a minor role in the reduced systemic glucose clearance found in NIDDM in the postabsorptive state and propose that reduced brain glucose clearance is largely responsible.
Hepatic and extrahepatic responses to insulin in NIDDM and nondiabetic humans. Assessment in absence of artifact introduced by tritiated nonglucose contaminants, It is well established that patients with non-insulin-dependent diabetes mellitus (NIDDM) are resistant to insulin. However. the contribution of hepatic and extrahepatic tissues to insulin resistance remains controversial. The uncertainty may be at least in part due to errors introduced by the unknowing use in previous studies of impure isotopes to measure glucose turnover. To determine hepatic and extrahepatic responses to insulin in the absence of these errors. steady-state glucose turnover was measured simultaneously with [6-3H]- and [6-14C]glucose during sequential 5- and 4-h infusions of insulin at rates of 0.4 and 10 mU.kg-1.min-1 in diabetic and nondiabetic subjects. At low insulin concentrations. [6-3H]- and [6-14C]glucose gave similar estimates of glucose turnover. Hepatic glucose release was equal to but not below zero in the nondiabetic subjects. but persistent glucose release (P less than 0.001) and decreased glucose uptake (P less than 0.001) was observed in the diabetic patients. At high insulin concentrations. both isotopes underestimated glucose turnover during the 1st h after initiation of the high-dose insulin infusion. More time (P less than 0.05) was required to reachieve steady state in NIDDM than nondiabetic subjects. At steady state. [6-3H]- but not [6-14C]glucose systematically underestimated (P less than 0.05) glucose turnover in both groups due to the presence of a tritiated nonglucose contaminant. The percentage of radioactivity in plasma due to tritiated contaminants was linearly related to turnover.
Metabolic effects of 1200-kcal diet in obese pregnant women with gestational diabetes, Calorie restriction is widely used as a primary therapy for obese pregnant women with gestational diabetes. To better understand the metabolic consequences of marked calorie restriction. we performed a randomized prospective trial under metabolic ward conditions. Obese gestationally diabetic women were randomized to control (n = 5) and calorie-restricted (n = 7) groups. All patients consumed an approximately 2400-kcal/day diet during the 1st wk of the study. and at the end of the 1st wk. metabolic features of the two groups were statistically indistinguishable. During the 2nd wk. the control group continued to consume approximately 2400 kcal/day. whereas the calorie-restricted group consumed approximately 1200 kcal/day. Twenty-four-hour mean glucose levels remained unchanged in the control group (6.7 +/- 0.8 mM wk 1 vs. 6.8 +/- 0.8 mM wk 2). although they dropped dramatically in the calorie-restricted group (6.7 +/- 1.0 mM wk 1 vs. 5.4 +/- 0.5 mM wk 2. P less than 0.01). Fasting plasma insulin also declined in the calorie-restricted group (265 +/- 165 pM wk 1 vs. 145 +/- 130 pM wk 2). resulting in a significant change between groups (P less than 0.02). Surprisingly. fasting plasma glucose and glucose tolerance measured by the 3-h oral glucose tolerance test did not change within or between groups. Fasting levels of beta-hydroxybutyrate rose in the calorie-restricted group (290 +/- 240 microM wk 1 vs. 780 +/- 30 microM wk 2) but not in the control group (P less than 0.01). Finally. urine ketones increased significantly (P less than 0.02) in the calorie-restricted group. whereas they remained absent in the control group.
Reduced membrane fluidity in platelets from diabetic patients, Platelets from diabetic patients are hypersensitive to agonists in vitro. Membrane fluidity modulates cell function. and reduced membrane fluidity in cholesterol-enriched platelets is associated with platelet hypersensitivity to agonists. including thrombin. Decreased membrane fluidity of these platelets is attributed to an increased cholesterol-phospholipid molar ratio in platelet membranes. We examined the response of platelets from diabetic subjects to thrombin. platelet membrane fluidity. and platelet cholesterol-phospholipid molar ratio. Twelve poorly controlled diabetic subjects were compared with 12 age- and sex-matched control subjects. In response to a low concentration of thrombin. mean values for release of [14C]serotonin from washed prelabeled platelets were not significantly different between diabetic and control subjects. but in 8 of 12 diabetic subjects. the release response was greater than in their paired control subjects. Mean steady-state fluorescence polarization values in 1.6-diphenyl-1.3.5-hexatriene-labeled platelets prepared from diabetic subjects were significantly greater than in control subjects; this indicates a decreased membrane fluidity in platelets from diabetic subjects. Total or very-low-density (VLDL). low-density (LDL). or high-density (HDL2. HDL3) lipoprotein cholesterol concentrations in plasma were not significantly different between groups; however. the ratio of VLDL + LDL to HDL2 + HDL3 was significantly greater in diabetic than in control subjects. There was no difference in the total platelet cholesterol-phospholipid molar ratio between groups.
Induction of insulin resistance in vivo by amylin and calcitonin gene-related peptide, During hyperinsulinemic glucose-clamp studies. intravenous infusion of calcitonin gene-related peptide (CGRP) in rats antagonized the ability of insulin to stimulate peripheral glucose disposal by 52% (196 +/- 7.2 vs. 105 +/- 10.5 mumol.kg-1.min-1. P less than 0.05) and to inhibit hepatic glucose output by 54% (P less than 0.01). CGRP also inhibited the in vitro effects of insulin to stimulate hexose uptake in cultured BC3H1 myocytes at all insulin concentrations studied. Amylin is a peptide isolated from amyloid deposits in pancreatic islets of type II (non-insulin-dependent) diabetic subjects. is present in normal beta-cells. and bears a striking homology to CGRP. When synthetic human amylin was infused during clamp studies. it inhibited the ability of insulin to stimulate glucose disposal by 56% (96.9 +/- 9.4 vs. 42.4 +/- 5.0 mumol.kg-1.min-1. P less than 0.05) and to suppress hepatic glucose output by 64%. Therefore. amylin and CGRP can cause insulin resistance in vivo and may be implicated in insulin-resistant states such as type II diabetes mellitus.
High frequency of aspartic acid at position 57 of HLA-DQ beta-chain in Japanese IDDM patients and nondiabetic subjects, The HLA-DQ beta-chain (DQB1) genes of 72 Japanese patients with insulin-dependent diabetes mellitus (IDDM) and 85 control subjects were studied with polymerase chain-reaction (PCR) amplification and allele-specific oligonucleotide hybridization. DQW4 (DQBBlank) and DQw9 (DQB3.3) were increased in IDDM patients compared with the control subjects. and DQB1.2. DQB1.9. and DQw7 (DQB3.1) were decreased. Thirty-five (48.6%) IDDM patients had both alleles carrying an aspartic acid at position 57 of the DQ beta-chain (Asp 57). 35 (48.6%) were Asp 57/non-Asp 57 heterozygous. and 2 (2.8%) had non-Asp 57 alleles only. Of 85 control subjects. the respective values for these three genotypes were 49 (57.6%). 29 (34.1%). and 7 (8.2%). respectively. The high frequency of Asp 57 alleles in both IDDM and control subjects contrasts with data for Whites. Therefore. the Asp 57 hypothesis that the presence of an aspartic acid at position 57 of DQ beta-chain provides protection against developing IDDM is not tenable for Japanese IDDM patients. The DRB1 gene. particularly position 57 of the DR beta-chain. may contribute to IDDM susceptibility in Japanese.
Local anesthesia for neonatal circumcisions: are family practice residents likely to use it, Dorsal penile nerve block with lidocaine (DPNB) is a local anesthetic technique for neonatal circumcision which is both effective and consistent with ethical concerns for infant welfare. As such. it should be included in training programs that prepare residents to care for newborns. To assess the current level of DPNB use by residents in a family practice training program and to identify attitudes and other factors that relate to use. a survey was sent to 127 residents in the Department of Family Practice and Community Health. University of Minnesota. Of the 101 respondents. 55% had used DPNB. and 17% could be characterized as high users. employing the technique for over one half of the circumcisions they performed. Residents with comprehensive understanding of the newborn's capacity to feel pain were more likely to be using DPNB than their less well-informed counterparts. Four factors were identified as predicting use: cooperation of nursery staff for the procedure. accessibility of instruction in PNB technique. belief that PNB is effective in reducing infant pain. and likelihood of parents giving consent for PNB. These results suggest strategies which may be implemented by family practice educators who wish to promote the principles and techniques of DPNB.
24-hour intragastric acidity and plasma gastrin after omeprazole treatment and after proximal gastric vagotomy in duodenal ulcer patients, The relationship between suppressed gastric acidity and the increase in plasma gastrin levels after pharmacological and surgical treatment of peptic ulcer disease were compared in this study. Eight patients with chronic duodenal ulcer and referred for proximal gastric vagotomy were studied. 24-hour intragastric acidity and plasma gastrin levels were investigated in the same patients on three consecutive occasions: preentry without any treatment; after 4 weeks of administration of 20 mg of omeprazole daily. and 4-6 months after proximal gastric vagotomy. Intragastric acidity was slightly more reduced by omeprazole (94%) than after proximal gastric vagotomy (78%). with no difference found during the day or night with either. Plasma gastrin levels increased slightly more after proximal gastric vagotomy [284% (median. 2120 pmol.h/L; range. 733-2831 pmol.h/L)] than after omeprazole administration [186% (median. 1586 pmol.h/L; range. 495-2573 pmol.h/L)]. There is strong evidence that the increased plasma gastrin concentration following omeprazole treatment is caused by the reduced intragastric acidity. The slight increase in plasma gastrin concentration following proximal gastric vagotomy despite a lesser reduction in intragastric acidity may be the result of additional effects on gastrin release by the vagotomy. Both treatments resulted in a modest increase in plasma levels of gastrin that were far below the gastrin levels observed in achlorhydric patients. e.g.. patients with pernicious anemia.
Detection of duodenal gastrinomas by operative endoscopic transillumination. A prospective study, The ability of operative endoscopic transillumination of the bowel wall to detect duodenal gastrinoma was evaluated prospectively in 26 patients with the Zollinger-Ellison syndrome. The results were assessed by exploratory laparotomy and compared with the results of other localization techniques. Twelve duodenal gastrinomas were resected from 10 patients. Operative endoscopic transillumination detected 10 of the 12 gastrinomas. a sensitivity of 83%. which was significantly greater (P less than 0.05) than that for either preoperative imaging (25%) or intraoperative ultrasonography and palpation (42%). The sensitivity of operative endoscopic transillumination was a result of the ability to detect focal areas that did not transilluminate on the serosal side of the duodenum. and not the mucosal appearances seen through the endoscope. which were not helpful. Operative endoscopic transillumination detected gastrinomas less than 1 cm in diameter throughout the duodenum. Of the patients in this study. 39% had duodenal gastrinomas. a greater frequency than previously reported. These results indicate that operative endoscopic transillumination is the most sensitive technique yet described for detecting duodenal gastrinomas and should be performed routinely in all patients with the Zollinger-Ellison syndrome who undergo exploratory laparotomy for cure.
Intravenous but not intracolonic epidermal growth factor maintains colonocyte proliferation in defunctioned rat colorectum, The role of epidermal growth factor in the proliferation of normal and premalignant colonocytes in vivo is not fully understood. In particular. the relative importance of its possible systemic and intraluminal routes of action has not been fully clarified. Rats with surgically defunctioned distal colorectums were used. and mini osmotic pumps were implanted to study the effects of intraluminal and IV administration of epidermal growth factor on colonocyte proliferation. Within 2 weeks of bypass. colonocyte proliferation in defunctioned colorectum has decreased to about one third the rate in normal colorectum or in colorectum proximal to the defunctioning colostomy. Intraluminal epidermal growth factor. infused from the time of operation did not reverse this hypoplasia. whereas IV epidermal growth factor maintained colonocyte proliferation at approximately the normal rate in bypassed colorectum. This model is suitable for testing other putative colonic mitogens for possible intraluminal and systemic effects.
Glucose disposal, beta-cell secretion, and hepatic insulin extraction in cirrhosis: a minimal model assessment, Factors controlling glucose metabolism after IV load were studied in nine patients with compensated cirrhosis and in six age-matched controls. The time courses of glucose. insulin. and C peptide were analyzed by means of the minimal model technique. In cirrhosis. insulin sensitivity was reduced by approximately 70% and glucose-dependent glucose uptake (glucose effectiveness) by 45%. Decreased glucose effectiveness explained 65% of the variance of glucose disappearance and correlated with the ratio of urinary creatinine to height. an independent measure of muscle mass (r = 0.839). beta-cell responsiveness to glucose. measured on C-peptide kinetics. was variable and increased on average by 170% and 107% (first-phase and second-phase. respectively). The total amount of insulin secreted by beta-cells in the course of the study was nearly doubled. whereas the basal insulin secretion rate was in the normal range. The time courses of hepatic extraction of insulin did not differ between groups. and basal extraction was on average 58% in controls and 56% in patients with cirrhosis. It was reduced to 30% in a single patient who had severe hepatocellular failure and large spontaneous portosystemic shunting. We conclude that the alterations in glucose metabolism of cirrhosis include a decreased insulin sensitivity. a reduced glucose effectiveness. and an increased pancreatic responsiveness to glucose. leading to hyperinsulinemia. The hepatic extraction of insulin is reduced only in the very advanced stages of the disease. possibly because of a large reserve capacity of the hepatic parenchyma.
Liver fatty acid-binding protein: a marker for studying cellular differentiation in gut epithelial neoplasms, Human liver fatty acid binding protein is a 127 residue cytoplasmic protein synthesized in liver and in the intestinal epithelium. Previous studies of normal and transgenic mice indicated that the liver fatty acid-binding protein gene is a sensitive marker of enterocytic differentiation. This study shows the use of immunohistochemical methods to examine liver fatty acid-binding protein gene expression in normal human colonic epithelium. colonic villoglandular adenomas. nonmucinous and mucinous adenocarcinomas. and several types of noncolonic epithelial neoplasms. Cells containing liver fatty acid-binding protein were found in normal colonic epithelium. in two thirds of colorectal villoglandular adenomas and nonmucinous adenocarcinomas. and in one third of mucinous adenocarcinomas but not in noncolonic. nonhepatic carcinomas. All liver fatty acid-binding protein-positive colonic adenomas and adenocarcinomas contained patches of immunoreactive cells distributed among histologically identical patches of cells without liver fatty acid-binding protein immunoreactivity. This "mosaicism" was also found in metastases from liver fatty acid-binding protein-positive colonic adenocarcinomas. Immunostaining of these liver fatty acid-binding protein-positive tissues for carcinoembryonic antigen did not show a mosaic cellular pattern in its expression. These data suggest that within a given neoplasm. differences exist in the differentiation programs of monoclonally-derived. malignant colonic epithelial cells and that liver fatty acid-binding protein is a useful marker for operationally defining these subpopulations. Liver fatty acid-binding protein is also a potentially useful diagnostic marker for colorectal and hepatic carcinomas.
Pathogenesis of ceftriaxone-associated biliary sludge. In vitro studies of calcium-ceftriaxone binding and solubility, Ceftriaxone. a semisynthetic third-generation cephalosporin. has recently been associated with biliary sludge formation. Analysis of the biliary concretions induced by this agent shows a calcium salt of ceftriaxone. The present in vitro studies were undertaken to provide insight into the pathogenesis of ceftriaxone-associated biliary sludge formation by evaluating possible interactions that may exist between calcium. bile salts. and ceftriaxone. Ceftriaxone possessed high calcium-binding affinity. The formation constant for the calcium ceftriaxone salt at 37 degrees C was about 157.3 L/mol; stoichiometry of the salt was 1:1. i.e.. calcium ceftriaxone. The calcium-binding property of ceftriaxone was observed to be additive to that of taurocholate in mixed taurocholate-ceftriaxone solutions. Although the solubility product constant for calcium ceftriaxone was only 1.62 x 10(-6) mol/L2. marked metastability was observed; neither visible nor microscopic precipitates developed until the [Ca2+] x [ceftriaxone] ion product exceeded the solubility product constant by a factor of 10.4. Metastability of the calcium ceftriaxone salt was also observed in human gallbladder bile in vitro. Estimates of human biliary calcium ceftriaxone solubility in vivo were than calculated from previously-reported values for biliary [Ca2+]. [ceftriaxone]. and from the solubility product constant as defined in this study. Calculated saturation indices for calcium-ceftriaxone in human bile generally increased (corresponding to a decrease in solubility) with increasing ceftriaxone dose. At doses less than or equal to 1 g. saturation index was well within the metastable range of this calcium-salt. However. at doses greater than or equal to 2 g. the saturation index surpassed the metastable limit. Under these conditions. precipitation of ceftriaxone could occur. It was concluded that the development of ceftriaxone-induced biliary sludge is a solubility problem that occurs in patients receiving high-dose treatment (greater than or equal to 2 g). This study proposes that the risk of developing ceftriaxone-associated biliary "pseudolithiasis" increases with increasing ceftriaxone dose and in patients with impaired gallbladder emptying.
Gallbladder motility in cholesterol gallstone disease. Effect of ursodeoxycholic acid administration and gallstone dissolution, Gallbladder motility was evaluated by ultrasonography in 75 cholesterol gallstone patients and in 77 matched control subjects. All 75 gallstone patients were candidates for oral bile acid therapy (radiolucent gallstones. less than 2 cm in diameter. in well-opacified gallbladder). and 38 of them were also studied during ursodeoxycholic acid administration. An additional 20 gallstone patients were studied 1 year after confirmed gallstone dissolution with oral bile acids. Gallstone patients showed significantly greater fasting and residual volumes. a decreased percent of gallbladder emptying. but a similar absolute emptying and emptying rate compared with the control subjects. Greater fasting volumes and reduced percents of gallbladder emptying were also found in gallstone-free patients who achieved complete dissolution with oral bile acids. After ursodeoxycholic acid administration. fasting gallbladder volumes were greater. and percents of gallbladder emptying were further decreased than in untreated gallstone patients. In conclusion. greater fasting volumes. and not reduced gallbladder contractility. account for the defective gallbladder function in radiolucent (cholesterol-rich) gallstone patients. This condition is likely to precede. and possibly to promote. gallstone formation because it persists after gallstone dissolution. Ursodeoxycholic acid administration worsens the defect observed in gallstone patients. This finding also suggests. although indirectly. that the expected normalization of cholesterol saturation during oral bile acid administration is not paralleled by an improvement in gallbladder function.
Primary biliary cirrhosis. Quantitation of autoantibodies to purified mitochondrial enzymes and correlation with disease progression, Primary biliary cirrhosis is characterized by the presence of antimitochondrial antibodies. Recently. six of the autoantigens have been identified as components of the 2-oxo acid dehydrogenase multienzyme complexes located within mammalian mitochondria. Immunoblotting studies have shown that two of these components. namely E2 and protein X of pyruvate dehydrogenase complex. are the major antigenic polypeptides recognized by autoantibodies. This study shows the development of an enzyme-linked immunosorbent assay to detect and quantitate antibodies to these two purified antigens. Coded serum samples from 166 patients with primary biliary cirrhosis. 140 patients with other liver and/or autoimmune disease. and 52 normal women were analyzed for reactivity using this immunoassay. These results indicate that this rapid. simple method has a 93% sensitivity and 96% specificity in the diagnosis of primary biliary cirrhosis. The titer of immunoglobulin G autoantibodies correlated not only with antimitochondrial antibody titer measured by indirect immunofluorescence (P less than 0.0001) but also with histological stage of disease (P less than 0.04) and prognostic biochemical variables such as higher serum bilirubin and lower serum albumin levels (P = 0.038 and 0.028. respectively). There was no significant correlation between titer of autoantibodies and serum globulin or immunoglobulin G levels. indicating that the positive correlation with disease progression was not secondary to hypergammaglobulinemia.
Long-term outcome after surgery for biliary atresia. Study of 40 patients surviving for more than 10 years, To define long-term prognosis of children who underwent surgery for biliary atresia. a retrospective study was undertaken in 122 children who underwent one of the Kasai procedures between 1968 and 1977. Forty of the 122 children (32.7%) were alive after 10 years. Firm hepatomegaly was present in 31 and splenomegaly in 29 children. Serum bilirubin or all liver function tests were normal in 21 and 11 children. respectively; survival rate decreased with the age at operation. but no significant difference was observed in the rate of children surviving with normal serum bilirubin whether they underwent surgery before age 2 months or between 2 and 3 months. Twenty-four had esophageal varices and 15 experienced gastrointestinal bleeding. Normal liver-function tests and absence of portal hypertension were observed in 11 of 122 children. These results indicate that Kasai's procedures were helpful in a significant proportion of children with biliary atresia who underwent surgery during this period. However. 80% of children who initially underwent surgery with Kasai's procedures should eventually undergo liver transplantation.
Microprocessor-assisted solvent-transfer system for gallstone dissolution. In vitro and in vivo validation, To improve the efficacy. safety. and convenience of contact dissolution of gallbladder stones. a microprocessor-assisted solvent transfer system was developed. The system's two pumps simultaneously infuse and aspirate solvent into and from the gallbladder at a high flow rate through a multilumen catheter. The microprocessor controls the pumps using a closed feedback loop control algorithm to regulate intragallbladder pressure to prevent solvent escape into the duodenum. Turbulent solvent flow at the catheter end in the gallbladder is designed to induce rapid stone dissolution and to suspend insoluble residue. thus promoting its aspiration. The system's response and gallbladder emptying capacity was 160-fold faster than the natural gallbladder emptying rate. The rate at which gallstones were dissolved by methyl tert-butyl ether using the system was compared with that achieved with a syringe pump. For 6 of 11 pairs of stones that totally dissolved. the mean dissolution time with the system was 10 +/- 6 minutes compared with 112 +/- 81 minutes for the syringe pump. In the 5 of 11 stone pairs which dissolved incompletely. insoluble residue was completely eliminated by the system in 21 +/- 9 minutes but not by the syringe pump even at 360 minutes. When the system was used in gallstone patients. solvent recovery was 99% +/- 1%. and the concentration of a nonabsorbable marker did not change. confirming the lack of appreciable absorption of methyl tert-butyl ether. These studies suggest that the microprocessor-assisted solvent transfer system is a device capable of safe. complete. and fully automatic contact dissolution of cholesterol gallbladder stones using methyl tert-butyl ether or similar solvents.
Endoscopic retrograde cannulation of the gallbladder: direct dissolution of gallstones, Percutaneous transhepatic catheterization of the gallbladder for dissolution of cholesterol stones by instillation of methyl tert-butyl ether (MTBE) is an invasive therapeutic procedure. The only non-invasive alternative available to now. endoscopic retrograde cannulation of the cystic duct. was difficult because of the cystic duct's tortuosity and spiral valves. We therefore developed a catheter system which. using conventional duodenoscopes during a routine endoscopic retrograde cholangiography (ERC) procedure. permits reliable and safe catheterization of the gallbladder without the need for endoscopic sphincterotomy. In 18 of 22 patients (82%) we were able to place a cysto-nasal catheter. and in 14 patients MTBE dissolution therapy was then performed. Eight patients (57%) were completely free of stones after treatment; the other six (43%) had residual debris. In 4 of 22 patients (18%) cannulation attempts failed. in 3 patients due to cystic duct blockage by a calculus. Endoscopic retrograde cannulation of the gallbladder (ERCG) represents a promising alternative to the invasive percutaneous transhepatic catheterization procedure.
Sphincter of Oddi manometry: decreased risk of clinical pancreatitis with use of a modified aspirating catheter, This study was undertaken to determine whether routine use of a modified triple-lumen five French sphincter of Oddi manometry catheter would reduce the frequency and severity of post-manometry pancreatitis and pancreatic enzyme elevation. Seventy-six patients were alternately assigned to undergo sphincter of Oddi manometry (SOM) with a standard perfusion (infused group) catheter or the newly developed aspiration (aspirated group) catheter. After SOM. there were significantly more patients in the infused group with both amylase and lipase values elevated at least two times the upper limits of normal at 2 (p less than 0.001). 6 (p = 0.01). and 18 hours (p = 0.03) after the procedure. As compared with the standard perfusion system. the aspiration catheter was associated with a decreased frequency of clinical pancreatitis (23.5% vs. 3%. p = 0.01) reduced hospital stay (5 +/- 1.83 days. mean +/- SE. versus 1 day; p = 0.03) and milder pancreatitis. The aspiration manometry catheter should be considered for standard use for SOM. particularly if the pancreatic duct sphincter is being evaluated.
Sincalide-aided ultrasonography of the common bile duct as a predictor of biliary obstruction determined by ERCP and biliary manometry, Sonographically observed changes in common bile duct caliber following intravenous sincalide injection were correlated with distal common duct pathology as defined by endoscopic retrograde cholangiopancreatography and biliary manometry. Thirty-two patients. 17 with prior cholecystectomies. were studied. In post-cholecystectomy patients. a 1-mm or greater diminution of duct caliber within 5 min represented a normal response. When gallbladder contraction occurred in normal patients with an intact gallbladder. no change or a diminution in duct caliber was observed. When gallbladder contraction was not observed. a normal response was considered to be the same as that in post-cholecystectomy patients with a diminution in duct caliber occurring. By using these criteria two false negatives. both with hypertensive sphincters of Oddi that responded normally to sincalide injection. were encountered. This technique was valuable in defining non-obstructed post-cholecystectomy dilated bile ducts which demonstrated a prompt diminution in caliber following sincalide injection.
Schatzki's ring: long-term results following dilation, The purpose of this study is to report long-term results of 61 patients with Schatzki's ring who were dilated for relief of dysphagia. The severity of Schatzki's ring was mild in 28 patients (46%). moderate in 26 (43%). severe in 5 (8%). and indeterminate in 2 (3%). Follow-up information was available in 56 of 61 patients (mean. 75 months). During follow-up. 35 patients (63%) developed recurrent dysphagia and required repeated dilations: 19 patients (34%) had one to two dilations. 9 patients (16%) had three to seven dilations. 6 patients (11%) had more than seven dilations; 1 patient underwent surgery for resection of the Schatzki's ring (2%). The mean (range) dilation-free interval was 50.1 months (11.8 to 100 months) in mild cases. 44.5 months (8.9 to 82 months) in moderate cases. and 28.6 months (9 to 76 months) in severe cases. There was no significant correlation between the severity of Schatzki's ring on initial presentation and the subsequent dilation-free interval. Our data indicate that recurrent dysphagia is common among patients with Schatzki's ring after a successful dilation. and that the severity of Schatzki's ring is not a good prognostic indicator of the need for subsequent dilation.
Witzel pneumatic dilation for achalasia: safety and long-term efficacy, Forceful dilation of the lower esophageal sphincter is considered primary therapy for achalasia. The Witzel pneumatic balloon dilator. unlike fluoroscopically placed dilators. is placed over a standard gastroscope allowing positioning and dilation under direct vision. We report our experience with the Witzel dilator in 45 patients with achalasia over a 5-year period. All patients had at least one major symptom score of 8 out of 10 for dysphagia and/or regurgitation before dilation. After Witzel dilation. symptomatic response was graded as excellent (score 0 to 2). good (score 3 to 5). fair (score 6 to 8). and poor (no improvement). Symptom response was assessed after 1 week. 1 month. 6 month. 1 year. and present. The mean period of follow-up was 25 months (range. 3 to 85 months). Passage of the balloon across the gastroesophageal junction was technically unsuccessful in three patients. Esophageal perforation occurred in two patients (4%) and transient chest pain greater than 2 days in three patients (7%). There was no bleeding or death. Symptomatic long-term improvement was excellent in 25 patients (63%). good in 6 patients (15%). fair in 4 patients (10%). and poor in 5 patients (12%). A repeat Witzel dilation was performed in five patients but resulted in good/excellent improvement in only one patient. We conclude that pneumatic dilation with the Witzel balloon is a safe. effective procedure for achalasia.
Performing screening flexible sigmoidoscopy using colonoscopes: experience in 500 subjects, There is still controversy regarding the optimal length of flexible sigmoidoscopes. We performed screening distal colon examinations using 168-cm colonoscopes in 500 asymptomatic subjects who were unsedated and had sigmoidoscopy cleansing preparation. The mean depth of penetration was 66 cm and was similar in persons in whom the examination was discontinued because of poor preparation versus those with discomfort. Polyps were detected in 87 patients. but only 5 subjects had polyps detected above 60 cm. We conclude that in a group of unsedated subjects scheduled for flexible sigmoidoscopy after a sigmoidoscopy prep. the use of instruments longer than 60 cm gives very little additional yield.
Arterial blood oxygen desaturation in infants and children during upper gastrointestinal endoscopy, Arterial blood oxygen desaturation and abnormal electrocardiographic changes have been reported in adults undergoing upper gastrointestinal endoscopy. We studied 32 infants and children less than 12 years of age using pulse oximetry and continuous electrocardiography before. during. and after upper gastrointestinal endoscopy performed under intravenous sedation. Sinus tachycardia was the most common electrocardiographic change. and no clinically significant electrocardiographic abnormalities were induced by the procedure. Desaturation to less than or equal to 90% was found in 37.5% of the patients and was most commonly noted during the endoscopy procedure and in patients with cardiopulmonary disease. The desaturation was unpredictable because there was no correlation between desaturation and medication. tolerance to the procedure. weight. or age of the child. Some patients who subjectively appeared to tolerate the procedure well had significant desaturation. The use of pulse oximetry should be considered for all children undergoing upper gastrointestinal endoscopy.
Soft tissue rheumatism of the upper extremities: diagnosis and management, Upper extremity tendinitis and bursitis are usually the result of repetitive microtrauma. probably resulting in disruption of fibers. A focus of inflammation often occurs. producing pain. spasm. and disability. With a careful history and physical exam. the diagnosis can be made. distinguishing soft tissue rheumatism from arthritis. Treatment consists of rest. heat or ice. and frequently. the use of non-steroidal anti-inflammatory drugs or injections to control the inflammatory response. Protection from repeated trauma may be beneficial in preventing recurrence.
Infection control in the nursing home: the physician's role, Infection control in the nursing home or long-term care facility is an increasingly complex activity. The high rates (approximately 15%) and special risks (group activities. crowding) for nosocomial infection demand special attention by attending physicians. Some specific responsibilities include: recognition of infection; knowledge and use of basic infection control principles; appropriate antibiotic use; review of immunizations; facilitation of communications among office. hospital. and long-term care facility; and involvement with infection control program(s).
Antibodies to nuclear lamin C in chronic hepatitis delta virus infection, Sera of patients with chronic hepatitis delta virus infection stained the nuclear periphery in indirect immunofluorescence. Using proteins of isolated nuclei. isolated nuclear matrices. the nuclear pore complex-lamina fraction and purified lamins A and C as antigen source in immunoblotting experiments. nuclear lamin C was identified as the reactive antigen. Most sera tested (8 of 10) recognized nuclear lamin C exclusively. but not the nuclear lamins A and B. Antibodies reacting with both nuclear lamins A and C. which share extensive sequence homologies. have been reported to occur in autoimmune hepatitis and primary biliary cirrhosis. The present findings suggest that the novel autoantibody associated with chronic hepatitis delta virus infection recognizes an epitope localized in the short carboxyterminal region of nuclear lamin C.
Selective intestinal decontamination increases serum and ascitic fluid C3 levels in cirrhosis, Selective intestinal decontamination for 7 days with norfloxacin was performed in 14 cirrhotic patients with ascites and low ascitic fluid total protein. Variations in serum and ascitic fluid of C3 and C4 and ascitic fluid total protein after therapy were compared with those of a control group of 14 untreated patients with similar characteristics. After oral norfloxacin administration. we saw a significant increase of C3 in serum (p less than 0.05) and ascitic fluid (p = 0.01). A significant increase was also observed in ascitic fluid total protein (p less than 0.05) but not in serum and ascitic fluid C4. There were no changes in serum C3. ascitic fluid C3. ascitic fluid C4 or in ascitic fluid total protein in group 2. These data demonstrate that selective intestinal decontamination increases serum and ascitic fluid C3 levels and. therefore. might be useful in preventing spontaneous infections in cirrhotic patients at high risk of infection.
Infection of mice with lactate dehydrogenase-elevating virus destroys the subpopulation of Kupffer cells involved in receptor-mediated endocytosis of lactate dehydrogenase and other enzymes, In previous experiments in rats. we have shown that the rapid plasma clearance of a number of clinically important enzymes is due to receptor-mediated endocytosis by Kupffer cells and other resident macrophages. Others have shown that infection of mice with lactate dehydrogenase-elevating virus. a virus that proliferates in macrophages. leads to reduced plasma elimination of these enzymes. This paper integrates these two sets of experiments. Plasma elimination of intravenously injected. radioactively labeled lactate dehydrogenase M4 and mitochondrial malate dehydrogenase in mice was shown to be caused in part by uptake in liver. spleen and bone. Uptake of lactate dehydrogenase M4 by these tissues was. to a large extent. saturable and the two dehydrogenases competitively inhibited each other's clearance. These results suggest that. also in mice. these enzymes are partly cleared from plasma by endocytosis by way of a common receptor on cells (probably macrophages) from liver. spleen and bone marrow. Morphometrical data showed that normal mouse liver contains 23 x 10(6) Kupffer cells/cm3. This number was reduced to about 30% of that of controls 24 hr after infection of mice with lactate dehydrogenase-elevating virus but returned to normal within the next 9 days. The saturable component of uptake of lactate dehydrogenase M4 by liver. spleen and bone had disappeared 24 hr after infection with the virus. and did not return after the Kupffer cell population had recovered. Our findings suggest that lactate dehydrogenase M4 is. to a large extent. removed from the circulation by way of a receptor on a subpopulation of macrophages that is permissive for replication of lactate dehydrogenase-elevating virus.
Hepatic injury induced by bile salts: correlation between biochemical and morphological events, Continuous intravenous infusion of taurochenodeoxycholate at a rate of 0.4 mumol.min-1.100 gm-1 for only 30 min in rats caused threefold to tenfold greater release of proteins (alkaline phosphatase. lactate dehydrogenase and albumin) into bile in comparison with animals infused with tauroursodeoxycholate at much higher rates (1.8 mumol.min-1.100 gm-1) for 2 hr. The simultaneous infusion of tauroursodeoxycholate and taurochenodeoxycholate (0.6 and 0.4 mumol.min-1.100 gm-1. respectively) for 2 hr prevented the marked biochemical changes in the bile induced by taurochenodeoxycholate for 15 to 60 min exhibited significantly more necrotic hepatocytes. especially in zone 1. in comparison with animals infused with tauroursodeoxycholate or a combination of taurochenodeoxycholate and tauroursodeoxycholate. A good correlation was observed between biochemical and morphological indices of bile acid-induced hepatocyte injury. These data suggest that (a) primary events induced by the acute infusion of toxic bile salts responsible for cholestasis include zone 1 hepatocellular necrosis and (b) this can be prevented by the simultaneous infusion of tauroursodeoxycholate.
Characteristics of biliary lipid metabolism after liver transplantation, Biliary lipid metabolism was studied after 10 liver transplantations with continuous drainage of bile. Within 3 wk after transplantation. the new liver produced bile with concentrations of biliary lipids in agreement with those reported for T-tube bile in cholecystectolized nontransplanted subjects. Although changes in biliary lipid composition occurred swiftly in response to various forms of disturbed liver function. they did not provide substantially more information than did standard serum tests or simple measurements of bile flow in most patients. Secretion rates of phospholipids and cholesterol were found to be completely bile acid dependent. For each micromole of bile acids. 0.22 and 0.08 mumol of phospholipids and cholesterol were secreted. respectively. When bile flow was related to bile acid output. a linear relationship was found (r = 0.89). with a positive intercept indicating a bile acid-independent bile flow of approximately 44 microliters/min. Analysis of individual bile acids showed almost exclusively primary bile acids. The relative proportion of chenodeoxycholic acid was more prominent during the first days after transplantation. Different explanations for this are discussed.
Early 24-hour blood pressure elevation in normotensive subjects with parental hypertension, Subjects with a family history of parental hypertension are reported to have a slightly higher office blood pressure in the prehypertensive stage. Whether this reflects a hyperreactivity to blood pressure measurement or a more permanent blood pressure elevation. however. is not known. In the present study. blood pressure was measured in 15 normotensive subjects whose parents are both hypertensive (FH++). 15 normotensive subjects with one hypertensive parent (FH(+)-). and 15 normotensive subjects whose parents are not hypertensive (FH--); among the three groups. subjects were matched for age. sex. and body mass index. The measurements were made in the office during a variety of laboratory stressors and during a prolonged resting period. and for a 24-hour period (ambulatory blood pressure monitoring). Office blood pressure was higher in the FH++ group than in the FH-- group (p less than 0.05). The pressor responses to laboratory stressors were similar in the two groups. but the FH++ group had higher prolonged resting and 24-hour blood pressure than the FH-- group; the difference was always significant (p less than 0.05) for systolic blood pressure. The FH++ group also had a greater left ventricular mass index (on echocardiographic examination) than the FH-- group (p less than 0.01). The blood pressure values and echocardiographic values of the FH(+)- group tended to be between those of the other two groups. Thus. the higher blood pressure shown by individuals in the prehypertensive stage with a family history of parental hypertension does not reflect a hyperreactivity to stress but an early permanent blood pressure elevation.
Calcitropic hormones, platelet calcium, and blood pressure in essential hypertension, Plasma ionized calcium. platelet cytosolic calcium (using the fura-2 method in gel-filtered platelets). parathyroid hormone (both the intact hormone and a midmolecule portion). calcitriol. and calcidiol were measured in 19 untreated male patients with essential hypertension and 19 age-matched normotensive male research subjects. Mean levels of platelet cytosolic calcium. parathyroid hormone. calcitriol. and calcidiol were all significantly higher. whereas plasma ionized calcium was significantly lower. in the hypertensive group compared with the normotensive group. Both platelet cytosolic calcium and intact parathyroid hormone were positively correlated with mean arterial pressure (r = 0.58. p less than 0.001; r = 0.54. p less than 0.001. respectively). whereas plasma ionized calcium was inversely correlated with mean arterial pressure (r = -0.60. p less than 0.001) in the combined group of all study subjects. All three of these correlations were significant in the hypertensive group alone but not in the normotensive group alone. When analyzed with plasma ionized calcium. body mass index. serum calcitriol. and calcidiol in a multivariable regression model. the significance of the partial regressions of platelet cytosolic calcium and parathyroid hormone with mean arterial pressure persisted. Intact parathyroid hormone was positively correlated to platelet cytosolic calcium (r = 0.43. p less than 0.01) and plasma ionized calcium was inversely correlated to platelet cytosolic calcium (r = -0.44. p less than 0.01). These results confirm previous reports of disturbances of calcium metabolism in essential hypertension and suggest that the elevated platelet cytosolic calcium observed in essential hypertension may be linked to one or more of these alterations of calcium metabolism.
Effects of angiotensin converting enzyme inhibitors and of hydralazine on endothelial function in hypertensive rats, The function of the endothelium is impaired in hypertension. In spontaneously hypertensive rats (SHR). acetylcholine-induced relaxation is decreased and serotonin-induced constriction is increased. The goal of our study was to evaluate the effect of a long-term treatment with cilazapril. a new angiotensin converting enzyme inhibitor. or hydralazine. a vasodilator. on the endothelium-dependent responses in aorta of SHR. Wistar-Kyoto rats were used as normotensive reference. Isolated aortic rings with or without endothelium were suspended in organ chambers. The rings with intact endothelium were contracted with norepinephrine. Acetylcholine-induced relaxation was markedly enhanced by cilazapril treatment. The tension achieved at maximal relaxation was 8 +/- 4% of norepinephrine contraction in the cilazapril-treated SHR versus 55 +/- 5% in the untreated SHR (p less than 0.001). Hydralazine had no significant effect. The effect of serotonin was also markedly modified by cilazapril. In untreated SHR. serotonin induced the release of a vasoconstrictor substance by the endothelium as assessed by the ratio of maximal tension induced by serotonin in rings with endothelium over maximal tension in rings without endothelium. which was greater than 1. This ratio was reversed in cilazapril-treated SHR but not in hydralazine-treated SHR. Captopril had effects similar to cilazapril. Finally. evaluation of carotid arteries showed that cilazapril also prevented morphological changes of the intima in SHR (i.e.. infiltration by mononuclear cells). We conclude that angiotensin converting enzyme inhibitors prevent the functional and morphological alterations in endothelium that are found in hypertension and speculate that this action might participate in their antihypertensive effect.
Intrarenal de novo production of angiotensin I in subjects with renal artery stenosis, To estimate the renal extraction and de novo production of angiotensin I and to assess the contribution of blood-borne renin to renal angiotensin I production. the aortic and renal venous plasma levels of renin and intact [125I]angiotensin I and endogenous angiotensin I during continuous systemic intravenous infusion of monoiodinated [125I]angiotensin I were measured in subjects with unilateral renal artery stenosis (n = 8) who were treated with captopril (50 mg b.i.d.). Results demonstrated that 80% of angiotensin I delivered by the renal artery was extracted both by the affected and the unaffected kidney and that on both sides a major part of angiotensin I in the renal vein was derived from intrarenal de novo production. Production of plasma angiotensin I was in excess over extraction (p less than 0.01) on the affected side. whereas extraction was in excess over production (p less than 0.01) on the contralateral side. The plasma level of de novo intrarenally produced angiotensin I in the renal vein was seven times higher on the affected side than the contralateral side. This difference was by far too big to be explained by a difference in the transit time of blood between the two kidneys. by an augmented production of angiotensin I in the circulating blood passing through the affected kidney due to the higher level of venous plasma renin activity in that kidney. or by the combination of both.
Pressor systems in hypertension and congestive heart failure. Role of vasopressin [clinical conference, Elevated peripheral vascular resistance. which characterizes hypertension and congestive heart failure (the latter regardless of absolute blood pressure level) is maintained to a large extent by the combined effects of three major neurohormonal pressor mechanisms: the renin-angiotensin system. the sympathoadrenal system. and arginine vasopressin. Blockade of one of these mechanisms may lead to compensatory stimulation of the others. thus offsetting in part the hemodynamic benefits of a specific intervention. Combination therapy. designed to attack all three systems (with use of an angiotensin converting enzyme inhibitor. a sympathetic blocker such as clonidine. and an antagonist of the vasopressor action of vasopressin). may help in the treatment of such cases. To illustrate this strategy. two experimental studies. one case of malignant hypertension. and one case of congestive heart failure are presented.
Desmopressin and antifibrinolytics, Desmopressin appears to be a safe and effective hemostatic agent for use during surgery in patients with mild to moderate hemophilia or von Willebrand disease. Uremic patients also benefit from substitution of desmopressin for cryoprecipitate to control bleeding. The highly variable response to desmopressin by individual patients with hemophilia or von Willebrand disease dictates that each patient receive a trial administration prior to surgery; surgery should proceed only following verification of a therapeutically effective increase in Factor VIII and vWF after desmopressin. Use of desmopressin in patients with normal baseline hemostatic function is not clearly advantageous. although certain patient subgroups might benefit. and prospective studies have documented the drug's safety in these cases. Data are lacking to clarify a role for desmopressin during surgery in patients taking aspirin. Antifibrinolytic therapy appears to decrease bleeding without increased risk after cardiac surgery. In addition. specific use after urological surgery may be beneficial in the absence of upper urinary tract bleeding. In the last ten years. other applications for antifibrinolytic therapy have been found--both surgical (intracranial aneurysms. oral and lacrimal surgery) and nonsurgical (in cancer patients and for gastrointestinal bleeding). Although anecdotal reports have fueled fears of increased thrombosis with antifibrinolytics. controlled studies indicate no increased risk.
Hemodialysis-associated febrile episodes: surveillance before and after major alteration in the water treatment system, Surveillance for bacteremic or pyrogenic episodes associated with hemodialysis was undertaken before and after the reconstruction of the water treatment system at our University medical center. The new water system included a holding tank with iodination treatment. The water delivered to individual dialysis stations had only occasional positive bacterial cultures (3 of 21 samples before completion of construction. 2 of 16 samples afterwards) and intermittent detection of endotoxin (6 of 21 samples before completion of construction. 9 of 16 samples afterwards) at monthly sampling. Among 51 individual dialysis treatments (25 patients) before reconstruction and 56 treatments (29 patients). after. only 2 and 3 febrile events were identified. respectively. All of these were associated with underlying infectious illness and not with the hemodialysis procedure itself. Overall. we conclude that pyrogenic episodes associated directly with hemodialysis treatment are infrequent. and that the addition of a water storage tank with iodination treatment does not appear to increase the risk of bacteremia or pyrogenic episodes.
Serious migraine: a study of some epidemiological aspects, Data are scant concerning some epidemiological aspects of those severe headaches which cause serious personal and economic morbidity. Our purpose was to study the incidence and other epidemiological features of patients suffering from severe migraine exacerbations. in an unselected population. The 64 patients who suffered from severe migraine bouts represented 10.5% of all the new walk-in neurological consultations in the area covered in this study. 70% of these patients were between 10 and 39 years old. Although females clearly predominated in all ages after fifteen. below this age there was a slight male predominance. The calculated incidence of serious migraine exacerbations was 90 per 100.000 people per year. the corrected incidence for females being 143/100.000 and for males 37/100.000. The highest incidence for females was in 15-19 year-olds (377/100.000) and for males in 10-14 year-olds (166/100.000). Our data seem to confirm the periodic nature of this condition since in 80% of patients the migraine bouts (ie: groups of attacks) lasted between two and nine months. Also they support the reported existence of genetic and hormonal factors in the susceptibility to migraine exacerbations. Our results may help in planning the public health aspect of migraine and add some light to the natural history of this common condition.
Platelet monoamine oxidase activity in female migraine patients, Platelet monoamine oxidase activity (MAO) in a group (n = 17) of white. female migraineurs during an acute migraine attack was similar to both the values obtained for the same group of patients two to three weeks after the headache episode (pain-free period) and to the results obtained for a group (n = 18) of sex and race-matched. age-comparable. drug-free healthy volunteers (blind study; substrate p-tyramine. 38.7 +/- 5.7. 41.9 +/- 8.8 and 43.0 +/- 3.4 or p-methoxybenzylamine. 178.9 +/- 11.3. 177.2 +/- 6.9 and 181.0 +/- 9.7 nmole/hr/10(9) platelets +/- SD respectively). With each patient serving as its own control. MAO activity during the migraine episode and when pain-free failed to show a significant trend. Neither a number of other medical conditions nor the use of several medications appeared to significantly influence our results. The present work. while dealing only with a small but well defined patient population. argues against the possible usefulness of platelet MAO activity as a biological marker for migraine headaches.
A protocol for butalbital, aspirin and caffeine (BAC) detoxification in headache patients, The abuse of the combination drug containing butalbital 50 mg. aspirin 325 mg and caffeine 40 mg (or BAC). is commonly recognized by headache specialists as causing headaches. Despite this widespread problem. there is not a published treatment regimen for the BAC detoxification of patients. I describe such a protocol which was used four times in three patients. These patients fulfilled the diagnostic criteria of the IHS Headache Classification for headaches induced by chronic substance abuse (8.2) and analgesics abuse headache (8.2.2). These patients took between 150 and 420 BAC/month for 2-15 years. Two patients had previously undergone inpatient detoxification. One patient unsuccessfully tried detoxification twice as an outpatient. All patients were required to have psychological support prior to hospitalization for this protocol. BAC was discontinued. A pentobarbital challenge test corroborated butalbital dosage. The patients were given phenobarbital and caffeine which were tapered over several days. Dihydroergotamine (DHE) with metoclopramide was used (Raskin). Propranolol 60 mg bid was started. No narcotics were permitted. After hospital discharge. patients were allowed to continue subcutaneous DHE. as needed. One patient restarted BAC use after 8 months without it. The other two patients were still BAC free 18 and 14 months after detoxification.
Dissociation between pain and autonomic disturbances in cluster headache, The relationship between pain and autonomic disturbances in cluster headache was studied in 54 patients whose attack always recurred on the same side. and in 7 others whose attack had affected either side on different occasions. In one of these seven patients. facial flushing and ocular sympathetic deficit was observed on the original side of headaches. In most patients. the orbital region was warmer on the painful side but in three cases this region was cooler during and between attacks. Lacrimation and rhinorrhoea were more common in severe attacks. and the temperature difference between the orbits increased with increasing severity of pain. These findings support the view that certain autonomic disturbances in cluster headache are provoked by pain. Residual autonomic dysfunction could influence autonomic activity during cluster headache. If so. residual dysfunction on the pain-free side could explain the dissociation between autonomic disturbances and pain observed in a few cases.
A study of the seasonal variation of migraine, Available evidence supports the contention that migraine involves a disturbance in serotonin function. Several parameters of serotonin function in humans have been found to vary seasonally and may underlie the seasonal fluctuations observed in many clinical neuropsychiatric phenomena that are thought to involve serotonin dysfunction. We therefore postulated that migraine headaches might also vary seasonally and examined the admissions to our hospital over a 20-year period with a primary diagnosis of migraine. Peak admissions were found to occur most frequently in the spring for females in comparison to males (p less than or equal to 0.04. chi-square). The implications of these findings are discussed.
Clinical characteristics of migraine and episodic tension-type headache in relation to old and new diagnostic criteria, Eighty-one patients were diagnosed as having migraine. tension headache or both according to previously used criteria. Then we performed a standardized interview to determine the frequency and severity of headache characteristics used in the new operational diagnostic criteria of the International Headache Society (IHS). In every patient the original diagnosis fulfilled also the IHS criteria. but in 9 patients the criteria were only fulfilled in half or less of the attacks. and applying the IHS criteria they also achieved an additional diagnosis. In one patient these attacks did not fulfill the pain criteria and in 8 (4 migraine. 4 tension headache) they did not fulfill the criteria for accompanying symptoms. Overall the IHS criteria are sensitive and specific. but they may possibly be improved with regard to accompanying symptoms. The present study suggests that recording of frequency and graded severity of characteristics using a headache diary may further improve the distinction between the different types of headache.
Clinical controversies surrounding thrombolytic therapy in acute myocardial infarction, The treatment of acute myocardial infarction has changed tremendously in the past decade because thrombolytic therapy has become the treatment of choice for the patient with acute myocardial infarction. Although many issues have been resolved. several controversial issues remain unresolved. This article addresses thrombolytic agents in terms of their superiority in achieving infarct vessel patency and mortality reduction as well as the role of thrombolysis in patients who present with chest pain of greater than 6 hours' duration. who are elderly. and who have an inferior infarction.
Effects of heparin versus saline solution on intermittent infusion device irrigation, The purpose of this study was to compare the effectiveness of 1 ml of 0.9% sodium chloride with 10 units of heparin in 1 ml sodium chloride solution. both containing benzyl alcohol. in maintaining patency and reducing the incidence of phlebitis in patients with intermittent infusion devices. The subjects (N = 32) were randomly assigned in a double-blind experimental design. Repeated-measures analysis of variance revealed no significant difference between the groups in phlebitis or patency variables. The results from this controlled study would suggest that 0.9% sodium chloride is as effective as 10 units of heparin in sodium chloride solution in maintaining intermittent infusion device patency and preventing phlebitis.
Effects of anxiety on family members of patients with cardiac disease learning cardiopulmonary resuscitation, The effects of anxiety on learning cardiopulmonary resuscitation (CPR) by family members of patients with cardiac disease was examined. Family members of hospitalized patients (n = 17). family members of nonhospitalized patients (n = 12). and a control group (n = 21) all took one of nine Heart Saver programs in which CPR was taught and performance evaluated. Subjects took the State Anxiety Inventory three times: immediately before the program. immediately after the performance test. and 2 months after completion of the program. Family members of hospitalized patients had significantly higher before-program anxiety scores than the other groups. This difference was not present immediately after the program or 2 months later. Family members of hospitalized patients showed a significant decline in anxiety over the three testing times. These outcomes support the benefit of teaching CPR to this group.
Chronic encephalitis caused by leukoencephalopathy, As mentioned previously. both MS and PML are demyelinating conditions of the CNS and pose diagnostic difficulties in their differentiation because of similarities in their clinical findings. However. certain features unique to each of these diseases are helpful in clinical diagnosis. MS. unlike PML. is a disease of unknown cause. Polygenetic influences in combination with exposure to an environmental agent and immune-mediated factors may be operative in the pathogenesis of MS. Age of onset peaks in the third to fourth decades with a predominance in women. as contrasted with PML. which peaks in the fifth to sixth decades in most non-AIDS-associated cases with a slight predominance in men. MS is more prevalent in areas farther from the equator: North America. Europe. Australia. and New Zealand. Common initial symptoms seen in MS include bilateral limb weakness (with the legs being affected twice as often as the arms). hyperreflexia. spasticity. optic neuritis. diplopia. incoordination. and paresthesias. (Paresthesias are typically found in the lower limbs in a symmetric pattern. but may follow no obvious anatomic distribution and often do not correspond to the distribution of sensory symptoms. Vibration and position sense are more frequently disturbed than pain and temperature.) Intellectual impairment and mental deterioration are uncommon early in MS. whereas they are a more frequent initial presentation in PML. In addition. the presence of speech impairment and monoparesis or hemiparesis with homonymous hemianopsia is more suggestive of PML. Brain stem involvement is infrequent.
Effects of tracheal irritation and hypercapnia on tracheal smooth muscle in humans, Both hypercapnia and tracheal irritation are known to constrict the airways in animals. To see whether similar responses occur in humans. we investigated tracheal smooth muscle (TSM) responses to hypercapnia and tracheal irritation with water in 14 paralyzed and anesthetized humans. TSM tone was monitored by measuring the pressure in the saline-filled cuff of the endotracheal tube. Although. tracheal irritation caused TSM constriction in 10 of 14 patients. 4 patients showed no TSM response. Administration of intravenous atropine attenuated the TSM constriction response. Hypercapnia did not cause any change in TSM tone in any of the 14 patients. These results indicate that in paralyzed and anesthetized humans. there exist interindividual differences in the TSM responses to tracheal irritation and that hypercapnia cannot be an effective stimulus for the TSM constriction.
Cerebral blood flow in acute mountain sickness, Changes in cerebral blood flow (CBF) were measured using the radioactive xenon technique and were related to the development of acute mountain sickness (AMS). In 12 subjects. ascending from 150 to 3.475 m. CBF was 24% increased at 24 h [45.1 to 55.9 initial slope index (ISI) units] and 4% increased at 6 days (47.1 ISI units). Four subjects had similar increases of CBF when ascending to 3.200 m 3 mo later. indicating the reproducibility of the measurements. In nine subjects. ascending from 3.200 to 4.785-5.430 m. CBF increased to 76.4 ISI units. 53% above estimated sea-level values. CBF and increases in CBF were similar in subjects with or without AMS. In six subjects. CBF was measured before and after therapeutic intervention. At 2 h CBF increased 22% (71.3 to 87.3 ISI units) above pretreatment values in three subjects given 1.5 g acetazolamide. while three subjects given placebo showed no change. Symptoms remained unaltered in all subjects during the 2 h of the study. Overall. the results indicated that increases in CBF were similar in subjects with or without AMS while acetazolamide-provoked increases of CBF in AMS subjects caused no acute change in symptoms. Alterations in CBF cannot be directly implicated in the pathogenesis of AMS.
Hydraulic conductivity of canine parietal pleura in vivo, The hydraulic conductivity (Lp) of the parietal pleura was measured in vivo in spontaneously breathing anesthetized dogs in either the supine (n = 8) or the prone (n = 7) position and in an excised portion of the chest wall in which the pleura and its adjacent tissue were intact (n = 3). A capsule was glued to the exposed parietal pleura after the intercostal muscles were removed. The capsule was filled with either autologous plasma or isotonic saline. Transpleural fluid flow (V) was measured at several transpleural hydrostatic pressures (delta P) from the rate of meniscus movement within a graduated pipette connected to the capsule. Delta P was defined as the measured difference between capsule and pleural liquid pressures. The Lp of the parietal pleura was calculated from the slope of the line relating V to delta P by use of linear regression analysis. Lp in vivo averaged 1.36 X 10(-3) +/- 0.45 X 10(-3) (SD) ml.h-1.cmH2O-1.cm-2. regardless of whether the capsule was filled with plasma or saline and irrespective of body position. This value was not significantly different from that measured in the excised chest wall preparation (1.43 X 10(-3) +/- 1.1 X 10(-3) ml.h-1.cmH2O-1.cm-2). The parietal pleura offers little resistance to transpleural protein movement. because there was no observed difference between plasma and saline. We conclude that because the Lp for intact parietal pleura and extrapleural interstitium is approximately 100 times smaller than that previously measured in isolated stripped pleural preparations. removal of parietal pleural results in a damaged preparation.
Fluctuation in timing of upper airway and chest wall inspiratory muscle activity in obstructive sleep apnea, An imbalance in the amplitude of electrical activity of the upper airway and chest wall inspiratory muscles is associated with both collapse and reopening of the upper airway in obstructive sleep apnea (OSA). The purpose of this study was to examine whether timing of the phasic activity of these inspiratory muscles also was associated with changes in upper airway caliber in OSA. We hypothesized that activation of upper airway muscle phasic electrical activity before activation of the chest wall pump muscles would help preserve upper airway patency. In contrast. we anticipated that the reversal of this pattern with delayed activation of upper airway inspiratory muscles would be associated with upper airway narrowing or collapse. Therefore the timing and amplitude of midline transmandibular and costal margin moving time average (MTA) electromyogram (EMG) signals were analyzed from 58 apnea cycles in stage 2 sleep in six OSA patients. In 86% of the postapnea breaths analyzed the upper airway MTA peak activity preceded the chest wall peak activity. In 86% of the obstructed respiratory efforts the upper airway MTA peak activity followed the chest wall peak activity. The onset of phasic electrical activity followed this same pattern. During inspiratory efforts when phasic inspiratory EMG amplitude did not change from preapnea to apnea. the timing changes noted above occurred. Even within breaths the relative timing of the upper airway and chest wall electrical activities was closely associated with changes in the pressure-flow relationship. We conclude that the relative timing of inspiratory activity of the upper airway and chest wall inspiratory muscles fluctuates during sleep in OSA.
Distribution of pulmonary capillary transit times in recruited networks, When pulmonary blood flow is elevated. hypoxemia can occur in the fastest-moving erythrocytes if their transit times through the capillaries fall below the minimum time for complete oxygenation. This desaturation is more likely to occur if the distribution of capillary transit times about the mean is large. Increasing cardiac output is known to decrease mean pulmonary capillary transit time. but the effect on the distribution of transit times has not been reported. We measured the mean and variance of transit times in single pulmonary capillary networks in the dependent lung of anesthetized dogs by in vivo videofluorescence microscopy of a fluorescein dye bolus passing from an arteriole to a venule. When cardiac output increased from 2.9 to 9.9 l/min. mean capillary transit time decreased from 2.0 to 0.8 s. Because transit time variance decreased proportionately (relative dispersion remained constant). increasing cardiac output did not alter the heterogeneity of local capillary transit times in the lower lung where the capillary bed was nearly fully recruited.
Rat soleus muscle ultrastructure after hindlimb suspension, The aim of the present investigation was to determine. by quantitative electron microscopy. the effects of a 5-wk tail-suspension period on rat soleus muscle ultrastructure. A marked decline (-60%) in muscle mass occurred. The mean fiber cross-sectional area decreased to a greater extent (-75%) than the capillary-to-fiber ratio (-37%). leading to a higher capillary density (+148%) after hypokinesia. The total mitochondrial volume density remained unchanged. whereas the volume density of myofibrils was slightly but significantly reduced (-6%). A shift from subsarcolemmal to interfibrillar mitochondria occurred. Interfibrillar mitochondrial volume density was highest near the fiber border and decreased toward the fiber center. An increase in volume density of satellite cells suggested muscle regenerative events. Soleus atrophy with tail suspension greatly decreases the muscular volume but leaves the ultrastructural composition of muscle fibers relatively unaffected.
Left ventricular asynchrony in patients with pulmonary hypertension, Left ventricular regional wall motion was evaluated in 11 patients with pulmonary hypertension and 18 control subjects. All 11 patients had secondary pulmonary hypertension and less than 20% measured diameter stenosis in any vessel. This study utilizes a video-intensity-based frame-by-frame computerized technique. All pulmonary hypertensive patients showed early diastolic asynchrony in the anterior or apical regions that lasted 100-200 ms. The size of the abnormal area varied from 2 to 20% of the ventricular silhouette. Four patients also showed systolic abnormalities. No abnormalities were detected in the control group. The cause of the asynchrony detected in pulmonary hypertension is probably due to interventricular interaction caused by pressure gradients across the septum.
Maximal O2 uptake of in situ dog muscle during acute hypoxemia with constant perfusion, We investigated the relationships among maximal O2 uptake (VO2max). effluent venous PO2 (PvO2). and calculated mean capillary PO2 (PCO2) in isolated dog gastrocnemius in situ as arterial PO2 (PaO2) was progressively reduced with muscle blood flow held constant. The hypothesis that VO2max is determined in part by peripheral tissue O2 diffusion predicts proportional declines in VO2max and PCO2 if the diffusing capacity of the muscle remains constant. The inspired O2 fraction was altered in each of six dogs to produce four different levels of PaO2 [22 +/- 2. 29 +/- 1. 38 +/- 1. and 79 +/- 4 (SE) Torr]. Muscle blood flow. with the circulation isolated. was held constant at 122 +/- 15 ml.100 g-1.min-1 while the muscle worked maximally (isometric twitches at 5-7 Hz) at each of the four different values of PaO2. Arterial and venous samples were taken to measure lactate. pH. PO2. PCO2. and muscle VO2. PCO2 was calculated using Fick's law of diffusion and a Bohr integration procedure. VO2max fell progressively (P less than 0.01) with decreasing PaO2. The decline in VO2max was proportional (R = 0.99) to the fall in both muscle PvO2 and calculated PCO2 while the calculated muscle diffusing capacity was not different among the four conditions. Fatigue developed more rapidly with lower PaO2. although lactate output from the muscle was not different among conditions. These results are consistent with the hypothesis that resistance to O2 diffusion in the peripheral tissue may be a principal determinant of VO2max.
Lung overexpansion increases pulmonary microvascular protein permeability in young lambs, To study the effects of inflation pressure and tidal volume (VT) on protein permeability in the neonatal pulmonary microcirculation. we measured lung vascular pressures. blood flow. lymph flow (QL). and concentrations of protein in lymph (L) and plasma (P) of 22 chronically catheterized lambs that received mechanical ventilation at various peak inflation pressures (PIP) and VT. Nine lambs were ventilated initially with a PIP of 19 +/- 1 cmH2O and a VT of 10 +/- 1 ml/kg for 2-4 h (base line). after which we overexpanded their lungs with a PIP of 58 +/- 3 cmH2O and a VT of 48 +/- 4 ml/kg for 4-8 h. QL increased from 2.1 +/- 0.4 to 13.9 +/- 5.0 ml/h. L/P did not change. but the ratio of albumin to globulin in lymph relative to the same ratio in plasma decreased. indicating altered protein sieving in the pulmonary microcirculation. Seven other lambs were mechanically ventilated for 2-4 h at a PIP of 34 +/- 1 cmH2O and a VT of 23 +/- 2 ml/kg (base line). after which their chest and abdomen were bound so that PIP increased to 54 +/- 1 cmH2O for 4-6 h without a change in VT. QL decreased on average from 2.8 +/- 0.6 to 1.9 +/- 0.3 ml/h (P = 0.08). and L/P was unchanged.
Effects of exercise on insulin-induced hypoglycemia, The purpose of this study was to determine the effect of exercise on the rate of onset of hypoglycemia induced by infusion of excess insulin (0.8 mU.min-1.100 g-1). Rats were either fasted overnight (FS) or fed ad libitum (FD). FS rats were killed after 5. 10. or 15 min of infusion at rest or after running on the treadmill at 21 m/min and 15% grade. FD rats were killed after 10. 20. or 40 min of infusion at rest or after exercise. Rats were also killed 15 min postexercise for FS and 60 or 120 min postexercise for FD with continued insulin infusion. The progressive decline in blood glucose was not altered by exercise in the FS rats. FD rats showed a significant difference due to exercise only after 40 min (rest 4.2 +/- 0.3 mM. exercise 3.2 +/- 0.2 mM). A significant postexercise repletion of glycogen was observed in red vastus and soleus muscles of FD rats despite the decreasing blood glucose values. These data indicate that exercise accelerates the rate of development of hypoglycemia in FD rats. In the FS rats. where the rate of decline in blood glucose was greater. exercise had no effect on the time course of development of hypoglycemia.
Two discharge patterns of carotid body chemoreceptors in the goat, Twenty-nine single carotid body chemoreceptor units recorded during normocapnic normoxia from 20 anesthetized goats were classified into two groups by discharge pattern. Thirteen fibers. which had interspike interval distributions with a prominent peak [24.0 +/- 9.8% (SD)] at 0- to 20-ms bin. were termed bursting fibers (BF). The 16 remaining fibers were termed nonbursting fibers (NBF); these had no notable peak in the interval distributions. During hypoxia and hypercapnia. the chemoreceptor fibers continued to discharge in their established patterns. The interval distribution of most NBF spike trains could be described with the Poisson process. but none of the BF could be. However. except for the intervals in the range of 0-20 ms. the interval distribution of the BF could be described as exponential. This study suggests that 1) there are two distinct populations of the goat chemoreceptor fiber. each with an inherent discharge pattern; 2) the chemoreceptor did not code information about arterial PO2 and PCO2 in different patterns; and 3) the basic chemotransduction mechanism is likely the same in BF and NBF. and the difference in discharge pattern is more likely to reflect processes downstream from the transducer.
Increased fatigue of isovelocity vs. isometric contractions of canine diaphragm, A comparison of fatigue as a loss of force with repeated contractions over time was performed in canine respiratory muscle by isometric (nonshortening) and isovelocity (shortening) contractions. In situ diaphragm muscle strips were attached to a linear ergometer and electrically stimulated (30 or 40 Hz) via the left phrenic nerve to produce either isometric (n = 12) or isovelocity (n = 12) contractions (1.5 s) from optimal muscle length (Lo = 8.8 cm). Similar velocities of shortening between isovelocity experiments [0.19 +/- 0.02 (SD) Lo/S] were produced by maximizing the mean power output (Wmax = 210 +/- 27 mW/cm2) that could be developed over 1.5 s when displacement was approximately 0.30 Lo. Initial peak isometric tension was 1.98 kg/cm2. whereas initial peak isovelocity tension was 1.84 kg/mc2 (P less than 0.01) or 93% of initial isometric tension. Fatigue trials of 5 min were conducted on muscles contracting at a constant duty cycle (0.43). At the end of the trials. peak isovelocity tension had fallen to 50% of initial isometric tension (P less than 0.01). whereas peak isometric tension had only fallen by 27%. These results indicate that muscle shortening during force production has a significant influence on diaphragm muscle fatigue. We conclude that the effects of shortening on fatigue must be considered in models of respiratory muscle function. because these muscles typically shorten during breathing.
Muscle oxidative capacity and work performance after training under local leg ischemia, Healthy young men executed supine one-legged cycle training four times per week for 4 wk with legs and the cycle ergometer inside a pressure chamber. the opening of which was sealed by a rubber membrane at the level of the crotch. Each training session started by training one leg under ischemic conditions induced by increased chamber pressure (50 mmHg) at the highest intensity tolerable for 45 min. Then the other leg was trained with the same power profile but normal atmospheric chamber pressure. Before and after the training period. both legs executed one-legged exercise tests under both normal and increased chamber pressure and muscle biopsies were taken from the vastus lateralis. Ischemic training increased performance more than normal training. the difference being greater for exercise executed under ischemic conditions. The difference in performance increase between the legs was paralleled by a greater muscle citrate synthase activity in the ischemically than in the normally trained leg.
Dealing with geographic variations in the use of hospitals. The experience of the Maine Medical Assessment Foundation Orthopaedic Study Group, Orthopaedists and other physicians in Maine organized the Maine Medical Assessment Foundation to deal with the problem of variations in the rates of hospitalization for orthopaedic conditions. Five musculoskeletal injuries and five orthopaedic procedures were selected for study. The variation in decision-making by orthopaedists was least for fractures of the ankle and fractures of the hip and was greatest for fractures of the forearm. derangement of the knee. and lumbosacral sprain. The rates in an area tended to be consistently high or low for the same treatments. The major reasons for the variations appeared to be related to lack of agreement about optimum treatment. Feedback of data to physicians on variations in patterns of practice reduced the variations.
Unexpected geographic variation in rates of hospitalization for patients who have fracture of the hip. Medicare enrollees in the United States, With the use of data from hospitals for fiscal year 1985. we calculated the rates of hospitalization for fracture of the hip. by state of residence. for all enrollees in Medicare who were sixty-five years old or older; we adjusted for age and race. The rate of fracture of the hip was highest in the South and lowest in the Northeast. especially in women. The cause of this difference is not known.
Arthrometric evaluation of knees that have a torn anterior cruciate ligament, We used the KT-1000 arthrometer to test the knees of 107 patients who had an acute tear of the anterior cruciate ligament. 153 patients who had a chronic tear. and 141 control subjects. for a total of 401 individuals. The three testing parameters were the extent of anterior translation at eighty-nine newtons of force and at maximum manual force. and the compliance index. The differences between the involved and the uninvolved knees were calculated. At eighty-nine newtons. all but one of the control subjects had anterior translation of ten millimeters or less. compared with 58 per cent of the patients who had a chronic tear. At maximum manual force. all but two of the control subjects had translation of ten millimeters or less. compared with 20 per cent of the patients who had an acute or a chronic tear. Analysis of variance showed that the clinical diagnosis correlated well with the results for all tests (p less than 0.001). However. when the uninjured knees of patients who had an acute or a chronic tear were compared with the knees of the control subjects. significant differences were noted (p less than 0.001 to 0.006). In the patients who had a chronic tear. there was no relationship between the time from injury to operation and the extent of anterior translation. The arthrometric test at maximum manual force was the strongest discriminant; it differentiated normal from abnormal knees (p less than 0.001) with high sensitivity (92 per cent). high specificity (95 per cent). and high positive predictive accuracy; the cut-off point was eleven millimeters or less.
Evaluation of an electrogoniometric instrument for measurement of laxity of the knee, Eight lower extremities from cadavera were tested for anterior-posterior laxity in two positions before and after transection of the anterior cruciate ligament. At critical points in the tests. electrogoniometric and radiographic measurements of tibiofemoral translation were compared. By direct measurement. we determined the accuracy of the radiographic method to +/- 0.4 millimeter (95 per cent) in measuring anterior-posterior translations of the tibia with respect to the femur. The electrogoniometer estimated displacement of the tibia with respect to the femur during the anterior drawer test to be 3.5 +/- 8.2 millimeters at 90 degrees of flexion of the knee and 11.1 +/- 16.1 millimeters at 30 degrees of flexion. Direct comparison of these measurements with those obtained by means of the radiographic technique showed that the electrogoniometer tended. on average. to overestimate the tibial translation. The amount of overestimation was 0.7 millimeter for intact knees and 1.9 millimeters after sacrifice of the anterior cruciate ligament. Despite this small average error in measurement of tibial translation. the difference between individual electrogoniometric and radiographic measurements varied greatly. with a 95 per cent confidence limit of +/- 5.5 millimeters. The error of the electrogoniometric measurements varied with the angle of flexion of the knee during testing. both the accuracy and the reliability of the electrogoniometric measurements being greatly diminished at 30 degrees of flexion. The electrogoniometric method also tended to overestimate tibial internal rotation (by an average of 10.5 degrees) and external rotation (by an average of 9.3 degrees); the reliability of these measurements was +/- 6.9 degrees.
Arthrodesis of the ankle with cancellous-bone screws and fibular strut graft. Biomechanical analysis, The stability of an arthrodesis with two cancellous-bone screws across the ankle joint was evaluated in eighteen ankles from fresh-frozen cadavera. Tibiotalar motion was recorded in response to the following loading modes: medial-lateral moment. plantar flexion-dorsiflexion moment. and internal-external tibial torque. The series of loading tests was performed with two cancellous-bone screws through the tibia into the talus and a lateral fibular strut graft fixed with a proximal and a distal screw. The tests were repeated after the strut graft was removed. and again after it had been reapplied. The amount of motion at the site of the arthrodesis was greatest with tibial torque and was least with medial-lateral bending; this was true for specimens with or without a fibular strut graft. Removal of the strut graft allowed increased tibiotalar motion for all modes of loading; increases in motion were far greater for specimens of poor bone quality.
Spondyloepiphyseal dysplasia of Maroteaux, The cases of four patients who had an unusual clinical entity of disproportionately short stature. referred to as spondyloepiphyseal dysplasia of Maroteaux. are described. In patients who have this syndrome. the abnormalities are confined to the musculoskeletal system. The patients do not have corneal opacities or increased excretion of keratosulphate. The mode of transmission appears to be autosomal dominant. Platyspondylysis is present but there are no anterior tongue-like deformities of the vertebral bodies. Because of the presence of spondyloepiphyseal dysplasia and normal intelligence. and the lack of abnormalities at birth. this entity seems to mimic Morquio syndrome. However. unlike Morquio syndrome. the disorder involves no biochemical abnormalities. Thus. the entity may be classified as new.
Replantation of the distal part of the leg, We successfully replanted five amputated legs in five patients and followed the patients for two years or more (average. six years and three months). Although some patients found it impossible to squat and to run because of joint contractures. muscle weakness. or deformities of the foot. all patients could perform other activities without difficulty. None had important pain or any intolerance to cold. and all were satisfied with the results of the replantation.
The osteogenic response to distant skeletal injury, We tested the hypothesis that when one bone of the skeleton is injured. others experience an osteogenic response. Although similar or related phenomena have been observed previously. the purposes of the study were to determine if this response was reproducible. to characterize it in terms of its magnitude and duration. and to show how it is related to the type of injury sustained. To obtain this information. a model was used in which an intramedullary nail was implanted in the femur and a standard closed fracture was subsequently produced. The osteogenic response was measured by histomorphometry. Eight-four nine-week-old male Sprague-Dawley rats were divided into seven groups of twelve animals each. Groups I and II consisted of control animals in which no injury was produced. In Group-III rats. cortical drilling of the intercondylar notch and piriformis fossa of the right femur was performed. without intramedullary nailing. In Groups IV through VII. half of each group received intramedullary nails only. and in the other half intramedullary nailing was done and a closed transverse diaphyseal fracture was produced. With two different fluorochrome labels. rates of mineral apposition were measured in the left and right tibiae of all animals. The labeling periods differed in each group and were designed to determine when the peak response occurred. how long it lasted. and whether aging during the course of the experiment affected the response.
Surgical treatment of aneurysm or dissection involving the ascending aorta and aortic arch, utilizing circulatory arrest and retrograde cerebral perfusion, Recently we replaced the ascending aorta and aortic arch in 8 patients with aneurysm or dissection. using profound hypothermic circulatory arrest with retrograde cerebral perfusion. There were no operative deaths. Open aortic anastomosis facilitated repair of the aortic arch without clamping the arch tributaries. and embolism due to particulate debris from clamping of the arch vessels was eliminated. Retrograde cerebral perfusion during profound hypothermic circulatory arrest is a simplified technique that may protect the brain. This method offers advantages over previously described methods. particularly in obviating dissection of the arch tributaries and the clamping thereof. and in protecting the central nervous system.
Measurement of resistance versus flow in assessing efficiency of aortocoronary bypass grafts, Measurement of flow in saphenous bypass grafts with an electromagnetic flowmeter is complicated and poorly reproducible. Since coronary flow is largely dependent on variable factors the stable value of resistance seems more appropriate for comparison. A simple method has been developed for intraoperative measurement of resistance in the respective coronary bed. Pressure is recorded in the saphenous graft by an electromanometer during continuous flushing with known amounts of blood. and resistance is calculated instantaneously. The procedure is very simple and takes less than one minute. The quality of the saphenous vein itself can be assessed simultaneously by the same method. Resistances were measured during coronary surgery in over 500 saphenous grafts. The results were highly reproducible and comparable. Excellent flows can be expected if resistance is below 200 Peripheral Resistance Units (PRU); if this is over 800 PRU flow is very poor.
The effect of enoximone and dobutamine on hemodynamic performance after open heart surgery. A clinical comparison, In a prospective. randomized study the phosphodiesterase inhibitor enoximone was compared to dobutamine after open heart surgery. In either group 25 patients were treated with enoximone and dobutamine. respectively. beginning immediately after weaning from cardiopulmonary bypass until 4 hours postoperatively. The drug was administered as a continuous infusion of 5 micrograms/min/kg body weight. Under enoximone a significant increase of cardiac output [enoximone (E): + 100%; dobutamine (D): + 38%] and a significant decrease of pulmonary vascular resistance (E: -34%. D: +65%) and of total systemic vascular resistance (E: -59%. D: -7%) was achieved. Systemic blood pressure and heart rate were not different. Side effects were not observed. Enoximone proved to be safe and superior to dobutamine in low cardiac output states after open heart surgery.
Submammary median sternotomy, A vertical skin incision is used as routine approach for sternotomy. The resulting scar is often disappointing and the top is visible and unpleasant. especially for young women. In 35 women ranging from 10 to 48 years (mean 29.2 years). median sternotomy was performed via a submammary skin incision. In all cases an open heart surgical procedure was performed. Adequate exposure of the heart was achieved in every case and there were no technical problems related to this approach. no hospital mortality or major complications. The cosmetic result is excellent and this approach is certainly justified in open heart surgery for young women.
Valvular and coronary surgery in renal transplant patients, The Authors report aortic valvular replacement (AVR) and coronary artery bypass graft surgery (CABG) successfully performed in two renal transplant patients. The postoperative blood urea and creatinine levels were comparable to the preoperative values. The first patient underwent isolated AVR. The second patient had an initial AVR combined with CABG followed two years later by a further AVR for prosthetic dysfunction. For many reasons. coronary artery (CAD) and valvular diseases are not uncommon in renal transplant patients. Cardiac surgery is feasible without impairment of the renal function provided some precautions are taken. ie good mean perfusion pressure during cardiopulmonary bypass (CPB). adequate volume replacement. and selected use of mannitol and dopamine.
Successful surgical treatment of subaortic stenosis caused by an accessory mitral valve, A 22-month-old boy with subaortic stenosis was found to have relatively mature mitral valve tissue beneath the aortic valve. associated with a hypertrophic and prominent interventricular septum. This tissue caused obstruction of the left ventricular outflow tract and resulted in a pressure gradient of 70 mmHg between the aorta and the left ventricle. Surgical treatment was successfully performed to excise the tissue and part of the hypertrophic ventricular septum. Results of microscopic examination of the resected specimen are shown and discussed.
Traction injury in the internal mammary artery. Report of a case and review of the literature, The internal mammary artery (IMA) is now used routinely along with saphenous vein for myocardial revascularization procedures. We have documented a particular form of non-perforating injury which may reduce blood flow during operation or may lead to early closure of the IMA bypass graft. Traction injury to the intima is well documented in other vessles but has not been previously reported in the IMA. We present a potentially disastrous example of traction injury to the IMA.
Assessment of major venous anomalies by computerized tomography, Congenital anomalies of major venous structures are not common but their identification and relative position. particularly in relation to an abdominal aortic aneurysm. are of significant value in planning and conducting aortic operations. Computed tomography (CT) has become a common method of preoperative evaluation of aortic disease. Its reliability in providing accurate information regarding aneurysmal size. configuration. and extension. as well as the presence of intraluminal thrombus and involvement of the renal and iliac arteries. has been demonstrated. Simultaneous visualization of the major adjacent venous structures with the use of contrast enhancement is obtained. but anatomic variants can be overlooked because they are commonly subtle and considered incidental. The preoperative diagnosis of these venous abnormalities is significant to the vascular surgeon. Such information can be accurately and reliably acquired with the present CT techniques without the need for further diagnostic studies.
Left retroperitoneal exposure for distal mesenteric artery repair, Distal disease in the mesenteric arteries has usually been repaired transabdominally since it is believed that only the proximal centimeter of each vessel is accessible through the retroperitoneum. We treated five patients with chronic visceral ischemia and lesions extending beyond the orifice using a retroperitoneal approach. Exposure was obtained with a left flank incision through the tenth interspace. The left crus of the diaphragm was divided in order to control the supraceliac aorta. The mesenteric vessels were identified and dissected until their entrance into the peritoneum. There were no difficulties in exposing the superior mesenteric artery (SMA) as it coursed under the pancreas and over the duodenum for an approximate length of 5 to 10 cm. The uncinate process of the pancreas was not a limiting factor for exposure of the SMA in this region and further distal exposure could be obtained by incising the peritoneum. The trifurcation of the celiac artery and the splenic artery were accessible through this exposure; however. only the first centimeter of the hepatic and gastric branches could be reached. Revascularization was performed with endarterectomy (2 patients) and bypass (3 patients). Bowel viability was assessed at the conclusion of the procedure by incising the peritoneum. There were no complications from this exposure and no patient required reoperation for ischemic bowel. We conclude that the left retroperitoneal approach is not only acceptable for orifice lesions but is also applicable for distal disease.
The effect of adjunctive arteriovenous fistula on prosthetic graft patency: a controlled study in a canine model, Bilateral 6 mm PTFE grafts were placed from the external iliac artery to the femoral artery with ligation of the intervening segment of the iliofemoral artery in 14 dogs. An arteriovenous fistula was constructed at the distal anastomosis on one randomly selected side in each animal while the contralateral graft served as a control. Graft follow-up ranged between 8 and 12 months in all animals. Serial arteriography was performed to confirm graft and fistula patency and demonstrated persistence of antegrade flow into the arterial tree distal to all patent bypasses. Femoral intraarterial pressures distal to patent grafts were identical on both sides in each animal throughout the study. Cumulative life-table patency rates showed higher patency for the arteriovenous fistula bypasses than the control grafts at all time intervals: 71% vs. 57% at 3 months. 48% vs. 25% at 6 months. and 40% vs. 22% at 12 months. respectively. This is the first controlled study that provides experimental evidence suggesting that these bypasses may produce increased patency of prosthetic arterial grafts and lends support to their use in a clinical. prospective. randomized study.
Effect of antiplatelet and anticoagulant therapy on patency of femorotibial bypass grafts, In a retrospective study. 210 autogenous femorotibial saphenous vein grafts inserted during the 15 years from 1967 to 1982 were followed-up for a mean period of 62.3 +/- 5.7 months. Seven patients. who had had eight grafts died in hospital. The remaining 202 grafts fell into three groups: (1) Sixty grafts in patients who received 325 mg of dipyridamole and 1.0 g of acetylsalicylic acid daily. starting on the second postoperative day and continuing for six months. (2) One hundred and two grafts in patients on no antithrombotic therapy. (3) Forty grafts in patients on warfarin therapy to maintain the prothrombin time (prothrombin-proconvertin method) within the therapeutic range (0.10 to 0.20). Medication was continued for six months. This group included more high-risk patients than the other two groups. The mean ages and the incidence of risk factors did not vary significantly between the groups. The patency rates in three groups at five years were 62.5%. 44.0% and 26.0% and at ten years 48.5%. 25.0% and 21.5% for the dipyridamole and acetylsalicylic acid. no therapy and warfarin groups. respectively. The limb salvage rates were 100%. 96% and 85% in the dipyridamole and acetylsalicylic acid. no therapy and warfarin groups respectively. Thus. the best results were seen in the aspirin/dipyridamole group.
Balloon dilatation versus surgical revision of infra-inguinal autogenous vein graft stenoses: long-term follow-up, Although infra-inguinal autogenous vein graft stenoses may be treated by balloon dilatation (PTA) or surgical revision. the optimal approach is undefined. Over the last 7 years 24 PTA procedures were performed on 37 vein graft stenoses in 19 grafts. Graft stenoses were diagnosed from 2 to 72 (mean = 17.3) months after implantation. PTA was successfully completed in 23 (96%) of the 24 procedures including 18 (95%) of the primary. and 5 (100%) of the secondary procedures. Recurrent vein graft stenosis or graft thrombosis developed in 12 (67%) grafts from 3 to 47 (mean = 12.5) months after primary PTA. Long-term patency after primary PTA was 69% at 6. 29% at 12. and 22% at 36 months; secondary patency was 81% at 6. 45% at 12. and 27% at 36 months. During the same period vein graft stenosis in 7 fem-pop and 2 fem-tib grafts were surgically revised with an initial success rate of 100%. and 2 (22%) complications. Four (44%) of these grafts occluded from 1-17 (mean 6.2) months after repair. yielding a primary 5-year patency of 62%. Although vein graft stenosis may be safely. effectively. and repeatedly treated with PTA. long-term durability appears to be superior after surgical revision.
Surveillance of in situ infrainguinal bypass grafts: conventional vs. color flow duplex ultrasonography, Surveillance of in situ saphenous vein bypass grafts with duplex scanning detects graft abnormalities which may lead to graft thrombosis. Correction of these defects. while grafts are still patent. potentially improves overall graft patency. In this study we compared color flow and conventional duplex to determine whether color flow provided additional information not obtainable by conventional duplex examination. The primary patency rate (patency maintained without intervention) for all 51 cases was 76% (39/51). The secondary patency rate (patency maintained by identification and correction of graft defects before failure) was 88% (45/51). Duplex scanning reduced the graft failure rate by 50%. Color flow and conventional duplex examination provided the same information regarding incipient graft failure. In 20 patients monitored with both techniques. the same number of proximal (100%) and distal (90%) anastomoses were imaged. The same number of graft defects (three vein graft stenoses. one proximal femoral artery stenosis) were identified. Velocity data obtained using the two techniques (peak systolic velocity in an area of stenosis and the duplex velocity ratio) were not always the same. making calculation of percent stenosis from this data inaccurate. Color flow duplex is useful in monitoring graft patency. but provides no additional information over that provided by conventional scanning.
Primary varicose veins: topographic and hemodynamic correlations, This study was conducted to correlate the clinical presentations of uncomplicated primary varicose veins with the topographic and anatomic source of reflux (escape points). One-hundred sixty-three patients with primary varicose veins (144 females. 19 males; 96 unilateral. 67 bilateral) in 230 involved limbs were examined. The origin and extent of venous reflux was traced with Doppler ultrasound. Three distinct groups were recognized. Group I. Typical saphenous varicosities with junctional escapes occurred in 164 (71.3%). Sapheno-femoral junction (SFJ) incompetence in 147. and sapheno-popliteal junction (SPJ) incompetence in 17 limbs. Group II. Atypical saphenous varicosities with non-junctional escapes occurred in 51 (22.17%) limbs. In 5 limbs. no escape was detected. Twenty-two limbs had escapes localized in the main perforators: mid-thigh perforator 17. upper calf 2. distal ankle in 3. Twenty-four limbs had their escapes in the auxiliary perforators: abdomino-pelvic 17. and circumflex iliac/external epigastric. 7 limbs. Group III. Non saphenous (lateral venous system) varicosities occurred in 15 (6.52%) limbs. Based on physical examination alone. 55 limbs would possibly have undergone unnecessary ankle to groin stripping and 83 limbs an unnecessary SFJ ligation. Doppler US is an essential diagnostic tool that can accurately map the origin and extent of the venous reflux. The obtained hemodynamic information will permit more selective. multimodal therapy and avoid the indiscriminate. often unnecessary stripping of the entire saphenous system in all cases of primary varicose veins.
Clinical review 15: Management of ovulatory disorders with pulsatile gonadotropin-releasing hormone, Pulsatile GnRH therapy has yet to achieve widespread acceptance as an alternative to exogenous gonadotropin therapy in women with hypothalamic amenorrhea and complete GnRH deficiency. However. when a physiologically based replacement regimen of pulsatile GnRH is used. a high rate of ovulation and conception can be anticipated in patients with complete GnRH deficiency and hypothalamic amenorrhea. Women with polycystic ovarian syndrome may also benefit from pulsatile GnRH. although rates of ovulation are lower. Pretreatment with a GnRH agonist may improve these rates considerably. but experience is limited. Whether an iv or sc route of administration is chosen. a simplified clinical monitoring protocol can be created which requires a minimum of patient monitoring while assuring maximum safety. Seventy five nanograms per kg appears to be a reasonable initiating dose. with subsequent increases in those who do not respond. The frequency of GnRH administration is best based on the GnRH pulse frequency in normal women. However. further information is needed to determine whether such a variable frequency is clearly superior to a fixed frequency regimen. When used appropriately. pulsatile GnRH is safe. effective. and offers an excellent alternative to conventional gonadotropin therapy for women with disordered endogenous GnRH secretion. Most importantly. and as opposed to exogenous gonadotropin therapy. pulsatile GnRH can be administered by most physicians in the office setting without the necessity of on-line E2 monitoring. This feature will enable more patients to receive treatment by their local physicians. whereas exogenous gonadotropin therapy should be administered by appropriately equipped referral centers. In the future. further studies will be required to determine which other categories of patients might benefit from pulsatile GnRH.
Reproducibility of growth hormone testing procedures: a comparison between 24-hour integrated concentration and pharmacological stimulation, The purpose of this study was to compare the reproducibility of two approaches to the evaluation of GH secretion: the integrated concentration of GH (IC-GH). a physiological test of GH secretion. and pharmacological stimulation tests. IC-GH was determined in 40 poorly growing children twice within 4 weeks. The first and second IC-GH were highly correlated r = 0.859. P less than 0.001. One hundred and thirteen poorly growing children underwent pharmacological GH stimulation tests twice within 6 weeks. A moderate correlation was found between the first and second pharmacological test r = 0.524. P less than 0.01. Among the three pharmacological stimuli studied. clonidine (n = 81) had the highest reproducibility followed by arginine (n = 20). and insulin (n = 12). We conclude that IC-GH is more consistently reproducible than the GH response to repeated pharmacological stimulation.
Thyroid hormones influences sex steroid binding protein levels in infancy: study in congenital hypothyroidism, In order to test the hypothesis of a role of thyroid hormones on the circulating levels of sex steroid binding protein (SHBG) in children. SHBG levels were determined in 15 infants with congenital hypothyroidism at diagnosis and during the first 18 months of T4 therapy and in a separate group of 13 children with congenital hypothyroidism (7.1 +/- 0.5 yr. mean +/- SD). treated before 1 month of age. both during adequate L-T4 therapy and 4 weeks after withdrawing therapy. SHBG levels were significantly lower in hypothyroid infants than in controls (48.2 +/- 6.5 vs. 77.8 +/- 7.9 nmol/L; P less than 0.01). and significantly lower in infants with athyreosis compared to those with ectopic or eutopic glands (P less than 0.05). In patients with low values at diagnosis. SHBG increased rapidly and remained normal during LT4 therapy. After 1.5-18 months of treatment. a positive correlation (P less than 0.01) was found between SHBG. FT4. and FT3 levels. In older hypothyroid children. 4 weeks after withdrawal of therapy a significant (P less than 0.05) decrease in SHBG concentrations was observed. Analysis of these results as well as previous reports in adults. indicates that thyroid hormones influence SHBG concentrations in infants and children. This study also indicates that thyroid hormones may play a role in the physiological postnatal increase of SHBG.
Defective fasciculata zone function as the mechanism of glucocorticoid-remediable aldosteronism, Glucocorticoid-remediable aldosteronism is characterized by unusual sensitivity of aldosterone secretion to ACTH. Suppressibility by glucocorticoid and continued stimulability by exogenous ACTH has provided the basis for diagnosis and treatment of the disorder. A qualitative biochemical abnormality consisting of marked overproduction of the products of the cortisol C-18 oxidation pathway. 18-hydroxycortisol and 18-oxocortisol. has been examined in 10 patients with the disorder and compared to the normal C-18 oxidation products of corticosterone. aldosterone. and 18-hydroxycorticosterone. The technique. based on stable isotope dilution mass fragmentography. measured the tetrahydro urinary metabolites of aldosterone. 18-hydroxycorticosterone. and 18-oxocortisol and unmetabolized 18-hydroxycortisol. All 4 C-18 oxygenated corticosteroids were markedly elevated in the untreated state and showed rapid parallel suppression with low doses of glucocorticoid. The proportional changes in C-18 oxygenated cortisols together with aldosterone and 18-hydroxycorticosterone suggested the mechanism of a common catalytic site of a cytochrome P450 methyl oxidase serving both cortisol and corticosterone substrates. The ACTH-dependent secretion of the C-18 oxidation products of both corticosterone and cortisol in the disorder is attributed to the acquisition of methyl oxidase activity by the fasciculata zone. where there are abundant pools of these precursors.
Hypothalamic-pituitary-adrenal function in patients with the premenstrual syndrome, Patients with primary affective disorders. such as melancholic depression and anorexia nervosa. frequently have a hyperactive hypothalamic-pituitary-adrenal (HPA) axis. characterized by hypersecretion of CRH and a blunted ACTH response to exogenous CRH. Premenstrual syndrome (PMS) is a luteal phase dysphoric disorder characterized by primarily affective and behavioral disturbances. HPA axis function was compared in PMS patients and control women. respectively. diagnosed by DSM3-R criteria or found to have no current psychiatric disorders. determined by the Schedule for Affective Disorders and Schizophrenia-Lifetime Interview. Urinary free cortisol excretion was the same in PMS and normal women. and no differences in urinary free cortisol excretion between the follicular and luteal phases occurred in either group. Two HPA axis abnormalities. however. were noted when PMS patients were compared to normal women. First. basal evening cortisol concentrations in plasma were significantly decreased. while the time-integrated response of plasma cortisol to ovine (o) CRH was significantly increased. Second. the negative correlation between time-integrated plasma ACTH and cortisol responses to oCRH and basal luteal progesterone concentrations present in normal control women was not seen in the PMS patients. These changes in basal and oCRH-stimulated plasma cortisol levels in association with normal urinary free cortisol excretion suggest that women with PMS might have transient or episodic disturbances of their HPA axis. which appear adequately corrected by this system's servomechanisms. This probably explains the maintenance of regular menstrual cycles in PMS patients. which contrasts with the irregular menses observed in patients with depression. anorexia nervosa. or women who participate in chronic strenuous exercise.
Insulin-like growth factor-II: possible local growth factor in pheochromocytoma, Pheochromocytomas. neural crest tumors. express an abundance of insulin-like growth factor-II (IGF-II). To assess further the potential for IGF-II to play an autocrine role for these tumors. we measured 1) IGF-II content by RRA in 7 pheochromocytomas and peripheral blood in these patients. 2) IGF-II receptors by Western analysis. and 3) characterized the tumor binding proteins by ligand blot studies. IGF-II levels in the tumors varied from 2.8-41 micrograms/g. Chromatography revealed that 60% of the peptide eluted as a large mol wt form of IGF-II (8.7-10 kDa); the remainder coeluted with mature peptide (7.5 kDa). This was in contrast to IGF-II levels in normal adrenal tissue (0.225 +/- 0.005 micrograms/g) or another neural crest-derived tumor. medullary carcinoma of the thyroid (0.63 +/- 0.02 micrograms/g). Serum IGF-II levels in the 7 patients with pheochromocytoma (720 +/- 71 ng/mL) were similar to those in 35 normal controls (762 +/- 69 ng/mL). Radiolabeled IGF-II (9 +/- 1%) and IGF-I (20 +/- 2%) bound specifically to pheochromocytoma membranes. Western analysis of these membranes using a specific antiserum directed against the type II receptor demonstrated a band at 210 kDa. Affinity cross-linking studies with [125I]IGF-I demonstrated a specific band at 140 kDa. Ligand blot analysis was performed on the void volume pools from the Sephadex G-75 column and demonstrated bands at about 30 and 25 kDa. In conclusion. these data 1) confirm that pheochromocytomas have increased levels of IGF-II; 2) demonstrate that despite high IGF-II concentrations in the tumors. peripheral levels are not elevated. suggesting that very little tumoral IGF-II is released into the circulation. unlike catecholamines; 3) demonstrate the presence of IGF-II and IGF-I receptors; 4) describe binding protein species similar to those present in other tissues. Thus. the presence of high levels of IGF-II and both type I and type II receptors suggests that IGF II may act through both receptors to alter tumor growth.
Short term treatment of acromegaly with the somatostatin analog octreotide: the first double-blind randomized placebo-controlled study on its effects, Several studies suggest that the somatostatin analog octreotide. or SMS 201-995. may effectively reduce GH hypersecretion. However. no double blind. placebo-controlled study has substantiated these findings. We present the results of a randomized double blind 14-day clinical trial with octreotide in 20 patients with acromegaly. The drug was given sc every 8 h and to the initial dose (50 micrograms) was added another 50 micrograms every other day up to 200 micrograms. GH levels. calculated as the mean values of 12 observations at hourly intervals during 0700-1800 h. and insulin-like growth factor-I (IGF-I) levels were significantly reduced during octreotide treatment. Responses varied from a reduction of 97% of the basal mean GH level to no significant reduction in 2 of 10 patients. There was a good correlation between the reduction of GH and IGF-I levels. The main side-effects were gastrointestinal and well tolerated. We found a spontaneous variation of daily mean GH and IGF-I levels (at 0700 h) in the placebo group. ranging from approximately 150% to 50% of the GH and 120% to 80% of the IGF-I levels noted on day 0. In patients treated with octreotide. the occurrence of GH rises between administration times suggests that it may be desirable to give octreotide every 6 h in some patients.
Glucose and gluconeogenic substrate exchange by the forearm skeletal muscle in hyperglycemic and insulin-treated type II diabetic patients, To determine the contribution of skeletal muscle to fasting hyperglycemia in noninsulin dependent type II diabetes (NIDDM). the forearm balance of glucose. lactate. and alanine was quantified in 25 control subjects. 21 hyperglycemic (blood glucose: 11.6 mmol/L). and 19 insulin-treated patients with NIDDM (blood glucose: 5.8 mmol/L). Forearm glucose uptake was similar in controls (4.6 +/- 0.6 mumol L-1 min-1) and in hyperglycemic diabetic patients (4.5 +/- 0.9 mumol L-1 min-1). In spite of this. in the diabetic patients lactate (5.1 +/- 0.8 mumol L-1 min-1) and alanine (2.6 +/- 0.4) release by the forearm was 3- and 2-fold higher than in the control group (lactate: 1.7 +/- 0.8. P less than 0.005; and alanine: 1.3 +/- 0.2. P less than 0.05. respectively). The ratio of lactate release to glucose uptake was 57% and 18% in diabetic and control subjects. respectively. Insulin administration did not affect either glucose uptake or the release of gluconeogenic substrates by the forearm. It is concluded that: 1) in fasting patients with NIDDM. glucose is taken up by the skeletal muscle in normal amounts but preferentially used nonoxidatively with lactate formation. This suggests that. although the muscle does not contribute directly to fasting hyperglycemia. it may play an indirect role through an increased delivery of glucose precursors; and 2) insulin-induced normoglycemia is maintained by mechanisms that do not involve the exchange of glucose and gluconeogenic substrates by the skeletal muscle.
Cold follicles in a multinodular human goiter arise partly from a failing iodide pump and partly from deficient iodine organification, To investigate whether the common cold follicles in human multinodular goiters are the consequence of a functional defect of the apical membrane peroxidase. a failure of the iodide transport system. or both deficiencies. we studied iodide accumulation and iodine organification in 30 fragments of a large multinodular goiter transplanted to nude mice and labeled with 125I. Transplants were frozen to -80 C immediately after removal to avoid diffusion of inorganic iodide. Autoradiographic assessment of over 1000 cryosections (exposed either at -20 C or after thawing and washing out unbound iodide) showed two types of cold follicles. namely those that failed to accumulate iodide and. therefore. did not organify iodine. and those that readily accumulated iodide but failed to bind it. suggesting a failure of apical membrane peroxidase. The two types of pathogenetically different cold follicles coexisted in an apparently randomly intermingled fashion throughout the whole goiter.
Transthyretin receptors on human astrocytoma cells, Transthyretin (TTR). a transport protein for T4 and retinol-binding protein. is the principal T4-binding protein of cerebrospinal fluid. Its function in regard to the delivery of its ligands and in other respects is unclear. The binding of [125I] TTR to cultured human astrocytoma cells was studied to determine whether these cells carry receptors for TTR. Scatchard analysis was consistent with a single class of binding sites with a Kd of 3 nM. No significant cross-reactivity with transferrin or serum albumin was observed. Internalization of TTR was temperature dependent and proportional to receptor occupancy. Dilutions of cerebrospinal fluid displaced [125I]TTR in proportion to their content of radioimmunoassayable TTR and in parallel with purified TTR. The uptake and internalization of TTR increased in the presence of high T4 or T3 concentrations. These results demonstrate that TTR binds to specific high affinity receptors on human astrocytoma cells. Receptor binding of TTR provides a potential mechanism for the delivery of its ligands within the central nervous system.
Effect of central obesity on regulation of carbohydrate metabolism in obese patients with varying degrees of glucose tolerance, It has been proposed that central obesity. by virtue of the enhanced lipolytic activity of abdominal adipose tissue. leads to higher plasma FFA concentrations. which. in turn. decrease both hepatic removal of insulin and insulin-stimulated glucose uptake by peripheral tissues. In short. the predicted consequences of abdominal obesity are elevations in circulating FFA and insulin levels as well as insulin resistance. The goal of this study was to evaluate the relationships predicted by the overall hypothesis; this study was carried out in 31 obese females. defined as having normal glucose tolerance (n = 12). impaired glucose tolerance (n = 8). or noninsulin-dependent diabetes mellitus (n = 11). Abdominal obesity was estimated by determining the ratio of waist to hip girth. fasting and postprandial plasma FFA and insulin concentrations were measured at hourly intervals from 0800-1600 h. and insulin-stimulated glucose disposal was quantified by the euglycemic hyperinsulinemic clamp technique. The first step in the postulated sequence of events to be tested was that the greater the WHR. the higher the total integrated plasma FFA response. The correlation coefficient between these two variables was 0.29. indicating that the results did not support the prediction. Furthermore. we could not demonstrate any relationship between the magnitude of the plasma FFA and insulin responses (r = 0.20; P = NS). However. there was a modest inverse relationship between height of circulating plasma insulin concentration and a decrease in insulin-stimulated glucose uptake (r = -0.43; P less than 0.03) in the group as a whole. On the other hand. when the three groups were analyzed individually. a significant inverse relationship was only seen in the control group (r = -0.67). and a direct relationship was actually seen in patients with impaired glucose tolerance (r = 0.88). Furthermore. when the mean responses for the variables in each of the three groups were compared. it was apparent that the postulated relationships between abdominal obesity. plasma FFA concentration. and insulin secretion and action were not present. Thus. the data presented do not support the hypothesis that differences in the degree of central obesity play an important role in regulation of plasma concentrations of either FFA or insulin or in modulation of insulin-stimulated glucose uptake in the patients we studied.
Beta-cell cytoadherent lymphocytes in some subjects at risk for type 1 (insulin-dependent) diabetes: progression to diabetes within 2 years, The increased binding in vitro of CD3 CD4 T-lymphocytes from type 1 (insulin-dependent) diabetic patients to beta-cell membrane antigens compared to lymphocytes from control subjects was previously shown to be a marker of cell-mediated immunity. called diabetic rosettes. In the present study diabetic rosettes were detected in some subjects at risk for type 1 diabetes (first degree relatives of type 1 diabetic patients or nondiabetic subjects with previous transient hyperglycaemia). The mean number of lymphocytes adherent to beta-cells (beta-CL) was significantly higher in subjects at risk for type 1 diabetes than in age- and sex-matched control blood bank donors (P less than 10(-6]. This number of beta-CL was higher in type 1 diabetic patients than in subjects at risk (P less than 10(-6]. and one-way analysis of variance by rank (Kruskal-Wallis) revealed that the three populations (controls. diabetics. and risk subjects) were different in terms of beta-CL values (P less than 0.001). The percentage of subjects at risk that had a positive test (arbitrarily defined as a beta-CL value higher than the 95th percentile of 228 controls) was 20%. No difference was observed between the two subgroups of subjects at risk in terms of either mean +/- SEM of beta-CL or percentages of individuals with a positive test. These diabetic rosettes were slightly associated with acute insulin response to iv glucose lower than the 5th percentile of controls (immunoreactive insulin at 1 +/- 3 min. 250 pmol/L; by chi 2. P = 0.04) and with HLA DR 3/4 heterozygosity (by chi 2. P = 0.04). They were not associated with islet cell antibodies (regardless of the threshold for positivity. expressed in Juvenile Diabetes Foundation units). insulin autoantibodies. activated (HLA DR+) T-lymphocytes. or sex. A statistical association was detected between HLA DR 3/4 heterozygosity and a low acute insulin response to iv glucose (by chi 2. P less than 0.003). The preliminary (2-yr) longitudinal follow-up revealed that out of five islet cell antibody-positive subjects who progressed to type 1 diabetes. three displayed beta-CL values higher than the 90th percentile of controls. Diabetic rosettes could. thus. be detected in some individuals at risk for type 1 diabetes as a marker of cell-mediated immunity.
Increased overnight growth hormone concentrations in diabetic compared with normal adolescents, To determine the extent to which spontaneous plasma GH concentrations are abnormal in adolescents with insulin-dependent diabetes mellitus we performed 12-h overnight plasma GH profiles in 21 diabetic adolescents (11 males and 10 females; aged 9.8-16.5 yr; median. 13.6 yr) and 34 healthy adolescent controls (17 males and 17 females; aged 9.1-20.9 yr; median. 13.1 yr). Data were analyzed using the pulse detection program Pulsar and time series analysis. and are presented with respect to age and puberty stage. Mean and maximum GH concentrations. sum of the peak amplitudes. and mean calculated baseline concentrations in the normal children were higher during puberty; highest levels were seen in girls at puberty stages 2-3. and in boys at stages 4-5. A similar pattern was observed in the diabetic adolescents. but all measures of pulse height and mean calculated baseline concentrations were significantly greater than those in the normal subjects (multivariate analysis. P less than 0.001). Pulse frequency did not change during puberty in the normal or diabetic subjects. and the dominant pulse periodicity in both groups was about 180 min. We conclude that the predominant change in GH release during puberty is in pulse amplitude. and that this is increased in diabetes. whereas pulse frequency remains constant in both normal and diabetic adolescents.
Serum HCG beta-core fragment is masked by associated macromolecules, To determine if beta-core fragment is present in serum from individuals with pregnancy and choriocarcinoma. samples were analyzed by gel filtration and fractions assessed by immunoassays (Mr = 15.000). In agreement with published reports. only minute amounts of beta-core fragment were detected (less than 0.1% of hCG level). A small amount of beta-core fragment activity was identified near the void volume of the column (Mr greater than 60.000). This high molecular weight material was pooled and dissociated with 3M ammonium thiocyanate. and gel filtration repeated. A much more significant beta-core fragment peak was then detected (Mr = 15.000). After dissociation. beta-core fragment was 18% (mol/mol) of the hCG level in early pregnancy serum. 91% in mid-pregnancy serum. 50% in term pregnancy serum. but only 1.3% in choriocarcinoma serum. pre-therapy. We conclude that the major form of beta-core fragment found in serum is associated with other macromolecules. which mask the beta-core fragment epitope to existing hCG beta antibodies. Measurements made on the dissociated beta-core fragment complex are much more in keeping with pregnancy levels found in urine.
Association of fasting glucose levels with a delayed secretion of insulin after oral glucose in subjects with glucose intolerance, Two hundred and nineteen second generation Japanese-American men were classified with a 75-g oral glucose tolerance test: 77 with normal glucose tolerance. 74 with impaired glucose tolerance (IGT). and 68 with noninsulin-dependent diabetes mellitus (NIDDM). The peak insulin response to the oral glucose load was progressively delayed with each of the 3 glucose tolerance categories. A similar finding was observed with the peak C-peptide response to oral glucose. except for the absence of distinction between IGT and NIDDM. Variables measuring the initial rate of insulin or C-peptide secretion (0-30 min) after oral glucose also demonstrated a progressive diminution with increasing glucose intolerance. The relative incremental insulin response at 30 min and the relative incremental C-peptide response at 30 min were highly correlated with the fasting glucose levels (r = -0.61 and r = -0.62; P less than 0.0001. respectively). Variables measuring the 0-30 min secretory response had high variances. whereas the variance for fasting glucose was low. Twelve men who were initially classified as IGT subsequently developed NIDDM. These 12 men had significantly higher fasting glucose levels at baseline than the remaining men who did not develop diabetes. but the 30 min secretory parameters after oral glucose. although lower in those who subsequently developed diabetes. were not significantly different at baseline. However. if fasting glucose is used as a surrogate measure of secretory response. these 12 men appear to have had an impairment of oral glucose-stimulated insulin secretion antedating the development of NIDDM. The inability of the secretory parameters to detect the abnormality may be due to a type II statistical error. which may be resolved by a larger sample size.
Alterations in aldosterone secretion and metabolism in low renin hypertension, Low renin essential hypertensives (LRH) have normal plasma aldosterone levels which are inappropriately high in relation to their PRA. Posture is the major determinant for plasma aldosterone and PRA levels. but it is not known whether postural increments (delta) of plasma aldosterone and (delta) PRA are also abnormal in LRH. To evaluate this. LRH (n = 8). normal renin hypertensives (NRH; n = 9). normotensive controls (n = 18). and subjects with idiopathic hyperaldosteronism (IHA; n = 5) were studied in a metabolic unit on a controlled diet over 7 days. Overnight supine and 4-h upright PRA. plasma aldosterone. and 24-h urinary tetrahydroaldosterone (THA) and aldosterone secretion rates (ASR) were measured. The delta in plasma aldosterone after 4 h of upright posture was not different in the four groups. The ratio of delta plasma aldosterone/delta PRA. however. was elevated in both IHA and LRH compared to that in NRH and normals. THA excretion was also elevated in IHA and LRH. but LRH had a normal ASR. This resulted in a higher fractional THA excretion (THA/ASR) in LRH compared to the other three groups. These data further support enhanced adrenal angiotensin-II sensitivity in LRH. Aldosterone was preferentially metabolized to THA in LRH. Since THA has reduced biological activity. this may be a compensatory mechanism to reduce mineralocorticoid activity in LRH.
Comparative study of the changes in insulin-like growth factor-I, procollagen-III N-terminal extension peptide, bone Gla-protein, and bone mineral content in children with Turner's syndrome treated with recombinant growth hormone, Six girls (7-13 yr old) with Turner's syndrome and short stature were treated for 1 yr with recombinant human GH (0.15 U/kg.day. sc) and had sequential determinations of serum insulin-like growth factor-I (IGF-I). osteocalcin. and procollagen-III. Bone mineral content and density of the spine and radius were measured before treatment and at 90 and 360 days. Two girls received small doses of ethinyl estradiol (0.025 micrograms/kg) in addition to GH. Height velocity increased by 144% after 3 months of treatment. IGF-I was normal (0.75 +/- 0.20 kU/L) before treatment and increased by 90% on day 1 and by 290% on day 360. Procollagen-III was low before treatment; it peaked at 53.0 +/- 14.7 micrograms/L (260% above baseline) on day 30. then decreased to the normal range. Serum osteocalcin increased more slowly to reach a plateau on day 90 of 23.7 +/- 1.2 micrograms/L (46% above baseline). Before treatment. bone mineral content of the spine was 25% lower than that of children matched for bone age. Bone mineral contents of the peripheral and axial skeleton were increased by 10% and 17%. respectively. after 1 yr of treatment. an increase commensurate with that of bone age in the four patients who did not receive estrogen. On day 90. however. although radius mineral density was already increased by 3%. the mineral density of the lumbar spine was significantly decreased by 4%. We conclude that treatment with GH increases IGF-I. collagen turnover. osteoblastic function. and height velocity in Turner's syndrome. However. there is no catch-up of bone mineral content after 1 yr of treatment. and an early effect of GH is to decrease spine mineral density.
Impaired growth hormone (GH) response to pyridostigmine in type 1 diabetic patients with exaggerated GH-releasing hormone-stimulated GH secretion, In the present study we investigated the effects of the acetylcholinesterase inhibitor pyridostigmine (PD). which is hypothesized to decrease hypothalamic somatostatin tone. alone and in association with GH-releasing hormone (GHRH) on GH secretion in 18 type 1 diabetic patients and 12 normal subjects using a randomized double blind placebo-controlled protocol. All subjects received either 120 mg oral PD or placebo 60 min before iv injection of either human GHRH-(1-29) NH2 (100 micrograms) or sterile water (2 mL). In normal subjects both PD alone and GHRH alone caused a significant increase in GH. PD and GHRH acted in a synergistic fashion when combined. In diabetic patients the GH response to GHRH was variable. To segregate the responses. the ratio between the GH increase after GHRH plus PD and after GHRH alone was calculated for each subject. In 10 diabetic patients (group A) the ratio was lower than 2 SD (P less than 0.05) from the mean response of normal subjects. These patients showed an exaggerated GH increase after GHRH and a lower GH increase after PD with respect to normal subjects. Eight diabetic patients (group B) showed a ratio similar to that in normal subjects and similar GH responses to the stimuli. No significant differences were found between groups A and B with respect to age. body mass index. and blood glucose levels. Duration of diabetes was longer and basal GH levels were higher in group A. Hemoglobin-A1c was higher in group A. but of only borderline statistical significance (P = 0.052). Our data demonstrate that in diabetic patients with exaggerated GH responses to GHRH an increase in cholinergic tone does not affect GH secretion. These data suggest that in some type 1 diabetic patients an altered somatostatinergic control of GH secretion may contribute to their abnormal GH response to GHRH.
Changes in basal and stimulated growth hormone secretion in the aging rhesus monkey: a comparison of chair restraint and tether and vest sampling, We studied basal serum GH and GH responses to iv clonidine and insulin-induced hypoglycemia in a group of four young (5-7 yr old) and four older (10-14 yr old) adult male rhesus monkeys under two restraint conditions. chair adaptation and a tether and vest system. to determine what changes in GH secretion occur with aging. The serum GH response to iv administration of GH-releasing hormone (GHRH) was also studied in the groups under tether and vest restraint. Serum samples were collected every 15 min and assayed for GH using a human GH RIA and for cortisol using an enzyme-linked immunosorbant assay. GH and cortisol concentrations in the young and older groups were analyzed with analysis of variance (ANOVA). In the chaired studies the older animals had a lower mean 6-h basal GH concentration than did the younger animals (2.7 +/- 0.8 vs. 3.5 +/- 0.5 micrograms/L; P = 0.0002). Prestimulation GH was lower before clonidine and insulin in the older chaired group (1.1 +/- 0.5 and 2.3 +/- 0.6 micrograms/L. respectively) compared to the younger group (3.6 +/- 0.8 and 3.8 +/- 0.7 micrograms/L. respectively; P less than 0.001). Poststimulation GH was lower after clonidine and insulin in the older chaired group (3.2 +/- 2.4 and 7.1 +/- 2.8 micrograms/L. respectively) compared to the younger chaired group (6.3 +/- 2.2 and 10.3 +/- 3.0 micrograms/L. respectively; P less than 0.05). but the differences in GH increments were not statistically significant. In the tether and vest studies the older animals had a lower mean 6-h basal GH concentration than did the younger animals (1.7 +/- 0.4 vs. 3.5 +/- 1.2 micrograms/L; P less than 0.0001). Prestimulation GH concentrations were also lower in the older tethered animals before clonidine (2.1 +/- 0.3 micrograms/L) and GHRH (1.4 +/- 0.2 micrograms/L) compared to levels in the younger animals (3.1 +/- 0.9 and 3.2 +/- 0.7 micrograms/L; P = 0.0023 and P = 0.0001. respectively). The younger tethered animals had greater poststimulation responses to clonidine (8.7 +/- 3.0 micrograms/L). insulin (8.8 +/- 3.6 micrograms/L). and GHRH (6.0 +/- 2.4 micrograms/L) than the older animals (3.8 +/- 0.9. 3.9 +/- 2.5. and 2.9 +/- 0.7 micrograms/L; P less than 0.0001. P = 0.0025. and P less than 0.03. respectively).(ABSTRACT TRUNCATED AT 400 WORDS).
Minimal model analysis of intravenous glucose tolerance test-derived insulin sensitivity in diabetic subjects, Although minimal model analysis of frequently sampled iv glucose tolerance tests (FSIGTs) to measure insulin sensitivity is well recognized. application has been limited by the need for endogenous insulin secretion. In the present study we determined whether use of exogenous insulin could permit minimal model assessment of insulin sensitivity (SI) to be extended to diabetic subjects. Normal volunteers had separate FSIGT assessments supplemented with both tolbutamide and insulin to accelerate glucose disappearance. while diabetics had a FSIGT supplemented only with insulin. There was a strong and highly significant correlation between the two assessments in normal subjects (r = 0.87; P less than 0.001). and the rank order of SI generally was maintained with the two assessments over a 3-fold range of SI; however. insulin-determined SI was 16% lower (3.4 +/- 0.4 vs. 4.1 +/- 0.4 x 10(-4) min/microU.microL; P less than 0.01). Diabetic subjects had markedly lower insulin sensitivity than controls (SI = 0.61 +/- 0.16; P less than 0.0001). Across all subjects. the level of fasting serum glucose was correlated inversely with both insulin sensitivity (r = -0.62; P less than 0.05) and acute insulin responses (r = -0.72; P less than 0.02); however. insulin sensitivity in diabetic subjects with little insulin secretion (0.6 +/- 0.2) was comparable to insulin sensitivity in diabetic subjects with near-normal responses (0.6 +/- 0.3). In subjects with fasting hyperglycemia. there were significant correlations between insulin sensitivity and body mass index. percent fat mass. and waist/hip ratio (all P less than 0.03). Among all female subjects. there was also a strong correlation between insulin sensitivity and upper body obesity. as measured by waist/hip ratio (r = -0.68; P less than 0.02). Model parameters also permitted glucose uptake to be estimated in diabetic vs. normal subjects at comparable hyperglycemia (11.1 mmol/L). Total glucose uptake was decreased in diabetic subjects (5.2 +/- 0.8 vs. 12.7 +/- 1.7 mg/min.kg in normals; P less than 0.001). insulin-dependent glucose uptake was diminished to a greater extent (1.3 +/- 0.4 vs. 6.2 +/- 1.2) than noninsulin-independent glucose uptake (3.9 +/- 0.5 vs. 6.4 +/- 0.9; both P less than 0.02). Administration of insulin permits minimal model FSIGT analysis to be applied to diabetic as well as normal subjects. yielding information about both insulin- and noninsulin-mediated glucose uptake as well as insulin sensitivity and insulin secretion.
Nonosmotic stimuli alter osmoregulation in patients with spinal cord injury, Studies on two quadriplegic patients who developed severe hyponatremia during episodes of acute respiratory distress were performed to determine whether differences in osmoregulation of vasopressin release could be identified in these patients compared to other quadriplegic subjects previously studied in a similar manner. Both patients were clinically stable and normonatremic. with no signs or symptoms of respiratory distress. when the studies were performed. However. both exhibited evidence of hemodynamic instability in the sitting posture. Linear regression analysis of the plasma vasopressin/plasma osmolality (Pavp:Posm) relationship during infusions of 0.85 M sodium chloride showed no significant differences in either the slope (sensitivity) or abscissal intercept (osmotic threshold) of this relationship compared to that of other quadriplegic subjects when the patients were supine. In contrast. when the patients were studied in the sitting posture there was a marked shift in the relationship of Pavp:Posm indicative of increased sensitivity and reduced osmotic threshold for vasopressin release. The slopes of the Pavp:Posm relationships were 0.249 and 0.178 for the two patients. respectively. compared to 0.092 +/- 0.03 ( +/- SD) for previously studied quadriplegic subjects. Oral water-loading studies performed on one patient revealed marked impairment of urine-diluting ability and free water clearance in the sitting posture compared with observations in similar studies performed when the patient was supine. Impairment of renal water excretion could not be attributed to an effect of vasopressin. which was reduced to unquantifiable levels by water loading. These studies have shown that hemodynamic stress related to autonomic dysfunction in quadriplegic patients may result in marked alteration of osmoregulation of vasopressin release in more severely affected individuals. Such altered osmoregulation. which may also be associated with vasopressin-independent impairment of renal water excretion in the sitting posture. may be a predisposing factor in the development of hyponatremia. especially in the presence of other potent nonosmotic stimuli.
Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man, Tumor necrosis factor-alpha (TNF) is believed to be an important mediator in many diseases that are associated with the sick euthyroid syndrome. To investigate the effect of TNF on thyroid hormone metabolism. we performed a controlled study in six healthy postabsorptive males. in whom plasma thyroid hormones and TSH were sequentially measured after iv bolus injections of recombinant human TNF (50 micrograms/m2) and isotonic saline. During the 10.5-h study TNF produced the characteristic changes in circulating thyroid hormones and TSH observed in the sick euthyroid syndrome. Compared with the control experiment. TNF induced significant decreases in T3 (-36 +/- 2%; saline. -20 +/- 3%; P less than 0.05) and TSH levels (-68 +/- 3%; saline. -44 +/- 8%; P less than 0.05) and a significant increase in rT3 values (+48 +/- 11%; saline. -12 +/- 7%; P less than 0.05). T4 and free T4 index were not affected by TNF. Free T4 showed a mean transient increase of 18% in five subjects (nonsignificant). which occurred synchronically with a transient 3.5-fold rise in circulating FFA levels. Our results suggest that TNF is involved. either directly or indirectly. in the pathogenesis of the sick euthyroid syndrome.
Brain glucose metabolism in noninsulin-dependent diabetes mellitus: a study in Pima Indians using positron emission tomography during hyperinsulinemia with euglycemic glucose clamp, To determine whether insulin or noninsulin-dependent diabetes mellitus affects brain glucose metabolism. brain glucose utilization was studied in the basal state and during hyperinsulinemic euglycemic glucose clamps in nondiabetic and diabetic Pima Indians by positron emission tomography with 2-[18F]fluoro-2-deoxy-D-glucose (18FDG). Glucose utilization in 75 brain areas was determined by analysis of single scans and by least squares estimation of the rate parameters for the FDG model; these data were compared to results in normal caucasian volunteers. No effect of ethnicity or diabetic status on brain glucose utilization was observed. During the hyperinsulinemic clamps (mean insulin. 11.708 +/- 3.026 pmol/L). clearance of 18FDG from blood was accelerated. and accumulation of brain radioactivity was reduced. However. glucose utilization by the brain was identical to results during sham glucose clamps (mean insulin. 204 +/- 56 pmol/L) performed in the same patients. During the studies with hyperinsulinemia. k4 (representing loss of tissue radioactivity) was increased in most brain areas (mean increase. 0.0031 +/- 0.0018 min-1; P less than 0.02). The possible mechanisms for this effect are multiple. and the physiological significance. if any. is unknown. Further studies of the effects of insulin on brain glucose metabolism are needed.
Endothelin family in human plasma and cerebrospinal fluid, To clarify whether endothelin may be present in human cerebrospinal fluid (CSF) and. if it exists. to compare its molecular forms with those of endothelin in human plasma. we analyzed pooled human CSF and plasma by high performance liquid chromatography with specific enzyme immunoassays for each endothelin peptide. Of the four human endothelin peptides hitherto identified. big endothelin-1 was the major molecular form of endothelin present in human CSF. In addition. there was a small but significant amount of endothelin-1 and endothelin-3 in CSF. while endothelin-2 was not detectable. Similarly. big endothelin-1. endothelin-1. and endothelin-3 were identified in human plasma. Although big endothelin-1 was the most abundant. a substantial amount of endothelin-1 and endothelin-3 was found in plasma with a resultant lower molar ratio of big endothelin-1 to endothelin-1 than in CSF. In all CSF samples from 17 patients requiring diagnostic lumbar puncture or lumbar anesthesia. endothelin was detectable. with a preponderance of big endothelin-1 relative to endothelin-1 and endothelin-3. The mean concentrations of endothelin-1 and endothelin-3 in simultaneously collected plasma were significantly (P less than 0.01) higher than those in CSF. while there was no significant difference between the mean big endothelin-1 concentration in plasma and that in CSF. There was no significant correlation among concentrations of big endothelin-1. endothelin-1. and endothelin-3 in each paired sample. These results indicate that endothelin is present in human CSF that is differently processed from endothelin in vascular endothelial cells and suggest a possible role for endothelin as a modulator of neuronal functions.
Effects of repetitive administration of corticotropin-releasing hormone combined with lysine vasopressin on plasma adrenocorticotropin and cortisol levels in secondary adrenocortical insufficiency, To examine the functioning of the hypothalamo-pituitary-adrenocortical axis in secondary adrenocortical insufficiency. we administered 100 micrograms synthetic human CRH. iv. plus 10 U lysine-8-vasopressin (LVP). im. three times daily for 3 consecutive days. The changes in plasma ACTH and cortisol levels during the administration and the response to an insulin tolerance test (ITT) conducted before and after the administration were determined. In three patients with isolated ACTH deficiency. basal plasma ACTH and cortisol levels were undetectablly low. and there was no response noted in the ITT or during CRH-LVP administration throughout the observation period. In four patients with adrenocortical insufficiency who had undergone successful transsphenoidal microadenomectomy for Cushing's disease and in six patients who had undergone curative unilateral adrenalectomy for Cushing's syndrome. basal plasma ACTH levels were low. but responded considerably to both stimulation tests. Along with the 3 days of CRH-LVP stimulation. however. neither the peak nor the time-integrated ACTH response was significantly enhanced. because of the variability of the responses among the patients. Compared with the ACTH response on the last day of CRH-LVP stimulation. the subsequent ITT tended to induce a lower ACTH response in the post-Cushing's disease patients and a higher response in the post-Cushing's syndrome patients. Regarding the plasma cortisol levels. the basal. peak. and integrated responses tended to increase daily during CRH-LVP administration. Conversely. the ITT after repetitive CRH-LVP administration induced a higher cortisol response than the test before CRH-LVP administration in the post-Cushing's disease patients. No serious complications were noted in any of the patients during or after the treatment. The present findings indicate that 1) repetitive administration of CRH in combination with LVP is a safe and valuable provocation test to examine the pituitary ACTH reserve and the integrity of the pituitary-adrenocortical axis; 2) isolated ACTH deficiency is usually due to a defect at the pituitary level; 3) with respect to adrenocortical responsiveness. post-Cushing's disease patients show a better accumulation of the provocative effect than do post-Cushing's syndrome patients; and 4) both hypothalamic and pituitary dysfunction are responsible for adrenal hypofunction in patients after hypercortisolemia. but post-Cushing's syndrome patients (especially those with a short period of hypercortisolemia) appeared to have less impairment of hypothalamic ACTH-releasing activity than post-Cushing's disease patients.
Anti-5 alpha-reductase autoantibodies in the serum of patients with prostatic cancer, Human sera were tested for their ability to inhibit 5 alpha-reductase binding of a potent inhibitor of the enzyme. Thirty one of 227 serum samples from patients diagnosed or suspected of prostatic cancer had a significant inhibitory activity. whereas 128 serum samples from other patients were inactive. The majority of the inhibitory activity was in the IgG fraction purified by chromatography on a protein A-Sepharose affinity column and an anti-human IgG-agarose column. IgG fractions from non-inhibitory sera were inactive. Inhibitory IgG also inhibited the enzymatic activity of microsomal 5 alpha-reductase from liver. ventral prostate and preputial gland of rat. and liver. prostate. and facial skin of human. The inhibitory IgG had no effect on NADH-menadione reductase or 17 beta-hydroxysteroid dehydrogenase. These results suggest that 5 alpha-reductase autoantibodies are present in the blood of some prostatic cancer patients.
Growth of cultured human cerebral meningiomas is inhibited by dopaminergic agents. Presence of high affinity dopamine-D1 receptors, We have found that microM concentrations of the dopamine agonist bromocriptine significantly decrease the proliferation rate of human meningioma cells in culture (25-56% inhibition). This effect was also seen with direct application of dopamine. as well as the dopamine-D1 agonist (+)-SKF-38393 (both applied in microM concentrations) to meningioma cell cultures. Receptor studies with the dopamine-D1 ligand (125I)SCH-23982 (dopamine-D1 antagonist) indicated that dopamine-D1 binding sites were present in the membranes of meningioma tissue. The mean dissociation constant (Kd) was 325 ( +/- 74.5 SEM) pM and the receptor density (Bmax) was 25.4 ( +/- 1.5 SEM) fmol/mg pellet protein in 5 human meningiomas. The pharmacological specificity was proven by (+)-SKF-38393. ( +/-SKF-83566 or (+)-butaclamol and their inactive isomers (-)-SKF-38393 and (-)-butaclamol in a 1000 fold excess. These results provide evidence that human meningiomas possess high affinity dopamine-D1 receptors and that dopamine agonists have an antiproliferative effect on these tumors in culture. We conclude that the proliferation of cerebral meningiomas may be under dopaminergic control and that dopamine agonists may have a role in the medical treatment of patients with meningiomas.
Endothelin-like immunoreactivity in human breast cyst fluid, Immunoreactive endothelin has been detected in 21 of 43 samples of breast cyst fluid (21 cases; 3.5 +/- 0.6 pmol/l. mean +/- SEM. Other 22 cases; not detectable. less than 0.5 pmol/l). Fast protein liquid chromatographic analysis of the immunoreactive endothelin of pooled breast cyst fluid showed two immunoreactive peaks; one in the void volume and the other in the position of endothelin-1. It is probable that endothelin-1 is produced by the epithelial cells lining breast cysts. but significance of the presence of endothelin-1 in breast cyst fluid remains to be elucidated.
In situ hybridisation with digoxigenin-labelled DNA probes for detection of viral genomes, The applicability of a recently developed non-radioactive DNA labelling and detection method. which uses the digoxigenin (DIG) enzyme linked immunosorbent assay (ELISA) system. for the detection of viral infections in pathology specimens by in situ hybridisation. was examined. Its efficacy was compared with that of biotin and radioisotope labelling methods. Three cases of progressive multifocal leucoencephalopathy. two of verruca vulgaris. and seven cases of laryngeal papilloma were studied. The sensitivity of the DIG labelled probe was almost the same as that of a 35S-labelled probe in the dot-blot hybridisation test. Using in situ hybridisation with 35S-labelled and DIG labelled probes. the levels of the hybridised signals detected were similar. The biotin labelled probe was less sensitive. particularly in the cases of laryngeal papilloma. The DIG labelling and detection method was highly sensitive and applicable to the detection of viral infection by ISH. and is preferable to a radiolabelled probe. especially when in situ hybridisation is done in the pathology laboratory.
Adenomyosis in Pakistani women: four year experience at the Aga Khan University Medical Centre, Karachi, As part of a quality assurance programme at the Aga Khan University Medical Centre. Karachi. Pakistan. all hysterectomy specimens were reviewed from January 1986 to December 1989. Adenomyosis was found in 237 of the 419 (56.5%) specimens studied. Of these 237 patients. 232 (97.9%) were parous and 196 (82.8%) were in the fourth and fifth decades of life. This high prevalence in parous women aged 40-59 years was significant. Fibroids. cervicitis. and endometrial hyperplasia were the most common associated diagnoses. Of all the associations studied. only endometrial hyperplasia was significantly more prevalent in the group with adenomyosis. Adenomyosis was stated as an indication for surgery in 69 patients and was confirmed by histopathology in 49 (71%). Preoperative suspicion of adenomyosis was present in 49 (20.6%) patients of all those ultimately found to have the disease. There is a high prevalence of adenomyosis in the population studied. which indicates that the condition may have been underdiagnosed in the past. especially as it is difficult to diagnose without surgery and hysterectomy is currently the only treatment.
Crypt cell proliferation and HLA-DR expression in pelvic ileal pouches, To investigate the nature of the morphological changes that occur in ileal pouches. 26 biopsy specimens from patients with functioning ileo-anal pouches (eight with pouchitis) were studied. Normal ileum (n = 10) was used as a control. Mucosal morphometry (using linear measurements). crypt cell proliferation (CCP) (using the monoclonal antibody Ki67). and epithelial HLA-DR expression (monoclonal antibody CR3/43) were assessed. CCP (expressed as the percentage of Ki67 positive nuclei for each crypt) was significantly higher in pouches with pouchitis. compared with those without. and in pouches without pouchitis compared with normal ileum. CCP values in some pouches without pouchitis approached values found in those with pouchitis. CCP was related inversely to villous height and an index of villous atrophy (VH/TMT). and directly to crypt depth. In the presence of pouchitis there was intense epithelial HLA-DR expression that extended into the crypts. In some pouches with high CCP values. but without clinically important inflammation. surface epithelial HLA-DR expression was weak and patchy. It is concluded that villous atrophy and crypt hyperplasia in ileal pouches are associated with high CCP values. These may be increased even in the absence of active inflammation. and this increase may occur as a response to the new luminal environment.
Tissue preparation for simultaneous flow cytometric quantitation of tumour associated antigens and DNA in solid tumours, A multiparameter flow cytometric assay for the simultaneous study of tumour associated antigens (TAA) and DNA in fresh solid tumours was devised. Cell suspensions were prepared by disaggregating unfixed solid tumour samples mechanically over a stainless steel mesh. Indirect immunofluorescence was used to identify the TAA. and DNA was stained with propidium iodide. Cell morphology was well preserved. cell clumping was negligible. and high quality indirect immunofluorescence quality indirect immunofluorescence and DNA staining were obtained. The technique is simple. rapid. and reproducible. Multiparameter assays can be developed to study prognostic indicators such as membrane oncoproteins. receptors. and multidrug resistance in solid tumours. With a suitable panel of antibodies the technique might become an aid in the differential diagnosis and biochemical diagnosis of some solid tumours.
Computer assisted selection and assessment of antibodies in the diagnosis of lymphomas, With increasing numbers of reagents the problem of selecting appropriate antibodies to solve problems in the diagnosis of lymphoma is becoming more complex. One approach is to use a computer program to optimise the selection process. Such a program was devised. incorporating data from an extensive literature search. When presented with a differential diagnosis it selects the most appropriate antibody panel and when given the results evaluates the relative likelihood of each possible diagnosis. In a retrospective study 81% of the tests used had been non-discriminatory. but using the results of the remaining 19% of the tests. the computer was able to select the "correct" diagnosis with a high degree of certainty. The development and use of this system illustrated several problems in the application of computer assisted diagnostic techniques in histopathology. These problems include incomplete data and lack of understanding of the process of histopathological diagnosis.
Immunocytochemical analysis of lymph node aspirates in patients with human immunodeficiency virus infection, Thirty four patients positive for human immunodeficiency virus (HIV) who had lymphadenopathy were investigated using fine needle aspiration. Cytological analysis included immunocytochemical investigation with the alkaline phosphatase-antialkaline phosphatase (APAAP) method. All patients had confirmation of cytological diagnosis by lymph node biopsy. Fifteen aspirates with follicular hyperplasia were evaluated. Eleven patients showed B cell predominance. The B cell population did not show light chain restriction. Ten patients with B cell non-Hodgkin's lymphoma (five with Burkitt's lymphoma and five with B cell immunoblastic lymphoma) were investigated. Nine out of 10 cases were monoclonal with respect to their light chain determinants; only one case with Burkitt's lymphoma with partial lymph node metastasis did not show light chain restriction. The cytological diagnosis included two mycobacterial infections and four cystic lesions. Histological investigation was necessary to diagnose the extent of lymph node disease caused by Kaposi's sarcoma. These findings indicate that the immunocytological investigation of lymph node aspirates is useful for evaluating lymphadenopathy in HIV positive patients.
Observations on the haemopoietic response to critical illness, Peripheral blood cytopenias are common in patients receiving intensive care. particularly in those with multiple organ failure. To assess the contribution of bone marrow hypoplasia in such patients 44 bone marrow samples from 24 patients under intensive care were studied by standard morphological techniques and by the granulocyte-macrophage colony forming cell (GM-CFC) assay. Frequently observed morphological abnormalities in the bone marrow included the following: (i) a reduction in overall cellularity in seven patients. with a progressive decrease in most patients studied sequentially; (ii) an increase in the number of actively phagocytic macrophages; and (iii) a disruption of normal bone marrow architecture with the accumulation of intercellular hyaluronic acid glycosaminoglycan. Mean GM-CFC growth was significantly reduced when compared with that in a group of normal controls. In four of five patients studied sequentially GM-CFC growth became subnormal in association with a reduction in bone marrow cellularity. Inhibitory serum factors were not identified. These morphological abnormalities are similar to the changes observed in gelatinous degeneration of the bone marrow. In both situations disruption of the haemopoietic microenvironment. with the accumulation of hyaluronic acid proteoglycan. may be an important factor in the inhibition of haemopoietic progenitor cell growth. The proliferation of macrophages. by the release of a variety of cytokines or reactive oxygen intermediates. may also be implicated in impaired haemopoiesis and the development of disordered erythropoiesis.
Use of latex agglutination technique for detecting Legionella pneumophila (serogroup 1) antibodies, Following the outbreak of Legionnaires' disease in Stafford in 1985. 500 serum samples were submitted to the indirect immunofluorescence antibody test and a latex agglutination. Latex agglutination using ultrasonically disrupted Legionella pneumophila antigens coupled to latex particles. proved a rapid. simple method for detecting circulating antibodies to L pneumophila in a one minute slide latex agglutination test. There was good correlation with the indirect immunofluorescence antibody test (IFAT). and the specificity and sensitivity with respect to a diagnostic result were 98.3% and 97.6%. respectively. using a series of well characterised sera. The latex agglutination test seems well suited as a screening test for presumptive cases of Legionnaires' disease; the latex reagent is easy to prepare and seems to remain stable at 4 degrees C for up to six months.
Identification of human immunodeficiency virus hybridizing sequences in the peripheral blood of a patient with systemic lupus erythematosus, Systemic lupus erythematosus. a multisystemic disorder. is considered a prototype of the autoimmune diseases. Although its cause remains unknown. a viral etiology has been proposed. We report that a rapid and sensitive messenger RNA in situ hybridization technique detected hybridizing sequences to the human immunodeficiency virus type in the peripheral blood cells of a woman with systemic lupus erythematosus in whom the presence of acquired immuno-deficiency syndrome was reasonably excluded.
Sodium lauryl sulfate-induced irritant contact dermatitis in vulvar and forearm skin of premenopausal and postmenopausal women, Reactivity of the skin of the forearm and labia majora to three concentrations (2%. 3%. 5%) of sodium lauryl sulfate was studied in 20 healthy women. 10 premenopausal and 10 postmenopausal. Patches with the irritant were applied on day 0 for 24 hours. Skin changes were monitored by visual scoring and by the measurement of transepidermal water loss and capacitance as indicators of stratum corneum hydration on days 2. 3. 7. and 10. In forearm skin. irritant dermatitis developed in the majority of subjects as indicated by visual scoring and increase of transepidermal water loss. These changes were not significantly dependent on the concentration of sodium lauryl sulfate. In labia majora skin. irritant dermatitis developed in 50% of the women as determined by visual scoring; however. because of the pigmentation. visual scoring readings were less reliable in labia majora skin. Transepidermal water loss did not increase. but a significant and immediate decrease in capacitance was noted in labia majora skin. In forearm skin. postmenopausal women reacted less frequently and more slowly to sodium lauryl sulfate than premenopausal women whereas no age-related differences were observed in reaction of the vulvar skin. It is concluded that labia majora skin is not more reactive to sodium lauryl sulfate than forearm skin and that capacitance is more sensitive than transepidermal water loss in monitoring vulvar irritant dermatitis. Age-related differences in irritant reaction are apparent in the forearm. but not the vulva.
Cutaneous manifestations of postthymic T cell malignancies: description of five clinicopathologic subtypes, This study was undertaken to identify the cutaneous manifestations among different prognostic subgroups of postthymic T cell malignancies. Cutaneous involvement was demonstrated in 43 of 88 cases. We recognized five clinicopathologic subtypes: type I. classical cutaneous T cell lymphoma (CTCL) or mycosis fungoides. six cases; type II. primary large cell type CTCL. Ki-1 antigen (Ki-1+ or Ki-1-). seven cases; type III. primary angioinvasive T cell lymphoma. three cases; type IV. human T-lymphotropic virus type I (HTLV-I+) adult T cell leukemia/lymphoma (ATL). eight cases; type V. secondary cutaneous involvement by peripheral T cell lymphoma (PTL). 19 cases. Primary CTCL and ATL tend to involve papillary dermis with or without epidermotropism. whereas PTL and angioinvasive T cell lymphoma predominantly affect skin adnexae. vessels. and subcutis. Cutaneous lesions in type V PTL are heterogeneous and may be confused with panniculitis. vasculitis. or an eczematous eruption. Classic CTCL. Ki-1+ lymphoma. and angioinvasive T cell lymphoma have a chronic course. whereas ATL. Ki-1- large cell lymphoma. and PTL are clinically aggressive.
Giant eccrine acrospiroma, Four cases of large eccrine acrospiroma (three benign. one malignant) are reported. The benign tumors involved the lower extremities of two women and one man (73 to 89 years of age). The duration of the lesions ranged from 10 to 20 years. The malignant tumor involved the left side of the chest of a 60-year-old man. Its occurrence in a lesion that had been present for 40 years suggested malignant transformation of a pre-existing benign eccrine acrospiroma. Each tumor showed little to no cellular atypia. Mitotic rates (mitotic figures per 10 high-power fields) varied both between and within lesions. Average mitotic rates did not differentiate the benign from the malignant tumors. The most important distinguishing features of large benign eccrine acrospiromas are the relative circumscription. the lack of cellular atypia. and the absence of stromal. perineurial. and angiolymphatic invasion.
Hypergammaglobulinemic purpura of Waldenstrom, Hypergammaglobulinemic purpura of Waldenstrom is characterized by hypergammaglobulinemia. recurring purpura. an elevated erythrocyte sedimentation rate. and the presence of rheumatoid factor indicative of circulating immune complexes. There is a significant association with autoimmune diseases. especially Sjogren's syndrome and lupus erythematosus. Hypergammaglobulinemic purpura is considered primary when there is no other associated disease or secondary when associated with other diseases. usually autoimmune. Immune derangements are fundamental in its pathogenesis. although its cause is still unknown. Therapy is unrewarding and is probably unnecessary for this usually benign condition. Three cases are presented that are representative of patients with hypergammaglobulinemic purpura.
Treatment of idiopathic guttate hypomelanosis with liquid nitrogen: light and electron microscopic studies, Idiopathic guttate hypomelanosis is a common skin disorder of unknown cause. Our studies have shown that significantly fewer dopa-positive melanocytes are in the white macules of idiopathic guttate hypomelanosis than in normal skin. By electron microscopy we observed that the melanocytes in the lesional skin were round and less dendritic with fewer melanosomes than in normal pigment cells. Lesions gently frozen with liquid nitrogen repigmented in 6 to 8 weeks. The number of dopa-positive melanocytes was significantly greater in the repigmented areas than in untreated lesions but less than in normal skin.
Treatment of molluscum contagiosum using a lidocaine/prilocaine cream (EMLA) for analgesia, Eighty-three 4- to 12-year-old children. scheduled for curettage of at least five molluscum contagiosum lesions. participated in a double-blind study. The children were randomly allocated to receive lidocaine/prilocaine (EMLA) cream (n = 58) or placebo cream (n = 25). applied 15. 30. or 60 minutes before treatment. The pain was assessed by the children and the physician as none. slight. moderate. or severe. In addition. the children rated the pain on a visual analog scale. EMLA cream effectively prevented the pain after all three application times (p less than 0.01). No significant difference in pain was observed among the 15-. 30-. and 60-minute EMLA-treated groups. but the proportion of children reporting no pain on the verbal scale increased from 36% in the 15-minute group to 61% in the 60-minute group. In the placebo group. only one of 24 children (4%) reported no pain. Transient local redness was the only skin reaction noted. In conclusion. an application time of EMLA cream of less than 60 minutes is satisfactory for the curettage of molluscum contagiosum in children.
A comparative histopathologic study of photodistributed and nonphotodistributed lichenoid drug eruptions, This study compares the histopathologic characteristics of photodistributed and nonphotodistributed lichenoid drug eruptions in 13 patients. Both types have been said to be. in an unknown proportion. different from idiopathic lichen planus in that they can involve the deep as well as the superficial plexus. can contain eosinophils. and have parakeratotic scale. We found that these features were most often present in nonphotodistributed lichenoid drug eruptions and were seldom present in photodistributed eruptions. Thus a biopsy specimen that shows the classic features of lichen planus should not be used as evidence against a drug eruption. especially if the lesions are photodistributed.
Prolonged remission after cyclosporine therapy in pemphigus vulgaris: report of two young siblings, We report the clinical evolution of two young siblings with severe pemphigus vulgaris treated with cyclosporine for 30 and 12 months. respectively. One was resistant to treatment with high-dose corticosteroids and azathioprine. A good clinical response was achieved in both cases. No major side effects were observed. The patients have remained disease free for more than 20 months after stopping cyclosporine therapy.
Buschke-Loewenstein tumor: verrucous carcinoma of the penis, The Buschke-Loewenstein tumor is an anogenital tumor of characteristic clinical and histologic pattern best considered as a low-grade. well-differentiated squamous cell carcinoma. This remarkable neoplasm and its features are reviewed in detail. stressing salient advances in our understanding of it.
Treatment of chromoblastomycosis, Treatment of chromoblastomycosis is frequently difficult and unsatisfactory. A representative case is presented of this chronic subcutaneous fungal infection. characterized by warty. cauliflower-like lesions usually on the extremities. Chromoblastomycosis and its treatment are reviewed. with attention to itraconazole. a new triazole compound. as the possible drug of choice.
Contact dermatoses from disposable glove use: a review, Contact dermatoses from disposable gloves are being reported with greater frequency. A variety of eruptions can occur. These have become increasingly relevant for dermatologists. who for most procedures now use disposable gloves. This article represents a review of the relevant issues about the use of disposable gloves by dermatologists. Methods of management and prevention of morbidity associated with disposable glove use will also be discussed.
Prevention of occupational contact dermatitis, Contact dermatitis is the most frequent type of occupational skin disease. Although prevention of contact dermatitis in the workplace should ideally be accomplished through total elimination of cutaneous exposure to hazardous substances. this is often not feasible. Therefore eight basic elements of a multidimensional approach to prevention have been identified. These elements include recognition of potential cutaneous irritants and allergens. engineering controls or chemical substitution to prevent skin exposure. personal protection with appropriate clothing or barrier creams. personal and environmental hygiene. regulation of potential allergens and irritants within the workplace. educational efforts to promote awareness of potential allergens and irritants. motivational techniques to promote safe work conditions and practices. and preemployment and periodic health screening. A comprehensive prevention program based on this multidimensional approach requires the cooperative efforts of employees. employers. engineers. chemists. industrial hygienists. safety and supervisory personnel. union representatives. governmental agencies. and occupational health practitioners.
History of antifungals, Until two to three decades ago. only a few drugs were available for the treatment of fungal infections. The status of antifungal therapy changed dramatically in the late 1960s with the introduction of newer broader spectrum agents. such as the iodinated trichlorophenols and the imidazoles. that acted by disruption of the fungal cell membrane. Some of the more recently developed broad-spectrum antifungal drugs include the triazoles terconazole. itraconazole. and fluconazole and the dimethylmorpholine amorolfine. The allylamines represent one of the newest classes of compounds shown to be effective in the management of fungal disorders. The two members of this unique chemical class that have been studied clinically. naftifine and terbinafine. are effective against a wide spectrum of fungal organisms. Terbinafine has the added advantage of both topical and oral activity.
A clinical trial of topical terbinafine (a new allylamine antifungal) in the treatment of tinea pedis, Twenty-three patients were enrolled in a randomized. double-blind trial of terbinafine 1% cream compared with placebo vehicle in the treatment of tinea pedis. Of the 20 patients who were evaluated for efficacy. 10 received terbinafine and 10 received placebo. Except for the terbinafine-treated patients being an average of 11 years older than the patients receiving placebo and the median duration of disease being 6 weeks longer in the placebo group. the two groups were demographically and clinically similar. Results of mycologic tests and clinical findings showed terbinafine to be significantly more effective than placebo in the treatment of tinea pedis. Significantly more terbinafine-treated patients than placebo-treated patients showed conversion to negative culture and microscopy at end of therapy and a significant reduction in scored signs and symptoms. Overall efficacy at follow-up (combined mycologic and clinical findings) was also significantly greater in the terbinafine group (78%) than in the placebo group (zero) (p less than 0.001). Unexplained elevation of liver function test results was noted in three placebo-treated patients and in one terbinafine-treated patient. but these changes were not considered clinically relevant or drug related.
Efficacy and tolerability of topical terbinafine in the treatment of tinea cruris, Thirty men with clinical and mycologic evidence of tinea cruris were enrolled in a controlled. randomized. double-blind trial comparing terbinafine 1% cream and its cream vehicle as placebo. Patients applied the test medications to the affected area twice daily for 2 weeks. Therapeutic response was evaluable in 18 patients after each week of treatment and at a follow-up visit 2 weeks after therapy ended. At each visit. terbinafine was found to be more effective than the cream vehicle in the reduction of the signs and symptoms of infection and in the conversion of culture and microscopy findings to negative or normal. At the end of treatment. therapy was effective in 67% of the nine terbinafine-treated patients compared with only 11% of the nine placebo-treated patients. At the follow-up examination. efficacy rates were 78% in the terbinafine treatment group and 33% in the placebo group--a difference of borderline statistical significance (p = 0.077). Possible reasons for this result may include the higher incidence of chronic disease in the terbinafine group and the large number of patients who were classified as delayed exclusions because of negative initial culture for dermatophytes. No side effects or significant alterations in laboratory or hematologic tests were observed in either treatment group.
Treatment of tinea cruris with topical terbinafine, Twenty-three patients were enrolled in a randomized. double-blind trial of terbinafine 1% cream versus its vehicle (placebo) in the treatment of tinea cruris. One patient had a negative initial culture and was excluded. and two patients were dropouts. one because of poor study compliance (terbinafine) and one because of an adverse event (placebo). Twenty patients were examined for efficacy of treatment (9 terbinafine-treated. 11 placebo-treated). Both groups were similar in age. sex. duration of disease. prior therapy. size and location of lesion. infecting organism. and predisposing factors. Terbinafine 1% cream was more effective than vehicle cream in the reduction of the signs and symptoms of tinea cruris. In addition. there was a higher conversion rate to negative culture and normal microscopy findings in the terbinafine-treated group. Clinical results combined with evaluation of mycologic tests at end of therapy showed terbinafine to be a rapid and significantly more effective treatment for tinea cruris than placebo (78% vs 18% cure rate. respectively). Follow-up cure rates confirmed these findings (89% and 18%. respectively). No significant adverse events occurred during terbinafine treatment.
Oral terbinafine versus griseofulvin in the treatment of moccasin-type tinea pedis, The safety and effectiveness of oral terbinafine. 125 mg twice daily. and griseofulvin. 250 mg twice daily. in patients with moccasin-type tinea pedis were examined in a double-blind randomized trial. At the end of the 6-week treatment period. both a clinical and mycologic cure or a mycologic cure with minimal signs of infection was noted in 12 (75%) of the 16 terbinafine-treated patients compared with only 3 (27%) of the 12 patients treated with griseofulvin. The overall response rate 2 weeks after the completion of treatment was 88% in the terbinafine-treated group and 45% in the griseofulvin-treated group. When contacted again 6 to 15 months after completion of the study. 94% of the terbinafine-treated patients reported sustained clearing of tinea pedis. and 88% of those with nail involvement at the time of treatment reported improvement. In contrast. tinea pedis remained cured in only 30% of the patients who had received griseofulvin. and onychomycosis improved in only 14%.
Management of onychomycosis with oral terbinafine, The safety and efficacy of oral terbinafine in the treatment of finger onychomycosis caused by Trichophyton rubrum were evaluated in an open study including 11 patients. Treatment consisted of 125 mg of terbinafine given twice daily for 6 months or until the infection cleared. At the end of the treatment period. all patients were clinically and mycologically normal. with the drug acting as a fungal barrier to prevent further distal fungal invasion into the nailplate. Mild gastric discomfort in one patient was the only side effect reported during this study. No laboratory abnormalities were detected.
Cutaneous melanoma and bilateral retinoblastoma, We report the case of an otherwise healthy 37-year-old man who had had bilateral enucleation during early childhood for bilateral retinoblastomas. in addition to two cutaneous melanomas (the first appearing at age 27 years). He also had dysplastic melanocytic nevi and a history of cutaneous melanoma in his mother. Retinoblastoma may aggregate in families and is associated with DNA abnormalities of chromosome 13. Recent reports have emphasized the appearance of second malignancies in retinoblastoma survivors. The second malignancies include osteosarcoma. soft tissue sarcoma. and cutaneous melanoma. Cutaneous melanoma also may aggregate in families. usually in the setting of dysplastic melanocytic nevi. The features of this case and of similar reported cases suggest that there may be a greater than expected association between retinoblastoma and cutaneous melanoma.
Subacute cutaneous lupus erythematosus lesions progressing to morphea, A women had annular lesions of subacute cutaneous lupus erythematosus that slowly resolved and were replaced by plaques of morphea. The immunologic implications of this unique transitional case of subacute cutaneous lupus erythematosus to morphea are discussed.
Leprotic involvement of peripheral nerves in the absence of skin lesions. Case report and literature review, In the absence of clinically apparent cutaneous lesions. primarily neural leprosy is uncommon. Primarily neural leprosy presents clinically as a peripheral neuropathy that most frequently affects motor nerves and that occasionally involves sensory nerves as well. The long incubation period for leprosy and its occurrence outside endemic areas often lead to delayed diagnosis. We present a case of glove and stocking hypoesthesia. weakness of the flexor muscle of the right great toe. palpable thickening of the right popliteal nerve. and hypoesthetic but normal-appearing areas on the back. which developed in a Trinidadian immigrant who lived in Canada for 16 years. A skin biopsy specimen obtained from a visibly normal but hypoesthetic area on the back demonstrated a few acid-fast bacteria in small dermal nerves. in arrector pili smooth muscle. and in rare perivascular histiocytes. associated with a sparse mixed inflammatory cell infiltrate. The patient responded well to therapy with dapsone. rifampin. and clofazamine. A classification and review of primarily neural leprosy is presented. Our patient represents the first reported case of primarily neural borderline lepromatous leprosy in Canada.
Persistent melanocytic lesions associated with cosmetic tanning bed use: "sunbed lentigines", A patient with persistent melanocytic lesions after tanning bed use is described. A review of the literature provides two additional examples of similar clinical and histologic presentations after UVA exposure without psoralen. To our knowledge. this is the first reported case of "sunbed lentigines" in the United States.
Linear porokeratosis: successful treatment with diamond fraise dermabrasion, A patient with linear porokeratosis was successfully treated with diamond fraise dermabrasion. Follow-up evaluation revealed an excellent cosmetic result with adequate repigmentation. no scarring. and no recurrence of lesions. Long-term follow-up will be necessary to determine whether dermabrasion treatment of linear porokeratosis provides adequate prophylaxis against the subsequent development of malignancy.
Balancing dental service requirements and supplies: epidemiologic and demographic evidence, As a counterpoint to negative interpretations of recent trends. this article presents a positive picture of dentistry in the 1990s and 21st century. Reported trends show large increases in older dentate adults who are retaining more of their natural dentition. new diagnosis and treatment technologies. increased incidence of dental caries in older adults. increased awareness of periodontal diseases. greater interest in esthetic dentistry. and generally higher expectations for health and fitness in our society. All of these factors point to a greater need for adult dental services. Therefore. in the next 30 years. the dental profession should be prepared to provide increased amounts of diagnostic. preventive. adult operative. fixed prosthodontic. and endodontic and orthodontic services. Declines in need should be expected in children's operative dentistry. extractions. and complete dentures.
Porcelain and resin veneers clinically evaluated: 2-year results, A clinical comparison of two different types of dental veneers--baked porcelain veneer and heat-and-pressure processed urethane resin veneer--was made after 2 years. Although the esthetic appearance and gingival response were equal for both systems. the resin veneers had a greater tendency to chip and fracture. By the end of 2 years. 20% of the resin veneers had failed. whereas all of the porcelain veneers remained.
The prevalence of periodontitis in a military treatment population, A group of 1.984 males and females (age range 13 to 84) at a military dental clinic were given oral examinations with full-mouth circumferential periodontal probing. Diagnoses were made both for individual quadrants and for the entire mouth using clearly defined diagnostic criteria. The results showed 37% of the subjects had gingivitis only. 33% had early periodontitis. 14% had moderate periodontitis. 15% had advanced periodontitis. 0.5% had juvenile periodontitis. and 0.5% had necrotizing gingivitis. The prevalence of periodontitis increased with age to a peak in the 45- to 50-year-age group. The proportion of periodontitis-affected quadrants. although initially lagging behind the overall case diagnoses. also increased with age.
Periodontics in general practice: professional plaque control, Traditionally the primary emphasis of preventive periodontics was daily patient performed plaque control. Recent studies indicate that frequent professional subgingival toothcleaning is a mandatory treatment for prevention of recurrent periodontitis. Pathogenic subgingival bacterial complexes are disrupted by frequent cleaning and require time to reestablish. Disease progression is prevented if the recall interval does not exceed the time required for reestablishment of a pathogenic plaque. Legally. patients have acquired the duty to comply with the prescribed recall interval. Both the patient and the practitioner will benefit from a preventive program that includes frequent professional subgingival toothcleaning.
Coronary Artery Surgery Study (CASS): comparability of 10 year survival in randomized and randomizable patients, The Coronary Artery Surgery Study (CASS) includes 780 patients with mild or moderate stable angina pectoris or asymptomatic survivors of a myocardial infarction who were randomized to either medical or surgical therapy and 1.319 patients who were eligible for randomization but were not randomized (randomizable patients). There were no substantial aggregate differences observed in any of the survival comparisons after 10 years of follow-up study between the randomized and randomizable patients assigned to the medical (79% versus 80%) or surgical (82% versus 81%) groups or in patient subgroups stratified according to coronary artery disease extent and left ventricular ejection fraction. Cox regression analyses were done with independent variables known to be predictors of survival. including surgical versus medical therapy and randomized versus randomizable group. to test the null hypothesis of a mortality difference between medical versus surgical assignment according to group assignment (randomized versus randomizable). In no case did the initial group category enter as a significant predictor of survival. The results in the randomizable group reinforce those in the randomized group with respect to the medical versus surgical comparison. Two subgroups are identified with a significant surgical advantage: 1) patients with proximal left anterior descending coronary artery stenosis greater than or equal to 70% and an ejection fraction less than 0.50. and 2) patients with three vessel coronary artery disease and an ejection fraction less than 0.50. In both groups. coronary bypass surgery had a statistically significant beneficial effect on survival (p less than 0.05). After a decade of follow-up. the CASS randomizable patients confirm conclusions reached on the basis of the CASS randomized trial.
Coronary lesion morphology in acute myocardial infarction: demonstration of early remodeling after streptokinase treatment, Coronary lesion morphology was analyzed in 72 patients 1 to 8 days after streptokinase treatment for acute myocardial infarction and compared with lesion morphology in a control group of 24 patients with stable angina. In the streptokinase group the infarct-related artery was patent in 55 patients (76%). Compared with stenoses in the stable angina group. there were no differences in the stenosis length. severity. calcification or in the proportion located at an acute bend or at a branch point. However. lesions in the streptokinase group were more often irregular (p less than 0.005) and eccentric (p less than 0.01). had a shoulder (p less than 0.0001). globular filling defects (p less than 0.01). linear filling defects (p less than 0.00005) and contrast staining (p less than 0.05). Plaque ulceration index was higher in the streptokinase than in the stable angina group (6.2 +/- 7.9 versus 3.5 +/- 3.4. p less than 0.001). Of the 72 streptokinase-treated patients. 35 were maintained on heparin infusion until angioplasty 2 to 10 days later. At repeat angiography before angioplasty. globular lesion filling defects seen in eight patients had disappeared. whereas linear filling defects persisted in 7 of 14 cases. Fewer lesions were irregular (p less than 0.0001) and the ulceration index decreased from 7.4 +/- 10.4 to 3.0 +/- 1.6 (p less than 0.001). These data show that the lesion in the infarct-related artery after streptokinase treatment is irregular and often associated with filling defects. perhaps corresponding to plaque fissuring and intraluminal thrombosis.
Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings, To characterize the neural excitatory state of heart failure. simultaneous measurements of efferent sympathetic nerve activity to muscle (by microneurography) and rest hemodynamics were obtained in 10 normal subjects (age 25 +/- 2 years. mean +/- SEM) and 29 patients with heart failure (age 49 +/- 2 years; New York Heart Association functional class II to IV; left ventricular ejection fraction 21 +/- 1%; cardiac index = 2.16 +/- 0.13 liters/min per m2; pulmonary capillary wedge pressure 23 +/- 2 mm Hg). Sympathetic nerve activity was significantly higher in the patients with heart failure (54.7 +/- 4.5 bursts/min) than in normal subjects (16.7 +/- 2.2 bursts/min. p less than 0.001). Multiple linear regression analyses indicated that sympathetic activity in these human subjects was most strongly and inversely correlated with left ventricular stroke work index (r = -0.86. p less than 0.0001) and stroke volume index (r = -0.85. p less than 0.0001). There was a strong positive correlation between sympathetic nerve activity and pulmonary artery diastolic (r = 0.82. p less than 0.0001) and mean (r = 0.81. p less than 0.0001) pressures. Similar correlations were seen when patients with heart failure were analyzed separately. There was no significant correlation between sympathetic nerve activity and mean arterial pressure. left ventricular ejection fraction (by radionuclide ventriculography). cardiac chamber size (by echocardiography) or arterial oxygen tension in the patients with heart failure. Direct measurements of sympathetic nerve activity correlated closely with plasma norepinephrine (r = 0.72. p less than 0.0001) in patients with heart failure. Thus. sympathetic nerve activity at rest parallels impairment of cardiac performance in patients with heart failure.
Simultaneous transesophageal atrial pacing and transesophageal two-dimensional echocardiography: a new method of stress echocardiography, The diagnostic use of exercise echocardiography has been widely reported. However. transthoracic exercise echocardiography is inadequate in up to 20% of patients because of poor image quality related to exercise. In an attempt to overcome these limitations. a system was developed in which transesophageal echocardiography is combined with simultaneous transesophageal atrial pacing by means of the same probe. In a prospective study. transesophageal echocardiography was performed before. during and immediately after maximal atrial pacing in 50 patients with suspected coronary artery disease. Results of transesophageal stress echocardiography were considered abnormal when new pacing-induced regional wall motion abnormalities were observed. Correlative routine bicycle exercise testing was carried out in 44 patients. Cardiac catheterization was performed in all patients. The success rate in obtaining high quality diagnostic images was 100% by transesophageal echocardiography. All nine patients without angiographic evidence of coronary artery disease had a normal result on the transesophageal stress echocardiogram (100% specificity). Thirty-eight of 41 patients with coronary artery disease (defined as greater than or equal to 50% luminal diameter narrowing of at least one major vessel) had an abnormal result on the transesophageal stress echocardiogram (93% sensitivity). The sensitivity of the technique for one. two or three vessel disease was 85%. 100% and 100%. respectively. compared with 44%. 50% and 83%. respectively. for bicycle exercise testing; the 12 lead electrocardiogram (ECG) during rapid atrial pacing showed a sensitivity of 25%. 64% and 86%. respectively. Thus. rapid atrial pacing combined with simultaneous transesophageal echocardiography is a highly specific and sensitive technique for the detection of coronary artery disease. Ischemia-induced wall motion abnormalities were detected earlier than observed ECG changes. The technique appears to be particularly suited to patients who are unable to perform an active stress test or those with poor quality transthoracic echocardiograms.
Dynamic positron tomographic imaging with nitrogen-13 glutamate in patients with coronary artery disease: comparison with nitrogen-13 ammonia and fluorine-18 fluorodeoxyglucose imaging, This study was designed to test the usefulness of nitrogen-13 (N-13) glutamate imaging with positron emission tomography in defining myocardial ischemia in humans. Seventeen patients who had undergone coronary arteriography were studied with N-13 glutamate at peak supine exercise using a bicycle ergometer. as well as with the flow tracer N-13 ammonia at peak exercise during a second similar exercise test. Six of the patients also underwent imaging with N-13 glutamate at rest before exercise testing; in the remaining 11 patients imaging with fluorine-18 (F-18) fluorodeoxyglucose was performed to assess glucose metabolism after the second exercise test. Seven patients had classic metabolism-flow mismatches consistent with ischemia (that is. decreased N-13 ammonia uptake in a region with relatively increased F-18 fluorodeoxyglucose uptake). There was no evidence of increased N-13 glutamate uptake in the ischemic mismatched regions in any of these patients. In all 17 patients. the uptake of N-13 glutamate during exercise paralleled the uptake of N-13 ammonia during exercise. suggesting that N-13 glutamate behaves as a flow tracer rather than as a metabolic marker of ischemia in humans.
Effects of nitroprusside on transmitral flow velocity patterns in extreme heart failure: a combined hemodynamic and Doppler echocardiographic study of varying loading conditions, To explore the mechanisms of change of left ventricular diastolic filling associated with preload and afterload reduction. the influence of nitroprusside on the transmitral flow velocity pattern. pulmonary capillary wedge pressure and left ventricular pressure interaction was studied in 11 patients with end-stage heart failure. Pulsed Doppler echocardiographic recordings of mitral inflow were obtained with simultaneous high fidelity left ventricular and phase-corrected pulmonary capillary wedge pressure recordings before and during levels of nitroprusside infusion. With nitroprusside. left ventricular systolic and end-diastolic pressures decreased by 14% and 41% (p less than 0.05. p less than 0.05). respectively. and cardiac output increased by 67% (p less than 0.05). The pulmonary capillary wedge-left ventricular crossover pressure decreased by 41% (p less than 0.05). but the time constant of isovolumetric left ventricular pressure decrease T was insignificantly changed. Isovolumetric relaxation time and acceleration and deceleration times of the early diastolic filling wave were significantly prolonged with nitroprusside infusion (p less than 0.05. p less than 0.05 and p less than 0.05. respectively). Peak early diastolic filling velocity was maintained (65 +/- 11 to 62 +/- 13 cm/s. p = NS) in spite of the decreased absolute crossover pressure. Changes in peak early diastolic filling velocity correlated weakly with changes in the crossover pressure (r = 0.48. p less than 0.05) and correlated better with the crossover to left ventricular minimal pressure difference (r = 0.78. p less than 0.05). Peak early diastolic filling velocity appears to be most affected by the early diastolic pulmonary capillary wedge to left ventricular pressure difference rather than the absolute pulmonary capillary wedge pressure. The lack of peak flow velocity change during nitroprusside infusion could be explained by either the associated decrease in left ventricular minimal pressure or downward shift of left ventricular diastolic pressure by the same amount as the decrease in pulmonary capillary wedge pressure. This may reflect a reduction of external constraint to ventricular distensibility produced by a reduction in filling volume in patients with a markedly dilated ventricle. Thus. a prolonged early diastolic filling period and preserved peak early diastolic filling velocity in spite of decreased left ventricular filling pressure and constant relaxation rate are associated with the beneficial effects of nitroprusside on left ventricular function in patients with severe congestive heart failure.
Comparison of ventricular arrhythmia induction with use of an indwelling electrode catheter and a newly inserted catheter, Two methods of serial electrophysiologic testing are in widespread use. Most commonly. the electrode catheter is removed after each study and a new catheter reinserted through the femoral vein for every subsequent test. An alternative method employs an electrode catheter that remains in place during several days of serial testing. Little is known about differences between these two methods with respect to the likelihood of induction of arrhythmia or the frequency of complications. To determine whether inducibility of sustained arrhythmia is altered or if the frequency of complications is unacceptably high with use of an indwelling catheter. a prospective randomized study was conducted in 78 patients. Each patient underwent baseline testing. several days of electropharmacologic testing with an indwelling catheter. a 24 h drug elimination period and placement of a new electrode catheter. Ventricular stimulation studies were then performed in each patient with both the indwelling and new electrode catheters. No differences were found between the indwelling and new catheter tests with respect to induction of arrhythmia. number of extrastimuli required to induce arrhythmia. rate of arrhythmia or requirement for cardioversion. Ventricular pacing thresholds were higher and effective refractory periods were slightly longer when measured with the indwelling catheter. Complications related to the 156 catheter insertions included two that may have been related to the indwelling catheter (one episode of staphylococcal sepsis and one presumed pulmonary embolism) and four that were related to invasive procedures (pneumothorax in all). There were no long-term adverse sequelae of these complications.
Determinants of the ventricular rate during atrial fibrillation, Determinants of the ventricular cycle length during atrial fibrillation were examined in 52 patients. Thirty-three patients had structural heart disease and none had an accessory atrioventricular (AV) connection. The AV node effective and functional refractory periods. the shortest atrial pacing cycle length associated with 1:1 conduction. the AV node conduction time and indexes of concealed conduction in the AV node were measured in the baseline state (36 patients) and after modification of sympathetic tone by infusion of isoproterenol or propranolol (8 patients each). Atrial fibrillation was then induced with rapid atrial pacing. and the mean. shortest and longest ventricular cycle lengths were measured. Variables that correlated most strongly with the mean RR interval during atrial fibrillation were the AV node effective refractory period (r = 0.93; p less than 0.001). AV node functional refractory period (r = 0.87; p less than 0.001) and shortest atrial pacing cycle length associated with 1:1 conduction (r = 0.91; p less than 0.001). The AH interval during sinus rhythm (r = 0.74; p less than 0.001) and during atrial pacing at the shortest cycle length with 1:1 conduction (r = 0.52; p less than 0.001) had weaker correlations. Measures of concealed conduction did not improve the prediction of the mean or longest ventricular cycle length during atrial fibrillation. In conclusion. the refractory periods and conductivity of the AV node are the best indicators of the potential of the node to transmit atrial impulses to the ventricles during atrial fibrillation. The degree of concealed conduction in the AV node is a less important determinant of the mean ventricular rate during atrial fibrillation.
Comparative value of transthoracic and transesophageal echocardiography in the assessment of congenital abnormalities of the atrioventricular junction, Information obtained from transthoracic and transesophageal echocardiography (two-dimensional echocardiography with spectral Doppler and color flow imaging) was compared in 17 patients with major congenital abnormalities of the atrioventricular (AV) junction (10 discordant AV connections. 1 criss-cross connection. 5 absent right connections and 1 absent left connection). The findings by either technique were correlated with findings at cardiac catheterization (12 patients) and at surgery (5 patients). In two of six patients with an absent AV connection as defined by transthoracic echocardiography. transesophageal imaging demonstrated an imperforate AV valve. In 11 of 11 patients with a discordant or criss-cross connection. assessment of AV valve and ventricular morphology (by defining the chordal attachments of both AV valves) was possible with transesophageal echocardiography (3 of 11 patients by transthoracic echocardiography); chordal straddling was detected in 1 patient and excluded in 3 others with an associated inlet ventricular septal defect. Anomalous pulmonary venous connection (one patient). atrial septal defect (three patients) and subpulmonary stenosis (five patients) were better assessed by transesophageal imaging. and atrial appendage morphology could be demonstrated in all. The transesophageal technique was less useful in demonstrating the anterior subaortic infundibulum or aortopulmonary shunt (two patients). Although systemic ventricular function could be assessed by either method with use of short-axis M-mode scans. transesophageal pulsed Doppler interrogation of AV valve and pulmonary venous flow patterns provided clues to diastolic dysfunction of the systemic ventricle.
Efficacy of propafenone in preventing ventricular tachycardia: inverse correlation with rate-related prolongation of conduction time, The efficacy of propafenone in preventing induction of ventricular tachycardia was evaluated in 25 consecutive patients (mean age 62 +/- 8 years) with remote myocardial infarction who underwent programmed electrical stimulation for ventricular arrhythmia using up to three extra-stimuli after basic drive at the right ventricular apex. In nine patients (Group A). propafenone prevented induction of sustained ventricular tachycardia (noninducible in four. nonsustained [less than 30 s] in five). In the other 16 patients (Group B). sustained ventricular tachycardia was still inducible; in 11 of the 16. the tachycardia configuration was unchanged but the cycle length was significantly longer (431 +/- 99 versus 284 +/- 44 ms. p less than 0.001). Propafenone did not significantly affect either sinus cycle length or AH and HV intervals. However. it prolonged QRS duration during sinus rhythm equally in both groups of patients. With ventricular pacing. propafenone also prolonged right ventricular effective and functional refractory periods and surface QRS duration. There was greater lengthening of the paced surface QRS duration when drug therapy was ineffective (for example. +35 +/- 12 ms in Group A versus +69 +/- 23 ms in Group B at a basic drive of 400 ms. p less than 0.01). Drug-induced prolongation of a paced QRS complex greater than 40 ms had a 94% positive predictive value for drug failure to prevent induction of ventricular tachycardia. Drug-induced percent prolongation of ventricular tachycardia cycle length in Group B did not correlate well with percent QRS prolongation.
Magnitude and time course of beta-adrenergic antagonism during oral amiodarone therapy, To examine the presence and time course of beta-adrenergic antagonism produced by amiodarone. the heart rate. QT interval and arrhythmia frequency in response to graded doses of isoproterenol were evaluated in eight patients treated with oral amiodarone for sustained ventricular tachycardia. Measurements were made before and every 2 days after beginning oral amiodarone therapy (600 mg twice daily). Isoproterenol was given in doses of 12.5. 25 and 50 ng/kg body weight per min. The mean heart rate at rest decreased from 73.1 +/- 17.8 beats/min on day 0 to 57.8 +/- 15.0 beats/min after 12 days of amiodarone therapy. A significant linear decline in heart rate at rest was observed until day 6 (p less than 0.05 for all comparisons). On all days isoproterenol produced a progressive increase in heart rate that reached 115.5 +/- 20.2 beats/min on day 0 and 94.2 +/- 18.5 beats/min on day 12. Amiodarone blunted the heart rate increase produced by isoproterenol on days 2 to 12 (p less than 0.05 versus day 0). This effect was present by day 2 and did not change significantly thereafter. The mean corrected QT (QTc) interval increased from 430 +/- 30 ms on day 0 to 449 +/- 63 ms on day 12. A significant linear increase in QTc interval was observed until day 6 (p less than 0.05 for all comparisons). There was no systematic effect of isoproterenol on the QTc interval. Five of eight patients had a significant number of isoproterenol-induced premature ventricular complexes. Ventricular ectopic activity in response to isoproterenol was abolished after 4 days of amiodarone therapy.
Surgical treatment of endomyocardial fibrosis: a new approach, Endomyocardial fibrosis has been treated surgically for many years. For complete removal of fibrosis from both ventricles by the classic technique. each atrioventricular (AV) valve was removed and replaced with a prosthesis. Relapse of endomyocardial fibrosis has not been observed after surgical correction. Reoperations have been carried out because of complications of valve prostheses. A new surgical technique for removal of ventricular fibrous tissue with preservation of the mitral and tricuspid valves was used in nine consecutive patients with endomyocardial fibrosis. Initial results show a reduction of pulmonary hypertension. mean right and left atrial pressures and end-diastolic pressures in both ventricles. Tricuspid annuloplasty was performed in seven patients and mitral annuloplasty in five. No valve prosthesis was used. There was no death and New York Heart Association functional class improved from class III or IV in the preoperative period to class I or II in the postoperative period. These data suggest that resection of endocardial fibrous tissue can be indicated early in the clinical course and performed with preservation of the AV valves.
Effect of intravenous streptokinase on the relation between initial ST-predicted size and final QRS-estimated size of acute myocardial infarcts, Thrombolytic therapy has been documented to reduce acute myocardial infarct size. The previously established relation between initial ST segment elevation and final electrocardiographic (ECG) myocardial infarct size in patients without coronary reperfusion might therefore be altered by thrombolytic therapy. The effect of intravenous streptokinase on this relation was therefore studied in 73 patients with initial acute myocardial infarction who had participated in the Second International Study of Infarct Survival (ISIS-2). Patients who received streptokinase were considered as one group and patients who did not receive streptokinase as a control group. Final myocardial infarct size. which was estimated from the QRS score. was predicted from the admission standard ECG by previously developed formulas based on ST segment elevation. In the 40 control patients there was no change from ST-predicted to final QRS-estimated infarct size (median 17.7% versus 18.3%; p = NS). In the 33 patients in the streptokinase group. there was a highly significant decrease from predicted to final myocardial infarct size (median 21.9% versus 16.2%; p less than 0.0002). This decrease was found for both anterior (median 23.7% versus 19.5%; p less than 0.03) and inferior (median 21.9% versus 12.0%; p = 0.001) infarct locations. Multiple regression analysis adjusting for differences in predicted infarct size confirmed the significance of streptokinase on the difference in infarct size (p = 0.006). Based on the variability of the percent change from predicted to final infarct size in the control group. a threshold decrease greater than or equal to 20% is required for identification of salvage.
Intraoperative assessment of regional myocardial perfusion using quantitative myocardial contrast echocardiography: an experimental evaluation, To test the hypothesis that myocardial contrast echocardiography can be used to quantitate regional myocardial flow in the arrested heart at the time of delivery of cardioplegic solution. data were acquired in 13 dogs on cardiopulmonary bypass. Different degrees of stenosis were placed in random order on the left anterior descending coronary artery. For each stenosis. myocardial contrast echocardiography was performed by injecting sonicated albumin microbubbles into the cross-clamped aortic root at the time of delivery of cardioplegic solution. The resultant echocardiographic images were analyzed on an off-line computer. Background-subtracted time-intensity plots were generated. and an exponential function. f(t) = Ce-alpha t + De- beta t. was applied to each plot. Variables that reflected the total number of microbubbles entering the coronary artery bed. such as the area under the curve and the peak height of the curve. correlated best with radiolabeled microsphere-measured myocardial flow (r = 0.92 and r = 0.91. respectively). Variables that reflected the appearance of contrast microbubbles in the myocardium. such as the initial slope and the slope at 1 s. also had a good correlation with myocardial flow (r = 0.84 and r = 0.89. respectively). Variables that reflected the washout of contrast medium from the myocardium. such as the slope of the descending portion of the curve. had only a fair correlation with myocardial flow (r = 0.65). In six dogs. the technique of injecting contrast medium into the cross-clamped aortic root was also examined. Although continuous infusion of contrast medium produced smaller perturbations in mean aortic and distal left anterior descending artery pressures compared with a bolus injection (p less than 0.01). the correlation between the variables of the time-intensity curves and flow was equally close with both techniques. It is concluded that it is possible to quantitate myocardial flow by using myocardial contrast echocardiography at the time of delivery of cardioplegic solution in dogs on cardiopulmonary bypass. The implementation of this technique in humans might be useful in guiding the sequence of graft placement and thereby improving myocardial preservation during coronary artery bypass operations.
Prostaglandin modulation of early afterdepolarizations and ventricular tachyarrhythmias induced by cesium chloride combined with efferent cardiac sympathetic stimulation in dogs, Prostaglandins inhibit efferent cardiac sympathetic nerve effects by acting at presynaptic sites and may act to suppress some arrhythmias. In the present study. the effects of intravenous administration of prostacyclin (PGI2) and prostaglandin E2 (PGE2) on early afterdepolarizations and ventricular tachycardia induced by cesium chloride (0.5 mmol/liter per kg body weight intravenously) combined with stimulation of bilateral ansae subclaviae in anesthetized dogs were examined. The right atrium was paced at a constant cycle length of 600 ms. A left ventricular endocardial monophasic action potential catheter was used to detect early afterdepolarizations. Prostacyclin (0.2 microgram/kg per min) reduced the amplitude of the early afterdepolarizations (39.2 +/- 8.4% of the monophasic action potential amplitude during control study to 28.7 +/- 5.5%. n = 10; p less than 0.001) as well as the prevalence of ventricular tachycardia (11 of 14 dogs during control study to 5 of 14 dogs; p = 0.031). Prostaglandin E2 (0.2 to 0.6 microgram/kg per min) did not significantly reduce the early afterdepolarization amplitude (34.7 +/- 8.9% to 25.1 +/- 10.7%. n = 8; p = 0.085) or the prevalence of ventricular tachycardia (8 of 10 versus 6 of 10 dogs; p = 0.50). Alpha- and beta-adrenoceptor blockade with combined intravenous administration of propranolol (0.5 mg/kg) and phentolamine (0.3 mg/kg) decreased the amplitude of the early afterdepolarizations induced by cesium chloride and bilateral ansae subclaviae stimulation from 38.6 +/- 11.2% to 18.8 +/- 3.3% (n = 6; p = 0.005). Additional administration of PGI2 further reduced the early afterdepolarization amplitude from 18.8 +/- 3.3% to 9.8 +/- 4.8% (n = 6; p = 0.001).
Effects of calcium channel blockers on coronary vasoconstriction induced by endothelin-1 in closed chest pigs, The purpose of this study was to determine the effects of endothelin-1 on the coronary vascular bed of closed chest pigs. Endothelin-1 (3 to 30 pmol/kg body weight) was selectively administered into the left anterior descending coronary artery. Coronary blood flow and epicardial vessel diameter were measured by quantitative arteriography. Arterial pressure increased after a 30 pmol/kg dose and heart rate was not changed. Coronary blood flow and vessel diameter of the left anterior descending artery significantly decreased by 74% and 32%. respectively (p less than 0.01 versus control) after the 30 pmol/kg dose. whereas these variables modestly decreased in the left circumflex artery. Endothelin-1 in doses of 10 to 30 pmol/kg produced electrocardiographic ST segment elevation associated with decreased oxygen saturation of coronary sinus venous blood. Endothelin-induced coronary vasoconstriction was significantly inhibited after treatment with intravenous diltiazem (0.2 mg/kg. n = 6) or nifedipine (0.1 mg/kg. n = 5). but not after vehicle administration (n = 4). This study demonstrates that intracoronary administration of endothelin-1 causes significant myocardial ischemia through coronary vasoconstriction. which is inhibited by a calcium channel blocker. The data suggest that calcium influx into the smooth muscle cells appears to be involved at least in part in the mechanism of endothelin-induced coronary vasoconstriction in vivo.
Cardiac teratogenesis of trichloroethylene and dichloroethylene in a mammalian model, Recent epidemiologic studies have demonstrated a greater than expected number of pediatric patients with congenital heart disease in areas where drinking water was contaminated by halogenated aliphatic hydrocarbons. Trichloroethylene. trichloroethane and dichlorethylene were the principal contaminants in the groundwater. A previous study of chick embryos demonstrated that when injected into the air sacs of fertilized eggs trichloroethylene produced more than three times the number of cardiac defects that are found in control embryos. This mammalian study demonstrates similar effects of trichloroethylene and dichloroethylene when applied under provocative circumstances (that is. solutions delivered through a catheter into the gravid uterus from an intraperitoneal osmotic pump) to the developing rat fetus in utero during the period of organ differentiation and development. Furthermore. the effect is dose dependent for both agents. Although only a very small number of congenital heart anomalies (3%) were found in the control group. 9% and 12.5% were found in the lower dose trichloroethylene and dichloroethylene groups and 14% and 21% in the higher dose groups. respectively (p less than 0.05). A variety of cardiac defects were found. Dichloroethylene appears to be at least as great a cardiac teratogen as trichloroethylene even though it was administered at a 10-fold lower concentration. These agents appear to be specific cardiac teratogens because only a single noncardiac anomaly was found. This study in a rat model demonstrates a dose-dependent relation between fetal exposure to trichloroethylene and dichloroethylene in utero during the period of organogenesis and the appearance of a variety of congenital cardiac defects.
Balloon expandable stent implantation in stenotic right heart valved conduits, Although valved conduits have been used successfully in severe forms of right ventricular-pulmonary artery discontinuity. progressive valved conduit stenosis is an important clinical problem. To determine the feasibility of reducing right heart valved conduit stenosis with a balloon expandable stent. a baboon model was used. in which the pulmonary artery was ligated and a right ventricular to pulmonary artery 14 mm bioprosthetic Dacron valved conduit implanted. In five baboons. at an average of 40 months after valved conduit implantation. fibrointimal stenosis at the valve site resulted in narrowing and a mean transconduit pressure gradient of 49 mm Hg (range 33 to 65). A tubular slotted steel stent (1.2 cm long) was deployed within the valved conduit after inflation of an 8 to 15 mm diameter balloon catheter that was introduced through the femoral vein. A stent was delivered to all valved conduits; however. in two baboons. balloon undersizing resulted in stent dislodgment. In the remaining three baboons. the transconduit gradient was reduced by 59% (49 to 20 mm Hg) and right ventricular systolic pressure decreased acutely by 35% (77 to 50 mm Hg). It is concluded that stent deployment is feasible in right ventricular to pulmonary artery stenotic valved conduits and may result in significant hemodynamic improvement. However. successful stent delivery is critically dependent on the proper selection of stent length and balloon diameter.
Transesophageal echocardiography to detect atrial clots in candidates for percutaneous transseptal mitral balloon valvuloplasty, Left atrial thrombi are common in patients with mitral stenosis. When percutaneous balloon mitral valvuloplasty is performed on such patients. there is a potential risk of thrombus dislodgment and embolization. In this study conventional transthoracic echocardiography and transesophageal echocardiography were performed for percutaneous balloon mitral valvuloplasty on 19 consecutive candidates (6 men. 13 women. 23 to 81 years old). In five patients (26%). transesophageal echocardiography revealed a left atrial thrombus; in only one of these was there a suspicion of left atrial thrombus on transthoracic echocardiography. Balloon mitral valvuloplasty was canceled in four of the five patients. Three underwent mitral valve surgery that confirmed the echocardiographic findings. Transesophageal echocardiography is better than conventional transthoracic echocardiography in detecting left atrial clots in candidates for balloon mitral valvuloplasty. Because of the potential risk of embolization. transesophageal echocardiography is recommended in all candidates for balloon mitral valvuloplasty.
Relation between beta-adrenergic blocker use, various correlates of left ventricular function and the chance of developing congestive heart failure. The Multicenter Diltiazem Post-Infarction Research Group, This study examined the relations among beta-adrenergic blocker use. various correlates of left ventricular function and the chance of developing congestive heart failure in patients after myocardial infarction. The study was performed with the placebo group of the Multicenter Diltiazem Post-Infarction Trial. Ejection fraction data were available in 1.084 patients; of these. 557 were receiving a beta-blocker and 527 were not. In addition to ejection fraction. other correlates of left ventricular function included the presence or absence of pulmonary rales. chest X-ray film evidence of pulmonary congestion and the presence of an S3 gallop. Beta-blocker use was less frequent in patients with an ejection fraction less than 30%. rales. an S3 gallop and pulmonary congestion on chest X-ray film. Twenty-one percent of patients with an ejection fraction less than 30%. 42% of patients with rales. 28% of patients with an S3 gallop and 28% of patients with pulmonary congestion were receiving beta-blocker therapy. For every correlate of left ventricular function. the chance of developing congestive heart failure was greater in patients with diminished left ventricular function than in those without. For each level of left ventricular function. the chance of developing congestive heart failure requiring treatment was greater in patients not taking a beta-blocker.
Single photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia: correlation with coronary arteriography, exercise thallium imaging and two-dimensional echocardiography, The feasibility. safety and diagnostic accuracy of single photon emission computed tomography (SPECT) with thallium-201 imaging during adenosine-induced coronary hyperemia were evaluated in 53 patients with and 7 without coronary artery disease proved by coronary angiography. Adenosine was infused intravenously at a dose of 0.14 mg/kg body weight per min for 6 min and thallium was injected at 3 min. Adenosine caused an increase in heart rate (68 +/- 12 at baseline versus 87 +/- 18 beats/min at peak effect. p less than 0.0001) but no change in blood pressure. The sensitivity and specificity were 92% (95% confidence intervals 81% to 98%) and 100% (95% confidence intervals 59% to 100%). respectively; 20 (61%) of 33 patients with multivessel coronary artery disease were also correctly identified. In 30 patients. the predictive accuracy of adenosine thallium imaging was slightly higher than that of exercise SPECT thallium imaging (90% versus 80%. p = NS) (95% confidence intervals 72% to 97% and 61% to 92%. respectively). In 25 patients. two-dimensional echocardiography during adenosine infusion disclosed a new wall motion abnormality in 2 (10%) of 20 patients with coronary artery disease; 80% of these patients had reversible thallium defects (p less than 0.001). Side effects were mild and transient; aminophylline was used in only three patients. Thus. adenosine SPECT thallium imaging provides a high degree of accuracy in the diagnosis of coronary artery disease. The results are comparable with those of exercise SPECT thallium imaging. Most reversible defects in the adenosine study are not associated with any transient wall motion abnormality.
Termination of acute atrial fibrillation in the Wolff-Parkinson-White syndrome by procainamide and propafenone: importance of atrial fibrillatory cycle length, The effects of intravenous procainamide (n = 30) or propafenone (n = 25) were evaluated in 55 patients with acute atrial fibrillation and the Wolff-Parkinson-White syndrome. All patients received either procainamide (12 to 15 mg/kg body weight) or propafenone (1 to 2 mg/kg) during sustained (greater than 10 min) atrial fibrillation or after termination of nonsustained atrial fibrillation. Termination of atrial fibrillation was attributed to a drug if it occurred less than or equal to 15 min after infusion. Measurements included mean cycle length of fibrillatory electrograms (mean AA interval) as measured at the high right atrium and shortest RR interval between pre-excited cycles during atrial fibrillation. Atrial fibrillation terminated more frequently after procainamide administration (65%) than after propafenone (46%). although this difference was not significant. Procainamide prolonged the shortest pre-excited RR interval (228 +/- 41 to 339 +/- 23 ms. p = 0.0001) as did propafenone (215 +/- 40 to 415 +/- 198 ms. p = 0.0001) and the magnitude of increase was greater for propafenone (p = 0.048). Patients with sustained atrial fibrillation had shorter mean AA intervals than did their counterparts with nonsustained atrial fibrillation (123 +/- 25 versus 186 +/- 35 ms. p = 0.0001). Termination of sustained atrial fibrillation by either drug was accompanied by prolongation of the mean AA interval but not necessarily by the shortest pre-excited RR interval. Termination of atrial fibrillation was heralded by a 68% increase in the mean AA interval after procainamide administration compared with a 30% increase when the arrhythmia persisted. For propafenone the increases were 90% and 68%. respectively.
Feasibility and cost savings of outpatient electrophysiologic testing, The feasibility of outpatient electrophysiologic testing was examined by reviewing 100 consecutive outpatient tests performed in 95 patients. Seventy-one of the patients (75%) had no underlying heart disease. The electrophysiologic tests were performed to evaluate supraventricular tachycardias (n = 47). nonsustained ventricular tachycardia (n = 20). unexplained syncope (n = 21). palpitation (n = 9) or intermittent heart block (n = 2). A mean of 2.8 +/- 0.5 6F electrode catheters were inserted through a femoral vein. An electrode catheter was inserted into a subclavian or internal jugular vein in 28 tests and a 5F cannula was inserted into a femoral artery to monitor the blood pressure in 20 tests. The results of 61 tests (61%) were abnormal. Patients were monitored for a mean of 3.8 +/- 1.2 h after the procedure and then discharged. No complications occurred. For cost analysis a subgroup of 60 of these patients was matched for age. gender. heart disease and indication for electrophysiologic testing with a group of 60 patients who underwent electrophysiologic testing as inpatients. Physicians' fees for the two groups were similar; however. the mean hospital charge was $5.845 +/- 3.763 for the inpatient group compared with only $2.120 +/- 1.244 for the outpatient group (p less than 0.001). Thus. outpatient electrophysiologic testing is feasible and safe and results in substantial cost savings in patients without life-threatening arrhythmias.
Plaque morphology and pathologic changes in arteries from patients dying after coronary balloon angioplasty, Morphologic correlates of pathologic success or failure were studied at autopsy in 28 patients with 40 coronary arteries that had been subjected to balloon angioplasty. The presence of the following histologic features was evaluated: plaque concentricity or eccentricity. calcification. fibrous or fibropultaceous plaque. medial disruption. luminal thrombus and inflammation. Angioplasty was considered successful (residual cross-sectional luminal area greater than 25%) on pathologic examination in 14 arteries and unsuccessful in 26 arteries. Eccentric plaques were more likely to be successfully dilated than were concentric lesions (p less than 0.05). Six (50%) of 12 fibropultaceous plaques were successfully dilated compared with only 8 (29%) of 28 fibrous plaques. Moderate to severe calcification did not preclude morphologic success. Medial stretching or dissection. or both. was more often associated with a successful result. Thus. plaque morphology may be an important determinant of pathologic outcome after coronary angioplasty.
Dissociation of changes in cardiovascular mass and performance with angiotensin-converting enzyme inhibitors in Wistar-Kyoto and spontaneously hypertensive rats, The effects of angiotensin-converting enzyme inhibitors on cardiovascular mass and function were measured in three groups of 22 week old male Wistar-Kyoto normotensive and spontaneously hypertensive rats treated with CGS-16617. cilazapril or quinapril. Left ventricular performance was assessed by electromagnetic flow meter during rapid whole blood infusion before and after arterial pressure and increased abruptly with aortic snare; aortic distensibility also was assessed in vitro. The systemic hemodynamic effects of these three agents were similar. yet their structural effects varied. Although left ventricular and aortic masses diminished and right ventricular mass remained unchanged (with all three agents) in the spontaneously hypertensive rats. CGS-11617 and cilazapril also reduced left ventricular mass in the normotensive Wistar-Kyoto rats without changing aortic mass. All three agents improved aortic distensibility whether or not mass was decreased. Left ventricular structural changes were associated with variable changes in pumping ability. These data show that reduced mass associated with angiotensin-converting enzyme inhibitor treatment was not consistent in ventricles and aorta. that a dissociation exists between structural and functional changes and that reduction of cardiac mass alone does not relate to changes in chamber mass or in function. Thus. biologic and pharmacodynamic differences exist among angiotensin-converting enzyme inhibitors as well as between classes of antihypertensive agents.
Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy [corrected and republished with original paging, article originally printed in J Am Coll Cardiol 1990 Oct;16(4):839-46, Heart-reactive antibodies are commonly observed in patients with myocarditis or cardiomyopathy. Such antibodies may be important in the pathogenesis of these disorders. yet the specific antigens recognized have not been studied systematically. This report characterizes circulating heart autoantibodies from patients with myocarditis (n = 17) or idiopathic cardiomyopathy (n = 71) and from healthy volunteers (n = 15). Indirect immunofluorescence demonstrated that high titer (greater than or equal to 1:20) immunoglobulin G (IgG) antibody activity occurred in 59% of the myocarditis samples. 20% of the cardiomyopathy samples and none of the normal samples. All samples were tested by Western immunoblotting for IgG activity against a normal human heart extract. The number of antigens recognized by each sample was enumerated and the molecular weight of each antigen estimated; the prevalence of reactivity against antigens in selected molecular weight classes was determined. There was no difference in the mean number of heart antigens recognized by serum from each group. For most weight classes. prevalence either did not differ significantly among the various groups or subgroups or was greatest among samples from healthy volunteers. Prevalence of reactivity with 190 to 199 kilodalton (kd) antigens was greatest (p less than 0.05) among low titer serum samples from patients with myocarditis. High titer cardiomyopathy serum differed from normal serum by an increased (p less than 0.05) prevalence of antibodies to 40 to 49 and 100 to 109 kd antigens. These results suggest that western immunostaining may ultimately contribute substantively to identifying patients with myocarditis or cardiomyopathy.
Diagnostic value of a new myocardial perfusion agent, teboroxime (SO 30,217), utilizing a rapid planar imaging protocol: preliminary results [corrected and republished with original paging, article originally printed in J Am Coll Cardiol 1990 Oct;16(4):855-61, Technetium-99m-labeled agents have advantages over thallium-201 in terms of photon statistics. cost and clinical availability. They have been suggested as an alternative to thallium for myocardial perfusion imaging. Teboroxime is a new boronic acid adduct of technetium dioxime (BATO) compound that demonstrates favorable characteristics in preliminary studies. With use of a novel (seated) patient positioning technique and a rapid dynamic acquisition protocol. 30 patients underwent planar imaging with teboroxoime while at rest and after maximal treadmill exercise. Postexercise scans were completed in an average time (mean +/- SD) of 4.4 +/- 1.6 min. with 4.8 +/- 1.5 min for the views at rest. These results were compared with coronary arteriography or thallium scintigraphy after treadmill exercise. or both. Diagnostic agreement (abnormal versus normal) was present in 28 of the 30 patients (p less than 0.001). Regarding physiologic assessment as compared with thallium scintigraphy. the finding of infarction and ischemia was concordant in 89% and 86% of patients. respectively. This report describes the initial use of teboroxime with a rapid dynamic planar imaging technique. resulting in a high correlation with exercise thallium scintigraphy. Delayed postexercise images obtained 5 to 10 min after exercise demonstrated rapid disappearance of exercise-induced defects noted on the initial (0 to 5 min) postexercise views. The rapid differential washout with teboroxime has not been previously described and the possible clinical significance is discussed.
Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography [corrected and republished with original paging, article originally printed in J Am Coll Cardiol 1990 Oct;16(4):862-70, Serum levels of DHEA sulfate are inversely associated with cardiovascular death in men. and urinary dehydroepiandrosterone (DHEA) levels are inversely associated with clinical manifestations of coronary artery disease. These observations may be related to the antiproliferative effects of DHEA. resulting in inhibition of atherosclerotic intimal hyperplasia. To examine the relation between these steroids and a direct measure of coronary atherosclerosis. plasma DHEA and DHEA sulfate levels were determined in 206 middle-aged patients (103 men. 103 women) undergoing elective coronary angiography. Plasma DHEA sulfate levels were lower in men with at least one stenosis greater than or equal to 50% compared with those without any stenosis greater than or equal to 50% (4.9 +/- 2.7 versus 6.1 +/- 3.5 nmol/ml. p = 0.05). Levels of DHEA sulfate were also inversely related to the number of diseased coronary vessels (r = -0.20. p = 0.05) and a continuous measure of the extent of coronary atherosclerosis (r = -0.25. p = 0.01) in men. The association between DHEA sulfate levels and extent of coronary artery disease was independent of age and other conventional risk factors for coronary disease. In women. there was no association between plasma DHEA or DHEA sulfate levels and coronary disease. These data demonstrate a consistent. independent. inverse. dose-response relation between plasma DHEA sulfate levels and angiographically defined coronary atherosclerosis in men. Plasma DHEA sulfate may be another important and potentially modifiable risk factor for the development and progression of coronary atherosclerosis.
Characteristics of patients with food-related complaints, Forty-five patients with classic food-allergic symptoms and/or subjective food-related complaints not traditionally associated with food allergy underwent evaluation. On the basis of a comprehensive clinical history. skin testing. and placebo-controlled. double-blind food challenges. patients were assigned to one of two groups: patients with reactions highly suggestive of IgE-mediated food hypersensitivity (group A. N = 22) and patients with atypical adverse food reactions that could not be confirmed by double-blind food challenge (group B. N = 23). Most patients in both groups were female. 77.3% and 91.3% of patients in group A and B. respectively. In group B. onset of symptoms occurred at an older age than in group A. 28.9 years +/- 17.2 versus 17.1 +/- 12.1 (p = 0.0015). respectively. and involved more foods. 25.6 +/- 22.1 versus 5.2 +/- 5.5 (p = 0.0002). Foods causing most prominent symptoms among patients in group A included legumes. tree nuts. crustaceans. and fish. In group B. milk. white sugar. wheat. egg. smoked/cured meat. and yeast were among the most troublesome foods. All but one patient in group A gave a positive skin test response to food; only four patients in group B had a positive response. We conclude that a subset of patients with food-related complaints can be accurately predicted to have a negative double-blind challenge with suspected foods on the basis of information obtained by history and skin testing.
A placebo-controlled trial of immunotherapy with two extracts of Dermatophagoides pteronyssinus in allergic rhinitis, comparing clinical outcome with changes in antigen-specific IgE, IgG, and IgG subclasses, A double-blind. placebo-controlled trial of immunotherapy was conducted in patients with Dermatophagoides pteronyssinus rhinitis. Thirty patients received an extract with a high content of Der p I (Pharmalgen). 20 received a conventional mite extract (Allpyral). and 30 patients received histamine chloride (placebo). Specific IgG and subclasses were measured before and after 3 and 12 months of treatment by RIA and/or ELISA. and specific IgE by RAST. Clinical outcome was assessed by skin prick tests. nasal challenge. visual analogue. and diary-card symptom and drug scores; from these findings. a clinical index was derived. An IgG response occurred only in the Pharmalgen-treated group: D. pter IgG and IgG1 increased by 3 months (p less than 0.05) and then plateaued to 12 months (p less than 0.05). IgG4 levels increased throughout treatment (p less than 0.05 and p less than 0.01). as did the IgG/IgE ratio. A subclass switch from IgG1 to IgG4 occurred. D. pter IgE rose at 3 months (p less than 0.05). Clinical improvement occurred at 3 and 12 months in the Pharmalgen-treated group only. Pretreatment levels of IgE. IgG1. or IgG4 did not predict clinical outcome. Our findings are compatible with the hypothesis that IgG subclasses may modulate antigen-IgE interactions. although the antibody response to this potent extract need not be causally related to improvement.
Immunoblot analysis of sera from patients with allergic bronchopulmonary aspergillosis: correlation with disease activity, Immunoblot analysis was used to evaluate the IgG. IgE. and IgA responses to Aspergillus fumigatus antigen with the sera of five patients with allergic bronchopulmonary aspergillosis (ABPA) before. during. and after suspected exacerbation of their disease. The results revealed a heterogenous antibody response. unique for each patient. to specific Aspergillus fumigatus antigens that correlated with the molecular weights of previously well-characterized antigens of importance in the immunopathogenesis of ABPA. A rating scale was devised for measuring band intensity that allowed the patient's antibody responses to be reproducibly semiquantitated. Immunoblot analysis demonstrated qualitative and semiquantitative information that is not available with other in vitro assays used in the study of patients with ABPA. such as ELISA. These initial results emphasize the need for additional evaluation of this technique to assess its potential clinical application in this disease.
Basophil histamine release by platelet-activating factor in aspirin-sensitive subjects with asthma, Histamine release induced by platelet-activating factor (PAF) from leukocytes of aspirin-sensitive subjects with asthma was higher than that from normal control subjects. despite the similarity of anti-IgE-induced histamine release. Moreover. basophils of some aspirin-sensitive subjects with asthma released histamine by PAF stimulation in the absence of cytochalasin B that affects histamine release and is required in PAF-induced histamine release from leukocytes of atopic subjects with asthma and normal control subjects. In addition to temperature dependency and inhibition by ethylenediaminetetraacetic acid reported previously. PAF-induced histamine release was enhanced by cytochalasin B and indomethacin and inhibited by dexamethasone. These features are common with IgE-mediated histamine release and suggest the existence of the common pathway to PAF-induced histamine release and IgE-mediated histamine release. The results in the present study indicate the pathophysiologic significance of PAF-induced histamine release and that activation of basophils by PAF may be relevant to the pathogenesis in some aspirin-sensitive subjects with asthma.
Neuropeptides and nasal secretion, Recent research has disclosed that neurotransmitters and neuropeptides released within the autonomic nervous system exert homeostatic control of nasal secretion. Although cholinergic and adrenergic influences have long been thought to be the predominant mechanisms. the nonadrenergic. noncholinergic responses may have more suitable. longer-lasting effects. Peptides from sensory nerves. such as calcitonin gene related peptide. substance P. and neurokinin A. may participate in axon response-mediated vasodilation and plasma extravasation. Substance P and gastrin releasing peptide may induce glandular secretion. Defensive responses to local mucosal injury may be amplified by axon response. which initiates these vascular and glandular reactions. Cholinergic effects are primarily responsible for mediating parasympathetic reflexes. but vasoactive intestinal peptide may regulate acetylcholine release. augment glandular secretory responses. and have a vasodilatory effect. In the sympathetic nervous system. neuropeptide Y probably functions as a long-acting vasoconstrictor. Integration of sympathetic and parasympathetic influence may regulate the normal nasal cycle. and sensory and parasympathetic defensive reflexes may respond to epithelial and mast cell stimulation. It is possible. then. that the pathophysiology of vasomotor rhinitis involves an exaggeration of these neural influences.
The role of antihistamines in atopic dermatitis, Although several lines of evidence support a role for histamine in the pathogenesis of atopic dermatitis. antihistamines have generally offered only marginal therapeutic benefit. The efficacy of the classic antihistamines has been severely limited by sedative effects. demonstrating the need for improved. nonsedating agents. Multifunctional antihistamines. or third-generation "antiallergic" drugs. appear to offer a variety of advantages beyond their ability to inhibit histamine release. such as inhibition of mediator release and interference with eosinophil migration. Double-blind studies of high-dose regimens are needed to help clarify the therapeutic efficacy of these antiallergic drugs.
Mechanisms involved in allergic contact dermatitis, Allergic contact dermatitis is a common inflammatory skin disease caused by agents such as plants. chemical compounds. and topical medications. Histologic features typically include edema within the epidermis and dermis and a lymphohistiocytic infiltrate with an admixture of basophils. Langerhans cells and keratinocytes play pivotal roles in allergic contact dermatitis reactions. Langerhans cells synthesize and express class II molecules that allow the presentation of exogenous antigens to T lymphocytes. Additionally. keratinocytes and Langerhans cells produce interleukin-1. which is thought to be a second signal that activates T cells. Mast cells and basophils also may play a proinflammatory role. Treatment primarily consists of removal of the offending agent. At times. systemic corticosteroids may be required. especially in the acute phase. In more chronic cases. topical corticosteroids may be beneficial. Antihistamines may be useful because of their soporific effects. but their usefulness is limited.
Arthritis and mast cell activation, The significance of the mast cell in the pathogenesis of rheumatic diseases continues to receive attention. Increased numbers of mast cells are found in the synovial tissue and fluid of patients with inflammatory arthritides. and these mast cells can be activated by many of the substances found in inflammatory synovial fluid. This activation results in the release of mediators that are capable of amplifying the inflammatory process within the joint space. Recent research has shown that mast cells also produce a variety of cytokines and hematopoietic growth factors that may have paracrine and autocrine functions that are important to the development of the inflammatory cell infiltrate. Increased numbers of mast cells are also found in many fibrotic conditions. including scleroderma. These mast cells. directly or through mediator generation. affect the function of endothelial cells. fibroblasts. and growth factors important to the proliferation and function of these cells. A clearer understanding of mast cell involvement in the inflammatory arthritides and fibrotic processes should lead to new therapeutic strategies.
The use of antihistamines in the prevention and treatment of anaphylaxis and anaphylactoid reactions, The pathophysiologic effects of histamine in anaphylaxis have been shown to be mediated through H1 and H2 receptors. individually and in combination. H1 receptors mediate coronary artery vasoconstriction. wheezing. cutaneous vascular permeability. and possibly an increase in pulse rate. H2 receptors stimulate ventricular and atrial inotropy. arterial chronotropy. coronary vasodilation. and rises in basophil cyclic adenosine 3':5' monophosphate (cyclic AMP). (Neither receptor mediates increases in cyclic AMP in mast cells.) H1 and H2 receptors in combination seem to be most potent in mediating flush. headache. increases in pulse pressure. and decreases in diastolic blood pressure. Clinical trials have been conducted to determine the efficacy of H1 and H2 antagonists in preventing anaphylactic reactions to plasma expanders. anesthesia-inducing agents. morphine. and radiocontrast material. Concurrently. retrospective observations of the prevention of anaphylactic reactions to chymopapain have been recorded. Despite some conflicting and inconclusive data. the sum of these studies indicates that pretreatment with a combination of H1 and H2 antagonists is more effective than H1 antagonists alone in preventing reactions to these agents. These results. when added to the available knowledge of the physiology of histamine release. support the preferential use of H1/H2 antagonist combinations in the prevention and treatment of anaphylaxis and anaphylactoid reactions.
Bioaerosols: prevalence and health effects in the indoor environment, Assessing the role of bioaerosols in residence-related symptoms involves (1) determining that symptoms are related to the residence by medical examination and careful questioning. (2) connecting reported symptoms with known or hypothesized effects of bioaerosols. (3) examining the residence for bioaerosol risk factors such as overcrowding/poor ventilation. inappropriate outdoor air intrusion. and dampness/standing water. (4) and finally. if no obvious risk factors are present. air sampling. Air sampling should always be a last resort and should use a reliable volumetric method. Particulate samplers. such as the Burkard personal spore trap. are inexpensive alternatives to viable particle samplers and will provide data on most organisms implicated in hypersensitivity diseases. Interpretation of residential bioaerosol sample data requires both qualitative and quantitative comparison with adjacent outdoor air and examination of aerosol changes related to domestic activities. Recommendations that should lead to a decrease in indoor bioaerosols include the use of air conditioning to allow limitation of outdoor aerosols. prevention of dampness or moisture intrusion. and discouraging the use of humidifying devices other than steam. Bioaerosol assessment in the workplace is often more complex than for residences. Because the symptomatic subjects are not in charge of the environment. such situations often lead to difficult employee/management relations and occasionally to litigation. It is essential that each step in workplace bioaerosol assessment be defensible and that the best possible methods are used. The approach is similar to the approach used for residences. but on a larger scale. Symptom assessment must include stress and ergonomic factors. Air sampling. if this is necessary. must usually be extensive with controls for ventilation rates. occupancy. and spatial variation.
Normal responsiveness of superficial hand veins to alpha- and beta-adrenergic stimuli in allergic asthma: effects of terbutaline and prednisolone on beta-adrenergic responsiveness, Impaired function of the adrenergic-receptor system has been postulated to contribute to the pathogenesis of bronchial asthma. Using the dorsal hand-vein compliance technique. we compared the changes in diameter of superficial hand veins in response to phenylephrine. an alpha-adrenoceptor agonist. and to isoproterenol. a beta-adrenoceptor agonist. in 14 untreated patients with allergic asthma and in 16 nonatopic control subjects. There were no significant differences in the median effective dose of phenylephrine that produced 50% of maximal venoconstriction (ED50) or in the maximal response (Emax) between the two groups. Bronchial hyperreactivity (assessed by methacholine-challenge tests) in the patients with asthma was uncorrelated with the ED50 or Emax of isoproterenol. These results demonstrate no evidence for a generalized change in alpha- or beta-adrenergic responsiveness on smooth muscle cells in asthma. Hand-vein responsiveness to isoproterenol was unchanged after treatment for 7 days with oral terbutaline (5 mg three times per day). Thus. unlike leukocytes. smooth muscle appears not readily susceptible to beta-adrenoceptor desensitization in vivo. Local infusions of prednisolone or dexamethasone during 2 hours and systemic administration of dexamethasone (24 hours) caused a significant fall in the Emax for isoproterenol. The mechanism of attenuation of beta-adrenoceptor responsiveness by corticosteroids remains to be determined.
Allergens as proteases: an Aspergillus fumigatus proteinase directly induces human epithelial cell detachment, Allergic bronchopulmonary aspergillosis (ABPA) is characterized by pulmonary and systemic allergic and inflammatory processes triggered by fungal antigens. Airway damage is a feature of this disorder. and although Aspergillus-derived proteinases have been described. the capacity of Aspergillus. however. to directly induce damage to human epithelium has not previously been studied. We therefore cultured Aspergillus fumigatus from two patients with ABPA. extracted mycelial products by sonication and filtration. and then evaluated their capacity to induce epithelial cell (EC) desquamation from basement membrane using an in vitro model that uses intact human amniotic EC and native basement membrane. A. fumigatus extracts induced detachment of EC in a dose-dependent fashion. producing up to 34% +/- 6% detachment (p less than 0.05 compared to medium alone). Enzyme analysis of A. Fumigatus extract using synthetic substrates revealed the presence of a number of different enzymes; therefore. studies with specific proteinase inhibitors were undertaken to identify the proteinase(s) responsible for detachment. A. Fumigatus-induced desquamation was partially inhibited by phenylmethylsulfonylfluoride and substantially inhibited by glutathione and N-acetylcysteine. but not by alpha 1-antitrypsin. 1.10 phenanthroline. ethylenediaminetetraacetic acid. aprotinin. or soybean trypsin inhibitor at concentrations that inhibit other serine- or metalloproteinases. Gel filtration of the extract with a Sepharose 6B column revealed that the major epithelium-detaching activity appeared in the 20 to 35 kd fraction. Comparison with proteinase standards suggested a role for a chymotrypsin-like proteinase. Thus. A. fumigatus releases a proteinase that is directly able to induce EC detachment.
Platelet-activating factor- and leukotriene B4-induced release of lactoferrin from blood neutrophils of atopic and nonatopic individuals, We found increased accumulation of neutrophils and their components. lactoferrin (Lf) and elastase. as well as platelet-activating factor (PAF) and leukotriene B4 (LTB4) at sites of ongoing human allergic reactions. To determine whether PAF or LTB4. could be the stimulus for in vivo Lf release. blood neutrophils of 17 subjects were incubated with PAF. LTB4. or the phorbol ester. phorbol myristate acetate (PMA). and the released Lf (ELISA assay) was compared with spontaneous release. Significantly increased Lf release was induced by PAF. 10(-5) to 10(-8) mol/L (p less than 0.002); LTB4. 10(-7) to 10(-8) mol/L (p less than 0.004); and PMA (0.05 micrograms/ml) in a dose-dependent reaction. Cytochalasin was not required for Lf secretion but did enhance such responses. PAF-induced Lf secretion was inhibited by the specific PAF antagonist. BN 52063. More Lf was released from neutrophils of atopic than from nonatopic subjects in response to PAF. 10(-6) mol/L (4.2 micrograms/ml +/- 0.2 versus 2.6 micrograms/ml +/- 0.2; p less than 0.001) but not to LTB4. PMA. or buffer (p. not significant). We conclude that (1) PAF and LTB4 released in vivo could stimulate local neutrophils to release Lf with possible pathogenic effects and (2) neutrophils of atopic subjects are more responsive to PAF than neutrophils of nonatopic subjects in this regard.
Salsalate cross-sensitivity in aspirin-sensitive patients with asthma, Ten aspirin (ASA)-sensitive patients with asthma underwent double-blind. placebo-controlled oral challenges with salsalate followed by ASA-sensitive confirmatory challenges. All 10 patients sustained asthmatic reactions to ASA. but only two developed respiratory reactions to 2 gm of salsalate. In these two patients. repeat confirmatory challenges with 2 gm of salsalate reproduced the same asthmatic reactions. Both patients were desensitized to ASA. and cross-desensitization with 2 gm of salsalate was then achieved. We conclude that salsalate. a weak inhibitor of cyclooxygenase in vitro. is less likely than ASA to induce asthma in known ASA-sensitive patients with asthma but may occasionally cross-react in these patients. Such reactions were mild and easily treated with beta 2-agonists.
The Hymenoptera venom study. III: Safety of venom immunotherapy, One thousand four hundred ten (44%) of the 3236 subjects in the Hymenoptera venom study accepted venom immunotherapy (VIT). Time to maintenance averaged 95 days. and the largest number achieved maintenance (147 subjects. 10.4%) at day 56. Ninety-two percent of the treated subjects achieved maintenance. and 84% continued therapy. most subjects (91%) until the study was terminated. One hundred seventy-one subjects (12%) experienced 327 treatment systemic reactions (Srs). The incidence of pruritus and angioedema/urticaria was similar with mild. moderate. or severe SRs. The SR severity did not correlate with the severity of the most recent sting before entry into the Hymenoptera-venom study. the most severe historical sting SR. the most severe SR during venom skin tests. the total dose of venom. the degree of skin test reactivity. or the lowest concentration yielding a positive skin test. Most SRs occurred between 1 and 50 micrograms and at maintenance; honeybee or wasp venoms were most likely to produce SR. This study. the largest of its kind with the use of standardized extracts. demonstrates (1) that there was good compliance. (2) that various historical and diagnostic criteria did not predict SRs to VIT. (3) that SRs to VIT were most likely to occur between 1 and 50 micrograms and at maintenance. (4) that honeybee or wasp venoms were most likely to produce an SR. and (5) that VIT is relatively safe.
Measurement of histamine in nasal lavage fluid: comparison of a glass fiber-based fluorometric method with two radioimmunoassays, The determination of histamine in nasal secretions and nasal lavage fluid may be of importance to monitor activation of histamine containing cells in the nasal cavity. However. such studies have been besieged by controversy. specifically to findings of changes in histamine levels in relation to allergenic stimulation. This controversy may be due to the specificity and accuracy of the various methods used to determine histamine in the nasal fluid. We have therefore applied and compared three new methods to determine histamine in nasal lavage fluids obtained before and after allergen challenge in normal subjects and patients with allergic rhinitis. We used a fluorometric glass fiber-based histamine method (FHR) and two RIAs. I and II. The FHR (detection limit. 7.0 nmol) and the RIA II (detection limit. 0.2 nmol) are specific for histamine itself. whereas the RIA I (detection limit. 18.0 nmol) measures mainly methylhistamine and cross-reacts to some extent with histamine. The histamine levels in the nasal lavage fluids from the nasal challenges demonstrated histamine values between 100 and 2000 nmol/L of histamine with significantly higher levels in the postallergen challenges for the allergic subjects as compared to the normal control subjects. The FHR correlated well with the RIA I and RIA II methods with correlation coefficients of 0.77 to 0.88 (p less than 0.001). respectively. However. the RIA I (methylhistamine antibody) always demonstrated absolute histamine values 5% to 20% of values measured by the RIA II (at the level of cross-reactivity to histamine).
Folate status of adolescents: effects of folic acid supplementation, This study was designed to determine the folate status of an adolescent population and to demonstrate the effect of folic acid supplementation on subjects with low folate status. In phase one. folate status was evaluated in a biracial sample of 164 adolescents 12 to 15 years old. Socioeconomic. demographic. anthropometric. and 7-day food record data were collected. and serum and erythrocyte folate levels were determined. Thirty-five adolescents considered to have had low folate status 6 months earlier participated in phase two. a 2-month supplementation period and reevaluation. No racial differences were observed in folate status. as indicated by amount of folate in the blood and diet. Boys had significantly (p less than .05) higher folate levels in serum and erythrocytes than did girls. Thirteen percent of the boys and 40% of the girls were folate deficient as judged by amount of erythrocyte folate less than 317 nmol/L (140 ng/mL). The folate-deficient subjects had significantly (p less than .05) lower values of hemoglobin than did the normal subjects. Seventeen percent of the boys and 42% of the girls had folate intakes below the recommended dietary allowance for folate. Supplementation of 400 micrograms folic acid daily for 2 months resulted in significant (P less than .05) increases in serum folate. erythrocyte folate. and hemoglobin values and a decrease in mean corpuscular volume. Evidence of high prevalence of low folate status. positive relationship between erythrocyte folate and hemoglobin. and responses of hemoglobin and mean corpuscular volume to the supplement indicated that folate consumption may not be optimal in some groups of adolescents. especially in girls.
The effects of moderate exercise training on nutrient intake in mildly obese women, The relationship between moderate exercise training (five 45-minute sessions per week. brisk walking at 62 +/- 2% VO2 max for 15 weeks) and changes in nutrient intake was investigated in a group of 36 sedentary. mildly obese women. The study was conducted using a 2 x 3 factorial design (two groups of subjects: exercise and nonexercise groups; three periods: baseline. 6-week. and 15-week testing sessions). Data were analyzed using repeated measures ANOVA. The pattern of change in caloric intake over time tended to be different between groups (F[2. 68] = 2.50. p = .089); the exercise group experienced a significant decrease in caloric intake by 15 weeks. Significant group x time interactions were found for intakes of carbohydrate. dietary fiber. thiamin. niacin. vitamin B-6. and folate. Intake tended to decrease in the exercise group and to increase in the nonexercise group. Change in intake of each of these nutrients was significantly correlated with change in bread and cereal consumption. The pattern of change in bread and cereal intake over time was significantly different between groups (Pillais Trace = 0.266. F[2. 33] = 5.99. p = .006); the exercise group had significant decreases in intake at 6 and 15 weeks vs baseline values. These data suggest that mildly obese women reduce energy intake subsequent to initiating an exercise program; concomitantly there is a decrease in the quality of nutrient intake from their diets compared with those of sedentary controls.
An interdisciplinary nutrition assessment and intervention protocol for children with disabilities, Because of the multifactorial nature of the nutrition problems associated with developmental disabilities. a well-organized. interdisciplinary effort is necessary to deal with such problems. A team composed of professional and support staff. the client. and the family needs to be involved in an integrated approach to service. The team members share their knowledge and expertise in developing an individual program plan to meet identified needs. This article describes the development and implementation of a prototype for interdisciplinary nutritional evaluation and intervention in an outpatient setting. In 1987. a Regional Nutrition and Feeding Diagnosis and Evaluation Clinic was established through a contractual agreement between the University of Georgia University Affiliated Program and St. Mary's Hospital in Athens. GA. The purposes of the clinic are twofold: to offer direct services to developmentally disabled infants and children who require outpatient services and to provide a unique community-based interdisciplinary training experience for graduate students in nutrition and other health disciplines. The interdisciplinary treatment protocol is based on current knowledge in the treatment of developmental disabilities.
A review of iodine toxicity reports, This article summarizes case reports. population studies. and experimental studies from the literature concerning adverse effects of exposure to iodine from the mid-1880s to 1988. Exposure to excessive iodine through foods. dietary supplements. topical medications. and/or iodinated contrast media has resulted in thyroiditis. goiter. hypothyroidism. hyperthyroidism. sensitivity reactions. or acute responses for some individuals. Reports of maternal iodine exposure during pregnancy or lactation affecting newborn or nursing infants are cited. Susceptibility to excess iodine is discussed as well as the relationship between dose and response. It is concluded that some individuals can tolerate very high levels of iodine with no apparent side effects and that iodine intakes less than or equal to 1.000 mg/day are probably safe for the majority of the population. but may cause adverse effects in some individuals. Determination of maximum tolerable levels of iodine intake will require human experimental studies at levels between 0.150 and 1.000 mg/day for normal subjects. subjects with autonomous thyroid tissue. and iodine-sensitive subjects.
The Senior Care Study. The optimal use of medications in acutely ill older patients, Geriatric assessment units have improved pharmacotherapy for their patients by decreasing the number of medications prescribed. The Senior Care Study. a randomized controlled trial. compared a multidisciplinary-team approach to patient care to the standard medical practice of the institution. As a part of the trial. the effectiveness of an interdisciplinary team intervention in improving the use of medications was studied. Study goals were to decrease medications used. decrease unnecessary medications. and improve medication choices in our acutely ill inpatient population. A pharmacist interviewed all experimental patients and patient records. and presented medication concerns and recommendations at a team conference. Medications were counted on admission and on the third day. sixth week. and third month after randomization. Medications were paired with patient problems. Medication:problem pairs were judged as inappropriate choices if there were potential side effects that would affect patient function. and if better alternatives were available. The 215 control and 221 experimental patients in the study were similar in age. sex. place of origin. and number of medications on admission. Experimental patients took fewer medications than controls on the third day (5.3 versus 5.9. P less than .05). Experimental patients received fewer multiple unpaired medications (11% versus 19%. P less than .025) and fewer inappropriate medication choices (20% versus 37%. P less than .005). The results suggest that the team intervention was effective in improving pharmacotherapy in the acute-care setting.
Cognitive function testing in comprehensive geriatric assessment. A comparison of cognitive test performance in residential and clinic settings, Tests of cognitive function are frequently used in geriatric assessment. but the effect of test setting has rarely been explored. To determine the effect of testing site on the performance of elderly patients undergoing a comprehensive geriatric assessment. we administered the Mini-Mental State Exam to 116 geriatric patients in the clinic and at their residence. Their cognitive abilities varied from normal to severely impaired. The patients' scores were 1.5 +/- 3.6 (mean +/- SD) higher at their residence. The clinical importance of a difference in score of 1.5 is not clear. For this reason a second analysis was performed in which a difference in scores of five points or greater between settings was considered clinically meaningful. Twenty-five percent (29 of 116) differed by five points or more. Of these 29 patients. 22 (76%) tested better in the residential setting. These differences were statistically significant (P = .001). We conclude that the testing site may affect test performance and that in-home assessment may reveal the optimal cognitive function of geriatric patients.
Foci of increased T2 signal intensity in MR images of healthy elderly subjects. A follow-up study, An 18-month follow-up study was conducted on 26 healthy elderly subjects with and without foci of increased T2 signal intensity on MR imaging. The subjects did not differ with respect to health status or cognitive performance as measured by the Cognitive Subscale of the Cambridge Mental Disorders of the Elderly Examination and the Mini Mental State Examination at follow-up. There was a significant decline in performance on the Digit Symbol Substitution Test in subjects who had evidence of T2 foci compared to the performance of subjects without T2 foci. This may indicate that the presence of T2 foci is correlated with subtle difficulties in learning and memory.
Musculoskeletal impairments and physical disablement among the aged, This article summarizes the results of a longitudinal investigation of the progression of sight. hearing. and musculoskeletal impairments and their association with change in physical disability. in 10 ADLs among members of the Massachusetts Health Care Panel Study. The findings confirm widely held clinical beliefs that specific types of musculoskeletal decrement are an important cause of physical disability among older persons. Decrement in hand function is a significant musculoskeletal impairment influencing limitations in Basic ADL. and progression of Instrumental ADL dysfunction is influenced by progression of lower extremity impairments. Progression of sight and hearing impairments was not associated with change in physical disability. Musculoskeletal impairments. one of the most prevalent and symptomatic chronic complaints of middle and old age. deserve increased attention from epidemiologists. disability researchers. and clinicians seeking ways to prevent disablement among the aged.
Hypertension and acculturation in elderly Mexican Americans: results from 1982-84 Hispanic HANES, The purpose of our study was to describe the relationship between acculturation and hypertension in elderly Mexican Americans. Two age groups. 55-64 and 65-74. were examined from data provided in the Hispanic Health and Nutrition Examination Survey (HHANES). The prevalence of hypertension among subgroups of different acculturation was ascertained based on the modified Cuellar Acculturation Scale. Each age group was also stratified using the HHANES poverty index. with those above the index compared to those below. A stepwise logistic regression was performed among the variables of poverty. gender. age. and acculturation in relation to hypertension. The results indicate that acculturation and age are stronger predictors of hypertension than poverty in elderly Mexican Americans. with acculturation being a stronger predictor among those age 55-64. Factors related to acculturation may have a stronger influence on the prevalence of hypertension in older Mexican Americans than differences related to socioeconomic status.
Crohn's disease: what about the pancreas? [editorial, Crohn's disease (CD) is now accepted as a systemic illness. The importance of extraintestinal manifestations is underlined by the fact that such "complications" can be more prominent and even more difficult to control than the intestinal disease itself. Lately. evidence for a more than accidental association of pancreatitis and exocrine pancreatic insufficiency with CD is growing. This might have a significant impact on the treatment of abdominal pain and diarrhea in CD. symptoms which have so far been attributed exclusively to the intestinal rather than the extraintestinal manifestations of the disease.
Oncogenes and suppressor genes: their involvement in colon cancer [editorial, Abnormalities in oncogenes. which are broadly classified into viral and cellular oncogenes. and suppressor genes appear critical for the development of colon cancer. Cellular oncogenes contribute to malignant transformation when they become activated by point mutation. translocation. amplification. or loss of regulator sequences. The properties of the oncoproteins. the proteins encoded by oncogenes which are essential for carcinogenesis. are unclear. Suppressor genes normally suppress the tumorigenic phenotype by keeping the growth of cells in check; it is their inactivation that contributes to malignant transformation. Development of colon cancer appears to take place by stepwise accumulation of multiple genetic alterations during the progression from normal colon to adenoma and carcinoma. Activation of ras. an early event in this sequence. is found in 50% of colon cancers; overexpression of c-myc is found in approximately 80%. Inactivation of suppressor genes. which occurs during later stages. is noted in greater than 70% of tumors. A current model of colonic tumorigenesis is presented.
Stasis syndromes following gastric surgery: clinical and motility features of 60 symptomatic patients, We retrospectively reviewed the records of 60 patients who had been referred for gastrointestinal manometry because of stasis after gastric surgery. Nausea. vomiting. bloating. abdominal pain. and weight loss were the most common symptoms. Two thirds of these patients had a well-documented history of peptic ulcer before their initial operations; in others. surgery was performed for other reasons. such as obesity (5%) or reflux esophagitis (8%). Twelve patients had undergone truncal vagotomy and a "drainage operation" and 48 had received a partial gastrectomy with a gastroenterostomy: Billroth I (n = 8). Billroth II (n = 11). Roux-en-Y (n = 29). All patients had recordings of gastrointestinal manometry; 16 also had a scintigraphic measurement of gastric emptying. Measurements were compared with data from healthy controls. Gastric manometry. which could be assessed only in the group with an intact antrum. was characterized by antral hypomotility (p less than 0.05). Gastric emptying studies showed rapid early emptying of liquids and delayed emptying of solids (both p less than 0.05). In the whole group. fasting jejunal motility was characterized by absence of phase II in 13. presence of bursts of phasic activity in 18. and abnormal propagation of phase III in 8. A significantly increased frequency of phase III of MMC was noted in the patients after Billroth II and Roux-en-Y operations. Postprandially. 19 patients failed to develop a "fed pattern.".
Rosacea and ulcerative colitis: a possible association, Although rosacea was formerly believed to be associated with gastrointestinal upsets. no one any longer finds a significant association between rosacea and the intestinal tract. We describe four patients with a combination of ulcerative colitis and rosacea. In all four. ulcerative colitis preceded the onset of severe papulopustular rosacea. and we therefore feel that the severity of rosacea could have been due to the associated bowel disorder. In one. the severity and poor initial response of rosacea to treatment was clearly related to the activity of the ulcerative colitis. and the rosacea improved only after proctocolectomy. While it is possible that this purported association is fortuitous. we report these cases in the hope that others may have seen this combination of diseases. to our knowledge previously unreported.
Limitations in the evaluation of therapy in inflammatory bowel disease: suggestions for future research, The current treatment of inflammatory bowel disease (IBD). though improved over earlier therapies. remains variable rather than consistent and supportive rather than curative. The similar management of ulcerative colitis (UC) and Crohn's disease (CD). which are thought to be differing though related disorders. suggests that therapy is nonspecific. The variation in therapeutic practices results from the fact that the etiologies of the diseases are obscure. from limited knowledge of the biological and pharmacological actions of drugs commonly prescribed (sulfasalazine. 5-ASA compounds. steroids. 6-MP and azathioprine). from an inadequate understanding of genetic differences influencing drug metabolism. from insufficient awareness of the factors influencing drug efficiency (concurrent use of antimotility drugs. cigarette smoking. food combinations). from the variability of the patient groups studied (extent and severity of disease). and from incomplete documentation of the clinical status of patients at the time of therapeutic trial. Future advances in treatment will depend on gaining new information about the nature of IBD and of drug pharmacology and bioavailability. derived from collaborative studies by clinicians. clinical investigators. and basic scientists. Important areas for IBD research include the biology of intestinal epithelium. the nature of the IBD inflammatory reaction and of gut mucosal immune regulation (via the application of new biotechnologies) and more representative experimental animal models. Decisive multicenter therapeutic studies require agreement on definitions of ulcerative colitis and Crohn's disease. accurate characterization of patient groups. acceptable objective criteria of IBD severity and activity. and reliable indicators of therapeutic response.
Frequency of recovery of Blastocystis hominis in clinical practice, We examined the frequency of isolation of Blastocystis hominis from stools of patients seen in an indigent-care teaching hospital. Over a 2-year period. 2.744 stool specimens were examined prospectively. B. hominis was found in 262 stools (9.5% of all stool specimens and 53.5% of the positive specimens). Clinical data were obtained from 80 patients with stools positive for B. hominis. B. hominis was the only parasite isolated in 39 of 47 (83%) of the adults. compared with 17 of 33 (52%) of the children (p = 0.006). All but 2 of 52 patients without concomitant parasitic infection or bacterial pathogens in stool had gastrointestinal symptoms (41 abdominal pain. 26 diarrhea. and 5 vomiting). but no association was seen with fever. peripheral leukocytosis. stool occult blood. fecal leukocytes. or endoscopic or radiologic evidence of colitis. Therefore. B. hominis was frequently recovered from stools examined in a hospital clinical parasitology laboratory. The clinical presentations of patients in our series did not suggest that B. hominis was invasive. Most patients with B. hominis probably do not require treatment since they will either have spontaneous resolution of symptoms or will be found to have an alternative explanation for their problem.
Liver transplant for metastatic neuroendocrine tumor, Generally. the results of liver transplantation for metastatic liver disease have not been favorable. One exception has been the unique group of neuroendocrine tumors. the slow growth of which allows liver transplantation to effectively palliate and control symptoms. We report two cases: (a) A 51-year-old man who underwent orthotopic liver transplantation and resection of the pancreatic primary tumor for a nonfunctioning malignant neuroendocrine tumor with features of both carcinoid and islet-cell glucagonoma remains symptom-free and without evidence of tumor recurrence at 13 months follow-up. (b) A 47-year-old man who underwent orthotopic liver transplantation and Whipple resection for a metastatic islet-cell tumor in the head of the pancreas is fully recovered at 5 months follow-up.
Clinical significance of cholelithiasis in patients with decompensated cirrhosis, There is general agreement that the prevalence of gallstones in cirrhotics is high (at least twice that in the general population). but the pathogenetic link between cirrhosis and cholelithiasis is still uncertain. The influence of cholelithiasis on survival in cirrhotics is also unknown. During an 8-year period. we observed 90 patients affected by decompensated cirrhosis: 36 of them (40%) turned out by cholecystographic/cholangiographic or ultrasonographic examination to have cholelithiasis. We were not able to demonstrate any correlation between cholelithiasis and sex. age of patients. etiology of cirrhosis. severity of the illness. degree of portal hypertension. previous gastrointestinal bleeding. number of pregnancies. or levels of serum cholesterol. bilirubin. and triglycerides. During the follow-up observation. (range. 1-91 months). 30 patients died. Survival curves analyzed by the log-rank test did not show any difference between patients with or without gallstones. We therefore confirm that cirrhosis is a lithogenic condition. but we were not able to explain the reasons for the close relationship between cholelithiasis and cirrhosis. Gallstones. however. did not affect the survival of these patients.
Gallstone disease in north India: clinical and ultrasound profile in a referral hospital, We studied the prevalence of gallstones in patients with upper abdominal pain. heaviness. or discomfort by ultrasound examination of the gallbladder. The actual ultrasound examination was performed by a clinical gastroenterologist blinded to the symptoms. Of 1.680 consecutive dyspeptic patients. 500 (29.8%) had gallstones. The gallbladder was contracted in 450 (91.2%). normal-size in 36 (7.2%). and distended in 8 (1.6%). Biliary colic was more frequently the presenting complaint in patients with a contracted gallbladder than in those with normal size gallbladder (p less than 0.001). Dyspepsia was more frequent in the presence of a normal size gallbladder than a contracted one (p less than 0.001). We conclude that ultrasonography of the gallbladder by the clinician has a high diagnostic yield. and the symptom complex has an excellent correlation with the sonographic appearance.
Mallory-Weiss syndrome after cardiopulmonary resuscitation, We report hematemesis from Mallory-Weiss tears after successful cardiopulmonary resuscitation (CPR). A computer search of the English language literature disclosed only 3 similar cases. and we review them. This complication of CPR may occur more frequently than recognized and should be prevented by careful technique.
Insulinoma after streptozotocin therapy for metastatic gastrinoma: natural history or iatrogenic complication, Islet cell carcinoma frequently produces more than one chemical product. although its clinical expression is usually restricted to a single hormone. We describe an unusual patient who presented with full-blown metastasizing gastrinoma. He was treated with cimetidine for five years and then streptozotocin therapy. which resulted in a regression in hepatomegaly and a fall in serum gastrin levels. Following one year's therapy with streptozotocin. he was admitted in hyperinsulinemic hypoglycemic stupor. This appears to be the first reported case of a "shift" from clinical gastrinoma to insulinoma possibly related to prolonged streptozotocin therapy.
Morphological study of cholesterol hepatolithiasis. Report of three cases, Three cases of pure cholesterol intrahepatic stones are compared morphologically to those of calcium bilirubinate stones. Cholesterol stones were found in the intrahepatic bile duct of the left lateral lobe in two cases and in both the left lateral and the right posterior lobe in one. Although the chronic inflammatory reaction and fibrous thickening of bile duct wall were similar in both types of hepatolithiasis. the proliferation of intrahepatic periductal glands and the production of mucin were rather mild. compared to that is the liner containing calcium bilirubinate stones. Multiple intramural cholesterol calculi and cholesterin granulomas (cholesterin crystals surrounded by foreign-body giant cells) were found within the cystically dilated small bile duct branches and/or conduits of periductal glands. The calculi and granulomas were characteristic for cholesterol hepatolithiasis. These findings suggest that the formation of the cholesterol stones differs from that of calcium bilirubinate stones; the perturbation of factors influencing cholesterol nucleation in the hepatic bile may be related to the changed microenvironment of the intrahepatic bile ducts. which is followed by the formation of cholesterol stones.
Ultrasound-Doppler diagnosis of Budd-Chiari syndrome, We report a case of apparently idiopathic Budd-Chiari syndrome. diagnosed by ultrasound and Doppler sonography. in a patient with latent myeloproliferative disease. This case proves that Doppler sonography shows in the hepatic veins a flow pattern suggestive of partial thrombotic obstruction. Moreover. we suggest that the search for a latent myeloproliferative disorder. by means of the spontaneous erythroid colonies formation in culture of bone marrow or blood mononuclear cells. should be routinely included in the diagnostic evaluation of each case of hepatic vein thrombosis without other recognizable causes.
Aberrant regulation of IL-1 expression in macrophages from young autoimmune-prone mice, IL-1 is a multifunctional. immunoregulatory polypeptide produced by many cell types. Because activated macrophages are a major source of IL-1 and have also been implicated in the pathogenesis of autoimmune disease. we investigated the regulation of IL-1 expression in several autoimmune-prone strains of mice. Peritoneal macrophages derived from the autoimmune-prone strains MRL/lpr. MRL/+. NZB. and NZB/W F1. as well as NZW. displayed transient expression of IL-1 in contrast to the stable expression characteristic of control normal strains including A. Thy. A/J. B10. B10.A. B10.D2. C57BL/6. BALB/c. and C3H/HeN. The down-regulation of IL-1 by macrophages from the autoimmune-prone mice was not attributable to inherently defective signal transduction because macrophages from both the normal and autoimmune-prone strains displayed substantial initial levels of cell-associated and secreted IL-1. However. during the first 2 to 3 days in culture. macrophages from autoimmune-prone mice became progressively refractory to both induction and maintenance of IL-1. a pattern that correlated with changes in the levels of IL-1 alpha and beta mRNA. The progressive reduction in IL-1 expression by macrophages from these autoimmune-prone strains was not due to a reduction in general metabolism or viability. because expression of cell surface antigens. including MHC class I and II Ag and LFA-1. was comparable to that of control macrophages. Because IL-1 plays a critical role in the homeostasis of a variety of cell lineages. defective expression. and maintenance of IL-1 (and perhaps other cytokines) by macrophages from the autoimmune-prone strains may contribute to the immune dysregulation that develops in these mice. Alternatively. cytokine dysregulation might not contribute directly to disease. but rather reflect a more basic defect related to specific signal transducing or gene regulatory pathways.
A small proportion of cationic antibodies in immune complexes is sufficient to mediate their deposition in glomeruli, Positively charged antibodies mediate enhanced deposition of circulating immune complexes at the glomerular basement membrane. The presented experiments demonstrate that when soluble immune complexes were prepared with a mixture of antibodies containing 10 to 25% cationic antibodies. then noncationic antibodies in the complexes were deposited in mouse glomeruli. One or two cationic antibodies in each immune complex sufficed for deposition of the complexes. Proof for this was obtained by two kinds of experiments. First. the injected immune complexes were prepared in Ag excess from mixtures of radiolabeled noncationic rabbit antibodies to human serum albumin (HSA) and unlabeled cationized rabbit antibodies to HSA. thus permitting the specific quantitation of the deposition of noncationic antibodies in glomeruli because of the presence of cationized antibodies within the same complexes. As a control experiment. immune complexes prepared only with noncationic antibodies resulted in very little deposition in kidneys over the same time period. Second. detection of the localization of the noncationic antibody in deposits in glomeruli by immunofluorescence microscopy was accomplished using immune complexes prepared with mixtures of noncationic goat antibodies to HSA and cationized rabbit antibodies to HSA. Thus. the synthesis of a small population of cationic antibodies during the immune response may lead to the formation of circulating immune complexes with enhanced propensity for deposition in glomeruli in patients with SLE or other immune complex diseases.
Ultraviolet cross-linking of helical oligonucleotides to two monoclonal MRL-1pr/1pr anti-DNA autoantibodies. Variations in H and L chain binding to DNA, Experiments were performed to determine whether both H and L chains of different anti-native DNA autoantibodies are uniformly involved in binding to DNA. Two purified monoclonal mouse (MRL-1pr/1pr) IgG autoantibodies. H241 and 2C10. were tested. They both bound synthetic helical oligonucleotides of 10 to 20 base pairs in a gel electrophoresis retardation assay but differed in their preferences for given base sequences. Exposure of antibody-radiolabeled oligonucleotide mixtures to UV light (254 nm) for 10 min led to specific covalent cross-linking of oligonucleotide to both the H and the L chains of H241 but only to the H chain of 2C10. Single labeling events were detected without higher aggregation. The oligonucleotides were not cross-linked to unrelated IgG. even after 2 h of irradiation. Cross-linked (radioactively labeled) H and L chains of H241 and 2C10 were isolated from denaturing electrophoresis gels and digested with lysyl endopeptidase and/or staphylococcal V8 protease. H241 and 2C10 H chains each yielded a major labeled peptide fragment. but the peptides from the two antibodies were different. These experiments measured only some of the antibody-DNA interactions. probably with bases in the major groove of the DNA. They indicated that two MRL-1pr/1pr IgG anti-native DNA antibodies differ in their H and L chain contacts with DNA and provide an approach to identifying affinity-labeled binding sites in the antibodies.
Monosodium urate crystals stimulate phospholipase A2 enzyme activities and the synthesis of a phospholipase A2-activating protein, Eicosanoids are important mediators of the inflammatory response to monosodium urate crystals (MSUC) that results in gout. Phospholipase enzymes cleave fatty acids from membrane phospholipids. and this is thought to be the rate-limiting step in eicosanoid production. To understand better the mechanism of eicosanoid production in this disease. we stimulated human peripheral blood neutrophils and monocytes with MSUC and measured phospholipase enzyme activities. MSUC stimulated both intracellular and secretory phospholipase A2 enzyme activities in a time and concentration-dependent manner. Specificity was observed. as phospholipase C activities were not affected. Pretreatment with colchicine. but not aspirin. indomethacin. allopurinol. or islet activating protein. abrogated the enhanced phospholipase A2 activities. We have recently isolated and characterized a phospholipase A2 activating protein termed PLAP from synovial fluid from patients with rheumatoid arthritis. and from murine and bovine cell lines. PLAP was detected in gouty synovial fluid by immunodot blotting and ELISA assays and expressed the same characteristics as PLAP identified from other sources. To examine the role of PLAP in MSUC-induced phospholipase A2 stimulation. we treated cells with MSUC and observed an increase in immunoreactive PLAP. This response also could be blunted by colchicine. but not other drugs. Both phospholipase A2 and PLAP induced production by human monocytes of PGE2 and leukotriene B4 by neutrophils. These findings suggest that phospholipase A2 activation in response to MSUC requires an intact microtubule structure. and that phospholipase A2 and PLAP may be important modulators of at least a portion of the gouty inflammatory response.
Developmental expression of plasminogen activator inhibitor type 1 by human alveolar macrophages. Possible role in lung injury, Urokinase activity is regulated by the specific endogenous plasminogen activator inhibitors type 1 (PAI-1) and type 2 (PAI-2). One of these inhibitors. PAI-1. has been directly implicated in connective tissue metabolism by virtue of its ability to bind extracellular matrix proteins. Because the normal lung is relatively rich in urokinase and abnormalities in urokinase activity have been associated with fibrotic lung diseases. we have explored the possibility of local production of PAI-1 and PAI-2 in human lung. Reverse transcription and subsequent amplification by the polymerase chain reaction of total lung RNA revealed PAI-1 mRNA in each of three normal samples and in two specimens from patients with the adult respiratory distress syndrome (ARDS). In situ hybridizations of lung biopsy specimens from a patient with ARDS with cRNA probes to PAI-1 and PAI-2 indicated that alveolar macrophages express PAI-1 mRNA during the acute injury phase. Subsequent reverse transcription and PCR amplification of normal human monocyte and alveolar macrophage mRNA revealed that neither cell type expressed mRNA for urokinase inhibitors. However. after 24 h stimulation with endotoxin in vitro. monocytes were strongly positive for PAI-2 but negative for PAI-1 mRNA whereas. under the same conditions. alveolar macrophages exhibited mRNA for both PAI-1 and PAI-2. Metabolic labeling of endotoxin-stimulated alveolar macrophages with 35S-methionine followed by immunoprecipitation with PAI-1 and PAI-2 antibodies revealed that macrophages synthesized both PAI-1 and PAI-2. As judged by immunoprecipitation and functional studies. PAI-2 was found to be the major intracellular PA inhibitor whereas PAI-1 was found to predominate outside the cell. Thus. mononuclear phagocytes exhibit a developmental potential for PAI-1 expression. The release of PAI-1 by stimulated macrophages. as observed in the setting of ARDS. may be one mechanism by which these cells promote connective tissue accumulation.
Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection, The proliferative response of PBMC to hepatitis B virus (HBV) envelope. core. and e Ag was analyzed prospectively in 21 patients with acute self-limited HBV infection and compared with the response of patients with chronic HBV infection and different levels of HBV replication (i.e.. hepatitis e Ag (HBeAg)- or anti-HBe-positive) and liver damage (i.e.. chronic active hepatitis or chronic asymptomatic carriers). Our results indicate that: 1) HBV-infected subjects who develop a self-limited acute hepatitis show a vigorous PBMC response to hepatitis B core Ag and HBeAg. as expression of T cell activation; 2) appearance of a detectable lymphocyte response to HBV nucleocapsid Ag is temporally associated with the clearance of HBV envelope Ag; 3) in patients with chronic HBV infection the level of T cell responsiveness to hepatitis B core Ag and to HBeAg is significantly lower than that observed during acute infection; 4) T cell sensitization to HBV envelope Ag in acute and chronic HBV infection is usually undetectable and when measurable is expressed transiently and at low levels. These results may reflect immune events of pathogenetic relevance with respect to evolution of disease and viral clearance.
Insulin-like growth factor-I supports proliferation of autocrine thymic lymphoma cells with a pre-T cell phenotype, We have studied the phenotypic characteristics and growth properties of murine T lymphoma cell lines derived from primary x-ray-induced thymic lymphomas at the earliest stage at which they can be detected. and well before spreading to other organs has occurred. These cell lines serve as model systems for the earliest events in T cell lymphoma induction. before tumor cell progression and spreading to other organs. We find that primary x-ray-induced T cell lymphoma lines have phenotypic characteristics of thymic pre-T cells and show no proliferative response to any of the IL tested nor to other hematopoietic growth factors. However. they do proliferate in response to insulin-like growth factor I (IGF-I) and to a small autocrine peptide distinct from IGF-I. which we term lymphoma growth factor. One of the earliest lesions in T cell lymphoma induction may therefore be an inhibition of differentiation at one of several specific points. In its early stages. T lymphoma cell growth may be restricted to an environment where local concentrations of specific growth factors such as IGF-I or lymphoma growth factor are sufficiently high.
In vivo immune selection of a Moloney murine leukemia virus-induced tumor results in the loss of viral- but not tumor-associated antigens, A protocol of in vivo immune selection has been used to isolate a variant of the Moloney murine leukemia virus (MuLV)-induced tumor MBL-2. Characterization of the tumor variant indicated that selection resulted in the isolation of a cell which is incapable of producing infectious virus and no longer capable of synthesizing viral proteins. Although the failure to express viral Ag has rendered the variant tumor cells resistant to lysis by CTL specific for MuLV viral Ag. the variant tumor cells retained their susceptibility to lysis by CTL which appear to be directed against an MuLV-induced tumor-associated Ag. The data indicate that the expression of nonviral tumor-associated Ag by MBL-2 is not dependent upon continued viral gene expression.
Regional and systemic distribution of anti-tumor x anti-CD3 heteroaggregate antibodies and cultured human peripheral blood lymphocytes in a human colon cancer xenograft, Anti-tumor antibody (317G5) covalently coupled to an anti-CD3 antibody (OKT3) produces a heteroaggregate (HA) antibody that can target PBL to lyse tumor cells expressing the appropriate tumor Ag. The i.v. and i.p. distribution of radiolabeled HA antibody 317G5 x OKT3 and of radiolabeled cultured human PBL were studied in athymic nude mice bearing solid intraperitoneal tumor established from the human colon tumor line. LS174T. Mice were injected with 125I-labeled HA antibody. 125I-labeled anti-tumor mAb. or 111In-labeled PBL. and at designated timepoints tissues were harvested and measured for radioactivity. 125I-317G5 x OKT3 localized specifically to tumor sites. Tumor radioactivity levels (percent injected dose/gram) were lower with 125I-317G5 x OKT3 HA antibody than with 125I-317G5 anti-tumor mAb. but were similar to levels reported for other anti-tumor mAb. The major difference in radioactivity levels observed between i.v. and i.p. administration of 125I-317G5 x OKT3 was an increase in hepatic radioactivity after i.v. HA antibody administration. HA antibodies produced from F(ab')2 fragments. which exhibit decreased m. w. and decreased Fc receptor-mediated binding. demonstrated improved tumor:tissue ratios as compared to intact antibody HA. 125I-317G5 F(ab')2 x OKT3 F(ab')2 antibody levels were equivalent to intact HA antibody levels in tumor. but were lower than intact HA antibody levels in the blood. bowel. and liver. Tumor:bowel ratios (20:1 at 48 h) were highest when 317G5 F(ab')2 x OKT3 F(ab')2 was injected i.p. Autoradiography confirmed that anti-tumor x anti-CD3 HA antibodies localized specifically to intraperitoneal tumor; that i.p. administered HA antibodies penetrated tumor directly; and that i.v. administered HA antibodies distributed along tumor vasculature. Cultured human PBL distributed in moderate concentrations to intraperitoneal tumor when administered i.p.. but not when administered i.v. The poor localization of i.v. injected PBL to tumor may reflect species disparity in homing receptors and/or endothelial ligands. a problem which may be overcome with a syngeneic model. These results suggest that regional therapy with HA antibodies and PBL may offer advantages over systemic therapy for initial clinical trials.
Isolation of a novel tumor protein that induces resistance to natural killer cell lysis, The human metastatic tumor cell line CAP-2. produces a soluble factor that induces resistance to NK lysis of K-562 susceptible leukemia cell line. and does not inhibit the cytotoxic capacity of effector cells. The use of sequential HPLC. hydrophobic interaction chromatography. and reverse phase chromatography. coupled with cytotoxic assays. resulted in the isolation and separation to homogeneity of a novel protein responsible for this biologic activity. Size estimation studies based on TSK HPLC columns showed that this protein has a mass of 8 to 12 kDa. The amino acid composition analysis of the CAP-2 protein calculated from HPLC chromatograms shows that this protein contains around 108 amino acids. Subsequent gas phase sequence analysis. however. was hampered because the N terminus of this protein was blocked and therefore unsuitable for sequencing by Edman degradation. The functional studies showed that the NK lysis-resistance activity of the CAP-2 protein is mediated by interaction with and nonspecific binding to NK target cells. The lymphokine-activated killer and macrophage-mediated cytotoxicity and mitogen-induced proliferation is not affected. Unexpectedly. the CAP-2 protein appears to be mitogenic to its own cell line. Thus. the induction of NK lysis-resistance and the mitogenic activity showed by CAP-2 protein could contribute to the tumor growth and metastatic establishment.
Lymphokine-activated killer (LAK) cells. V. 8-Mercaptoguanosine as an IL-2-sparing agent in LAK generation, Guanine ribonucleosides. substituted at the C8 position with either a bromine or a thiol group. have recently been shown to regulate several immunologic responses. We have previously shown that 8-mercaptoguanosine (8MG) can replace the requirement for cytokines in the generation of MHC-restricted CTL. In this paper. we examined the ability of 8MG to induce MHC-nonrestricted killer cells. We found that 8MG did not induce significant lytic activity from normal resting lymphocytes. However. 8MG was able to synergize with minimal amounts of IL-2 in inducing lytic activity similar to lymphokine-activated killers (LAK) in that both NK-sensitive and NK-resistant tumor cells were killed. Both the precursors and effectors of 8MG-LAK activity were similar to NK cells and were CD4- CD8- asialo-GM1+ NK1.1+. Similar to IL-2-induced LAK. 8MG-LAK were B220+. 8MG appeared to "stage" these precursor lymphocytes to become more responsive to IL-2 because optimal induction of 8MG-LAK required preincubation with 8MG before the addition of IL-2. This "staging" appeared to be due to the release of a "second signal" since it was readily inhibited by cyclosporine A. Anti-IFN-alpha beta was as efficient as cyclosporine A in inhibiting 8MG-LAK generation. whereas anti-IFN-gamma and anti-IL-1 did not exhibit significant inhibition. These findings suggest that 8MG can be of possible utility as an IL-2-sparing agent in LAK generation from NK cells.
Epidermal growth factor/transforming growth factor alpha receptors and psoriasis, The abnormal growth and differentiation in psoriasis is reflected in the abnormal regulation of Epidermal Growth Factor/Transforming Growth Factor Alpha (EGF/TGF alpha) receptor metabolism. In psoriasis and other hyperproliferative skin conditions these receptors are persistently expressed throughout the interfollicular epidermis as long as the growth stimulatory signal persists. One of the first biochemical signs of effective therapy of psoriasis is the return of the EGF/TGF alpha receptor pattern toward the primarily basilar distribution seen in normal human adult skin. Whether the abnormal expression of TGF alpha in the involved skin induces the persistent expression of EGF receptors is not known nor is the signal that causes the increased production of TGF alpha. Studies to determine what factors regulate EGF receptor expression and TGF alpha induction may yield important new insights into the pathogenesis and therapy of psoriasis.
Immunologic mechanisms in psoriasis, The demonstration of activated T lymphocytes. HLA-DR+. I-CAM1+. gamma IP-10+ keratinocytes. and increased levels of lymphokines in active plaques suggests that immunologic mechanisms may play a role in the pathogenesis of psoriasis. Epidermal hyperplasia and inflammation in psoriasis may be linked by those cytokines many of which are produced by both keratinocytes and leukocytes. Epidermal acanthosis and keratinocyte mitoses have been observed in delayed-type hypersensitivity reactions and after the intradermal injection of gamma interferon. Gamma interferon and its induced proteins have been demonstrated in active psoriatic plaques. Increased levels of the keratinocyte autocrine cytokines. transforming growth factor (TGF)-alpha and interleukin (IL)-6. have been detected in active plaques. The apparent overexpression of IL-6 in hyperplastic psoriatic tissue may explain features of psoriasis that link keratinocyte proliferation with immune activation and tissue inflammation. Both IL-6 and gamma interferon increased TGF-alpha expression in normal cultured keratinocytes. Cytokines produced during immune activation and other inflammatory processes may lead to epidermal hyperplasia.
Psoriasis vulgaris: a genetic approach, Evidence for a genetic contribution in psoriasis comes from direct examination of a large segment of the population in an isolated island environment. epidemiologic and questionnaire studies presented to psoriatic patients. twin studies collected from the literature and from twin registries. and splitsibship analysis. The concordance of psoriasis in monozygotic twins was 65-72%. whereas psoriasis in dizygotic twins was 15-30%. Determination of concordance in older twin pairs from a national twin registry in Denmark revealed nearly 90-100% heritability. In order to link psoriasis with known markers within the human genome. serologic studies have been carried out with a variety of blood group and polymorphic protein antigens. A weak association with the MNS and Lewis Blood Groups Systems (relative risk. 3.5) has been identified. Stronger associations with class I B locus and class II D locus genes (relative risk. 8-12) have also been determined by studies of the human lymphocyte-antigen system. Finally. a strong association with HLA Cw6 has been determined; this marker is thought to be in linkage disequilibrium with B and D locus genes previously associated with psoriasis. The relative risk of developing psoriasis in HLA Cw6 positive individuals is about 24. A few large kindred have been reported in the dermatology literature. These support the hypothesis of autosomal dominant inheritance with penetrance of approximately 60%. In cooperation with The National Psoriasis Foundation. we have now identified over 90 families with psoriasis in three generations. We have begun the process of ascertainment. the construction of family trees. and the collection of leukocyte DNA for linkage analysis with established restriction fragment polymorphisms (RFLP). Our initial assessment is being directed to four RFLP that span approximately 30 centiMorgans of the short arm of human chromosome 6. Although karyotyping is uncommonly done in patients because of psoriasis. we now seek evidence of translocations of chromosome 6 in association with psoriasis.
Speculations on the immunopathogenesis of psoriasis: T-cell violation of a keratinocyte sphere of influence, The thesis is advanced that the differences in antigen processing and presentation described for "fresh" and "cultured" Langerhans cells in vitro reflect similar differences between intraepidermal and intranodal Langerhans cells in vivo. The functional properties of Langerhans cells are dependent upon the microenvironment in which they reside; thus. intraepidermal Langerhans cells are under the influence of cytokines secreted by keratinocytes. whereas intranodal Langerhans cells come under the influence of lymphokines from T lymphocytes. It is speculated that a genetic lesion in psoriasis robs keratinocytes of their capacity to create an "appropriate" epidermal microenvironment. As a consequence. intraepidermal Langerhans cells adopt the functional program of intranodal cells. When "uninvolved" psoriatic skin receives a cutaneous challenge with antigen. Langerhans cells. by activating naive T cells in situ. unwittingly engender a microenvironment that is more appropriate to a lymph node. This skin becomes "involved" as it gradually acquires features associated with lymph nodes (such as high endothelial venules). And the derangement is further complicated by abnormalities of proliferation and differentiation among keratinocytes and dermal fibroblasts as they respond to the inappropriate T-cell-derived lymphokines. giving rising to the typical. active psoriatic lesion.
Lymphocyte chemoattractants in psoriasis and normal skin, The local production of lymphocyte attractants may influence both physiologic lymphocyte trafficking in the skin as well as the infiltration of these cells in pathologic states. Recent evidence for the production of acidic lipid lymphocyte chemoattractants. particularly 12[R]-hydroxyeicosatetraenoic acid. in psoriatic lesions is reviewed. Water extractable lymphocyte attractant activity may also be recovered from both normal skin samples and psoriatic lesional stratum corneum. and may be important in the pathophysiology of lymphocyte trafficking. Less than 10 kD activity from normal skin has undergone the most detailed characterization. This has led to the isolation of a novel. as yet unidentified compound from normal skin. which we have termed "plasma-associated lymphocyte chemoattractant" (PALC).
Interleukin-1 in human skin: dysregulation in psoriasis, Cytokine dysregulation is an attractive concept to explain many of the observed abnormalities in psoriasis. IL-1. in particular. can potentiate immune cellular activation. activate fibroblasts. and increase endothelial cell adhesiveness to leukocytes. Here. we review IL-1 regulation in normal and psoriatic skin in vivo in relation to normal skin and cultured keratinocytes. Contrary to expectations. IL-1 functional activity in psoriatic lesions is reduced. not increased. relative to normal skin. The reduction is attributable to the presence of IL-1 inhibitors. reduced IL-1 alpha levels. and an IL-1 beta that lacked function in T-cell assays. IL-1 beta protein is actually significantly increased in psoriatic lesions. but the mechanism of its non-functionality remains unclear. Unlike cultured keratinocytes. which accumulate large. inactive IL-1 beta precursors. both normal and psoriatic skin process IL-1 beta to a mature form. Novel mechanisms of post-translational processing by epidermis in vivo may generate a novel form of IL-1 beta with unknown functions. The marked abnormalities of IL-1 regulation in psoriatic skin suggest that this molecule may be important in normal skin homeostasis.
The role of epidermal cytokines in inflammatory skin diseases, Cytokines (hormone-like polypeptide mediators) play a major role in inflammatory and immunoregulatory responses. Skin. and particularly keratinocytes in the skin. represent a potent source for many cytokines. including interleukins 1. 6. 8. and the hemopoietic colony stimulating factors. Cytokines initiate their biologic action by interacting with target cells bearing cytokine receptors and then initiating a cascade of cellular interactions. Certain inflammatory skin diseases have been associated with overproduction of cytokines. alteration in cytokine receptors. or dysregulation of cytokines. While data is still quite preliminary. it is likely that cytokines contribute to the pathogenesis of many inflammatory skin diseases.
Lymphocyte adhesion to psoriatic dermal endothelium: mechanism and modulation, Psoriasis is characterized by the hyperproliferation of keratinocytes in the epidermis and the accumulation of activated CD4+ T lymphocytes in the upper dermis. We have recently tested the hypothesis that the abnormal endothelial proliferation in the dermal papillae of psoriatic lesions may be mechanistically linked to the expression of endothelial ligands capable of promoting lymphocytes binding and extravasation. The results indicated that specialized endothelial cells lining the post-capillary venules of psoriatic lesions are capable of promoting the selective adherence of human CD4+ T cells and its memory subset. In contrast. B cells. CD8+ T cells. and CD45RA+ T cells are deficient in their capacities to bind. The adhesion process is energy and calcium dependent and involves tissue-specific lymphocyte receptors. with LFA-1 molecules playing an accessory role. We concluded that transformation of the dermal endothelium into a lymphocyte-receptive phenotype by defined growth factors or cytokines may represent a positive feedback mechanism promoting lymphocyte migration into the diseased sites.
The role of the immune system in the pathogenesis of psoriasis, Psoriatic involved skin contains an increased number of activated T cells. The mechanism through which these T cells achieve and maintain their activated state is unknown. and both antigen-dependent and -independent mechanisms may contribute. Recently a novel pathway of antigen-independent T-cell activation has been described. This pathway is identified by a monoclonal antibody that binds to a T-cell membrane surface molecule termed "UM4D4.". This molecule is expressed on a minority (20%) of psoriatic peripheral blood T cells but on a majority (75%) of the T cells in lesional skin. Thus. UM4D4 could play a role in antigen-independent T-cell activation in psoriasis. Indeed the monoclonal antibody anti-UM4D4 consistently induces proliferation of psoriatic UM4D4+ T-cell clones. The activity of antigen-dependent pathways are also enhanced in psoriatic epidermis in as much as involved skin relative to uninvolved skin contains an increased number and function of antigen-presenting cells. Upon activation. the lesional T cells release lymphokines. Central to the immune hypothesis of psoriasis is that some of these T-cell lymphokines act on keratinocytes to induce changes characteristic of psoriasis. Indeed lymphokines from lesional psoriatic T-cell clones directly alter in vitro keratinocyte phenotype through induction of intercellular adhesion molecule-1 (ICAM-1) and HLA-DR cell-surface expression. Furthermore. the lymphokines also enhance keratinocyte growth. These data suggest a critical role for the immune system in the pathogenesis of psoriasis.
Lymphocyte trafficking in psoriasis: a new perspective emphasizing the dermal dendrocyte with active dermal recruitment mediated via endothelial cells followed by intra-epidermal T-cell activation, Prominent within the inflammatory infiltrate of psoriasis are HLA-DR positive T lymphocytes and factor XIIIa positive dermal dendrocytes. Many investigators studying psoriasis have assumed that the HLA-DR positive T cells are activated. and thereby capable of producing lymphokines such as gamma interferon. However. by immunohistochemical analysis. greater than 95% of the dermal T cells in psoriatic lesions are Ki-67 negative. which suggests that they are in a resting or non-cycling (Go) state. In contrast to the dermal T-cell population. the epidermal T-cell population contains a greater population of Ki-67 positive lymphocytes. The entry of the T cells into the epidermis is. therefore. apparently associated with an important activation event. which in all likelihood involves interaction with the keratinocyte. The presence of activated intraepidermal T cells has been substantiated by the ability to detect gamma interferon mRNA by polymerase chain reaction in epidermal sheets of psoriatic lesions. The pathophysiologic implication in psoriasis for these distinctions and compartmentalization involving dermal and epidermal T cells are placed into the context of a cascade of cellular trafficking events. which are further dissected into a specific network of molecular mediators of inflammation. This report suggests that more attention should be placed on the microenvironment of the skin. with specific emphasis on the mechanism by which T cells accumulate in the dermis and epidermis. and elucidation of the selective inductive and recruitment capabilities of endothelial cells. perivascular dermal dendrocytes. and keratinocytes.
The expression of retrovirus-like particles in psoriasis, Retrovirus-like particles have been isolated from patients with psoriasis. Antigens crossreacting with the major internal protein. pso p27. of these particles have been demonstrated in the wall of dermal vessels and in a subfraction of cells in psoriatic lesions. The antigen has also been observed in blood lymphocytes from psoriatic patients. Pso p27 antigen and anti-pso p27 antibodies are present as complement-activating immune complexes in psoriatic scale and in the blood of patients with psoriasis and psoriatic arthritis. The potential contribution of the circulating immune complexes to the inflammatory process in psoriasis is discussed.
Cytotoxic and immunologic effects of methotrexate in psoriasis, Based on recent experience that Cyclosporin A. an immunosuppressive drug. produces marked improvement in psoriasis. possible immunomodulatory activities of methotrexate (MTX) have been reviewed to look for alternate mechanisms of MTX action in psoriasis. It is generally considered that the therapeutic results of MTX in psoriasis are related to a direct effect on epidermal cell hyperplasia through inhibition of DNA synthesis. Several studies in the literature now suggest possible effects of MTX on the immune system of psoriatics as well as in animal models that may have some pathogenic similarities to psoriasis. In psoriatics receiving MTX. neutrophil chemotaxis is suppressed. resulting in a possible alteration in the potential pathologic activity of neutrophils commonly found in lesional skin. MTX does improve both psoriatic and rheumatoid arthritis. Animal studies of the latter using adjuvant arthritis and graft vs host disease (GVHD) have indicated several possible mechanisms for MTX that affect these processes. In GVHD. MTX selectively destroys cycling CD8+ cells. and in adjuvant arthritis the activation of macrophages is prevented by inhibition of T-cell function. While MTX generally has not been clinically utilized as an immunomodulatory drug for immunologically related diseases. it may. nonetheless. have selective actions that could be specific for some diseases. MTX and Cyclosporin A could work mechanistically in similar ways but at different steps in the activation of T cells and macrophages. It may be that the major direct effect of MTX on epidermal cell proliferation is complemented or even mediated by subtle immunoregulatory effects on the melange of cells in the affected skin and the systemic immune response.
Psoriasis: the application of genetic technology and mapping, Recent progress in molecular genetics has led to the creation of a map of the human genome utilizing RFLP. Given a sufficient family structure. genetic diseases can now be placed on this map. Genetic studies of psoriasis can both help resolve and be confounded by problems of disease heterogeneity. environmental effects on disease expression. and lack of a clear model of inheritance.
Excision repair of pyrimidine dimers induced by simulated solar radiation in the skin of patients with basal cell carcinoma, One prominent lesion induced in DNA by ultraviolet (UV) radiation is the cyclobutyl pyrimidine dimer formed between adjacent pyrimidines on the same DNA strand. We investigated whether people who have developed basal cell carcinoma on sun-exposed skin have an altered ability to repair UV-induced pyrimidine dimers in DNA. Twenty-two patients with at least one basal cell carcinoma. aged 31-84 years. and 19 healthy volunteers. aged 25-61 years. took part in the study. Both groups were given one minimal erythema dose (MED) of simulated solar radiation on the lower back. DNA was extracted from the irradiated skin 0 to 6 h later. and the number of UV-induced pyrimidine dimers was determined using a dimer-specific endonuclease. At time 0. the average number of dimers per unit of DNA was similar in the two groups. After 6 h. an average of 22 +/- 4% of the dimers were removed in the group with basal cell carcinoma compared to 33 +/- 4% in the cancer-free group. In the basal cell carcinoma group. only 23% of the patients repaired more than 30% of the dimers after 6 h. compared with 53% of the cancer-free subjects (p less than 0.05). We conclude that patients who develop basal cell carcinoma on sun-exposed skin may have a decreased ability to repair pyrimidine dimers induced in skin exposed to simulated solar radiation.
Cyclosporine A in the treatment of psoriasis: a clinical and mechanistic perspective, Cyclosporine A. a unique immunomodulatory agent. has been used increasingly over the last 5 years in the management of severe psoriasis. The remarkable efficacy of this drug coupled with its known immunosuppressive properties have enabled a further appreciation of the role of the immune system in the induction and maintenance of psoriatic plaques. Although acting primarily on T lymphocytes. there is also evidence for an effect of cyclosporine A on other constitutive cell types within the skin. The future use of systemically administered cyclosporine A in the treatment of psoriasis and other cutaneous diseases is dependent on the successful balance of efficacy and side-effect profile; namely. the dose-related problems of hypertension and nephrotoxicity. As a result of the toxicity encountered with systemically administered cyclosporine A. attempts to formulate a successful topical preparation for use in cutaneous disease are being made. The advent of cyclosporine A provides the dermatologist with a new therapeutic strategem in the management of psoriasis. although the long-term safety of such interventional therapy remains to be discerned.
Premalignant lesions and cancers of the skin in the general population: evaluation of the role of human papillomaviruses, To evaluate the role of human papillomaviruses (HPV) in the development of premalignant lesions and cancers of the skin in the general population. 314 biopsies obtained from 227 patients with benign neoplasms. premalignant lesions. and cancers of the skin and from 25 patients with squamous cell carcinoma of the lip were analyzed by Southern blot hybridization. DNA probes specific for various cutaneous and genital HPV types were used in hybridizations conducted under nonstringent or stringent conditions. HPV DNA sequences were only detected in eight specimens obtained from six patients: HPV 34 in one case of periungual Bowen's disease. HPV 36 and an as yet uncharacterized HPV in two cases of actinic keratosis. HPV 20 in one case of basal cell carcinoma. an as yet unrecognized HPV in one case of squamous cell carcinoma. and HPV 16 in one case of squamous cell carcinoma of the lip. None of the specimens of cutaneous horn and keratoacanthoma contained detectable HPV DNA. In contrast. HPV DNA sequences. mostly HPV 16. were detected in 13 of 23 cases of anogenital Bowen's disease and invasive Bowen's carcinoma. HPV DNA sequences were not detected in 90 cutaneous samples further analyzed by the polymerase chain-reaction technique. using amplification primers that contain conserved sequences among the genomes of HPV. These results strongly suggest that the known HPV types play only a minor role. if any. in skin carcinogenesis in the general population.
Sodium lauryl sulphate for irritant patch testing--a dose-response study using bioengineering methods for determination of skin irritation, The dose-response relationship in patch testing with sodium lauryl sulphate (SLS) was studied. The irritant skin response was quantified by visual scoring as well as by the following noninvasive methods: measurement of transepidermal water loss (TEWL) by an evaporimeter. measurement of skin color by a colorimeter. measurement of superficial blood flow by laser Doppler flowmetry. and measurement of edema in the skin by ultrasound A-scan. Twelve volunteers were patch tested with 0.12. 0.25. 0.50. and 1.00% SLS. and the skin response was evaluated after 24 and 48 h. respectively. We found a statistically significant linear dose-response relationship between dose of SLS and skin response evaluated by measurement of TEWL. skin color. superficial blood flow. and edema. Statistical evaluation by regression analysis proved measurement of TEWL to be the method best suited overall for quantification in relation to patch testing with SLS. whereas colorimetry was found to be the least sensitive of the applied methods. Ultrasound A-scan was found to be a promising method for quantification of the inflammatory response. being consistently more sensitive than measurement of skin color.
Experimental models for psoriasis, Evidence suggests that inherent in skin of psoriatic subjects are cells. architectural structures. and/or mediators. which are. at a minimum. responsible for its hyperproliferative epidermis. An objective of our laboratory has been to establish an in vitro definition of this inherent aberration. Fibroblasts are important to epidermal proliferation/differentiation. This. and an unconfirmed report that fibroblasts from psoriatic subjects might drive the abnormal epidermal proliferation in psoriasis. have caused further focus on the fibroblast. Data show that fibroblasts from patients with psoriasis. both involved and uninvolved. in the presence of human serum. either normal or psoriatic. have an increased rate of proliferation. Fibroblasts from uninvolved psoriatic sites are most responsive. To determine if fibroblasts from psoriatics could induce the psoriasiform phenotype on normal keratinocytes. an interactive skin equivalent system has been developed. With this system. fibroblasts from uninvolved and involved sites cause normal keratinocytes to have an enhanced outgrowth. Uninvolved fibroblasts cause the greatest changes. The nature of the skin equivalent system calls for this to occur via message over distance. We conclude that fibroblasts from psoriatic subjects can induce a psoriasiform phenotype via a soluble message.
Immunosuppressive effects of clonidine on the induction of contact sensitization in the balb/c mouse, The clonidine transdermal therapeutic system (clonidine-TTS) has been associated with a significant incidence of allergic contact sensitization. This incidence was not predicted by premarket skin sensitization testing in animals or humans. One possible explanation lies in recent findings in guinea pigs that clonidine exposure could inhibit the elicitation of skin reactions to unrelated strong contact sensitizers. However. these studies also showed that clonidine pretreatment did not appear to affect the induction of contact sensitization. On this basis. we sought to specifically evaluate the induction phase of sensitization to clonidine as an alternative means of assessing its sensitization properties. The method selected was the assay of in situ lymphocyte proliferation in lymph nodes draining the sites of clonidine exposure. a method recently promoted as an alternative means to assess contact allergenic potential. Utilizing various induction application techniques and regimens. we were consistently unable to demonstrate clonidine's allergenic potential through such an assessment of lymphocyte proliferation. We were also unable to demonstrate sensitization by in vivo ear swelling or in vitro lymphocyte blastogenesis assay techniques. However. a subsequent assessment of the effect of clonidine exposure on the induction of sensitization to unrelated strong contact allergens demonstrated a consistent 40-70% inhibition of the proliferative response to the contact allergens oxazolone and trinitrochlorobenzene. This was similar to the degree of suppression produced by the corticosteroids fluocinonide and hydrocortisone when they were tested at 80 and 10 times lower concentrations. In addition. we observed a comparable inhibition of the ear swelling response to oxazolone. These data extend our knowledge of the immunomodulatory effects of clonidine and offer additional mechanistic insights into the failure of short-term predictive patch-test methods to detect this chemical's potential to induce allergic contact sensitization.
Growth factor and proto-oncogene expression in psoriasis, The expression of several proto-oncogenes and growth factors was analyzed in normal skin and psoriatic lesions by RNA blot hybridization. Isolation of intact RNA from frozen biopsy samples required immediate exposure to denaturants during tissue homogenization. Lipocortin II and cyclophilin transcripts were used as internal controls. These transcripts were abundant and slightly but significantly elevated in psoriatic lesions. When results were normalized according to these reference transcripts. there was no increase in the expression of c-myc. c-Ha-ras. c-erbB (EGF receptor). c-jun. or transforming growth factor-beta (TGF-beta) transcripts in psoriatic lesions. and lesional c-fos transcripts were decreased relative to normal skin. In contrast. expression of TGF-alpha mRNA transcripts were markedly increased in psoriatic lesions even after normalization. Placement of normal or psoriatic tissue in organ culture for 2 to 4 h resulted in strong induction of c-fos. c-jun. and c-myc transcripts. but not of the other genes studied. Thus. overexpression of proto-oncogenes may be more characteristic of the epidermal response to acute injury than of the steady-state hyperplasia characteristic of psoriasis. Interferon-gamma (IFN-gamma) increased TGF-alpha mRNA levels in cultured human KC at long time intervals (24-48 h). However. of various cytokines tested. only EGF and TGF-alpha induced TGF-alpha mRNA after short time intervals (2-4 h). These results as well as the selective overabundance of TGF-alpha mRNA in psoriatic lesions among various cytokines tested suggest that activation of the EGF receptor tyrosine kinase by TGF-alpha is important in the pathogenesis of psoriatic epidermal hyperplasia.
Measles antibody: reevaluation of protective titers, A school blood drive before a measles outbreak permitted correlation of preexposure measles antibody titers with clinical protection using the plaque reduction neutralization (PRN) test and an EIA. Of 9 donors with detectable preexposure PRN titer less than or equal to 120. 8 met the clinical criteria for measles (7 seroconfirmed) compared with none of 71 with preexposure PRN titers greater than 120 (P less than .0001). Seven of 11 donors with preexposure PRN titers of 216-874 had a greater than or equal to 4-fold rise in antibody titer (mean. 43-fold) compared with none of 7 with a preexposure PRN titer greater than or equal to 1052 (P less than .02). Of 37 noncases with preexposure PRN titer less than 1052. 26 (70%) reported one or more symptoms compared with 11 (31%) of 35 donors with preexposure PRN titers greater than or equal to 1052 (P less than .002). By EIA. no case had detectable preexposure antibody; the preexposure geometric mean titer of asymptomatic donors (220) was not significantly higher than that of symptomatic donors who did not meet the clinical criteria for measles (153) (P = .10). The study suggests that PRN titers less than or equal to 120 were not protective against measles disease and illness without rash due to measles may occur in persons with PRN titers above this level.
Measles incidence, vaccine efficacy, and mortality in two urban African areas with high vaccination coverage, Measles incidence. vaccine efficacy. and mortality were examined prospectively in two districts in Bissau where vaccine coverage for children aged 12-23 months was 81% (Bandim 1) and 61% (Bandim 2). There was little difference in cumulative measles incidence before 9 months of age (6.1% and 7.6%. respectively). Between 9 months and 2 years of age. however. 6.1% contracted measles in Bandim 1 and 13.7% in Bandim 2. Even adjusting for vaccination status. incidence was significantly higher in Bandim 2 (relative risk 1.6. P = .04). Even though 95% of the children had measles antibodies after vaccination. vaccine efficacy was not more than 68% (95% confidence interval [CI] 39%-84%) and was unrelated to age at vaccination. Unvaccinated children had a mortality hazard ratio of 3.0 compared with vaccinated children (P = .002). indicating a protective efficacy against death of 66% (CI 32%-83%) of measles vaccination. These data suggest that it will be necessary to vaccinate before age 9 months to control measles in hyperendemic urban African areas.
Monoclonal antibody to mouse lipopolysaccharide receptor protects mice against the lethal effects of endotoxin, Specific endotoxic lipopolysaccharide (LPS) binding sites on the cell membranes of murine lymphocytes and macrophages that may serve as functional receptors for LPS have recently been identified using photoactivatable cross-linking LPS derivatives. A monoclonal antibody (Mab 5D3) with specificity for this 80-kDa protein has also been generated and characterized. The capacity of MAb 5D3 to protect mice against the lethal effects of endotoxin was investigated. Pretreatment of CF1 mice with as little as 15 micrograms of MAb 5D3 provided virtually complete protection against a dose of endotoxin 10-fold greater than that required to kill all mice in an untreated control group using the galactosamine sensitization model. Significant protection was also afforded normal mice given MAb 5D3 relative to saline. Several lines of evidence suggest that MAb 5D3-mediated protection is due to the agonist properties of this antibody rather than a receptor blockade mechanism.
Platelet-activating factor or a platelet-activating factor antagonist decreases tumor necrosis factor-alpha in the plasma of mice treated with endotoxin, When L-platelet-activating factor (PAF) or alprazolam (a PAF antagonist) was administered to lipopolysaccharide (LPS)-treated mice. the level of plasma tumor necrosis factor (TNF alpha) determined by either ELISA or a cytotoxic assay using WEHI cells was significantly lowered. The inactive stereoisomer. D-PAF. was not effective in lowering plasma TNF alpha levels in LPS-treated mice. The decrease in plasma TNF alpha induced by L-PAF or alprazolam was partly reversed by indomethacin. Despite a decrease in plasma TNF alpha. L-PAF or alprazolam caused an increase in the amount of TNF alpha mRNA present in the kidneys and the livers of LPS-treated mice. suggesting that a posttranscriptional event leading to the synthesis or release of TNF alpha was inhibited by these agents.
Protective effects of polyclonal sera and of monoclonal antibodies active to Salmonella minnesota Re595 lipopolysaccharide during experimental endotoxemia, Mice were passively immunized with sera from blood donors active for rough lipopolysaccharides (LPS). the J5 (Rc chemotype) mutant of Escherichia coli O111:B4. and the Re595 (Re chemotype) mutant of Salmonella minnesota. All protected the mice against lethal challenge with smooth E. coli WF96 LPS. E. coli and Salmonella rough mutant LPS. or free lipid A. Epitopes recognized by monoclonal antibodies (MAbs) reacting with the LPS of S. minnesota Re595 or lipid A were localized in the 2-keto-3-deoxy-D-manno-octulosonic acid (KDO) region and on lipid A. Core-reactive MAbs reacted with their homologous Re LPS and with free lipid A. One. GL11. cross-reacted with the KDO alone. MAbs GL6. GL11. L.4. L.6. and L.8 protected the actinomycin D-sensitized mice against the lethal effects of LPS from E. coli WF96. Salmonella enteritidis. E. coli J5. S. minnesota Re595. and free lipid A. The GL11 antibody was also protective when injected after LPS challenge. These results indicate that antibodies directed against the core glycolipid of S. minnesota Re595 LPS may be useful as an additive form of therapy that may enable decreased mortality during gram-negative bacterial sepsis.
Antimicrobial resistance of Shigella isolates in the USA: the importance of international travelers, A nationwide sample of Shigella isolates was collected and tested for resistance to 12 antimicrobial agents to assess the prevalence and epidemiologic correlates of antimicrobial resistance in Shigella. Of the isolates. 32% were resistant to ampicillin. 7% to trimethoprim-sulfamethoxazole. and 0.4% to nalidixic acid. Fifty (20%) of 252 isolates were associated with foreign travel. The best predictor of clinically important resistance was a history of foreign travel: 20% of isolates from foreign travelers showed trimethoprim-sulfamethoxazole resistance. compared with only 4% of isolates from those without such a history. Quinolone resistance was not identified in travel-related isolates. and quinolones may be more appropriate for initial therapy of travel-related shigellosis than is trimethoprim-sulfamethoxazole.
Cefuroxime treatment failure of nontypable Haemophilus influenzae meningitis associated with alteration of penicillin-binding proteins, A 10-year-old boy presented with nuchal rigidity and cerebrospinal fluid (CSF) leukocytosis initially and again on day 6 of intravenous cefuroxime therapy (200 mg/kg/day). Both CSF specimens yielded nontypable beta-lactamase-negative Haemophilus influenzae that were susceptible by disk tests but relatively resistant to cefuroxime (MIC. 8- to 16-fold greater than that of control isolates). To define the mechanism of resistance. the cefuroxime resistance marker was transformed to a susceptible H. influenzae recipient; inactivation and permeability of beta-lactam substrate were tested and the penicillin-binding protein (PBP) profiles were examined. Inactivation of beta-lactam substrate was not detected and reduced permeability was not found. However. reduced beta-lactam binding to PBPs 4 and 5 was observed; 18- to 27-fold more penicillin and 2.5-to 4-fold more cefuroxime was required to saturate or block 50% of the binding sites of these PBPs. respectively. Thus. reduced affinity of PBPs 4 and 5 for beta-lactam substrate appears to be the mechanism of cefuroxime resistance in this strain. The reduced affinity of these targets appears to have contributed to the bacteriologic and clinical failure in this patient.
Restriction endonuclease analysis of total cellular DNA of Aspergillus fumigatus isolates of geographically and epidemiologically diverse origin, No typing system exists for Aspergillus fumigatus. though isolates are distinguishable by phenotypic characteristics. DNA was prepared by lysis of protoplasts. followed by deproteination. phenolchloroform extraction. and dialysis. DNA prepared was of uniform size and exceeded 60 kb. After digestion with SalI and XhoI endonucleases. DNA was electrophoresed. stained. and photographed. Differences in the mobilities of 10- to 50-kb bands distinguished isolates. Reproducibility was shown by repeated preparations and animal passage. By use of a proposed notation system for describing restriction fragment length polymorphism patterns. 31 epidemiologically characterized isolates from three continents revealed 24 patterns (DNA types). Three DNA types were represented by 3 isolates each and 1 DNA type by 2 isolates; 20 types were unique. Two groups of 3 isolates of the same DNA type were from Stanford University Hospital. One patient isolate from Stanford was the same DNA type as a sewage isolate from New Jersey. Another Stanford isolate was the same as a German isolate. These observations indicate widespread dispersal of some clones and restricted locales for others. Paired isolates from airway fluids of three patients had two DNA types in each. Restriction endonuclease typing shows promise for investigating the epidemiology and ecology of A. fumigatus.
A randomized controlled trial of glucocorticoid prophylaxis against experimental rhinovirus infection, The effects of combined intranasal and systemic glucocorticoid steroids on the local inflammatory response. and symptoms due to experimental rhinovirus infection were studied in 45 adults randomized to prophylaxis with either placebo or steroids. Intranasal beclomethasone (168 micrograms twice a day) was begun 4 days before viral challenge and continued 5 days after challenge. Oral prednisone (30 mg twice daily) was given for 3 days beginning 1 day before challenge. During the first 48 h after viral inoculation. nasal obstruction. nasal mucus weights. and kinin concentrations in nasal lavages were lower in steroid recipients. but subsequent increases in these variables in the steroid group resulted in no significant cumulative differences between treatment groups. These data suggest that steroid prophylaxis may suppress nasal inflammation and cold symptoms during the first 2 days in experimental rhinovirus colds.
Detection of interleukin-3 in the serum of mice infected with Mycobacterium lepraemurium, Infection of mice by Mycobacterium lepraemurium is accompanied by ablation of erythropoiesis in the bone marrow and gross enlargement of the spleen. This. together with increased monocytopoiesis and the earlier demonstration of macrophage colony-stimulating factor in the serum of infected mice. suggested the activity of additional cytokines. Eight weeks after infection of mice by M. lepraemurium. interleukin-3 (IL-3) activity was demonstrated in the serum (titer. 1:3200). The serum titer of IL-3 activity was maximal after 13 weeks (greater than 1:6400) and was slightly reduced after 18 weeks (1:6400). That the IL-3 activity detected in the serum of the M. lepraemurium-infected mice reflected the presence of IL-3 itself was confirmed by a neutralization assay using anti-murine IL-3 antibodies; IL-3 activity in the serum of mice 13 weeks after infection was completely abolished by the anti-IL-3 antibodies. Finally. a 1-kb signal of IL-3 RNA was detected in the spleens of M. lepraemurium-infected mice 13 weeks after infection.
Activation of the complement system in human immunodeficiency virus infection: relevance of the classical pathway to pathogenesis and disease severity, In vitro studies implicate classical and alternative complement pathway activation in the pathogenesis of human immunodeficiency virus (HIV) infection. To ascertain their importance in vivo. activation fragments of the classical (C4d). alternative (Ba). and common (C3d) pathways were measured and fragment to parent molecule ratios derived in 74 HIV-infected individuals and related to circulating immune complex (CIC) levels. Centers for Disease Control (CDC) stage. and beta 2-microglobulin. neopterin. and CD4-positive (CD4+) lymphocyte levels. All fragments and ratios were significantly higher in patients (P less than .01) than controls. C4 conversion indices (C4d and C4d to C4) increased linearly with increasing CDC stage (P less than .001). while CD4+ lymphocytes decreased linearly (P less than .001). C4d. C3d. C4d to C4. and C3d to C3 correlated with increasing CIC and beta 2-microglobulin. and C4d and C4d to C4 correlated with decreasing CD4+ lymphocytes (P less than .05). The relationship of classical complement pathway activation to disease progression and CD4+ lymphocytes suggests its involvement in the pathogenesis of HIV infection.
AZT demonstrates anti-HIV-1 activity in persistently infected cell lines: implications for combination chemotherapy and immunotherapy, A sensitive and quantitative focal immunoassay has been used to measure the effects of three different therapeutic agents on tissue culture cells infected with human immunodeficiency virus (HIV). The effects of the drugs were studied on both acutely and persistently infected CD4+ cell lines. The three agents. azidothymidine (AZT). interferon-alpha (IFN-alpha). and an anti-HIV envelope antibody coupled to ricin A chain. were tested alone and in combination. AZT was found to have its greatest effect during early stages of the infection. but also had an action on persistently infected T cell lines. The effect of AZT on persistently infected cells was seen within 24 h. increased with extended exposure to the drug. and persisted after its removal. IFN-alpha had variable effects on acutely infected cells but suppressed chronic infection. Combinations of the therapeutic agents were studied. Using a model that allowed for treatment during both acute and persistent stages of infection. the most effective combination in suppressing HIV infection was the continual use of both AZT and IFN-alpha at the highest tolerable doses. Knowledge of the efficacy of AZT on persistently infected cells will allow for the most effective design of clinical protocols.
Analysis of lymphocytes, monocytes, and neutrophils from human immunodeficiency virus (HIV)-infected persons for HIV DNA, The human immunodeficiency virus (HIV) infects and depletes or alters the function of cells involved in immune responsiveness. While both T helper lymphocytes and monocyte/macrophages can be infected via cell-surface CD4 in vitro. previous studies showed that few blood cells express HIV RNA in vivo. This study used DNA amplification to determine the levels of HIV DNA in purified lymphocytes. monocytes. and neutrophils from HIV-infected asymptomatic individuals and persons with AIDS. The average numbers of HIV DNA copies in lymphocytes from AIDS patients and asymptomatic individuals were similar (approximately 100-140 copies/150.000 cells). However. when expressed on the basis of numbers of CD4+ T cells. AIDS patients' cells contained approximately 2.5 times more HIV DNA. While HIV DNA was present in lymphocytes from all 27 subjects. little or no HIV DNA was observed in monocytes or neutrophils. Only 1 asymptomatic person contained levels of HIV DNA in monocytes (125 proviral copies/150.000 cells) that were comparable to levels expressed in lymphocytes (160/150.000). While expression of monocyte HIV DNA in this person was persistent over at least 8 months. it was not observed in neutrophils. suggesting that monocyte HIV DNA did not originate in myeloid precursors. This study shows that in AIDS or asymptomatic HIV infection. lymphocytes are the predominant infected cell found in blood.
Cytomegalovirus in the brain: in vitro infection of human brain-derived cells, Models for human cytomegalovirus (HCMV) brain infection have been developed in a variety of brain-derived cells in which the factors governing virus infectivity might be studied in vitro. Studies were initiated with brain endothelial cells. the likely portal of entry for virus into the central nervous system. Primary explant cultures of brain endothelial cells. derived from homogenates of healthy human brain. supported complete viral gene expression and cytopathic effect (CPE). Endothelial cells do not appear to be a barrier for HCMV passage into the central nervous system. Astroglial lines (primary explant or tumor-derived) varied in their ability to support HCMV replication. Some (T98G) supported incomplete (immediate-early) gene expression while others (A-172) did not support any detectable gene expression. Some astroglial lines (HS-683) supported extensive virus replication with minimal viral CPE. Neuronal cell lines (SK-N-MC) were fully permissive. The more differentiated glial lines (astrocytoma) were fully permissive to HCMV infection; however. the less differentiated glial lines (glioblastoma) were partly or nonpermissive.
Occurrence of groups A and B of respiratory syncytial virus over 15 years: associated epidemiologic and clinical characteristics in hospitalized and ambulatory children, Over 15 years respiratory syncytial virus (RSV) isolates from 1209 hospitalized and ambulatory children were examined for strain group and in a subset for subgroup to determine the associated epidemiologic and clinical characteristics. Three patterns of yearly outbreaks existed: (1) strong predominance of group A strains (9 years with 83%-100% A strains). (2) relatively equal proportions of group A and B strains (4 years). and (3) strong predominance of group B strains (78%-85%) in 2 years. separated by a decade. The first pattern of highly dominant A strains occurred in cycles of 1 or 2 consecutive years with a single intervening year in which B strains were greater than or equal to 40% of the isolates. Subgroups A1 and A2 predominated. while B2. 3. and 4 occurred almost equally. A greater clinical severity for Group A strains was suggested by children with group A infections requiring intensive care significantly more often (15.4 vs. 8.3%. P = .008). Further. strongly dominant A strain years were associated with higher proportions of RSV admissions requiring intensive care (16.6% vs. 5.5%. P less than .01). Strains of subgroups A2 and B4 were more frequently found in hospitalized patients and A1 in outpatients. and the 2 years with the highest rates of intensive care admissions were those in which subgroup A2 dominated.
Effect of vaccination on serotype-specific antibody responses in infants administered WC3 bovine rotavirus before or after a natural rotavirus infection, In an evaluation of WC3 bovine rotavirus (serotype 6) vaccine in infants. some subjects experienced a natural serotype 1 rotavirus infection before vaccination and others after. Therefore. the effects of both WC3 and natural rotavirus strains as either primary or boosting immunogens on serotype-specific neutralizing antibody responses could be determined. After primary natural infection (symptomatic or asymptomatic). neutralizing antibody titers were highest to serotype 1 but were consistently high to serotype 3. and low titers (greater than or equal to 20) to serotypes 2 and 4 were often detected. Previous vaccination with WC3 had little effect on the magnitude of these responses. In contrast. subjects infected with serotype 1 strains before vaccination experienced large (average. 12-fold) rises in neutralizing antibody to human serotypes 1-4 when vaccinated with WC3. Thus. although WC3 and the natural strains are distinct serotypes. their epitopes were sufficiently similar that reinfection with WC3 could boost neutralizing antibody titers to human serotypes in subjects primed by a previous natural infection.
A large outbreak of antibiotic-resistant shigellosis at a mass gathering, In July 1987. a large outbreak of shigellosis occurred among attendees at a mass gathering in a national forest. the annual Rainbow Family Gathering. Sanitation in the campsite was poor. allowing widespread transmission of disease. probably by food. water. and person-to-person spread. The attack rate may have been greater than 50% among the estimated 12.700 attendees. The outbreak was caused by Shigella sonnei. resistant to ampicillin. tetracycline. and trimethoprim-sulfamethoxazole; the organism was of colicin type 9 and contained a 90-kilobase plasmid not found in non-outbreak-related strains. The dispersal of the group resulted in nationwide dissemination of the organism. and outbreaks in three states were linked to transmission from attendees at the Gathering. This outbreak demonstrates the potential for rapid dissemination of disease in such a setting and the necessity for careful planning of mass gatherings.
Prevalence and diagnosis of Legionella pneumonia: a 3-year prospective study with emphasis on application of urinary antigen detection, During a 3-year period the frequency of legionellosis in hospitalized patients with community-acquired and nosocomial pneumonias was 3.4% (23/684 cases) and 5.9% (33/559). respectively. Of the diagnostic tests evaluated. detection of Legionella pneumophila serogroup 1 antigen in urine had the highest sensitivity. with 86% of culture-proven cases being positive. Sensitivities of serologic tests and examination of respiratory secretions (culture and direct immunofluorescence) were 36% and 26%. respectively. The diagnostic value of serology and of examination of respiratory secretions can be low when specimens are obtained and processed under the typical conditions of hospitalization. Urinary antigen detection represents an important diagnostic addition. and examination of postmortem lung tissue from fatal cases with pneumonia is an important adjunct for estimating the prevalence of legionellosis and for assessing the effectiveness of premortem diagnostic tests.
Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum, Tumor necrosis factor-alpha was detected in supernatants collected from BALB/c mouse peritoneal macrophages incubated continuously with Histoplasma capsulatum. The levels of TNF alpha measured by actinomycin D bioassay peaked within hours after exposure and then greatly declined by 24 h. TNF alpha was also measured in bronchoalveolar lavage fluid from BALB/c mice challenged intranasally with H. capsulatum. Lavage fluid TNF alpha levels exhibited the same pattern as the in vitro supernatants; they peaked within hours after challenge and lower levels were detected at 24 h. Treatment of mice with anti-TNF alpha antibody accelerated mortality in response to systemic infection and significantly increased tissue colony counts in the liver and spleen. In the murine model. TNF alpha is produced in response to H. capsulatum and appears to play some role in host defense to infection.
Diagnosis of intestinal amebiasis using salivary IgA antibody detection, This investigation sought to determine whether detection of salivary IgA antibodies to Entamoeba histolytica could identify intestinal amebic infections among 223 school children. Four groups of children were identified through coproparasitoscopic examination: E. histolytica as other parasites only (20%); and parasite-free (25%). The diagnostic accuracy of salivary IgA antibodies to an E. histolytica membrane extract was 91.5% (sensitivity. 85%; specificity. 98%). maintaining high predictive value at different prevalences. Also. a positive correlation (r = .753. P less than .001) was observed between fecal E. histolytica membrane antigen levels and salivary IgA antibody activity. Measurement of IgA antibodies in saliva may be useful in diagnosing intestinal infections with E. histolytica within a wide range of prevalences. Moreover. sampling of saliva may be a useful non invasive test for immunoepidemiologic surveys.
Frequency of indeterminate western blot tests in healthy adults at low risk for human immunodeficiency virus infection. The NIAID AIDS Vaccine Clinical Trails Network, As part of a phase 1 trial of a candidate AIDS vaccine. blood specimens were collected from 168 healthy adult volunteers at minimal or no risk for becoming infected with human immunodeficiency virus type 1 (HIV-1). These specimens were screened for evidence of HIV-1 infection by enzyme immunoassay (EIA) and the Biotech/Du Pont Western blot (n = 168). culture (n = 122). and polymerase chain reaction assay (n = 20). None of the subjects had a positive test result by any of these assays. but 32% had indeterminate Western blot tests. most of which demonstrated a single band of low intensity. The most common bands were p24 (47%). p55 (34%). and p66 (36%); envelope bands were unusual (gp41. 2%; gp120. 2%). No serum specimen collected after 2-11 months from individuals with indeterminate Western blot results was positive by EIA or Western blot. There was 91% agreement in the test results of the first and second serum samples when the same lot of Western blot kit was used but only 36% agreement when different lots were used. The Biotech/Du Pont Western blot kit thus frequently yields indeterminate test results in the absence of HIV-1 infection. the reproducibility of which is subject to lot-to-lot variability.
Occurrence of secondary attenuating mutations in avirulent Salmonella typhimurium vaccine strains, The attenuating delta aroA554 mutation in Salmonella typhimurium strain SL3261 was complemented in vitro by selecting for AroA+ recombinant DNA clones. SL3261 containing cloned aroA+ genes did not require exogenous phenylalanine. tryptophan. tryosine. p-aminobenzoic acid. or dihydroxybenzoic acid for growth in defined media. Cloned aroA+ genes did not restore wild-type virulence to SL3261. however. in a murine typhoid model. The delta aroA554 mutation was transduced into S. typhimurium strain SR-11. a mouse-virulent strain recently passaged in mice. The SR-11 delta aroA554 mutant was highly attenuated for mice challenged parenterally. The same cloned aroA+ genes isolated in SL3261 restored the virulence of the SR-11 delta aroA554 mutant to that of wild-type SR-11. These results suggest that while the delta aroA554 allele remains effective in reducing S. typhimurium virulence. laboratory passage of attenuated vaccine strains may lead to the accumulation of additional attenuating defects.
Nasal carriage of Staphylococcus aureus: correlation with hormonal status in women, In view of recent observations on hormone-microorganism interactions. a study of Staphylococcus aureus nasal carriage in relation to sex-hormone status was undertaken. Prospectively in 479 women attending a colpocytologic clinic. hormonal status was assessed by determining the karyopyknotic index (KI) on smears stained by the Papanicolaou method. Rates of S. aureus nasal carriage were 29.3% in premenopausal women and 21.9% in postmenopausal women (P not significant). Carriage rates were significantly higher (P = .026. chi 2 7.32) for women with high KIs (40.7%) than for those with intermediate and low KIs (27.03% and 25.1%. respectively). S. aureus nasal carriage also correlated independently and significantly with previous antibiotic use and the presence of insulin-treated diabetes mellitus. This preliminary observation confirms an association between levels of sex hormones as reflected by the KI and S. aureus nasal carriage rates.
Effects of albendazole on Echinococcus multilocularis infection in the Mongolian jird, Albendazole chemotherapy of larval Echinococcus multilocularis was studied in the Mongolian jird by administration of medicated feed at various concentrations and durations. The effects were evaluated by comparison of treated and control groups in terms of host mortality. larval metastases to the lungs. and final weight and histologic appearance of larval tissue. Viability of larval tissue at necropsy of each animal was tested by inoculation into two noninfected jirds. Albendazole-medicated feed (0.05%-0.10%) significantly inhibited larval growth. Other effects of the drug included larval degeneration and necrosis. inhibition of protoscolex formation. decreased pulmonary metastases. and reduced mortality of hosts. Adverse effects on the parasite correlated significantly with serum albendazole metabolite levels and duration of therapy. However. serum albendazole levels in jirds equal to or exceeding concentrations achieved in humans receiving daily doses of 10 mg/kg of body weight did not kill the parasite.
Conjugated catecholamines in human plasma: where are they coming from, The origins of conjugated catecholamines remain poorly known. The aim of the present study was to see whether a major contribution comes from the sympathetic nervous system. We have assumed some kind of parallelism between the activity of the sympathetic nervous system. the amount of catecholamines released and taken up. and the amount of conjugated catecholamines circulating in plasma. Accordingly. an increase in sympathetic activity should be followed by an increase in the plasma level of conjugated catecholamines. The plasma levels of sulfoconjugated and glucuroconjugated catecholamines were measured in 10 patients with mental disease resistant to drug treatment. before and after electroconvulsive therapy. As expected. blood pressure. norepinephrine concentration. and epinephrine concentration in plasma were transiently increased. Neither sulfoconjugated nor glucuroconjugated catecholamines were significantly changed. Conjugated catecholamines were measured in 10 volunteers before and at the nadir of insulin-induced hypoglycemia. As expected. plasma levels of norepinephrine and epinephrine were drastically increased. Plasma levels of sulfoconjugates were decreased and glucuroconjugates increased; these were narrow but statistically significant variations. Data reported in the present article do not support a major role for the activity of the sympathetic system in fixing the level of conjugated catecholamines in human plasma. This is a negative. but nonetheless important. observation. In human subjects. currently available information suggests an important role for the intestinal wall and renal function in determining the level of circulating sulfoconjugates.
Substance P, acetylcholinesterase, and beta-endorphin levels in the plasma and pericardial fluid of patients with and without angina pectoris, We measured substance P-like immunoreactivity (SPLI). beta-endorphin-like immunoreactivity (BELI). acetylcholinesterase activity. and total protein content in pericardial fluid and plasma of patients with angina pectoris and patients with no angina pectoris. SPLI and BELI levels. acetylcholinesterase activity. and total protein content were determined by radioimmunoassay. a colorimetric method. and by the method of Lowry et al. (J Biol Chem 1951; 193:265-75). respectively. In the pericardial fluid. patients with angina had SPLI. BELI. acetylcholinesterase. and total protein values of 1.69 +/- 0.23 fmol/mg protein. 0.16 +/- 0.13 fmol/mg protein. 0.06 +/- 0.02 units. and 25.7 +/- 3.2 mg/ml. respectively. Patients with no angina had SPLI. BELI. acetylcholinesterase. and total protein values of 0.93 +/- 0.17 fmol/mg protein. 0.19 +/- 0.10 fmol/mg protein. 0.16 +/- 0.02 units. and 44.6 +/- 5.3 mg/ml. respectively. SPLI levels were significantly higher (p less than 0.03). and acetylcholinesterase (less than 0.002) and total protein content (less than 0.004) were significantly lower in the pericardial fluid of patients with angina when compared with those of patients with no angina. BELI levels were not significantly different between the two groups. In the plasma. no significant differences were found in SPLI. BELI. acetylcholinesterase. and total protein values between the two groups of patients. Patients with angina had SPLI. BELI. acetylcholinesterase. and total protein values of 0.47 +/- 0.26 fmol/mg protein. 0.06 +/- 0.06 fmol/mg protein. 0.29 +/- 0.15 units. and 68.2 +/- 8.7 mg/ml. respectively.
Effect of fasting on the lung glutathione redox cycle in air- and oxygen-exposed mice: beneficial effects of sugar, Fasting increases susceptibility to hyperoxic lung damage in mice. at least in part. by decreasing lung glutathione level. To determine whether fasting alters other components of the glutathione redox cycle. and whether a diet of sugar alone reverses fasting's effects. normally fed. sugar-fed. and fasted mice were exposed to room air or 100% oxygen for up to 4 days. In air-exposed mice. fasting decreased glutathione peroxidase (GP) and glutathione reductase (GR) activities 15% to 20% on days 3 and 4 (p less than 0.01) and glutathione level 25% to 30% on days 2 to 4 (p less than 0.05). When corrected for protein concentration. GP and GR values were similar to those in the fed mice. but glutathione levels remained lower on days 2 and 3 (p less than 0.05). Oxidized glutathione (GSSG) was unchanged. but the ratio of GSSG to total glutathione (reduced glutathione plus GSSG) increased on day 2 (p less than 0.05). In oxygen-exposed fed mice. GP increased 62% and GR increased 39% on day 4 (p less than 0.05). the time when the lung injury was most severe; glutathione increased 30% on days 3 and 4 (p less than 0.05); and GSSG increased threefold and eightfold on days 3 and 4 (p less than 0.01). Oxygen-exposed fasted mice were all dead by day 3 (versus no deaths in the fed mice). failed to increase GR and total glutathione in response to the oxidant stress. and increased GP and GSSG on day 3 to the same extent as the fed mice did on day 4.
Unterberger stepping test: a useful indicator of peripheral vestibular dysfunction, Deviation of gait in a stepping test has been proposed as a useful indicator of peripheral labyrinthine dysfunction. A prospective study of 26 patients suspected of having uncompensated peripheral labyrinthine dysfunction and 49 normal patients with normal labyrinthine dysfunction showed no significant difference in performance of the Unterberger stepping test between patients with electronystagmographically significant canal paresis and those with normal vestibular function.
Ligmaject system for local anaesthesia in otology, The Ligmaject syringe for local anaesthetic injection incorporates a pistol-grip handle and a ratchet system designed to inject a very tiny aliquot of anaesthetic per 'click'. This instrument was used to provide local anaesthesia for 22 otological procedures on consenting adults. The performance of the Ligmaject syringe compared favourably with that of the conventional dental syringe in terms of patient acceptability and user convenience.
Delayed facial palsy following uncomplicated stapedectomy, We report six cases of partial lower motor neurone facial palsy occurring between four and ten days after uncomplicated stapedectomy. The aetiology is unclear but recovery was rapid and complete in all patients.
Comparison of electro and chemical cautery in the treatment of anterior epistaxis, In the ENT Department of the Royal Victoria Hospital. Belfast. the impression (supported only by anecdotes) was that electro-cautery was superior to chemical cautery in the treatment of simple anterior epistaxis. Since no evaluation of the relative merits of electro and chemical cautery has been reported. a prospective randomized study was conducted to assess the effectiveness of electro-cautery and cautery with silver nitrate. The results of the study showed that there was no statistically significant difference between the two methods in either controlling the epistaxis or in the incidence of complications. It is concluded that since cautery with a silver nitrate tipped applicator is simpler. and of equal effectiveness. it would appear to be the treatment of choice for simple anterior epistaxis.
Alternating cisplatinum and VAC ineffective in end stage squamous cell carcinoma of the head and neck, Sixteen patients with end stage squamous cell carcinoma of the head and neck were admitted to a phase II study of alternating courses of cisplatinum (100 mg/m2) and VAC (vincristine 1.4 mg/m2. adriamycin 50 mg/m2. cyclophosphamide 750 mg/m2) given at three weekly intervals. Only two patients achieved a response (12 per cent). The median survival time was 62 days which is much the same as that of a similar group of patients who received no chemotherapy in a previous trial (70 days).
Head and neck cancer and ageing: a retrospective study in 438 patients, To evaluate whether age over 70 years represents a prognostic factor in head and neck cancer. we reviewed all cases observed between 1981 and 1984. Four hundred and thirty-eight (438) patients were considered in relation to three age groups (less than or equal to 59. 60-69. and greater than or equal to 70 years. defined as non-elderly. mid-elderly and elderly respectively). The main parameters analyzed included histological diagnosis (no difference emerged among the three age groups); anatomical site (hypopharyngeal carcinoma was most frequent in non-elderly patients); TNM stage (an higher incidence of early stages was seen in the elderly); performance status (better in the non-elderly); previous illnesses (life-style related diseases were more frequent in the non-elderly); contraindications to surgery (more frequent in the elderly); surgical treatment ('en bloc' resections were more often employed in the non-elderly); post-operative complications and local control (no difference between the three groups); multiple primary malignancies (head and neck. oesophagus and lung were more frequent in non-elderly patients) and survival (no difference). Although age affects several features of head and neck cancer patients. it does not appear from the present study to be an independent prognostic factor for local control and survival. With regard to survival. stage appeared to be the most important prognostic factor.
Adenoid cystic carcinoma: a comparison between CT, MR and Gd MR imaging techniques, Nasopharyngeal carcinoma continues to be a difficult diagnostic problem in many patients. It is well known that amongst the many and varied manifestations of this disease. a unilateral middle ear effusion in an adult should be regarded with suspicion. Such a case in a 42-year-old patient is presented. In this case the benefit of Gadolinium enhanced magnetic resonance imaging over and above computerized tomography is demonstrated.
Decline in the prevalence of childhood deafness in the Jewish population of Jerusalem: ethnic and genetic aspects, A longitudinal study was performed on 147 Jewish children with bilaterally sensorineural hearing loss of moderately severe to profound degree. born in Jerusalem during the eighteen years 1968-85. The prevalence rate of these children declined during the years 1977-85. and at the same time the rate of consanguinity of their parents decreased; this decline was more evident in the genetic group among children with non-Ashkenazi ethnic origin. No such decline was found among the Ashkenazi children and no consanguinity among parents of these children was recorded. Our study supports the assumption that restriction of consanguineous matings may affect the prevalence of genetic deafness in children in a well-defined population. We have tried to remain unbiased and concede certain shortcomings in our present study.
Dysequilibrium and otitis media with effusion: what is the association, An association between non-suppurative otitis media (NSOM) and symptoms of dysequilibrium has been observed but not previously quantified in children (Gates. 1980; Busis. 1983; Blayney and Coleman. 1984). This study compared the incidence of balance related problems in 154 children with surgically proven glue ear and 51 children with normal ear function. Symptoms ranging from true vertigo to mild ataxia were discovered in 22 per cent of the children with NSOM but in none of those within the control group (p less than 0.001). Periods of dysequilibrium were associated with episodes of otalgia in 64 per cent of the children but were not increased in those with unilateral compared to those with bilateral effusions. Complete resolution of symptoms occurred in 85 per cent of children following the insertion of grommets. A history of balance disturbance should be actively sought in all children with otitis media with effusion. and when present. provides a strong indication for early operative intervention.
Tympanosclerosis of the middle ear: late results of surgical treatment, The late results of one stage operation for middle ear tymanosclerosis in 73 patients during the period January 1965 to December 1980 are presented. Mean observation time was 11.2 years (range 3-20.2 years). with a follow-up rate 86 per cent. Among 64 patients with stapes fixation. 59 had removal of tympanosclerotic masses and stapes mobilization. and five cases underwent stapedectomy. The series was divided into six groups and the results analyzed. The best and most stable results occurred in the group with stapes mobilization and an intact ossicular chain followed by the group with stapes mobilization and Type II tympanoplasty with incus interposition. The poorest late results were obtained in ears with lacking stapes crura and stapes mobilization. and in ears subjected to stapedectomy. No case of post-operative sensorineural hearing loss occurred. We recommend that care is taken to preserve an intact ossicular chain at stapes mobilization performed at the same stage as myringoplasty. Also in ears with a defective ossicular chain but intact stapes with tympanosclerotic fixation we recommend stapes mobilization in one stage. In ears with fixation of the stapes footplate and defective crura. we recommend stapedectomy or stapedotomy in two stages.
Mucosal thickening on sinus X-rays and its significance, Mucosal thickening is commonly seen on X-rays of the paranasal sinuses taken in the ENT department. This sometimes leads to a sinus washout. which is clear. even though the X-rays were strongly suggestive of disease. This paper examines the prevalence of sinus X-ray anomalies in a general population. having facial X-rays for conditions other than possible sinus disease. The study suggests that up to 50 per cent of the so-called normal population may have sinus X-ray appearances consistent with sinus disease. and this may partly explain clear returns on sinus washout.
Unusual type of foreign body in the maxillary sinus, A broken end of the spear presenting as a foreign body in the nasopharynx and right maxillary sinus in a 19-year-old Papua New Guinean is described. The types of foreign bodies and their mechanisms of introduction into this site are summarized.
Field performance of the Intoxilyzer 5000: a comparison of blood- and breath-alcohol results in Wisconsin drivers, Intoxilyzer 5000 and blood-alcohol results from drivers arrested for operating a motor vehicle while intoxicated and for related offenses were compared during a two-year period. Three hundred and ninety-five pairs of results were studied. The breath- and blood-alcohol specimens in this study were collected within 1 h of each other. The mean blood-alcohol concentration obtained was 0.180 g/dL. with a range from zero to 0.338 g/dL. By comparison. the mean Intoxilyzer 5000 result was 0.16 g/210 L with a range from zero to 0.32 g/210 L. Compared with the blood-alcohol result. Intoxilyzer 5000 results were lower by more than 0.01 g/210 L 67% of the time. within 0.01 g/210 L 31% of the time. and higher by more than 0.01 g/210 L 2% of the time.
Fatal ethanol intoxication from household products not intended for ingestion, Fatal acute ethanol intoxication is frequently encountered in medicolegal practice. Although the vast majority of acute ethanol toxicity deaths follow the ingestion of conventional alcoholic beverages. ethanol can be obtained from a variety of commercial products. which often contain high levels of ethyl alcohol but are not manufactured or designed for consumption. Such products may be easily purchased in locales where statutory limitations restrict liquor availability on Sundays or during the early morning hours. Several acute ethanol fatalities have been encountered in New Mexico that were directly related to consumption of non-beverage ethanol-containing products. all of them occurring during times when alcoholic beverage sales were restricted. Despite the fact that manufacturers deliberately include compounds in these products that discourage ingestion. this policy apparently does little to deter individuals who are searching for a source of ethanol when no conventional beverages are available. The products that were consumed in these fatalities also contained other compounds which would be toxic at much greater concentrations. but which were inconsequential in their effects in comparison with the direct toxic effect of ethanol. Investigation of the scene and awareness that alcohol-containing products can be fatally abused are essential to detecting these unconventional ethanol sources.
Liberty and tardive dyskinesia: informed consent to antipsychotic medication in the forensic psychiatric hospital, This paper addresses informed consent to antipsychotic medication of those incarcerated in a forensic psychiatric hospital. The ways in which the unique setting of the forensic psychiatric hospital impinge upon the three components of informed consent--information. voluntariness. and competency--are explored. Special attention is given to the risk-benefit ratio of receiving antipsychotic medication in terms of the liberty interests at stake--freedom of movement. that is. the effects of tardive dyskinesia. and freedom of space. that is. release from the forensic psychiatric facility.
An elliptical incised wound of the breast misinterpreted as a bite injury, Bite injuries upon homicide victims are most often initially identified by the forensic pathologist during the course of the autopsy examination. Following such recognition. the injury or photographs of the traumatized site are then referred to a forensic odontologist for his or her examination. further characterization. and subsequent comparison with any suspect's dentition. However. if the pathologist misidentifies an injury caused by another mechanism as a human bite. this mistake can potentially be perpetuated by the dental consultant. since relatively few dentists regularly examine traumatic injuries other than those arising from bites. To illustrate such an event. a case is presented involving an incised wound of the breast. which was originally identified as an avulsive bite wound. Detailed examination by two odontologic consultants confirmed the wound as having been caused by human teeth. and further. they related the "bite injury" to a specific individual. The bite injury interpretation represented the only scientific evidence implicating the suspect at a subsequent trial for capital murder. Later examination of the tissues and photographs by a forensic pathologist and another dental consultant revealed that the injury was not due to human dentition. but rather resulted from a sharp-edged instrument. These consultants conducted a unique experiment to reduplicate the injury and prove its causation. This information was presented to the jury during the suspect's trial and resulted in his acquittal on all charges.
Compliance, reliability, and validity of self-monitoring for physical disturbances of Parkinson's disease. The Parkinson's Symptom Diary, Previous clinical research in Parkinson's disease has recognized the value of self-monitoring procedures in which patients observe and record the frequency and severity of their own symptoms as these occur within the patient's social and work environment. We discuss issues of methodology and report a study of compliance. test-retest reliability. and validity with a new self-monitoring instrument. the Parkinson's Symptom Diary. Two recordings of frequency (loss of balance. hesitation-freezing) and two ratings of severity (tremor. difficulty walking) were made four times daily for one week by patients (N = 73) who were without apparent loss of cognitive or memory functions. A total of 91% of the diaries received (97% of requested) met strict compliance criteria so that independent sampling over days could be assumed. Test-retest stability over one month was demonstrated for each score (all Spearman rho greater than .85) in a representative subsample of 28 patients. Criterion validity was demonstrated for each score by an expected pattern of correlations with independently obtained observer ratings of the same or related indices of disease. and by comparison with Hoehn and Yahr disability stages. By its simplicity. this self-assessment device can be an invaluable complement to traditional methods of clinical and laboratory assessment in the care and evaluation of Parkinson patients.
Hyperemesis gravidarum as conversion disorder, Psychosocial factors have long been believed to be important in the pathogenesis of emesis gravidarum (morning sickness) and hyperemesis gravidarum (HG). Although this has been confirmed during extensive studies over the last 30 years. HG has never been described as a conversion reaction. We describe two women presenting with hyperemesis who clearly fulfill diagnostic criteria for conversion. We suggest that strong psychodynamic conflicts are expressed by this potentially dangerous symptom in a subset of individuals and that dynamic interventions have a role in treating certain patients with HG.
Untying the gordian knot: the genetics of Tourette syndrome, A review of the current status of the genetics of Tourette syndrome is presented. Over the course of the 104 years since Gilles de la Tourette described the syndrome that bears his name. a body of carefully collected. described. and analyzed data has produced a model of the genetics that implicates a single dominant gene that is variably penetrant in males and females. Moreover. the locus of action of this gene is most likely in the dopaminergic system of the midbrain. A systematic search for this gene using recombinant DNA techniques is under way.
Electroencephalographic activity related to palatal myoclonus in REM sleep, Polysomnography. including electroencephalography. electromyography and electro-oculography was performed in three patients with palatal myoclonus (PM). The amplitude of the myoclonus decreased during sleep. The frequency did not change during non-REM sleep. but increased during REM sleep in two patients. Ocular myoclonus synchronized with PM disappeared during deep sleep stages in two patients and reappeared during REM sleep in one of them. In the other patient. ocular myoclonus was noted only in REM sleep. being absent even when the patient was awake. All patients showed episodic EEG activities synchronous with myoclonic jerks only in REM sleep. These episodes were noted 5-15 times throughout the night. and each episode lasting for 1-7 s. They were negative or positive waves of saw-tooth appearance which were distributed predominantly in the central region. During the episodes. the frequency of myoclonic jerks increased in two patients. Although it is known that REM sleep influences PM and ocular myoclonus. this is the first report demonstrating the electroencephalographic activity associated with PM.
Serial studies of evoked potentials and circulating lymphocyte subsets for multiple sclerosis: attempts to monitor progress, A concurrent change in evoked potential measurements and quantitation of circulating T-suppressor (CD8) lymphocyte subpopulations might indicate increased subclinical disease activity. Eight untreated patients with clinically definite multiple sclerosis were monitored monthly for changes in the numbers of cells positive for CD8 markers. and hence in the ratio of CD4: CD8 positive cells. Such changes were found not to be associated with changes in evoked potentials or clinical status.
Fatal or severely disabling cerebral infarction during hospitalization for stroke or transient ischemic attack, Six (1%) of 578 patients admitted for cerebral infarction or transient ischemic attack (TIA) suffered a fatal or severely disabling in-hospital cerebral infarction following a period of stabilization or improvement lasting more than 1 day. These infarctions were characterized by the sudden onset of stupor or coma and subsequent development of transtentorial herniation due to carotid or middle cerebral artery territory infarction. or widespread brain-stem infarction due to basilar occlusion. Only one patient survived. Four patients had large-vessel disease documented by Doppler. angiography. or at autopsy. Each of these six infarcts occurred during the morning hours. 4-9 days after the initial event. 3-8 days after initiation of intravenous heparin. and within 4-8 h after intravenous heparin had been discontinued. No coagulation abnormalities were documented. We believe that these cases indicate that among patients admitted for cerebral infarction or TIA. fatal or severely disabling in-hospital cerebral infarction after a period of stabilization or improvement may occur in patients having an initially mild to moderate clinical deficit. that those suffering large artery disease may be at greater risk. and that there may be a relationship between heparin withdrawal and cerebral infarction in some patients.
Unusual blink reflex with four components in a patient with periodic ataxia, Characteristic findings in blink reflex are reported in a 55-year-old female with periodic ataxia. The blink reflexes on the side ipsilateral to the stimulation consisted of four components with latencies of 11. 21. 35 and 47 ms. instead of the usual two components seen in normal subjects. On the contralateral side. the last three components were also present. The second component was different from the normal R2 response in that its latency was shorter than normal and it did not habituate by stimulation at a rate of 10 Hz. In addition. it was more affected by diazepam than the third or fourth components. It is considered that R2 may have consisted of three components and that a shorter latency of the second component could be explained by facilitation.
Cardiac transplantation in female Emery-Dreifuss muscular dystrophy, A young woman with humeroperoneal muscular dystrophy and contractures received a heart transplant for a severe dilated cardiomyopathy. Cardiac histopathology consisted of myocyte hypertrophy. interstitial fibrosis. and nuclear hyperchromaticity without mitochondrial abnormalities. Myopathy and heart disease were not clinically evident in her family. although three relatives had unexplained shortened Achilles tendons without weakness. Tendon contractures may be a partial expression of this myopathic disorder. suggesting an autosomal dominant inheritance with variable penetrance. A muscular dystrophy clinically similar to that of the Emery-Dreifuss (EDMD) type can thus occur in women. Rather than the cardiac arrhythmias typical of EDMD. a dilated cardiomyopathy may occur and present with severe congestive heart failure. This is the first report of cardiac transplantation in such a case.
Placement of esophageal stethoscope by acoustic criteria does not consistently yield an optimal location for the monitoring of core temperature, The esophageal stethoscope has evolved into a device for both acoustic and core temperature monitoring. To test whether routine placement according to acoustic criteria results in placement of the core temperature sensor in the region of contiguity between the esophagus and the heart. we determined the depth of placement electrocardiographically. All patients were undergoing nonthoracic elective operations requiring general anesthesia and tracheal intubation. First. we established that different observers selected the same esophageal depth within +/- 1 cm electrocardiographically. using the criterion of a symmetric biphasic P wave of maximal amplitude (7 patients). Then. in 30 more patients. we compared routine acoustic placements with the depths of the maximal-amplitude biphasic P wave. Stethoscopes placed according to acoustic criteria were within +/- 3 cm of P-wave depths in 15 of 30 patients. In the remaining patients. measured discrepancies ranged up to 13.5 cm. We conclude that the prevailing stethoscope design. with a thermistor at the tip. below the acoustic window. does not ensure placement of the thermistor within the optimal region for monitoring of core temperature. A modification in design that would take advantage of the reliability of electrocardiographic positioning is suggested.
Observer reliability in detecting surreptitious random occlusions of the monaural esophageal stethoscope, The esophageal stethoscope is used often during anesthesia to monitor ventilation and cardiac function. Deficiencies in observer vigilance may limit the effectiveness of this monitoring instrument. The aim of this study was to determine how long it took for an observer to detect a surreptitiously occluded monaural esophageal stethoscope in the setting of clinical anesthesia. During routine anesthesia. where an esophageal stethoscope was in use. a computer-guided device would artificially. silently. and at random time intervals. occlude the stethoscope tubing. Personnel using the stethoscope noted when they perceived the absence of stethoscope sounds. We studied 320 stethoscope occlusions in 32 patients. The time between stethoscope occlusion and detection was 34 +/- 59 seconds (mean +/- SD). Eighty-seven percent of detections were made in less than 60 seconds. However. 13% of detections were delayed for more than 60 seconds. and 2.3% for more than 240 seconds. While anesthesia personnel using an esophageal stethoscope could detect most stethoscope occlusions. failure to appreciate such episodes occurred in a small but significant number of cases. This suggests that the esophageal stethoscope has some definite limitations as a continuous monitor and that other monitoring techniques. such as oximetry. capnography. and ventilator disconnect alarms. as well as visual/tactile inspection of the patient. should be used as well.
Treatment of testicular cancer: a new and improved model, Testicular cancer has become a model for a curable neoplasm. Prior to the advent of cisplatin combination chemotherapy. standard chemotherapy consisted of dactinomycin. alone or in combination with chlorambucil and methotrexate. Disseminated germ cell tumors were chemosensitive to these older regimens. with a 50% objective response rate and a 10% to 20% complete remission rate; however. the cure rate was only 5% to 10%. In 1974. we began our initial cisplatin plus vinblastine plus bleomycin (PVB) chemotherapy. Thirty-three of 47 patients with disseminated germ cell tumors treated from 1974 to 1976 achieved a complete remission (CR). and an additional five (11%) were rendered disease-free with post-PVB resection of teratoma or carcinoma. Twenty-seven (57%) of these patients are continuously disease-free with a minimal follow-up of 13 + years. Thus. cisplatin-based chemotherapy produced a one-log increase in the cure rate compared with dactinomycin. A subsequent phase III study performed from 1976 to 1978 demonstrated that the vinblastine dosage could be reduced 25% from 0.4 mg/kg to 0.3 mg/kg with a reduction in toxicity but without any decrement in therapeutic efficacy. A third-generation PVB study from 1978 to 1981 documented that optimal cure rates were achieved with 12 weeks of induction therapy with PVB and that long-term maintenance therapy with vinblastine was unnecessary. In 1978. we initiated salvage therapy with cisplatin plus etoposide (VP-16) in patients not cured with PVB. and 25% of these patients were subsequently cured with this regimen. This represented the first time an adult solid tumor had been cured with a second-line regimen. In 1983. we began studies with third-line therapy with cisplatin plus ifosfamide combination chemotherapy. and even in this refractory setting. approximately 20% of patients are curable. From 1981 to 1984. we compared cisplatin plus VP-16 plus bleomycin (PVP16B) with PVB as first-line chemotherapy. There was a significant reduction in neuromuscular toxicity favoring the VP-16 arm. and furthermore. 78% of these patients were continuously disease-free compared with 66% with PVB. Approximately 75% of patients with disseminated germ cell tumors will be cured with PVP16B. and an additional 10% are curable with salvage chemotherapy. This represents the highest cure rate in any adult malignancy.
Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix, The prognostic effect of c-myc oncogene overexpression was assessed in a multivariate analysis of 93 patients with invasive carcinoma of the cervix. stage Ib. IIa. and IIb proximal. The treatment was based on the association of brachytherapy-colpohysterectomy and lymphadenectomy. Analysis of c-myc gene expression was done using Northern and slot blot hybridization techniques. Overexpression of c-myc (ie. levels at least three times the mean observed in normal tissues) was present in 33% of the tumors. The proportion of carcinomas with c-myc overexpression significantly increased with the size of the primary tumor (P = .04). No relationship was found between c-myc overexpression and the other clinical and histologic parameters. including the nodal status. The relative risk of relapse (overall. pelvic failure. distant metastases) was analyzed in a Cox's proportional hazards model. Three factors were significantly related to the risk of overall relapse when the multivariate analysis was performed. namely. the tumor size. the nodal status. and c-myc expression. A combination of c-myc expression and the nodal status provided a very accurate indication of the risk of relapse. Indeed. patients with negative nodes had a 3-year disease-free survival rate of 93% (95% confidence interval [Cl]. 79% to 98%) when c-myc was expressed at a normal level. whereas this rate was only 51% (95% Cl. 26% to 63%) when c-myc was overexpressed (log-rank test. P = .02). In addition. in the subgroup of patients with positive nodes. this rate was 44% (95% Cl. 25% to 77%) and 15% (95% Cl. 4% to 49%) when c-myc gene was expressed at normal level. or overexpressed. respectively. Finally. c-myc gene overexpression was. in the multivariate analysis. the first factor selected by the model regarding the risk of distant metastases.
Treatment of small-cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest Oncology Group pilot study, We designed an intensive. weekly treatment regimen for patients with small-cell lung cancer (SCLC) using six of the most active chemotherapeutic agents for this disease (doxorubicin [DOX]. cyclophosphamide [CTX]. vincristine [VCR]. etoposide [VP-16]. cisplatin [CDDP]. and methotrexate [MTX]). The goal of this program was to gain rapid. repetitive exposure to multiple. active drugs. Treatment was administered weekly for a total of 16 weeks. Seventy-six SCLC patients (limited disease. 34; extensive disease. 42) were treated. The overall complete plus partial response rate was 82%. Complete response rates of 47% and 38% were observed in patients with limited (LD) and extensive disease (ED). respectively. The median survivals for patients with LD and ED were 16.6 and 11.4 months. respectively. Toxicities were tolerable and were primarily hematologic. Twenty-six patients had one or more transient life-threatening toxicities. but only one patient developed a fatal toxicity. Eighty-four percent of the patients received 80% or greater of the intended protocol dosages over the entire 16-week treatment period. We conclude that this intensive. short-duration treatment regimen is at least as good as other "standard" regimens. and we are encouraged aged by the complete response rate and median survival in patients with ED SCLC.
Human tumor fluorouracil trapping: clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy pharmacokinetics, We previously reported that fluorouracil (5FU) accumulation and metabolism in human livers and tumors can be studied by in vivo nuclear magnetic resonance spectroscopy (NMRS). We have extended these observations by evaluating the pharmacokinetics of 5FU in the tumors of 11 patients with carcinoma of the breast. colon. endometrium. cervix. and kidney. using 19F-NMRS in a 1.5 Magnetom (Siemens Medical Systems. Cerrito. CA) magnetic resonance imaging unit (MRI). These NMRS measurements detected a long-lived tumor pool of 5FU in six of 11 tumors in our patients including carcinomas in the pelvis. breast. lung. and liver. The half-life (T1/2) of this tumor pool of "trapped" 5FU was 0.33 to 1.3 hours (20 to 78 minutes). much longer than the T1/2 of 5FU in blood (5 to 15 minutes). Neither the anabolites of 5FU (fluorinated nucleosides. nucleotides. 5FU-RNA. or 5FU-thymidylate synthase) nor the catabolites (eg. fluorobetaalanine [FBAL]) were detectable by 19F NMRS. Patient response to chemotherapy appeared to correlate with the extent of trapping of free 5FU in the human tumors: in the seven patients receiving 5FU. or 5FU or FUdR plus leucovorin. four of four patients whose tumors trapped 5FU responded to fluorinated pyrimidine chemotherapy. whereas three patients in whom there was a failure to detect tumor trapping were resistant to 5FU. We conclude that NMRS is clinically feasible. and enables investigators to study 5FU pharmacokinetics and metabolism in tumors in vivo. 19F-NMRS of 5FU allows for in vivo evaluation of 5FU metabolic modulation and might be able to guide therapeutic decisions.
Changes in the clearance of total and unbound etoposide in patients with liver dysfunction, The disposition of total and non-protein-bound etoposide was investigated in 21 cancer patients receiving etoposide and cisplatin combination chemotherapy. Etoposide plasma concentrations were determined using a specific high-performance liquid chromatography (HPLC) method. and etoposide plasma protein binding was determined by equilibrium dialysis. The patients had a wide range of renal function (creatinine clearance. 32 to 159 mL/min/m2) and hepatic function (total bilirubin range. 0.3 to 21.5 mg/dL; aspartate aminotransferase [AST] range. 14 to 415 IU/L; serum albumin range. 2.7 to 4.1 g/dL). The mean etoposide total systemic clearance was not different in 15 patients with total bilirubin less than 1.0 mg/dL versus six patients with total bilirubin 1.1 to 21.5 mg/dL (18.7 +/- 5.9 mL/min/m2 v 26.4 +/- 10.7 mL/min/m2; t-test P = .06). with a trend toward higher total clearance in the patients with abnormal bilirubin values. However. the mean clearance of unbound etoposide was significantly lower in patients with increased total bilirubin (220 +/- 90 mL/min/m2 v 135 +/- 61 mL/min/m2; t-test P = .027). The fraction of etoposide unbound (fu) in plasma was significantly higher in patients with increased bilirubin (9% +/- 3% v 27% +/- 15%; t-test P = .002). explaining the trend toward higher total clearance in these patients. Etoposide clearance (total or unbound) in the 14 patients with measurable hepatic metastases was not different from the clearance in the seven patients without hepatic metastases. This study provides an explanation for why patients with increased bilirubin do not have lower total systemic clearance of etoposide. and indicates that such patients have a higher exposure to unbound etoposide. The results of ongoing pharmacodynamic studies of total and unbound etoposide in patients with increased bilirubin will determine the clinical relevance of altered etoposide protein binding.
Clinical evaluation of a side entry access port: a novel dual-lumen venous access device, The initial clinical experience with a low-profile side entry access (SEA) dual-lumen implantable venous access port for cancer chemotherapy administration is summarized in this report. The catheter material is polyurethane. The overall experience in 35 patients in this study was a total of 6.224 patient days. with a mean of 178 days per patient. A variety of chemotherapeutic agents. biologic response modifiers. and antibiotics were administered. In 26% of the patients. the device chambers were in simultaneous use during the treatment period. A 6% incidence of clinical subclavian vein thrombosis was noted. There was no infectious complications. Inconsistencies in blood withdrawal and temporary catheter dysfunction were comparable to other access ports in clinical use. The novel design of this side entry port and the catheter material of low thrombogenicity make this device a good option in patients requiring a low-profile system and dual access. Nursing staff should be made aware of the side entry design and that in-service training for accessing the septum is required in centers where such devices are not routinely used.
A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver, Over a 4-year period (1982 to 1986). 91 patients with solitary or multiple metastases from colorectal cancer were stratified. based on findings at laparotomy. to one of three groups and then prospectively randomized to one of two treatment arms within each group. Group A patients had solitary resectable metastases. group B patients had multiple. resectable metastases. and group C patients had multiple. unresectable metastases. Patients were randomized to one of two treatment arms within a group: group A-arm A1: resection only. arm A2: resection and continuous hepatic artery infusion (CHAI) of fluorodeoxyuridine (FUdR); group B-arm B1: resection and CHAI. arm B2: CHAI only; group C-arm C1: CHAI. arm C2: systemic fluorouracil followed by CHAI. Median time to failure (TTF) was 31.8. 11.1. and 8.8 months for groups A. B. and C. respectively. Arm A2 had an improved TTF when compared with arm A1 (P = .03). Median survival correlated with extent of disease and was 37.3. 22.4. and 13.8 months for groups A. B. and C. respectively. Survival was not changed by treatment variation (arms) within each group. Two- and 5-year cumulative survivals for groups A. B. and C were 72.7% and 45.4%; 45.8% and 16.7%; and 31.7% and 3.2%. respectively. In patients with multiple metastases (groups B and C). those patients whose original tumor was a Dukes' B had a significantly improved TTF and survival over those patients whose tumor was a Dukes' C (P less than or equal to .02).
The unique aspects of acute promyelocytic leukemia, Acute promyelocytic leukemia (APL) accounts for approximately 10% of cases of acute myeloid leukemia (AML). Distinctive features of this disorder at the time of diagnosis include leukopenia coexisting with a marrow replaced with granulated dysplastic promyelocytes. disseminated intravascular coagulopathy. lack of Ia (HLA-DR) antigen expression. and translocation between the long arms of chromosomes 15 and 17 (t[15;17]). Heparin is widely but not universally used to interfere with the coagulopathy during the initial phases of treatment. Serial bone marrow examinations during the induction period demonstrate the achievement of remission despite the persistence of malignant-appearing promyelocytes. Patients with APL are generally younger than those with other subtypes of AML. have a 70% to 80% likelihood of entering remission. and are thought to have a more favorable prognosis than other individuals with AML. Remission may be achieved with a conventional anthracycline-cytarabine combination. anthracycline alone. or. apparently. all-trans retinoic acid. Genes potentially important in myeloid differentiation such as granulocyte colony-stimulating factor (G-CSF) and myeloperoxidase are located close to the breakpoint in the t(15;17) but have not been conclusively shown to be rearranged in the translocation. A better understanding of the unique aspects of APL may well shed light on the pathogenetic processes of AML.
Intraperitoneal yttrium-90-labeled monoclonal antibody in ovarian cancer, From March 1987 to March 1988. a phase I to II study was carried out in 25 patients with ovarian cancer. They received escalating doses of intraperitoneally (IP) administered yttrium-90 (Y-90)-labeled monoclonal antibody. HMFG1. against a tumor cell-surface antigen. Myelosuppression prevented an escalation of the administered Y-90 activity above 25 mCi. Y-90-labeled antibody was absorbed from the peritoneal cavity into the circulation. Maximum blood Y-90 activity was observed 40 hours after the IP injection with a mean of 21% of the injected activity (range. 14.2% to 26.4%) in the circulation. The radiation dose the bone marrow received from circulating Y-90-labeled antibody (the blood radiation dose) was calculated by applying the Medical Internal Radiation Dose (MIRD) formulation to the measured Y-90 activity in patients blood. Myelosuppression occurred following calculated blood radiation doses to bone marrow of only 10 to 30 cGy. The excessive myelosuppression following such modest radiation doses from circulating Y-90-labeled antibody could be explained by the uptake of Y-90 by bone. In an attempt to reduce bone absorption of Y-90. seven patients received an intravenous (IV) infusion of EDTA (Sinclair Pharmaceuticals Ltd. Godalming. United Kingdom). This increased the urinary excretion of Y-90 from a mean of 11.1% to 32.3% of the injected activity (P = .0001). Fourteen patients had assessable tumor at laparoscopy. Tumor regression was observed in one patient. and palliation of ascites in a further patient.
Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma, Durable complete remissions (CRs) can be achieved in patients with diffuse large-cell lymphoma (DLCL) with multidrug chemotherapy. The length of time to reach CR may be predictive of treatment outcome. However. defining CR by chest radiograph or computed tomography (CT) is often difficult since residual abnormalities do not always indicate residual disease. We have prospectively evaluated the ability of gallium-67 citrate (Ga-67) imaging to define residual disease and predict outcome in 37 consecutive patients with DLCL. Patients received 296 to 370 megabecquerels (MBq) Ga-67 and were imaged prior to. following cycles 4 to 6. and at completion of intensive chemotherapy. Ga-67 scan results were correlated with radiographic studies. Seventeen of 37 patients (46%) showed persistent. abnormal Ga-67 uptake halfway through chemotherapy. Of these. four were in CR. 11 were in partial remission (PR). and two showed no change in tumor size. At follow-up. 10 (59%) have died (three who were scored as CR and seven who were in PR halfway through therapy). two are alive with active tumor. one relapsed and survives following bone marrow transplant. and four (three in PR and one in CR at the therapeutic halfway point) are without disease at a median of 28 months from presentation. Of the 20 patients who were Ga-67-negative halfway through therapy. 11 were in CR and nine were in PR. Five of 20 patients (25%) have died. Three. in radiographic CR died at 11. 26. and 28 months. and two in radiographic PR died at 15 and 17 months. One patient is alive with active tumor. and 14 patients (70%) are alive without disease at a median of 34 months from presentation. Ga-67 imaging proved to be an excellent indicator of residual viable tumor; a positive scan halfway through therapy predicted for a poor outcome and may well justify a change in treatment.
Pediatric osteosarcoma: therapeutic strategies, results, and prognostic factors derived from a 10-year experience, Ninety-eight pediatric patients were treated with three separate protocols (Treatment and investigation of Osteosarcoma [TIOS] I. II. and III) and 47 developed recurrent disease (metastases and/or local recurrence). Actuarial overall disease-free survival (hereafter designated survival) was 43%. Over 90% of the patients were treated initially with preoperative intraarterial cisplatin (CDP). Postoperative chemotherapeutic regimens comprised high-dose methotrexate with leucovorin rescue (MTX-CF). Adriamycin [( ADR] doxorubicin; Adria Laboratories. Columbus. OH). and cyclophosphamide. Primary definitive treatment comprised amputation or limb salvage (TIOS I and TIOS III). Patients treated with preoperative CDP and surgery (TIOS I and III) had a 62% survival. Patients in TIOS II refused surgical extirpation; they were treated exclusively with chemotherapy and had a 23% survival. Survival in patients treated with amputation was 55% and limb salvage 58%. Prognostic factors considered significant in relation to development of pulmonary metastases comprised tumor burden (P = .04) and the percentage of tumor necrosis induced by preoperative chemotherapy (P = .01). Histopathologic subtype was marginally significant: chondroblastic was more favorable as opposed to osteoblastic (P = .05). These findings are compared with results and prognostic factors published in the literature.
Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma, We conducted a phase II clinical trial of fluorouracil (5FU) and recombinant interferon alfa-2a (rIFN alpha-2a) in 52 previously untreated patients with bidimensionally measurable metastatic colorectal cancer. During week 1. 5FU was administered as a continuous intravenous infusion. 750 mg/m2/d for 5 consecutive days. Intravenous bolus administration of 5FU 750 mg/m2 was given weekly for 7 weeks starting on day 12. rIFN alpha-2a (Roferon; Hoffman-LaRoche. Nutley. NJ). 9 x 10(6) U. was administered subcutaneously three times weekly during weeks 1 to 8. Patients were evaluated for response on week 9. Of 52 patients enrolled in the study. 51 were assessable for toxicity. and 45 were assessable for response. Fifteen patients experienced partial response. and one patient achieved a clinical complete response for an overall response rate of 35% (95% confidence interval [CI]. 22%. 50%). Median duration of response is 7.5 months (range. 4 to 11 months). Seventy percent of patients entered on the study are alive with a median follow-up duration of 7 months. Twenty-five percent of patients developed grade 4 toxicity. and 82% developed grade 3 toxicity. One drug-related death in the presence of sepsis was reported. and two treatment-related seizures occurred. Our experience with this schedule produced a lower response rate with greater toxicity than previously reported. Current randomized trials comparing this schedule of 5FU with rIFN alpha-2a to 5FU plus folinic acid (leucovorin) or single-agent 5FU may determine its role in the treatment of advanced colorectal carcinomas.
Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial, Between 1976 and 1985. 391 patients (202 premenopausal. 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide. methotrexate. and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years. both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS. P less than .001; S. P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age. with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years. development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS. P = .9; S. P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.
Node-negative breast cancer: prognostic subgroups defined by tumor size and flow cytometry, Adjuvant systemic therapy for women with node-negative breast cancer is most easily justified for those patients at highest risk of relapse. We have examined the impact of tumor size. histologic grade. estrogen receptor (ER) status. tumor ploidy. and S-phase fraction (SPF) on relapse-free survival (RFS) for 169 patients with node-negative breast cancer in order to identify groups of patients at high and low risk of relapse. Patients with small tumors (less than or equal to 1.0 cm) had a significantly better RFS than those with larger tumors (P = .005). with 96% remaining relapse-free at 5 years. Patients with tumors less than or equal to 1.0 cm were thus excluded from analysis when attempting to define a group with a poor prognosis. Within the group of patients with tumors greater than 1.0 cm. tumor ploidy (P = .63). ER status (P = .3). or progesterone receptor (PgR) status (P = .24) did not predict for RFS. Patients with grade 1 or 2 infiltrating ductal tumors had a significantly better prognosis than those with grade 3 tumors (P = .04). The prognostic factor that gave the widest separation between subgroups. however. was SPF. Patients whose tumors were greater than 1.0 cm with an SPF less than or equal to 10% had a 5-year RFS of 78% compared with a 5-year RFS of 52% for those with an SPF greater than 10% (P = .006). We have combined tumor size and SPF to identify three prognostic groups: (1) tumor less than or equal to 1.0 cm. 5-year RFS 96%; (2) tumor greater than 1.0 cm plus SPF less than or equal to 10%. 5-year RFS 78%; 3) tumor greater than 1.0 cm plus SPF greater than 10%. 5-year RFS 52%. These prognostic groupings may help identify patients most suitable for adjuvant therapy.
The relative value of conventional staging procedures for developing prognostic models in extensive-stage small-cell lung cancer, Published prognostic models for small-cell lung cancer (SCLC) have either combined limited- and extensive-stage patients or have not included standard anatomic staging information to assess the relative value of the knowledge of specific sites and number of sites of metastases in predicting survival in extensive-stage disease. We studied 136 extensive-stage patients in whom traditional staging procedures were performed and in whom other previously demonstrated significant pretreatment variables were determined. Using the Cox proportional hazards model. when all data were included. three variables were significant: performance status (PS) (P = .0001). number of sites of metastases (P = .0010). and age (P = .0029). A prognostic algorithm was developed using these variables. which divided the patients into three distinct groups. When the anatomic staging data were omitted. the serum albumin (P = .0313) was the only variable in addition to PS (P = .0001) and age (P = .0064) that was significant. An alternative algorithm using these three variables was nearly as predictive as the original. Therefore. in extensive-stage patients. reasonable pretreatment prognostic information can be obtained without using the number or specific sites of metastases as variables once the presence of distant metastases has been demonstrated.
Phase I clinical and pharmacologic study of intraperitoneal cisplatin and fluorouracil in patients with advanced intraabdominal cancer, Fluorouracil (5-FU) and cisplatin display marked therapeutic synergy in preclinical models and are effective in the treatment of a number of solid tumors when combined and administered intravenously (IV). Each drug has also been administered intraperitoneally (IP) and displays a favorable pharmacologic profile and acceptable clinical toxicity. We therefore undertook a phase I study to determine the feasibility and toxicity of combination IP chemotherapy with these agents. Thirty-one patients with histologically documented malignancy confined to the peritoneal space were treated with cisplatin 90 mg/m2 mixed with 5-FU in 2 L of lactated Ringer's solution and given IP for 4 hours every 28 days. Cohorts of at least three patients received starting 5-FU concentrations ranging from 5 mmol/L (1.300 mg in 2 L) to 20 mmol/L. The dose-limiting toxicity was neutropenia with a median granulocyte nadir of 156 cells per microliter occurring at a 5-FU dose of 20 mmol/L. Intrapatient escalation of the 5-FU dose was permitted and 15 cycles of chemotherapy were delivered at 5-FU concentrations greater than 20 mmol/L. the highest concentration being 30.7 mmol/L (8 g of 5-FU in 2L). Other toxicities included mild to moderate nausea during all cycles of therapy. vomiting in 54% of cycles. and diarrhea in 15% of cycles. Abdominal pain. renal dysfunction. peripheral neuropathy. and oral mucositis occurred infrequently and were not related to the 5-FU dose. Peritoneal fluid and plasma 5-FU concentrations were measured by high-performance liquid chromatography (HPLC) in selected patients. Mean peak plasma 5-FU concentrations ranged from 6.19 mumol/L to greater than 60 mumol/L. and peritoneal fluid to plasma 5-FU area under the curve (AUC) ratios ranged from 85 to 1.150. Nine of 15 patients with nonbulky disease had resolution of malignant ascites or at least a 50% reduction of peritoneal studding by tumor at repeat laparotomy. We conclude that combination IP chemotherapy with cisplatin and 5-FU is technically feasible and has acceptable clinical toxicity and a favorable pharmacologic profile. The recommended starting 5-FU dose for phase II trials is 3.900 mg mixed with 90 mg/m2 of cisplatin in 2 L of isotonic fluid.
Drug-induced DNA damage and tumor chemosensitivity, Cytotoxic drugs act principally by damaging tumor-cell DNA. Quantitative analysis of this interaction provides a basis for understanding the biology of therapeutic cell kill as well as a rational strategy for optimizing and predicting tumor response. Recent advances have made it possible to correlate assayed DNA lesions with cytotoxicity in tumor cell lines. in animal models. and in patients with malignant disease. In addition. many of the complex interrelationships between DNA damage. DNA repair. and alterations of gene expression in response to DNA damage have been defined. Techniques for modulating DNA damage and cytotoxicity using schedule-specific cytotoxic combinations. DNA repair inhibitors. cell-cycle manipulations. and adjunctive noncytotoxic drug therapy are being developed. and critical therapeutic targets have been identified within tumor-cell subpopulations and genomic DNA alike. Most importantly. methods for predicting clinical response to cytotoxic therapy using both in vitro markers of tumor-cell sensitivity and in vivo measurements of drug-induced DNA damage are now becoming a reality. These advances can be expected to provide a strong foundation for the development of innovative cytotoxic drug strategies over the next decade.
Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions, Among 91 patients with unruptured intracranial arteriovenous malformations (AVM's). 16 patients had 26 unruptured intracranial saccular aneurysms. An actuarial analysis showed the risk of intracranial hemorrhage among patients with coexisting aneurysm and AVM to be 7% per year at 5 years following diagnosis compared to 1.7% for patients with AVM alone. The difference in length of survival free of hemorrhage was significant (log-rank. p less than 0.0007). Several angiographic and clinical parameters were investigated to better understand the relationship of these lesions. The aneurysms occurred in similar percentages in patients with small. medium. and large AVM's. Twenty-five aneurysms were on arteries feeding the malformation system. almost equally distributed proximally and distally. Eleven aneurysms were atypical in location. and all arose from primary or secondary branch feeders to the malformation; 24 were on enlarged feeding arteries. Eleven (16%) of the 67 patients with high-flow AVM's had associated aneurysms. compared with five (21%) of the 24 patients with low-flow AVM's. Four (16%) of 25 low-shunt malformations and 12 (18%) of 65 high-shunt malformations had associated aneurysms. All five aneurysms associated with low-shunt malformations were on a direct arterial feeder of the malformation. These data suggest that the intracranial AVM's predispose to aneurysm formation within AVM feeding systems and that the mechanism is not simply based upon the high blood flow or high arteriovenous shunt in these systems.
Characterization of periventricular edema in normal-pressure hydrocephalus by measurement of water proton relaxation times, The magnetic resonance longitudinal relaxation time (T1) and transverse relaxation time (T2) of the water proton of the periventricular white and cortical gray matter were measured for 17 control patients and 21 patients with suspected normal-pressure hydrocephalus (NPH). Of the latter group. 14 showed good response to shunting (true-NPH group) and seven showed no response (false-NPH group). In the true-NPH group. both the T1 and the T2 of the periventricular white matter were significantly prolonged compared to the control values. and slowly shortened after cerebrospinal fluid (CSF) shunting. The true-NPH group showed significantly longer T1 and T2 of the white matter than did the false-NPH group. The T1 and T2 of the white matter were longer than those of the gray matter in this group. which was the reverse of the relationship observed in the control patients. In the white matter of the false-NPH group. there was a significant prolongation of T1 only; no difference was seen in the T2 compared to control values. There was no change in either T1 or T2 of this region after CSF shunting. The false-NPH group showed no significant difference in either T1 or T2 between the white and the gray matter. There was no difference in either T1 or T2 of the gray matter between the false-NPH and control groups or between preshunt and postshunt measurements in each patient group. It is suggested that a distinction between true- and false-NPH. which cannot be made from the radiographic appearance alone. may be possible from measurement of relaxation times. The mechanism of varied relaxation behavior between two entities may be explained by a difference in properties of the biological water and its environment.
Systems analysis of cerebrovascular pressure transmission: an observational study in head-injured patients, In an observational study in head-injured patients. cerebrovascular pressure transmission was investigated using a systems analysis approach whereby the blood pressure (BP) waveform was used as a measure of an input stimulus to the cerebrovascular bed (CVB) and the intracranial pressure (ICP) waveform as the response to that stimulus. The transfer function is a measure of how much pressure is transmitted through the CVB at a given frequency and is calculated using Fourier analysis of the pressure waveforms. The transfer function allows quantification of the pressure transmission performance of the CVB. thus providing a basis for comparison between normal and abnormal function. Fifteen hundred samples of ICP and BP waveforms were collected from 30 head-injured patients via microcomputer. Off-line spectral analysis of the waveform database revealed four main classes of transfer function: those with an overall flat transfer function (curve type 1); those with an elevated low-frequency response (curve type 2); those with an elevated high-frequency response (curve type 3); and those exhibiting both an elevated low- and high-frequency response (curve type 4). Curve types 2 and 4 were most often associated with raised ICP (greater than 20 mm Hg). whereas curve types 1 and 3 were most often affiliated with ICP less than 15 mm Hg. Studies of this type may provide insight into the pathophysiology of the CVB and ultimately aid in the prediction and treatment of raised ICP.
Motility factor produced by malignant glioma cells: role in tumor invasion, To better understand the cellular mechanism of tumor invasion. the production of a cell motility-stimulating factor by malignant glioma cells was studied in vitro. Serum-free conditioned media from cultures of rat C6 and human T98G cell lines contained a factor that stimulated the locomotion of the producer cells. This factor was termed the "glioma-derived motility factor." The glioma-derived motility factor is a heat-labile protein with a molecular weight greater than 10 kD and has relative stability to acid. The factor showed not only chemotactic activity but also chemokinetic (stimulated random locomotion) activity in the two types of glioma cells studied. Although glioma-derived motility factors in conditioned media obtained from two different cell origins are likely to be the same. chemokinetic migration of T98G cells to their conditioned medium was much stronger than that of C6 cells to theirs. Coincubation of cells with cytochalasin B. which disrupts the assembly of cellular actin microfilaments. almost completely inhibited the cell migration stimulated by glioma-derived motility factor. Cytochalasin B also induced marked alterations in cell morphology. including cell retraction and arborization. while the drug did not affect cell attachment to culture dishes. These results indicate that glioma cells produce a motility factor which may play a role particularly when tumor cells are detached and migrate away from the original tumor mass. thus promoting tumor invasion. Also. glioma cell migration stimulated by the motility factor requires the normal organization of cytoskeletons such as actin microfilaments.
Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury, An increase in extracellular K+ concentration ([K+]c) of the rat hippocampus following fluid-percussion concussive brain injury was demonstrated with microdialysis. The role of neuronal discharge was examined with in situ administration of 0.1 mM tetrodotoxin. a potent depressant of neuronal discharges. and of 0.5 to 20 mM cobalt. a blocker of Ca++ channels. While a small short-lasting [K+]c increase (1.40- to 2.15-fold) was observed after a mild insult. a more pronounced longer-lasting increase (4.28- to 5.90-fold) was induced without overt morphological damage as the severity of injury rose above a certain threshold (unconscious for 200 to 250 seconds). The small short-lasting increase was reduced with prior administration of tetrodotoxin but not with cobalt. indicating that neuronal discharges are the source of this increase. In contrast. the larger longer-lasting increase was resistant to tetrodotoxin and partially dependent on Ca++. suggesting that neurotransmitter release is involved. In order to test the hypothesis that the release of the excitatory amino acid neurotransmitter glutamate mediates this increase in [K+]c. the extracellular concentration of glutamate ([Glu]c) was measured along with [K+]c. The results indicate that a relatively specific increase in [Glu]c (as compared with other amino acids) was induced concomitantly with the increase in [K+]c. Furthermore. the in situ administration of 1 to 25 mM kynurenic acid. an excitatory amino acid antagonist. effectively attenuated the increase in [K+]c. A dose-response curve suggested that a maximum effect of kynurenic acid is obtained at a concentration that substantially blocks all receptor subtypes of excitatory amino acids. These data suggest that concussive brain injury causes a massive K+ flux which is likely to be related to an indiscriminate release of excitatory amino acids occurring immediately after brain injury.
Antigen related to cell proliferation in malignant gliomas recognized by a human monoclonal antibody, A human monoclonal antibody (CLN-IgG) was produced from a human-human hybridoma derived from lymphocytes of a patient with cervical carcinoma. The reactivities of this antibody with various human glioma tissues and cultured glioma cells and the characterization of the antigen recognized by CLN-IgG on malignant glioma cells were analyzed and reported. CLN-IgG reacted with various human glioma cells and glioma tissues. especially glioblastoma. but did not react with normal brain tissues or fetal brain tissues. A large amount of antigen recognized by CLN-IgG was expressed on cell membranes of undifferentiated glioma cells and of glioma cells at the G2/M tumor growth phase in cycling cells. Antigen recognized by CLN-IgG was detected in only one of seven samples of cyst fluid. and was not detected in 27 serum samples or 18 samples of cerebrospinal fluid from glioma patients. CLN-IgG exhibited antibody-dependent cell cytotoxicity against U-25 1 MG glioma cells and primary cultured cells of glioblastomas and anaplastic astrocytomas. These data suggest that the antigen recognized by CLN-IgG might be related to cell proliferation in malignant gliomas. Thus. CLN-IgG might be useful for immunotherapy or immunoimaging of malignant gliomas.
Cerebrovascular and metabolic effects on the rat brain of focal Nd:YAG laser irradiation, To investigate the effects of focal neodymium:yttrium-aluminum-garnet (Nd:YAG) laser irradiation (lambda = 1060 nm) on regional cerebral blood flow. cerebral protein synthesis. and blood-brain barrier permeability. the parietal brain surface of 44 rats was irradiated with a focused laser beam at a constant output energy of 30 J. Survival times ranged from 5 minutes to 48 hours. Laser irradiation immediately caused well-defined cortical coagulation necrosis. Within 5 minutes after unilateral irradiation. 14C-iodoantipyrine autoradiographs demonstrated severely reduced blood flow to the irradiation site and perilesional neocortex. but a distinct reactive hyperemia in all other areas of the forebrain. Apart from a persistent ischemic focus in the vicinity of the cortical coagulation necrosis. blood flow alterations in remote areas of the brain subsided within 3 hours after irradiation. Autoradiographic assessment of 3H-tyrosine incorporation into brain proteins revealed rapid onset and prolonged duration of protein synthesis inhibition in perifocal morphologically intact cortical and subcortical structures. Impairment of amino acid incorporation proved to be completely reversible within 48 hours. Immunoautoradiographic visualization of extravasated plasma proteins using 3H-labeled rabbit anti-rat immunoglobulins-showed that. up to 1 hour after irradiation. immunoreactive proteins were confined to the neocortex at the irradiation site. At 4 hours. vasogenic edema was present in the vicinity of the irradiation site and the subcortical white matter. and. at later stages (16 to 36 hours). also extended into the contralateral hemisphere. Although this was followed by a gradual decrease in labeling intensity. resolution of edema was still not complete after 48 hours. Analysis of sequential functional changes in conjunction with morphological alterations indicates that the evolution of morphological damage after laser irradiation does not correlate with the time course and spatial distribution of protein synthesis inhibition or vasogenic edema. Although the central coagulation necrosis represents a direct effect of radiation. the final size of the laser-induced lesion is determined by a delayed colliquation necrosis due to persistent perifocal ischemia. Extent and severity of ischemia in a zone with initial preservation of neuroglial cells can be explained by the optical properties of the Nd:YAG laser; extensive scattering of light within brain parenchyma associated with a high blood-to-brain absorption ratio selectively affects blood vessels outside the irradiation focus.
Long-term evaluation of hemiparkinsonian monkeys after adrenal autografting or cavitation alone, Autografts of adrenal medulla were implanted into preformed cavities in the caudate nuclei of four rhesus monkeys with hemiparkinsonism induced by 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP). Five other hemiparkinsonian monkeys underwent caudate cavitation. but received no tissue implant. All of the animals had marked bradykinesia of the affected arm and stable apomorphine-induced turning before cavitation or implantation. Moderate behavioral recovery was seen in all five monkeys with cavitation and two of the three monkey with long-term adrenal autografts (the fourth adrenal recipient was sacrificed 10 days after grafting). The improvement occurred months after the procedure and was not as early or as complete as that seen after fetal dopaminergic grafts. Surviving adrenal tissue was found only in the animal that showed no behavioral recovery. The other two adrenal autograft recipients (with no surviving adrenal medulla) and all of the animals with cavitation had ingrowth of dopaminergic fibers from the area olfactoria and nucleus accumbens into the caudate. oriented toward the cavity. These findings show that the mechanism of improvement after adrenal medullary implants for parkinsonism is not dopamine secretion by chromaffin cells. but may be related to the sprouted host fibers. The results also indicate that the limited recovery after adrenal implants in parkinsonian patients may be a result of the cavitation. and not necessarily the result of tissue implantation.
Biologically inert synthetic dural substitutes. Appraisal of a medical-grade aliphatic polyurethane and a polysiloxane-carbonate block copolymer, Two types of artificial membranes. a medical-grade aliphatic polyurethane and a polysiloxane-carbonate block copolymer. were tested as substitutes for dura in 24 and 12 rabbits. respectively. The films were placed either epidurally. subdurally. or as dural grafts in equal subgroups of animals. The postoperative course was uneventful with no manifestations of convulsive disorder or cerebrospinal fluid leak. The animals were sacrificed 3. 6. or 9 months after implantation of the artificial membranes. Both types of artificial membranes were easily removed from the underlying nervous and the other surrounding tissues. The histological examination failed to reveal adhesions. neomembrane formations. or any type of foreign body reactions to the polyurethane film. The implantation of the polysiloxane-carbonate film caused no reaction when it was applied epidurally. As a dural graft. the polysiloxane-carbonate copolymer induced the formation of a thin neomembrane of one to two layers of fibroblasts which formed a watertight seal of the dural defect. A similar thin neomembrane was found to encase this artificial membrane in the group of animals in which it was implanted subdurally. There was no foreign body reaction to the polysiloxane-carbonate film. The authors conclude that these materials hold promise as dural substitutes or in the prevention of spinal dural scarring. and should be evaluated clinically.
Spontaneous regression of giant arteriovenous fistulae during the perinatal period. Case report, A unique case of spontaneous regression of giant arteriovenous fistulae during infancy is described in this report. A female infant. the product of normal labor and delivery. demonstrated severe ventriculomegaly and an intracranial hemorrhage at birth. Cerebral angiography at 5 days of age revealed several large fistulae fed by the anterior and middle cerebral arteries draining into the deep venous system through a dilated internal cerebral vein and ectatic vein of Galen. Two days following the angiogram. a second intracranial hemorrhage occurred. Active hydrocephalus developed over the next 6 months and was treated with ventriculoperitoneal shunting. When the child was 8 months of age. angiography failed to demonstrate the fistulae. It was postulated that pressure effects from the intracranial hematoma and long-standing intracranial hypertension as well as stenosis in the anomalous venous outflow resulted in vascular stasis. venous thrombosis. and selective arterial occlusion. Hydrocephalus was a result of the compression of the intraventricular foramina by dilated embryonic vessels. This anomaly. predominantly involving the anterior circulation. may be homologous to the vein of Galen aneurysm in the posterior circulation.
Quantification of the reversibility of stress-induced thallium-201 myocardial perfusion defects: a multicenter trial using bull's-eye polar maps and standard normal limits, A multicenter trial was performed on 140 patients from four centers to determine the accuracy of quantitative analysis of stress/delayed thallium-201 myocardial tomograms using normal limits to assess the relative amount of reversibility of stress-induced defects. The patients were found to have 85 fixed and 124 reversible defects. as determined by visual interpretation. Reversibility bull's-eye polar maps were compared to gender-matched normal limits from 36 normals. Regions were identified as reversible if their normalized difference between stress and 4 hr greater than 1.5 s.d.s. from the mean normal limits. Overall agreement between experts at multicenter sites and reversibility maps was 73% for reversible defects and 80% of fixed defects. Sensitivity in detecting reversibility was highest for the left circumflex (88%) and lowest for the right coronary (60%). These results indicate that reversibility polar maps and normal limits offer an objective. accurate technique for determining the reversibility of stress-induced perfusion defects.
Limited precision of lumbar spine dual-photon absorptiometry by variations in the soft-tissue background, The estimation error due to variations in soft-tissue baseline in lumbar bone mineral content (BMC) measured by dual-photon absorptiometry (DPA) was calculated with a new method of automatic baseline subtraction. In water phantom measurements. the s.d. of the soft-tissue (ST) baseline matched closely (r = 0.98) to the random error. calculated using 44 keV and 100 keV count rates and the directly determined baseline variations. In 21 volunteers and in 70 patients with osteoporosis. the ST variations were larger than the expected random error. revealing a source of error related to the inhomogeneity of soft tissue. The estimation error in BMC caused by ST variations was 0.7% in healthy subjects (mean BMC 40.5 gHA) and 1.5% in patients (mean BMC = 26.4 gHA). These results indicate that ST-related errors are an important limit to the precision of lumbar DPA measurements.
Immunoscintigraphy of ovarian cancer with indium-111-labeled OV-TL 3 F(ab')2 monoclonal antibody, The safety and diagnostic accuracy of immunoscintigraphy with the indium-111-labeled monoclonal antibody OV-TL 3 F(ab')2(111In-OV-TL 3 F(ab')2) for diagnosis and follow-up of ovarian cancer was prospectively studied in 31 patients. Planar and SPECT scintigraphy were performed up to 4 days after i.v. injection of 140 MBq 111In-OV-TL 3 F(ab')2. Surgical evaluation was possible in 22 out of 31 patients. Imaging results were compared with X-ray computed tomography. ultrasound. and CA 125 serum level using the histologically confirmed surgical findings as a "gold standard." Apart from a transient rash observed in two patients. no other immediate or delayed adverse reactions were observed. Within the surgically evaluated group. ovarian cancer lesions were detected in 16 out of 17 patients (94%). Of 45 distinct tumor deposits found at operation. 67% were detected and localized with immunoscintigraphy while X-ray computed tomography and ultrasound visualized 53% and 23%. respectively.
A comparative study of renal scintigraphy and clearance with technetium-99m-MAG3 and iodine-123-hippurate in patients with renal disorders, The aim of this study was to compare kit prepared technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) with our routine radiopharmaceutical. iodine-123-hippurate our routine radiopharmaceutical. iodine-123-hippurate ([123I]OIH) for renal dynamic scintigraphy. Seventeen patients with different nephrologic disorders or hypertension were first studied with OIH and then reinvestigated with MAG3 2-8 days later. Renal MAG3 gamma camera images were almost identical with those of OIH except for higher (p less than 0.01) liver-to-background ratios at 20 min postinjection. irrespective of kidney function. Urinary peristalsis was visible longer and more clearly in the MAG3 studies. MAG3 and OIH renograms showed identical relative kidney uptake (r = 0.99). but elimination of MAG3 from the kidneys was slower (p less than 0.01). The plasma clearance of MAG3 was lower than that of OIH. but correlated (r = 0.92) significantly. The plasma distribution volume and content in blood cells was lower (p less than 0.01). but the binding of MAG3 to plasma proteins was higher. 90%. as compared with 74% for OIH. p less than 0.01. Urinary excretion expressed as a percent of the given dose 60 min after injection was the same for the two substances. Thus. there are some significant differences in the renal handling. plasma distribution. and cell penetration between MAG3 and [123I]OIH. MAG3. however. seems to have particular qualifications as a radionuclide for dynamic renal scintigraphy. especially in patients who require acute investigations or in those with low renal function.
The potential of 2-deoxy-2[18F]fluoro-D-glucose (FDG) for the detection of tumor involvement in lymph nodes, To assess the potential of FDG for PET imaging of nodal tumor metastases. we evaluated its uptake into normal lymph nodes. tumor-involved lymph nodes. and subcutaneous tumor xenografts in rodents. Normal lymph nodes in mice and rats accumulate FDG moderately. developing node/blood ratios of 1.3-11.9/1 at 2 hr following i.v. injection. By contrast. FDG given subcutaneously to healthy Sprague Dawley rats developed very high normal draining lymph node/blood ratios (272/1) versus 7.7/1 by i.v. injection. In nude mice. subcutaneous human ovarian cancer xenografts had 1.27-fold more uptake relative to blood than did normal popliteal lymph nodes. Subcutaneous tumor xenografts of rat breast cancer developed tumor/normal node uptake ratios of 4.91 +/- 0.43/1 and tumor/blood ratios of 6.6 +/- 0.9 at 2 hr postinjection. Mouse nodes involved with 38C13 murine B-cell lymphoma had mean node/blood ratios of 42.9 +/- 6.7/1 and tumored node/normal lymph node uptake of 6.3/1. Thus. FDG given intravenously but not subcutaneusly (due to high normal nodal uptake) has potential as an agent for the detection of metastatic tumors in regional lymph nodes using PET scanning.
Diagnostic use of angiotensin converting enzyme (ACE)-inhibited renal scintigraphy in the identification of selective renal artery stenosis in the presence of multiple renal arteries: a case report, In patients with renovascular hypertension. it is unknown whether the angiotensin converting enzyme-(ACE) inhibited renal scan will identify stenosis of a segmental branch of a single renal artery or of an accessory artery where multiple renal arteries are present. Since multiple renal arteries may be present in approximately 25% of all individuals. it will be important to establish whether the ACE-inhibited renal scan is useful in this population. We report a case of stenosis involving a renal artery in a patient with multiple renal arteries. successfully identified by ACE-inhibited renal scintigraphy.
Radioimmunoscintigraphy using iodine-131-anti-CEA monoclonal antibodies and thallium-201 scintigraphy in medullary thyroid carcinoma: a case report, This case report demonstrates the use of thallium-201 (201Tl) scans versus iodine-131- (131l) anti-CEA F(ab')2 scans in a patient with high serum CEA levels due to metastases of medullary thyroid carcinoma in the suprarenal region and sacroiliacal region. Scintigraphy using monoclonal antibodies directed against CEA showed a higher tumor uptake (0.26% dose and 0.64% dose. respectively) than a thallium scan and is believed to be promising for future radiotherapeutic applications.
Treatment planning for internal radionuclide therapy: three-dimensional dosimetry for nonuniformly distributed radionuclides, A calculational approach is described that provides the spatially varying radiation absorbed dose. presented as isodose contours superimposed on CT images. from nonuniform and/or irregular cumulated activity distributions. CT images are read from magnetic tape and are displayed on a high-resolution color graphics display monitor. Source tissue geometries are defined on a series of contiguous CT images automatically (by an edge detection algorithm) or manually (using a trackball). thereby obtaining a three-dimensional representation of the various source volumes of activity. Dose calculations are performed using a radionuclide-specific absorbed dose point kernel in the form of a lookup table. The method described yields the spatially varying dose delivered to tumor and normal tissue volumes from a patient-specific cumulated activity distribution in a clinically implementable manner. This level of accuracy in determining normal tissue and tumor doses may prove valuable in the evaluation and implementation of radionuclides and radiolabeled compounds for therapeutic purposes.
Management of asymptomatic chronic aortic regurgitation with left ventricular dysfunction: a decision analysis, STUDY OBJECTIVE: To determine the optimal strategy for the timing of aortic valve replacement in patients with chronic. severe aortic regurgitation with left ventricular dysfunction. DESIGN: Decision analysis comparing early surgery (timed at the onset of left ventricular dysfunction) with delayed surgery (timed at the onset of symptoms) using data from the literature and expert opinion for variables in a representative case scenario (40-year-old man with bicuspid aortic valve disease). SETTING: Tertiary care center doing valve replacement surgery. MEASUREMENTS AND MAIN RESULTS: The early-surgery approach was preferred based on quality-adjusted life years. Sensitivity analysis showed that the result was not affected by the following variables within their derived ranges: rate of symptom development after onset of left ventricular dysfunction for the delayed-surgery approach. perioperative mortality for both approaches. and occurrence of major nonfatal stroke or congestive heart failure for both approaches. Although the decision was sensitive to the yearly postoperative mortality rates. the delayed-surgery operative mortality rate had to be almost as low as the early-surgery rate to change the preference to the delayed-surgery approach. The preference could also change if survival were much more important to the patient in the first five years than after five years or if the patient disliked living on anticoagulants enough to value a year on anticoagulants as worth only 80% of a year not on anticoagulants. CONCLUSION: This decision analysis provides quantitative support for the impression that patients similar to the case scenario do better with surgery timed at the onset of ventricular dysfunction than with surgery delayed until symptoms develop. It thus supports the practice of following these patients noninvasively in order to time surgery.
Implementation of cancer prevention guidelines in clinical practice, Data from several sources. including consumer surveys. physician surveys. and medical record audits. indicate that consumers do not receive cancer screening tests as recommended by the National Cancer Institute. the American Cancer Society. and the U.S. Preventive Services Task Force. Performance rates are consistently below published standards for all tests except Pap tests. Major reasons physicians do not perform the recommended tests include physician forgetfulness. disagreement with recommendations. lack of time. and patient refusal. Physicians also tend to overestimate their own performance rates. Barriers to screening test performance can be categorized into patient factors. physician factors. test factors. and health care delivery system factors. Interventions. such as computerized reminder systems. physician audits with feedback. and patient education and reminders. can be effective in promoting performance of such screening. Interventions that target both physician and patient may be particularly effective.
Breast cancer screening: who should be included, The recommendations of the U.S. Preventive Services Task Force are reviewed in regard to screening for breast cancer. In contradistinction to those issued by some other national organizations. screening for breast cancer using mammography at ages 40-49 is not recommended. It is concluded that the scientific evidence is insufficient at present to recommend mammography screening for women aged 40-49. The recommendations of the task force are: all women over age 40 should receive an annual breast examination; all women should have mammography every one or two years beginning at age 50 and concluding at approximately age 75 unless disease has been detected; and it may be prudent to begin mammography at an earlier age for women at high risk of breast cancer. These recommendations are appropriate in light of the available evidence; though at present there is no evidence that clinical examination of the breasts at any age reduces breast cancer mortality; the upper age beyond which breast cancer screening no longer has a significant effect in reducing breast cancer mortality is unknown; and there is no evidence that women at high risk for breast cancer benefit to a different degree from screening than women not at high risk.
Colorectal cancer: have we identified an effective screening strategy, Three currently used screening methods are aimed at detecting colorectal cancer when it is asymptomatic and curable. and at detecting polyps so that they can be removed before they can progress to cancer. Digital rectal examinations are relatively cheap and easy but can detect only a small fraction of large-bowel cancers. Sigmoidoscopy is more sensitive. but its low acceptability to patients has been only partially mitigated by the introduction of the 35-cm flexible instrument. Fecal occult blood testing has limited sensitivity because blood from cancers and polyps is neither continuously shed nor uniformly distributed in feces; specificity and positive predictive value are also low because of other sources of blood in the stool. Prudent judgment suggests that all of these screening tests may prevent death from colorectal cancer in some patients. However. none has been proven effective in general use by well-controlled studies. Case-control studies can provide timely and valuable new evidence in this regard; the authors' investigations in progress are described. The current lack of strong evidence in support of these screening tests should not be interpreted as evidence against their use.
The impact of the U.S. Preventive Services Task Force guidelines on cancer screening: perspective from the National Cancer Institute, The U.S. Preventive Services Task Force evaluated the medical literature. utilizing strict criteria to judge the merits of experimental trials designed to show benefit in screening for cancer. For individuals at normal risk. the task force was not able to make recommendations for or against screening for colorectal. prostate. skin. oral. or testicular cancers. Only one physical-examination cancer-screening procedure has ever been tested in a randomized trial. During the past 27 years. the National Cancer Institute (NCI) has funded six randomized screening trials. Thus far. only one has shown a decrease in mortality. Recognizing the limitations of such trials. the NCI published "Working Guidelines for Early Cancer Detection." Designed for the practicing physician. these guidelines were based upon the best available evidence and on the judgment of representatives of medical professional organizations.
Glaucoma screening: too little, too late, Screening for glaucoma. usually by measuring intraocular pressure. has been popular. but repeated analysis indicates poor sensitivity and specificity. More extensive testing is required. Such testing should be focused on high-risk groups. including blacks and the elderly. Regular comprehensive eye examinations. on a schedule adjusted for these and other risk factors. are probably the most cost-efficient means of identifying patients with glaucoma. The primary care provider has a pivotal role: to encourage patients to undergo such examinations when warranted; and to encourage those on intraocular-pressure-lowering medications to comply with their medication use.
Screening for psychiatric and substance abuse disorders in clinical practice, Psychiatric disorders. particularly depression and alcohol abuse. represent a large burden of illness to the society. Many individuals with these disorders receive all of their care from health care providers who are not mental health specialists. There is evidence that non-psychiatric physicians frequently do not recognize these disorders in their patients. Screening questionnaires have been introduced to improve detection of these patients. Several studies have found that these screening questionnaires can increase detection rates. but no important impact on patient outcomes has been demonstrated. This review article outlines several reasons why it has been difficult to discern improvement in patient outcomes: inadequate study design. insufficient physician education. interdependence of psychiatric and medical conditions. and vague treatment guidelines. Practical use of the current psychiatric screening questionnaires and key areas for further investigation are considered.
Prenatal screening: when and for whom, This report discusses the role of prenatal screening in preventing congenital abnormalities or. when prevention is not possible. in avoiding the conception or the birth of those who would have untreatable abnormalities. Women who are found by screening not to be immune to rubella can be safely vaccinated prior to pregnancy; those found to be at risk of having children with genetic disorders such as Tay-Sachs disease or thalassemia have the option of avoiding the conception of affected offspring. Screening during pregnancy permits the primary prevention of Rh disease and its sequelae when it results in the prophylactic administration of Rh-immune globulin to unsensitized Rh-negative women. Maternal serum alpha-fetoprotein screening identifies pregnant women who are at increased risk of carrying fetuses with neural tube defects or Down's syndrome. giving them the option of avoiding the birth of affected fetuses through abortion. Recombinant DNA technology will permit screening for many more genetic disorders as the disease-related genes and mutations are identified. For many of these disorders. the ability to predict the risk of disease will antedate preventive and therapeutic interventions by many years. During this lag phase. issues concerning the validity of the tests. the severity of the conditions for which screening is offered. the safety of the interventions. and the autonomy of the pregnant women in deciding to be screened are important.
The physician's role in injury prevention: beyond the U.S. Preventive Services Task Force report, Injuries and their prevention have received little attention by the medical community. despite the fact that injuries are the leading cause of premature death. However. much can be done to reduce the number and severity of injuries. and the practicing physician has an important role to play in this process. This report outlines the U.S. Preventive Services Task Force report recommendations for prevention strategies to reduce injuries and then seeks to define a broader role for the physician in prevention injuries that extends beyond the confines of office-based practice. While screening and counseling have proven effectiveness in certain situations. interventions that are passive or automatic in action. such as air bags. have proven to be more effective long-term solutions to reduce both the number and the severity of injuries. The author outlines and provides examples of seven areas where physicians can have a major impact either directly or through implementing effective injury-control strategies. These are: treatment. education. screening. hazard identification. research. advocacy. and policy making. Using all of these approaches. physicians can play a truly effective role in reducing the burden of injuries for their patients.
Nicotine dependence: a preventable risk factor for other diseases, Nicotine meets all critical criteria for an addictive drug. Furthermore. there is no evidence that there would be widespread compulsive use of tobacco without nicotine. These findings have led to consideration of the cigarette as a contaminated vehicle for an addictive drug (nicotine). Nevertheless. nicotine itself may also be used therapeutically to reduce exposure to carcinogens and other tobacco toxins. Nicotine replacement is a useful adjunct in treating tobacco dependence. For example. nicotine replacement in the form of a polacrilex resin (chewing gum) can alleviate physically based signs and symptoms of tobacco abstinence. The fact that this form of nicotine replacement is not attractive to non-users of tobacco has opened the door to the use of nicotine in a therapeutic modality. permitting hope of eliminating tobacco dependence.
The costs of prevention, A prevention program is cost-effective if it yields more health benefits than do alternative uses of health care resources. Some prevention programs meet this standard: either they actually save more health care resources than they utilize. or their net costs per healthy year of life gained are lower than those of alternatives such as curative or palliative medicine. Other prevention programs. however. are less cost-effective than are medical treatments for the same disease. One lesson for public policy is that generalizations about the cost-effectiveness of "prevention" are unwise. Another lesson is that prevention programs should not be subjected to a higher standard than other health programs: they should not be expected to save money. but they should be expected to yield improved health at a reasonable price.
Facial trauma in women resulting from violence by men, In a 2 1/2-year period. 546 women with facial injuries were treated. In 8.2%. the injury was related to some form of violence exerted by a man. In cases where the individual was known. it was usually the husband or boyfriend (almost 67%). The assault consisted of a beating with the hands in over 70% of the cases. Fracture of the mandible was the most common injury. There were also 62 cases of home accidents.
Conventional radiographic and computed tomographic findings in cases of fracture of the mandibular condylar process, A total of 40 patients with 46 fractures of the mandibular condylar process were examined an average of 47 months after the injury. The conventional radiologic examination consisted of panoramic radiography and lateral transcranial view of the fracture in the mouth-open and mouth-closed positions. Sixteen patients with 21 fractures of the condylar process were examined additionally by computed tomography (CT) because of temporomandibular joint problems in the sagittal and coronal projection. Computed tomography revealed bony changes in the fractured mandibular condyle and its position in the mandibular fossa more exactly than conventional radiographic examinations. Furthermore. the results showed that disturbances in the position and function of the articular disc may be more common than was earlier anticipated. suggesting the more frequent use of CT examinations to evaluate temporomandibular joint changes after condylar process fractures.
Evaluation of anterior maxillary alveolar ridge resorption when opposed by the transmandibular implant, Fifteen edentulous patients with complaints regarding denture comfort and/or function were treated with the transmandibular implant. All patients were restored with conventional maxillary dentures opposed by implant-supported removable prostheses. Two to 4 years after surgery. these patients were evaluated for vertical and horizontal maxillary bone loss with a radiographic analysis developed by the authors. With this technique. attention was focused on vertical alveolar ridge resorption in the anterior maxilla. Although the sample size was small. the findings from this study indicate that vertical bone loss in the anterior maxilla does occur when a maxillary denture is opposed by an implant-supported overdenture. Comparison of these results with a previous study that evaluated anterior maxillary resorption when a complete maxillary denture opposed natural mandibular anterior teeth and a distal extension removable partial denture demonstrated no statistically significant difference.
Squamous cell carcinoma-antigen for detection of squamous cell and mucoepidermoid carcinoma after primary treatment: a preliminary report, This study evaluated the efficacy of using the periodic measurement of the serum level of squamous cell carcinoma antigen (SCC-antigen) for determining the local recurrence and/or metastasis of squamous cell and mucoepidermoid carcinomas after primary treatment. It was found that at the time of clinical recognition of recurrence. the SCC-antigen level was normal. but metastasis to regional lymph nodes or to remote organs generally was accompanied by an increase of SCC-antigen. Changes in the SCC-antigen level with mucoepidermoid carcinoma seemed to be less sensitive than with squamous cell carcinoma.
Facial muscle reanimation using the trigeminal motor nerve: an experimental study in the rabbit, Surgical repair of facial nerve deficits may be marred by lack of muscle control and donor region paresis. Using New Zealand white rabbits. a study was undertaken to evaluate facial muscle reanimation with a donor source not previously used: the motor division of the trigeminal nerve. The results were compared with the severed facial nerve and hypoglossal-facial coaptation. An atrophy scale was calibrated for facial muscles of the rabbit. Clinical. electromyographic. and histomorphometric findings confirmed that the trigeminal nerve was a suitable donor source. The neurorrhaphy produced an exponential rate of repair.
Poly(L-lactide) implants in repair of defects of the orbital floor: an animal study, Because of the life-long presence of alloplastic. nonresorbable orbital floor implants and the complications of their use mentioned in literature. the use of a resorbable material appears to be preferable in the repair of orbital floor defects. A high-molecular-weight. as-polymerized poly(L-lactide) (PLLA) was used for repair of orbital floor defects of the blowout type in goats. An artificial defect was created in the bony floor of both orbits. Reconstruction of the orbital floor was then carried out using a concave PLLA implant of 0.4-mm thickness. At 3. 6. 12. 19. 26. 52. and 78 weeks postoperatively. one goat was killed. Microscopic examination showed full encapsulation of the implant by connective tissue after 3 weeks. After 6 weeks. resorption and remodeling of the bone at the points of support of the implant could be detected. A differentiation between the sinus and orbital sides of the connective tissue capsule was observed. The orbital side showed a significantly more dense capsule than the antral side. which had a loose appearance. At 19 weeks. a bony plate was progressively being formed. and at 78 weeks. new bone had fully covered the plate on the antral and orbital side. No inflammation or rejection of the PLLA implant was seen.
Ectopic pregnancy in adolescents: a clinical review for pediatricians, Pediatricians caring for sexually active female adolescents and young adults need to be aware of the history. symptoms. and signs of an ectopic pregnancy. A thorough history and physical examination. including the pelvic examination. as well as specific diagnostic tests such as repeated quantitative hCG measurements. and ultrasonography when indicated. are crucial to proper and early diagnosis of a nonruptured ectopic pregnancy manageable by laparoscopy. The key to early diagnosis is to include ectopic pregnancy in the differential diagnosis in any sexually active female patient who has abnormal vaginal bleeding or abdominal pain. With early diagnosis. close observation. and appropriate management. the outcome is more likely to be favorable. with minimal morbidity and risk of death.
Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection, OBJECTIVE: To determine whether a short course of 2'.3'-dideoxycytidine (ddC) could provide safe antiretroviral activity in children with symptomatic human immunodeficiency virus infection and whether it could be used with azidothymidine (AZT. zidovudine). The goal was to maintain uninterrupted antiretroviral therapy while sparing AZT-related myelosuppression and ddC-related neuropathy. METHODS: In a pilot study. we evaluated four dosage levels of ddC--0.015. 0.02. 0.03. and 0.04 mg/kg. given orally every 6 hours--in 15 children between 6 months and 13 years of age with Centers for Disease Control P2 (i.e.. symptomatic) human immunodeficiency virus infection. Thirteen patients had not had any prior antiretroviral therapy; two patients had received and benefited from AZT. but dose-limiting neutropenia had developed. At each dosage level. ddC was given for 8 consecutive weeks and then stopped. After a 30-day rest. a schedule of ddC for 1 week was followed by 3 weeks of AZT therapy (180 mg/m2 every 6 hours); this alternating schedule was repeated for as long as tolerated. Age-appropriate psychometric testing was performed before the start of ddC therapy and after 8 weeks. RESULTS: During the 8 weeks of therapy with ddC alone. no neutropenia or anemia was observed; 6 of 9 patients had decreases in p24 antigen levels. and 8 of 15 had an increased CD4 cell count. At the 0.04 mg/kg level. a rash developed in three patients; mild mouth sores developed in 9 of 15 patients. On the alternating ddC/AZT schedule. no neuropathy was observed. CONCLUSIONS: 2'.3'-Dideoxycytidine has antiretroviral activity in some children and appears to be safe for short intervals. Longer courses of ddC at lower dosage levels. and schedules integrating ddC into combination regimens. deserve to be explored.
Azathioprine in the treatment of children with inflammatory bowel disease, During a 6-year period. we treated 21 patients with azathioprine. 2 mg/kg/day. as an adjunct to their customary regimen. Nine patients had ulcerative colitis and 12 patients had Crohn disease; the patients' ages ranged from 3 to 17 years. The median duration of disease before the start of azathioprine therapy was 2 years. and median follow-up was 2 years. Sixteen patients seemed to respond to azathioprine therapy: six patients in each disease group had complete responses and four patients (one with ulcerative colitis and three with Crohn disease) had partial responses. Two patients with ulcerative colitis and three patients with Crohn disease did not respond. The median time until patients responded was less than 3 months for patients with ulcerative colitis and 4 months for those with Crohn disease. Reduction of corticosteroid dose was possible for all patients who responded to azathioprine therapy. Only minimal side effects were attributable to the drug. We conclude that azathioprine is an effective adjunctive agent for the treatment of inflammatory bowel disease in childhood. but because questions remain regarding its long-term safety. its use should be reserved for children with refractory disease or severe and unacceptable side effects of corticosteroids.
Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia, Because trimethoprim-sulfamethoxazole (TMP-SMX) causes neutropenia in children with leukemia. we investigated the possibility that pharmacokinetic interaction between methotrexate (MTX) and TMP-SMX causes accumulation of the antileukemia agent. We studied the pharmacokinetics of MTX given intravenously or orally to nine children with acute lymphoblastic leukemia. once with and once without TMP-SMX. There was an increase in free MTX fraction during TMP-SMX therapy in all patients. from (mean +/- SD) 37.4 +/- 11% without TMP-SMX to 52.2 +/- 6.4% with TMP-SMX (p less than 0.01). Plasma clearance of total MTX did not change significantly. whereas clearance of free MTX decreased significantly (from 12.5 +/- 4 to 7.6 +/- 1.5 ml/kg/min; p less than 0.05). There was a consistent decrease in the renal clearance of free MTX (from 12.1 +/- 6.8 to 5.6 +/- 2.4 ml/kg/min; p less than 0.05). Elimination half-life of MTX was not affected significantly by TMP-SMX. There was a significant correlation between serum concentrations of TMP-SMX and the percentage of decrease in the renal clearance of free MTX (r = 0.91; p less than 0.05). These changes in protein binding and tubular clearance of MTX. caused by competition with TMP-SMX. result in a mean 66% increase in systemic exposure to MTX and may explain the myelotoxicity often observed with the coadministration of the two drugs.
Evaluation of the AIDS dementia complex in clinical trials, The AIDS dementia complex (ADC) is one of the most common and important causes of morbidity associated with infection by human immunodeficiency virus type 1 (HIV-1). The evaluation of ADC in clinical trials is significant not only because of the clinical impact of this syndrome. but also because of the value of measuring its cardinal features as an index of drug efficacy and because of its emerging role as a major clinical end point. The objectives of therapy include both prevention of ADC in the presymptomatic patient and alleviation of established disease. At present. the pathogenesis of ADC is incompletely understood in several critical aspects. particularly the processes underlying the clinical manifestations of central nervous system (CNS) HIV-1 infection and. further. how such processes are related to systemic disease. Consequently. it is not yet clear to what extent. or in which patients. it is necessary to achieve "therapeutic" drug levels within the CNS. Nevertheless. the assessment of ADC prevention and treatment relies principally on the complementary approach of neurological examination for diagnosis and neuropsychological testing for quantitative serial measurement of treatment effects. Additionally. surrogate markers in cerebrospinal fluid (CSF) may hold promise for objective. rapid assessment of treatment response and dose adjustment. Other measurements. including more routine CSF analysis. neuroimaging. and neurophysiological assessments. are used principally for differential diagnosis rather than for monitoring ADC status. Accumulating experience with available antiviral agents suggests that ADC can be effectively prevented and treated. at least for some period of time. and that assessment of this condition is indeed a valuable approach for measuring antiviral therapy.
Evaluation of active control trials in AIDS, In settings in which effective standard treatment exists. active control trials provide an ethically appealing approach to evaluating experimental therapies by allowing all patients to be randomized either to a promising new regimen or to the standard as it would be routinely delivered in clinical practice. This paper describes an appropriate statistical approach for analyzing the clinical efficacy of new treatments in such studies. Confidence intervals for the relative efficacy of the new treatment vis-a-vis standard therapy are used to provide information required to determine whether the experimental treatment has an improved therapeutic index. Desirable properties of this approach include the ability to implement standard group sequential guidelines for early trial termination. the ability to use valid surrogates for hard clinical outcomes. and the availability of straightforward formulas for sample size calculations.
Laparoscopic management of ovarian cysts, One hundred two women with ovarian cysts were managed laparoscopically over a 13-year period. Thirteen were treated with laparoscopic inspection followed by laparotomy. 6 with laparoscopic fine needle aspiration followed by laparotomy and 83 with laparoscopic fenestration and biopsy. with or without coagulation or removal of the cyst lining. Satisfactory results were noted in patients treated completely with laparoscopy. Only 1 of 56 functional. simple or paraovarian cysts recurred during the study period. Two of the 18 ovarian endometriomas treated with fenestration and coagulation or removal of the lining recurred. whereas 8 of 9 such lesions recurred when treated with fenestration alone. There were no surgical complications.
Effect of interleukin-1 on gamete interaction and mouse embryo development, Early stages of endometriosis have been shown to be associated with infertility. The pathophysiology of this relationship is unclear. To determine if interleukin-1 (IL-1). a peritoneal macrophage product. has any effect on gamete interaction and early embryo development. human recombinant IL-1 was added to the coincubation of gametes in the sperm penetration assay (SPA). human zona pellucida assay (ZPPA) and culture medium (Ham's F-10) used for processing semen samples with the layering method. with analysis of velocity and motility after 24 hours. IL-1 was also added to mouse embryos (two cells) cultured for 72 hours. The results showed that IL-1 caused impairment of SPA and ZPPA when compared to control medium. without significant alterations in sperm velocity and motility. Also. IL-1 demonstrated significant inhibition of mouse embryo development. These results help explain subfertility associated with early stages of endometriosis.
Stress incontinence and low urethral closure pressure. Correlation of preoperative urethral hypermobility with successful suburethral sling procedures, Forty-eight women with genuine stress incontinence and low urethral closure pressure were treated with a suburethral sling procedure using polytetrafluoroethylene. All patients underwent a preoperative clinical evaluation and multichannel urodynamic testing. The clinical examination included a "Q-tip" test to determine the presence or absence of urethral hypermobility. Urethral hypermobility was defined as a maximal angle change of greater than or equal to 30 degrees from the horizontal. measured during straining or coughing in the lithotomy position. Thirty-four patients underwent repeat multichannel urodynamic testing three months postoperatively to determine the objective surgical success. Ninety-three percent of patients (27/29) with a positive preoperative Q-tip test were cured. Of patients with a negative preoperative Q-tip test. only 20% (1/5) were cured. Preoperative urethral hypermobility was a good prognostic indicator of operative success when a suburethral sling procedure was used to treat genuine stress incontinence and low urethral closure pressure.
Perinatal outcomes of twin pregnancies at term, A review of a two-year experience in our community disclosed that 57% of twin pregnancies (118/207) deliver at term. Little attention has been focused on perinatal outcomes of twin pregnancies remaining undelivered after 36 completed weeks. Therefore. we reviewed our experience to determine whether our practice should change to maximize perinatal care. Nearly all the study pregnancies (115/117. or 97.5%) delivered by the estimated date of confinement. Fetal malpresentation. failure to progress and the patient's lack of desire for a vaginal birth after cesarean delivery were common reasons for the high cesarean rate (62/117. or 52%). The neonatal outcomes were favorable regardless of the route or interval between deliveries. Discordant fetal growth was found in only eight cases (6.8%). No perinatal deaths occurred. and five-minute Apgar scores less than 7 (2/234. or 0.9%) and rates of anomalies (5/234. or 2.1%) were not different from those in singleton pregnancies delivering during the same period. Using the principles of obstetric practice used in our community. we would expect the perinatal outcomes in term twin gestations to be favorable.
Training obstetrics-and-gynecology residents to manage breast disease. Incorporation into a breast care clinic, The American Board of Obstetricians and Gynecologists recently issued a directive that education in breast disease be incorporated into all residency training programs. At the University of Michigan Medical Center. the Comprehensive Breast Care Center (BCC) provides the vehicle for the education and training of residents in the area of breast disease. The department of obstetrics and gynecology is fully integrated and participates actively in the care of patients in the BCC.
Midtrimester tubal pregnancy with markedly elevated maternal serum alpha-fetoprotein. A case report, Elevated maternal serum alpha-fetoprotein levels have been reported to occur in a variety of pathologic conditions. including early tubal pregnancy. In this case. markedly elevated maternal serum alpha-fetoprotein was associated with a midtrimester tubal pregnancy. The breakdown of the normal fetomaternal circulatory barrier. allowing the transplacental exchange of alpha-fetoprotein. was the likely etiology of the elevation.
Expression of the MDR1 gene in human gastric and colorectal carcinomas, We measured expression of the MDR1 gene (also known as the PGY1 gene) in the human gastrointestinal tract. MDR1 messenger RNA (mRNA) levels were elevated in 13 of 15 colorectal carcinoma specimens and in six of 13 gastric carcinoma specimens. Well-differentiated colorectal carcinomas contained significantly higher concentrations of MDR1 mRNA than moderately differentiated colorectal carcinomas. Similarly. moderately differentiated gastric carcinomas contained higher concentrations of MDR1 mRNA than poorly differentiated gastric carcinomas. MDR1 gene expression in normal colorectal and gastric tissues adjacent to carcinomas was similar to that in the carcinomas. MDR1 gene expression in xenografts of colorectal and gastric carcinomas in nude mice was also investigated. Elevated expression of the MDR1 gene was seen in only four of 18 xenografts of colorectal carcinoma and was not seen in any xenografts of gastric carcinoma. P-glycoprotein was distributed over the luminal surface of the colorectal carcinoma. These results imply that the higher levels of MDR1 mRNA found in well-differentiated carcinomas derived from colorectal tissues are the results of increased expression of the MDR1 gene in the luminal surface cells. The level of expression of the MDR1 gene in colorectal and gastric carcinomas appears to correlate with the degree of differentiation and also appears to be affected by transplantation into nude mice.
Race, nutritional status, and survival from breast cancer, The effects of nutritional status on differences in the survival of black and white women with breast cancer were studied in a cohort of 1.960 Georgia women diagnosed during 1975-1979. After data were adjusted for stage of disease. socioeconomic status. and other prognostic factors. poorer survival rates were shown in black women. Within each stage classification. lower levels of serum albumin and hemoglobin and higher relative body weight were more common among blacks and were independently associated with poorer survival. Among women with stage 3 disease. adjustment for these variables substantially reduced the excess mortality rate among blacks. suggesting that racial differences in survival may be partly explained by differences in nutritional status or extent of disease within stage.
Effect of tamoxifen on serum insulinlike growth factor I levels in stage I breast cancer patients, Insulinlike growth factor I (IGF-I) has been shown to be a potent mitogen for breast cancer cells in vitro. and IGF-I receptors have been demonstrated on human primary breast neoplasms. In a randomized. placebo-controlled study. we document that administration of the antiestrogen tamoxifen to patients with breast cancer was associated with a statistically significant (P = .002) reduction in the serum level of IGF-I. The mean IGF-I level was 1.4 U/mL in the placebo-treated group and 0.9 U/mL in the tamoxifen-treated group. Because serum IGF-I level is growth hormone (GH) dependent and because data suggest that the pubertal surge in GH and IGF-I levels is sex steroid dependent. we speculate that the mechanism underlying our observation may involve blockade by tamoxifen of estrogen action in the hypothalamic-pituitary axis. We conclude that tamoxifen treatment reduces IGF-I levels and that this reduction may contribute to the therapeutic effect of the drug.
Prediction of postoperative clinical course by autologous tumor-killing activity in lung cancer patients, Fifty patients with primary localized lung cancer were tested at the time of surgery for the ability of their lymphocytes to kill autologous. freshly isolated tumor cells. and the assay was evaluated for prognostic significance. Peripheral blood lymphocytes of 27 patients (54%) demonstrated significant autologous tumor-killing activity in 6-hour 51Cr-release assays. Twenty-three of the 27 patients with autologous tumor-killing activity remained tumor free and survived more than 5 years after curative surgery. while all 23 who were negative for autologous tumor-killing activity relapsed by 18 months after surgery and died within 42 months after surgery. The differences in survival curves for the two groups were highly significant (P less than .00003). Autologous tumor-killing activity was not correlated with natural killer (NK) cell activity against K562 human myeloid leukemia cells or proliferation of lymphocytes stimulated with autologous. freshly isolated tumor cells in mixed culture. There were no differences in total survival between patients with positive results and those with negative results in tests of NK cell activity and autologous mixed lymphocyte-tumor culture reaction. These results indicate that autologous tumor-killing activity is a meaningful prognostic indicator and provide evidence for immunological control of tumor growth and metastasis. According to our preliminary data. it is unlikely that lung cancer patients who remain tumor free after 60 months of follow-up will develop recurrence or die from the disease. We are conducting a study to determine whether induction of autologous tumor-killing activity before surgery. by treatment with biological response modifiers.can improve the clinical outcome in patients who do not naturally have this potential.
Reduction of the membrane fluidity of human breast cancer cells by tamoxifen and 17 beta-estradiol, The intracellular steady-state levels of methotrexate were previously shown to be reduced in estrogen receptor (ER)-negative human breast cancer MDA-MB-436 cells and ER-positive human breast cancer MCF7 cells following treatment with pharmacologically relevant concentrations of 17 beta-estradiol (E2). We now report that both E2 and tamoxifen (TMX) significantly decreased the fluidity of MCF7 and MDA-MB-436 cellular membranes. With E2 or TMX at concentrations greater than 1 microM. perturbations in membrane fluidity were accompanied by apparently non-ER-mediated cytotoxicity. Alterations in membrane structure may have contributed to the cytotoxicity of high-dose endocrine therapy and to the ability of E2 to inhibit methotrexate transport and cytotoxicity in some human breast cancer cells.
Antitumor activity of liposome-encapsulated doxorubicin in advanced breast cancer: phase II study, Previous studies in animals have demonstrated liposome-encapsulated doxorubicin (LED) has substantially less cardiac toxicity than free doxorubicin but retains antitumor activity. In a phase I clinical study of LED. the maximum tolerated dose was 90 mg/m2 and dose-limiting toxicity was considered to have been reached when granulocytopenia was produced. We used LED to treat 20 patients with advanced. measurable breast cancer. LED was given at doses of 60-75 mg/m2 every 3 weeks as an intravenous infusion. Regression of disease was objectively measured in nine patients; in five of these patients. complete regression of the index lesion occurred. The mean duration of the responses was 7 months. Hematologic toxicity consisted of grade 1-2 leukopenia in some patients. Gastrointestinal toxicity and mucositis were generally mild and tolerable. Alopecia occurred in all patients and usually was complete. Twelve patients received cumulative doses of LED of greater than 400 mg/m2 and were evaluated with radionuclide ventriculograms. In eight patients. the cumulative dose was greater than 500 mg/m2. and five had endomyocardial biopsies. Four of these biopsy results were Billingham grade 0. while one (cumulative LED dose. 750 mg/m2) showed grade 1 changes with mild myofibrillar loss and dilatation of the sarcoplasmic reticulum involving less than 5% of cardiac myocytes. Two patients had decreases in left ventricular ejection fraction. One of these patients had received a total dose of LED of 630 mg/m2 and had a decline of 13% in left ventricular ejection fraction. but had no clinical evidence of congestive heart failure and had a Billingham grade 0 endomyocardial biopsy.
Oral zidovudine, continuous-infusion fluorouracil, and oral leucovorin calcium: a phase I study, A phase I clinical. pharmacologic. and biochemical evaluation of escalating oral zidovudine (AZT) given over 2 days with a fixed dose of continuous-infusion fluorouracil (800 mg/m2 per day X 3 days) and oral leucovorin calcium was performed. Eighteen patients were treated with doses of AZT ranging from 1.0 to 9.0 g/m2 per day. Nausea and vomiting were dose limiting. with a maximally tolerated dose of 7.5 g/m2 per day. Rash and mucositis occurred but were not dose limiting. A dose-related increase in peak plasma levels of AZT was observed. and the alpha half-life of AZT in plasma (75 min) was unaffected by these high doses. At doses above 4.0 g/m2 per day. trough levels significantly increased. perhaps reflecting prolonged absorption from the gut. No responses were observed; however. a significant increase in DNA single-strand breaks was observed in peripheral blood cells after a threshold dose of 4.0 g/m2 per day. confirming a biological effect of AZT in this regimen. Further trials with an intravenous formulation capable of maintaining plasma levels and circumventing dose-limiting toxicity are warranted.
Validation of intermediate end points in cancer research, Investigations using intermediate end points as cancer surrogates are quicker. smaller. and less expensive than studies that use malignancy as the end point. We present a strategy for determining whether a given biomarker is a valid intermediate end point between an exposure and incidence of cancer. Candidate intermediate end points may be selected from case series. ecologic studies. and animal experiments. Prospective cohort and sometimes case-control studies may be used to quantify the intermediate end point-cancer association. The most appropriate measure of this association is the attributable proportion. The intermediate end point is a valid cancer surrogate if the attributable proportion is close to 1.0. but not if it is close to 0. Usually. the attributable proportion is close to neither 1.0 nor 0; in this case. valid surrogacy requires that the intermediate end point mediate an established exposure-cancer relation. This would in turn imply that the exposure effect would vanish if adjusted for the intermediate end point. We discuss the relative advantages of intervention and observational studies for the validation of intermediate end points. This validation strategy also may be applied to intermediate end points for adverse reproductive outcomes and chronic diseases other than cancer.
Anti-idiotype monoclonal antibody carrying the internal image of ganglioside GM3, Murine anti-idiotype monoclonal antibodies were generated against a human IgM monoclonal antibody (L612) that recognizes ganglioside GM3 on human melanoma. Hybridomas secreting antibodies that bound specifically to L612 were selected by enzyme-linked immunosorbent assay using L612 and three negative control human IgMs. including monoclonal anti-GM2 and anti-GD2 antibodies. as well as purified serum IgM. as antigen sources. GM3-binding inhibition and cell-binding inhibition assays were used to identify seven anti-idiotype monoclonal antibodies that recognized determinants located within the antigen-combining sites of L612. To determine whether these anti-idiotype monoclonal antibodies possessed the internal image of the original antigen. we immunized syngeneic BALB/c mice with one of the anti-idiotype monoclonal antibodies. 4C10. coupled with keyhole limpet hemocyanin. Sera from the immunized mice reacted strongly with an antigen-positive M12 melanoma cell line and with purified GM3. Because L612 detects and kills melanoma tumor cells in vitro and in vivo in the presence of complement without affecting normal tissues. anti-idiotype monoclonal antibodies carrying the internal image of GM3 may be an effective tool for active specific immunotherapy in patients with melanoma.
Mutagen sensitivity in patients with head and neck cancers: a biologic marker for risk of multiple primary malignancies, Eighty-four patients with head and neck cancers were evaluated for in vitro sensitivity to mutagens and then followed longitudinally for development of multiple primary malignancies. We assessed mutagen sensitivity by exposing lymphocytes to bleomycin in vitro and quantitating the bleomycin-induced chromosomal breaks per cell. The mutagen-hypersensitive patients. ie. those who expressed greater than 1.0 break per cell. were significantly more likely to develop multiple primary cancers than were patients who were less sensitive (less than or equal to 1.0 break per cell) (relative risk = 4.4; 95% confidence limits = 1.2. 15.8). This relationship was independent of age. sex. site. and treatment of first primary cancer and tobacco or alcohol exposures. Sensitivity to bleomycin-induced chromosomal damage serves as an indicator of genetic susceptibility to multiple primary malignancies in patients with head and neck cancers.
Facial bone fracture associated with carotid-cavernous sinus fistula, Out of 989 cases of facial bone fracture. ten patients had carotid-cavernous sinus fistulas (1.01%). Their ages ranged from 25 to 48 years. Seven were male and three female. Two of the ten patients had lower third. three patients had middle third. three patients had upper third. and two patients had combined middle and lower third facial bone fractures. The signs and symptoms of a fistula appeared from the first postinjury day up to 50 days after the injury (mean. 21 days). Four patients had symptoms after operation for facial bone fracture. Most fistulae were identified by arteriography before treatment. Followup ranged from 1 year. 8 months. to 5 years. 9 months (mean. 2 years. 9 months). One patient had a malocclusion. Nine patients had complete resolution of their bruits. Complications included unilateral complete visual loss (two). CSF rhinorrhea (two). and stroke in one of the two CSF rhinorrhea patients. One patient expired due to a severe head injury. and there was one death from an unrelated cause.
Diagnostic peritoneal lavage: accuracy in predicting necessary laparotomy following blunt and penetrating trauma, The purpose of this study was to evaluate the ability of diagnostic peritoneal lavage (DPL) to predict intra-abdominal injuries that required surgical repair. To do this. we retrospectively reviewed 944 patients with blunt and penetrating abdominal trauma who underwent 975 DPLs. Initial DPL in 608 patients sustaining blunt trauma had a sensitivity of 87%. a specificity of 97%. an accuracy of 95%. a positive predictive value (PPV) of 85%. and a negative predictive value (NPV) of 97%. Initial DPL in 336 patients with penetrating trauma had a sensitivity of 87%. a specificity of 89%. an accuracy of 89%. a PPV of 75%. and a NPV of 95%. When utilizing final lavage results on the 944 patients. DPL had a sensitivity of 91%. a specificity of 94%. an accuracy of 93%. a PPV of 80%. and a NPV of 98% in predicting intra-abdominal injury requiring surgical repair.
The Major Trauma Outcome Study: establishing national norms for trauma care, The Major Trauma Outcome Study (MTOS) is a retrospective descriptive study of injury severity and outcome coordinated through the American College of Surgeons' Committee on Trauma. From 1982 through 1987. 139 North American hospitals submitted demographic. etiologic. injury severity. and outcome data for 80.544 trauma patients. Motor vehicle related injuries were most frequent (34.7%). Twenty-one per cent of patients had penetrating injuries. The overall mortality rate was 9.0%. The mortality rate for direct admissions was strongly related to the presence of serious head injury. 5.0% and 40.0%. when head injuries were less than or equal to AIS (Abbreviated Injury Scale) 3 or greater than or equal to AIS 4. respectively. Survival probability norms use the Revised Trauma Score. Injury Severity Score. patient age. and injury mechanism. Patients with unexpected outcomes were identified and statistical comparisons of actual and expected numbers of survivors made for each institution. Results provide a description of injury and outcome and support evaluation and quality assurance activities.
Basophil releasability in severely burned patients, Thermal injury is known to induce dysregulation of the immune system; however. the precise mechanisms have to be clarified. We investigated the histamine release of basophil granulocytes from severely burned patients (n = 12) after stimulation with anti-IgE or the Ca-ionophore A 23187. respectively. The anti-IgE-induced basophil histamine release of all patients was reduced in comparison to healthy donors beginning at day one postburn (p.b.) (5.0 +/- 2.3% vs. 30.5 +/-3.4%). while the Ca-ionophore-induced release was not decreased before day two p.b. Basophils of patients who finally succumbed to their injuries showed poor responsiveness (to zero levels) over the total time. In contrast. the basophil releasability of surviving patients returned to nearly normal levels (fifth to seventh week p.b.). Already in the second week p.b. there was a significant difference in histamine release between survivors and nonsurvivors [e.g.. days 6-9 p.b.: 23.7 +/- 4.0 vs. 6.9 +/- 2.7 (p less than 0.005) after Ca-ionophore stimulation]. The altered basophil histamine release was neither due to a diminished dose- or a delayed time-response to the stimuli nor due to differences in the basophil counts or the cellular histamine content. Our data indicate that the decrease of the basophil releasability. which may be secondary to altered signal transduction pathways in severely burned patients correlates with the clinical outcome.
Studies on B-lymphocyte dysfunctions in severely burned patients, We studied in vitro functional parameters of peripheral blood B-lymphocytes from severely burned patients (n = 10; burn injuries ranging from 25 to 72% TBSA). While the number of B-cells remained unchanged. B-cell proliferation induced by Staphylococcus aureus strain Cowan I (SAC) was normal or even enhanced at early and late phases postburn. but showed a marked suppression during the second to fourth week. A similar pattern was observed for the pokeweed mitogen (PWM)- or SAC-stimulated synthesis of immunoglobulin M (IgM). whereas IgG production was decreased over the whole postburn period monitored. Cytokine (interleukin 4)-induced B-cell activation as indicated by the expression of the CD23 surface antigen was impaired throughout the second to fifth week. In parallel. the release of the proteolytic cleavage product sCD23 which represents a B-cell growth and differentiation factor was reduced. Our data provide evidence that activation. proliferation. and differentiation processes of B-lymphocytes are impaired in severely burned patients. which may contribute to their enhanced susceptibility to infection and sepsis.
Disability from bicycle-related injuries in children, Bicycle crashes are a major cause of injuries in childhood. The goal of this study was to determine the long-term disabilities caused by bicycle-related injuries. and to clarify the long-term treatment priorities of injured children. Hospital records of 372 children (ages 2-15 yr. median 9 yr; 232 boys and 140 girls) admitted with bicycle-related injuries from 1979 through 1986 provided clinical information. social service visits. in-hospital and outpatient rehabilitative interventions. and physical status at discharge. More complete evaluations were made by contacting parents by telephone (82 children). and by personal interview and physical examinations (27). Head injuries predominated (69.1%). Twelve (3.2%) died. all from major head injuries. Four suffered permanent severe impairment from cervical spinal injuries and head injuries and remain institutionalized (1.4%). One third had a persistent disability noted at the time of discharge in the medical record (33.6%). reported by telephone interview (31.7%). or confirmed by physical examination (37.0%). Still. only 11.0% received physical therapy consultations during hospitalization. and 22.8% received social service assistance. Only 39.0% were seen by a surgeon or pediatrician after discharge. and few (7.3%) received outpatient physical therapy. Cognitive or behavior changes were noted in 31.7%. many noting changes in school performance (worse in 20.7%). behavior (13.4%). and sleep. particularly nightmares (34.1%). Recurrent injuries occurred in 52 children (14.4%). of whom ten (2.8%) required further hospital admission. Bicycle-related injuries cause significant short- and long-term disabilities among children.
Subxiphoid pericardial windows--helpful in selected cases, There is a small group of patients who sustain multiple penetrating injuries who present with haemodynamic changes. making it difficult to clinically exclude or prove the presence of penetrating cardiac injury. It is in this select group of patients that we found subxiphoid pericardial windows to be extremely useful to prove or disprove the existence of a cardiac injury and thereby prevent a delay in diagnosing these injuries.
Bilateral sacroiliac joint fracture-dislocation: a case report, Bilateral sacroiliac joint fracture-dislocation of the sacrum with displacement is a rare injury. We found only four such injuries previously reported in the literature. Nonoperative management in this case led to complete functional return and acceptable alignment.
Brachial plexus injury associated with chest restraint seatbelt: case report, Rapid deceleration while wearing a lap-shoulder strap seatbelt may result in a traction injury to the brachial plexus on the side of the shoulder strap. Occult vascular injury should be considered in patients with this injury pattern. The deficit will recover after a neuropraxic type injury.
Bilateral simultaneous fractures of the femoral neck: case report, A case of bilateral fractures of the femoral neck resulting from high-voltage electric injury is reported. Surgeons caring for patients with electrical injuries must be aware of the possibility of this injury as well as other skeletal injuries which may result from muscle contraction or falls related to electric shock. Without vigilance for these injuries. diagnosis may be delayed.
Organ injury scaling, II: Pancreas, duodenum, small bowel, colon, and rectum, The Organ Injury Scaling (O.I.S.) Committee of the American Association for the Surgery of Trauma (A.A.S.T.) has been charged to devise injury severity scores for individual organs to facilitate clinical research. Our first report (1) addressed O.I.S.'s for the Spleen. Liver. and Kidney; the following are proposed O.I.S.'s for Pancreas (Table I). Duodenum (Table II). Small Bowel (Table III). Colon (Table IV). and Rectum (Table V). The grading scheme is fundamentally an anatomic description. scaled from 1 to 5. representing the least to the most severe injury. We emphasize that these O.I.S.'s represent an initial classification system which must undergo continued refinement as clinical experience dictates.
Health locus of control beliefs and alcohol-related factors that may influence treatment outcomes, Treatment programs have based their treatment approach on the premise that alcoholics should exert internal control over situations and events that affect them. Since chronic alcohol use affects the health of an individual. Walston and Walston's Multidimensional Health Locus of Control Scale was administered to 47 alcoholics in a treatment program. The population reflected a higher belief that health status is more under their own control than under the control of chance or powerful others. However. the results indicated that recovering alcoholics with a more powerful other health orientation tended to maintain membership longer with Alcoholics Anonymous. would seek help sooner. would begin heavy drinking at a later age. and would attempt formal treatment more often.
Cranial electrostimulation (CES) use in the detoxification of opiate-dependent patients, This paper reviews the scientific literature on cranial electrostimulation (CES) as a non-chemical means to alleviate opiate withdrawal symptoms. CES involves applying small amounts of electrical stimulation through electrodes applied to the skin surface over the cranium. The paper summarizes major theories (gate. endorphin. and Chinese acupuncture) which attempt to explain how CES may help alleviate drug withdrawal and craving. Two of the studies reviewed show that CES patients experienced more severe withdrawal during the early part of treatment than comparison groups of methadone patients. Other studies show that CES patients did better than methadone patients. The findings from all studies reviewed. however. were limited because of low participation rates. high dropout rates. difficulties in blinding subjects and evaluators. and the absence of standardized procedures and equipment. The evidence reviewed suggests that CES is a promising line of inquiry for continued efforts to develop nonchemical ways to detoxify opiate-dependent individuals. Improved research designs. larger sample sizes. more integrity in data collection. and improved data analysis are needed in the future.
Case management in addictions treatment, The need for case management in addictions treatment systems has been recognized for at least 10 years. As more attention is paid to developing this treatment component and as more data are available concerning the implementation of case management in addictions. it is becoming apparent that there is a lack of consensus concerning who should provide case management and how it should be defined. This paper reviews sources of variability of case management services identified in the mental health field and discusses the implications for the development of case management in addictions programs.
The role of buspirone in the management of alcohol withdrawal: a preliminary investigation, One hundred eighteen patients. 77 men and 23 women ranging in age from 18 to 70 years of age. admitted to an inpatient facility in Central New York were administered buspirone HCl for treatment of the alcohol withdrawal syndrome. Although one patient had an unwitnessed seizure. none of the subjects required discontinuance of buspirone HCl because of symptoms of dizziness. nausea. headache. nervousness. or lightheadedness. typical side effects described by the manufacturer. All but one of the individuals given buspirone HCl for alcohol detoxification completed that phase of treatment within six days in a manner which effectively controlled their withdrawal symptoms. The findings were suggestive of an important role for buspirone HCl in the detoxification of the alcohol-dependent patient using a pharmacologic agent other than traditional medications such as benzodiazepines. phenobarbital. beta blockers. magnesium sulphate. or clonidine.
The effects of fluoxetine in the overdose patient, Fluoxetine (Prozac) is a new antidepressant. first marketed in the United States in January 1988. Only limited toxicologic information during a fluoxetine overdose is available. The goal of this prospective multi-center study was to develop a toxicity profile of initial signs and symptoms observed in fluoxetine overdose. A standardized data collection form was used on all patients ingesting fluoxetine as reported to four poison centers. Information obtained included age. dose. co-ingested drugs. presenting symptoms. vital signs. EKG abnormalities and lab values. Of the 127 cases of acute fluoxetine overdose collected. 106 cases met the criteria of the study. Of these. 69/106 ingested other drugs. including ethanol and 37/106 ingested fluoxetine alone. Of the latter group. the amounts ingested ranged from 20 to 1500 mg. It was observed that 48.6% (18/37) remained asymptomatic. 16.2% (7/37) were sleepy. 24.3% (9/37) had a sinus tachycardia (of 100 beats per minute or greater). and 8.1% (3/37) had a diastolic pressure over 100 mm Hg. Data collection is ongoing. Based upon our initial experience. fluoxetine in overdose appears to be relatively benign.
Toxicological screening: a three year experience in poisonings in Kuwait, The results of toxicological screening of body fluids (urine. blood and gastric lavage) from pediatric patients were analyzed for the period January 1985 - December 1988. Of the 119 cases. approximately one half were positive for at least one foreign substance. In about one fifth of the cases. multiple substances were detected. The most commonly implicated drugs were those acting on the central nervous system including the barbiturates. tricyclic antidepressants. phenothiazines. benzodiazepines and carbamazepine.
Anatomical relationship between the renal venous arrangement and the kidney collecting system, The anatomical relationships between the renal venous arrangement and the pelviocaliceal system were studied in 52. 3-dimensional polyester resin corrosion endocasts. In 53.8% of the cases. there were 3 large venous trunks and in 28.8% there were 2 venous trunks joining to form the main renal vein. Intrarenal veins demonstrated free anastomoses that were disposed in 3 systems of longitudinal arcades (stellate. arcuate and interlobar veins). There were large venous collars around caliceal necks and also horizontal arches crossing over calices to link anterior and posterior veins. In 84.6% of the cases the upper caliceal group was encircled anteriorly and posteriorly by venous plexuses. which coursed parallel to the infundibulum. In 50.0% of the cases the lower caliceal group also was enriched by 2 venous plexuses. A close relationship existed between a large inferior tributary of the renal vein and the anterior aspect of the ureteropelvic junction in 40.4% of the cases. In 69.2% of the cases there was a posterior (retropelvic) vein: in 48.1% this vein had a close relationship to the junction of the pelvis with the upper calix and in 21.1% it crossed the middle posterior surface of the renal pelvis.
Patient acceptance of and satisfaction with an external negative pressure device for impotence, Patient acceptance of and satisfaction with an external negative pressure device as a treatment for impotence were retrospectively analyzed among 100 men. The over-all satisfaction rate was 68%. Reasons for dissatisfaction with and discontinuing the use of the device included premature loss of penile tumescence and rigidity. pain or discomfort either during application of suction or during intercourse and inconvenience. Negative pressure therapy is an effective treatment for impotence of various etiologies and should be among treatment options offered to the impotent patient.
Mohan's urethral valvotome: a new instrument, Electrothermic fulguration of posterior urethral valves with a resectoscope is difficult in newborns. especially in small for gestation date and premature newborns because of a small caliber urethra. This difficulty has prompted the innovation of the valvotome described. The outer diameter of the valvotome is 3 mm. and it can be easily introduced without stretching the urethra. This instrument has been used successfully in 8 patients to date. Patient age ranged from 3 days to 3 1/2 years with varying degrees of hydronephrosis and hydroureter. All patients have a good urinary stream with regression of the hydronephrosis and hydroureter.
The urethral plug: a new treatment modality for genuine urinary stress incontinence in women, A new modality. the urethral plug. was used to treat 22 women with genuine urinary stress incontinence. The plug is made of thermoplastic elastomer (Kraton G). and consists of a meatal plate. a soft stalk and 1 or 2 spheres along the stalk. The spheres were located according to the result of the urethral pressure profile. The midpoint of the proximal sphere was placed at the bladder neck and the distal sphere was placed just above the maximum urethral pressure point. At voiding the plug was removed and afterwards a new plug was inserted. The plug with 2 spheres was tested in week 1 (period 1) and the plug with only the distal sphere was tested in week 2 (period 2). A total of 22 patients completed period 1. Eight patients did not complete period 2. mostly due to either unchanged incontinence during period 1 or a repeated loss of the plug with 1 sphere. In periods 1 and 2. 73 and 79% of the patients were subjectively and objectively continent or improved. A total of 14 patients completed both periods. Eight patients preferred the plug with 2 spheres. 1 preferred the other plug and 5 had no preference. The side effects were few. This preliminary study shows that the urethral plug seems to be a promising alternative treatment for female genuine urinary stress incontinence.
Long-term urinary continence and renal function in neonates with posterior urethral valves, Posterior urethral valves are known to be associated with considerable morbidity and mortality especially in the neonate. Recently the role of bladder dysfunction in the pathophysiology of renal function impairment and urinary incontinence after valve ablation has been questioned. From 1976 to 1986 we treated 50 male newborns with posterior urethral valves at our institution. Initial treatment in all cases consisted of bladder drainage by a urethral catheter. and correction of existing fluid and electrolyte abnormalities. Subsequent treatment was dictated by the degree of upper tract abnormalities and it included valve ablation alone in 24 patients. vesicostomy and later valve ablation in 8. valve ablation and later upper tract reconstruction in 14 and cutaneous ureterostomy in 4. Followup ranges from 2 to 12 years (mean 6.8). Long-term renal functional impairment was related to the serum creatinine at age 1 year. If the serum creatinine was below 1.0 mg.% all patients (31) had normal values at long-term followup and if it was greater than 1.0 mg.% (19) then only 7 patients had normal values at followup. Urinary continence was assessed in 42 patients and it was normal in 34 (81%). The etiology of incontinence in the remaining 8 patients was bladder dysfunction in 6 and sphincter incompetence in 2. Those patients with urinary incontinence also had a high incidence of upper tract abnormalities (6 of 8. 75%) compared to continent valve patients (10 of 34. 29%).
The management of posterior urethral valves by initial vesicostomy and delayed valve ablation, We managed 32 neonates and infants with temporary vesicostomy and delayed valve ablation. The criterion on which successful management was gauged was estimated creatinine clearance. Renal failure or death occurred in 30% of the patients and 7% required transplantation. There was no apparent difference between our patients managed initially with vesicostomy and other series managed initially with valve ablation in preventing the complications of posterior urethral valves.
Embolization of a giant renal arterial aneurysm, A 49-year-old man presented with right flank pain. Angiography revealed a giant right renal arterial aneurysm. Giant renal arterial aneurysms are typically treated by nephrectomy. In this patient the aneurysm was embolized successfully with multiple Gianturco-Wallace coils and polyvinyl alcohol. This case indicates that embolization may be a reasonable alternative to nephrectomy.
Polyarteritis nodosa masquerading as a primary testicular neoplasm: a case report and review of the literature, We report a case of polyarteritis nodosa presenting as a mass in the testis mimicking a neoplasm. The diagnosis was confirmed by radical orchiectomy. This is an unusual presentation of this systemic disease. We discuss the physical findings. ultrasonographic features and pathological findings. as well as review the literature for previous similar cases.
Burkitt's lymphoma of the testicle: report of 2 cases occurring in elderly patients, Burkitt's lymphoma is rare in patients older than 50 years and almost never presents as a testicular tumor. We report 2 cases of primary Burkitt's lymphoma of the testicle in men 68 and 79 years old. In 1 man the extragonadal tumor had a rapid and lasting response to combination chemotherapy. The cases are of interest for the unusual presentation of the disease and for the possibility to control Burkitt's lymphoma in older patients without undue toxicity. The management of testicular lymphoma requires radical orchiectomy and prophylactic irradiation of the contralateral testis. Chemotherapy is indicated for advanced disease and may prevent relapses in patients with early disease. The role of central nervous system prophylaxis is controversial.
Mechanical properties of the urethra in healthy and stress incontinent females: dynamic measurements in the resting urethra, The relationship between pressure and cross-sectional area in the resting urethra during its inflation and deflation was examined in 30 healthy females and in 30 patients with genuine stress incontinence (GSI). Measurements were performed at the bladder neck. in the high-pressure zone and distally in the urethra. The mechanical properties of the urethra were found to vary significantly as a function of time after induction of a cross-sectional area (stress episode) in both groups of women. The pattern of response of the urethra showed significant differences between normals and GSI particularly during dynamic conditions. Our results indicate that mechanical laxity of the urethra at the bladder neck and midurethrally especially at dynamic events (stress episodes) is of pathophysiological importance in GSI.
Determination of norepinephrine levels in the adult human prostate, Tissue levels of norepinephrine were measured in prostate tissue from 24 men ranging in age between 41 and 83 years. Prostatic tissue was obtained from men with subtle palpable prostate nodules undergoing transperineal needle biopsy. None of the patients were shown to have histologic evidence of adenocarcinoma. The severity of the symptoms of prostatism was evaluated prospectively using a standardized micturition symptom score questionnaire. Norepinephrine levels were quantified using a sensitive radioenzymatic assay (REA). Overall. the prostates contained relatively high levels of norepinephrine (1666 +/- 124 ng./gm.). Inverse correlations were observed between tissue norepinephrine levels and severity of symptoms of prostatism (r = -0.58; p = 0.003); age (r = -0.53; p = .008); and prostate size (r = -0.48; p = .02). Norepinephrine levels were also measured in tissue specimens obtained from men undergoing enucleation prostatectomy and transurethral resection of the prostate (TURP). The level of norepinephrine in these prostatectomy specimens (115 ng./gm.) was only 14% the level of the prostate biopsy specimens. The relatively low level of norepinephrine in the specimens obtained from patients with symptoms necessitating prostatectomy provides further evidence that norepinephrine levels are inversely related to the degree of symptomatic bladder outlet obstruction.
Time-course of alterations of bladder function following acetone-induced cystitis, Although chemical cystitis is known clinically to cause decreased bladder function. there are few experimental studies on the progression of. and recovery from chemical cystitis. Mature male rabbits underwent intravesical instillation of 50% acetone solution through a urethral catheter. Micturition profiles showed a marked decrease of the mean and maximal micturition volume and an increase in number of micturitions as early as one day after treatment. The micturition profile gradually normalized between four and eight weeks after instillation. In vivo cystometry showed a very small bladder capacity and low compliance during the first week following instillation. and gradually recovered to control levels by four weeks. Functional studies using the in vitro whole bladder model showed a significant decrease in the ability of the bladder to generate pressure and to empty at three days after instillation. These parameters recovered partially by two weeks. and completely by four weeks. Chemical cystitis induced by intravesical acetone instillation resulted in a severe decrease in the bladder function. i.e. contracted bladder with low compliance and poor ability to generate pressure and empty. However. these changes were reversible within the two month period of study.
Effects of intracavernosal trazodone hydrochloride: animal and human studies, Trazodone hydrochloride is an oral antidepressant agent which has been associated with the improvement of erections in impotent men and the development of prolonged erections or priapism in potent men. An in vivo study in animal and human subjects was performed to gain experience with the effect of intracavernosal trazodone. In the anesthetized New Zealand White rabbit. intracavernosal trazodone or its major metabolite m-chlorophenylpiperazine (m-CPP) produced full penile erection in 76% and 84% of animals studied respectively with doses ranging from one to 15 mg. On the other hand. intracavernosal administration of five mg. papaverine resulted in a prolonged erection in 90% of animals studied. In 13 selected volunteer patients. intracavernosal trazodone caused tumescence but not full penile erection with corporal body pressures of 28.2 +/- 5.8 mm. Hg. Intracavernosal papaverine or papaverine and phentolamine in these subjects resulted in significantly higher corporal body pressures of 58 +/- 18 mm. Hg (p less than .05). Intracavernosal administration of alpha adrenoceptor agonists but not normal saline resulted in complete detumescence of trazodone- or m-CPP-induced prolonged erection in the animal studies. Intracavernosal trazodone results in erectile activity that appears in part based on its local alpha blocking activity but like other intracavernosal alpha-blocking agents is not as effective in initiating penile erections as are intracavernosal agents that directly induce smooth muscle relaxation.
Hyperfiltration-induced renal injury in normal man: myth or reality, Current knowledge fails to support the notion that adaptive hyperfiltration of the remnant kidney after donor nephrectomy is deleterious. Rather than being maladaptive. hyperfiltration appropriately compensates for the loss of functional renal mass. Accordingly. most kidney donors can be expected to maintain a stable level of renal function without proteinuria or hypertension. Essential to this is proper selection of donors for nephrectomy and exclusion of high risk potential donors. bearing in mind the fact that apparently healthy. asymptomatic relatives of end stage renal disease patients are prone to the same disease processes that inflict the general population and have a higher risk of underlying renal disease.
Triamterene nephrolithiasis: renewed attention is warranted, Although triamterene has been known to contribute to urinary calculus formation. it has been presumed to be a rare phenomenon. Our review of stone analyses performed during the last decade by a single laboratory reveals an increasing incidence of triamterene stones. Awareness of the calculogenic potential of triamterene-containing medications should be re-emphasized.
Prospective comparison of plain abdominal radiography with conventional and digital renal tomography in assessing renal extracorporeal shock wave lithotripsy patients, Most publications citing the effectiveness of renal extracorporeal shock wave lithotripsy have used plain abdominal radiography to assess residual calculi after treatment. We compared radiologist sensitivity and specificity in the detection of calculi on plain abdominal radiographs versus conventional film-screen and digital renal tomograms in extracorporeal shock wave lithotripsy patients. Of the patients 50 were imaged before and within 24 hours after lithotripsy. Six radiologists evaluated the resultant 300 studies for the presence and location of calculi. The mean sensitivity for digital tomograms was 83% for pre-lithotripsy and post-lithotripsy studies. which was significantly higher than for plain abdominal radiography and conventional tomography after lithotripsy. However. there were significantly more false positive stone diagnoses associated with digital tomogram interpretation. Signal detection analysis verified the over-all superiority of digital tomography for post-extracorporeal shock wave lithotripsy imaging. Calculus detection by conventional and digital tomography is superior to detection by plain abdominal radiography. However. because we did not perform delayed imaging. it is not possible to say what impact digital tomography might have on the management of extracorporeal shock wave lithotripsy patients.
Extracorporeal shock wave lithotripsy in patients with bleeding diatheses, Five patients with known bleeding diatheses were treated with extracorporeal shock wave lithotripsy. Specific therapy was administered before extracorporeal shock wave lithotripsy to reverse the bleeding disorder. After treatment each patient was monitored with serial hemoglobin determinations and renal ultrasonography. The course during and after lithotripsy was uneventful in all patients. We conclude that extracorporeal shock wave lithotripsy is a viable option for patients with significant bleeding diatheses provided that specific therapy to reverse the coagulopathic condition is available and used before treatment.
Outcome of renal transplantation after urinary diversion and enterocystoplasty: a retrospective, controlled study, A total of 17 patients with intestinal urinary diversion of enterocystoplasty underwent renal transplantation between 1970 and 1988. Patient age ranged from 4 to 35 years (mean age 20 years). The patients were divided into 2 groups. In group 1 (10 patients. 2 of whom required retransplantation) the ureter of the transplanted kidney was implanted into an ileal (7) or colonic (1) conduit or enterocystoplasty (2). In group 2 (7 patients. 1 of whom required a second transplant) the diversion was taken down and the transplanted ureter was implanted into the defunctionalized bladder. There were 14 living related and 6 cadaveric kidneys transplanted. Graft survival rates were 58 and 87% in groups 1 and 2. respectively. with an over-all rate of 70% (14 of 20 kidneys). There was no statistical difference in the graft survival rate between the 2 groups. The complications in group 1 included ureteroileal anastomotic leak (3 patients). ureteroileal stenosis (1). calculus formation (1). urosepsis (1). hyperchloremic metabolic acidosis (1). and wound infection and dehiscence (1). There were no complications in group 2. Renal transplantation into a pre-existing urinary intestinal conduit or augmented bladder does not statistically adversely affect patient or graft survival. However. the complication rate is much higher when the ureter is implanted into an intestinal segment. Therefore. it is preferable whenever possible to implant the ureter into the native bladder.
The detubularized right colonic segment as urinary reservoir: evolution of technique for continent diversion, Continent diversion of urine via a cecal-right colonic reservoir has been performed at our university hospital since 1977. Several modifications of surgical technique have been devised to prevent problems of urinary leakage and difficulties in catheterization. The current technique. used during the last 3 years on 14 patients. involves use of a detubularized right colonic segment as a reservoir. ileal mesenteric exclusion. fashioning the intussuscepted ileal nipple valve with staples and anchoring of a fascia strip sling around the nipple base to the anterior rectus sheath. Complication from the reservoir outlet occurred in only 1 patient.
Salvage posterior urethroplasty after failed initial repair of pelvic fracture membranous urethral defects, Experience with 20 salvage urethroplasties in patients with pelvic fracture membranous urethral defects who failed previous delayed urethroplasty is presented. A total of 15 patients was successfully managed by 1-stage procedures. 14 by bulboprostatic reanastomosis and 1 by a tubed pedicled island of skin. Substitution urethroplasty with a staged perineoscrotal skin tube inlay was performed in 5 patients in whom an anastomosis could not be achieved either due to an excessively long urethral defect or inelasticity of the anterior urethra precluding its elongation for an anastomosis free of tension. A successful result was achieved in 19 of the 20 patients (95%). The rationale for procedure selection is discussed.
The natural history of Peyronie's disease, The natural history of Peyronie's disease was evaluated in 97 men by means of a questionnaire. Disease duration ranged from 3 months to 8 years. Questions addressed pain. bending. ability for intercourse. over-all effect of the disease. psychological effects. treatments received and degree of disease progression. Approximately 40% of the patients found pain. bending. ability for intercourse and over-all effects to be unchanged during the course of the disease. Bending and ability for relations worsened in 40% of the patients during the same interval. while only 6% had worsening of pain. Of the patients 77% reported psychological effects due to Peyronie's disease. which improved in 28%. did not change in 36% and worsened in 36%. Over-all. 13% of the patients believed the disease to be one of gradual resolution. 47% believed there had been little or no change and 40% believed that the disease pattern was one of gradual progression. We found no statistically significant association between disease duration and spontaneous improvement in penile bending. A similar lack of statistical significance was found when improvement in a variety of categories was compared in patients who received no therapy versus those who received a variety of conventional medical therapies.
A dose titration study evaluating terazosin, a selective, once-a-day alpha 1-blocker for the treatment of symptomatic benign prostatic hyperplasia, The efficacy and safety of terazosin. a selective long-acting alpha-1-adrenergic blocker. were evaluated in 45 normotensive patients with symptomatic benign prostatic hyperplasia ranging from 50 to 76 years old. All patients underwent a complete urodynamic evaluation and transrectal prostatic ultrasonography before enrollment into the study. The dose of terazosin was titrated to 5 mg. per day for a 1-month interval. provided adverse drug reactions were not observed. Of the patients 39 (87%) completed the dose titration study. The parameters used to assess the effectiveness of terazosin included peak and mean urinary flow rates. micturition symptom scores and the global assessment by the patient of symptomatic improvement. Over-all. the mean systolic and diastolic blood pressures changed by less than 1%. The peak and mean urinary flow rates increased by 42 and 48%. respectively. The obstructive and irritative symptom scores improved by 63 and 35%. respectively. Over-all. 30 of the 45 participants (67%) indicated that the voiding symptoms were markedly improved while on terazosin. Five patients did not complete the dose titration study due to development of adverse drug reactions. including erectile dysfunction (7%). tiredness (7%). light-headedness (4%). palpitations (4%). nasal congestion (2%) and asymptomatic hypotension (2%). There were 25 patients (55%) followed on terazosin for 4 to 10 months (mean 6.5 months). The improvements in urinary flow rates and symptom scores were maintained for this interval. Although this preliminary experience with terazosin is encouraging. the ultimate role of terazosin for the long-term treatment of benign prostatic hyperplasia needs further evaluation.
Flutamide in hormone-resistant prostatic cancer, Flutamide (250 mg. orally 3 times daily) yielded a subjective response in 5 of 25 fully evaluable patients with hormone-resistant prostatic cancer. Four additional patients had early progression. A 40% or greater decrease in the pre-treatment prostate specific antigen level was observed in 7 of 24 patients and this finding was correlated with improved survival. Toxicity was mainly gastrointestinal and resulted in permanent discontinuation of flutamide in 5 patients. Flutamide or similar antiandrogens may have a role in the management of hormone-resistant prostatic cancer when relief of subjective symptoms should be an important treatment goal together with improvement of survival. However. before the drug should be used routinely in the management of hormone-resistant prostatic cancer phase 3 studies must confirm its effectiveness. especially in comparison to less expensive drugs.
Total pelvic exenteration with simultaneous bowel and urinary reconstruction, The technique of total pelvic exenteration with simultaneous bowel and urinary reconstruction is described as a surgical option for the management of pelvic sarcoma in adults and for highly selected patients with other types of advanced pelvic malignancy. The surgical technique is presented in detail as performed in a 43-year-old man who presented with extensive primitive pelvic sarcoma. We believe that this approach may provide the benefits of an exenterative operation without the undesirable psychosocial sequelae of a permanent colostomy and external urinary diversion.
Renal autotransplantation in children: a successful treatment for renovascular hypertension, Renovascular hypertension in children is not a common disease. With improved surgical technique the incidence of nephrectomy has decreased and renovascular reconstruction is currently the preferred method to manage this entity. Between 1977 and 1988. 21 patients with renovascular hypertension were treated at our hospital: 7 patients 6 to 16 years old underwent renal autotransplantation. Of the children 4 had unilateral and 3 had bilateral disease requiring bilateral autotransplantation. Autotransplantation was performed by anastomosis of each renal artery end-to-side to the common iliac artery. The renal veins were anastomosed end-to-side to the common iliac veins. The ureters were left intact in all but 1 patient who required a bench operation. Of the 4 patients who had a unilateral procedure 3 are cured and 1 is improved with a normal blood pressure on a small dose of antihypertensive medication. The 3 patients with bilateral autotransplants are cured. These results. with normalization of the blood pressure in 86% of the patients and improvement in blood pressure in 14% with a patency rate of 87%. are similar to other reported reconstructive modalities in children.
The kinetics of cellular proliferation in rat urinary bladder treated with N-butyl-N-(4-hydroxybutyl)nitrosamine, The cellular proliferation of the bladder epithelium was determined sequentially in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). The incorporation of bromodeoxyuridine (BrdUrd) into the DNA synthesis phase was determined by an in vitro labeling technique. The percentage of labeled cells was expressed as the labeling index (LI). The average LI values in normal subjects and cancer-bearing subjects were 5.1(%) and 24.2(%) respectively. With the transition of the bladder epithelium from simple hyperplasia to cancer. the LI values of the bladder epithelium were increased. Cases of papillary or nodular (PN) hyperplasia were divided into two types according to the localization of the BrdUrd-labeled cells. The LI in PN hyperplasia was 12.4(%); the difference from cancer was significant. In another experiment. the effect of partial cystectomy on bladder tumors was examined. The group with partial cystectomy showed increases in grade and stage of cancer. and the LI of cancer was more than that in the group without partial cystectomy. The results indicate that partial cystectomy may play a role as promotor for bladder tumors. The current study may be of more practical value than is the conventional one for investigating the histogenesis and progression of human bladder cancer.
The use of prostaglandin F2 alpha for the prophylaxis of cyclophosphamide induced cystitis in rats, It is well-established that cystitis is a significant cause of morbidity after cyclophosphamide administration in clinical populations. We induced hemorrhagic cystitis in rats using cyclophosphamide and compared controls to those pretreated with prostaglandin F2 alpha. Rats were then evaluated for differences in bladder weights. gross edema. gross bleeding. and histologic changes. The weights of the bladders which had been treated with cyclophosphamide were 94% greater than the controls. The weights of the bladders which were pretreated with prostaglandin F2 alpha before cyclophosphamide were only 19% greater than controls. Significant differences were found between cyclophosphamide controls and prostaglandin F2 alpha pretreated groups for gross weight (p less than .0005). gross edema (p less than .0005). and histology (.0005 less than p less than .005). We conclude that prostaglandin F2 alpha may be helpful in preventing cyclophosphamide induced cystitis.
Cell injury associated calcium oxalate crystalluria, Renal tubular cell damage. resulting in membranuria. was induced by the administration of subcutaneous gentamicin to male Sprague-Dawley rats. One group of rats received gentamicin only. while a second group was given gentamicin plus ethylene glycol in drinking water at a concentration which increased urine oxalate but alone did not cause calcium oxalate crystalluria. Crystalluria occurred early in the combined treatment groups and persisted for the duration of the experiment. Crystalluria was not present in animals receiving gentamicin or ethylene glycol only. These results suggest that cellular fragments can serve as heterogeneous foci for the nucleation of calcium oxalate crystals.
Doppler color-flow images from a stenosed arterial model: interpretation of flow patterns, The capability of the recently introduced Doppler color-flow mapping devices to accurately detect flow patterns in the region of an arterial stenosis was evaluated by use of an in vitro flow model. Pulsatile flow simulating that in a low-resistance vessel was induced through a straight acrylic tube. which alternatively contained axisymmetric stenoses of 0%. 20%. 40%. 60%. and 80% diameter reduction. Doppler color-flow mapper images were taken in realtime along the tube midplane from 0 to 8 diameters downstream of each stenosis. Comparison of the Doppler color-flow mapping results with similarly recorded flow visualization (hydrogen bubble) images showed a close correspondence of key features of the flow. including detection of a high-velocity. centerline jet and near-wall separated flow zones. Distinctive flow patterns exist with each stenotic case. and these should be of considerable value in diagnosing clinical disease conditions.
Everted cervical vein for carotid patch angioplasty, Because of the theoretic benefits of autologous vein we undertook an investigation to evaluate cervical veins (facial. external jugular) as patch material after carotid endarterectomy. A device that stimulated both circumferential fixation by sutures and radial tension exerted on in vivo patches was constructed to measure burst strength of tissue. Mean bursting pressure for groin saphenous vein (n = 10) was 94.5 +/- 15.1 pounds per square inch (psi). 75.5 +/- 8.9 psi for ankle saphenous vein (n = 10). 83.3 +/- 14.5 psi for everted (double layer) cervical vein (n = 5) and 10 +/- 3.3 psi for single layer cervical vein (n = 5). No significant differences between saphenous vein at any level and everted (double layer) cervical vein. but all were significantly different from single layer cervical vein (p less than 0.05). From June 1987 through November 1989. 19 patients underwent 21 carotid endarterectomies complemented with adjunctive everted cervical vein patch angioplasty. Indications for surgery were asymptomatic stenosis (53%). transient ischemic attack (29%). and cerebrovascular accident with recovery (18%). All patients were studied after surgery with duplex scanning. Asymptomatic recurrent stenosis was observed in one patient. Transient hypoglossal nerve dysfunction occurred in one other patient. One postoperative death occurred as a result of massive aspiration. These results indicate that everted cervical vein is comparable to the saphenous vein in resistance to bursting and can yield similar results as patch material after carotid endarterectomy. Accordingly. saphenous vein can be spared and lower extremity incisions avoided.
The effects of an iron chelator on cellular injury induced by vascular stasis caused by hypothermia, Rewarming of a cooled rabbit leg was associated with the generation of oxygen-derived free radicals. shown to be instrumental for tissue injury occurring during rewarming. The present study used a compound that. by its ability to bind with free iron. can remove hydroxyl radical (OH.) from tissue. Deferoxamine reduced tissue injury during cooling and rewarming. as evidenced by its ability to decrease tissue release of lactic acid dehydrogenase and creatine kinase. Deferoxamine also reduced the formation of OH. and lipid peroxidation during the rewarming phase. This compound did not have any effect on the arterial blood flow pattern. which uniformly decreased during cooling and was restored during rewarming. The results of this study indicate the efficacy of deferoxamine in reducing cellular injury associated with cold and rewarming and further suggest a role for oxygen-derived free radicals in the pathophysiology of cold-rewarming injury.
Intraoperative peripheral Nd:YAG laser-assisted thermal balloon angioplasty: short-term and intermediate-term follow-up, Laser-assisted thermal balloon angioplasty was performed in 48 arteries (iliac. superficial femoral. and popliteal). Indications for surgery were limb salvage (25%). rest pain (38%). and claudication (38%). Patients were categorized into three groups: lesions less than 5 cm. greater than 5 to 10 cm. or greater than 10 cm in length. Demographic characteristics. risk factors. and outcome measures were compared by use of Fisher's exact test and Student's t test. The time for vascular patency failure was compared by use of a standard Kaplan-Meier survival analysis for the three groups. Initial failure to recanalize was noted in 14% in lesions less than 5 cm. 40% in lesions greater than 5 to 10 cm. and 73% in lesions greater than 10 cm. The overall success rate was 38%. with a mean follow up of 1 year. The less than 5 cm lesion group had a significantly higher rate of overall success (59%. p = 0.005) than the other two groups combined. The greater than 10 cm lesion group did significantly worse (9%) than the other two groups combined (p = 0.028). Patients in the less than 5 cm group had significantly longer patency than the other two groups (p less than 0.01). Iliac lesions had a higher overall success rate (73%) than superficial femoral and popliteal artery lesions (35%) (p = 0.038). In conclusion. the widespread application of laser-assisted thermal balloon angioplasty cannot be justified without further long-term clinical and laboratory investigation. Conversely. the potential of this technique should not be dismissed out of hand. Proper patient selection. length and nature of the lesion to be treated. and the appropriate forms. doses. and method of delivery of laser energy. remain to be defined.
Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study, The prevalence of comorbid alcohol. other drug. and mental disorders in the US total community and institutional population was determined from 20.291 persons interviewed in the National Institute of Mental Health Epidemiologic Catchment Area Program. Estimated US population lifetime prevalence rates were 22.5% for any non-substance abuse mental disorder. 13.5% for alcohol dependence-abuse. and 6.1% for other drug dependence-abuse. Among those with a mental disorder. the odds ratio of having some addictive disorder was 2.7. with a lifetime prevalence of about 29% (including an overlapping 22% with an alcohol and 15% with another drug disorder). For those with either an alcohol or other drug disorder. the odds of having the other addictive disorder were seven times greater than in the rest of the population. Among those with an alcohol disorder. 37% had a comorbid mental disorder. The highest mental-addictive disorder comorbidity rate was found for those with drug (other than alcohol) disorders. among whom more than half (53%) were found to have a mental disorder with an odds ratio of 4.5. Individuals treated in specialty mental health and addictive disorder clinical settings have significantly higher odds of having comorbid disorders. Among the institutional settings. comorbidity of addictive and severe mental disorders was highest in the prison population. most notably with antisocial personality. schizophrenia. and bipolar disorders.
Ten-year follow-up of behavioral, family-based treatment for obese children, Using a prospective. randomized. controlled design. we examined the effects of behavioral family-based treatment on percent overweight and growth over 10 years in obese 6- to 12-year-old children. Obese children and their parents were randomized to three groups that were provided similar diet. exercise. and behavior management training but differed in the reinforcement for weight loss and behavior change. The child and parent group reinforced parent and child behavior change and weight loss. the child group reinforced child behavior change and weight loss. and the nonspecific control group reinforced families for attendance. Children in the child and parent group showed significantly greater decreases in percent overweight after 5 and 10 years (-11.2% and -7.5%. respectively) than children in the nonspecific control group (+ 7.9% and + 14.3%. respectively). Children in the child group showed increases in percent overweight after 5 and 10 years (+ 2.7% and + 4.5%. respectively) that were midway between those for the child and parent and nonspecific groups and not significantly different from either. At 10 years. child height was related strongly to the height of the parent of the same sex (r = .78 children were 1.8 cm taller than their parents. with no differences in height between groups.
Anaphylaxis following ingestion of a psyllium-containing cereal, Recently. psyllium hydrophilic mucilloid. a bulk-forming laxative. has been added to breakfast cereals for cholesterol-lowering effects. We report a case of a 60-year-old woman with no prior history of psyllium ingestion who developed anaphylactic symptoms after eating a psyllium-containing cereal. Her only previous exposure was dispensing a psyllium-containing laxative as a nurse. Immunoglobulin E-mediated sensitization was documented by skin testing and basophil histamine release. The literature is reviewed regarding allergic reactions to psyllium. Health care workers and pharmaceutical workers handling psyllium may be at increased risk due to sensitization from inhalation. Physicians and consumers should be aware of potential serious reactions from eating psyllium-containing cereals even without prior history of ingestion of psyllium.
Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women [published erratum appears in JAMA 1991 Apr 10;265(14):1828], We prospectively examined the use of estrogen replacement therapy in relation to breast cancer incidence in a cohort of women 30 to 55 years of age in 1976. During 367 187 person-years of follow-up among postmenopausal women. 722 incident cases of breast cancer were documented. Overall. past users of replacement estrogen were not at increased risk (relative risk. 0.98; 95% confidence interval. 0.81 to 1.18). including even those with more than 10 years since last [corrected] use (relative risk after adjustment for established risk factors. 0.70; 95% confidence interval. 0.45 to 1.10). However. the risk of breast cancer was significantly elevated among current users (relative risk. 1.36; 95% confidence interval. 1.11 to 1.67). Among current users. a stronger relationship was observed with increasing age but not with increasing duration of use. These data suggest that long-term past use of estrogen replacement therapy is not related to risk of breast cancer but that current use may modestly increase risk.
Excess deaths from nine chronic diseases in the United States, 1986, To assess excess mortality from chronic disease in the United States. state age-adjusted combined mortality rates for nine chronic diseases in 1986 were compared with three "minimum" rates--two calculated from rates actually achieved in states and a third estimated as the mortality remaining after elimination of one risk factor for each disease. Hawaii had the lowest mortality rate of combined diseases (305/100.000); state excesses ranged from 0% to 37%. The sum of lowest disease-specific rates in any state was 284 per 100.000. indicating excesses of between 7% and 41%. A minimum mortality rate of 224 per 100.000 was estimated to result from elimination of one risk factor for each of the nine diseases. indicating state excesses from 26% to 54%. or 524.000 US deaths. Reduction of US mortality from the nine diseases to the risk factor--eliminated rate is estimated to be associated with an increased life expectancy at birth of 4 years.
Primary hypertriglyceridemia with borderline high cholesterol and elevated apolipoprotein B concentrations. Comparison of gemfibrozil vs lovastatin therapy, A common pattern of dyslipidemia is elevated levels of plasma triglyceride. borderline high total cholesterol. reduced high-density lipoprotein. and increased apolipoprotein B. This pattern of dyslipidemia frequently is associated with premature coronary heart disease. Nicotinic acid is the drug of first choice for this pattern. In this study. gemfibrozil and lovastatin were compared for their effects on the overall lipoprotein profile in 13 men with this type of dyslipidemia. Both drugs significantly reduced very-low-density lipoprotein and intermediate-density lipoprotein cholesterol levels. and both modestly raised high-density lipoprotein cholesterol levels. Gemfibrozil therapy. however. failed to reduce total cholesterol or total apolipoprotein B levels. whereas lovastatin therapy lowered levels of total cholesterol by 28%. low-density lipoprotein cholesterol by 33%. and total apolipoprotein B by 32%. Moreover. lovastatin therapy caused greater declines in lipoprotein cholesterol ratios than gemfibrozil therapy. Lovastatin thus seems to have certain advantages over gemfibrozil for treatment of elevated plasma triglyceride levels accompanied by borderline high total cholesterol and raised apolipoprotein B levels; therefore. lovastatin therapy should be considered as one approach for management of this condition.
The HIV-testing policies of US hospitals, To determine the human immunodeficiency virus-testing policies adopted by US hospitals. we surveyed a stratified random sample of all nonfederal general acute care hospitals. drawn from the American Hospital Association's 1987 database. Interviews were completed with the chief administrator in 561 hospitals (response rate. 78.4%). Two thirds of hospitals have admitted at least one patient with the acquired immunodeficiency syndrome. and over 83% have formal written policies about human immunodeficiency virus testing. Most contain provisions protecting patients' rights; eg. 78% require pretest informed consent. 66% require a special human immunodeficiency virus-testing consent form. and 75% require that patients who test seropositive be so informed. Many policies also contain provisions that protect providers; eg. 56% require that test results appear in patients' records. 38% require review of treatment plans when a patient tests seropositive. and 3% require transferring such patients. Hospital characteristics are not strongly associated with the adoption of testing policies.
Adult open heart surgery in New York State. An analysis of risk factors and hospital mortality rates, This study analyzes data from New York State's new Cardiac Surgery Reporting System. which contains information about cardiac preoperative risk factors. postoperative complications. and hospital discharge. The purposes of the study were to determine the set of significant clinical risk factors and to identify cardiac surgical centers most likely to have serious quality-of-care problems. Significant risk factors for in-hospital death were age. gender. ejection fraction. previous myocardial infarction. number of open heart operations in previous admissions. diabetes requiring medication. dialysis dependence. disasters (acute structural defect. renal failure. cardiogenic shock. gunshot). unstable angina. intractable congestive heart failure. left main trunk narrowed more than 90%. and type of operation performed. Four of the 28 hospitals had significantly higher mortality rates than expected. given the risk factors of their patients. Subsequent site visits and medical record reviews confirmed that these facilities had high percentages of quality-of-care problems among cases resulting in mortality.
Glomerular hyperfiltration indicates early target organ damage in essential hypertension, In 111 patients with essential hypertension (World Health Organization stage I or II). we examined the relationship between renal hemodynamics and left ventricular hypertrophy. Left ventricular structure was determined by two-dimensional guided M-mode echocardiography. renal blood flow by iodine I 131 aminohippuric acid clearance. and glomerular filtration rate by creatinine clearance. The glomerular filtration rate correlated with left ventricular mass (r = .52) and left ventricular cross-sectional area (r = .21). Conversely. at a similar age. body mass index. body surface area. and arterial pressure. hypertensive patients with left ventricular hypertrophy disclosed a higher glomerular filtration rate and filtration fraction than those without left ventricular hypertrophy. whereas renal blood flow and renal vascular resistance measurements were not significantly different. Thus. at similar levels of arterial pressure and renal blood flow. glomerular hyperfiltration was linked to early cardiac structural changes in essential hypertension. We conclude that. in a hypertensive patient with normal renal function. a high glomerular filtration rate may be an indicator for early target organ damage in essential hypertension.
The epidemiology and natural history of pressure ulcers in elderly nursing home residents, We analyzed prospective data from 19.889 elderly residents of 51 nursing homes from 1984 to 1985 to determine the prevalence. incidence. and natural history of pressure ulcers. Among all residents admitted to nursing homes. 11.3% possessed a stage II through stage IV pressure ulcer. For those residents admitted to the nursing home without pressure ulcers during the study period. the 1-year incidence was 13.2%. This increased to 21.6% by 2 years of nursing home stay. People already residing in a nursing home at the start of the study had a 1-year incidence of 9.5%. which increased to 20.4% by 2 years. Pressure ulcers were associated with an increased rate of mortality. but not hospitalization. Longitudinal follow-up of residents with pressure ulcers demonstrated that a majority of their lesions were healed by 1 year. Most of the improvement occurred early in a person's nursing home stay. Although nursing home residents with pressure ulcers have a higher mortality. with good medical care pressure ulcers can be expected to heal.
Positive Lyme serology in subacute bacterial endocarditis. A study of four patients, Lyme borreliosis is a multisystem inflammatory disorder caused by the tick-borne spirochete Borrelia burgdorferi. Clinical manifestations are protean. involving the skin. joints. peripheral and central nervous systems. and the heart. However. the presentation of Lyme disease often overlaps with that of other conditions. We describe four patients from a region endemic for Lyme disease who had elevated levels of antibodies reactive to B burgdorferi and whose signs and symptoms were initially attributed to Lyme borreliosis but whose subsequent blood cultures established a diagnosis of nonspirochetal subacute bacterial endocarditis. Although immunoblots on serum samples from three of the four patients were consistent with prior infection from B burgdorferi. a positive immunoblot does not establish active infection. Similarly. seropositivity to B burgdorferi only indicates possible exposure to this organism. The occurrence of positive serologies to B burgdorferi in the presence of other diseases can lead to diagnostic confusion.
Is exogenous fructose metabolism truly insulin independent, Although fructose is widely regarded as an insulin-independent fuel source. its in vivo conversion to glucose represents a theoretical limitation to its clinical usefulness in diabetics. particularly if given in large doses. To determine whether small amounts of fructose can be well utilized in the setting of insulinopenia. we administered a low-dose fructose infusion (4.2 g/hr) to a fasting type 1 diabetic patient receiving continuous subcutaneous insulin at a dose that had previously maintained stable euglycemia for 72 hr (plasma glucose = 80-110 mg/dl). Despite the low infusion rate (less than 20% of calorie requirement). fructose caused an immediate and marked rise in plasma glucose (to 370 mg/dl after 27 hr). Glucose loss in the urine and accumulation in plasma could account for fully half of the administered hexose load. Thus. the utilization of even small quantities of exogenous fructose is profoundly impaired under hypoinsulinemic conditions. It is misleading to regard fructose as a truly insulin-independent fuel source.
What getting sick means, The concepts of health. disease and death have intrigued man since the beginning of time and are continually evolving. In the nonwestern societies the models which have been proposed for the etiology of disease have a dichotomous view of disease causation which is derived from either natural or supernatural forces. In the Western societies these concepts are well defined. The numerous advances in the fields of genetics and molecular biology have added a new dimension to the understanding of the various factors involved in the pathogenesis of disease processes. These advances have allowed a greater understanding of numerous disease processes including the inborn errors of metabolism. endocrine disorders and human neoplasia. Several recent advances in the areas of molecular biology and physiology allowing this increased understanding of human disease are presented.
A phenomenological interpretation of the variation in dialysate volume with dwell time in CAPD, Intraperitoneal fluid volume (IPV) changes versus time were followed in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) using a simple volume recovery method. In each patient dialysates containing 1.36 and 3.86 percent glucose as an osmotic agent were investigated. The patients' IPV versus time data were fitted to a function determined by four "arbitrary" coefficients. from which both the initial ultrafiltration (UF) rate immediately following intraperitoneal (i.p.) fluid instillation and the "final" peritoneal-to-blood fluid absorption rate could be assessed. The peritoneal osmotic conductance to glucose. that is. the peritoneal ultrafiltration coefficient (Kf). times the peritoneal osmotic reflection coefficient to glucose (sigma g). Kf sigma g. was determined using two related approaches. Kf sigma g is a major determinant of the transperitoneal volume exchange. and it was calculated to be 3.54 +/- 0.85 (+/- SE) and 3.81 +/- 0.52 microliters/min/mm Hg. respectively. depending on the assumption employed. Kf sigma g was further analysed according to a three-pore model of membrane permeability to determine the possible range of Kf and sigma g compatible with a peritoneal small solute sieving coefficient (phi) ranging from 0.3 to 0.61. According to these calculations both Kf and sigma g ranged from 0.043 to 0.081 (ml/min/mm Hg and dimensionless. respectively). The maximal peritoneal lymph flow (L) realistic according to this analysis. and compatible with a measured total peritoneal-to-blood fluid absorption rate of 1.25 +/- 0.14 ml/min. was 0.75 ml/min. the most plausible values. however. falling between 0.3 to 0.5 ml/min.
Improvement of brain function in hemodialysis patients treated with erythropoietin, To evaluate the effects of recombinant human erythropoietin (rHuEPO) on brain function. 15 chronic hemodialysis patients were studied by event-related P300. stimulus-related evoked potentials. and trailmaking before (hematocrit 22.7%) and after rHuEPO (hematocrit 30.6%). P300 peak latency elicited by a tone discrimination paradigm improved (391 before vs. 366 ms after; Cz = vertex; P less than 0.01) confirming beneficial effects on cerebral cognitive processing. P300 amplitude (13.6 vs. 15.8 microV; P = 0.06) and trailmaking tended to improve (55 vs. 43 s). P300 measures were influenced by low hemoglobin levels before rHuEPO (P less than 0.01). suggesting that severe anemia may contribute to uremic brain dysfunction. Furthermore. decrease of stimulus-related auditory brainstem I-V interpeak latency (4.28 before vs. 4.17 ms after; P less than 0.05) and increase of somatosensory N20/P25 amplitude (4.8 vs. 7.0 microV; P less than 0.05) pointed to improvement of sensory pathways by mechanisms unrelated to cognition. Brain dysfunction in chronic hemodialysis patients may. beside other factors. in part be caused by severe anemia and can be improved by rHuEPO treatment.
Peritoneal transport in CAPD patients with permanent loss of ultrafiltration capacity, During a 10 year period. 14 out of 227 patients (6.2%) undergoing continuous ambulatory peritoneal dialysis (CAPD) developed permanent loss of ultrafiltration capacity (UFC). The risk of UFC loss increased from 2.6% after one year to 30.9% after six years of treatment. A six hour. single dwell study with glucose 3.86% dialysis fluid was carried out in nine of the UFC loss patients and in 18 CAPD patients with normal UFC. Intraperitoneal dialysate volumes were calculated using 131I-tagged albumin (RISA) as volume marker with a correction applied for its elimination from the peritoneal cavity. The RISA elimination coefficient (KE). which can serve as an estimation of the upper limit of the lymphatic flow. was also calculated. Diffusive mass transport coefficients (KBD) for investigated solutes (glucose. creatinine. urea. potassium. total protein. albumin and beta 2-microglobulin) were calculated during a period of dialysate isovolemia. Two patterns of UFC loss were observed: (a) seven patients had high KBD values for small solutes resulting in rapid uptake of glucose. whereas KBD values for proteins were normal; (b) two patients had normal KBD values but a threefold increase both in the fluid reabsorption rate and KE. We conclude that loss of the osmotic driving force (due to increased diffusive mass transport for small solutes) and increased fluid reabsorption (possibly due to increased lymphatic reabsorption) are the two major causes of permanent loss of UFC in CAPD patients.
Removal of an inorganic acid load in subjects with ketoacidosis of chronic fasting, When a large inorganic acid load is ingested by normals. the proton load is eliminated because the rate of excretion of ammonium can rise to 200 to 300 mmol/day. In subjects with ketoacidosis of chronic fasting. such a large increase in the rate of excretion of ammonium might not be possible because of ATP balance considerations in proximal cells. Subjects with ketoacidosis of chronic fasting excreted less net acid as defined in the conventional way when they consumed a large inorganic acid load (136 +/- 6 vs. 176 +/- 26 mmol/day in control fasted subjects). Nevertheless. the vast majority of this inorganic acid load was eliminated because they were in steady state and had only a slightly lower concentration of bicarbonate (13 +/- 0.6 vs. 15 +/- 0.5 mmol/liter) and ketoacid anions (3.3 +/- 0.2 vs. 5.5 +/- 0.2 mmol/liter) in their blood. Using a definition of net acid excretion where the component of bicarbonate loss was expanded to include "potential bicarbonate" (ketoacid anions) in the urine. the rate of excretion of net acid was higher in subjects who ingested the inorganic acid load. owing to a much lower rate of excretion of ketoacid anions (9 +/- 2 vs. 120 +/- 7 mmol/day). This lower rate of excretion was not only due to a lower filtered load. but also to a higher fractional reabsorption of ketoacid anions during acidosis (97 +/- 0.1 vs. 77 +/- 0.2%). This higher fractional reabsorption could not be explained by a lower filtered load of ketoacid anions or to a restricted intake of sodium.
Angiotensin II receptor regulation in anti-glomerular basement membrane nephritis, The expression of the glomerular receptor for angiotensin II (Ang II-R) was examined longitudinally following the induction of anti-glomerular basement membrane (GBM) nephritis in the rat. The specific aim of the project was to determine whether immunologically-induced glomerular injury led to significant abnormalities of the relationship between glomerular Ang II-R and its circulating ligand. Ang II. Scatchard analysis was used to measure Ang II-R on purified glomeruli at selected time intervals over two months following a single dose of sheep anti-rat GBM antibody. Corresponding values for plasma Ang II were determined. Receptor density fell to approximately 50% by 16 hours following the injection of antibody (control 96.4 +/- 9.3 x 10(6); nephritic 52.6 +/- 5.6 x 10(6) receptors/glomerulus; P less than 0.001) and there was a corresponding threefold increase in plasma Ang II (control 21.0 +/- 2.5; nephritic 66.6 +/- 20.6 pg/ml; P less than 0.01). However. this reduction in receptor binding could not be explained by the rise in plasma Ang II concentration. as effective blockade of the RAS by enalapril did not alter receptor expression (56.1 +/- 4.6 x 10(6) receptors/glomerulus). Subsequently. a rise in receptor density and a corresponding fall in plasma Ang II were observed: three days after antibody administration. receptor concentration had increased significantly above control values (150.5 +/- 11.9 x 10(6] while plasma Ang II was undetectable (that is. less than 5 pg/ml). Ang II-R remained elevated for the next two weeks but returned to normal four to eight weeks after the administration of nephrotoxic antibody.
Alcohol consumption by college undergraduates: current use and 10-year trends, In a carefully executed study with a high response rate. a random sample of 10% of the undergraduate student body at a rural New England university was surveyed as to the subjects' use of alcohol in 1987. Over 87% of the surveyed students returned questionnaires. The results were compared to similar studies conducted on the campus in 1977 and 1983. "Daily or almost daily" use of alcohol was registered by 4.7% of the respondents. which represents a continuing decrease in daily consumption from earlier studies. One-fourth of the sample indicated drinking only one drink or fewer per week. contrary to the common perception on the campus. Nevertheless. 25.5% recorded a hangover. 7.5% recorded vomiting from drinking too much and 4.4% recorded a blackout. all "in the last week." Compared to the U.S. population. alcohol consumption appears to be more evenly distributed in the college sample but. still. most of the drinking is done by one-fifth of both groups.
Alcohol consumption and problem drinking in Vietnam era veterans and nonveterans, The relationship between Vietnam era veteran status and 13 indicators of alcohol consumption and problem drinking is examined using data from the 1977. 1983 and 1985 National Health Interview Surveys conducted by the National Center for Health Statistics. Compared to a group of nonveterans frequency matched on age. a greater proportion of Vietnam era veterans are currently heavy drinkers and a smaller proportion are abstainers. after simultaneous adjustment for seven demographic factors (age. region of the U.S.. urbanization. ethnicity. marital status. education and income). Further. both white veterans and white nonveterans demonstrate an effect of increasing abstention with increasing age across the 3 interview years. In all race and veteran groups the proportion of lifetime abstainers can be ranked in increasing order as follows: white veterans. white nonveterans. non-white veterans and non-white nonveterans. This ranking is reversed for lifetime heavy drinking. Nearly half of the white veterans report drinking heavily at some point in their lives. Among both whites and non-whites. a significantly greater proportion of veterans than nonveterans report alcohol-related motor vehicle crashes or violations.
Recall of alcohol consumption during pregnancy, This is a test-retest reliability study of self-reported alcohol use during pregnancy. in which two groups of women provided two reports about their first trimester drinking over a 3-month interval (Group 1) and over a 5-month interval (Group 2). Women in Group 1 (n = 91) were queried about first trimester alcohol consumption during their fourth month of pregnancy and again during their seventh month. a 3-month recall interval. Group 2 women (n = 88) provided first trimester drinking reports during their fourth month of pregnancy and again at delivery. a 5-month recall interval. The test-retest Pearson correlation coefficient for recall of first trimester average daily volume (ADV) was .61 (p = .000) for Group 1 and .53 (p = .000) for Group 2. When the ADV scores were grouped into five ordinal categories. 51.6% of Group 1 and 56.8% of Group 2 remained in the same category at test and retest. This leads to the conclusion that self-reported alcohol consumption is moderately reliable over a 3-month and a 5-month time period.
Agreement between two dietary methods in the measurement of alcohol consumption, This study compares estimates of alcohol consumption from two dietary methods: a self-reported diet diary and a quantitative food frequency questionnaire. In the 1984-85 University of Michigan Food Frequency Study. 228 black and white. male and female respondents. ages 23-51 years. kept diet diaries covering 16 days during a 1-year period. At the end of the year. the same respondents completed a dietary quantity-frequency questionnaire that included alcoholic beverages. The two methods showed excellent agreement in estimated group mean ethanol consumption and good agreement in the ranking of individual respondents. Respondents described alcohol consumption in abstract terms on the questionnaire in a way that was consistent with the consumption recorded in the diary. However. the two methods showed only poor to moderate agreement in classifying individuals as infrequent. moderate or heavier drinkers. suggesting that such classifications should be used cautiously. These results suggest that in general population studies a dietary quantity-frequency questionnaire and a diet diary covering several weeks can measure moderate levels of alcohol consumption similarly. The degree of consistency suggests that. for moderate levels of intake. measures of alcohol consumption derived from the two methods are equally valid.
Anomie, alcohol abuse and alcohol consumption: a prospective-analysis, Cross-sectional and 36-month prospective analyses of the relationships among anomie and both alcohol abuse and alcohol consumption patterns provided little support that anomie was directly associated with ethanol ingestion patterns in a sample of 302 male air traffic controllers. This lack of association was observed for self-reported alcohol consumption. interview-established alcohol abuse and biochemical markers of alcohol intake. In addition. anomie was not predictive of change in alcohol use/abuse over 36 months. controlling for baseline levels of alcohol use and abuse and for relevant demographic factors. Measurement of anomie and alcohol use/abuse. the relative importance of anomie in various socioeconomic groups and issues related to prospective research on this topic are discussed.
The situational riskiness of alcoholic beverages, Using face-to-face interview data on a sample of young adults. this study investigates the perceived risk of alcohol consumption in drinking and driving. interactions with police and the probability of intoxication. Results show that beer is perceived as less risky than liquor in two risk situations. with men and drinkers in particular ranking beer as a lower risk beverage. When intoxication is considered. drinkers rank their preferred beverage as less risky than their alternative. Finally. an analysis of the relative riskiness of beer in comparison to liquor reveals that beer is perceived as less risky than liquor. This consensus does not vary significantly by sex or most other respondent characteristics.
Portrayals of alcohol on prime-time television, Alcohol portrayals were analyzed for a 3-week composite sample of prime-time fictional television programs aired in the fall of 1986. Approximately 64% of the 195 episodes contained one or more appearances of alcohol. Alcohol was ingested on 50% of all programs. Overall. there were 8.1 alcohol drinking acts per hour. Movies made-for-television had the highest rate of drinking acts per hour (10.0) followed by situation comedies (9.2) and then theatrical movies (7.4) and dramas (7.4). Within the category of dramas. evening soap operas stand out with 13.3 acts per hour. Drinking and nondrinking characters were compared on a number of attributes relevant to role modeling. Regularly appearing characters were more likely to drink than nonregular characters. Drinking characters also tended to be of high status. largely being white. upper-class professionals. A time trend analysis showed a regular increase in alcohol on television from 1976 to 1984. reaching 10.2 acts in 1984. After 1984 the trend appears to reverse.
Public support for policy initiatives regulating alcohol use in Minnesota: a multi-community survey, Public support for policies to control alcohol sales and consumption was surveyed in seven Minnesota communities. A total of 438 women and 383 men were asked to indicate their level of support of or opposition to nine different proposals designed to regulate alcohol. There was general support for all policies. which was strongly related to characteristics of respondents and type of policy proposed. Women were significantly more supportive of all items than were men. Marriage. older age and low alcohol consumption were also associated with support. Education and voter status generally were not. Policies and activities that serve primarily to protect youth received the strongest support. Restrictions and prohibitions such as limiting advertisements were less popular. The least support was expressed for increases in taxes on alcohol and for measures that would eliminate an existing practice such as prohibiting wine-cooler sales at convenience stores. The majority of respondents also indicated that they felt the individual. as opposed to the manufacturer or retailer. was responsible for problems associated with alcohol and should be the focus of intervention. Strategies for shifting the focus from the individual to environmental and regulatory control are discussed.
A comparison of familial and nonfamilial male alcoholic patients without a coexisting psychiatric disorder, Both family history of alcoholism and the presence of additional psychiatric disorder in male alcoholic patients are associated with an earlier onset of problem drinking. greater alcoholism severity and poorer clinical outcomes. To assess the relative contribution of family history alone. a sample of 212 male alcoholics not positive for any other psychiatric disorder was selected and divided into those with a family history of alcoholism (FH+) or no family history of alcoholism (FH-) among first degree relatives. Although FH+ alcoholics reported a younger age of onset of problem drinking and greater severity of some alcohol-related sequelae. the differences were not as extensive or pronounced as those found in a previous study of a sample of psychiatrically heterogeneous patients (Penick et al.. 1987). A bi-dimensional typology of alcoholism incorporating both additional psychiatric diagnoses and a positive family history of alcoholism is suggested.
The relationship between ethanol intake and DSM-III-R alcohol dependence, The purpose of this investigation was to quantify the relationship between ethanol consumption and DSM-III-R alcohol dependence using mathematical modeling techniques that allowed for the control of confounding and assessment of interaction. Although sex. education. ethnicity and marital status were not identified as actual confounders in the logistic regression model. the ethanol intake-dependence association was stronger among younger as opposed to older respondents. For 20 year olds. the average log odds for dependence increased .62 for each additional ounce of ethanol consumed daily. while the corresponding increase in risk among 60 year olds was .26. Implications of these results are discussed in terms of age differences in drinking patterns and differential social control of drinking behavior. Separate analyses in which aggregates of the alcohol dependence criteria served as outcome measures helped qualify the interpretation of the overall ethanol intake-dependence relationship. The need to examine components of global classifications of alcohol dependence using better operationalizations is highlighted.
The MAC scale in a normal population: the meaning of "false positives", The MAC scale has been very successful in identifying alcoholics and. in studies of clinical populations. is often considered a test for predisposition to alcoholism. MacAndrew. however. holds that the MAC scale assesses a more general personality trait characterized by sociability. boldness. rebelliousness and pleasure seeking. The present study examines the distribution of MAC scale scores in a normal population and tests for correlates of high MAC scores other than alcohol-related problems (e.g.. arrest history). The sample consisted of 1.117 men. participants in the Normative Aging Study (mean age = 61.6). As expected. heavier drinkers and problem drinkers reported significantly higher MAC scale scores than did lighter and nonproblem drinkers. However. arrestees without drinking problems had MAC scale scores nearly identical to those of problem drinkers without arrest histories (23.19 and 23.42. respectively). Further. 36% of the sample without problem drinking or arrest histories had MAC scale scores of 24 or above. the clinical indicator of alcoholism. and more than 32% of these had scores above 27. In the entire sample. of the 152 men who had MAC scores above 27. 71% had no problems. either with arrest or drinking. Results are interpreted as supporting MacAndrew's interpretation of the meaning of the MAC scale as a general personality measure rather than a specific alcoholism instrument.
The effect of gender and subtype on platelet MAO in alcoholism, Decreased platelet MAO activity has been identified in male alcoholics with suggestions that this is primarily true of Type 2 alcoholics as defined by criteria from the Stockholm Adoption Study. Little information has been available regarding platelet MAO activity in female alcoholics. This study evaluated a group of 71 alcoholics receiving inpatient treatment. including 16 female alcoholics. for platelet MAO activity compared to controls. Female alcoholic's platelet MAO was significantly lower than controls and not different from activity levels in male alcoholics. Among male alcoholics. both Type 1 and Type 2 subgroups were lower than controls and Type 2 levels did not differ from Type 1 levels. Thus. we were unable to replicate a gender and subgroup low platelet MAO specificity among alcoholics. but did find significant differences between alcoholics and controls.
The acute effects of alcohol on the blood pressure of young, normotensive men, Alcohol's acute effects on arterial blood pressure (BP) were examined. To separate the effects of alcohol on BP from those of fluid volume and expectancy. normotensive men were divided into three groups. The alcohol group received 1.0 ml of absolute alcohol/kg of body weight. The expectancy group expected alcohol but received only tonic. The control group expected and received only tonic. With age as a covariate. significant changes in systolic BP were found only in the alcohol group. indicating that the changes in systolic BP were not attributable to subject expectancy or volume of fluid consumed. The expectancy control groups did not differ from each other. A significant quadratic trend was found for systolic BP in the alcohol group. suggesting that alcohol may have an acute biphasic effect on systolic BP. with an initial decrease as the alcohol is ingested followed by an increase toward the basal level during detoxication. No significant effects were found for diastolic BP.
Preoperative cell-mediated immune function and the prognosis of patients with gastric carcinoma, The cell-mediated immune function of 83 patients with gastric carcinoma was assessed preoperatively and the results were compared to that of 52 patients with benign lesions. The data were subjected to an analysis in order to evaluate their prognostic significance. The abilities to induce allogeneic cytotoxicity and to produce interleukin 2 (IL2) in patients with stage IV carcinoma were significantly depressed. as compared to those in patients with benign lesions. whereas natural killer (NK) cell activity was not significantly impaired. There was no significant correlation among these immune functions. When the patients were stratified into two groups. those who had high (greater than the mean value in patients with benign lesions) and low (less than the same value) values of these immune reactivities. the survival of patients with high NK activity (greater than or equal to 43%) was significantly better. as compared to that of patients with low cytotoxicity (less than 43%). However. there was no correlation between the survival and allogeneic cytotoxicity in these patients. The high ability to produce IL2 (greater than or equal to 1.3 U/ml) correlated with the better survival in the patients. but not in the group of patients who underwent curative resection.
Toxicity comparison of neoadjuvant versus adjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) in radical cystectomy patients, A reduction in the toxicity of M-VAC chemotherapy has been postulated for patients who receive these drugs prior to radical cystectomy for muscle invasive bladder carcinoma. A review of the toxicity and patient dropout rates from a group of 9 patients who received neoadjuvant M-VAC was little different from 9 patients who were treated with M-VAC after radical cystectomy. This similarity suggests that preoperative M-VAC should not be favored on the basis of reduced patient morbidity.
Neoadjuvant Cis-DDP in esophageal cancers: an experience at a regional cancer centre, India, We are analysing the results of 80 patients who underwent surgery during 1983-84 for esophageal cancer. Forty patients who received pre-operative single agent Cis-DDP were grouped under "A" and 40 patients who went for surgery directly were grouped under "B". Twenty-two patients (55%) of Group A showed tumor necrosis. Both groups underwent resection and hand-sewn anastamosis of the esophagus. There were 10 post-operative deaths among 80 resected cases. 9 of them being from anastomatic leak. Cis-DDP has induced negligible side effects. A comparatively high survival rate during early years in patients who responded to Cis-DDP suggests that neoadjuvant chemotherapy might be of value.
In vivo selection and characterization of a murine mammary tumor subline with high potential for spontaneous lymph node metastasis, A transplantable mammary adenocarcinoma. grown in Balb/c mice. with a marked enhancement in its draining lymph node metastatic ability (MM3LN). was obtained through an in vivo procedure from a variant tumor moderately metastatic to lymph nodes (MM3). Both MM3 and MM3LN presented a similar latency and tumor growth rate and reached the same tumor mean diameter at death. MM3LN tumor-bearing mice exhibited a larger mean survival time. The new variant showed a 2.5-fold higher incidence of tumor-draining lymph node metastases than MM3 line. with no differences in the incidence of lung metastases. Morphology as well as cytogenetic and in vitro adhesion properties were studied in order to characterize the new subline. This murine tumor model has potential application in the study of the metastatic process in lymphoid tissue.
Ampullary carcinoma in patients under 50 years of age with a poor prognosis, Clinicopathologic features of 145 Japanese patients with ampullary carcinoma were compared among three age groups. The 145 patients were divided into three groups by the patient's age at the time of operation; there were 24 patients in group I (younger) aged less than or equal to 50 years. 99 in group II (ordinary) aged 51-69. and 22 in group III (elderly) aged greater than or equal to 70. The three groups showed no significant difference in sex. icterus. duration of icterus. size of the tumor. year of operation. macroscopic type. histopathologic type. tumor margin. lymphatic permeation. venous invasion. or pancreatic invasion. The survival curve of group I was worse than those of groups II and III. Multivariate regression analysis using 11 prognostic variables failed to reveal that the age of the patient at the time of operation was an independent factor. The younger patients aged less than or equal to 50 fared worse than the elderly patients aged greater than or equal to 70. because the group I tumors included a significantly greater number of advanced ampullary carcinoma with more frequent perineural invasion than did the group III tumors.
Repair of transposition of the great arteries with intact ventricular septum and left ventricular outflow tract obstruction, Repair of transposition of the great arteries in patients with intact ventricular septum and fixed left ventricular outflow tract obstruction has been restricted to atrial baffle procedures. with or without attempts to relieve or bypass the left ventricular outflow obstruction. However. the suboptimal results of these procedures. coupled with excellent functional results with the arterial switch operation in patients without obstruction. has made anatomic correction the goal in repairing these anomalies. We report a technique for the anatomic correction of transposition of the great arteries. intact ventricular septum. and fixed left ventricular outflow tract obstruction. Its consideration in these difficult cases is advocated.
The effects of dopamine on myocardial functional recovery after reversible ischemic injury, Dopamine frequently is used to improve cardiac performance after acute myocardial ischemia. Inotropic agents. however. increase myocardial oxygen demand and could potentially delay recovery from ischemic injury. To evaluate this problem. we studied eight chronically instrumented dogs in the conscious state and performed two 15-minute coronary occlusions 48 hours apart. After one of the occlusions. either dopamine (15 micrograms/kg/min) or saline placebo was administered intravenously from 1.0 to 1.5 hours of reperfusion. The alternative infusion was given during the second study. Preload recruitable work area. the area beneath the stroke work versus end-diastolic length relationship. was used to assess intrinsic myocardial performance. Ischemia decreased preload recruitable work area to 13% of control after both occlusions. After reperfusion. a 30-minute dopamine infusion acutely increased myocardial function nearly threefold as compared with placebo. Myocardial performance after dopamine administration. however. was significantly depressed compared with placebo throughout the remaining 24 hours of reperfusion (p less than 0.01). These data indicate that dopamine may impair functional recovery after ischemic myocardial injury and suggest that inotropic interventions should be used in this setting only when absolutely indicated.
Studies of controlled reperfusion after ischemia. XVIII. Reperfusion conditions: attenuation of the regional ischemic effect by temporary total vented bypass before controlled reperfusion, This study tests the hypothesis that total vented bypass can attenuate the regional ischemic effect during a defined time interval before controlled blood cardioplegic reperfusion. Thirty-three dogs underwent 2 or 4 hours of occlusion of the left anterior descending coronary artery and then received a regional blood cardioplegic reperfusate on total vented bypass. Cardiopulmonary bypass and reperfusion were started after 2 hours of ischemia in eight dogs. and after 4 hours of ischemia in 25 others. Among the 25 dogs. seven had total vented bypass started after the first 2 hours of the 4 hours of regional ischemia. Segmental shortening (ultrasonic crystals). tissue water content (wet/dry weight). and histochemical damage (triphenyltetrazolium chloride stain) were assessed 2 hours after reperfusion. Dogs reperfused after 2 hours of ischemia recovered 73% +/- 8% of control systolic shortening and sustained only 11% triphenyltetrazolium chloride nonstaining. Dogs undergoing 4 hours of regional ischemia. but with total vented bypass 2 hours before reperfusion had improved recovery of systolic shortening (49% versus 31%. p less than 0.05). limited epicardial edema (79.6% versus 81.1% water content. p less than 0.05). and reduced histochemical damage (24% versus 39% triphenyltetrazolium chloride nonstaining. p less than 0.05). These findings imply that institution of total vented bypass during ischemia attenuates the infarct process. increases regional recovery of contractility. limits edema and restricts histochemical damage. and may be a useful adjunct to myocardial salvage when controlled reperfusion can be provided.
Simulated left ventricular aneurysm and aneurysm repair in swine, Patch reconstruction of left ventricular aneurysm may be superior to linear closure. but this hypothesis has not been tested experimentally. Accordingly. six anesthetized domestic pigs were instrumented to measure regional left ventricular wall thickening. stroke volume. systolic left ventricular pressure. and myocardial oxygen consumption. With total bypass and cardioplegia. a 6 by 8 cm Dacron patch was inserted into the anteroapical left ventricle. Simulations were as follows: left ventricular aneurysm. patch open; patch reconstruction. 50% patch plication; standard repair. ventriculotomy edges approximated. Global function. from stroke work (stroke volume x integral of left ventricular pressure)-left ventricular end-diastolic pressure curves. was depressed in all three simulations compared with control. A tendency for stroke work to be greater for standard repair than for left ventricular aneurysm and patch reconstruction at higher preloads was not statistically significant. Mechanical efficiency. from stroke work/myocardial oxygen consumption (joules per milliliter oxygen per beat). was 2.43 +/- 0.52 (mean +/- standard error of the mean) (control). 2.22 +/- 0.94 (standard repair). 1.27 +/- 0.39 (patch reconstruction). and 1.09 +/- 0.37 (left ventricular aneurysm) (no significant differences). Regional work was calculated as regional left ventricular wall thickening x integral of left ventricular pressure. The slope of the regional work-end-diastolic wall thickness relation decreased in the posterior wall 14.0 +/- 2.9 (control) versus 8.4 +/- 2.0 (left ventricular aneurysm). 6.9 +/- 1.4 (patch reconstruction). and 7.4 +/- 1.4 (standard repair) (p less than 0.05). In the anterior wall. contractility did not change significantly (7.4 +/- 1.2. control; 7.8 +/- 2.7. left ventricular aneurysm; 5.0 +/- 0.4. patch reconstruction; and 5.3 +/- 0.4. standard repair). Decreased end-diastolic wall thinning anteriorly suggested tethering. These results in the normal left ventricle suggest that patch ventriculoplasty is of no greater benefit than linear repair. Either repair may impede function of adjacent myocardium through restriction of regional diastolic lengthening.
Intraoperative transesophageal color-coded Doppler echocardiography for evaluation of residual regurgitation after mitral valve repair, Because mitral valve competence after mitral valve reconstruction is awkward to assess during this procedure. we evaluated in this respect transesophageal color-coded Doppler echocardiography in 23 patients undergoing mitral valve reconstruction for severe mitral regurgitation. Transesophageal echocardiographic examinations were performed after induction of anesthesia but before sternotomy (baseline). after mitral valve repair before decannulation. and at sternal closure. all at similar mean aortic pressure and echocardiographic instrument settings. The degree of mitral regurgitation by transesophageal color Doppler flow mapping was visually quantified on a 5-point scale (0 to 4). pending the left atrial extent of the regurgitant jet. This was compared with the degree of mitral regurgitation by left ventricular cineangiography performed within several weeks after operation and also visually quantified on a 5-point scale (0 to 4). with use of the right anterior oblique projection. There was good correlation between the two methods (r = 0.83; p less than 0.001). We conclude that residual mitral regurgitation. as assessed by transesophageal color flow mapping in the operating room. highly correlates with the ultimate mitral regurgitation by cineangiography. Therefore transesophageal echocardiography can be helpful for evaluation of mitral valve competence during mitral valve reconstruction. and hence. in case of repair failure. allow valve replacement in the same surgical session. thus avoiding reoperation.
Mitral valve replacement in the first year of life, From 1973 through 1987 25 patients underwent mitral valve replacement in the first year of life for mitral stenosis and mitral regurgitation. The patients with mitral stenosis included two with mitral arcade. two with supravalvular mitral stenosis with hypoplastic mitral valve. and one with parachute mitral valve. Included in the group of patients with mitral regurgitation were 12 with atrioventricular canal defect. six with chordal and leaflet defects. one with Marfan's syndrome. and one with bacterial endocarditis. Prostheses included 12 Bjork-Shiley (17 mm). seven St. Jude Medical (19 mm in four. 21 mm in three). five stent-mounted dura mater valves (12 mm to 16 mm). and one porcine xenograft (19 mm). In four patients the valves were placed in the left atrium in a supraannular location. There were nine operative (atrioventricular canal defect seven. mitral regurgitation two) and five late (atrioventricular canal defect four. mitral stenosis one) deaths. giving actuarial 1- and 5-year survival rates of 52% and 43%. respectively. All 6 patients with tissue valves died; the four with supraannular mitral valve replacement survived. Since 1983 operative mortality has been reduced to 0% (70% confidence limits 0% to 24%). Nine patients required a second mitral valve replacement for prosthetic stenosis 5 to 69 (mean 30) months after the original mitral valve replacement (one operative death). Because of improvements in repair of atrioventricular canal defect in infancy. the need for mitral valve replacement at atrioventricular canal defect repair has decreased. Although valvuloplasty has been advocated for repair of congenital mitral valve disease and is applicable in some infants with mitral regurgitation. mitral valve replacement is frequently unavoidable for congenital mitral disease and can now be accomplished at a low operative risk. even when the prosthesis has to be positioned supraannularly.
Parathyroid hormone-related peptide in lactation and in umbilical cord blood, Parathyroid hormone-related peptide (PTHrP) is expressed in lactating rat mammary glands after suckling. as a result of increases in prolactin rather than suckling per se. In addition. PTHrP produced in the fetal parathyroid glands and placenta may be responsible for stimulation of placental calcium transport. In the current study. we used a radioimmunoassay for human PTHrP to measure levels of the peptide in (1) human breast milk. cow's milk. and two infant formulas; (2) sequential plasma samples in prepartum and postpartum lactating women; (3) women with pathologic hyperprolactinemia; and (4) human umbilical cord blood. In normal subjects. plasma PTHrP levels ranged from less than 2 to 5 pmol/liter. In contrast. human breast milk contained substantially increased levels of immunoreactive PTHrP. Similar elevations were found in cow's milk and in one infant formula. Column chromatography of breast milk demonstrated that PTHrP immunoreactivity included a region of adenylate cyclase stimulating activity. consistent with the presence of biologically active PTHrP. Plasma prepartum PTHrP values did not differ from corresponding postpartum values in lactating women. Women with hyperprolactinemia had a mean plasma PTHrP value in the high-normal range. Umbilical cord blood had considerably suppressed parathyroid hormone values but PTHrP levels that were indistinguishable from those in normal human plasma. Thus. PTHrP is present in high concentrations in breast milk but apparently does not gain access to the maternal circulation in significant amounts. In addition. women with pathologic hyperprolactinemia seem not to have increased levels of circulating PTHrP.
Paraneoplastic cerebellar degeneration: a clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies, In a review of 32 patients with paraneoplastic cerebellar degeneration (PCD). 16 (all of whom were women) had Purkinje cell cytoplasmic antibodies (PCAb) and 16 (8 women) did not. Most patients (15 of 16 seropositive and 12 of 16 seronegative patients) had active cancer at the time of neurologic diagnosis. Gynecologic or breast cancers were found in 14 of 16 seropositive and in 2 of 8 seronegative female patients; lung cancer was diagnosed in 7 of 16 seronegative patients but in no seropositive patient. In seropositive patients. the onset of the syndrome was more often abrupt and abnormalities of affect. mentation. ocular motility. and cerebrospinal fluid IgG index were more common than in seronegative patients. Additional paraneoplastic neurologic syndromes were present in five seronegative patients but in no seropositive patient. Clinical impairment was equivalent in both groups; approximately 75% of patients were confined to a wheelchair or bed at last follow-up. Four of 16 seropositive patients died (4 to 18 months after onset of PCD). and 7 of 16 seronegative patients died (7 to 120 months after onset of PCD). Thus. PCAb seem to be a marker for a clinical subset of female patients with gynecologic or breast cancer. The high frequency of other autoimmune paraneoplastic syndromes in patients with seronegative PCD suggests that PCD in both seropositive and seronegative patients may have a common pathogenic basis that involves an as yet unidentified antineuronal autoimmune mechanism.
Assessment of functional gastrointestinal disease: the bowel disease questionnaire, A need exists for a self-report questionnaire that reliably and accurately measures symptoms and that distinguishes patients with functional gastrointestinal disease from those with other conditions. We have developed such an instrument. the bowel disease questionnaire. and herein describe details of its discriminatory validity. Data from 399 subjects were analyzed. Patients with gastrointestinal symptoms were ultimately diagnosed as having functional gastrointestinal disease (82 with the irritable bowel syndrome and 33 with functional dyspepsia) or organic gastrointestinal disease (N = 101). There were 145 healthy control subjects and 38 patients with a psychiatric disease. somatoform disorder (which includes those with a diagnosis of hypochrondriasis. psychogenic pain. and somatization or conversion disorder). All subjects completed the questionnaire before undergoing an independent diagnostic assessment by experienced physicians. Functional gastrointestinal disease could be distinguished from organic disease. somatoform disorder. and health by using models derived from logistic discriminant analysis. With use of these models. the estimated probability of functional gastrointestinal disease was then calculated. Descriptive symptom scores were of less value than the scores derived from the data sets by logistic discriminant analysis. Age did not significantly affect the responses to the questionnaire items. We conclude that. in the population studied. the bowel disease questionnaire is a valid measure of symptoms of functional gastrointestinal disease. and this instrument may have clinical and research applications.
Polymyositis: a case history approach to the differential diagnosis and treatment, A wide range of conditions can mimic polymyositis. Thus. diagnosing this condition can be a challenge. Although no single criterion is diagnostic of polymyositis. the following criteria have been proposed and widely used: (1) symmetric proximal muscle weakness; (2) characteristic violaceous rash on the hands. elbows. and knees; (3) increased muscle enzymes in the serum; (4) characteristic electromyographic findings (insertional activity. fibrillation potentials. motor unit potentials of increased frequency and decreased duration. and normal conduction velocity in nerves); and (5) muscle biopsy specimen with characteristic inflammatory and myopathic changes. Although polymyositis primarily involves muscle. up to 20% of patients may have extramuscular problems. The main treatment for polymyositis is high-dose corticosteroids. In corticosteroid-resistant patients. methotrexate is often effective. In this report. case histories are presented to highlight the usefulness and the limitations of the common diagnostic criteria for polymyositis.
Hypersecretion of luteinising hormone, infertility, and miscarriage, The relation between prepregnancy follicular-phase serum luteinising hormone (LH) concentrations and outcome of pregnancy was investigated prospectively in 193 women with regular spontaneous menstrual cycles. The group included 26 nulliparous and 167 multiparous women with various obstetric histories. Of the 147 women with LH concentrations of less than 10 IU/l (normal LH group) 130 (88%) conceived. whereas only 31 (67%) of the 46 women with LH values of 10 IU/l or more (high LH group) did so. In the high LH group. 20 (65%) of the pregnancies ended in miscarriage. whereas only 15 (12%) of pregnancies in the normal LH group did so. The adverse effect of a high prepregnancy LH concentration on fertility and outcome of pregnancy was seen in primigravidae. women with previously successful pregnancies. and women with a history of recurrent miscarriage. These data indicate an important role for hypersecretion of LH before conception in miscarriage. This finding offers the possibility of a simple predictive test for women before pregnancy. and could also be used to identify patients with an endocrine abnormality that can be remedied.
Changing epidemiology of group A streptococcal infection in the USA, To see whether changes in the epidemiology of group A streptococcal disease in the USA have been accompanied by a corresponding change in serotype distribution. epidemiological and M-typing and T-typing data for 5193 strains sent to the Centers for Disease Control. Atlanta. between 1972 and 1988 were analysed. The proportions of M-types 1. 3. and 18 increased significantly during the study period. These M-types were more likely to be invasive. to cause fatal infection. and to occur in a cluster of infections than were other types. By contrast. the proportions of M-types 4 and 12 decreased; they were less invasive and were less likely to be found in clusters than were other types. These data suggest that changes in the epidemiology of group A streptococcal disease may be related to changes in the distribution of M-types causing infection.
Features of "near-death experience" in relation to whether or not patients were near death, The medical records of 58 patients. most of whom believed they were near death during an illness or after an injury and all of whom later remembered unusual experiences occurring at the time. were examined. 28 patients were judged to have been so close to death that they would have died without medical intervention; the other 30 patients were not in danger of dying although most of them thought they were. Patients of both groups reported closely similar experiences but patients who really were close to death were more likely than those who were not to report an enhanced perception of light and enhanced cognitive powers. The claim of enhancement of cognitive functions despite the likelihood that brain function had probably become disturbed and possibly diminished. deserves further investigation.
Preliminary report: the antegrade continence enema, The principles of antegrade colonic washout and the Mitrofanoff non-refluxing catheterisable channel were combined to produce a continent catheterisable colonic stoma. The intention was that antegrade washouts delivered by this route would produce complete colonic emptying and thereby prevent soiling. The procedure has been successfully carried out in five patients with intractable faecal incontinence.
Increased cholecystectomy rates in Saudi Arabia, Gallstones have become increasingly prevalent in Saudi Arabia. where cholecystectomy is now one of the commonest major abdominal operations. 2854 people underwent cholecystectomy in the 14 hospitals of the country's Eastern Province in the years 1977 to 1986. During this period the overall frequency of cholecystectomy increased by 978%. a finding not explained by the 67% increase in population or the 87% increase in other operations. Simultaneously. the average daily individual consumption of total calories. fat. and sugar increased by 81%. 197%. and 164%. respectively. and consumption of high-fibre grain fell by 75%. This striking increase in the frequency of cholecystectomy. which presumably reflects the incidence of gallstones. cannot be explained by demographic changes and seems more closely linked to the concomitant changes in dietary habits.
Cytomegalovirus and Rasmussen's encephalitis, In-situ hybridisation with a biotinylated cytomegalovirus (CMV) DNA probe was done on brain biopsy specimens from 10 patients with Rasmussen's encephalitis (RE) and 46 age-matched control patients with other neurological diseases. All 10 patients with RE had intractable epilepsy and focal neurological deficits. and there was perivascular cuffing. microglial nodules. astrogliosis. and neuronal loss. CMV genomic material was demonstrated in 7 of the 10 patients with RE (in neurons. astrocytes. oligodendrocytes. and endothelial cells) and in 2 of the 46 control patients. Probes for herpes simplex virus and hepatitis B virus were negative in all patients and in fibroblast controls. The results suggest that CMV is a likely cause of Rasmussen's encephalitis.
Acute hypervolaemic haemodilution to avoid blood transfusion during major surgery, 16 patients underwent acute hypervolaemic haemodilution with dextran 40 and Ringers lactate. to see whether this procedure could avoid preoperative blood transfusion. Packed cell volume (PCV) and oxygen extraction decreased. and cardiac index and pulmonary wedge pressure increased. although end-systolic area was unchanged. PCV was not significantly different between patients who lost less than or greater than 20% of their initial blood volume. This preoperative manoeuvre. which reduces loss of red blood cells. allowed major surgery to be completed safely without blood transfusion.
Child abuse of one of a pair of twins in Japan, A nationwide survey in Japan on child abuse and neglect revealed that 10% of the victims were products of multiple births. None of the victims who were singletons had multiple-birth siblings. and only in a few cases were both twins abused. The findings indicated that one rather than both of a pair of twins was likely to be abused in Japan. Abuse of both twins was likely when there were serious parental or family problems. whereas abuse of one twin was associated with the child's medical problems or non-home care. There was no instance of abuse of a pair of twins when both were handicapped. Comparisons of the abused twin with the non-abused co-twin and examination of the abuser's attitude to the victim suggested that the difference between twins in their development or in their response to parents increased the stress of child-rearing and encouraged favouritism. which resulted in abuse of only one twin. Comparison by parents of children with their siblings may be a common factor in general child abuse because it is a natural thing for parents to do.
Binding to human jejunum of serum IgA antibody from children with coeliac disease, Jejunal histology and the presence of serum IgA antibodies (JAB) binding to human jejunum in vitro were studied in 139 children with severe malabsorptive symptoms. Among 33 children with confirmed coeliac disease (ESPGAN criteria). 13 (93%) of 14 sampled before starting on a gluten-free diet had JAB. none of 21 sampled had JAB while on a gluten-free diet of long duration. and 90% of 30 sampled during gluten challenge had JAB. 53 children had severe jejunal villous atrophy (probable coeliac disease): 71% of those younger than 2 years and 94% of those aged 2-18 years had JAB during gluten intake. JAB could not be detected in 53 disease control patients (normal jejunal histology) and in 3 coeliac disease patients with selective IgA deficiency. Simultaneous determination of antigliadin (AGA) and antiendomysium (EMA) levels. and gliadin and tissue absorption studies. showed that JAB and AGA are different. whereas JAB and EMA are probably identical. IgA JAB could be the target-organ-related autoantibodies in coeliac disease.
Protection against allergen-induced asthma by salmeterol, The effects of the long-acting beta 2-agonist salmeterol on early and late phase airways events provoked by inhaled allergen were assessed in a group of atopic asthmatic patients. In a placebo-controlled study. salmeterol 50 micrograms inhaled before allergen challenge ablated both the early and late phase of allergen-induced bronchoconstriction over a 34 h time period. Salmeterol also completely inhibited the allergen-induced rise in non-specific bronchial responsiveness over the same time period. These effects were shown to be unrelated to prolonged bronchodilatation or functional antagonism. These data suggest novel actions for topically active long-acting beta 2-agonists in asthma that extend beyond their protective action on airways smooth muscle.
Auditory-evoked responses in benign intracranial hypertension syndrome, In this study. auditory brainstem-evoked responses were conducted on 28 patients with otologic symptoms (pulsatile tinnitus. hearing loss. aural fullness) secondary to benign intracranial hypertension syndrome. Abnormalities consisting mainly of prolonged interpeak latencies were detected in one third of these patients. It is speculated that the pathophysiologic mechanisms responsible for these auditory brainstem-evoked abnormalities are stretching-compression of the cochlear nerve and brainstem caused by the intracranial hypertension and/or primary edema of the same structures due to the benign intracranial hypertension syndrome itself. Normalization or improvement was noticed in the majority of the patients after management. Since the number of patients in this study is small. it is felt that the diagnostic and prognostic value of this test needs further evaluation.
The efficacy of brainstem auditory evoked potentials in acoustic tumor surgery, As the identification of patients with small acoustic neuromas and salvageable hearing increases. intraoperative auditory nerve monitoring has been used increasingly in an attempt to improve the hearing preservation rate. Far-field recordings obtained by brainstem auditory evoked potentials (BAEP). at times enhanced by electrocochleography. have become a standard method of intraoperative auditory nerve assessment. To evaluate the usefulness of this monitoring technique. the hearing preservation results of a series of unmonitored acoustic tumor removals were compared to a series of patients monitored via the standard brainstem auditory evoked potentials. With comparable average tumor sizes. 4 of 7 unmonitored patients had hearing preserved at preoperative levels compared to 4 of 9 monitored patients. Neither preoperative BAEP assessments nor absolute tumor size were predictive of hearing preservation. This report brings into question the effectiveness of far-field intraoperative BAEP monitoring during acoustic tumor resection and suggests that direct auditory nerve monitoring may be more appropriate.
Vocal cord paralysis in children, Bilateral vocal cord paralysis is a common cause of stridor in infants and children. There are significant differences in this entity between children and adults with regard to etiology. diagnosis. management. and outcome. A review of 10 years' experience at Children's Hospital of Philadelphia identified 51 children seen with the diagnosis of vocal cord paralysis. These cases were evaluated with respect to etiology of paralysis. whether unilateral or bilateral. delay in diagnosis. need for tracheotomy. abnormality of voice. surgical treatment. and outcome. Guidelines for management for a child with vocal cord paralysis are presented with emphasis on flexible endoscopic evaluation and conservative management.
Myogenic influences on the electrical auditory brainstem response (EABR) in humans, Two cases demonstrating the effects of myogenic artifact on the electrical auditory brainstem response (EABR) when using a promontory stimulation site are presented. Intensity-response functions were obtained in the unparalyzed condition. then repeated after infusion of a neuromuscular paralyzing agent. In both cases. the myogenic response was observed at lower stimulus intensities than the EABR components. As intensity increased. the myogenic responses grew at extremely rapid rates and made any subsequent identification of auditory responses virtually impossible. To alleviate the adverse influence of myogenic components. general anesthesia and a paralyzing agent must be incorporated into the test protocol when acquiring the EABR using a promontory site of stimulation.
Evaluation of neonatal subglottic stenosis: a 3-year prospective study, Subglottic stenosis is the most common cause of chronic airway obstruction. It results in prolonged tracheal cannulation of infants and children. Following the widespread adoption over the past 20 years of prolonged intubation for respiratory support in neonates. the incidence of acquired subglottic stenosis increased dramatically. On January 1. 1987. we began a 3-year prospective study to delineate potential etiologic factors involved in the development of subglottic stenosis in neonates. The present study analyzes data from 289 infants. Relationships between birth weight. gestational age. endotracheal tube size. duration of intubation and ventilation. number and difficulty of intubations. and the subsequent need for medical and surgical therapy are discussed. Whole organ larynges from autopsy specimens provide histological correlation.
1990 Ogura memorial lecture: moral dilemmas in head and neck cancer, Neither morality nor dilemma can be defined meaningfully in the concept of the practical management of head and neck cancer. Although both have important implications. particularly with regard to ethnic and social factors. they play a relatively minor role in determining management policy. With little knowledge of the intrinsic causes of cancer and with a treatment strategy limited to radiotherapy and surgery. our desire for cure must be tempered by concern to avoid any increase in patient privations. My philosophy. based upon the care of more than 3500 patients over almost 30 years. reflects some of the difficulties of applying the concept "do nothing that may cause harm." while offering each patient the opportunity for long-term cure.
Carcinoma of the external auditory canal: an update, This review is a continuation of the series of 35 cases of carcinoma of the external auditory canal originally reported by the senior author and colleagues. Eighteen additional cases have been evaluated and treated since 1976. Preoperative high-resolution computed tomographic scanning has replaced polytomography. and improved surgical skull base approaches have allowed for extended resections of advanced lesions. A revised classification for local and extensive lesions is presented. The prognosis for localized tumors treated by en bloc resection remains excellent. whereas prognosis for extensive lesions might be more dependent on histologic type and grade of tumor.
Artificial restoration of voice. I: Experiments in phonatory control of the reinnervated canine larynx, Coordinated electronic pacing of implanted nerve pedicles into paralyzed laryngeal muscles has allowed selective dynamic control of abduction. adduction. and elongation of the vocal cords. Modifications of the original circuit in a cervical muscle model has added fine tuning to basic "all-or-none" pacing. Rehabilitation of phonation illustrated the sophisticated nature of voice and the need for restoration of fine tuning. Five mongrel dogs received nerve-muscle pedicles into the thyroarytenoideus. cricothyroideus. and posterior cricothyroideus after denervation of one hemilarynx. Following appropriate reinnervation time. pedicles and intact recurrent laryngeal nerves were injected with currents of variable amplitudes and pulse widths to achieve graded vocal fold control while air was blown intratracheally towards the glottic chink. Videoscopic and spectral analyses indicated that artificial phonation could be restored to frequencies measured in the normal state. These experiments suggested that rehabilitation of the impaired voice by servocontrol might eventually be feasible.
Indications of the carbon dioxide laser in tracheobronchial pathology of the infant and young child: 14 cases, Fourteen children aged between 6 months and 7 years (mean age = 3.5 years) were treated by CO2 broncholaser in the ENT Department of Trousseau Hospital. Three groups of diagnostic indication were identified: 1. Granulomas treated after mucosal trauma (tracheotomy. foreign body). 2. Granulomas due to pulmonary and/or lymph node tuberculosis. 3. Adhesions and stenosis secondary to neonatal ventilation. The operative and anesthetic technique is described in detail. together with any possible adverse events. The CO2 broncholaser appears to be a technique of choice in this age group. in which the narrowness of the airways makes any endoscopic procedure difficult. The broncholaser allows the early treatment of obstructive tracheobronchial pathology with its risks of severe ventilatory sequelae.
Lasers for otosclerosis--which one if any and why, Laboratory stapedotomy and stapedectomy revisions were performed in human temporal bones while pyroelectric wave energy analyzers and ultrasensitive thermocouples measured energy absorption at the stapes footplate and in the vestibule. Analysis of these data shows that the visible lasers (argon and KTP-532) possess ideal optical properties and precision for otosclerosis surgery but conversely have less than ideal tissue characteristics. The CO2 laser possesses ideal tissue characteristics. Recent advances in optical engineering and pulsing the energy have increased the precision of this laser to now provide the accuracy required for delicate microsurgery. Two clinical studies analyze the long-term hearing results and complications in patients who had undergone CO2 laser stapedectomy revision (59 patients) and CO2 laser stapedotomy (153 patients). The advantages that these laser techniques provide over conventional surgery methods are discussed.
Pulsed carbon dioxide laser ablation of burned skin: in vitro and in vivo analysis, Pulsed lasers produce efficient and precise tissue ablation with limited residual thermal damage. In this study. the efficiency of pulsed CO2 laser ablation of burned and normal swine skin was studied in vitro with a mass loss technique. The heats of ablation for normal and burned skin were 2.706 and 2.416 J/cm3 of tissue ablated. respectively. The mean threshold radiant exposures for ablating normal skin and eschar were 2.6 J/cm2 and 3.0 J/cm2. respectively. Radiant exposures greater than 19 J/cm2 produced a plasma. which decreased the efficiency of laser ablation. Thus the radiant exposures for efficient ablation range from 4 to 19 J/cm2. and within this radiant exposure range 20-40 microns of tissue are ablated per pulse. We also examined. on a gross and histopathologic basis. in vivo burn eschar excision with a pulsed CO2 laser. The laser allowed bloodless excisions of full thickness burns on the backs of male hairless rats. The zone of thermal damage was approximately 85 microns over the subjacent fascia. The pulsed CO2 laser can ablate burn eschar efficiently. precisely. and bloodlessly and may prove valuable for the excision of burned and necrotic tissue.
Cutaneous phototoxic occurrences in patients receiving Photofrin, Incidence of cutaneous phototoxic reactions induced by intravenous injection of Photofrin polyporphyrin was assessed in a series of 180 patients (266 injections) undergoing photodynamic therapy (PDT) at Roswell Park Cancer Institute during the period 1986-1989. In addition to the usual verbal questions regarding phototoxic reactions solicited at follow-up. forty-two patients in this group also responded to a written questionnaire designed to solicit answers to specific questions. Photofrin doses ranged from 0.5 to 2.0 mg/kg. Overall. 20-40% of patients reported some type of phototoxic response.
Effects of menstrual phase and amenorrhea on exercise performance in runners, There are few well controlled studies in terms of subject selection. menstrual classification. and exercise protocol that have examined both maximal and submaximal exercise responses during different phases of the menstrual cycle in eumenorrheic runners and compared these runners to amenorrheic runners. Thus. the purpose of this study was to measure selected physiological and metabolic responses to maximal and submaximal exercise during two phases of the menstrual cycle in eumenorrheic runners and amenorrheic runners. Eight eumenorrheic runners (29.0 +/- 4.2 yr) and eight amenorrheic runners (24.5 +/- 5.7 yr) matched for physical. gynecological. and training characteristics were studied. The eumenorrheic runners performed one maximal and one submaximal (40 min at 80% VO2max) treadmill run during both the early follicular (days 2-4) and midluteal (6-8 d from LH surge) phases. The amenorrheic runners performed one maximal and one submaximal (40 min at 80% VO2max) treadmill run. Cycle phases were documented by urinary luteinizing hormone and progesterone assays and by plasma estradiol and progesterone assays. No differences were observed in oxygen uptake. minute ventilation. heart rate. respiratory exchange ratio. rating of perceived exertion. time to fatigue (maximal). and plasma lactate (following the maximal and submaximal exercise tests) between the follicular and luteal phases in the eumenorrheic runners and the amenorrheic runners. We conclude that neither menstrual phase (follicular vs luteal) nor menstrual status (eumenorrheic vs amenorrheic) alters or limits exercise performance in female athletes.
Circulatory and thermal adjustments to prolonged exercise in paraplegic women, The circulatory and thermal responses to 90 min of wheelchair ergometer exercise were examined in five wheelchair dependent (WD) women with low level spinal dysfunction and five able-bodied (AB) women who served as a comparison group. Metabolic rate during exercise was 221 W for WD and 255 W for AB (P greater than 0.05). Oral temperature (Tor). mean skin temperature (Tsk). oxygen uptake (VO2). heart rate (HR). and cardiac output (Qc) were assessed periodically throughout the exercise period. Ambient conditions were 24-25 degrees C and 38-52% relative humidity. A significant group X time interaction was found for Tor (P less than 0.001) and Tsk (P less than 0.001). Tor of the WD group steadily increased during the exercise. whereas the AB group showed a stable Tor. Tsk of WD increased rapidly during the first 5-10 min of exercise and continued to rise at a slower rate throughout the exercise. In contrast. Tsk of AB rose to a peak during the first 10 min and then showed a decreasing trend. VO2 and HR remained stable in both groups throughout the exercise period. Following an initial increase in Qc from minute 10 to minute 20 in both groups. values for WD continually decreased until Qc at 80 min was 14% lower than at 10 min. The findings suggest that the WD women had greater thermoregulatory strain than the AB women as indicated by a higher Tor and Tsk and by an inability to maintain Qc due to paralysis of the lower limbs and perhaps an increase in cutaneous blood volume.
Daily pattern of %VO2max and heart rates in normal and undernourished school children, The pattern of usage of the VO2max. expressed as %VO2max during ordinary school days. with minute-by-minute heart rate recording. was studied in 106 boys and 83 girls. 6-16 yr of age divided into three age groups (6-8. 10-12. and 14-16 yr). living under economically deprived conditions in Colombia and classified as nutritionally normal or marginally malnourished. In a 12-h period. the 12 groups of children spent. on the average. 7-10 h at less than 30% VO2max. 1.5-4 h at 30-50% VO2max. and an accumulated time of 20-60 min above 50% VO2max. The latter occurred in short bursts rather than during sustained periods. There was a statistically significant but small decrease (approximately -3%) in the average 12 h %VO2max with age but no effects of sex or nutritional status. The overall average was about 25% VO2max in all groups. The data may suggest the existence of the regulation of physical activity to some level easily sustainable for long periods. Expressing the data as 30 min averages during 5 h of school and 5 h of free-time activity allows for the possibility of seeing group differences during shorter periods of time. This may prove useful in exercise training programs and studies of effort in the workplace.
The health belief model: predicting compliance and dropout in cardiac rehabilitation, We investigated the health belief model and the health locus of control constructs as predictors of group membership (compliers or dropouts) with cardiac rehabilitation and whether they added predictive utility to routinely assessed patient demographics and health behaviors. Questionnaires were completed on entry into the study by 120 patients with coronary artery disease. and by the end of the 6 month program there were 58 compliers and 62 dropouts. Discriminant function analyses were carried out to determine prediction of group membership. The health belief model predicted group membership 64.6% of the time. explaining 5.2% of the variance. Demographics. health behaviors. and health belief model factors accounted for 21.1% of the variance between compliers and total dropouts with group membership correctly predicted 74.4% of the time; avoidable and unavoidable dropout was correctly predicted 84.2% of the time with 56.9% of the variance explained. Health locus of control did not distinguish between compliers and dropouts. The addition of the health belief model provided additional information about compliance with cardiac rehabilitation beyond that explained by demographic and health behavior variables alone. particularly when predicting avoidable/unavoidable dropout.
The accuracy of self-reports of physical activity, This investigation determined the accuracy of self-reports of physical activity compared to observations obtained surreptitiously. Subjects were 44 adults engaged in 1 h of their preferred physical activity while actual activity levels were surreptitiously obtained and compared to immediate self-reported estimates of physical activity. Results indicated that subjects were moderately accurate in recalling their physical activity levels (R = 0.62) but underestimated sedentary activities and overestimated aerobic activities by over 300%. Males overestimated their activity relative to females. and obese subjects underestimated their activity levels compared to normal-weight subjects. Finally. a number of two-way interactions that moderated the accuracy of those subjects engaging in high chronic levels of physical activity were observed.
Genucom knee analysis system: reproducibility and database development, The Genucom is a relatively new computerized system that performs a multidimensional analysis of knee laxity. Therefore. the purposes of the present investigation were twofold: 1) to estimate the reproducibility of the testing system in its ability to obtain similar test values on the same test subject within a back-to-back two-test protocol and 2) to develop a database of normal values as a standard against which values of suspected ligament injury can be compared to reliably determine whether. in fact. ligament injury has occurred. In the reproducibility phase of the study. 20 subjects were tested in two trials each of eight tests. yielding 20 separate test values per trial. accounting for each angle of flexion and plane of force tested. Both legs were tested. providing an N of 40. Test-retest correlations of the two trials and dependent t-tests indicated that the Genucom provided generally stable and reproducible results. In the normal value database phase of the study. 218 different subjects were given one trial of the same eight tests. Testing of both legs provided an N greater than 400. Means and standard deviations were calculated for each test.
Multiple-pulse stimulation and dantrolene in malignant hyperthermia, A potentially fatal condition. yet preventable. malignant hyperthermia (MH) lacks a satisfactory noninvasive diagnostic test. Studying the effects of intravenous dantrolene (3 mg/kg) on electrically stimulated skeletal muscle. we found that this approach does not conclusively distinguish between normal humans and those susceptible to malignant hyperthermia but nonetheless yielded important information about the action of dantrolene in man and in MH. Supramaximal single- and multiple-pulse stimulation of the common peroneal nerve produced stable torque responses of the dorsiflexor muscles (monitored in vivo). which dantrolene suppressed. With the multiple-pulse stimulation (5-6 pulses) this torque suppression was significantly less in MH-susceptible subjects than in control subjects. This distinction. also observed in MH swine. confirms this animal as a good model for human MH. That dantrolene's effect in MH can be more completely reversed with high frequency stimulation is intriguing; presumably. excitation-contraction coupling differs in MH and normal muscle.
Isometric features of orthostatic tremor: an electromyographic analysis, A patient is described with "orthostatic" tremor. Electromyography revealed tremor bursts of 15 Hz in the lower extremities while standing and with isometric activation of the muscles. but the bursts disappeared with isotonic activation of muscles. Similar tremor was recorded in the arms with isometric. but not isotonic activation. Review of previously reported cases confirms these findings. The clinical and electrophysiologic features of this tremor distinguish it from other recognized forms of tremor.
Electrophysiological spectrum of inclusion body myositis, We present electrodiagnostic data on 30 patients with inclusion body myositis (IBM) in order to better delineate its electrophysiological features. Comprehensive electromyography (EMG) and nerve conduction studies (NCS) were performed in all cases. Twelve patients had single fiber electromyography (SFEMG). EMG showed abundant short-small motor unit potentials (MUP) with fibrillations and positive sharp waves in 56.6% of patients. and a mixed pattern of large and small MUP in 36.7%. In 6.7%. only "neurogenic" features were seen. NCS were slow in 33.3%. SFEMG revealed a mildly abnormal jitter and a slightly increased fiber density. IBM demonstrates a heterogeneous EMG profile. A pattern of large and small MUP is highly suggestive of IBM but is seen in only about one third of cases.
Quantitative electromyography in polymyositis: a reappraisal, Manual analysis of motor unit action potentials (MUAPs) was performed in 33 patients with polymyositis of whom 16 were studied in the acute stage and 17 in the chronic stage. Contrary to common description of "myopathic potentials" as being of low amplitude. short duration. and polyphasic shape. the quantitated study revealed no difference as to amplitude of short duration MUAPs in patients and normal subjects though short-duration MUAP and short duration polyphasic potentials were 4 and 3 times. respectively. more common in patients than in controls. Although the mean duration of MUAPs usually was significantly shorter in polymyositis than in controls. the average scatter of MUAPs duration was the same in the 2 groups. The average incidence of polyphasic MUAPs was 4 times higher in patients than in controls. as was the incidence of those of long duration. To avoid misinterpretation of EMG findings due to an excess of polyphasic MUAPs. a greater number of individual potentials than usually recommended should be collected allowing a valid estimate of the mean duration of MUAPs of simple configuration.
Responses of intercostal muscle biopsies from normal subjects and patients with myasthenia gravis, In order to evaluate the mechanisms of weakness in muscles of patients with myasthenia gravis (MG). intercostal muscle biopsies were obtained from 9 normal subjects and 6 MG patients. and the compound muscle action potential (AP) and tension responses to nerve and muscle stimulation. and contracture responses on exposure to caffeine. were monitored in vitro. In normal muscle. on stimulation of the nerve or muscle at 30 to 100 Hz. the AP responses showed decrement in amplitude. one-third of which was attributable to failure of neuromuscular transmission and two-thirds to failure of muscle membrane excitation. On stimulation at 1 to 5 Hz. the AP responses showed very little decrement. while the contractile responses showed significant fade in tension. due to failure of E-C coupling or contractility. In muscle from patients with generalized MG. stimulation of the nerve at all frequencies (1 to 100 Hz) caused much greater decrement in APs and fade in tension responses than in normal muscle. due mainly to failure of neuromuscular transmission. However. at 100 Hz. 40% of the decrement in APs was due to failure of muscle membrane excitation. and at 1 to 5 Hz. 40% of the fade in tension was due to failure of E-C coupling or contractility. as in normal muscle. On direct stimulation the contraction and half-relaxation times were slower and the tetanic tension was smaller than in normal muscle. especially in the MG patient with thymoma. Caffeine-induced contractures were smaller in MG muscle than in normal muscle. These results indicate that while the weakness of MG muscle is due mainly to failure of neuromuscular transmission. it is also partly due to reduced E-C coupling or contractility.
Sensitivity for detecting fibrillation potentials: a comparison between concentric and monopolar needle electrodes, The sensitivity of monopolar and concentric electrodes for detecting fibrillation potentials (FP) has never been formally compared. We studied 35 muscles with FP. sampling 20 sites each with concentric and monopolar needles. The concentric needle identified 0.88 +/- 3.44 (mean +/- standard deviation) more sites with spontaneous activity. Although statistically significant (Wilcoxon signed rank test P less than .03). this difference in sensitivity did not appreciably affect diagnostic interpretation. Subjects described the concentric needles as more painful. Needle insertions in 25 other muscles demonstrated that needle movement generated the majority of FP. We suggest that the increased tissue injury caused by concentric needles may account for both their increased sensitivity and discomfort.
Time course of sprouting during muscle reinnervation in vitamin E-deficient rats, A typical aspect of motoneuron plasticity is the sprouting which occurs during muscle reinnervation. resulting in a transitory multiple innervation of the muscle cells. In order to verify the effect of a decreased protection from free radical attack on the sprouting. the multiple innervation in the extensor digitorum longus muscle. following sciatic nerve crush and regeneration. was studied in vitamin E-deficient rats. Thus. the innervated end-plates and the end-plates with multiple innervation were studied with histochemical and electrophysiological techniques. The percentage of innervated end-plates was similar in both groups at 30 as well as at 60 days after nerve crush. Nevertheless. multiple innervation was found in a larger part of the muscle and it lasted longer in the deficient rats. This finding is discussed in relation to some of the major hypotheses of sprouting; it may be relevant in the treatment of some lesions of peripheral nerve.
A review of techniques employed to estimate the number of motor units in a muscle, Being the smallest functional units under neural control. motor units play an integral role in muscle physiology. However. at the present time. there does not exist any widely accepted technique for quantifying or estimating the number of motor units in a muscle. Specifically. the existing techniques are the increment-counting technique. a technique based on spike-triggered averaging. and a macro-EMG based technique which vary in invasiveness from noninvasive to highly invasive. respectively. We discuss each of these techniques. along with their associated shortcomings. in detail.
Spatial dispersion of magnetic stimulation in peripheral nerves, To assess the longitudinal dispersion of the stimulus induced by the magnetic coil. collision experiments were performed in seven normal ulnar nerves. A supramaximal electrical stimulus S1 was delivered at the wrist. and followed by a supramaximal stimulus S2 in the upper arm. which was either electrical (electrical collision studies). or magnetic (magnetic collision studies). The interstimulus interval was varied by 0.2 msec increments from the time of complete cancellation of the S2 evoked motor response onwards. to include the entire span of recovery of that compound motor action potential. Collision curves were obtained for both magnetic and electrical stimuli by plotting the amplitude of the motor response elicited by S2 as a function of the interstimulus interval. In all seven normal ulnar nerves. comparison of the collision curves showed that the S2 evoked motor response is restored significantly more slowly when magnetic stimulation is used. This finding is best explained by longitudinal dispersion of the stimulus induced by the magnetic coil relative to conventional electrical stimulation. the large fibers being stimulated further away from the coil than the small ones. This interpretation is confirmed by the findings obtained with the same method in two cases of ulnar neuropathy. and by comparison of different intensities of magnetic stimulation.
AAEM minimonograph #35: Clinical experience with transcranial magnetic stimulation, We elicited motor evoked potentials (MEPs) using transcortical magnetic stimulation in 150 control subjects aged 14 to 85 years and 275 patients with a variety of diseases. There were no significant side effects. Cortex-to-target muscle latencies measured 20.2 +/- 1.6 ms (thenar). 14.2 +/- 1.7 ms (extensor digitorum communis). 9.4 +/- 1.7 ms (biceps). and 27.2 +/- 2.9 ms (tibialis anterior). Central motor delay between the cortex and the C-7 and L-5 measured 6.7 +/- 1.2 ms and 13.1 +/- 3.8 ms. respectively. Mean spinal cord motor conduction velocity measured 65.4 m/s. MEP amplitude expressed as a percentage of the maximum M wave was never less than 20% of the M wave. A value of less than 10% is considered abnormal. MEP latency increases linearly with age and central motor delay is longer in older subjects. Compound muscle action potentials and absolute MEP amplitudes decreased linearly with age. In multiple sclerosis (MS). MEP latency and central delay were often very prolonged. The MEP was more sensitive than the SEP in MS. In amyotrophic lateral sclerosis. MEP latencies were only modestly prolonged; the characteristic abnormality was reduced amplitude. When pseudobulbar features predominated MEPs were often absent. The MEP was of normal latency in Parkinson's disease. but age-related amplitude was often increased. MEP latency and amplitude were normal in Huntington's disease. Abnormal MEPs persisted several months after stroke despite good functional recovery. The MEP could be used to advantage to demonstrate proximal conduction slowing and block in demyelinating neuropathies. In plexopathy. ability to elicit an MEP several days after onset of paresis was good evidence of neuronal continuity in motor fibers.
The anatomy and physiology of nerve injury, Nerves have a structure of considerable complexity with features of special relevance to nerve injury and nerve regeneration. These include variations in the cross-sectional areas devoted to fascicular and epineurial tissue. the fascicular redistribution and mixing of different branch fibers brought about by fascicular plexuses. and the numbers of nerve fibers representing individual branches. The elasticity and tensile strength of nerve trunks and their capacity to resist traction deformation reside in the fascicular tissue. while the epineurium provides a protective cushion against compression. The microstructure of nerve trunks provides the basis for a classification of nerve injuries into five degrees of severity with partial and mixed types--each with a clearly defined pathology and distinguishing clinical features. Following a transection injury. changes occur in the severed axons. endoneurial tubes. fasciculi. and nerve trunk. The type of injury and the nature of these changes determine the outcome of axon regeneration.
Use of single fiber EMG and macro EMG in study of reinnervation, The use of single fiber EMG and macro EMG in studies of reinnervation is discussed. SFEMG gives information about changes in the topography of the motor unit and in function of transmission in terminal nerve. motor endplate and muscle fiber. Dynamics of reinnervation may be studied with this technique. The amount of reinnervation is obtained from macro EMG studies. The capacity for reinnervation is discussed for a few conditions as well as factors that limit the reinnervation process.
Fibrillation potential amplitude and muscle atrophy following peripheral nerve injury, Maximum peak-to-peak fibrillation potential amplitude was measured in 69 subjects between 7 days and 10 1/2 years post complete or partial peripheral nerve injury. Mean amplitude during the first 2 months was 612 muV; third and fourth months 512 muV. fifth and sixth months 320 muV. After the first year. no population of fibrillation potentials greater than 100 muV was recorded. The sciatic nerve was sectioned in 13 guinea pigs and animals studied up to 17 weeks. Fibrillation potential amplitude in gastrocnemius muscles declined paralleling that in humans. By the end of the study. type I fibers had lost almost half of their initial diameter and type II fibers had atrophied more than twice this amount. Fibrillation potential amplitude may be useful in estimating the time post nerve injury and appears to correlate with the surface area and fiber diameter of a type I muscle fiber.
The little women of Loja--growth hormone-receptor deficiency in an inbred population of southern Ecuador, BACKGROUND AND METHODS. Laron-type dwarfism. which is characterized by the clinical appearance of isolated growth hormone deficiency with elevated serum levels of growth hormone and decreased serum levels of insulin-like growth factor I (IGF-I). has been described in approximately 50 patients. This condition is caused by a deficiency of the cellular receptor for growth hormone. and it is transmitted as an autosomal recessive trait. as indicated by an equal sex distribution and a high rate of consanguinity in affected families. We studied 20 patients (19 females and 1 male. 2 to 49 years of age). from an inbred Spanish population in southern Ecuador. who had the clinical features of Laron-type dwarfism. RESULTS. Seventeen patients were members of two large pedigrees. Among the 13 affected sibships. there were 19 affected and 24 unaffected female siblings and 1 affected and 21 unaffected male siblings. The patients' heights ranged from 10.0 to 6.7 SD below the normal mean height for age in the United States. In addition to the previously described features. 15 patients had limited elbow extensibility. all had blue scleras. affected adults had relatively short extremities. and all four affected women over 30 years of age had hip degeneration. Basal serum concentrations of growth hormone were elevated in all affected children (30 to 160 micrograms per liter) and normal to moderately elevated in the adults. The serum level of growth hormone-binding protein ranged from 1 to 30 percent of normal; IGF-I concentrations were low--less than or equal to 7 micrograms per liter in the children and less than or equal to 66 micrograms per liter in the adults (normal for Ecuadorean women. 98 to 238). Serum levels of IGF-II and growth hormone-dependent IGF-binding protein-3 were also low. CONCLUSIONS. We describe an inbred population with a high incidence of growth hormone-receptor deficiency resulting in a clinical picture resembling Laron-type dwarfism but differing principally in showing a marked predominance of affected females. This population. of Mediterranean origin. may be genetically related to other reported populations with Laron-type dwarfism. but with the genetic defect linked to a trait resulting in the early fetal death of most affected males.
A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children against invasive Haemophilus influenzae type b disease, BACKGROUND. Haemophilus influenzae type b is the leading cause of invasive bacterial disease in young children. The capsular polysaccharide vaccine does not protect children at greatest risk (those under the age of 18 months). but a polysaccharide-protein conjugate vaccine has proved to be more immunogenic in this age group. METHODS. We enrolled 114.000 infants in Finland in an open. prospective. randomized trial of a H. influenzae type b capsular polysaccharide-diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate-diphtheria toxoid [PRP-D]). Children born on odd-numbered days were vaccinated at the ages of 3. 4. 6. and 14 to 18 months; those born on even-numbered days formed the control group and received the same vaccine at the age of 24 months. RESULTS. After three doses of the vaccine there were 4 cases of verified bacteremic H. influenzae type b disease in the group receiving early vaccination. as compared with 64 cases in the control group. between the ages of approximately 7 and 24 months. The protective efficacy of the vaccine was thus 94 percent (95 percent confidence interval. 83 to 98). No serious adverse effects were reported. The immune response to the conjugate vaccine was characteristic of a T-cell-dependent response when studied in a cohort of 120 infants. The primary immunization series resulted in a geometric mean concentration of anticapsular antibody of 0.53 micrograms per milliliter at the age of seven months. and the fourth dose evoked an anamnestic response. with a mean antibody concentration of 45.22 micrograms per milliliter. CONCLUSIONS. A new conjugate vaccine consisting of the capsular polysaccharide of H. influenzae type b covalently linked to a protein carrier (PRP-D). administered to infants beginning at the age of 3 months. is highly effective in protecting young Finnish children (7 to 24 months old) against invasive H. influenzae type b infections.
Limited efficacy of a Haemophilus influenzae type b conjugate vaccine in Alaska Native infants. The Alaska H. influenzae Vaccine Study Group, BACKGROUND. The prevention of invasive Haemophilus influenzae type b disease requires a vaccine that is effective when administered during the first six months of life. The infants of Alaska Natives are at particularly high risk of invasive H. influenzae type b disease. METHODS. To evaluate the protective efficacy of a H. influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (polyribosylribitol phosphate-diphtheria toxoid [PRP-D]). we enrolled 2102 Alaska Native infants in a randomized. double-blind. placebo-controlled trial in which either the vaccine or a saline placebo was administered at approximately two. four. and six months of age. RESULTS. After 3969 subject-years of follow-up and 32 episodes of H. influenzae type b disease. the overall incidence of invasive disease was not reduced significantly in the vaccinated subjects (6.0 cases per 1000 patient-years). as compared with the placebo controls (9.6) or with other Alaska Native infants (6.0). After one. two. or three doses there was no significant protective efficacy with the vaccine; after three doses the efficacy was only 35 percent (95 percent confidence interval. -57 to 73). The lack of efficacy was not related to the age at onset of disease. age at immunization. type of disease. degree of Alaska Native heritage. time after immunization. or year of the study. Levels of H. influenzae type b anticapsular antibody in recipients of the vaccine became significantly higher than levels in those who received placebo only after the second and third doses. Even after the third dose. only 48 percent of the vaccinated infants had antibody levels of more than 0.1 microgram per milliliter (geometric mean titer. 0.18). Antibody responses did not vary with the level of maternally acquired antibody. degree of Alaska Native ancestry. or age at time of the first or second immunizations. but they increased with increasing age at time of the third dose (P less than 0.001). CONCLUSIONS. We found no evidence that the PRP-D vaccine provides significant protection. at least for Alaska Native infants. against invasive diseases caused by H. influenzae type b. The ineffectiveness of the vaccine paralleled its limited immunogenicity.
The relation between genotype and phenotype in cystic fibrosis--analysis of the most common mutation (delta F508), BACKGROUND AND METHODS. Both the clinical manifestations of cystic fibrosis and the genotypes of patients are heterogeneous. but the associations between the two are not known. We therefore studied blood samples from 293 patients with cystic fibrosis for the presence of the most common disease-causing mutation (delta F508) on chromosome 7 and compared the results with the clinical manifestations of the disease. RESULTS. The prevalence of the delta F508 allele in the cohort was 71 percent; 52 percent of the patients were homozygous for the mutation. 40 percent were heterozygous. and 8 percent had other. undefined mutations. The patients who were homozygous for the mutation had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency; pancreatic insufficiency was present in 99 percent of the homozygous patients. but in 72 percent of the heterozygous patients and only 36 percent of the patients with other genotypes. The patients with pancreatic insufficiency in all three genotype groups had similar clinical characteristics. reflected by an early age at diagnosis. similar sweat chloride values at diagnosis. similar severity of pulmonary disease. and similar percentiles for weight. In contrast. the patients in the heterozygous-genotype and other-genotype groups who did not have pancreatic insufficiency were older and had milder disease. They had lower sweat chloride values at diagnosis. normal nutritional status. and better pulmonary function after adjustment for age. CONCLUSIONS. The variable clinical course in patients with cystic fibrosis can be attributed at least in part to specific genotypes at the locus of the cystic fibrosis gene.
Molecular defect of the band 3 protein in southeast Asian ovalocytosis, BACKGROUND. Southeast Asian ovalocytosis is a form of hereditary elliptocytosis in which the red cells are rigid and resistant to malaria invasion. The underlying molecular defect is unknown. METHODS AND RESULTS. We studied the red cells of 54 patients with ovalocytosis and 122 normal controls. We found that ovalocytes contain a structurally and functionally abnormal band 3 protein. the principal transmembrane protein of red cells. The structural lesion of ovalocyte band 3 was revealed by limited proteolytic cleavage of the protein. which produced fragments of abnormal size that were derived from the cytoplasmic domain of the protein. The structural lesion was present in all the subjects with ovalocytosis but none of the controls. This region of band 3 serves as the principal binding site for the membrane skeleton. a submembrane protein network composed of ankyrin. spectrin. actin. and protein 4.1. The structural defect is dominantly inherited. being tightly linked with the inheritance of ovalocytosis (the probability of linkage is in excess of 10 million to 1). Ovalocyte band 3 bound considerably more tightly than normal band 3 to ankyrin. which connects the membrane skeleton to the band 3 protein. This tight binding of ovalocyte band 3 to the underlying skeleton containing ankyrin was directly confirmed in intact cells by the finding that ovalocyte band 3 had markedly reduced lateral mobility in the membrane. CONCLUSIONS. The red cells in Southeast Asian ovalocytosis carry a structurally and functionally abnormal band 3 protein. This molecular defect may underlie the increased rigidity of the red cells and their resistance to invasion by malaria parasites.
Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease, BACKGROUND. The maintenance of cellular levels of high-energy phosphates is required for myocardial function and preservation. In animals. severe myocardial ischemia is characterized by the rapid loss of phosphocreatine and a decrease in the ratio of phosphocreatine to ATP. METHODS. To determine whether ischemic metabolic changes are detectable in humans. we recorded spatially localized phosphorus-31 nuclear-magnetic-resonance (31P NMR) spectra from the anterior myocardium before. during. and after isometric hand-grip exercise. RESULTS. The mean (+/- SD) ratio of phosphocreatine to ATP in the left ventricular wall when subjects were at rest was 1.72 +/- 0.15 in normal subjects (n = 11) and 1.59 +/- 0.31 in patients with nonischemic heart disease (n = 9). and the ratio did not change during hand-grip exercise in either group. However. in patients with coronary heart disease and ischemia due to severe stenosis (greater than or equal to 70 percent) of the left anterior descending or left main coronary arteries (n = 16). the ratio decreased from 1.45 +/- 0.31 at rest to 0.91 +/- 0.24 during exercise (P less than 0.001) and recovered to 1.27 +/- 0.38 two minutes after exercise. Only three patients with coronary heart disease had clinical symptoms of ischemia during exercise. Repeat exercise testing in five patients after revascularization yielded values of 1.60 +/- 0.20 at rest and 1.62 +/- 0.18 during exercise (P not significant). as compared with 1.51 +/- 0.19 at rest and 1.02 +/- 0.26 during exercise before revascularization (P less than 0.02). CONCLUSIONS. The decrease in the ratio of phosphocreatine to ATP during hand-grip exercise in patients with myocardial ischemia reflects a transient imbalance between oxygen supply and demand in myocardium with compromised blood flow. Exercise testing with 31P NMR is a useful method of assessing the effect of ischemia on myocardial metabolism of high-energy phosphates and of monitoring the response to treatment.
Frequency and costs of diagnostic imaging in office practice--a comparison of self-referring and radiologist-referring physicians, BACKGROUND. To assess possible differences in physicians' practices with respect to diagnostic imaging. we compared the frequency and costs of imaging examinations as performed by primary physicians who used imaging equipment in their offices (self-referring) and as ordered by physicians who always referred patients to radiologists (radiologist-referring). METHODS. Using a large. private insurance-claims data base. we analyzed 65.517 episodes of outpatient care by 6419 physicians for acute upper respiratory symptoms. pregnancy. low back pain. or (in men) difficulty urinating. The respective imaging procedures studied were chest radiography. obstetrical ultrasonography. radiography of the lumbar spine. and excretory urography. cystography. or ultrasonography. RESULTS. For all four clinical presentations. the self-referring physicians obtained imaging examinations 4.0 to 4.5 times more often than the radiologist-referring physicians (P less than 0.0001 for all four). For chest radiography. obstetrical ultrasonography. and lumbar spine radiography. the self-referring physicians charged significantly more than the radiologists for imaging examinations of similar complexity (P less than 0.0001 for all three). The combination of more frequent imaging and higher charges resulted in mean imaging charges per episode of care that were 4.4 to 7.5 times higher for the self-referring physicians (P less than 0.0001). These results were confirmed in a separate analysis that controlled for the specialty of the physician. CONCLUSIONS. Physicians who do not refer their patients to radiologists for medical imaging use imaging examinations more frequently than do physicians who refer their patients to radiologists. and the charges are usually higher when the imaging is done by the self-referring physician. From our results it is not possible to determine which group of physicians uses imaging more appropriately.
Long-term outcome after surgical repair of isolated atrial septal defect. Follow-up at 27 to 32 years, BACKGROUND. Atrial septal defects have been surgically correctable for more than 30 years. The long-term survival rates among patients treated in the early era of cardiac surgery are poorly documented. but such data are of critical importance to the future medical care. employability. and insurability of these patients. METHODS. To determine the natural history of surgically corrected atrial septal defects. we studied all 123 patients who underwent repair of an isolated defect (ostium secundum or sinus venosus) at the Mayo Clinic between 1956 and 1960. 27 to 32 years after the procedure. The follow-up status of all patients was determined by written questionnaires and telephone interviews. Hospital records and death certificates were obtained if interim hospitalization or death had occurred. RESULTS. The overall 30-year actuarial survival rate among survivors of the perioperative period was 74 percent. as compared with 85 percent among controls matched for age and sex. The perioperative mortality was 3.3 percent (four deaths). Actuarial 27-year survival rates among patients in the younger two quartiles according to age at operation (less than or equal to 11 years and 12 to 24 years) were no different from rates among controls--97 percent and 93 percent. respectively. In the two older quartiles (25 to 41 years and greater than 41 years). 27-year survival rates were significantly less (P less than 0.001)--84 percent and 40 percent. respectively--than in controls (91 and 59 percent). Independent predictors of long-term survival according to multivariate analysis were age at operation (P less than 0.0001) and systolic pressure in the main pulmonary artery before operation (P less than 0.0027). When repair was performed in older patients. late cardiac failure. stroke. and atrial fibrillation were significantly more frequent. CONCLUSIONS. Among patients with surgically repaired atrial septal defects. those operated on before the age of 25 have an excellent prognosis. but older patients require careful. regular supervision.
Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women, BACKGROUND. The rates of colon cancer in various countries are strongly correlated with the per capita consumption of red meat and animal fat and. to a lesser degree. inversely associated with the consumption of fiber. METHODS. We conducted a prospective study among 88.751 women 34 to 59 years old and without a history of cancer. inflammatory bowel disease. or familial polyposis who completed a dietary questionnaire in 1980. By 1986. during 512.488 person-years of follow-up. 150 incident cases of colon cancer had been documented. RESULTS. After adjustment for total energy intake. animal fat was positively associated with the risk of colon cancer (P for trend = 0.01); the relative risk for the highest as compared with the lowest quintile was 1.89 (95 percent confidence interval. 1.13 to 3.15). No association was found for vegetable fat. The relative risk of colon cancer in women who ate beef. pork. or lamb as a main dish every day was 2.49 (95 percent confidence interval. 1.24 to 5.03). as compared with those reporting consumption less than once a month. Processed meats and liver were also significantly associated with increased risk. whereas fish and chicken without skin were related to decreased risk. The ratio of the intake of red meat to the intake of chicken and fish was particularly strongly associated with an increased incidence of colon cancer (P for trend = 0.0005); the relative risk for women in the highest quintile of this ratio as compared with those in the lowest quintile was 2.49 (95 percent confidence interval. 1.50 to 4.13). A low intake of fiber from fruits appeared to contribute to the risk of colon cancer. but this relation was not statistically independent of meat intake. CONCLUSIONS. These prospective data provide evidence for the hypothesis that a high intake of animal fat increases the risk of colon cancer. and they support existing recommendations to substitute fish and chicken for meats high in fat.
Overall mortality and cancer mortality around French nuclear sites, Higher than expected mortality from leukaemia has been observed in the population under age 25 living around Sellafield and Dounreay. nuclear reprocessing plants in the United Kingdom. We report the results of a similar study for the population residing around nuclear sites in France. The number of leukaemia deaths was 58. comparable to the 62 in control areas. and slightly less than the 67 expected from national mortality statistics. Twelve deaths due to Hodgkin's disease were observed around nuclear sites; this is about twice the number of Hodgkin's deaths observed in control areas and twice the number expected from national mortality statistics. This observation must. however. be interpreted in light of the fact that several causes of deaths were studied. increasing the play of chance.
HIV-1 tropism for mononuclear phagocytes can be determined by regions of gp120 outside the CD4-binding domain, Cells of the mononuclear phagocyte system are the predominant cell producing HIV-1 in most tissues including the central nervous system (CNS). spinal cord. lung and skin; infection is associated with dementia. neuropathy. pneumonitis. and dermatitis respectively. Different HIV-1 isolates vary markedly in their ability to infect mononuclear phagocytes productively. Here we describe molecular clones of a CNS-derived isolate. HIV-1(JR-FL). which can replicate efficiently in mononuclear phagocytes. Analysis by polymerase chain reaction of early events after infection indicates that the early phase of viral replication before reverse transcription determines tropism. Genetic mapping of the macrophage-tropic phenotype by construction of recombinant viruses indicates that mononuclear phagocyte infectivity can be determined by a 157-amino-acid region of the gp 120 glycoprotein of HIV-1(JR-FL). Significantly. this region is upstream from the previously defined CD4-binding domain. We propose that at least one determinant for mononuclear phagocyte tropism involves target cell interactions with regions of gp120 distinct from the CD4-binding domain.
Analysis of a human DNA excision repair gene involved in group A xeroderma pigmentosum and containing a zinc-finger domain, Xeroderma pigmentosum (XP) is an autosomal recessive disease. characterized by a high incidence of sunlight-induced skin cancer. Cells from people with this condition are hypersensitive to ultraviolet because of a defect in DNA repair. There are nine genetic complementation groups of XP. groups A-H and a variant. We have cloned the mouse DNA repair gene that complements the defect of group A. the XPAC gene. Here we report molecular cloning of human and mouse XPAC complementary DNAs. Expression of XPAC cDNA confers ultraviolet-resistance on several group A cell lines. but not on lines of other XP groups. Almost all group A lines tested showed abnormality or absence of XPAC messenger RNAs. These results indicate that a defective XPAC gene causes group A XP. The human and mouse XPAC genes are located on chromosome 9q34.1 and chromosome 4C2. respectively. Human XPAC cDNA encodes a protein of 273 amino acids with a zinc-finger motif.
A downstream initiation element required for efficient TATA box binding and in vitro function of TFIID, The gfa gene encodes glial fibrillary acidic protein. an intermediate filament protein expressed in glial cells. In vitro transcription analysis has shown that the human gfa promoter contains two initiation elements that can independently specify the transcription startpoint. One of the elements is a TATA box 25 base pairs (bp) upstream from the transcription startpoint; the other is located between 10 and 50 bp downstream from the transcription initiation site. We have now shown by transfection that both elements are required for efficient transcription in cultured cells. A partially purified natural human TATA box-binding factor (TFIID) from HeLa cells gave footprints that extended from upstream of the TATA box through the downstream initiator. Deletion of the downstream initiator inhibited both TFIID binding to the TATA box and transcription in vitro. In contrast to natural human TFIID. clone human and yeast TFIIDs expressed in bacteria gave footprints covering only the TATA box region. although hypersensitive sites were observed in the downstream region. The cloned TFIIDs also showed less dependence than natural human TFIID on the downstream initiator for both TATA box binding and in vitro transcription. These results suggest that natural human TFIID contains an additional component(s) that contribute(s) to stable TFIID binding and effective transcription by interacting with the downstream initiator.
Bidirectional incompatibility between conspecific populations of Drosophila simulans, Cytoplasmic incompatibility (CI) describes the phenomenon whereby eggs fertilized by sperm from insects infected with a rickettsial endosymbiont fail to hatch. Unidirectional CI between conspecific populations of insects is a well documented phenomenon. Bidirectional CI has. however. only been described in mosquito populations. and recently between closely related species of parasitic wasps. where it is of interest as both an unusual form of reproductive isolation and as a potential means of insect population suppression. Here we report on the first known example of bidirectional CI between conspecific populations of Drosophila simulans. Further. we show that defects as early as the first cleavage division are associated with CI. This observation suggests that the cellular basis of CI involves disruption of processes before or during zygote formation and that CI arises from defects in the structure and/or function of the sperm during fertilization.
Structure, expression and function of a schwannoma-derived growth factor, During the development of the nervous system. cells require growth factors that regulate their division and survival. To identify new growth factors. serum-free growth-conditioned media from many clonal cell lines were screened for the presence of mitogens for central nervous system glial cells. A cell line secreting a potent glial mitogen was established from a tumour (or 'schwannoma') derived from the sheath of the sciatic nerve. The cells of the tumour. named JS1 cells. were adapted to clonal culture and identified as Schwann cells. Schwann cells secrete an autocrine mitogen and human schwannoma extracts have mitogenic activity on glial cells. Until now. neither mitogen has been purified. Here we report the purification and characterization of a mitogenic molecule. designated schwannoma-derived growth factor (SDGF). from the growth-conditioned medium of the JS1 Schwann cell line. SDGF belongs to the epidermal growth factor family. and is an autocrine growth factor as well as a mitogen for astrocytes. Schwann cells and fibroblasts.
A rat femoral artery model for vasospasm, A new animal model for vasospasm using rat femoral artery has been developed. Whole blood. washed erythrocytes. or leukocytes in platelet-rich plasma were selectively applied to the adventitial surface of the femoral artery for 7 days in 15 rats. after which the vessels were perfusion-fixed and examined by light and transmission electron microscopy and immunohistochemistry. As compared with matched control arteries. there was a prominent reduction in luminal cross-sectional area after 7 days in vessels exposed to whole blood or washed erythrocytes. but not in those exposed to leukocytes in platelet-rich plasma. In arteries with luminal narrowing. light and transmission electron microscopy demonstrated marked morphological changes throughout the vessel wall similar to those seen in cerebral vasospasm after subarachnoid hemorrhage. Immunohistochemistry disclosed a prominent loss of immunoreactive actin in smooth muscle cells of arteries exposed to whole blood or erythrocytes. To assess the time course of arterial narrowing in this model. whole blood was selectively applied to the adventitial surface of femoral arteries in 23 rats for periods from 2 to 20 days. As compared with control arteries. arterial narrowing was variably present at 2 days. progressively increased by 5 days. was maximal at 7 to 10 days. and returned to near control levels by 20 days. The presence and severity of ultrastructural changes in vessel wall corresponded to the degree of arterial narrowing over time. These results suggest that chronic narrowing in rat femoral artery exposed to periadventitial blood is analogous to that observed in cerebral arterial vasospasm after subarachnoid hemorrhage. This new model represents a simple and reliable means to investigate pathogenic mechanisms and potential therapies for vasospasm.
The frequency-dependent behavior of cerebral autoregulation, Cerebral autoregulation is a complex physiological process composed of both fast and slow components that may respond differently to different rates and patterns of blood pressure variation. To assess the temporal nature of autoregulation. transcranial Doppler velocity recordings of the middle cerebral artery obtained over prolonged periods were compared with blood pressure recordings in 5 patients without cerebral disease and in 13 patients with intracranial pathological changes. Correlations between the velocity and pressure wave forms at various frequencies of variation were measured with systems analysis techniques. Patients with aneurysmal subarachnoid hemorrhage had high correlations indicating pressure-dependent flow and impaired autoregulation. Patients without cerebral disease had significantly lower correlations (P less than 0.01). indicating intact autoregulation. Examples of increasing correlations and correlations at new frequencies emerging as the clinical condition worsened are given. These preliminary examples suggest that the application of systems analysis techniques to velocity and pressure data allow measurement of the temporal nature of cerebral autoregulation.
Acute changes in the dynamics of the cerebrospinal fluid system during experimental subarachnoid hemorrhage, Early changes in intracranial pressure (ICP). ICP volume index. and resistance to absorption of cerebrospinal fluid induced by experimental subarachnoid hemorrhage were studied in cats. After SAH. the ICP was slightly elevated. and there was a decrease in the buffering capacity of the intracranial space and a sharp rise in outflow resistance. During infusion of blood into the cisterna magna with a constant infusion rate. an extensive increase in ICP could be demonstrated in contrast to the infusion of saline. which caused only slight elevation of ICP. Furthermore. during blood infusion. the ICP level did not reach a plateau phase of pressure. as was demonstrated during infusion of saline. It is suggested that the marked increase in ICP during blood infusion into the subarachnoid space is caused by intracranial volume loading and the simultaneous increase in cerebrospinal fluid outflow resistance. It is concluded that the reported relationship between increased cerebrospinal fluid outflow resistance and increased ICP supports the hypothesis of a strong increase in ICP during subarachnoid hemorrhage in human subjects.
Inhibition of tumor growth in a glioma model treated with boron neutron capture therapy, This investigation attempts to determine whether increased survival time seen when the F98 glioma model is treated with boron neutron capture therapy (BNCT) is a result of inhibition of tumor growth caused by radiation-induced alterations in endothelial cells and normal tissue components. This indirect effect of radiation has been called the tumor bed effect. A series of tumor-bearing rats was studied. using a standardized investigational BNCT protocol consisting of 50 mg/kg of Na2B12H11SH injected intravenously 14 to 17 hours before neutron irradiation at 4 x 10(12) n/cm2. Ten rats. serving as controls. received no treatment either before or after tumor implantation. A second group of 10 rats was treated with BNCT 4 days before tumor implantation; these animals received no further treatment. The remaining group of 10 rats received no pretreatment but was treated with BNCT 10 days after implantation. Histological and ultrastructural analyses were performed in 2 animals from each group 17 days after implantation. Survival times of the untreated control animals (mean. 25.8 days) did not differ statistically from the survival times of the rats in the pretreated group (mean. 25.5 days). The rats treated with BNCT after implantation survived significantly longer (P less than 0.02; mean. 33.2 days) than the controls and the preirradiated animals. Tumor size indices calculated from measurements taken at the time of death were similar in all groups. These results indicate that. with this tumor model. BNCT does not cause a tumor bed effect in cerebral tissue. The therapeutic gains observed with BNCT result from direct effects on tumor cells or on the peritumoral neovascularity.
Multiple intracranial tumors of different cell types, Multiple intracranial tumors of different cell types are rare. We report nine patients with multiple intracranial tumors. who did not have a history of trauma. irradiation. or phacomatosis. The clinical. radiological. and histopathological findings as well as indications for operations in patients with asymptomatic second tumors are discussed.
Brain stem and spinal metastases of supratentorial glioblastoma multiforme: a clinical series, Although the spread of supratentorial glioblastoma multiforme to the brain stem and spine has been extensively described in published autopsy series. information on the diagnosis. treatment. and subsequent clinical course of patients manifesting symptoms of glioblastomatous dissemination ante mortem remains scant. We report a series of 11 patients having the signs and symptoms of neuraxis dissemination of supratentorial glioblastoma multiforme. All patients had radiographic documentation of metastases by either contrast-enhanced myelograms or enhanced magnetic resonance imaging scans. Ten presented with spinal involvement. whereas one presented with lower cranial neuropathies secondary to diffuse involvement of the basal cisterns. The mean age of the patients was 38.5 years. and the mean time interval between diagnosis of intracranial disease and diagnosis of metastases was 14.1 months. After diagnosis of tumor spread. subsequent mean survival time was 2.8 months. All patients received additional radiotherapy to the areas of metastasis. but the clinical response to radiotherapy was quite poor. This study confirms previous reports in the literature suggesting that metastases occur in younger patients and in patients with extended survival. The findings suggest that the relatively infrequent clinical incidence of the symptomatic spread of glioblastoma multiforme. as compared with the frequent incidental discovery of such spread at autopsy. may be the result of the limited survival of the affected patients. and not due to the biology of the tumor.
Ultrastructural evidence for differentiation in a human glioblastoma cell line treated with inhibitors of eicosanoid metabolism, Human glioblastoma cells incubated in the presence of inhibitors of eicosanoid biosynthesis show decreased cellular proliferation without cytotoxicity. We studied the ultrastructural morphology of a human glioblastoma cell line cultured with nordihydroguaiaretic acid (NDGA). a lipoxygenase inhibitor. or 5.8.11.14-eicosatetraynoic acid. a cyclooxygenase and lipoxygenase inhibitor. When glioblastoma cells were treated for 3 days with antiproliferative concentrations of either agent. they shared many morphological characteristics. including evidence for increased astrocytic differentiation with only limited signs of toxicity. The inhibited glioma cells demonstrated an increase in the number and length of astrocytic processes containing greater numbers of glial filaments. and the NDGA-treated cells also demonstrated extensive lateral pseudopod formation along the processes. The glioblastoma cell shape also became more elongated. losing the usual nuclear lobularity and nuclear inclusions. especially in NDGA-treated cells. Many cytoplasmic organelles packed the cytosol of the inhibited glioma cells. including prominent Golgi apparatus. dilated smooth endoplasmic reticulum evolving into dilated vesicles. cytoplasmic vacuoles. and numerous concentric laminations. There was limited evidence for toxicity. however. as the mitochondria were more pleomorphic with some mitochondrial distention and disruption of the cristae along with an increase in cytoplasmic vacuolization. We conclude that the inhibitors of eicosanoid biosynthesis. NDGA and 5.8.11.14-eicosatetraynoic acid. not only suppress glioblastoma cell proliferation. but also induce increased astrocytic differentiation.
Limited selective posterior rhizotomy for the treatment of spasticity secondary to infantile cerebral palsy: a preliminary report, A limited selective posterior rhizotomy was performed on 30 children suffering from spasticity secondary to infantile cerebral palsy. As opposed to standard techniques that stimulate and divide the dorsal rootlets from L2 to S1. we dissected L4. L5. and S1 dorsal roots through an L5 to S1 laminectomy. Eight to 12 rootlets from each root were electrically stimulated with two unipolar electrodes (pulse width. 50 microseconds; 10-50 V). The muscle responses were observed visually and registered by electromyography. Those rootlets associated with an abnormal motor response as evidenced by sustained muscular contraction or by prolonged electromyographic response were divided. Spasticity was scored from 0 to +. The muscular groups assessed were those involved in the flexion of the shoulder. elbow and wrist in the upper limbs. and those involved in flexion and adduction of the hip. flexion of the leg. and plantar flexion in the lower limbs. The patients were assessed 1 week before and 6 months after the operation. Reduction of spasticity was observed in all the muscular groups. and all the patients presented functional improvement of motor abilities. These preliminary results indicate that a limited procedure that reduces the extension of the laminectomy and the length of the operation could be effective for treating spasticity secondary to infantile cerebral palsy.
Radical osteoclastic craniectomy in sagittal synostosis, We report our experience in the surgical treatment of sagittal synostosis using radical osteoclastic craniectomy in 60 consecutive patients. After surgery in children aged 6 months or younger (Group I). reossification usually started 2 weeks postoperatively and was complete within 6 months. resulting in an optimal skull contour. In children aged 7 to 12 months (Group II). reossification was prolonged and lasted for 12 months or longer. The skull contour normalized in its biparietal width and improved in sagittal diameter. remaining. however. slightly abnormal. In children older than 12 months (Group III). the skull contour partly improved in the biparietal diameter but did not change in the sagittal direction. Reossification was incomplete with persistent pseudosutures. Enlarged frontal subarachnoid spaces were reversible or improved in all patients independent of age at the time of surgery. We encountered no complications in our series. In our opinion. radical osteoclastic craniectomy is the simplest. most efficient. and most physiologically sound method for the treatment of sagittal synostosis in patients up to 6 months of age. This procedure allows the rapidly growing brain to form its skull vault. thus providing optimal cosmetic results. In older children. osteoplastic morcellation procedures should be the treatment of choice.
Distribution of angiographic vasospasm after subarachnoid hemorrhage: implications for diagnosis by transcranial Doppler ultrasonography, A study was undertaken to determine how frequently angiographic vasospasm occurs outside the normal access range of transcranial Doppler ultrasound in patients who have suffered a subarachnoid hemorrhage. Vasospasm located in the basal vessels is readily identifiable using transcranial Doppler ultrasound whereas spasm affecting the more distal. vertically oriented arteries is outside the standard detection range. It is therefore speculated that the sensitivity of the technique would be adversely affected by a high incidence of distal vasospasm. A total of 136 angiograms performed on 68 patients after a subarachnoid hemorrhage from anterior circulation aneurysms were reviewed to determine the typical distribution of vasospasm. Of the 40 cases that showed greater than or equal to 25% vessel narrowing. 50.0% had spasm restricted to the basal vessels. 42.5% had spasm involving both basal and distal segments. and 7.5% had spasm of the distal segments only. None of the patients with distal vasospasm alone developed delayed ischemic deficits. It is concluded that most patients with anterior circulation aneurysms who develop vasospasm will have involvement of the basal vessels. but a small number of patients may develop vasospasm only in distal vessels.
Pharmacological reversibility of experimental cerebral vasospasm, Using a morphometric technique. the pharmacological reversibility of luminal narrowing after experimental subarachnoid hemorrhage (SAH) was investigated. For vasodilation. a "cocktail" consisting of 10(-4) M papaverine. 2 x 10(-4) M sodium nitroprusside. and 10(-5) M adenosine was administered intra-arterially. Forty-two rabbits were divided into six groups: control (normal animals); control plus cocktail (normal animals perfused with the cocktail before fixation); SAH (animals sacrificed 48 hours subsequent to intracisternal injection of 1.5 ml/kg of arterial blood); SAH plus cocktail (SAH plus perfusion with the cocktail); BaCl2 (animals sacrificed 10 minutes after intracisternal injection of 2 ml of 3 x 10(-3) M BaCl2); and BaCl2 plus cocktail (BaCl2 animals perfused with the cocktail). The diameter of the basilar arteries in the control and the control plus cocktail groups was not significantly different. BaCl2 reduced the diameter 44% and SAH reduced the diameter 27%. There were no significant differences between the diameter of the BaCl2 plus cocktail group and SAH plus cocktail group when compared with the control or the control plus cocktail group. Morphological examination by light and transmission electron microscopy showed luminal narrowing and corrugation of the elastic lamina with few degenerative or proliferative changes of the vessel wall in animals with SAH. These results suggest that cerebral vasospasm is caused initially by smooth muscle contraction rather than by proliferative vasculopathy and that it is not an irreversible process.
Fractures of the clivus: classification and clinical features, Fractures of the clival complex were diagnosed in a series of 17 patients admitted to the Maryland Institute for Emergency Medical Services System and the University of Maryland Medical System over a 30-month period. These fractures were divided pathologically into three types based upon their appearance on computed tomography: longitudinal. transverse. and oblique. The mechanisms of injury were similar in all groups. and the Glasgow Coma Scale scores at admission were comparable. regardless of fracture type. in survivors and nonsurvivors. Longitudinal fractures were associated with severe injury to the central nervous system and with brain stem infarction. and 4 of 6 (67%) of these patients died. Transverse fractures of the clival complex were found in 6 patients. 3 of whom (50%) died. All of these patients had fractures of the petrous ridge; 2 of the 3 survivors had multiple cranial nerve deficits. and one patient developed a carotid-cavernous fistula. Of the 5 patients with oblique clival fractures. 2 survived (40%). both of whom had multiple cranial nerve palsies; in addition. one of these patients developed a carotid-cavernous fistula. Using the present generation of computed tomographic scanners. fractures of the clival complex can be reliably diagnosed; they are probably more common than previously believed and can be separated into three groups based on the characteristics on computed tomographic scans and clinical findings.
An operative complication in a patient with a true posterior communicating artery aneurysm: case report and review of the literature, Intraoperative oculomotor nerve injury in a patient with a true posterior communicating artery aneurysm is reported in detail. A comparison of internal carotid artery aneurysms at the posterior communicating artery junction with true posterior communicating artery aneurysms deserves special attention. because the vascular relationships of the aneurysm are more complex. A clip along the internal carotid artery does not occlude blood flow to the aneurysm. and the aneurysmal neck and the distal posterior communicating artery are closer to the oculomotor nerve. This is the 27th reported case of a true posterior communicating artery aneurysm. The incidence of true posterior communicating artery aneurysms ranges from 0.1 to 2.8% of all aneurysm patients. Such aneurysms constitute 4.6 and 11% of so-called posterior communicating aneurysms in two series. Difficulty associated with a preoperative diagnosis has been documented in at least 4 cases. An awareness of this rare aneurysm is stressed in order to avoid operative complications.
Mechanism of stroke in patients taking aspirin, During a 1-year period. we prospectively studied the mechanism and severity of stroke in 47 patients sustaining a cerebral infarction while taking aspirin. The mechanism of stroke was undetermined in 12 patients (26%). In the remaining 35 patients. we identified 39 potential mechanisms: large-artery atherosclerosis (19 patients. 40%). cardioembolism (15 patients. 32%). and small-vessel occlusive disease (5 patients. 11%). Of 11 patients with carotid atherosclerosis and stroke. 9 (82%) had greater than 90% carotid stenosis or occlusion; of 12 patients with stroke of undetermined mechanism. 10 (83%) had previous stroke. of which 8 were also of undetermined mechanisms. Disability after stroke was moderate or severe in 27 patients (57%). These data suggest that (1) stroke in patients taking aspirin has a variety of etiologies and frequently causes moderate or severe disability; (2) patients with carotid disease failing aspirin often have high-grade carotid stenosis or occlusion; (3) stroke of undetermined mechanism may recur more frequently than other stroke subtypes in patients taking aspirin.
A case-control study of Alzheimer's disease in Australia, We conducted a case-control study of clinically diagnosed Alzheimer's disease (AD) on 170 cases aged 52 to 96 years. and 170 controls matched for age. sex and. where possible. the general practice of origin. Trained lay interviewers naive to the hypotheses and to the clinical status of the elderly person carried out risk-factor interviews with informants. Significant odds ratios were found for 4 variables: a history of either dementia. probable AD. or Down's syndrome in a 1st-degree relative. and underactivity as a behavioral trait in both the recent and more distant past. Previously reported or suggested associations not confirmed by this study include head injury. starvation. thyroid disease. analgesic abuse. antacid use (aluminum exposure). alcohol abuse. smoking. and being left-handed.
The opposite pupil in herniation, I serially examined the pupil opposite the one already enlarged from transtentorial herniation in 13 patients. The main abnormalities. stereotyped in most patients. were an initially diminished light reaction with a 2.5- to 4-mm-diameter pupil. followed by slight reduction in size. and then reenlargement to greater than original size. all with preserved roundness. Subsequent deterioration varied among patients. but a transitional oval shape was infrequent and oculomotor function was preserved until both pupils were enlarged and fixed. Once the pupil on the side of a mass enlarges. heralding herniation. subsequent deterioration can be appreciated through changes in reactivity and size of the opposite pupil.
Spatiotemporal contrast sensitivity differs in normal aging and Parkinson's disease, We measured contrast sensitivity for static and laterally drifting vertical gratings in 12 young adults. 7 normal elderly adults. and 8 patients with Parkinson's disease (PD). We compared static and motion contrast sensitivity for spatial frequencies of 0.25. 1. and 4 cycles per degree (cpd). and temporal frequencies of 1. 3. and 9 Hz. Results show that normal aging leads to a reduction of motion sensitivity for the spatial frequency of 0.25 cpd. Compared with elderly controls. PD patients do not present specific abnormalities in this domain. However. for spatial frequencies of 1 and 4 cpd and temporal frequencies of 1 and 3 Hz. motion sensitivity is worse than static sensitivity in PD patients and not in elderly controls. These findings suggest a specific deficit of motion perception in PD. and possible dopaminergic involvement in the control of visuospatial behavior.
Hemiparkinsonism-hemiatrophy syndrome: clinical and neuroradiologic features, We evaluated 11 patients with hemiparkinson-hemiatrophy syndrome. 6 with body and contralateral cerebral hemispheric hemiatrophy. 4 with only body hemiatrophy. and 1 with just brain hemiatrophy. The mean age of symptom onset was 38.1 years (range. 18 to 54) with 5.2 +/- 3.1 (mean +/- SD) years of illness until the last follow-up visit. The presenting symptom was unilateral tremor in 6 patients. hand dystonia in 2. bradykinesia in 2. and abnormal gait in 1 patient. Three patients had a good response to levodopa. 4 had moderate response. and 2 patients had a poor response. During a mean follow-up period of 1.7 years (range. 4 months to 5 years). the Hoehn and Yahr score changed in only 3 patients: 2 gained 1.5 points and 1 gained 3 points over 2.5 years. We discuss the association between hemiparkinsonism-body hemiatrophy and contralateral hemispheric hemiatrophy. and raise the possibility of early childhood brain insult with delayed-onset parkinsonism.
Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure, The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients with recurrent malignant astrocytomas after radiation and nitrosourea failure with successive courses of PCB 150 mg/m2/d for 28 days every 8 weeks. After 2 courses. 2 patients had complete responses. 7 had partial responses. 11 had stable disease. and 15 had progression. Significantly more patients receiving PCB had complete or partial responses or stable disease than a similar group of patients in a previous trial who received intra-arterial (IA) cisplatin (DDP). There is a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ). Our results suggest that PCB is a more effective 2nd agent than IA DDP or AZQ following radiation and nitrosourea failure.
Anti-GM1 IgM antibodies in motor neuron disease and neuropathy, We found anti-GM1 IgM antibodies in 23% of 56 patients with motor neuron disease (MND). in 19% of 69 patients with neuropathy. and in 7% of 107 controls with other neurologic and nonneurologic diseases. Most of these patients had anti-GM1 IgM antibody titers of 1:80 or less; slightly higher antibody titers (up to 1:640) were found in 3 patients. 1 with MND and 2 with neuropathy. and very high titers (1:20.480) in a patient with MND and an IgM kappa M protein that reacted with GM1. GD1b. and asialo GM1. Six other patients with anti-GM1 IgM that also bound to GD1b. Reactivity with GD1b did not correlate with anti-GM1 titers but was only present in patients with MND or neuropathy. Anti-GM1 IgM antibodies may be a normal constituent of the human antibody repertoire but their frequency and. in some cases. their levels are higher in patients with MND and neuropathy. The origin and the pathogenetic role of these antibodies in neural impairment remain to be established.
Proton magnetic resonance spectroscopy in multiple sclerosis, Regional in vivo proton magnetic resonance spectroscopy provides quantitative data on selected chemical constituents of brain. We imaged 16 volunteers with clinically definite multiple sclerosis on a 1.5 tesla magnetic resonance scanner to define plaque-containing volumes of interest. and obtained localized water-suppressed proton spectra using a stimulated echo sequence. Twenty-five of 40 plaque-containing regions provided spectra of adequate quality. Of these. 8 spectra from 6 subjects were consistent with the presence of cholesterol or fatty acids; the remainder were similar to those obtained from white matter of normal volunteers. This early experience with regional proton spectroscopy suggests that individual plaques are distinct. These differences likely reflect dynamic stages of the evolution of the demyelinative process not previously accessible to in vivo investigation.
Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals, We derived a total of 146 T lymphocyte lines specific for human myelin basic protein (MBP) from the peripheral blood of 20 MS patients and from a control group of 12 healthy donors. and determined the reactivities of T cell lines by [3H]thymidine incorporation on exposure to MBP and MBP peptides 1-44. 45-89. and 90-170. We defined HLA restriction of the T lines by using monoclonal antibodies against monomorphic determinants on human HLA-DR. HLA-DQ. and HLA-DP molecules. MBP-specific T cell lines could be isolated with a comparable efficiency from MS patients and healthy individuals. In both groups. MBP-specific T lymphocytes recognized at least 4 different epitopes in the MBP molecule. and specificities showed comparable patterns for different MBP peptides. MBP-specific T cell lines derived from MS patients and controls were restricted by DR products of the human major histocompatibility class II locus. Notable phenotypic differences of T cell lines existed between the 2 groups. Lines isolated from MS patients expressed predominantly the CD3+ CD4+ CD8- phenotype. while some control lines were composed of up to 87% CD3+CD4+CD8+ T lymphocytes. These findings illustrate the presence of MBP-specific T cells in MS patients and controls that are similarly sensitized to MBP and restricted by HLA-DR products.
Neuroleptic malignant syndrome: a unique association with a tricyclic antidepressant, We report the lst case of neuroleptic malignant syndrome occurring in a patient receiving desipramine. a tricyclic antidepressant. with no exposure to neuroleptics. Our case suggests that this syndrome may be caused by a central imbalance between norepinephrine and dopamine. and not by dopamine depletion alone.
Observer variability in the scoring of colpophotographs, Colposcopy and cervicography are accepted tools for assessing the cervix for an atypical transformation zone. We studied the validity of the colpophotograph as a measurement tool by determining the agreement of experienced colposcopists using colpophotographs of 50 women. Interobserver agreement was generally fair to good (kappa greater than or equal to 0.40) for the presence of the squamocolumnar junction and the area of ectopia but it was poor (kappa less than 0.40) for the area. border. and color characteristics of an atypical transformation zone. Intra-observer agreement was fair to good for the color characteristics of an atypical transformation zone. but it was poor for the area and border characteristics. We conclude that observer agreement studies should play a role in the validation of methods used in the visual diagnosis of cervical intraepithelial neoplasia. Considerable lack of agreement in reporting cytologic findings is a well-known problem. and lack of agreement might be an even bigger problem in reporting colposcopic findings.
Basement membrane of cervical adenocarcinoma: an immunoperoxidase study of laminin and type IV collagen, The basement membrane components type IV collagen and laminin were examined immunohistochemically in 14 cases of adenocarcinoma of the cervix. The patterns of staining in adenocarcinoma in situ. invasive adenocarcinoma. and early invasive adenocarcinoma were compared to see whether characteristic patterns could be delineated. Adenocarcinoma in situ had a uniform intact basement membrane. whereas the basement membrane of invasive adenocarcinoma was fragmented and irregular. Cases of early stromal invasion showed early gland buds and outpouchings with defective basement membrane staining. The degree of histologic differentiation of the tumor was not clearly related to the amount of basement membrane component staining. The concept of early stromal invasion in cervical adenocarcinoma. as supported by our immunohistochemical studies. is discussed as it relates to a possible pathogenic mechanism in early invasion and infiltration of adenocarcinoma of the cervix.
Treatment of fallopian tube carcinoma with cisplatin, doxorubicin, and cyclophosphamide, Primary carcinoma of the fallopian tube is uncommon and is often treated using regimens active in ovarian carcinoma. Evidence is scant that such therapies benefit patients with fallopian tube carcinoma. Between December 1979 and July 1988. we treated 18 patients who had adenocarcinoma of the fallopian tube with the combination of cisplatin (50 mg/m2). doxorubicin (50 mg/m2). and cyclophosphamide (500 mg/m2) administered intravenously on 1 day every 28 days. Histologic confirmation of fallopian tube carcinoma was obtained before entry in the study. Three patients had stage I disease. five had stage II. nine had stage III. and one had stage IV. Sixteen patients received the combination therapy as first-line treatment after cytoreductive surgery. and two patients received it for recurrent carcinoma. Seven patients had clinically measurable disease at the start of therapy. Two of these patients had a complete clinical response. two had stable disease. and three had progressive disease. Eight of the 15 patients with stages II-IV disease underwent second-look laparotomy; four had a complete response to therapy and four had a partial response. making the overall response rate 53%. The toxicity of the regimen was moderate. The median survival was 81 months. Patients with stages II-IV disease had a median survival of 43.9 months and a progression-free survival of 22.5 months. This regimen appears to be active in fallopian tube carcinoma and can result in response rates comparable to those reported for epithelial ovarian cancer.
Maternal serum screening for aneuploid pregnancy by alpha-fetoprotein, hCG, and unconjugated estriol, A number of serum screening protocols are either currently in use or proposed to identify pregnant women under 35 years of age who are at increased risk for a Down syndrome fetus. It has been suggested that these same screening methods be applied to gravidas over 35 years of age to identify those women who should be offered amniocentesis. To evaluate the efficacy of screening for detection of aneuploid pregnancy in this age group. the serum samples of 34 women who underwent amniocentesis and who had confirmed fetal aneuploidy were assayed for alpha-fetoprotein (AFP). hCG. and unconjugated estriol (E3). These concentrations were compared with those of 85 women with known euploid pregnancy who underwent amniocentesis for advanced maternal age. The mean multiple of the median (MoM) for each of the three markers was significantly different from control values in cases of trisomy 21 (AFP median MoM = 0.82; unconjugated E3 median MoM = 0.77; and hCG median MoM = 1.89). These differences were not found when other aneuploidies were considered. Likelihood ratios were calculated for cases and controls and examined for their ability to predict the need for amniocentesis. based on currently recommended risk levels. There was a significant difference between the mean likelihood ratio for cases of trisomy 21 compared with that of controls (mean likelihood ratio = 13.48); there was no significant difference for other aneuploidies (mean likelihood ratio = 1.08). Of the 16 cases of trisomy 21 analyzed. four would not have been diagnosed antenatally if recommendation against amniocentesis had been made based on each woman's individual age-specific risk as modified by her likelihood ratio.
Early amniocentesis: report of 407 cases with neonatal follow-up, Amniocentesis was performed for prenatal diagnosis in 407 pregnancies between the gestational ages of 11-14 weeks. The safety and accuracy of the procedure were compared with data obtained from collaborative studies of amniocentesis performed later in the second trimester. There were no differences observed with respect to accuracy. pseudomosaicism. or maternal-cell contamination related to the timing of the procedure. The fetal loss rate within 4 weeks of the procedure was 2.3%. Fetal losses appeared to be related to maternal complications such as bleeding and leakage of fluid that occurred within a day of the procedure. No major maternal complications were noted. Information regarding neonatal outcome. including pulmonary complications and congenital orthopedic postural deformities. was found to be similar to that in previous reports.
Elevated maternal serum alpha-fetoprotein and amniotic fluid alpha-fetoprotein after multifetal pregnancy reduction, Forty patients underwent fetal reduction at approximately 12 weeks' gestation for multiple pregnancy. Twenty-two had maternal serum alpha-fetoprotein (MSAFP) determinations and all but one was elevated. with a mean value of 9.41 multiples of the median (MOM). A total of 53 amniotic fluid specimens were evaluated for AFP; 25% were elevated above 2.0 MOM and one sample was positive for acetylcholinesterase. None of these elevations were associated with a neural tube defect. although two neural tube defects were detected by other means. Routine MSAFP is not recommended for patients with multifetal pregnancy reduction.
Effect of maternal smoking and age on congenital anomalies, The incidence of congenital anomalies was examined by the level of maternal and paternal smoking during pregnancy for 17.152 infants. A multiple regression analysis was used to control for the possible confounding effects of maternal age. formal education. ethnic origin. religion. marital status. parity. social class. and work outside the home. Neither maternal nor paternal smoking habits were significantly associated with the occurrence of congenital malformations. Maternal age was significantly (P less than .005) related to the incidence of major anomalies. Mothers aged 35 years and older who smoked were found to have a significantly (P less than .002) higher risk for minor malformations and a nonsignificantly increased rate of major malformations. Maternal cigarette smoking may be an important preventable risk factor for congenital anomalies among mothers aged 35 years or older.
Maternal mortality in the United States, 1979-1986, To understand better the epidemiology and to describe the causes of maternal death. we reviewed all identified maternal deaths in the United States and Puerto Rico for 1979-1986. The overall maternal mortality ratio for the period was 9.1 deaths per 100.000 live births. The ratios increased with age and were higher among women of black and other minority races than among white women for all age groups. The causes of death varied for different outcomes of pregnancy; pulmonary embolism was the leading cause of death after a live birth. Unmarried women had a higher risk of death than married women. The risk of death increased with increasing live-birth order. except for primiparas. In order to develop strategies to reduce the risk of maternal death in the United States. future studies should include expanded information about each death. which will allow better understanding of factors associated with maternal mortality.
Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study, Preeclampsia is a disease unique to pregnancy that contributes substantially to maternal and fetal morbidity and mortality. The condition has been thought to be one of hypoperfusion in which increased vascular resistance characterizes the associated hypertension. This study was designed to test an alternative hypothesis. that preeclampsia is characterized by high cardiac output. In a blinded longitudinal study of nulliparas with uncomplicated pregnancies. cardiac output was measured serially by Doppler technique. Cardiac output was elevated throughout pregnancy in patients who became preeclamptic (P = .006). Six weeks postpartum. the hypertension of the preeclamptic subjects had resolved but cardiac output remained elevated (P = .001) and peripheral resistance remained lower than in the normotensive subjects (P = .001). This study demonstrates that preeclampsia is not a disease of systemic hypoperfusion and challenges most current models of the disease based on that assumption.
Does indomethacin alter the hemodynamic response to magnesium sulfate infusion and hemorrhage in gravid ewes, The purpose of this study was to determine whether indomethacin alters the maternal and fetal hemodynamic response to magnesium sulfate (MgSO4) infusion and hemorrhage in gravid ewes. We studied seven chronically instrumented animals between 0.8 and 0.9 of timed gestation. The experimental sequence included: 1) at time 0. indomethacin. 2 mg/kg. or vehicle only intravenously (IV) over 5 minutes; 2) at 60 minutes. MgSO4 4 g IV over 5 minutes; 3) at 65 minutes. MgSO4 infusion at 4 g/hour; 4) at 150 minutes. maternal hemorrhage. 20 mL/kg. over 60 minutes; and 5) at 215 minutes. reinfusion of maternal blood over 60 minutes. Each animal was studied with and without indomethacin. Indomethacin. but not vehicle only. transiently increased maternal and fetal mean arterial pressure (MAP). decreased maternal and fetal heart rate. and decreased maternal cardiac output. Magnesium sulfate significantly decreased uterine vascular resistance and increased uterine blood flow both with and without indomethacin. Hemorrhage significantly decreased maternal MAP. heart rate. cardiac output. and uterine blood flow in both groups. The magnitude of each change was similar between the groups. For example. at the end of hemorrhage. maternal MAP was 36 +/- 7% below baseline (P = .0001) with indomethacin and 41 +/- 2% below baseline (P = .0001) in the vehicle-only group (P = not significant between groups). Hemorrhage significantly decreased fetal heart rate. pH. and PO2. and increased fetal MAP and PCO2 in both groups. We conclude that indomethacin did not alter the maternal or fetal hemodynamic response to MgSO4 infusion and hemorrhage in gravid ewes.
Pregnancy and liver transplantation, To define the risks and outcomes associated with pregnancy and liver transplantation. we reviewed our experience in managing eight pregnant women who had undergone orthotopic liver transplantation. Seven patients conceived after transplantation; the interval from transplantation to conception ranged from 3 weeks to 24 months. One patient received an allograft at 26 weeks' gestation for hepatic failure secondary to acute fulminant hepatitis B. Of the seven patients who conceived after transplantation. six had live births and one electively terminated her pregnancy. Five patients developed worsening hypertension and/or preeclampsia. Three patients developed severe preeclampsia and required delivery. One patient suffered acute allograft rejection during pregnancy which was successfully treated with corticosteroids. Two patients had persistent elevation of serum transaminases and two had severe anemia. The mean gestational age at delivery was 32.8 weeks. Of the six live births to women who conceived after transplantation. five infants survived and are well and one infant died. There were no congenital anomalies. All mothers are alive at this time. Pregnancy in recipients of hepatic allografts is associated with good perinatal outcome. but there is an increased risk of preeclampsia. worsening hypertension. and preterm delivery. Pregnancy does not appear to have a deleterious effect on hepatic graft function or survival. Joint management of these patients by a transplant specialist and a perinatologist is essential.
Objective tocodynamometry identifies labor onset earlier than subjective maternal perception, The ability of women instructed in self-detection of uterine contractions to identify the abrupt rise in uterine activity known to precede the onset of labor has not been evaluated. This study was designed to assess the temporal relationship between objective uterine activity monitoring. subjective maternal perception of uterine activity above a commonly used threshold value (four or more contractions per hour). and progressive cervical change. Daily tocodynamometry (7-9 AM) was recorded in 79 women with preterm premature rupture of the membranes from admission until the onset of spontaneous labor (5.3 +/- 6.3 days). The subjects were at bed rest. received no tocolytic therapy. and were instructed in the signs of labor and uterine self-palpation. Patients simultaneously provided a subjective assessment of uterine activity (four or more contractions per hour). The majority of uterine activity recordings (78%) revealed fewer than four contractions per hour. and the patients' subjective reports agreed in almost all instances (97.6%). On 91 days. four or more contractions per hour were recorded objectively. but the patients' subjective reports agreed in only 25 instances (27%). On the day of labor onset. significantly more women had an objective assessment (32%) (P less than or equal to .01). Patients subjectively identified labor onset 10.6 +/- 6.7 hours after objective monitoring indicated increased uterine activity. and when subjectively identified. both cervical dilatation (4.9 +/- 2.5 cm) and effacement (85 +/- 30%) were significantly advanced (P less than or equal to .001) compared with the admission examination (1.1 +/- 1.2 cm; 20 +/- 30%).
Effect of angiotensin II infusion during normal pregnancy on flow velocity waveforms in the uteroplacental and umbilical circulations, Women destined to develop preeclampsia show an increased systemic pressor response to infused angiotensin II. and the angiotensin sensitivity test has been accepted as an appropriate means of identifying these women. However. the effect of angiotensin II infusion on uteroplacental blood flow is unknown and may be deleterious. Patients undergoing angiotensin sensitivity tests as part of a protocol examining the effect of aspirin on the incidence of preeclampsia were studied with Doppler velocimetry performed before and during the angiotensin II infusion. Fetal well-being was documented with biophysical profiles performed before and after the infusions. Neither the systolic-diastolic ratios in the uterine and umbilical arteries nor the biophysical profile scores were altered significantly (P = .43. P = .23. Wilcoxon signed-rank median test. and P = .35. Fisher exact test. respectively). These findings suggest that the angiotensin sensitivity test does not increase resistance to flow in the uterine or umbilical circulation. and therefore may be used safely in screening for preeclampsia.
Doppler umbilical artery studies in the twin-twin transfusion syndrome, Eleven patients with twin pregnancies were identified as having twin-twin transfusion syndrome on the basis of like-sex twins with monochorionic placentation and umbilical venous blood hemoglobin differences exceeding 50 g/L at delivery. Umbilical artery velocity-time waveform studies had been performed in these pregnancies as part of a large series of 456 twin pregnancies. In all 11 cases. the systolic-diastolic (S-D) ratio differences between the twins were less than 1 unit (mean 0.4 +/- 0.2). indicating that in twin-twin transfusion. umbilical artery S-D ratios are concordant even in the presence of discordancy in fetal size.
Serum estradiol as an aid in the diagnosis of ectopic pregnancy, The value of serum beta-hCG measurement in the diagnosis of ectopic pregnancy is well established. and there have been recent studies on the use of serum progesterone levels. However. we have been unable to find any reports on the potential application of serum estradiol (E2) assays in the diagnosis of ectopic pregnancy. We therefore concurrently measured serum E2. progesterone. and beta-hCG in 100 women with ectopic pregnancies. as well as in 69 controls with normal intrauterine pregnancies and 36 women with threatened abortion. The mean (+/- standard deviation) E2 levels for ectopic-pregnancy patients. the normal controls. and the women with threatened abortion were 281.1 +/- 115.6. 788.2 +/- 45.5. and 788.8 +/- 40.6 pg/mL. respectively; the mean levels in the ectopic group were significantly different (P less than .0001) from those of the other two groups. All but one of the ectopic pregnancies had values below 650 pg/mL for E2 and 23 ng/mL for progesterone. and all but one of the normal intrauterine pregnancies had values above these levels. Our data suggest that the addition of the estradiol assay. with or without progesterone. to the early evaluation of patients suspected of having an ectopic pregnancy may be helpful in diagnosis.
Debulking of pelvic and para-aortic lymph node metastases in ovarian cancer with the cavitron ultrasonic surgical aspirator, Six patients with metastatic ovarian cancer with extensive involvement of the pelvic and/or para-aortic lymph nodes underwent surgical debulking with the Cavitron Ultrasonic Surgical Aspirator. Intraoperative and postoperative morbidity was minimal. It is suggested that this technique may be used for cytoreductive surgery in combination with standard surgical techniques.
Influence of the menstrual cycle on systemic diseases, Physiological changes associated with the menstrual cycle influence the clinical course of some diseases such as bronchial asthma. allergies. anaphylaxis. epilepsy. migraine. dermatoses. and porphyria. Hormonal manipulation can be beneficial in some patients.
Menorrhagia, Excessive vaginal bleeding. or menorrhagia. is one of the most common presenting symptoms for gynecologic patients. Although this disorder has many possible etiologies. it is generally possible to approach its diagnosis and management in an orderly fashion. When evaluating the menorrhagic patient. it important to gear the work-up toward a differential diagnosis that includes pregnancy-related causes. hormonal problems. iatrogenic etiologies. mechanical intrauterine disorders. infections of the lower genital tract. and gynecologic cancers (PHIMIC). This differential approach can guide the types of historical data obtained from the patient. focus the physical examination. and alert the practitioner to the most appropriate laboratory and radiologic evaluation. Therapy can differ widely. depending on the cause of the bleeding. Most types of menorrhagia respond to medical therapy with oral contraceptives. oral synthetic estrogens or progestins. and long-acting intramuscular progestins or GnRH agonists. Surgical approaches. such as dilatation and curettage or hysterectomy. are less and less a first-line therapy; but innovative surgical techniques such as hysteroscopy and laparoscopic surgery are becoming increasingly important. With rapid. goal-directed diagnosis and specific therapy. the medical complications. anxiety. and discomfort suffered by the woman with menorrhagia can be alleviated quickly.
Amenorrhea, Amenorrhea. the lack of menstruation. is a gynecologic disorder that may arise from a variety of causes. If a logical and orderly schema is followed. the correct diagnosis and appropriate management plan can be formulated.
Abnormal bleeding in the climacteric, In the perimenopausal years. we encounter a situation where the normal diminution in reproductive capacity. with its resulting disruption of the normal menstrual hormonal pattern. coincides with a very real risk of pelvic pathology. Limitation in the ability to diagnose and to treat these patients conservatively has in the past resulted in a high rate of hysterectomy. With increased understanding of the normal physiology of this stage of transition and with improved diagnostic tools. we are now able to come to a definitive diagnosis in most patients. This ability to assure the diagnosis has made it much easier to counsel the patient confidently about the appropriate course of action. We will continue to encounter the problem of hysterectomy for bleeding with no histologic lesion being found. Although reviewers' letters may be considered an unnecessary thorn in the side. the improved practice that has resulted from these efforts gives strong support to their continued activities. We can have confidence that our treatment plan evolved in a logical manner and offers our patients a high probability of benefit at justifiable risk.
Cyclic pelvic pain, Cyclic pelvic pain is a common gynecologic problem caused by relatively few diseases. which usually can be diagnosed and remedied quickly. Some complaints reflect normal physiologic aspects of the menstrual cycle (mittelschmerz. menstrual awareness). Premenstrual syndrome can be diagnosed. but an effective and convenient treatment is lacking. Dysmenorrhea is the commonest source of cyclic pain. diagnosed by its characteristic history and rapid relief on administration of antiprostaglandin agents. Endometriosis is diagnosed surgically and best treated either surgically then. or medically by danazol or GnRH agonists. In contrast. adenomyosis is a problem commonly encountered in later life. and hysterectomy is usually needed for both definitive diagnosis and treatment.
Premenstrual syndrome: an update for the clinician, Premenstrual syndrome is a complex disorder in which a variety of symptoms can occur in the luteal phase of the menstrual cycle. The symptoms should occur each cycle only from the time near ovulation to soon after the onset of menses. There should be at least 1 week in follicular phase that is symptom-free. Symptoms should be severe enough to significantly interfere with the ability of the patient to function within her normal lifestyle. Diagnosis is based on clinical information from prospective charting of symptoms. Up to 50 per cent of patients who think they have PMS really suffer from another type of mental illness. usually a depressive disorder. Laboratory tests are not generally helpful in the diagnosis. Treatment is based on the type(s) of symptom(s). Available treatments are reviewed with documentation of results from double-blind placebo-controlled experimental designs. The etiology of PMS is not known. However. there are good empiric therapies available that can help most PMS patients.
Management of postoperative inflammation: dexamethasone versus flurbiprofen, a quantitative study using the new Flare Cell Meter, A consecutive. random. prospective study was conducted to compare the effect of topical dexamethasone and flurbiprofen drops on postoperative inflammation in patients undergoing extracapsular cataract extraction with lens implantation. Objective. quantitative measurements were made postoperatively. using the Kowa FC-1000 Flare Cell Meter. The two treatments were equally effective.
Increase of neuroretinal rim area after surgical intraocular pressure reduction, The Optic Nerve Head Analyzer was used to measure the optic disc structure of 18 eyes (13 adult glaucoma patients) before and after surgical intraocular pressure reduction. Neuroretinal rim area markedly increased (from +0.15 mm2 to +0.45 mm2) in eight eyes. but changed either very little (less than +/- 0.1 mm2) or not at all in the remaining 10 eyes. The mean increase was from 0.75 +/- 0.26 mm2 to 0.92 +/- 0.36 mm2. The increased neuroretinal rim area found at this time remained in all eyes reexamined 1 to 3 years after surgery. Our data support previous findings that glaucomatous disc cupping may be reversed even in adult eyes. perhaps as the result of adequate pressure reduction.
Evaluation of visual fields by ophthalmologists and by OCTOSMART program, The introduction of Goldmann perimetry standardized measuring conditions as much as possible. In spite of this. it had been possible for the perimetrist to influence the results of perimeter measurements. The introduction of computer-controlled perimetry. however. has largely eliminated the influence of the investigator on perimetry results. Nevertheless. the interpretation of a perimetric result in the everyday clinical situation is still extensively subjectively coloured and is liable to vary. depending on the doctor carrying it out. The OCTOPUS Program G1 was introduced a few years ago and used above all for glaucoma. This program greatly simplified visual field assessment thanks to its visual field indices. The indices make it possible to compare visual field results with those of a normal population. The present introduction of the OCTOSMART program represents a further step forward. This program analyses measured visual fields with the aid of standardized. statistical criteria based on a large. normal value study. This analysis standardizes and thereby simplifies the interpretation of visual field results. This study compares the outcome of the OCTOSMART program with visual field interpretations by eye doctors.
Unusual exudative retinal detachment 9 months after scleral buckling surgery, A 49-year-old man developed exudative retinal detachment 9 months after uncomplicated scleral buckling surgery in the left eye. The subretinal exudates were strictly localized along the buckle and showed remarkable response to steroid. The cause would be noninfectious inflammation like posterior scleritis. triggered by the buckle itself or its associated factors. It is important to note that subretinal exudates long after scleral buckling can occur in consequence of steroid-responsive inflammation as well as insidious bacterial or fungal infection described previously.
The epidemiology of ophthalmic malignancies in New York State, The epidemiologic characteristics of more than 1400 primary eye cancers (ICD-9. site 190) diagnosed among New York State (NYS) residents between 1975 and 1986 are described. Among NYS male residents. the average annual age-adjusted incidence rate was 7.5 per 1.000.000. and among NYS female residents. the rate was 5.4 per 1.000.000 (male:female rate ratio. 1.39). The majority of ophthalmic malignancies were included within three histologic groupings: melanomas (70.4%). retinoblastomas (9.8%). and squamous cell carcinomas (9.2%). The average annual incidence of retinoblastoma among persons in NYS who were less than 5 years of age was 9.5 per 1.000.000 for boys and 8.7 per 1.000.000 for girls (male:female rate ratio. 1.09). The average annual incidence (age-adjusted) of ocular melanomas was 4.9 per 1.000.000 among men and 3.7 per 1.000.000 among women in NYS (male:female rate ratio. 1.32). Expanded knowledge of the epidemiology of ophthalmic cancers can help to develop a foundation on which to monitor disease patterns and can serve to stimulate further etiologic research involving these rare malignancies.
Early magnetic resonance imaging in acute traumatic internuclear ophthalmoplegia, Adduction deficiency following acute head trauma may result not only from orbital damage but also from internuclear ophthalmoplegia. and in most instances this resolves over weeks to months. To date. noninvasive imaging studies during the acute phase following injury have not been definitive in localizing the pathology. Three cases of adduction deficiency following head trauma that were caused by internuclear ophthalmoplegia are reported. A lesion in the brain stem was found in all three cases by magnetic resonance imaging in the subacute post-traumatic period. These lesions were not visible on routine x-ray computed tomography obtained at the time of injury.
Signs distinguishing spasmus nutans (with and without central nervous system lesions) from infantile nystagmus, Clinical findings as well as eye and head movement recordings were analyzed from 23 patients with spasmus nutans without central nervous system (CNS) changes. 10 patients with spasmus nutans-like disease (head nodding. intermittent nystagmus associated with intracranial anomalies or visual pathway disorders). and 25 patients with infantile nystagmus. Ten diagnostic signs were established to differentiate between the patient groups. Although they were helpful in separating patients with infantile nystagmus from those with spasmus nutans. no difference was found between the patients with spasmus nutans with and without CNS lesions. This study indicates that eye and head movement recordings do not allow differentiation between benign spasmus nutans and spasmus nutans-like disease. The differentiation must be made on the basis of neuroimaging.
Late juvenile-onset Krabbe's disease, Krabbe's disease is an autosomal recessive leukodystrophy characterized by a lack of galactocerebroside beta-galactosidase activity. In contrast to the classic early infantile-onset form of Krabbe's disease. less recognized. late-onset variants exist. The authors present a case of late juvenile-onset Krabbe's disease. including the associated magnetic resonance imaging (MRI) findings. Most patients with late-onset Krabbe's disease present with visual loss due to optic atrophy. Associated gait abnormalities and parental consanguinity should increase the clinician's suspicion that a child may have late-onset Krabbe's disease. Because of the prolonged survival in late-onset Krabbe's disease. the recent development of bone marrow transplantation for these patient makes diagnosis of this disorder particularly important.
Macular dystrophy of the cornea. A systemic disorder of keratan sulfate metabolism, The serum of most patients with type 1 macular corneal dystrophy (MCD). the most prevalent subtype. lacks detectable antigenic keratan sulfate (KS). and it has been postulated that such individuals may lack antigenic KS in their cartilage as well. To test this hypothesis. we studied the cornea. serum. and nasal cartilage from an MCD patient using light and electron microscopy. immunohistochemistry. and a quantitative enzyme-linked immunosorbent assay (ELISA) which uses a monoclonal antibody against a sulfated epitope on the KS chain to measure KS content. Histologically. corneal deposits seen were characteristic of MCD. No abnormal deposits were noted in the cartilage. The lack of immunoreactivity in corneal sections with antibodies against sulfated epitope on KS and the absence of this epitope in serum showed that the patient had type 1 MCD. The cartilage specimen showed no immunoreactivity in the chondrocytes or extracellular matrix. Quantitative analysis by ELISA demonstrated that the antigenic KS content of the cornea and cartilage was at least 800 times lower than that in normal controls. This provided direct evidence that the abnormality in the sulfation of keratan in type 1 MCD involves the cornea and cartilage.
Glaucomatous optic nerve atrophy in small discs with low cup-to-disc ratios, Glaucomatous optic nerve damage has generally been associated with high cup-to-disc ratios. Fifteen eyes of nine patients with increased intraocular pressure and glaucomatous visual field loss but low cup-to-disc ratios are reported. The optic disc area was significantly (P less than 0.01) smaller than in 429 normal subjects and 556 glaucoma patients with high cup-to-disc ratios. Parapapillary chorioretinal atrophy was significantly larger and retinal nerve fiber bundles were significantly less visible than in the normal group. The latter two parameters were not significantly different in the glaucoma groups with low and high cup-to-disc ratios when the groups were matched for mean perimetric loss. The authors conclude that in eyes with small optic discs. glaucomatous optic nerve damage may be indicated more sensitively by parapapillary changes than by cup-to-disc ratios. Glaucomatous eyes with small optic nerve heads can have misleadingly low cup-to-disc ratios.
Psoriatic arthropathy of the temporomandibular joint, A case of psoriatic arthritis of both temporomandibular joints is described with a brief review of the literature and discussion on the management of this condition. To date. psoriatic arthritis has been successfully treated by conservative means. In the case reported. surgical replacement of the condyles became necessary to eliminate pain and restore function.
Histologic evaluation of the width of soft tissue necrosis adjacent to carbon dioxide laser incisions, This study evaluated the width of tissue necrosis lateral to carbon dioxide laser incisions on human intraoral excisional biopsy specimens. Measurements were made on specimens including epithelium. muscle. dense and loose connective tissue. and salivary gland. Results showed a mean width of tissue necrosis of 86 microns in epithelium. 85 microns in muscle. 51 microns in loose connective tissue. 96 microns in dense connective tissue. and 41 microns in salivary gland. The range of thermal necrosis in different tissue types is probably based on the water content within each type. A cellular partially homogenized zone of reversible thermal damage up to 500 microns in width was visible adjacent to the zone of thermal necrosis. The relatively narrow width of tissue necrosis with this technique may account for the claimed superior properties of laser-induced wounds compared with those created by electrosurgery.
Unilateral mydriasis caused by transdermal scopolamine, Contamination of the eye after handling of a transdermal scopolamine patch may cause accidental mydriasis. A simple office test is discussed to identify this pharmacologic blockade and thereby avoid an extensive neurologic workup.
Epithelial rests' function in replantation: is splinting necessary in replantation, The problem of resorption during replantation in relationship to the epithelial rests and a lack of splinting was studied. Ten mongrel dogs were used. Two dogs served as control subjects. while eight had their mandibular incisors intentionally replanted and studied histologically. It was observed that where rests of Malassez were present we did not see resorption. and the lack of splinting did not result in resorption or loss of teeth. It appears we can stain epithelial rests of Malassez with immunofluorescent antibodies and use this technique for further study of this tissue.
Quantitative evaluation of digital dental radiograph imaging systems, Two digital imaging systems. a video camera and analog-to-digital converter. and a charge-coupled device linear photodiode array slide scanner. were tested for their suitability in quantitative studies of periodontal disease. The information content in the original films was estimated. and digital systems were assessed according to these requirements. Radiometric and geometric performance criteria for the digital systems were estimated from measurements and observations. The scanner-based image acquisition (digitization) system had no detectable noise and had a modulation transfer function curve superior to that of the video-based system. The scanner-based system was equivalent to the video-based system in recording radiographic film densities and had more geometric distortion than the video-based system. The comparison demonstrated the superiority of the charge-coupled device linear array system for the quantification of periodontal disease extent and activity.
Cross-sectional radiography for implant site assessment, An accurate tomographic technique is described for acquisition of optimal cross-sectional images of implant sites before implant surgery. The described technique is applicable to tomographic systems equipped with a cephalometric head positioner. This cross-sectional tomographic technique was performed on a series of patients and the images of the first 20 patients subsequently evaluated. The cross-sectional images allowed for the characterization of the alveolar crest and visualization of anatomic structures in a buccolingual dimension while providing an accurate estimation of available vertical space from the crest.
Antinociception and cardiovascular responses produced by electrical stimulation in the nucleus tractus solitarius, nucleus reticularis ventralis, and the caudal medulla, In experiment 1. quantitative regional comparisons of the antinociceptive and cardiovascular responses produced by electrical stimulation in the caudal medulla. including regions such as the nucleus tractus solitarius (NTS). nucleus reticularis ventralis (NRV). nucleus reticularis gigantocellularis (NRGC). nucleus reticularis paragigantocellularis (NRPGC). nucleus raphe obscurus (NRO). and medial portions of the lateral reticular nucleus (LRN). were made in the rat. Electrical stimulation in all of these regions resulted in inhibition of the nociceptive tail-flick reflex. although the threshold intensity for inhibition was greater for sites in NTS compared to many sites ventral to the NTS. Antinociception was generally accompanied by an increase in mean arterial blood pressure. with the exception of sites in the NRO. where depressor responses were evoked by stimulation. Detailed comparisons between the NTS and NRV revealed that greater intensities of electrical stimulation were required to produce antinociception for sites in the NTS as compared to the NRV. There were no significant differences in threshold intensities for antinociception as a function of rostrocaudal subdivisions of the NTS. but the lateral subdivision of the NTS was significantly more efficacious than the medial subdivision. This mediolateral difference within NTS was primarily due to stimulation in medial sites producing overt movements in some animals. probably due to stimulation of adjacent midline nuclei or pathways. Within the NRV. thresholds for inhibition of the tail-flick reflex were greater for sites in the dorsal subdivision as compared to the ventral subdivision. which contains spinopetal projections from the NRM. The slopes of the lines of recruitment for inhibition of the tail-flick reflex at stimulation sites in either the NTS or NRV were both very steep. similar to other forms of antinociception. In experiment 2. the pulse duration of electrical stimulation was varied for sites of stimulation in the lateral NTS and NRV to generate strength-duration curves. This experiment confirmed that stimulation sites in the lateral NTS required greater current intensities to inhibit the tail-flick reflex than sites in the NRV. However. the chronaxies derived from the strength-duration functions for the NTS or NRV were both approximately 170 microseconds. indicating that the antinociceptive effects in these regions may not be exclusively due to the stimulation of fibers of passage. These results are discussed in terms of the role of the NTS. NRV. and caudal medulla in the modulation of nociceptive responses and cardiovascular function.
Leakage of fluid administered epidurally to rats into subcutaneous tissue, Epidural catheters were implanted in rats under halothane/nitrous oxide anaesthesia. Contrast medium (Iopamidol) was injected via the catheter under fluoroscopic control 24-48 h after implantation. In 15 of 20 rats contrast could be seen leaking out of the epidural space. usually after only 25 microliters was administered. Leakage was associated with diminished antinociceptive response to morphine administered via the catheter. Both leakage and decreased response to morphine could be largely prevented by applying a drop of Supa-Glue over the site of entry of the catheter to the epidural space at the time of catheter implantation. Investigators using epidurally cannulated rats should document that leakage does not occur or discard results from rats showing evidence of leakage.
Low dose amitriptyline in chronic pain: the gain is modest, In the double-blind placebo-controlled study presented here. the effects were investigated of a low dose of amitriptyline (75 mg) in patients with chronic pain of various origins. The active drug was superior to placebo in reducing pain intensity. The reduction was small. In the second treatment week. the amitriptyline treated patients slept longer. No differences between active drug and placebo were found with respect to daily activities or use of analgesics. Based on our data and those of other studies. it is concluded that amitriptyline (and other antidepressants) in low doses does have a positive effect on the intensity and some other aspects of chronic pain. but that the effect is modest. It must be kept in mind that chronic pain is a very treatment-resistant condition. Therefore. even modest positive effects may be worthwhile.
Serologic evidence of subclinical pertussis in immunized children, Incidental to a vaccine study involving 783 immunized children conducted at two study sites. inner city children had significantly higher geometric mean pertussis agglutinin titers compared with suburban children just before the fourth dose of diphtheria-tetanus-whole cell pertussis vaccine (47 vs. 25; P less than 0.001). Higher titers in the inner city were correlated with residence in census tracts where cases of pertussis were reported. Three hundred thirty-two children in a placebo arm of the study who were clinically observed and had paired serum samples taken during a 2- to 4-month period were analyzed for evidence of natural Bordetella infection. Twelve (11%) inner city children and three (1.3%) suburban children had spontaneous 4-fold or greater rises in at least two different pertussis antibodies measured (agglutinin. antitoxin or enzyme-linked immunosorbent assay for IgG to pertussis toxin. IgG and IgA to filamentous hemagglutinin). Eighty percent of these children had IgA to filamentous hemagglutinin. Nine of 12 inner city children with serologic evidence of pertussis lived within 6 blocks of a case of pertussis reported within 1 month of the observed antibody rise in study subjects; none had a household member with pertussis and none had symptomatic disease.
Current epidemiology of pertussis in Japan, Since the introduction of whole cell pertussis vaccine into general use as part of the routine immunization in 1947 under the Preventive Immunization Law. a steady decrease in reported cases of pertussis was noted until 1974. At that time the number of reported cases reached an all time low and no deaths caused by pertussis were reported. The vaccine (diphtheria-tetanus-whole cell pertussis vaccine) had been given to infants 12 weeks old or older in a 0.5-ml dose by deep subcutaneous injection; three doses were given at intervals of 3 to 8 weeks and the fourth dose (booster) was given 12 to 18 months after the third dose. The immunization was completed with those four doses. Because whole cell vaccine appeared to be associated with severe neurologic illnesses. it was temporarily suspended in 1975. The vaccine was resumed soon thereafter but the age of administration was raised to 24 to 48 months. Under these circumstances acceptance rates of pertussis occurred. reaching a peak in 1979. Although whole cell vaccine was used even after temporary suspension. it was considered to be unacceptable by the public. As a result the acellular pertussis vaccine was developed and has totally replaced whole cell vaccine since 1981. A steady decrease in reported cases of pertussis as well as the number of deaths has been noted since 1979 in accordance with increase in vaccine acceptance rates. The national surveillance system begun in 1981 demonstrated also a steady decrease in the incidence of pertussis during the past 9 years.
Immunoglobulin G subclasses in serum and circulating immune complexes in patients with Kawasaki syndrome, IgG subclass concentrations in sera of 17 patients with Kawasaki syndrome were determined. Significantly increased IgG1 (P less than 0.001) and IgG3 (P less than 0.001) were found in the patients compared with 22 age-matched healthy children. whereas IgG2 and IgG4 were normal or slightly decreased. IgG immune complexes were measured by protein A-enzyme-linked immunosorbent assay (ELISA) combined polyethylene glycol precipitations. Eight of 17 patients (47.1%) were found to have circulating immune complexes (CIC) values above the normal control range (geometric mean +2 SD). IgG subclass composition in CIC was analyzed. The subclasses in CIC were predominantly IgG1 and IgG3. Because the antibody responses to different antigens exhibit IgG subclass restriction. it would suggest that the change of serum and CIC IgG subclasses in Kawasaki syndrome may have relevance to the pathogenesis of the disease.
The use of prophylactic furazolidone to control a nosocomial epidemic of multiply resistant Salmonella typhimurium in pediatric wards, The nosocomial spread of enteric pathogens is often difficult to control in overcrowded pediatric wards. During 1983 and 1984. despite cohorting of patients and enforced hand washing. more than 200 cases of nosocomial multiply resistant Salmonella typhimurium phage type R-9 were observed on two adjacent pediatric wards. Most cases occurred during the summer months. After 19 new cases were detected early in the summer of 1985. oral administration of furazolidone throughout their entire hospital stay (2.5 mg/kg twice daily) was recommended for all subsequently hospitalized infants. Among the 114 (65%) infants who were appropriately treated. only one additional case (1%) was detected. In contrast 11 (19%) cases occurred among the 59 infants who were inappropriately treated: 5 of 35 (14%) of those who were not treated and 6 of 24 (25%) in whom treatment with furazolidone was delayed greater than 24 hours (P less than 0.001 between the appropriately and inappropriately treated groups). In pediatric wards where infection control measures cannot be optimally applied. prophylactic furazolidone administration may be helpful in preventing the spread of enteric pathogens.
Safety evaluation of PRP-D Haemophilus influenzae type b conjugate vaccine in children immunized at 18 months of age and older: follow-up study of 30,000 children, We evaluated the safety of the PRP-D conjugate Hib vaccine (ProHIBit. Connaught) in 29.309 children vaccinated at 18-60 months of age in the Southern California Kaiser Permanente medical clinics during the period April 1. 1988. to July 31. 1989. Surveillance for potential reactions involved postcard questionnaires. telephone surveys. reports of Kaiser staff and review of hospitalizations and covered two periods following immunization: (1) the first 48 hours and (2) days 2 through 30. Surveillance for invasive Hib disease involved the above methods in addition to systematic reviews of laboratory and hospital records through January 31. 1990. Rates of local and systemic reactions within 48 hours of vaccination with PRP-D alone were low (less than or equal to 2% for fever greater than 102 degrees F. local redness or swelling) and similar to those previously reported after vaccination with PRP. Hospitalization and seizures (0.15% and 0.09% of vaccinated children. respectively) occurring within 1 month of immunization appeared to be unrelated to vaccination. One 29-month-old child had onset of a fatal episode of Hib sepsis/meningitis within 48 hours of vaccination. Also. a 30-month-old child developed Hib meningitis 10 months after PRP-D vaccination. We conclude that PRP-D is safe when given alone or in combination with other childhood vaccines between 18 and 60 months of age.
Pre-discharge immunization among hospitalized Filipino children, Identifying opportunities to vaccinate eligible children is one way to boost rates of immunization especially in countries with low immunization coverage and where convalescence from infectious illness is a contraindication to vaccination. To determine the safety and immunogenicity of diphtheria-tetanus toxoid-pertussis and oral polio immunization. 210 convalescing infants and children and community controls. comparable image and nutritional status. were studied. Using the pertussis agglutination and poliovirus neutralization tests. quantitative serologic responses were compared in the two study groups. No significant differences in the incidence rates of febrile reactions (23% in controls; 28% in convalescents) of local reactions (92% in controls; 87% in convalescents) and of seroconversion (P greater than 0.05) were noted between the two groups. Our investigation suggests that infants and children convalescing from infectious illnesses can be safely and effectively vaccinated. This study further suggests that hospitalization provides an opportunity to vaccinate such children.
Antigenic recognition by intravenous gamma-globulin of selected bacteria isolated from throats of patients with Kawasaki syndrome, Kawasaki syndrome (KS) or mucocutaneous lymph node syndrome is an acute febrile exanthematous illness of unknown etiology. Therapy with intravenous gamma-globulin (IVGG) results in rapid defervescence. disappearance of signs and symptoms of inflammation and prevention of coronary artery aneurysms. We hypothesized that IVGG might neutralize a bacterial toxin produced by a staphylococcus or streptococcus present in the nasopharynx. We further speculated that this toxin might be detectable in serum or urine of patients. The goal of this work was to identify microbial antigens in different materials taken from patients with a clinical diagnosis of KS. We tested 23 aerobic bacterial isolates from throat cultures from 15 patients with KS. acute serum from 121 patients and 38 acute urine specimens from patients with KS. The patients ranged in age from 1 to 6 years. Specimens were tested in a standard system of counterimmunoelectrophoresis and reacted against IVGG prepared in a 25% solution. Ten of 23 aerobic bacteria (43.5%) isolated from throat cultures demonstrated a precipitation reaction with IVGG. Counterimmunoelectrophoresis testing of IVGG against acute serum and acute urine specimens was uniformly negative. IVGG contains precipitating antibody against a limited number of aerobic throat organisms. It is possible that antigenic products of one of these bacteria may be involved in the pathogenesis of KS.
Immunogenicity of Haemophilus b conjugate vaccine (meningococcal protein conjugate) in children with prior invasive Haemophilus influenzae type b disease, Children younger than 2 years of age with previous invasive Haemophilus influenzae (Hib) type b disease may not develop protective antibodies to antigens of Hib and may be at risk of developing a second episode of Hib disease. Twenty-three children with prior Hib disease were immunized with Haemophilus b conjugate vaccine (meningococcal protein conjugate). Children 12 to 24 months of age were given one dose of vaccine and children younger than 12 months of age were given 2 doses 2 months apart. Antibody to the polysaccharide capsule of Hib (PRP) was measured by radioimmunoassay. Eighteen children had preimmunization serum antibody concentrations less than 0.150 micrograms/ml. All 18 children responded with greater than 0.150 micrograms/ml of antibody after a single dose of vaccine. Only 1 of the 23 children had a preimmunization serum antibody concentration greater than 1.000 micrograms/ml. Seventeen children ultimately responded with greater than 1.000 micrograms/ml of antibody (P less than 0.0001). concentrations of antibody thought to correlate with protection. Haemophilus b conjugate vaccine (meningococcal protein conjugate) is immunogenic in children with invasive Hib disease. Children younger than 2 years of age with invasive Hib disease should be subsequently immunized with a Hib conjugate vaccine.
Children riding in the back of pickup trucks: a neglected safety issue, Motor vehicle-related trauma is the leading cause of death in children in the United States. All states have pediatric restraint requirements for passenger vehicles to help prevent these deaths and injuries. Only a few states. however. possess safety laws or restrictions for passengers who ride in the back of pickup trucks. A retrospective review of medical records for a 40-month period revealed 40 patients whose injuries were a direct result of being a passenger in the cargo area (bed) of a pickup truck. Their injuries and other pertinent data are discussed. Representatives from the Highway Safety Commission of each state were surveyed about their specific highway safety laws. The responses revealed that all states and the District of Columbia have child restraint requirements for passenger automobiles. 34 states have adult restraint laws. but only 17 states have any type of restriction for passengers riding in the back of pickup trucks. Seventy-one percent of the states with pickup truck regulations include only the preschool-age child. Data from the National Highway Traffic Safety Administration concerning pickup trucks and passenger fatality are presented and discussed.
Hair dryer burns in children, Three children with burn injuries caused by home hair dryers are described. In one patient the injury was believed to be accidental. and in the other two cases the injuries were deliberately caused by a caretaker. The lack of prior experience with hair dryer burns initially led to suspicion of other causes. The characteristics of each case aided in the final determination of accidental vs nonaccidental injury. These cases prompted testing of home hair dryers to determine their heat output. At the highest heat settings. the dryers rapidly generated temperatures in excess of 110 degrees C. After the dryers were turned off. the protective grills maintained sufficient temperatures to cause full-thickness burns for up to 2 minutes. These cases and the results of testing demonstrate that hair dryers must be added to the list of known causes of accidental and nonaccidental burns in children.
Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome, Previous prognostic studies of infants with intrauterine growth retardation (IUGR) have not adequately considered the heterogeneity of IUGR in terms of cause. severity. and body proportionality and have been prone to misclassification of IUGR because of errors in estimation of gestational age. Based on a cohort of 8719 infants with early-ultrasound-validated gestational ages and indexes of body proportionality standardized for birth weight. the consequences of severity and cause-specific IUGR and proportionality for fetal and neonatal morbidity and mortality were assessed. With progressive severity of IUGR. there were significant (all P less than .001) linear trends for increasing risks of stillbirth. fetal distress (abnormal electronic fetal heart tracings)O during parturition. neonatal hypoglycemia (minimum plasma glucose less than 40 mg/dL). hypocalcemia (minimum Ca less than 7 mg/dL). polycythemia (maximum capillary hemoglobin greater than or equal to 21 g/dL). severe depression at birth (manual ventilation greater than 3 minutes). 1-minute and 5-minute Apgar scores less than or equal to 6. 1-minute Apgar score less than or equal to 3. and in-hospital death. These trends persisted for the more common outcomes even after restriction to term (37 to 42 weeks) births. There was no convincing evidence that outcome among infants with a given degree of growth retardation varied as a function of cause of that growth retardation. Among infants with IUGR. increased length-for-weight had significant crude associations with hypoglycemia and polycythemia. but these associations disappeared after adjustment for severity of growth retardation and gestational age.
Predicting risk for bronchopulmonary dysplasia: selection criteria for clinical trials, Early identification of neonates in whom bronchopulmonary dysplasia is most likely to develop permits appropriate enrollment into clinical trials testing early intervention therapies for the prevention or treatment of bronchopulmonary dysplasia. Analysis of 160 neonatal intensive care unit survivors to 28 days revealed that supplemental oxygen requirement at 28 days could be predicted by a logistic regression including (1) birth weight. gestational age. 5-minute Apgar score. and peak inspiratory pressure at 12 hours for 12-hour-old neonates and (2) birth weight. gestational age. peak inspiratory pressure at 12 hours. and mean airway pressure at 10 days for 10-day-old neonates. These two regression analyses were applied prospectively to three new data sets totaling 238 neonates to test their predictive ability. Neonates were classified into low-. moderate-. or high-risk groups on the basis of their predicted probability of requiring oxygen supplementation at 28 days; low = probability of less than 25%. moderate = probability of 25% to 75%. and high = probability greater than 75%. Although these populations were demographically distinct from the original group. the regression analyses performed well. The regression analysis for 12 hours of age classified 125 neonates at low risk of whom 9% required supplemental oxygen at 28 days. and the regression analysis for 10 days classified 141 neonates at low risk of whom 7% required supplemental oxygen. The 12-hour regression analysis classified 80 neonates at moderate risk of whom 33% required supplemental oxygen at 28 days and the 10-day regression analysis classified 49 neonates at moderate risk of whom 24% required supplemental oxygen.
Screening for neuroblastoma at 3 weeks of age: methods and preliminary results from the Quebec Neuroblastoma Screening Project, A large neuroblastoma screening study was recently started in the province of Quebec. Canada. This project. a collaboration between the Quebec Network for Genetic Medicine and the University of Minnesota. is studying the impact of screening infants for the preclinical detection of neuroblastoma on the population-based mortality caused by this tumor. All infants born in Quebec during a 5-year period will be screened twice. at 3 weeks and at 6 months. Urinary homovanillic acid and vanillylmandelic acid determination from dried filter paper samples is used for screening. Initial qualitative screening is done by means of thin-layer chromatography with confirmatory quantitative screening by gas chromatography-mass spectrometry (GC-MS). During the initial 6 months of 3-week screening. 41.673 neonates (92% compliance rate) were screened and 10.6% of them were tested also by GC-MS. Nine of these neonates had positive results on two GC-MS tests and were referred for evaluation to rule out the presence of neuroblastoma. Four had the tumor. 1 had a calcified adrenal gland. and 4 had no tumor detected. Three additional neonates had clinical diagnosis of neuroblastoma before they reached the screening age of 3 weeks. A neuroblastoma that did not secrete homovanillic acid or vanillylmandelic acid was diagnosed clinically in 1 additional patient who tested negative by screening.
Pediatric acquired immunodeficiency syndrome: an unusually high incidence of twinning, Surveillance data on incidence of twins among reported cases of pediatric AIDS in New York City are presented. Most pairs are concordant for HIV infection. Three discordant pairs have been described elsewhere. Possible reasons for the association are discussed. including the most likely explanation that twins show symptoms early and are overrepresented in the early years of surveillance of pediatric AIDS.
Assessment of patient laboratory data in the acutely ill, Laboratory test results are a valuable source of information. Nurses need to assess laboratory test results as part of the physical assessment of their patients. Comparison of laboratory test results and changes with abnormal physical findings provides the basis for changes in the nursing care plan. Progressive monitoring of laboratory results and prompt interventions might lessen the seriousness of the health problem. In acute care units. the initial group of laboratory tests serves as a baseline for assessing additional test results. Several reference values should be remembered. particularly the electrolytes (potassium. sodium. and calcium). glucose. BUN. creatinine. and albumin. Specific group profiles assist in identifying and in monitoring the patient's health status. Incorporating laboratory test results into the plan and evaluation of care will result in safer and more effective patient care. Referring to laboratory test findings and comparing them with physical assessment findings are required for the delivery of professional nursing care.
Advanced assessment of the abdomen and gastrointestinal problems, There are many unique physical assessment findings that are associated with specific gastrointestinal disorders. The detection of these findings enables the nurse to manage gastrointestinal emergencies on the patient unit in a timely fashion. preventing deterioration and maintaining the safety of the patient. These skills build well on the traditional. detailed. and comprehensive assessments the nurse makes when using the nursing process. Specific abdominal assessments include detection of signs associated with appendicitis such as rebound tenderness and McBurney's. Rosvig's. and Aaron's signs. The nurse must always be alert to the possibility of peritonitis and the urgency of early detection and treatment. The patient with cirrhosis of the liver presents a distinct clinical picture. There is a need for subtle evaluation of mental status to detect early signs of hepatic coma. Another extra-abdominal assessment of this complication is asterixis. Finally. the assessment of the patient is enhanced when the nurse is able to help identify the location of bleeding. Improving abdominal and gastrointestinal system assessment leads to early detection of nursing problems and appropriate interventions.
Neurologic assessment, Neurologic nursing assessment requires the knowledge of anatomic and physiologic principles as well as the mastery of complex assessment skills. The nurse who is often the first and most consistent health team member interacting with clients may provide the key to the early recognition. prevention. and treatment of neurologic problems. The nurse. as the dynamic member of the health team. may then be the first line of defense in initiating cost-effective and perhaps life-saving measures in neurologically impaired clients.
Assessing acquired ocular diseases, When assessing a patient's ocular complaint. one must listen carefully to the description of the symptoms. A decrease in vision is most frequently the symptom that prompts a person to seek attention. Pain in and around the eye is the next most frequent symptom complained about. Discomfort is often tolerated for long periods before professional attention is obtained. Visual acuity must be checked. for this is the vital sign by which exacerbation or improvement of many conditions is measured. We all take our eyes for granted until we suddenly cannot see. then the world takes on a completely different complexity. for loss of vision may mean loss of livelihood and independence.
Pain in children, The assessment and management of children's pain is a topic that has received a great deal of attention since the late 1970s. Nurse researchers have played a dominant role in all areas of pediatric pain relief and likely will continue to do so. There are currently a number of pediatric pain assessment instruments developed that are used in selected practice settings. but their use should be extended to document the existence of pediatric pain and its relief. Pharmacologic interventions for pediatric pain relief have been hampered by incorrect beliefs about analgesic risks. prescribing and administrating habits. and a virtual explosion of information in the area of analgesics. Although nurses have traditionally used nonpharmacologic interventions for pain relief. these methods have not been well researched. Continued research efforts in this important area will result in improved diagnosis and management of pediatric pain.
Diarrhea, Diarrhea is one manifestation of GI disturbance. Symptoms may be acute if caused by such things as infections. drug reactions. alterations in diet. heavy metal poisoning. or fecal impaction. Chronic diarrhea is a symptom of GI diseases such as irritable bowel syndrome. lactase deficiency. cancer of the colon. inflammatory bowel disease. and malabsorption diseases. Chronic diarrhea may also be associated with GI surgery. radiation therapy. laxative abuse. alcohol abuse. and chemotherapeutic agents. When interventions are required to deal with diarrhea. they may include such things as alteration in tube feeding products and methods of administration. fluid replacement by oral rehydration procedures. a rapid return to feeding. and education aimed at the health information clients need to prevent or control the symptom of diarrhea.
Confusion, The term confusion describes a plethora of possible cognitive deficits and behavioral manifestations. A subjective assessment of confusion must be followed by an objective systematic evaluation to develop the cognitive-behavior profile. Because of age-associated physiologic and pathologic changes. elderly patients are at high risk for developing acute confusion. The management of confusion presents a challenge to nursing. Nursing can play a significant role in the prevention and the early detection of acute confusion. Preventing or identifying confusion early will decrease the physical and psychological stress of the patient as well as decrease the cost of hospitalization by shortening length of stay. Additional research is needed to determine the efficacy of present nursing activities and to identify new approaches for management.
Urinary incontinence, Symptoms of urinary incontinence are distressing and disruptive to everyday life. They can also be indicative of more serious underlying disorders. Many methods of symptom management are available. Matching the affected person to the most effective and appropriate treatment method is a significant challenge for nursing. Just as pressing is the need to develop and test a cogent conceptual model for symptom management that includes primary prevention.
Dyspnea, A multidimensional model of dyspnea that includes sensation. perception. distress. response. and reporting components is presented. Assessment tools currently available are evaluated as are recent research findings for pharmacologic. oxygen. physical. and psychologic treatments. This article concludes by suggesting a role for the nurse in dyspnea amelioration.
Fatigue, Fatigue is a pervasive. protective phenomenon affecting the totality of the individual. Assessment and management involve a wide range of activities to address the total human being's physical. psychological. cognitive. and spiritual dimensions. When elimination or neutralization of the effect of an antecedent condition is not an option. redesigning one's life-style may be the primary avenue of fatigue management. This protective mechanism. fatigue. may in fact herald the return of quality and purpose to one's life.
Cytomegalovirus. An update for primary care physicians, Cytomegalovirus infection is spread in various ways--from mother to fetus or baby. from small children in day-care centers to caregivers and parents. by blood transfusions. by sexual contact. Although the illness is usually inconsequential. congenital infection can have severe consequences. including mental retardation and hearing loss. Dr Bean describes the different aspects of this virus and discusses a promising vaccine that may prevent congenital disease.
Colonoscopy in critically ill patients. What conditions call for it, Indications for colonoscopy in the intensive care unit include acute lower intestinal bleeding. sigmoid volvulus. pseudo-obstruction of the colon. and suspicion of pseudomembranous colitis. Although the incidence of cardiorespiratory complications may be higher in these critically ill patients. the procedure can be done safely with proper attention to detail. Because of colonic dilatation. endoscopy can often be done without bowel preparation.
Treating diabetes in the elderly. What are the special considerations, Management of diabetes in elderly patients generally follows the same lines as in younger patients; that is. improvement of blood glucose status with diet. oral hypoglycemic. and insulin therapy as required. Older patients are more fragile. however. and more caution must be used with therapeutic interventions.
What to do about pruritus scroti, Pruritus scroti is a common clinical disorder that is caused by various inflammatory disorders. infections. infestations. and neoplasms. Laboratory evaluation. including bacterial and fungal cultures. microscopic examination. skin biopsies. and measurement of blood glucose levels. is useful in establishing the diagnosis. Management of pruritus scroti includes avoidance of irritants. allergens. and restrictive clothing and use of topical and systemic agents that provide both symptomatic relief and specific treatment of the underlying cause.
Viral pneumonias. A diagnostic and therapeutic challenge, Viral pneumonias are both a diagnostic and a therapeutic challenge for primary care physicians. The illness should be suspected when an upper respiratory tract infection progresses to include dyspnea and cyanosis. Rapid diagnostic tests are now available to detect most of the viruses that cause pneumonias. Fortunately. viral pneumonias usually resolve without specific antiviral therapy; however. ribavirin is indicated for respiratory syncytial virus pneumonia in children and ganciclovir sodium (Cytovene) for cytomegalovirus pneumonia in immunocompromised patients. Acyclovir (Zovirax) is indicated for pneumonias due to herpes simplex virus and varicella-zoster virus infections. A high index of suspicion for bacterial superinfections is essential to reduce the risk of death from this complication.
Mycoplasmal pneumonia. Are you thinking of atypical presentations, The presentations of mycoplasmal pneumonia can be varied and sometimes complicated. The atypical nature of this illness. as opposed to the clear pattern of findings in classic bacterial pneumonias. leads the physician to the diagnosis. Appropriate therapy then allows quick improvement as a rule. with few sequelae.
Postinduction repression of the beta-interferon gene is mediated through two positive regulatory domains, Virus induction of the human beta-interferon (beta-IFN) gene results in an increase in the rate of beta-IFN mRNA synthesis. followed by a rapid postinduction decrease. In this paper. we show that two beta-IFN promoter elements. positive regulatory domains I and II (PRDI and PRDII). which are required for virus induction of the beta-IFN gene are also required for the postinduction turnoff. Although protein synthesis is not necessary for activation. it is necessary for repression of these promoter elements. Examination of nuclear extracts from cells infected with virus reveals the presence of virus-inducible. cycloheximide-sensitive. DNA-binding activities that interact specifically with PRDI or PRDII. We propose that the postinduction repression of beta-IFN gene transcription involves virus-inducible repressors that either bind directly to the positive regulatory elements of the beta-IFN promoter or inactivate the positive regulatory factors bound to PRDI and PRDII.
Aberrant splicing of androgen receptor mRNA results in synthesis of a nonfunctional receptor protein in a patient with androgen insensitivity, Androgen insensitivity is a disorder in which the correct androgen response in an androgen target cell is impaired. The clinical symptoms of this X chromosome-linked syndrome are presumed to be caused by mutations in the androgen receptor gene. We report a G----T mutation in the splice donor site of intron 4 of the androgen receptor gene of a 46.XY subject lacking detectable androgen binding to the receptor and with the complete form of androgen insensitivity. This point mutation completely abolishes normal RNA splicing at the exon 4/intron 4 boundary and results in the activation of a cryptic splice donor site in exon 4. which leads to the deletion of 123 nucleotides from the mRNA. Translation of the mutant mRNA results in an androgen receptor protein approximately 5 kDa smaller than the wild type. This mutated androgen receptor protein was unable to bind androgens and unable to activate transcription of an androgen-regulated reporter gene construct. This mutation in the human androgen receptor gene demonstrates the importance of an intact steroid-binding domain for proper androgen receptor functioning in vivo.
Estrogen receptor level determines sex-specific in vitro transcription from the Xenopus vitellogenin promoter, Female-specific expression of the Xenopus laevis vitellogenin gene was reconstituted in vitro by addition of recombinant vaccinia-virus-produced estrogen receptor to nuclear extracts from male livers. in which this gene is silent. Transcription enhancement was at least 30 times and was selectively restricted to vitellogenin templates containing the estrogen-responsive unit. Thus. in male hepatocytes. estrogen receptor is the limiting regulatory factor that in the female liver controls efficient and accurate sex-specific expression of the vitellogenin gene. Furthermore. the Xenopus liver factor B. which is essential in addition to the estrogen receptor for the activation of this gene. was successfully replaced in the Xenopus extract by purified human nuclear factor I. identifying factor B of Xenopus as a functional homolog of this well-characterized human transcription factor.
Accumulation of p21ras.GTP in response to stimulation with epidermal growth factor and oncogene products with tyrosine kinase activity, The ras gene product (p21) is a GTP-binding protein and has been thought to transduce signals regulating proliferation or differentiation of cells. Like other GTP-binding proteins. p21.GTP is an active conformation. which can transduce the signals downstream. whereas p21.GDP is an inactive one. Recently. we have shown that p21.GTP levels increased in cells treated with fetal bovine serum or platelet-derived growth factor to initiate DNA synthesis. In this paper. we report that epidermal growth factor can also increase the amounts of p21.GTP in the cells. Effects of epidermal growth factor and platelet-derived growth factor are not additive. In contrast. mutant [Val12]p21. which has transforming activity. responded neither to platelet-derived growth factor nor to epidermal growth factor. We also found that the ratio of p21.GTP to p21.GDP increased 3- to 4-fold in transformants carrying activated erbB-2/neu or v-src oncogenes. These results strongly suggest an important role of p21 in transduction of signals for both normal proliferation and malignant transformation through growth factor receptors with tyrosine kinase activity or related oncogene products.
Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors, A panel of 20 human myelin basic protein (hMBP)-specific T-lymphocyte lines was generated from the peripheral blood of eight multiple sclerosis (MS) patients and two healthy donors. most of them expressing the HLA-DR2 haplotype. which is associated with an increased susceptibility to MS. Using HLA-DR gene-transfected mouse L-cell lines as antigen-presenting cells. we established that of the 20 hMBP-specific T-lymphocyte lines. 7 were restricted by the DR2a gene products of the DR2Dw2 haplotype. Four T-cell lines recognized hMBP in the context of the DR2b products of the DR2Dw2 haplotype. DR2b-restricted T-cell responses were demonstrable only in T-cell lines derived from MS patients. The hMBP epitopes presented by the DR2a heterodimer were mapped to peptides covering amino acid residues 1-44. 76-91. 131-145. or 139-153 and to a region spanning the thrombin-cleaved bond at Arg130-Ala131. DR2b-restricted T-cell lines recognized epitopes within amino acids 80-99 and 148-162. Peptide 139-153 was also presented in the context of HLA-DR1 molecules. Our data show that (i) in MS patients both the DR2a and DR2b products of the DR2Dw2 haplotype function as restriction elements for the myelin autoantigen hMBP. (ii) the DR2a molecule presents at least five different epitopes to hMBP-specific T lymphocytes. and (iii) anti-hMBP T-cell lines derived from individual donors can differ in their antigen fine specificity as well as in their HLA restriction.
Expression of murine renin genes in subcutaneous connective tissue, A renin promoter-large tumor antigen (T antigen) fusion gene was constructed to provide a reporter function for renin expression in transgenic mice. These transgenic mice gave rise to tumors in subcutaneous soft tissue. which was attributed to transgene expression at this site. An immunohistochemical analysis of transgenic fetuses from several independent lines revealed scattered T-antigen-containing mesenchymal cells and fibroblasts in the subcutaneous layer of the skin between the panniculus carnosus muscle of the skin and the skeletal muscle of the body wall. This localization is consistent with the location of overt tumorigenesis in adult mice. This pattern was specific for the renin-T antigen fusion gene as no immunohistochemical staining was observed in transgenic fetuses containing a heterologous promoter-T antigen fusion gene. Northern blot analysis of tumor RNA indicated that most of the tumors expressed both T antigen and the endogenous renin gene Ren-1c. In addition. when multiple renin genes were introduced by crossing transgenic mice with nontransgenic DBA/2J mice. which contain another allele of the Ren-1 locus as well as the duplicated locus Ren-2. the resultant tumors expressed the Ren-2 gene. Northern blots were then used to analyze renin expression in the subcutaneous tissue of normal mice. Fully processed renin mRNA was detected in eviscerated 15.5-day postcoitus fetal and newborn carcasses and in newborn skin. Our data indicate that there is a renin-expressing cell population in fetal and newborn subcutaneous tissue.
E1a-dependent expression of adenovirus genes in OTF963 embryonal carcinoma cells: role of E1a-induced differentiation, Some undifferentiated F9 embryonal carcinoma cells allow adenovirus genes to be expressed independently of the E1a oncogene normally required for their activation; this has been attributed to a cellular equivalent of E1a in F9 cells. However. transcription of all early genes was low in undifferentiated OTF963 embryonic carcinoma cells during the first 48 hr after infection with adenovirus type 5 (Ad5). Transcription then increased to about the level seen 16 hr after infection of cells induced to differentiate by retinoic acid (RA) (referred to as RA-dF9 cells). but this increase did not occur in cells infected by the E1a deletion mutant dl312. Addition of E1a in trans. or of RA. had no immediate effect on viral transcription in OTF963 cells. but viral transcription increased about 48 hr after these additions. Ad5 induced transcription of several differentiation-specific genes in OTF963 cells with about the same kinetics as their induction by RA. These genes were superinduced in RA-dF9 cells by cAMP or infection by adenovirus. We suggest the small amount of E1a produced early in infection of OTF963 cells activates cellular genes. some of which are differentiation specific and required for efficient transcription of viral genes. so that E1a both induces and is induced by differentiation. The simple hypothesis of a cellular equivalent to E1a does not adequately explain the complex interactions between viral and cellular genes in OTF963 embryonic carcinoma cells.
Diastrophic dysplasia gene maps to the distal long arm of chromosome 5, We have used polymorphic DNA markers to map the gene for a clinically well-characterized form of osteochondrodysplasia. diastrophic dysplasia (DD). an autosomal recessive disorder of unknown pathogenesis. Linkage was analyzed in 13 families with two or three affected sibs comprising a total of 84 individuals. Positive two-point logarithm-of-odds (lod) scores were obtained between the DD locus and three polymorphic markers on chromosome 5. The highest pairwise lod score estimate of 7.37 with zero recombination to locus D5S72 suggests very tight linkage. There was no evidence of heterogeneity. Multipoint linkage analysis against the published order of the three loci gave the result centromere-D5S84-(DD. D5S72)-D5S61-terminus with a four-point lod score of 9.11. The present findings place the DD locus distal to the gene for adenomatous polyposis coli on the distal part of the long arm of chromosome 5. Our results provide a basis for refining the map position of the DD locus followed by physical localization. isolation. and characterization of the gene.
The human immunodeficiency virus type 2 vpr gene is essential for productive infection of human macrophages, The human immunodeficiency virus (HIV) genetic determinant(s) responsible for tropism in human T cells or macrophages are not well defined. We studied the role of the HIV type 2 (HIV-2) nef and vpr genes in viral tropism. HIV-2 mutants. lacking either vpr or nef genes. or both vpr and nef. were obtained by site-specific mutagenesis of a biologically active HIV-2 proviral clone (HIV-2sbl/isy). which is infectious in both human T cells and macrophages. Viral progeny carrying mutations of nef. vpr. or of both nef and vpr genes replicated more efficiently than the parental virus in primary human peripheral blood cells and in the human Hut 78 T-cell line. In contrast. the HIV-2 nef- mutant infected human macrophages as efficiently as the parental virus. whereas viruses lacking the vpr gene either alone or in conjunction with the lack of the nef gene did not replicate in macrophages. Thus. some lack of nef in HIV-2 enhances viral replication in T cells and does not interfere with viral replication in primary macrophages. whereas vpr is essential for replication of HIV-2 in human macrophages. Because the parental HIV-2sbl/isy cloned virus also infects rhesus macaques. the use in animal studies of these HIV-2 mutants with differences in cell tropism and rates of replication will be highly useful in understanding the mechanism of viral infectivity and possibly pathogenicity in vivo.
Steroids induce acetylcholine receptors on cultured human muscle: implications for myasthenia gravis, Antibodies to the acetylcholine receptor (AChR). which are diagnostic of the human autoimmune disease myasthenia gravis. block AChR function and increase the rate of AChR degradation leading to impaired neuromuscular transmission. Steroids are frequently used to alleviate symptoms of muscle fatigue and weakness in patients with myasthenia gravis because of their well-documented immunosuppressive effects. We show here that the steroid dexamethasone significantly increases total surface AChRs on cultured human muscle exposed to myasthenia gravis sera. Our results suggest that the clinical improvement observed in myasthenic patients treated with steroids is due not only to an effect on the immune system but also to a direct effect on muscle. We propose that the identification and development of pharmacologic agents that augment receptors and other proteins that are reduced by human genetic or autoimmune disease will have broad therapeutic applications.
Human colorectal cancers display abnormal Fourier-transform infrared spectra, Fourier-transform infrared spectroscopy (FT-IR) was applied to the study of tissue sections of human colorectal cancer. Pairs of tissue samples from colorectal cancer and histologically normal mucosa 5-10 cm away from the tumor were obtained from 11 patients who underwent partial colectomy. All cancer specimens displayed abnormal spectra compared with the corresponding normal tissues. These changes involved the phosphate and C-O stretching bands. the CH stretch region. and the pressure dependence of the CH2 bending and C = O stretching modes. Our findings indicate that in colonic malignant tissue. there are changes in the degree of hydrogen-bonding of (i) oxygen atoms of the backbone of nucleic acids (increased); (ii) OH groups of serine. tyrosine. and threonine residues (any or all of them) of cell proteins (decreased); and (iii) the C = O groups of the acyl chains of membrane lipids (increased). In addition. they indicate changes in the structure of proteins and membrane lipids (as judged by the changes in their ratio of methyl to methylene groups) and in the packing and the conformational structure of the methylene chains of membrane lipids. The cell(s) of the malignant colon tissues responsible for these spectral abnormalities is unknown. Cultured colon adenocarcinoma cell lines displayed similarly abnormal FT-IR spectra. The diagnostic potential of the observed changes is discussed.
Transfer of secretory proteins from the endoplasmic reticulum to the Golgi apparatus: discrimination between homologous and heterologous transfer in intact heterokaryons, To examine aspects of the transfer of secretory proteins from the endoplasmic reticulum to the Golgi apparatus in situ. heterokaryons were formed between Hep G2 human hepatoma cells and WI-38 human fibroblasts. The cells were appropriately treated with cycloheximide before fusion. which emptied them of their respective secretory proteins. serum albumin for the Hep G2 cells and procollagen I for the WI-38 cells. After fusion was complete. the cycloheximide was washed out. protein synthesis was resumed. and the rates of reappearance of serum albumin and procollagen I in the two separated Golgi apparatuses within each heterokaryon were followed by immunofluorescence microscopy. Serum albumin was found to always reappear first in the Golgi apparatus contributed by the Hep G2 half of the heterokaryon. and procollagen I in the Golgi apparatus of the WI-38 half. These results suggest that the endoplasmic reticulum-to-Golgi apparatus transfer in situ is not simply a stochastic process but is either spatially restricted or exhibits cell-type specificity or both.
Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2, Interleukin 1 (IL-1) has been obtained from the Epstein-Barr virus-infected B-lymphoblastoid cell line 3B6 and shown to be involved in autocrine growth of 3B6 B cells. Independently. adult T-cell leukemia-derived factor (ADF) was purified from human T-lymphotropic virus I-infected leukemic T-cell line (ATL-2) and reported as an interleukin 2 (IL-2) receptor-inducing factor. We have previously reported the same molecular mass. pI. and NH2-terminal amino acid sequence for both 3B6-derived IL-1 and ADF. cDNA cloning of ADF demonstrated high homology with the prokaryotic disulfide reducing enzyme thioredoxin. We show here that ADF and 3B6-derived IL-1 are identical. By RNA blot. 3B6 and ATL-2 cells were shown to contain high levels of 0.6-kilobase mRNA corresponding to ADF. Such message was not detected in resting peripheral blood lymphocytes but could be weakly induced by lymphocyte activation. Antibodies have been raised against synthetic peptides corresponding to the NH2 terminus and the COOH terminus of ADF. Immunoblotting and sequential immunoprecipitation with these antibodies revealed the same 13-kDa protein in 3B6 and ATL-2 cells. Recombinant ADF could sustain growth of 3B6 and ATL-2 cells at low cellular concentration without fetal calf serum; ADF. thus. appears involved in their autocrine growth. Similarly. recombinant ADF could enhance growth of other B-cell lines. including the Epstein-Barr virus-negative Burkitt lymphoma line BL41 and the lymphoblastoid cell lines CRAG8. CRB95. and 1G8. Finally. recombinant ADF exhibits marked synergism with other cytokines. such as IL-1 and IL-2. allowing virally infected lymphocytes to respond to suboptimal amounts of a variety of growth factors.
The recombinant immunotoxin anti-Tac(Fv)-Pseudomonas exotoxin 40 is cytotoxic toward peripheral blood malignant cells from patients with adult T-cell leukemia, Anti-Tac(Fv)-PE40 is a recombinant single-chain immunotoxin containing the heavy and light variable regions of the anti-Tac monoclonal antibody fused to a mutant form of Pseudomonas exotoxin (PE). Anti-Tac binds to the p55 subunit of the human interleukin 2 (IL-2) receptor. and anti-Tac(Fv)-PE40 kills human or monkey cell lines that contain either the intact IL-2 receptor or its p55 subunit alone. To assess the usefulness of anti-Tac(Fv)-PE40 in treatment of IL-2 receptor-positive leukemia. we tested peripheral blood mononuclear cells from six patients with adult T-cell leukemia. In each of the six patients. anti-Tac(Fv)-PE40 was extremely cytotoxic to the malignant cells. Metabolic activity and sensitivity of the fresh cells improved when a small amount of IL-2 (10 units per ml) was present during incubation. The toxin concentration necessary to inhibit protein synthesis by 50% after 16-hr incubation of cells with immunotoxin varied from 1.6 to 16 ng/ml (2.5-25 x 10(-11) M). In every case. binding was by means of the Tac antigen because anti-Tac(Fv)-PE40 cytotoxicity was prevented by adding excess anti-Tac antibody. Moreover. anti-Tac alone or an inactive mutant of anti-Tac(Fv)-PE40 without ADP-ribosylation activity had very little cytotoxic activity. Peripheral blood mononuclear cells from normal controls. from a patient with Tac-negative leukemia. and from adult T-cell leukemia patients without significant peripheral blood involvement were not sensitive to anti-Tac(Fv)-PE40. These results indicate that anti-Tac(Fv)-PE40 is a potent cytotoxin against adult T-cell leukemia cells in vitro and warrants clinical testing.
A 170-kDa membrane-bound protease is associated with the expression of invasiveness by human malignant melanoma cells, Malignant spreading of cancer cells requires cell surface proteases that cleave the crosslinked collagenous matrix of connective tissues. From correlating the morphologically defined invasiveness of tumor cells with the presence of specific membrane-associated proteases. we have identified a malignant human melanoma cell line. LOX. that invades crosslinked gelatin films in vitro and contains uniquely a neutral 170-kDa gelatinase in the cell membrane. A similar gelatinase was found in membranes recovered from culture media conditioned with LOX. The 170-kDa gelatinase is a wheat germ agglutinin-binding protein. The proteolytic activity is maximal at neutral pH. enhanced by EDTA and dithiothreitol. inhibited by the cysteine protease inhibitors N-ethylmaleimide. HgCl2. and phenylmethylsulfonyl fluoride. and can bind to an organomercurial adsorbent. suggesting that it is a neutral sulfhydryl-sensitive protease. This 170-kDa gelatinase of LOX cells was not found in a control melanoma cell line. SK-MEL28. or in 32 other tumor cell lines that did not show extracellular gelatin degradation. Thus. we have identified a large membrane-bound protease that may be a specific marker molecule for melanoma cell invasiveness.
Transforming growth factor beta and noncytopathic mechanisms of immunodeficiency in human immunodeficiency virus infection, This study examines the contribution of transforming growth factor beta (TGF beta). one of the most potent endogenous immunosuppressive factors. to the development of immunodeficiency in human immunodeficiency virus (HIV) infection. Increased titers of TGF beta were found in supernatants of peripheral blood mononuclear cells (PBMCs) from HIV-infected donors as compared to uninfected controls (P less than 0.001). This correlated closely with defective responses of CD4+ lymphocytes to the recall antigens tuberculin purified protein derivative or tetanus toxoid. The addition of TGF beta-neutralizing antibody to PBMCs partially restored these defective T-cell responses. Furthermore. purified TGF beta or HIV+ PBMC culture supernatants preferentially inhibited proliferation of CD4+ lymphocytes as compared to CD8+ cells. The increased expression of the TGF beta protein was associated with increased TGF beta mRNA as determined by a polymerase chain reaction assay. This increase in TGF beta protein and mRNA was due to a selective upregulation of the TGF beta 1 isoform. These results indicate that overexpression of TGF beta 1 occurs in HIV-infected individuals and that this cytokine can contribute to impaired immune functions and to depletion of CD4+ T lymphocytes.
Fructose-induced aberration of metabolism in familial gout identified by 31P magnetic resonance spectroscopy, The hyperuricemia responsible for the development of gouty arthritis results from a wide range of environmental factors and underlying genetically determined aberrations of metabolism. 31P magnetic resonance spectroscopy studies of children with hereditary fructose intolerance revealed a readily detectable rise in phosphomonoesters with a marked fall in inorganic phosphate in their liver in vivo and a rise in serum urate in response to very low doses of oral fructose. Parents and some family members heterozygous for this enzyme deficiency showed a similar pattern when given a substantially larger dose of fructose. Three of the nine heterozygotes thus identified also had clinical gout. suggesting the possibility of this defect being a fairly common cause of gout. In the present study this same noninvasive technology was used to identify the same spectral pattern in 2 of the 11 families studied with hereditary gout. In one family. the index patient's three brothers and his mother all showed the fructose-induced abnormality of metabolism. in agreement with the maternal inheritance of the gout in this family group. The test dose of fructose used produced a significantly larger increment in the concentration of serum urate in the patients showing the changes in 31P magnetic resonance spectra than in the other patients with familial gout or in nonaffected members. thus suggesting a simpler method for initial screening for the defect.
Temporary amelioration of hyperlipidemia in low density lipoprotein receptor-deficient rabbits transplanted with genetically modified hepatocytes, Familial hypercholesterolemia is an inherited disease in humans that is associated with coronary artery disease and is caused by a deficiency of the receptor that mediates the internalization of low density lipoprotein (LDL). We have used an animal model for familial hypercholesterolemia. the Watanabe heritable hyperlipidemic (WHHL) rabbit. to design a therapeutic approach for this disease. which attempts to correct the hepatic defect in LDL receptor expression. Hepatocytes were harvested from WHHL rabbits. plated in primary cultures. and exposed to recombinant retroviruses capable of efficiently transferring a functional human LDL receptor gene. Genetically modified cells were harvested and infused into the portal vein of WHHL recipients. who were analyzed for metabolic consequences of human LDL receptor expression. Each animal exhibited a statistically significant decrease in total serum cholesterol 2-6 days after transplantation. with an eventual return to pretreatment levels. Proviral DNA sequences and virus-directed transcripts were detected in liver tissue 24 hr after transplantation. In situ hybridization demonstrated provirus expression in a small population of hepatocytes distributed in periportal sections of the liver. This study illustrates the potential of somatic gene therapy in ameliorating hyperlipidemia associated with familial hypercholesterolemia.
MyoD induces growth arrest independent of differentiation in normal and transformed cells, MyoD is a gene involved in the control of muscle differentiation. We show that MyoD causes growth arrest when expressed in cell lines derived from tumors or transformed by different oncogenes. MyoD-induced growth inhibition was demonstrated by reduction in the efficiency of colony formation and at the single-cell level. We further show that MyoD growth inhibition can occur in cells that are not induced to activate muscle differentiation markers. The inhibitory activity of MyoD was mapped to the same 68-amino acid segment necessary and sufficient for induction of muscle differentiation. the basic-helix-loop-helix motif. Mutants with alterations in the basic region of MyoD that fail to bind or do not activate a muscle-specific enhancer inhibited growth; mutants with deletions in the helix-loop-helix region failed to inhibit growth. Thus. inhibition of cell growth by MyoD seems to occur by means of a parallel pathway to the one that leads to myogenesis. We conclude that MyoD is a prototypic gene capable of functionally activating intracellular growth inhibitory pathways.
Role of tryptophan repeats and flanking amino acids in Myb-DNA interactions, The c-myb protooncogene codes for a sequence-specific DNA-binding protein that appears to act as a transcriptional regulator and is highly conserved through evolution. The DNA-binding domain of Myb has been shown to contain three imperfectly conserved repeats of 52 amino acids that constitute the amino-terminal end. Within each repeat. there are three tryptophans that are separated by 18 or 19 amino acids and are flanked by basic amino acids. To determine the role of tryptophans and the flanking basic amino acids in the DNA-binding activity of Myb proteins. we have selectively mutagenized individual tryptophans as well as some of the amino acid residues that flank these tryptophans. Replacement of these tryptophans with glycine. proline. or arginine abolished the DNA-binding activity whereas replacement with other aromatic amino acids or leucine or alanine did not appreciably affect this activity. On the other hand the replacement of two amino acids. asparagine and lysine. that flank the last tryptophan with acidic amino acids completely abolished their DNA-binding activity. These results are consistent with a model we present in which the tryptophans form a hydrophobic scaffold that plays a crucial role in maintaining the helix-turn-helix structure of the DNA binding domain. Basic and polar amino acids adjacent to these tryptophans seem to participate directly in DNA binding.
Introduction of nerve growth factor (NGF) receptors into a medulloblastoma cell line results in expression of high- and low-affinity NGF receptors but not NGF-mediated differentiation, Expression of the cloned human nerve growth factor receptor (NGFR) cDNA in cell lines can generate both high- and low-affinity binding sites. Since the inability to respond appropriately to differentiation factors such as NGF may contribute to determining the malignant phenotype of neuroblastomas. we sought to determine whether the same is true of medulloblastomas. To generate a human central nervous system neuronal cell line that would respond to NGF. we infected the medulloblastoma cell line D283 MED with a defective retrovirus carrying the cDNA coding for the human NGFR. The resultant cells (MED-NGFR) expressed abundant low- and high-affinity NGFRs. and NGF treatment induced a rapid transient increase of c-fos mRNA in the NGFR-expressing cells but not in the parent line or in cells infected with virus lacking the cDNA insert. However. the MED-NGFR cells did not internalize the NGFR at high efficiency. nor did they differentiate in response to NGF. Three important conclusions emerge from this study: (i) internalization of NGFRs is not necessary for some early rapid transcriptional effects of NGF; (ii) an unknown factor(s) that cooperates with the cloned NGFR in allowing high-affinity NGF binding is found in a primitive central nervous system cell line; and (iii) NGFRs introduced into and expressed by D283 MED (i.e.. MED-NGFR) cells are partially functional but are unable to induce differentiation in these primitive neuron-like tumor cells. implying that high-efficiency receptor-mediated endocytosis of NGF and its receptor may be a necessary step in the cascade of events leading to NGF-mediated differentiation.
Dioxin-inducible, Ah receptor-dependent transcription in vitro, We have developed a homologous in vitro transcription system that requires (i) 2.3.7.8-tetrachlorodibenzo-p-dioxin (called TCDD or dioxin). (ii) the Ah receptor. and (iii) a dioxin-responsive enhancer for activity. Unfractionated nuclear extracts from mouse hepatoma cells contain an inhibitor and fail to direct transcription in vitro. However. following phosphocellulose chromatography and reconstitution. the fractionated nuclear extract directs accurate transcription in vitro. using as a template the promoter/enhancer region from the mouse cytochrome P1-450 gene (Cyp1a1) linked to a "G-free cassette" (which generates a transcript with no guanosine residues). Extracts from TCDD-treated cells exhibit higher activity than extracts from untreated cells when transcribing a template containing both the promoter and enhancer but not when transcribing a template containing the promoter alone. Extracts from Ah receptor-defective cells fail to direct in vitro transcription in a TCDD-inducible fashion. A regulatory element that contains two binding sites for the liganded Ah receptor plus a truncated Cyp1a1 promoter suffices to direct TCDD-inducible. Ah receptor-dependent transcription in vitro. The inducible. receptor-dependent. enhancer-dependent properties of this system make it appropriate for analyzing in vitro the mechanism of dioxin action and the function of the Ah receptor.
Molecular structure of a major insulin/mitogen-activated 70-kDa S6 protein kinase, The molecular structure of a rat hepatoma 70-kDa insulin/mitogen-stimulated S6 protein kinase. obtained by molecular cloning. is compared to that of a rat homolog of the 85-kDa Xenopus S6 protein kinase alpha; both kinases were cloned from H4 hepatoma cDNA libraries. The 70-kDa S6 kinase (calculated molecular mass of 59.186 Da) exhibits a single catalytic domain that is most closely related in amino acid sequence (56% identity) to the amino-terminal. kinase C-like domain of the rat p85 S6 kinase (calculated molecular mass of 82.695 Da); strong similarity extends through a further 67 residues carboxyl-terminal to the catalytic domain (40% identity). corresponding to a region also conserved among the kinase C family. Outside of this segment of approximately 330 amino acids. the structures of the p70 and p85 S6 kinases diverge substantially. The p70 S6 kinase is known to be activated through serine/threonine phosphorylation by unidentified insulin/mitogen-activated protein kinases. A model for the regulation of p70 S6 protein kinase activity is proposed wherein the low activity of the unphosphorylated enzyme results from the binding of a basic. inhibitory pseudosubstrate site (located carboxyl-terminal to the extended catalytic domain) to an acidic substrate binding region (located amino-terminal to the catalytic domain); substrate binding is thereby prevented. S6 kinase activation requires displacement of this inhibitory segment. which is proposed to occur consequent to its multiple phosphorylation. The putative autoinhibitory segment contains several serine and threonine residues. each followed directly by a proline residue. This motif may prevent autophosphorylation but permit transphosphorylation; two of these serine residues reside in a maturation promoting factor (MPF)/cdc-2 consensus motif. Thus. hormonal regulation of S6 kinase may involve the action of MPF/cdc-2 or protein kinases with related substrate specificity.
Mutations in src homology regions 2 and 3 of activated chicken c-src that result in preferential transformation of mouse or chicken cells, src homology regions 2 and 3 (SH2 and SH3) of proteins encoded by src and closely related genes are conserved domains believed to modulate the protein-tyrosine kinase activity of this class of proteins. perhaps through interactions with other proteins. To explore the possibility of using src mutants as probes for such interactions. we have compared mouse NIH 3T3 cells with chicken embryo fibroblasts as host cells for 24 previously described substitution and deletion mutants with lesions in the SH2- and SH3-encoding regions of a transformation-competent allele of chicken c-src. Although several of these mutants are equally competent or equally defective for transformation of the two cell types. four mutants (three of which map within SH3) preferentially transform NIH 3T3 cells. and seven mutants (all of which map within SH2) preferentially transform chicken cells. Some of the SH2 mutants least able to transform mouse cells exhibit augmented transforming activity in chicken cells. In general. the in vitro protein-tyrosine kinase activities of the mutants correlated with transforming activities. Thus. in many cases. the catalytic activity of a mutant protein depended upon the host cell in which the protein was made. Such host-dependent mutants may be especially useful reagents for biochemical and genetic studies of the src gene family.
Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas, The epidermal growth factor receptor gene has been found to be amplified and rearranged in human glioblastomas in vivo. Here we present the sequence across a splice junction of aberrant epidermal growth factor receptor transcripts derived from corresponding and uniquely rearranged genes that are coamplified and coexpressed with non-rearranged epidermal growth factor receptor genes in six primary human glioblastomas. Each of these six tumors contains aberrant transcripts derived from identical splicing of exon 1 to exon 8 as a consequence of a deletion-rearrangement of the amplified gene. the extent of which is variable among these tumors. In spite of this intertumoral variability. each intragenic rearrangement results in loss of the same 801 coding bases (exons 2-7) and creation of a new codon at the novel splice site in their corresponding transcripts. These rearrangements do not. however. affect the mRNA sequence for the signal peptide. the first five codons. or the reading frame downstream of the rearrangement.
Molecular mapping of the mouse db mutation, Diabetes (db) is an autosomal recessive mutation located in the midportion of mouse chromosome 4 that results in profound obesity with hyperphagia. increased metabolic efficiency. and insulin resistance. To clone this gene and generate a molecular map of the region around this mutation. two genetic crosses were established: an intraspecific backcross between C57BL/6J db/db females and C57BL/6J db/db x DBA/2J +/+ F1 (B6D2 db/+ F1) male mice and an interspecific intercross between B6D2 db/+ F1 males and C57BL/6J db/db x Mus spretus F1 (B6spretus db/+ F1) females. The progeny of both crosses were characterized for genotype at the db locus to map a series of restriction fragment length polymorphisms relative to the db locus. Measurements of body weight. body length. and plasma concentrations of glucose and insulin in the animals allowed the assignment of genotype (db/db vs. db/+ or +/+). A total of 132 progeny of the intraspecific cross and 48 db/db progeny of the interspecific cross were typed for individual restriction fragment length polymorphisms to generate a gene order of: centromere-brown (Mt4)-P lambda Mm3(2)-Ifa (Inta)-Cjun-db-D4Rp1-Glut1-Mtv-13-Lck. Several of the genes that are linked to db [Cjun. glucose transporter (Glut1) and Lck] map to human chromosome 1p. suggesting that db may be part of a syntenic group between human 1p and the distal portion of mouse chromosome 4. In addition. phenotyping of the progeny of these crosses revealed a wide range in plasma concentrations of glucose and insulin among the obese progeny. with some animals developing overt diabetes and other remaining euglycemic. Distributions of age-controlled plasma [glucose] and [insulin] among the intraspecific-cross obese progeny were not bimodal. suggesting a role for polygenic differences between the progenitor strains (C57BL/6J and DBA/2J) in the development of overt diabetes.
Breathing exercises for the medical patient: the art and the science, The art of breathing exercises can be traced to the late 1800s. In the past 10 years. the increased demand for treatment for respiratory muscle failure of dysfunction has resulted in numerous studies evaluating methods of treatment or training. This article provides an overview of research and practice. focused on treating the medical patient experiencing dyspnea or loss of respiratory muscle strength and endurance.
Controlling stability of a complex movement system, Human movement systems have frequently been treated as one-dimensional. single-axis. rigid bodies in order to simplify the gathering. analysis. and interpretation of data. The problem with this approach is that the results of such assumptions often lead to conclusions about the production and control of movement that do not relate to the control demands placed on the central nervous system. In order to truly understand how the central nervous system plans and produces movements to match environmental demands. we must take into account the many variations available within the body. The purpose of this article is to examine two movement systems that have the potential to act in multiple spatial dimensions with variable muscle action patterns when performing a stabilizing task. Methods of analyzing how the systems operate under differing task constraints and results of the experiments will be presented. Hypothetical models that have been proposed to explain how complex movement systems operate will also be discussed.
Correcting a stairstep deformity secondary to lower abdominal scars by the use of a decorticated hypogastric flap, The author describes a decorticated hypogastric flap used in the correction and prevention of retracted scars and suprapubic stairsteps. These deformities are common after cesarean sections and in patients who undergo liposuction followed by the retrieval of excess skin. The surgical technique is described. The author also analyzes the advantages and results that occur without an increase in either the time of surgery or complications.
Improved primary surgical and dental treatment of clefts, The improved combination of surgical and dental teamwork in the primary treatment of clefts presented here is consistent with principles. In fact. this is a staged design for correction of classic clefts of the lip and palate that. based on biological principles. facilitates the continuance of the failed embryonic "migrations" toward a normal end point. Positioning of the alveolar segments. dissection of mucoperiosteum out of the cleft. and union of mucoperiosteum across the alveolar and anterior hard palate cleft make it possible to create a periosteal tunnel across the bony gap and set up a condition conducive to bone formation and eventual tooth eruption in the cleft area. Lip closure by adhesion reduces the tension of the primary lip closure and allows gentle molding until solidification of the arch occurs. Thus a complete cleft has been rendered an incomplete cleft. With a balanced. stabilized maxillary platform. the definitive lip and nose corrections can be carried to completion early (by 2 to 4 years of age). These planned actions bypass a persistent cleft. fistulas. raw areas. malposition of alveolar segments. and probably the necessity for later bone grafting. The only question not totally answered is the effect of this approach on final growth. Although most reports seem to indicate that growth has and will proceed within normal limits. another 10 years of careful follow-up is indicated and. in fact. is in progress.
Primary repair of the bilateral cleft lip nose: a 15-year review and a new treatment plan, For 15 years a forked flap has been used for columella reconstruction in primary repair of the bilateral cleft lip nose. With the adolescent growth spurt. three unfavorable features have become apparent: (1) the columella may grow too long and the nostrils too large. (2) often the nasal tip remains broad. and (3) there is a drift of the columellar base and the lip-columellar angle is transgressed by scar. This procedure has therefore been discontinued. A new treatment plan is presented in which the columella is reconstructed from tissues in the splayed-out nasal tip.
Simultaneous reconstruction of cervical soft tissue and esophagus with a gastro-omental free flap, A microvascular transfer of gastric tube and omentum was used to simultaneously reconstruct cervical soft-tissue and esophageal defects in five patients. All patients had previous high-dose radiation and multiple flap reconstructions. The largest esophageal and soft-tissue defects were 10 cm and 160 cm2. respectively. All wounds healed primarily except for one orocutaneous fistula. There was one death from an intraoperative stroke. The gastro-omental flap is useful in cases where the reconstructive surgeon is faced with both esophageal and soft-tissue defects--particularly in heavily irradiated patients who have few reconstructive options.
The radial forearm flap for reconstruction of the upper extremity, The radial forearm flap. owing to its good-caliber arteries of long length and equally well distributed venous system. has proved very reliable. It has not only earned its place and recognition in reconstructive hand surgery. but also has emerged as a workhorse for the microvascular surgeon. We have used 14 radial forearm flaps for upper extremity reconstruction. and we present herein our experience. The technique of extracorporeal tissue transfer. which has been published elsewhere. was used in two patients and is detailed. Four representative patients are presented.
A prospective clinical evaluation of autogenous vein grafts used as a nerve conduit for distal sensory nerve defects of 3 cm or less, The purpose of this study was to determine the efficacy of autogenous vein grafts as nerve grafts (AVNC) for bridging of small peripheral sensory nerve gaps as compared with direct repair and with conventional nerve grafting techniques (ANG). Patients with painful neuroma or segmental nerve injury of 3 cm were chosen as the test group. Those amenable to direct repair were classified as controls. Between 1982 to 1988. a total of 22 patients were enrolled in this study. A total of 34 nerves were repaired. 15 with a venous nerve conduit. 4 with a sural nerve graft. and 15 with direct repair. Significant symptom relief and satisfactory sensory function return were uniformly observed. The two-point discrimination measurements indicated superiority of direct repair and probably of conventional nerve grafting. However. the universally favorable patient acceptance and the return of measurable two-point discrimination indicates the effectiveness of autogenous vein grafts as nerve conduits when selectively applied to bridge a small nerve gap (less than or equal to 3 cm) on nonessential peripheral sensory nerves.
Calcium carbonate gel therapy for hydrofluoric acid burns of the hand, Hydrofluoric acid is used extensively as an industrial cleaning agent for metals and glass. Many workers are injured by cutaneous contact of the acid with exposed skin surfaces. particularly hands. Hydrofluoric acid burns are characterized by delayed onset of symptomatology with skin ulceration. and severe pain may be of extended duration. Treatment of hydrofluoric acid burns traditionally has consisted of local infiltration or intraarterial injections of calcium solutions. These injections are painful and frequently require retreatment. A new treatment utilizing a topical gel of calcium carbonate is described. Nine patients have been treated for hydrofluoric acid burns of the hand with calcium carbonate gel applied topically and covered with occlusive glove dressings. A gel slurry is compounded from calcium carbonate tablets and K-Y Jelly. Fingernails of the affected fingers are removed if a subungual burn is obvious. The gel is put into a surgeon's glove and placed over the burned hand. The patient replaces the glove and slurry every 4 hours for 24 hours. After the first day. the glove is discontinued unless there is resumption of painful symptoms. Full range of motion is encouraged during this interval. The calcium carbonate gel technique was successfully utilized in nine patients with no further need for injection therapy. In these patients. pain relief was obtained within 4 hours of treatment. with no further progression of skin ulceration. No reconstructive procedures were required in any patient. and only one patient did not return to full-duty work within 1 week. There were no long-term sequelae from burns treated with this topical therapy. except one patient. who presenting 24 hours after the burn. developed a digital tip neuroma that was excised.
The use of conchal cartilage graft in involutional entropion, A simple and stable technique for repairing involutional entropion is described. Through a transconjunctival incision between the lower border of tarsus and the lower lid retractor. the eyelid is divided between the tarsus and the orbicularis oculi muscle into external and internal layers. The internal layer is moved upward until the eyelashes turn outward. and then through-and-through sutures are placed to fix it in this corrected state. The resultant defect between the lower end of the tarsus and the retractor is filled with a conchal cartilage graft. The raw surface of the cartilage is epithelialized from the surrounding mucosa within 1 to 2 weeks without shrinkage. This technique is more stable than any other technique that we have performed.
Dacron fabric-enveloped hydroxyapatite prosthesis for sternal tumor defect: an autopsy report, A 38-year-old housewife with solitary plasmacytoma of the manubrium who underwent a subtotal sternectomy treated by resection of the lesion is reported. This was followed by replacement with a Dacron fabric-enveloped hydroxyapatite prosthesis. The Dacron fabric was sutured to the surrounding tissues. and then the clavicle was passed through the cylindrical-shaped Dacron fabric to form a sternoclavicular joint capsule. The patient returned to her daily life 3 months after the operation. She had no trouble in her daily living. without any dislocation of the sternoclavicular joints or any displacement of the artificial sternum. The autopsy examination about 1 year after the operation showed that the Dacron fabric enveloping the artificial sternum became stronger with time. The sternoclavicular joint also was stably fixed. and the Dacron fabric fulfilled its function as an artificial articular capsule and biologic fixation of the surrounding supporting tissues.
Controlled tissue expansion of a groin flap for upper extremity reconstruction, A large upper extremity defect in an 8-year-old girl was resurfaced with an expanded groin flap. Tissue expansion allowed complete coverage of the defect while minimizing the donor deformity. Pretransfer expansion of pedicled flaps offers an alternative to free-flap reconstruction of complex upper extremity defects. This is especially valuable in the pediatric patient. in whom donor-site morbidity can be significant.
Secondary correction of the unilateral cleft lip nose using a conchal composite graft, The secondary deformity of the unilateral cleft lip nose has many components. One is the dorsal dislocation of the lateral crus of the alar cartilage. We used a conchal composite graft positioned between the piriform aperture and the lateral crus and the upper lateral cartilage to correct this dislocation in nine patients. We believe that this graft is effective because it elevates the lateral crus of the alar cartilage off the depressed piriform aperture. This technique is very simple to perform. and it is easy to achieve nasal symmetry. Our results have been quite satisfactory. with no recurrence of dorsal dislocation. The donor site was covered by a subcutaneous pedicled flap from the cephaloauricular sulcus. leaving an inconspicuous deformity.
The use of liposuction to contour cherubism, Yet another application of suction lipectomy equipment is presented to remove the pathologic tissue in cherubism. Owing to the variations of consistency of the material in this condition. this technique may not be successful in all patients. but it is certainly recommended when indicated.
Therapy for hypercholesterolemia, For most patients. hypercholesterolemia can be effectively lowered with drug therapy but only after several issues have been considered. First. drug therapy should never be considered without adequate dietary intervention. Dietary therapy may be effective for many patients with mild to moderate elevations in cholesterol. None of the drugs used to treat lipid disorders are benign agents. There is still debate about the interpretations of recent studies. the ability to generalize from studies to the whole population. and the cost effectiveness of drug treatment. Within the framework of the AHA and NCEP guidelines. an individualized approach to therapy is prudent. This should be initiated with maximal patient education because drug therapy will be maintained for the long-term or for life. The LDL and HDL levels. age. sex. other CHD risk factors. cost of treatment. patient awareness. and motivation must all be assessed when making treatment decisions. When drug therapy is considered for patients with isolated hypercholesterolemia. bile acid sequestrants are the drugs of choice.
Antidiabetic agents, Although either insulin or oral hypoglycemics may be used in conjunction with diet and exercise in the management of type II diabetes. drug therapy for type I diabetes involves only insulin. C-peptide levels can be tested to assess whether the patient has remaining pancreatic endocrine function. Patients being started on insulin for the first time should receive a single injection of an intermediate-acting insulin of "human" origin at a dose of approximately 0.5 U/kg. Thereafter. fasting. mid-morning. mid-afternoon. bedtime. and possibly early morning blood sugars should be examined periodically to determine if the insulin dose needs to be increased. decreased. split. or if the patient needs to be on a two-insulin regimen. Intensive insulin therapy has become commonplace to control plasma glucose levels in the majority of patients receiving insulin therapy. Proper patient education regarding the insulin regimen. injection techniques. blood glucose monitoring. as well as diet. exercise. and foot care are essential if the patient's diabetes is to be controlled adequately. Guidelines for "adequate" glycemic control are outlined in Table 6. Recent evidence suggests that tight control of plasma glucose levels may decrease the macrovascular complications of diabetes. Although there is also evidence to suggest that the onset of microvascular complications might be delayed with strict glycemic control. the data are conflicting. The benefits of strict control must be weighted against the problems of hypoglycemia experienced by many patients who attempt tight control of their blood glucose levels. Biguanide compounds are available in Europe. but the sulfonylureas comprise the only class of oral agents in the United States commercially available for the treatment of type II diabetes. The two generations of these drugs reflect their potency and possible side-effect profiles. Of the first-generation agents. tolbutamide and chlorpropamide are the most widely prescribed. Tolbutamide is the weakest of the sulfonylureas. possibly making it a good drug for initiating oral therapy in the elderly. Chlorpropamide is becoming a less popular agent because of its long duration of action and its increased incidence of side effects. Of the second-generation agents. glyburide offers a better dosing schedule (once daily compared with twice daily for glipizide); however. glyburide may produce a greater incidence of hypoglycemia. particularly in the elderly or in patients with significant renal impairment. There are few good studies comparing these two drugs so that recommending one over the other is difficult. Drug interactions are numerous with the first-generation drugs. but less so with the newer second-generation agents.(ABSTRACT TRUNCATED AT 400 WORDS).
Estrogen therapy during menopause and the treatment of osteoporosis, Estrogen remains the single most effective agent in the treatment of menopausal symptoms and prevention of bone loss. This article focuses on the use of estrogen therapy during menopause and the pharmacotherapy of osteoporosis. Risks and benefits of hormonal therapy and regimen selection for menopausal women are discussed. The second section of the article focuses on current treatment strategies for osteoporosis.
Chronic obstructive pulmonary disease, Chronic obstructive pulmonary disease is indeed a multifaceted illness. The obstructive picture is the result of multiple pathologic processes. The most common cause is cigarette smoking. The key to decreasing the incidence of this disease is education to prevent people from starting to smoke and to educate those who do smoke to stop. The therapeutic management involves numerous medications. oxygen. and physiotherapy. Unfortunately. the pharmacologic management remains largely empiric with sympathomimetics. anticholinergics. methylxanthines. and corticosteroids. These agents. especially methylxanthines and corticosteroids. are not without considerable toxicity. Therefore. embarking on a pharmacologic plan requires weighing the risk to benefit ratio carefully and having a comprehensive plan to assess subjectively and objectively the efficacy and toxicity of the chosen therapy.
Factors determining success and energy requirements for cardioversion of atrial fibrillation, Factors thought to affect the success of and energy requirements for cardioversion of atrial fibrillation were studied in 80 (49 male. 31 female) patients aged 21-88 (mean 61.5 years). Transthoracic impedance was measured in advance of the countershock using a 30 kHz low amplitude AC current passed through self-adhesive ECG/defibrillator pads (diameters 8-12 cm) applied to the chest in the antero-posterior (AP) position in 57 patients and the anteroapical (AA) position in 23 patients. Mean transthoracic impedance for all patients was 69.3 +/- 16 (SD) ohms (range 39-131 ohms). but transthoracic impedance was significantly greater in the AA than the AP position (75.4 +/- 13 vs. 66.7 +/- 16 ohms. p = 0.02). Initial energy was 50 J (delivered) and was gradually increased to a maximum of 360 J if required. Cardioversion was successful in 73 of 80 (91.2 per cent). and low energy shocks (less than or equal to 200 J) were successful in 45 of 80 (56.2 per cent) patients. Using single factor analysis. sex. left atrial enlargement. electrode pad positions. aetiology of atrial fibrillation. presence of left ventricular failure. and prior treatment with verapamil or beta-adrenergic blockers were not significant determinants of cardioversion success or success of low energy shocks but prior treatment with digoxin was. both for cardioversion success and success at low energies. In patients with transthoracic impedance less than or equal to 70 ohms. low energy shocks were more often successful (33 or 50. 66 per cent) than in patients with transthoracic impedance greater than 70 ohms (12 of 30. 40 per cent). p = 0.04. Using univariate analysis. cardioversion success with low energy shocks was not only significantly associated with prior treatment with digoxin but also with the duration of atrial fibrillation (24 hours to one month and one month to three years) and for shocks of less than or equal to 100 J. with prior treatment with amiodarone. Multifactorial linear regression analysis selected. in rank order. only duration of atrial fibrillation of 24 hours to less than one month and one month to three years as significant predictors of both cardioversion success irrespective of shock strength. and success of low energy shocks.
Asian osteomalacia is determined by dietary factors when exposure to ultraviolet radiation is restricted: a risk factor model, Twenty-seven previously osteomalacic and 77 normal Asian women participated in a seven-day survey of dietary intake and daylight outdoor exposure. Individual levels of daylight outdoor exposure discriminated poorly between normal and osteomalacic women. The presence of osteomalacia was strongly related to varying degrees of vegetarianism. Lactovegetarianism (no meat. fish or egg consumption) was associated with significantly greater osteomalacic risk than ovolactovegetarianism (no meat or fish consumption). Unlike Asian rickets. high-extraction wheat cereal as chapatti was not a significant risk factor for osteomalacia in Asian women and dietary fibre was a less important risk factor than absent dietary meat. fish or egg. When exposure to ultraviolet radiation is limited. Asian osteomalacia (and Asian rickets) are determined by dietary factors.
Interventional radiology of the biliary tract. Transcholecystic intervention, Diagnostic and therapeutic biliary intervention by percutaneous access to the gallbladder is an important new area in interventional radiology. The anatomy of the gallbladder. biliary tree. and surrounding viscera is reviewed in this article as a preliminary to discussion of the diagnostic techniques of aspiration. cholangiography. biopsy. and the therapeutic techniques of gallbladder drainage and cholelithotomy. Recently there has been a bewildering proliferation of procedures aimed at removal. fragmentation. and dissolution of gallbladder stones. Several of these are discussed in this article. Removal of common bile duct stones by percutaneous cholecystostomy also is discussed.
Interventional gallbladder procedures, Interventional radiologic procedures in the gallbladder are influencing both the diagnosis and therapy of many gallbladder disorders. Current diagnostic and therapeutic percutaneous techniques offer important alternatives for their management. This article highlights the spectrum of interventional radiologic techniques available for gallbladder diseases.
Percutaneous balloon dilatation of benign biliary strictures, Percutaneous biliary dilatation is an effective alternative to surgical management of benign biliary strictures that has low morbidity and no reported mortality. Reported success rates for this procedure range from 40% to 90% depending on the size of the series. the type of patient being treated. and the length of follow-up period. The procedure is done in the fluoroscopy suite with an angioplasty balloon catheter. Transhepatic access is most common. but the procedure may be done via existing T-tube tracts or specially created jejunal loops. As the frequency of radical liver surgery such as liver transplant and radical trisegmentectomy rises. so too. the rate of biliary stricture is likely to rise. making percutaneous balloon dilatation an increasingly important tool in the interventional radiologist's armamentarium.
Interventional radiology of the biliary tract. Metallic stents, Biliary metallic stents were placed in 18 patients with bile duct obstruction. Six patients received Gianturco stents and 14 Wall-stents. Results of these tests are discussed.
Biliary endoprostheses. Plastic versus metal stents, Plastic biliary endoprostheses relieved malignant obstructive jaundice in 80% to 90% of the patients. The comfort of a completely indwelling endoprosthesis should be offered to all palliatively treated tumor patients. and external-internal catheters should be reserved for the minority of patients who return with reoccluded endoprostheses. These patients have bacterial flora that rapidly contaminates the endoprosthesis and causes encrustations and reocclusions. Thus. a second endoprosthesis also would reocclude quickly. The mechanism of reocclusion of plastic and metal endoprostheses is completely different. In plastic endoprostheses. bacterial contamination causes decomposition of the bile and subsequent encrustation. In metal endoprostheses tumor ingrowths between the struts of the stent cause reocclusion. Tumor ingrowths were observed in only 6.5% of metal prostheses with a narrow woven mesh (Wallstent). whereas prostheses with large distances between the struts (Gianturco stent) had ingrowth rates of 19% to 50%. This fact shows that tumor ingrowths can be reduced by narrowing the spaces between the metallic network. and. therefore. improvements in the design of the metal stents should reduce the occlusion rate to or below that of plastic endoprostheses. which currently have a lower encrustation rate. The major advantages of expandable metal prostheses are the relative ease and the minimal trauma of the implantation procedure. The Wallstent endoprosthesis. in particular. can be inserted through a 7-F introducer sheath and offers the chance of single-step placement. The 30-day mortality rate. therefore. was only 5%. This is significantly lower than the 30-day mortality rate after insertion of plastic prostheses (15% to 24%). Even simple external catheter drainage procedures have a higher reported 30-day mortality rate (27%). Expandable metal endoprostheses would be the most useful device if the occlusion rate could be kept under 10% in large series. Increasing the length of the endoprostheses to 10 cm in the expanded state could also improve the long-term patency rates.
Percutaneous biliary drainage for high obstruction, PBD is the preferred route of palliative drainage for patients with high biliary obstruction. The frequency of bifurcational obstruction in this setting requires familiarity with drainages from both the right and the left transhepatic approach. The preferred right transhepatic approach is fluoroscopically guided; on the left. ultrasonography is the guidance of choice. Large caliber drainage catheters are required. and dilatation of the necessary transhepatic tracts is extremely painful unless adequate inhalation anesthesia or. preferably. epidural anesthesia. is provided. Long-term biliary drainage requires a choice between internal-external external drainage catheters and endoprostheses that is made by considering the patient's life expectancy and his or her adjustment to a stent extending to the outside. The feasibility of corrective procedures if an internal-external drainage catheter or an endoprosthesis becomes blocked needs to be considered before definitive placement. The interventional radiologist becomes intimately involved in the follow-up care of patients and frequently has to direct appropriate patient evaluation. Familiarity with antibiotic regimens is important.
Interventional radiology of the biliary tract. Intraductal radiation, One palliative method of treating patients with a high duct cholangiocarcinoma is the use of 192Ir wire. This is placed through the tumor. which has been previously intubated. and delivers a high local dose of radiation. The mean survival time in 30 patients treated with intraductal radiation was 16.8 months. an improvement compared to surgical bypass or endoscopic and radiologic drainage procedures.
Intracorporeal biliary lithotripsy, Most bile duct calculi can be removed with standard percutaneous or endoscopic techniques. Very large stones are the most common cause for failure. Intracorporeal lithotripsy. and EHL in particular. can be used safely in either the biliary tree or gallbladder to fragment these large stones and allow percutaneous removal or passage. Intracorporeal EHL requires direct vision to prevent damage to the bile duct mucosa. Intracorporeal laser lithotripsy may offer some safety advantages. but the laser requires much more expensive equipment than intracorporeal EHL. Additional studies are needed to determine the technique that is better in each circumstance.
Technical aspects of biliary extracorporeal shock wave lithotripsy, Radiologic imaging procedures play a major role in the evaluation of the potential patient for biliary extracorporeal shock wave lithotripsy. both during the procedure and in follow-up evaluation. The treating physician must have a thorough knowledge of ultrasonography techniques. Lithotripsy requires continual monitoring and frequent reassessment to optimize targeting and fragmentation of the gallstones while maintaining patient comfort.
Ablation of the cystic duct and the gallbladder. Experimental basis and initial clinical observations, Bipolar radiofrequency electrocoagulation of the cystic duct by catheter can be performed safely and reproducibly using fluoroscopic control and induces endoluminal scar formation. The scar within the cystic duct forms a reliable barrier between the gallbladder and the biliary system and avoids recanalization of the cystic duct at a later date. Sclerotherapy of the isolated gallbladder with 95% ethanol and 3% STS can be performed without toxic or otherwise adverse effects and is suitable to ablate the porcine gallbladder. Initial clinical trials with this new technique on a small number of patients are promising and have demonstrated that the protocol can be applied safely to humans. The electrocoagulation technique by catheter appears suitable to ablate the human cystic duct. Follow-up evaluation of our first patients is under way and must determine whether our regimen is appropriate to ablate the human gallbladder on a long-term basis. Further development of this new approach may eventually enable definitive nonoperative treatment of cholecystolithiasis in selected patients.
Combined radiologic and retrograde endoscopic and biliary interventions, Methods of treating complex biliary duct problems by a team composed of an endoscopist and interventional radiologist are described. These procedures are of two types: Those in which all manipulations are performed through the endoscope and those in which an antegrade transhepatic and a retrograde endoscopic approach are combined.
Early postoperative care of the cardiac transplantation patient: routine considerations and immunosuppressive therapy, The authors have attempted to outline the current state of the art with respect to the early postoperative management of the cardiac transplant recipient with special attention to immunosuppressive therapies. The commonly used agents. as well as the most successful combination regimens. have been described along with the current levels of expectation regarding rates of rejection and infection. Much has been learned regarding the management of these problems. Much remains to be learned to further decrease the incidence of postoperative infection and rejection and. equally if not more importantly. studies to investigate the etiology of transplant coronary artery disease need to be undertaken such that measures to delay or prevent its occurrence and/or arrest its progression can be instituted.
Comparison of species distribution and antimicrobial susceptibility of aerobic actinomycetes from clinical specimens, To compare the species distribution and antimicrobial susceptibility of aerobic actinomycetes. we evaluated 366 isolates referred to the Centers for Disease Control from October 1985 through February 1988. We used conventional biochemical tests to identify the various species. Four species accounted for 191 (52%) of aerobic actinomycete isolates: Nocardia asteroides (98 isolates). Actinomadura madurae (42 isolates). Streptomyces griseus (28 isolates). and Nocardia brasiliensis (23 isolates). Sputum and wounds were the most common sources. No isolate was resistant to amikacin. no N. brasiliensis isolate was resistant to sulfamethoxazole or trimethoprim-sulfamethoxazole. and no A. madurae isolate was resistant to ceftriaxone or imipenem. In summary. our findings show that unusual species of aerobic actinomycetes can cause infection. colonization. or both and that antimicrobial resistance varies markedly by species.
Enterobacter bacteremia in pediatric patients, Enterobacter has emerged as an important human pathogen. particularly in sick. hospitalized patients. Previous reports of nonepidemic enterobacter bacteremia have focused on adult patients. In this report. the epidemiologic factors. clinical characteristics. treatment. and outcome for 33 patients with enterobacter bacteremia in a large children's hospital during a 5-year period are reviewed. The ratio of males to females was 1.2:1. The patients' ages ranged from 2 days to 24 years. and 18 patients were less than 18 months old. Twenty-two cases were nosocomially acquired; six were polymicrobial in nature. Significantly underlying conditions were present in 32 patients. The biliary tract and central venous catheters were the most common sources of bacteremia. Two-thirds of patients had preceding antibiotic therapy. The overall mortality was 24%; mortality attributable to enterobacter bacteremia was 18%. Statistically significant differences in mortality were associated with an age less than 18 months (P = .031) or thrombocytopenia (P = .017); presence of fever was of borderline significance (P = .098). Enterobacter bacteremia is an important cause of morbidity and mortality in pediatric patients.
Quinolone antibiotics in the treatment of Salmonella infections, The 4-fluoroquinolones are a new class of antimicrobial agents that possess broad in vitro antibacterial activity. including efficacy against enteric pathogens such as Salmonella. Shigella. Campylobacter. Yersinia. and Vibrio species. These drugs are clinically effective against both drug-sensitive and multiresistant strains of Salmonella typhi and Salmonella paratyphi that cause enteric fever. In salmonella enterocolitis. the quinolones--unlike older antimicrobial agents that may have little impact on the duration of symptomatic illness and can in fact prolong fecal carriage of salmonellae--actually shorten the course of clinical disease and terminate excretion of these organisms in the stool. Similarly. for chronic carriers of both typhoidal and nontyphoidal Salmonella strains. the quinolones are effective in eradicating biliary and fecal reservoirs of infection. Immunosuppressed persons with salmonellosis. such as those with AIDS. may benefit from both short-term treatment and prolonged prophylaxis with a quinolone antibiotic. The optimal agent. dose. and duration of quinolone therapy for all salmonella syndromes remain to be determined by larger controlled trials.
Infectious diseases as a Canadian subspecialty, with projections to the year 2000, Infectious diseases is a relatively new subspecialty in Canada. During the past decade. however. important advances have been made. These include the formation of the Canadian Infectious Diseases Society and the development of the first Royal College of Physicians and Surgeons examinations in the subspecialty of infectious diseases. The majority of Canadians training for practice in the field of infectious diseases are now enrolled in programs in Canada. Despite predictions in the United States of an excess of physicians who specialize in infectious diseases. such a situation has not occurred in Canada. More physicians with training in infectious diseases will be required in Canada in the next decade to fill positions in patient care. microbiology (for individuals with both clinical and laboratory training). research. epidemiology and infection control. programs related to human immunodeficiency virus infections. geographic and international medicine. the pharmaceutical industry. and education and administration. In Canada. the extent to which infectious diseases physicians are involved in these areas varies from that in the United States. This review suggests a continued need for physicians with appropriate training in infectious diseases.
Laboratory methods in the diagnosis and prognostic staging of infection with human immunodeficiency virus type 1, Laboratory evaluation of infection with human immunodeficiency virus type 1 (HIV-1) may involve detection of antibodies to HIV-1. direct detection of HIV-1 itself. and measurement of an individual's immunologic status at the time of presentation. The ELISA is currently the preferred initial screening test. although a variety of other rapid immunoassays have also been developed. Methods defining the antigenic specificity of the antibody response. such as the western blot. have become standard confirmatory tests in this setting. CD4+ cell enumeration and the HIV-1 antigen capture assay are useful in predicting the course of HIV-1 infection and in monitoring antiretroviral therapies. Newer techniques of HIV-1 co-cultivation permit the characterization of viral isolates and the stratification of patients and facilitate monitoring of the effects of antiretroviral agents. The polymerase chain reaction is of value in identifying HIV-1 infection in individuals with inconclusive serologic results. Judicious use of other laboratory tests. including surrogate markers such as beta 2-microglobulin. also provides prognostic information potentially useful in clinical management of HIV-1-infected patients.
Therapeutic approaches to neoplasms in AIDS, The multifactorial etiology of Kaposi's sarcoma (KS). which is seen primarily in men. includes genetic predisposition and immunosuppression. Recently. the KS seen in association with human immunodeficiency virus (HIV) infection has been shown to be mediated by the production of certain growth factors. HIV per se may also play an etiologic role via its tat gene. Therapeutic options include irradiation for local or cosmetic control. interferon-alpha. combinations of antiretroviral agents and interferon-alpha. and chemotherapy. The use of antineoplastic agents. either individually or in combination. in cases of advanced disease has been somewhat successful. but resultant immunosuppression and neutropenia may predispose patients to further infection. thereby adversely affecting survival. AIDS-related lymphoma. a late manifestation of HIV infection. often presents with widespread extranodal disease; the median survival time in all series has been approximately 6 months. Two-thirds of patients may have central nervous system involvement at some time in the course of illness. Intensive chemotherapeutic regimens are associated with an increased likelihood of opportunistic infection and do not prolong survival. Combinations of antineoplastic agents given at low doses for short periods may be associated with long-term remissions.
New antiretroviral agents in the clinic, Since the first controlled clinical trial of zidovudine (ACT) was terminated in the fall of 1986. much has been learned concerning the use of this agent in the treatment of human immunodeficiency virus (HIV) infection. The recent report of HIV resistance associated with long-term AZT therapy has accelerated the sense of urgency about the development of additional agents for use--either alone or in combination with AZT--against this infection. Several new agents are in various stages of preclinical or clinical evaluation. Some. such as dideoxycytidine. dideoxyinosine. dideoxydidehydrothymidine. azidouridine. and foscarnet. inhibit viral DNA synthesis through inhibition of reverse transcriptase. Other potentially useful agents presumably act at different stages of infection. Soluble CD4. for example. is a soluble form of the receptor to which HIV must bind to infect cells. and castanospermine represents a new class of compounds that block the maturation process of the viral glycoprotein. An apparently more potent and less toxic analogue of the latter agent. N-butyl-deoxynojirimycin. is currently in phase I testing.
Measles in Israel, the West Bank, and Gaza: continuing incidence and the case for a new eradication strategy, Measles continues to occur in epidemic waves in Israel. Gaza. and the West Bank. causing morbidity and mortality. In Israel. immunization of infants against measles began in 1967. and 90% had been immunized by the mid-1980s. In Gaza and the West Bank. where immunization of infants against measles began in 1973 and 1976. respectively. the immunization rate reached 75% in the late 1970s and increased to greater than 90% in the 1980s. Measles epidemics. which previously had occurred in 5- to 7-year cycles. occurred every 2-4 years in the 1980s and affected individuals who were older than those affected in previous years. Israel's commitment to eradicating measles by 1992 will require a substantially expanded immunization program in comparison with the traditional program that requires immunization of infants alone. The benefits of several alternative immunization strategies considerably exceed their costs. A new. two-dose immunization will be needed as a minimal strategy. and a campaign for administering booster doses to school-aged children may be required as well to achieve control and eradication of measles. Measles is a serious but preventable public health problem; appropriate strategies must be devised by national and international public health officials to control the disease in developing and developed countries.
Cytomegalovirus: where have we been and where are we going, Nearly 30 years have elapsed since Rowe and Weller and their colleagues discovered human cytomegalovirus (CMV). Because of its complex structure. long replicative cycle. low yield in vitro. and highly species-specific cell-substrate requirement. the cellular and molecular biologic analyses of human CMV have been slow. but recombinant DNA and monoclonal antibody technologies are bringing about rapid changes. Because of the long period of latency and wide range of disease presentations. epidemiologic and medical insights have also come slowly. However. the clinical events that occur during iatrogenic immunosuppression (transplantation and cancer therapy) and as a result of immunocompromise due to human immunodeficiency virus infection are currently promoting our understanding of the epidemiology of CMV disease and the definition of its clinical spectrum. Rapid diagnostic methods. antiviral drugs. and vaccines for CMV are becoming available. We may not yet understand completely the impact of this agent on the nonimmunosuppressed or aspects of its pathogenesis: e.g.. the immune functions controlling recrudescence and the possibility of increased disease severity in those with no detectable immune defect. With the availability of new approaches. other issues should be clarified. such as the functions of host and virus involved in the mechanism of persistence.
Epidemiology of cytomegalovirus infections, The determinants of cytomegalovirus (CMV) infection and disease can now be understood from studies of newborns. recipients of organ or bone marrow transplants. subjects infected with human immunodeficiency virus. and recipients of blood transfusions. CMV is transmitted to the neonate transplacentally. by passage through a contaminated birth canal. or by ingestion of infected breast milk; to the adult by heterosexual and homosexual sex with an infected partner; and to the transplant recipient by infected organs. A major unsolved problem in the study of CMV is the nature of viral latency. Knowledge regarding the requirements for activation of latent infection at the molecular. cellular. or host level is incomplete. Both viral and host factors may contribute to the successful transmission of CMV by latently infected cells in transplanted organs and transfused blood.
Virologic and pathogenetic aspects of cytomegalovirus infection, Cytomegalovirus (CMV) is a ubiquitous agent that rarely causes disease in immunocompetent humans but is an important cause of morbidity and mortality in the immunocompromised. A number of host and viral factors are associated with pathology following CMV infection. CMV can be found at many sites in the body but only causes disease at some of these and then only in certain patient populations. In some situations the mechanism underlying disease is direct viral replication. but in others. particularly CMV pneumonitis in allogeneic transplant recipients. an immunopathologic basis is strongly implicated. An important factor in the pathogenesis of infection and the expression of symptomatic disease is the source of CMV infection-whether it arises from an exogenous source or is due to reactivation of latent endogenous virus. Exogenous infection can occur in previously seronegative individuals or in those with prior exposure to the virus. In renal transplant recipients both types of exogenous infection have been associated with disease. Another factor that affects the interaction between CMV and its host is the modulating effect of the virus on the host immune response. the mechanism of which remains unknown.
Congenital and perinatal cytomegalovirus infections, Cytomegalovirus is the most common cause of congenital and perinatal viral infections throughout the world. Congenital infection occurs in 1% of all live births in developed countries and in an even higher percentage in developing nations. As a result of transmission during birth. by breast milk. and by blood transfusion. perinatal infections are much more prevalent than congenital infections. The vast majority of these infections are chronic. subclinical forms. but symptomatic infections are sufficiently prevalent and dangerous to represent a major unsolved public health problem throughout the world. In this review the epidemiologic. clinical. immunologic. and therapeutic facets of cytomegaloviral infections in pregnant women and their offspring will be discussed.
Impact of cytomegalovirus infection on organ transplant recipients, Cytomegalovirus (CMV) is the single most important infectious agent affecting recipients of organ transplants. with at least two-thirds of these patients having CMV infection 1-4 months after transplantation. Latently infected allografts are the major exogenous source of CMV infection in transplant recipients. although leukocyte-containing blood products can also transmit the virus. Three patterns of CMV infection are recognized: primary infection. reactivation infection. and superinfection. Primary infection has the greatest clinical impact. The clinical effects of CMV infection include infectious disease syndromes such as pneumonia and chorioretinitis; an immunosuppressed state that predisposes to potentially lethal opportunistic infection; and the initiation of a process that can result in allograft injury. Progress has been made in controlling CMV infection; hyperimmune anti-CMV globulin and certain antiviral drugs appear promising for prophylaxis. and the combination of hyperimmunoglobulin and ganciclovir appears promising for therapy.
Cytomegalovirus infections after allogeneic bone marrow transplantation, Cytomegalovirus (CMV) infection occurs in approximately 50% of all recipients of allogeneic bone marrow transplants and is seen more frequently in CMV-seropositive patients than in CMV-seronegative patients. Sources of infection include reactivation of latent endogenous virus. blood products from CMV-seropositive blood donors. and the use of marrow from a CMV-seropositive donor for a CMV-seronegative recipient. The most common and severe clinical syndrome associated with CMV infection in allogeneic transplant recipients is interstitial pneumonia. which occurs in approximately 15% of patients. Risk factors for CMV pneumonia include old age. conditioning with total-body irradiation. and severe graft-vs.-host disease. The rapid diagnosis of CMV pneumonia has been facilitated by immunochemical staining of bronchoalveolar lavage fluid or by centrifugation of cell cultures with CMV monoclonal antibodies. The treatment of CMV pneumonia remains problematic. but therapy with a combination of intravenous immune globulin (IVIG) plus ganciclovir has resulted in survival rates substantially better than those achieved in previous trials of antiviral therapy. In CMV-seronegative patients. CMV infection and pneumonia can be prevented or modified by the use of CMV-seronegative blood products and IVIG. IVIG may also have the additional benefits of preventing other infectious complications and graft-vs.-host disease in patients receiving CMV-seronegative blood products. For CMV-seropositive patients. effective prophylaxis for CMV reactivation and pneumonia has not yet been established. but a clinical trial of prophylactic ganciclovir is now under way.
Cytomegalovirus in the setting of infection with human immunodeficiency virus, Human cytomegalovirus (CMV) has several possible roles in the pathogenesis of AIDS. CMV causes a number of clinical syndromes. including retinitis. pneumonitis. and gastroenteritis in patients infected with human immunodeficiency virus type 1 (HIV-1). In addition. CMV may potentiate the cellular immunodeficiency observed in patients with HIV infection either directly or through enhancement of HIV replication. Finally. CMV may predispose the host to bacterial or fungal infection by compromising the integrity of mucosal barriers to infection. Therapy with ganciclovir for CMV infection may result in a decrease in morbidity related to the virus. but problems with drug toxicity and resistance to the agent mandate the development of additional therapeutic approaches.
Cytomegalovirus infection in children with AIDS, Data for 38 children perinatally exposed to human immunodeficiency virus (HIV) were evaluated to determine the impact of cytomegalovirus (CMV) infection on the course of perinatally acquired HIV infection. Thirteen children belonged to the P0 (indeterminate) group. one to the P1 (asymptomatic) group. and 24 to the P2 (symptomatic) group. per the classification of the Centers for Disease Control. Of the 24 children in the P2 group. 10 died. The mean follow-up time was 22.8 months for the 10 children who died and 16.3 months for the 13 children in the P0 group. Serial cultures of urine were performed for all 38 patients. CMV was isolated from seven of 10 children who died and from four of 14 children who survived (P less than .05). Only one of the 13 P0 children was culture-positive for CMV. as compared with 11 of 24 P2 children (P less than .05). All CMV-infected children continued to demonstrate CMV viruria in serial cultures. The mean age at the time of the first culture positive for CMV was 13 months. Microcephaly was present in 15 (65%) of 23 P2 children but in none of the P0 and P1 children (P less than .05). Eight of 11 CMV-infected children were microcephalic; seven of 12 children not infected with CMV were microcephalic (P greater than .05). These data suggest that the prevalence of active CMV infection is significantly higher in P2 children than in P0 and P1 children. In addition. there is a significant association between CMV infection and mortality among P2 children.
Protection of mice against the Lyme disease agent by immunizing with recombinant OspA, Lyme borreliosis is a tick-borne illness caused by Borrelia burgdorferi. The gene for outer surface protein A (OspA) from B. burgdorferi strain N40 was cloned into an expression vector and expressed in Escherichia coli. C3H/HeJ mice actively immunized with live transformed E. coli or purified recombinant OspA protein produced antibodies to OspA and were protected from challenge with several strains of B. burgdorferi. Recombinant OspA is a candidate for a vaccine for Lyme borreliosis.
Increased activity of calcium leak channels in myotubes of Duchenne human and mdx mouse origin, Elevated free Ca2+ concentrations found in adult dystrophic muscle fibers result in enhanced protein degradation. Since the difference in concentrations may reflect differences in entry. Ca2+ leak channels in cultures of normal and Duchenne human myotubes. and normal and mdx murine myotubes. have been identified and characterized. The open probability of leak channels is markedly increased in dystrophic myotubes. Other channel properties. such as mean open times. single channel conductance. ion selectivity. and behavior in the presence of pharmacological agents. were similar among myotube types. Compared to the Ca2+ concentrations in normal human and normal mouse myotubes. intracellular resting free Ca2+ concentrations ([Ca2+]i) in myotubes of Duchenne and mdx origin were significantly higher at a time when dystrophin is first expressed in normal tissue. Taken together. these findings suggest that the increased open probability of Ca2+ leak channels contributes to the elevated free intracellular Ca2+ concentration in Duchenne human and mdx mouse myotubes.
Down-regulation of LFA-1 adhesion receptors by C-myc oncogene in human B lymphoblastoid cells, The function of the c-myc gene and its role in tumorigenesis are poorly understood. In order to elucidate the role of c-myc oncogene activation in B cell malignancy. the phenotypic changes caused by the expression of c-myc oncogenes in human B lymphoblastoid cells immortalized by Epstein-Barr virus were analyzed. C-myc oncogenes caused the down-regulation of lymphocyte function-associated antigen-1 (LFA-1) adhesion molecules (alpha L/beta 2 integrin) and loss of homotypic B cell adhesion in vitro. Down-regulation of LFA-1 occurred by (i) posttranscriptional modulation of LFA-1 alpha L-chain RNA soon after acute c-myc induction. and (ii) transcriptional modulation in cells that chronically express c-myc oncogenes. Analogous reductions in LFA-1 expression were detectable in Burkitt lymphoma cells carrying activated c-myc oncogenes. Since LFA-1 is involved in B cell adhesion to cytotoxic T cells. natural killer cells. and vascular endothelium. these results imply functions for c-myc in normal B cell development and lymphomagenesis.
Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor, The Wilms tumor locus on chromosome 11p13 has been mapped to a region defined by overlapping. tumor-specific deletions. Complementary DNA clones representing transcripts of 2.5 (WIT-1) and 3.5 kb (WIT-2) mapping to this region were isolated from a kidney complementary DNA library. Expression of WIT-1 and WIT-2 was restricted to kidney and spleen. RNase protection revealed divergent transcription of WIT-1 and WIT-2. originating from a DNA region of less than 600 bp. Both transcripts were present at high concentrations in fetal kidney and at much reduced amounts in 5-year-old and adult kidneys. Eleven of 12 Wilms tumors classified as histopathologically heterogeneous exhibited absent or reduced expression of WIT-2. whereas only 4 of 14 histopathologically homogeneous tumors showed reduced expression. These data demonstrate a molecular basis for the pathogenetic heterogeneity in Wilms tumorigenesis.
Regulation of gene expression with double-stranded phosphorothioate oligonucleotides, Alteration of gene transcription by inhibition of specific transcriptional regulatory proteins is necessary for determining how these factors participate in cellular differentiation. The functions of these proteins can be antagonized by several methods. each with specific limitations. Inhibition of sequence-specific DNA-binding proteins was achieved with double-stranded (ds) phosphorothioate oligonucleotides that contained octamer or kappa B consensus sequences. The phosphorothioate oligonucleotides specifically bound either octamer transcription factor or nuclear factor (NF)-kappa B. The modified oligonucleotides accumulated in cells more effectively than standard ds oligonucleotides and modulated gene expression in a specific manner. Octamer-dependent activation of a reporter plasmid or NF-kappa B-dependent activation of the human immunodeficiency virus (HIV) enhancer was inhibited when the appropriate phosphorothioate oligonucleotide was added to a transiently transfected B cell line. Addition of phosphorothioate oligonucleotides that contained the octamer consensus to Jurkat T leukemia cells inhibited interleukin-2 (IL-2) secretion to a degree similar to that observed with a mutated octamer site in the IL-2 enhancer. The ds phosphorothioate oligonucleotides probably compete for binding of specific transcription factors and may provide anti-viral. immunosuppressive. or other therapeutic effects.
Prevalence of previously undiagnosed hypothyroidism in residents of a midwestern nursing home [published erratum appears in South Med J 1991 Jul;84(7):936, Hypothyroidism in the elderly may be associated with nonspecific symptoms. To determine the prevalence of undiagnosed hypothyroidism in residents of a skilled nursing facility. we screened 434 male and 137 female residents. aged 60 years or older. for thyroid dysfunction. Overt hypothyroidism was found in three men and two women. Subclinical hypothyroidism was diagnosed in 42 men (9.7%) and 20 women (14.6%). Tests for thyroid antibodies were positive in all patients with overt hypothyroidism and in 12 (34%) of the 35 men and 12 (67%) of the 18 women with subclinical hypothyroidism who had thyroid antibody testing. All residents with newly diagnosed overt hypothyroidism and 54 (87%) of the 62 with subclinical hypothyroidism had been under medical observation for 1 year or longer. The institutionalized elderly should be screened for hypothyroidism because this abnormality may otherwise remain undiagnosed. The detection of subclinical hypothyroidism is important. as affected individuals are at risk for further decline in thyroid function.
Mitral valve prolapse: comparison of diagnosis by physical examination and echocardiography, To determine how well physical examination findings suggestive of mitral valve prolapse (MVP) correlate with echocardiographic evidence of MVP. we retrospectively reviewed the charts of 104 patients referred to an Air Force Cardiology Clinic for echocardiography to rule out MVP. In each case. the referring physician's specialty and his findings on cardiac physical examination were recorded. All patients had M-mode echocardiography. and half of the patients had two-dimensional echocardiography. Sensitivities. specificities. and likelihood ratios for the physical examination were calculated using echocardiography as the comparison standard. The combination of a systolic click and a systolic murmur was the physical examination finding most predictive of echocardiographic MVP. with a positive likelihood ratio of 2.43. Other combinations of physical findings yielded likelihood ratios close to 1. No differences were found based on the specialty of the examining physician. We conclude that when practicing physicians find a systolic click and murmur. MVP is likely to be present on echocardiography. though one third of the patients will have normal echocardiograms. Other combinations of physical findings are of little help in predicting echocardiographic MVP.
Pursuing mild elevations of liver enzyme values to exclude hemochromatosis, To determine whether physicians in an academic medical center excluded hemochromatosis as a diagnosis in a population of patients with mildly elevated liver enzyme values. we reviewed 100 charts of patients with both aspartate aminotransferase and alkaline phosphatase levels that were less than twice the upper limit of normal. We analyzed each chart to determine if hemochromatosis would have been excluded by a subsequent workup. Those patients who did not have a complete workup were assigned to one of three categories: (1) no mention was made of abnormal liver enzyme values; (2) liver enzyme values were ascribed to some condition other then hemochromatosis and no definitive workup was done; and (3) the condition of the patient was so poor that assessment did not seem indicated. Ninety of 100 patients were not given a workup to exclude hemochromatosis. Physicians often ignore mild elevations in liver enzyme values.
Survey of Alabama physicians' use of mammography, 1989, In early 1989 we surveyed by questionnaire Alabama primary care physicians (N = 1800) concerning their attitudes toward and use of mammography. There were 681 respondents (37.8%). The majority (83%) recommend mammograms for their patients according to the American Cancer Society guidelines and obtain baseline studies in asymptomatic women between the ages of 35 and 40 years. It appears that the cost of mammograms is decreasing in Alabama; a screening study was available for $50 or less to 34% of responding physicians. Almost one half (48%) of the physician respondents believe that more than 50% of their patients have had at least one mammogram.
Trabecular or Merkel's cell carcinoma, Two cases of trabecular cell carcinoma of the skin are presented. The clinical presentation and behavior. and the histologic findings. of the tumor are described. Surgical excision of the primary lesion with regional lymph node dissection. if indicated. is the treatment of choice. Distant metastasis is treated by local irradiation.
Cytomegalovirus in a macerated second trimester fetus: persistent viral inclusions on light and electron microscopy, The macerated stillborn fetus represents at least one third of all perinatal deaths. Microscopic examination of these specimens is often unrewarding. We have reported a clinically unsuspected cytomegalovirus infection in a second trimester macerated fetus. Cells suggestive of CMV inclusions were identified by light microscopy. but electron microscopy confirmed the presence of viral infection and proved valuable in making the diagnosis even though necrosis was severe.
1990 Volvo Award in experimental studies. Anulus tears and intervertebral disc degeneration. An experimental study using an animal model, An animal model was developed to test the hypothesis that discrete peripheral tears within the anulus lead to secondary degenerative changes in other disc components. In 21 adult sheep. a cut was made in the left anterolateral anulus of three randomly selected lumbar discs. The cut was parallel and adjacent to the inferior end-plate. and had a controlled depth of 5 mm. This left the inner third of the anulus and the nucleus pulposus intact and closely reproduced the rim Lear lesion described by Schmorl. Animals were randomly allocated to different groups in relation to the length of time interval between operation and death. varying from 1 to 18 months. At death. the lumbar spine was cut into individual joint units and each disc sectioned into six parasagittal slabs. After observation of the slabs under the dissecting microscope. two of the six slabs. the one containing the anulus lesion and a contralateral. were processed for histology. The results of this study suggest that. despite the great care taken at operation to ensure that the inner anulus was left intact. progressive failure of the inner anulus was seen in all sheep and occurred in the majority of discs between 4 and 12 months after the operation. Although the outermost anulus showed the ability to heal. the defect induced by the cut led initially to deformation and bulging of the collagen bundles. and eventually to inner extension of the tear and complete failure. These findings suggest that discrete tears of the outer anulus may have a role in the formation of concentric clefts and in accelerating the development of radiating clefts. Peripheral tears of the anulus fibrosus therefore may play an important role in the degeneration of the intervertebral joint complex.
The role of spinal flexibility in back pain complaints within industry. A prospective study, Commonly used clinical measurements of spinal flexibility in the sagittal and frontal planes were examined as predictors of future back pain reports within industry. The study sample consisted of 3.020 aircraft manufacturing employees who were examined and tracked for more than 4 years for reports of back pain. Modified Schober. sit-and-reach. and lateral bending measurements were not significantly associated with risk of future back pain reporting. nor were any trends present. There was a statistically significant relationship between decreased flexibility and reports of current or previous back problems. However. the differences in flexibility between subjects with and without a history of back problems were too small to be of practical significance.
The loads on the lumbar spine during work at an assembly line. The risks for fatigue injuries of vertebral bodies, This study was performed in an attempt to determine the total spinal compressive load during assembly line work to find a possible association with the many complaints of back pain. A flexion analyzer was used to register trunk movements. and analysis of postures and lifted weights was done from video recordings. The load on the spine at the L3 level was calculated through a biomechanical model. meant for analysis of static. sagittally symmetric postures and lifting tasks. Maximum lift tests were performed before and after a full work day. The peak load on the L3-L4 level when lifting corresponded to an average 22% of the load at the lift test. The mean load during a work cycle was 818 N. It was concluded that the many complaints of back pain could not be attributed to high peak loads. repetitivity of the lifts. or large load doses. Monotony. stress. and low job satisfaction are more likely factors of greater importance.
Comparison of structure, mechanical properties, and functions of lumbar spinal ligaments, The organization of collagen in the supraspinous. interspinous. and longitudinal ligaments. as well as the ligamenta flava. in lumbar spines from human cadavers has been investigated by polarized light microscopy. scanning electron microscopy. and x-ray diffraction. These experiments were performed on ligaments in situ. with their bony attachments undisturbed. and on excised ligaments at a range of applied strains. Results were related to the composition (investigated by standard histologic techniques) and gross structures (investigated by light microscopy) of the ligaments. More importantly. the results were related to the mechanical properties of the ligaments. which include stiffness. failure conditions. stress relaxation. and hysteresis. Where necessary. results were supplemented by or compared with those obtained from pig ligaments. Mechanical properties were related to postural changes by ligament strains induced in cadaveric specimens. using results from the literature. Thus. ligament structures could be related to their physiologic functions.
Computer-assisted tomography of scoliosis operated with or without Harrington's rod. Biomechanics aspects of the fusion, Forty-eight cases of posterior vertebral arthrodesis for scoliosis. performed with or without instrumentation. were examined using computed tomography (CT) scanning to study the evolving fusion mass. The authors observed that the fusion mass area is more voluminous in the cases performed without instrumentation than in the ones performed with instrumentation. and that 2 years after fusion the bone mass shows already a considerable increase. For the cases operated with Harrington's technique. the increase of the fusion mass is very slow and becomes considerable 5 years after operation. In both series. the section of the fusion masses at the apex of the curve is asymmetric (with prevalence on the concave side). with an area of central resorption that shows the structure of a long bone (box section).
Factors influencing the result of posterior spinal fusion in the treatment of adolescent idiopathic scoliosis, Sixty-six consecutive patients with adolescent idiopathic scoliosis treated by posterior spinal fusion using Harrington distraction compression instrumentation were followed for a minimum of 3 years. Initial surgical correction was satisfactory. but during the follow-up period. mean 4.4 years (3-5 years). there was a loss of correction. Several factors (age. sex. the number of vertebrae in the fusions. and the use of cross wires) were important influences on correction. A method of assessing the balance of a posterior spinal fusion is described that is useful when assessing radiographs.
The operative treatment of progressive early onset scoliosis. A preliminary report, Thirteen patients with progressive early onset scoliosis have been managed operatively in an attempt to achieve correction without bracing and to allow the spine to grow. All had posterior segmental spinal instrumentation (SSI) without fusion and 9 of 13 had anterior apical growth arrest as a separate additional procedure. At 2-year follow-up. curve correction averaged 46%. Patients who had anterior apical growth arrest and SSI without fusion had less curve deterioration than those who had SSI alone. New methods are described for 1) measuring growth of the instrumented segment of the spine and 2) calculating the predicted growth of the instrumented segment. Eight of the 13 had more than 50% of predicted growth. three had 30-50% of predicted growth. and two had less than 30% of predicted growth. Operative treatment has been successful in the short term in all but the most malignant form of infantile idiopathic scoliosis.
An analysis of the effect of the Zielke operation on S-shaped curves in idiopathic scoliosis. A follow-up study revealing some skeletal and soft tissue factors involved in curve progression, This article analyzes the fate of S-shaped idiopathic spinal curves during follow-up in 18 patients having the Zielke VDS operation. The spinal radiographs were evaluated by Cobb angle. end-vertebra angles (EVAs). vertebral rotation. and by a new method using the tilt of the surgically fused spinal block in the frontal plane. Spinal growth was measured. Using the conventional criterion for Cobb angle progression. 83% of the lower curves and 50% of the upper curves progress. The use of EVAs shows that progression occurs mainly in the middle (thoracolumbar) segment of the spine. Curve progression occurs in the frontal plane without any significant change in vertebral rotation. The progression of the upper curve Cobb angle is not related to the progression of the Cobb angle of the lower curve; but it is related to 1) tilt of the spinal block. 2) growth of the spine below the block and 3) overall linear spinal growth (T1-S1). Progression of the upper EVA of the upper curve is associated with skeletal immaturity. The key features leading to curve progression after the Zielke operation appear to be spinal asymmetry in the frontal plane. linear spinal growth. and concave lumbar muscle tether (myostatic contracture). The surgical implications of the findings are outlined.
Effects of rib elongation on the spine. I. Distortion of the vertebral alignment in the rabbit, Elongation of one rib on the right side by 1 cm was achieved in two groups of adult rabbits of different age. by osteotomy and application of a metallic expander. The procedure resulted in immediate deviation of the spine in the frontal and sagittal planes. with moderate scoliosis. convex to the left. and a significant decrease in the normal cervicothoracic lordosis and thoracolumbar kyphosis. Moreover. computed tomography (CT) scanning demonstrated rotation of vertebra about the longitudinal axis relative to the anterior midline of the body. and deviation of the spinous process toward the convex. left side. of the scoliotic deformity. Rib hump developed on the right side--that of the elongated rib. These changes. which occurred simultaneously in the three planes. were less pronounced in the group of older animals. Two weeks after the operation. the distorted configuration of the spine remained unchanged. The observed changes in the alignment of the vertebrae--changes that. except for their direction on the horizontal plane. resembled those associated with idiopathic scoliosis in man--support the earlier proposed link between the early stage of development of this condition and asymmetry of rib growth.
Effects of rib elongation on the spine. II. Correction of scoliosis in the rabbit, Three intercostal nerves on the right side of growing rabbits were resected partially. From 1 to 3 months later. moderate left-convex thoracic scoliosis with rotation of vertebrae had developed. and the sagittal curvatures of the spine had diminished. In one group of these animals. a mechanically produced increase of 1 cm in the length of one rib on the side of the convexity resulted in an immediate correction of the scoliotic deformity. an improvement that was still evident 3 weeks after the operation. In two other groups of rabbits. a further resection of three intercostal nerves. this time on the left convex side. 1 and 2 months after the first operation. resulted in regression of scoliosis or halted its progression. These results further support a new concept in which the precipitating factor in the development of scoliosis is ascribed to asymmetric longitudinal growth of the ribs. They also suggest that regulation of the rib length could be a promising approach to the effective correction of progressive scoliosis at an early stage in man.
Stapling or suturing for anastomoses of the left side of the large intestine, Two hundred and fifty patients undergoing elective surgical treatment involving anastomoses of the left side of the colon or colon and rectum have been studied in a randomized trial in which the EEA (U. S. Surgical Corp.) circular stapler has been compared with single layer sutured anastomoses. Only patients in whom either technique was feasible were included in the analysis. The operative techniques were largely standardized. Patients were studied by means of a limited barium enema on the ninth or tenth postoperative day. The data have been analyzed for leakage rate (clinical and roentgenologic). other complications and degree of experience of the surgeon. Eleven patients were excluded from the analysis because the selected technique could not be carried out; of these. eight were in the stapled group in which it was possible to perform a sutured anastomosis. There were no instances in which it was possible to staple but not possible to suture. The remaining three exclusions were patients in whom either a coloanal anastomosis or a Hartmann procedure was performed. There was no over-all difference in the leakage rate--roentgenologic. clinical or total--between the two groups. However. when analyzed by the surgeon. the clinical leakage rate for surgeons in training was greater for sutured anastomoses than for stapled anastomoses (p = 0.053). Thus. it appears that the benefits of experience are more pronounced for sutured anastomoses but that. in experienced hands. neither technique is superior.
Deleterious effects of testicular venous occlusion in young rats, To determine the differences between testicular arterial and venous obstruction. the spermatic artery or vein. or both. were occluded for varying periods of time in young rats. Two months later. at the conclusion of the study. the testes were examined. Histologic degeneration after vascular obstruction was graded by a modified Johnsen's tubular biopsy score (TBS). The testicular concentrations of enzymes (lactic dehydrogenase and sorbitol dehydrogenase). known to decrease with testicular injury. were measured. TBS and seminiferous tubule diameter (STD) were found to decrease significantly after two hours of vascular occlusion and were similar regardless of whether the obstruction was produced by occlusion of arterial inflow or venous drainage. or both. Testicular concentration of enzymes decreased significantly after permanent ligation of the spermatic artery and vein. but decreased minimally when the vascular obstruction lasted less than 120 minutes. Testicular injury produced by venous occlusion was equally severe and occurred as rapidly as injury produced by arterial or combined arteriovenous occlusion. No significant injury was noted in the contralateral testes in any group.
Time to recurrence varies inversely with thickness in clinical stage 1 cutaneous melanoma, The thickness of a tumor has been identified as the principal prognostic factor in cutaneous malignant melanoma. However. time to recurrence has not conclusively been related to thickness. A retrospective study of 216 patients with a primary cutaneous malignant melanoma that recurred was conducted to clarify this relationship and investigate possible independent relationships between age at diagnosis and sex of patients to time to recurrence. The results of analysis of linear regression revealed an inverse linear relationship between thickness and time to recurrence (p less than 0.001). Patients more than 50 years of age at the time of diagnosis were shown to relapse sooner than those less than 50 years of age (p = 0.014). Sex was not a significant factor in predicting time to recurrence (p greater than 0.10). These results suggest that thickness of tumor provides an indication of time to recurrence in those patients destined to recur and stress the need for long term surveillance in patients with a history of malignant melanoma because of the possibility of late relapse even with thin lesions.
The justification for surgical treatment of metastatic melanoma of the gastrointestinal tract, Fifty-six patients with symptomatic metastatic melanoma of the gastrointestinal tract (GIT) treated surgically at the Sydney Melanoma Unit between 1974 and 1989 were reviewed. The majority of these patients presented with abdominal pain or symptoms of anemia. The small intestine was the site of metastasis in more than 80 per cent. The mean over-all survival time was 11.7 months (range of one to 60 months) after surgical treatment of a first metastasis to the GIT and 3.6 months (range of zero to 12 months) postoperatively for a second GIT metastasis. Forty-four of the patients reported complete relief of their symptoms postoperatively. The results suggest that an aggressive approach to symptomatic GIT metastases from malignant melanoma is justified both to relieve distressing symptoms and to prolong life.
The contributions of John B. Murphy to thoracic surgery, John B. Murphy was a prominent surgeon who lived in Chicago from the 1880s until his death in 1916. During his career. he was associated with both Rush Presbyterian and Northwestern Medical Schools. He was responsible for popularizing the use of an artificial pneumothorax as an effective adjunct in the treatment of pulmonary tuberculosis. This modality was not. however. his original concept. In addition to all of the fields of general surgery. Murphy undertook the management of empyema and lesions of the chest wall and also performed thoracoplasty procedures. Although he had done several thoracotomy procedures in his laboratory. he rarely undertook this operation in a clinical setting. Drop ether anesthesia was used for all surgical procedures. Murphy did not use closed water seal drainage of the chest. His oration on thoracic surgery. given at the annual meeting of the AMA. in 1898. was an excellent monograph on the subject and undoubtedly contributed to the increased interest and progress in this field of surgery. Murphy was a wise surgeon. an able technician and a scholarly teacher. The high regard in which he was held by his contemporaries is best expressed by the remark of William Mayo. "...he was the surgical genius of our generation".
Caspar Stromayr: sixteenth century ophthalmologist, Caspar Stromayr. ophthalmologist and hernia surgeon. is credited with writing the first German ophthalmic work of known authorship. Written in about 1559 as an appendix to Practica Copiosa. a larger work on hernia surgery. the ophthalmic chapters describe Stromayr's thoughts on the etiology and treatment of cataract. Stromayr. a master craftsman. also expresses his hostility to the shams and ignorance of the charlatan eye surgeons of his day. This interesting historical article provides a biographical sketch of Stromayr. a description of his book. and a translation of two chapters. "On Cataract of the Eye: How They Take Their Beginning and Whence they Come" and "How You Recognize the Cataract. When It is Ripe to Recline or to be Taken Away.".
Decollateralization with silicone rubber sheeting for advanced hepatocellular carcinoma: a preliminary report, A new treatment method. interception of collaterals with a silicone rubber sheet. was applied to three patients with advanced hepatocellular carcinoma in whom arterial chemoembolization was assessed as ineffective because of the developed collateral feeding arteries. This procedure was followed by arterial chemoembolization or intraportal infusion chemotherapy or both. Follow-up celiac angiography confirmed that the long-term decollateralization was achieved by shielding the liver with silicone rubber sheeting. This technique resulted in partial responses without serious complications in all the patients including two who had no responses to chemoembolization before the procedure. The response durations were 5. 21. and 27. months. respectively. One patient died of gastrointestinal bleeding 7 months after the decollateralization. The other two patients are still alive. and the survivals after the procedure are 28 and 30 months. respectively. This therapy is considered promising and may be worth choosing as an adjuvant treatment for advanced hepatic malignancies uncontrolled by arterial chemotherapy or chemoembolization.
Traumatic disruptions of the thoracic aorta: treatment and outcome, Of 27 patients admitted to our level I trauma center with acute disruption of the thoracic aorta. two patients died of exsanguination before aortic repair. One patient had massive leakage from the aneurysm after aortography and died during surgery. All patients suffered from multiple injuries. Eighty-three percent of the patients had major operations in addition to the aortic repair. "Clamp and sew" technique was used in 18 patients (75%). two of whom had multiple tears of the aortic arch. Heparin-coated shunts were used in five patients (20.8%). and a cardiopulmonary bypass was performed in one patient who had multiple tears. Three postoperative deaths were related to polytrauma. cardiogenic shock. and sepsis. Paraplegia developed in three patients. two of whom had multiple aortic lesions necessitating longer ischemia time during the repair. Only one patient had complete neurologic deficit at the 1-year follow-up. In our series. neither surgical procedure proved superior. We conclude that the "clamp and sew" technique for repair of the disrupted thoracic aorta may allow for a more favorable outcome.
Sequential gradient pneumatic compression enhances venous ulcer healing: a randomized trial, The treatment of venous ulcers has remained largely unchanged for centuries. The application of properly applied graduated compression bandages. the use of graduated compression stockings. and surgery have been shown to achieve healing. However. some ulcers persist despite appropriate management. A randomized study was undertaken to compare two regimens of treatment for such patients. Both regimens included ulcer debridement. cleaning. nonadherent dressing. and graduated compression stockings. In one regimen. sequential gradient intermittent pneumatic compression was applied for 4 hours each day. Only one of 24 patients in the control group had complete healing of all ulcers compared with 10 of 21 patients healed in the intermittent pneumatic compression group. The median rate of ulcer healing in the control group was 2.1% area per week compared to 19.8% area per week in the intermittent pneumatic compression group. The results indicate that sequential gradient intermittent pneumatic compression is beneficial in the treatment of venous ulcers.
Esophageal reflux before and after isolated myotomy for achalasia, Four patients with achalasia underwent 24-hour esophageal pH measurements as ambulatory patients before and after limited myotomy without fundoplication. Resting lower esophageal sphincter pressure was reduced from 24.3 +/- 1.3 mm Hg to 7.5 +/- 4.3 mm Hg. No significant differences (p greater than 0.05) were found before and after operation in the total 24-hour pH data distribution (pH 6.24 +/- 0.84 vs 5.75 +/- 1.03). the fraction of time below pH 4.0 (4.8% +/- 5.3% vs 8.0% +/- 6.9%). or the mean duration of reflux episodes greater than 5 minutes (22.8 +/- 18.8 minutes vs 23.0 +/- 10 minutes). all +/- SD. Effective relief of esophageal obstruction in achalasia is feasible by isolated limited myotomy without producing gastroesophageal reflux.
Rejection of multivisceral allografts in rats: a sequential analysis with comparison to isolated orthotopic small-bowel and liver grafts, Multivisceral isografts and allografts were transplanted to Lewis rats. and the histopathologic changes were studied in the liver. intestine. and other constituent organs. Rats receiving isografts had indefinite survival with maintenance of weight. With multivisceral allografts (from Brown-Norway donors). the intestinal component was rejected more severely than the companion liver and with about the same severity as when intestinal transplantation was performed alone. Intestinal rejection in either circumstance was a lethal event. causing death in 10 to 12 days. The earliest (by day 4) and most intense cellular rejection was in the Peyer's patches and mesenteric lymph nodes. This was associated with or followed by cryptitis. epithelial cell necrosis. focal abscess formation. mural necrosis. and eventual perforation. Liver allografts transplanted alone or as part of multivisceral grafts also had histopathologic evidence of rejection. but this was self-limiting and spontaneously reversible when the liver was transplanted alone. Thus the Achille's heel of multivisceral grafts is the intestinal component that is not protected by the presence of the liver in the organ complex. Better immunosuppression should permit successful experimental and clinical transplantation of such grafts.
Molecular biology of circulatory shock. Part III. Human hepatoblastoma (HepG2) cells demonstrate two patterns of shock-induced gene expression that are independent, exclusive, and prioritized, During shock and resuscitation. parenchymal cells of solid organs are exposed to a rapidly changing microenvironment. which may include a reduced oxygen tension and an increased concentration of certain cytokines including tumor necrosis factor alpha and interleukin-1. In vivo experiments that testedl iver biopsied from pigs undergoing cardiogenic shock and resuscitation demonstrated several patterns of gene expression. To study the independent and additive influences of hypoxia and of cytokines in vitro. human hepatoblastoma (HepG2) cells were perturbed by hypoxia/reoxygenation (H/R). by heat shock. and by the cytokines interleukin-1 and tumor necrosis factor alpha alone and in combination. H/R induces new patterns of protein synthesis and secretion that are indistinguishable from those induced by heat shock and independent of the acute-phase response mediated by the cytokines. The H/R (heat-shock) response has priority over and will extinguish gene expression supported by the cytokines. This previously unrecognized hierarchy of stress gene expression could well form the molecular basis of shock-related cell and organ failure.
Regression of intracardiac thrombus after embolic stroke, Using two-dimensional echocardiography. we studied the pathophysiology of intracardiac thrombus regression accompanied by anticoagulant therapy in 82 consecutive patients with acute cardiogenic cerebral embolism. We noted intracardiac thrombus in 15 patients; nine of the 15 were started on anticoagulant therapy with warfarin potassium to maintain the prothrombin time between 2.5 and 3.5 (international normalized ratio). Serial two-dimensional echocardiograms were obtained for these nine patients before and after anticoagulation. with the plasma levels of fibrinopeptide A. fibrinopeptide B beta 15-42. and D-dimer measured at the same time. In eight of the nine patients the intracardiac thrombi gradually decreased in size while the plasma level of fibrinopeptide A fell to within the normal range and the plasma levels of fibrinopeptide B beta 15-42 and D-dimer remained above the normal ranges. In the other patient the thrombus disappeared. with embolization to the right arm immediately after starting anticoagulant therapy. Mobile or small thrombi regressed earlier than nonmobile or large ones. We conclude that regression of intracardiac thrombi after anticoagulation may be based on the relative predominance of plasma fibrinolytic activity over anticoagulation-inhibited thrombin activity.
Correlation of clinical and computed tomographic findings in stroke patients, We evaluated the correlation between clinical features and computed tomographic findings in a prospective study of 1.191 consecutive patients with acute cerebrovascular disease seen during 1 year. In the 386 patients in whom symptoms and signs initially suggested a cerebrovascular disorder. computed tomography revealed a relevant lesion in 154 (hemorrhagic in 52 [33.8%]. ischemic in 102 [66.2%]) and a significant nonstroke abnormality in 14 (3.1%). Among the remaining 805 patients with symptoms and signs suggesting some central nervous system disorder other than stroke. computed tomography revealed a cerebrovascular lesion in 38 (4.7%); 35 of these lesions were ischemic. The computed tomographic findings was compatible with the final clinical diagnosis in 192 (84.2%) of the 228 patients with lesions. In the entire sample of 1.191 patients. a cerebrovascular disorder would have been missed in 38 (3.2%) without computed tomography. On the other hand. computed tomography failed to visualize a cerebrovascular lesion in 40 patients in whom such a lesion was clinically obvious. Our results emphasize that both careful neurologic assessment and a policy of early computed tomography are of crucial importance in the diagnosis of stroke and for therapeutic considerations.
Ultrasonic evaluation of early carotid atherosclerosis, We investigated the prevalence of carotid atherosclerosis. including mild early lesions. and its association with cervical bruits and various risk factors (age. male sex. hypertension. hyperlipidemia. diabetes mellitus. obesity. and cigarette smoking) in 232 consecutive Japanese patients. High-resolution real-time B-mode ultrasonography was performed to determine the extent of atherosclerosis. and it was quantified by using a scoring system. The prevalence of carotid atherosclerosis was 49%. 59%. and 41% in all 232 patients. the 100 symptomatic patients. and the 132 asymptomatic patients. respectively. Although carotid lesions were detected frequently (87%) in the 30 patients with cervical bruits. bruits were noted in only 30% of the 88 examined patients with carotid atherosclerosis. Independent risk factors for carotid atherosclerosis in these patients were found to be age. male sex. and hyperlipidemia; diabetes mellitus was a possible risk factor for carotid atherosclerosis. Our study did not show a close association between hypertension and carotid atherosclerosis. and this might be caused by the high prevalence of hypertension in our patients. Our findings suggest an increasing prevalence of carotid atherosclerosis in the Japanese. though this should be confirmed in a population-based study. Our study demonstrates the clinical usefulness of high-resolution B-mode ultrasonography for the evaluation of early carotid atherosclerosis.
Effect of ischemia induced by middle cerebral artery occlusion on superoxide dismutase activity in rat brain, Acute cerebral ischemia increases the generation of free radicals. causing cell damage. and theoretically may decrease the activity of the scavenging enzyme superoxide dismutase. To investigate the role of superoxide dismutase in cerebral ischemia. we used a model of middle cerebral artery occlusion in rats. In this model an infarct is produced in the pyriform and frontoparietal cortices. extending into the lateral basal ganglia. We measured superoxide dismutase activity by using the xanthine oxidase cytochrome c reduction assay in these areas of rat brains. Tissue samples were analyzed 20 minutes. 2. 6. or 24 hours. or 7 days after middle cerebral artery occlusion and 2 or 24 hours or 7 days after sham operation (n = 8-10 at each time). There was no significant change in superoxide dismutase activity relative to control values in any brain area at any time up to 24 hours after surgery. However. 7 days after middle cerebral artery occlusion a significant decline in superoxide dismutase activity. to 55%-68% (p less than 0.05) of that in unoperated controls. was observed in all brain areas. Our results do not support an important role for changes in the activity of endogenous superoxide dismutase during the acute phase of cerebral ischemia. However. the decrease in superoxide dismutase activity 7 days after ischemia could indicate ongoing additional damage to peri-infarct tissue.
Progressing cerebral infarction in relation to plasma glucose in gerbils, We studied neurologic morbidity and its evolution during hyperglycemia induced immediately after permanent unilateral common carotid artery ligation in Mongolian gerbils. A total of 60 animals were divided into five groups: one experiencing severe hyperglycemia for 1 hour after the onset of ischemia (brief hyperglycemia group. n = 13). a normoglycemic control group for the brief hyperglycemia group (n = 12). a group with severe hyperglycemia for 4 hours after the onset of ischemia (prolonged hyperglycemia group. n = 11). a normoglycemic control group for the prolonged hyperglycemia group (n = 13). and a hyperosmolar normoglycemic control group for the prolonged hyperglycemia group (n = 11). Neurologic morbidity and mortality were higher in the two hyperglycemic groups than in the three normoglycemic control groups. The neurologic deficit progressed according to the duration of severe hyperglycemia. In the three normoglycemic control groups neurologic status stabilized 120 minutes after the onset of ischemia. in the brief hyperglycemia group stabilization occurred at 210 minutes. and in the prolonged hyperglycemia group neurologic deficit progressed for approximately 360 minutes. coinciding with the death of all but one gerbil. in which the neurologic deficit remained stable until death 23 hours after ischemia. We suggest that hyperglycemia is another cause of progressing cerebral infarction.
Giant basilar aneurysm in the course of subacute bacterial endocarditis, We describe a man aged 42 years with mitral valve regurgitation who suffered from subacute bacterial endocarditis caused by Streptococcus morbillorum. The clinical picture began with a toxic syndrome. Five months later. the patient had an embolic episode and a right rostral pontine stroke. which was followed a few days later by an adversive focal seizure on the right. Despite antibiotic treatment. he suffered complete third nerve palsy. Arteriography. magnetic resonance imaging. and computed tomography of the brain showed a giant aneurysm in the rostral end of the basilar artery; the aneurysm was clipped. We discuss the clinical features. radiology. and characteristics of this aneurysm as a unique case of a giant bacterial aneurysm in the vertebrobasilar system.
Embolic stroke after smoking "crack" cocaine, A 39-year-old woman had an embolic upper division middle cerebral artery branch occlusion 3 hours after smoking the free base of cocaine ("crack"). Radionuclide ventriculography demonstrated cardiomyopathy. and echocardiography documented a left atrial thrombus. This case demonstrates that embolism is one mechanism of ischemic stroke after cocaine use. and that cardiomyopathy. possibly cocaine induced. may be the source of embolus. A cardiac source of embolus should be sought in patients with cocaine-associated cerebral infarction.
Protein phosphorylation during ischemia, Many investigations have shown that calcium and adenosine triphosphate are crucial to central nervous system functions. It is probable that alterations of these substances during central nervous system ischemia are involved in the processes that cause irreversible neural damage. Calcium regulates several protein kinases that are responsible for phosphorylation of proteins vital for many central nervous system functions. Using a rabbit spinal cord ischemia model. we found protein kinase C and calcium/calmodulin-dependent kinase were severely affected during the first hour of ischemia. Protein kinase A was not significantly affected. The time course of lost protein kinase C enzyme activity closely corresponded to irreversible loss of neurologic function. and there is evidence that protein kinase C inhibitor activity is generated. Also. drugs that inhibit protein kinase C increased neurologic damage when administered during the early phases of ischemia. These results suggest that protein phosphorylation. particularly by protein kinase C. is critical to maintenance of neurologic function.
Growth factor expression after stroke, Fibroblast growth factors are polypeptides with potent trophic effects on central nervous system cells. Both acidic and basic forms of fibroblast growth factor are found in the mammalian brain. We have examined the expression of these factors after focal brain injury or stroke. After infarction of the lateral cerebral cortex in the mature rat brain. we found a twofold to threefold increase during the first 3 weeks after stroke in levels of fibroblast growth factors in tissue surrounding infarcts. This increase persisted for at least 2 months and appeared mainly to be due to increased levels of basic. but not acidic. fibroblast growth factor. Because of its gliotrophic. angiogenic. and neuronotrophic properties. basic fibroblast growth factor may play an important role in the cascade of cellular reactions that contributes to wound healing and functional recovery after stroke.
Molecular biology of atherothrombotic brain infarction, Because reduced high density lipoproteins may contribute to atherothrombotic brain infarction. we performed molecular biologic and metabolic studies to characterize high density lipoprotein metabolism with respect to its role in reverse cholesterol transport. to clone the high density lipoprotein receptor. and to determine gene polymorphism for apolipoprotein A-I. the major protein of high density lipoprotein. because altered structure may impair reverse cholesterol transport. For high density lipoprotein metabolism measurements. high density lipoprotein 3 was isolated. purified. and labeled with iodine-125. The radiolabeled high density lipoprotein 3 was reinjected. and daily blood samples were taken for 10 days. Synthesis rates and fractional catabolic rates were determined from the specific activities and daily decrements. Preliminary data indicate that stroke-prone individuals' fractional catabolic rates for high density lipoprotein 3 are twice those of normal individuals. Also. the conversion of high density lipoprotein 3 to high density lipoprotein 2 is reduced in these individuals. suggesting that high density lipoprotein may be abnormally processed in individuals prone to atherothrombic brain infarctions. We surveyed more than 100 patients with carotid stenosis using a 2.2-kb probe for the apolipoprotein A-I gene. A subset of these patients displays polymorphism with restriction enzymes SacI or PstI. These preliminary findings suggest that gene polymorphism for apolipoprotein A-I may provide a molecular clue of atherothrombic brain infarction.
Pharmacology of recovery after stroke, Laboratory research during the past decade has begun to provide insights into the neurobiologic basis of functional recovery after brain injury. It is clear that drugs influencing specific neurotransmitters also can influence the recovery process. Some of these drugs may be beneficial. but others may be detrimental. Some of the difficulties in interpreting the results of these behavioral studies are reviewed. and potential mechanisms of drug effects are discussed. These types of studies are leading to an increased awareness of the potentially harmful effects of some drugs often given to stroke patients. Pharmacotherapy designed to enhance functional recovery after stroke may be possible in the future.
Influence of amphetamine treatment on somatosensory function of the normal and infarcted rat brain, The consequences of acute amphetamine administration on the metabolic responsiveness of the cerebral cortex to physiologic activation were studied in normal and infarcted rats. Treated rats received a 4 mg/kg intravenous injection of d-amphetamine 1 hour before unilateral vibrissae stimulation and 2-deoxyglucose study. In nontreated normal rats. metabolic activation was restricted to the major relay stations of the vibrissae-barrel circuit. In amphetamine-treated rats. stimulation-induced increased glucose utilization was widespread. including ipsilateral and contralateral cortical regions outside the barrel field circuit. For example. an 84% increase in glucose utilization above control was seen in cortical areas anterior to the barrel field region. Increased glucose utilization induced by stimulation was severely depressed in nontreated rats that had undergone infarction of the left cortical barrel field 2 weeks previously. Vibrissae stimulation failed to increase glucose utilization significantly in cortical areas remote from the infarct. In contrast. bilateral increases in glucose utilization were observed within cortical regions of treated infarcted rats. For example. a 50% increase in glucose utilization was detected in cortical areas bordering the infarct. Thus. in the normal and infarcted rat. amphetamine appears to promote alternate circuit activation--a pharmacologic property that may be advantageous for recovery after injury.
Effects of MK-801 on recovery from sensorimotor cortex lesions, Histologic evidence suggests that drugs acting as noncompetitive antagonists at the N-methyl-D-aspartate receptor can have beneficial or pathologic effects on central nervous system neurons. In the present experiments we examined the effects of MK-801 on recovery of behavioral function after unilateral lesions in the rat somatic sensorimotor cortex. In the first experiment. rats with unilateral sensorimotor cortex lesions were given either MK-801 (1 mg/kg) or saline 12-16 hours after surgery. Additional injections were given on postoperative days 2. 4. and 6. Behavioral tests measured somatosensory asymmetries (i.e.. bilateral tactile stimulation tests) and forelimb placing. After creation of sensorimotor cortex lesions. rats showed an ipsilateral somatosensory bias and an impairment in placing the contralateral forelimb. Rats treated with MK-801 recovered slightly faster than saline-treated animals as measured by a bilateral tactile stimulation test (p less than 0.05). In contrast. there was no significant difference between the groups in the recovery of forelimb placing. In a second experiment. rats with sensorimotor cortex lesions were treated with a single injection of MK-801 after behavioral recovery. Twenty hours after the MK-801 injection. rats with sensorimotor cortex lesions showed a reinstatement of the placing deficits. The impairment endured for at least 7 days after injection. These behavioral data support the idea that MK-801 can have either beneficial or detrimental effects when administered after brain damage.
Ionic channels, cholinergic mechanisms, and recovery of sensorimotor function after neocortical infarcts in rats, Unilateral photochemical infarcts were produced in the hind limb sensorimotor neocortex of 243 rats by intravenous injection of the fluorescein derivative Rose Bengal and focal illumination of the intact skull surface. Facial contact stimuli governed the degree and recovery rate of contralateral tactile/proprioceptive forelimb placing reactions. Contralateral forelimb placing recovered. whereas hind limb placing was resistant to recovery. Infarcted rats displayed marked recovery of spontaneous limb usage (beam traversing). However. deficits in isolated tactile/proprioceptive hind limb placing reactions endured. Posttreatment with the class IV calcium antagonist flunarizine after neocortical infarction protected sensorimotor function in a dose-dependent manner. This protective effect may be due to the peculiar ionic channel blocking profile of flunarizine. Scopolamine hydrobromide reinstated contralateral placing errors in infarcted rats at a dosage that did not affect neurologically intact rats. The cognitive enhancer sabeluzole. a novel benzothiazol derivative. dose-dependently blocked the anticholinergic-induced deterioration of a sensorimotor deficit in rats.
Magnetic resonance imaging demonstrates that electric stimulation of cerebellar fastigial nucleus reduces cerebral infarction in rats, We sought to determine whether high spatial resolution magnetic resonance imaging is useful for noninvasive quantitation of the ischemic infarct produced by occlusion of the middle cerebral artery and for detection of reduced infarct volume elicited by electric stimulation of the cerebellar fastigial nucleus. Male rats of the spontaneously hypertensive strain were anesthetized. the middle cerebral artery was occluded. and the fastigial nucleus was stimulated for 1 hour. Twenty-four hours later. rats were reanesthetized and T1- and T2-weighted images were obtained. Rats were killed and the volume and distribution of the lesion was established by histopathology. Magnetic resonance imaging estimates of the lesion volume were 271 +/- 41.0 mm3 (middle cerebral artery. n = 5) and 148 +/- 8.4 mm3 (middle cerebral artery + fastigial nucleus stimulation. n = 6; 45% reduction. p less than 0.05). Histopathological analysis revealed a lesion of 229.8 +/- 15.4 mm3 involving somatosensory cortex. lateral caudate putamen. and lateral hippocampus. Fastigial nucleus stimulation resulted in a 36% reduction in infarct volume to 146.0 +/- 10.3 mm3. The retrieved zone was largely in the cortex dorsal and ventral to the lesion and mostly posterior to the lesion. The estimates of lesion volume by magnetic resonance imaging and histopathology did not differ and were highly correlated (r = 0.90; p less than 0.001). This study confirms our previous finding that fastigial nucleus stimulation reduces the volume of a focal ischemic infarct and demonstrates that magnetic resonance imaging not only accurately estimates the volume of the lesion but also can detect changes as small as 50-100 mm3.
Spreading depression-like depolarization and selective vulnerability of neurons. A brief review, If oxygen is withdrawn from rat hippocampal slices. a spreading depression-like response occurs earlier and is of larger amplitude in the CA1 area than in the dentate gyrus. After reoxygenation. recovery of synaptic transmission correlates inversely with the time spent in spreading depression. Recovery occurs more frequently in dentate gyrus than in CA1. Chlorpromazine and the gangliosides GM1 and AGF2 promote recovery from hypoxic depression of synaptic transmission in CA1. Prevention of irreversible loss of function correlates closely with a shortening of the time spent in spreading depression. If Ca2+ is withdrawn before hypoxia. then synaptic function recovers upon restoration of oxygen and [Ca2+]o. despite prolonged spreading depression. When spreading depression lasting more than 6-9 minutes is induced in fully oxygenated slices by superfusion with high-K+ solution. then transient recovery is followed by long-lasting loss of synaptic function. In intact brain of anesthetized rats. synaptic transmission in CA1 recovers after spreading depression-like depolarization lasting more than 30 minutes. but is lost irreversibly after 60 minutes. We conclude that entry of Ca2+ into neurons caused by spreading depression-like depolarization is important in the selective vulnerability of neurons; the duration of depolarization is critical to cell survival; and in the presence of a normal blood supply. neurons resist protracted spreading depression-like depolarization.
Symptomatic carotid endarterectomy trials, The possible benefit of carotid endarterectomy in stroke prevention is being evaluated in three major clinical trials. To date. the European Carotid Surgery Trial has randomized 2.200 patients. 30% of whom have a carotid stenosis of greater than 70% appropriate to their symptoms. The North American Symptomatic Carotid Endarterectomy Trial has randomized 1.000 patients. of whom more than half have this severity of appropriate stenosis. Quality control and the evaluation of outcome events in this trial is achieved by a three-tier review. including review by medical and surgical adjudicators who are blinded to the treatment arm of each patient. Baseline characteristics of the patients eligible but not randomized are similar to those of patients who have been randomized. Two percent of the patients randomized to the surgical arm have declined surgery and crossed over to the medical arm. and 3% have elected surgery after randomization to the medical arm. Both of these studies. as well as a Veterans Administration trial. are continuing to randomize patients.
Possible mechanisms limiting N-methyl-D-aspartate receptor overactivation and the therapeutic efficacy of N-methyl-D-aspartate antagonists, Cytotoxic overactivation of neuronal N-methyl-D-aspartate receptors is postulated to contribute to the pathogenesis of neuronal loss in hypoxia-ischemia. However. several events associated with hypoxia-ischemia may limit N-methyl-D-aspartate receptor-mediated injury. Perhaps the most important of these events is the development of extracellular acidosis. These limiting events may help explain why N-methyl-D-aspartate receptors contribute to injury more in focal ischemia or hypoxia in vitro than in global ischemia.
Comparison of phenytoin with noncompetitive N-methyl-D-aspartate antagonists in a model of focal brain ischemia in rat, Recent in vitro and in vivo experiments have suggested that excitatory amino acid antagonists. particularly those active at the N-methyl-D-aspartate receptor subtype. are effective in ameliorating ischemic injury due to their antiexcitotoxic activity. However. these drugs are also potent and effective in vivo anticonvulsants. The present experiments compared the noncompetitive N-methyl-D-aspartate antagonists phencyclidine and MK-801 with the anticonvulsant phenytoin in a model of focal brain ischemia. Fisher F-344 rats were subjected to tandem occlusion of the middle cerebral and ipsilateral common carotid arteries under halothane anesthesia. Compounds were administered intravenously 30 minutes and 24 hours after arterial occlusion; infarct size was assessed at 48 hours after occlusion. Phencyclidine had no effect on infarct volume at 1 mg/kg. significantly reduced (by 36%) infarct volume at 3 mg/kg. and produced a nonsignificant 26% decrease at 10 mg/kg. The more potent and selective noncompetitive antagonist MK-801 reduced (by 32%) infarct volume significantly at 0.1 mg/kg. produced a nonsignificant 23% decrease at 0.3 mg/kg. and had no effect at 0.5 mg/kg. Phenytoin. which is not a glutamate antagonist. reduced the infarct volume by 45% at 28 mg/kg. A single dose of phenytoin (28 mg/kg) administered 30 minutes after occlusion was neuroprotective. but delaying drug administration for more than 2 hours was ineffective. These data suggest that blockade of the N-methyl-D-aspartate receptor is effective in reducing the infarct size after focal cerebral ischemia. The neuroprotective activity of phenytoin suggests that this may be related to the common anticonvulsant action.
Putative neuroexcitation in cerebral ischemia and brain injury, Involvement of neuroexcitatory mechanisms in cerebral ischemia and brain injury was explored in experimental models of repetitive forebrain ischemia by temporary occlusion of carotid arteries in gerbils and cryogenic injury to the cerebral cortex in rats and gerbils. Our observations in these models revealed a pattern of injury that involved some anatomic structures outside the areas of direct ischemic or traumatic insult. Such foci of injury revealed conspicuously abnormal uptake of 45Ca associated with slight or moderate neuronal alteration. whereas severely injured areas showed no 45Ca uptake. Electron microscopic observations revealed a characteristic presence of calcium in swollen dendrites. closely resembling pictures obtained in neuroexcitatory conditions such as epileptic seizures. Abnormal uptake of 45Ca was associated with apparent blood-brain barrier changes characterized by intracytoplasmic uptake of extravasated albumin into the neurons. Protein synthesis assayed by in vivo [3H]leucine incorporation was reduced in regions showing calcium accumulation. Our observations suggest that neuroexcitation may play an important role in development of secondary and chronic changes after ischemic or traumatic brain insults.
Platelet-activating factor. A putative mediator in central nervous system injury, Platelet-activating factor (1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphorylcholine) is a potent lipid autacoid produced by many cell types. Platelet-activating factor is produced by cerebellar granule cells in culture and has been extracted from brain tissue. Multiple platelet-activating factor receptors have been demonstrated in brain tissue. Activation of platelet-activating factor receptors in transformed neuronal cell lines involved increases in intracellular calcium. Platelet-activating factor has potent actions on cerebral vessels and cerebral metabolism when administered in vivo. but may not have direct effects on brain microvessels. Excessive platelet-activating factor production in pathological states of the nervous system such as neurotrauma and stroke has been shown in only a few models (e.g.. spinal cord ischemia and reperfusion or focal repercussion brain injury). In multiple studies using highly specific and potent platelet-activating factor antagonists. reversal or prevention of key consequences of brain injury such as hypoperfusion following ischemia. reperfusion and edema. inflammatory cell accumulation. neurologic/motor deficits. and neuronal salvage were demonstrated. This review provides and analyzes evidence in support of the role that platelet-activating factor might have in modulation of brain function and pathophysiological processes in brain ischemia and trauma.
The prevalence of antibody to HTLV-I/II in United States plasma donors and in United States and French hemophiliacs, Antibody to HTLV-I/II was detected in 19 (0.3%) of 6286 plasma donors from five regions of the United States (US). This seroprevalence rate is approximately 10 times that in whole blood donors. The regional distribution of infection was as follows: Southwest. 0.68 percent; Southeast. 0.45 percent; Midwest. 0.28 percent; Northwest. 0.1 percent; and Northeast. 0.0 percent. Rates of HTLV-I/II infection in blacks (0.74%) and Hispanics (0.66%) were higher (both. p less than 0.001) than those in whites (0.08%). All 19 infected units were donated by subjects aged 30 or older. even though 52.9 percent of the donations came from persons less than 30 years old. Equal rates of HTLV-I/II infection were found in men (0.31%) and women (0.29%). No HTLV-I/II antibody was detected in 154 French and 25 US hemophiliacs who were transfused regularly with noninactivated plasma or its derivatives. This suggests that the transfusion of HTLV-I/II-seropositive plasma products does not transmit the viral infection.
American blood donors seropositive for human T-lymphotropic virus types I/II exhibit normal lymphocyte subsets, Recent reports have demonstrated that some lymphocyte subsets are abnormal in Japanese blood donors who are seropositive for human T-lymphotropic virus type I (HTLV-I). To determine if similar changes characterize American blood donors who are seropositive for HTLV-I/II. lymphocyte subsets were measured in 42 HTLV-seropositive and 42 HTLV-seronegative blood donors. The seronegative individuals were matched by age. race. and gender to the seropositive individuals. Peripheral blood mononuclear cells were treated with a panel of 12 monoclonal antibody pairs and then analyzed by two-color flow cytometry. No significant differences were observed between the seropositive and seronegative groups with respect to the absolute number of circulating lymphocytes or the percentages of lymphocytes belonging to the subsets assessed. These subsets included B. T. CD4. and CD8 cells and subpopulations of CD4 and CD8 cells defined by the coexpression of markers that appear (CD25. HLA-DR. CD38) or disappear (Leu 8. CD45RA) after activation. These findings indicate that HTLV-seropositive persons in the American blood donor pool do not exhibit the lymphocyte subset alterations reported for HTLV-I-seropositive blood donors in Japan.
Viral infections in transfusion-dependent patients with beta-thalassemia major: the predominant role of cytomegalovirus, For 9 months. 38 transfusion-dependent patients with beta-thalassemia. ranging in age from 3.4 to 19.1 years. were observed for serologic evidence of viral infections. by the collection of serial serum samples. Seventy-six age-matched healthy subjects. two for each patient. were followed as controls. Samples taken at the beginning. middle. and end of the study were tested against 18 viral antigens by complement fixation (CF). In addition. tests for antibodies to HIV. Epstein-Barr virus. hepatitis A virus. and markers for hepatitis B virus were performed. When changes in the antibody titer on CF tests (greater than or equal to 2-fold increase or decrease) or persistently high titers (greater than or equal to 64) were revealed. specific enzyme immunoassays (EIAs) for IgM and IgA antibodies were performed concomitant with CF tests in all sera. When symptomatic infections occurred. viral cultures and/or direct detection of antigens were carried out by immunofluorescence methods. EIA. or latex agglutination tests. Thalassemic patients and controls had similar (p greater than 0.05) overall rates of serologically confirmed viral infections (53 versus 132). but the former group had a higher (p less than 0.01) incidence of cytomegalovirus (CMV) infections (9 versus 4). CMV infections were associated in the thalassemic patients with hepatitis (2 cases). lymphadenitis (2 cases). and upper respiratory tract infection (1 case). while the remaining cases of CMV had a subclinical course. Moreover. the thalassemic patients had a lower (p less than 0.01) incidence of symptomatic infections (27 versus 110) than controls. Therefore. this study showed that both symptomatic and subclinical CMV infections may occur often in thalassemic patients. who otherwise have subclinical viral infections at an overall rate similar to that in healthy subjects.
Evaluation of the manual hexadimethrine bromide (Polybrene) technique in the investigation of autoimmune hemolytic anemia, The use of the direct manual hexadimethrine bromide (Polybrene) test (DPT) in the investigation of patients for autoimmune hemolytic anemia (AIHA) was evaluated. Seventy-nine blood samples from 68 patients were tested. A direct antiglobulin test (DAT) using monospecific reagents and the DPT were performed. and a concentrated ether eluate was tested. The DAT was positive in 62 (78%) of 79 patients and negative in 17 (22%). There is a good correlation among DAT. eluate. and DPT in demonstrating the presence of immunoglobulin on the red cell surface. In contrast. the DPT does not detect C3d and is often negative in cases of AIHA in which C3d alone is demonstrated by the DAT. In DAT-negative cases. DPT results correlated with reactive eluates. However. in four cases of steroid-responsive. DAT-negative hemolytic anemia. the DPT supported the diagnosis of AIHA when the eluate did not react. The DPT is a useful additional screening test for the investigation of AIHA. but it is not recommended as a replacement for either eluate testing or the DAT.
Life-threatening, antiglobulin test-negative, acute autoimmune hemolytic anemia due to a non-complement-activating IgG1 kappa cold antibody with Pra specificity, A 21-year-old man with fulminant cold autoantibody hemolytic anemia (CAHA) was hospitalized with hemoglobinemia. hemoglobinuria. hemoglobin concentration of 3.3 gm per dL. a negative direct antiglobulin test (DAT) with polyspecific and anti-C3d reagents. a negative Donath-Landsteiner test. and a cold agglutinin titer of 80. He failed to respond to corticosteroids. multiple plasma exchanges. and cyclophosphamide; he required 54 transfusions in 10 days to maintain a hemoglobin concentration of 6.0 to 10.0 g per dL. He improved dramatically after a splenectomy was performed. The wide-thermal-amplitude cold agglutinin proved to be an IgG1 kappa antibody with Pra specificity. The patient's serum exhibited normal complement activation. When the DAT was carried out at 0 to 4 degrees C. the result was strongly positive for IgG; the indirect antiglobulin test at 0 to 4 degrees C was positive with the patient's serum diluted 1 in 640. Within 6 months. he was in complete remission and receiving no therapy. As compared with eight patients with CAHA that was exclusively IgG-mediated. this patient is remarkable for his requirement for many transfusions and for DATs that were consistently negative for C3d.
Whole bladder photodynamic therapy: critical review of present-day technology and rationale for development of intravesical laser catheter and monitoring system, Present-day whole bladder photodynamic therapy (WBPDT) is cumbersome and time consuming because cystoscopic and ultrasonic manipulations are necessary to position the light emitter within the bladder. More important. WBPDT is inherently unsafe and often ineffective since neither uniform photoirradiation nor accurate light dosimetry can be achieved with the techniques employed to photoirradiate the bladder wall. The intravesical laser catheter (IVLC) eliminates the need for cystoscopy and ultrasonography because passage of the treatment fiber into the catheter's central lumen automatically positions its light-diffusing tip within the center of the bladder. Use of the IVLC delivery system also assures accurate photoirradiation of the bladder wall since inflation of the catheter's balloon transforms the asymmetric bladder into a sphere of known diameter. The light sensor incorporated in the balloon wall provides a method to monitor light fluence and measure total light dose. When provided the parameters of bladder volume. laser energy output. and desired light dose. the computerized control system calculates treatment time and automatically adjusts the period of photoirradiation to compensate for variations in laser light production. energy losses during transmission. and for variations in light intensity resulting from the integrating sphere effect of the bladder wall. This delivery system also increases the safety of WBPDT since the monitor automatically discontinues treatment if any unsafe situation. with respect to light fluence. develops during photoirradiation.
Stress incontinence: a new endoscopic approach, We describe our experience in using a new endoscopic technique for suspending the bladder neck and urethra in 16 patients with stress incontinence. The procedure was started by dissecting the retropubic space. first with a sound and then with a Foley catheter before passing an absorbable suture from the abdominal fascia to the bladder neck using an elbowed needle introduced into the bladder through the neck and exteriorized through the urethra. The dissection of the retropubic space helped to form postoperative adherences which fixed the bladder neck and the urethra firmly to the pubic symphysis. The technique is simple. it does not require vaginal surgery. and the incidence of complications is minimal.
Prognostic implications of disappearance rate of biologic markers following radical prostatectomy, Six patients with localized prostatic carcinoma undergoing radical prostatectomy were studied by serial sample collection from the time of surgical removal of the prostate up to one week in the postoperative period. Of the three markers studied (PAP. PSA. LASA). half-life of specific prostatic markers were calculated. Half-life of PAP was found to be 7.25 hours +/- SE of 0.7 hours. For PSA the half-life could be obtained in 4 of 6 patients and was found to be 45.5 hours +/- SE 4.9 hours. In 2 patients PSA did not fall in a regular fashion and half-life could not be obtained. In both patients metastatic disease has developed within six months of surgery. LASA demonstrated progressive increase following surgery. most likely due to associated inflammatory reaction. These studies confirm previous observations that PSA is a more sensitive marker than PAP. and that the presence of an elevated PSA after radical prostatectomy denotes the presence of residual disease.
Use of distal Thiersch-Duplay urethroplasty for proximal hypospadias repairs in conjunction with short island pedicle flap, Experience with 8 boys having proximal hypospadias with severe chordee and a foreshortened dorsal hooded foreskin is presented. Use of a distal Thiersch-Duplay tube was incorporated in addition to an island pedicle flap to achieve the correct meatal location on the glans. One boy with perineal hypospadias required both proximal and distal Thiersch tube with an island flap interposition. Follow-up of nine months to 3.5 years demonstrated excellent cosmetic and functional results with no recurrent chordee or urethral stenosis. The only fistula noted developed at the proximal Thiersch tube-island flap anastomosis in the boy with perineal hypospadias. Advantages of the aforementioned procedure include decreasing the risk of chordee on the basis of a foreshortened island pedicle flap. use of vascularized flaps. and completing the procedure in one stage with a satisfactory result.
Magnetic resonance imaging of cystic, partially differentiated nephroblastoma, The magnetic resonance imaging (MRI) appearance of a cystic. partially differentiated nephroblastoma is described. together with pathologic correlation. The difficulty in reaching a correct preoperative diagnosis even with multimodal imaging techniques is emphasized. MRI is an adjunct to ultrasonography and may be superior to computerized tomography (CT) scan in the evaluation of a child with multiloculated cystic renal mass.
Urodynamic tests for female geriatric urinary incontinence, Most urodynamic tests currently in use in the evaluation of female urinary incontinence have not been applied to a community-based sample to determine their specificity. In this study of a random sample of noninstitutionalized elderly. 258 self-reported continent and 198 self-reported incontinent women sixty years and older. who participated in a household survey. underwent a clinic evaluation (history. physical examination. and urinalysis); of these 67 continent and 100 incontinent female respondents underwent urodynamic testing. The uroflowmetry. cystometry. and supine static urethral pressure profilometry (UPP) findings did not differ significantly between continent and incontinent subjects (whether based on a self-report or a clinician's diagnosis of urinary continence status). Standing static and dynamic UPP and lateral cystography showed significant differences between self-reported continent and incontinent respondents. The provocative stress test significantly distinguishes continence from incontinence. and stress incontinence from other types. The sensitivity of the provocative stress test was 39.5 percent. whereas its specificity is 98.5 percent. Urodynamic testing including uroflow study. static UPP. and lateral cystography should not be used as a screening test but rather selectively as a confirmatory test. and to determine the therapeutic approach. and to assess the outcome of therapy.
Influence of high-energy shock waves and cisplatin on antitumor effect in murine bladder cancer, The potential application of high-energy shock waves (HESW) for control of experimental bladder cancer was investigated. Subcutaneous 3-d murine bladder cancer (MBT-2) in C3H mice were exposed to HESW alone (250 to 1.500 shocks) or in combination with cisplatin (5 to 10 mg/kg. i.p.). Although HESW alone showed no influence on tumor growth. HESW/cisplatin combination therapy suppressed tumor growth more than cisplatin alone. Subsequent studies revealed that an air-fluid interface relative to tumor location played a pivotal role for the chemosensitizing effect of HESW. HESW treatment was able to enhance the cisplatin cytotoxicity only when the tumors were placed adjacent to the air-fluid interface.
Constitutional symptoms in patients with germ cell neoplasms, A patient with a mediastinal germ cell neoplasm evidenced fever. weight loss. pruritus. and painful adenopathy on ingestion of alcohol. Retrospective review revealed that 9 percent of 104 patients with advanced germ cell neoplasm evidence constitutional symptoms at presentation.
In treating impotence, urology and sex therapy are complementary, Urologists and mental health professionals are neither competitors nor adversaries. The principles of sex therapy represent a thoughtful and sensitive way to approach patients with almost any clinical problem so that they are more comfortable with the recommended tests or treatments. Sex therapy may be very helpful as an adjunct in treating "organic" as well as primarily emotional erectile dysfunction. We believe that with information we can help build a bridge between urologists and mental health professionals.
Applications of prostate ultrasonography, Transrectal ultrasonography is a relatively new imaging modality that may be useful in the evaluation and management of patients with prostate cancer. Although cancer may have a characteristic appearance. it cannot always be reliably differentiated from benign conditions. While this technique has clinical applications in staging. monitoring tumor response to therapy. and assisting in biopsy. it is unclear as to whether useful information is obtained in the evaluation of patients with palpable disease. The role of transrectal ultrasonography in patients with nonpalpable disease or as a screening tool has yet to be determined. Other diagnostic tests in conjunction with ultrasound may in the future prove to be useful. Carefully performed prospective investigations with state-of-the-art equipment are still needed to further define the role of this diagnostic modality.
Measles update, The incidence of measles in the United States dramatically increased in the 1980s. from a low of 1.497 cases in 1983 to over 17.000 cases in 1989. Family physicians can help reverse this trend by following the revised immunization schedule. which includes a measles-mumps-rubella (MMR) booster for preschool-age children. New guidelines also recommend that either the two-dose MMR schedule or serologic evidence of immunity be required for all persons entering college or employed in the medical field. Immunization policies for physician's offices should ensure that all office staff have acquired measles immunity and that a triage policy separating patients with rash from those with other illnesses is utilized. Mild upper respiratory illness. a history of seizures. nonanaphylactic egg allergy and asymptomatic human immunodeficiency virus infection are not contraindications to measles vaccine. All cases of measles should be reported to the local health department.
Coarctation of the aorta, Coarctation of the aorta is a common cardiovascular disorder with an unknown etiology. In the preductal type. blood flows from a patent ductus into the distal aorta. When the coarctation is juxtaductal or postductal. blood flows to the lower extremities by way of the subclavian arteries and collaterals. Plain films may show the reverse sign in postductal coarctation. Arteriography is the gold standard for making the diagnosis. However. magnetic resonance imaging will probably become an increasingly important diagnostic tool. The treatment of choice is surgery. with complete resection of the stenosed segment.
Estrogen prophylaxis. The U.S. Preventive Services Task Force, Recommendation: Although routine postmenopausal estrogen replacement is not recommended. estrogen therapy should be considered for asymptomatic women who are at increased risk for osteoporosis. who lack known contraindications and who have received adequate counseling about potential benefits and risks.
Venous ulcers: pathophysiology and medical therapy, Venous ulcers may occur as a result of lower extremity calf pump failure. with ensuing edema. trapping of white blood cells and deposition of pericapillary fibrin. Acute. smaller lesions are easily treated with adequate compression and occlusive dressings. Larger. more chronic wounds often benefit from some form of external compression. Occlusive dressings and local wound care are most effective when used simultaneously with compression. Sequential compression pumps merit study and may prove to be of therapeutic and prophylactic value. In refractory cases. long-term use of compression devices may be required to prevent ulcer recurrence.
Constipation: pathophysiology and treatment, Although many physicians consider constipation a trivial problem. it is one of the most frequent and chronic digestive disorders in the United States. affecting 4.53 million people and causing considerable morbidity. More than $200 million are spent for over-the-counter laxatives and untold millions of dollars are spent for prescription drugs and other medical services to manage this disorder. Successful management requires an appreciation of the magnitude of the problem. an understanding of colorectal function and a clear assessment of the causes. Careful examination of the patient's anorectal anatomy and improvement in the patient's dietary habits are the first steps in management. Therapeutic options include behavioral modification strategies. diet and lifestyle changes. pharmacologic therapy and. rarely. surgical intervention.
Tartrazine sensitivity, Tartrazine (FD & C Yellow No. 5) is an approved azo dye present in many drugs and food products. During the 1970s. many cases of tartrazine sensitivity were reported. This led to new regulations that required the listing of azo dyes on package inserts of drugs and on packages of food products. Tartrazine sensitivity is most frequently manifested by urticaria and asthma. Although azo dyes have been implicated in accentuating hyperkinetic syndromes. tartrazine is not considered an offender. Vasculitis. purpura and contact dermatitis infrequently occur as manifestations of tartrazine sensitivity. Cross-sensitivity in aspirin-sensitive and NSAID-sensitive patients may also occur. The mechanism of sensitivity is obscure and has been called pseudoallergic. Management consists mainly of avoidance of drugs and food products that contain tartrazine.
Silent myocardial ischemia: dilemma or blessing, Developing an optimal strategy for the evaluation and management of patients with silent myocardial ischemia is extremely difficult. Although otherwise healthy. asymptomatic individuals may be at risk of dying suddenly during exercise. neither exercise testing nor Holter monitoring reliably identifies those at greatest risk. In patients with underlying coronary artery disease. silent ischemia increases the risk of an adverse outcome.
Approaching the protein-sparing modified fast, The protein-sparing modified fast is a safe and effective method for losing a large amount of weight relatively quickly. This diet should be used in combination with an exercise program. behavior modification and patient education. Caloric intake is in the range of 400 to 800 per day. Candidates for the diet should be generally healthy; they should have at least 40 lb to lose or be at more than 120 percent of their ideal body weight.
Persistent uptake of indium-111-antimyosin monoclonal antibody in patients with myocardial infarction, Indium-111(111In)-antimyosin scintigraphy was investigated in 27 patients with myocardial infarction. 111In-antimyosin Fab was administered intravenously. and planar and single photon emission computed tomographic images were obtained 48 hours later. Uptake of 111In-antimyosin was present in 9 of 10 patients (90%) studied within 6 days of infarction. During the second week positive scans were seen in 16 of 16 patients (100%) including 13 (81%) who had normal creatine kinase levels. The mechanism of persistent positive antimyosin images in the subacute stage of myocardial infarction remains to be clarified. 111In-antimyosin scintigraphy may be useful as a noninvasive method for the detection of myocardial injury late and early after a suspected acute myocardial infarction.
Coronary perfusion catheter: its effectiveness in an experimental model of acute coronary occlusion, The effectiveness of a coronary perfusion catheter was studied in an animal model of acute coronary occlusion. Systemic hemodynamic variables. regional myocardial blood flow (RMBF) in the subepicardium and subendocardium. and regional systolic function (systolic segmental shortening) of the area perfused by the circumflex coronary artery (CX) were measured in eight anesthetized dogs. After baseline measurements. the CX coronary artery was occluded with a silk snare and measurements were repeated after 5 minutes of ischemia (occlusion No. 1). The snare was released and 1 hour later the snare occlusion was repeated after placement of a perfusion catheter in the CX coronary artery. After 5 minutes. measurements were repeated (occlusion No. 2). To determine the long-term effectiveness of the catheter. hemodynamic variables and regional function measurements were then obtained every 15 minutes for a total of 60 minutes. During occlusion No. 1. RMBF decreased from 1.30 +/- 0.20 to 0.41 +/- 0.13 ml.min-1.gm-1 (p less than 0.01). and subendocardial RMBF decreased from 1.44 +/- .24 to 0.34 +/- 0.15 ml.min-1.gm-1 (p less than 0.01). After insertion of the perfusion catheter (occlusion No. 2). subepicardial RMBF was maintained at 0.97 +/- 0.16 and subendocardial RMBF was maintained at 0.78 +/- 0.13 ml.min-1.gm-1; during occlusion No. 2 subepicardial RMBF was greater (p less than 0.05) than occlusion No. 1 and was not different from baseline.
Dose-dependent reduction of myocardial infarct size with the perfluorochemical Fluosol-DA, The perfluorochemical Fluosol-DA has been shown to reduce infarct size. However. the dose-response relationship of the agent is unknown. Because perfluorochemicals (PFC) can potentially saturate the reticuloendothelial system and decrease carbon clearance as well as cause a transient elevation in liver enzymes. the present study was conducted to determine the lowest effective dose. New Zealand White rabbits (n = 73) were randomly selected prior to infarction to receive 10. 15. 20. 25. or 30 ml/kg PFC or an equivalent volume of 5% dextran (control) intravenously. Animals underwent 30 minutes of coronary artery occlusion with PFC or dextran infused over a 30-minute period starting at 20 minutes into the occlusion. Animals were put to death at 24 hours and infarct size was determined histologically and quantitated by computerized planimetry. Neutrophil infiltration into the ischemic myocardium was evaluated semiquantitatively. No hemodynamic differences were noted within groups. Infarct size was similar to that of controls in animals treated with 10 or 15 ml/kg PFC. Significant infarct size reduction. however. was noted in animals treated with 20. 25. and 30 ml/kg PFC versus controls; (p = 0.05. 0.04. and 0.02. respectively). Maximal infarct size reduction was seen with 30 ml/kg PFC (35%). Neutrophil infiltration was significantly decreased in all groups treated with PFC. These results show that intravenous Fluosol-DA significantly reduces infarct size at a minimal dose of 20 ml/kg.
Left ventricular asynchrony: an indicator of regional myocardial dysfunction, There is a marked heterogeneity of myocardial wall thickening within the left ventricle and among different individuals. It is therefore difficult to detect regional myocardial dysfunction from absolute values of systolic wall thickening. We tested whether the extent of left ventricular asynchrony during ischemia and reperfusion can be used to quantify the severity of regional myocardial dysfunction when nonischemic baseline function is not known. In six anesthetized. open-chest dogs regional myocardial wall thickness was measured by means of sonomicrometry under control conditions. at three degrees of ischemic dysfunction (mild. moderate. and severe). and after release of a 15-minute occlusion of the left circumflex coronary artery. when degrees of moderate and mild reperfusion dysfunction similar to the preceding ischemic dysfunction were present. Two indexes of left ventricular asynchrony were calculated: (1) postejection thickening (PET) and (2) the phase difference of the first Fourier harmonic of posterior versus anterior myocardial wall motion (PD). Systolic myocardial wall thickening was decreased from 15.3 +/- 3.1 (standard deviation) % (control value) to 9.7 +/- 1.4% (mild ischemia). 4.2 +/- 1.6% (moderate ischemia). and -3.7 +/- 3.1% (severe ischemia). Conversely PET increased from 0.02 +/- 0.04 mm (control value) to 0.15 +/- 0.22 mm (mild ischemia). 0.19 +/- 0.15 mm (moderate ischemia). and 0.50 +/- 0.26 mm (severe ischemia). PD increased from 9 +/- 28 degrees (control value) to 22 +/- 19 degrees (mild ischemia). 54 +/- 18 degrees (moderate ischemia). and 107 +/- 21 degrees (severe ischemia). After release of the 15-minute left circumflex coronary artery occlusion. PET and PD recovered to 0.34 +/- 0.19 mm and 36 +/- 24 degrees (moderate dysfunction) and 0.25 +/- 0.31 mm and 29 +/- 8 degrees (mild dysfunction). respectively. There were inverse linear relationships between systolic wall thickening and PET (r = -0.86. p less than 0.001) and between systolic wall thickening and PD (r = -0.87. p less than 0.001). Inotropic stimulation by postextrasystolic potentiation increased regional systolic myocardial posterior and anterior wall thickening but did not alter the extent of left ventricular asynchrony. Thus. when normal baseline function is not known. the severity of regional myocardial dysfunction at a given inotropic state can be determined by analysis of left ventricular asynchrony. There was no significant correlation between the extent of PET and PD during ischemia and at early reperfusion and the recovery of contractile function at late reperfusion. Thus PET does not provide a prospective marker for the functional outcome of reperfusion.
Detection and quantitation of ischemic left ventricular dysfunction using a new video intensity technique for regional wall motion evaluation, Eighty patients with ischemic heart disease and 17 normal subjects were evaluated for left ventricular regional wall motion by means of a new method. The wall motion analysis is based on video intensity. This technique uses a temporally sliding analysis to evaluate the cardiac cycle in 100 msec intervals. Presence of coronary artery disease was defined as more than 50% measured diameter stenosis. Wall motion abnormalities in regions perfused by stenotic vessels were most common in early diastole (76%). Sensitivity of this method at rest in patients with coronary artery disease was 79.7% (p less than 0.0001) and overall accuracy was 84.2% (p less than 0.0001). Abnormalities in both systole and diastole were more common in regions perfused by severe lesions (greater than 75%) than in those perfused by moderately stenotic (less than 75%) vessels (p less than 0.05). A comparison of the new method with phase and amplitude analysis was performed in 15 patients and with two-frame analysis in 40 patients. This new method yielded a higher sensitivity than either of the other two methods.
Angiography, angioscopy, and ultrasound imaging before and after percutaneous balloon angioplasty, We report two patients undergoing peripheral percutaneous transluminal angioplasty in whom angiography. angioscopy. and ultrasound imaging were performed before and after balloon angioplasty. The first case with smooth atheroma diagnosed by angiography was found to have unrecognized partially occlusive thrombus by angioscopy. After angioplasty. an intimal tear was identified by angioscopy and ultrasound but it was not seen by angiography. The intravascular ultrasound image showed the tear to extend to the adventitia. In the second case. an apparently smooth intimal surface as imaged by angiography was found by angioscopy and ultrasound to have extensive damage. including subintimal hemorrhage. intimal flaps. and arterial dissection at the angioplasty site. These data suggest that the type of information derived from the three imaging techniques is quite different. and that each may have a specific role in intravascular diagnosis.
Clinical significance of simple heart rate-adjusted ST segment depression in supine leg exercise in the diagnosis of coronary artery disease, To evaluate the clinical significance of simple heart rate-adjusted ST segment depression (delta ST/delta HR) in the diagnosis of coronary artery disease. 42 patients with stable exertional angina underwent supine leg exercise testing and cardiac catheterization. During exercise. heart rate. a multilead electrocardiogram. and pulmonary artery wedge pressure were recorded. The sensitivity and accuracy of the delta ST/delta HR criteria (greater than or equal to 3.0 microV/beat/min) were significantly greater than the conventional analysis of ST segment depression criteria (greater than or equal to 0.2 mV) for detecting three-vessel coronary artery disease at a matched specificity of 72% (100% versus 46%. 81% versus 64%. p less than 0.01). A significant linear correlation was found between maximum pulmonary artery wedge pressure increments during exercise (delta PAWP) or Gensini score and the delta ST/delta HR (delta PAWP: r = 0.51. p less than 0.001; Gensini score: r = 0.47. p less than 0.001). There were no statistically significant differences in the delta PAWP or Gensini score between patients with three-vessel disease who had delta ST/delta HR greater than or equal to 3.0 microV/beat/min and those with one- or two-vessel disease who had delta ST/delta HR greater than or equal to 3.0 microV/beat/min (delta PAWP: 18.1 +/- 2.0 versus 21.9 +/- 3.3. p = NS; Gensini score: 68.5 +/- 6.6 versus 66.3 +/- 11.3. p = NS). These findings demonstrate that delta ST/delta HR is more useful than a conventional analysis of ST segment depression for identifying not only anatomically severe coronary artery disease but also functionally severe coronary artery disease.
Electrophysiologic effects of exogenous phosphocreatine in cardiac tissue: potential antiarrhythmic actions, The cellular electrophysiologic effects of exogenous phosphocreatine (PCr) were analyzed to ascertain its purported antiarrhythmic properties during myocardial ischemia and reperfusion. Transmembrane potentials were recorded from isolated guinea pig papillary muscles and Purkinje fibers studied in vitro. Under control. normoxic conditions. 10 mmol/L PCr significantly increased the action potential duration (measured at 90% of repolarization) in ventricular muscle by 14.6 +/- 3.3 msec and the effective refractory period by 11.5 +/- 3.8 msec (both p less than 0.01). Under ischemic-like conditions (hypoxia. lactic acidosis. elevated [K+]o. zero substrate) PCr had no effect. Phosphocreatinine. a related compound that is not a direct substrate in the creatine kinase reaction. acted similarly to PCr suggesting that alterations induced by PCr did not involve a change in the energy state of cells. However. PCr reduced free [Ca2+]o by nearly 20%. and its electrical effects under normoxic conditions could be largely reversed by a concomitant 20% increase in [Ca2+]o. In Purkinje fibers superfused with low [K+]o-Tyrode's solution to elicit conditions of Ca2+ overload. delayed afterdepolarizations and triggered responses were reversibly inhibited by PCr. These data suggest that the antiarrhythmic effects of PCr in situ may involve prolongation of the effective refractory period in nonischemic tissue or attenuation of membrane changes elicited by Ca2+ overload in ischemic cells. The mechanism by which PCr produces these effects may be related in part to changes in extracellular Ca2+ composition.
ACE inhibition improves vagal reactivity in patients with heart failure, The deranged autonomic control of heart rate was studied in 34 patients with heart failure (New York Heart Association [NYHA] functional class II to III) by examining the carotid sinus baroreflex. The carotid sinus baroreceptors were stimulated by graded suction. The slope of the regression line between increases in cycle length and the degree of neck suction was taken as an index of baroreflex sensitivity. The reflex response is mediated by a selective increase of vagal efferent activity. Baroreflex sensitivity therefore represents a measure of vagal reactivity. Using multiple regression analysis. baroreflex sensitivity (BS) correlated positively to stroke volume index (SVI) and inversely to plasma renin activity (PRA) and to age: BS = 0.47 SVI - 0.38 PRA - 0.23 age + constant (r = 0.74; p less than 0.0005). In addition to digitalis and diuretics. angiotensin-converting enzyme (ACE) inhibitors (captopril or enalapril) were given to 16 patients for a mean of 17 +/- 3 days. The patients with hemodynamic improvement (group A) exhibited improved baroreflex sensitivity (1.4 +/- 0.4 to 3.6 +/- 1.2 msec/mm Hg; p less than 0.01). Baroreflex sensitivity remained unchanged (3.1 +/- 0.8 to 2.4 +/- 1.0 msec/mm Hg; n.s.) in the patients without hemodynamic improvement (group B). The increase in reflex sensitivity did not correlate with hemodynamic alterations. Baroreflex sensitivity during ACE inhibition (BSD) was only related to the baseline baroreflex sensitivity (BSB): BSD = 2.8 BSB - 0.46 (r = 0.84; p less than 0.005). In patients with heart failure. reflex bradycardia decreases with age and with PRA and increases with stroke volume. Chronic therapy with ACE inhibitors enhances vagal reactivity in patients with hemodynamic improvement.
Are ioxaglate and iopamidol equally safe and well tolerated in cardiac angiography? A randomized, double-blind clinical study, A randomized. double-blind. parallel-group study was performed in 50 patients undergoing left ventriculography and coronary arteriography to evaluate ECG changes and the effects on left ventricular function of a low-osmolar ionic contrast agent. ioxaglate. as compared with a low-osmolar nonionic contrast medium. iopamidol. Twenty-five patients received ioxaglate (group 1) and 25 patients received iopamidol (group 2). All patients underwent 48 hours of continuous ECG recording beginning 24 hours before the cardiac catheterization. Left ventricular systolic and end-diastolic pressure. peak positive dp/dt. and dp/dt/P ratio were measured immediately before and after left ventriculography and 3 minutes later. Left ventricular systolic pressure did not change after injection of either contrast medium. Left ventricular end-diastolic pressure increased by 30% in group 1 (p less than 0.01) and by 22% in group 2 (p less than 0.01) immediately after left ventriculography. A further increase by 45% in group 1 (p less than 0.01) and by 24% in group 2 (p less than 0.01) was observed 3 minutes later. No differences were observed between values obtained in the two groups. Peak positive dp/dt did not change immediately after injection of either contrast medium but decreased by 5% (not significant) in group 1 and by 7% (p less than 0.02) in group 2 three minutes after left ventriculography. There were no significant differences between the two groups. Analysis of continuous 48-hour ECGs showed that both ioxaglate and iopamidol induced a slight increase (by 8% and 7%. respectively; p less than 0.05) in heart rate during injection with early and complete recovery.
Color Doppler diagnosis of mechanical prosthetic mitral regurgitation: usefulness of the flow convergence region proximal to the regurgitant orifice, In prosthetic or paravalvular prosthetic mitral regurgitation. transthoracic color Doppler flow mapping can sometimes fail to detect the regurgitant jet within the left atrium because of the shadowing by the prosthetic valve. To overcome this limitation. we assessed the utility of color Doppler visualization of the flow convergence region (FCR) proximal to the regurgitant orifice in 20 consecutive patients with mechanical prosthetic mitral regurgitation documented by surgery and cardiac catheterization (13 of 20 patients). In addition. we studied 33 patients with normally functioning mitral prostheses. Doppler studies were performed in the apical. subcostal. and parasternal long-axis views. An FCR was detected in 95% (19 of 20) of patients with prosthetic mitral regurgitation. A jet area in the left atrium was detected in 60% (12 of 20) of patients. In 18 of 19 patients with Doppler-detected FCR. the site of the leak was correctly identified by observing the location of the FCR. A trivial jet area was detected in eight patients with a normally functioning mitral prosthesis; in none was an FCR identified. Thus color Doppler visualization of the FCR proximal to the regurgitant orifice is superior to the jet area in the diagnosis of mechanical prosthetic mitral regurgitation. Moreover. FCR permits localization of the site of the leak with good accuracy.
Patients at risk for cardiac death late after aortic valve replacement, A total of 100 patients aged 24 to 78 years were screened prospectively a mean of 71 months after aortic valve replacement for the presence of left ventricular hypertrophy (LVH) on the ECG (Estes scores greater than or equal to 5.0) and for repetitive ventricular premature beats VPBs greater than or equal to 2 couplets/24 hr) during 24-hour Holter monitoring. During the subsequent 41-month follow-up (range 10 to 50 months). the yearly cardiac mortality rate was 1.3% in patients with LVH. 2.9% in patients with VPBs. and 8.0% in patients with LVH plus VPBs but only 0.6% when none of these factors was present (p less than 0.05 chi 2 test). The patient groups did not differ with regard to age. time elapsed since operation. underlying valve lesion. and coronary artery disease. Both LVH and VPBs occurred more frequently in patients with left ventricular dysfunction. We conclude that after aortic valve replacement cardiac mortality is markedly increased in patients with LVH and repetitive VPBs. since they are noninvasive markers of left ventricular dysfunction.
Transesophageal echocardiography in the awake elderly patient: its role in the clinical decision-making process, To assess the impact on the management and safety of transesophageal echocardiography (TEE) in the elderly population. the results and limitations of this technique were retrospectively analyzed in 88 patients. TEE was indicated whenever the transthoracic approach was not diagnostic or was inconsistent with the clinical setting. The most frequent clinical indications were to investigate the source of emboli. assess valvular regurgitation. and identify valvular vegetations. In 72 patients (82%) TEE significantly influenced management decisions. In selected patients TEE avoided the use of more invasive diagnostic procedures. Adverse effects included occasional premature atrial or ventricular beats (11 patients). sinus bradycardia (six patients). and protracted nausea (one patient). We conclude that in elderly patients with cardiovascular diseases. TEE plays a significant role in the decision-making process without adding a significant risk.
Noninvasive assessment of cardiac output in children using impedance cardiography, This study evaluated the effect of intracardiac shunting on the accuracy of thoracic bioimpedance-derived cardiac output determinations. Twenty-six patients. ranging in age from 3 months to 17 years. underwent cardiac catheterization during which simultaneous Fick and impedance measurements of cardiac output were obtained. The subjects were divided into three groups: 10 children with no intracardiac shunts. nine children with predominant left-to-right intracardiac shunts. and seven children with predominant right-to-left intracardiac shunts. Positive correlations between impedance and Fick-derived cardiac output determinations were obtained in the non-shunt group (r = 0.84). with lower correlations in the left-to-right shunt group (r = 0.70). In the right-to-left shunt group. the impedance derived cardiac output correlated with Fick pulmonary flow (r = 0.82). but the variability was unacceptably large. Although further study is needed. impedance cardiography appears to have validity as a methodology in pediatric critical care and cardiovascular health research.
A hematologist's view of contrast media, clotting in angiography syringes and thrombosis during coronary angiography, While ionic contrast media (CM) are stronger anticoagulants and antiplatelet agents. both nonionic and ionic CM retard clotting. fibrinopeptide A generation and platelet aggregation (at least by Born-O'Brien aggregometry). Thus. nonionic CM do not cause clots and thrombi. Rather. the driving force for clot or thrombus formation. when it occurs. is blood contact with and activation by the foreign surface of a syringe or catheter itself. A marked enhancement of clotting by glass syringes in comparison to plastic ones supports this view. Blood in any syringe or catheter. therefore. will clot more slowly in the presence of nonionic or ionic CM. the inhibitory effects of the latter being more profound. With respect to models of thrombosis at sites of vascular injury or stenosis. the antithrombotic effects of CM may either be transient owing to the dynamic nature of blood flow (local endothelial cell denudation model). or as in the case of ionic CM. actually to enhance local platelet aggregation (stenosis model). In these situations. preservation of the antithrombotic functions of endothelium with nonionic CM may be quite critical.
Clinical cardiovascular magnetic resonance imaging, Magnetic resonance imaging (MRI) is a powerful tool providing high-resolution images of the heart and great vessels without the use of ionizing radiation or contrast agents. MRI systems currently in use at many hospitals can be used effectively in the routine. clinical evaluation of many forms of cardiovascular disease. including great vessel disease. ischemic cardiac disease and congenital cardiac disease. Moreover. quantitative and cine MRI techniques are now available. which provide highly accurate measures of chamber size. wall motion and wall thickening. Recent developments in the areas of myocardial tagging. high-speed imaging and MR assessments of flow and perfusion suggest potential for an increasing role of MRI in the clinical evaluation of the cardiovascular system.
Clinical nuclear magnetic resonance spectroscopy: insight into metabolism, Nuclear magnetic resonance (NMR) spectroscopy can nondestructively evaluate changes in metabolites with different disease states. as well as with therapeutic interventions. Animal studies have provided the basis for understanding changes in high-energy phosphates with myocardial ischemia. Studies of graded ischemia due to partial coronary stenosis have shown the sensitivity of the ratio of phosphocreatinine to inorganic phosphate to small reductions in myocardial blood flow and its relation to myocardial function. The application of NMR spectroscopy to humans requires precise localization techniques to avoid acquiring contaminating information from structures around the heart. such as the chest wall and diaphragm. With these localization techniques. metabolic evidence of ischemia has been demonstrated in patients with myocardial infarction and patients with known coronary disease. although the sensitivity of this technique for the diagnosis of inducible ischemia is unknown. At rest. patients with dilated and hypertrophic cardiomyopathies often have an elevated phosphodiester resonance. possibly signifying abnormal breakdown of membrane phospholipids. Increasing oxygen demand in these patients does not usually alter high-energy phosphates. suggesting that oxidative energy metabolism is preserved under these conditions. NMR spectroscopy is a powerful tool to increase understanding of metabolic changes in a variety of pathologic conditions.
Positron emission tomography and interventional cardiology, Current noninvasive diagnostic techniques have limited accuracy for detection of coronary artery disease (CAD) in symptomatic and (particularly) asymptomatic patients with silent disease. Furthermore. no standard noninvasive method provides reliable diagnostic information on the location of the coronary arteries involved. the severity of stenosis. the presence of collaterals and myocardial viability. Based on greater than 1.000 cardiac studies at the University of Texas. cardiac positron emission tomography (PET) with either generator-produced rubidium-82. cyclotron-produced N-13 ammonia. or F-18 deoxyglucose is suitable for 4 routine diagnostic purposes: (1) noninvasive diagnosis of CAD in either symptomatic or asymptomatic subjects with a sensitivity of 95 to 98% and specificity of 95 to 100%. This accuracy is now sufficient to schedule diagnostic catheterization and multivessel angioplasty with surgical backup on the basis of the PET scan. At the University of Texas we carry out PET in asymptomatic and symptomatic patients to direct those with mild disease to cholesterol-lowering reversal therapy and those with severe disease to percutaneous transluminal coronary angioplasty (PTCA); (2) assessment of physiologic severity of coronary artery stenosis as compared to automated quantitative coronary arteriographic analysis. Changes in stenosis severity are followed before and after interventions including PTCA. bypass surgery. vasodilator drugs and cholesterol control regimens for reversal of coronary atherosclerosis; (3) imaging myocardial infarction. ischemia. viability. zone at risk and sizing of these pathophysiologic processes.
Role of magnetic resonance contrast agents in cardiac imaging, Improvements in magnetic resonance imaging (MRI) technology allow adequate spatial and temporal resolution to capture cardiac anatomy and contractile function in exceptional detail and with little risk. However. tissue characterization of the pathophysiologic state of the myocardium may require special indicators or MR contrast agents. These must be tailored for detection by the MRI process. but available agents are effective at low dose and provide a wide range of indicator properties (e.g.. myocardial extracellular space. blood pool. capillary permeability and membrane transport). Each agent has a dynamic washin and washout time-intensity curve that may reflect myocardial perfusion or consequences of ischemia. The combined use of MRI and MR contrast agents may provide a single diagnostic examination that fully and quantitatively assesses all indexes of cardiac performance. Such information would be both global and regional. and would be well tolerated by patients. The cost. value and cost-effectiveness of such studies remain speculative.
Beta blockers and the primary prevention of nonfatal myocardial infarction in patients with high blood pressure, A population-based. case-control study was conducted to determine whether beta blockers. used for the treatment of high blood pressure. prevent first events of coronary heart disease. All study subjects were health-maintenance organization enrollees with pharmacologically treated hypertension. Patients presented in 1982 to 1984 with new coronary heart disease. and control subjects were a probability sample of eligible hypertensive enrollees free of coronary heart disease. With the investigators blind to case-control status. the subjects' medical records were reviewed for other coronary risk factors. and the health-maintenance organization's computerized pharmacy database was used to ascertain the use of beta blockers. A larger proportion of controls than cases were using beta blockers. This difference was confined to the subgroup with nonfatal myocardial infarctions. For current use. the estimated relative risk for nonfatal myocardial infarction was 0.62 (95% confidence interval. 0.39 to 0.99). Among current users of beta blockers. higher doses conferred greater protection. Past use and total lifetime intake of beta blockers were only weakly associated with case-control status. The current use of beta blockers may prevent first events of nonfatal myocardial infarction in patients with high blood pressure.
Timing and triggers of transient myocardial ischemia, Use of exercise tolerance testing and new techniques of ambulatory electrocardiographic monitoring to more objectively measure myocardial ischemia have enabled clinicians to better recognize the magnitude. timing and variable characteristics of transient ischemic events. These commonly occurring events in patients with coronary artery disease have a diurnal pattern strikingly similar to that reported for catastrophic cardiovascular events such as myocardial infarction. sudden cardiac death and stroke. Whether those factors that contribute to reversible ischemic events are similar to those causing infarction and sudden death has not been resolved. However. the parallel increase in morning activity for these related phenomena suggests that a better understanding of the triggers of reversible myocardial ischemia may help improve understanding of the causes of myocardial infarction and sudden cardiac death.
Application of time series analysis to circadian rhythms: effect of beta-adrenergic blockade upon heart rate and transient myocardial ischemia, Circadian variations of transient myocardial ischemia and heart rate have been identified. but the rhythms and their response to beta blockade have not been fully characterized. Time-series analysis. a mathematical technique to describe oscillatory activity occurring within a continuous data set was used. to address these issues. Nine men with coronary artery disease underwent 72 hours of ambulatory electrocardiographic monitoring during therapy with placebo or metoprolol. During administration of placebo. ischemic time and heart rate showed a primary peak with a periodicity of approximately 24 hours with a tight coupling between the 2 variables and a secondary peak with a periodicity of 5 to 8 hours. During metoprolol therapy. heart rate and ischemic variation were reduced and the 24-hour periodicity for heart rate only remained. The 24-hour periodicity for ischemia was eliminated. but the data with 5- to 8-hour periodicity became the major component of the signal.
Transient myocardial ischemia and its relation to determinants of myocardial oxygen demand, Because of conflicting data and a clear need to establish the relative role of increase in myocardial oxygen demand versus reduction in coronary blood flow in the causation of transient ischemia. the role of heart rate and blood pressure changes immediately preceding and during the transient ischemic events observed during daily life were evaluated in 25 patients with coronary artery disease. Elevations in heart rate before onset of ischemia were observed in 61% of the episodes. Similarly. 73% of the ischemic events were preceded by an increase in arterial pressure. These data provide evidence for a significant role of increased myocardial oxygen demand in the genesis of transient myocardial ischemia.
Mental stress as an acute trigger of ischemic left ventricular dysfunction and blood pressure elevation in coronary artery disease, Acute mental stress may be a frequent trigger of transient myocardial ischemia. myocardial infarction and sudden cardiac death. In an experimental setting. the effect of mental stress on hemodynamics and left ventricular wall motion abnormalities (as detected by radionuclide ventriculography) was measured in 29 patients with exercise-induced myocardial ischemia. Seventy-five percent of the patients demonstrated mental stress-induced wall motion abnormalities. Patients frequently exhibited greater increases in peak systolic arterial pressure during mental stress than during exercise. Personally relevant mental stress is the most potent type of mental stress. both in terms of frequency and magnitude of ischemia. Most mental stress-induced ischemic episodes are clinically and electrocardiographically silent and occur at heart rates significantly lower than those seen during exercise. Both systolic and diastolic blood pressure increased during mental stress-induced ischemia. suggesting that increased myocardial oxygen demand plays a role in the pathophysiology of mental stress-induced transient ischemia. The significant magnitude and acute onset of this mental stress-induced blood pressure elevation may in some manner contribute to atherosclerotic plaque rupture. These findings may provide a pathophysiologic link to the epidemiologic association between mental stress and acute ischemic coronary events. A new ambulatory radionuclide detector that can concurrently monitor left ventricular ejection fraction and electrocardiographic ST-segment change may enhance the detection and evaluation of transient myocardial ischemia in ambulatory coronary patients.
Potential usefulness of combined thromboxane A2 and serotonin receptor blockade for preventing the conversion from chronic to acute coronary artery disease syndromes, Evidence suggests that unstable angina. non-Q-wave myocardial infarction and Q-wave myocardial infarcts represent a continuum. such that transient reduction in coronary blood flow associated with platelet aggregation and dynamic vasoconstriction at sites of coronary artery stenosis and endothelial injury lead to abrupt development of unstable angina. Factors potentially responsible for the conversion from chronic to acute coronary artery disease include endothelial injury at sites of stenosis. The endothelial injury may be the result of plaque fissuring or ulceration. hemodynamic factors (including systemic arterial hypertension or flow shear stress). infection. smoking. coronary arteriography or balloon angioplasty. Clinical and experimental animal studies suggest that interference with thromboxane and serotonin contributions to platelet aggregation and dynamic coronary artery constriction may prevent chronic coronary artery disease syndromes from converting to acute disease. To protect against this process may require both thromboxane and serotonin receptor antagonists or a combination of thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist. Further studies are needed to test this hypothesis.
Beta-blocker duration of action and implications for therapy, Two studies were conducted to measure the effect of serum half-life on beta-blocker-related heart rate reduction throughout the 24-hour period. In the first study. nadolol. atenolol and pindolol were associated with significant (p less than 0.01) heart rate reduction even at 24 hours after dose. Nadolol. with a plasma half-life of 15.5 hours. had the most pronounced heart rate-lowering effect 24 hours after the daily dose compared to pindolol. which had a half-life of 5.5 hours. In a randomized. double-blind. crossover study. nadolol and atenolol had similar effects 3 to 4 hours after the daily dose. Nadolol. however. produced greater suppression of heart rate and double product (blood pressure x heart rate) than atenolol (compared to placebo) 24 hours after ingestion of the daily dose. On ambulatory electrocardiography 24 hours after medication administration. 80 to 100% of the heart rate-attenuating effect of nadolol was maintained versus only 20 to 45% of atenolol's effect. Statistically significant (p less than 0.05) reductions in heart rate were produced by nadolol. but not by atenolol. between 4 and 5 A.M.. 6 and 7 A.M.. 8 and 9 A.M. and 9 and 10 A.M. Furthermore. nadolol remained at 52% of peak blood level at 24 hours. whereas atenolol was at 20%. The data from these 2 studies indicate that significant differences in duration of action exist between beta blockers.
Effect of beta-adrenergic blocking agents on the circadian occurrence of ischemic cardiovascular events, Clinical observations suggest that beta-adrenergic blocking agents can modify the circadian occurrence of a variety of ischemic events. Morning awakening is associated with a rapid increase in blood pressure and pulse. serum catecholamine content and platelet activation. at a time of decreased blood thrombolytic activity. Beta-adrenergic blocking agents have the potential to modify many of these events. Current data indicate that these agents modify blood pressure and pulse. but do not prevent their early morning increase. In addition. beta-adrenergic blocking agents decrease ventricular ectopy and its circadian variation. Recent studies in humans indicate. however. that metoprolol does not affect the circadian increase in platelet activity or serum catecholamines. The specific mechanism by which beta blockers affect the circadian occurrence of ischemic events remains uncertain.
Reduction of mortality, sudden death and non-fatal reinfarction with beta-adrenergic blockers in survivors of acute myocardial infarction: a new hypothesis regarding the cardioprotective action of beta-adrenergic blockade, Beta-adrenergic blockers have been shown definitely to reduce the incidence of total mortality. cardiovascular mortality. sudden death and nonfatal reinfarction in survivors of an acute myocardial infarction. The mechanisms to explain this protective action of beta blockers have never been elucidated conclusively. and include the antiarrhythmic and myocardial oxygen demand-reducing effects of the drugs. An antithrombotic mechanism has also been suggested. However. beta blockers have relatively weak antiplatelet activity. suggesting that their antithrombotic effects may be related to prevention of coronary artery plaque rupture and the subsequent propagation of an occlusive arterial thrombus rather than direct anticoagulant action. The therapeutic ability of beta blockers to attenuate the hemodynamic consequences of catecholamine surges. may protect a vulnerable atherosclerotic plaque from fracture. thereby reducing risk of coronary thrombosis. myocardial infarction and death.
Exercise test predictors of ambulatory silent ischemia during daily life in stable angina pectoris, The predictive value of several exercise test parameters in identifying stable angina patients at risk of silent myocardial ischemia during daily life were examined. A total of 97 patients with coronary artery disease. stable angina and ambulatory electrocardiographic data were evaluated. Of the 86 patients with a positive exercise test. 39 (group 1) had greater than or equal to 1 episodes of ST-segment depression and 47 (group 2) did not develop ST changes during ambulatory electrocardiographic monitoring. Comparison of the exercise test parameters between the 2 groups revealed early onset of ischemia during exercise tests as the single most significant (p less than 0.0005) predictor of ambulatory silent ischemia. The other exercise test parameters showing significant differences between the 2 groups were the peak exercise heart rate (117 +/- 23 vs 126 +/- 20 beats/min. p less than 0.05) and peak systolic blood pressure (160 +/- 27 vs 176 +/- 27 mm Hg. p less than 0.01). both of which were significantly lower in the group 1 patients. These data were used to derive simple mathematical formulas for calculating the risk of ambulatory silent ischemia. These results demonstrate that stable angina patients at risk of silent ischemia during daily life can be accurately identified by evaluation of selected exercise test parameters.
Effects of theophylline, atenolol and their combination on myocardial ischemia in stable angina pectoris, The effects of theophylline (400 mg twice a day). atenolol (50 mg twice a day) and their combination on myocardial ischemia were studied in 9 patients with stable angina pectoris in a randomized. single-blind. triple crossover trial. Placebo was administered to the patients during the run-in and the run-off periods. A treadmill exercise test and 24-hour ambulatory electrocardiographic monitoring were obtained at the end of each treatment period. Compared with placebo. theophylline significantly improved the time to onset of myocardial ischemia (1 mm of ST-segment depression) from 7.8 +/- 3.7 to 9.5 +/- 3.7 minutes (p less than 0.03) and the exercise duration from 9 +/- 3.4 to 10.1 +/- 3.5 minutes (p less than 0.04). During atenolol and during combination treatment. the time to the onset of ischemia and the exercise duration were similar (10.8 +/- 4.2 and 11.2 +/- 3.2 minutes. 11.2 +/- 3.6 and 11.5 +/- 3.2 minutes. respectively) and longer than during theophylline administration (p less than 0.05). Ambulatory electrocardiographic monitoring showed that. during theophylline administration. the heart rate was higher than during placebo throughout the 24 hours (p less than 0.05). During atenolol and during combination treatment the heart rate was similar and in both cases lower than during placebo (p less than 0.05). Compared with placebo. theophylline decreased the total ischemic time from 97 +/- 110 to 70 +/- 103 minutes (p less than 0.05).
Effects of two types of fish oil supplements on serum lipids and plasma phospholipid fatty acids in coronary artery disease, Fish oil has consistently been shown to lower triglyceride levels. but its effects on low-density lipoprotein (LDL) cholesterol remain controversial. The current study compares the long-term effects of 2 different fish oil preparations (ethyl ester and triglyceride) versus olive oil in patients with coronary artery disease. Eighty-nine subjects were randomly assigned to receive capsules containing 6 g/day (triglyceride group) or 7 g/day (ethyl ester group) of n-3 fatty acids. or capsules containing 12 g/day of olive oil for 6 months. Mean triglyceride levels decreased by 28% in the ester and 32% in the triglyceride fish oil groups (p less than 0.05 for both). LDL cholesterol levels increased by 3% (difference not significant) in the ester and 12% (p less than 0.05) in the triglyceride fish oil groups; in hypertriglyceridemic subjects the increase was 23% (p less than 0.01) and 14% (difference not significant). respectively. Plasma phospholipid fatty acid analysis showed a fivefold increase in eicosapentaenoic acid levels in both fish oil groups (p less than 0.001). and a long-term decrease in arachidonic acid levels (p less than 0.001). Achieved eicosapentaenoic acid level correlated with the degree of increase in LDL cholesterol (r = 0.38. p less than 0.05). These data suggest that fish oil administration is associated with an increase in LDL cholesterol levels in a diverse group of patients with coronary artery disease; this change appears to be correlated with n-3 fatty acid absorption. The impact of this increase in LDL is unknown. but should be considered as potentially adverse.
Predictive value of lipoprotein (a) and other serum lipoproteins in the angiographic diagnosis of coronary artery disease, To determine the relation among lipids in predicting coronary artery disease (CAD). 213 patients undergoing diagnostic angiography for suspected CAD were prospectively studied. Twenty-one patients had normal coronary arteries and 192 had CAD in 1 to 3 arteries at arteriography with measurements obtained with digital calipers. Lipoproteins were measured and lipoprotein (a) [Lp(a)] was also assayed in a subset of 98 patients with CAD. Statistical analysis was performed using uni- and multivariate techniques to test the association among age. gender. systemic hypertension. diabetes mellitus. cigarette smoking. family history. total cholesterol. triglycerides. high-density lipoprotein (HDL) cholesterol. low-density lipoprotein (LDL) cholesterol. very low density lipoprotein cholesterol. apolipoproteins (apo) A-I and apo B. ratio of apo A-I to apo B. and ratio of HDL cholesterol to total cholesterol. to Lp(a) and to CAD. All factors except gender. systemic hypertension. diabetes mellitus and cigarette smoking were univariate predictors of CAD. Multivariate predictors were. in decreasing order of significance. family history. age. HDL/total cholesterol ratio and apo B. When Lp(a) was included. multivariate predictors were age. family history. apo B and Lp(a). in that order. Lipid parameters alone showed that the HDL/total cholesterol ratio and that Lp(a) provide the best predictive tests for the detection of CAD in this referral population and may ultimately become important screening tests for CAD.
Videodensitometry versus digital calipers for quantitative coronary angiography, Single-plane left coronary angiograms in 18 patients were prospectively analyzed using videodensitometry (XR-70 system) and handheld digital calipers to compare arterial dimensions. stenosis dimensions. intraobserver variability and interobserver variability for the methods. A total of 648 arterial segments were measured. yielding a highly significant correlation between videodensitometry and caliper-determined cross-sectional area (r = 0.96. p = 0.0001). Similarly. a highly significant linear relation was observed between videodensitometry and caliper-determined diameter (r = 0.95. p = 0.0001). When data subsets for small. medium and large arterial segments were examined. higher variability in the correlation between videodensitometry and caliper-determined area was observed in the large segments (greater than 10 mm2). In addition. caliper-estimated areas tended to be slightly smaller than videodensitometry-estimated areas in these segments. For diameter estimations. correlations between caliper and videodensitometry data were similar for the entire range of arterial segment sizes. Intra- and interobserver variability was low for both caliper and videodensitometry determination of diameter or area. Thus. over a wide range of arterial dimensions. results obtained with caliper estimates of luminal area and diameter are comparable to those obtained with videodensitometry using the XR-70 system.
Frequency of myocardial indium-111 antimyosin uptake after uncomplicated coronary artery bypass grafting, The reported incidence of myocardial damage after coronary artery bypass grafting (CABG) is highly related to the methods used. Since indium-111 monoclonal antimyosin antibody scintigraphy has been shown to be highly specific and sensitive for myocardial necrosis. even in small lesions. uptake of this radiotracer was evaluated after CABG. In 23 consecutive patients without previous myocardial infarction who underwent CABG for stable angina. 80 MBq indium-111 antimyosin was injected on the third postoperative day. Planar images were obtained 48 hours later and analyzed for myocardial uptake of indium-111 antimyosin. Scintigraphic results were related to creatine kinase MB levels. duration of both aortic cross-clamping and cardiopulmonary bypass. and electrocardiographic changes. In all patients surgical procedure and postoperative course was uncomplicated. Indium-111 antimyosin uptake was present in 19 of 23 patients (82%). It was diffused in 7 patients and localized in 12. No pathologic Q waves occurred postoperatively. Fourteen patients exhibited ST-segment changes. No good relation was found among indium-111 antimyosin uptake and creatine kinase MB levels. duration of cross-clamping or bypass. and ST-T changes. It is concluded that some degree of myocardial damage. though silent. is common after CABG.
Prognostic value of predischarge low-level exercise thallium testing after thrombolytic treatment of acute myocardial infarction, Low-level exercise thallium testing is useful in identifying the high-risk patient after acute myocardial infarction (AMI). To determine whether this use also applies to patients after thrombolytic treatment of AMI. 64 patients who underwent early thrombolytic therapy for AMI and 107 patients without acute intervention were evaluated. The ability of both the electrocardiogram and thallium tests to predict future events was compared in both groups. After a mean follow-up of 374 days. there were 25 and 32% of cardiac events in the 2 groups. respectively. with versus without acute intervention. These included death. another AMI. coronary artery bypass grafting or angioplasty with 75% of the events occurring in the 3 months after the first infarction. The only significant predictors of outcome were left ventricular cavity dilatation in the intervention group and ST-segment depression and increased lung uptake in the nonintervention group. The sensitivity of exercise thallium was 55% in the intervention group and 81% in the nonintervention group (p less than 0.05). Therefore. in patients having thrombolytic therapy for AMI. nearly half the events after discharge are not predicted by predischarge low-level exercise thallium testing. The relatively weak correlation of outcome with unmasking ischemia in the laboratory before discharge may be due to an unstable coronary lesion or rapid progression of disease after the test. Tests considered useful for prognostication after AMI may not necessarily have a similar value if there has been an acute intervention. such as thrombolytic therapy.
Usefulness of combined propranolol and verapamil for evaluation of surgical ablation of accessory atrioventricular connections in patients without structural heart disease, Successful surgical ablation of atrioventricular (AV) accessory connections may be confirmed during postoperative electrophysiologic testing by the absence of accessory connection conduction in both the anterograde and retrograde directions. Whereas the former may be readily apparent by examination of the surface electrocardiogram during sinus rhythm or atrial pacing. assessment of the latter may be complicated by the frequent presence of enhanced retrograde AV nodal conduction in the postoperative period. Consequently. availability of interventions that selectively affect AV nodal conduction and refractoriness without concomitant effects on accessory connections may be helpful for assessing the success of the surgical procedure. In this study the effects of combined propranolol and verapamil administration on electrophysiologic properties of the AV node and the accessory AV connection were assessed both pre- and postoperatively in 17 patients (12 men and 5 women. mean age 33 years) undergoing surgical ablation of accessory connections. Preoperatively. electrophysiologic characteristics of all but 1 of the accessory AV connections were unaffected by propranolol and verapamil administration. Postoperatively. on the other hand. propranolol and verapamil significantly prolonged both the retrograde AV node effective refractory period (baseline: 272 +/- 34 ms vs after drugs: 384 +/- 70 ms [p less than 0.0001]) and the shortest cycle length maintaining 1:1 ventriculoatrial conduction (baseline: 357 +/- 99 ms vs after drugs: 485 +/- 64 ms [p less than 0.0001]). Late postoperative electrophysiologic evaluation (7 +/- 3 weeks) revealed no evidence of residual accessory AV connection conduction. and all patients remain asymptomatic at 21 +/- 10 months follow-up.
Long-term effect of mexiletine on left ventricular function and relation to suppression of ventricular arrhythmia, The effects of oral mexiletine on left ventricular (LV) ejection fraction (EF) and ventricular arrhythmias--and a possible relation between these effects--were evaluated during 3 months of therapy in 29 patients with chronic ventricular premature complexes (VPCs) and a moderately reduced to normal LVEF by 24-hour Holter monitoring and by radionuclide ventriculography at rest and during maximum tolerable exercise testing. After an average titration period of 13 days. a mean daily mexiletine dose of 739 mg was maintained throughout the treatment. At the end of titration and after 3 months of treatment. patients with a baseline LVEF less than or equal to 40% (group 2) responded with a median reduction of the hourly VPC rate by 90 and 81%. respectively. compared with 79 and 72% in those with a baseline LVEF greater than 40% (group 1). Couplets and runs of ventricular tachycardia were almost completely suppressed in nearly all patients. A single patient had a proarrhythmic increase in VPCs during treatment. Compared with baseline. there were no significant changes in resting or exercise LVEF after 1 or 3 months of treatment in either of the 2 groups of patients. No correlation was found between treatment-induced changes in arrhythmia frequency and in resting EF. No symptoms of congestive heart failure developed. The study confirms that long-term use of mexiletine is efficacious and relatively free of cardiac depressant effects even in patients with diminished LV function.
Effectiveness of the once-daily calcium antagonist, lacidipine, in controlling 24-hour ambulatory blood pressure, The efficacy of the new once-daily dihydropyridine calcium antagonist. lacidipine. in reducing ambulatory intraarterial blood pressure (BP) was examined in 12 untreated hypertensive patients. The intraarterial recording was commenced 24 hours before the first 4-mg dose and was continued for a further 24 hours thereafter. After dose titration and chronic therapy. a second 24-hour ambulatory BP recording was made. There was a steady onset of drug action. maximal at 2 hours. but with reflex tachycardia after the first dose. Chronic administration reduced BP throughout the 24-hour period. without tachycardia. Mean daytime reduction in BP was 20 mm Hg systolic (p less than 0.005) and 12 mm Hg diastolic (p less than 0.02). Mean nighttime reduction was 8-mm Hg systolic (p less than 0.05) and 6-mm Hg diastolic (difference not significant). There was no postural decrease in BP on 60 degrees head-up tilting and hypotensive action was maintained during isometric exercise (reduction at peak of 32/18 mm Hg. p less than 0.05) and throughout dynamic exercise (reduction at peak of 23/14 mm Hg. p less than 0.05). Lacidipine is an effective once-daily antihypertensive agent. with good control of stress response.
Atenolol therapy for exercise-induced hypertension after aortic coarctation repair, After successful repair of coarctation of the aorta in childhood. exercise-induced upper body systolic hypertension is well documented. Beta blockade has been shown to reduce the arm/leg gradient in untreated coarctation of the aorta; treatment before coarctation repair has decreased paradoxical hypertension after repair. Ten patients with successful surgical repair of coarctation. defined as a resting arm/leg gradient of less than or equal to 18 mm Hg. were evaluated by treadmill exercise before and after beta blockade with atenolol. Mean age was 5.5 years at repair and 18 at study. At baseline evaluation. systolic blood pressures at termination of exercise ranged from 201 to 270 mm Hg (mean 229 mm Hg). Arm/leg gradients at exercise termination ranged from 30 to 143 mm Hg (mean 84). Follow-up treadmill exercise studies were performed after beta blockade. Upper extremity systolic pressures at exercise termination were normalized in 9 of 10 patients. Maximal systolic blood pressure recorded at exercise termination ranged from 163 to 223 mm Hg (mean 196 mm Hg. p less than or equal to 0.005). Arm/leg gradient at termination of exercise also decreased significantly to a mean of 51 mm Hg (p less than 0.05). No patient had symptoms on atenolol and exercise endurance times were unchanged. The study results in this small series suggest that cardioselective beta blockade can be used to treat exercise-induced upper body hypertension effectively after surgical repair of coarctation. Because a high incidence of premature cardiovascular disease has been well documented after satisfactory surgical repair. the findings are of importance for this group of postoperative patients.
Subnormal parasympathetic activity after cardiac transplantation, Heart period variability (standard deviation of 120 consecutive RR or PP intervals) was used to assess baseline parasympathetic activity in 18 patients with congestive heart failure before and after orthotopic cardiac transplantation. and was compared to that of 16 age-matched control subjects. Mean heart period variability (+/- standard error of the mean) was significantly greater (p less than 0.05) in control subjects (58 +/- 5 ms) than in the patients at any time before or after transplantation. Heart period variability of innervated recipient atria did not change significantly early (1 to 4 weeks) after transplantation (16 +/- 2 to 24 +/- 5 ms; p = 0.11). but increased significantly between weeks 15 and 37 after transplantation (30 +/- 5 ms. p less than 0.002 versus before transplantation). A stepwise regression model (R2 = 0.35; p = 0.01) showed that heart period variability was directly related to time after transplantation and inversely related to systolic arterial pressure after transplantation and degree of rejection. Heart period variability of the denervated donor atria did not change from early to late periods after transplantation. suggesting that vagal reinnervation of the donor heart had not occurred. These data indicate that baseline parasympathetic activity does not increase significantly during the first month after transplantation but increases significantly between months 3 and 6.
Natural history of cardiac rhabdomyoma in infancy and childhood, Although spontaneous regression of cardiac rhabdomyoma has been reported. prognosis is still considered to be poor and surgery continues to be indicated. The experience with rhabdomyoma diagnosed in live infants over a 20-year period was reviewed. Diagnosis by angiography or echocardiography was accepted only if multiple tumors were present or if tuberous sclerosis was also diagnosed. Nine patients (3 diagnosed prenatally and the remaining 6 at age less than 8 months) were identified as having a total of 24 tumors. Measurements in 2 planes demonstrated at least some evidence of regression in 24 patients (100%). with 20 of 24 having complete resolution. One patient required delayed surgery for excision of a subaortic ridge that appeared at the site of a resolved tumor. Our findings suggest that pediatric cardiac rhabdomyoma is most often a benign condition in which spontaneous regression is the rule. Surgery is recommended only for patients with refractory dysrhythmias or severe hemodynamic compromise.
Growth, thermogenesis, and hyperphagia, Resting metabolic rate is demonstrated to be a function of fat-free mass and a growth variable related to food-energy-input imbalance rate. By use of obligatory energy expenditure terms. the two-reservoir energy model applied to hyperphagia shows that growth of the fat-free mass is rapid whereas that of the fat store is slow and that the growth of both is bounded. Most of the excess energy at the onset of hyperphagia initially goes into the fat store. but this decreases with time until the greater fraction is diverted to the fat-free mass. The two-reservoir model predicts that weight gain per unit of excess energy is not constant but decreases monotonically until ultimately reaching an asymptotic value. Departure of theory and experiment in the long term suggests that facultative considerations become increasingly important.
Diet and female sex hormone concentrations: an intervention study for the type of fat consumed, A possible mechanism by which dietary fat may influence the development of breast cancer is by influencing the concentration of female sex hormones. This study investigated the effect of alteration in the type of fat consumed on concentrations of female sex hormones in serum. Female volunteers were randomly assigned to continue on their usual meat-eating diet. change to a vegetarian diet. or change to a diet that was predominantly vegetarian but where fish was consumed at least three times per week. Change to the vegetarian or fish diet had little effect on diet total hormone concentrations; however. the amount of estradiol was significantly decreased in the vegetarian group. When nutrient consumption was correlated with hormone concentrations. prolactin was directly associate with fat consumption. sex-hormone-binding globulin was inversely associated with fat consumption (particularly cholesterol consumption). and the proportion of nonprotein-bound estradiol was directly associated with complex carbohydrate consumption.
Impaired thermoregulation and thyroid function in iron-deficiency anemia, Ten women with iron-deficiency anemia. 8 with depleted iron stores (nonanemic). and 12 control women. all of similar body fatness. were exposed to a 28 degrees C water bath to test the hypothesis that iron-deficiency anemia impairs thermoregulatory performance. The anemic women had lower rectal temperatures than did control women (36.0 +/- 0.2 vs 36.2 +/- 0.1 degree C. respectively. P = 0.001) and a lower rate of oxygen consumption (5.28 +/- 0.26 vs 5.99 +/- 0.29 mL.min-1.kg body wt-1. respectively. P = 0.04) at 100 min of cold exposure. Plasma thyroxine and triiodothyronine concentrations were significantly (P less than 0.002) lower in anemic than in control women at baseline and during cold exposure. Responses of iron-depleted subjects were similar to those of control subjects. Iron supplementation corrected the anemia. significantly (P = 0.03) improved rectal temperature at 100 min. and partially normalized plasma thyroid hormone concentrations. Plasma catecholamines were unaffected by iron status. This experiment demonstrates a functional consequence of iron-deficiency anemia in the balance of heat production and loss and suggests that thyroid-hormone metabolism may be responsible.
Obesity and iron status in menstruating women, The relationship between iron stores and obesity in menstruating women was studied in 20 obese and 20 nonobese women matched for age and contraception. Although no difference was observed in serum iron or total-iron-binding capacity. the obese group showed significantly higher hemoglobin (137 +/- 9 vs 10 g/L. mean +/- SD; P less than 0.01). hematocrit (0.41 +/- 0.02 vs 0.39 +/- 0.03. P less than 0.05). and serum ferritin concentrations (48.0 +/- 44.3 vs 25.8 +/- 19.5 micrograms/L. P less than 0.05). There was no difference between obese and nonobese women in either the menstrual-cycle interval or the duration of the menstrual flow. Iron intake was significantly higher in the obese group (15.9 +/- 2.9 vs 14.1 +/- 2.9 mg/d. P less than 0.05). These results suggest that obese menstruating women are at low risk of depleting iron stores. possibly because of high iron intake. Iron-fortification programs might thus be undesirable in such subjects.
Mother-daughter pairs: spinal and femoral bone densities and dietary intakes, Bone mineral density (BMD) of the lumbar spine (L1-L4) and femur (femoral neck. Ward's triangle. and trochanter) was measured in 37 healthy. white mother-daughter pairs by dual-photon absorptiometry. Mothers and daughters were aged 52 +/- 7 and 25 +/- 4 y (mean +/- SD). respectively. Three-day dietary intakes were evaluated. Significant correlations between mother-daughter pairs for BMD of all lumbar and femoral areas [except for L2 (r = 0.26. P = 0.054)] indicated familial resemblances in bone mineralization. Total calcium intake was significantly correlated with three BMD values for the daughters (L2. femoral neck. and trochanter) but not for the mothers. When mothers were classified as pre- (n = 20) or postmenopausal (n = 17). correlation coefficients for BMD were higher for premenopausal mothers and their daughters and lower for postmenopausal mothers and their daughters. except for the trochanter. The results suggest that the nature of inheritance of bone mass of women may have at least two components. one influencing the level of peak bone mass and one related to bone loss at menopause.
Dietary fat and risk of breast cancer, The relationship between dietary fat and subsequent risk of breast cancer was studied in 3988 initially cancer-free Finnish women aged 20-69 y. During a follow-up period of 20 y. 54 breast-cancer cases were diagnosed. Risk of breast cancer was significantly inversely related to energy intake and nonsignificantly inversely related to absolute fat intake. A positive association between energy-adjusted total fat intake and occurrence of breast cancer was also observed. The relative risk in the highest tertile as compared with the lowest tertile was 1.7 (95% confidence limits 0.6-4.8). The corresponding relative risks were 1.4 (0.5-3.7) for saturated fatty acids. 2.7 (1.0-7.4) for monounsaturated fatty acids. 1.2 (0.6-2.8) for polyunsaturated fatty acids. and 2.2 (1.0-5.0) for cholesterol intake. Adjustment for different potential confounding factors did not alter the results. The present data suggest that breast cancer is associated inversely with energy intake and weakly positively with energy-adjusted fat intake.
Breast cancer and dietary and plasma concentrations of carotenoids and vitamin A, A case-control study of breast cancer was conducted in Buffalo. Participants completed a food frequency questionnaire and donated a fasting blood sample before definitive workup for breast masses. Dietary and plasma concentrations of carotenoids and retinol for 83 women found to have breast cancer were compared with those of 113 women found to be free of breast cancer (control subjects). There were no case-control differences in dietary estimates of vitamin A intake or in plasma alpha-carotene and lycopene. However. subjects with breast cancer had lower concentrations of plasma beta-carotene than did control subjects (P = 0.02). There was no overall association between plasma retinol and breast cancer but a positive relationship was observed between retinol and breast cancer in the subgroup with low beta-carotene values. These results suggest that low plasma beta-carotene is associated with increased risk of breast cancer. Other studies will need to determine whether low carotene concentrations are a subtle effect of the disease or might be causally related to breast cancer.
Urinary organic acid excretion during feeding of medium-chain or long-chain triglyceride diets in patients with non-insulin-dependent diabetes mellitus, Medium-chain triglycerides (MCTs) are absorbed and metabolized differently from long-chain triglycerides (LCTs). Recent data indicate that MCTs may be useful as a dietary substitute in a variety of clinical disorders. The current studies were undertaken to characterize urinary organic acid excretion in patients with non-insulin-dependent diabetes mellitus during 4 d of an LCT or MCT diet. Urinary excretion of the dicarboxylic acids adipic. suberic. and 3-hydroxysebacic and the (omega-1) hydroxylation products 5-hydroxyhexanoic acid and 7-hydroxyoctanoic acid. was increased during MCT feeding as compared with LCT feeding. Urinary suberic and 7-hydroxyoctanoic acid excretions were increased 55- and 30-fold. respectively. during the MCT-substituted diet. Urinary organic acid profiles provide information on the fate of lipids during MCT feeding and may also be useful in assessing complicance during clinical trials employing MCT-substituted diets.
Cholesterol-lowering effect of skim milk from immunized cows in hypercholesterolemic patients, The effect of skim milk from cows immunized against a variety of human intestinal bacteria on serum cholesterol concentrations was examined in 11 patients with primary hypercholesterolemia in a 24-wk. randomized. double-blind. placebo-controlled. crossover study. After a 4-wk baseline period. patients were treated for 8 wk either with skim milk from immunized cows (active) or with control skim milk (placebo) followed by an 8-wk period with the treatment order reversed. Eight weeks of active treatment with skim milk from immunized cows reduced serum total cholesterol concentrations by 0.52 +/- 0.59 mmol/L (mean +/- SD; P less than 0.025). or 8%. LDL cholesterol by 0.16 +/- 0.59 mmol/L (NS). or 4%. and the atherogenic index (total cholesterol/HDL cholesterol) by 0.42 +/- 1.85 (P less than 0.05). or 8%. compared with the placebo treatment. Reversal of the favorable development occurred upon cessation of active treatment. We conclude that daily supplementation of a normal diet with skim milk from immunized cows can result in a significant reduction of elevated blood cholesterol concentrations.
Cholesterol-lowering effects of soluble-fiber cereals as part of a prudent diet for patients with mild to moderate hypercholesterolemia, Soluble-fiber breakfast cereals were examined for their cholesterol-lowering ability in 58 male patients with mild to moderate hypercholesterolemia in a randomized. double-blind. placebo-controlled study. Patients followed a step 1 diet for a minimum of 6 wk. then were randomly assigned to groups incorporating either corn flakes or one of two soluble-fiber cereals (pectin enriched or psyllium enriched) in the diet for an additional 6 wk. During the diet-only phase. total cholesterol dropped 3.8%. During the cereal-plus-diet phase. total and LDL cholesterol values of the pectin-enriched cereal group dropped an additional 2.1% (P = 0.243) and 3.9% (P = 0.16). respectively. and they dropped 5.9% (P = 0.005) and 5.7% (P = 0.034). respectively. in the psyllium-enriched cereal group. During the cereal-plus-diet phase. no significant effects on HDL cholesterol. triglyceride. or body weight were found within or between any cereal groups. These results support use of soluble-fiber cereals as an effective and well-tolerated part of a prudent diet in the treatment of mild to moderate hypercholesterolemia.
Erythrocyte fatty acids, plasma lipids, and cardiovascular disease in rural China, Cardiovascular disease (CVD) mortality (coronary heart disease. hypertensive heart disease. and stroke). plasma lipids. and red blood cell fatty acid composition were examined in an ecologic study in 65 rural counties in the People's Republic of China. Means of plasma total cholesterol. triglyceride. low-density-lipoprotein (LDL) cholesterol. and high-density-lipoprotein (HDL) cholesterol concentrations were substantially lower and the ratio of HDL cholesterol to total cholesterol was higher in this Chinese population than in Western populations. Mortality rates for CVD in China were well below Western values. Within China neither plasma total cholesterol nor LDL cholesterol was associated with CVD. A strong inverse correlation between red blood cell oleate concentrations and CVD was observed. However. red blood cell oleate concentrations were not associated with plasma cholesterol but were strongly negatively associated with arachidonate concentrations. suggesting potential diminution of CVD by oleate through reduced platelet aggregability. The results indicate that geographical differences in CVD mortality within China are caused primarily by factors other than dietary or plasma cholesterol.
Continuous glucose for treatment of patients with type 1 glycogen-storage disease: comparison of the effects of dextrose and uncooked cornstarch on biochemical variables, Responses to uncooked cornstarch (UCS). dextrose (Dex). and a 3:1 mixture (UCS:Dex) were determined in seven children with type 1 glycogen-storage disease (GSD-1). UCS maintained blood glucose (BG) and serum insulin concentrations between 3.5 +/- 0.3 and 4.0 +/- 0.4 mmol/L (mean +/- SEM) and 50 +/- 7 and 79 +/- 22 pmol/L. respectively. in six of the seven patients for 4 h. Only four of seven patients completed the 4-h test after UCS:Dex (BG 2.9 +/- 0.3 mmol/L): After Dex. tests had to be stopped in all patients by 150 min after initiation (BG 2.7 +/- 0.4 mmol/L). Two methods of providing dietary glucose overnight. continuous intragastric glucose infusion (COG) and intermittent UCS at 2100 and 0200. were compared by monitoring metabolites and glucoregulatory hormones. The use of UCS in amounts equal to the calculated glucose production rate is an effective method of providing a continuous dietary source of glucose overnight to patients with GSD-1.
Physical growth and development of children with type 1 glycogen-storage disease: comparison of the effects of long-term use of dextrose and uncooked cornstarch, Thirteen patients with type 1 glycogen-storage disease (GSD-1) were studied to compare the effects on biochemical control and growth of 2 y of therapy with intermittent feedings of uncooked cornstarch (UCS) at the fasting glucose production rate and therapy with continuous overnight glucose (COG) and dextrose feedings during the day. Mean biochemical abnormalities for the groups were minimized but not normalized by either COG or UCS. Growth progressed normally when COG was started by 1.2 y of age and normal growth rate was maintained by UCS. Weight increased from 101 +/- 3% ideal body weight at onset of COG to 127 +/- 5% during COG and the first year of UCS therapy but did not increase further in the second year. When growth failure occurred before onset of COG [-3.7 SD score for chronological age (SDSCA)]. only partial correction (-1.9 SDSCA) to genetic potential for height occurred. Intermittent feeding of UCS provides an effective alternative to COG for the treatment of GSD-1.
Vitamin A status in preschool-age Indonesian children as assessed by the modified relative-dose-response assay, The modified relative-dose-response (MRDR) assay has been validated in rats as a function of vitamin A status and tested in a group of American children. In this study the MRDR assay was applied to West Javan children who are at risk of being vitamin A deficient. Of 86 children enrolled. 75 were tested. In a time-course study involving 22 children aged 3.7-5.3 y. blood samples were taken at different times after doses of 0.35 mumol 3.4-didehydroretinyl acetate/kg body wt. Generally. the ratio of dehydroretinol to retinol (DR-R ratio) peaked between 4 and 8 h. Thereafter. in a survey of 53 children aged 0.6-4.8 y. single blood samples were drawn 5 h after the dehydroretinyl acetate dose. The DR-R ratio ranged from 0.0028 to 0.169. With a DR-R ratio of 0.03 as the cutoff value. 62% of the children were judged to be of marginal vitamin A status.
Iodine and selenium deficiency associated with cretinism in northern Zaire, Selenium status was determined in an endemic-goiter area and in a control area of Zaire. Compared with the reference values of a noniodine-deficient area. serum selenium in subjects living in the core of the northern Zaire endemic-goiter belt (Karawa villages) was seven times lower in 52 school-children and similarly low in 23 cretins; erythrocyte glutathione peroxidase (RBC-GPX) was five times lower in schoolchildren and still two times lower in cretins (P = 0.004). In a less severely iodine-deficient city of the same endemia (Businga). selenium status was moderately altered. RBC-GPX activity was linearly associated with serum selenium concentration up to a value of 1140 nmol/L and leveled off at approximately 15 U/g Hb at greater selenium concentration. At Karawa villages. selenium supplementation normalized both the serum selenium and the RBC-GPX. This combined iodine and selenium deficiency could be associated with the elevated frequency of endemic myxedematous cretinism in Central Africa.
Self-reported weight and height, The error in self-reported weight and height compared with measured weight and height was evaluated in a nationally representative sample of 11.284 adults aged 20-74 y from the second National Health and Nutrition Examination Survey of 1976-1980. Although weight and height were reported. on the average. with small errors. self-reported weight and height are unreliable in important population subgroups. Errors in self-reporting weight were directly related to a person's overweight status--bias and unreliability in self-report increased directly with the magnitude of overweight. Errors in self-reported weight were greater in overweight females than in overweight males. Race. age. and end-digit preference were ancillary predictors of reporting error in weight. Errors in self-reporting height were related to a person's age--bias and unreliability in self-reporting increased directly with age after age 45 y. Overweight status was also a predictor of reporting error in height.
Evidence for a secular change in obesity, height, and weight among Navajo Indian schoolchildren, A survey measuring heights and weights of 1969 schoolchildren residing on the Navajo Indian Reservation was conducted in 1989. The findings were compared with National Center for Health Statistics (NCHS) reference data and with surveys of Navajo children from 1955. 1968. and 1981. Approximately twice as many children exceeded the 95th percentile of weight-for-age (11.2% of girls. 12.5% of boys) than would be expected for the NCHS reference population. The mean weight-for-height z scores exceeded those for the NCHS reference population for all ages in both sexes. Compared with data from 1955. mean heights increased 6.1% among boys and 4.4% among girls whereas mean weights increased 28.8% among boys and 18.7% among girls across all age groups. The data suggest that there has been a secular change in height. weight. and obesity in Navajo Indian children over the past 35 y.
Demonstration of Lipiodol in paraffin sections using a modified silver impregnation technique, To demonstrate postangiographic Lipiodol (LIP) in hepatocellular carcinoma (HCC) in paraffin sections. direct impregnation of formalin-fixed tissue blocks with silver nitrate (AgNO3) was followed by routine processing. LIP appeared as black globules in the sinusoids. Ninety-four tissue blocks from 13 postangiographic LIP HCCs and 69 from 8 non-LIP HCCs and 4 fatty livers were studied. Seventy-two of 73 negative controls and all positive blocks as seen on soft tissue radiographs (STRs) were correctly coded (specificity 98.6%. sensitivity 100%). Twenty-six of the 44 LIP-negative areas on STRs from LIP cases contained scanty globules of less than 10 microns in diameter. Fatty change gave no positive readings. Thus. modified AgNO3 impregnation is a simple. accurate means of detecting LIP in high-quality paraffin sections suitable for tumor diagnosis and. if applied to postangiographic LIP. ultrasonographically guided liver biopsy. can verify that a biopsy has reached a suspected tumor focus.
Immunophenotypic aberrancy in adult acute lymphoblastic leukemia, Some recent reports indicate a high frequency of immunophenotypic aberrancy in acute lymphoblastic leukemia (ALL). To investigate this issue with regard to adult ALL. the authors reviewed the immunophenotyping data from 39 cases analyzed in their clinical laboratory. Flow cytometric analysis of peripheral blood and/or bone marrow was performed with the use of a panel of 21 B-cell. T-cell. and myeloid monoclonal antibodies (MoAbs). The surface antigen profiles of the leukemic cells were compared with those of normal bone marrow and thymic counterparts. as defined by current models. Twenty-six cases were B-precursor ALL. 8 were T-ALL. and 3 were B-ALL (Burkitt's leukemia). Only two cases coexpressed lymphoid and myeloid antigens. In contrast. intralineage aberrancy was quite common. Immunophenotypes from 13 of 26 B-precursor ALL cases deviated from normal B-lineage marrow cells as defined by a recent classification. The T-ALL cases were also immunophenotypically heterogeneous. This high incidence of aberrant antigen expression in adult ALL suggests that leukemogenesis also involves aberrant differentiation rather than purely a process of maturational arrest.
Histiocytosis X. S-100 protein, peanut agglutinin, and transmission electron microscopy study, Twenty-seven cases of histiocytosis X (HX) for which paraffin blocks were available were studied with the use of S-100 protein immunohistochemistry. peanut agglutinin affinity histochemistry. and transmission electron microscopy. The results show that these techniques did enable identification of Langerhans'-type histiocytes in 88.5%. 75%. and 47.4% of cases. respectively. All techniques were proved to be of some diagnostic value for HX. but none was able to confirm the diagnosis in all instances and none could foretell the prognosis of the patients. This study shows that besides the Langerhans' cells. the indeterminate cells of the skin and the interdigitating dendritic reticulum cells of the lymph node may also be involved in this process. Moreover. some multinucleate giant cells and foamy cells may be derived from Langerhans' and related cells.
Malignant rhabdoid tumor of the liver. A distinct clinicopathologic entity, A malignant rhabdoid tumor occurring as a primary hepatic neoplasm in a six-month-old white infant is reported. It was treated by an attempt at total resection involving right hepatic lobectomy and by chemotherapy with cis-platinum. VP-16. and Adriamycin. Despite this. recurrence of the tumor resulted in the girl's death within three months. The neoplasm showed typical light microscopic features of malignant rhabdoid tumor as well as filamentous cytoplasmic inclusions by electron microscopic examination and staining for both cytokeratin and vimentin by immunohistochemistry. The classic clinicopathologic features of this tumor support the concept that malignant rhabdoid tumors similar to those of the kidney may occur in extrarenal sites.
Primary malignant melanoma of the lower respiratory tract. Report of a case and literature review, The authors report a case of primary bronchial malignant melanoma. occurring in a 34-year-old woman presenting with persistent cough. At bronchoscopic examination. a polypoid mass was found to occlude the left mainstem bronchus. Biopsies showed a malignant epithelioid tumor resembling an atypical carcinoid. Histochemistry. electron microscopic study. and immunohistochemistry confirmed the diagnosis of melanoma. Physical examination and additional clinical history to exclude other possible primary sites were negative. The patient underwent thoracotomy with left pneumonectomy. Nineteen months after resection she was found to have a histologically similar tumor involving her left adrenal gland. Review of the literature shows that melanoma of the lower respiratory tract has been reported only in adults and has a tendency to present as a central polypoid growth that may be responsive to surgical resection.
Racial, social, and environmental risks for childhood asthma, Unlike a number of childhood problems. it is not clear that there are racial or socioeconomic disparities in the prevalence of childhood asthma. We analyzed data from the Child Health Supplement to the 1981 National health Interview Survey. a population-based survey with information concerning 15.416 children. to address the following questions: are there racial or socioeconomic differences in rates of childhood asthma; if yes. what is the contribution of social and environmental characteristics to the observed differences? In this sample. black children were more likely to have asthma than were white children (4.4% vs. 2.5%). Racial disparities in prevalence emerged early and at all childhood ages were due to higher black rates of onset between the ages of 1 and 3 years. Poverty status. maternal cigarette smoking. large family size. smaller size of home. low birth weight. and maternal age younger than 20 years at the child's birth were all associated with increased rates of childhood asthma. When available social and environmental characteristics were controlled for using multivariate analyses. the increased risk for asthma among black and poor children was reduced to statistical insignificance. We conclude that black and poor children in the United States do have higher rates of asthma. that social and environmental factors exert substantial influences on rates of asthma. and that much of the racial and economic disparity in prevalence can be accounted for by a variety of social and environmental characteristics.
Total and differential leukocyte counts in clinically well children. Information or misinformation, To determine whether the total and differential leukocyte count is of value as a case-finding test. we applied the evaluation criteria developed by the US Preventive Services Task Force. The criteria comprise review of the current burden of suffering of the disease to be prevented. the attributes of the intervention to be used. and the quality of the evidence available. A literature search revealed no evidence in the form of data from patients. so a chart review of all complete blood cell counts ordered during a 1-year period by one group of pediatricians was undertaken. At least one value outside of published normal ranges was found on 74.7% of the tests performed on clinically well children. No unsuspected illness was discovered as a result of an abnormal total and differential leukocyte count.
Immune complexes in pediatric human immunodeficiency virus infection, Circulating immune complexes (CIC) were analyzed in a cohort of 30 children infected with the human immunodeficiency virus. Elevated CIC were detected by the C1q assay in 70% (21/30) of all patients and by the Raji cell assay in 93% (28/30) of all patients. While only less than one third of patients with elevated CIC had free serum antibodies to Epstein-Barr virus. 80% (16/20) of them had detectable antibodies to Epstein-Barr virus associated with CIC. Enriched CIC in human immunodeficiency virus-infected children contained low levels of complement. These findings document that. as an expression of the humoral immunodeficiency. CIC in human immunodeficiency virus-infected children are deficient in complement and can thus be underestimated if complement-precipitating methods are used for their detection.
Pediatrician's knowledge and practices regarding parental use of alcohol, Problems with alcohol are common in the United States but are too frequently ignored by physicians. particularly those working with children. We explored pediatricians' knowledge and practices regarding parental use of alcohol and compared these attributes with those of family practitioners. Child health care providers attending three continuing medical education courses in general pediatrics were surveyed using a closed-item questionnaire. One hundred ninety (69%) of the participants responded. including 90 pediatricians and 39 family practitioners. Forty-six percent of responding pediatricians. compared with 90% of family practitioners. stated that they ask about problems with alcohol in taking a routine family history. Thirty-eight percent of pediatricians who knew the frequency of alcoholism. compared with 47% of those who did not. indicated that they include it in taking a routine family history. Forty-six percent of pediatricians who have experienced a problem with alcohol in their own family. compared with 20% of pediatricians without such personal experience. routinely address the issue of alcohol use with parents and children. Similar analyses among the family practitioners revealed no significant differences. We conclude that fewer than half of pediatricians ask about problems with alcohol in taking a family history. The likelihood of asking about such problems was not influenced by the health care provider's knowledge of alcoholism. but it was influenced by the provider's personal family history of problems with alcohol. Because of the important morbidity associated with alcohol use in families. and because intervention can improve functioning and adaptation of the child. training and Continuing Medical Education courses should address this issue.
Neurodevelopmental performance of very-low-birth-weight infants with mild periventricular, intraventricular hemorrhage. Outcome at 5 to 6 years of age, The neurodevelopmental outcome of 38 very-low-birth-weight neonates (birth weight. less than 1501 g) was followed up prospectively from birth to 5 to 6 years of age to assess the neurodevelopmental sequelae of mild periventricular. intraventricular hemorrhage (grades I and II). All neonates were screened for periventricular. intraventricular hemorrhage at 5 to 10 days of age. Eleven incurred a mild periventricular. intraventricular hemorrhage (group 1) and 27 had no periventricular. intraventricular hemorrhage (group 2). Each of the infants was neurodevelopmentally normal at 1 to 2 years of age. The 38 children were matched by race. age. sex. and socioeconomic status with control children (group 3) who had been born at term. On outcome measurements at 5 to 6 years of age. groups 1 and 2 scored significantly lower than group 3 on the combined test measurements and on three of the four individual measurements. Group 1 scored significantly lower than group 2 on the combined test measurements only. These data indicate that very-low-birth-weight infants are at risk for learning problems. Although children with mild periventricular. intraventricular hemorrhage did not demonstrate a significant deficit on individual test scores. the significant difference on the combined battery suggests that mild periventricular. intraventricular hemorrhage has an adverse effect on global performance.
Percutaneous central venous catheterization. Three years' experience in a neonatal intensive care unit, Prolonged venous access is desirable in very-low-birth-weight infants and infants for whom feedings are contraindicated. We prospectively evaluated 481 small-diameter venous catheters placed percutaneously in 317 patients over 3 years. Of 478 catheters. 241 (50%) were placed in infants weighing 1 kg or less. Mean catheter stay was 13 days (range. less than 1 to 77 days). Almost half (49%) of the central and thoracic catheters (91% of placements) were removed nonelectively: 43% due to problems such as leaking or clotting and 6% to suspicion of sepsis or venous occlusion. Of the 23 episodes of possible sepsis in the 478 catheter stays. six (1.3%) were confirmed catheter-related sepsis; 12 (2.5%) were confirmed alternate locus sepsis. Three factors specific to percutaneous central venous catheter-related sepsis were prolonged catheter stay (3 to 5 weeks). Staphylococcus epidermidis. and weight less than or equal to 1 kg. Four factors specific to alternate locus sepsis were presence of an alternate infection site. earlier infection (1 to 2 weeks). extremely low birth weight. and prolonged clinical instability. Percutaneous central venous catheterizations reduced the need for the stress of repeated venipuncture. resulting in lower complication rates than those reported with surgically placed central venous catheters. and leading to identification of risk factors specific to catheter sepsis and alternate locus sepsis.
Physical features of Prader-Willi syndrome in neonates, A retrospective study of 16 patients was undertaken to identify physical features that may typify neonates with Prader-Willi syndrome. Several features known to be typical of Prader-Willi syndrome in early infancy were confirmed. including hypotonia and genital hypoplasia. A number of features that have not previously been emphasized as characterizing Prader-Willi syndrome were also identified. most notably abnormal cry and. in males. signs of genital hypoplasia but with an apparently normal phallus. Other features included disproportionately large head circumference. disproportionately large anterior fontanelle. mild micrognathia. mild anomalies of the gingivae or alveolar ridges. and changes in the appearance of the skin. Appreciation of these features may assist the pediatrician in recognizing the child with Prader-Willi syndrome during the neonatal period. before the appearance of better-known findings of later onset. such as obesity and acromicria.
Effect of omeprazole and high doses of ranitidine on gastric acidity and gastroesophageal reflux in patients with moderate-severe esophagitis, Thirty to fifty percent of patients with reflux esophagitis fail to heal after treatment with conventional doses of H2-receptor antagonists. whereas omeprazole administration induces more than 90% healing. To investigate the effect of omeprazole and higher-than-presently-recommended doses of H2-blockers. we evaluated gastric acidity and gastroesophageal reflux in 17 patients with severe-moderate esophagitis before and after treatment with 300 mg ranitidine twice daily or 20 mg omeprazole once daily. Three pH-metric studies were performed. in a cross-over design. before and after 8 days of treatment with omeprazole or ranitidine. Both drugs significantly reduced intragastric acidity (p less than 0.001) during both night and day hours. Median hourly 24-h intragastric pH was 1.8 in the basal study. 2.9 after ranitidine. and 3.4 after omeprazole. Intragastric acidity fell from 84.0 mmol/L in the basal study to 14.2 mmol/L (79% inhibition) with ranitidine and 9.3 mmol/L (84% inhibition) with omeprazole. Patients with esophagitis were significantly more exposed to acid than healthy subjects. in both the supine and upright position (p less than 0.01). The time with esophageal pH less than 4 dropped from 23.9% in the basal study to 8.5% with ranitidine and to 7.2% with omeprazole (p less than 0.001). Both drugs significantly reduced esophageal exposure to acid in both the supine and upright positions (p less than 0.001). whereas neither had any effect on esophageal acid clearance.
Esophageal 24-h pH monitoring: is prior manometry necessary for correct positioning of the electrode, In 24-h esophageal pH monitoring. the electrode is usually positioned 5 cm above the manometrically localized esophagogastric junction. In order to replace esophageal manometry for this purpose. we tested whether the esophagogastric junction can be identified correctly by fluoroscopy or the determination of the pH-step between stomach and esophagus. compared with esophageal manometry. The distance from the nares to the esophagogastric junction was determined three times with each of the three methods in 46 patients and 14 volunteers. Fluoroscopy assumed the esophagogastric junction 1.23 +/- 0.23 cm (mean +/- SE) lower than the peak pressure point determined at manometry. pH-step only 0.45 +/- 0.16 cm. With pH-step. only one subject had a difference of more than 3 cm to the manometrically defined esophagogastric junction. whether gastroesophageal reflux disease (as proven by pH monitoring) was present or not. We conclude that the esophagogastric junction can usually be identified with sufficient accuracy by the measurement of the pH-step between stomach and esophagus. Fluoroscopy is far less accurate than pH-step. and should not be used.
Granular cell tumor of the esophagus: endoscopic ultrasonographic demonstration and endoscopic removal, A 35-yr-old Japanese man with a granular cell tumor of the esophagus that was removed by endoscopic polypectomy is presented. Radiography and endoscopy showed a 20 x 12 mm sessile protrusion in the distal esophagus. Endoscopic ultrasonography demonstrated the hypoechoic mass in the submucosa without continuity to the muscularis propria. The lesion was successfully treated by endoscopic polypectomy without complications. The cross-sections of the resected specimen were quite in agreement with the ultrasonographic findings. Endoscopic ultrasonography is valuable to assess the exact location and extent of the tumor. and to determine the indication for endoscopic polypectomy.
Primary abscess of the omentum, A 65-yr-old man presented with upper abdominal pain and fever due to a primary abscess of the omentum. The finding of microscopic-size foreign particles within the abscess raised the possibility of antecedent clinically silent perforation of the bowel or appendix. Surgical resection and antibiotic therapy were curative.
A chance to cut is a chance to cure, Fifty-seven patients underwent local excision of an invasive distal rectal cancer as an initial operative procedure with curative intent. Five-year survival was 82.5%. and the rectal cancer specific mortality rate was only 10.5%. The level of wall invasion. vascular permeation. tumor ulceration. mobility. and differentiation were the criteria studied for prognosis. Poor prognostic factors included mucinous cell differentiation and full thickness invasion. and in these cases. abdominoperineal resection was recommended. None of the 27 patients without these adverse prognostic factors died from rectal cancer. The other factors did not appear to influence the outcome. and local excision of distal rectal cancer would be the treatment of choice in such selected patients.
Oral dissolution therapy for cholelithiasis: mix and match, The authors conducted a prospective. randomized trial of chenodeoxycholic and ursodeoxycholic acid versus ursodeoxycholic acid alone in patients with cholelithiasis to determine their efficacy for dissolution of gallstones. One hundred and twenty patients with radiolucent gallstones. less than or equal to 15 mm and who had a functioning gallbladder were enrolled. The patients were divided into two groups based on the diameter of their largest stones. Seventy patients had stones larger than 5 mm but less than 15 mm. whereas 50 patients had stones that measured 5 mm or less. The patients were randomly assigned to treatment with chenodeoxycholic acid plus ursodeoxycholic acid (5 mm/kg of each) or ursodeoxycholic acid (10 mm/kg) alone. Oral cholecystography. plain abdominal x-rays. and ultrasonography of the gallbladder were done at 6. 12. and 24 months. Dissolution was deemed to be complete if not stones were visualized on two examinations. partial dissolution was defined as a 50% reduction in stone size and/or number. Stones that were not detected by cholecystography but still detected during ultrasonography were considered to be partially dissolved. Plasma triglycerides. serum cholesterol. HDL. and serologic liver function tests were determined at 1. 3. 6. 12. 18. and 24 months. In a select group of patients. bile-rich duodenal aspirates were aspirated and analyzed for biliary lipid contents. In the group with small stones. defined as less than or equal to 5 mm. complete stone dissolution occurred significantly more often utilizing combination therapy at 6 months (52% vs 24%). and this trend persisted. although no longer significant. at 12 and 24 months. Combination therapy also achieved an improved rate of dissolution for large stones within 6 months; however. this did not persist at 12 and 24 months. Although not statistically significant. stone calcification occurred less often with combined therapy. All treatment regimens were well tolerated. with only minor changes in bowel habits and mild elevations in serum transaminase levels. Serum lipid levels did not change with either therapy. The authors concluded that the combination of chenodeoxycholic acid and ursodeoxycholic acid was the preferred therapy for gallstone dissolution. because it dissolves stones more rapidly. with a lower incidence of stone calcifications. and thus might reduce the long-term cost of treatment.
"Cloggology" revisited: endoscopic or surgical decompression of malignant biliary obstruction, In this study. 50 consecutive patients over age 60 with obstructive jaundice secondary to malignant stricture of the distal common bile duct were identified by endoscopic cholangiography. The patients were then randomized to palliative therapy with either endoscopic endoprosthesis or bypass surgery. Prospective indices of survival time. complication rates. hospitalization requirements. and quality of life were followed. All 25 patients randomized to endoprosthesis were treated by this procedure. whereas only 19 of 25 patients randomized to bypass surgery underwent operative biliary-digestive anastomosis. No difference in the above indices were found between the two groups. The authors concluded that palliation of obstructive jaundice due to a malignant bile duct stricture with endoscopically placed biliary stent is as effective as operative bypass.
Extracorporeal removal of anti-HLA antibodies in transplant candidates, We report on the results of a clinical trial in which 14 transplant candidates were treated with an extracorporeal immunoadsorption system using Protein A that selectively removes immunoglobulin from plasma; we also assessed the dynamics of anti-HLA antibody as a model of IgG removal and re-equilibration. as well as the clinical safety of the procedure. At the end of a treatment course. plasma IgG levels were reduced by 90% +/- 8% of control values (P less than 0.01). In contrast. albumin levels were reduced by only 15% (P less than 0.05). Specific cytotoxic anti-HLA antibody titers were reduced by approximately 18-fold. Panel reactivity was measured as the proportion of a 40-member cell donor panel killed by patients' serum in the presence of complement; in nine of the 14 patients. there was a significant reduction in this parameter (range. 23% to 87%). During the 4-week follow-up period. anti-HLA antibody titers returned to baseline levels. There were no remarkable changes observed in blood chemistries. nor were there any unanticipated adverse reactions seen in the patients treated. We conclude that selective extracorporeal immunoadsorption is a safe and effective way of removing IgG-type antibodies. with potential application to reduction of HLA antibodies in transplant candidates.
Adult minimal change glomerulopathy with acute renal failure, Oliguric acute renal failure occurs in some adult patients with minimal change glomerulopathy. To look for clinical and pathologic factors that increase the risk for developing acute renal failure. 21 adults with minimal change glomerulopathy and a serum creatinine greater than 177 mumol/L (mean. 486 mumol/L; range. 194 to 1.344 mumol/L) (greater than 2.0 mg/dL [mean. 5.5 mg/dL; range. 2.2 to 15.2 mg/dL]) were compared with 50 adults with minimal change glomerulopathy and a serum creatinine less than 133 mumol/L (mean. 88 mumol/L; range. 53 to 124 mumol/L) (less than 1.5 mg/dL [mean. 1.0 mg/dL; range. 0.6 to 1.4 mg/dL]). Minimal change glomerulopathy patients with acute renal failure were older (59.5 v 40.3 years. P less than 0.001). and had higher systolic blood pressure (158 v 138 mm Hg. P = 0.001). more proteinuria (13.5 v 7.9 g/24 h. P = 0.01). and more arteriosclerosis in the renal biopsy specimen (1.7 + v 0.7 + on a scale of 0 to 4+. P = 0.005). Tubular epithelial simplification identical to that observed with ischemic acute renal failure (acute tubular necrosis) was observed in 71% of the patients with serum creatinine greater than 177 mumol/L (greater than 2.0 mg/dL) and 0% of those with less than 133 mumol/L (less than 1.5 mg/dL). All 18 patients with renal failure for whom follow-up data were available had recovery of function (mean creatinine. 539 +/- 301 mumol/L [6.1 +/- 3.4 mg/dL] at the time of biopsy and 106 +/- 27 mumol/L [1.2 +/- 0.3 mg/dL] at last follow-up). but sometimes only after weeks of dialysis support.
Bioavailability of iron in hemodialysis patients treated with erythropoietin: evidence for the inhibitory role of aluminum, The dose of recombinant human erythropoietin (r-HuEPO) required to correct the anemia of end-stage renal disease (ESRD) varies among patients. The response to r-HuEPO is impaired if absolute or relative iron deficiency exists. Aluminum may cause a microcytic anemia in patients with ESRD. but the mechanism remains incompletely defined. Twenty-two patients in the Canadian Multicentre EPO trial were studied for 6 months. In this randomized double-blind placebo-controlled trial. free erythrocyte protoporphyrin (FEP) was used as an indicator of iron-deficient deficient erythropoiesis. The relationship of FEP to the estimates of iron availability (serum iron. transferrin saturation. ferritin) and iron utilization (corrected reticulocyte count. hemoglobin) was evaluated by multiple linear regression analysis. The effect of aluminum on FEP was evaluated by adjusting the statistical model for this variable. All patients were iron replete as assessed by serum ferritin. FEP was not related to serum aluminum before administration of r-HuEPO. but it was significantly correlated with aluminum in the treated group. In hemodialysis patients treated with r-HuEPO. the proportion of the variability explained by the parameters of iron utilization and iron availability was 0.27. The effect of aluminum increased this to 0.59. In hemodialysis patients not receiving r-HuEPO. the proportion of variability in FEP explained by the model increased from 0.16 to 0.28 by adjusting for aluminum. The data support the hypothesis that aluminum interferes with the bioavailability of stored iron for erythropoiesis and thus may result in a microcytic anemia in patients with ESRD or may blunt their response to r-HuEPO therapy.
Brachial-jugular polytetrafluoroethylene fistulas for hemodialysis, A retrospective analysis was made of 16 patients who had received a brachial-jugular polytetrafluoroethylene (PTFE) graft for hemodialysis. In four patients. the procedure was used to treat malfunctioning brachio-axillary fistulas due to long venous stenosis in the axillary vein. In 12 other patients. the operation was chosen in cases of exhaustion of the veins in the upper extremity because of previous multiple failed fistulas. Two patients died with a functioning fistula 7 and 10 months after placement of the graft of causes unrelated to the vascular access. The other 14 patients retained functioning fistulas between 8 and 26 months after construction of the shunt. Three patients needed graft thrombectomy to treat occlusive episodes. No venous stenosis was found in a postoperative fistulography made in those patients. One patient needed substitution of a graft segment due to stenosis of the prosthesis crossing over the clavicle. We believe that the brachial-jugular graft is a procedure that can be considered as vascular access for hemodialysis in cases where the use of veins in the upper extremity and the axilla is not possible.
The renal concentrating defect associated with potassium depletion is independent of prostaglandin E2, Prostaglandin E2 (PGE2) impairs the hydrosmotic effect of vasopressin in toad bladder and mammalian kidney. Because some studies in animals have suggested that potassium depletion enhances renal PGE2 production. the present study examined whether the renal concentrating defect of potassium depletion in humans is mediated by PGE2. Five normal volunteers were studied before and after moderate potassium depletion achieved by 10 days of dietary potassium restriction and administration of a polystyrene sulfonate potassium exchange resin (Kayexalate). Maximal urinary osmolality (Umax) decreased from 1.094 +/- 58 (mean +/- SEM) to 820 +/- 26 mmol/kg (mOsm/kg) (P less than 0.01) following potassium depletion. but urinary PGE2 excretion did not change (496 +/- 145 and 435 +/- 186 ng/d. respectively). Indomethacin suppressed PGE2 excretion significantly. but failed to increase Umax in either the normal or the potassium-depleted state (1.094 +/- 34 and 825 +/- 56 mmol/kg. respectively). It is concluded that the renal concentrating defect produced by moderate potassium restriction in humans is not mediated by PGE2.
The NT 1311 polymorphism of G6PD: G6PD Mediterranean mutation may have originated independently in Europe and Asia, A polymorphic site exists in exon 11 of G6PD: in the wild-type enzyme. nucleotide (NT) 1311 is a C. but is some individuals from diverse populations a T is present instead. Nine of 54 X chromosomes from Europeans of mixed origins. nine of 41 X chromosomes of Ashkenazi Jewish subjects. three of 18 X chromosomes of Sicilians. five of 20 African X chromosomes. and nine of 20 Asian Indian X chromosomes had the mutant genotype. In contrast. the mutation was found in only three of 59 Oriental X chromosomes and in three of 30 Central/South American X chromosomes. The mutation was absent from four samples of chimpanzee DNA. Twenty-one of 22 male subjects from Mediterranean countries who had the G6PD Mediterranean 563T genotype investigated in the present study or reported previously had a T at NT 1311. Only one had the normal C at NT 1311. In contrast. both G6PD Mediterranean563T males from the Indian subcontinent had the normal C at NT 1311. These findings suggest that the same mutation at nucleotide 563 giving rise to G6PD Mediterranean may have arisen independently in Europe and in Asia.
Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East, A common glucose-6-phosphate dehydrogenase (G6PD) variant characterized by severe enzyme deficiency and B-like electrophoretic mobility is called "G6PD-Mediterranean" because it is found in different populations around the Mediterranean Sea. Sequence analysis of Italian subjects has revealed that the molecular basis of G6PD-Mediterranean is a single C-T transition at nucleotide position 563. causing a serine phenylalanine replacement at amino acid position 188. Most G6PD-Mediterranean subjects also have a silent C-T transition (without amino acid replacement) at nucleotide position 1311. Twenty-one unrelated individuals from Saudi Arabia. Iraq. Iran. Jordan. Lebanon. and Israel with both severe G6PD deficiency and B-like electrophoretic mobility were tested for both mutations by using amplification followed by digestion with appropriate restriction enzymes. All but one had the 563 mutation. and. of these. all but one had the 1311 mutation. Another 24 unrelated Middle Eastern individuals with normal G6PD activity or not known to be G6PD deficient were similarly tested. Four had the silent mutation at position 1311 in the absence of the deficiency mutation at position 563. We conclude that (1) the large majority of Middle Eastern subjects with the G6PD-Mediterranean phenotype have the same mutation found in Italy. (2) the silent mutation is an independent polymorphism in the Middle East. with a frequency of about .13. and (3) the mutation leading to the G6PD-Mediterranean deficiency has probably arisen on a chromosome that already carried the silent mutation.
Recombination between two 14-bp homologous sequences as the mechanism for gene deletion in factor IX Seattle 1, Factor IXSeattle 1 is a 10-kb intragenic deletion identified in a family that has hemophilia B. By sequencing across the site of the deletion. we discovered at the deletion junction a 13-bp sequence (5' . . . TAGAA-GTTCACTT . . . 3') that was homologous to two 14-bp sequences 10 kb apart in introns D and F of the normal factor IX gene. The presence of these homologous sequences in two different regions of the normal gene allows us to propose that genetic recombination has occurred between the sequences. resulting in the gene deletion. The precise recombination site was able to be localized to one of 5 bp (5' . . . AGTTC . . . 3') in the middle of the homologous sequences. The exact length of the deletion is 10.000 bp.
Maternal serum alpha-fetoprotein screening activities of state health agencies: a survey, Maternal serum alpha-fetoprotein (MSAFP) screening has been demonstrated to be cost-effective on a population basis and is becoming standard practice. The American Society of Human Genetics has twice published policy statements to define the essential elements of a quality screening program. The present study reviewed the impact of these policy statements on state public-health agencies with respect to regulation or provision of MSAFP screening in their jurisdictions. With a few exceptions. states have not elected to play a major role in provision or regulation of this test. There is need to address issues of funding. standards. and data collection in a collaborative effort. if policy statements on genetic services are to be translated into effective state population screening.
Localization of the microsatellite probe DXS426 between DXS7 and DXS255 on Xp and linkage to X-linked retinitis pigmentosa, The microsatellite marker DXS426 maps to the interval Xp21.1-Xp11.21. the chromosomal region which contains two loci for X-linked retinitis pigmentosa (XLRP; RP2 and RP3). We have refined the localization of DXS426 both physically. by mapping it to a deletion which spans the interval Xp21.3-Xp11.23. and genetically. by studying multiply informative crossovers which indicate that DXS426 lies between DXS7 and DXS255 (i.e.. Xp11.4-Xp11.22). As this is the region which contains the RP2 gene. RP2 families could be identified on the basis of linkage of XLRP to DXS426. Multiply informative crossovers in two RP2 families indicate that the most likely location of the RP2 gene is between DXS426 and DXS7. DXS426 is therefore an important highly informative marker for the purposes of carrier detection and early diagnosis of RP2 and for the localization of the disease gene.
Autosomal dominant retinitis pigmentosa: absence of the rhodopsin proline----histidine substitution (codon 23) in pedigrees from Europe, In exon 1 at codon 23 of the rhodopsin gene. a mutation resulting in a proline-to-histidine substitution has previously been observed in approximately 12% of American autosomal dominant retinitis pigmentosa (ADRP) patients. The region around the site of this mutation in the rhodopsin gene has been amplified and analyzed in affected individuals from 91 European ADRP pedigrees. The codon 23 mutation has been found to be absent in all cases. including a large Irish pedigree in which the disease gene has previously been shown to be closely linked to the rhodopsin locus. This indicates the presence of either allelic or nonallelic heterogeneity in ADRP.
Analysis of DNA polymorphisms suggests that most de novo dup(21q) chromosomes in patients with Down syndrome are isochromosomes and not translocations, Down syndrome is rarely due to a de novo duplication of chromosome 21 [dup(21q)]. To investigate the origin of the dup(21q) and the nature of this chromosome. we used DNA polymorphisms in 10 families with Down syndrome due to de novo dup(21q). The origin of the extra chromosome 21q was maternal in six cases and paternal in four cases. Furthermore. the majority (eight of 10) of dup(21q) chromosomes were isochromosomes i(21q) (four were paternal in origin. and four were maternal in origin); however. in two of 10 families the dup(21q) chromosome appeared to be the result of a Robertsonian translocation t(21q;21q) (maternal in origin in both cases).
Localization of the human angiogenin gene to chromosome band 14q11, proximal to the T cell receptor alpha/delta locus, The gene encoding angiogenin. a potent inducer of blood vessel formation. has been localized within the human genome. It is present as a single copy per haploid genome and is located on chromosome 14. on the basis of discordancy analysis of human-rodent hybrid cell lines. This localization was refined to 14q11 by in situ hybridization of an angiogenin probe to metaphase chromosomes prepared from both normal human lymphocytes and RPMI 8402 cells. The results from the RPMI 8402 cells also establish that the angiogenin gene resides proximal to a translocation breakpoint within the T cell receptor alpha/delta locus and therefore upstream from that locus. An AvaII RFLP. present at a frequency of 29% in an unselected collection of human placental DNAs. was identified in the coding region of the gene and results from a single silent transversion.
Replication patterns of the fragile X in heterozygous carriers: analysis by a BrdUrd antibody method, The replication status of the fragile X chromosomes was studied in short-term cultures of lymphocytes from six female heterozygous carriers. The fragile X was induced by adding 0.1 microM fluorodeoxyuridine during the last 24 h of culturing. The replication status of the X chromosomes was studied using a bromodeoxyuridine (BrdUrd) antibody method. BrdUrd was added (1) at a final concentration of 0.2 micrograms/ml during the early S phase of chromosome replication (16-10 h before harvest). (2) at 0.2 microgram/ml during the late S phase (the last 6 h of culturing). (3) at 20 micrograms/ml during the early S phase. and (4) at 20 micrograms/ml during the late S phase. BrdUrd that was incorporated into replicating chromosomes was detected by using a nuclease and BrdUrd monoclonal antibody. The frequency of the fragile X was reduced by BrdUrd treatment. The degree of reduction was more severe in the 20 micrograms/ml than in the 0.2 microgram/ml series and was more severe with late S than with early S treatment. Of the early- and late-replicating fragile X chromosomes. those which were actively replicating during a BrdUrd treatment were more reduced than the others. Thus. the average rate of early and late S treatment with 0.2 microgram BrdUrd/ml was assumed to be the closest reflection of the situation in vivo. There was no correlation between the average rate of the early replicating. active fragile X and the intelligence of the heterozygous carriers studied.
A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome, PURPOSE: Currently. there is no established therapy for chronic fatigue syndrome (CFS). a recently defined illness that has been associated with a variety of immunologic abnormalities. Based on the hypothesis that a chronic viral infection or an immunoregulatory defect is involved in the pathogenesis of CFS. the therapeutic benefit of intravenous immunoglobulin G (IV IgG) was evaluated in a group of patients with CFS. Additionally. serum immunoglobulin concentrations and peripheral blood lymphocyte subset numbers were measured at the outset of the study. and the effect of IV IgG therapy on IgG subclass levels was determined. PATIENTS AND METHODS: Thirty patients with CFS were enrolled in a double-blind. placebo-controlled trial of IV IgG. The treatment regimen consisted of IV IgG (1 g/kg) or intravenous placebo (1% albumin solution) administered every 30 days for 6 months. Participants completed a self-assessment form prior to each of the six treatments. which was used to measure severity of symptoms. functional status. and health perceptions. Patients were also asked to report adverse experiences defined as worsening of symptoms occurring within 48 hours of each treatment. RESULTS: Twenty-eight patients completed the trial. At baseline. all 28 patients complained of moderate to severe fatigue. and measures of social functioning and health perceptions showed marked impairment. Low levels of IgG1 were found in 12 (42.9%). and 18 (64.3%) had low levels of IgG3. At the end of the study. no significant therapeutic benefit could be detected in terms of symptom amelioration or improvement in functional status. despite restoration of IgG1 levels to a normal range. Major adverse experiences were observed in 20% of both the IV IgG and placebo groups. CONCLUSION: The results of this study indicate that IV IgG is unlikely to be of clinical benefit in CFS. In addition to the ongoing need for placebo-controlled trials of candidate therapies for CFS. an expanded research effort is needed to define the etiology and pathogenesis of this disorder.
A bleeding risk index for estimating the probability of major bleeding in hospitalized patients starting anticoagulant therapy, PURPOSE: To construct and test prospectively a bleeding risk index for estimating the probability of major bleeding in hospitalized patients starting long-term anticoagulant therapy. PATIENTS AND METHODS: In an inception cohort of 617 patients starting long-term anticoagulant therapy in one hospital. data were gathered retrospectively and bleeding was classified using reliable explicit criteria. We constructed a bleeding risk index by identifying and weighting independent predictors of major bleeding using a multivariate proportional-hazards model. The bleeding risk index was tested in 394 other patients prospectively identified in a second hospital. The index was compared to physicians' predictions. RESULTS: Major bleeding developed before discharge in 61 of all 1.011 patients (6%). The bleeding risk index included four independent risk factors for major in-hospital bleeding: the number of specific comorbid conditions; heparin use in patients aged 60 years or older; maximal prothrombin or partial thromboplastin time 2.0 or more times control; liver dysfunction worsening during therapy. In the testing group. the index predicted major bleeding. which occurred in 3% of 235 low-risk patients. 16% of 96 middle-risk patients. and 19% of 63 high-risk patients (p less than 0.001). The bleeding risk index performed as well as physicians' predictions. and integration of the bleeding risk index with physicians' predictions led to a classification system that was more sensitive (p = 0.03) than physicians' predictions alone. In 86% of patients with a high risk of major bleeding. we identified specific ways of improving therapy. e.g.. avoiding overanticoagulation and nonsteroidal anti-inflammatory agents. CONCLUSION: The bleeding risk index provides valid estimates of the probability of major bleeding in hospitalized patients starting long-term anticoagulant therapy and complements physicians' predictions. The possibility that bleeding can be prevented in high-risk patients warrants prospective evaluation.
Interrelationships between age, thyroid volume, thyroid nodularity, and thyroid function in patients with sporadic nontoxic goiter, PURPOSE: To test the hypothesis that during the natural history of sporadic nontoxic goiter (SNG). a diffuse goiter precedes a multinodular goiter with gradual development of autonomous thyroid function. PATIENTS AND METHODS: A cross-sectional survey of 102 consecutive patients with SNG (seven male. 95 female) was performed. Thyroid volume was measured by ultrasonography. and plasma thyroid-stimulating hormone (TSH) by a sensitive assay (TSH immunoradiometric assay). RESULTS: Patients with a multinodular goiter were older and had a larger thyroid volume than patients with a diffuse or uninodular goiter. Plasma free thyroxine (T4) and total triiodothyronine (T3) were higher and plasma TSH was lower in patients than in normal subjects. Free T4 was higher in the subgroup of patients with a multinodular goiter and a decreased TSH response to thyrotropin-releasing hormone. Plasma TSH (y. in mU/L) was negatively related to thyroid volume (x. in mL): y = 8.2x-0.667 (r = 0.578. p less than 0.001). Thyroid volume (y. in mL) was positively related to age (x. in years): y = -21.8 + 2.0x (r = 0.455. p less than 0.001); and to duration of goiter (x. in years): y = 40.6 + 2.1x (r = 0.505. p less than 0.001). The annual increase in thyroid volume was calculated at 4.5%. CONCLUSION: The data suggest a continuous growth of SNG and provide support for the concept of increasing thyroid nodularity and autonomy of thyroid function--related to increasing thyroid volume--during the natural history of this disorder.
Developing improved observational methods for evaluating therapeutic effectiveness, Therapeutic efficacy is often studied with observational surveys of patients whose treatments were selected nonexperimentally. The results of these surveys are distrusted because of the fear that biased results occur in the absence of experimental principles. particularly randomization. The purpose of the current study was to develop and validate improved observational study designs by incorporating many of the design principles and patient assembly procedures of the randomized trial. The specific topic investigated was the prophylactic effectiveness of beta-blocker therapy after an acute myocardial infarction. To accomplish the research objective. three sets of data were compared. First. we developed a restricted cohort based on the eligibility criteria of the randomized clinical trial; second. we assembled an expanded cohort using the same design principles except for not restricting patient eligibility; and third. we used the data from the Beta Blocker Heart Attack Trial (BHAT). whose results served as the gold standard for comparison. In this research. the treatment difference in death rates for the restricted cohort and the BHAT trial was nearly identical. In contrast. the expanded cohort had a larger treatment difference than was observed in the BHAT trial. We also noted the important and largely neglected role that eligibility criteria may play in ensuring the validity of treatment comparisons and study outcomes. The new methodologic strategies we developed may improve the quality of observational studies and may be useful in assessing the efficacy of the many medical/surgical therapies that cannot be tested with randomized clinical trials.
Effects of calcium channel blockade on calcium homeostasis in mild to moderate essential hypertension, Calcium channel blockers may alter parathyroid hormone secretion in vitro. which would alter calcium homeostasis. To determine the chronic effect of calcium channel blockade in vivo. we conducted a randomized. double blind. 16 week study comparing the effects of two pharmacologic antihypertensive agents. the calcium channel blocker diltiazem and the angiotensin-converting enzyme inhibitor captopril on parameters of calcium homeostasis. Both diltiazem and captopril lowered blood pressure to a similar degree. Neither drug produced any significant change in blood levels of total and ionized calcium. magnesium. or phosphorus. which affect the regulation of parathyroid hormone and vitamin D. In addition. at eight or 16 weeks following initiation. neither drug altered the serum levels of parathyroid hormone (PTH) or 1.25-(OH)2-vitamin D3 (1.25-D). Chronic calcium channel blockade with diltiazem does not alter serum parameters of calcium homeostasis and. thus. should not affect bone mineralization.
Epidemiology of Lyme disease in Virginia, Prior to January 1986. only one case of Lyme disease was reported from Virginia. In 1986-87. however. the Virginia Department of Health observed an increase in reports of suspected Lyme disease by physicians. despite the fact that Ixodes dammini is not highly prevalent in the Virginia tick population. Twenty-eight cases of Lyme disease were identified in Virginia. of which eight cases occurred in 1986 and 20 in 1987. Lyme disease appears to be increasing in frequency in Virginia and moving southward along the Eastern Atlantic Seaboard.
Disseminated intravascular coagulation due to intravenous administration of hetastarch, Disseminated intravascular coagulation occurred in a patient after intravenous administration of hetastarch. The onset was acute within 3 hours after exposure to the agent and the course was fulminating. The patient died in 48 hours. Clinical. hematologic. and pathologic features are presented and possible pathophysiologic mechanism is discussed. In view of this experience and documented effects of hetastarch on coagulation. the use of hetastarch should be avoided if the patient has a history of coagulation disorder. and the patient receiving the agent should be closely monitored with appropriate coagulation tests.
Molecular biology in cardiology: recent developments and opportunities for clinical applications, The revolution in molecular biology that has taken place in the last decade has provided powerful research methods that are changing our understanding of cardiovascular physiology and disease. This editorial commentary will highlight several areas of current research activity within the broad and expanding field of molecular cardiology. with a special emphasis on prospects for clinical applications in cardiovascular medicine.
Human oocyte and preembryo donation: an evolving method for the treatment of infertility, The utilization of oocyte and preembryo donation in the treatment of infertility has recently expanded. Since 1983. modifications in the retrieval of donated female gametes have enhanced both the safety and the efficacy of the procedure. Pregnancy rates in women receiving donated preembryos are remarkably high. with success occurring in 25% to 50% of transfer cycles. The technology used for preembryo donation continues to evolve. and the current and future role ovum donation in the treatment of infertility.
The effect of physical activity during pregnancy on preterm delivery and birth weight, The relationship between physical activity during pregnancy. preterm birth. and gestational age-adjusted birth weight was investigated prospectively in a cohort of 7101 women. This study is one of few to evaluate both employment- and non-employment-related physical activity. Prolonged periods of standing were associated with a modestly increased risk of preterm delivery (adjusted odds ratio for greater than or equal to 8 hours/day of standing = 1.31). Heavy work or exercise was not associated with preterm delivery (adjusted odds ratio for greater than or equal to 4 hours per day of heavy work = 1.04). The proportion of infants born preterm did not differ among women working in predominantly standing. active. and sedentary occupations. Physical activity was not associated with gestational age-adjusted birth weight after controlling for confounding variables. These data suggest that unmeasured socioeconomic differences among women reporting different levels of activity may account for previously described associations between physical activity and pregnancy outcome. Most pregnant women who report increased levels of physical activity are not at increased risk of preterm delivery or reduced intrauterine growth. However. these data do not address the role of activity restriction in the management of selected women at high risk for adverse pregnancy outcome.
Prenatal diagnosis of laryngeal atresia, In a patient in whom preeclampsia developed at 23 weeks' gestation. ultrasonographic examination of the fetus showed enlarged edematous lungs. a compressed fetal heart. severe ascites. fetal hydrops. and placental edema. Autopsy of the hydropic stillborn infant showed laryngeal atresia. The ultrasonographic appearance of this rare malformation is presented.
Continuous or interrupted fascial closure: a prospective evaluation of No. 1 Maxon suture in 402 gynecologic procedures, During a 14-month period of using a long-term absorbable suture (No. 1 Maxon). 402 patients were entered into a prospective. randomized trial of fascial closure. Patients were randomized between a continuous closure (201 patients) and an interrupted en bloc (201 patients) technique. Each patient was subjected to a preoperative and intraoperative protocol for wound management. There were no acute wound failures. Wound infection rates and risk of hernia were not apparently affected by closure technique.
Corpus luteum function in early pregnancies is primarily determined by the rate of change of human chorionic gonadotropin levels, Regulation of human corpus luteum activity was studied with radioimmunoassays and bioassays of sera drawn serially from women suspected of having ectopic pregnancies. Progesterone values exhibited considerable overlap in pregnancies that were subsequently classified as normal intrauterine (n = 21). ectopic (n = 35). or spontaneous abortion (n = 14). The rate of change of human chorionic gonadotropin concentration was significantly correlated with progesterone levels in ectopic (r = 0.64) and all pregnancies (r = 0.70). There was no correlation (r = -0.18) between the rate of change of human chorionic gonadotropin and the bioactivity produced per volume of serum. Ectopic pregnancies and normal intrauterine pregnancies did not differ in their ratio of in vivo bioactivity to immunoactivity. From these data we conclude that corpus luteum activity is primarily regulated by the rate of change of human chorionic gonadotropin concentration. without the involvement of other serum factors. We also conclude that reduced corpus luteum function in ectopic pregnancies is not a result of biochemical modification of the human chorionic gonadotropin molecule. Finally. we discourage the use of single progesterone values in screening for ectopic pregnancies because of the considerable overlap in progesterone values among these and normal intrauterine pregnancies.
Postmortem chorionic villus sampling is a better method for cytogenetic evaluation of early fetal loss than culture of abortus material, In utero chorionic villus sampling at the time of diagnosis of intrauterine fetal death is compared with more traditional use of cultured fetal skin. products of conception. or amniocentesis. A total of 102 specimens from early fetal losses were evaluated for success in karyotyping and chromosomal results. We found postmortem chorionic villus sampling is technically possible. offers the highest likelihood of getting a cytogenetic result. and is a rapid. reliable. and safe technique. The extraembryonic component of intrauterine fetal deaths appears to remain viable and continues to grow long after the embryo has died. Samples obtained at the time of diagnosis of fetal death offer the greatest changes of successfully obtaining a karyotype. The incidence of chromosome abnormalities associated with fetal loss. particularly trisomies. is higher than previous data suggested.
The perinatal impact of cocaine, amphetamine, and opiate use detected by universal intrapartum screening, Universal urine testing for cocaine. amphetamines. and opiates was performed on 1643 women admitted to an obstetric service for a 1-year period with 20.5% having positive results. There were 299 patients with positive toxicology results matched for race and discharge date with patients having negative toxicology and drug history. Significant differences in age. prior obstetric history. prenatal care. alcohol history. and smoking were noted between groups. There was a significant decrease in birth weight. head circumference. length. and gestational age for the drug-positive group. which was most marked in cocaine and multiple drug users. These differences persisted after we controlled for smoking. prenatal care. and prior preterm births. Differences in birth weight and head circumference remained after we controlled for gestational age. Rates of congenital anomalies and abruptio placental were similar between groups. Perinatal substance abuse is independently associated with growth retardation and prematurity. Multiple risk factors are frequently present. necessitating a comprehensive approach to prenatal care.
A reappraisal of the need for autologous blood donation in the obstetric patient, There has been recent interest in autologous blood donation in obstetric patients. but little attention has been paid to whether such programs are needed or whether the patients that will require transfusion can be accurately predicted. At the University of California San Diego Medical Center from July 1 to Dec. 31. 1988. there were 2265 deliveries; 13 women (0.57%) received blood transfusions. Traditionally accepted risk factors were identified in 251 patients. with only four (1.6%) requiring transfusion. Among the 150 patients delivered by repeat cesarean section. only one (0.7%) required blood. one of 27 (3.7%) multiple gestations. two of eight (25%) patients with placenta previa. and none of the 66 grandmultiparous women had transfusions. These data suggest that autologous blood donation may not be beneficial or cost effective when the low frequency of blood transfusions in this high-risk obstetric population and the difficulty in accurately predicting those likely to require transfusions are considered.
Direct ultrasonographic measurement of fetal lung length in normal pregnancies and pregnancies complicated by prolonged rupture of membranes, Fetal lung length was measured directly with ultrasonography in 20 patients with prolonged rupture of membranes. commencing before 25 weeks' gestation. Measurements were made weekly and compared with data collected from 310 normal pregnancies. Measurement of fetal lung length by ultrasonography was a good predictor of pulmonary hypoplasia. predicting greater than 90% of cases. There was a good correlation between lung size assessed by the last ultrasonographic examination and lung weight postmortem (r = 0.783. p less than 0.05). Lung length measurements were superior to fetal chest circumference measurements in the identification of pulmonary hypoplasia. There was a significant negative association between the amount of amniotic fluid and pulmonary hypoplasia (p less than 0.05). There were fetuses with pulmonary hypoplasia that had respiratory movements seen at the majority of ultrasonographic examinations.
Screening for trisomy 21 with ultrasonographic determination of biparietal diameter/femur length ratio, Ultrasonographic determination of biparietal diameter/femur length ratios performed at 16 or 17 weeks' gestation in fetuses with trisomy 21 were not statistically different from those of 155 normal fetuses. It appears that this test could not be used for screening for trisomy 21.
Surgical staples in cesarean section: a randomized controlled trial, This randomized controlled trial compares the use of the Auto Suture Poly CS 57 disposable surgical stapler (n = 98) with standard hysterectomy (n = 102) in low transverse cesarean sections. Subjective assessment of blood loss by the surgeon resulted in lower mean (+/- SEM) total blood loss estimates in the stapled group (492 +/- 24 ml) than in the nonstapled group (579 +/- 38 ml) (p = 0.05). However. surgeon's estimation of blood loss as a result of the hysterotomy and blood loss estimated by the hemoglobin deficit measured on the second postoperative day did not significantly differ between the two groups. The use of the stapling device tended to lengthen the total operating time. which averaged 42.5 minutes in the group with the staples and 39.2 minutes in the group with the standard hysterotomy (p = 0.05). The risk of febrile morbidity. the frequency of endometritis. and the length of hospitalization were similar in the two groups. Our results do not support the routine use of the Auto Suture Poly CS 57 disposable surgical stapler in low transverse cesarean sections.
Increase of beta 1-6-branched oligosaccharides in human esophageal carcinomas invasive against surrounding tissue in vivo and in vitro, The -GlcNAc beta 1-6Man- (beta 1-6) branched N-glycosidic oligosaccharides expressed on tumor cells have been found to contribute to malignant and metastatic potential in experimental tumor models. Phaseolus vulgaris leukoagglutinin (L-PHA) requires the beta 1-6-linked lactosamine antenna for high-affinity binding and was used histochemically to characterize the distribution of these sugar structures in human esophageal squamous cell carcinomas from 42 patients. Leukoagglutinin-reactive carcinoma cells in the invasive tumors were distributed predominantly on the outer surface of the tumor adjacent to the surrounding tissue. Furthermore. when TE 1 cells. a human esophageal squamous cell carcinoma line. were cultured in a collagen gel matrix to obtain colonies in a three-dimensional form. these colonies exhibited high affinity for L-PHA binding only in the outer cell layer facing the collagen matrix. unrelated to the cell growth cycle. These findings suggest that the increase in beta 1-6-branched oligosaccharides in esophageal carcinomas is an important trait of the tumor in the invasion into the surrounding tissue.
Neuroendocrine features of reactive bile ductules in cholestatic liver disease, Various cholestatic liver diseases are accompanied by a striking increase in the number of bile ductules. This so-called ductular reaction is thought to arise both from ductular metaplasia of hepatocytes and from proliferation of pre-existing bile ductules. Previous studies have shown that these reactive bile ductules differ from their normal counterpart in enzyme and immunohistochemical make-up. Using monoclonal antibodies directed to neuroendocrine markers and immunohistochemistry. we found that reactive bile ductules in cholestatic liver disease display neuroendocrine features. In all cases of primary biliary cirrhosis (PBC). primary sclerosing cholangitis (PSC). extrahepatic obstruction. and acute hepatitis A. reactive bile ductules expressed the neural cell adhesion molecule (N-CAM) and reacted with monoclonal antibody A2B5. Both N-CAM and the ganglioside. recognized by A2B5. are restricted to neuroendocrine cells and tissues. In all but four of these cases. the same bile ductules expressed chromogranin-A. present in the matrix of neuroendocrine granules. Furthermore. in three cases of longstanding cholestasis. scattered periportal hepatocytes expressed chromogranin-A but not N-CAM. Other neuroendocrine markers such as neuron-specific enolase. synaptophysin. or myelin-associated glycoprotein were lacking from both bile ductules and hepatocytes. The neuroendocrine phenotype of bile ductules and hepatocytes was confirmed on electronmicroscopy. demonstrating various numbers of dense-cored. neuroendocrine granules near the peripheral cell membrane in bile ductules as well as in cells intermediate between hepatocytes and bile ductular cells. In 10 cases of normal liver tissue without ductular reaction. bile ductules lacked neuroendocrine markers except in two cases in which very weak reactivity for chromogranin-A was observed. These findings illustrate the presence of a new. neuroendocrine cell type that emerges in the liver during cholestasis. Elucidation of the significance of the neuroendocrine substance(s) produced in the dense cored granules of reactive bile ductules awaits their isolation and characterization. We can speculate that this molecule plays an autocrine or paracrine regulatory role in the process of ductular metaplasia of hepatocytes or growth of bile ductules.
Mechanisms of edema formation in experimental autoimmune encephalomyelitis. The contribution of inflammatory cells, Most of the central nervous system (CNS) endothelium regulates the passage of solutes and functions as a blood-brain barrier (BBB). During experimental autoimmune encephalomyelitis (EAE). an inflammatory demyelinating disease of the CNS. loss of BBB function occurs. The authors have previously shown an increase in endothelial transcytotic activity associated with decreased mitochondrial content as evidence of BBB dysfunction in EAE. These changes occurred in the capillary bed and correlated with CNS edema and clinical signs. In the present report. a fixation procedure before infusion of the intravascular tracer horseradish peroxidase (HRP) in rats at the height of clinical EAE has been used. In these animals. tracer leakage was only noted in inflamed venules with diameters of 12 to 19 mu. The authors detected several mechanisms of passive leakage: 1) increased junctional permeability; 2) increased interendothelial space; 3) leakage alongside migrating inflammatory cells. Some small capillaries showed necrotic changes with minimal tracer leakage. This report demonstrates that BBB disruption also occurs via nonendocytic mechanisms that may be induced by inflammatory cells.
Hodgkin's disease and CD30-positive anaplastic large cell lymphomas--a continuous spectrum of malignant disorders. A quantitative morphometric and immunohistologic study, The authors have examined cellular areas of lymphoma tissue in 28 cases of Hodgkin's disease (HD) or anaplastic large cell lymphoma (ALCL. 'Ki-1 cell lymphoma') to evaluate the boundaries between the two entities. Methods applied included conventional histology; test point analysis; semiautomated morphometry of nuclear profile features of Reed-Sternberg and other atypical large cells (RSALCs); and immunohistochemistry of these elements on all paraffin sections and. in 15 cases. on frozen sections. Mean nuclear profile morphotypes of RSALCs per case varied independently of immunophenotype and histologic diagnosis. Conversely. immunohistochemistry demonstrated significant. although not consistent. preferential positivities of these CD30+ elements for CD15 in HD. and for epithelial membrane antigen (EMA) and CD43 in ALCLs. In the latter. RSALCs also exhibited a tendency for CD45 and CD45RO positivity and for the expression of T-cell-associated antigens. However. there were considerable overlaps. This continuous spectrum of RSALC nuclear profile morphotypes and immunophenotypes. ranging from HD over questionable cases. intermediate between HD and ALCL. to ALCLs. was paralleled by differences in the reactive component of lymphomas. Lymphocytes and granulocytes were significantly deficient in ALCLs.
Metaplastic change in mesenchymal stem cells induced by activated ras oncogene, 3T3 T murine mesenchymal stem cells have the potential to differentiate into a variety of different cell types even though they show a predilection to undergo adipocyte differentiation in vitro. The possibility that the activated c-Ha-ras (EJras) oncogene might influence the pathway of differentiation of these stem cells is investigated in the current study. Activated ras oncogene was transfected and stably expressed in 3T3 T cells; assays then were performed to determine its effect on differentiation. The results show that all EJras-transfected cell lines lose their ability to differentiate to adipocytes and instead differentiate into cells that express many characteristics of macrophages. Such cells contain numerous cytoplasmic granules. extensive nonspecific esterase activity. and anchorage-independent growth. The modulation of differentiation pathway from an adipocyte lineage to a macrophagelike cell lineage does not result from the transforming effect of EJras. because a nontransformed cell clone that expresses p21EJras protein also exhibits this modified differentiation pathway. These data suggest that the EJras oncogene specifically modulates the differentiation pathway of 3T3 T mesenchymal stem cells. This experimental system should therefore provide an excellent model to evaluate the mechanistic role of EJras in the process of metaplasia.
Ultrastructural localization of proteinase 3, the target antigen of anti-cytoplasmic antibodies circulating in Wegener's granulomatosis, To investigate the distribution of proteinase 3. the target antigen of anti-cytoplasmic antibodies (ACPA or C-ANCA). within the organelles of resting normal human polymorphonuclear leukocytes and monocytes. the authors used immunocytochemical techniques on thin frozen sections. To obtain valuable tools for immunolabeling. two murine monoclonal antibodies (MAbs) directed against the ACPA antigen were produced. In neutrophils. the authors observed immunogold label for the ACPA antigen. predominantly in myeloperoxidase-positive azurophil granules. and in smaller amounts on the plasma membrane. In monocytes. the ACPA antigen could be detected in small granules. which occasionally also contained myeloperoxidase. and rare labeling was found on the monocyte membrane. The finding that the ACPA antigen is expressed on the plasma membrane of neutrophils and monocytes. thereby becoming accessible to circulating autoantibodies. supports the supposition that ACPA are not only markers of disease activity. but also are involved in the pathogenesis of Wegener's granulomatosis.
Coexpression patterns of vimentin and glial filament protein with cytokeratins in the normal, hyperplastic, and neoplastic breast, The authors studied by immunohistochemistry the intermediate filament (IF) protein profile of 66 frozen samples of breast tissue. including normal parenchyma. all variants of fibrocystic disease (FCD). fibroadenomas. cystosarcoma phylloides. and ductal and lobular carcinomas. Monoclonal antibodies (MAbs) to cytokeratins included MAb KA 1. which binds to polypeptide 5 in a complex with polypeptide 14 and recognizes preferentially myoepithelial cells; MAb KA4. which binds to polypeptides 14. 15. 16 and 19; individual MAbs to polypeptides 7. 13. and 16. 17. 18. and 19. and the MAb mixture AE1/AE3. The authors also applied three MAbs to vimentin (Vim). and three MAbs to glial filament protein (GFP). Selected samples were studied by double-label immunofluorescence microscopy and by staining sequential sections with some of the said MAbs. an MAb to alpha-smooth muscle actin. and well-characterized polyclonal antibodies for the possible coexpression of diverse types of cytoskeletal proteins. Gel electrophoresis and immunoblot analysis also were performed. All samples reacted for cytokeratins with MAbs AE1/AE3. although the reaction did not involve all cells. Monoclonal antibody KA4 stained preferentially the luminal-secretory cells in the normal breast and in FCD. whereas it stained the vast majority of cells in all carcinomas. Monoclonal antibody KA1 stained preferentially the basal-myoepithelial cells of the normal breast and FCD while staining tumor cell subpopulations in 4 of 31 carcinomas. Vimentin-positive cells were found in 8 of 12 normal breasts and in 12 of 20 FCD; in most cases. Vim-reactive cells appeared to be myoepithelial. but occasional luminal cells were also stained. Variable subpopulations of Vim-positive cells were noted in 9 of 20 ductal and in 1 of 7 lobular carcinomas. Glial filament protein-reactive cells were found in normal breast lobules and ducts and in 15 of 20 cases of FCD; with rare exceptions. GFP-reactivity was restricted to basally located. myoepithelial-appearing cells. Occasional GFP-reactive cells were found in 3 of 31 carcinomas. Evaluation of sequential sections and double-label immunofluorescence microscopy showed the coexpression of certain cytokeratins (possibly including polypeptides 14 and 17) with vimentin and alpha-smooth muscle actin together with GFP in some myoepithelial cells. The presence of GFP in myoepithelial cells was confirmed by gel electrophoresis and immunoblotting. Our results indicate that coexpression of cytokeratin with vimentin and/or GFP is comparatively frequent in normal basal-myoepithelial cells of the breast.(ABSTRACT TRUNCATED AT 400 WORDS).
Cytokine production (IL-1 alpha, IL-1 beta, and TNF alpha) and endothelial cell activation (ELAM-1 and HLA-DR) in reactive lymphadenitis, Hodgkin's disease, and in non-Hodgkin's lymphomas. An immunocytochemical study, Cryostat sections of 58 lymph nodes were immunostained with a polyclonal rabbit serum against IL-1 alpha. and with monoclonal antibodies directed to IL-1 alpha (Vmp18). IL-1 beta (Vhp20 and BRhC3). and tumor necrosis factor alpha (TNF alpha) (B154.7). Furthermore the presence of cytokine-containing cells was correlated with the expression of endothelial leukocyte adhesion molecule (ELAM-1; 29F2) and of human leukocyte antigen (HLA-DR) (OKIa-1) by endothelial cells. Cells containing IL-1 and/or TNF alpha were detected mainly in pathologic conditions characterized by reactive or neoplastic expansion of the lymph node paracortex. Cells positive for IL-1 were detected in 16 of 21 cases of Hodgkin's disease. in 4 of 4 cases of T-NHL. and in 5 cases of diffuse or mixed lymphadenitis. Interleukin-1 alpha was detected in macrophages. interdigitating reticulum cells (IDRCs). endothelial cells. and neoplastic Hodgkin's and Reed-Sternberg (H-RS) cells. Cells positive for IL-1 beta were much fewer and consisted mainly of macrophages. Hodgkin's Reed-Sternberg cells were negative for IL-1 beta even after in vitro stimulation with bacterial endotoxin. Tumor necrosis factor alpha (TNF alpha) was present in macrophages and H-RS cells. Endothelial leukocyte adhesion molecule-1 expression by endothelial venules was detected in 17 of 20 cases of Hodgkin's disease. in 2 of 4 cases of T-NHL. and in 5 of 5 cases of diffuse lymphadenitis. In these pathologic conditions. HLA-DR antigens also were expressed frequently by endothelial cells. Cytokine-containing cells and ELAM-1-positive high endothelial venules (HEV) were extremely rare in lymph nodes involved by follicular lymphadenitis (12 cases) or B-NHL (16 cases). In cases of reactive or neoplastic B-cell proliferations. HLA-DR-positive HEVs still were present often. Our results indicate that IL-1/TNF alpha production at tissue level is often associated with ELAM-1 expression by HEVs. but is less well correlated with expression of HLA-DR antigens by endothelial cells.
Expression of aminopeptidase N (CD13) in mesenchymal tumors, For a long time. CD13 molecules have been considered to be restricted to myeloid cells and related neoplasms. Meanwhile. however. expression of CD13 has also been detected in some hepatocellular. gallbladder. renal. and lung carcinomas. and even in some fibrosarcomas and malignant melanomas. In this study. expression of CD13 antigen was immunohistochemically examined in non-neoplastic mesenchymal cells. along with 33 benign and 83 malignant mesenchymal tumors (MET) using CD13 monoclonal antibodies (MAb) My7. U71. WM-15. and MoU48. In non-neoplastic mesenchymal cells. expression of CD13 was restricted to perivascular fibrocytes/blasts. tissue histiocytes. osteoclasts. and to the perineurium of peripheral nerve trunks. Under neoplastic conditions. CD13 was detectable in some tumors of smooth muscle. fibrous. fibrohistiocytic. synovial. osteogenic. and peripheral nerve sheath origin. and even in some tumors of adipose tissue. Tumors of striated muscle origin. of autonomic ganglia. and of cartilage-forming tissues were CD13-negative throughout. Thus in most but not all tumors studied the pattern of expression of CD13 mirrors the situation found in their cells of origin. These findings enrich the data on expression of leukocyte differentiation antigens in extra-hematopoietic tissues. Expression of CD13. which meanwhile is known to be identical to aminopeptidase N. an important peptide-cleaving enzyme. in only some MET might reflect a special functional state of these neoplasms.
Immunocytochemical localization of progesterone receptors in endocrine cells of the human pancreas, Progesterone receptors (PgR) have been immunocytochemically localized in the nuclei of several (40% to 75%) endocrine cells of the human pancreas and in a more variable number of neoplastic cells of 7 of 18 endocrine pancreatic tumors. Conversely the exocrine epithelial cells of the pancreas did not exhibit any PgR immunoreactivity in normal as well as in different pathologic conditions. including pancreatic adenocarcinomas. Estrogen receptors were not detected in any of the pancreatic samples investigated. Double immunocytochemical experiments have documented that PgR immunoreactivity in normal Langerhans islets is a consistent feature of most (75%) glucagon-producing A cells. of approximately 5% to 20% of insulin-producing B cells. and of a variable percentage of pancreatic polypeptide (PP)-producing cells. ranging from 5% to 70%. These figures were not affected by the sex. age. or underlying disease of the patients. The reported findings corroborate previous clinical and experimental evidence indicating that sex steroid hormones may have some regulatory effects on the functional activity of the endocrine pancreas.
Clustering of atherogenic behaviors in coffee drinkers, We studied the clustering of coffee consumption and selected atherogenic behaviors in older adults living in a southern California community. Men were somewhat more likely to drink caffeinated coffee while women were more likely to drink decaffeinated coffee. In men. but not women. caffeinated coffee drinking decreased with age and decaffeinated coffee drinking increased. Caffeinated coffee drinkers drank more alcohol. consumed more dietary saturated fats and cholesterol. were more likely to be current smokers and less likely to be current exercisers than were non-coffee drinkers. Smoking and exercise also showed a dose-response relationship to the amount of caffeinated coffee consumed. Risk factor levels among drinkers of decaffeinated coffee were more like those of caffeinated coffee than non-drinkers. These data illustrate the clustering of atherogenic behaviors with coffee drinking and highlight their potential importance in interpreting the growing body of literature about coffee and health.
Effects of individually motivating smoking cessation in male blue collar workers, Adverse demonstrable health effects linked to the individual's smoking were shown to 2.689 American workers to motivate cessation during routine examinations to detect asbestosis. This intervention was evaluated six to 25 months later by a mailed questionnaire and by telephone to non-responders. Results were compared to yearly quit rates of 2.5 percent to 5 percent for 736 workers who were ex-smokers at the initial examination. Of the 504 men who responded by mail. 29.8 percent had quit smoking. 35.9 percent had cut down from a mean of 28 to 13 cigarettes per day. and 34.3 percent were smoking as before. Subsequent follow-up at one year showed that 25.6 percent remained quit. and that 23 percent of those who cut down had quit. for an overall quit rate of 34 percent. Of 101 non-responders contacted by telephone. 17 percent had quit and 53 percent had reduced smoking. In both samples. those who quit were more likely to have had lower alveolar carbon monoxide (COa) levels. to be older. and to have had asbestosis. Responders by mail were the same age as non-responders but had smoked longer. had higher prevalences of asbestosis. emphysema. chronic bronchitis and higher COa. Demonstration of the adverse personal effects of smoking appear to have contributed to the quit rates or reduced smoking rates in 65 percent of the responding workers.
Epidemiologic differences between chlamydia and gonorrhea, To assess the prevalence. demographics. and transmission patterns of genital chlamydia infection. we screened 3.078 patients. and compared identified cases (N = 511) to gonorrhea cases (N = 291) diagnosed in the same setting. Chlamydia cases were younger and more likely to be White than their gonorrhea counterparts. Chlamydia cases were distributed diffusely; geographic overlap between the two diseases was only about 40 percent. Gonococcal coinfection was noted in less than 10 percent of patients with chlamydia. Nearly half of men with chlamydia and four-fifths of women were asymptomatic and most cases were identified through screening or contact tracing. Populations at high risk for chlamydia are seemingly different from those for gonorrhea. Differences may be due to control interventions (active for gonorrhea. passive for chlamydia). Chlamydia case reporting and control initiatives are recommended.
The association between Type A behavior and change in coronary risk factors among young adults, The association of Type A/B behavior pattern and changes in blood pressure. total serum cholesterol. serum triglyceride. body mass. and smoking was estimated in a cohort of 375 young Black and White men and women from a rural county in Central Kentucky between 1978-79 and 1985-88. Type A participants experienced significant increases in systolic (2.90 +/- 1.29 mmHg) and diastolic (3.80 +/- 1.17 mmHg) blood pressure and in cigarette smoking (3.26 +/- 0.89 cigarettes per day) over the eight-year follow-up period. but Type B participants experienced no change. Type A and B individuals showed similar changes in total serum cholesterol. serum triglyceride. or body mass. Differences between behavioral types in blood pressure were present for women but not men. and for Blacks but not for Whites. These findings suggest a possible significance of the Type A pattern for the development of cardiovascular risk of young adults.
Behavioral covariates of waist-to-hip ratio in Rancho Bernardo, We examined lifestyle and dietary habits in 685 men and 943 women (mean age 67 years) who completed an interview. examination. and food frequency questionnaire in 1984-87. Waist-to-hip ratio increased with age and body mass index in both men and women. In multiple regression. waist-to-hip ratio was independently associated with smoking. alcohol consumption. and exercise in men. and with smoking and alcohol consumption in women. The data suggest that waist-to-hip ratio is affected. at least in part. by behavioral. and potentially modifiable. factors.
The Framingham Disability Study: relationship of various coronary heart disease manifestations to disability in older persons living in the community, The relation between coronary heart disease and disability was examined in 2.576 community-dwelling women and men ages 55-88 years. These Framingham Study participants were originally recruited in 1948-51 for an examination of cardiovascular disease. Twenty-seven years later. remaining members of the cohort were interviewed to ascertain physical abilities. and a score on a disability scale was assigned. Multivariate logistic analyses examined disability in relation to uncomplicated angina pectoris (AP). complicated AP. and coronary heart disease other than AP. controlling for possible confounders. In younger and older women and men. uncomplicated and complicated AP were associated with disability. Coronary heart disease other than AP was associated with disability only in the younger men. Congestive heart failure predicted disability only in the women. These results suggest that onset of AP should be recognized as a critical point in the development of disability and that AP is a better predictor of disability than is myocardial infarction or coronary insufficiency.
The buddy volunteer commitment in AIDS care, Buddy volunteers provide crucial assistance to people with HIV-related illnesses. Based on volunteers' self-administered questionnaires. our study describes the nature of buddy work. Volunteers indicated their satisfaction with both personal performance and buddy program administration. Several factors were associated with volunteer satisfaction. This report is a first attempt to describe this special relationship created in response to the human immunodeficiency virus (HIV) epidemic.
Prior cesarean delivery in women with secondary tubal infertility, The history of cesarean delivery was evaluated in a population-based case-control study of secondary infertility in King County. Washington. Sixty-one married women diagnosed with secondary infertility due to tubal problems who had a previous viable pregnancy were compared to 343 married women who had a previous viable pregnancy and then had a live birth that was conceived at the same time the infertile women began trying to conceive. The risk of tubal infertility was not substantially elevated in women who had a previous cesarean delivery in the most recent viable pregnancy compared to women with vaginal delivery (odds ratio = 1.2; 95% confidence interval = 0.4. 3.7).
Hypertension prevalence and the status of awareness, treatment, and control in the Hispanic Health and Nutrition Examination Survey (HHANES), 1982-84, The prevalence rates of hypertension among adult (ages 18-74) Mexican Americans. Cuban Americans. and Puerto Ricans were estimated using data from the 1982-84 Hispanic Health and Nutrition Examination Survey (HHANES). Hypertension is defined as diastolic greater than or equal to 90 mm Hg. or systolic greater than or equal to 140 mm Hg. or currently taking antihypertensive medication. Among Mexican Americans in the Southwestern United States. 16.8 percent of the males and 14.1 percent of the females were found to be hypertensive. Among Cuban Americans in Dade County. Florida 22.8 percent of the males and 15.5 percent of the females were hypertensive. Among Puerto Ricans in the New York City area 15.6 percent of the males and 11.5 percent of the females were hypertensive. The age-adjusted rates are significantly lower than comparable rates for Whites and Blacks as measured in the second National Health and Nutrition Examination Survey (NHANES II). 1976-80. Control of hypertension in the HHANES populations fall short of the 1990 Objectives for the Nation established by the US Public Health Service 60 percent (34 percent controlled Mexican American hypertensives. 27.8 percent controlled Cuban American hypertensives. and 29 percent controlled Puerto Rican hypertensives.
A note on the measurement of hypertension in HHANES, Using data from the HHANES. we found the rates of elevated blood pressure readings on clinical examination to be extremely low for a sample of Mexican American and Puerto Rican women. The prevalence rates were one-fourth to one-fifth the rates found for a comparable sample of White women from NHANESII. These findings are discrepant with the little that is known about hypertension prevalence among Hispanics and with estimates of hypertension prevalence for Mexican Americans and Puerto Ricans drawn from NHANESII. While our HHANES samples women had much lower rates of clinical high blood pressure than Whites. they reported hypertension histories in excess of Whites. Rates of medicine usage among Hispanics were insufficiently large for effective treatment to explain the disparity. The prevalence estimates increased. but the relative discrepancies remained when we altered our sample specifications and clinical high blood pressure measure. A possible explanation for these discrepancies is that few physicians performed the majority of blood pressure readings in our HHANES sample. This may have been statistically inefficient. The discrepancies noted suggest that HHANES may not be a reliable source of information on hypertension among Hispanic women.
Day care characteristics associated with Haemophilus influenzae disease. Haemophilus influenzae Study Group, To identify characteristics of day care facilities associated with H. influenzae disease. we compared 92 licensed facilities in which a case of H. influenzae disease had occurred with randomly selected facilities at which no cases occurred. Matched univariate analysis showed that personnel at facilities where H. influenzae disease occurred were more likely than those at control facilities to use towels or handkerchiefs to wipe children's noses. admit children who were not toilet trained or had diarrhea ("liberal fecal policy"). had a narrower age range. were more likely than control facilities to be for-profit and less likely to use volunteers. In a multivariate model that adjusted for age range. profit status and liberal fecal policy. towel or handkerchief use (OR 5.5. 95% CI: 1.1. 30) was the only variable independently associated with case facilities. This is the first association of a specific day care practice with H. influenzae disease.
Injury and disability in matched men's and women's intercollegiate sports, Eight matched men's and women's intercollegiate varsity teams were studied prospectively for one academic year to determine the incidence of athletic injury and resulting disability. Sports in which both men and women participated in a comparable manner were chosen: basketball. fencing. gymnastics. swimming. tennis. indoor track. outdoor track. and volleyball. Men (232) and women (150) were injured at comparable rates. 42 percent versus 39 percent. When adjusted for exposure time. seven of the eight sports continued to show similar injury rates. Women gymnasts. however. experienced .82 injuries per 100 person-hours of exposure as compared to .21 injuries for the men (p = .0001). Disability was greater in women gymnasts. 7.44 days per 100 person-hours versus 1.15 days for men (p = .0004). Percent of season lost to injury was also greater for women gymnasts. Types and sites of injury were similar for men and women. with sprains and strains accounting for over half of all injuries. We found no evidence for gender differences in matched sports except for gymnastics. in which technically diverse events may have accounted for the differences observed.
Coding external causes of injury (E-codes) in Maryland hospital discharges 1979-88: a statewide study to explore the uncoded population, We examined the trends in hospital discharge E-coding in Maryland over a 10-year period. The overall proportion of E-coded discharges has increased from 40 percent in 1979 to 55 percent in 1988. E-coding was lower in the severely injured. the elderly. and patients with long hospital stays. Our findings demonstrate that E-code reporting varies because of the limited number of data fields available for coding of discharge diagnoses. Universal. systematic reporting of E-codes in hospital discharge data is essential if these data are to provide critically needed information about nonfatal injuries. Hospital discharge data formats should contain separate fields for E-codes and the use of these codes. we believe. should be mandated.
Long-term impact of smoking cessation on the incidence of coronary heart disease, Using a simulation model of the US male population. we estimated the long-term impact that future smoking cessation programs would have on the distribution and occurrence of coronary heart disease in males ages 35-84. For interventions that reduce the number of smokers by 25 percent in 1990. the number of men free of coronary heart disease is projected to increase by 416.787 (0.7 percent) in 2015. and the age-standardized absolute incidence to decline by 2.3 percent. Incidence rates and absolute incidences are projected to fall in men under age 65. but absolute incidence would rise in men over age 65. in large part because of the increased number of men who were at risk for coronary heart disease because of a reduction in non-coronary smoking-related mortality. These trends were more marked for greater smoking reductions and were generally unaffected in a variety of analyses using alternative assumptions. which considered smoking as a risk factor in the elderly. a lag-time before benefits from smoking cessation were realized and secular declines in smoking prevalence. Subject to the assumptions of our model. we conclude that smoking reductions will markedly reduce coronary heart disease. especially in younger age groups. and that this benefit will be slightly offset by a small increase in absolute incidence in elderly men.
Overcoming potential pitfalls in the use of Medicare data for epidemiologic research, We used Medicare data bases and US Census data to address two questions critical to the use of Medicare files for epidemiologic research. First. we examined the degree to which the population enrolled in the Medicare program is similar to the elderly resident population of the United States. as estimated by the US Census. We found small differences in the total population estimates but substantial differences by age and race. Second. we found that among Medicare enrollees. physician claims identify a small proportion of hip fracture cases which are not documented in the hospital discharge files. This proportion varies by age. region. and state within the United States. Calculation of rates based on Medicare hospital discharge data. and probably other hospital discharge data sets as well. must take these limitations into account. Use of all available Medicare data files can overcome these limitations.
Evidence for gonococcal transmission within a correctional system, In a study to examine sexually transmissible disease occurring within a large correctional system where sexual activity is prohibited. 27 male inmates acquired culture-proven gonorrhea from in-jail sexual activity during a three-month period. These results provide evidence to encourage inmate education about the acquired immunodeficiency syndrome (AIDS) and to support condom distribution programs in correctional facilities.
HIV seroconversion in two homosexual men after receptive oral intercourse with ejaculation: implications for counseling concerning safe sexual practices, Seroconversion for HIV antibody occurred in two homosexual men who reported no anal intercourse for greater than or equal to 5 years and multiple episodes of receptive oral intercourse with ejaculation. Neither man reported intravenous drug use or receipt of blood products. The last antibody-negative specimen was also negative by the polymerase chain reaction and p24 antigen assays. All sexually active persons should be clearly counselled that receptive oral intercourse with ejaculation carries a potential risk of HIV transmission.
The AIDS-related experiences and practices of primary care physicians in Los Angeles: 1984-89, Telephone interviews of random samples of Los Angeles primary care physicians in 1984. 1986. and 1989 obtained information about their AIDS-related practice experiences. and sexual history taking. Data from mid-1989 reveal almost 74 percent have worked up at least one patient for AIDS or HIV infection in the past six months and 39.5 percent are caring for at least one patient with AIDS or AIDS-related complex. Self-reported use of appropriate sexual history questions has improved substantially over this five-year period.
Evaluation of the efficacy and cost effectiveness of health education methods to increase medication adherence among adults with asthma, We randomized 135 adult asthma patients to a control group. and 132 patients to an experimental group which received a special health education intervention. Four adherence measures were documented at baseline and 12-month follow-up: correct inhaler use. inhaler adherence. medication adherence. and total adherence rating. Costs to routinely deliver the intervention were $32.03/patient. Experimental group patients exhibited a significantly higher level of improvement in adherence (44 percent) than control group patients (2 percent).
Variations in malaria transmission rates are not related to anopheline survivorship per feeding cycle, Anopheline survivorship. vectorial capacity. and mosquito infection probability estimates from mosquito infection rates were determined 4 times in 1 year in a Papua New Guinea village. Estimates of survivorship over the length of the extrinsic incubation period differed significantly during the year. However. survivorship per feeding cycle. individual mosquito vectorial capacity. and mosquito infection probability did not vary significantly. Estimates of these parameters were then compared to estimates of survivorship. individual vectorial capacity. and mosquito infection probability in mosquito populations in other villages in the study area. Since survivorship per feeding cycle did not vary significantly among the mosquito populations in these villages. changes in malaria transmission potential can be better gauged from estimates of survivorship over the length of the extrinsic incubation period. However. as measurements of relative inoculation rates are easier to perform and have been related to parasite prevalences in children in this area. estimates of inoculation rates are a preferred option for estimating malaria transmission in the Madang area of Papua New Guinea.
Geographical distribution of Plasmodium falciparum erythrocyte rosetting and frequency of rosetting antibodies in human sera, Uninfected erythrocytes bind spontaneously to those infected with certain strains of Plasmodium falciparum. This is known as spontaneous erythrocyte rosetting. We have studied the occurrence and frequency of rosetting in 75 fresh patient isolates and have identified rosetting strains from Africa. South America. and Asia. Rosetting was present in 49% of the isolates tested; the frequency of rosetting red blood cells (RBC) in individual isolates was 0-75% when scored during the first cycle of in vitro growth. Rosetting antibodies were found in 15 out of 73 (21%) Liberian sera as measured by disruption of rosettes in vitro. However. antibodies able to inhibit CD36 dependent cytoadherence of P. falciparum-infected RBC were not detected in these sera. Erythrocyte rosetting is a geographically widespread phenomenon. Rosetting antibodies seem to be induced by natural infection and the molecular mechanism of rosette formation seems distinct from that of endothelial cytoadherence.
Studies in owl monkeys leading to the development of a synthetic vaccine against the asexual blood stages of Plasmodium falciparum, During the development of a synthetic vaccine for human use against the asexual blood stages of Plasmodium falciparum. monkey trials were performed to assess safety. immunogenicity. and protectivity. We determined the minimal infective dose of the P. falciparum FVO strain. the kinetics of the immune response induced by vaccination with the synthetic peptide mixture (S7 + S12 + S17) or the synthetic hybrid polymeric protein SPf66. and the induction of protective immunity against the experimental challenge with 2 P. falciparum strains. A clear boosting effect was observed. determined by the increased antibody titers against synthetic peptides S7. S12. S17. and SPf66. and by improvement in the protective immune response against the challenge. These studies suggest that either the peptide mixture or the synthetic hybrid polymeric protein are excellent choices for the development of a vaccine against P. falciparum.
Immunization of owl monkeys with a combination of Plasmodium falciparum asexual blood-stage synthetic peptide antigens, A mixture of 3 synthetic peptides (35.1. 55.1. and 83.1) corresponding to portions of the 35 kDa. 55 kDa. and 83 kDa proteins from the asexual blood stages of Plasmodium falciparum and a polymer of a syntheic peptide incorporating the 3 individual peptides (SPf66) were tested as candidate malaria vaccine antigens in Aotus nancymai. Monkeys were immunized with combinations of the 3 peptides from 2 separate sources (Centers for Disease Control [CDC]. Atlanta. GA or Colombia) or with the synthetic polymer. Animals immunized with a combination of the 3 peptides from CDC had higher antibody titers to the 35.1 and 55.1 peptides than to the 83.1 peptide. Monkeys immunized with a combination of the 3 peptides produced in Colombia developed higher levels of antibody to the 55.1 than to the 83.1 and 35.1 peptides. Animals immunized with the polymer produced detectable antibodies to the 55.1 peptide alone. Following challenge with P. falciparum. no differences were observed between the 3 vaccine groups and 2 control groups with respect to the number of animals with parasitemias greater than or equal to 10%. The inconsistency of serologic response to all 3 peptides in these animals contrasted with previous trials performed in Colombia where the monkeys developed high antibody titers against the 3 peptides and were protected against the experimental infection.
Ultrasonographical investigations of onchocerciasis in Liberia, The efficiency of ultrasonography (US) for the diagnosis and clinical characterization of onchocerciasis was evaluated. US was performed on 120 probands in Liberia. Ninety-two patients had generalized onchocerciasis. 21 patients suffered from the chronic hyperreactive form of onchocerciasis (sowda). and 7 probands served as controls. Patients were examined by US with linear (7.5 MHz and 5 MHz) and sector (3.5 MHz) scanners. US results were evaluated by examination of extirpated nodules. The US structure of nodules revealed a typical pattern consisting of a homogeneous echogenicity with small echodense particles and a lateral acoustic shadow. and differentiation from lymph nodes. lipoma. or fibroma was achieved. Within the onchocercomata. calcifications or fluid were identified. Regarding the estimation of the worm burden. it is important to note that in 24 patients. additional nodules not previously palpated were found by US. Also. the number of worm centers in palpable conglomerate nodules were determined more exactly by US than by palpation. In 4 of 16 sowda patients. impalpable nodules were found by US. In 13 patients with positive microfilaria counts. no nodules could be detected. The highly characteristic ultrasonographical pattern of onchocercomata may serve as a basis for further US investigations in onchocerciasis.
Recombinant capsular antigen (fraction 1) from Yersinia pestis induces a protective antibody response in BALB/c mice, Yersinia pestis produces a glycoprotein capsule. the biosynthesis of which appears to be temperature dependent. The fraction I (F1) component of this capsule is specific to Y. pestis and the detection of F1 antibodies is the basis for several serological tests. We report the cloning of the F1 gene and its expression in Escherichia coli using the phagemid vector lambda ZAPII and a F1-specific monoclonal antibody. The recombinant F1 antigen had a molecular weight of 17 kDa. which proved to be identical to that of the F1 antigen produced by Y. pestis. The recombinant cells produced F1 antigen at 37 degrees C but only minimal amounts at 27 degrees C. suggesting that the genetic features affected by temperature in Y. pestis may be operating in the E. coli clone. It is not known if their similar molecular weights reflect the glycosylated nature of both proteins. F1 antigen purified from the E. coli recombinant induced a protective immune response in BALB/c mice challenged with up to 10(5) virulent Y. pestis. The resistance of immunized mice to plague infection correlated with high titers of F1 antibody. The cloned gene expresses an immunogenically competent F1 antigen suitable for use in plague serodiagnostics and vaccine development.
Quantitative in vitro drug potency and drug susceptibility evaluation of Leishmania ssp. from patients unresponsive to pentavalent antimony therapy, Quantitative in vitro drug sensitivity of 32 Leishmania isolates (16 from patients failing pentavalent antimony [SbV] therapy) was determined using a radiorespirometric microtechnique (RAM). Of 30 isolates with histories. 22 (73%) RAM tests agreed with patient history; the remaining 8 (27%) did not. There was no difference in RAM drug sensitivity: clinical correlation between 15 isolates tested blindly and 15 with known clinical history (4 did not agree with clinical history in both). Test sensitivity appeared to be limited only by the sensitivity of the Leishmania to SbV and could be detected at 2 micrograms/ml Sb (about 10% of serum drug level). An isolate from a patient with untreated self-healing cutaneous disease was drug resistant. Using RAM. parasite drug sensitivity can be quantified apart from patient physiologic and immunologic variables intrinsic to clinical data. Potency differed a maximum of 100% (weight% Sb:weight% Sb) among drug lots and also between Glucantime and Pentostam. Potency changes between drug lots were not explainable based on Sb content or test-to-test variability. This microtest offers a rapid method for evaluating the drug sensitivity of patient isolates and for determining of the activity of pentavalent antimonials and other candidate anti-leishmanials prior to the initiation of therapy.
Parasite antigenemia in untreated and treated lymphatic filarial infections, To evaluate the merit of antigen detection assays as a tool to monitor the efficacy of chemotherapy for lymphatic filariasis. we serially measured antigen levels in sera from jirds infected with Brugia malayi and from humans with bancroftian filariasis. Antigenemia was detected in all animals with parasitologically proven infection and was present in jirds with prepatent or occult filariasis. Antigen levels correlated with worm burdens. and progressively declined in drug-cured animals. Treatment with diethylcarbamazine (DEC) triggered a transient increase in serum levels of filarial antigens bearing the epitope recognized by the monoclonal antibody HC 11. All patients with bancroftian filariasis became amicrofilaremic within one week after DEC treatment. Antigenemia levels slowly declined over a period of several months in all but one treated individual. Forty-two months after treatment. progressively rising antigen levels are present in 10 patients. Six of these remain amicrofilaremic; in the other 4. elevated antigenemia levels preceded or were detected at the same time as recurrent parasitemia. Periodic monitoring of antigenemia levels after treatment of patients with lymphatic filariasis can be used to identify individuals who are likely to develop recurrent microfilaremia before the parasites become detectable in blood samples. thereby allowing timely retreatment.
Immediate versus delayed shoulder exercises after axillary lymph node dissection, A total of 144 evaluable patients with breast cancer were enrolled in a multicenter. randomized. prospective study to establish the role of delayed shoulder exercises on wound drainage and shoulder function after axillary lymph node dissection. Patients in group 1 (n = 78) started active shoulder exercises 1 day postoperatively. Patients in group 2 (n = 66) started on the eight postoperative day. following 1 week of immobilization of the arm. Patients in group 2 had 14% less wound drainage volume than those in group 1 (600 +/- 436 mL versus 701 +/- 398 mL); this difference. however. was not significant. Also. no differences could be established between the two groups when duration and volume of wound drainage. number and volume of seroma aspirations. wound complication rates. and shoulder function were compared 6 months after surgery.
Outpatient laparoscopic laser cholecystectomy, Laparoscopic laser cholecystectomy has been performed clinically in the United States since 1988. After refinement of the technique. the procedure was offered on an outpatient basis. Eighty-three patients underwent laparoscopic laser cholecystectomy during the study period. Thirty-seven (45%) had the procedure as an outpatient. Younger patients were more suited for the outpatient procedure and those without previous surgery were more likely to have the procedure done as an outpatient. Weight. operating time. and gallbladder pathology were similar. although patients with acute inflammation of the gallbladder were more likely to require hospitalization. The primary reason for patient admission was patient preference.
Fish oil supplementation in patients with stable claudication, Increased blood viscosity occurs in patients with claudication. This increase in viscosity. which is mainly due to elevated fibrinogen levels and a decreased red cell deformability. adversely influences blood flow. In addition to a positive effect on blood pressure. blood lipids. and platelet responsiveness. fish oil may improve blood flow due to a favorable influence on hemorrheology. In a prospective. randomized. double-blind study. we evaluated the effect of six capsules of fish oil (1.8 g eicosapentaenoic acid and 1.2 g docosahexaenoic acid) versus six capsules of corn oil (3 g linoleic acid). administered for 4 months. on walking distances. pressure indices during rest and after exercise. blood pressure. red cell deformability. fibrinogen. and lipid levels in 32 patients with stable claudication. No significant changes in walking distances and pressure indices during rest and after exercise occurred. despite a significant increase in red cell deformability in the fish oil group. Fibrinogen levels did not change in either group. In the fish oil group. a favorable change in blood lipids was noted; high-density cholesterol increased and triglycerides decreased. Mean arterial blood pressure declined to a similar extent in both groups. Thus. short-term supplementation with fish oil does not lead to clinically significant improvement of symptoms in patients with stable claudication. This suggests that red cell deformability is of minor importance in the arterial blood flow in the legs of these patients.
Effects of spermatic vascular division for correction of the high undescended testis on testicular function, Orchiopexy with division of the spermatic artery and veins is a commonly used technique for correcting the high undescended testis. although the longterm results have not been clearly defined. The left spermatic artery and veins of 22 adult Wistar albino rats were divided while preserving the vessels associated with the vas and cremaster muscle (DT). A sham operation was performed on the left testicle of six additional rats (ST). At 3 weeks postoperatively. both testes from all rats were removed. All testes were viable and bled when incised. although bleeding was considerably reduced in testes with DT. Mean testicular weights after DT were 1.061 +/- 423 mg compared with 1.634 +/- 125 mg for ST rats (p less than 0.02) and 1.508 +/- 119 mg for contralateral testes. The mean tubular diameter after DT was 220 +/- 37 mu compared with 303.1 +/- 10.7 mu for ST testes (p less than 0.02). The testicular biopsy score based upon the morphology of the spermatic tubules was 4.46 +/- 3.32 for DT testes and 8.65 +/- 0.23 for ST testes (p less than 0.02) compared with 8.38 +/- 0.18 for contralateral testes and an absolute normal value of 10. No morphologic abnormalities were observed in the contralateral unoperated testes from any of the rats. The contralateral testes in 12 additional rats were removed before DT. The mean testosterone values in these rats with one testicle was 1.43 +/- 0.75 ng/mL. Three weeks after DT. testosterone values were 0.19 +/- 0.31 ng/mL (p less than 0.01). It is concluded that division of the main spermatic artery and vein in rats produces testicular atrophy with spermatogenic arrest and interstitial cell dysfunction. Although collateral blood flow to the testis may be demonstrated. tissue perfusion is inadequate for normal spermatogenesis and endocrine function.
Comparison of blood flow assessment between laser Doppler velocimetry and the hydrogen gas clearance method in ischemic intestine in dogs, Blood flow of the colon and the ileum was measured before and after intestinal devascularization by laser Doppler velocimetry and the hydrogen gas clearance technique in 10 dogs in order to evaluate the clinical usefulness of laser Doppler velocimetry. The submucosal blood flow of the colon and the ileum measured by the hydrogen gas clearance method was significantly decreased. as was the subserosal blood flow of both sites measured by laser Doppler velocimetry. There was a linear relationship between the flow values using the two methods both in the colon (r = 0.7192. p less than 0.001) and in the ileum (r = 0.7646. p less than 0.001). These data suggested laser Doppler velocimetry may be a useful method to assess the degree of intestinal ischemia because of its noninvasiveness and good correlation with submucosal blood flow by the hydrogen gas clearance technique.
Relationship of oxygen dose to angiogenesis induction in irradiated tissue, This study was accomplished in an irradiated rabbit model to assess the angiogenic properties of normobaric oxygen and hyperbaric oxygen as compared with air-breathing controls. Results indicated that normobaric oxygen had no angiogenic properties above normal revascularization of irradiated tissue than did air-breathing controls (p = 0.89). Hyperbaric oxygen demonstrated an eight- to ninefold increased vascular density over both normobaric oxygen and air-breathing controls (p = 0.001). Irradiated tissue develops a hypovascular-hypocellular-hypoxic tissue that does not revascularize spontaneously. Results failed to demonstrate an angiogenic effect of normobaric oxygen. It is suggested that oxygen in this sense is a drug requiring hyperbaric pressures to generate therapeutic effects on chronically hypovascular irradiated tissue.
Variations in sensitivity after sectioning the intercostobrachial nerve, The authors present a prospective study of the variations in sensitivity that appear in the armpit and arm after the intercostobrachial nerve has been sectioned in a modified radical mastectomy. Of a total of 208 patients studied between 1978 and 1987. the intercostobrachial nerve was sectioned in 139 patients. whereas in 30 it remained intact; in 39 patients only peripheral branches of the nerve were sectioned. The patients were examined at regular postoperative intervals in order to evaluate their sensitivity both to touch and to pain in the axilla and arm. Four hundred thirty-three examinations were carried out and the 3 operative groups were assessed accordingly. After the nerve was sectioned. there was increasing anesthesia in the armpit and hypoesthesia on the posterointernal face of the arm. while for the patients in whom the intercostobrachial nerve remained intact. these alterations were less intense and long-lasting. Significant statistical differences between the two groups also exist. In the absence of axillary lymphatic ganglia infiltrated by the tumor. the conservation of the intercostobrachial nerve is recommended.
Rectal prolapse in infants and children, Rectal prolapse that is intractable to the usual medical therapy was successfully managed without significant complications in 10 patients by simple subcutaneous encirclement of the anus with a heavy nonabsorbable suture. which was in place until the suture was removed or broke after 4 to 6 months. Four patients required two sutures and one needed a third insertion. Since this procedure is simple. has no serious complications. and controls rectal prolapse. it is recommended as the preferred initial surgical treatment of this condition.
Prevention of pancreatic fistula by modified pancreaticojejunal anastomosis, A major cause of morbidity after pancreatoduodenectomy is leakage from the pancreaticojejunal anastomosis. To prevent this complication. we have employed mucosal stripping from the proximal jejunum prior to end-to-end anastomosis in 19 patients with good results.
Intravenous fluid load and recovery. A double-blind comparison in gynaecological patients who had day-case laparoscopy, The effect of intra-operative fluid and dextrose administration upon recovery was tested in a randomised. double-blind trial. Three groups of 25 patients. each undergoing laparoscopic examination as day cases. were studied. The two groups who received fluid (20 ml/kg compound sodium lactate solution) showed significant improvement (p less than 0.05) in the variables that reflected hydration. The fluid group who also received dextrose (1 g/kg) exhibited further significant improvement. Intra-operative fluid and dextrose administration appears to confer some benefit upon recovery in patients who have minor surgery.
Treatment of atelectasis of upper lung lobes. Selective bronchial suctioning with J-shaped catheter tip and guide mark, We developed a technique for blind bronchial suction using a curved-tip catheter with a guide mark. for the treatment of atelectasis of the lower and middle lobes of the lung. Suction of the upper lobe bronchi could not be performed because of the combination of the peculiar anatomy of the upper lobe bronchi with catheter design. We treated successfully two cases of atelectasis of the right upper lobes using a Rusch Metras bronchography catheter with a guide mark which is not readily available. Therefore we devised a J-shape tipped catheter with a guide mark. We have successfully treated 13 episodes of atelectasis of the right upper lobe in 10 patients and one episode in the left upper lobe in one patient with this new catheter.
The Woolley and Roe case. A reassessment, In 1953. two patients. Cecil Roe and Albert Woolley. sued their anaesthetist for alleged negligence because they had developed painful spastic paraparesis after spinal anaesthesia. The court found that phenol. which was used to sterilise the outside of the ampoules of local anaesthetic. had percolated the glass through invisible cracks. contaminating the solution. but that the anaesthetist could not have been aware of this risk. The case was important. despite the fact that judgement was in favour of the anaesthetist. because of the fears that it generated over the incidence of paralysis after spinal anaesthesia. The 'invisible crack' theory has been the subject of much scepticism. New information has been obtained. and the case re-examined objectively. The most probable source of contamination. which led to paralysis in the two patients. and in a third who received spinal anaesthesia on the same day. has been identified. A similar explanation may lie behind a number of other episodes of paralysis associated with spinal anaesthesia.
Minitracheotomy: complications and follow-up with fibreoptic tracheoscopy, Complications and changes in tracheal mucosa after minitracheotomy were evaluated in 28 patients. Tracheal mucosa was inspected fibreoptically after the insertion of a minitracheotomy cannula. and then at 3-day intervals until the cannula was removed. Thereafter. assessments were made every third day until the mucosa was considered normal. Three significant complications occurred: mediastinal puncture. paratracheal entrance of the cannula and subcutaneous emphysema. Difficulties at insertion of the minitracheotomy cannula were encountered in 15 of 28 patients (54%). Air flow detected through the cannula in one patient. and lack of air flow in another patient. were misleading signs of the position of the cannula. Passing a suction catheter in three patients and a normal end-tidal carbon dioxide tracing in one patient. were also found to be misleading. The correct position and possible complications could be verified only by fibreoptic tracheoscopy. Changes in the tracheal mucosa were independent of the duration of minitracheotomy therapy.
Effects of famotidine and cimetidine on plasma levels of epidurally administered lignocaine, The effects of two H2-receptor antagonists. famotidine and cimetidine. on the plasma levels of epidurally administered lignocaine were studied. Group A (n = 20) received famotidine 20 mg orally the night before surgery and 20 mg intramuscularly 60 minutes before induction of anaesthesia. Group B (n = 15) received cimetidine 200 mg orally the night before the surgery and 400 mg orally 60 minutes before the anaesthetic induction. Group C (n = 20) received neither famotidine nor cimetidine and served as controls. Twelve millilitres of 2.0% lignocaine with adrenaline 1:200.000 was injected into the epidural space in all patients. after the establishment of general anaesthesia with nitrous oxide. oxygen. and enflurane (0.3-0.5%). The patients who received cimetidine showed significantly higher plasma concentrations of lignocaine compared with either group A or group C at all investigation times (p less than 0.01). The mean peak plasma concentrations were 2.4 (SEM 0.1). 3.2 (SEM 0.2) and 2.3 (SEM 0.1) micrograms/ml in group A. B. and C. respectively. This study suggests that famotidine is preferable to cimetidine for control of gastric acidity before the use of lignocaine as the epidural anaesthetic.
Loss of consciousness after emergence from anaesthesia. A case of suspected micturition syncope, A case of postanaesthesia micturition syncope with respiratory arrest is described. If syncope occurs. the temporary myocardial ischaemia and cerebral hypoperfusion may increase anaesthetic risk in the marginally compensated patient. The loss of airway protection during the syncopal period is also a cause of concern. We recommend the use of an indwelling bladder catheter during any prolonged surgical procedure.
Prolonged neuromuscular blockade with vecuronium in a neonate with renal failure, An 11-day-old neonate with renal failure caused by dysplastic kidneys was anaesthetised with thiopentone. vecuronium. nitrous oxide and oxygen. for insertion of a long-term peritoneal dialysis catheter. Complete neuromuscular block of 210 minutes' duration ensued after the initial dose of vecuronium (97 micrograms/kg). Partial block persisted for a further 30 minutes. The prolonged neuromuscular block in this case may have been because of proportionately greater dependence on renal clearance of vecuronium in neonates.
Intravenous diclofenac sodium. Does its administration before operation suppress postoperative pain, Intravenous diclofenac sodium was evaluated in a double-blind randomised trial relative to intramuscular diclofenac. intravenous fentanyl. and intramuscular placebo in 160 patients undergoing extraction of impacted lower third molar teeth. The test drug was administered before operation in an attempt to alleviate postoperative pain. A 10-cm visual analogue scale was used to assess pain at 30 minutes and one day after surgery. if the patients stayed overnight. Patients who received intravenous diclofenac had significantly less pain than the other groups 30 minutes after operation. They also had significantly less pain one day after surgery than the placebo or opioid groups. but not less than the intramuscular diclofenac group. Capillary bleeding time. in comparison with placebo. was significantly prolonged after the use of intramuscular diclofenac. and a similar but nonsignificant trend was observed in the intravenous diclofenac group. No problems were encountered with excessive bleeding in any group.
Relief of injection pain in adults. EMLA cream for 5 minutes before venepuncture, The effectiveness of skin anaesthesia after 5 minutes' topical application of a lignocaine-prilocaine cream was evaluated. One hundred and twenty patients estimated the pain of antecubital venepuncture both on a linear scale and verbally after use of the cream for either 5 or 60 minutes. a placebo cream or no treatment. Reported pain was significantly less after only 5 minutes of the lignocaine-prilocaine cream (p = 0.002). The cream can be used to relieve the pain of all routine injections.
Effect on outcome of prolonged exposure of patients to nitrous oxide, Prolonged (several days or repeated) exposure to nitrous oxide (N2O) can cause injury or death. To assess whether relatively prolonged anesthesia with N2O in normal patients might similarly cause untoward effects. we investigated whether the addition of N2O to isoflurane anesthesia caused injury to patients having surgical resection of acoustic neuroma lasting approximately 10 h. Twenty-six patients undergoing surgical resection of acoustic neuroma were randomly assigned to a regimen that included or excluded N2O (50%-60%) during isoflurane anesthesia plus intravenous adjuvants. On average. slightly less isoflurane (0.24%) was used during anesthesia with N2O. We measured standard clinical variables (blood pressure. heart rate). oxygen saturation. neurologic status. pain. and the incidence and type of morbid outcomes. Exposure to N2O did not increase the incidence of morbid outcomes (including hepatic injury. infection. or hypoxemia). prolong hospitalization. or increase common postoperative complaints such as nausea. vomiting. coughing. or headache. Patients anesthetized with either regimen were equally satisfied with their anesthetic.
No finding of increased myocardial ischemia during or after carotid endarterectomy under anesthesia with nitrous oxide, Nitrous oxide (N2O) has been implicated as a cause of myocardial ischemia. We investigated whether substitution of N2O for a portion of the anesthesia supplied by isoflurane increased myocardial ischemia in patients at risk for such ischemia. Seventy patients having carotid endarterectomies (63 patients) or other carotid surgery (seven patients) were prospectively. randomly assigned to an anesthetic regimen that included or excluded N2O. All other aspects of anesthetic management were similar. except for greater concentrations of oxygen and isoflurane in patients not given N2O. Perioperative monitoring for myocardial ischemia and infarction included 12- or 5-lead electrocardiography. transesophageal echocardiography. and creatine kinase isoenzyme levels. By transesophageal echocardiographic or electrocardiographic criteria. 44% of patients given oxygen but only 21% of those given N2O had myocardial ischemia intraoperatively (P = 0.065). Similarly. myocardial infarction. identified by changes in creatine kinase isoenzymes. occurred in only one patient given N2O but in three given oxygen (not significantly different). Thus we found no trend indicating a greater incidence of myocardial ischemia or infarction associated with the use of N2O.
Postoperative hypoxemia after nonabdominal surgery: a frequent event not caused by nitrous oxide, We tested whether anesthesia that includes nitrous oxide (N2O) results in the development of intraoperative and postoperative pulmonary complications. including hypoxemia. We also tested whether aging contributes to the development of such complications. particularly when anesthesia includes N2O. We randomly allocated patients having total hip replacements. carotid endarterectomies. or transsphenoidal hypophysectomies (total n = 270) to an anesthetic regimen with and without N2O (stratified within surgical group). A heat-and-moisture exchanger was included in the anesthetic circuit of all patients. Patients were monitored perioperatively and for 1 wk after surgery using intermittent and continuous pulse oximetry to determine oxyhemoglobin saturation. Intraoperatively. mean oxygen (O2) saturations were lower in patients given N2O. particularly older patients. Hypoxemia (O2 saturation less than 86%) developed in five patients receiving N2O and in one receiving O2. This difference was not significant. Administration of N2O did not decrease postoperative O2 saturation. nor did it alter the incidence of postoperative hypoxemia. cough. or sputum production.
Nitrous oxide and epinephrine-induced arrhythmias, We asked whether the sympathomimetic effect of nitrous oxide (N2O) predisposed patients receiving N2O to arrhythmias in response to epinephrine administration. We also asked whether aging contributed to the development of arrhythmias. with or without N2O. One hundred patients having transsphenoidal hypophysectomy were randomly assigned to receive anesthesia including (n = 49) or excluding (n = 51) N2O. All patients were given an injection of epinephrine 1:200.000. with 0.5% lidocaine to produce hemostasis. Using intermittent 12-lead and continuous lead II electrocardiography. we determined the incidence of premature ventricular contraction. isorhythmic atrioventricular (AV) dissociation. and changes in T-wave morphology. Patients given N2O had a significantly higher incidence of isorhythmic AV dissociation (61.2% vs 41.2%). A trend toward a higher incidence of multiple premature ventricular contractions (16.3% vs 7.8%) was not statistically significant. Both anesthetic groups had a high incidence of postoperative changes in T-wave morphology (46.9% in the N2O group vs 50.9% in the group not given N2O). Aging alone did not affect the incidence of ventricular ectopic beats. isorhythmic AV dissociation. or changes in electrocardiographic morphology. but correlated with the development of ventricular ectopy during N2O anesthesia. We conclude that the use of N2O correlated with a higher incidence of isorhythmic AV dissociation in response to injection of epinephrine with lidocaine.
Thoracic epidural anesthesia improves global and regional left ventricular function during stress-induced myocardial ischemia in patients with coronary artery disease, The aim of the present investigation was to study the effects of high thoracic epidural anesthesia (TEA). including the cardiac sympathetic segments. on ischemic ST-segment changes and left ventricular global and regional wall motion abnormalities. Ten patients with a two- or three-vessel coronary artery disease. all treated with the beta-adrenergic blocker metoprolol because of severe stable angina pectoris. performed two identical exercise stress tests. the first without TEA (control exercise) and the second with TEA (TEA exercise). Before each stress test. intravenous metoprolol was given to achieve maximal or near maximal beta-adrenoceptor blockade. Systolic and diastolic arterial pressures (radial artery cannula). heart rate. and rate-pressure product. as well as global and regional ejection fractions. using equilibrium radionuclide angiography in the left anterior oblique projection. were measured at rest and during maximal exercise. ST-segment analysis (V3 or V5) was performed. and the regional wall motion score was calculated at control exercise and TEA exercise. Intravenous metoprolol or intravenous metoprolol plus TEA at rest did not cause any significant changes of any of the variables. During TEA exercise. systolic arterial pressure. diastolic arterial pressure. and rate-pressure product. but not heart rate. were significantly lower compared to control exercise. The global and anterolateral ejection fractions were significantly higher (52.8% versus 46.5% and 53.2% versus 46.0%. respectively. P less than 0.05). and the regional wall motion score was significantly lower (8.8 versus 11.8. P less than 0.01) during TEA exercise than during control exercise. ST-segment depression was significantly lower during TEA exercise (-1.03 versus -1.84 mV. P less than 0.01).
Pulmonary hypertension after heparin-protamine: roles of left-sided infusion, histamine, and platelet-activating factor, Severe pulmonary hypertension after protamine neutralization of heparin is an infrequent but life-threatening event following cardiopulmonary bypass. The effect of left ventricular infusion of protamine on pulmonary hypertension as well as a possible role of platelet-activating factor (PAF) or histamine in the heparin-protamine reaction was investigated in 30 pigs in four different groups during general anesthesia. Group 1 animals received 250 IU/kg heparin. followed by 100 mg protamine intravenously after 15 min. In group 2 protamine was infused into the left ventricle. Group 3 animals received the histamine H1- and H2-antagonists clemastine and ranitidine 5 min before protamine infusion. In group 4 the PAF receptor blocker WEB 2086 was given 5 min before protamine. Platelet-activating factor was measured by a bioassay in serum samples of group 1 and group 4 animals. In all four groups protamine caused severe pulmonary hypertension. thromboxane A2 release. and a transient decrease in leukocyte counts. No PAF release was detected after protamine infusion. Neither left ventricular infusion of protamine nor histamine or PAF antagonists prevented or attenuated the reactions after protamine infusion. The authors conclude that left ventricular infusion of protamine provides no protection from pulmonary hypertension. and that histamine and PAF are not involved in the acute pulmonary vasoconstriction after protamine neutralization of heparin.
Resistance to atracurium-induced neuromuscular blockade in patients with intractable seizure disorders treated with anticonvulsants, Previous studies have demonstrated that. with the exception of atracurium. resistance to the neuromuscular blocking effects of various muscle relaxants develops in patients receiving anticonvulsant therapy. We studied the effects of 0.5 mg/kg IV atracurium in 53 neurosurgical patients: 21 nonepileptic patients receiving no anticonvulsant therapy (MED = 0); 14 epileptic patients treated with carbamazepine for years (MED = 1); and 18 epileptic patients treated with carbamazepine plus either phenytoin or valproic acid for years (MED = 2). The evoked compound electromyogram of the adductor pollicis brevis was recorded. and results were analyzed using analysis of covariance. with weight and age as covariables. The onset time was not significantly different among the three groups. Times for recovery of baseline and train-of-four responses to stimuli were significantly shorter in the MED = 1 and MED = 2 groups than in control patients (MED = 0). The recovery index (time between 25% and 75% recovery of baseline electromyogram values) was progressively shorter in the three groups (MED = 0: 8.02 min; MED = 1: 5.93 min; MED = 2: 1.96 min; P less than 0.001). This study demonstrates that atracurium. when used on epileptic patients requiring long-term (that is. years of) anticonvulsant therapy. has a shorter duration of action than when used in nonepileptic patients.
Lidocaine local anesthesia for arthroscopic knee surgery, Forty-five patients were evaluated during knee arthroscopy performed using local anesthesia produced by lidocaine with epinephrine to determine the dose-response relationship for operative analgesia. Serum lidocaine concentrations were also measured. Patients were randomized prospectively to receive 20 mL of 0.5%. 1.0%. or 1.5% lidocaine with epinephrine intraarticularly. Intraoperative discomfort was measured by verbal response on an 11-point linear pain scale. Pain scores were significantly higher in patients receiving 0.5% lidocaine during the first 45 min of surgery (P = 0.03). After 45 min. pain scores continued to be higher in the 0.5% lidocaine group than in the 1.0% or 1.5% groups. but the differences were not statistically significant. Ninety-four percent of patients in the 1.5% lidocaine group were willing to repeat this anesthetic technique for surgery compared with 83% of those in the 1.0% lidocaine group and 75% of those in the 0.5% lidocaine group (P greater than 0.05). The duration of postoperative analgesia was similar in all groups. Serum lidocaine concentrations before and 15. 30. 60. and 120 min after instillation of lidocaine were highest in the 1.5% lidocaine group with a peak concentration of 278 ng/mL. No patient had symptoms of lidocaine toxicity. We recommend that lidocaine concentrations of 1.0% or 1.5% be used when 20 mL is instilled intraarticularly for knee arthroscopy based on patient comfort and absence of lidocaine toxicity.
Effects of thoracic epidural anesthesia on coronary arteries and arterioles in patients with coronary artery disease, The effect of cardiac sympathetic blockade by high thoracic epidural anesthesia (TEA) (T1-T6. bupivacaine) on the luminal diameter of normal and diseased portions of epicardial coronary arteries was determined by quantitative coronary angiography in patients (n = 27) with severe coronary artery disease (CAD). In a separate group of patients (n = 9) with severe CAD. the effects of TEA on coronary arterioles (resistance vessels) were studied. by measuring total and regional myocardial blood flow and metabolism with the retrograde coronary sinus thermodilution technique. At the stenotic segments. TEA induced an increase in luminal diameter from 1.34 +/- 0.11 to 1.56 +/- 0.13 mm (P less than 0.002). but did not change the diameter of the nonstenotic segments (3.07 +/- 0.13 to 2.99 +/- 0.13 mm). In the second group of patients. TEA induced no changes in coronary perfusion pressure. total or regional myocardial blood flow. coronary venous oxygen content. coronary blood flow distribution. regional myocardial oxygen consumption. or lactate extraction or uptake. Two patients had chest pain in the control situation and had regional myocardial lactate production that was attenuated by TEA. We conclude that TEA may increase the diameter of stenotic epicardial coronary artery segments in patients with CAD without causing a dilation of coronary arterioles. These effects may be beneficial when high TEA is used to treat severe ischemic chest pain in patients at rest.
Clinical evaluation of clonidine added to lidocaine solution for epidural anesthesia, The effects of clonidine added to lidocaine solution used for epidural anesthesia were assessed in 92 women scheduled for surgery and premedicated with diazepam 10 mg po. Patients received 18 ml 2% lidocaine with clonidine 5 micrograms.ml-1 (group C-5. n = 26). with clonidine 10 micrograms.ml-1 (group C-10. n = 20). with epinephrine 5 micrograms.ml-1 (group E. n = 26). or plain (group P. n = 20). No significant difference in the number of segments of analgesia was found at any observation period among the four groups of patients. The decreases in mean blood pressure (BP) observed 20 min after epidural injection in those given clonidine (5 +/- 8% for C-5. 10 +/- 11% for C-10. mean +/- SD) were similar to those given plain lidocaine (7 +/- 12%) but significantly less than those given epinephrine (18 +/- 12%. P less than 0.01 vs. C-5 or P). The response of BP to ephedrine given for restoring BP during anesthesia was not attenuated in patients who received epidural clonidine. Heart rate (HR) decreased significantly in patients given clonidine 10 micrograms.ml-1 (7 +/- 8%. P less than 0.01). but not in those given clonidine 5 micrograms.ml-1. whereas HR increased significantly in those given lidocaine plain or with epinephrine (10 +/- 8% and 28 +/- 14%. respectively. P less than 0.01). The incidence of sinus bradycardia was similar among the four groups of patients. Significant differences were also observed in sedation score between clonidine groups and groups P or E; sedation appeared approximately 10-20 min after epidural injection in both clonidine groups.
Chloroprocaine antagonism of epidural opioid analgesia: a receptor-specific phenomenon, Sixty healthy patients scheduled for elective cesarean delivery under epidural anesthesia were randomized to receive either lidocaine or 2-chloroprocaine as the primary local anesthetic agent. When patients first complained of postoperative pain in the recovery room. they were given either fentanyl 50 micrograms or butorphanol 2 mg. epidurally. in a randomized. blinded fashion. Postoperative analgesia. quantitated on a visual analogue scale. as well as time elapsed until first request for supplemental opioid. did not differ for patients receiving butorphanol after either 2-chloroprocaine or lidocaine anesthesia. In contrast. epidural fentanyl produced a shorter and lesser degree of sensory analgesia after 2-chloroprocaine use. whereas epidural fentanyl after lidocaine anesthesia provided pain relief similar to that seen in the butorphanol groups. Side effects were limited to somnolence with butorphanol and pruritus with fentanyl. No evidence of respiratory depression was seen in any patient. We conclude that 2 mg of butorphanol epidurally provides approximately 2 to 3 h of effective analgesia after cesarean delivery with either lidocaine or 2-chloroprocaine anesthesia. Epidural fentanyl seems to be antagonized when 2-chloroprocaine. but not lidocaine. is used as the primary local anesthetic agent. We suggest a possible mu-receptor-specific etiology for this effect.
Exogenous opioids in human breast milk and acute neonatal neurobehavior: a preliminary study, Opioid analgesia requirements. distribution into breast milk. and influence on neonatal neurobehavior were evaluated in ten parturient-neonate pairs nursing after elective cesarean section during epidural anesthesia. Five patients received first a loading dose of intravenous meperidine after umbilical cord clamping. then patient-controlled analgesia (PCA) with intravenous meperidine. and finally meperidine tablets as needed. Five patients received morphine in the same manner. Treatment groups showed no differences with respect to neonatal Apgar scores or visual analog scale (VAS) pain or satisfaction scores at 24 and 48 h postpartum. Breast milk specimens. obtained at 12. 24. 36. 48. 72. and 96 h postpartum and analyzed for opioids and metabolites. showed persistently elevated normeperidine concentrations in the meperidine group. A blinded psychologist evaluated each infant once on the 3rd day of life with the Brazelton Neonatal Behavioral Assessment Scale (NBAS). A priori. the "alertness" and three "human orientation" outcomes of the NBAS were chosen for analysis as best measures of opioid-induced effects. On all four outcomes. neonates in the morphine group scored significantly higher (P less than 0.05) than neonates in the meperidine group. We conclude that post-cesarean delivery PCA with morphine provides equivalent maternal analgesia and overall satisfaction as that provided by PCA with meperidine. but with significantly less neurobehavioral depression among breast-fed neonates on the 3rd day of life.
Functional residual capacity in anesthetized children: normal values and values in children with cardiac anomalies, To assess the increase in functional residual capacity (FRC) with growth. FRC was measured after induction of anesthesia in two groups of children. One group consisted of 74 children. 0.1-11.2 yr of age. without signs of cardiorespiratory disease (referred to here as "normal" children). and the other of 21 children. 0.2-6.9 yr of age. with cardiac malformations. Anesthesia was maintained with halothane in the normal children and with fentanyl. droperidol. and nitrous oxide in the children with cardiac anomalies. All patients were paralyzed. their tracheas intubated. and their lungs mechanically ventilated. FRC was measured with an automated tracer gas washout technique. In 70 patients the measurements were performed in duplicate with a mean coefficient of variation of 2.0%. FRC correlated significantly with height. weight. and age in both groups. Multiple regression analysis for both groups considered together indicated no significant improvement when factors for the sex of the child or for the presence of cardiac anomalies were incorporated into the model. In normal children the simple linear and nonlinear regression equations for FRC (in milliliters) versus height (in centimeters) were: FRC = -529 + 9.48 x height. r = 0.96; and FRC = 0.00175 x height2.66. r = 0.97. respectively. The corresponding equations for FRC (in milliliters) versus weight (in kilograms) were: FRC = -92 + 29.9 x weight. r = 0.93; and FRC = 9.51 x weight1.31. r = 0.95.
Hypoxemia in the postanesthesia care unit: an observer study, To determine the incidence and duration of hypoxemia in the postanesthesia care unit (PACU). 200 patients were investigated in a single-blind observer study. The number of unrecognized hypoxemic episodes. as well as risk factors and possible association between hypoxemia and postoperative morbidity. were studied. Oxygenation was monitored continuously with a pulse oximeter. One or more hypoxemic episodes (SpO2 less than or equal to 90%) were noted in 55% of the patients. SpO2 values less than or equal to 80% were noted in 13% of the patients. Supplementary oxygen was given during 55% of the 447 hypoxemic episodes registered. The hypoxemic episodes were unrecognized by the staff in 95% of the cases. With stepwise multiple logistic regression analyses. risk factors associated with a higher incidence of hypoxemia were: duration of anesthesia (P less than 0.0001). age (P less than 0.002) and a history of smoking (P less than 0.01). Patients who had undergone regional anesthesia had a lower risk of hypoxemia (P less than 0.0002). The occurrence of hypoxemia in the PACU could not be correlated to postoperative morbidity. We conclude that hypoxemic episodes in our PACU are common and that the routine use of supplemental oxygen combined with normal clinical surveillance did not prevent hypoxemic episodes.
Anesthesia for craniotomy: a double-blind comparison of alfentanil, fentanyl, and sufentanil, Using a prospective. randomized. and double-blind study design. alfentanil (n = 15). fentanyl (n = 14). or sufentanil (n = 16). in combination with N2O. were administered to patients undergoing craniotomy for supratentorial tumor resection. Physicians were given two syringes. one of which was labeled as "load" for the initial loading dose and the other as "maintenance" for continuous infusion. The concentration of drug in each syringe was adjusted to permit administration on a milliliter per kilogram basis. The target loading doses for alfentanil. fentanyl. and sufentanil were 75. 10. and 1 microgram/kg. respectively. and initial infusion rates were 33.5. 2.0. and 0.3 microgram.kg-1.h-1. respectively. Additional supplementary boluses and changes in maintenance infusion rate were made according to predetermined guidelines. Isoflurane. in increasing 0.2% inspired increments. was used only when the maximum allowed opioid dose had been given (i.e.. supplementary bolus doses equal to 75% of the calculated loading dose or supplementary bolus doses equal to 50% of the calculated loading dose combined with a 50% increase in the maintenance infusion rate). Opioid infusions were stopped at the time of bone flap replacement. Antihypertensive medications and naloxone were subsequently given at the discretion of the anesthesiologist. Group demographics were not different. Total volumes of drug were similar among groups indicating equipotent preparations. Administration of isoflurane. antihypertensive medications. and naloxone were not different among groups. Although decreases in blood pressure seen with induction were similar among groups. alfentanil-treated patients received ephedrine more frequently before intubation. Thirty minutes after entry into the postanesthesia recovery area. respiratory rate and pH were lowest in sufentanil-treated patients.
Effects of ketamine on the cardiac papillary muscle of normal hamsters and those with cardiomyopathy, The effect of ketamine (10(-5) and 10(-4) M) on the intrinsic contractility of left ventricular papillary muscle from normal hamsters and those with cardiomyopathy (BIO 82.62. 6-month old) was investigated. At these concentrations. ketamine induced a positive inotropic effect on normal papillary muscle. as shown by an increase in maximum unloaded shortening velocity (+19 +/- 4 and +34 +/- 5%. P less than 0.05). active isometric force (+32 +/- 8 and +57 +/- 11%. P less than 0.05). and peak power output (+40 +/- 8 and +80 +/- 16%. P less than 0.05). and induced a slight decrease in sarcoplasmic reticulum function. Ketamine had no effect on the curvature of the total force-velocity curve. suggesting that it does not modify myothermal economy. Contractility of papillary muscle from hamsters with cardiomyopathy was less than that of controls. as shown by the decrease in isometric active force (-41%. P less than 0.02). peak power output (-33%. P less than 0.05). and sarcoplasmic reticulum function. The positive inotropic effect of ketamine on papillary muscle from hamsters with cardiomyopathy was less marked than in controls and almost suppressed in some cases: only the maximum unloaded shortening velocity was significantly increased with 10(-5) M ketamine (+7 +/- 6%. P less than 0.05). whereas no significant changes were observed in active isometric force (+14 +/- 8 and +13 +/- 11%; nonsignificant [NS]) and peak power output (+9 +/- 5 and +13 +/- 8%; NS) with ketamine (10(-5) and 10(-4) M. respectively).
Differential effect of oncotic pressure on cerebral and extracerebral water content during cardiopulmonary bypass in rabbits, To study the effect of oncotic pressure on brain water content during cardiopulmonary bypass (CPB). 14 anesthetized New Zealand White rabbits underwent 60 min of nonpulsatile CPB at normothermia. Animals were grouped according to the composition of the circuit priming fluid. Group 1 animals (n = 7) received a priming fluid (6.5% hydroxyethyl starch in 0.72 N NaCl; 323 +/- 13 mOsm/kg [mean +/- SD]) that maintained normal colloid oncotic pressure (COP) during CPB (19.0 +/- 1.5 mmHg). Group 2 animals (n = 7) received a priming fluid (0.9 N NaCl; 324 +/- 23 mOsm/kg) that led to a hypooncotic state (COP = 6.2 +/- 1.2 mmHg). Blood chemistries and hemodynamics were recorded every 15 min during CPB. Animals were given additional priming fluid and sodium bicarbonate during CPB to maintain a circuit flow of 85 ml.kg-1.min-1 and arterial pH greater than 7.35. There were no significant differences between groups 1 and 2 with respect to temperature. central venous pressure. mean arterial pressure. PaO2. PaCO2. plasma sodium concentration. or osmolality at any time during CPB. although osmolality increased in both groups. After 60 min of bypass. animals were killed and organ water contents were determined by wet/dry weight ratios. A separate group of nine similarly prepared and anesthetized animals that did not undergo cannulation or CPB also underwent measurement of plasma chemistries and tissue water contents and served as nonbypass controls (group 3). Brain and kidney water contents were unaffected by oncotic pressure. whereas duodenum and skeletal muscle had significantly greater water content (P = 0.003 and P = 0.008. respectively) after hypooncotic CPB.
Local and global function of the right ventricle in a canine model of pulmonary microembolism and oleic acid edema: influence of ventilation with PEEP, Right ventricular (RV) dysfunction may occur due to increased RV afterload and. hence. might also contribute to the decrease in cardiac output following institution of PEEP in patients with adult respiratory distress syndrome (ARDS). To test this hypothesis. the authors examined the influence of PEEP on local and global RV function in 12 anesthetized dogs with experimental ARDS (eARDS) induced by pulmonary microembolization with glass beads and oleic acid. Local RV function was analyzed in the RV inflow tract (RVIT) and RV outflow tract (RVOT) by assessing both diastolic segment length. systolic segment shortening. and segment work (sonomicrometry). Global RV contractility was quantified by measuring maximum rate of pressure rise (dRVP/dtmax) and maximum velocity of contractile element shortening (Vmax). In eARDS. despite a fivefold increase in pulmonary vascular resistance. there was no change in cardiac index (CI). global RV contractility. RVIT and RVOT work. and RVIT shortening. whereas RVOT shortening decreased from 12.4 to 7.4% (P less than 0.01). Diastolic segment length increased in RVIT (P less than 0.05) but not in RVOT. PEEP of 10 cmH2O did not alter global RV contractility. RVIT and RVOT shortening. and RVIT work but reduced RVOT work (-35%; P less than 0.01) and CI (-11%; P less than 0.001). Cardiac index further decreased during PEEP of 20 cmH2O (-38%; P less than 0.001). while global RV contractility remained intact despite decreased RVIT and RVOT shortening (-32% and -69%; P less than 0.05) and work (-26% and -59%; P less than 0.01) in the presence of reduced fiber preload in both regions. From these findings. it was concluded that 1) the decreased CI during mechanical ventilation with PEEP at constant right ventricular end-diastolic pressure (RVEDP) is not caused by depressed global RV contractility in dogs with eARDS and a normal myocardium prior to insult. Decreased diastolic segment length and segment shortening during PEEP suggest that 2) PEEP reduces stroke volume by the Starling mechanism rather than by ischemia of the RV free wall. Finally. regionally incongruent changes of fiber preload indicate that 3) local differences in RV wall compliance are likely to occur subsequent to eARDS and PEEP.
Prehospital cardiac arrest: the impact of witnessed collapse and bystander CPR in a metropolitan EMS system with short response times, OBJECTIVE: Numerous studies have shown initiation of bystander CPR to significantly improve survival from prehospital cardiac arrest. However. in emergency medical services (EMS) systems with very short response times. bystander CPR has not been shown to impact outcome. The purpose of this study was to determine the effect of bystander CPR on survival from out-of-hospital cardiac arrest in such a system. DESIGN: Prehospital. hospital. and death certificate data from a medium-sized metropolitan area were retrospectively analyzed for adult. nontraumatic cardiac arrest during a 16-month period. RESULTS: A total of 298 patients met study criteria. One hundred ninety-five arrests (65.4%) were witnessed. and 103 (34.6%) were unwitnessed. Twenty-five witnessed victims (12.8%) were discharged alive. whereas no unwitnessed victims survived (P less than .001). Patients suffering a witnessed episode of ventricular fibrillation/tachycardia (VF/VT) were more likely to survive (21.9%) than were other patients (2.0%. P less than .0001). Among witnessed patients. initiation of bystander CPR was associated with a significant improvement in survival (20.0%) compared with the no-bystander CPR group (9.2%. P less than .05). Bystander CPR was also associated with improved outcome when witnessed patients with successful prehospital resuscitation were evaluated as a group; 18 had bystander CPR. of whom 13 (72.2%) survived compared with only 12 of 38 patients with no bystander CPR (31.6%. P less than .01). CONCLUSION: Our data revealed improved survival rates when bystander CPR was initiated on victims of witnessed cardiac arrest in an EMS system with short response times.
Prehospital prophylactic lidocaine does not favorably affect outcome in patients with chest pain, STUDY OBJECTIVES: The purpose of our study was to determine the morbidity and mortality in initially stable patients presenting to paramedics with chest pain; to examine possible beneficial effects of its use. including reduction of sudden death syndrome in the prehospital and emergency department setting; and to determine if prophylactic lidocaine is associated with adverse effects in this patient population. DESIGN AND SETTING: This was a randomized. prospective study using prophylactic lidocaine in patients complaining of chest pain who presented to our paramedic system between January 1984 and January 1988. TYPE OF PARTICIPANTS: All patients aged 18 years or older with chest pain of suspected cardiac origin who presented to paramedics during the study period were included. Excluded were patients presenting with warning arrhythmias. second- or third-degree heart block. bradycardias of less than 50. hypotension of less than 90 mm Hg systolic. or known allergy to lidocaine. INTERVENTIONS: Patients were randomized into two groups. the lidocaine-treated group and the control group. An initial bolus of 1 mg/kg IV lidocaine was administered to the lidocaine-treated group. A simultaneous 2 mg/min IV drip was established. Ten minutes after the first dose of lidocaine. a second bolus of 0.5 mg/kg was administered. MEASUREMENTS AND MAIN RESULTS: During the study period. 1.427 patients were entered; 704 received lidocaine. and 723 did not. Discharge diagnoses included acute myocardial infarction (31%). unstable angina (33%). other cardiac problems (7%). and noncardiac problems (29%); overall mortality rate was 7.4%. There was an equal distribution of deaths between the lidocaine-treated group (57) and the control group (48). Six patients had a cardiac arrest in the prehospital setting. and 15 had a cardiac arrest in the ED. Malignant ventricular arrhythmias as the precipitating arrest rhythm in patients with acute myocardial infarctions were similar for the lidocaine-treated and control groups. The incidence of adverse effects. including hypotension. bradycardias. second- or third-degree heart blocks. tinnitus. and altered mental status. was similar in both groups. CONCLUSION: There are no benefits from the administration of prehospital prophylactic lidocaine in stable patients with chest pain; therefore. routine use in this setting appears unwarranted.
The diagnostic impact of prehospital 12-lead electrocardiography, STUDY HYPOTHESIS: It is feasible to apply prehospital 12-lead electrocardiography to most stable prehospital chest pain patients. Prehospital diagnostic accuracy is improved compared with single-lead telemetry. POPULATION: One-hundred sixty-six stable adult patients who sought paramedic evaluation for a chief complaint of nontraumatic chest pain. METHODS: One-hundred fifty-one prehospital 12-lead ECGs of diagnostic quality were obtained by paramedics on 166 adult patients presenting with nontraumatic chest pain. Paramedics and base station physicians were blinded to the information on acquired prehospital 12-lead ECGs and treated patients according to current standard of care-clinical diagnosis and single-lead telemetry. Final hospital diagnoses were classified into three groups: acute myocardial infarction (24); suspected angina or ischemia (61); and nonischemic chest pain (66). Paramedics and base station physicians' clinical diagnoses and prehospital and emergency department ECGs were similarly classified and compared. Prehospital and ED 12-lead ECGs were read retrospectively by two cardiologists. RESULTS: Paramedics achieved a high success rate (98.7%) in obtaining diagnostic quality prehospital 12-lead ECGs in 94.6% of eligible prehospital patients. For patients with acute myocardial infarction. prehospital ECG alone had significantly higher specificity than did the paramedic clinical diagnosis (99.2% vs 70.9%; P less than .001). and significantly higher positive predictive value (92.9% vs 32.7%; P less than .001). For patients with angina. combining the paramedic clinical diagnosis and the prehospital ECG significantly improved sensitivity (90.2% vs 62.3%; P less than .001) and increased negative predictive value (88.9% vs 71.3%; P less than .02) compared with paramedic clinical diagnosis alone. There was a high concordance between prehospital and ED ECG diagnosis (99.3% for acute myocardial infarction and 92.8% for angina). Furthermore. ten patients whose prehospital ECGs demonstrated ischemia and who had final hospital diagnoses of angina or acute myocardial infarction were mistriaged by paramedics and/or received no base station physician-directed therapy. CONCLUSION: It is feasible to apply prehospital 12-lead electrocardiography to most stable prehospital chest pain patients. Prehospital 12-lead ECGs have the potential to significantly increase the diagnostic accuracy in chest pain patients. approach congruity with ED 12-lead ECG diagnoses. and may allow for consideration of altering and improving prehospital and hospital-based management in this patient population.
The delta (delta) gap: an approach to mixed acid-base disorders, The anion gap (AG) is a helpful. yet underused. clinical tool. Not only does the presence of a high AG suggest a certain differential. but knowledge of the relationship between the rise in AG (delta AG) and the fall in bicarbonate (delta HCO3) is important in understanding mixed acid-based disorders. Simple arithmetic converts this relationship into a numerical value. the delta gap (delta gap). The delta gap = delta AG - delta HCO3. If the delta gap is significantly positive (greater than +6). a metabolic alkalosis is usually present because the rise in AG is more than the fall in HCO3. Conversely. if the delta gap is significantly negative (less than -6). then a hyperchloremic acidosis is usually present because the rise in AG is less than the fall in HCO3. Familarity with the relationship between the changes in AG and HCO3 can be useful in unmasking occult metabolic disorders.
Rapid visual colorimetry of peritoneal lavage fluid, STUDY HYPOTHESIS: That visual colorimetry can be used to rapidly and precisely estimate the erythrocyte count of 1:5 dilutions of simulated peritoneal lavage fluid. POPULATION: Fifty-four normal adult human subjects. METHODS: The automated or chamber RBC count is often used on fluid obtained by peritoneal lavage in patients with abdominal trauma to help determine the need for surgery. Unfortunately. this method sometimes results in excessive delay. We designed and built a simple colorimeter that facilitated rapid direct visual comparison of unknown samples with known color standards. A radiograph view box was used as a light source. Standards were prepared in 16-mm glass tubes to simulate peritoneal lavage fluid with RBC counts ranging from 0 to 140.000 in 10.000 cell/microL increments; 1:5 dilutions with water were used throughout to reduce opacity. Thimerosal was added to unknowns and standards to stabilize color; all samples were kept refrigerated at 4 C when not in use. In a double-blind in-vitro study. each subject matched 20 randomly distributed unknowns ranging from 12.000 to 131.000 erythrocytes/microL to the nearest standard. RESULTS: The mean absolute error for all 1.080 determinations was 3.560 RBC/microL (95% CI = 4.290-4.830; SD = 4.560; t = 39.6; df = 1.079; P less than .001). This method correctly predicted the RBC count to within 9.000 cells/microL 95% of the time. CONCLUSION: Visual comparison of 1:5 dilutions of simulated peritoneal lavage fluid with known color standards can be used to rapidly and precisely estimate the erythrocyte count.
Effect of education on the use of universal precautions in a university hospital emergency department, STUDY OBJECTIVES: To determine if an educational program would improve both knowledge and practice of universal precautions by nursing personnel. DESIGN: Participants were given a 14-question test and observed for their. practice of universal precautions during routine IV catheter placement or phlebotomy and trauma care before and six months after an education in-service. SETTING: University hospital emergency department. TYPE OF PARTICIPANTS: Nursing personnel. INTERVENTIONS: One-hour lecture addressing the occupational risk of human immunodeficiency virus (HIV) infection and the recommended use of universal precautions. MEASUREMENTS AND MAIN RESULTS: The mean overall correct response rates to the questionnaire before and after the in-service were 70% and 73%. respectively (P = NS). The pattern of incorrect responses suggested that the perceived risks of HIV transmission are underestimated. particularly among healthy-appearing patients. For care of critical trauma patients. there were significant increases between the frequency rates before and after the in-service of glove and protective eyewear use (66.7% vs 87.7%. P less than .025; 0.0% vs 17.3%. P less than .05. respectively). The frequency rates of glove use for IV placement or phlebotomy in noncritical patients and of gown use for trauma patient care also increased (52.6% vs 65.2% and 25% vs 39.5%. respectively); however. these changes were not statistically significant. CONCLUSION: An intensive educational program was associated with a modest increase in the compliance of ED nursing personnel with universal precautions and had no long-term effect on their general knowledge of HIV risk. The practice of universal precautions is still far from universal in this ED.
Scapular dislocation (locked scapula), We report the case of a 19-year-old woman who presented to the emergency department with pain and inability to move her right shoulder after falling backwards and striking it on a cart. Radiographs of the shoulder revealed a dislocated scapula. Closed reduction in the ED was successful. This rare case of scapular dislocation serves to emphasize that a heightened awareness for this injury is necessary if it is to be recognized and treated appropriately. Its treatment and prognosis are reviewed.
Transtelephonic defibrillation, STUDY OBJECTIVES: This study was undertaken to assess the safety and reliability of a device for transtelephonic defibrillation. DESIGN: The transtelephonic system consists of a patient unit and a base station. The patient unit contains a monitor-defibrillator. electrode pads. microphone. microprocessor. and DC defibrillator. The base station comprises a control panel. computer. and ECG display. SETTING: Fifteen patients who were treated in our emergency department for cardiac arrest were placed on patient units that activated our base station in a remote location within the ED. TYPE OF PARTICIPANTS: Thirteen patients were treated for ventricular fibrillation. and two patients were treated for ventricular tachycardia. INTERVENTIONS: Thirty-one shocks were delivered transtelephonically. MEASUREMENTS AND MAIN RESULTS: In all cases. voice and ECG transmission were established without difficulty. CONCLUSIONS: We conclude that this system represents a safe and reliable method for the treatment of ventricular fibrillation. and we advocate additional use to study the prehospital applications of transtelephonic defibrillation.
Tetanus immunization status and immunologic response to a booster in an emergency department geriatric population, STUDY OBJECTIVES: Although effective procedures for the prevention of tetanus have long been available. serosurveys done since 1977 demonstrate that 49% to 66% of the elderly population lacks a protective antitoxin level (more than 0.01 IU/mL). This study was undertaken to assess the tetanus immunization status of patients presenting to an emergency department and to evaluate their immunologic response to a tetanus booster. SETTING: The study was conducted in a tertiary care ED. TYPE OF PARTICIPANTS: The patients enrolled were 65 or more years old and had breaks in their skin barriers. DESIGN: At each patient's initial presentation. pertinent demographic data and tetanus immunization history were recorded. The patient was then followed for 21 days. INTERVENTIONS: Each patient's antitoxin titer was determined on a serum sample by ELISA. and. if required by the Advisory Committee on Immunization Practices criteria. a booster was administered at the first visit. MEASUREMENTS AND MAIN RESULTS: Serum antitoxin assays were repeated on days 7. 14. and 21 after the initial visit until seroconversion (titer more than 0.01 IU/mL). Forty-four patients (55%) had protective levels at initial presentation. and in 36 (45%) the levels were not protective. Age and sex were not predictive of protection. Past military service and a definite history of three or more previous immunizations were good predictors of protection. Of 34 patients who were followed serially for inadequate initial titers. only 19 (56%) seroconverted by day 14. Patients who did not seroconvert were more likely to be older (P less than .05). CONCLUSIONS: This study demonstrated that a significant number of elderly patients lacked an initial protective level of tetanus antitoxin. Of these. 44% failed to seroconvert within 14 days and carried a potential risk of developing tetanus.
Submersion in The Netherlands: prognostic indicators and results of resuscitation, STUDY OBJECTIVES: To analyze prognostic indicators and the outcome of resuscitation in submersion victims (drowning and near drowning). DESIGN: Retrospective study. SETTING: Intensive and Respiratory Care Unit. Between January 1. 1979. and December 31. 1985. 87 submersion victims were admitted. The files of 83 victims were available for statistical analysis. There were 66 male victims and 17 female victims; the average age was 31.4 +/- 25.8 years. There were ten salt water and 73 fresh water submersions. MEASUREMENTS AND MAIN RESULTS: Predictors for better survival potentials were a young age. submersion of less than ten minutes. no signs of aspiration. and a central body temperature of less than 35 C at admission. We did not detect factors that accelerated a decrease in core body temperature at admission and assume that lethal hypoxia had preceded protective hypothermia in our submersion victims. The Orlowski score had a predictive value but at the same time we found nonindependent indicators in this score. Neurologic outcome in our patients. who were not treated according to a brain protection protocol. was not worse than the outcome published by authors who have used such a protocol. Thirty-three percent of the victims with a cardioventilatory arrest (15) and all victims with a ventilatory arrest (11) survived resuscitation and were discharged. Five nonarrest victims died due to late complications. CONCLUSION: This study shows that no indicator at the rescue site and in the hospital is absolutely reliable with respect to death or survival.
Geriatric injury: an analysis of prehospital demographics, mechanisms, and patterns, STUDY OBJECTIVE: To evaluate emergency medical services (EMS) system use. injury mechanisms. and prehospital assessments among elderly victims of trauma. DESIGN: We analyzed all prehospital data for injuries among patients 70 years old or older for whom 911 EMS dispatch was requested in a medium-sized metropolitan area during a 12-month period. RESULTS: A total of 1.154 cases occurred (women. 65.1%). which represented 30.3% of all 911 dispatches involving elderly patients. Injury mechanisms were fall (60.7%). motor vehicle accident (MVA; 21.5%). fight (2.4%). accidental poisoning (2.3%). and choking (2.1%). Persons in their 90s had a lower frequency of MVAs (3.4%) than did younger patients (23.0%) (P less than .005). The most frequent injuries determined by prehospital assessment were head or face (25.1%). upper extremity (17.2%). hip (14.5%). lower extremity (13.8%). back (9.8%). and chest or abdomen (5.0%). The frequency of serious neurologic injuries was less for falls or MVAs than for other mechanisms (P less than .005). Suspected hip (P less than .001) and pelvic (P less than .005) injuries occurred more frequently during falls than during other mechanisms of injury. whereas back injuries occurred most frequently in MVAs (P less than .001). Seventy-one fall victims (10.1%) had suspected medical causes of their fall. Twelve patients (1.0%) were in cardiac arrest. CONCLUSION: We report injury patterns and mechanisms among elderly victims of trauma presenting to an EMS system. A knowledge of these patterns will be useful to emergency physicians and EMS administrators.
Neurologic complications of cocaine abuse, The neurologic complications of cocaine toxicity are responsible for a major portion of the morbidity and mortality associated with cocaine. Most of the complications appear to be related to the hyperadrenergic state induced by cocaine and may be treated symptomatically. Diazepam is the most effective drug for cocaine-induced seizures.
Atypical presentation of pulmonary embolism, Today we have discussed an interesting patient with an atypical presentation of pulmonary embolism. We have outlined a suggested algorithm to aid in the diagnosis and management of this disease. References 8 through 24 in the reference section are suggested readings that offer further insight into the diagnosis and management of this entity.
A family study of the variability of pulmonary function in alpha 1-antitrypsin deficiency. Quantitative phenotypes, A group of 52 alpha 1-antitrypsin-deficient individuals of phenotype Pi Z and 117 of their relatives underwent a protocol including pulmonary function testing. completion of a questionnaire. and blood donation. Our population permitted a minimum frequency estimate (7 x 10(-4)) for Pi null alleles. Five quantitative phenotypes were measured. including FEV1. FEF25-75. total serum alpha 1AT. oxidized serum alpha 1AT. and total serum IgE. We found that (1) total alpha 1AT levels were higher in Pi Z subjects with lung function impairment (FEV1 less than or equal to 65% of predicted) than in Pi Z subjects who were not impaired; (2) Pi Z subjects with lung function impairment had elevated serum levels of oxidized alpha 1AT; and (3) IgE levels were relatively elevated in first-degree Pi MZ relatives of impaired Pi Z subjects. Moreover. FEV1 tended to be relatively reduced in heterozygous parents of impaired Pi Z subjects. suggesting that a subset of Pi MZ individuals are at risk for development of lung disease because of familial factors. These results represent an initial step toward the development of intermediate phenotypes that will be predictive of a severe course in alpha 1AT deficiency; they suggest that. in addition to cigarette smoking. atopic predisposition and undetermined familial factors may be important codeterminants of lung disease progression.
The single-breath nitrogen test, mortality, and cancer, The relationship between indices of the single-breath nitrogen test and mortality. overall cancer incidence. and respiratory cancer incidence was examined in a cohort of 876 men. 46 to 69 yr of age. examined in 1974 and followed until June 1985. Closing volume. closing capacity. and slope of phase III were not related to mortality or cancer. In contrast. FEV1 was related to mortality. with an estimated relative mortality risk of 1.37 (95% confidence interval. 1.11 to 1.70) per liter under the expected FEV1. given height. age. and smoking. but FEV1 was not related to cancer. Inability to perform acceptable single-breath nitrogen test tracings was related to mortality with a relative mortality risk of 2.03 (1.45 to 2.85). but not to cancer. We conclude that indices of the single-breath nitrogen test have no predictive value concerning overall mortality and cancer incidence.
Pulmonary denervation in humans. Effects on dyspnea and ventilatory pattern during exercise, The role of the pulmonary autonomic nerves in the mediation of respiratory sensation is unclear. Pulmonary neurogenic mechanisms may contribute to dyspnea either directly or indirectly via an influence on the pattern of ventilation. Using human heart-lung transplantation as a model of pulmonary denervation. we studied the ventilatory response. respiratory drive (P0.1). and sensation of breathlessness (modified Borg scale) during maximal incremental bicycle exercise. The subjects were four female heart-lung transplant recipients 3 to 9 months post-transplant and 10 age-matched control subjects. The ventilatory response to increasing CO2 output (VCO2) was higher (p less than 0.001) in transplant recipients than in control subjects. such that ventilation at peak exercise was similar in the two groups despite a lower peak VCO2 in transplant recipients. The ratio of tidal volume to inspiratory capacity increased with increasing ventilation in a similar fashion in both groups. Although the respiratory rate increased more quickly in transplant recipients. it was similar at peak ventilation in the two groups. Ventilatory timing and duty cycle at half-peak and peak ventilation were similar in transplant recipients and control subjects. Dyspnea ratings were not different between the two groups at similar levels of ventilation. Dyspnea as a function of P0.1 was also similar in transplant and control groups. These results indicate that pulmonary neurogenic mechanisms play a role in determining the level. but not the pattern. of ventilation during exercise. Furthermore. these pathways do not appear to contribute significantly to the perception of breathlessness in normal humans.
Determination of serum concentrations of type III procollagen peptide in mechanically ventilated patients. Pronounced augmented concentrations in the adult respiratory distress syndrome, Type III procollagen peptide (PCP) is a byproduct of type III collagen synthesis and a potential marker of collagen secretion. In chronic diffuse interstitial lung diseases. elevated PCP concentrations have been found in serum as well as in bronchoalveolar lavage fluid. It has been proposed that PCP is a marker of early. active stages of fibrosis. As severe fibrosis is a frequent complication in adult respiratory distress syndrome (ARDS). we investigated PCP in patients with ARDS and compared the results with those from patients requiring mechanical ventilation because of heart failure and after neurosurgical and surgical interventions. and those from spontaneously breathing patients. including healthy volunteers and patients with pneumonia. liver cirrhosis. and renal failure. PCP concentrations in patients with ARDS were extremely elevated compared with those in control subjects (p less than 0.001) and correlated positively with FiO2 (r = 0.71. p less than 0.01). These results support the pathophysiologic concept of early fibrogenesis in ARDS. As preventing pulmonary fibrosis in ARDS is essential in improving survival rate. we believe PCP can be a valuable diagnostic tool in ARDS.
The penetration of aminoglycosides into the alveolar lining fluid of rats. The effect of airway inflammation, The concentration-time profile of gentamicin and tobramycin in the alveolar lining fluid (ALF) of rats was determined after intravenous bolus injection using bronchoalveolar lavage (BAL). BAL can be used for evaluating the penetration of both aminoglycosides into the ALF if highly sensitive detection methods are used. and an endogenous marker (urea) can be applied to avoid the unpredictable dilutional effect of the lavage procedure. The concentration of gentamicin and tobramycin in ALF reached a peak after 5 and 10 min. respectively. and remained high when plasma concentrations were declining. suggesting an accumulation reservoir in the lung acini. The ratio of the AUC of the concentration-time profile in ALF and plasma was 0.67 and 0.45 for gentamicin and tobramycin. respectively. The penetration of both aminoglycosides into the ALF was significantly higher after induction of airway inflammation by inhalation of endotoxin. The ratio of the AUC in ALF and plasma in the endotoxin-exposed animals was 0.76 and 0.55 for gentamicin and tobramycin. respectively. The ratio of the AUC of the concentration-time profile of gentamicin in ALF to that of tobramycin was 1.27 without inflammation and 1.44 after endotoxin exposure. Thus. both with and without inflammation. gentamicin penetrates better into the ALF than does tobramycin.
Asthmatic airways have a disproportionate hyperresponsiveness to LTE4, as compared with normal airways, but not to LTC4, LTD4, methacholine, and histamine, Airways responsiveness to leukotriene (LT) C4. LTD4. LTE4. histamine. and methacholine have been studied in eight asthmatic and six normal subjects. Airways responsiveness to each bronchoconstrictor agonist was assessed by constructing cumulative dose-response curves. and the dose that produced a 35% decrease in specific airways conductance (PD35) was obtained by linear interpolation. Airways of subjects with asthma were approximately 14-. 15-. 6-. 9-. and 219-fold more responsive to histamine. methacholine. LTC4. LTD4. and LTE4. respectively. than were normal subjects. Thus. there was a substantially augmented level of hyperresponsiveness to LTE4 in bronchial asthma. which was not observed for the other bronchoconstrictor agents. when compared to normal subjects. In contrast to LTC4 and LTD4. as histamine and methacholine responsiveness increase. the dose ratio of histamine to LTE4 (PD35 histamine/PD35 LTE4) and the dose ratio of methacholine to LTE4 also tended to increase. This suggests that as the nonspecific airways responsiveness increases. the relative potency of LTE4 also increases. whereas potency of LTC4 and LTD4 decrease. These results suggest that the mechanism of the bronchoconstriction induced by LTE4 may be distinct from that produced by LTC4 or LTD4 in subjects with asthma. This may reflect leukotriene subtype receptor heterogeneity in asthmatic airways.
Effects of inflammatory mediators on the responsiveness of isolated human airways to methacholine, Several studies have suggested that in asthmatics the quantities of inflammatory mediators such as histamine. thromboxane A2 (TxA2). prostaglandin D2 (PGD2). prostaglandin F2 alpha (PGF2 alpha). and leukotriene C4 (LTC4) that are present in the airway lumen are related to the degree of bronchial responsiveness to inhaled methacholine (MCh). Therefore. we studied the effect of these mediators on the cholinergic responsiveness of isolated human airway segments. Lung tissue collected at thoracotomy from 30 patients was studied. Dose-response curves to MCh were obtained from bronchial segments before. during. and after incubation with either a subthreshold or a threshold concentration of histamine (10(-10) or 10(-8) M). the stable TxA2 analogue U46619 (10(-11) or 10(-9) M). PGD2 (5 x 10(-9) or 5 x 10(-7) M). PGF2 alpha (10(-9) or 10(-7) M). or LTC4 (10(-11) or 10(-9) M). With the exception of LTC4. the presence of any of these mediators at either concentration increased the sensitivity to MCh by a factor of 1.1 to 2 (p less than 0.05. ANOVA). This increase did not depend on the dose of the mediator (p greater than 0.05. ANOVA). These data indicate that mediator-induced muscle hypersensitivity can explain a small part of the leftward shift of the dose-response curve to inhaled MCh as observed in asthma.
Bronchodilator response to ipratropium bromide in infants with bronchopulmonary dysplasia, Although the muscarinic antagonist Ipratropium bromide is used clinically as a bronchodilator in infants ventilated because of bronchopulmonary dysplasia (BPD). no studies have compared the response or efficacy of different dosages or its effectiveness in combination with beta-adrenergic agonists. We measured the response of respiratory system mechanics in 10 ventilated infants (25 +/- 2 days of age) to 75. 125. and 175 micrograms ipratropium bromide (IB). 125 micrograms IB plus 0.04 mg salbutamol (SAL). 175 micrograms IB plus 0.04 mg SAL. and saline vehicle. delivered via nebulizer into the ventilator circuit. Respiratory system resistance (Rrs) and compliance (Crs) were measured by the passive flow-volume technique. Rrs and Crs were measured before and at 1 to 2 h and at 4 h after delivery of the five drug dosages or saline. All six studies were completed within a 72-h period. Saline had no significant effect on mechanics. Significant responses to ipratropium alone were seen only after 175 micrograms where Rrs decreased 20 +/- 3% (SEM) (p less than 0.05) at 1 to 2 h and 16 +/- 5% (p less than 0.05) at 4 h. After 125 micrograms IB + SAL and 175 micrograms IB + SAL. Rrs was significantly decreased both at 1 to 2 h and at 4 h. and Crs was significantly increased 20 +/- 6% and 20 +/- 4%. respectively. at 1 to 2 h. The greatest decrease in Rrs (26 +/- 6%) was seen 1 to 2 h after 175 micrograms IB + salbutamol.
Bronchial responsiveness to histamine in infants and older children, Normal infants have been shown to respond to a relatively low concentration of inhaled histamine. However. those studies used partial maximal expiratory flow volume (PMEFV) curves to assess lung function. In order to directly compare responsiveness between infants and older children. we compared bronchial responsiveness to histamine between a group of 45 normal infants. median age 4 wk (range 2 to 6 wk) and a group of 30 nonasthmatic older children. median age 10 yr (range 5 to 15 yr) using PMEFV curves in both groups to assess lung function. In the infant group. PMEFV curves were generated using the forced expiratory flow volume technique. For the older children. PMEFV curves were generated by voluntary effort. The provocative concentration of histamine that produced a 40% fall (PC40) in maximum flow at functional residual capacity (VmaxFRC) was calculated from the PMEFV curves. The geometric mean PC40 of the infants (1.02 g/L) was lower than the geometric mean of the older children (3.4 g/L) (p less than 0.001). However. these results were then corrected for dilution of the aerosol due to air entrainment (AE). Corrected values of PC40 were not significantly different between infants and older children. These results demonstrate the importance of accounting for AE in the evaluation of histamine responsiveness and suggest that bronchial responsiveness may be similar in normal infants and older children.
Circadian basis of the late asthmatic response, The late asthmatic response (LAR) to an allergen challenge has a marked impact on lung function in the patient with asthma. Virtually all studies on the LAR have been done during the daytime. This study evaluated the LAR as a function of the time of day an inhaled allergen challenge was performed. An allergen challenge given in the morning produced a LAR in 4 of 10 subjects. while the same challenge in the evening caused a LAR in 9 of 10 (p less than 0.05). The time to onset of the LAR following the morning and evening challenges was 9.4 +/- 2.0 h versus 3.1 +/- 0.3 h. respectively (p less than 0.05). The maximal decrease in FEV1 for the LAR was 32.8 +/- 5.6% for the morning challenge versus 43.0 +/- 3.1% in the evening (p less than 0.05). Additionally. the bronchial responsiveness to methacholine was significantly greater at 24 h following evening allergen challenge than after the morning (p less than 0.05) challenge. Thus. it is important to take into account the time of day a patient is exposed to an allergen in regard to the development of the LAR.
Clearance of 99mTc-DTPA in pigeon fancier's hypersensitivity pneumonitis, The rate of clearance of inhaled 99mTc-DTPA was measured in 20 nonsmoking pigeon fanciers and 7 control subjects. The degree of their avian contact and pigeon-related symptoms were noted. humoral immune response in the form of IgG antibody to pigeon gamma globulin was quantified. and diffusing capacity and total lung capacity were measured. Thirteen fanciers who had a high level of antibody had increased rates of clearance of 99mTc-DTPA (mean half-time clearance of 16.8 [+/- SEM 2.02] min [p = 0.001]) even if they were asymptomatic and even if their diffusing capacity and total lung capacity were normal. Seven control subjects without exposure to pigeon-derived antigens had normal clearance (mean 72.6 [+/- 5.98] min). and seven fanciers with antigen exposure but without an antibody response had intermediate rates of clearance (mean 42.57 [+/- 5.11] min). Clearance was not directly related to the indices of intensity and duration of antigen exposure. The measurement of rate of clearance of 99mTc-DTPA in pigeon fanciers can identify an alteration in pulmonary integrity more subtle than found with conventional pulmonary function tests and may therefore be a useful test for studying the pulmonary response to inhaled antigen and for detecting the earliest stages in the evolution of hypersensitivity pneumonitis.
Respiratory health effects of the indoor environment in a population of Dutch children, The effect of indoor exposure to nitrogen dioxide on respiratory health was studied over a period of 2 yr in a population of nonsmoking Dutch children 6 to 12 yr of age. Lung function was measured at the schools. and information on respiratory symptoms was collected from a self-administered questionnaire completed by the parents of the children. Nitrogen dioxide was measured in the homes of all children with Palmes' diffusion tubes. In addition. information on smoking and dampness in the home was collected by questionnaire. There was no relationship between exposure to nitrogen dioxide in the home and respiratory symptoms. Respiratory symptoms were found to be associated with exposure to tobacco smoke and home dampness. There was a weak. negative association between maximal midexpiratory flow (MMEF) and exposure to nitrogen dioxide. FEV1. peak expiratory flow. and MMEF were all negatively associated with exposure to tobacco smoke. Home dampness was not associated with pulmonary function. Lung function growth. measured over a period of 2 yr. was not consistently associated with any of the indoor exposure variables. The development of respiratory symptoms over time was not associated with indoor exposure to nitrogen dioxide. There was a significant association between exposure to environmental tobacco smoke in the home and the development of wheeze. There was also a significant association between home dampness and the development of cough.
Dissecting aneurysm of the pulmonary artery with pulmonary hypertension, Pulmonary artery dissection was observed in a 64-yr-old female patient with severe pulmonary hypertension. which was probably primary (pulmonary vascular resistance. 817 dyn.s.cm-5; normal range less than or equal to 200 dyn.s.cm-5). The patient was admitted to the hospital because of severe dyspnea on exertion. Echocardiography demonstrated a dissecting aneurysm of the pulmonary artery. Right heart catheterization revealed severe pulmonary hypertension (mean pulmonary artery pressure. 64 mm Hg; normal range. 10 to 22 mm Hg); dissection of the pulmonary artery was confirmed by pulmonary arteriography. One-year follow-up was uneventful. In the literature. 28 patients with dissecting aneurysm of the pulmonary artery are reviewed. The dissection has only been diagnosed in life in one patient (by echocardiography).
The rise of tuberculosis in America before 1820, Bills of mortality. newspaper and gazette articles. journals. and other records with specific references to "consumption." "phthisis." and other terms for tuberculosis were reviewed to determine the occurrence and importance of tuberculosis in the American colonies before 1820. Review of these sources indicates a marked increase in the proportional mortality from tuberculosis in the United States in the 18th century. "Consumption" may have been the leading cause of death in adult American colonists.
Six-month isoniazid-rifampin treatment for pulmonary tuberculosis in children, One hundred and seventeen children with pulmonary tuberculosis underwent treatment with a 6-month daily regimen of rifampin (15 mg/kg/day) and isoniazid (10 mg/kg/day). The criteria for the diagnosis of pulmonary tuberculosis were (1) clinical symptoms and signs in 93 children (79%). (2) history of direct contact with an adult with tuberculosis in 106 children (91%). (3) tuberculin reaction of 5 mm or more. without previous bacillus Calmette-Guerin (BCG). in 45 children (38%). (4) suggestive radiologic alterations in all patients. and (5) positive bacteriology or histology in four patients (3%). The treatment was completed by 97 children (83%). The mean weight gain during therapy was 2.145 g. There was an excellent clinicoradiologic response to the treatment. and improvement in chest roentgenograms was observed in all patients at the end of therapy. No relapses occurred among the patients followed for an average of 21.4 months. This study indicates that the treatment of primary pulmonary tuberculosis in children with a combination of rifampin and isoniazid daily for 6 months is efficacious and does not result in any relapse.
The inactivation of antithrombin III by serum elastase in patients with surgical infections, The relationship between serum elastase and antithrombin III was determined in septic surgical patients as a possible mechanism for intravascular thrombosis and hypercoagulability during sepsis. Eighteen patients with surgical infections and elevated white blood cell counts had their blood assayed daily for white blood cell count. serum elastase. and antithrombin III. until the patient's white blood cell count returned to normal. Antithrombin III was significantly lower (0.87%) when elastase was above the normal range (greater than 14.2 micrograms/ml). Elastase was significantly higher (30.6 micrograms/ml). when antithrombin III was less than normal. These data indicate that elevated serum elastase is associated with a significant reduction in circulating antithrombin III. Stimuli that increase serum elastase. i.e. surgery. trauma. or sepsis may promote intravascular thrombosis by the inhibition of antithrombin III at the blood-endothelial cell interface.
An objective appraisal of the role of computed tomographic (CT) guided drainage of intra-abdominal abscesses, Computed tomographic (CT) guided drainage is an important tool in the treatment of intra-abdominal abscess. Its most important role is in the treatment of small. unilocular. well-placed abscesses. Success rates in our experience diminish considerably in abscesses involving necrotic tumors or those infected with yeast. As is frequently characteristic of new technologic procedures. the initial evaluation of the success rate of the procedure is overly optimistic. The procedure carries a considerable complication rate (13%) and mortality rate (15%). Most importantly. success is usually evident early; within the first 24 to 48 hours. After this length of time. careful evaluation to consider further treatment should be contemplated.
Porta hepatis disruption from blunt trauma, Extrahepatic porta hepatis injuries from blunt abdominal trauma are exceedingly rare; all recently reported cases involve disruption of the common bile duct at its intrapancreatic portion. We herein report a patient with lacerations of the proper hepatic artery and bile duct occurring from deceleration/torsion of the porta hepatis after high speed vehicular collision.
Femoral arteriovenous fistula as a complication of percutaneous transluminal coronary angioplasty. A report of five cases, Arteriovenous fistula (AVF) associated with invasive and diagnostic angiographic procedures is rare. The incidence is increased with procedures such as percutaneous transluminal coronary angioplasty (PTCA) but is still quite low. We report five cases of AVF within a 17-month period. representing 0.15 per cent of all cardiac catheterizations and 0.87 per cent of PTCAs. All five patients presented with groin bruits. There were two associated pseudoaneurysms and one patient with deep vein thrombosis. All patients underwent uneventful division of the fistula. A thorough understanding of the anatomy of the femoral triangle is necessary in order to avoid this complication. That all fistulas were in the superficial or profunda femoris arteries emphasizes the importance of avoiding a low groin puncture. Early angiography and surgical intervention are recommended for optimal results.
Normal angiograms and carotid pathology, Nonstenotic ulcerated atherosclerotic plaques of the carotid arteries may be associated with symptoms of transient ischemic attacks. amaurosis fugax. and stroke. Preoperative evaluation of patients with these symptoms has traditionally included ultrasound and arch aortography angiograms of the area of the carotid bifurcation. Recent evidence has shown that ultrasound is more accurate in detection and morphologic delineation of these nonstenotic lesions. We analyzed the hospital records of 21 patients with ultrasonographic evidence of disease in whom arteriograms were negative. The patient group comprised 15 men and six women. with an average of 66 years. All patients had symptoms of hemispheric transient ischemic attacks and were evaluated with B-mode ultrasound and arteriography. Ultrasound was positive and arteriogram "negative" in all of the patients (i.e.. described by the radiologist as without hemodynamic significant disease or ulceration. or as normal). The ultrasound diagnosis was confirmed at operation with findings of 20 to 50 per cent stenosis and ulcerative plaques. At retrospective review of the arteriograms. three ulcerations were found in the 21 patients. We conclude that B-mode ultrasound better defines nonstenotic ulcerative lesions and decisions to perform carotid endarterectomy may be based on either positive test. An ulcerative plaque by B-mode ultrasound and appropriate symptoms. therefore. may not require angiography before operation.
Endoscopic extraction of an entrapped nasogastric tube, Inadvertent entrapment of a nasogastric tube within a stapled gastrointestinal anastomosis is a preventable and infrequent surgical complication. We report our experience with this complication and describe a successful endoscopic approach to management.
Management of premature removal of the percutaneous gastrostomy, Percutaneous endoscopic gastrostomy (PEG) has become the preferred method of enteral access for nutritional support. With increased use of this modality. complications are encountered more frequently. Premature withdrawal. inadvertent removal of the gastrostomy tube within the first seven days after insertion. before adherence of the gastric serosa to the parietal peritoneum. has been an indication for laparotomy. This report describes the treatment of premature withdrawal by immediate endoscopic replacement. Over an 18-month period. 271 patients underwent insertion of a PEG. Five patients (1.8%) who inadvertently removed their gastrostomy tube within seven days of insertion were treated with immediate replacement using the retrograde string technique. avoiding laparotomy. All five PEGs were successfully replaced through the same gastrostomy site. Despite the presence of pneumoperitoneum. no patient developed peritonitis or other septic complications. Premature gastrostomy tube withdrawal is safely managed by endoscopic replacement and observation. Laparotomy is unnecessary and potentially meddlesome.
Low bone density is an etiologic factor for stress fractures in athletes, OBJECTIVE: To determine whether low bone density and other risk factors for osteoporosis are associated with stress fractures in athletes. DESIGN: Case-control study. SETTING: Institutional sports injury clinic with primary and secondary care. PARTICIPANTS: Twenty-five athletes (nineteen women) with scintigraphically confirmed stress fractures matched for sex. age. weight. height. and exercise history with 25 control athletes with no history of bone injury. MEASUREMENTS AND MAIN RESULTS: Bone mineral density measured by dual-energy x-ray absorptiometry was significantly lower in athletes with fractures than in control athletes: In the spine. bone mineral density was 1.01 +/- 0.14 g/cm2 in athletes with fractures and 1.11 +/- 0.13 g/cm2 in control athletes (P = 0.02). In the femoral neck. it was 0.84 +/- 0.09 g/cm2 in athletes with fractures and 0.90 +/- 0.11 g/cm2 in control athletes (P = 0.005). It was also significantly lower in the Ward triangle (P = 0.01) and the greater trochanter (P = 0.01). Eight athletes with fractures and no control athletes had less than 90% of predicted age-related spine density (P = 0.01). and three athletes with fractures had bone mineral densities that were 2 SDs or more below this predicted level. More athletes with fractures than control athletes had current menstrual irregularity (amenorrhea or oligomenorrhea) (P less than 0.005). Fewer athletes with fractures were using oral contraceptives (P less than 0.05). Seven-day diet records indicated similar energy and nutrient intakes. except athletes with fractures had lower calcium intakes (697 +/- 242 mg/d compared with 832 +/- 309 mg/d; P = 0.02). Dairy product intake was lower in athletes with fractures since leaving high school (P less than 0.05). The incidence of a family history of osteoporosis was similar in both groups. CONCLUSIONS: In athletes with similar training habits. those with stress fractures are more likely to have lower bone density. lower dietary calcium intake. current menstrual irregularity. and lower oral contraceptive use.
Colorectal cancer: evidence for distinct genetic categories based on proximal or distal tumor location, PURPOSE: To examine studies of normal colon and colorectal cancer for evidence that the location of the primary tumor proximal or distal to the splenic flexure of the colon may determine distinct genetic categories of this disease. DATA IDENTIFICATION: Studies were identified through a manual search of journals. through MEDLINE. and through review of bibliographies in identified articles. STUDY SELECTION: Approximately 300 articles were examined. About 150 articles were excluded because tumor location was not reported or was reported in a way that did not permit correlation with results or conclusions. DATA EXTRACTION: Articles were selected either because the presentation of data permitted correlation of results with anatomic regions of the colon or because they were relevant to inherited colorectal cancer. RESULTS OF THE ANALYSIS: Differences were noted in biologic properties of proximal and distal segments of normal fetal and adult colonic epithelium and in the epidemiologic. pathologic. cytogenetic. and molecular features of proximal and distal colorectal cancer. Some differences correlated with the features of inherited colorectal cancer (proximal. nonpolyposis or distal. and polyposis forms). CONCLUSIONS: Developmental and biologic differences in proximal and distal colon may reflect differing susceptibilities to neoplastic transformation. Differences in proximal and distal colorectal cancer suggest that each may arise through different pathogenetic mechanisms. Proximal tumors appear to represent a genetically more stable form of the disease and may arise through the same mechanisms that underlie inherited nonpolyposis colon cancer. Distal tumors show evidence of greater genetic instability and may develop through the same mechanisms that underlie polyposis-associated colorectal cancer syndromes.
Sexual and physical abuse in women with functional or organic gastrointestinal disorders, STUDY OBJECTIVES: To determine the prevalence of a history of sexual and physical abuse in women seen in a referral-based gastroenterology practice. to determine whether patients with functional gastrointestinal disorders report greater frequencies of abuse than do patients with organic gastrointestinal diseases. and to determine whether a history of abuse is associated with more symptom reporting and health care utilization. DESIGN: A consecutive sample of women seen in a university-based gastroenterology practice over a 2-month period was asked to complete a brief questionnaire. MEASUREMENTS: The self-administered questionnaire requested information about demographics. symptoms. health care utilization. and history of abuse. Physicians indicated the primary diagnosis for each patient and whether she had ever discussed having been sexually or physically abused. RESULTS: Of 206 patients. 89 (44%) reported a history of sexual or physical abuse in childhood or later in life; all but 1 of the physically abused patients had been sexually abused. Almost one third of the abused patients had never discussed their experiences with anyone; only 17% had informed their doctors. Patients with functional disorders were more likely than those with organic disease diagnoses to report a history of forced intercourse (odds ratio. 2.08; 95% CI. 1.03 to 4.21) and frequent physical abuse (odds ratio. 11.39; CI. 2.22 to 58.48). chronic or recurrent abdominal pain (odds ratio. 2.06; CI. 1.03 to 4.12). and more lifetime surgeries (2.7 compared with 2.0 surgeries; P less than 0.03). Abused patients were more likely than nonabused patients to report pelvic pain (odds ratio. 4.05; CI. 1.41 to 11.69). multiple somatic symptoms (7.1 compared with 5.8 symptoms; P less than 0.001). and more lifetime surgeries (2.8 compared with 2.0 surgeries; P less than 0.01). CONCLUSIONS: We found that a history of sexual and physical abuse is a frequent. yet hidden. experience in women seen in referral-based gastroenterology practice and is particularly common in those with functional gastrointestinal disorders. A history of abuse. regardless of diagnosis. is associated with greater risk for symptom reporting and lifetime surgeries.
Gallium nitrate for advanced Paget disease of bone: effectiveness and dose-response analysis, OBJECTIVE: To evaluate whether a brief course of treatment with gallium nitrate can reduce biochemical parameters of accelerated bone turnover in patients with advanced Paget disease. DESIGN: Unblinded trial. decreasing dose schedules of gallium nitrate. SETTING: University hospital with primary orthopedic and metabolic bone disease specialty. PATIENTS: Ten patients with advanced Paget disease who had previously received conventional therapy consisting of calcitonin. etidronate. or mithramycin. INTERVENTIONS: Five patients were entered into each of three dose schedules: 2.5 mg/kg body weight per day by continuous intravenous infusion for 7 days; 0.5 mg/kg per day for 14 days by subcutaneous injection; and 0.25 mg/kg per day for 14 days by subcutaneous injection. Several patients were treated with different dose schedules. Patients were followed until relapse. RESULTS: Fifteen courses of treatment were administered to ten patients. Reductions in serum alkaline phosphatase and urinary hydroxyproline excretion were observed after treatment with each dose schedule. After treatment with high. intermediate. and low doses. the median maximum decreases in serum alkaline phosphatase activity were 49%. 39%. and 18%. respectively. The median maximum decreases in urinary hydroxyproline excretion were 50%. 52%. and 16%. respectively. The maximum decrease in urinary hydroxyproline excretion occurred within a median of 2 weeks from the start of treatment. whereas the maximum decrease in serum alkaline phosphatase activity occurred substantially later at a median of 6 weeks. All treatment schedules were well tolerated. Response duration was highly variable (range. 6 to 42 weeks). CONCLUSIONS: Short-term treatment with gallium nitrate can reduce biochemical parameters of disease activity in patients with advanced Paget disease of bone. Larger trials using low-dose intermittent treatment schedules are required to evaluate the safety and effectiveness of this therapy.
Improving outcomes of analgesic treatment: is education enough?, Frequent undertreatment of analgesic-responsive acute pain and chronic cancer pain persists. despite intensive efforts to provide clinicians with information about analgesics. A set of background factors must be addressed in interventions to improve pain treatment: Traditional patterns of clinician and patient interaction on the ward. quality assurance. and drug regulatory practices do not support prompt recognition and treatment of pain. Possible interventions to modify these patterns of daily practice include monitoring and displaying patient pain ratings routinely. making available educational tools to assist optimal drug ordering. encouraging patients to communicate about unrelieved pain. reviewing quality assurance of pain treatment regimens. increasing behavioral research into analgesic prescribing. and selectively modifying narcotics regulatory practices.
Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents, OBJECTIVE: To determine whether insulin resistance or insulin deficiency is primary in the pathogenesis of type II diabetes. DESIGN: Cohort analytic study of persons with normal glucose tolerance but with a high risk for developing type II diabetes (average follow-up time. 13 years). SETTING: Outpatients had an intravenous glucose tolerance test and were contacted periodically to ascertain diagnoses of diabetes. PARTICIPANTS: One hundred and fifty-five normal offspring. ranging in age from 16 to 60 years. of two parents with type II diabetes and 186 normal control subjects in the same age range who had no family history of diabetes. MEASUREMENTS AND MAIN RESULTS: Two phenotypic characteristics distinguished the offspring of diabetic parents from control subjects. They had slower glucose removal rates (Kg) (P less than 0.01) and higher insulin levels (fasting and during the second phase of insulin response to intravenous glucose; P less than 0.0001) than did control subjects. even after adjustment for differences in obesity. Sixteen percent of the offspring developed type II diabetes. Mean Kg at baseline was 1.7%/min among offspring who subsequently developed diabetes. 2.2%/min among offspring who remained nondiabetic. and 2.3%/min among control subjects. Corresponding means for first-phase insulin were 498. 354. and 373 pM. respectively. whereas second-phase insulin means were 329. 117. and 87 pM. respectively. In multivariate analysis. low Kg and high serum insulin levels independently increased the risk for developing diabetes among the offspring of diabetic parents. CONCLUSIONS: One to two decades before type II diabetes is diagnosed. reduced glucose clearance is already present. This reduced clearance is accompanied by compensatory hyperinsulinemia. not hypoinsulinemia. suggesting that the primary defect is in peripheral tissue response to insulin and glucose. not in the pancreatic beta cell.
Clarifying confusion: the confusion assessment method. A new method for detection of delirium, OBJECTIVE: To develop and validate a new standardized confusion assessment method (CAM) that enables nonpsychiatric clinicians to detect delirium quickly in high-risk settings. DESIGN: Prospective validation study. SETTING: Conducted in general medicine wards and in an outpatient geriatric assessment center at Yale University (site 1) and in general medicine wards at the University of Chicago (site 2). PATIENTS: The study included 56 subjects. ranging in age from 65 to 98 years. At site 1. 10 patients with and 20 without delirium participated; at site 2. 16 patients with and 10 without delirium participated. MEASUREMENTS AND MAIN RESULTS: An expert panel developed the CAM through a consensus building process. The CAM instrument. which can be completed in less than 5 minutes. consists of nine operationalized criteria from the Diagnostic and Statistical Manual of Mental Disorders (DSM-III-R). An a priori hypothesis was established for the diagnostic value of four criteria: acute onset and fluctuating course. inattention. disorganized thinking. and altered level of consciousness. The CAM algorithm for diagnosis of delirium required the presence of both the first and the second criteria and of either the third or the fourth criterion. At both sites. the diagnoses made by the CAM were concurrently validated against the diagnoses made by psychiatrists. At sites 1 and 2 values for sensitivity were 100% and 94%. respectively; values for specificity were 95% and 90%; values for positive predictive accuracy were 91% and 94%; and values for negative predictive accuracy were 100% and 90%. The CAM algorithm had the highest predictive accuracy for all possible combinations of the nine features of delirium. The CAM was shown to have convergent agreement with four other mental status tests. including the Mini-Mental State Examination. The interobserver reliability of the CAM was high (kappa = 0.81 - 1.0). CONCLUSIONS: The CAM is sensitive. specific. reliable. and easy to use for identification of delirium.
Selection of patients with acute myocardial infarction for thrombolytic therapy, PURPOSE: To critically review the current recommendations regarding the eligibility of patients with myocardial infarction for thrombolytic therapy. DATA IDENTIFICATION: Relevant studies published from January 1980 to January 1990 were identified through a computerized search of the English-language literature using MEDLINE and by a manual search of the bibliographies of all identified articles. STUDY SELECTION: All randomized. controlled trials of intravenous thrombolysis in acute myocardial infarction and unstable angina were reviewed. Smaller. observational studies and previous review articles were included when relevant to the discussion. DATA EXTRACTION: Key data were extracted from each article. including the proportions of patients eligible for thrombolysis. the reasons for exclusion from thrombolytic therapy. and the clinical outcomes of patients treated and of those excluded from treatment. The validity of certain exclusion criteria was examined using subgroup analysis from the large. randomized mortality trials of intravenous thrombolysis and observations from smaller. nonrandomized studies. RESULTS OF DATA SYNTHESIS: To date. relatively few patients with myocardial infarction have been considered eligible for fibrinolytic therapy. In this group. both early and late mortality have been significantly reduced. Patients excluded from thrombolysis. however. continue to have a high early mortality. The data suggest that the potential benefits of this treatment might be extended to selected high-risk subgroups. In particular. the risk-benefit ratio may favor the inclusion of otherwise healthy elderly patients; certain patients presenting more than 6 hours after the onset of symptoms; and patients with a history of controlled systolic hypertension or brief. nontraumatic cardiopulmonary resuscitation. The data do not support the use of fibrinolytic therapy as primary treatment in patients with unstable angina or suspected myocardial infarction in the absence of confirmatory electrocardiographic changes. CONCLUSIONS: The full potential of thrombolytic therapy to alter the natural history of acute myocardial infarction can only be realized through the continued evaluation of selection criteria and the identification and treatment of the greatest possible number of eligible patients.
Effect of intravenous streptokinase on early mortality in patients with suspected acute myocardial infarction. A meta-analysis by anatomic location of infarction  [published erratum appears in Ann Intern Med 1991 Mar 15;114(6):522], PURPOSE: To determine the effect of intravenous streptokinase on early mortality in patients with suspected acute anterior and acute inferior myocardial infarctions. DATA IDENTIFICATION: A literature search of English-language studies on the use of intravenous streptokinase in the treatment of suspected acute myocardial infarction for the period 1966 to 1989 using Medlars II and the bibliographies of relevant articles. In a number of instances. additional details on early mortality by location of myocardial infarction were provided by the authors. STUDY SELECTION: Of 140 originally identified articles. 6 that specifically met our inclusion criteria were selected: randomized trials that used intravenous streptokinase in a dose of 1.5 million units. with or without additional agents. compared with a group that differed only by the absence of streptokinase. Trials were selected by review of the methods section without regard for the results. DATA EXTRACTION: Data were extracted independently by two observers using specific methodologic criteria for infarct location and early mortality. After they conferred. the observers agreed completely on the data. RESULTS OF DATA SYNTHESIS: Among the 9155 patients with suspected acute anterior myocardial infarction. the mortality rate in the control group was 17.4%. In contrast. patients treated with streptokinase had a 12.5% mortality. The mean risk difference was -4.8% (95% CI. -7.5% to -2.1%) and the summary risk ratio was 0.72 (CI. 0.65 to 0.79). A total of 9650 patients with suspected inferior infarction had a mortality rate in the control group of 7.6% [corrected]. The mortality for streptokinase-treated patients was 6.6%. The mean risk difference was -0.8% (CI. -1.8% to 0.2%) and the summary risk ratio was 0.87 (CI. 0.76 to 1.01). CONCLUSIONS: Intravenous streptokinase clearly confers a protective effect against early mortality in patients with suspected acute anterior myocardial infarction. The magnitude of this effect is on the order of a 5% absolute reduction in risk of death by 21 to 35 days. For these patients. 21 need to be treated to save 1 additional life. For patients with suspected acute inferior infarction. the benefit of treatment on reducing early mortality is of smaller magnitude and less certain. These patients have an estimated absolute reduction of early mortality of approximately 1%. which would require treating 125 patients to save 1 additional life.
Arachnoid granulation cerebrospinal fluid otorrhea, A case report and review of the temporal bone (TB) collection in the Department of Otolaryngology at SUNY Health Science Center in Syracuse demonstrated the occurrence of arachnoid granulations (AGs) in the posterior fossa surface of the TB and their role in cerebrospinal fluid (CSF) otorrhea. A large AG responsible for CSF otorrhea in a 64-year-old man was excised with soft tissue repair of the dural defect. Sixteen of 188 TBs (8.5%) in the collection contained 24 AGs ranging in size from 0.07 to 80.65 mm3. Nine AGs (37%) were small (less than 1 mm3) and did not demonstrate enlargement. Twelve (50%) were of intermediate size (2.50 to 9.32 mm3). and three (13%) were large (49.82 to 80.65 mm3). The intermediate and large AGs were associated with bone erosion and a high incidence of communication with a pneumatized mastoid complex (serous otitis media or meningitis). These findings suggest that AGs of sufficient size to produce bone erosion are the primary responsible lesions in adult-onset spontaneous CSF otorrhea.
Head stability and gaze during vertical whole-body oscillations, To understand head and eye stabilities during upright locomotion. we investigated head and eye movements during vertical whole-body oscillations of various amplitudes (1 to 10 cm) and frequencies (1 to 3 Hz) in both normal subjects (n = 10) and patients with bilateral labyrinthine loss (n = 5). Vertical oscillations produced pitching motions of the head. of which the amplitude was markedly altered by a change in the oscillation frequency or the displacement. Vertical eye movements. being correlated with pitching head movements. were scarcely modified by gaze at 2 and 3 Hz. Acquired bilateral lesions presented deteriorated head stability and physically induced eye movements under stronger stimulations. However. significant increase of head movement upon stepping and suppression of pitching motion upon running. both characteristically found in bilateral lesions. were not reproduced by passive oscillations. Thus. these features during active locomotion may result from imbalance produced by alternate bipedal motions and from adaptation to minimize oscillopsia. respectively.
Management of tracheobronchial foreign bodies in children: an update, Tracheobronchial foreign bodies continue to be a source of morbidity and mortality in the pediatric population. Technical advances in anesthesia and equipment have made the removal of these troublesome objects more feasible. Diligence must still be exercised and a coordinated team effort must be employed in order to achieve a satisfactory and safe outcome for the patient. The appropriate use of diagnostic studies and management techniques are discussed.
Tracheotomy in the first year of life, Much has been written concerning complications of pediatric tracheotomies. but few studies have reviewed the complication rates of tracheotomies performed in the first 12 months of life. We reviewed the records of 60 patients who underwent tracheotomy in the first year of life between 1976 and 1988. This study includes 30 full-term infants and 30 premature infants. 16 of whom were very low birth weight preterm infants (less than or equal to 32 weeks' gestation and less than 1.500 g birth weight). Overall complication rates were 3% intraoperative. 13% early postoperative. and 38% late postoperative. The early postoperative complication rate in preterm infants was nearly double that of full-term infants. The late postoperative complication rate of patients undergoing tracheotomy for airway obstruction was more than double that of patients requiring tracheotomy for pulmonary indications. Duration of tracheotomy. however. was felt to be the most important factor in the development of a late postoperative complication.
Systems architecture for quantification of dynamic myoelectric and kinematic activity of the human vocal tract, This paper describes a systems architecture useful for scientific investigations that require the acquisition and analysis of multiple. time-synchronous signals in large volume. The architecture has recently been developed by this group to enhance our capability to research and quantify central nervous system function in the production of normal and pathologic speech. The architecture utilizes modern advances in desktop microcomputers and has been designed so that vocal motor control laboratories (or similar settings) with modest funding can more fully participate in comprehensive investigations of speech production. Research experiments organized with this architecture may involve many more subjects and measures than previously possible without significant increases in time and personnel resources. This paper will demonstrate the technique and practicality of this architecture as it is being used to successfully guide research to map hierarchic central nervous system regions of involvement in two speech disorders: spasmodic dysphonia and stuttering. The architecture has broad usefulness to many areas of otolaryngology and health science.
Auras and subclinical seizures: characteristics and prognostic significance, The characteristics and prognostic significance of subclinical seizures and independent auras were studied in 40 patients with partial epilepsy who had long-term electroencephalographic (EEG) monitoring with intracranial electrodes. Focal. restricted subclinical seizures were noted in 23 patients. and 11 patients experienced auras that were accompanied by ictal EEG discharges. Auras and subclinical seizures usually were identical in EEG appearance. but were distributed differently among patients. The subclinical seizures and auras usually had the same origin as complex partial seizures. but did not always reliably indicate complex partial seizure origin. Subclinical seizures and auras were of favorable prognostic significance for patients undergoing temporal lobectomy. A majority (greater than 80%) of individuals with subclinical seizures and auras were free of complex partial seizures after surgery. whereas a minority (29%) of patients without subclinical seizures and auras became free of complex partial seizures.
Substantia nigra: a site of action of muscle relaxant drugs, Sites of action of centrally active muscle relaxant drugs are not well defined. Clinical experience with such drugs suggests that the spinal cord may be one of the important regions from which pathologically increased muscle tone may be relieved. Supraspinal centers that may also be involved in the expression of muscle relaxant action have not yet been defined. We report here that microinjections of therapeutically relevant muscle relaxants into the midbrain tegmentum of genetically spastic rats decrease muscle tone. The substantia nigra is the region from which midazolam. baclofen. and tizanidine (drugs used clinically in the treatment of spasticity). or gamma-vinyl-GABA. (-)-2-amino-7-phosphonoheptanoate. and [D-pro2-D-phe7-D-trp9]-substance P (experimental drugs active in animal models of spasticity). reduce muscle tone in genetically spastic rats and Hoffmann reflexes in normal rats. The effects of muscle relaxant drugs are topographically restricted to the substantia nigra pars reticulata and are receptor specific. These observations disclose a previously unknown function of the substantia nigra in mediating muscle relaxation.
IgM deposits at nodes of Ranvier in a patient with amyotrophic lateral sclerosis, anti-GM1 antibodies, and multifocal motor conduction block, We studied a patient with amyotrophic lateral sclerosis. multifocal motor conduction block. and IgM anti-GM1 antibodies. A sural nerve biopsy demonstrated deposits of IgM at nodes of Ranvier by direct immunofluorescence. The deposits were granular and located in the nodal gap between adjacent myelin internodes. and in some instances. they extended along the surface of the paranodal myelin sheath. When injected into rat sciatic nerve. the serum IgM bound to the nodes of Ranvier. and the binding activity was removed by preincubation with GM1. These observations suggest that anti-GM1 antibodies may have caused motor dysfunction by binding to the nodal and paranodal regions of peripheral nerve.
Electroencephalography laboratory diagnosis of prolonged QT interval, Patients with prolongation of the QT interval are at risk for significant neurological morbidity and mortality secondary to ventricular tachyarrhythmias. These patients frequently undergo electroencephalographic (EEG) examination to evaluate episodes of loss of consciousness. which may be associated with convulsions. Electrocardiogram recording as a part of the EEG is a simple and common practice. but analysis for possible QT prolongation is not routinely performed by electroencephalographers. This is. in part. due to the fact that while calculation of the corrected QT interval is straight forward. a calculator is generally required. A nomogram that is presented simplifies determination of the corrected QT interval. facilitating diagnosis of prolongation of the QT interval in the EEG laboratory.
The nasolabial flap as a single-stage procedure, The nasolabial flap is a useful reconstructive technique for the repair of defects on the nose. An improved technique used in 32 patients is presented. which allows use of this procedure as a single-stage rather than the more commonly seen two-stage procedure. The alterations include the following: (1) the excision of a Burow's triangle superior edge of the defect toward the inner canthus; (2) the use of a periosteal or suspension suture to minimize tenting across the concave junction of the nose and cheek; (3) wide undermining of the skin surrounding the defect to create a stabilizing platelike scar; (4) significant thinning of the donor flap; and (5) adjust the size of the flap to recreate the original preincisional skin tension on the flap after suturing. None of the 32 patients presented required a second-stage procedure to correct trapdoor defects or to recreate natural folds or creases.
Cicatricial pemphigoid. Identification of two distinct sets of epidermal antigens by IgA and IgG class circulating autoantibodies, A patient with severe cicatricial pemphigoid demonstrated both in vivo bound and circulating anti-basement membrane zone antibodies of the IgA and IgG classes. Complement component 3 (C3) was also deposited in the basement membrane zone of lesional skin as well as in normal-appearing buccal mucosa of the patient. However. C1q was absent. while granular deposits of two factors of the alternative complement activating pathway. properdin and properdin factor B. were present only in the basement membrane zone of lesional skin. but not in normal buccal mucosa. Deposition of alternative complement pathway reactants in the lesion suggests that complement activation by IgA was associated with lesion development. Western blot analysis of the patient's serum on electrophoresed cultured keratinocyte antigens identified two distinct sets of epidermal antigens. While IgG bound antigens of 230. 205. 140. and 90 kd. the patient's IgA antibodies bound a distinct set of antigens. 180 and 130 kd. The potential pathogenic role of IgA in cicatricial pemphigoid is discussed.
Dermatitis herpetiformis bodies. Ultrastructural study on the skin of patients using direct preembedding immunogold labeling, Skin samples from three adult patients with dermatitis herpetiformis (DH) and granular IgA deposits in the papillary tips were studied using ultrastructural immunogold technique. IgA positive. so-called DH bodies were identified as amorphous clumps--most probably immunocomplex aggregates--scattered throughout the upper papillary dermis. Dermatitis herpetiformis bodies were seen underneath the basement membrane. sometimes along microfibrillar bundles. as well as adjacent to the papillary collagen fibers and within the surface (microfibrillar) region of elastic tissue. Some DH bodies. however. were not related to any fibrillar components. The collagen and elastic fibers. microfibrillar bundles. anchoring fibrils. and elastic microfibrils themselves were unlabeled. Dermatitis herpetiformis bodies were not found in normal human skin. The results of our ultrastructural study indicate that DH bodies either are bound to a nonfibrillar component of dermal connective tissue or represent deposits of immune complexes trapped in DH skin.
The familial occurrence of bullous mastocytosis (diffuse cutaneous mastocytosis), We studied four patients (a mother. her two daughters. and her son) with bullous mastocytosis. or diffuse cutaneous mastocytosis. whose genetic inheritance suggested an autosomal dominant pattern. The clinical characteristics included extensive bullae. numerous urticaria. pruritus. flushing. and pseudolichenified skin over all body surfaces without systemic organ involvement. The histopathologic findings disclosed a pronounced accumulation of mast cells in the dermis. Electron microscopic studies of lesional skin obtained in infancy showed round or spindle-shaped mast cells with numerous fingerlike villous protrusions. The cytoplasmic granules varied in size and shape. and the appearance of degranulation was markedly noted. In the adult. most mast cells had markedly decreased numbers of granules and cytoplasmic villi. Some cells displayed degenerative or necrotic appearances. These findings correlated well with the clinical course of these cases. which improved spontaneously over time.
Preoperative stabilisation in congenital diaphragmatic hernia, Between January 1983 and November 1986. 26 newborn infants with congenital diaphragmatic hernia were treated by early operation at a mean of 7 hours of age. A further 23 infants admitted between December 1986 and December 1989 were stabilised for a mean period of 40 hours before operation. There was no significant difference in survival between the two groups. Delayed operation is not detrimental to infants with congenital diaphragmatic hernia.
Amniotic fluid insulin concentration as a predictor of obesity, Longitudinal correlations were obtained between amniotic fluid insulin concentration at 32 to 38 weeks' gestation and anthropometric characteristics at the age of 6 years in 56 children of diabetic mothers. The prospective studies indicated that at the age of 6 years. as at birth. the greatest increase in weight in relation to height (relative obesity) was seen in children who experienced the greatest exposures to insulin in the uterus (as judged by amniotic fluid insulin concentration). Significant correlations between amniotic fluid insulin and relative obesity at the age of 6 years were found after adjustment for maternal obesity and macrosomia at birth. The highest amniotic fluid insulin values are clustered in the subgroup of 14 children who were obviously obese by the age of 6 years. These findings are consistent with the hypothesis that there is an association between anthropometric development and intrauterine metabolism. and suggest that premature and excessive exposure to insulin during gestation may predispose to obesity in childhood. The amniotic fluid insulin concentration may predict this eventuality.
Skin conductance and arousal in the newborn, We measured skin conductance continuously from the sole of a foot in babies of different conceptional ages before. during. and for 10 minutes after a 'heel prick' carried out for routine blood sampling. We studied 82 healthy babies whose gestational and postnatal ages ranged from 25-42 weeks. and 1-73 days. The median skin conductance level (preheel prick) in babies of 40-43 weeks' conceptional age was 0.6 microS (microsiemens) and differed significantly between awake babies (1.2 microS) and those who were asleep (0.5 microS). In contrast babies less than 40 weeks had a significantly lower median skin conductive level (0.3 microS) which was identical in awake and asleep babies. In response to the heel prick all babies became aroused and skin conductance rose sharply and immediately in 21 out of 22 (95%) babies 40-43 weeks' conceptional age. and in seven out of 23 (30%) babies 36-39 weeks. The median rise at one minute in babies of 40-43 weeks was significantly higher than those 36-39 weeks (2.7 microS compared with 0.5 microS). No babies less than 36 weeks had a change in their skin conductance after the heel prick. These results are consistent with the notion that 'emotional sweating' is a function of maturity and does not develop until 36 weeks' conceptional age.
Gut blood flow velocities in the newborn: effects of patent ductus arteriosus and parenteral indomethacin, The effects on gut blood flow velocities of parenteral indomethacin (0.2 mg/kg) given either quickly as a bolus or slowly as an infusion were compared in consecutive studies of two groups of infants with symptomatic patent ductus arteriosus. In the presence of patent ductus arteriosus the range of velocities in the superior mesenteric artery before indomethacin was given was characterised by pronounced abnormalities including absent--or in some cases even retrograde--diastolic flow. In eight subjects the first rapidly given bolus dose of indomethacin (duration 20 seconds or less) caused a pronounced and sustained fall in the velocity of the superior mesenteric artery blood flow (mean peak systolic velocity (cm/second): before 74; after 38; median time to maximum fall 7.4 minutes; median time to recovery 50 minutes). A further 10 subjects received their first dose of indomethacin by slow infusion (duration 30-35 min) and the percentage fall in peak systolic velocity was both substantially less (22% compared with 47%) and later (median time to maximum fall 37.3 minutes) than after rapid infusion. Qualitatively similar but smaller changes were seen in the coeliac axis. Return of antegrade end diastolic flow in the superior mesenteric artery within one hour of the first dose of indomethacin was a good predictor of subsequent closure of the ductus. These data suggest that there is a profound disturbance in mid gut perfusion in infants with patent ductus. which is exacerbated by indomethacin given rapidly by intravenous bolus. They may also provide a rational explanation for the well recognised association between necrotising enterocolitis and both patent ductus arteriosus and indomethacin administration.
Hiccups and breathing in human fetuses, Serial recording in 45 low risk fetuses throughout the second and third trimesters showed that hiccups were the predominant diaphragmatic movement before 26 weeks' gestational age and that there was a significant negative correlation with gestational age. There was a pronounced reduction between 24 and 26 weeks. which was the result of a decrease in the number of episodes of hiccups rather than a change in the duration of episodes. In contrast. fetal breathing was positively correlated with gestational age. the greatest increase in breathing occurring between 26 and 32 weeks' gestation. This was the result of both an increase in the number and duration of episodes. From the time that rest-activity cycles of behaviour could be determined in recordings. both breathing and hiccups were dependent on behavioural state or cycle. occurring predominantly during active episodes. This association between quiet and active behaviour and breathing did not alter with increasing gestational age. and the variables in fetal behavioural state became increasingly closely linked. The importance of prolonged and repeated recording. and also the need to take account of other variables in fetal behaviour. before any sinister conclusions can be drawn about the absence of fetal breathing is emphasised.
Localization and peptide content of endocrine pancreatic tumors, Endocrine pancreatic tumors contain and frequently secret neurohormonal peptides. This phenomenon can be used as a diagnostic and classifying tool. This study analyzes 31 patients operated on because of an endocrine pancreatic tumor. including the diagnostic procedures and the localization methods. In 15 insulinoma cases only 6 patients had a positive arteriography. while all 11 selective pancreatic vein samplings were positive. The immunoreactivity showed that. besides insulin. most tumors also contained other peptides. Of four gastrinoma cases the arteriography was positive in three. but the selective vein sampling localized the tumor in all. The tumor's content of peptides showed mixed patterns. In the four glucagonomas. the arteriography was positive in all and the venous sampling performed in three of the cases also was positive. In five pancreatic polypeptide-containing tumors (PP-omas) the arteriography was positive in four and sampling performed in two was positive in both. In the PP-omas the peptide pattern showed that these tumors frequently contain several peptides. We used selective pancreatic vein sampling in 21 cases with positive result in all. In the cases in which arteriography was negative. the sampling results helped the surgeon to find the tumor. The peptide pattern in the tumors varied greatly and most tumors were multihormonal.
Localization and surgical treatment of occult insulinomas, Management of patients with biochemical evidence of insulinoma and negative preoperative imaging studies (occult) tumors is controversial. varying from primarily medical management to aggressive. blind nearly total pancreatectomy to extirpate the tumor. Since 1982. 12 consecutive patients with occult insulinoma underwent preoperative portal venous sampling (PVS) for insulin followed by surgical exploration with intraoperative ultrasound (IOUS). Eleven of twelve patients (92%) had insulinoma removed and were cured. Portal venous sampling correctly predicted the location of the insulinoma in 9 patients (75%) and that no tumor would be found in another patient. A fourfold insulin gradient in the pancreatic tail of one patient correctly predicted that a distal pancreatectomy would remove the insulinoma despite the fact that neither palpation nor IOUS identified any tumor. Intraoperative ultrasound was the single best method to identify occult tumors because it correctly identified 10 of 11 insulinomas that were found. including five pancreatic head tumors that were not palpable. Palpation identified five insulinomas. Of the 10 tumors that were identified during operation by palpation or ultrasound. IOUS identified significantly more (100% versus 50%. p = 0.03) and guided the successful enucleation of each. The results support the strategy of preoperative PVS and operation with IOUS to localize and remove insulinoma in patients with occult tumors. Most tumors (75%) will be correctly localized to a specific pancreatic region by preoperative PVS and identified by IOUS (83%). allowing simple enucleation and biochemical correction of hypoglycemia. Morbid blind pancreatic resections are no longer indicated and long-term medical management of hypoglycemia should be reserved for the occasional patient (8%) who fails preoperative PVS and operation guided by IOUS.
Repair of supravalvar aortic stenosis: cardiovascular morphometric and hemodynamic results, Supravalvar aortic stenosis is associated with normal systolic pressure in the aorta and its branches with the singular exception of the coronary arteries. which are hypertensive. This uncommon lesion has been treated by patch aortoplasty of several types. We examined hemodynamics and morphometrics in 13 patients who underwent operation for supravalvar aortic stenosis from 1979 through 1988. They ranged in age from 2 to 43 years (mean age. 14.5 +/- 3.8 years [+/- standard error of the mean]). There were no operative deaths. Preoperative and postoperative (1 to 5 years) catheterization or echocardiography or a combination of these was done in all but 3 patients (1 died late suddenly without a postmortem examination; 1 was lost to follow-up; and 1 has not yet been restudied). Pressure gradients across the stenosis in patients treated with a single-sinus patch (n = 4) were 65 +/- 18 mm Hg preoperatively and 5 +/- 3 mm Hg postoperatively (p less than 0.05) and in patients with a bisinus patch (n = 6). 83 +/- 15 mm Hg preoperatively and 6 +/- 2 mm Hg postoperatively (p less than 0.05); the two groups were not significantly different. Measurements of the diameters of the coronary arteries. aortic annulus. and descending aorta were made. and calculation of the ratio of the coronary artery and annulus diameters to the descending aortic diameters both preoperatively and postoperatively was possible in 5 patients. The left coronary artery was larger than normal before and after operation. Preoperatively there was a disproportionate increase in left coronary artery and annulus size during systole. Left ventricular wall thickness decreased significantly postoperatively (p less than 0.05). Repair of supravalvar aortic stenosis (localized and diffuse) by both single sinus and bisinus patch repair is safe and hemodynamic results are good.
Clinical performance of St. Jude and Medtronic-Hall prostheses: a randomized comparative study, Newer and improved models of mechanical prostheses are regularly added to surgeons' armamentarium. This study was designed to compare the clinical performance of two of the most used current models of mechanical prostheses. From August 1983 through July 1985. 182 white patients were prospectively randomized to implantation of the St. Jude Medical (95 patients) or Medtronic-Hall (87 patients) prostheses. There were 84 mitral. 85 aortic. and 13 double (mitral and aortic) valve replacements. There were no differences between the two groups with regard to sex distribution. age. functional class. emergency operation. and site of implantation. Early mortality was 3.2% for patients with the St. Jude valve and 5.7% for those with the Medtronic-Hall (p = NS). The survivors were followed for 3 to 5 years (mean. 4.2 +/- 0.6 years; cumulative follow-up. 559 patient-years). Late mortality was 7.1%/patient-year for the St. Jude group and 3.2%/patient-year for the Medtronic-Hall group (p less than 0.05). However. the valve-related mortality was equal (1.4%/patient-year) for both groups. Noncardiac causes accounted for most of the difference between the St. Jude and Medtronic-Hall groups (2.5%/patient-year and 0.4%/patient-year. respectively). There were no cases of thrombotic obstruction. whereas serious systemic thromboembolism occurred at the rate of 1.8%/patient-year (5 episodes) for the St. Jude group and 2.5%/patient-year (7 episodes) for the Medtronic-Hall group (p = not significant); there were another nine episodes of systemic embolism that left no sequelae. Three patients (St. Jude. 2; Medtronic-Hall. 1). all of whom had aortic valve replacement. required reoperation (0.5%/patient-year) because of prosthetic endocarditis. with two deaths.
Air contamination in open heart surgery with disposable coveralls, gowns, and drapes, The effect of a polypropylene coverall. replacing shirt and trousers. combined with sterile laminated gowns and drapes compared with an all-cotton system was studied in regard to the dispersion of bacteria and particles in a conventionally ventilated operating theater. The operations carried out were open heart procedures in 30 adult patients. Blood agar sedimentation plates were placed in the operative. anesthesia. and perfusion areas. The mean sedimentation values during 1 hour after the start of operation were as follows in the laminate group: 63 colony-forming units (cfu)/m2 in the operative area; 77 cfu/m2 in the anesthesia area; and 143 cfu/m2 in the perfusion area. The corresponding figures in the cotton group were 350 cfu/m2. 364 cfu/m2. and 437 cfu/m2. respectively (p less than 0.0002). At the beginning of the operation. the mean values noted for colony-forming units in the air at the operative site were 8.0 cfu/m3 in the laminate group and 31 cfu/m3 in the cotton group. One hour later. the values were 10 cfu/m3 and 22 cfu/m3. respectively (p less than 0.0002). At the end of the operation. the number of particles 5 microns or larger in the air at the operative site was 278/m3 in the laminate group and 592/m3 in the cotton group. It is concluded that the use of a polypropylene coverall and laminated gowns and drapes significantly reduces the particle and bacterial contamination of the air and the bacterial sedimentation during cardiac operations.
Prolonged extracorporeal life support of pediatric and adolescent cardiac transplant patients, Options for mechanical support of pediatric patients with severe heart failure who are awaiting transplantation or have undergone transplantation are limited. This report examines 3 patients placed on extracorporeal life support (ECLS) while awaiting transplantation and 3 patients who underwent transplantation and suffered subsequent heart failure due to rejection or postoperative myocardial dysfunction. The overall survival rate was 2 of 6. The 2 surviving patients had a failing transplanted heart. There were no survivors among the patients placed on ECLS as a bridge to transplantation. In each case a contraindication to transplantation developed before a donor heart could be obtained. The mean time of ECLS support was 147.5 hours (range. 70 to 370 hours). The ECLS circuit did not affect cyclosporin levels or antirejection therapy. Extracorporeal life support can be used to support pediatric cardiac transplant patients with biventricular failure due to acute rejection or postoperative dysfunction. Although the results have been discouraging. ECLS may still have a role as a bridge to transplantation. However. complications can develop during ECLS that may preclude transplantation.
Antimicrobial prophylaxis for open heart operations, Between 1986 and 1988. 450 adults undergoing coronary artery bypass. cardiac valve replacement. or both were enrolled into a prospective. randomized. comparative trial of cephalothin versus cefamandole as perioperative prophylaxis. They were assessed during their hospitalization and at 6 weeks and 6 months after discharge for postoperative infectious complications. Eleven patients had major postoperative infections including 5 with sternal wound infections (three bacteremic). 6 with bacteremia. 1 with prosthetic valve endocarditis. and 3 with severe venous donor graft site infections. Eight major infections occurred in patients receiving cephalothin prophylaxis and three in patients receiving cefamandole. with all five sternal wound infections occurring in the cephalothin group. Postoperative pathogens responsible for the major infections included gram-negative aerobes in 5 patients. Staphylococcus aureus in 4. and Staphylococcus epidermidis in 2. Preoperative colonizing staphylococcal isolates were not predictive of postoperative staphylococcal pathogens. Although there was no statistically significant difference in rate of major postoperative infectious complications using either cephalothin or cefamandole prophylaxis. there was a trend in favor of cefamandole. Gram-negative aerobes are becoming increasingly important pathogens in this setting.
Tension pneumopericardium as a complication of single-lung transplantation, Tension pneumopericardium is distinctly uncommon in the adult population. We present a case of tension pneumopericardium as a complication of lung transplantation in a 54-year-old woman with thromboembolic pulmonary hypertension who underwent single-lung transplantation.
Successful Fontan-type operation for a nonresectable right ventricular tumor, A large intracavitary right ventricular tumor in a 24-year-old patient was considered nonresectable because it involved the interventricular septum. the free ventricular walls. and the tricuspid valve. Surgical palliation consisted of closure of the tricuspid and pulmonary valves. and the right atrium was anastomosed to the pulmonary artery bifurcation. The patient is asymptomatic 7 years after operation. and the neoplasm (a rhabdomyoma) has not increased in size.
Norwood operation for univentricular heart with subaortic stenosis in the neonate, In the setting of a single ventricle. subaortic stenosis may be enhanced by pulmonary artery banding and may later contraindicate a Fontan operation. The Norwood operation may prove a preferable alternative in some infants as a preparatory procedure. We have successfully used this procedure as the initial operation to palliate a newborn with tricuspid atresia. transposition of the great arteries. coarctation. and severe arch hypoplasia secondary to a restrictive bulboventricular foramen.
Mediastinal hibernoma, a rare tumor, Hibernoma is an uncommon soft tissue tumor that is derived from the remnants of fetal brown fat. Review of the world medical literature revealed 90 cases. 6 of which were intrathoracic. We present the seventh case of intrathoracic hibernoma; in this case. the hibernoma was within the mediastinum without direct invasion of other structures.
Collis gastroplasty: origin and evolution, In 1957 J. Leigh Collis published his innovative operation for treating the difficult problem of the irreducible hiatal hernia. esophagitis. and stricture. The design of the operation was based on the relatively primitive understanding of hiatal hernia and the newly emerging concept of reflux esophagitis. A variety of antireflux operations by different surgeons emerged over the years to follow. The original Collis gastroplasty has been subsequently modified with the addition of both partial and complete fundoplication procedures. The place of the modified Collis gastroplasty-fundoplication operations in today's approach to the problems of hiatal hernia and gastroesophageal reflux disease remains unsettled.
Blood conservation in cardiac surgery, We reviewed current blood conservation techniques and their use in cardiac surgery. Avoidance of aspirin preoperatively is an important blood conservation measure. Patients scheduled for an elective operation should participate in autologous predonation programs. With careful monitoring. patients with major coronary artery disease can safely donate blood preoperatively. Intraoperative processing of blood withdrawn before cardiopulmonary bypass provides autologous platelet-rich plasma for infusion after reversal of heparin sodium. Blood collected from the field during operation and blood remaining in the oxygenator after bypass can also be processed to yield washed and concentrated red blood cells for reinfusion. Randomized. prospective studies document that postoperative autotransfusion is both safe and effective in reducing homologous blood use. Aprotinin reduces plasma protein activation and platelet damage during bypass. The integration of available blood conservation techniques into a comprehensive program combined with careful consideration of the indications for transfusion may allow more patients to avoid transfusion entirely.
New technique for the arterial switch operation in difficult situations, The technique described here. a modification of the Aubert operation. avoids coronary reimplantation and also eliminates the need to use artificial material to transfer coronary circulation.
Postinfarction ventricular septal defect repair: retrospective thoughts and historical perspectives, Evolution of surgical techniques for repair of postinfarction ventricular septal rupture initially involved differentiation of these lesions from prior experience with surgical approaches to congenital ventricular septal defects. which were in the main not applicable. Second. understanding of the differing anatomical locations of postinfarction ventricular septal defects required innovation in terms of the location of the cardiotomy and type of repair necessary to achieve a successful result in any given patient. The gradual appreciation of different clinical courses pursued by patients after postinfarction ventricular septal rupture both in terms of location of the defect and the degree of right ventricular functional impairment has led to increased urgency relative to the timing of surgical repair. The incorporation of specific anatomical concepts of surgical repair and better understanding of the time course of physiological deterioration of patients can ultimately lead to an integrated approach aimed toward improved salvage of patients suffering this catastrophic complication of acute myocardial infarction.
Continuous epidural hydromorphone for postthoracotomy pain relief, Forty-four patients were treated with a continuous infusion of lumbar epidural hydromorphone (0.05%) after thoracic operations. Postoperatively. visual analog pain scores were obtained. On postoperative day 1 and 2. more than 90% of the patients experienced either no pain (visual analog pain scale = 0) or mild pain (visual analog pain score = 1 to 3) at rest. The incidence of side effects (hypoventilation. pruritis. and nausea) was less than reported with other epidurally administered opioids. Continuous infusion of lumbar epidural hydromorphone produced safe. predictable analgesia after thoracotomy.
Cardiac transplantation for hypoplastic left heart syndrome: a modified technique [see comment, A modified technique of infant orthotopic cardiac transplantation with arch reconstruction using bicaval cannulation is described. and the results in 4 infants with hypoplastic left heart syndrome are presented. This technique minimizes donor myocardial ischemic time and recipient circulatory arrest time.
Tracheal reconstruction with polytetrafluoroethylene graft in dogs, Use of prosthetic materials for long-segment tracheal reconstruction has been limited owing to infection. graft migration. ingrowth of fibrous tissue. and stenosis. Polytetrafluoroethylene (PTFE) is flexible and porous. and it may resist infection more than previously used materials. We evaluated PTFE for use in long-segment tracheal reconstruction. A 5-cm segment of trachea was resected in 9 dogs and replaced with a 20-mm reinforced PTFE graft using 4-0 Vicryl sutures. In 2 control dogs. one tracheal arch was resected and a primary anastomosis was performed. The animals were followed up with weekly bronchoscopy and endoscopic photography. Euthanasia was performed at 16 weeks or when signs of respiratory distress developed. At postmorten examination. the anastomoses were examined grossly and with light and scanning electron microscopy. In all 9 dogs that underwent tracheal replacement with PTFE. granulation tissue developed at the anastomoses resulting in airway obstruction after 3 to 8 weeks. No epithelial growth occurred over the graft between the anastomoses. The control animals did well. We conclude that granulation tissue formation at the anastomosis and the lack of respiratory epithelial ingrowth across the graft makes PTFE unsuitable for long-segment tracheal reconstruction.
Repair of flail anterior leaflets of tricuspid and mitral valves by cusp remodeling, We present an alternative approach to extensive rupture of the chordae tendineae leading to flail anterior leaflets. Resection of the affected cusp segment. suture of the cut edges. and extensive plication of the segment of annulus devoid of leaflets abolished massive regurgitation while maintaining an adequate valve orifice.
Cardioplegia-induced damage to ischemic immature myocardium is independent of oxygen availability, The known benefits of hypothermic pharmacological cardioplegia in protecting the ischemic adult heart may not extend to children. Protection of the ischemic immature rabbit heart with hypothermic Krebs-Henseleit bicarbonate buffer is better than with hypothermic St. Thomas' II cardioplegic solution. We investigated whether the availability of oxygen in the preischemic perfusate is responsible for the increased tolerance to ischemia of immature (7- to 10-day-old) hearts perfused with Krebs buffer in comparison with St. Thomas' II solution immediately before ischemia. After obtaining preischemic control data in the "working" mode. we perfused hearts (n = 8 per group) for 3 minutes with hypothermic (14 degrees C) Krebs buffer or hypothermic St. Thomas' II solution saturated with 0%. 25%. or 95% oxygen. This was followed by 2 hours of global ischemia at 14 degrees C. Hearts were reperfused for 15 minutes in the Langendorff mode and 35 minutes in the working mode. and recovery of function was measured. For preischemic oxygen concentrations of 0%. 25%. and 95%. recovery of aortic flow in hearts protected by hypothermia alone during ischemia was 74% +/- 9%. 82% +/- 4%. and 99% +/- 2% of preischemic values. respectively. In hearts protected by hypothermia plus cardioplegia. the values were 69% +/- 6%. 72% +/- 3%. and 86% +/- 5%. respectively. Thus. at equal oxygen concentrations. recovery of postischemic function was better in hearts protected by hypothermia alone compared with hypothermia plus cardioplegia. We conclude that factors other than oxygen availability are responsible for the damaging effect of St. Thomas' II solution on the ischemic immature rabbit heart.
Pleuropulmonary morbidity: internal thoracic artery versus saphenous vein graft, Although use of the internal thoracic artery (ITA) for coronary artery bypass grafting results in superior graft patency and improved patient survival. our initial clinical observations suggested an increased incidence of pleuropulmonary morbidity with its use. One hundred consecutive patients with left ITA grafts were studied prospectively and compared with a consecutive retrospective group of 100 patients undergoing coronary artery bypass grafting with saphenous vein grafts only. Preoperative. postoperative day (POD) 2. POD 6. and postoperative week 8 chest roentgenograms were analyzed for atelectasis and effusion. Postoperative left lower lobe atelectasis was common in both groups on both POD 2 (saphenous vein. 43%. versus ITA. 53%; not significant) and POD 6 (saphenous vein. 40%. versus ITA. 41%; not significant). There was a significantly higher incidence of pleural effusion on POD 6 in the ITA group (84% versus 47%; p less than 0.05) but most of these were small. There was more chest tube drainage (1.413 versus 1.028 mL; p less than 0.01) and a greater need for secondary thoracostomy or thoracentesis (4% versus 0%) in the ITA group. The left pleural space was opened in 67 of the 100 ITA patients but pleurotomy did not appear to influence postoperative morbidity. We conclude that use of the internal thoracic artery for coronary artery bypass grafting results in a small but significant increase in pleuropulmonary morbidity.
Systemic therapy in metastatic colorectal cancer, Fluorouracil-based chemotherapy regimens have been utilized in metastatic colorectal cancer for more than 30 years. Early attempts at defining an optimal treatment schedule and use in combination with other drugs failed to significantly improve results. In contrast. the clinical effectiveness of fluorouracil has been improved by continuous infusion administration and modulation with folinic acid. Both approaches have increased the response rate compared with results achieved with traditional bolus schedules; the effect on survival has been less significant. Unfortunately. expense and. in some instances. toxicity have also been increased. which detracts from their overall usefulness. Clinical studies that evaluate fluorouracil chemotherapy in combination with biological-response modifiers are ongoing and will be areas of intense research during the next few years.
Misdiagnosis in patients with amyotrophic lateral sclerosis, To confirm our impression that a high percentage of patients with amyotrophic lateral sclerosis are initially misdiagnosed. we reviewed records of 33 patients with a definitive diagnosis of amyotrophic lateral sclerosis seen over 10 years. Fourteen patients (43%) were initially misdiagnosed. Mean time to correct diagnosis was significantly greater for the misdiagnosed group (16.0 +/- 9.3 months) than for the rest of the patients (7.6 +/- 4.1 months). Two of three patients with an initial symptom of dyspnea were misdiagnosed. Three patients underwent laminectomies because of misdiagnosis. Age. stage of disease. and unusual presenting symptoms were not identified as causes of misdiagnosis. Most likely causes were physicians' failure to consider the diagnosis and lack of familiarity with the common clinical presentations of amyotrophic lateral sclerosis. Earlier diagnosis of amyotrophic lateral sclerosis may help prevent medical mismanagement and may benefit patients both medically and psychologically.
Syncope and presyncope associated with probable adverse drug reactions, The purpose of this study was to determine whether syncope and presyncope were associated with drug therapy in 70 patients referred to a tertiary care ambulatory clinic. Drug use information was obtained. validated. and classified by its potential to cause syncope and presyncope. Utilizing a standardized adverse drug reaction algorithm. nine (13%) of the 70 patients were rated as having probable drug-induced syncope and presyncope events. Overall. 12 medications were implicated. Patients with probable adverse drug reactions were older. and taking more medications. or taking an antihypertensive. Seven of the nine patients with probable adverse drug reactions were previously classified as having syncope of unknown origin after their initial clinic evaluation. Syncope and presyncope are commonly associated with adverse drug reactions. especially in the elderly and those taking multiple medications.
The relationship between sex hormones and high-density lipoprotein cholesterol levels in healthy adult men, The objective of this study was to clarify the complex and uncertain relationship between endogenous sex hormones and high-density lipoprotein (HDL) cholesterol levels in healthy men. Fifty-five healthy adult men were consecutively recruited from an ongoing cross-sectional study of cardiovascular disease risk factors from a lipid research clinic at the University of Washington. Seattle. Subjects receiving medication were excluded. Multiple linear regression analysis identified several factors that correlated highly significantly with HDL cholesterol levels. including alcohol intake; frequency of strenuous exercise; age; levels of total cholesterol. low-density lipoprotein cholesterol. and triglyceride; and carbohydrate intake. Nearly 80% of the heterogeneity in HDL cholesterol levels could be accounted for by these factors. Despite finding significant correlations with factors known to influence HDL cholesterol levels. no correlation with estradiol level. testosterone level. or the ratio of estradiol to testosterone levels was apparent. In conclusion. endogenous sex hormones do not appear to influence HDL cholesterol levels in healthy adult men. Alternatively. a large proportion of the heterogeneity in HDL levels in this group of men can be accounted for by environmental factors. The disparity between this conclusion and others may be partially due to differences in accounting for these confounding variables.
Seroprevalence of Helicobacter pylori in Seventh-Day Adventists and other groups in Maryland. Lack of association with diet, To evaluate the possible role of diet in the transmission of Helicobacter pylori. we compared H pylori seroprevalence among Seventh-Day Adventists (who are vegetarian and abstain from alcohol. caffeine. and meat; n = 94) and two non-Seventh-Day Adventist control groups (n = 168). With the use of an enzyme-linked immunosorbent assay H pylori antigen prepared in a French pressure cell. we found no difference in seroprevalence among these groups; however. seropositivity strongly correlated with age and black race.
Profile of bronchospastic disease in Puerto Rican patients in New York City. A possible relationship to alpha 1-antitrypsin variants, A high prevalence of asthmalike symptoms was noted among patients of Puerto Rican descent attending Beth Israel and North Central Bronx Medical Centers in New York City. as compared with other ethnic groups. An evaluation of family and medical histories. pulmonary function data. and alpha 1-antitrypsin phenotypes was undertaken in such Puerto Rican patients and control subjects without asthma. The patients showed a higher proportion of MS and MV phenotypes. All the patients in both MM and variant phenotype groups. with the exception of four MM patients. had features indicative of asthma. with labile airway obstruction. and elevated serum immunoglobulin E and eosinophil levels. The latter was significantly higher in the patients with variant phenotypes than in MM patients. Patients with alpha 1-antitrypsin variants also had much shorter smoking histories as compared with the MM group. and all reported histories of asthma in first-degree relatives. as compared with 66% among the MM patients. We conclude that there is an increased incidence of asthma among Puerto Ricans in New York City. and that the antitrypsin variant phenotypes (specifically S and V) play a role in this incidence and its expression.
Treatment of severe reactive hypoglycemia with a somatostatin analogue (SMS 201-995), Reactive (or postprandial) hypoglycemia can sometimes represent a severe disorder refractory to conventional therapeutic measures. We present in this first individual trial. to our knowledge. that the administration of a somatostatin analogue (SMS 201-995) may alleviate the severity of complaints and does not appear to be diabetogenic. The effects of the somatostatin analogue were documented in a 5-hour oral glucose tolerance test. where not only the glucose-induced and C-peptide rise was clearly attenuated. but also the blood glucose concentration did not fall low enough to induce hypoglycemic symptoms.
The hippocampus and parahippocampus in schizophrenia, suicide, and control brains [published erratum appears in Arch Gen Psychiatry 1991 May;48(5):422, Recent postmortem studies in schizophrenia have shown abnormalities in medial temporal lobe structures. including the hippocampus and parahippocampus. We tried to replicate previous studies and to explore the specificity of this finding to schizophrenia. The anterior hippocampus and parahippocampal cortex were evaluated for area and shape in postmortem tissue from 12 schizophrenic. 17 nonschizophrenic suicide. and 10 nonpsychiatric control brains. No significant differences were found in hippocampal area. but the parahippocampal cortex was significantly smaller in the schizophrenic group than in the control group. When parahippocampi from right and left sides were analyzed separately. both the suicide and schizophrenic groups had smaller parahippocampi on the right side than did the controls [corrected]. The suicide group exhibited greater parahippocampal areas in the left than in the right tissue samples within the group. while such a difference did not exist in the schizophrenic or control groups. This study demonstrated changes in temporal lobe structures in both schizophrenic and nonschizophrenic suicide groups.
Neuropsychological assessment of monozygotic twins discordant for schizophrenia, A comparison of monozygotic twins discordant for schizophrenia controls for genetic variance and reduces variance due to environmental circumstances. thus serving to highlight differences due to phenotypic-related variables. In this study. we assessed 16 such twin pairs on a wide range of neuropsychological tests. The affected twins tended to perform worse than their unaffected counterparts on most of the tests. Deficits were especially severe on tests of vigilance. memory. and concept formation. suggesting that dysfunction is greatest in the frontotemporal cortex. While manifest symptoms were not highly associated with neuropsychological scores. global level of functioning was. To address the issue of genetic liability. we also compared the sample of discordant unaffected twins with a sample of seven pairs of normal monozygotic twins. No significant differences between the groups were found for any neuropsychological test. In fact. the results suggest that neuropsychological dysfunction is a consistent feature of schizophrenia and that it is related primarily to the clinical disease process and not to genetic or nonspecific environmental factors.
Gilles de la Tourette syndrome is not linked to D2-dopamine receptor, Gilles de la Tourette syndrome has an important genetic component; the pathophysiology of this disorder may involve the dopamine system. We tested a D2-dopamine receptor (locus DRD2. recognized by probe hD2G1) for genetic linkage with Gilles de la Tourette syndrome. Using a genetic linkage map of the region of DRD2 on the long arm of chromosome 11 and restriction fragment length polymorphism data from a total of four markers (DRD2 itself. D11S84. D11S29. and PBGD). we were able to exclude linkage of this candidate gene and Gilles de la Tourette syndrome in two extended kindreds segregating for Gilles de la Tourette syndrome. This rules out causation of Gilles de la Tourette syndrome by mutation in DRD2 in the kindreds studied under the genetic assumptions we employed; use of the map and multipoint linkage analyses also allowed us to exclude a Gilles de la Tourette syndrome susceptibility locus from a larger genetic region.
Bilateral phrenic nerve palsy associated with open-heart surgery, The incidence of phrenic nerve palsy after open-heart surgery has been estimated at 10%. but it is usually unilateral and does not cause symptoms. Bilateral phrenic nerve injury after coronary artery bypass surgery is a rare complication. This case report describes a patient who developed bilateral phrenic nerve palsies and required prolonged ventilatory support. Denervation of both hemidiaphragms was documented by needle electromyography four weeks after bypass surgery. The patient required total ventilatory support for three months and partial ventilatory support for an additional three months. This case demonstrates the usefulness of electromyographic screening for documentation and prognostication after phrenic nerve injury. The cause of the lesion was unclear. but hypothermia and stretch were leading hypotheses. This patient developed the phrenic nerve palsies despite using a cardiac insulation pad.
A new orthosis for central cord syndrome and brachial plexus injuries, Proximal upper extremity weakness may develop secondary to central cord syndrome due to spinal cord injury or brachial plexus injury. Functional deficits. pain. decreased upper extremity arm swing during gait. and shoulder subluxation are common sequelae of these injuries. This report describes a new orthotic design that can be easily fabricated in two to four hours from readily available materials to compensate for these deficits. This orthosis allows for early participation in activities of daily living for patients with greater proximal than distal upper extremity weakness. The orthosis consists of a figure-eight shoulder harness and unilateral or bilateral forearm cuffs of orthoplast connected to the harness by flexible rubber tubing. The length of the tubing is adjustable through clamps connected to the forearm cuff to allow for variable arm positioning. Three patients. aged 14. 64. and 68. two with central cord syndrome and one with injury to the upper portion of the brachial plexus (Erb palsy) are described. Shoulder girdle musculature was less than 2. biceps less than 2. triceps less than 4. and hands less than 5 in all patients. Benefits from use of this orthosis may include improved arm swing and balance during ambulation. reduced shoulder pain and subluxation. and increased independence for tasks such as carrying lightweight objects. lower extremity dressing. bathing. light homemaking. and leisure activities such as gardening.
Quantitative evaluation of sway as an indicator of functional balance in post-traumatic brain injury, The test of sway. using different conditions of stance with measurements of the average radial deviation of the center of pressure and its path length of sway per unit of time. has been shown to be a useful clinical tool in determining balance problems in traumatic brain injury (TBI) patients. Normative values were established to determine if an individual patient's sway values fell within the normal range (mean +/- 2SD). The tests have shown good test-retest reliability for TBI patients. In addition. it has been shown that the sensitivity of the test is sufficient to identify changes in patients' performances as their clinical conditions change. It has been demonstrated that the different stance conditions of the battery of tests become progressively more difficult to perform (from comfortable stance. eyes open and eyes closed. through narrow stance. eyes open and eyes closed. to tandem stance with right or left foot forward. eyes open and eyes closed). By using these subtests. it is easy to distinguish between the performances of able-bodied patients and TBI patients with very mild balance problems. The validity of the measure has been documented by correlating the sway performance with clinical functional performance tests. The test performance also correlates with the patient's own assessment of his or her gait difficulties. The limited data available suggest that the test of sway relates difficulties in static balance to the frequency of falls. Finally. subtests permit identification of specific problems in maintaining balance as a basis for therapeutic intervention.
Age effect on prognosis for functional recovery in acute, traumatic central cord syndrome, The purpose of this study was to determine if age is significant in functional recovery in acute. traumatic central cord syndrome (CCS). Recovery of ambulation. ADL status. and bowel and bladder function were evaluated. A retrospective study tested the hypothesis that functional recovery in 51 consecutive CCS patients was better in younger patients than in older patients. Four patients. all more than 50 years. died. Ability to ambulate independently at discharge was compared in 30 patients younger than 50 years with 21 patients 50 years or older. Results showed that 29 of 30 (97%) of the younger patients were ambulatory compared to seven of 17 (41%) of the older patients (p less than .002). The younger patients were also able to achieve independence in self-care and bowel and bladder function in a significantly greater proportion. The prognosis for functional recovery in acute traumatic CCS should consider the patient's age. The prognosis is less optimistic in older patients. but it is considerably more favorable in younger patients than previously reported.
Sensory nerve evoked responses in spinal cord injury, Previous studies have documented the presence of fibrillations. positive waves. and decreased motor evoked response amplitudes in spinal cord injury (SCI) subjects. The purpose of this study was to further evaluate sensory nerve status in this population. Twenty-eight subjects with SCI for at least five months and evidence of spasticity were included. Sural sensory and tibial motor evoked response amplitudes were measured. The mean sural sensory amplitude was 8.0 +/- 5.9 microV (normal = 15.0 +/- 5.3 microV). The mean tibial motor amplitude was 5.1 +/- 4.3 mV (normal = 11.7 +/- 3.8 mV). In six subjects with significantly reduced sural sensory amplitudes. more extensive electrodiagnostic testing was performed. These studies showed diffusely decreased lower extremity sensory and motor evoked response amplitudes and diffuse positive waves and fibrillations in no particular distribution. Thus. subjects with SCI may have sensory as well as motor nerve abnormalities. An intact connection between the second order and primary sensory neuron may be necessary for maintenance of axonal integrity of the primary neuron.
Myotonic dystrophy: quantification of muscle weakness and myotonia and the effect of amitriptyline and exercise, The purpose of this study was to quantify the degree of muscle weakness and myotonia in 12 patients with myotonic dystrophy (MD). and to quantitatively determine the effects of a four- to six-month therapeutic trial of amitriptyline. Patients had exercised with weights for one or more years. Some had shown initial improvement in muscle strength. but had reached a plateau; others had not improved when the study began. Muscle weakness was quantified by comparing the five-second maximum voluntary contraction (MVC) in newtons (N) per kg (body weight) of 12 patients and 20 healthy subjects. Knee extensor. elbow flexor. and first dorsal interosseous (FDI) muscles were compared. Myotonia was quantified by measuring relaxation times (RTs) at the end of the five-second MVC produced by FDI. as the time taken for the MVC to decrease by 50% and 75% (referred to as 1/2 and 3/4RT). The results were as follows: (1) the mean muscle strength of each of the three muscles of the patients was significantly (p less than .001) reduced compared with healthy subjects; and (2) 1/2 and 3/4RT means of the patients (vs healthy subjects) were significantly prolonged (p less than .01). Eight of the patients participated in a therapeutic trial of amitriptyline. Therapeutic effects were quantified by measuring muscle strength. 1/2 and 3/4RT. and percent change in evoked muscle action potential (MAP) from the FDI muscle after a ten-second MVC. to determine change in excitability. Mean muscle strength of FDI improved from .27 to .33N/kg. (p less than .05).
Needle-localized mammographic lesions. Results and evolving treatment strategy, From January 1981 to December 1987. 932 needle-localization breast biopsies were performed at our institution for mammographically detected abnormalities. We reviewed 531 needle-localization breast biopsy procedures performed during two periods (January 1981 to June 1984. n = 311; and January to August 1987. n = 220) to compare results and treatment patterns. and to determine the prevalence of the missed lesions. Mammographic abnormalities detected on routine screening accounted for a larger proportion of needle-localization breast biopsies in the later series (94 [30%] of 311 vs 94 [43%] of 220). However. the rate at which carcinoma was identified remained constant at 29% as did the percentage of cancers that were invasive (46% vs 51%). Overall. the rate of malignant diagnoses after needle-localization breast biopsy was lowest in asymptomatic women undergoing routine screening mammography (44 [24%] of 188) and significantly higher in women undergoing mammographic follow-up of the contralateral breast after treatment for breast cancer (28 [43%] of 65). There were seven missed lesions in 531 needle-localization breast biopsies. necessitating a second procedure in six and interval mammograms in one.
Hepatic vein reconstruction for preserving remnant liver function, Hepatic malignancies often infiltrate to the major hepatic vein. Recently. we performed hepatic resection combined with hepatic vein reconstruction for preserving remnant liver function in three such patients. One patient had a saphenous vein graft. Postoperative liver function of the patients who underwent hepatic vein reconstruction was compared with those of eight patients who underwent hepatic resection of segments VII and VIII. The right hepatic vein in four of them was resected and in the remaining four was preserved by skeletalization using an ultrasonic aspirator. Although four patients with right hepatic vein resection showed severe lowering of liver function after surgery. the postoperative course of patients with preservation or reconstruction of the right hepatic vein maintained good liver function. Liver regeneration of three patients with hepatic vein reconstruction was good on computed tomography. Besides this report. to our knowledge. there is no other report of hepatic vein reconstruction for preserving the remnant liver function. Problems with hepatic resection combined with hepatic vein reconstruction are discussed. We conclude that hepatic vein reconstruction is one of the means for extending indication of the malignant tumor resection of the liver.
Evaluation of methods for detecting venous reflux. Perspectives in venous insufficiency, Using 793 limbs with nonobstructive venous reflux. we evaluated a number of techniques used for the assessment of venous reflux. The venous Doppler examination was found to be a reliable screening tool with excellent sensitivity and good specificity. Photoplethysmography was 97% sensitive in patients with ambulatory venous hypertension; however. in milder forms of reflux. it was less sensitive. The major drawback of photoplethysmography was the large number of false-positive results obtained. Ambulatory venous pressure measurement and another pressure-based technique. Valsalva-induced foot venous pressure measurement. defined overlapping but different normal and abnormal limbs. Descending venography. when performed as described by Kistner et al. was found to be a reliable tool to assess reflux with more than a 90% sensitivity. The horizontal technique of performing descending venography and nucleotide descending venographies had unacceptably low sensitivity and were abandoned. Features of venous reflux as outlined by these modern technical tools are described.
Does survival depend on the amount of autotransplanted splenic tissue, Susceptibility to Streptococcus pneumoniae infection was studied in 11 groups of rats allocated to sham operation. splenectomy. or splenic autotransplantation of 10%. 20%. 30%. 40%. 50%. 60%. 70%. 80%. or 90% of the removed spleen. Three months later. all rats were exposed intravenously to type 1 Streptococcus pneumoniae (median lethal dose. LD50. for control group). Survivors were killed 13 days after the bacterial challenge. Autopsy showed that more splenic tissue was recovered in rats that received less than 50% splenic tissue compared with those that received 50% or more. More survivors were found among sham-operated rats (47.5%; 95% confidence intervals. 32 to 68) and rats that had 40% splenic tissue implanted (35%; confidence interval. 20 to 54) or those that were found to have regenerated 40% splenic tissue. We conclude that 40% of the spleen should be autotransplanted to protect the rat optimally against infection after splenectomy.
Aortic occlusion and vascular isolation allowing avascular hepatic resection, Occlusion of the supraceliac abdominal aorta and hepatic vascular isolation were employed in a series of 15 patients as a definitive method to allow avascular hepatic resection. The series was compared with an earlier group of patients treated conventionally. In the avascular hepatic resection group there was no mortality; hypotension did not occur at the time of hepatic vascular isolation; rapid. accurate excision of the hepatic lesions could be achieved in a bloodless field; resection of midline lesions and those involving the great veins was possible; and "segmentectomies." or resections crossing segmental boundaries. could be performed where previously formal hepatic lobectomies were required. Concomitantly. the greatest amount of uninvolved hepatic parenchyma remained in situ. There was increased ease of operative management. reduced blood loss. and reduced operating time (mean. 2.8 hours).
The papillary-cystic neoplasm of the pancreas. An increasingly recognized clinicopathologic entity, The clinical course of the papillary-cystic neoplasm of the pancreas is contrasted with that of the pancreatic ductal adenocarcinoma. The former occurs predominantly in young women. has a low malignant potential. and is highly curable with surgical treatment. Three cases are reported that illustrate the typical clinical features and the indolent nature of the tumor. One case was discovered after blunt abdominal trauma resulted in rupture of the tumor and hemoperitoneum. All cases were treated by pancreatic resection with preservation of the spleen. an important consideration in younger patients. All patients were free of disease at long-term follow-up. Increasing awareness of this tumor has resulted in the reclassification of several tumors and should lead to better recognition by surgeons caring for patients with pancreatic diseases.
Circadian variation in onset of acute ischemic stroke, A circadian pattern for the onset of myocardial and cerebral infarction has been identified. To evaluate this phenomenon further. we analyzed prospectively collected data from 151 patients with acute ischemic stroke. The number of strokes per 6-hour period were the following: midnight to 6 AM. 20 (13%); 6 AM to noon. 86 (57%); noon to 6 PM. 21 (14%); and 6 PM to midnight. 24 (16%). This pattern was not affected by previous use of aspirin. The most frequent time of onset was 6 AM to noon for all subgroups of ischemic stroke: small artery. 71%; cardioembolic. 62%; large artery atherothrombotic. 57%; large artery atheroembolic. 46%; and "other" or unknown cause. 40%. We also investigated the time between awakening and stroke onset in 145 patients and found that 24% of ischemic strokes occurred within the first hour after awakening. Our data demonstrate that an early morning peak exists for all subtypes of stroke. Our data also suggest that the most critical period is the first hour after awakening.
Nontraumatic coma. Glasgow coma score and coma etiology as predictors of 2-week outcome, In 1987 and 1988. we carried out a prospective study of patients older than 10 years with nontraumatic coma in the intensive care units of Columbia-Presbyterian Medical Center. New York. NY. Of 188 patients with Glasgow Coma Scale (GCS) determinations within 72 hours. 61% were dead or in persistent coma by 2 weeks from onset. Age. sex. and ethnicity did not influence outcome. The 2-week outcome for patients with initial GCS of 3 to 5 was 14.8% awake; 85.2% were dead or in persistent coma. For the GCS 6 to 8 group. 53.1% were awake and 46.9% were dead or in persistent coma. Hypoxic or ischemic coma had the worst 2-week outcome (79% dead or comatose); coma caused by metabolic disease or sepsis (68%). focal cerebral lesions (66%). and general cerebral diseases (55%) were intermediate. while drug-induced coma had a favorable outcome (27% dead or comatose). The independent predictors of 2-week outcome were the first GCS and drug-induced coma. The predicted probability of waking at 2 weeks was eight times better for drug-induced coma than other causes when GCS was held constant. Patients with an initial GCS score of 6 to 8 were seven times more likely to waken than those with a score of 3 to 5. The motor subscore alone was a significant independent predictor of 2-week outcome. Modification of coma score to include etiology may give more accurate predictions of 2-week outcome after nontraumatic coma.
Screening for early dementia using memory complaints from patients and relatives, This study examined whether the subjective impression of memory function might differentiate healthy elderly subjects from patients with memory complaints. and whether memory complaints differed between patients with and without a dementing illness. Both self-assessment and relatives' responses on a new memory questionnaire differentiated patient groups from control subjects. The relatives' form measuring deterioration in memory function over time identified dementing individuals from those with non-dementing causes for their memory complaints. Factor analysis indicated that patients' memory complaints correlated with depression rather than objective memory performance. while relatives' ratings correlated with objective memory scores. not depression. Stepwise discriminant function analyses showed that objective memory testing greatly improved specificity but not sensitivity of the subjective memory questionnaire alone.
Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia, Cerebrospinal fluid (CSF) amino acid neurotransmitters. related compounds. and their precursors. choline levels. and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized. double-blind. crossover. placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid. methionine. and choline levels. adjusted for age. were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.
Long-term effect of dopaminergic drugs in restless legs. A 2-year follow-up, Thirty patients with restless legs syndrome. who initially had all responded well to treatment with levodopa and benserazide. were studied as to the long-term effect of the drugs (at least 2 years). During the 2-year period. two patients were switched from levodopa to bromocriptine. Two patients no longer needed levodopa; one of them had developed paraplegia and in the other the symptoms of restless legs syndrome had disappeared completely. The remaining 26 patients continued to use levodopa. Eight patients maintained the original dose. nine had to use an increased dose. and nine found a decreased dose to be sufficient. The only side effect was transient nausea reported by two of the 30 patients. The study showed that the relief of symptoms of restless legs syndrome by dopaminergic drugs does not wear off with the passage of time. that side effects are minimal even with long-term use. and that the dose needed to obtain relief may increase as well as decrease.
Hemifacial spasm in Rochester and Olmsted County, Minnesota, 1960 to 1984, The incidence of hemifacial spasm in residents of Olmsted County. Minnesota. was studied by reviewing the medical records of patients residing in the community between 1960 and 1984. The average annual incidence rate was 0.74 per 100.000 in men and 0.81 per 100.000 in women. age-adjusted to the 1970 US white population. The average prevalence rate was 7.4 per 100.000 population in men and 14.5 per 100.000 in women. The incidence and prevalence rates were highest in those from 40 to 79 years of age.
Temporoparietal cortex in aphasia. Evidence from positron emission tomography, Forty-four aphasic patients were examined with (F18)-fluorodeoxyglucose positron emission tomography in a resting state to determine whether consistent glucose metabolic abnormalities were present. Ninety-seven percent of subjects showed metabolic abnormalities in the angular gyrus. 89% in the supramarginal gyrus. and 87% in the lateral and transverse superior temporal gyrus. Pearson product moment correlations were calculated between regional metabolic measures and performance on the Western Aphasia Battery. No significant correlations were found between the Western Aphasia Battery scores and right hemisphere metabolic measures. Most left hemisphere regions correlated with more than one score from the Western Aphasia Battery. Temporal but not frontal regions had significant correlations to the comprehension score. The left temporoparietal region was consistently affected in these subjects. suggesting that common features in the aphasias were caused by left temporoparietal dysfunction. while behavioral differences resulted from (1) the extent of temporoparietal changes. and (2) dysfunction elsewhere in the brain. particularly the left frontal and subcortical areas.
The Marinesco-Sjogren syndrome examined by computed tomography, magnetic resonance, and 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography, The Marinesco-Sjogren syndrome is an autosomal recessive degenerative disorder characterized by congenital cataracts. cerebellar ataxia. spasticity. mental deficiency. and skeletal abnormalities. We studied two adult siblings with Marinesco-Sjogren syndrome using anatomic and metabolic brain imaging techniques to characterize the pattern and nature of abnormalities in the brain. Computed tomographic and magnetic resonance imaging showed diffuse brain atrophy of mild to moderate degree. involving primarily the white matter of the cerebrum. cerebellum. brain stem. and cervical spinal cord. The pattern of atrophy resembled that seen in diffuse leukoencephalopathies. Measurements of local cerebral glucose metabolic rates with positron emission tomography revealed no statistically significant differences from normal control subjects in most regions. but metabolic rate was decreased in the thalamus in one patient. The findings support a diffuse white matter disorder in Marinesco-Sjogren syndrome.
Background review and current concepts of reperfusion injury, We define the concept of reperfusion injury. and we present a background chronology of experimental work supporting and questioning this concept. We identify several new influences. such as current clinical interest in thrombolytic therapy for acute ischemia of heart and brain and the growing recognition of endothelium as a regulator of homeostasis. We propose that these influences will encourage a reexamination of reperfusion injury as a factor in the ultimate outcome of tissue exposed to reversible ischemia. We briefly discuss the major mechanisms presently implicated in reperfusion injury--loss of calcium homeostasis. free radical generation. leukocyte-mediated injury. and acute hypercholesterolemia.
Aplasia cutis congenita and arteriovenous fistula. Case report and review, We describe a child with congenital aplasia cutis congenita of the scalp and an occult giant posterior fossa arteriovenous fistula. Previous case reports of central nervous system malformations associated with aplasia cutis congenita are reviewed. The exact incidence of such malformations is unknown. All patients with aplasia cutis congenita should undergo a neurologic evaluation. and their families should be examined for similar lesions. Early central nervous system imaging and other workup may be required. especially if plastic surgery in the head region is being planned.
The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hand, Clinical criteria for the classification of symptomatic idiopathic (primary) osteoarthritis (OA) of the hands were developed from data collected in a multicenter study. Patients with OA were compared with a group of patients who had hand symptoms from other causes. such as rheumatoid arthritis and the spondylarthropathies. Variables from the medical history. physical examination. laboratory tests. and radiographs were analyzed. All patients had pain. aching. or stiffness in the hands. Patients were classified as having clinical OA if on examination there was hard tissue enlargement involving at least 2 of 10 selected joints. swelling of fewer than 3 metacarpophalangeal joints. and hard tissue enlargement of at least 2 distal interphalangeal (DIP) joints. If the patient had fewer than 2 enlarged DIP joints. then deformity of at least 1 of the 10 selected joints was necessary in order to classify the symptoms as being due to OA. The 10 selected joints were the second and third DIP. the second and third proximal interphalangeal. and the trapeziometacarpal (base of the thumb) joints of both hands. Criteria derived using the "classification tree" method were 92% sensitive and 98% specific. The "traditional format" classification method required that at least 3 of these 4 criteria be present to classify a patient as having OA of the hand. The latter sensitivity was 94% and the specificity was 87%. Radiography was of less value than clinical examination in the classification of symptomatic OA of the hands.
Aspirin, hydroxychloroquine, and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis, Levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) in patients with rheumatoid arthritis from 5 centers involved in the Arthritis. Rheumatism. and Aging Medical Information System were correlated with the use of specific antirheumatic medications. Elevated levels of SGOT and SGPT were most frequent in patients taking salicylates and methotrexate (MTX) and least frequent in patients taking hydroxychloroquine. The combination of MTX and salicylates greatly increased the frequency of abnormal liver enzyme values. In contrast. the addition of hydroxychloroquine to a regimen of either MTX or aspirin essentially eliminated the SGOT and SGPT abnormalities. Results from all 5 centers were consistent and remained so after adjustment for age. sex. and disease duration. Knowledge of these important drug interactions may permit continuation of MTX therapy in patients in whom the drug might otherwise be discontinued.
Type XI collagen-degrading activity in human osteoarthritic cartilage, Homogenates of 6 samples of human osteoarthritic cartilage were shown to degrade exogenous type XI collagen. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis. the cleavage products generated by each homogenate were similar. and they were identical to those obtained by cleavage of the substrate with purified gelatinase. Enzyme activity. which was inhibited by EDTA. was greater in extracts of fibrillated osteoarthritic cartilage than in extracts of grossly normal cartilage from the same joint or in extracts of cartilage from joints with osteonecrosis. Activation with APMA enhanced digestion. but breakdown was apparent in extracts of fibrillated osteoarthritic cartilage even without APMA. Enzymatic degradation of type XI collagen could play a significant role in the turnover of articular cartilage in health and disease states.
Activation of T cell subsets in the peripheral blood of patients with Sjogren's syndrome. Multicolor flow cytometric analysis, Using 3-color flow cytometry. we determined the proportions of activated T cells (DR+). including CD4+ cells. CD8+ cells. and their subsets. in the peripheral blood of 17 patients with Sjogren's syndrome (SS). Activated T cells were significantly increased in CD4+ cells. CD8+ cells. and T suppressor inducer (CD4+. Leu-8+). T helper (CD4+. Leu-8-). and T cytotoxic (CD8+. CD11-) subsets. but not the T suppressor/natural killer subset (CD8+. CD11+). in patients with SS as compared with the controls. Furthermore. the proportions of activated T cells in the CD4+. Leu-8- subset. the CD8+ subset. or the CD8+. CD11- subset showed a positive correlation with serum gamma globulin levels in the SS patients. Our findings suggest that a certain immunoregulatory balance between T helper and T suppressor activities is maintained in SS patients. although this balance seems to occur at highly activated levels. and that quantitative changes of some lymphocyte subsets are important factors in maintaining this balance. We discuss the possibility that CD4+. Leu-8+ cells recirculate into peripheral lymph nodes. while CD4+. Leu-8- cells migrate into inflammatory tissues such as salivary glands. since the Leu-8 antigen is reported to be a homing receptor in peripheral lymph nodes. This process might be accelerated in SS. and each T cell subset may further participate in immunologic activation in the lymph nodes or target tissues.
Functional studies of soluble low-affinity interleukin-2 receptors in rheumatoid synovial fluid, Since abnormal regulation of interleukin-2 (IL-2) has been demonstrated in rheumatoid arthritis (RA). the functional role of low-affinity soluble IL-2 receptors (sIL-2R) purified from RA synovial fluids (SF) was studied. Picomolar levels of sIL-2R were detected in RA SF using an enzyme-linked immunosorbent assay. Levels were higher in serum and SF from RA patients than in controls (P less than 0.001) and higher in RA SF than in paired RA serum (P less than 0.01). Soluble IL-2R from RA SF had estimated molecular weights of 40-50 kd and 80-100 kd by gel filtration analysis. The 80-100-kd peak is likely to be a dimer of the 40-50-kd peak. since a single 45-kd peak was found after elution from sodium dodecyl sulfate-polyacrylamide gels. Since inhibitory activity for lymphocyte proliferation was found in the 80-100-kd range. the sIL-2R were purified with an anti-CD25 affinity column and further analyzed. The purified fractions did not interfere with the proliferation of mitogen-stimulated lymphocytes or with the binding of radiolabeled IL-2 to CTLL-2 cells. although direct binding of IL-2 was demonstrated. The affinity of sIL-2R from RA SF for binding IL-2 was in the range of 25 nM. which is similar to the affinity of sIL-2R purified from a human T cell clone. indicating that both sIL-2R are low-affinity receptors for IL-2. We conclude that the concentration and binding affinity of low-affinity sIL-2R purified from RA SF render them unable to interfere with IL-2-related activities.
Dermal mast cell degranulation in systemic sclerosis, Paired biopsy samples from involved and uninvolved skin were obtained from 19 patients with generalized scleroderma (11 with early. progressive disease and 8 with late. improving disease). Skin biopsy samples were double stained for mast cell granules and for mast cell membrane. The number of mast cells was increased in patients with systemic sclerosis (SSc). in both involved and uninvolved skin and in both early and late disease. There was an increase in the number of degranulated mast cells in the involved skin of patients with both early and late disease and in the not-yet-involved skin of patients with early disease; however. there was no increase in the number of degranulated mast cells in areas of previously involved but now normal skin of patients with late disease. Increases in mast cell number and degranulation precede clinically apparent dermal fibrosis in SSc. These observations and the absence of mast cell degranulation in regressing skin suggest a participatory role of the mast cell in the clinical progression of skin changes in SSc.
Spontaneous rheumatoid-like arthritis in a line of mice sensitive to collagen-induced arthritis, Twenty-eight percent of 13-month-old male mice of the high antibody responder line of Biozzi's selection I (HI) spontaneously developed a long-lasting inflammatory arthritis. This disease was clinically and histologically similar to human rheumatoid arthritis. The synovium of joints and some tendons was hypertrophied. with thickening of the synovial cell layer and infiltration by polymorphonuclear and mononuclear leukocytes. In some cases. synovial pannus formation led to destructive damage of articular cartilage and bone. Rheumatoid factor and antinuclear. anti-DNA. and anti-type II collagen (CII) antibodies were often found in the sera of both arthritic mice and clinically normal littermates. The presence of CII autoantibodies in this line of mice suggests that a potentially harmful anti-CII T cell autoimmunity can also develop spontaneously and lead to joint damage. Moreover. HI mice are also susceptible to collagen-induced arthritis. while a closely related mouse line (HII) is resistant to both diseases. These data support the hypothesis that collagen-induced arthritis is pathogenetically related both to this spontaneous arthritis and to rheumatoid arthritis.
Treatment of psoriatic arthritis with oral 1,25-dihydroxyvitamin D3: a pilot study, We conducted a 6-month open-label trial in which 10 patients with active psoriatic arthritis received 2 micrograms of oral 1.25-dihydroxyvitamin D3 daily. Statistically significant improvement was noted in the tender joint count and physician global impression. Of these 10 patients. 4 had substantial (greater than or equal to 50%) improvement. and 3 had moderate (greater than or equal to 25%) improvement in the tender joint count. Two patients were unable to receive therapeutic doses because of hypercalciuria. High-dose vitamin D may be a useful therapeutic agent for psoriatic arthritis.
Rescue of interleukin-1 activity by leucovorin following inhibition by methotrexate in a murine in vitro system, We have recently shown that methotrexate (MTX) inhibits interleukin-1 (IL-1) activity in vitro. This effect may play an important role in the rapid antiinflammatory action of MTX in rheumatoid arthritis. In the present study. we showed that the inhibition of IL-1 activity in vitro by MTX is dependent on folate pathways since. after the addition of leucovorin. the inhibitory effect of MTX was abolished. These findings may shed more light on the mechanism of action of MTX in rheumatoid arthritis. They also point to the fact that some IL-1 activities may be dependent on intracellular folate pathways.
Molecular phenotype of a pediatric small round cell tumor, Molecular probes were used to characterize an unusual small round cell abdominal tumor arising from the fallopian tube of a 15-year-old girl. DNA and RNA extracted from the tumor and adjacent normal tissue was subjected to Southern and Northern blot analysis using a variety of different probes. N-myc oncogene RNA was greatly expressed in the tumor. but was not expressed in normal tissue or amplified in chromosomal DNA. Insulin-like growth factor II RNA was similarly overexpressed in the neoplasm. but not in normal tissue. While histopathologic studies could not distinguish between a neuroectodermal neoplasm and Wilms' tumor. electron microscopy and the pattern of gene expression was most consistent with Wilms' tumor.
Neurodevelopmental outcome of children with evidence of periventricular leukomalacia on late MRI, Fifteen children. 8 months of age or older. from a neonatal follow-up program underwent magnetic resonance imaging and neurologic. cognitive. and language evaluations. Magnetic resonance imaging findings in all children included increased white matter signal on T2-weighted images and ventricular enlargement adjacent to regions of abnormal white matter. The extent of degree of abnormal white matter signal and the degree of sulcal prominence were variable. Twelve children had cerebral palsy; 5 children. 4 of whom had cerebral palsy. manifested significant sensory impairments. The median score on cognitive testing was 89; only 2 children exhibited severe-to-profound cognitive disability. Cognitive scores were stable on retesting. The degree of motor disability was correlated with the extent of white matter signal abnormality; however. cognitive outcome was not related to the extent and degree of white matter signal abnormality or to the degree of sulcal prominence. Despite the association of a major handicapping condition and periventricular leukomalacia. cognitive and language functioning may be relatively spared.
Decrease in cerebral metabolic rate of glucose after high-dose methotrexate in childhood acute lymphocytic leukemia, We measured changes in the regional cerebral metabolic rate of glucose (rCMRGlu) using 18F-fluorodeoxyglucose and positron emission tomography for the assessment of neurotoxicity in childhood acute lymphocytic leukemia treated with high-dose methotrexate (HD-MTX) therapy. We studied 8 children with acute lymphocytic leukemia (mean age: 9.6 years) treated with HD-MTX (200 mg/kg or 2.000 mg/M2) therapy. CMRGlu after HD-MTX therapy was most reduced (40%) in the patient who had central nervous system leukemia and was treated with the largest total doses of both intrathecal MTX (IT-MTX) and HD-MTX. CMRGlu in the whole brain after HD-MTX therapy was reduced by an average of 21% (P less than 0.05). The reductions of CMRGlu in 8 patients were correlated with total doses of both IT-MTX (r = 0.717; P less than 0.05) and systemic HD-MTX (r = 0.784; P less than 0.05). CMRGlu of the cerebral cortex. especially the frontal and occipital cortex. was reduced more noticeably than that of the basal ganglia and white matter. We suggest that the measurement of changes in rCMRGlu after HD-MTX therapy is useful for detecting accumulated MTX neurotoxicity.
Ultrasonography and magnetic resonance imaging in Leigh disease, An infant with Leigh disease. who was the younger sister of a similarly affected infant. had been examined before the onset of the disease. Ultrasonography revealed hyperechoic lesions in the putamen and caudate nucleus during the preclinical stage. At onset. these changes extended into the cerebral cortex and medulla. These lesions were also detected by T2-weighted magnetic resonance imaging (MRI) as areas of increased signal intensity. Her brother demonstrated the same ultrasonographic results; cranial computed tomography disclosed low-density areas in the basal ganglia which were detected as hyperechoic lesions by ultrasonography. These findings suggest that ultrasonography is useful in detecting early intracranial lesions in Leigh disease.
Rett syndrome: findings suggesting axonopathy and mitochondrial abnormalities, We report the histopathologic findings of 3 sural nerve biopsies and 1 muscle biopsy from 3 patients with Rett syndrome. The 3 sural nerve biopsies demonstrated a few ultrastructural abnormalities. including the presence of many Pi-granules and mitochondrial changes in the cytoplasm of Schwann cells. occasional bands of Bungner and onion-bulb formations. and mitochondrial alterations in myelinated axons. Morphometric analysis disclosed reduction in the number of large myelinated fibers with normal densities in comparison to those of an age-matched normal control. Light microscopic examination of the biopsied muscle from a 6-year-old patient with Rett syndrome revealed the existence of many small. dark. angulated fibers with NADH-TR staining. Ultrastructural investigation of the muscle confirmed the presence of the dumbbell-shaped mitochondria. Peripheral nerve involvement and the possibility of mitochondrial abnormalities in Rett syndrome were suggested by the results.
Osmiophilic deposits in cytosomes in Hallervorden-Spatz syndrome, A young child with Hallervorden-Spatz syndrome is presented. She was well until 8 years of age when she lost interest in activities and her school performance declined. At age 11 years. she began having episodes of blepharospasm. accompanied by bilateral ptosis and occasional episodes of oculogyric crisis. By age 12 years. her motor coordination had declined and she began to exhibit evidence of dementia. dystonia. dysarthria. and tremor. Motor incoordination. dystonia. and tremor progressed until the patient was wheel-chair-bound. Multiple tests were performed. including metabolic studies. magnetic resonance imaging. bone marrow biopsy. and electron microscopy of the buffy coat. Both bone marrow and buffy coat revealed inclusions in the cytosomes which were granular and osmiophilic. To our knowledge. this is the third case report of inclusion bodies found in patients with manifestations of Hallervorden-Spatz syndrome. These findings suggest that obtaining a buffy coat and bone marrow biopsy may aid in the diagnosis of Hallervorden-Spatz syndrome and ultimately provide information regarding etiology.
Quantitative histologic study of the sural nerve in Lesch-Nyhan syndrome, The sural nerve of a 31-year-old man with Lesch-Nyhan syndrome obtained at autopsy was studied histologically. Large. myelinated nerve fibers were reduced in number and no myelinated nerve fibers larger than 5 microns were seen. Diameter distribution of myelinated nerve fibers did not demonstrate a bimodal pattern. The density of myelinated nerve fibers was 5.530/mm2 and was decreased as compared to the controls. On electron microscopic examination. lipid-like inclusions were observed in the cytoplasm of some Schwann cells. The role of these inclusions could not be elucidated. but reduction of larger myelinated nerve fibers suggests a peripheral nervous disorder in patients with this syndrome; therefore. patients with Lesch-Nyhan syndrome must be reappraised for disorders of the peripheral nervous system.
Photodynamic therapy in the treatment of squamous cell carcinoma of the head and neck, Photodynamic therapy is an experimental modality for tumor treatment based on the combined action of the tumor-localizing agent. ie. hematoporphyrin derivative. and red light. From 1985 through 1989. 26 patients were treated using hematoporphyrin-derived drugs and 630-nm light delivered by a tunable dye laser. All patients had biopsy-proved squamous cell carcinoma of the head and neck. and they had either failed the traditional treatment modalities or refused conventional therapies. Histological complete responses were achieved in 20 (77%) of 26 patients and partial responses in 5 (19%) of 26 patients for periods up to 48 months. Only minimal toxic reaction was noted in the group. As a guide to treatment planning for a patient group with large tumors. we used an optical dosimetry model based on tissue optics. The rate of complete responses to this treatment was 8 (73%) of 11. Our data indicate that photodynamic therapy is capable of inducing significant clinical and histological responses in the majority of those treated. and in some patients a prolonged response is produced. In certain select head and neck malignancies. photodynamic therapy has an important role as a treatment modality.
Epstein-Barr virus-related antibody. Changes in titers after therapy for nasopharyngeal carcinoma, Using long-term follow-up data from a prospective. collaborative study of 182 North American patients. we evaluated the significance of various serologic tests for antibody to Epstein-Barr virus in predicting outcome after treatment in patients with nasopharyngeal carcinoma. We restudied these patients by examining repeated measurements of each titer at various times after diagnosis and treatment. We looked for associations between trends of titers. measured as the slope of log(titer) against time. and titer level. measured as the mean of log(titer). with the outcome: alive and no evidence of disease; alive with recurrence; or dead of nasopharyngeal carcinoma. We found that posttreatment sequential measurements do not predict outcome.
Improving diagnostic accuracy of cervical metastases with computed tomography and magnetic resonance imaging, Elective neck dissection in patients with head and neck cancer continues to be controversial. The management of these patients would be greatly facilitated by improvements in predicting cervical metastases. Recent investigations have suggested that computed tomography and magnetic resonance imaging are more sensitive in detecting cervical metastases than physical examination. The Department of Otolaryngology at the Ohio State University Hospitals. Columbus. undertook a prospective study to compare the preoperative sensitivities of physical examination. computed tomography. and magnetic resonance imaging with pathologic findings in 27 patients undergoing neck dissections for head and neck cancer. The results indicate that computed tomography and magnetic resonance imaging were more sensitive (84% and 92%. respectively) than physical examination (75%). although the results did not achieve statistical significance. The sensitivity of combined computed tomography and magnetic resonance imaging was 90%.
Distortion product otoacoustic emissions in normal and impaired adult ears, Distortion product otoacoustic emissions (DPOEs) were recorded in a group of normally hearing subjects (29 ears) and a group of subjects whose conditions were diagnosed as sensorineural hearing loss (23 ears) to study any correlation that might exist between DPOE characteristics and hearing impairment of different configurations. Three different DPOE paradigms have been used to investigate the influence of different test parameters on the DPOE data for normal and hearing-impaired ears. All normally hearing ears demonstrated detectable DPOEs. provided that the primary tone level was above a certain value. Hearing-impaired ears produced substantially reduced DPOEs compared with normally hearing subjects when the primary frequencies f1 and f2 corresponded to the region of hearing loss. Our data also suggested that. in general. more than one f2/f1 ratio is needed to examine any particular frequency region. The DPOEs provide frequency-specific information about cochlear function. which after further development. may form a basis for a noninvasive. objective method of evaluating cochlear function.
Audiometric and subjective assessment of hearing handicap, This study compares self-perceived assessment of hearing handicap with audiometrically derived measures of hearing handicap in a sample of elderly persons. Subjects were evaluated by traditional audiometric tests. the Speech Perception in Noise test. and the Hearing Handicap Inventory for the Elderly. a self-assessment questionnaire. Hearing handicap was also calculated by the audiometrically derived American Academy of Otolaryngology (1979) method. Our results are consistent with other studies that indicate a low correspondence between audiometric measures of hearing handicap and self-assessment of hearing handicap. Furthermore. if the Hearing Handicap Inventory for the Elderly is considered the true measure of hearing handicap. our data indicate that the American Academy of Otolaryngology method tends to overestimate handicap among persons with no self-perceived hearing handicap and underestimates handicap among persons with significant self-perceived hearing handicap.
Genetic and familial predisposition to eclampsia and pre-eclampsia in a defined population, Familial predisposition and patterns of genetic inheritance of eclampsia and pre-eclampsia were investigated through three or four generations in 94 families from the homogenous island population of Iceland. The families descended from index women delivered in the years 1931-47 and who had either eclampsia (n = 38) or severe pre-eclampsia (n = 69). Inheritance was followed both through sons and daughters. The prevalence of pre-eclampsia and eclampsia in daughters was significantly higher (23%) than that in daughters-in-law (10%). No difference was noted in the prevalence of these diseases by whether the daughter was born of an eclamptic or pre-eclamptic mother or whether she was a first or later born daughter. There was a non-significantly higher occurrence of pre-eclampsia among grand-daughters than in grand-daughters-in-law. No difference was seen by whether grand-daughters descended through sons or daughters. With increasing numbers of affected daughters or grand-daughters the probability rose of finding more affected women in a family. Hypotheses of single recessive and dominant gene inheritance were compared and maximum likelihood estimates for gene frequency obtained. For a single recessive gene model this was 0.31 reflecting a population prevalence of 9.6%. whereas a dominant model with incomplete penetrance gave 0.14 at 48% gene penetrance. corresponding to a population prevalence of 0.9% homozygous expression of severe disease and 11% heterozygous expression of milder disease. Either genetic model could fit the data.
The use of obstetric analgesia in Sweden 1983-1986, The use of obstetric analgesia was investigated in a Swedish population-based prospective study of 335.207 births. which represents almost all women who had vaginal deliveries in Sweden between 1983 and 1986. Lumbar epidural analgesia (EDA) was used in 16%. paracervical block (PCB) in 12%. pethidine or morphine in 49% and pudendal block in 62%. All four types of analgesia were much more commonly used by nulliparae than multiparae. Variables such as maternal age. smoking. nationality. relationship with the infant's father and gestational age had only moderate influence on the rates of different types of analgesia. EDA and PCB were more frequently used in larger than in smaller hospitals and in the daytime than at night. No such differences were found for pethidine or morphine. or pudendal block. which were administered routinely by midwives.
Experience with a 'physiological' steroid replacement regimen for the establishment of a receptive endometrium in women with premature ovarian failure, Eighteen women with a premature menopause underwent assessment of serial serum oestradiol (E2) and progesterone levels and endometrial histology and function. Patients received continuous transdermal E2. and progesterone either orally or vaginally for 14 days. Physiological levels of E2 were attained. Significantly higher levels of progesterone were achieved with vaginal progesterone (P less than 0.01). Endometrial biopsies obtained during E2 replacement demonstrated normal proliferative features. Expression of an oestrogen related antigen (ER-Ag) was localized in the cytoplasm of the epithelium. After 3 days of progesterone replacement the endometrium showed normal secretory features and expression of ER-Ag in the stroma as well as in the glands. After 7 days of progesterone supplementation. vaginal administration produced a more consistent physiological appearance than oral administration. Thus transdermal E2 combined with vaginal progesterone is a highly satisfactory combination for establishing a physiological endometrium in women with premature ovarian failure.
Reliability of colposcopy and directed punch biopsy, A group of 118 women underwent laser cone biopsy. Data were collected routinely on proforma case notes and entered into a computerized database. The histology of the cone biopsies was compared with that of previous. colposcopically directed punch biopsies. with the cytology of smears taken in the clinic and with the colposcopic diagnosis. The punch biopsy had a 54% false negative rate and neither of the two microinvasive carcinomas biopsied in this way were detected by the biopsy. Ten of 24 women with negative punch biopsies had CIN III in the cone. When the punch biopsy showed CIN II or worse. the cone biopsy confirmed the presence of CIN in 86%. There was some evidence of false negative cone biopsies. The data suggest that management should not be based solely upon the punch biopsy result but should include consideration of the cytology and colposcopy findings. Excisional methods of treatment are more likely to reveal early invasion and adenocarcinoma-in-situ.
The rate of rise of corticotrophin releasing factor and endogenous digoxin-like immunoreactivity in normal and abnormal pregnancy, Maternal plasma concentrations of corticotrophin releasing factor (CRF) and endogenous digoxin-like immunoreactivity (EDLI) were estimated in 80 normal and 88 abnormal pregnancies which were sampled sequentially from 24 weeks gestation to delivery. A slope was fitted for each woman's antenatal EDLI and CRF values. both of which rose significantly during gestation. and the mean of the slopes for the normal and abnormal groups for each value compared. There was no evidence of significant mean differences between groups for EDLI but there was evidence of a significant mean difference for CRF (P less than 0.05). After adjustment for other variables which may affect pregnancy outcome. the slopes for CRF were found not to be significantly related to outcome.
Vitamin B6 in the treatment of the premenstrual syndrome--a review [published erratum appears in Br J Obstet Gynaecol 1991 Mar;98(3):329-30], A search of the literature yielded 12 controlled trials on vitamin B6 in the treatment of the premenstrual syndrome. These are discussed with emphasis on methodological aspects. A major drawback of the trials is the limited number of patients included. The existing evidence of positive effects of vitamin B6 is weak. and some well-designed trials with positive results would be needed to change this view.
Serum soluble interleukin-2 receptor is associated with clinical and pathologic disease status in hairy cell leukemia, Hairy cell leukemia is a chronic lymphoproliferative disorder of B-cell lineage. whose malignant cells express the interleukin-2 (IL-2) receptor. A soluble form of the IL-2 receptor is released by these cells in culture. and the sera of patients with hairy cell leukemia contain elevated levels of this soluble receptor. Four hundred twenty-seven serum samples from 101 patients were analyzed for soluble IL-2 receptor (sIL-2R). The clinical status of patients appeared to be associated with the serum level of sIL-2R. The hairy cell index (a measure of tumor cell burden) was correlated with the square root of the serum sIL-2R level (r = .77). Improved clinical status was associated with decreasing serum sIL-2R levels. whereas disease relapse was associated with increasing levels. Notably. every patient who responded to therapy had a decline in serum sIL-2R level. and every patient with disease progression had an increase in serum sIL-2R level. This phenomenon was observed for several different treatments. including standard-dose interferon. low-dose interferon. and deoxycoformycin. The predictive reliability of this test is currently being prospectively evaluated.
Differentiating agents facilitate infection of myeloid leukemia cell lines by monocytotropic HIV-1 strains [published erratum appears in Blood 1991 Apr 1;77(7):1624, Monocytotropic human immunodeficiency virus type 1 (HIV-1) isolates from patients with acquired immunodeficiency syndrome (AIDS) infect mononuclear phagocytes as well as activated T cells. but do not usually infect immature human myeloid cell lines in vitro. The HL-60 promyelocytic/myeloblastic cell line and the promonocytic line. U937. were susceptible to productive infection by monocytotropic HIV-1 isolates (HIV-1JR-FL and HTLV-IIIBa-L) after treatment with retinoic acid. dimethyl sulfoxide. dibutyryl cAMP. 1.25-dihydroxyvitamin D3 (1.25(OH)2D3). or 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Virus production was only detected when these compounds were added before virus infection. Virus replication did not correlate with CD4 receptor expression because undifferentiated HL-60 cells express CD4 and the level of CD4 expression did not increase after differentiation in the presence of retinoic acid. 1.25(OH)2D3. or TPA. A mature monocytic cell line (THP-1) was capable of infection without pretreatment. and treatment with differentiating agents enhanced virus production. A chronically infected cell line (J-HL-60) was isolated after HIV-1JR-FL infection of HL-60 cells treated with retinoic acid. Virus production in this cell line was enhanced more than 10-fold after differentiation in the presence of 1.25(OH)2D3 or TPA. The majority of virus production by 1.25(OH)2D3-treated J-HL-60 cells was associated with the mature. adherent population. Molecular analysis of a cloned line of J-HL-60 showed integration of a single DNA provirus. These results suggest that cellular factors associated with precursor cell differentiation along the myelomonocytic pathway are required for optimal replication of monocytotropic HIV-1 strains in vitro.
Parvovirus B19-induced perturbation of human megakaryocytopoiesis in vitro, Parvovirus B19 infection leads to transient aplastic crises in individuals with chronic hemolytic anemias or immunodeficiency states. An additional unexplained sequela of B19 infection is thrombocytopenia. Because B19 is known to have a remarkable tropism for human erythropoietic elements. and is not known to replicate in nonerythroid cells. the etiology of this thrombocytopenia is uncertain. We sought to define the pathobiology of B19-associated thrombocytopenia by examining the role of B19 on in vitro megakaryocytopoiesis. B19 infection of normal human bone marrow cells significantly suppressed megakaryocyte (MK) colony formation compared with mock-infected cells. No such inhibition was observed with a nonpathogenic human parvovirus. the adeno-associated virus 2 (AAV). The B19-MK cell interaction was also studied at the molecular level. Whereas low-density bone marrow cells containing erythroid precursor cells supported B19 DNA replication. no viral DNA replication was observed in B19-infected MK-enriched fractions as determined by the presence of viral DNA replicative intermediates on Southern blots. However. analysis of total cytoplasmic RNA isolated from B19-infected MK fractions showed a low-level expression of the B19 genome as detected by quantitative RNA dot blots as well as by Northern analysis. Furthermore. a frame-shift mutation in a recombinant AAV-B19 hybrid genome segment that encodes the viral nonstructural (NS1) protein significantly reduced the observed inhibition of MK colony formation. These studies indicate tissue-tropism of B19 beyond the erythroid progenitor cell. and lend support to the hypothesis that B19 genome expression may be toxic to cell populations that are nonpermissive for viral DNA replication.
Analysis of platelet aggregation disorders based on flow cytometric analysis of membrane glycoprotein IIb-IIIa with conformation-specific monoclonal antibodies, Normal primary platelet aggregation requires agonist-mediated activation of membrane GPIIb-IIIa. binding of fibrinogen to GPIIb-IIIa. and cellular events after ligand binding. PAC1 monoclonal antibody distinguishes between resting and activated states of GPIIb-IIIa. and other antibodies preferentially recognize GPIIb (PMI-1) or IIIa (anti-LIBS1) after the binding of fibrinogen or fibrinogen-mimetic peptides. such as GRGDSP. Using these antibodies and platelet flow cytometry. we studied two distinct persistent platelet aggregation abnormalities. Platelets from a thrombasthenic variant. which contained near-normal amounts of GPIIb-IIIa. failed to aggregate or bind PAC1 in response to agonists. In addition. GRGDSP. which binds to normal GPIIb-IIIa without prior cell activation. failed to increase the binding of PMI-1 or anti-LIBS1 to the thrombasthenic platelets. suggesting a primary defect in ligand binding. Chromatography of detergent-solubilized platelets on a KYGRGDS affinity column confirmed that the patient's GPIIb-IIIa lacked the fibrinogen binding site. In another patient with myelofibrosis and defective aggregation. PAC1 failed to bind to adenosine diphosphate-stimulated platelets. but did bind when protein kinase C was directly activated with phorbol myristate acetate. Furthermore. the binding of PMI-1 and anti-LIBS1 increased in response to GRGDSP. confirming a defect in agonist-mediated fibrinogen receptor activation rather than in fibrinogen binding or events distal to binding. These studies indicate that this immunochemical approach is useful in classification of clinical abnormalities of platelet aggregation as defects in either (a) fibrinogen receptor activation. (b) fibrinogen binding. or (c) postoccupancy events.
Cell membrane expression and functional role of the p75 subunit of interleukin-2 receptor in lymphoproliferative disease of granular lymphocytes, The cell membrane expression and functional role of the interleukin-2 receptor (IL-2R) was analyzed in nine patients with lymphoproliferative disease of granular lymphocytes (LDGL) using monoclonal antibodies (MoAbs) specific for the p75 (TU27) and the p55 (anti-Tac) subunits of IL-2R. Four patients were characterized by the proliferation of CD3+CD8+ granular lymphocytes (GL) expressing the alpha/beta T-cell receptor (T alpha beta) and one case by the proliferation of CD3+CD4-CD8- GL expressing the gamma/delta T-cell receptor (T gamma delta); in four additional cases proliferating cells were CD3 negative GL. Consistent with data observed on normal GL. phenotypic analysis demonstrated that patients' GL lack the expression of the p55 IL-2R. whereas the p75 subunit is constitutionally expressed by expanding GL of both T-cell (either T alpha beta and T gamma delta) and natural killer (NK) origin in variable proportions (11% to 94% of cells). The analysis of the cytotoxic and proliferative activity demonstrated that the anti-p55 MoAb failed to inhibit IL-2-mediated activation. whereas a marked inhibition of both cytotoxicity and proliferation were obtained using the anti-p75 chain specific MoAb. These data indicate that the p75 chain of IL-2R is responsible for IL-2 signal transduction in both CD3+ and CD3- LDGL patients' GL.
Response patterns of hairy cell leukemia to B-cell mitogens and growth factors, The effect of mitogens and/or recombinant B-cell growth factors (M/GFs) on the in vitro growth of hairy cells was examined. Tumor cells were isolated from the spleens of four patients with hairy cell leukemia (HCL) by Ficoll-Hypaque sedimentation and E-rosetting. Enrichment for tumor cells was confirmed with intracytoplasmic immunoglobulin (Ig) staining. tartrate resistant acid phosphatase (TRAP) staining. and staining using monoclonal antibodies (MoAbs) directed at B. T. myeloid. and monocytoid antigens (Ags) in indirect immunofluorescence assays. Tumor cells were B1(CD20)+ B2(CD21)- B4(CD19)+ IL-2R(CD25)+ PCA-1 +/- TRAP+. HCLs neither synthesized DNA nor secreted Ig in response to culture with granulocyte-macrophage colony-stimulating factor (GM-CSF). interleukin-1 alpha (IL-1 alpha). IL-1 beta. IL-2. IL-3. IL-4. IL-5. or IL-6. However. a proliferative response (stimulation index greater than or equal to 3.0) without Ig secretion was triggered in HCLs by mitogens or combinations of GFs. Specifically. DNA synthesis was induced at 3 days in three of four HCL samples cultured with Staphylococcus aureus Cowan A (SAC) or the combination of phorbol ester (TPA) and the calcium ionophore A 23187 (Ca2+); DNA synthesis was triggered later (day 7) by tumor necrosis factor (TNF) or by IL-4 and IL-5. In contrast. the fourth patient. a nonresponder to SAC or TPA/Ca2+. demonstrated increased DNA synthesis at day 3 when cocultured with IL-4 and IL-5. Both autoradiography and staining with antibromodeoxyuridine (BrdU) MoAb conjugated to fluorescein confirmed DNA synthesis by only a minority (5% to 23%) of tumor cells within each patient. Dual staining confirmed that responsive cells were both BrdU+ and TRAP+. DNA synthesis induced by TPA/Ca2+ was blocked specifically by anti-IL-6 Ab; in contrast. the HCL proliferative response to SAC. TNF. or IL-4 and IL-5 was not inhibited by anti-IL-6 Ab. alpha-Interferon inhibited the response to TPA/Ca2+. TNF. or IL-4 and IL-5 without any effect on response to SAC. Finally. peroxidase-antiperoxidase staining demonstrated that HCLs are induced by TPA/Ca2+. but not by SAC. to produce intracytoplasmic IL-6. These data demonstrate IL-4. IL-5. and IL-6 mediated DNA synthesis by HCLs in vitro and suggest a possible in vivo role for these growth factors in the pathophysiology of HCL.
Sickle erythrocytes inhibit human endothelial cell DNA synthesis, Patients with sickle cell anemia experience severe vascular occlusive phenomena including acute pain crisis and cerebral infarction. Obstruction occurs at both the microvascular and the arterial level. and the clinical presentation of vascular events is heterogeneous. suggesting a complex etiology. Interaction between sickle erythrocytes and the endothelium may contribute to vascular occlusion due to alteration of endothelial function. To investigate this hypothesis. human vascular endothelial cells were overlaid with sickle or normal erythrocytes and stimulated to synthesize DNA. The erythrocytes were sedimented onto replicate monolayers by centrifugation for 10 minutes at 17 g to insure contact with the endothelial cells. Incorporation of 3H-thymidine into endothelial cell DNA was markedly inhibited during contact with sickle erythrocytes. This inhibitory effect was enhanced more than twofold when autologous sickle plasma was present during endothelial cell labeling. Normal erythrocytes. with or without autologous plasma. had a modest effect on endothelial cell DNA synthesis. When sickle erythrocytes in autologous sickle plasma were applied to endothelial monolayers for 1 minute. 10 minutes. or 1 hour and then removed. subsequent DNA synthesis by the endothelial cells was inhibited by 30% to 40%. Although adherence of sickle erythrocytes to the endothelial monolayers was observed under these experimental conditions. the effect of sickle erythrocytes on endothelial DNA synthesis occurred in the absence of significant adherence. Hence. human endothelial cell DNA synthesis is partially inhibited by contact with sickle erythrocytes. The inhibitory effect of sickle erythrocytes occurs during a brief (1 minute) contact with the endothelial monolayers. and persists for at least 6 hours of 3H-thymidine labeling. These results indicate that interaction between sickle erythrocytes and the endothelium may result in altered endothelial function. This altered endothelial function may contribute to the development of vascular occlusive phenomena in patients with sickle cell anemia.
Prevalence of symptoms of Raynaud's phenomenon in general practice, OBJECTIVE--To investigate the prevalence of Raynaud's phenomenon in the populations of five general practices. DESIGN--Two populations studied. A questionnaire was given to all new patients attending five general practices over four weeks. and the same questionnaire was sent by post to a random sample of adults from two of the practices. SETTING--General practices in inner London. Merseyside. and Cheshire. SUBJECTS--1532 Patients who completed questionnaires (1119 who attended the surgeries (response rate unknown) and 413 respondents to the postal survey (response rate 69%)). MAIN OUTCOME MEASURES--Response to questionnaire on symptoms of Raynaud's phenomenon: patients were regarded as having the disease if they had episodes of blanching of the fingers that were precipitated by cold and accompanied by sensory symptoms (pins and needles or numbness). Subsequent interview and clinical appraisal of patients with the disease according to their responses to the questionnaire. RESULTS--The prevalence of Raynaud's phenomenon was 11% (26/231) and 19% (34/182) respectively in men and women who completed the postal questionnaire and 16% (56/357) and 21% (157/762) respectively in those who completed the questionnaire when attending their general practice. Thus the overall rates were slightly higher in women. but there was no effect of age even after adjustment of the rates for practice and method of survey. CONCLUSION--The prevalence of Raynaud's phenomenon is high compared with the low number of patients who seek treatment for the disease.
The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. II. Late effects on cutaneous and subcutaneous tissues, The late effects of irradiation with single and fractionated doses of X rays (250 kV) and fast neutrons (42 MeVd----Bc). on the cutaneous and subcutaneous tissues of the pig. have been evaluated from measurements of changes in relative field length. These were determined at intervals of 26-104 weeks after irradiation. For fractionated irradiation with X rays the average fractions exponent. N. obtained from a log-log plot of iso-effect dose (ED50) against fraction number was 0.41. This was independent of the period of assessment. with no significant indication of a time factor. However. the exponent N did vary with the level of effect and was in the range 0.33-0.51. It was greatest for a greater than or equal to 10% reduction in relative field length. Assuming the validity of the linear quadratic model of cell survival. the alpha/beta ratio was 1.95 Gy. However. this model fitted the data less well for the least severe levels of damage. and for these the alpha/beta ratios were not significantly different from zero. Irradiation with fast neutrons showed a small effect of fractionation for doses given in greater than or equal to 6 fractions compared with a single dose. There was no significant increase in iso-effect dose when the dose was given in 30 fractions compared with 6 fractions. The relative biological effectiveness for late cutaneous and subcutaneous damage for the energy of fast neutrons used did not vary with the period of assessment. i.e. 26-52 weeks compared with 65-104 weeks. and was not significantly different from that previously obtained for ischaemic dermal necrosis. seen after higher doses. at 12-20 weeks after irradiation.
Lipiodol computerized tomography: how sensitive and specific is the technique in the diagnosis of hepatocellular carcinoma, Computerized tomography (CT) following the intra-arterial injection of Lipiodol (Lipiodol-CT) was performed on 60 patients suspected of having a hepatocellular carcinoma (HCC). Four main patterns of uptake of the Lipiodol within the liver were seen on CT. Of the 14 well circumscribed lesions with dense homogeneous uptake of Lipiodol. 13 were confirmed to be HCCs. Of the 25 lesions with dense patchy uptake of Lipiodol at the periphery and/or in the centre. 19 were confirmed to be HCCs. In 18 patients. in whom only ill defined faint patchy uptake of Lipiodol was present in the liver. or in whom no hepatic uptake was present at all. only one patient was found later to have an HCC. Of the three hypodense lesions in the liver with no Lipiodol uptake. one was found to be necrotic HCC. one a cholangiocarcinoma and one a regenerative nodule. In the diagnosis of HCC. Lipiodol-CT had an overall sensitivity of 97.1%. an accuracy of 88.3% and a specificity of 76.9%. Of the 34 patients with HCC. only 23 were solitary at diagnosis. The size of the HCCs ranged from 0.8 cm to 11 cm in diameter with the median size at 2.2 cm. Eleven of 34 HCCs (32.3%) were resectable. We conclude that. as part of a screening programme for high risk patients. Lipiodol-CT is useful in the early detection of HCCs. The technique also plays an important role in determining whether the tumour should be resected or managed with chemotherapy. By detecting HCCs while still small. the resectability rate can also be improved.
Current status of antitachycardia devices, With the limitations of currently available modalities for treating clinically important tachycardias. the role of implanted antitachycardia devices will continue to expand. The challenge of the future will not only involve continued technological advances but the socioeconomic impact of this efficacious but expensive mode of therapy in an era of increasing financial restraints. Further studies to definitively prove the efficacy of more widespread use of antitachycardia device therapy will be needed.
An analysis of randomized trials evaluating the effect of cholesterol reduction on total mortality and coronary heart disease incidence, The primary aim of this study was to estimate the relation between cholesterol reduction and total mortality and coronary heart disease (CHD) incidence. Secondarily. the clinical issues of whether the efficacy of cholesterol lowering is dependent on the treatment modality. presence of CHD at baseline. or the simultaneous introduction of other interventions was explored. All randomized clinical intervention trials of cholesterol reduction were used in an overview analysis of total mortality rate and CHD incidence; analysis was performed with weighted linear regression. The trials include those that used primary and secondary intervention. diet and drugs. and single or multifactor design. Nineteen trials were analyzed for total mortality. and of the 19. 16 were analyzed for CHD incidence rate. Net difference in cholesterol change between study groups was used as the independent variable. and the three previously mentioned dichotomous design characteristics were used as additional independent variables. For every 1% reduction in cholesterol. an estimated 2.5% reduction in CHD incidence is indicated (95% CL: 1.1. 3.9). With regard to CHD drug trials tended toward better efficiency in cholesterol lowering than did dietary trials. With regard to total mortality. this efficiency was higher in secondary than in primary preventive trials. The efficiency was also somewhat dependent on the baseline cholesterol level. This study shows that cholesterol reduction is effective in lowering CHD incidence. but cholesterol reduction must be at least 8-9% to be effective in lowering total mortality.
Intermittent claudication, heart disease risk factors, and mortality. The Whitehall Study, In the Whitehall study. 18.388 subjects aged 40-64 years completed a questionnaire on intermittent claudication. Of these subjects. 0.8% (147) and 1% (175) were deemed to have probable intermittent claudication and possible intermittent claudication. respectively. Within the 17-year follow-up period. 38% and 40% of the probable and possible cases. respectively. died. Compared with subjects without claudication. the probable cases suffered increased mortality rates due to coronary heart disease and cerebrovascular disease. but the mortality rate due to noncardiovascular causes was not increased. Possible cases demonstrated increased mortality rates due to cardiovascular and noncardiovascular causes. This difference in mortality pattern may be due to chance. Possible and probable cases still showed increased cardiovascular and all-cause mortality rates after adjusting for coronary risk factors (cardiac ischemia at baseline. systolic blood pressure. plasma cholesterol concentration. smoking behavior. employment grade. and degree of glucose intolerance). Intermittent claudication is independently related to increased mortality rates. It is not a rare condition. and simple questionnaires exist for its detection. The latter can be usefully incorporated in cardiovascular risk assessment and screening programs.
Inotropic effects of angiotensin II on human cardiac muscle in vitro, The direct effects of angiotensin II (Ang II) on human cardiac muscle were investigated using isolated trabecular muscles from failing and functionally normal hearts. Atrial and ventricular trabeculae were studied. Results demonstrated a positive inotropic effect of Ang II on human cardiac muscle. Comparison of the effects of Ang II among groups indicated that the responsiveness tended to be greater in atrial and normal muscle compared with failing muscle. Results of this study also demonstrated heterogeneity in the responsiveness to Ang II among human muscles. which was not correlated with patient age. sex. diagnosis. prior treatment with angiotensin converting enzyme inhibitor. or heart function. A significant correlation between response to Ang II and response to isoproterenol was demonstrated in failing ventricular trabeculae. which may suggest that defects in beta-adrenergic responsiveness in the failing human ventricle are accompanied by a loss of responsiveness to Ang II. Studies were extended to the Syrian cardiomyopathic hamster and its control. A dose-dependent inotropic response occurred in normal hamster ventricular muscle but was significantly diminished in cardiomyopathic muscle. Ang II did not shorten the timing of contraction. and pretreatment with adrenergic-blocking agents did not shift the dose-response curve. indicating that the response was not cyclic AMP mediated. This study demonstrates for the first time that Ang II can exert an inotropic effect directly on human cardiac muscle and confirms that there is a direct effect of Ang II on hamster cardiac muscle. The study further suggests. however. that the inotropic response to Ang II in cardiac muscle is heterogeneous and may be diminished by heart failure.
Functional chiral asymmetry in descending thoracic aorta, To determine whether rotational blood flow or chiral asymmetry exists in the human descending thoracic aorta. we established the ability of color Doppler ultrasound to detect rotational flow in a tornado tube model of a vortex descending fluid column. In a model of the human aortic arch with a pulse duplicator. color Doppler was then used to demonstrate that rotational flow occurs first in the transverse arch and then in the proximal descending thoracic aorta. With the use of color Doppler esophageal echocardiography. 53 patients (age range. 25-78 years; mean age. 56.4 years) were prospectively examined for rotational flow in the descending thoracic aorta. At 10 cm superior to retro-left ventricular position. 22 of 38 patients (58%) revealed rotational flow with obvious diastolic counterclockwise rotation but less obvious systolic clockwise rotation. At 5 cm superior to retro-left ventricular position. 29 of 46 patients (63%) revealed rotational flow with a tendency toward systolic clockwise and diastolic counterclockwise rotation. At the retro-left ventricular position. 47 of 53 patients (89%) revealed rotational flow. usually of a clockwise direction. occurring in systole. Our data suggest that aortic flow is not purely pulsatile and axial but has a rotational component. Rotational flow begins in the aortic arch and is carried through to the descending thoracic aorta. where flow is chirally asymmetric with systolic clockwise and diastolic counterclockwise components. These data demonstrate an aortic rotational flow component that may have physiological implications for organ perfusion.
Abnormal blood pressure response during exercise in hypertrophic cardiomyopathy, To investigate the incidence of abnormal exercise blood pressure responses in hypertrophic cardiomyopathy (HCM) and the potential role of hemodynamic instability as a mechanism of sudden death. 129 consecutive patients with HCM underwent maximal symptom-limited treadmill exercise testing with blood pressure recording. Four patterns of blood pressure response were observed. Forty-three patients had significant exercise hypotension. with either a continuous fall in systolic blood pressure (n = 5) from the start of exercise or a sudden fall in systolic blood pressure (20-100 mm Hg; mean. 40 mm Hg) from the peak value (n = 38). 23 patients had a normal response during exercise but an abnormal blood pressure response in the recovery period. and the remaining 62 patients demonstrated a normal blood pressure response. Patients with exercise hypotension were younger (33 +/- 14 versus 46 +/- 14 years) and more of them had a family history of HCM and sudden death compared with those with a normal blood pressure response (15 of 43 versus 6 of 62 patients). Similarly. the 23 patients with abnormal recovery blood pressure responses were younger (43 +/- 16 versus 46 +/- 14 years) and had a higher incidence of a family history of sudden death (10 of 24 versus 6 of 62 patients). Left ventricular cavity dimensions were smaller in those with exercise hypotension. but 11 other clinical. echocardiographic. and arrhythmic variables were similar. To assess the mechanism of exercise hypotension. 14 patients who demonstrated exercise hypotension and 14 symptomatic patients with a normal exercise blood pressure response underwent invasive hemodynamic exercise testing.
Beta-adrenergic receptors in lymphocyte subsets after exercise. Alterations in normal individuals and patients with congestive heart failure, Dynamic exercise increases the number of beta-adrenergic receptors in mixed lymphocytes by a mechanism that is incompletely understood. In a set of in vivo studies. we have investigated the effects of dynamic exercise on the subset distribution of circulating lymphocytes and on the number of beta-adrenergic receptors in each of these subsets in two groups of patients. In healthy subjects. exercise increased plasma norepinephrine and epinephrine and caused lymphocytosis. Whereas the number of Thelper cells increased only modestly. the number of Tsuppressor/cytotoxic and natural killer cells more than tripled. The number of beta-adrenergic receptors varied among subsets but was not significantly altered by dynamic exercise in any subset except natural killer cells (35% increase. p = 0.0302). In a group of patients with congestive heart failure. dynamic exercise increased plasma norepinephrine but did not alter plasma epinephrine and did not cause significant lymphocytosis. We did not detect any significant alterations of circulating leukocyte subsets or beta-adrenergic receptors in any of these subsets after exercise. A combined analysis of healthy patients and heart failure patients revealed a significant correlation between increases in plasma epinephrine and increases in circulating lymphocytes. We conclude that the exercise-induced increase in beta-adrenergic receptors of mixed lymphocytes is predominantly caused by a redistribution of circulating cell subsets that differ in their beta-adrenergic receptor number. This appears to be mediated by epinephrine rather than norepinephrine.
Prostacyclin and acetylcholine as screening agents for acute pulmonary vasodilator responsiveness in primary pulmonary hypertension, Epoprostenol sodium (prostacyclin) administered intravenously is considered the standard for assessing the ability of the pulmonary circulation to vasodilate. At present. epoprostenol sodium is an investigational drug that has limited availability. In contrast. acetylcholine. also a pulmonary vasodilator. is readily available. Therefore. we assessed the feasibility of using acetylcholine as an alternative to prostacyclin in testing for the capacity of the pulmonary vasculature to vasodilate. Twenty-three patients with primary pulmonary hypertension (mean pulmonary arterial pressure. 58.5 +/- 13.4 mm Hg) received incremental infusions of prostacyclin and acetylcholine to predetermined maximal infusion rates as part of a battery of vasodilator agents administered according to standard protocols (mean. 5.4 +/- 1.2 agents/patient; range. 3-8 agents/patient); the administration of the different agents was timed to avoid synergistic effects. Of all the agents tested. prostacyclin and acetylcholine were most consistently effective in evoking acute pulmonary vasodilation. and both seemed to distinguish patients capable of manifesting acute pulmonary vasodilation from those who were not. However. at maximal doses set by protocol. prostacyclin generally elicited a greater vasodilator response than acetylcholine. The difference in magnitude of response may have been due to use of prescribed dosages of acetylcholine that were submaximal. In other respects. the two agents were similar; both were equally well-tolerated. and side effects were mild and resolved rapidly when the vasodilator infusions were stopped. We conclude that in the majority of patients with primary pulmonary hypertension. acetylcholine appears to be an effective and available substitute for prostacyclin in screening for pulmonary vasodilator responsiveness.
Differentiation of ventricular tachyarrhythmias, Implantable devices capable of several modes of therapy will require differentiation of various ventricular tachyarrhythmias. Three methods of arrhythmia analysis. magnitude-squared coherence. ventricular rate. and irregularity of cycle length were performed for 45 episodes of induced ventricular tachyarrhythmia in 15 patients. Differentiation of monomorphic ventricular tachycardia from polymorphic ventricular tachycardia and ventricular fibrillation was possible by mean magnitude-squared coherence. less possible by rate. and not possible by beat-to-beat irregularity. Faster monomorphic ventricular tachycardia overlapped with rates of polymorphic ventricular tachycardia and ventricular fibrillation. Differentiation of polymorphic ventricular tachycardia and ventricular fibrillation was not possible by rate or irregularity. A progressive decrease in mean magnitude-squared coherence from monomorphic ventricular tachycardia to polymorphic ventricular tachycardia to ventricular fibrillation strengthens previous observations that coherence is a measure of rhythm "organization.".
Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features, The clinical. electrocardiographic. and coronary hemodynamic responses to sequential 90-second occlusions of the left anterior descending coronary artery in 12 patients undergoing elective percutaneous transluminal coronary angioplasty were examined. Transmyocardial lactate metabolism was examined in an additional group of seven patients with clinical and hemodynamic features similar to the first group. We noted that in comparison with the initial balloon occlusion the second occlusion was characterized by less subjective anginal discomfort. less ST segment shift (0.44 +/- 0.13 versus 0.21 +/- 0.07 mV. p = 0.01). and lower mean pulmonary artery pressure (25 +/- 1.0 versus 20 +/- 1.7 mm Hg. p = 0.005). In addition. for the same heart rate-blood pressure product. cardiac vein flow during the second inflation was significantly lower than that recorded during the first inflation (96 +/- 1.4 versus 83 +/- 2.4 ml/min. p = 0.005). Finally. there was significantly less myocardial lactate production during the second inflation (lactate extraction ratio: first inflation. -0.11 +/- 0.03; second inflation. -0.03 +/- 0.02; p = 0.04). We conclude that the lessened clinical. electrocardiographic. hemodynamic. and metabolic evidence of myocardial ischemia during the second of two periods of coronary artery occlusion during percutaneous transluminal coronary angioplasty supports the concept of adaptation to myocardial ischemia (ischemic preconditioning).
Intracoronary urokinase for intracoronary thrombus accumulation complicating percutaneous transluminal coronary angioplasty in acute ischemic syndromes, Intracoronary urokinase was used to treat flow-limiting intracoronary thrombus accumulation that complicated successful percutaneous transluminal coronary angioplasty (PTCA) during acute ischemic syndromes in 48 patients who were followed up through the acute phase of their illness. The study group comprised 10 patients with unstable angina pectoris. 18 patients with an evolving acute myocardial infarction. and 20 patients with postinfarction angina. The initial mean percent coronary diameter stenosis for the entire population was 95 +/- 7% and decreased with initial PTCA to 41 +/- 20% (p less than 0.001). with improved corresponding coronary flow by Thrombolysis in Myocardial Infarction trial (TIMI) grade. However. thrombus accumulation then resulted in a significant increase in percent diameter stenosis to 83 +/- 17% (p less than 0.001); a corresponding significant reduction in coronary flow also occurred by TIMI grade. After administration of intracoronary urokinase (mean dose. 141.000 units; range. 100.000-250.000 units during an average period of 34 minutes). with additional PTCA. mean percent diameter stenosis significantly decreased to 34 +/- 17% (p less than 0.001); a correspondingly significant improvement in mean coronary flow by TIMI grade occurred to 2.9 +/- 0.2. Overall. the angiographic success rate was 90%. There were no ischemic events requiring repeat PTCA and no procedure-related myocardial infarctions or deaths before hospital discharge. One patient was referred for urgent coronary artery bypass graft surgery after a successful PTCA. Plasma fibrinogen levels were obtained in 15 patients. and in no patient was the level below normal for our laboratory.
Coronary atherosclerosis is associated with left ventricular dysfunction and dilatation in aortic stenosis, Patients with aortic stenosis develop widely variable patterns of left ventricular hypertrophy and dysfunction. We postulated that coronary atherosclerosis (CAD) may be associated with impaired left ventricular function and chamber dilatation in patients with aortic stenosis. Left ventricular mass and volumes were quantified from two-dimensional echocardiography and correlated with coronary angiography in 78 patients with severe aortic stenosis and no previous myocardial infarction or regional wall motion abnormalities. Eighteen patients (group 1) had smooth coronary arteries. 25 patients had irregular coronary arteries with 50% or less stenosis (group 2). and 35 patients had obstructive CAD (group 3). Even though the calculated valve area was similar in all three study groups. group 1 patients had higher values for ejection fraction (65 +/- 9%. 51 +/- 17%. and 48 +/- 13%; p = 0.0002). systolic mass-to-volume ratio (9.2 +/- 3.9. 5.6 +/- 2.8. and 5.2 +/- 2.2; p = 0.0001). and cardiac index (2.9 +/- 0.7. 2.5 +/- 0.7. and 2.3 +/- 0.6 l/min.min2; p = 0.015) than patients in groups 2 and 3. respectively (mean +/- SD). Mean circumferential wall stress was inversely related to severity of CAD. Multivariate analysis showed that CAD is an independent predictor of ejection fraction and mass-to-volume ratio in this group of patients. Thus. in an elderly population with severe aortic stenosis. patients with both obstructive and nonobstructive CAD have an increased incidence of left ventricular enlargement and systolic dysfunction.
Left ventricular regional wall stress in dilated cardiomyopathy, Left ventriculography with simultaneous pressure micromanometry was performed in 11 normal control subjects and 17 patients with dilated cardiomyopathy (DCM). Left ventricular silhouettes in the right anterior oblique projection were divided into eight areas. and regional wall stress was computed by Janz's method in each area excluding the two most basal areas. Wall stress was higher in DCM patients than in control subjects (p less than 0.01). The percent area changes from end diastole to end systole in each area were lower in DCM patients than in control subjects (mean for six areas. 22 +/- 14% versus 54 +/- 9%. respectively. p less than 0.01). but the coefficient of variation for the percent area changes in the six areas of the left ventricle in DCM patients was greater than that in control subjects (32 +/- 17% versus 15 +/- 4%. respectively. p less than 0.01). indicating regional differences in hypokinesis. There was a significant negative correlation between end-systolic regional wall stress and percent area change (r = -0.60 to -0.86. p less than 0.05) in each area. Thus. excessive regional afterload may play an important role in causing regional hypokinesis in DCM.
Body surface mapping of high-frequency components in the terminal portion during QRS complex for the prediction of ventricular tachycardia in patients with previous myocardial infarction, To study the clinical significance of terminal QRS high-frequency components for the prediction of ventricular tachycardia. an 87-lead body surface signal-averaged mapping was performed in 21 healthy subjects (control) and in 41 patients with previous myocardial infarction (anterior. 20; inferior. 21). Mapping data were analyzed and averaged (129.7 +/- 26.5 beats) for 160 seconds. and the signal-averaged beat was filtered with a bidirectional bandwidth (80-250 Hz) digital filter. J-point was determined from the 87-lead RMS voltage of nonfiltered QRS. For each lead. we calculated the sum of the absolute value of filtered QRS from 20 msec ahead of the J-point to the J-point (A-20). The body surface distribution of A-20 was expressed as A-20 map. The maxima in A-20 maps were mainly located on the upper sternal region in healthy subjects. on the left anterior chest in patients with previous anterior myocardial infarction. and on the central anterior chest in patients with previous inferior myocardial infarction. In the patients in both the group with anterior myocardial infarction and the group with inferior myocardial infarction. the value of maximum was significantly greater than in the subjects in the control group (0.181 +/- 0.086 and 0.138 +/- 0.048. respectively. vs. 0.075 +/- 0.031 mV.msec; p less than 0.01). In patients with myocardial infarction (n = 41). the value of maximum was significantly greater with ventricular tachycardia (n = 11) than without ventricular tachycardia (n = 30) (0.240 +/- 0.076 vs. 0.130 +/- 0.043 mV.msec; p less than 0.01).
Effect of nontransmural necrosis on epicardial potential fields. Correlation with fiber direction, The effect of nontransmural necrosis on epicardial potential distributions was studied in 13 dogs. In previous studies. left ventricular epicardial pacing generated epicardial potential maps at QRS onset with a negative central area and two positive areas that faced the portions of the wavefront propagating along fibers. Subsequently. the positive areas expanded in a counterclockwise direction by 90 degrees to 120 degrees. In those studies. the rotatory expansion of the positive areas was tentatively attributed to the spread of excitation through deep myocardial layers. where fiber direction rotated counterclockwise from epicardium to endocardium. To test this hypothesis. we tried to interrupt the counterclockwise expansion of the positive area by creating localized. nontransmural necrosis at various depths in the left ventricular wall by injection of formalin or application of laser energy. Epicardial potential maps were obtained from a grid of 12 x 15 electrodes on a 44 x 56-mm area. Epicardial pacing from selected sites generated epicardial maps in which some positive areas were missing compared with controls. The direction of the straight line joining the pacing site to the site of missing positivity correlated well with the average fiber direction in the necrotic mass (r = 0.82. p less than 0.01). Angle between epicardial fiber direction and the straight line described above correlated well with the average depth of the necrosis. expressed as percent of the wall thickness (r = 0.95. p less than 0.01). These data support the hypothesis that the counterclockwise expansion of the epicardial positivity occurring after epicardial pacing results from excitation spreading along deep fibers.
Bleeding time prolongation with streptokinase and its reduction with 1-desamino-8-D-arginine vasopressin, The mechanism by which treatment with thrombolytic agents causes bleeding is not known. Recently. frequency of bleeding events has been shown to correlate with bleeding time. particularly in individuals treated with aspirin. We examined the effects of streptokinase (20.000-60.000 IU/kg) on bleeding time in 40 rabbits pretreated with aspirin. a model for fibrinolytic therapy. We then tested the effects of 1-desamino-8-D-arginine vasopressin (DDAVP) (0.3 microgram/kg). an agent known to reduce bleeding time in a variety of bleeding disorders. in 20 rabbits and compared the results with those of a control group of rabbits receiving normal saline placebo. Aspirin increased the bleeding time from a baseline mean +/- SEM value of 119 +/- 15 to 191 +/- 34 seconds in the control group and from 114 +/- 6 to 188 +/- 18 seconds in the experimental group. The addition of streptokinase increased the bleeding time to 592 +/- 119 seconds in the control group and 810 +/- 114 seconds in the experimental group (p = NS). Subsequent infusion of DDAVP decreased the bleeding time in the experimental group to 302 +/- 29 seconds (p less than 0.01 versus streptokinase) compared with 572 +/- 79 seconds (p = NS versus streptokinase) in the control animals given saline placebo. In a subset of rabbits receiving aspirin and streptokinase (40.000-60.000 IU/kg). samples were obtained for platelet aggregation (n = 16). von Willebrand factor antigen concentration (n = 17). and von Willebrand factor multimer distribution (n = 14). Maximal rates of ADP-induced platelet aggregation were not affected by DDAVP infusion. nor was the plasma concentration of von Willebrand factor antigen. quantified by an immunoradiometric assay. significantly affected by DDAVP infusion. Furthermore. the von Willebrand factor multimer ratio decreased with DDAVP administration. These findings indicate that aspirin and streptokinase combined result in a marked increase in bleeding time that can be reduced by DDAVP. This effect of DDAVP is not accompanied by an increase in platelet aggregation response. plasma von Willebrand factor antigen concentration. or von Willebrand factor multimer ratio.
Area-at-risk determination by technetium-99m-hexakis-2-methoxyisobutyl isonitrile in experimental reperfused myocardial infarction, In a canine model of reperfused myocardial infarction. we tested the hypothesis that after reperfusion. technetium-99m-hexakis-2-methoxyisobutyl isonitrile (Tc-MIBI) tomographic imaging still reflects occlusion blood flow when the tracer is injected before reperfusion. Nine anesthetized dogs underwent 2 hours of coronary occlusion followed by 3 hours of reperfusion ending by being killed. Reference coronary blood flow was determined by radioactive microspheres injected during occlusion and after reperfusion. Biopsies in normal and ischemic myocardium and single photon emission computed tomography were obtained during occlusion and after reperfusion. Circumferential profiles were applied to axial slices divided into 5-degree sectors. The sectors were divided into 3 groups selected on the occlusion acquisition (normal. mildly reduced. and severely reduced) and compared with the postreperfusion acquisition. Tissular Tc-MIBI kinetics was assessed both by Tc-MIBI time-activity curves of normal and ischemic tissue obtained by biopsy and by the relative gradient between normal. ischemic. and necrotic postmortem tissue samples. In biopsy samples. Tc-MIBI content remained unchanged during occlusion and after reperfusion in normal as well as in ischemic tissue (4.662 +/- 2.237 counts/min/mg vs. 4.599 +/- 1.577 counts/min/mg in normal tissue. NS; 941 +/- 903 counts/min/mg vs. 1.087 +/- 721 counts/min/mg in ischemic tissue. NS). In postmortem tissue samples. there was a good correlation between occlusion microsphere blood flow and Tc-MIBI activity (r = 0.91). In the necrotic samples. mean normalized Tc-MIBI activity (10 +/- 17%) was slightly higher than the normalized microsphere blood flow (3 +/- 3%. p less than 0.001) but markedly lower than the normalized microsphere reperfusion blood flow (63 +/- 31%. p less than 0.001). Comparing the single photon emission computed tomographic acquisitions before and after reperfusion. Tc-MIBI activity remained unchanged in normal as well as in mildly reduced or severely reduced segments. Thus. our data are consistent with the hypothesis that Tc-MIBI traces blood flow. does not redistribute significantly despite reperfusion. and can be used for imaging the area at risk.
Effects of brief coronary occlusion and reperfusion on porcine coronary artery reactivity, The loss of coronary vasodilator reserve after ischemia-reperfusion may be due to endothelial injury. and this vascular dysfunction may contribute to functional alterations observed after ischemia. To determine whether endothelial dysfunction occurs after relatively brief periods of moderate low-flow ischemia in vivo. open-chest swine were subjected to 15 minutes of critical. subtotal left anterior descending coronary artery occlusion (80%) followed by 60 minutes of reperfusion. Serial measurements of regional coronary flow were made with the radiolabeled microsphere technique. After 60 minutes of reperfusion. the left anterior descending coronary artery was excised together with a section of the normally perfused left circumflex coronary artery to examine in vitro the relaxations to the endothelium-dependent dilators ADP and bradykinin and to the endothelial-independent dilators sodium nitroprusside and adenosine. Contractions to serotonin in quiescent rings were also examined. Endocardial and transmural blood flows recovered to preocclusion levels within 60 minutes of reperfusion. as did the epicardial-to-endocardial ratio. Vascular responses in isolated. reperfused left anterior descending coronary artery rings were significantly different from responses in control left circumflex coronary artery rings. Endothelium-dependent relaxations to adenosine diphosphate and bradykinin were significantly depressed in the left anterior descending coronary artery rings compared with left circumflex coronary artery rings (p less than 0.05). Serotonin-induced contractions were significantly greater in occluded-reperfused left anterior descending than in left circumflex coronary arteries (p less than 0.05). Relaxations to adenosine and sodium nitroprusside were not significantly different between the two groups.
Fibrinopeptide A is released into the coronary circulation after coronary spasm, To examine whether acute myocardial ischemia activates the coagulation system and platelet activation in the coronary circulation. we measured plasma levels of fibrinopeptide A and beta-thromboglobulin in the coronary sinus and the aortic root simultaneously in 15 patients with coronary spastic angina before and after the left coronary spasm induced by intracoronary injection of acetylcholine and in 15 patients with stable exertional angina before and after acute myocardial ischemia induced by rapid atrial pacing. Fifteen patients with chest pain but normal coronary arteries and no coronary spasm served as controls. The coronary sinus-arterial difference of fibrinopeptide A increased markedly (p less than 0.001) from 0.1 +/- 0.2 to 4.3 +/- 0.7 ng/ml after the anginal attacks in the coronary spastic angina group. However. fibrinopeptide A levels remained unchanged after the attacks in the stable exertional angina group and after intracoronary injection of acetylcholine in the control group. Plasma beta-thromboglobulin levels remained unchanged after the attacks in both patient groups and after acetylcholine in the control group. Our data indicate that coronary spasm induces thrombin generation and may lead to thrombus formation in the coronary artery involved. but pacing-induced ischemia does not activate the coagulation system.
Increased endothelin in experimental heart failure, Recent studies demonstrate that endothelin. a potent endogenous vasoconstrictor peptide. circulates in plasma of normal animals and humans. However. the role of this peptide in pathophysiological states remains unclear. The present study was designed to test the hypothesis that circulating endothelin concentrations are increased in experimental congestive heart failure (CHF). a pathophysiological state characterized by activation of vasoconstrictor mechanisms. In anesthetized dogs with CHF produced by 8 days of rapid ventricular pacing (n = 28). circulating plasma endothelin was increased compared with values for normal controls (n = 28; 20.4 +/- 1.4 versus 9.7 +/- 0.9 pg/ml. respectively; p less than 0.0001). A plasma endothelin level of more than 14.0 was a sensitive and specific indicator of significant CHF. Moreover. within the group with experimental CHF. right atrial pressure and pulmonary capillary wedge pressure correlated independently with circulating endothelin levels. Based on recent studies demonstrating the physiological actions of twofold increases in circulating endothelin. as observed in the present study. a possible role for endothelin in the pathophysiology of CHF is advanced.
Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias, Although work on class III antiarrhythmics remains at an early stage. these agents still appear to possess greater efficacy and less proarrhythmia than conventional class I agents in those experimental arrhythmia models considered to be most representative of the clinical situation. Although prolongation of repolarization carries with its own tendency for pause-dependent arrhythmogenesis (i.e.. torsade de pointes). available data suggest that this may be a function of nonspecificity in potassium channel block rather than a general characteristic of class III activity. The availability of new and more selective blockers of specific cardiac potassium channels under development as class III agents have already helped to clarify basic questions about the ionic mechanism of repolarization in the heart. and one hopes that a growing clinical data base will eventually determine the relative safety and efficacy of these agents in preventing symptomatic and life-threatening arrhythmias.
Clinical management of port-wine stain in infants and young children using the flashlamp-pulsed dye laser, The flashlamp-pulsed dye laser (FLPDL) at 585 nm. a wavelength well absorbed by oxyhemoglobin. causes highly selective vascular injury. In addition. the 450 microsecond pulse duration produced by this laser approximates the thermal relaxation time for dermal blood vessels thereby confining the energy to the target. This new laser effects excellent lightening of port-wine stain (PWS) in infants and young children without the adverse complications of hypertrophic scarring. permanent pigmentation abnormality. or textural changes. complications often seen with conventional laser systems. The FLPDL now permits treatment of this patient population expected to gain the most benefit from early laser therapy in a much safer manner. before the psychological complications of being a "marked" person develop. The purpose of this report is to: (1) describe the theoretical considerations behind achieving selective removal of PWS that can be understood and used by a nonsurgically-oriented practitioner; and (2) describe the practical application of the device used in the clinical management of infants and young children.
A combined electromyographic and cineradiologic investigation in patients with defecation disorders, Records from 20 patients on whom defecography and electromyography were performed simultaneously because of defecation disorders were analyzed. According to the electromyographic investigation. the patients could be divided into three main groups: 1) normal sphincter reaction; 2) paradoxical sphincter reaction; and 3) combined reaction. Group A was characterized by a marked reduction of muscular activity during emptying and a pronounced closing reflex after emptying. This was followed by return of normal tonic activity. Patients in group B had no relaxation of the sphincters during emptying but a pronounced increased activity in the external sphincter and the puborectalis muscle. They also had severe emptying difficulties at defecography. No closing reflex was seen. In group C the electrical activity in the sphincters increased during moderate straining and when emptying was complete a clear closing reflex was seen. In this study. a dynamic visualization of the defecation together with a registration of electromyographic activity in the striated anal sphincters was performed. It was shown that patients with paradoxical sphincter reaction were lacking a closing reflex after emptying was complete. This has not been reported previously and is important evidence for the paradoxical defecation pattern. It was also shown that the patients with rectoceles had paradoxical sphincter reaction.
Erythrocyte stearic acid desaturation in patients with colorectal carcinoma, The erythrocyte stearic:oleic acid ratio (saturation index) was investigated as a means of differentiating between control subjects (n = 146) and patients with benign (n = 48) and malignant (n = 117) colorectal disease and patients undergoing postoperative follow-up after curative resection (n = 49). Erythrocyte fatty acid profiles were determined by gas liquid chromatography. Neither age. sex. Dukes' stage. nor degree of differentiation of the tumors had a significant effect on the erythrocyte saturation index. The erythrocyte saturation index was lower in patients with primary and recurrent colorectal cancer compared with control subjects and patients with inflammatory bowel disease or benign colonic polyps (P less than 0.0001). The erythrocyte saturation index was not found to be useful in the postoperative follow-up of these patients. Using both saturation index and age as a means of differentiating between patients with primary colorectal cancer and control subjects gave a sensitivity of 67 percent and a specificity of 81 percent.
Characterization in vitro of a human tumor necrosis factor-binding protein. A soluble form of a tumor necrosis factor receptor, Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammatory responses. A cysteine-rich. highly glycosylated 30-kD TNF-binding protein (TNF-BP) purified from urine may have a role in regulation because it protects in vitro against the biological effects of TNF. The cytotoxic effect of TNF on the fibrosarcoma cell line WEHI 164 was inhibited by 50% at a 10-fold excess of TNF-BP. The binding of TNF to the receptor was partially reversed after the addition of TNF-BP. Results from biosynthetic labeling of cells with 35S-cysteine followed by immunoprecipitation with anti-TNF-BP indicated that TNF-BP is formed and released at the cell surface by cleavage because no corresponding cellular polypeptide was observed. A cellular 60-kD polypeptide. which was immunoprecipitated with anti-TNF-BP. may correspond to the transmembrane TNF-receptor molecule and be the precursor of TNF-BP. Thus. TNF-BP appears to be a soluble form of a transmembrane TNF-receptor. Moreover our results demonstrate that the production of TNF-BP is increased when the TNF receptor is downregulated in cells by treatment with TNF or by activation of protein kinase C with phorbol esters. TNF-BP may be an important agent that blocks harmful effects of TNF. and. therefore. useful in clinical applications.
Glucocorticoids inhibit neurogenic plasma extravasation and prevent virus-potentiated extravasation in the rat trachea, Capsaicin increases the permeability of blood vessels in the rat tracheal mucosa through a mechanism involving the release of tachykinins from sensory nerves. This capsaicin-induced increase in vascular permeability is potentiated by viral infections of the respiratory tract. The present study was done to determine whether this "neurogenic plasma extravasation" can be inhibited by glucocorticoids. to learn the time course of this inhibition. and to determine whether glucocorticoids can prevent the potentiating effect of viral respiratory infections on neurogenic plasma extravasation. Groups of pathogen-free F344 rats were treated with dexamethasone for 2 or 8 h (4 mg/kg i.p.) or 48 or 120 h (0.5-4 mg/kg per d i.p.). Another group of rats was treated with dexamethasone for 120 h following the intranasal inoculation of Sendai virus. The magnitude of plasma extravasation produced by capsaicin or substance P was assessed after this treatment by using Monastral blue pigment and Evans blue dye as intravascular tracers. We found that dexamethasone reduced. in a dose-dependent fashion. the magnitude of plasma extravasation produced in the rat trachea by capsaicin and substance P. Significant inhibition was produced by a dose of dexamethasone as small as 0.5 mg/kg i.p. The effect of dexamethasone had a latency of several hours and reached a maximum after 2 d of treatment. Furthermore. dexamethasone prevented the potentiation of neurogenic plasma extravasation usually present after 5 d of Sendai virus respiratory infection.
Uroporphyrinogen decarboxylase: a splice site mutation causes the deletion of exon 6 in multiple families with porphyria cutanea tarda, Uroporphyrinogen decarboxylase (URO-D) is a cytosolic heme-biosynthetic enzyme that converts uroporphyrinogen to coproporphyrinogen. Defects at the uroporphyrinogen decarboxylase locus cause the human genetic disease familial porphyria cutanea tarda. A splice site mutation has been found in a pedigree with familial porphyria cutanea tarda that causes exon 6 to be deleted from the mRNA. The intron/exon junctions on either side of exon 6 fall between codons. so the resulting protein is shorter than the normal protein. missing only the amino acids coded by exon 6. The shortened protein lacks catalytic activity. is rapidly degraded when exposed to human lymphocyte lysates. and is not detectable by Western blot analysis in lymphocyte lysates derived from affected individuals. The mutation was detected in five of 22 unrelated familial porphyria cutanea tarda pedigrees tested. so it appears to be common. This is the first splice site mutation to be found at the URO-D locus. and the first mutation that causes familial porphyria cutanea tarda to be found in more than one pedigree.
Immunogenicity in animals of a polysaccharide-protein conjugate vaccine against type III group B Streptococcus, The native capsular polysaccharide of type III group B Streptococcus elicits a specific antibody response in only 60% of nonimmune human subjects. To enhance the immunogenicity of this polysaccharide. we coupled the type III polysaccharide to tetanus toxoid. Prior to coupling. aldehyde groups were introduced on the polysaccharide by controlled periodate oxidation. resulting in the conversion of 25% of the sialic acid residues of the polysaccharide to residues of the 8-carbon analogue of sialic acid. 5-acetamido-3.5-dideoxy-D-galactosyloctulosonic acid. Tetanus toxoid was conjugated to the polysaccharide by reductive amination. via the free aldehyde groups present on the partially oxidized sialic acid residues. Rabbits vaccinated with the conjugate vaccine produced IgG antibodies that reacted with the native type III group B streptococcal polysaccharide (3/3 rabbits). while rabbits immunized with the unconjugated type III polysaccharide failed to respond (0/3 rabbits). Sera from animals receiving conjugate vaccine opsonized type III group B streptococci for phagocytic killing by human peripheral blood leukocytes. and protected mice against lethal challenge with live type III group B streptococci. The results suggest that this method of conjugation to a carrier protein may be a useful strategy to improve the immunogenicity of the type III group B Streptococcus polysaccharide in human subjects.
Noncoordinate regulation of alpha-1 adrenoreceptor coupling and reexpression of alpha skeletal actin in myocardial infarction-induced left ventricular failure in rats, To determine the effects of myocardial infarction-induced left ventricular failure on the regulation of surface alpha-1 adrenoreceptors and signal transduction. large infarcts were produced in rats and the animals killed seven days later. After the documentation of impaired left ventricular pump performance. radioligand binding studies of the alpha-1 adrenoreceptor. norepinephrine-stimulated phosphoinositol turnover. and ADP ribosylation of 41 kD substrate by pertussis toxin were examined in the hypertrophying unaffected myocardium. Moreover. the expression of sarcomeric actin isoforms was analyzed by Northern blots and hybridization with specific oligonucleotide probes. Alpha-1 adrenoreceptor density was found not to be altered in membranes obtained from the spared left ventricular tissue. whereas phosphoinositol turnover was increased 3.1-fold in the viable myocytes of infarcted hearts. Furthermore. pertussis toxin substrate was augmented 2.5-fold in membranes prepared from the surviving left ventricular myocardium. Finally. an upregulation of the skeletal actin isoform was detected in the tissue of the failing left ventricle. In conclusion. the possibility is raised that in the presence of severe myocardial dysfunction and ongoing reactive hypertrophy. effector pathways linked to the alpha-1 adrenoreceptor may stimulate the myocyte hypertrophic response which would tend to normalize cardiac hemodynamics. The reexpression of alpha skeletal actin may be a molecular indicator of the persistance of an overload on the myocardium.
A mutation in the gene for type III procollagen (COL3A1) in a family with aortic aneurysms, Experiments were carried out to test the hypothesis that familial aortic aneurysms. either thoracic or abdominal. are caused by mutations in the gene for type III procollagen (COL3A1) similar to mutations in the same gene that have been shown to cause rupture of aorta and other disastrous consequences in the rare genetic disorder known as Ehlers-Danlos syndrome type IV. A family was identified through a 37-yr-old female captain in the United States Air Force who was scrutinized only because many of her direct blood relatives had died of ruptured aortic aneurysms. The woman was heterozygous for a single-base mutation that converted the codon for glycine 619 of the alpha 1(III) chain of type III procollagen to a codon for arginine. Studies on cultured skin fibroblasts demonstrated the mutation caused synthesis of type III procollagen that had a decreased temperature for thermal unfolding of the protein. The same mutation was identified in DNA extracted from pathologic specimens from her mother who had died at the age of 34 and a maternal aunt who died at the age of 55 of aortic aneurysms. Examination of DNA from samples of saliva revealed that the woman's daughter. her son. a brother. and an aunt also had the mutation. The results demonstrated that mutations in the type III procollagen gene can cause familial aortic aneurysms and that DNA tests for such mutations can identify individuals at risk for aneurysms.
Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy, Lymphoid cells were thought to be uniquely susceptible to excess 2'-deoxyadenosine (dAdo). when exposed to inhibitors of adenosine deaminase (ADA). However. we now find that human monocytes are as sensitive as lymphocytes to dAdo or to the ADA-resistant congener 2-chloro-2'-deoxyadenosine (CldAdo). Monocytes exposed in vitro to CldAdo. or to dAdo plus deoxycoformycin rapidly developed DNA strand breaks. Both the DNA damage and the toxicity of CldAdo or dAdo toward monocytes were blocked by deoxycytidine. but not by inhibitors of poly(ADP-ribose) polymerase. A partial decrease in RNA synthesis and a gradual decline of cellular NAD were early biochemical events associated with monocyte DNA damage. Low CldAdo concentrations (5-20 nM) inhibited monocyte phagocytosis and reduced the release of interleukin 6. Higher CldAdo concentrations led to a dose- and time-dependent loss of monocyte viability. Circulating monocytes disappeared within 1 wk in patients with cutaneous T cell lymphoma or with rheumatoid arthritis during continuous CldAdo infusion. The marked sensitivity of human monocyte function and survival to CldAdo in vitro. together with the monocyte depletion in patients receiving CldAdo chemotherapy. suggests that CldAdo or other dAdo analogues offer a novel therapeutic strategy for chronic inflammatory and autoimmune diseases characterized by inappropriate monocyte deployment or function.
Elevated insulin receptor content in human breast cancer, The growth of breast cancer cells is under the regulation of hormones. growth factors. and their receptors. In the present study. we have employed a new. sensitive. and specific radioimmunoassay for the direct measurement of insulin receptors in surgical specimens of breast cancers. In 159 specimens the insulin receptor content was 6.15 +/- 3.69 ng/0.1 mg protein. This value was more than sixfold higher than the mean value found in both 27 normal breast tissues obtained at total mastectomy (0.95 + 0.68. P less than 0.001) and in six normal specimens obtained from reduction mammoplasty (0.84 +/- 0.78. P less than 0.001). The insulin receptor content in breast cancer tissues was also higher than in any normal tissue investigated including liver (Pezzino. V.. V. Papa. V. Trischitta. A. Brunetti. P.A. Goodman. M.K. Treutelaar. J.A. Williams. B.A. Maddux. R. Vigneri. and I.D. Goldfine. 1989. Am. J. Physiol. 257:E451-457). The insulin receptor in breast cancer retained its ability to both bind insulin and undergo insulin-induced tyrosine kinase activation. Immunostaining of the specimens revealed that the insulin receptor was present in malignant epithelial cells. but was not detected in stromal and inflammatory cells. Univariant analysis revealed that the insulin receptor content of the tumors correlated positively with tumor size (P = 0.014). histological grading (P = 0.030). and the estrogen receptor content (P = 0.035). There were no significant correlations between insulin receptor content and the age. body weight. menopausal status. and nodal involvement of the patients. These studies indicate. therefore. that the insulin receptor content is increased in breast cancers and raise the possibility that the insulin receptor may have a role in the biology of these tumors.
Angiotensin and thromboxane in the enhanced renal adrenergic nerve sensitivity of acute renal failure, The roles of intrarenal angiotensin (A) and thromboxane (TX) in the vascular hypersensitivity to renal nerve stimulation (RNS) and paradoxical vasoconstriction to renal perfusion pressure (RPP) reduction in the autoregulatory range in 1 wk norepinephrine (NE)-induced acute renal failure (ARF) in rats were investigated. Renal blood flow (RBF) responses were determined before and during intrarenal infusion of an AII and TXA2 antagonist. Saralasin or SQ29548 alone partially corrected the slopes of RBF to RNS and RPP reduction in NE-ARF rats (P less than 0.02). Saralasin + SQ29548 normalized the RBF response to RNS. While combined saralasin + SQ29548 eliminated the vasoconstriction to RPP reduction. similar to the effect of renal denervation. appropriate vasodilatation was not restored. Renal vein norepinephrine efflux during RNS was disproportionately increased in NE-ARF (P less than 0.001) and was suppressed by saralasin + SQ29548 infusion (P less than 0.005). It is concluded that the enhanced sensitivity to RNS and paradoxical vasoconstriction to RPP reduction in 1 wk NE-ARF kidneys are the result of intrarenal TX and AII acceleration of neurotransmitter release to adrenergic nerve activity.
Pathogenesis of hyperadrenergic orthostatic hypotension. Evidence of disordered venous innervation exclusively in the lower limbs, The pathogenesis of hyperadrenergic orthostatic hypotension was studied in eight patients. Correction of the abnormal orthostatic changes by an inflated pressure suit (MAST) confirmed previous evidence of excessive gravitational pooling of blood in the leg veins. Intravenous L-norepinephrine infusion raised diastolic blood pressure in the same relationship to the infusion-induced increments in plasma norepinephrine concentrations as in normal subjects. indicating normal arteriolar responses. Contractile responses of the veins to infused L-norepinephrine were measured with a linear variable differential transformer (LVDT). The venous responses of hand veins in the patients fell within the 95% confidence limits of the responses of normal hand veins. as did the responses of foot veins in the seven normal subjects. However. foot veins of the patients with hyperadrenergic orthostatic hypotension. and both hand and foot veins of patients with "diffuse" autonomic failure. were supersensitive to norepinephrine. as reflected by a steeper slope of the regression of log (norepinephrine infusion rate) on percentage reduction in venous distensibility. and a significantly lower ED50 (i.e.. norepinephrine infusion rate that induced 50% reduction in venous distensibility). The findings suggest anatomical or functional postganglionic denervation of lower limb veins causing excessive gravitational blood pooling with consequent orthostatic hypotension in these patients.
Reduced beta-cell glucose transporter in new onset diabetic BB rats, Previous studies from our laboratories have suggested a defect in glucose transport in islets isolated from BB rats on the first day of overt diabetes. To quantitate by immunostaining the glucose transporter of beta-cells (GLUT-2) before and at the onset of autoimmune diabetes we employed an antibody to its COOH-terminal octapeptide. On the first day of overt diabetes. defined as the day the daily blood glucose first reached 200 mg/dl. the volume density ratio of GLUT-2-positive to insulin-positive beta-cells was only 0.48 +/- 0.06. compared to 0.91 +/- 0.02 in age-matched nondiabetic diabetes-resistant controls (P less than 0.001). In age-matched nondiabetic diabetes-prone rats. most of which would have become diabetic. the ratio was 0.85 +/- 0.02. also less than the controls (P less than 0.05). Protein A-gold labeling of GLUT-2 in beta-cells of day 1 diabetic rats revealed 2.17 +/- 0.16 gold particles per micrometer length of microvillar plasma membranes compared to 3.91 +/- 0.14 in controls (P less than 0.001) and 2.87 +/- 0.24 in the nondiabetic diabetes-prone rats (P less than 0.02). Reduction in GLUT-2 correlates temporally with and may contribute to the loss of glucose-stimulated insulin secretion that precedes profound beta-cell depletion of autoimmune diabetes.
A novel X-linked combined immunodeficiency disease, A novel X-linked combined immunodeficiency disease was found in five living males in an extended family in the United States. The age of the affected males ranged from 2.5 to 34 yr. The most prominent clinical abnormalities were a paucity of lymphoid tissue; recurrent sinusitis. otitis media. bronchitis. and pneumonia; severe varicella; and chronic papillomavirus infections. The principal immunologic features of the disorder were normal concentrations of serum immunoglobulins but restricted formation of IgG antibodies to immunogens; normal numbers of B cells and NK cells but decreased numbers of CD4+ and CD8+ T lymphocytes. particularly the CD45RA+ subpopulations; diminished proliferative responses of blood T cells to allogeneic cells. mitogens and antigens; and decreased production of IL-2 by mitogen stimulated blood lymphocytes. Thus. affected males in this family carry an abnormal gene on their X chromosome that results in a combined immunodeficiency that is distinct from previously reported disorders.
Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin, Cisplatin (DDP) is the most effective drug for the treatment of human ovarian cancer. but the mechanisms that determine sensitivity to the cytotoxic action of DDP are not well understood. Treatment of two human ovarian carcinoma cell lines with epidermal growth factor (EGF) simultaneously increased sensitivity to DDP and caused a persistent change in morphology in the absence of any mitogenic effect. Sensitization to DDP was shown to be dependent on both EGF concentration and EGF receptor number in C127 mouse fibroblasts expressing the human EGF receptor after transfection with a pBPV plasmid construct containing the human EGF receptor gene under control of the transferrin receptor 3'-inducible regulator. Sensitization of human ovarian carcinoma cells to DDP was not blocked by inhibition of protein synthesis. EGF did not enhance sensitivity to DDP or alter morphology in DDP-resistant human ovarian carcinoma cells despite the presence of functional EGF receptors on these cells. These results showed that elements of the signal transduction pathway activated by EGF determined cellular sensitivity to DDP. and that a DDP-resistant phenotype is associated with a defect in this signal transduction pathway.
Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo, Whether parenchymal or nonparenchymal liver cells play a predominant role in the pathophysiology of hepatic fibrosis has not been firmly established in vivo. We have addressed this question by quantitating the relative abundance of specific mRNAs for collagen types I. III. and IV. and laminin in purified populations of hepatocytes. sinusoidal endothelial cells. and lipocytes from normal and fibrotic rat liver. In normal liver. type I collagen gene expression was minimal in all cell types; mRNA for types III and IV collagen were apparent in endothelial cells and lipocytes. but not in hepatocytes. Laminin mRNA was present in all cell types. Induction of fibrogenesis by either bile duct ligation or carbon tetrachloride administration was associated with a substantial increase in mRNA for types I and III collagen in nonparenchymal cells. Lipocytes from fibrotic animals exhibited a greater than 30-fold increase in type I collagen mRNA relative to normal lipocytes. and greater than 40-fold relative to hepatocytes. Type III collagen mRNA reached 5 times that in normal lipocytes and greater than 120 times that in hepatocytes. Endothelial cells exhibited an isolated increase in type I collagen mRNA. reaching five times that in normal liver. Type IV collagen and laminin gene expression were not significantly increased in nonparenchymal cells during fibrogenesis; in fact. mRNA for type IV collagen and laminin decreased by up to 50% in endothelial cells. Despite the pronounced changes that occurred in matrix gene expression in nonparenchymal cells during fibrogenesis. no change was noted in hepatocytes. We conclude that nonparenchymal liver cells. particularly lipocytes. are important effectors of hepatic fibrosis in vivo.
A phosphatase activity present in peripheral blood myeloid cells of chronic myelogenous leukemia patients but not normal individuals alters nuclear protein binding to transcriptional enhancers of interferon-inducible genes, Cytoplasmic protein from peripheral blood myeloid cells of chronic myelogenous leukemia (CML) patients altered the electrophoretic mobility of complexes formed between nuclear proteins and interferon-inducible transcriptional enhancers. Immature myeloid marrow cells (blasts and promyelocytes) have a higher level of this activity than do mature myeloid marrow cells (bands and polys). This activity. which is not detectable in the peripheral blood cells of normal individuals. is at least 50-fold higher in CML marrow blasts and promyelocytes than that found in marrow blasts and promyelocytes of normal individuals. This activity was inhibited by in vivo incubation of immature myeloid cells with the phosphatase inhibitor. sodium orthovanadate (0.2 mM). and by adding orthovanadate (20 mM) directly to cytoplasmic proteins of myeloid cells. Interferon-alpha (1.000 U/ml) reduced the effects of the CML myeloid cell cytoplasmic protein on the electrophoretic mobility of nuclear protein-DNA complexes. These data suggest that a unique phosphatase may be involved in the abnormalities in CML which are modulated by interferon-alpha.
A substitution at a non-glycine position in the triple-helical domain of pro alpha 2(I) collagen chains present in an individual with a variant of the Marfan syndrome, A substitution for a highly conserved non-glycine residue in the triple-helical domain of the pro alpha 2(I) collagen molecule was found in an individual with a variant of the Marfan syndrome. A single base change resulted in substitution of arginine618 by glutamine at the Y position of a Gly-X-Y repeat. and is responsible for the decreased migration in SDS-polyacrylamide gels of some pro alpha 2(I) chains of type I collagen synthesized by dermal fibroblasts from this individual. Family studies suggest that this substitution was inherited from the individual's father who also produces abnormally migrating pro alpha 2(I) collagen chains and shares some of the abnormal skeletal features. This single base change creates a new Bsu36 I (Sau I. Mst II) restriction site detectable in genomic DNA by Southern blot analysis when probed with a COL1A2 fragment. The analysis of 52 control individuals (103 chromosomes) was negative for the new Bsu36 I site. suggesting that the substitution is not a common polymorphism.
Human neutrophil cytochrome b light chain (p22-phox). Gene structure, chromosomal location, and mutations in cytochrome-negative autosomal recessive chronic granulomatous disease, A membrane-bound cytochrome b. a heterodimer formed by a 91-kD glycoprotein (heavy chain) and a 22-kD polypeptide (light chain). is an essential component of the phagocyte NADPH-oxidase responsible for superoxide generation. Cytochrome b is absent in two subgroups of chronic granulomatous disease (CGD). an inherited disorder characterized by the lack of oxidase activity. Mutations in the cytochrome heavy chain gene. encoded by the CYBB locus in Xp21.1. result in the X-linked form of CGD. A rare subgroup of autosomal recessive CGD also lacks cytochrome b (A- CGD). but the genetic defect has not previously been identified. In order to search for possible mutations in the cytochrome light chain locus. CYBA. the structure of this gene was characterized. The CYBA locus was localized to 16q24. and the approximately 600-bp open reading frame determined to be encoded by six exons that span approximately 8.5 kb. Three unrelated patients with A- CGD were studied for evidence of mutations in the light chain gene. One patient. whose parents were first cousins. was homozygous for a large deletion that removed all but the extreme 5' coding sequence of the gene. The other two patients had a grossly normal light chain transcript on Northern blot of mononuclear cell RNA. The light chain transcript was amplified by the polymerase chain reaction and sequenced. One patient was a compound heterozygote for two alleles containing point mutations in the open reading frame that predict a frame shift and a nonconservative amino acid replacement. respectively. The second patient. whose parents were second cousins. was homozygous for a different single-base substitution resulting in another nonconservative amino acid change. These results indicate that A- CGD can results from defects in the gene encoding the 22-kD light chain of the phagocyte cytochrome b.
Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy, Schindler disease is a recently recognized infantile neuroaxonal dystrophy resulting from the deficient activity of the lysosomal hydrolase. alpha-N-acetylgalctosaminidase (alpha-GalNAc). The recent isolation and expression of the full-length cDNA encoding alpha-GalNAc facilitated the identification of the molecular lesions in the affected brothers from family D. the first cases described with this autosomal recessive disease. Southern and Northern hybridization analyses of DNA and RNA from the affected homozygotes revealed a grossly normal alpha-GalNAc gene structure and normal transcript sizes and amounts. Therefore. the alpha-GalNAc transcript from an affected homozygote was reverse-transcribed. amplified by the polymerase chain reaction (PCR). and sequenced. A single G to A transition at nucleotide 973 was detected in multiple subclones containing the PCR products. This point mutation resulted in a glutamic acid to lysine substitution in residue 325 (E325K) of the alpha-GalNAc polypeptide. The base substitution was confirmed by dot blot hybridization analyses of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Furthermore. transient expression of an alpha-GalNAc construct containing the E325K mutation resulted in the expression of an immunoreactive polypeptide which had no detectable alpha-GalNAc activity.
Chronic illness and depressive symptoms in the elderly: a population-based study, A cross-sectional study of the distribution of depressive symptoms and association between depressed mood and chronic illness was conducted in a geographically defined population in southern California of 1617 men and women aged 65 years and older. The prevalence of depressed mood for the total population was 5.2%. Women exhibited a significantly higher mean depressive symptom score and a prevalence rate almost twice that of men. Depressive symptoms were associated with several risk factors in both sexes. including age. self-perception of current health status. number of reported chronic diseases and medications and amount of exercise. However. the relationship between physical illness and depressive symptoms appeared to differ by sex with respect to the nature of the disease or disability and the type of medication currently used. These findings indicate that the risk of depression does not diminish with age among the elderly as other studies have suggested.
Effect of normal MSAFP screening on maternal age for genetic amniocentesis, Routine maternal serum alpha-fetoprotein (MSAFP) screening for neural tube defects is considered by many to be standard obstetrical care. and recently many have encouraged this test to screen for Trisomy-21 (Down's syndrome). We questioned whether. after a normal MSAFP screen. the risk of Trisomy-21 decreases enough to warrant modifying the recommended age for genetic amniocentesis for Down's syndrome. A logistic regression was developed which. using reported values for sensitivity and specificity for MSAFP detection of Trisomy-21 and assuming a constant threshold risk in opting for amniocentesis. indicates that genetic amniocentesis for Trisomy-21 may be deferred in some women who have a normal MSAFP screening. Sensitivity analysis of varying thresholds for a normal MSAFP demonstrates that a 37 year old woman with a median MSAFP level has the same risk for Trisomy-21 as an unscreened women who is 4.5 years younger. An abnormal MSAFP is useful in screening for neural tube defects and possibly for Trisomy-21. A normal MSAFP may allow for delaying the potentially risky amniocentesis in otherwise low-risk pregnancies.
Quality control practices in centralized tumor registries in North America, A survey of quality control practices was mailed to 73 central registries in the U.S. and Canada. The response rate was 88%. with respondents representing a wide range of registry characteristics and reporting strategies. While registries expressed different priorities in data use. 80% of respondents felt quality control data were important in the identification of problems. The most common method of quality control was acceptance sampling (used by 97% of respondents). and took the form of visual review. recoding and edit checking. Computer-based edit checks were almost universally used (95%). Process control methods of any sort were used by only 22% of respondents with less than 4% of registries reporting formal quantitative criteria. Sixty-one percent of respondents reported conducting one or more designed studies (e.g. reabstracting or casefinding studies) but only 20% of those made the results public. Greater emphasis should be placed on development of quantitative process controls. experimental design of quality control studies. and formal analyses and reporting of study results.
The protective effect of the oral contraceptive pill on rheumatoid arthritis: an overview of the analytic epidemiological studies using meta-analysis, The oral contraceptive pill (OCP) has been implicated as having a protective effect on the development of rheumatoid arthritis (RA). The results of 12 studies have now been reported and produced differing results and conclusions. Because of the discrepancy in results and the importance of the issue we undertook a review of the studies and performed a meta-analysis. In all. 9 independent studies satisfied the criteria for selection. 6 case-control design and 3 longitudinal. Using standard meta-analysis techniques. the overall pooled odds ratio for all the studies was 0.68 for the crude results (95% CI 0.58-0.78) and 0.73 for the adjusted results (95% CI 0.61-0.85). The graphical odd-man-out method produced a 94% interval of 0.70-0.72. The pooled odds ratio of the case-control studies was lower than for the longitudinal studies. However. subdividing studies by the type of case source produced a pooled odds ratio for studies using hospital-based cases of 0.49 (95% CI 0.39-0.63) which was considerably less than that of studies using population-based cases: 0.95 (0.78-1.16). This difference was unlikely to have explained by bias due to selection of controls. We suggest that OCP use may not have a "protective effect" on the development of RA but may prevent the progression to severe disease by modifying the disease process.
Health status reports in the care of patients with rheumatoid arthritis, We examined the use of formal health status reports every 3 months over 1 year in the clinical care of patients with rheumatoid arthritis (RA). The reports consisted of single-page. computer-generated summaries of scores derived from either the AIMS (Arthritis Impact Measurement Scales) or the MHAQ (Modified Health Assessment Questionnaire) health status questionnaires. A total of 1920 subjects from 27 community practice sites were randomly assigned to three study groups in each practice: intervention. attention placebo and control. Results showed that 55% of the physicians found the reports to be at least moderately useful as an aid to patient management. primarily for improving the doctor-patient relationship. However. no detectable differences among the three groups were seen in terms of medication compliance. number of physician visits. number of referrals. frequency of major medication changes. attitudes towards the physician. patient satisfaction or change in health status over 1 year. The failure to demonstrate objective benefits of health status reports in this study may be due to physician unfamiliarity with health status scores. failure to link the report with an office visit. the relative stability of clinical status in the subjects over 1 year and the relatively short time-frame of the study.
The need for accurate nutrition survey methodology: the South Carolina experience, Assessment of two nutrition-related risk factors. obesity and fat intake. was completed on a representative sample of South Carolina adults. Obesity estimates determined from self-reported heights and weights were less than prevalences determined from direct measurements (white males 21.4% vs. 28.2%; white females 20.8% vs. 24.5%; black males 29.2% vs. 30.1%; black females 43.6% vs. 50.6%; and total 24.9 vs. 29.8%). Nine fat-intake habits were identified from dietary mannerisms involving the consumption of red meat. fat on meat. fried fish/chicken. butter. eggs. whole milk. bacon/sausage. and cheese and the use of solid fats when cooking vegetables. The mean number of the nine habits exhibited was four. The total number of habits did not correlate well with serum cholesterol. as 27% of the individuals with none of the nine fat intake habits had blood cholesterol values greater than 6.2 mmol/L (239 mg/100 mL). while only 17% of the individuals with seven habits had the high level of cholesterol. These nine habits explained less than 10% of the variability of serum cholesterol values.
Iron: nutrition monitoring and nutrition status assessment, The majority of anemias in the United States are characterized by low mean corpuscular volume and thus are classified as microcytic. Iron deficiency. chronic disease and thalassemia traits are the three leading causes of microcytic anemia. The true cause of anemia must always be sought so that the prevalence estimates of iron deficiency are accurate and so that appropriate treatment can be initiated for the anemic individual. In both the clinical setting and in surveys. the most frequent differential diagnosis of microcytic anemia will involve distinguishing between iron deficiency and chronic disease. Erythrocyte sedimentation rate (ESR). zeta-sedimentation rate (ZSR). and C-reactive protein (CRP) are elevated in a variety of diseases. These indicators may help differentiate the anemia of chronic disease from iron deficiency. so that iron deficiency is not overestimated in hospitalized and aged populations. The red cell distribution width (RDW) appears to be elevated to a greater extent in iron deficiency than in chronic disease or thalassemia traits. RDW and CRP are two of several indicators of iron status in the third National Health and Examination Survey (NHANES III).
The importance of context in choosing nutritional indicators, Nutritional indicators are used to screen. diagnose. and evaluate interventions in individuals. They are also used in populations to ascertain and place under surveillance the magnitude of nutritional problems. their location and causes. and to evaluate the impact of programs and policies. Nutritional indicators are also used for research to make inferences about biological and social mechanisms affecting or being affected by nutrition. All these activities include measurements of nutritional indicators. but the choice of indicators. their measurements. analyses. and the need for other data can be very different for inferences from research. for patient management. for making public policy. or for planning or evaluating programs. There is no best indicator. best measure of an indicator. or best analysis of an indicator in a generic sense. The definition of "best" depends ultimately on what is most appropriate for the decision that must be made. This paper gives examples.
Mathematical models of HIV infection. I. Threshold conditions for transmission and host survival, This is the second in a series of papers modeling human immunodeficiency virus (HIV) infections at four levels: transmission. interaction with the immune system. gene regulation. and selection of mutants. In the previous paper (1) we described and presented a theory of the HIV cytopathic effect based upon the models (and a review of the literature). In this article we give mathematical equations of threshold conditions that connect infectivity. length of host survival. and frequency of acts conducive to transmission. The formula is derived not only for homogeneous populations but also for populations of an arbitrary number of subgroups with varying frequencies of risk behavior. varying rates of infection and latency periods. and varying frequencies of interaction with other groups.
Tracking the spread of the HIV infection epidemic among young adults in the United States: results of the first four years of screening among civilian applicants for U.S. military service, Because the period from infection to clinically apparent disease is long. variable. and changing as new therapies are developed and applied. AIDS data are inadequate for tracking current values of critical parameters of HIV infection epidemics: prevalence of infection. rate of acquisition of new infections (incidence rate). and direction and rate of change of infection incidence over time (acceleration). These "vital signs" of infection epidemics can be tracked using serial cross-sectional seroprevalence data. however. From October 1985 through September 1989. more than 2.3 million applicants for U.S. military service were screened for antibody to HIV. The overall seroprevalence was 1.31 per 1.000 (3.014/2.300.675). Seroprevalences were highest near urban centers of the AIDS epidemic and were independently associated with age. race/ethnicity. and gender. Based on age seroprevalence trends. it was crudely estimated that at least one of 2.000 young men and one of 7.000 young women are infected with HIV annually in the U.S. Infection incidence rates. estimated from age and temporal trends. were estimated to be highest among black males (1.40/1.000/year) and lowest among white females (0.03/1.000/year). Poisson regression analysis of seroprevalence trends suggested that infection incidence rates accelerated among black females during the first 3 years of screening. Since selection factors undoubtedly changed over the period. estimates based on these data probably underestimate actual values in the general population. particularly near urban AIDS epicenters. Nonetheless. even crude estimates of these critical values. particularly among adolescents and young adults. are useful to guide policy development. to allocate resources. and to monitor program effects.
Relapse from safer sex: the next challenge for AIDS prevention efforts, Prevention campaigns to reduce sexual transmission of human immunodeficiency virus (HIV) typically emphasize the initial adoption of safer sex techniques. We present data from a 5-year prospective study to show that the vast majority of resident gay men in San Francisco have made these initial risk reductions. Rather. relapse from safer sex techniques is now the predominant predominant kind of high-risk sex. accounting for approximately two thirds of all prevalent high-risk sex in the 1988 wave of data collection. Predictors of relapse from safer sex are identified. and these are discussed in terms of their implications for preventing relapse from the exclusive practice of safe sex. In communities that have already manifested widespread behavioral risk reductions and in which HIV infection is highly prevalent. finding ways to prevent relapse of behavioral risk reductions will be the next important challenge in the fight against acquired immune deficiency syndrome.
Seroprevalence of HIV-2 infection in Greece (Crete), The seroprevalence of HIV-2 was evaluated in 20.407 consecutive normal blood donors. 100 homo- and/or bisexuals. and 7.020 heterosexuals presenting for an HIV test using an EIA test. Sixty-seven sera were revealed to be repeatedly positive. Analysis by Western blot confirmed the infection in four cases. an indeterminate (antibodies against only the gag-encoded proteins) pattern was revealed in 25 cases. whereas 38 sera were negative. Three of the four HIV-2-positive sera also reacted with two distinct. but close. synthetic peptides homologous to viral gp36. The fourth serum. which did not display antibodies against gp36 on Western blot. did not react with gp36-derived synthetic peptides. None of these sera reacted with native HIV-1 antigens or synthetic peptides homologous to gp41. Sera with an indeterminate HIV-2 Western blot did not react with gp36-derived synthetic peptides. Although 10 of them also displayed an indeterminate HIV-1 Western blot. no serum sample reacted with two gp41-derived synthetic peptides or proved to be positive when they tested for p24 antigen. One bisexual and one heterosexual HIV-2 positive subject reported sexual contacts with West Africans. whereas two other heterosexuals had had multiple sexual partners from different countries.
Seroprevalence of HIV infection in the general population of the Cote d'Ivoire, West Africa, A seroepidemiological survey to determine the prevalence of human immunodeficiency virus (HIV) infection in the general population of the Ivory Coast was carried out in February 1989. Sera were collected from subjects between 15 and 65 years old in urban areas (not including Abidjan) and rural areas using the cluster sample technique. A total of 1.700 people were tested in urban areas. and 125 (7.3%) were HIV positive. This rate varied significantly with age and sex; a maximum rate of 16.3% was observed among men between 35 and 44 years old. In rural areas. a total of 3.199 people were tested. and 159 (4.9%) were positive for HIV; the highest rate (10.7%) was noted in the men aged 25-34 years. The high seroprevalence recorded in the general population in urban and rural areas is compatible with the incidences of acquired immune deficiency syndrome (AIDS) cases reported in hospitals all over the country.
L-tyrosine potentiates the anorexia induced by mixed-acting sympathomimetic drugs in hyperphagic rats, The effects of L-tyrosine (L-TYR) on the anorectic activity of several mixed-acting sympathomimetics were determined during the dark cycle in rats made hyperphagic by food deprivation. L-TYR (200 mg/kg) significantly potentiated the anorectic activity of phenylpropanolamine. (-)-ephedrine and (+)-amphetamine by 48. 50 and 37%. respectively. When the dose of L-TYR was varied (25-400 mg/kg). a significant dose-dependent relationship was noted. The observed potentiation was positively correlated with increases in brain TYR concentrations; blockade of L-TYR uptake into the brain by the coadministration of L-valine prevented this potentiation. Various other L-amino acids. as well as D-TYR. failed to mimic the potentiating action of L-TYR. As determined by alpha-methyl-p-TYR pretreatment. the L-TYR-induced potentiation was dependent upon increased catecholamine synthesis. Although various other mixed-acting sympathomimetic anorexiants were similarly potentiated by L-TYR. the direct-acting beta-2 adrenoceptor anorexiants. salbutamol and methoxyphenamine. were not. These results indicate that L-TYR specifically potentiates the anorectic activity of the studied mixed-acting sympathomimetics and are consistent with the requirement of the central conversion of L-TYR to catecholamines via TYR hydroxylase for this response. The possibility that the effect of mixed-acting sympathomimetics is normally limited by the availability of L-TYR is suggested.
Suppressive effects of morphine pellet implants on in vivo parameters of immune function, Chronic morphine treatment elicits a variety of immunosuppressive effects in mice. Most of the work describing this immuno-suppressive activity of the opioid is based on in vitro assessments of the performance of certain components of the immune system in morphine-treated animals. Relatively little has been done by way of tracking the effects of chronic morphine treatment on immunologic parameters in the intact animal. Therefore. this study used several classic in vivo determinations of immune function in mice treated chronically with morphine. Morphine pellet (75 mg) implantation led to a significant inhibition (91%) of paw swelling in a picryl chloride-induced delayed type hypersensitivity response. Uptake of iododeoxyuridine in an in vivo lymphocyte proliferation assay and splenomegaly in a graft vs. host reaction were also significantly suppressed by morphine pellet implantation (34 and 52%. respectively). Coimplantation of a naltrexone pellet (10 mg) completely reversed the suppressive responses to morphine in each assay. Naltrexone alone had no significant effect in any of the assays. The suppressive effects of morphine were less pronounced in adrenalectomized mice in the graft vs. host assay (51% vs. 9% reduction in morphine-pelleted shams relative to morphine-pelleted adrenalectomized mice). These findings indicate the pathophysiologic significance of the previously reported suppression of in vitro correlates of immune function in morphine-pelleted mice. The results further demonstrate that the immunosuppressive effects observed after morphine pellet implantation are naltrexone reversible and suggest that activation of the adrenal is one potential mechanism for this effect.
Pharmacology of pravadoline: a new analgesic agent, Pravadoline is a new chemical entity with analgesic activity in humans. This report describes the pharmacology of pravadoline and compares the activity of pravadoline with that of two major classes of analgesics. the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Like the NSAIDs. pravadoline inhibited the synthesis of prostaglandins (PGs) in mouse brain both in vitro (IC50. 4.9 microM) and ex vivo (ED50. 20 mg/kg p.o.) and displayed antinociceptive activity in rodents subjected to a variety of chemical. thermal and mechanical nociceptive stimuli. Administration of pravadoline prevented the writhing response induced by i.p. administration of acetylcholine (ED50. 41 mg/kg p.o.) or PGE2 (ED50. 24 mg/kg p.o.) and prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees C (minimum effective dose. 100 mg/kg s.c.). In the rat. treatment with pravadoline prevented acetic acid-induced writhing (ED50. 15 mg/kg p.o.). brewer's yeast-induced hyperalgesia (Randall-Selitto test) (minimum effective dose. 1 mg/kg p.o.). the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50. 41 mg/kg p.o.) and bradykinin-induced head and forepaw flexion (ED50. 78 mg/kg. p.o.). The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism. because pravadoline-induced antinociception was not antagonized by naloxone (1 mg/kg s.c.) and pravadoline did not bind to opioid receptors at concentrations up to 10 microM. However. like the opioid analgesics. pravadoline diminished the electrically induced twitch response of mouse vas deferens preparations. but. in contrast to opioids. this action of pravadoline was not attenuated by naloxone. The possibility is discussed that this effect of pravadoline upon isolated tissues may contribute to its antinociceptive activity. In contrast to NSAIDs. pravadoline was more potent ex vivo as an inhibitor of the formation of PGs in brain vs. stomach. In addition. pravadoline failed to produce gastrointestinal lesions when administered p.o. to rats or mice. and did not possess significant anti-inflammatory activity at antinociceptive doses. Also unlike NSAIDs. pravadoline inhibited rat gastrointestinal transit when administered at doses similar to those which were antinociceptive. The overall pharmacologic profile of pravadoline suggests that the compound may be capable of managing more diverse or more severe pain than is achieved by anti-inflammatory analgesics. without producing side effects commonly associated with either the opioid or the nonopioid analgesics.
Effect of the leukotriene B4 receptor antagonist SC-41930 on colonic inflammation in rat, guinea pig and rabbit, Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that includes ulcerative colitis and Crohn's disease. Leukotriene B4 is thought to be a prominent proinflammatory mediator in these diseases. in that leukotriene B4 levels are increased in the colonic mucosa of inflammatory bowel disease patients and there is increased polymorphonuclear leukocyte infiltration of these tissues. We evaluated the efficacy of 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-3.4-dihydro-8-propyl -2H-1-benzopyran-2-carboxylic acid (SC-41930). a potent. orally active leukotriene B4 receptor antagonist. in a model of inflammatory bowel disease. Colonic mucosal inflammation was induced in rats. guinea pig and rabbits by rectal instillation of a dilute solution of acetic acid. Twenty-four hours later. mucosal levels of myeloperoxidase (a marker enzyme for neutrophil infiltration) and extravasation of i.v. administered Evans blue dye (a marker of vascular disruption and increased permeability) were measured. Tissues were also evaluated histologically. The animals received either SC-41930 or vehicle. intrarectally. 30 min after or 1 hr before and 1 hr after the acetic acid. When given 30 min after acetic acid instillation SC-41930 prevented the rise in myeloperoxidase and dye extravasation observed in the acetic acid inflammed tissue. The SC-41930-treated tissues were less edematous and had fewer neutrophils within the subepithelial space. Median effective dose (ED50) values for vascular protection were approximately 20 mg/kg for both rat and guinea pig. ED50 values for inhibition of granulocyte accumulation were 20 mg/kg for rat. 24 mg/kg for guinea pig and 30 mg/kg for rabbit. These data indicate that SC-41930 is effective locally to prevent acute colonic inflammation.
Both d-cis- and l-cis-diltiazem have anti-ischemic action in the isolated, perfused working rat heart, The effect of diltiazem (d-cis-diltiazem) on the ischemic myocardium was compared with that of l-cis-diltiazem. an optical isomer having less potent calcium channel-blocking action. in the isolated. perfused working rat heart. Ischemia decreased mechanical function and tissue levels of ATP and creatine phosphate. and increased tissue levels of nonesterified fatty acids (NEFA). AMP and lactate. Reperfusion did not restore mechanical function. but restored incompletely the levels of metabolites (except NEFA) that had been altered by ischemia. The ischemia-induced changes in NEFA were prevented by d-cis-diltiazem completely and by l-cis-diltiazem incompletely. Other metabolic changes induced by ischemia were attenuated by d-cis-diltiazem but not by l-cis-diltiazem. In heart pretreated with d-cis- or l-cis-diltiazem. both the mechanical function and the levels of metabolites recovered during reperfusion. the degree of recovery with both drugs being similar. These results indicate that not only d-cis-diltiazem but also l-cis-diltiazem has an anti-ischemic action probably due to inhibition of the tissue NEFA accumulation. These results also suggest that the mechanism of the protective effect of d-cis-diltiazem on the ischemic myocardium is not entirely due to the calcium channel-blocking action. Treatment with low Ca2+ (1.0 mM CaCl2) also attenuated the ischemia-induced changes. The interval between reoxygenation and start of function in the reperfused heart that had been treated with low Ca2+ was significantly longer than that with d-cis- or l-cis-diltiazem. The effect of these isomers to shorten this interval may contribute to their common anti-ischemic action.
Acute opioid physical dependence in humans: effect of varying the morphine-naloxone interval II, Previous studies have demonstrated antagonist-precipitated withdrawal from 45 min to 24 hr after acute opioid administration in nondependent human subjects. The purpose of this study was to examine longer postagonist intervals and to determine the maximum interval between agonist administration and antagonist challenge at which precipitated withdrawal can be observed. During this study 6 nondependent male volunteers who reported using opiates an average of 4 times per week received naloxone challenges (10 mg/70 kg i.m.) at 6. 12. 24. 36. 48. 60. or 72 hr after single i.m. injections of morphine (18 mg/70 kg or 30 mg/70 kg). Each interval was tested independently in random order. Naloxone reliably precipitated withdrawal signs and symptoms at 6 and 12 hr postmorphine. Withdrawal symptoms were greatly diminished in intensity at 24-hr postmorphine and were not elicited at postmorphine intervals longer than 24 hr. Withdrawal precipitation persisted somewhat longer than pupillary constriction because pupils had returned to predrug diameters by 24 hr postmorphine but. generally. there appeared to be correspondence between offset of agonist effects and dissipation of precipitated withdrawal. This study extends observations about the time course of acute physical dependence effects which begin within minutes after acute morphine exposure. dissipate within 36 hr. are associated with the onset and offset of agonist effects and do not require chronic opioid administration.
Peripheral opioid receptors mediating antinociception in inflammation. Evidence for activation by enkephalin-like opioid peptides after cold water swim stress, This study utilized inhibitors of the enzymatic degradation of enkephalins to investigate the possibility that this class of opioid peptides contributes to the stress-induced antinociception seen in inflamed peripheral tissues of rats with Freund's complete adjuvant-initiated unilateral hind paw inflammation. Following a 1-min cold water swim stress. rats previously injected in both hind paws with vehicle showed a transient elevation of paw pressure threshold. which was much greater in inflamed than in noninflamed paws and returned to control levels within 15 min. This preferential antinociception was significantly pronounced and prolonged in rats previously injected bilaterally with a cocktail of the enkephalinase inhibitors thiorphan (0.2 mg intraplantar) and bestatin (0.2 mg intraplantar). The enhancement of stress-induced antinociception by thiorphan/bestatin was dose-dependently antagonized by tertiary naloxone (0.125-2 mg kg-1 s.c.). Evidence for a peripheral site of action of enkephalin-like peptides in this model was provided by the antagonism of the actions of thiorphan/bestatin by quaternary naltrexone (10-20 mg kg-1 s.c.). Systemic administration of the orally active enkephalinase inhibitor SCH 34826 (5-40 mg kg-1 i.p.) was also able to dose-dependently potentiate the preferential stress-induced antinociception in a naloxone (1 mg kg-1 s.c.) reversible manner.
Carotid endarterectomy: a ten-year analysis of outcome and cost of treatment, Between 1978 and 1988. 215 patients with an average age of 67 years. underwent 246 carotid endarterectomies. Two hundred ten (85.4%) patients were symptomatic. and 36 (14.6%) were asymptomatic. Six patients (2.4%) had a postoperative stroke. and all had immediate reoperation. One of these patients died (30 day mortality rate. 0.4% for the series). and two (0.8%) recovered completely. whereas three (1.2%) had a mild permanent neurologic deficit. Two patients (0.8%) had nonfatal myocardial infarction. Mean follow-up of 42.2 months (range. 1 to 126 months) was achieved. At 5 and 8 years actuarial survival rates of 82% and 66% and stroke-free survival rates of 67% and 37% were observed. Actuarial stroke free rates of 90% at 5 and 8 years were noted. By introducing and observing guidelines that required preoperative study of most clearly defined classes of patients before admission for surgical treatment. the average length of stay for carotid endarterectomy was lowered from 9.5 days in the first 5 years of the study to 5.8 days in the second 5 years (p = 0.001). Average hospital charges. expressed in constant dollars. decreased from $3113 in the first 5 years to $2620 in the second 5 years (p = 0.02) despite an 88% inflationary increase in medical consumer price index. This experience shows that the length of hospitalization of patients with carotid endarterectomy can be reduced and the cost of admission lowered without untoward effect on perioperative morbidity and mortality rates.
The value of pulmonary artery and central venous monitoring in patients undergoing abdominal aortic reconstructive surgery: a comparative study of two selected, randomized groups, One hundred two patients undergoing abdominal aortic reconstructive surgery were prospectively. randomly allocated to two groups. one of which was monitored with a central venous catheter and the other with a pulmonary artery catheter. Patients with uncompensated cardiopulmonary or renal disease were excluded from the study. General anesthesia was administered for the surgical procedure. and the patients were followed through hospital discharge. No statistically significant differences occurred between the two groups with regard to morbidity (perioperative cardiac. pulmonary or renal sequelae). mortality rate. duration of intensive care. postoperative hospital stay. or cost of hospitalization. The one statistically significant difference between groups was the professional fee charged for anesthetic care. which was higher for patients with pulmonary artery catheters than for those with central venous catheters. In conclusion. we prospectively gathered data from most patients presented for abdominal aortic reconstructive surgery. Our data seem to indicate that the choice of central venous catheter or pulmonary artery catheter monitoring makes little difference in outcome after abdominal aortic reconstructive surgery. and that for many patients pulmonary artery catheters are not necessary to give appropriate. adequate care. Because of the size of the sample. however. declarations of epidemiologic significance would be unfounded. Therefore large-scale. multicenter studies addressing such outcomes remain necessary.
Relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking. A preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group, Investigators in eight communities collected aortas. right coronary arteries. blood. and associated information from 390 males. 15 to 34 years of age. who died of violent causes. Pathologists at central laboratories graded the arteries for atherosclerotic lesions. and serum lipoprotein cholesterol and thiocyanate concentrations were measured. The percentage of intimal surface involved with atherosclerotic lesions in both the aorta and the right coronary artery was positively associated with serum very low-density lipoprotein + low-density lipoprotein cholesterol concentration and negatively associated with serum high-density lipoprotein cholesterol concentration. The serum thiocyanate concentration. a marker for smoking. was strongly associated with prevalence of raised lesions. particularly in the abdominal aorta. The effect of smoking was not explained by lipoprotein levels. Blacks had more extensive total surface involvement of the aorta after adjustment for lipoprotein cholesterol levels and smoking. These associations indicate that serum lipoprotein cholesterol concentrations and smoking are important determinants of the early stages of atherosclerosis in adolescents and young adults.
Use of cholesterol measurements in childhood for the prediction of adult hypercholesterolemia. The Muscatine Study, This article describes the validity and utility of screening tests for total cholesterol levels in school-age children to predict those who. when adults. will have cholesterol levels that the National Cholesterol Education Program suggests need continuing surveillance and intervention. Two thousand three hundred sixty-seven children aged 8 to 18 years were examined on several occasions and were followed up to ages 20 to 30 years. Of children with cholesterol concentrations exceeding the 75th percentile on two occasions. 75% of girls and 56% of boys would not qualify for intervention as adults by the National Cholesterol Education Program criteria. Of children with cholesterol levels exceeding the 90th percentile on two occasions. 57% of girls and 30% of boys would not qualify for intervention as adults. Because the efficacy. safety. acceptability. and cost of treatment for high cholesterol concentrations in childhood is evolving. the need for universal screening of childhood cholesterol levels must be considered carefully in view of the number of children with high levels of cholesterol who. as adults. do not meet the criteria for intervention suggested by the National Cholesterol Education Program.
The case against childhood cholesterol screening, Because some authorities have proposed blood cholesterol screening for children to prevent coronary heart disease. we reviewed published studies to estimate the potential risks and benefits of such screening. Childhood cholesterol levels are a poor predictor of high cholesterol levels in young adulthood and will be an even poorer predictor of coronary heart disease later in life. There is no evidence that blood cholesterol levels can be lowered more easily in children than in adults. and it seems unlikely that cholesterol reduction in childhood will be much more effective at preventing coronary heart disease than cholesterol reduction begun in middle age. Screening and interventions to lower blood cholesterol levels for millions of children would be expensive. could lead to labeling and family conflicts. and may cause malnutrition and increased noncardiovascular mortality. Because the benefits of cholesterol screening are unlikely to exceed these risks. we conclude that children should not be screened for high blood cholesterol levels.
Gadolinium-enhanced magnetic resonance imaging in Bell's palsy, Inflammation of the facial nerve in Bell's palsy can be demonstrated on gadolinium-enhanced magnetic resonance imaging. We have studied a series of 17 Bell's palsy patients with gadolinium-enhanced magnetic resonance imaging. and the purpose of this paper is to report our findings and discuss their significance. Most acute Bell's palsy cases demonstrate facial nerve enhancement. usually in the distal internal auditory canal and labyrinthine/geniculate segments. Other segments demonstrate enhancement less often. Gadolinium enhancement occurs regardless of the severity of the paralysis and can persist after clinical improvement of the paralysis. The findings of this study corroborate other evidence that the segments of the facial nerve most often involved in Bell's palsy are the only segments that are most often enhanced with gadolinium-enhanced magnetic resonance imaging. The role of gadolinium-enhanced magnetic resonance imaging in the management of Bell's palsy patients is discussed.
Small fenestra stapedotomy using a fiberoptic hand-held argon laser in obliterative otosclerosis, Obliterative otosclerosis has been a challenge since the advent of stapes surgery. "Drill-out" procedures have had a generally poorer prognosis than conventional stapes surgery because of excessive bleeding. acoustic trauma from the burr. and reclosure of the oval window by otosclerosis. In this report. we describe our early experience using a hand-held fiberoptic argon laser for small fenestra stapedotomy in 10 cases of obliterative otosclerosis. Closure of the air-bone gap to within 10 dB was seen in 100% of the patients. There was no significant sensorineural hearing loss. vertigo. or facial weakness. Argon-laser stapedotomy using a hand-held fiberoptic system is a safe and effective alternative to drill-out stapedotomy in cases of obliterative otosclerosis.
Avoiding a wrapped endotracheal tube in laser laryngeal surgery: experiences with apneic anesthesia and metal laser-flex endotracheal tubes, Ninety-one laser laryngeal procedures using the apneic technique of anesthesia were performed in 28 patients between 2 months and 64 years of age. Seventy-two procedures (79%) were performed on children and 19 on adults. There were no complications. Eight laser laryngoscopies were performed using a new metal Laser-Flex endotracheal tube. Obstruction of the endotracheal tube with a mucous plug occurred in one case. The apneic technique described in this paper provides a laser operative field free of an endotracheal tube. virtually eliminating the danger of a laser fire. It is a relatively safe and effective means of performing laser laryngeal surgery. In addition. the Laser-Flex endotracheal tube appears to be an acceptable alternative to a metallic tape-wrapped endotracheal tube.
Pediatric penetrating head and neck trauma, Penetrating head and neck trauma in children causes uncommon and potentially life-threatening injuries. We reviewed the charts of 21 patients who sustained penetrating injuries to the face or upper neck. Seventeen males and 4 females. aged 32 weeks' gestation to 19 years (mean = 10.2 years) comprised the study population. There were 15 gun-shot wounds. 1 shotgun injury. and 5 stab wounds. Significant problems included 7 vascular injuries. 6 central nervous system injuries. 5 ocular injuries. 3 airway compromises. 2 facial nerve injuries. 1 cervical esophageal penetration. and 2 cases of pneumothorax. Three deaths occurred. but the majority of the patients survived and sustained minimal permanent disability. Included in this review is a unique case of an intrauterine gunshot wound to the face at approximately 32 weeks' gestation. The treatment protocol. differences from adult patients. and management highlights are reviewed.
Chondrogenic potential of tragal perichondrium: a cause of hearing loss following stapedectomy, Tragal perichondrium is a widely used tissue seal in the oval window following stapes surgery. Autogenous and easily accessible. it is a suitable substance to cover the vestibule in total stapedectomy. and to seal around the prosthesis in small-fenestra stapedotomy. The incidence of complications from the use of perichondrium in this manner is exceedingly low. We report a case where tragal perichondrium in the oval window resulted in the proliferation of cartilage. The cartilage displaced the stapes prosthesis. resulting in a conductive loss. Although the chondrogenic potential of perichondrium is known. we are not aware of other reports implicating this as a cause of failure in stapes surgery. The pertinent clinical and experimental literature regarding chondrogenesis is reviewed. This information suggests that the formation of cartilage from perichondrium in the oval window might be influenced by mechanical trauma and tissue orientation.
The use of gadolinium-enhanced magnetic resonance imaging to determine lesion site in traumatic facial paralysis, Gadolinium-enhanced magnetic resonance imaging has been used to evaluate 20 patients with surgically confirmed facial nerve lesions. When the nerve could be seen. gadolinium-enhanced magnetic resonance imaging accurately revealed the lesion site as well as the known extent. which in some cases was not predicted by topognostic testing. This technique appears to provide accurate lesion-site testing and may have importance in surgical planning. Currently used topognostic tests of facial nerve function are frequently inaccurate and can only determine the most proximal lesion site when there are multiple or extensive lesions. The focal nerve enhancement seen in nerve injury. globally increased signal intensity within the temporal bone after trauma. and increased signal intensity within the dura after surgery can occasionally mask nerve lesions and may be confused with tumors.
Chondrosarcoma of the head and neck, Chondrosarcoma is a malignancy rarely encountered in the head and neck. In an attempt to define this tumor's characteristics and response to therapy. all cases of chondrosarcoma treated at the University of Michigan over the past 25 years were retrospectively studied. Fourteen cases originating in the nose and paranasal sinuses. mandible. temporal bone. and larynx were reviewed. Aggressive surgical resection was the mainstay of treatment. and resulted in an overall survival of 70%. with an average follow-up of 3.5 years. Survival was highest in primary temporal bone lesions. and lowest in paranasal sinus lesions. Unresectable lesions were not cured by other modalities. This study. therefore. continued to support the crucial role of wide surgical resection in the treatment of head and neck chondrosarcoma. but conservative resection. when needed to preserve important structures. has resulted in long-term survival.
Selective management of early glottic cancer, Seventy patients with stage I and II glottic cancer were treated at the University of Utah School of Medicine hospitals from 1980 through 1987. Forty-four patients had stage I cancer and 26 patients had stage II. The overall survival in the stage I group was 82%. Primary site control was 93% with only three deaths due to laryngeal cancer. Local control rates were 93% with CO2 laser excision. 80% with CO2 laser and irradiation. and 67% with radiation alone. Stage II glottic patients had an overall survival of 61.5% with a local control rate of 76%. Twenty-one of 24 patients were treated by full-course irradiation. Of the eight patients who recurred at the primary site. all were irradiation failures who had initial bulky disease and impaired vocal cord mobility. Selective CO2 laser excision was highly effective. whereas radiation therapy results were somewhat disappointing. Open partial laryngectomy should be considered in bulky stage II disease patients.
The melanocyte and melanoma, This paper reviewed some of the interesting biological aspects of melanocytes and their relationship to the nevus and to melanoma. It also proposed a rationale for "adequate" surgery in the management of melanoma according to level. depth. margins. and trends in treatment. These propositions were derived from an analysis of 995 cases of melanoma of the head and neck.
The Cancer Prevention Reminder System, The Cancer Prevention Reminder System is a computer-based system designed to increase the delivery of periodic health maintenance procedures. The program provides printed reminders that identify patients' overdue procedures. prints summary reports of the percentage of patients who are eligible and overdue for a procedure. and prints mailing labels for patients. We performed a randomized. controlled trial in which the effects of computer-based reminders were compared with those of two other interventions among residents in a university-based group practice.
A computerized laboratory alerting system, A computerized laboratory alerting system (CLAS) has been developed as part of an ongoing effort to improve the quality of care at LDS Hospital. The system identifies potentially life-threatening conditions on the basis of laboratory findings and then generates appropriate warnings and transmits them to clinicians. Use of the system has led to a significant increase in the proportion of patients in life-threatening situations who have received appropriate care (50.8% before implementation vs. 62.5% afterward. P less than 0.05). Among patients with hypokalemia. falling potassium levels. hyperkalemia. hypokalemia during treatment with digoxin. hyponatremia. falling sodium levels. hypernatremia. hypoglycemia. or hyperglycemia. the average length of time spent in the life-threatening situation has decreased from 30.4 to 15.7 hours (P less than 0.05) and the average length of stay has decreased from 14.6 to 8.8 days (P less than 0.05). There has been little change in the proportion of patients with findings indicating metabolic acidosis who have received appropriate care (32.3 vs. 34.6%). We conclude that CLAS has an important role in patient care at our hospital.
Trends in lung cancer incidence and mortality--United States, 1980-1987 [published erratum appears in MMWR Morb Mortal Wkly Rep 1990 Dec 14;39(49):906, Lung cancer is the most common fatal malignant neoplasm in the United States. Based on current smoking patterns. the substantial public health burden of smoking-related lung cancer will continue during the next several decades. This report describes trends in lung cancer incidence from 1980 through 1986 and lung cancer mortality from 1980 through 1987.
Increased testosterone in type I diabetic subjects with severe retinopathy, Diabetic retinopathy rarely occurs before puberty. suggesting that changes in sex hormones may influence the development of this condition. The authors measured serum testosterone. estradiol. DHEA-S. and sex hormone binding globulin levels in 26 men and 22 women with type I diabetes from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). a population-based study of diabetic complications. The mean age was 23 years and the mean duration of diabetes was 14 years. Subjects with proliferative or preproliferative retinopathy (greater than or equal to retinopathy level 51-80) were matched by duration of diabetes (+/- 2 years) and sex to subjects with minimal or no retinopathy (less than or equal to retinopathy level 21). Seven stereoscopic retinal photographs of each eye were obtained and photographs were read by the University of Wisconsin Reading Center. Serum testosterone concentrations were significantly higher in male diabetic subjects with proliferative retinopathy (648 +/- 36 ng/dl) than in male diabetic subjects with minimal or no retinopathy (512 +/- 43 ng/dl) (P = 0.017). No other statistically significant differences in sex hormones between subjects with and without proliferative retinopathy were observed. Although these results should be regarded as preliminary because of the small number of subjects. they support the hypothesis that testosterone concentrations may be associated with the development of retinopathy in type I diabetic patients.
Lateral wall advancement in orbital decompression, Treatment of dysthyroid orbitopathy can be enhanced with a modified craniofacial approach using a lateral wall osteotomy. and anterolateral advancement and osteosynthesis in conjunction with medial and inferior wall orbital decompression. The technique of lateral wall advancement is described. and the results are discussed. While the authors advocate orbital decompression for dysthyroid optic neuropathy. advancement of the lateral orbital wall can easily be performed as an adjunct to the two- or three-wall decompression procedure. Advancement appears to increase the overall decompressive effect by providing a potential space where lateral expansion can occur and by enlarging the bony orbital volume. It also appears to lessen lid retraction and facilitates (and in some cases. obviates) the need for further lid retraction surgery.
Assessment of tear drainage after canalicular obstruction using fluorescein dye disappearance, Assessment of tear drainage impairment after monocanalicular obstruction can be difficult. The authors used fluorescein dye disappearance to evaluate tear drainage after experimental obstruction of upper. lower. neither. or both canaliculi in 20 subjects. Marked impairment was noted in all subjects when both canaliculi were occluded (P less than 0.004). Monocanalicular obstruction (either upper or lower) generally resulted in minimal or no impairment. though 10% of subjects showed marked impairment. Fluorescein dye disappearance proved a reliable. rapid method for assessing tear drainage and detecting lacrimal obstruction.
The national immunization program of The Netherlands, After a brief explanation of the immunization policy in the Netherlands. the national immunization program is described. with special attention given to coupling of the municipal population records with a computerized database of individual immunization records at the provincial level. The Dutch program achieves coverage rates greater than 90% for all routine immunizations. Participation in the program is free of charge to every child living in the country up to the age of 13 years. but there is no obligation or requirement to be immunized. Financing of the program is also discussed.
Excess injury mortality among children in the United States: comparison of recent international statistics, Using data from the National Center for Health Statistics and the World Health Organization. child injury death rates in the US were compared to those of Canada. England and Wales. France. Netherlands. and Norway. Except for the 1981 Canadian figure. overall US childhood injury mortality was greater than childhood injury mortality rates of all countries studied during each year from 1980 to 1986. Injury mortality steadily declined in most other countries. whereas the US rate appears to be increasing. Attention to specific causes reveals that much of the difference is explained by motor vehicle injuries and homicide. but in every childhood age group US death rates due to drowning. firearms. homicide. poisoning. and fire are among the highest. Excess US injury mortality is largely attributable to deaths among children younger than 5 and older than 14 years of age. the most vulnerable groups in all countries. Especially high rates among US minorities account for little of the observed differences; for many injuries. the mortality rate of US nonblacks is several times those reported by the comparison nations. Behavioral strategies are inadequate to deal with excess death rates of this magnitude. Limiting exposure through regulation of handguns. greater use of public transportation. and affordable and accessible day care are among the measures that should be implemented.
Unintended injuries in children: the French situation, The French situation with respect to mortality from unintentional injuries in children is far from satisfactory. International comparison is made difficult by statistical bias. but although excess injury mortality is decreasing in France. rates are higher than in most advanced European countries. Many regulations have been enacted during the past 30 years to reduce the economic and social burden of injuries. but political will is insufficient to establish a consolidated national program and enforcement of existing legislation is inadequate. Evaluation of preventive and educational programs is less than optimal; many attempts have not met basic methodologic requirements. The situation is improving. partly because of growing social concern. New regulations are in preparation. but solution of this major public health problem also demands behavioral change. which is much more difficult to effect than other measures. Greater commitment to research. proper evaluation of sound programs. and enforcement of existing law doubtless would reduce the excess morbidity and mortality resulting from unintended injuries to children.
Childhood injuries: where we are, In this paper we present the leading causes of fatal childhood injury in the United States. We examine three types of explanations for why injury rates are so high in the United States compared with what they could be and actually are in a number of industrialized European countries. Our conclusions are based on what we learn when we look at specific injury problems and apply that knowledge to the field of childhood-injury prevention as a whole. To decrease the number of fatal injuries to children. we should: 1. Recognize injuries as a major public health problem. Injuries have been perceived not as problems to be solved but as "accidents" which are determined by fate. not understandable. and consequently not preventable. In addition. injuries have not been addressed in the multidisciplinary fashion that typifies the successful public health approach to other problems. 2. Address intentional injury as part of the problem. Intentional injury has been treated as a separate field entirely and not addressed scientifically as a public health problem. One consequence of this is that injuries due to firearms have been addressed most frequently as a problem of "unintentional injury." As a result. 93% of all firearm injuries. ie. those which are intentional. have not been studied or addressed adequately. This situation is like studying motor vehicle injuries but excluding drunk driving and speeding as contributing factors. or like studying acquired immunodeficiency syndrome but ignoring anal intercourse or intravenous drug use. 3. Develop and support organizations that can plan and coordinate effectively a national approach to injury control.
Postneonatal infectious disease mortality: the French situation, Mortality caused by infectious and parasitic diseases represents a limited part of all postneonatal deaths in France. which have been stable for the past decade. This component is worthy of careful analysis because it is at least partially preventable. Statistics are presented and interpreted. with discussion on which disorders should be included in assessing the impact of infection on morbidity and mortality. Figures and international rankings change according to the inclusiveness of the definition chosen. There is need for epidemiologic and statistical research to make comparisons of mortality more clear. Morbidity is also important because of high incidence. frequent hospitalization. and a heavy social cost. Policy and services in France that relate to control and treatment of infection are described. as are shortcomings that call for further efforts.
Postneonatal mortality in Norway: a study of recent trends and comparison with other mortality rates in Norwegian children, Postneonatal mortality in Norway decreased rapidly from 1956 to 1980 but subsequently remained stable. In recent years the postneonatal death rate appears to be increasing. primarily due to greater numbers of deaths attributed to the Sudden Infant Death Syndrome. During the same period. mortality among older children has also decreased. with the decline evident in all leading causes. Only among people aged 15 to 19 years have recent trends been less than encouraging. with the number of fatal traffic accidents in particular remaining stable or increasing. Although there is room for continued improvement. the widely held belief that the health status of Norwegian children is good is supported by the trends in mortality.
Evaluating hematuria in children. Where to start and how to proceed, Bleeding from somewhere along the urinary tract is not unusual in children. Of the many causes. systemic infection and trauma are among the most common. History taking and physical examination should be careful and complete. because the results obtained help direct the laboratory evaluation. Diagnostic testing always begins with urinalysis but may progress to intravenous urography. voiding cystourethrography. endoscopic procedures in the upper and lower urinary tract. sonography. arteriography. or renal biopsy. Some cases remain unexplained and require follow-up to assess renal function.
Skiing and snowboarding injuries. When schussing is a pain, Downhill and cross-country skiing and snowboarding are growing rapidly in popularity. With the ever-increasing number of participants. physicians must be prepared to deal with the injuries specific to these sports. More important. physicians need to use epidemiologic data to advise patients of methods to minimize the risk of injury as they participate in these healthy and vigorous winter sports.
Hypothermia. Safe and efficient methods of rewarming the patient, Hypothermia. a relatively common problem in the winter months. can cause significant morbidity. It presents in a variety of situations and affects a wide age range. Diagnosis requires a high index of suspicion. because the symptoms. which are primarily related to the central nervous system. are not distinctive. Appropriate management requires accurate measurement of core body temperature. Treatment is centered on rewarming the patient safely and efficiently while providing other supportive measures. Care should be taken to avoid arrhythmias. Simple precautions greatly reduce the risk of hypothermia.
Frostbite. Methods to minimize tissue loss, If frostbite is to be treated successfully. direct and indirect effects of injury must be understood. Rapid rewarming helps to preserve tissue by limiting the amount of direct cellular injury. Selective management of blisters helps protect the subdermal plexus. and application of Aloe vera cream (eg. Dermaide Aloe Cream) combats the local vasoconstrictive effects of thromboxane. Oral administration of ibuprofen decreases systemic levels of thromboxane.
The effect of early fronto-orbital advancement on frontal sinus development and forehead aesthetics, The frontal sinuses make an important contribution to normal forehead and glabellar contour. This study was designed to test our clinical impression that early fronto-orbital ("frontal bone") advancement could have an adverse effect on frontal sinus development and consequently on forehead aesthetics. A retrospective study was conducted on 11 patients who had undergone fronto-orbital advancement and also had a long period of follow-up at the Institute of Reconstructive Plastic Surgery at New York University. The longitudinal cephalometric data were compared with unoperated controls. With one exception. no patient who underwent bilateral fronto-orbital advancement developed a frontal sinus. and all such patients had a flattened brow contour when compared with unoperated patients. of whom 82 percent developed at least one frontal sinus. Of the three patients who underwent unilateral fronto-orbital advancement for plagiocephaly (flattened forehead). two developed a frontal sinus but only on the unoperated side and one developed bilateral frontal sinuses. The two patients with unilateral frontal sinus development had a particularly obvious deformity resulting from normal glabellar projection on the unoperated side and a flattened contour on the operated side. Fronto-orbital advancement affects forehead aesthetics and should be performed only in infant patients with moderate to severe deformities. patients with plagiocephaly whose deformity is sufficiently severe to warrant surgery should preferably undergo bilateral fronto-orbital advancement (by the technique described) rather than unilateral advancement in order to avoid the brow asymmetry that results from unilateral frontal sinus development.
585 nm for the treatment of port-wine stains, Although the flashlamp-pulsed-dye laser has been successfully used for the treatment of port-wine stains (PWS) at 577 nm. a number of adult patients had incomplete clearance of their birthmarks with this treatment modality because of residual vessels lying beyond the 0.75-mm penetration depth of 577-nm irradiation. Fifteen adult patients. of whom nine were previously treated with limited success at 577 nm (group A). and six untreated patients (group B) were included in the study. For the group A patients. treatment with 585 nm produced successful clearance of the birthmark. For the six patients in group B. parallel treatment of different sites of the same lesion coupled with skin biopsies and histologic examination revealed that a change in the wavelength from 577 to 585 nm allowed the laser light to penetrate from the midreticular dermis into the subcutaneous fat. This explained the clearance achieved at 585 nm and not at 577 nm.
Reasons why mastectomy patients do not have breast reconstruction, Breast reconstruction after mastectomy is valuable. yet only a small percentage of eligible patients ever have reconstruction. Little has been done to determine why so few patients proceed with reconstructive surgery. A homogeneous population of mastectomy patients. some of whom underwent breast reconstruction while others did not. were surveyed regarding their attitudes about breast reconstruction. A total of 245 women were surveyed. One-hundred and fifty-eight (64 percent) responded. 71 of whom had been reconstructed while 87 had not. Comparison of the responses of the two groups suggests factors that play a role in determining whether the mastectomy patient will accept or decline the option of breast reconstruction. Considerations that made it less likely that a woman would pursue reconstruction included advanced age at the time of mastectomy. concern about complications from further surgery. uncertainty about outcome. and fear about the effect of reconstruction on future problems with breast cancer. Marital status. receiving chemotherapy. or knowing a patient who had a bad result from reconstruction did not affect the decision. An awareness and understanding of these factors may be helpful to physicians in counseling patients and in increasing the number of women who enjoy the benefits of breast reconstruction.
Mammographic measurements before and after augmentation mammaplasty, Thirty-five augmented women underwent mammography using both the standard implant-compression technique and. when possible. the implant-displacement technique; all had preaugmentation film-screen mammography available for evaluation. The area of mammographically visualized breast tissue before and after augmentation mammaplasty was measured using a transparent grid. Patients with subglandular implants had a mean decrease of 49 percent of measurable tissue area with compression mammography and a 39 percent decrease with displacement mammography. Patients with submuscular implants had a 28 percent decrease in measurable tissue area with compression mammography and a 9 percent decrease with displacement mammography. Anterior breast tissue was seen better with displacement mammography; posterior breast tissue. with compression mammography. Most patients had some degree of parenchymal scarring and lower image quality after augmentation. State-of-the-art mammography was not possible in most patients augmented with silicone-gel-filled implants.
The lateral arm fascial free flap: its anatomy and use in reconstruction, Free fascial transfer has been used for reconstruction of gliding surfaces of the upper and lower extremities or when thin. pliable coverage is required (hand. heel. nose. and ear). In our experience with the lateral arm fasciocutaneous flap. we have found that the fascia alone is an excellent source of tissue for free flap transfer. A thorough investigation of the microscopic. gross. and radiographic anatomy of the lateral arm fascia was undertaken by the study of 25 fresh cadavers. Vascular pathways were mapped. their locations were analyzed. and then they were correlated with the elevation. design. and transfer of the flap. The lateral arm has a large fascial component located anterior and posterior to the lateral intermuscular septum. which itself lies between the triceps and the brachialis and brachioradialis muscles. It is perfused by the posterior radial collateral artery (PRCA). one of the terminal branches of the profunda brachii. This vessel (PRCA) provides at least four fascial branches from 1 to 15 cm proximal to the lateral epicondyle. the largest of which is located an average of 9.7 cm superior to the lateral epicondyle. Fascia up to 12 x 9 cm may be used with good axial perfusion. The histologic cross sections demonstrate the complex anatomy of the fascia itself. as well as its relation to the nutrient vessels. We have applied the lateral arm fascial flap in five cases of upper extremity reconstruction. We have also found this flap valuable in preservation of underlying anatomic detail for total reconstruction of the ear and nose when local tissue and more conventional flaps were not available.
The efficacy of methylprednisolone in reducing flap edema, It has been suggested that systemic steroids reduce postoperative flap edema. This has been poorly documented by several reports based on subjective clinical observations. In an effort to provide quantitative data on methylprednisolone and edema. a flap edema model in the rat was developed based on the inferior epigastric vessels. Significant edema developed after 48 hours. Differing intraoperative doses of methylprednisolone were studied. producing a dose-response curve. A single low dose of intraoperative steroid is effective in reducing flap edema; previously recommended doses are probably excessive.
Treatment of chronic facial palsy by transplantation of the neurovascularized free rectus abdominis muscle, We performed neurovascularized free rectus abdominis muscle transplantations in two patients with chronic facial palsy. In one patient. the postoperative course was uneventful. but the patient died from rupture of esophageal varices. In the other patient. both morphologic and functional results were satisfactory. Therefore. the rectus abdominis muscle is considered to be a suitable donor for muscle transplantation for the treatment of chronic facial palsy. The rectus abdominis muscle is advantageous in that (1) simultaneous operations by two teams are possible with the patient in the supine position. (2) it is supplied by long nerves and long and large vessels. (3) it is flat and consists of segments with appropriate lengths. (4) the force and distance of contraction are appropriate. and (5) the tendinous intersections are suitable for anchoring sutures.
Combined tensor fasciae latae musculocutaneous flap and sartorius musculocutaneous flap for the repair of wide defects of the lower leg, The tensor fasciae latae musculocutaneous flap has great advantages for reconstruction of the abdominal wall. but the medial border of its territory is limited to the thigh. In order to expand the territory. a combined tensor fasciae latae musculocutaneous flap and sartorius musculocutaneous flap was devised. This flap was successfully used to resurface a large defect in the lower leg as a distally based musculocutaneous flap. The advantages of this flap are its extremely large territory. the fact that total necrosis of the flap cannot occur. and that as a proximally or distally pedicled flap it is suitable for large defects in the abdominal wall. lower leg. and gluteal region.
Surgical treatment for secondary retracted nose, This surgical technique is presented to correct nasal tip retraction. which is frequently associated with other surgical sequelae that can be corrected simultaneously. It is based on the use of a shield. an anchor. or half an anchor of otocartilage. with one or two posterior supports that are sutured together forming a small L and are fixed to the bed to project the nasal tip and. if necessary. to correct the unilateral or bilateral alar collapse.
Simplified technique for isolating vascularized rib periosteal grafts, A modified technique for obtaining a vascularized rib periosteal segment utilizing the posterolateral approach is presented. The technique avoids the inclusion of a large muscle cuff or the pleura around the isolated rib segment and therefore minimizes donor-site morbidity and chest complications previously associated with this approach.
A new method for the dressing of free skin grafts, Using adhesive drapes and a disposable suction drain. a new method for the dressing of free skin grafts has been devised. The graft is compressed by pressure that is equivalent to the negative pressure of the suction drain. This method can apply uniform and constant pressure on the graft. Moreover. the graft can be observed through a transparent drape so that the existence of hematomas can be detected easily.
Arthritis: roles of radiography and other imaging techniques in evaluation, Imaging studies are performed on patients with arthritis for a variety of reasons: to determine whether an arthritic condition is present; to establish the specific diagnosis; to determine the extent of disease; to assess the activity of disease; to detect complications of disease; to evaluate progression of disease; to judge the efficacy of drug treatment; to help in selection of surgical candidates; to aid in the choice of surgical procedures; to size. design. or fabricate prostheses; and to identify complications of surgery. Conventional radiography is still the mainstay of all examinations in arthritic patients. Arthrography is best applied to evaluate complications of disease and of surgery. although it may be useful in disease detection and in determining the specific diagnosis. Nuclear medicine studies are best used to identify complications of surgery and may also be useful to assess disease activity or extent. Ultrasound is useful to detect dissecting synovial cysts and deep venous thrombosis. The most valuable role of computed tomography is in the design and fabrication of prostheses and in evaluating complex anatomy of involved joints. Magnetic resonance imaging may be useful in early detection of articular cartilage damage and may assist in determination of the specific diagnosis; enhancement with contrast material may aid in assessment of disease activity.
Early cerebral infarction: gadopentetate dimeglumine enhancement, Gadopentetate dimeglumine was administered prospectively to 50 patients who presented for magnetic resonance (MR) imaging within 2 weeks after a cortical cerebral infarction. Twenty-two patients (44%) were imaged within 3 days after clinical ictus. Abnormalities detected with gadopentetate dimeglumine enhancement were observed in 46 (92%) of 50 patients. Classic parenchymal enhancement was a late finding. observed in all patients (17 of 17) imaged at 7-14 days after infarction. Before this time. three additional phases of contrast material-related abnormalities were observed. Enhancement of vessels supplying the infarct ("intravascular enhancement sign") was the earliest finding. seen in 17 (77%) of 22 infarcts aged 1-3 days. From day 2 to day 6. abnormal enhancement of meninges adjacent to the infarct was frequently noted ("meningeal enhancement sign"). Finally. a transition phase that combined intravascular or meningeal enhancement with early parenchymal enhancement was seen from day 3 to day 6. Gadopentetate dimeglumine-enhanced MR imaging in early stroke reveals evidence of vascular engorgement and sluggish flow. which precede the development of classic parenchymal enhancement.
Metabolism of human gliomas: assessment with H-1 MR spectroscopy and F-18 fluorodeoxyglucose PET, Localized hydrogen-1 magnetic resonance (MR) spectroscopy and fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) were employed to obtain metabolic information from intracranial gliomas. Advantages and difficulties associated with comparison of results from the two modalities were realized. Forty patients were studied with H-1 MR spectroscopy. MR signal intensities from lactate. N-acetylaspartate (NAA). choline. and creatine from a volume of interest containing the tumor and a contralateral volume were obtained and evaluated. NAA signal intensities were generally decreased in the tumor spectra. and choline signal intensities were elevated. H-1 MR spectroscopy was unsuccessful in eight patients. and FDG PET scans were not obtained in four of the patients with successful MR spectroscopic examinations. Lactate signal intensity was detected in 10 of the 28 patients who had successful H-1 MR spectroscopic and FDG PET studies. Lactate signal intensities were observed in lesions shown at FDG PET to be hypermetabolic. as well as in lesions found to be hypometabolic.
Chemical shift imaging of human brain: axial, sagittal, and coronal P-31 metabolite images, Multivoxel magnetic resonance (MR) spectroscopy and novel data analysis techniques were developed to obtain high-quality phosphorus-31 metabolite images from the human brain and to overlay each metabolite distribution directly onto corresponding hydrogen-1 MR images. The P-31 MR spectroscopic data were acquired by means of three-dimensional chemical shift imaging (phase encoding in three spatial dimensions) on a 1.5-T clinical instrument equipped with a specially designed quadrature P-31 birdcage coil constructed in the authors' laboratory. Axial. sagittal. and coronal metabolite images based on the area for any one of five peak regions (phosphodiester; phosphocreatine; gamma. alpha. and beta adenosine triphosphate) were generated from 8 X 8 X 8 or 12 X 12 X 8 CSI arrays with voxel sizes of 27 cm3 and 12 cm3. respectively. The positions of these images were aligned with anatomic features by means of the voxel-shifting capability of the Fourier transform. Direct overlays of these metabolite images on corresponding proton images demonstrated excellent correlation with anatomy. factors indicating the utility of this technique for viewing P-31 metabolite levels in all areas of the brain simultaneously.
Parotid gland: plain and gadolinium-enhanced MR imaging, The purpose of this study was to show the typical appearance of lesions of the parotid gland with plain MR imaging and MR imaging enhanced with gadopentetate dimeglumine. Seventeen patients with inflammatory changes and 43 with benign and malignant tumors were studied. The examinations were carried out with plain T1-weighted sequences with a repetition time (TR) of 500 msec and an echo time (TE) of 25 msec (TR/TE = 500/25). T2-weighted sequences (1.600/90). and gadolinium-enhanced T1-weighted sequences in axial. coronal. and sagittal orientations. For identifying normal anatomic structures such as the facial nerve and the main duct. the administration of gadopentetate dimeglumine was helpful. In inflammatory changes. gadolinium-enhanced images showed no diagnostic advantages. Gadopentetate dimeglumine proved helpful in delineating tumorous lesions and in differentiating benign and malignant lesions. However. an exact differentiation of the different histologic types was not possible. Post-operative fibrosis could be differentiated from recurrent tumors after administration of gadolinium. If a question regarding infiltration or definition of the boundaries of a lesion cannot be answered with non-enhanced MR imaging. gadopentetate dimeglumine administration is advised. However. for routine imaging of the parotid gland. its use is not recommended.
Rhabdomyosarcomas in the head and neck: MR imaging evaluation, To determine the typical magnetic resonance (MR) signal intensity characteristics of rhabdomyosarcomas. short repetition time (TR)/short echo time (TE) (T1-weighted) and long TR (proton density and T2-weighted) images of 13 patients with rhabdomyosarcomas of the head and neck were retrospectively reviewed. Seven patients received gadopentetate dimeglumine injections. The most common MR appearance was that of a homogeneous mass. hyperintense to both muscle and fat on long TR/long TE images and isointense or minimally hyperintense to muscle on short TR/short TE images. All lesions of the patients who received gadopentetate dimeglumine enhanced markedly. Two lesions had intratumoral hemorrhage. and six were markedly heterogeneous in signal intensity. Similar MR signal intensity patterns have been described for lymphomas and nasopharyngeal carcinomas. The forte of MR imaging lies in its ability to delineate precisely the extent of the rhabdomyosarcoma.
Epiphora: treatment by means of dacryocystoplasty with balloon dilation of the nasolacrimal drainage apparatus, A new interventional radiologic procedure was developed for treatment of epiphora. A small-bore. soft-tipped guide wire was introduced through the superior canaliculus and guided under fluoroscopic control through the nasolacrimal drainage system for retrieval through the nasal aperture. A small-bore angioplasty catheter was then introduced in a retrograde direction into the nasolacrimal drainage apparatus and dilated under fluoroscopic control. The procedure was attempted in 18 eyes of 17 patients with moderate to severe epiphora and was technically completed in 16; 13 of these cases demonstrated improvement. with 11 patients showing complete resolution of symptoms. In the three patients whose epiphora did not improve. no worsening of symptoms occurred. These results are preliminary; follow-up ranged from 7 weeks to 6 months. The authors believe that this technique may hold promise in the treatment of epiphora and may obviate the use of more invasive procedures.
Colorectal tumors: an in vitro study of high-resolution MR imaging, To study the potential utility of magnetic resonance (MR) imaging in staging colorectal tumors. 15 resected colonic segments containing 17 elevated lesions were examined on a 1.5- or 1.9-T superconductive MR system. The whole intestinal wall was apparent as three or five layers on images obtained with a short repetition time (TR) and short echo time (TE) and as six or eight distinct layers. including the intestinal wall proper as well as an adherent mucus layer and an outer layer of pericolonic fat. on the long TR/TE images. In cases of colonic carcinoma. MR images correlated well with the pathologic findings. including the macroscopic growth pattern. depth of mural invasion. and the presence of foci of calcific tumor necrosis and pools of extracellular mucin (colloid). These features suggest that MR imaging may be valuable in the clinical evaluation of colorectal tumors.
Feasibility of digital teleradiology for imaging evaluation of patients with acute right upper quadrant abdominal pain, To assess the utility of a commercially available digital teleradiology system in evaluating patients with acute pain in the right upper quadrant. hard-copy images from 100 examinations (50 hepatobiliary scintigrams and 50 sonograms of the right upper quadrant) were digitized. transmitted via standard telephone lines. and viewed remotely on a video monitor. Video and hard-copy interpretations were then compared for degree of concordance. For the scintigraphic studies. hard-copy and video images were equal in demonstrating gallbladder and bile duct activity. Video images failed to depict the presence of bowel activity in one case. Gallstones were depicted equally well on hard-copy and video sonographic images. The video interpreters overestimated the presence of abnormal hepatic parenchyma and overlooked one case of right hydronephrosis. The video interpretations of the scintigrams and sonograms showed an overall error rate of 4%. comparable to the rate obtained when radiographs are interpreted remotely with digital teleradiology systems.
Hepatic tumors: signal enhancement at Doppler US after intravenous injection of a contrast agent, Experiments were carried out to detect and establish the origin of Doppler and echo signal enhancement in small vessels of the systemic circulation and of tumors after intravenous injection of a contrast agent. Eight woodchucks (Marmota monax) were studied; each woodchuck had naturally occurring hepatocellular carcinoma. Injections of 0.1-4.0 mL of air-filled human serum albumin microspheres were administered into a hind limb or jugular vein. Ultrasound (US) examination included transabdominal duplex scanning. color Doppler imaging. placement of a Doppler transducer on the exposed tumor. and surgical implantation of pulsed Doppler cuffs. Doppler signals were assessed by recording color Doppler images and results of spectral analysis. While subjective echo level was unaffected within the tumors. dramatic Doppler signal enhancement was recorded in both normal and tumor vessels. At optimum dose levels. a signal gain of approximately 10 dB was recorded from the tumor. Analysis showed that the echo enhancement was due to the presence of the contrast agent in branches of the hepatic artery. These results suggest that tumor detection may be enhanced by intravenous administration of a US contrast agent.
Extracorporeal cholecystolithotripsy without oral chemolitholysis, One hundred thirty-six patients completed extracorporeal biliary lithotripsy (EBL) for symptomatic cholecystolithiasis. Sonographic evidence of complete clearance of all stone fragments was the only criterion for treatment success. which occurred in 32 of the 71 patients (45%) followed up for 24 weeks and in 36 of the 59 patients (61%) followed up for 52 weeks. The authors' protocol varied from protocols of other researchers primarily in that no adjuvant chemolitholysis was used. However. the number of treatment sessions and total number of shock waves (a maximum of 4.000 shock waves per treatment session. 12.000 shock waves in a patient demonstrating no significant fragmentation. and 20.000 shock waves in a patient whose stones responded well to fragmentation) was higher than those in other reports. The results of treatment and complication rates in this study are comparable with those at centers using both shock-wave lithotripsy and chemotherapy. The authors conclude that EBL is developing into an important alternative to surgery. which was obviated in all patients with complete clearance of fragments from the gallbladder.
Receptor imaging: application to MR imaging of liver cancer, A new contrast agent for magnetic resonance (MR) imaging. directed to asialoglycoprotein (ASG) receptors on hepatocytes. was used for detection of liver cancer in rats. Ultrasmall superparamagnetic (mean size. 12 nm) particles of iron oxide (USPIOs) were targeted to ASG receptors by coating particles with arabinogalactan (AG). Liver T2 relaxation times decreased more effectively after a single intravenous administration of AG-USPIO than after an equal dose of a conventional superparamagnetic liver MR contrast agent (AMI-25; mean size. 72 nm). Receptor affinity studies demonstrated that receptor-mediated attachment and subsequent cellular endocytosis do not occur in primary malignant (hepatocellular carcinoma) or metastatic (adenocarcinoma) tumors. because the surface ASG receptors are lost during malignant dedifferentiation. In vitro relaxation and in vivo MR imaging experiments of liver tumors show that targeting USPIO to hepatocytes rather than to the mononuclear phagocytic system allows a considerable dose reduction. increases tumor-liver contrast. and potentially allows distinction of ASG-positive (benign hepatocellular) and ASG-negative (malignant hepatocellular) tumors.
Persistent right umbilical vein: an ominous prenatal finding, The persistence of a right umbilical vein is an uncommon finding. with only a dozen cases reported since 1826. The persistent right umbilical vein may replace the normal left umbilical vein or be supernumerary. The anomaly is associated with numerous and occasionally lethal malformations. In this series. only three of six fetuses (and another two in the literature) had no associated anomalies. All the others had a variety of associated lesions ranging from minor to lethal. The appearance at ultrasound is easy to recognize: The intrahepatic portion of the umbilical vein is lateral to the gallbladder. and the portal vein curves toward the stomach. instead of parallel to it. Since the recognition of the persistent right umbilical vein is simple and does not require additional scanning (it is visible in the section used to measure the abdominal perimeter). the author suggests using it as an indicator for more in-depth scanning.
In vivo human testicular function assessed with P-31 MR spectroscopy, The clinical feasibility of assessing testicular metabolic integrity with phosphorus-31 magnetic resonance (MR) spectroscopy was investigated in six healthy volunteers and 23 patients with azoospermia. MR spectroscopic findings were compared with sperm count and motility in all patients and with findings at testicular biopsy in 23 patients. Significant differences (P less than .05) were found between the P-31 spectra of normal and azoospermic testicles in the following peak area ratios: phosphomonoester (PM)/beta-adenosine triphosphate. PM/phosphodiester. and inorganic phosphate/PM. In the patients with azoospermia. there were significant differences in these same peak area ratios between patients with primary testicular failure and those with chronic tubular obstruction. Although the differences between these two groups were statistically significant. there was a large overlap in numbers. and therefore a study with a larger patient population will be required. P-31 MR spectroscopy is a sensitive tool for assessment of testicular metabolic integrity and differentiation of normal testicles from those with markedly decreased spermatogenesis.
Intrauterine spermatic cord torsion in the newborn: sonographic and pathologic correlation, In five newborn patients with spermatic cord torsion. sonography demonstrated an enlarged and globular testis. hydrocele. and skin thickening. In four of these patients the testicular parenchyma was heterogeneous. Peripheral hypoechoic areas were seen in two of the four patients; the other two had a central hypoechoic region and a peripheral echogenic rim. The testis in the fifth patient was diffusely hyperechoic. Duplex Doppler sonography performed in two patients failed to demonstrate any signal in the spermatic cord in either the abnormal or contralateral hemiscrotum. Scintigraphic findings were positive for testicular torsion in two patients and equivocal in three patients. Surgery was performed 2-12 days after sonography and established the diagnosis of spermatic cord torsion. Pathologic examination demonstrated hemorrhagic infarction of the entire testis as well as scattered calcifications. The authors conclude that a solid globular testicular mass seen during the neonatal period is suggestive of intrauterine spermatic cord torsion.
Focal fibrocartilaginous dysplasia associated with tibia vara, Focal fibrocartilaginous dysplasia of the tibia at the insertion of the pes anserinus (the expanded tendinous insertion of the gracilis. sartorius. and semitendinous muscles) is a rare unilateral lesion with a characteristic deformity of the proximal tibial metadiaphysis. It is associated with unilateral tibia vara in toddlers. Three cases of this entity are described. and the radiologic features are presented. Recognition of this disease is important because the response to conservative therapy is excellent.
Inferior vena caval filter thrombi: evaluation with intravascular US, A 20-MHz intravascular ultrasound (US) transducer inside a percutaneously inserted catheter was used to evaluate inferior vena caval (IVC) filters for thrombi in vitro and in vivo. Six different IVC filters were studied with intravascular US in a saline-filled model. Each filter had a characteristic. recognizable US pattern. Experimental thrombi as small as 0.5 cm3 were easily detected. Intravascular US was used clinically 25 times to evaluate the IVC in 23 patients with 24 IVC filters. Positive-contrast cavograms were available for comparison in all 25 cases. In 13 cases. no thrombi were identified in the filter or IVC with either intravascular US or cavography; in five of 12 cases with thrombi. intravascular US and cavography demonstrated the thrombi equally well. In six cases. intravascular US was superior to cavography in detection or delineation of thrombus in the IVC or filter. Intravascular US was considered superior to external duplex US in evaluation of caval thrombi in all 21 cases available for comparison. No complications from intravascular US were noted.
Obstructive jaundice: use of expandable metal endoprosthesis for biliary drainage. Work in progress, Expandable metal endoprostheses were implanted transhepatically in 61 patients with obstructive jaundice. Fifty-three patients had malignant and eight had benign obstructions. Because of the small diameter of the compressed stent (7 F). primary implantation of the stent without a previous catheter drainage was preferred. Postprocedural complications occurred in three patients (5%) (biliary pleuritis. peritonitis. hepatic artery aneurysm). The 30-day mortality rate was 8.2%. Reocclusions were observed in six of the patients with malignant obstructions (11%) (observation period. 1-10 months; mean. 4.5 months) and in two of the patients with benign stenoses (25%) (observation period. 3-21 months; mean. 9 months). The higher reocclusion rate of benign obstructions must be interpreted with care because of the small number of patients. From their preliminary experience. the authors conclude that expandable metal endoprostheses offer patency rates equal to those of plastic stents. The implantation trauma is reduced due to the small 7-F introducing catheter system.
Iliac artery stenosis and occlusion: preliminary results of treatment with Gianturco expandable metallic stents, Ten patients with atherosclerotic stenosis or occlusion of the iliac artery were treated with Gianturco expandable metallic stents. In the five cases of stenosis. only balloon dilation was performed prior to placement of stents. The five patients with occluded arteries were given intraarterial infusions of urokinase before balloon dilation and stent placement. Clinical symptoms improved in all patients. and no technical failures or complications occurred. Doppler ankle-brachial index studies were performed in nine cases. and in all nine cases the indexes improved after stent placement. During follow-up of 2-18 months (mean. 10.3 months). all arteries remained patent. Follow-up angiograms showed slight intimal thickening and no restenosis. Long-term follow-up and more clinical experience will be necessary to evaluate the efficacy of this stent. However. preliminary results suggest that the Gianturco expandable metallic stent is of value in the treatment of arterial occlusive disease.
Invasive papillary carcinoma of the breast: mammographic appearance, The mammographic findings in 18 patients with invasive papillary carcinoma were studied retrospectively. The mammograms of 10 patients showed a multinodular pattern. and seven patients had solitary nodules. One patient had an irregular. ill-defined mass in the retroareolar region. Two patients were found to have carcinoma in the contralateral breast. and two patients had intraductal carcinoma adjacent to the invasive papillary carcinoma. The varied mammographic features that may occur with this rare breast malignancy are discussed.
Neuromuscular diseases: evaluation with high-frequency sonography, Forty-four patients with clinically suspected neuromuscular disease and 12 healthy volunteers underwent high-frequency ultrasound examination of the rectus femoris. vastus medialis. vastus lateralis. and biceps brachii muscles. and the number of perimysial septa was determined. These numbers and muscle/soft-tissue ratios of the lower extremity were compared. Findings were correlated with results of muscle biopsy in all patients with suspected disease. Using the number of perimysial septa in the lower extremity. the authors found significant differences between the muscles of healthy volunteers and those of patients with Duchenne muscular dystrophies. other muscular dystrophies. and spinal muscular atrophies: The receiver operating characteristic curve showed that an average of 12 perimysial septa within 1 cm of muscle is the ideal cutoff value to differentiate subjects without morphologic changes from those with pathologic findings. The authors conclude that this measurement is useful for differentiation of neuromuscular diseases and may be a noninvasive. reproducible means with which to evaluate disease progression.
Search and nonsearch protocols for radiographic consultation, Six radiologists. acting as radiograph reviewers. used two different consultation protocols to differentiate among 292 ambiguous chest radiographic findings: 120 simulated nodules and 172 normal findings (previous readers' false-positive reports of nodules). The nonsearch protocol identified each finding (by film location). and reviewers rated the likelihood of each finding's being a pulmonary nodule. The search protocol asked reviewers to report and rate all locations regarded as possible nodules on each radiograph and assigned a default negative rating to any unreported finding (nodule or normal structure). Receiver operating characteristic analyses demonstrated a significantly higher accuracy for each reviewer's search-protocol discriminations between these nodules and ambiguous normal findings. This superiority-of-search result suggests that radiologists' second opinions about suspected lesions might be more accurate when consultants follow a search protocol. independently reviewing radiographs without prior knowledge of the specific findings that concerned the primary radiograph readers.
Potential usefulness of an artificial neural network for differential diagnosis of interstitial lung diseases: pilot study, An artificial neural network approach was applied to the differential diagnosis of interstitial lung diseases. The neural network was designed to distinguish between nine types of interstitial lung diseases on the basis of 20 items of clinical and radiographic information. A data base for training and testing the neural network was created with 10 hypothetical cases for each of the nine diseases. The performance of the neural network was evaluated by means of receiver operating characteristic analysis. The decision performance of the neural network was high; it was comparable to that of chest radiologists and superior to that of senior radiology residents. The preliminary results strongly suggest that the neural network approach has potential utility in the computer-aided differential diagnosis of interstitial lung diseases.
Pulmonary masses: contrast enhancement, Radiographic studies to discriminate benign from malignant pulmonary masses have previously focused on the morphologic and. more recently. the computed tomographic (CT) attenuation characteristics of the lung mass. Experience with the use of an intravenously administered iodinated contrast medium in examining the enhancement properties of lung masses was reviewed. Distinctive differences in the vascularity. pathophysiologic features. and pharmacodynamics of malignant versus benign pulmonary masses were identified. Forty-five patients with peripheral pulmonary masses were examined. Enhancement was evaluated by means of optical density values measured on trispiral tomograms of the lung masses before and after bolus injection of contrast medium. Results suggest that contrast enhancement of pulmonary masses can be measured on sectional images and that this may become a feasible diagnostic method in the detection of lung cancer. CT offers a simplified technique that is now being explored by the authors.
Retroviral recombination and reverse transcription, Recombination occurs at a high rate in retroviral replication. and its observation requires a virion containing two different RNA molecules (heterodimeric particles). Analysis of retroviral recombinants formed after a single round of replication revealed that (i) the nonselected markers changed more frequently than expected from the rate of recombination of selected markers; (ii) the transfer of the initially synthesized minus strand strong stop DNA was either intramolecular or intermolecular; (iii) the transfer of the first synthesized plus strand strong stop DNA was always intramolecular; and (iv) there was a strong correlation between the type of transfer of the minus strand strong stop DNA and the number of template switches observed. These data suggest that retroviral recombination is ordered and occurs during the synthesis of both minus and plus strand DNA.
Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms, Familial cancer syndromes have helped to define the role of tumor suppressor genes in the development of cancer. The dominantly inherited Li-Fraumeni syndrome (LFS) is of particular interest because of the diversity of childhood and adult tumors that occur in affected individuals. The rarity and high mortality of LFS precluded formal linkage analysis. The alternative approach was to select the most plausible candidate gene. The tumor suppressor gene. p53. was studied because of previous indications that this gene is inactivated in the sporadic (nonfamilial) forms of most cancers that are associated with LFS. Germ line p53 mutations have been detected in all five LFS families analyzed. These mutations do not produce amounts of mutant p53 protein expected to exert a trans-dominant loss of function effect on wild-type p53 protein. The frequency of germ line p53 mutations can now be examined in additional families with LFS. and in other cancer patients and families with clinical features that might be attributed to the mutation.
Diet-induced hypercholesterolemia in mice: prevention by overexpression of LDL receptors, The current studies were designed to determine whether chronic overexpression of low density lipoprotein (LDL) receptors in the liver would protect mice from the increase in plasma LDL-cholesterol that is induced by high-fat diets. A line of transgenic mice was studied that express the human LDL receptor gene in the liver under control of the transferrin promoter. When fed a diet containing cholesterol. saturated fat. and bile acids for 3 weeks. the transgenic mice. in contrast to normal mice. did not develop a detectable increase in plasma LDL. The current data indicate that unregulated overexpression of LDL receptors can protect against diet-induced hypercholesterolemia in mice.
A borna virus cDNA encoding a protein recognized by antibodies in humans with behavioral diseases, Borna disease virus (BDV) causes a rare neurological disease in horses and sheep. The virus has not been classified because neither an infectious particle nor a specific nucleic acid had been identified. To identify the genome of BDV. a subtractive complementary DNA expression library was constructed with polyadenylate-selected RNA from a BDV-infected MDCK cell line. A clone (B8) was isolated that specifically hybridized to RNA isolated from BDV-infected brain tissue and BDV-infected cell lines. This clone hybridized to four BDV-specific positive strand RNAs (10.5. 3.6. 2.1. and 0.85 kilobases) and one negative strand RNA (10.5 kilobases) in BDV-infected rat brain. Nucleotide sequence analysis of the clone suggested that it represented a full-length messenger RNA which contained several open reading frames. In vitro transcription and translation of the clone resulted in the synthesis of the 14- and 24-kilodalton BDV-specific proteins. The 24-kilodalton protein. when translated in vitro from the clone. was recognized by antibodies in the sera of patients (three of seven) with behavioral disorders. This BDV-specific clone will provide the means to isolate the other BDV-specific nucleic acids and to identify the virus responsible for Borna disease. In addition. the significance of BDV or a BDV-related virus as a human pathogen can now be more directly examined.
Biopsy of the breast for mammographically detected lesions, We prospectively studied 718 women who underwent biopsy of the breast for suspicious. mammographically detected mammary lesions in an attempt to identify key clinical risk factors. as well as roentgenographic characteristics associated with the appearance of early carcinoma of the breast. Patients with a benign outcome had an average age of 55 years versus 63 years for patients with carcinoma of the breast. Seventy-six per cent of these patients had no previous history of mammary problems. 20 per cent had a positive family history for carcinoma of the breast. 58 per cent were premenopausal and 21 per cent had used birth control pills. Except for age (p less than 0.001). the distribution of clinical risk factors was equal among patients with benign or malignant outcomes. Suspicious mammographic findings included mass lesions (53 per cent). calcifications (36 per cent) and the association of both (11 per cent). The predominant Wolfe pattern on mammography was P1 (36 per cent). No relationship was observed between Wolfe pattern and malignant conditions. In this group of patients. mammography was poorly specific; however. the positive predictive value increased with age and is related to the age-specific prevalence of carcinoma of the breast. Eight hundred and twenty-five lesions were removed. Twenty-five per cent (n = 203) of the specimens taken at biopsy contained carcinoma. Stellate mass lesions were highly suggestive of a malignant growth (p less than 0.0001). No relationship between the size of the suspicious mammographic mass and the malignant lesion was observed. A marked correlation (chi-square test with Yate's correction) was observed between malignant tumor and lesions with a linear or branching pattern. more than 15 calcifications. or small sized calcifications. The presence of a mass with calcifications was associated with carcinoma in 34 per cent. The incidence of invasive carcinoma was much higher for mass lesions (81 per cent) than for suspicious calcifications (56 per cent) (p less than 0.0001).
Trends in conserving treatment of invasive carcinoma of the breast in females, This population-based study presents trends in the treatment of node-negative invasive carcinoma of the breast in females during the 1980s in the Detroit metropolitan area. It was done to determine whether or not there has been a significant shift toward conservation of the breast from 1980 to 1987. Trend analyses of surgical treatment. tumor size. node status. year of diagnosis. age and race were performed for 13.217 patients drawn from the Metropolitan Detroit Cancer Surveillance System. A significant increase in the use of conserving the breast was observed. with younger women receiving this treatment option more often than older women. Implications for a continuing shift in the biologic findings and treatment of carcinoma of the breast are discussed.
Correlation between hyperthermoradiosensitivity and clinical effect in carcinoma of the esophagus, The correlation between hyperthermoradiosensitivity evaluated by an in vitro succinate dehydrogenase inhibition (SDI) test and the histopathologic effects of hyperthermochemoradiotherapy (HCR therapy) were investigated in 43 patients with carcinoma of the esophagus. The succinate dehydrogenase (SD) activity of tissue fragments taken at biopsy was assayed after exposure to heat (43 degrees C.) and radiation (6 grays) was done. The sensitivity to radiation plus heat treatment was estimated by the percentage of SD activity of the treated cells. compared with that of the control cells. The 43 patients were divided into three groups according to the degree of SD activity after exposure to radiation plus heat treatment. The SD activity was less than 50 per cent in group 1 (highly sensitive). between 50 and 70 per cent in group 2 (moderately sensitive). more than 70 per cent in group 3 (less sensitive). Eighteen of 20 in group 1. 11 of 17 in group 2 and two of six in group 3 were classified as being histopathologically "effective" for HCR therapy. The two year survival rate for groups 1. 2 and 3 were 55.5. 34.9 and zero per cent. respectively. while there were no statistical differences with regard to prognostic factors. These data suggest that in vitro activities of SD correlate well with the clinical effectiveness of HCR therapy. Therefore. it is recommended that a SD inhibition test be included among the guidelines for clinical management.
The role of preoperative radionuclide ventriculography in defining outcome after revascularization of the extremity, Revascularization of the extremity was performed upon 110 patients after preoperative radionuclide ventriculography (RNVG). Mean ejection fraction (EF) was 50 +/- 13 per cent. Ventricular wall motion abnormalities were present in 46 per cent. Revascularization included inflow procedures. such as aortofemoral (n = 25) or extraanatomic bypass (axillofemoral or femorofemoral. n = 11); infrainguinal reconstruction. including femoropopliteal or distal bypass (n = 43). and other procedures to improve perfusion of the limb or correct complications after previous vascular reconstruction upon the extremity (n = 31). Perioperative (30 days) mortality rate was 0.9 per cent and 97.0 per cent of the patients were discharged alive from the hospital. Myocardial infarction (MI) occurred in 3.6 per cent. new ventricular arrhythmia in 1.8 per cent and congestive heart failure in 6.4 per cent of the patients during the perioperative period. During follow-up study (607 +/- 363 days). 7.3 per cent required major amputation. ipsilateral to reconstruction. 5.5 per cent required surgical or angiographic revision for hemodynamic failure of the reconstruction prior to thrombosis and 12.7 per cent thrombosed part or all of the reconstruction. Revascularization failure did not appear to be related to the level of cardiac function. Those with normal (greater than 50 per cent) EF had greater over-all survival by life table analysis than those with EF less than or equal to 50 per cent (p = 0.0006. Mantel-Cox test). Ventricular wall motion abnormalities were associated with reduced over-all survival (p = 0.008. Mantel-Cox test). The presence of angina or previous MI. singularly or in combination. did not have an adverse effect on over-all survival. whereas diabetes (p = 0.0058. Mantel-Cox test) and cigarette smoking (p = 0.0137. Breslow test) were associated with significantly diminished over-all survival. Preoperative RNVG can identify subgroups at a survival disadvantage after revascularization of the extremity in a population in which the presence of angina or previous MI does not predict survival.
Therapeutic dilemmas associated with antenatally detected ovarian cysts, Fifteen instances of ovarian cysts detected antenatally are reported. Seven cysts more than 5 centimeters in diameter were treated surgically because of clinical signs. such as palpable abdominal mass. vomiting and abdominal distension. Seven cysts less than 5 centimeters in diameter. and one cyst more than 5 centimeters in diameter began to regress spontaneously within six months after birth. Because the pathophysiologic nature of neonatal ovarian cysts has not been elucidated and because the borderline between physiologic and pathologic factors is still unclear. we propose a more conservative approach in the management of neonatal ovarian cysts to avoid unnecessary operations.
Simplified technique for control of femoral arterial bleeding after coronary angioplasty, A method of achieving arterial control by inserting an embolectomy catheter through the femoral introducer sheath in the patient with femoral arterial bleeding after PTCA is described herein. This approach allows quick control with less dissection and negligible blood loss.
Virologic and immunologic aspects of acquired immunodeficiency syndrome, From the initial clinical descriptions of the acquired immunodeficiency syndrome (AIDS) in 1981 to the present time. much has been discovered concerning the epidemiologic factors. pathogenesis. treatment and prevention of this disease. Recent advances in epidemiology have included a better understanding of the occupational risk of human immunodeficiency virus (HIV) infection after percutaneous exposure (responsible for approximately 0.4 per cent of instances). an appreciation of the potential variability in the time interval between infection and seroconversion (generally on the order of three months but occasionally longer) and establishment of the need for intimate contact to transmit infection. Following the discovery of HIV-1 as the etiologic agent of AIDS. many rapid advances have been possible including the development of screening tests. elucidation of the HIV-1 genome and the discovery that the CD4 T lymphocyte is the predominant cell destroyed by HIV-1. Progressive destruction of CD4 T cells results in a progressive decline in immunologic function that may take a variety of clinical forms. ranging from no symptoms to severe opportunistic infections. The delineation of the life cycle of HIV-1 has helped in the development of antiretroviral therapies. including agents that interfere with reverse transcription (nucleoside analogues. such as zidovudine. dideoxycytidine. dideoxyinosine and azidodideoxyuridine) and agents that interfere with viral assembly (protease inhibitors and interferon alpha). A more precise understanding of the nature of the immune response elicited after HIV-1 infection has resulted in the development of several candidate HIV-1 vaccines. including recombinant vaccinia viruses expressing the HIV-1 envelope and recombinant envelope proteins.
Cerebral blood flow velocities in the anterior cerebral arteries and basilar artery in hydrocephalus before and after treatment, We studied Pourcelot's index (PI). which shows cerebral vascular resistance. in the anterior cerebral arteries and basilar artery. and the PI ratio (Pourcelot's index in the anterior cerebral artery/Pourcelot's index in the basilar artery) in 11 measurements of hydrocephalus. The mean values of PI in the anterior cerebral artery. basilar artery. and the PI ratio before treatment were significantly higher than those after treatment and those in normal infants. Before treatment. the mean PI in the anterior cerebral arteries was significantly higher than the mean PI in the basilar artery. All PI ratios increased to 1.00 or more. After treatment and in normal infants. the mean PI in the anterior cerebral arteries was significantly lower than the mean PI in the basilar artery. All PI ratios decreased to less than 1.00. We believe that the PI ratio is useful to evaluate the need or effect of treatment in hydrocephalus.
Cerebral hemodynamics in patients with normal pressure hydrocephalus: correlation between cerebral circulation time and dementia, Regional cerebral blood flow and regional cerebral circulation time were measured in 13 demented patients with chronic hydrocephalus. mostly normal pressure hydrocephalus. The average hemispheric. frontal. and temporal cerebral blood flows were significantly reduced. The average regional cerebral circulation time values were significantly prolonged in the frontal. temporal. and thalamic regions. most markedly in the frontal white matter. where periventricular lucency was observed on computed tomography. Clinical improvement was obtained in all patients after operation. While postoperative regional cerebral blood flow values did not change compared with preoperative ones. postoperative regional cerebral circulation time values were significantly reduced in all the regions measured. and most markedly in the frontal white matter. The present results suggest that microcirculation in the frontal lobe is closely correlated with dementia in association with pressure exerted on the nerve fibers in the frontal white matter in patients with normal pressure hydrocephalus.
Effects of 1.32-micron Nd-YAG laser on brain thermal and histological experimental data, Considering that the 1.32-microns Nd-YAG laser should have physicothermal properties close to those of the CO2 laser. a series of experiments were conducted on rat cortex (N = 51). Three laser wavelengths were compared: CO2 laser (10.6 microns). 1.06-microns Nd-YAG. and 1.32-microns Nd-YAG lasers. For each shot. temperature measurements were recorded with an infrared thermographic videocamera. The digitized signals were figured as thermal profiles and temperature developments. Ninety-five shots were correctly studied and analyzed: CO2. N = 29; 1.06-microns Nd-YAG. N = 20; 1.32-microns Nd-YAG. N = 46. The histological lesions produced by these three lasers were compared on animals killed 24 hours (N = 20). 8 days (N = 20). and 30 days (N = 5) after the laser impacts. For equivalent densities of energy. the depth of cortical necrosis was comparable for the CO2 laser (200-250 microns) and the 1.32-microns Nd-YAG laser (210-260 microns) whatever the date of death; the 1.06-microns Nd-YAG laser shots were responsible for much more important damage (400-550 microns). Because of its important absorption in water and nervous tissue. the authors consider the 1.32-microns Nd-YAG laser most suitable for neurosurgery. particularly because it is conducted through optic fibers. and therefore is easy to handle during neurosurgical procedures.
Magnetic resonance imaging and the nonoperative treatment of spinal epidural abscess, This report describes three patients with spinal epidural abscess diagnosed by magnetic resonance imaging and treated nonoperatively. Prior to treatment. one patient was neurologically intact. one patient demonstrated a moderate neurological deficit. and one patient was severely paraparetic with loss of bladder and bowel control. Following identification of the pathogenic organism. antibiotic therapy was continued until the patients demonstrated clinical improvement and radiological resolution of the abscess. All patients remained stable or improved neurologically. Analysis of 33 previously reported patients treated with antibiotics suggests that nonoperative treatment may be a reasonable alternative therapy under certain clinical conditions. These include (1) identification of the pathogenic organism. (2) a stable neurological condition. (3) access to magnetic resonance imaging or computed tomography for potentially rapid reevaluation. and (4) appropriate neurosurgical consultation and nursing care. Nonoperative treatment may also be considered as a reasonable alternative for patients who have severe concurrent medical illness.
Magnetic resonance imaging of vertebral osteoblastoma: a report of two cases, Two patients with vertebral osteoblastoma evaluated with computed tomography and magnetic resonance imaging are presented. A literature review revealed that cases of osteoblastoma originating within the vertebral body are exceedingly rare.
Spinal synovial cyst: case report using magnetic resonance imaging, The case of a 65-year-old woman who developed a spinal synovial cyst at the L4-5 disk space is reported. Her clinical signs and symptoms are presented. A comparison among her preoperative myelogram. computed tomography scan. and magnetic resonance imaging showed magnetic resonance imaging to be more accurate in detailing both the intraoperative and pathological findings.
Computed tomography and bronchoscopy in chest radiographically occult main-stem neoplasm diagnosis and Nd-YAG laser treatment in 8 patients, We studied 8 adult patients with variable symptoms of cough. dyspnea. stridor. wheezing. or hemoptysis. Fiberoptic bronchoscopy in all showed complete or nearly complete endobronchial obstruction of a main-stem bronchus by neoplasm with a mean bronchial diameter of 1.9 mm +/- 1.6 mm (mean +/- standard deviation). In 4 patients. a lobar bronchus was also completely obstructed. No mass was visible on chest radiographs of any patient; however. computed tomography in each showed main-stem endobronchial obstruction. lobar obstruction (4 instances in 3 patients). and in 6 patients hypoperfusion of the involved lung. Computed tomographic scan showed additional abnormalities that were unsuspected on viewing chest radiographs or at bronchoscopy. including mediastinal adenopathy in 3 patients and an extraluminal tumor component in 4. After therapy with Nd-YAG laser. main-stem airway diameter increased to a mean of 9.6 mm +/- 1.0 mm (P less than .05) and pulmonary functions improved. Results suggest the complementary role of computed tomography and fiberoptic bronchoscopy in the detection and laser-treatment planning of chest radiographically occult severe neoplastic obstruction of the main-stem bronchus.
Botulism among Alaska Natives. The role of changing food preparation and consumption practices, Alaska Natives have one of the highest rates of food-borne botulism worldwide. All outbreaks have been associated with the consumption of native foods. but in recent years outbreaks have occurred in previously unaffected areas and have involved new food items. Five botulism outbreaks occurred between 1975 and 1985 in an area of southwestern Alaska without previous confirmed outbreaks and among one ethnic group. the Yupik Eskimo. Of the 5 outbreaks. 3 were associated with fermented beaver tail. a nontraditional native food recently introduced into the region. Preparation techniques vary widely within villages and among ethnic groups. Traditional fermentation techniques have changed over the past 50 years; current preparation methods used by some families and ethnic groups may be more favorable for Clostridium botulinum growth. Prevention efforts should be targeted at high-risk subgroups of Alaska Natives who appear to have modified traditional practices and increased their risk of food-borne botulism.
Medical management of congestive heart failure, The syndrome of congestive heart failure can result from a variety of cardiac disorders of which left ventricular dysfunction is the most common. The clinical presentation is determined by the interaction between cardiac dysfunction and a series of compensatory mechanisms that are activated throughout the body. Therapy for this disorder is best approached through an understanding of this complex relationship and an appreciation for the influence of preload. afterload. and contractility on cardiac performance. Recent important advances in therapy include the use of combined diuretic therapy. a better understanding of the value of the digitalis glycosides. and evidence that angiotensin-converting enzyme (ACE) inhibitors can relieve symptoms and prolong life. More intensive therapy earlier in the course of congestive heart failure appears to have some clinical benefit. The use of ACE inhibitors during this phase may delay progression of the underlying left ventricular dysfunction. Future therapy will be influenced by the results of ongoing trials that are testing both new agents and expanded indications for drugs that are currently available.
Amiodarone: a postmarketing evaluation of monitoring for drug-induced toxicity, Amiodarone. an antiarrhythmic drug with predominantly class III effects. has demonstrated serious adverse drug reactions and interactions. The Departments of Pharmacy and Cardiology retrospectively evaluated the monitoring parameters at this institution. Criteria based on current literature were developed. Twenty-six patients were administered amiodarone. qualifying for entry into the audit. Of these patients. seven were excluded because their medical records were unavailable or incomplete. The 19 eligible patients were hospitalized during initiation of therapy and followed in the Outpatient Cardiology Clinic. The collected data extracted from the medical charts were compared with the following elements of the criteria selected: baseline evaluation prior to the start of therapy; monitoring for signs of pulmonary. hepatic. thyroid. cardiac. ophthalmologic. neurologic. and dermatologic toxicity; and evaluation of potential drug interactions with digoxin and warfarin-type anticoagulants. The percentage of criteria elements appropriately monitored on each patient ranged from 82 to 100 percent. with an average of 91 percent. The most frequently overlooked parameters were warning the patient of a possible photosensitivity reaction. decreasing the digoxin dose if the patient was concurrently taking amiodarone. and performing a slit-lamp examination every six months. Frequent examination of the patient's total organ system and laboratory tests. in addition to patient education. are essential to safe monitoring of amiodarone therapy.
Flurbiprofen versus diclofenac for the treatment of osteoarthritis of the knee, Seventy-four patients were enrolled in this double-blind. randomized single-center study to evaluate the therapeutic effectiveness of 50 mg tid regimens of flurbiprofen or diclofenac sodium in patients with osteoarthritis of the knee. By chance. the flurbiprofen patients had a significantly more advanced disease status at baseline than their diclofenac-treated counterparts. However. at subsequent follow-up evaluations. both treatment groups experienced a significant reduction in disease severity regardless of the baseline differences. No serious safety problems were associated with either investigational therapy. The frequency of reported medical events were distributed equally between the flurbiprofen and diclofenac groups. Although the imbalance in disease severity between treatment groups made a rigorous statistical interpretation of the results very difficult. the data from this clinical trial tend to support the equiefficacy of 50 mg tid regimens of flurbiprofen versus diclofenac for treating osteoarthritis of the knee.
Correlation of free phenytoin to serum albumin in cancer patients, The objectives of this study were to compare the total and free phenytoin serum concentrations of cancer patients with hypoalbuminemia with those of cancer patients with normal serum albumin and to correlate the percentage of free phenytoin with the albumin concentration. A total of 22 patients were studied. 13 with normal albumin concentration and 9 with low albumin. The mean free phenytoin in the normal albumin group was 9.9 (+/- 1.3) percent and 17.6 (+/- 4.6) percent in the low albumin group. With the groups combined. the mean free phenytoin was 13.1 percent (range 8.3-22.2) with the albumin range of 20-45 g/L. There was a significant negative correlation (r = -0.9. p less than 0.001) between the percentage of free phenytoin and the measured serum albumin. In cancer patients. the serum albumin concentration appears to be the key factor that determines the percentage of free phenytoin. In cancer patients with low serum albumin concentration. the total and free phenytoin concentration should be measured for adequate assessment of phenytoin therapy.
Sodium loading treatment for amphotericin B-induced nephrotoxicity, The increased frequency and duration of antifungal treatment with amphotericin B in immunocompromised patients has stimulated a great deal of research into the mechanisms of its nephrotoxic effects and treatment modalities designed to attenuate these effects. A review of amphotericin B-induced nephrotoxicity. the underlying pathophysiologic mechanisms. and the role of salt loading as a means of minimizing renal impairment are described. Both animal and human studies regarding the efficacy of sodium loading are presented as well as a case report describing the use of salt supplementation over a prolonged course of therapy.
A profile of alcohol and prescription drug abuse in a high-risk community-based elderly population, Substance abuse among the elderly is relatively common but often remains undetected or ignored by health and social workers. Psychosocial and health factors related to the aging process are the major contributors to alcoholism and other drug abuse. It is estimated that between two and ten percent of individuals over the age of 60 suffer from alcoholism. This article profiles alcohol and prescription drug abuse among the geriatric clientele of Elderly Services of Spokane (ESS). a division of the Spokane (Washington) Community Mental Health Center. In addition to traditional channels. ESS uses a unique gatekeeper network to identify high-risk. community-based elderly. Elderly persons referred by gatekeepers are regarded as "hidden" elderly and at highest risk; notably. 37 percent of ESS clients are referred via this mechanism. Case management records of 1668 ESS clients were reviewed for a history of alcoholism. and a total of 161 persons (9.6 percent) were diagnosed with either primary or secondary alcohol abuse. Fifty subjects (about five percent of the average active ESS caseload) were referred for prescription drug abuse. Misused prescription drug classes were sedative-hypnotics. antianxiety agents. and analgesics. Diazepam. codeine. meprobamate. and flurazepam were the top four agents. and 92 percent of the subjects were found to have a duration of prescription drug abuse in excess of five years. A 60 percent correlation between prescription drug abuse and previous or active alcoholism was found. Additional characteristics of the geriatric study population are discussed in detail. including specific psychosocial factors. source of referral. age. gender. living situation. marital status. psychiatric history. and presence of polypharmacy.
Flumazenil: a benzodiazepine antagonist, Although benzodiazepines have been proven safe and effective for the induction and maintenance of sedation. some instances require the reversal of these events prior to the natural process of metabolism and elimination. Flumazenil. a 1.4-imidazobenzodiazepine. is an antagonist that can reduce or terminate benzodiazepine effects in a dose-dependent manner. The antagonist acts by the competitive inhibition of benzodiazepines at their central nervous system receptor sites. When administered intravenously in incremental doses. flumazenil allows for optimal patient response on an individual basis. Despite its short elimination half-life. small doses of flumazenil are usually effective in producing benzodiazepine reversal. Flumazenil's short duration of activity is due to its rapid hepatic metabolism and elimination. Intravenous antagonist doses of 0.2 mg followed by 0.1 mg/min to a total dose of 1 mg have produced significant results in reversing benzodiazepine sedation. As much as 5 mg of flumazenil have been necessary when treating benzodiazepine or mixed-agent intoxications. In such situations. response rarely exceeds a duration of one hour. If resedation occurs. additional doses or an infusion of the antagonist may provide the desired response. Flumazenil is well tolerated locally as well as systemically. Nausea and vomiting occurring after anesthesia is the most documented adverse effect in both placebo and treatment populations. However. there has been no significant difference in the occurrence of vomiting in placebo compared with flumazenil-treated subjects. Careful observation and slow reversal of central nervous system depression is crucial in the avoidance of benzodiazepine withdrawal in those patients dependent upon these agents. Flumazenil appears to provide a mechanism for the safe and effective reversal of benzodiazepine-induced sedation.
Treatment of digitalis intoxication with emphasis on the clinical use of digoxin immune Fab, Many studies and cases of digitalis intoxication have been reported since the time of William Withering's first publication in 1785. Recognition and management of digitalis toxicity is challenging. Before digoxin immune Fab was commercially available. treatment consisted of managing the signs and symptoms of toxicity until the digitalis was eliminated. Digoxin immune Fab offers a safe. effective. and specific method of quickly reversing digitalis toxicity. Factors that must be considered with the clinical use of this agent include the dosage calculation. administration technique. postdose monitoring. pharmacokinetics. mechanism of action. interference with commercially available digoxin assays. partial neutralizing dosing. rebound of free digoxin. and indications for use. For severe. life-threatening toxicity. digoxin immune Fab is the treatment of choice.
Metoprolol for aggressive behavior in persons with mental retardation, Persons with mental retardation sometimes exhibit behaviors that are difficult to control. Use of neuroleptic medications may be limited by side effects or ineffectiveness. Beta blockers such as propranolol and metoprolol have been shown to decrease aggressive and impulsive behaviors in some patients with mental retardation.
Long-term prognosis of myocardial ischemia detected by Holter monitoring in peripheral vascular disease, To assess the long-term prognostic significance of myocardial ischemia. as measured by ambulatory electrocardiographic monitoring. in patients with occlusive peripheral arterial disease. 176 eligible patients scheduled for elective peripheral arterial surgery at Brigham and Women's Hospital were prospectively studied. All patients were monitored preoperatively without alterations to baseline medications. Prospective follow-up was obtained during routine medical care as provided by blinded. independent physicians and by subsequent telephone contact with the patients. Thirty-two patients (18%) had a total of 75 episodes of myocardial ischemia. 73 (97%) of which were asymptomatic. During a mean follow-up period of 615 days. there were 9 cardiac deaths. 1 occurring in-hospital after peripheral vascular surgery. and 13 nonfatal myocardial infarctions. 4 occurring in-hospital after peripheral vascular surgery. Cardiac events occurred in 12 of 32 patients with ischemia (38%). including 6 cardiac deaths. and in 10 of 144 patients without ischemia (7%). including 3 cardiac deaths (risk ratio 5.4. 95% confidence interval 2.6 to 11.4). The sensitivity of ischemia was 55%. the specificity was 87%. the positive predictive value was 38%. and the negative predictive value was 93%. In a multivariate Cox proportional-hazards model controlling for age. gender. coronary risk factors. history of angina. myocardial infarction. coronary artery disease and antianginal medications. the presence of ischemia was the only independent predictor of outcome. In patients with peripheral arterial disease. who often are unable to perform adequate exercise testing. ambulatory monitoring for myocardial ischemia is a significant independent predictor of 1- to 2-year prognosis.
Coronary artery disease in the octogenarian: angiographic spectrum and suitability for revascularization, The angiographic findings of 84 consecutive octogenarians presenting with symptoms of coronary artery disease (CAD) were examined to determine the extent of CAD as well as suitability for both coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA). The frequency of 0-. 1-. 2-. and 3-vessel and left main CAD was 7. 14. 21. 57 and 13%. respectively. Based on angiographic criteria. 69 of 78 patients (88%) with significant CAD had suitable coronary anatomy for CABG. Only 24 patients (31%) had coronary anatomy amenable to PTCA. CABG was performed in 19 patients with an operative mortality of 16% and major complication rate of 37%. PTCA was performed in 12 patients with a clinical success rate of 83%. mortality of 8% and major complication rate of 8%. It is concluded that in octogenarians with CAD. cardiac catheterization will often reveal coronary anatomy that is suitable for CABG but less suitable for PTCA. The morbidity and mortality associated with these interventions are high.
Changes in plasma free fatty acids and glycerols during prolonged exercise in trained and hypertensive persons taking propranolol and pindolol, The extent to which lipolysis is attenuated during prolonged submaximal exercise during beta blockade was determined in 12 normotensive endurance-trained and 12 hypertensive sedentary men using nonselective drugs with and without intrinsic sympathomimetic activity (ISA). Initially. subjects performed a graded treadmill test to determine maximal oxygen uptake (VO2max). This was followed by 2-hour walks at 25 and 45% of the subject's VO2max under each of 3 treatments: pindolol (ISA). propranolol (non-ISA) and placebo. The distribution of medication was randomized and double blinded. Blood samples taken at rest and every 30 minutes during the 2-hour walks were analyzed to determine the concentrations of free fatty acids (FFA) and glycerol. On the basis of the respective changes in FFA. glycerols and the respiratory exchange ratio. beta-adrenergic blockade did not attenuate lipolysis in the untrained hypertensive subjects when compared with the placebo administration. However. beta blockade did demonstrate a tendency to attenuate lipolysis in the trained. normotensive subjects when compared with results after placebo administration. This was particularly evident at 30 minutes of exercise. when both glycerol and FFA concentrations were not increased above resting values under both conditions of beta blockade. No differences between pindolol and propranolol were observed. Therefore. a beta-blocking agent with ISA properties appears to have no clear benefit with respect to lipid metabolism during low and moderate intensity exercise. Furthermore. these data demonstrate that beta blockade does not inhibit exercise-induced lipolysis at low and moderate intensities of exercise as formerly believed. and is unlikely to be the cause of fatigue normally observed during work in patient populations taking beta-blocking medication.
Effects of renin inhibition in systemic hypertension, The effect of the direct renin inhibitor enalkiren (Abbott Laboratories) was examined in 8 healthy patients with essential hypertension. With an unrestricted sodium diet. plasma renin concentration was inhibited within 10 minutes by intravenous enalkiren and remained essentially undetectable for greater than or equal to 6 hours (11.9 +/- 4 to 1.0 +/- 0.6 ng angiotensin I/ml/hour. p less than 0.05). Mean arterial blood pressure declined gradually (108 +/- 5 to 84 +/- 4 mm Hg. p = 0.02). as did plasma aldosterone concentration (14.4 +/- 3.8 to 4.4 +/- 0.8 ng/dl. p = 0.03). whereas plasma immunoreactive active renin concentration increased progressively (35 +/- 14 to 160 +/- 60 pg/ml. p greater than 0.05). Urinary excretion of the stable metabolite of prostacyclin (6-keto-prostaglandin F1 alpha) decreased slightly. but not significantly (42 +/- 10 to 33 +/- 11 ng/g creatinine. p = 0.13). The addition of a diuretic decreased baseline blood pressure and increased baseline plasma renin and aldosterone values. Blood pressure responses to enalkiren were slightly (though not significantly) greater than those observed before diuretic administration. We conclude that enalkiren is effective in decreasing blood pressure and in inhibiting the renin system. without significantly altering urinary prostacyclin excretion. in patients with essential hypertension. These results suggest that the renin system contributes to the maintenance of elevated blood pressure in some patients with essential hypertension.
Fine-needle aspiration cytology and flow cytometry of intracystic papillary carcinoma of breast, To define criteria for cytologic diagnosis of intracystic papillary carcinoma (ICPC). the authors retrospectively reviewed the fine-needle aspiration (FNA) cytologic specimens of eight cases of histologically proven ICPC of breast. The patients were five black and three white women. 56-87 years of age. The FNA specimen was cyst fluid in four cases (bloody in three. clear in one). All the aspirates showed cellular smears with small and large clusters of cells with papillary and/or cribriform configurations and numerous single epithelial cells. The cells were cuboidal to columnar with minimal atypia. ICPC was suggested by FNA in each case. and all the patients underwent surgical excision or mastectomy. Flow cytometry. performed on fresh FNA specimen in one case and on paraffin-embedded surgical tissue in all eight cases. showed seven tumors to be aneuploid and one to be diploid. The authors contend that ICPCs of breast have distinct cytomorphologic features that can be recognized by FNA. Because ICPC may present in cyst fluid. either bloody or clear. all breast cyst fluids from postmenopausal women should be examined cytologically. Flow cytometric demonstration of an aneuploid population may assist in confirming malignancy in this lesion.
Immunocytochemical profile of benign and carcinomatous effusions. A practical approach to difficult diagnosis, One of the great challenges in the cytodiagnosis of effusions is the distinction between reactive mesothelium/histiocytes and cancer cells. This is notably true in patients having undergone radiation and/or chemotherapy. To establish whether monoclonal antibodies (MoAbs) could be used as reliable diagnostic adjuvants. the authors retrospectively and blindly studied 60 cases diagnosed by standard cytologic criteria (malignant. benign. and equivocal). with a panel of seven readily available MoAbs (cytokeratins. vimentin. EMA. B72.3. alpha-CEA. HMFG-2. and Leu-M1) and the lectin Ulex europaeus I. All 18 (100%) malignant cases showed reactivity with EMA and HMFG. whereas 17 (95%) and 11 (61%) reacted with B72.3 and alpha-CEA. respectively. Combinations of (1) EMA + B72.3. (2) EMA + alpha-CEA. and (3) EMA + alpha-CEA + B72.3 displayed positivity in 17 (95%). 11 (61%). and 10 (56%) malignant cases. respectively. Of the 18 benign cases. 7 reacted with HMFG and 2 each with EMA and B72.3. Only one case (5.5%) reacted with both EMA and B72.3. Based on these results. the 24 equivocal cases were regrouped into 14 malignant and 10 benign cases. Follow-up effusions obtained within the ensuing three months in all these patients allowed the authors to unequivocally confirm the diagnosis in all but five. The combination of EMA and B72.3 MoAbs detected malignant cells in 95% of the cases. with a 3.5% incidence of false positive cases in this study. A panel of EMA. B72.3. and alpha-CEA MoAbs should prove the most useful and simple approach to the correct diagnosis in most questionable effusions. Some of the potential pitfalls are discussed.
Midfacial hypoplasia associated with long-term intubation for bronchopulmonary dysplasia, Six preterm infants with bronchopulmonary dysplasia were nasotracheally intubated for 68 to 243 days. Gestational age at birth ranged from 24 to 35 weeks. Endotracheal tube size was changed to account for growth and varied from 2.5 to 4.0 mm. These infants developed features of midfacial hypoplasia. namely. depressed nasal bridge. small-tipped nose. long philtrum. underdeveloped malar areas. and carplike mouth. These features have not been associated with long-term intubation in premature infants. We suggest that features of prolonged nasotracheal intubation. such as direct compression by the tube and the method of tube fixation. decreased air flow through the developing nares and sinuses and reduced faciomuscular activity. resulting in the observed midfacial hypoplasia. The degree to which growth corrects these deformations is unknown.
Cytomegalovirus infections in pediatric liver transplantation, From 1986 to 1989. 26 consecutive pediatric liver transplant recipients were followed up at The Hospital for Sick Children. Toronto. Canada. The patients were reviewed to assess the incidence of infection with cytomegalovirus. the severity of disease. and the relationship of recipient and donor serostatus to cytomegalovirus disease. Overall. the incidence of infection was 54% (14/26). Over 90% of patients who were seropositive or whose donors were seropositive developed evidence of cytomegalovirus infection after transplantation. Forty-three percent (6/14) of those with cytomegalovirus infections developed severe. fatal cytomegalovirus disease. despite treatment with immunoglobulins and ganciclovir (Syntex Laboratories Inc. Palo Alto. Calif) or foscarnet sodium (Astra. Pharmaceutical Products Inc. Westborough. Mass). Of all posttransplant deaths. two thirds were associated with severe cytomegalovirus infection. Cytomegalovirus-related deaths occurred in three of four seronegative patients with seropositive donors and three of six seropositive patients with seropositive donors. Therefore. a seropositive donor appeared to be a major risk factor for severe cytomegalovirus disease.
Impetigo. Current etiology and comparison of penicillin, erythromycin, and cephalexin therapies, We attempted to determine the causative bacterial pathogens of impetigo in children in our area. to compare the effectiveness of three frequently used oral antimicrobial treatment regimens. and to correlate the antimicrobial sensitivity of the bacterial isolates with clinical responses to treatment. Seventy-three children with impetigo were randomly assigned to receive penicillin V potassium or cephalexin monohydrate. both administered in dosages of 40 to 50 mg/kg per day. or erythromycin estolate administered in a dosage of 30 to 40 mg/kg per day. All drugs were given in three divided doses for 10 days. Treatment failure was defined as persistence of lesions 8 to 10 days after initiation of drug therapy as determined by examiners blinded to the treatment therapies. Forty-five (62%) cultures showed Staphylococcus aureus only. 14 (19%) showed S aureus and group A beta-hemolytic streptococci. six (8%) showed group A beta-hemolytic streptococci only. and eight (11%) showed no growth or other organisms. Treatment failure occurred in six (24%) of 25 patients treated with penicillin V. one (4%) of 25 patients treated with erythromycin estolate. and no patients treated with cephalexin. We conclude that S aureus is the most common cause of impetigo in children in our study population. that cephalexin is the most effective treatment. that erythromycin estolate is nearly equally effective and may be preferred on a cost-effectiveness basis. and that penicillin V is inadequate for treatment of this infection.
Parenchymal and vascular magnetic resonance imaging of the brain after extracorporeal membrane oxygenation, Three-dimensional (volume) magnetic resonance angiography is a new and noninvasive method for imaging the intracranial vasculature. The combination of magnetic resonance angiography and conventional magnetic resonance imaging was used to evaluate brain parenchyma and vessels in 30 survivors of extracorporeal membrane oxygenation. Magnetic resonance imaging findings were abnormal in 33% of the patients. with no increased frequency of right hemispheric lesions. Magnetic resonance angiography demonstrated good intracranial flow in all infants and demonstrable right internal carotid arterial flow in 35% of those patients with permanent carotid ligation. An abnormal magnetic resonance imaging study was found more often in infants with abnormal predischarge neurologic examination results. These techniques have several advantages over other neuroimaging modalities. including better definition of deep structures. myelin formation. and intracranial vasculature. the absence of bone artifact. and the elimination of catheter or contrast use.
Lung function in children following empyema, Spirometry was performed and response to exercise was measured in 15 children following recovery from empyema to evaluate the impact of pleural infection on subsequent lung function. Seven children underwent chest tube drainage; eight did not. The two groups were similar in age (mean +/- SD. 6 +/- 5 years). sex distribution. bacterial pathogen-producing empyema. and age at follow-up evaluation (12 +/- 5 years). Only one child reported recurrent respiratory symptoms. No child had restrictive spirometric changes (total lung capacity. less than 80%; vital capacity. less than 80% predicted) but seven of 15 had a reduced forced expiratory volume in 1 second (less than 80% predicted) or forced expiratory flow during the middle half of the vital capacity (less than 75% predicted). suggesting mild airway obstruction. No child demonstrated reduced exercise tolerance due to restrictive ventilatory limitations. Mild obstructive abnormalities in lung function were identified with equal frequency in children treated with and without chest tube drainage.
Newborn screening for sickle cell disease. When is an infant 'lost to follow-up', Success of programs to screen newborns for sickle cell disease depends on timely follow-up. Education regarding fever and splenic palpation. and initiation of prophylactic penicillin therapy. will reduce morbidity and mortality and should occur prior to 4 months of age. However. contacting parents to permit implementation of care may be difficult. particularly in large urban populations; only nine (36%) of 25 infants recently identified as having sickle cell disease arrived at our institution for initial appointments. Medical providers must be aware of medical and legal obligations related to follow-up of newborns with sickle cell disease to prevent untoward events in "missed cases.".
Growth in obese children treated for obesity, This study assesses the growth patterns during a 5-year period in children aged 6 to 12 years treated for obesity using behavioral family-based treatment procedures. Previous studies have suggested a decrease in height velocity after weight reduction. but these results did not consider either the height of the parent or the greater height of obese than nonobese children. Results show that at entry. obese children are taller than their nonobese peers (74th percentile). and that even after 5 years. they remain taller than the norm (65th percentile). Child weight and level of physical maturity accounted for 54% of the variance in predicting baseline height percentile. Entrance height and parental height accounted for 9% of the variance in changes in height percentile. both adjusted for parental height. Weight change did not correlate with growth adjusted for parental height. These results do not suggest that negative effects on height are a long-term side effect of child weight control.
Asymptomatic congenital cytomegalovirus infection. Audiologic, neuroradiologic, and neurodevelopmental abnormalities during the first year, Twenty-eight infants with asymptomatic congenital cytomegalovirus infection and 13 control infants were followed up prospectively. Congenital sensorineural hearing loss was documented by auditory brain-stem responses in four infected infants (two had mild bilateral loss. one had mild unilateral loss. and one had extreme unilateral loss) but in no controls. Four infected infants had diffuse periventricular radiolucencies on computed tomographic scan; none had calcifications or ventriculomegaly. No differences between groups were noted on neurologic examination results or on the Bayley Mental Developmental Index; however. one infected infant had a severely delayed Bayley Psychomotor Developmental Index score. In addition. the mean Mental Developmental Index score of the four infected infants with diffuse periventricular radiolucencies was significantly below that of the remaining infected infants (93 +/- 8 vs 109 +/- 13). These data suggest that asymptomatic congenital cytomegalovirus infection may be associated with a broad range of audiologic. subtle neuroradiologic. and neurodevelopmental differences in early infancy.
The deja vu experience: remembrance of things past?, The deja vu experience is a common phenomenon. occurring in pathological as well as nonpathological conditions. It has been defined as any subjectively inappropriate impression of familiarity of a present experience with an undefined past. The authors discuss the epidemiologic data. clinical features. and etiology of the phenomenon of deja vu. They also review the different hypotheses on the psychopathogenesis of the deja vu experience and introduce an explanation based on the hologram as a mnestic model.
Brainstem auditory evoked response and subcortical abnormalities in autism, Previous studies of the neurobiology of autism that have used the brainstem auditory evoked response have given contradictory results. The authors of this study considered two supplementary aspects; they added an ipsilateral masking procedure. and they compared the results for every subject to the values (corrected for age and sex) of a large number of normal children. Twenty autistic (according to DSM-III-R criteria) and 13 mentally retarded (nonverbal IQ less than 75) subjects were assessed. Eighty percent of the autistic subjects had abnormal interpeak latencies. compared to 15% of the mentally retarded subjects. The I-V and III-V prolonged interpeak latency values were seen only in the autistic subjects. The ipsilateral masking procedure doubled the rate of detection of higher-brainstem abnormalities in the autistic children.
The UCLA-University of Utah epidemiologic survey of autism: the etiologic role of rare diseases, Twelve rare diseases known to cause CNS pathology were found in 26 (11%) of 233 autistic probands identified during a recent epidemiologic survey of Utah. These 26 probands had significantly lower mean IQs than the remaining patients (43 versus 60) but similar sex distribution and prevalence of abnormal EEGs and seizures. The rarity and diversity of these 12 diseases make it highly unlikely that they randomly occurred with autism. Their presence in this epidemiologic survey is the most compelling evidence to date to support the hypothesis that different diseases producing different types of CNS pathology can play an etiologic role in autism.
Effects of pill-giving on maintenance of placebo response in patients with chronic mild depression, Fifty outpatients with mild. chronic. mood-reactive depression whose mood improved markedly after a 10-day single-blind placebo trial were randomly assigned in a double-blind design either to have their placebo medication discontinued or to have it maintained for an additional 6 weeks. Half of the patients in each condition relapsed within 6 weeks. indicating that pill-taking itself does not influence maintenance of placebo response. Placebo response was more likely to be maintained in patients who were currently married. At the end of 3 months. the overall relapse rate was 58%. The authors raise questions about the utility of the initial 10-day placebo washout in antidepressant clinical trials. and they discuss limits on the generalizability of their findings.
Outcome of patients with chronic affective disorder: a five-year follow-up, Patients with major depression. mania. or schizo-affective disorder that had been present without remission for 2 years or more at intake (N = 129) were followed prospectively for 5 years. as were 580 patients who had been ill for shorter periods at intake. Despite very substantial durations of episode. three-quarters of the chronic patients recovered. although recovery occurred much later in the follow-up period than it did among the nonchronic patients. Factors associated with recovery were less severe illness at intake. lack of psychotic features. good friendship patterns in adolescence. and. most important. a relatively high maximum level of functioning in the 5 years preceding intake.
Late luteal phase dysphoric disorder in young women, The authors determined the prevalence of late luteal phase dysphoric disorder in 217 university women aged 17-29 years. Unaware of the focus on premenstrual syndrome (PMS). the participants rated DSM-III-R symptoms of late luteal phase dysphoric disorder over 90 days. Using a 30% or greater premenstrual change as an index of luteal variation. the authors found that 10 women (4.6%) met the symptom criteria during two menstrual cycles. Compared to 25 young women seeking treatment for PMS who met the same diagnostic criteria. the 10 women from the university sample reported significantly less fatigue and impaired concentration and somewhat less severe depression and overall symptoms.
Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients, Fifty-nine elderly residents of long-term care facilities who had DSM-III diagnoses of dementia were studied in an 8-week randomized. double-blind comparison trial of haloperidol. oxazepam. and diphenhydramine to test the efficacy of these agents in the treatment of clinically significant behavioral disturbances in patients with dementia. All three agents demonstrated modest but significant efficacy as measured by clinician ratings of agitated behavior and activities of daily living. The absolute magnitude of improvement was greater for haloperidol and diphenhydramine than for oxazepam. but differences among groups did not approach statistical significance. Frequencies of acute adverse events during the trial were similar across the drug treatment groups. Although these drugs may differ in terms of long-term safety and efficacy. they appear to be equivalent for short-term management of agitated behavior in severely demented patients.
Dyskinetic movements, cognitive impairment, and negative symptoms in elderly neuropsychiatric patients, The presence or absence of tardive dyskinesia. cognitive status. and psychopathology were assessed in a group of elderly male psychiatric patients (N = 49) in a nursing home setting. Twenty-five patients were found to have tardive dyskinesia. which was associated with a greater degree of cognitive impairment and negative symptoms. This finding was not related to obvious macroscopic organic pathologies. which were less prevalent in the dyskinetic patients. In fact. patients with frontal lesions (primarily lobotomies) had a significantly lower prevalence of tardive dyskinesia.
Circumferential quantitative analysis of planar 201T1 myocardial scintigraphy in the diagnosis of coronary artery disease, Methodology for the computer analysis of 201T1 myocardial perfusion images has been developed by several laboratories. Substantial evidence of the advantage of this approach over visual inspection alone has been reported. The currently available computer analyses use different algorithms to analyze 201T1 kinetics in the myocardium. The authors evaluated and compared two widely used software programs. Medical Data System (MDS): a mean-count profile. and the Cedars Sinai (CS): a maximal-count profile. of planar 201T1 scintigraphy for their ability to detect coronary artery disease (CAD).
B-mode imaging and histomorphometric evaluation of carotid atherosclerosis, The quantitative and qualitative evaluation of atherosclerotic lesions by the ultrasonography has presented several problems. above all. the determination of accuracy and reproducibility of this methodology in humans. The present study aims to evaluated the results of B-mode imaging of extracranial carotid arteries in patients selected for surgery as compared with histologic results of the observations of the samples obtained by endarterectomy. Shrinkage effects of the histologic samples were taken into consideration. Several bidimensional images of atherosclerotic lesions. as obtained by ultrasound at different incident angles. were used to establish their maximum thickness. The maximum degree of the vessel stenosis calculated by ultrasound showed a high correlation (Y = 0.47X + 42.4. se = 0.11. r = 0.5. p less than 0.001) compared with the one obtained by histology. The imaging methodology provided however. a mean overestimation of the stenosis of about 7%. Relationships among the amount of calcium (p less than 0.03); necrotic core p less than 0.056); and echogenic types. ie. soft. mixed. and hard; have been suggested by a statistical trend. The results suggested that of the vascular lumen due to advanced atherosclerotic lesions. Qualitative interpretation of atherosclerosis by B-mode imaging. ie. morphologic characteristics. seem. at present. to be of value. but more investigations in depth are needed.
Doppler diagnostics, indications, and control of surgical treatment in patients with carotid pathology, Major stroke is a relatively common cause of death or disabling invalidism in patients with atherosclerosis. In a large percentage of cases it is caused by stenotic/thrombotic processes in carotid arteries and this emphasizes the importance of the problem of early diagnosis and treatment of carotid pathology. Recently Doppler sonography has become a leading non-invasive method of early screening of stenotic processes in carotid arteries. The aim of the present study was to ascertain the diagnostic abilities of Doppler sonography for screening of carotid pathology. assessment of extra-cranial and intracranial hemodynamics. defining of indications. and control of vascular reconstructions of carotids.
Conduction system injury after aortic valve dilation in the dog single- versus double-balloon catheters, The range of morbidity induced by valvuloplasty is not fully known. but transient conduction disturbances are common. The authors performed aortic valve balloon dilatation on 10 closed-chest dogs with normal aortic valves. using a femoral cutdown approach and fluoroscopic guidance. Four were done with a single 15 mm balloon catheter. and in the other 6 two 12 mm balloon catheters were used. Balloons were inflated to 5 to 12 atms pressure with contrast solution. After several inflations the dogs were sacrificed. the hearts removed and examined. Gross examinations revealed subendocardial hemorrhage in the outflow tract in 5 of the 6 in which double balloons had been used. Microscopically. all aortic valve areas showed hemorrhage. mostly in loose connective tissues of the valve leaflets. The severity of injury appeared greater when two balloons had been used. Histologic examination showed definite injury to the myocytes of the left bundle branch in all 6 of the double-ballooned dogs. but in none of those subjected to the single-balloon procedure. During aortic valve dilation the only manifestation of conduction system injury was prolongation of the QRS complex in 3 of the 6 dogs in which a double-balloon catheter had been used. The results suggest that electrocardiographic conduction disturbances observed in patients undergoing aortic valvuloplasty may be the result of direct injury of conduction tissue and may be more likely to occur when larger balloons are used.
A pitfall in azygos vein cannulation in cirrhotic patients: mistaken cannulation of the mammary vein, Azygos venous flow can be measured by a thermodilution catheter in patients with cirrhosis. This is a useful technique since azygos flow is thought to reflect the superior portosystemic collateral flow in these patients. The authors report 3 cases in which mistaken internal mammary vein cannulation mimicked azygos vein cannulation in the supine fluoroscopic view. A lateral fluoroscopic view confirmed internal mammary cannulation. They suggest that if the azygos arch is unpronounced or flow measurements are unexpectedly low in patients with portal hypertension due to cirrhosis. a lateral view be performed to rule out internal mammary vein cannulation.
Bronchiolar morphology after systemic arterial interruption, To assess ischemic lesions as a factor in obliterative bronchiolitis after lung transplantation. the authors severed the left bronchial arteries of 15 dogs. together with the left stem bronchus. the latter being immediately reanostomosed. They examined the bronchioles at weekly interfals up to three and a half months. On the week chosen each dog was anesthetized. totally heparinized. and exsanguino-perfused with saline. Just after heart arrest. the thoracic aorta was injected with a barium solution until this white medium appeared in the bronchial arteries. The heart-lung blocs were excised en bloc. submitted to soft-tissue x ray. fixed. and then sliced to 1 cm. Corresponding right and left 5-mm-thick samples of these slices were prepared for contact microradiography followed by histologic 5-to-20-micron-thick. stained. correlated specimens. For two weeks the left bronchial arteries remained empty. but there was no necrosis or edema. Between two and four weeks barium solution appeared in the bronchial arteries. and the bronchiolar epithelium had become multistratified. Later the left bronchiangiogram became similar to the right. but there were more folds of the mucosa and a little submucosal fibrosis. These studies provide proof that no significant ischemic lesions occurred during repermeation of the bronchiolar vascular bed. Ischemia. if existent. is not a significant factor in obliterative bronchiolitis.
Silk-induced asthma in children: a report of 64 cases, A total of 64 children less than 15 years of age with asthma caused by silk were studied. The diagnosis was based on a history of wheezing. positive skin tests to silk. positive conjunctival or nasal provocation tests. or serum IgE-Sw (silk waste). The average age of onset was 4 years 2 months. Sex ratio (M:F) was 3.6:1. A positive skin test is essential for the diagnosis. Conjunctival provocation tests were performed in 80% of cases because of reliability. safety. and convenience. The first symptom appeared an average of 10 months after initial exposure to silk. In 61% of patients. asthma was accompanied by allergic rhinitis but in only 14% of cases by conjunctivitis. In most cases. asthma occurred in winter. due to seasonal use of bed quilts or clothes filled with silk. Silk is a highly potent allergen. The average mean wheal diameter elicited by silk in prick testing was larger than two histamine equivalent prick tests. A cross reactivity exists among mulberry silk. and silkworm cocoons. batryticated silkworms. and silkworm chrysalis.
Low level atmospheric sulfur dioxide pollution and childhood asthma, Quarterly analysis (1983-1987) of childhood asthma in Hong Kong from 13.620 hospitalization episodes in relation to levels of pollutants (SO2. NO2. NO. O3. TSP. and RSP) revealed a seasonal pattern of attack rates that correlates inversely with exposure to sulfur dioxide (r = -.52. P less than .05). The same cannot be found with other pollutants. Many factors may contribute to the seasonal variation of asthma attacks. We speculate that prolonged exposure (in terms of months) to low level SO2 is one factor that might induce airway inflammation and bronchial hyperreactivity and predispose to episodes of asthma.
A random double-blind trial of the combination of nebulized atropine methylnitrate and albuterol in nocturnal asthma, The combination of nebulized atropine methylnitrate (AMN) and a beta-agonist has been shown to produce greater and longer lasting bronchodilation than either drug alone. We examined the efficacy of the combination in diminishing the "morning dipping" in PEFR in eight hospitalized but stable asthmatics. The patients received nebulized albuterol along with either AMN (AMN + ALB) or placebo (ALB) in a random double-blind cross-over fashion at 10 PM on four nights. PEFR and FEV1 were recorded at 6 PM. 10 PM. and 6 AM before the administration of bronchodilators. There was no statistically significant difference between ALB and AMN + ALB in reducing the morning dipping in these patients.
Effect of procaterol on arterial blood gas in asthmatic children, We determined changes in arterial blood gas after the inhalation of procaterol. a highly beta 2-selective and long-acting adrenergic agonist. in 11 asthmatic children. Seven of the patients. with a maximum fall of 14 mmHg (63.6%). showed a decrease in PaO2 (mean +/- SD = -7.1 +/- 4.0 mmHg) and had poorer pulmonary function with a lower initial PaO2 than four subjects who had an increase in PaO2 after inhalation. There was a statistically significant correlation between values of the PaO2 before and after inhalation (P less than .05).
Anaphylaxis to grand keyhole limpet (abalone-like shellfish) and abalone, We report five patients who developed moderate to severe anaphylactic reactions induced by the ingestion of grand keyhole limpet (GKL) and abalone. Specific IgE-mediated hypersensitivity to these shellfish was demonstrated by history. prick skin test. and RAST. RAST inhibition technique revealed the cross-antigenicity between GKL. abalone. and keyhole limpet hemocyanin.
Diagnosis of mold allergy by RAST and skin prick testing, Sera from 33 patients with mold allergy proven by bronchial provocation were analyzed for specific IgE against six mold species comparing an improved Phadebas RAST with four other techniques. The new method was more sensitive and gave significantly higher IgE antibody concentrations for all tested molds except Cladosporium herbarum.
Ultrasonic forms of posterior staphyloma, The most frequent deformations of the globe encountered in pediatric ophthalmology are staphylomas and colobomas. In this paper we reviewed 16 ultrasonographically diagnosed staphylomas and classified the ultrasonographic patterns produced by staphyloma cases into four types: (1) staphylomas involving the posterior pole but not the optic nerve head. (2) staphylomas involving the posterior pole and the optic nerve head. (3) peripapillary staphylomas. and (4) giant peripapillary staphylomas. Morphologic and ultrasonographic characteristics are described.
Effect of local anesthesia and ocular massage on central corneal curvature, Using a standard Javal keratometer. we obtained central corneal curvature measurements in 19 patients before and after the administration of local anesthesia. We noted flattening of mean average keratometry which approached statistical significance. along with an increase in overall astigmatism. Decreased intraocular pressure was not found to be a factor.
Histopathologic grading of salivary gland neoplasms: III. Adenoid cystic carcinomas, Histopathologic grading of adenoid cystic carcinomas can provide valuable prognostic information. particularly when the presence or absence of a solid growth architecture is noted. Other growth patterns. exemplified by a tubuloductal or cribriform-cylindromatous differentiation. are associated with a more protracted biologic course and less rapid mortality. A three-tiered grading system based on the three growth patterns of the carcinoma is presented.
Removal of blunt foreign bodies from the esophagus, Historically. removal of blunt foreign bodies from the esophagus by esophagoscopy under general anesthesia has been considered to be relatively safe and effective. In recent years. alternative techniques of blind removal with balloon catheters or bougies have been advocated. This paper reports 246 esophagoscopies performed over a 19-year period to remove blunt esophageal foreign bodies. Eighty-one percent of the foreign bodies were coins and 74% were in children under 3 years of age. There were no deaths. no perforations. and no instances of mediastinitis. The only complications encountered were those due to esophageal erosion and/or respiratory problems secondary to long-standing foreign bodies. In the author's opinion. esophagoscopy is the best method for removal of all esophageal foreign bodies. There simply does not seem to be a need for alternative methods involving blind removal.
Bilateral semicircular canal aplasia with near-normal cochlear development. Two case reports, Congenital malformations of the vestibular labyrinth (pars superior) are rare. We present two patients with computed tomographic findings of bilateral semicircular canal aplasia with normal or near-normal cochleas. Initial bone conduction thresholds were within normal limits. although both patients had significant conductive hearing losses due to congenital middle ear malformations. Bithermal caloric responses were absent in both. To our knowledge these are the first reports of vestibular aplasia concomitant with normal or near-normal cochlear development. These findings conflict with conventional hypotheses that state that inner ear malformations result from arrested development during the normal stages of inner ear embryogenesis.
Effects of cyclophosphamide on the pathogenesis of cytomegalovirus-induced labyrinthitis, Cyclophosphamide was used in this study to define the contribution of the inflammatory response relative to direct cytopathic effects of guinea pig cytomegalovirus (GPCMV) in inducing sensorineural hearing loss in the guinea pig. The eighth nerve compound action potential (CAP) threshold on day 7 after inoculation of GPCMV into the scala tympani was an average of 35 dB greater for control animals than for those that were immunosuppressed with daily intraperitoneal injections of cyclophosphamide (20 mg/kg body weight). The amount of GPCMV antigen in the cochlea. detected immunohistochemically did not correlate with the CAP threshold. However. the greater the inflammatory response to GPCMV in the cochlea. the higher the CAP threshold and thus the greater the hearing loss. This study demonstrates that the inflammatory response to GPCMV may be more important than direct cytopathic effects of the virus in producing sensorineural hearing loss in GPCMV-induced labyrinthitis.
Histologic study of eustachian tube cartilage with and without congenital anomalies: a preliminary study, We investigated histopathologically the development of the eustachian tube (ET) cartilage at a cellular level in individuals with and without congenital anomalies. Fourteen specimens were obtained from 14 individuals ranging in age from 24 weeks' gestation to 3 years who had cleft palate or trisomy 21 (Down) syndrome; the 49 specimens in the nonanomaly (control) group were from 49 individuals ranging from 26 weeks' gestation to 85 years of age. All temporal bone specimens included the ET and its accessory structures. and all were processed and stained with hematoxylin and eosin for histologic study in a routine manner. The number of cartilage cells in the midcartilaginous portion of the ET was determined by light microscopy. In all groups. cartilage cell density of the ET decreased with increasing age. However. cell density tended to be higher at all ages for individuals with cleft palate and microtia versus controls. and tended to be lower at all ages for individuals with Down syndrome.
The association of selected cancers with service in the US military in Vietnam. II. Soft-tissue and other sarcomas. The Selected Cancers Cooperative Study Group, As part of a series of investigations into the health of Vietnam veterans. we conducted a population-based. case-control study of soft-tissue and other sarcomas between 1984 and 1988. All men born between 1929 and 1953 and diagnosed in an area covered by eight cancer registries were considered eligible. Controls were selected by random-digit dialing. Analyses of 342 men with pathologically confirmed sarcoma and 1776 controls showed that Vietnam veterans had a relative risk of 1.0 for sarcoma in comparison with men who did not serve in Vietnam (95% confidence interval. 0.6 to 1.6). Restriction of the analysis to the 254 men with soft-tissue sarcoma yielded a relative risk of 0.9 (95% confidence interval. 0.5 to 1.6). Several attributes of military service in Vietnam (eg. branch. duration of service. military region. and other characteristics that may have been associated with the use of Agent Orange) were examined. and none was associated with an increased risk for the development of sarcoma. Furthermore. no morphologic type of sarcoma was overrepresented among Vietnam veterans. Results were unchanged if Vietnam veterans were compared with (1) other veterans or (2) men who never served in the military. This study. which had 97% power to detect a relative risk of 2.0 for all sarcomas. provides no evidence that the risk for the development of soft-tissue or other sarcomas is increased among veterans 15 to 25 years following service in Vietnam.
Determinants of vertebral mineral density in patients receiving long-term glucocorticoid therapy, This study addresses the impact of clinical and biochemical factors on the bone density of patients receiving glucocorticoid therapy. Vertebral mineral density was measured by quantitative computed tomography in 35 patients aged 17 to 77 years who had received therapeutic glucocorticoid drugs for 0.1 to 22 years. The mean (+/- SEM) vertebral mineral density z score in the subjects was -1.7 +/- 0.2. z score was unrelated to underlying diagnosis. sex. or age but was significantly related to the duration of previous steroid therapy (r = -.38) and to the total cumulative glucocorticoid dose (r = -.50). The rate of change of bone density in 16 of these subjects followed up over a period of 12 months was -8.9% and was significantly greater in subjects taking more than 12.5 mg of prednisone per day. Bone loss was not influenced by sex. age. duration of previous steroid treatment. or diagnosis and was not predictable from biochemical measures of calcium metabolism.
Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women, The relationship among postmenopausal estrogen use. coronary stenosis. and survival was examined retrospectively in 2268 women undergoing coronary angiography. The patients were selected for study if their age was 55 years or older at the time of angiography or if they had previously undergone bilateral oophorectomy. Postmenopausal estrogen use in 1178 patients with coronary artery disease (greater than 70% stenosis) and 644 patients with mild to moderate coronary artery disease (5% to 69% stenosis) was compared with 446 control subjects (0% stenosis) using life-table analysis. Over 10 years of follow-up. there was no significant difference in survival among patients initially free of coronary lesions on arteriography who had either never used (377) or ever used (69) estrogens. Among patients with mild to moderate coronary stenosis. 10-year survival of those who had never used estrogens was 85.0% and it was 95.6% among 99 "ever users." Survival was 60.0% among those with more than 70% coronary stenosis who had never used estrogen and it was 97.0% among 70 ever users. The "never users" group were older (65 vs 59 years). had a lower proportion of cigarette smokers (40% vs 57.1%). a higher proportion of subjects with diabetes (21.7% vs 12.9%) and hyperlipidemia (58% vs 44%). and approximately equal numbers of hypertensives (56.0% vs 54.3%). Cox's proportional hazards model was used to estimate survival as a function of multiple covariables. Estrogen use was found to have a significant. independent effect on survival in women. We conclude that estrogen replacement after menopause prolongs survival when coronary artery disease is present. but it has less effect in the absence of coronary artery disease.
Impact of a public cholesterol screening program, The National Cholesterol Education Program (NCEP) has endorsed physician case finding as the primary method to detect individuals with elevated cholesterol levels. Despite this recommendation. promotional and for-profit public screening programs have flourished. We surveyed participants of a mall-based cholesterol screening program 1 year after their screening. Sixty-four percent of those screened had not previously known their cholesterol levels. Those who were newly screened were less likely to benefit from this testing than the general public. since they were older (mean age. 55.3 years). more likely to be female (67.4%). and nonsmokers (88%). Screenees had excellent recall of their cholesterol level (mean absolute reporting error. 0.24 mmol/L [9 mg/dL]) and a good understanding of cholesterol as a coronary heart disease risk. Those with elevated cholesterol levels reported high distress from screening but no reduction in overall psychosocial well-being and an actual decrease in absenteeism. Only 53.7% of all who were advised to seek follow-up because of an elevated screening value had done so within the year following the screening program. However. of those with values greater than 6.2 mmol/L (240 mg/dL). 68% had sought follow-up. Many of those who participate in public screening programs have been previously tested. fall into low-benefit groups. or fail to comply with recommended follow-up. We therefore conclude that cholesterol screening programs of the type now commonly offered are unlikely to contribute greatly to the national efforts to further reduce coronary heart disease.
Group B streptococcus endocarditis following second-trimester abortion, An 18-year-old woman who underwent an elective second-trimester abortion developed Streptococcus agalactiae (group B streptococcus) endocarditis characterized by a large. pedunculated vegetation involving a previously normal tricuspid valve. Polyarthritic symptoms. as well as multiple pulmonary emboli. were experienced. and cure followed a course of treatment using intravenous penicillin G potassium combined with gentamicin sulfate. Endocarditis caused by this pathogen usually occurs among individuals compromised by underlying chronic disorders and. today. is a rare sequela of pregnancy and abortion. When planning therapy. consideration should be given to the possibility of tolerance among clinical isolates and the need for operative intervention in selected patients.
Three-year outcomes for maintenance therapies in recurrent depression, We conducted a randomized 3-year maintenance trial in 128 patients with recurrent depression who had responded to combined short-term and continuation treatment with imipramine hydrochloride and interpersonal psychotherapy. A five-cell design was used to determine whether a maintenance form of interpersonal psychotherapy alone or in combination with medication could play a significant role in the prevention of recurrence. A second question was whether maintaining antidepressant medication at the dosage used to treat the acute episode rather than decreasing to a "maintenance" dosage would provide prophylaxis superior to that observed in earlier trials in which a maintenance dosage strategy was employed. Survival analysis demonstrated a highly significant prophylactic effect for active imipramine hydrochloride maintained at an average dose of 200 mg and a modest prophylactic effect for monthly interpersonal psychotherapy. We conclude that active imipramine hydrochloride maintained at an average dose of 200 mg is an effective means of preventing recurrence and that monthly interpersonal psychotherapy serves to lengthen the time between episodes in patients not receiving active medication.
Delta sleep ratio. A biological correlate of early recurrence in unipolar affective disorder, Slow wave sleep abnormalities have long been described in depression but were considered to be nonspecific indicators of psychopathology. Computerized techniques. including amplitude frequency measures and spectral analyses. are permitting new approaches to the examination of delta sleep. Early studies suggested that many depressed patients demonstrate lower delta wave intensity during the first non-rapid eye movement period than the second one. This finding. prominent in middle-aged depressed patients. has led to an examination of the ratio between the first and second non-rapid eye movement periods. This delta sleep measure seems to be a more robust predictor of recurrence than rapid eye movement latency. Analysis of data on 74 patients in a long-term maintenance treatment study for a minimum of 24 months demonstrates that the delta sleep ratio can predict survival time following discontinuation of drug treatment. Individuals with a high delta sleep ratio remain clinically remitted five times longer than those with a low delta sleep ratio.
Longitudinal study of diagnoses in children of women with unipolar and bipolar affective disorder, School-age children of unipolar depressed. bipolar. chronically medically ill. or normal women were diagnosed every 6 months for up to 3 years. Offspring of unipolar women had the highest rates of disorder at all evaluations. but children of bipolar and medically ill mothers also experienced significant rates of disorder. Observing diagnoses from both past lifetime and prospective follow-up assessments. it appeared that most children who had diagnoses had onsets in preadolescence and continued a chronic or intermittent course of disorder. Thus. risk to offspring of ill mothers is not transitory and indicates a pernicious course that commonly includes effective disorders alone or in combination with behavior and anxiety disorders.
Rapid eye movement sleep deprivation as a probe in elderly subjects, The effects of a 2-night rapid eye movement (REM) sleep deprivation (RSD) procedure on electroencephalographic sleep and mood were examined in 15 healthy elderly control subjects. 14 elderly patients with endogenous depression. and 15 patients with primary degenerative dementia. Compared with control subjects. both patient groups maintained a higher amount of REM sleep time and REM activity during RSD. Unexpectedly. depressed patients showed little rebound in visually scored or automated REM sleep measures following RSD. and they showed stability of REM activity temporal distribution from baseline to recovery conditions. This contrasted with the rebound in REM sleep activity seen in control subjects. and the more modest increase in demented patients. The RSD was fairly specific. with some impact on delta sleep during the procedure but not during recovery sleep. Mood ratings were unaffected by RSD. These findings demonstrated a greater plasticity of REM sleep regulation in the healthy elderly control subjects and suggested a higher REM "pressure" with a "ceiling effect" in depressed patients. Patients with dementia appeared to have an impaired capacity to respond to the challenge of RSD.
Reappraisal of pancreatic and duodenal injury management based on injury severity, We evaluated the effectiveness of treatment protocols for pancreatic and duodenal injuries according to the severity of injury. Of 81 patients. 65 survived initial injury. Pancreatic injuries without ductal involvement occurred in 21 patients and were treated by drainage. No late deaths occurred. Pancreatic injuries with ductal disruption occurred in 18 patients and were treated by pancreatic resection. Abscesses developed in seven (39%) of the patients. but no late deaths occurred. Nineteen patients had duodenal injuries without pancreatic injury. and no duodenal complications occurred. Simple closure sufficed for injuries affecting up to 40% of the duodenal circumference. Wounds affecting up to 40% of the duodenal circumference can be treated by suture closure alone. Adjunctive duodenal tube decompression should be reserved for wounds affecting greater than 40% of the duodenal circumference. closure under tension. and associated injuries to the head of the pancreas. Pyloric exclusion was rarely necessary in our patients.
Chronic alcohol ingestion increases aortic lipid levels in rats, We evaluated the effects of alcohol ingestion on aortic lipid concentrations in 15 pair-fed Sprague-Dawley rats divided into three groups of five animals each. Control rats were fed a liquid diet. with 36% of their energy provided by maltose-dextrin for 28 days. and the remaining two groups of rats were fed an equivalent proportion of their energy as alcohol for 28 days or 18 months. Alcohol-fed rats exhaled significantly greater quantities of ethane than did controls at 28 days and 18 months. Serum cholesterol levels increased by 40% and triglyceride levels increased by 80%. but phospholipid levels remained unchanged in alcohol-fed rats compared with controls. Aortic concentrations of cholesterol and phospholipids increased twofold and threefold. respectively. in alcohol-fed rats. with a corresponding alteration of the cholesterol-phospholipid ratio at both time intervals. Tissue triglyceride levels were only elevated at 28 days. and no differences in aortic lipid peroxide levels were detected between alcohol-fed rats and controls. The results of the study indicate that alcohol ingestion increases aortic cholesterol. phospholipid. and triglyceride levels at 28 days and cholesterol and phospholipid but not triglyceride levels at 18 months. The mechanisms underlying the accumulation of lipids in aortic tissue need further elucidation.
Generation of human monoclonal antibodies against colon cancer, Lymphocytes from regional lymph nodes of patients with colon cancer were fused with a human lymphoblastoid cell line with or without in vitro immunization. The efficacy of these two protocols for the generation of human monoclonal antibodies against colon cancer was investigated. The hyperplastic lymph nodes adjacent to the tumor were the best source of B lymphocytes. Fusion frequency and the number of tumor-reactive clones were markedly increased when the in vitro immunization protocol was applied prior to fusion. As a stimulant in in vitro immunization. the supernatant of pokeweed mitogen-stimulated T lymphocytes was superior to the supernatant of mixed lymphocytes culture. Carcinoembryonic antigen at 20 micrograms/L seemed to be the optimal dose for in vitro immunization. The reactivities of human monoclonal antibodies thus generated were measured by enzyme-linked immunosorbent assay and confirmed by immunoperoxidase staining. Combining in vitro immunization with lymphocytes of cancer patients may lead to the successful production of clinically useful human monoclonal antibodies.
Detection of primary colorectal cancer with indium 111 monoclonal antibody B72.3, B72.3 is a murine monoclonal antibody of the immunoglobulin subclass IgG1 directed against TAG-72. a cell surface antigen present on colorectal carcinoma cells. We investigated the utility of scanning with indium 111-labeled B72.3 in 16 patients with a high clinical suspicion of or biopsy-proven primary colorectal cancer. Each patient received 1 or 2 mg of B72.3 monoclonal antibody labeled with 152 MBq of indium 111. Patients underwent scanning 2 to 3 days and 7 days after infusion by planar and emission computed tomography. Nineteen lesions were confirmed in 12 patients. Three patients with benign polyps had true-negative monoclonal antibody scans. Indium 111-labeled imaging of B72.3 detected nine of 19 lesions. Unsuspected tumor sites were identified by monoclonal antibody scan in three patients. By detection of additional abdominal disease and extra-abdominal spread. indium 111-labeled scanning of B72.3 directly affected treatment in 18% of patients.
Calcium and calcium binding in human gallstone disease, Precipitation of calcium salts from bile is important in pigment gallstone formation and may serve as a nidus for cholesterol precipitation. We compared gallbladder bile from patients with symptomatic gallstone disease (40 with cholesterol gallstones and 12 with pigment gallstones) with bile from 10 patients undergoing surgery for non-biliary tract disease. Bile from patients with gallstone disease was less concentrated. with decreased sodium. bile salt. and phospholipid concentrations. but elevated biliary calcium concentrations were not observed. The relationship between free ionized calcium and total calcium was similar in all groups. indicating no difference in calcium binding by gallstone-containing bile. We cannot exclude elevated biliary calcium level as a factor in gallstone pathogenesis. as it could be a transient event. The importance of calcium precipitation was supported by our finding that more than half of the samples were saturated or supersaturated with at least one calcium salt. calcium carbonate.
The influence of prior therapy on the success of trabeculectomy, The role of early surgery in the management of primary open angle glaucoma is under debate. To determine whether previous medical therapy influences the outcome of subsequent trabeculectomy. we retrospectively reviewed the results of surgery in two groups of patients. The first group underwent primary trabeculectomy. having had an average of 2 weeks of preoperative medical therapy. and this group was compared with a group of patients who had received at least 1 year of topical glaucoma therapy before undergoing trabeculectomy (the multiple-treatment group). The two groups were similar in terms of a number of variables. including race. age. sex. presenting intraocular pressures. and presenting visual fields. and they differed only in the known duration of their disease. The success rate of trabeculectomy was significantly higher in the primary trabeculectomy group as compared with that in the multiple-treatment group (P less than .001). We discuss the possible reasons for this difference and its implications for the future management of primary open angle glaucoma.
Early intraocular pressure rise after trabeculectomy, Intraocular pressure (IOP) was measured 4 to 6 hours after surgery and on the first postoperative day in 35 eyes of 35 consecutive patients undergoing initial trabeculectomy. In 27 eyes. the anterior chamber was re-formed at the completion of surgery with balanced salt solution. and in eight eyes it was reformed with hyaluronate sodium. A total of six eyes (17%) had an IOP of 40 mm Hg or greater 4 to 6 hours after surgery. Patients who received hyaluronate to maintain the depth of the anterior chamber had a significantly greater chance of experiencing a marked postoperative IOP rise. both at 4 to 6 hours (P = .005) and on the first postoperative day (P = .0038). There was no correlation between the postoperative IOP rise and the patient's age. sex. glaucoma diagnosis. preoperative IOP. use of 5-fluorouracil. or the number of sutures used to close the scleral flap. Hyaluronate may contribute to an early increase in IOP that could result in further visual field loss in eyes with severe glaucomatous damage. We recommend early monitoring of IOP after trabeculectomy and avoiding the routine use of hyaluronate.
Serous retinal detachment following glaucoma filtering surgery, We report the occurrence of serous retinal detachment in association with choroidal effusion and hypotony in six eyes that had undergone glaucoma filtering surgery. Hypotony with choroidal effusion was documented in five patients before the onset of serous retinal detachment. While one patient underwent vitrectomy. treatment was conservative in the other patients. Serous retinal detachment and choroidal effusions resolved spontaneously as the intraocular pressure normalized. Although one patient regained preoperative visual acuity. all other patients lost at least one line of Snellen acuity.
Surgical techniques and reattachment rates in retinal detachment due to macular hole, We evaluated reattachment rates of the transvitreal and transscleral techniques for treating 250 eyes with retinal detachment due to macular hole. The initial success rate of the transvitreal approach was 56% (53/94). There was no difference between the results of gas tamponade alone and vitrectomy and gas tamponade. The initial success rate of the transscleral approach was 83% (130/156). Macular diathermy and macular buckling showed a higher reattachment rate than macular diathermy alone. The final success rates were the same (95%). regardless of which approach was selected as an initial technique. The patients whose initial transvitreal reattachment failed and who underwent additional transvitreal procedures (including macular laser photocoagulation) showed a success rate of 93%. We believe that gas tamponade. which has possibility of better visual prognosis. should be selected as an initial technique because the final success rate was found to be the same regardless of the initial surgical techniques.
Graves' ophthalmopathy. Correlation of saccadic eye movements with age, presence of optic neuropathy, and extraocular muscle volume, Quantitative infrared oculography was used to record saccadic eye movements of 49 patients with Graves' ophthalmopathy. Peak saccadic velocities were decreased in those patients who developed or presented with optic neuropathy. This effect was more pronounced for larger eye movements. Peak saccadic velocity also decreased as total extraocular muscle volume and limitation of ocular motility increased. For any given extraocular muscle volume. peak saccadic velocity was 40 degrees/s slower in patients 40 years or older than in younger patients. The relationship between velocity and motility limitation was most pronounced for intermediate muscle volumes (8% to 15% of total orbital volume). Saccadic velocities in those patients with optic nerve compression often improved following treatment. This study demonstrated that eye movement recording was a useful adjunct in evaluation of patients with Graves' ophthalmopathy. Furthermore. age-related lowering of peak saccadic velocities implicated changes of extraocular muscle structure as a factor in the development of optic neuropathy.
Hydrogen peroxide localization in experimental optic neuritis, The association of reactive oxygen species to altered permeability of the blood-brain barrier in acute experimental encephalomyelitis was investigated by ultrastructural cytochemical localization of hydrogen peroxide (H2O2) to sites in the optic nerve previously identified by extravasation of intravascular horseradish peroxidase. Using a modified cerium method. we found electron-dense cerium-derived H2O2 reaction product was localized to the perivascular space at the lamina retinalis. lamina choroidalis. and lamina scleralis. In the optic nerve head. electron-dense reaction product was observed in the presence of intravascular leukocytes. although adjacent perivascular and interstitial inflammatory cells at this site were scant. In the myelinated retrobulbar optic nerve. cerium-derived H2O2 reaction product was seen in the intravascular space of blood vessels and surrounding perivascular and interstitial foci of inflammatory cells. Reaction product was also observed in the extracellular space adjacent to the plasmalemma of axons and glial cells in the optic nerve head and retrobulbar nerve. The perivascular and intravascular distribution of cerium-derived reaction product suggests that H2O2 may play a role in the pathogenesis of altered vascular permeability in experimental optic neuritis and supports our previous observations of suppression of blood-brain barrier permeability by detoxification of H2O2 with the exogenous administration of antioxidant enzymes.
Whitnall's sling for poor function ptosis, Severe unilateral ptosis with poor levator function has previously been treated with maximal levator muscle resection or bilateral or unilateral frontalis suspension. One of us (R.L.A.) has developed a technique called "Whitnall's sling." where only the levator aponeurosis is resected. preserving Whitnall's ligament and its attachments. Whitnall's ligament and the underlying resected levator muscle are sutured to the superior portion of the tarsal plate. This surgery preserves levator muscle. Muller's muscle. and Whitnall's ligament without altering the structures that produce the three-layer tear film. In 69 eyelids operated on between July 1976 and July 1986. in which a minimum of 1 year of follow-up by one of use was obtained. results have been satisfactory and directly related to levator function. We believe this technique to be anatomically and physiologically superior to "maximal levator resection" with similar long-term results. More recent results have shown that the addition of a 5-mm superior tarsectomy provides an additional elevation of 1 to 1.5 mm. Whitnall's sling is best suited for cases where the opposite fissure height is 9 mm or less and levator function of the ptotic eyelid is 3 to 5 mm.
Biplane transesophageal echocardiography: technique, image orientation, and preliminary experience in 131 patients, Transesophageal echocardiography with use of a uniplane phased-array transducer with a transverse or horizontal scanning plane has become a well-established tool for evaluating cardiovascular diseases. Recent introduction of biplane probes has enhanced the diagnostic capability of this imaging technique. This article discusses the technique of biplane transesophageal echocardiographic examination and image orientation. The diagnostic value and advantages of various biplane transesophageal images of the heart. aorta. and aortic arch from various esophageal positions are described.
Transesophageal echocardiography in the diagnosis of ostial left coronary artery stenosis, The diagnosis of ostial stenosis of the left main coronary artery is usually made by use of coronary angiography. However. positioning of the catheter across the obstruction may obscure this diagnosis during contrast injection. Although a damping of arterial pressure when the catheter enters the left coronary artery may suggest ostial stenosis. it may not be possible to make this diagnosis with certainty during cardiac catheterization. We report a series of four patients in whom the left coronary ostium and proximal left coronary arteries were visualized by means of transesophageal echocardiography. Both ostial narrowing by plaque and abnormally fast flow velocities were seen. In each case the echocardiographic findings contributed to the subsequent management of the patients.
Transesophageal echocardiography during percutaneous balloon mitral valvuloplasty, To ascertain the value of transesophageal echocardiography during percutaneous balloon mitral valvuloplasty. the present study was undertaken in 26 anesthesized patients (21 women and 5 men; mean age. 47 years) with symptomatic rheumatic mitral valve stenosis. In all but one patient the balloon dilation of the mitral valve was successful and Doppler-derived valve area increased (0.9 +/- 0.3 to 1.9 +/- 0.4 cm2). Transesophageal echocardiography provides continuous monitoring. as well as guidance of the procedure. Crossing the arterial septum. as well as delivery of the sheath through the mitral valve orifice and correct positioning of the balloon. was highly facilitated and reduced x-ray exposure time. The degree of mitral regurgitation and the presence of interatrial shunting at the end of the procedure could be readily assessed. making cineangiography not necessary. Complications of the procedure. such as pericardial effusion. could be detected before hemodynamic deterioration had occurred (one patient). The advantages of transesophageal echocardiography for routine monitoring of percutaneous mitral valvuloplasty. however. should be weighted against the added risk and expense of this support.
Intraoperative transesophageal versus epicardial ultrasound in surgery for congenital heart disease, Twenty-eight patients (age range. 0.7 to 65 years; median age. 6.1 years) who were undergoing correction for congenital heart disease were entered into a prospective study with both intraoperative transesophageal and epicardial ultrasound to determine the relative values of these techniques before and after bypass surgery. Introduction of the transesophageal probe was successful in 26 patients (93%); children were studied with use of dedicated pediatric transducers. Epicardial studies were performed in all 28 patients. Epicardial studies allowed for higher resolution imaging and a more complete assessment before bypass surgery of the intracardiac morphological condition (ventricular septum and right ventricular outflow tract) than the assessment that was obtained by the transesophageal approach. In the period immediately after bypass surgery. the transesophageal technique allowed a more detailed insight into atrioventricular valve function (valvar regurgitation [five patients] and ventricular inflow patterns) and the continuous monitoring of left ventricular function and volume. Residual interventricular shunting (three patients) or residual outflow tract obstruction (four patients) could not be reliably documented by transesophageal studies. It is concluded that intraoperative transesophageal and epicardial ultrasound in surgery for congenital heart disease are complementary rather than alternative techniques.
Transesophageal echocardiography in the diagnosis of left atrial appendage aneurysm, Intrapericardial left atrial appendage aneurysm is rare. We describe the transthoracic and transesophageal echocardiographic findings in a 42-year-old man with atrial arrhythmia and an abnormal left atrial appendage on chest roentgenogram. Presence of an intrapericardial left atrial appendage aneurysm was confirmed at surgery.
Evidence of hibernating myocardium by a new transesophageal echocardiographic technique, Reversal of resting wall motion abnormalities after successful coronary angioplasty were documented in a patient with the use of a novel approach to stress testing. Transesophageal stress echocardiography utilizes transesophageal atrial pacing to provoke myocardial ischemia while the left ventricular contractility is being monitored by means of transesophageal echocardiography. The potential use of this technique is illustrated in this report.
Prevalence of coronary heart disease in Scotland: Scottish Heart Health Study, Data from 10.359 men and women aged 40-59 years from 22 districts in the Scottish Heart Health Study were used to describe the prevalence rates of coronary heart disease in Scotland in 1984-1986 and their relation to the geographical variation in mortality in these districts. Prevalence was measured by previous history. Rose chest pain questionnaire. and the Minnesota code of a 12 lead resting electrocardiogram. The prevalence of coronary heart disease in Scotland was high compared with studies from other countries that used the same standardised methods. A history of angina was more common in men (5.5%) than in women (3.9%). though in response to the Rose questionnaire 8.5% of women and 6.3% of men reported chest pain. A history of myocardial infarction was three times more common in men than women. as was a Q/QS pattern on the electrocardiogram. There were significant correlations between the different measures of coronary prevalence. District measures of angina correlated well with mortality from coronary heart disease. and these correlations tended to be stronger in women than in men. There was no significant correlation between mortality from coronary heart disease and measures of myocardial infarction. The study provides data on the prevalence of coronary heart disease in men and women that are valuable for the planning of cardiological services.
Transient myocardial ischaemia after acute myocardial infarction, The prevalence and characteristics of transient myocardial ischaemia were studied in 203 patients with recent acute myocardial infarction by both early (6.4 days) and late (38 days) ambulatory monitoring of the ST segment. Transient ST segment depression was much commoner during late (32% patients) than early (14%) monitoring. Most transient ischaemia (greater than 85% episodes) was silent and 80% of patients had only silent episodes. During late monitoring painful ST depression was accompanied by greater ST depression and tended to occur at a higher heart rate. Late transient ischaemia showed a diurnal distribution. occurred at a higher initial heart rate. and was more often accompanied by a further increase in heart rate than early ischaemia. Thus in the first 2 months after myocardial infarction transient ischaemia became increasingly common and more closely associated with increased myocardial oxygen demand. Because transient ischaemic episodes during early and late ambulatory monitoring have dissimilar characteristics they may also have different pathophysiologies and prognostic implications.
Relation between intraventricular pressure and volume in diastole, The pressure-volume curves for 10 patients with various types of heart disease were studied throughout mid to late diastole when both pressure and volume were increasing. The results were used to test a currently held theory that the form of this relation is exponential. It was found that for the patients examined this hypothesis was not valid.
Operative findings after percutaneous pulmonary balloon dilatation of the right ventricular outflow tract in tetralogy of Fallot, Since 1983 percutaneous balloon dilatation of the right ventricular outflow tract has been performed as an alternative to surgical palliation in selected cases of tetralogy of Fallot at the Royal Liverpool Children's Hospital. From 31 December 1984 to 31 December 1988. 27 of these patients underwent subsequent surgical correction. Age at operation ranged from 7 to 58 months (median 2.7 years). The mean interval between balloon dilatation and correction was 15.6 months (range 3-39 months). Two patients had a systemic pulmonary shunt operation performed before dilatation and a further five required one afterwards. Overall 20 (74%) patients had some anatomical alteration as the result of balloon dilatation. while in seven (26%) there was no discernible change in the right ventricular outflow tract. There was no consistent relation between the ratio of balloon size to pulmonary annulus diameter and the morphological findings. Balloon dilatation may obviate the need for systemic-pulmonary shunt at the expense of some structural damage. particularly to the posterior cusp. The present data suggest that dilatation does not bring about growth of the annulus to such an extent that transannular patch is no longer needed at intracardiac repair.
Diagnostic echocardiographic features of the sinus venosus defect, To establish the diagnostic criteria for a sinus venosus atrial septal defect cross sectional echocardiograms. cineangiograms. and surgical notes of all patients with this diagnosis seen at the Children's Hospital of Pittsburgh between 1986 and 1988 were reviewed. Seven patients were identified. In each the extent of the atrial septum and the nature of the junction of the superior vena cava with the atria were evaluated echocardiographically from the subcostal position. All had overriding of the superior vena cava and abnormally connected right pulmonary veins. Six patients had undergone cardiac catheterisation and cineangiography. Five patients underwent surgical repair. The operative findings were consistent with the expected morphology in all five. and these features were additionally confirmed in a specimen from the cardiopathological museum. Therefore. the basic anatomical feature of a superior sinus venosus interatrial communication is a biatrial connection of the superior vena cava. This. together with anomalous drainage of the right sided pulmonary veins. results in an interatrial communication outside the confines of the true atrial septum. Overriding of the superior vena cava across the upper rim of the oval fossa is suggested as the pathognomonic diagnostic feature that can clearly be demonstrated echocardiographically from the subcostal position. In essence the lesion is an interatrial communication rather than an atrial septal defect.
Coarctation of the aorta and post-stenotic aneurysm formation, Despite earlier angiography. post-stenotic aneurysm of the aorta was an unexpected finding at operation in two patients with coarctation. One aneurysm was found in an intercostal artery in a 19 year old man and the other was a false aneurysm just distal to the coarctation site in a 7 year old boy. These aneurysms are fragile. apt to rupture. and difficult to diagnose preoperatively. Though local factors such as jet streams and bacterial endocarditis may influence their formation there must be an underlying generalised weakness in the arterial wall. A coarctation should not be regarded as an isolated arterial abnormality because it may be a feature of a more generalised disease. Because of the risk of rupture. which may not be prevented by antihypertensive treatment. operation should not be delayed in any age group.
Aortic atresia: survival to adulthood without surgery, Aortic atresia is a rare congenital cardiac defect. It usually leads to death in the neonatal period. A patient with aortic atresia has survived to the age of 24 years without any surgical procedure. In view of the uncertain results of reconstructive surgery this case may have therapeutic implications.
Balloon dilatation of the mitral valve by a single bifoil (2 x 19 mm) or trefoil (3 x 15 mm) catheter, The efficacy of balloon dilatation of the mitral valve by a bifoil (2 x 19 mm) or trefoil (3 x 15 mm) catheter (single catheter technique) was assessed in 53 patients (mean age 28) with mitral stenosis. most of whom were women. The procedure was unsuccessful in three patients. After balloon dilatation the left atrial pressure decreased from 22 mm Hg to 13 mm Hg and the mitral valve gradient from 12 mm Hg to 4 mm Hg. The mitral valve area increased from 0.7 cm2 to 2.1 cm2. Exercise time on the standard Bruce protocol increased from 3.9 minutes to 7.2 minutes. In 22 (44%) patients mitral regurgitation developed or the grade of regurgitation increased. Left to right shunts with pulmonary to systemic flow ratios greater than 1:5 were detected in four patients. Transient cerebrovascular episodes developed in two patients. One patient died after emergency valve replacement for severe mitral regurgitation. Balloon dilatation of the mitral valve by the single catheter technique with the bifoil or trefoil catheters is an effective treatment for patients with mitral stenosis. Mild mitral regurgitation is a frequent complication of the procedure.
Myelopathy associated with human T cell lymphotropic virus type I (HTLV-I) in natal, South Africa. A clinical and investigative study in 24 patients, Unexplained spastic myelopathy in black (Zulu) patients. similar to that seen in the tropics. has previously been described from Natal. South Africa. Following reports linking the human T cell lymphotropic virus type I (HTLV-I) to spastic myelopathy. we undertook a prospective and retrospective search for HTLV-I antibodies in 36 patients who were labelled as having unexplained myelopathy; 24 (66%) were positive and HTLV-I was isolated from 4 out of the 6 patients whose peripheral blood lymphocytes were cultured. Eighteen (75%) gave a short history (less than 6 months). There was a female preponderance (71%). spinothalamic dysfunction was common (55%) and as many as half were severely disabled (50% wheelchair bound). Routine laboratory studies showed no specific trends apart from hypergammaglobulinaemia and CSF pleocytosis (greater than 5 cells/microliter in 66% of patients). The total CSF protein was raised (greater than 0.4 g/l) in 45% of patients. The IgG index was greater than 0.7 in 15 of 19 patients. Conventional myelography did not show any specific abnormalities. Computer assisted myelography was undertaken in 22 patients; 3 showed arachnoiditis and 2 spinal cord atrophy. Periventricular lucencies were seen in 1 of 10 patients who had computed tomography of the head. Nerve conduction studies demonstrated abnormalities in 46% of the patients indicating that subclinical peripheral nerve dysfunction was common. Visual evoked responses were abnormal in only 1 patient but brainstem auditory evoked response studies showed some abnormality in 42% of the patients. The finding of HTLV-I antibodies in a significant number. and the isolation of HTLV-I from the blood in 6 of our black patients with noncompressive myelopathy. represents a substantial clinical advance. Future studies should define more clearly the role of the virus in this disorder.
Cerebral blood flow in progressive aphasia without dementia. Case report, using 133xenon inhalation, technetium 99m hexamethylpropyleneamine oxime and single photon emission computerized tomography, We report a case of progressive aphasia without clinical signs of intellectual or behavioral impairment. satisfying Mesulam's clinical criteria of primary progressive aphasia. as 4 yrs of extensive psychometric testing and radiological imaging. comprising CT and MRI. failed to detect evidence of relevant involvement outside the left perisylvian regions. Cranial CT was normal but MRI showed multiple bilateral lesions in the deep white matter. Cerebral blood flow (CBF) studies by single photon emission computerized tomography. however. showed an initial frontotemporal focus of hypoperfusion that progressively extended to include most of the ipsilateral hemisphere and the contralateral frontal lobe. This suggests that CBF imaging may yet be the most sensitive technique in revealing subclinical injury in the degenerative brain diseases of focal onset.
Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications, From an extensive serial magnetic resonance imaging (MRI) study in multiple sclerosis (MS) we have identified 4 cases in which disruption of the blood-brain barrier. as detected by gadolinium-DTPA enhancement. preceded other MRI abnormalities and in 1 case clinical evidence of the new lesion. This supports the view that a defect in the blood-brain barrier. and therefore inflammation. is an early and possibly crucial event in the pathogenesis of the new lesion in MS. These cases showed a marked discrepancy between MRI abnormality and symptoms. The mechanisms contributing to this disparity are discussed. and it is concluded that far from being surprising it is to be expected.
Innervation territories for touch and pain afferents of single fascicles of the human ulnar nerve. Mapping through intraneural microrecording and microstimulation, The peripheral distribution of the fibre content of individual ulnar nerve fascicles supplying skin and muscles of the hand in human volunteers was indirectly mapped by tracing the fields of projected sensation evoked by intraneural electrical microstimulation (INMS) and by tracing receptive fields delineated through intraneural recording of afferent impulse activity elicited by natural stimulation of end organs. Moderate intensity suprathreshold INMS. delivered in cutaneous fascicles. induced nonpainful sensations projecting to stereotyped and coherent areas of skin. the fascicular projected fields (FPFs). Fascicular receptive fields (FRFs) were mapped during microneurographic recording by determining the area of skin which. when activated by light tactile stimuli. elicited afferent neural discharges recorded intraneurally. It was found that at a given electrode position in a skin nerve fascicle. moderate intensity INMS induced nonpainful sensations projecting to a cutaneous field (FPF) that coincides with the FRF. while high intensity INMS induced painful sensations projecting within the cutaneous field of nonpainful sensations. Pain induced by INMS in muscle nerve fascicles was projected to the muscles innervated by that fascicle and. in most instances. to areas beyond the muscular receptive field. The study demonstrates that individual ulnar nerve fascicles. at wrist levels. subserve well-defined cutaneous territories in the hand. and that the area of skin covered by the sum of all ulnar fascicular receptive or projected fields matches the maximal possible cutaneous distribution of the ulnar nerve. Insights of practical relevance regarding clinical expression of fascicular nerve injuries are also brought up by this study.
Volume conduction of the parietal N20 potential to the prerolandic frontal area, Somatosensory evoked potentials were recorded from the frontal and parietal areas in patients with various lesions in the central nervous system on stimulation of the median nerve. Five representative cases who showed a selective loss of the positive potential from the frontal area are reported. In each case. the parietal N20 potential was relatively well preserved. and the midposition between the frontal and central areas (FC area) showed a negative potential following P14. The peak of this negative potential was synchronous with that of the parietal N20 potential. This negativity on the FC area is considered to be a volume conducted potential from the parietal N20 to the prerolandic frontal area. Such an anterior volume conduction of the parietal N20 would not be explained by the concept of a tangentially oriented dipole generated in the posterior bank of the central sulcus. Instead. for the generator of the parietal N20 potential. a radically oriented dipole generated mainly in the parietal area is postulated.
Selective spatial attention in patients with visual extinction, The present study was designed to verify the attentional performance of patients with parietal lesions in the experimental condition in which they had to pay attention to 3 spatial positions located on the left. on the right and directly above the fixation stimulus (Experiment 1) and to only 1 of the 3 spatial positions at a time (Experiment 2). Twelve patients (6 subjects with right parietal lesions and 6 subjects without neurological deficits) participated in the experiment. The results of Experiment 1 showed that in patients with right parietal lesions the speed and accuracy of response to horizontally aligned stimuli increased gradually from right to left. whereas the control group showed only the effect due to the different retinal eccentricities of the 3 stimuli. that is. responses to central stimuli were faster and more accurate than responses to left and right stimuli. The results of Experiment 2 showed that both the neurological and control groups were faster to respond to central than to left and right stimuli. and that the neurological group was faster to respond to right than left stimuli. whereas no difference in RTs between two visual fields was obtained in the control group. Furthermore. when the patients had to respond to 3 spatial locations aligned horizontally (Experiment 1). the speed and accuracy of response to the right stimulus were the same as when they had to focus attention on it (Experiment 2). These results showed that the focus of attention in patients with visual extinction is on the rightmost stimulus and that the increased attention to the right is accompanied by a decreased attention to the left.
Oral contraceptives and breast cancer. Review and meta-analysis, To evaluate the relation between use of oral contraceptives and the incidence of breast cancer. the authors reviewed the epidemiologic literature and used quantitative methods to summarize the data. Study results for any use of oral contraceptives were pooled using a model that accounted for both interstudy and intrastudy variability. The authors also explored interstudy variability and modeled a duration-effect relation between oral contraceptive use and breast cancer. Case-control and follow-up studies were considered separately. Overall. the authors observed no increase in the risk of breast cancer for women who had ever used oral contraceptives. even after a long duration of use. These results were consistent across study design. However. data combined from case-control studies revealed a statistically significant positive trend (P = 0.001) in the risk of premenopausal breast cancer for women exposed to oral contraceptives for longer duration. This risk was predominant among women who used oral contraceptives for at least 4 years before their first term pregnancy (relative risk = 1.72; 95% confidence interval = 1.36 to 2.19). Additional study is required to determine whether this finding in a subgroup of exposed women is confirmed and whether the risk remains increased with advancing age.
Predictive value of tumor estrogen and progesterone receptor levels in postmenopausal women with advanced breast cancer treated with toremifene, The predictive value of estrogen receptor (ER) concentrations was evaluated in a group of 113 postmenopausal patients with estrogen-receptor-positive (ER greater than 7 fmol/mg protein) advanced breast cancer. In 103 patients. tumors were also sampled for progesterone receptor (PgR) determination. All patients were treated with toremifene. a novel antiestrogen. 60 mg daily. The median ER in 51 responders was 78 fmol/mg protein. and in 62 nonresponders. 51 fmol/mg protein; the median PgR levels were 40 and 37 fmol/mg protein. respectively. The response rate in patients with ER less than 50 fmol/mg protein was 38%. and 51% in the group with ER greater than 50 fmol/mg protein (not significant [NS]). The response rate in patients with PgR less than 10 fmol/mg protein was 42%. and in patients with greater than 10 fmol/mg protein. 44%. The duration of response in patients with ER greater than 50 fmol/mg protein was significantly longer than with lower ER levels (P = 0.002). PgR was not associated with the duration of response. In Cox's multiple regression analysis. ER was an independent prognostic factor (P = 0.005) for response duration. Thus. the ER concentration of tumor tissue predicts the duration of response but not the response rate to toremifene in patients with advanced breast cancer. The PgR status does not predict the response rate or the duration of response.
Low-dose preoperative radiation postpones recurrences in operable rectal cancer. Results of a randomized multicenter trial in western Norway, A randomized. multicenter clinical trial was conducted in Western Norway to study the effectiveness of preoperative radiation therapy in operable rectal cancer. given at a dosage of 3150 cGy in 18 fractions. 2 to 3 weeks before radical surgery. Three hundred nine patients were entered into the trial between May 1976 and December 1985. After radiation no tumor was seen in 4.5% of the patients. There was no increased morbidity or mortality at surgery. The 5-year survival for evaluable patients was 57.5% in the control group and 56.7% in the radiotherapy group. For patients operated on for cure the 5-year survival was 60.9% and 64.2% in the control group and radiotherapy group. respectively. Radiation significantly delayed both local and distant recurrences in patients in the radiation group who had curative resection from 13.3 months in controls to 27.1 months. The local recurrence rate in the corresponding groups was 21.1% and 13.7%. respectively. We conclude that higher preoperative radiation doses should be used in new trials as a higher dosage may transform the observed positive effects into a survival benefit.
Comparison of lymphangiography and computed tomography scanning in evaluating abdominal disease in stages III and IV Hodgkin's disease. A Southwest Oncology Group study, The authors reviewed the records of 139 patients who had laparotomy plus computed tomography (CT) and/or lymphangiograms (LAG) as part of a their staging workup for Hodgkin's disease. in accordance with Southwest Oncology Group (SWOG) protocol 7808. They evaluated the relative ability of CT and LAG to detect disease in the abdomen. Two regions of the abdomen were designated. the upper and the lower. to further examine the capabilities of CT and LAG in the lower abdomen and CT in the upper abdomen. A LAG was more sensitive (P less than 0.05) than CT in detecting positive lower abdominal nodes. In the upper abdomen. CT scan had low sensitivity for detecting positive nodes. liver. or spleen. This study suggests that LAG of the lower abdomen provided more information than CT. and therefore should not be abandoned as a valid method for detecting nodal disease.
Diffuse sclerosing variant of papillary carcinoma of the thyroid. Clinical importance, surgical treatment, and follow-up study, A diffuse sclerosing variant is not very rare among papillary carcinomas of the thyroid when the patients are female and younger than 30 years of age. The variant is characterized by diffuse involvement of one or both thyroid lobes. with dense sclerosis. patchy lymphocytic infiltration. and abundant psammoma bodies. Controversy still exists concerning its prognosis. We reviewed our experience with 14 patients treated between 1958 and 1988. All patients were young females. their age being from 10 to 28 years with a mean of 19.6. Hashimoto's thyroiditis had been suspected in nine patients before they came to our clinic. Nowadays the diagnosis of this cancer is possible when we have this entity in mind and detect abundant psammoma bodies either by ultrasonography or by soft-tissue roentgenography of the neck. Total thyroidectomy with modified neck dissection was carried out in eight patients. subtotal thyroidectomy with neck dissection in five. and lobectomy with neck dissection in one. All of them are alive and well without distant metastasis at a mean follow-up of 16 years. Because most of the patients with this variant of papillary carcinoma are young women and the prognosis is favorable. a complete resection without causing later recurrence. but also cosmetic and complication-free surgery. should be considered.
Can internal mammary chain treatment decrease the risk of death for patients with medial breast cancers and positive axillary lymph nodes, The effect of internal mammary chain treatment on each type of malignant death-related event was analyzed in 1195 patients with operable breast cancer and histologically involved axillary lymph nodes. A group of 135 patients who had no internal mammary chain treatment was compared with a control group of 1060 patients who were treated by surgery and/or postoperative radiation therapy. In a multivariate analysis taking into account age. clinical size of the tumor. histoprognostic grading. and the number of positive axillary lymph nodes. quantitative interaction tests were used to determine whether the effects of internal mammary chain treatment on each type of malignant event were significantly different for patients with a lateral tumor compared with those with a medial tumor. The authors found that the effects of this treatment on the risks of distant metastases and of secondary breast cancer were not the same for the patients with a medial tumor as for those with a lateral tumor. For the untreated patients with a medial tumor. the risks of distant metastases and second breast cancer were. respectively. 1.6 (P = 0.02) and 2.9 (P = 0.02). compared with the treated patients. Conversely. for women with lateral tumor. no difference between the two treatment groups was observed. Thus. internal mammary chain treatment may improve long-term survival rate in patients with a medial tumor and positive axillary lymph nodes essentially by decreasing the risk of development of distant metastases (mainly brain. distant lymph nodes. multiple simultaneous metastases) and/or a secondary breast cancer.
The concept of locally advanced gastric cancer. Effect of treatment on outcome. The Gastrointestinal Tumor Study Group, In previous Gastrointestinal Tumor Study Group (GITSG) reports. gastric cancer patients with locally unresectable disease. treated with combined radiation and chemotherapy had a shorter median survival (40 weeks) but more remained alive at 4 years (18%) when compared to those randomized to receive chemotherapy alone (76 weeks and 6%. respectively). To further test the concept that combined modality therapy might increase the number of long-term survivors. a second protocol was designed. but with three major modifications. A course of chemotherapy would precede the 5-fluorouracil-potentiated radiation therapy. Doxorubicin would be added to the 5-fluorouracil plus methyl-CCNU combination. Radiation therapy would be given as a single course of 4320 cGy. with 5-fluorouracil given daily for 3 days at the beginning and end of the course. Median survival of 46 patients treated with chemotherapy alone was 59 weeks. with 11% alive after 3 years. Following combined modality therapy. median survival was 62 weeks. but only 7% lived 3 years. Although the problem of early deaths in the combined modality group was resolved. long-term survival with combination therapy was not demonstrated in this study.
Lack of relationship between perioperative blood transfusion and survival time after curative resection for gastric cancer, To better comprehend the relationship between perioperative blood transfusion and survival time after curative gastrectomy for advanced gastric cancer. the authors reviewed retrospectively data on 568 patients treated in their clinics from 1965 to 1983. Of these 568. 195 (34.3%) required no blood transfusion and 373 (65.7%) required transfusions within the perioperative period. Univariate analysis indicated that the survival time of the transfusion recipients was significantly less than that of the patients who had no transfusions (P less than 0.01). In subgroups of the authors' patients stratified to adjust for stage of disease. there was. however. no significant difference between the survival rates. Subsequently. multivariate analysis. using the Cox regression analysis. which adjusted for sex. age. and other covariates. indicated that perioperative blood transfusion was not a useful factor for predicting survival time. Multivariate analysis suggested that tumor size (P less than 0.01). degree of invasion into the gastric wall (P less than 0.01) and status of lymph node metastasis (P less than 0.01) were the most important covariates after curative gastrectomy for advanced gastric cancer. The authors' findings revealed the lack of any relationship between perioperative blood transfusion and survival time of patients who underwent curative resection for advanced gastric cancer.
Transfusion-induced graft-versus-host disease in patients with malignant lymphoma. A case report and review of the literature, A case of transfusion-induced graft-versus-host disease (GVHD) occurring in a 31-year-old female with Hodgkin's disease in complete remission is reported. Clinical features are similar to 19 other reported cases of transfusion-induced GVHD associated with malignant lymphoma. The lack of relationship with underlying histology or disease stage and the nearly uniformly fatal outcome underscores the importance of prophylactic irradiation of blood products given to patients with malignant lymphoma undergoing therapy.
The effect of dietary omega-3 fatty acids (fish oil) on azoxymethanol-induced focal areas of dysplasia and colon tumor incidence, MaxEPA (MA). a fish oil high in omega-3 fatty acids. was combined with various levels of corn oil (CO). rich in omega-6 fatty acids. and fed to female CF1 mice. The three fish oil blends with CO and the two CO levels of the diets studied were as follows: 16.0% CO + 4.4% MA (Diet 1); 10.2% CO + 10.2% MA (Diet 2); 4.4% CO + 16.0% MA (Diet 3); 20.4% CO (Diet 4); and 4.4% CO (Diet 5). The diets were provided 2 weeks before weekly subcutaneous injection of saline or azoxymethanol (AOM). Studies of epithelial cell proliferation and the incidence of focal areas of dysplasia (FAD) involved six weekly AOM injections. One week after the last AOM injection and 1 hour before killing. mice were injected with tritiated thymidine (3HTdR). No differences in any proliferative parameters were found among the five groups of saline-treated mice. Among the AOM-treated animals. those fed Diet 3 showed significantly fewer cells per crypt and significantly fewer labeled cells/gland than CO Diets 4 and 5. Additionally. the distribution of S-phase cells in crypts of AOM-treated mice fed Diet 3 most closely resembled that of the saline controls. The greatest alteration in the distribution of proliferative cells was observed in the high-CO diet (Diet 4) and the lowest MA level (Diet 1). Mice fed Diets 2 and 3 had significantly fewer FAD/500 microns of distal colonic serial sections than those fed the high CO diet (Diet 4). Mice involved in chronic tumor incidence studies received only three weekly injections of the same dose of AOM. Regardless of diet. approximately 88% of all tumors arose in the distal colon. A significantly larger tumor-bearing population was observed in both the high-CO Diet 4 and the lowest MaxEPA (MA) diet (Diet 1) compared with the incidence in MA Diets 2 and 3 and the low-CO Diet 5. A diet with a ratio of omega-6 to omega-3 fatty acids of approximately 1.0 apparently prevented the development of an adenoma-type proliferative pattern thereby reducing FAD numbers and subsequent tumor incidence.
Interleukin-2-induced lung permeability is mediated by leukotriene B4, Interleukin (IL)-2 therapy leads to respiratory dysfunction due to increased vascular permeability. This study examines the role of the chemoattractant. immunomodulator. and permeability-promoting agent leukotriene (LT) B4 in this setting. Sheep with chronic lung lymph fistulae were given IL-2. 10(5) U/kg as an IV bolus (n = 6). Within 2 hours this led to a significant increase in LTB4 levels in both plasma and lung lymph. The mean pulmonary artery pressure (MPAP) rose while the pulmonary artery wedge pressure was unchanged. Arterial oxygen tension (PaO2) fell. Lung lymph flow (QL) was tripled (P less than 0.05) at 3 hours. coinciding with an increase in the lymph/plasma (L/P) protein ratio (P less than 0.05) resulting in an increase in the lymph protein clearance (P less than 0.05). data documenting increased microvascular permeability to protein. Mild leukopenia and thrombocytopenia (P less than 0.05) occurred. Body temperature rose and shaking chills were common. Pretreatment with the lipoxygenase inhibitor diethylcarbamazine (DEC; n = 6) reduced baseline plasma LTB4 levels and prevented the IL-2-induced increases in LTB4 in plasma and lung lymph (P less than 0.05). In contrast to IL-2 treatment alone. DEC blunted the increase in MPAP and prevented the rises in QL (P less than 0.05). L/P protein ratio (P less than 0.05). and lymph protein clearance (P less than 0.05). DEC also prevented the IL-2-induced leukopenia. the fall in platelet count. and the rise in body temperature (P less than 0.05. respectively). Infusion of IL-2 excipient control (n = 5) did not affect plasma or lymph LTB4 levels but there were mild increases in MPAP (P less than 0.05). The QL also rose but this occurred while the L/P protein ratio fell (P less than 0.05). Body temperature rose moderately. The PaO2. leukocyte. and platelet counts were unaffected. These data indicate that IL-2 administration leads to pulmonary dysfunction manifest by pulmonary hypertension and increased vascular permeability. events associated with LTB4 synthesis and prevented by DEC. Leukotriene B4 appears therefore to mediate the IL-2-induced lung injury.
The role of herpes simplex virus in the development of oral mucositis in bone marrow transplant recipients, Herpes simplex virus (HSV) has been implicated as a major etiologic factor in the development of ulcerative mucositis in bone marrow transplant (BMT) recipients. In this study. 60 patients who received BMTs were evaluated for at least 30 days post-transplant for ulcerative mucositis and the presence of culturable HSV. Fifty-nine patients received prophylactic acyclovir. Forty-six patients developed ulcerative lesions and 45 of these were culture negative for HSV. Neither the source of transplant (autologous versus allogenic) nor the HSV antibody status of the patient affected the frequency of mucositis. The conditioning regimen appeared to be the most significant factor contributing to the severity of ulcerative mucositis. While the majority of ulcers occurred on movable nonkeratinized mucosa in BMT recipients. the usual sites of reactivation of intraoral HSV are nonmovable. keratinized mucosa. We conclude that HSV is probably not a major etiologic agent of mucositis in BMT recipients and that acyclovir is an effective agent in preventing HSV reactivation.
Comparative study of cutaneous T-cell lymphoma and adult T-cell leukemia/lymphoma. Clinical, histopathologic, and immunohistochemical analyses, An important disease entity distinct from cutaneous T-cell lymphoma (CTCL) in Japan is adult T-cell leukemia/lymphoma (ATL). which usually shows the same phenotype as CTCL. i.e.. a helper/inducer T-cell phenotype (CD4+CD8-). and usually involves the skin. Clinically. both CTCL and ATL are heterogeneous in nature. In this study. we demonstrated differences between CTCL and ATL in terms of clinical and immunopathologic cell surface features. In patients with ATL. the predominant clinical findings were peripheral lymph node involvement. skin lesions. hepatosplenomegaly. leukemic manifestations. and an aggressive course. In patients with CTCL. by contrast. only skin lesions predominated at the onset of the disease and a relatively good prognosis was demonstrated. Phenotypic heterogeneity of ATL in the skin. i.e.. CD4-CD8-. CD4+CD8-. and CD4-CD8+. was demonstrated. Expression of Leu8. CD7 (Leu9). and CD45RA (2H4) was high in both the skin-infiltrating ATL cells and peripheral blood and lymph node ATL cells compared with that in the skin-infiltrating CTCL cells. Expression of CD25 (IL-2R). CD71 (OKT9). HLA-DR. and HLA-DQ was higher in the skin-infiltrating ATL cells than in CTCL cells. Expression of CD29 (4B4) was high. and that of CD45RA (2H4) was low in both the skin-infiltrating ATL and CTCL cells compared with the peripheral blood and lymph node ATL cells. Expression of CD45RO (UCHL-1) was not significantly high in the skin-infiltrating CTCL cells compared with that in ATL cells. The most significant phenotypic difference between ATL cells and CTCL cells was the expression of Leu8 (lymph node homing receptor). CD7 and CD25 antigens on the cell surface. and the main phenotypic difference between skin-infiltrating ATL and CTCL cells and peripheral blood and lymph node ATL cells was the expression of CD29 and CD45RA. These findings confirm that the difference in antigen expression on the cell surface might reflect the clinical features of ATL and CTCL. and suggest that the predominant phenotype of peripheral blood and lymph node ATL cells is that of naive. relatively immature or activated T-cells. and that CTCL cells are previously activated (memory) T-cells. In other words. CTCL cells do not share the same origin as ATL cells. These observations support the concept that ATL is a disease distinct from CTCL.
von Willebrand factor in head and neck cancer, Laboratory abnormalities in blood coagulation factors are common in patients with cancer but the significance is unknown. Twenty-eight patients with head and neck cancer were studied at the time of diagnosis. Twenty-five were advanced-stage (III or IV) patients. Levels of clotting factors. antithrombin III. and plasminogen were normal. Levels of von Willebrand factor (vWF). both antigenic and functional (ristocetin cofactor). were elevated. This group of patients were followed for a minimum of 41 months (median. 48 months). Fifteen patients died within the follow-up period. von Willebrand factor levels were significantly higher in these 15 than the 13 survivors. Extreme elevation of ristocetin cofactor (greater than 300 U/dl) was seen in six of the 15 patients who died and in none of the survivors. Plasma vWF is elevated in head and neck cancer and the level measured at the time of diagnosis may have prognostic and potentially therapeutic implications.
Serum concentrations of CA 125 and aminoterminal propeptide of type III procollagen (PIIINP) in patients with endometrial carcinoma, Serum CA 125 (a marker of coelomic epithelial cells) and aminoterminal propeptide of type III procollagen (PIIINP; an indicator of collagen metabolism) concentrations were measured in 148 patients with endometrial carcinoma. An initial serum concentration of CA 125 was pathologic in 17% of the patients. the frequency of abnormal values being higher (P = 0.0001) in advanced (63%) than in early disease (10%). The serum PIIINP concentration was increased in 35% of the patients and more often (P less than 0.05) so in advanced (63%) than in early disease (31%). Among all the patients. at least one of the tumor markers was increased in 43% of the cases. In early disease 12 of 108 patients contracted recurrent cancer. The accuracy of the pathologic CA 125 (9%) and PIIINP (18%) concentrations in their prediction was poor. In the total material. pathologic CA 125 and PIIINP concentrations appeared simultaneously in 11 patients. of whom eight had poor prognoses. In monitoring of treatment response of 24 patients. regression was accompanied by normal or decreasing CA 125 and PIIINP values. The persistence of pathologic CA 125 and/or PIIINP concentration predicted relapse of the malignancy. In progressive disease. CA 125 and PIIINP concentrations together or separately remained at a pathologic level or increased continuously. In clinically stable endometrial carcinoma. CA 125 gave false-negative results in 71% of the determinations and PIIINP only in 12%. The current results suggest the use of CA 125 and PIIINP. simultaneously. in monitoring the clinical course of advanced endometrial carcinoma.
Abnormal vitamin B6 status in childhood leukemia, Vitamin B6 is involved in many biological processes of potential relevance to carcinogenesis and tumor growth. including DNA synthesis and maintenance of immunocompetence. yet very little information exists on B6 nutritional status in childhood leukemia. Using a radioenzymatic assay. the authors measured plasma pyridoxal 5'-phosphate (PLP). the biologically active form of B6. in 11 newly diagnosed untreated children with leukemia and 11 age-matched controls. The children with leukemia had significantly lower PLP levels than the controls. In 26 additional leukemia patients and 26 additional controls. a high-performance liquid chromatography assay also demonstrated lower plasma PLP levels in childhood leukemia compared with controls. These differences were significant for both acute lymphoblastic leukemia (ALL) and for acute nonlymphoblastic leukemia (ANLL). The PLP values did not correlate with indices of leukemia cell burden. but did correlate with reported B6 intake. suggesting that illness-related diet changes are at least partially responsible for the low PLP levels. Before any chemotherapy. overall nutritional status was suboptimal in 53% of ALL cases and 57% of ANLL cases. Newly diagnosed children with leukemia have suboptimal overall nutrition as well as suboptimal vitamin B6 status.
Melanoma and soft tissue sarcoma in seven patients, Seven patients with both melanoma and sarcoma were seen at the Dana Farber Cancer Institute (Boston. MA) over a 4-year period. Three had additional malignant neoplasms; one of these patients also had the hereditary cutaneous malignant melanoma. dysplastic nevus syndrome. These observations suggest the possibility of a biologic relationship between melanoma and sarcoma. the nature of which remains unknown.
The epidemiology of cancer among Hispanic women. The experience in Florida, To explore cancer incidence among Hispanic women living in Dade County. Florida. data were analyzed from the statewide cancer registry. For all but three sites. Hispanics had lower rates of the 15 most prevalent cancers than non-Hispanics. However. higher rates of cancer among Hispanics were noted for cancers of the gallbladder. liver. and heart and soft tissue. Subgroups of women had significantly higher rates of cervical cancer and thyroid cancer. Lower rates among Hispanics were observed for cancers of the esophagus. vagina. breast. colon. buccal cavity and pharynx. and malignant melanoma. These data suggest that most cancer sites traditionally higher among US Latino women were not higher among Dade Hispanics. and that sites more common among non-Hispanics have not yet shown an increased incidence among Hispanic women in Dade County.
Increasing incidence of cecal and sigmoid carcinoma. Data from the Connecticut Tumor Registry, We have studied both the distribution and incidence of colorectal cancer using The Connecticut Tumor Registry. the oldest tumor registry in the United States. During the time period 1973 to 1985. left-sided colon cancers accounted for 63% of the cancers. right-sided cancers 33%. and cancers with unspecified sites 4%. Indeed. this pattern of distribution has remained constant for 25 years. For the period 1935 to 1985. we calculated the sex-specific. age-adjusted (normalized to the 1970 U.S. Census) incidence. Age-adjusted incidence of rectal cancer has remained stable for 50 years: for men. 22.8 cases/100.000/year. and for women. 13.9 cases/100.000/year. During these 50 years. the age-adjusted incidence of cecal carcinoma for men has increased from 3.6 to 16.7 cases/100.000/year. while for women. it has increased from 4.9 to 14.2 cases/100.000/year. Sigmoid carcinoma for men has increased from 8.8 to 18.7 cases/100.000/year. and for women. it has increased from 7.7 to 12.8 cases/100.000/year. The incidence of colon cancer at each site has been and continues to be increasing at a constant rate. Age-adjusted incidence for all colorectal cancers has increased from 35.2 to 70.2 cases/100.000/year for men and from 32.1 to 49.2 cases/100.000/year for women. Thus. distribution of colorectal cancers by site in Connecticut has remained stable for 25 years. More importantly. however. the age-adjusted incidence of colon cancer has continued to increase for 50 years. whereas that of rectal cancer has remained relatively stable.
L-arginine augments endothelium-dependent vasodilation in cholesterol-fed rabbits, Evidence exists that an endothelium-derived relaxing factor is nitric oxide and that L-arginine is the precursor for the synthesis of nitric oxide in vitro. Whether exogenous L-arginine contributes to the modulation of vascular smooth muscle tone in vivo is still controversial. In hypercholesterolemia. resistance vessels do not relax normally in response to pharmacological stimuli that release endothelium-derived relaxing factor; bioassay experiments have suggested that impaired synthesis or release of endothelium-derived relaxing factor accounts. in part. for this blunted relaxation. We hypothesized that hypercholesterolemia reduces arginine metabolism and thereby impairs endothelium-derived relaxing factor synthesis. Accordingly. we designed a study to determine whether exogenous L-arginine could augment endothelium-dependent vasodilation of hind limb resistance vessels in anesthetized cholesterol-fed rabbits. Femoral blood flow was recorded with an electromagnetic flow probe in 16 cholesterol-fed and 12 control rabbits. The hind limb vasodilator responses to incremental intra-arterial infusions of acetylcholine (0.3-9.0 micrograms/kg/min) and nitroprusside (0.3-9.0 micrograms/kg/min) were studied before and during intravenous administration of L-arginine (10 mg/kg/min). D-arginine (10 mg/kg/min). or saline. The vasodilator response to acetylcholine was impaired in cholesterol-fed rabbits as compared with control rabbits. L-Arginine augmented vasodilation to acetylcholine in cholesterol-fed but not in control rabbits. L-Arginine did not alter the effect of nitroprusside in either group. Neither saline nor D-arginine changed the response to either acetylcholine or nitroprusside. Our data demonstrate that exogenous L-arginine normalizes the endothelium-dependent vasodilation of hind limb resistance vessels in cholesterol-fed rabbits.
Baroreflex control of renal sympathetic nerve activity is potentiated at early phase of two-kidney, one-clip Goldblatt hypertension in conscious rabbits, Conscious normotensive and two-kidney. one-clip Goldblatt hypertensive rabbits were studied to determine the sensitivity of the arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate. The relations of the mean arterial pressure-RSNA and mean arterial pressure-heart rate were examined over a wide range of blood pressures produced by infusions of phenylephrine and nitroglycerin. The maximum slope obtained by logistic function analysis was considered to represent the baroreflex sensitivity. In the early hypertensive group (n = 8; mean arterial pressure +/- SEM. 88 +/- 2 mm Hg) on day 5 after renal clip application. the maximum slope of the mean arterial pressure-RSNA relation was -11.3 +/- 1.2. which was significantly greater than that of the sham normotensive group (-6.9 +/- 0.3. p less than 0.05). The maximum slope (-4.3 +/- 0.2) of the mean arterial pressure-RSNA relation in the late hypertensive group (n = 8; mean arterial pressure. 96 +/- 3 mm Hg) on day 21 after renal clipping was significantly smaller than that of another sham group (-7.2 +/- 0.2. p less than 0.05). In contrast to these changes in the baroreflex control of RSNA. the control of heart rate was attenuated according to the magnitude of mean arterial pressure. To elucidate the mechanisms underlying the potentiated baroreflex. the effects of endogenous neuropeptides were investigated. First. plasma concentrations of angiotensin II and arginine vasopressin that are known to affect the baroreflex were determined. Plasma concentrations of vasopressin (3.1 +/- 0.6 pg/ml) as well as of angiotensin II (34 +/- 7 pg/ml) were increased in the early hypertensive group. and the plasma vasopressin returned to a similar level to the sham group in the late hypertensive group (1.3 +/- 0.4 pg/ml). Second. to study endogenous effects of these neuropeptides on the baroreflex. the maximum slopes of the baroreflex curves during infusions of antagonists for the peptides were determined in the early hypertensive group. The maximum slope of mean arterial pressure-RSNA during intravertebral arterial [Sar1. Ala8]-angiotensin II (-16.4 +/- 1.5) was significantly greater (p less than 0.05). whereas the maximum slope during intravertebral arterial infusion of d(CH2)5Tyr(Me)arginine vasopressin (-4.7 +/- 0.5) was significantly smaller (p less than 0.05) than that during vehicle infusion (-11.3 +/- 1.2).(ABSTRACT TRUNCATED AT 400 WORDS).
Effect of chemodenervation on the cerebral vascular and microvascular response to hypoxia, This study evaluated the effect of bilateral carotid chemodenervation on the cerebrovascular response to hypoxia in conscious rats. Cerebral blood flow was measured using 4-iodo[N-methyl-14C]antipyrine. and the total and perfused microvasculature was studied by injection of fluorescein isothiocyanate dextran and alkaline phosphatase staining. To maintain constant PCO2. hypoxia was achieved in chemoreceptor-intact rats by the use of 4% CO2-8% O2-88% N2 and in chemodenervated rats by the administration of 8% O2-92% N2. Blood gas and hemodynamic parameters were similar in the two groups of rats. Chemodenervation had no significant effect on either resting blood flow or the perfused microvasculature during normoxia. A significant increase in cerebral blood flow (from 71 +/- 3 to 138 +/- 9 ml/min/100 g in control and from 91 +/- 5 to 127 +/- 7 ml/min/100 g in chemodenervated rats) and in the percent of cerebral arterioles and capillaries perfused occurred in both hypoxic control and chemodenervated rats. In chemoreceptor-intact rats. the greatest increase in blood flow and in perfused microvasculature occurred in caudal structures (medulla and pons) in comparison with rostral structures (cortex. thalamus. and hypothalamus). In chemodenervated rats. a similar increase in blood flow and perfused microvasculature occurred in all brain regions. with no regional differences. Thus. chemodenervation did not affect the overall cerebral blood flow or the microvascular response to hypoxia; however. rostral-to-caudal regional differences in the hypoxic response were lost after chemodenervation.
Chronic calcium channel blockade prevents the progression of myocardial contractile and electrical dysfunction in the cardiomyopathic Syrian hamster, The programmed onset of myocardial dysfunction and its progression to congestive heart failure in the cardiomyopathic Syrian hamster is hallmarked by alterations in myocellular calcium regulation. To determine whether calcium channel blockade is effective in halting the progressive depression of myocardial contractile performance in this animal model of congestive heart failure. oral verapamil therapy was instituted at 50 days of age. and treatment continued for various durations until the time of study at either 150 or 250 days of age. Left ventricular papillary muscle isometric and isotonic performance. as well as transmembrane electrical characteristics. was depressed in diseased hamsters at 150 days of age and deteriorated further by 250 days of age. These changes were evidenced by prolongation of contraction duration. a marked depression in the load-velocity relation. and a significant prolongation in the repolarization phase of the transmembrane action potential. Myocardial functional and electrical alterations associated with the progression of life in myopathic hamsters were completely halted by verapamil therapy that was continuous from 50 days after birth until death by diastolic arrest. at 150 or 250 days of age. However. premature termination of verapamil treatment before death resulted in a progressive renewal of the functional and electrical alterations for the duration of drug termination. It is concluded that the pathological changes seen during the lifetime of the cardiomyopathic hamster can be prevented by continuous calcium channel blockade and that intermediate prevention can be attained by protracted verapamil therapy. Thus. chronic verapamil therapy may be a useful adjunct in the prevention of human congestive heart failure of similar etiology.
Intrathoracic current flow during transthoracic defibrillation in dogs. Transcardiac current fraction, To achieve transcardiac threshold current during transthoracic defibrillation. a considerably larger current must be delivered to the thorax to compensate for the shunting effect of the lungs. the thoracic cage. and other elements of the torso. This shunting effect is thus an important determinant of transthoracic defibrillation threshold and can be quantified by the transcardiac current fraction (FC. the ratio of transcardiac to transthoracic threshold currents). Previous estimates of FC have ranged from as low as 3% to as high as 45%. The purpose of of this study was to quantify both FC and the major intrathoracic current pathways. Transthoracic and intrathoracic voltages and currents were simultaneously measured during high-voltage transthoracic shocks in 20 dogs. With correction factors determined from another set of 12 dogs. these raw data were corrected to compensate for field distortion caused by the presence of the intrathoracic electrodes. and the adjusted data were fit to a resistive network model. The results showed that 82% of the transthoracic current was shunted by the thoracic cage. while 14% was shunted by the lungs. The remaining 4% (FC) is the portion that passed through the heart. There was good agreement between the two independent methods used to calculate FC. Analysis based on the model indicated that FC was 3.7%. whereas FC determined by direct measurement with calibrated electrodes was 4.2%. Therefore. the results of this study. in contrast to earlier estimates of FC. show that defibrillation in dogs is achieved by only 4% of the total transthoracic current.
Relation between transcardiac and transthoracic current during defibrillation in humans, Conceptually. transthoracic defibrillation threshold current can be considered a function of at least two quantities. It is directly proportional to the transcardiac threshold current and inversely proportional to the transcardiac current fraction (FC) or the ratio of transcardiac and transthoracic current. Although experimental and theoretical estimates of FC have been as high as 45%. previous measurements in humans have not been made. This study was designed to quantify FC in humans. During intraoperative testing of the automatic implantable cardioverter defibrillator. transthoracic rescue shocks of 200-400 J were delivered when the device failed to defibrillate. Simultaneous transthoracic voltage (VT) and transcardiac voltage (VC) between two implanted epicardial patch electrodes were measured. The ratio. VC/VT. was 0.04 +/- 0.03 (mean +/- SD) in 10 patients. In 16 dogs. a comparison was made between direct measurement of FC and VC/VT. FC was determined with a specially designed electrode system. which was calibrated to account for field distortion introduced by the electrodes. There was no significant difference between FC and VC/VT. which were both approximately 0.05. suggesting that VC/VT was statistically equivalent to FC. The results of this study. therefore. indicate that during transthoracic defibrillation in humans. approximately 4% of transthoracic current traverses the heart. This relatively small percentage of current results from the existence of parallel pathways. such as the thoracic cage and lungs. which shunt current around the heart.
Enhanced chemiluminescence as a measure of oxygen-derived free radical generation during ischemia and reperfusion, It has been suggested that oxygen-derived free radicals may contribute to the myocardial injury associated with ischemia and reperfusion. As the presence of enhanced free radical generation is a prerequisite for such damage. several techniques have been used to provide evidence of increased oxygen free radical production during reperfusion; however. all such techniques have substantial limitations. In this study. we used enhanced chemiluminescence to evaluate oxygen free radical generation during ischemia and reperfusion in the isolated Langendorff-perfused rat heart. The chemiluminescent technique. which has high sensitivity and can monitor radical generation continuously. avoids some of the limitations of earlier methods. Chemiluminescence (expressed as counts per second) decreased from 219 +/- 11 at baseline to 142 +/- 9 during ischemia and markedly increased to a peak of 476 +/- 36 during the first 3-5 minutes of reperfusion. This was followed by a slow decline over 11-16 minutes to a steady-state level of 253 +/- 14 (each sequential change in chemiluminescence was highly significant; p less than 0.001). Superoxide dismutase (2.000 units/min) significantly decreased peak reperfusion chemiluminescence to 316 +/- 17 (p less than 0.01). Hearts subjected to a second period of ischemia and reperfusion had a higher peak chemiluminescence (626 +/- 62). which also was significantly attenuated by 1.000 units/min superoxide dismutase (398 +/- 16; p less than 0.01).
Collagen phenotypes during development and regression of myocardial hypertrophy in spontaneously hypertensive rats, The myocardium contains collagen matrix that is a major determinant of its architecture. structural integrity. and mechanical properties. This fibrillar matrix consists primarily of type I and type III collagens having epimysial. perimysial. and endomysial components. The present study shows the alteration of collagen phenotypes during the evolution of hypertensive hypertrophy. Therapy with captopril. an angiotensin-converting enzyme inhibitor that regresses cardiac hypertrophy. not only reduces the total amount of collagen but reverses the altered distribution of type I and type III collagen. In normotensive rats. captopril did not significantly reduce collagen content or alter the ratio of type I to type III collagen.
Regeneration of myocardial phosphocreatine in pigs despite continued moderate ischemia, The effects of 1 hour of mild and moderate reductions in coronary blood flow on myocardial high-energy phosphate levels were evaluated. Thirty anesthetized pigs were instrumented with left anterior descending arterial and venous catheters. crystals for instantaneous wall thickness. and a fluid-filled occluder. Measurement of myocardial blood flow was performed with microspheres. and a series of myocardial biopsies also was performed. In 10 pigs. overall coronary blood flow was lowered by 22%. with a fall in subendocardial-to-subepicardial flow ratio from 1.11 to 0.54 and in wall thickening from 33% to 15%. Subendocardial flow fell 48%. Coronary blood flow and thickening were constant during 1 hour of ischemia. Phosphocreatine (mumol/g wet wt) in the subendocardial third of the ischemic zone fell from 7.6 to 3.8 at 5 minutes of ischemia (p less than 0.005 versus control) and returned to normal (7.9) at 60 minutes (p = NS). despite ongoing ischemia. Subendocardial ATP (mumol/g wet wt) fell slowly from 4.3 and leveled off at 2.1 at 60 minutes of ischemia (p less than 0.001 versus control). Similar regeneration of phosphocreatine was found in seven additional pigs. with a 43% transmural reduction in coronary blood flow and a 66% reduction in subendocardial flow. No significant changes in ATP and phosphocreatine were noted in two different control groups (n = 13 pigs). The regeneration of phosphocreatine despite ongoing ischemia and low ATP levels was not related to changes in myocardial oxygen demand or consumption. or in regional function during the period of ischemia. This may reflect 1) a successful downregulation of the energy needs of the ischemic myocardium to maintain cell viability. or 2) a metabolic abnormality in the ability of the cells to produce ATP primarily or by use of phosphocreatine.
Capacitive coupling as an adjunctive treatment for avascular necrosis, The purpose of this study was to determine the effectiveness of capacitive coupling. a noninvasive method for applying electrical stimulation to biologic tissues. when used as an adjunct to decompression and grafting in the treatment of avascular necrosis (AVN) of the femoral head. It also compared the results of core decompression and grafting with nonoperative management. Forty patients with Stages I-III AVN of the femoral head were treated with core decompression and grafting. All wore capacitive coupling units with electrodes placed over the femoral head continuously for six months. One-half of these units were active and one-half were inactive. Patients were followed for two to four years. Results were determined by preoperative and postoperative Harris ratings. quantitative roentgenographic measurements. and the number of hips that required total hip arthroplasty (THA). After all evaluations were completed. patients were divided into stimulated and nonstimulated groups. Patients in both groups were similar regarding gender. etiology. and roentgenographic stage of involvement. Results were also compared to 55 hips previously treated symptomatically. without surgery or electrical stimulation. There were no fractures. infections. or other significant complications in any of the hips operated on. Hips treated with decompression and grafting. both with and without electrical stimulation. were more satisfactory than hips treated symptomatically in regard to roentgenographic progression and the need for THA. There was. however. no indication that the addition of capacitive coupling gave better results than decompression and grafting alone.
Osseointegration of titanium implants in total hip arthroplasty, Osseointegration is defined as direct contact on the light microscopic level between living bone tissue and the implant. Using titanium screw dental implants in the jaw. a lasting interface under loaded conditions extending over a 20-year follow-up period has been demonstrated. This demonstration brings up the question whether a similar interface can be achieved in total hip arthroplasty (THA) between living bone and a titanium alloy implant under necessitated conditions of immediate loading. Two series of cases are reported. The first series used a femoral. press-fit. titanium alloy component and the second used a press-fit titanium acetabular component and redesigned femoral. press-fit. titanium alloy component. Both demonstrated a high percentage of good to excellent results. Roentgenograms showed that the geometrical changes in the redesigned femoral component gave early indications of a better fixation with loading in valgus. less subsidence. and less evidence of distal stress transfer. A two-and-one-half-year postoperative anatomic specimen study confirmed osseointegration to the press-fit titanium alloy femoral component. Multiple areas of contact between bone and metal without fibrous interposition were seen. Examination by electron microscopy supported the light microscopic findings. These findings support further use of smooth. press-fit titanium components in THAs without the need for porous coating. mesh. or other surface modifications.
Making core decompression work, Meaningful assessment of a treatment modality for osteonecrosis (ON) must take into account a number of factors: (1) an accurate diagnosis. (2) consistent staging of the disease process. (3) understanding of the variability of the disease. (4) consistent application of the treatment modality (or the surgical technique). and (5) a clear understanding of the goal of the treatment used. This article reviews the important steps of a diagnostic algorithm that has been used to accurately diagnose and stage the disease process of ON. A consistent surgical technique with clearly defined goals is also outlined. The results of two clinical studies that were based on these diagnostic and therapeutic philosophies and that assess the role of core decompression in the treatment of ON are reviewed. The first study compared core decompression to conservative management in a prospective randomized study of 55 hips. Decompression provided more predictable pain relief and changed the indications for further surgical intervention more consistently than did conservative management. The second study represents a preliminary review of a ten-year study of the decompression procedure; it showed that core decompression was particularly useful in Stage I and Stage II ON. Roentgenographic stabilization was most predictable for Stage I hips. Core decompression can be a safe. effective. and predictable procedure in the treatment of Stage I and Stage II ON.
The effect of stem stiffness on femoral bone resorption after canine porous-coated total hip arthroplasty, Bilateral noncemented total hip arthroplasty (THA) was produced in dogs to determine the effect of stem stiffness on stress-related bone resorption. Two porous-coated femoral implants of substantially different stiffnesses were designed for direct comparison. One was manufactured from cobalt-chromium (CoCr) alloy. the other from titanium alloy. The titanium stem was hollowed out to a wall thickness of 1 mm to further reduce its stiffness. The cumulative stiffness differences were about 5.4-fold axially and 3.6-fold in bending and torsion. Staged bilateral THA was performed on eight dogs. Each dog received a stiff CoCr stem on one side and a flexible titanium stem on the other. After death. the femora were removed and processed for undecalcified thin-section histology. Bone ingrowth and remodeling were quantified by computer-aided image analysis and compared between stem designs. All femoral specimens showed bone ingrowth fixation of both stiff and flexible stems along the implant length. Tetracycline labeling indicated active bone turnover in the femoral cortex and in regions of ingrowth. However. gross differences in femoral bone remodeling were observed both roentgenographically and histologically. Femora with the flexible stems consistently showed much less bone resorption than those with the stiff stems. Quantitative analysis of paired cross-sections indicated an average of 25%-35% more cortical bone area in the femora with flexible stems. Severe resorption of the cortex in the midstem region occurred in three of the femora with the stiff stems but in none with the flexible stems. Stem stiffness strongly influences bone remodeling. The flexible stem results in more uniform load transfer and less stress shielding.
Intraoperative dexamethasone irrigation in lumbar microdiskectomy, In 45 lumbar hemilaminectomy/microdiskectomy patients. a control group of 23 patients had the standard operative procedure. The remaining 22 patients were treated with intraoperative irrigation of long-acting dexamethasone before incision closure. Age. weight. gender ratio. mean postoperative hospital stay. mean in-hospital narcotics usage. and incidence of perioperative complications among the two groups were compared. Age and gender ratios were comparable. although the control group was significantly heavier in body weight than the steroid-irrigated group. The steroid-irrigated group had a significant reduction in hospitalization and a marked reduction in narcotics usage compared with the control group. Postoperative fever occurred in one patient in the steroid group. The control group had three postoperative complications. These preliminary observations suggest that dexamethasone irrigation during lumbar diskectomy is a safe and effective adjunct to surgical management.
Knee function after complex femoral fractures treated with interlocking nails, Twenty-three complex femoral fractures were treated with interlocking nails. After fracture healing. knee function was analyzed. including alignment. quadriceps and hamstring strength. thigh atrophy. and range of motion (ROM). Similar to previous studies in the preinterlocking nail era. knee function was impaired in comparison with the contralateral limb. Seventy-three percent of patients had decreased quadriceps strength. and 60% had decreased hamstring strength. Sixty-five percent had thigh atrophy. The ROM and alignment were satisfactory. Despite the advantages of early ROM with femoral fractures treated with interlocking nails. knee function is often unsatisfactory once fracture union has occurred. Therefore. a formal knee rehabilitation program is recommended to achieve an optimal result.
Echinococcus infestation of the biceps brachii. A case report, Echinococcus is a genus of tapeworm endemic in certain parts of the world but found only rarely in the United States. An extremely unusual case of an intramuscular infestation involving an extremity occurred in a 41-year-old man. Since the infestation closely resembled a soft-tissue tumor on clinical and roentgenographic examination. the patient was treated with an incisional biopsy of the mass. which consisted of a cystic cavity filled with clear fluid. The diagnosis of an Echinococcus cyst was made only after permanent section analysis revealed numerous scoleces within the cyst lining. The patient was asymptomatic six months after cyst excision but still remains at risk for recurrence of the infestation. The present report serves to alert the reader to this rare but potentially fatal condition. Preoperative diagnosis is imperative to avoid inadvertant rupture of a hydatid cyst. which releases viable scoleces into the systemic circulation and may precipitate an anaphylactic reaction.
Cartilage begets bone versus endochondral myelopoiesis, Observations on the cellular events involved in embryonic long-bone formation. ectopic osteogenesis. fracture repair. and the analysis of mesenchymal stem-cell potential provide evidence of the intimate and direct relationship of osteogenesis to angiogenesis and vasculature. The sequence of cellular events is that cartilage is not replaced by bone but. rather. is a target for vascularization and myelopoiesis. With this in mind. it may be necessary to replace the term "endochondral bone formation" with "endochondral myelopoiesis.".
Bipolar versus total hip arthroplasty for avascular necrosis of the femoral head. A comparison, In a relatively small series of cases the results of bipolar prostheses in avascular necrosis were inferior to those of total hip arthroplasty (THA). Femoral loosening rates were not reduced by using bipolar prostheses. THA produced more inferior results in avascular necrosis than in degenerative joint disease. Early results of noncemented THA for avascular necrosis were good but also must withstand the test of time. A fixed noncemented acetabular component was preferable over a bipolar prosthesis for avascular necrosis of the femoral head.
The case for porous-coated hip implants. The femoral side, A series of 1163 total hip arthroplasties (THAs) using porous-coated femoral components were roentgenographically assessed for implant fixation. For 959 primary THAs followed from two to 12 years. the femoral revision rate was 1% and the ten-year survivorship rate was 96.4%; 150 young patients had a fixation failure incidence of only 1.3% at a mean follow-up period of 6.4 years; in 204 revision THAs. the femoral re-revision rate was 4% at a mean follow-up period of 53.4 months. Failures were largely related to inadequate femoral canal filling. Because of refinements in implant design and surgical techniques. a press fit of the implant is currently achieved in 94% of cases compared to 36% during the first five years. Porous-coated femoral components have yielded results equivalent to those with cement in primary THAs. Excellent results were observed in relatively young patients and patients with revisions.
Histologic, biochemical, and ion analysis of tissue and fluids retrieved during total hip arthroplasty, Large amounts of metal and polyethylene debris and high ion readings are found in capsule and fibrous membranes of both loose titanium and cobalt-chromium stems. Prostaglandin E2. interleukin-1. and collagenase levels are elevated when compared to control values with collagenase having the highest and most consistent elevations. Synovial fluid and blood ion readings were elevated in loose cemented and cementless stems made from both materials. Blood ion readings were not elevated in fixed stems. Fixed stems had much less particulate debris in soft tissues. The data showed that failure of most metal hip stems was initially due to a mechanical cause. with high debris and ion counts occurring secondarily in capsule and fibrous membranes. Particulate debris and high ion readings are primarily a focal problem contained by the periprosthetic fibrous connective-tissue encapsulation within the femoral canal and joint capsules. No systemic problems were manifest in any of the patients examined and followed in this study.
Magnetic resonance imaging evaluation of congenital dislocation of the hips, Magnetic resonance (MR) images were obtained preoperatively and postoperatively for 12 pediatric patients with congenital dislocation of the hip (CDH). The images were compared with arthrograms and computed tomography scans. The MR images were more accurate in defining soft-tissue anatomy. hip position. and obstructive factors to relocation. MR imaging is an efficient diagnostic tool in CDH.
Initial evaluation of human monoclonal anti-lipid A antibody (HA-1A) in patients with sepsis syndrome, HA-1A. a human monoclonal immunoglobulin M antibody that binds specifically to the lipid A domain of endotoxin. was administered to septic patients to evaluate the safety. pharmacokinetics. and immunogenicity of the antibody. Thirty-four patients received a single infusion of either 25 mg. 100 mg. or 250 mg. and were followed clinically for 14 to 21 days after treatment. HA-1A serum levels were measured before infusion and frequently after infusion with a radiometric assay. A one-compartment pharmacokinetic model was fit to the measured serum levels. and accurately described the changes in HA-1A level over time in each dose group (r2 = .99). The mean +/- SEM apparent volume of distribution of HA-1A was 48.5 +/- 4.5 ml/kg. and the mean serum clearance was 2.8 +/- 0.4 ml/kg.h. The mean serum half-life of HA-1A was 15.9 +/- 1.5 h. The mean serum level one hour after a 100-mg dose was 33.2 +/- 2.4 micrograms/ml. and the mean concentration 24 h later was 9.1 +/- 1.6 micrograms/ml. The dose administered and presence of Gram-negative bacterial infection did not significantly influence the volume of distribution or serum clearance. No adverse reactions to HA-1A were observed. and no antibodies against HA-1A were detected in any patient. These data indicate that the pharmacokinetics of HA-1A are well described by a one-compartment pharmacokinetic model. and that HA-1A is safe and nonimmunogenic in patients with sepsis.
Dependence of oxygen consumption on oxygen delivery in children with hyperdynamic septic shock and low oxygen extraction, We studied the effect of increasing systemic oxygen delivery (DO2) by packed RBC (PRBC) transfusion on oxygen consumption (VO2) in children with hyperdynamic septic shock. After routine resuscitation with volume loading and pharmacologic support. patients were studied if they had significant derangements of oxygen transport variables defined as: baseline VO2 less than 180 ml/min.m2 and oxygen extraction (O2 extr) less than 24%. Eight studies were performed. PRBC transfusion increased DO2 from 636 +/- 167 to 828 +/- 266 ml/min.m2 (p less than .01) without increasing cardiac index (5.2 +/- 1.3 vs. 5.0 +/- 1.4 L/min.m2). VO2 increased from 112 +/- 36 to 157 +/- 60 ml/min.m2 (p less than .01) while O2 extr was unchanged (18 +/- 3% vs. 19 +/- 6%). Despite initial low O2 extr. VO2 can be increased in pediatric septic shock by a further increase in DO2. Since VO2 correlates with survival. one should consider enhancing DO2 further despite initial low O2 extr and high DO2. Effects on morbidity and mortality require further study.
Continuous removal of middle molecules by hemofiltration in patients with acute liver failure, In patients with acute liver failure and hepatic coma. an increase in the abnormal "middle molecules" seen on the chromatograms of the sera is suspected of playing an etiologic role in the coma. A pilot study of continuous hemofiltration using a high-performance membrane was conducted in 16 such patients in an attempt to decrease the serum levels of the middle molecules. The procedure was used alternately with plasma exchange. High-performance liquid chromatography showed a notable removal of the substances in the filtrates and a sequential removal from the serum by hemofiltration. Eight (50%) of the 16 patients had amelioration in level of consciousness and were weaned successfully from hemofiltration. Although only three of the 16 patients survived the acute illness. 13 others lived an average of 15 days and five patients survived greater than 3 wk. While the continuous removal of middle molecules from the serum may not reverse liver failure. this procedure used in conjunction with plasma exchange may provide a means of life support. e.g.. for patients awaiting a liver transplant.
Accuracy in early prediction of prognosis of patients with septic shock by analysis of simple indices: prospective study, In 26 consecutive septic shock patients. we analyzed the clinical. hemodynamic. and metabolic data before and during volume infusion to test their circulatory reserve in response to fluid repletion. These patients were investigated to identify early variables that could predict outcome. There were 15 survivors (group A) and 11 nonsurvivors (group B). As a mean. group A patients were hemodynamically evaluated 2.3 h after onset of the sepsis syndrome. whereas group B patients underwent cardiac catheterization after a 12-h interval. At the initial evaluation. both groups demonstrated similarly decreased mean arterial pressure. mean heart rate. and mean cardiac filling pressure. Only group A patients evidenced elevated cardiac index (CI) (greater than 4 L/min.m2) associated with low systemic vascular resistance index (less than 7400 dyne.sec/cm5.m2). which is generally recognized as hyperdynamic cardiac state. However. none of the initial cardiovascular variables could serve as a predictor for survival. Fluid challenge increased left ventricular preload from 6 to 12.4 and from 7.8 to 12.7 mm Hg in group A and group B. respectively. The increases were associated with significant increases in CI from 4.4 to 6.9 and from 3 to 3.8 L/min.m2. However. at the end of fluid challenge. only group A patients exhibited normal cardiac response. as evidenced by the change in left ventricular stroke work index (LVSWI) for a given increase in the pulmonary capillary wedge pressure (WP) that was referred to as left cardiac preload.
Alterations in pulmonary mechanics after transfusion in anemic preterm infants, Pulmonary mechanics were studied in ten anemic preterm infants using an esophageal balloon and mask. before and after transfusion with 10 ml/kg of packed RBC. Their mean birth weight was 1212 +/- 323 g and gestational age was 29.27 +/- 2.4 wk. Transfusions were carried out at a mean postnatal age of 41.9 +/- 21.8 days. The mean Hct increased from 28 +/- 3.1 to 38.3 +/- 3.3%. Dynamic lung compliance decreased in all infants after transfusion. There was a 33.8% increase in resistance; the work of breathing increased after transfusion. These changes might be due to volume overload or increased lung water content.
Respiratory response and pharmacokinetics of intravenous salbutamol in infants with bronchopulmonary dysplasia, The effects of iv salbutamol on respiratory mechanics were studied in six infants with bronchopulmonary dysplasia. Salbutamol was infused at a dose of 30 micrograms/kg over 30 min in five infants; a sixth infant received 66.7 micrograms/kg over 4 min. Salbutamol caused improvement in total respiratory system compliance and in airflow resistance. There was no correlation between salbutamol serum concentration and pulmonary function. Elimination half-time appears to be dictated in these infants more by the distribution volume (Vd) than by clearance (Cl). The area under concentration-time curve of salbutamol correlated inversely to the change in heart rate (HR). There was a significant positive correlation between Vd and percent HR change. These data provide evidence that preterm infants have measurable activity of bronchiolar beta 2 receptor responsive to salbutamol.
Cardiac arrhythmias in critically ill patients: epidemiologic study, The general prevalence of cardiac arrhythmias in 2.820 consecutive patients was 78%. ranging from 44% in multiple trauma patients to 90% in primary cardiovascular patients. Patients without recorded arrhythmias (22%. n = 621) were used as control subjects. No clinical group was free from cardiac arrhythmias. Atrial tachyarrhythmias had the highest prevalence in the population as a whole (28%) and in all clinical groups except multiple trauma. Atrial fibrillation was the most common atrial arrhythmia (52%); ventricular arrhythmias followed. Patients with atrial tachyarrhythmias. nodal rhythm ventricular bradyarrhythmias. and ventricular rapid rhythms had significantly (p less than .01) increased mortality rates (40%. 44%. 77%. and 51%. respectively) when compared with patients without arrhythmias (35%). The relative risk of dying (RRD) of these clinical groups was increased by 1.16. 1.27. 2.20. and 1.47. respectively. Patients with cardiorespiratory precipitating disease and any arrhythmia except atrial bradyarrhythmia had a mortality rate between 32% and 74%. significantly (p less than .05) different from that of patients within the same clinical groups without arrhythmias. The RRD was increased by 1.67 to 3.40. Septic patients with atrial tachyarrhythmia or nodal rhythm and neurologic patients with nodal or ventricular arrhythmias also had significantly (p less than .01 and .05. respectively) increased mortality and were at higher RRD (1.53 to 2.81). Our data suggest that severe illness may be present in some clinical groups of critically ill patients with cardiac arrhythmias.
Pentoxifylline attenuates edema formation in proteolytic enzyme-induced lung injury, Ex vivo canine lung lobes were exposed to a pancreatic proteolytic enzyme (chymotrypsin) alone or chymotrypsin after pretreatment with a continuous infusion with pentoxifylline. The lobes exposed to chymotrypsin gained 133 g. while the pentoxifylline-treated lobes gained only 65 g (p less than .05) over the 3-h experimental period. These results suggest that pentoxifylline significantly attenuates the lung weight gain associated with chymotrypsin.
Effect of calcium entry blocker nitrendipine on renal function after renal vascular occlusion, The ability of the Ca entry blocker nitrendipine to improve postischemic renal function was studied in nine groups (n = 70) of rats. After anesthesia. nitrendipine was administered for 15 min through the femoral vein. The dose administered depended on the group. Group 1 (n = 7). the control. received only 0.9% NaCl. group 2 (n = 12) 0.25 mg/kg; group 3 (n = 10) 0.50 mg/kg; group 4 (n = 8) 0.75 mg/kg; group 5 (n = 6) 1.00 mg/kg; group 6 (n = 7) 1.50 mg/kg; group 7 (n = 7) 2.00 mg/kg; group 8 (n = 6) 2.50 mg/kg; and group 9 (n = 7) 3.00 mg/kg. After the administration of nitrendipine. the kidneys were rendered ischemic for one hour by cross-clamping the renal vessels. Comparison of 24-h creatinine clearances for 72 h after reversal of ischemia demonstrated that nitrendipine was capable of providing a degree of protection against renal ischemia and the protective effect was dose dependent (p less than .05).
Endotracheal tube cuff pressure assessment: pitfalls of finger estimation and need for objective measurement, Estimation of endotracheal (ET) cuff pressure by finger palpation is one of the methods currently used in the clinical setting. We compared the accuracy of this method with instrumental intracuff pressure measurement in tracheal model tests by 20 members of our ICU team. Four different ET tubes at three different pressure levels were examined. Accuracy for the estimated method by finger palpation was 69% for high pressures. 58% for normal pressures. and 73% for low pressures. We observed differences in terms of sensitivity. specificity. and positive predictive power between different tubes reflecting differences in tube characteristics and interobserver variability. We conclude that precise intracuff pressure measurement is mandatory to prevent complications of over- or underinflation.
Prototype volume-controlled resuscitator for neonates and infants, Twenty-five infants receiving assisted ventilation in an ICU were manually ventilated for 5-min periods using either a new prototype volume-controlled resuscitator (VCR) or a standard self-inflating resuscitator (SIR). Variables monitored during these 5-min periods included heart rate. respiratory rate. mean arterial pressure. mean airway pressure (Paw). end-tidal CO2 (PetCO2). pulse oximetry oxygen saturation. PaO2. and PaCO2. Significant differences in posttrial values for the following variables were: a) PetCO2 (31.2 +/- 9.1 vs. 25.6 +/- 8.2 torr. p less than .001); b) PaCO2 (38.0 +/- 4.9 vs. 33.2 +/- 6.7 torr. p less than .01); and c) pH (7.4 +/- 0.6 vs. 7.5 +/- 0.1. p less than .04) at comparable Paw (9.5 +/- 7.6 vs. 8.0 +/- 6.0. NS). Eighty-four percent (21/25) of infants in the VCR group had normal PaCO2 values (35 to 45 torr) while only 44% (11/25) in the SIR group achieved normocarbia (p less than .001). Measurements of the highest (Pmax) and lowest (Pmin) inspiratory pressure (cm H2O) in 15 patients demonstrated marked variation in Pmax with the SIR. Differences in Pmax (SIR minus VCR) were significant (10.8 +/- 3.7. p less than .02) but not in Pmin (0.5 +/- 3.5. NS). Our study demonstrates that ventilation with the VCR resulted in less hyperventilation with minimal pressure variability as compared with the SIR. Further studies in the neonate are warranted.
Utility of fiberoptic bronchoscopy in nonresolving pneumonia, Although fiberoptic bronchoscopy (FOB) has been traditionally used to evaluate nonresolving pneumonia. its efficacy is unknown. We. therefore. reviewed FOB in 35 consecutive patients who had (1) a roentgenographic infiltrate. (2) cough. (3) either temperature greater than 38.1 degrees C. leukocytosis. sputum production. (4) symptoms present for at least ten days. and antibiotic therapy for at least one week. Known lung cancer and AIDS were excluded. Fiberoptic bronchoscopy was diagnostic in 86 percent (12/14) in whom a specific cause was found. No patient had endobronchial cancer. Two patients with nondiagnostic FOB and persistent systemic symptoms had open lung biopsy specimens showing Wegener's granulomatosis and bronchiolitis obliterans with organizing pneumonia (BOOP). Twenty-one patients with nondiagnostic FOB had no final diagnoses other than community-acquired pneumonia. We conclude that FOB is extremely useful in finding a specific diagnosis for a nonresolving pneumonia when a specific diagnosis can be made. Fiberoptic bronchoscopy was most likely to yield a specific diagnosis in nonsmoking patients with multilobar infiltrates of long duration and could have been avoided in older. smoking. or otherwise compromised patients with lobar or segmental infiltrates with no decrease in diagnostic yield in our series.
Use of pulmonary artery catheters in patients with acute myocardial infarction. Analysis of experience in 5,841 patients in the SPRINT Registry. SPRINT Study Group, This study analyzes the use of PAC in a registry comprising 5.841 hospitalized patients with AMI. A total of 371 patients received PAC. In-hospital mortality was higher in patients with CHF who received PAC. while there was no difference in patients with cardiogenic shock or persistent hypotension. Mortality in patients receiving PAC was higher irrespective of the presence or absence of "pump failure." A separate analysis of discharge summaries of 364 patients with CHF showed that PAC was used more frequently in sicker patients and that when severity of CHF was assessed. no difference in mortality was found in patients with mild or moderate CHF. We conclude that while a higher in-hospital mortality is found in patients receiving PAC. this excess is likely related to difference in severity of CHF. which had not been assessed in every individual. It is unlikely that PAC increases mortality.
A limited diagnostic investigation for obstructive sleep apnea syndrome. Oximetry and static charge sensitive bed, A simplified sleep apnea investigation consisting of combined oximetry and respiration movement monitoring was compared with conventional polysomnography. These two types of recordings were performed simultaneously during one night in 77 patients with suspected obstructive sleep apnea syndrome (OSAS). A static charge sensitive bed (SCSB) was used in the simplified recording because it provides a comfortable and reliable means of recording respiration movements. Periods of obstructive apneas gave a diamond-shaped periodic respiration movement pattern in the SCSB. usually accompanied by repetitive oxygen desaturations. The average number of desaturations greater than or equal to 4 percent per sleeping hour was termed the oxygen desaturation index (ODI) and compared with the apnea index (AI). In the whole population they were well correlated (p less than 0.0001. R2 = 0.41). but in individual cases there were considerable discrepancies. Patients with periodic respiration movements less than 18 percent of total sleeping time and ODI less than 2 never had AI greater than or equal to 5. whereas patients with periodic respiration greater than 45 percent and ODI greater than 6 always had AI greater than or equal to 5. Fifty-one of the 77 patients fulfilled these criteria. A bradycardia response to apneas was absent in 29 percent of patients with AI greater than or equal to 5. A combination of respiration movement and oximetry recording thus seems to give sufficient information to confirm or negate a diagnosis of OSAS in a majority of patients with clinical symptoms. In borderline patients. further investigations should be performed.
Predicting the need for hospitalization in children with acute asthma, In an attempt to identify factors which influence the decision of physicians to admit patients with acute asthma to the hospital. we studied prospectively 200 children (age 5.6 +/- 3.1 years. mean +/- SD) presenting to our emergency room with acute asthma. The children were assessed on arrival. and on disposition from the Emergency Room by one of the investigators. After obtaining historic data. a clinical score was assigned. and oxygen saturation and pulmonary function were measured. Of the 134 (67 percent) children who were discharged home from the Emergency Room. five returned within seven days and one was subsequently admitted. The clinical score on disposition was the sole variable found to best predict the decision for hospitalization (sensitivity 73 percent. specificity 95 percent). Of the variables obtained at presentation. the resulting decision tree found the clinical score to predict the decision for hospitalization (sensitivity 79 percent. specificity 75 percent). When the individual components of the clinical score were analyzed. the degree of dyspnea. as assessed by the investigator. was chosen as the rule to predict the hospitalization decision (sensitivity 88 percent. specificity 71 percent). We conclude that the decision with respect to the need for hospitalization in acute childhood asthma. is in practice based mainly on careful clinical evaluation. Pulmonary function and SaO2 measurements. although helpful adjuncts in the assessment of acute asthma. do not appear to contribute to the identification of patients who need hospital admission.
Reduction in bleeding after heart-lung transplantation. The importance of posterior mediastinal hemostasis, To reduce perioperative hemorrhage following heart-lung transplantation. several technical modifications were introduced in June 1988 to secure better posterior mediastinal hemostasis. The intraoperative and postoperative use of blood and blood products. as well as the chest tube drainage in the first 24 hours postoperatively. were compared in the seven patients operated on since June 1988 with the nine patients operated on before that date. Significant (p less than 0.05) reductions were demonstrated in the intraoperative and postoperative transfusion of packed cells. in the postoperative administration of fresh frozen plasma. and in the chest tube drainage within the first 24 hours postoperatively. The one-month and total hospital mortality rates were 6 percent and 12.5 percent. respectively. It is concluded that newer techniques to obtain optimal posterior mediastinal hemostasis have significantly reduced blood loss following heart-lung transplantation in our experience and have contributed to our excellent early postoperative results.
Clinical antecedents to in-hospital cardiopulmonary arrest, While the outcome of in-hospital cardiopulmonary arrest has been studied extensively. the clinical antecedents of arrest are less well defined. We studied a group of consecutive general hospital ward patients developing cardiopulmonary arrest. Prospectively determined definitions of underlying pathophysiology. severity of underlying disease. patient complaints. and clinical observations were used to determine common clinical features. Sixty-four patients arrested 161 +/- 26 hours following hospital admission. Pathophysiologic alterations preceding arrest were classified as respiratory in 24 patients (38 percent). metabolic in 7 (11 percent). cardiac in 6 (9 percent). neurologic in 4 (6 percent). multiple in 17 (27 percent). and unclassified in 6 (9 percent). Patients with multiple disturbances had mainly respiratory (39 percent) and metabolic (44 percent) disorders. Fifty-four patients (84 percent) had documented observations of clinical deterioration or new complaints within eight hours of arrest. Seventy percent of all patients had either deterioration of respiratory or mental function observed during this time. Routine laboratory tests obtained before arrest showed no consistent abnormalities. but vital signs showed a mean respiratory rate of 29 +/- 1 breaths per minute. The prognoses of patients' underlying diseases were classified as ultimately fatal in 26 (41 percent). nonfatal in 23 (36 percent). and rapidly fatal in 15 (23 percent). Five patients (8 percent) survived to hospital discharge. Patients developing arrest on the general hospital ward services have predominantly respiratory and metabolic derangements immediately preceding their arrests. Their underlying diseases are generally not rapidly fatal. Arrest is frequently preceded by a clinical deterioration involving either respiratory or mental function. These features and the high mortality associated with arrest suggest that efforts to predict and prevent arrest might prove beneficial.
Elevated serum procollagen III aminopeptide levels in sarcoidosis, Procollagen III aminopeptide (P-III-P). a peptide released during the conversion of type III procollagen to type III collagen. is considered a potential marker of fibroblast activity in a variety of pulmonary and extrapulmonary diseases. The aim of the present article was to investigate the levels of P-III-P in serum samples (sP-III-P) from a large number of sarcoid patients. in particular looking at its relationship with other markers of disease activity and its presumed role as a marker of pulmonary fibrosis. sP-III-P has been radioimmunoassayed in an overall series of 57 patients and the levels were higher (19.18 +/- 9.17 ng/ml) than in 25 age- and sex-matched controls (11.32 +/- 2.15 ng/ml; p less than 0.001). The elevation was neither sex-related nor related to obvious liver sarcoid localization. Although sP-III-P levels were slightly higher in patients with stage II. there was no significant difference in patients with stage I or III. We found a positive relationship with serum angiotensin-converting enzyme (S-ACE) levels (p less than 0.04). but not with other markers of disease activity (67Ga uptake. bronchoalveolar lavage [BAL] lymphocyte percent. vital capacity. and lung diffusing capacity). The relationship with S-ACE was confirmed in a longitudinal follow-up study. where sP-III-P strictly paralleled the S-ACE behavior. Finally. the initial sP-III-P levels did not predict cases either with disease relapse or resistance to corticosteroid treatment. We conclude that. in our study. sP-III-P levels failed to characterize sarcoid patients with radiologic fibrotic pattern (stage III). and. in addition. were unable to predict which patients would have a poor prognosis. Rather. they reflect a metabolic activity of sarcoid granuloma cells. Thus. the usefulness of sP-III-P in the treatment of patients with sarcoid may be considered similar to that of S-ACE.
Maxillofacial surgery and nasal CPAP. A comparison of treatment for obstructive sleep apnea syndrome, Nasal continuous positive airway pressure (CPAP) is the primary therapy for obstructive sleep apnea syndrome (OSAS). Recent reports have indicated. however. that there is a small but significant number of failures related to patient compliance. Primary surgical treatment. which has been uvulopalatopharyngoplasty (UPPP). has declined because of poor results. A reviewed of UPPP failures has shown that while UPPP eliminated palatal obstruction. it failed to eliminate base of tongue obstruction. Maxillofacial surgery has been reported as treatment of OSAS by correcting base of tongue obstruction. Thirty patients with severe OSAS were evaluated to compare nasal CPAP and maxillofacial surgery. The goal was to determine if our surgical protocol was as effective as nasal CPAP. All patients initially underwent baseline diagnostic polysomnography to document OSAS. A nasal CPAP study was performed to determine the appropriate positive end-expiratory pressure. The patients in this study were using nasal CPAP. but they found it unacceptable as long-term treatment and elected surgery. Maxillofacial surgery consisted of maxillary. mandibular. and hyoid advancement. Polysomnography was performed six months following surgery and compared with the night 2 CPAP results. The parameters included in the investigation were the respiratory disturbance index (RDI). lowest SaO2. number of SaO2 falls below 90 percent. total sleep time (TST). REM sleep percent. stage 3-4 sleep percent. and wake after sleep onset. The mean RDI before treatment was 72.0 (SD 25.7). After completing therapy. the RDI from surgery and CPAP was 8.8 (SD 6.0) and 8.6 (SD 4.1). respectively. The mean low SaO2 prior to treatment was 61.0 (SD 13.5). and the CPAP results and postsurgical results were 86.2 (SD 5.5) and 86.1 (SD 4.2). respectively. An analysis of variance was used to examine the results. and there was no statistical difference between nasal CPAP and surgery for all respiratory variables.
Effect of inhaled methacholine on inspiratory flow, One hundred consecutive outpatients with symptoms suggestive of asthma who came to the Pulmonary Function Laboratory for a methacholine challenge test were studied. In addition to the forced expiratory maneuvers. forced inspiratory maneuvers were performed before and after the maximal response to methacholine. In 24 patients. the methacholine challenge suggested that they had asthma (forced expiratory volume in 1 s [FEV1] decrease greater than or equal to 20 percent). Six of these 24 patients also had a decrease in maximal forced inspiratory flow (FIFmax) greater than or equal to 20 percent and nine had a decrease in forced inspiratory flow at 50 percent of vital capacity (FIF50) greater than or equal to 20 percent. suggesting that bronchoconstriction can cause decreased inspiratory as well as expiratory flows. In 76 patients. the methacholine challenges were "negative" (FEV1 decrease less than or equal to 20 percent). suggesting that they did not have asthma. Nevertheless. in 11 of these 76 patients the FIFmax decrease was greater than or equal to 20 percent. and in 14 patients the FIF50 decrease was greater than or equal to 20 percent. suggesting that intermittent central airway obstruction is responsible for these patients' symptoms.
Measurements of right ventricular volumes during fluid challenge, The effects of fluid loading on RV function were studied in 41 acutely ill patients monitored with a modified pulmonary artery catheter equipped for measuring RVef. Hemodynamic evaluation was performed before and after infusion of 300 ml of 4.5 percent albumin solution in 30 min. Changes in SI did not correlate with Pra or Ppao but did with RVEDVI. For the entire group. RVef was unchanged (27 +/- 9 vs 27 +/- 9 percent). In the eight patients with an initial RVEDVI greater than 140 ml/m2. the fluid challenge increased Pra and Ppao and reduced LVSWI without any other significant effect. There was no significant correlation between RVEDVI and Pra and only a weak correlation between RVESVI and Ppa. However. there was a highly linear correlation between both RVEDVI and RVESVI and changes in RVEDVI and in RVESVI. suggesting that in the absence of severe pulmonary hypertension RV output is primarily dependent on RV preload.
Pseudomonas aeruginosa compared with Escherichia coli produces less endotoxemia but more cardiovascular dysfunction and mortality in a canine model of septic shock, We investigated the effects of two different Gram-negative bacteria and radiation-induced leukopenia on endotoxemia. cardiovascular abnormalities. and mortality in a canine model of septic shock. Serial hemodynamics were measured in conscious dogs using radionuclide heart scans and thermodilution cardiac output catheters. Plasma endotoxin concentrations were determined with a chromogenic Limulus amebocyte lysate assay. Viable Pseudomonas aeruginosa or Escherichia coli implanted intraperitoneally produced concordant hemodynamic patterns of septic shock (p less than 0.01). Endotoxin concentrations were more than tenfold lower in dogs infected with P aeruginosa compared with E coli (p less than 0.0001). Despite lower endotoxin levels. P aeruginosa-infected dogs had a higher mortality (p less than 0.01). more severe hypotension (p less than 0.05). and greater depression of the left ventricular ejection fraction (p less than 0.05) than dogs with E coli sepsis. A nonlethal E coli challenge combined with leukopenia (induced by a nonlethal dose of radiation) resulted in a mortality of 60 percent (p less than 0.01) without greater cardiovascular dysfunction or higher endotoxin concentrations. These findings suggest that bacterial products other than endotoxin and host-related factors may be important contributors to the toxicity. cardiovascular instability. and mortality of Gram-negative septic shock. Quantitative determinations of plasma endotoxin are unlikely to correlate with the clinical severity of septicemia in heterogeneous patient populations infected with different Gram-negative organisms.
Selection and evaluation of recipients for heart-lung and lung transplantation, Heart-lung and lung transplantation is being successfully performed with increasing frequency in patients with end-stage cardiopulmonary and pulmonary disease. Transplantation must now be considered as a therapeutic option in selected patients. and physicians are required to understand the principles involved for determining suitable candidates and operative procedures of choice. Indications. contraindications. and choice of operation with respect to underlying disease are discussed herein. as are methods of evaluation and appropriate timing for transplantation. Special considerations regarding specific patient populations are also addressed. In properly selected patients. heart-lung and lung transplantation provide a viable therapeutic option in those with end-stage disease who are unresponsive to conventional management.
Bronchogenic carcinoma in situ on the carina eradicated by endobronchial biopsy, Squamous cell carcinoma in situ of the bronchus is a rare disorder in an isolated clinical setting. We present a case of carcinoma in situ located on the carina with excisional biopsy via a fiberoptic bronchoscope and no recurrence after five years. To our knowledge. this represents the only case of carcinoma in situ treated solely with excisional biopsy. This case further emphasizes the importance of securing biopsy specimens for all mucosal abnormalities and raises the possibility of limited excision as sole therapy for carcinoma in situ.
Rapid oral desensitization to isoniazid and rifampin, A 45-year-old black woman. sputum positive for acid-fast bacilli. developed hypersensitivity to both isoniazid and rifampin. She was admitted to the hospital and desensitized to both medications using modified penicillin protocols. Skin testing was negative to both drugs. Desensitization to isoniazid was complicated by a drug fever that was controlled by prednisone. The patient was able to maintain once-a-day dosing without incident even with steroid taper. To our knowledge. this is the first reported case of dual isoniazid and rifampin hypersensitivity with rapid oral desensitization.
Bilious pleural effusion following liver biopsy, Pleural effusions in patients with chronic liver disease are common and usually are of little consequence. Bilious pleural effusion can occur following percutaneous biopsy or cholangiography procedures if the pleura is traversed. This report emphasizes the role of biliary tract obstruction in the development of a bilious effusion and the importance of biliary tract decompression in treatment. We discuss the laboratory evidence supporting the diagnosis of bilious effusion and review the reported experience with this complication.
Lack of change in neurochemical markers during the postepileptic phase of intrahippocampal tetanus toxin syndrome in rats, The chronic epileptic syndrome induced by injecting tetanus toxin into rat hippocampus causes functional changes that essentially are permanent. outlasting the period of active seizures by at least 1 year. These long-term changes have been characterized by an impaired performance on a range of behavioral tasks. which in turn have been associated with a physiologic depression of hippocampal evoked responses but not with any discernible histopathology. In the present study. we examined the hippocampi of rats in the postseizure phase of the tetanus toxin model and observed no significant changes in the concentration of neurochemical markers for six neurotransmitters. Therefore. the long-term reduction in hippocampal excitability cannot be attributed to any major loss of afferents or hippocampal neurons using aspartate. acetylcholine. gamma-aminobutyric acid (GABA). glutamate. norepinephrine (NE). or serotonin as their transmitters.
Some endorphin derivatives and hydrocortisone prevent EEG limbic seizures induced by corticotropin-releasing factor in rabbits, Corticotropin-releasing factor (CRF) injected into the cerebral ventricles of small mammals induces EEG limbic seizures. behavioral excitability. stereotyped behavior. and tardive enhancement of hippocampal theta voltage and frequency. Because we addressed this phenomenon when we explained the pathogenesis of infantile spasms in children. we wished to study the interference exerted by some gamma-endorphin fragments on EEG epileptiform and behavioral symptoms induced by CRF in the rabbit. Animals were implanted intracerebroventricularly (i.c.v.) with semichronic cortical and hippocampal electrodes. together with a cannula into the left lateral ventricle. When some gamma-endorphin derivatives (DT gamma E. DE gamma E) were injected intravenously (i.v.) for 4 days (or hydrocortisone once). they prevented the EEG ictal seizures induced in the hippocampus of rabbits by CRF injected i.c.v. Hydrocortisone and DE gamma E also prevented the appearance of scattered spiking and partially prevented tardive enhancement of theta voltage in the hippocampal EEG. Finally. DE gamma E also prevented stereotyped behavior and excitability induced by CRF. These results confirm the regulatory role exerted by CRF in limbic structure excitability and suggest that the above peptides may be involved in a regulatory feedback mechanism of CRF metabolism or activity. The possibility that these peptides may also have interesting antiepileptogenic properties should be considered.
Neonatal monosodium glutamate abolishes corticotropin-releasing factor-induced epileptogenic activity in rats, Intracerebroventricular (i.c.v.) injection of rat corticotropin-releasing factor (rCRF) at doses of 5-20 micrograms in rats induces epileptogenic activity characterized by pacemaker-like spikes localized in the hippocampal leads. Such an effect was still present in rats neonatally treated with saline but was absent in those neonatally treated with monosodium glutamate (MSG). a treatment that caused marked changes in the concentration of several brain neurotransmitters and neuropeptides in hypothalamic nuclei where CRF is highly concentrated and is believed to induce endocrinologic and behavioral effects. The present results suggest the rCRF-induced spiking activity is mediated by activation of neuronal pathways sensitive to MSG neurotoxic effect.
Triiodothyronine and brain excitability, We investigated mechanisms involved in thyroid hormone action on brain excitability. The effect of acute exposure of triiodothyronine (T3) to rat hippocampal slices in vitro was studied. No significant changes could be detected in prevolley. field excitatory postsynaptic potentials (fEPSP) and population spike amplitude. while there was a minor. nonsignificant trend toward shortening of the population spike latency time. T3 had no effect on penicillin-induced epileptiform activity. There was. however. an active accumulation of radioactively labeled T3 in the slices. A rat cervaux-isole preparation was used to determine focal seizure thresholds in the visual cortex. and no acute (2-4 h) effects were demonstrated. No significant acute effects of T3 on brain excitability in the hippocampus and visual cortex was observed. despite an active accumulation of T3. Thus. the effect of T3 on brain excitability most likely is due to delayed effects.
Electrocorticographic confirmation of focal positron emission tomographic abnormalities in children with intractable epilepsy, The relationship between focal disturbances of glucose utilization demonstrated by positron emission tomography (PET) and electrophysiologic abnormalities defined by intraoperative electrocorticography (ECoG) was studied in eight children (aged 13 months to 12 years) who underwent cortical resection because of intractable seizures. None of the children had pure temporal lobe epilepsy. Computed tomography (CT) and/or magnetic resonance imaging (MRI) were normal in four of the eight children. The scalp electroencephalogram (EEG) showed lateralized interictal epileptiform abnormalities in all eight and lateralized ictal onset in five of eight. In seven children. interictal PET showed focal hypometabolism; the eighth child had focal. ictal hypermetabolism. ECoG at the time of surgery showed epileptiform spiking. slowing. and/or suppression of normal background activity that in every case corresponded to the focus on PET scan. The ECoG findings support the notion that in children with epilepsy focal metabolic abnormalities on PET correspond to electrophysiologically abnormal areas of cortex. which are presumably also the epileptogenic regions. Such areas can appear normal on anatomic imaging studies (CT and MRI). When ictal scalp EEG data are ambiguous or contradictory. PET provides a less invasive means than chronic grid or depth electrode recording for evaluating whether a localized epileptogenic area exists.
Lateralized effects of subclinical epileptiform EEG discharges on scholastic performance in children, The interaction between lateralization of subclinical epileptiform discharges and cognitive tasks was investigated in 21 children (12 girls and 9 boys. mean age 10.6 years). Seventeen had a diagnosis of epilepsy (partial or secondarily generalized). Testing was by reading. arithmetic. and intelligence subtests during continuous telemetric EEG and video monitoring. Children with left-sided discharges had significantly lower reading performance than children with right-sided discharges. During reading. epileptiform discharges occurred relatively less frequently and with a shorter total duration over the left hemisphere than the right. This supports the view that cognitive tasks suppress epileptiform discharges when they activate a region of the brain within the epileptogenic zone. Discharges from other epileptogenic zones not directly activated by the tasks are increased. however.
Comparison of endometrial biopsy and urinary pregnanediol glucuronide concentration in the diagnosis of luteal phase defect, To determine if pregnanediol glucuronide (PG) excretion is useful in luteal phase assessment. we compared daily first morning urinary PG concentrations during the luteal phase in nine normal and nine deficient cycles. Total luteal pregnanediol excretion (44.1 +/- 11.3 versus 64.0 +/- 11.6 area units +/- SEM) was not different. However. significantly less pregnanediol was excreted by the abnormal group during the 1st 5 days of the luteal phase (12.7 +/- 1.2 versus 18.0 +/- 1.7 area units +/- SEM. respectively). Thus. delayed PG excretion may be characteristic of luteal phase defect and measurement of urinary PG may be useful only if daily samples during the early luteal phase are obtained.
Evaluation of the stimulated menstrual cycle by magnetic resonance imaging, Changes in uterine zonal anatomy in six women during a cycle of treatment with clomiphene citrate is studied by magnetic resonance imaging. There was a rapid rate of increase in endometrial thickness during the periovulatory period that was similar to the pattern seen in a prior study of women with normal (nonstimulated) cycles. Junctional zone thickness did not parallel the endometrial pattern and differed from the response seen in nonstimulated cycles. Results of large scale studies may help to further understand the effects of these medications.
Basal body temperature and endometriosis, This investigation examined the association between pelvic endometriosis and altered basal body temperature (BBT). The study population consisted of infertile women who have been diagnosed as having endometriosis. A significant association was found between the presence of pelvic endometriosis (without previous treatment) and the appearance of a late decline in BBT during the early follicular phase of the menstrual cycle. A temperature greater than 97.8 degrees F on the first 3 days of menses is associated with pelvic endometriosis. The findings of this study support the early clinical diagnosis of endometriosis in infertile women. Basal body temperature chart analysis may be useful as a clinical adjunct when endometriosis is suspected.
The placebo response of subfertile couples to attending a tertiary referral centre, The objective of this study was to determine whether there was a placebo response to clinic attendance in couples with prolonged (greater than 4 years) subfertility. From 4 to 18 years of subfertility we observed a treatment independent cumulative conception rate of 22%. which was independent of the length of subfertility. Twenty-seven women conceived after 1 to 4 years' subfertility. and 30 conceived after greater than 4 years' subfertility. The fecundity of the latter group was significantly greater than that of women with 1 to 4 years' subfertility. being similar to "normal" subjects who had stopped contraception. This study demonstrates that a subgroup of apparently normal women with greater than 4 years' subfertility responded positively to clinic attendance independent of any investigation(s) or therapy.
Home monitoring of gonadotropin ovulation induction using the Ovarian Monitor, The safe use of gonadotropins relies on close hormonal and/or ultrasound monitoring to assess the response to treatment. requiring multiple hospital visits. Home monitoring with the Ovarian Monitor (St. Michael Research Foundation. Macleod. Victoria. Australia) minimizes hospital visits and overcomes many of the logistic difficulties associated with gonadotropin use. It utilizes a system of homogenous enzyme immunoassay using lysozyme conjugates to measure quantitatively either urinary estrone-3 or pregnanediol-3-glucuronide. Results obtained by 24 patients in 57 cycles using the Ovarian Monitor at home correlate closely with results obtained in the laboratory (estrone-3-glucuronide r = 0.955; pregnanediol-3-glucuronide r = 0.958). Cycle outcomes (ovulation. 74%/cycle; clinical pregnancy. 30%/cycle; multiple pregnancy. 13%/pregnancy; hyperstimulation. 11%/cycle) are no different from those achieved in laboratory-monitored patients. Home monitoring can be as safe and effective as laboratory monitoring. offers significant social benefits. and improves access to this form of therapy.
Cryopreserved/thawed semen for in vitro fertilization: results from fertile donors and infertile patients, We evaluated the in vitro fertilization (IVF) outcome in 54 cycles using cryopreserved/thawed semen from fertile donors. Controls were other IVF patients matched by time frame. female age. stimulation protocol. number of pre-embryos transferred. and absence of a male factor using freshly ejaculated normal semen samples. In the study group and controls. respectively. post-thaw swim-up motility was 83.1% and 89.5%; fertilization rate of preovulatory oocytes (91.8%. 95.7%) and ongoing pregnancy rate (PR) per transfer (21.1%. 25.0%) were similar. The excellent fertilization rate with frozen/thawed semen was achieved through high-concentration insemination (0.5 x 10(6) motile sperm/mL). With use of frozen/thawed samples from infertile men (normal and subfertile samples). PR was similar but fertilization rate was lower. Cryopreserved semen is a valuable option for infertile couples in IVF therapy.
Fertility prognosis for infertile men: results of follow-up study of semen analysis in infertile men from two different populations evaluated by the Cox regression model, Using the Cox proportional hazard regression model on one material (group I = 765. 1950 to 1951) we have identified four variables of semen analysis with significant prognostic information about fertility. The four variables were combined into a model for establishing the probability of the individual male to achieve pregnancy as a function of time. This model is tested first on another material (group II = 321. 1977 to 1985). A Goodness-of-fit test indicates excellent agreement between the expectations from the model and the observed number of pregnancies in group II. Second. the two groups are pooled (= 1.086). Then only three variables give significant prognostic information about the time until pregnancy: (1) the man's age at semen analysis (years); (2) the percentage of morphologically normal spermatozoa (ln %); and (3) the degree of motility (good/poor). These three important variables enter into a new and better prognostic model.
Correlation between quantitative antibody titers of sperm immobilizing antibodies and pregnancy rates by treatments, Immunological infertility in women who possessed sperm immobilizing (SI) antibodies made it very difficult to conceive using the usual treatments. We examined SI antibodies by the quantitative Sperm Immobilization Test and found the antibody titers (50% sperm immobilization unit: SI50 unit) associated with pregnancy rates. Patients with high SI50 titers (greater than 10 units) did not conceive by ordinary or repeated artificial inseminations with husband's semen (AIH) except when treated with in vitro fertilization (IVF) and embryo replacement. Patients with relatively low SI50 titers (less than 10 units) could conceive either by repeated or ordinary AIH. though the success rates were lower than by IVF-embryo replacement. It is important to assess the SI50 titers by the quantitative method to select treatments for infertile women with SI antibodies. In follow-up studies of the patients who conceived successfully. it was found that SI50 titers tended to decline as pregnancy proceeded.
Hyaluronic acid (Sperm Select) improves retention of sperm motility and velocity in normospermic and oligospermic specimens, The effects of Sperm Select (Pharmacia AB. Uppsala. Sweden). a hyaluronic acid medium. on the motility and membrane integrity properties of sperm were studied. In 15 normospermic specimens after overnight incubation. the motility parameters in the control versus the Sperm Select group were as follows (mean +/- SEM): motility. 18.8% +/- 2.8% versus 27.4% +/- 2.9%; velocity. 21.5 +/- 2.4 versus 27.2 +/- 2.2 microns/s; linearity. 3.8 +/- 0.3 versus 4.4 +/- 0.2; lateral head displacement. 1.5 +/- 0.2 versus 1.9 +/- 0.1 microns; and tail beat/cross frequency. 8.8 +/- 1.3 versus 10.8 +/- 1.4 Hz. The density of motile sperm was 10.8 +/- 2.3 versus 18.5 +/- 2.5 X 10(6) sperm/mL. Finally. the velocity coefficient. the multiple of the sperm motility and linear velocity. was 4.6 +/- 1.1 versus 8.1 +/- 1.4. However. we found no Sperm Select related differences when testing sperm membrane integrity with hypoosmotic swelling and supravital staining. Thus. Sperm Select improves the retention of sperm motility (most prominently velocity) apparently due to a direct action of hyaluronic acid on sperm metabolism or contractility rather than to preservation of sperm membrane integrity. In 20 oligospermic specimens. Sperm Select caused similar improvements in sperm motility. and the duration of motility could be predicted from the degree of enhancement in sperm velocity after short-term Sperm Select exposure. A modified Sperm Select protocol is described that further increases motile sperm yield without a centrifugation step.
Twin pregnancy after diagnosis and treatment of ectopic implantation by retrograde selective salpingography and intraluminal methotrexate injection, In this case report. a patient with a right tubal pregnancy was managed by a new procedure combining retrograde salpingography and local MTX injection. A twin pregnancy occurred shortly after treatment. We conclude that retrograde tubal cannulation may provide an alternative method for the diagnosis and treatment of selected EPs.
Establishment of pregnancies in humans after transcervical transfer of gametes immediately after oocyte retrieval, This study. like that of Veersema et al. demonstrates the feasibility of direct intrauterine transfer of gametes in initiating pregnancy. Whether the success of this procedure can be further improved with modification (preincubation. in vitro insemination) remains the subject of continued investigation. Notwithstanding this uncertainty. we feel that transcervical transfer of gametes may be an alternative to IVF for patients with ethical concerns regarding IVF.
The prevalence of subfertility: a review of the current confusion and a report of two new studies, The difficulties inherent in measuring the prevalence of subfertility are discussed. Four subtypes of subfertility are defined. enabling comparisons to be made between the widely different approaches previously reported. A detailed assessment was made of the prevalence of subfertility in two different samples of British women aged 25 to 44 years. using interviews. postal questionnaires. and medical record searches. Data were collected on 872 women from a general practice and 702 hospital patients. The combined data showed that 24% of all women attempting to conceive experience an episode of subfertility at some stage in their reproductive life. Thirteen percent experience this in attempting to conceive their first child. and 17% when attempting to conceive a subsequent child. Three percent of women are involuntarily childless and 6% of parous women are not able to have as many children as they would wish.
Neosalpingostomy for distal tubal obstruction: prognostic factors and impact of surgical technique, We reviewed the clinical records of all women who underwent microsurgical terminal neosalpingostomy for distal tubal obstruction between January 1983 and June 1988. We identified 95 women whose preoperative evaluation revealed no other contributory factors for infertility and analyzed their pregnancy outcome after this procedure. Pregnancy success was inversely related to the extent of tubal distortion (dilation. rugal integrity. and status of the fimbria) and degree of adnexal adhesions. Using our classification system for distal tubal obstruction. patients with mild disease had an 80% pregnancy rate. whereas patients with moderate and severe disease had a 31% and 16% success rate. respectively. We found no statistically significant difference in pregnancy outcome when we compared this series with our previous group. reported in 1978. where contemporary microsurgical technique was not used. Although we feel that optimal surgical technique is important to maximize success. we conclude that the most important prognostic factor in pregnancy outcome after neosalpingostomy for distal tubal disease is the anatomical and functional integrity of the tube.
Repair of the uterine cavity after hysteroscopic septal incision, We performed a follow-up hysteroscopy with multiple biopsies at different intervals after surgery in 19 women who underwent hysteroscopic septal incision. Seven days after operation the sectioned areas were very evident and not epithelialized (3 patients). At 14 days. the incised zone was depressed with scattered epithelialization (5 subjects). At 1 month. the sectioned surfaces were still depressed and uniformly covered by thin endometrium (5 cases). After 2 months the uterine cavity was almost normal with minimal tendency to central fundal adhesions (6 women). Thus. spontaneous healing processes after hysteroscopic metroplasty progressed regularly and completely and there is probably no reason to delay attempts at pregnancy for longer than two cycles after surgery.
Ultrasound-guided transcervical metroplasty, A new technique of metroplasty is described. The septum is divided with 4-mm endoscopic scissors introduced into the uterine cavity through the cervix. The whole procedure is monitored by a real-time ultrasound scanner. Twenty-four patients were operated on with this technique. No complication was encountered. Fifteen patients had third trimester deliveries or ongoing pregnancies. Among 12 patients who had suffered repetitive pregnancy losses. 11 desired pregnancy: 10 have been successfully pregnant beyond the second trimester (91.7%). 8 are delivered. and the living birth rate is 72.7%. These results equal those obtained after hysteroscopic metroplasty. The procedure is short. safe. requires no special equipment. and does not necessitate concomitant laparoscopy.
Experimental diabetes increases insulinlike growth factor I and II receptor concentration and gene expression in kidney, Insulinlike growth factor I (IGF-I) is a mitogenic hormone with important regulatory roles in growth and development. One of the target organs for IGF-I action is the kidney. which synthesizes abundant IGF-I receptors and IGF-I itself. To study the involvement of IGF-I and the IGF-I receptor in the development of nephropathy. one of the major complications of diabetes mellitus. we measured the expression of these genes in the kidney and in other tissues of the streptozocin-induced diabetic rat. The binding of 125I-labeled IGF-I to crude membranes was measured in the same tissues. We observed a 2.5-fold increase in the steady-state level of IGF-I-receptor mRNA in the diabetic kidney. which was accompanied by a 2.3-fold increase in IGF-I binding. In addition to this increase in IGF-I binding to the IGF-I receptor. there was also binding to a lower-molecular-weight material that may represent an IGF-binding protein. No change was detected in the level of IGF-I-peptide mRNA. Similarly. IGF-II-receptor mRNA levels and IGF-II binding were significantly increased in the diabetic kidney. IGF-I- and IGF-II-receptor mRNA levels and IGF-I and IGF-II binding returned to control values after insulin treatment. Because the IGF-I receptor is able to transduce mitogenic signals on activation of its tyrosine kinase domain. we hypothesize that. among other factors. high levels of receptor in the diabetic kidney may also be involved in the development of diabetic nephropathy. Increased IGF-II-receptor expression in the diabetic kidney may be important for the intracellular transport and packaging of lysosomal enzymes. although a role for this receptor in signal transduction cannot be excluded. Finally. the possible role of IGF-binding proteins requires further study.
Multigenic basis for type I diabetes. Association of HRAS1 polymorphism with HLA-DR3, DQw2/DR4, DQw8, We analyzed extended haplotypes composed of DNA loci on the short arm of chromosome 11 for segregation with insulin-dependent (type I) diabetes mellitus. The markers for these loci are tyrosine hydroxylase. insulin. and c-Ha-ras-1 proto-oncogene (HRAS1). We report. in a study of 27 families. that a specific haplotype (H). containing a 3-kilobase (kb) HRAS1-Taq I DNA polymorphism. segregated differentially in diabetic and nondiabetic siblings (P = 0.005). A parallel population study showed that the 3-kb HRAS1-Taq I polymorphism is increased in frequency in type I patients having two strong HLA-susceptibility haplotypes compared with other type I patients or healthy control blood donors (P less than 0.010 and P less than 0.025. respectively). The polymorphic variable. enhancer. and promoter regions flanking the human insulin gene on the H haplotype were not associated with type I diabetes. These results indicate that the HRAS1 locus or genes in linkage disequilibrium with this locus are involved in the pathogenesis of HLA-DR3/4 type I diabetes mellitus.
Role of two types of glucose transporters in enlarged adipocytes from aged obese rats, The mechanism of insulin-resistant glucose-transport activity in enlarged aged adipocytes was examined. Glucose-transport activity was assessed by measuring 3-O-methylglucose transport and the concentration of HepG2 erythrocyte/glucose transporter (GLUT1). and the muscle/adipose tissue transporter (GLUT4) was estimated by immunoblotting. Basal glucose-transport activity increased 6.3-fold/cell but remained constant per unit cellular surface area due to cell enlargement. Maximal insulin-stimulated transport activity remained constant per cell but decreased per unit cellular surface area. On a per protein basis. GLUT1 and GLUT4 from aged rats decreased to approximately 60 and 10% of those from young rats. respectively. However. when the protein content of each fraction and the recoveries of marker enzymes were used for estimating the amount of transporters in intact adipocytes. the amount of GLUT1 per cell remained relatively constant. whereas that of GLUT4 decreased. In basal cells from young rats. 31% of the total GLUT1 per cell was located in the plasma membrane. whereas in those from aged rats. 63% was located in the plasma membrane. Thus. in comparing basal adipocytes from aged rats with those from young rats. GLUT1 per cell in the plasma membrane increased 2.8-fold. but this increase was less than that of transport activity (6.3-fold). In basal cells from young rats. 8% of the total GLUT4 was located in the plasma membrane. and a 4.5-fold increase was observed with insulin treatment. but the amount of GLUT4 in each fraction from aged rats markedly decreased.
Mild hypoglycemia and impairment of brain stem and cortical evoked potentials in healthy subjects, To evaluate the impact of mild hypoglycemia on CNS function in healthy adults. we measured brain stem auditory evoked potentials and P300 potentials (elicited by cognitive processing of auditory stimuli) during hypoglycemic or euglycemic insulin clamps (80 mU.m-2.min-1). In the hypoglycemic clamp study (n = 8). plasma glucose was allowed to fall from 4.6 to 3 mM in hourly approximately 0.5-mM steps and subsequently returned to euglycemic baseline levels. In the euglycemic clamp study (n = 8). plasma glucose was maintained at baseline levels throughout. Neither brain stem nor P300 responses changed during the euglycemic control study; symptoms and counterregulatory hormones were also unaffected. During the hypoglycemia study. epinephrine and growth hormone rose once plasma glucose reached 3.4 +/- 0.1 mM. Brain stem and P300 potentials remained unchanged until the 3-mM glucose step. when neurophysiological changes suddenly developed in conjunction with reported symptoms. At this glucose level. the wave V component of the brain stem potential was selectively altered in 7 of 8 subjects. Furthermore. P300 latency significantly increased. and amplitude diminished. Changes in both brain stem and cortical (P300) responses reversed when euglycemia was restored. We conclude that modest reductions in plasma glucose (to 3 mM) produce marked alterations in both brain stem and cortical responses to auditory stimuli. These changes in neural function appear at the same time as symptoms and follow rather than precede the rise in counterregulatory hormones during hypoglycemia. Our data suggest that the adverse effects of mild hypoglycemia on brain function are not limited to higher centers but also involve the brain stem.
Changes in phosphoinositide turnover, Ca2+ mobilization, and protein phosphorylation in platelets from NIDDM patients, Enhanced platelet functions have been demonstrated in patients with non-insulin-dependent diabetes mellitus (NIDDM). This study evaluated abnormalities in platelet signal transduction in diabetic patients. including turnover of phosphoinositides. mobilization of intracellular Ca2+. and phosphorylation of 20.000- and 47.000-Mr proteins (P20 and P47). Washed platelets were obtained from 6 patients with NIDDM whose platelet aggregation rates were abnormally elevated (DM-A group). 11 NIDDM patients with normal platelet aggregation rates (DM-B group). and 8 age-matched healthy control subjects. The mass and specific radioactivity of phosphatidylinositol 4.5-bisphosphate (PIP2). phosphatidylinositol 4-phosphate (PIP). phosphatidylinositol (PI). and phosphatidic acid (PA) in 32P-labeled platelets were not different among the three groups. Hydrolysis of PIP2. PIP. and PI; accumulation of PA; and phosphorylation of P20 in platelets stimulated by 0.05 U/ml thrombin were significantly increased in the DM-A group compared with the control or DM-B group. There was no difference in P47 phosphorylation among the three groups. On the contrary. P20 and P47 phosphorylation induced by 50 nM of 12-O-tetradecanoylphorbol-13-acetate. an activator of protein kinase C. was significantly decreased in the DM-A group. Additionally. the intracellular free Ca2+ concentration [( Ca2+]i) was measured with the fluorescent Ca2+ indicator fura 2. Although the basal [Ca2+]i value was similar in the three groups. the rise in [Ca2+]i induced by 0.05 U/ml thrombin in the presence and the absence of extracellular Ca2+ was significantly higher in the DM-A group than the other groups.
Tumor necrosis factor-increased hepatic very-low-density lipoprotein production and increased serum triglyceride levels in diabetic rats, Previous studies demonstrated that administration of tumor necrosis factor (TNF) to diabetic rats rapidly increases serum triglyceride levels and stimulates hepatic lipogenesis without affecting the activity of adipose tissue lipoprotein lipase or serum insulin levels. The purpose of this study was to determine the mechanism by which TNF increases serum triglyceride levels and stimulates hepatic fatty acid synthesis in diabetic animals. The maximal increase (approximately 2-fold) in serum triglyceride levels in diabetic rats is seen with a dose of 10 micrograms TNF/200 g body wt. and the half-maximal effect is observed with 5 micrograms TNF/200 g body wt. The clearance of labeled triglyceride-rich lipoproteins from the circulation is not affected by TNF administration (triglyceride t 1/2; diabetic vs. TNF-administered diabetic. 3.5 +/- 0.7 vs. 4.0 +/- 0.6 min. respectively; NS). The production of triglyceride. measured by the Triton WR-1339 technique. is increased twofold in diabetic animals after TNF administration. These results indicate that the rapid increase in serum triglyceride levels after TNF treatment is accounted for by increased hepatic lipoprotein secretion. TNF administration did not alter either the amount or activation state of hepatic acetyl-CoA carboxylase. a key regulatory enzyme in fatty acid synthesis. There was also no change in the hepatic levels of fatty acyl-CoA. an allosteric inhibitor of acetyl-CoA carboxylase. However. there was a 71% increase in hepatic citrate concentrations. Citrate is an allosteric activator of acetyl-CoA carboxylase. and changes in hepatic citrate concentrations have been shown to mediate changes in the rates of fatty acid synthesis.
Coupling of beta-cell desensitization by hyperglycemia to excessive stimulation and circulating insulin in glucose-infused rats, Nondiabetic rats were infused with glucose for 48 h to maintain moderate or marked hyperglycemia (mean blood glucose 13.2 +/- 0.7 or 22.8 +/- 0.3 mM. respectively). The two levels of hyperglycemia increased plasma insulin levels severalfold but decreased the insulin response to 27 mM glucose by 19 and 95%. respectively. versus saline infusion. Diazoxide (5 mg.kg-1.h-1). when continuously infused during the hyperglycemia protocols. completely inhibited the glucose-induced rise in plasma insulin levels. Diazoxide transformed beta-cell insensitivity to stimulation: glucose-induced insulin release was thus increased 318% after moderate hyperglycemia and 707% after marked hyperglycemia. These stimulatory effects of diazoxide were reversed by exogenous insulin infusion (8 or 2 U/24 h) in a dose-dependent manner. It is concluded that excessive beta-cell stimulation rather than glucotoxicity underlies hyperglycemia-induced beta-cell insensitivity. Effects of hyperinsulinemia can form part of the mechanisms whereby excessive stimulation affects beta-cell secretion.
Premenstrual syndromes defined by symptom-sets, An analysis is made of the pattern of presenting premenstrual symptoms in randomly selected general practice patients from the Wellington region. New Zealand. Participants. 1826 healthy women 16-54 years old whose characteristics were reasonably representative of the adult female population. were asked about their general. obstetrical and gynaecological health. For the 1456 women who had menstruated within the last month or so. detailed questions were asked about the last menstrual cycle. Each woman was assigned to one of seven premenstrual symptom sets. Three groups had 'pure' symptoms. ie a predominant single symptom (breast tenderness. bloating or irritability). Three groups had 'mixed' symptom-sets. The largest of the 'mixed' groups was formed by the women who reported breast tenderness. bloating and irritability together with tension and depression. Women in this group were most likely to rate their symptomatology as severe. The last group contains a large number of women with miscellaneous symptoms. Characteristics of these groups are outlined. The study highlights the importance of distinguishing among premenstrual syndromes as this can foster more effective clinical management.
Should family doctors screen asymptomatic children for high blood pressure, Whereas the United States Task Forces on Blood Pressure Control in Children have recommended annual blood pressure screening in all children. a working party of the British Hypertension Society has formed the opposite opinion. Relevant literature is reviewed here. and the conclusion reached that on epidemiological and ethical grounds. screening children for hypertension cannot at present be justified.
Liver transplantation: the shadow side, For a relatively large number of patients with liver disease. a liver transplant does not always provide a successful solution. What does confrontation with this modern technology mean for those involved? We interviewed 30 relatives of patients who had died after they had been turned down for a transplant. or during or shortly after a liver transplant operation performed in the Groningen Liver Transplant Programme. Quantitative data were obtained by means of a questionnaire. One-third of the respondents were of the opinion that the patient would have been better off if he/she had not entered the programme. Over half found the loss more difficult to accept because the patient had been involved in the programme. Nevertheless. many had the feeling of satisfaction that everything possible had been done. However fruitful transplantation technology may be for a specific group of patients. it also involves undesirable side-effects which should be included in the careful judgement of this technology.
Geographic variation of inflammatory bowel disease within the United States, One approach to learn about possible environmental risks in inflammatory bowel disease relates to studying its geographic pattern of occurrence. The geographic variation of inflammatory bowel disease within the United States was analyzed using the accumulated 17.5 million hospital discharges of all U.S. Medicare beneficiaries during two consecutive years. To validate the geographic pattern shown by the Medicare data. hospitalization was compared with mortality from inflammatory bowel disease among different states. Mortality and hospitalization statistics both suggested that the occurrence of inflammatory bowel disease was determined by environmental factors that had a marked geographic variation within the United States. Both Crohn's disease and ulcerative colitis appeared to be more frequent in northern parts of the United States than in southern and in urban more than rural parts. These trends were observed for men and women and for blacks and whites alike. Similar geographic patterns of Crohn's disease and ulcerative colitis suggested the influence of one or more identical risk factors for both diseases.
Expression of leukocyte adhesion molecules by mucosal mononuclear phagocytes in inflammatory bowel disease, Leukocyte adhesion molecules are important in cell-cell interactions of the immune system. Lymphocyte function-associated antigen 1 (cluster designation 11a) mediates interactions between T cells and mononuclear phagocytes through its ligand. the intercellular adhesion molecule 1 (CD54). whereas complement receptors 3 (CD 11b) and 4 (CD11c) are involved in complement-mediated phagocytosis. Expression of CD11 molecules and intercellular adhesion molecule 1 was studied in colonic biopsy specimens from 20 patients with inflammatory bowel disease and 10 normal controls. In normal colon. few mononuclear phagocytes expressed lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1 at high densities. The major adhesion molecule was CD11c. Thus. the largest population of normal colonic mononuclear phagocytes was represented by quiescent. resident macrophages with likely phagocytic function. In inflammatory bowel disease. mononuclear phagocytes showed only a slight increase in CD11a expression and no significant change in expression of CD11b and CD11c. By contrast. the percentage of mononuclear phagocytes expressing intercellular adhesion molecule 1 was increased from 6.9% +/- 3.9% in controls to 69.2% +/- 12.8% in ulcerative colitis (P less than 0.001) and to 45.7% +/- 22.8% in Crohn's disease (P less than 0.01). showing a close relationship with histological activity. The increased expression of intercellular adhesion molecule 1 in inflammatory bowel disease indicates a state of immunological activation induced by local release of inflammatory cytokines. Such induction of intercellular adhesion molecule 1 on mononuclear phagocytes may be important in the maintenance of chronic inflammation by facilitating interactions with T cells and T-cell antigen recognition.
Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study, One hundred Chinese patients who received induction cytotoxic therapy for malignant lymphoma were prospectively studied to determine the incidence. morbidity. mortality. and predisposing factors for reactivation of hepatitis B virus replication during cytotoxic therapy. In 18 (67%) hepatitis B surface antigen-positive and 10 (14%) hepatitis B surface antigen-negative patients. hepatitis developed during cytotoxic therapy (P less than 0.0001). Hepatitis could be attributed to exacerbation or reactivation of chronic hepatitis B in 13 (72%) hepatitis B surface antigen-positive patients but in only 2 (20%) hepatitis B surface antigen-negative patients (P less than 0.0001). Sudden increase or reactivation of hepatitis B virus replication gave rise to icteric hepatitis. nonfatal hepatic failure. and death in 22.3%. 3.7%. and 3.7% of patients who were positive for hepatitis B surface antigen; in 2%. 2%. and 0% of those positive for hepatitis B antibodies; and in none of those who were seronegative. Among the hepatitis B surface antigen-positive patients. male sex was the only factor that was associated with an increased risk of reactivation of hepatitis B virus replication. We recommend that hepatitis B surface antigen-positive patients with malignancies receiving cytotoxic therapy be closely monitored.
Effects of short-term pancreatic duct obstruction in rats, The short-term effects of rat pancreatic duct obstruction were evaluated and compared with those recently reported to follow obstruction of the rabbit pancreatic duct. In both species pancreatic edema and hyperamylasemia are noted. and the lysosomal hydrolase cathepsin B is redistributed from the lysosome-enriched to the zymogen granule-enriched subcellular fraction. Theoretically. this redistribution phenomenon might lead to digestive enzyme activation because cathepsin B is known to be capable of activating trypsinogen. The hyperamylasemia and pancreatic edema (but not the cathepsin B redistribution) that follow rat pancreatic duct obstruction were increased by infusion of a submaximally stimulating dose of the cholecystokinin analogue cerulein. Administration of the cholecystokinin-receptor antagonist L-364.718 reduced the hyperamylasemia but did not alter the pancreatic edema or cathepsin B redistribution. These observations indicate that cholecystokinin may modulate some but not all of the effects of duct obstruction. Secretin administration increased the degree of pancreatic edema and had no demonstrable protective effect. The rat duct-obstruction model described in this report may prove particularly useful in future studies designed to clarify the early events underlying the development of acute pancreatitis.
Physicochemical determinants of in vitro shock-wave biliary lithotripsy, Human gallstones were studied by visual inspection. computerized tomographic imaging. and chemical analysis to assess physicochemical characteristics that may determine the outcome of in vitro shock-wave fragmentation. Eighty-five stones (mean diameter: 13.2 +/- 5 mm) were each collected from different patients. Fifty-five (65%) calculi were angular and 30 (35%) round or oval-shaped. Three easily obtained measures were derived from each stone's optimal computerized tomographic image including the mean stone density. a measure corresponding to the standard deviation of the mean stone density value which we termed the stone density distribution index and which may reflect the physicochemical heterogeneity of a given gallstone. as well as the density range. After the administration of 2500 shock waves using an electrohydraulic generator. fragmentation was noted in 68 calculi (80%) and was satisfactory in 27 (32%) (where the largest resulting fragment diameters were all less than or equal to 5 mm). Strong determinants of satisfactory fragmentation on multivariate analysis included a stone diameter of less than or equal to 15 mm. the presence of an angular stone shape. and a stone density distribution index of greater than or equal to 60 Hounsfield units. The other parameters did not independently determine satisfactory fragmentation. Prospective clinical trials are needed to assess whether these findings result in a better prediction of the success of extracorporeal biliary lithotripsy and a broadening of its indications.
Intrahepatic cholesterol stones: a rationale for dissolution therapy, A case of primary cholesterol hepatolithiasis is reported. Stone composition was documented by infrared spectroscopy. and the presence of cholesterol saturated bile was demonstrated using standard biochemical techniques. The patient was treated with operative stone extraction. choledochoscopy. biliary enteric anastomosis. and oral dissolution therapy. The administration of oral dissolution agents has altered the composition of the patient's bile and may prevent further stone formation. We advocate the use of both stone and biliary biochemical analysis for patients with primary hepatolithiasis to facilitate optimal therapy.
Clinical application of ras gene mutation for diagnosis of pancreatic adenocarcinoma, Most pancreatic adenocarcinomas are known to have ras gene (oncogene) mutations. The site of the mutations is localized in codon 12 of K-ras gene. Such high incidence and localization of the ras gene mutations have not been observed in any other human malignancies. Polymerase chain reaction and direct sequencing method enabled us to analyze DNA sequence around codon 12 of K-ras gene in small quantities of specimens obtained from needle biopsies and aspirate samples for pathological diagnosis. All the materials obtained from 12 patients with pancreatic adenocarcinoma showed the mutations. whereas those obtained from 6 patients with chronic pancreatitis showed no mutations. In several cases using the mutations of K-ras gene as a marker. this analysis supplemented conventional pathology and cytology in making the diagnosis of pancreatic adenocarcinoma. The analysis of ras-gene mutations was useful for the clinical diagnosis of pancreatic adenocarcinoma.
Insulin resistance in noncirrhotic idiopathic portal hypertension, To explore further the pathogenesis of glucose intolerance and insulin resistance observed in patients with cirrhosis and portal hypertension. we studied a 35-year-old woman with presinusoidal portal hypertension without cirrhosis due to nodular regenerative hyperplasia of the liver. After oral glucose ingestion. glucose tolerance remained normal; however. this occurred at the expense of a markedly hyperinsulinemic plasma response. suggesting the presence of insulin resistance. To examine this question more directly. we performed a stepwise euglycemic insulin clamp study in combination with an infusion of [6-3H]glucose and [1-14C]palmitate and indirect calorimetry. The ability of insulin to promote total body (primarily muscle) glucose uptake was markedly impaired. whereas its effect to suppress hepatic glucose production was normal compared with results obtained in nine healthy subjects. Moreover. insulin failed to normally suppress plasma free fatty acid turnover and oxidation in this patient. This informative case demonstrates that portal hypertension alone. without hepatic dysfunction from cirrhosis. is associated with impaired insulin-mediated glucose and plasma free fatty acid metabolism and may also play a predominant role in the development of insulin resistance in many cirrhotic patients.
Airway responsiveness to inhaled methacholine in patients with irritable bowel syndrome, We examined whether patients with irritable bowel syndrome have increased airway responsiveness by measuring forced expiratory volumes in 1 second (FEV1) after inhalation of increasing concentrations of methacholine. Responses obtained in 11 IBS patients were compared with those obtained in 11 normal subjects and in 11 subjects with organic disease of the gut or its related organs. All subjects were selected so that other factors that might contribute to increased airway responsiveness were excluded. The methacholine concentration that caused a 20% fall in the FEV1 (PC20). as well as the reduction in FEV1 induced by each methacholine concentration. were used to assess airway responsiveness. The geometric mean PC20 was 197.6 mg/mL (%SEM. 1.15) for normal subjects. 83.9 mg/mL (%SEM. 1.51) for subjects with organic bowel disease (P = 0.012). and only 12.8 mg/mL (%SEM. 1.74) for IBS patients (P less than 0.0001). The 22.5% +/- 2.5% decrease in FEV1 induced by 64 mg/mL of methacholine in IBS patients was significantly greater than that of 12.3% +/- 1.5% observed in healthy subjects (P = 0.003). In contrast. the 15.7% +/- 2.0% decrease in FEV1 observed in patients with organic disease was not different from that seen in normal subjects (P = 0.189). We conclude that IBS is associated with increased airway responsiveness following challenge with methacholine.
Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term, Our study examines the long-term cardiovascular effects after a brief period of angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR). SHR were treated with perindopril (3 mg/kg/day) by gavage from 2 to 6. from 6 to 10. or from 2 to 10 weeks of age. Systolic blood pressure was measured in the tail weekly until 25 weeks of age. Corresponding control groups received distilled water for the same periods. In each treatment group blood pressure was reduced significantly during treatment. rose when treatment stopped. but plateaued significantly below control SHR thereafter. This difference in blood pressure at 25 weeks of age was due to reduced total peripheral resistance as determined by microsphere methods. but plasma renin activity and angiotensin II concentrations were not different. Cardiac hypertrophy was also reduced in treated SHR. In a separate experiment. perindopril treatment from 6 to 10 weeks of age resulted in a significant reduction in the media/lumen ratios of mesenteric resistance vessels at 32 weeks of age. Concomitant administration of angiotensin II with perindopril from 6 to 10 weeks of age not only prevented the long-term effects on blood pressure seen with perindopril treatment alone but was associated with cardiovascular hypertrophy in excess of untreated control SHR. Finally. perindopril given for a shorter period (6 to 7 weeks) or later in life (20 to 24 weeks) had no significant long-term effects on blood pressure. These results demonstrate that a 4-week period of ACE inhibitor treatment in young SHR is sufficient to prevent the full expression of genetic hypertension and cardiovascular hypertrophy and that angiotensin II might be important in the development of hypertension in this model. its role in later life being less important.
"White coat" versus "sustained" borderline hypertension in Tecumseh, Michigan, During a survey of young subjects not receiving treatment for hypertension in Tecumseh. Michigan. clinic and self-monitored blood pressures taken at home (14 readings in 7 days) were obtained in 737 subjects (387 men. 350 women. average age 31.5 years). Hypertension in the clinic was diagnosed if the clinic blood pressure exceeded 140 mm Hg systolic or 90 mm Hg diastolic. In the absence of firm criteria for what constitutes hypertension at home. subjects whose average home blood pressure was in the upper decile of the whole population were considered to have hypertension at home. By these criteria. 7.1% of the whole population had "white coat" hypertension (i.e.. high clinic but not elevated home readings). The prevalence of "sustained" hypertension (i.e.. high readings in the clinic and at home) was 5.1%. Subjects with white coat and sustained borderline hypertension in Tecumseh were very similar. Both groups showed. at previous examinations (at ages 5. 8. 21. and 23 years). significantly higher blood pressure readings than the normotensive subjects. As young adults (average age 33.3 years). the parents of both hypertensive groups had significantly higher blood pressure readings than the parents of normotensive subjects. Both hypertensive groups had faster heart rates. higher systemic vascular resistance. and higher minimal forearm vascular resistance. Both hypertensive groups were more overweight. had higher plasma triglycerides. insulin. and insulin/glucose ratios than normotensive subjects. The white coat hypertensive group also had lower values of high density lipoprotein than the normotensive group. White coat hypertension is a frequent condition.
Thromboxane A2 and development of genetic hypertension in the Lyon rat strain, To determine whether the increased renal biosynthesis of thromboxane A2 observed in young genetically hypertensive rats of the Lyon strain could be involved in the development of their hypertension. Lyon hypertensive female rats received either thromboxane synthetase inhibitors (Dazmegrel or OKY 046) or a thromboxane A2 receptor antagonist (AH 23848) during their prehypertensive stage. Treatment from 5 to 9 weeks of age with Dazmegrel failed to reduce systolic blood pressure. When given from 3 to 9 weeks of age. Dazmegrel and OKY 046 induced a similar progressive and specific reduction (60%) in the urinary excretion of thromboxane B2 that was associated with a transient decrease in blood pressure level with Dazmegrel and a longer lasting blood pressure-lowering effect with OKY 046. AH 23848. given according to the same schedule. normalized the blood pressure level. This effect persisted 1 week after the cessation of the treatment. Interestingly. active doses of thromboxane synthetase inhibitors or of thromboxane A2 receptor blocker required a 3-week delay to exhibit their antihypertensive properties. It is concluded that 1) the elevated production of thromboxane A2 observed in young Lyon hypertensive rats is likely to participate actively in their blood pressure regulation and 2) this effect may be independent of its direct vasoconstrictor properties.
Role of endothelium in the response to endothelin in hypertension, The relation between endothelin and acetylcholine (ACh) was examined and compared in aortas from Wistar-Kyoto (WKY) rats and from stroke-prone spontaneously hypertensive rats (SHRSP). The relaxation produced by ACh in an endothelin-induced contraction was less in aortas from WKY rats than in those from SHRSP. In aortas from WKY rats but not in those from SHRSP. the contraction produced by endothelin was augmented when the intact aortic rings were treated with methylene blue (10(-5) M). This augmentation was also found in preparations of the WKY rat aortic rings in which the endothelium had been removed. The augmentation was not present in SHRSP aortic rings that had been similarly denuded. Treatment with indomethacin (5 x 10(-6) M) had no effect on endothelin-induced contraction in either WKY rat or SHRSP aortic rings. Our findings indicate that endothelin and ACh have in common the ability to release endothelium-derived relaxing factor (EDRF) in WKY rat aortic rings. The reduced endothelium-dependent relaxation in response to ACh in the WKY rat probably reflects the fact that endothelin had already released the EDRF in rings from this strain of rats. The release of EDRF by endothelin is less in SHRSP than it is in WKY rats. Because of this failure of endothelin to release EDRF in SHRSP. endothelin may contribute to the increase in total peripheral resistance in this form of hypertension.
Fish oil amplifies the effect of propranolol in mild essential hypertension, Forty-seven male patients with mild essential hypertension were randomly allocated to three subgroups. After a run-in period of 4 weeks. the first subgroup (n = 16) received propranolol (80 mg/day) for 36 weeks followed by a placebo period of 4 weeks. The second subgroup (n = 15). after a run-in period of 4 weeks. was given a supplement of encapsulated fish oil (9 g/day) for 36 weeks with a subsequent period of 4 weeks in which fish oil placebo was given. The third subgroup (n = 16). after a run-in period of 4 weeks. was given propranolol (80 mg/day) for 12 weeks. propranolol (80 mg/day) plus fish oil capsules (9 g/day equivalent to 1.8 g/day of eicosapentaenoic acid and 1.1 g/day of docosahexaenoic acid) for 12 weeks. propranolol plus fish oil placebo (same doses for 12 weeks) with a subsequent period of 4 weeks when propranolol placebo was administered. The results indicate a blood pressure-lowering effect of fish oil. which was comparable with that of propranolol. The simultaneous intake of fish oil plus propranolol was more effective than propranolol or fish oil alone. Propranolol treatment resulted in a decrease of plasma norepinephrine. plasma renin activity. and thromboxane B2 formation. After fish oil supplementation. plasma norepinephrine and thromboxane B2 formation were likewise reduced. whereas plasma renin activity appeared increased. The decrease of serum triglycerides. total and low density lipoprotein cholesterol as well as the rise of high density lipoprotein cholesterol are concomitant beneficial effects. which justify the consideration of fish oil alone or in combination with antihypertensive drugs for the treatment of mild hypertension.
Insulin resistance and blood pressure in young black men, Insulin resistance. independent of obesity or non-insulin-dependent diabetes mellitus. has been demonstrated to be associated with high blood pressure. To determine if insulin resistance could be an antecedent to hypertension in a high-risk population. we studied normotensive (112 +/- 12/70 +/- 10 mm Hg) and borderline hypertensive (135 +/- 8/85 +/- 5 mm Hg) lean young black men (22-26 years old) with the euglycemic hyperinsulinemic clamp technique. All subjects had clinically normal oral glucose tolerance. Body mass index and percent adipose mass were the same in both groups. Fasting plasma insulin concentration was significantly higher in the borderline hypertensive group (p less than 0.01). Insulin-directed exogenous glucose metabolism at the same degree of steady-state hyperinsulinemia was significantly lower in the borderline hypertensive group (5.98 +/- 2.22 versus 8.22 +/- 1.96 mg/kg/min; p less than 0.01). For the total population. a significant inverse correlation existed between the glucose infusion rate and systolic blood pressure (p less than 0.01). These data indicate that there is a relation between insulin-mediated glucose uptake and blood pressure. Furthermore. in this high-risk population insulin resistance may precede the onset of established essential hypertension.
Similar frequencies of renin gene restriction fragment length polymorphisms in hypertensive and normotensive subjects, A prospective study was conducted to compare the frequency of renin gene polymorphisms in normotensive and hypertensive subjects. Hypertensive (n = 102. blood pressure 168 +/- 17/103 +/- 9 mm Hg) and normotensive (n = 120. blood pressure 122 +/- 10/75 +/- 9 mm Hg) subjects were white. had similar age and sex distributions (hypertensive group. 45 +/- 10 years old and 52% female; normotensive group. 44 +/- 9 years old and 55% female) and similar body mass index (hypertensive group. 23.2 +/- 2.6; normotensive group. 22.5 +/- 2.4 kg/m2. p = 0.048). The familial susceptibility to hypertension was defined as at least one parent and one sibling who were hypertensive before age 65; subjects in the normotensive group had no familial history of hypertension. Renin gene polymorphisms located throughout the renin gene were identified by using three restriction enzymes (Taq I. HinfI. HindIII). For each polymorphic restriction site. allele frequencies were similar in the hypertensive and the normotensive groups. In the absence of parental genotypes. the haplotype frequencies combining the three restriction fragment length polymorphisms were estimated by using maximum likelihood techniques and were similar in both groups (hypertensive group. 0.429. 0.277. and 0.177; normotensive group. 0.453. 0.245. and 0.195 for the three most common haplotypes). A rare haplotype detected by Taq I/Hind III was apparently more frequent in the hypertensive than in the normotensive group (hypertensive group. tH 0.086. th 0.022; normotensive group. tH 0.038. th 0.050). but the difference was not statistically significant. In conclusion. no association between renin gene polymorphisms and essential hypertension was demonstrated in the present study.
The surprising kidney-fluid mechanism for pressure control--its infinite gain, In this short paper. I have tried to explain the elation that we felt when we first realized that the kidney-fluid mechanism for controlling the arterial pressure has an infinite feedback gain property. Because of this. all the other pressure control mechanisms. none of which has ever been shown to have a similar infinite gain property. must themselves alter the kidney-fluid mechanism if they are to succeed in causing long-term changes in the arterial pressure. We have not been able to refute this principle despite many experiments over the last 2 decades. For this reason. our first understanding of the infinite gain property of the kidney-fluid mechanism was like a light at the end of the tunnel. I hope that I can explain to the reader the excitement of those few seconds when we first recognized the principle in 1966.
Late pulmonary allergic responses in actively but not passively IgE-sensitized rats, Previous studies suggested that although rats that were passively sensitized [monoclonal murine immunoglobulin E (IgE)] would respond to pulmonary antigen challenge with an immediate increase in resistance. they exhibited no late increases in resistance. unlike late changes in rats actively sensitized to preferentially produce IgE antibody. We hypothesized that passively sensitized rats also would not develop antigen-induced pulmonary inflammation. In a blinded protocol we compared immediate responses and pulmonary resistance and inflammation at 8. 19 and 24 h after challenge with placebo antigen. with dinitrophenol-bovine serum albumin (DNP-BSA) to elicit a passively sensitized response. or with ovalbumin (OA) to elicit an actively sensitized response. Despite similar immediate responses to OA and DNP-BSA. only the rats challenged with OA had marked inflammatory changes and a significant incidence of late elevations in resistance. Inflammation scores and lung resistance were significantly correlated only in the OA group. We also observed that anesthesia with fentanyl/droperidol significantly attenuated the immediate but not the late responses to antigen challenge. compared with rats anesthetized with ketamine. We conclude that IgE-mediated immediate responses to pulmonary antigen challenge are insufficient. and may be unnecessary. to initiate antigen-induced late inflammatory changes.
Muscle blood flow and muscle metabolism during exercise and heat stress, The effect of heat stress on blood flow and metabolism in an exercising leg was studied in seven subjects walking uphill (12-17%) at 5 km/h on a treadmill for 90 min or until exhaustion. The first 30 min of exercise were performed in a cool environment (18-21 degrees C); then subjects moved to an adjacent room at 40 degrees C and continued to exercise at the same speed and inclination for a further 60 min or to exhaustion. whichever occurred first. The rate of O2 consumption. 2.6 l/min (1.8-3.3) (average from cool and hot conditions). corresponded to 55-77% of their individual maximums. In the cool environment a steady state was reached at 30 min. When the subjects were shifted to the hot room. the core temperature and heart rate started to rise and reached values greater than 39 degrees C and near-maximal values. respectively. at the termination of the exercise. The leg blood flow (thermodilution method). femoral arteriovenous O2 difference. and consequently leg O2 consumption were unchanged in the hot compared with the cool condition. There was no increase in release of lactate and no reduction in glucose and free net fatty acid uptake in the exercising leg in the heat. Furthermore. the rate of glycogen utilization in the gastrocnemius muscle was not elevated in the hot environment. There was a tendency for cardiac output to increase in the heat (mean 15.2 to 18.4 l/min). which may have contributed to the increase in skin circulation. together with a possible further reduction in flow to other vascular beds. because muscle blood flow was not reduced.
Glucocorticoid-induced muscle atrophy prevention by exercise in fast-twitch fibers, Exercise has been shown to be effective in preventing glucocorticoid-induced atrophy in muscles containing high proportions of type II or fast-twitch fibers. This investigation was undertaken to further evaluate this response in type IIa and IIb fibers. determined by histochemical staining for myofibrillar adenosinetriphosphatase with alkaline and acid preincubation. Steroid [cortisol acetate (CA). 100 mg/kg body wt] and exercise (running 90 min/day. 29 m/min) treatments were initiated simultaneously for 11 consecutive days in female rats. Fiber distribution and area measurements were performed in a deep and superficial region of plantaris muscle. The exercise regimen spared approximately 40% of the CA-induced plantaris muscle atrophy. In the deep region. the fiber population. which contained approximately 13% type I (slow-twitch). 24% type IIa. and 63% IIb fibers. was not affected by either treatment. In the superficial section. which consisted solely of type II fibers. the proportion of type IIa fibers was higher (27 vs. 9%. P less than 0.01) in the steroid- than in the vehicle-treated groups. Within each region. type IIa fibers were less susceptible to atrophy than type IIb fibers. and within each fiber type. the deep region had less atrophy than the superficial region. Type I fibers were unchanged by steroid treatment. For type IIa fibers. exercise prevented 100% of the atrophy in the deep region and 50% in the superficial region. For type IIb fibers. the activity spared 67 and 40% of the atrophy in these same regions. respectively. These results show that glucocorticoids are capable of changing the myosin phenotype.
Vascular flow capacity of hindlimb skeletal muscles in spontaneously hypertensive rats, Total and regional skeletal muscle flows (radiolabeled microspheres) were determined in isolated maximally vasodilated hindquarters of spontaneously hypertensive rats (SHR) and age-matched (11-12 mo) normotensive Wistar-Kyoto rats (WKY) to assess the vascular flow capacity of the skeletal muscle vascular beds. Vascular flow capacity was estimated by measuring total hindquarters and regional muscle blood flows (under conditions of maximal vasodilation with papaverine or papaverine plus isoproterenol) over a wide range of perfusion pressures in WKY and SHR. Capillary exchange capacity was estimated by determining the capillary filtration coefficient. Isogravimetric capillary pressures and segmental vascular resistances were determined in each hindquarter. Isogravimetric flows and capillary pressures were not different between WKY and SHR. However. total and precapillary vascular resistances were significantly elevated in SHR. and postcapillary resistances were not different compared with WKY. Maximal capillary filtration coefficient values for the SHR group averaged 20% lower than WKY values. suggesting that hypertension was associated with a reduction in the microvascular surface area available for fluid exchange and. therefore. the capillary exchange capacity. Over the perfusion pressures studied. total hindquarters flows averaged 60% lower in SHR than in WKY. Flows to individual skeletal muscles averaged 76% lower in SHR than in WKY regardless of the muscle fiber type. Thus. modifications exist in the hindlimb skeletal muscle vasculature of SHR that reduces the capillary exchange capacity and limit the capacity of deliver flow at a given perfusion pressure gradient.
Stress adaptation and low-frequency impedance of rat lungs, At transpulmonary pressures (Ptp) of 7-12 cmH2O. pressure-volume hysteresis of isolated cat lungs has been found to be 20-50% larger than predicted from their amount of stress adaptation (J. Hildebrandt. J. Appl. Physiol. 28: 365-372. 1970). This behavior is inconsistent with linear viscoelasticity and has been interpreted in terms of plastoelasticity. We have reinvestigated this phenomenon in isolated lungs from 12 Wistar rats by measuring 1) the changes in Ptp after 0.5-ml step volume changes (initial Ptp of 5 cmH2O) and 2) their response to sinusoidal pressure forcing from 0.01 to 0.67 Hz (2 cmH2O peak to peak. mean Ptp of 6 cmH2O). Stress adaptation curves were found to fit approximately Hildebrandt's logarithmic model [delta Ptp/delta V = A - B.log(t)] from 0.2 to 100 s. where delta V is the step volume change. A and B are coefficients. and t is time. A and B averaged 1.06 +/- 0.11 and 0.173 +/- 0.019 cmH2O/ml. respectively. with minor differences between stress relaxation and stress recovery curves. The response to sinusoidal forcing was characterized by the effective resistance (Re) and elastance (EL). Re decreased from 2.48 +/- 0.41 cmH2O.ml-1.s at 0.01 Hz to 0.18 +/- 0.03 cmH2O.ml-1.s at 0.5 Hz. and EL increased from 0.99 +/- 0.10 to 1.26 +/- 0.20 cmH2O/ml on the same frequency range. These data were analyzed with the frequency-domain version of the same model. complemented by a Newtonian resistance (R) to account for airway resistance: Re = R + B/ (9.2f) and EL = A + 0.25B + B . log 2 pi f. where f is the frequency.
Control of total peripheral resistance during hyperthermia in rats, To elucidate the effect of blood volume on the circulatory adjustment to heat stress. we studied alpha-chloralose-anesthetized rats at three levels of blood volume: normovolemia (NBV). hypervolemia (HBV; +32% plasma volume by isotonic albumin solution infusion). and hypovolemia (LBV; -16% plasma volume by furosemide administration). Body surface heating was performed with an infrared lamp to raise arterial blood temperature (Tb) at the rate of approximately 0.1 degree C/min. Before heating. central venous pressure (CVP) was significantly higher in HBV (0.41 +/- 0.25 mmHg) and lower in LBV (-1.44 +/- 0.22 mmHg) than in NBV (-0.41 +/- 0.10 mmHg). The Tb at which CVP started to decrease was approximately 40 degrees C in HBV. approximately 41 degrees C in NBV. and approximately 42 degrees C in LBV. and it decreased by 1.53 +/- 0.14. 1.92 +/- 0.24. and 0.62 +/- 0.14 mmHg from 37 to 43 degrees C of Tb in HBV. NBV. and LBV. respectively. Stroke volume was closely correlated with CVP. and this relationship was not affected by Tb. Heart rate responses to the raised Tb were similar among the three groups. Mean arterial pressure (MAP) was not affected by blood volume modification or CVP and was maintained at preheating (Tb 37 degrees C) level until Tb rose to 40 degrees C. Above this Tb. MAP increased until Tb reached 43 degrees C (+30-40 mmHg) for all three groups. Total peripheral resistance (TPR) was inversely correlated with CVP. and the slope of the linear relationship between TPR and CVP in LBV was three- to fourfold steeper than in NBV or HBV.
Altered function of pulmonary surfactant in fatty acid lung injury, To determine whether acute fatty acid lung injury impairs pulmonary surfactant function. we studied anesthetized ventilated rabbits given oleic acid (55 mg/kg iv. n = 11) or an equivalent volume of saline (n = 8). Measurements of pulmonary mechanics indicated a decrease in dynamic compliance within 5 min of injury and a decrease in lung volume that was disproportionately large at low pressures. consistent with diminished surfactant activity in vivo. Bronchoalveolar lavage fluid obtained 1 h after injury had significantly increased erythrocytes and total leukocytes. largely polymorphonuclear cells. The phospholipid content and composition of the cell-free fraction had only minor changes from those of controls. but the protein content was increased 35-fold. Measurements of lavage surface activity in vitro showed an increase in average minimum surface tension from 1.3 +/- 0.4 (SE) dyn/cm in controls to 20.2 +/- 3.9 dyn/cm in injured animals. The alterations in static pressure-volume curves and decrease in lavage surface activity suggest a severe alteration of surfactant function in this form of lung injury that occurs despite the presence of normal amounts of surfactant phospholipids.
Modeling human performance in running, This paper focuses on the characteristics of a model interpreting the effect of training on athletic performance. The model theory is presented both mathematically and graphically. In the model. a systematically quantified impulse of training produces dual responses: fitness and fatigue. In the absence of training. both decay exponentially with time. With repetitive training. these responses satisfy individual recurrence equations. Fitness and fatigue are combined in a simple linear difference equation to predict performance levels appropriate to the intensity of training being undertaken. Significant observed correlation of model-predicted performance with a measure of actual performance during both training and tapering provides validation of the model for athletes and nonathletes alike. This enables specific model parameters to be estimated and can be used to optimize future training regimens for any individual.
Pulmonary blood volume and edema in postpneumonectomy lung growth in rats, After pneumonectomy in young animals. the contralateral lung undergoes compensatory growth and generally attains the same weight and air space volume as both lungs in age-matched controls. In this study. we determined the contribution of lung edema and increased blood volume to the weight gain in rats. Three weeks after pneumonectomy (n = 18) or sham pneumonectomy (n = 17). the pulmonary blood volume and the extravascular water and albumin were evaluated by use of 51Cr-labeled erythrocytes and 125I-labeled albumin. The air space volume. blood-free lung weights. and DNA and protein content were also compared. The data show that the total pulmonary blood volumes and the blood volume per gram of blood-free dry lung were similar in pneumonectomized and age-matched sham controls. The total extravascular albumin and the extravascular albumin per gram of blood-free dry lung were also similar as well as the extravascular lung water. wet-to-dry weight ratios. DNA and protein content. and air space volumes. These data indicate that the increased weight of the postpneumonectomy lung was due to cellular and stromal proliferation. The blood volume and interstitial fluid increased in proportion to the increase in lung parenchyma. Neither vascular congestion nor increased extravascular protein and water contributed to the observed weight gain.
Muscle maximal O2 uptake at constant O2 delivery with and without CO in the blood, In the present study we investigated the effects of carboxyhemoglobinemia (HbCO) on muscle maximal O2 uptake (VO2max) during hypoxia. O2 uptake (VO2) was measured in isolated in situ canine gastrocnemius (n = 12) working maximally (isometric twitch contractions at 5 Hz for 3 min). The muscles were pump perfused at identical blood flow. arterial PO2 (PaO2) and total hemoglobin concentration [( Hb]) with blood containing either 1% (control) or 30% HbCO. In both conditions PaO2 was set at 30 Torr. which produced the same arterial O2 contents. and muscle blood flow was set at 120 ml.100 g-1.min-1. so that O2 delivery in both conditions was the same. To minimize CO diffusion into the tissues. perfusion with HbCO-containing blood was limited to the time of the contraction period. VO2max was 8.8 +/- 0.6 (SE) ml.min-1.100 g-1 (n = 12) with hypoxemia alone and was reduced by 26% to 6.5 +/- 0.4 ml.min-1.100 g-1 when HbCO was present (n = 12; P less than 0.01). In both cases. mean muscle effluent venous PO2 (PVO2) was the same (16 +/- 1 Torr). Because PaO2 and PVO2 were the same for both conditions. the mean capillary PO2 (estimate of mean O2 driving pressure) was probably not much different for the two conditions. even though the O2 dissociation curve was shifted to the left by HbCO. Consequently the blood-to-mitochondria O2 diffusive conductance was likely reduced by HbCO.
Mechanical deficit persists during long-term muscle hypertrophy, Hypotheses were tested that the deficit in maximum isometric force normalized to muscle cross-sectional area (i.e.. specific Po. N/cm2) of hypertrophied muscle would return to control value with time and that the rate and magnitude of adaptation of specific force would not differ between soleus and plantaris muscles. Ablation operations of the gastrocnemius and plantaris muscles or the gastrocnemius and soleus muscles were done to induce hypertrophy of synergistic muscle left intact in female Wistar rats (n = 47) at 5 wk of age. The hypertrophied soleus and plantaris muscles and control muscles from other age-matched rats (n = 22) were studied from days 30 to 240 thereafter. Po was measured in vitro at 25 degrees C in oxygenated Krebs-Ringer bicarbonate. Compared with control values. soleus muscle cross-sectional area increased 41-15% from days 30 to 240 after ablation. whereas Po increased 11 and 15% only at days 60 and 90. Compared with control values. plantaris muscle cross-sectional area increased 52% at day 30. 40% from days 60 through 120. and 15% at day 240. Plantaris muscle Po increased 25% from days 30 to 120 but at day 240 was not different from control value. Changes in muscle architecture were negligible after ablation in both muscles. Specific Po was depressed from 11 to 28% for both muscles at all times. At no time after the ablation of synergistic muscle did the increased muscle cross-sectional area contribute fully to isometric force production.
Tachyphylaxis to inhaled methacholine in normal but not asthmatic subjects, Methacholine inhalation tests measure airway responsiveness in asthmatic and normal subjects. Tachyphylaxis occurs with repeated methacholine inhalations in normal subjects. The purpose of this study was to examine the time course and mechanisms of methacholine tachyphylaxis in normal subjects and to determine whether this occurs in mildly asthmatic subjects. Fifteen normal and nine asthmatic subjects were studied on 2 study days. at least 48 h apart. Each day. two inhalation tests were carried out. On one day. subjects performed two methacholine inhalation tests 3 h later by a methacholine test. Results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1). (PC20). All normal subjects developed methacholine tachyphylaxis. The mean PC20 increased from 47.3 mg/ml (%SE 1.34) to 115.6 (%SE 1.51) (P less than 0.0001) in a 3-h interval. This increase lasted for greater than or equal to 6 h (P = 0.012). Asthmatic subjects did not develop methacholine tachyphylaxis. Their mean methacholine PC20s were 1.6 mg/ml (%SE 1.4) and 1.5 (%SE 1.4) (P = 0.75) 3 h later. In two other series of experiments. normal subjects were pretreated with the cyclooxygenase inhibitors indomethacin (100 mg/day) or flurbiprofen (150 mg/day) or a placebo for 3 days before two methacholine tests 3 h apart. Both indomethacin and flurbiprofen significantly inhibited the development of methacholine tachyphylaxis. These results confirm that methacholine tachyphylaxis occurs in normal subjects. lasts greater than or equal to 6 h. and may occur through the release of inhibitory prostaglandins. By contrast. methacholine tachyphylaxis does not occur in asthmatic subjects.
Effect of thromboxane antagonists on ozone-induced airway responses in dogs, Airway hyperresponsiveness after inhaled ozone in dogs may occur as a result of thromboxane release in the airway. In this study. two thromboxane receptor antagonists. L-655.240 and L-670.596. were used in doses that inhibit the response to an inhaled thromboxane mimetic. U-46619. to determine further the role of thromboxane in ozone-induced airway hyperresponsiveness. Dogs were studied on 2 days separated by 1 wk. On each day. the dogs inhaled ozone (3 ppm) for 30 min. On one randomly assigned day. 10 dogs received an infusion of L-655.240 (5 mg.kg-1.h-1) and 5 dogs received an infusion of L-670.596 (1 mg.kg-1.h-1); on the other day dogs received a control infusion. Airway responses to doubling doses of acetylcholine were measured before and after inhalation of ozone and were expressed as the concentration of acetylcholine giving a rise in resistance of 5 cmH2O.l-1.s from baseline (acetylcholine provocation concentration). The development of airway hyperresponsiveness after ozone was not inhibited by the thromboxane antagonists. The mean log difference in the acetylcholine provocative concentration before and after ozone on the L-655.240 treatment day was 0.62 +/- 0.12 (SE) and on the control day was 0.71 +/- 0.12 (P = 0.48); on the L-670.596 treatment day the mean log difference was 0.68 +/- 0.15 (SE) and on the control day it was 0.75 +/- 0.19 (P = 0.45). These results do not support an important role for thromboxane in causing ozone-induced airway hyperresponsiveness.
Intra-osseous pressure and oxygen tension in avascular necrosis and osteoarthritis of the hip, The intra-osseous pressure. PO2. and PCO2 were measured in 32 hips (21 patients) which were painful but showed no severe degenerative changes. Pre-operative scintigraphy and radiography was performed in all patients. Thirteen hips showed early osteoarthritis. eight had early osteonecrosis. and 11 had no changes. Core biopsies were performed and the bone was examined histologically and graded for necrosis. Histologically. necrosis was present in 27 specimens. Scintigraphic findings did not correlate with the histological results but were more closely related to the radiographic findings. The intra-osseous pressure in hips with histological necrosis (mean 47 mmHg) was significantly higher than in hips without necrosis (mean 26 mmHg). The PO2 was lower in bone with histological necrosis (mean 44 mmHg) than in bone without (mean 71 mmHg). PO2 increased and intra-osseous pressure decreased after decompression. The results confirm that ischaemia plays a central role in the development of necrotic changes in bone. Histological necrosis was found in hips with radiographic signs of osteonecrosis and in those with osteoarthritis. Radiography. and scintigraphy are shown to be insensitive methods for differentiating between those disorders.
Biomechanical strength of non-vascularised and vascularised diaphyseal bone transplants. An experimental study, We studied the healing and torsional strength of non-vascularised (28) and vascularised (28) sections of tibial diaphyses in 56 cats. Both types of graft achieved fracture union in the same period of time. and at 12 and 16 weeks the non-vascularised grafts were as strong as the vascularised grafts.
Results of a 25-year screening programme for neonatal hip instability, From 1962 to 1986. 117.256 neonates were screened for congenital dislocation of the hip (CDH). When the primary physical examination was performed by the junior paediatric staff there was a persistent late diagnosis rate of 0.5 per 1000 live births. When the primary examination was undertaken by experienced orthopaedic personnel (1982 to 1984) the late diagnosis rate fell and fewer infants were splinted.
Modified Van Nes rotationplasty for osteosarcoma of the proximal tibia in children, Above-knee amputation has been the traditional treatment for osteosarcoma of the proximal tibia. Recent advances in chemotherapy have encouraged the development of limb-salvage techniques. Van Nes rotationplasty for malignant lesions of the distal femur has increased in popularity as a reconstructive technique. but no similar procedure has been described for lesions of the proximal tibia. We have developed a modified rotationplasty for this lesion and have performed it in four children. The surgical technique. postoperative management and results of the procedure are described. Two patients had delayed wound healing. No other complications have developed and our patients were disease-free at follow-up. while the appearance of the leg was well accepted by the patients and their parents. This procedure is a useful addition to the armamentarium of the tumour surgeon for the treatment of malignant lesions of the proximal tibia.
Extending intramedullary rods in congenital pseudarthrosis of the tibia, Five patients with Boyd type II congenital pseudarthrosis of the tibia underwent excision of the pseudarthrosis and double onlay bone grafting. Stability was maintained by extending intramedullary rods. Clinical union was achieved in all cases at a mean of 8.6 months (range six to 11). The rods extended by 15.7% (range 2% to 31.4%) as growth occurred. One rod was removed because of infection and a vascularised free fibular graft was subsequently performed. The extending rods provided stability while union occurred and did not require revision as the legs grew. The rods can be removed easily and have not jeopardized further surgical options.
Parosteal osteosarcoma. Treatment by wide resection and prosthetic replacement, We have reviewed 20 cases of parosteal osteosarcoma treated by wide local resection and prosthetic replacement and followed up for six to 17 years. Limb function was excellent in 85%. One patient with grade III histological disease developed pulmonary metastases. Four patients had local recurrences. which were related to repeated preliminary biopsies. inappropriate siting of biopsy and vascular encroachment by the tumour. After this mode of treatment. the outcome was not related to medullary invasion by the tumour.
Aggressive granulomatous lesions in cementless total hip arthroplasty, We describe six patients with aggressive granulomatous lesions around cementless total hip prostheses. Two patients previously had a cemented prosthesis in the same hip. The Lord prosthesis was used in five patients. the PCA in one. Both prostheses were made of chrome-cobalt alloy. Pain on weight-bearing occurred on average 3.2 years after the cementless arthroplasty. and at that time radiography revealed aggressive granulomatosis around the proximal femoral stem and the acetabular component in five of the patients; one had a large solitary granuloma in the proximal femur. Revision was performed on average 4.8 years after the cementless arthroplasty. At that time all granulomas had grown large in size; while waiting for revision operation. two femoral stem components fractured. All the granulomas showed a uniform histopathology. which included histiocytosis; the cause for these lesions was thought to be plastic debris from the acetabular socket.
Reduction of contamination at total hip replacement by special working clothes, We assessed wound. air and operative field contamination at 50 total hip operations. performed in a zonal ventilation system. Theatre staff wore either a specially designed polypropylene non-woven coverall or conventional cotton shirt and trousers. The surgeons wore partially impermeable operating gowns. The polypropylene coverall was associated with significantly lower air and wound counts. The coverall was warmer than cotton but judged to be acceptable. The combined use of zonal ventilation and the coverall achieved ultra-clean air conditions.
Cup containment and orientation in cemented total hip arthroplasties, We reviewed the radiographs of 864 Charnley and STH (Zimmer) cemented total hip arthroplasties with a mean follow-up of seven years (maximum 16 years). Survivorship analysis was used to assess the correlation between radiographic performance and the bony containment or the coronal orientation of the acetabular cup. The cup orientation and containment were interrelated; all vertically oriented cups were completely contained. whereas 25% of more horizontal cups were only partially contained. Completely contained cups had significantly lower incidences of complete cement-bone radiolucency (p = 0.02) and of wear (p = 0.09). Vertically oriented cups had a lower incidence of continuous radiolucency than neutrally oriented cups. but this was not statistically significant (p = 0.25). Our results confirm the importance of complete bony containment. and also indicate that it is better to accept vertical orientation and obtain full bony coverage than to have a more horizontal orientation with partial containment.
Morphine pharmacokinetics during anesthesia and surgery in patients with burns, The plasma clearance. plasma half-life. and apparent volume of distribution of morphine during anesthesia and surgery were determined in seven patients with burns and compared with seven age-matched control subjects. The burn group had a significantly lower clearance. longer terminal half-life. and smaller volume of distribution than the control group. The clearance was 12 +/- 2 ml/min/kg. the half-life was 123 +/- 24 minutes. and the volume of distribution was 2.2 +/- 0.4 L/kg for the subjects with burns compared with 25 +/- 3 ml/min/kg. 89 +/- 18 minutes. and 3.2 +/- 0.8 L/kg for the control subjects (p less than 0.001. less than 0.02. and less than 0.02. respectively). These data contrast with the theory that patients with burns have a tolerance to narcotics and suggest the need for further study of the pharmacologic effects of burn injury and surgery.
Comparison of resting energy expenditures and caloric intake in children with severe burns, Nutritional support is provided to children after severe burn injuries in amounts derived from empirical formulas or measurements of resting energy expenditure. To scrutinize these methods. indirect calorimetry measurements were performed on 74 survivors of burns (greater than or equal to 40% total body surface area) and compared to their actual caloric intake. percent weight change. and optimal caloric requirements formulated from the Curreri and Shriners' equations. These parameters showed that in spite of an initial deficit in actual caloric intake as compared to formulated goals. weight was maintained. whereas resting energy expenditures ranged from 30% to 40% below the actual caloric intake. Furthermore. a subgroup of patients (n = 42) who met +/- 20% of their formulated needs were stratified by extent of burn; this illustrated a significant weight gain in the more severely burned children. In conclusion. nutritional formulas in popular use overestimate caloric requirements in severe burns. whereas resting energy expenditure measurements require an additional factor of 30% to maintain body weight.
Cyclosporine A for prolonging allograft survival in patients with massive burns, Cyclosporine A (CsA) immunosuppression was used in three patients with massive burns to prolong skin allograft survival. Cyclosporine A kinetic studies in patients with burns revealed markedly accelerated blood clearance and high variability in drug absorption when compared with studies in renal transplantation patients. Doses required to maintain therapeutic levels varied widely. While patients were receiving adequate maintenance therapy with CsA immunosuppression the allograft was tightly adherent without gross or microscopic rejection and was indistinguishable from autograft. Ultimately. patients' wounds were permanently covered with sequential autografts by recropping limited donor sites. There were not unusual septic complications. although prophylaxis for opportunistic infections was used. The disadvantage of allograft use is its early rejection and obligatory replacement until permanent coverage with autograft can be accomplished. Cyclosporine A can prolong allograft survival and allow autograft coverage from limited donor sites in a sequential fashion. This may lead to increased survival in patients with massive burns.
A survey of wound monitoring and topical antimicrobial therapy practices in the treatment of burn injury, A survey was done to determine how burn wound microbial monitoring is performed and how topical antimicrobial agents are employed. The survey was sent to 90 burn-care facilities. which comprised most of the major burn centers in the United States. The survey contained questions concerning frequency and techniques of wound monitoring. personnel involved in monitoring. as well as questions about how decisions were made to initiate topical antimicrobial therapy. which agents were selected. and how they were administered. Sixty of 90 facilities (66%) responded to the survey. Although there were few areas of unanimous agreement. several trends did emerge. Most facilities monitored burn wounds for microbes (92%). Wound monitoring was typically done at least twice weekly by either surface swab or quantitative biopsy. Nursing staff played a significant role in specimen collection in 69% of facilities and were solely responsible for obtaining biopsy specimens in 29% of facilities that used biopsies exclusively. All responding facilities used topical antimicrobial agents; silver sulfadiazine was the most popular (95%). Only 33% of facilities surveyed had their own laboratory for microbial monitoring. Rapid techniques for early diagnosis of wound sepsis were used in 20% of units. and topical antimicrobial testing was used in 17% of facilities surveyed.
The use of intestinal antibiotics to delay or prevent infections in patients with burns, Bacterial colonization and infection of wounds in seriously burned patients often comes from the patient's indigenous bowel flora. A prospective randomized clinical trial that involved 30 patients with 20% or greater total body surface area burns was undertaken to evaluate the use of a standard antibiotic bowel preparation in the delay or prevention of bacterial colonization of the burn wound and sepsis. Certain enteric bacteria were seen less frequently in the treated group (Enterobacter organisms). but other bacteria appeared more often in the treated group (Proteus organisms and enterococci). The average time of colonization of the burn wounds was 6.1 days in the treated group and 6.7 days in the control group. Blood cultures were positive for enteric organisms earlier in the treatment group. Pseudomonads appeared earlier in the wound and blood cultures of the treated group than in the control group. The effect of antibiotic bowel suppression in patients with burns is varied and unpredictable. The bowel preparation may select certain organisms and lead to earlier colonization of the wounds. Overall outcome and survival was not improved by the use of an antibiotic bowel preparation in these patients.
Gasoline burns: the preventable cause of thermal injury, Gasoline related burns are a significant cause of thermal injuries each year in the United States. In this retrospective review of 1858 admissions to our Regional Burn Center from 1979 to 1988. 270 (14.5%) were persons with gasoline-related injuries. Natural gas and other distillates were excluded. Most victims were male (228 of 270); mean age was 27 years; mean burn size was 25% total body surface area. There were 299 skin grafts performed on 172 patients. and there were 16 deaths. The mean length of stay decreased from 38 to 17 days (p less than 0.001) between the first and second 5-year time periods. even though there was no significant change in age or mean burn size. The majority (59%) of gasoline-related burns were the result of inappropriate or unsupervised use of gasoline. The general public is largely unaware of the dangers of gasoline. and further education in this area is needed.
Carburetor burns: preventable injuries associated with high morbidity and frequent litigation, We have identified carburetor burns as a significant cause of preventable morbidity. both from long-term functional and cosmetic standpoints. The epidemiology of carburetor burns and our experience are described. All of our patients were male. with a mean age of 35 years. Average burn size was 11.3%. The anatomic distribution of these burns. most often on the dominant hand and on the face. contributes to the morbidity of these burns. This injury has been associated with increasingly frequent litigation. We believe that an active education campaign and the addition of warning labels to car engine compartments would make an impact in decreasing the incidence of carburetor burns.
Discharge videotaping: a means of augmenting occupational and physical therapy, Regional burn centers commonly receive patients from medical facilities that are geographically distant. Logistic problems that may hamper follow-up care in the burn center can lead to a decrease in function as a result of contractures and hypertrophic scar formation. Inexperience on the part of therapists at community facilities serves to intensify this problem. Discharge videotaping. with respect to physical and occupational therapy programs. is a means of documenting range of motion at the time of discharge and providing visual documentation of the therapy program to be followed on an outpatient basis. The video tapes are forwarded to the outlying community hospital's therapy department in order to accomplish these goals.
Familial values as factors influencing long-term psychological adjustment of children after severe burn injury, This study replicates earlier findings that children who survive severe burn injury do make positive psychological adjustment. Family support and a family value of autonomy were predicted to be critical variables in promotion of psychological adjustment. In addition. the study presents the hypothesis that length of time after burn injury and level of intelligence are contributing factors in psychological adjustment. Forty-four adolescents with a mean of 60% total body surface area (TBSA) full-thickness burns were studied. Half of the subjects scored within the normal range on a measure of psychological adjustment. Familial value patterns were critical in the prediction of psychological adjustment. Positive psychological adjustment was predicted by greater family cohesion. independence. and more open expressiveness within the family. Level of intelligence did not contribute to adjustment. Length of time after injury. if it is important to psychological healing. appears to be a factor only during the initial 2 years after burn injury.
Embryologic fusion planes and the spread of cutaneous carcinoma: a review and reassessment, It has long been held that embryologic fusion planes influence the spread of skin cancer. Embryologic fusion planes have been implicated in the depth of invasion. horizontal spread. and recurrence of cutaneous carcinoma. However. these structures have never been studied in detail. A review of the surgical literature reveals considerable confusion regarding the exact nature. location. and tumor interactions of these fusion planes. We review the gross and microscopic development of sites of embryologic fusion. We examine histologic sections through fusion sites in normally developed adult and fetal fresh cadaver specimens. Our studies. supported by our review of developmental anatomy. indicate that fusion planes do not persist as identifiable anatomic structures that would influence tumor spread.
Use of Mohs micrographic surgery to establish quantitative proof of heightened tumor spread in basal cell carcinoma recurrent following radiotherapy, We compared 27 basal-cell carcinomas (BCCs) recurrent following radiotherapy and subsequently excised by Mohs micrographic surgery to a control group of BCCs recurrent following other treatment modalities and similarly excised. Mohs technique permitted precise. quantitative tumor assessment. obtained via a novel method utilizing three parameters: the number of surgical stages required for complete excision. the percentage increase between clinical preoperative tumor area and final postoperative defect area. and the presence of deep subcutaneous tissue invasion. Figures for the postradiation group were larger in all three categories. with the latter two revealing statistically significant differences versus the nonradiation group. This study gives strong. direct quantitative support to the clinical impression that BCC recurrent following radiotherapy is a uniquely aggressive. invasive subset of recurrent BCC.
Hydroquinone-induced localized exogenous ochronosis treated with dermabrasion and CO2 laser, Exogenous localized ochronosis can result from the repeated use of hydroquinone-containing creams. many of which are available over the counter. We report a case that was managed by dermabrasion and CO2 laser. The incidence and proposed etiologies of hydroquinone-induced exogenous ochronosis are reviewed.
Disturbance in daily sleep/wake patterns in patients with cognitive impairment and decreased daily activity, The sleep/wake patterns of 121 chronically ill. mentally and physically handicapped patients were visually monitored hourly for 14 consecutive days. Four types of sleep/wake patterns were found. In order to investigate how cognitive and physical functions correlated with sleep disorders. patients were classified based on a scale of mental function and the grading of daily activity. The percent of total sleep hours and the sleep rating. showing disturbances in sleep/wake pattern. were evaluated. We found a high degree of individuality in sleep/wake patterns. Sleep disturbance was associated with daily activity as well as with cognitive impairment. This monitoring system provides medical personnel with valuable information for clinical management.
Are stressful life events risk factors for herpes zoster, To determine if psychologically stressful life events are risk factors for herpes zoster. we conducted a case-control study of zoster and self-reported recent negative life events and major changes in spousal relationships. The subjects were 101 healthy community-dwelling cases of zoster and 101 healthy controls matched for age. sex. and race and generated by random digit dialing. The Geriatric Scale of Recent Life Events was administered to case and control subjects. and additional questions were asked regarding the perception of the life event. The results showed that case subjects experienced negative life events significantly more often than subjects in the control groups in the 2 months before zoster onset by analysis of discordant pairs (26 versus 10. odds ratio 2.60. 95% confidence interval [CI] 1.13. 6.27. P = .012). 3 months before (29 versus 11. odds ratio 2.64. 95% CI 1.20. 6.04. P = .007). or 6 months before (35 versus 16. odds ratio 2.00. 95% CI 1.04. 3.93. P = .012). The mean number of total life events was significantly higher in cases at 6 months before zoster (case means = 2.64. control means = 1.82. P = .008). but there were no significant differences at 2. 3. or 12 months before. There were no significant differences between case subjects and control subjects for spousal events. or any given single life event. In conclusion. we found that whereas patients with herpes zoster experienced the same kinds of life events in the year preceding the illness as did control subjects. recent events perceived as stressful were significantly more common among patients with zoster.
Lack of association between medication use and the presence or absence of bacteriuria in elderly women, This study was undertaken to determine if there is an association between medication use and the presence or absence of bacteriuria in elderly ambulatory women. Of 198 women who participated in three urine culture surveys (every 6 months) during the 18-month study period. 66 (34.4%) had bacteriuria on at least one survey. Both univariate and multivariate analyses for the demographics. age. place of residence. and medication use (by drug class) revealed that only place of residence had a significant association with the presence or absence of bacteriuria. In this regard. bacteriuric subjects more commonly resided in the nursing home and less commonly lived in the apartment-house complex compared with nonbacteriuric subjects (P less than .05). Therefore. this study demonstrates that in elderly ambulatory women. medication use does not appear to be associated with the presence or absence of bacteriuria.
Absence of significant bacteremia during urinary catheter manipulation in patients with chronic indwelling catheters, The objective of this study was to quantify the microorganisms present in blood at urinary catheter removal and at reinsertion in patients with chronic indwelling urinary catheters. This was a prospective study during a 4-month period at a university-affiliated geriatric medical center. Our subjects were 33 patients with chronic indwelling urinary catheters and positive urinary cultures; the urinary catheter was usually changed once a month. A peripheral vein line was used for blood withdrawal and urinary cultures and quantitative blood cultures (Isolator) were performed during and shortly after urinary catheter removal and insertion. All patients had significant bacteriuria (greater than 10(5) cfu/mL) with an average of 2.3 microorganisms. Among the 46 sequential quantitative blood cultures performed. only two patients had bacteremia from the urinary source and at a very low concentration; one patient had 0.13 cfu/mL Str. faecalis in blood 5 minutes after removal of the urinary catheter. and the other 0.1 cfu/mL Proteus mirabilis 5 minutes after reinsertion of a new urinary catheter. None of the patients had any subjective or objective clinical problem during the 36 hours after the urinary manipulation. Clinical symptoms and bacteremia are rare events. and prophylactic antibiotics do not appear necessary during urinary catheter removal and reinsertion in elderly institutionalized patients. Further studies are necessary to identify risk factors in the rare instances of patients with bacteremia.
What practicing physicians in North Carolina rate as their most challenging geriatric medicine concerns, We recently surveyed a random sample of 500 physicians in family practice. general practice. and internal medicine in North Carolina. to discover their most challenging geriatric concerns. Using a three-stage survey technique. respondents were asked to answer two open-ended questions about the most challenging geriatric problems they face and what specific geriatric content areas would attract their participation in an educational program. They were then asked to rank 34 topics on which they would like more information. A total of 242 responses were received for a 55% response rate (63 of the 500 were undeliverable). Responses indicated that physicians are more concerned with management than diagnosis and revealed considerable evidence of empathy and concern. The top three topics had to do with the management of dementia. multiple problems. and depression. Approximately 25% of physicians consider problems of financing health care as among the most challenging problems.
Delirium: masquerades and misdiagnosis in elderly inpatients, Delirium is an organic mental disorder defined as transient. fluctuating global dysfunction of cognition. It is common in elderly medical inpatients. yet its varied presentation is often missed or misdiagnosed.
Pathogenesis and therapy of peptic ulcer disease, The epithelial cells of the stomach and duodenum are normally protected from the damaging effects of acid and pepsin by a balancing mechanism of mucosal resistance. If an imbalance occurs. peptic ulcer may result. Traditional teaching has emphasized the importance of acid (and pepsin) as the cause of this imbalance; however. it is clear that acid and pepsin are not the only important factors in the pathogenesis of peptic ulcer. More recent investigative efforts have been directed at what constitutes mucosal resistance and how it can be disrupted to produce. in the presence of gastric acid. a peptic ulcer. Depletion of endogenous prostaglandins and Helicobacter pylori gastritis have emerged as prominent theories. As evidence exists both to support and refute these theories in humans. any definitive conclusions cannot be made at this time. The acute management of peptic ulcer disease is directed at relieving pain. accelerating ulcer healing. and preventing complications. Peptic ulcers can be healed with antisecretory agents (i.e.. H2-receptor antagonists. omeprazole). antacids. prostaglandins. and sucralfate. Because they are effective. safe. and convenient. the H2-receptor antagonists are the most widely used agents for the management of peptic ulcer disease. Because the H2-receptor antagonist agents are equally effective in their indicated uses and are equally safe based on scientifically valid data. selection should be based primarily on cost. Omeprazole is the newest antisecretory agent: a single morning dose of 20 mg suppresses acid secretion for 24 h. The agent offers little advantage over H2-receptor antagonists for the majority of patients with peptic ulcer.
NSAID-induced gastrointestinal damage. A critical review of prophylaxis and therapy, Nonsteroidal anti-inflammatory drugs (NSAIDs) cause acute diffuse injury to the gastroduodenal mucosa. and also cause chronic focal ulcers that may bleed or perforate without warning symptoms. Acute and chronic lesions are distinct. are pathogenetically different. respond differently to drugs. and require different management strategies. The principal rationale for antiulcer therapy in NSAID users is to prevent or reduce potentially fatal outcomes; to date no evaluated drug meets this criterion for efficacy. Antacids and H2-receptor antagonists. based on open uncontrolled studies. appear to heal both gastric and duodenal ulcers. and maintain them healed during continued NSAID use; larger gastric ulcers show delayed healing with conventional doses of H2-receptor antagonists during NSAID therapy. No such delay occurs with omeprazole therapy. The suggests that if NSAID-associated gastric ulcers are treated with H2-receptor antagonists. larger doses should be given for longer periods. In patients with no pre-existing ulcer disease. H2-receptor antagonists given prophylactically prevent duodenal but not gastric ulcers; sucralfate does the same. In individuals without peptic ulcer disease taking NSAIDs. misoprostol. given as prophylaxis. reduces the development of gastric ulcers; its beneficial effects on ulcer healing or symptoms during continued NSAID therapy. or its ability to prevent duodenal ulcers or ulcer complications. are not established. Because of diarrhea. the 400 micrograms/day dosage is recommended. especially in the elderly.
Gastroesophageal reflux disease: an update on management, Gastroesophageal reflux is commonplace; all humans experience it. For many patients. gastroesophageal reflux disease (GERD) is a manageable condition. For others. GERD can progress to severe symptoms. inflammation. and disruption of the mucosal lining. Effective therapy calls for a clear understanding of the pathogenesis of GERD. The final common denominator to GERD is a lower esophageal sphincter mechanism that relaxes or is incompetent and allows gastroesophageal reflux to occur. Key factors associated with GERD are (a) gastric content. (b) potency of refluxate. (c) esophageal clearance. (d) tissue resistance. and (e) disruption of the anatomic hiatus. GERD is generally a chronic condition characterized by recurrent symptoms. Treatment goals for the GERD patient need to be defined: is therapy directed toward eliminating the symptoms or is therapy designed to eliminate gastroesophageal reflux? Unfortunately. effective therapy for GERD usually does not affect the mechanism(s) underlying the problem. The broad goals of therapy in GERD are to decrease gastroesophageal reflux and neutralize it. to enhance esophageal clearance. and to protect esophageal mucosa. The therapeutic modalities related to each of these situations are numerous and overlap. but treatment strategies for managing the GERD patient can be used in clinical "stages" or as the clinical situation dictates. H2-receptor antagonist therapy has become the "keystone" in management of GERD. Unfortunately. not all GERD patients respond to conventional H2-receptor antagonist dosage treatment; high-dose H2-receptor antagonist therapy recently has been demonstrated to be more effective in a greater number of GERD patients with severe esophagitis.
Endoscopic control of upper gastrointestinal bleeding, It has been estimated that gastrointestinal (GI) bleeding occurs in more than 100.000 patients with peptic ulcer disease each year. In 75-80% of the cases. bleeding will be self-limited. A major predictor of persistent or recurrent bleeding is the magnitude of blood loss before the initial evaluation. Endoscopy has an important role in the evaluation of the patient with suspected or presumed upper GI bleeding. Active bleeding at the time of the endoscopy correlates with the more likely probability of persistent bleeding. which carries a higher morbidity and mortality. In addition. there has been continued interest in the finding of a visible vessel. Although there is some controversy as to what a visible vessel actually is and how closely observations will agree about its recognition. there is general agreement that it is an important endoscopic finding and that it carries a high likelihood of rebleeding. In addition to the finding of a visible vessel. many endoscopists feel that ulcers found in the posterior-inferior wall of the duodenal bulb and high on the lesser curve of the stomach should be considered in a separate category. Owing to their proximity to large vessels. some feel that endoscopic management carries a greater risk because of the possibility of inducing bleeding. A wide variety of endoscopic approaches are available for the therapy of upper GI bleeding. It is convenient to divide these therapies into four categories: (a) topical. (b) injection. (c) mechanical. and (d) thermal. Endoscopic therapy for bleeding ulcers has generally been performed with a high degree of safety.
Should safety concerns with available ulcer treatment influence drug selection, With the identification of the parietal cell receptors for gastric acid secretion coupled with the introduction of cimetidine in 1977. treatment of acid-peptic diseases was transformed from empiric therapy to an approach based on a clearer understanding of human physiology. Today. physicians are confronted with an array of antiulcer agents that differ within their drug class (e.g.. the H2-receptor antagonists) as well as in their mechanisms of action (e.g.. neutralize acid. alter mucosal defensive factors. or suppress acid secretion). With minor exceptions. the clinical efficacy of the available antiulcer drugs can be regarded as comparable. Thus. the safety profile becomes the next consideration when choosing among similarly effective drug products. Of the available antiulcer agents. the H2-receptor antagonists as a class have an excellent safety profile. as indicated by more than 25 years of cumulative clinical experience and postmarketing surveillance. Important safety issues with currently available antiulcer drugs. i.e.. H2-receptor antagonists. sucralfate. prostaglandin E analogues. and the newest antiulcer agent. omeprazole. are reviewed to place them into perspective for the clinician.
The clinical importance of drug interactions with antiulcer therapy, The overall safety of a given drug is determined by its toxicity. side effects. and drug-drug interactions. Thus. a clarification of the mechanisms. importance. and clinical implications of any drug-drug interaction with antiulcer therapy is critical to the use of antiulcer medications. Drug-drug interactions may occur as a result of changes in absorption. metabolism. distribution. or excretion. Fortunately. drug distribution or protein binding is unchanged by antiulcer therapy. Antiulcer drugs may affect absorption by several mechanisms. Ionized medications may bind to the divalent cations of antacids and sucralfate to result in poorly absorbed complexes. Reduced gastric acid may decrease the absorption of medications that are weak bases while enhancing the absorption of weak acids. Drug absorption may be impaired by delayed gastric emptying. Several H2-receptor antagonists. including cimetidine and to a lesser extent ranitidine. and the proton pump inhibitor. omeprazole. may reduce the hepatic degradation of drugs metabolized by the cytochrome P450 system. The degree to which such agents alter drug metabolism is determined by the patient's age. genetics. duration of therapy. degree of cytochrome P450 binding. and the regimen. Because the clinical importance of this interaction cannot always be predicted. caution is recommended whenever drugs metabolized by this system are used concurrently. Development of an understanding of the ways in which drug metabolism interactions occur may lead to more effective and safe use of these medications.
Serologic, biologic, and western blot analysis of a T suppressor factor with specificity for the hapten 4-hydroxy-3-nitrophenyl acetyl derived from serum-free medium, A T cell hybridoma producing a T suppressor factor (TsF) with specificity for the hapten nitrophenyl was converted to long term growth in serum-free medium and its product tested by serology. bioactivity. and Western blot analysis. Results indicated that Ag-specific suppressive activity was present in serum-free medium and this TsF could exhibit the characteristics ascribed to it by various groups: it could bind nominal Ag with specificity. it was bound by anti-TsF mAb. and it could mediate Ag-specific suppression both in vivo and in vitro. Western blot and SDS-PAGE analysis of this purified TsF revealed a 43-kDa single chain protein.
[125I]fibrin deposition occurs at both early and late intervals of IgE-dependent or contact sensitivity reactions elicited in mouse skin. Mast cell-dependent augmentation of fibrin deposition at early intervals in combined IgE-dependent and contact sensitivity reactions, When elicited in the skin of mice. either IgE-dependent immediate hypersensitivity reactions or T cell-dependent contact sensitivity (CS) reactions result in local extravasation of [125I]fibrinogen and deposition of [125I]fibrin. However. these two types of reaction differ in kinetics and in requirement for IgE. mast cells. or T cells. In the present study. we investigated the kinetics and magnitude of [125I]fibrin deposition in combined IgE-dependent and CS reactions elicited simultaneously at the same site and compared the results with those obtained when the two reactions were elicited at separate sites. We found that [125I]fibrin deposition in pure IgE-dependent reactions was greater at 2 or 6 h after challenge than at 24 h. but that significant fibrin deposition persisted at those sites 24 h after challenge. In CS reactions. [125I]fibrin deposition was detected as early as 2 h after challenge. indicating that fibrin deposition accompanies the "early component" of CS detected by Van Loveren et al. with the use of measurements of tissue swelling. But much more [125I]fibrin deposition was present in CS reactions at 24 h than at 2 or 6 h after Ag challenge. When IgE-dependent and CS reactions were elicited at the same site. [125I]fibrin deposition at early intervals (2 to 6 h) after challenge was increased three- to 25-fold compared with that seen in isolated CS reactions. but at 24 h the results in the combined reactions were virtually identical to those in CS responses. Studies in genetically mast cell-deficient and congenic normal mice indicated that mast cells were required for expression of the IgE-dependent augmentation of [125I]fibrin deposition observed at early intervals in combined IgE-dependent and CS reactions. but not for the [125I]fibrin deposition associated with "pure" CS reactions. These findings indicate that the net effect of IgE-dependent mast cell activation on CS responses is to increase the fibrin deposition associated with these responses. but this effect is appreciated only at early intervals after elicitation of the reaction.
Hemorrhage in mice produces alterations in pulmonary B cell repertoires, Nosocomial pneumonia occurs frequently after hemorrhage and trauma and contributes to the increased incidence of morbidity and mortality after severe injury. The production of secretory antibodies by mucosally associated B cells is an important component of pulmonary host defense mechanisms. To determine the effects of hemorrhage on pulmonary B cell function. we examined hemorrhage induced alterations in pulmonary B cell repertoires. There were no changes in the relative distribution of T or B cells among intraparenchymal pulmonary lymphocytes after blood loss. Hemorrhage induced decreases of between 5- and 10-fold in the frequencies and numbers of pulmonary B cell clonal precursors specific for the bacterial Ag levan and Pseudomonas aeruginosa polysaccharide. These decreases in numbers and frequencies of bacterial Ag-specific pulmonary B cell clonal precursors were present between 3 and 10 days after blood loss. Similar decreases in numbers and frequencies were found among pulmonary clonal precursors specific for the autoantigen mouse transferrin. but not for the autoantigen dsDNA or the external antigens OVA and keyhole limpet hemocyanin. These results demonstrate that hemorrhage produces marked alterations in pulmonary B cell repertoires. which may contribute to postinjury abnormalities in host defenses.
IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway, IL-1. like other agents that have been shown a capacity to induce protein kinase C. is a potent transcriptional activator of the metalloproteinase. stromelysin. in synovial and other fibroblasts. cAMP has been shown to inhibit stromelysin transcription in fibroblasts of nonsynovial origin. and is regarded as an important second messenger for IL-1. In addition to stimulating metalloproteinase transcription. IL-1 also induces PGE2 production in synoviocytes. We determined that rIL-1 alpha led to the time-dependent accumulation of intracellular cAMP in serum-starved rheumatoid synovial fibroblasts. and that the effect was blocked by indomethacin. The cAMP agonists forskolin. 3-isobutyl-1-methylxanthine. and PGE2 suppressed the IL-1 induction of stromelysin; conversely. indomethacin superinduced IL-1-elicited stromelysin mRNA. These results were recapitulated on the transcriptional level in cells transfected with the rat transin/stromelysin promoter in a reporter (CAT) construct. 2'.5'-Dideoxyadenosine. an inhibitor of adenylate cyclase. also augmented the IL-1 induction of stromeylsin mRNA. as did H-8. a specific inhibitor of the cAMP-dependent protein kinase A. Staurosporine and H-7. inhibitors of protein kinase C. blocked the IL-1 induction of stromelysin mRNA. We conclude that IL-1 appears to stimulate at least two transduction pathways in synovial fibroblasts from patients with rheumatoid arthritis. and that these have antagonistic effects on the regulation of stromelysin transcription.
Requirement of endogenous tumor necrosis factor/cachectin for recovery from experimental peritonitis, By intrasplenic immunization we raised a rat mAb (mAb V1q; IgG2a. kappa) with a potent neutralizing activity against natural mouse TNF (1 microgram/ml mAb V1q/100 U/ml TNF). mAb V1q was used to study the role of endogenous TNF in experimental peritonitis induced by sublethal cecal ligation and puncture. mAb V1q persisted for over 5 days in the serum of mice injected with 100 micrograms of the antibody and. therefore. proved useful for in vivo experiments. As little as 20 micrograms mAb V1q/mouse prevented lethal shock of the animals by 400 micrograms LPS/mouse. In sublethal cecal ligation and puncture i.p. injection of mAb V1q directly and up to 8 h after induction of experimental peritonitis lead to death of the animals within 1 to 3 days. The lethal effect of mAb V1q was compensated by injection of recombinant mouse TNF. Similar mAb V1q effects as in immunocompetent mice were shown in severe combined immune deficiency mice deficient of mature functional B and T cells. Taken together. these data suggest that during the early phase of peritonitis endogenous TNF may stimulate nonlymphoid cells such as granulocytes. macrophages. platelets. and fibroblasts to ingest bacteria and to localize inflammation. respectively. These beneficial effects of TNF may determine survival. Thus. our data may have implications for the therapeutic management of a beginning peritonitis.
Growth factor-dependent differentiation along the myeloid and lymphoid lineages in an immature acute T lymphocytic leukemia, Bone marrow cells from a child with an immature (CD2+. CD5+. CD7+) acute T lymphocytic leukemia (T-ALL) were cultured in the presence and absence of human rIL-2. IL-3. or granulocyte-macrophage (GM)-CSF. Cells cultured without growth factors failed to divide and those initiated in the presence of IL-2 or GM-CSF underwent maturation and terminal T lymphoid or myelomonocytic differentiation. respectively. In contrast. a permanent growth factor-dependent cell line. designated TALL-103/3. was established upon culture in IL-3. The TALL-103/3 cells gradually lost the T cell-specific markers and acquired a myeloid phenotype (CD15+. CD33+). Switching of the IL-3-dependent cells at an early passage to medium containing only human rIL-2 resulted in the establishment of a subline. named TALL-103/2. with a T lymphoid phenotype (CD3+. CD8+. TCR-gamma delta +. CD7+). The TALL-103/2 cells strictly require IL-2 for growth. are irreversibly committed to the lymphoid lineage. and cannot survive in the presence of any other hemopoietic growth factor tested so far. In contrast. the IL-3-dependent TALL-103/3 cells could be adapted to grow in synthetic (serum-free) medium also in the presence of either GM-CSF or IL-5. in which they retain a myeloid phenotype. Interestingly. after 18 mo in culture in IL-3. the TALL-103/3 cells can still be phenotypically converted to the lymphoid lineage upon addition of IL-2. thus maintaining its bipotentiality. Despite the marked phenotypic differences. the TALL-103/2 and TALL-103/3 cell lines show the same karyotypes with multiple abnormalities present in the primary malignant clone and have identical rearrangements of the TCR-gamma and -delta loci. thus confirming their derivation from a common precursor cell. Together. these findings indicate that the phenotype of immature T-ALL cells can be drastically modified by the presence of specific hemopoietic growth factors in the environment. leading to either lymphoid or myeloid lineage commitment while leaving their karyotype and genotype intact.
Antigen-induced cross-linking of the IgE receptor leads to an association with the detergent-insoluble membrane skeleton of rat basophilic leukemia (RBL-2H3) cells, Cross-linking of the IgE receptor on the surface of rat basophilic leukemia cells by multivalent Ag (DNP-BSA) causes a rapid conversion to a detergent-insoluble form. There is a concurrent increase in the amount of filamentous actin associated with the plasma membrane. Both the degree of receptor detergent insolubility and the rise in F-actin content are rapid with a half-maximal response of less than 1 min and can be rapidly reversed by the addition of monovalent Ag (DNP-lysine). These two early steps in the triggering of rat basophilic leukemia cells can be dissociated from each other by pretreatment of the cells with either cytochalasin or sodium azide. These reagents block the increase in F-actin but have no effect on receptor detergent insolubility. This indicates that microfilaments are not responsible for detergent insolubility of the receptor and that it may be the membrane skeleton that is interacting with the complex. This was further confirmed by the finding that cross-linking of the IgE receptors on the surface of purified plasma membranes also leads to detergent insolubility of the receptor. Therefore. all of the components necessary for detergent insolubility of the receptor are present in the plasma membrane. and cytoplasmic components are not needed. These results suggest that detergent insolubility and immobility of the cross-linked receptors are caused by multivalent interaction with the membrane skeleton. Actin filaments may then interact with these receptor-membrane skeletal complexes in order to produce large scale clustering and capping. The membrane skeleton may therefore be acting as an intermediate structure between the cell-surface receptors and microfilaments.
Mapping of epitopes on the La(SS-B) autoantigen of primary Sjogren's syndrome: identification of a cross-reactive epitope, Autoepitopes on the ribonucleoprotein La(SS-B) were identified by using recombinant La(SS-B) polypeptides and sera from 166 patients with the antinuclear autoantibody anti-La(SS-B). The La(SS-B) polypeptides were encoded by polymerase chain reaction-derived overlapping or nonoverlapping fragments of the La(SS-B) gene. which encodes a protein of 408 amino acids (aa). Of the 166 sera tested. 99% reacted with a fusion protein comprising the first 107 N-terminal aa (LaA); 91% reacted with a fusion protein comprising aa 111 to 242 (LaC). and 91% reacted with a fusion protein comprising aa 346 to 408 (LaL2/3) at the C terminus of La(SS-B). The order of immunodominance as assessed by the number of sera reacting with each epitope and the strength of the reactivity was LaA (aa 1 to 107) greater than LaC (aa) 111 to 242) much greater than LaL2/3 (aa 346 to 408). Cross-reactivity was observed between antibodies eluted from LaC (aa 111 to 242) and LaL2/3 (aa 346 to 408). but there was no significant primary sequence homology between the two regions. The LaC region contained at least two epitopes. one encompassing a putative RNA-binding motif (aa 112 to 187) which was recognized by 83% of patient sera. Serial serum samples from three patients showed that the antibody response to La(SS-B) was initially directed to the N terminus (LaA. aa 1 to 107). but over a period of time all three major epitopes. including that encompassing the putative RNA-binding motif. were recognized. This result suggests that the primary immune response to La(SS-B) is restricted to an immunodominant epitope. As the specificity of the autoantibody response broadens. it includes the RNA-binding motif. which may have important implications for the expression of disease.
Mapping the site of interaction between murine IgE and its high affinity receptor with chimeric Ig, We have investigated the interaction of mouse (m) IgE with its Fc epsilon RI on rat basophilic leukemia cells using a set of chimeric Ig that were constructed by exchanging homologous H chain C domains between human (hu) IgG1 and mIgE. Binding affinities were examined with equilibrium and kinetic measurements. and we found that epsilon/C gamma 3 (mIgE with C epsilon 4 replaced by C gamma 3) was indistinguishable from mIgE. The huIgG1 and the other chimeric Ig. which did not contain both C epsilon 2 and C epsilon 3. did not bind detectably to rat basophilic leukemia cells (Ka less than 10(6) M-1). The ability of these chimeric Ig to stimulate a cellular response (degranulation) in the presence of multivalent Ag was also tested. The epsilon/C gamma 3 was indistinguishable from mIgE in eliciting a high level of degranulation. whereas the other chimeric Ig stimulated no response even when they were preaggregated to enhance their binding avidity. These results demonstrate that C epsilon 4 may be replaced by C gamma 3 without affecting the binding and cell activating properties of mIgE. The lack of binding by the other chimeric Ig indicates that both C epsilon 2 and C epsilon 3 are necessary for the binding interaction.
IgE receptor-mediated phosphatidylinositol hydrolysis and exocytosis from rat basophilic leukemia cells are independent of extracellular Ca2+ in a hypotonic buffer containing a high concentration of K+, In isotonic buffer. IgE receptor-mediated exocytosis from rat basophilic leukemia cells is dependent on extracellular Ca2+. with half-maximal degranulation requiring 0.4 mM Ca2+. No significant exocytosis occurs in the absence of extracellular Ca2+. This absolute requirement for Ca2+ is eliminated by suspending the cells in a hypotonic buffer containing 60 to 80 mM K+; Na+ cannot substitute for K+. Optimal Ca2(+)-independent exocytosis occurs in a buffer containing 20 mM dipotassium Pipes. pH 7.1. 40 mM KCl. 5 mM glucose. 7 mM Mg acetate. 0.1% BSA. and 1 mM EGTA. The cells maintain this Ca2(+)-independent exocytosis even if they are preincubated with 1 mM EGTA for 40 min at 37 degrees C before triggering. Exocytosis is eliminated as isotonicity is approached by adding sucrose. NaCl. KCl. or potassium glutamate to the buffer. Quin 2 fluorescence measurements reveal only a very small rise in [Ca2+]i when the cells are triggered in hypotonic buffer in the absence of extracellular Ca2+ and the presence of 1 mM EGTA. In isotonic buffer. degranulation does not occur under conditions that lead to such a small rise in [Ca2+]i. Sustained IgE receptor-mediated phosphatidylinositol hydrolysis. which is also Ca2+ dependent in isotonic buffer. becomes independent of Ca2+ in the hypotonic buffer. In fact. the rate of phosphatidylinositol hydrolysis in hypotonic buffer in the absence of Ca2+ (and presence of 1 mM EGTA) is twice that observed in isotonic buffer in the presence of 1 mM Ca2+. These data show that in hypotonic buffer. the requirement of IgE receptor-mediated PI hydrolysis for extracellular Ca2+ is eliminated. and degranulation proceeds with a [Ca2+]i of 0.1 microM. the baseline level of [Ca2+]i found in resting cells. These results are consistent with the hypothesis that. in isotonic buffer. the Ca2+ requirement for mast cell degranulation is for the generation of second messengers via hydrolysis of membrane phosphatidylinositols.
Mycobacterium leprae-specific T cells from a tuberculoid leprosy patient suppress HLA-DR3-restricted T cell responses to an immunodominant epitope on 65-kDa hsp of mycobacteria, The polar tuberculoid type (TT) of leprosy. characterized by high T cell reactivity to Mycobacterium leprae. is associated with HLA-DR3. Surprisingly. DR3-restricted low T cell responsiveness to M. leprae was found in HLA-DR3-positive TT leprosy patients. This low responsiveness was specifically induced by M. leprae but not by M. tuberculosis and was seen only in patients and not in healthy controls. We studied this patient-specific. M. leprae-induced. DR3-restricted low T cell responsiveness in depth in one representative HLA-DR3-positive TT leprosy patient by using T cell clones. From this patient two types of T cell clones were obtained: one type was cross-reactive with M. tuberculosis and recognized an immunodominant epitope (amino acids 3 to 13) on the 65-kDa heat shock protein (hsp) the other type was M. leprae specific and reacted to a protein other than the 65-kDa one. To examine whether these M. leprae-specific T cell clones were responsible for the DR3-restricted low responsiveness to M. leprae. we tested them for the ability to suppress the proliferation of the DR3-restricted. 65-kDa. hsp-reactive clones. The DR3-restricted. M. leprae-specific T cells completely suppressed the proliferative responses of DR3-restricted. cross-reactive T cell clones to the 65-kDa hsp from the same patient as well as from other individuals. Also. DR3-restricted responses to an irrelevant Ag were suppressed by the M. leprae-specific T cell clones. However. no suppression of non-DR3-restricted T cell responses was seen. Although the mechanism must still be elucidated. this M. leprae-induced. DR3-restricted immunosuppression may at least partly explain the observed DR3-associated low T cell responsiveness in TT leprosy patients.
B cell responses to paramyosin. Isotypic analysis and epitope mapping of filarial paramyosin in patients with onchocerciasis, To examine the fine specificity of the human immune response to filarial paramyosin. the antigenicity of an expressed rcDNA (2.55 kb) of Dirofilaria immitis paramyosin was detailed by ELISA. Using sera from patients infected with Onchocerca volvulus. we analyzed both the entire paramyosin molecule and six subcloned fragments for their IgG. IgG subclasses. and IgE responses. Patients from both Guatemala (64% positive) and Ghana (100% positive) reacted to paramyosin with specific IgG levels above normal controls. Although there was no anti-paramyosin subclass restriction common to all patients. the IgG3 response in the Ghananians was significantly greater than that of Guatemalans (p less than 0.001). IgE anti-paramyosin responses showed positive correlations with IgG2 (p less than 0.001). IgG4 (p less than 0.002). and IgG1 (p less than 0.04) responses. Epitope mapping using the IgG response to the six subclones demonstrated preferential recognition of the amino terminal end of the molecule (nucleotides 1 to 360). IgG2 reactivity was clearly localized to the most amino-terminal 120 amino acids. and the IgG4 antibodies recognized amino acids immediately adjacent to this fragment. These studies examining the fine specificity of anti-filarial immune reactions should provide a method for understanding how parasites either evade or induce host immune responses.
Recognition of a B cell lymphoma by anti-idiotypic T cells, Idiotypic IgM derived from a B cell lymphoma can act as a tumor-associated Ag. in that immunization with this purified protein generates an anti-idiotypic immune response that specifically suppresses tumor development. Spleens of immune mice contain T cells that proliferate in response to idiotypic IgM. However. idiotypic Ag is presented to the T cells most efficiently in its natural form at the surface of the lymphoma cells. than as soluble IgM plus presenting cells. Variant tumors that display either little or no idiotypic IgM at the cell surface. but which are otherwise indistinguishable from parental tumor. induce a weak response or fail to stimulate the T cells. respectively. Anti-idiotypic lines and clones have been derived from the splenic T cells by growth in the presence of irradiated tumor cells. Phenotypic analysis revealed that cells from both lines and clones express CD3 and CD4 Ag. but not CD8. Recognition of tumor Id. which required no added presenting cells. was inhibited by antibody against MHC class II Ag. and variably by anti-CD4. Proliferative responses were inhibited by anti-idiotypic antibodies. but also by antibodies against the constant region of the mu H chain. indicating that perturbation of the surface IgM abrogates availability of idiotypic determinants to the T cells.
A constitutive antibody in normal human serum directed against rabbit bone marrow cells: lack in parturients, neonates, and hematologic disorders, Normal human serum effectively inhibits a bioassay for erythropoietin based on DNA synthesis by rabbit erythroid precursors. This heat-sensitive inhibitory activity is readily lost on dilution of serum. revealing the presence of erythropoietin-potentiating activity. Inhibitory activity is caused by a rapid cytotoxic effect on rabbit bone marrow cells; mouse cells are less sensitive. Cytotoxic activity is removed from serum by adsorption to protein A. is not expressed at 4 degrees C. and is neutralized by anti-C3c complement antibody. Cytotoxicity is inhibited by EGTA; the effect of EGTA is reversed by addition of Ca2+ ions. These findings show that cytotoxicity is exerted through an antibody via the classical pathway of complement-dependent cell lysis. Although serum from healthy. adult human donors consistently contains cytotoxic activity. no such activity is observed in most serum samples from neonates. parturients. and patients with severe anemia. Patients with polycythemia or chronic renal failure occasionally lack cytotoxic activity in their serum. Serum samples lacking cytotoxic activity were found to be deficient in the antibody component in 34 out of 35 cases examined. These results show that an antibody directed against rabbit cells is constitutively present in normal human serum but is absent in a number of pathologic situations as well as being absent in neonates and parturients.
Increased incidence of monoclonal gammopathy of undetermined significance in blacks and its age-related differences with whites on the basis of a study of 397 men and one woman in a hospital setting, Serum samples from 398 individuals (270 whites and 128 blacks) exhibiting quantitatively normal amounts of five typically seen fractions (albumin. alpha 1-globulin. alpha 2-globulin. beta-globulin. and gamma-globulin) in serum protein electrophoresis and showing no evidence of multiple myeloma. other immunoproliferative diseases. or any of the other diseases known to produce monoclonal proteins were tested for monoclonal gammopathy of undetermined significance (MGUS) by immunofixation electrophoresis. No individual in the study had a serum protein electrophoresis pattern suggestive of monoclonal protein gammopathy. Except for one 37-year-old woman. all subjects were men. Subjects were divided into seven age groups: 20 to 29 years (I). 30 to 39 years (II). 40 to 49 years (III). 50 to 59 years (IV). 60 to 69 years (V). 70 to 79 years (VI). and all over 79 years (VII) of age. Considering all subjects in a given race. blacks had two times (14.8%) higher incidence of MGUS than whites (7.8%); this difference was statistically significant. An increased incidence of MGUS in blacks when compared with whites prevailed in each age group. and the difference was statistically significant in all age groups except group II. No MGUS was found in groups I and III in either race. Both races showed a threefold increase in incidence of MGUS from group II to group VII. No routine laboratory test such as erythrocyte sedimentation rate in subjects with MGUS was significantly different than that in age- and race-matched individuals without MGUS. These results show that the incidence of MGUS is higher in the group (blacks) also known to have a higher prevalence of multiple myeloma.
Effects of prostaglandin E1 on platelet attenuation of oxidant-induced edema in isolated rabbit lungs, Numerous studies suggest that platelets may contribute to preservation of normal endothelial cell permeability in models of lung injury. We have previously shown that washed human platelets prevent xanthine oxidase-induced edema in the isolated perfused lung and that protective mechanisms depend on the platelet glutathione redox cycle. It is uncertain. however. whether platelets preserve endothelial function by reducing toxic oxygen metabolites or by aggregating and releasing endothelial cell supportive factors-an activity that may require the glutathione redox cycle. In this study. we present data demonstrating that platelet prevention of oxidant lung injury occurs independent of platelet aggregation and release. Isolated rabbit lungs perfused with a cell-free medium were instilled with purine (2 mmol/L) and xanthine oxidase (0.003 U/ml) to generate oxidant lung edema. The infusion of washed human platelets (1 x 10(10) cells) prevented lung edema formation as measured by lung weight gain. wet-to-dry lung weight ratios. and lung histology. Incubation of platelets with prostaglandin E1 (PGE1). a potent inhibitor of platelet aggregation and release. did not inhibit platelet attenuation of lung edema. Additionally. with the instillation of PGE1 into the perfusate to further inhibit platelet aggregation. no prevention of lung protection by PGE1-treated platelets was seen when these results were compared with those from studies in which lungs were infused with xanthine oxidase and PGE1. Aggregometry studies documented that the inhibitory effect of PGE1 on platelet aggregation persisted for up to 60 minutes. which was the duration of the isolated lung protocol. We conclude that platelet aggregation and release of platelet factors is not required for platelet attenuation of oxidant lung edema.
Identification and isolation of a phospholipase A2 activating protein in human rheumatoid arthritis synovial fluid: induction of eicosanoid synthesis and an inflammatory response in joints injected in vivo, Eicosanoids are important mediators of the destructive arthropathy observed in rheumatoid arthritis. The rate-limiting step in the eicosanoid synthesis pathway is the availability of free arachidonic acid. The phospholipase enzymes release arachidonic acid from membrane phospholipids and thus play an important role in the regulation of eicosanoid production. We have previously demonstrated enhanced phospholipase A2 and C enzyme activities in cells from patients with rheumatoid arthritis and have also described a phospholipase A2 activating protein (PLAP) in mammalian cell lines. In an attempt to determine the biochemical basis of enhanced phospholipase A2 activity found in patients with inflammatory joint disease. we examined synovial fluid from patients with rheumatoid arthritis for PLAP. To determine whether PLAP was specific for rheumatoid disease. we assayed specimens from patients with other arthropathies. Histologic examination of rheumatoid joint tissue. with the use of immunohistochemical techniques. demonstrated high concentration of PLAP in monocytes. macrophages. chondrocytes. vascular smooth muscle. and endothelial cells. Human PLAP could be biochemically isolated from synovial fluid from patients with rheumatoid arthritis and was found to be similar to PLAP previously isolated from murine and bovine sources. To determine whether PLAP could directly mediate any aspect of inflammatory disease. purified PLAP was injected into rabbit knee joints. This resulted in an acute inflammatory arthritis with synovial cell proliferation and synovial fluid leukocytosis. Purified PLAP also induced eicosanoid formation both in vivo and in vitro. With enzyme-linked immunosorbent assays. we found more PLAP in synovial fluid specimens from patients with rheumatoid arthritis compared with samples from patients with other inflammatory arthropathies as well as osteoarthritis. a noninflammatory arthropathy. These data suggest that PLAP may be responsible. at least in part. for some aspects of the destructive inflammatory arthropathy that is observed in patients with rheumatoid arthritis.
Negative screening for sickle cell diseases with a monoclonal immunoassay on newborn blood eluted from filter paper, The most common method of blood sample collection for neonatal screening programs for inherited diseases-blood spots on filter paper--is poorly suited for screening of sickle cell diseases by conventional assays because of the denaturing effects of this medium on hemoglobins that affect their electrophoretic identifications. The monoclonal antibody beta 6-1 specifically recognizes the hemoglobin A beta-chain residue 6 (glutamic acid). that is. the normal counterpart of hemoglobins S and C. and this recognition is unaffected by changes in hemoglobins induced by filter paper storage. The beta 6-1 immunoassay analysis of 67 prescreened samples extracted from filter paper permitted unambiguous group identification. by virtue of nonreactivity. of the pathologic sickle cell disease phenotypes SS (sickle cell anemia) and SC (sickle cell-hemoglobin C disease). along with the homozygous hemoglobin C phenotype (hemoglobin CC disease). Other phenotypes identified by beta 6-1 nonreactivity would include S-beta degrees thalassemia. C-beta degrees thalassemia. and beta degrees thalassemia (Cooley's anemia). As systems for collecting newborn blood specimens on filter paper and their transmittal to centralized laboratories are already established in many states. this assay for sickle cell and hemoglobin C diseases could rapidly be combined with other mass screening programs for inborn errors of metabolism.
Production of thrombi on intact endothelium by use of antiheparin agents in vivo, It had been suggested that antithrombin activity on the surface of intact endothelial cells may play a role in inhibiting platelet adhesion and thrombus formation. The antithrombin activity may be due to thrombomodulin or to activation of antithrombin III by glycosaminoglycans or thrombomodulin. or possibly a combination of these. This inhibitory activity has been shown to be affected by such antiheparin agents as protamine. hexadimethrine bromide (Polybrene; Aldrich Chemical Co.. Milwaukee. Wis.) and platelet factor 4. as well as by such enzymes as heparinase and heparitinase. We have used a hamster cheek pouch preparation to observe thrombus formation in vivo in a normal vascular flow. to determine whether the production of thrombi by thrombin can be enhanced by antiheparin agents. After intra-arterial injection or topical application of protamine or hexadimethrine bromide. platelet adhesion and thrombus formation on intact arteriolar endothelium was produced by a dose of thrombin. which when injected alone had no effect. No thrombi were found in venules or capillaries. Injection of heparin before or after the antiheparin agents necessitated a larger dose to enhance the action of thrombin. On electron microscopy the thrombi were found to consist primarily of platelets adherent to an intact endothelium. The possible clinical implications of these observations are discussed.
Rheologic properties of mixed hemoglobin gels: deoxyhemoglobins S and A, To obtain new information concerning the behaviors. and in turn the structures. of gels formed from mixtures of S and A hemoglobins. their physical properties have been characterized by stress relaxation with a rotational rheometer. The variables manipulated were (1) initial total hemoglobin concentration. (2) mole fraction of hemoglobin S present in the mixture. (3) hemoglobin A as intact tetramer only or as both tetramer and hybridized hemoglobin AS. (4) annealing time. (5) shear history. (6) temperature. and (7) temperature and time of annealing. Characteristics monitored to gain information about the effect of these variables on gel properties were (1) lag time. (2) polymer mass. (3) polymer fraction. (4) polymer composition. (5) equilibrium total hemoglobin activity. and (6) solidity/total or hemoglobin S polymer mass (or total or hemoglobin S fraction). As expected. mixed hemoglobin SA gels were less solid than those of pure S of similar initial hemoglobin concentrations because of lower polymer mass. and gel properties were influenced by shear history. annealing time. temperature. and temperature and time of annealing. However. when solidities were compared on the basis of similar quantities of gel present. mixed hemoglobin SA gels were found to be more solid than those of pure S as the mole fraction of hemoglobin S decreased in the initial mixture. This is explained by the predominant influence on gel properties of high hemoglobin activity incurred by the volume exclusion effect of the total hemoglobin concentration. The presence of hemoglobin A with hemoglobin S results in polymers and gels that differ from those found in pure hemoglobin S. Pathophysiologic implications of these findings for sickle cell disorders are proposed.
Rheologic properties of mixed hemoglobin gels: deoxyhemoglobins S and F, To obtain new information concerning the behaviors--and in turn. the structures--of gels formed from mixtures of S and F hemoglobins. their rheologic properties have been characterized by stress relaxation. The variables manipulated were (1) initial total hemoglobin concentration; (2) mole fraction of hemoglobin S present in the mixture; (3) hemoglobin F as only intact tetramer or as both tetramers and hybridized hemoglobin; (4) hemoglobin F as predominantly G gamma. A gamma. or a mixture of gamma chain types; (5) annealing time; (6) shear history. (7) temperature; and (8) temperature and time of annealing. Characteristics monitored to gain information about the effect of these variables on gel properties were (1) lag time. (2) polymer mass. (3) polymer fraction. (4) polymer composition. (5) equilibrium total hemoglobin activity. and (6) solidity/total or hemoglobin S polymer mass (or total or hemoglobin S fraction). As expected. mixed hemoglobin S and F gels were less solid than pure hemoglobin S gels of similar initial total hemoglobin concentrations because of lower polymer mass. and gel properties were influenced by annealing time. shear history. temperature. and temperature and time of annealing. However. when solidities were compared on the basis of similar quantities of gel present. mixed hemoglobin S and F gels were found to be more solid than those of pure S as the mole fraction of hemoglobin S decreased in the initial mixture. This is explained by the predominant influence on gel properties of high hemoglobin activity incurred by the volume exclusion effect of the total hemoglobin concentration. Pathophysiologic implications of these findings for various sickle cell disorders are proposed.
The effect of rifampicin on rhinoscleroma: an electron microscopic study, Twenty-five cases suffering from rhinoscleroma were divided into two groups. The first group consisted of 15 patients treated with rifampicin systemically. The other group consisted of 10 patients treated locally with rifampicin in the form of ointment. Electron microscopic study of the pathological changes in the lesions showed that rifampicin is highly effective both systemically and locally in the treatment of rhinoscleroma.
Technetium-99m(v) dimercaptosuccinic acid planar scintigraphy in head and neck cancer: clinical, scintigraphic and radiological study, Technetium-99m (Tc99m)(v) Dimercaptosuccinic Acid (DMSA) is an imaging agent which has been proposed as a scintigraphic marker for head and neck squamous cell carcinoma. Fifty-four patients were studied of whom 51 had a head and neck tumour. All patients were examined and then imaged using Tc99m(v) DMSA scintigraphy and computerized tomography. Scintigraphy was less sensitive than clinical examination in the detection of patients with cancer. patients with primary tumours and patients with metastatic neck disease. CT was as sensitive and as accurate as clinical examination but more sensitive than Tc99m(v) DMSA in detecting patients with cancer and with primary tumours. CT was more sensitive and more accurate than both clinical examination and Tc99m(v) DMSA scintigraphy in predicting which patients had metastatic neck disease. Although Tc99m(v) DMSA is accumulated by squamous cell carcinoma. its inability to detect low volume disease and apparent low specificity means it has no role to play in the management of patients with head and neck squamous cell carcinoma.
Late development of a squamous carcinoma in a reconstructed pharynx, We report a case in which a squamous cell carcinoma was found to have arisen from a delto-pectoral skin flap used in pharyngeal reconstruction. The flap had been forming a neo-pharynx for 24 years. No other signs of recurrent disease had developed in this period. This raises the possibility of tumour induction in heterotopic skin used for oropharyngeal reconstruction.
Haemangiosarcoma of the maxillary antrum, Angiosarcomas are extremely rare in the head and neck and the histological diagnosis is often difficult. We present a case of a haemangiosarcoma of the maxillary antrum in a 33 year old male. The histological diagnosis and subsequent management are discussed.
Management of hypercholesterolemia in a family practice setting, A study was undertaken to assess physician adherence and patient compliance with the National Cholesterol Education Program guidelines for the management of newly detected hypercholesterolemia. The study site was the Department of Family Medicine. Medical University of South Carolina. Charleston. a university-based family medicine residency program. All serum cholesterol levels measured between July 1. 1988. and September 30. 1988. were reviewed. Patients were classified as normal. borderline. or hypercholesterolemic based on serum cholesterol levels and coronary heart disease risk factors. Patients previously recognized to be hypercholesterolemic were excluded. Six months later. medical record reviews were performed for the 192 hypercholesterolemic and 107 borderline hypercholesterolemic patients. Only 39 of the hypercholesterolemic patients (20%) had received appropriate dietary therapy and follow-up. Patient compliance with physician recommendations was excellent. There was minimal unnecessary testing or treatment of borderline hypercholesterolemia. Low rates of appropriate management of hypercholesterolemia may be related to inadequate physician knowledge. low physician-perceived self-efficacy regarding dietary counseling. or time constraints.
Human immunodeficiency virus and the primary care physician, As the scope and size of the human immunodeficiency virus (HIV) epidemic grows. the primary care physician will need to assume a greater role. A knowledge of HIV risk factors and the ability to perform pretest and posttest counseling for HIV testing is essential. Counseling patients on HIV risk reduction should be part of the HIV risk interview. An understanding of the benefits and contraindications of testing. as well as a respect for the impact of testing. is important. All HIV-seropositive individuals should undergo a complete history and review of symptoms as soon as test results are known. Judicious use of laboratory testing. including monitoring of CD4 cell counts. is recommended. Pneumocystis carinii prophylaxis and zidovudine therapy should be offered to patients with appropriately low CD4 counts.
Multiple muscle enzyme release with psychiatric illness, Associations (p less than .001) between serum concentrations of lactate dehydrogenase (LDH) and glutamic oxaloacetic transaminase (SGOT) were observed in physically well patients with mania (N = 100. r = .70). depression (N = 138. r = .51). chronic schizophrenia (N = 85. r = .68). and schizoaffective or atypical psychosis (N = 39. r = .52) discharged from 1978 through 1981. In contrast. there was a negligible association between these enzymes in 90 nonpsychiatric inpatient control subjects. Patients with mania (229.0 +/- 106.1 IU/l) showed significantly (t = 3.16. p less than .002. two-tailed) higher lactate dehydrogenase (LDH) levels than control subjects (191 +/- 41.7 IU/l) and a 14% incidence of abnormally high serum LDH levels vs. 1% among control subjects. Results were unchanged when patients taking neuroleptics were excluded. These results indicate that psychiatric illness. especially mania. induces release of LDH and SGOT. occasionally to unusually high levels. This is similar to previous reports of muscle creatine phosphokinase release in psychiatric patients. Presumably. these enzymes are released from skeletal muscle in association with agitation. with muscle tension. or with blood stasis and local tissue hypoxia consequent to hypoactivity.
Infarction in the territory of the medial branch of the posterior inferior cerebellar artery, We report 10 cases of cerebellar infarction in the territory of the medial branch of the posterior inferior cerebellar artery (mPICA). Axial sections on MRI through the middle of the medulla and the cerebellum showed the infarction as a triangular area with a dorsal base and a ventral apex directed towards the fourth ventricle. The infarct also involved the lateral and dorsal medulla when the mPICA supplied all or part of these regions. Three clinical patterns were observed: 1) pseudolabyrinthine signs with or without dysmetria and ataxia when the medulla was spared; marked axial lateropulsion was present in most cases; 2) complete or incomplete Wallenberg's syndrome. when the medulla was involved; 3) silent infarction. These syndromes are precisely those previously attributed to PICA occlusion without distinction of the branch involved. No alteration of consciousness was recorded and spontaneous recovery was the rule. Cerebellar infarction in the distribution of the mPICA can be regarded as a benign condition with a good prognosis.
Motor unit discharge characteristics and short term synchrony in paraplegic humans, Frequency of firing and regularity of discharge of human motor units. and short term synchrony between pairs of motor units. have been assessed in extensor digitorum communis (EDC) and tibialis anterior (TA) muscles in control subjects and in clinically complete paraplegic subjects. The discharge pattern of TA motor units in paraplegia ranged from extremely regular to very irregular for different motor units whereas in the control population. and in EDC of both groups. there was a narrow. but intermediate. range of regularity. There was little difference in the incidence and degree of short term synchrony (STS) in EDC between paraplegic and normal subjects. In contrast. virtually no STS of motor units was observed in the TA muscles of the paraplegic group whereas control subjects exhibited approximately the same amount of STS in their TA and EDC muscles. It is concluded that the extra burden placed on arm muscles in paraplegia does not change the amount of synchronisation between motor units. Furthermore. section of the spinal cord does not increase STS as predicted from lesions of the reticulospinal tract in cats. This may reflect the coincidental removal of supraspinal synchronising inputs of motoneurons or the reorganisation of synaptic inputs in chronic paraplegia.
Involvement of the central nervous system in chronic inflammatory demyelinating polyneuropathy: a clinical, electrophysiological and magnetic resonance imaging study, In a consecutive series of 30 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) minor clinical evidence of CNS involvement was found in five. Cranial magnetic resonance imaging (MRI) was performed in 28 and revealed abnormalities consistent with demyelination in nine patients aged less than 50 years and abnormalities in five aged 50 years or over. Measurements of central motor conduction time (CMCT) were obtained in 18 and showed unilateral or bilateral abnormalities in six. It is concluded that subclinical evidence of central nervous system (CNS) involvement is common. at least in patients with CIDP in the United Kingdom. but that clinically evident signs of CNS disease are infrequent. The association of a multiple sclerosis-like syndrome with CIDP is rare.
Clues to the electrocardiographic diagnosis of subtle Wolff-Parkinson-White syndrome in children, The electrocardiographic diagnosis of Wolff-Parkinson-White syndrome (WPW) may be missed because delta waves can be subtle in children. so we examined 66 electrocardiograms from patients with proven WPW. 24 from those with questionable WPW ("subtle WPW"). and 369 consecutive electrocardiograms from control patients to identify additional clues that WPW might be present. Three features were notable in WPW: no Q wave in left chest leads (88%). PR interval less than 100 milliseconds (80%). and left axis deviation (33%). In subtle WPW these findings were similar: 79%. 67%. and 46%. respectively. By comparison. 5% of control subjects had no Q wave. 16% had a PR interval of less than 100 milliseconds. and 4% had left axis deviation (all p less than 0.001). The coexistence of two of these features was common (74%) in WPW and subtle WPW (63%) but rare (2%) in control subjects (p less than 0.001). A PR interval of less than 100 milliseconds was less specific before 1 year of age. but 89% of patients with WPW had a QRS duration of greater than 80 milliseconds versus 2% of control subjects (p less than 0.001). Obvious WPW disappeared later in 11 patients; however. left axis deviation or lack of a Q wave persisted in eight (p less than 0.01). We conclude that the diagnosis of WPW in children. even when subtle. is suggested by the presence of these four changes. Preexcitation may persist in some patients in whom overt delta waves are no longer present.
Value of a multiantigen radioallergosorbent test in diagnosing atopic disease in young children, The purpose of this study was to investigate the value of a new multiantigen radioallergosorbent test. Phadiatop Paediatric. in the diagnosis of atopy in children less than 7 years of age. The diagnosis of atopic disease was established by history. physical examination. total serum IgE concentration. and the results of prick skin tests or radioallergosorbent tests or both. and then compared with the result of the Phadiatop Paediatric test for each patient. One hundred two patients (62 boys) between the ages of 4 months and 7.3 years were enrolled (median age 3.2 years). After the history and physical examination. 42% of the patients were believed to be atopic and 32% to be nonatopic; the diagnosis was uncertain in 26%. Skin prick test reactions to a variety of foods and inhalants were positive in 41 of 63 children tested; results of radioallergosorbent tests were positive in 35 of 61 children. Overall. atopy was diagnosed in 53 children and 49 were found to be nonatopic. When the clinical diagnosis was used as the gold standard. the Phadiatop test resulted in a correct diagnosis of atopy in 49 of 53 cases and of no atopy in 43 of 49 cases: sensitivity = 92%. specificity = 88%. and efficiency = 90%. Although the Phadiatop Paediatric test does not indicate specific sensitivities. it provides the clinician with a useful screening test for atopic disease in children 7 years of age or less. and the researcher with a means of validating atopic populations.
Adult height in boys and girls with untreated short stature and constitutional delay of growth and puberty: accuracy of five different methods of height prediction, To determine how accurately several methods of height prediction estimate adult height. we compared height predictions calculated by the Bayley-Pinneau. Roche-Wainer-Thissen (RWT). target height. and Tanner-Whitehouse Mark I (TW-MI). and Mark II (TW-MII) methods with final adult height in 37 boys and 32 girls with short stature and constitutional delay of growth and puberty. They were first seen at a chronologic age (mean +/- SD) of 14.80 +/- 1.70 years (boys) and 12.87 +/- 2.56 years (girls). Adult height at 23.14 +/- 1.95 years and 21.05 +/- 2.02 years was 170.4 +/- 5.4 cm (boys) and 157.8 +/- 4.2 cm (girls). respectively. and thus within the lower range of normal. Height predictions were calculated for the total group and for patients with parents of normal (group 1) as well as short stature (group 2). For boys. the RWT method gave very accurate results. underestimating adult height by -0.6 cm for the total group. The prediction errors for the other methods were -7.3 cm (TW-MI). -4.2 cm (TW-MII). and +3.1 cm (Bayley-Pinneau method) or +1.7 cm (target height). For girls. no method was superior in estimating adult height. The mean prediction error was -0.8 cm. -2.1 cm. and -1.8 cm with the Bayley-Pinneau. TW-MI. and TW-MII methods. respectively. In contrast. adult height was overpredicted by +2.3 cm and +1.2 cm with the RWT and target height methods. We conclude that patients with short stature and constitutional delay of growth and puberty reach an adult height in the lower range of normal. Height prediction methods differ with respect to their accuracy and their tendency to overestimate or underestimate adult height.
Late-onset ornithine transcarbamylase deficiency in male patients [published erratum appears in J Pediatr 1991 Feb;118(2):326, We report on 21 male patients who presented after 28 days of age with ornithine transcarbamylase (OTC) deficiency. which we define as late-onset OTC deficiency. These patients appeared normal at birth. but irritability. vomiting. and lethargy. which were often episodic. later developed. The age at presentation ranged from 2 months to 44 years. Biochemical testing revealed hyperammonemia. hyperglutaminemia. hypocitrullinemia. increased urinary orotate excretion. and decreased liver OTC activity measured in vitro. which ranged from 0% to 15% of normal. Male patients who were older at presentation had a somewhat different pattern of presenting symptoms and were more likely to die. These data illustrate the phenotypic variability of OTC deficiency. Unexplained episodes of repetitive or protracted vomiting in association with progressive alterations in behavior or neurologic findings should suggest the diagnosis of a urea cycle defect (or another symptomatic inborn error of metabolism). regardless of the age or medical history of the patient.
Effect of continuous-infusion zidovudine therapy on neuropsychologic functioning in children with symptomatic human immunodeficiency virus infection, Neuropsychologic function was assessed in 13 children with symptomatic human immunodeficiency virus disease (Centers for Disease Control Class P2). ranging in age from 14 months to 12 years. Before the initiation of treatment. eight patients were classified as having encephalopathy. Psychologic tests were administered both before and after 6 and 12 months of continuous-infusion azidothymidine (AZT; zidovudine) treatment. After 6 months of treatment a significant increase of 15.5 (+/- 3.3) IQ points was demonstrated in general cognitive functioning (p less than 0.001). Follow-up for 10 of these patients indicated that after 12 months of AZT therapy. they had maintained their gains in IQ points. Improvements in adaptive behavior after 6 months of therapy. assessed with a standardized interview. paralleled the findings on the IQ data. No significant differences in the amount of change was observed for the different subgroups. The magnitude of these improvements could not be explained by practice effects. environmental changes. or general improvement in physical state. We conclude that neuropsychologic function was significantly improved with continuous infusion AZT treatment.
A glance at the urodynamic database, Three hundred sixty-four patients with urinary incontinence as their presenting complaint were evaluated in the urogynecology laboratory. Department of Obstetrics and Gynecology. University of Rochester. Rochester. New York. Of them. 226 (62%) were found to have genuine stress urinary incontinence (GSI). This subset of demonstrably incontinent patients was characterized as to symptoms of stress and urge incontinence. incidence of nulliparity. occurrence of incontinence during intercourse and influence of weight on bladder pressure. Using clusters of symptoms did not accurately distinguish GSI from the other types of urinary incontinence. Four percent of the GSI patients were nulliparous. All had a reasonable explanation for incontinence other than anatomic relaxation. Twenty-three percent of the 154 sexually active GSI patients acknowledged having incontinence with intercourse. None of the anatomic and urodynamic parameters evaluated distinguished that group from their GSI counterparts who did not lose urine with intercourse. Increasing weight. expressed as the body mass index. correlated with an increase in the vesical pressure in the supine and standing positions.
Laser therapy for vaginal intraepithelial neoplasia after hysterectomy, In recent years there has been a marked increase in the number of reported cases of vaginal intraepithelial neoplasia (VAIN) after hysterectomy. Until about 10 years ago radiation or surgery had been the therapeutic modality mostly used for this disease. More recently. topical drugs. such as bleomycin and 5-fluorouracil cream. have been used. but they are often ineffective and poorly tolerated. For the last 14 years we have used the CO2 laser for the treatment of VAIN and have treated a total of 143 patients. Our use of a combination of wire sutures through the vaginal mucosa and the introduction of fluids into the underlying submucosal areas allows retraction and ballooning of the recesses and scars and permits us to place the vaginal mucosa at right angles to the laser beam to allow complete treatment.
C-reactive protein in assessing antimicrobial treatment of acute pelvic inflammatory disease, Serial serum C-reactive protein (CRP) determinations were used in the evaluation of antimicrobial treatment of acute pelvic inflammatory disease (PID) as proven by laparoscopy and endometrial biopsy or microbiologic findings in the upper genital tract in 36 women. Sixteen patients were treated with ciprofloxacin and 20 with doxycycline plus metronidazole. The mean CRP levels did not differ significantly in patients with severe and moderate salpingitis in comparison with mild salpingitis on admission or during treatment. nor was there any significant difference between the mean CRP levels in patients with acute chlamydial/gonococcal and nonchlamydial/nongonococcal PID. The mean CRP levels decreased by the third day of treatment in all treatment groups. and the decrease by the sixth day of treatment was significant (P less than .05). reflecting the clinical response to therapy faster than did serial ESR determinations. After the documentation of acute PID. serial serum CRP determinations were a useful predictor of the short-term response to antimicrobial therapy.
The cytobrush for evaluating routine cervicovaginal-endocervical smears, While the conventional wooden spatula/cotton-tipped applicator has remained the method of obtaining Papanicolaou smears for most clinicians at the University of California at Los Angeles. the Student Health Service (SHS) adopted the Zelsmyr cytobrush as its sole method of obtaining cervical samples in late 1986. A study was done to define changes in both the adequacy of sampling and the detection rate for both squamous and glandular epithelial abnormalities with the cytobrush. To accomplish this goal. 1.000 cytobrush and 244 conventionally obtained smears were analyzed prospectively. and 3.864 SHS samples obtained in 1986 prior to the change in method were reviewed retrospectively. As compared to cervical samples obtained by conventional methods. the cytobrush smears contained significantly more endocervical cells and had fewer drying artifacts. Both methods obtained equivalent squamous samples and had similar final class distributions. No case of endocervical adenocarcinoma carcinoma in situ or invasive adenocarcinoma was detected. SHS patients who had initial "no endocervical cells" samples but whose repeat sample did contain endocervical cells retained the same class in more than 75% of cases. This study confirmed that the cytobrush technique produces Papanicolaou smears with improved sampling of the squamocolumnar junction but questioned whether that results in an increased detection rate for cervical pathology.
Initiating a chorionic villus sampling program. Relying on placental location as the primary determinant of the sampling route, In initiating a chorionic villus sampling (CVS) protocol. we relied upon placental locations as the determinant in the choice of technique. An anterior or fundal location prompted a transabdominal (TA) CVS. while the transcervical (TC) approach was reserved for posterior placentas. A coaxial needle system was used for TA CVS (18-gauge. 15-cm guide needle and 20-gauge. 20-cm sampling needle). while TC CVS was accomplished with a 5.8-French. 27-cm polyethylene catheter. Between July 1988 and February 1989 our initial 118 procedures were performed for 115 consecutive pregnancies using this protocol. Testing indications and antenatal characteristics of the TA (n = 56) and TC (n = 63) groups were similar. One procedure failure occurred in the TC group. and a single aspiration was sufficient in 59% of the cases (TA. 30/55; TC. 39/63). In TC procedures an increased aggregate sample weight was observed as compared to TA cases (25.8 g vs. 16.9 g. respectively; P less than .001). This difference was not attributable to an increased number of placental aspirations in TC cases. One abnormal karyotype was observed (45X). and four pregnancy losses occurred (TC. 3; TA. 1). Using placental location to determine the choice of CVS technique appears to be feasible and may be associated with a lower failure rate during a facility's initial experience (when compared to reliance upon one technique alone). Trials comparing the safety of these two methods should consider placental location an independent variable before randomization.
Aggressive evaluation for atypical squamous cells in Papanicolaou smears, A retrospective study was done on women who had atypical Papanicolaou smears and were referred for immediate colposcopy. The smears were obtained during January 1985 to March 1989 at Edwards Air Force Base. California. Excluded from the evaluation were abnormal Papanicolaou smears with hyperkeratosis. parakeratosis and koilocytotic atypia suggestive of human papillomavirus (HPV) infection. The evaluation included colposcopy. colposcopically directed biopsies. endocervical curettage and repeat Papanicolaou smears. A total of 101 patients were included in the study. Cervical intraepithelial neoplasia (CIN) was seen in 29.7% (30 patients): 12.9% (13) CIN I. 12.9% (13) CIN II and 3.9% (4) CIN III. Carcinoma was seen in 3.9% (4) of the patients: 2.9% (3) was carcinoma in situ. and 0.99% (1) was invasive squamous cell carcinoma. stage IIb. HPV and dysplastic lesions were seen together in 19.8% (20) of the patients. HPV was seen alone in 45% (46). Twenty-one patients (20.8%) had no apparent lesions on colposcopy. although one developed microinvasive keratinizing squamous cell carcinoma within 36 months of colposcopy. Many significant lesions can go undetected for extended periods of time in women with atypical Papanicolaou smears. resulting in delayed management. Referral for immediate colposcopy is advocated strongly.
Intrapartum cocaine use. A case report, The use of cocaine during pregnancy appears to be reaching epidemic proportions. In the first reported case of intrapartum cocaine use. fetal heart rate abnormalities were detected.
A comparison of coarctation resection and subclavian flap angioplasty using ultrasonographically monitored postocclusive reactive hyperemia, The reported relatively high incidence of early restenosis at the coarctation repair site with subclavian flap angioplasty. especially in infants less than 3 months of age. prompted a physiologically oriented analysis of relief of obstruction from coarctation after subclavian flap angioplasty versus resection and end-to-end anastomosis in infancy. Twenty-one patients who had undergone repair of coarctation in infancy by either subclavian flap angioplasty (nine patients) (median age 8 years) or resection and end-to-end anastomosis (12 patients) (median age 8 years) were evaluated by Doppler spectrum analysis of the blood flow velocities in the femoral artery at rest and during reactive hyperemia. The median resting right upper to lower limb systolic pressure difference (with interquartile range) was similar in the angioplasty. resection and anastomosis. and control groups: -5 mm Hg (18 mm Hg). 0 mm Hg (12 mm Hg). and -2.5 mm Hg (10 mm Hg). respectively. Also. similar resting values for the maximum frequency of the advancing curve and the pulsatility and resistance indices were measured in the three groups. During reactive hyperemia of the leg. however. a significant hemodynamic obstruction across the repair site became clinically manifest in the angioplasty group only. as documented by a lower pulsatility index in comparison with the control group (p = 0.01. Mann-Whitney U test). Comparison of the hemodynamic results between the angioplasty and resection and anastomosis groups in subdivisions of infants operated on at an age of less or greater than 3 months. both at rest and during reactive hyperemia. showed. already at rest. a significantly lower value for the pulsatility index in the former angioplasty subdivision (p = 0.05. Student's t test). indicating a significant resistance at the coarctation repair site in the angioplasty patients operated on before the third month of life. A disadvantage of angioplasty (compared with resection and anastomosis) was noted when angioplasty was performed before the third month of life. and an unequivocal lack of advantage was noted when performed beyond that period regarding relief of obstruction from coarctation. In addition. a definite potential for adverse long-term effects on the hemodynamics of the left upper limb after subclavian flap angioplasty in infancy has been documented. For these reasons we prefer to perform resection and end-to-end anastomosis for repair of coarctation in infancy.
Studies of myocardial protection in the immature heart. II. Evidence for importance of amino acid metabolism in tolerance to ischemia, This study tests the importance of amino acid transamination in determining the tolerance of immature hearts to ischemic damage. Amino acid transamination was inhibited metabolically by pretreatment with aminooxyacetic acid. The aminooxyacetic acid dose and duration were determined by incubating in vitro tissue homogenate and showing that an 8 mmol/L AOA dose for 5 minutes blocked 90% of alanine aminotransferase and aspartate aminotransferase activity. Control studies in nonischemic hearts showed that coronary perfusion with aminooxyacetic acid for 5 minutes did not impair myocardial performance. In contrast. pretreatment of immature puppies with aminooxyacetic acid severely impaired recovery after 45 minutes of normothermic global ischemia (30% versus 85% recovery in untreated hearts. p less than 0.05). Biochemical analyses of hearts undergoing ischemia showed aminooxyacetic acid to limit lactate production. impair glutamate utilization. prevent alanine production. and limit succinate accumulation (p less than 0.05). These data suggest that amino acid transamination is an important adaptive process in the immature heart that improves its resistance to ischemic damage.
Warm induction blood cardioplegia in the infant. A technique to avoid rapid cooling myocardial contracture, The use of profound hypothermia and total circulatory arrest for repair of heart defects in neonates usually involves a period of systemic and myocardial bypass cooling. Rapid cooling of muscle (skeletal. smooth. and myocardial) can result in contracture through elevation of cytosolic calcium levels. The increased myocardial tone caused by cooling might render the heart more vulnerable to a subsequent period of cardioplegic ischemic arrest. Infants may be more susceptible to contracture because their small body mass allows more rapid myocardial temperature change when prearrest bypass cooling is used. The influence of avoiding rapid myocardial cooling before induced cardioplegic arrest was analyzed in a group of infants weighing less than 6 kg at the time of open cardiac operation. Myocardial ischemic arrest by warm (37 degrees C) induction blood cardioplegia was used in 57 infants and compared with results in 440 infants treated with standard blood cardioplegia. Multivariate logistic regression analysis revealed that patient diagnosis. weight. and age at operation were significant risk factors for operative mortality. The use of warm induction blood cardioplegia had a strongly positive independent effect on survival (p = 0.0003) for any patient weight. age. or diagnostic group. We recommend the avoidance of rapid myocardial cooling on bypass in all patients before induction of cardioplegic ischemic arrest.
Efficacy and safety of low- and high-dose sotalol versus propranolol in the prevention of supraventricular tachyarrhythmias early after coronary artery bypass operations, Supraventricular tachyarrhythmias are reported in up to 40% of patients early after coronary artery bypass graft operations. In a randomized study. we compared the efficacy and safety of the class III antiarrhythmic beta-blocking drug sotalol versus propranolol at low and high doses in the prevention of supraventricular tachyarrhythmias in 429 consecutive patients after coronary artery bypass graft operations. Patients with severely depressed left ventricular function and other contraindications for beta-blockers were excluded. From the fourth hour up to the sixth day after coronary artery bypass. 74 patients received low-dose sotalol (40 mg every 8 hours). 66 patients low-dose propranolol (10 mg every 6 hours). 133 patients high-dose sotalol (80 mg every 8 hours). and 156 patients high-dose propranolol (20 mg every 6 hours). Baseline characteristics were comparable in all groups. Supraventricular tachyarrhythmia was observed in 10 of 72 (13.9%) who received low-dose sotalol. 12 of 64 (18.8%) who received low-dose propranolol. 13 of 119 (10.9%) who received high-dose sotalol. and 19 of 139 (13.7%) who received high-dose propranolol (not significant). Drug-related adverse effects necessitating discontinuation of the drug occurred in four receiving low doses (2.9%) and in 31 receiving high doses (10.7%) (p less than 0.02). In conclusion. no medication was found to be superior. although supraventricular tachyarrhythmias tended to be less prevalent in patients treated with sotalol than in those treated with propranolol. Moreover. significantly fewer adverse effects were noted in both low-dose groups. Therefore. low-dose beta-blocking treatment. especially low-dose sotalol. seems preferable.
A general model of sexually transmitted disease epidemiology and its implications for control, Achieving control of STDs may be possible by integrating the activities discussed previously with further research to provide additional empiric data on sex behavior. to develop innovative strategies to access and communicate with those most at risk of STD (i.e.. core-group members). and to foster biologic study of STD pathogens with the goal of vaccine development. New strategies to identify core-group members aside from the currently used STD-repeater status would be of immense help in targeting educational efforts. laboratory screening. and vaccines. Achieving more complete control of STDs may be possible if recent advances in our understanding of their epidemiology and transmission dynamics can be translated into effective new interventional strategies.
Syphilis in adults, This article reviews the clinical manifestations of syphilis. diagnostic tests that might help to diagnose accurately the disease. and current recommendations for therapy. The association of syphilis and human immunodeficiency virus infection raises additional questions related to transmission. diagnosis. and therapy of both diseases.
Regular inhaled beta-agonist treatment in bronchial asthma, 89 subjects with stable asthma took part in a double-blind. placebo-controlled. randomized. crossover study of the effects of regular versus on-demand inhaled bronchodilator therapy. The subjects inhaled fenoterol or placebo by a dry powder delivery system for 24 weeks. Control of asthma was judged by daily morning and evening peak expiratory flow rates. symptom diaries. use of additional inhaled bronchodilator. and requirement for short courses of prednisone. Of 64 subjects who completed the trial. 57 showed a clear difference in degree of control of asthma between the fenoterol and placebo periods: in 17 (30% [95% confidence interval 18.4-43.4%]) asthma was better controlled during regular inhaled bronchodilator treatment. whereas in 40 (70% [56.6-81.6%]) control was better during placebo treatment with bronchodilator for symptom relief only. Mean airway responsiveness to methacholine increased slightly during the fenoterol period. The adverse effect of regular bronchodilator inhalation occurred not only among subjects who used a bronchodilator as sole treatment (2 were better and 10 were worse during regular bronchodilator treatment) but also among those who took inhaled corticosteroids (14 were better and 29 were worse). Thus. regular inhalation of a beta-sympathomimetic agent was associated with deterioration of asthma control in the majority of subjects. The trends to use of regular. higher doses or longer-acting inhaled beta-sympathomimetic treatment may be an important causal factor in the worldwide increase in morbidity from asthma.
Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma, The airway response and cardiovascular and hypokalaemic effects of fenoterol. salbutamol. and terbutaline given in multiples of standard doses from metered-dose inhalers were studied in ten patients with mild asthma. In a double-blind. crossover. placebo-controlled study the subjects received 2. 6. and 18 puffs of each drug with intervals of 90 min. and forced expiratory volume in 1 s. heart rate. QTc interval. plasma potassium concentration. tremor. and bronchial reactivity to histamine were measured. All three drugs produced similar bronchodilatation. However. the rises in heart rate. QTc interval. and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline. The maximum mean (SD) increases in heart rate for fenoterol. salbutamol. and terbutaline were 29 (24) bpm. 8 (9) bpm. and 8 (14) bpm. respectively; falls in plasma potassium were 0.76 (0.62) mmol/l. 0.46 (0.32) mmol/l. and 0.52 (0.39) mmol/l. respectively. Fenoterol afforded no additional protection against histamine compared with salbutamol. These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline. The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists; fenoterol may in addition be less selective for beta 2 receptors.
Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis, 72 adults with erythema migrans (early Lyme borreliosis) were enrolled in a randomised prospective trial comparing amoxycillin 500 mg plus probenecid 500 mg three times a day with doxycycline 100 mg twice a day for 21 days. These antibiotic regimens were chosen because of the known in-vitro sensitivity of Borrelia burgdorferi. the antibiotic tissue penetration. the pharmacokinetics of the drugs. and because the organism can disseminate early in the course of infection. 72 patients were evaluable (35 in the doxycycline group and 37 in the amoxycillin/probenecid group). The two regimens were equally effective for treatment of erythema migrans. Mild fatigue or arthralgia were the only post-treatment complaints. which resolved within 6 months. None of the patients needed further antibiotic treatment for Lyme borreliosis.
Human recombinant GM-CSF in allogeneic bone-marrow transplantation for leukaemia: double-blind, placebo-controlled trial, In a randomised. double-blind trial 20 patients with leukaemia received human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF) and 20 received placebo. for 14 days after allogeneic. matched sibling. bone-marrow transplantation. The neutrophil count recovered to 0.5 x 10(9)/l 3 days earlier in the GM-CSF group than in the placebo group (not significant). and the median neutrophil count at 14 days was significantly higher in the GM-CSF group (1.90 vs 0.46 x 10(9)/l). The lymphocyte count was significantly higher in the GM-CSF than in the placebo group between days 10 and 15 after transplantation. but this difference was not associated with a higher incidence of graft-versus-host disease. There was no evidence that GM-CSF was associated with a greater incidence of leukaemic relapse. The GM-CSF group had lower haemoglobin concentrations and platelet counts and higher plasma urea. creatinine. and bilirubin than the placebo group. The duration of hospital stay was the same for both patient groups. Further studies are now indicated to assess the overall effect of GM-CSF on outcome after allogeneic bone-marrow transplantation.
Bird attack on milk bottles: possible mode of transmission of Campylobacter jejuni to man, A case-control study was carried out to test the hypothesis that the rise in the rate of Campylobacter jejuni infection in the Brigend area of South Wales during May was due to the consumption or handling of milk from bottles that had been attacked by birds. 32 of 36 cases meeting the case definition were interviewed. along with 2 controls per case. matched for age. sex. and area of residence. There were strong associations between campylobacter infection and doorstep delivery of milk bottles. a history of milk bottle attack by birds. milk bottle attack by birds during the week before illness. and consumption of milk from attacked bottles during the week before illness. There was a very strong dose-response relation between frequency of bird attack and illness. Controls with a history of milk bottle attack by birds were more likely than cases to have taken preventive measures against bird attack and consumption of contaminated milk. Although few people witnessed the attacks. the likely culprits are magpies (Pica pica) and jackdaws (Corvus monedula).
Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist, BACKGROUND. Exercise is a common stimulus of bronchoconstriction in subjects with asthma. who also have bronchoconstriction after inhaling the sulfidopeptide leukotriene D4 (LTD4). The purpose of this study was to investigate the importance of LTD4 as a mediator of exercise-induced bronchoconstriction. METHODS. In a double-blind. randomized. crossover study. 12 subjects with stable asthma were treated intravenously with MK-571 (160 mg). a selective and potent LTD4-receptor antagonist. or placebo. 20 minutes before each of two challenges involving exercise at a level previously demonstrated to cause a fall of at least 20 percent in the forced expiratory volume in one second (FEV1). The two exercise challenges were separated by one week. The results of the challenges were expressed as both the maximal fall in FEV1 after exercise and the time to recovery from bronchoconstriction. RESULTS. Treatment with MK-571 attenuated exercise-induced bronchoconstriction in all the subjects. The mean (+/- SEM) maximal percent decrease in FEV1 after exercise was 25.2 +/- 3.5 percent in the subjects taking placebo and 9.2 +/- 2.5 percent in the subjects taking MK-571 (P less than 0.001). The mean percent inhibition for the entire group was 69.5 percent. The mean time to recovery after exercise was 33.4 +/- 4.0 minutes in the placebo group and 8.4 +/- 2.5 minutes in the MK-571 group (P less than 0.001). CONCLUSIONS. This study demonstrates that pretreatment with a potent and selective LTD4 antagonist markedly attenuates exercise-induced bronchoconstriction. and it suggests that LTD4 is a major mediator of this type of bronchoconstriction.
The effects of a 5-lipoxygenase inhibitor on asthma induced by cold, dry air, BACKGROUND. The enzyme 5-lipoxygenase catalyzes the metabolism of arachidonic acid to form products that have been implicated in the airway obstruction of asthma. We hypothesized that if products of the 5-lipoxygenase pathway are important in mediating this obstruction. then prevention of their formation should decrease the severity of an induced asthmatic response. METHODS. In a randomized. double-blind. placebo-controlled. crossover study. we examined the effect of A-64077. a 5-lipoxygenase inhibitor. on the bronchoconstriction induced by hyperventilation of cold. dry air in 13 patients with asthma. The completeness of 5-lipoxygenase inhibition was confirmed by examining the profile of eicosanoids produced in whole blood ex vivo after activation with the calcium ionophore A-23187. RESULTS. A-64077 decreased the mean (+/- SEM) ionophore-induced synthesis of leukotriene B4. a 5-lipoxygenase product. by 74 percent (from 265.3 +/- 30.3 to 69.5 +/- 21.5 ng per milliliter. P less than 0.001). but it did not affect the ionophore-induced synthesis of thromboxane B2. a cyclooxygenase metabolite of arachidonic acid (80.0 +/- 17.1 ng per milliliter before A-64077 vs. 75.8 +/- 14.3 ng per milliliter after A-64077). In concert with the selective inhibition of 5-lipoxygenase by A-64077. the amount of cold. dry air (expressed as respiratory heat exchange) required to reduce the forced expiratory volume in one second by 10 percent was increased by 47 percent after A-64077 (3.0 kJ per minute for placebo vs. 4.4 kJ per minute for A-64077. P less than 0.002). Similar results were obtained when minute ventilation was used as an indicator of outcome (27.5 liters per minute for placebo vs. 39.8 liters per minute for A-64077. P less than 0.005). CONCLUSIONS. Selective inhibition of 5-lipoxygenase by A-64077 is associated with a significant amelioration of the asthmatic response to cold. dry air. suggesting that 5-lipoxygenase products are involved in this response. This approach may be useful in the treatment of asthma.
Late pulmonary sequelae of bronchopulmonary dysplasia, BACKGROUND. Bronchopulmonary dysplasia is a chronic lung disease that often develops after mechanical ventilation in prematurely born infants with respiratory failure. It has become the most common form of chronic lung disease in infants in the United States. The long-term outcome for infants with bronchopulmonary dysplasia has not been determined. METHODS. We studied the pulmonary function of 26 adolescents and young adults. born between 1964 and 1973. who had bronchopulmonary dysplasia in infancy. We compared the results with those in two control groups: 26 age-matched adolescents and young adults of similar birth weight and gestational age who had not undergone mechanical ventilation. and 53 age-matched normal subjects. RESULTS. Sixty-eight percent of the subjects with bronchopulmonary dysplasia in infancy (17 of the 25 tested) had airway obstruction. including decreases in forced expiratory volume in one second. forced expiratory flow between 25 and 75 percent of vital capacity. and maximal expiratory flow velocity at 50 percent of vital capacity. as compared with both control groups (P less than 0.0001 for all comparisons). Twenty-four percent of the subjects with bronchopulmonary dysplasia in infancy had fixed airway obstruction. and 52 percent had reactive airway disease. as indicated by their responses to the administration of methacholine or a bronchodilator. Hyperinflation (an increased ratio of residual volume to total lung capacity) was more frequent in the subjects with a history of bronchopulmonary dysplasia than in either the matched cohort (P less than 0.0006) or the normal controls (P less than 0.0004). Six of the subjects who had bronchopulmonary dysplasia in infancy had severe pulmonary dysfunction or current symptoms of respiratory difficulty. CONCLUSIONS. Most adolescents and young adults who had bronchopulmonary dysplasia in infancy have some degree of pulmonary dysfunction. consisting of airway obstruction. airway hyperreactivity. and hyperinflation. The clinical consequences of this dysfunction are not known.
Genetic evidence equating SRY and the testis-determining factor, The testis-determining factor gene (TDF) lies on the Y chromosome and is responsible for initiating male sex determination. SRY is a gene located in the sex-determining region of the human and mouse Y chromosomes and has many of the properties expected for TDF. Sex reversal in XY females results from the failure of the testis determination or differentiation pathways. Some XY females. with gonadal dysgenesis. have lost the sex-determining region from the Y chromosome by terminal exchange between the sex chromosomes or by other deletions. If SRY is TDF. it would be predicted that some sex-reversed XY females. without Y chromosome deletions. will have suffered mutations in SRY. We have tested human XY females and normal XY males for alterations in SRY using the single-strand conformation polymorphism assay and subsequent DNA sequencing. A de novo mutation was found in the SRY gene of one XY female: this mutation was not present in the patient's normal father and brother. A second variant was found in the SRY gene of another XY female. but in this case the normal father shared the same alteration. The variant in the second case may be fortuitously associated with. or predisposing towards sex reversal; the de novo mutation associated with sex reversal provides compelling evidence that SRY is required for male sex determination.
A human XY female with a frame shift mutation in the candidate testis-determining gene SRY, The primary decision about male or female sexual development of the human embryo depends on the presence of the Y chromosome. more specifically on a gene on the Y chromosome encoding a testis-determining factor. TDF. The human sex-determining region has been delimited to a 35-kilobase interval near the Y pseudoautosomal boundary. In this region there is a candidate gene for TDF. termed SRY. which is conserved and specific to the Y chromosome in all mammals tested. The corresponding gene from the mouse Y chromosome is deleted in a line of XY female mutant mice. and is expressed at the expected stage during male gonadal development. We have now identified a mutation in SRY in one out of 12 sex-inversed XY females with gonadal dysgenesis who do not lack large segments of the short arm of the Y chromosome. The four-nucleotide deletion occurs in a sequence of SRY encoding a conserved DNA-binding motif and results in a frame shift presumably leading to a non-functional protein. The mutation occurred de novo. because the father of the sporadic XY female that bears it has the normal sequence at the corresponding position. These results provide strong evidence for SRY being TDF.
Long-term potentiation of electrotonic coupling at mixed synapses, Long-term potentiation of chemical synapses is closely related to memory and learning. Studies of this process have concentrated on chemically mediated excitatory synapses. By contrast. activity-dependent modification of gap junctions. which also widely exist in higher structures such as hippocampus and neocortex. has not been described. Here we report that at mixed synapses between sensory afferents and an identified reticulospinal neuron. the electrotonic coupling potential can be potentiated. as well as the chemically mediated excitatory postsynaptic potential. for a prolonged time period using a stimulation paradigm like that which produces long-term potentiation in hippocampus. The effect on coupling is due to an increase in gap-junctional conductance. Our data indicate that the potentiation of both synaptic components requires an increase in intracellular calcium. involves activation of NMDA (N-methyl-D-aspartate) receptors. and is specific to the tetanized pathway.
Interleukin-1 receptor antagonist reduces mortality from endotoxin shock, About five out of 1.000 patients admitted to hospital develop bacterial sepsis leading to shock. the mortality rate for which is high despite antibiotic therapy. The infection results in hypotension and poor tissue perfusion. and eventually leads to the failure of several organ systems. Bacterial endotoxin is thought to be the direct cause of shock in Gram-negative sepsis. because it can cause shock in animals. and antibodies against endotoxin prevent Gram-negative shock in animals and in humans. But. the symptoms of septic shock are the result of the actions of host cytokines induced by the endotoxin. The cytokine interleukin-1 has been implicated as an important mediator of septic shock because it can induce tachycardia and hypotension and act synergistically with tumour necrosis factor to cause tissue damage and death. We now report that a specific interleukin-1 receptor antagonist reduces the lethality of endotoxin-induced shock in rabbits. indicating that interleukin-1 does indeed play an important part in endotoxin shock.
Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth, Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy. haemangiomas. arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin. a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice. but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.
Indications for thymectomy in myasthenia gravis, Fifty-six board-certified neurologists with interest and expertise in myasthenia completed a survey of indications for thymectomy in myasthenia gravis. Thymectomy was advocated for virtually all patients with thymoma. for a variable subset of patients with generalized myasthenia without thymoma. and occasionally for selected patients with disabling ocular myasthenia.
Phenotypic heterogeneity of spinal muscular atrophy mapping to chromosome 5q11.2-13.3 (SMA 5q), We made phenotypic analysis of 14 families with spinal muscular atrophy (SMA) linking to chromosome 5q11.2-13.3 (SMA 5q). and 2 that may not map to this locus. to assess clinical symptoms among SMA families known to result from mutation at the identical gene/locus. Although the current number of families is still small. the correlation of clinical phenotype and molecular genotype supports 2 observations. First. SMA mutations at the 5q locus present with a broad continuum of clinical abnormalities. and 2nd. the single clearly unlinked family presents with an unusual phenotype characterized by relatively late onset and early death. Thus. there are as yet no unambiguous cases of typical SMA families that are clearly unlinked to the locus at 5q-ie. no clear cases of nonallelic heterogeneity. Analysis of SMA 5q families supports the view that. with certain exceptions. there is little phenotypic intrafamilial variability. When families were ranked by severity of disease there was a strong correlation with age of onset. Onset within the 1st few months was associated with early death. but not in all cases. With rare exception. onset after 1 year of age was associated with less severe disease and greater longevity.
Routine and quantitative EEG analysis in Gilles de la Tourette's syndrome, Gilles de la Tourette's syndrome (GdlT) is a neurobehavioral disorder. with a reportedly high frequency of EEG abnormalities. We performed EEGs on 48 consecutive patients with GdlT. and frequency analysis in 26 patients (17 males). and compared the results with those from age- and sex-matched normal controls. Routine 18-channel EEG revealed minimal diffuse nonspecific slowing in only 3 of 48 patients (6%) and in 2 of 26 controls (7.7%). The frequency analysis of the EEG of the 26 GdlT patients and their normal controls showed similar brain activity. We conclude that no significant differences exist between the EEG activity in GdlT patients as compared with that in sex- and age-matched controls in routine as well as in quantitative EEG.
Conjugal temporal arteritis, We report the simultaneous occurrence of biopsy-proven temporal arteritis in husband and wife. Serologic and viral studies were negative. including viral culture of the wife's temporal artery. The concurrent incidence of giant cell arteritis in a married couple would suggest a common exogenous exposure.
Defective dystrophin in Duchenne and Becker dystrophy myotubes in cell culture, We examined normal and dystrophic human myotubes in cell culture for expression of dystrophin. the protein product of the Duchenne muscular dystrophy locus. Dystrophin levels in developing myotubes detected by Western blotting increased after 24 hours and reached maximum levels after 10 days in fusion medium. We did not detect dystrophin in myotubes cultured from Duchenne myoblasts (7 cases). Myotubes from a Becker muscular dystrophy patient's biopsy produced a lower molecular weight (approximately 408 kd) dystrophin. which was the same size in a whole muscle preparation from the same biopsy. This 408-kd dystrophin was the expected size for this Becker patient whose DNA was deleted for exons 45-48 of the Duchenne gene. This cell culture system will allow a detailed analysis of the effects of potential pharmacologic agents on steady-state dystrophin levels.
Deteriorating ischemic stroke: risk factors and prognosis, To determine a risk profile of deterioration in cerebral infarction of less than 8 hours' duration. we studied prospectively a series of clinical and radiologic data in 98 patients. We evaluated the Canadian Neurological Scale Score and Barthel index during a follow-up period of 3 months. There was deterioration in the 1st 48 hours in 40.8% of the patients. High systolic blood pressure. elevated blood sugar concentration at admission. and carotid territory involvement were independently related with deterioration in the logistic regression analysis. Death occurred in 35% of the patients with deteriorating infarcts and in 8.6% of those with stable infarcts. At the end of the study. functional capacity was lower in those with deteriorating infarcts. but the 2 groups improved in parallel from the 4th day onward.
Infantile CNS spongy degeneration--14 cases: clinical update, We studied 14 Arab infants with infantile spongy degeneration. 13 of whom were products of consanguineous marriages. They presented in infancy with macrocephaly. poor visual behavior or blindness. and axial hypotonia with appendicular spasticity. Brain CT and MRI showed diffuse symmetric leukoencephalopathy. even before neurologic symptoms. There were relatively normal EEGs. The visual evoked responses (P100) were either absent or delayed early in the course. The brainstem auditory evoked responses showed milder abnormalities. with loss of later components before the earlier ones. Deficient aspartoacylase activity in cultured fibroblasts or brain biopsy confirmed the diagnosis in all patients.
Dominantly inherited apathy, central hypoventilation, and Parkinson's syndrome: clinical, biochemical, and neuropathologic studies of 2 new cases, We describe 2 new patients from a family in which 10 persons in 3 successive generations had a dominant neuropsychiatric disorder characterized by apathy. central hypoventilation. and parkinsonism. Neuropathologically. both patients showed severe neuronal loss and reactive gliosis in the substantia nigra. Neurochemical studies showed a marked depletion of dopamine in substantia nigra. putamen. and caudate nucleus. as well as reduction in serotonin content in the substantia nigra. Glutamate contents were low in frontal cortex and thalamus. and gamma-aminobutyric acid (GABA) contents were low in thalamus and substantia nigra of both patients. In addition. phosphoethanolamine contents were reduced in all brain regions of both patients. especially in the substantia nigra. One patient with severe symptoms had low levels of homovanillic acid. 5-hydroxyindoleacetic acid. and GABA in his CSF repeatedly for 3 years before death (aged 58). while the 2nd patient died (aged 51) of an unrelated cause before developing any symptoms of the familial disorder. Because brain deficiencies of multiple neurotransmitters appear to be involved. this disorder is unlikely to respond to treatment; however. neurochemical studies of CSF may make presymptomatic diagnosis feasible.
Biology of retroviruses. Detection, molecular biology, and treatment of retroviral infection, Although human retrovirology can trace its roots to the early part of this century. it has been within the last decade that the field has seen its greatest advances. including the description of the first human retroviruses. HTLV-I. and the subsequent discovery of HTLV-II and the AIDS retroviruses. HIV-1 and HIV-2. The growth this field has undergone in recent years would not have been possible had it not been for key advances in the fields of cell biology. immunology. biochemistry. and molecular biology. Nowhere has this been more evident than in the description of HIV as the etiologic agent of AIDS. In the relatively short time since the disease was initially described. the agent responsible has been isolated. much of its complex biology has been defined. and a drug that helps combat it has been licensed for use. The rapidity with which these events have transpired is largely unprecedented. There remain many unanswered questions regarding HIV and AIDS. and there still is no effective vaccine or cure. Significant questions regarding the immune response to HIV and the HIV response to immune or chemotherapeutic challenge. the establishment and maintenance of HIV latency. and the all-important mechanisms of HIV cytopathicity remain unanswered. It is clear that HIV offers no easy answers. and that significant work remains to be done before death from AIDS can be halted.
Influence of human immunodeficiency virus infection on reproductive decisions, This article discusses the role of the practitioner in the pregnancy decision-making process of the HIV-infected woman. Literature on women's decisions is reviewed. and variables that influence decisions are discussed. The author concludes that HIV infection does not have a significant impact on pregnancy decisions. Other cultural and psychosocial variables may have more importance.
Care of the infant born exposed to human immunodeficiency virus, The expanding epidemic of HIV infection in reproductive-age women. the availability of antiretroviral therapy for children. and recommendations for increased case identification activities augur a time when more and more pediatricians are going to be called on to care for HIV-exposed infants. This article outlines a comprehensive medical framework for the care of these children from the labor and delivery setting to the nursery. outpatient clinic. and the emergency room. It includes issues of infection control; medical. developmental. and psychosocial care; and laboratory evaluations. Finally. it address the need for long-term follow-up of all children born exposed to HIV.
The selective serotonin reuptake inhibitor paroxetine is effective in the treatment of diabetic neuropathy symptoms, The effect of the selective serotonin reuptake inhibitor paroxetine on diabetic neuropathy symptoms was examined in comparison to imipramine and placebo in a randomised. double-blind. cross-over study. Paroxetine was given as a fixed dose of 40 mg/day. while the dose of imipramine was adjusted to yield optimal plasma levels of imipramine plus desipramine of 400-600 nM. Paroxetine significantly reduced the symptoms of neuropathy as measured by both observer- and self-rating. but was somewhat less effective than imipramine. However. patients showing a weaker response to paroxetine than to imipramine had lower plasma concentrations of paroxetine than patients with similar response to the 2 drugs. On imipramine 5 patients dropped out because of intolerable side effects and 4 of 19 patients completing the study reported withdrawal symptoms after discontinuing imipramine. On paroxetine no patients dropped out due to side effects and no withdrawal symptoms were reported. Self-rating showed no depressive symptoms at baseline. and no changes during the study. Neither paroxetine nor imipramine caused changes in objective measures of peripheral nerve function. In conclusion. 40 mg paroxetine/day significantly reduced the symptoms in peripheral diabetic neuropathy. and it was suggested that by dose adjustment on the basis of drug level monitoring. paroxetine may become as effective as imipramine. Paroxetine was devoid of the often disturbing autonomic side effects limiting the use of imipramine in several patients.
Study of verbal description in neuropathic pain, The aim of this paper is to study the quality of verbal description and its diagnostic value in neuropathic pain. The verbal description of pain as assessed by a French adjective list questionnaire (QDSA) is compared between a group of 100 patients with neuropathic pain and a mixed group of 97 chronic benign and cancer non-neuropathic pain patients. Seventeen descriptors of the 61 QDSA descriptors have a significant intergroup frequency difference. By principal component analysis and Varimax rotation of the intercorrelation matrix of descriptors in the neuropathic group. 7 factors accounting for 66.0% of the total variance are derived. Six factors reflect purely sensory or affective aspects of the pain experience. Seven descriptors from the discriminant analysis function correctly assign 77% of neuropathic pain patients and 81% of the non-neuropathic pain patients. In a second neuropathic pain group of 32 patients. the discriminant function coefficient permits correct diagnostic categorization in 66% of the cases. Implications for clinical practice and trials are discussed.
Psychosocial correlates of temporomandibular joint pain and dysfunction, This study examines psychological differences between temporomandibular joint pain and dysfunction (TMJPD) patients. pain controls. and healthy controls. Two hundred and two patients were classified. according to the diagnostic criteria of Eversole and Machado. as either myogenic facial pain (n = 42). internal derangement type I (n = 69). internal derangement type II (n = 85). or internal derangement type III (n = 6). Patients completed the Basic Personality Inventory. the Illness Behavior Questionnaire. the Multidimensional Health Locus of Control. the Perceived Stress Scale. and the Ways of Coping Checklist. Subjects also answered question pertaining to TMJPD symptomatology. including chronicity and severity. After conservative treatment with simple jaw exercise and ultrasound. patients were contacted again at 5 months to complete follow-up questionnaires similar to those previously completed. Comparison groups were comprised of 79 patients attending outpatient physiotherapy clinics for pain-related injuries not involving the temporomandibular joint and 71 pain-free. healthy students. Data were analyzed using multivariate statistics. The results indicate a significant relationship between pain intensity (and to some extent chronicity) and diverse measures of personality among the pain controls but not among the TMJPD patients. This calls into question the validity of assuming individual pain disorders are subsets of a larger. homogenous pain disorder population. TMJPD patients and pain controls score higher on hypochondriasis and anxiety than the pain-free controls but these elevations are not clinically significant. The elevations decrease to normal levels in response to a positive treatment outcome. There were no differences between the TMJPD patients and the pain controls on any of the measures. These results suggests that TMJPD patients do not appear to be significantly different from other pain patients or healthy controls in personality type. response to illness. attitudes towards health care. or ways of coping with stress.
Transsynaptic degeneration in the superficial dorsal horn after sciatic nerve injury: effects of a chronic constriction injury, transection, and strychnine, The lumbar and cervical spinal dorsal horns of adult rats with a chronic (8 days) constriction injury of the sciatic nerve on one side (and a sham operation on the other) were examined for signs of transsynaptic degeneration. The incidence of neurons with signs of degeneration (pyknosis and hyperchromatosis; 'dark neurons') was significantly increased in the lumbar dorsal horn on both sides. The ipsilateral lumbar increase was significantly greater than the contralateral increase. There was no increase in the incidence of dark neurons in the cervical dorsal horns of the same rats. The distribution of lumbar dark neurons was similar bilaterally. The majority of the dark neurons were found in the sciatic nerve's territory in laminae I-II. A second group of rats received the same surgery but in addition received a series of 7 daily subconvulsive doses of strychnine. Dark neurons were again found bilaterally (with ipsilateral predominance) in the sciatic nerve's territory in lumbar laminae I-II. but the incidence was significantly greater than that found in the group that did not receive strychnine. The same result was obtained in a third group of strychnine-treated rats when the sham operation was omitted. Thus the appearance of contralateral dark neurons is not dependent on unintentional nerve damage created by the sham procedure. An additional group of rats was sacrificed 8 days after receiving a unilateral sciatic nerve transection. a contralateral sham operation. and the 7 daily strychnine injections. There was no increase in the incidence of dark neurons in any of these rats.
Quantitative evaluation of hypnotically suggested hyperaesthesia and analgesia by painful laser stimulation, The ability to reduce both clinically and experimentally induced pain by hypnotic suggestion of analgesia is well known. However. the nature of hypnotic analgesia still remains uncertain. Attempts to demonstrate and identify specific psychophysiological mechanisms have. so far. been unsatisfactory. Methodological problems in inducing pain and monitoring physiological responses may be the reason for this lack of success. In the present study. we have attempted to eliminate some of these methodological problems. The sensory and pain thresholds to laser stimulation were determined. and the laser-evoked brain potentials were measured for 8 highly hypnotically susceptible subjects in 3 conditions: (1) waking state. (2) suggestion of hyperaesthesia. (3) suggestion of analgesia. The thresholds were reduced during induced hyperaesthesia and increased during analgesia. During hyperaesthesia sensations could be evoked by laser intensities which were below intensities that could be perceived in the awake state. The amplitude of the evoked brain potentials increased during hyperaesthesia and decreased during analgesia. The latency of the potential remained constant. The perception of pain during hypnosis can change very fast. indicating that slow endogenous mechanisms may play only a minor role in suggested hyperaesthesia/analgesia.
Filler DNA is associated with spontaneous deletions in maize, We have determined the structure of five spontaneous deletions within the maize waxy (Wx) gene. Of these. four were found in spontaneous wx mutants (wx-B. wx-B1. wx-B6. wx-C4) and include exon sequences; the fifth is restricted to an intron and represents a restriction fragment length polymorphism of a nonmutant allele (Wx-W23). The deletions. which range in size from 60 to 980 base pairs (bp). cluster in a G+C-rich region of approximately 1000 bp that is capable of forming stable secondary structures. Most striking is our finding that all of the alleles have DNA insertions (filler DNA) of 1-131 bp between the deletion endpoints. For three of the five deletions. the filler DNA and sequences at the deletion termini appear to be derived from sequences near one deletion endpoint. A previously reported spontaneous deletion of the maize bronze gene (bz-R) also contains filler DNA. The association of filler DNA with maize deletion endpoints contrasts dramatically with the rarity of similar events in animal germ-line and bacterial mutations.
Selective induction of toxicity to human cells expressing human immunodeficiency virus type 1 Tat by a conditionally cytotoxic adenovirus vector, The human immunodeficiency viruses (HIVs) primarily infect CD4+ T lymphocytes. leading eventually to the development of a systemic immune dysfunction termed acquired immunodeficiency syndrome (AIDS). An attractive strategy to combat HIV-mediated pathogenesis would be to eliminate the initial pool of infected cells and thus prevent disease progression. We have engineered a replication-defective. conditionally cytotoxic adenovirus vector. Ad-tk. whose action is dependent on the targeted expression of the herpes simplex virus type 1 thymidine kinase gene (tk). cloned downstream of the HIV-1 long terminal repeat. in human cells expressing the HIV-1 transcriptional activator Tat. Infection of Tat-expressing human HeLa or Jurkat cells with Ad-tk resulted in high-level tk expression. which was not deleterious to the viability of these cells. However. in the presence of the antiherpetic nucleoside analog ganciclovir. Ad-tk infection resulted in a massive reduction in the viability of these Tat-expressing cell lines. As adenoviruses are natural passengers of the human lymphoid system. our results suggest adenovirus vector-based strategies for the targeted expression. under the control of cis-responsive HIV regulatory elements. of cytotoxic agents in HIV-infected cells for the therapy of HIV-mediated pathogenesis.
Purification and characterization of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients, Serum ultrafiltrates (SUF) from human patients with different types of cancer contain a blocking factor (BF) that inhibits the cytolytic activity of human tumor necrosis factor alpha (TNF-alpha) in vitro. BF is a protein with a molecular mass of 28 kDa on reducing sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS/PAGE). The active material was purified to homogeneity by a combination of affinity chromatography. PAGE. and high-pressure liquid chromatography. Amino acid sequence analysis revealed that BF is derived from the membrane TNF receptor. Purified BF blocks the lytic activity of recombinant human and mouse TNF-alpha and recombinant human lymphotoxin on murine L929 cells in vitro. However. BF inhibits the lytic activity of TNF-alpha more effectively than it does that of lymphotoxin. The BF also inhibits the necrotizing activity of recombinant human TNF-alpha when coinjected into established cutaneous Meth A tumors in BALB/c mice. The BF may have an important role in (i) the regulation and control of TNF-alpha and lymphotoxin activity in cancer patients. (ii) interaction between the tumor and the host antitumor mechanisms. and (iii) use of systemically administered TNF-alpha in clinical trials with human cancer patients.
Isolation of human T-cell lymphotropic virus type 2 from Guaymi Indians in Panama, Human T-lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia/lymphoma and with a chronic degenerative myelopathy. However. another major type of HTLV. HTLV-II. has been isolated only sporadically. and little is known of disease associations. transmission routes. and risk factors for HTLV-II infection. Recent studies indicate that a high percentage of certain groups of i.v. drug users and blood donors are infected with HTLV-II. Seroepidemiologic studies have found an elevated rate of seroreactivity to HTLV among Guaymi Indians from Bocas del Toro Province. Panama. To identify the cause of seroreactivity among this unique population we used HTLV-II-specific polymerase chain reaction techniques to detect HTLV genetic sequences from blood leukocytes of three seropositive Guaymi Indians. The HTLV-II primer-amplified polymerase chain reaction products from two of these subjects were partially sequenced and matched published HTLV-II nucleotide sequences in both p24 gag (94% of 107 bases) and pol (98% of 112 bases) regions. A CD4+ T-lymphocyte line established from one of these same subjects produced HTLV-II-specific proteins when tested in antigen-capture and immunoblot assays. as well as mature HTLV particles. The demonstration of HTLV-II infection in this geographically and culturally isolated Central American Indian population without typical risk factors for HTLV infection suggests that HTLV-II infection is endemic in this population and provides an important clue to potential natural reservoir for this virus.
Putative tyrosine kinases expressed in K-562 human leukemia cells, Tyrosine phosphorylation is important in the transmission of growth and differentiation signals; known tyrosine kinases include several oncoproteins and growth factor receptors. Interestingly. some differentiated cell types. such as erythrocytes and platelets contain high amounts of phosphotyrosine. We analyzed tyrosine kinases expressed in the K-562 chronic myelogenous leukemia cell line. which has a bipotential erythroid and megakaryoblastoid differentiation capacity. Analysis of 359 polymerase chain reaction-amplified cDNA clones led to the identification of 14 different tyrosine kinase-related sequences (JTK1-14). Two of the clones (JTK2 and JTK4) represent unusual members of the fibroblast growth factor receptor gene family. and the clones JTK5. JTK11. and JTK14 may also belong to the family of receptor tyrosine kinases but lack a close relationship to any known tyrosine kinase. Each of these different genes has its own characteristic expression pattern in K-562 cells and several other human tumor cell lines. In addition. the JTK11 and JTK14 mRNAs are induced during the megakaryoblastoid differentiation of K-562 cells. These tyrosine kinases may have a role in the differentiation of megakaryoblasts or in the physiology of platelets.
Acylation-stimulatory activity in hyperapobetalipoproteinemic fibroblasts: enhanced cholesterol esterification with another serum basic protein, BP II, Cultured fibroblasts from patients with familial hyperapobetalipoproteinemia (hyperapoB) were used to determine if a defect in lipid metabolism was present. Three basic proteins (BP I. BP II. and BP III) were isolated from normal human serum by preparative isoelectric focusing. preparative SDS/PAGE. and reversed-phase HPLC. The Mr and pI values of these proteins were 14.000 and 9.10 for BP I. 27.500 and 8.48 for BP II. and 55.000 and 8.73 for BP III. These proteins differed significantly in their content of arginine. cysteine. proline. histidine. serine. and methionine. BP I appears to be the same protein as acylation-stimulating protein. but BP II and BP III appeared different from acylation-stimulating protein and other lipid carrier proteins. BP I. BP II. and BP III stimulated the incorporation of [14C]oleate into lipid esters in normal fibroblasts. an effect that was time and concentration dependent. In hyperapoB cells. BP II markedly increased (up to 9-fold) the incorporation of [14C]oleate into cholesteryl ester compared with that in normal cells; in addition. there was a 50% decrease in the stimulation of triglyceride acylation and cholesterol esterification with BP I. No difference between normal and hyperapoB cells was observed with BP III. In summary. the identification of another serum basic protein. BP II. led to the elucidation of another cellular defect in hyperapoB fibroblasts. enhanced cholesterol esterification. which may be related to the precocious atherosclerosis and abnormal lipoprotein metabolism seen in hyperapoB.
Site and strand specificity of UVB mutagenesis in the SUP4-o gene of yeast [published erratum appears in Proc Natl Acad Sci U S A 1991 Mar 1;88(5):2035, DNA sequencing was used to characterize 208 mutations induced in the SUP4-o tRNA gene of the yeast Saccharomyces cerevisiae by UVB (285-320 nm) radiation. The results were compared to those for an analysis of 211 SUP4-o mutations induced by 254-nm UVC light. In each case. greater than 90% of the mutations were single base-pair changes but G.C----A.T transitions predominated and accounted for more of the mutations induced by UVB than UVC. Double substitutions. single base-pair deletions. and more complex events were also recovered. However. UVB induced 3-fold more tandem substitutions than UVC and nontandem double events were detected only after irradiation with UVC. Virtually all induced substitutions occurred at sites where the pyrimidine of the base pair was part of a dipyrimidine sequence. Although the site specificities were consistent with roles for cyclobutane dimers and pyrimidine-pyrimidone(6-4) lesions in mutation induction. preliminary photoreactivation data implicated cyclobutane dimers as the major form of premutational DNA damage for both agents. Intriguingly. there was a preference for both UVB- and UVC-induced mutations to occur at sites where the dipyrimidine was on the transcribed strand.
Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging, Diabetes and aging are commonly accompanied by arterio- and atherosclerosis. Infiltration of the arterial subendothelial intima by macrophages/monocytes is an important early event preceding the development of atheromatous lesions; these macrophages are known to produce mitogenic factors in early atherosclerotic lesions. It has been previously shown that. over time. vascular matrix accumulates proteins nonenzymatically modified by advanced glycosylation end products (AGEs). In view of the fact that macrophages/monocytes have AGE-specific receptors associated with the expression of several growth factors. we investigated the possibility that AGEs mediate initial monocyte-vessel wall interactions that occur before overt formation of vascular lesions. This study demonstrates that (i) in vitro- and in vivo-formed AGEs are chemotactic for human blood monocytes. (ii) sub-endothelial AGEs can selectively induce monocyte migration across an intact endothelial cell monolayer. and (iii) subsequent monocyte interaction with AGE-containing matrix results in the expression of platelet-derived growth factor. These results support the existing hypothesis that in vivo-forming glucose-derived protein adducts can act as signals for the normal turnover of senescent tissue protein by means of the AGE-specific receptor system. Time-dependent glucose-induced deposition of AGEs on matrix proteins may promote monocyte infiltration into the subendothelium. Subsequent AGE-triggered macrophage activation and consequent elaboration of proliferative factors may normally coordinate remodeling but may also lead to the diverse pathogenic changes typical of arterio- and atherosclerosis in diabetic or aging populations.
Immunological studies of the basis for the apathogenicity of simian immunodeficiency virus from African green monkeys, Potential reasons for the lack of pathogenicity of the simian immunodeficiency virus SIVagm in its natural host. the African green monkey (AGM. Cercopithecus aethiops). were investigated with respect to immunological mechanisms. The functional immune response of monkeys to infection was similar (though not identical) to that of humans to infection with human immunodeficiency virus type 1 (HIV-1). In the sera of infected animals. neutralizing antibodies were found to be low or absent. and in particular there was no neutralization of the various isolates by homologous sera. There was no detectable antibody/complement cytotoxicity. though AGM sera were able to initiate antibody-dependent cellular cytolysis of infected cells in the presence of healthy effector peripheral blood lymphocytes. As in the human/HIV system. macrophages from AGMs are readily infected by SIVagm. Two possibly important differences between the AGM/SIVagm system and the human/HIV system are (i) the low immune response of the AGMs to the core protein of SIVagm and (ii) the significantly lower inhibitory effect of SIVagm proteins on the proliferation of AGM lymphocytes.
Pathogenesis of gallstones, The many developments in nonoperative methods for the treatment of gallstone disease underscore the importance of understanding the pathogenesis of these stones. Elucidation of the factors responsible for nucleation of crystals and the mechanism by which it occurs would appear to be the challenge if we are to define the cascade of events that results in gallstone formation.
Gallstone dissolution, Many methods are available for gallstone dissolution. including oral bile salts; cholesterol solvents such as mono-octanoin or methyl tert-butyl either; and calcium or pigment solvents such as EDTA and polysorbate. Which of these approaches will be appropriate for an individual patient depends on the type of stones; whether they are in the gallbladder or the bile ducts; whether access to the biliary tree is available; the patient's age and general medical condition; and the availability of necessary expertise. In the US. both chenodeoxycholate and ursodeoxycholate are now available. Ursodeoxycholate is more expensive but appears to produce fewer side effects and may be more efficacious. These agents are most effective in thin women with small floating. radiolucent cholesterol stones in a functioning gallbladder. Only about half of the small subset of patients will experience partial or complete dissolution of stones within a year. Stone recurrence and the potential toxicity of long-term therapy are problems with this approach. Therefore. for most patients. cholecystectomy. either in the traditional fashion or using a laparoscopic approach (see article later in this issue by Gadacz et al). is the most cost-effective and perhaps the safest option. Intragallbladder instillation of methyl tert-butyl ether probably will be applicable only to a small subset of patients. and treatment is likely to be followed by a high recurrence rate. In patients with retained common duct cholesterol stones and access to the biliary tree. mono-octanoin therapy is advantageous in that it can be initiated as soon as cholangiography demonstrates no extravasation. In properly selected patients. a 90% success rate with this technique can be expected within 7 days.
Extracorporeal shock wave lithotripsy for biliary stones, Extracorporeal shock wave lithotripsy is a noninvasive technique for treatment of patients with gallbladder and bile duct stones. Selected patients with gallbladder stones can be treated on an outpatient basis without general anesthesia and may return to full activity within 1 or 2 days. Stone-free rates of 40% to 60% at 6 months have been achieved in most reported series with minimal morbidity. Bile duct stone lithotripsy has achieved stone clearance in 80% of patients in whom conventional methods were unsuccessful and therefore constitutes a valuable second-line treatment for these patients.
Nonoperative management of bile duct stones, The treatment of choice for most retained bile duct stones is by nonoperative means. If a T-tube is in place. percutaneous techniques via the T-tract are indicated. Percutaneous access via puncture of a Roux-en-Y loop is also practical. In the absence of a T-tube. retrograde endoscopic techniques should be used. Both techniques are very effective and safe. Stones in the intrahepatic and extrahepatic ducts also can be treated nonoperatively. Endoscopic sphincterotomy has a role in the treatment of selected patients with gallstone pancreatitis. acute cholangitis. and choledocholithiasis with in situ gallbladders. In difficult cases. endoscopic and percutaneous techniques are employed in combination.
Surgical management of bile duct stones, The biliary surgeon in the 1990s must be familiar with all of the available techniques for the treatment of bile duct stones. Experience and judgment are important in the successful management of the individual patient with intrahepatic or extrahepatic stones. Knowledge of the nonsurgical methods of stone removal is important in the decision-making process. However. the biliary surgeon must resist the temptation to do less than a thorough removal of all stones at the operation lest the patient be subjected to additional procedures. which carry their own risks of morbidity and death. The goal should be to clear the stones from the biliary system with the fewest procedures offering the lowest morbidity and mortality risks to the patient.
Postoperative bile duct strictures, Bile duct strictures are an uncommon but serious complication of primary operations on the gallbladder or biliary tree. Most strictures occur as a result of injury to the bile duct during cholecystectomy. In addition. strictures can occur at the site of previous biliary anastomoses for reconstruction of the biliary tree. Most patients with benign bile duct strictures present soon after their initial operation; however. in some cases. presentation is delayed for years. Cholangiography is essential for defining the anatomy of the biliary tree prior to management. In many cases. nonoperative biliary drainage is useful to treat sepsis and biliary fistulas. A number of alternatives exist for elective repair of bile duct strictures. Experience would suggest. however. that a choledochojejunostomy or hepaticojejunostomy performed through a Roux-en-Y limb of jejunum is the preferable management in most cases. Postoperative biliary stenting may be valuable in optimizing the results. Nonoperative management by percutaneous transhepatic or endoscopic balloon dilatation has been reported to be successful in a number of small series. Long-term results are limited. however. Comparative data suggest that surgical repair for benign postoperative strictures is associated with fewer long-term problems and with similar overall morbidity and costs.
Primary sclerosing cholangitis, Primary sclerosing cholangitis is a rare disease of unknown etiology. Sclerosis of the bile ducts may actually be the final result of multiple factors such as autoimmune. bacterial. congenital. drug. or viral injury. The most commonly associated diseases are ulcerative colitis and chronic pancreatitis. Except in the earliest stages of the disease. liver histologic findings are not specific. Most patients present with jaundice. pain. and pruritus. although an increasing number of asymptomatic patients with inflammatory bowel disease and abnormal liver function are being identified. Cholangiography is key to the diagnosis and is usually pathognomonic except in the unusual case where primary sclerosing cholangitis is confused with cholangiocarcinoma. Many forms of medical therapy have been tried. including antibiotics. azathioprine. cholestyramine. colchicine. cyclosporine. D-penicillamine. steroids. and ursodeoxycholic acid. To date. none of these medications has been proved to alter the course of this disease. Recent reports of ursodeoxycholic acid trials have been encouraging. but long-term results of ongoing randomized trials have yet to be published. In recent years. balloon dilatation of biliary strictures has been accomplished via endoscopic and percutaneous transhepatic approaches. However. in patients with primary sclerosing cholangitis. these nonoperative manipulations must be done repeatedly. may entail multiple general anesthetics. and are difficult to perform. We believe that a direct surgical approach to the biliary tree with long-term transhepatic stenting is indicated in selected patients with severe hilar or extrahepatic stricturing. persistent jaundice or recurrent cholangitis. and no evidence of cirrhosis. Hepatic transplantation should be reserved for patients with primary sclerosing cholangitis who have well-established cirrhosis and have not responded to other therapeutic measures.
Carcinoma of the gallbladder, Gallbladder cancer remains difficult to diagnose preoperatively. However. recent work suggests that ultrasound may be effective. Gallbladder cancer remains highly lethal despite aggressive therapy. Extension of the disease beyond the mucosa predicts a poor chance of long-term survival.
Cholangiocarcinoma, The diagnosis of cholangiocarcinoma can now be made with greater rapidity and accuracy. In the clinical setting of obstructive jaundice. a CT scan or sonogram may suggest cholangiocarcinoma if dilated intrahepatic ducts are seen with a nondilated extrahepatic biliary tree. The diagnosis is confirmed by cholangiography. and the tumor is staged by the combination of cholangiography and angiography. If the tumor extensively involves both lobes of the liver or involves the main portal vein or hepatic artery. the lesion is considered unresectable. These patients are best palliated nonoperatively. but they should still have an attempt at a tissue diagnosis. as various other lesions can masquerade as cholangiocarcinoma. In comparison. if the tumor is confined to or is distal to the hepatic duct bifurcation. extends into only one lobe of the liver. or involves only the right or the left portal vein or hepatic artery. the lesion may be resectable. and exploration is indicated. As many as half of all patients explored with curative intent will have a successful resection. Various surgical options are appropriate for patients undergoing tumor resection. depending on the site and extent of the lesion. Similarly. several surgical options are possible for palliation in patients with unresectable cholangiocarcinoma. The role of radiotherapy in the management of cholangiocarcinoma is uncertain. Our results. like those of many other retrospective analyses. suggest that radiotherapy prolongs survival after curative resection as well as after palliative stenting. However. further data from randomized studies are necessary to support or refute this impression. Further studies of adjuvant chemotherapy or hormonal therapy will also be necessary to improve patient survival.
Oral calcium load test: diagnostic and physiologic implications in hyperparathyroidism, An oral calcium load test (CLT) (1 gm Ca/50 kg) was administered to 11 control subjects and 35 patients with overt hyperparathyroidism to assess its efficacy in diagnosis of hyperparathyroidism. All participants were placed on a low-calcium diet 3 days before the CLT. Intact parathormone and ionized calcium (Cai) levels were measured 0. 1. 2. and 3 hours after CLT. Initial Cai and parathormone (mean +/- SE) were 1.22 +/- 0.01 mmol/L and 2.94 +/- 0.03 pmol/L in the control group compared with 1.43 +/- 0.02 mmol/L and 10.6 +/- 2.2 pmol/L in the group with hyperparathyroidism. Both groups had a similar percent increase in Cai values (control. 5.9% +/- 0.8%; hyperparathyroidism. 6.3% +/- 0.6% (p greater than 0.1). A decline in parathormone levels of 47.6% +/- 2.8% in patients with hyperparathyroidism was significantly less than the 75.3% +/- 5.3% decline observed in control subjects (p less than 0.025). Three hours after CLT. parathormone was suppressed in control subjects. whereas a rebound occurred in patients with hyperparathyroidism. Postoperative CLT demonstrated a higher mean percent Cai increase and percent parathormone decline (Cai. 8.9% +/- 1.1%; parathormone. 67.9% +/- 1.8%) compared with preoperative values (Cai. 6.0% +/- 1.0%; PTH. 49.6% +/- 4.3%) (p less than 0.025). and 3 hours after calcium intake. parathormone remained suppressed. similar to control subjects. After surgery. three patients had elevated parathormone and low normal Cai levels and parathormone response to a CLT confirmed the diagnosis of secondary hyperparathyroidism. In conclusion. a CLT (1) can confirm the diagnosis of hyperparathyroidism and successful parathyroidectomy. (2) distinguished postoperative secondary from persistent primary hyperparathyroidism. (3) demonstrated nonautonomy of abnormal parathyroid glands with a parathormone response to a calcium load characterized by an earlier nadir. decreased suppressibility. and more rapid recovery. and (4) produced dynamic changes that did not distinguish patients with hyperparathyroidism from control subjects or hyperplasia from adenoma.
Hyperparathyroidism and cellular mechanisms of gastric acid secretion, Patients with hyperparathyroidism appear to be a particular risk for peptic ulcer disease. To test the hypothesis that hypercalcemia or parathyroid hormone plays a role in promoting ulcer disease. we studied the effect of varying concentrations of extracellular calcium on acid secretion using in vitro isolated rabbit gastric glands. Acid secretion was assessed by the accumulation of carbon 14-labeled aminopyrine (14C-AP). Glands were incubated with varying calcium concentrations in the unstimulated state and with histamine or carbachol (10(-7) to 10(-4) mol/L) in 1 or 2 mmol/L calcium medium. The effect of parathyroid hormone was also examined under identical conditions. Compared to 1 mmol/L standard calcium medium. unstimulated 14C-AP accumulation was significantly inhibited (p less than 0.05) at both lower (0.33 mmol/L) and higher (2 and 2.5 mmol/L) calcium concentrations. Accumulation of 14C-AP in response to histamine stimulation was unaffected by alteration of extracellular calcium (p greater than 0.2). Carbachol-stimulated 14C-AP accumulation was significantly augmented (p less than 0.01) by an increase in calcium concentration from 1 to 2 mmol/L. The addition of parathyroid hormone (10(-7) to 10(-4) mmol/L) alone or in combination with carbachol or histamine (10(-6) mmol/L) incubation did not alter 14C-AP accumulation. These data suggest that elevations in extracellular calcium play an active role in the potentiation of cholinergic-mediated gastric gland acid secretion and may thereby play a role in hyperparathyroid-related ulcer disease.
Effects of tamoxifen and somatostatin analogue on growth of human medullary, follicular, and papillary thyroid carcinoma cell lines: tissue culture and nude mouse xenograft studies, The knowledge that (1) the normal thyroid contains somatostatin. (2) polypeptide growth factors influence thyroid cell function. and (3) thyroid cells contain steroid hormone receptors prompted us to add somatostatin analogue No. 201-995 (SMS) (5 ng/ml) and/or tamoxifen citrate (TAM) (5 mumol/L) to 7-day monolayer cultures (50.000 cells/well) of three separate human thyroid carcinoma cell lines: DR081 (medullary). WR082 (follicular). and NPA'87 (papillary). Results. tabulated as cell numbers/well (X10(5) on day 7. revealed that TAM inhibited growth of medullary and follicular cells and that TAM plus SMS inhibited growth of papillary cells. In vivo studies of subcutaneous tumor cell xenografts in nude mice have documented that TAM (5 mg subcutaneous pellet) significantly inhibits the growth of medullary implants. Flow cytometric DNA studies of medullary cell cultures demonstrated a reduced G2 + M phase with TAM treatment. For papillary cell implants. TAM plus SMS (5 micrograms subcutaneously. twice daily) did not suppress tumor growth. All three cell lines were negative for estrogen receptor; addition of estradiol (5 ng/ml) to medullary cell cultures neither stimulated replication nor reversed the inhibitory effects of TAM in vitro. We conclude that (1) TAM slowed the growth of a cell line of human medullary carcinoma. both in vitro and in vivo; (2) this effect was not reversed by estradiol; (3) TAM plus SMS inhibited replication of a papillary carcinoma cell line in vitro. but not in vivo; and (4) TAM alone and TAM plus SMS inhibited replication of cultures of a human follicular thyroid carcinoma cell line. TAM and SMS may be useful in treatment of some human thyroid carcinomas.
Time to recovery of the hypothalamic-pituitary-adrenal axis after curative resection of adrenal tumors in patients with Cushing's syndrome, The recovery time of the hypothalamic-pituitary-adrenal (HPA) axis after curative resection of adrenal tumors in patients with Cushing's syndrome is poorly documented. Eight consecutive patients were treated with a standardized hydrocortisone replacement strategy after curative resection of a cortisol-secreting tumor and the time to recovery of the HPA axis was determined. Hypercortisolism was documented by elevated 24-hour urinary free cortisol levels. Cure was documented by undetectable postoperative morning serum cortisol levels. Each patient received replacement hydrocortisone after surgery and was reevaluated every 3 to 6 months with an adrenocorticotrophic hormone (ACTH) stimulation test. Each patient was also monitored carefully for symptoms and signs of adrenal insufficiency. which was defined as symptoms consistent with this diagnosis that responded to increases in hydrocortisone levels. After surgical resection. each patient was cured of hypercortisolism. Subsequently. despite replacement hydrocortisone. each patient had symptoms of hypocortisolism. and in four of eight patients the dose of hydrocortisone was increased to relieve the symptoms. Patients required a median time of 15 months (range. 9 to 22 months) to recover a normal ACTH stimulation test and 19 months (range. 12 to 24 months) to allow discontinuation of replacement doses of hydrocortisone. The results suggest that surgical resection of a cortisol-secreting adrenal tumor will result in rapid cure of hypercortisolism. but complete recovery of the HPA axis and discontinuation of replacement steroids will require between 1 and 2 years. Normal adrenal function. as assessed by the cortisol response to ACTH. returns despite replacement doses of hydrocortisone. and replacement doses of hydrocortisone can be tapered rapidly or discontinued after a normal ACTH stimulation test.
Calcitonin gene-related peptide levels are elevated in patients with sepsis, Calcitonin gene-related peptide (CGRP). an endogenous vasoactive peptide encoded by the calcitonin gene in nerve cells. is distributed throughout the cardiovascular system and is a potent vasodilator. Plasma levels of CGRP have been elevated in animal models with sepsis. This study was designed to determine whether plasma CGRP levels are elevated in patients with sepsis and perhaps contribute to the hyperdynamic cardiovascular state in sepsis. Plasma CGRP levels were obtained from normal healthy volunteers and from patients with sepsis. Volunteers were afebrile and had normal pulse and blood pressure. Patients with sepsis were selected according to the following criteria: (1) temperature higher than 38.5 degrees C. (2) white blood count greater than 14.000/ml. (3) positive blood culture of bacterial organisms. (4) hemodynamic parameters consistent with hyperdynamic sepsis. and (5) negative history of thyroid or other endocrine abnormalities. CGRP was extracted and assayed by radioimmunoassay for iodine 125-labeled human CGRP. In patients with sepsis. the cardiac index was 5.4 +/- 0.5 L/min/m2 (normal. 3.0); systemic vascular resistance was 7.1 +/- 0.5 mm Hg/L/min (normal. 16); oxygen delivery was 1496 +/- 137 ml/min (normal. 1000). Plasma CGRP levels were significantly elevated in the patients with sepsis. 14.9 +/- 3.2 pg/ml. compared to plasma CGRP levels in control volunteers. 2.0 +/- 0.3 pg/ml (p less than 0.0005). These elevated levels of CGRP may contribute to the decreased vascular resistance and increased cardiac output in the hyperdynamic septic state.
Posttranslational gastrin processing depends on tumor morphology, Extracellular matrices have recently been demonstrated to alter cell morphology in culture. Altered cell morphology has been associated with changes in gene transcription and translation. but it is not known whether it also affects posttranslational processing. Using tyrosine-O-sulfation as a marker of processing. we studied the effects of various substrates on biologically active gastrin (IRG) production and sulfation in gastrin-containing tumor cells (GT cells). Dispersed GT cells were plated onto different substrates and then incubated. Culture media from days 4. 7. and 28 were assayed with specific antibodies that recognize total IRG and nonsulfated IRG. Cells cultured on plastic and dried films of laminin. collagen. and Matrigel (Collaborative Research Inc.. Lexington. Mass.) flattened and formed monolayers of GT cells. Cells cultured on a porous membrane and hydrated gels of collagen and Matrigel did not flatten but formed spheroids of GT cells. The monolayer cultures showed an increase in sulfation with time but a decrease in IRG production. The spheroid cultures maintained a constant level of sulfation over time and. with the exception of Matrigel (gel). also showed a decrease in IRG production. These results indicate that the level of sulfation was unchanged from that of the original tumor when cells were grown in spheroids but increased when cultured as monolayers. It appears that alteration of the cellular milieu alters colony morphology. which in turn alters gastrin processing.
Extraadrenal retroperitoneal paragangliomas: natural history and response to treatment, Extraadrenal retroperitoneal paragangliomas (RP) are uncommon tumors. Because of their rarity. little is known of their natural history or response to treatment. We reviewed 22 patients with RP who were seen at our center between 1949 and 1990. The distribution of male and female patients was nearly equal. and the mean age was 42. Most patients were admitted with pain or a mass. and eight of 22 tumors were functional. No significant difference was noted in duration of symptoms. size of the tumor. or survival between functional and nonfunctional tumors. Eleven of 22 (50%) RP metastasized and were therefore classified as malignant. Five-year and 10-year disease free survival rates were 19% and 19% for tumors not resected and 75% and 45% for those completely resected. Once metastases occurred. the 5-year survival rate was 36%. but no patient survived beyond 76 months. Predictors of survival included complete resection of the tumor but not size or functional status. Although some patients who received chemotherapy or radiotherapy had clinical responses. a survival benefit could not be shown. RP have a high rate of malignant behavior and should be treated aggressively with operation. Late metastases are not uncommon. and prolonged follow-up is necessary. Once metastases have occurred. some patients may have prolonged survival.
The effect of somatostatin on 5-hydroxytryptamine release from a carcinoid tumor, One of the major manifestations of the carcinoid syndrome is secretory diarrhea thought to be due to overproduction of 5-hydroxytryptamine (5-HT). Synthetic somatostatin analogues have proved to be clinically effective in controlling this diarrhea. We have established a continuous cell line from a human pancreatic carcinoid tumor that secretes 5-HT. We examined the ability of the somatostatin analogue. SMS 201-995. to inhibit 5-HT release in vitro. Tumor cells were exposed to SMS 201-995 (10(-6) mol/L). pentagastrin (10(-9) mol/L). acetylcholine (10(-5) mol/L). and isoproterenol (10(-5) mol/L) alone and in combination; 5-HT release was assayed with high pressure liquid chromatography. We found that pentagastrin (6.43 +/- 0.64 ng/ml). isoproterenol (20.24 +/- 2.17 ng/ml). and acetylcholine (12.39 +/- 1.10 ng/ml) each stimulated release of 5-HT compared to control values (4.38 +/- 0.42 ng/ml). SMS 201-995 significantly reduced release of 5-HT in response to isoproterenol and acetylcholine but did not inhibit the effect of pentagastin. These data suggest that different agents do not act through the same pathway to stimulate 5-HT release from human pancreatic carcinoid cells.
Intraatrial extension of thyroid cancer: technique and results of a radical surgical approach, An occlusion of the superior vena cava by a tumor thrombus extending into the right atrium was diagnosed in three patients with a follicular thyroid cancer. All patients showed the typical clinical picture of the superior vena cava syndrome. A right parasternal thoracotomy was performed for preparation of the major vessels. The superior vena cava was opened and the entire intravascular tumor thrombus was removed. The cavotomy was closed directly in two patients. In the third patient the left brachiocephalic trunk was resected and reconstructed with a vascular (polytetrafluoroethylene) graft. This patient had bone and brain metastases and an occlusion of the graft 3 months after surgery after anticoagulation was stopped. The other two patients were clinically symptom free without local recurrence 13 and 50 months after surgery. An aggressive surgical approach is justified in grossly invasive thyroid cancer to decrease local recurrence and death rates. to correct the disturbing clinical symptoms of superior vena caval occlusion. and to prevent tumor embolism and the development of distant metastases. By reducing tumor mass. an even better basis for radioiodine treatment can be prepared.
Intraoperative decision making during thyroid surgery based on the results of preoperative needle biopsy and frozen section, Prognostic factors in well-differentiated thyroid cancer are age of the patient and grade. size. distant metastasis. and extracapsular spread of the disease. However. the surgeon is often not sure about the pathologic diagnosis of thyroid nodules. The accuracy of preoperative studies. such as ultrasonography and thyroid scanning. is limited. The most cost-effective test is fine-needle aspiration. the accuracy of which exceeds 80% in most series. However. a large group of nodules exist for which aspiration cytologic studies are considered to be either suspicious or indeterminate. The decision about the extent of thyroidectomy may be difficult in these patients. Intraoperative frozen section may help the surgeon to distinguish benign from malignant lesions. but as in fine-needle aspiration. the major problem is the distinction between follicular adenoma and follicular carcinoma. The frozen section diagnosis of follicular adenoma was changed to follicular carcinoma in one third of the cases (13 of 38 cases). The decision about the extent of thyroidectomy in patients with follicular adenomas was based on other prognostic factors. such as age and sex of the patient and the size of the nodule. The accuracy of frozen section diagnosis was 95%. Our experience suggests that decisions regarding the extent of thyroidectomy can best be made by preoperative fine-needle aspiration with confirmation by frozen section diagnosis in equivocal cases.
Prognostic significance of nondiploid DNA determined by flow cytometry in sporadic and familial medullary thyroid carcinoma, To clarify the role of DNA measurements in predicting outcome after surgical treatment of medullary thyroid carcinoma (MTC). we performed flow cytometric analysis in nuclear suspensions of 119 MTC tumors. Of the 119 patients. 63 (53%) patients had sporadic tumors and 56 (47%) patients had familial tumors; survivors were followed for a mean of 13 years. DNA content was normal in 92 (77%) patients and abnormal (nondiploid) in 27 (23%) patients. Ten-year cause-specific mortality rates were 12%. 42%. and 49% with diploid. tetraploid/polyploid. or aneuploid tumors (p = 0.0009) and were greater with nondiploid tumors both in the sporadic (p = 0.012) and multiple endocrine neoplasia (familial) cases (p = 0.114). None of 27 patients with TNM stage I disease died of MTC. In patients with TNM stages II. III. and IV disease. DNA nondiploid tumors were associated with increased deaths from MTC. In a Cox proportional hazards model involving all 119 patients and adjusted for disease stage and inheritance pattern. nondiploid DNA was independently associated with increased deaths from MTC (p = 0.008). In an identical Cox model restricted to the 92 DNA diploid tumors. an S-phase fraction of 15.0% or more remained a significant variable (p = 0.034) after adjustment for stage and inheritance pattern. We therefore conclude that DNA measurements do have a role to play in predicting outcome after surgical treatment of MTC.
Actin architecture of cultured human thyroid cancer cells: predictor of differentiation, The actin cytoskeleton is important for cell structure and motility. A disordered actin architecture has been correlated with a high metastatic potential in melanoma. fibrosarcoma. and colon cancer models. Thyrotropin is known to induce growth and differentiation in cultured thyroid cells. whereas the carcinogenic phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) causes dedifferentiation and malignant transformation in many cell lines. We therefore assessed the effect of thyrotropin and TPA on the actin architecture of FTC-133 human follicular thyroid cancer cells in continuous culture. Staining of filamentous actin with rhodamine phalloidin showed that 1 mU/ml or 30 mU/ml thyrotropin-induced actin polymerization was detectable at 1 hour but more notable at 24 hours. Similarly TPA (0.008 to 10 mumol/L) caused rapid actin fiber disruption and redistribution to the cell periphery. Secondary antibody staining for alpha-actinin. a protein that binds and crosslinks actin. was more prominent after treatment with thyrotropin but decreased after TPA. These findings indicate that the actin cytoskeleton has a dynamic response to trophic factors. Thyrotropin promoted actin polymerization. but TPA caused depolymerization. These effects may correlate with cellular alpha-actinin levels. Actin architecture may therefore reflect the state of differentiation of thyroid tumor cells.
Use of inhaled corticosteroids in patients with mild asthma, A double blind. parallel group study was carried out to investigate the effect of inhaled budesonide in a moderate (200 micrograms) and a low (100 micrograms) twice daily dosage compared with the effect of placebo in 103 adults with mild symptomatic asthma. Subjects recorded peak expiratory flow (PEF). asthma symptoms. and beta 2 agonist consumption at home for a period of seven weeks (a one week run in and six weeks' treatment). Morning baseline PEF (around 80% of predicted normal) increased non-significantly to 88% with 200 micrograms budesonide daily and to 90% (p less than 0.05) with 400 micrograms. compared with 81% with placebo. Evening PEF (around 94% of predicted normal) did not change significantly with active or placebo treatment. By comparison with placebo. there was a significant decrease in nocturnal asthma symptoms and beta 2 agonist consumption. The changes during the day were less pronounced and significant only for 400 micrograms budesonide daily. No significant differences between the two active treatments were detected. It is concluded that low doses of inhaled budesonide are effective in patients with mild symptomatic asthma. particularly for night time symptoms and early morning lung function. The early introduction of inhaled corticosteroids for patients with mild asthma and night time symptoms may improve their quality of life during the night and early morning.
Do large volume spacer devices reduce the systemic effects of high dose inhaled corticosteroids, When used in high doses. inhaled corticosteroids may cause suppression of the hypothalamo-pituitary-adrenal axis. The influence of the mode of drug inhalation on the degree of this suppression is not clear. Hypothalamo-pituitary-adrenal function was assessed by measurement of 0900 h serum cortisol concentrations. a short tetracosactrin test. and 24 hour urine free cortisol excretion in 48 adults with asthma taking 1500-2500 micrograms beclomethasone dipropionate daily via a metered dose aerosol. Twelve patients had hypothalamo-pituitary-adrenal suppression. as judged by subnormal results from at least two of the three tests or (in one patient) by an abnormal insulin stress test response. These patients then changed to inhaling the same dose of beclomethasone dipropionate through a 750 ml spacer device (Volumatic). The endocrine tests were repeated from nine days to eight weeks later in 10 patients. Comparison with initial values showed that adding the spacing device caused an increase in the median 0900 h cortisol concentration from 126 nmol/l to 398 nmol/l. in the post-tetracosactrin cortisol concentration from 402 nmol/l to 613 nmol/l and in 24 hour urine free cortisol excretion from 54 nmol to 84 nmol. The rise in serum cortisol concentration in response to tetracosactrin did not change. Evidence of persisting hypothalamo-pituitary-adrenal axis suppression was present in only four of the 10 patients; the most pronounced improvements in function tended to occur in those who had never required long term oral corticosteroids. The results from this uncontrolled study suggest that asthmatic patients taking high dose beclomethasone dipropionate may minimise adverse effects by using a large volume spacer device.
Respiratory muscle function in cystic fibrosis, Maximal static expiratory and inspiratory mouth pressures (PEmax and PImax) and quadriceps femoris muscle strength were measured in 25 patients aged 16-28 years with cystic fibrosis (mean FEV1 46% predicted). Mean (SD) PEmax was 64% (18%) predicted (below 75% predicted in 16 of the 25 patients). and PImax was 64% (24%) predicted (below 75% predicted in 14 patients). Quadriceps muscle strength was 68% (20%) predicted (below 75% predicted in 17 patients). The relatively small reduction in respiratory muscle strength in these patients was unlikely to have contributed appreciably to their respiratory problems.
Intraluminal irradiation for the palliation of lung cancer with the high dose rate micro-Selectron, Fifty patients with inoperable. symptomatic endobronchial carcinoma were treated by a single exposure of intraluminal radiotherapy. A high dose rate afterloading system (the micro-Selectron-HDR) was used to minimise radiation exposure for staff. Haemoptysis was relieved in 24 of 28 patients. breathlessness in 21 of 33 patients. and cough in nine of 18 patients. Radiological collapse resolved in 11 of 24 patients. Treatment was given on an outpatient basis and was well tolerated. Intraluminal radiotherapy appears to offer an effective alternative to conventional fractionated external beam radiotherapy.
Posterior mediastinal teratoma with abdominal extension, Posterior mediastinal benign teratomas are uncommon neoplasms in infancy; nine cases have been reported so far. A one month old baby was found to have a benign posterior mediastinal teratoma infiltrating the lower oesophagus from the level of the carina through the oesophageal hiatus into the upper abdomen. Partial oesophagectomy provided a successful outcome.
Transrectal sonographic cystourethrography: studies in stress urinary incontinence, Transrectal ultrasonic sagittal transducer is an excellent modality to image the bladder and urethra in dynamic change. In female patients. we found it is also helpful for the diagnosis of urinary stress incontinence. The posterior urethrovesical (PUV) angle is measured with the transrectal sonoprobe under strain and non-strain conditions. We compared the results of sonographic cystourethrogram with the radiographic chain cystourethrogram. The sonographic cystourethrography is superior to the radiography. The former may estimate the PUV angle accurately and differentiate between the patients with and without stress urinary incontinence. Furthermore. we also use the transrectal sagittal probe intraoperatively to adjust the suspension force as well as PUV angle in patients who underwent vesical neck suspension for stress urinary incontinence (SUI).
Continence level following radical prostatectomy, The relationship of the urethral anastomosis and postoperative continence following radical prostatectomy is uncertain. The objective of this study was to determine radiographically the functional level of continence following radical prostatectomy relative to the site of the intraoperative urethral anastomosis. In 8 patients having a radical prostatectomy. an intraoperative hemoclip was placed at the site of the urethral anastomosis and the postoperative functional level of continence was determined using a standing lateral cystogram. The functional level of continence was 9 mm (SD = 3.0) distal to the site of the urethral anastomosis. The level in the urethra that continence occurs may be a function of the intrinsic continence parameters of each individual patient.
The overlooked, retained Double J stent, A series of 4 patients with long overlooked. retained ureteral stents is presented to illustrate the variable. unpredictable. and at times. hazardous course of such patients. These cases are cited to re-emphasize the need for careful documentation. observation. and follow-up of patients in whom stents are placed.
Development and prospective application of quantitative 2-day stress-rest Tc-99m methoxy isobutyl isonitrile SPECT for the diagnosis of coronary artery disease, The clinical diagnostic accuracy of 2-day stress/rest quantitative Technetium-99m (Tc-99m) methoxy-isobutyl-isonitrile (Tc-sestamibi) single photon emission computerized tomography (SPECT) was assessed in a validation population of 61 patients from two different sites using two different camera/computer systems. The study population was made up of 53 catheterized patients. 29 from Cedars-Sinai Medical Center (CSMC) and 24 from the University of Texas Southwestern Medical Center (UTSMC). and eight UTSMC patients with a less than 5% pre-test likelihood of coronary artery disease. Interpretation employed gender-specific normal limits developed in an additional 15 men and 8 women at CSMC with less than a 5% likelihood of significant coronary artery disease. The results from CSMC compared with those from UTSMC were not different from each other. The overall sensitivity for detection of patients with coronary artery disease (greater than or equal to 50% stenosis) was 94% (CSMC: 92%. UTSMC: 95%). Overall specificity in the five patients with normal coronary arteriograms was 80% (CSMC: 67%. UTSMC: 100%). The normalcy rate in patients with a low likelihood of coronary artery disease was 88%. Vessel sensitivity was 85% (CSMC: 84%. UTSMC: 85%). while vessel specificity was 71% (CSMC: 72%. UTSMC: 69%). There was also no significant difference in the sensitivities and specificities between male and female populations. In addition. the agreement with coronary angiography for assessment of disease extent (normal coronary arteriogram. single or multivessel disease) was 75% (kappa = 0.6 +/- 0.1). This study demonstrated that Tc-sestamibi SPECT by quantitative analysis is accurate for the detection and localization of coronary artery disease. Furthermore. the CSMC quantitative method was shown to provide similar diagnostic accuracy when applied to data acquired at a different site using a different camera/computer system.
The estimation of post-test probability of coronary disease following exercise testing using the sequential application of two Bayesian methods, Recent studies have revealed that Bayesian methods to estimate post-test probability following exercise testing differ in their sensitivity and specificity across the range of post-test probability. To take advantage of the relative strengths of each method. we combined two of these methods into a single method (DUAL BAYES) and compared it with the two original methods in 436 patients who underwent stress testing followed within 2 months by coronary arteriography. All patients had post-test probabilities determined using CADENZA (better sensitivity). Those CADENZA-derived probabilities greater than or equal to 50% were substituted with post-test probabilities determined by Diamond and Forrester's original TABULAR method (better specificity). Mean post-test probabilities were as follows: TABULAR 34. CADENZA 48. DUAL BAYES 37 (actual incidence 38%). Comparison of sensitivity and specificity at every fifth percentile of post-test probability revealed that the sensitivity of DUAL BAYES was better than that of TABULAR and equal to that of CADENZA at thresholds less than or equal to 10 and that the specificity was better than that of CADENZA and equal to that of TABULAR at thresholds greater than or equal to 60. Therefore using both methods as indicated above was better than using either method alone.
Clinical and electrophysiological characteristics of ventricular tachycardia in children with normal hearts, Characteristics of 18 patients with clinical ventricular tachycardia (VT) and normal hearts documented by physical examination. echocardiography. and angiocardiography were analyzed. There were 13 males and 5 females. aged 1 to 16 years (mean +/- SD. 9.7 +/- 4.8 years). Six patients had hemodynamic instability during VT and the other 12 patients were hemodynamically stable. Two patients (11%) presented with sustained VT and 16 (89%) with episodes of nonsustained VT at varying intervals (3 of 16 with repetitive monomorphic VT). Among 14 patients on whom exercise tests were performed. seven had exercise-induced VT. During electrophysiologic studies. VT was induced in 16 of 18 (89%) (in 13 patients with morphology identical to clinical VT). VT was induced by programmed stimulation (single. double. and burst stimulation of the right atrium or right ventricular apex during sinus rhythm or during pacind for eight beats) in 5 of 18 (28%) patients; with isoproterenol. VT was aggravated spontaneously in 6 of 15 (40%) patients; and during stimulation VT was induced in 8 of 15 (53%) patients. Among patients whose VT was not induced during programmed stimulation. VT was induced with the addition of isoproterenol in 11 of 12 (92%). All 14 patients in follow-up are in stable condition. seven patients with medication and seven without medication. Pediatric patients with normal hearts and clinically detected VT usually have VT induced by programmed stimulation. either with or without isoproterenol stimulation.
The role of beta-blockade therapy for ventricular tachycardia induced with isoproterenol: a prospective analysis, Isoproterenol is sometimes required for ventricular tachycardia (VT) induction. However. the role of beta-blockade for treatment of such VT has not been critically assessed. The use of beta-blockade was evaluated prospectively in 14 consecutive patients who required isoproterenol 2.4 +/- 1.3 (+/- S.D.) micrograms/min to induce sustained monomorphic VT (greater than 30 seconds. or requiring termination due to hemodynamic collapse) after a negative baseline study. The VT mechanisms were enhanced automaticity (group A. six patients). triggered automaticity (group B. three patients). and reentry (group C. five patients). Groups A and B had serial intravenous electropharmacologic tests with propranolol alone (0.2 mg/kg). verapamil alone (0.15 mg/kg). and propranolol plus verapamil. and group C had serial tests with propranolol alone. procainamide or quinidine (class Ia drug) alone. and propranolol plus a class Ia drug until VT could no longer be induced. All six patients in group A responded to propranolol alone. In group B. one patient responded to verapamil alone. and two patients responded to propranolol plus verapamil. In group C. three patients responded to propranolol alone. one patient responded to a class Ia drug alone. and one patient responded to propranolol plus a class Ia drug. During a follow-up of 7 to 37 (17.9 +/- 10.7) (+/- S.D.) months. VT has not recurred in any patient. Three patients treated initially with propranolol alone have required substitution of amiodarone due to refractory congestive heart failure. In patients requiring isoproterenol for VT induction. beta-blockade alone appears to be effective in preventing reinduction of VT caused by enhanced automaticity. A heterogeneous response occurs when the VT mechanisms are triggered automaticity or reentry.
Double-peaking circadian variation in the occurrence of sustained supraventricular tachyarrhythmias, We studied 251 patients less than or equal to 65 years of age admitted for treatment of symptomatic supraventricular tachyarrhythmia to assess whether these arrhythmias begin evenly throughout the day or manifest circadian variation in occurrence. The arrhythmias included 152 episodes of atrial fibrillation. 50 episodes of supraventricular reentry tachycardia. 30 episodes of atrial flutter. and 19 cases of ectopic atrial tachycardia. A total of 209 patients could tell the exact time their symptoms had started. In 38 of them (18%). the arrhythmia had begun between midnight and 6:00 AM. in 63 (30%) between 6:01 AM and noon. in 46 (22%) between noon and 6:00 PM. and in 62 (30%) between 6:01 PM and midnight. This distribution differed significantly from uniform occurrence (chi square 8.7. p less than 0.05). Fifty patients were using beta-adrenoceptor blocking agents when the arrhythmia occurred. Compared with the other 159 patients. they had no morning surge of arrhythmias (20% versus 33.3% of episodes between 6:01 AM and noon). but instead a much higher incidence at night (34% versus 13.2% of episodes between midnight and 6:00 AM) (chi square 14.4. p less than 0.005). We conclude that the frequency of onset of sustained supraventricular tachyarrhythmias varies with the time of day. showing nearly equal peaks in the morning and in the evening and a trough at night. The modifying effect of beta-adrenoceptor blockage suggests that many morning arrhythmias are of adrenergic origin while other. probably vagal arrhythmogenic mechanisms. prevail at night.
Effects of xamoterol on inotropic and lusitropic properties of the human myocardium and on adenylate cyclase activity, The purpose of the present study was to characterize the effects of xamoterol in the human myocardium. In the presence of forskolin or milrinone. xamoterol increased isometric force of contraction. contraction velocity. and relaxation velocity in isolated. electrically driven preparations from human myocardium. but had no effect alone. There was no difference in the effect of xamoterol between right atrial myocardium and left ventricular myocardium from nonfailing (NF). moderately failing (NYHA II-III). and severely failing (NYHA IV) human hearts. The positive inotropic and lusitropic effects of isoprenaline were reduced depending on the severity of heart failure in left ventricular myocardium (i.e.. NF greater than NYHA II-III greater than NYHA IV). In the presence of norepinephrine. xamoterol produced negative inotropic effects similar to those of the beta-adrenoceptor antagonists pindolol and propranolol. Xamoterol alone had no effects on force of contraction. whereas pindolol and propranolol markedly reduced contractile force. In NYHA class IV. isoprenaline stimulated adenylate cyclase about twofold but xamoterol. like pindolol or propranolol. had no effect. Experiments with the beta 1- and beta 2-selective antagonists CGP 207.12A and ICI 118.551. respectively. showed that the positive inotropic and lusitropic effects of xamoterol were mediated by beta 1-adrenoceptors. Consistently. xamoterol had a selectivity of 13.8 at beta 1-adrenoceptors as measured in radioligand binding experiments. It is concluded that xamoterol acts as a beta 1-adrenoceptor antagonist with a selectivity of 13.8 in human ventricular myocardium. The compound has an intrinsic sympathomimetic activity. as it produces beta 1-adrenoceptor-mediated positive inotropic and lusitropic effects in the presence of forskolin. The beneficial effects of xamoterol in patients with heart failure could be due to prevention of the detrimental effects of norepinephrine such as beta 1-adrenoceptor downregulation of an increase of Gi (inhibitory guanine-nucleotide binding protein).
New calcium antagonists: relevance of vasoselectivity, The calcium antagonists are a heterogeneous class of drugs used to treat a number of cardiovascular disorders. A new generation of calcium antagonists under development have a higher degree of selectivity for vascular smooth muscle and coronary vasculature compared with verapamil. nifedipine. and diltiazem. The clinical relevance of vasoselectivity and its impact on drug selection are discussed. The newer calcium antagonists are important alternatives to older agents and may be associated with improved tolerance and a reduced incidence of adverse effects. Their place in therapy has yet to be defined by comparative studies of efficacy and safety.
Fascinating rhythm: a primer on chaos theory and its application to cardiology, Nonlinear dynamics is an exciting new way of looking at peculiarities that in the past have been ignored or explained away. We have attempted to give a general introduction to the basics of the mathematics. applications to cardiology. and a brief review of the new tools needed to use the concepts of nonlinear mathematics. The careful mathematical approach to problems in cardiac electrical dynamics and blood flow is opening a window on behaviors and mechanisms previously inaccessible.
Epidemiologic aspects of heart failure, The prevalence of heart failure in Northwest London is 0.4%. a lower figure than that quoted for the United States. Heart failure is a common reason (5%) for medical admission to the hospital in the London area. The problem of heart failure is predominantly in persons over 65 years. Coronary artery disease is the most frequent cause. and hypertension is relatively uncommon. In those patients admitted to the hospital. the prognosis is poor.
Can heart failure be prevented, delayed, or reversed, A review of the clinical course of chronic heart failure demonstrates that current outcomes remain highly unsatisfactory both in mortality and perhaps more important in morbidity. The extraordinary satisfactory functional responses seen in patients who undergo cardiac transplantation clearly identify the primary cause as the status of the heart itself. whatever the pathophysiologic adjustments of the neuroendocrine system. and interventions of the wide variety of drugs. Since donor hearts are unlikely to be available even from younger sufferers of these clinical syndromes. prevention must be the hallmark. Protection of the viability of myocytes. such as in acute myocarditis and acute infarction. is essential. Myocardial collagen undergoes continual synthesis. and production is greatly stimulated in the presence of hypertrophy caused by increased wall stress. It is possible that excess collagen is intimately involved with diastolic ventricular dysfunction. but that this may be a reversible process if the collagen-producing stimulus is removed. Thus reduction in wall stress and reversibility of ventricular hypertrophy appear to be promising directions. However. to limit the catastrophic effects of chronic heart failure. early recognition of the precursors of these syndromes. prevention of progression. and surgical intervention in valvular heart disease at an optimal point in time are essential.
Regional blood flow supply and demand in heart failure, Heart failure results not only in a fall in cardiac output but also in a redistribution of blood flow favoring some regional beds (the brain and the heart) at the expense of others (the kidney and working skeletal muscle). The chronic resting hypoperfusion of striated muscle is further compromised with exercise. Maladaptive vasoconstrictor control mechanisms prevent the redirection of blood flow from nonworking muscle and liver to working muscle. This inappropriate preservation of nonworking organ perfusion further compromises the functional capacity of working muscle and is associated with evidence for metabolic deconditioning with reduced oxygen extraction and impaired oxidative phosphorylation. It is becoming increasingly clear that the clinical response to the inotropic and vasodilator therapy used in heart failure is in part dependent on the differing regional blood flow profiles of the various agents studied. The ability of the angiotensin-converting enzyme inhibitors to redirect blood flow away from nonworking regional beds to exercising muscle. and thereby to reestablish an appropriate physiologic response to changing metabolic needs. may be the overriding reason for their long-term efficacy. Certainly in the future the comprehensive therapy of heart failure will have to take into consideration not only central hemodynamic but also regional blood flow/supply and demand issues.
Compensation and overcompensation in congestive heart failure, The compensatory mechanisms that develop in response to heart failure have been well defined. In this review. it is argued that each compensatory mechanism leads to overcompensation and that there is no way to distinguish between the beneficial aspects of the former and the harmful effects of the latter. Therapeutic agents that maintain rather than decrease blood pressure might perhaps be more beneficial because of the crucial role of hypotension in initiating both compensation and overcompensation.
Medical management of chronic heart failure: inotropic, vasodilator, or inodilator drugs, On the basis of pathophysiologic mechanisms. the medical therapy of today for chronic heart failure is reviewed. The advantages and disadvantages of the vasodilator drugs and the inotropic drugs are presented. Finally. the therapeutic value of the inodilator drugs. which combine the central myocardial effects of positive inotropic agents with those of peripheral vasodilators. is discussed. In particular. the orally available dopaminergic agents. such as ibopamine. which interact with beta-receptors in the heart (mediating a positive inotropic effect) as well as with dopaminergic receptors in the peripheral vessels (mediating a systemic vasodilator effect) and in the kidneys (potentiating the natriuretic effect of diuresis). seem to be an advancement in the modern medical therapy of chronic heart failure. Data are shown during long-term treatment with ibopamine. in which the sustained clinical benefit in heart failure was not diminished. despite a decrease of the adrenergic receptors in blood cells. Dopamine plasma concentration was permanently normalized during long-term treatment. The discrepancy between clinical improvement and the measured adrenergic downregulation may be due to the interference of the inodilator with neurohormonal systems at multiple sites and is probably independent of receptor activation. It is suggested that the biosynthesis of noradrenaline is improved by increasing intracellular dopamine transport.
Physiology and pharmacology of cardiovascular catecholamine receptors: implications for treatment of chronic heart failure, In the sympathetic nervous system the physiologic effects of the endogenous catecholamines noradrenaline (NA) and adrenaline (A) are mediated by alpha- and beta-adrenoreceptors (ARs). Both AR-types can be subdivided into two major subtypes: alpha-ARs into alpha-1 (predominant effect: vasoconstriction) and alpha-2 (presynaptic: inhibition of NA-release; postsynaptic: vasoconstriction). beta-ARs into beta-1 (cardiac effects. renal renin release. and lipolysis) and beta-2 (presynaptic: facilitation of NA-release; postsynaptic: vascular. bronchial. and uterine smooth muscle relaxation. glycogenolysis and possibly part of the A-mediated cardiac effects). During the last 30 years growing evidence has accumulated that dopamine (DA). the third endogenous catecholamine and the immediate precursor of NA. may also cause peripheral effects through stimulation of specific DA-receptors. in addition to its known action at alpha- and beta-ARs. It is now well accepted that at least two different DA-receptors are present in many peripheral tissues (DA1 and DA2). including those of the cardiovascular and autonomic nervous system. They seem to be involved in dilation of certain vascular beds. inhibition of NA-release during nerve stimulation. natriuresis. and aldosterone release. In chronic heart failure cardiac beta-AR function decreases (presumably due to endogenous "down-regulation" by the elevated catecholamines). and this decrease is related to the severity of heart failure (judged clinically by New York Heart Association functional class). The human heart contains both functional beta-1 and beta-2 ARs; cardiac beta-1 and beta-2 ARs seem to be differentially affected by different kinds of heart failure; in end-stage dilated cardiomyopathy beta-1 ARs are selectively reduced. whereas beta-2 ARs are nearly normal.
How to select a drug for the long-term treatment of chronic heart failure, First-line drugs for the treatment of chronic congestive heart failure should produce immediate symptomatic benefit. improve exercise tolerance. and thereby improve the quality of life. They should preferentially be active as monotherapy or at least reduce the need for comedication. The drugs must be safe and well tolerated by patients and change. in the end. the natural history of the disease. so that sudden death will be prevented and life expectancy improves. None of the currently available drugs satisfies all these criteria. Diuretics. digitalis. converting-enzyme inhibitors. and ibopamine come close to the described ideal.
The placebo effect in heart failure, Many patients who are enrolled in controlled clinical trials of new drugs for the treatment of heart failure show favorable hemodynamic and clinical responses to placebo therapy. This "placebo effect" results from both the creation of a supportive therapeutic environment and the spontaneous improvement that is commonly seen when measurements of symptoms and cardiac function are repeated frequently over long intervals of time. Three months of treatment with a placebo produces a reduction in symptoms in 25% to 35% of patients. an increase in cardiac output and a decrease in pulmonary wedge pressure. and an increase in exercise tolerance of up to 90 to 120 seconds. Physicians commonly seek to maximize the "placebo effect." since the goal of treatment in the clinical setting is to improve the quality of the patient's life. On the other hand. clinical investigators seek to minimize the "placebo effect." since the goal of a research study is to test the hypothesis that the new drug is superior to a placebo.
Efficacy of ibopamine in the treatment of heart failure, Loss of myocardial contractility. reflexly enhanced vasoconstriction. and neuroendocrine excitation are the pathophysiologic hallmarks of low-output heart failure. Drugs that counter both consequences afford considerable therapeutic potential in retarding and perhaps even in staying the consequences of the syndrome. Ibopamine possesses such potential through its unique ability to stimulate both dopaminergic- and beta-adrenoreceptors in the heart and circulatory system. Stimulation of dopaminergic- receptors and beta 2-adrenoreceptors results in vasodilatation in all regional vascular territories. beta 2-Adrenoreceptor agonist activity also affords mild positive inotropic activity in the heart. whereas stimulation of presynaptic dopaminergic- receptors (DA2) attenuates the increased sympathetic neural outflow. The drug also suppresses the renin-angiotensin-aldosterone system in addition to having a direct natriuretic activity. The pharmacodynamic effects of ibopamine. exerted through its metabolite epinine. are translated into measurable therapeutic benefits in patients with chronic heart failure. The increase in peripheral blood flow induced in all regional vascular territories. including the kidneys. is associated with increased cardiac output and stroke volume and reduction in left ventricular pressure work. wall stress. and myocardial oxygen consumption. Plasma norepinephrine. angiotensin. and aldosterone are also reduced. and renal sodium excretion is enhanced. These hemodynamic and neuroendocrine activities. which are not subject to tolerance during sustained administration of the drug. are accompanied by clinically significant improvement in symptoms. exercise tolerance. and the New York Heart Association classification of disability. More important. no proarrhythmic effects have been observed during sustained treatment. and the minimal side effects observed during long-term treatment enhance the safety profile of the drug.
Cardioprotective effects of amlodipine on ischemia and reperfusion in two experimental models, The cardioprotective effect of amlodipine. a long-acting dihydropyridine derivative. was studied in 2 experimental models of ischemia and reperfusion. Isolated and blood-perfused feline hearts were made globally ischemic for 60 minutes and then reperfused for 60 minutes. Alterations of left ventricular developed pressure and compliance were monitored in both amlodipine-treated hearts and saline-treated control animals. Changes in perfusion pressure indicated that amlodipine significantly reduced myocardial oxygen consumption and coronary vascular resistance. Furthermore. a progressive increase in resting left ventricular diastolic pressure indicated that amlodipine. administered before the onset of global ischemia. attenuated the development of ischemic contracture. Return of contractile function 60 minutes after reperfusion and maintenance of tissue concentrations of electrolytes were significantly better in the amlodipine-treated group than in the control animals. In intact canine hearts. regional myocardial ischemia was induced for 90 minutes. followed by 6 hours of reperfusion. Although the hemodynamic variables and the size of the region of risk did not differ significantly between treated animals and control animals. the infarct size was significantly smaller in the amlodipine-treated group than in the control animals. and a gradual reduction in coronary blood flow was observed in the control group that was prevented in the amlodipine group. A comparison of these findings with those observed with oxygen radical scavengers also is discussed. A detailed report of these studies was published in The American Journal of Cardiology (1989;64:101I-116I). This review is included here to maintain continuity of the symposium for the convenience of the reader.
Role of echocardiography in acute myocardial infarction, Interventional therapies such as thrombolytic agents. angioplasty and surgery have emerged as important options in the management of patients with myocardial infarction. These therapies are aimed at improving myocardial perfusion with the ultimate improvement or restoration of myocardial function. Two-dimensional echocardiography with digital storage and display is an ideal technique for temporally monitoring regional ventricular function and the effectiveness of interventional therapy. By design. 2-dimensional echocardiography is noninvasive and can be performed conveniently at the bedside. For these reasons. echocardiography is the principal imaging technique at Indiana University Hospital for patients with acute myocardial infarction. Computer retrieval of echocardiograms can be achieved in about 10 seconds at the nurses' station in the coronary care unit. With the availability of such an examination. the physician has a better understanding of the site. size and function of the infarct area. The state of the noninfarcted myocardium is also assessed and may be critical to the patient's prognosis. With the digital recordings. serial studies can be displayed side-by-side. making it easier for the physician to follow the natural history or to judge the effect of therapy. Echocardiography also is useful in identifying many complications that can occur with myocardial infarction. For these reasons. and because echocardiography will also show related cardiac problems. it is indispensable in the management of acute myocardial infarction.
Progress in cardioprotection: the role of calcium antagonists, Calcium antagonists are now widely used for the treatment of clinical hypertension and angina pectoris. They are efficacious for the treatment of vasospastic. fixed atherosclerotic and mixed angina; they reduce the incidence of silent ischemia; and they have been shown to reduce postmyocardial infarct angina. Experimental data suggest that they may have certain cardioprotective properties in cases of acute myocardial ischemia and infarction. stunned myocardium. diastolic dysfunction. left ventricular hypertrophy and atherosclerosis. Moreover. they have been shown to improve exercise performance. as well as the diastolic abnormalities in patients with hypertrophic cardiomyopathy. In animals. they may delay or reduce the extent of myocardial necrosis after coronary occlusion or coronary occlusion followed by reperfusion. and in low doses that do not alter the hemodynamic profile. they have been shown to enhance the return of ventricular function in animals with stunned myocardium. However. the early first-generation calcium antagonists (nifedipine. verapamil. diltiazem) have not been shown to reduce myocardial infarct size or to enhance survival in patients with acute myocardial infarction. There now are clinical studies that suggest that. unlike beta blockers or nitrates. nifedipine may slow the development of atherosclerotic progression in humans over a 2-year period. and it seems likely that in the 1990s there will be further expansion of the use of calcium antagonists for not only angina and hypertension but also for aspects of cardioprotection. That calcium antagonists may delay. prevent or possibly regress atherosclerotic lesions is an exciting possibility.
Bone mineral density in spontaneous hypertension: differential effects of dietary calcium and sodium, Dietary calcium and sodium have been postulated to modify both bone mineral status and blood pressure regulation in humans and animals. The spontaneously hypertensive rat (SHR) manifests several defects in calcium metabolism that may contribute to its hypertension. Blood pressure and bone mineral status were measured in SHR and normotensive Wistar-Kyoto rats (WKY) as a marker of whole animal calcium metabolism. In addition. the effect of alterations in dietary calcium and sodium on bone status were examined. At 6 weeks of age. seven male SHR and seven male WKY were placed on a control diet. At the same age. 28 SHR and 28 WKY were randomized to four diets containing either 2.0% or 0.1% calcium and 1.0% or 0.25% sodium. Four markers of bone mineral status were analyzed: bone density measured by direct photon absorptiometry. and total bone calcium. phosphorus. and magnesium content measured by atomic absorption spectrophotometry. The SHR exhibited significantly lower levels (p less than 0.001) of bone density and bone magnesium content than the WKY. whereas bone phosphorus and calcium did not differ between the two strains. The 2.0% calcium diets resulted in increased bone density and bone calcium content. and lower bone magnesium in both strains. The 1.0% sodium diets were associated with decreased bone density in the SHR. but not in the WKY. These findings identify another indicator of disturbed calcium metabolism in the SHR that may be related to impaired renal calcium handling. They are consistent with previously reported reductions in renal calcium reabsorption and decreased intestinal calcium transport in older SHR.
Possible triggering of paroxysmal atrial fibrillation in normal hearts by psychological stressors: a report of two cases, Paroxysmal atrial fibrillation was triggered by psychological stress in two patients. both of whom had normal echocardiograms and coronary angiography. Neither patient was alcoholic or had ingested ethanol in relation to the onset of atrial fibrillation and both were free of metabolic derangements. Possible mechanisms involved in the triggering of atrial fibrillation are discussed.
Southern blood club symposium: an update on selected aspects of hemochromatosis, Genetic epidemiology studies have indicated that hereditary hemochromatosis (HH) occurs in caucasians with a frequency of 3 to 13 per thousand. Clinical recognition however occurs far less frequently. The disparity is best resolved by defining HH as homozygosity for the HLA-linked hemochromatosis allele. regardless of the total body iron burden. Variability of clinical expression is explained in part by physiologic iron loss in women but variability in males may be due to environmental factors. gene-gene interactions or polymorphisms in mutated hemochromatosis alleles. Although clinical variability is great. the laboratory phenotype of HH is fairly constant and is marked by elevation of the transferrin saturation. The elevated transferrin saturation occurs early in life. before organ iron loading occurs and can be used as a screening tool to detect HH before organ damage occurs. Cloning and characterizing the HH gene. which is located within 1 centimorgan of the HLA-A locus should resolve some of the issues concerning clinical variability.
Immunohistologic study of epiretinal membranes in proliferative vitreoretinopathy, We performed an immunohistologic study on 11 specimens of epiretinal membranes surgically obtained from patients who had rhegmatogenous retinal detachment with proliferative vitreoretinopathy. Immunostaining procedures were used to identify immunoglobulin and complement deposits. to visualize class II antigen expression by proliferating cells. and to determine eventual infiltration by cells of the immune system. Diffuse deposits of IgG. IgA. IgE. C1q. C3c. and C3d were found in epiretinal membranes. whereas numerous cells. including glial or pigmented epithelial cells. expressed HLA-DR and HLA-DQ antigens. Some macrophages and B or T8 lymphocytes were identified. These results suggest activation of the immune system during the course of proliferative vitreoretinopathy. Class II antigen expression could be dependent upon growth-promoting factors and interferon gamma and could play a crucial role in this immune reaction. which resulted in immunoglobulin deposition and activation of complement. However. the eventual role of immune phenomena in the extension of proliferative processes remains to be determined.
Parental age in sporadic hereditary retinoblastoma, Of 104 children with sporadic hereditary retinoblastoma born between 1945 and 1970. we studied the age of their parents at the birth and compared this age with the mean age of parents at the birth of their children during the same period in The Netherlands. The mean age of fathers at the birth of their children with sporadic hereditary retinoblastoma (33.7 years) was significantly higher than the mean age of fathers at the birth of their children in the general population (32.5 years) (P less than .05. one sided). Similarly. the mean age of mothers at the birth of their children with sporadic hereditary retinoblastoma (31.2 years) was significantly higher than the mean age of mothers at the birth of their children in the general population (29.5 years) (P less than .05. one sided). We further analyzed this parental age factor by measuring the relative risk of age groups and comparing the incidence of sporadic hereditary retinoblastoma in the various parental age groups with the incidence of sporadic hereditary retinoblastoma in the total population. Mothers 35 years of age or older had a relative risk of 1.7 to have a child with sporadic hereditary retinoblastoma compared with mothers in the population in general (P = .006. one sided). Similarly. fathers 50 years of age or older had a relative risk of 5.0 to have a child with sporadic hereditary retinoblastoma compared with fathers in the population in general (P = .04. one sided). No parental age effect was found in children with nonhereditary retinoblastoma. We conclude that a high paternal and a high maternal age are significant risk factors for sporadic hereditary retinoblastoma.
Experimental endoretinal biopsy, We performed transvitreal endoretinal biopsy in rabbit eyes to develop a reliable and safe technique to obtain retinal specimens from attached retina. Pars plana vitrectomy without lensectomy was followed by injection of Ringer's solution into the subretinal space to produce a focal retinal detachment. The apex of the focal detachment was excised by intraocular scissors and removed from the eye by pneumohydraulic expulsion. A fluid-air exchange reattached the retina. The biopsy sites were evaluated clinically and by light and electron microscopy at regular intervals up to 20 weeks postoperatively. The initial five procedures were performed without heparin in the infusion fluid. and they were complicated by severe fibrin reaction and early retinal detachment. Of the remaining 17 eyes. 15 were without intraoperative complication and maintained attached retinas. The biopsy site developed an early ring of hyperpigmentation along the border. and the biopsy bed became increasingly hyperpigmented because of cytoplasmic hyperplasia and hypertrophy of the pigment epithelium. Epiretinal membranes and subretinal neovascularization were observed histologically. Retinal biopsy specimens were reproducible and suitable for diagnostic studies.
Topical use of cyclosporine in the treatment of vernal keratoconjunctivitis, We treated 11 patients with vernal keratoconjunctivitis for four to nine months with topical cyclosporine as a 2% dilution in castor oil. No significant side effects occurred. except for mild and transient burning upon administration. Within the first 15 days. both symptoms and signs of the condition improved significantly. and these results were maintained throughout the entire treatment. Relapses of the disease occurred two to four months after the end of the therapy. A double-masked clinical trial of nine patients (2% cyclosporine in castor oil vs castor oil alone) confirmed the results. Treated eyes improved significantly for both signs and symptoms as compared to control eyes. Topical cyclosporine may. therefore. be considered an effective substitute for corticosteroids. with an excellent anti-inflammatory activity in patients with both corticosteroid-dependent and corticosteroid-resistant vernal keratoconjunctivitis.
The corneoscleral limbus in human corneal epithelial wound healing, We studied re-epithelialization of the ocular surface in 17 human eyes (14 patients) with large corneal and conjunctival abrasions. We focused on the healing of the limbal region. During re-epithelialization. cell movement was found to occur circumferentially along the corneoscleral limbus and centripetally from the corneoscleral limbus. In no patient did the central corneal defect close before the corneoscleral limbus had first re-epithelialized completely. Normal limbal healing was observed to occur by circumferentially migrating tongue-shaped corneal limbal epithelium. These tongue-shaped projections developed from either side of the remaining intact epithelium and advanced along the corneoscleral limbus until they met. A centripetal movement of cells from the corneoscleral limbus then completed the healing process. In three patients. however. the advancing conjunctival epithelium extended across the corneoscleral limbus before the tongue-shaped projections of corneal limbal epithelium had met. The surface of the cornea covered by conjunctival epithelium was thin and irregular. and later showed peripheral scarring. vascularization. and recurrent erosions.
Ocular movements in essential blepharospasm, In essential blepharospasm histopathologic and electrophysiologic evidence supports the existence of lesions in proximity to brainstem nuclei controlling ocular movements. We studied horizontal ocular movements in eight patients who had been treated previously with surgery or botulinum toxin injection to control essential blepharospasm (mean age. 58 years) and compared these with seven control subjects who did not have blepharospasm (mean age. 68 years). We examined fixation stability. saccades. the vestibulo-ocular reflex. visual enhancement and suppression of the vestibulo-ocular reflex. optokinetic nystagmus. and pursuit by using digitally sampled. direct current electro-oculography. Patients with blepharospasm exhibited no ocular movement abnormalities. Since quantitative aspects of ocular movements are sensitive to nonspecific brainstem lesions. the absence of abnormal ocular movements suggests that the lesion in blepharospasm is specifically limited to neurons regulating the facial muscles.
Addition of clonidine enhances postoperative analgesia from epidural morphine: a double-blind study, This study was undertaken to evaluate the analgesic effect of the combination of epidural morphine and clonidine versus epidural morphine alone in patients with postoperative pain. A randomized double-blind design was used. and 91 patients scheduled for post-operative pain relief by epidural morphine were studied. Patients received either a continuous epidural infusion of morphine and clonidine (group 1; n = 45) or morphine alone (group 2; n = 46) over the 72 h after major abdominal surgery. In the first 24 h. the dose of morphine was 6 mg per 24 h; during the second 24 h. it was decreased to 4 mg per 24 h; and in the final 24 h. it was decreased to 2 mg per 24 h in both groups. Group 1 patients received clonidine (450 micrograms) during each 24-h period. Additional epidural bolus injections of 2 mg morphine and intravenous meperidine were given on demand. The pain score. blood pressure. heart rate. respiratory rate. and relative forced vital capacity were measured at fixed times during the first 72 h after operation. Total consumption of analgesics and side effects were recorded. Although the total consumption of analgesics was significantly higher in group 2 (P less than 0.05). pain scores were lower in group 1 than group 2 during the entire observation period (P less than 0.05). Epidural clonidine produced a significant decrease (P less than 0.05) in heart rate and blood pressure. whereas the respiratory rate was not affected. Due to the better pain relief in group 1. the forced vital capacity was increased (P less than 0.05).
Incidence of perioperative myocardial ischemia detected by different electrocardiographic systems, To determine the extent to which different electrocardiographic systems account for differences in reported incidence of perioperative myocardial ischemia. the authors simultaneously recorded in 109 patients undergoing coronary artery bypass grafting (CABG) the V5 or modified CM5 lead on five ECG systems by means of a specially constructed common V5 lead. The systems included a Spacelabs Alpha 14 Model Series 3200 ECG Cardule at bandwidths of 0.05-125 Hz and 0.5-30 Hz (a typical operating room monitor). a Marquette Electronics MAC II ECG at 0.05-40 Hz and 0.05-100 Hz (a standard ECG). and a Del Mar Holter recorder at 0.1-100 Hz. Relative ST-segment position and incidence of new ischemia compared to the preoperative ECG were determined in 109 sets of preinduction traces and 877 sets of intraoperative traces. ST-segment position on the three recording systems conforming with the American Heart Association (AHA) low-frequency response recommendations (0.05 Hz) were similar. Compared to the standard ECG. ST-segment position on the Spacelabs at 0.5-30 Hz was consistently more negative. Displacement on the Holter was consistently less negative and less positive. By the 0.1-mV displacement criterion for diagnosis of myocardial ischemia on any one ECG system. 16.5% of patients on arrival and 32.1% of patients intraoperatively suffered new myocardial ischemia. Based on the operating room monitor. arrival and intraoperative ischemia were present in 15.6 and 27.5% of patients. respectively. Ischemia at the same periods was less frequent by the standard ECG system (5.5 and 12.8%. respectively) and least frequent by the Holter recorder (4.6 and 8.3%. respectively).
Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization, Intraoperative administration of the proteinase inhibitor aprotinin causes reduction in blood loss and homologous blood requirement in patients undergoing cardiac surgery. To ascertain the blood-saving effect of aprotinin and to obtain further information about the mode of action. 40 patients undergoing primary myocardial revascularization were randomly assigned to receive either aprotinin or placebo treatment. Aprotinin was given as a bolus of 2 x 10(6) kallikrein inactivator units (KIU) before surgery followed by a continuous infusion of 5 x 10(5) KIU/h during surgery. Additionally. 2 x 10(6) KIU were added to the pump prime. Strict criteria were used to obtain a homogeneous patient selection. Total blood loss was reduced from 1.431 +/- 760 ml in the control group to 738 +/- 411 ml in the aprotinin group (P less than 0.05) and the homologous blood requirement from 838 +/- 963 ml to 163 +/- 308 ml (P less than 0.05). In the control group. 2.3 +/- 2.2 U of homologous blood or blood products were given. and in the aprotinin group. 0.63 +/- 0.96 U were given (P less than 0.05). Twenty-five percent of patients in the control group and 63% in the aprotinin group did not receive banked blood or homologous blood products. The activated clotting time as an indicator of inhibition of the contact phase of coagulation was significantly increased before heparinization in the aprotinin group (141 +/- 13 s vs. 122 +/- 25 s) and remained significantly increased until heparin was neutralized after cardiopulmonary bypass (CPB).
Tolerance and dependence in neonates sedated with fentanyl during extracorporeal membrane oxygenation, We undertook a retrospective chart review of 37 neonates who received fentanyl by continuous infusion while undergoing extracorporeal membrane oxygenation (ECMO) between May 1986 and October 1988. We quantified the doses of all sedatives utilized. determined the incidence of neonatal abstinence syndrome (NAS). and identified risk factors associated with NAS. We determined peak fentanyl infusion rate. mean fentanyl infusion rate. total fentanyl dose. and duration of ECMO therapy. NAS was observed in 21 of 37 neonates (57%). In both the NAS and non-NAS neonates. mean infusion rate increased steadily during ECMO therapy. from a mean of 11.6 +/- 6.9 (SD) micrograms.kg-1.h-1 on day 1 to a mean of 52.5 +/- 19.4 (SD) micrograms.kg-1.h-1 by day 8. Total fentanyl dose and duration of ECMO were significantly greater in neonates with NAS. We found that neonates with a total dose greater than 1.6 mg/kg or an ECMO duration greater than 5 days had a significantly greater incidence of NAS (chi-squared test. P less than 0.01 and P less than 0.005; odds ratios = 7.0 and 13.9. respectively). With multiple logistic regression. ECMO duration was found to be the most powerful predictor of the occurrence of NAS. We also measured plasma fentanyl concentrations in a separate group of 5 neonates receiving fentanyl by continuous infusion for sedation. Fentanyl concentrations increased steadily during the period of infusion. suggesting the development of tolerance to the sedating effects. We conclude that continuous administration of fentanyl for sedation is associated with the uniform development of tolerance and a significant incidence of dependence. Alternative approaches to sedation should be investigated.
Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy, The antinociceptive interaction on the tail flick (TF) and hot plate (HP) tests between opioid analgesics and medetomidine after intravenous (iv) or intrathecal administration were examined by isobolographic analysis. Male Sprague-Dawley rats received fixed ratios of medetomidine to morphine. fentanyl. and meperidine of 1:10 and 1:30. 10:1. and 1:3. respectively. by iv administration or 10:1. 3:1 and 10:1. and 1:3 by intrathecal administration. respectively. Data were expressed as the percentage maximal possible effect (%MPE). The A50 (dose producing 50% MPE) for each drug or drug combination was determined from the dose-response curve. Isobolographic analysis revealed that the effect of medetomidine combined with fentanyl. morphine. or meperidine was additive after iv administration. The intrathecal administration of combinations of medetomidine with the opioids produced a synergistic antinociceptive effect in the TF but not HP test. These data confirmed that the interaction between medetomidine and opioids in producing antinociception may be additive or synergistic. depending on the route of administration. drug ratio administered. and level of processing of the nociceptive input (i.e.. spinal vs. supraspinal). Moreover. these results were consistent with a spinal role for alpha-2 adrenoceptors in mediating antinociception. The authors suggest that the interaction between the opioid and alpha-2 adrenergic receptors occurs within the spinal cord.
Alterations in brain electrical activity may indicate the onset of malignant hyperthermia in swine, The time course of changes in brain electrical activity during halothane anesthesia was examined in 12 malignant hyperthermia-susceptible (MHS) and 14 normal (nMHS) swine. Power densities in selected frequency bands were calculated from the electroen-cephalogram (EEG). EEG and systemic variables were determined over a period of 60 min after starting halothane (1% inspired). Malignant hyperthermia (MH) was triggered in all susceptible pigs. Initial changes in the EEG during development of MH consisted of a decrease in total power and a shift to lower frequencies (delta-theta activity) in all animals. These EEG alterations were noted when there was an increase in heart rate. but other systemic variables were still normal. EEG changes in all MHS animals started at an arterial oxygen tension (PaO2) greater than 90 mmHg and an arterial carbon dioxide tension (PaCO2) less than 50 mmHg. In 5 MHS animals EEG became isoelectric at a PaO2 of 61-82 mmHg and a PaCO2 of 53-68 mmHg. Mean arterial blood pressure at this time was 54-66 mmHg. To determine the effects of hypoxia on the EEG in 7 nMHS animals. oxygen was decreased over a period of 45-60 min to 7% inspired. In 7 other nMHS animals. hypercarbia was produced by admixture of carbon dioxide to the fresh gas supply to achieve incremental increases of PaCO2 to 110-120 mmHg. Significant EEG changes during hypoxia comparable to those seen at the onset of MH were noted at a PaO2 below 40 mmHg and during hypercarbia at a PaCO2 greater than 68 mmHg.
Effect of halothane and isoflurane on postischemic "stunned" myocardium in the dog, Short periods of coronary artery occlusion are known to produce prolonged periods of ventricular dysfunction. The effects of halothane or isoflurane on contractility and metabolism in postischemic "stunned" myocardium were studied in an open-chest canine model in which the left anterior descending artery (LAD) was occluded for 15 min and then reperfused. Regional function in the LAD and circumflex artery (CIRC) areas were measured with sonomicrometry. and metabolic data were determined from simultaneous arterial and venous measurements of oxygen and lactate. Halothane and isoflurane produced equivalent decreases in systolic shortening in both normal (CIRC) and stunned (LAD) areas of the heart. Furthermore. the amount of depression was similar with either halothane or isoflurane. Halothane 0.75 MAC significantly decreased systolic shortening in both the LAD region (from 38.8 +/- 25.9% to 11.0 +/- 21.8%) and in the CIRC region (from 116.7 +/- 24.7% to 87.5 +/- 23.3%). At equivalent MAC concentrations of isoflurane. the values were 42.5 +/- 45.7 to -7.0 +/- 49.9% in the LAD region and 91.5 +/- 11.9% to 66.9 +/- 23.9% in the CIRC area. At 1.5-MAC halothane. systolic shortening in the LAD region decreased from 47.9 +/- 47.2% to -0.6 +/- 20.3% and in the CIRC area from 114.6 +/- 16.8% to 76.0 +/- 18.7%. Isoflurane at 1.5 MAC produced significant decreases. from 23.4 +/- 54.5% to -15.6 +/- 27.1% in the LAD region and from 94.4 +/- 33.2% to 61.3 +/- 28.2 in the CIRC area.
Pilot study of nicardipine for acute ischemic stroke, The author performed a pilot study of nicardipine (NC). a Ca(+)+ channel blocker. to study its dosing. toxicity. and possible efficacy for hemispheric cerebral infarction within 12 hours (mean 6.9 hr) of onset to determine the advisability of proceeding with a multi-centered controlled trial. NC was administered IV (3 to 7 mg/hr) X 72 hours by titrating dose to mean arterial blood pressure (MABP not less than 10% of baseline). then orally X 30 days. Forty-three patients have been entered; mean age 63 (range 34-89). 25 male and 18 female. Only 3 had CT evidence of infarct on entry. Results have shown improvement in a 100-point (pt) graded exam (40 pts at entry. 68 pts at 3 months). Of 20 patients completing 3 months' evaluation. 17 improved and none worsened. Sixteen out of 20 were at home and 8 had minimal or no impairment. Mean Barthel's index was 72. Mean maximal serum NC level was 75 ng/mL. MABP decreased from 103 (entry) to 83 (72 hours). A larger controlled study is warranted to determine the efficacy of NC for acute cerebral infarct.
Extraorbital use of a disinserted superior oblique as a sling in third nerve palsy: a new single-stage surgical technique, The management of third cranial nerve palsy is surgical. The usual technique is to correct alignment of the eyes in the first stage. followed by ptosis correction by a sling operation in the second stage. A new single-stage surgical technique involved the disinsertion of superior oblique muscle to bring the eye in a midline position. Simultaneously it is used extraorbitally as a sling to raise the ptotic upper eyelid. Postoperatively a fairly good cosmetic effect was achieved. but the upper eyelid showed a paradoxic aberrant elevation on eso-depression.
Monoscleral fixation for posterior chamber intraocular lenses in cases of posterior capsule rupture, A method for monoscleral fixation of posterior chamber intraocular lenses in posterior capsule rupture is described. Five lenses fixated with this technique are reviewed.
Contact transscleral laser cyclocoagulation in glaucoma, A new way to treat glaucoma by laser coagulation of the ciliary body was developed. The laser beam is channeled to the eye through the fiberoptic system. The tip of the fiberoptic probe is placed in direct contact with the surface of the eye to be treated. The technical equipment developed for contact transscleral laser cyclocoagulation is simple. practical. and easy to use. The method was investigated experimentally (on animals and on human eyes to be enucleated) and tried in clinical practice. Only patients facing glaucoma surgery (on whom all other methods of conservative therapy failed) were selected for this kind of treatment. The immediate hypotensive effect was approximately 13 mmHg during the first 24 hours; then there was a gradual elevation of the tension. reducing the initial effect on average by 30%. This method has definite advantages over surgical cyclocoagulation as far as safety and simplicity are concerned. The use of contact fiberoptic systems may open up new possibilities in other fields of laser treatment of glaucoma. including techniques to channel the laser beam to the structures of the anterior chamber angle.
X linked hypophosphataemia: treatment, height gain, and nephrocalcinosis, The clinical data of 18 patients with X linked hypophosphataemia were analysed retrospectively. The height data were expressed as SD scores. There was no difference in the final height of patients treated with vitamin D (or 1.25-dihydroxyvitamin D) and phosphate for at least two years (n = 12) and that of 16 hypophosphataemic family members who had never been treated. The mean final SD score (-2.07) of treated patients. however. was significantly higher than the value before treatment (-2.79). which indicated an average absolute height gain of 4-4.5 cm compared with the expected height values. Six of the treated patients developed ultrasonographically detectable nephrocalcinosis with normal renal function. The daily phosphate intake and excretion of patients with nephrocalcinosis was significantly higher than that of patients with normal renal morphology. There was no difference in the doses of vitamin D between the two groups. The average urinary calcium:creatinine ratio of the two groups was similar to and below the hypercalciuric 0.6 mmol:mmol limit. The group with nephrocalcinosis. however. had a higher incidence of hypercalciuric episodes than the group without nephrocalcinosis (12 in 130 observations compared with six in 334 observations. respectively). The benefits and risks of treatment of patients with X linked hypophosphataemia must be further evaluated. The high dose of phosphate seems to be an important factor in the development of nephrocalcinosis in this group of patients.
Reappraisal of thyroxine treatment in primary hypothyroidism, The optimum daily dose of thyroxine was calculated for 13 children aged 3-16 years with primary hypothyroidism by titrating their doses at monthly intervals. The condition of the thyroid was assessed by sensitive assay of thyroid stimulating hormone concentrations. as well as measurement of total and free thyroid hormone concentrations and systolic time interval ratios. Serum thyroid stimulating hormone concentration was found to be the most responsive to small changes in thyroxine. The calculated optimum daily replacement dose of thyroxine (102 micrograms/m2 or 3.5 micrograms/kg) was fractionally lower than that previously recommended. and was more closely related to surface area (coefficient of variation 8.2%) than to body weight (coefficient of variation 16.2%). Our results suggest that though monthly may be the optimal time interval for increases in the dose of thyroxine. any reduction in the dose should be made more gradually.
Survey of adolescents with severe intellectual handicap, A diagnostic survey was undertaken of children aged 11 to 19 years in Tameside with severe learning difficulties (intelligence quotient less than or equal to 50). Eighty-two children were identified and their medical records reviewed. A specific diagnosis for the retardation was documented in 25 (30%) of the children. 18 of whom had Down's syndrome. A probable aetiology or a disorder of unknown aetiology had been identified in a further 21 (26%) children. To confirm the existing diagnosis. identify new diagnoses. and offer genetic counselling. the parents of 63 children were offered detailed reassessment of their child. Fifty three children were reviewed. and a specific disorder identified in 25 out of 31 previously undiagnosed children. The most frequent diagnoses made were fragile X syndrome and Rett's syndrome. On completion of the survey. 61 of the 82 children (74%) had a specific diagnosis or probable aetiology identified. 12 (15%) had associated disorders such as cerebral palsy. and in only nine of the 82 children (11%) were there no clues at all to the cause of their retardation.
Normal small bowel biopsy followed by coeliac disease, We report four patients (two children. one adolescent. and one adult) having normal small bowel mucosa shown on a biopsy specimen taken before the initial diagnosis of coeliac disease was made. The first biopsy was undertaken in two cases because of suspected malabsorption. in the third because of suspected dermatitis herpetiformis. and in the fourth as part of a coeliac disease family study. After a further 2.6 to 9 years on a diet containing gluten. small bowel villous atrophy with crypt hyperplasia compatible with coeliac disease was found on a second biopsy specimen. The HLA type of the patients was that typical for coeliac disease; all were DR3 positive. Within the families three other patients with coeliac disease have been diagnosed. two earlier and one at the time the first biopsy was undertaken. Four other HLA-DR3 positive haploidentical first degree relatives were found and had biopsies. All four had normal small bowel villous architecture. one had an increased intraepithelial cell count. and another was positive for reticulin and endomysium antibodies. Coeliac disease may exist latent in patients having normal mucosa when eating a normal diet containing gluten.
5 alpha-reductase deficiency without hypospadias, A boy aged 4 with penoscrotal hypospadias and his brother aged 12 with micropenis had typical changes of homozygous 5 alpha-reductase deficiency. After three injections of chorionic gonadotrophin there was a trivial rise in plasma dihydrotestosterone with a normal increase in plasma testosterone. Urine steroid chromatography showed abnormally high 5 beta: 5 alpha ratios and 5 alpha-reductase activity was appreciably reduced in genital skin fibroblasts. The results indicate that 5 alpha-reductase deficiency is not invariably associated with genital ambiguity.
Corticosteroids in primary tuberculosis with bronchial obstruction, The usefulness of prednisolone in combination with the modern potent antituberculous drugs has been studied in 29 children with primary lung tuberculosis and hilar adenopathy causing bronchial obstruction. These children were divided at random in two groups of 15 and 14 patients. Both groups were treated similarly except that one group received prednisolone. Both groups were very similar before the onset of treatment for most variables. Tuberculous infection healed in both groups but the group on steroids improved earlier and had significantly fewer complications. both on radiography and bronchoscopy. Only two of the patients on steroids still had progressive lesions: a very young baby probably because he developed two severe viral infections consecutively. and another infant of 7 months whose treatment was unreliable. as the parents were not very compliant. Some patients initially not treated with prednisolone improved only after it was given. Prednisolone treatment is not recommended when the reliability of the treatment cannot be guaranteed. as the hazard of harm would exceed the expected benefit.
Ventilator dependency in the United Kingdom, There are 24 children who are currently long term ventilator dependent in the UK. Nine of these are cared for entirely at home. An additional 11 children have been long term ventilator dependent since March 1983. The prevalence of these children appears to be increasing. The financial and manpower resources needed for these children whether at home or in hospital is considerable. There are reasons to suppose that the apparent increase in prevalence will continue.
Effects of newborn screening of cystic fibrosis on reported maternal behaviour, Screening for cystic fibrosis is highly controversial. Concerns have been expressed that newborn screening may cause mothers. who had considered their child to be healthy before diagnosis. to overprotect their child. Some critics of screening also suggest that a period of delay from onset of symptoms to diagnosis may help a mother adjust to the reality of the child's lethal condition. This study compared the strength of overprotective child rearing attitudes of 29 mothers whose children were screened (13 had symptomatic children and 16 asymptomatic children) with the attitudes of 29 mothers whose children were diagnosed after the onset of symptoms. Results indicate that newborn screening had not increased a mother's tendency to overprotect her child with cystic fibrosis and in some cases the tendency had decreased. Further. delay in diagnosis when screening was not conducted usually caused mothers considerable personal distress.
Reproducibility of 24 hour oesophageal pH studies in infants, Thirteen infants who had undergone 24 hour oesophageal pH monitoring to diagnose gastro-oesophageal reflux had a second study carried out to see if the results were reproducible. The studies were done without restricting the babies' activities. Appreciable differences were found. the percentage of the total time during which the pH was less than 4 varying by up to 3.7-fold between the two tests. The differences were largely the result of biological rather than technical variability. From these results estimates were made of the reliability of a single diagnostic study and the size of changes that would be necessary to show the effect of treatment. These findings have a considerable impact on the diagnosis of abnormal gastro-oesophageal reflux and its response to treatment whether using 24 hour pH monitoring or any other method of measurement.
Recognising failure to thrive in early childhood, The maximum weight centile achieved by a child between 4 and 8 weeks of age was found to be a better predictor of the centile at 12 months than the birth weight centile. Children whose weight deviated two or more major centiles below this maximum weight centile for a month or more showed significant anthropometric differences during the second year of life from those who showed no such deviation. It is suggested that this leads to a logical and practical definition of failure to thrive.
Visceral leishmaniasis in a Scottish child, A Scottish girl acquired visceral leishmaniasis (kala-azar) while on holiday in Majorca. She presented with the infection. six months later. in Scotland. Because of inexperience with the disease and a degree of scepticism unnecessary investigations were carried out resulting in a delay in treatment.
Intravenous immunoglobulin in virus associated haemophagocytic syndrome, A 1 year old boy with virus associated haemophagocytic syndrome caused by cytomegalovirus infection is described. Persistent severe thrombocytopenia responded to repeated intravenous infusions of immunoglobulin.
Patient profiling: individualization of hypertension therapy, Although the stepped-care approach remains the cornerstone of antihypertensive therapy. the patient's profile must also be considered. Important issues include the patient's age. race and activity level. potential for hypertensive complications. presence of other diseases. cost of medications and probability of adherence to the recommended drug regimen. Nonpharmacologic treatment based on lifestyle changes is a useful adjunct to drug therapy. but it is not sufficient to control hypertension in most patients. Selection of pharmacologic therapy must be based on a knowledge of each drug's mode of action and side effects. as well as the characteristics of special patient populations.
Carotid body tumors, The surgical management of carotid body tumors requires identification and preservation of neural and vascular structures without compromising resection of the neoplasm. Fifteen patients were examined and treated for carotid body tumors at the Cleveland (Ohio) Clinic Foundation from 1979 through 1987. The benchmark of diagnosis is bilateral carotid angiography. When neural structures are free of tumor. meticulous dissection facilitates their preservation. Large tumor size increases risk for arterial resection necessitating reconstruction. The use of a vascular shunt minimizes the risk of cerebral ischemia. Postoperative intravenous digital subtraction angiography allows for evaluation of arterial repair. A retrospective review of 15 carotid body tumor resections performed in 14 patients revealed no evidence of tumor recurrence. no mortality associated with surgical intervention. no postoperative cerebrovascular accident. and limited morbidity associated with unavoidable sacrifice of neural elements.
Oncogene amplification in squamous cell carcinoma of the head and neck, Cellular oncogenes appear to be involved in the control of normal cell growth and differentiation. The abnormal activation of these genes in naturally occurring and experimentally induced cancers may have an important role in the expression of the malignant phenotype in cancer cells. Mechanisms for the activation of these genes include chromosomal translocation. point mutation. and DNA amplification. The amplification of specific oncogenes correlates with clinical prognosis in several human malignancies. including breast cancer and neuroblastoma. We examined 21 fresh-frozen human squamous cell carcinomas of the aerodigestive tract for amplification of 10 known cellular oncogenes (c-myc. N-myc. L-myc. N-ras. H-ras. K-ras. erb-B. erb-B2. raf. and int-2). using Southern blotting techniques. Eleven of 21 tumors demonstrated a two-fold to 11-fold amplification of the int-2 oncogene. one member of a family of genes related to basic fibroblast growth factor. Amplification of c-myc. a gene that codes for a DNA-binding protein involved in the regulation of cell growth. was seen in two tumors. None of the other eight genes studied were amplified in any of the tumor specimens.
Simultaneous 'dual system' rehabilitation in the treatment of facial paralysis, Simultaneous dual system rehabilitation of facial paralysis involves using two independent reanimation techniques to optimize facial movement in both a quantitative and qualitative manner. These techniques involve the use of nerve grafting or crossover procedures combined with a dynamic muscle transfer. A group of 37 patients who underwent five different combinations of reanimation was analyzed. The techniques were evaluated using a standard rating scheme for judging success of reanimation procedures. The combination of a masseter muscle transfer to the lower region of the face and a cable graft of the upper facial nerve division appeared to offer excellent results in terms of independent motion of the upper and lower regions of the face and good eye closure. while allowing spontaneous mimetic function in 50% of cases. The advantages and disadvantages of the other techniques are described. The clinical situations in which these techniques have advantage over single reanimation techniques are outlined.
The efficacy of oral steroids in the treatment of persistent otitis media with effusion, One hundred thirty-six children with otitis media with effusion of at least 2 months' duration were investigated in a strict. double-blind. randomized prospective study to evaluate the efficacy of oral steroids in the treatment of this disease. The results of our study showed a significant complete and partial recovery from otitis media with effusion in the group treated by a combination of antibiotics (amoxicillin) and oral steroids (prednisone). compared with an amoxicillin-treated group and a placebo-treated group. We believe that this treatment mostly benefits children aged 4 to 10 years without oversized adenoids. The findings of our study imply that a combined course of antibiotics and oral steroids deserves its place as a routine conservative trial before surgery.
Localized antigen challenge of the nasal mucosa, We describe a localized nasal antigen challenge and the measurement of mediators found at the same site. Eight ragweed-allergic subjects were challenged on 2 days. 1 week apart. Challenges consisted of six sequential provocations. beginning with two control challenges (diluent for antigen-phenol-buffered saline) followed by four increasing antigen doses (0.6. 6. 60. and 160 protein nitrogen units) (antigen day) or an additional four control challenges (control day). The number of sneezes and the symptom scores increased significantly with increasing antigen doses. The levels of histamine and N-alpha-tosyl-L-arginine methyl ester-esterase activity increased in the eluted secretions on the antigen day. but not on the control day. The amount of secretions collected also increased per unit of time on the antigen day. We found no significant increase in the concentration level of either histamine or N-alpha-tosyl-L-arginine methyl ester-esterase in nasal secretions on either day. We conclude that the total amount of histamine and N-alpha-tosyl-L-arginine methyl ester-esterase activity increased per unit of time while their concentration did not.
Intraoperative radiation of canine carotid artery, internal jugular vein, and vagus nerve. Therapeutic applications in the management of advanced head and neck cancers, As a step in the application of intraoperative radiotherapy (IORT) for treating advanced head and neck cancers. preliminary information was obtained on the radiation tolerance of the canine common carotid artery. internal jugular vein. and vagus nerve to a single. high-dose electron beam. Both sides of the neck of eight mongrel dogs were operated on to expose an 8-cm segment of common carotid artery. internal jugular vein. and vagus nerve. One side of the neck was irradiated. using escalating doses of 2500. 3500. 4500. and 5500 cGy. The contralateral side of the neck served as the unirradiated control. At 3 and 6 months after IORT. one dog at each dose level was killed. None of the dogs developed carotid bleeding at any time after IORT. Light microscopic investigations using hematoxylin-eosin staining on the common carotid artery and internal jugular vein showed no consistent changes that suggested radiation damage; however. the Masson trichrome stain and hydroxyproline concentration of irradiated common carotid artery indicated an increase in the collagen content of the tunica media. Marked changes in the irradiated vagus nerve were seen. indicating severe demyelination and loss of nerve fibers. which appeared to be radiation-dose dependent. Four patients with advanced recurrent head and neck cancer were treated with surgical resection and IORT without any acute or subacute complications. The role of IORT as a supplement to surgery. external beam irradiation. and chemotherapy in selected patients with advanced head and neck cancer needs further exploration.
Use of the levator scapulae muscle flap in head and neck reconstruction, There are numerous techniques available for reconstruction of defects following composite resection of oral cavity and oropharyngeal tumors. No single technique is applicable in all situations. The levator scapulae muscle flap is well known for its application in carotid protection. Little attention is paid to its usefulness in other aspects of head and neck reconstruction. We have been using the levator scapulae muscle flap for a variety of reconstructive problems. The flap is useful for buttressing intraoral suture lines. closing intraoral defects. and providing soft tissue to fill in dead spaces and bulk out lateral and anterior oral defects. The levator flap was found to be easy to elevate. safe. and reliable with a minimum of wound complications. A review of 18 patients. representative case studies. and a discussion of surgical technique and relevant anatomy and blood supply is presented.
Comparison of i.m. ketorolac trometamol and morphine sulphate for pain relief after cholecystectomy, I.m. ketorolac trometamol 30 mg was compared with morphine sulphate 10 mg after cholecystectomy in a double-blind. multiple dose. randomized study of 100 patients. Assessments of pain were made immediately after operation (day 1). and the next morning (day 2). Pain intensity (verbal response score and visual analogue scale) was recorded before injection and then over a 6-h period. Pain relief was assessed also. The effect of ketorolac on operative blood loss and platelet function was examined. Time to commencing oral intake and the duration of administration of i.v. fluids were recorded. Adverse events were noted. Ketorolac produced significantly less analgesia than morphine on day 1. but on day 2 the two drugs produced a similar effect. Blood loss was not increased by ketorolac. although platelet function was impaired. Repeated i.m. administration of ketorolac did not produce any serious adverse effects.
Preoperative piroxicam for postoperative analgesia in dental surgery, Fifty patients were allocated randomly to receive placebo or piroxicam 40 mg. 2.5 h before surgical removal of lower third molars under general anaesthesia. A significantly greater number of patients in the piroxicam group did not require opioid analgesia after operation (P less than 0.05). The piroxicam group also required fewer doses of paracetamol in the first 24 h after recovery from anaesthesia (P less than 0.05). and the time from recovery to first postoperative analgesia was longer in those patients who had received piroxicam (P less than 0.05). Piroxicam did not significantly prolong the duration of recovery from anaesthesia.
Effects of nimodipine on cerebral blood flow and neuropsychological outcome after cardiac surgery, Thirty-five patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) were allocated randomly in a prospective double-blind study to receive either nimodipine 0.5 micrograms kg-1 min-1 or placebo. Cerebral blood flow (CBF) was measured during and immediately after CPB. Neuropsychological tests were performed 6 months after surgery to determine any relationship between ischaemic damage and CBF and administration of nimodipine. There were no differences in CBF between the nimodipine (n = 18) and placebo groups (n = 17). Significant changes in neuropsychological tests were found in six patients tested 6 months after surgery but there were no conclusive signs of ischaemic damage. The nimodipine-treated group performed better in tests of verbal fluency and visual retention. suggesting that some memory functions were preserved better in this group.
Functional and metabolic effects of bupivacaine and lignocaine in the rat heart-lung preparation, We have examined the effects of bupivacaine and lignocaine on myocardial metabolism in the rat isolated heart-lung preparation. Bupivacaine 1. 5 or 25 micrograms ml-1 or lignocaine 4. 20 or 100 micrograms ml-1 was administered 5 min after the start of perfusion. Both bupivacaine 25 micrograms ml-1 and lignocaine 100 micrograms ml-1 reduced heart rate significantly. Bupivacaine 25 micrograms ml-1 was associated with a higher incidence of arrhythmias than the other groups. Three hearts in the bupivacaine 25 micrograms ml-1 group (n = 8) and two hearts in the lignocaine 100 micrograms ml-1 group (n = 8) failed (zero cardiac output) at the end of the experiment. Although there were no significant differences in myocardial lactate and glycogen concentrations between groups. ATP content in the bupivacaine 25 micrograms ml-1 and lignocaine 100 micrograms ml-1 groups was significantly less than that in the control group. The results suggest that myocardial depression and subsequent metabolic deterioration occurred with both the high doses of local anaesthetics; these findings do not account for the apparent increased cardiotoxicity of bupivacaine.
Effect of motion artefact on pulse oximeters: evaluation of four instruments and finger probes, The ability of the Ohmeda 3700. Nellcor N200. Datex Satlite Plus and Simed S100 pulse oximeters to detect induced hypoxaemia in the presence of motion artefact was assessed. under conditions of controlled vibration using an industrial vibration facility. Vibration at 4 Hz and 8 Hz induced increases in detection time for hypoxaemia and spurious decreases in the displayed SaO2 in some of the oximeters tested. Finger-dependent differences in oximeter performance and pulse rate registration were noted especially in those oximeters without ECG linkage (Ohmeda 3700 and Simed S100). Subsequently. eight different pulse oximeter finger probes were assessed for those characteristics that may predispose to motion artefact. There were marked differences in the mass of the probes. the forces exerted on the test finger and in the force required to displace the probes from the subject's finger. Differences in both the microprocessor programmes and the physical characteristics of the finger probes may explain the observed differences in function. Similar studies should form part of the standard evaluation of new pulse oximeters.
Effect of oral omeprazole on intragastric pH and volume in women undergoing elective caesarean section, We have studied in obstetric patients the efficacy of omeprazole in increasing intragastric pH to more than 2.5 and reducing volume to less than 25 ml. Omeprazole 40 mg was given orally the night before and again on the morning of surgery to 30 Asian women scheduled to undergo elective Caesarean section. After induction of anaesthesia. a gastric tube was inserted and intragastric contents aspirated. Volume and pH were recorded and measurements were repeated on completion of surgery. The median (range) volume was 2 (1-13) ml before surgery and 4 (0-14) ml at the end of surgery. There was insufficient volume to measure pH in all patients. The median (range) pH was 6.7 (4.6-7.4) before surgery in 20 patients and 6.6 (4.6-7.8) at the end of surgery in 28 patients. No adverse drug reactions were noted in mothers or neonates. Omeprazole 40 mg orally twice before elective Caesarean section appeared to be effective in reducing intragastric volume and acidity to acceptable values.
Diclofenac for day-care arthroscopy surgery: comparison with a standard opioid therapy, Sixty unpremedicated patients presenting for day-care arthroscopy surgery were allocated randomly to receive diclofenac 1 mg kg-1 i.m.. fentanyl 1 microgram kg-1 i.v. or no analgesic during the course of anaesthesia. Patients receiving fentanyl had slightly. although not significantly prolonged recovery times. Patients receiving diclofenac had significantly improved postoperative visual analogue pain scores compared with patients receiving placebo medication (P less than 0.05). With fentanyl. pain scores were reduced also. but the effect was not statistically significant. Both fentanyl and diclofenac produced significant reduction in postoperative analgesic requirements (P less than 0.05). We conclude that diclofenac 1 mg kg-1 i.m. was an effective analgesic for arthroscopic procedures on the knee and is a useful alternative to opioids for day-care patients.
Effect of indomethacin on pain relief after thoracotomy, The effect of indomethacin on postoperative pain was studied in 60 adult patients undergoing thoracotomy in a prospective. randomized. double-blind manner. Patients receiving indomethacin required significantly less opioid after operation and had significantly lower pain scores compared with the control group. Pain on movement and on coughing were reduced also. No major adverse effects were encountered.
Preanaesthetic medication with clonidine, The purpose of this study was to evaluate oral clonidine in a dose of 0.3 mg as a routine premedicant. Sixty-nine normotensive female patients were studied in a randomized double-blind investigation in which clonidine was compared with an inert treatment. Clonidine produced a significant reduction in anxiety (P less than 0.05) and sedation and a reduction in the sleep dose of methohexitone (P less than 0.05). Tachycardia in response to intubation was attenuated by clonidine (P less than 0.05). However. the magnitude of the increase in arterial pressure after intubation was not affected. Intraoperative and postoperative hypotension were common after premedication with clonidine 0.3 mg and caution is urged in its use as a premedicant.
Quantitative assessment of extradural bupivacaine analgesia, Bupivacaine (0.5%) 20 ml was administered extradurally to six healthy volunteers. It was found that simultaneous application of 10 needles to the skin could evoke pain when analgesia was obtained to one needle stimulation. In addition. a laser beam was used as a quantitative technique to activate simultaneously many cutaneous nociceptors. For 7 h. thresholds (sensory and pain) and pain-evoked brain potentials (amplitude and latency) to laser stimulation were monitored and used for quantitative assessment of onset. efficacy and duration of analgesia at various dermatomes (C7. T8. T10. T12. L1. L3. S1). The onset time of analgesia was shortest and conduction delay longest at the dermatome related to the site of injection (L3). Full analgesia was obtained at L1. L3 and S1. although the peak efficacy at S1 was delayed for 120-180 min after injection. A minor effect was found at dermatome C7 approximately 60 min after injection.
Onset phase of spinal bupivacaine analgesia assessed quantitatively by laser stimulation, Analgesia was assessed quantitatively at various dermatomes (C7. T8. T10. T12. L1. L3. S1) for the first 30 min after subarachnoid administration of 0.5% bupivacaine 3.5 ml. Stimulation with 10 needles and laser stimulation could evoke pain in dermatomes with adequate analgesia to single needle stimulation. Analgesia was assessed by thresholds (sensory and pain) and by pain-related brain potentials (amplitude and latency) to laser stimulation. Little analgesia was found at T10. but it increased gradually towards caudal segments. The dermatome related to the site of the injection (L3) was not blocked to a greater extent than the surrounding dermatomes. Conduction time (the latency of the evoked brain potential) was increased relatively more from the S1 dermatome compared with L1.
Effects of 2% lignocaine on somatosensory evoked potentials recorded in the extradural space, We have studied the effects of extradural administration of 2% lignocaine at the L3-4 interspace on somatosensory evoked potentials recorded in the cervical extradural space before corrective surgery for idiopathic adolescent scoliosis. Eight patients in whom the equivalent volume of 0.9% sodium chloride solution was administered into the lumbar extradural space acted as a control group. Lignocaine 2% resulted in a decrease in overall amplitude. but its main effect was a significant decrease in the amplitude of the second and third peaks. suggesting an action on the dorsal columns of the spinal cord. A significant increase in latency was found in both the lignocaine and sodium chloride groups. We conclude that the use of extradural 2% lignocaine in patients undergoing scoliosis surgery may interfere with the intraoperative monitoring of somatosensory evoked potentials.
Late postoperative episodic and constant hypoxaemia and associated ECG abnormalities, Twenty-two patients without cardiopulmonary disease and undergoing elective major abdominal surgery were monitored continuously with a Holter tape recorder and a pulse oximeter on one night before operation and the first two nights after operation (23:00 to 07:00). without oxygen therapy. Mean heart rate increased 16 beat min-1 (P less than 0.001) and mean oxygen saturation (SaO2) decreased 2.6% (P less than 0.001) after operation. Episodic oxygen desaturation to less than 80% occurred in four patients before operation. but in 13 patients after operation (P less than 0.05). ECG abnormalities were observed in 10 patients before operation and in 16 patients after operation (ns). Individual maximum ST depression was more pronounced after than before operation (P less than 0.05). Episodic desaturation was related closely to tachycardia in six patients before operation and one patient after operation; before operation to atrioventricular block in one patient. and after operation to ST depression in two patients. Mean SaO2 on the second night after operation correlated with total dose of opioid for pain relief (rs = -0.48; P less than 0.05). and postoperative decrease in SaO2 correlated with postoperative increase in heart rate (rs = -0.43; P less than 0.05). No patient had postoperative cardiac complications indicating treatment.
Nitrous oxide antagonizes CNS stimulation by laudanosine in mice, We have investigated whether nitrous oxide antagonizes or augments the CNS stimulant action of laudanosine in mice by comparing the mean convulsive doses (CD50 (SE] of a control group and those following pretreatment with 65% nitrous oxide in oxygen for 20 and 180 min. Nitrous oxide significantly increased CD50 from 46.8 (1.4) mg kg-1 of control to 57.3 (1.3) mg kg-1 at 20 min and 53.5 (1.7) mg kg-1 at 180 min. The attenuation of the effect of nitrous oxide at 180 min. suggestive of possible partial drug tolerance. was not statistically significant. These findings indicate that nitrous oxide antagonizes the CNS stimulating action of laudanosine.
Induction of ornithine decarboxylase following sellotape stripping in normal and psoriatic skin, Ornithine decarboxylase (ODC) was measured in the epidermis of healthy volunteers and the uninvolved skin of psoriatic patients at various times after sellotape stripping. Basal levels were less than 1 pmol/min/mg protein. Activity peaked to a maximum of 86 pmol/min/mg protein after 8 h; this was followed by an abrupt decline to a lower level which remained relatively constant for at least 36 h. No difference was seen between the response of controls and psoriatic patients. Pretreatment with topical corticosteroids reduced peak ODC levels to about one-half. but oral indomethacin had no effect.
Effect of long-term PUVA treatment of psoriasis on the collagen and elastin gene expression and growth of skin fibroblasts in vitro, The proliferation rate. collagen metabolism and collagen and elastin messenger-RNA levels were studied in fibroblasts derived from patients who had received many courses of either systemic 8-methoxypsoralen or topical trioxsalen PUVA treatment. The proliferation rate of fibroblasts as measured by the incorporation of 3H-thymidine or by cellular division was decreased in those obtained from patients who had PUVA treatment as compared with controls. Collagen synthesis was slightly increased in the cells from PUVA-treated patients. but the relative collagen synthesis and the ratio between types I and III collagen were unchanged. The levels of collagen and elastin mRNAs were increased in fibroblasts derived from the PUVA-treated patients. No significant differences in histology or immunochemistry could be found in the biopsies taken from topical and systemic PUVA-treated patients.
Enhanced percutaneous absorption of a novel topical cyclosporin A formulation and assessment of its immunosuppressive activity, No clinically successful topical cyclosporin A (CyA) formulation has been produced. mainly due to the apparent lack of drug penetration. This study has produced the first in vitro kinetic data on CyA penetration across human cadaver stratum corneum and has shown that addition of the penetration enhancers (PE) Azone and propylene glycol to the CyA vehicle significantly enhanced drug permeation across the skin barrier. Using flow-through permeability cells with 5% w/v CyA (Sandimmun) alone (CyA) or with PE (CyA + PE) in olive oil in the donor chamber. the penetration rate (mean +/- SD microgram/cm2/h) into receptor fluid was 53 +/- 43 (n = 13) for CyA and 660 +/- 175 (n = 7) for CyA + PE. The in vivo efficacy of this formulation was assessed in guinea-pigs undergoing delayed-type hypersensitivity (DTH) reactions to dinitrofluorobenzene (DNFB). CyA was applied topically at the time of challenge and twice daily thereafter. At 24 h. skin reactions revealed that compared with appropriate drug vehicles. concentrations of 0.25. 0.5 and 5% CyA +/- PE had a significant inhibitory effect upon the erythema response and this corresponded with significant reductions in T-cell infiltrates (0.5 and 5% CyA). No statistically significant reductions in erythema were demonstrated with 0.05% CyA +/- PE. but there was a reduction in the number of infiltrating lymphocytes in sites receiving 0.05% CyA + PE compared with vehicle-treated sites (P less than 0.01). This suggests that PE permitted some penetration of an otherwise non-immunosuppressive concentration of CyA through the skin.
Cyclosporin A in combination with photochemotherapy (PUVA) in the treatment of psoriasis, Forty patients with relapsing plaque psoriasis involving more than 20% body surface were treated either with cyclosporin A (CyA) plus PUVA or the retinoid etretinate plus PUVA (RePUVA). They initially received either CyA (2 weeks) or etretinate (1 week) alone and then PUVA was given concomitantly until complete remission. The patients were monitored over a period of 6 months and any relapse recorded. With each combined treatment regimen. CyA plus PUVA and RePUVA. the patients cleared within comparable periods of time (mean treatment period of 5.3 vs. 4.7 weeks after initiation of therapy and 3.3 vs. 3.7 weeks after initiation of PUVA). However. the cumulative UVA dose required for clearance (110.9 J/cm2 vs. 62.1 J/cm2 (P less than 0.05)) and the incidence of severe and early relapses were significantly higher in the CyA cohort. Within 6 months severe relapses had occurred in 58% of CyA plus PUVA but only in 15% of RePUVA-treated patients (P less than 0.001). This suggests that the CyA plus PUVA regimen as performed in this study is less effective than RePUVA.
Profound digital collagen atrophy: a new cutaneous presentation of adrenal-dependent Cushing's syndrome, A 59-year-old Caucasian housewife presented with a 2-year history of marked loss of tissue substance from the finger and toe pulps and the heel pads. There was no clinical evidence or history of urticaria or other inflammatory change. Investigations demonstrated a raised plasma cortisol secondary to a left adrenal adenoma. Skin biopsies showed abnormalities of dermal collagen. but no evidence of elastin destruction. This case presents an unusual variant of the cutaneous atrophy associated with Cushing's syndrome.
Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure, OBJECTIVE--To find out whether changes in the daily prothrombin time are of prognostic importance in patients with paracetamol induced fulminant hepatic failure. DESIGN--Retrospective study. SETTING--The Liver Unit. King's College Hospital. London. PATIENTS--150 Consecutive patients with paracetamol induced fulminant hepatic failure admitted between October 1986 and February 1989. MAIN OUTCOME MEASURE--Death. RESULTS--Of the 150 patients. 72 (48%) died. In all. 34 of the 37 (92%) patients with a peak prothrombin time of greater than or equal to 180 seconds died as did 20 of the 41 (49%) with a time of 130-179 seconds. nine of the 25 (36%) with a time of 90-129 seconds. and nine of the 47 (19%) with a time of less than 90 seconds. Of the 42 patients with a continuing rise in prothrombin time between days 3 and 4 after overdose. 39 died (93%) compared with 21 of the 96 (22%) in whom the prothrombin time fell. CONCLUSIONS--These data indicate that a continued increase in prothrombin time on day 4 after overdose and a peak prothrombin time of greater than or equal to 180 seconds identify at an early stage those patients with a less than 8% chance of survival. Liver transplantation should be considered in patients meeting either of these criteria.
What causes cryptogenic fibrosing alveolitis? A case-control study of environmental exposure to dust, OBJECTIVE--To investigate the role of occupational and domestic exposure to dust in the aetiology of cryptogenic fibrosing alveolitis. DESIGN--Matched case-control study. SUBJECTS--40 Patients with cryptogenic fibrosing alveolitis and 106 community controls matched for age and sex who responded to a questionnaire. MAIN OUTCOME MEASURE--Responses to self administered questionnaire asking about lifetime exposure to dust. animals. and smoke at home and at work. RESULTS--The patients with cryptogenic fibrosing alveolitis were more likely to report occupational exposure to metal dust (matched odds ratio 10.97 (95% confidence interval 2.30 to 52.4). p less than 0.001) or wood dust (2.94 (0.87 to 9.90). p = 0.08). to have worked with cattle (10.89 (1.24 to 96.0). p = 0.01). and to have lived in a house heated by a wood fire (12.55 (1.04 to 114). p = 0.009). A history of smoking and social class based on occupation were not significantly related to disease state. CONCLUSION--Environmental exposure to dust may be an important factor in the aetiology of cryptogenic fibrosing alveolitis.
Rising mortality from cryptogenic fibrosing alveolitis, OBJECTIVE--To determine the pattern of mortality ascribed to cryptogenic fibrosing alveolitis and to identify factors that might be important in the aetiology of the disease; and to assess the validity of death certification of the disease. DESIGN--A retrospective examination of mortality ascribed to cryptogenic fibrosing alveolitis in England and Wales between 1979 and 1988 with analysis. by multiple logistic regression. of independent effects of age. sex. region of residence. and social class as indicated by occupation on data for 1979-87; also a retrospective review of hospital records of patients certified as having died of cryptogenic fibrosing alveolitis in Nottingham and of the certified cause of death of patients known to have had the disease. MAIN OUTCOME MEASURES--Time trends in mortality nationally; effects on mortality of age. sex. and region of residence; validity of death certification in Nottingham. RESULTS--The annual number of deaths ascribed to cryptogenic fibrosing alveolitis doubled from 336 in 1979 to 702 in 1988. the increase occurring mainly at ages over 65. Mortality standardised for age for both sexes likewise increased steadily over the period. Deaths due to cryptogenic fibrosing alveolitis were commoner in men (odds ratio 2.24. 95% confidence interval 2.11 to 2.33) and increased substantially with age. being 7.84 (7.24 to 8.49) times higher in subjects aged much greater than 75 than those aged 45-64. Odds ratios of death due to cryptogenic fibrosing alveolitis adjusted for age and sex were increased in the traditionally industrialised central areas of England and Wales (p less than 0.02. maximum odds ratio between regions 1.25). but no significant increase in odds of death was found for manual occupations. Of 23 people whose deaths were registered in Nottingham as having been due to cryptogenic fibrosing alveolitis. 19 were ascertained from clinical records to have had the disease. Only 17 of 45 patients known to have had cryptogenic fibrosing alveolitis in life were recorded as having died from the disease. CONCLUSIONS--The diagnostic accuracy of death certification of cryptogenic fibrosing alveolitis is high. but the number of deaths recorded as being due to the disease may underestimate the number of patients dying with the disease by up to half. Mortality due to the disease is increasing. and the male predominance and regional differences in mortality suggest that environmental factors are important in its aetiology.
Home treatment for acute psychiatric illness, OBJECTIVE--To determine the factors influencing the successful outcome of community treatment for severe acute psychiatric illnesses that are traditionally treated in hospital. DESIGN--All patients from a single electoral ward who were either admitted to hospital or treated at home over a two year period (1 October 1987 to 30 September 1989) were included in the study and their case notes audited. The second year of the study is reported. SETTING--Electoral ward of Sparkbrook. Birmingham. SUBJECTS--99 Patients aged 16-65 with severe acute psychiatric illness. RESULTS--65 Patients were managed by home treatment alone; 34 required admission to hospital. The location of treatment was significantly (all p less than 0.05) influenced by social characteristics of the patients (marital state. age (in men). ethnicity. and living alone) and by characteristics of the referral (occurring out of hours; assessment taking place at hospital or police station). DSM-III-R diagnosis was more weakly associated with outcome. Violence during the episode was significantly related to admission. although deliberate self harm was not. CONCLUSIONS--Home treatment is feasible for most patients with acute psychiatric illness. A 24 hour on call assessment service increases the likelihood of success because admission is determined more strongly by social characteristics of the patient and the referral than by illness factors. Admission will still be required for some patients. A locally based mental health resource centre. a 24 hour on call service. an open referral system. and an active follow up policy increase the effectiveness of a home treatment service.
Measurement of activity of urea resistant neutrophil alkaline phosphatase as an antenatal screening test for Down's syndrome, OBJECTIVE--To investigate the value of measuring maternal urea resistant neutrophil alkaline phosphatase activity as an antenatal screening test for Down's syndrome. DESIGN--Case-control study of blood samples collected at nine to 27 weeks of pregnancy. SETTING--Antenatal clinics in London and Oxford. PATIENTS--72 Women whose fetuses had been diagnosed by amniocentesis or chorionic villus sampling as having Down's syndrome and 156 women whose fetuses did not have the syndrome. Only singleton pregnancies were studied. MAIN OUTCOME MEASURE--Activity of urea resistant neutrophil alkaline phosphatase measured cytochemically. RESULTS--The median enzyme activity in the index patients was 1.65 times the expected median for the controls at the same duration of pregnancy (p less than 0.0001; 95% confidence interval 1.56 to 1.74). A cut off value that identified the 5% of control patients with the highest activities yielded a rate of detection of Down's syndrome of 79% (95% confidence interval 70 to 89%). CONCLUSION--Activity of urea resistant neutrophil alkaline phosphatase is an effective maternal blood marker for Down's syndrome. Its use in antenatal screening could lead to a substantial improvement in the detection of this disorder. Before introducing the test into routine medical practice it will have to be automated so that it can be used on a large scale and is less subjective.
Double-blind, placebo-controlled, cross-over study of flavoxate in the treatment of idiopathic detrusor instability, Detrusor instability occurs in approximately 10% of the adult population. producing troublesome symptoms. The pharmacotherapy currently available is usually only partially effective and cannot be adequately evaluated except under "blind" conditions because of the significant component attributable to placebo effects. The results of the present study revealed no advantage resulting from treatment with flavoxate. as assessed both subjectively and objectively. We suggest that this therapy does not appear to be beneficial in the medical management of detrusor instability.
Foley catheter balloon puncture and the risk of free fragment formation, The incidence of free fragment formation following balloon puncture or spontaneous bursting was examined in 294 Foley catheters immersed for 48 h in urine. The catheters were divided into 3 groups: 100 were inflated to the manufacturer's recommended volume. 100 to twice the volume and 94 to 3 times the recommended volume. The catheter balloons were punctured by pricking with a hypodermic needle. The overall incidence of free fragment formation was 27.3%. For both types of catheter examined. increasing balloon volume was not associated with an increased risk of free fragment formation following puncture. However. increasing volume was associated with increased free fragment formation when the balloon burst spontaneously. In view of the high risk of free fragment formation. cystoscopy should be performed in all cases of spontaneous catheter balloon rupture or after percutaneous balloon puncture.
Serum levels of sex hormone binding globulin and oestradiol in patients with testicular cancer, Serum testosterone (T). oestradiol (E-2) and sex hormone binding globulin (SHBG) were measured in 84 orchiectomised testicular cancer patients before further treatment and 4 to 6 and 12 to 15 months after therapy. Patients were divided into 3 groups according to treatment: Group 1: cisplatin-based chemotherapy (27 patients); Group 2: abdominal radiotherapy (32 patients); Group 3: no antiproliferative treatment (chemotherapy/radiotherapy) (25 patients). Between 4 and 6 months after antiproliferative treatment. particularly after chemotherapy. a reversible significant increase in E-2 and SHBG was observed. Patients without antiproliferative treatment showed no significant changes in their comparable hormone levels; 15% of all normal T values were associated with elevated levels of SHBG and E-2. Although the aetiology of these hormonal changes remains unknown. they may be related to the clinical symptoms of hypogonadism displayed by 10 to 30% of patients undergoing treatment for testicular cancer.
Treatment with desmopressin in severe nocturnal enuresis in childhood, A series of 22 patients with severe nocturnal enuresis were treated with desmopressin in a randomised double-blind cross-over study. Treatment with 20 and 40 micrograms was highly effective compared with placebo. No difference in dry nights was found between the 2 dosages. Desmopressin proved to be a safe and effective treatment.
Vasa aplasia and cystic fibrosis, Bilateral vasa aplasia is considered an invariable finding in cystic fibrosis. but such patients are rarely seen in male infertility clinics. The improved survival beyond 20 years of age is likely to change this. In a clinical study of a group of male cystics the vasa were absent in 8 of 11 boys and epididymal abnormalities were palpable in the majority. The main cause of infertility appears to be mechanical obstruction. Whether the absence is due to a primary failure of mesonephric duct development or secondary to luminal obstruction and subsequent atrophy is not known.
The effect of post-pubertal varicocele on testicular volume, Paediatric varicocele is a well known entity but its effect on adult infertility has not been adequately clarified. Since measurement of testicular volume is currently the best method of estimating the male reproductive potential. 945 boys aged between 13 and 18 years were examined with regard to testicular volume and the incidence of varicocele. The average volumes for right and left testes were 15.087 +/- 0.237 and 14.514 +/- 0.347 ml respectively. and the incidence of varicocele was 16.7%. The incidence increased from 14.5 to 21.7% as the ages increased from 14 to 18. The differences in volume of the 2 testes in boys with varicocele were statistically significant when compared with the normal group. but this significance failed to become more pronounced when the slight varicocele group (grade I) was included with the normal group and compared with the severe varicocele group (grades II and III). There may be no significant differences between the volumes of the 2 testes in boys with varicocele when careful measurement and strict statistical analyses are applied. However. some boys in the varicocele group were found to have testicular volumes below the confidence interval (mean - SE) or under 1 SD. and the 2 testicular volumes differed in certain age groups. This group requires further follow-up. The results of this study have added further contradictory findings to the issue of paediatric varicocele in terms of testicular atrophy. estimation of potential fertility and the indications for immediate surgery. There is a need for further prospective controlled trials.
A miniaturized vitrectomy system for vitreous and retinal biopsy, The author has developed a miniaturized vitrectomy system and its accessories with the size of a 23-gauge needle. The hand-piece can be inserted inside the eye through a Ziegler knife track. This instrument can be used for "atraumatic" removal of vitreous biopsy specimens and for removal of small pieces of retina. The system also seems to have application in vitreous surgery in premature infants' eyes.
The importance of congenital hypertrophy of the retinal pigment epithelium in familial adenomatous polyposis, We describe a family with familial adenomatous polyposis (FAP) and congenital hypertrophy of the retinal pigment epithelium (RPE). Three of five members with FAP showed flat. well-demarcated. round to oval pigmented patches of congenital hypertrophy of the RPE. We stress the importance of congenital hypertrophy of the RPE as a clinical marker in identifying patients with FAP since they are at risk for cancer.
Possible significance of cilioretinal arteries in low-tension glaucoma, Cilioretinal arteries arise from the short posterior ciliary artery circulation or directly from the choroidal circulation. The presence of a cilioretinal artery may in compromised discs steal flow from the peripapillary circulation and account for worsening glaucoma damage. We reviewed the records of 33 patients with unilateral cilioretinal arteries admitted for investigation of low-tension glaucoma. We looked for absolute difference between the affected and unaffected eyes as well as percent difference relative to the mean value for the two eyes and to the value for the unaffected eye in the following variables: mean defect. corrected loss variance or corrected pattern standard deviation. and adjusted neuroretinal rim area. No statistically significant differences were found. The mean disc area for the eyes with cilioretinal arteries was significantly larger than that previously reported for normal eyes. The results suggest that if vascular steal exists because of the presence of this artery. it is not of major clinical importance.
Recession of the superior oblique tendon in A-pattern strabismus, We performed 9 to 12 mm of recession of the superior oblique tendon for A-pattern strabismus in 10 patients. The average preoperative A-pattern measured 29.4 prism dioptres (PD). and the average pattern correction was 29.3 PD. All patients had a residual pattern of 6 PD or less (average 2.3 PD). No patient experienced significant underaction of the superior oblique. and other surgical complications. such as ptosis. Brown's syndrome. and laceration of the vortex vein or superior rectus. did not occur. The procedure corrected 14 to 40 PD of A-pattern. The amount of pattern corrected was correlated with the size of the preoperative A-pattern but not with the total amount of recession done. No significant shift in esodeviation in primary position was noted in the patients who underwent only superior oblique recession. The procedure appears to be of particular value in patients with moderate superior oblique overaction. The advantages of recession of the superior oblique tendon include the potential for reversibility and reoperation. low risk of induced superior oblique palsy. allowance for asymmetric surgery and potential for adjustable suture technique.
The Patterns of Care Outcome Study for cancer of the uterine cervix. Results of the Second National Practice Survey, This report summarizes the outcome results of the Patterns of Care Study (PCS) of cancer of the uterine cervix from 565 patients treated in 1978. The 5-year survival with no evidence of disease was: Stage I. 74%; Stage II. 56%; and Stage III. 33%. The 5-year local in-field failure rate was: Stage I. 12%. Stage II. 27%; and Stage III. 51%. Extent of parametrial involvement. unilateral versus bilateral. may be important in determining survival and local failure. The four-year actuarial survival was 58% for unilateral involvement versus 47% for bilateral (P = 0.06). and the local failure rate was 32% for unilateral versus 45% for bilateral (P less than 0.05). When analyzed by stage. patients with Stage IIb disease with unilateral parametrial involvement showed a trend toward improved survival and decreased local failure compared with those with bilateral Stage IIb cancers (P = 0.1). The use of intracavitary irradiation significantly improved survival and reduced local failures. Furthermore. the number of intracavitary applications was important. When two or more intracavitary applications were used compared with one application. local in-field failure was significantly reduced. 29% versus 17% at 4 years (P less than 0.001). and four-year survival was improved. 60% versus 73% (P = 0.01). The four-year actuarial rate of major complications depended on the stage: Stage I. 8%; Stage II. 15%; and Stage III. 13%. There was a statistically significant increase in major complications in patients undergoing laparotomy for staging versus no laparotomy 23% versus 11% at 4 years (P less than or equal to 0.01) and a trend toward increased major complications in patients who were thin or had prior abdominal surgery. This study confirmed the stage-dependent outcome of treatment of cancer of the uterine cervix with radiation and indicated that further division of Stage IIb to indicate prognostic significance of unilateral or bilateral parametrial involvement may be warranted. This study also confirmed the importance of intracavitary radiation in optimizing control established by the 1973 PCS. It further suggests that where possible. two intracavitary insertions may yield better results than one insertion.
Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial, Between October 1985 and March 1988. Children's Cancer Study Group institutions entered 95 patients with recurrent brain tumors into a Phase II trial of carboplatin 560 mg/m2 every 4 weeks. Complete or partial responses were observed for one of 19 evaluable children with brainstem glioma. two of 14 with ependymoma. six of 19 with medulloblastoma or central nervous system primitive neuroectodermal tumor (PNET). and none of 15 with high-grade astrocytoma. Of 33 children with medulloblastoma. ependymoma. or central nervous system PNET. five of 12 with no prior cisplatin exposure had responses. and two of 21 with prior cisplatin exposure had responses (P = 0.03). Thirty-four percent of patients had absolute neutrophil count nadirs less than 500/microliters. and 37% had platelet count nadirs less than 25.000/microliters. Sixteen percent had moderate to severe otoxicity. 10% had nausea and vomiting. and none had nephrotoxicity.
Interferon alpha-2a and 5-fluorouracil for advanced colorectal carcinoma. Assessment of activity and toxicity, Preclinical data showed that the cytotoxic effects of 5-fluorouracil (5-FU) are augmented by interferon (IFN). In a small study. 13 of 17 patients with advanced colorectal cancer responded to a regimen of 5-FU with IFN. Using the same dose and schedule as in this pilot study. 38 previously untreated patients with metastatic colorectal carcinoma were treated with continuous intravenous (IV) infusion of 5-FU 750 mg/m2 daily for 5 days. followed by weekly bolus 5-FU at 750 mg/m2 and subcutaneous IFN at 9 million units three times per week. Of 35 evaluable patients. nine (26%) had a partial response (95% confidence limit. 11% to 41%). with a median response duration of 7.5 months (range. 4.4 to greater than 11.7 months). Seven patients (20%) had a minor response. and ten (28%) had stable disease. The most common toxicities observed were stomatitis (52%) and diarrhea (43%). Neurotoxicity was seen in 34% of patients and consisted of gait disturbance. dizziness. confusion. memory loss. and dementia. Because of toxicity. 84% of patients required a reduction of the IFN dose by at least 50%. and 63% required reduction of the 5-FU dose by at least 25%. Although the combination of 5-FU and IFN in patients with advanced colorectal carcinoma has some activity. the regimen was toxic. and the observed response rate (26%) was not substantially superior to alternative 5-FU programs.
The role of ifosfamide plus cisplatin-based chemotherapy as salvage therapy for patients with refractory germ cell tumors, A prospective study of four cycles of etoposide with ifosfamide and cisplatin (VIP) chemotherapy was conducted in 42 germ cell tumor (GCT) patients who were refractory to cisplatin with etoposide/vinblastine-based therapy. Forty patients were evaluable for response. Ten patients (25%) had a complete response: seven to chemotherapy alone and an additional three patients after surgical resection of viable GCT. With a median follow-up of 15 months. four complete responders relapsed. and six patients (15%) remain in remission. Hematologic and nephrotoxicity were moderately severe. Durable complete responses with VIP as second salvage were achieved and suggests that ifosfamide adds efficacy to standard first-salvage therapy. The observed nephrotoxicity and myelotoxicity are considerations in the design of ifosfamide-cisplatin-based regimens. Hematopoietic growth factors may be useful in ameliorating myelotoxicity. The early use of ifosfamide-based chemotherapy may reduce the nephrotoxicity exacerbated by prior cisplatin. A trial of VIP as first salvage after a relapse from a complete response to platinum-based induction therapy is warranted. The modest proportion of patients who achieve a durable remission to VIP as second salvage emphasizes the need for more efficacious salvage therapy for patients who do not achieve a durable complete response.
Conservative surgery and radiation therapy for soft tissue sarcoma of the wrist, hand, ankle, and foot, Seventy-eight patients with soft tissue sarcoma (STS) arising in the distal extremities--wrist. hand. finger. ankle. foot. and toe--who were treated with conservation surgery and radiation therapy were studied retrospectively with respect to survival. local recurrence. functional limb preservation. complications. and distant metastasis. After a median follow-up of 7.9 years. actuarial 5-year and 10-year survival rates were 80% and 69%. respectively. and disease-free rates were 61% and 51% at the same times. Actuarial local control rates were 80% and 74% at 5 and 10 years. respectively. Fifteen patients (19%) had local recurrence. but 12 of these were salvaged. Ultimately. 53 patients (68%) retained a normal or fairly normal extremity. six (8%) needed amputation for complications. and 13 (17%) needed amputation to control recurrent disease. The functional outcome was significantly better for patients with upper extremity lesions than for those with lower extremity tumors; even for the latter. this treatment strategy was preferable to amputation. The incidence of hematogenous metastases from distal extremity sarcomas depends on the size of the primary tumor. It was concluded that conservation surgery and radiation therapy (XRT) is an acceptable treatment strategy for STS arising in distal extremities; it yielded a high rate of disease control and functional limb preservation.
A standard dose of radiation for "microscopic disease" is not appropriate, Elective irradiation of sites of potential occult tumor spread is often part of a patient's radiation therapy program. The required radiation dose (D) depends on the probability that occult disease exists (P(occ)). the number of sites at risk (A). the number of tumor clonogens present (Ni). their radiation sensitivity. and the desired control rate. An exponential model of cell survival is used to quantify the importance of these factors. Control Probability = [1 - Pocc x (1 - e-Ni x (SF2)D/2)]A; SF2 = surviving fraction after 2 Gy. Implications for clinical radiation therapy include: 1. Since the number of clonogens in an occult site may vary from 10 degrees to 10(8). Ni is the major determinant of the required dose. The intrinsic radiation sensitivity of the clonogens (SF2) is also extremely important in determining the dose. Other factors are less influential since they vary less. 2. The variability of Ni (8 logs) is larger than the variation in cell number seen with gross disease (1 cm3 versus 1000 cm3. 3 logs). When Ni approximately 10(8). the required dose approaches that needed for small volume gross disease (10(9) cells. 1 cm3). 3. The dose prescribed to elective sites should reflect the risk of occult disease based on the primary tumor site. stage. and grade. 4. Regions where clinicoradiologic evaluation is difficult (e.g.. pelvis and obese neck) require higher doses because macroscopic tumor deposits may exist. 5. Relatively low doses (10 to 30 Gy) are often thought to be inadequate for microscopic tumor. However. similar doses have been reported to sterilize microscopic tumor in ovarian. rectal. bladder. breast. and head and neck carcinomas. Relatively low doses should not be discounted since they may be useful in select cases when normal tissue tolerances and/or previous irradiation treatment limit the radiation dose.
The interplay of local and distant control in the cure of cervical cancer, From 1978 to 1986. 183 women with cervical cancer received definitive radiation therapy after extraperitoneal surgical staging. Relapse-free rates were strong functions of pelvic lymph node metastases and cervical size. The recurrence distribution consisted of 4% isolated local. 13% isolated distant. and 17% combined local and distant failures. With the assumption of independent local and distant failure probabilities. Suit et al.'s method was extended to assess potential improvement in cure attainable with perfect local and distant control. yielding local (LSA) and distant (DSA) survival advantages of 17% and 28%. Various subsets of clinical stage. cervical size. pelvic node metastases. periaortic metastases. and peritoneal metastases had LSA from 12% to 27% and DSA from 12% to 71%. For any prognostic group. LSA never exceeded DSA. showing that effective systemic therapy would have a greater impact on improving survival than would advances in local and regional tumor control. Therapeutic implications and limitations of the extended LSA-DSA model are discussed. This form of analysis can be used to guide the intensity of local and distant treatment to maximize the cure of the patient with cancer.
The role of elective lymph node dissection in the management of patients with thick cutaneous melanoma, A retrospective search of patients seen at the Duke Melanoma Clinic from 1970 to 1986 identified 308 clinically Stage I patients. with 4.0 to 10.0 mm cutaneous melanomas. Five-year and ten-year survival was 56% and 43%. respectively. Elective lymph node dissection (ELND) was done in 116 patients (37.7%); there was no difference in disease-free interval (DFI) or survival between these patients versus patients treated with wide excision only (P = 0.9). Thirty-two patients (27.6%) had pathologically positive nodes on ELND. These patients had a shorter DFI (P = 0.05) and survival (P = 0.03) compared with patients with negative node dissections. When further divided by Breslow's thickness. this difference persisted in patients with 4.0 to 6.0 mm lesions (P = 0.01). However. for thicker lesions (greater than 6.0 mm). there was no difference in survival between the node-negative and node-positive groups (P = 0.9). The mean follow-up was 7.1 years. Elective lymph node dissection was not done in 192 patients; 78 of these recurred first in the regional nodes. These 78 patients were compared with the 32 patients who had pathologically positive nodes by ELND to see if patient survival was improved by early removal of nodal disease. There was no difference in DFI (P = 0.5) or survival (P = 0.3) between these two groups. It is concluded that ELND may provide prognostic information for patients with thick cutaneous melanomas. However. there was no change in DFI or ultimate survival when patients were followed. and nodes removed when clinically positive. The authors do not recommend ELND for patients with thick melanomas because the risk of distant metastases outweighs any benefit of regional node dissection.
Endoscopic and radiographic evaluation of the murine colon, Endoscopic and radiographic techniques have not been widely applicable in the evaluation of chemically induced murine colon cancer. The authors investigated methods of cleansing the rat colon and refined endoscopic and radiographic techniques. They compared total colonoscopy (TC) and air-contrast (ACBE) and single-contrast barium enema (SCBE) findings with those obtained at necropsy in rats with 1.2-dimethylhydrazine (DMH)-induced colon cancer. Gastrograffin enemas with bisacodyl suppositiories showed complete evacuation of solid feces. Sprague-Dawley rats treated with DMH had their colons cleansed and then underwent TC (5.0-mm Olympus bronchoscope) and either SCBE or ACBE. Colonoscopy and ACBE were equally sensitive (81.5% and 76.3%. respectively). although SCBE was significantly insensitive in identifying lesions (P less than 0.001). This study demonstrates that: (1) mechanical cleansing of the rat colon is feasible. (2) TC and barium radiology can be done routinely after mechanical cleansing. and (3) TC and double-contrast BE are sensitive in identifying colon lesions. These techniques will provide a means for manipulation of murine tumors and in vivo surveillance.
Immunohistochemical differentiation of basal cell epithelioma from cutaneous appendages using monoclonal anti-glycoprotein antibody TNKH1. Its application in Mohs' micrographic surgery, TNKH1. which was primarily developed to detect differentiated melanocytic tumor cells. was found to recognize basal keratinocytes of hair follicle and some basal keratinocytes of human epidermis. Thus. TNKH1 decorated the basal cells of following structures: epidermis (39 of 54. only part of each specimen [OPES]). upper hair follicle (one of 24. OPES). lower hair follicle (21 of 21. very high rate of each specimen [VHES]). sebaceous duct (14 of 15. VHES). sebaceous gland (ten of 14. germinative cells near duct). eccrine duct (three of 19. OPES). Epithelial tumors. considered to be derived from or differentiating toward hair follicle such as trichilemmoma (one of one. VHES) and basal cell epithelioma (BCE) (32 of 32. VHES) were labeled not only in the peripheral cells but in their entirety. On the other hand. epidermal tumors. such as seborrheic keratosis (ten of 11. OPES). actinic keratosis (two of three. OPES). and squamous cell carcinoma (one of two. OPES). showed an irregular peripheral basal cell staining as in normal epidermis. The apocrine sweat apparatus and eccrine secretory portion were negative. Eccrine ductal tumors such as syringoma (two tested). eccrine acrospiroma (one). and eccrine carcinoma (two) were TNKH1 negative. Taking advantage of this total labeling of BCE versus peripheral labeling of the hair follicle. the authors could distinguish BCE tissue from other structures clearly. Among confusing structures the upper hair follicle and the eccrine duct were excluded easily because of their negative staining with TNKH1. The lower hair follicle was TNKH1 positive but only in the outer basal layer. whereas the BCE was TNKH1 positive in its entire basaloid cells. The result indicated that TNKH1 will be a useful antibody in Mohs' micrographic surgery.
Histopathologic, immunophenotypic, and genotypic analysis of Ki-1 anaplastic large cell lymphomas that express histiocyte-associated antigens, CD30/Ki-1 antigen expression in 243 cases of malignant lymphomas was examined using Ber-H2 monoclonal antibody. Among them 20 cases were categorized as Ki-1 anaplastic large cell lymphoma. In two of these cases histiocyte-associated markers were also expressed. In these cases histopathologic and extensive in situ immunophenotypic analyses were used with genotypic studies in the determination of cell lineage. A sinusoid histologic pattern of involvement with partial lymph node infiltration by pleomorphic neoplastic cells was noticed in the nodes from both patients. Solid areas of node replacement resembling metastatic carcinoma were seen in Patient 1. Immunohistologically. tumor cells of both cases were positive for CD30. CD25. CD71. LN3 (HLA-DR). EMA. CD45. CD74. vimentin. alpha-1-antichymotrypsin. and CD68. Patient 1 was also CD45RO+. CD43+. whereas Patient 2 was positive for alpha-1-antitrypsin and CD4 tumor cells. Genotypic studies revealed that TCR beta and TCR gamma chain genes were clonally rearranged in Patient 1. whereas no rearrangements were detected in Patient 2. This study supports the view that some Ki-1 anaplastic large cell lymphomas may express multiple histiocyte-associated antigens and confirms that this group of neoplasms have immunophenotypic heterogeneity. The results of genotypic analyses used with immunophenotyping does not exclude that the tumor cells in these cases may be of true histiocytic origin despite the Ki-1-positive phenotype.
Immunohistochemical demonstration of the placental form of glutathione S-transferase, a detoxifying enzyme in human gliomas, Expression of the human placental form of glutathion S-transferase (GST-pi) in human gliomas was investigated by immunohistochemical methods. and the result was compared with that of normal human glial cells. The gliomas in this study were composed of five benign astrocytomas (Grade 2). ten anaplastic astrocytomas (Grade 3). and 16 glioblastomas (Grade 4). Normal human glial cells showed only a weak immunostaining response for GST-pi in the cytoplasm or some nuclear membranes. All of benign astrocytomas had diffusely weak GST-pi immunostaining. resembling that of normal glial cells. With increasing grade. gliomas showed a strongly positive reaction for GST-pi. The positive reactions were remarkable especially in the gemistocytes and giant cells in the high-grade gliomas. These results suggest that cells of gliomas have some detoxifying function and the expression of this detoxifying enzyme. GST-pi. is related to the degree of malignancy of the gliomas.
Expression of placental alkaline phosphatase in gastric and colorectal cancers. An immunohistochemical study using the prepared monoclonal antibody, The authors developed monoclonal antibodies (MoAb) against human placental alkaline phosphatase (PLAP). Four specific MoAb reacting only with PLAP and two nonspecific MoAb reacting equally with isozymes of alkaline phosphatase (hepatic. intestinal. and placental) were obtained. Immunohistochemical staining with the specific MoAb showed that the cell membrane and cytoplasm of cancer cells were stained in gastric and colorectal carcinoma. The incidence of PLAP positivity was 23% (25 of 107) of all gastric carcinomas. Among gastric carcinomas. the 42% (13 of 31) positivity of highly differentiated carcinoma (papillary adenocarcinoma and well-differentiated tubular adenocarcinoma) was a significantly higher rate than that found in poorly differentiated carcinoma (poorly differentiated adenocarcinoma and signet-ring cell carcinoma. five of 41. 12%). The incidence of PLAP positivity was 11% (four of 35) in colorectal carcinoma. In contrast. gastric adenoma. intestinal metaplasia. and noncancerous tissue adjacent to cancer did not show staining. These results indicated that expression of PLAP was apt to occur in more highly differentiated gastric carcinoma and was highly specific for carcinoma in the gastrointestinal tract. although its incidence was not high.
Cancer antigen 125, carcinoembryonic antigen, and carbohydrate determinant 19-9 in ovarian tumors, The authors studied data of combination assays of tumor markers. because simultaneous elevation of different types of tumor markers in the serum was puzzling. They interpreted such phenomena regarding cancer antigen 125. carcinoembryonic antigen. and carbohydrate determinant 19-9 in ovarian tumors. The tissue expression of the antigens was compared with preoperative serum levels. Several different factors were found to cause the simultaneous elevation of two or three of these markers in the serum. Furthermore. even when the levels of some of the tumor markers were raised in the serum. the ovarian tumor did not always produce the marker by itself. This study indicates that immunohistochemical identification of a marker in tumor tissue is prerequisite to the use of that marker in the serum to monitor disease status.
Chondrolipoangioma. A cartilage-containing benign mesenchymoma of soft tissue, The clinical and pathologic features of four cases of benign mesenchymoma in which mature cartilage represented the predominant component are reported. The distinctive histologic feature in all four cases was a lobular proliferation of cartilaginous tissue exhibiting a spectrum of hyaline cartilage. fibrocartilage. myxoid cartilage. and cartilage with ossification and even bone marrow formation. intimately associated with mature adipose tissue and vascular elements. The localization of these tumors was in the proximity of a bone. but not attached to the periosteum or in continuity with a joint. Because these lesions may be mistaken for other cartilaginous neoplasms of soft tissue. recognition of this entity has potentially important diagnostic and therapeutic implications in that mutilating surgery may be avoided.
Recovery of morphine from a controlled-release preparation. A source of opioid abuse, MS-Contin (Purdue-Fredrick. Norwalk. CT) is a controlled-release preparation of morphine sulfate that has demonstrated efficacy in the management of chronic cancer pain problems. It has recently come to the attention of the authors that MS-Contin represents a potential source of opioid abuse through the extraction and intravenous injection of the morphine from this preparation. The authors describe a simple aqueous extraction method that was used to quantitatively determine the extent to which morphine could be obtained from MS-Contin tablets.
Fallopian tube cancer. The Roswell Park experience, Sixty-four patients with primary fallopian tube cancer treated at Roswell Park Memorial Institute from 1964 to 1987 underwent retrospective clinicopathologic review. In 40 patients fallopian tube cancer was the only primary. but in 24 patients primary fallopian tube cancer was part of a multifocal upper genital tract malignancy. Of the 40 patients with unifocal fallopian disease. the median survival was 28 months. Only 15% of patients were alive and disease free with follow-up ranging from 22 to 141 months (median. 90.5 months). Survival was not associated with stage of disease. tumor histology. grade. or depth of invasion in this series. Fourteen patients who received cisplatin-based chemotherapy were evaluable for response. Three patients (21%) responded; two complete and one partial. Twelve patients without clinical evidence of disease underwent second-look procedures. ten laparotomy and two laparoscopy. Four of ten second-look laparotomies were negative. Secondary debulking was done in three of four patients with gross disease. one of which had a negative third-look laparotomy. Negative laparotomy. second-look or third-look. was associated with improved survival (P = 0.016). One of the two laparoscopies was negative. but the patient recurred. In the remaining 24 patients cancer of the fallopian tube was part of a multifocal upper genital tract malignancy. In 12 patients tubal disease was invasive. and in 12. it was in situ. Separate primaries occurred in the ovaries (n = 20); uterus (n = 7); and cervix (n = 2). This represents 1.3% of ovarian malignancies treated at Roswell Park Memorial Institute during the study period. Fallopian tube cancer seems as virulent as ovarian cancer with few long-term survivors. It is frequently associated with other sites of upper genital tract malignancy. Second-look laparotomy is an important predictor of survival. Second-look laparoscopy may be useful if positive.
Cancer of the urinary bladder in blacks and whites. A case-control study, Racial differences in the risk of cancer of the urinary bladder associated with cigarette smoking and alcohol consumption were examined in a study of 1663 cases (1534 whites and 129 blacks) and 4930 controls matched 3:1 by sex. race. and age to the cases. Significant increases in cancer risk associated with cigarette smoking were observed in whites and blacks; however. the dose-response patterns appeared to differ by race. In whites. statistically significant elevations of threefold and higher were observed in the odds ratios at all smoking levels above 20 pack-years. whereas in blacks. the corresponding point estimates did not increase significantly until greater than 60 pack-years of smoking. Although these risk patterns are compatible with the higher incidence of bladder cancer in white men. the sample of blacks was small. and tests of significance were only suggestive of higher risks for whites at specific amounts of smoking (P less than 0.15). Effects of alcohol consumption were inconsistent. and there was no detectable synergism between smoking and drinking. Additional study of race-specific risk factors and tobacco metabolism will be needed to determine the true nature of the apparent racial differences in the risk of urinary bladder cancer associated with cigarette smoking.
Extrahepatic metabolism of morphine occurs in humans, The pharmacokinetics of morphine was studied in six patients in whom a radiologic localization of an insulinoma was to be performed under general anesthesia. Sampling was done in the peripheral artery. the mesenteric vein in five of the six patients. the hepatic vein. and the peripheral vein. as well as in urine. Hepatic blood flow was estimated by an indocyanine green infusion technique at the end of the radiologic procedure. Morphine terminal half-life was 92 +/- 9 minutes. total body clearance was 1260 ml.min-1. and the hepatic extraction ratio was 0.65 +/- 0.11. No concentration gradient was observed between the artery and the superior mesenteric vein. showing that no gut wall metabolism of morphine occurred. The total body clearance exceeded the hepatic clearance by 38%. It was concluded that the extrahepatic extraintestinal clearance of morphine probably occurred through the kidney.
Xipamide disposition in liver cirrhosis, The pharmacokinetics of the sulfonamide-type diuretic xipamide was studied in patients with liver cirrhosis and ascites and compared with healthy control subjects. After oral administration of 40 mg xipamide. the diuretic was rapidly distributed in the blood and the ascites. The ratio of the area under the concentration-time curve (AUC) of plasma and ascitic fluid was 7:2. as was the protein content in the respective compartments. The AUC in plasma of cirrhotic patients was significantly greater than in control subjects (p less than 0.001). The most striking finding was the increase of the amount (Ae) of parent drug and main metabolite excreted into the urine (p less than 0.001). The renal clearance of xipamide was only moderately reduced in patients with liver cirrhosis. Both AUC and Ae were positively correlated to the plasma concentration of direct bilirubin of the patients (p less than 0.05). We concluded that nonrenal drug clearance in patients with liver cirrhosis was reduced as a result of the blockade of hepatobiliary excretion during cholestatic conditions.
Combined alpha/beta-blockade versus beta 1-selective blockade in essential hypertension in black and white patients, The purpose of this multicenter investigation was to determine the efficacy and safety of the alpha/beta-blocker labetalol versus the beta 1-selective beta-blocker atenolol in white and black patients with essential hypertension. Equal numbers of black and white patients were enlisted to form four treatment groups (white patients taking either labetalol or atenolol and black patients taking either labetalol or atenolol). Two hundred ninety-two patients (152 white and 140 black patients) with essential hypertension characterized by a standing diastolic blood pressure of 105 to 119 mm Hg (inclusive) were recruited for this trial. Patients were randomized to either labetalol (dosage titrated from 200 to 1600 mg/day) or atenolol (dosage titrated from 50 to 100 mg/day). The therapeutic goal was achievement of a standing diastolic blood pressure of 90 mm Hg or less or a fall of 15 mm Hg in diastolic pressure from baseline value at the end of the placebo run in period. At the end of the study there were no significant differences in blood pressure or heart rate changes in the supine position between the labetalol and atenolol groups. In contrast. labetalol produced greater reduction in both the standing systolic and diastolic blood pressure (-12/-13 mm Hg. respectively) compared with atenolol (-7/-9 mm Hg; p less than 0.05; p less than 0.005. respectively). The greatest decrease in blood pressure was observed in white patients receiving labetalol. In black patients the decrease in blood pressure was greater in those treated with labetalol compared with atenolol. particularly with respect to the systolic blood pressure. We conclude that the alpha 1-blocking property of labetalol provides an additional lowering of the blood pressure over that seen with beta 1-blockade alone. especially in the standing position. and this enhanced efficacy is not confined to one radical group.
Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine, The analgesic efficacy and kinetics of a single oral dose of 75 mg codeine was investigated in 12 extensive metabolizers and 12 poor metabolizers of sparteine in a double-blind. placebo-controlled crossover study. The cosegregation of the O-demethylation of codeine to morphine with the sparteine oxidation polymorphism was confirmed. Hence morphine could not be detected in the plasma of any of the poor metabolizers. whereas detectable morphine plasma levels were found in 10 of 12 extensive metabolizers. Pain thresholds to laser stimuli were determined before drug intake and 90. 150. and 210 minutes after drug intake. Codeine significantly increased the pricking pain thresholds in the extensive metabolizers (p less than 0.05). whereas there were no significant changes in the poor metabolizers. No change in pain thresholds occurred with placebo in any of the two phenotypes. In the extensive metabolizers there was a significant positive correlation between the increase in pain threshold and plasma concentration of codeine. The study supports the hypothesis that morphine formation is essential for achievement of analgesia during codeine treatment.
Elevated plasma noradrenaline concentrations in patients with low-output cardiac failure: dependence on increased noradrenaline secretion rates, 1. Plasma noradrenaline concentrations are elevated in patients with congestive heart failure; however. the pathogenesis of these elevated noradrenaline levels is controversial. 2. Possible mechanisms for elevated noradrenaline concentrations in patients with congestive heart failure include increased noradrenaline secretion. decreased clearance of noradrenaline. and a combination of increased secretion and decreased clearance. 3. In the present study. plasma noradrenaline clearance and apparent secretion rates were determined using a whole-body steady-state radionuclide tracer method in six otherwise healthy patients with moderate degrees of low-output cardiac failure and in six normal control subjects. 4. The venous plasma noradrenaline level was elevated in the patients with congestive heart failure as compared with the control subjects (4.18 +/- 1.34 versus 1.54 +/- 0.16 nmol/l. P less than 0.05). There was no stimulation of the adrenal medulla as evident by normal plasma adrenaline levels in both groups (0.19 +/- 0.04 versus 0.18 +/- 0.02 nmol/l. not significant). The apparent secretion rate of noradrenaline was elevated in the patients with congestive heart failure (4.75 +/- 1.95 versus 1.78 +/- 0.18 nmol min-1 m-2. P less than 0.05). whereas the clearance rate of noradrenaline was similar in the two groups (1.26 +/- 0.27 versus 1.16 +/- 0.02 l min-1 m-2. not significant). 5. We conclude that the high peripheral venous plasma noradrenaline concentrations in patients with mildly decompensated low-output cardiac failure are initially due to increased secretion. rather than to decreased metabolic clearance. perhaps in response to diminished effective arterial blood volume.
Pineal hyperactivity in spontaneously hypertensive rats: muscarinic regulation of indole metabolism, 1. Choline acetyltransferase activity and [3H]quinuclidinyl benzylate-binding sites were detected in the pineal gland of normotensive Wistar-Kyoto rats and of spontaneously hypertensive rats. 2. In vitro. muscarinic activation by pilocarpine increased the pineal metabolic production of hydroxyindole derivatives up to 5-hydroxytryptamine and produced a less marked stimulation of melatonin biosynthesis. 3. Electrical field stimulation of pineal gland slices caused similar metabolic effects. 4. Muscarinic blockade with atropine inhibited the effects on hydroxyindole metabolism. 5. [3H]Quinuclidinyl benzylate-binding sites. indicative of muscarinic receptors. were more numerous. and basal 5-hydroxytryptamine and melatonin levels were higher. in the pineal gland of spontaneously hypertensive rats compared with Wistar-Kyoto rats. 6. The atropine-sensitive metabolic effects of pilocarpine and electrical field stimulation on the pineal gland were increased in spontaneously hypertensive rats compared with Wistar-Kyoto rats.
Effects of acute and chronic ethanol administration and its withdrawal on the level and binding of somatostatin in rat brain, 1. Acute ethanol administration resulted in an increase in the total number of specific somatostatin receptors in rat frontoparietal cortex and hippocampus. and a decrease in the level of somatostatin-like immunoreactivity in the hippocampus but not in the frontoparietal cortex. 2. Chronic administration of ethanol caused a decrease in the number of somatostatin receptors in the frontoparietal cortex but not in the hippocampus. although the level of somatostatin-like immunoreactivity was unchanged in both brain areas. 3. A week after suppressing ethanol the value for specific binding of tracer to somatostatin receptors in the frontoparietal cortex was not significantly different from that of the control rats. although the actual number of receptors was slightly lower. 4. These results suggest a possible role for somatostatin in the nervous system during alcoholism and the post-withdrawal reaction.
Evidence for abnormal Na+/H+ antiport activity detected by phosphorus nuclear magnetic resonance spectroscopy in exercising skeletal muscle of patients with essential hypertension, 1. Exercise-induced pH changes in skeletal muscle were studied in a group of eight subjects with essential hypertension by using 31P n.m.r. spectroscopy. 2. Leucocyte Na+/H+ antiport activity was measured in vitro in the same subjects using a pH-sensitive fluorescent dye. 3. Resting skeletal muscle pH and unstimulated leucocyte pH values were similar to those in control subjects. but increased Na+/H+ antiport activity was demonstrated in the leucocytes from hypertensive subjects by acid loading in vitro. Decreased skeletal muscle acidification and an increased rate of pH recovery was also demonstrated in vivo in these same patients during an acid load induced by isotonic exercise. 4. These findings suggest that the increased cellular Na+/H+ antiport activity. which has been demonstrated in vitro in essential hypertension. also affects the biochemical response of skeletal muscle to physiological levels of exercise. This strengthens the argument that increased Na+/H+ antiport activity in hypertension is a generalized and physiologically relevant cellular abnormality.
Systolic wall stress and ventricular arrhythmia: the role of acute change in blood pressure in the isolated working rat heart, 1. The effect of a sudden acute change in blood pressure upon arrhythmia provocation has been studied in an isolated working heart model from the Wistar-Kyoto strain of rat. Twenty-four hearts were studied. 2. They were perfused with two different. modified. Krebs-Henseleit solutions at a fixed left atrial pressure. 3. Acute changes in pressure. both increases and decreases. were arrhythmogenic. Whilst ectopic activity was more predictably produced by pressure reductions. this consisted of simple ventricular ectopics only. Pressure increases. in contrast. were capable of provoking more complex and sustained arrhythmias. 4. The effect of pressure changes were highly dependent upon electrolyte concentrations in the perfusate. Low potassium and magnesium concentrations increased the amount of arrhythmia provoked by pressure increases but tended to reduce that provoked by pressure reductions. 5. We conclude that the direct effect of an acute change in pressure upon the myocardium is arrhythmogenic. However. the myocardial response to a pressure change is interdependent upon prevailing electrolyte concentrations.
Thoracic empyema: causes, diagnosis, and treatment, Thoracic empyema is a disease that has been recognized for centuries. The principles of management as stated by Hippocrates remain more or less unchanged. Diagnosis can be masked by the underlying cause. preemptive antibiotic treatment. or the now frequently associated debilitating diseases. With no other specific investigation. the main diagnostic test remains diagnostic thoracentesis. When an empyema is encountered. the objectives are to save life; eliminate the empyema. its complications. and chronicity; return pulmonary mechanics to normal; and reduce the duration of the hospital stay. The introduction of antibiotics has dramatically influenced the spectrum of the disease now encountered. If the original infection is adequately treated. empyema rarely occurs. Penicillin has removed the major cause of empyema. and further developments in antibiotics now mean that the majority of empyemas occur when patients are disabled by other disease processes or malnutrition. or where there remains a delay in medical attention. These patients are often less able to withstand the prolongation of the infective processes that is sometimes encountered with the staged approach to treatment. Developments in operative and postoperative care have meant that these patients can best be treated by more aggressive and definitive surgical management.
The adult respiratory distress syndrome, The adult respiratory distress syndrome remains an enigmatic disorder with a high mortality rate. although it can sometimes be managed effectively. Recognizing the conditions with which it is associated is the first step in preventing its occurrence. Decreasing the risk factors of developing ARDS remains the fundamental goal of initial management. Once the syndrome has developed in a particular patient. the clinician's goals in management are to stabilize the patient. avoid further insults. maximize the support therapies available. and be cognizant of and avoid the potential adverse effects of these supportive therapies.
Esophageal motility in an adult with a congenital H-type tracheoesophageal fistula, Congenital H-type tracheoesophageal fistulas (TEF) are rare. Long-standing respiratory symptoms are the most common presenting complaints. Patients with these fistulas have a congenital esophageal motor abnormality characterized by uncoordinated. low-amplitude peristalsis of the esophageal body; both low and normal lower esophageal sphincter pressures have been described. These findings persist despite fistula repair. A case history of an adult patient with congenital TEF is presented and the literature is reviewed. This patient is unusual in that esophageal symptoms (dysphagia) were more prominent than the usual respiratory symptoms.
Motility changes in primary achalasia following pneumatic dilatation, The changes in esophageal motility after pneumatic dilatation were evaluated prospectively in 51 patients with achalasia. The patients were evaluated for a median of 14 months. Pneumatic dilatation led to a clinical improvement in 41 patients. On manometric evaluation. a significant decrease in lower esophageal sphincter pressure was observed (28.4 +/- 14.9 mmHg vs. 13.5 +/- 7.2 mmHg; p = 0.001); the resting pressure of the esophageal body dropped from 4.8 +/- 4.2 mmHg above gastric baseline to 0.1 +/- 3.9 mmHg below gastric baseline. After therapy. peristaltic activity was present in 10/51 (20%) patients; in 1 case. complete relaxation of the lower esophageal sphincter was recorded. Treatment-induced motility changes could not be predicted by clinical history or the lower esophageal sphincter pressure before or after therapy. However. the resting pressure of the esophageal body before and after therapy was significantly lower in these patients in whom peristalsis recurred after therapy than in patients with an unchanged motility pattern. The reappearance of peristaltic activity after pneumatic dilatation was unrelated to lower esophageal sphincter pressure. In conclusion. motility disturbances of the esophageal body in patients with achalasia do not simply reflect the functional obstruction of the lower esophageal sphincter. These findings support the hypothesis that achalasia is not a distinct motility disturbance but should be regarded as part of a broad spectrum of different interrelated esophageal motility disorders.
The effects of parathyroid hormone (PTH) and PTH-related peptide on osteoclast resorption of bone slices in vitro: an analysis of pit size and the resorption focus, The mechanism whereby PTH. a potent stimulator of bone resorption. may under certain circumstances exert anabolic effects on bone is not known. but it is possible that it involves reduction of the size of osteoclast resorption lacunae. We have therefore made a detailed in vitro study of the effects of PTH and PTH-related peptide (PTHrP) on resorption by neonatal rat osteoclasts paying particular attention to the plan area of resorption pits. In order to distinguish between increased resorption at a particular site and increased numbers of sites. we have used an eyepiece graticule to define a focus of resorption. namely an area occupying 1/116th of the bone slice. which may contain either one or several pits. In addition we have studied the relationship between the number of pits in a resorption focus and the total area of bone resorbed at the focus. We found that PTH and PTHrP. at doses between 2 x 10(-10) M and 2 x 10(-8) M. while exerting significant stimulatory effects on bone resorption. caused a reduction in the median plan area of pits. An increase in the number of resorption foci was the primary stimulatory effect of PTH and PTHrP. occurring within 6 h in the case of PTH. However. the plan area of bone resorbed at a focus showed no significant increase. despite an increase in the number of pits per focus. because as more pits were formed at a focus. the pits were smaller. thus partially dissipating the stimulatory effect of PTH on resorption. These results are consistent with the activation of new remodeling sites by PTH in vivo. Furthermore. the formation of smaller pits under the resorptive influence of PTH may. together with the maintenance of coupling between formation and resorption. play a role in the preservation of cancellous bone recorded in cases of primary hyperparathyroidism and the anabolic effect of exogenous PTH.
Expression of rat prolactin-like protein B in deciduoma of pseudopregnant rat and in decidua during early pregnancy, The rat PRL-like protein-B (rPLP-B) complementary DNA (cDNA). originally cloned from a late term placental library. hybridizes to transcripts in the deciduoma tissue artificially produced in pseudopregnant rats. The expression of rPLP-B in deciduoma is first observed 48 h (pseudopregnancy day 7) after the deciduogenic stimulus and increases to a maximum by 96-120 h (pseudopregnancy day 9-10). In situ hybridization studies show that rPLP-B hybridizes specifically to the antimesometrial cells of deciduoma tissue in day 9 pseudopregnant rats and to the homologous cells of the decidua that surround the embryo-trophoblastic structure at day 9 of pregnancy. A temporal study on the expression of rPLP-B during pregnancy shows that rPLP-B is concomitantly expressed by the decidual cells of maternal origin and the cytotrophoblast of fetal origin around day 13 of pregnancy.
Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: correlation with estrogen receptor status, Breast tumor cell lines have been shown to secrete several distinct polypeptide growth factors. although conflicting results exist for the insulin-like growth factors (IGFs). In contrast a limited number of breast tumor cell lines have definitely been shown to secrete the high affinity IGF binding proteins (IGFBPs) that modify IGF actions. To characterize the types of IGFBPs that are secreted by breast tumor cell lines. conditioned medium was collected from seven separate tumor cell lines. three of which were estrogen receptor (ER) negative. and four of which were ER positive. All three of the ER negative cell lines. MDA-231. MDA-330. and HS578T. secreted binding proteins of 49.000 and 43.000 Mr (IGFBP-3) as well as 29.000 (IGFBP-1) and 24.000 Mr. In contrast. all four ER positive cell lines secreted 34.000 (IGFBP-2) or 24.000 Mr forms. and none secreted the 49.000 and 43.000 or 29.000 Mr forms. BT-20. a cell line that is positive for ER messenger RNA (mRNA) but negative for ER protein. secreted predominantly a 34.000 Mr protein. The amount of total IGFBP activity released in 24 h ranged between 0.4 and 5.6 nM equivalents of IGFBP-1. and there was no significant difference between the ER positive and negative cell lines. The MCF-7 cells that produced predominantly 34.000 and 24.000 Mr forms showed a 1.8-fold increase in IGFBP secretion after estrogen stimulation. Immunoblotting and a specific RIA for IGFBP-1 showed that only the ER negative lines MDA-330. MDA-231. and HS578T secreted this form. Northern blotting analysis for the mRNA encoding this protein showed that both MDA-330 and MDA-231 contained a single 1.6 kilobase mRNA species that hybridized with an IGFBP-1 complementary DNA (cDNA) probe. Immunoblotting analysis of the other cell lines showed that only the 34.000 Mr form secreted by the ER positive cell lines reacted with IGFBP-2 antisera. Exposure of the conditioned media from the three ER negative cell lines to N-glycanase revealed that the 49.000 and 43.000 Mr forms of IGFBP were glycosylated and therefore probably represent IGFBP-3. We conclude that ER negative cell lines secrete three forms of IGFBPs. IGFBP-1. IGFBP-3. and a 24.000 Mr form. In contrast. the ER positive cell lines secrete predominantly IGFBP-2 and the 24.000 Mr form but do not secrete IGFBP-3 or 1.(ABSTRACT TRUNCATED AT 400 WORDS).
Preliminary characterization of angiogenic activity in media conditioned by cells from luteinized rat ovaries, Angiogenic activity was detected in media conditioned by ovarian cells from superovulated. pseudopregnant (PMSG/human CG treated) immature Holtzman rats. Media conditioned by cells from luteinized rat ovaries stimulated the directed migration of rabbit endothelial cells or mouse Balb/c3T3 cells. but was not mitogenic to either cell type. That endotheliotropic activity was not associated with a steroid was indicated by the finding that chemoattractant activity was detected in fractions after reversed-phase C18 chromatography. which removes more than 95% of steroids present in the media. and that chemoattractant activity was precipitated by ammonium sulfate and by ethanol. Full chemoattractant activity was recovered after boiling (95 C for 30 min). lyophilization. dialysis. Sephadex G-25 desalting columns. and pH changes from 3-10. After Sephadex G-200 chromatography. chemoattractant activity emerged at elution volumes corresponding to 20.000-30.000 mol wt. Chemoattractant activity was not retained by Concanavalin A-Sepharose or gelatin-Sepharose. and was only partially retained by heparin-agarose. Chemoattractant activity was also partially retained on both cation and anion exchange columns. Our collective findings indicate the presence of a nonsteroidal. heat-stable. pronase-sensitive factor. nominal mol wt of 20.000-30.000. in media conditioned by cells from luteinized rat ovaries; this factor is chemoattractive but not mitogenic to endothelial cells. Ovarian-derived chemoattractant activity appears to be distinct from fibroblast growth factor because it lacked detectable mitogenic activity. and because fibroblast growth factor was not active in our cell migration bioassay. Because stimulation of endothelial cell migration is a key event during angiogenesis. demonstration of an ovarian endotheliotropic chemoattractant is consistent with our hypothesis that angiogenesis factors play a role in the paracrine regulation of ovarian function.
Hypothalamic glucocorticoid implants prevent fetal ovine adrenocorticotropin secretion in response to stress, We evaluated the role of the hypothalamic paraventricular nucleus (PVN) in control of ACTH secretion in fetal sheep. Dexamethasone (DEX. 700 micrograms) (n = 6) or cholesterol (CHOL. 700 micrograms) (n = 5) implants were placed bilaterally 2 mm lateral to PVN of fetal sheep at 108 to 111 days of gestation (dga). After 5 days recovery. fetuses were challenged with: 1) hypotension (50% drop of blood pressure). 2) hypoxemia (fall of greater than 5 mm Hg in fetal PaO2). and 3) corticotropin-releasing hormone (CRH) (10 micrograms iv. single injection to fetus). Hypotension and hypoxemia were repeated after 125 dga. Compared with CHOL. DEX fetuses had lower average concentrations of ACTH in plasma after hypotension [23 +/- 0.5 vs. 149 +/- 83.8 and 31 +/- 13.1 vs. 101 +/- 31.3 pg ml-1 at less than 125 and more than 125 dga. respectively (mean +/- SEM. P less than 0.05)] and during hypoxemia [11 +/- 1.6 vs. 292 +/- 152.8 and 33 +/- 9.4 vs. 304 +/- 91.3 pg ml-1 at less than 125 and more than 125 dga. respectively (P less than 0.05)]. DEX and CHOL responses to CRH at 122 to 127 dga (10 micrograms iv) were not different (38 +/- 23.9 vs. 92 +/- 26.7 pg ml-1. respectively). Immunocytochemistry demonstrated that CRH was decreased in PVN and eliminated from median eminence in DEX. but not in CHOL fetuses. Arginine vasopressin (AVP) immunostaining of PVN of DEX and CHOL fetuses was similar; however. unlike CHOL. DEX fetuses showed no AVP immunostaining of the external zone of median eminence. These results show that. in fetal sheep. high concentrations of glucocorticoid near the fetal PVN prevent increases in plasma ACTH secretion seen in controls in response to hypotension and hypoxemia. and exert at least part of their effect at the level of the CRH- and AVP-producing neurons located in the PVN.
Alterations in opioid parameters in the hypothalamus of rats with estradiol-induced polycystic ovarian disease, The distribution and density of selectively labeled mu-. delta-. and kappa-opioid binding sites were examined by in vitro radioautography in the hypothalamus of normal. estradiol valerate (EV)-injected. and estradiol (E2)-implanted female rats. Hypothalamic beta-endorphin concentration was also examined by RIA in these three groups of animals. Quantitative analysis of film radioautographs demonstrated a selective increase in mu-opioid binding in the medial preoptic area of EV-treated. but not of E2-implanted rats. However. both these estrogenized groups exhibited a reduction in the density of delta-opioid binding in the suprachiasmatic nucleus. Statistically significant changes between either estrogenized groups were not observed for kappa-opioid binding. Results on the hypothalamic concentration of beta-endorphin indicated a marked reduction in EV-injected animals with respect to controls. In contrast. the E2-implanted animals exhibited beta-endorphin concentrations similar to controls. The present results confirm the increase in opioid receptor binding previously reported in the hypothalamus of EV-treated rats and further demonstrate that this increase is confined to the medial preoptic area and exclusively concerns mu-opioid receptors. The concomitant reduction in beta-endorphin levels observed in the same group of animals suggests that the observed increase in mu-opioid binding could reflect a chronic up-regulation of the receptor in response to compromised beta-endorphin input. Given the restriction of this effect to the site of origin of LHRH neurons and the demonstrated inhibitory role of opioids on LHRH release. it is tempting to postulate that such up-regulation could lead to the suppression of the plasma LH pattern that characterizes polycystic ovarian disease in the EV-treated rat.
Rapid inactivation and phosphorylation of pyroglutamyl peptidase II in Y-79 human retinoblastoma cells after exposure to phorbol ester, Pyroglutamyl peptidase II (EC 3.4.19.-). a membrane-bound metalloproteinase. is a highly specific TRH-degrading enzyme. Exposure of Y-79 human retinoblastoma cells to 12-0-tetradecanoyl phorbol 13-acetate (TPA) decreased the activity of this enzyme in a time- and concentration-dependent manner (IC50 5 x 10(-9) M). After 15 min of TPA treatment. only 10% of pyroglutamyl peptidase II activity remained. TPA treatment did not affect the activity of the cytosolic enzyme pyroglutamyl peptidase I (EC 3.4.19.3) or the membrane-bound enzyme dipeptidyl peptidase IV (EC 3.4.19.3). Pretreatment of the cells with the protein kinase C inhibitors H-7 or sphingosine prevented the inactivation of pyroglutamyl peptidase II by TPA. The time course of the TPA-mediated effect paralleled the time course of translocation and activation of protein kinase C in this cell line. Immunoblot analysis demonstrated that inactivation of pyroglutamyl peptidase II was not due to dissociation or internalization of this enzyme molecule. Incubation of TPA-activated Y-79 cell membranes with gamma-[32P]-ATP followed by immunoprecipitation revealed a time-dependent phosphorylation of a 48 kilodalton subunit of pyroglutamyl peptidase II. These studies indicate that the phorbol ester effect is mediated by protein kinase C. and reveal a mechanism of potentiation of the action of TRH at its target sites.
Mechanisms of impaired growth hormone secretion in genetically obese Zucker rats: roles of growth hormone-releasing factor and somatostatin, GH secretion is markedly blunted in obesity; however. the mechanism(s) mediating this response remains to be elucidated. In the present study we examined the involvement of the two hypothalamic GH-regulatory hormones. GH-releasing factor (GRF) and somatostatin (SRIF). using the genetically obese male Zucker rat. Spontaneous GH. insulin. and glucose secretory profiles obtained from free moving. chronically cannulated rats revealed a marked suppression in amplitude and duration of GH pulses in obese Zucker rats compared to their lean littermates (mean 6-h plasma GH level. 3.9 +/- 0.4 vs. 21.5 +/- 3.8 ng/ml; P less than 0.001). Obese rats also exhibited significant hyperinsulinemia in the presence of normoglycemia. The plasma GH response to an iv bolus of 1 microgram rat GRF-(1-29)NH2. administered during peak and trough periods of the GH rhythm. was significantly attenuated in obese rats at peak (137.4 +/- 26.1 vs. 266.9 +/- 40.7 ng/ml; P less than 0.02). although not at trough. times. Passive immunization of obese rats with a specific antiserum to SRIF failed to restore the amplitude of GH pulses to normal values; the mean 6-h plasma GH level of obese rats given SRIF antiserum was not significantly different from that of obese rats administered normal sheep serum. Both pituitary wet weight and pituitary GH content and concentration were reduced in the obese group. Measurement of hypothalamic GRF immunoreactivity revealed a significant (P less than 0.05) reduction in the mediobasal hypothalamic GRF content in obese rats (503.2 +/- 60.1 pg/fragment) compared to that in lean controls (678.1 +/- 50.2 pg/fragment). although no significant difference was observed in hypothalamic SRIF concentration. Peripheral SRIF immunoreactive levels were significantly (P less than 0.01) elevated in both the pancreas and stomach of obese rats. These results demonstrate that the genetically obese Zucker rat exhibits 1) marked impairment in both spontaneous and GRF-induced GH release. which cannot be reversed by SRIF immunoneutralization. 2) significant reduction in pituitary GH concentration. 3) depressed hypothalamic GRF content. and 4) elevated gastric and pancreatic. but not hypothalamic. SRIF levels. The findings suggest that the defect in pituitary GH secretion observed in the genetically obese Zucker rat is due. at least partially. to insufficient stimulation by hypothalamic GRF. and that SRIF does not play a significant role.
Transplantable rat choriocarcinoma cells express placental lactogen: identification of placental lactogen-I immunoreactive protein and messenger ribonucleic acid, The purpose of this investigation was to evaluate the abilities of a transplantable rat choriocarcinoma (Rcho) to produce placental PRLs. The Rcho tumor was analyzed biochemically and histologically for the expression of placental PRLs. Expression of placental PRL mRNAs was determined by Northern blot and in situ hybridization analyses. Expression of placental PRL proteins was determined by Western blot and immunocytochemical analyses. Histologically. Rcho tumors were characterized by the appearance of giant cell surrounding hemorrhagic regions. Female rats bearing the Rcho tumor beneath their kidney capsule showed extensive mammary gland development. The Rcho tumors expressed placental lactogen-I (PL-I) mRNA and protein. but there was no evidence of placental lactogen-II (PL-II). PRL-like protein-A (PLP-A). or PRL-like protein-B (PLP-B). Rcho PL-I mRNA and proteins migrated as a 1-kilobase species and a 36- to 40-kDa species similar to those expressed by normal rat trophoblast tissues. The cell type responsible for Rcho PL-I production was the giant cell. similar to that observed in normal rat trophoblast tissues. In summary. we have demonstrated the production of PL-I by a transplantable rat choriocarcinoma (Rcho). The Rcho tumor resembles rat trophoblast tissue at early postimplantation stages (days 6-10 of gestation) and may be a useful tool for studying placental PRL expression during trophoblast differentiation.
Hyperinsulinemia increases the amount of GLUT4 mRNA in white adipose tissue and decreases that of muscles: a clue for increased fat depot and insulin resistance, To mimick a state of hyperinsulinemia. normal rats were infused with insulin for 4 days via minipumps. and compared to saline infused rats. At the end of the experimental period. the abundance of mRNA was increased in white adipose tissue (WAT) and decreased in muscles of "insulinized" rats compared to controls. These findings were accompanied. in all tissues considered. except the diaphragm. by parallel changes in the amount of the glucose transporter protein and by parallel changes in the in vivo glucose utilization index. Hyperinsulinemia is thus a driving force in stimulating adipose tissue metabolic activity. while bringing about incipient muscle insulin resistance.
Depletion of alcohol (hexanol) dehydrogenase activity in the epidermis and jejunal mucosa in Sjogren-Larsson syndrome, Using a histochemical technique. we have demonstrated a consistent deficiency of alcohol (hexanol) dehydrogenase activity within the epidermis and jejunal mucosa of patients with Sjogren-Larsson syndrome. Biochemical assay of the fatty alcohol: NAD oxidoreductase activity in cultured fibroblasts and leukocytes from these patients showed deficient activities compared with controls. The histochemical and biochemical results are complementary. and the simpler histochemical method can be used reliably for initial screening of patients with ichthyosis in whom a diagnosis of Sjogren-Larsson syndrome is suspected.
Quantitative estimation of hair growth. I. androgenetic alopecia in women: effect of minoxidil, Quantitative growth of hair over a 40-week period is reported for eight women with androgenetic alopecia. Using a random. double-blind protocol. the women were given either a 2% minoxidil solution or a placebo of vehicle only. Hair in a permanently marked site on the fronto-parietal scalp was pulled through a 1-cm-square clear plastic template. and the outline of the template was drawn on the scalp. The hair was carefully hand clipped and collected at five eight-week intervals (one untreated and four treated). using great care to collect only hairs within the marked area. Subsequent measurements included the total weight of hair grown in the marked area. the total number of hairs. and. on a randomized 50-hair subsample. the weight. lengths. and optical diameters. Calculated quantities included average weight per hair. average length. and average optical width. The average total hair weight of minoxidil-treated subjects increased over the 32-week test period by 42.5%. compared to 1.9% for the placebo-treated subjects (average p = 0.018). Changes for the average number count were 29.9% and -2.6%. respectively (average p = 0.022). These increases. observed using an unusually small number of subjects. clearly distinguished the treated subjects from the untreated. During the same test period. the averaged quantities of weight. diameter. and length from the 50-hair subsample showed insignificant change (p usually greater than 0.5). In addition to showing a larger percentage increase than did the total number. the total weight is not only easier to obtain. but less prone to error during sampling and measurement. Therefore. we recommend that total weight from a defined area be considered as the primary quantitative estimator for hair growth.
Extracellular collagenase, proteoglycanase and products of their activity, released in organ culture by intact dermal inflammatory lesions produced by sulfur mustard, Peak (1 and 2 d) and healing (3. 6. and 10 d) inflammatory lesions were produced in rabbits by the topical application of the military vesicant. bis(2-chloroethyl)sulfide. commonly called sulfur mustard (SM). SM produces an acute sterile dermal inflammatory reaction with little or no necrosis. except in the epidermis. which dies during the first day. After an animal was killed. its lesions were excised intact. as full-thickness 1.0-cm2 explants. They were then organ-cultured for 3 d in order to maintain the viability of both local and infiltrating cells. The extracellular fluid in each lesion equilibrated with the culture fluid. which was collected daily and analyzed for collagenase and proteoglycanase activities. These metalloproteinase activities were measured after we had i) destroyed the alpha-macroglobulin inhibitors with KSCN. ii) destroyed the tissue inhibitor of metalloproteinases (TIMP) by reduction and alkylation. and iii) activated the latent proteinase activity with aminophenylmercuric acetate (APMA). Hydroxyproline-containing peptides and glycosaminoglycans (GAG) released into the culture fluids were also measured as indicators of local collagenase and proteoglycanase activity within the inflammatory lesions. In general. the levels of both the metalloproteinases and the products of their activity were higher in second- and third-day culture fluids than in first-day culture fluids. and higher in fluids from SM lesions than in those from normal skin. The activated fibroblast was apparently the major cell type producing the collagenase and proteoglycanase. The hydrolysis of collagen and ground substance occurs pericellularly. An excess of inhibitors exists outside the pericellular region. The daily change in culture fluids apparently decreased such inhibitors. so that by the second and third day of culture we could detect the changes in pericellular enzyme activity that were not detectable on the first day of culture. As the inflammatory lesions healed. the extracellular enzyme products (hydroxyproline and GAG) increased more than the enzymes that produced these products. With healing. a decrease occurs in the extravasation of all serum components. especially the large ones such as the alpha-macroglobulin inhibitors. We propose that during healing. the decrease in these inhibitors allows the metalloproteinases to begin the remodeling process. and that during the peak phase of inflammation. these same inhibitors protect extracellular matrix against hydrolysis by such proteinases.
Ability of circular extrachromosomal DNA molecules to carry amplified MYCN proto-oncogenes in human neuroblastomas in vivo, Amplification of the proto-oncogene MYCN (also known as N-myc) in neuroblastomas has been shown to correlate with both disease stage and prognosis. yet little is known about the DNA structures that carry amplified MYCN genes in neuroblastomas in vivo. We have used DNA irradiation and pulsed-field gel electrophoresis to analyze MYCN amplification structures in eight neuroblastomas from separate patients (four primary tumors and four metastatic lesions exhibiting MYCN amplification). Six of the eight neuroblastomas (three primary tumors and three metastatic lesions) exhibited MYCN DNA irradiation profiles consistent with the presence of circular extrachromosomal DNA amplification structures. Five neuroblastomas possessed amplification structures within the size range of double minute chromosomes. and one contained smaller DNA circles. Two neuroblastomas exhibited MYCN DNA irradiation patterns consistent with larger (presumably chromosomal) amplification structures. Multiple sizes of DNA circles were observed in the neuroblastomas of four different patients. implying in vivo multimerization of amplification structures. The presence of circular MYCN amplification structures in six of eight neuroblastomas examined suggests that circular DNA molecules are important structures in in vivo gene amplification.
Monoclonal antibodies to immunogenic lymphoma cell variants displaying impaired neoplastic properties: characterization and applications, Immunogenic. nontumorigenic cell variants derived from the highly tumorigenic mouse lymphoma cell line S-49 were used to raise monoclonal antibodies (MAbs) in syngeneic BALB/c mice. MAbs of the following specifications were derived: (a) MAbs that interacted preferentially with the immunogenic variants. (b) MAbs that interacted with both immunogenic variants and parental tumorigenic cells. and (c) a MAb that interacted with both immunogenic and tumorigenic S-49 cells and the normal BALB/c splenocytes. Six MAbs raised in this way were found to recognize at least five different cell-surface epitopes. Functional analysis of the different MAbs suggested their potential usefulness in passive immunization against parental tumorigenic cells as well as in enrichment of immunogenic cells from a mixed population containing a preponderance of tumorigenic cells.
Segregation analysis of breast cancer from the cancer and steroid hormone study: histologic subtypes, The segregation pattern of breast cancer in white families from the Cancer and Steroid Hormone Study was investigated. Families were categorized into four groups based on the histologic type of breast cancer in the probands:ductal cancer. lobular cancer. adenocarcinoma. and medullary cancer. The ductal cancer sample was further split into a premenopausal-proband and a postmenopausal-proband subset. Results for six complex segregation analyses are presented; the findings suggest heterogeneity in the transmission of breast cancer. For all analyses. there was no evidence for a multifactorial component in the mixed model. ie. a major locus plus other transmission. genetic and/or cultural. Interpretation of the medullary cancer. adenocarcinoma. and lobular cancer analyses does not permit discrimination among the major locus models. Segregation of breast cancer in the entire ductal sample was consistent with autosomal recessive transmission. In the ductal subanalyses. a recessive gene was sufficient to explain the breast cancer distribution when the proband had postmenopausal breast cancer. In contrast. when the proband had premenopausal breast cancer. the transmission model was consistent with a dominant major gene. with sporadic cases of disease.
Results of stereotactic brachytherapy used in the initial management of patients with glioblastoma, Recent studies have shown a survival benefit for patients with recurrent glioblastomas treated with stereotactic brachytherapy. On the basis of these encouraging results. we began a prospective study in 1987 to evaluate the use of brachytherapy in patients with newly diagnosed glioblastoma. Patients were considered eligible for this study if they met the following criteria: Karnofsky performance status 70% or greater; tumor size not greater than 5 cm in any dimension; a radiographically well delineated. supratentorial lesion not involving the ependymal surfaces; and pathologically confirmed glioblastoma. We treated 35 such patients between 1987 and 1990 with stereotactic brachytherapy as part of their initial therapy. The treatment protocol involved surgery. partial brain external-beam radiotherapy (59.4 Gy in 33 fractions). and stereotactic brachytherapy with temporary high-activity iodine 125 sources giving an additional 50 Gy to the tumor bed. Chemotherapy was not used in the initial management of these 35 patients. To compare our results with those obtained in a matched control group. we identified 40 patients with glioblastoma treated with surgery and external radiotherapy. with or without chemotherapy. between 1977 and 1986 at our institution. These patients had clinical and radiographic characteristics that would have made them eligible for the brachytherapy protocol. Survival rates at 1 and 2 years after diagnosis were 87% and 57%. respectively. for patients receiving brachytherapy versus 40% and 12.5%. respectively. for the controls (P less than .001). We conclude that stereotactic brachytherapy improves the survival of patients with glioblastoma when it can be incorporated into the initial treatment approach. Unfortunately. only about one in four patients with glioblastoma are suitable candidates for brachytherapy at the time of initial presentation.
Effects of FUdR on primary-cultured colon carcinomas metastatic to the liver, Hepatic arterial infusion of fluorodeoxyuridine (FUdR) has demonstrated efficacy in the treatment of metastatic colorectal carcinoma of the liver. In this study. the direct cytotoxic effect of FUdR was measured on ten metastatic and two primary-site colorectal carcinomas in a primary culture assay system. Overall. clinically achievable concentrations of FUdR (0.4 to 4 microM) induced partial cell kill in 75% of tumors. including a greater than 50% reduction in viable tumor cell number in only two tumors and less than 50% in the remaining seven. Total cell kill was not observed in any tumor. Three tumors were resistant to these FUdR concentrations. Tumor sensitivity correlated with the size of the tumor growth fraction. Increasing the exposure time to FUdR from 3 to 7 days approximately doubled the magnitude of the response. 5-Flurouracil and cisplatin. at clinically achievable concentrations. were more toxic to metastatic tumor cells than FUdR. Because of the limited chemosensitivity of metastatic colorectal tumor cells to FUdR in vitro. we postulate that other mechanisms besides direct cytotoxicity contribute to the clinical efficacy of FUdR in vivo.
Cryoprobe as a "handle" for resection of metastatic liver tumors, Resection of metastatic liver tumors can be a difficult and risky procedure. Using a cryoprobe as a "handle" can greatly facilitate resection by providing a taut surface for transection and improving visualization of ductal and vascular structures. In addition. this technique may decrease the risk of contaminating surrounding tissues with cancer cells. and may inhibit tumor recurrence within the margins of resection.
Extended neck dissection, From the time Crile described radical neck dissection in 1906. this surgical procedure became popular in the management of metastatic cancer in the neck. Over the past two decades. the modified neck dissection has been effectively utilized for conservation of function and cosmesis while achieving the same oncologic goals. However. there are several instances where the above standard procedures are not adequate for resection of malignant tumors. Although there is a definite trend toward conservation procedures. extended neck dissection is often necessary especially in patients with N2 and N3 disease. Apart from the standard structures removed in radical neck dissection. the other structures removed in extended neck dissection include skin. the digastric muscle. hypoglossal nerve. vagus nerve. sympathetic chain. ramus mandibularis. carotid artery. tracheo-esophageal nodes. etc. Over the past seven years. we have performed 40 extended neck dissections. All the patients had N2 or N3 disease in the neck. Nine patients had unknown primaries. Thirteen patients had their primary tumors in the oral cavity and 11 in the laryngopharynx. Five patients had primary tumor in the salivary glands and two patients had metastatic melanoma. Patients who underwent extensive skin excision had pectoralis myocutaneous flap reconstruction. All patients received postoperative radiation therapy. One patient died of cardiac problems 4 weeks after operation. Local control was achieved in 70%. The most difficult region for local control was the disease behind the mastoid process. and the most difficult problems were patients with involvement of the subdermal lymphatics. Our data suggests that there are definite situations where extended neck dissection is indicated with satisfactory local control of the nodal disease.
Gamma-detecting probe and autoradiographic studies of radiolabeled antibody B72.3 in CX-1 colon xenografts, Nude mice bearing CX-1 colon tumors were injected with 50 microCi 125I-labeled monoclonal antibody (MAb) B72.3. Radioactivity in tumors was studied with the gamma detecting probe (GDP) on days 1. 3. 7. and 10 after MAb injection. On each day. two mice were sacrificed and sections were examined with autoradiography (ARG). immunoperoxidase methods (IMP). and routine stains. Mean probe counts showed increasing tumor to background ratios and ARG demonstrated a progressive increase in radionuclide in the tumors. The distribution of 125I was primarily around the vascular spaces on day 1. but by day 3 and progressively it appeared in tumor gland lumina and necrotic areas. A regional correlation was shown between radionuclide in vascular spaces and its sequestration in tumor elements.
Long survival and prognostic factors in hepatocellular carcinoma, We studied survival and prognostic factors in all cases of hepatocellular carcinoma seen at a Midwestern teaching hospital from 1947 through 1986. Of the 70 cases. 56 were diagnosed during life and 14 at autopsy. There were 47 males and 23 females with age at diagnosis ranging from 14 to 88. Median survival for the 56 patients diagnosed during life was 106 days. Only 11 patients lived longer than one year. Two patients were long survivors and presumed cured. one living 27 years after diagnosis and surgical treatment and the other 19 years. Cox regression model showed young age at diagnosis and low stage of disease at diagnosis to be significant predictors of long survival. White patients survived nearly twice as long as black patients but the difference was not significant. Gender and year of diagnosis did not appear to be important determinants of survival. Pathologic material was still available for one of the two long survivors and the histology was that of fibrolamellar carcinoma of young adults.
Community lifestyle characteristics and risk of acute lymphoblastic leukaemia in children, High rates of leukaemia in children and young people have been associated with features of community isolation and population growth. Incidence data collected by two specialist registries were used to compare incidence rates at ward level with relevant ward characteristics derived from routine census and Ordnance Survey data for England and Wales. An excess risk of childhood acute lymphoblastic leukaemia (ALL) was found for wards which are farthest from large urban centres. The excess was greatest for wards of higher socioeconomic status and for children aged 1-7 years (the childhood peak). for which a two-fold excess was seen. These findings in general support the hypothesis that childhood leukaemia has an infectious aetiology.
Loss of photosynthetic and chlororespiratory genes from the plastid genome of a parasitic flowering plant, Photosynthesis is the hallmark of plant life and is the only plastid metabolic process known to be controlled by plastid genes. The complete loss of photosynthetic ability. however. has occurred on several independent occasions in parasitic flowering plants. Some of these plants are known to lack chlorophyll and certain photosynthetic enzymes. but it is not known to what extent changes have occurred in the genes encoding the photosynthetic apparatus or whether the plants even maintain a plastid genome. Here we report that the nonphotosynthetic root parasite Epifagus virginiana has a plastid chromosome only 71 kilobases in size. far smaller than any previously characterized land plant plastid genome. The Epifagus plastid genome has lost most. if not all. of the 30 or more chloroplast genes for photosynthesis and most of a large family of plastid genes. the ndh genes. whose products may be involved in a plastid respiratory chain. The extensive changes in Epifagus plastid gene content must have occurred in a relatively short time (5-50 x 10(6) yr). because Striga asiatica. a related photosynthetic parasite. has a typical complement of chloroplast genes for photosynthesis and chlororespiration. The plastid genome of Epifagus has retained transcribed ribosomal RNA and ribosomal protein genes. suggesting that it expresses one or more gene products for plastid functions not related to photosynthesis.
Induction of RNA-stabilized DNA conformers by transcription of an immunoglobulin switch region, A deletion DNA rearrangement is associated with immunoglobulin class switching from IgM to IgG. IgA or IgE This recombination occurs in immunoglobulin switch regions. which are complex. highly repetitive regions of DNA. As switch regions become transcriptionally active just before switch recombination. analysis of the behaviour of these sequences during transcription could elucidate the mechanism of switch recombination. Here. we report that transcription of a supercoiled plasmid containing the murine IgA switch region (S alpha) leads to a loss of superhelical turns. The resulting series of less supercoiled plasmids is stabilized by RNA-DNA hybrids formed by the nascent RNA transcripts. which remain base-paired with their DNA templates.
Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages, Insulin-dependent diabetes mellitus (IDDM) is a disease with an autoimmune aetiology. The non-obese diabetic mouse is a good spontaneous animal model of the human disease. with IDDM developing in 50-80% of female mice by the age of 6 months. The disease can be transferred by splenic T cells from diabetic donors and is prevented by T-cell depletion. The mechanism(s) by which the beta cell is specifically destroyed is not known. but T cells and macrophages have both been implicated. based on the presence of macrophages in the infiltrated islet and the ability of chronic silica treatment to prevent disease. The monoclonal antibody 5C6 is specific for the myelomonocytic adhesion-promoting type-3 complement receptor (CR3 or CD11b/CD18) and does not bind to T cells. Here we show that blockade of macrophage CR3 in vivo prevents intra-islet infiltration by both macrophages and T cells and inhibits development of IDDM. We conclude that both T cells and macrophages have an essential role in the onset of IDDM.
Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity, The receptors for erythropoietin and other cytokines constitute a new superfamily. They have no tyrosine-kinase or other enzyme motif and their signal-transducing mechanism is unclear. Here we describe two classes of activating mutations in the erythropoietin receptor (EPOR). A single point mutation in the exoplasmic domain enables it to induce hormone-independent cell growth and tumorigenesis after expression in nontumorigenic. interleukin-3-dependent haematopoietic cells. A C-terminal truncation in the cytoplasmic domain of the EPOR renders the receptor hyperresponsive to erythropoietin. but is insufficient to induce hormone-independent growth or tumorigenicity. The activating point mutation retards intracellular transport and turnover of the receptor. These alterations in metabolism and tumorigenicity caused by the EPOR with activating point mutations are similar to those observed in erythropoietin-independent activation of the wild type EPOR by association with gp55. the Friend spleen focus-forming virus glycoprotein.
Current trends in suture fixation of posterior chamber intraocular lenses, Corneal surgeons were surveyed with regard to their technique of suture fixation of posterior chamber intraocular lenses in the absence of posterior capsular support. Fifty-nine percent of the 260 respondents stated they perform the procedure almost exclusively during penetrating keratoplasty. Scleral fixation was marginally favored over iris fixation by these surgeons. Most intraoperative problems reported were related to the relative technical difficulty of the procedure. although transient hemorrhage from the ciliary body was also mentioned. Postoperative complications cited included mechanical problems involving the lens and iris. cystoid macular edema. glaucoma. and endophthalmitis.
Glaucoma secondary to epithelial downgrowth and 5-fluorouracil, Since epithelial downgrowth involves an actively proliferating intraocular tissue. it is possible that the antimetabolite 5-fluorouracil may inhibit it. We report a case of secondary glaucoma caused by epithelial downgrowth in which filtration surgery was performed with adjunctive use of subconjunctival 5-fluorouracil. On cessation of the injections. the retrocorneal membrane grew rapidly to involve the entire posterior cornea. The eye eventually became blind and painful and was enucleated. The use of 5-fluorouracil given in the usual manner appears to have been a failure.
Use of a symblepharon ring for treatment of over-filtration and leaking blebs after glaucoma filtration surgery, We report the use of a symblepharon ring in the treatment of seven cases of flat anterior chamber (six cases of total iridocorneal touch. and one of corneallens touch) secondary to overfiltration or to bleb leak. In all cases. the anterior chamber reformed within 24 hours after the symblepharon ring was used. Advantages of using the ring are: (a) it permits testing of visual acuity. tonometry. and intraocular examination without removing it; (b) it does not require suturing to the conjunctiva; (c) it does not disturb the corneal epithelium; (d) it may be available at institutions lacking other shells; and (e) it is cost-effective.
Hemihang-back recession: description of the technique and review of the literature, We describe a modification of the hang-back and loop techniques that we call the hemihang-back recession. in which the muscle is reattached to the sclera posterior to the original insertion with a single. absorbable suture. We recommend it for difficult strabismus cases. specifically when recessions of 7 mm or more are required.
Posterior horizontal and vertical tightening to treat combined punctal ectropion with medial canthal tendon laxity, The classical operations to treat either medial canthal tendon laxity or punctal aversion occurring alone possess drawbacks if they are used to treat these conditions when they occur simultaneously. A simplified procedure is described whereby tissue is removed via a posterior eyelid approach so that the eyelid may be tightened both horizontally and vertically. thus inverting the punctum and fixating it in the lacrimal lake. This procedure is quite easy to perform and can be done under local anesthesia in the office.
Learning curve for radial keratotomy, I prospectively evaluated my own learning curve for radial keratotomy (RK) by comparing the results achieved in two groups: 20 consecutive eyes on which I performed RK without having had previous experience with the procedure (group 1); and 20 other eyes. matched for age. sex. and preoperative refractive error. on which I performed RK after I had performed the procedure 250 times (group 2). Although there were nine microperforations in group 1 and none in group 2. the postoperative refractions and uncorrected visual acuities were similar in both groups. Since the microperforations had no adverse effect on the visual results. it is reasonable to conclude that there was. in effect. no learning curve involved in my experience with RK.
Role of communities in decision-making eye care programs, The concept of primary health care involves educating people to live their lives in ways beneficial to their health. Communities as a whole must participate in the decision-making that is involved in such education. be it promotive. preventive. curative. or rehabilitative. I refer to this participation as "participatory communication." It is based on two fundamental tenets: 1) Everyone in a community has some special knowledge to contribute to the development of the health of that community; and 2) No person is superior to another. Subsequent to sociological and anthropological studies of communities in the Southern Sudan by the Norwegian Church Aid. the Norwegian Association of the Blind and Partially-Sighted conducted village workshops based on this concept.
Visual results and complications of transsclerally sutured intraocular lenses in penetrating keratoplasty, We retrospectively reviewed the charts of 56 consecutive patients who had undergone penetrating keratoplasty with transscleral fixation of a posterior chamber intraocular lens. Follow-up ranged from 3 to 28 months (mean. 11.1 months). Postoperative visual acuity improved in 46 patients (82%). remained the same in eight (14%). and worsened in two (3.6%). In 32 patients with at least 10 months' follow-up. best corrected visual acuity as measured with a pinhole or hard contact lens was 20/40 or better in 12 (38%). 20/50 to 20/10 in 10 (31%). and 20/200 or worse in 10 (31%). Problems with lens decentration. tilt. or scleral suture-related infections were minimal. Glaucoma was the msot common cause of decreased vision in patients with 10 or more months' follow-up. Three patients (5.4%) developed rhegmatogenous retinal detachments early in the postoperative course.
Central retinal vein obstruction and axial length, The axial lengths of 24 consecutive adult eyes with unilateral central retinal vein obstruction (CRVO) were compared with those of contralateral unaffected eyes and those of a control population. The lengths of the two eyes of persons with a unilateral CRVO were not significantly different. By contrast. eyes of persons with CRVO averaged 0.67 mm (approximately 2 diopters) shorter than their control counterparts (P = .03). This anatomic difference may be a factor in the development of CRVO.
Phacofragmentation of a hard lens nucleus in the posterior segment, Foreign body forceps were used to stabilize a hard lens nucleus during phacofragmentation in the posterior segment. This technique allows removal of the hard lens nucleus with minimal manipulation and without the need for a larger incision.
A new ophthalmic microtrephine, We present a new instrument designed to facilitate the microtrephination of tissues required in various ophthalmic procedures. This microtrephine is a 21-gauge stainless steel tube. 0.81 mm in diameter and 16 mm long. with a sharpened cutting end and a plastic finger-grip area to facilitate micro-rotation. A standard plastic luer hub allows the trephine to be used with a syringe. either a standard type or one with a spring-assisted plunger. Scar tissue. biopsy specimens. or abnormal inflammatory fluids can be suctioned into the syringe for subsequent pathologic examination.
The viscous fluid pump, We describe a device useful for injection of viscoelastic material into the vitreous cavity for internal tamponade. The instrument has proven to be reliable and "user friendly" in a clinical setting.
Changes in thermal and mechanical pain thresholds in hand amputees. A clinical and physiological long-term follow-up, In a previous study. allodynia to cold and vibratory stimuli was found in the finger stumps of 24 patients with amputations. control values being obtained from fingers of the intact contralateral hand. When treated with regional intravenous guanethidine block (RGB). some of the patients only had short-lasting relief of symptoms. whereas others experienced a more long-lasting beneficial effect. In the present long-term follow-up study the patients were re-examined 6 years after the RGB treatment. The aim was to investigate whether the earlier symptoms and signs persisted. and whether there were any differences in these respects. between patients with long-lasting (group 1) and short-lasting relief of symptoms after RGB (group 2). All 24 patients were asked to answer a questionnaire concerning their clinical symptoms. In addition. 14 of them visited the laboratory for determination of thermal and vibration-induced pain thresholds. Comparisons were made with values obtained at the first examination before RGB treatment and with values from 14 healthy subjects tested in a similar way on 2 occasions with an interval of 8 years. Twenty of 23 patients reported that cold exposure still evoked stump pain. However. the threshold measurements showed that with time the patients had become more tolerant to thermal stimuli not only in the injured but also in the uninjured hand. A rise in pain threshold was also observed when vibration-induced pain was tested in the injured hand. There was no significant difference between groups 1 and 2. Similar changes in pain thresholds with time were not observed in the group of healthy control subjects.
Health locus of control, gender differences and adjustment to persistent pain, Locus of control (LOC) beliefs. long thought important in adjustment to persistent pain. were studied among 160 subjects (67 males and 93 females) referred to a comprehensive pain rehabilitation program. The subscale structure of the Multidimensional Health Locus of Control (MHLC) was factorially replicated in our sample. Three unique MHLC profile clusters were identified for both males and females. Among men. cluster assignment was related to age only. The younger male patients reported a stronger internal attributional style. Older male patients relied more heavily on both chance and powerful other factors. Among women. cluster assignment was related to the use of coping strategies. For example. patients with high internal scores only. reflecting a strong internal orientation towards self-management of health care needs. were more likely to utilize Information-Seeking. Self-Blame. and Threat Minimization coping strategies than patients with high scores on both the Internal and Powerful Other factors. It appears that the presence of both Internal and Powerful Other health attributional styles is associated with less frequent use of cognitive self-management techniques. In understanding the LOC scores it is important to rely on pattern analysis of scores. Implications for clinical treatment are discussed.
Neonatal facial and cry responses to invasive and non-invasive procedures, Evaluation of pain in neonates is difficult due to their limited means of communication. The aim was to determine whether behavioural reactions of cry and facial activity provoked by an invasive procedure could be discriminated from responses to non-invasive tactile events. Thirty-six healthy full-term infants (mean age 2.2 h) received 3 procedures in counterbalanced order: intramuscular injection. application of triple dye to the umbilical stub. and rubbing thigh with alcohol. Significant effects of procedure were found for total face activity and latency to face movement. A cluster of facial actions comprised of brow bulging. eyes squeezed shut. deepening of the naso-labial furrow and open mouth was associated most frequently with the invasive procedure. Comparisons between the 2 non-invasive procedures showed more facial activity to thigh swabbing and least to application of triple dye to the umbilical cord. Acoustic analysis of cry showed statistically significant differences across procedures only for latency to cry and cry duration for the group as a whole. However. babies who cried to two procedures showed higher pitch and greater intensity to the injection. There were no significant differences in melody. dysphonation. or jitter. Methodological difficulties for investigators in this area were examined. including criteria for the selection of cries for analysis. and the logical and statistical challenges of contrasting cries induced by different conditions when some babies do not always cry. It was concluded that facial expression. in combination with short latency to onset of cry and long duration of first cry cycle typifies reaction to acute invasive procedures.
Effects of lesions in the anterolateral columns and dorsolateral funiculi on self-mutilation behavior in rats, The possible role of the anterolateral columns (ALCs) and dorsolateral funiculi (DLF) in pain mechanisms was examined from the effects of lesions in these tracts (alone or combined) on tests for chronic deafferentation pain (autotomy) in rats. Spinal lesions alone (i.e.. without denervation) in either ALC or DLF or combined DLF-ALC did not lead to any form of self-mutilation behavior. Cervical surgery. without spinal lesion. followed by limb denervation (sham) resulted in similar autotomy characteristics to those observed following limb denervation alone (control). Both results were considered as one set of controls. ALC lesions simultaneous with. or 1-2 weeks prior to limb denervation (ipsilaterally or contralaterally) produced significant delay in onset of autotomy and decrease in percentage of rats showing this behavior. DLF lesions followed by limb denervation produced significant acceleration of onset of autotomy and increase in percentage of rats showing this behavior. Combined DLF-ALC lesions with limb denervation produced intermediate effects between those observed following either ALC or DLF lesions alone. These results give further support to the concept that autotomy is related to rostral transmission of nociceptive information and that a spino-bulbo-spinal inhibitory loop involving the DLF and ALC is triggered by chronic deafferentation pain.
Characterization of descending inhibition and facilitation from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat, Descending influences on the spinal nociceptive tail-flick (TF) reflex produced by focal electrical stimulation and glutamate microinjection in the nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGC alpha) were examined and characterized in rats lightly anesthetized with pentobarbital. Both inhibition and facilitation of the TF reflex were produced by electrical stimulation at identical sites in the NGC/NGC alpha; glutamate microinjection only inhibited the TF reflex. The chronaxie of stimulation for inhibition of the TF reflex was 169 +/- 28 microseconds. Inhibition of the TF reflex by stimulation was produced throughout the NGC and NGC alpha; intensities of stimulation for inhibition were least in the ventral NGC and in the NGC alpha. At threshold intensities of stimulation. inhibition of the TF reflex did not outlast the period of stimulation. Facilitation of the TF reflex was produced at many of the same sites at which stimulation inhibited the TF reflex. but always at lesser intensities of stimulation (mean. 10 microA vs. 43 microA for inhibition. n = 25). Stimulation in the NGC/NGC alpha at threshold intensities for facilitation or inhibition of the TF reflex did not significantly affect blood pressure. Strength-duration characterization of electrical stimulation and microinjection of glutamate into identical sites in the NGC and NGC alpha suggest that descending inhibition of the TF reflex results from activation of cell bodies in the NGC and NGC alpha.
Transcranial electrical stimulation with high frequency intermittent current (Limoge's) potentiates opiate-induced analgesia: blind studies, Transcutaneous cranial electrical stimulation (TCES) with high frequency (166 kHz) intermittent current (100 Hz: Limoge current) has been used for several years in cardiac. thoracic. abdominal. urological and micro-surgery. The main benefits are a reduced requirement for analgesic drugs. especially opiates. and a long-lasting postoperative analgesia. We have confirmed these clinical observations in rats using the tail-flick latency (TFL) test to measure pain threshold. TCES was not found to modify the pain threshold in drug-free rats. but it potentiated morphine-induced analgesia (systemic injection). To obtain a maximal effect. the stimulation must be initiated 3 h before the drug injection and be maintained throughout the duration of its pharmacological action. TCES potentitation was found to depend on the dose of the drug. the intensity of the current and the polarity of electrodes. These findings were confirmed by blind tests of the efficiency of TCES on several opiate analgesic drugs currently used in human surgery (morphine. fentanyl. alfentanil and dextromoramide). The analgesic effect of these 4 opiates (TFL as % of baseline without or with TCES) were respectively: 174%. 306%; 176%. 336%; 160%. 215%; and 267%. 392%. The results were obtained not only after systemic opiate treatment. but also after intracerebroventricular injection of morphine (10 micrograms; analgesic effect 152%. 207% with TCES) suggesting that TCES potentiation of opiate-induced analgesia is centrally mediated.
The influence of warning signal timing and cognitive preparation on the aversiveness of electric shock, Many medical and dental procedures are noxious. Finding an optimal way of warning patients concerning the aversive procedures could help them to cope better. A model for the effective use of a warning signal in coping with pain posited that a person needs enough time to be able to react and should possess the skills necessary to utilize the time effectively. It was felt that a very short warning period. e.g.. 5 sec. could not be long enough. while a 180 sec warning period would in and of itself become aversive. Reactions to electric shock were obtained from 36 paid. volunteer subjects who were each tested on a within-subject. counterbalanced order at 4 different warning periods: 5. 30. 60. and 180 sec. The subjects were divided into 3 groups: (1) the experimental group was provided with a pretested self-instructional booklet to learn a variety of pain control techniques; (2) the placebo group was provided with a self-instructional booklet on citizenship; (3) the control group waited quietly for 13 min. No significant results were obtained for the different pain-coping conditions. Significant differences. however. were obtained for the various warning periods. Maximum skin resistance changes. higher ratings of pain and of anxiety were obtained for the 60 and 180 compared to the 5 and 30 sec warning periods. Maximum heart rate was obtained for the 30 sec warning. Results were discussed in terms of the psychological meaning of the various measures as well as their clinical implications.
Annual summary of vital statistics--1989, US infant mortality continued to decline slowly and the provisional 1989 rate. 9.7 per 1000 live births. was the lowest ever recorded. Final 1988 data showed no change in cause of death distribution or in the wide discrepancy between white and black infant mortality. State rates varied from 6.8 in Vermont to 12.6 in Georgia. Worldwide. the US rate of 10.0 was bettered by 21 other countries. with Japan lowest at 4.8. Births increased in number and rate. because of a higher fertility rate and more women in the childbearing years. The birth rate to mothers 17 years of age and younger increased again. The proportion of women who had no or inadequate prenatal care was essentially unchanged. Deaths. crude death rate. and age-adjusted death rate decreased. The excess of births over deaths added almost 1.9 million persons to the US population. the highest rate of natural increase since 1971. The marriage rate was essentially unchanged. whereas the divorce rate decreased slightly. to the lowest level since 1973. With the exception of human immunodeficiency virus infection. homicide. and pulmonary malignancies. rates for most causes of death declined from 1988 to 1989. In comparison with 1940. most declines were substantial. led by pneumonia. down about 80%. and perinatal conditions. down about 75%. The only large-scale increases among major causes in the half century were in two diseases related to cigarette smoking: chronic obstructive pulmonary disease. up eightfold. and respiratory cancer. up almost sixfold. Death rates from all other cancers. as a group. decreased by some 20% and from cardiovascular diseases by some 60%.
Efficacy of tetracaine-adrenaline-cocaine topical anesthetic without tetracaine for facial laceration repair in children [published erratum appears in Pediatrics 1991 Feb;87(2):185, To determine whether the tetracaine component traditionally used in tetracaine-adrenaline-cocaine (TAC) is necessary to obtain effective topical anesthesia. a prospective study was performed to compare TAC and adrenaline-cocaine preparations for the repair of facial lacerations in children. Physicians were "blind" to which preparation was being used. Of 55 patients studied. 24 received TAC (103 sutures placed) and 31 received adrenaline-cocaine (151 sutures placed). The anesthetic efficacy of each preparation was approximately 95%; there were no adverse reactions related to administration of either medication or complications of wound healing noted in either group. The tetracaine component of TAC is superfluous for obtaining topical anesthesia of minor dermal lacerations of the face in children. The TAC formulation can be simplified by omitting tetracaine without compromising anesthetic efficacy.
Health of homeless children and housed, poor children, Homeless children in families are increasing in numbers across the country and have been noted to have frequent health problems. The health status of homeless children was assessed on multiple dimensions through parental report in a survey conducted with 196 homeless families in 10 shelters in Los Angeles and 194 housed poor families after March 1987 through January 1988. During the month before the survey. the homeless and housed poor children experienced high rates of illness symptoms. disability. and bed days. Homeless and housed poor children were frequently rated by their parents to be in fair or poor health (17% vs 13%. P = .14). Homeless children. however. were reported to have more behavior problems and school failure [30% vs 18%. P = .06] than housed poor children. Homeless children also had high rates of other health problems such as developmental delay (9%) and overweight (13%). The diets of homeless children were frequently imbalanced. dependent on food from "fast-food" restaurants. and characterized by repeated periods of deprivation. Family problems were more common among homeless families. especially among single-parent homeless families compared with single-parent housed families (spousal abuse. 68% vs 41%. P less than .01; parental drug and alcohol abuse. 60% vs 39%. P less than .01). It is concluded that homeless children have significant child behavior and developmental problems and disorders of nutrition and growth. which are associated with multiple risk factors in their environment.
Increasing incidence of varicella hospitalizations in United States Army and Navy personnel: are today's teenagers more susceptible? Should recruits be vaccinated, Hospital records for 10.687 United States Army and Navy adult varicella (chickenpox) admissions were reviewed. Annual hospital admission rates for varicella increased more than fourfold in the active-duty army during 1980 to 1988 and more than 18-fold among active-duty navy enlisted personnel during 1975 to 1988. Fifty-seven percent of varicella admissions occurred in the most junior military members. aged 17 to 20. More than half of the total varicella admissions occurred in personnel with less than a year of military service. Multivariate analysis of the navy data confirmed increasing time-related trends of risk. suggesting a national temporal trend of increased varicella susceptibility in US teenagers and young adults. Administering a safe and effective varicella vaccine to army and navy recruits could prevent more than 7260 hospital-bed days during the first year of use.
Breast-feeding and diarrheal morbidity, This study used a unique longitudinal survey of more than 3000 mother-infant pairs observed from pregnancy through infancy. The sample is representative of infants from the Cebu region of the Philippines. The sequencing of breast-feeding and diarrheal morbidity events was carefully examined in a longitudinal analysis which allowed for the examination of age-specific effects of feeding patterns. Because the work controlled for a wide range of environmental causes of diarrhea. the results can be generalized to other populations with some confidence. The addition to the breast-milk diet of even water. teas. and other nonnutritive liquids doubled or tripled the likelihood of diarrhea. Supplementation of breast-feeding with additional nutritive foods or liquids further increased significantly the risk of diarrhea; most benefits of breast-feeding alone or in combination with nutritive foods/liquids became small during the second half of infancy. Benefits of breast-feeding were slightly greater in urban environments.
High-fat semielemental diet in the treatment of protracted diarrhea of infancy, The capacity for greater fat absorption relative to carbohydrate absorption in protracted diarrhea of infancy was studied in a developed and a developing country (Buffalo. NY. and Bangkok. Thailand). Fifty patients with protracted diarrhea in the first year of life (defined as liquid stools of more than 20 mL/kg per day with more than a 14-day duration) were randomly assigned to receive either a standard semielemental diet (Pregestimil) or a high-fat semielemental diet that contained 40% more fat. The increased fat was largely in the form of medium-chain triglycerides. with the new diet providing 60% of the fat as medium-chain triglycerides compared with 40% in the standard diet. Tolerance to both diets was good in both studies. Both groups showed adequate weight gain and an improvement in anthropometric and biochemical parameters. The patients receiving the high-fat diet showed no initial weight loss. however. and their weight gain was initiated earlier. Cumulative weight gain was also higher in the group receiving the high-fat semielemental diet. Fecal fat analyses were performed after 1 week of therapy. There was no difference observed in the coefficient of fat absorption between the groups receiving the two formulas. indicating that infants with protracted diarrhea may be able to tolerate a higher fat intake than is normally provided. As carbohydrate intolerance is known to be a complicating factor when using semielemental enteral feeds for infants with protracted diarrhea. a higher-fat semielemental diet may be the most appropriate way to provide adequate caloric intake.
Efficacy of methylphenidate among mentally retarded children with attention deficit hyperactivity disorder, Twelve children with IQ scores of 50 to 74 (educable mental retardation) who met rigorous diagnostic criteria for attention deficit hyperactivity disorder participated in a double-blind crossover study of the efficacy of two doses of methylphenidate compared with placebo. Dependent measures included behavioral ratings. classroom work output. laboratory measures of attention and learning. and direct observations of social behavior. Improvement with medication on the Conners Hyperactivity Index was observed in 75% of subjects. Significant increases in work output. on-task behavior. and attentional skills were associated with methylphenidate. However. gains in measures of attention were not associated with improvement in learning. as measured by a paired associate learning task. Additionally. no significant increases in appropriate social interactions during free play were associated with methylphenidate. The results suggest that mentally retarded children with attention deficit hyperactivity disorder respond to methylphenidate at similar rates and in similar domains to that of the nonretarded population.
Arthropathy of Down syndrome, A juvenile rheumatoid arthritis-like arthropathy has previously been documented in 12 patients with Down syndrome. An additional 9 patients are described and the literature is reviewed. It is unknown whether these patients have juvenile rheumatoid arthritis or a unique arthropathy in light of the genetic and immunologic abnormalities associated with Down syndrome. Most of the patients had a progressive course with polyarticular disease complicated by subluxations and a long lag time to diagnosis. The purpose of reporting these children is to increase awareness of this association and facilitate more appropriate and timely diagnosis of arthritis in Down syndrome patients.
Neonatal ethics: development of a consultative group, Experience of a neonatal ethics advisory group in a tertiary care setting was reviewed to identify which aspects of the experience have been most valuable in the development of a consultative group. Consultations were requested for 31 patients seen from August 1984 through December 1988. Review of these patients indicated that 21 of 31 infants were born after full-term gestations. 11 of 31 infants were seen beyond the neonatal period. and some type of congenital anomaly was the principal diagnosis for 64.7% of the patients. The reasons for seeking consultation primarily involved decisions regarding withdrawal or withholding of treatment. For 22 of the 31 patients. the consensus of the group supported the decision of the health care team. In the remaining consultations. the recommendation of the group was that more information and/or communication was needed. In the analysis of the neonatal ethics advisory group's experience with consultations the characteristics of neonatal patients were identified and the value of having a forum for discussing the difficult ethical issues facing members of the health care team were validated.
Quantifying language development from birth to 3 years using the Early Language Milestone Scale, A point-scoring technique for the Early Language Milestone Scale is described. Normative data based on the original 1982 cross-sectional sample and validation data based on a separate longitudinal sample are presented. Mean Early Language Milestone Scale point scores. standard deviations. and percentile equivalents for raw point scores are presented for all ages from birth to 36 months. Correlations between point scores on the Early Language Milestone Scale and scores on other standardized developmental tests such as the Stanford-Binet Intelligence Scale. the Peabody Picture Vocabulary Test. and the Illinois Test of Psycholinguistic Abilities are presented. The clinical and research advantages of this point-scoring technique are presented and compared with the original pass/fail scoring method.
Delayed detection of coarctation in infancy: implications for timing of newborn follow-up, During a recent 5-year period. 74 patients younger than 6 months of age were diagnosed with coarctation of the aorta. Coarctation was correctly diagnosed in only 22% of patients prior to referral despite readily apparent femoral pulse abnormalities in 86%. Infants whose symptoms were detected between 5 and 14 days of age were significantly more ill than infants outside this age range and had a high mortality rate (25%). The number of associated cardiac defects was not related to the severity of clinical illness in this group. suggesting that closure of the ductus arteriosus is the primary determinate of disease severity. Observations in two patients suggested that a detectable pulse discrepancy occurs between 3 and 5 days postnatally. Upper extremity hypertension was found commonly in infants after 5 days of age despite the presence of congestive heart failure. Earlier detection of coarctation in the newborn requires a diligent cardiovascular and peripheral pulse examination between 3 and 7 days of life. upper extremity and lower extremity blood pressure measurement. and a high index of suspicion.
Differential regulation of human immunodeficiency viruses (HIVs): a specific regulatory element in HIV-2 responds to stimulation of the T-cell antigen receptor, The human immunodeficiency viruses (HIVs) types 1 and 2 have similar genetic organization but differ significantly in nucleic acid sequence. Although infection by either agent leads to symptoms of immunodeficiency. recent studies suggest potential differences in the time course and severity of these diseases. In this report. the transcriptional regulation and induction of these retroviruses were analyzed. We report that the regulation of HIV-2 differs from that of HIV-1: a distinct T-cell activation pathway. triggering of the CD3 component of the T-cell receptor complex. stimulates HIV-2 but not HIV-1 gene expression. The response to T-cell receptor stimulation in HIV-2 is mediated partly by an upstream regulatory element. termed CD3R. which is recognized by a sequence-specific DNA binding protein. NF-CD3R. Jurkat T leukemia cell lines containing HIV-2 provirus also showed increased viral replication after stimulation of the T-cell receptor complex. in contrast to HIV-1. These findings suggest that transcriptional regulation and induction of HIV-2 differ from HIV-1 and raise the possibility that different cofactors contribute to the activation of HIV-1- and HIV-2-associated AIDS.
A retroviral promoter is sufficient to convert proto-src to a transforming gene that is distinct from the src gene of Rous sarcoma virus, The src genes of four natural isolates of avian sarcoma viruses differ from cellular proto-src in two genetic substitutions: the promoter of the cellular gene is replaced by a retroviral counterpart. and at least six codons from the 3' terminus are replaced by retroviral or heterologous cell-derived elements. Since virus constructs with a complete proto-src coding region failed to transform avian cells but acquired transforming function by point mutations of various codons. it has been proposed that point mutation is sufficient to convert proto-src to a transforming gene. However. promoter substitution is sufficient to convert two other proto-onc genes. proto-ras and proto-myc. to retroviral transforming genes. In view of this. we have reexamined whether promoter substitution. point mutation. or both are necessary to convert proto-src into a retroviral transforming gene. It was found that a recombinant virus (RpSV). in which the src gene of Rous sarcoma virus (RSV) was replaced by the complete coding region of proto-src. transformed quail and chicken embryo cells. The oncogene of RpSV differs from the src gene of RSV in three genetic properties: (i) it is weaker--e.g.. transformed cells are flatter; (ii) it is slower--e.g.. focus formation takes 9 to 12 days compared to 4 days for RSV; and (iii) its host range is narrower than that of RSV--e.g.. only subsets of heterogeneous embryo cells are transformed by RpSV even after weeks or months. Replacement of the proto-src 3' terminus of RpSV by that of src from RSV generates a recombinant virus (RpvSV) that equals RSV in transforming function. It is concluded that a retroviral promoter. naturally substituted via illegitimate recombination with retroviruses. is sufficient to convert at least three proto-onc genes. src. myc. and ras. to retroviral transforming genes.
Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum, Respiratory distress and progressive lung destruction in cystic fibrosis can be attributed to bacterial persistence and the accumulation of viscous purulent secretions in the airways. More than 30 yr ago it was suggested that the large amounts of DNA in purulent secretions contribute to its viscosity and that bovine pancreatic DNase I could reduce the viscosity. To evaluate the potential clinical utility of recombinant human DNase I (rhDNase) in the treatment of cystic fibrosis. we have cloned. sequenced. and expressed rhDNase. Catalytic amounts of rhDNase greatly reduce the viscosity of purulent cystic fibrosis sputum. transforming it within minutes from a nonflowing viscous gel to a flowing liquid. The reduction in viscosity is associated with a decrease in size of DNA in the sputum. Inhalation of a rhDNase aerosol may be a simple direct approach that will help individuals with cystic fibrosis and other patients with pneumonia or bronchitis to clear their airways of purulent secretions.
Multisurface method of pattern separation for medical diagnosis applied to breast cytology, Multisurface pattern separation is a mathematical method for distinguishing between elements of two pattern sets. Each element of the pattern sets is comprised of various scalar observations. In this paper. we use the diagnosis of breast cytology to demonstrate the applicability of this method to medical diagnosis and decision making. Each of 11 cytological characteristics of breast fine-needle aspirates reported to differ between benign and malignant samples was graded 1 to 10 at the time of sample collection. Nine characteristics were found to differ significantly between benign and malignant samples. Mathematically. these values for each sample were represented by a point in a nine-dimensional space of real variables. Benign points were separated from malignant ones by planes determined by linear programming. Correct separation was accomplished in 369 of 370 samples (201 benign and 169 malignant). In the one misclassified malignant case. the fine-needle aspirate cytology was so definitely benign and the cytology of the excised cancer so definitely malignant that we believe the tumor was missed on aspiration. Our mathematical method is applicable to other medical diagnostic and decision-making problems.
Embryonic stem cell virus, a recombinant murine retrovirus with expression in embryonic stem cells, The expression of Moloney murine leukemia virus and vectors derived from it is restricted in undifferentiated mouse embryonal carcinoma and embryonal stem (ES) cells. We have developed a retroviral vector. the murine embryonic stem cell virus (MESV). that is active in embryonal carcinoma and ES cells. MESV was derived from a retroviral mutant [PCC4-cell-passaged myeloproliferative sarcoma virus (PCMV)] expressed in embryonal carcinoma cells but not in ES cells. The enhancer region of PCMV was shown to be functional in both cell types. but sequences within the 5' untranslated region of PCMV were found to restrict viral expression in ES cells. Replacement of this region by related sequences obtained from the dl-587rev retrovirus results in MESV. a modified PCMV virus that confers G418 resistance to fibroblasts and ES cells with similar efficiencies. Expression of MESV in ES cells is mediated by transcriptional regulatory elements within the 5' long terminal repeat of the viral genome.
Molecular characterization of inherited medium-chain acyl-CoA dehydrogenase deficiency, Deficiency of medium-chain acyl-CoA dehydrogenase (MCAD) is a common inherited defect in energy metabolism. Characterization of the mRNA encoding MCAD in a Dutch MCAD-deficient patient revealed an A----G change at nucleotide position 985 of the MCAD mRNA coding region. This point mutation results in the substitution of a glutamic acid for a lysine at amino acid position 304 of the mature protein. The single base change was not found in any wild-type MCAD mRNAs. A mutant allele-specific oligonucleotide probe was used in a hybridization analysis of amplified genomic DNA of MCAD-deficient family members. a carrier. and normal individuals. The hybridization analysis specifically identified individuals who were heterozygotes or homozygotes. In addition to the point mutation. a significant proportion of the index patient's MCAD mRNA contained a variety of deletions and insertions as a result of exon skipping and intron retention. The missplicing occurred in multiple regions throughout the MCAD mRNA. Analysis of the patient's MCAD gene in the regions where the missplicing occurred most frequently did not reveal a mutation in the splicing acceptor or donor sites. Therefore. the molecular characterization of this family revealed a crucial point mutation in the MCAD gene and an unusual abnormality in MCAD pre-mRNA splicing.
Glucocorticoids locally disrupt an array of positioned nucleosomes on the rat tyrosine aminotransferase promoter in hepatoma cells, Transcriptional activation by steroid hormones is often associated with the appearance of a DNase I hypersensitive site resulting from a local alteration of the nucleoprotein structure of the promoter. For the mouse mammary tumor virus long terminal repeat. a viral promoter under glucocorticoid control. a model has been proposed: the appearance of the hormonodependent DNase I hypersensitive site reflects the displacement of a single precisely positioned nucleosome associated with the glucocorticoid responsive elements. To determine if such a mechanism is of general relevance in transcriptional activation by steroid hormones. we have investigated the nucleosomal organization of the rat tyrosine aminotransferase promoter over a 1-kilobase region that contains the glucocorticoid regulatory target. This region displays a hormonodependent DNase I hypersensitive site. In the absence of hormone. micrococcal nuclease digestion of nuclei demonstrates the presence of positioned nucleosomes. with cutting sites centered around positions -3080. -2900. -2700. -2800. -2255. and -2040. Treatment of the cells with dexamethasone induces a disruption of the chromatin structure over a relatively short stretch of DNA (approximately positions -2400 to -2650) that overlaps two nucleosomes. These observations suggest a strong similarity in the role of chromatin structure in glucocorticoid-dependent transcriptional activation of mouse mammary tumor virus and tyrosine aminotransferase promoters.
Transformed and nontransformed cells differ in stability and cell cycle regulation of a binding activity to the murine thymidine kinase promoter, A DNA binding activity to an upstream region of the murine thymidine kinase gene is regulated differently in a transformed and nontransformed cell line pair. Differences in regulation were observed (i) after serum levels were reduced. (ii) when serum levels were returned to initial high levels. and (iii) while protein synthesis was inhibited. After reduction of serum levels. the binding activity was unstable in nontransformed BALB/c 3T3 clone A31 cells but was significantly more stable in benzo[a]pyrene-transformed BALB/c 3T3 cells. After serum concentration was returned to high levels. the kinetic pattern of the binding activity differed between nontransformed and transformed cells. While protein synthesis was inhibited. the binding activity was unstable in nontransformed cells and stable in transformed cells. Partial inhibition of protein synthesis--a more stringent condition to test instability--prevented the induction of the binding activity in nontransformed cells. Previously. the labile protein hypothesis set forth the criterion that a protein regulating the onset of DNA synthesis should be unstable in nontransformed cells and stable in transformed cells. The DNA binding activity described here satisfies this criterion.
Evidence against a requisite role for defective virus in the establishment of persistent hepadnavirus infections, The factors involved in the establishment of persistent hepadnavirus infection are poorly understood. Recent findings demonstrate that the sequence of the genome of hepatitis B virus (HBV) is variable in infected individuals and that. in some cases. virus mutants predominate. Our objectives in the present study were to analyze the variability of woodchuck hepatitis virus (WHV) genomes in an infected animal and to determine whether sequence heterogeneity played a critical role in the ability of WHV to induce chronic infection. We cloned and determined the complete nucleotide sequence of three supercoiled genomes from an animal that became infected after inoculation with a standardized WHV serum pool (i.e.. the WHV7 virus pool). We found that there were four nucleotide substitutions among the three genome sequences as well as a 73-nucleotide deletion in one of the recombinants. DNA transfection experiments revealed that only one of the three recombinants was capable of independent replication. These data suggest that a significant proportion of replicative templates in woodchucks that are infected with WHV are defective virus genomes. Next. we compared the outcome of acute infection after inoculation with a serum pool containing a uniform population of replication competent virus (i.e.. the WHV7R pool) with a serum pool composed of WHV genomes of variable sequence. The WHV7R serum pool originated from a woodchuck that became a chronic carrier after in vivo transfection of the liver with the infectious WHV7 recombinant. Neonatal woodchucks were inoculated with 5 x 10(6) WHV genome equivalents of either the WHV7 pool or the WHV7R pool. All animals in the study became acutely infected with WHV. Of the animals infected with the WHV7 serum pool. 65% became chronic carriers. while 80% of the animals infected with the WHV7R serum pool developed chronic infection. Thus. infection of woodchucks with a serum pool containing defective virus resulted in a rate of chronic WHV infection that was similar to. or even lower than. a rate from a pool containing only wild-type virus. This suggests that the presence of defective virus in the inoculum is not a prerequisite for the establishment of persistent hepadnavirus infections.
Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig, Lipoprotein(a) [Lp(a)] is an extremely atherogenic lipoprotein. Lp(a) has been found in the plasma of humans and other primates. but until now only in a few other species. The mechanism by which it exerts its atherogenicity is still poorly understood. We observed that Lp(a) has been found in the plasma of several species unable to synthesize ascorbate and not in other species. We have now detected apoprotein(a) in the plasma of the guinea pig. We induced atherosclerosis in this animal by dietary ascorbate depletion and. using SDS/PAGE and subsequent immunoblotting. we identified Lp(a) as accumulating in the atherosclerotic plaque. Most importantly. adequate amounts of ascorbate (40 mg per kg of body weight per day) prevent the development of atherosclerotic lesions in this animal model and the accumulation of Lp(a) in the arterial wall. We suggest an analogous mechanism in humans because of the similarity between guinea pigs and humans with respect to both the lack of endogenous ascorbate production and the role of Lp(a) in human atherosclerosis.
Inactivation of human alpha-globin gene expression by a de novo deletion located upstream of the alpha-globin gene cluster, Synthesis of normal human hemoglobin A. alpha 2 beta 2. is based upon balanced expression of genes in the alpha-globin gene cluster on chromosome 16 and the beta-globin gene cluster on chromosome 11. Full levels of erythroid-specific activation of the beta-globin cluster depend on sequences located at a considerable distance 5' to the beta-globin gene. referred to as the locus-activating or dominant control region. The existence of an analogous element(s) upstream of the alpha-globin cluster has been suggested from observations on naturally occurring deletions and experimental studies. We have identified an individual with alpha-thalassemia in whom structurally normal alpha-globin genes have been inactivated in cis by a discrete de novo 35-kilobase deletion located approximately 30 kilobases 5' from the alpha-globin gene cluster. We conclude that this deletion inactivates expression of the alpha-globin genes by removing one or more of the previously identified upstream regulatory sequences that are critical to expression of the alpha-globin genes.
Vaccination against tumor cells expressing breast cancer epithelial tumor antigen, Ninety-one percent of breast tumors aberrantly express an epithelial tumor antigen (ETA) identified by monoclonal antibody H23. Vaccinia virus recombinants expressing tumor antigens have considerable promise in the active immunotherapy of cancer. and we have evaluated the potential of vaccinia recombinants expressing the secreted (S) and cell-associated (transmembrane. T) forms of H23 ETA to elicit immunity to tumor cells expressing ETA. Tumorigenic ras-transformed Fischer rat fibroblast lines FR-S and FR-T. expressing the S or T form of H23 ETA. respectively. were constructed for use in challenge experiments. Expression of H23 ETA in these lines was confirmed by Western blotting and immunofluorescence. When challenged by subcutaneous seeding of tumor cells. 97% (FR-S) and 91% (FR-T) of syngeneic Fischer rats rapidly developed tumors that failed to regress. Vaccination with recombinant vaccinia virus expressing ETA-T prior to challenge prevented tumor development in 82% of animals seeded with FR-T cells but in only 61% of animals seeded with FR-S. The vaccinia recombinant expressing the S form was a less effective immunogen. and vaccination protected only 29-30% of animals from developing tumors upon challenge with either FR-S or -T cells. The increased immunogenicity of the recombinant expressing ETA-T was reflected in elevated levels of ETA-reactive antibody in vaccinated animals. confirming that secreted antigens expressed from vaccinia virus are less effective immunogens than their membrane-associated counterparts.
Biomechanics of mammalian terrestrial locomotion, Mammalian skeletons experience peak locomotor stresses (force per area) that are 25 to 50% of their failure strength. indicating a safety factor of between two and four. The mechanism by which animals achieve a constant safety factor varies depending on the size of the animal. Over much of their size (0.1 to 300 kilograms). larger mammals maintain uniform skeletal stress primarily by having a more upright posture. which decreases mass-specific muscle force by increasing muscle mechanical advantage. At greater sizes. increased skeletal allometry and decreased locomotor performance likely maintain stresses constant. At smaller sizes. skeletal stiffness may be more critical than strength. The decrease in mass-specific muscle force in mammals weighing 0.1 to 300 kilogram indicates that peak muscle stresses are also constant and correlates with a decrease in mass-specific energy cost of locomotion. The consistent pattern of locomotor stresses developed in long bones at different speeds and gaits within a species may have important implications for how bones adaptively remodel to changes in stress.
Detection of a human intracisternal A-type retroviral particle antigenically related to HIV, Sjogren's syndrome is an autoimmune disease that is characterized by dryness of the mouth and eyes. The loss of salivary and lacrimal gland function is accompanied by lymphocytic infiltration. Because similar symptoms and glandular pathology are observed in certain persons infected with human immunodeficiency virus (HIV). a search was initiated for a possible retroviral etiology in this syndrome. A human intracisternal A-type retroviral particle that is antigenically related to HIV was detected in lymphoblastoid cells exposed to homogenates of salivary tissue from patients with Sjogren's syndrome. Comparison of this retroviral particle to HIV indicates that they are distinguishable by several ultrastructural. physical. and enzymatic criteria.
Recognition by ELAM-1 of the sialyl-Lex determinant on myeloid and tumor cells, Endothelial leukocyte adhesion molecule-1 (ELAM-1) is an endothelial cell adhesion molecule that allows myeloid cells to attach to the walls of blood vessels adjacent to sites of inflammation. ELAM-1 recognizes the sialyl-Lewis X (sialyl-Lex) determinant. NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc-. a granulocyte carbohydrate also found on the surface of some tumor cell lines. Binding of myeloid cells to soluble ELAM-1 is inhibited by a monoclonal antibody recognizing sialyl-Lex or by proteins bearing sialyl-Lex. some of which may participate in humoral regulation of myeloid cell adhesion. Stimulated granulocytes also release an inhibitor of ELAM-1 binding that can be selectively adsorbed by monoclonal antibody to sialyl-Lex.
AIDS, minority patients, and doctors: what's the risk? Who's talking, We asked 39 physicians providing primary care for a mostly minority patient population to respond to a questionnaire concerning their attitudes and behavior toward AIDS risk assessment and preventive counseling and to indicate their beliefs concerning patients' knowledge and behavior. Most of the 36 physicians who responded (92%) agreed that physicians must educate their patients about AIDS. They also reported that patients who engage in risk-taking behavior may not know much about AIDS transmission and prevention. Despite these beliefs. these doctors reported that they gave advice to only 11% of their male patients and 14% of their female patients. More than one third of physicians reported feeling uncomfortable talking about patients' sexual preferences and practices. To identify patients at risk and to help prevent AIDS. methods must be found to make physicians more comfortable discussing sexual issues with their patients. especially their minority patients.
Chancroid: results from an outbreak in Houston, Texas, A recent (and continuing) epidemic of chancroid in Houston has included morphologic variation in the disease. including so-called dwarf. classic. giant. transient. follicular. phagedenic. and pseudogranuloma inguinale types. Most cases were clearly acquired by unprotected sexual encounters with local prostitutes. The strain of Haemophilus ducreyi responsible for this outbreak was relatively easily cultured on routine media; unexpected sensitivity of this strain to vancomycin rendered the recommended "selective" growth medium much less optimal for isolation. Therapeutic success uniformly followed the use of intramuscular ceftriaxone sodium; one case responded to oral ciprofloxacin hydrochloride.
Morbidly obese patients' perceptions of social discrimination before and after surgery for obesity, Morbidly obese patients' perceptions of obesity-related prejudice and discrimination were assessed before and 14 months after operation for obesity. Preoperatively. the 57 consecutive patients perceived overwhelming prejudice and discrimination at work. within the family. and in public places. After a weight loss of more than 45.5 kg (100 lb). these patients perceived little or no prejudice or discrimination. We examine factors contributing to the change in patients' perceptions and comment upon patients' perceptions of the negative attitudes held by health professionals toward obese patients.
Head and neck paragangliomas: a clinicopathologic study with DNA flow cytometric analysis, A total of 11 head and neck paragangliomas were the subject of pathologic study. including histologic. immunohistochemical. and DNA flow cytometric analyses. We cannot absolutely predict aggressive clinical behavior using histologic parameters alone. but we can use such parameters to segregate patients into low-risk and high-risk groups. Several trends were observed in the current study. Tumors with higher S-phase fractions. G2/M fractions. or aneuploid cell populations tended to behave "aggressively." The presence of sustentacular cells in the primary tumors cannot be used as an absolute indicator of tumor metastatic potential. as two metastatic paragangliomas in this study contained sustentacular cells in both the primary and metastatic lesions. DNA ploidy status cannot be used as an absolute prognostic parameter as the two metastatic tumors were composed of diploid primary and metastatic lesions. The three tumors with aneuploid cell populations showed "aggressive" histologic and clinical features. but the length of the follow-up period for these cases is too limited to draw any conclusions. Although no absolute criteria can be used at present to gauge aggressiveness. close follow-up of these patients is essential. especially if pathologic findings suggest an "aggressive" course (ie. "malignant" histology. higher S-phase fractions. G2/M fractions. aneuploid cell populations. or decreased sustentacular cell density).
Breast cancer: the military's experience at Wilford Hall USAF Medical Center, We reviewed the experience with breast cancer at Wilford Hall USAF Medical Center for the years 1978 through 1988. A total of 868 cases were identified in the Wilford Hall Tumor Registry; overall 5-year and 10-year survivals were 63% and 39%. respectively. Infiltrating ductal carcinoma represented the principal histologic category. The other predominant variants included invasive lobular carcinoma. lobular carcinoma in situ. and ductal carcinoma in situ. Until recently. most of these patients (90%) had modified radical mastectomy as their definitive surgical therapy. with chemotherapy reserved primarily for patients with advanced disease.
A resurgence of acute rheumatic fever in a mid-South children's hospital, A resurgence of acute rheumatic fever (ARF) has been reported in many areas of the United States in recent years. We retrospectively reviewed the medical records of inpatients with a new diagnosis of ARF from 1982 through 1988 at a children's hospital that serves a six-state referral area in the mid-South. Thirty patients were identified. 21 of whom were seen in 1987 (13) and 1988 (8). The rate of new cases of ARF per 1000 hospital discharges (0.7) was significantly greater for 1987 and 1988 than it was (0.15) from 1982 through 1986. Patients with recently diagnosed ARF were predominantly from nonurban areas. and polyarthritis was the most common recent major manifestation. Reasons for the resurgence of ARF in the US. including the mid-South. are unclear. but our experience serves to support recently published guidelines for the diagnosis and management of streptococcal pharyngitis in light of this resurgence of ARF.
Apical hypertrophic cardiomyopathy in a non-Oriental man, Japanese investigators first described apical HCM in 2.9% of patients who had diagnostic left ventricular catheterization for suspected ischemic heart disease or cardiomyopathy. This entity was initially thought to be limited to individuals of Asian origin and has been uncommonly described in patients of Western origin. Patients of Western origin differ in several ways from those in the original description of Yamaguchi et al. but they both share the same classic criterion of hypertrophy of the left ventricular apex. The major differences probably relate to the anatomic variation in the distribution of the left ventricular hypertrophy as described by Maron et al. It is not known whether racial. genetic. or environmental factors account for the variation of disease expression in Asian and Western patients. Our case illustrates that this diagnosis should be considered in patients who have chest pain (anginal or atypical) and markedly abnormal findings on electrocardiograms in the absence of hypertension or significant coronary artery disease.
Multiple arterial fenestrations, multiple aneurysms, and an arteriovenous malformation in a patient with subarachnoid hemorrhage, We report the case of a 49-year-old. right-handed man with multiple vascular pathologies. including a fenestrated anterior communicating artery and middle cerebral artery. an aneurysm of the anterior communicating artery. multiple aneurysms of the middle cerebral artery. and an arteriovenous malformation. Diagnoses were made through computed tomography. cerebral angiography. magnetic resonance imaging. and intraoperative dissection. The lesions were managed surgically in stages with satisfactory results. Congenital and hemodynamic factors may have combined to manifest in the anomalies present in this unique case. We believe that no similar combination of vascular pathology has been reported previously.
Familial trigeminal neuralgia and Charcot-Marie-Tooth neuropathy. Report of two families and review, Typical trigeminal neuralgia has occasionally occurred in multiple members of the same family over several generations. The clinical features of such cases. including the increased incidence in females. and the absence of other apparent hereditary. neurologic. metabolic. or structural abnormalities were identical to those of sporadic cases. More rarely. familial trigeminal neuralgia has been described in the setting of hereditary peripheral neuropathy. especially Charcot-Marie-Tooth disease. We describe patients from two different families with Charcot-Marie-Tooth disease and medically intractable trigeminal neuralgia. Both patients were successfully treated by percutaneous retrogasserian glycerol rhizolysis. The occurrence of cranial nerve symptoms in patients with demyelinating peripheral neuropathies is discussed in light of the current hypotheses regarding the etiology of trigeminal neuralgia.
Two cases of fatal atlantoaxial distraction injury without fracture or rotation, Atlantoaxial injuries. regardless of mechanism. typically result in bony injury. We present two unusual cases of fatal traumatic C-1-C-2 distraction without associated fracture or rotation. The ligamentous anatomy. common underlying structural/medical predispositions. and the possible mechanism of injury are discussed.
Eosinophilic granuloma of the cervical spine. A case report and review of the literature, This is a report of a case of eosinophilic granuloma involving the second cervical vertebra in a 33-year-old woman. There have been 32 case reports in the literature describing eosinophilic granuloma presenting as cervical spine disease. Due to its intimate relation to the central nervous system. the opportunity for neurological sequelae and neurosurgical intervention is common in cervical eosinophilic granuloma. In this report a brief history of eosinophilic granuloma is reviewed and case histories from the literature with cervical spine involvement are summarized. The therapeutic options are described and a recommended protocol for management is outlined.
Changes in myocardial ischemic threshold during daily activities, This study assesses the variations in myocardial ischemic threshold (heart rate at the onset of ischemia) during daily activities in patients with ischemic episodes on Holter monitoring. Eighty patients with known coronary artery disease. positive treadmill stress test results and greater than or equal to 2 ischemic episodes during a 24-hour period of Holter monitoring were studied. The lowest and the highest ischemic thresholds were determined for each patient. The mean lowest ischemic threshold was 85 beats/min. and the mean highest ischemic threshold was 109 beats/min. The highest ischemic threshold was identical to ischemic threshold values noted during exercise. Of the 895 ischemic episodes. 654 (74%) were preceded by a moderate (greater than 10%) increase in heart rate. The variability of ischemic threshold (difference in percentage between the highest and lowest ischemic thresholds) increased with the number of ischemic episodes (range 2 to 60%). However. in different patients with a similar number of ischemic episodes. different variability was observed. These differences in ischemic thresholds are probably indirect indicators of the vasomotor activity of the coronary arteries in different patients.
Determinants and significance of diltiazem plasma concentrations after acute myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group, A total of 1.975 plasma diltiazem concentrations were obtained from 1.067 patients enrolled in a multicenter secondary intervention study of diltiazem after acute myocardial infarction. To evaluate the determinants and significance of diltiazem concentrations in this patient population. we related drug concentrations to a variety of clinical variables recorded on the case history forms. Multiple linear regression analysis showed that (1) time from the last drug dose. (2) drug dose taken. (3) patient height (an index of lean body weight). and (4) patient age were important determinants of plasma concentration. For an equivalent dose. plasma diltiazem concentrations in a 75-year-old patient were about double those of a 25-year-old patient. Total weight and drug dose prescribed did not significantly affect plasma concentrations. Whereas drug concentrations were higher (p = 0.01) among patients with left-sided heart failure. they were not altered by renal dysfunction. hepatic disease or beta blockers. Diltiazem concentrations were a significant determinant of diastolic arterial pressure (p less than 10(-9). but neither systolic pressure nor heart rate were significantly related to diltiazem concentration. The overall incidence of adverse experiences was not related to drug concentrations. but the occurrence of second- and third-degree atrioventricular block in the coronary care unit and the need for a temporary pacemaker were substantially higher among patients with a drug concentration greater than 150 ng/ml (7.4 and 1.9%. respectively) than among patients with lower concentrations (2.6% for atrioventricular block. 0.3% for pacemaker; p = 0.02 for each). The risk of atrioventricular block was particularly increased by high diltiazem concentrations in the face of acute inferior infarction. These results suggest that diltiazem's pharmacologic and clinical effects in a large population are concentration-related. and that the consideration of patient size. age. and left ventricular function in selecting a diltiazem dose may allow for effective drug therapy with a reduced likelihood of adverse effects.
Prehospital thrombolysis in acute myocardial infarction, The benefit and risk of prehospital thrombolysis for acute myocardial infarction (AMI) were evaluated in a double-blind randomized trial. Patients presenting less than 4 hours after symptom onset received 2 million units of urokinase as an intravenous bolus either before (group A. n = 40) or after (group B. n = 38) hospital admission. The mean time interval from onset of symptoms to thrombolytic therapy was 85 +/- 51 minutes in group A and 137 +/- 50 minutes in group B (p less than 0.0005). In 91% of the patients. thrombolytic therapy was administered less than 3 hours after symptom onset. Complication rates during the pre- and in-hospital period were low and did not differ between groups. Three patients died (1 in group A. 2 in group B) from reinfarction 7 to 14 days after admission. Left-sided cardiac catheterization before discharge revealed a patency rate in the infarct-related artery of 61% in group A and 67% in group B (difference not significant). Global left ventricular function and regional wall motion at the infarct site did not differ significantly between group A and B (ejection fraction 51 +/- 10%. n = 28 vs 53 +/- 14%. n = 28; wall motion -2.3 +/- 1.3 vs -2.2 +/- 1.1 standard deviation. respectively). Also. peak creatine kinase did not differ significantly (838 +/- 634 U/liter in group A vs 924 +/- 595 U/liter in group B). Prehospital thrombolysis using a bolus injection of urokinase has a low risk when performed by a trained physician with a mobile care unit. The saving of 45 minutes in the early stage of an acute infarction through prehospital thrombolysis did not appear to be important for salvage of myocardial function.
Comparison of thallium-201 and technetium-99m hexakis 2-methoxyisobutyl isonitrile single-photon emission computed tomography for estimating the extent of myocardial ischemia and infarction in coronary artery disease, Single-photon emission computed tomography (SPECT) using thallium-201 (Tl-201) was compared with technetium-99m hexakis 2-methoxyisobutyl isonitrile (Tc-99m MIBI) in 24 patients with coronary artery diseaes. Patients exercised to the same work load as each isotope was studied. Normal and hypoperfused left ventricular mass was determined with an automated method. Estimated total left ventricular mass was similar for both stress/redistribution Tl-201 and stress/rest Tc-99m MIBI images. The mean estimated defect size in the redistribution Tl-201 images was 32 +/- 34.7 vs 33 +/- 38.4 g in the resting Tc-99m MIBI studies (difference not significant). The individual determinations of defect mass were highly correlated (r = 0.93; p less than 0.0001). Estimated defect size in the stress Tl-201 images (52 +/- 46.2 g) was significantly larger than the exercise Tc-99m MIBI estimates of defect mass (42 +/- 39.9 g; p less than 0.05). A linear correlation existed between stress thallium and technetium estimates of defect size (r = 0.85) but 15 of 24 Tc-99m MIBI defects were smaller than the Tl-201 defects. Partial redistribution of Tc-99m MIBI could explain the discordance. Stress Tc-99m MIBI SPECT defect size determined by visual interpretation or by the use of isocount analysis may be smaller than what is seen with stress Tl-201 SPECT.
Prevalence and prognostic significance of exercise-induced ventricular arrhythmias after coronary artery bypass grafting, Exercise-induced ventricular arrhythmias occur often after coronary artery bypass grafting (CABG). but their prognostic significance is unknown. Two hundred patients examined by exercise electrocardiography and cardiac catheterization (including left ventriculography. bypass graft and native coronary artery angiography) before and 3 months after CABG were prospectively followed up. Exercise-induced ventricular arrhythmias occurred more often after (49 of 200 patients. 24.5%) than before (32 of 200 patients. 16.0%) CABG (p less than 0.05). There were no differences between the patients with and without ventricular arrhythmias in the prevalence of graft patency (79 vs 80%) or the postoperative ejection fraction (57 +/- 9 vs 57 +/- 12%). Ten cardiac deaths occurred during the mean follow-up time of 61 +/- 19 months. 8 of which were witnessed sudden cardiac deaths. All cardiac deaths occurred in patients who did not have exercise-induced ventricular arrhythmias after CABG. The postoperative ejection fraction was lower in the cardiac death patients (42 +/- 16%) than in the survivors (58 +/- 10%) (p less than 0.01). No other clinical or angiographic variable predicted the occurrence of cardiac death. Thus. the prevalence of exercise-induced ventricular arrhythmias increases after CABG. but the occurrence of ventricular arrhythmias does not indicate an increased risk of cardiac death.
Temporal relation between left ventricular dysfunction and chest pain in coronary artery disease during activities of daily living, Forty-three ambulatory patients with angina of increasing frequency underwent continuous monitoring of left ventricular (LV) function for an average of 2.9 +/- 1.9 hours to determine the incidence and temporal sequence of LV dysfunction. ST-segment depression and chest pain. Indicators of ischemia were: a decrease in ejection fraction greater than 5% lasting greater than 1 minute; horizontal or downsloping ST-segment depression of greater than or equal to 1 mm; or onset of the patient's typical chest pain complex. or a combination of these. During the monitoring interval. subjects performed daily activities such as sitting. walking. climbing stairs and eating. In 11 patients. 22 episodes of chest pain or ST-segment depression. or both. were observed. Eighteen episodes were accompanied by a decrease in ejection fraction (9 patients); chest pain accompanied the decrease in ejection fraction during 13 episodes. whereas ST-segment changes occurred during 7. In 12 of 13 episodes the decrease in ejection fraction began earlier than the onset of chest pain. whereas in 1 patient ejection fraction decrease and chest pain onset started at the same time. The average interval from a decrease in ejection fraction to the onset of chest pain was 56 +/- 41 seconds (range 0 to 120). ST changes occurred after the onset of a decrease in ejection fraction in 6 of 7 episodes. The average interval from the onset of ejection fraction decrease and the onset of ST change was 99 +/- 91 seconds. These data suggest that LV dysfunction manifested by a decrease in ejection fraction is an earlier indicator of myocardial ischemia than is angina pectoris or electrocardiographic evidence of ischemia.
Recanalization of chronic, totally occluded coronary arteries by new angioplasty systems, The benefit and safety of new angioplasty equipment as compared with the conventional guidewire approach was evaluated in 154 consecutive patients. with chronic. totally occluded coronary arteries. The protocol followed a stepwise design: first. conventional guidewires and low-profile balloons were used. followed by "balloon-on-the-wire" systems (Probe. Ace) or by a shaft-enforced. tip-deflecting catheter (Omniflex). In 97 patients with occlusions of 2 to 12 weeks' duration. recanalization was achieved in 51 patients (53%) with the conventional approach and in 29 patients with the new devices (balloon-on-the-wire [n = 5]. Omniflex [n = 24]). thereby raising the success rate to 82%. In 57 occlusions of greater than 12 weeks' duration. the recanalization attempt was successful in 58%. mediated in 16 patients (28%) by the Omniflex catheter and in 5 patients by balloon-on-the-wire systems. There were no life-threatening complications and only 1 (0.6%) emergency bypass operation was necessary. New angioplasty devices are therefore of considerable value in the attempt to improve the results of coronary angioplasty in chronic total occlusions.
Low-dose aspirin versus anticoagulants for prevention of coronary graft occlusion, The prevention of graft occlusion by aspirin (100 mg/day) or heparin followed by phenprocoumon was investigated in a randomized trial in 235 patients after aortocoronary bypass operation. Aspirin treatment started 24 hours before. and heparin 6 hours and phenprocoumon 2 days after surgery. The results of the vein graft angiography and the clinical outcome 3 months postoperatively did not differ: 22% of 218 vein graft distal anastomoses in the aspirin group and 20% of 272 in the anticoagulant group were occluded. At least 1 occluded distal anastomosis was present in 38% of 74 patients in the aspirin-treated group and in 39% of 86 in the anticoagulant group. Worst-case analysis of all randomized patients showed graft occlusions. cardiovascular complications or lost to follow-up in 42% of 122 aspirin-treated patients compared with 41% of 113 patients treated with anticoagulants. For grafts with endarterectomy the occlusion rate was lower in the aspirin (12% of 49) than in the anticoagulant (22% of 41) group (p less than or equal to 0.05). Increased perioperative blood loss in the aspirin group (1.211 +/- 814 ml in the first 48 hours vs 874 +/- 818 ml in the anticoagulant group [p less than or equal to 0.001]) without a higher reoperation rate indicates effective platelet inhibition with low-dose aspirin. Because occlusion rates were equal but high in these patients with advanced stage of coronary artery disease. a combination of low-dose aspirin and anticoagulation should be investigated to reduce graft occlusion rates further.
Arterial vasodilator effects of the dihydropyridine calcium antagonist amlodipine alone and in combination with verapamil in systemic hypertension, The arterial vasodilator properties of the dihydropyridine calcium antagonist amlodipine were compared with the effects of vascular muscle cyclic guanosine monophosphate production by sodium nitroprusside and with the effects of a combined infusion of amlodipine and the nondihydropyridine calcium antagonist verapamil in 8 untreated patients with primary hypertension. Arterial vasodilation was assessed by measurement of changes of forearm blood flow by mercury in Silastic strain-gauge plethysmography during brachial artery drug infusions. Forearm blood flow increased during amlodipine infusions (0.4 to 45 micrograms/min/100 ml forearm tissue) from 2.9 +/- 1.7 to a maximum of 23.6 +/- 7.6 ml/min/100 ml (687%). while sodium nitroprusside caused an increase from 3.0 +/- 1.8 to 16.2 +/- 5.4 ml/min/100 ml (449%). attesting to the importance of transmembrane calcium influx for the maintenance of vascular tone. The addition of verapamil 40 micrograms/min/100 ml to an infusion of amlodipine 44.5 micrograms/min/100 ml resulted in a further increase of forearm blood flow. from 23.6 +/- 7.6 to 34.4 +/- 9.8 ml/min/100 ml (p less than 0.05). The precise mechanisms of this finding have yet to be elucidated but may be due to interactions of the effects of the binding of these 2 chemically and pharmacologically different calcium antagonists to distinct binding sites at calcium channels. The clinical relevance of this observation for the treatment of coronary artery disease and systemic hypertension needs further study.
Left ventricular filling impairment in asymptomatic chronic alcoholics, Systolic left ventricular dysfunction is relatively common in even asymptomatic alcoholics. but whether diastolic function is also altered is much less well-studied. We used M-mode and Doppler echocardiography to study left ventricular size. mass. systolic function and diastolic filling in 32 alcoholics free of clinically detectable heart disease and in 15 healthy control subjects. Left ventricular mass index and posterior wall thickness were higher in alcoholics than in controls. but there was no statistically significant difference either in end-diastolic size or in systolic ventricular function. More abnormalities were found in the Doppler indexes of diastolic function. however. The alcoholics had a prolonged relaxation time (200 +/- 6 vs 184 +/- 5 ms [mean +/- standard error]. p less than 0.05). a decreased peak early diastolic velocity (52 +/- 2 vs 60 +/- 3 cm/s. p less than 0.05). a slower acceleration of the early flow (410 +/- 18 vs 552 +/- 43 cm/s2. p less than 0.01). and a higher atrial-to-early peak velocity ratio (0.74 +/- 0.04 vs 0.60 +/- 0.05. p less than 0.05). This pattern of changes suggests a primary abnormality in the relaxation of the left ventricle. In multivariate analyses. the abnormalities in the Doppler indexes were independent of the duration of alcoholism. the quantity of the most recent ethanol exposure and the increased mass of the left ventricle. Impaired early filling of the left ventricle due to delayed relaxation is common in asymptomatic alcoholics and may in fact be the earliest functional sign of preclinical alcoholic cardiomyopathy.
Physiologic peripheral pulmonic stenosis in infancy, We studied 14 premature infants with the clinical diagnosis of peripheral pulmonic stenosis (PPS) and 15 normal full-term neonates by echocardiographic Doppler examinations. The PPS group had an average main pulmonary artery (PA) diameter similar to the control group (0.91 vs 0.96 cm. difference not significant). but had smaller branch PA diameters: right PA = 0.41 vs 0.50 cm. p less than 0.001. and left PA = 0.41 vs 0.49 cm. p less than 0.001. The PPS group also had greater peak velocities in the main PA (76 vs 63 cm/s. p less than 0.05). right PA (193 vs 118 cm/s. p less than 0.001) and left PA (187 vs 123 cm/s. p less than 0.001). Similarly. the ratio of peak velocity in the branch/main PA was greater for the PPS group: right/main PA peak velocity = 2.91 vs 1.92. p less than 0.01. and left/main PA peak velocity = 2.73 vs 1.99. p less than 0.05. The calculated right ventricular output for the PPS group was more than the control group: 437 vs 261 ml/min/kg. p less than 0.001. Hematocrits were not done on the control group. but the PPS group had an average hematocrit which was low (34%). It is concluded that patients with PPS have mild underdevelopment of the PA branches. with consequent increased flow velocity and turbulent flow. This turbulent flow may be contributed to by increased cardiac output and mild anemia.
Spectrum of hemodynamic changes in cardiac tamponade, To investigate the pathophysiology of cardiac tamponade. the hemodynamics of 77 consecutive patients with greater than 150 ml of pericardial effusion were studied. Patients were classified into 3 groups based on the equilibration of intrapericardial with right atrial and pulmonary arterial wedge pressures (mm Hg): group I (n = 16). intrapericardial pressure was less than right atrial and pulmonary arterial wedge pressures; group II (n = 13). intrapericardial pressure was equilibrated with right atrial but not pulmonary arterial wedge pressures; group III (n = 48). intrapericardial pressure was equilibrated with right atrial and pulmonary arterial wedge pressures. Pericardiocentesis produced the following changes: group I--significant (p less than 0.03) decreases in intrapericardial pressure (7 +/- 2 mm Hg). right atrial pressure (3 +/- 2 mm Hg). pulmonary arterial wedge pressure (2 +/- 2 mm Hg). and the inspiratory decrease in arterial systolic pressure (3 +/- 4 mm Hg) but no significant change in cardiac output; group II--significant (p less than 0.02) decreases in intrapericardial pressure (11 +/- 5 mm Hg). right atrial pressure (6 +/- 4 mm Hg). pulmonary arterial wedge pressure (4 +/- 5 mm Hg). and inspiratory decrease in arterial systolic pressure (8 +/- 7 mm Hg). and increase in cardiac output (1.1 +/- 1.2 liters/min); group III--significant (p less than 0.001) decreases in intrapericardial pressure (16 +/- 7 mm Hg). right atrial pressure (9 +/- 4 mm Hg). pulmonary arterial wedge pressure (8 +/- 5 mm Hg). inspiratory decrease in arterial systolic pressure (17 +/- 11 mm Hg). and increase in cardiac output (2.8 +/- 1.5 liters/min). The changes after pericardiocentesis in all parameters were significantly (p less than 0.05) greater in group III than in groups I or II except for the change in right atrial pressure. which was not significantly different in groups II versus III. The changes after pericardiocentesis indicate pericardial effusion caused the greatest abnormalities in group III but also caused significant abnormalities of pressure and flow in group II and of pressure alone in group I.
Transesophageal echocardiography in critically ill patients, The feasibility. safety and clinical impact of transesophageal echocardiography were evaluated in 51 critically ill intensive care unit patients (28 men and 23 women; mean age 63 years) in whom transthoracic echocardiography was inadequate. At the time of transesophageal echocardiography. 30 patients (59%) were being mechanically ventilated. Transesophageal echocardiography was performed without significant complications in 49 patients (96%). and 2 patients with heart failure had worsening of hemodynamic and respiratory difficulties after insertion of the transesophageal probe. The most frequent indication. in 25 patients (49%). was unexplained hemodynamic instability. Other indications included evaluation of mitral regurgitation severity. prosthetic valvular dysfunction. endocarditis. aortic dissection and potential donor heart. In 30 patients (59%). transesophageal echocardiography identified cardiovascular problems that could not be clearly diagnosed by transthoracic echocardiography. In the remaining patients. transesophageal echocardiography permitted confident exclusion of suspected abnormalities because of its superior imaging qualities. Cardiac surgery was prompted by transesophageal echocardiographic findings in 12 patients (24%) and these findings were confirmed at operation in all. Therefore. transesophageal echocardiography can be safely performed and has a definite role in the diagnosis and expeditious management of critically ill cardiovascular patients.
Drug therapy for Helicobacter pylori infection: problems and pitfalls, Antibacterial chemotherapy against Helicobacter pylori is currently being assessed by open or randomized controlled clinical studies for its efficacy in eradicating this bacterium from the stomach of patients with gastritis or gastroduodenal ulcer. Whereas there is presently no "optimal" agent and treatment scheme. the combination of some antibiotics (metronidazole. tinidazole. amoxicillin) with bismuth salts proves definitely superior in vivo to either of these agents administered alone. Several reasons have been proposed. to explain the clinical failure after treatment: insufficient concentration of active drugs in gastric mucus. instability of some agents at an acidic pH. inappropriate formulation of drug. insufficient duration of treatment. and variable compliance of patients. Recently. it has appeared from several clinical trials that H. pylori may rapidly acquire resistance to some antibiotics. and that this event might also account for clinical failure. A critical review of the literature on H. pylori treatment indicates that association of bismuth and antibiotics or of antibiotics alone both may efficiently reduce the risk of emergence of resistance and improve the therapeutic outcome. Guidelines of treatment are suggested in order to avoid the future misuse of antibiotics that would increase selection of antibiotic-resistant H. pylori and negatively affect the ecology of the gastric microflora. Likewise. an accurate definition of a subset of patients with H. pylori who really will require treatment needs to be rapidly established.
Incidence and prevalence of ulcerative colitis in the upper Galilee, Northern Israel, 1967-1986, An epidemiological study of ulcerative colitis was performed in the Upper Galilee. Israel. over a 20-yr period (1967-1986). The average annual incidence of ulcerative colitis was 2.23 per 100.000 population. and the prevalence on December 31. 1986. was 44.58 per 100.000. Considering the fact that strict steps were taken to include only definite cases. these figures are probably an underestimation. An increase of the average annual incidence from 0.88 in the period 1967-1976 to 3.79 in 1977-1986 was found. When the data were stratified according to ethnic groups. the highest average annual incidence and the highest point prevalence was found in Israeli-born Jews (6.9 and 138.2 per 100.000 population. respectively). When Jewish residence patterns were compared. the highest average annual incidence and point prevalence were found among Kibbutz members (5.52 and 110.39. respectively). and the lowest (1.94 and 38.76) among Moshav inhabitants. There were 10 Arab patients with an average annual incidence of 0.96 and a point prevalence of 19.27. There were 25 women and 28 men (female:male ratio of 0.89). Among the Jews. the female:male ratio was 1.04. Peak incidence was found in the 25- to 34-yr-old range. No second peak was noticed. Anemia was demonstrated in 66.6% of the women and 27.5% of the men in our study. We suggest that the increase in UC incidence and prevalence in Israeli and Asia/africa-born Jew and in Arabs in the Upper Galilee points toward environmental factors in the etiology of this disease.
Failure of hepatitis B immunization in liver transplant recipients: results of a prospective trial, Twenty patients with advanced liver disease. in need of transplantation. were given three injections of 20 micrograms and three injections of 40 micrograms hepatitis B vaccine to see if an antibody response could be obtained. Only 20% of patients developed measurable anti-HBs. One who failed to develop anti-HBs developed chronic hepatitis B after exposure to her infected sexual partner. Type of liver disease in the native liver. age. sex. sexual preference. timing of immunization (before or after transplantation). and dosage of hepatitis B vaccine did not seem to explain the lack of immunologic response to hepatitis B vaccine. It is presumed that immunosuppression. both from the underlying disease and from immunosuppressive medications. best explains our findings. Liver transplantation patients infrequently benefit from hepatitis B vaccine. It is possible that other vaccines given to prevent viral and bacterial illness may also fail to elicit immunologic response in such patients.
Increasing prevalence of gallstones in male veterans with alcoholic cirrhosis, Cases of alcoholic cirrhosis identified at necropsy were studied for the prevalence and type of gallstones. compared with age- and race-matched autopsy controls. Data were examined from 1970-1977 and 1980-1987. In the early sample of 460 cirrhotic patients. 33% had gallstone disease. contrasted with 12% in the controls. In the 1980s. among 299 patients. 46% had gallstone disease. whereas it was present in 13% of the controls. The prevalence of stones was significantly greater in the patients than in the controls for both time periods and. among the patients. was significantly greater in the 1980s than in the 1970s (p less than 0.05). A comparison of cirrhotic patients with and without gallstones indicated a significantly higher incidence of ascites in the patients with gallstones. The gallstones in cirrhotics were more frequently pigmented than in the controls in both time periods. In 100 living patients with advanced cirrhosis studied by sonography during 1987 and 1989. the prevalence of gallstones was 43%. almost the same as the autopsy sample from 1980-1987. In these cirrhotics. ascites. encephalopathy. and varices were more prevalent in the patients with stones than those without. We conclude that pigmented gallstones are increasing in cirrhosis of the liver related to the severity of the liver disease.
Plasma fatty acid profile in advanced cirrhosis: unsaturation deficit of lipid fractions, Fatty acid (FA) profile of plasma total lipids. phospholipids (PL). cholesteryl esters (CE). and triglycerides (TG) were measured in 101 patients with advanced liver cirrhosis and in 44 age- and sex-matched healthy controls. Plasma levels of lipidic phosphorus. esterified cholesterol. and TG also were measured. and the unsaturation index (UI) was calculated for each fraction. Total plasma concentrations of saturated FA. linoleate. and polyunsaturated FA (PUFA) were lower in cirrhotics than in controls. This profile was also found in plasma levels of PL- and CE-associated FA. No detectable amounts of C20:3n9 were found in cirrhotic patients. Percent FA distribution of lipid fractions showed a lower percentage of linoleate and PUFA and a higher relative amount of saturated and monoenoic FA in cirrhotics than in controls. As a consequence. the UI of PL and CE was diminished in liver cirrhosis. Linoleate and PUFA deficiency was more marked in CE than in PL. as shown by the number of patients with values below the 5th percentile of the control group. suggesting an attempt to maintain the unsaturation of PL as the most important component of cell membranes. Hepatic failure. poor essential FA intake. and malnutrition are some of the possible etiologic factors for PUFA deficiency in cirrhosis. Their relative contribution to plasma FA abnormalities. as well as the clinical and pathophysiological consequences of PUFA deficit in cirrhotic patients. requires further investigation.
Hemodynamic changes in splenic blood flow during and after distal splenorenal shunt, The purpose of this study was to examine the hemodynamic changes of the spleen and the subsequent influence on the numbers of blood cells both during and 1 month after distal splenorenal shunt (DSRS) with splenopancreatic disconnection in 20 patients with portal hypertension. The intraoperative splenic blood flow. measured with an electromagnetic flowmeter. significantly increased after shunt insertion: the mean percentage increases within the splenic vein and artery were 60% (p less than 0.01) and 37% (p less than 0.05). respectively. The splenic venous blood flow. measured with a pulsed Doppler flowmeter. had not changed significantly 1 month postoperatively (676 +/- 501 to 540 +/- 306 ml/min). The WBC and platelet counts significantly (p less than 0.05 and p less than 0.01. respectively) increased 1 month postoperatively. whereas there was a small. but significant (p less than 0.05). decrease in RBC count. We concluded that splenic blood flow increases immediately after DSRS with splenopancreatic disconnection. but this increase may be only short term. The influence of the postoperative hemodynamic changes on blood cell count is uncertain.
Pedunculated giant lipoma of the esophagus, A patient with a giant lipoma of the esophagus presented with progressive dysphagia and odynophagia. fever. and recurrent melena. Two years previously. when the symptoms were less pronounced. it had been misdiagnosed as achalasia. After surgical removal of the lipoma. the patient became symptom free.
Primary leiomyoma of the liver, A 30-yr-old woman with right upper quadrant abdominal pain was found to have a hepatic leiomyoma. This is the youngest patient in whom this rare tumor has been found. The diagnostic approach toward gastrointestinal leiomyomata is emphasized. including the role of immunohistochemistry.
Hospitalization decision in patients with community-acquired pneumonia: a prospective cohort study, PURPOSE: To identify a low-risk subset of patients with community-acquired pneumonia that could safely be treated in the ambulatory setting; and to assess how clinicians make the hospitalization decision. PATIENTS AND METHODS: We performed a prospective. observational study of 280 ambulatory and hospitalized adults with clinical and radiographic evidence of pneumonia. Patients were followed to assess all potential morbid complications and 6-week mortality. Physicians responsible for managing these patients were surveyed to assess the reasons for treating in a hospital or ambulatory setting and the therapies that dictate hospitalization. RESULTS: Sixty-one percent (170 of 280) of patients did not have an indication for admission at presentation using modified Appropriateness Evaluation Protocol criteria (a severe vital sign abnormality. alteration in mental status. suppurative complication. arterial hypoxemia. severe laboratory abnormality. or an acute coexistent medical problem requiring admission independent of the pneumonia). Among these 170 patients. 38% had a complicated course defined as death within 6 weeks. development of a new suppurative or medical complication due to pneumonia. intensive care unit admission. persistent fever or use of intravenous fluids or oxygen beyond 3 days. hospitalization lasting more than 3 days. or subsequent hospitalization in patients initially treated in the ambulatory setting. Five predisposing factors for a complicated course were identified in logistic regression models. The odds ratio for age more than 65 years was 2.7; for comorbid illness. 3.2; for temperature more than 38.3 degrees C (101 degrees F). 4.1; for immunosuppression. 12.0; and for a high-risk etiology. 23.3. The risk of a complicated course increased linearly with the number of risk factors. from 12% with none to 100% with four or more factors (p less than 0.001). Physicians most often relied on the general clinical appearance of the patient when making the triage decision. and most commonly cited intravenous antibiotics and chest physical therapy as treatments requiring hospitalization. CONCLUSIONS: If validated. our findings could improve physicians' assessment of prognosis. and may identify a low-risk subset of patients with community-acquired pneumonia who could safely be managed in the ambulatory setting.
Treatment with 13-cis-retinoic acid in transfusion-dependent patients with myelodysplastic syndrome and decreased toxicity with addition of alpha-tocopherol, PURPOSE: The purpose of this study was to determine the response and tolerance to long-term treatment using 13-cis-retinoic acid (13-CRA) in transfusion-dependent patients with the myelodysplastic syndrome (MDS) and to determine the effects of therapy on the natural history of the disease. PATIENTS AND METHODS: Sixty-six consecutive patients with transfusion-dependent MDS seen in a medical school hospital and outpatient clinic from 1981 to 1988 were studied. The first 21 patients were treated with 13-CRA alone and the next 45 patients with 13-CRA plus alpha-tocopherol (AT). We compared responses to and toxicities of therapy. rates of transformation. and survival from onset of therapy in 20 evaluable patients treated with 13-CRA alone and 43 patients treated with 13-CRA plus AT. RESULTS: Four patients responded (20%) at 4 to 8 months to 13-CRA alone. but this response was associated with considerable toxicity and resulted in cessation of therapy. Among the responders. only one continued therapy and is currently in remission. whereas three discontinued therapy because of toxicity and have had a relapse and died. In the 13-CRA plus AT group. we observed one prolonged complete remission and 10 partial remissions (26%). with a decrease in skin and constitutional toxicities by the addition of AT. which enabled the continuation of 13-CRA indefinitely. Although the response rates were similar in both groups. fewer patients (28% versus 60%) experienced progression to acute leukemia in the 13-CRA plus AT group than in the group receiving 13-CRA alone. who terminated treatment (p = 0.018). A twofold increase in median survival of the RA/RARS and RAEB/CMML patient groups was observed with 13-CRA plus AT but was not significant (p greater than 0.5). CONCLUSION: This study shows a 20% to 26% response rate to 13-CRA and suggests that 13-CRA. if given continuously. decreases the rate of progression or transformation to acute leukemia in patients with MDS. The addition of AT ameliorates the toxicity of 13-CRA and allows for long-term treatment with 13-CRA. Since the standard treatment for MDS is currently unsatisfactory. these findings indicate that longer treatment with a non-marrow-suppressive agent such as 13-CRA is important. and further trials to determine the role of 13-CRA plus AT in combination with new recombinant growth factors in the therapy for transfusion-dependent MDS should offer a new approach to a disease common in the elderly population.
Aspirin in the primary prevention of angina pectoris in a randomized trial of United States physicians, PURPOSE: The objective of this study was to examine the effect of low-dose aspirin (325 mg on alternate days) on the primary prevention of angina pectoris in the United States Physicians' Health Study. Despite a postulated role of platelets in atherogenesis and myocardial ischemia. the effect of chronic platelet inhibition on the development of clinical angina pectoris is unknown. SUBJECTS AND METHODS: The Physicians' Health Study is a randomized. double-blind. placebo-controlled trial among 22.071 male physicians aged 40 to 84 years. free from previous myocardial infarction. stroke. and transient cerebral ischemia at entry. and followed for an average of 60.2 months. The 21.738 physicians who were also free from angina pectoris at baseline constituted the study population for the present analyses. RESULTS: During 106.652 person-years of follow-up. 331 patients with confirmed angina pectoris were diagnosed. 194 of whom underwent a coronary revascularization procedure (coronary artery bypass graft surgery or coronary angioplasty). As compared to participants assigned placebo. the relative risk of confirmed angina pectoris in the aspirin group was 1.10 (95% confidence interval [CI]. 0.88 to 1.38). For coronary revascularization. the relative risk was 1.19 (95% CI. 0.88 to 1.59). After simultaneous control for other coronary risk factors in a proportional-hazards model. these relative risks remained near unity at 1.07 (95% CI. 0.84 to 1.36) and 1.11 (95% CI. 0.81 to 1.52). respectively. When the risks of angina pectoris were examined according to year of randomization in the trial. there was no pattern of increasing benefit with longer duration of treatment. CONCLUSION: These randomized trial data indicate that chronic platelet inhibition with low-dose aspirin for an average duration of 60.2 months does not reduce the incidence of angina pectoris.
Disease control priorities in developing countries: health policy responses to epidemiological change, Health systems in developing countries are facing major challenges in the 1990s and beyond because of a growing epidemiological diversity as a consequence of rapid economic development and declining fertility. The infectious and parasitic diseases of childhood must remain a priority at the same time the chronic diseases among adults are emerging as a serious problem. Health policymakers must engage in undertaking an epidemiological and economic analysis of the major disease problems. evaluating the cost-effectiveness of alternative intervention strategies; designing health care delivery systems; and. choosing what governments can do through persuasion. taxation. regulation. and provision of services. The World Bank has commissioned studies of over two dozen diseases in developing countries which have confirmed the priority of child survival interventions and revealed that interventions for many neglected and emerging adult health problems have comparable cost-effectiveness. Most developing countries lack information about most major diseases among adults. reflecting lack of national capacities in epidemiological and economic analyses. health technology assessment. and environmental monitoring and control. There is a critical need for national and international investment in capacity building and essential national health research to build the base for health policies.
The role of attitudes, beliefs, and personal characteristics of Italian physicians in the surgical treatment of early breast cancer, The influence of Italian physicians' attitudes. beliefs. and personal characteristics on medical decision making is examined in the case of surgical treatment of early breast cancer. Responses to a mail survey of 657 physicians from different specialties were analyzed comparing doctors recommending a radical procedure (9%) to those preferring a conservative procedure for younger patients only (25%). and those considering conservative surgery the treatment of choice regardless of patients' age (66%). The findings suggest that the likelihood of physicians' preferring a conservative procedure is influenced by their specialty and the extent to which they feel that a patient should have a role in the treatment decision more than by differences in the beliefs of treatment outcomes. Only preferences of the small group indicating radical surgery as the sole admissible treatment can be accounted for by ignorance or distrust of results of recent trials. These findings suggest that other than scientific factors guide many doctors in their decision making; they may help to explain why the diffusion of research results into clinical practice is often disappointingly slow.
AIDS-related knowledge, sexual behavior, and condom use among men and women in Kinshasa, Zaire, This study was conducted in 1988 among a random sample of 6.625 men and women of reproductive age in all 24 administrative zones of Kinshasa. the capital city of Zaire. to determine existing levels of knowledge regarding AIDS (acquired immunodeficiency syndrome). sexual behavior. knowledge and use of condoms in marital and extramarital relations; perceived risk of AIDS. and attitudes toward testing for the human immunodeficiency virus (HIV). Awareness of AIDS is almost universal. and the vast majority know the four main modes of transmission. Almost half believed in transmission by mosquitoes and in a vaccine or cure for AIDS. The majority of male respondents knew of condoms. but negative attitudes toward condom use are widespread. and few respondents perceived them to play a central role in combatting AIDS.
The impact of HIV-related illness on employment, We used structured telephone interviews to determine the extent of work loss following onset of symptoms. the interval between onset of symptoms and cessation of work. and the risk factors for work loss among 193 persons with symptoms of human immunodeficiency virus (HIV)-related illness attending the AIDS Clinic at the University of California. San Francisco. between October 1. 1988. and September 30. 1989. Estimates of the duration of time between onset of HIV-related symptoms and work loss derive from the life table method of Kaplan and Meier. A Cox proportional hazards model is used to estimate the effect of risk factors on the probability of withdrawing from work in each time interval. Eighty-six percent of the respondents worked prior to onset of the first symptom of HIV-related illness; 40 percent were working at the time of the most recent interview. a mean of 958 days later. The total number of hours worked declined by 59 percent during this time. Kaplan-Meier analysis indicates that 50 percent who worked prior to onset of HIV-related illness stopped working within two years and all had stopped within 10 years after onset of the first symptom.
Reporting of occupational injury and illness in the semiconductor manufacturing industry, In the United States. occupational illness and injury cases meeting specific reporting criteria are recorded on company Occupational Safety and Health Administration (OSHA) 200 logs; case description data are submitted to participating state agencies for coding and entry in the national Supplementary Data System (SDS). We evaluated completeness of reporting (the percentage of reportable cases that were recorded in the company OSHA 200 log) in the semiconductor manufacturing industry by reviewing company health clinic records for 1984 of 10 manufacturing sites of member companies of a national semiconductor manufacturing industry trade association. Of 416 randomly selected work-related cases. 101 met OSHA reporting criteria. Reporting completeness was 60 percent and was lowest for occupational illnesses (44 percent). Case-description data from 150 reported cases were submitted twice to state coding personnel to evaluate coding reliability. Reliability was high (kappa 0.82-0.93) for "nature." "affected body part." "source." and "type" variables. Coding for the SDS appears reliable; reporting completeness may be improved by use of a stepwise approach by company personnel responsible for reporting decisions.
A routine tool for detection and assessment of epidemics of influenza-like syndromes in France, A regression model for the nonepidemic level of influenza-like syndrome has been estimated from the 55.200 cases collected between October 1984 and August 1988 using the French Communicable Diseases Computer Network. The start of a major epidemic in 1988-89 was detected early. The size of the epidemic. for the entire country. was estimated at approximately 4.3 million cases. The excess cost of sick-leave. among those of working age. was estimated at $86 million.
Antibiotic use among children in an urban Brazilian slum: a risk factor for diarrhea? [published erratum appears in Am J Public Health 1991 Apr;81(4):417, Among a cohort of children in a poor urban setting in Brazil. the relative risk for the occurrence of a new episode of diarrhea in the two weeks following antibiotic use vs all other weeks was 1.44 (95% confidence interval (CI) = 1.33. 2.45). Among children ever [corrected] exposed to antibiotics. the odds ratio was 1.34 (95% CI = 0.84. 2.16) after stratifying by individual child and controlling for previous diarrhea. Further research is needed to confirm whether antibiotics are a risk factor for diarrhea in such settings.
Pathologic synovial plica of the knee. Results of conservative treatment, Observations of 136 cases of pathologic synovial plica of the knee were analyzed with regard to etiology. symptoms. and the results of conservative treatment. The results obtained with conservative treatment were good in 40% of cases. average in 20%. and poor in 40%. In our opinion. these results justify the treatment of this condition with physical therapy before proceeding with surgical correction. The objective of physical therapy was to decrease the compressive forces in the anterior compartment of the knee by increasing the structural flexibility of the flexor and extensor muscles. This increase in flexibility was obtained by instituting stretching exercises for the hamstrings. gastrocnemius. and quadriceps.
Anterior cruciate ligament injury: evaluation of intraarticular reconstruction of acute tears without repair. Two to seven year followup of 155 athletes, To evaluate the effectiveness of our treatment regimen. we retrospectively studied the surgically treated knees of 155 athletes. aged 15 to 42 years. who had sustained acute ACL tears. All were treated with ligament excision and intraarticular bone-patellar tendon-bone reconstruction followed by early motion with emphasis on full extension. The follow-up period ranged from 2 to 7 years. Of the 155 patients. 140 were available for final followup at a minimum of 2 years after reconstruction. The patients were evaluated by objective measures (KT-1000. Cybex. Lachman test. range of motion. and postoperative competition level) and subjective assessment scores (pain. swelling. stability. activity level. walking. stair climbing. running. jumping. or twisting). The subjective scores were tabulated for stability level. total score. and activity level. After the patients achieved full range of motion. the KT-1000 measurements at a 20 pound force revealed an average difference of 1.3 mm between the injured and noninjured knees. All but 3 of the 140 patients had a firm endpoint on the Lachman test. and the Cybex tests showed a mean hamstring strength of 98% and mean quadriceps strength of 90%. Sixty of the 69 varsity athletes who were eligible to play returned to preinjury competition level the following season. One had reconstruction failure and eight chose not to continue competition for academic reasons. The questionnaire score average was 92.7 (maximum. 100 points. normal athletic knee score 93.5). We concluded that the surgical procedure. with emphasis on early full extension postoperatively. achieved excellent results and provided a stable knee.
Anteromedial tibial tubercle transfer without bone graft, We followed 30 patients for more than 2 years after anteromedial tibial tubercle transfer for persistent patellofemoral pain associated with patellar articular degeneration. Twelve of these patients were followed more than 5 years. We report 93% good and excellent results subjectively and 89% good and excellent results objectively. The quality of improvement was sustained in all 12 of the patients who were evaluated again after more than 5 years from surgery. When examined separately. 75% of those patients with advanced patellar arthrosis achieved a good result; none of these patients achieved an excellent result. Postoperative continuous passive motion has markedly reduced the incidence of stiffness. Serious complications such as compartment syndrome. infection. and skin slough were avoided completely in 51 consecutive cases. Patellofemoral contact pressure studies in five cadaver knees have shown that anteromedial tibial tubercle transfer can provide substantial reduction of patellofemoral contact stress while helping to balance medial and lateral facet pressures. This surgical procedure is mechanically and clinically successful for alleviating intractable pain related to patellar malalignment and articular degeneration. This procedure enables the majority of appropriately selected patients with malalignment and patellar articular degeneration to resume increased levels of activity with substantially diminished pain.
Comparison of support provided by a semirigid orthosis and adhesive ankle taping before, during, and after exercise, The purpose of this study was to compare the relative effectiveness of athletic taping and a semirigid orthosis in providing inversion-eversion range restriction before. during. and after a 3 hour volleyball practice. The effect of each support method on the subjects' vertical jumping ability was also assessed. Fourteen ankles were treated with both methods of support. Passive inversion-eversion range of motion was measured on an ankle stability test instrument during five testing sessions: 1) before support. 2) before exercise. 3) 20 minutes during exercise. 4) 60 minutes during exercise. and 5) after exercise. The two-way analysis of variance and posthoc comparisons revealed maximal losses in taping restriction for both inversion and eversion at 20 minutes into exercise. The orthosis demonstrated no mechanical restrictive failure until before and after exercise comparisons were made. and then only eversion range of motion was compromised. Neither support system affected subjects' vertical jumping ability. These results suggest that the semirigid orthosis may be more effective than taping in providing initial ankle protection and in guarding against ligamentous reinjury.
Incidence of cervical spinal stenosis in professional and rookie football players, Sagittal canal/vertebral body ratios were measured on cervical spine lateral radiographs of 124 professional football players and 100 rookie football players. A total of 894 levels were measured in 224 players. Thirty-two percent (40) of the 124 professional football players. and 34% of the 100 rookies had a ratio of less than 0.80 at one or more levels from C3 to C6. The 0.80 ratio has been considered indicative of cervical spinal stenosis. This is the first time that the incidence of spinal stenosis. as determined by Torg's ratio. has been demonstrated in a population of professional and rookie football players. Because one-third of this population has cervical spinal stenosis as determined by the Torg ratio. other factors should be considered in the evaluation of a player with a transient quadriplegic episode when making continued play decisions.
Living with artificial grass: a knowledge update. Part 2: Epidemiology, Part 2 of our study evaluated the effect of artificial grass on the athletes that play on it. In this section we have reviewed the epidemiological studies that have evaluated the influence that artificial grass has on the frequency and site of injury to American football players. From this review we have concluded that play and practice on an artificial surface is probably responsible for an increase in the relative risk of injury to the lower extremity of the participants. However. it is evident that more well controlled studies are necessary to completely clarify this issue.
Arterial abnormalities of the shoulder in athletes, Vascular lesions of the shoulder may be misinterpreted as one of the more familiar shoulder abnormalities by a treating physician. We are reporting on 13 athletes who were found to have symptoms related to compression of the subclavian or axillary artery or their tributaries. Nine were amateur or professional baseball pitchers. Severe arm fatigue or finger ischemia. secondary to embolization. were presenting symptoms. Arm fatigue was noted in all pitchers. After complete history and physical examination. including auscultation for bruits in functional positions. all athletes were evaluated by noninvasive tests (Doppler and Duplex scanning). Arteriography was performed with positional testing. recreating overhead activity. and complete radiographic visualization of the dye to the digital arteries. Two patients were found to have subclavian artery aneurysm. The remaining athletes were found to have compression of the subclavian artery beneath the anterior scalene muscle (five patients). the axillary artery beneath the pectoralis minor (two patients). both arterial segments (two patients). and one was found to have arterial compromise at the level of the humeral head. Branch artery compression was also noted. One pitcher occluded the posterior circumflex humeral artery with embolization to the digit. The two patients with subclavian aneurysms underwent saphenous vein bypass with cervical rib resection. All of the other athletes except one underwent resection of a 2 to 3 cm segment of the anterior scalene muscle or pectoralis minor muscles. All returned to their previous level of activity except one patient who developed impingement type symptoms and required acromioplasty. He is currently undergoing rehabilitation. Proper recognition of vascular compromise in the upper extremity of athletes is essential to avoid the catastropic complications of arterial thrombosis.
Injury patterns in Scottish heavy athletics, As interest and participation in the athletics of Scottish-American Highland games has increased throughout the United States. the aim of this study was to define injury patterns and risk factors. Field events of modern track and field evolved in part from the seven events of the "heavy athletics." A retrospective and prospective study of 170 athletes with at least 3 years of experience was carried out over 10 years. There were 729 injuries. 60% of which involved the upper extremities and back. The incidence of injury was 42.9%; there was an injury exposure rate of 0.3 per 40 hours of competition or training. With appropriate instruction. a consistent weight program. and exercise. few injuries were serious.
In vitro and in vivo evaluation of intraluminal ultrasound in normal and atherosclerotic arteries, This study evaluated the dimensional and morphologic precision of arterial images obtained using intraluminal rotating A-scan ultrasound catheters [5.0F (30 mHz) and 8.0F (20 mHz)]. Dimensions of in vitro ultrasound images from human arteries (eight normal and nine arteriosclerotic) were compared with those from histologic sections of the vessels. In addition. in vivo ultrasound studies (23 normal and 22 arteriosclerotic) of canine femoral arteries were compared with luminal dimensions obtained from angiograms of the vessels. The correlation of in vitro ultrasound images to luminal diameters (n = 22. r = 0.96). adventitial diameters (n = 19. r = 0.83). and wall thickness (n = 19. r = 0.68) in normal human vessels was significant (p less than 0.05). In vitro measurements of images and histologic specimens from human atherosclerotic arteries also correlated significantly (p less than 0.05) with luminal diameters (n = 27. r = 0.91). adventitial diameters (n = 24. r = 0.60). and wall thickness (n = 24. r = 0.62). Morphologically. in vitro images of the wall of normal human arteries had a concentric laminated appearance and atherosclerotic vessels had patchy echodense and echolucent areas. In vivo studies showed significant correlation of diameters for both normal (n = 16. r = 0.91. p less than 0.05) and arteriosclerotic (n = 16. r = 0.57. p less than 0.05) canine arteries compared with luminal dimensions measured from uniplanar angiograms. We conclude that rotating A-scan intraluminal ultrasound accurately defines both normal and atherosclerotic arterial wall morphology and dimensions. This technology may be valuable for intravascular guidance of angioplasty devices by identifying the location and consistency of lesions.
Early detection of myocardial contusion and its complications in patients with blunt trauma, Myocardial contusion remains an elusive clinical entity. which consumes a disproportionate amount of scarce and expensive critical care resources for the purpose of cardiac monitoring. This study attempts to define a group of patients at high risk who can be identified from the available data present at the time of admission. All patients admitted with the suspicion of a myocardial contusion over a 3-year period were retrospectively studied. The records were examined for history. physical findings. electrocardiographic (ECG) results. creatine kinase levels. Injury Severity Score (ISS). and echocardiographic findings. A diagnosis of a myocardial contusion was made if patients had an ECG consistent with acute injury. increased creatine kinase-MB. or an abnormal echocardiogram consistent with acute injury. Patients were stratified into two groups: Group 1 patients satisfied the criteria for a myocardial contusion and Group 2 patients lacked sufficient evidence to substantiate this diagnosis. The records were then examined for the presence of factors available in the emergency room that might be predictive of a myocardial contusion or its complications. A total of 88 patients were evaluated; 27 of these were found to have a myocardial contusion (Group 1) with 61 patients placed in Group 2 (no myocardial contusion). Group 1 patients had an abnormal admission ECG (p less than 0.05). and an ISS greater than or equal to 10 (p less than 0.05). Multivariate analysis identified two factors predictive of a myocardial contusion: an abnormal ECG and an ISS greater than 10. When these two predictors were absent. the probability of a myocardial contusion was 1%. No predictors of a complication of a myocardial contusion were identified. These data suggest that a combination of easily obtained variables in the emergency department can be used to select a patient population at high risk for myocardial contusion. Prospective evaluation of these variables is necessary.
Trend toward nonoperative management of splenic injuries, Treatment of splenic injuries has evolved over the past decade to reflect more effort to conserve function of the spleen. Records of 169 patients admitted over a 6-year period were identified as documenting the treatment of splenic injuries. We collected data regarding patient age. gender. degree of hemodynamic stability. number of units of blood required. severity of splenic injury. Injury Severity Score. and results of treatment. There were 143 adults (age greater than 16 years) and 26 pediatric patients (age less than 17 years). with mean age in the 2 groups of 31.6 and 11.4 years. respectively. Males comprised 72% of the group. and blunt injury occurred in 154 of the 169 patients. In the adults. splenectomy. splenorrhaphy. laparotomy without operative treatment of the spleen. and nonoperative management were observed 48%. 30%. 14%. and 8% of the time and in the pediatric group 31%. 27%. 19%. and 23% of the time. respectively. By using operative splenic repair techniques and increased use of nonoperative management. the splenic salvage rate has increased in the last 6 years from 41% to 61% without an increase in morbidity and mortality. Incidence of spleen salvage correlated with severity of spleen and overall injury and cardiovascular stability.
Open versus closed diagnostic peritoneal lavage in the evaluation of abdominal trauma, Two hundred forty-two patients underwent diagnostic peritoneal lavage (DPL) over a 12-month period. One hundred sixteen patients (48%) were randomized to an open lavage technique and 126 (52%) to a percutaneous (closed) guide wire procedure. The closed procedure required an average of 16 minutes to complete with one operator. whereas the open method required two operators and an average time of 26 minutes (p less than 0.001). Technical complications occurred in 31 patients undergoing closed lavage (25%) and 4 patients undergoing open lavage (3%) (p less than 0.01). Fifty-eight percent of the closed lavage complications were related to fluid return and 42% to guide wire placement. All the open lavage complications were caused by inadequate fluid return. These data do not support the initial use of percutaneous lavage. The open technique is favored and certainly used when the closed method fails or when direct visualization of the peritoneal cavity is indicated. Physicians involved in the management of abdominal trauma must be familiar with both methods of DPL.
Community hospital carotid endarterectomy in patients over age 75, We compared the prevalence of stroke and death in 133 patients aged 75 and older in whom 170 carotid endarterectomies were performed with that in 501 patients less than age 75 in whom 640 carotid endarterectomies were performed. There were three strokes (2%) in patients aged 75 and older and nine strokes (1%) in younger patients (p = 0.7). There were 8 deaths (5%) in patients aged 75 and older and 14 deaths (2%) in younger patients (p = 0.1). After controlling for the possible confounding effects of diabetes. prior stroke. history of angina. prior carotid artery disease. previous vascular surgery. history of myocardial infarction. preoperative hypertension requiring medication. and female gender. a logistic regression model showed that patients aged 75 and older were no more likely to have a stroke or death than patients under age 75. We conclude that age alone is not a contraindication to the safe performance of carotid endarterectomy in the community hospital.
Effect of electrocautery on wound healing in midline laparotomy incisions, The effect of electrocautery on midline fascial wound healing was studied in 108 Sprague-Dawley rats. Midline wound tensile strength was significantly reduced in fascia incised with the coagulation current compared with the cutting current or scalpel. In addition. tissue necrosis and inflammation as well as adhesion formation between the incision and abdominal viscera were more extensive in animals with incisions made using coagulation current. The results of the study indicate that the use of electrocautery coagulation current is associated with increased tissue damage and a significant reduction in the tensile strength of healing wounds. The contribution of electrocautery to wound complications in patients needs further evaluation.
Characteristics of duodenal wall gastrinomas, Fifteen patients with duodenal wall gastrinomas (DWGs) and the Zollinger-Ellison syndrome have been treated since 1960. In 6 of 11 patients. DWGs were recognized at operation and totally excised. In four patients. the tumor was subsequently found in the proximal duodenum of the surgical specimens. In 12 patients. DWGs were single and lymph node metastases were present in 8. In three patients. DWGs were multiple and lymph node metastases were present in two. All DWGs were submucosal and all were located in the first or second portions of the duodenum except one found in the fourth portion. Tumor size ranged from 1 to 15 mm. and nine were less than 5 mm. Of 12 patients with single DWGs. 9 have remained eugastrinemic after resection (mean follow-up: 5.5 years). None of the patients with multiple DWGs became eugastrinemic after surgery. DWGs are characteristically single. small or microscopic. submucosal. located in the proximal duodenum. rarely metastasize to the liver. and are usually curable by surgical resection.
The asymptomatic patient with suspected myocardial contusion, Diagnostic criteria and guidelines for hospital admission for suspected myocardial contusion (MCC) remain unclear. This study defines and examines the clinical sequelae of patients admitted with a suspicion of MCC. Criteria for observation following isolated. minor blunt chest trauma are suggested. Hospital and trauma registry records of patients admitted over a 33-month period with suspected MCC were reviewed. Conventional evaluation criteria. cardiac-related complications. and associated injuries were analyzed for 524 patients. Twenty-eight cardiac-related complications occurred in 27 of 524 patients (5%). These complications included 23 dysrhythmias. 3 infarctions. and 2 pericardial effusions. There were 23 patients with abnormal admission electrocardiograms and 4 with normal ones. Of the latter. one patient developed dysrhythmia 4 hours after admission. and three had other major multi-system injuries requiring admission to the intensive care unit. The overall incidence of cardiac-related complications in minimally injured patients was 0.1%. There were no complications in patients with isolated chest wall contusions. a normal admission electrocardiogram. and a normal rhythm at 4 hours. There was no significant association between creatine phosphokinase isoenzymes or echocardiogram and cardiac-related complications. The complete absence of significant cardiac sequelae in patients with isolated chest wall contusion. normal admission and 4-hour electrocardiograms. and no other associated major injuries suggests that these patients need not be admitted.
Stunned myocardium during extracorporeal membrane oxygenation, The "stunned myocardium" is a syndrome of reversible myocardial dysfunction that may be mediated by oxygen-derived free radicals. This phenomenon has been seen in some neonates undergoing extracorporeal membrane oxygenation. We performed echocardiograms and measured creatine phosphokinase isoenzymes and lipid peroxide levels in 16 neonates before. during. and after extracorporeal membrane oxygenation. Infants who developed stunned myocardia by echocardiography did so shortly after initiation of bypass and exhibited concurrent elevations of the MB fraction of creatine phosphokinase. Lipid peroxide levels did not simultaneously rise. These data suggest that oxygen-derived free radicals may not cause the stunned myocardium seen in neonates undergoing extracorporeal membrane oxygenation.
Hypoxic events in the surgical intensive care unit, An oxygen-monitoring protocol was established in the surgical intensive care unit (SICU) at the Denver General Hospital in July 1988. A 3-month surveillance audit ending March 1989 prospectively documented 100 consecutive hypoxic events in 51 of 241 (21%) SICU patients. These episodes occurred during mechanical ventilation in 46 patients. during spontaneous ventilation in 15 patients with artificial airways. and the remaining 39 occurred in nonintubated patients. Hypoxemia was recognized by pulse oximetry in 59. arterial blood gas analysis in 24. mixed venous oximetry in 15. and transcutaneous oxygen monitoring in 2. These events were due to problems with the ventilator or airway in 42. recent interventions in 21. new pulmonary process in 19. progression of underlying disease in 11. and unknown causes in 7. Two thirds resulted from mechanical problems amenable to simple intervention; there were two adverse outcomes. In conclusion. acute hypoxia is a frequent potentially morbid SICU event. Advances in continuous oxygen monitoring permit early identification and thereby may limit adverse outcomes. but should not prompt an expensive diagnostic work-up.
Tertiary trauma care in a rural state, Trauma patients in rural areas usually have no access to regional trauma systems or designated trauma centers. Efforts to provide quality trauma care in small hospitals may seriously overextend local capabilities. The urban trauma center retains an important role in trauma care even when the initial care must be provided at the local level. Twenty-five trauma patients were transferred to University Hospital between 1985 and 1988 after definitive care was initiated in community hospitals. During the same time period. a total of 147 trauma patients were transferred to the trauma service. No information was available on the total incidence of trauma. Medical records were reviewed to determine the reasons for transfer. Major reasons included the need for further complex surgery. better critical care support. and inadequate blood banks. Trauma centers serving rural areas provide a valuable resource well beyond the initial 24 hours.
Improved trauma care in a rural hospital after establishing a level II trauma center, A study of motor vehicle accident deaths occurring in Napa County. California. from 1979 through 1983 showed that there was a preventable death rate of 42% for deaths that were not related to central nervous system injuries. After developing a Level II trauma center at our hospital. the preventable death rate decreased to 14%. This was statistically significant (total chi-square. 0.01 less than p less than 0.025). There was a significant increase in the average Injury Severity Score (34 versus 45. p less than 0.005) as well as significant improvements in the surgeon's response time (32 minutes versus 11 minutes. p less than 0.005) and in the time from hospital arrival to the start of surgery (3.6 hours versus 1.9 hours. 0.01 less than p less than 0.025). We conclude that these changes are indicative of improved trauma care and reflect favorably upon the effectiveness of a rural trauma center that meets Level II trauma center guidelines established by the American College of Surgeons Committee on Trauma.
Selective nonoperative management of patients referred with abnormal mammograms, Screening mammography provides a means of detecting clinically occult breast carcinoma. but the question of whether all abnormal mammograms require biopsy remains unanswered. We retrospectively reviewed records of 214 women referred over an 8-year period for abnormal mammograms. They were selectively assigned to biopsy or mammographic follow-up based on specific mammographic criteria. Of 114 women initially observed mammographically. 2 were later found by biopsy to have carcinoma. Initial assignment to mammographic observation delayed the recommendation for biopsy 3 and 12 months. respectively. in these patients. but no effect on outcome was documented. Because they have benign lesions by clinical and mammographic criteria. 102 women (53%) have been spared biopsy; they continue to be monitored closely. We believe these data support the use of a selective approach to biopsy based on specific mammographic criteria.
Multimodal therapy in locally advanced breast carcinoma, Among 879 patients treated for breast cancer between 1975 and 1984. advanced disease was found in 125 (14%). A subgroup of 34 (4%) presented with untreated locally advanced disease without demonstrable distant metastases at the time of diagnosis (stage IIIB = T4abed. NX-2.MO). During the first 5 years (1975 through 1979). 17 patients were treated primarily with sequential radiotherapy and chemotherapy (Group A). From 1980 to 1984 (Group B). the management consisted of four courses of induction multi-drug chemotherapy followed primarily by mastectomy and additional chemotherapy. The mean follow-up for the most recent group (Group B) is 48 months. Follow-up was complete. While the local disease control rate was the same for both groups (76%). the survival was remarkably different. Group A patients experienced a median survival of 15 months. and only one survived 5 years. In Group B. the median survival was 56 months with nine patients (53%) alive between 40 and 76 months. seven (41%) of whom are 5-year survivors. While the overall mortality of patients with inflammatory breast cancer was greater in both groups when compared with the group with noninflammatory disease. the survival of patients in Group B was better than in Group A for both inflammatory and noninflammatory cancers (p less than 0.01). Estrogen receptor. nodal. and menopausal status did not influence survival. These data suggest that neoadjuvant chemotherapy improves survival for patients with stage IIIB breast carcinoma and delays the establishment or progression of distant metastases. Mastectomy is an important component in the treatment of this disease.
Alkalinisation of prilocaine for intravenous regional anaesthesia. Suitability for clinical use, Eighty unpremedicated patients undergoing day-case hand surgery under intravenous regional anaesthesia were randomly allocated to receive. in a double-blind study. either 40 ml 0.75% prilocaine hydrochloride. with 5 ml 8.4% sodium bicarbonate or 5 ml 0.9% saline. The alkalinised group had significantly less pain on injection (p = 0.0045). during surgery (p = 0.0074) and 5 minutes after the tourniquet was deflated (p = 0.0027). The time elapsed between insertion of the block and commencement of surgery was not affected.
Flumazenil in ketamine and midazolam anaesthesia, A double-blind. parallel group study using flumazenil and placebo was carried out to determine whether patients who received flumazenil would awake more quickly and whether this drug would reverse the protection conferred by midazolam on the psychic sequelae of ketamine. Fifty female patients were studied. The results showed that there was a significant reduction in awakening time (p = 0.02) and a very significant increase (p = 0.001) in the incidence of dreams in the flumazenil group.
The use of diazepam in chloroquine poisoning, A 39-year-old patient was found to be unconscious after having taken 2.5 g of chloroquine. Treatment consisted mainly of gastric lavage and diazepam. Experimental and clinical evidence is presented to show that diazepam in varying doses significantly decreases the mortality rate.
An evaluation of the Level 1 blood warmer series, The Level 1 blood warmer series comprises three infusion sets and two blood warmers of different power outputs. All systems were found to be extremely efficient. with the larger 500 series capable of warming the equivalent of 80 units of blood an hour almost to body temperature.
pH-adjustment and discomfort caused by the intradermal injection of lignocaine [published erratum appears in Anaesthesia 1991 Mar;46(3):242, One hundred adult day-case patients who required intravenous access had cannulae inserted using local anaesthesia with 1% lignocaine. 1% lignocaine with adrenaline or the corresponding pH-adjusted solutions. The local anaesthetic solutions were modified by the addition of 1 ml 8.4% sodium bicarbonate to 10 ml lignocaine. Pain scores at different stages of cannulation were noted and showed a significant reduction after use of pH-adjusted solutions (p less than 0.02 for the plain lignocaine. and less than 0.001 for the lignocaine with adrenaline). Modification of the pH of lignocaine solutions by the addition of sodium bicarbonate is a simple method significantly to reduce the discomfort caused by the infiltration of the local anaesthetic.
Was CEPOD right, This retrospective study found that the long-term (greater than 6 months) postoperative survival in ASA 4E and 5E patients was 41% and 21% respectively. in 1986. This supports the Confidential Enquiry into Peri-operative Deaths' recommendation that life-saving surgery should not be withheld from patients who present in so serious a condition that they are unlikely to survive surgery.
Intact epithelial barrier function is critical for the resolution of alveolar edema in humans, Within 15 min of endotracheal intubation. the resolution of pulmonary edema was studied over the next 12 h in 34 mechanically ventilated patients by (1) serial measurements of the alveolar-arterial oxygen difference. (2) the extent of edema on the initial and follow-up chest radiograph. and (3) by an initial and final measurement of total protein and albumin concentration in sequential samples of pulmonary edema fluid. Based on the oxygenation and chest radiographic data. 24 patients clinically improved and 10 patients did not improve. In the 10 patients who did not clinically improve (3. hydrostatic edema; 7. permeability edema). there was no change in the final edema fluid protein concentration (4.1 +/- 1.1 g/100 ml) compared with the initial edema fluid protein concentration (4.2 +/- 1.0 g/100 ml) (p = ns). However. in the 24 patients who clinically improved (15. hydrostatic edema; 9. permeability edema). there was an increase in every patient's final edema protein concentration (5.6 +/- 2.3 g/100 ml) compared with their initial edema protein concentration (3.8 +/- 1.2 g/100 ml) (p less than 0.01). In 13 of these 24 patients. the final edema fluid concentration (7.3 +/- 1.6 g/100 ml) exceeded the final plasma protein concentration (5.6 +/- 0.8 g/100 ml) by a mean value of 1.7 g/100 ml protein. The data provide the first evidence in humans to support the hypothesis that active ion transport across the alveolar epithelial barrier is the primary mechanism for clearance of edema fluid from the air spaces of the lung.
Circulating plasma platelet activating factor in persistent pulmonary hypertension of the newborn, Platelet activating factor (PAF) is an endogenous phospholipid mediator that causes pulmonary hypertension and thrombocytopenia in experimental animal models. To investigate circulating PAF in persistent pulmonary hypertension of the newborn (PPHN). we studied PAF and its degradative enzyme. acetylhydrolase. Thirteen neonates with PPHN. diagnosed by routine clinical methods including echocardiography. were compared to six age-matched control patients with respiratory distress. Overall. plasma PAF levels were elevated in patients with PPHN compared to control patients (20.1 +/- 3.9 versus 1.6 +/- 0.7 ng/ml. p less than 0.01). In addition. plasma PAF concentrations in patients with PPHN correlated with the severity of disease as defined by the delta AaPO2 (r = 0.65. p = 0.015). In three patients with elevated PAF levels. as the clinical status improved. the plasma PAF values decreased. Acetylhydrolase activity was similar in both groups (3.96 +/- 0.90 versus 3.78 +/- 1.44 nmol/ml/min. p = NS). We conclude that PAF production is increased in PPHN and that abnormal production of PAF may be associated with pulmonary hypertension.
Surfactant replacement improves lung recoil in rabbit lungs after acid aspiration, We tested the hypothesis that surfactant replacement would be beneficial in the acid-aspiration model of acute lung injury. HCl (0.1 N. 2 ml/kg) was injected into the trachea of excised rabbit lungs (n = 8). Control lungs (n = 4) had no intervention. All were perfused with Tyrode's solution mixed 1:1 with autologous whole blood at 40 ml/min/kg for 30 min. and then degassed. A modified natural surfactant (Survanta. Ross Laboratories) was then injected into the trachea of four lungs injured with HCl (100 mg/kg at 25 mg/ml). Two quasi-static pressure-volume curves were determined. The mean alveolar pressures at 50. 60. 70. 80. and 90% of TLC were greater in the HCl group than in the control group (p less than 0.05). However. no difference was observed between the control lungs and those that received HCl + Survanta. In 13 anesthetized. paralyzed. and ventilated rabbits. deflation pressure-volume curves were determined from TLC to FRC (measured by helium dilution). Then. 0.1 N HCl (3 ml/kg) was injected into the trachea and. in seven. Survanta was instilled 5 min later. The mean alveolar pressures at 60. 70. 80. and 90% TLC were higher at 15 and 60 min in the HCl group compared with their pre-HCl time point (p less than 0.05). In the HCl + Survanta group. no differences were seen at 15 min. and only slight increased were seen at 60 min. No effect of surfactant replacement on arterial blood gases was observed. HCl aspiration increased recoil in both excised and in vivo lungs. and surfactant replacement with Survanta returned recoil to normal.
Inspiratory flow dynamics during mechanical ventilation in patients with respiratory failure, We studied the effect of inspiratory flow rate on respiratory resistance during mechanical ventilation in 15 patients with acute respiratory failure (ARF). Resistance was measured by both constant flow inflation and occlusion methods as inspiratory flow rates were increased from 0.66 to 2.0 L/s. Endotracheal tube resistance was subtracted from total resistance to obtain respiratory resistance. In contrast to the flow-dependent increase in endotracheal tube resistance. respiratory resistance decreased continuously as flow rate and airway pressure increased. except in four of six patients with asthma in whom respiratory resistance increased as flow increased. Mechanical airway dilatation. tissue resistance. stress relaxation. and time-constant inequalities may contribute to the decrease in respiratory resistance. In status asthmaticus. however. the effects of turbulence. noncompliant airways. and/or "reflex" bronchoconstriction may be sufficient to cause a flow-dependent increase in resistance.
Risk factors for Staphylococcus aureus nosocomial pneumonia in critically ill patients, Staphylococcus aureus nosocomial pneumonia has become an important infection not only because of an apparently increasing incidence but also because of its high mortality rate. A total of 50 episodes of nosocomial pneumonia in critically ill patients in which etiologic diagnosis was well established were prospectively followed in a medical-surgical intensive care unit (ICU). S. aureus was isolated in a total of 13 episodes. In the univariate analysis the variables significantly associated with S. aureus nosocomial pneumonia were below 25 yr of age. coma. nonuse of corticosteroids. and antecedent trauma. A step-forward logistic regression analysis defined only coma as significantly influencing the risk of developing S. aureus nosocomial pneumonia. We suggest that antimicrobial drugs active against S. aureus must be included in the initial empirical antimicrobial regimen for treating nosocomial pneumonia in patients with coma. The identification of factors influencing the etiology and the possibility of earlier effective antimicrobial treatment may represent a further step in the control of nosocomial pneumonia in critically ill patients by improving its prognosis.
Mineralogic parameters related to amosite asbestos-induced fibrosis in humans, We have previously shown that in the lungs of a group of chrysotile miners and millers. grade of interstitial fibrosis (asbestosis) is directly proportional to tremolite fiber or chrysotile fiber concentration but is inversely proportional to mean fiber length and length-related parameters. To compare the effects of the commercial amphibole asbestos amosite on parenchymal fibrosis. we histologically graded fibrosis in four different sites in the lungs of 20 shipyard and insulation workers with heavy amosite exposure and measured by analytic electron microscopy fiber concentration and size in corresponding portions of lung tissue. Fibrosis grade was found to be strongly positively correlated with amosite concentration and negatively correlated with mean fiber size parameters. including fiber length. width. surface area. and mass. A comparison of our present results with our data on the chrysotile miners and millers showed that the regression lines of fibrosis grade versus concentration for amosite. chrysotile. and tremolite were statistically different. These findings indicate that amosite concentration. like chrysotile and tremolite concentration. is closely and directly related to fibrosis at the local lung level. Furthermore. these observations again raise the possibility that short fibers may be more important than is commonly believed in the genesis of fibrosis in man. Last. the concentration comparison data indicate that. fiber for fiber. amosite is more fibrogenic than is chrysotile or tremolite. and indirectly suggest that tremolite is more fibrogenic than is chrysotile.
Comparative airway response to inhaled bradykinin, kallidin, and [des-Arg9]bradykinin in normal and asthmatic subjects, Bradykinin. kallidin (lys-bradykinin). and [des-Arg9]bradykinin are oligopeptides that may contribute as mediators in the pathogenesis of asthma by interacting with specific receptors designated B1 and B2. In this study. we have investigated the airway response to inhaled bradykinin. kallidin. and [des-Arg9]bradykinin in normal and asthmatic subjects. Changes in airway caliber were followed as maximum expiratory flow at 30% of the vital capacity (Vp30) and as forced expiratory volume in 1 s (FEV1). Only one of the six normal subjects responded to bradykinin at the maximum cumulative concentration (5.33 mg/ml). Neither kallidin nor [des-Arg9]bradykinin had any measurable bronchoconstrictor effect in the normal subjects whether airway caliber was measured as Vp30 or FEV1. In the 10 subjects with asthma. bradykinin and kallidin. but not [des-Arg9]bradykinin. produced a concentration-related fall in FEV1. The geometric mean provocation concentrations of inhaled agonist reducing FEV1 by 20% of baseline were 0.03. 0.08. and 0.44 mg/ml for bradykinin. kallidin. and histamine. respectively. Bronchoconstriction produced by bradykinin and kallidin was maximal within 3 to 5 min with recovery occurring over 30 to 45 min. Because bradykinin and kallidin are agonists of B2 receptors and [des-Arg9]bradykinin is an agonist for B1 receptors. these in vivo structure activity studies suggest that asthmatic. but not normal. airways are hyperresponsive to kinins when compared to histamine and that this potent bronchoconstrictor action is a specific pharmacologic effect compatible with the stimulation of B2 receptors or a variant of these.
Methacholine responsiveness among working populations. Relationship to smoking and airway caliber, It has been suggested that the development of bronchial hyperresponsiveness (BHR) in some smokers may be an intermediate event in the progression to chronic obstructive pulmonary disease in this group. If this is true. prevalence data on BHR in a general population should show an independent association between BHR and smoking status. To test this. we analyzed BHR to inhaled methacholine in 654 white men without known asthma. in relation to smoking. skin-test reactivity. type of work (office versus industrial). and indicators of baseline airway caliber (FEV1 % predicted and FEV1/FVC). BHR was measured in the traditional way (PC20) and as the slope of FEV1 versus the methacholine concentration (linear scale). A PC20 of less than 16 mg/ml was considered "responsive" for analyses of this outcome. We found that although a positive skin test. smoking. and being an industrial worker all appeared to be significant predictors of increased BHR (p less than 0.05). once FEV1 (% predicted) and FEV1/FVC% were taken into account. none of these variables alone remained significantly associated with BHR. The strongest predictors of BHR were prechallenge FEV1 and FEV1/FVC (both p less than 0.01). The combination of smoking. atopy. and work groups. which identified a small subgroup of atopic smokers who were office workers. also remained significantly associated with increased BHR. We also used a regression model that allowed for comparison of predictors for BHR between the most responsive subset of the population (n = 84) and the remainder of the study population.
Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma, We have used immunohistochemistry and monoclonal antibodies to analyze the phenotypic composition and activation status of the cellular infiltrate of bronchial biopsies obtained by fiber optic bronchoscopy of 11 atopic asthmatic subjects (FEV1% predicted range 78 to 114). 9 atopic nonasthmatic control subjects. and 10 normal healthy subjects. Examination of mucosal biopsies obtained from both central (level I) and subsegmental (level II) bronchi showed that the highest number of CD45-. DC3-. DC4-. and CD8-positive cells were found in the group with asthma. There was a significant increase in the number of interleukin-2 receptor (CD25)-positive cells (a marker of lymphocyte activation) at airway level I in the asthmatic group compared with both nonasthmatic atopic (p less than 0.05) and normal control subjects (p less than 0.01). Eosinophil numbers were significantly increased in asthma at both airway levels and at airway level II in the nonasthmatic atopic group when compared with normal healthy control subjects (p less than 0.05). EG2-positive cells (an index of secretion of eosinophil cationic protein following activation) were found at both airway levels in the asthmatic group and at level I in the nonasthmatic atopic control group (p less than 0.05). When asthmatic subjects were compared with normal healthy subjects. there was a reduction in the number of neutrophil elastase-positive cells in the asthmatic subjects which. as a percentage of leukocytes. was significant (p = 0.05).
Activated eosinophils increase vascular permeability and resistance in isolated perfused rat lungs, The effects of eosinophils activated with phorbol myristate acetate (PMA) on isolated perfused rat lungs were examined. Eosinophils were obtained from lungs of rats infected with Toxocara canis by bronchoalveolar lavage. incubated with PMA. and administered to an isolated perfused rat lung preparation. Vascular endothelial permeability was assessed by measuring the capillary filtration coefficient (Kf.c) in the perfused lungs. In lungs receiving either no eosinophils (control) or nonactivated eosinophils. there were no changes in pulmonary hemodynamics or Kf.c. However. in lungs receiving 2 x 10(6) eosinophils activated with PMA. there was a transient 4.8-fold increase in pulmonary vascular resistance that peaked at 30 min. primarily due to the constriction of small arteries and veins. After the initial pressor response. Kf.c was increased to 7.5 times control at 130 min and resulted in marked lung edema. increased wet-dry weight ratios. and edema on histologic examination. Pulmonary arterial pressure and Kf.c responses were dose related for eosinophil numbers between 1 x 10(6) and 4 x 10(6) cells. Peak airway pressure (Paw) during constant tidal volume ventilation also increased in lungs receiving activated eosinophils compared to the control and nonactivated eosinophil groups. These findings indicate that activated eosinophils are potent effector cells and can cause pulmonary vasoconstriction. bronchoconstriction. and vascular endothelial injury without widespread plugging of capillaries by aggregated eosinophils.
Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig, To investigate the long-term effect of cigarette smoke on pulmonary structure and function. we exposed groups of guinea pigs to the smoke of 10 cigarettes each day. 5 days per week. for 1. 3. 6. and 12 months. We found that the guinea pigs developed progressive lung destruction (emphysema) and alterations in their pulmonary function tests similar to that seen in humans with cigarette smoke-induced chronic obstructive lung disease. This method of smoke-induced lung destruction should provide a good model for the study of the early changes of emphysema.
Inhalation injury to tracheal epithelium in an ovine model of cotton smoke exposure. Early phase (30 minutes), The purpose of this study was to evaluate lung cell injury during the acute phase of smoke inhalation injury. A group of 10 sheep were anesthetized with halothane and pancuronium followed by endotracheal intubation. In the first experiment 5 sheep were given air (sham group) and 5 were insufflated with cooled cotton smoke with a modified bee smoker. In the second part of our study (Experiment 2) the animals were insufflated with the following number of smoke breaths: 1 x 12 (n = 3); 2 x 12 (n = 4); 3 x 12 (n = 4) 4 x 12 (n = 4); and sham control (n = 1). After 30 min the animals were killed with KCl and the trachea prepared for scanning. transmission electron. and light microscopy. Our initial observation with scanning electron microscopy revealed a large amount of mucus on the surface of the epithelia. Numerous ciliated cells had been sloughed from the epithelium and were observed on the surface of the remaining ciliated cells. The sloughed cells were intact. and the cilia remained on the apical cell surface. Light and transmission electron microscopy revealed that most goblet cells were in the process of extruding mucus. The cytoplasm of goblet and basal cells appeared normal. Ciliated cells had a slightly vesiculated cytoplasm. and many were in the process of being sloughed from the epithelial surface. In these cells desmosomal attachment had been separated. The light microscope evaluation of the tracheal epithelium showed there was no dose-dependent effect between the four treatment groups.
Bombesin stimulation of mitogenesis. Specific receptors, signal transduction, and early events, Quiescent cultures of Swiss 3T3 cells can be stimulated to recommence DNA synthesis by polypeptide growth factors. neuropeptides. and various pharmacologic agents that act via multiple signal transduction pathways. Neuropeptides of the bombesin family provide potent mitogens to elucidate these pathways. These peptides bind to specific receptors that have been characterized by radioligand binding and sensitivity to antagonists and identified as glycoproteins with a Mr of 75.000-85.000 by chemical cross-linking. After binding. bombesin elicits a cascade of early molecular events including stimulation of phosphorylation of the acidic Mr 80.000 cellular protein. which is a major substrate of protein kinase C; Ca2+ mobilization mediated by Ins(1.4.5)P3. Na+ and K+ fluxes. transmodulation of EGF receptor. enhancement of cAMP accumulation. and expression of the proto-oncogenes c-fos and c-myc. Studies using membrane preparations and permeabilized 3T3 cells indicate that G proteins play a role in the transduction of the mitogenic signal triggered by the binding of bombesin to its receptor. A pertussis toxin-insensitive G protein couples the bombesin receptor to the generation of a signal that activates protein kinase C. whereas a pertussis toxin-sensitive G protein mediates cross-talk between transmembrane signaling pathways. Bombesin-mediated mitogenesis can be blocked by different antagonists and by interrupting the signal-transduction process at various postreceptor levels. Thus. prolonged treatment with vasopressin causes heterologous desensitization to the mitogenic action of bombesin. This mitogenic block is mediated by uncoupling the receptor from its signaling system. Loss of responsiveness to bombesin-stimulated DNA synthesis is also induced by down-regulation of protein kinase C.
Tyrosine kinase and control of cell proliferation, The usefulness of phosphotyrosine antibodies for the detection of physiologically regulated or deregulated tyrosine kinases is discussed in this report. This rather rare enzymatic activity is shared by receptors for some polypeptide growth factors and by the products of Class 1 oncogenes. The antibodies are able to detect proteins phosphorylated on tyrosine in fibroblasts stimulated with growth factors such as EGF and PDGF. The major phosphorylated protein species are the receptors themselves. which undergo phosphorylation only after the addition of the exogenous factor and only transiently. Phosphotyrosine antibodies were able to detect the products of the retroviral Class 1 oncogenes. which are endowed with deregulated tyrosine kinase activity. In fact. in these cases a constitutive phosphorylation of the relevant proteins was observed. which occurred continuously and independently of the presence or lack of exogenous ligands. A tyrosine kinase constitutively activated in human gastric carcinoma cells was detected by P-Tyr antibodies. This molecule has been characterized at the molecular level. and the mechanisms responsible for its enzymatic activation have been investigated. The question of whether the tyrosine kinase identified is responsible for the induction and the maintenance of the transformed phenotype in gastric carcinomas remains to be answered. It is reasonable to suggest that this might be the case by analogy with other situations such as Class 1 oncogenes activated by transduction by retroviruses. abnormal expression of EGF receptors. or deregulated activity of c-abl-encoded proteins in chronic myelogenous leukemia and acute lymphoblastic leukemia. Thus. the search for deregulated kinases by means of phosphotyrosine antibodies seems to be useful for identifying new activated oncogenes in clinical oncology.
Recessive oncogenes in lung cancer, The observation that carcinogen exposure is strongly associated with the probability of developing pulmonary neoplasms has suggested for many years that acquired somatic mutations play a key role in the genesis of these environmentally induced cancers. With the advent of new techniques in cytogenetics and in the molecular analysis of DNA extracted from lung tumors. it has now become possible to test this hypothesis and to search for candidate genes that may be targeted by the chronic exposure of these environmental insults. Early work in this field. studying lung tumors of different histologic types. appears to implicate several distinct chromosomal loci (at chromosomes 3p. 13q. 17p. and others). suggesting that sequential genetic events occur during the initiation and progression pathways to pulmonary tumorigenesis. Identifying the candidate gene products and understanding the chronology and stringency of mutational events at these loci will be an essential goal to understanding the cellular basis of lung tumors and for developing strategies for the next generation of diagnostic and therapeutic studies.
Internists' practices in health promotion and disease prevention. A survey, OBJECTIVE: To estimate internists' use of disease prevention and health promotion activities. and to explore demographic. professional. behavioral. psychological. cognitive. and organizational factors associated with the use of such practices. DESIGN: Mail survey. SETTING AND SUBJECTS: A sample of 2610 members and fellows of the American College of Physicians (ACP) participated in the study. They engaged in patient care activities more than 20 hours per week and were stratified by gender and region. They lived in four geographic areas of the United States (Northeast. Southeast. Central. and West). comprising 21 ACP regions. MEASUREMENTS: A questionnaire requesting background information as well as information about personal health; record keeping; use of immunizations (pneumococcal. influenza. tetanus. hepatitis B); use of screening tests and procedures for detecting cancer (breast examination. Papanicolaou smear. stool occult blood test) and other diseases (electrocardiograms. cholesterol level tests. chest radiographs); and behavioral counseling to promote health (in the areas of smoking. exercise. and alcohol and seat belt use). MAIN RESULTS: Internists used effective preventive interventions less frequently and ineffective practices more frequently than experts recommend. Internists' use of health promotion and disease prevention activities is associated with habit. attitude. and a lack of adequate knowledge. Younger physician age. general internal medicine practice. and personal health promotion and disease prevention practices were strongly associated with more appropriate use of recommended practices (P less than 0.01). CONCLUSIONS: Internists' use of disease prevention and health promotion activities falls short of expert recommendations. Programs to improve the delivery of preventive services might be aimed at improving physicians' personal health practices. might be directed toward patients. and might include the development of effective systems to remind physicians.
Motor unit numbers and contractile properties after spinal cord injury, The number of motor units in the thenar muscle group was estimated in 11 patients with cervical spinal cord injuries. The surface electromyogram and twitch force. in response to maximal stimulation of the median nerve was divided by the average surface electromyogram and twitch of single units. The average single unit size was obtained by intramuscular microstimulation of motor nerve branches and by graded whole nerve stimulation. which provided three independent estimates. two based on the electromyogram and one based on force. The motor unit estimates from the patients covered a wide range. Some had essentially normal motor units both in numbers and contractile properties. while others had varying reductions in numbers of units. Those patients who showed a large reduction in motor unit numbers also had greatly enlarged units. which produced an average of up to sixfold the normal force. These enlarged units summed to produce maximal compound action potentials and twitches that were sometimes indistinguishable from normal. Magnetic resonance imaging scans of the cervical spine obtained from some patients provided independent evidence that patients with low motor unit counts had sustained direct injury to the anterior aspect of the spinal cord at the relevant segmental levels. Some patients showed a normal number of motor units long after the injury. No evidence of transneuronal degeneration could be demonstrated in the thenar group in these patients with the current techniques.
Synaptic transmission in human neocortex removed for treatment of intractable epilepsy in children, Synaptic transmission to pyramidal cells was studied in slices of neocortex resected from infants and children (n = 10. age 8 months to 13 years) undergoing surgical treatment for intractable epilepsy. Most specimens were from the least abnormal area of the resection. Stable intracellular recordings could be obtained for up to 8 hours. Most of the recorded neurons had electrophysiological characteristics similar to those of regular-firing pyramidal cells and were in layers III to V. which was confirmed by intracellular staining with Lucifer yellow. Local extracellular stimulation evoked a sequence of excitatory and inhibitory postsynaptic potentials. After application of the gamma-aminobutyric acid antagonist. bicuculline (10-30 microM). extracellular stimulation induced large excitatory postsynaptic potentials and epileptiform bursts. Spontaneous bursts occasionally occurred in bicuculline. This effect of bicuculline was observed in all the tissue samples. even those from infant patients (n = 4. age 8-16 months). Kynurenic acid depressed or abolished both spontaneous and stimulation-induced bursts. The competitive antagonist for N-methyl-D-aspartate receptors. DL-2-amino-5-phosphonopentanoic acid decreased the duration of bicuculline-induced bursts. These data provide evidence that. similar to rat and cat neocortex. excitatory and inhibitory amino acids are important transmitters to pyramidal cells in immature human neocortex.
Hypoglycemia alters striatal amino acid efflux in perinatal rats: an in vivo microdialysis study, In adult brain. during insulin-induced hypoglycemia. striatal extracellular fluid concentrations of the excitatory amino acids glutamate and aspartate rise markedly (fourfold to tenfold). In this study. we used in vivo microdialysis to determine if insulin-induced hypoglycemia altered striatal amino acid efflux in similar fashion in the immature brain. Microdialysis probes were inserted into the right striatum of rats on postnatal day 7. After a 2-hour recovery period. in each animal a 30-minute baseline sample was obtained. Then insulin (0.6 mu/kg. intraperitoneal injection) was administered (n = 6) and dialysate sampling was continued over the next 210 minutes (terminal blood glucose level less than 5 mg/dl). Untreated control rats (n = 6) were sampled over the same time interval. After pre-column derivatization with o-phthaldialdehyde. dialysate samples were assayed by high-pressure liquid chromatography with electrochemical detection to measure their amino acid content; eight amino acids (glutamate. aspartate. taurine. glutamine. alanine. serine. glycine. and asparagine) were consistently detected. In controls. amino acid efflux did not change over 4 hours. In hypoglycemic animals. glutamate efflux increased (peak: 238 +/- 85% of baseline. p = 0.02. repeated measures analysis of variance [ANOVA]). glutamine efflux declined (to 44 +/- 5% of baseline. p = 0.002. ANOVA). and taurine efflux increased (up to 310 +/- 120% of baseline; p less than 0.06. ANOVA). In contrast with 9- to 12-fold increases in aspartate efflux reported in adult striatum. aspartate efflux increased only slightly (to 174 +/- 69% of baseline; not significant).
NMDA antagonists potentiate antiparkinsonian actions of L-dopa in monoamine-depleted rats, Systemically administered N-methyl-D-aspartate (NMDA) antagonists. MK-801 ((+)5-methyl-10.11-dihydro-5H-dibenzo(a.d)cyclohepten-5.10-imine maleate) and CPP (3-[(+-)-2-carboxypiperazin-4-yl]-propyl-1-phosphonate). potentiate the ability of L-dopa (L-3.4-dihydroxyphenylalanine) to reverse akinesia and to alleviate muscular rigidity in monoamine-depleted rats. On the basis of these findings. it is proposed that NMDA antagonists may be beneficial as adjunctive treatment in the therapy of Parkinson's disease. CPP locally injected into the subthalamic nucleus. entopeduncular nucleus--the rat homologue of the internal pallidal segment--or substantia nigra pars reticulata of monoamine-depleted rats stimulates locomotor activity and alleviates rigidity. whereas local microinjection of CPP into the neostriatum is ineffective. These results make it unlikely that the neostriatum is the site of the antiparkinsonian action of NMDA antagonists in monoamine-depleted rats. whereas the subthalamic nucleus. internal pallidal segment. and substantia nigra pars reticulata appear to be important for the effects of NMDA antagonists.
Failure of nine-month phenobarbital administration to reverse amygdaloid-kindled seizure susceptibility in cats, Upon completion of left amygdaloid kindling. 4 cats underwent long-term phenobarbital administration during the subsequent 5- to 9-month rest period. Plasma phenobarbital levels were maintained above 15 to 20 micrograms/ml and were restimulated following plasma phenobarbital washout. Three cats served as nonmedicated controls. All 7 cats were subjected to repeated 6-hour sleep monitoring for observation of interictal discharges. which were observed most often in the immediate postictal period. Their frequency decreased gradually throughout the experiment in both the medicated and control animals. but they never completely disappeared except from the contralateral amygdala in 1 medicated animal. Upon primary site restimulation. all of the medicated animals responded with a generalized convulsion once the afterdischarge was induced. When these animals underwent secondary-site amygdaloid kindling. 3 showed a positive transfer effect. The findings suggest that although phenobarbital is a potent anticonvulsant. it has little effect on the acquired seizure susceptibility of previously amygdaloid kindled cats.
HTLV-I sequences are not detected in peripheral blood genomic DNA or in brain cDNA of multiple sclerosis patients, Human T-cell lymphotropic virus (HTLV-I) was recently reported to be etiologically associated with multiple sclerosis (MS). Genomic DNA from peripheral blood lymphocytes and brain plaques of patients with MS was analyzed for the presence of sequences homologous to the HTLV-I pol gene using the polymerase chain reaction and dot blot techniques. Comparison of DNA amplification patterns between patients with MS. and with control subjects who have other autoimmune conditions. with those in healthy control subjects and with an HTLV-I-infected cell line indicates that HTLV-I pol sequence is not present in the peripheral blood of patients with MS. and that the virus is not active in MS brain plaques.
Effect of digitalis on clinical symptoms and conduction variables in patients with multiple sclerosis, Digitalis has been shown to reverse conduction block in demyelinated nerve fibers in experimental animals. In the search for a symptomatic treatment of multiple sclerosis. digoxin (0.02 mg per kilogram of body weight) was given intravenously to 7 patients with probable or clinically definite multiple sclerosis. All of these patients had temperature-dependent symptoms. In 3 patients. improvement of clinical deficits was observed concurrent with significant changes in evoked potential findings. Digitalis derivatives may be useful in ameliorating symptoms in selected patients with multiple sclerosis.
An analysis of outcome following percutaneous transluminal coronary artery angioplasty. An autopsy series, We analyzed autopsy findings on 26 patients who died following percutaneous transluminal coronary angioplasty (PTCA). Twenty-one patients died within 3 weeks of undergoing PTCA; demonstrable cardiac complications were found in 19 patients: platelet-fibrin thrombi (10 patients [48%]). coronary artery dissections (17 patients [81%]). thromboemboli (13 patients [62%]). atheroemboli (seven patients [33%]). and myocardial infarcts (17 patients [81%]). An increased incidence of coronary platelet-fibrin thrombi was noted when compared with a non-PTCA cardiac autopsy population (five of 53 patients). Apparently there was an increased incidence of coronary atheroemboli and thromboemboli in the patients with coronary platelet-fibrin thrombi (eight patients) when compared with patients who did not have platelet-fibrin thrombi (five patients). although this was not statistically significant. There was no evidence of a systemic hypercoagulable state or of disseminated intravascular coagulation. The pathogenesis of this is unclear; however. vasospasm and a disruption of the endothelial surface induced by PTCA with subsequent platelet activation are possible causes. Although not statistically significant. there was a proponderance of female subjects (seven patients) and an increased incidence of diabetes mellitus (six patients) and hypertension (13 patients) when compared with a control population of all patients undergoing PTCA at The Cleveland (Ohio) Clinic Foundation in 1987. suggesting that diabetes mellitus. hypertension. and female sex may be clinical risk factors for fatal complications following PTCA.
The distribution of enkephalins in human carotid bodies showing cellular proliferation and chronic glomitis, Human carotid bodies obtained at necropsy that showed prominence of either the sustentacular cell or the dark variant of chief cell or chronic carotid glomitis were studied by an immunogold labeling technique. The peptides methionine and leucine enkephalin had a similar distribution to that found in the normal human carotid body. They were localized prominently and predominantly in the dark and progenitor variants of chief (type I) cells. The sustentacular (type II) cells showed no immunoreactivity for the enkephalins. Cell counts on immunolabeled chief cells in cases of sustentacular cell hyperplasia and chronic carotid glomitis were found to be at the lower end of the normal range. whereas those in dark cell prominence occurred nearer the upper limit.
Normal reticulin level in iliac bone marrow, While the level of marrow reticulin may be a factor that is used when the presence of a hematologic disorder is being considered. to our knowledge no study has graded the amount of reticulin present in normal iliac bone marrow. Grading reticulin stains of bone biopsy specimens from 100 hematologically normal patients documented that the normal amount of reticulin in the marrow is low. Twenty-seven percent of the patients had marrow reticulin grade 0 using the Bauermeister scale. 42% had grade N. 27% had grade 1. and 4% had grade 2; no patient had a Bauermeister grade 3 or 4 reticulin level. Knowledge of the normal range of reticulin is essential when the reticulin level is used as a factor in evaluating the possibility of a hematologic disorder.
Enhanced expression of c-myc and H-ras oncogenes in Letterer-Siwe disease. A sequential study using colorimetric in situ hybridization, Tissues from two patients with disseminated histiocytosis X (Letterer-Siwe disease) in which histiocytosis X cells exhibited histologic and cytologic features of malignancy were evaluated by in situ hybridization with the use of biotinylated nucleic acid probes to c-myc and H-ras oncogenes. Enhanced expression of these oncogenes was observed in mononucleated and multinucleated cells of histiocytosis X in the terminal proliferative phase but not in the early quiescent phase of Letterer-Siwe disease in both patients. Our findings indicate that deregulation of c-myc and H-ras in histiocytosis X are late events that likely confer a selective growth advantage to histiocytosis X cells.
Monocytoid B-cell lymphoma in a patient with human immunodeficiency virus infection. Demonstration of human immunodeficiency virus sequences in paraffin-embedded lymph node sections by polymerase chain reaction amplification, There is a significantly increased incidence of malignant lymphoma in patients with acquired immunodeficiency syndrome (AIDS). The lymphomas are usually of a high grade and of B-cell phenotype. While the frequent presence of reactive monocytoid B lymphocytes in patients with AIDS-related lymphadenopathy has recently been documented in several studies. to our knowledge. there are no reported cases of monocytoid B-cell lymphoma. the neoplastic counterpart of monocytoid B lymphocytes. in patients with AIDS. We now describe a human immunodeficiency virus (HIV)-positive patient with HIV-related lymphadenopathy in whom monocytoid B-cell lymphoma developed during the course of his disease. The morphologic and immunologic features of the lymphoma were characteristic of monocytoid B-cell lymphoma. and the involved lymph node exhibited a reversed CD4/CD8 ratio. Moreover. using the polymerase chain reaction. we were able to demonstrate HIV genome in DNA extracted from the lymph node tissue. To our knowledge. this is the first report of a case of monocytoid B-cell lymphoma occurring in an HIV-positive patient and in which we were able. by using a sensitive molecular biologic technique. to demonstrate HIV sequence in paraffin-embedded. fixed lymph node sections.
Bilateral familial carotid body paragangliomas. Report of a case with DNA flow cytometric and cytogenetic analyses, A case study of bilateral familial carotid body paragangliomas with DNA flow cytometric and cytogenetic analyses is presented. Analysis of tumor cell nuclear DNA content by flow cytometry revealed aneuploid cell populations in both tumors. Standard cytogenetic analysis (Giemsa-banding technique used) of the right carotid body paraganglioma showed no evidence of numerical or structural abnormalities. We describe parameters currently used to "predict" biological behavior in these tumors.
Soft-tissue tumor with abnormal amianthoid collagen fibers, Electron microscopic examination of a solitary soft-tissue tumor from the face demonstrated large areas with abnormal amianthoid collagen fibers in the neoplasm. The lesion was classified as a benign neoplasm of myofibroblasts and tentatively named a myofibroblastoma. The significance of the amianthoid collagen fibers is unknown. Normal native collagen fibers were found in some parts of the neoplasm.
Fetal homotransplants (ventral mesencephalon and adrenal tissue) to the striatum of parkinsonian subjects, Fetal ventral mesencephalon and fetal adrenal tissue grafted to the caudate nucleus of four and three parkinsonian patients. respectively. have been shown to be an alternative treatment for the amelioration of the signs of the disease. The ventral mesencephalon patients had a significant amelioration of rigidity. bradykinesia. postural imbalance. gait disturbance. and facial expression. Three of these four patients have returned to work. The fatal adrenal group only showed amelioration of rigidity and bradykinesia. Though these patients are now able to perform their basic daily living activities. and one of them has renewed her household tasks. the other two have not yet been able to return to work. The differences observed between the ventral mesencephalon- and the fetal adrenal-transplanted patients may be related to the heterogeneity of their disease and/or the type of graft implanted. However encouraging our results may be. this experimental procedure obviously requires further studies. and should not be practiced outside of highly qualified clinical research centers.
Stereotactic biopsy of an active multiple sclerosis lesion. Immunocytochemical analysis and neuropathologic correlation with magnetic resonance imaging, Stereotactic biopsy of an active multiple sclerosis lesion in a 23-year-old patient with unilateral symptoms and an isolated high-signal-intensity magnetic resonance abnormality yielded 10 serial tissue cores (1.0 x 0.5 cm) spanning 40 mm within and around the lesion. We performed semiquantitative analysis of lymphocyte phenotype. using antisera to CD3. CD4. CD8. and CD22 molecules. in 11 separate perivascular cuffs in three tissue sections from the lesion edge. Total cells in the cuffs varied from 10 to 100; ratios of CD4+/CD8+ cells in individual cuffs varied from 1.3 to 4.7. Although intense parenchymal infiltrates bordered the least cellular cuffs. parenchymal and perivascular cell phenotypes were indistinguishable. arguing against selective trafficking of lymphocytes into tissue. Individual microfoci of cells displaying CD45RA. CD25. and TQ1 antigens were present. The remarkable phenotypic heterogeneity of T lymphocytes in the multiple sclerosis lesion border is consistent with exposure in situ to a diversity of differentiating stimuli. Histologic demyelination correlated very closely with the signal-intensity abnormality observed on magnetic resonance imaging. These studies provide unusual insight into the histologic and immunocytochemical morphologic appearance of the active multiple sclerosis plaque.
White matter hyperintensities in dementia of Alzheimer's type and in healthy subjects without cerebrovascular risk factors. A magnetic resonance imaging study, T2-weighted (0.5 T) magnetic resonance images were used to study the prevalence of subcortical white matter hyperintensities (WMHIs) in 22 patients with dementia of Alzheimer's type (DAT). 20 age-matched older healthy control subjects. and 10 younger healthy control subjects. Exclusionary criteria for all groups included cerebrovascular risk factors. All subjects had Hachinski Ischemic Index scores of less than 2 and computed tomographic scans showing no infarct. The WMHIs were classified as periventricular WMHIs or deep WMHIs and graded 0 through 3 (0 indicated absent. and 3. severe). For the group with DAT and older control subjects. periventricular WMHIs and deep WMHIs were graded 2 or 3 in fewer than 17% and 27% of subjects. respectively. whereas in the younger control subjects. all ratings were grade 1 or less. Serum cholesterol and systolic blood pressure values. although within the normal range. were elevated significantly in older control subjects when compared with those in younger control subjects. No significant differences in WMHI ratings. blood pressure. cholesterol. or triglyceride levels were found between patients with DAT and age-matched control subjects. Systolic blood pressure levels correlated with the severity of periventricular WMHIs only in older control subjects. Age correlated with periventricular WMHIs and deep WMHIs within both the older control subjects and the patients with DAT. There was no significant correlation between WMHIs and the severity of dementia in the group with DAT. These results suggest that. in subjects screened for cerebrovascular risk factors. WMHIs are rare and occur with identical frequency in patients with DAT as in age-matched healthy control subjects.
Tuberculous meningitis. Short course of chemotherapy, In March 1986. we began a 6-month short course trial of therapy for tuberculous meningitis. in which 28 patients were analyzed. The diagnosis was based on the following cerebrospinal fluid test results: in 53.5% of the cases. Mycobacterium tuberculosis was identified by direct smear; in 57%. culture in Lowenstein-Jensen medium was positive; in 83.3%. the detection of anti-bacille Calmette-Guerin (BCG) antibodies by enzyme-linked immunosorbent assay was positive; and in 74%. the dosification of adenosine deaminase activity was positive. In addition. in 21.4% of the cases. the diagnosis was established by means of autopsy findings. Moreover. the diagnosis was supported by bacteriological analyses from another tissue or body fluids. Despite the administration of an antituberculous therapy. 32.4% of the patients died: all of the decreased had reached the last stage of the disease by the beginning of treatment. Sixteen percent of the patients who survived after more than 18 months of follow-up after therapy had ended suffered neurological sequelae. With the 6-month therapeutic regimen. the morbidity/mortality is similar to that found in the longer-course therapies. The latter regimen is therefore thought to be a good and acceptable therapeutic option for the treatment of tuberculous meningitis.
Primary progressive aphasia. Longitudinal course, neuropsychological profile, and language features, Four patients with the clinical syndrome of primary progressive aphasia and a nonfluent aphasia profile were followed up over a period of 3 to 5 years. Extensive neuropsychological data for three patients revealed a progressive. quantitative decline of language with relative stability of memory. visuospatial skills. and reasoning. Comportment and most activities of daily living were preserved even when speech was unintelligible. Although several aphasia types may be associated with primary progressive aphasia. a nonfluent aphasia profile and phonemic paraphasic errors are most useful in differentiating it from the much more common clinical syndrome. "probable Alzheimer's disease." The clinicopathological correlates of probable Alzheimer's disease differ from those associated with primary progressive aphasia. Therefore. the clinical distinction between the two syndromes may be important for predicting the underlying pathophysiologic changes during the life of the patient.
Plasticity in the aging brain. Reversibility of anatomic, metabolic, and cognitive deficits in normal-pressure hydrocephalus following shunt surgery, The course of idiopathic normal-pressure hydrocephalus was studied in a 78-year-old woman with a 4-year history of progressive dementia who underwent neuropsychologic testing. quantitative x-ray computed tomography. magnetic resonance imaging. and positron emission tomography with fludeoxyglucose F 18 to measure rates of regional cerebral glucose utilization. Preshunt cognitive testing demonstrated progressive deterioration during 2 years. and positron emission tomography showed significant reductions in regional cerebral glucose utilization of 34% to 49% as compared with age- and sex-matched control subjects in frontal. temporal. parietal. and whole brain regions. Periodic testing. carried out during a 2-year period after shunt surgery. showed steady improvement in clinical status. Parallel to the clinical changes. there was a significant reversal in neuropsychologic test scores with increased brain volume and increased regional cerebral glucose utilization in several brain regions. These results documented the considerable potential for recovery of compromised brain function in older subjects even after 4 years of progressive brain disease.
Reduced cerebral blood flow in early stages of human immunodeficiency virus infection, In order to determine if brain perfusion abnormalities. which are known in patients with acquiredimmunodeficiency syndrome dementia. occur in early stages of human immunodeficiency virus infection. technetium 99m hexamethyl-propyleneamine oxime-single-photon emission computed tomography studies were performed in 20 patients infected with human immunodeficiency virus who belonged to Walter Reed stages I through IV. None of these patients demonstrated signs of dementia or severe neurological dysfunction. Pathological patterns of hexamethyl-propyleneamine oxime uptake were seen in 14 patients. seven of whom had normal results during neurological examination. Only four patients had signs of cerebral atrophy on cranial computed tomographic scan. These data suggest that subtle changes in cerebral perfusion seem to arise early in the course of human immunodeficiency virus infection and may indicate human immunodeficiency virus encephalopathy before neurological symptoms or noticeable structural damage occurs.
Effects of physostigmine on spatial attention in patients with progressive supranuclear palsy, We tested patients with progressive supranuclear palsy and control subjects on a task of visuopatial attention. Targets preceded by cues on the same side were termed validly cued; and those on the opposite side. invalidly cued. For all subjects. validly cued targets were responded to faster than those that were invalidly cued. The difference between reaction times for invalidly and validly cued targets. which is hypothesized to measure attentional movement. was significantly increased for the patients. The performance of the controls on certain neuropsychological tests was correlated with their attentional ability. These correlations were altered by progressive supranuclear palsy. Physostigmine treatment of the patients induced a speeding of responses to invalidly cued targets as a function of the duration of the disease. These studies show defects in cognition and attention in patients with progressive supranuclear palsy and demonstrate that physostigmine reduces some of the abnormal visual attentional performance.
An HIV-1 and HIV-2 cross-reactive cytotoxic T-cell epitope, The HLA-B27-restricted HIV gag cytotoxic T-lymphocyte (CTL) epitope. 265-279. is highly conserved amongst HIV-1 isolates. only one. HIV-1ELI. having a single amino acid substitution. Over the same region HIV-2 differs by five amino acids. As a broadly cross-protective AIDS vaccine should protect against infection from all isolates of HIV-1 and HIV-2. we tested CTL specific for the HIV-1 265-279 epitope with peptide analogues from HIV-1ELI. HIV-2 and two simian immunodeficiency virus (SIV) isolates. and with recombinant vaccinia viruses expressing the respective gag genes. to determine whether there was any cross-reactivity for this CTL epitope. CTL from the HIV-1-infected donor could recognize the HIV-1ELI peptide. the HIV-2 peptide and recombinant vaccinia virus-infected target and one of the two SIV peptide-treated targets. Epitopes that exhibit such cross-reactivity may be valuable in vaccine design.
Genomic divergence of an HIV-2 from a German AIDS patient probably infected in Mali, The complete nucleotide sequence of an HIV-2 isolate derived from a German AIDS patient with predominantly neurological symptoms is reported. The HIV-2BEN sequence is highly divergent from those of previously described HIV-2 and SIV strains. Evolutionary tree analysis of eight HIV-2 sequences reveals the existence of three HIV-2 groups. HIV-2BEN belongs to a group with two isolates from Ghana and The Gambia. Based on a comparison of HIV-2BEN with six HIV-2 isolates. SIVsmm and SIVmac. the variability of the structural env and gag proteins is similar within the HIV-2/SIVsmm/mac and HIV-1 groups. In contrast. the regulatory HIV-1 proteins are more highly conserved than those from HIV-2 strains. Multiple sequence alignments reveal that some domains of the envelope and regulatory proteins are well conserved among HIV-1. HIV-2/SIVsmm/mac. SIVagm and SIVmnd. The identification of conserved domains within the external glycoprotein could help to develop broadly active vaccines.
Rapid and specific diagnosis of HIV-1 and HIV-2 infections: an evaluation of testing strategies, To identify cost-effective testing strategies for HIV-1 and HIV-2 infections. we evaluated different combinations of tests on serum specimens from 1134 consecutive patients attending tuberculosis treatment centers in Abidjan. Cote d'lvoire. Virus-specific whole-virus enzyme-linked immunosorbent assay (WVE). Western blot (WB) and synthetic peptide enzyme-linked immunosorbent assay (SPE) were used in sequential fashion to determine the true prevalence of infection; 27% were reactive to HIV-1. 5% to HIV-2. and 10% to both viruses. Of 239 specimens positive on WB for both HIV-1 and HIV-2. SPE diagnosed 38% as HIV-1-reactive and 16% as HIV-2-reactive. while 46% remained reactive to both viruses. Using WVE or one of two rapid (5-10 min) mixed (HIV-1 and HIV-2) antigen tests (RMATs) as a screening test. followed by SPE as a supplemental test. gave results with sensitivity of 97.3-99.2%. specificity of 99.5-99.7%. and positive predictive value for diagnosing HIV infection of 99.4-99.6%. with important savings in time and reagent costs. SPE allows more specific distinction between HIV-1 and HIV-2 infections than WB. and could replace it as a supplemental test in many settings. WB may be required for specimens reactive on screening tests but negative on SPE. until sensitivity of the SPE is further evaluated. A mixed antigen screening test followed by SPE seems to be an efficient testing strategy for diagnosing HIV-1 and HIV-2 infections.
Differences in knowledge of and risk factors for AIDS between Hispanic and non-Hispanic women attending an urban family planning clinic, Risk factors for AIDS. contraceptive use. seroprevalence of HIV. and level of knowledge before and after an AIDS education session were assessed for 657 clients attending a family planning clinic in Los Angeles. USA. History of a partner who was bisexual. an intravenous drug user. or a blood transfusion recipient were the most common risk factors. Spanish speakers reported fewer traditional risk factors than English speakers. They were also less likely to report a history of drug or alcohol use or sexually transmitted diseases. and to have had fewer sexual partners. Less than one-third of the women identified as being at risk of exposure were using condoms. None of 351 consecutive patients tested for HIV antibodies was positive. English speakers scored higher on both pre- and post-tests of knowledge about AIDS. Cultural factors may lower the personal risk of HIV exposure for Spanish-speaking women. but lack of knowledge about AIDS and partner behavior may increase risk.
High HIV risk-taking among young gay men, Previous research has shown younger age to be correlated with greater HIV sexual risk-taking among gay men. The purpose of this study was to identify variables associated with HIV risk-taking among younger gay men. Ninety-nine gay men aged 18-25 in three medium-sized West Coast communities completed self-report questionnaires regarding HIV-related behaviors and attitudes. Of the respondents. 43% reported having engaged in unprotected anal intercourse during the previous 6 months. Men who engaged in unprotected anal intercourse reported greater enjoyment of unprotected anal intercourse. perceived less risk of unprotected anal intercourse. labeled themselves as more at risk for AIDS. reported poorer communication skills with sexual partners. and were more likely to have a boyfriend/lover than men who had not engaged in high-risk sex. In addition. respondents perceived the likelihood of acquiring HIV from unprotected anal intercourse with young gay men to be significantly lower than with older gay men. These findings highlight the need for HIV risk-reduction interventions designed specifically for young gay men and identify critical areas to be targeted in such interventions.
Immunology of HIV infection, I: Biology of the interferons, Interferons (IFN) are the prototypic biologic response modifiers. They comprise a multigene family of regulatory proteins and glycoproteins that affect a variety of cellular functions. including normal and neoplastic cell growth. immune reactivity. and host-parasite interactions. Their importance to basic cell biology and cellular immune defense. and their interactions with human immunodeficiency viruses (HIV) on the molecular and cellular levels. form the basis for this review.
Naturally occurring HIV-1 isolates with differences in replicative capacity are distinguished by in situ hybridization of infected cells, Replication of human immunodeficiency virus type 1 (HIV-1) isolates in peripheral blood mononuclear cells (PBMC) has been studied by in situ hybridization using the riboprobe BH10-R3 from HTLV-IIIB. Two series of isolates were tested: (a) 20 isolates from individuals with varying severity of HIV-1 infection and (b) sequential isolates from 5 subjects showing signs of clinical progression over a 45 month observation period. The results show that HIV-1 isolates with distinct replicative capacity can be distinguished by the intensity of radioactive labeling over single infected cells after in situ hybridization. Sequential isolates from patients with clinically progressive HIV-1 infection show a gradual increase in replicative capacity over time. In PBMC cultures infected with such sequential isolates. intensity of radioactive label over single infected cells increases and is strongest with isolates obtained at the time of low CD4 counts in blood. The results suggest that the restriction of virus replication that operates in the early stages of HIV-1 infection is gradually lost with progression of the disease.
Search for epitope-specific antibody responses to the human immunodeficiency virus (HIV-1) envelope glycoproteins signifying resistance to disease development, It is essential for the development of strategies for prevention and therapy of human immunodeficiency virus (HIV-1) infections to define host factors playing a dominant role in determining the clinical outcome of infection. Antibodies directed against restricted regions of the HIV-1 glycoproteins gp120 and gp41 are likely to represent important factors involved in host defense against HIV-1. Definition of qualitative and quantitative differences in the spectrum of anti-gp120 and anti-gp41 antibodies between two vastly different groups of HIV-1-infected individuals. long-term asymptomatic carriers. and individuals with acquired immunodeficiency syndrome (AIDS) who died. might reveal the epitope specificity of antibodies contributing to prevention of clinical disease. To accomplish this goal. sera from both groups were assayed for antibodies recognizing synthetic peptides from gp120/gp41 which were shown in earlier experiments to mimic epitopes on the two HIV-1 glycoproteins. None of the sera recognized all of the distinct 27 peptides from gp120 and gp41. The spectrum of antibodies was distinct for each of the sera from both groups of HIV-1-infected individuals. Nevertheless. antibody responses distinguishing the two groups from each other were discerned. In particular. it was possible to predict the unfavorable outcome of disease by comparative measurements of levels of antibodies to a peptide (303-338). corresponding to the entire V3 hypervariable loop of gp120 and/or by providing evidence for declining levels of these antibodies during the course of infection. Antibodies recognizing additional peptides [(219-245). (280-306). (425-452). (658-682). (729-758). (808-845). and (845-862)] were significantly less prevalent in AIDS patients than in asymptomatic carriers. It appears possible that maintenance of high levels of the respective antibodies would contribute to preventing AIDS in HIV-1-infected individuals. Active immunization with antigens containing epitopes defined by the respective peptides and/or administration of the corresponding antibodies may be considered as a modality for therapy of HIV-1 infections.
The real impact of mechanical bridge strategy in patients with severe acute infarction, Results obtained in the past 3 years in patients referred with acute myocardial infarction (AMI) and cardiogenic shock for a mechanical bridge to urgent transplantation permit one to assess the real impact of the present strategy in clinical practice. Ten patients (mean age = 49) were admitted in serious condition (CI = 1.8 +/- 0.2 L/min/m2. PCWP = 28 +/- 6 mmHg. systolic aortic pressure = 88 +/- 20 mmHg. urine output 11 +/- 20 ml/hr) and were treated by maximal sympathomimetic support and i.v. enoximone. Two had to be implanted with a total artificial heart (TAH) and one with a left ventricular assist device (LVAD) for recurrent fibrillation despite hemodynamic improvement. within 8 hr. Two have received transplants and are living well after 20 months. Seven who initially improved markedly have been listed as urgent transplant candidates: two of these have been successfully transplanted. and three died suddenly after 6. 25. and 45 days. respectively. One has undergone successful coronary surgery. One patient (age 62. diabetic) was secondarily rejected for a transplant and died. This experience clearly shows that despite initial spectacular hemodynamic improvement. which was due to optimized medical management. death rate before transplant because of sudden ventricular fibrillation remains unacceptably high. This should prompt early mechanical support. with less invasive systems. in patients with AMI.
Patterns of bacterial infection in calves implanted with artificial hearts, Device-related infection is one of the most serious potential consequences of total artificial heart (TAH) implantation. This complication must be addressed before the full potential benefit of these devices. especially fully implantable devices. can be realized. A review of research reports and clinical data was conducted to ascertain if similarities existed between the patterns of infection reported in human TAH recipients and those seen in the experimental animal models. Infection was reported in approximately 57% of the human TAH recipients and approximately 47% of the implanted animals. Implant periods ranged from 1-620 days for the humans. and 32-287 days for the animals. The spectrum of organisms isolated from both groups were similar. with a high proportion of infections caused by Pseudomonas aeruginosa and Staphylococcus epidermidis. In addition. numerous isolates of Enterobacter and Enterococci were obtained from the animals. Positive blood cultures have often been observed in animals within 2-4 weeks following implantation of the devices. The similarities noted in this review suggest that the calf may be an appropriate animal model in which to study the pathogenesis of TAH-related infection.
Shortening of the hemodialysis procedure and mortality in "healthy" dialysis patients, The influence of shortening chronic hemodialysis on mortality was studied by following cumulative survival in "ideal" nondiabetic dialysis patients. who had no other diseases besides their renal disease when beginning dialysis. It was hoped that thereby problems of shortening dialysis could be separated from problems inherent in the patient. Otherwise healthy dialysis patients (n = 556) were divided into age groups (less than 50. 51-75. and greater than 75 years) and studied during four periods. 1966-75. 1976-82. 1983-85. and 1986-88. Dialysis time was shortened from 17 to 2.7 hr per treatment during that time. but a Kt/V of 1.3 maintained. Generally. both first- and four-year cumulative survival improved as dialysis was shortened. and four-year cumulative survival was best in all age groups during 1986-88 when dialysis was shortest. During this time. the four-year cumulative survival was no different from that of the age-matched total U.S. population. Shortening of dialysis time and increasing efficiency while keeping at least a 4.0. stable. weekly Kt/V has not been harmful to healthy patients on dialysis. but has led to continued improvement on cumulative survival.
Morbidity and mortality in hemodialysis patients, Increase in mortality in hemodialysis patients in the United States is a rising concern. In this study. the annual mortality rate from 1981 to 1989 was determined and the morbidity and mortality of 136 patients dialyzed during 1988 was analyzed. All patients were followed with urea kinetics (UK). Patients were divided according to NCDS mapping of BUN and protein catabolic rate (pcr): Group 1. inadequate protein intake (n = 28); Group 2. adequate dialysis (n = 51); Group 3. excessive dialysis (n = 28); Group 4. undefined domain (n = 13); and Group 5. transitional domain (n = 16). The UK parameters measured were midweek predialysis BUN. pcr. and Kt/V. Group 1 by definition had the lowest pcr (0.7 g/kg/day vs. greater than 1.0 in the other groups). Patients in Group 1 had significantly lower BUN. creatinine. hematocrit. and serum albumin. Results of all other laboratory tests were not significantly different. Numbers of hospitalizations and days in the hospital were higher in Group 1. Causes of hospitalization were similar in all groups. Mortality rate was 8% in Group 1 vs. 4.4% in Group 2. Dialysis prescription using UK has maintained the annual mortality rate at about 14% for the past nine years.
Kt/V and hemodialysis morbidity revisited, Analysis of the National Cooperative Dialysis Study (NCDS) showed that dialysis morbidity was related to Kt/V. Recently. various formulae have been shown to be accurate for easier calculation of Kt/V. We calculated Kt/V in an outpatient unit utilizing Kt/V = -In (R - 0.03 - UF/W) in 51 patients. Kt/V was less than 0.8 in 16 patients (Group A). 0.8-1.0 in 20 (Group B). and greater than 1.0 in 15 (Group C). There was no difference in hematocrit (Hct). BUN. creatinine. serum phosphorus. and albumin. Ratio of men to women was 11/5. 15/5. and 4/11; mean age was 54. 63. and 58 years; mean body weight 177. 144. and 122 lb in Groups A. B. and C. respectively. Dialysis-related hospital admissions were similar (p greater than 0.05). These data suggest patients with higher body weights. and men. frequently had a Kt/V less than 0.8. Kt/V that did not influence biochemical parameters or hospitalizations in this population. This indicates that Kt/V may not be a good predictor of morbidity. and/or some heavier patients may do fairly well even with a Kt/V less than 0.8. The search for a better index of dialysis adequacy should be continued.
Income and survival in chronic dialysis patients, The relationship between income and survival rates for chronic dialysis patients in Michigan was examined. To evaluate the relative risk (RR) of dying. by income. a Cox survival regression model was used to adjust for age. race (black versus white). gender. dialytic treatment modality. year of first end-stage renal disease (ESRD) therapy. and primary cause of ESRD. The average household income reported from census data for the ZIP Code of residence for each patient was analyzed as a socioeconomic indicator. Treatment modality on day 120 of ESRD was classified as either center hemodialysis (HD) or CAPD. All new patients. aged 20-59 and registered at the Michigan Kidney Registry between 1/1/80 and 12/31/87 were included in the study. Patients were followed from day 180 of ESRD until death. censoring at transplant. or 12/31/87. The adjusted relative risk of dying decreased for black patients by 3.3% per $1.000 increase in income (p less than 0.01). while the trend by income for white patients was negligible (p greater than 0.10). The difference in trends for the two groups was statistically significant (p less than 0.01). This is a surprising result. since white patients have higher death rates. overall. than do black patients. particularly among subgroups with diabetes and hypertension whose RR was 1.77 and 1.82. respectively. Poor socioeconomic status of the area of residence has a strongly negative effect on survival for black patients. but not for white patients. The reasons for the relationship of death rates with income. especially for black patients. need to be examined in greater detail.
In vivo nonthrombogenicity of heparin immobilized polymer surfaces, The authors developed two different methods to immobilize heparin on polymer surfaces. One method involves in situ heparin immobilization on a segmented polyurethane urea (Biomer) surface via hydrophilic poly(ethylene oxide) (PEO. Mn = 4.000) spacers. The other method uses PEO/poly(dimethylsiloxane) (PDMS) block co-polymer and heparin covalently linked in a block co-polymer system (PEO-PDMS-Hep). These surfaces have demonstrated high heparin bioactivity in vitro and excellent blood compatibility in in vitro-ex vivo experiments. This report evaluates the long-term in vivo blood compatibility of these heparin immobilized surfaces. Vascular grafts (6 mm ID. 7 cm in length) were fabricated with Biomer. and heparin was immobilized in situ with PEO spacers (B-PEO4K) and coated on their luminal surfaces with PEO-PDMS-Hep. Biomer and PEO (Mn = 4.000) grafted Biomer (B-PEO4K) were used as controls. The grafts were implanted in the abdominal aorta of dogs and retrieved at 3 months or when graft occlusion was suspected. Retrieved grafts were evaluated with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). TEM measured the thickness of the adsorbed protein layer on the surface and the protein distribution (albumin. fibrinogen. and IgG) visualized by an immunogold method. All heparin immobilized grafts were patent at 3 months. whereas Biomer and B-PEO4K grafts occluded within 1 month. SEM pictures of heparin immobilized surfaces after 3 months demonstrated minimal platelet adhesion and activation without detectable fibrin formation. Heparin immobilized surfaces showed a thin protein layer (300-600 A) even after 3 months. with high concentrations of albumin and IgG and less fibrinogen.
Monitoring platelet interactions with prosthetic graft implants in a canine model, This study shows that prosthetic arterial grafts stimulate platelets for as long as 1 year after implantation in a canine model. Carotid-to-distal aorta Dacron (DuPont. Wilmington. DE) grafts (0.8 x 50.0 cm) were tunneled subcutaneously over the right dorsal side. allowing for percutaneous arterial sampling. Thromboxane B2 (TxB2) levels were evaluated at the proximal anastomosis (w). 5.0 (x). 25.0 (y). and 50.0 (z) cm distal from w. and platelet counts and mean platelet volumes were monitored at sites w and z. TxB2 levels increased after blood entered the graft and progressively increased until the blood exited at the distal anastomosis. Platelet counts did not significantly change across the graft. Over time. systemic platelet counts decreased to approximately 50% of each dog's pregraft baseline levels and remained depressed over a 1 year period. Mean platelet volumes peaked 1-3 weeks after implant and remained greater than pregraft levels. Examination of the graft luminal surface showed a developed pseudointima characteristically similar to that which develops in mature human vascular grafts. These results suggest that healed vascular grafts in canines continue to stimulate platelet release of TxB2. reduce systemic platelet counts. and increase mean platelet volumes over 1 year. These data further suggest that platelets are stimulated by the graft and consumed.
Complement activation and use of a cell saver in cardiopulmonary bypass, Complement activation was evaluated in ten patients undergoing cardiopulmonary bypass (CPB) and intraoperative blood salvage with a cell saver (CS) to assess the inflammatory response related to the CS. The washed red blood cell concentrate was reinfused after protamine injection. Plasma C3a was measured by radioimmunoassay preoperatively. 5 min before CPB. at 5. 60. and 90 min during CPB. 5 min after protamine infusion. at the end of surgery. and after 24 hr. In addition. a clinical score based on renal. pulmonary. neurologic. and myocardial postoperative evolution was given (0-8) to every patient. Results were compared with the C3a changes and clinical scores obtained from 26 routine (no CS) cardiac surgical patients. Results showed maximal C3a generation after protamine and no further activation in cases of CS concentrate reinfusion. which ranged from 400 ml to 2.000 ml. No difference in clinical score was observed between the CS (1 +/- 1) and control (0.85 +/- 0.6) groups. The authors conclude that the CS does not enhance complement activation resulting from extracorporeal circulation and can be safely used as a blood saving strategy in cardiac surgery.
Differential light scattering cuvettes for the measurement of thromboemboli in high shear blood flow systems, Newly developed optical scattering cuvettes were constructed as a modification of our existing 1.0 mm and 3.0 mm internal diameter (ID) cuvettes to facilitate the measurement of platelet microemboli ranging from 20 microns to 1.000 microns diameter in whole blood in 0.9 mm ID flows ranging from 250 to 4.000 ml/min. A perturbation solution to the one-speed radiative transport equation was used in the design and calibration of these cuvettes. A series of tests were performed with these cuvettes in an extracorporeal left ventricular assist device bovine model. and in a recirculating closed-loop flow system containing anticoagulated whole baboon blood. to determine to what extent they affect platelet and erythrocyte function ex vivo and in vitro. Serial hemolysis tests. thromboxane radioimmunoassay measurements. platelet counts. and activated partial thromboplastin times were measured. All of these tests with cuvettes in the extracorporeal and in vitro circuits were statistically indistinguishable from baseline measurements. suggesting the usefulness of this system for the measurement of microemboli in blood-contacting materials of extracorporeal circuits and cardiac assist devices.
Shear stress induces not only platelet aggregation but also platelet-tumor cell interaction, To investigate the interaction between platelets and tumor cells under well-defined flow conditions. the effect of tumor cells on platelet aggregation induced by shear stress was studied using a cone and plate viscometer adapted for measuring transmitted light intensity. Aggregation was markedly enhanced by HMV-1 cells in a cell number-dependent fashion under shear stress of 12 dyne/cm2. Enhancement was not observed at a high shear stress of 108 dyne/cm2. A monoclonal antibody against GPIIb/IIIa. 7E3 completely abolished enhancement of aggregation by HMV-1. Apyrase had similar inhibitory effects. Scanning electronmicroscopy showed that direct contacts of platelets with HMV-1 cells could be demonstrated when platelet-platelet interaction was inhibited by 7E3 or apyrase. These results may indicate that. at a shear stress of 12 dyne/cm2. direct contacts of platelets and HMV-1 cells may trigger enhancement of platelet aggregation.
Development of a new transvenous patent ductus arteriosus occlusion technique using a shape memory polymer, A novel percutaneous patent ductus arteriosus (PDA) occlusion technique. without the potential problems associated with conventional techniques. has been long awaited. The development of a novel transvenous PDA occlusion technique using a temperature-shape changeable occluder device. and the verification of its in vitro performance. were demonstrated in this study. The principles of this technique are: 1) the bar form device was inserted into the PDA transvenously by a guide wire and a pushing catheter. 2) the device was dashed with hot water through catheters. 3) the device was expanded by hot water in the PDA. and the PDA was occluded. The occluder device. made of a shape memory polymer (polynorbornene). was designed to have the monobloc configuration of a thin disk with a hole for a guide wire in the center and a cone. The barlike device by hot press was fully expanded within 10 sec upon immersion into 45 degrees C water. The mock-circulation test with the "great arteries" and a specially designed "PDA" showed 1) the introduction of hot water (45 degrees C) through the catheters caused expansion of the device which stayed in the "PDA" without any support. 2) the "aortic" pressure and the distal "aortic" flow increased rapidly. and the "pulmonary" flow reduced promptly. This resulted in a drastically reduced shunt ratio at the PDA from 68% to 30%. Thus. the novel PDA occlusion technique developed here functioned well to occlude the PDA in a great arteries model.
Safety, stability, and effectiveness of immunoadsorption under membrane plasmapheresis treatment for myasthenia gravis, Nine patients (five women and four men. average age 50.4 years) with refractory myasthenia gravis (MG) underwent thymectomy and were then treated with immunoadsorption under membrane plasmaphersis (IAP). Thymic histology showed hyperplasia in nine patients. An immunoadsorption column (ASAHI. Med. Co) was made with tryptophan. A Plasouto 1.000 (ASAHI. Med. Co) was used as the machine. The plasma separator was a first filter (ASAHI. Med. Co). and immunoadsorption columns were used for plasma perfusion. IAP treatment was performed three times weekly for a total of six times. after which IAP was done every 3 weeks. The removal rate of anti-Ach-R titer was 54 +/- 12%; IgG. IgA. and IgM levels improved in nine of nine patients after IAP treatment. and improvement of gait disturbances were seen in two of two. Muscle strength improved in all nine patients. whereas speech disturbances improved in two of three. Eye ptosis improved in nine of nine patients. Subjective improvement was reported by nine of nine patients. and none had severe side effects with IAP. In conclusion. IAP is a safe. stable. effective. and clinically useful treatment. for MG.
Basic studies on a new material for inducing antitumor immune cells, Recently. adoptive immunotherapy for cancer with lymphokine activated killer (LAK) cells has been widely used experimentally. The therapy has several problems. including difficulty in handling. sterilization. and time consumption. To solve these problems. new materials able to induce antitumor immune cells were investigated. Pokeweed mitogen (PWM) and PWM-conjugated materials (CMC-1) could induce strong killer cells by short-term stimulation of human peripheral blood lymphocytes (PBL). The induced killer cells showed a wide killing spectrum in vitro against human tumor cell lines (MKK-1. PRMI4788. NBT-2. ZR-7530. H-1. Hela. KB. HMV-1. PC-10. C-1). Human PBL stimulated for a short time by CMC-1 also showed a tumoricidal effect on tumor bearing (MKN-1. MKN-45) nude mice. These results suggest that CMC-1 may solve the problems with currently used LAK therapy and may provide easily applicable extracorporeal immunotherapy for cancer.
Non-heparin hemodialysis with oral administration of newly developed antiplatelet agent, Non-heparin hemodialysis (HD) was successfully done in anuric dogs with the oral administration of a newly developed antiplatelet agent. 4-cyano-5.5-bis(4-methoxyphenyl)-4-pentenoic acid. (E5510. Eisai Pharmaceutical Co.. Japan). In the current study. the antithrombotic effect of E5510 during HD was investigated. Eleven mongrel dogs with bilateral ureteral ligation were given 0.1 mg/kg of E5510 orally 1 hr before undergoing 4 hr HD using hollow fiber dialyzers. (PMMA 5. regenerated cellulose 6) without heparin and under general anesthesia. Blood samples were taken before the administration of E5510 and before and 1. 2. 3. and 4 hr after starting HD; blood counts. hematocrits. blood chemistries. and plasma thromboxane levels (TxB2) were examined. Platelet aggregation. activated clotting times (ACT). and activated partial thrombin times (APTT) were also measured. and sequential plasma E5510 concentrations were determined. In 10 of 11 anuric dogs. non-heparin HD was successfully done with minimal clotting in the dialyzer and drip chambers. The maximum aggregation rate was depressed to less than 20% of the initial value throughout HD. Plasma TxB2 concentration was depressed. and ACT and APTT were mildly. but not significantly prolonged. Neither hemorrhagic complications nor other side effects of E5510 were observed.
A total artificial heart for neonates allowing bridging to transplantation, Since the early 1980s. a rapid increase in successful pediatric heart transplantation has improved the chance of survival for many children suffering from otherwise fatal cardiomyopathies or congenital cardiac defects. During the last 5 years. heart transplantation in neonates and infants (0-28 days and 1-12 months. respectively) has been the most rapidly growing area within the pediatric patient population. No adequate mechanical circulatory support system. designed to be used as a bridge to transplantation. is available for many of these pediatric patients. Neonates are the smallest candidates to potentially benefit from heart transplantation. and their often acute need for either heart transplantation or temporary circulatory support indicates that any new development of a pediatric bridging device should focus on this youngest group. Subsequently. such a device may be modified to any weight or age group. An innovative total artificial heart design was developed in an attempt to meet the anatomic and physiologic requirements of neonates and infants. This report discusses the rapidly growing pediatric heart transplantation patient population. as well as an innovative total artificial heart design.
Design mediated thrombus reduction in the Utah-100 total artificial heart, The Utah-100 total artificial heart was initially designed and tested in 1983. General design goals. including improved fit for human application. improved reliability. and elimination of thrombus formation. were identified as improvements over the clinically used Jarvik-7 artificial heart. previously developed at the Institute for Biomedical Engineering. University of Utah. Specific design goals included 1) elimination of connector and valve-associated thrombus formation and 2) elimination of gross mineralization. thrombus formation. and creases on the blood-pumping diaphragm of the device. Explant retrieval results from 29 calves and sheep implanted with the Jarvik-7 artificial heart were compared with results from 25 calves and sheep implanted with the Utah-100 artificial heart. Macroscopic thrombus formation was found in 44% of the connectors of the Jarvik-7 artificial-hearts. compared with 2% (p less than or equal to 0.01) in animals with the Utah-100 artificial heart. Subvalvular and supravalvular thrombi were observed in 33% of the valves in the Jarvik-7 artificial heart and 10% (p less than or equal to 0.01) of the valves in the Utah-100 artificial heart. Mineralization of the pumping diaphragm was observed in 12% of the animals implanted with the Jarvik-7 artificial heart and in 4% of the animals with the Utah-100 diaphragms. Thrombus formation in the diaphragm-housing interface occurred in 2% of Jarvik-7 ventricles and in 6% of the Utah-100 ventricles. There were no identifiable diaphragm creases in the Utah-100 diaphragms. but a 10% incidence was found in Jarvik-7 devices. These results validate substantial progress toward improved design and fabrication methods in the Utah-100 total artificial heart.
Another way of pumping blood with a rotary but noncentrifugal pump for an artificial heart, This article describes an alternative mode of pumping blood inside the body. The device is a non centrifugal. valveless. low speed rotary pump. electrically powered. based on Wankel engine principle. The authors developed an implantable electrical actuator resulting in a compact. sealed motor-pump unit with electrical and magnetic components insulated from fluids. The results in the flow curve and in the pumping action show some common points but also some basic differences compared to classical pulsatile pumps or centrifugal pumps. The blood coming from the atrium follows a continuous movement without any stop flow but with variations creating pulsatility. Ejection and filling of the pump are simultaneous. It is always an active filling. Hydraulic efficiency depends on clearance in the pumping chamber and outlet port pressure. A 60 cc device allows flows up to 8-9 liters. The implantable motor is cyclindrical in shape. has a moderate weight (490 grams) and presents a good efficiency (32% for a rotary speed of 90 rpm against a mean aortic pressure of 150 mm of Hg). The authors conclude that their device could be proposed after further experimental studies. as an LVAD for shortterm assistance with a good promise for permanent application.
Improved biocompatibility by postfixation treatment of aldehyde fixed bovine pericardium, Long-standing release of locally cytotoxic aldehyde concentrations is responsible for lack of spontaneous endothelialization and increased calcification of glutaraldehyde fixed bovine pericardium. Postfixation treatment with amino acids made in vitro endothelialization of bioprosthetic heart valves possible. Such treated pericardium calcified significantly less (13 +/- 4 micrograms/mg dry weight) than did conventionally processed pericardium (114 +/- 25 micrograms/mg) after 63 days of subcutaneous implantation in rats. To test the ability for spontaneous in vivo endothelialization. 5 sheep had 6 mm grafts made from postfixation treated pericardium (PTP) implanted into the carotid artery. compared to PTFE grafts on the contralateral side. which spontaneously endothelialize in animal models. In a pregnant animal. both grafts occluded. All remaining pericardial grafts remained patent. but one additional PTFE graft occluded and another one was stenosed. The area covered with red thrombus was significantly smaller in the PTP grafts (3.05 +/- 3.9%) than in the PTFE grafts 42 +/- 14% (p = 0.0036); TEM and SEM showed endothelial cells growing directly on the PTP. but only on myofibroblasts in PTFE grafts. Postfixation treatment of glutaraldehyde fixed pericardium aids spontaneous endothelialization and decreases tissue calcification.
Sterile versus non-sterile dialysis fluid in chronic hemodialysis treatment, As the quality of water in the dialysis fluid varies considerably. and in view of the fact that endotoxin or active derivatives can cause acute side effects in patients. the dialysis fluid must be sterile. Therefore. we introduced ultrafiltration of dialysis fluid before entering the dialyzer. Fifteen patients. (ten women. five men) were treated for 4 weeks with nonsterile. and then with sterile dialysis fluid. The bacterial loading in the dialysis fluid before hemodialysis was 1.34 X 10(5)/ml. and after hemodialysis 2.9 X 10(3)/ml; the endotoxin concentration was high and varied between less than 1 EU/ml and greater than 10 EU/ml before and after hemodialysis. After ultrafiltration of the dialysis fluid by a polyamide hollow fiber membrane. all samples were free of bacteria and the concentration of endotoxin was lower than the detectable limit (less than 0.03 and less than 0.5 EU/ml). With ultrafiltration of dialysis fluid we can obtain sterile dialysate. which is endotoxin free. Interleukin-1 and tumor necrosis factor in the patients with ultrafiltration was significantly lower than without ultrafiltration.
Ionic strength affects diffusive permeability to an inorganic phosphate ion of negatively charged dialysis membranes, Electrolytes undergo electrostatic resistances in reaching membrane surfaces and passing through membrane pores when weakly charged dialysis membranes are used in hemodialysis treatments. Diffusive permeability to an electrolyte of weakly charged dialysis membranes depends upon the effective charge density of the membranes. which varies with ionic strength. The authors carried out dialysis experiments at a temperature of 310 K. with 32P-Na2HPO4 in aqueous NaCl and bovine serum. to obtain diffusive permeability to an inorganic phosphate ion of regenerated cellulose. and polymethylmethacrylate membranes of various fixed charge densities at varying ionic strengths ranging from 1.66 to 100 mol/m3. Diffusive permeability to an inorganic phosphate ion increased with ionic strength. Bovine serum. having an ionic strength of approximately 150 mol/m3. gave higher diffusive permeability to an inorganic phosphate ion. The internal structure of dialysis membranes. such as pore size. surface porosity. and tortuosity. also affects diffusive permeability. The electrolyte diffusion theory gives an effective charge density of -5.3 mol/m3 for the cellulosic membrane. In conclusion. ionic strength enhances diffusive permeability to an inorganic phosphate ion in both aqueous NaCl and bovine serum. Inorganic phosphate ion transport through negatively charged dialysis membranes depends upon the degree of dissociation of inorganic phosphate. the molecular size and valence of hydrated inorganic phosphate ion. the effective charge density and internal structure of the membrane. and ionic strength.
Acellular matrix allograft small caliber vascular prostheses, We have developed an acellular matrix vascular prosthesis (AMVP) made by detergent and enzymatic extraction of natural arteries. yielding a tissue framework of collagen and elastin from the original vessel. with preservation of the natural basement membrane at the blood flow surface. These biografts have excellent handling characteristics and suturability. as well as low thromboreactivity. Whole vessel static testing of circumferential compliance (8.9 +/- 1 [SEM] X 10(-2)% mmHg at 100 mmHg) revealed behavior virtually identical to the paired natural vessel from which each AMVP was derived in nine canine carotid arteries. We implanted 16 canine-origin AMVPs into nine dogs (12 femoral and three carotid arteries. and one infrarenal aorta) with no antithrombotic drugs. Angiographic patency was maintained in 15 of 16 (one occlusion within 3 days) for follow-up from 3 days to 6 years. with no aneurysm formation in three AMVP at over 4 1/2 years. Explant analysis revealed preservation of AMVP elastica and collagen with no inflammation or dystropic calcification of the AMVP. and almost total thrombus free flow surfaces. These results suggest that allograft AMVPs could achieve long-term patency equivalent to saphenous veins.
Development of a soft, pliable, slow heparin release venous graft, To prevent their collapse. a certain amount of stiffness is generally required for prosthetic venous grafts. so EPTFE grafts have been used. However. the native vein is pliable without any stiffness. We developed a soft and pliable graft that can maintain patency of the lumen because of its compliance. Fresh porcine ureter was incubated in a ficin solution to remove cell components and noncollagenous proteins. One percent protamine sulfate solution was injected into the ureter lumen to impregnate the inner surface. The ureter was then crosslinked with a 1% glutaraldehyde solution. dipped into a 1% heparin solution for 5 hours. and rinsed with distilled water. This procedure made the ureter very soft and pliable. and also conferred antithrombogenicity to the graft by heparinization. The grafts were implanted into the posterior vena cavae of 20 dogs and were removed from 1 to 878 days after implantation. Eighteen grafts were patent. but two grafts were occluded at the anastomotic site at 218 and 107 days. respectively. As a control experiment. nonheparinized grafts were implanted into 15 dogs; all were occluded with fresh thrombi. All the patent grafts kept their original elasticity. which allowed them to heave in unison with the heartbeat. and were similar in appearance to the native vena cava. Heparinization was effective in preventing thrombus formation. These results indicate that this type of graft is an ideal prosthesis as a venous graft. having physiologic properties such as compliance and antithrombogenicity.
Endothelialization of vascular prostheses by transplantation of venous tissue fragments, A method to accelerate the endothelialization of vascular prostheses by seeding venous tissue fragments was developed. A piece of peripheral vein was obtained. chopped into small fragments. and stirred into 20 ml of saline. making a tissue suspension. This suspension was sieved through the wall of a highly porous vascular prosthesis (water porosity: 3.600-4.000). The prostheses. (7 mm ID and 5.7 cm in length) seeded with tissue fragments. were implanted into the thoracic descending aortae of 20 dogs. and were removed from 1 to 371 days after implantation. Ten prostheses. preclotted with fresh blood. were used as controls. In the seeded grafts. an infinite number of endothelial cells migrated and proliferated from the fragments. These had produced numerous capillaries by 5 days after implantation that had reached and opened onto the luminal surface of the prosthesis. From these openings. numerous endothelial cells spread out and formed colonies. With the increase in the size of the colonies. the inner surface was completely endothelialized within 5 weeks. This quick neointimal formation by seeding venous tissue fragments might be applicable to several artificial organs.
In vitro and in vivo testing of a new valved intravascular catheter design, Long-term intravascular catheterization carries a finite risk of catheter occlusion. A catheter tip valve design is presented (Buchwald-Wigness. Strato Medical Corporation. Beverly. MA) which incorporates features designed to decrease the risk of thromboembolism and reduce the need for maintenance procedures. Aspiration and infusion are controlled by separate valves. making it possible to engineer optimized inlet and outlet parameters. The outlet valve is an elastic sleeve expanded around the sidewall outlet ports which opens under injection pressure. The inlet valve is a tubular elastic element compressed against the inlet port from within the lumen. opening under aspiration pressure. A series of valves were prototyped with outlet pressures ranging from 2 to 100" H2O. and inlet pressures ranging from -40-70" H2O. and flowrates at 36" H2O of greater than 1.400 ml/hr. Dog implants of two prototypes with outlet valve pressures of 10" H2O. and inlet pressures of -40" H2O. demonstrated that dormant periods of up to 7.5 weeks could be achieved without detectable blood cell entry into the lumen. No significant hemolysis was observed in blood samples aspirated with a 6 cc syringe (8% scored "slightly hemolyzed" vs. 44% with the nonvalved controls) indicating that a hemodialysis application is likely.
Rapid methods of estimating Kt/V: three formulas compared, Three rapid formulas for Kt/V were compared: 1) Kt/V-PRU = 0.04*PRU-1.2; 2) Kt/V-PRUopt = 0.026*PRU-0.46; and 3) KTV-LN = -In(R-0.03-UF/W). Accuracy was compared in a database of 339 3/week modeling sessions in 256 patients. The standard of comparison was Kt/V obtained by 3 point variable volume single pool modeling. using K values estimated from KoA. Qb. Qd. and UF rate. The most accurate formula was Kt/V-LN. which correlated with Kt/V to a high degree (0.994). and with a [%ERROR] of only 2.2 +/- 1.7 (SD). There was no correlation of %ERROR with the modeled Kt/V. The least accurate formula was Kt/V-PRU. Although the correlation of Kt/V-PRU with modeled Kt/V was high (0.962). the [%ERROR] was 12.0 +/- 11. and %ERROR correlated significantly with modeled Kt/V (0.68). The Kt/V-PRUopt showed a high correlation with modeled Kt/V (0.962). and a [%ERROR] of 5.0 +/- 3.8; the latter had a minimal correlation with modeled Kt/V (-0.168). The relative accuracies of the three formulae were: Kt/V-LN vs. Kt/V-PRU = 5.98. Kt/V-LN vs. Kt/V-PRUopt = 2.45. The results suggest that Kt/V-LN is a more accurate estimate of Kt/V than any formula based on PRU alone.
Various methods for calculation of Kt/V: a clinical comparison, Analysis of the National Cooperative Dialysis Study (NCDS) showed that dialysis morbidity and mortality was related to Kt/V of urea. Various formulas have been derived to make calculation of Kt/V simpler. We compared the kinetically measured Kt/V (A) to estimated Kt/V derived from approximate total body water (0.6 body weight) and uniform dialyzer clearance (B). Kt/V = 0.04 PRU-1.2 where PRU is % reduction in BUN (C) and Kt/V = In(R-0.03-UF/W) where R is post/pre BUN. UF is ultrafiltration L/HD and W is postdialysis weight (D) in 26 patients. The correlation coefficient (r) was 0.14 (p less than 0.05) for A vs. B; 0.75 (p less than 0.01) A vs. C; 0.77 (p less than 0.01) A vs. D; and 0.97 for C vs. D. In an additional 51 patients. Kt/V was calculated using formulas B. C. and D. The r was 0.91 C vs. D. 0.70 B vs. D. and 0.68 B vs. C. With B. greater than 30% of the patients could have been misclassified using NCDS criteria for adequacy of dialysis. The study suggests that use of formulas C and D. but not B. is appropriate and accurate for Kt/V calculation. Formula C may be simpler and easier than D. as UF and W are not required. Serial Kt/V could be easily and accurately calculated using C and D for quality assurance and quantitation of dialysis.
In vitro and in vivo evaluation of a right ventricular assist device, A simple right ventricular assist device (RVAD) has been developed. This device will be useful in situations where biventricular failure has been partially treated by placement of a left ventricular assist device. or when right ventricular failure occurs in isolation. This pneumatically actuated. R-wave synchronized. sac type pump contains no valves. and is connected by a graft to the pulmonary artery. The RVAD was tested in a circulation simulator to verify its hemodynamic efficacy and then implanted in six calves for 2-4 weeks to evaluate its biocompatibility. In vitro testing of the RVAD demonstrated that it restored normal hemodynamics in the presence of severe simulated RVF. In six animal implantations. a small amount of thrombus was found in one pump. No anticoagulants were employed. Thrombus was present in the connecting graft in three animals; in two this was clearly related to technical implant errors. No evidence of significant hemolysis was found. This simple RVAD has been found to be hemodynamically effective. is simple to use. and is well tolerated. Refinements in the interconnection graft between the pulmonary artery and the device are necessary.
Functional heart replacement with the spindle pump: first results, The spindle pump is a nonpulsatile blood pump with a double function. i.e.. it works centrifugally and represses simultaneously. The first experiences with this type of pump used as a biventricular assist device in four short-term animal experiments (up to 13 hours) are described. It can be demonstrated that in cases of a normally beating heart. this BVAD decompresses both ventricles by 60-70%. while the aortic pressure is slightly increased; on the other hand. in case of ventricular fibrillation. the BVAD with two spindle pumps maintained the entire circulation. at an arterial pressure between 80 and 90 mmHg with a flow volume between 3.5 and 4 L/min.
Pulmonary artery counterpulsation with a skeletal muscle power source, We evaluated the feasibility of using skeletal muscle (SM) to provide pulmonary artery (PA) counterpulsation in an acute pulmonary hypertension (PHT) model. PA counterpulsation was achieved in six dogs with a dual chambered pump powered by the latissimus dorsi muscle. A rate-responsive stimulator was used to make the muscle contract in counterpulsation. Graded PHT was induced by infusing 150 microns glass beads into the PA. while RV and PA pressures were monitored. With PA pressures ranging from 19/10 to 115/62 mmHg. effective counterpulsation was observed. The degree of counterpulsation was influenced by the extent of PHT induced. with the amount of RV tension-time index (TTI) unloading correlated with the level of PA systole (r = 0.92). Therefore. results were divided into two groups (Group 1: PA systole less than or equal to 40 mmHg. and Group 2: PA systole greater than 40 mmHg). In Group 1. RV TTI decreased from 11.29 +/- 0.76 to 9.99 +/- 0.72 mmHg.sec. PA diastole increased from 20 +/- 2.3 to 31 +/- 3.0 mmHg. and PA mean increased from 24 +/- 2.2 to 2.9 +/- 2.2 mmHg (all p less than 0.05). In Group 2. RV TT1 decreased from 15.12 +/- 1.83 to 10.99 +/- 0.90 mmHg.sec. PA diastole increased from 41 +/- 3.5 to 64 +/- 6.2 mmHg. and PA mean increased from 49 +/- 4.8 to 55 +/- 5.7 mmHg (all p less than 0.05).
Novacor left ventricular assist filling and ejection in the presence of device complications, In order to better understand the relationship among certain device related complications and Novacor left ventricular assist system (LVAS) pumping parameters. a Mock Circulatory Loop was utilized to simulate the following clinically realistic conditions: 1) inflow valve regurgitation. 2) inflow cannula obstruction. 3) outflow valve regurgitation. and 4) outflow cannula obstruction. Various pumping parameters (e.g.. pump rate. stroke volume. pump output) were recorded at baseline (control) and during each simulation. Additionally. pump volumes were continuously recorded and differentiated for calculation of rates of pump filling (FR) and ejection (ER). The results indicate that perfusion pressures and rates of filling and ejection change significantly in the presence of device complications. The implications of these findings. as relates to assessment of pump operation in LVAS patients. are discussed.
Maintenance of circulation during ventricular fibrillation with the simultaneous use of two "counterpulsation" devices, Two valveless. single orifice counterpulsation devices. with pumping stroke volumes of 65 ml each. were implanted on the ascending aorta and pulmonary artery of seven open chest anesthetized dogs. After completion of the preparation. ventricular fibrillation was induced. The devices were synchronized to pump simultaneously at a rate of 85-100 bpm. The combined use of the counterpulsation devices provided maximal aortic pressure of 111.4 +/- 25.1 mmHg during ventricular fibrillation for a period of 15-60 min. The mean left ventricular pressure was 17.7 +/- 4.4 mmHg. and the cardiac index 64.5 +/- 23.6 ml/kg/min. Cardioversion of ventricular fibrillation to sinus rhythm restored normal hemodynamics. The counterpulsation device implanted on the ascending aorta was not able to maintain circulation for more than 5 min after the induction of ventricular fibrillation. if used alone. In conclusion. the use of two counterpulsation devices implanted on the ascending aorta and pulmonary artery was able to maintain circulation in experimental animals during ventricular fibrillation.
A novel mechanical cardiac assist device for reversing left ventricular failure, Diastolic augmentation of aortic pressure is an efficacious means of improving coronary perfusion in heart failure. A novel mechanical cardiac assist device (MCAD). that has advantages over a conventional intraaortic balloon pump and left ventricular assist devices. has been developed. It consists of a high efficiency rotary solenoid. coupled to a pair of actuator plates that clamp on a shunt aortic graft section. and operates in a diastolic counterpulsation mode. The system has been evaluated in six anesthetized. thoracotomized dogs with myocardial ischemia. The MCAD was activated 30-40 min after coronary artery occlusion and synchronized with the R-wave. As illustrated by a representative sample of the data obtained from one of several trials. the preliminary experimental results demonstrated that the MCAD worked effectively to fulfill the primary functions of a counterpulsation assist device. i.e.. augmentation of coronary perfusion and reduction in the vascular impedance to ventricular ejection.
Effect of a pulsing electromagnetic field on metabolically derived osteoporosis in rats: a pilot study, The literature suggests that a pulsating electromagnetic field (PEMF) is effective against bone loss in disuse osteoporosis. This study was conducted to evaluate the effects of PEMF on metabolically derived osteoporosis in rats. Sixteen 5 month old female Sprague-Dawley rats were divided into three groups (G-1.2.3). G-1 was given a normal diet and no exposure to PEMF; G-2.3 were oophrectomized and fed a low calcium diet for 8 months; and G-3 was also exposed for 24 hr/day to PEMF generated by applying a 15 Hz. 5.6 A peak to peak square wave to Helmholtz coils (64 cm I.D.. 200 turns/coil). The rats were sacrificed at 4. 6. and 8 months. Skeletal changes were analyzed by measurements of acid extracted bone calcium and bone mineral content (BMC) using single photon absorptiometry (SPA). Although all animals started at approximately the same weight (mean of 290.0 g). G-2 showed a more progressive increase. While the mean weight after 8 months in G-1 was 350.0 g. and 352.5 g for G-3. that in G-2 was 400.0 g. The calcium content of the femur in G-2 and G-3 at 8 months was lower than that of G-1. but there were no significant differences among the three groups.
Excitation thresholds for nerves reinnervating the paralyzed canine larynx, Electrical stimulation of paralyzed laryngeal muscles implanted with nerve-muscle pedicles (NMP) has resulted in documented return of motion. No study. however. has yet determined how NMP excitability correlates with that of normal muscle or nerve. In six anesthetized dogs. one hemilarynx was denervated and the paralyzed thyroarytenoid. cricothyroid. and posterior cricoarytenoid muscles were reinnervated via NMPs originating from the ansa hypoglossi nerve. After 4.6 to 5.7 months. an electric stimulator delivering biphasic pulses of variable amplitude and widths was used to test thresholds for contraction in nine stimulatable NMPs. six intact recurrent laryngeal nerves (RLN). and five normal cervical muscles. With one exception (2.1 mA). NMP rheobases varied between 0.0002 and 0.04 mA (mean = 0.020 SD +/- 0.012. n = 6). Two NMPs belonging to animals stimulated for several hours had higher values (0.1 mA). Rheobase varied from 0.01 to 0.09 mA for control RLNs (mean = 0.058 SD +/- 0.025). and from 0.05 to 0.35 mA for muscles (mean = 0.144 SD +/- 0.109). Histologic correspondence with reinnervation was established in implanted muscles by type grouping on ATPase stains. These data suggest that 1) nerve pedicles may offer promise for the eventual construction of implantable low energy consuming laryngeal devices. and 2) the appropriate charge to be injected over time remains to be determined.
Prevention of infection in a porous tracheal prosthesis by omental wrapping, The ideal tracheal prosthesis has to permit complete incorporation by epithelialization of the luminal surface. This is not possible with the currently available impermeable solid silicone tube. The authors developed a reinforced. porous polyurethane tubular prosthesis which has the potential for complete incorporation. However. because these prostheses are implanted in a contamined area such as the airway. they all become infected. In order to prevent infection. the authors evaluated the effect of omental wrapping in guinea pigs. The authors' tubular prosthesis was implanted subcutaneously in the abdominal area with the ends open to the air. Ten prostheses were wrapped with omentum and 10 prostheses were not. In 4 weeks. all control prostheses were infected and marsupialized. All the wrapped prostheses remained in place and were macroscopically not infected. Microscopically. all wrapped prostheses were well vascularized and were incorporated by granulation tissue. which did not occur in the prostheses of the control group. From these results the authors conclude that omental wrapping would be an effective way to prevent infection of porous tracheal prostheses in an open-to-the-air situation. and allow rapid tissue ingrowth and incorporation in the host.
Evaluation of plasma sodium concentration during hemodialysis by computerization of dialysate conductivity, Kinetics modeling based on sodium mass balance and changes in conductivity at the dialysate outlet compared to that at the dialysate inlet. led to predicting the plasma water conductivity of the blood inlet. Conductivity transducers. with temperature compensation. located at the dialysate inlet and outlet ports of the dialyzer and connected to a conductimeter. were interfaced with a portable computer for data acquisition. In 38 dialysis sessions. a close relationship was found between estimated plasma water conductivity (CdBi) and measured plasma sodium concentration [Na]Bi. according to the formula: CdBi = 0.101[Na]Bi + 0.37 (n = 38; r = 0.922). The study shows that plasma sodium concentration at the dialyzer inlet could be evaluated. with a standard error of +/- 1.5 mEq/L. by continuous measurement of conductivity gradient between dialysate inlet and outlet.
Pressure effects on roller pump blood flow during hemodialysis, Accurate measurement of blood flow during hemodialysis is essential to avoid underdialysis. When blood roller pumps are pushed to the high-flow rates demanded by high performance dialyzers. flow may be overestimated. This study examined the effect of inflow (Pa) and outflow (Pv) pressures induced by hemodialysis roller pumps on flow in vitro and in vivo. Blood flow was measured volumetrically. and with an ultrasonic flow probe. whereas Pa was adjusted from -50 to -400 torr and Pv from 50 to 300 torr. Only Pa influenced flow. At -200 torr. true flow measured volumetrically averaged 8.5% +/- 1.3% less than the blood pump revolutions per minute (RPM) meter reading. At -400 torr. the difference was 33.0% +/- 1.9%. There was no visible indication that flow was reduced to less than pump meter readings. Pv. hematocrit. and the source of pump tubing had no significant effect. Flow measured with an ultrasonic transit-time probe during routine hemodialysis in 64 patients was 9.0% +/- 2.7% less than pump meter readings when Pa varied from -180 to -220 torr. Blood pump meter readings greater than 400 ml/min were usually inaccurate because of low Pa. Prepump monitoring of arterial inflow pressure can prevent hidden reductions in blood flow that decrease dialysis efficiency.
Modulation of peritoneal macrophage antimicrobial activity by peritoneal dialysis fluid, Ca++, and 1,25(OH)2D3 in CAPD patients, Previous in vitro studies showed that Ca++ and 1.25(OH)2D3 modulate peritoneal macrophage (PM0) antimicrobial activity in CAPD patients. Twenty-four CAPD patients were evaluated in vivo (12 who had never had peritonitis. and 12 with an overall peritonitis incidence of more than one episode per 8 patient/months). for the effects of different peritoneal dialysis fluids (PDF) and Ca++ concentrations (1.25. 1.75. and 2.25 mmol/L) on PM0: cytoplasmic Ca++ concentration; superoxide generation; leukotriene B4 (LTB4) release; and bacterial killing for Staphylococcus epidermidis. The same parameters were also evaluated after adding 1.25(OH)2D3 (0.25 microgram/L) to the PDF. Results showed a direct correlation between the PDF Ca++ concentration and PM0 Ca++ levels. superoxide and LTB4 generation. and bacterial killing such that. with 2.25 mmol/L of Ca++. these values were significantly higher than those seen with 1.75 mmol/L. The addition of 1.25(OH)2D3 potentiated the Ca(++)-induced effects. On the other hand. with PDF Ca++ levels of 1.25 mmol/L. an inhibition of the aforementioned parameters was seen. However. this effect was reversed by the addition of 1.25(OH)2D3. These in vivo results confirm the importance of Ca++ and 1.25(OH)2D3 in PM0 antibacterial function in CAPD patients. and may be useful in determining the prophylaxis and therapy of peritonitis.
ECMO assisted angioplasty for cardiomyopathy patients with unstable angina, Patients who are otherwise unsuitable candidates for coronary bypass surgery or standard coronary angioplasty (PTCA) may be successfully treated with PTCA during ECMO. Five patients (3 men. 2 women). with a mean age of 57 years. are reported on here. They were not considered good candidates for standard therapy because of poor left ventricular function (mean EF. 24; range. 16 to 28%). Patients were supported by percutaneous femoral bypass using a BARD CPS machine. and underwent successful PTCA of either two vessels (three patients) or three vessels (two patients); in addition. one patient had dilatation of a stenotic aortic valve. Patients were supported with ECMO for 26 to 140 (mean 104) minutes. and required transfusion with 0 to 4 (mean 2) units of blood during or after the procedure. Complications included groin hematoma in two patients. All were discharged within 4 days of the procedure. Follow-up of the patients has been completed (4-7 mo) with no further hospitalizations for unstable angina. All patients remain in NYHA Class II or III. These data suggest that ECMO-assisted angioplasty is a safe and effective method of palliation of unstable angina associated with cardiomyopathy.
Long-term experience with Swan Neck Missouri catheters, The Swan Neck Missouri catheters are designed to reduce major complications including 1) exit/tunnel infections. by a downward directed exit hole; 2) pericatheter leaks. by placement of the deep cuff in the rectus muscle; 3) catheter tip migration. by caudal direction of the intraperitoneal segment; and 4) outer cuff extrusion. by a permanent bend between the 5 cm or 3 cm spaced cuffs in SN-M2 and SN-M3 catheters. respectively. Between April 1986 and April 1990. 103 swan neck catheters were implanted. Comparison of prospective data from 103 swan neck catheters and retrospective data from 148 standard (Tenckhoff and Toronto Western Hospital) catheters implanted between January 1982 and June 1985 showed reduced complication rates with swan neck catheters. An overall survival of 64% at 36 months for swan neck catheters is significantly better than that of 29% for standard catheters.
Bioenergetic recovery processes of injured myocardium, We employed cervically transplanted nonworking myocardium to simulate the condition of a heart supported by a ventricular assist device. and to investigate the bioenergetic recovery processes of injured myocardium with 31P nuclear magnetic resonance (NMR) techniques. A heterotopic graft was placed in the cervical portion of a recipient rat. One week later. a control 31P NMR spectrum was obtained from the graft. On the same day. the aorta of the graft was clamped for 30 minutes at room temperature. After this procedure. 31P NMR measurements of the graft were performed for 1 week. The phosphocreatine (PCr)/Inorganic phosphate (Pi) ratio. and beta-phosphate from adenosine triphosphate (beta-ATP)/Pi ratio on the first and second day after injury were significantly lower than control (p less than 0.05). However. these ratios recovered to a significant extent on the third and fourth day. These results suggest that 3 or 4 days are required for bioenergetic recovery of reversibly injured myocardium. even under nonworking conditions.
Additional salutary hemodynamic effects of the combined use of the paraaortic counterpulsation device and intraaortic balloon pump versus a paraaortic counterpulsation device alone, The hemodynamic effects of the combined use of the paraaortic counterpulsation device (PACD) (stroke volume 65 ml) implanted on the ascending aorta. and a 20 ml intraaortic balloon pump (IABP) placed in the descending aorta. were compared with the PACD working alone in 12 dogs after the induction of heart failure. Heart failure was characterized by left ventricular end-diastolic pressure (LVEDP) greater than 18 mmHg and systolic aortic pressure (SAP) in stage A: 116 mmHg greater than or equal to SAP greater than 70 mmHg; in stage B: 70 mmHg greater than or equal to SAP greater than 30 mmHg; and in stage C: SAP less than or equal to 30 mmHg. Both modalities of mechanical assistance produced significant salutary hemodynamic effects in stages A and B. No difference was observed in stage C. In conclusion. the combined use of PACD and IABP is more effective than the use of either of these devices alone. This modality of mechanical assistance may easily be applied in patients that cannot be weaned from extracorporeal circulation. and in whom IABP was unsuccessfully applied.
Hemodynamic effects of a new right ventricular assist device, A right ventricular assist device (VAD) based on the principle of counterpulsation has been developed at our institution. The device is a valveless. pneumatically actuated. 40 cc. sac-type pump. with a single inlet-outlet port. For right ventricular support. the "Uniport" pump is anastamosed end-to-side to the pulmonary artery. In previous experimental trials. the device has been shown to impart minimal trauma to blood components. In this study. biventricular failure was induced in eight Holstein calves by normothermic ischemia during cardiopulmonary bypass. A Pierce-Donachy left VAD (LVAD) was used for left ventricular support following the ischemic insult. Hemodynamic measurements were obtained throughout the study. and each animal served as its own control. A significant increase in post injury cardiac output (33.5 +/- 11.4%) was obtained with use of the Uniport and LVAD. as compared to use of the LVAD alone (p less than or equal to 0.005). Other hemodynamic parameters of right heart failure. including right atrial pressure (RAP). pulmonary artery pressure (PAP). and left atrial pressure (LAP) were not significantly affected. These data suggest that the Uniport right ventricular assist device significantly improves cardiac output in this model of moderate right ventricular failure. Additional studies are required. however. to optimize pump stroke volume. and to further define the performance envelope of the device.
Light scattering detection of microemboli in an extracorporeal LVAD bovine model, Thromboembolization studies were performed on two calves supported by extracorporeal left ventricular assist devices (LVAD) using a light scattering (He Ne Laser) microemboli detector (LSMD). The LSMD system was placed on the outflow cannula of the LVAD in the extracorporeal loop of each animal. The measurements included the size. number. and rate of production of circulating microemboli in the range 20 microns less than microemboli diameter less than 1.000 microns. These data were compared to independently and concurrently obtained measurements of emboli shear rate (CPF). platelet count. red blood count (RBC). leukocyte count (WBC). plasma free hemoglobin. factors XIII. X. and V. and sorbitol dehydrogenase. Embolic number and volume were seen to be most dynamic in the very early phases of acute thromboembolization (0-40 minutes) with a peak embolic response within the first 30 minutes. The dynamics of reduced emboli volume. rather than number. may be implicated in the later stages of the thromboembolic passivation of these ventricles. The LSMD results generally showed an inverse correlation of microemboli volume rate with CPF measurements for each ventricle. LSMD. CPF. and leukocyte and platelet counts. showed a direct correlation with reduced counts for each additional ventricle for both calves. Factor XII was seen to have a more direct correlation in time with LSMD measurements for each ventricle than other parameters under investigation. This study represents the first time laser scattering and filtration methods have been applied simultaneously with hematologic assays in order to study the dynamics of device associated thrombogenesis.
Comparison of right ventricular and biventricular circulatory support in a porcine model of right heart failure, The effects of right ventricular (RVAD) and biventricular assist devices (BVAD) in an acute porcine model of right heart ischemic failure produced by occluding the right coronary artery for 2 min (RCAO) were compared. Right and left ventricular pressures were measured with Millar transducers and respective septal-to-free wall dimensions (RVSFWD. LVSFWD) with ultrasonic crystals. RCAO alone resulted in significant right heart failure. marked by a 36 +/- 5% reduction in cardiac output (pulmonary artery flow) and a 54 +/- 16% reduction in RV stroke work. Isolated RVAD significantly improved the hemodynamic conditions by restoring pulmonary blood flow and left heart filling to control levels. RVAD also resulted in reduced RVSFWD to control levels and increased LVSFWD via a rightward septal shift due to right heart unloading. Biventricular support resulted in the same hemodynamic improvement. but estimated LV peak systolic wall stress was reduced by 65 +/- 15% compared with control. due to concomitant LV unloading and reductions in LVSFWD. Therefore. either right or biventricular devices are effective in treating RV failure. The advantage of biventricular support is that the left ventricle is also unloaded. thus allowing improved circulatory support with minimal LV wall stress.
Long-term echocardiographic follow-up of patients with a tricuspid bioprosthesis, To clarify the long-term results of bioprosthetic valve function in the tricuspid position. 29 consecutive patients who underwent tricuspid valve replacement (TVR) were evaluated. There were 20 girls/women and 9 boys/men. with ages ranging from 6 to 61 years (mean 41.4 years). The bioprosthetic valves included Hancock in 2. and Carpentier-Edwards in 27. The follow-up period ranged from 32 to 145 months (mean 89 months). Regurgitant flow of the tricuspid bioprosthesis was studied by color Doppler echocardiography. Peak velocity (Vp) and pressure half time (PHT) were measured by continuous wave Doppler echocardiography. Operative mortality was 13.7% (4/29). with the actuarial survival rate. including operative deaths. 75% at 10 years. Valve thrombosis developed in one patient 4 years after TVR. Color Doppler showed regurgitation in 7 of the 20 patients who were completely followed up. but they were all asymptomatic and required no special intervention. Cusp tear or calcification requiring reoperation was not observed in this study. including 8 patients younger than 35 years of age. The Vp was significantly slower. and PHT was significantly prolonged. in the tricuspid rather than the mitral position. These data demonstrate that bioprosthetic valves in the tricuspid position can be used safely. Doppler examination should be performed taking these different flow dynamics into account.
Hemodynamic influence of LVAD on right ventricular failure, Left ventricular assist device (LVAD) pumping has hemodynamic and anatomic influences on right ventricular performance. A total artificial heart (TAH) model was employed to better understand the hemodynamic influence of an LVAD on the failing right ventricle. Biventricular failure was simulated by reducing both ventricular drive pressures of the TAH. After getting hemodynamic data. LVAD pumping in the case of right ventricular failure was simulated by increasing just the left ventricular drive pressure. In the LVAD-simulating condition. cardiac output increased and right atrial pressure decreased significantly (p less than 0.05) compared with the biventricular failure condition. whereas right ventricular function and minute work were the same in these two conditions. Even though changes were accompanied by adaptive increases in pulmonary resistance. substantially lower pulmonary artery and left atrial pressures resulted in the LVAD-simulating condition. From a hemodynamic perspective. these results indicate that an LVAD can increase right ventricular volume work by decreasing right ventricular pressure work. whereas right ventricular net pressure-volume work is unchanged and right ventricular failure is not worsened.
Left ventricular versus left atrial cannulation for the Thoratec ventricular assist device, In a retrospective study of 28 patients (23 men. 5 women) supported with ventricular assist devices greater than 3 days. the effect of LV cannulation versus LA cannulation on device performance was compared. Patients ranged in age from 12 to 67 years (mean 46 years) and were supported for 3-81 days (mean 15 years). Fifteen patients were supported with left VADs (6 LV and 9 LA). and 13 patients were supported with BVADs (5 LV and 8 LA). The mode of operation 91% of the time was the fill-to-empty mode. Ten data points were taken for each patient. LV cannulation results in higher VAD flow index at decreased preload. lower VAD systolic and vacuum pressures. and shorter diastolic durations. Eleven of the 28 patients survived. Although survival was greater in patients with LV cannulation. survival was more dependent upon reversibility of myocardial damage. eligibility for transplantation. or the development of complications. These data indicate that LV cannulation provides better VAD performance than LA cannulation in the fill-to-empty mode.
Early and late tamponade with the Novacor left ventricular assist system, Cardiac tamponade can be a major complication after implantation of the Novacor left ventricular assist system (LVAS). Between 1987 and 1989. 14 patients received an LVAS as a bridge to cardiac transplantation: 3 developed early tamponade (33 +/- 12 hr postoperatively) and 5 were diagnosed with a late tamponade (9.4 +/- 3.2 days postoperatively). One patient had both early and late tamponade. Early tamponade was more common in those with increased perioperative blood loss (5.270 +/- 1.942 ml vs. 1.420 +/- 1.160 ml in other patients. p less than 0.05). Early tamponade was suggested by reduction in mean arterial pressure (74 +/- 1 to 64 +/- 3 mmHg). LVAS output (5 +/- 0.5 to 2.7 +/- 0.7 L/min). LVAS stroke volume (55 +/- 4 to 23 +/- 5 ml). and an increase in central venous pressure (13 +/- 1 to 21 +/- 1 mmHg. p less than 0.05 for all values). Late tamponade was associated with a marked rise in central venous pressure (14 +/- 1 to 22 +/- 2 mmHg. p less than 0.05). with only a mild decrease in LVAS output (4.9 +/- 1 to 3.8 +/- 0.9 L/min) and stroke volume (49 +/- 8 to 36 +/- 3 ml). without a significant change in mean arterial pressure. Two of these five late episodes occurred in patients who were anticoagulated with heparin (PTT 52 and 100 sec). and in one other with warfarin (PT 27 sec. PTT 55 sec); two patients were not on any anticoagulants. Surgical drainage of pericardial effusions. and especially of clotted blood found frequently posterior to the left ventricle in the space created by the LVAS decompressed left ventricle. resulted in an immediate return of all hemodynamic measurements to normal in both early and late tamponade.
Phenotypic characterization of monocytes and macrophages from CAPD patients, The purpose of this study was to phenotypically characterize and compare peripheral blood monocytes from CAPD patients with peritoneal macrophages isolated from their peritoneal dialysis effluents. Monocytes/macrophages were labeled with fluorescent ligands or monoclonal antibodies specific for 1) receptors for C5a. formyl-met-leu-phe (fMLP); Fc region of IgG; C3b (CR1); and C3bi (CR3). 2) Class II histocompatibility antigens HLA-DR and HLA-DQ; and 3) monocyte/macrophage surface antigen CD14. The cells were analyzed using flow cytometry. Results indicated that there were no differences between monocytes and peritoneal macrophages in their receptor expression for fMLP. CR1. or CR3. However. paired t-testing indicated that peritoneal macrophages had significantly increased expression of Fc and C5a receptors. as well as enhanced antigen expression of HLA-DR. HLA-DQ. and CD14. These results suggest that peritoneal macrophages from CAPD patients are activated with increased expression of receptors and antigens important in host defense.
Influence of phosphatidylcholine on ultrafiltration and solute transfer in CAPD patients, Fifteen patients (mean age 59.9 +/- 16.1 years) treated by CAPD for a mean of 21.6 +/- 14 months. underwent peritoneal clearances before and after 15 days of intraperitoneal phosphatidylcholine (PC) treatment (50 mg/L). No difference was observed in urea. creatinine. uric acid. and reverse dextrose clearances. A statistically significant increase in phosphate clearances (4 and 6 hr dwell times) (1.36%) and a reduction in drainage volume (2 hr dwell time) (1.36%) were observed after treatment. Urine output and percent dextrose reabsorption were unchanged. The ultrafiltration (UF) showed a tendency to increase. which lasted for 15 days after discontinuation of treatment. This tendency allowed the patients to reduce. during the same period. the amount of hypertonic solution (23.8 L vs. 21.3 L) required. The tendency to increase UF over time deserves further study.
Chronic nightly tidal peritoneal dialysis, Nightly tidal peritoneal dialysis (NTPD) is a technique in which. after an initial fill of the peritoneal cavity. only a portion of dialysate is rapidly cycled. Five anuric. stable. PD patients entered a 4 month study to determine the NTPD session length necessary for clinically adequate dialysis and creatinine clearance similar to those on four daily 2 L CAPD exchanges. NTPD was performed using a modified PAC-X-2 cycler. with the drain phase regulated by a target volume. One patient completed 3.5 months of study. one 4 months. three 6 months. and one patient each continued on NTPD for 13. 14. and 32 months. The mean NTPD session time was 9 hr 24 min (range 8 hr 35 min to 9 hr 55 min) at the end of 4 months. All patients had clinically adequate dialysis. Three patients preferred NTPD over CAPD. particularly because of an empty abdomen during the daytime. One patient required an increase in NTPD time. and an addition of one daytime exchange. because of low creatinine clearance. In conclusion. NTPD provides weekly creatinine clearances comparable to CAPD. with an acceptable duration of nightly dialysis sessions in most anuric patients. A new PD machine providing inexpensive dialysis solution in large quantities. as well as safe and false alarm free dialysis sessions. is needed for practical NTPD implementation.
In vitro and in vivo testing of an electrocatalytic glucose sensor, A prerequisite for the development of an implantable artificial pancreas is the availability of a stable. long-life glucose sensor. Platinum (Pt) catalyzed electrodes have been demonstrated in vitro to show high sensitivity to glucose and long cycle life but are more sensitive to co-reactants compared with enzymatic methods. The authors developed a special data processing method (compensated net charge ratio. or CNCR) in which the measured electrode response is very sensitive to glucose. completely insensitive to urea. and only moderately sensitive to amino acids. Other endogenous and exogenous co-reactants show only minor interferences. The CNCR method involves the determination of the ratio of net oxidation charge to total charge during one complete cycle of a cyclic voltammogram. Prototype electrodes tested in vitro in spiked plasma have shown typical sensitivities of greater than 2 x 10(-4) CNCR units per 1 mg/dl change in glucose concentration. with linear response up to 400 mg/dl. For in vivo testing. a modified 5 F vascular catheter with membrane covered surface mounted electrodes was used at a vena cava site in swine. Several sensor designs were tested in vivo. with sensitivities of 1-5 x 10(-4) CNCR units (mg/dl).
Effects of prostaglandin I2, superoxide dismutase, and catalase on ischemia-reperfusion injury in liver transplantation, This study evaluated the effects of a prostaglandin I2 analogue (aPGI2). superoxide dismutase (SOD). and catalase (CAT) on hepatic injury after warm ischemia and reperfusion in terms of survival. mitochondrial function. serum enzymes. and histology. Hepatic ischemia was created in rats by clamping the hepatoduodenal ligament for 90 min with splenofemoral bypass. Reperfusion was induced by unclamping the vessels and disconnecting the splenofemoral bypass. Then aPGI2 (350 ng/kg/min) was infused for 60 min just before hepatic ischemia. and SOD and CAT (5.000 units/kg each) were administered immediately before the start of reperfusion. Serum enzyme and mitochondrial function assessments of livers were made just after ischemia. and after 2 hr of reperfusion. Survival rate was also assessed in a separate group of rats. Liver enzymes such as SGOT. SGPT. and LDH showed no correlation to liver viability. The administration of aPGI2 alone showed no effect on ischemically injured mitochondria; however. the free radical scavengers (SOD. CAT). in combination with aPGI2. showed significant improvement of mitochondrial function together with extension of survival. The ultrastructure of hepatocytes was better preserved in the treated groups. These agents improved the viability of ischemic-reperfused injured livers.
An efficient method for removing bilirubin, Bilirubin is tightly bound to albumin. making hemoperfusion an ineffective treatment for hyperbilirubinemia. By adding a safe unbinding agent to the blood (solutizer). which itself is adsorbed. hemoperfusion can become efficient and practical. Canines were made hyperbilirubinemic with an intravenous infusion of a 5 mg/ml solution (with Na2CO3) for 1 hour. Peak concentrations of 14-22 mg/dl were reached in adult dogs (25-35 kg). Hemoperfusion was then initiated with or without (control) the solutizer (sodium benzoate). The bilirubin unbinding effect of sodium benzoate was rapid and effective. Because of the simultaneous adsorption of sodium benzoate. a small activated carbon section that was presaturated with the solutizer was located proximal to the main hemoperfusion column. in addition to continuous infusion to reach 20 mM in the blood. Comparison of the normalized bilirubin concentration for benzoate augmented hemoperfusion with the average for control dogs. shows that benzoate results in a threefold decrease in the normalized bilirubin concentration after 1.5 hr of hemoperfusion. Sodium benzoate may also have the advantage of protecting platelets during hemoperfusion.
Comparison of Delphin and BioMedicus pumps, There is an increasing use of centrifugal pump systems for cardiopulmonary bypass (CPB) and circulatory assistance. The BioMedicus and Delphin centrifugal pump systems were tested in two side-by-side. identical in vitro flow loops for blood trauma and flow probe accuracy. Blood parameters tested were hemoglobin. hematocrit. lactate dehydrogenase. free plasma hemoglobin. and platelet counts. The Delphin pump demonstrated significant increases in plasma hemoglobin levels at the three flow rates tested: 2 L/min (p less than 0.05). 4 L/min (p less than 0.005). and 6 L/min (p less than 0.05). After 4 hr of pumping. the drop in platelet counts was significantly greater in the BioMedicus loop as compared with the Delphin loop (p less than 0.05) at the 2 L/min and 4 L/min flow rates; however. platelet levels remained within normal ranges in both systems. At 6 L/min. no statistical difference in platelet counts was noted. The flow probe readings were found to deviate by as much as 58% of stopwatch timed flow rate comparisons at low flow rates. but improved to within 10% or better at 6 L/min.
Hemopump ventricular support for patients undergoing high risk coronary angioplasty, Prophylactic implantation of a Hemopump (Johnson and Johnson. Skillman. NJ) has been evaluated in nine patients selected for high risk coronary angioplasty. They were unstable patients. refractory to maximal pharmacology. with indications for revascularization. but contraindications for surgery such as low ejection fraction and lack of material for bypass. In all. the target lesion was located on the last patent vessel. The pump was inserted under local anesthesia. without any graft. A specially designed occluder permitted avoidance of retrograde bleeding during implantation. The bypass flow ranged from 2.5 to 3.2 L/min. and permitted a rise in cardiac index from 2.05 to 2.55 L/min/m2. with a drop in capillary wedge pressure from 13 (7-18) to 10 (7-13) mmHg. During balloon inflation. no electrocardiographic changes were observed. because only minor ventricular arrhythmias occurred. No significant hemolysis was seen (plasma free hemoglobin less than 10 mg/dl in all) after 2 hr of pumping. The only limitation of the technique appears to be difficulty at the time of implantation from narrow. stenosed. or tortuous iliofemoral arteries (3 patients). This experience strongly supports the benefit of temporary left ventricular Hemopump support in high-risk situations and clearly shows the need for a smaller pump.
Biocompatibility of dialysis membranes is of no importance for objective or subjective symptoms during or after hemodialysis, The clinical importance of biocompatibility of hemodialysis membranes is a matter of controversy. The authors studied the relationship between biocompatibility and acute symptoms during hemodialysis (HD). Twenty-three patients underwent 12 different bicarbonate HD using Cuprophan. Hemophan. or Polyamide membranes for short (2 hr) and long (4 hr) treatments. with small or large membrane areas. Subjective and objective symptoms were registered during HD and 12 and 36 hours thereafter. Type of membrane. membrane area. or Kt/V were of no importance for the occurrence of subjective or objective symptoms. The patients registered fewer symptoms during 2 hr HD with high blood flow than during 4 hr HD with slow blood flow (p = 0.04). Headache was particularly more frequent during the 4 hr HD. Blood pressure. and to some extent subjective symptoms. were influenced by ultrafiltration volume but not by type of membrane. Biocompatibility is not a determinant of acute side effects of hemodialysis.
Clinical effects of a polyethylene glycol grafted cellulose membrane on thrombogenicity and biocompatibility during hemodialysis, The biocompatibility and thrombogenicity of polyethylene-glycol (PEG)-grafted cellulose hemodialysis (HD) membranes (PEGC) were investigated in cross-over HD of five HD patients with ordinary cellulose (OC). The PEGC significantly suppressed transient leukocyte and thrombocytopenia. and release of C3a. beta-thromboglobulin and platelet factor 4. in corresponding with the quantity of grafted PEG. HD with PEGC resulted in lower granulocyte elastase production. protein and blood cells adsorption on the membrane surface than those with OC. Minimum heparin in HD with PEGC was three times lower than that with OC. with the thrombin-antithrombin III complex elevation lower than that in HD with OC. The results indicate that the grafted PEG effectively suppresses blood and membrane interaction. thus improving biocompatibility and reducing thrombogenicity in clinical HD.
Difference in beta 2-microglobulin removal between cellulosic and synthetic polymer membrane dialyzers, Several kinds of dialyzers. with highly permeable membranes (HPM). have been designed to specifically remove beta 2-microglobulin (BMG). To clarify their solute transport characteristics. nine types of HPM dialyzers were evaluated during in vivo and in vitro studies using human plasma and aqueous solutions. No BMG membrane adsorption and/or plugging was seen with cellulosic membrane dialyzers during in vitro experiments using human plasma. On the other hand. all synthetic polymer membrane dialyzers had adsorptive properties. and in a dialyzer with a polymethylmethacrylate membrane. a large amount of BMG was removed by adsorption alone. Dialyzers with cellulose triacetate and polyacrylonitril membranes showed higher values of BMG diffusive dialysance (greater than 20 ml/min) and sieving coefficient (greater than 0.9). From in vitro experiments using an aqueous solution containing several solutes with relatively small or middle molecular weights. all HPM dialyzers had a higher overall mass transfer coefficient than any conventional membrane dialyzer.
A blood-liquid interface for prolonged extracorporeal oxygenation with excellent antithrombogenicity, The authors verified the excellent antithrombogenicity of a blood-liquid interface (BLI) and introduced an oxygenator based on the principle of gas exchange across direct BLI. In a newly developed oxygenator. three layers of liquid flowed horizontally. contacting one another: O2 saturated silicone oil on the top. O2 saturated fluorcarbon at the bottom. and blood in the middle. Gas exchange was carried out across both direct BLIs. This system provided excellent antithrombogenicity as well as good gas exchange. The results indicate that this method will become a promising modality for prolonged extracorporeal oxygenation.
Increase of intraplatelet free calcium ion during extracorporeal circulation with a hollow fiber oxygenator: arterial filter and dynamics of platelet thrombosis on oxygenator and filter in a pig model, Intraplatelet free calcium (IPFC) ions provide a common pathway for platelet activation leading to thrombosis and embolization. IPFC levels were determined by chlorotetracycline fluorometry during extracorporeal circulation (ECC) with systemic heparin in eight Yorkshire pigs (weighing 30-40 kg; 3 control and 5 ECC); the ratio of slow phase organelle calcium sequestration to fast phase platelet-membrane binding is an index of free calcium. During 3 hr of ECC with a hollow fiber oxygenator (HFO) (Bentley CM-50) and AF (Bentley 1025). seven blood samples were collected 5 min before and during ECC. The platelet deposition (CPM/microCi) on HFO (PDHFO) was simultaneously measured with In-111-labeled autologous platelets (300-400 microCi) and a Geiger probe detector at -5. 0. 5. 30. 45. 60. 120. and 180 min. During ECC. IPFC and HFO thrombus increase significantly (p less than 0.05) at 45 min with respect to control IPFC values of 0.4 +/- 0.1. suggesting direct participation of calcium activated platelets in thrombosis on HFO. The decline of IPFC is due to extrusion and sequestration by dense granules. and decline in HFO thrombus is due to embolization. On the other hand. the embolus in the arterial filter was trapped in a linear fashion. with a consistent increase with time of ECC.
One year of rHuEPO therapy prolongs RBC survival and may stabilize RBC membranes despite natural progression of chronic renal failure to uremia and need for dialysis, rHuEPO was administered to eight patients with chronic renal failure (CRF) and uremia (U) for 1 year. Creatinine Clearance (GFR) averaged 14.3 (9-25) ml/min at an Hct of 28% (26-30). Baseline RBC survival by 51Cr T1/2 was highly correlated with GFR (r = 0.66). p less than 0.05 (2). average 21.6 days. Repeat 51Cr T1/2 at 3 months with GFR 10 ml/min at Hct 38% was prolonged by 7 days to 28.6 (p less than 0.005). and at 1 year remained increased to 28 days (p less than 0.001) with Hct 39%. despite further decreased GFR to less than 4 ml/min and need for dialysis. Reticulocytes varied from 1.6% to 7.4 (3-6 weeks) to 3.1 (3 months) and 1.5% (1 year). Bone marrow cellularity increased from 36% to 47% (3 months) and 44% (1 year). M:E ratio decreased from 3.9:1 to 1.7:1 (3 months) to 1.6:1 (1 year). Marrow iron decreased from 4.1/6 to 2.4/6 (3 months) to 1.8/6 (1 year). Doses of rHuEPO had to be reduced to avoid polycythemia. rHuEPO stimulates erythropoiesis in pts with progressive CRF and U for 1 year. The initial increase in hematocrit is due to the early peak of reticulocytes. At 3 months. rHuEPO maintains the increased hematocrit by three mechanisms: 1) increased reticulocytosis. 2) a trend to increased bone marrow erythroid cellularity. and 3) lengthened RBC survival. At 1 year of rHuEPO therapy. the trend to increased marrow cellularity persists. however. the maintenance of target hematocrit is via a lengthened RBC survival. Despite progression of CRF and U. rHuEPO produced RBCs with longer survival than expected. RBC membranes may have been stabilized by rHuEPO.
LVAS pump performance following initiation of left ventricular assistance, Prevention of disturbed flow (e.g.. flow stasis) and consequent thrombosis in heart pumps is based upon design characteristics determined during laboratory bench tests. These tests employ optimal filling and emptying characteristics. such as the full-fill to complete empty mode in the Novacor left ventricular assist system. Filling characteristics of the Novacor LVAS were examined during the first 48 hours after implantation in 14 patients. Fill volume of the pump was reduced in pathologic states. such as cardiac tamponade. and following the initiation of right ventricular mechanical circulatory support. In addition. multiple regression analysis revealed that right ventricular function measured by the amount of inotropic support required. the right ventricular ejection fraction. and the total pulmonary resistance. significantly predicted left ventricular assist pump fill volume during the first 48 hours of support. Flow visualization simulating these clinical conditions of incomplete filling suggest inadequate valve washing. particularly around the inlet valve and its conduit. which may predispose to thrombus formation.
Clinical use of the Berlin Biventricular Assist Device as a bridge to transplantation, The Berlin Artificial Heart System/Biventricular Assist Device (BVAD) was used in 38 patients. 1) Twenty-eight patients were awaiting cardiac transplantation (Tx) (age 23-56 yrs). All patients had contraindications not allowing immediate Tx. 2) Five patients were emergency cases not on our Tx list (postcardiotomy cardiac failure. acute myocarditis) (age 28-59). 3) Five patients were post Tx patients with graft failure (age 22-52). Extracorporal circulation was used for implantation of the BVAD. In group 1. 21 of 28 patients (pts) recovered. and all were subsequently transplanted after 6 hours to 39 days. when all organ function was restored. In 7 pts. mechanical circulation was terminated after 1-40 days because of further deterioration. Five of the transplanted pts died. 14 pts survived (greater than 30 days). and 2 pts were just transplanted with satisfactory postoperative courses. Of group 2 and 3 pts. two were successfully weaned. In one patient the allograft recovered after 11 days of support.
Effect of beta cell distribution on the performance of a bioartificial pancreas, The insulin response of available prototype hollow fiber bioartificial pancreas devices remains unacceptably slow. Although previous experimental and theoretical investigations provide insight into the factors governing the performance of these devices. there are currently no results on the effects of beta cell distribution on insulin response. The authors have developed a detailed theoretical model for insulin response in a hollow fiber bioartificial pancreas. Model predictions have been shown to be in good agreement with literature data on the insulin release from an in vitro hollow fiber device. In this study. model simulations were used to evaluate the effects of axial and radial variations in beta cell density on the insulin response. For a device with no convective recirculation (i.e.. a diffusion controlled device). the radical distribution of cells in the matrix and shell plays a critical role in determining device response. but the insulin response is essentially independent of the axial beta cell distribution. In contrast. for a device with substantial recirculation. there is a very strong dependence on the axial beta cell distribution. with a weaker dependence upon the radial distribution. These results clearly demonstrate the potential importance of beta cell distribution in the analysis of in vivo and in vitro experimental data. and in the design of effective clinical devices.
An implanted peritoneal oxygen tonometer that can be calibrated in situ, Oxygen tension in the peritoneum has been continuously measured with a Silastic tonometer having an integral oxygen electrode and inlet and outlet tubes for gasequilibrated electrolyte solution. Remote kinetic calibration of the system is periodically performed. Tonometers were implanted in six rabbits. Peritoneal oxygen tension was measured in awake and anesthetized rabbits under various oxygen breathing conditions.
Development of a small caliber biologic vascular graft: evaluation of its antithrombogenicity and the early healing process, The authors previously showed that a small caliber xenograft using our crosslinking technique was applicable to aortocoronary bypass grafting. In this study of the graft. the antithrombogenicity and healing process was evaluated at an early stage after implantation. Fresh sheep carotid artery (3mm ID) was obtained and cross-linked with polyepoxy compounds. and then used as a small caliber vascular graft. The graft was white and soft. Six cm segments of the graft were implanted into the carotid arteries bilaterally in nine dogs. Sodium heparin was given during the surgery. but no anticoagulant was used postoperatively. Fifteen grafts from eight dogs were removed from 1 hr to 30 days after implantation. and 13 of 15 grafts were found to be patent. Two grafts. one at 3 days. and the other at 14 days. were occluded. The anastomotic area of the occluded grafts felt hard when touched from the outside. In one dog. the grafts were shown angiographically to be patent at 14 days after implantation. and this dog was kept for long-term observation. Macroscopically. no thrombus was observed on any of the patent grafts. Microscopically. the inner surface near the anastomotic lines was covered with endothelial cells. and infiltration of fibroblasts was observed from the outside 7 days after implantation. No foreign body reactions were seen around the graft. After 30 days of implantation. a thin layer of plasma protein at the middle of the graft was observed by scanning electron microscopy (SEM). From these observations. it was concluded that the grafts exhibited satisfactory early antithrombogenicity and healing after implantation.
Proliferation and substrate effects on endothelial cell thrombogenicity, The effects of the cellular differentiation status and the adhesive-substrate on endothelial cell function in cell culture were measured with an enzyme based assay of surface thrombogenicity. A solid plastic. microporous polymeric. and fibronectin (FN) treated microporous polymeric were used as substrates for growth of endothelial cells. The microporous and FN treated synthetic substrates have been shown to aid in the induction of cellular differentiation mechanisms. Cells were studied under proliferative and nonproliferative growth conditions. The thrombogenicity of the surface created by the endothelial cell monolayers under various experimental conditions was determined using an enzyme based assay of fibrin deposition. Actively proliferating cells on the solid plastic substrate produced the most thrombogenic surface. while confluent endothelial cell monolayers grown on FN treated microporous substrate were the least thrombogenic surfaces. These data suggest that endothelial cell surface thrombogenicity is under substrate control. and also related to the cellular differentiation status. These findings are being used to design a novel approach to the small diameter synthetic vascular graft problem.
Effect of complement and arachidonic acid pathway inhibition on white blood cell count and deposition on vascular grafts, To determine the role of complement and arachidonic acid metabolites in the decrease in peripheral white blood cell count (pWBC) observed with graft implantation. Dacron aortic grafts were implanted in control rabbits (Group I. n = 13). or rabbits pretreated with cobra venom factor (80 U/kg) to deplete complement (Group II. n = 13). indomethacin (2.5 mg/kg) to inhibit cyclooxygenase (Group III. n = 7). or diethylcarbamazine (DEC. 90 mg/kg) to inhibit leukotriene synthesis (Group IV. n = 7). pWBC was measured 15 min and 1 hr after graft implantation. After graft removal. the WBC count on grafts (gWBC) was determined by light microscopy (LM) and scanning electron microscopy (SEM). One hr after graft implantation. pWBC decreased significantly in Groups I-IV to 46%. 52%. 40%. and 45% of preoperative pWBC. respectively. There was no significant difference among the groups. LM revealed gWBC per 63x field of 8.0. 12.3. 5.8. and 6.8 in Groups I-IV. respectively. Similarly. SEM showed gWBC per 2000x field of 2.5. 5.6. 0.7. and 1.5 in Groups I-IV. respectively. SEM gWBC was significantly greater in Group II than I (p less than 0.01). and significantly less in Group III than I (p less than 0.05). Results suggested that complement and arachidonic acid pathways alone do not affect the fall in pWBC. but may influence gWBC.
The dynamics of platelet thrombus formation rate, thrombus retention time, and rate of embolization on a control and heparin bonded polyurethane angio-catheter, The dynamics of platelet deposition and embolization from control and heparin bonded polyurethane catheters (CPC and HBPC) was evaluated with In-111 labeled autologous platelets (IN-PLT) and a computerized gamma camera (CGC). Ten non-heparinized dogs (18-25 kg) were catheterized in both femoral arteries with 10 cm of CPC and HBPC (5 Fr.. Cordis) 24 hr after injection of 300-420 microCi of In-PLT. and imaged for 3 hr with the computerized gamma camera. The regional platelet deposition curves (RPDC) indicated multiple peaks and valleys; the curves were analyzed for early rate of thrombus formation (upswing). thrombus retention time (full width at half maxima of the RPDC-peak). and rate of embolization (downswing) on both catheters. The four parameters (mean +/- SD) of thrombosis on catheters and integral of the radioactivity time curve for the 3 hr duration of imaging were calculated from normalized counts/sec. The rate of thrombus formation and rate of embolization are higher for the control than HBPC. suggesting that heparin-bonding decreases the early rate of thrombosis and embolization. The thrombus adhesivity and retention time appear shorter for the control catheter. indicating that the control thrombogenic catheter forms multiple thrombi and emboli than HBPC. The integral appears larger for the control catheter than HBPC. In vivo (dynamic) studies. in vitro studies. and critical analyses of the radioactivity time curve were essential for complete evaluation of thrombogenicity of catheters and other cardiovascular prostheses.
Suppression of immunoglobulin and interleukin-6 production from peripheral blood mononuclear cells by dialysis membranes, The influence of dialysis membranes on immunoglobulin and interleukin-6 production was estimated in vitro. Peripheral blood mononuclear cells from 11 patients undergoing hemodialysis were incubated for 7 days on Cuprophan. Hemophan. and polyacrylonitrile flat sheet membranes. IgG. IgA. IgM. and IL-6 were assayed in the supernatants with the aid of enzyme-linked immunosorbent assay (ELISA) techniques. Pokeweed mitogen-stimulated IgG production declined significantly from 319 +/- 40 ng/ml on polystyrole to 162 +/- 26 ng/ml on Cuprophan; 135 +/- 25 ng/ml on Hemophan; and 109 +/- 20 ng/ml on polyacrylonitrile. A similar pattern was observed for IgA and IgM production. IL-6 production was significantly reduced in the presence of Cuprophan (151 +/- 45 pg/ml). Hemophan (167 +/- 6 pg/ml). and polyacrylonitrile (108 +/- 33 pg/ml) when compared with polystyrole (724 +/- 34 pg/ml). It was concluded that the long-term exposure of mononuclear cells to artificial surfaces during dialysis may contribute to the impaired humoral response observed in dialysis patients. This effect may be due to a decline in B cell stimulation by monocytes. a possibility suggested by the reduction in monocytic IL-6 production.
The use of rectus abdominis myocutaneous flaps following excision of vulvar cancer, Rectus abdominis myocutaneous flaps have been used in 16 women following radical excision of extensive vulvar cancer. In two women the procedure was part of the primary surgery. in 11 for recurrence of vulvar cancer and in three for symptomatic palliation. Fifteen (94%) of the grafts took with primary healing. Thirteen of the 16 patients are alive 6-60 months (median 29 months) after surgery and the three who died benefited from symptomatic palliation. Simultaneous vulvar reconstruction allows good cosmetic rehabilitation and is an important part of the armamentarium for the management of patients with advanced primary or recurrent vulvar carcinoma. This technique offers excellent surgical clearance of massive offensive and painful vulvar tumors.
Changes in circulating alphafetoprotein following administration of mifepristone in first trimester pregnancy, The occurrence of fetomaternal haemorrhage was investigated in 30 women by measuring maternal serum alphafetoprotein (AFP) levels before and after the administration of mifepristone (RU 486) for termination of first trimester pregnancy. A significant rise in AFP levels was seen in 21 women (70%). the increase ranging from 6 to 660% of baseline levels. The apparent frequency of fetomaternal haemorrhage was similar to that reported previously for surgical termination of first trimester pregnancies.
A morphological and immunological study of human placental bed biopsies in miscarriage, Placental bed biopsies were examined in three groups of pregnant women for maternal vascular response to placentation as well as for the presence of cells associated with local immunosuppression activity. In the group of women undergoing legal abortion. the histological appearance of trophoblastic invasion was normal in all but one. and the proportion of immunosuppressor cells was also normal. In the missed miscarriage group the histological appearances were abnormal except in one patient. In women with a history of recurrent miscarriage who had miscarried after immunization. placentation was normal in some and defective in others. Immunosuppressor cells appeared to be diminished in number. although there was no correlation between the cytotoxic status of their sera and their pregnancy outcome.
Total perinatal wastage. A clarification of priorities, The pregnancy outcome of 16.971 women carrying 17.352 living fetuses after 16 weeks gestation was studied. As well as recording perinatal deaths. all losses before 28 weeks and up to one year after delivery were recorded to give a total perinatal wastage rate of 21.6 per 1000 fetuses alive at 16 weeks compared with a perinatal mortality rate (stillbirths plus early neonatal deaths) of 7.8 per 1000 births. All deaths were then classified according to pathological sub-groups. The concept of auditing perinatal care using perinatal mortality was then compared with that using total perinatal wastage.
Socioeconomic conditions in childhood and ischaemic heart disease during middle age, OBJECTIVE--To examine the association between socioeconomic conditions in childhood and ischaemic heart disease in middle aged men. including the role of physiological and behavioural risk factors. DESIGN--Prevalence study with extensive examination and testing and with recall of childhood conditions. SETTING--Population based study in Kuopio. Finland. SUBJECTS--Representative sample of 2679 men aged 42. 48. 54. and 60. MAIN OUTCOME MEASURES--Ischaemic findings on progressive maximal exercise test. RESULTS--Low socioeconomic style in childhood was associated with significantly higher prevalence of findings indicating ischaemias. Compared with those in the highest tertile of childhood socioeconomic conditions. the age adjusted odds ratio for subjects in the lowest tertile was 1.44 and for those in the middle tertile 1.35. Adjustment for years of cigarette smoking times the average number of cigarettes smoked. ratio of high density lipoprotein to low density lipoprotein cholesterol. fibrinogen and serum selenium concentrations. and adult height did not appreciably weaken the association. Adjustment for adult socioeconomic state resulted in a 16% decline in the association. The association was reduced to non-significance by adjustment for measures of prevalent cardiovascular illness. CONCLUSIONS--Socioeconomic state in childhood was significantly associated with ischaemic heart disease in middle aged men. Levels of risk factors measured at middle age did not account for this association. nor did adult height. Because childhood socioeconomic conditions precede the development of ischaemic heart disease the substantial impact of prevalent illness on the observed association suggests that ischaemic heart disease develops earlier in those with lower socioeconomic state during childhood.
Famine in southern Ethiopia 1985-6: population structure, nutritional state, and incidence of death among children, OBJECTIVE--To assess the effects of drought on mortality in children. DESIGN--Prospective epidemiological study forming part of nutritional monitoring during famine relief work. SETTING--24 Food distribution sites in Arero and Borana provinces in southern Ethiopia. PATIENTS--A monthly average of 14.173 and 5.334 children under 5 were examined in 1985 and 1986. respectively. Altogether 148.966 child months (105.872 for 1985 and 43.094 for 1986) were available for analysis. INTERVENTION--The families of all children were supplied with food each month. Basic medical care was also provided. MAIN OUTCOME MEASURE--Mortality in children under 5. RESULTS--A 40% increase in crude mortality was observed among children living in traditional and stable societies. The severe consequences were observed mainly among children living in relief shelters. where a threefold to fourfold increase in crude mortality was recorded among children. Increased childhood mortality was also associated with high prevalence of malnutrition. living in the most arid areas. and the dry season. A long period of food aid was needed to normalise the nutritional state. especially for children living in relief shelters. CONCLUSIONS--The most severe consequences of the widespread famine that occurred in the Arero and Borana provinces of southern Ethiopia during 1985-6 were seen among children living in relief shelters. Early food intervention may decrease the scale of migration and thus also reduce the severe consequences of a famine.
Management of "brittle" diabetes with a preprogrammable implanted insulin pump delivering intraperitoneal insulin, OBJECTIVE--Glycaemic control in a young woman with "brittle" diabetes. DESIGN--Use of a preprogrammable fully implanted pump (Infusaid) to deliver insulin intraperitoneally at variable rates. giving a total dose of about 60 units/24 h. SETTING--Endocrinology department in a teaching hospital. PATIENT--Thirty year old woman with 15 years' history of "brittle" diabetes. MAIN OUTCOME MEASURES--Glycated haemoglobin concentration; plasma glucose concentration. RESULTS--After implantation of the pump there was an immediate and sustained improvement in diabetic control. The patient's glycated haemoglobin concentration decreased from 15.2% to 9.2% over seven months. Her daily glucose concentrations were in the range 3.5-12 mmol/l. She has not been admitted to hospital since implantation of the pump. which was eight months before the time of writing. CONCLUSION--The implanted programmable intraperitoneal insulin pump may be of value in the management of patients with "brittle" diabetes in whom other attempts at glycaemic control have failed.
Aids for visual impairment, This article provides only a flavour of the type and range of aids available to the visually impaired person. Many other aids for leisure. learning. and daily living are illustrated in the RNIB equipment and games catalogue.
Magnetic resonance imaging in idiopathic retroperitoneal fibrosis: measurement of T1 relaxation time, Magnetic resonance imaging at 0.08 Tesla was performed in nine patients with proven idiopathic retroperitoneal fibrosis. A total of 11 scans was performed. Three patients were scanned before diagnosis; one of these also had two follow-up scans. A further six patients were scanned a variable time after diagnosis and treatment. On each scan. a periaortic soft-tissue mass was readily identified. the distribution corresponding to that seen on computed tomography. There was no difference in the mean T1 relaxation time of the mass between patients scanned before diagnosis and those scanned after treatment. However. the patient followed with serial scans showed a progressive reduction in the T1 value of the mass with time. Comparison with results obtained in patients with lymphoma suggests that the T1 values in retroperitoneal fibrosis are lower than in lymphoma. particularly non-Hodgkin's lymphoma.
The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues. III. Effects on lung function, The effect of single and fractionated doses of fast neutrons (42 MeVd----Be) on the early and late radiation responses of the pig lung have been assessed by the measurement of changes in lung function using a 133Xe washout technique. The results obtained for irradiation schedules with fast neutrons have been compared with those after photon irradiation. There was no statistically significant difference between the values for the relative biological effectiveness (RBE) for the early and late radiation response of the lung. The RBE of the neutron beam increased with decreasing size of dose/fraction with an upper limit value of 4.39 +/- 0.94 for infinitely small X-ray doses per fraction.
Fine needle aspiration biopsy in the diagnosis and management of fibroadenoma of the breast, Cytological and histological biopsies were obtained on 75 breast lumps clinically diagnosed as fibroadenomas. Of these. 95 per cent of lesions were benign. In 51 (68 per cent) confirmed as fibroadenomas histologically. cytology was benign in 78 per cent. but inadequate for diagnosis in 16 per cent. The remaining 24 lesions included three breast cancers and one lymph node with Hodgkin's disease. In this group cytology was inadequate for diagnosis in 54 per cent. including one breast cancer. No lesion with benign cytology was subsequently shown to be malignant. The study supports the view that clinical diagnosis and cytology are accurate in the diagnosis of benign breast disease of this type. Breast cancer may rarely present with the clinical features of a fibroadenoma and too few lesions have been studied to assess fully the performance of cytological biopsy in detecting these small mobile lesions. A non-excisional policy should therefore include prolonged follow-up and repeat biopsy.
Development and reversibility of T lymphocyte dysfunction in experimental obstructive jaundice, This study evaluates the effect of experimental biliary obstruction by bile duct ligation (BDL) and biliary drainage on cell-mediated immunity in Wistar rats. Immune status has been assessed by a mitogen stimulation test of T lymphocytes with phytohaemagglutinin. Animals were followed for up to 35 days after BDL. Regression analysis showed a significant negative correlation between lymphocyte function and the period of jaundice (correlation coefficient -0.57. P less than 0.001). Following BDL for 21 days. groups of animals had internal biliary drainage for 7. 14 and 28 days. and external drainage for 14 days. Compared with obstructed animals. 14 days internal drainage was required to improve lymphocyte function (P less than 0.05). Animals which had 14 days of external drainage had significantly lower lymphocyte stimulation than internal drainage animals (P less than 0.05). The results demonstrate that obstructive jaundice produces a progressive reduction of T lymphocyte function. This can be reversed by biliary drainage. internal drainage being more effective than external drainage.
Assessment of the biliary tract after liver transplantation: T tube cholangiography or IODIDA scanning, Biliary tract obstruction or anastomotic leakage are common problems following liver transplantation. In a sequential study. 31 patients with a liver transplant were investigated by 99mTc-IODIDA (IODIDA) scanning and T tube cholangiography (TTC) and the results were compared with clinical outcome. Seven patients had an extrahepatic biliary obstruction and one patient had a biliary leak. In the detection of biliary complications TTC and IODIDA scanning were similar in terms of sensitivity (63 per cent for both) but TTC had a better specificity (79 per cent versus 60 per cent) and accuracy (74 per cent versus 60 per cent) than IODIDA scanning. When liver function was taken into account. the diagnostic efficacy of both tests in patients with bilirubin levels of less than 200 mumol/l was similar. With levels greater than 200 mumol/l there was a greater number of false positive results with IODIDA scanning (12 per cent versus 54 per cent). The only significant biliary leak was clearly detected by TTC but not IODIDA scanning. TTC remains the more effective way of evaluating the biliary tract after transplantation. IODIDA scanning has limited value when bilirubin levels are elevated. but may provide additional information about blood supply. hepatocyte function and intrahepatic cholestasis.
Regional chemotherapy for colorectal liver metastases: a phase II evaluation of targeted hepatic arterial 5-fluorouracil for colorectal liver metastases, The results of systemic chemotherapy in patients with liver metastases from colorectal cancer remain dismal. Regional chemotherapy has been advocated as a method of improving the delivery of cytotoxic drugs to tumour. while minimizing systemic toxicity. The use of vasoactive agents to redistribute arterial blood flow towards tumour. and of biodegradable microspheres to slow tumour blood flow. have also been suggested as methods of further improving tumour exposure to drug. We present 21 patients who received intrahepatic arterial chemotherapy for colorectal liver metastases. Combined treatment (angiotensin II. albumin microspheres and 5-fluorouracil) was administered 4-6 weekly. and bolus 5-fluorouracil was given in the intervening weeks. Toxicity was minimal. Responses were seen in seven patients. Fewer than half of the deaths were from liver metastases; a quarter of the patients died from non-cancer-related causes. Survival was prolonged in the treated group compared with historical controls. These results suggest that this regimen has activity in patients with colorectal liver metastases.
Hepatic metastases from colorectal carcinoma: impact of surgical resection on the natural history, From 1960 to 1987. 1209 patients with colorectal liver metastases were recorded. and followed until 1 January 1990. In 242 cases the diagnosis was based on external imaging. whereas 967 patients had operative confirmation and staging of their liver disease. Three groups of patients were analysed: group 1 involved 921 cases. of whom 902 were deemed non-resectable whereas 19 could not be unequivocally classified. Only 21 patients lived for longer than 3 years. seven survived for 4 years. but there were no 5-year survivors. Group 2 comprised 62 highly selected patients who at laparotomy demonstrated resectable metastatic spread confined to the liver. but this was not treated mainly because of a formerly different therapeutic approach. These patients had a significantly longer median survival time (14.2 versus 6.9 months). but also failed to achieve 5-year survival. The 226 patients forming group 3 underwent hepatic resection with intent to cure. Nine of them had minimal macroscopic disease left. and 34 with all gross tumour removed had positive margins. Survival of patients with these 43 eventually non-radical resections followed an identical course as in group 2 (median survival 13.3 months. maximum 42 months). Of the 183 patients with potentially curative resection ten died after surgery (5.5 per cent). Actuarial 5 and 10-year survival rates in the remaining 173 patients were 40 and 27 per cent with 25 and seven patients alive at respective periods of time. Until 1 January 1990. 64 patients remained free from recurrent disease for up to 24 years. In three patients the tumour status at death was unclear. The other 106 patients developed definite cancer relapse. Nevertheless they demonstrated a prolongation of survival time by a median of 1 year when compared with the 43 non-radically resected patients or the 62 untreated patients with resectable liver-only metastases. and accomplished a maximum survival time of 8 years. Radical excision of colorectal secondaries to the liver therefore offers effective palliation. and in a small number the chance of a cure.
Free radical inhibition and serial chemiluminescence in evolving experimental pancreatitis, Oxygen free radical activity and inhibition were examined in experimental pancreatitis. Twenty-five rats were randomized to five groups: controls received intravenous saline. to simulate pancreatitis one group received intravenous caerulein (5 micrograms kg-1 h-1). and three groups received sodium taurocholate via the pancreatic duct (0.2 ml. 5 per cent). either alone. following allopurinol or immediately before superoxide dismutase. Chemiluminescence (a phenomenon based on the emission of light during chemical reactions and which is dependent on oxygen free radical activity) was used as an index of oxygen free radical activity and was measured in tissue samples at 5-min intervals following induction of pancreatitis. The control mean(s.e.m.) serum amylase level 1 h after induction of pancreatitis was 635(13) units. It was significantly elevated in caerulein-induced pancreatitis. 1833(118) units (P less than 0.05) and exceeded 3000 units in all taurocholate-infused animals. Mean(s.e.m.) chemiluminescence ranged from 44 (8) mV 100 mg-1 at time zero to 404(113) mV 100 mg-1 at 1 h in controls. In caerulein-induced pancreatitis mean(s.e.m.) chemiluminescence peaked at 20 min (1399(239) mV 100 mg-1. P less than 0.02) and in taurocholate-induced pancreatitis at 15 min (2316(95) mV 100 mg-1. P less than 0.004). Superoxide dismutase significantly reduced chemiluminescence and hyperamylasaemia in taurocholate groups. Increasing oxygen free radical activity paralleled evolving pancreatitis. Superoxide dismutase may have a therapeutic role in pancreatitis.
Gallstone clearance: a randomized study of extracorporeal shock wave lithotripsy and chemical dissolution, Following extracorporeal shock wave lithotripsy it is not known whether gallstone fragments are cleared from the gallbladder without the use of oral dissolution therapy. To assess the efficacy of lithotripsy and dissolution therapy. alone or in combination. 35 patients were randomized to one of three treatment groups: lithotripsy alone. dissolution therapy alone or combined lithotripsy and dissolution therapy. All patients had symptomatic gallstones. functioning gallbladders and comparable stone profiles. Lithotripsy was administered using a piezoelectric lithotripter. Dissolution therapy consisted of combined bile acid and terpene. Clearance was assessed at 6 months using ultrasound and oral cholecystography. Patients with less than 50 per cent stone clearance at the end of 6 months were considered failures. The number of patients with total or partial clearance in the combined group (7/10) was significantly greater than those in the lithotripsy alone group (0/10. P less than 0.002). Gallstone clearance following lithotripsy appears to be dependent upon dissolution therapy.
Association between extent of colonic mucosal sialomucin change and subsequent local recurrence after curative excision of primary colorectal cancer, Two interrelated studies were carried out to determine whether extent of sialomucin change adjacent to a primary colorectal carcinoma predicted local tumour invasiveness and risk of local recurrence. In the first. depth of tumour penetration was correlated with the length of the sialomucin band adjacent to 72 primary colorectal cancers. There was a significant (P less than 0.05) increase in sialomucin band length adjacent to tumours invading adjacent structures compared with those which had not (Mann-Whitney U test). although there was no overall correlation between depth of penetration. Duke's classification or degree of differentiation (Kruskal-Wallis test). A sialomucin band of greater than 3 cm was associated with a 70 per cent probability of adjacent structure (T4) invasion. These observations were then tested prospectively in a second study involving 256 patients to determine whether the presence of a greater than 3 cm sialomucin band could predict local recurrence. Presence of a greater than 3 cm sialomucin band was a significant (x2 = 7.12. d.f. = 1. P less than 0.001) and independent predictor of local but not distant recurrence. In addition both the interval to local recurrence and survival were significantly shorter if a greater than 3 cm sialomucin band was present. However the accuracy of greater than 3 cm sialomucin band as a predictive test for local recurrence was only 70 per cent. The extent of sialomucin adjacent to a primary colorectal cancer does provide a crude assessment of tumour invasiveness and risk of local recurrence.
Buerger's colour, Cyanosis of the hands and feet in Buerger's disease is known as 'Buerger's colour'. This characteristic skin colour is produced by the subpapillary venous plexus. The reactions of the subpapillary venous plexus in patients with Buerger's disease were observed by analysing the fractional blood volume of tissue using a visible light reflective spectrophotometer. Capillary morphology was investigated using an intravital video-microscopic system. Twenty-seven subjects. comprising 13 normals and 14 patients with Buerger's disease. were studied. In the nailbeds of patients with Buerger's disease. an increase in the number of loops. cyanotic colour change and dilatation were observed. In this condition there was incompetence of venular tonus and regurgitation at venular valves. Buerger's colour is probably due to excessive congestion of venous blood in the subpapillary venous plexus which is produced by these mechanisms.
Cardiovascular response of a continuous variable rate alfentanil infusion for abdominal aortic surgery, A prospective study was undertaken to determine the cardiovascular response of a continuous alfentanil infusion during abdominal aortic surgery (AAS). Each subject (n = 20) received a beta-blocking drug preoperatively. and was premedicated with oral lorazepam. Anaesthesia was induced with alfentanil 50 micrograms.kg-1 and thiopentone 3 mg.kg-1. and was maintained with a variable rate infusion of alfentanil and 66 per cent nitrous oxide in oxygen. During the infusion. boluses of alfentanil. 7.5 micrograms.kg-1. were administered to maintain heart rate and blood pressure within 20 per cent of awake baseline values. Haemodynamic stability during surgery was achieved with infusion rates varying between 0.5 and 2.5 micrograms.kg-1. which resulted in mean alfentanil serum concentrations ranging from 186 +/- 53 to 315 +/- 98 ng.ml-1. The mean cumulative alfentanil dose was 15.4 +/- 6.2 mg.patient-1 for surgery which lasted an average of 141 +/- 41 min. Throughout surgery. no patient required inhalational anaesthetic agents or vasoactive drugs. Fifteen of the 20 patients had perioperative Holter monitoring. No myocardial ischaemia was detected during the intraoperative period. However. there was a 33 per cent incidence of myocardial ischaemia on the first postoperative day. There were no myocardial infarcts and no deaths. We conclude that in beta-blocked patients undergoing aortic reconstructive surgery. a variable rate alfentanil infusion administered with 66 per cent nitrous oxide provides anaesthesia characterized by good haemodynamic control without the need for supplemental agents or vasoactive drugs.
Lead, This article reviews historical and current uses of lead and sources of absorbed lead. such as water. lead-based paint. cookware. and bullet wounds. The means of absorption. collection of specimens. quantification methods. and effects of lead toxicity are discussed.
The importance of calcium regulation in toxic cell injury. Studies utilizing the technology of digital imaging fluorescence microscopy, The regulation of ions within the cell is of critical importance in both acute and chronic toxicology. Recently. new methods have been developed for measuring such changes in living cells and correlating them with studies of structure. function. and biochemistry. A major revolution has occurred from the linkage between the computer and the light microscope. which has resulted in the use of digital imaging fluorescence microscopy and video intensification microscopy coupled with image analysis. These methods have already yielded much additional information and it is anticipated that their further application by pathologists and toxicologists will continue to uncover the important role of ion deregulation and toxic cell injury.
Patterns of dyspepsia in patients with no clinical evidence of organic diseases, We studied 2000 dyspeptic patients with no obvious signs of organic disease at their first examination. in order to (1) verify how many diagnoses of idiopathic dyspepsia had really been made after exhaustive diagnostic procedures and (2) evaluate the diagnostic power of the symptoms in distinguishing organic from idiopathic dyspepsia. This latter was considered only when no structural abnormalities were found. In all the other cases. a distinction was made between "related" and "associated" organic dyspepsia according to whether or not there was a certain relationship between the abnormalities and the dyspeptic symptoms. The patients were referred to us as follows: (1) spontaneously. (2) sent by physicians collaborating with us. (3) referred to our open access endoscopic service. The results show the frequency of idiopathic dyspepsia was 26%. whereas associated structural abnormalities were present in 45.4%. Obvious organic causes of dyspepsia were seen in 28.6% (24% benign and 4.6% malignant diseases). When considered separately. no symptom alone allows a correct diagnosis. The simultaneous evaluation of the symptoms with linear discriminant analysis distinguishes between idiopathic and organic dyspeptic patients in about 70% of the cases. A higher discrimination percentage in about 70% of the cases. A higher discrimination percentage could probably be obtained using a wider range of clinical parameters and/or a more complex statistical analysis of the interrelationships which exist between the clinical symptoms and the final diagnosis.
Antimony and glass pH electrodes can be used interchangeably in 24-hour studies of gastric acidity, Antimony and glass pH electrodes show almost identical experimental errors in continuously measuring buffer solutions at constant temperature over 24 hr. These errors are lower than the nominal quantization error of the instruments and are not properly described by the 24-hr drift determination. The addition of food particles to the solutions can induce severe reading artifacts. The longer response time reported in vitro of antimony electrodes when moving from pH 1 to pH 7 (3.4 sec vs 0.8 sec with glass electrodes) is irrelevant during in vivo pH-metry studies. because we found that the greatest absolute difference between raw fast acquired (4-6 sec) consecutive pH readings of two commonly used devices was 0.7 pH units in circadian profiles obtained from 413 subjects with various clinical conditions. In our in vivo studies. gastric acidity was monitored continuously with two side-by-side minielectrodes. which were variously combined (antimony-glass. A-G; antimony-antimony A1-A2; glass-glass. G1-G2) and applied on groups of 27 subjects matched for clinical condition. The 24-hr pH means and the 24-hr [H+] means calculated from the acidity profiles obtained with the three electrode combinations. lie on the identity line in each group. Using the Bland-Altman technique for assessing measurement agreement. the differences between the 24-hr pH means and the 24-hr [H+] means obtained with the three combined systems are similar (P = .903 and P = 0.824. respectively) and their 95% confidence limits are comprised within the range (+/-) of the reading error of the measuring systems (namely. +/- 0.3 pH units and +/- 12 mmol/liter in terms of [H+]).
Cigarette smoking, gastric acidity and peptic ulceration. What are the relationships, The influence of cigarette smoking on intragastric acidity was assessed in duodenal ulcer patients in symptomatic remission and in healthy volunteers in a retrospective study. Continuous 24-hr pH recordings in 150 nonsmokers and 174 smokers receiving placebo treatment were compared. Daytime intragastric acidity was higher in smokers with a median pH (interquartile range) of 1.56 (1.34-1.80) than in nonsmokers. who had a median pH of 1.70 (1.45-1.97) (P less than 0.001). There was no difference in 24-hr and nighttime median pH between the two groups. The small difference in daytime intragastric acidity in smokers and nonsmokers is unlikely to account for the increased prevalence of peptic ulcer disease in smokers. The analysis of smoking status in duodenal ulcer patients and healthy controls and males and females supports the general trend towards higher daytime acidity in smokers. Again. no differences in pH during the 24-hr or night period were found between the groups. The epidemiological and clinical correlation between smoking and duodenal ulcer disease is not adequately explained by increased intragastric acidity.
Gastric mucosal PGE2 levels in gastric non-ulcer and ulcer patients with chronic renal failure or without renal diseases and in healthy subjects, PGE2-like immunoactivity in mucosal specimens from gastric corpus and antrum was measured in individuals with chronic uremia or without renal diseases in absence or presence of gastric ulcerations and in healthy subjects. Regardless the group of patients. compared to normal mucosa. a significant decrease in PGE2-like immunoactivity (50-70%) was found in mucosa from atrophic. but not from superficial gastritis. Whenever patients of the control group or patients with renal diseases suffered from ulcers. PGE2-like immunoactivity. compared to nonulcer subjects. revealed a decrease of about 60-70% in the nonulcerated mucosa. Compared to nonulcerated mucosa. the tissue of the ulcer rim in all patients with gastric ulcer showed a relative increase in PGE2-like immunoactivity. eg. PGE2-like immunoactivity was twice as high in tissue from the ulcer rim. The output of PGE2-like immunoactivity into the gastric juice of subjects without renal diseases was comparable to that found in patients with chronic uremia in both basal and pentagastrin-stimulated conditions. We therefore conclude that gastric mucosal formation is probably not influenced by chronic uremia.
From disease to delirium: managing the declining elderly patient, Many geriatric patients have concurrent physical and psychiatric illnesses. but at times it may be difficult to determine which is primary. Delirium. a transient syndrome that presents with psychiatric symptoms. is usually the manifestation of an organic disorder and. if undetected and untreated. can be fatal. Clinicians. therefore. must learn to recognize the syndrome. search diligently for the underlying etiology. and treat accordingly.
Minimizing urinary incontinence in the nursing home, In the nursing home. urinary incontinence is a common problem that all too often is treated as an irremediable "problem of aging" by physicians. nurses. and patients. Its etiologies are numerous. as are approaches to treatment in this setting. However. with a thoughtful approach to diagnosis and care. the primary care physician may be able to determine which patients. with which forms of urinary incontinence. will benefit from specific therapies.
Tardive dyskinesia: managing a common neuroleptic side effect, Neuroleptics are useful medications for the treatment of psychosis and severe behavioral disturbances in the elderly. Unfortunately. older patients are at a high risk of developing deleterious side effects from these medications. especially persistent tardive dyskinesia (TD). Diagnosis. risk factors. and cause and treatment of TD are discussed. It is important to do a careful assessment as to the indications for neuroleptic use. monitor closely for the development of TD and other side effects. and work closely with the patient and family in making decisions about neuroleptic use.
Relation of Helicobacter pylori to the human gastric mucosa in chronic gastritis of the antrum, The spatial relations between bacteria and the affected tissues can indicate pathogenic mechanisms. This study was undertaken to define the spatial relation of Helicobacter pylori to the human gastric mucosa. Antibodies against gastric mucus and ruthenium red were used to stabilise the glycoprotein structure of the mucus and glycocalyces in antral biopsy specimens from eight patients infected with H pylori. The location of organisms and ultrastructural features were assessed using systematic scanning and transmission electron microscopy: 92 (2)% (mean (SE] of H pylori were in the pit mucus. and 7 (3)% were in the surface mucus; 60 (12)% of H pylori were close to epithelial cells. with only 5 (2)% located near the epithelial intercellular junctions. Fine filamentous strands extended between organisms and nearby epithelial cells. with few organisms in membrane to membrane contact. H pylori were not observed between. beneath. or within cells of the gastric mucosa. The preferred location of H pylori in the gastric antrum is within the pit mucus close to the epithelial cell surface. with no evidence that they have a direct toxic effect on the mucosa.
Evaluation of 13C-urea breath test in the detection of Helicobacter pylori and in monitoring the effect of tripotassium dicitratobismuthate in non-ulcer dyspepsia, Sixty nine patients with non-ulcer dyspepsia have been studied with endoscopy. biopsy. quick urease (CLO) test. Helicobacter pylori culture. and the 13C-urea breath test before and after treatment with tripotassium dicitratobismuthane (DeNol) two tablets twice daily for four weeks. Symptoms of non-ulcer dyspepsia were recorded using a standard questionnaire. Using H pylori culture as the gold standard. the sensitivity of the 13C-urea breath test was 90%. the specificity 98.6%. and the accuracy 94.8% with a positive predictive value of 98.2% and a negative predictive value of 92.5%. Conversion rate from H pylori positive to negative status after treatment with tripotassium dicitratobismuthate was 17.9%. Symptoms of non-ulcer dyspepsia improved appreciably after treatment irrespective of H pylori status. The 13C-urea breath test is an accurate research tool suitable for serial testing and population surveys.
Paf-acether synthesis by Helicobacter pylori, Clinical studies suggest that Helicobacter pylori may play a role in the pathogenesis of gastroduodenal ulcers in man but direct evidence of mucosal injury by this microorganism is still lacking. Paf-acether (paf) causes a number of disorders including ischaemic bowel necrosis and gastroduodenal ulceration. Since paf is produced by Escherichia coli. we investigated whether it could be synthesised by H pylori. Five H pylori isolates were collected from antral biopsy specimens from patients with gastritis and duodenal ulcer and cultured with selective antibiotics. Colonies obtained from both blood agar and brucella broth medium were used. Paf was determined by platelet aggregation assay after ethanolic extraction and subsequent purification by high performance liquid chromatography. Paf was detected in H pylori in blood agar plates (680 (390) pg paf/1 x 10(6) organisms) but not in bacteria cultured on brucella broth medium. Supplementation of the latter medium with lyso paf and acetyl-CoA. two paf precursors present in high amounts in the mammalian intestine. induced paf production in three of five isolates. The platelet aggregating material extracted from H pylori exhibited biological and physiochemical characteristics identical to those of paf released from eukaryotic cells. These findings suggest that H pylori may add to the local production of paf in inflamed gastric mucosa.
Crohn's disease in the city of Derby, 1951-85, An epidemiological survey of Crohn's disease in the city of Derby showed that the incidence of the condition increased from 0.7/10(5) per year between 1951 and 1955 to 6.67/10(5) per year between 1981 and 1985 but seemed to reach a plateau between 1976 and 1985. Large bowel Crohn's disease was more common in patients presenting aged 60-79 years than in those aged 20-39 years. The increase in incidence was not solely due to the detection of milder disease. There was no evidence that the Asian (Indian subcontinent) population of Derby was resistant to the development of Crohn's disease.
Disposition of 5-aminosalicylic acid by olsalazine and three mesalazine preparations in patients with ulcerative colitis: comparison of intraluminal colonic concentrations, serum values, and urinary excretion, To compare the disposition of 5-aminosalicylic acid (5-ASA) and its acetylated metabolite during treatment with olsalazine and mesalazine. 14 patients with inactive ulcerative colitis were randomly assigned to olsalazine (1 g twice daily) and the mesalazines. Asacol (800 + 400 + 800 mg daily). Pentasa (750 + 500 + 750 mg daily). and Salofalk (750 + 500 + 750 mg daily) in a crossover design trial so that all received each drug for seven days. Intraluminal colonic concentrations of 5-ASA were estimated after five days by the method of equilibrium in vivo dialysis of faeces. A predose serum sample and a 24 hour urine collection were obtained on day seven. The 5-ASA and acetyl-5-aminosalicylic acid (Ac-5-ASA) values were determined by high performance liquid chromatography. Olsalazine almost doubled the colonic concentrations (mean 23.7 (SEM) (1.9) mmol/l) of its therapeutically active ingredient (5-ASA) compared with equimolar doses of Pentasa (12.6 (2.2) mmol/l; p less than 0.0003) and Salofalk (15.0 (2.0) mmol/l; p less than 0.003). At the same time. olsalazine treatment was associated with lower serum concentrations and urinary excretions (p less than 0.05) of 5-ASA and Ac-5-ASA compared with the mesalazine preparations. The low systemic load of 5-ASA provided by olsalazine reduces the potential risk of nephrotoxicity during long term treatment.
Role of ultrasound guided fine needle aspiration biopsy in the diagnosis of hepatocellular carcinoma, In 170 cases of hepatocellular carcinoma. ultrasound showed a high sensitivity in identifying focal liver lesions. Fine needle aspiration biopsy guided by ultrasound yielded a pathological diagnosis in the majority of cases. The advantages of this technique. its high diagnostic yield and low cost. render the older technique of blind percutaneous biopsy using a coarse needle obsolete. Laparoscopy retains its essential role in selected cases. Complementary use of fine needle aspiration biopsy under ultrasound guidance and laparoscopy assures the highest rate of diagnostic accuracy in hepatocellular carcinoma. We confirm the poor sensitivity of alpha fetoprotein.
Lipid peroxidation and hepatic antioxidants in alcoholic liver disease, The generation of hepatic liver peroxidation by free radicals has been proposed as a mechanism for ethanol induced hepatotoxicity. To investigate this hypothesis. lipid extracts from hepatic needle biopsy specimens from alcoholic subjects were examined for evidence of lipid peroxidation by measuring total conjugated dienes by derivative spectroscopy and. after hydrolysis of hepatic lipid extract and reverse phase high performance liquid chromatography. the molar ratio between a diene-conjugated linoleic acid isomer (18:2 (9.11)) and the parent linoleic acid isomer (18:2(9.12)). Changes were related to hepatic histology. iron deposition. glutathione and vitamin E values. Derivative spectroscopy minima suggestive of diene conjugation were identified at 233 and 242 nm and correlated weakly. suggesting these two minima may represent different classes of lipid dienes. There was a weak relation with inflammatory histological changes in the biopsy specimen but no correlation with hepatic iron grade. glutathione. or vitamin E lipid ratio. The proportion of 18:2(9.11) linoleic acid in hepatic lipids correlated significantly with inflammatory histological features and inversely with hepatic glutathione. Furthermore. hepatic glutathione was lower in biopsy specimens with greater iron staining. The ratio of vitamin E to lipid was not related to histological group. inflammation. or iron grade. These findings suggest that excess alcohol consumption leads to hepatic inflammation and lipid peroxidation.
Monitoring enzyme replacement treatment in exocrine pancreatic insufficiency using the cholesteryl octanoate breath test, The cholesteryl-14C-octanoate breath test was used to monitor the intraluminal enzymatic activity of pancreatin preparations in six patients with severe pancreatic insufficiency. Conventional enzyme replacement. with cimetidine as an adjunct. was compared to supplementation with enteric coated microspheres. In healthy control subjects. 14CO2 excretion rose rapidly and peaked at 90-120 minutes; mean (SD) cumulative recovery at four hours was 51 (8)%. In patients with pancreatic insufficiency on no treatment mean (SD) cumulative recovery was only 6 (4)%. After pancreatin. with previous administration of cimetidine. it increased to 27 (11)% with a time course resembling that in controls. With 2 mm enteric coated microspheres. 14CO2 excretion did not rise significantly before 120 minutes and cumulative recovery after four hours was 15 (11)%. In a control study. 2 mm radio-opaque microspheres did not empty from the stomach until two hours after ingestion. The results suggest that the cholesteryl octanoate breath test can be successfully used to monitor the intraluminal enzymatic activity after treatment with different forms of enzyme replacement in pancreatic insufficiency. In contrast to treatment with conventional pancreatin and cimetidine as an adjunct. 2 mm enteric coated microspheres did not show in vivo enzymatic activity until two hours after administration.
Activity of type 1 erythrocyte complement receptors in uremia and after renal transplantation, The effect of uremia on the activity of the erythrocyte complement receptors type 1 (CR1). and the changes occurring after renal transplantation. were studied. The complement receptor activity was measured by immune adherence utilizing a rosette technique. Patients with terminal kidney failure on the hemodialysis program exhibited significantly lower values of the erythrocyte CR1 activity in comparison with healthy controls. The circulating immune complexes did not affect erythrocyte CR1 activity. After successful renal transplantation. irrespective of the immunosuppressive program used. a significant increase in erythrocyte CR1 activity appeared. similar to control group values. However. the activity of erythrocyte CR1. in the graft recipients under cyclosporin A treatment. was significantly higher than in the patients receiving azathioprine with prednisone. Therefore. it is possible that cyclosporin A. transported in the erythrocytes. modifies the complement receptor function.
Comparison of two methods for the estimation of urea kinetics and introduction of a third simplified method, It has been claimed that computed urea kinetic (UK) modelling in hemodialysed patients. for the estimation of protein intake. leads to an overestimation of protein catabolic rate (PCR). In the present study. three different methods of kinetic modelling for the determination of PCR and Kt/V are compared in 24 patients. The first method was the direct quantification method (DDQ) based on the collection of all urea eliminated from the body. The first computed method (ICMI) was the urea kinetic modelling method as described by Sargent. Dialyzer clearances were measured directly and not estimated by theoretical extrapolation. The second computed method (ICMII) is based on the indirect calculation of urea distribution volume (Vu). according to Watson. and of dialyzer clearances from this Vu and from pre- and post-dialysis urea concentrations. All three methods resulted in PCR's that were not significantly different (DDQ: 1.03 +/- 0.19; ICMI: 1.04 +/- 0.22; ICMII: 1.08 +/- 0.25 mg/Kg BW.24 hrs; p greater than 0.05). When the results were correlated. the following results were obtained: ICMI vs ICMII: r = 0.89. p less than 0.001; ICMI vs DDQ: r = 0.68. p less than 0.01; DDQ vs ICMII: r = 0.78. p less than 0.001. Intermutual comparison of Kt/V values resulted in virtually identical results. especially when comparing ICMI and ICMII. where the regression line equalled the identity line. In conclusion. all methods seem equally reliable in determining mean PCR and Kt/V. Our data. obtained with directly measured dialyzer urea clearances. do not confirm the earlier held opinion that computed modelling results in an overestimation of PCR.
Prerandomization: an alternative to classic randomization. The effects on recruitment in a controlled trial of arthroscopy for osteoarthrosis of the knee, Possibly the greatest threat to the success of a randomized clinical trial is the inability to recruit an adequate number of subjects. Concern that the randomized clinical trial will adversely affect the physician-patient relationship is the most common reason for physicians' reluctance to enroll patients in such trials. We report a modification of a prerandomized design. first described by Zelen. which was implemented in a randomized clinical trial of arthroscopy for patients who had osteoarthrosis of the knee. The method was associated with a sixfold increase in the rate of accrual of patients as compared with the use of a classic randomization trial. We propose the design as a potential solution to the problem of recruitment of subjects. particularly for clinical studies.
Function after amputation, arthrodesis, or arthroplasty for tumors about the knee, We studied the function of twenty-two patients who had had a malignant skeletal tumor adjacent to the knee. An above-the-knee amputation was done in seven; a resection arthrodesis. in nine; and a replacement arthroplasty. in six. The patients all walked at a similar speed (sixty-one to sixty-six meters per minute). which is slower than normal (eighty meters per minute). They all walked with comparable efficiency at three velocities: the mean consumption of oxygen was 0.210 milliliter per kilogram of body weight per meter at free velocity. 0.215 milliliter per kilogram of body weight per meter when they walked 25 per cent faster. and 0.211 to 0.240 milliliter per kilogram of body weight per meter when they walked 50 per cent faster. The three groups of patients and a normal control group consumed oxygen at similar rates. The patients who had had an amputation were very active. and they were the least worried about damaging the affected limb. but they had difficulty walking on steep. rough. or slippery surfaces. The patients who had had an arthrodesis had a more stable limb and performed the most demanding physical work and recreational activities. but they had difficulty sitting. The patients who had had an arthroplasty led sedentary lives and were the most protective of the limb. but they were the least self-conscious about the limb.
Subtle injuries of the Lisfranc joint, In fifteen patients. a subtle injury of the Lisfranc joint (tarsometatarsal articulation) was found. The lesion was defined as a diastasis of two to five millimeters between the bases of the first and second metatarsals. as seen on anteroposterior radiographs. There often was a long delay between injury and diagnosis. Eight patients were treated with a below-the-knee cast only. three had treatment with a cast and then tarsometatarsal arthrodesis. two had no initial treatment but later had arthrodesis. and two had open reduction and internal fixation. The duration of follow-up ranged from two to thirteen years after the diagnosis. There was no correlation between the severity of the diastasis and the patient's functional result. Marked disability and pain persisted in seven patients. and six of them had flattening of the longitudinal arch. Maintenance of the longitudinal arch usually was associated with a better functional outcome. When a patient has a subtle injury of the Lisfranc joint. weight-bearing lateral radiographs of both feet are needed to identify flattening of the longitudinal arch. Such radiographs should be made routinely in the evaluation of all injuries of the foot that may involve the Lisfranc joint.
Shielding of the patient's gonads during intramedullary interlocking femoral nailing, Levels of exposure to radiation were recorded at sixty sites in fifteen patients during intramedullary interlocking femoral nailing. Radiation film dosimeters were placed at four gonadal sites on each subject. A standard male-gonad cup or a pelvic drape of 0.5-millimeter-thick lead-equivalent was put in place to shield the gonads. A second set of four dosimeters was placed external to the shield to approximate unprotected exposure. The total duration of the fluoroscopy averaged five minutes (range. thirty seconds to fourteen minutes). The total exposure to radiation external to the shield was 35 +/- 34 millirems at the male gonadal sites and 17 +/- 11 millirems at the female gonadal sites. With use of the gonadal shield. exposure to radiation was not measurable in thirteen of the fifteen patients. The differences between the exposures of the shielded and unshielded sites to radiation were statistically significant (p less than 0.001). The highest level of gonadal exposure was found with the treatment of proximal femoral fractures and with the use of statically locked nails. Regardless of the conditions. and for all types of fractures and locations. our results demonstrated that gonadal shielding is justified.
The Van Nes tibial rotationplasty. A functionally viable reconstructive procedure in children who have a tumor of the distal end of the femur, Twelve patients who had a malignant tumor of the distal end of the femur were treated with a Van Nes tibial rotationplasty. The survival rates were comparable with those for above-the-knee amputees and patients who had an endoprosthetic replacement. The results of functional testing showed that these patients performed as well as those who had endoprosthetic replacement and better than those who had above-the-knee amputation. Rotationplasty is therefore a favorable alternative to amputation or endoprosthetic replacement. either as a primary or as a salvage procedure.
Developmental adaptations in cytosolic phosphate content and pH regulation in the sheep heart in vivo, This study examines adaptations in myocardial cytosolic phosphate content and buffering capacity that occur in vivo as a function of development. Phosphate metabolites were monitored in an open chest sheep preparation using a 31P magnetic resonance surface coil over the left ventricle. Newborn lambs (aged 4-9 d. n = 5) underwent exchange transfusion with adult blood to reduce blood-borne 2.3-diphosphoglycerate contamination of the heart monophosphate and phosphomonoester resonances. thus allowing determination of these phosphate concentrations. The blood-exchanged newborns and mature controls (aged 30-60 d. n = 5) were infused with 0.4 N hydrochloric acid to decrease pH from greater than 7.35 to less than 7.00. Simultaneously. intracellular and extracellular pH were determined from the chemical shifts of the respective phosphate peaks and compared to arterial blood pH. Findings were as follows: (a) diphosphoglycerate contribution to the cardiac spectrum was found to be negligible. (b) significant decreases in cytosolic phosphate (P less than 0.03) and phosphomonoester (P less than 0.01) content occurred with maturation. and (c) large decreases in extracellular pH (greater than 0.5 U) in both groups were similarly associated with only small changes in intracellular pH (less than 0.1 U). Change in cytosolic phosphate content implies that alterations occur in the phosphorylation potential with resulting effects on regulation of myocardial respiration. and cardiac energetics.
An adherent subline of a unique small-cell lung cancer cell line downregulates antigens of the neural cell adhesion molecule, Small-cell lung cancer (SCLC) lines are distinguished from non-small-cell lung cancer (NSCLC) lines by their growth in floating aggregates. in contrast to the adherent monolayers formed by NSCLC cells in culture. Of 50 well-characterized SCLC lines recently described by the National Cancer Institute (NCI)-Navy Medical Oncology Branch. only four variant cell lines (SCLC-v) grew as adherent monolayers. One line. NCI-H446. was unique in growing long-term with coexisting floating and surface adherent subpopulations. We have physically segregated these two populations over many passages in vitro to enrich for relatively pure cultures of floating and adherent cells. No differences in c-myc expression. keratin pattern. or cytogenetic appearance were found between the adherent and floating sublines. However. expression of the neuroendocrine marker neuron-specific enolase in the floating cells was three times that found in the adherent cells. The floating subline also had much greater surface expression of neuroendocrine tumor antigens detected by monoclonal antibodies UJ13A and HNK-1. which have been recently shown to detect the neural cell adhesion molecule (NCAM) on SCLC cells. Two other adherent SCLC-v lines were also found to be unreactive with UJ13A and HNK-1. generalizing the association between NCAM expression and the growth of most SCLC cultures as floating aggregates. In conclusion. we have an interesting model to study expression of NCAM as related to the adhesive properties of SCLC cells.
Basis for defective proliferation of peripheral blood T cells to anti-CD2 antibodies in primary Sjogren's syndrome, Anti-CD2-induced T cell proliferation was analyzed in the peripheral blood samples of 31 primary and 8 secondary untreated Sjogren's syndrome patients. Anti-CD2-stimulated PBMC proliferation was very low in about one-third of primary Sjogren's syndrome samples. despite the number of CD2+ cells being similar in primary and secondary Sjogren's syndrome and normal PBMC samples. The depressed response to anti-CD2 was mainly found in anti-Ro+/La+ patients. Experiments on purified T cells demonstrated that a defect at the T cell level was responsible for the anti-CD2 unresponsiveness. Cell proliferation failure was associated with poor IL-2 and IL-2 receptor mRNA expression and. consequently. IL-2 and IL-2 receptor synthesis. Since defective anti-CD2-induced mitogenesis could be reversed by phorbol myristate acetate. but not calcium ionophore A23187. it is probably correlated with impaired protein kinase C activation. Comparison of anti-CD2-triggered PBMC proliferation in treated and untreated patients and a long-term study of nine patients showed that the defect is a stable characteristic in primary Sjogren's syndrome patients. but that it can be reversed by pharmacological immunosuppression.
Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. Effects on coronary resistance, contractility, and relaxation, We compared the activity and physiologic effects of cardiac angiotensin converting enzyme (ACE) using isovolumic hearts from male Wistar rats with left ventricular hypertrophy due to chronic experimental aortic stenosis and from control rats. In response to the infusion of 3.5 X 10(-8) M angiotensin I in the isolated buffer perfused beating hearts. the intracardiac fractional conversion to angiotensin II was higher in the hypertrophied hearts compared with the controls (17.3 +/- 4.1% vs 6.8 +/- 1.3%. P less than 0.01). ACE activity was also significantly increased in the free wall. septum. and apex of the hypertrophied left ventricle. whereas ACE activity from the nonhypertrophied right ventricle of the aortic stenosis rats was not different from that of the control rats. Northern blot analyses of poly(A)+ purified RNA demonstrated the expression of ACE mRNA. which was increased fourfold in left ventricular tissue obtained from the hearts with left ventricular hypertrophy compared with the controls. In both groups. the intracardiac conversion of angiotensin I to angiotensin II caused a comparable dose-dependent increase in coronary resistance. In the control hearts. angiotensin II activation had no significant effect on systolic or diastolic function; however. it was associated with a dose-dependent depression of left ventricular diastolic relaxation in the hypertrophied hearts. These novel observations suggest that cardiac ACE is induced in hearts with left ventricular hypertrophy. and that the resultant intracardiac activation of angiotensin II may have differential effects on myocardial relaxation in hypertrophied hearts relative to controls.
The core polypeptide of cystic fibrosis tracheal mucin contains a tandem repeat structure. Evidence for a common mucin in airway and gastrointestinal tissue, A cystic fibrosis trachea cDNA library was constructed and probed with a synthetic oligonucleotide containing a consensus sequence recently identified in human intestinal mucin. One of the isolated clones. AMN-22. has been characterized extensively. The cDNA sequence of this 884-bp fragment was determined. and revealed a tandem repeat structure rich in threonine and proline residues. The repeating sequence of AMN-22 was similar but not identical to that determined for gut mucin. When examined by Northern analysis. the mRNA hybridizing to AMN-22 is extremely polydisperse in cystic fibrosis (CF) trachea. with apparent message length varying from approximately 2 kb to greater than 10 kb. A similar pattern was observed. with less abundant message. in CF bronchiectatic lung parenchyma. The lung cDNA hybridized to a similarly polydisperse message in ulcerative colitis colon RNA. but did not hybridize to control RNA from U937 lymphoma cells or stomach RNA. Pedigree analysis of restriction digests of genomic DNA revealed a pattern indicating a single polymorphic locus for the mucin gene expressed in the lung and the intestine. Southern analyses of human:mouse somatic cell hybrid cell lines allow a chromosomal localization for the mucin gene to human chromosome II. within the region 11p13-11pTer. Taken together. these data demonstrate that a polymorphic gene encodes a mucin core polypeptide expressed in both lung and intestine.
Glucagon, catecholamine and pancreatic polypeptide secretion in type I diabetic recipients of pancreas allografts, Successful pancreas transplantation in type I diabetic patients restores normal fasting glucose levels and biphasic insulin responses to glucose. However. virtually no data from pancreas recipients are available relative to other islet hormonal responses or hormonal counterregulation of hypoglycemia. Consequently. glucose. glucagon. catecholamine. and pancreatic polypeptide responses to insulin-induced hypoglycemia and to stimulation with arginine and secretin were examined in 38 diabetic pancreas recipients. 54 type I diabetic nonrecipients. and 26 nondiabetic normal control subjects. Glucose recovery after insulin-induced hypoglycemia in pancreas recipients was significantly improved. Basal glucagon levels were significantly higher in recipients compared with nonrecipients and normal subjects. Glucagon responses to insulin-induced hypoglycemia were significantly greater in the pancreas recipients compared with nonrecipients and similar to that observed in control subjects. Glucagon responses to intravenous arginine were significantly greater in pancreas recipients than that observed in both the nonrecipients and normal subjects. No differences were observed in epinephrine responses during insulin-induced hypoglycemia. No differences in pancreatic polypeptide responses to hypoglycemia were observed when comparing the recipient and nonrecipient groups. both of which were less than that observed in the control subjects. Our data demonstrate significant improvement in glucose recovery after hypoglycemia which was associated with improved glucagon secretion in type I diabetic recipients of pancreas transplantation.
Lack of 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase in fibroblasts from a child with urinary excretion of 3 beta-hydroxy-delta 5-bile acids. A new inborn error of metabolism, Cultured fibroblasts were shown to be capable of catalyzing the conversion of 7 alpha-hydroxy-cholesterol to 7 alpha-hydroxy-4-cholesten-3-one. an important reaction in bile acid synthesis. The apparent Km was approximately 7 mumol/liter and Vmax varied between 3 and 9 nmol/mg protein per h under the assay conditions used. The assay was used to investigate fibroblasts from a patient who presented with a familial giant cell hepatitis and who was found to excrete the monosulfates of 3 beta. 7 alpha-dihydroxy-5-cholenoic acid and 3 beta. 7 alpha. 12 alpha-trihydroxy-5-cholenoic acid in urine (Clayton. P. T.. J. V. Leonard. A. M. Lawson. K. D. R. Setchell. S. Andersson. B. Egestad. and J. Sjovall. 1987. J. Clin. Invest. 79:1031-1038). In addition 7 alpha-hydroxy-cholesterol was found to accumulate in the circulation. Cultured fibroblasts from this boy were completely devoid of 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase activity. Fibroblasts from his parents had reduced activity. compatible with a heterozygous genotype. The results provide strong evidence for the suggestion that this patient's liver disease was caused by a primary defect in the 3 beta-hydroxy-delta 5-C27-steroid dehydrogenase/isomerase involved in bile acid biosynthesis.
Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus. Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism, To assess the mechanisms responsible for increased gluconeogenesis in noninsulin-dependent diabetes mellitus (NIDDM). we infused [3-14C]lactate. [3-13C]alanine. and [6-3H]glucose in 10 postabsorptive NIDDM subjects and in 9 age- and weight-matched nondiabetic volunteers and measured systemic appearance of alanine and lactate. their release from forearm tissues. and their conversion into plasma glucose (corrected for Krebs cycle carbon exchange). Systemic appearance of lactate and alanine were both significantly greater in diabetic subjects (18.2 +/- 0.9 and 5.8 +/- 0.4 mumol/kg/min. respectively) than in the nondiabetic volunteers (12.6 +/- 0.7 and 4.2 +/- 0.3 mumol/kg/min. respectively. P less than 0.001 and P less than 0.01). Conversions of lactate and alanine to glucose were also both significantly greater in NIDDM subjects (8.6 +/- 0.5 and 2.4 +/- 0.1 mumole/kg/min. respectively) than in nondiabetic volunteers (4.2 +/- 0.4 and 1.8 +/- 0.1 mumol/kg/min. respectively. P less than 0.001 and P less than 0.025). The proportion of systemic alanine appearance converted to glucose was not increased in NIDDM subjects (42.7 +/- 1.9 vs. 44.2 +/- 2.9% in nondiabetic volunteers). whereas the proportion of systemic lactate appearance converted to glucose was increased in NIDDM subjects (48.3 +/- 3.8 vs. 34.2 +/- 3.8% in nondiabetic volunteers. P less than 0.025); the latter increased hepatic efficiency accounted for approximately 40% of the increased lactate conversion to glucose. Neither forearm nor total body muscle lactate and alanine release was significantly different in NIDDM and nondiabetic volunteers. Therefore. we conclude that increased substrate delivery to the liver and increased efficiency of intrahepatic substrate conversion to glucose are both important factors for the increased gluconeogenesis of NIDDM and that tissues other than muscle are responsible for the increased delivery of gluconeogenic precursors to the liver.
Increased hepatic mitochondrial capacity in rats with hydroxy-cobalamin[c-lactam]-induced methylmalonic aciduria, Treatment of rats with the vitamin B12 analogue hydroxy-cobalamin[c-lactam] (HCCL) impairs methylmalonyl-CoA mutase function and leads to methylmalonic aciduria due to intracellular accumulation of propionyl and methylmalonyl-CoA. Since accumulation of these acyl-CoAs disrupts normal cellular regulation. the present investigation characterized metabolism in hepatocytes and liver mitochondria from rats treated subcutaneously with HCCL or saline (control) by osmotic minipump. Consistent with decreased methylmalonyl-CoA mutase activity. 14CO2 production from 1-14C-propionate (1 mM) was decreased by 76% and 82% after 2-3 wk and 5-6 wk of HCCL treatment. respectively. In contrast. after 5-6 wk of HCCL treatment. 14CO2 production from 1-14C-pyruvate (10 mM) and 1-14C-palmitate (0.8 mM) were increased by 45% and 49%. respectively. In isolated liver mitochondria. state 3 oxidation rates were unchanged or decreased. and activities of the mitochondrial enzymes. citrate synthetase. succinate dehydrogenase. carnitine palmitoyltransferase. and glutamate dehydrogenase (expressed per milligram mitochondrial protein) were unaffected by HCCL treatment. In contrast. activities of the same enzymes were significantly increased in both liver homogenate (expressed per gram liver) and isolated hepatocytes (expressed per 10(6) cells) from HCCL-treated rats. The mitochondrial protein per gram liver. calculated on the basis of the recovery of the mitochondrial enzymes. increased by 39% in 5-6 wk HCCL-treated rats. Activities of lactate dehydrogenase. catalase. cyanide-insensitive palmitoyl-CoA oxidation. and arylsulfatase A in liver were not affected by HCCL treatment. Hepatic levels of mitochondrial mRNAs were elevated up to 10-fold in HCCL-treated animals as assessed by Northern blot analysis. Thus. HCCL treatment is associated with enhanced mitochondrial oxidative capacity and an increased mitochondrial protein content per gram liver. Increased mitochondrial oxidative capacity may be a compensatory mechanism in response to the metabolic insult induced by HCCL administration.
The molecular basis of hereditary 1,25-dihydroxyvitamin D3 resistant rickets in seven related families, Hereditary 1.25-dihydroxyvitamin D3 [1.25(OH)2D3] resistant rickets (HVDRR) is an autosomal recessive disease caused by target organ resistance to the action of 1.25(OH)2D3. the active form of the hormone. The defect in target cells is heterogenous and commonly appears to be a mutation in the gene encoding the vitamin D receptor (VDR). We have studied cultured skin fibroblasts and Epstein-Barr virus transformed lymphoblasts of seven family branches of an extended kindred having eight children affected with HVDRR. We have previously shown that cells from three affected children in this group contain an "ochre" nonsense mutation coding for a premature stop codon in exon 7 within the steroid-binding domain of the VDR gene. In the current studies. we found that cells from affected children failed to bind [3H]1.25(OH)2D3 and had undetectable levels of VDR as determined by immunoblots using an anti-VDR monoclonal antibody. Measurement of VDR mRNA by hybridization to a human VDR cDNA probe showed undetectable or decreased abundance of steady-state VDR mRNA. Parents. expected to be obligate heterozygotes. showed approximately half the normal levels of [3H]1.25(OH)2D3 binding. VDR protein. and mRNA. The mutation at nucleotide 970 (counting from the mRNA CAP site) results in the conversion of GTAC to GTAA. which eliminates an Rsa I restriction enzyme site and facilitates identification of the mutation. We found that polymerase chain reaction (PCR) amplification of exons 7 and 8 from family members and subsequent Rsa I digestion allows detection of the specific genotype of the individuals. When Rsa I digests of PCR-amplified DNA are subjected to polyacrylamide gel electrophoresis. children with HVDRR exhibit a homozygous banding pattern with loss of an Rsa I site. Parents exhibit a heterozygotic DNA pattern with detection of both normal and mutant alleles. In summary. our data show that the genetic abnormality is a point mutation within the steroid-binding domain of the VDR in all seven related families with HVDRR. Analysis of restriction fragment length polymorphism at the 970 locus of PCR-amplified DNA fragments can be used to diagnose this mutation in both affected children and parents carrying the disease.
Familial hypercatabolic hypoproteinemia. A disorder of endogenous catabolism of albumin and immunoglobulin, The metabolism of albumin and IgG was investigated in two siblings. products of a first-cousin marriage. a female aged 34 yr and a male aged 17. who had a marked reduction in their respective serum concentrations of IgG (1.3 and 3.1 mg/ml) and albumin (19 and 21 mg/ml). The metabolism of radioiodinated IgG and albumin was studied in the two patients. The total circulating and body pools of IgG were less than 28% of normal. The IgG synthetic rates were within the normal range. However. the IgG survival was short. with their respective fractional catabolic rates increased fivefold to 31% and 36% of the intravenous pool per day (normal. 6.7 +/- 2%/d). Furthermore. the patients had reduced total body pools. normal synthetic rates. and increased fractional catabolic rates for albumin. There was no proteinuria or abnormality of renal or liver function. In addition. the patients did not have circulating antibodies directed toward IgG. IgA. or albumin. Furthermore. both patients had normal fecal 51Cr-labeled albumin tests. thus excluding excessive gastrointestinal protein loss. We propose that these siblings have a previously unrecognized familial disorder characterized by reduced serum concentrations of IgG and albumin caused by a defect in endogenous catabolism. leading to a short survival of these proteins that is associated in this family with chemical diabetes and a skeletal deformity.
Phenotypic and functional characterization of T cells from patients with myasthenia gravis, A study of cell surface phenotypes of PBL of myasthenia gravis (MG) patients showed that their T cells had a significantly higher percentage of 4B4+ T cells (the helper/inducer subset) than age- and sex-matched controls. The PBL of MG patients proliferated significantly higher than those of normal subjects (NS) in response to the purified alpha chain of the acetylcholine receptor (AChR). Anti-AChR antibody was present in sera of 88% of MG and none of the NS. The PBL B cells from MG only. when cultured with autologous T cells and stimulated with either pokeweed mitogen (69%). or AChR-alpha chain (38%). secreted antibody to AChR-alpha chain. whereas T and B cells alone secreted no antibody. T cells from PBL of MG patients were more readily cloned than T cells of NS. by limiting dilution. in the presence of recombinant IL-2 and in the absence of AChR-alpha chain. About 50% of T cell clones from MG patients. compared to none from NS. proliferated to AChR-alpha chain. This response was HLA-DR restricted. MG T cell clones did not display significant cytotoxic activity. as compared to control T cell clones. Our results indicate that in MG. 4B4+ regulatory T cells play their role in the pathogenesis of MG. not by cytotoxicity. but more likely by their ability to stimulate specific antibody production by B cells.
Active specific immunotherapy in patients with melanoma. A clinical trial with mouse antiidiotypic monoclonal antibodies elicited with syngeneic anti-high-molecular-weight-melanoma-associated antigen monoclonal antibodies [published erratum appears in J Clin Invest 1991 Feb;87(2):757, In two clinical trials the mouse antiidiotypic monoclonal antibody (MAb) MF11-30. which bears the internal image of human high-molecular-weight-melanoma-associated antigen (HMW-MAA) was administered by subcutaneous route without adjuvants to patients with stage IV malignant melanoma on day 0. 7. and 28. Additional injections were administered if anti-antiidiotypic antibodies were not found or their titer decreased. In the first phase I trial with 16 patients the initial dose was 0.5 mg per injection and escalated to 4 mg per injection. Neither toxicity nor allergic reactions were observed despite the development of anti-mouse Ig antibodies. Minor responses were observed in three patients. In a second clinical trial MAb MF11-30 was administered to 21 patients at a dose of 2 mg per injection. since this dose had been shown in the initial study to be effective in inducing anti-antiidiotypic antibodies. Two patients were inevaluable; in the remaining 19 patients. the average duration of treatment was 34 wk. In this trial as well. neither toxicity nor allergic reactions were observed. 17 of the 19 immunized patients increased the levels of anti-mouse Ig antibodies and 16 developed antibodies that inhibit the binding of antiidiotypic MAb MF11-30 to the immunizing anti-HMW-MAA MAb 225.28. One patient increased the level of anti-HMW-MAA antibodies. One patient achieved a complete remission with disappearance of multiple abdominal lymph nodes for a duration of 95 wk. Minor responses were observed in three patients. These results suggest that mouse antiidiotypic MAb that bear the internal image of HMW-MAA may be useful reagents to implement active specific immunotherapy in patients with melanoma.
Anti-(U1) small nuclear RNA antibodies in anti-small nuclear ribonucleoprotein sera from patients with connective tissue diseases, Small nuclear ribonucleoprotein (snRNP) particles are a class of RNA-containing particles in the nucleus of eukaryotic cells. Sera from patients with connective tissue diseases often contain antibodies against the proteins present in these snRNPs. Antibodies against the RNA components of snRNPs. the U snRNAs. are thought to be rare. We tested 118 anti-snRNP sera for the presence of anti-snRNA antibodies and found them in 45 sera (38%). In all sera the antibodies (IgG and F(ab)2 fragments thereof) were exclusively directed against U1 snRNA. The anti-(U1) RNA antibodies were always accompanied by anti-(U1)RNP antibodies but were not found in sera which contain antibodies of the Sm serotype directed against all nucleoplasmic U snRNP particles. Like anti-RNP antibodies. anti-U1 RNA activity is confined to sera from patients with SLE or SLE overlap syndromes and is rarely found in patients with other connective tissue diseases. By analyzing binding to subfragments of U1 snRNA made in vitro. it was demonstrated that anti-(U1)RNA antibodies recognize epitopes distributed throughout the U1 RNA molecule. In most sera. however. either the second or the fourth hairpin loop is the main target of the antibody. The possible mechanisms that could lead to the production of this new type of autoantibody are discussed.
Hyperglycemia-induced B cell toxicity. The fate of pancreatic islets transplanted into diabetic mice is dependent on their genetic background, The role of pancreatic B cell dysfunction in the phase preceding clinical onset of insulin-dependent and non-insulin-dependent diabetes mellitus has been much debated. In this investigation. the impact of a prolonged diabetic environment on pancreatic islet B cells transplanted syngeneically under the kidney capsule of C57BL/6 (B6) and C57BL/Ks (BKs) mice was studied. Alloxan-diabetic mice bearing a subcapsular islet graft insufficient to normalize the blood glucose level were rendered normoglycemic by a second intrasplenic islet graft after various period of hyperglycemia to examine the reversibility of hyperglycemia-induced B cell dysfunction. Using a perfusion technique of the graft-bearing. it was found that both strains of mice exhibited a diminished glucose-induced insulin secretion after 6 wk of hyperglycemia. when compared with normoglycemic mice carrying islet grafts. When normoglycemia was restituted by the splenic graft after 4 or 12 wk. there was a normalization of glucose-stimulated insulin secretion in the renal islet grafts in B6 mice. whereas insulin secretion from the grafted BKs islets remained impaired. Morphometric measurements of the islet grafts demonstrated a 50% reduction in the graft volume in diabetic BKs mice after 12 wk. compared with normoglycemic animals. whereas no such decrease was observed in B6 mice. Islet grafts removed from hyperglycemic mice of both strains exhibited diminished insulin mRNA contents. and in the BKs mice there was also a reduced glucose oxidation rate in the islet grafts in vitro. This metabolic dysfunction can only partly be explained by a reduced graft size. The present findings emphasize the genetic constitution as a decisive factor for the survival and function during a period of sustained stress on a limited B cell mass.
Multiple keratoacanthomas treated with oral retinoids, Multiple eruptive keratoacanthoma of Witten and Zak is a rare disorder characterized by numerous small. eruptive tumors and larger. more typical keratoacanthomas. Affected patients have features of Grzybowski-type keratoacanthomas and Ferguson Smith type. Two patients with multiple keratoacanthomas were treated with oral retinoids. Both patients had hundreds of follicular papules on the trunk and extremities. Less common lesions included nodules with central horn-filled craters more characteristic of classic keratoacanthomas. Retinoid therapy resulted in regression of the larger. more typical keratoacanthomas in both patients. The small follicular keratoacanthomas remained unaffected. Thus oral retinoids are only partially beneficial for the treatment of the Grzybowski type or the Witten and Zak type of multiple eruptive keratoacanthomas.
Molecular identification of major and minor bullous pemphigoid antigens, The skin antigens defined by basement membrane zone antibodies in 38 patients with bullous pemphigoid were analyzed by Western immunoblot. Thirty-four patients (89%) had antibodies to a major bullous pemphigoid antigen with a molecular weight of approximately 230 kD. Twelve patients (32%) had antibodies to a minor bullous pemphigoid antigen with a molecular weight of approximately 160 kD; this included four patients who did not have antibodies to the 230 kD antigen. Depending on the epidermal extract used. a variable number of patients (up to 75%) also had antibodies to minor bullous pemphigoid antigens with molecular weights of approximately 180 and 200 kD. The results of this study confirm that bullous pemphigoid antigens are heterogeneous at the molecular level. Approximately 10% of patients have antibodies directed solely to a minor bullous pemphigoid antigen.
Polypoid melanoma: a virulent variant of nodular melanoma. Report of three cases and literature review, We report the cases of three patients with polypoid melanoma. In no case was there microscopic evidence of melanoma cell invasion below the papillary dermis. In the polypoid variant of nodular melanoma. melanoma cells accumulate in large volume above the skin's surface. This increase in tumor volume encourages dislodgment of melanoma cells that are carried to superficial lymphatic vessels without invading the reticular dermis; this feature differentiates polypoid melanoma from the nonpolypoid nodular variant. Although polypoid melanoma is considered the most malignant form of melanoma. our findings. albeit limited to three cases. suggest that early diagnosis and prompt surgical excision may provide a favorable 5-year survival rate.
Photopheresis for the treatment of cutaneous T cell lymphoma, We investigated the use of extracorporeal chemotherapy (photopheresis) in eight patients with cutaneous T cell lymphoma. Initially described by Edelson et al. for the treatment of erythrodermic cutaneous T cell lymphoma. we have expanded the treatment to include patients with extensive patch/plaque disease as well as tumor-stage disease. Four of five patients with erythrodermic stage disease had either a complete or a partial clinical remission with photopheresis alone. One patient with extensive patch/plaque disease continued to have a partial clinical remission of 7 months' duration with photopheresis alone. Of the two patients with tumor-stage disease. one remained without evidence of clinical disease at 10 months with photopheresis alone. whereas the second patient had a partial clinical remission of 5 months with a combination of local radiation therapy followed by monthly photopheresis. The skin biopsy specimen obtained from the patient with tumor-stage disease in complete clinical remission did not show cutaneous T cell lymphoma. We conclude that photopheresis is an effective modality alone or in combination with adjunctive therapy for erythroderma. extensive patch/plaque disease. and some tumor-stage disease.
Colony-stimulating factors, Recombinant hematopoietic colony-stimulating factors have profound effects on developing and mature granulocytes. macrophages. and lymphocytes. Use of these agents for treatment of disease may result in a variety of adverse cutaneous reactions. The recent discovery of colony-stimulating factor production by keratinocytes and dermal cells suggests that these agents may also be significant in cutaneous homeostasis and in the pathogenesis of cutaneous diseases.
Digital imaging techniques in dermatology, Digital imaging is a versatile technique that has been infrequently used in dermatology to record visual images. We have used this technology for 10 patients to follow cutaneous lesions. including alopecia mucinosa. psoriasis. and dysplastic nevi. The setup included a personal computer. digitizer board. monitor. video camera. and lights. An introduction to electronic (digital) imaging is given and some of the many possible applications in dermatology are discussed.
Apical segmental dysfunction in hypertrophic cardiomyopathy: subgroup with unique clinical features, A segmental wall motion abnormality is an unusual finding in patients with hypertrophic cardiomyopathy. To clarify its clinical significance. 48 patients with hypertrophic cardiomyopathy were analyzed. Eight patients (Group A) had apical segmental dysfunction; 40 (Group B) had normal wall motion. No patient in either group had coronary artery stenosis on selective coronary arteriography. In all patients in Group A. apical segmental dysfunction was revealed by left ventriculography; however. it could be detected by echocardiography in only two patients in Group A. Left ventricular hypertrophy by electrocardiogram (ECG) was more common in Group B (p less than 0.05). Abnormal Q waves were more frequently discovered in Group A (p less than 0.005) and were recognized predominantly in the lateral leads. On serial ECGs. a gradual development of abnormal Q waves was noted in six of eight patients in Group A. Malignant arrhythmias were more common in Group A (p less than 0.001). In two patients in Group A. left ventricular dilation and congestive heart failure developed during the follow-up period. Thus. the presence of a Q wave in the lateral leads on an ECG in patients with hypertrophic cardiomyopathy may indicate the presence of apical segmental dysfunction. Left ventriculography should be performed to examine the presence of this abnormality and 24 h ambulatory ECG monitoring should be done to detect malignant arrhythmias in patients who have abnormal Q waves in the lateral leads. Patients with this unique type of hypertrophic cardiomyopathy need careful follow-up evaluation.
Contrast echocardiographic mapping of collateralized myocardium in humans before and after coronary angioplasty, Conventional coronary arteriography is able to demonstrate the presence of coronary collateral vessels but cannot delineate the specific region of myocardium to which they supply blood. To test the hypothesis that contrast echocardiography can specifically identify collateralized myocardium. contrast echocardiographic perfusion "maps" were compared in patients with (n = 12) and without (n = 12) angiographic evidence of coronary collateral flow. both before and after coronary angioplasty. Contrast echocardiographic images of the mid-left ventricle in the short-axis view at end-diastole were obtained after separate injections of a sonicated contrast agent into both the right and the left coronary arteries. A computer-based contouring system was used to determine the individual areas of myocardium perfused by each of the two coronary arteries and then to superimpose the images of the two perfusion beds. The resulting area of overlapping perfusion represented myocardium receiving blood flow from both coronary systems and was defined as collateralized myocardium. To normalize for heart size. overlap area was expressed as a percent of total myocardial area. which was the area between endocardium and epicardium in the short-axis view. To adjust for differences in vascular distribution. overlap area was expressed as a percent of the perfusion area of the recipient vessel. In patients with angiographic collateral flow. the recipient vessel was that vessel receiving the collateral flow. In patients without angiographic collateral flow. the right coronary artery was considered the recipient vessel. Overlap area was 1.3 +/- 0.4% of total myocardial area and 6.6 +/- 1.7% of recipient vessel area in patients without angiographic evidence of collateral flow compared with 30.6 +/- 2.5% and 89.2 +/- 6.4%. respectively. in patients with angiographic collateral flow (p less than 0.001 for both). In four patients in whom angiographic collateral flow was abolished by angioplasty. overlap area decreased from 30.3 +/- 5.3% to 6.8 +/- 2.7% of total myocardial area and from 100% to 18.5 +/- 5.4% of recipient vessel area (p less than 0.05 for both). Thus. contrast echocardiography is able to map the specific myocardial territory perfused by coronary collateral flow and document an immediate reduction in perfusion in this territory when collateral flow is abolished by angioplasty.
Ventricular stroke work loss: validation of a method of quantifying the severity of aortic stenosis and derivation of an orifice formula, Because aortic stenosis results in the loss of left ventricular stroke work (due to resistance to flow through the valve and turbulence in the aorta). the percentage of stroke work that is lost may reflect the severity of stenosis. This index can be calculated from pressure data alone. The relation between percent stroke work loss and anatomic aortic valve orifice area (measured by planimetry from videotape) was investigated in a pulsatile flow model. Thirteen valves were studied (nine human aortic valves obtained at necropsy and four bioprosthetic valves) at stroke volumes of 40 to 100 ml. giving 57 data points. Valve area ranged from 0.3 to 2.8 cm2 and mean systolic pressure gradient from 3 to 84 mm Hg. Percent stroke work loss. calculated as mean systolic pressure gradient divided by mean ventricular systolic pressure x 100%. ranged from 7 to 68%. It was closely related to anatomic orifice area with an inverse exponential relation and was not significantly related to flow (r = -0.15). An orifice formula was derived that predicted anatomic orifice area with a 95% confidence interval of +/- 0.5 cm2 (orifice area [cm2] = 4.82 [2.39 x log percent stroke work loss]. r = -0.94. SEE = 0.029). These results support the clinical use of percent stroke work loss as an easily obtained index of the severity of aortic stenosis.
Origin and significance of diastolic Doppler flow signals in the left ventricular outflow tract, Diastolic Doppler flow signals (greater than or equal to 0.2 m/s) in the left ventricular outflow tract have not been well characterized. and their origin and significance remain controversial. Fifty-nine patients (55 +/- 16 years of age) with technically good Doppler echocardiographic studies were studied prospectively. There were 14 normal subjects. 21 patients with left ventricular hypertrophy. 10 with dilated cardiomyopathy and 14 with other cardiac disease. The rhythm was sinus in 55 and atrial fibrillation in 4. Two distinct Doppler flow signals were detected in the left ventricular outflow tract during diastole. These were termed E' (early) and A' (active) because they occurred 40 to 100 ms after higher velocity mitral inflow E (passive filling) and A (atrial contraction) signals. Among 59 patients. E' signals were present in 48 (81%) and had a mean velocity of 0.41 +/- 0.23 m/s. In 55 patients with normal sinus rhythm. A' signals were present in 52 (95%) and had a mean velocity of 0.52 +/- 0.24 m/s. No A' signals were present in the four patients with atrial fibrillation. The E' and A' velocities by pulsed wave Doppler ultrasound were low at the left ventricular apex and increased along the basal septum in the left ventricular outflow tract. Prominent A' velocities (greater than or equal to 0.45 m/s) were seen in 62% of patients with left ventricular hypertrophy. 50% of normal subjects and 10% of patients with dilated cardiomyopathy. The A' velocity was higher in patients with left ventricular hypertrophy (0.63 +/- 0.26 m/s) than in those with a normal heart (0.45 +/- 0.16 m/s; p less than 0.05) or dilated cardiomyopathy (0.25 +/- 0.13 m/s; p less than 0.01). The major determinants of diastolic outflow tract velocity were the mitral inflow E and A velocities and left end-diastolic dimension. particularly when combined (r = 0.64. p less than 0.0001 for E'; r = 0.72. p less than 0.0001 for A'). Distinctive E' and A' Doppler outflow tract signals result from mitral inflow and may be detected in most patients with normal heart size. These E' and A' velocities increase from apex to base and are more prominent in patients with a small. normally contracting heart or left ventricular hypertrophy.
Demonstration of an area of slow conduction in human atrial flutter, Ten patients with chronic atrial flutter were studied prospectively using electrophysiologic mapping and pacing techniques to assess the mechanism of atrial flutter and the presence of an area of slow conduction in the atria. Electrograms recorded from greater than or equal to 30 right atrial sites for each patient during atrial flutter demonstrated that right atrial free wall activation was craniocaudal and that the interatrial septum activation was caudocranial. consistent with a reentrant circuit involving the right atrium. In six patients. slow conduction occurred during atrial flutter in the inferior right atrium and was spatially associated with fractionated electrographic recordings. In the other four patients. a "missing" interval of electrical activity occurred in the inferior right atrium for an average of 40% of the atrial flutter cycle. Transient entrainment criteria were demonstrated in each patient during rapid high right atrial pacing. The mean activation time from the high right atrial pacing site to the coronary sinus (inferior left atrial) recording site was long (228 ms) and consistent with activation through an area of slow conduction. During rapid pacing of atrial flutter from the coronary sinus site. no transient entrainment criteria could be demonstrated. The mean activation time from the coronary sinus pacing site to the high right atrial recording site was relatively short (134 ms) and consistent with orthodromic activation of the high right atrium not through an area of slow conduction. High right atrial pacing during sinus rhythm at rates similar to atrial flutter demonstrated a short activation time to the coronary sinus and low right atrial sites (mean 169 and 88 ms. respectively). indicating activation that did not traverse an area of slow conduction. Coronary sinus pacing during sinus rhythm demonstrated the same phenomena. Low right atrial electrograms recorded during sinus rhythm and during rapid pacing of sinus rhythm were not fractionated. although they were during atrial flutter. Thus. atrial mapping and pacing data were complementary. indicating that human atrial flutter in the patients studied was generated by a reentrant circuit in the right atrium. with an area of slow conduction in the low right atrium present only during atrial flutter.
Prevalence of additional cardiovascular anomalies in patients referred for transcatheter closure of patent ductus arteriosus, Catheter closure of the patent ductus arteriosus is now a reality. The purpose of this study was to establish the prevalence of associated cardiovascular defects and the accuracy of echocardiography in patients referred for transvenous ductal closure. This study reviewed 146 patients seen from 1981 to 1988: 126 with only a patent ductus arteriosus (Group I) and 20 with additional cardiovascular anomalies (Group II). Groups I and II did not differ significantly in age. gender or physical examination except for the presence of a continuous murmur (Group I 100% versus Group II 80%. p less than 0.001). A left patent ductus arteriosus was visualized by two-dimensional echocardiography in 96% of patients and was evident by Doppler study in 100%. A patent ductus arteriosus was not seen in six patients including a patient who was found to have only a collateral network from the aorta to the main pulmonary artery. The 12 patients with noncardiovascular abnormalities such as Down's syndrome were more likely than the overall group to have additional cardiovascular anomalies (6 of 12. p = 0.001). The cardiovascular anomalies encountered were varied. Eight of the 20 patients with such anomalies had only a restrictive ventricular septal defect in addition to the patent ductus arteriosus. Significant anomalies found at catheterization included two thoracic arteriovenous malformations and an isolated right carotid artery draining into the right pulmonary artery by way of a right ductus arteriosus. This study indicates that echocardiography is an effective diagnostic technique in this patient group. A thorough cardiac catheterization with angiography should be performed before implantation of a ductal device.
Intraoperative echocardiography in infants and children with congenital cardiac shunt lesions: transesophageal versus epicardial echocardiography, To determine the utility and limitations of intraoperative transesophageal echocardiography in infants and children with congenital intracardiac shunts. intraoperative transesophageal (n = 50) and epicardial (n = 49) echocardiograms were performed before and after cardiopulmonary bypass in children from 4 days to 16 years old and 3 to 45 kg in body weight. A miniaturized transesophageal probe (6.9 mm maximal diameter) was used in 36 patients weighting less than or equal to 20 kg. Epicardial imaging was performed with a 5 MHz precordial probe. The intraoperative transesophageal echocardiographic findings before and after cardiopulmonary bypass were correct and complete in 94% of patients. Transesophageal echocardiography correctly identified atrial septal defects. most types of ventricular septal defects. anomalous pulmonary veins. atrioventricular septal defects. tetralogy of Fallot. truncus arteriosus and double inlet ventricles. It failed to provide a correct diagnosis in only three patients. all of whom had doubly committed subarterial ventricular septal defects. Epicardial echocardiography identified all cases that had a doubly committed subarterial ventricular septal defect. A correct and complete intraoperative diagnosis was obtained with the use of epicardial imaging in 92% before and after cardiopulmonary bypass. but this technique required interruption of surgery and could not be completed in three patients because of induced arrhythmias and hypotension. These results demonstrated that intraoperative transesophageal echocardiography consistently defined important morphologic. color and pulsed Doppler ultrasound features of most congenital shunt lesions. Lesions that involved the right ventricular outflow tract are sometimes difficult to image with uniplane transesophageal echocardiography. There were no complications in any of the 50 subjects.
Increased birth prevalence of cardiac defects in Yuma, Arizona, A systematic study was undertaken to estimate the birth prevalence of congenital heart disease because there was a clinical impression that a disproportionate number of cases occurred in Yuma. Arizona. Control data were obtained from Sierra Vista. Arizona. a region with similar demographic characteristics. and from the Baltimore-Washington Infant Study. Patients with chromosomal or syndromal associations were excluded. In the Baltimore-Washington Infant Study only echocardiographic and invasively documented cases were included. From 1983 to 1988 the birth prevalence was significantly higher in Yuma (10.5/1.000) than in Sierra Vista (5.4/1.000. p less than 0.0001). As assessed only by invasive or echocardiographic diagnosis. there was a higher birth prevalence of congenital heart disease in the study population (6.7/1.000) compared with both the Baltimore-Washington Infant Study (3.7/1.000. p = 0.0008) and Sierra Vista (4.6/1.000. p = 0.04). Families were interviewed to exclude cases in which the mother did not spend the month before conception and the first trimester in Yuma or Sierra Vista. The birth prevalence for Yuma (6.0/1.000) remained significantly greater than that for Sierra Vista (3.8/1.000. p = 0.03). The exclusion of cases in which the mother resided elsewhere suggests. but does not prove. that an environmental influence may have played a role in the increased birth prevalence of congenital heart disease in this community.
Reduction in incidence of inducible ventricular tachycardia after myocardial infarction by treatment with streptokinase during infarct evolution, The aim of this study was to determine whether intravenous streptokinase administered with or without oral aspirin to patients with evolving myocardial infarction reduces the inducibility of ventricular tachycardia at electrophysiologic study and thus the risk of sudden death in infarct survivors. Of 159 patients randomized at Westmead Hospital to the multicenter Second International Study of Infarct Survival (ISIS-2) after streptokinase and aspirin in acute myocardial infarction. 87 underwent electrophysiologic testing 6 to 28 days after infarction to determine their risk of subsequent ventricular arrhythmias (streptokinase 20 patients; aspirin 25 patients; streptokinase and aspirin 21 patients; both placebos 21 patients). Patients who underwent electrophysiologic testing had similar clinical characteristics to those of patients who did not. The stimulation protocol comprised up to and including four extrastimuli applied to the right ventricular apex at twice diastolic threshold. An abnormal result was defined as ventricular tachycardia with a cycle length greater than or equal to 230 ms lasting greater than or equal to 10 s. Ventricular tachycardia was inducible at electrophysiologic study in 8 patients who received placebo streptokinase. but in no patient who received active streptokinase (8 of 46 versus 0 of 41; p = 0.005. Fischer's exact test). Ventricular tachycardia was inducible in 4 patients who received aspirin therapy and 4 who did not (4 of 41 versus 4 of 46; p = NS). During a mean follow-up period of 39 +/- 9 months. there were no spontaneous episodes of ventricular tachycardia. ventricular fibrillation or witnessed sudden death in the streptokinase-treated group compared with three such events in the placebo-treated group (p = 0.13). When compared with placebo therapy. intravenous streptokinase substantially reduced the incidence of inducible ventricular tachycardia in infarct survivors. No similar benefit was attributable to aspirin therapy.
Effects of nicardipine, a calcium antagonist, on myocardial salvage and high energy phosphate stores in reperfused myocardial injury, The current study determined the effectiveness of nicardipine. a 1.4-dihydropyridine calcium antagonist. in preserving reperfused myocardium in a cat model of temporary coronary occlusion and ascertained if replenishment of myocardial phosphate stores during reperfusion as defined by phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy was indicative of salvage. Twenty open chest. anesthetized cats were studied with use of a snare ligature around the proximal left anterior descending coronary artery. with a coil sutured to the epicardial surface overlying the distribution of the artery. Peak areas of phosphocreatine. inorganic phosphate and adenosine triphosphate (ATP) NMR signals were measured during 1 h of occlusion followed by 1.5 h of reperfusion. Infarct size and jeopardy area were determined in vitro by simultaneous infusion of phthalocyanine blue dye and triphenyltetrazolium chloride into the aorta and the left anterior descending coronary artery. respectively. after 5 h of myocardial reperfusion. Nicardipine-treated and control groups had similar jeopardy area values (41.2 +/- 1.6% versus 47.4 +/- 3.1% of the left ventricle). but infarct area was significantly reduced in the nicardipine-treated group (3.2 +/- 1.1% versus 24.9 +/- 7.5% of jeopardy area. p less than 0.01). High energy phosphate compounds remained markedly altered during reperfusion in both groups. No significant improvement in phosphocreatine or inorganic phosphate recovery was observed in animals pretreated with nicardipine despite an 87% reduction in infarct size. Myocardial ATP was greater during reperfusion in the nicardipine-treated compared with the control group (average over initial 90 min of reperfusion 58 +/- 6% versus 46 +/- 3% of baseline values. p less than 0.05). suggesting improved recovery of ATP. However. the measured levels of high energy phosphate compounds during reperfusion and their ratios did not correlate with infarct size and thus were not predictive of myocardial salvage.
Hemodynamic efficacy of rapid saline infusion and dobutamine versus saline infusion alone in a model of cardiac rupture, Despite recent reports describing survival after cardiac rupture. the effectiveness of circulatory support while awaiting definitive surgical treatment is controversial. To assess the efficacy of volume expansion and pharmacologic support in cardiac tamponade due to cardiac rupture. a model of hemorrhagic cardiac tamponade was developed and treatment with rapid saline infusion and dobutamine was compared with rapid saline infusion alone in 15 closed chest dogs. A right ventricular wound of reproducible size was produced by deflating an aortic valvuloplasty balloon that had previously been passed by way of the internal jugular vein into the pericardial space and through a stab wound in the right ventricular free wall. Hemodynamic values were compared at baseline. during tamponade and after a rapid infusion (1 liter at 100 ml/min) of either saline solution alone or saline solution plus dobutamine (20 micrograms/kg per min). Atrial and pericardial pressures increased significantly in both groups. Mean arterial pressure. cardiac output and stroke volume increased with combined saline and dobutamine infusion to values similar to those at baseline (91 +/- 19%. 114 +/- 43% and 94 +/- 37% of baseline. respectively). In contrast. saline infusion alone caused a small increase in cardiac output but failed to significantly increase mean arterial pressure or stroke volume (76.8 +/- 14.2%. 55 +/- 18% and 51 +/- 17% of baseline. respectively). Combined rapid infusion of saline solution and dobutamine infusion has a more beneficial hemodynamic effect and may be more effective than rapid saline infusion alone in resuscitating patients with hemorrhagic cardiac tamponade due to cardiac rupture.
Alterations in endocardial vascular resistance after reperfusion in a low flow, high demand model of ischemia: effects of dipyridamole and WEB-2086, a platelet-activating factor antagonist, To determine if alterations in regional coronary vascular resistance could occur in the type of myocardial ischemia present in severe angina pectoris. regional perfusion and function were studied in 35 conscious sedated dogs. A stenosis producing severe hypokinesia of the perfused segment was created for 2 h on the left anterior descending coronary artery and 10 episodes of 1 min of high demand ischemia (atrial pacing at a rate sufficient to induce dyskinesia in the hypoperfused segment) were superimposed before reperfusion. The dogs were randomized into three treatment groups: control (n = 13). dipyridamole (n = 10) or WEB-2086 (n = 12). an antagonist of the effects of the endogenous platelet-activating factor. During stenosis. residual endocardial blood flow in the ischemic but nonnecrotic area averaged 0.72 +/- 0.14. 0.38 +/- 0.13 and 0.68 +/- 0.17 ml/min per g in the control. WEB-2086 and dipyridamole groups. respectively. Twenty-four hours after reperfusion. endocardial blood flow in the ischemic area was significantly lower in control dogs (1.04 +/- 0.15 ml/min per g) than in dogs treated with WEB-2086 (1.44 +/- 0.28 ml/min per g; p less than 0.03) or dipyridamole (3.00 +/- 0.83 ml/min per g; p less than 0.01). Accordingly. in control dogs. endocardial coronary vascular resistance in the ischemic area was increased after reperfusion from 85 +/- 11 to 124 +/- 27 mm Hg/(ml/min per g) (p less than 0.05) after 24 h. In contrast. coronary vascular resistance in the ischemic area remained unchanged in dogs receiving WEB-2086 (77 +/- 8 to 79 +/- 9 mm Hg/(ml/min per g); p = NS) and it decreased significantly in dogs receiving dipyridamole (72 +/- 8 to 44 +/- 8 mm Hg/(ml/min per g); p less than 0.01). Regional function after 24 h remained depressed in all three groups. These data indicate that low flow. high demand ischemia induces alterations in the subendocardial microvasculature. Such alterations in regional coronary vascular resistance might play a role in several forms of ischemic heart disease such as in severe angina. but they appear susceptible to improvement by therapeutic interventions that influence granulocyte and platelet activation.
Early readmission of elderly patients with congestive heart failure, Repetitive hospitalizations are a major health problem in elderly patients with chronic disease. accounting for up to one fourth of all inpatient Medicare expenditures. Congestive heart failure. one of the most common indications for hospitalization in the elderly. is also associated with a high incidence of early rehospitalization. but variables identifying patients at increased risk and an analysis of potentially remediable factors contributing to readmission have not previously been reported. We prospectively evaluated 161 patients 70 years or older that had been hospitalized with documented congestive heart failure. Hospital mortality was 13% (n = 21). Among patients discharged alive. 66 (47%) were readmitted within 90 days. Recurrent heart failure was the most common cause for readmission. occurring in 38 patients (57%). Other cardiac disorders accounted for five readmissions (8%). and noncardiac illness led to readmission in 21 cases (32%). Factors predictive of an increased probability of readmission included a prior history of heart failure. four or more admissions within the preceding 8 years. and heart failure precipitated by an acute myocardial infarction or uncontrolled hypertension (all P less than .05). Using subjective criteria. 25 first readmissions (38%) were judged possibly preventable. and 10 (15%) were judged probably preventable. Factors contributing to preventable readmissions included noncompliance with medications (15%) or diet (18%). inadequate discharge planning (15%) or follow-up (20%). failed social support system (21%). and failure to seek medical attention promptly when symptoms recurred (20%). Thus. early rehospitalization in elderly patients with congestive heart failure may be preventable in up to 50% of cases. identification of high risk patients is possible shortly after admission. and further study of nonpharmacologic interventions designed to reduce readmission frequency is justified.
Injuries in an elderly inner-city population, Even though injuries are a leading cause of morbidity and mortality among the elderly in the United States. no comprehensive population-based study of nonfatal and fatal injuries has been carried out in an elderly minority inner-city population. To study injuries in this population. we developed an active surveillance system as part of a large injury prevention program in a poor urban black community. We report 577 cases of nonfatal and fatal injuries in a community of 12.139 persons 65 years of age and older that resulted in emergency room treatment or death between March 1. 1987. and February 29. 1988. Nearly 5% of the elderly population was treated at an emergency room for. or died as a result of. an injury during the study period; the overall injury rate was 48 injuries per 1.000 persons. Injury rates for older women exceeded those for older men and increased with advancing age in both sexes. Fall injuries accounted for 312 (54%) of all injuries and 75% of all hospitalizations for injury. Motor vehicle incidents and violence were the second and third most common injuries. accounting for 13% and 7% of injuries. respectively. Given the predominance of falls relative to other injuries. prevention of falls should receive major emphasis in injury prevention efforts in inner-city minority populations.
Effects of nonparticipation in trauma center system on emergency department utilization, The University of Illinois Hospital (UIH) serves an inner-city urban population in one of the highest crime rate districts in Chicago. On May 20. 1986. the city's Level I Trauma ordinance took effect with the University of Illinois Hospital declining to participate. To measure the impact of the ordinance on a nonparticipating hospital. we undertook a retrospective analysis of our trauma patient utilization statistics. Consecutive monthly patient census data of 71 months was compiled with emphasis on patient presenting complaints and related subspecialty evaluation. We observed significant decreases of patients presenting with head injuries. fractures. and animal bites as well as with major trauma. minor trauma. and general surgery hospital admission. The final disposition of the patients arriving by ambulance was consistent with the observed decrease in major traumatic conditions and in minor traumatic conditions. However. the mean number of patient presentations per day (ppd) admitted to regular medical or surgical beds decreased from 2.70 ppd to 2.30 ppd while the mean number of ppd sent home increased from 2.64 ppd to 3.49 ppd. These data suggest that loss of trauma center status designation has a profound effect on utilization of emergency departments not participating in the trauma system. Nonparticipation appears to be associated with a significant decrease in utilization rates for major and minor trauma patients and a significant increase in the number of patients discharged who had arrived by the Chicago Fire Department Paramedic System (CFD). This effect on the emergency department extends to utilization of inpatient services.
Sialolithiasis: case studies and review, Three cases of sialolithiasis are presented. each representative of acute and chronic presentations of this problem. The evaluation and treatment of salivary gland and duct stones are outlined. The primary axiom is. "Treat the gland. not the stone." and the essential aspects of emergency medical management are antibiotics. sialogogues. warm compresses. mechanical stimulation. and appropriate referral to an otolaryngologist.
Case report: severe ethylene glycol intoxication with normal osmolal gap--"a chilling thought", This is a case of a 23-year-old male presenting with altered sensorium. vomiting. and right flank pain. Despite a normal osmolal gap. he was found to be suffering from ethylene glycol intoxication. This little-described presentation can result in the clinician failing to consider ethylene glycol as a causative agent.
Analysis of base station morphine orders: assessment of supervising physician consistency, Paramedic contact with a base station should gemerate consistent recommendations reflecting a consensus of base station physician care. In our urban EMS system. paramedics must contact a single base station to provide morphine sulfate (MS) for a patient with chest pain. We performed a retrospective cohort analysis of all prehospital MS requests for chest pain to determine the consistency of the circumstances for which the paramedic team was refused MS. These MS requests represented 123 of the 1.715 (7%) on-line physician consultations during the 6-month study. Only 15 of the 123 (12%) MS requests were refused. Neither the mean patient age. sex distribution. or presenting vital signs correlated with MS refusal. A maximum estimate of transport time to the hospital of less than or equal to 5 minutes was noted for 7 of 15 (47%) medication refusals compared to only 11 of 96 (11%) approvals with documented estimated transport times (P less than or equal to 0.005). A simultaneous request for nitroglycerin (NTG) was noted for 6 of the 15 (40%) medication refusals and 15 of the 108 (14%) approvals (P less than 0.05). We found refusal of MS administration to be uncommon. Supervising physicians tended to refuse MS when the transport time was short and when NTG was requested for concomitant administration. We also noted physician inconsistencies in refusal scenarios. These findings can guide physician consensus development to avoid sending mixed messages to paramedics.
Blunt trauma to the heart: the pathophysiology of injury, Blunt injuries to the heart are common and potentially lethal. These injuries often go undetected while more obvious problems are treated. A cardiac injury should be suspected in any patient who sustains severe chest trauma. The spectrum of cardiac trauma ranges from injuries with no actual cellular damage (myocardial concussion) to cardiac chamber rupture. The pathophysiology. diagnosis. and treatment of these injuries are discussed.
The scapular manipulation technique for the reduction of acute anterior shoulder dislocations, Anterior shoulder dislocations are a common occurrence in busy emergency departments. Numerous techniques for treating this problem have been reported. The majority of these techniques use traction and leverage of the humerus. often requiring considerable force and causing significant patient discomfort. We report a simple. relatively painless. and atraumatic method of shoulder reduction involving manipulation of the scapula as well as the humerus. This technique has been used in our emergency department with considerable success and no complications.
Ovarian response to exogenous gonadotropins during pregnancy, Multiple ovarian follicles were successfully induced in a patient undergoing superovulation for a gamete intrafallopian transfer (GIFT) procedure despite the presence of an undiagnosed ectopic pregnancy. Midluteal gonadotropin releasing hormone agonist (GnRH-a) treatment should be coupled with mechanical contraception in the previous cycle in patients with patent tubes.
The establishment of an ovum donation program using a simple fixed-dose estrogen-progesterone replacement regimen, Most ovum donation (OD) programs involve cycle synchronization between recipient and donor for normally cycling recipients and a complex estrogen-progesterone replacement regimen for recipients with ovarian failure. In 1987. Serhal and Craft (1) suggested the use of a fixed-dose estrogen-progesterone regimen for recipients who were normally ovulatory and to those with ovarian failure. Following this protocol. and simplifying it still. the authors administered 6 mg estradiol valerate (E2) daily orally starting on day 2-6 of induced withdrawal bleeding. augmented with 100 mg progesterone in ethyl oleate (P) intramuscularly daily. starting any time between 4 days prior to and the day of oocyte pickup. All recipients underwent embryo transfer at a 2-pronuclei (2PN)-10-cell stage. A group of 21 patients underwent 26 treatment cycles. resulting in 16 pregnancies. Twelve of the patients gave birth. one to triplets. two to twins. and nine to singletons. Four patients miscarried in the first trimester of pregnancy.
The value of hysteroscopy in elderly women prior to in vitro fertilization-embryo transfer (IVF-ET): a comparative study, Two hundred eighty-four hysteroscopies were performed in 312 (91%) candidates for in vitro fertilization and embryo transfer (IVF-ET) who were divided into two groups. Group I consisted of elderly women over 40 years. and group II of women below this age. Although visualization revealed uterine abnormalities in 29.9% of all patients. abnormal findings were significantly increased in the former group in comparison to the latter (P less than 0.001). This difference was attributed mainly to uterine rather than cervical pathology. Furthermore. in elderly women age-related uterine pathology such as submucous myomata. endometrial hyperplasia. and polyps were more prominent. while in younger patients other uterine lesions such as adhesions and tubal ostia occlusion were more common. Moreover. treatment prior to IVF-ET resulted in 7 clinical pregnancies (8.9%) in group I and in 41 clinical pregnancies (19.9%) in group II. all of which failed in one to three cycles previously. It seems that hysteroscopic evaluation may reduce the IVF-ET failure rate due to intrauterine abnormalities in elderly as well as young patients. thus it becomes an absolute prerequisite for all patients scheduled for an IVF program.
Gamete intrafallopian transfer (GIFT) in women with bicornuate uteri, Fourteen women with bicornuate uteri underwent a total of 30 gamete intrafallopian transfer procedures. All patients responded adequately to ovarian stimulation. Eight women conceived. two of them twice. Five women delivered at term and three had a premature delivery. There was one spontaneous abortion and an ectopic pregnancy. No neonatal deaths occurred in this series. No increase in the incidence of spontaneous abortion was noted but there appeared to be an increase in the incidence of premature labor. These findings suggest that the prospects of conception for infertile women with bicornuate uteri treated with gamete intrafallopian transfer are similar to those of the rest of the infertile population treated at our center.
Serum lipoproteins, apolipoproteins and very low density lipoprotein subfractions during 6-month fibrate treatment in primary hypertriglyceridaemia, Serum lipoproteins and apolipoproteins were studied in 14 hypertriglyceridaemic (HTG) patients during a 24-week period of treatment with gemfibrozil. and after a 6-week washout period. A marked decrease in very low density lipoprotein (VLDL) cholesterol and triglyceride was observed. There was an increase in high density lipoprotein (HDL) cholesterol. particularly the HDL3 component. A slight increase in low density lipoprotein (LDL) cholesterol was observed after 12 weeks. but this had almost disappeared after 24 weeks. The treatment resulted in an increase in serum apolipoprotein A-II levels and a reduction in serum apo C-III and apo E. VLDL subfractionation by density gradient centrifugation in four subfractions of decreasing size (A. B. C and D) showed a predominant reduction of the large subfractions A. B and C. while the decrease in VLDL-D was less marked. Percentage changes from the baseline level of VLDL-A and VLDL-D cholesterol were found to be inversely correlated with percentage changes in HDL and LDL cholesterol. respectively. This might reflect a transfer of cholesterol from VLDL-A to HDL. and from VLDL-D to LDL. The above data suggest fibrate-induced stimulation of lipoprotein lipase. and indicate that the enhanced transfer of cholesterol from VLDL to LDL. induced by fibrates in HTG patients. is less pronounced after a prolonged period of treatment.
Are blood pressure levels increasing in Denmark, The Copenhagen City Heart Study is a prospective cardiovascular population study designed to evaluate the incidence of and risk factors for cardiovascular disease. A random population sample comprising approximately 20.000 individuals was invited to participate. Blood pressure was measured. and information regarding the use of antihypertensive medication was collected in an initial survey during the period 1976-1978 (attendance rate 74%) and from a second survey during the period 1981-1983 (attendance rate 70%). A significant increase in systolic and diastolic blood pressure between survey 1 and survey 2 was found among both men and women greater than 40 years of age and not using antihypertensive medication. The increase in blood pressure in the follow-up survey could not be explained by changes in methods. changes in the prescription of antihypertensive medication. or selection bias. Factors associated with changes in systolic and diastolic blood pressure were examined by multiple linear regression analysis. Both increase in body mass index and increase in alcohol consumption were positively correlated with changes in systolic and diastolic blood pressure. while use of antihypertensive medication. a high value of body mass index at survey 1 and a high level of education were negatively correlated with changes in systolic and diastolic blood pressure. Female sex and advanced age were also negatively correlated with changes in diastolic blood pressure. Consumption of tobacco and alcohol. income and changes in consumption of tobacco were not significantly correlated with changes in systolic and diastolic blood pressure.
Continuous subcutaneous insulin infusion (CSII), multiple injections (MI) and conventional insulin therapy (CT) in self-selecting insulin-dependent diabetic patients. A comparison of metabolic control, acute complications and patient preferences, Continuous subcutaneous insulin infusion (CSII) and multiple injections (MI) have been shown to have metabolic advantages in highly-selected insulin-dependent diabetics (IDDs). but there have been few comparative studies in self-selected IDDs. With MI. the optimal insulin preparation for overnight insulin delivery has not been defined. We compared conventional 2-3 injection therapy (CT). CSII and MI with human isophane insulin (MI/human isophane) and human ultralente insulin (MI/human ultralente). respectively. at bedtime in self-selected IDDs. Of 275 IDDs who were invited to participate. 52 individuals (18.9%) entered the study. Most indices of glycaemic control showed better values on CSII and also on MI compared to CT. but the differences were small. Fasting blood glucose was higher on MI/human ultralente than on MI/human isophane. Only one subcutaneous abscess and one case of ketoacidosis requiring hospitalization occurred on CSII. Serious hypoglycaemic episodes were non-significantly increased on intensified therapy. Most patients clearly preferred intensified insulin therapy; approximately one half CSII.
Rebound increase in serum thyrotropin, anti-'microsomal' antibodies and thyroglobulin after discontinuation of L-thyroxine, We assayed serum thyrotropin (TSH). antimicrosomal antibodies (MSA). antithyroglobulin antibodies and thyroglobulin in seven individuals with subclinical autoimmune hypothyroidism during two 6-month periods with L-thyroxine substitution and placebo. respectively. Serum TSH decreased during L-thyroxine administration. with a rebound increase in serum TSH of about 6 months duration during placebo treatment. and a parallel increase in serum thyroglobulin. In agreement with previous observations by other groups. we found decreased serum concentrations of MSA during L-thyroxine treatment in three individuals. In addition. a slow but significant transient increase in serum MSA was recorded during placebo administration in the four individuals who showed the most pronounced increase in serum TSH (greater than 20 mU l-1). This association between serum levels of MSA and TSH is most probably related to antigen presentation at the surface of the thyrocyte. We conclude that changes in serum TSH concentration should be taken into account in the interpretation of MSA in patients with thyroid disease. whether untreated or treated with L-thyroxine.
Nisoldipine--effects on the renin-angiotensin-aldosterone system and catecholamines. Studies in normotensive and hypertensive subjects, We have studied the effects of nisoldipine. a new calcium channel antagonist. on the renin-angiotensin-aldosterone system and on plasma catecholamines in 10 healthy volunteers and in 29 patients with primary essential hypertension. Of these 29 patients. thirteen had normal renin hypertension (NRH). and sixteen had low renin hypertension (LRH). Eight healthy volunteers received placebo. Short-term (24 h) effects were measured in all subjects and long-term (up to 6 months) effects of 10-40 mg nisoldipine daily were monitored in the 29 hypertensive patients. Plasma renin activity (PRA) increased slightly. although this rise was not statistically significant. 1 h after the first dose of nisoldipine in both normotensive subjects and hypertensive patients. After 2 h PRA had returned to the pre-treatment level. No change in PRA was observed after administration of placebo. Plasma angiotensin II (AII) levels showed considerable variation after nisoldipine administration. Plasma aldosterone levels decreased despite the increase in PRA and AII concentrations. However. no concomitant reduction in urinary aldosterone excretion was observed. Plasma noradrenaline levels increased slightly 2-4 h after administration of nisoldipine. and decreased again thereafter. but no changes in plasma adrenaline levels were seen. Nisoldipine had no long-term effects on the renin-angiotensin-aldosterone system or on serum catecholamine levels.
Metabolic control and complications over 3 years in patients with insulin dependent diabetes (IDDM): the Stockholm Diabetes Intervention Study (SDIS), In a planned 5-year study. 97 patients with insulin dependent diabetes mellitus (IDDM). non-proliferative retinopathy and unsatisfactory blood glucose control were monitored for 3 years. The patients were randomized to an intensified conventional treatment (ICT. n = 44) or a regular treatment (RT. n = 53) group. HbA1c (normal range 3.9-5.7%) was reduced from 9.5 +/- 0.2 (mean value +/- SEM) to 7.4 +/- 0.1% in the ICT group (P = 0.0001). and from 9.5 +/- 0.2 to 9.0 +/- 0.2% in the RT group (P = 0.004). Nerve conduction velocities in the sural and peroneal nerves (P = 0.01-0.0001) were impaired in the RT group. but not in the ICT group. Retinopathy increased in both groups. The condition of 22 ICT patients (50%. 95% confidence interval 34-66%) and 37 RT patients (73%. 61-84%) deteriorated with regard to at least one microvascular complication (retinopathy. nephropathy. neuropathy) (P = 0.024). Lower HbA1c levels during the study significantly reduced the risk of deterioration (P = 0.01). In total. 57% of the ICT patients had at least one episode of serious hypoglycaemia. compared with 23% in the RT group (P = 0.001). The patients in the ICT group also gained weight (P = 0.0001). Improved blood glucose control slowed down the progression of microangiopathy during a 3-year period in patients with non-proliferative retinopathy. but at the price of an increased frequency of serious hypoglycaemic episodes. and some gain in body weight.
Components of delay time in suspected acute myocardial infarction with particular emphasis on patient delay, Two hundred and thirty-four patients admitted to a coronary care unit (CCU) were interviewed a few days after arrival in hospital to determine reasons for patient delay and the various components of total delay time from onset of symptoms to arrival in CCU. Of the three major components of delay. decision time (time from onset of symptoms to decision to go to hospital). and hospital procedure time (time from arrival in hospital to arrival in the CCU). were of the same magnitude. 1 h 15 min and 1 h 30 min (median). whereas the median time for preparation and transportation to hospital was somewhat shorter. being 45 min. Decision time appeared to be similar in patients with confirmed and non-confirmed acute myocardial infarction (AMI) and was not associated with intensity of pain or infarct size. Half of the patients hesitated to go to hospital. which resulted in a prolonged decision delay (3 h). It is concluded that patient indecision to seek medical help is the most important reason for delay in hospital arrival in patients with suspected AMI.
Parents' vs physicians' utilities (values) for clinical outcomes in potentially bacteremic children, Our previous analyses of decision strategies in children 3-24 months with acute-onset fever greater than or equal to 39 degrees C and no evident bacterial focus of infection indicated that the risks of routine blood cultures (the unnecessary hospitalization and treatment of children who clear their bacteremia spontaneously) outweigh its benefits (the prevention of a few cases with major infectious sequelae). Because those analyses were based on parents' values for beneficial and adverse clinical outcomes. we wished to examine whether those values differed in physicians and. if so. whether the differences were sufficient to change the results of the decision analysis. Using a pre-tested linear analog utility (value) scale. we evaluated eight potential clinical outcomes in potentially bacteremic children by surveying 121 parents of healthy 3-24-month-old children attending a private pediatric group practice and 57 attending physicians of a tertiary-care children's hospital emergency room. Utilities were based on a 0-1 normalization. where 0 is the utility of the worst outcome (meningitis or other major bacterial infection. plus venipuncture). and 1 the utility of the best outcome (complete recovery without venipuncture or hospitalization). and were analyzed using a recently developed statistical model of utility. The majority of parents and physicians combined the imputed components of the outcomes (disease. pain of venipuncture. and stress of hospitalization) in a nonlinear fashion. Parents assigned substantially lower utility (i.e. greater disutility) to venipuncture. minor infection. and hospitalization than did physicians. and these utilities were even lower in parents with other children at home.
Prevalence of Raynaud phenomenon in the adult population of South Carolina, A prevalence estimate for Raynaud phenomenon among adult residents of South Carolina was based on data obtained from respondents in a statewide health survey. followed by face-to-face interviews and clinical screening for Raynaud phenomenon. using a screening procedure developed by the authors. The survey obtained 5246 personal interviews from a probability sample of over 3000 households. and 494 survey subjects participated in the clinical screening. The prevalence estimates and their standard errors were computed using survey case weights. design-based estimation. and logistic modelling techniques. The prevalence of Raynaud phenomenon among adult residents of South Carolina was determined to be 3.5%. with a standard error of 0.6%. Prevalence was higher for females (4.3%. SE = 0.7%) than for males (2.7%. SE = 0.6%). These figures are much lower than most estimates in the existing literature on Raynaud phenomenon.
Low gastric acid as a risk factor for cholera transmission: application of a new non-invasive gastric acid field test, Although gastric acid is thought to be an important host defense against certain enteric infections. field studies of the role of gastric acid in preventing enteric infections have been hampered by the lack of a suitable non-invasive test. Because low gastric acid output (GAO) is an established risk factor for cholera. we assessed after validation. whether a new non-invasive test which estimates GAO by measuring breath hydrogen excess after ingestion of magnesium and a stimulant of gastric acid secretion. could discriminate between persons at high and at low risk of developing cholera. Fifteen age-matched pairs. participants in the field trial of two oral cholera vaccines in rural Bangladesh. were tested. In each pair the "case" was a person who had recovered from severe cholera at least 6 months before testing and the "control" was a person who resided in the home of a cholera patient but remained uninfected. The stimulated breath hydrogen was higher in controls (median hydrogen excess = 369 mumol/80 min) than in cases (median hydrogen excess = 150 mumol/80 min) (p less than 0.05) and was higher in controls in 12 out of 15 pairs. The results. which are consistent with past invasive assessments of the association between hypochlorhydria and cholera. suggest that this non-invasive test may be useful in evaluating GAO in epidemiological field studies.
Tampon absorbency, composition and oxygen content and risk of toxic shock syndrome, Tampon use has been identified as a major risk factor for toxic shock syndrome. although the etiologic role of tampons is not clearly understood. Two epidemiologic studies conducted to date have reported an association between tampon absorbency and risk of toxic shock syndrome. This finding is not corroborated by laboratory studies. however. which have suggested that absorbency may be a marker for other characteristics that create an environment conductive to the elaboration of toxic shock syndrome toxin 1. We used data from the previously reported Tri-state study to estimate simultaneously the effects of tampon oxygen content. absorbency and chemical composition. Although the data are sparse. oxygen content was more strongly associated with risk of toxic shock syndrome than either absorbency or chemical composition. The results suggest that it may be possible to develop a highly absorbent tampon that is not associated with a high risk of toxic shock syndrome.
A method of pharmacoepidemiologic analysis that uses computerized Medicaid, A method of pharmacoepidemiologic data analysis that utilizes computerized Medicaid data is presented. A cohort design in which Medicaid enrollees receiving drugs that are normally used to treat similar underlying conditions is described. A period of time in which Medicaid service transactions are evident is required before an individual is eligible for selection into a cohort. Selection of study subjects and descriptions of cohorts are based on Medicaid service histories occurring during the preliminary. prerequisite period. Time at risk is considered to begin after a prescription for a study drug is dispensed and continues until either a refill is dispensed. a prescription for an alternative drug within the same therapeutic class is dispensed. or a predetermined number of days has passed. Subjects are followed forward in time and relevant health care transactions that are suggestive of suspected adverse drug reactions are noted. Incidence densities associated with sequentially ranked prescriptions within sequential courses of therapy are compared. Methods to increase the accuracy of case ascertainment are briefly discussed. Separate validation studies may be used to evaluate the validity of computerized case ascertainment methods and to compensate for misclassification of outcome. The proposed method is intended to provide timely estimates of risk for selected outcomes. For outcomes that cannot be accurately ascertained from computerized data. this method may be useful in determining the feasibility of more customized studies.
Interobserver variation in histopathological grading of cervical dysplasia, In order to assess the variability among histopathologists in grading cervical dysplasia. four experienced histopathologists examined the same set of 106 biopsy specimens and assigned them to one of five diagnostic categories. These were: no dysplasia. mild dysplasia. moderate dysplasia. severe dysplasia and carcinoma in situ. The histopathologists did not discuss the grading criteria beforehand. There was considerable disagreement among the pathologists: unweighted group kappa 0.28. weighted group kappa 0.56. It appeared that all grades of dysplasia were equally difficult to distinguish from adjacent categories. Various explanations for this interobserver variation are put forward.
Predictors of quitting smoking: the NHANES I followup experience, There are no published prospective studies on the predictors of spontaneously quitting cigarette smoking in a nationally-representative U.S. population. This paper describes such a study. using a cohort taken from the First National Health and Nutrition Examination Survey (NHANES I. 1971-1975) and traced by the NHANES I Epidemiologic Followup Survey (1982-1984). "Successful" quitting (for at least 1 year at time of followup) was ascertained among 4779 adults (age 25-74 years) who were smokers at the time of NHANES I and not disabled at followup. Independent predictors of quitting (by proportional hazards multiple regression) were: (1) older age; (2) White race; (3) fewer cigarettes smoked/day; (4) higher household income; and (5) hospitalization in the followup period. Predictors of relapse (ex-smokers at NHANES I who were smoking again at time of followup) were: (1) younger age; (2) urban residence; and (3) female gender. These findings have implications for intervention strategies. public health projections and further research.
Alcohol consumption and blood pressure: a comparison of native Japanese to American men, We compared the cross-sectional association of alcohol consumption with blood pressure in 810 Japanese men (JM) living in Tokyo and 946 white men (WM) living in New York. Mean systolic (JM and WM. p less than 0.001) and diastolic blood pressure (JM. p less than 0.002; WM. p less than 0.001) were associated with alcohol consumption in both groups. Compared to abstainers. the heaviest drinkers had the highest systolic (JM. p = 0.001; WM. p less than 0.01) and diastolic (JM. p less than 0.002; WM. p less than 0.05) blood pressures. The relation of blood pressure to alcohol intake was J-shaped in the Americans. but linear in the Japanese. Exploratory analyses revealed that the J-shape may have been due to under-reporting of heavy alcohol ingestion by American abstainers. When abstainers were excluded. the relationships were similar in both the American and Japanese. The positive association between blood pressure and alcohol consumption persisted after adjustment for age. cigarette smoking. use of antihypertensive medications. body mass index. heart rate. abdominal skinfold thickness. hematocrit. fasting blood glucose. serum uric acid levels and urinary sodium/potassium ratio. Alcohol use was also related to prevalence of hypertension. These findings confirm the presence of an independent association between alcohol intake and blood pressure in both JM and WM and suggest that. despite differences in the metabolism of alcohol. the relation of alcohol consumption to blood pressure is similar in both nationalities.
Palmar keratoses in family members of individuals with bladder cancer, A total of 270 bladder cancer cases. 178 first-degree relatives and 127 spouses of the bladder cancer cases and 329 hospital controls were studied to evaluate the association between palmar keratoses. bladder cancer and environmental and genetic factors. Crude prevalences of keratoses in the 4 groups were 67. 54. 42 and 23%. respectively. Logistic regression models showed that bladder cancer patients had a raised risk of having palmar keratoses relative to hospital controls (odds ratio = 6.95; 95% CI: 4.77-10.12) whereas blood-relatives and spouses had significantly increased odds ratios only if the case in their family (or some other blood-relative) possessed keratoses. Among several environmental and behaviour factors. only cigarette smoking was significantly associated with increased risk (odds ratio = 2.32; 95% CI: 1.63-3.29). The data suggest a genetic component may influence the occurrence of palmar keratoses. but some unknown environmental agent appears to be causing the association between spouses.
CD4+ monocyte counts in persons with HIV-1 infection: an early increase is followed by a progressive decline, In this study. we asked whether there is a difference in the number of CD4+ and CD4- peripheral blood monocytes as CD4+ T cells decrease during HIV-mediated immunodeficiency. Monocytes and T cells from 90 HIV-positive and 43 HIV-negative persons were analyzed by flow cytometry. The 90 HIV-positive patients represented the entire spectrum of CD4+ T-cell counts. We report that as CD4+ T cells decrease. the number of CD4+ monocytes decrease in parallel. Moreover. significantly higher CD4+ monocyte counts were observed in persons with early stage HIV disease. i.e.. greater than 800 CD4+ T cells/mm3. than in HIV-negative persons with greater than 800 CD4+ T cells/mm3. Potential implications of these findings are discussed.
Is the incubation period of AIDS lengthening, Data from a cohort study of 1.637 homosexual men in Los Angeles are used to estimate the distribution of times from HIV infection to AIDS. and to detect any changes in the distribution. We find weak. but not statistically significant. evidence that the incubation period is lengthening. When the incubation period distribution is assumed not to have changed. we estimate that the proportion developing AIDS within 6 years of HIV infection is 27%. with a 95% confidence interval of (23%. 31%). However. if we assume that the incubation period distribution began to change in July 1987. then we estimate that for individuals infected in the first half of 1979. 28% develop AIDS within 6 years. and for those infected in the first half of 1983. 25% develop AIDS in 6 years. Four different hypotheses are suggested for a lengthening of the incubation period; these are a treatment hypothesis. a cofactor hypothesis. a better health care hypothesis. and a changing virus and disease hypothesis. The statistical method used is semiparametric modeling of the joint distribution of the date of infection and the incubation period for the participants in the study. These methods. although computationally intensive. are an attractive way of analyzing data from a prevalent cohort because only minimal parametric assumptions are made.
Epidemiology of acquired immune deficiency syndrome in persons aged 50 years or older, Acquired immune deficiency syndrome (AIDS) has afflicted persons of all ages. yet only recently has attention been devoted to AIDS in older persons. To examine the epidemiology of AIDS in persons greater than or equal to 50 years old in the United States. we analyzed cases reported to the Centers for Disease Control. The number reported annually in persons greater than or equal to 50 years old increased from 13 in 1981 to 3.562 in 1989. Through December 1989. 11.984 had been reported. representing 10% of all cases. Although male homosexual contact accounted for most cases in persons aged 50-69. blood transfusion became a more common means of exposure with increasing age. accounting for 28% of cases in persons aged 60-69 and 64% of cases in individuals aged greater than or equal to 70. The proportion of women increased from 6.1% in persons with AIDS aged 50-59 to 28.7% of those aged greater than or equal to 70. The proportion of AIDS diagnoses made in the same month as death increased from 16% in persons aged 50-59 to 37% in those aged greater than or equal to 80. suggesting either more rapid progression of disease or increasing delay in diagnosis. As the incidence in older persons continues to increase. clinicians caring for older patients must become more familiar with AIDS.
Clinical, laboratory and radiographic features in early rheumatoid arthritis, We evaluated disease status in relation to age. sex and disease duration using some short term indices of disease activity. laboratory tests. and radiological features in 315 patients with rheumatoid arthritis of duration varying from 3 to 36 months (mean 12 months). No differences were observed among various age groups in disease duration. female/male ratio. incidence of radiologic lesions and other indices of disease process. Some clinical markers of the disease process such as involvement of the flexor tendons of the hands and Ritchie's index (score greater than 9) were significantly more frequent in the women (p less than 0.0013 and p less than 0.04. respectively). In the patients with disease of recent onset women were slightly more numerous (56%) than men; however. in those with disease duration of 36 months there were significantly more women (72%) (p less than 0.039). suggesting a greater tendency to chronic disease in this sex. Radiological lesions of the small joints of the hands. feet. and/or wrists were found in 37% of the cases with disease duration of up to 4 months and in 91% at 36 months (p less than 0.0001). The lesions were associated significantly more frequently with Ritchie index (p less than 0.02) and with laboratory indices of inflammatory activity (erythrocyte sedimentation rate greater than or equal to 25 mm/h) (p less than 0.001) and immune response (latex test greater than or equal to 80) (p less than 0.0001). Logistic regression analysis showed that the duration of illness is the most important factor correlating with radiologic lesions.
Clinical and laboratory effects of prolonged therapy with sulfasalazine, gold or penicillamine: the effects of disease duration on treatment response, Serial observations for up to 5 years of clinical score (a subjective global assessment). serum C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were analyzed in 3 groups of patients with active rheumatoid arthritis (RA) requiring treatment with a second line drug. The groups comprised 315 patients (243 women. 72 men) who had sulfasalazine (SAS); 203 patients (141 women. 62 men) who had sodium aurothiomalate (gold) and 163 patients (131 women. 32 men) who had penicillamine. The groups matched in most respects but the gold group had a smaller proportion of women. a shorter median disease duration and a higher median CRP than the remaining 2 groups. The penicillamine group contained a higher proportion of seropositive patients. In each group there were significant improvements in clinical score. CRP and ESR for all time points from 6 to 30 months; these improvements were maintained for longer (up to 60 months for SAS) in the SAS and gold groups but the differences between the drugs after 30 months were probably a consequence of falling number of patients. not differing drug potencies. The mean ESR and CRP levels fell to about 30 mm/h and 20-30 mg/l. respectively. Response was defined as (1) treatment duration greater than 6 months. (2) clinical score improvement greater than 4 by 6 months. (3) ESR fall to less than 30 mm/h by 6 months. By these criteria 142 of 681 patients (20.9%) responded; the response rates were SAS 20.3%. gold 24.1%. penicillamine 17.8%.
Phenotypic characteristics of dissociated mononuclear cells from rheumatoid synovial membrane, The phenotypic characteristics of enzymatically dissociated synovial membrane mononuclear cells from 8 patients (14 samples) with rheumatoid arthritis (RA) were assessed by fluorescence activated flow cytometry and compared to peripheral blood (PB) mononuclear cells from 18 patients with RA and 14 normal controls. There was no significant difference between the percentage of CD4+ and CD8+ lymphocytes in synovial membrane compared to RA and normal PB. Double labelling experiments revealed similar percentages of CD4+ CDw29+ (helper-inducer) and CD4+ CD45R+ (suppressor-inducer) cells in RA and normal PB. In contrast. SM CD4+ CDw29+ cells were present in significantly higher proportions than in RA and normal PB (p less than 0.001). Conversely. synovial membrane CD4+ CD45R+ cells were present in significantly lower proportions than in RA and normal PB (p less than 0.001). A similar pattern of CDw29 and CD45R antigen expression was noted on CD8+ lymphocytes reflecting increased killer-effector (p less than 0.001) and decreased suppressor-effector (p less than 0.001) cells. respectively. Other experiments revealed a significant increase in the percentage of synovial membrane CD20+ cells (B lymphocytes) and HLA-DR+ cells compared to RA PB (p less than 0.02 and p less than 0.001) and normal PB (p less than 0.01 and p less than 0.005). and similar proportions of CD14+ cells (monocytes/macrophages). Our results suggest that RA synovial membrane contains populations of T and B lymphocytes that differ quantitatively and qualitatively from those in PB. These may account for some of the abnormalities in intraarticular humoral and cellular immune responses in patients with RA.
Joint inflammation provoked by a local synovial allergic reaction, Homocytotropic antibody was stimulated in animals by administering protein antigens in a vaccine with B. pertussis adjuvant. The titers of the allergic antibody responses were judged by passive cutaneous anaphylaxis reactions. Sera or globulin fractions containing high titers of antibody activity were injected into the knee joints of experimental animals. After sufficient delay for unfixed proteins to be cleared from the knee joints. animals were challenged intravenously with the corresponding antigen. The resultant local reaction of swelling and warmth (passive synovial anaphylaxis) was judged visually and by scanning procedures. Histological studies showed evidence of mast cell degranulation concurrent with synovial reaction.
The temporomandibular joint in rheumatoid arthritis. Correlations between clinical and computed tomography features, Clinical and computed tomography (CT) examination of the temporomandibular joint (TMJ) was performed in 26 patients with rheumatoid arthritis (RA) and 26 control subjects. Each examination was scored. In the group with RA 61.2% had physical signs in the stomatognathic system compared to 42.3% in a control group (NS); 88.4% of the group with RA had erosive or cystic lesions of the TMJ compared to 57.6% of control subjects (p less than 0.05). The clinical dysfunction score did not correlate with the CT TMJ score in RA. It correlated with the number of slow acting antirheumatic drugs used. the rheumatoid factor titer and radiographic scores of the hands and cervical spine. In agreement with others. we believe that the only specific CT lesions of RA are erosions and cysts of the mandibular condyle. that there is no correlation between clinical and CT findings of TMJ in RA. and that the intensity of destructive lesions of TMJ on CT in RA is well correlated with the severity of the disease.
Defective expression of p70/75 interleukin 2 receptor in T cells from patients with systemic lupus erythematosus: a possible defect in the process of increased intracellular calcium leading to p70/75 expression, Phytohemagglutinin (PHA) stimulated T cells from patients with systemic lupus erythematosus (SLE) showed hyporesponsiveness to interleukin 2 (IL-2) and expressed less p70/75 IL-2R than healthy controls. Ionomycine (IM. calcium ionophore) which selectively upregulated p70/75 expression. induced less p70/75 in patients with SLE than in healthy controls. However. intracellular calcium levels of T cells from patients with SLE increased as much as those from healthy controls. when T cells were stimulated by IM or PHA. Our results suggest that an impaired expression of p70/75 IL-2R in T cells from patients with SLE is not due to a defective calcium influx but to the events after the rise of calcium levels.
Specificity of anti-Scl-70 antibodies in scleroderma: increased sensitivity of detection using purified DNA topoisomerase I from calf thymus, A large scale purification of DNA topoisomerase I from calf thymus was obtained using the combinations of 62% ammonium sulfate precipitation. Biorex 70. hydroxylapatite and phenylagarose chromatography. Silver staining of the preparation separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed 2 bands of apparent molecular weight of 70 and 60 kDa. Immunoblotting with a serum of anti-Scl-70 specificity also recognized both proteins. Anti-Scl-70 antibodies were detected in 24/32 (75%) patients with diffuse scleroderma by ELISA and 28/32 (87%) had the ability to neutralize the topoisomerase I activity. All of 14 sera with anticentromere antibodies did not react with DNA topoisomerase I by both assays. The presence of anti-Scl-70 antibodies remained disease specific despite the increase in sensitivity of both assays.
Role of membrane proteins in monosodium urate crystal-membrane interactions. II. Effect of pretreatments of erythrocyte membranes with membrane permeable and impermeable protein crosslinking agents, Intact. human erythrocytes were pretreated with membrane permeable. dimethyl adipimidate (DMA) and dimethyl suberimidate (DMS) and membrane impermeable 3.3' dithiobis (sulfosuccinimidylpropionate) (DTSSP) protein crosslinking agents and incubated with monosodium urate monohydrate (MSUM) crystals. The percent inhibition of lysis values for pretreated cells relative to untreated cells were determined. All 3 agents caused a concentration dependent inhibition of MSUM induced hemolysis that was not due to a decrease in MSUM binding to the pretreated membranes. It was proposed that the inhibition of lysis was due to crosslinking of integral and cytoskeletal membrane proteins. resulting in a reduced mobility of the proteins. inhibition of lateralization of integral proteins into aggregates and decreased "pore" formation in the membrane.
HLA antigens and nailfold capillary microscopy studies in patients with insulin dependent and noninsulin dependent diabetes mellitus and limited joint mobility, We investigated the HLA status of patients with diabetes associated with limited joint mobility and microvascular complications. An increased frequency of HLA-B8. DR3 and DR4 in patients with insulin dependent diabetes mellitus (IDDM) compared to controls and patients with noninsulin dependent diabetes mellitus (NIDDM) was confirmed. HLA antigen DQw1 was detected less frequently in patients with IDDM and was negatively associated with limited joint mobility and retinopathy. Limited joint mobility was significantly correlated with disease duration in IDDM. and was associated with neuropathy in both IDDM and NIDDM and with retinopathy in IDDM. No correlation was found between DR3. DR4 and limited joint mobility or diabetic complications. We also investigated the usefulness of nailfold capillary microscopy in a large group of patients with IDDM and NIDDM. Although capillary enlargement and avascular areas were noted in a few patients. nailfold capillary microscopy was not felt to be a useful tool in the evaluation of diabetes.
Development and potential use of antibody directed against lipopolysaccharide for the treatment of gram-negative bacterial sepsis, Gram-negative bacterial sepsis remains a major cause of lethality in hospitalized patients. despite routine therapy consisting of antimicrobial agents. hemodynamic monitoring and fluid resuscitation. and metabolic support. Because a large body of evidence supports the concept that Gram-negative bacterial lipopolysaccharide (endotoxin. LPS) is responsible for many of the direct and host mediator-induced deleterious effects. recent work has been centered on the development and use of anti-LPS antibody preparations in order to ameliorate lethality. Both polyclonal and monoclonal antibody preparations directed against the common deep core/lipid A region of LPS are cross-reactive in vitro and cross-protective in vivo against a wide range of challenge organisms and LPS. and preliminary clinical trials indicate that a reduction in lethality may be possible. The precise endotoxin epitope against which antibody should be directed in order to maximize protection. however. has not been established. This modality most probably will become a standard form of adjunctive therapy within the next several years for the treatment of Gram-negative bacterial sepsis.
Biliary and gut function following shock, The aim of this study was to characterize the alterations in gallbladder and intestinal function after hemorrhagic shock and blood reperfusion in opossums. Animals were subjected to a shock of 30 mm Hg of arterial blood pressure for 60 minutes and resuscitated with blood reinfusion. Gallbladder epithelial ion transport. gallbladder motility in vitro and in vivo. gastrointestinal motility. and flora of the stomach and small bowel were studied 2 and 24 hours after shock. Changes at 2 hours included decreased gallbladder contractility in vitro and decreased emptying in vivo. loss of coordination with intestinal motor activity. decrease in frequency of intestinal electrical slow waves. and reduced duration of the intestinal migrating motor complex cycle. By 24 hours. gallbladder epithelial permeability was increased and in vitro contractility remained reduced but the in vivo functions showed partial recovery. Gastrointestinal flora was not affected by these changes. These data demonstrate that hemorrhagic shock and reperfusion affect digestive motility. The early timing of the alterations observed and the partial recovery 24 hours post shock suggest an ischemia-hypoxia mechanism of injury.
Altered Ca2+ homeostasis and functional correlates in hepatocytes and adipocytes in endotoxemia and sepsis, Decreased cytosolic [Ca2+] and impaired Ca2+ release in response to an IP3 challenge are among perturbations in hepatocyte Ca2+ homeostasis associated with endotoxemia and sepsis. These changes are consistent with the accompanying alterations in appropriate physiologic functions. e.g.. activation of glycogen phosphorylase and gluconeogenesis. mediated by [Ca2+]c and defective phosphorylation of relevant enzymes. Attenuation of IP3 binding to the subcellular fractions that are imputed to be targets of IP3 and a decrease in the size of the IP3-sensitive pool of releasable Ca2+ are underlying components of the mechanism of the reduced Ca2+ release upon IP3 stimulation and its metabolic sequelae. ET treatment leads to a significant increase in Ca2+ associated with the cell surface compartment of adipocytes. a reduction in 45Ca2+ uptake by endoplasmic reticulum and higher cytosolic [Ca2+] under basal conditions and upon ACTH stimulation than that observed in cells of control rats. The reduced 45Ca2+ uptake is also manifest in adipocytes of septic rats. Alterations in adipocyte metabolism induced by ET include increased oxidation of glucose to CO2 (an insulin-like effect) and increased lipolysis upon NE and ACTH stimulation.
Assessing nutritional needs for the burned patient, Assessment of nutritional needs following thermal injury remains an important adjunct to providing dietary therapy designed to minimize the detrimental effects of hypermetabolism and subsequent catabolism. Most anthropometric measurements. frequently utilized in nonburned patients. have relatively little usefulness in assessing burned individuals. Energy expenditure can be adequately estimated for most patients by direct calorimetry. indirect calorimetry. or formulae. Direct calorimetry is the most expensive and complicated method. while use of a formula is the most inexpensive and least complicated. All yield good results in the clinical setting. Differences in estimated energy expenditure by the multiple formulae may be statistically significant. but rarely are clinically significant. Therefore selection of a formula should be based on simplicity. Estimations by formula require readjustment at intervals of 1 to 2 weeks. In general. enteral feedings remain superior to parenteral delivery of nutrients. Finally. current animal research suggests significant differences in metabolic and immunologic effects of the diet depending on qualitative make-up of dietary fat sources.
Effect of early feeding on the postburn hypermetabolic response in rats, The effect of early enteral feeding on the hypermetabolic response following burn injury in a rat burn model has been investigated. The rates of heat production and partitioned heat loss were determined on the fourteenth postburn day for five treatment groups: I) burn. fed rat chow ad libitum starting 2 hours postburn; II) burn. fed by gastrostomy beginning 2 hours postburn; III) burn. fed by gastrostomy. delayed until 72 hours postburn; IV) controls. fed by gastrostomy 2 hours post anesthesia; and V) controls. fed rat chow ad libitum 2 hours post anesthesia. Gastrostomy feedings delivered 175 kcal/kg.day. The mean rates of heat production and heat loss for the three burn groups did not differ significantly whether rats were fed chow ad libitum. or by gastrostomy early or late. Contrary to previous studies using a guinea pig model. method and timing of feeding in this burned rat model had no significant effect on the postburn increment in the rate of heat loss and the corresponding increment in the rate of heat production.
Antibiotics and the postburn hypermetabolic response, Severe burn injury has been documented to significantly increase resting metabolic energy expenditure. This increase in metabolic rate appears to be possibly correlated with the degree of burn wound colonization and infection with bacteria. Prevention of such colonization and infection through the use of topical antimicrobial agents appears to decrease the metabolic alterations resulting from burn injury. These findings indicate that appropriate use of topical antibacterial agents may decrease the metabolic demands seen in burned patients. Burn-induced translocation of intestinal bacteria has also been hypothesized to contribute to the postburn hypermetabolic response. Attempts at preventing this entity in a burned guinea pig model through the use of selective decontamination of the digestive tract by the administration of enteral antibiotics have failed to demonstrate any measurable effect.
Pulmonary circulation and burns and trauma, The lung is a critical organ in victims of thermal injury or multiple trauma since the blood that drains injured organs circulates through the pulmonary circulation before passing through any other organ. The lung therefore will receive the first volley of cytotoxins released postinjury. In addition to being a target of injury. the lung may also contribute to the injury of systemic organs. This injury may be the result of a reduced delivery of oxygenated blood or the direct release of cytotoxins into the systemic circulation. The injury to the lung may be to the pulmonary microvasculature or the airway. The bronchial circulation responds to injury by a marked elevation in its blood flow and microvascular permeability. These latter effects may be important in mediating the changes which occur in the lung parenchyma.
Evaluation and management of patients with inhalation injury, Inhalation injury. present in approximately one third of burned patients treated at burn centers. increases mortality by a maximum of 20% in relation to age and extent of burn. The development of animal models of inhalation injury has made possible the identification of both the airway and vascular responses evoked by smoke inhalation. Inflammatory occlusion of terminal bronchioles and necrosis of the endobronchial mucosa render the airway and pulmonary parenchyma susceptible to infection and the resulting pneumonitis further increases mortality. Early diagnosis. best achieved by endoscopic bronchoscopy and 133xeon ventilation perfusion scan. permits timely application of high-frequency ventilation that appears to reduce the incidence of pneumonia and to decrease mortality. Pharmacologic agents give promise of ameliorating the deleterious changes of the vasculature. The recent advances in understanding inhalation injury have identified the research needed to further improve patient salvage.
Pathophysiologic events related to thermal injury of skin, Acute thermal injury of skin equivalent to second-degree injury and involving approximately 25% of total body surface results in a series of pathophysiologic events which lead to both local and distant tissue/organ injury. The distant effects involve intravascular hemolysis and acute lung injury. both of which can be attributed to complement activation and intravascular stimulation of neutrophils. resulting in oxygen radical production. which results in injury of red cells and pulmonary vascular endothelial cells. At the local site of thermal injury. the progressive increase in vascular permeability is linked to complement activation and histamine release. the outcome of which is interaction of histamine with xanthine oxidase. resulting in enhanced catalytic activity of the enzyme. Toxic oxygen products of xanthine oxidase. including H2O2 and its conversion product. the hydroxyl radical. appear to be linked to the damage of dermal vascular endothelial cells. resulting in progressive vascular permeability. The increased vascular permeability can be greatly attenuated by the use of inhibitors of xanthine oxidase. the inhibitor of histamine release (cromolyn). catalase. an iron chelator (deferoxamine). or scavengers of the hydroxyl radical. Interestingly. neutrophils appear to play little if any role in dermal vascular injury in this animal model of thermal trauma. Those studies suggest that pathophysiologic events following local thermal trauma are complex and involve a variety of mediator pathways.
The percutaneous operative gastrostomy for gastric decompression in major urological surgery, When postoperative gastric decompression is necessary a percutaneous gastrostomy tube is an alternative to nasogastric intubation. The percutaneous insertion of a suprapubic bladder catheter is an easy procedure without notable complications that increases the comfort of the patient in the immediate postoperative period. We advocate its use in all major urological abdominal operations.
Short-term and long-term changes in renal function after donor nephrectomy, We retrospectively examined the effect of nephrectomy on renal function in 55 living related donors. Renal function was measured with 131iodine-orthoiodohippurate scans. All patients were studied preoperatively. and 1 week and 1 year postoperatively. In 20 patients 10-year followup was available. Compensatory hypertrophy was complete 1 week postoperatively: effective renal plasma flow of the remaining kidney was 32.5% higher than preoperatively. The increase remained stable for at least a year. The degree of compensatory hypertrophy was significantly greater in male patients (46.9% after 1 week) than in female patients (26.7%). Compensatory hypertrophy occurred in all age groups studied and it was most pronounced in patients less than 30 years old. In the patients followed for 10 years effective renal plasma flow decreased from 387.7 ml. per minute 1 week after nephrectomy to 367.4 ml. per minute at 10 years. This result is similar to the decrease seen in the normal population. According to our results. renal donation by living related persons does not lead to long-term decrease in renal function.
Treatment of idiopathic retroperitoneal fibrosis by immunosuppression, Idiopathic retroperitoneal fibrosis is exceedingly uncommon in childhood and its etiology is uncertain. Support for an immunological basis for the disease is given by a report of a 14-year-old girl with severe retroperitoneal fibrosis causing progressive azotemia in whom azathioprine and prednisolone were used successfully. This case supports the efficacy of immunotherapy in the treatment of idiopathic retroperitoneal fibrosis.
Ischiopagus tetrapus twins: urological aspects of separation and 10-year followup, Conjoined twins occur once in 50.000 births. Only 6% of conjoined twins are of the ischiopagus type in which the twins are joined symmetrically at the pelvis and fusion begins at the level of the common umbilicus. The longitudinal axis extends in a straight line in opposite directions and the genitourinary and gastrointestinal tracts are shared. Tetrapus is a subtype in which all 4 lower extremities are present and oriented at right angles to the axis of the common trunk. Two sets of female ischiopagus tetrapus twins were born in 1977 and successfully separated at the St. Louis Children's Hospital in the following year. We describe the genitourinary and associated anomalies. surgical separation and long-term urological followup of these 2 sets of ischiopagus tetrapus twins.
Screening for prostatic carcinoma, Routine testing for prostatic carcinoma by digital rectal examination. transrectal ultrasonography and prostate specific antigen determination has been proposed to reduce deaths by earlier diagnosis. The questionable reliability of results. cost of screening. and inability to establish a balance between the benefits of treatment and the adverse effects on the quality of life of the men screened make screening experimental until controlled studies prove its value.
En bloc transplantation of kidneys from donors weighing less than 15 kg. into adult recipients, En bloc transplantation of kidneys from donors who weighed less than 15 kg. into 20 adult patients is described. Intraperitonealization of the medial kidney allowed adequate renal positioning and growth. Graft venous thrombosis occurred in 1 patient and irreversible graft rejection occurred in 4 patients. Graft survival was 65% with excellent function at a mean followup of 8.8 months. En bloc transplantation of pediatric cadaver kidney grafts in adults is an acceptable procedure.
Enhancing effect of partial cystectomy on rat urinary bladder carcinogenesis, The effects of 5% and 50% partial cystectomies on bladder tumorigenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine(BBN) were investigated in Wistar rats by examining the histological findings and cell proliferative activity. The incorporation of bromodeoxyuridine (BrdUrd) into the DNA synthesis phase was determined by an in-vitro labeling technique. After eight weeks of treatment with drinking water containing 0.05% BBN. 5% or 50% partial cystectomy was performed at the end of week 16. and the resected bladder was sutured with dexon or silk. There was no difference in the incidence of papillary or nodular (PN) hyperplasia between the control and partial cystectomy groups. However. the incidence of cancer in the group given partial cystectomy was much higher than that in the control. All the cancers in the control group were grade-1 superficial tumors. whereas grade-2 or invasive tumor was observed in six of 40 animals in the partial cystectomy group. The 31.0% labeling index of cancer in the partial cystectomy group was greater than the 24.1% in the control group. There was also a significant difference in the number of BrdUrd-labeled cells in PN hyperplasia between the control and partial cystectomy groups. These findings indicate that partial cystectomy enhances BBN-initiated bladder carcinogenesis and the increase in DNA synthesis found in PN hyperplasia and cancer may be associated with the induction of bladder tumors.
Immunotherapy of murine bladder cancer by irradiated tumor vaccine, This investigation explored the efficacy of irradiated autologous mouse bladder tumor (Ir-MBT2) as an active specific immunotherapeutic agent and as adjuvant therapy with Bacillus Calmette-Guerin (BCG) against a subcutaneously transplanted murine bladder tumor. Tumor incidence was significantly reduced in groups receiving BCG (27%. p less than 0.005) or Ir-MBT2 with BCG (53%. p less than 0.025). compared to control (93%). Survival was significantly improved in groups treated with BCG (100%. p less than 0.005). 10(5) Ir-MBT2 with BCG (53%. p less than 0.01). or 10(7) Ir-MBT2 with BCG (47%. p less than 0.025) compared with control (13%). Surprisingly. Ir-MBT2 consistently reduced the efficacy of BCG alone. Ir-MBT2 alone (10(7)) appeared to enhance tumor growth. Autologous irradiated bladder tumor vaccine. alone or in combination with BCG. displayed no immunotherapeutic advantage. The use of irradiated tumor cell vaccine for bladder cancer therapy may reduce the results achievable with BCG alone.
The effects of basic fibroblast growth factor and suramin on cell motility and growth of rat prostate cancer cells, Suramin. a new type of cancer chemotherapeutic agent with growth factor antagonist properties. has been reported to affect growth of prostate cancer metastatic lesions. Partin et al. have previously reported that prostate cancer cell motility was essential for tumor cell metastasis. We have studied the effects of suramin on cell motility and cell growth in a prostate cancer cell model. We have demonstrated that suramin has differential effects on rat prostate cancer cells in vitro. The effects of suramin on cell growth were biphasic. At low concentrations of 0.01 mM and 0.1 mM. suramin stimulated growth while it was inhibitory at a higher concentration of 1.0 mM. and 10 mM suramin resulted in cell death. Cell motility was inhibited at a suramin concentration above 0.1 mM. The inhibition of cell motility by suramin may be through the blockage of growth factor effects. Reducing serum growth factor concentration reduced cell motility and the motility was restored by the addition of basic fibroblast growth factor (bFGF) to the media. Motility which had been restored by bFGF could then be blocked by the presence of suramin. The inhibition of cell motility by suramin is reversible on washout of the drug. Suramin inhibits cell motility in both the human prostate cancer cells (LNCaP) and the rat (MLL).
Endourological experience with cystine calculi and a treatment algorithm, Between May 1984 and January 1988. 18 patients (31 pyeloureteral units) with documented symptomatic cystine stones were treated. Stone size ranged from 5 to 56 mm. in largest diameter. with an average of 21 mm. All pyeloureteral units were treated initially by endourological methods. including ureteroscopy in 10. percutaneous ultrasonic lithotripsy in 9. extracorporeal shock wave lithotripsy (ESWL) in 10 and chemolysis in 2. Of the patients 10 required a combination of these technologies and 2 required an open operation. Of the 31 units 23 were free of stones when the patient was discharged from the hospital. Of 8 patients with retained stones only 3 had fragments greater than 3 mm. in diameter. Based on this experience an algorithm was developed for the urological management of cystine stones. Ureteral calculi may be removed by ureteroscopic techniques or manipulated into the renal pelvis and managed as renal stones. Cystine renal calculi of less than 1.5 cm. may be treated with ESWL monotherapy. Stones of 1.5 to 3 cm. may be treated with ESWL and dissolution. or percutaneous ultrasonic lithotripsy plus dissolution. Staghorn calculi may be treated by percutaneous ultrasonic lithotripsy plus ESWL and/or dissolution for retained fragments.
Afferent nipple valve malfunction caused by anchoring collar: an unexpected late complication of the Kock continent ileal reservoir, In the construction of a Kock continent ileal reservoir for urinary diversion. significantly high rates of late postoperative complications regarding nipple valves. the efferent limb in particular. have been reported. There are only a few reports on afferent nipple valve malfunction. A total of 42 patients who underwent a Kock pouch operation and were observed for more than 12 months (mean 38 months) was evaluated in terms of afferent nipple valve malfunction. Late afferent nipple valve complications were observed in 10 of the 42 patients (24%). These complications included erosion of the polyester fiber fabric used as a collar (5 patients). stenosis of the afferent limb (2) and obstruction of the afferent nipple by a mucous plug or fungus ball (3). The latter 2 complications were due to mechanical or dynamic obstruction of urine flow caused by a nonabsorbable collar. None of the 10 patients had problems with efferent nipple valve function. Our results suggest that the peristaltic direction of the intestine and the use of nonabsorbable material as a collar are primarily responsible for the late afferent nipple valve complications. Further modifications are needed to produce a stable nipple valve. Otherwise. simpler and more reliable alternative techniques of antireflux anastomosis should be considered.
Intracavernous injection of prostaglandin E1 in combination with papaverine: enhanced effectiveness in comparison with papaverine plus phentolamine and prostaglandin E1 alone, We compared the erectile response to intracavernous injection of a combination of papaverine and prostaglandin E1 with that of a combination of papaverine and phentolamine (49 patients). and prostaglandin E1 alone (38). The degree of erection achieved was significantly better with papaverine plus prostaglandin E1 than with papaverine plus phentolamine and the duration of erection was less. although the incidence of prolonged erections (greater than 5 hours) was similar with both combinations. Papaverine with prostaglandin E1 likewise resulted in a significantly better degree of erection than prostaglandin E1 alone (prolonged erections occurred only after the drug combination). All erections subsided spontaneously and none required medical intervention throughout the study. Pain was noted only after injection of prostaglandin E1. The incidence was clearly lower (7 of 38 versus 13 of 38) after the injection of only 5 micrograms. prostaglandin E1 in combination with papaverine (although the difference is not statistically significant). Subjectively. the side effects caused by the drug combination were described as much less dramatic by the patients than after prostaglandin E1 alone. The combination of papaverine and prostaglandin E1 shows a clearly synergistic effect and might suitably replace papaverine plus phentolamine or prostaglandin E1 alone in patients who do not respond well or suffer side effects after high single doses.
The fate of residual fragments after extracorporeal shock wave lithotripsy monotherapy of infection stones, We reviewed 53 patients with infection stones treated by extracorporeal shock wave lithotripsy (ESWL*) monotherapy to determine the long-term rate free of stones and the stone recurrence rate as correlated with the pre-treatment stone burden and the radiological presence of sand or fragments after the procedure. Long-term followup (mean 26.6 months) was available on 33 patients representing 38 kidneys. Although only 3 kidneys were free of stones immediately after ESWL. 20 were without stones at 3 months and 18 (47%) were stone-free at followup. Of 9 kidneys with fragments of more than 5 mm. after the final treatment 7 (78%) had residual fragments at 3 months and experienced stone progression. Of 9 kidneys with sand remaining 6 (66%) and all 3 kidneys that appeared to be free of stones after ESWL were without stones at followup. The 3-month plain film of the kidneys. ureters and bladder was a reliable indicator of eventual outcome. Of 20 kidneys that were free of stones at 3 months 16 remained without stones. Of 18 kidneys with residual stone particles at 3 months 14 showed disease progression. 2 had stable disease and 2 passed residual sand. Only 1 of 17 patients who were free of stones or had stable stone disease had a positive urine culture at followup. Patients with infection stone fragments 3 months after ESWL monotherapy have a high rate of stone progression (78%) and should undergo further treatment. ESWL monotherapy of infection stones requires close patient followup to assure that all residual fragments have passed and urine remains sterile.
Pathophysiology of prolonged penile erection associated with trazodone use, Treatment with the antidepressant trazodone has been associated with the occurrence of prolonged penile erection and priapism. To evaluate the effect of trazodone on erection we monitored the periodic physiological sleep-related erections in 6 healthy volunteers in a double-blind crossover study comparing the effect of trazodone. trimipramine (a tricyclic antidepressant) and placebo. In addition. to determine the effects of trazodone on the neurovascular control of penile smooth muscle we performed in vitro studies on corpus cavernosum tissue obtained from patients undergoing penile prosthesis implantation. Trazodone significantly increased the total interval of nocturnal erectile activity. while trimipramine had no effect. During the high dose treatment (nights 4 and 5) the average duration of erectile activity per night with placebo was 158 +/- 41 minutes (mean +/- standard deviation) for night 4 and 177 +/- 21 minutes for night 5. During trazodone treatment the erectile activity per night was significantly prolonged to 285 +/- 115 minutes during night 4 and 232 +/- 86 during night 5 (p less than 0.01). Analysis of the erectile activity in relation to the rapid eye movement sleep period during which erectile activity usually occurs revealed that the detumescence phase of erection. under sympathetic control. was significantly prolonged an average of 2.4 times by trazodone compared to placebo (p less than 0.05). In vitro. trazodone at concentrations comparable to those reached in plasma significantly impaired corporeal smooth muscle contractions elicited by electrical stimulation of adrenergic nerves and antagonized contractions induced by exogenous norepinephrine. We conclude that trazodone can enhance penile erection in man and propose a mechanism related to the alpha-adrenoceptor blocking properties of trazodone by interference with the sympathetic control of penile detumescence.
Biochemical analysis of electroejaculates in spinal cord injured men: comparison to normal ejaculates, To address the consistent finding of asthenospermia in spinal cord injured men we compared the biochemical constituents of antegrade fractions of electroejaculates of 6 such patients with the manual ejaculates of 6 volunteers. Semen samples in each group were analyzed for 19 biochemical parameters. pH and osmolality. Organic components included triglycerides. glucose. fructose. uric acid. creatinine. urea. total protein. albumin and cholesterol. Metabolic enzymes. including glutamic oxaloacetic transaminase (GOT). glutamic pyruvic transaminase. lactate dehydrogenase and alkaline phosphatase. were measured. Inorganic constituents included chloride. sodium. potassium. zinc and phosphorous. Although not significant. higher levels of blood urea nitrogen and creatinine were demonstrated in most electroejaculates suggesting urinary contamination of the antegrade specimens. In electroejaculates significantly lower levels (p less than 0.05) of fructose. albumin. GOT and alkaline phosphatase as well as significantly higher levels (p less than 0.05) of chloride were noted. No significant difference in osmolality or pH was found. Moreover. in the electroejaculates the levels of glucose. uric acid and all inorganic constituents approached their corresponding levels in serum. We conclude that biochemical abnormalities of the seminal plasma may contribute to seminal dysfunction of spinal cord injured men and may result from neurological injury to the accessory sex glands or from the electroejaculation procedure itself.
Prostate cancer: comparison of digital rectal examination and transrectal ultrasound for screening, A prostate cancer screening study of 315 asymptomatic men comparing digital rectal examination and transrectal ultrasound identified 23 cancers. for a detection rate of 7.3%. Of the cancers 17 (5.4%) were diagnosed by digital rectal examination. Contrary to the experience of others. this was a higher rate than achieved by transrectal ultrasound (14 cases or 4.4%). Systematic multiple needle biopsies of both lobes with ultrasound guidance were routinely performed. As a result of this technique 7 of 23 cancers (30%) were fortuitously diagnosed. In addition. only unilateral disease was suspected in 4 of 7 patients with bilateral disease on biopsy. Digital rectal examination and transrectal ultrasound identified the same number of patients with small (less than 1.5 cm.) cancers. contrary to other reports that found transrectal ultrasound to be superior. Digital rectal examination is considered an effective screening examination. equivalent to transrectal ultrasound and preferable because of lower cost. An algorithm for screening is outlined with digital rectal examination and prostate specific antigen determinations.
Trace elements and urinary stone formation: new aspects of the pathological mechanism of urinary stone formation, The urinary stone. serum and 24-hour urine concentrations of 14 trace elements were determined in urinary stone patients by inductively coupled plasma atomic-emission spectroscopy. The data obtained for 25 active stone patients and 32 whose last stone episode had occurred at least 12 months previously were compared with those of 25 healthy individuals. Urinary nickel. manganese and lithium excretion. and serum nickel. manganese and cadmium concentrations were statistically significantly lower for active stone patients compared to those with previous stone episodes and healthy individuals. No difference in the concentrations of trace elements could be found. however. for patients with previous stone episodes and healthy individuals. Nickel. manganese. lithium and cadmium could be of significance in the pathological mechanism of stone formation. not from mineralogical or crystallographic viewpoints but for the smooth flow of enzymatic reactions in biological systems.
Population and pedigree studies reveal a lack of association between the dopamine D2 receptor gene and alcoholism, Using the dopamine D2 receptor clone lambda hD2G1. Blum et al recently found that the D2/Taq I allele (A1) was present in 69% of 35 deceased alcoholics but in only 20% of an equal number of controls. To assess this association further. we evaluated the D2/Taq I polymorphism and a single-strand conformation polymorphism detected by polymerase chain reaction and nondenaturing gel electrophoresis (PCR-SSCP) of the 3' noncoding region of the D2 receptor gene. We studied 40 unrelated white alcoholics. 127 racially matched controls. and two white pedigrees. The Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) clinical diagnostic interviews were rated blindly by two clinicians. The SADS-L interviews and other data were then used to ascertain diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders. Revised Third Edition (DSM-III-R) criteria. Alcoholics were subtyped according to age of onset. severity. presence of antisocial personality. and family history. No significant differences in either D2/Taq I or PCR-SSCP allele frequencies were observed between alcoholics. subpopulations of alcoholics. or controls. The PCR-SSCP polymorphism provided independent information against linkage at the D2 receptor locus. Several recombinants between the D2/Taq I locus and alcoholism were observed in two white families with an alcoholic parent who possessed the A1 allele. This study does not support a widespread or consistent association between the D2 receptor gene and alcoholism.
Barrier contraceptive methods and preeclampsia, Recent investigations have suggested that women who use barrier methods of contraception may be at increased risk for preeclampsia. We used data from two prospective pregnancy studies to examine the relationship between contraceptive use before conception and preeclampsia. The preeclampsia rates among women using barrier contraceptives were not significantly higher than the rates in women using nonbarrier contraceptives or the rates in women using no contraceptives in either study. The odds ratios for preeclampsia in barrier contraceptive users in the two studies were 0.89 (95% confidence interval [Cl]. 0.71 to 1.12) and 0.85 (95% Cl. 0.49 to 1.45) compared with nonbarrier contraceptive users and 0.91 (95% Cl. 0.71 to 1.16) and 0.81 (95% Cl. 0.48 to 1.35) compared with women using no contraceptives. After adjusting for other risk factors. we found no association between preeclampsia and barrier contraceptive use. Additional studies are needed to resolve this issue; however. we would recommend that women not be advised to avoid barrier contraceptives unless more data linking their use to preeclampsia appear.
Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism, Certain proteins (called apolipoproteins B and E) on the surface of lipoprotein particles are responsible for mediating the binding of cholesterol-rich particles to specific lipoprotein receptors on the surface of cells and represent a major pathway controlling blood cholesterol levels. Three important disorders of lipoprotein metabolism. which provide insights into the molecular mechanisms responsible for the elevation of specific atherogenic lipoproteins. are the following: (1) Type III hyperlipoproteinemia results from specific mutations in apolipoprotein E that prevent the normal binding of chylomicron remnants and very-low-density lipoprotein remnants to lipoprotein receptors. Patients with this disorder who have elevated levels of these remnant lipoproteins develop atherosclerosis. (2) Familial defective apolipoprotein B-100 results from a single amino acid substitution in apolipoprotein B that prevents low-density lipoprotein from binding normally to the low-density lipoprotein receptor and elevates plasma cholesterol levels. (3) Familial hypercholesterolemia. which results in elevated levels of plasma low-density lipoprotein and premature atherosclerosis. is caused by a variety of mutations in the low-density lipoprotein receptor that interfere with the normal binding of lipoproteins to this receptor. These observations not only provide insights into the mechanisms responsible for normal lipoprotein metabolism. but also highlight the potential role of specific lipoproteins in atherogenesis.
Selected measures of health status for Mexican-American, mainland Puerto Rican, and Cuban-American children, The 1987 National Vital Statistics System and the Hispanic Health and Nutrition Examination Survey (1982 through 1984) were used to assess the health status of Mexican-American. mainland Puerto Rican. and Cuban-American children by examining the prevalences of pregnancy outcomes and chronic medical conditions. The low-birth-weight rate among Hispanics (7.0%) compared favorably with that of non-Hispanic whites (7.1%) despite the greater poverty and lower levels of education among Hispanics. When examined by Hispanic subgroup. however. significant differences were present. with mainland Puerto Ricans having the highest prevalences of low-birth-weight infants. Premature births were more common among all three Hispanic subgroups than among non-Hispanic whites. Mexican-American and Cuban-American children had a similar prevalence of (3.9% and 2.5%. respectively) chronic medical conditions compared with non-Hispanic white children; Puerto Rican children had a higher prevalence of chronic medical conditions (6.2%). When assessed by these health status indicators. Hispanic children seem to have a health status similar to non-Hispanic white children. However. mainland Puerto Rican children seem at greater risk for poor health. reflecting the US Hispanic population's heterogeneity. Health programs targeted at US Hispanics should appropriately consider these group differences.
Health issues at the US-Mexican border, With a rapidly growing population. increasing manufacturing activity. and increased interdependence. health issues on the US-Mexican border are demanding greater attention. It is unlikely that any other border in the world separates two nations having such variety in health status. entitlements. and utilization. Binational initiatives in the areas of environmental health and sanitation are clearly needed. Further cooperation between the United States and Mexico in provision of health services is warranted and will probably require enhanced federal funding or subsidies to be successful.
Nicotine-replacement therapy with use of a transdermal nicotine patch--a randomized double-blind placebo-controlled trial, The rate of smoking was significantly reduced in volunteer subjects by providing effective nicotine replacement. self-help material. and weekly visits with a nurse for 6 weeks. Nicotine-replacement therapy with a transdermal nicotine patch (Nicolan) almost doubled the 6-week smoking-cessation rate in comparison with that in a placebo group (77% versus 39%; P = 0.002) among subjects who were smoking at least 20 cigarettes per day at baseline. Although most subjects who used the active nicotine patches had skin reactions. the reactions were primarily mild. For use of both active and placebo patches. the level of patient compliance was high. Among subjects who continued to smoke. the use of cigarettes was decreased to less than 50% of the baseline smoking level in 7 of 7 with active nicotine patches and in 15 of 19 with placebo patches. Outcomes beyond 6 weeks showed a substantial relapse rate in both groups. Thus. when nicotine-replacement therapy is provided. a need exists for concurrent behavioral intervention and training for prevention of a relapse. neither of which was part of this protocol.
Safety of same-day sequential extracorporeal shock wave lithotripsy and dissolution of gallstones by methyl tert-butyl ether in dogs, Passage of stone fragments after extracorporeal shock wave lithotripsy (ESWL) of gallstones has resulted in biliary colic. duct obstruction. and pancreatitis in some patients. Rapid dissolution of these fragments with methyl tert-butyl ether (MTBE) may prevent such side effects and achieve complete clearance of gallstones within hours rather than several months to a year or longer. This study examines the safety of same-day ESWL fragmentation and MTBE dissolution of surgically implanted human gallstones in 15 dogs. The animals were randomly assigned to one of four treatment groups to assess MTBE absorption from the gallbladder and to observe hematology and chemistry profiles after 0. 400. and 1.200 shock waves from a lithotriptor followed by MTBE dissolution therapy. They were sacrificed either immediately after treatment (12 dogs) or 2 weeks later (3 dogs). The results demonstrated that although ESWL causes moderate trauma to the gallbladder. this did not result in increased MTBE absorption or histologic evidence of mucosal disruption. Blood profiles demonstrated an increase in only the level of aspartate aminotransferase. The three dogs that were sacrificed 2 weeks after the combined treatment had no residual evidence of gallbladder injury or remaining stone material. In all animals. severe injury occurred where shock waves passed through lung or air-filled colon. This study suggests that same-day sequential fragmentation of gallstones by ESWL followed by dissolution of stone fragments with use of MTBE may be associated with only mild to moderate and reversible gallbladder trauma and can rapidly achieve clearance of gallstones.
Endorectal ultrasonographic staging of rectal carcinoma, Endorectal ultrasonography is a valuable imaging method for examination of the rectum and perirectal tissues. We assessed 50 patients with known rectal carcinoma prospectively by using a 7.0-MHz endorectal transducer to determine the depth of invasion of the rectal wall by tumor and the presence of lymphadenopathy. Tumors were staged by using the Astler-Coller modification of the Dukes staging system. and the results were compared with histologic staging of the surgical specimen. Ultrasonography had an accuracy of 80%. a sensitivity of 92%. and a specificity of 76% for detection of invasion of the perirectal fat. Ultrasonography was sensitive in the detection of perirectal lymphadenopathy but was not specific in distinguishing benign from malignant nodes.
Fatal hypernatremia from exogenous salt intake: report of a case and review of the literature [published erratum appears in Mayo Clin Proc 1991 Apr;66(4):439], Hypernatremia is a common electrolyte disturbance. most often caused by volume depletion. Hypernatremia due to sodium excess occurs less frequently. and fatal hypernatremia solely from ingestion of table salt is rare. We describe a 41-year-old man who had seizures and hypernatremia after ingestion of a supersaturated salt water solution intended for gargling. He had consumed approximately a third cup of table salt (approximately 70 to 90 g of salt or 1.200 to 1.500 meq of sodium). His initial serum sodium concentration was 209 meq/liter. Hypotonic fluid therapy was given to provide free water and to correct the hypernatremia gradually. Our patient. however. failed to recover from the initial insult and died 3 days later. Review of the literature revealed 10 adult and 20 pediatric cases of hypernatremia attributable to exogenous intake of salt. The type of therapy (fluid or peritoneal dialysis). the type of fluid used. and the rate of correction of hypernatremia did not influence survival. The age of the patient and the initial serum sodium concentration were the most important prognostic indicators. Both very young patients and those with lesser degrees of hypernatremia had a better rate of survival than did other patients. In addition. our review illustrates the surprisingly small amount of salt that can cause severe hypernatremia and the danger of using salt or saline as an emetic.
Breast milk and neonatal necrotising enterocolitis, In a prospective multicentre study on 926 preterm infants formally assigned to their early diet. necrotising enterocolitis developed in 51 (5.5%). Mortality was 26% in stringently confirmed cases. In exclusively formula-fed babies confirmed disease was 6-10 times more common than in those fed breast milk alone and 3 times more common than in those who received formula plus breast milk. Pasteurised donor milk seemed to be as protective as raw maternal milk. Among babies born at more than 30 weeks' gestation confirmed necrotising enterocolitis was rare in those whose diet included breast milk; it was 20 times more common in those fed formula only. Other risk factors included very low gestational age. respiratory disease. umbilical artery catheterisation. and polycythaemia. In formula-fed but not breast-milk-fed infants. delayed enteral feeding was associated with a lower frequency of necrotising enterocolitis. With the fall in the use of breast milk in British neonatal units. exclusive formula feeding could account for an estimated 500 extra cases of necrotising enterocolitis each year. About 100 of these infants would die.
T-cell-directed hepatocyte damage in autoimmune chronic active hepatitis, To investigate the function of activated T lymphocytes in autoimmune chronic active hepatitis. 7 of 15 T-cell clones from the peripheral blood of 8 patients were studied. These clones showed specificity for liver-membrane antigen with proliferation when stimulated by rabbit liver cell membranes. 6 of these clones reacted with liver-specific lipoprotein complex. and 1 clone (and 3 subclones) responded to the asialoglycoprotein receptor (ASGPR). both known targets of immune attack in autoimmune chronic active hepatitis. 2 of these clones stimulated autologous B lymphocytes to produce liver-membrane-specific autoantibodies and antibody to the ASGPR. These results suggest that liver-membrane-specific activated T lymphocytes in peripheral blood may be important in the autoimmune attack of chronic active hepatitis.
Serological and molecular survey for HTLV-I infection in a high-risk Middle Eastern group, To define the extent of human T-cell leukaemia virus (HTLV-I) infection among a group of Jewish immigrants to Israel with an increased frequency of adult T-cell leukaemia. various serological and molecular screening methods. including enzyme-linked immunosorbent assay (ELISA) for anti-HTLV-I. ELISA for antibody to recombinant HTLV-I p40tax protein. and molecular detection of infection by polymerase chain reaction (PCR) amplification of HTLV-I proviral DNA from peripheral blood mononuclear cell DNA. were used. By HTLV-I ELISA the overall rate of infection was 12% (24 of 208) among immigrants from Khurusan. northeastern Iran; no HTLV-I carriers were detected among 111 unselected Jewish immigrants from other parts of Iran. There was unexplained clustering of HTLV-I infection within a cohort of 32 elderly women of similar geographic origin in a home for old people--14 were seropositive by ELISA and 19 of 29 were positive by PCR. The findings in this newly identified high-risk population suggest that in addition to ELISA. other screening techniques may be required to detect all carriers in high-risk populations.
Preliminary report: protection of cynomolgus macaques against simian immunodeficiency virus by fixed infected-cell vaccine, Cynomolgus macaques were vaccinated with inactivated simian immunodeficiency virus-infected cells and 'Quil-A' as adjuvant at 0. 4. 8. and 36 weeks or at 0. 4. 8. and 16 weeks. 2 weeks later these animals. together with a similar unvaccinated group. were challenged with 10 MID50 (50% monkey infectious doses) of a pool of SIVmac251 previously titrated in vivo. Virus was repeatedly isolated from unvaccinated animals on at least five separate occasions and proviral DNA was detected in circulating lymphocytes by polymerase chain reaction amplification. By contrast. virus and proviral DNA were not found in any of the vaccinated animals. However. the same vaccination regimen used after live virus challenge did not eliminate virus from previously infected macaques.
Neonatal screening and staggered early treatment for congenital dislocation or dysplasia of the hip, In 14 264 consecutive newborn babies the results of screening and early treatment for congenital dislocation and/or dysplasia of the hip (CDH) were evaluated in a prospective follow-up study. Barlow's test was done and the family history was recorded. Babies who were positive (n = 140) were immediately given abduction treatment. If the screening result was doubtful (133) or if the test was negative but the family history positive (685) the child was radiographed at 5 months and abduction treatment was started if any form of CDH was seen. Among Barlow-negative children with no family history (13.306). two reference groups were selected--at age 5 months (596) and at age 2 years (4365). Dislocation was missed at screening in 0.02%. Dysplasia was seen at 5 months in 15% of Barlow-negative children with a positive family history and in 2-3% of the reference group children. Crude estimates of the lower limits of validity indices for the screening test showed that the test is efficient in the identification of dislocation but probably has no value for dysplasia. Of the babies in whom treatment was started immediately 17% had relapse dysplasia after withdrawal of therapy. 3% had avascular necrosis. and 78% were normal at 2 years. When treatment was started at 5 months we found no relapse dysplasia. only 1% avascular necrosis. and 53-63% success at 2 years. In children with dislocatable hips we propose a wait-and-see treatment strategy. with early ultrasonography or radiography at 5 months.
Controlled trial of immediate splinting versus ultrasonographic surveillance in congenitally dislocatable hips, 79 infants with congenitally dislocatable hips diagnosed clinically soon after birth were examined sonographically and randomised in a controlled trial to immediate splinting (n = 41) or sonographic surveillance for 2 weeks (38). Infants from this second group were splinted at age 2 weeks if instability persisted (11 of 38) or if sonographic abnormality had shown no improvement (4 of 38). Sonographic findings or clinical outcome did not differ between the two groups at birth or at 6 and 12 months' follow-up. We conclude that dislocatable hips may be safely watched for 2 weeks after birth to allow spontaneous resolution. but that this approach requires considerable resources and attention to detail. Our experience confirms the importance of the dynamic sonographic scan. The low specificity (70%) of sonographic examination in the first week of life makes it an unsatisfactory primary method of screening at birth. but it is a most useful adjunct to the clinical screening and management of congenital dislocation of the hip.
Molecular basis of different forms of metachromatic leukodystrophy, BACKGROUND. Metachromatic leukodystrophy is an autosomal recessive inherited lysosomal storage disorder caused by a deficiency of arylsulfatase A. Three forms of the disease can be distinguished according to severity and the age at onset: late infantile (1 to 2 years). juvenile (3 to 16). and adult (greater than 16). METHODS AND RESULTS. To understand the molecular basis of the different forms of the disease. we analyzed arylsulfatase A alleles associated with metachromatic leukodystrophy. Two alleles (termed I and A) were identified and accounted for about half of all arylsulfatase A alleles among 68 patients with metachromatic leukodystrophy whom we examined. Sufficient information was available for 66 of the patients to allow classification of their disease. Of the six instances of homozygosity for allele I. all were associated with the late-infantile form of the disease; of the eight instances of homozygosity for allele A. five were associated with the adult form and three with the juvenile form. When both alleles were present. the juvenile form resulted (seven of seven instances). Heterozygosity for allele I (with the other allele unknown) is usually associated with late-infantile disease. and heterozygosity for allele A with a later onset of the disease. The clinical variability can be explained by the different levels of residual arylsulfatase A activity associated with these genotypes. CONCLUSIONS. Like many lysosomal storage disorders. metachromatic leukodystrophy shows clinical heterogeneity that seems to reflect genetic heterogeneity. One of the known alleles (allele I) is associated with earlier and more severe disease than the other (allele A).
Familial occurrence of inflammatory bowel disease, BACKGROUND AND METHODS. We assessed the familial occurrence of inflammatory bowel disease in Copenhagen County. where there has been a long-term interest in the epidemiology of such disorders. In 1987 we interviewed 662 patients in whom inflammatory bowel disease had been diagnosed before 1979. asking whether their first- and second-degree relatives had this disorder. Ninety-six percent of the patients (504 with ulcerative colitis and 133 with Crohn's disease) provided adequate information. RESULTS. As compared with the general population. the first-degree relatives of the 637 patients with ulcerative colitis or Crohn's disease had a 10-fold increase in the risk of having the same disease as the patients. after standardization for age and sex. The risk of having the other of the two diseases was also increased. but less so. and the increase in the risk of having Crohn's disease was not significant in the relatives of patients with ulcerative colitis. The risk of ulcerative colitis in first-degree relatives of patients with ulcerative colitis appeared to be virtually independent of the generation to which the first-degree relative belonged and of the sex of the patient and the relative. The risk of ulcerative colitis in first-degree relatives tended to be higher if the disease had been diagnosed in the patient before the age of 50. but the risk seemed to be independent of the current age of the relatives. The prevalence of the same disease as that of the patient (either ulcerative colitis or Crohn's disease) among second-degree relatives was increased; the prevalence of the other disease was not increased. CONCLUSIONS. The 10-fold increase in the familial risk of ulcerative colitis and Crohn's disease strongly suggests that these disorders have a genetic cause.
A strategy to reduce infant mortality, Using maternal mortality reviews as an historic model. fetal and infant mortality reviews are proposed to reduce infant mortality in the United States. The national program has three elements: 1) guidelines and direction from a national multidisciplinary steering panel and staff. 2) a technical advisory capacity to translate guidelines and to work with local and regional review committees. and 3) local review committees. A special emphasis. lacking in the limited efforts of previous infant mortality reviews. would be given to fetal mortality. The plan proposes a broad classification of potential contributing causes of mortality. from those related strictly to medical care. to the health system. and to individual patient factors. This will allow different and more effective targeted responses to factors identified locally. Critical impetus will be gained with The American College of Obstetricians and Gynecologists leading the effort from the private medical sector in partnership with national. state. and local public health agencies and other national medical societies.
Umbilical artery Doppler velocimetry as a labor admission test, Doppler ultrasound of the umbilical artery flow velocity waveform was studied prospectively as an admission test at the labor ward. Recordings were made in 575 women in various stages of labor before. during. and after uterine contractions. and evaluated in relation to intrapartum and fetal outcome variables. No association was found between abnormal flow velocity waveforms and cord complications. meconium-stained amniotic fluid. or abnormal fetal heart rate tracing. nor was there any association with operative delivery for fetal distress or low Apgar scores at 1 and 5 minutes. Small for gestational age fetuses had significantly more abnormal flow velocity waveforms than appropriate for gestational age fetuses. and so had those with umbilical artery acidemia compared with those with normal pH. The results indicate that Doppler recording of the umbilical artery flow velocity waveform as an admission test at the labor ward is not a good predictor of fetal distress in an unselected population.
Clinical and pathologic correlation of endometrial cavity fluid detected by ultrasound in the postmenopausal patient, A registry of ultrasound procedures spanning nearly 5 years was searched retrospectively to discover cases of endometrial cavity fluid collections in postmenopausal women. Twenty cases were identified; all medical records were available for review. One patient was lost to follow-up. Seventeen patients had surgical procedures: 11 had only a D&C. and six had a primary evaluation of laparotomy with removal of the uterus and adnexa. Five women had cancer (two ovarian. one tubal. one endometrial. and one cervical); eight women had benign gynecologic conditions. including uterine fibroids (five). ovarian serous cystadenoma (two). and cervical dysplasia (one). There were two cases of apparent subclinical pyometra. Five women had endometrial pathology consistent with prescribed hormone therapy for breast cancer (four) or endometrial hyperplasia (one).
Cocaine abuse is associated with abruptio placentae and decreased birth weight, but not shorter labor, Many of our patients report having ingested cocaine hoping to decrease the duration of labor. We reviewed the computerized records of 592 women who abused cocaine. Compared with 4687 controls. women who ingested cocaine were older and had higher parity. Birth weight. birth weight percentile. and gestational age at delivery were significantly decreased among their neonates. and the incidence of abruptio placentae was nearly doubled among these women. Although these factors tend to shorten labor. the total duration of labor was not significantly different between the two groups. These data add to the accumulating evidence that cocaine abuse is associated with increased obstetric morbidity. but do not support the belief that cocaine shortens labor.
Vulvar Paget disease: fluorescein-aided visualization of margins, Two women with extramammary Paget disease of the vulva were given fluorescein intravenously in order to visualize disease margins with the use of an ultraviolet light. As a diagnostic modality. the technique was found to have a positive predictive value of 97.4% and a negative predictive value of 99.9%. The accuracy of the fluorescein technique was compared with gross visualization using a histologic mapping technique. A total of 2424 fields were mapped and the predictive accuracy of each test was determined. A chi 2 test demonstrated fluorescein visualization to be a significantly better predictor of a disease state. Fluorescein visualization is suggested as an adjunct to surgical management of patients with primary vulvar Paget disease.
Successful use of gamete intrafallopian transfer does not reverse the decline in fertility in women over 40 years of age, To assess the impact of assisted reproductive technologies on the potential fertility of older women. we report our experience with gamete intrafallopian transfer (GIFT) in a large number of women 40 years of age and older. One hundred twenty-two GIFT cycles were initiated in 59 women over 18 months. Seventy-three tubal transfers were performed. resulting in seven clinical pregnancies. a rate of 9.6% per transfer. This contrasts with a 27.3% clinical pregnancy rate per transfer in women under 40. Thus. older patients require thorough counseling regarding the decreased likelihood of success despite the use of assisted reproductive technologies.
Poloxamer 407 as an intraperitoneal barrier material for the prevention of postsurgical adhesion formation and reformation in rodent models for reproductive surgery, Comtemporary adhesion-prevention regimens for infertility surgery emphasize the use of barrier materials to effect physical separation of injured surfaces before reperitonealization. Poloxamer 407 is a biocompatible polymer that displays reverse thermal gelation characteristics; that is. the material exists as a liquid at room temperature and as a solid at body temperature. These properties make it an ideal material for use in laparoscopic surgery. The antiadhesion properties of poloxamer 407 were evaluated in two models. In the first experiment. Golden hamsters were subjected to a standardized adhesion-producing lesion in the left uterine horn. Poloxamer solutions in concentrations ranging from 15-35% were applied to the injured horn. Location. thickness. and extent of adhesion formation were assessed 14 days later. Significant reduction in post-traumatic adhesion formation was observed following treatment with the 30-35% solutions. The second experiment was designed as a paradigm of the typical situation encountered in infertility surgery: prevention of adhesion reformation after lysis of established adhesions. New Zealand White rabbits were subjected to three laparotomies at 14-day intervals for placement of the adhesion-producing lesion. evaluation (prescore) and surgical lysis of induced adhesions. and subsequent evaluation of adhesion reformation (post-score). The effect of applying poloxamer 407 after adhesiotomy was compared with controls (no treatment). Adhesion reformation (post-score) was markedly reduced by poloxamer-407 treatment. Further trials of this material in the clinical setting are indicated.
Sensitivity and specificity of screening for Down syndrome with alpha-fetoprotein, hCG, unconjugated estriol, and maternal age [published erratum appears in Obstet Gynecol 1991 May;77(3):462], The sensitivity and specificity of maternal serum screening for Down syndrome with different biochemical markers were evaluated. Detection rates with different combinations of maternal serum alpha-fetoprotein (MSAFP). hCG. and unconjugated estriol (uE3) were established by retrieving and analyzing 54 serum specimens from women with confirmed Down syndrome pregnancies. compared with 657 specimens from women with normal outcomes. With a risk cutoff of 1:270 at the second trimester. the detection rate with MSAFP. hCG. and uE3 was two to three times higher than with MSAFP alone. With all three markers. the detection rate for Down syndrome increased from 50 to 77% as maternal age increased. and was 60% in a representative screened population. If uE3 was omitted. the detection rate decreased from 60 to 48%. One thousand women were screened prospectively. either with MSAFP or with all three markers prospectively. either with MSAFP or with all three markers and 4.1% with MSAFP. With the three markers. the positive predictive value for Down syndrome was 2.2% overall and as high as 5.9% in older women. Therefore. the addition of hCG and uE3 to the maternal serum screen increases the positive predictive value by 50-300%. depending on maternal age. These results confirm the efficacy of screening for Down syndrome using maternal age and three serum markers.
Factors associated with postpartum hemorrhage with vaginal birth, A case-control study was performed to study risk factors for postpartum hemorrhage. Cases of hemorrhage were defined by a hematocrit decrease of 10 points or more between admission and post-delivery or by the need for red-cell transfusion. Patients with antenatal bleeding were excluded. Among 9598 vaginal deliveries. postpartum hemorrhage occurred in 374 cases (3.9%). Three controls were matched to each case and multiple logistic regression was used to control for covariance among predictor variables. Factors having a significant association with hemorrhage were prolonged third stage of labor (adjusted odds ratio 7.56). preeclampsia (odds ratio 5.02). mediolateral episiotomy (4.67). previous postpartum hemorrhage (3.55). twins (3.31). arrest of descent (2.91). soft-tissue lacerations (2.05). augmented labor (1.66). forceps or vacuum delivery (1.66). Asian (1.73) or Hispanic (1.66) ethnicity. midline episiotomy (1.58). and nulliparity (1.45). These data may help predict postpartum hemorrhage and may be useful in counseling patients about the advisability of home delivery. intravenous access in labor. or autologous blood donation.
The Glaucoma Laser Trial (GLT). 2. Results of argon laser trabeculoplasty versus topical medicines. The Glaucoma Laser Trial Research Group, The Glaucoma Laser Trial. a multicenter. randomized clinical trial involving 271 patients. was designed to assess the efficacy and safety of argon laser trabeculoplasty (ALT) as an alternative treatment with topical medication for controlling intraocular pressure (IOP) in patients with newly diagnosed. previously. untreated primary open-angle glaucoma (POAG). Each patient had one eye randomly assigned to ALT (the laser first [LF] eye) and the other eye assigned to timolol maleate 0.5% (the medication first [MF] eye). Medication was initiated or changed for either eye according to the same stepped regimen if the IOP was not controlled. Throughout the 2-year follow-up. LF eyes had lower mean IOPs than MF eyes (1-2 mmHg). and fewer LF eyes than MF eyes required simultaneous prescription of two or more medications to control IOP (P less than 0.001). After 2 years of follow-up. 44% of LF eyes were controlled by ALT. 70% were controlled by ALT or ALT and timolol. and 89% were controlled within the stepped medication regimen. After 2 years. 30% of MF eyes remained controlled by timolol. and 66% were controlled within the stepped regimen. There were no major differences between the two treatment approaches with respect to changes in visual acuity or visual field over the 2 years of follow-up.
Effects of topical glaucoma drugs on fistulized rabbit conjunctiva, Conjunctival fibroblastic proliferation with contracting scar formation has been implicated as a possible cause of glaucoma filtering surgery failure. The effects of glaucoma medications on bulbar conjunctiva were evaluated in both eyes of 20 pigmented rabbits. with 5 rabbits per group each receiving singular topically applied daily doses of either 0.5% timolol. 1% epinephrine. 4% pilocarpine. or artificial tears in a masked fashion for 4 months. Posterior lip sclerectomies were performed in 16 rabbits--4 from each treatment group. The remaining four rabbits served as nonsurgical controls. Four additional rabbits. which had not received eye drops. were included as a nonmedicated control group. with one rabbit serving as a nonsurgical control. Immunostaining was performed to identify the presence of myofibroblasts in fistulized conjunctiva. Treated surgical eyes. regardless of medication. had higher myofibroblastic cell proliferation than treated nonsurgical eyes. Among fistulized eyes. all medications increased cell proliferation. with pilocarpine eliciting the most dramatic increase compared with all other groups.
Nystagmus in Down's syndrome, The incidence and characteristics of nystagmus in Down's syndrome are unclear. In 188 consecutive patients. 56 had nystagmus. Most had no clinically recognizable ocular pathology to account for the nystagmus. Twenty-nine had fine rapid horizontal nystagmus. 14 had a dissociated nystagmus which appeared pendular. whereas 9 had a form of latent or manifest latent nystagmus. Of the total patients with nystagmus. 41 had esotropia. Our findings suggest that fine rapid horizontal nystagmus. sometimes dissociated. occurs frequently in patients with Down's syndrome.
Intraocular lens implantation after penetrating keratoplasty. Improved unaided visual acuity, astigmatism, and safety in patients with combined corneal disease and cataract, Twenty-two eyes with combined corneal disease and cataract were followed prospectively after nonsimultaneous intraocular lens (IOL) placement after penetrating keratoplasty; the majority had a penetrating keratoplasty and planned extracapsular cataract extraction (ECCE) followed later by the placement of an IOL. The mean follow-up after IOL placement was 25 months (range. 3-55 months). No graft failures occurred after secondary surgery. All graft sutures were removed in 86% (19/22) of eyes before IOL surgery. Ninety-five percent (21/22) of the eyes achieved refractive errors within 2 diopters (D) of the desired result. Corneal astigmatism decreased from 4.88 to 2.92 D after secondary surgery and wound revision. Unaided visual acuity was 20/40 or better in 68% (15/22) and 20/100 or better in 91% (20/22) of the eyes. The advantages of excellent unaided visual acuity. reduced astigmatism. and lack of anisometropia and graft failure outweigh the disadvantage of some delay in final visual rehabilitation (11 months) and increased secondary capsulotomy rate (85%) in this series with two separate surgeries compared with previously reported triple procedure results.
Immunopathology of cicatricial pemphigoid affecting the conjunctiva, Conjunctival biopsy specimens from 13 patients with cicatricial pemphigoid and from 13 age-matched healthy individuals undergoing cataract surgery were analyzed by light microscopy and immunohistochemical techniques. including a panel of monoclonal antibodies used to characterize inflammatory mononuclear cell phenotypes. Results of histologic examination of cicatricial pemphigoid specimens showed typical squamous metaplasia. vasculopathy. increased numbers of mast cells. and abundant plasma cells. All cicatricial pemphigoid specimens demonstrated immunoreactants at the epithelial basement membrane zone (BMZ). Epithelium of cicatricial pemphigoid conjunctiva showed significantly more T-helper cells (CD4+). dendritic cells (CD1+). and macrophages (CD14+). and a significantly higher helper/suppressor ratio than did controls. In the substantia propria. pemphigoid specimens showed dramatically increased inflammatory infiltrate with significantly more cells staining. in order of frequency. for T cells (CD3+. CD5+). T-helper cells (CD4+). T-suppressor cells (CD8+). macrophages (CD14+. Mac-1+). and dendritic cells (CD1+. HLA-DR+). Ten percent of these cells expressed interleukin-2 receptor protein (CD25+). indicating T-cell activation.
Bicarbonate-buffered lidocaine-epinephrine-hyaluronidase for eyelid anesthesia, A double-masked. randomized clinical trial was conducted to determine if subcutaneous eyelid injections of a bicarbonate-buffered lidocaine-epinephrine-hyaluronidase mixture were less painful than unbuffered injections. Twenty-one patients received both buffered (pH = 7.4) and unbuffered (pH = 4.6) injections. After each injection. patients recorded pain on a scale of 0. "no pain." to 10. "severe pain." Mean pain score for buffered injections was 2.0 versus 4.1 for unbuffered injections (P = 0.0003). Seventeen (81%) of 21 patients ranked the buffered injection less painful. Use of a bicarbonate-buffered lidocaine-epinephrine-hyaluronidase mixture is effective in making ophthalmic anesthesia less painful.
Results of blepharoptosis surgery with early postoperative adjustment, The authors reviewed 157 cases (207 eyes) of blepharoptosis corrected by external levator resection. Twenty-eight patients (29 eyelids) had unsatisfactory results. The authors adjusted 13 eyelids within 1 week of surgery. Eleven eyelids were reoperated 6 or more weeks after surgery. The mean delay between the initial and final surgery in the early group was 2.0 weeks; and. for the late group. 33.5 weeks. For those having reoperations. there was no difference in the number of procedures required to achieve satisfactory outcomes. Four patients (5 eyelids) with unsatisfactory results were offered. but declined. late repair. Early or late reoperation is effective in correcting unsatisfactory results after external levator resection. The benefits of early surgery are a reduction in time to final result. the ease with which it is performed. potential cost savings. and the opportunity one has to correct unsatisfactory results.
Optic nerve sheath meningoceles. Clinical and radiographic features in 13 cases with a review of the literature, Thirteen patients with dilated intraorbital optic nerve sheaths with an expanded. patulous cerebrospinal fluid (CSF) space were studied with high-resolution computed tomography (CT) or magnetic resonance imaging (MRI). Eleven patients had bilateral findings. Headache or visual complaints. or both. were present in all patients. Signs of optic nerve dysfunction were present in eight patients. Three patients had visual acuity worse than 20/200. Cerebrospinal fluid pressure was mildly elevated in two patients. Three patients underwent a surgical procedure; visual acuity improved in one. The authors propose the term meningocele for this condition and suggest MRI with fat-suppression techniques and off-axis sagittal views as the radiographic procedure of choice.
Visual prognosis correlated with the presence of internal-limiting membrane in histopathologic specimens obtained from epiretinal membrane surgery, Forty-one patients with a unilateral. macular epiretinal membrane (ERM) underwent pars plana vitrectomy and membrane peeling to improve the visual acuity. The authors retrospectively reviewed the histopathology of the vitrectomy specimen in each instance to determine whether the presence of internal-limiting membrane (ILM) had an adverse effect on visual acuity. Eleven specimens contained long segment of ILM. as determined by light microscopy. With a minimum of 6 months of follow-up. none of these 11 eyes achieved a visual acuity of better than 20/60. Of 30 eyes that did not have ILM present. 41% achieved a visual acuity of 20/60 or better. Overall. 29% of the eyes in the entire series achieved 20/60 or better visual acuity. The difference between the group with ILM versus that without ILM was statistically significant (P = 0.01). The presence of long segments of ILM within the histopathologic specimen after vitreous surgery for removal of a macular ERM appears to indicate a less favorable visual outcome.
Semiconductor diode laser photocoagulation in retinal vascular disease, The authors successfully performed clinical transpupillary retinal photocoagulation in 30 eyes of 26 patients with retinal vascular disease using a gallium-aluminium-arsenide (GaAlAs) diode laser emitting at 805 nm. Retinal photocoagulation was performed at treatment powers of 300 to 1300 mW and exposure durations of 0.2 to 0.5 seconds with a 200-microns diameter treatment spot. Patients treated with both diode and argon green lasers required 4.5 +/- 1.8 times greater mean laser energy with diode compared with argon to create ophthalmoscopically similar lesions. Parallel experimental retinal photocoagulation in Chinchilla rabbits required 3.1 +/- 0.9 times more power to create ophthalmoscopically similar lesions with the diode laser than with the argon laser. Intraoperative subretinal hemorrhage occurred rarely in patients with an incidence of 4 (0.44%) of 9021 treatment spots. Patients complained of moderate-to-marked pain in 10 (43%) of 23 treatments initiated under topical anesthesia. A transpupillary diode laser may be used clinically to perform therapeutic retinal photocoagulation.
The repair of rhegmatogenous retinal detachments. American Academy of Ophthalmology, Current techniques of rhegmatogenous retinal detachment repair allow most retinal detachments to be repaired successfully. The success of repair depends on a careful preoperative examination and choice of an appropriate surgical procedure. The surgical procedure must be tailored to the individual eye based on a detailed preoperative examination of the retina and vitreous. Postoperative complications are not infrequent compared to many other ophthalmic surgical procedures such as cataract extraction and strabismus repair. The surgeon must observe the eye carefully in the postoperative period to monitor and treat any complications as they arise. Improvements in surgical techniques coupled with a better understanding of the pathophysiology of rhegmatogenous retinal detachment continue to improve the anatomic and functional success of retinal detachment repair.
Strategies underlying the control of disordered movement, The purpose of this article is fourfold. First. a theory of motor control--the dual-strategy hypothesis--is outlined. Second. the methodologies and theoretical framework that are used to develop this theory are examined. Third. motor dysfunction is discussed in the context of this theory. In particular. Down syndrome. Parkinson's disease. cardiovascular accidents. and spasticity are discussed. Finally. potential applications of the theory to physical therapy are considered.
A new challenge--robotics in the rehabilitation of the neurologically motor impaired, Rehabilitation robotics is a research area. originating in engineering. that has emerged in the last decade. Its broad aim is to use robot technology to assist people with movement dysfunction. The neurologically impaired population might gain considerably from the provision of robots as "assistants" or "therapy aides." but the interface with the machine must match both the physical and intellectual abilities of the user. We therefore consider a multidisciplinary approach. encompassing both behavioral and engineering perspectives. to be essential in achieving this aim. However. to date. published reports have been largely restricted to engineering journals or conference reports. and relatively little has appeared in the therapy literature. This article seeks to introduce physical therapists to robotics. describe possible applications to the rehabilitation of neurologically impaired patients. and suggest issues deserving further investigation.
Brain potentials associated with movement in traumatic brain injury, Brain potentials may be used to assess the functional abnormalities that underlie impairments of movement. The purpose of this article is to illustrate the usefulness of examining these potentials. In addition to an overview of the topic. the article includes a report of a study demonstrating that there were differences between the brain potentials of five patients with traumatic brain injury and those of four healthy control subjects. All five patients were in the postacute phase of hemiplegia. Slow cortical potentials associated with simple goal-directed forearm and finger movements were recorded from frontal and parietal electrodes. Two seconds of movement-related electroencephalographic activity (movement-related potential) were recorded. The patients showed reduced brain potentials for movements associated with their paretic limb and. to a lesser extent. reduced brain potentials for movements associated with their nonparetic limb. The waveforms obtained from the patients were unusual. with uncharacteristic cross-cortical movement-related potential correlations associated with specific electrode configurations. as well as with specific movement conditions. Brain potentials associated with the fore-period interval of a simple reaction time paradigm were later recorded in two of the patients with traumatic brain injury and in a control subject to help determine the functional significance of the relative positivity apparent in their movement-related potential data. This preliminary study indicates that electroencephalographic potentials obtained during the preparation for and execution of movement can provide information regarding the basis for motor dysfunction.
Movement disorders--limb movement and the basal ganglia, The primary concern of this article is to review experimental methods that may lead to a better understanding of the functional role of the basal ganglia in the control of movement. Two models of basal ganglia impairment are considered: Parkinson's disease and Huntington's disease. The review focuses primarily on akinesia and bradykinesia because they are key abnormalities of basal ganglia dysfunction. In general. through electromyography and kinematic analysis of movement. it may be possible to characterize specific movement disorders. Specifically. if damage sustained by the central nervous system is traced to a certain structure. it may provide insight on the extent of involvement and functional role of that structure in the control of movement. Much of the data reviewed suggests that the basal ganglia may play a specific role in the initiation and regulation of force control.
Prefabrication of composite free flaps through staged microvascular transfer: an experimental and clinical study, The feasibility of prefabricating free flaps by inducing. through the process of staged reconstruction. an arteriovenous bundle and its surrounding fascia to perfuse a selected block of tissue was investigated experimentally and clinically. Sixteen rat knee joints were wrapped with their ipsilateral superficial inferior epigastric (SIE) fascia. In 8 joints. the composite flaps were resected en bloc and were immediately replaced orthotopically pedicled upon the superficial inferior epigastric vessels. In the remaining joints. the resection and orthotopic transfer were performed 2 weeks later. Only the joints in the latter group. which benefited from the staging period. were found to be perfused. The long finger proximal interphalangeal joint of a child was reconstructed by the staged microvascular transfer of his second toe proximal interphalangeal joint. At the first stage. a temporalis fascia flap was wrapped around the toe proximal interphalangeal joint and revascularized to the dorsalis pedis vessels. Six weeks later. the joint and its temporalis fascia envelope were dissected. and the "prefabricated" joint flap was transferred to the hand and revascularized to the wrist vessels. Bony union progressed uneventfully with excellent recovery of the range of motion. We conclude that regardless of the indigenous vascular anatomy. an unlimited array of composite free flaps can be constructed and transferred based on induced large vascular pedicles.
Increase in skin-flap survival by the vasoactive drug buflomedil, The effect of buflomedil to protect skin tissue from ischemia and necrosis was studied in random cutaneous flaps. Measurements were performed by intravital microscopy on the microcirculatory level of capillary perfusion in a flap model in the hairless mouse. In 30 hairless mice. single-pedicle flaps measuring 6 x 16 mm were raised perpendicular to the spine of the animal. This flap develops a reliable amount of necrosis at its distal edge over a period of 7 days. A group of 10 mice received intravenous injections of buflomedil in doses of 3 mg/kg per day diluted in 0.1 ml normal saline beginning 4 hours before flap elevation and for 6 consecutive days postoperatively. In addition. 10 further animals received the same treatment except that it was started 5 minutes after flap elevation. In 10 mice serving as controls. normal saline in equal volumes as in the experimental groups was applied. By means of intravital microscopy. functional vessel density (FVD) was determined in 2.5-mm increments from the flap's base to its distal edge at 1. 6. and 24 hours after elevation. Skin-flap survival was quantified by measuring the necrotic area on day 7 by means of digital planimetry. Functional vessel density was preserved in the distal flap of animals pretreated with buflomedil. revealing a higher functional vessel density at 10.0 mm (p less than 0.01). 12.5 mm (p less than 0.05). and 15.0 mm (p less than 0.001) from the flap's base as compared with controls.
A case of sideburn reconstruction using a temporoparieto-occipital island flap, A preliminary case is reported in which a large temporal bald scar including the sideburn was successfully reconstructed using a temporoparieto-occipital island flap in combination with a tissue expander. This flap is considered to be a kind of reverse-flow island flap of the occipital artery by means of the fine vascular connections with the temporal branch of the superficial temporal artery. This new method is potentially a good solution for sideburn reconstruction.
A new dynamic lumbrical simulating splint for claw hand deformity, The claw hand deformity. resulting from low ulnar or combined low ulnar and median nerve palsy. is an incapacitating situation. The splint described herein reverses the clawing by substituting for the lumbricals and interossei. If started early. it not only prevents the permanent stiffness of fingers in the claw position. but also effectively restores function without hampering day to day work because it is a surface splint.
Abdominal wall reconstruction (the "mutton chop" flap), Reconstruction of full-thickness abdominal wall defects can be a difficult surgical challenge. Reconstructing the epigastrium may be especially vexing. The use of prosthetic mesh has significant drawbacks. and the use of pedicled myofascial and myocutaneous flaps should be advantageous. We present 15 consecutive cases demonstrating highly successful reconstructions of massive abdominal wall defects using myofascial and myocutaneous flaps without prosthetic mesh. The extended rectus femoris flap. or "mutton chop" flap. which is capable of resurfacing the epigastrium. is described. Complications were minimal. and use of myofascial units. particularly the rectus femoris. should be considered as the technique of choice for reconstruction of major abdominal wall deficits.
The surgical treatment of noma, Noma is a gangrenous stomatitis affecting children from developing countries. It may leave dreadful mutilations around the mouth. with amputation of the lips. cheek. nose. lids. maxilla. palate. or mandibula. Reconstruction should take into account the size of the defect. the presence of trismus or constriction of the mandible. the age of the child. and the child's general condition. During the last 3 years. eight patients were treated at the Unit of Plastic and Reconstructive Surgery of the Hopital Cantonal Universitaire. Except in one case. tracheostomy was avoided. thanks to intranasal intubation by fibroscopy. These children. aged 2 to 9 years. underwent 31 general anesthesias and complex reconstructive procedures. including latissimus dorsi musculocutaneous pedunculated and free flaps. cranial flaps with galea. cranial bone and skin grafts. and retroauricular temporal skin flaps. All patients were able to return to Africa with dramatic functional and cosmetic improvements. However. satisfactory mouth opening and mandibular function were not always obtained.
Cross-sectional physiology of the lung, It is well known that gravity influences the physiology of the lung and thereby affects the intrapulmonary localization of disease processes. Less well known are the anatomic and physiologic differences in the axial or cross-sectional plane. which also affect the distribution of disease. Physiologic gradients in ventilation. perfusion. and lymph flow and stresses in the lung are present in the axial plane. Anatomic difference in branching patterns. interstitial design. and development of the secondary pulmonary lobules are also found. These regional disparities in anatomy and physiology can be applied to an old concept--the corticomedullary organization of the lung--and are used to consider why some diseases exhibit a propensity for the central or peripheral portions of the lung. The same analysis is applied to the anatomy and physiology in the secondary pulmonary lobule.
Retained intrahepatic stones: treatment with piezoelectric lithotripsy combined with stone extraction, Extracorporeal shock wave lithotripsy (ESWL) was performed in 11 patients with oriental cholangiohepatitis and intrahepatic stones associated with segmented strictures of intrahepatic ducts. All patients had previously undergone biliary surgery and basket extraction via a T-tube tract at the time of lithotripsy. The indication for ESWL was failure of. or anticipated difficulty with. basket extraction of the stones via a T-tube tract. A piezoelectric lithotriptor was used in all procedures. The average total number of shock waves administered was 29.756 (range. 10.000-61.395). The average number of treatment sessions was 3.1 (range. 1-6); the number of shock waves used in a single session ranged from 10.000 to 15.000 with a frequency of five shots per second and 30%-50% power. In six patients. the stones were successfully fragmented and completely removed; in three of the others of the stones were fragmented and removed. The overall success rate. including complete (54%) and incomplete (27%) success. was 82%. Difficulty in targeting stones. and severe strictures and deformities of intrahepatic ducts. were the factors responsible for failure. No significant complications were observed.
Analysis of brain and cerebrospinal fluid volumes with MR imaging: impact on PET data correction for atrophy. Part II. Aging and Alzheimer dementia, A new. computerized segmentation technique. in which magnetic resonance (MR) imaging produces accurate volumetric measurements of brain and cerebrospinal fluid (CSF) without the limitations of computed tomography. was used in a retrospective analysis of digitized T2-weighted MR images of 16 healthy elderly control subjects and 16 patients with Alzheimer dementia. Ventricular and extraventricular CSF was quantified. and the effects of aging were studied; in both groups. the atrophy measurement was used to correct metabolic values obtained with positron emission tomography. Patients with Alzheimer dementia had higher total CSF; extraventricular. total ventricular. and third ventricular CSF volumes (49%. 37%. 99%. and 74%. respectively); and 7% lower brain volumes than the control group. The patients also showed a more marked decline in brain volumes and a greater increase in CSF volumes with advancing age than the control group. They had a 25.0% increase in corrected whole-brain metabolic rates; the control group had only a 15.8% increase. The use of this technique may provide a basis for further studies of aging and dementia. including regional volume analysis.
Invasive lobular carcinoma: mammographic findings in a 10-year experience, From January 1. 1976 to December 30. 1985. 1.966 cases of breast carcinoma were diagnosed and treated at Malmo General Hospital. Malmo. Sweden. Of these cases. 185 (9.4%) involved invasive lobular carcinoma (ILC). Mammography in 137 cases demonstrated the following findings: spiculated opacity (53%). architectural distortion (16%). poorly defined opacity (7%). normal or benign findings (16%). and parenchymal asymmetry (4%). Radiographic definition of the ILC lesion varied greatly with projection: The craniocaudal view demonstrated significant findings more frequently than either the oblique or lateral views. Secondary radiographic findings were present in 31%. microcalcifications were rare. and physical findings were present in 89%. Because of its diffuse growth pattern and tendency to form lesions with opacity equal to or less than that of the parenchyma. ILC can be extremely difficult to detect mammographically. Therefore. the radiologist must be alert for subtle mammographic signs of malignancy and highly suspicious of any abnormal physical findings regardless of the mammographic appearance.
Mammographic follow-up of low-suspicion lesions: compliance rate and diagnostic yield, All recommendations for mammographic follow-up of low-suspicion lesions seen at mammography during a 6-month period were reviewed to establish compliance rate and eventual outcome. One hundred forty-four of 2.650 mammograms (5%) showed minimal abnormalities that warranted short-term and periodic mammographic follow-up. Rates of compliance at 4 months and at 1. 2. and 3 years were 88%. 71%. 60%. and 47%. respectively. Progressive mammographic change was found in 10 patients. only one of whom had a carcinoma. It was concluded that mammographic follow-up of low-suspicion lesions is a reasonable alternative to surgical biopsy. although patient compliance remains a significant problem.
Airway evaluation in children with use of ultrafast CT: pitfalls and recommendations, Ultrafast computed tomographic (CT) evaluation of the airway can be performed with either 50-msec low-resolution images (cine CT) or 100-msec high-resolution images (high-resolution CT). To determine the best imaging strategy for ultrafast CT of the pediatric airway. the authors prospectively compared ultrafast CT and endoscopy in 20 children. Both studies were performed in 11 patients; cine CT alone was performed in six and high-resolution CT alone in three. Six patients had normal anatomy. Six patients had focal tracheal stenoses. four had tracheomalacia or laryngomalacia. one had a laryngoesophageal cleft. one had irregularity and narrowing in the subglottic area. one had laryngeal papillomas. and one had focal stenosis with stoma granuloma. Cine CT results agreed with those of endoscopy in 10 of 17 cases. In five cases focal stenosis was misinterpreted with cine CT as tracheomalacia. High-resolution CT results agreed with those of endoscopy in 10 of 14 cases. The results of a technique that combined high-resolution CT for the entire airway and cine CT at selected areas agreed with those of endoscopy in 10 of 11 cases; only a tracheoesophageal cleft was missed with the combined technique. For the greatest diagnostic accuracy with ultrafast CT in evaluation of the pediatric airway. both cine and high-resolution modes should be used.
Blunt trauma in children: significance of peritoneal fluid, Seven hundred ninety consecutively seen children who had not undergone peritoneal lavage underwent imaging with computed tomography (CT) after blunt trauma. Collections of peritoneal fluid were prospectively characterized as small (51 children). moderate (32 children). or large (40 children). Associated injuries included hepatic or splenic injury in 74%. isolated renal or pancreatic injury in 5%. isolated pelvic fracture in 5%. isolated hollow viscus injury in 5%. and a combination of the above in 7%. Peritoneal fluid was the only CT abnormality in three children. A significant correlation was found between presence and increasing size of peritoneal fluid collections and clinical signs of hemodynamic instability such as lower trauma score (P = .0008 by analysis of variance). the presence of arterial hypotension (P = .0001 by chi 2 test). and hematocrit less than 30% (0.30) (P = .0001 by chi 2 test). Additionally. the presence and amount of peritoneal fluid correlated with need for laparotomy and with mortality (P = .0001 by chi 2 test for both).
Nonpalpable cancer of the prostate: assessment with transrectal US, Palpable cancer of the prostate is widely believed to be clinically significant. The authors compared the clinical significance of palpable prostate cancer with nonpalpable prostate cancer discovered with transrectal ultrasound (US). A strong association between lesion volume measured with preoperative transrectal US and volumetric measurements in 60 radical prostatectomy specimens permitted the use of tumor size measured with transrectal US as a reasonable estimation of gross tumor volume. In a subsequent clinical series. 147 biopsy-proved cancers were grouped according to size measured at US. the findings at digital rectal examination (DRE). and the Gleason score. For the 147 patients with known prostate cancer. a statistically significant difference between Gleason scores of palpable and nonpalpable cancers could not be demonstrated when the size of the tumor and its location within the prostate were held constant. Assuming that the Gleason score is a reliable indication of malignant potential and clinical significance. the authors conclude that nonpalpable prostatic cancer detected with transrectal US alone may be just as clinically significant as prostatic cancer discovered with DRE.
Hysterosalpingo-contrast sonography of the uterus and fallopian tubes: results of a clinical trial of a new contrast medium in 120 patients, The feasibility. diagnostic efficacy. and patient tolerance of a new diagnostic modality. hysterosalpingo-contrast sonography (HyCoSy). were evaluated in a clinical study of 120 patients with suspected infertility. A new echogenic contrast medium for ultrasound was administered transcervically with conventional tools for hysterosalpingography or a balloon catheter. The flow of multiple fractions of the contrast medium through each fallopian tube was observed in real time in appropriate imaging planes by means of a transvaginal probe. All patent tubes were diagnosed correctly with HyCoSy. results comparing well with findings at hysterosalpingography or laparoscopy. With B-mode scanning only. sensitivity was 88% for the right tube and 90% for the left; specificity was 100% for each tube. The supplementary use of Doppler techniques (duplex. color Doppler) provided additional information in special cases of suspected tubal occlusion and led to an improvement in diagnostic accuracy. The contrast agent was well tolerated. HyCoSy demonstrates normal anatomy and tubal patency with high reliability and permits advance selection of patients in whom more invasive diagnostic procedures may be required.
Insulinomas: localization with selective intraarterial injection of calcium, To facilitate the noninvasive preoperative localization of islet cell tumors less than 15 mm in diameter. the authors examined the use of calcium as an insulin secretagogue in an arterial stimulation venous sampling (ASVS) technique. In four patients with episodic hypoglycemia. calcium gluconate (0.01-0.025 mEq Ca2+/kg) was injected directly into branches of the celiac plexus (gastroduodenal. splenic. and hepatic arteries) and the superior mesenteric artery. In all patients. serum levels of insulin rose abruptly in blood samples taken from the right hepatic vein 30 and 60 seconds after the infusion of calcium into the artery supplying the tumor; injection into an artery not supplying the tumor did not result in a similar rise. Accurate localization of the insulinomas was verified at surgery in three patients. In the fourth patient. who did not undergo surgery. arteriographic results were positive for insulinoma at the predicted site. On the basis of these results. the authors believe noninvasive ASVS may replace invasive portal venous sampling as the most effective method for the localization of occult insulinomas.
The clinical efficacy of triple-injection wrist arthrography, Triple-injection wrist arthrography has been demonstrated to increase the likelihood that all the ligamentous perforations in an injured wrist will be diagnosed. However. compared with imaging after single injection of contrast material into the radiocarpal joint. triple-injection arthrography not only increases patient expense but also significantly increases the time required of both patients and arthrographers to obtain the diagnosis. With the goal of decreasing the number of triple injections. the author reviewed 50 consecutive triple-injection wrist arthrograms. Using a technique based on high-volume injection of contrast material to achieve complete distention of the joint. the author achieved a false-negative rate for demonstration of complete perforations with radiocarpal injection alone of only 2% (10% if partial perforations were included). In none of these cases was patient treatment altered by the additional information provided by the second and third injections. This false-negative rate is significantly lower than that reported previously and raises the question of whether there are circumstances in which the easier and less time-consuming single radiocarpal injection might be appropriate.
Selective catheterization of the inferior petrosal sinuses: new catheter design, Catheters for selective catheterization of the right and left inferior petrosal sinuses have been developed to replace the complex tip-deflector catheter-guide-wire system currently used. The new catheters are easily formed from commonly available straight catheters with the use of steam. They have been successfully tested in 22 patients; the only complications were minor groin hematomas.
Petrosal sinus sampling: technique and rationale, Bilateral simultaneous sampling of the inferior petrosal sinuses is an extremely sensitive. specific. and accurate test for diagnosing Cushing disease and distinguishing between that entity and the ectopic ACTH syndrome. It is also valuable for lateralizing small hormone-producing adenomas within the pituitary gland. The inferior petrosal sinuses connect the cavernous sinuses with the ipsilateral internal jugular veins. The anatomy of the anastomoses between the inferior petrosal sinus. the internal jugular vein. and the venous plexuses at the base of the skull varies. but it is almost always possible to catheterize the inferior petrosal sinus. In addition. variations in size and anatomy are often present between the two inferior petrosal sinuses in a patient. Advance preparation is required for petrosal sinus sampling. Teamwork is a critical element. and each member of the staff should know what he or she will be doing during the procedure. The samples must be properly labeled. processed. and stored. Specific needles. guide wires. and catheters are recommended for this procedure. The procedure is performed with specific attention to the three areas of potential technical difficulty: catheterization of the common femoral veins. crossing the valve at the base of the left internal jugular vein. and selective catheterization of the inferior petrosal sinuses. There are specific methods for dealing with each of these areas. The sine qua non of correct catheter position in the inferior petrosal sinus is demonstration of reflux of contrast material into the ipsilateral cavernous sinus. Images must always be obtained to document correct catheter position. Special attention must be paid to two points to prevent potential complications: The patient must be given an adequate dose of heparin. and injection of contrast material into the inferior petrosal sinuses and surrounding veins must be done gently and carefully. When the procedure is performed as outlined. both inferior petrosal sinuses can be catheterized in more than 98% of patients. The complication rate is low. and the theoretical risk of major morbidity or death is less than 1% (neither has yet occurred. to our knowledge). The most common complication is groin hematoma.
Oral cholecystography in contemporary gallstone imaging: a review, The introduction of nonoperative alternatives to elective cholecystectomy in the management of gallstones has resurrected use of oral cholecystography (OCG). This article reviews basic principles involved in the proper performance of OCG and interpretation of the resulting images. The role of OCG in the current management of gallstones is discussed.
Sarcoidosis: abdominal manifestations at CT, There are few data in the literature on the abdominal manifestations of sarcoidosis at computed tomography (CT). To determine whether differences in nodal distribution and appearance can be reliably used to distinguish between sarcoidosis and non-Hodgkin lymphoma (NHL). the authors retrospectively reviewed the abdominal and pelvic CT scans of 16 patients with biopsy-proved sarcoidosis and 20 patients with biopsy-proved NHL. Eleven of the 16 patients with sarcoidosis had abdominal and/or pelvic lymphadenopathy. which was common at all nodal sites except for the retrocrural and pelvic locations. There was a statistically significant lower frequency of retrocrual adenopathy in sarcoidosis than in NHL. Mean nodal size was significantly greater in NHL. Nodes tended to be confluent in NHL and discrete in sarcoidosis. Hepatomegaly was seen in six of the 16 patients (38%) with sarcoidosis and splenomegaly was present in nine of 15 (60%). CT depicted hepatic lesions in only three of eight patients (38%) with biopsy-proved hepatic involvement. Splenic lesions were seen at CT in five of the 15 patients (33%). The authors believe that the overlap in nodal appearance and distribution poses a limitation for use of these criteria in accurate disease characterization.
Disruption of the human SCL locus by "illegitimate" V-(D)-J recombinase activity, A fusion complementary DNA in the T cell line HSB-2 elucidates a provocative mechanism for the disruption of the putative hematopoietic transcription factor SCL. The fusion cDNA results from an interstitial deletion between a previously unknown locus. SIL (SCL interrupting locus). and the 5' untranslated region of SCL. Similar to 1;14 translocations. this deletion disrupts the SCL 5' regulatory region. This event is probably mediated by V-(D)-J recombinase activity. although neither locus is an immunoglobulin or a T cell receptor. Two other T cell lines. CEM and RPMI 8402. have essentially identical deletions. Thus. in lymphocytes. growth-affecting genes other than immune receptors risk rearrangements.
Bronchial hyperresponsiveness in young students of southern China: relation to respiratory symptoms, diagnosed asthma, and risk factors, A cross sectional study was carried out to determine the prevalence of bronchial hyperresponsiveness and asthma in 3067 students aged 11-17 years in an urban and a rural area of Guangzhou (Canton). China. The methods used included a self administered questionnaire. a histamine bronchial provocation test. and allergen skinprick tests. Bronchial hyperresponsiveness was defined as a 20% fall in FEV1 and peak expiratory flow at a provoking dose of histamine (PD20) less than 7.8 mumol on two occasions four weeks apart. The response rate was 98.0% and 99.2% in the two areas. The prevalence of bronchial hyperresponsiveness was 4.1% and of diagnosed asthma 2.4% in the total population. There were no significant differences in prevalence between the urban and the rural area or between boys and girls. The 11-12 year group had a higher prevalence of bronchial hyperresponsiveness (7.6%) than the older groups. Of the 125 with bronchial hyperresponsiveness. 12.0% were defined as having severe or moderate (PD20 less than 0.8 mumol). 26% mild (0.9-3.2 mumol). and 62% slight bronchial hyperresponsiveness (3.3-7.8 mumol). The severity of bronchial hyperresponsiveness was closely related to diagnosed asthma. wheezing. and cough. though half the students with bronchial hyperresponsiveness were symptom free. The most common allergens were house dust and house dust mite in the city. and hay dust. pollen. and feathers in the rural area. The odds ratios for having respectively slight. mild or moderate. and severe bronchial hyperresponsiveness were 5.9. 21.0. and 30.4 for atopy; 1.9. 1.9. and 7.3 for early respiratory infection; and 3.1. 2.5. and 5.6 for a history of parental asthma.
A simple method for correcting single breath total lung capacity for underestimation, The single breath method underestimates total lung capacity by comparison with the multiple breath method (TLCmb) because of inhomogeneity of ventilation distribution. This study proposes a simple correction for the single breath TLC (TLCsb). using inert gas phase III slope to account for the effects of uneven ventilation distribution. A model of a non-uniform lung ventilation was designed. composed of a serial dead space and two alveolar compartments arranged in parallel. whose relative ventilations were determined from the phase III plateau. Before correction TLCsb was 104-44% of TLCmb in 64 subjects (17 with diffuse interstitial disease. 42 with chronic obstructive pulmonary disease. and five healthy subjects). The limit of acceptability for the correction (TLCcorr) was determined from the 95% confidence interval of TLCsb/TLCmb in the healthy subjects. The correction resulted in a significant increase in TLCsb (p less than 0.004). TLCcorr remained under the limit of acceptability for only 12 patients with emphysema. and all 12 showed a large improvement in the TLC estimate. The presence of poorly ventilated zones during a single breath in these patients may explain this partial correction.
Collagen of the dystrophic hamster diaphragm, The collagen content of the diaphragm was measured in normal and dystrophic hamsters aged 130 and 270 days. The diaphragm collagen content was greater in dystrophic hamsters than in control hamsters of the same age. The effect was greater in the older hamsters whether the collagen content was expressed in terms of the percentage of dry weight. in relation to surface area. or as total collagen. This increase was apparently at the expense of muscle tissue and may be a major factor contributing to respiratory muscle weakness as dystrophy advances.
Lung fibrosis induced by Thorotrast, A 63 year old woman developed progressive shortness of breath. pulmonary hypertension. and respiratory failure and died from pulmonary fibrosis 45 years after thoracic fistulography with Thorotrast. Bouts of acute respiratory failure occurred with features of noncardiogenic pulmonary oedema. Lung tissue obtained by biopsy and at necropsy showed abundant radioactive particles of thorium dioxide in the lungs. The particles were congregated in the walls of blood vessels and in perivascular fibrous zones. consistent with a causal role of Thorotrast in the development of lung fibrosis. It is suggested that the fibrosis was due to the combined effects of alpha radiation on the interstitial perivascular zones and of recurrent pulmonary oedema due to endothelial damage.
Effects of long-term verapamil therapy on serum lipids and other metabolic parameters, Calcium antagonists have been used successfully in the management of hypertension for more than a decade. but less is known about their long-term metabolic effects. To define the impact of one calcium antagonist. verapamil. on serum lipids and other metabolic parameters. we placed 45 hypertensive patients on verapamil monotherapy and followed them for 4 to 8 years. After a mean treatment period of 5.3 years. total cholesterol and triglyceride levels were not significantly different from baseline. whereas the mean high-density lipoprotein cholesterol value increased significantly from 1.17 +/- 0.41 mmol/L at the initiation of treatment to 1.39 +/- 0.36 mmol/L at 5.3 years (p less than 0.05). Other important biochemical parameters. including serum glucose. potassium and uric acid levels were unaffected by verapamil therapy. No serious side effects or adverse cardiovascular events occurred during verapamil therapy. and there were no study dropouts. It therefore seems likely that this agent will become increasingly useful in the long-term management of essential hypertension.
Anti-atherosclerotic and vasculoprotective actions of calcium antagonists, Treatment of hypertension may prevent many of the complications attributable to blood pressure elevation. particularly those that are "pressure-related." such as stroke. However. the atherosclerotic complications of hypertension. e.g.. coronary artery disease manifested as coronary morbidity and mortality. have not been reduced significantly with antihypertensive therapy. This disappointing outcome may reflect the adverse metabolic effects of the traditional therapies. diuretics and beta blockers. and their lack of specific vasoprotective properties. Increasing attention is thus being paid to the newer antihypertensive agents. which typically have fewer adverse effects and perhaps more physiologic mechanisms of antihypertensive action. Since calcium plays a key role in the genesis of atherosclerosis. calcium antagonists may positively affect the course of vascular disease. Investigators have observed that calcium antagonists display clear antiatherosclerotic properties in experimental as well as clinical studies. In one recently published clinical study. coronary artery disease was shown to develop more slowly. with a slower progression of individual stenoses. higher regression rate and less frequent occurrence of new lesions in patients treated chronically with verapamil compared to those receiving conventional therapies. Other similar investigations are currently under way to evaluate the antiatherogenic properties of calcium antagonists. including the Frankfurt Isoptin Progression Study (FIPS). the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). the International Nifedipine Trial on Atherosclerosis Coronary Therapy (INTACT). and the large-scale Montreal Heart Institute Study. Results of these studies. which use precise end points such as myocardial infarction. cerebral infarction and peripheral vascular disease. may revolutionize the treatment of hypertension by identifying therapeutic approaches that control both the pressure-related and atherosclerotic complications of the disease.
Secondary prevention with verapamil after myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction, The effect of verapamil on death and major events (i.e.. death or reinfarction) after an acute myocardial infarction was studied in a double-blind. randomized. placebo-controlled. multicenter trial. the Danish Verapamil Infarction Trial II (DAVIT II). Eight hundred seventy-eight patients started treatment with verapamil 360 mg/day and 897 patients with placebo. Treatment continued for up to 18 months (mean 16 months). Ninety-five deaths and 146 major events occurred in the verapamil group and 119 deaths and 180 major events in the placebo group. Eighteen-month mortality rates were 11.1 and 13.8% (hazard ratio 0.80. 95% confidence limits 0.63 to 1.05. p = 0.108). and major event rates 18.0 and 21.6% (0.80. 0.64 to 0.99. p = 0.027) in the verapamil and placebo groups respectively. When combining the results of this trial with the results of the first Danish study on verapamil in myocardial infarction. the meta-analysis demonstrated that treatment with verapamil from the second week after an acute myocardial infarction resulted in a reduction of pooled odds ratios of 0.22 (95% confidence interval 0.01 to 0.37. p = 0.04) for death. 0.21 (0.05 to 0.35. p = 0.02) for major events. and 0.27 (0.06 to 0.43. p = 0.02) for first reinfarctions. It is concluded that long-term treatment with verapamil after an acute myocardial infarction is associated with a significant reduction in overall mortality as well as major event and reinfarction rates.
Relation between lipids and atherosclerosis: epidemiologic evidence and clinical implications, Coronary artery disease (CAD) is the leading cause of death in most developed countries. Therefore. elucidation of risk factors and associated mechanisms for CAD has been a high priority. Data from the Framingham Heart Study and other large-scale epidemiologic studies have identified major risk factors associated with CAD. demonstrating the adverse effects of increased total and low-density lipoprotein cholesterol levels and the protective effect of high-density lipoprotein cholesterol. Other more recent investigations. including the Lipid Research Clinics Trial and the Helsinki Heart Study. have shown that lowering total cholesterol and raising high-density lipoprotein cholesterol significantly reduce the risk for CAD. Because hypertension is also a significant risk factor for CAD. the assumption has been that blood pressure reduction should offer significant benefits in terms of CAD risk. However. despite their antihypertensive efficacy. diuretics and beta blockers have failed to significantly reduce CAD morbidity or mortality. The adverse effects of these antihypertensive agents on lipid profiles. glucose metabolism and other metabolic parameters may account for their disappointing performance in reducing CAD morbidity and mortality. As a result. newer agents such as angiotensin-converting enzyme inhibitors and calcium antagonists that appear to be free of such adverse effects have garnered considerable attention for their potential to reduce CAD risk.
Body composition in myelomeningocele, Body composition and measures of obesity were evaluated in 59 subjects with myelomeningocele (MMC). aged 0.3-29 y. by anthropometry and measures of body cell mass (BCM) and intra- and extracellular water (ICW and ECW). derived from total body potassium and deuterium-isotope dilution; these results were compared with reference data. Body composition was normal in preambulatory children with MMC. Beyond ages 3-4 y there was significant depletion of BCM and total body water. with maldistribution of water (increased ECW and decreased ICW) and increased percentage body fat above that expected for age and sex. These findings were more pronounced in females and in those with high lesions. and were less pronounced in those who remained ambulatory. These changes may result in metabolic and nutritional maladaption during stress. The relation of BCM. total body water depletion and increased ECW to decreasing ambulatory activity suggests that early nutritional and mobility programs warrant further study.
Effect of chronic alcohol administration on transketolase in the brain and the liver of rats, To estimate the nutritional and the pathological states in thiamin-deficiency-related diseases. especially Wernicke-Korsakoff syndrome. we studied the relationship among transketolase activity. transketolase concentration. and thiamin phosphate esters in rats chronically fed alcohol. In the brain of alcohol-fed rats. the enzyme activity and concentration decreased although there was no positive correlation between the two. On the contrary. transketolase activity in the liver correlated positively with concentration. and both transketolase activity and concentration were decreased in the thiamin-deficient groups. These findings suggest that transketolase in the brain may be different from that in the liver and that the alteration of the enzyme activity in the brain may be based on the conformational change of the protein molecule caused by chronic alcohol administration.
Lipid infusion increases oxygen consumption similarly in septic and nonseptic patients, This investigation compared the metabolic effects of lipid infusion in five septic and five nonseptic patients. Oxygen consumption was determined by indirect calorimetry over 1 h of rest and during 2 h when Intralipid (20%) was infused [166 mL/h; 23 kJ/min (5.5 kcal/min)]. Septic patients had a resting metabolic rate 17% higher than that of their nonseptic control subjects and a significant (P less than 0.05) rise (13%) in oxygen uptake was measured in both groups of subjects during the 2-h infusion of lipid. Preinfusion respiratory quotient (RQ) was 7% higher in the septic patients (P less than 0.05). and during the infusion period RQ decreased similarly (approximately 6%; P less than 0.05) in both groups. Plasma catecholamines were elevated in the septic patients preinfusion and the concentrations remained unaltered during the infusion. Norepinephrine rose significantly in the nonseptic group with the lipid infusion. The results show that sepsis has little or no influence on the characteristic rise in metabolic rate that occurs with intravenous lipid.
Influence of breakfasts with different nutrient contents on glucose, C peptide, insulin, glucagon, triglycerides, and GIP in non-insulin-dependent diabetics, To examine the influence of coingestion of fat and protein in a mixed meal on carbohydrate metabolism. subjects with non-insulin-dependent diabetes mellitus (NIDDM) received three different breakfasts varying in the amount of fat and protein (group 1) or only in the amount of fat (group 2). Compared with the changes after a standard breakfast. insulin increased after the protein-rich meal and decreased after the fat-rich meal in group 1. Glucose and gastric inhibitory polypeptide (GIP) remained constant. In contrast. only GIP showed a significant increase after a high-fat meal in group 2. Thus. in NIDDM subjects. glucose and insulin responses to different mixed meals do not appear to be exclusively mediated by GIP. Protein was confirmed as a potent stimulator of insulin secretion. Other factors. such as an altered beta-cell response in diabetics to GIP or other incretions. must be considered to explain the reported results.
Resting and total energy expenditure in patients with inflammatory bowel disease, Patients with inflammatory bowel disease often present with weight loss. Among possible causes. an elevated energy expenditure has frequently been suggested but is the least documented. In this study resting metabolic rate (RMR) and total daily energy expenditure (TDEE) were measured in 15 outpatients with inflammatory bowel diseases and in eight healthy control subjects. Measured RMR as a percentage of that predicted from fat-free mass was not significantly different for control subjects (102 +/- 9.8%. mean +/- SD) and patients (100 +/- 13.3%). TDEE. expressed as a multiple of RMR. was 1.70 +/- 0.31 for control subjects and 1.78 +/- 0.24 for patients. When patients were subgrouped as greater than or equal to 90% or less than 90% desirable body weight. a mean increase over RMR predicted from fat-free mass was seen in the underweight patients (106 +/- 9.3%) but not in normal-weight patients (99.0 +/- 15.6%). Mean TDEE/RMR values for the patient subgroups were 1.70 +/- 0.30 and 1.88 +/- 0.08. respectively. We conclude that stable outpatients with inflammatory bowel disease have only a minimal increase in energy needs.
Protein metabolism in obesity: effects of body fat distribution and hyperinsulinemia on leucine turnover, To examine whether moderate obesity and differences in body fat distribution are associated with abnormalities of protein metabolism. leucine turnover was measured in three groups of age-matched premenopausal women. Ten upper-body-obese (UB Ob). 10 lower-body-obese (LB Ob). and 10 nonobese (Non Ob) women were studied in an overnight postabsorptive condition (basal) and again during an infusion of low physiologic amounts of insulin (insulin clamp). Results showed that basal leucine carbon flux was greater (P less than 0.05) in UB Ob and LB Ob women than in Non Ob women (2.96 +/- 0.08 vs 3.14 +/- 0.16 vs 2.68 +/- 0.08 mumol.kg lean body mass-1.min-1. respectively; mean +/- SEM). Leucine carbon flux was not suppressed during the insulin-clamp study in UB Ob women but was in the LB Ob and Non Ob women. We conclude that moderate obesity is associated with increased proteolysis and that insulin's antiproteolytic actions are impaired in upper-body obesity. These findings could have implications for future studies of and treatment of obesity.
Dietary alpha-linolenic acid and immunocompetence in humans, We examined the effect of dietary alpha-linolenic acid (ALA) on the indices of immunocompetence in 10 healthy free-living men (age 21-37 y) who consumed all meals at the Western Human Nutrition Research Center for 126 d. There was a stabilization period of 14 d at the start when all 10 subjects consumed basal diet (BD) and there were two intervention periods of 56 d each. Five of the subjects consumed the basal diet and the other five consumed flax-seed-oil diet (FD) during each intervention period. Feeding of FD suppressed the proliferation of peripheral blood mononuclear cells when they were cultured with phytohemagglutinin-P (P = 0.041) and concanavalin A (P = 0.054) and the delayed hypersensitivity response to seven recall antigens (NS). Concentrations of immunoglobulins in serum. C3. C4. salivary IgA. the numbers of helper cells. suppressor cells. and total T and B cells in the peripheral blood were not affected by the diets.
Effect of trestatin, an amylase inhibitor, incorporated into bread, on glycemic responses in normal and diabetic patients, The effect of incorporating the pancreatic alpha-amylase inhibitor trestatin into bread on postprandial plasma glucose and insulin excursions was tested in healthy volunteers and non-insulin-dependent diabetic patients. At both dose levels of trestatin (3 and 6 mg/75 g starch) the peak values of plasma glucose and insulin were reduced markedly (compared with placebo) after the ingestion of 75 g starch in the form of bread. In healthy control subjects as well as in diabetic patients. trestatin produced significantly lower insulin excretions but also significant reductions in incremental plasma glucose areas in a dose-dependent fashion. It is concluded that it is technologically feasible to incorporate trestatin into starchy foods without loss of activity or impairment of taste. Furthermore. the positive effect of trestatin on glycemic and insulinemic responses in diabetics and the lack of serious side effects offer a great potential in the dietary treatment of diabetic patients.
Percent body fat in obese white females predicted by anthropometric measurements, The percent body fat (PBF) and 15 anthropometric measurements were measured in 221 obese white females randomly assigned to validation and cross-validation groups. Two new anthropometric equations for the prediction of the percent of body fat were generated by multiple regression. Equation 1 includes the residual lung volume (RV) as a factor and had a correlation coefficient (r) of 0.85 and a standard error of the estimate (SEE) of 3.9%. Equation 2 does not include the RV and has an r of 0.82 and an SEE of 4.3%. Both equations were more precise than two previous widely used equations. In a subgroup of 37 subjects who underwent weight loss. equation 1 gave a more precise estimate of the change in PBF. We conclude that the new equations permit a better prediction of the PBF in obese white females.
Potential prenatal predictions of Down syndrome: a statistical analysis, To determine the feasibility of combining several screening tests for the prenatal detection of Down syndrome. we evaluated the potential relationship among three proposed predictors. We determined the concentration of chorionic gonadotropin in frozen serum samples from women of known maternal age and weight. fetal biparietal diameter. and femur length. and alpha-fetoprotein concentration. When corrected for gestational age and maternal weight. the potential predictors were independent. except for a slight correlation (r = 0.10) between maternal serum alpha-fetoprotein and maternal serum human chorionic gonadotropin. Both maternal serum human chorionic gonadotropin and biparietal diameter/femur length demonstrated an approximately log-normal distribution similar to maternal serum alpha-fetoprotein. Therefore it is scientifically sound to use any or all of these variables in combination for the identification of pregnancies at increased risk for Down syndrome.
The course of labor after endurance exercise during pregnancy, This study was designed to test the hypothesis that continuation of a regular running or aerobics program. or both. during the latter half of pregnancy would have a negative effect on the course and outcome of labor. The onset. course. and outcome of labor were independently monitored in 131 well-conditioned recreational athletes who had an uneventful first half of pregnancy. Daily exercise performance was quantitated before conception and throughout pregnancy. Comparisons were made between the 87 women who continued to exercise regularly at or above 50% of their preconceptional level throughout pregnancy and the 44 who discontinued their regular exercise regimen before the end of the first trimester. The incidence of preterm labor was similar in the two groups (9%). Labor began significantly earlier in the exercise group (277 +/- 6 vs 282 +/- 6 days). The women who continued to exercise had a lower incidence of abdominal (6% vs 30%) and vaginal (6% vs 20%) operative delivery. and active labor was shorter (264 +/- 149 vs 382 +/- 275 min) in those who were delivered vaginally. Finally. clinical evidence of acute fetal stress (meconium. fetal heart pattern. and Apgar score) was less frequent in the exercise group (50% vs 26%). although birth weight was reduced (3369 +/- 318 vs 3776 +/- 401 gm). These data negate the initial hypothesis and indicate that. in well-conditioned women who regularly perform aerobics or run. continuation of these exercise regimens has a beneficial effect on the course and outcome of labor.
Growth factor activity in the blood of women in whom preeclampsia develops is elevated from early pregnancy, Preeclampsia is a pregnancy-specific disorder of uncertain cause and pathophysiology that appears to be associated with endothelial cell injury. Our current studies demonstrate that a pregnancy growth factor activity is elevated compared with postpartum values in the blood of women with preeclampsia months before the onset of clinical manifestations of toxemia. A cohort of primigravid women was followed throughout pregnancy and multiple serial plasma samples from six women with preeclampsia and six matched normal women were assayed for mitogenic activity. The data indicated that the ratio of predelivery/postdelivery plasma mitogenic activity was greater in women predestined to meet strict criteria for the diagnosis of preeclampsia compared with matched normal primigravid women. Growth factor activity could distinguish women in whom preeclampsia would develop from their normal peers throughout pregnancy. and as early as the first trimester of gestation (p less than 0.05). Similar studies performed with plasma obtained greater than 6 weeks post partum. when the two groups of patients were clinically indistinguishable. revealed no differences in this index of mitogenic activity. Our results indicate that elevated mitogenic activity ratios of prepartum versus postpartum plasma antedate the clinical recognition of preeclampsia. and return to normal with the resolution of the syndrome.
The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term, Twenty patients with preeclampsia at a gestational age of 26 to 35 weeks were treated with oral nifedipine until delivery. The mean oral daily dose was 45.1 +/- 11 mg/day (range. 40 to 80 mg/day). Fetal aorta. internal carotid artery. umbilical artery. and uteroplacental Doppler flow velocity waveforms were recorded before treatment and then serially. The mean nifedipine concentration at the time of the Doppler studies was 60.3 ng/ml (range. 10 to 90 ng/ml). The use of nifedipine therapy was associated with a significant decrease in both maternal systolic blood pressure (baseline. 154 to 135 mm Hg. p less than 0.001) and diastolic blood pressure (baseline. 100 to 88 mm Hg. p less than 0.001). However. there was no significant difference in the resistance index between baseline and postnifedipine Doppler studies in either the fetal or uteroplacental vessels. The use of oral nifedipine to control blood pressure in preeclampsia does not affect the resistance indices in fetal or uteroplacental vessels as measured by the Doppler technique.
Inhibition of spontaneous uterine contractions during the last trimester in pregnant baboons by an oxytocin antagonist, The effect of a potent oxytocin antagonist. produced in our laboratories. on spontaneous uterine contractions in the pregnant baboon was examined. Three types of uterine contractions were studied: immediately after operation. during the nocturnal period. and near or at labor. Bolus intravenous injections of oxytocin antagonist were given and uterine activity was examined +/- 1 hour after the injection. The oxytocin antagonist caused a precipitate decrease (approximately 70%) in contractile force (mean amplitude x frequency) in the first 15 minutes after injection (p less than 0.05); this force diminished to approximately 90% at the end of 1 hour for both nocturnal and labor contractions. In contrast. uterine contractions immediately after operation were diminished by only 60% within 60 minutes after the oxytocin antagonist. These results indicate that the oxytocin antagonist is a potent inhibitor and suggest that oxytocin is a primary regulator of spontaneous nocturnal and labor uterine contractions in the pregnant baboon.
The effect of maternal hyperoxia on behavioral activity in growth-retarded human fetuses, Thirteen pregnant women who subsequently were delivered of infants with birth weights less than the 3rd percentile were studied for examination of fetal heart rate and fetal activity patients during maternal administration of oxygen at a concentration of 50% or room air for 2 hours. None of the fetuses was acidotic at birth. Maternal transcutaneous PO2 levels increased from 79 +/- 3 mm Hg to 158 +/- 10 mm Hg for the 2 hours of observation. The results indicated that maternal hyperoxia produced sustained fetal breathing activity that was almost 100% higher than that in room air (analysis of variance. p = 0.024). Gross fetal body movements. fetal heart rate accelerations. and fetal heart rate variability increased significantly with increasing observation time (analysis of variance. p less than 0.01). but were not significantly altered by maternal hyperoxia or room air. We conclude that despite significant change in fetal breathing activity. ultrasonographic observation of fetal behavioral activity during maternal hyperoxia could not be used to differentiate severely growth-retarded from normally grown human fetuses. We speculate that altered fetal heart rate and fetal body movement patterns usually associated with intrauterine growth retardation might be related to altered development of the fetal central nervous system and are not reversible during prolonged maternal administration of oxygen.
Observations on the cause of oligohydramnios in prolonged pregnancy, There is increasing evidence that implicates reduced amnionic fluid volume as a major determinant of fetal risk in prolonged pregnancy. We sought to determine whether reduced fetal urine production might be associated with oligohydramnios in pregnancies that reach 42 weeks or more. Ultrasonographic measurements of the fetal bladder were obtained every 2 to 5 minutes for 1 hour in 38 gestations verified to be at least 42 weeks. Oligohydramnios was present in eight of the prolonged pregnancies. Similar measurements were performed in 15 normal pregnancies delivered by elective repeat cesarean section between 38 and 40 weeks' gestation. Hourly fetal urine production rates were calculated with sequential bladder volume measurements. The result of this investigation suggest that diminished fetal urine production is associated with oligohydramnios in prolonged pregnancy. The mechanism by which fetal urine production is reduced in prolonged pregnancy remains unknown. A likely possibility is reduced fetal swallowing because of already diminished amnionic fluid volume. the latter a result of placental senescence.
A mechanism leading to reduced lung expansion and lung hypoplasia in fetal sheep during oligohydramnios, Our aim was to determine the mechanism whereby oligohydroamnios causes reduced fetal lung expansion and eventual lung hypoplasia. We studied 20 fetal sheep during 2 to 9 days of oligohydramnios produced by drainage of amniotic and allantoic fluids during the last third of gestation. Oligohydramnios led to a reversible reduction in lung liquid volume of 19.5% within 48 hours. During oligohydramnios tracheal pressure. relative to amniotic pressure. rose by 1.7 mm Hg (p less than 0.001); pressures also tended to rise in the fetal pleural space and abdomen. relative to amniotic pressure. and to fall in the amniotic sac. Pressure increments. relative to amniotic pressure. which normally occur in the fetal trachea. pleural cavity. and abdomen during nonlabor uterine contractions. were significantly increased by 1.9 to 2.5 mm Hg during oligohydramnios. Oligohydramnios increased flexion of the fetal thoracolumbar spine. quantified as a reduction in the ratio of spinal radius of curvature to spine length (0.76 in controls vs 0.40 after oligohydramnios. p less than 0.001). In three sets of twins. only the fetus exposed to oligohydramnios was affected. A similar degree of spinal flexion imposed on normal fetal sheep cadavers increased abdominal (1.6 mm Hg). pleural (1.5 mm Hg). and tracheal (2.0 mm Hg) pressure. and caused a significant reduction in fetal lung expansion. We conclude that oligohydramnios in fetal sheep increases spinal flexion. leading to compression of abdominal contents. upward displacement of the diaphragm. and lung compression. favoring loss of fetal lung liquid. These changes. which are accentuated during nonlabor uterine contractions and are reversible. may lead to pulmonary hypoplasia if prolonged.
Isolation and characterization of the gene from a human genome encoding 17 beta-estradiol dehydrogenase: a comparison of Jar and BeWo choriocarcinoma cell lines, 17-beta-Estradiol dehydrogenase is required for the enzymatic interconversion of estradiol and its weaker related sex steroid. estrone. We isolated and sequenced a complementary deoxyribonucleic acid clone for 17 beta-estradiol dehydrogenase from the BeWo choriocarcinoma cell line. Comparison of the BeWo complementary deoxyribonucleic acid sequence to a previously derived placental complementary deoxyribonucleic acid sequence yields greater than 98% homology. We also isolated the gene for 17 beta-estradiol dehydrogenase from the Jar human choriocarcinoma cell line and elucidated its primary nucleic acid structure. Significant differences in the Jar-deduced complementary deoxyribonucleic acid sequence clearly differentiate it from both the human placental and BeWo forms of 17 beta-estradiol dehydrogenase. indicating the existence of two genes for 17 beta-estradiol dehydrogenase in the human genome. Evaluation of 17 beta-estradiol dehydrogenase gene expression in BeWo and Jar cells was compared with expression in luteinized granulosa cells. Messenger ribonucleic acid for human placental 17 beta-estradiol dehydrogenase was identified in all three cell types as a 1.3 kilobase band on Northern blot analysis. A second messenger ribonucleic acid species measuring 2.1 kilobase was abundantly present in the granulosa cells. Whether these two species of messenger ribonucleic acid are involved in the regulation of the estradiol dehydrogenase genes is yet to be determined.
Factors affecting the enterohepatic circulation of oral contraceptive steroids, Oral contraceptive steroids may undergo enterohepatic circulation. but it is relevant for only estrogens. because these compounds can be directly conjugated in the liver. Animal studies show convincing evidence of the importance of the enterohepatic circulation. but studies in humans are much less convincing. The importance of the route and the rate of metabolism of ethinyl estradiol are reviewed. Some antibiotics have been reported anecdotally to reduce the efficacy of oral contraceptive steroids. but controlled studies have not confirmed this observation. Although gut flora are altered by oral antibiotics. the blood levels of ethinyl estradiol are not reduced. and one antibiotic at least (cotrimoxazole) enhances the activity of ethinyl estradiol.
Interpleural analgesia after thoracotomy, We examined the effects of the following variables on interpleural analgesia after thoracotomy: addition of epinephrine to local anesthetic. thoracostomy drainage. two-catheter placement. and location of catheter tips. Twenty patients were randomized to have one catheter (paravertebral tip location) or two catheters (paravertebral and lateral thoracic wall tip locations). Interpleural catheters were sutured to the parietal pleura by the surgeon at time of wound closure. Patients were then randomly assigned to receive 20 mL of 0.5% bupivacaine with 1:200.000 epinephrine through the single catheter or 10 mL of 0.5% bupivacaine with or without 1:200.000 epinephrine through each of the two catheters while supine. Bupivacaine concentrations in whole blood and in thoracostomy drainage fluid were assayed by gas chromatography. Actual content of bupivacaine in the drainage fluid was calculated. Degree of analgesia was assessed by verbal numerical pain scores over the first 4 h and opioid demand thereafter. Addition of epinephrine to bupivacaine did not influence the degree of analgesia. Approximately 30%-40% of any administered dose of bupivacaine was lost via the thoracostomy tube over a 4-h period. There was no correlation between the true initial dose (100 mg minus thoracostomy drainage) and Cmax. Use of two catheters resulted in significantly less opioid requirements after an initial 8-h period. Failure to achieve adequate interpleural analgesia in postthoracotomy patients may be related to loss of anesthetic via thoracostomy drainage. presence of extravasated blood and tissue fluid in the pleural space. and possibly sequestration and channeling of flow of local anesthetic by restricted motion of an operated lung.
Effects of hydralazine and prostaglandin E1 on regional myocardial function in the ischemic canine heart, The effects of hydralazine and prostaglandin E1 on regional myocardial function were studied in dogs. Sixteen dogs were randomly assigned to one of two drug treatment groups of eight dogs each. The first group (G1) was treated with 0.4 mg/kg hydralazine administered as a bolus. The second group (G2) received prostaglandin E1 given as an infusion for a total dose of 0.8 micrograms/kg. Regional myocardial function was assessed through the measurement of myocardial segment shortening during systole. We call this index percent systolic shortening (%SS). An ischemic heart preparation was created by partial occlusion of coronary blood flow. The degree of induced ischemia was determined by following the reduction in %SS. Hydralazine reduced %SS of the ischemic myocardium while increasing the cardiac index. stroke volume index. and coronary blood flow. Prostaglandin E1 increased %SS. cardiac index. and stroke volume index in the ischemic heart preparation. Hydralazine. therefore. induced dissociation between global ventricular function and regional myocardial function whereas prostaglandin E1 did not. The present findings emphasize that evaluation of vasoactive drugs should consider their effects on regional myocardial function as well as on global hemodynamics.
A blinded comparison of noninvasive, in vivo phosphorus nuclear magnetic resonance spectroscopy and the in vitro halothane/caffeine contracture test in the evaluation of malignant hyperthermia susceptibility, Malignant hyperthermia (MH) is a potentially fatal. anesthetic-induced syndrome. Currently. the only accurate means of diagnosing susceptibility to this syndrome is the testing of biopsied skeletal muscle for its contracture response to halothane and caffeine. A less invasive means of diagnosis is needed. The authors previously reported that MH-susceptible patients studied by in vivo phosphorus nuclear magnetic resonance (31P NMR) spectroscopy demonstrated a higher resting inorganic phosphate (Pi) to phosphocreatine (PCr) ratio in their skeletal muscle. as well as a slower postexercise recovery of PCr/Pi. when compared to normal controls. In the present blinded study. the authors compared in vivo 31P NMR determination of resting Pi/PCr and recovery rate of PCr/Pi in forearm muscles to in vitro halothane/caffeine contracture test results in 42 patients. Forty-three control subjects were studied to establish normal NMR values of resting Pi/PCr and recovery rate of PCr/Pi. Their findings were compared with those of 27 patients shown to be MH-susceptible and 15 patients MH-negative by contracture testing. The MH-susceptible group had a significantly (P less than 0.005) higher resting Pi/PCr value (0.202 +/- 0.044) than either the MH-negative (0.152 +/- 0.043) or the control (0.141 +/- 0.026) group. The MH-susceptible group also had a significantly (P less than 0.02) slower postexercise recovery rate of PCr/Pi (1.50 +/- 0.872 PCr.Pi-1.min-1) than either the MH-negative (2.11 +/- 1.07 PCr.Pi-1.min-1) or control (2.25 +/- 0.828 PCr.Pi-1.min-1) group. Twenty-six of the 27 MH-susceptible patients demonstrated abnormal NMR test results (a resting Pi/PCr greater than or equal to 0.18 or recovery rate less than 1.0 PCr.Pi-1.min-1). and 13 of the 15 MH-negative patients had normal NMR results. Although neither NMR parameter alone was diagnostically reliable. an NMR test utilizing both parameters was quite accurate. The NMR test and contracture test demonstrated an overall agreement of 93% with a copositivity of 96% and conegativity of 87%. The sensitivity and specificity of the NMR test is estimated to be 98.8% +/- 11.8% and 95.3% +/- 20.3%. respectively. The role of 31P NMR in the diagnosis of MH susceptibility and possible mechanisms underlying the observations are discussed.
Effective doses of epidural morphine for relief of postcholecystectomy pain, Having previously established the effective dose of intrathecal morphine for relief of postcholecystectomy pain. we determined in this study the effective dose of epidural morphine for relief of postcholecystectomy pain in 154 patients given epidural injections of a placebo (group 1. n = 49). 2 mg morphine (group 2. n = 54). or 4 mg morphine (group 3. n = 51) intraoperatively mixed in 1.5% lidocaine. The percentage of patients who did not request an analgesic. 30 mg IM pentazocine. for relief of pain during the first 24 postoperative hours was significantly greater in groups 2 and 3 than in group 1. In patients who did need 30 mg IM pentazocine postoperatively. the number of times pentazocine was administered was also significantly greater in group 1 than in groups 2 and 3. The percentage of patients developing respiratory depression or vomiting in the first 48 postoperative hours was similar in the three groups. Based on the present data and those we previously reported for intrathecal morphine. we conclude that an epidural morphine dose of 2-4 mg and an intrathecal morphine dose of 0.06-0.12 mg are equipotent for relief of postcholecystectomy pain.
Individual patterns of immediate skin reactivity to mold extracts, One hundred atopic patients were skin tested intradermally over a 2-year period with 30 different mold extracts. Subjects were monitored for immediate reactions. Data suggest that to evaluate mold sensitivity in atopic patients one must use multiple mold extracts.
Rice pollen allergy in Taiwan, A panel of tests including intracutaneous skin testing (ST). radioallergosorbent test (RAST). immunoblotting and allergen-induced lymphoproliferation was done to study rice pollen allergy in asthmatic children and to characterize the allergens. Of the 312 asthmatic patients skin tested. 29 (9.3%) had positive reactions (wheal greater than or equal to 6 mm) to rice pollen extract at a concentration of 10(-5) g/mL and the remaining 283 (90.7%) were negative. While eight (34.8%) of the 23 ST-positive patients were also RAST-positive. RAST was negative in all 34 ST-negative patients and 20 normals. Immunoblotting revealed three major allergens. with molecular weights of 16 kD. 26 kD. and 32 kD. respectively. Interestingly. RAST-positive patients showed IgE responses to most allergens but only a few of them had IgG antibodies. while normal controls had stronger IgG responses to the same allergens. particularly to 32 kD. but none had IgE antibody. The preliminary results of rice pollen protein induced-lymphoproliferation were not informative; thus. rice pollen proteins do elicit a specific response in asthmatic children and normals. but its pathogenic role in bronchial asthma needs further study.
Effect of sulfurous (thermal) water on T lymphocyte proliferative response, We studied the effect of sulfurous water thermal therapy on the phenotype and the proliferative response of peripheral lymphoid cells from ten subjects affected by chronic upper respiratory disease and from six suffering from articular and periarticular disorders. Sulfurous water (S-H2O) therapy did not modify the phenotype and function of peripheral blood mononuclear cells (PBMC) nor did it modify systemic immunologic reactivity. A different result was obtained by analyzing the response to mitogens of peripheral blood mononuclear cells in cell cultures containing graduated amounts of S-H2O. These "in vitro" studies have shown an important dose-dependent inhibitory effect of S-H2O on mitogen induced T lymphocyte proliferation and on IL2 production. H2S present in S-H2O seems to be the primary component responsible for inhibition. Our results are consistent with a local immunosuppressive role of S-H2O. which may explain part of the observed therapeutic effect of inhalation therapy on upper respiratory allergic disorders.
Anaphylaxis to pinon nuts, A 21-year-old white male developed life threatening systemic anaphylaxis within seconds of ingesting a small amount of a cookie containing pinon nuts. Skin testing. ELISA. and basophil histamine release studies demonstrated pinon nut-specific IgE. Electrophoresis of the pinon nut extract demonstrated 30 bands. three of which (in the 66 to 68.000 dalton range) bound IgE in the patient's serum in an immunoblot. Ingestion challenge was not performed due to the severity of the patient's reaction. Although used for centuries in certain cultures. pinon nuts are now being eaten more frequently in the American diet. Physicians should be aware of the potential for anaphylactic reactions following ingestion of this food.
Bronchial challenge to house dust can induce immediate bronchoconstriction in allergic asthmatic patients, The goal of the study was to evaluate whether natural exposure to house dust could elicit immediate bronchoconstriction. Two groups of asthmatic patients were studied: 12 asthmatics allergic to house dust mites and seven nonallergic asthmatics. The baseline FEV1 was similar in the two groups. Each subject was challenged through a nasal mask connected to nebulizer filled with house dust. Patients were randomly assigned to inhale dust with high or low Group I allergenic level. All allergic patients had an FEV1 drop larger than 20% of the baseline value. This drop was maximal at the 30th minute after challenge. FEV1 remained unchanged in nonallergic asthmatics. Allergic patients challenged with high Group I allergenic house dust (8.4 micrograms/g) had a mean FEV1 drop larger (P less than .01) than those challenged with the low Group I allergenic house dust (0.66 micrograms/g). Late asthmatic reactions were found in only two patients who were challenged with the high Group I allergenic house dust. These two patients had immediate FEV1 drops greater than 50% of the baseline value. Occurrence of symptoms during the test and the drop in FEV1 were correlated (r = .3; P less than .05). Natural exposure to house dust can induce immediate bronchial in allergic asthmatics in a dose-dependent manner.
Methicillin-resistant staphylococcal colonization and infection in a long-term care facility, OBJECTIVE: To determine the natural history of colonization by methicillin-resistant Staphylococcus aureus (MRSA) among patients in a long-term care facility. We specifically sought to determine if MRSA colonization was predictive of subsequent infection. DESIGN: Cohort study. SETTING: Long-term Veterans Affairs Medical Center. PATIENTS: A total of 197 patients residing on two units were followed with regular surveillance cultures of the anterior nares. MAIN OUTCOME MEASUREMENT: The development of staphylococcal infection. RESULTS: Thirty-two patients were persistent carriers of MRSA and 44 were persistent carriers of methicillin-susceptible strains (MSSA). Twenty-five percent of MRSA carriers had an episode of staphylococcal infection compared with 4% of MSSA carriers and 4.5% of non-carriers (P less than 0.01; relative risk 3.8; 95% CI. 2.0 to 6.4). The rate of development of infection among MRSA carriers was 15% for every 100 days of carriage. Using logistic regression analysis. persistent MRSA carriage was the most significant predictor of infection (P less than 0.001; odds ratio. 3.7). Seventy-three percent of all MRSA infections occurred among MRSA carriers. Isolates of MRSA from 7 patients were typed. Colonizing and infecting strains had the same phage type in all 7 patients and the same pattern of plasmid EcoRI restriction endonuclease fragments in 5 patients. CONCLUSIONS: Colonization of the anterior nares by MRSA predicts the development of staphylococcal infection in long-term care patients; most infections arise from endogenously carried strains. Colonization by MRSA indicates a significantly greater risk for infection than does colonization by MSSA. The results offer a theoretic rationale for reduction in MRSA infections by interventions aimed at eliminating the carrier state.
The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate vaccine in humans. NIAID AIDS Vaccine Clinical Trials Network, OBJECTIVE: To evaluate the safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant envelope glycoprotein (rgp 160) candidate vaccine in humans. SUBJECTS: Healthy adults (72) who were seronegative for HIV-1 were randomly assigned to one of four groups. INTERVENTIONS: The subjects were randomly assigned to receive 40 or 80 micrograms of rgp 160. 10 micrograms of hepatitis B vaccine. or placebo in three doses (on days 0. 30. and 180). with an elective. nonblinded administration of a fourth dose on day 540. MEASUREMENTS AND MAIN RESULTS: Neither clinical nor laboratory toxicity was encountered during a follow-up period exceeding 21 months. No effect of immunization was noted on lymphocyte counts. mitogenic responses. or delayed-type hypersensitivity. Serum antibody responses to HIV envelope proteins detected by Western blot were seen in 30 of 33 subjects (91%; 95% CI. 71% to 97%) receiving either 40- or 80-micrograms doses of rgp160 and were most commonly of weakly reactive intensity. Responses were first noted by Western blot after the second dose. They markedly increased in frequency after the third dose and declined over the next 12 to 18 months. The administration of a fourth dose resulted in homologous neutralizing activity in sera from 5 to 24 subjects (21%; CI. 7% to 37%) as well as in complement-mediated antibody-dependent enhancement in sera from 6 of 24 subjects (25%; CI. 10% to 42%). Antibody responses were detected by enzyme-linked immunosorbent assay (ELISA) less frequently than by Western blot. and these responses persisted for a shorter time. CONCLUSIONS: The administration of rgp160 was well tolerated and safe. resulted in a high rate of antibody response by Western blot after the administration of the third and fourth doses. and generated serum neutralizing activity and complement-mediated antibody-dependent enhancement in some subjects after the fourth dose.
An increase in plasma cholesterol independent of thyroid function during long-term amiodarone therapy. A dose-dependent relationship, OBJECTIVE: To determine whether long-term amiodarone treatment is associated with a rise in plasma cholesterol. and. if so. to analyze its relation with thyroid function. DESIGN: Consecutive entry trial. including cardiac patients who initiated amiodarone medication but excluding those with abnormal thyroid function (defined as peak thyroid-stimulating hormone [TSH] response to thyrotropin-releasing hormone [TRH] less than 2.8 or greater than 22.0 mU/L) either before or during amiodarone treatment. PATIENTS: Twenty-three patients who remained euthyroid were studied. INTERVENTION: Oral administration of amiodarone (mean duration of treatment. 17 months; range. 6 to 30 months). MEASUREMENTS: Fasting plasma lipids. thyroid hormones. and peak TSH to TRH values were recorded before and every 6 months during amiodarone treatment. RESULTS: Plasma cholesterol gradually increased from 5.1 +/- 0.2 mmol/L before treatment to 6.9 +/- 0.8 mmol/L after 30 months of amiodarone medication (P less than 0.001); the peak TSH response to TRH did not change. When age- and sex-specific reference values were applied. 30% of the patients had cholesterol values above the 75th percentile before treatment; this number rose to 69% after 2 years of treatment. The rise in plasma cholesterol was associated with an equal increase in apoprotein B. Plasma cholesterol was not related to the daily dose of amiodarone or to plasma concentrations of amiodarone. desethylamiodarone. thyroxine (T4). triiodothyronine (T3). or reverse triiodothyronine (rT3). Linear regression analysis indicated a positive relation between plasma cholesterol and the cumulative dose of amiodarone (r = 0.25. P less than 0.05). CONCLUSION: Long-term amiodarone treatment is associated with a dose-dependent increase in plasma cholesterol that is independent of thyroid function.
Caffeine and cardiac arrhythmias, PURPOSE: To review the evidence supporting the belief that caffeine causes cardiac arrhythmias. DATA SOURCES: Studies published since 1982 identified through computerized searches of MEDLINE. TOXLINE. and Chemical Abstracts and a review of bibliographies of relevant articles on the subject of caffeine and cardiac arrhythmias. STUDY SELECTION: All clinical studies examining caffeine as a cause of cardiac arrhythmias and a selection of basic science experiments to illustrate caffeine's effects in vitro. DATA EXTRACTION: Study quality was assessed and all available clinical data pertaining to caffeine as a cause of arrhythmias were summarized. RESULTS OF DATA ANALYSIS: In one electrophysiologic study. caffeine was associated with an increased susceptibility to provoked cardiac arrhythmias. In five placebo-controlled trials. caffeine in doses up to 500 mg daily (equivalent to 5 to 6 cups of coffee) did not increase the frequency or severity of ventricular arrhythmias. One large epidemiologic study reported an increase in the frequency of ventricular extrasystoles in persons consuming 9 or more cups of coffee daily. CONCLUSION: Moderate ingestion of caffeine does not increase the frequency or severity of cardiac arrhythmias in normal persons. patients with ischemic heart disease. or those with pre-existing serious ventricular ectopy.
Anogenital warts in children. Clinical and virologic evaluation for sexual abuse, Seventy-three children with anogenital warts were examined for sexual abuse during a 2-year period. Our data suggest that nonsexual transmission is common. particularly in children under 3 years of age. Approximately 25% of these children were younger than age 1 year. and another 50% were between the ages of 1 and 3 years. No evidence of sexual abuse was detected in 66 children.
Spindle and epithelioid cell nevus (Spitz nevus). Natural history following biopsy, A clinical follow-up study of 49 cases of spindle and epithelioid cell nevus is presented to address the question about the potential for local recurrence. Only 19 (39%) of the 49 lesions were initially excised en toto. and the remainder (30 cases) had positive margins; six of the latter spindle and epithelioid cell nevi were reexcised. and no evidence of a residual nevus was found in five of the six cases. There were no recurrences in the 49 patients during an average follow-up period of 5.0 years (range. 1 to 10 years). The rarity of recurrent spindle and epithelioid cell nevus would justify a conservative approach to management. with clinical follow-up alone recommended after a subtotal excision. when the pathologic diagnosis is unequivocal.
Primary dapsone-resistant Hansen's disease in California. Experience with over 100 Mycobacterium leprae isolates, We found that in the years 1978 through 1981 only one of 54 previously untreated patients with Hansen's disease was found to harbor dapsone-resistant Mycobacterium leprae. That single strain was only partially resistant. ie. it was resistant to 0.0001% dapsone in a mouse diet but not to higher concentrations. During the years 1983 through 1988. M leprae from 47 previously untreated patients presenting to clinics in San Francisco. Calif. and Los Angeles. Calif. grew in mice. None of these strains was found to be dapsone resistant. Thus. from 1978 through 1988 only one of 101 M leprae isolates obtained from skin biopsy specimens from patients with leprosy was found to be resistant to dapsone. We have concluded that primary dapsone resistance still does not appear to be a significant problem in California. Owing to the fact that our single resistant case and those reported from international sources are. in general. partially resistant. the potential importance of partial dapsone resistance is discussed.
Type VII collagen and 19-DEJ-1 antigen. Comparison of expression in inversa and generalized variants of recessive dystrophic epidermolysis bullosa, The expression of type VII collagen and 19-DEJ-1 antigen was examined in 73 and 71 patients. respectively. with recessive dystrophic epidermolysis bullosa (RDEB). comprising gravis. mitis. inversa. and indeterminant subsets. to better determine the specificity and sensitivity of two monoclonal antibodies directed against these dermoepidermal junction-specific epitopes. Type VII collagen (LH 7:2 epitope) was usually absent (in 90%) in patients with the gravis variant of RDEB. whereas its expression was most often diminished (in 67%) in those with the mitis form of the disease. Only 2% and 5% of patients with gravis and mitis variants. respectively. had apparent normal amounts of type VII collagen within their skin. In contrast. six (86%) of seven patients with the inversa variant had normal expression of the antigen. Only 25% of all patients with RDEB lacked the 19-DEJ-1 antigen; of these. however. most had the gravis variant. although absence or diminution was also infrequently observed in those with the mitis and inversa forms. Intermediate findings were noted in patients classified as having indeterminant forms of RDEB. Some variability in antigen expression was also noted among affected siblings. We conclude that assessment of expression of the LH 7:2 epitope of type VII collagen may be diagnostically useful. although considerable overlap does exist between individual patients with gravis and mitis forms. 19-DEJ-1 expression is a far less sensitive probe in RDEB. although such data may prove useful in the assessment of newborns lacking the characteristic features of gravis disease. In addition. based on our experience with inversa RDEB. it would appear that altered expression of type VII collagen cannot be attributed to blister formation in this latter rare subset. since this antigen is usually strongly detected along the dermoepidermal junction. even in perilesional skin sites.
Abnormal function of CD4+ helper/inducer T lymphocytes in a patient with widespread human papillomavirus type 3-related infection, Human papillomavirus-induced infections may be associated with cellular immunodeficiency. However. very little is known about the dysfunctional interactions among T lymphocytes. B lymphocytes. and antigen-presenting cells. A 30-year-old heterosexual man with a 10-year history of persistent multiple refractory flat wart lesions containing human papillomavirus type 3-related DNA sequence was studied. The patient had a severe depletion of CD4+ T lymphocytes and a compensatory increase in the number of CD8+ T lymphocytes. Impaired T-lymphocyte response to various stimuli was found. Depletion of the increased number of CD8+ T lymphocytes. which suppressed immunoglobulin production in vitro. did not restore the impaired T-lymphocyte response. Immobilized anti-CD3 beads that stimulate the T lymphocyte antigen complex in the absence of antigen-presenting cells indicated a T-lymphocyte defect. rather than a decreased antigen-presenting cell function. Thus. the pronounced cellular immunodeficiency was due to abnormal function of the CD4+ helper/inducer T lymphocytes.
Occupational sunlight exposure and melanoma in the U.S. Navy, Melanoma is the second most common cancer. after testicular cancer. in males in the U.S. Navy. A wide range of occupations with varying exposures to sunlight and other possible etiologic agents are present in the Navy. Person-years at risk and cases of malignant melanoma were ascertained using computerized service history and inpatient hospitalization files maintained at the Naval Health Research Center. A total of 176 confirmed cases of melanoma were identified in active-duty white male enlisted Navy personnel during 1974-1984. Risk of melanoma was determined for individual occupations and for occupations grouped by review of job descriptions into three categories of sunlight exposure: (1) indoor. (2) outdoor. or (3) indoor and outdoor. Compared with the U.S. civilian population. personnel in indoor occupations had a higher age-adjusted incidence rate of melanoma. i.e.. 10.6 per 100.000 (p = .06). Persons who worked in occupations that required spending time both indoors and outdoors had the lowest rate. i.e.. 7.0 per 100.000 (p = .06). Incidence rates of melanoma were higher on the trunk than on the more commonly sunlight-exposed head and arms. Two single occupations were found to have elevated rates of melanoma: (1) aircrew survival equipmentman. SIR = 6.8 (p less than .05); and (2) engineman. SIR = 2.8 (p less than .05). However. there were no cases of melanoma or no excess risk in occupations with similar job descriptions. Findings on the anatomical site of melanoma from this study suggest a protective role for brief. regular exposure to sunlight and fit with recent laboratory studies that have shown vitamin D to suppress growth of malignant melanoma cells in tissue culture. A mechanism is proposed in which vitamin D inhibits previously initiated melanomas from becoming clinically apparent.
Accumulation of erythrocyte nucleotides and their pattern in lead workers, Nucleotides in erythrocytes of lead-exposed subjects were analyzed by high-performance liquid chromatography (HPLC). Most of the pyrimidine levels correlated well with blood lead concentrations (Pb-B) and pyrimidine 5'-nucleotidase (P5N) activity. Highly significant correlations were found between Pb-B and uridine 5'-diphosphate-glucose (UDPG). cytidine 5'-triphosphate (CTP). or CDP-choline (CDPC). The levels of these compounds were sharply elevated when P5N activity was reduced to levels less than 7 mumole/h.g hemoglobin (Hb). which corresponded to a Pb-B of 60 micrograms/100 g. Therefore. concentration of these nucleotides may provide a useful index of lead poisoning. Adenosine 5'-triphospate (ATP) concentrations were correlated negatively with Pb-B. whereas adenosine 5'-monophosphate (AMP) concentrations were correlated positively with Pb-B. These results suggest that lead affects not only pyrimidine nucleotide metabolism but also purine nucleotide metabolism (energy production system).
Occult exposure to asbestos in steel workers revealed by bronchoalveolar lavage, To investigate the asbestos burden in a steelplant environment. we counted asbestos bodies (ABs) in the bronchoalveolar lavage fluid (BALF) of 65 steel workers who had retired during the previous 5 y. They had worked for at least 15 y in the same area of the plant (coke oven or blast furnace) as maintenance or production workers. On the basis of occupational anamnesis. 28 had occasional past professional exposure to asbestos; the remaining 37 workers denied any contact with asbestos. A total of 54 white-collar workers who had no occupational exposure to asbestos were included in the study as controls. An increased prevalence and concentration of ABs was found in the BALF of steel workers. Electron microscopy and EDAX analysis of AB from steel workers revealed that the core fibers were mainly amphiboles. More ABs were found in the BALF of maintenance workers than in production workers. However. the BALF from steel workers who denied any contact with asbestos revealed an increased AB burden v. controls. This demonstrates that steel workers may be subject to an occult exposure to amphiboles in the steelplant environment.
High mortality and shortened life-span in patients with itai-itai disease and subjects with suspected disease, A follow-up study was conducted from 1967 to 1987 for patients diagnosed as having itai-itai disease. subjects who were suspected of having the disease. and controls. Ninety-five subjects per category were selected after matching for age. sex. and residential area. The cumulative survival rate of the patients who had a definite diagnosis of itai-itai disease was significantly lower than that of the control group in every period after the first 3 y. The cumulative survival rate of the subjects who were suspected of having itai-itai disease and who had severe renal dysfunction due to cadmium pollution was significantly lower than that of the control group. These results demonstrate (1) the enduring negative influence of itai-itai disease on prognosis and (2) that the cadmium pollution-induced renal disorder adversely affects the health of the inhabitants of a cadmium-polluted area.
Hepatic abscess. Changes in etiology, diagnosis, and management, Most recent reviews of pyogenic hepatic abscess emphasize percutaneous versus open surgical management and devote little time to studying the etiology or the clinical condition of the patient. In this study a detailed review was performed with a computerized analysis of multiple clinical parameters in 73 patients treated for pyogenic hepatic abscess during a 17-year period. The mean age of the patients was 55 years and 38 of them (52%) were male. The mortality rate was comparable for solitary (17%) and multiple (23%) abscesses. The likelihood of death was higher with antibiotic treatment alone (45%) or percutaneous treatment (25%) than with surgical treatment (9.5%). The primary determinant of outcome. however. was the underlying disease. i.e.. malignancy or an immunocompromised patient. rather than solitary versus multiple abscesses. In addition the incidence of hepatic abscess seen at this center has doubled from the first half to the second half of the review. reflecting a population of more severely ill patients. It is apparent that in current clinical practice several methods of management are effective. and the choice of therapy should be determined by individualized selection. The principle of timely diagnosis and prompt institution of treatment appropriate to the specific patient remains the standard of care in this potentially grave disease.
Efficacy of octreotide acetate in treatment of severe postgastrectomy dumping syndrome, The present study evaluates the acute and chronic use of a long-acting somatostatin analog. octreotide acetate. in the treatment of patients with severe postgastrectomy dumping syndrome. In the acute phase. 10 patients with severe dumping were studied over 2 consecutive days before and for 3 hours after the ingestion of a 'dumping breakfast' in a randomized double-blind fashion. On one day octreotide (100 micrograms) was given subcutaneously 30 minutes before the test meal and on the other day an equal volume of vehicle was injected. An additional group of six postgastrectomy patients without dumping were studied in a similar fashion and these acted as controls. During placebo treatment the test meal resulted in an immediate increase (p less than 0.01) in the pulse rate and in plasma levels of glucose. glucagon. pancreatic polypeptide. neurotensin. and insulin. Similar changes were seen in the control group with respect to placebo; however glucagon and neurotensin (p less than 0.05) did not show the same magnitude of increase as seen with placebo. Treatment with octreotide acetate prevented the development of both vasomotor and gastrointestinal symptoms and completely ablated all of the above responses in plasma peptides. These changes were associated with complete ablation of diarrhea (p less than 0.001). Pretreatment with octreotide acetate completely suppressed the rise in plasma insulin response to the meal and this ablated the late hypoglycemia of dumping. Treatment with octreotide acetate resulted in delayed gastric emptying and transit time (578 +/- 244 minutes) versus 76 +/- 23 minutes with placebo and 125 +/- 36 minutes in controls (p less than 0.05). Chronic daily treatment with octreotide acetate resulted in minimal side effects. These patients demonstrated a stable fasting plasma glucose. normal liver function tests. and an average weight gain of 11% during a 12-month period. In addition most patients were able to resume employment. The long-acting somatostatin analog. octreotide acetate. is highly effective in preventing the development of symptoms of severe dumping syndrome. both vasomotor and gastrointestinal.
Reperfusion inhibits elevated splanchnic prostanoid production after hemorrhagic shock [published erratum appears in Ann Surg 1991 Feb;213(2):91, The effect of reperfusion following hemorrhagic shock on splanchnic prostanoid release was studied. Anesthetized male rats were bled to a mean arterial blood pressure of 30 mmHg for 30 minutes and either killed or treated with shed blood for 60 minutes and then killed. The superior mesenteric arterial bed was cannulated and perfused in vitro with oxygenated Krebs. Collected venous effluent (up to 180 minutes) was analyzed for 6-keto-PGF1 alpha (PGI2 metabolite). PGE2. PGF2 alpha. and thromboxane B2 by radioimmunoassay in shock. shock plus reperfusion. and sham groups. The major prostanoid released was 6-keto-PGF1 alpha and was three times higher in the shock group compared to the sham group (p less than 0.05). Reperfusion of shed blood abolished the increase in 6-keto-PGF1 alpha found in the shock group (p less than 0.05). These data show that the attempt of the rat splanchnic bed to compensate for hemorrhagic shock by increasing release of PGI2 (potent vasodilator) was abolished during reperfusion of blood.
Blunt traumatic cardiac rupture. A 5-year experience, Blunt traumatic cardiac rupture is associated with a high rate of mortality. A review of the computerized trauma registry (1983 to 1988) identified 32 patients with this injury (ages 19 to 65 years; mean age. 39.5 years; 21 men and 11 women). Twenty-one patients (65.6%) were injured in vehicular crashes. 3 (9.4%) in pedestrian accidents. 3 (9.4%) in motorcycle accidents; 3 (9.4%) sustained crush injury; 1 (3.1%) was injured by a fall; and 1 (3.1%) was kicked in the chest by a horse. Anatomic injuries included right atrial rupture (13[40.6%]). left atrial rupture (8 [25%]). right ventricular rupture (10[31.3%]). left ventricular rupture (4[12.5%]). and rupture of two cardiac chambers (3 [9.4%]). Diagnosis was made by thoracotomy in all 20 patients presenting in cardiac arrest. In the remaining 12 patients. the diagnosis was established in seven by emergency left anterolateral thoracotomy and in five by subxyphoid pericardial window. Seven of these 12 patients (58.3%) had clinical cardiac tamponade and significant upper torso cyanosis. The mean Injury Severity Score (ISS). Trauma Score (TS). and Glasgow Coma Scale (GCS) score were 33.8. 13.2. and 14.3. respectively. among survivors and 51.5. 8.3. and 7.0 for nonsurvivors. The overall mortality rate was 81.3% (26 of 32 patients). the only survivors being those presenting with vital signs (6 of 12 patients [50%]). All patients with rupture of two cardiac chambers or with ventricular rupture died. The mortality rate from myocardial rupture is very high. Rapid prehospital transportation. a high index of suspicion. and prompt surgical intervention contribute to survival in these patients.
The role of inhalation injury in burn trauma. A Canadian experience, From 1977 to 1987. 1705 thermally injured patients were admitted to the Firefighters' Burn Center at the University of Alberta Hospitals. Thirteen hundred forty-four were male (78.8%) and 361 were female (21.2%). with a mean total burn surface area (TBSA) of 15.1 (SEM +/- 0.4%) and a range of 1% to 99% TBSA. Sixteen hundred thirty-five patients survived to be discharged from hospital. with an overall survival rate of 95.9%. One hundred twenty-four burn patients (7.3%) suffered concomitant inhalation injury diagnosed by bronchoscopy. Patients with inhalation injury suffered from larger TBSA (39.7% +/- 2.8% versus 12.2% +/- 0.3%; p less than 0.01) than those without inhalation injury. Inhalation injury increased the number of deaths from burn injury (34.7% versus 1.7%; p less than 0.01) independent of age and TBSA. Inhalation injury was associated with a threefold prolongation of hospital stay (23.7 +/- 0.7 versus 74.4 +/- 6.2 days; p less than 0.01) and was independent of age and TBSA. Multifactorial probit analysis was performed for both inhalation- and noninhalation-injured burned patients to allow TBSA and age adjusted rates of mortality for the burn population presented. The maximum detrimental effects of inhalation injury in burn patient outcome occurred when it coexisted with moderate (15% to 29% TBSA) to large (30% to 69% TBSA) thermal injuries. These data demonstrate that inhalation injury is an important comorbid factor in burn injury that increases the number of deaths substantially. Most importantly such injuries also independently prolong the duration of hospitalization in a highly unpredictable fashion as compared to patients with cutaneous burns only. As such our data illustrate the extreme importance of inhalation injury as a comorbid factor following thermal injury and reveal the present limitations for accurate quantification of the magnitude of respiratory tract injury accompanying thermal trauma.
Return to work for persons with traumatic brain injury: a supported employment approach, Supported employment was used to place 41 persons into competitive employment during 30 months. All individuals had experienced severe head injuries; almost 70% of injuries were due to motor vehicle accidents. A mean of seven years had passed since injury for all referred clients. who had been unconscious a mean of 53 days. Only 36% of referred clients had achieved any competitive postinjury employment. compared with 91% of the same group who were competitively employed before injury. A job retention rate of 71% was reported. with most jobs in warehouse. clerical. and service-related occupations. A mean of 291 hours of job coaching was required to place and maintain all clients in supported employment.
Functional evaluation of quadriplegic patients using a hand neuroprosthesis, The objective of this retrospective study was to compare the abilities of quadriplegic patients to complete activities of daily living with and without the use of a portable hand neuroprosthesis. The neuroprosthesis provided synthetic hand grasp through functional neuromuscular stimulation of paralyzed forearm and hand muscles. Data were obtained from telephone interviews. patient records. and videotapes. Twenty-two quadriplegic patients were included in the study; 15 were functional at a C5 spinal cord injury level and seven at a C6 level. The median success rate (ie. the percentage of patients who could complete each activity) across the ten activities was 89% with the hand neuroprosthesis but was only 49% without the hand neuroprosthesis. All patients could perform more tasks when the neuroprosthesis was used. although the relative improvement of C5 patients was larger than that of C6 patients.
Impaired awareness of behavioral limitations after traumatic brain injury, Sixty-four traumatically brain injured patients were divided into three groups. Patients in Group I overestimated their behavioral competencies. Patients in Group II showed behavioral ratings similar to relatives' reports concerning behavioral competencies. Patients in Group III underestimated their behavioral competencies. Group I patients had greater evidence of bilateral and multiple-site lesions than group II and III patients. Speed of left-hand finger tapping was also worse in Group I than groups II and III. but other standard neuropsychologic test findings failed to separate the groups. Specific brain lesion sites were not related to group membership. Impaired awareness of behavioral limitations after traumatic brain injury may be related to neuropsychologic changes not measured by standard tests. Bilateral impairment of heteromodal cortex may be important to this phenomenon when it exists several months or years postinjury.
Maximal exercise testing of mentally retarded adolescents and adults: reliability study, Few data are available regarding maximal exercise testing of mentally retarded individuals. No data are available on the reliability of maximal exercise testing of mentally retarded individuals. The purpose of this study was to determine the reliability of graded exercise testing of mentally retarded adolescents and adults. The testing was conducted at two geographically different centers. At Center A. 14 mentally retarded adolescents (11 boys. three girls) with Down syndrome. who were educable or trainable. were recruited from a nonresidential school. The subjects completed two Balke-Ware treadmill protocols until exhaustion. The treadmill time and heart rate (HR) were recorded. The time between tests was approximately one week. At Center B. 21 mentally retarded adults (14 women. seven men means IQ = 56) were recruited from local workshops and group homes. These subjects completed a treadmill walking protocol. with metabolic measurements. until exhaustion. The time between tests varied from one to four months. At Center A. the subjects achieved a mean treadmill time of 8.72min on test one and 8.84min on test two (means HR = 174 and 175bpm. respectively). The reliability coefficient between the two tests was .94. At Center B. the subjects achieved a mean V0(2)max of 27.2mL.kg-1.min-1 on test one and 26.9mL.kg-1.min-1 on test two. The reliability coefficient was .93. These data show that maximal exercise testing is reliable for these populations of mentally retarded individuals. exhibiting similar values to their nonretarded peers.
Cardiac rehabilitation after coronary artery bypass grafting: effects on exercise performance and risk factors, After coronary artery bypass grafting (CABG). 49 nonselected patients followed a cardiac rehabilitation program that included medical follow-up and physical training. both in outpatient groups and on an individual basis at home. The effect of the program on exercise test variables. coronary risk factors. and medication one year after surgery was compared to a nonexercised control group (n = 98). The study group showed less increase in the rate-pressure product. indicating a favorable effect on myocardial oxygen consumption (0.7 +/- 5.4 vs 2.8 +/- 5.6. p less than .05); a lower frequency of angina at exercise testing (6% vs 18%. p less than .01); a reduction in resting systolic and diastolic blood pressure (9/4mmHg. p less than .01); fewer smokers (6% vs 17%. p less than .05); and fewer patients taking long-acting nitrates (0% vs 10.2%. p less than .05). It is suggested. therefore. that an organized cardiac rehabilitation program may be advantageous after CABG.
Retinal pigment epithelial tears through the fovea with preservation of good visual acuity, We describe two patients with spontaneous retinal pigment epithelial tears through the fovea who have maintained at least 20/40 visual acuity for 1 year and 3 years following the rip. Both patients had long-standing serous detachments of the retinal pigment epithelium associated with age-related macular degeneration prior to the development of the tear. Each tear was at least five disc areas in size and centered on the fovea. Foveal fixation was documented despite the presumed absence of pigment epithelium. This observation suggests either that there may be remaining or redundant pigment epithelium or that pigment epithelium directly beneath the central macula is not required for maintenance of 20/40 visual acuity.
Color matching and foveal densitometry in patients and carriers of an X-linked progressive cone dystrophy, We describe a family with an as yet undescribed form of X-linked progressive cone dystrophy in a five-generation pedigree. from which we report here the results of 17 male patients and 31 obligate and 13 possible female carriers. The affected males showed the characteristic picture of cone dystrophy. Foveal cone photopigment density was impaired (judged from anomaloscope settings and foveal densitometry). even at an early stage of the disease. The carriers showed no fundus abnormalities. except occasional changes due to myopia. The anomaloscope demonstrated mild pseudoprotanomaly in 27 of 31 obligate carriers and in six of 13 possible carriers. Foveal densitometry findings performed in 11 carriers always agreed with the anomaloscope findings. We conclude that the findings of pseudoprotanomaly and abnormal density differences in females of this family were the only ocular abnormalities and thus are indicative of the carrier state.
Familial trigeminal anesthesia, Familial congenital trigeminal anesthesia as an isolated abnormality is an unusual disorder. To our knowledge. only one family has previously been reported. We report here a family with three affected members demonstrating facial anesthesia. bilateral corneal changes. and nasal septal damage secondary to self-traumatization. Magnetic resonance imaging demonstrated hypoplasia of gasserian ganglia and trigeminal nerves in the affected father of two affected sons. The pathogenesis of this disorder appears to be congenital hypoplasia of the trigeminal nerves and gasserian ganglia that is inherited in a dominant fashion.
Vitreous fluorophotometry in insulin-dependent diabetes mellitus. Correlation with microalbuminuria and diastolic blood pressure, Vitreous fluorophotometry was performed on 240 eyes of 120 young subjects who had insulin-dependent diabetes mellitus (type I) and various grades of retinopathy. The concentration of fluorescein was measured in the anterior chamber and posterior vitreous 1 hour after intravenous injection of fluorescein. There was a significant association (P less than .001) between the grade of retinopathy and the level of posterior vitreous leakage. The amount of posterior vitreous leakage in each eye also had a significant association with borderline elevation of diastolic blood pressure. Subjects with excessive posterior vitreous leakage had significantly higher levels of urinary microalbumin excretion. In a multiple linear regression analysis for posterior vitreous leakage. retinal grade consistently entered the model at a significant level (P less than or equal to .00001 to .003). Blood pressure also entered the model for posterior vitreous leakage at a significant level for retinal grades of the right and left eyes and of the worst eye. These results demonstrate an association between leakage of retinal and renal vessels. possibly linked at least in part to elevation in diastolic blood pressure.
Inflammatory mediators in postoperative aphakic and pseudophakic baboon eyes, We measured prostaglandin E2 and leukotriene B4 in the aqueous humor of baboon eyes. 1 or 8 days after phacoemulsification. with or without posterior chamber lens implantation. We also evaluated the effects of steroid eye drops and cyclooxygenase inhibitor eye drops on the synthesis of these mediators of inflammation. Eyes that had undergone phacoemulsification showed significant elevation of prostaglandin E2 at both postoperative periods compared with normal. phakic control eyes. The level of prostaglandin E2 was significantly (P less than .05) higher in eyes with posterior chamber lens implantation than in those without it. and was significantly (P less than .05) higher on the eighth than on the first postoperative day. The amount of leukotriene B4 was below the detection limit. except in the few eyes in which complications developed. Cyclooxygenase inhibitor eye drops significantly reduced the amount of prostaglandin E2 on both postoperative days. while steroid eye drops had no such effect.
A frameshift mutation leading to type 1 antithrombin deficiency and thrombosis, Type 1 antithrombin III (ATIII) deficiency. which is the commonest form of inherited ATIII defect. is characterized by a quantitative reduction in both immunologically and functionally detectable protein. This condition is associated with a high incidence of thromboembolic disorder. Previous investigations have shown that the ATIII genes in the majority of cases are grossly intact. but the precise underlying molecular defects remain unknown. We have investigated the molecular basis of a type 1 ATIII deficiency in an Italian kindred by enzymatic amplification of the ATIII gene sequences in affected family members and direct sequencing of the amplified genomic DNA. A novel mutation. the deletion of a single T in the second position of codon 119. was identified in each of the affected individuals. The resulting frameshift leads to a premature termination in codon 126. effectively resulting in a null allele.
Bone marrow transplantation with interleukin-2-activated bone marrow followed by interleukin-2 therapy for acute myeloid leukemia in mice, We have investigated approaches to induce graft-versus-leukemia (GVL) effect in autologous bone marrow transplantation (ABMT) without graft-versus-host disease to improve survival and cure in leukemia. The present study shows that bone marrow transplantation (BMT) using syngeneic bone marrow activated with interleukin-2 (ABM) for 24 hours in vitro. followed by interleukin-2 (IL-2) therapy. was superior to BMT with fresh. syngeneic bone marrow (FBM) in terms of survival and cure in mice with acute myeloid leukemia (P less than .001) and led to normal hematopoietic reconstitution. Addition of IL-2 therapy after BMT with FBM did not improve the results over BMT with FBM alone (P = .98). These results suggest that the GVL effect of ABMT can be enhanced by using ABM for BMT followed by IL-2 therapy without compromising engraftment.
Direct relationship between remission duration in acute myeloid leukemia and cell cycle kinetics: a leukemia intergroup study, Cell cycle characteristics including labeling indices (LI). duration of S-phase (Ts). and total cell cycle time (Tc) were determined in 54 standard-risk. newly diagnosed patients with acute myeloid leukemia following an infusion of bromodeoxyuridine. Remission induction therapy consisting of cytosine arabinoside and daunomycin was then administered to all patients. followed by three courses of consolidation to those who achieved complete remissions (CR). Older patients appeared to have more rapidly cycling cells (P = .003). No unique cell cycle characteristics were identified for patients who achieved remission versus those who had resistant disease. However. the pretherapy cell cycle characteristics were a strong prognosticator for remission duration. CR patients were divided into those whose leukemic cell Tc were above median (A) and below median (B). Among 14 B patients. median duration of response was 211 days. and all relapsed by day 600. Among 18 A patients. the median has not as yet been reached. with nine patients in continuous complete remission (log rank P = .007. Wilcoxon P = .04). We conclude that cell cycle characteristics of leukemic cells play a role in determining remission duration. perhaps because the leukemic cells of the former patients regrow slowly between courses of chemotherapy.
Control of interleukin-1 beta expression by protein kinase C and cyclic adenosine monophosphate in myeloid leukemia cells, We have examined the signal transduction pathways leading to the expression of the interleukin-1 beta (IL-1 beta) gene in human myeloid leukemia cells lines. Two cell lines representing different stages of differentiation were used (HL-60. promyelocytic. and THP-1. mature monocytic). In accordance with previous studies. it was observed that a protein kinase C (PKC) activator. phorbol myristate acetate (PMA). was a sufficient stimulus for induction of the IL-1 beta messenger RNA (mRNA) expression and IL-1 beta protein production in both of these cell lines. A structural analog of cyclic adenosine monophosphate (dbcAMP) or agents elevating the endogenous cAMP levels (prostaglandin E2. forskolin) were not alone able to induce IL-1 beta expression. but they strongly enhanced the PMA-induced IL-1 beta production and IL-1 beta mRNA accumulation. Nuclear run off analysis showed that this elevation in IL-1 beta mRNA levels was due to an increased rate of transcription. If dbcAMP was added 6 hours before PMA to the cultures. no enhancement in the IL-1 beta production was seen. implying that for this enhancing effect both of these signals must be present simultaneously. PKC inhibitor. H7. also blocked effectively the PMA plus dbcAMP induced IL-1 beta production. while the protein kinase A (PKA) inhibitor. HA1004. had no effect. suggesting that PKA activation is not involved in the mechanism of action of cAMP in this case. Collectively. the present findings show that cAMP-dependent signals can have a positive regulatory effect on the PKC-dependent activation of the IL-1 beta gene in cells derived from different stages of myeloid differentiation.
Potentiation of the erythropoietin response by dimethyl sulfoxide priming of erythroleukemia cells: evidence for interaction of two signaling pathways, Erythropoietin (Epo) and dimethyl sulfoxide (DMSO) are believed to induce the differentiation of transformed erythroid cells by different signal transduction pathways. We have now obtained evidence for the interaction of these pathways. We used a Rauscher murine erythroleukemia cell line with a relatively low (8% to 10%) hemoglobinization response to Epo alone. Pretreatment of these cells for 1 day with DMSO followed by its removal and the addition of Epo resulted in a marked enhancement of the Epo specific hemoglobinization. We have designated this effect "DMSO priming." This priming effect of DMSO on the Epo response was both time-dependent and DMSO concentration-dependent. DMSO priming potentiated the Epo response in three ways. Firstly. DMSO priming increased the total number of Epo responsive cells from 8% to 10% to 40% to 60%. Secondly. DMSO priming reduced the time required to reach the optimal Epo-induced response from 4 days to 2 days. Thirdly. the Epo dose-response curve was left-shifted approximately 20-fold. DMSO priming was also associated with a marked increase in Epo receptor density characterized by an apparently new receptor population and by the appearance of positive cooperativity between receptors. Our results suggest that the DMSO priming effect is due to potentiation of the Epo signaling pathway. thus resulting in a much more rapid and dramatic Epo-induced hemoglobinization response.
Benzylacyclouridine reverses azidothymidine-induced marrow suppression without impairment of anti-human immunodeficiency virus activity, Increased extracellular concentrations of uridine (Urd) have been reported to reduce. in vitro. azidothymidine (AZT)-induced inhibition of human granulocyte-macrophage progenitor cells without impairment of its antihuman immunodeficiency virus (HIV) activity. Because of the clinical toxicities associated with chronic Urd administration. the ability of benzylacyclouridine (BAU) to effect. in vivo. AZT-induced anemia and leukopenia was assessed. This agent inhibits Urd catabolism and. in vivo. increases the plasma concentration of Urd in a dose-dependent manner. without Urd-related toxicity. In mice rendered anemic and leukopenic by the administration of AZT for 28 days in drinking water (1.5 mg/mL). the continued administration of AZT plus daily BAU (300 mg/kg. orally) partially reversed AZT-induced anemia and leukopenia (P less than .05). increased peripheral reticulocytes (to 4.9%. P less than .01). increased cellularity in the marrow. and improved megaloblastosis. When coadministered with AZT from the onset of drug administration. BAU reduced AZT-induced marrow toxicity. In vitro. at a concentration of 100 mumol/L. BAU possesses minimal anti-HIV activity and has no effect on the ability of AZT to reverse the HIV-induced cytopathic effect in MT4 cells. The clinical and biochemical implications of these findings are discussed.
Isolation and characterization of an acquired antithrombin antibody, A 68-year-old man. following mitral valve replacement. presented with a low-grade chronic consumptive coagulopathy. Laboratory analysis showed mild fibrinolysis. minimal effect of coumadin therapy. and a prolonged thrombin time (greater than 150 seconds using bovine IIa). When purified human IIa was used the thrombin time normalized to within 17 seconds of controls. suggesting a possible inhibitor of bovine IIa. An anti-IIa antibody was isolated by protein A-Sepharose (Sigma. St Louis. MO) chromatography followed by affinity chromatography using a bovine IIa-Sepharose column. The effects of this purified anti-IIa antibody on both bovine and human IIa procoagulant and anticoagulant functions were studied. The isolated immunoglobulin G (IgG) was observed to inhibit bovine IIa in all assays tested. This IgG was also able to slightly prolong fibrinogen clotting by human IIa. Using an enzyme-linked immunosorbent assay it was observed that the IgG bound to bovine IIa. bovine II. human IIa. but not to human II. Further. binding was detectable at approximately 50-fold lower concentrations to bovine IIa (1 nmol/L IgG concentration) than to human IIa (50 nmol/L IgG concentration). The effect of the antibody on the reaction between IIa and AT III/heparin was investigated. Human IIa was found to be protected from AT III/heparin neutralization in the presence of this antibody. These results suggest that this patient developed an antibody that strongly binds to and inhibits the bovine IIa in all assays tested. However. the antibody only significantly affects human IIa neutralization by AT III/heparin. and has little effect on the human IIa procoagulant activity. These data suggest that the decreased effect of AT III/heparin on this patient's IIa may have been a contributing factor in his coagulopathy. The exact cause of this antibody development is unclear. but the role of bovine topical thrombin used during cardiac valve replacement surgery is suspect.
Fibrinogen Baltimore I: polymerization defect associated with a gamma 292Gly----Val (GGC----GTC) mutation, Fibrinogen Baltimore I is one of the very first congenital abnormal fibrinogens reported over several decades ago; however. the molecular defect of this dysfibrinogen has eluded identification. In fact. several reports misidentified the functional defect of Baltimore I. which has impaired fibrin monomer polymerization. Reversed-phase high-performance liquid chromatography analysis of lysyl endopeptidase digest of the purified Baltimore I gamma-chain showed an abnormal peptide not found in the co-existing normal gamma-chain of this heterozygote. Amino acid sequencing of this peptide indicated that gamma-chain Gly292 is replaced by valine. This observation was confirmed. and the genetic defect was determined by direct nucleotide sequencing of a polymerase chain reaction product containing codon gamma 292. which is mutated: GGC----GTC. The molecular defect of Fibrinogen Baltimore I lies in a region of the gamma-chain required for fibrin polymerization. suggesting that the integrity of gamma Gly292 is critical for fibrin assembly.
Sra, a private platelet antigen on glycoprotein IIIa associated with neonatal alloimmune thrombocytopenia, A new platelet alloantigen. Sra. is described that was defined by an alloantibody detected in the serum of a healthy mother who delivered a child with typical clinical signs of neonatal alloimmune thrombocytopenia (NAIT). The antibody reacted strongly with the child's and father's platelets. but not with platelets of the mother or with those of a highly selected panel representing all known platelet alloantigens. Platelets from 300 unselected normal blood donors also tested negative. suggesting a phenotype frequency in the German population of less than 0.01. The antigen was present in 9 of 20 members within three generations of the paternal family. indicating autosomal codominant inheritance. By immunochemical analysis using a glycoprotein (GP)-specific immunoassay and a variety of GP IIb/IIIa-specific monoclonal antibodies for antigen immobilization (MAIPA assay). radioimmunoassay. and Western blotting. we could show that the antigen resides on a 68-Kd proteolytic fragment of GP IIIa. Immunogenetic data and gene dosage studies revealed that the Sra antigen is not related to any of the other known platelet alloantigens. In accordance with established criteria. the Sra antigen represents the first example of a "private" platelet alloantigen that bears significance in rare instances of NAIT.
In vitro drug sensitivity of cells from children with leukemia using the MTT assay with improved culture conditions, The knowledge about drug resistance in childhood leukemias and acute lymphoblastic leukemia (ALL) in general is limited. This is because of the lack of a suitable in vitro drug sensitivity assay. which is in part due to low in vitro ALL cell survival. We recently adapted the highly efficient 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyl tetrazolium bromide (MTT) assay to test cells from ALL patients and showed that its results were comparable with those of the DiSC assay. up to now the most valid but laborious assay. In this study. in vitro drug sensitivity was assessed in cells from 82 children with leukemia. 79 of whom had ALL. with the MTT assay. Dose response curves were obtained for 6-mercaptopurine. 6-thioguanine (6-TG). prednisolone (Pred). daunorubicin (DNR). vincristine (VCR). cytosine arabinoside (Ara-C). L-asparaginase (L-Asp). mafosfamide. and mustine. A cytotoxic effect of methotrexate could be detected in only a few cases. Large interindividual differences in drug sensitivity were detected. Compared with leukemia cells from newly diagnosed patients. leukemia cells from relapsed patients were significantly more in vitro resistant to 6-TG. Pred. Ara-C. mafosfamide and mustine but not to DNR. VCR. and L-Asp. Improvements of culture medium and methods to increase MTT reduction were studied. From 10 components tested. addition of insulin and bovine serum albumin to serum-containing medium improved ALL cell survival. Addition of succinate did not increase the amount of MTT reduction. We conclude that the in vitro MTT assay highly facilitates large-scale studies on drug resistance of ALL patients that can lead to rational improvements in existing treatment protocols.
Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment, Recombinant human interferon-alpha (IFN-alpha) can induce a hematologic remission in patients with chronic myeloid leukemia. However. some patients are resistant and others develop late resistance to the IFN-alpha treatment. To understand the molecular mechanism of this resistance. we have analyzed the expression of 10 IFN-inducible genes in the cells of three resistant patients. two responsive patients. and six healthy controls. Northern blot hybridizations showed that all the genes were induced in in vitro IFN-alpha treated peripheral blood cells of the patients and healthy controls. These genes were also inducible in peripheral blood and bone marrow cells of two out of two resistant patients administered an injection of IFN-alpha. We conclude that the resistance to the IFN-alpha treatment of the chronic myeloid leukemia patients we studied is not due to (1) the absence of induction of any of the 10 IFN-inducible genes we studied. including the low-molecular-weight 2'-5'oligoadenylate synthetase; (2) the presence of an antagonist of IFN-alpha in the peripheral blood or bone marrow cells; and (3) the presence of neutralizing anti-IFN-alpha antibodies.
Serum erythropoietin levels in patients receiving intensive chemotherapy and radiotherapy, To investigate the potential role of recombinant human erythropoietin (rhEpo) in patients receiving intensive cytotoxic therapy. we measured the endogenous levels of Epo in 31 patients undergoing bone marrow transplantation (BMT). Seventeen patients underwent allogeneic BMT and 14 underwent autologous BMT. On average. 10 +/- 4 units of red blood cells (RBCs) were transfused per patient. The mean RBC transfusion requirement of the autologous BMT patients was significantly greater than that of the allogeneic recipients (12 +/- 3 v 8 +/- 4. P less than .01). although both groups were maintained at comparable hematocrits. Epo levels were measured by radioimmunoassay (RIA). For each patient. baseline serum Epo levels were determined at time of admission to the hospital. Subsequent samples were collected within 24 hours of completing chemotherapy and/or radiotherapy. and on days 7. 14. and 28. after BMT. Hematocrits (Hcts) were measured daily. All patients had an initial serum creatinine less than or equal to 1.5 mg/dL. Despite considerable differences in absolute Epo levels among individuals. a characteristic pattern was observed. Following admission to the hospital and initiation of cytotoxic therapy. the average Hct decreased and the average Epo level initially increased. The mean serum Epo levels peaked on day 7 post-BMT (284 +/- 190 mU/mL) and fell steadily thereafter. While the average Hcts on day 7 and on day 28 post-BMT were not significantly different (28 +/- 4.6% v 29 +/- 3.3%. respectively). the average serum Epo levels decreased fourfold (P less than .01) during this same period. Moreover. day 28 post-BMT mean Epo levels were inappropriately low (P less than .05) when compared with a reference population with bone marrow failure and normal controls who had not received cytotoxic therapy. We conclude that the endogenous Epo response appears to be blunted during the 3 to 4 weeks immediately post-BMT. Therefore. clinical trials assessing the efficacy of the administration of rhEpo in the treatment of anemias associated with cytotoxic therapy are warranted.
Human neutrophils release the Leu-8 lymph node homing receptor during cell activation, The Leu-8 molecule. the human homologue of the murine MEL-14 peripheral lymph node homing receptor. is expressed on neutrophils in both species and may be important in localization of cells to sites of inflammation. Most circulating human neutrophils express the Leu-8 molecule. and activation of neutrophils with phorbol myristate acetate causes a rapid decline in Leu-8 membrane fluorescence staining within 15 minutes. Northern blot analysis of total cellular RNA from neutrophils demonstrated two species of Leu-8 messenger RNA. a major one of 2.4 kb and a minor one of 1.9 kb. Because two different Leu-8 cDNA clones were obtained from human lymphocytes that were predicted to encode both transmembrane and phosphatidylinositol (PI)-anchored forms of the molecule. experiments were conducted to determine whether Leu-8 is anchored to neutrophils by a PI-anchor. There was a slight decrease in expression of Leu-8 on neutrophils when they were treated with PI-specific phospholipase C (PI-PLC). However. Leu-8 was abundant on neutrophils obtained from a patient with paroxysmal nocturnal hemoglobinuria. To determine the fate of the Leu-8 molecule during cell activation. neutrophils were labeled with 125I-anti-Leu-8. During activation antibody was rapidly lost from the cell surface and was not internalized. suggesting that Leu-8 is released from the cell membrane during cell activation. When cell extracts of neutrophils were compared with extracts of lymphoid cells by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. the Leu-8 species expressed on neutrophils had a significantly higher and more variable relative mobility (70 to 120 Kd for neutrophils v 70 Kd for Jurkat T cells). In addition. Leu-8 molecules were detected in the supernatants of activated neutrophils. These results indicate that human neutrophils express a high-molecular-weight form of the Leu-8 molecule that has a conventional transmembrane anchor and is rapidly released from the membrane during activation. The loss of the Leu-8 membrane glycoprotein during activation may be a mechanism for rapid alteration of neutrophil adhesion characteristics.
Combined syngeneic bone marrow transplantation and immunotherapy of a murine B-cell lymphoma: active immunization with tumor-derived idiotypic immunoglobulin, Recurrence of the underlying malignancy remains a major cause of treatment failure after autologous bone marrow transplantation (BMT) for patients with lymphoma. In this regard. we have developed an immunotherapeutic approach designed to induce resistance against residual tumor cells persisting after BMT. Previous studies in the model system of 38C13. a lethal B-cell lymphoma of C3H origin. have shown that active immunization with purified tumor-derived surface immunoglobulin (Id). as a tumor-associated antigen. produces resistance to tumor growth. Id immunization of lethally irradiated mice at 3 or 5 weeks after reconstitution with syngeneic bone marrow resulted in significantly prolonged survival after tumor challenge compared with nonspecifically immunized controls. Low levels of idiotype-specific antibody were also demonstrated in the sera of specifically immunized mice at this early time. when other functional studies in the literature of immunocompetence after syngeneic reconstitution might have predicted incomplete recovery. Immunization of mice before lethal irradiation and syngeneic marrow reconstitution also induced significant resistance to tumor challenge. suggesting the persistence of established host antitumor immunity through total body irradiation. These studies demonstrate the feasibility of id immunization in conjunction with bone marrow transplantation.
Synovial fluid polymorphonuclear leucocytes from patients with rheumatoid arthritis have reduced MPO and NADPH-oxidase activity, Synovial fluid (SF) polymorphonuclear leucocytes (PMN) from patients with rheumatoid arthritis (RA) were compared to RA and normal circulating blood PMN. RA SF PMN were as viable as blood PMN and remained viable for up to 24 h in culture. Measurement of myeloperoxidase indicated that RA SF PMN had degranulated and secreted their myeloperoxidase prior to isolation. 26.5 +/- 11.7% being found extracellularly compared to less than 2.9% in RA and normal blood PMN. RA SF PMN alone showed a decrease in basal NADPH-oxidase activity as well as an increase in responsiveness to stimulation by chemotactic peptide during culture. Stimulation of PMN with phorbol-12-myrisitate-13-acetate evoked equivalent responses in each population before and after culture. These results demonstrate a major difference in resting and receptor-mediated activation of superoxide release by RA SF PMN. Together. these results have important implications in identifying the role of the activated PMN in RA.
Limiting dilution analysis of autocytotoxic and autosuppressor T-cells in rheumatoid arthritis, Limiting dilution analysis has shown that the autologous mixed lymphocyte reaction is regulated by at least two cell populations. the autocytotoxic and the autosuppressor. Limiting dilution analysis in nine patients with rheumatoid arthritis has shown that there is a significant decrease in both populations when compared to 10 control subjects. The mechanism and the consequences of this decrease are not known.
A laboratory and clinical study of pneumatic 'grip strength' devices, The use of inflated bags or cuffs to measure grip strength is now a well established technique. The method does have a number of problems. Bags of different diameter and volume were seen to give statistically significantly different pressure readings when squeezed by the same subjects. Different initial pressures (from 20 mmHg to 60 mmHg) also gave significantly different results both in laboratory tests on a materials testing machine and when patients with rheumatoid arthritis squeezed the bag. The technique of squeezing also affected the results. Despite the intrinsic drawbacks of the system. it is likely to remain in general use because of familiarity and convenience. We recommend the minimum details required when pneumodynamometer-derived data are published.
The cycling of combination antirheumatic drug therapy in rheumatoid arthritis, In this open pilot study a combination of hydroxychloroquine. prednisolone and alternating months of treatment with sulphasalazine or oral weekly pulse methotrexate has been investigated in 16 patients with rheumatoid arthritis (RA) refractory to a total of 67 disease suppressive medications. Results at 3 months indicated significant improvements in visual analogue score for pain. joint count. Ritchie index. scale of disability related to activities of daily living. ESR. rheumatoid factor and C-reactive protein. This degree of improvement. however. was not maintained 6 and 12 months after commencement of treatment. Pain score. Ritchie index and ESR were the only parameters demonstrating significant improvement at 12 months. Therapy was terminated in eight patients. half due to lack of efficacy and half because of side effects.
The lack of relationship between acetylator phenotype and idiopathic systemic lupus erythematosus in a South-east Asian population: a study of Indians, Malays and Malaysian Chinese, An association of idiopathic systemic lupus erythematosus (ISLE) with genetically determined N-acetylation polymorphism has been suspected from previous studies. mainly on Caucasian populations in which there is an approximate incidence of 50% of slow and rapid acetylators. The present study is of the incidence of ISLE and acetylator status in a mixed population of Malaysia. The results did not support an association between ISLE and acetylator status: the frequencies of slow acetylators in the ISLE patients who were Malaysian Chinese and Malay were 13 and 38% respectively. This did not differ significantly from the respective healthy groups (20 and 29%). The small number of Indians in the survey did not allow a valid comparison. but the figures did suggest a lack of association between ISLE and acetylator status.
Methylsulphasalazine in rheumatoid arthritis, Methylsulphasalazine. which differs from sulphasalazine by the addition of one methyl group. may provide the benefits of the parent drug with fewer side-effects in rheumatoid arthritis (RA). We describe the outcome of its use in RA. Of 21 patients entered into the study. 10 successfully completed 6 months of therapy; five developed adverse effects. four withdrew for reasons unrelated to drug treatment and two stopped because of inefficacy. No serious adverse effects were reported. A statistically significant improvement in most clinical assessments was observed from weeks 8-12 onwards. Significant improvement in plasma viscosity was observed and there was a trend towards improvement in serum CRP. histidine and IgM concentrations. There was a good correlation between mean serial changes in clinical and biochemical assessments indicating that the drug may exhibit the properties of a second-line agent. Median steady-state serum concentrations of methylsulphasalazine and methylsulphapyridine were 26.6 micrograms/ml and 2.85 micrograms/ml respectively.
Incidence and etiology of hyponatremia in an intensive care unit, To evaluate the incidence and causes of hyponatremia in intensive care unit (ICU) patients. retrospective and prospective studies were done. Hyponatremia was defined as a serum sodium concentration equal to or less than 134 mmol/l (134 mEq/l). Prospectively. 29.6% of patients displayed hyponatremia. Relevant data were obtained in twelve patients. Two patients did not have serum hypoosmolality. In the ten patients with serum hypoosmolality. urine osmolality was not maximally dilute and urine sodium concentration was greater than 30 mmol/l (30 mEq/l) suggesting inappropriate antidiuretic hormone secretion (SIADH). However. three patients exhibited suppressed ADH levels despite absence of maximal urinary dilution. The data suggest that hyponatremia is common in ICU patients and that renal diluting defects are frequent. Therefore. hypotonic fluid should be administered cautiously.
Knowledge of hemodialysis and CAPD patients about their prescribed medicines, A questionnaire was designed to determine and compare the extent of knowledge of 40 continuous ambulatory peritoneal dialysis (CAPD) and 40 hemodialysis (HD) patients about their medicines. It was administered orally to outpatients attending a clinic by an investigator unknown to the patients. Data were collected pertaining to the following target drugs: calcium supplements. phosphate binders. vitamins B and C and folic acid. HD and CAPD groups were closely matched for age and sex. Sixty percent of CAPD and 49% of HD patients were taking four or more medications. The dose of folic acid was accurately recalled by 91% and 71% of CAPD and HD patients. Indications for calcium supplements and phosphate binders were known by only 8% and 30% of CAPD patients compared to 72% and 73% of HD patients. More HD patients knew the indications for all target drugs (p less than 0.01). More CAPD than HD patients knew the expected duration of therapy (p less than 0.01). There was a trend between decreased knowledge of whether the medication was working with increasing age of CAPD patients. Most drug information was supplied by physicians. but many CAPD patients (21%) obtained information from lay sources. When given the opportunity to ask questions about their medicines. only 56% CAPD and 46% HD patients did so. The knowledge of CAPD and HD patients studied was grossly deficient in terms of indications. effectiveness. duration and action to be taken if doses were missed.
Autologous implant of peritoneal mesothelium in rabbits and man, With the purpose of studying peritoneal physiology. original biopsy methods were devised and human and rabbit peritoneal mesothelial cells cultured and characterized. It was then decided to verify whether these cells could be implanted autologously during peritoneal dialysis in cases of acute loss of mesothelial surface. Staphylococcal peritonitis was induced in 12 rabbits and after 4 days of antibiotics. 6 of them were autoimplanted with cultured mesothelial cells. previously marked in 3 cases with thymidine (H3TdR). Implanted rabbits sacrificed after 3 and 6 days showed taking of the new mesothelial cells both by direct morphological observation and by autoradiography. Four uremic CAPD patients recovering from severe peritonitis were implanted with 300 million of their own peritoneal mesothelial cells. previously cultured and frozen. Morphological signs of taking were evident by laparoscopy and from peritoneal biopsies performed 3 and 6 days after implant. The fact that such implants are possible may have interesting applications in medicine and surgery.
Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin, Characteristic features of alcoholic liver injury include fibrosis and striking membrane alterations. with associated phospholipid changes. To offset some of these abnormalities. a 10-yr study was conducted in baboons: 12 animals (eight females. four males) were fed a liquid diet supplemented with polyunsaturated lecithin (4.1 mg/kcal) for up to 8 yr. with either ethanol (50% of total energy) or isocaloric carbohydrate. They were compared with another group of 18 baboons fed an equivalent amount of the same diet (with or without ethanol). but devoid of lecithin. In the two groups. comparable increases in lipids developed in the ethanol-fed animals. but striking differences in the degree of fibrosis were seen. Whereas at least septal fibrosis (with cirrhosis in two) and transformation of their lipocytes into transitional cells developed in seven of the nine baboons fed the regular diet with ethanol. septal fibrosis did not develop in any animals fed lecithin (p less than 0.005). They did not progress beyond the stage of perivenular fibrosis (sometimes associated with pericellular and perisinusoidal fibrosis) and had a significantly lesser activation of lipocytes to transitional cells. Furthermore. when three of these animals were taken off lecithin. but continued on the same amount of the ethanol-containing diet. they rapidly (within 18 to 21 mo) progressed to cirrhosis. accompanied by an increased transformation of their lipocytes to transitional cells. These results indicate that some component of lecithin exerts a protective action against the fibrogenic effects of ethanol. Because we had previously found that choline. in amounts present in lecithin. has no comparable action. the polyunsaturated phospholipids themselves might be responsible for the protective effect.
Quantitative analysis of serum IL-6 and its correlation with increased levels of serum IL-2R in HIV-induced diseases, We have devised a luminescence sandwich ELISA for the quantification of IL-6 in both sera and cell culture supernatants. which had a detection limit of 100 fg/ml of test sample. By using the luminescence sandwich-ELISA. low but measurable levels of IL-6 (9.5 pg/ml on average) were found in the sera from normal individuals. The serum levels of IL-6 were elevated in HIV-seropositive asymptomatic carriers (55.5 pg/ml on average). and the IL-6 levels were correlated with the degree of HIV-induced disease progression (AIDS-related complex 106.8 pg/ml on average and (AIDS 283 pg/ml). IL-6 immunoreactivity in the sera of AIDS patients eluted at a 25.000 m.w. major peak. which was biologically active and heat-stable. and a 500.000 m.w. minor peak in size-exclusion HPLC. Interestingly. a significant correlation was observed between the serum IL-6 levels and soluble IL-2R levels. In vitro. HIV infection of PHA-activated PBMC led to enhanced release of IL-6 into the culture supernatants. Moreover. soluble IL-2R release was markedly increased by adding exogenous IL-6. whereas it was decreased by adding the neutralizing anti-IL-6 mAb to the cultures. These results demonstrate that increased IL-6 levels are significantly associated with sIL-2R levels. and suggest a cause of the increased levels of this receptor in patients with HIV infection. Furthermore. both serum IL-6 and serum IL-2R levels in HIV infection reflect the stage of the HIV-induced disease.
Antibody-dependent cellular cytotoxicity against HIV-coated target cells by peripheral blood monocytes from HIV seropositive asymptomatic patients, Cytotoxic effector cells like cytotoxic T cells. NK cells. monocytes/macrophages. and neutrophils can lyse directly HIV-infected or HIV-coated cells in the absence or presence of anti-HIV antibodies. Therefore. these cytotoxic mechanisms can be invoked either in the control of HIV infection at early stages of the disease or in the generalized immunosuppression observed at later stages of the disease. The relationship between anti-HIV effector mechanisms and disease. however. remains elusive. The present study investigates in HIV+ seropositive asymptomatic patients peripheral blood monocytes (PBM)-mediated antibody dependent cellular cytotoxicity (ADCC) against HIV-coated target cells in the presence of heterologous or autologous anti-HIV serum. To test for specific ADCC against HIV Ag. a T4+ CEM.TR line resistant to TNF and macrophage-mediated cytotoxicity was selected in vitro. ADCC was performed in an 18-h 51Cr-release assay using CEM.TR cells coated with inactivated HIV. Unlike PBM from normal controls. significant ADCC was observed by PBM from HIV+ seropositive patients in the presence of pooled HIV+ antiserum. The ADCC activity was specific for HIV and was dependent on the E:T ratio and the antiserum dilution used. Upon activation of PBM with rIFN-gamma. both normal and HIV+ PBM-mediated ADCC against HIV-coated CEM.TR. Furthermore. ADCC activity by PBM from HIV+ seropositive patients in the presence of their autologous serum was examined. Significant ADCC activity was observed and was dependent on the E:T ratio and serum dilution used. The findings demonstrating anti-HIV ADCC activity by PBM from HIV+ seropositive individuals and their autologous sera support the notion that monocyte-mediated ADCC may be operative in vivo.
Evidence by peptide mapping that the region CD4(81-92) is involved in gp120/CD4 interaction leading to HIV infection and HIV-induced syncytium formation, Peptide fragments of the CD4 molecule were compared in their ability to 1) inhibit CD4-dependent HIV-induced cell fusion; 2) inhibit CD4-dependent HIV infection in vitro; and 3) block gp120 envelope glycoprotein binding to CD4. Peptides from the region CD4(81-92). although inactive when underivatized. were equipotent inhibitors of CD4-dependent virus infection. cell fusion. and CD4/gp120 binding when derivatized via benzylation and acetylation. Peptides of identical chemical composition. but altered sequence and derivatization pattern that blocked gp120 binding to either CD4-positive cells or solubilized CD4. also blocked infection and fusion with similar potencies. Those that did not block gp120/CD4 interaction were also inactive in HIV-1 infection and cell fusion assays. No other peptide fragments of the CD4 molecule inhibited fusion. infection. or CD4/gp120 interaction. The peptide CD4(23-56). derived from a region of CD4 implicated in binding of CD4 antibodies that neutralize HIV infection and cell fusion. had no effect on CD4-dependent cell fusion. HIV-1 infection. or CD4/gp120 binding. but did reverse OKT4A and anti-Leu 3a blockade of gp120 binding to CD4. These data provide evidence that the 81-92 region of CD4 is directly involved in gp120 binding leading to CD4-dependent HIV infection and syncytium formation. Previous observations with structural mutants of CD4 suggest that the CDR2-homologous region of CD4 is also involved. either directly or indirectly. in binding of gp120 to CD4. The CDR2- and CDR3-like domains of CD4 may both contribute to the binding of the HIV envelope necessary for HIV-1 infection and HIV-1-induced cell fusion.
Immunodominance in the graft-vs-host disease T cell response to minor histocompatibility antigens, Immunodominance controls the generation of CTL in the C57BL/6By (B6) anti-BALB.B H-2b-matched strain combination. Despite the potential of responding to numerous individual minor histocompatibility (H) Ag on BALB.B APC. the focus of the CTL response is largely specific for only a limited number of target Ag. These minor H Ag could be distinguished by their differential expression on a panel of target cells from the CXB recombinant inbred strains. the E. G. I. J. and K (all H-2b). which express different composites of the original BALB minor H Ag. A hierarchy was observed in which first-order immunodominant Ag were present on both CXBK and CXBG cells. whereas second-order dominant Ag were found on CXBE. CXBJ. and CXBI cells. To test whether immunodominance also plays a role in the development of lethal graft-vs-host disease (GVHD) directed to multiple minor H Ag. B6 T cells were transplanted along with T cell depleted bone marrow. to irradiated (825 rad) recipients of either the BALB.B or CXB recombinant inbred strains. The results indicate that a hierarchy of immunodominance does exist in GVHD. but it differs from that predicted from the in vitro CTL studies. GVHD was observed in BALB.B. CXBE. CXBI. and CXBJ recipients. but not in CXBG and CXBK recipients. Presensitization of B6 donor mice to CXBG or CXBK splenocytes 3 wk before transplant did not significantly increase the overall GVHD potential in the corresponding CXBG or CXBK recipients. Evidence for second-order immunodominance was provided by the transfer of CXBE T cells and ATBM to irradiated CXBG and BALB.B recipients with resultant. potent GVHD.
Cardiac myosin-induced myocarditis. Heart autoantibodies are not involved in the induction of the disease, We recently demonstrated that cardiac myosin is capable of inducing autoimmune myocarditis in genetically predisposed mice. This disease parallels coxsackievirus B3-induced autoimmune myocarditis in many respects and is associated with high-titer autoantibodies specific for cardiac myosin. The following lines of evidence suggest that these autoantibodies are not involved in the induction of autoimmune myocarditis: 1) immunoperoxidase staining of heart sections from cardiac myosin-immunized A/J and A.SW mice revealed IgG depositions only along damaged muscle fibres in infiltrated areas. but not in intact tissue; 2) myosin autoantibodies did not bind to the surface of viable cardiac myocytes isolated from mice. but only reacted with myocytes permeabilized with detergent; 3) mice treated with a single high dose of cyclophosphamide. which reduces the humoral immune response. still developed severe myocarditis. despite the fact that their autoantibody titers were reduced to the level of adjuvant-injected controls; and 4) passive transfer of high-titer myosin autoantibodies failed to induce myocarditis. although the titers in the recipients were comparable to those found in mice with cardiac myosin-induced disease. Together. the results suggest that high-titer myosin autoantibodies are secondary rather than primary to the disease.
Analysis of IL-1 and TNF-alpha gene expression in human rheumatoid synoviocytes and normal monocytes by in situ hybridization, Human IL-1 alpha. IL-1 beta. and TNF-alpha mRNA expression was examined in peripheral blood monocytes (PBM) from normal individuals and in primary synoviocytes isolated from patients with rheumatoid arthritis by Northern blot and in situ hybridization. Cells cultured in the presence or absence of LPS were analyzed using in vitro synthesized 35S-labeled sense or antisense RNA probes to determine the relative abundance and the cell type expressing each of the mRNA for these potent inflammatory mediators. The results indicated that 72% of the LPS-stimulated PBM expressed detectable levels of IL-1 alpha mRNA. 89% IL-1 beta mRNA. and 10% TNF-alpha transcripts. Thus. the majority of activated PBM produced both IL-1 alpha and IL-1 beta. Experiments combining immunofluorescence for IL-1 beta protein with in situ hybridization for TNF-alpha mRNA demonstrated that monocytes expressing TNF-alpha mRNA also produced IL-1 beta. Primary synoviocytes from four patients with RA were also examined for the mRNA expression of each cytokine. Northern blot analyses of total RNA isolated from 0 to 72 h after LPS- or mock-stimulation showed that IL-1 beta mRNA was the most abundantly expressed. followed by TNF-alpha. In situ hybridization revealed that IL-1 beta and TNF-alpha transcripts were detected exclusively in synovial tissue macrophages. IL-1 alpha mRNA was not detected in these cultures by either method.
Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production, Inhibitory factors towards IL-1 have been identified in the urine and in the supernatants of human monocyte cultures and have been shown to act as receptor antagonists. We have investigated whether a natural inhibitor purified from human urine (uIL-1ra) and a recombinant molecule expressed using the gene for an IL-1 antagonist isolated from monocytes (rIL-1ra) can alter responses to human rIL-1 alpha in organ cultures of fetal rat long bones and neonatal mouse calvariae. The two preparations probably contained similar or identical molecules. because an antibody to rIL-1ra reacted with uIL-1ra by Western blot analysis. uIL-1ra and rIL-1ra specifically blocked stimulation of bone resorption by rIL-1 in both culture systems. as well as the increase in PGE2 production in cultured calvariae. Resorptive effects of parathyroid hormone and TNF-alpha were not blocked. The uIL-1ra preparation had some intrinsic resorbing activity. but on gel chromatography this appeared in fractions that eluted earlier than uIL-1ra. Concentration ratios of rIL-1ra to rIL-1 as low as 10 could block the resorptive response of fetal rat long bones. whereas concentration ratios of 100 to 1000 were required to block IL-1 action on neonatal mouse calvariae. The inhibitory effects appeared to be competitive. because increasing concentrations of IL-1 overcame the block of bone resorption in both systems and the inhibition of PGE2 production in calvariae.
cAMP mediates IL-1-induced lymphocyte penetration through endothelial monolayers, Endothelial cell incubated with IL-1 have been shown adhere more lymphocytes than nontreated endothelial cells. Here we demonstrate that IL-1 can also increase lymphocyte penetration through endothelial monolayers in vitro. IL-1 induced a transient increase in the number of lymphocytes penetrated through the endothelial monolayer into a filter in a time- and dose-dependent manner. This effect could be mimicked by increasing the cytosolic cAMP levels in the endothelial cells either by forskolin or dibutyryl-cAMP. Concomitantly we were able to show that IL-1 increased the cytosolic cAMP levels in endothelial cells. An inhibitor of adenylate cyclase. ddAdo. decreased both the IL-1-induced cAMP elevation and lymphocyte penetration. A protein kinase A inhibitor HA 1004 could inhibit the IL-1-induced lymphocyte penetration. where as protein kinase C (N-(2-guamidino-ethyl)-5-isoquinolinesyl foamide hydrocloride) and calcium-calmodulin (N-(6-aminohexyl)-5-chloro-1-naphthalensulfanamide) inhibitors had no effect. Adding dibutyryl-cGMP or calcium ionophore to the endothelial cells could not mimic IL-1-induced penetration and finally IL-1 did not induce PKC translocation in endothelial cells. These data support the view that IL-1 acts via cAMP as a second messenger in regard to lymphocyte penetration through endothelial cells. The above data demonstrate that IL-1-induced lymphocyte penetration through endothelial cells and that this IL-1-induced signal is transduced via cAMP in endothelial cells.
Human and murine anti-DNA antibodies induce the production of anti-idiotypic antibodies with autoantigen-binding properties (epibodies) through immune-network interactions, To examine the potential role of immune-network interactions in the production of lupus autoantibodies. normal NZW rabbit antibody responses were analyzed after immunization with one of the following Ig preparations: human lupus serum anti-dsDNA antibodies. human lupus serum anti-ssDNA antibodies. a mixture of human lupus serum anti-dsDNA and anti-ssDNA antibodies. the MRL-lpr/lpr anti-dsDNA mAb H241. and the MRL-lpr/lpr anti-ssDNA mAb H130. Four of five rabbits produced Ig typical of lupus autoantibodies: individual rabbit Ig cross-reacted with multiple autoantigens including nucleic acids. cardiolipin. SmRNP. glomerular extract. laminin. and exogenous Ag. Rabbit anti-Id against human anti-dsDNA antibodies were highly specific for dsDNA. Notably. in each serum the autoantibody activity was confined to the anti-Id Ig fraction. A similar spontaneously occurring Id-anti-Id interaction was also found between anti-ssDNA and anti-dsDNA antibodies isolated from an individual lupus patient. These results indicate that lupus autoantibodies which share Ag binding properties with pathogenic Ig. including both cross-reactive and anti-dsDNA antibodies. can induce the production of Ig with similar autoantigen binding properties through immune-network interactions. This phenomenon. if unregulated. could lead to the amplification of pathogenic autoantibody production in individuals with systemic lupus.
Staphylococcus aureus infection of human endothelial cells potentiates Fc receptor expression, Vasculitis. a recognized complication of staphylococcal-endovascular infections. may result in part. from the expression of FcR by Staphylococcus aureus-infected endothelial cells. FcR were measured using [51]Cr labeled SRBC preincubated with rabbit anti-SRBC IgG. FcR were not detected on uninfected endothelial cells. but were demonstrated on S. aureus infected cells using IgG. but not IgM labeled SRBC. FcR expression was dependent on the initial bacterial density (greater than or equal to 8 x 10(7) cfu/ml) and on phagocytosis of the staphylococci. but not on new protein synthesis. IgG labeled SRBC binding was blocked by aggregated IgG but not IgM. SRBC coated with the F(ab')2 portion of IgG did not bind. thus confirming that FcR were specifically involved in this interaction. FcR are expressed after S. aureus invasion of human endothelial cells and may contribute to the vasculitis which often accompanies S. aureus-endovascular infections.
Filarial-specific IgG4 response correlates with active Wuchereria bancrofti infection, The filarial-specific humoral immune response of adult residents of two areas of Papua New Guinea. differing in transmission of Wuchereria bancrofti infection was compared. The majority of residents of the village of Bonahoi. in an area where transmission of filariasis had been interrupted by a 20-year insecticide spray program to control malaria. showed no parasitologic signs of active W. bancrofti infection and were negative for both circulating phosphorylcholine Ag and peripheral blood microfilariae. In contrast. adult residents of the village of Nanaha were in an area exposed to infection. and were phosphorylcholine-Ag- and microfilariae-positive. The antibody response of these two groups to both adult worm excretory/secretory (ES) Ag and somatic antigen extract was examined to determine which components of the filarial-specific immune response were dependent on active infection. Identification of these immune responses may point to immunologic methods to evaluate control programs for lymphatic filariasis. Adults from Bonahoi were found to have significant immune responses to [35S] methionine-labeled ES Ag by immunoprecipitation and to adult somatic antigen extracts by ELISA and by immunoblotting. This result is consistent with the fact that these individuals were previously exposed to and/or infected with W. bancrofti. Similarly. residents of the endemic village had detectable immune responses to these Ag irrespective of if they were microfilaremic. The most striking immunologic difference observed between the two groups was that residents of Bonahoi had a dramatically reduced filarial-specific IgG4 antibody response to both adult somatic Ag and adult ES Ag. These data suggest that longitudinal measurement of filarial-specific IgG4 levels may be a useful seroepidemiologic indicator of changes in W. bancrofti infection status.
Serum resistance of metacyclic stage Leishmania major promastigotes is due to release of C5b-9, The mechanism of serum resistance for infective promastigotes of Leishmania major was investigated. Prior results suggested that the mechanism of resistance was mediated at a step after C3 deposition. Equivalent amounts of C3b were deposited on serum-susceptible. noninfective promastigotes harvested from log stage cultures (LOG) and on C-resistant. infective. metacyclic promastigotes (MP) purified from stationary stage cultures. Whereas binding of C9 to LOG was stable during incubation in serum. C9 binding to MP was minimal and unstable. because molecules bound initially to MP were released with continued incubation. Failure to bind C9 was not a result of inability to activate C; the kinetics of C3. C6. and C9 consumption were similar for LOG and MP. Deposition of C5b-7 on MP was stable. indicating that the initial steps in terminal complex formation were intact. Instead. the majority of C5b-9 formed on MP was spontaneously released into the serum as SC5b-9. Residual C5b-9 on MP was released with 1 M NaCl. These data show that developmental modification of the promastigote membrane during transition from a noninfective to an infective stage blocks insertion of lytic C5b-9 into the promastigote membrane.
Hepatitis B virus nucleocapsid/pre-S2 fusion proteins expressed in attenuated Salmonella for oral vaccination, Hybrid HBV nucleocapsid-pre-S(2) fusion proteins were stably expressed in several aromatic-dependent attenuated Salmonella typhimurium and Salmonella dublin strains. When these live recombinant bacteria were administered i.p. to BALB/c mice they induced high titer anti-hepatitis B virus core Ag (HBc) and detectable anti-pre-S2 serum antibodies. Upon oral feeding of the recombinant salmonellae to mice. the rate of seroconversion to anti-HBc was dependent on the salmonella strain used. With the best carrier strain high titer anti-HBc antibodies and lower titer anti-pre-S2 serum IgG antibodies were observed two weeks after a single oral immunization. The Ig class and IgG subclass distribution of anti-HBc antibodies after i.p. and oral immunization is consistent with the induction of functional T cell help.
Isolation and characterization of cDNA encoding a human nuclear antigen predominantly recognized by autoantibodies from patients with primary biliary cirrhosis, Autoantibodies to a novel nuclear Ag. Sp100. have recently been described that recognize a nuclear protein with an apparent molecular mass of 95 to 100 kDa and a dot-like distribution within cell nuclei. By immunoscreening of a lambda gt11 cDNA expression library derived from HeLa cells with an anti-Sp100 autoimmune serum a 0.7-kb cDNA (Sp26) coding for a fragment of Sp100 was isolated. Expression of this cDNA and use of the recombinant protein in ELISA revealed that the fragment carries major Sp100 autoepitopes and that anti-Sp100 autoantibodies predominantly occur in patients suffering from primary biliary cirrhosis (50/184). The Sp26 cDNA was used as hybridization probe for isolation of longer cDNA from human liver- and placenta-derived lambda gt10 cDNA libraries. Overlapping fragments were assembled to generate a full length cDNA coding for a protein with a molecular mass of 53 kDa and an isoelectric point of 4.7. The Sp100 autoantigen expressed in vitro from this cDNA and authenticated by a capture immunoblot assay. comigrated in SDS-PAGE with the authentic HeLa autoantigen of 95 to 100 kDa and thus showed an aberrant electrophoretic mobility. Computer based protein sequence analysis of the Sp100 autoantigen revealed regions of striking sequence similarities to the alpha 1 and alpha 2 domains of various human and non-human MHC class I Ag and to several transacting transcriptional regulatory proteins.
Cellular and metabolic requirements for induction of macrophage procoagulant activity by murine hepatitis virus strain 3 in vitro, The cellular basis for the variation in induction of monocyte procoagulant activity (PCA) by murine hepatitis virus strain 3 (MHV-3) was examined using a set of recombinant inbred strains of mice derived from the resistant (A/J) and susceptible C57B1/6J (B) progenitors. Induction of PCA by MHV-3 required live virus and host protein and RNA synthesis. Absolute restriction for induction of PCA was observed at the level of the macrophage. Peritoneal macrophages from resistant parental A/J and RI strains (AXB5) could not be induced to express PCA when stimulated by MHV-3 alone or in the presence of lymphocytes from susceptible and H-2 compatible RI mice (AXB3) although they did respond to endotoxin (LPS). In contrast. macrophages from both susceptible (AXB3) and semisusceptible (AXB1) RI strains of mice expressed a similar increase in PCA after stimulation with MHV-3 in the absence of lymphocytes. The levels of PCA expressed by macrophages in the presence of Thy-1.2+ lymphocytes correlated with susceptibility to disease. Thy-1.2+ lymphocytes from susceptible RI AXB3 mice could induce levels of PCA in macrophages from semisusceptible RI AXB1 mice equivalent to that seen in cultures of macrophages and lymphocytes from susceptible mice. Further subfractionation of Thy-1.2+ cells demonstrated that L3T4+ cells instructed macrophages to produce PCA. Thy-1.2+ cells from MHV-3 immunized resistant AXB5 mice. but not from non-immunized mice. were able to suppress induction of PCA. This suppressor cell activity could be detected 4 days after immunization. reaching maximal activity at day 7 with significant suppression even at 28 days. The PCA was shown to have direct prothrombin cleaving activity (prothrombinase) by ELISA and immunofluorescence staining using the mAb 3D4.3. These results demonstrate that induction of a unique PCA (prothrombinase) is restricted at the level of the macrophage and define a regulatory role for T lymphocytes in its induction.
Analysis of the permissive association of a malaria T cell epitope with DR molecules, In this study we examined the association of a promiscuous malaria T cell epitope. CS.T3. to different HLA-DR alleles. A large series of singly substituted or truncated variants of CS.T3 was prepared and tested for the ability to be recognised in association with. or to bind to. three distinct HLA-DR alleles (DR1. DRw11. and DRw14(w6)) and three natural variants of HLA-DRw11. We found that although association with the different DR molecules mapped to identical or closely overlapping regions of the peptide. distinct substitutions could drastically influence the capacity of the peptide to interact with one but not another of the three DR molecules tested. Based on analysis of the distribution of residues recognized by T cell clones restricted to the different DR alleles. we suggest that the peptide CS.T3 is not bound. at least for the three DR examined. as an alpha-helix. In addition we tested three subtypes of DRw11 as APC for the CS.T3 analogues and observed that the peptide is most likely bound in the same conformation to the three natural variants of the DRw11 molecule.
Induction of NF-KB during monocyte differentiation by HIV type 1 infection, The production of human immunodeficiency virus type 1 (HIV-1) progeny was followed in the U937 promonocytic cell line after stimulation either with retinoic acid or PMA. and in purified human monocytes and macrophages. Electrophoretic mobility shift assays and Southwestern blotting experiments were used to detect the binding of cellular transactivation factor NF-KB to the double repeat-KB enhancer sequence located in the long terminal repeat. PMA treatment. and not retinoic acid treatment of the U937 cells acts in inducing NF-KB expression in the nuclei. In nuclear extracts from monocytes or macrophages. induction of NF-KB occurred only if the cells were previously infected with HIV-1. When U937 cells were infected with HIV-1. no induction of NF-KB factor was detected. whereas high level of progeny virions was produced. suggesting that this factor was not required for viral replication. These results indicate that in monocytic cell lineage. HIV-1 could mimic some differentiation/activation stimuli allowing nuclear NF-KB expression.
B cell activation during HIV-1 infection. II. Cell-to-cell interactions and cytokine requirement, This study examined the mechanisms underlying the intense activation of HIV-1-specific B cells observed in peripheral blood of HIV-1-infected subjects. Spontaneous in vitro synthesis of anti-HIV-1 antibodies. as well as total Ig production. were dramatically reduced by accessory cell. but not T cell removal. This fall was counteracted by addition of rIL-6. but not other cytokines. to monocyte-depleted cultures; moreover. antisera against IL-6 suppressed spontaneous anti-HIV-1 antibody synthesis in a dose-dependent manner. Although IL-6 apparently sustained HIV-1-specific B cell activation. no increase in serum IL-6 levels was observed; PBMC from seropositive subjects did not produce increased amounts of IL-6 in vitro. compared to seronegative controls. both spontaneously and in the presence of LPS stimulation; finally. no constitutive expression of IL-6 gene could be documented in freshly isolated PBMC. These findings indicate that IL-6 may play a central role in HIV-1-specific B cell activation in seropositive patients. and further stress the importance of this cytokine during HIV-1 infection.
IgE-dependent cytokine production by human peripheral blood mononuclear phagocytes, These studies demonstrate the IgE-dependent production of IL-1 beta and TNF-alpha by circulating blood monocytes. IL-1 beta production was demonstrated biologically as the stimulation of proliferation of the cloned IL-1-dependent murine T cell line D10.G4.1 in the presence of a submitogenic concentration of PHA. In a representative experiment. 3H-thymidine uptake increased from 57826 cpm in the presence of supernatants obtained from unstimulated cells to 200774 cpm with supernatants from monocytes stimulated by IgE/alpha IgE immune complexes. By ELISA. IgE complexes increased IL-1 beta production from 0.54 +/- 0.06 ng (per 10(6) monocytes) to 2.60 +/- 0.62 ng (p less than 0.01; mean of eight experiments) and TNF-alpha production from 0.17 +/- 0.10 ng to 3.00 +/- 0.54 ng (p less than 0.01; mean of four experiments). No IL-1 alpha secretion was observed. RNA hybridization analysis demonstrated that IL-1 beta production represented de novo synthesis of the cytokine. Stimulated RNA production was observed after a minimal 1/2-h incubation and was maximal at 2 h. The IgE-dependent secretion of these pro-inflammatory cytokines by mononuclear phagocytic cells may contribute to the inflammation characteristic of allergic responses.
Evidence for the targeting by 2-oxo-dehydrogenase enzymes in the T cell response of primary biliary cirrhosis, Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease that includes the presence of lymphoid infiltrates in portal tracts. high titer autoantibodies against pyruvate dehydrogenase-E2 (PDH-E2) and branched chain ketoacid dehydrogenase-E2 (BCKD-E2). and biliary tract destruction. The mechanism by which the autoimmune response is induced. the specificity of damage to the biliary epithelium. and the role of T cells in PBC are still unknown. To address these issues. we have taken advantage of a mouse mAb. coined C355.1. and studied its reactivity against a panel of liver tissue from normal subjects as well as a panel of liver specimens from patients with PBC. progressive sclerosing cholangitis. and chronic active hepatitis (CAH). C355.1. much like human autoantibodies to PDH-E2. reacts exclusively by immunoblotting with PDH-E2. binds to the inner lipoyl domain of the protein. and inhibits PDH-E2 activity in vitro. In addition. we have also attempted to develop cloned T cell lines that react with PDH-E2 and/or BCKD-E2 using liver biopsies from patients with PBC. compared with CAH. Although monoclonal C355.1 produced typical mitochondrial fluorescence on sections of normal liver. pancreas. lung. heart. thyroid. and kidney. it produced a distinct and intense reactivity when used to stain the bile ducts of patients with PBC. Nine of 13 PBC liver biopsies studied herein contained bile ducts on light microscopy. all of which reacted intensely at a 1:100 culture supernatant dilution of monoclonal C355.1. In contrast. although bile ducts of liver specimens from normals. CAH. and progressive sclerosing cholangitis also reacted with C355.1. such reactivity was exclusively mitochondrial and readily detectable only at a dilution of 1:2. More importantly. we generated CD4+. CD8-. alpha beta TCR+ cloned T cell lines from patients with PBC. but not from CAH. that produced IL-2 specifically in response to PDH-E2 or BCKD-E2.
Evidence for an epidermal cytokine network, Cytokines are (glyco)proteins that are synthesized and secreted by various cells. which bind to specific receptors on target cells and which regulate activation. proliferation. and differentiation of immune as well as non-immune cells. Keratinocytes upon injury release interleukin (IL)-1. IL-6. IL-8. colony-stimulating factors. and tumor-necrosis factor. as well as growth and suppressor factors. There is also strong evidence for a network of interacting cytokines. which has been only partially characterized so far. maintaining a proper balance. However. excessive or insufficient production of these mediators may contribute to certain disease states. particularly those with infectious and autoimmune genesis. Therefore the understanding of cytokine interactions may be helpful in elucidating the pathomechanisms of such diseases. Moreover. certain cytokines. as well as their analogues and antagonists. may prove to be of therapeutic value.
Leukocyte chemoattractant cytokines of the epidermis, The constitutive production of interleukin-1 alpha-like material in normal human epidermis. its inflammatory properties. and the mechanism of its inflammatory action are briefly reviewed. The isolation of interleukin-8 from psoriatic lesions. its in vitro production. and leukocyte chemoattractant properties are also described. Available evidence suggests that interleukins-1 and -8 are inflammatory cytokines of major potential importance in the induction of leukocyte infiltrates in human skin.
Interleukin-1 and interleukin-6 in psoriasis, We report on the levels of expression of IL-1 and IL-6 in skin from psoriasis patients. Different approaches were pursued. Initially. the levels of IL-1 beta and IL-6 were measured in suction blister fluid from lesional and uninvolved skin from psoriasis patients. using a sensitive enzyme-linked immunoabsorbent assay (ELISA) and bio-assay. Skin sections were also examined for the presence of IL-1 and IL-6 using IL-1 beta- and IL-6-specific antibodies. Finally. the expression of IL-1 and IL-6 mRNA was determined in cultured keratinocytes (KC) and fibroblasts from psoriasis skin. Suction blister fluid from lesional and uninvolved psoriasis skin and from skin of healthy individuals did not contain detectable levels (greater than 100 pg/ml) of IL-1 beta. Blister fluid from psoriasis lesions contained low but significant levels of IL-6. whereas the serum levels of IL-6 in these patients was undetectable. Using cryostat skin sections and an IL-1 beta-specific monoclonal antibody (MoAb) in an indirect immunoperoxidase technique. a diffuse staining in the entire epidermis was observed in sections of uninvolved skin from psoriasis patients. In cryostat sections of psoriasis lesions. a faint diffuse staining of the epidermis and a pronounced "dot-like" intracellular staining pattern was observed. On the other hand. the same IL-1 beta-specific MoAb showed. in a indirect immunofluorescence technique using unfixed epidermal cells. bright membrane staining in epidermal cell suspensions from psoriasis lesions. Slightly elevated levels of IL-1 beta and IL-1 alpha mRNA were observed in cultured KC from psoriasis lesions as compared to those in normal KC and in the HEp-2 cell line. Very low levels of IL-6 mRNA were expressed in KC from psoriasis lesions and healthy individuals. Fibroblasts from psoriasis lesions expressed extremely low levels of IL-1 alpha and IL-1 beta. but high levels of IL-6 mRNA. The results point to a paradoxical situation in psoriatic skin: blister fluid from psoriasis lesions contains no IL-1 beta. whereas IL-1 beta is overexpressed on the plasma membrane and in the intracellular compartment of epidermal cells. This finding may help in explaining the observed absence of IL-1 in aqueous extracts of psoriatic scales. Because cultured KC from psoriasis lesions express minimal levels of IL-6 mRNA. dermal fibroblasts. probably together with the inflammatory infiltrate. may represent a major source of IL-6 in psoriasis lesions in vivo.
A possible role for transforming growth factor-beta in systemic sclerosis, The cause of systemic sclerosis remains unknown. but cellular and molecular mechanisms possibly responsible for the characteristic clinical manifestations of fibrosis and vascular damage (Raynaud's phenomenon. telangiectasis. digital infection. and renal arteriopathy) are becoming understood in greater detail. One possibly important cytokine is transforming growth factor-beta (TGF-beta); its involvement is reviewed here. With regard to vascular lesions. TGF-beta has variably been shown to inhibit endothelial cell growth in vitro but to promote angiogenesis in vivo. a paradox that remains unresolved. Nonetheless. an injurious activity of TGF-beta on microvascular endothelial cells could help to explain the intimal proliferation and microvascular obliteration seen. Whether as a result of or as a cause of endothelial cell damage. platelet activation has been well documented in systemic sclerosis and the platelet alpha granule pool contains a large quantity of TGF-beta. TGF-beta is also produced by activated macrophages and T cells. both of which are known to occur within systemic sclerosis lesions. An important effect of TGF-beta is its stimulation of fibroblast collagen and fibronectin synthesis and their deposition into the extracellular matrix. Stimulation by TGF-beta may therefore account for the fibrosis seen in the dermis and in the internal organs. Direct evidence of TGF-beta involvement in systemic sclerosis is scanty. and awaits discovery of either an abnormal expression of or response to TGF-beta. The biologic effects of TGF-beta appear to be regulated at the level of activation from a latent polypeptide precursor form. Descriptions of the importance of this cytokine in pathologic conditions will need to account for this activation and its regulation. Nonetheless. the physiologic effects so far attributed to TGF-beta make its involvement in systemic sclerosis an attractive possibility to explain some of the manifestations of this enigmatic disease.
Abnormal cutaneous topobiology: the molecular basis for dermatopathologic mononuclear cell patterns in inflammatory skin disease, Because of the identification and characterization of various adhesion molecules (lymphocyte function associated antigen-1. intercellular adhesion molecule-1). chemotactic factors (interleukin-8. monocyte chemotactic/activating factor). and their modulatory cytokines (gamma interferon. tumor necrosis factor). it is possible to begin to ascribe specific molecules to cutaneous cellular reaction patterns. The abnormal topobiology. or altered spatial distribution. of mononuclear cells. which gives rise to disease-specific patterns. was described in molecular terms. A large number of diverse skin diseases were classified into six different groups. with each group highlighting distinctive cell types. adhesion molecules. chemotactic factors. and cytokines. The diseases within each group. which share functional anatomical reaction zones. were postulated to share common pathophysiologic pathways. Thus. it is now possible. as one scans the microscopic field. to look past the static images of red- and blue-stained cells and appreciate a dynamic and detailed medley of molecularly defined events emanating from the eyepiece.
Response of discoid and subacute cutaneous lupus erythematosus to recombinant interferon alpha 2a, Ten patients suffering from discoid lupus erythematosus (DLE) or subacute cutaneous lupus erythematosus (SCLE) were treated with interferon alpha 2a. A marked improvement or clearing of cutaneous lupus erythematosus lesions was observed in eight of them. However. the response to interferon was of short duration and within a few weeks after interferon withdrawal all patients who were improved or cleared relapsed. This study suggests that interferon alpha 2a represents a new interesting approach in the treatment of DLE and SCLE. Ongoing trials will define the optimal treatment schedule for the maintenance of interferon-induced improvement of cutaneous lupus erythematosus.
Application of beta-interferon in virus-induced papillomas, Eighty patients with bilateral common warts of the extremities were treated at weekly intervals with intralesional injections of either human fibroblast interferon or placebo. Lyophilized interferon (3 X 10(6) units) was diluted with 3 ml of normal sterile saline matched with identical vials of placebo. Eighty sets of three vials of human fibroblast interferon or placebo were labeled either A or B by a controller who maintained the code until the experiment was completed. Each patient received 0.1 X 10(6) units of interferon into the warts on one side and placebo injections into those on the matching extremity. Warts were measured each week and the progress or lack thereof was scored on a scale of -1 (worse) to 3 (cured). Therapy continued until either at least one extremity had cleared or the patient had received 10 weekly injections. A final evaluation was scored by measuring the total progress of each patient during the study. Sixty-four patients were treated to completion. More than 81% of the interferon-treated extremities were either cured or responded effectively to therapy. Only 17% of the placebo-treated lesions responded in this fashion. A statistical analysis of these data confirms the effectiveness of intralesional interferon therapy. The average number of interferon injections until cure was 5.9 +/- 1.7. No adverse effects were observed. The applications of interferon in patients with epidermodysplasia verruciformis and flat warts were also studied. Intralesional interferon beta was. to a certain degree. effective for benign lesions of epidermodysplasia verruciformis. but systemic treatments were not effective. Subcutaneous interferon beta was. in an uncontrolled study. effective in 45% of patients with flat warts.
Efficacy of interferons on bowenoid papulosis and other precancerous lesions, Preliminary results of an open randomized trial of recombinant interferon gamma in patients suffering from bowenoid papulosis are described. Recombinant interferon gamma was given subcutaneously to 12 patients at a daily dose of 4 X 10(6) I.U. by injection. Four patients each were assigned to one of three treatment groups consisting of continuous therapy (group A) with three subcutaneous injections per week for 13 weeks; intermittent block therapy (group B) with four six-week cycles consisting of five injections on days 1. 3. 5. 7. and 9 of each cycle; and intermittent single-dose therapy (group C) with six four-week cycles consisting of only one subcutaneous injection on day one of each cycle. At the twenty-sixth week after onset of therapy. complete responses were seen in three of four patients of treatment group A. whereas in the treatment groups B and C only one patient. respectively. responded partially. These results suggest that in contrast to condylomata acuminata bowenoid papulosis lesions respond better to continuous than to intermittent interferon gamma injections.
Interferon in the treatment of AIDS-associated Kaposi's sarcoma: the American experience, This report is intended to summarize the use of Interferon in the treatment of Kaposi's sarcoma (KS) associated with AIDS. The review is basically focused on the trials in the United States. which resulted in approval by the Food & Drug Administration (FDA) of the use of recombinant interferon alpha for the treatment of Kaposi's sarcoma.
Long-term combined rIFN-alpha-2a and zidovudine therapy for HIV-associated Kaposi's sarcoma: clinical consequences and side effects, Interferon alpha (IFN-alpha) has been shown to be effective in treating HIV-associated KS in at least 30% of patients. and Zidovudine has proved beneficial for AIDS patients. Moreover. both drugs have demonstrated an inhibitory effect on HIV replication. Based on the above. we combined IFN-alpha and zidovudine for treatment of HIV-associated KS in order to evaluate tolerance and clinical efficacy. Twenty-one homosexual men with histologically proved HIV-associated KS were treated in an open trial with rIFN-alpha-2a 18 X 10(6) IU every second day and zidovudine 800-1200 mg/d. Treatment was discontinued within the first month in six patients: three of them developed subjective intolerance. and three others contracted severe opportunistic infections or HIV-cachexia. Fifteen evaluable patients received combination treatment over a period of 2-20 months (average 10 months). The dosage was reduced as required based on drug-induced cytotoxicity. Complete remission was observed in four patients. partial remission in three. stable disease in two. and progression in six. resulting in an overall response rate of 46%. Negative p24 expression prior to treatment was a positive predictor. Although extracutaneous involvement had a negative influence on tumor remission. even patients with a mean initial T-helper cell count below 100 mm3 responded positively. In conclusion. combination therapy of rIFN-alpha-2a with AZT may effectively control HIV-related Kaposi's sarcoma in more than 40% of patients. In contrast to monotherapy with IFN-alpha. patients with severely reduced immune systems will also benefit from combined treatment.
Non-AIDS-associated Kaposi's sarcoma (classical and endemic African types): treatment with low doses of recombinant interferon-alpha, In the treatment of the classical and endemic African forms of Kaposi's sarcoma (KS). radiation therapy and chemotherapy have been widely used with varying degrees of success and morbidity. We here report our preliminary experiences with low doses of recombinant interferon alfa-2b (rIFN alpha-2b) in the treatment of these types of KS. non-linked to the acquired immunodeficiency syndrome (AIDS). Ten consecutive patients (eight patients with classical and two with endemic KS) with a median age of 62 years were treated long-term with 5 X 10(6) units of rIFN alpha-2b (Introna) given subcutaneously three times weekly for at least 6 months. Of the 10 patients. six presented with cutaneous disease only. and four had additional visceral involvement. After 6 months of treatment. seven of the 10 patients had a major response of the cutaneous lesions. and three patients showed stable skin diseases. Of the four patients with additional visceral disease. one patient showed a complete regression of an intramyocardial tumor involving the right atrium and ventricle. whereas in the three other patients stabilization of the visceral lesions with marked symptomatic improvement occurred. On the whole. the long-term results over a median duration of 12 months (range. 7 to 30) are also satisfactory: IFN-alpha continued to control KS in all patients. The treatment was generally well tolerated; no serious side effects were observed. Our preliminary data suggest that low-dose rIFN alpha-2b regimens are effective in classical and endemic African KS. However. further studies are needed to establish the exact role for IFN-alpha as alternative to radiation and chemotherapy.
Clinical evaluation of interferons in malignant melanoma, The evaluation of interferons in the treatment of malignant melanoma has been mainly in the treatment of advanced disease using interferons as the sole agent or in combination with other agents. Studies of the value of interferons as adjuvant therapy in high-risk primary melanoma patients are necessary. but no results have been published to date. Human interferon alpha produces low response rates as a sole agent. but in combination with cimetidine. a 30% response rate has been achieved. Recombinant alpha interferons give responses of 15%-20% in advanced melanomas. and combination with cimetidine does not enhance the response rate. Recombinant alpha interferons have been used in combination with other interferons. cimetidine. monoclonal antibodies. and cytotoxics. with either no or small improvement in response rates. DTIC with recombinant interferon alpha-2a has been shown to produce objective response rates of 26%. with low toxicity and maintenance of quality of life. A randomized trial with DTIC as the sole agent. compared with combination treatment. is being conducted to determine the significance of this finding.
Long-term adjuvant therapy of high-risk malignant melanoma with interferon alpha 2b, Fifty-three high-risk melanoma patients in stage I and 15 patients in stage II were treated after standard surgical intervention with adjuvant therapy with recombinant interferon alpha-2b (rIFN alpha 2b) therapy for a total period of 20 months. Concomitant patients (stage I. n = 82; stage II. n = 33) with identical stages and prognostic factors without adjuvant therapy were used to evaluate the efficacy of rIFN alpha 2b therapy. No difference in 5-year relapse incidence and overall survival rates could be detected. However. it appears that patients of both stage I and stage II benefit from long-term adjuvant rIFN alpha 2b therapy. because during the treatment period (20 months). the incidence of relapses was lower in comparison to controls. After stopping treatment the incidence of relapse is equal in treated and control groups. According to the results of our study. we suggest using continuous low-dose rIFN alpha 2b therapy for adjuvant treatment of malignant melanoma.
Interferon alpha and etretinate combination treatment of cutaneous T-cell lymphoma, Eleven patients suffering from cutaneous T-cell lymphoma (mycosis fungoides) were treated with recombinant interferon alpha-2A in combination (seven patients) or alone. Two patients. one in combined treatment. went into clinical complete remission. and five experienced partial remission. Two patients progressed during therapy. and two were nonevaluable because they stopped treatment early due to side effects. Dosages of interferon were from 3 to 36 million units daily for 3 months. and thereafter 3 times weekly. Etretinate (0.7 mg/kg) was given orally. The study showed that recombinant interferon alpha-2A in combination with etretinate or alone can induce remission of cutaneous T-cell lymphoma.
Cytostatic and cytotoxic effects of recombinant tumor necrosis factor-alpha on sensitive human melanoma cells in vitro may result in selection of cells with enhanced markers of malignancy, Monolayer cultures of the human melanoma cell lines StML-12. StML-11. StML-14 (third. respectively. twenty-fifth subculture). and SKMel-28 derived from specimens representing different stages of tumor progression were treated with 10-10.000 U/ml rTNF-alpha applied for 72 h. The effects of rTNF-alpha on cell proliferation. DNA synthesis. cell viability. cloning efficiency. cell division. cell morphology. and the immunophenotype were studied in triplicate experiments. The cell line StML-14(3) revealed a significantly dose-dependent reduction of growth due to both cytostatic and cytotoxic activities of rTNF-alpha as well as a decrease of CE. Increased numbers of cells in prophase were observed 24 h after addition of r-TNF-alpha. In addition. dislocation of chromosomes in the metaphase. formation of micronuclei. and dose-dependent increases of cells exhibiting micronuclei and the DNA amount per cell were detected at the end of treatment. On the other hand. only a slight sensitivity to the anti-proliferative effect of rTNF-alpha was observed with StML-14(25) and SKMel-28. whereas StML-12 and StML-11 were significantly resistant. The last four cell lines were serially subcultivated and presented common phenotypic patterns with more malignant characteristics than the cell line StML-14(3) before treatment. Overall. rTNF-alpha enhanced the malignant immunophenotype of the cell lines tested. It increased the expression of the "late" melanoma progression markers A.10.33 and A.1.43. and Ki67. and it decreased the expression of the "early" progression marker K.1.2. The expression of HLA-I. HLA-DR. and ICAM-1 was also enhanced after rTNF-alpha treatment. whereas in contrast to other cytokines. rTNF-alpha did not induce the de novo expression of HLA-DR in HLA-DR-negative melanoma cell lines. These findings indicate that rTNF-alpha induces cytostasis and decreases cell viability of certain rTNF-alpha-sensitive melanoma cells. These effects may result in selection of rTNF-alpha-non-sensitive human melanoma cell populations with higher proliferation rates and a more aggressive immunophenotype in vitro.
Biologic effects of interferons, If one were to review articles on IFN published between 1957 and 1967 it would become apparent that virtually none of the tenets held then are still valid today. Whereas IFN was long considered to be a specific antiviral substance without any effect on normal cellular metabolism. we accept today that it affects normal cell division and many specialized cellular functions. In this respect it is not unique; IFN is a prototype of a family of similar substances now called cytokines that all appear to function as regulatory molecules. It was held that the production of IFN constituted a specific response to a viral infection. Today we believe that IFN is an integral part of a cytokine network and that they and other cytokines may be produced constitutively at low levels. These substances exert multiple effects on virtually all cells. They play an important role in host defense against viral and parasitic infections. and in the resistance to experimental tumors. IFN can be shown to exert effects on the immune system and on lymphocyte circulation. Lastly. because of the multiplicity of their biologic effects. they may even contribute to the pathogenesis of certain diseases. Thus. when large amounts of IFN are administered or induced in newborn mice they can cause liver. kidney. and pulmonary disease. The field of IFN and cytokine research continues to expand and there is an increasing number of therapeutic applications. Twenty years from now. scientists and clinicians may be surprised that we understood so little of how IFN act and how inadequately we used them to treat disease.
Interferons and collagen production, The immunoregulatory. antiviral. and antiproliferative agents known as the interferons have profound effects on collagen synthesis. Interferons alpha. beta. and gamma suppress collagen synthesis by dermal fibroblasts. In addition. interferon gamma (IFN-gamma) inhibits the constitutively increased collagen synthesis characteristic of fibroblasts derived from lesions of patients with scleroderma. IFN-gamma also inhibits collagen synthesis by myofibroblasts and synovial fibroblast-like cells. Inhibition of collagen synthesis by IFN-gamma is associated with a coordinate inhibition of transcription for types I and III collagen. In addition. IFN-gamma suppresses levels of procollagen mRNA and type II collagen synthesis in human articular chondrocytes. In vivo studies in mice have demonstrated that IFN-gamma inhibits the collagen synthesis associated with the fibrotic response to an implanted foreign body. bleomycin-induced pulmonary fibrosis. and the healing response to cutaneous thermal burns. In the latter case. while collagen content of the wound scar was decreased. hyaluronic acid was increased in mice receiving IFN-gamma compared to controls. This is in accord with in vitro studies showing that. while interferons alpha and beta decrease production of glycosaminoglycans. IFN-gamma increases production of glycosaminoglycans. Of interest. acute inflammation at sites of thermal injury. or when elicited by proinflammatory agents in separate experiments. also was suppressed in mice treated with IFN-gamma. The means by which IFN-gamma inhibits collagen synthesis involves transcriptional regulation. There is a single report that interferon alpha can decrease the size of a keloid of recent onset in a human patient. Because the interferons can inhibit collagen synthesis in vivo. further studies may be warranted to evaluate the usefulness of these agents in the treatment of disease states characterized by abnormal fibrotic responses as well as their potential for altering the healing response associated with particular therapeutic interventions.
Mucosal immunity induced by enhance-potency inactivated and oral polio vaccines, Oral polio vaccine (OPV) is recommended for routine immunization in the United States in part because of its ability to induce intestinal and pharyngeal immunity to reinfection. Mucosal immunity produced by OPV and enhanced-potency inactivated polio vaccine (E-IPV) was compared by challenging vaccines with type 1 OPV. Fewer OPV (25%) than E-IPV (63%) vaccinees excreted OPV virus in stool after challenge. The mean stool virus titer was higher and the duration of shedding longer among E-IPV excreters. Only one E-IPV and three OPV vaccinees shed virus in the pharynx after challenge. Prechallenge serum neutralizing antibody levels were not statistically different among E-IPV vaccinees who did and did not shed virus; these levels were much higher than those of OPV vaccinees. Poliovirus-specific IgA levels in stool did not correlate with viral excretion. E-IPV was less effective than OPV in preventing and limiting intestinal infection. even though it induced higher postvaccination serum antibody levels.
Measles among the Amish: a comparative study of measles severity in primary and secondary cases in households, An outbreak of measles among a predominantly unvaccinated and susceptible Amish population in Lebanon County. Pennsylvania. offered the opportunity to test the hypothesis that secondary cases in households are more severe than primary cases because the former have more intense exposure and receive a greater virus inoculum. Of 130 measles cases reported between April and June 1988. 119 (92%) constituted a study of disease severity. Severity was assessed by determining frequency and duration of symptoms. length of any hospitalization. and number of days in bed. In a univariate analysis. fewer secondary cases had conjunctivitis (relative risk [RR]. 0.67; 95% confidence interval [CI]. 0.48-0.96) and headache (RR. 0.37; CI. 0.15-0.86). but more had earache (RR. 9.69; CI. 1.8-202.9) compared with primary cases. Secondary cases had a shorter mean duration of coryza (4.0 vs. 5.0 days. Student's t test. P = .08). However. a logistic regression model that matched by family and controlled for age and sex indicated that there were no significant differences in measles severity among primary and secondary cases in households.
Immunization of mice with antibiotic-treated Escherichia coli results in enhanced protection against challenge with homologous and heterologous bacteria, The murine immune response to Escherichia coli exposed to subminimal inhibitory concentrations of four antibiotics was investigated. Groups of mice were injected for 8 weeks with formalin-killed bacteria and subsequently challenged with 10 x LD50 of viable E. coli. Mice receiving saline only (controls) died within 24 h. The mortality of mice immunized with ciprofloxacin-treated E. coli was significantly lower than that of mice immunized with E. coli untreated or treated with other antibiotics. Sera from mice immunized with ciprofloxacin-treated bacteria showed better bacteriostatic capacity and enhanced production of antibodies that bound to homologous and heterologous lipopolysaccharide isolated from several smooth and rough gram-negative strains. The better protection observed in mice immunized with ciprofloxacin-treated E. coli was probably due to an enhanced production of antibodies to epitopes on lipopolysaccharide that became better exposed and so more accessible after treatment with ciprofloxacin.
Human serologic response to envelope-associated proteins and adenylate cyclase toxin of Bordetella pertussis, The human serologic response to several envelope-associated proteins and adenylate cyclase toxin of Bordetella pertussis was examined using immunoblot techniques. Antigens recognized by sera from individuals with culture-confirmed pertussis and by sera from infants immunized with three doses of conventional whole-cell pertussis vaccine included a 63.000-Da protein that was shown to be antigenically related to a mycobacterial heat-shock protein. A 29.000-Da protein reacted with sera from convalescent individuals. whereas a 91.000-Da protein reacted with sera from vaccinated individuals. Antibodies to adenylate cyclase toxin were common in sera from individuals diagnosed with pertussis. B. pertussis lipooligosaccharide was also recognized by antibodies in some of these sera. These data suggest that some of these antigens may play a role in immunity to pertussis.
Use of brain biopsy for diagnostic evaluation of patients with suspected herpes simplex encephalitis: a statistical model and its clinical implications. NIAID Collaborative Antiviral Study Group, Using the decision analysis technique and multivariate regression methods. a statistical model was established to define the utility of brain biopsy for diagnostic evaluation of patients with suspected herpes simplex encephalitis (HSE). Two strategies were compared: strategy I. brain biopsy with acyclovir (ACV) treatment for 10 days in biopsy-positive patients. and strategy II. ACV therapy without brain biopsy. Strategy I resulted in a greater 6-month survival rate when the likelihood of patients having HSE was less than 70%. Based on the current estimated prevalence of HSE (for patients with suspected HSE) of 35%. strategy I showed a slight advantage of a 3.2% increase in 6-month survival rate. An individual patient's chance of a positive brain biopsy can be predicted using a mathematical equation based on several important clinical assessments. This equation in conjunction with the decision analysis is a useful guide for the clinical management of patients with regard to brain biopsy.
Instillation of vancomycin into a cerebrospinal fluid reservoir to clear infection: pharmacokinetic considerations, Vancomycin instilled in an Ommaya reservoir was used to treat a reservoir-associated infection. Vancomycin concentrations in cerebrospinal fluid (CSF) were measured. and derivation of pharmacokinetic parameters allowed tailoring of dosing. First-order kinetics were observed. The calculated half-life of 3.52 h was less than reported by others. and the apparent volume of distribution (60 ml) was less than anticipated. The elimination constant was 0.197 h-1. Empiric dosing based on schedules suggested in the literature would have led to high peak and low mean concentrations of intrareservoir vancomycin. Patients with reservoir-associated infections have a variety of pathophysiologic conditions that can result in alteration of normal CSF dynamics. Pharmacokinetic analysis is useful to individualize dosing and to optimize therapy with intrareservoir vancomycin.
High incidence of antibodies to HTLV-I tax in blood relatives of adult T cell leukemia patients, Adult T cell leukemia (ATL) is caused by the human T cell leukemia virus type I (HTLV-I). Although the mechanisms of the leukemogenic process are unknown. the tax gene may have a role in this process. Because clustering occurs with HTLV-I and ATL. members of ATL families were examined for antibodies to the tax protein and compared with matched HTLV-I-positive blood donors. To investigate the antibody response to this protein. a plasmid. pBHX-4. was constructed to express a recombinant tax protein (r-tax). For ATL patients and their HTLV-I antibody-positive blood relatives. the rate of seroreactivity with the r-tax protein was 67.3% (35/52). compared with 51.6% (97/188) for HTLV-I antibody-positive control blood donors (P less than .05). The difference between direct offspring of ATL patients and matched HTLV-I blood donors was even greater (84.2% [16/91] vs. 44.2% [42/95]; P less than .005). Thus. tax antibody positivity in direct offspring of ATL patients may reflect differences in time or route of HTLV-I infection. Alternatively. it might reflect genetic differences in host susceptibility or virus strain.
Antibody to human retroviruses among drug users in three east coast American cities, 1972-1976, Between 1972 and 1976. 585 persons attending methadone maintenance clinics at East Coast veterans hospitals were enrolled in a survey of hepatitis antibody prevalence. Sera were tested for human immunodeficiency virus (HIV) and human T lymphotropic virus (HTLV) using both HTLV-I and HTLV-II immunoblots. Clinical and death records were also reviewed. None of the sera had HIV antibodies (upper 95% confidence limit. 0.5%); however. 103 (18%) had reactivity to HTLV. The profile of reactivity suggested that these subjects had been exposed to HTLV-II rather than to HTLV-I. Prevalence was as high in the early 1970s as today and correlated with duration of drug use rather than age. Neither cancers. specific neurologic diseases. nor excess deaths from any cause (overall 14%) could be ascribed to seropositivity. Therefore. HTLV (probably HTLV-II) has been a common infection of drug users for many years but adverse outcomes following infection were not demonstrated.
Use of a new CD4-positive HeLa cell clone for direct quantitation of infectious human immunodeficiency virus from blood cells of AIDS patients, A new CD4-positive HeLa cell line (clone 1022) with increased sensitivity for human immunodeficiency virus (HIV) isolates derived from AIDS patients could titer infectivity of HIV from most isolates at a level equal to that observed using normal human phytohemagglutinin (PHA)-stimulated lymphocyte cultures. By use of this clone with a focal immunoassay (FIA). peripheral blood mononuclear cells (PBMC) producing HIV were detected in 15% of seropositive asymptomatic patients and 23% of AIDS patients at a frequency of 1 in 2 x 10(4) to 3 x 10(6) PBMC. HIV detection by primary FIA correlated with low CD4-positive cells counts. HIV activation in cocultures with PHA blasts resulted in increasing numbers of cells releasing HIV starting 3-4 days after cocultivation. The low incidence of HIV detection by direct FIA compared with the high incidence of HIV isolation after cocultivation with PHA blasts provided quantitative infectivity data suggesting that HIV was in a state of latency or low expression in most PBMC of AIDS patients.
The role of secretory immunity in hepatitis A virus infection, Because the role of intestinal immunity remains uncertain in hepatitis A. samples of feces and saliva from infected primates and humans were tested for virus neutralizing activity. Only two of eight owl monkeys infected by the intragastric route developed neutralizing antibody detectable in extracts of feces collected up to 88 days after viral challenge. although serum neutralizing antibody was present in all monkeys by day 33. Similarly. neutralizing antibody was detected in fecal extracts from none of three experimentally infected human volunteers and only 1 of 15 naturally infected humans. The single positive human specimen contained occult blood. Only 2 of 19 saliva samples from naturally infected humans had significant viral neutralizing activity. In contrast. neutralizing antibody to type 2 poliovirus was present in most human fecal or saliva specimens tested. These data suggest that intestinal immunity does not play a significant role in protection against hepatitis A.
Atlantoaxial stabilization in rheumatoid arthritis, Atlantoaxial subluxation in patients with rheumatoid arthritis is common. Operative stabilization is clearly indicated when signs and symptoms of spinal cord compression occur. However. many recommend early operative fusion before evidence of appreciable neural compression occurs because 1) the myelopathy in these patients may be irreversible; 2) the overall prognosis is poor once symptoms of cord compression are present; and 3) the risk of sudden death associated with atlantoaxial subluxation is increased even in asymptomatic patients. The authors believe that rheumatoid arthritis patients in relatively good health without advanced multisystem disease and less than 65 years of age should be considered for operative stabilization if mobile atlantoaxial subluxation is greater than 6 mm. Seventeen patients with severe rheumatoid arthritis and atlantoaxial subluxation treated with a posterior arthrodesis are presented. A new method of fusion. devised by the senior author (V.K.H.S.). was utilized in all cases. Indications for operative therapy in these patients included evidence of spinal cord compression in 11 patients (65%) and mobile atlantoaxial subluxation greater than 6 mm but no signs or symptoms of cord compression in six patients (35%). Thirteen patients developed a stable osseous fusion. two patients a well-aligned fibrous union. one patient a malaligned fibrous union. and one patient died prior to evaluation of fusion stability. The details of the operative technique and management strategies are presented. Several technical advantages of this method of fusion make this approach particularly useful in patients with rheumatoid arthritis. Because of multisystem involvement of this disease. a high rate of osseous fusion is often difficult to achieve.
Enhanced in vitro uptake and retention of 3H-tetraphenylphosphonium by nervous system tumor cells, Photodynamic therapy is a promising treatment for human brain tumors because of the selective retention of certain compounds by tumor cells. Certain lipophilic cationic compounds. such as tetraphenylphosphonium (TPP). are selectively taken up by a variety of carcinomas. Although preferential retention of TPP has been demonstrated for the breast carcinoma cell line MCF-7. this compound had not been tested previously on cells derived from nervous system tumors. In the present study. tritiated-TPP (3H-TPP) uptake and retention for eight different cell cultures of three histologically different types of nervous system tumors was measured and the data were compared to a positive control (MCF-7) and negative controls (normal African Green monkey kidney epithelium (CV-1) and the normal human fibroblast (WI-38) cell lines). Uptake and retention characteristics could be grouped by specific pathological tumor types. but individual tumor variability was notable. Malignant astrocytoma (grade III/III glioblastoma) and malignant neurofibrosarcoma cells showed preferential uptake and retention of 3H-TPP relative to meningioma cells and normal controls. A clonogenic assay utilizing the cytotoxic lipophilic cationic compound dequalinium showed strong retainers of 3H-TPP to be more susceptible to the effects of dequalinium than weak retainers. These data demonstrate that certain human and experimental animal nervous system tumor cell lines retain lipophilic compounds possessing a delocalized positive charge. Lipophilic cationic compounds may be useful in the intraoperative delineation of tumor margins and in the photodynamic therapy of certain nervous system tumors.
Tension pneumocephalus: treatment with controlled decompression via a closed water-seal drainage system. Case report, The successful treatment of a patient with tension pneumocephalus by controlled decompression via external drainage is described. The advantage of the technique includes the immediate release of high pressure and the capability of maintaining constant low pressure to enable and facilitate sealing of dural tears. The method has been used in three other patients. leading to resolution of the tension pneumocephalus without recurrence or other complications.
Movement of hemostatic clips from the ventricles through the aqueduct to the lumbar spinal canal. Case report, The authors report a patient in whom rebleeding after operation for a left temporal arteriovenous malformation resulted in the dislocation of multiple hemostatic clips. Several clips. including a Yasargil aneurysm clip. were detected incidentally in the lumbar spinal canal. No clinical signs or symptoms were noted. Retrospectively. passage of the aneurysm clip through the aqueduct could be detected on computerized tomography scans performed to evaluate a series of epileptic seizures.
The fastigial pressor response. Case report, A distinct vasomotor and cardioregulatory response first identified experimentally was elicited intraoperatively in a 6-year-old girl by local mechanical stimulation in the vicinity of the fastigial nucleus of the cerebellum. These findings are discussed in the light of current experimental knowledge of the anatomy and physiology of the fastigial pressor response.
Cerebrospinal fluid rhinorrhea following acoustic neurinoma surgery. Technical note, The authors describe a method of preventing cerebrospinal fluid (CSF) rhinorrhea following surgery for acoustic neurinoma. Mastoid air cells exposed during craniectomy are skeletonized and packed with bone dust. then covered with Surgicel soaked with Tisseel fibrin glue. The use of this technique has reduced the number of acoustic neurinoma cases requiring secondary mastoidectomy for CSF leakage from 16% to 5%.
Correlates of survival and the Daumas-Duport grading system for astrocytomas, In order to examine the correlation between prognosis and the histological features of nuclear atypia. mitosis. endothelial proliferation. and necrosis in supratentorial adult astrocytomas. the authors reviewed 251 such cases treated at the Massachusetts General Hospital between 1972 and 1980. One point was given for the presence of each feature. The total number of features was translated into a grade as follows: none of the four features = Grade 1 (one patient). one feature = Grade 2 (36 patients). two features = Grade 3 (33 patients). and three or four features = Grade 4 (181 patients). The period of survival was significantly associated with grade. the presence or absence of each of the four histological features. patient's age. type of operation. radiation therapy. and extent of tumor (log rank. p less than 0.05). The variables associated with grade were age (p less than 0.001) and radiation therapy (p less than 0.02). After adjustment for these variables using a Cox proportional-hazards model. the difference in overall survival time between patients in Grades 2 and 3 was not statistically significant. When comparable groups of patients were examined in terms of age or receipt of radiation therapy. the median survival times differed markedly. Patients 50 years of age or less had a median survival time of 68 months (Grade 2 tumors). 29 months (Grade 3 tumors). and 13 months (Grade 4 tumors). Patients over 50 years of age had a median survival time of 6 months (Grade 2 and 4 tumors) and 9 months (Grade 3 tumors). Those patients who had received radiation therapy had a median survival time of 68 months (Grade 2 tumors). 21 months (Grade 3 tumors). and 11 months (Grade 4 tumors). Those patients who did not receive radiation therapy had a median survival time of 1 month (Grade 2 tumors) and 2 months (Grade 3 and 4 tumors); over half of these patients died within 2 months of surgery. This grading system. originally proposed by Daumas-Duport. et al.. is simple. objective. and reproducible. and correlates well with survival times. The authors recommend that astrocytomas be graded on a scale of 1 to 4. with Grade 1 reserved for the rare adult supratentorial astrocytoma with none of the four histological features.
The effect of glucose administration on carbohydrate metabolism after head injury, The role of intravenous infusion of glucose in limiting ketogenesis and the effect of glucose on cerebral metabolism following severe head injury were studied in 21 comatose patients. The patients were randomly assigned to alimentation with or without glucose. Systemic protein wasting. arterial concentrations of energy substrates. and cerebral metabolism of these energy substrates were monitored for 5 days postinjury. Both groups were in negative nitrogen balance. and had wasting of systemic proteins despite substantial protein intake. Blood and cerebrospinal fluid (CSF) glucose concentrations were highest on Day 1. but remained higher than normal fasting levels on all days of study. even in the patients who received no exogenous glucose. Although there were no differences in blood or CSF glucose concentrations in the two groups of patients. the glucose group had higher plasma insulin levels. with a mean +/- standard deviation of 14.8 +/- 7.3 microU/ml compared to 10.3 +/- 4.2 microU/ml in the saline group. The blood concentrations of beta-hydroxybutyrate. acetoacetate. pyruvate. glycerol. and the free fatty acids were higher in the saline group than in the glucose group. Cerebral oxygen consumption was similar in the two groups. while the cerebral metabolism of glucose and of the ketone bodies was dependent on whether glucose was administered. In the glucose group. glucose was the only energy substrate utilized by the brain. In the saline group. the ketone bodies beta-hydroxybutyrate and acetoacetate replaced glucose to the extent of 16% of the brain's total energy production. Cerebral lactate production and CSF lactate concentration were lower in the saline group. These studies suggest that administration of glucose during the early recovery period of severe head injury is a major cause of suppressed ketogenesis. and may increase production of lactic acid by the traumatized brain by limiting the availability of nonglycolytic energy substrates.
Long-term outcome following anterior cerebral artery ligation for ruptured anterior communicating artery aneurysms, The long-term prognosis (15 years) was determined for 17 patients who had undergone anterior cerebral artery (ACA) ligation as the sole treatment for an anterior communicating artery aneurysm. The number of early and late rebleeds was lower than expected from previously ruptured aneurysms. Late ischemia was not a major complication while late postoperative epilepsy occurred in 19% of survivors. In a review of previously published series. ACA ligation appears to have significantly reduced the rates of both early and late rebleeding. This study helps to define the late results of "conservative" operations for ruptured aneurysms.
Intratumoral oxygen pressure in malignant brain tumor, Oxygen pressure (pO2) in brain tumors. pO2 in brain cortex surrounding the tumors. and PaO2 were measured simultaneously during total resection in 16 patients with previously untreated brain tumors in order to detect hypoxic regions within the tumors. When the inhaled O2:N2O ratio was 1:3 under enflurane anesthesia. mean PaO2 was 109.2 +/- 5.8 mm Hg. a rather high value when compared with that obtained when air is inhaled under atmospheric pressure. The simultaneously measured intratumoral pO2 and pO2 in brain cortex surrounding the tumor were 15.3 +/- 2.3 and 59.8 +/- 6.5 mm Hg. respectively. Each intratumoral pO2 value was significantly lower than that of pO2 in brain cortex surrounding the tumor (mean less than 30 mm Hg. Wilcoxon signed rank test. p less than 0.005) and influenced the oxygen effects on radiation. These results appear to confirm that there are hypoxic regions within human brain tumors. A comparison between intratumoral pO2 and either the angiographic or contrast-enhanced computerized tomography scans of the tumor vasculature disclosed no correlation.
Iopamidol myelography: morbidity in patients with previous intolerance to iodine derivatives, The records of 1005 patients who underwent iopamidol myelography between January and September. 1988. were reviewed. In this group. 50 patients had histories suggestive of untoward sequelae associated with iodine intake. contact. or administration. The charts of these patients were carefully reviewed. and none of them had any reactions or sequelae suggestive of toxicity or an allergic response after iopamidol myelography. It is concluded that. even in patients with a previous history suggestive of intolerance to iodine administration. iopamidol myelography is generally a safe procedure.
Management of meralgia paresthetica, Meralgia paresthetica is a syndrome of pain or dysesthesia. or both. in the anterolateral thigh caused by entrapment or neurinoma formation of the lateral femoral cutaneous nerve. Conservative treatment was successful in relieving symptoms in 91% of 277 patients with this syndrome; however. 24 patients required surgical treatment for intractable symptoms. Although neurolysis with transposition is the most common procedure. sectioning of the lateral femoral cutaneous nerve was performed in 24 cases and was successful in 23. One patient had early symptomatic relief. but subsequently developed different neurological signs and symptoms because of an undetected pelvic neoplasm. Anatomical variations of the nerve and neurinomas. which occur frequently. are easily handled with sectioning but may lead to recurrence with neurolysis and transposition.
Treatment of severe intraventricular hemorrhage by intraventricular infusion of urokinase, Six patients with severe intraventricular hemorrhage were treated with direct intraventricular infusion of urokinase. In each case. hemorrhage extended into all ventricular chambers. and a cast formation and expansion of the third and fourth ventricles were found. Immediately after the therapy was started (within 7 days from onset of symptoms). reduction of intraventricular hematoma volume was observed on computerized tomography. On average. both the third and fourth ventricles became clear on the third day after hemorrhage; there was one exception. a case of ruptured aneurysm. Five of the six patients showed excellent or good outcome. although two developed delayed hydrocephalus. No infection or rebleeding was observed. The outcome in a retrospectively studied group of five patients not treated with urokinase is also reported. The authors conclude that this relatively easy method of treatment will greatly improve the prognosis of severe intraventricular hemorrhage.
Photodynamic therapy of spontaneous cancers in felines, canines, and snakes with chloro-aluminum sulfonated phthalocyanine, This is the first report on the photodynamic treatment with a second-generation sensitizer. chloro-aluminum sulfonated phthalocyanine (CASPc) of spontaneously arising tumors and on the photodynamic therapy (PDT) of snake neoplasms. Each of 10 cats. 2 dogs. and 3 snakes presenting with a variety of tumor types (squamous cell carcinoma. mast cell malignant tumor. and mixed carcinoma/sarcoma) was given an intravenous injection of 1 mg of CASPc per kilogram body weight 48 hours prior to irradiation with 675-nm light. Some larger tumors (greater than 1.5 cm deep) were surgically debulked prior to PDT. No significant systemic toxicity or skin photosensitization was observed in any animal. The tumor responses were comparable to those seen with conventional cryotherapy. hyperthermia. or surgery. PDT with CASPc of these cases led to 67% (12 of 18) complete response. 22% (4 of 18) partial response. and 11% (2 of 18) no response (less than 50% reduction in tumor size). Four cases could not be evaluated. Since the overall tumor response to CASPc is very good. and the problem of skin photosensitivity is nonexistent. it is expected that using CASPc-PDT to eradicate human tumors would also yield comparable results. Further studies with long-term follow-up are necessary to optimize the use of CASPc-PDT in veterinary and human medicine.
Increased expression of the laminin receptor in human colon cancer, It has been proposed that among the various cell-surface proteins capable of interacting with laminin. the 67-kd high-affinity laminin receptor plays a crucial role during tumor invasion and metastasis. In this study. the expression of laminin-receptor-precursor messenger RNA (mRNA) and 67-kd protein was analyzed in human colon adenocarcinoma. In 22 of 23 patients with colon cancer. we found a 2- to 23-fold increase in levels of laminin-receptor-precursor mRNA in the cancer tissues compared with those in matched normal adjacent colonic mucosa. In 10 of 11 cases studied. the level of 67-kd laminin receptor. detected by affinity-purified anti-laminin-receptor synthetic peptide antibodies on immunoblots of matched tumor and normal tissue extracts. was higher in the colon carcinoma tissue. Immunodetection of laminin receptor in tissue sections using anti-laminin-receptor-peptide antibodies confirmed that the increased expression of laminin receptor was specifically associated with the cancer cells. In a series of 72 paraffin sections of colon lesions. we observed a correlation between the expression of the laminin receptor and the Dukes' classification. Our observations indicate that increased expression of laminin-receptor-precursor mRNA is associated with enhanced levels of the 67-kd laminin receptor as well as with the invasive phenotype of colon carcinoma. Detection of this metastasis-associated gene product may be a valuable adjunct in the evaluation of human colon cancer.
Effect of prior cancer chemotherapy on human tumor-specific cytotoxicity in vitro in response to immunopotentiating biologic response modifiers, Tumor-specific cytotoxicity was measured in fresh human biopsy specimens by a modification of the differential staining cytotoxicity assay. ImuVert. a cytokine inducer derived from Serratia marcescens. which produces broad-spectrum activation of both macrophages and lymphocytes. was dramatically more effective when it was tested in tumors obtained from patients with previously treated. chemotherapy-responsive adenocarcinomas (breast and ovary) than when it was tested in tumors obtained from either previously untreated patients or previously treated patients with chemotherapy-refractory adenocarcinomas (colon. lung. pancreas. stomach. kidney. gallbladder. uterus. and prostate). Similar findings. relating to prior chemotherapy treatment status. were obtained for tumor necrosis factor and interferon gamma. but not for interleukin-2 or interferon alpha. On the basis of these findings and on other evidence in the literature. we speculate that response to chemotherapy produces massive release and processing of tumor antigens. We further speculate that this response leads to a state in which the human immune system is primed (via in situ vaccination) to respond to exogenous macrophage-activation signals with potent. specific antitumor effects.
Comparisons of diet and biochemical characteristics of stool and urine between Chinese populations with low and high colorectal cancer rates, In an investigation of the roles of diet and stool biochemistry in human colorectal carcinogenesis. 24-hour food. urine. and stool samples were collected from randomly selected participants from two populations with a fourfold difference in colorectal cancer risk: Chinese in Sha Giao. People's Republic of China (low risk). and Chinese-Americans of similar ages in San Francisco County. Calif. in the United States (high risk). The findings supported the hypotheses that colorectal cancer risk is increased by the consumption of high-fat. high-protein. and low-carbohydrate diets and is associated with high levels of cholesterol in stool as well as increased daily outputs of 3-methyl-histidine and malonaldehyde in urine. However. risk does not increase with low stool bulk and low total stool fibers.
Phase I trial of piritrexim capsules using prolonged, low-dose oral administration for the treatment of advanced malignancies, A phase I trial of piritrexim was conducted by use of a prolonged. low-dose oral schedule. A number of different regimens were tested. including daily dosing for 21 days followed by 7 days of no drug therapy; continuous dosing; and daily dosing for 5 of 7 days for 3 consecutive weeks followed by a week of rest. Dose escalation was accomplished by increasing the dosing frequency from once a day to twice a day and then to three times a day and by increasing the number of days of administration. Fifty-one patients with advanced cancer were entered in the study. One hundred twenty-four (96%) of 129 courses were considered assessable. Myelosuppression proved to be the dose-limiting toxic effect. Other toxic effects included stomatitis. nausea and vomiting. anorexia. diarrhea. skin rash. fatigue. and elevation of liver transaminase levels. Antitumor activity was observed in patients with melanoma and bladder cancer. and disease stabilization occurred in those with sarcoma and pheochromocytoma. The recommended dosing schedule for phase II clinical trials is 25 mg three times a day for 5 days for 3 consecutive weeks followed by 1 week of no drug therapy.
Continuous arteriovenous rewarming: experimental results and thermodynamic model simulation of treatment for hypothermia, We evaluated a technique for treating hypothermia that uses extracorporeal circulation but does not require heparin or pump assistance. Hypothermia to 29.5 degrees C was induced in eight anesthetized dogs. and thermistors placed in the pulmonary artery. liver. bladder. esophagus. rectum. muscle. and skin. Four experimental animals were rewarmed by creating a fistula which connected arterial and venous femoral lines to an interposed counter-current heat exchanger. External rewarming was used in four controls. Bleeding time (BT). coagulation profile (PT. PTT. TT). and cardiac output (CO) were measured during rewarming. Core temperature (T) rose significantly faster with CAVR (0.00001). Average time to rewarming was 45 min. vs. 4 hrs in controls. Haptoglobin. platelet. fibrinogen. and fibrin split product levels were unaffected. Continuous arteriovenous rewarming (CAVR) improved T. CO. BT. and coagulation profile faster than any method yet reported not requiring heparin or cardiac bypass. The application of CAVR in post-traumatic hypothermia warrants further investigation.
Conservative management of duodenal trauma: a multicenter perspective, The experience of eight trauma centers with duodenal injuries was analyzed to identify trends in operative management. sources of duodenal-related morbidity. and causes of mortality. During the 5-year period ending December 1988. 164 duodenal injuries were identified. Patient ages ranged from 5 to 78 years. There were 38 Class I. 70 Class II. 48 Class III. four Class IV. and four Class V injuries. Injury mechanism was penetrating in 102 (62%) patients and blunt in 62. Primary repair of the duodenal injury was performed in 117 (71%) patients. including 27 patients also managed with pyloric exclusion and 12 with tube duodenostomy. Duodenal resection with primary anastomosis was used in six (4%) patients and pancreatoduodenectomy was necessary in five (3%). There were 30 (18%) deaths. The cause of death was uncontrolled hemorrhage from severe hepatic or vascular injuries in 22 (73%) patients. In only two (1%) patients could death be attributed to the duodenal injury; each as the result of duodenal repair dehiscence and subsequent sepsis. Duodenal-related morbidity was documented in 29 (18%) patients. including 22 patients with intra-abdominal abscess. six with duodenal fistula. and five with frank duodenal dehiscence. In summary. this analysis demonstrated: 1) the great majority of duodenal injuries can be managed by simple repair; 2) tube duodenostomy is not a mandatory component of operative treatment; 3) pyloric exclusion is a useful adjunct for more complex injuries; 4) pancreatoduodenectomy is rarely necessary for civilian duodenal trauma; 5) morbidity following duodenal trauma is more dependent on associated intra-abdominal injuries than the extent of duodenal trauma; and 6) mortality following duodenal injuries is primarily related to associated vascular and hepatic trauma.
Mortality in trauma patients: the interaction between host factors and severity, Data on host factors influencing mortality in trauma patients is sparse and contradictory. To develop a model for health policy decisions. we examined all trauma admissions to acute care hospitals in the state of California in the year 1986. We looked at the influence of the following host factors: age. gender. and preinjury medical conditions. on mortality stratified by injury severity. The study group (N = 199.737) had an overall mortality rate of 1.9%. Mortality increased starting at age 40 years and was independently influenced by gender. the presence of pre-existing disease. and the body region injured. In patients with minor injury. mortality rates became higher in the elderly at age 65+. However. in patients with injuries of moderate severity. mortality increased in both middle age (40-64) and elderly groups (65+). Male gender was also a risk factor. present in both the elderly and middle age groups. While the presence of both pre-existing medical disease or injury to head or abdomen was related to increased mortality in middle-aged patients at all severity levels. neither accounted for the effect of gender. Conclusion. Age and gender influence mortality in trauma patients. These effects are not explained by documented pre-existing disease or region of injury. Age and gender serve only as observable markers for subgroups of patients with impaired response to injury. Middle-aged males comprise a previously unrecognized high-risk subgroup for this impaired response.
The management of large soft-tissue defects following close-range shotgun injury, Large soft-tissue defects following close-range shotgun blasts remain a major technical challenge to trauma surgeons. During the period 1980 through 1988. 43 patients who survived greater than 48 hours following this injury were managed in our center. The locations of their soft-tissue defects were: extremity. 22; abdomen/chest. 18; and head/neck. three. All patients underwent immediate surgical exploration and wide debridement of all devitalized tissue along with repair of associated injuries. Management included mandatory frequent dressing changes. debridement. irrigation in the operating room. and the perioperative administration of broad-spectrum antibiotics. Four patients whose abdominal wall defects could not be initially closed had temporary placement of rayon cloth to prevent evisceration. Overall. four patients underwent delayed primary closure. eight were covered with split-thickness skin grafts. nine had closure with myocutaneous flaps. and 19 closed by secondary intent. Two patients. who were transferred to us following initial management. developed wound sepsis due to inadequate debridement and both eventually required amputation as did one patient who developed early myonecrosis following lengthy arterial repair. Frequent operative dressing changes. adequate debridement. and irrigation minimize sepsis following close-range shotgun blasts and should be the treatment of choice for this devastating injury. Techniques of wound closure need to be individualized to the particular situation.
Nonoperative management of blunt liver injuries in adults: the need for continued surveillance, Computed tomography (CT) scanning after blunt abdominal trauma has allowed nonoperative management of selected patients with liver injuries. This report describes 52 adult patients with liver injuries who were treated without immediate surgery. Thirty-four of these hepatic injuries were relatively minor (Grade I-II). and 18 were considered major (Grade III-V). Free intraperitoneal blood in small to large amounts was evident on CT in 37 patients. There were no deaths in this series. no major complications. no known missed intra-abdominal injuries. and no delayed hemorrhage. While most liver injuries appear to heal rapidly by serial CT scans. a small percentage of these patients have residual liver defects persisting for several months and may be at risk for future complications.
Dynamic computerized tomography of the occiput-atlas-axis complex in trauma patients with odontoid lateral mass asymmetry, Over a 23-month period. 25 patients aged 11 to 74 years presented to our Level I trauma center with odontoid lateral mass asymmetry of 2 to 5 mm on properly centered AP open-mouth X-rays: 32% of patients were asymptomatic. 68% had cervical pain. and 32% had limited range of motion. Patients with cervical spine fractures or dislocations and those with fixed deformity were excluded. The clinical significance of asymmetry was determined utilizing dynamic axial CT scanning of the occiput (C0). atlas (C1) and axis (C2) with the head neutral and with 15 degrees to 30 degrees active rotation. Nineteen patients demonstrated greater than 5 degrees of relative motion of C1 on C2 bilaterally. Three patients had less than 5 degrees of relative motion bilaterally and three patients had less than 5 degrees relative motion with left rotation only. No patient had formal treatment and all had nearly normal cervical range of motion on clinical examination at the time of hospital discharge. The finding of an asymmetric odontoid-lateral mass interspace on properly centered open-mouth AP X-rays in the presence of otherwise normal cervical spine X-rays. in conscious patients without fixed deformity. appears to be incidental and requires no further evaluation or treatment.
Complications in evaluating abdominal trauma: diagnostic peritoneal lavage versus computerized axial tomography, We reviewed our experience with 2.809 DPL's and 1.331 CT's obtained in the resuscitative phase over a 3-year period in our trauma system to determine the significant complications associated with each modality. There were 25 DPL complications: eight false negatives. three false positives. and 14 technical errors. There were 46 CT complications including 25 false negative scans. three false positive scans. and 18 delays to the operating room from obtaining abdominal CT evaluation. with two of these delays resulting in preventable deaths. Although both modalities had low complication rates (0.9% DPL vs. 3.4% CT). DPL was associated with less preventable mortality and morbidity than CT in the evaluation of abdominal trauma.
The morbidity and financial impact of colostomy closure in trauma patients, During a 10-year period. 87 patients who had undergone elective colostomy closure at Bellevue Hospital were retrospectively reviewed in order to evaluate the morbidity of colostomy closure after traumatic injury and its financial impact. Sixty-two per cent of the colostomies were in the left colon and 38% were right sided. The interval from the original injury to colostomy takedown varied from 20 to 465 days. with a mean of 144 days. The mean postoperative hospital stay for the entire group was 15.13 days at a cost of $13.995. There were no deaths and no anastomotic leaks in the entire series. but a morbidity rate of 25% ensued. Small bowel obstruction was the most frequent significant complication. occurring in ten patients (11.5%) and resulting in a prolongation of hospital stay by 7 days at an additional cost of $6.500 per patient. One additional patient developed a subphrenic abscess which required operative drainage. necessitating an additional 24 days in the hospital at an increased cost of $22.200. Other complications which did not prolong hospital stay included eight superficial wound infections. one transient respiratory failure. and two patients who returned at a later date with incisional hernias at the stoma site. The 25% morbidity encountered in this series suggests that colostomy closure is not a low-morbidity procedure and should be considered as an important factor favoring primary repair. Coupled with the significant financial impact of both colostomy formation and takedown. ample justification exists for greater efforts in avoiding colostomy formation whenever feasible.
Blunt carotid artery dissection: incidence, associated injuries, screening, and treatment, Blunt carotid dissection (BCD) is a rare injury occurring in less than one in 1.000 victims of blunt injuries. Using a 4-year experience in a trauma system with 14 cases of BCD. we performed a matched blunt trauma patient case-control analysis to determine if there were patterns of injuries that were associated with increased risk of BCD. Patients with combinations of head. facial. and cervical spine injuries with or without extremity fractures proved to be at significantly increased risk for BCD. Duplex scanning appears to be a useful screening tool for these patients. Anticoagulation was the preferred treatment once neurologic deficits were present.
Unintentional injury death rates in rural Appalachia, Rural unintentional injury (UI) death rates are higher than rates for urban regions. Our trauma center serves 49 rural Appalachian (AP) counties in a 120-county rural state. We investigated the impact of prehospital and hospital resources on UI death rates in our referral area. Age-adjusted and average age- and sex-specific UI death rates from 1979-1985 were compared among 49 rural AP counties. the 71 non-Appalachian (NAP) counties. and the United States. Counties were grouped for comparisons by level of prehospital care (Advanced Life Support [ALS] vs. Basic Life Support [BLS]) and by presence (H) or absence (NH) of a hospital. Death rates were calculated using data from the 1980 population census. the National Center for Health Statistics (NCHS). and state vital statistics. Within AP. all 49 counties have ambulance service. Only 9/49 (18%) have ALS service and 13/49 (26%) have no hospital. Age-specific AP rates were higher than NAP and US rates in the 25-44 and 45-64 year age groups. AP death rates were highest for BLS and NH counties across all age groups. Rural UI death rates in the region remain unacceptably high. The reason(s) that AP death rates exceed the NAP rates is uncertain. ALS service and an available hospital were associated with lower death rates. We propose both educational and epidemiologic programs to better identify and define additional problems.
Do trauma centers improve outcome over non-trauma centers: the evaluation of regional trauma care using discharge abstract data and patient management categories, Development of regional medical care systems to treat patients who sustain major accidental injuries (trauma victims) has been based on autopsy studies which demonstrate that hospitals that meet certain accepted criteria of readiness (trauma centers) can prevent needless deaths of trauma victims. However. since only autopsy data have been available from non-trauma centers. it has not previously been possible to compare morbidity data between trauma centers and non-trauma hospitals. This study examines discharge abstract data and a new patient classification system called patient management categories (PMC) which are generated from this abstract data to evaluate length of stay (LOS). complications. and death to compare morbidity and mortality data from trauma centers and non-trauma centers. Discharge abstracts for 1.332 patients with the PMC of femoral shaft fracture with operation were obtained from all hospitals in Western Pennsylvania and Maryland for 1 year. Data from trauma centers were identified and compared to non-trauma centers using the following criteria: time to OR (less than or equal to 2 days vs. greater than 2 days). age (0-12. 13-55. greater than 55 years). associated injuries. and development of complications and death. Patients treated in trauma centers had significantly fewer complications (21% vs. 33%; p less than 0.001) and lower mortality rates (p less than 0.05) than those treated in non-trauma centers. Associated injuries. age. complications. and/or delay in time to OR significantly increased intensity and length of stay in both trauma and non-trauma centers. This significantly increased the cost of care provided to these patients in both types of centers.
Management issues for trauma patients with alcohol, An estimated 20-25% of patients treated in emergency departments or as inpatients for trauma have been drinking and most of them have BACs of 0.10 gm/dL (22 mmol/L) or higher. Many are problem drinkers or alcoholics. smokers. and also abuse other drugs. Both acute ingestion and chronic abuse of alcohol increase the frequency and severity of injury. and may complicate patient management by mimicking head trauma. masking intra-abdominal injury. causing circulatory collapse. reducing immune response. altering hepatic metabolism. or causing delirium tremens. Proper management of a trauma patient with alcohol includes BAC determination. careful history taking for alcoholism with referral for further evaluation or treatment when indicated. and determination whether other drugs are also being misused. Failure to do these may put a physician at legal risk both for improper care of the patient and for exposing others to injury if the patient crashes after being discharged from the emergency department while still impaired by alcohol.
Metabolism of platelet activating factor (PAF) and lyso-PAF in polymorphonuclear granulocytes from severely burned patients, We studied the metabolism of 3H-platelet activating factor (PAF) and lyso-PAF in human polymorphonuclear granulocytes (PMN) from severely burned patients (n = 6) on days 1. 5. 9. 15. and 25 post-trauma. All patients suffered from a severe burn trauma of more than 30% total body surface area. Stimulation of PMN in healthy donors (n = 10) with the Ca-ionophore resulted in the conversion of 3H-lyso-PAF into PAF (18 +/- 2% of total radioactivity) and alkyl-acyl-glycero-phosphorylcholine (alkyl-acyl-GPC. 50 +/- 6%). In burned patients a significantly reduced formation of 3H-PAF was observed between days 1 and 15 post-trauma (day 9: 1 +/- 1%. p less than 0.0001). This pattern was normalized again in patients (n = 5) who survived the trauma after septic periods and was observed during the second week post-trauma. In one patient who succumbed to his injuries a sustained inhibition of PAF formation was observed up to his death. The decreased formation of PAF correlated weakly with the appearance of immature granulocytes within the analyzed cell fraction (ratio of immature cells versus PAF-formation. r = -0.55. p = 0.02).
Post-traumatic intracerebral pneumatocele: case report, Pneumocephalus occurs in 0.5 to 1.0% of head trauma. but may also occur after neurologic surgery. or as a result of eroding infection or neoplasm. The pathophysiology involves the presence of craniodural fistula allowing ingress of air. A ball-valve mechanism may allow air to enter but not exit the cranium. or CSF leak permits air entrance as fluid leaves the intracranial space. While a "succession splash" is considered diagnostic of pneumocephalus. most patients have nonspecific signs and symptoms such as headache. Therefore. a high index of suspicion in a patient with recent head trauma is necessary. The diagnosis is made radiographically by CT scan. This is generally performed to rule out intracranial hematoma or cerebral contusion in head trauma. but will reveal even very small quantities of air to the unsuspecting physician. Therapy is often noninvasive. allowing the craniodural defect to heal spontaneously. Selected situations require immediate operative repair of the fistula.
Management of close-range shotgun injuries to the chest by diaphragmatic transposition: case reports, A method of reconstructing the chest wall following close-range shotgun injuries is described. This technique requires detaching the diaphragm peripherally and suturing it above the chest wall defect. resulting in an intact chest cavity and an abdominal wall defect. This latter problem can then be addressed by a variety of standard methods. Two patients are presented with excellent long-term results of diaphragmatic transposition. which should be in the armamentarium of all surgeons who deal with trunk trauma.
Post-traumatic priapism treated with metaraminol bitartrate: case report, A 30-year-old male with post-traumatic priapism for 7 days was treated successfully by metaraminol bitartrate injection into the corpus cavernosum. This result suggests that an alpha-adrenagic agent injection into the corpus cavernosum should be considered in post-traumatic priapism at first.
Fractures of the coracoid process: presentation of seven cases and review of the literature, Coracoid process fracture is a rare and uncommon clinical entity. Seven cases of the base of the coracoid process are presented. This fracture was isolated in one case. being in the other six cases combined with injuries. either to acromioclavicular dislocation or to fracture of the superior glenoid cavity disorder. One of these patients had associated fractures of the clavicle and the coracoid process. The treatment was conservative in all cases. Results were satisfactory and therefore nonoperative management is advocated.
Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen, To measure the effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. the incidence of Plasmodium falciparum malaria and of adverse reactions was compared in Peace Corps volunteers in West Africa who took mefloquine every 2 weeks and in volunteers who took chloroquine phosphate weekly. Mefloquine was only 63% more effective than chloroquine; the monthly incidence of P falciparum infections was one case per 100 volunteers who took mefloquine and 2.7 cases per 100 volunteers who took chloroquine. Using daily proguanil (chloroguanide) hydrochloride in addition to chloroquine did not provide additional protection. All mefloquine prophylaxis failures occurred during the second week of the every-2-weeks dosing regimen in volunteers who had used mefloquine for more than 2 months. Blood concentrations of mefloquine were lower during the second week of the alternate-week regimen than during the first week. suggesting that blood levels are too low during the second week to suppress parasitemia. No serious adverse reactions were observed. The results indicate that a dosing regimen of 250 mg of mefloquine weekly should be considered for travelers to areas with chloroquine-resistant P falciparum malaria.
Contaminant blood cultures and resource utilization. The true consequences of false-positive results, To determine whether contaminant blood cultures increase resource utilization. we studied charge and length of stay data for episodes in which blood cultures were obtained from hospitalized adults. Compared with 1097 negative episodes. 94 false-positive episodes were associated with increased subsequent length of stay (median. 12.5 vs 8 days) and subsequent total charges (median. $13.116 vs $8731). pharmacy charges (median. $1456 vs $798). and laboratory charges (median. $2057 vs $1426). In multivariate analyses. contaminants were independently correlated with 20% and 39% increases in total subsequent laboratory charges and intravenous antibiotic charges. respectively. Thus. the true costs of contaminants may greatly exceed those of the test itself. Identifying patients at very low risk of bacteremia and attention to sterile technique may reduce costs by decreasing the frequency of contaminants.
Imported Plasmodium falciparum malaria in American travelers to Africa. Implications for prevention strategies, Data from the US National Malaria Surveillance System were analyzed to assess characteristics of travelers who acquired Plasmodium falciparum infections in Africa and evaluate the impact of chloroquine resistance on the incidence of imported malaria. Although the number of cases acquired in East Africa has stabilized. the number of imported P falciparum infections acquired in West Africa increased threefold from 1985 to 1988. and the proportion of travelers who reported failure of chloroquine prophylaxis increased from 10% to 48%. Fifty-eight percent of patients who acquired malaria in West Africa had not used chemoprophylaxis. To curb the rising incidence of P falciparum infections in American travelers. the Centers for Disease Control revised malaria prophylaxis recommendations to include the use of mefloquine in areas of chloroquine resistance. Use of malaria protection measures by travelers to West Africa must also be improved.
Circadian variations in myocardial ischemia. Implications for management, Extended ambulatory electrocardiographic monitoring in the patient's customary environment provides clear evidence of circadian patterns in myocardial ischemic episodes. In patients with effort angina. the highest activity occurs between 6 AM and noon. This coincides with peaks in diurnal variation of frequency of acute myocardial infarction. stroke. and sudden death. A number of potential underlying common triggering mechanisms. including catecholamine secretion. sympathetic nervous system activity. blood pressure. heart rate. cortisol secretion. and aggregability of platelets. exhibit similar surges. As a result of these coinciding morning peaks. myocardial oxygen demand is increased and oxygen supply reduced after a person arises in the morning. Attention to this vulnerable period is merited in the timing and choice of medication. both to prevent or reduce ischemia and to modify potential disease-triggering mechanisms.
Angiotensin II and the maintenance of GFR and renal blood flow during renal artery narrowing, The time course of the renal blood flow and GFR responses to narrowing of the renal artery in conscious dogs is reviewed. The initial response to this threat to renal perfusion is renal vasodilatation. but within minutes a secondary vasoconstriction mediated by angiotensin II begins to develop. Angiotensin II-mediated contraction of mesangial cells is also demonstrable. but this does not apparently reduce the filtration surface area of the glomerular capillaries. The intrarenal effects of angiotensin II restore GFR back to normal within one to two weeks. by which time circulating plasma angiotensin II levels are no longer elevated. In contrast to its effects on GFR. angiotensin II has minimal effects on renal blood flow after stenosis. This may be because. (i) blood flow is mainly determined by the hydraulic resistance of the stenosis; (ii) renal vasoconstriction has relatively little effect on flow due to the particular hemodynamic properties of the stenoses. and (iii) a major site of action of angiotensin II may be within the glomerulus. Thus angiotensin II has a homeostatic role in the maintenance of GFR during renal artery narrowing and one component of this role may involve mesangial contraction.
Angiotensin converting enzyme inhibitors and progression of chronic renal failure, Renal failure. once established by loss of a critical amount of functional renal mass. tends to be progressive. A large body of experimental evidence supports the hypothesis that glomerular capillary hypertension is important in the pathogenesis of progressive chronic renal failure of diverse types. including subtotal renal ablation and diabetic nephropathy. Converting enzyme inhibitors are effective in slowing or arresting the progression of glomerular injury in these experimental models. in association with normalization of both systemic and intrarenal pressures. Clinical studies of diabetic nephropathy and chronic renal failure of other etiologies support the concept that these same renal hemodynamic factors are important in human renal disease and that treatment with converting enzyme inhibitors may prove to be a useful therapeutic intervention. Whether the converting enzyme inhibitors have specific advantages over other antihypertensive agents due to beneficial renal hemodynamic effects. as suggested by experimental studies. is a question that awaits further investigation. Furthermore. the pathogenesis of hypertensive glomerular injury is complex and involves the participation of diverse biologic systems. We predict that a wide variety of therapeutic maneuvers. with disparate mechanisms of action. may be effective in arresting or preventing glomerular injury.
Molecular biology of the renal renin-angiotensin system, This paper describes an interrelated series of studies designed to examine molecular and cellular aspects of renin expression and release within the kidney. Using immunocytochemical techniques. Northern blot analysis. in situ hybridization. measurement of renin activity. and the reverse hemolytic plaque assay. it has been possible to demonstrate that the intrarenal distribution of renin. renin gene expressing cells and the number of renin secretory cells vary during diverse physiologic and pathologic conditions. Overall. these studies demonstrate that the renal preglomerular vasculature has the plasticity and capacity to elicit a recruitment of renin containing and/or renin gene expressing cells.
Angiotensin I-forming angiotensinogenases in extrarenal vasculature and in the kidney, The intention of this study was to characterize angiotensin I-forming angiotensinogenases (AIFAs) in rat extrarenal arterial walls and to clarify whether these enzymes are also present in the kidney. A further aim was to identify AIFAs in human vasculature and to establish whether they are affected in essential hypertension. Sprague-Dawley rats and vascular sections of patients undergoing corrective surgery were studied. Enzyme kinetic assays were performed using angiotensin I radioimmunoassay and purified natural angiotensinogens. Fast protein liquid chromatography was employed for biochemical characterization. A series of AIFAs with various isoelectric points. molecular weights and pH optima was detected in rat extrarenal vascular and. with differing distributions of enzyme activities. in renal tissues. In extrarenal arteries the main form of renal renin was present with a relatively low activity only. AIFAs were also demonstrable in human extrarenal vasculature and behaved like plasma renin in essential hypertension. The results indicate the existence of an intrinsic human vascular RAS in extrarenal (and renal) arteries. Extrarenal arterial AIFAs are not generally stimulated in essential hypertensives. as previously postulated.
Role of angiotensin in the renal vasoconstriction observed during the development of genetic hypertension, Studies have examined renal function to determine the role of the kidney in the pathogenesis and maintenance phases of hypertension in the Okamoto-Aoki strain of spontaneously hypertensive rat (SHR). As compared to age-matched Wistar-Kyoto rats (WKY). 4- to 6-week old SHR are moderately hypertensive and have a reduced glomerular filtration rate (GFR) and renal blood flow (RBF). and an increased renal vascular resistance. Cross-breeding studies indicate the reduction in RBF and GFR in young SHR is genetically linked to the hypertension and thus may be of primary pathogenetic importance. The combination of an elevated vascular resistance and reduced RBF and GFR in young SHR implicates increased activity of a vasoconstrictor system(s). decreased activity of a vasodilator system(s). or both. Observations from several laboratories support the notion that endogenous angiotensin II contributes to the renal vasoconstriction in young SHR during the developmental phase of hypertension. Acute and chronic inhibition of angiotensin converting enzyme reduce arterial pressure. reduce renal vascular resistance and increase renal blood flow in young and adult SHR. Renal vascular tone in SHR is more dependent on angiotensin converting enzyme activity than that in WKY. The ability of angiotensin converting enzyme inhibitors to produce renal vasodilation may be responsible. at least in part. for its antihypertensive effects. Other studies indicate that renal vascular reactivity to angiotensin II is exaggerated in young SHR. The strain differences in renal reactivity to angiotensin II can be abolished by cyclooxygenase inhibition with indomethacin. indicating that endogenous prostanoids counteract some of the constrictor action of angiotensin II. with more pronounced buffering activity in WKY.
Influences of angiotensin on renal function in renal vascular hypertension, The scope and the magnitude of the roles which angiotensin plays in the generation and maintenance of elevated blood pressure in models of renal vascular hypertension are continuing to expand. It is now clear that specific angiotensin dependent mechanisms contribute importantly to the pathophysiology of hypertension and altered renal function in models of two-kidney. one clip hypertension in rats. The generation of angiotensin in the local intrarenal environment of the kidney is a new and potentially important mechanism contributing to altered renal function in these models. Application of antagonists of the renin-angiotensin system to rat models of renal vascular hypertension indicate that the effects of angiotensin attenuate renal hemodynamic and excretory behavior. particularly in the nonclipped kidney. Further. angiotensin may attenuate the efficiency of autoregulation of renal hemodynamics in the nonclipped kidney. Evidence that inhibition of angiotensin reverses or improves these altered hemodynamic and excretory functions indicate that angiotensin may contribute importantly to the pathophysiology of hypertension in these models by altering or impairing the ability of the nonclipped or normal kidney to excrete sodium and volume.
Fat myringoplasty in the guinea pig, Fat myringoplasty is a simple office technique for repairing tympanic membrane perforations. It involves wedging a piece of fat from the ear lobule into the perforation. A search of the literature failed to reveal any controlled studies on the efficacy of this method. which may allow patients to avoid more invasive procedures. Controlled perforations in guinea pig tympanic membranes were treated with fat myringoplasties. paper patches. or no intervention. Four weeks following the procedures. ears were examined and photographed under the microscope and studied histologically. The fat myringoplasty healing rate exceeded the rates of both the control and paper-patch groups. Results were stratified with respect to location and size of perforations. The results and histological studies suggest that controlled studies in humans are warranted.
Hematoporphyrin photodynamic therapy: is there truly a future in head and neck oncology? Reflections on a 5-year experience, Photodynamic therapy. which consists of the selective destruction of tumors using a combination of a photosensitizer administered systemically (dihematoporphyrin ether) and an argon dye-pumped laser. has provoked profound interest amongst oncologists and has particularly titillated head and neck oncologists with its potential. Unfortunately. no multi-institutional trials for head and neck tumors have been introduced. and the literature is replete with anecdotal reports from individual researchers on the management of advanced cancers for palliation. superficial early cancers. and field cancerization of the mucosa ("condemned mucosa"). A personal 5-year experience with 41 head and neck cancers was reviewed. as was the current literature. An attempt was made to place in perspective the true role and future direction of this technology.
Monothermal differential caloric testing in patients with Meniere's disease, The monothermal differential caloric test allows determination of vestibular recruitment and decruitment. variables which may help discriminate peripheral from central vestibular lesions. Previous reports indicated a strong association between vestibular recruitment and Meniere's disease. This study examined patients having unilateral Meniere's disease. Nystagmus beat frequency (NBF) and slow-component velocity (SCV) responses were recorded by electronystagmography (ENG). Electronystagmographic findings showing unilateral dysfunction were present in 54% of patients by slow-component velocity and in 31% by nystagmus beat frequency. Unilateral hypofunction was the most frequent lateralizing ENG finding. Absolute vestibular recruitment occurred in less than 10% of patients but relative recruitment was found in nearly 20% of patients. Slow-component velocity had higher sensitivity than nystagmus beat frequency. with excellent clinical concordance. Monothermal caloric testing as described in this study best detects peripheral vestibular disease in Meniere's patients using slow-component velocity to determine unilateral hypofunction and relative vestibular recruitment.
Paranasal sinus bony anatomic variations and mucosal abnormalities: CT analysis for endoscopic sinus surgery, Coronal plane computerized tomographic (CT) scanning has dramatically improved the imaging of paranasal sinus anatomy as compared to sinus radiographs. Increasingly. subtle bony anatomic variations and mucosal abnormalities of this region are being detected. Data regarding the "background" prevalence of these findings are needed to determine their clinical relevance. A detailed analysis of coronal plane CT scans of the paranasal sinuses obtained in 202 consecutively imaged patients was conducted. Special attention was directed toward identifying bony anatomic variations and mucosal abnormalities. Anatomic variations studied included pneumatization of the middle turbinate. paradoxical curvature of the middle turbinate. Haller's cells. and pneumatization of the uncinate process. Such bony anatomic variations were detected in 131 (64.9%) of 202 patients and were found with a similar frequency in patients scanned for sinus complaints and in those scanned for nonsinus reasons. Mucosal abnormalities were detected in 168 (83.2%) of 202 patients. For those patients scanned during the evaluation of sinus-like complaints. mucosal abnormalities were noted in 153 (92.2%) of 166 cases. and were predominantly detected in the anterior ethmoid region. For patients scanned during nonsinus evaluations. mucosal abnormalities were detected in 15 (41.7%) of 36 cases. without predilection for the anterior ethmoid region. Discussion regarding the prevalence and clinical significance of paranasal sinus bony anatomic variations and mucosal abnormalities is included as a guide to assist the otolaryngologist and/or radiologist in the evaluation of coronal sinus CT scans.
Extended retrolabyrinthine transtentorial approach to petroclival lesions, In this communication. an extension of the retrolabyrinthine approach that has permitted safe. effective access to the petrous tip and clivus is presented. The basic technique involved complete mastoidectomy. preservation of the middle and inner ear structures. removal of the sigmoid and middle fossa plates. middle and posterior fossa craniotomies. ligation of the superior petrosal sinus. and division of the tentorium. Nine cases that exemplified the versatility of this approach constituted the basis of this paper: 2 cholesteatomas. 2 basilar artery aneurysms. 2 chordomas. and 3 meningiomas. The indications for. and complications of. this method have been discussed.
Whole-blood filterability in sudden deafness, Sixteen patients with sudden deafness (SD). diagnosed on the basis of a battery of audiometric tests. but with no other medical or surgical pathology requiring drug treatment. underwent monitoring of their hemorheological profiles to see whether disturbances in the microcirculation could be linked to SD. Plasma viscosity. the filterabilities. (using a low-shear positive pressure system) through 5-microns-diameter pore Nuclepore filters. of whole blood and red and unfractionated white cells were monitored in 16 SD patients and 32 controls matched for age. sex and socioeconomic status. Whole blood filterability and the filterability of the red blood cells were significantly impaired in the SD patients. which suggests that alterations in the microcirculation are linked. in some way. to sudden deafness.
Hilger facial nerve stimulator: a 25-year update, Percutaneous nerve excitability testing using the Hilger facial nerve stimulator was introduced about 25 years ago. The test is reliable. easy to use. and inexpensive; it continues to be the most frequently used method for predicting prognosis of facial nerve disorders. Between 1966 and 1974. we recorded 10.243 nerve excitability tests on 865 patients with a mean of 3.29 tests for each peripheral branch and 3.43 for the trunk. Using a multiple regression model. we determined the effect on nerve stimulation values of age. sex. race. diabetes. hypertension. partial or complete clinical paralysis. diagnosis of herpes zoster. year of testing. and eventual facial paralysis recovery profile. We discuss statistical reliability. provide a table of interpretive results. and offer "tips and traps" invaluable to the practitioner. A prospective study of 25 patients with residual facial paralysis was evaluated by two separate otolaryngologists to determine intertester reliability.
Headache. Public health problem, Headache is. and apparently always has been. a frequent pain syndrome. It is reported in American and Western European societies in very high percentages of the population. Headache. and specifically severe headache. have also been reported as prevalent from a variety of societies worldwide. although prevalence rates have varied (they are very low. for example. in the People's Republic of China). Whether prevalence varies with different socioeconomic groups remains uncertain. Severe headache and specifically migraine is. for reasons still unknown. much more common in women. and. in most studies. is reported to decrease in prevalence in older age groups. Positive family histories are common. but the precise role of genetics is unknown. A major problem in the epidemiologic studies remains the difficulty of uniform definition of headache syndromes.
The classification and diagnosis of headache disorders, Headache disorders recently have been reclassified. and new operational diagnostic criteria assist in making the correct diagnosis. These diagnostic criteria have been accepted worldwide.
Basic mechanisms in vascular headache, To better understand and treat painful conditions. one needs to identify the cause. discover the source. and develop knowledge of peripheral and central pain transmission; headaches are no exception. The development of appropriate animal models is important. Accordingly. we have reviewed the anatomy. neurochemistry. electrophysiology. and pharmacology of the trigeminovascular system in experimental animals and emphasized whenever possible the relevance of this final common pathway to migraine. cluster. and other headache syndromes in humans. For example. based on recent anatomic dissections. the pericarotid cavernous sinus plexus was suggested as an important focus to investigate cluster headache pathophysiology. This plexus is an anatomic point of convergence for the nerves giving rise to the signs of sympathetic and parasympathetic activity and sensory symptoms that develop in cluster patients. As in other nociceptive systems. trigeminovascular axons assume at least two important roles. One concerns the transmission of nociceptive information. Electrophysiologic evidence supports the trigeminal nucleus caudalis as an important site for the convergence of visceral (vessel) and somatic (forehead) inputs to mediate the referral of vascular pain to superficial tissues. A second important role concerns the initiation of local increases in blood flow and enhanced protein permeability (sterile inflammation) via the axonal release of vasoactive neuropeptides. Plasma extravasation develops within the dura mater following trigeminal stimulation. Extravasation can be blocked by the administration of ergot alkaloids or sumatriptan. a new serotonin-like agonist. and a prejunctional (neuronal) mechanism of action for these drugs (such as blockade of release) was suggested based on experimental evidence. Whether vasoconstriction also relates to the therapeutic efficacy remains to be determined. As in other organ systems. real or threatened tissue injury provides an important stimulus for depolarizing sensory fibers. The stimulus may come from external conditions such as reduced blood flow or hypoglycemia. The brain may also possess intrinsic neuronal mechanisms by which nociceptors may be synthesized (e.g.. glutamate-induced neurotoxicity. seizures). Molecules of relevance include bradykinin. prostaglandins. leukotrienes. and potassium. Experimental evidence was presented demonstrating that the trigeminal nerve mediates hyperemia within cortical gray matter by axon-reflex like mechanisms. An important role for this nerve was established during the hyperemic period of recirculation after ischemia or during severe hypertension above the limits of autoregulation.(ABSTRACT TRUNCATED AT 400 WORDS).
The concept of migraine as a state of central neuronal hyperexcitability, This article explores the hypothesis that migraine with aura is associated with a state of central neuronal hyperexcitability. The authors propose that this central neuronal hyperexcitability involves overactivity of the excitatory amino acids. glutamate. and possibly aspartate. Stimuli that activate the migraine attack evoke neuronal depolarization. slow depolarization shifts. and spreading suppression of spontaneous neuronal activity possible by glutamate and K+ dependent mechanisms. A low brain Mg2+ and consequent reduced gating of glutamatergic receptors may provide the link between the physiologic threshold for a migraine attack and the mechanisms of the attack itself by promoting glutamate hyperactivity. neuronal hyperexcitability. and susceptibility to glutamate-dependent spreading depression.
Developments in 5-hydroxytryptamine receptor pharmacology in migraine, Because a satisfactory animal model for migraine does not exist. attempts to determine a common mechanism of action for effective antimigraine agents may be of benefit in elucidating the pathogenesis of this neurologic syndrome. The present review demonstrates that the clinical data that has developed over the past 30 years may allow for the elucidation of the role of specific 5-HT receptor subtypes in the pathophysiology of migraine. A large number of both acute and prophylactic antimigraine agents share an ability to interact with 5-HT receptor subtypes in human brain. As summarized in Table 3. acute antimigraine drugs (e.g.. ergots. sumatriptan) share high affinity for 5-HTID receptors and somewhat lower affinity for 5-HT1A receptors. These receptors are present in certain intracranial blood vessels. 5-HT1D receptors are also located on nerve terminals where they act to inhibit the release of 5-HT and other neurotransmitters. Theoretically. 5-HTID receptor agonists may acutely inhibit the release of vasoactive or pain-inducing substances in the perivascular space. Conceivably. drugs acting at this receptor would stop the progression of this perivascular process. In addition. a number of prophylactic antimigraine drugs display a relatively high affinity for both 5-HT2 and 5-HT1C receptors in human brain. Although these receptors are also found in certain blood vessels. they are present throughout the nervous system. The receptors appear to mediate neuronal depolarizations at the cellular level. Moreover. the 5-HT2 receptor appears to play a key role in the development of inflammation in certain smooth muscle systems. Theoretically. the ability of 5-HT2 antagonists to protect perivascular inflammation may account for their efficacy in the prophylactic treatment of migraine. These data offer a novel approach to the analysis of antimigraine agents. Drugs could be selected for use in clinical migraine studies based on their selectivity for a specific 5-HT receptor subtype. For example. an agent that displays both high affinity and selectivity for 5-HT1D receptors could be clinically evaluated. Its effectiveness. or lack thereof. would indicate the importance of this specific 5-HT receptor site in the pathogenesis of migraine. Future attempts to determine a common mechanism of action for effective antimigraine agents should facilitate the elucidation of the pathogenesis of this neurologic syndrome.
Manifestations of migraine, Migraine is a disorder with multiple manifestations affecting the circulation. gastrointestinal tract. and the central nervous system. Involvement of the autonomic nervous system is responsible for many of the clinical features. An attack of migraine can vary from a fragment of the clinical spectrum to one with several phases and potentially permanent sequelae.
Modern pharmacotherapy of migraine, Rectal ergotamine and naproxen are the major candidates for the ad hoc treatment of migraine attacks; for particularly dramatic episodes. intravenous DHE with prochlorperazine is the author's preference. For long-term stabilization. after simpler measures fail. valproate appears to be a major addition to migraine therapy.
Advances in cluster headache, The physician may have to combine the art and science of medicine in the management of this most fascinating of human ailments. The choice of drugs and the length of treatment prescribed are greatly influenced by the individual physician's experience. convictions. and reasoning. Needless to say. chronic use of narcotics should be avoided. The author's own regimen is to use combinations of ergotamine prophylaxis with either verapamil or prednisone in episodic cluster headache and with lithium for chronic cluster headache. Management of the treatment-resistant patient remains problematic. but a carefully performed trigeminal radiofrequency thermocoagulation procedure may be worthwhile.
Drug-induced headache, Headache induced by medications used for nonheadache conditions. and more importantly. headache perpetuated by symptomatic medications used for primary headache disorders are discussed in detail in this article. The clinical features and mechanisms of drug-induced headaches are reviewed. Ergotamine and analgesic rebound phenomena are described. Management strategies for drug-induced headaches are outlined.
Oromandibular disorders and headache. A critical appraisal, Oromandibular disorders are functional disorders and associated pains in the anatomic region of the temporomandibular joint. Their diagnosis and treatment are controversial because of the lack of conformity concerning these disorders among health care providers. This article provides a clear classification of these disorders and critically reviews their evaluation and treatment.
Psychologic and behavioral aspects of chronic headache, It is important for physicians to be aware of the expectations and psychologic needs patients have. to understand how psychologic and personality variables can impact care. to realize the importance of patient education. and to be cognizant of how environmental factors can influence headache pain behaviors. Empirical data indicate that the nonpharmacologic treatments of biofeedback. relaxation. and stress coping training can serve as useful adjunctive or alternative procedures. and that the combined use of medication and nonpharmacologic treatments yields the greatest clinical outcome. Certain headache types show minimal response to nondrug therapies alone (cluster. menstrual. and post-traumatic headache). Age and personality variables have a bearing on nondrug treatment outcome as well.
A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas, A gene has been identified that is expressed specifically in stromal cells surrounding invasive breast carcinomas. On the basis of its sequence. the product of this gene. named stromelysin-3. is a new member of the family of metalloproteinase enzymes which degrade the extracellular matrix. The suggestion is that stromelysin-3 is one of the stroma-derived factors that have long been postulated to play an important part in progression of epithelial malignancies.
Localization of dystrophin to postsynaptic regions of central nervous system cortical neurons, Moderate non-progressive cognitive impairment is a consistent feature of Duchenne muscular dystrophy (DMD). although no central nervous system (CNS) abnormality has been identified. Recent studies have elucidated the molecular defect in DMD. including the absence of the protein dystrophin in affected individuals. Normal brain tissue contains dystrophin messenger RNA and dystrophin is present in low abundance in the brain and seems to be regulated in this tissue. at least in part. by a promoter that differs from that in muscle. Until now. antibodies and immunocytochemical methods used to demonstrate dystrophin at the plasma membrane of mouse and human muscle have proven inadequate to localize precisely dystrophin in the mammalian CNS. We have now made an antibody (anti 6-10) which is much more sensitive than those previously available to immunolabel dystrophin in the CNS. Using this antibody. we found that in the mouse. dystrophin is particularly abundant in the neurons of the cerebral and cerebellar cortices. and that it is localized at postsynaptic membrane specializations. Dystrophin may have a different role in neurons than in muscle. and an alteration at the synaptic level may be the basis of the cognitive impairment in DMD.
A gene in the human major histocompatibility complex class II region controlling the class I antigen presentation pathway, Major histocompatibility complex (MHC) class I molecules export peptides to the cell surface for surveillance by cytotoxic T lymphocytes. Intracellular peptide binding is critical for the proper assembly and transport of class I molecules. This mechanism is impaired as a result of a non-functional peptide supply factor gene (PSF) in several human mutant cell lines with genomic lesions in the MHC. We have now identified PSF in the MHC class II region by deletion mapping in mutants and chromosome-walking. PSF is homologous to mammalian and bacterial ATP-dependent transport proteins. suggesting that it operates in the intracellular transport of peptides.
Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome, Tumour suppressor genes. whose usual function seems to be controlling normal cell proliferation. have been implicated in many inherited and sporadic forms of malignancies Much evidence supports the concept of tumour formation by loss-of-function mutations in suppressor genes. as predicted by the two-hit model of Knudson and DeMars. The suppressor gene. p53. is affected in such a manner by numerous mutations. which occur in a variety of human tumours. These mutations usually represent the loss of one allele and the substitution of a single base in the other. We have now analysed the p53 gene in a family affected by Li-Fraumeni syndrome. a rare autosomal dominant syndrome characterized by the occurrence of diverse mesenchymal and epithelial neoplasms at multiple sites. In some instances the neoplasms seem to be related to exposure to carcinogens. including ionizing radiation. The Li-Fraumeni family that we studied had noncancerous skin fibroblasts (NSF) with an unusual radiation-resistant phenotype. DNA derived from the NSF cells of four family members. spanning two generations. had the same point mutation in codon 245 (GGC----GAC) of the p53 gene. This mutation leads to substitution of aspartic acid for glycine in one of the regions identified as a frequent target of point mutations in p53. The NSF cell lines with the mutation also retained the normal p53 allele. This inherited p53 mutation may predispose the members of this family to increased susceptibility to cancer.
Civilian gunshot wounds to the head: a prospective study, Previous retrospective studies of cranial gunshot wounds have failed to determine whether aggressive field resuscitation. triage to a neurosurgical center. and early surgical intervention can improve the assumed poor outcome of these severely injured patients. Therefore. we studied 100 consecutive patients prospectively to establish a systematic approach to treatment. If the patient retained two or more neurological signs after aggressive field resuscitation/intubation. a computed tomographic scan was performed. Rapid surgical debridement was done unless the patient deteriorated to clinical brain death. The Glasgow Coma Scale (GCS) score after resuscitation was 3 to 5 in 58 patients. 6 to 8 in 8 patients. 9 to 12 in 12 patients. and 13 to 15 in 22 patients. Seventy-six computed tomographic scans and 43 craniotomies were performed. The Glasgow Outcome Scale scores showed that 60 patients died. 2 were vegetative. 6 were severely disabled. 20 were moderately disabled. and 13 had good outcomes. There were 10 postoperative deaths. No patient with a GCS score of 3 to 5 had a satisfactory outcome; however. outcome progressively improved as the GCS score increased. We conclude that all cranial gunshot patients should initially receive aggressive resuscitation. Patients with stable vital signs should be examined by computed tomographic scan. If the patient's GCS score after resuscitation is 3 to 5 and no operable hematomas are present. then no further therapy should be offered. All patients with a GCS score greater than 5 should receive aggressive surgical therapy.
Median nerve somatosensory evoked potentials and the Glasgow Coma Scale as predictors of outcome in comatose patients with head injuries, Median nerve somatosensory evoked potential (SSEP) grades and Glasgow Coma Scale (GSC) scores were obtained from 51 patients with head injuries within 1 week after the injury to determine the relationship of these scores. both individually and combined. to outcome scores obtained more than 6 months after the injury. SSEP grading was based on the presence or absence of the cortical evoked potential. the amplitude of the early cortically generated P22 wave form. and the conduction time through the brain (P/N13-N20 interpeak latency). SSEP responses from both sides of the brain were combined and graded from 1 to 6. The GCS was graded without the verbal component (maximum score. 10). because all patients were intubated. All patients were unresponsive to commands. Median SSEP grades correlated better with Glasgow Outcome Scale and Barthel Index scores (R = 0.57 and 0.64. respectively; P less than 0.00001) than GCS scores did (R = 0.35 and 0.37. respectively. P less than 0.00001). and combining SSEP grades and GCS scores did not improve the predictive power of the model (R = 0.57 and 0.64. respectively; P less than 0.00001). All SSEP Grade 1 patients (n = 13) either died or remained in a vegetative state. In contrast. all SSEP Grade 6 patients (n = 7) had a moderate disability or good recovery. This study demonstrates the prognostic value of early quantitative median nerve SSEP grading for patients with head injuries who are unresponsive to commands within 1 week after the injury.
Surgical decompression without transposition for ulnar neuropathy: factors determining outcome, Fifty-one surgical decompressions without nerve transposition for ulnar neuropathy were performed in 46 patients. All of the patients were men with an average age of 59 years at the time of surgery. The follow-up range was between 5 and 32 months (average. 17.8 months). The disease involved the nondominant arm in 24 patients (52%) and was bilateral in 5 (11%). In 23 cases (50%). no predisposing condition could be identified. whereas 15 patients (33%) abused alcohol and 8 patients (17%) had diabetes mellitus. Fifty-seven percent of the patients helped by surgery had symptoms for less than 1 year. whereas only 30% of patients with symptoms for more than 1 year had symptomatic improvement. The relative magnitude of the slowing of ulnar nerve conduction velocity across the elbow was not significantly correlated with the success of decompression in relieving symptoms. Ulnar nerve conduction velocities across the elbow were 36.13 +/- 11.76 m/s in those responding to surgery and 38.97 +/- 13.91 m/s in those not responding (c = 0.06. dF = 50. P less than 0.3). A total of 37 patients showed symptomatic improvement after decompression. Simple decompression of the ulnar nerve was performed under local anesthesia without transposition of the nerve. In all of these cases. compression of the nerve occurred predominantly in the epicondylar groove. Narrowing of the nerve in the groove was present in 28 cases (55%); scar tissue was found adhering to the nerve in 21 cases (41%); and two pseudoneuromas were found (4%). Forty-one operations (80%) resulted in symptomatic improvement. typically noted by the patient within the first month postoperatively.
The operative management of basilar impression in osteogenesis imperfecta, Four patients with osteogenesis imperfecta and neurologically significant basilar impression have been treated over the past 8 years. The experience has resulted in changes in our therapeutic strategy for this particularly difficult problem. These cases are discussed with respect to the disease process. neurological involvement. radiological findings. and modes of surgical therapy. The errors in management as well as the success resulting from our learning experience are described. Currently. we recommend the extensive removal of the anterior bony compression by a transoral approach. This should be followed by a posterior rigid fixation that transfers the weight of the head to the thoracic spine. in an effort to prevent further basilar invagination.
Persistent primitive trigeminal artery-cavernous sinus fistulas: report of two cases, Two cases of persistent primitive trigeminal artery-cavernous sinus fistulas are presented. In one case. the fistula was treated by using a two-balloon tandem technique. This method was accomplished by introducing. inflating. and detaching a silicone balloon into the trigeminal artery. thus preserving the carotid and basilar blood flow. An unusual case of a similar fistula with only contralateral exophthalmos is also reported. The relationship between this type of fistula and the presence of aneurysms on the persistent primitive trigeminal artery and the relationship with traumatic events are discussed.
Intracerebral solitary plasmacytoma, We report a rare occurrence of intraparenchymal plasmacytoma and review the literature. The clonal nature of the neoplasm is demonstrated by immunohistochemical and molecular techniques. The importance of the latter techniques in ruling out other pathological entities is stressed.
Concepts of soft-tissue trauma repair, The proper evaluation and treatment of soft-tissue trauma to the face is extremely important because of the psychologic. cosmetic. and functional sequelae that can occur from these injuries. The facial trauma surgeon should have a wide armamentarium of techniques to manage soft-tissue facial trauma and should approach the repair in a meticulous and scientific fashion. Although the best possible repair of the acute trauma is the goal. it is usually necessary to perform later some camouflage or revision procedures on the scar because of the high likelihood of hypertrophic scarring or inappropriate healing in the trauma scar.
Mohs micrographic surgery, Mohs micrographic surgery is a versatile technique for the treatment of nonmelanoma skin cancers. especially recurrent. invasive. or infiltrating basal cell carcinomas. It provides unsurpassed cure rates by using 100% surgical margin control. and it achieves maximal preservation of normal tissue. At the conclusion of tumor extirpation. the defect is ready for immediate reconstruction. With better understanding of the Mohs micrographic surgery technique. it can be more effectively used as part of a coordinated multidisciplinary approach to the treatment of patients with difficult cutaneous and paracutaneous neoplasms.
Scar revision and camouflage, The successful revision and camouflage of facial scars is as much an art as a science. and the best teacher is continued experience; however. common sense. a broad knowledge of available options. technical ability. and patience are all necessary if one chooses to practice in this challenging field. Patients with facial scars are vulnerable in a way that few others are. and it is the responsibility of the facial plastic surgeon to evaluate these patients properly and realistically. to prepare them for a process that may involve multiple procedures. and to see them through this process with all the expertise and compassion possible. If this is done. the rewards to the patient and to the surgeon can be immeasurable.
Diagnosis and management of precocious puberty, The onset of pubertal development before the age of 8 years in girls or 9 years in boys constitutes precocious puberty. There are numerous causes of precocious puberty. which can be classified as central or peripheral precocious puberty. Central precocious puberty results from premature activation of the hypothalamic-pituitary-gonadal axis and thus presents with physical and hormonal findings similar to those found in normal puberty. Peripheral precocious puberty results from extrapituitary gonadotropin secretion or secretion of sex steroids independent of pituitary gonadotropins. All types of precocious puberty are characterized by rapid growth and advancement of skeletal age. leading to the paradox of the tall child becoming a short adult as a result of premature epiphyseal fusion. Long-acting GnRH agonists afford effective. selective. and reversible therapy of central precocious puberty without significant toxicity. GnRH agonists are not effective in managing the premature sexual maturation associated with peripheral precocious puberty. but a number of other agents have been used with some success. These agents include testolactone. ketoconazole. and medroxyprogesterone acetate. GnRH agonist treatment leads to an increase in predicted final height. To determine the true benefit of any of these agents in increasing ultimate height. there is a need for continuing studies in treated cohorts to follow growth patterns until adult stature is achieved.
Hyperthyroidism in children and adolescents, Hyperthyroidism in infants and children usually is caused by Graves' disease; however. several other diseases can also produce hyperthyroidism in these age groups. Because the pathophysiology and clinical course of these conditions differ. optimal treatment depends on precise diagnosis.
The Cushing syndromes, The 10 years since this journal's last review of CS have seen extraordinary advances in our understanding of many aspects of its causes. diagnosis. and treatment. The spectrum of what are now called the Cushing syndromes has expanded considerably to include CD. multiple sources of ectopic ACTH secretion. and an apparent autoimmune cause. Improved assays of ACTH and the availability of CRF have provided new insight into the physiology and pathophysiology of the HPA axis and new tools for diagnosis of CS. especially in combination with selective catheterization and sampling. New imaging technology has improved our visualization of pituitary adenomas and has provided powerful methods for identifying tumors ectopically secreting ACTH and primary adrenal tumors. Finally. the refinement of transsphenoidal surgery and its success in treating CD have provided a safe and effective therapy for this disease. For those occasional patients who require medical therapy. drugs are available that decrease steroid biosynthesis. We now have a much better understanding of a fascinating disease process and are able to diagnose and treat it more correctly. One is impatient to see which new pieces of this puzzle will fall into place over the next ten years.
Primary and secondary testicular insufficiency, The possibility of testicular insufficiency is a common problem for the pediatric practitioner. Presentation varies with the severity of the defect. the developmental age achieved before onset. and the presence of associated other abnormalities. Most commonly. primary and secondary testicular insufficiency present at the time of puberty. but the presentation may be at birth or in the early neonatal period. Appropriate investigations may uncover the diagnosis at the time and allow intervention later at the appropriate age. Secondary testicular failure. although more difficult to diagnose and to differentiate from simple delay of development. offers the possibility of later development of spermatogenesis and the attainment of fertility through the use of gonadotropins or GnRH replacement programs. In primary testicular failure. because it implies an intrinsic abnormality of the functioning elements of the testis. spermatogenesis is not inducable by hormonal stimulation. Treatment of testicular failure in the neonatal period is unnecessary unless micropenis is associated. In the pubertal boy. testosterone replacement is the treatment of choice and should be initiated carefully. taking into consideration the age of the subject. his bone age. and the psychosocial circumstances. The goal of therapy is to achieve a normal progression of physical changes of puberty to physical maturity and the normal potential for sexual function.
Adolescent gynecomastia. Differential diagnosis and management, Gynecomastia signifies a transient or permanent disturbance in steroid hormone physiology and occurs when the male breast is exposed to a decreased ratio of androgen to estrogen. This article discusses pubertal and pathologic gynecomastia. diagnostic approach. and treatment.
Disorders of sexual differentiation and development. Psychological aspects, Children with abnormalities in sexual differentiation and development can have a smooth course of psychosocial development in spite of the significant risks and challenges they face. Chances for a positive emotional outcome are made more likely by the careful handling of these patients at the time of first presentation. Parents' unambiguous acceptance of the child's sex of rearing and early surgical intervention to normalize the child's external genital appearance are critical elements in a positive outcome. Further. the patterns of behavior documented in the materials reviewed in this article suggest difficulties of immaturity and social development rather than significant psychopathology. Parent-child interactions were repeatedly found to be central to the child's emotional well-being. underscoring the need to provide parents with adequate counsel and support. These patterns. however. represent findings across groups of patients and cannot predict the emotional. social. or academic functioning of any individual. Within all these clinical syndromes there is great individual variation in social. emotional. and physical presentation. Finally. rather than minimizing problems. physicians need to educate parents so they can be active advocates for their children in the educational and social arenas.
Turner syndrome and its variants, Turner syndrome is suspected in females with short stature. gonadal dysgenesis. and lymphedema; however. there are no pathognomonic features of Turner syndrome. and the disorder should be considered in any girl with short stature or delayed puberty. This article discusses the natural history of Turner syndrome and complications that occur in various organ systems; it reviews the physical features and complications seen with various karyotypic changes in Turner syndrome. Age-specific screening and therapies are covered.
Surfactant treatment of full-term newborns with respiratory failure, Surfactant inactivation has been shown to be a significant factor in animal models of lung injury and may also be important in some forms of respiratory failure in full-term newborns. Fourteen full-term newborns with respiratory failure associated with pneumonia (7 patients) and meconium aspiration syndrome (7 patients) were treated with 90 mg/kg of a calf lung surfactant extract. given intratracheally up to every 6 hours for a maximum of four doses. The group mean fraction of inspired oxygen (FI02) before treatment was 0.99 +/- 0.01 SEM. and the mean airway pressure (MAP) was 14.6 +/- 1.0 cm H2O. Patients showed significant improvement in oxygenation after initial surfactant treatment. with the arterial-alveolar oxygenation ratio (a/A ratio) rising from 0.09 +/- 0.01 before surfactant treatment to 0.22 +/- 0.05 by 15 minutes (P = .03) and remaining improved for 6 hours. The oxygenation index. incorporating MAP as well as oxygen variables. also improved significantly from 26.2 +/- 3.1 to 11.2 +/- 1.7 at 15 minutes (P less than .001). with improvement sustained for more than 6 hours. Chest radiographs were blindly scored from 0 (normal) to 5 (severe opacification). and these improved with marginal significance after initial surfactant treatment (from 2.9 +/- 0.2 to 2.5 +/- 0.2. P = .05).
Controlled trial of a home and ambulatory program for asthmatic children, Care of asthmatic children is often episodic and more therapeutic than preventive. A 2-year randomized. controlled trial involving 95 children measured the impact of a comprehensive home and ambulatory program for pediatric asthma management using objective outcome measures. Interventions for the study group during the first year included 3-month clinic visits. education. and home visits by a specially trained research nurse. Control subjects continued to receive regular care from a family physician or pediatrician. Eight-nine subjects (93%) completed the study. Study subjects had less school absenteeism than control subjects (10.7 vs. 16.0 days. P = .04) and showed significantly better small airway function after 1 year. Asthma severity improved in 13 study subjects and worsened in 5. The reverse was true for control subjects. Study subjects exhibited better metered aerosol technique than control subjects (P = .0005). Fewer days were spent in hospital by the study subjects admitted compared with control subjects (3.67 vs 11.2 days. P = .02). After 1 year. more study than control families (72.1% vs 33.1%. P = .006) reported that their asthmatic child took responsibility for the asthma management. The intervention failed to reduce exposure to secondhand smoke or to household pets. There were no significant differences in medical visits. theophylline levels. or records of asthma symptoms. One year after discontinuing the intervention. a marked "washout" effect was observed. Comprehensive ambulatory programs of childhood asthma management can improve objective measures of illness severity but must be sustained.
Microcomputer reconstruction for analysis of spinal deformity and lung volume in hypokyphotic scoliosis, Current techniques for imaging chest deformity are limited to two-dimensional representations. and clinical testing for lung volume measurements are based on pulmonary function studies that are effort-dependent. The authors evaluated spine deformity and lung volume by using a new three-dimensional microcomputer imaging technique. Results from preoperative and postoperative chest computed tomograms underwent boundary detection by expert human observers. Data were then processed by polygon surface tiling to create three-dimensional color images of the spine and lungs for display. This computer technique allowed: 1) visualization of the anatomic relationships from any angle. 2) assessment of spinal deformity in relation to lung volume. and 3) measurement of individual lung volumes. Three-dimensional microcomputer imaging is a useful technique in objectively measuring lung volume and assessing postoperative changes.
Cobb angle versus spinous process angle in adolescent idiopathic scoliosis. The relationship of the anterior and posterior deformities, The standard clinical measurement for adolescent idiopathic scoliosis is the Cobb angle. measured from the end-plates of the end vertebral bodies in a standing radiograph. This measurement of anterior column structures describes the anterior spinal deformity. The posterior spinal deformity can be described by the "spinous process angle." measured from a curve joining the tips of the spinous processes. A computer model. and a radiographic study of Cobb angle. spinous process angle and vertebral rotation show that adolescent idiopathic scoliosis results in larger angulations of the anterior elements than posterior elements. This helps to explain some of the inherent limitations of posterior instrumentation. including Cotrel-Dubousset instrumentation. and of noninvasive posterior surface measurement systems.
Digital radiography can reduce scoliosis x-ray exposure, Digital radiology is a new computerized system of acquiring x-rays in a digital (electronic) format. It possesses a greatly expanded dose response curve that allows a very broad range of x-ray dose to produce a diagnostic image. Potential advantages include significantly reduced radiation exposure without loss of image quality. acquisition of images of constant density irrespective of under or over exposure. and reduced repeat rates for unsatisfactory films. The authors prospectively studied 30 adolescents with scoliosis who had both conventional (full dose) and digital (full. one-half. or one-third dose) x-rays. They found digital made AP and lateral image with all anatomic areas clearly depicted at full and one-half dose. Digital laterals were better at full dose and equal to conventional at one-half dose. Cobb angles were easily measured on all one-third dose AP and on 8 of 10 one-third dose digital laterals. Digital clearly depicted the Risser sign at one-half and one-third dose and the repeat rate was nil in this study. indicating digital compensates well for exposure errors. The study indicates that digital does allow radiation dose to be reduced by at least one-half in scoliosis patients and that it does have improved image quality with good contrast over a wide range of x-ray exposure.
Results of treatment of idiopathic scoliosis with the Charleston bending orthosis, The authors present a preliminary retrospective review of the treatment of 32 patients with idiopathic scoliosis with the Charleston bending thoracolumbosacral orthosis (TLSO). a new. low-profile spinal orthosis. At the onset of treatment. the patients' mean age was 12.5 years and the mean Risser stage was 0.4. Females achieved menarche at an mean of 1.8 months after starting orthotic treatment. Single structural curves were treated in all patients. At this time. 2 patients have failed treatment. their curves progressing 12 degrees and 8 degrees. respectively. An additional 11 patients have successfully completed treatment. having reached skeletal maturity with no more than 5 degrees of curve progression. Their mean curve change was a 2.2 degrees decrease. The other 19 patients remain under treatment. The Charleston bending TLSO is worn only during nighttime sleeping hours. It is well tolerated. with excellent patient compliance and low psychological stress. and it may be as successful at curve control as other orthoses. Experience with more patients and longer follow-up is needed.
Surface electrical stimulation versus brace in treatment of idiopathic scoliosis, Surface electrical stimulation using the ScoliTron device was applied to 40 adolescent patients for treatment of idiopathic scoliosis. Adequate follow-up was available for 30 of these patients. The overall failure rate was 15 of 30 or 50%. Due to curve progression while using the ScoliTron. these patients either went on to a fusion (9 of 15) or were changed to a brace (6 of 15). The remaining 15 patients were considered successes with no curve progression (10 of 30 or 33%) or successful/failures with slight curve progression not requiring a change in treatment (5 of 30 or 17%). None of the various parameters analyzed were found to be useful indicators of successful treatment using the ScoliTron device. Electrical stimulation was found to be ineffective in preventing curve progression for idiopathic scoliosis.
Fusion levels and hook patterns in thoracic scoliosis with Cotrel-Dubousset instrumentation, This study reports the results of treatment of adolescents with King Types 2. 3. and 4 idiopathic curves using Cotrel-Dubousset instrumentation. Imbalance was seen in Types 2 and 4 curves when distraction direction hook patterns crossing the thoracolumbar junction were employed. Imbalance was not seen when a modified hook pattern employing compressing forces across the thoracolumbar junction was employed. No imbalance was observed in Type 3 curves using the basic right thoracic curve hook pattern. In Type 4 curves. a second modified hook pattern is required to obtain improved correction and balance. The mechanism of production of imbalance is explained by a three dimensional analysis of the deformity and of the forces generated by the Cotrel-Dubousset system.
Sagittal plane analysis in idiopathic scoliosis patients treated with Cotrel-Dubousset instrumentation, One hundred sixty patients with idiopathic scoliosis underwent preoperative and postoperative sagittal plane analysis of the thoracic spine. thoracolumbar junction. and lumbar spine. The data suggest that mild to moderate improvements in thoracic hypokyphosis are possible. When crossing the thoracolumbar junction. reversal of rod bend and reversal of hooks on the derotation rod appears to provide the most physiologic sagittal contour. Cotrel-Dubousset instrumentation to the mid and distal lumbar spine can preserve and. at times. enhance lumbar lordosis.
Immediate complications of Cotrel-Dubousset instrumentation to the sacro-pelvis. A clinical and biomechanical study, The authors reviewed the early complications in all patients fused to the sacro-pelvis using Cotrel-Dubousset instrumentation at the Texas Scottish Rite Hospital. Sixteen patients were studied with an average follow-up of 13 months. Three methods of sacro-pelvis fixation were evaluated: iliosacral screws. sacral screws. and a technique whereby the caudle ends of the Cotrel-Dubousset rods were fashioned and inserted into the posterior iliac crest using the Galveston technique. Seven of the 16 sets of sacral screws (44%) failed during and after surgery. Two of the 7 sets of iliosacral screws failed postoperatively (28%). No failures occurred in the 8 sets of Cotrel-Dubousset rods placed with the Galveston technique. Seven of the nine medical complications observed (77%) occurred in the sacral screw group. Using calf spines. a biomechanical evaluation of each system was undertaken to determine strength of fixation. Each system was failed in flexion 3 times. The sacral screws were the weakest. pulling directly out of the sacrum at 40 N-M. Cotrel-Dubousset rods inserted with the Galveston technique were the strongest. experiencing rod deformities before flexion failure at 70 N-M. Iliosacral screws were of intermediate strength failing by rotation on the axis of the screws or pulling directly out of the ilium at 55 N-M. The authors conclude that using Cotrel-Dubousset rods inserted with the Galveston techniques was the strongest and safest method of sacro-pelvis fixation of the three tested.
Surgical treatment of scoliosis in a spinal muscular atrophy population, Seventy-eight patients were diagnosed with spinal muscular atrophy between 1969 and 1988. Scoliosis developed in 34 of these patients. an incidence of 60%. Thirty-one patients could be retrospectively reviewed by chart review or interview. The average follow-up was 11.5 years. Onset of scoliosis averaged 8.8 years. Twenty-two patients were treated nonsurgically and nine surgically. Patients had improved sitting balance and endurance after surgery. Complications of surgery included loss of correction in one patient. one pseudarthrosis. and one patient who required prolonged ventilatory support. The prolonged survival of patients with spinal muscular atrophy justifies aggressive orthopaedic management of scoliosis to prevent progression of deformity and improve sitting comfort.
Sagittal index in management of thoracolumbar burst fractures, In an effort to quantify the risk for late progression in burst fractures. the sagittal index (SI) was defined to help to assess the segmental deformity at the level of the fracture. The SI is a measurement of the kyphotic segmental deformity corrected for the normal sagittal contour at the level of the deformed segment. A prospective study was devised in 1986 for burst fracture treatment. Complete data were available on 35 patients (22 males. 13 females). with an average follow-up of 27 months. SI was greater than 15 degrees in the first group. the members of which were treated surgically. The technique is described. SI was less than 15 degrees in the third group. the members of which were treated conservatively. The second control group included patients with SI greater than 15 degrees but who were not treated according to the authors protocol for independent reasons. The results suggest that SI is a useful criteria to assess deformity and predict progression of segmental kyphosis.
Blood flow direction in the lumbar nerve root, The effect of clipping on lumbar nerve root blood flow rates in the region of the nerve root canal was studied experimentally in the hog. Blood flow rate was measured using the hydrogen washout technique. When the entrance zone was clipped with a microvascular clip. blood flow rate of the nerve root was decreased by 37% in comparison with the initial control rate; clipping at the exit zone reduced blood flow rate by 69%. Blood flow direction in the lumbar nerve root within the nerve root canal was found to be predominantly proximal. The current data indicate that the more lateral the impingement of the nerve root occurs. the more ischemic changes are induced.
Quantification of leakage pressures after durotomy repairs in the canine, This study was undertaken to investigate the relative strengths of dural repair using standard suture techniques. suture supplemented with tissue adhesive. and tissue adhesive alone. Uniform 2 mm dural defects were created in adult beagles. repaired. and then subjected to pressurization testing. Defects repaired with suture alone initially leaked within the range of physiologic pressurization. while those supplemented with tissue adhesive or repaired with tissue adhesive alone failed at higher pressurization levels. Histologic sections obtained from the dura treated with fibrin adhesive sealant demonstrated minimal inflammatory response not significantly different than those sections examined at sites repaired by suture alone. A new substance. fibrin adhesive sealant. appears to be useful in effecting dural repair due to its ability to withstand pressures greater than those obtained with suture alone.
Factors affecting fusion rate in adult spondylolisthesis, The authors examined factors affecting fusion rate in the surgical treatment of 89 consecutive adult patients with spondylolisthesis. Two factors significantly improved fusion rate: combined anterior and posterior fusion and rigid postoperative immobilization in the cast. In 65 patients with isthmic spondylolisthesis. the fusion rate was raised from 70% when posterior fusion alone was used to 88% when combined anterior and posterior fusion was used. In 20 patients with degenerative spondylolisthesis. frequent use of combined anterior and posterior fusion contributed to a high overall fusion rate of 95%. Among patients with isthmic spondylolisthesis. postoperative cast immobilization resulted in a higher fusion rate of 90% compared with a fusion rate of 63% obtained after brace immobilization.
Transhepatic portal vein catheterization for localization of insulinomas: a ten-year experience, One of the most important factors in the management of insulinomas is the ability to localize the tumor accurately either before or during surgery. We prospectively carried out transhepatic portal venous sampling (THPVS) for tumor localization in 35 of 40 patients with organic hyperinsulinism during a 10-year period. In 32 patients who underwent THPVS and in whom a single tumor was subsequently identified surgically. the maximal insulin gradient was located in the vicinity of the tumor in 100% of cases. Specific regionalization of the tumor on the basis of the site of the maximal insulin gradient to one of three regions (the tail. the body/neck region. and the head/uncinate region) gave a sensitivity of 81% and a specificity of 91%. In contrast. the use of specific cutoff levels for the insulin gradient as a guide to the presence of a tumor in one of these three regions did not increase the accuracy. leading instead to a significant loss of sensitivity with no comparable increase in specificity. There were no major complications from the procedure in any patient. The initial use of computed tomographic/ultrasound scanning and selective angiography localized only 46% of tumors. whereas subsequent THPVS led to the accurate preoperative localization of 100% of all tumors submitted to surgery. Although the surgeon would have identified 81% of the tumors correctly at operation. in 19% (n = 6) he would have failed. Four tumors were in the uncinate and two were in the head. It seems that in patients with proved or established organic hyperinsulinism. THPVS may continue to be of value. if only to regionalize the tumor. especially those in the pancreatic head and uncinate process so as to preclude noncurative operations on the body and tail of the pancreas.
Nonoperative observation of clinically occult arterial injuries: a prospective evaluation, Forty-seven patients with 50 clinically occult injuries of major arteries were studied prospectively to determine the natural history of these lesions and the safety of nonoperative management. Penetrating trauma was the predominant mechanism and lower extremity arteries were most commonly involved. The morphology of these arterial injuries included 22 cases of intimal flaps. 21 cases of segmental arterial narrowing. 6 pseudoaneurysms. and 1 acute arteriovenous fistula. There was one death as a result of unrelated causes and another three injuries operated on immediately after arteriographic diagnosis. The remaining 46 injuries were followed up nonoperatively by serial arteriography (39) or clinical examination (7) during a mean interval of 3.1 months (range. 3 days to 27 months). Complete resolution was documented for 29 injuries (63%). whereas 3 improved. 9 remained unchanged. and 5 worsened during the period of follow-up. All worsened cases involved small or occult pseudoaneurysms that subsequently enlarged and then underwent immediate surgical repair without subsequent morbidity. Because 89% of the followed injuries never required surgery. nonoperative observation appears to be a safe and effective management option for clinically occult arterial injuries.
Thromboxane biosynthesis in cardiovascular diseases, Sudden fissuring of an atherosclerotic plaque has been suggested as the primary trigger of transient spontaneous ischemia in both the coronary and cerebral circulation. Measurements of urinary 11-dehydro-TXB2 and 2.3-dinor-TXB2. as well as results of Aspirin trials. have suggested that episodic platelet activation at the site of this acute vascular lesion is mediated. at least partly. by enhanced thromboxane (TX) A2 biosynthesis. Thus. episodic increases in metabolite excretion have been detected in unstable angina. Aspirin (75-325 mg/day) prevents about one third of all fatal and nonfatal thrombotic events in this setting. That a similar "dynamic" thrombotic process occurs during the early phase of acute myocardial infarction is suggested by thromboxane metabolite measurements and by the results of the ISIS-2 trial showing a similar impact of short-term Aspirin therapy to that seen in unstable angina. Percutaneous transluminal coronary angioplasty is associated with transiently enhanced TXA2 biosynthesis and Aspirin-suppressable periprocedural thrombotic complications. On the other hand. both non-insulin-dependent diabetes mellitus and type IIa hypercholesterolemia are associated with a relatively reproducible and persisting abnormality of TXA2-dependent platelet function. This association is likely to reflect a systemic rather than localized stimulus to platelet activation and a continuous rather than episodic alteration. Low-dose (50 mg/day) Aspirin can largely suppress thromboxane metabolite excretion in both diseases. Thus. low-dose Aspirin and/or selective prostaglandin H2/TXA2-receptor antagonists may be important tools to test the hypothesis that TXA2-dependent platelet activation represents an important transducer of the enhanced thrombotic risk associated with these metabolic abnormalities.
Effect of Bay U 3405, a new thromboxane antagonist, on collagen-induced thromboembolism in rabbits, Bay U 3405 [(3R)-3-(4-fluorophenylsulfonamido)-1.2.3.4-tetrahydro-9- carbazolepropanoic acid] potently inhibits platelet aggregation. thromboxane A2-induced contraction of smooth muscles. and coronary artery thrombosis. We have previously demonstrated inhibition of arachidonic acid-induced sudden death by Bay U 3405. The purpose of this study was to investigate the effects of Bay U 3405 on thromboembolism provoked by collagen. Collagen fibrils dissolved in an isotonic glucose solution were injected into a marginal ear vein of anesthetized rabbits. Sudden death occurred within a few minutes due to elevated thromboxane A2 levels causing intravascular platelet aggregation and myocardial ischemia. In the vehicle-treated group. 100% of the animals died. One of the most prominent parameters was the massive fall in blood pressure. All animals pretreated with 10 mg/kg orally Bay U 3405 survived. showing only a transient hypotensive effect. Tracings of the electrocardiogram and heart rate were unchanged. Bay U 3405 will therefore be useful to elucidate the role of thromboxane A2 in various cardiovascular and respiratory diseases.
Preventing stroke by the modification of risk factors, Epidemiologic research has revealed the major risk factors in cerebrovascular disease. This review will concentrate on three important risk factors: elevated blood pressure. the most common and important. since it is responsible for up to 70% of all strokes; raised cholesterol; and smoking. These factors are important not only because they increase the risk of stroke. but also because they are amenable to modification by drugs. diet. or other interventions. Strategies to avoid stroke can either 1) try to produce substantial reductions. usually with drugs. in the level of the risk factor in the few individuals in the population with high levels (the "high-risk" approach). or 2) try to produce modest reductions in the level of the risk factor in every individual in the population. usually not with drugs but with lifestyle modification (the "mass" approach). The prevention of stroke could best be achieved through continuing medical efforts to deal with high-risk individuals and through political strategies to encourage a healthier lifestyle in the population as a whole.
Aspirin reduces the growth of medial and neointimal thickenings in balloon-injured rat carotid arteries, We analyzed the effect of Aspirin on the growth of experimentally induced vascular thickenings in rat carotid arteries. Vascular thickenings were induced by denudation of the endothelium in the left carotid artery with a balloon catheter. Administration of Aspirin-rich food (17.4 g/kg body wt/day) was started 1 week before and continued 2 weeks after injury. Nine rats were used. A control group of equal size received normal food. Sizes of the tunica media. the neointima. and the open vessel lumen were measured on cross sections of carotid segments with the aid of a videomorphometry system. The results show that in the Aspirin group. neointimal lesions are significantly smaller than in the control group (0.14 mm2 versus 0.23 mm2; p less than 0.5). Thickenings of the tunica media are also reduced (0.11 mm2 versus 0.12 mm2; p less than 0.5). It is suggested that Aspirin reduces both medial hypertrophy and neointimal outgrowth in injury-induced atherosclerosis.
Cytosolic free calcium during focal cerebral ischemia and the effects of nimodipine on calcium and histologic damage, The role of calcium as a mediator in neuronal death during ischemia is now quite strong. Evidence supporting this link includes studies in cell cultures and measurements of calcium accumulation in the mitochondria during ischemia. as well as direct measurements of shifts in extracellular calcium using microelectrodes. Since it is dangerously high concentrations of the intracellular free calcium that have been hypothesized to lead to neuronal damage. direct in vivo measurements of this parameter in ischemia are important. A technique for the measurement of intracellular free calcium is described. along with data from studies that dramatically demonstrate the time course of changes in intracellular free calcium induced by focal ischemia. Additional data are also presented that indicate that cellular damage can be attenuated by the use of agents that block calcium channels (nimodipine. which blocks voltage-sensitive calcium channels. and MK-801. which blocks receptor-operated channels) and support the concept that these agents owe their beneficial effects to their ability to reduce the accumulation of intracellular calcium.
Effect of nimodipine on acute ischemic stroke. Pooled results from five randomized trials, In a review of pooled data from five double-blind. placebo-controlled studies of nimodipine in acute ischemic stroke. we compared the effect of 120 mg nimodipine given orally with that of placebo. In the five studies. 871 patients were followed. and 781 adhered to entry and inclusion criteria. End points were mortality and outcome at the end of the treatment period (21 or 28 days). Outcome was assessed with Mathew's scale and the physician's clinical judgement. The treatment and control groups were well matched with respect to demographic data. risk factors. and baseline Mathew scores. In the treatment group. 34 patients (7.9%) died during the treatment period. whereas 54 (12.3%) in the control group died. corresponding with a mortality reduction of 36%. Significantly less neurologic impairment at the end of the treatment period was documented under nimodipine treatment. and this impairment improved more in patients with moderate-to-severe stroke (baseline Mathew score less than 66) if administration of nimodipine occurred within 12 hours after stroke onset or if the patient was more than 65 years old. The overall incidence of adverse reactions was relatively modest. and these were of minor severity; only a few appeared to have more than a remote relation to the study medication.
Effect of naproxen and sulindac on blood pressure response to atenolol, Twenty-eight patients with mild to moderate essential hypertension well controlled by atenolol entered a five-week. double-blind. placebo-controlled trial of the effects of sulindac and naproxen on blood pressure (BP) control. Atenolol alone was administered during weeks 1. 3. and 5. Naproxen or sulindac was administered with atenolol during week 2. with crossover during week 4. Data were analyzed for 27 of the patients (one dropped out after developing a skin rash). Naproxen significantly increased the systolic BP compared with placebo (mean 4.0 mm Hg; 95 percent confidence interval. 1.1-7.0; p less than 0.05). There were no significant differences in systolic BP during sulindac administration compared with placebo or naproxen. No significant effects on diastolic BP were observed. Weight was increased by naproxen and sulindac compared with placebo (mean 0.6-0.8 kg. p less than 0.05). although not to a clinically significant extent. One-week therapy with naproxen has a greater potential than sulindac to increase systolic BP in well-controlled hypertensive patients receiving atenolol; however. the increase is minor and unlikely to be of clinical significance.
Intravenous streptomycin, Streptomycin is an effective drug for the treatment of tuberculosis. It is currently recommended for use only by the intramuscular route. This method of drug delivery is accompanied by considerable pain which is unacceptable to many patients. With the advent of many improvements in intravenous therapy that have occurred in the past 40 years. reevaluation of the intravenous use of this drug is warranted. We describe the short-term use of intravenous streptomycin in four patients with pulmonary tuberculosis.
The pharmacist as a health consultant--ten years later, Pharmacists remain a readily accessible and trusted source of information about health. In order to assess the quality of counseling on health matters and the progress of the profession in this activity over the last decade. a study similar to one reported in 1978 was conducted. We visited 46 community pharmacies and requested advice from the pharmacists concerning the proper treatment of an infant with diarrhea. Interviewers volunteered no additional information. but questions asked by the pharmacist were answered according to a predetermined hypothetical case involving an 18-month-old infant with diarrhea and vomiting. Findings include the following: approximately one-third of the pharmacists recommended a product without caution and less than 20 percent inquired about fever. nausea. vomiting. diet. or the infant's condition. We believe pharmacists should approach health counseling with an increased awareness of the harmful potential in providing inappropriate medical information.
The potential for mental status changes associated with systemic absorption of anticholinergic ophthalmic medications: concerns in the elderly, Several cases have been reported of anticholinergic toxicity following the administration of commonly used parasympatholytic cycloplegics and mydriatics. Cases have been reported in children. adults. and the elderly. The risk of developing mental status changes secondary to anticholinergic ophthalmic medications is of particular concern in the elderly. Drug-induced mental status or behavior changes should not be mistaken for exacerbation of an underlying disorder or the onset of a new disease (e.g.. Alzheimer's disease. dementia). Clinicians should be aware of these potential complications. monitor for changes in mental status. and take appropriate action.
Fluconazole: a new triazole antifungal agent, Fluconazole is a fluorine-substituted. bis-triazole antifungal agent. Its mechanism of action. like that of other azoles. involves interruption of the conversion of lanosterol to ergosterol via binding to fungal cytochrome P-450 and subsequent disruption of fungal membranes. Activity against Aspergillus spp.. Blastomyces dermatitidis. Candida spp.. Coccidioides immitis. Cryptococcus neoformans. Histoplasma capsulatum. and Paracoccidioides brasiliensis has been demonstrated in several animal models. Fluconazole can be administered both orally and intravenously. Mean peak serum concentrations achieved in human volunteers after 50 and 100 mg (oral) are 3.1 and 7.0 mumols/L respectively. Protein binding is low (11 percent) and cerebrospinal fluid to serum ratio is 0.58 to 0.89. Serum half-life is long (22-32 hours) and elimination is via renal clearance of unchanged drug. Clinical trials and reports support the use of fluconazole in treatment of candidiasis. particularly oropharyngeal and esophageal infections in immunocompromised hosts. Fluconazole is also approved for initial and suppressive therapy of cryptococcal meningitis. Its role in management of systemic fungal infections will be further defined once results of other comparative trials become available. Fluconazole is well tolerated and its effects on steroidogenesis are markedly less than those of ketoconazole. Antipyrine clearance is not altered at low doses (50 mg) of fluconazole; however. drug interactions with the use of larger doses can be anticipated with agents such as cyclosporin. phenytoin. oral hypoglycemics. and warfarin. Rifampin appears to decrease metabolic clearance of fluconazole. Fluconazole is available as oral and parenteral formulations. Once-daily doses of 100-400 mg are recommended. Dosage reduction is advised for patients with impaired renal function.
Warner-Lambert/Parke-Davis Award lecture. Pathobiology of the intestinal epithelial barrier, The major route of passive permeation across intestinal epithelia is paracellular. The intercellular tight junction lies in and serves as the rate-limiting barrier in this paracellular pathway. Once viewed as static. it is now clear that the structure and permeability of the tight junction is highly dynamic. Not only may inflammatory events (cytokines. neutrophil transmigration) reversibly effect the tight junction but this key barrier also is regulated by physiologic events such as activation of absorptive cell Na(+)-nutrient cotransporters. Such physiologic regulation of the junction is of major importance to the absorption of nutrients via parcellular solvent drag.
Myogenic regulatory protein (MyoD1) expression in childhood solid tumors: diagnostic utility in rhabdomyosarcoma, Transcripts for the muscle regulatory gene MyoD1 are expressed during normal skeletal muscle myogenesis and in rhabdomyosarcomas but not in other tissues or in soft-tissue sarcomas. Here we report the distribution of MyoD1 protein. determined by reactivity with anti-MyoD1 polyclonal sera in normal tissues. rhabdomyosarcoma cell lines. and in a variety of pediatric solid tumors. The distribution of MyoD1 protein was highly restricted in normal tissues and was detected only in fetal skeletal muscle and more faintly in adult skeletal muscle. All six human rhabdomyosarcoma cell lines analyzed expressed MyoD1 mRNA transcripts as well as immunoreactive protein. The immunohistochemical expression of MyoD1 protein was then examined in 49 surgical specimens from a variety of pediatric solid tumors. Each of 16 rhabdomyosarcoma specimens was positive for MyoD1. including four that did not express the intermediate filament protein desmin. Two of five specimens originally designated sarcoma type indeterminate (STI) and two of three specimens originally designated extraosseous Ewing's sarcoma (EOE) were positive for MyoD1. suggesting commitment to myogenic differentiation. Three of eight Wilms' tumors. which also expressed desmin and had clearly evident myogenic elements. also were positive for MyoD1. Tumors that failed to express MyoD1 protein included neuroblastoma. primitive neuroectodermal tumor. non-Hodgkins lymphoma. embryonal sarcoma of the liver. malignant fibrous histiocytoma. malignant rhabdoid tumor. and Ewing's sarcoma of the bone. These results indicate that expression of MyoD1 protein is highly restricted in normal human tissues and that expression of this gene product in malignant tissue may be diagnostic for rhabdomyosarcoma. Furthermore MyoD1 staining may be a valuable adjunct in the classification of pediatric soft-tissue sarcomas.
Vimentin expression appears to be associated with poor prognosis in node-negative ductal NOS breast carcinomas, Vimentin expression in tumors from 83 node-negative and 112 node-positive patients with infiltrative ductal not otherwise specified (NOS) breast carcinomas has been compared with 5-year survival. For node-negative. but not for node-positive patients. there was a significant inverse relation between vimentin expression and survival. Five-year survival of node-negative patients with vimentin-positive tumors was significantly worse compared with vimentin-negative tumors (P less than 0.0001). In the node-negative group. only 36% of patients with vimentin-positive tumors but 82% of patients with vimentin-negative tumors survived 5 years. Tumors of all eight node-negative patients with ductal NOS cancer who died in the first 27 months expressed vimentin. Multivariate analysis of the node-negative group showed a strong correlation of vimentin expression and overall survival. but weak and not significant correlation between histologic grade or size and overall survival at 5 years. Thus vimentin expression seems to be a strong indicator of poor prognosis in node-negative ductal NOS breast carcinomas.
Study of neu-protein expression in mammary Paget's disease with and without underlying breast carcinoma and in extramammary Paget's disease, Correlation between neu/c-erbB-2/Her-2 gene amplification and overexpression of the neu gene product has been reported in tumors of glandular origin. especially ductal breast carcinomas. Formalin-fixed and dewaxed sections from 23 cases of mammary (MPD) and 9 cases of extramammary (EPD) Paget's disease were immunohistochemically stained by means of the monoclonal antibody 3B5 directed against an intracellular domain of the neu gene protein. All MPDs exhibited a distinct membrane staining of tumor cells independent of the presence of ductal breast carcinomas found in 18 cases. All these breast carcinomas also were positive for neu staining. In contrast to MPD. all EPDs were negative. Normal epidermis was always negative. Northern blot analysis sustained the immunohistologic findings in that the presence of neu mRNA could be demonstrated in two of three cases with MPD. Negativity in one case was due to dilution effects by nontumor cells. Our results suggest that Paget cells of mammary and extramammary localization. although very similar phenotypically. derive from different genetic accidents. Furthermore neu positivity in all MPDs and all underlying ductal carcinomas suggests common genetic alterations for both tumors. However the finding of five neu protein-positive MPDs without associated ductal breast carcinomas may suggest a somewhat different transformation process.
Detection of HTLV-I proviral sequences in CD30-positive large cell cutaneous T-cell lymphomas, To investigate the possibility that cutaneous T-cell lymphomas of large cell type may be associated with human T-cell leukemia/lymphoma virus type I infection in nonendemic regions. tissue samples from six cases of large cell cutaneous T-cell lymphoma and four cases of small cell cutaneous T-cell lymphoma were screened for the presence of integrated proviral human T-cell leukemia/lymphoma virus type I DNA. Combined use of Southern blot hybridization and enzymatic DNA amplification revealed human T-cell leukemia/lymphoma virus type I-specific sequences in all cases of large cell cutaneous T-cell lymphoma and in none of the cases of small cell cutaneous T-cell lymphoma. These results suggest that in nonendemic areas. a significant proportion of large cell cutaneous T-cell lymphoma cases are associated with human T-cell leukemia/lymphoma virus type I.
Capillary leakage in inflammation. A study by vascular labeling, The local injection of pure inflammatory mediators induces venular leakage. To test the effect of endogenous mediators from dying tissue on vascular leakage. the authors devised an experimental model simulating an infarct. whereby living vessels would be exposed to fragments of organs undergoing aseptic necrosis. Tissues from donor rats were implanted aseptically in the cremasteric sac. Control rats were implanted with materials deemed to be as close as possible to nonirritating: boiled tissues and spheres of Teflon or glass. At different points the rats were injected intravenously with carbon black and killed an hour later. Whole cremaster mounts showed that vascular labeling was strictly venular up to 8 hours. mixed with capillary labeling between 12 and 24 hours. and mainly or exclusively capillary at 48 hours. Histology showed an acute inflammatory infiltrate in the labeled areas. A similar but weaker labeling pattern accompanied by milder inflammation was seen in controls. These results indicate that the vascular leakage in aseptic inflammation is biphasic. first venular. then capillary; and that the capillary phase is induced by the inflammatory reaction itself. possibly through a form of diffuse angiogenesis.
Immunodetection of the metastasis-associated laminin receptor in human breast cancer cells obtained by fine-needle aspiration biopsy, Fine-needle aspiration biopsy of the breast is a very useful technique for the evaluation of a suspect lesion before surgical removal. Increased expression of the 67-kd laminin receptor has been associated with the metastatic phenotype of cancer cells. particularly in colon and breast cancers. In this study. the expression of laminin receptor was evaluated using the immunoperoxidase technique in 81 breast aspirates (26 benign and 55 neoplastic lesions). Cells obtained from benign samples exhibited a low level of laminin receptor antigen detected by affinity-purified antibody raised against a cDNA-derived laminin receptor peptide. In contrast. 71% of smears obtained from malignant breast lesions contained cells that were strongly stained by the antibody. Heterogeneous expression of the laminin receptor was noted in both breast aspirates and fixed tissue specimens. These data suggest that the immunodetection of laminin receptor in cells obtained by fine-needle aspiration of breast lesions could be a valuable adjunct in the prognostic evaluation of breast lesions.
Pathophysiologic effect of interleukin-1b in the rabbit retina, Interleukin-1 is a potent immunomodulator and has been shown to initiate many aspects of the inflammatory response. To determine the effects of IL-1b in the central nervous system (CNS). the rabbit retina was used. adjacent to which factors can be injected with minimal trauma and both pathologic and physiologic effects can be monitored. Intravitreal injection of 300 units of IL-1b induced an alteration in the visual evoked potentials (VEP) that was associated with marked intravascular red blood cell accumulations. hemorrhage. and cellular inflammation of the epiretinal vessels. Analysis of these events showed slowing and occasional hyper-excitability of the compound action potential of the optic tract and of the cortical VEP that correlate with the maximum inflammatory response. Histologic studies show the following: no apparent response occurs within the first 1.5 hours after intraocular challenge; and between 3 and 6 hours after injection an extensive intravascular red blood cell accumulation and progressive hemorrhage is accompanied by an increase in the number of mononuclear (MN) cells and the appearance of polymorphonuclear (PMN) cells. Polymorphonuclear cells continue to increase with time to give a single wave of inflammation that peaks 24 hours after injection. while the number of MN cells steadily increases. These events are associated with changes in the permeability of the blood-brain barrier and correlate with the electrophysiologic dysfunctions. Forty-one hours after injection. MN inflammation. reactive gliosis. and residual PMN inflammation are evident. Neutralization with specific antibody inhibited the responses through 6 hours after injection. It is concluded that the rabbit retina provides a valuable model for the in vivo analysis of CNS inflammation.
Discordant expression of antigens between intraepidermal and intradermal T cells in mycosis fungoides, Using immunohistochemical methods. the authors studied the expression of pan-T- and majority-T-cell antigens (CD5. CD2. CD3. TCR-beta. CD7) and T-cell subset antigens (CD4. CD8) in cutaneous T cells in mycosis fungoides (MF) (177 biopsies from 124 patients) and a variety of inflammatory lesions (45 biopsies from 45 patients). The authors detected the absence of pan-T- or majority-T-cell antigens. or of both T-cell subset antigens. from T cells in the epidermis but not the dermis in 15 MF biopsies (8%) from 11 MF patients (9%). but in none of the inflammatory skin lesions. The opposite picture. characterized by lack of antigen expression by the dermal T cells only. was not seen in any of the MF or inflammatory lesions. The absence of antigen expression by epidermal but not dermal T cells. which the authors have termed antigen discordance. was most prevalent for CD5. CD7. and TCR-beta. each being discordant in 6% to 7% of MF cases or patients tested. Among the MF biopsies showing antigen discordance. 14 of 15 biospies (93%) from 10 of 11 patients (91%) were discordant for two or more antigens. Antigen discordance was not an artifact of treatment. because none of the patients showing discordance was receiving treatment at the time of their initial discordant biopsy. The discordance was the only immunophenotypic abnormality detected in 8 of 15 (53%) of the discordant MF biopsies. Thus. this antigen discordance was an important diagnostic feature that allowed the immunophenotypic distinction of MF from a variety of inflammatory skin lesions.
Distribution of endogenous albumin in the glomerular wall of proteinuric patients, Glomerular proteinuria seems to be related. in part. to loss or impairment of the normal barrier function of the glomerular capillary wall. To investigate the functional properties of this barrier. endogenous albumin was revealed in the glomerular wall of proteinuric patients and compared with a nonproteinuric control by immunoelectron microscopy using the protein A-gold method. In the control biopsy. peaks of albumin accumulation were noted in the subendothelial area and in the inner portion of the lamina densa. with gradual tapering of the distribution toward the epithelial side of the basement membrane. The urinary space and epithelial cells were weakly labeled. In tissues from proteinuric patients. albumin was distributed throughout the entire width of the glomerular basement membrane. although the pattern of accumulation varied between patients. The urinary space showed significant labeling associated with some flocculent material. Mesangial areas were heavily labeled in tissues from both control and proteinuric patients. In the latter. lysozomes in glomerular and tubular epithelial cells also accumulated albumin. which is evidence of reabsorption. These results reveal the existence. in normal conditions. of a barrier located in the subendothelial area of the glomerular basement membrane. the loss of which. as in the idiopathic nephrotic syndrome. leads to diffuse distribution of albumin in the glomerular capillary wall.
Proliferation markers Ki-67 and p105 in soft-tissue lesions. Correlation with DNA flow cytometric characteristics, Frozen tissue immunoreactivity with Ki-67. a monoclonal antibody that recognizes a nuclear antigen in nonresting or proliferating cells. was compared to DNA flow cytometry results (from fresh tissue) in a diverse group of 60 soft-tissue lesions. Both DNA index and Ki-67 score were independently reported to be associated with grade and prognosis in sarcomas. but no direct comparison of these two variables was made. It was attempted to measure proliferative activity in fixed paraffin-embedded tissues immunohistochemically in a subset of lesions using an antibody to another nuclear proliferation antigen. p105. Lesions were given a grade according to lesion category (reactive. 1; benign. 2; low-grade malignant. 3; and high-grade malignant. 4). Ki-67 reactivity correlated relatively well with this grading system (r = 0.59); benign lesions usually exhibited a low Ki-67 score and malignant lesions usually but not always exhibited a high score. For example. some malignant fibrous histiocytomas contained only rare positive cells. Some disparity between Ki-67 score and grade and within histologic types indicates some independence from these features. a fact that may be important when correlation with prognosis is performed. However Ki-67 did not correlate well with flow data such as percentage S phase (r = 0.30). percentage S + G2M phases (r = 0.37). or DNA index (r = 0.39). This probably is due to the fact that Ki-67 also marks cells in the G1 phase. whereas these are excluded in flow data analyses. Anti-p105 highlighted almost all nuclei in all cases tested. including fibromatosis. and did not correlate with Ki-67 score. histologic grade or DNA flow cytometric data. Results with p105 could not be favorably affected by titration experiments. It is reasonable to conclude that the Ki-67 score is a variable related to but independent of histologic grade. histologic type. and DNA flow values. Whether it is prognostically important in human sarcomas. as has been suggested. awaits further clinicopathologic study.
Alternative splicing of endothelial cell fibronectin mRNA in the IIICS region. Functional significance, Transforming growth factor-beta 1 (TGF-beta 1) is thought to play a role in modulating vascular cell function in vivo. In vitro. it decreases endothelial cell proliferation and migration. We postulated that these biologic activities could be mediated through TGF-beta 1 modulation of specific gene expression. Therefore we differentially screened a human umbilical vein endothelial cell cDNA library with cDNAs prepared from both untreated and TGF-beta 1-treated bovine aortic endothelial cells. Using this technique. we isolated many TGF-beta 1-induced cDNA clones. Sequence analysis of these cDNAs showed that many of them corresponded to alternatively spliced fibronectin mRNAs. These fibronectin clones all contained the extradomain I (ED I) but three different forms of the type III connecting segment (IIICS). These different fibronectin cDNAs were expressed in bacteria and the recombinant proteins used to study the effects of IIICS alternative splicing on cell attachment. spreading. and migration in bovine aortic endothelial and smooth muscle cells and B16F10 melanoma cells. The results of these experiments show that attachment and spreading of bovine aortic endothelial and smooth muscle cells depend primarily on the presence of the Arg-Gly-Asp-Ser (RGDS) sequence in the recombinant fibronectin proteins. However attachment and spreading of bovine aortic endothelial cells are modulated by alternative splicing in the IIICS region. Specifically splicing of the IIICS region decreases spreading and increases migration rates of the endothelial cells. On the contrary. using a cell line (B16F10 melanoma cells) that is known not to require the RGDS sequence for adhesion confirmed previous findings that B16F10 melanoma cells do not require the presence of the RGDS sequence for attachment and spreading. Indeed B16F10 cells were able to attach and spread on two recombinant proteins that did not contain the RGDS sequence. However attachment and spreading of B16F10 were dramatically inhibited when a 75-base pair DNA fragment was removed from the 5' end of the IIICS region. These results suggest that various regions of the fibronectin molecule may be able to interact with different cell populations to promote cell attachment and spreading. and that alternative splicing may modulate this process.
A three-dimensional system for long-term culture of human colorectal adenomas, Studies of the adenoma-carcinoma sequence in the colon and rectum have been limited by the paucity of experimental models of adenoma growth and progression. Progress recently was reported in the development of monolayer culture systems. The principal objective of this study was to develop a primary culture system for colorectal adenomas that would simulate three-dimensional in vivo growth. We used a calcium alginate encapsulation technique that was previously described for established tumor cell lines. Briefly. fresh resected specimens were washed. minced into small multicellular particles called microadenomas. and encapsulated in 1% calcium alginate pellets. The pellets were maintained in minimum essential medium containing 10% fetal bovine serum at 37 degrees C in humidified atmosphere of 95% air. 5% CO2. Ten of eleven adenomas. including six tubular. three tubulovillous. and one villous have been successfully cultured for 34 to 162 days. Cell viability was confirmed histologically by light and electron microscopy. The cells were characterized as epithelial by morphologic features and ultrastructural studies. which showed a high degree of cellular differentiation. including villous brush borders and many desmosomes. Both tubular and villuslike structures have been observed in vitro. correlating in some cases with the histology of the parent adenoma. Measurements of proliferative activity by [3H]thymidine autoradiography or immunohistochemical staining with the monoclonal antibody Ki-67 demonstrated growth fractions of 9% to 25%. A simple. highly efficient primary culture system was developed for the long-term maintenance of adenomas that promotes three-dimensional growth patterns and growth rates analogous to those seen in vivo. This model provides an opportunity to develop an experimental system for longitudinal studies of pathologic and molecular parameters in adenoma progression to carcinoma.
Childhood traumas: an outline and overview, Childhood psychic trauma appears to be a crucial etiological factor in the development of a number of serious disorders both in childhood and in adulthood. Like childhood rheumatic fever. psychic trauma sets a number of different problems into motion. any of which may lead to a definable mental condition. The author suggests four characteristics related to childhood trauma that appear to last for long periods of life. no matter what diagnosis the patient eventually receives. These are visualized or otherwise repeatedly perceived memories of the traumatic event. repetitive behaviors. trauma-specific fears. and changed attitudes about people. life. and the future. She divides childhood trauma into two basic types and defines the findings that can be used to characterize each of these types. Type I trauma includes full. detailed memories. "omens." and misperceptions. Type II trauma includes denial and numbing. self-hypnosis and dissociation. and rage. Crossover conditions often occur after sudden. shocking deaths or accidents that leave children handicapped. In these instances. characteristics of both type I and type II childhood traumas exist side by side. There may be considerable sadness. Each finding of childhood trauma discussed by the author is illustrated with one or two case examples.
Axis II comorbidity in substance abusers, OBJECTIVE: To assess the complex relationship between substance abuse and personality disorders. the authors determined the prevalence of personality disorders in a group of middle-class substance abusers and compared the subjects who had personality disorders with those who did not. METHOD: The subjects were drawn from patients consecutively admitted to an inpatient substance abuse program in a private psychiatric hospital; they were the first 100 who agreed to participate. Substance dependence was diagnosed according to DSM-III-R. and the patients were assessed with the Structured Clinical Interview for DSM-III-R Personality Disorders. Alcohol Use Inventory. MMPI. Health and Daily Living Form. Shipley Institute of Living Scale. and measures of chemical use and life satisfaction. RESULTS: Of the 100 substance abusers. 57 had personality disorders. These patients differed significantly from the 43 patients without personality disorders in several ways: they had greater involvement with illegal drugs. had different patterns of alcohol use. had greater psychopathology. were less satisfied with their lives. and were more impulsive. isolated. and depressed. CONCLUSIONS: Because of the marked differences between the substance abusers with and without personality disorders. a uniform approach to substance abuse treatment may be inadequate.
Psychiatric morbidity in adult inpatients with childhood histories of sexual and physical abuse, OBJECTIVE: To extend the knowledge on long-term effects of childhood abuse in psychiatric patients to a large sample. the authors explored childhood sexual and physical abuse in adult inpatients over 1.040 consecutive admissions. METHOD: The 947 patients were admitted to a tertiary-care military medical center. Each patient was interviewed. and abuse history. DSM-III-R diagnosis. and other characteristics were recorded. RESULTS: The prevalence of reported childhood abuse was 18% overall: 9% for sexual abuse (with or without physical abuse). 10% for physical abuse (with or without sexual abuse). and 3% for combined abuse. More female than male patients reported abuse. Alcohol use disorders were more common in victims of physical or combined abuse than in sexually abused or nonabused patients. Axis II diagnoses. particularly borderline personality disorder. were more frequent in abuse victims than in nonabused patients. Histories of drug and alcohol abuse were more common in patients reporting physical or combined abuse than in nonabused patients. Suicidality was also more frequent in abused than nonabused inpatients and was noted in 79% of the patients with histories of combined abuse. Combined abuse in women and physical abuse in men were associated with a family history of psychiatric illness. most commonly alcoholism in male relatives. CONCLUSIONS: These findings emphasize the need for greater attention to family dynamics. aggressive diagnosis and treatment of alcoholism within the family. and. especially. determination of patients' abuse histories. even if repeated questioning is necessary.
Sleep disturbances in survivors of the Nazi Holocaust, OBJECTIVE AND METHOD: Sleep disturbances are commonly reported by victims of extraordinary stress and can persist for decades. This study was designed to test the hypothesis that survivors of the Nazi Holocaust would have significantly more and different sleep problems than depressed and healthy comparison subjects and that the severity of the survivors' problems would be correlated with length of time spent in a concentration camp. Forty-two survivors. 37 depressed patients. and 54 healthy subjects of about the same age. all living in the community. described their sleep patterns over the preceding month on the Pittsburgh Sleep Quality Index. a self-rating instrument that inquires about quality. latency. duration. efficiency. and disturbances of sleep. use of sleep medication. and daytime dysfunction. RESULTS: The survivors had significantly greater sleep impairment than the healthy comparison subjects. as measured by all subscales of the index. but had less impairment than the depressed patients except on the sleep disturbances and daytime dysfunction subscales. However. for specific items within these subscales. survivors had significantly more frequent awakenings due to bad dreams and had less loss of enthusiasm than the depressed subjects. Sleep disturbances and frequency of nightmares were significantly and positively correlated with the duration of the survivors' internment in concentration camps. CONCLUSIONS: These findings suggest that for some Holocaust survivors. impaired sleep and frequent nightmares are considerable problems even 45 years after liberation.
Cognitive and behavioral effects of the coadministration of dextroamphetamine and haloperidol in schizophrenia, OBJECTIVE: The authors sought to determine if an acute dose of dextroamphetamine might have positive effects on affect and cognition in schizophrenic patients maintained on a regimen of haloperidol and. if so. what variables might predict such improvements. METHOD: Twenty-one patients with chronic schizophrenia who were hospitalized on a research ward received a single oral dose of dextroamphetamine (0.25 mg/kg) in a double-blind. placebo-controlled. crossover study. All patients were receiving 0.4 mg/kg per day of haloperidol. Cognitive tests. motor tests. global ratings. mood ratings. and videotape ratings were used to determine the effect of the coadministration of these drugs. Ventricle-brain ratios derived from CT scans were used to predict response to the coadministration of these drugs. RESULTS: Amphetamine improved performance on a measure of concept formation on the Wisconsin Card Sorting Test but did not result in changes in performance on tests of memory or attention. As a group. the patients were more active and performed psychomotor tests more quickly while receiving amphetamine. Six patients were judged by clinical raters to have improved in terms of affect. cooperation. and engagement with the environment. Improvement was associated with enlarged cerebral ventricles and increases in blink rate from the placebo to the active drug condition. No patient unequivocally worsened. CONCLUSIONS: These results may be consistent with the theory that coadministration of amphetamine and haloperidol produces relatively selective enhancement of cortical dopaminergic activity. However. because of the acute nature of the trial and the specialized research environment in which it was conducted. the authors do not advocate amphetamine as a routine clinical treatment of schizophrenia.
Rational ordering of electrolytes in the emergency department, STUDY OBJECTIVE: To validate the predictive abilities of a retrospectively developed set of clinical criteria for detecting clinically significant electrolyte abnormalities. using a different patient population. DESIGN: Cross-sectional study. SETTING: The emergency department of a busy public hospital. TYPE OF PARTICIPANTS: Nine hundred eighty-two patients on whom the emergency physician ordered serum electrolytes. INTERVENTIONS: The predictive properties of ten clinical criteria were evaluated; these included poor oral intake. vomiting. chronic hypertension. taking a diuretic. recent seizure. muscle weakness. age of 65 years or more. alcoholism. abnormal mental status. and recent history of electrolyte abnormality. MEASUREMENTS AND MAIN RESULTS: Seven hundred thirty patients (74.3%) had one or more electrolytes outside of the laboratory normal range. but only 143 (14.6%) had clinically significant electrolyte abnormalities. The clinical criteria predicted 135 of the clinically significant electrolyte abnormalities (sensitivity. 94.4%). When the eight "false-negative" cases were reviewed. none of the electrolyte abnormalities affected patient outcome. Implementation of the criteria would have avoided unnecessary testing in 233 patients (23.7%). CONCLUSION: Although no set of clinical criteria can eliminate the need for clinical judgment. use of a set of clinical criteria could substantially decrease electrolyte ordering without compromising patient care.
High-dose epinephrine improves outcome from pediatric cardiac arrest, STUDY OBJECTIVE: Animal studies suggest that the standard dose of epinephrine (SDE) for treatment of cardiac arrest in human beings may be too low. We compared the outcome after SDE with that after high-dose epinephrine (HDE) in children with refractory cardiac arrest. DESIGN: Prospective intervention versus historic control groups. TYPE OF PARTICIPANTS: Two similar groups of 20 consecutive patients each (median ages. 2.5 and 3 years) with witnessed cardiac arrest who remained in arrest after at least two SDEs (0.01 mg/kg). INTERVENTIONS: Treatment with an additional SDE versus HDE (0.2 mg/kg). MEASUREMENTS AND MAIN RESULTS: The rates of return of spontaneous circulation and long-term survival were compared. Fourteen of the HDE group (70%) had return of spontaneous circulation. whereas none of the SDE group did (P less than .001). Eight children survived to discharge after HDE. and three were neurologically intact at follow-up. No significant toxicity from HDE was observed. CONCLUSION: HDE provided a higher return of spontaneous circulation rate and a better long-term outcome than SDE in our series of pediatric cardiac arrest. HDE may warrant incorporation into standard resuscitation protocols at an early enough point to prevent irreversible brain injury.
A prospective analysis of intramuscular meperidine, promethazine, and chlorpromazine in pediatric emergency department patients, STUDY OBJECTIVE: To examine physiologic responses and efficacy of 2. 1. and 1 mg/kg IM meperidine. promethazine. and chlorpromazine (MPC). respectively. in children. DESIGN: Prospective. unblinded trial. SETTING: A university and community emergency department. PATIENTS: Sixty-three hemodynamically and neurologically stable children. INTERVENTION: Single dose of IM MPC. MEASUREMENTS AND MAIN RESULTS: Serial respirations. heart rate. arterial systolic blood pressure. oxygen saturation. and Glasgow Coma Scale were measured at 30-minute intervals. Effectiveness was assessed by two independent observers using separate visual analog scales for cooperation and sedation. Times to sleep (27 +/- 24 minutes). sitting upright (103 +/- 87 minutes). ED discharge (4.7 +/- 2.4 hours). eating (11 +/- 7.9 hours). and normal behavior (19 +/- 15 hours) were acceptable. Minor. but statistically significant. changes in respiration rate (-1.9 +/- 0.4). heart rate (+4.5 +/- 1.8). oxygen saturation (-0.7 +/- 0.3%). and Glasgow Coma Scale (-2.5 +/- 0.6) occurred for 120 minutes after MPC. No serious complications or resuscitation were required. Mean visual analog scale scores were 5.0/10.4 or more in 71% of cases. with interobserver agreement very good (cooperation. r = .79; effectiveness. r = .80). Twenty-nine percent of children were judged insufficiently sedated. CONCLUSION: IM MPC is a safe and generally effective agent for ED procedures in selected children.
Comparison of rectal, axillary, and tympanic membrane temperatures in infants and young children, STUDY OBJECTIVE: To evaluate the reliability of a tympanic membrane thermometer in detecting fever in young children presenting to the emergency department. SETTING: Pediatric emergency department in an urban teaching hospital. DESIGN/MEASUREMENT/PARTICIPANTS: Temperature measurements were obtained sequentially at three body sites in children less than 3 years old presenting to the pediatric ED. Axillary and rectal temperatures were obtained with an electronic thermistor probe (Diatek 500). and tympanic membrane temperatures were obtained with a noncontact. infrared sensing device (First TEMP). Patients were stratified by age. ear canal patency. presence of otitis media. and rectal temperature. RESULTS: Of 224 patients enrolled. 87 (39%) were febrile. Overall correlation of axillary and tympanic membrane measurements to rectal for all strata was .75 (P = .001) and .81 (P = .001). respectively. Sensitivity in detecting fever for axillary and tympanic membrane sites was .48 and .55. respectively. Otitis media and ear patency did not influence correlation of tympanic membrane measurements. Low tympanic membrane temperature sensitivity may be a result of probe configuration. CONCLUSION: Tympanic membrane and axillary temperatures should be viewed with caution in children less than 3 years old as neither can detect fever reliably.
Clinical features of misdiagnosed appendicitis in children, STUDY OBJECTIVE: To compare clinical features of children with misdiagnosed appendicitis with those of children with appendicitis initially diagnosed correctly. DESIGN: Retrospective review of hospital. emergency department. and clinic records. SETTING: University medical center with annual ED census of 40.000 patients. PARTICIPANTS: Children less than 13 years old admitted between May 1. 1979. and April 30. 1989. with a discharge diagnosis of appendicitis. MEASUREMENTS: Records were reviewed for historical. physical examination. laboratory. and pathologic features for all patients on their initial presentation to a physician and on final presentation during which the correct diagnosis was made. Using chi 2 analysis and Student's test. clinical features of misdiagnosed patients and patients diagnosed correctly were compared. RESULTS: One hundred eighty-one cases were identified with 50 initially misdiagnosed. On initial presentation. misdiagnosed patients were younger and more likely to have vomiting before pain onset. constipation. diarrhea. dysuria. and signs and symptoms of upper respiratory infections. Misdiagnosed cases were less likely to have right lower quadrant tenderness and documentation of bowel sounds. peritoneal signs. and rectal examinations. On final presentation. misdiagnosed patients were more likely to have pain duration of more than two days. temperature of more than 38.3 C. and to appear lethargic and irritable (P less than .05 for all measurements). CONCLUSION: Clinical features of children with misdiagnosed appendicitis differ from those of children with appendicitis initially diagnosed correctly.
Systemic atropine administration during cardiac arrest does not cause fixed and dilated pupils, OBJECTIVES: Systemic administration of atropine during CPR may postpone brain death determination because of its reputed ability to produce fixed and dilated pupils. We studied the effect of atropine administered in the usual doses as an adjunct to endotracheal intubation and for cardiac arrest to determine if it would interfere with neurological assessment. DESIGN: Two groups of children were studied. Group 1 consisted of 28 patients who received atropine (0.03 +/- 0.003 mg/kg) prior to endotracheal intubation. Group 2 consisted of 21 patients previously without evidence of brainstem disease who suffered a witnessed arrest and had prompt return of spontaneous circulation and received an atropine dose of 0.03 +/- 0.01 mg/kg. RESULTS: In group 1. pupillary size averaged 4.02 +/- 0.78 mm before and 4.75 mm +/- .84 mm after atropine (P less than .001). In group 2. the pupillary examination was conducted 30 minutes after return of spontaneous circulation. The pupillary diameter was 4.80 +/- 0.91 mm. All pupils were reactive to light in both groups. CONCLUSION: Atropine administration in conventional dose causes slight pupillary dilation but does not abolish pupillary light reactivity.
Accidental firearm fatalities among New Mexico children, STUDY HYPOTHESIS: Risk factors associated with unintentional gunshot fatalities among children include gender and race of the decedent. type of firearm used. and whether loaded guns are stored within the home. STUDY POPULATION: All New Mexico children 0 to 14 years old unintentionally killed by a firearm between 1984 and 1988. METHODS: The New Mexico Office of the Medical Investigator master mortality file was reviewed retrospectively to identify all unintentional firearm fatalities occurring in New Mexico children during a five-year period. Medical investigator. autopsy. and police reports were analyzed to identify epidemiologic factors associated with these deaths. Chi-square and Fisher's exact tests were used to analyze the data. RESULTS: Twenty-five unintentional firearm fatalities were identified. These deaths occurred most frequently among children playing with loaded firearms found within the home. A disproportionate number involved handguns. CONCLUSIONS: The study results provide a basis for preventive strategies that limit accessibility or decrease lethality of loaded firearms within the home.
Core temperature measurement in hypovolemic resuscitation, STUDY OBJECTIVES: Accurate core temperature measurement in severely hypovolemic patients can be difficult to achieve. We used a dog model to determine both a convenient method of measuring core temperature and the relative accuracy of the multiple sites. DESIGN: Prospective laboratory (animal model) study. SETTING: Operating suites in the Animal Care Department. PARTICIPANTS: Eight adult. anesthetized greyhound dogs. INTERVENTIONS: Continuous temperature monitoring by thermistors placed in the brain. central vein. tympanic membrane. bladder. rectum. esophagus. and subcutaneous tissue. Hemorrhage to 65% initial intravascular volume and autologous transfusion of cooled blood. during which serial temperature measurements were recorded. MEASUREMENTS AND MAIN RESULTS: The readings were analyzed with Pearson's correlation coefficient. Brain temperature correlated very well with tympanic membrane temperature throughout the course (r = .869. P less than .0005). Rectum. bladder. and esophagus also correlated well with brain. Central venous temperature. however. correlated poorly with temperatures at all other sites. reflecting the marked swings in intravascular temperature caused by cold transfusion. These wide variations were damped at the other sites. The best correlation of central venous temperature was with brain and bladder. although tympanic membrane correlation was fair. CONCLUSIONS: Because intravascular hypothermia appears to be the source of the arrhythmias and hemostatic abnormalities often seen during the early resuscitation of hypovolemic patients. our results suggest bladder or tympanic membrane as the initial temperature site. After the initial resuscitation. end organ (eg. brain) temperature is the most important and is most accurately reflected by tympanic membrane temperature.
Under-reporting of contaminated needlestick injuries in emergency health care workers, STUDY HYPOTHESIS: There is considerable under-reporting of contaminated occupational needlestick and other sharp object injuries among emergency health care workers. POPULATION: A convenience sample of emergency physicians. emergency nurses. and emergency medical technicians (EMTs). METHODS: A survey instrument eliciting demographic and work-related factors was developed and administered; survey items included age. sex. occupation. years in occupation. number of procedures performed per week. number of contaminated needlestick (and other "sharps") injuries recalled. and number of these injuries formally reported during the previous five years. Nonsegmented visual analog scales were used to assess eight attitudes possibly associated with nonreporting. Analysis was by analysis of variance and multiple linear regression with stepwise variable election. RESULTS: Two hundred fifty-nine subjects recalled 643 contaminated exposures during the five-year study period. but only 228 (35%) were formally reported. One or more injuries occurred in 55% of EMTs compared with 72% of nurses and 80% of physicians (P less than .05). Physicians recalled a mean of 3.8 contaminated exposures. whereas nurses recalled 2.8 and EMTs recalled only 1.8 (P less than .05). Physicians formally reported a mean of 0.26 exposures. whereas EMTs reported 0.85 and nurses reported 1.25 (P less than .05). Physicians formally reported only one eighth of their injuries compared with EMTs and nurses. who each reported two thirds of these events (P less than .05). Perception of risk. occupation. years in occupation. and concern about excessive paperwork were the most powerful predictors of low reporting rate (P less than .05). CONCLUSIONS: Work-related contaminated sharp object injuries are under-reported by emergency health care workers. especially emergency physicians.
Code 9: a systematic approach for responding to medical emergencies occurring in and around a hospital, Members of the public expect to receive efficient and appropriate medical care if they become acutely ill or injured while in or around a hospital. Our institution became aware of the need for an organized system to respond to such emergencies involving patients. visitors. local community residents. and hospital employees. both inside the hospital and on the grounds surrounding the building. A search of the literature did not provide information regarding such a response; a survey of surrounding hospitals revealed no such plan in effect in other institutions. We therefore designed a plan to be superimposed onto our existing system for responding to in-house cardiac and respiratory arrests ("codes"). The results after one and one-half years appear encouraging. We recommend the establishment of such an emergency response system in all health care institutions.
Hangman's fracture in a 7-week-old infant, The "hangman's fracture" in infancy and childhood is a bilateral avulsion of the pedicles or their synchondroses from the C-2 vertebral body. frequently with anterior dislocation of C-2 or C-3. We present the case of the youngest infant in the medical literature with a hangman's fracture and discuss anatomy. kinematics of injury. radiographic diagnosis. and treatment.
Transmission of 'toxic strep' syndrome from an infected child to a firefighter during CPR, Several cases of a toxic shocklike syndrome have been reported in the United States during the past five years in association with Streptococcus pyogenes infection. We report a case of a firefighter exposed during attempted CPR to the secretions of an S pyogenes-infected child. The firefighter developed an infection of the hand and subsequent febrile illness with hypotension. erythematous rash. renal failure. and hypocalcemia. Bacterial isolates of blood and cerebrospinal fluid from the deceased child were identical in type and exotoxin production with isolates grown from the hand wound of the firefighter. This is the first reported case of documented transmission of S pyogenes. causing a toxic shocklike syndrome in an emergency medical technician.
Central pulmonary embolism with normal ventilation/perfusion scan-diagnosis by nuclear pulmonary artery flow studies, Pulmonary embolism. although uncommon in children. occurs in as many as 104 per 100.000 pediatric patients. Undiagnosed and untreated pulmonary embolism has a high mortality rate; thus. a high index of clinical suspicion and reliable diagnostic modalities are necessary to ensure prompt and accurate diagnosis. We report the case of a patient with severe central pulmonary embolism with a normal ventilation-perfusion scan. The embolus was identified by a nuclear pulmonary flow study using dynamic imaging. which obviated the need for contrast pulmonary angiography. The traditional ventilation-perfusion scan may appear normal despite severe central pulmonary embolism. In this situation. early dynamic imaging is necessary to detect severe obstruction of the central pulmonary arteries. This approach may obviate the need for contrast pulmonary angiography in hemodynamically stable patients.
Echocardiographic left ventricular mass and electrolyte intake predict arterial hypertension, OBJECTIVE: To identify predictors of arterial hypertension. PATIENTS: One hundred thirty-two normotensive adults from a large employed population. METHODS: Echocardiography. standard blood tests. and 24-hour urine collection. at baseline and after an interval of 3 to 6 years (mean. 4.7 +/- 0.8 years). RESULTS: At follow-up. 15 subjects (11%; 7 men. 8 women) had a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg or both (mean. 143 +/- 7 and 87 +/- 6 mm Hg. respectively). At baseline. subjects who developed hypertension had a greater left ventricular mass index than those who did not (92 +/- 25 compared with 77 +/- 19 g/m2 body surface area; P less than 0.005) and higher 24-hour urinary sodium/potassium excretion ratio (3.6 +/- 1.7 compared with 2.6 +/- 1.4; P less than 0.04); there were no differences in race. initial age. systolic or diastolic blood pressure. coronary risk factors. or plasma renin activity. The likelihood of developing hypertension rose from 3% in the lowest quartile of sex-adjusted left ventricular mass index to 24% in the highest quartile (P less than 0.005); a parallel trend was less regular for quartiles of the sodium/potassium excretion ratio (P less than 0.04). In multivariate analyses. follow-up systolic pressures in all subjects and in the 117 who remained normotensive were predicted by initial age. systolic blood pressure. black race. and sex-adjusted left ventricular mass index; final diastolic blood pressure was predicted by its initial value. plasma triglyceride levels. urinary sodium/potassium ratio. low renin activity. black race. and plasma glucose level. CONCLUSIONS: Echocardiographic left ventricular mass in normotensive adults is directly related to the risk for developing subsequent hypertension. Left ventricular mass improves prediction of future systolic pressure. whereas diastolic pressure is more related to initial metabolic status. Black race is also an independent determinant of higher subsequent blood pressure.
Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. A meta-analysis, PURPOSE: To evaluate the effectiveness of oral corticosteroid therapy in patients with stable chronic obstructive pulmonary disease. DATA IDENTIFICATION: An English-language literature search using MEDLINE (1966 to 1989) and a bibliographic review of all retrieved articles identified 33 original studies of oral corticosteroid use in chronic obstructive pulmonary disease published since 1951. STUDY SELECTION: We submitted a photocopy of each study's "methods" section to three nonstudy physician-investigators who used nine explicit criteria to independently assess study quality. Ten studies met all criteria and five studies met some of the criteria. DATA EXTRACTION: To compare outcomes across all qualifying studies. we defined response to therapy as a 20% or greater increase in the baseline forced expiratory volume in 1 second (FEV1); we defined the treatment effect size for each study as the proportion of patients who responded to corticosteroid therapy minus the proportion of patients who responded to placebo. Potential confounding variables as related to eligibility criteria and treatment protocols were also assessed for each study. RESULTS OF DATA SYNTHESIS: Among ten studies that met all nine criteria. we found no significant differences in eligibility criteria. treatment protocol. or study design. No association was found between treatment effect size and publication date. study size. mean patient age. or FEV1. These studies had reported effect sizes ranging from 0% to 56%; we calculated a weighted mean effect size of 10% (95% CI. 2% to 18%). When studies meeting only some of the criteria were included in the calculation. the weighted mean effect size was 11% (95% CI. 4% to 18%). CONCLUSIONS: Patients with stable chronic obstructive pulmonary disease receiving oral corticosteroid therapy have a 20% or greater improvement in baseline FEV1 approximately 10% more often than similar patients receiving placebo.
Large-scale neurocognitive networks and distributed processing for attention, language, and memory, Cognition and comportment are subserved by interconnected neural networks that allow high-level computational architectures including parallel distributed processing. Cognitive problems are not resolved by a sequential and hierarchical progression toward predetermined goals but instead by a simultaneous and interactive consideration of multiple possibilities and constraints until a satisfactory fit is achieved. The resultant texture of mental activity is characterized by almost infinite richness and flexibility. According to this model. complex behavior is mapped at the level of multifocal neural systems rather than specific anatomical sites. giving rise to brain-behavior relationships that are both localized and distributed. Each network contains anatomically addressed channels for transferring information content and chemically addressed pathways for modulating behavioral tone. This approach provides a blueprint for reexploring the neurological foundations of attention. language. memory. and frontal lobe function.
A comparison of neurological, metabolic, structural, and genetic evaluations in persons at risk for Huntington's disease, We compared four diagnostic data sets for the assessment of individuals at risk for Huntington's disease. Fifty-four chorea-free persons were evaluated by neurological examination. positron emission tomography measurement of glucose metabolism. radiographic computerized tomographic measurement of caudate size. and genetic testing at the polymorphic DNA loci D4S10. D4S43. and D4S125. Twelve (22%) persons had abnormal caudate metabolism. 6 (11%) had subtle abnormalities of motor control. and 7 (13%) had computed tomographic evidence of caudate atrophy. compared with an expected gene frequency of 34% for this population. In 20 persons with unambiguous genetic test results or the subsequent phenotypic expression of Huntington's disease (chorea). there was a greater sensitivity of the positron emission tomographic measurement of caudate metabolism (75%) relative to computed tomography (33%) or the clinical examination (17%) for the determination of a subpopulation of probable Huntington's disease gene carriers. Hypometabolism of the putamen and globus pallidus. and hypermetabolism of the precentral gyrus were also associated with a high probability of carrying the Huntington's disease gene. The findings support the hypothesis that abnormalities of cerebral metabolism precede clinical or structural (computed tomographic) abnormalities in gene-positive individuals at risk for Huntington's disease.
Impairment of sequences of memory-guided saccades after supplementary motor area lesions, Different paradigms of saccades were recorded electro-oculographically in 2 patients with infarction affecting the left supplementary motor area. Saccades made toward visual targets (visually-guided saccades) or away from them (antisaccades) were normal in both patients. Memory-guided saccades. made to the remembered position of a flash occurring 2 seconds before. were preserved in 1 patient and only slightly impaired in the other. However. sequences of two or three memory-guided saccades were severely impaired in both patients. It has previously been reported that the supplementary motor area plays an important role in programming sequential limb movements. Our data suggest that this area plays a similar role in the control of sequential eye movements.
Guanidino compounds that are increased in cerebrospinal fluid and brain of uremic patients inhibit GABA and glycine responses on mouse neurons in cell culture, Four guanidino compounds that have been found to be markedly increased in cerebrospinal fluid and brain tissue of uremic patients. namely. guanidine. methylguanidine. creatinine. and guanidinosuccinic acid. were applied to mouse spinal cord neurons in primary dissociated cell culture to evaluate their effects on postsynaptic responses to gamma-aminobutyric acid (GABA) and glycine. Intracellular microelectrode recording techniques were used. Guanidine. methylguanidine. creatine. and guanidinosuccinic acid reversibly and in a dose-dependent manner inhibited both GABA and glycine responses. Guanidinosuccinic acid was the most potent inhibitor of the amino acid responses. followed in decreasing potency by methylguanidine. guanidine. and creatinine. Guanidinosuccinic acid inhibited responses to GABA and glycine. at concentrations similar to those found in cerebrospinal fluid and brain tissue of patients with terminal renal insufficiency. The other guanidino compounds tested exerted their effects only at concentrations higher than those found in uremic biological fluids and tissues. The inhibitory effect of guanidine and methylguanidine on responses to GABA was additive. The effect of the guanidino compounds on GABA responses was not antagonized by coapplication of the benzodiazepine-receptor antagonist CGS 9896. The results suggest that guanidine. methylguanidine. creatinine. and guanidinosuccinic acid inhibited responses to the inhibitory neurotransmitters GABA and glycine by blocking the chloride channel. The observed action of the studied guanidino compounds might contribute to the pathogenesis of the complex neurological symptomatology encountered in uremia.
Quadriceps myopathy: forme fruste of Becker muscular dystrophy, We examined dystrophin. the protein product of the Duchenne muscular dystrophy gene. in muscle biopsy specimens from 4 male patients with quadriceps myopathy. all of whom showed a mild and slowly progressive myopathy confined to the quadriceps muscles. All 4 patients had clear abnormalities of dystrophin. and were diagnosed as having Becker muscular dystrophy by both immunofluorescence and immunoblot examinations; that is. dystrophin of an abnormal molecular mass was visualized in muscle cryosections as "patchy" or discontinuous immunostaining at the surface membrane of the muscle fibers. One patient had a brother who showed widespread myopathic changes consistent with typical Becker muscular dystrophy. We conclude that the syndrome called quadriceps myopathy includes a group of forme fruste Becker muscular dystrophy.
Noninvasive detection of occlusive disease of the carotid siphon and middle cerebral artery, Recently. transcranial Doppler sonography has been introduced into clinical practice for noninvasive investigation of the large intracranial arteries. To determine its accuracy for detection of stenosing or occluding lesions. 133 consecutive patients were studied by both transcranial Doppler sonography and selective cerebral arteriography. Statistical analysis of findings was done separately for various arterial segments. High values for sensitivity and specificity were found for detecting obstruction of the carotid siphon and main stem of the middle cerebral artery. Diagnostic reliability of transcranial Doppler sonography was also confirmed by the calculation of a chance-corrected measure of agreement (kappa). which was close to + 1 in all subanalyses. Transcranial Doppler sonography seems to be a valuable tool for noninvasive detection of intracranial lesions of the middle cerebral artery and carotid siphon.
Eyelid movements before and after botulinum therapy in patients with lid spasm, Quantitative analysis of lid motility is presented for 4 individuals with hemifacial spasm and 1 with Meige's syndrome. The data were obtained. by means of a magnetic search coil technique. prior to and 1 week after injection of botulinum toxin into the orbicularis oculi muscle. Before treatment. the peak velocity of blink-related lid lowering and lid raising was slower than normal. yet lid saccades were normal. After botulinum treatment. significant decreases occurred in (1) the amplitude of blinks and lid saccades. and (2) the peak velocity of the blink down-phase. Botulinum treatment significantly alters blink lid-lowering kinematics. while saccadic lid-lowering kinematics are normal. providing further evidence that the orbicularis oculi muscle does not play a primary role in downward lid saccades.
Brain pH in head injury: an image-guided 31P magnetic resonance spectroscopy study, It has been suggested that brain acidosis may follow head trauma. and therapies aimed at correcting acidosis have been proposed. Direct measurements of intracellular pH. however. have thus far not been possible in clinical situations. We have studied the intracellular brain pH in 22 patients after head injury (mean Glasgow Coma Score 6.1). Patients were investigated by a combined approach of phosphorus 31 magnetic resonance spectroscopy and magnetic resonance imaging (overall examination time 50-75 min) at a mean time of 11 days after injury (36 hours to 24 days). 31P spectra were obtained in 11 patients on assisted ventilation and in 11 patients on spontaneous ventilation. These spectra were analyzed to yield the pH in the regions studied in all the patients. All pH values were in the normal or alkalotic range when compared with 6 age-matched normal controls. No differences were found between patients on assisted ventilation and patients on spontaneous ventilation. When analyzed as a group. the brain pH in the focal lesions appeared to increase in the first days. to reach a peak in the alkalotic range in the second week. and to return toward normal within 3 weeks from acute injury. Our results suggest that there is no evidence of posttraumatic intracellular brain acidosis in recent human head injury. and therefore. therapies aimed at alkalinizing brain cells need to be reconsidered.
Dystrophin analysis in Duchenne and Becker muscular dystrophy carriers: correlation with intracellular calcium and albumin, Immunocytochemical localization and immunoblot analysis of dystrophin in muscle fibers of 11 obligate and probable. and 7 possible carriers of Duchenne and Becker muscular dystrophy revealed an abnormal expression of the protein in 3 of them. Localization of calcium and albumin. as endogenous markers of extracellular fluid penetration. showed the presence of both molecules inside some fibers lacking dystrophin. Our morphological studies show that the initial stages leading to fiber necrosis in Duchenne muscular dystrophy are present in carriers with mosaicism. Comparison of dystrophin studies with restriction fragment length polymorphism analysis and creatine kinase levels showed that neither immunocytochemical nor immunoblot techniques for dystrophin are sensitive enough to provide a basis for genetic counseling.
Magnetic motor-evoked potentials in epilepsy: effects of the disease and of anticonvulsant medication, Magnetic motor-evoked potentials were recorded in 53 patients with medically intractable. mainly temporal lobe epilepsy and compared with potentials of 110 healthy volunteers. The motor-evoked potentials were reevaluated in 16 of the 53 patients after substantial reduction of antiepileptic drug doses. The objective was to assess the effect of epilepsy and of anticonvulsant medication on the central motor system. In subjects receiving antiepileptic treatment. cortical threshold intensities were markedly elevated and peripheral latencies were prolonged. Cortical threshold intensities and peripheral latencies decreased to approach control values after anticonvulsant medication was reduced but were increased in patients treated with 2 or 3 anticonvulsant agents instead of 1. Additionally. high levels of interictal epileptiform activity and a high frequency of seizures significantly decreased the central motor conduction time and. in part. threshold intensities. The central motor conduction time was further diminished after reduction of anticonvulsant treatment and increased when several drugs were administered. The duration of epilepsy. the location of the epileptic focus. and the type of the epileptic seizure did not affect motor-evoked potentials. Conclusively. central motor pathways are endogenously facilitated by epileptiform activity even if clinical signs of their involvement are absent. Anticonvulsant medication exerts major reversible effects on magnetic motor-evoked potentials.
A follow-up study of intractable seizures in childhood, One hundred forty-five children with seizures that were refractory to medical therapy for at least 2 years were followed 5 to 20 years after onset. The majority of children with uncontrollable seizures (61%) were mentally retarded. and most of these (73%) had onset of seizures at younger than 2 years of age. Age of onset was significantly later (mean 5.0 +/- 0.5 yr [SEM]) in the group of children with borderline to normal intelligence. Follow-up data showed remission of seizures in a significant proportion of children with borderline or normal intelligence. with a linear decrease of the percentage with persistent seizures at a rate of about 4% per year. Remission of seizures was much less frequent (1.5%/yr) in the group with mental retardation. Seizure type had some effects on outcome. Children with focal atrophic brain lesions did no worse than those without definable pathology on brain-imaging studies.
Normal dystrophin in McLeod myopathy, Dystrophin and its gene were studied in a patient with McLeod syndrome. This X-linked recessive myopathy has been localized to Xp21. as has the Duchenne muscular dystrophy gene locus. which codes for dystrophin. Histopathological study of the patient's muscle showed mild subclinical myopathy. Immunological studies of dystrophin in two separate biopsy specimens and analysis of dystrophin gene DNA from a blood sample did not detect an abnormality. This suggests that the Duchenne muscular dystrophy gene. albeit close to the McLeod locus. is not involved in McLeod myopathy.
Suicide in twins, Suicide appears to cluster in families. suggesting that genetic factors may play a role in this behavior. We studied 176 twin pairs in which one or both twins had committed suicide. Seven of the 62 monozygotic twin pairs were concordant for suicide compared with two of the 114 dizygotic twin pairs (11.3% vs 1.8%). The presence of psychiatric disorder in the twins and their families was examined in a subsample of 11 twin pairs. two of whom were concordant for suicide. Eleven of these 13 twin suicide victims had been treated for psychiatric disorder. as had eight of their nine surviving cotwins. In addition. twins in 10 pairs had other first- or second-degree relatives who had been treated for psychiatric disorder. Thus. these twin data suggest that genetic factors related to suicide may largely represent a genetic predisposition for the psychiatric disorders associated with suicide. However. they leave open the question of whether there may be an independent genetic component for suicide.
Psychiatric disorders in relatives of probands with opiate addiction, Previous research has documented high rates of major depression and antisocial personality in opiate addicts. This study was designed to investigate the relationship of dual diagnosis in opiate-addicted probands to family history of psychiatric disorders and substance use disorders in biological relatives. Psychiatric disorders and substance use disorders were evaluated using direct interview and family history in a sample of 877 first-degree relatives of 201 opiate addicts and 360 relatives of 82 normal controls. Results indicate that (1) compared with relatives of normal subjects. opiate addicts' relatives had substantially higher rates of alcoholism. drug abuse. depression. and antisocial personality; (2) relatives of depressed opiate-addicted probands had elevated rates of major depression and anxiety disorders but not of other disorders. suggesting the validity of subtyping opiate addicts by the presence or absence of major depression; and (3) in contrast. relatives of antisocial opiate addicts had rates of disorders that were not significantly different from those of relatives of opiate addicts without antisocial personality. Implications of these findings for the classification and treatment of substance abuse are discussed.
Psychiatric diagnoses of treatment-seeking cocaine abusers, In a sample of 298 cocaine abusers seeking inpatient (n = 149) or outpatient (n = 149) treatment. rates of psychiatric disorders were determined by means of the Schedule for Affective Disorders and Research Diagnostic Criteria. Overall. 55.7% met current and 73.5% met lifetime criteria for a psychiatric disorder other than a substance use disorder. In common with previous reports from clinical samples of cocaine abusers. these overall rates were largely accounted for by major depression. minor bipolar conditions (eg. hypomania. cyclothymic personality). anxiety disorders. antisocial personality. and history of childhood attention deficit disorder. Affective disorders and alcoholism usually followed the onset of drug abuse. while anxiety disorders. antisocial personality. and attention deficit disorder typically preceded drug abuse.
Symptoms of tobacco withdrawal. A replication and extension, Smokers (n = 315) who wished to quit were randomly assigned in a double-blind manner to groups using either nicotine or placebo gum. Self-reported and observed symptoms of tobacco withdrawal were collected before cessation and at follow-ups of 1 to 2 weeks. 1 month. and 6 months. Self-reported and/or observed anger. anxiety. craving. difficulty concentrating. hunger. impatience. and restlessness were the most prominent symptoms of tobacco withdrawal. These symptoms had returned to precessation levels by 1 month except increased weight. hunger. and craving continued for 6 months in many smokers. Nicotine gum decreased most symptoms. including craving and hunger but not weight. Abstinent smokers with more intense withdrawal were not more likely to relapse. Abstinent smokers who gained more weight were less likely to relapse.
Valproate in the treatment of acute mania. A placebo-controlled study, We conducted a placebo-controlled. double-blind study of valproate. a drug originally developed as an antiepileptic. in 36 patients with acute manic episodes who had previously failed to respond to or to tolerate lithium carbonate. Treatment duration was 7 to 21 days. with no other psychotropic medications permitted except lorazepam up to 4 mg/d during the first 10 days of treatment. Serum valproate concentrations were measured three times weekly; an unblinded investigator then adjusted dosage to produce serum concentrations between 50 and 100 mg/L. Valproate proved superior to placebo in alleviating manic symptoms. The 17 patients randomized to active drug demonstrated a median 54% decrease in scores on the Young Mania Rating Scale as compared with a median 5.0% decrease among the 19 patients receiving placebo. On the 100-point Global Assessment Scale of overall psychiatric functioning. patients receiving valproate improved by a median of 20 points as compared with a zero-point change with placebo. Significant differences also emerged on the Brief Psychiatric Rating Scale and in the number of supplemental doses of lorazepam required by the patients in each group. Substantial antimanic effects appeared within 1 to 4 days of achieving therapeutic serum valproate concentrations. Adverse effects were infrequent. with no adverse effect appearing significantly more frequently with valproate than with placebo. We conclude that valproate represents a useful new drug for the treatment of manic patients.
Carbamazepine maintenance treatment in outpatient schizophrenics, A double-blind crossover trial was used to evaluate carbamazepine as the sole maintenance treatment of chronic. nonmanic schizophrenic outpatients whose conditions had been stabilized with the use of neuroleptics prior to study. Criteria of treatment effectiveness included the number of patients relapsing and time to relapse over a 95-day neuroleptic-free period during which either carbamazepine or placebo was administered. Relapse was determined by the concordance of psychiatric ratings and independent clinical judgements indicating significant worsening. Results for 27 patients (13 receiving carbamazepine and 14 receiving placebo) involved in the first phase of this treatment comparison were nondifferentiating. Corroborating descriptive findings in the second phase were available for 14 of these patients. There was no evidence supporting the existence of a treatment-relevant subgroup defined by episodic dyscontrol phenomena.
Hyperactive boys almost grown up. V. Replication of psychiatric status, We previously reported a prospective follow-up study of 101 young adult males whose conditions had been diagnosed as hyperactivity in childhood. Compared with controls. probands had significantly higher rates of attention-deficit. antisocial. and drug use disorders at follow-up (mean age. 18 years). The present study was an attempt to replicate these findings on an independent sample of 94 hyperactive boys who were seen at the same clinic. compared with 78 normal controls. Assessments were made by clinicians who were blind to group membership. Information was obtained for 90% of the original cohort. As in the previous study. significantly more probands than controls were given ongoing diagnoses of attention-deficit disorder (43% vs 4%). antisocial disorders (32% vs 8%). and drug use disorders (10% vs 1%). Furthermore. the absolute rates of these disorders were comparable for corresponding groups across studies. and the adjusted odds ratios did not differ significantly. As previously. there was no increased risk for affective disorders in the grown hyperactive children. The present study provides a powerful replication of the nature of the young adult outcome of childhood hyperactivity.
Magnetic resonance imaging of sacroiliac joint inflammation, A consecutive series of 27 patients with symptoms compatible with sacroiliitis underwent magnetic resonance imaging (MRI) of the sacroiliac joints. The diagnostic sensitivity of MRI was similar to that of computed tomography or conventional radiography. However. MRI seems to have the potential of providing unique information about the disease process in sacroiliitis by demonstrating abnormalities in subchondral bone and periarticular bone marrow. The results of this study suggest that early inflammatory changes in sacroiliitis occur in the subchondral structures of the sacroiliac joints.
HLA antigens in juvenile arthritis. Pauciarticular and polyarticular juvenile arthritis are immunogenetically distinct, Using DNA techniques. we investigated the role of HLA-DR. DQ. and DP alleles in susceptibility to juvenile arthritis (JA). We studied 2 groups of patients with JA having a different disease prognosis and course. The pauciarticular form is usually benign. while the polyarticular disease frequently leads to joint destruction and disability. Persistent pauciarticular disease developed preferentially in patients having HLA-DRw13-Dw18 and DQw6-Dw18. but these antigens did not confer susceptibility in patients whose disease converted to the polyarticular form. HLA-DPw2.1 was an additional susceptibility factor for patients with JA of pauciarticular onset. In the polyarticular form of JA. HLA-DPw3 was the major factor for susceptibility. giving a relative risk of 10.3 (P less than 0.0001). In addition. we found that DRw8.1 and DQw4 were increased. and HLA-DR4 was markedly decreased. in patients with pauciarticular and polyarticular disease. These results indicate that in addition to some shared factors. distinct HLA class II alleles are important in pauciarticular or polyarticular JA. We conclude that typing with oligonucleotide probes may be useful in predicting the outcome in some children with arthritis.
Autoantibody to Th ribonucleoprotein (nucleolar 7-2 RNA protein particle) in patients with systemic sclerosis, We studied sera of 371 consecutive new patients with systemic sclerosis (SSc; scleroderma) who were first evaluated during 1984-1988. All sera were tested for antinuclear antibodies by immunofluorescence staining using HEp-2 cells as substrate. We excluded 219 sera showing dark nucleoli and screened for antibodies to Th in the remaining 152 sera by immunoprecipitation of a 32P-labeled HeLa cell extract. Fifteen (4.0%) of 371 sera were anti-Th+. Anti-Th antibodies were present in 14 (8.4%) of 167 SSc patients with limited cutaneous involvement. in 1 of 167 with diffuse cutaneous involvement. and in 0 of 37 with SSc overlap syndrome. Among 244 controls with other connective tissue diseases. anti-Th was detected in only 3 patients. all having primary Raynaud's phenomenon of less than 2 years duration. In the subgroup with SSc with limited cutaneous involvement. the 14 anti-Th+ patients had a significantly greater frequency of puffy fingers. small bowel involvement. and hypothyroidism. and a significantly lower frequency of arthralgia and/or arthritis. Their cumulative survival rate from the time of onset of symptoms was lower than that for anti-Th- patients (78% versus 91% at 10 years). primarily due to 3 deaths from pulmonary arterial hypertension (2 from primary pulmonary hypertension and 1 from pulmonary hypertension secondary to pulmonary interstitial fibrosis). Serum anti-Th antibodies are present almost exclusively in patients with SSc with limited cutaneous involvement or in those with primary Raynaud's phenomenon whose disease may evolve to SSc with limited cutaneous involvement. and these antibodies may identify those patients who are at greater risk for reduced survival.
Increased expression of type VI collagen genes in systemic sclerosis, The expression of type VI collagen genes in affected skin from patients with systemic sclerosis (SSc) was examined by in situ hybridizations with a human alpha 2(VI) collagen sequence-specific complementary DNA. Five patients with diffuse. rapidly progressive SSc of recent onset (less than 12 months) were studied. The results showed increased expression of alpha 2(VI) collagen messenger RNA transcripts in the skin of scleroderma patients compared with that in the skin of normal subjects. These findings indicate that alterations in the expression of type VI collagen genes. similar to those previously described for types I and III collagen. are present in the affected skin of SSc patients. These alterations may result in excessive tissue accumulation of type VI collagen and may play a role in the progressive skin induration and sclerosis that are prominent features of SSc.
Increased expression of intercellular adhesion molecule 1 on the fibroblasts of scleroderma patients, The surface expression of intercellular adhesion molecule 1 (ICAM-1) and class I and class II major histocompatibility complex molecules on cultured dermal fibroblasts from 7 scleroderma patients and 6 control donors was compared. Scleroderma fibroblast lines contained 41.0 +/- 3.0% (mean +/- SEM) cells with high levels of ICAM-1 expression (ICAM-1-high). whereas 26.9 +/- 1.5% of control fibroblasts were ICAM-1-high (P = 0.0003). There were no differences in the expression of class I and class II molecules. ICAM-1-high and ICAM-1-low fibroblasts produced equal amounts of total protein and procollagen. The increase in the number of ICAM-1-high fibroblasts in scleroderma patients may facilitate T cell activation and lymphokine production. and thus indirectly contribute to the fibrotic process.
Relationship of clinical features with psychological status in primary fibromyalgia, Clinical features and psychological status determined by the Minnesota Multiphasic Personality Inventory (MMPI) in 103 patients with primary fibromyalgia syndrome (PFS) were analyzed by univariate and multivariate techniques to determine if clinical features were related to psychological status or were intrinsic to PFS per se. The central features of PFS. e.g.. number of pain sites. number of tender points. fatigue. and poor sleep. were independent of psychological status. However. discriminant analysis identified 4 variables--patient-reported depression. anxiety. stress. and pain severity--which together predicted 3 MMPI subgroups with an accuracy of 55% (P less than 0.001); the only musculoskeletal feature--pain severity--alone provided an accuracy of only 34% (P greater than 0.05). These data suggest a new concept. that the central features of fibromyalgia are independent of the psychological status and are more likely related to the PFS itself. However. pain severity may be influenced by psychological factors.
Chondrons from articular cartilage. III. Morphologic changes in the cellular microenvironment of chondrons isolated from osteoarthritic cartilage, Chondrons were isolated from human and canine osteoarthritic cartilage using low-speed homogenization techniques. Changes in chondron morphology were evaluated using differential interference-contrast microscopy. phase-contrast microscopy. and histochemical and ultrastructural methods. Chondrocyte viability was assessed using fluorescein diacetate staining. and chondron metabolism was investigated using autoradiography. The results suggest that initial changes in the collagen and proteoglycan distribution within the chondron are followed by chondrocyte proliferation to form clusters. These techniques offer the potential to study cell matrix interactions in degenerative osteoarthritis.
Progression of osteoarthritis of the hand and metacarpal bone loss. A twenty-year followup of incident cases, We examined the prospective relationship between metacarpal bone mass and osteoarthritis (OA) of the hand. using incidence data from the historical cohort in the Tecumseh Community Health Study (Tecumseh. MI). Women were examined for radiographic evidence of OA and for bone mass twice. 20-23 years apart (1962-1965 and 1985; 683 subjects with an age range of 55-74 in 1985). Two measures of OA were evaluated: the highest score assigned to any of the 32 wrist/hand joints. and the sum of scores for all wrist/hand joints. After adjustment for age. women who were classified as having OA (by either measure of OA) in 1985 were more likely to have more cortical area at baseline. which indicates greater bone mass. Women who developed OA in the 23-year period were more likely to experience a significantly greater widening of the medullary cavity over time. an indicator of increased bone resorption. Women with increasing levels of OA involvement also had an increased likelihood of greater cortical area loss. We conclude that women who later developed OA were more likely to have higher baseline bone mass than women who did not develop OA. but these women also had a greater likelihood of bone loss over time.
Association of HLA-Dw16 with rheumatoid arthritis in Yakima Indians. Further evidence for the "shared epitope" hypothesis, Rheumatoid arthritis (RA) is prevalent in Yakima Indians. a Native American tribe. HLA-DR4. the HLA specificity commonly associated with RA in Caucasians. is rare among the Yakima. Using a specific oligonucleotide probe that recognizes DR4 nucleotide sequences associated with RA. a rare HLA-Dw16 gene was identified in 83% of Yakima patients with RA and in 60% of Yakima control subjects. This shared sequence encodes a discrete class II epitope that is highly correlated with RA in both DR4 positive and DR4 negative individuals.
Suppression of type II collagen-induced arthritis by monoclonal antibodies, Some mouse monoclonal antibodies raised against chicken type II collagen suppressed or delayed the onset of chicken type II collagen-induced arthritis in DBA/1 mice. This was correlated with the suppression of anti-mouse type II collagen antibody responses following immunization with chicken type II collagen. The epitopes recognized by the suppressive antibodies were found to be present on cyanogen bromide (CB)-digested collagen peptides CB-11 and CB-12. This was also confirmed by the finding that administration of the CB-11 or CB-12 peptide suppressed the induction of arthritis.
Restoration of the DNA binding activity of estrogen receptor in MRL-lpr/lpr mice by a polyamine biosynthesis inhibitor, Diverse data link estrogen influences to both the frequency and severity of systemic lupus erythematosus in humans and to murine lupus. A fundamental mechanism of action of estrogen involves the interaction of the hormone with its receptor protein. which is then transformed into the DNA binding form. We measured the concentration of uterine estrogen receptor and its DNA binding in normal BALB/c mice. lupus-prone MRL-lpr/lpr mice. and MRL-lpr/lpr mice that had been treated with 1% difluoromethylornithine (DFMO). Uterine estrogen receptor levels in 20-week-old mice from the 3 groups were not significantly different. In contrast. DNA binding activity was significantly higher in BALB/c mice (mean +/- SD 775 +/- 100 fmoles/mg of DNA) than in untreated MRL-lpr/lpr mice (80 +/- 16 fmoles/mg of DNA) (P less than 0.001). Treatment with 1% DFMO was associated with an increase in uterine estrogen receptor DNA binding (1.100 +/- 218 fmoles/mg of DNA) in MRL-lpr/lpr mice (P less than 0.001). Polyamine levels were 2-6-fold higher in the uterine tissues of untreated MRL-lpr/lpr mice compared with the BALB/c mice and were significantly reduced by DFMO treatment. Our results link uterine polyamine production to a dysfunction of the estrogen receptors in MRL-lpr/lpr mice. Reduction of the polyamine level by the irreversible inhibition of ornithine decarboxylase with DFMO restores estrogen receptor function.
Antibody profile of early HTLV-I infection [published erratum appears in Lancet 1990 Dec 22-29;336(8730):1596], To define the antibody profile of early seroconversion in infection with human T-cell lymphotropic virus type I (HTLV-I). consecutive serum samples from 10 subjects presumed to have seroconverted on the basis of the particle agglutination test were studied by three enzyme immunoassays and two confirmatory tests (radioimmunoprecipitation and western blot). 3 samples positive and 1 sample indeterminate in the confirmatory tests were reactive in one enzyme immunoassay. which used recombinant envelope antigen. but not in the other two enzyme immunoassays. 2 of 38 particle-agglutination-negative samples had a prozone effect. The confirmatory tests identified 8 seroconverters (7 women. 1 man); their serum samples were used to study the antibody reactivity by western blot assays to HTLV-I specific antigens (three recombinant proteins spanning the N-terminal. middle. and C-terminal env glycoprotein gp46; a recombinant transmembrane protein gp21; a recombinant tax protein; and three gag proteins [p28. p24. and p19]). All 8 seroconverters had antibody reactivities to the C-terminal region (aminoacid residues 229-308) of gp46 and to gag p19 and p24 when their seroconversion was detected.
Pediatrics residents' attitudes about insulin-dependent diabetes mellitus and children with diabetes, Nationwide. pediatricians provide a substantial portion of the health care of children with diabetes. Their beliefs and attitudes about diabetes and children with the illness have an important influence on their treatment decisions. The attitudes and beliefs of a 1988 sample of pediatrics residents were compared with data from a 1987 national survey of practicing pediatricians' beliefs and attitudes about children with insulin-dependent diabetes mellitus and about the disease itself. Pediatrics residents in their second and third years of training were considerably more negative about diabetes and diabetic children than were either the members of the national sample of practicing pediatricians or the residents' first-year colleagues.
Reactions of first-year medical students to their initial encounter with a cadaver in the dissecting room, This study reports the results of a 1986 questionnaire survey of 100 first-year medical students regarding their preparation for and reactions to their first encounter with a human cadaver in the dissecting room. The students were aware of psychological and physical reactions to this experience. and although they felt adequately prepared prior to the class. expressed a desire for greater preparation afterwards. particularly through more discussion of the experience with the anatomy staff. A surprising number of the students (62) had had prior exposure to a dead human body. which was a significant influence upon their reactions. The results of this study suggest a need for improving both the preparation for coping with dissection and the follow-up opportunities for dealing with professional and emotional issues raised during human dissection.
AIDS in the minds of Swedish people: 1986-1989, In order to assess changes in knowledge. attitudes and behaviour related to AIDS. annual mail surveys (1986-1989) were sent to random samples of the general public. aged 16-44 years. In total. 16.900 individuals were sampled. with an average response rate of 71%. Knowledge about the major routes of infection was generally good during the entire study period. The fear of unverified infection risks and of contact with HIV-infected people decreased during the period studied. but still remained high in 1989. Over the entire period. respondents expressed a strong fear concerning the spread of HIV in the population. Although an increasing percentage of respondents reported altered sexual habits as a result of fear of AIDS. overall sexual behaviour did not change sufficiently to reduce the risk of spread of any sexually transmissible disease. Progress toward knowledge. attitudes. and behaviour aimed at prevention of transmission of infection and unnecessary fear and counteraction of prejudice was most rapid during the middle of the study period when public debate concerning AIDS was at its peak. Knowledge and attitudes did not change during the last year of the study. but. in some respects. reverted to previous levels.
Complement-mediated enhancement of HIV-1 infection of the monoblastoid cell line U937, To assess the role of complement and complement receptors in HIV-1 infection of monocytes and macrophages. we studied the infectivity of HIV-1. isolated from the peripheral blood of a patient with subacute AIDS-related encephalopathy. on the human monoblastoid cell line U937. HIV-1 and HIV-1-infected cells were capable of activating the complement system via the classical and the alternative pathways. respectively. Low concentrations of HIV-1 were able to infect U937 cells more easily in the presence than in the absence of complement. At higher virus concentrations. infectivity was no longer facilitated by the presence of complement. Infection of U937 cells was reduced in the presence of any of the monoclonal antibodies (MAbs). OKT4a (anti-CD4). OKM1 (anti-CR3). or M522 (anti-CR3). A combination of all three of these MAbs reduced the infection by an even greater amount. These data indicate that complement receptors may be a port of entry for complement-coated HIV-1.
Immunological changes in primary HIV-1 infection, Homosexual men with symptomatic primary HIV-1 infection displayed a pronounced lymphopaenia with significantly depressed numbers of CD3+. CD4+ and CD8+ cells and B cells during the first week of illness. Subsequently. the CD8+ cell counts rose in parallel with numbers of CD3+ cells. atypical lymphocytes and activated (CD38+ and HLA-Dr+) cells to attain maximal levels about a month following onset of illness. In contrast CD4+ and B cell numbers remained low for an extended period of time. Early signs of a host response included a transient appearance of interferon-alpha in the blood and raised levels of neopterin and beta 2-microglobulin (beta 2-M). Neither CD4+/CD8+ cell ratio nor beta 2-M resumed completely normal values during a follow-up period of 2 years. These findings shed some light on pathogenetic events during early HIV-1 infection and suggest that the infection. following the acute symptomatic stage. usually enters a stage of chronic active rather than latent infection.
Heterosexual transmission of HIV-1 among employees and their spouses at two large businesses in Zaire, To better understand the reasons why up to 80% of all HIV-1 infections in Zaire. but less than 5% in North America and Europe. are acquired through heterosexual transmission. and to assess the impact of HIV-1 infection on a large urban African workforce. we enrolled 7068 male employees. 416 female employees and 4548 female spouses of employees at two large Kinshasa businesses (a textile factory and a commercial bank) in a prospective study of HIV-1 infection. The HIV-1 seroprevalence rate was higher in male employees (5.8%) and their spouses (5.7%) at the bank than among male employees (2.8%) and their spouses (3.3%) at the textile factory. At both businesses HIV-1 seroprevalence was higher among employees in managerial positions (5.0%) than among workers in lower-level positions (3.0%; P less than 0.0001). In a multivariate analysis of male employees. receipt of a transfusion. a history of genital ulcer disease. working at the bank. urethritis. or being divorced or separated were independently associated with HIV-1 infection. During 1987 and 1988. AIDS was the most common cause of death among recently employed workers. accounting for 20 and 24% of all deaths at the textile factory and the commercial bank. respectively. The HIV-1 seroprevalence rate was higher among female workers (7.7%) than among the spouses of male workers (3.9%; P = 0.001). In multivariate analysis of the wives of workers. having an HIV-1-seropositive spouse. receipt of a blood transfusion. or a history of genital ulcer disease were independently associated with HIV-1 infection.
Transition dynamics of HIV disease in a cohort of African prostitutes: a Markov model approach, The progression of HIV-related disease from infection to death is represented as a staged Markov model. Transitions between stages are considered reversible. The model is fitted to data from a cohort of African prostitutes by means of maximum likelihood. It appears that the progression to symptomatic disease (Centers for Disease Control stage IV) in this population is considerably more rapid than that reported from studies in Western countries.
Recreational drug use and sexual behavior change in a cohort of homosexual men. The Multicenter AIDS Cohort Study (MACS), The relationship between use of recreational drugs and high-risk (HIV-transmitting) homosexual behavior was examined in the Multicenter AIDS Cohort Study (MACS) population. Among the 3916 men who completed both the baseline (1984) and first 6-month follow-up evaluations and were sexually active during the 6 months prior to enrollment. self-reported use of each of 10 classes of recreational drugs in conjunction with sexual activity was analyzed for both cross-sectional and prospective relationships with pattern of sexual behavior using a four-level sexual risk behavior index. At baseline. the proportion of men in the highest risk category (unprotected anal exposures with multiple partners) increased from 36 to 85% when men not using any drugs to men using three or more drugs plus volatile nitrites were examined. In multivariate logistical analyses. volatile nitrite use was significantly associated with failure to maintain or attain lower sexual risk levels after controlling for the effects of age. educational level and numbers of high-risk partners. These results suggest that volatile nitrite use may play an important role in the association between recreational drug use and high-risk sexual behavior among homosexual/bisexual men.
World Health Organization quality assessment programme on HIV testing, A serum panel comprising 19 samples of known (five positives and 14 negatives) but undisclosed HIV-1-antibody content was distributed to 30 national reference laboratories for HIV serology. In order to simulate normal circumstances of referral. participants were asked to test the panel for HIV-1-antibody status using their normal procedures. Results of testing were returned by 28 participants. There were great variations in the number and combinations of tests used. The number used ranged from one to five assays per laboratory and none of the 24 laboratories using two or more tests employed the same combination. A high average success rate of 99% was seen with the positive samples. More errors occurred with the negative samples. with an average of 87% correct negative reports. Only four of the 14 negative specimens were reported as negative by all participants.
Use of quinapril in the elderly patient, Quinapril hydrochloride is a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor that has been extensively tested and found effective when administered once-a-day to hypertensive patients of both sexes and all degrees of hypertension and cardiac compromise. including those with left ventricular hypertrophy. with and without congestive heart failure. Observations with earlier ACE inhibitors led to reports that this class of drugs was relatively ineffective in older hypertensive patients. To ascertain the role of quinapril (greater than or equal to 10 mg/day) in older patients. its blood pressure-lowering effects in 1.175 hypertensive patients less than or equal to 65 years of age were compared with those in 304 patients greater than 65 years of age. An excellent response was observed in patients greater than 65 years of age with mild to moderate hypertension (diastolic BP. 95 to 105 mm Hg) and moderate to severe hypertension (diastolic BP. 106 to 115 mm Hg). The reductions in blood pressure achieved with quinapril were at least comparable to those obtained in the younger hypertensives. and were numerically (but not statistically) greater in the mild to moderate group (-14 mm Hg v-12 mm Hg). In addition. the percentage of patients who experienced adverse experiences was lower in the greater than 65 group than in the less than or equal to 65 group (15% v 19%). The main adverse experiences reported included dizziness. headache. cough. fatigue. and hypotension. These findings indicate that quinapril is at least as safe and effective in older hypertensives as in younger patients.
Quinapril in chronic heart failure, Angiotensin converting enzyme inhibitors are now firmly established in the treatment of patients with chronic heart failure (CHF). Their beneficial acute and chronic hemodynamic effects are not associated with reflex tachycardia or drug tolerance. Angiotensin converting enzyme inhibitors produce symptomatic improvement and improve exercise capacity in all grades of heart failure. They also improve the prognosis of patients with severe heart failure. Quinapril is a recently introduced. nonsulfhydryl ACE inhibitor. whose intermediate half-life makes it well-suited for the treatment of patients with CHF. The acute and chronic hemodynamic effects of quinapril are similar to those of other ACE inhibitors. In a large. multicenter. randomized. placebo-controlled study of 225 patients with mild to moderate CHF. 10 to 40 mg/day quinapril significantly improved clinical status and exercise capacity in a dose-related manner. The incidence of side effects did not differ significantly from that of placebo. The initial studies with quinapril are promising and warrant further clinical investigation of this compound.
Elevated insulin, norepinephrine, and neuropeptide Y in hypertension, To investigate the relationship between insulin and sympathetic activity. plasma norepinephrine. neuropeptide Y. serum glucose and insulin concentrations were measured in ten age-. weight-. and sex-matched normotensive and untreated hypertensive subjects at fasting and 2 h following ingestion of a 75 g oral glucose dose. Hypertensives had higher fasting serum insulin (27 +/- 6 v 12 +/- 2 microU/mL; P = .02) and plasma norepinephrine (356 +/- 38 v 235 +/- 35 pg/mL; P = .03) concentrations than normotensives. Glucose load increased serum insulin (P less than .001) and plasma norepinephrine concentrations (P = .001) in both groups and hypertensives had still higher postglucose insulin (P = .003) and norepinephrine levels (P = .003) than normotensives. Fasting neuropeptide Y was higher in hypertensives than in normotensives (P = .03) and correlated with age in both groups (r = 0.7; r = 0.77). Postglucose serum insulin correlated positively with plasma norepinephrine (r = 0.75; P = .013) in normotensives. but these parameters correlated negatively in hypertensives (r = -0.7; P = .036). We hypothesize that elevated plasma norepinephrine and neuropeptide Y levels reflect an increased level of sympathetic nervous activity in hypertensives. which in turn may be responsible for the abnormal relationship between plasma NE and insulin levels.
Dietary calcium, vascular reactivity, and genetic hypertension in the Lyon rat strain, In order to examine the relationship existing between dietary calcium and the development of hypertension. we developed a long-term study in the Lyon hypertensive rat strain (LH) and two control strains. the Lyon normotensive (LN) and low blood pressure rats (LL) given enriched (HCa. 2.5%). deprived (LCa. 0.03%) and normal (NCa. 0.6%) calcium diets. Evolution of body weight. systolic blood pressure (BP). plasma calcium and magnesium was monitored from 4 to 23 weeks of age. Total cardiovascular reactivity and contractile response of isolated aorta to norepinephrine were measured at 23 weeks of age. LH rats on HCa diet failed to develop hypertension (BP less than 150 mm Hg) whereas LH rats on LCa diet exhibited higher blood pressure levels than their controls fed the NCa diet. Moreover. in LN rats HCa diet slightly decreased BP whereas LCa had no effect. In the LL rats. on the contrary. only LCa diet slightly increased BP. In vivo responsiveness to NE was significantly higher in LH compared to LL and LN rats fed a NCa diet. HCa and LCa diets both induced a significant decrease in this response in LH rats. HCa diet increased the response in LN rats but decreased it in LL. In contrast. at the same age. the in vitro contractile response of isolated aorta to NE was significantly decreased in LH compared to LN and LL rats receiving NCa diet. Moreover in LH and LN rats on HCa diet the contractile response was markedly increased but no significant difference was observed with LCa diet.
Sodium sensitive and sodium retaining hypertension, The differences between sodium sensitive and sodium retaining hypertension were theoretically considered using a water tank model of body fluid volume-blood pressure regulation. If an outlet valve is attached to a tank with a base area corresponding to the reciprocal of total peripheral resistance (TPR) and water is poured into this tank at a rate corresponding to the amount of Na+ intake. then equilibrium should be achieved at a certain water level. volume and output from the outlet. which represent mean arterial pressure (MAP). cardiac output (CO) and urinary Na+ excretion. The height of the outlet from the tank bottom and the size cross-sectional area. of the outlet correspond to the x-intercept and slope of the renal function (pressure-natriuresis) curve. respectively. In both nonsodium sensitive hypertension. due to the shift of the curve toward a higher blood pressure level (elevated height of the outlet) without change in the slope (size of the outlet). and sodium sensitive hypertension. due to the depressed slope of the curve (reduced outlet size). not only MAP (water level) but also CO (water volume) are increased. resulting in sodium retaining hypertension. if TPR (reciprocal of base area) remained unchanged. while CO is relatively unchanged. resulting in nonsodium retaining hypertension. if TPR is elevated. Thus. the MAP and its sensitivity to sodium intake is determined by the renal function curve. Since body fluid volume is determined by both the renal function curve and TPR. however. changes in TPR during the development of hypertension is a major factor in determining whether or not the body fluid volume has to change only a small amount or a large amount. Therefore. the sodium sensitivity of blood pressure and sodium retention must be considered separately.
Hemodynamic and endocrine effects of mental stress in untreated borderline hypertension, Mental arithmetic and mirror tracing were compared in 40 untreated patients with borderline hypertension. tested in random sequence in standardized protocols. Both tasks significantly increased systolic and diastolic blood pressure. heart rate. cardiac index. plasma renin. and decreased peripheral resistance. Mental arithmetic also increased cholesterol. triglycerides and HDL; plasma catecholamines were not changed significantly. Lipid changes were correlated with blood pressure changes. These methods will be useful in exploring the relationships between hemodynamic reactivity to stress. and the presence and progression of atherosclerosis. as well as testing the effects of antihypertensive drugs on stress-induced changes that may influence atherosclerotic complications of hypertension.
The role of protein kinase C and calcium in the regulation of norepinephrine release from the vascular adrenergic neurons in hypertension, This study was designed to investigate the role of protein kinase C and calcium in vascular adrenergic transmission in hypertension. In perfused mesenteric vasculatures of spontaneously hypertensive rats (SHR. 7 to 10 weeks old) and age-matched Wistar-Kyoto rats (WKY). we have examined the effects of the protein kinase C inhibitor H-7 on endogenous norepinephrine release and vascular responsiveness during nerve stimulation. Endogenous norepinephrine release and pressor responses during periarterial nerve stimulation were significantly greater in SHR than in WKY. The protein kinase C inhibitor H-7 inhibited the stimulation-induced norepinephrine release and pressor responses in a dose-dependent manner. The magnitude of these suppressive responses were more pronounced in SHR than in WKY. Calcium removal from extracellular fluid also reduced the norepinephrine release more strongly in SHR than in WKY. These results demonstrate that the regulation of norepinephrine release might be more dependent on protein kinase C and calcium in the blood vessels of SHR. which could contribute. at least partially. to the pathogenesis of this form of hypertension.
Vascular renin and hypertension. Uptake versus synthesis, Conventional radioimmunoassay techniques demonstrated in the aortic wall a renin-like activity which is derived from plasma but has a longer half-life than plasma renin. Blood pressure elevation after renin injection into nephrectomized rats correlates better with aortic renin than with plasma renin. Vascular and other extrarenal tissue can also synthesize renin. Using a ribonuclease protection technique for the detection of renin messenger RNA we have been able to demonstrate that a wide variety of extrarenal tissues contain the renin message. In at least two of these. the brain and the liver. renin messenger RNA levels are unaffected by changes in dietary salt or by changes in systemic blood pressure. Functional studies using isolated human resistance vessels also demonstrate the presence of renin-like activity by a contractile response to added renin substrate. It is suggested that extrarenal tissues therefore contain renin-like activity derived both from uptake and from local synthesis. These systems may be regulated in different ways and may carry out different functions.
Alterations in renal medullary hemodynamics and the pressure-natriuretic response in genetic hypertension, The concept that the kidney plays a major role in the long-term control of arterial pressure is based on the pressure-natriuretic response. According to this hypothesis. hypertension can only develop when the relationship between sodium excretion and arterial pressure is altered. Transplantation studies have indicated that some form of renal dysfunction underlies the development of genetic forms of hypertension in the spontaneously hypertensive rat (SHR) and in the Dahl salt-sensitive (S) rat. Nonetheless. the factors responsible for "resetting the kidney in hypertension" remain unknown. We have reported that the pressure-natriuretic relationships of SHR and Dahl S rats of the Brookhaven and Rapp strains are shifted toward higher pressures prior to the development of the disease. Papillary blood flow is also reduced in very young "prehypertensive" SHR. Recent studies on the mechanism of pressure-diuresis indicate that it is mediated by inhibition of sodium reabsorption in the proximal tubule and/or thin descending limb of Henle of deep nephrons. It is also associated with changes in renal interstitial pressure and the pressure and flow in the vasa recta circulation. These observations suggest that an elevation in renal medullary vascular resistance may be responsible for shifting the pressure-natriuresis relationship toward higher pressures in hypertension.
Identification of a platelet dense granule membrane protein that is deficient in a patient with the Hermansky-Pudlak syndrome, Monoclonal antibodies were raised after injecting mice with isolated human dense granules. Several of these monoclonals were found to recognize a 40-Kd dense granule membrane protein. Western blot and immunofluorescent analysis confirmed the dense-granule specificity. After thrombin activation. the protein was found in patches on the external platelet membrane. By Western blot and slot blot analysis. the protein was found to be markedly deficient in a patient with the Hermansky-Pudlak syndrome. Studies of neutrophils and endothelial cells show the presence of immunologically related granule-membrane protein(s). Western blots using four anti-synaptophysin antibodies and three antibodies to the platelet 40-Kd protein suggest that the protein may share some homology with. but is not identical to. the synaptosomal membrane protein synaptophysin.
Chromatin structural analysis of the 5' end and contiguous flanking region of the myeloperoxidase gene, Myeloperoxidase (MPO) synthesis is known to be associated with the promyelocyte stage of myeloid differentiation. In particular the downregulation of MPO gene transcription is associated with myeloid cell maturation. We examined the changes in the deoxyribonuclease I hypersensitive sites within the 5' end of the MPO gene and its 5' flanking region during dimethyl sulfoxide (DMSO)-induced differentiation of HL-60 cells to determine the changes in chromatin structure that accompany this process. The locations of hypersensitive sites surrounding the 5' end of the gene in proliferating. uninduced cells were determined: three were observed in the 5' flanking region and one within the gene. Progressive changes in all sites accompanied the downregulation of MPO transcription after treatment with DMSO. No evidence of hypersensitivity was observed in the chromatin region examined after 8 days of DMSO exposure. The results provide an example of the changes that occur in the chromatin structure of a gene as it is inactivated during differentiation.
Molecular basis of spectrin and ankyrin deficiencies in severe hereditary spherocytosis: evidence implicating a primary defect of ankyrin, While varying degrees of spectrin deficiency have been found in the majority of patients with hereditary spherocytosis (HS). a combined severe deficiency of both spectrin and the spectrin-binding protein. ankyrin. has been reported only in two patients with severe HS. To elucidate the molecular basis of these protein deficiencies. we have studied the synthesis. assembly. and the mRNA levels of spectrin and ankyrin in peripheral blood reticulocytes in one of the previously reported probands. Pulse-labeling studies showed that in HS reticulocytes. the synthesis of alpha-spectrin was comparable with control reticulocytes while that of beta-spectrin was increased about fourfold. presumably reflecting increased erythropoietic drive. On the HS reticulocyte membrane. the amount of newly assembled spectrin was reduced to about half of the control values. presumably reflecting a decrease in the synthesis of the spectrin binding protein. ankyrin: the ankyrin synthesis was nearly absent in the cytosol and the amounts of membrane-associated ankyrin were reduced to about half of the normal values. The changes in the amounts of spectrin and ankyrin mRNAs quantitated by slot blot and Northern blot analyses were comparable with changes in the synthesis of these proteins: The alpha spectrin mRNA was within a control range and the beta-spectrin mRNA was slightly increased. while the amounts of ankyrin mRNA were reduced to about 50% of control values. We conclude that the primary defect underlying the combined spectrin and ankyrin deficiency is a deficiency of ankyrin mRNA leading to a reduced synthesis of ankyrin which. in turn. underlies the decreased assembly of spectrin on the membrane.
Variation in hemoglobin F production among normal and sickle cell adults is not related to nucleotide substitutions in the gamma promoter regions, Single nucleotide substitutions in the promoter regions of the A gamma- and G gamma-globin genes have been associated with increased fetal hemoglobin (HbF) production. We wished to determine whether these or other unrecognized substitutions in the gamma promoter regions are responsible for the 20-fold variation in HbF production in sickle cell patients or normal adults. From a random sampling of 250 sickle cell (SS) patients and 125 normal adults. 17 individuals representing the highest and lowest HbF producers were selected for study. All three common restriction fragment length polymorphism beta-globin region haplotypes (Benin. Central African Republic. and Senegal) were found in both the highest and lowest HbF producers with SS disease. Using the polymerase chain reaction amplification and direct sequencing of the amplified DNA product. we examined the promoter regions of both the A gamma and G gamma genes from -350 bp to +50 bp of the CAP site. No mutations were found in either gamma gene promoter region. We conclude that nucleotide substitutions in the promoter regions (-350 to +50 bp) of both gamma genes are not responsible for the marked variation in HbF production among SS or normal individuals.
Hemoglobin Montreal: a new variant with an extended beta chain due to a deletion of Asp, Gly, Leu at positions 73, 74, and 75, and an insertion of Ala, Arg, Cys, Gln at the same location, The unstable hemoglobin Montreal with a deletion of three amino acid residues (Asp. Gly. Leu) at positions 73. 74. and 75 of the beta chain and an insertion of four residues (Ala. Arg. Cys. Gln) at the same location was observed in a 7-year-old Canadian boy suffering from a moderate hemolytic anemia. The introduction of an extra amino acid residue and of other changes in the crevice where the heme group is located is the likely cause of the instability of this hemoglobin variant. The above listed changes were detected through analyses of tryptic peptides of the beta-Montreal chain. sequencing of amplified DNA. and hybridization of amplified DNA with appropriate. 32P-labeled. oligonucleotide probes. It is suggested that a mispairing involving the AGTG sequences at codons 66 and 67 and at codons 72 and 73 of the normal beta gene caused a repetition of a 16-bp segment. while a deletion of 10 nucleotides due to recombination or slippage followed by a second short deletion during DNA repair resulted in the modified sequence of the beta-Montreal gene.
Toxicity and efficacy of anti-T-cell ricin toxin A chain immunotoxins in a murine model of established graft-versus-host disease induced across the major histocompatibility barrier, Graft-versus-host disease (GVHD) was induced across the murine major histocompatibility complex by injecting C57BL/6 (H-2b) bone marrow and splenocytes into lethally irradiated B10.BR (H-2k) murine recipients. An immunotoxin (IT) composed of a pan T-cell monoclonal antibody called anti-Ly1 (the murine homologue to human anti-CD5) was conjugated to ricin toxin A chain (anti-Ly1-RTA) and used to treat recipient mice. In vitro. IT was as active as free RTA. bound selectively. and inhibited T-cell proliferation even in the absence of potentiators. Mice administered anti-Ly1-RTA in vivo during ongoing GVHD. at a dose of 10 micrograms/d for 5 days. showed lower numbers of splenic Thy1.2+ T cells and significantly improved survival as compared with mice given phosphate-buffered saline (PBS) or irrelevant control RTA IT. Protection was transient because GVHD and weight loss occurred when injections ceased. Survival could not be enhanced by crosslinking RTA30. a low oligosaccharide-containing fraction of purified RTA. Treatment with anti-Ly1-RTA caused a significant elevation in neutrophils. and higher doses were associated with mild hepatotoxicity. In contrast. infusion of identical doses and schedules of another pan T-cell immunotoxin. anti-Thy1.2-RTA. caused a significant decrease in lymphocytes. but not neutrophils; a precipitous increase in weight; a decrease in total plasma protein (TPP); and an increase in pleural and peritoneal effusions reminiscent of vascular leak syndrome (VLS). Although the toxic effects of anti-Thy1.2-RTA were too severe to show a survival advantage in a GVHD model. histopathologic studies showed a definite anti-GVHD effect. The most significant decline in GVHD as compared with the PBS-treated controls was observed in skin. and to a lesser extent. in liver and lung. To investigate the cause of IT toxicity. anti-Thy1.2-RTA was administered intraperitoneally to lethally irradiated B10.BR (H-2k) recipients of syngeneic bone marrow. These recipients showed the same weight gain. hypoproteinuria. and VLS observed in the GVHD model. Death occurred at higher anti-Thy1.2-RTA doses (30 or 50 micrograms/daily injections administered days 8 through 12 posttransplant). Anti-Thy1.2-RTA had a negligible effect on renal function. but histologic studies showed patchy dropout of the renal tubules. Treatment resulted in pulmonary vascular congestion. but there was no pathologic evidence of liver. brain. or colon toxicity. Weight gain was enhanced by irradiation because nonirradiated normal mice did not undergo such a precipitous weight increase.(ABSTRACT TRUNCATED AT 400 WORDS).
Observations on the effect of chimeric anti-CD4 monoclonal antibody in patients with mycosis fungoides, Chimeric (murine/human) anti-CD4 monoclonal antibody was infused into seven patients with mycosis fungoides. Successive patients received doses of 10. 20. 40. and 80 mg of antibody twice a week for 3 consecutive weeks. All patients had some clinical improvement. but responses were of relatively short duration. Serum levels of chimeric antibody varied as a function of dose. At the 80-mg dose level. antibody was readily observed in biopsied skin lesions. Although there was coating by antibody of most CD4 positive cells in the blood. there was no significant depletion of CD4 positive cells. Low-level antibody responses against the mouse Ig variable region and human Ig allotypic constant region determinants were observed in several patients. but none were of clinical significance. All but two patients made primary antibody and T-cell proliferative responses to a simultaneously administered foreign protein test antigen. However. there was marked suppression of the mixed lymphocyte reaction. We conclude that at the dose levels studied. a chimeric anti-CD4 monoclonal antibody (1) had some clinical efficacy against mycosis fungoides; (2) was well tolerated; (3) had a low level of immunogenicity; (4) had immediate immunosuppressive effects; and (5) did not induce tolerance to a co-injected antigen.
Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel, Glanzmann thrombasthenia is a rare. inherited disorder of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex. We previously identified two distinct populations with this disorder in Israel. Iraqi-Jews and Arabs. The groups are indistinguishable in hemorrhagic symptoms and platelet GP IIB/IIIa receptor deficiency. but they differ in their platelet immunodetectable GP IIIa (beta 3). with the Iraqi-Jewish population expressing no detectable GP IIIa and the Arab population expressing small amounts. We have now examined the platelets of these two populations as well as normal platelets for the alpha v beta 3 vitronectin receptor. Normal platelets contained between approximately 50 to 100 alpha v beta 3 vitronectin receptors as judged by the binding of antibodies to both alpha v (LM142) and the intact alpha v beta 3 vitronectin receptor complex (LM609). In addition. normal platelets bound to immobilized vitronectin in the presence of 1 mmol/LMnCl2; the adhesion was mediated predominantly through GP IIb/IIIa. but with a distinct contribution by the alpha v beta 3 vitronectin receptor. as determined by monoclonal antibody inhibition studies. Iraqi-Jewish patients' platelets had a profound decrease in immunodetectable alpha v beta 3 vitronectin receptors. and their platelets did not adhere well to vitronectin. In contrast. Arab patients' platelets had normal or increased numbers of platelet alpha v beta 3 vitronectin receptors. and these receptors functioned well in the vitronectin adhesion assay. taking over much of the adhesion mediated by GP IIb/IIIa in normal platelets. These studies define further the heterogeneity of the molecular basis of Glanzmann thrombasthenia; they also have more widespread implications for understanding the synthesis and function of the beta 3 family of integrin receptors.
Incidence of advanced chronic renal failure and the need for end stage renal replacement treatment, OBJECTIVE--To determine the age related incidence of advanced chronic renal failure in two areas of England. DESIGN--Prospective study of patients newly identified as having advanced chronic renal failure within a two year period; subsequent monitoring of patients' clinical course for a further 26 months. SETTING--Devon and Blackburn. SUBJECTS--Those patients in a population of 708.997 who developed advanced chronic renal failure (serum creatinine concentration greater than 500 mumol/l) for the first time during a two year period. MAIN OUTCOME MEASURES AND RESULTS--210 Patients (148 per million population per year) developed advanced chronic renal failure. 117 (51%) of whom were over 70. The age related incidence rose from 58 per million per year in those aged 20-49 to 588 per million per year in those aged 80 or over. Only 54% (113) of patients were referred to a nephrologist; 120 patients (57%) needed dialysis or died within three months of presenting without receiving dialysis. and 187 (89%) died or needed dialysis within three years. After those unsuitable for further treatment had been excluded. 78 patients per million population per year aged under 80 needed to start long term renal replacement treatment. CONCLUSIONS--Many patients suitable for renal replacement treatment are still not referred for nephrological opinion and are denied treatment. If the treatment rate in the United Kingdom rose from the 1988 rate of 55.1 per million per year to 78 per million per year then the number of patients receiving treatment would rise to about 800 per million. This is double the present number and has considerable but predictable resource implications for the NHS.
Prevalence of advanced renal failure in Northern Ireland, OBJECTIVE--To determine the prevalence of advanced chronic renal failure in Northern Ireland as part of an assessment by the Renal Association of the level of service provision for treatment of such patients. DESIGN--Prospective notification of patients reaching a defined level of advanced chronic renal failure (serum creatinine concentration greater than or equal to 500 mumol/l or blood urea concentration greater than or equal to 25 mmol/l) within one year and follow up for at least three. and. at most. four years after notification. SETTING--Northern Ireland. PATIENTS--122 Patients with a serum creatinine or blood urea concentration higher than the defined level newly detected from 1 March 1985 to 28 February 1986. MAIN OUTCOME MEASURE--Survival after notification. RESULTS--77 Patients of all ages/million population/year had advanced chronic renal failure compared with 67/million/year between the ages of 5 and 80 found in an earlier study of the same population. 62% Of the patients were older than 50 years. Seventeen (14%) of the patients either required dialysis or died within one month of notification. 51 (42%) survived for at least three months. and 23 (19%) for one year or longer. Three patients. all of whom were attending a renal clinic. survived for periods of 43. 45. and 46 months respectively without renal replacement treatment. CONCLUSIONS--The increased number of new patients disclosed in this survey compared with the earlier survey is mainly owing to an increased number of older patients. Such patients often have disabilities other than renal failure. are less likely to be capable of self treatment. may develop complications more often and require more frequent hospital admissions. and may not be suitable for transplantation and consequently have considerable resource implications for the NHS.
Six years' audit of laboratory workload and rates of referral for colposcopy in a cervical screening programme in three districts, OBJECTIVE--To determine laboratory workload and rates of referral for colposcopy in a three district cervical screening programme during 1983-9 to assess the feasibility of accommodating call up of all women at risk. recall at three year intervals (now five year intervals). and investigation of women with all degrees of abnormality. DESIGN--Analysis of computerised screening histories dating back to 1977 of women screened in the Avon cervical screening programme. SETTING--Three district health authorities covering the population of Bristol and Weston-super-Mare. comprising 800.000 people. of whom 250.000 were female residents aged 20 to 64. SUBJECTS--196.977 Women aged 20 to 64 screened in cervical screening programme since 1983. RESULTS--Laboratory workload devoted to follow up of women with abnormalities increased sharply between 1987-8 and 1988-9. with increases of 54% (from 2075 to 3196) in the number of smears for follow up of severe dyskaryosis and invasive cancer. 40% (from 1925 to 2695) for mild and moderate dyskaryosis. and 49% (from 1793 to 2677) for borderline change. The increases were partly explained by the introduction in April 1988 of protocols for follow up and investigation based on guidance in an intercollegiate working party report. The proportion of women with mild and moderate dyskaryosis who were recommended for referral for colposcopy increased steadily from 9.9% in 1983-4 to 79.9% in 1988-9. and for borderline change the proportions were 3.5% and 13.6% respectively. Of all women tested in 1988-9. referral for colposcopy was recommended in 3%. CONCLUSIONS--The increase in laboratory follow up work identified. if it continued. could result in half of existing laboratory capacity in Avon being devoted to follow up work by 1993. with little prospect of maintaining call. recall. and quality control. Investigation of all women with minor cytological abnormalities is neither justifiable nor sustainable and will undermine the benefits of screening by increasing the rate of false positive results and the financial costs.
Audit of major colorectal and biliary surgery to reduce rates of wound infection, OBJECTIVE--To reduce the rates of wound infection for major colorectal and biliary surgery. DESIGN--Prospective audit of antibiotic prophylaxis by keeping copies of typed notes of operations and annotating them at discharge and at first follow up visit and annual review of prophylactic regimen according to yearly rate of wound infection and modification if necessary. SETTING--The work of one consultant surgeon working in a district general hospital. PATIENTS--All patients having major colorectal resection during 1976-89 (400) and cholecystectomy during 1981-9 (500). MAIN OUTCOME MEASURES--Wound infection. defined as any discharge from the wound as detected by observation during inpatient stay and by specific questioning at the first follow up visit six weeks later. RESULTS--Serial changes in prophylaxis for colorectal surgery resulted in a progressive reduction in the rate of wound infection from 43% in 1976. with no prophylaxis. to 1% during 1986-9 with single intravenous doses of metronidazole and cefuroxime intraoperatively and with lavage of the peritoneal cavity and wound with 0.1% tetracycline. During 1981-7. with no prophylaxis. the rate of infection in biliary surgery was 12% whereas in 1988-9. after the introduction of lavage with tetracycline alone. the rate was reduced to 2%. IMPLICATIONS AND ACTION--Simple prospective audit identified the need for changes in antibiotic prophylaxis; successive rounds of audit resulted in improved rates of wound infection. and lavage with 0.1% tetracycline seemed to be a major factor in achieving this.
How district health authorities organise cervical screening [published erratum appears in BMJ 1990 Nov 24;301(6762):1209, OBJECTIVES--To examine how district health authorities organised cervical screening with respect to Department of Health guidelines and to determine their assessment of the problems encountered. DESIGN--Postal questionnaire sent to all 190 district health authorities in England in 1989. PARTICIPANTS--190 District health authorities in England. MAIN OUTCOME MEASURES--Population coverage of screening. quality of smear testing. and follow up of abdominal test results in comparison with national guidelines for district cervical screening services. and problems encountered by districts. RESULTS--Replies were received from 178 (94%) of districts. in 143 of which the person named as responsible for cervical screening contributed. All districts implemented a computer managed scheme. 150 by the target date of 31 March 1988. but not all of these conformed with the guidelines. At the time of the survey only just over half called women in the target age group of 20-64 and only 70% expected to meet the target date of 13 March 1993 for completing the call. Considerable variation was evident among the schemes with regard to how they dealt with issues related to population coverage. quality of testing. and follow up of abnormal results. The problems most commonly identified by the districts (n = 174) were laboratory workload (107. 61%). computer software (104. 60%). availability of resources (78. 45%). non-attendance (77. 44%). rate of opportunistic screening (62. 36%). and investigation and treatment (60. 34%). CONCLUSIONS--Current practice in running cervical screening schemes needs to be examined to determine the extent to which it contributes to the goal of reducing mortality from cervical cancer.
Brain death and organ donation in a neurosurgical unit: audit of recent practice, OBJECTIVE--To assess the potential for increasing the yield of donors by comparing the current pattern of brain death and organ donation in a neurosurgical unit with that reported in 1981 and with a recent national audit. DESIGN--Retrospective review of all deaths for 1986. 1987. and 1988 and prospective data for 1989. SETTING--A regional neurosurgical unit serving 2.7 million population. RESULTS--Of 553 deaths. 35% (191) patients died while on a ventilator and 17% (92) after discontinuation of ventilation. Medical contraindications to donation were found in 23% (32) of 141 patients tested for brain death. in 38% (19) of 50 patients who died while being ventilated who were not tested. and in 12% (11) of 92 patients no longer being ventilated. Consent for donation was sought in 88% (96) of 109 medically suitable brain dead patients and granted in 70% (67) of these. Half those with permission for multiorgan donation had only the kidneys removed. CONCLUSIONS--More organs may be lost owing to transplant team logistics than by failure to seek consent from relatives of brain dead patients. The estimated size of the pool of potential donors depends on what types of patients might be considered. Ensuring that all who die while being ventilated are tested for brain death and considering the potential for donation before withdrawing ventilation could yield more donors. Ventilating more patients who are hopelessly brain damaged to secure more donors raises ethical and economic issues.
Effect of tetrahydroaminoacridine on cognition, function and behaviour in Alzheimer's disease, OBJECTIVE: To determine the efficacy of tetrahydroaminoacridine (THA) in Alzheimer's disease. DESIGN: Randomized. double-blind. multiple crossover trial with three treatment periods. each consisting of 3 weeks of active drug therapy and 3 weeks of placebo administration. SETTING: Referral-based geriatric practice in a community hospital. PATIENTS: Thirty-four patients with moderate to severe Alzheimer's disease. Subjects were included if they had stage 3 to 6 disease (as determined by the Reisberg scale) and had not been taking psychotropic drugs for at least 1 month and if informed consent had been obtained from the patients and their next of kin. INTERVENTIONS: Fifty to 100 mg of THA daily and matched placebo. RESULTS: Of the initial 34 patients 14 experienced liver toxicity and 3 gastrointestinal side effects during the study; however. all 22 who completed the study were able to tolerate at least the minimum dose. For the 22 patients there was no clinically or statistically significant effect of THA on cognition. functional status or behaviour. The results for individual patients showed no subgroup of THA-responsive patients. CONCLUSION: THA has no clinically important benefits in Alzheimer's disease and is associated with appreciable toxic effects.
Mechanism of bronchodilator effect in chronic airflow limitation, OBJECTIVE: To examine the mechanisms through which two bronchodilators (theophylline and salbutamol) influence dyspnea during daily activities. METHODS: Twenty-four patients with chronic airflow limitation participated in a multiple crossover. randomized. placebo-controlled trial. The effect of theophylline and salbutamol. alone or combined. on pulmonary function and dyspnea during daily activities was examined. Correlations of changes in forced expiratory volume in 1 second (FEV1) and maximum expiratory pressures (MIPs) (independent variables) and changes in dyspnea score during daily activities (dependent variable) were also examined. RESULTS: The two drugs proved to be beneficial the effects in general were additive rather than synergistic. The drugs improved the FEV1; theophylline significantly improved the MIPs. The correlation between the changes in FEV1 and those in dyspnea score. after adjustment for the changes in MIPs. was 0.55 (p less than 0.001). The correlation between the changes in MIPs and those in dyspnea score. after adjustment for the changes in FEV1. was 0.39 (p less than 0.001). CONCLUSIONS: Changes in airway calibre and in respiratory muscle strength play an independent and important role in dyspnea during daily activities in patients with chronic airflow limitation. Changes in airway calibre may be of greater importance.
Etoposide. Current and future status, Etoposide (VP-16-213) is an antineoplastic agent with demonstrated efficacy against a broad spectrum of human malignancies. including testicular. germ cell. lung. and other cancers. Etoposide can be synergistic with other agents. As part of combination chemotherapy. etoposide has become a so-called standard in therapies for testicular cancer and small cell lung cancer. Its activity in tumors such as lymphoma and leukemia. as well as solid tumors. identifies etoposide as a highly important chemotherapeutic agent. Cellular and animal models have shown that the cell kill and tumor response depend on both dose and time of exposure. Recent clinical studies again show that dose and schedule of etoposide can have important effects on clinical response to the drug. Further research should now continue: (1) on the use of etoposide as part of initial therapy in several cancers. and (2) in higher doses and prolonged schedules to optimize this agent's potential.
Etoposide therapy for testicular cancer, During the past two decades. dramatic strides have been made in the treatment of metastatic testicular cancer. In the early 1970s. cisplatin. vinblastine. and bleomycin (PVB) produced durable complete remissions (CR) in approximately 70% of treated patients. In the early 1980s. etoposide emerged as the only drug with single-agent activity in cisplatin-refractory patients. Based on preclinical data demonstrating synergy of cisplatin plus etoposide. the two-drug combination proved to be a useful salvage therapy. curing approximately 25% of such patients. Further evaluation of etoposide as part of initial therapy by the Southeastern Cancer Study Group (SECSG) compared PVB with bleomycin. etoposide. and cisplatin (BEP) in previously untreated patients with metastatic germ cell tumors. Not only did BEP have significantly less toxicity. it proved to be superior to PBV in patients with advanced disease. Varying the dose and schedule of etoposide also may provide patients with potentially useful avenues of treatment. High-dose etoposide plus carboplatin in drug-refractory patients has produced durable CR in a cohort of treated patients; it is currently being evaluated as part of initial salvage therapy. The schedule dependency of etoposide in small cell lung cancer led us to evaluate daily oral administration of etoposide in patients refractory to previous etoposide therapy; objective response rates of approximately 15% to 25% were observed. In summary. etoposide remains an integral part of the treatment regimen for testis cancer. However. the incorporation of innovative dose and schedule combinations for etoposide may further improve its therapeutic index for this disease.
New chemotherapies for ovarian cancer. Systemic and intraperitoneal podophyllotoxins, The epipodophyllotoxin derivatives etoposide and teniposide have been evaluated intermittently for possible use in the treatment of ovarian cancer. Conflicting studies suggest that variables such as dose and prior treatment have a major influence on outcome. Response rates ranged from 0% to 40% in five series with teniposide. and from less than a 10% overall response rate to greater than a 10% complete response rate in nine studies with etoposide. One study documented activity with oral etoposide. However. because all patients had received various prior chemotherapies. firm conclusions regarding the activity of etoposide could not be drawn. These results. and the expectation of synergy with etoposide and cisplatin. led to several studies that combined etoposide with platin compounds by the systemic and intraperitoneal (IP) routes. Various studies have used intravenous drug combinations of these agents in both previously treated and untreated patients. One study. which used carboplatin instead of cisplatin. reported only seven failures among 26 previously untreated patients. Conversely. the prominent toxicities reported by another study were discouraging. and responses did not exceed what might be expected from cisplatin alone. Studies of analogous combinations administered IP are ongoing. A favorable experience. which was initially reported by the University of California (San Diego group). is being confirmed by other investigators. This has prompted the incorporation of etoposide into first-line strategies. The pharmacologic advantage of etoposide by the IP route (related to its high protein binding) may provide appropriate dose intensity against IP disease while sparing systemic toxicities. Finally. systemic dose intensity with autologous bone marrow support indicates some promise for etoposide in combination with high-dose alkylating drugs.
Current status of etoposide in the management of small cell lung cancer, Etoposide is a schedule-dependent drug with excellent activity against small cell lung cancer (SCLC). Single-agent etoposide achieves overall response rates ranging from 15% to 84%. depending on the schedule of drug administration and the characteristics of the treated population. The route of etoposide administration (intravenous versus oral) has little impact on response rate. provided appropriate dose adjustments are made for oral therapy. In combination with other active agents. etoposide has proven particularly effective in the management of SCLC. Etoposide can be substituted for doxorubicin or vincristine in the cyclophosphamide. doxorubicin. and vincristine (CAV) regimen without loss of efficacy. The etoposide and cisplatin (EP) combination is thought to be synergistic and has proven to be an effective salvage regimen for CAV failures. A regimen that alternates CAV and EP has been found by some investigators to be modestly more effective against SCLC than CAV alone; however. EP alone may be as useful as an alternating regimen. Most studies to date have demonstrated that EP induction is at least as effective as any other standard induction regimen. However. EP has the potential advantage of being more easily integrated with thoracic radiation therapy (RT). This is particularly important in limited-disease patients: two recent pilot studies employing EP induction with hyperfractionated thoracic RT yielded 2-year survival rates of greater than 50%. These promising results are being evaluated further in an ongoing Phase III trial in the United States. The available data indicate that etoposide is one of the most active agents against SCLC and therefore should be included as a component of induction therapy in all patients. New schedules of etoposide administration warrant further study.
A randomized trial to compare intravenous and oral etoposide in combination with cisplatin for the treatment of small cell lung cancer, In a randomized multi-center study. 83 patients with small cell lung cancer were randomly assigned to treatment with cisplatin 100 mg/m2 intravenously (IV) day 1 and etoposide 120 mg/m2 IV days 1. 2. and 3 or cisplatin 100 mg/m2 IV day 1 and etoposide 120 mg/m2 IV day 1 and 240 mg/m2 orally days 2 and 3. Both regimens were repeated every 4 weeks. Prior to randomization. patients were stratified by extent of disease. performance status. and gender. A total of 41 patients were randomly assigned to the parenteral treatment only regimen. and 42 patients received cisplatin and IV/oral etoposide therapy. Both treatment arms were comparable regarding patient characteristics. Limited disease (LD) patients constituted 52% and 49% of the patient population for the oral and IV etoposide regimens. respectively. The overall complete response (CR) and partial response (PR) rate was 50% (95% confidence interval [CI] 35% to 65%) for the oral etoposide regimen and 59% (95% CI 44% to 74%) for the IV etoposide regimen (P = 0.438). For both regimens. 55% of the LD patients achieved either CR or PR. Time to progression and survival were comparable for both treatment arms. Hematologic toxicity was comparable in both treatment arms. with 80% of patients experiencing grade 3 or 4 neutropenia or thrombocytopenia. Moderate to severe anemia and weight loss were more predominant with the IV than with the oral regimen.
Current strategies in the management of locoregional and metastatic gastric carcinoma, Gastric carcinoma remains a significant cause of death worldwide. A patient's prognosis depends on the degree of gastric wall penetration. presence of lymph node metastases. and location of the primary site. Metastatic gastric carcinoma is currently incurable. However. chemotherapy continues to evolve at a rapid pace. Active agents include 5-fluorouracil (5-FU). doxorubicin. cisplatin. methotrexate. mitomycin. and etoposide. Combination etoposide. doxorubicin. and cisplatin (EAP) has been reported to result in encouragingly high response rates. including a 10% complete response rate in patients with metastatic gastric carcinoma. Trials are now under way to confirm these results. Similarly. another etoposide-based combination. etoposide. leucovorin. and 5-FU (ELF). has resulted in an equally good response rate but less toxicity than EAP. The 5-FU. doxorubicin. and methotrexate (FAMTX) regimen. previously reported to have an excellent response rate. is also being investigated further. For patients with locoregional carcinoma. curative resection rate is often unsatisfactorily low; however. curative resection is consistently associated with improved survival (between 23 and 26 months). In patients with potentially resectable carcinoma. two significant problems must be recognized: (1) a low rate of curative resection and (2) the development of widespread carcinoma despite curative resection. Despite many attempts. the postoperative strategies of adjuvant chemotherapy have been ineffective. New strategies must be investigated aggressively. Combination etoposide. 5-FU. and cisplatin (EFP) has been administered preoperatively and postoperatively to patients with resectable gastric carcinoma. resulting in an encouraging curative resection rate (greater than 70%) and manageable toxicity. Based on promising results reported with EAP in patients with unresectable locoregional carcinoma of the stomach. a trial of preoperative and postoperative EAP in potentially resectable carcinoma of the stomach is now under way.
Etoposide in the management of metastatic breast cancer, Etoposide. despite extensive use in other malignancies. has played a minor role in the treatment of patients with breast cancer. Single-agent trials in which etoposide is administered to heavily pretreated patients with metastatic breast cancer have demonstrated a low overall response rate (6.6% of 383 patients). with no convincing evidence for either schedule dependence or a relationship between dose intensity and response. The sole single-agent trial in previously untreated patients suggested that the drug has an approximately 15% response rate in untreated patients. Combination therapy trials in which etoposide has been combined with either cyclophosphamide. doxorubicin. or cisplatin have not yet convincingly demonstrated superiority over any of these drugs as single agents. although cisplatin plus etoposide appears to be superior to either agent alone. In vitro studies suggest that pretreating hormone-sensitive breast cancer cells with estradiol may increase their sensitivity to etoposide-induced DNA cleavage. This may represent a future direction in the use of etoposide in breast cancer. Currently. however. the use of etoposide in breast cancer should be considered investigational.
The evolving role of etoposide in the management of lymphomas and Hodgkin's disease, Etoposide. a derivative of epipodophyllotoxin. is one of the most important new drugs that was introduced into the management of the malignant lymphomas during the past decade. A growing number of specific protocols include this useful agent in the management of malignant lymphoma. both at the time of primary treatment and at relapse. The broad activity of etoposide across several histologic subtypes of malignant lymphoma and Hodgkin's disease indicates a potential that is only now being fully exploited. Used according to optimal doses and schedules. etoposide has single-agent activity that rivals earlier drugs such as the alkylating agents and doxorubicin. Functioning as a protein synthesis and topoisomerase II inhibitor. it offers the potential for non-cross-resistant cytotoxicity. After a brief comment on the single-agent activity of etoposide. this report will focus on the integration of etoposide into multiagent protocols used in the primary treatment of malignant lymphoma and Hodgkin's disease. The specific findings from protocols such as prednisone. methotrexate. doxorubicin. cyclophosphamide. etoposide-cytarabine. bleomycin. vincristine. and methotrexate (Pro-MACE-CytaBOM) (US National Cancer Institute [NCI]) and etoposide. doxorubicin. cyclophosphamide. vincristine. prednisone. and bleomycin (VACOP-B) (Vancouver) for the primary treatment of malignant lymphoma. and vinblastine. etoposide. cyclophosphamide. doxorubicin. bleomycin. vincristine. and prednisone (VECABOP) (Vancouver) for the treatment of previously untreated patients with advanced Hodgkin's disease will be discussed.
Etoposide in leukemia, Etoposide (VP16-213. NSC 141540) induces a complete response (CR) in 15% to 25% of previously treated patients with acute nonlymphocytic leukemia (ANLL) when used as a single agent. Etoposide has been used successfully in combination with cytarabine. daunorubicin. and amsacrine for salvage and consolidation therapies. Previously untreated ANLL patients 15 to 70 years of age were randomly assigned to cytarabine (100 mg/m2) on days 1 to 7 plus daunorubicin (50 mg/m2) on days 1 to 3 (7-3) or to the same drugs plus etoposide (75 mg/m2) on days 1 to 7 (7-3-7). Patients achieving a CR received two consolidation courses (5-2. attenuated 7-3 or 5-2-5). Among 264 eligible patients. there was a 56% CR rate with 7-3 therapy and a 59% CR rate with 7-3-7 therapy. Remission duration was significantly improved with 7-3-7 (median. 12 months with 7-3 and 18 months with 7-3-7; P = 0.01). but survival was not. Subset analysis in patients younger than 55 years of age revealed prolonged remission (median. 12 months with 7-3 and 27 months with 7-3-7; P = 0.01) and survival (median. 9 months with 7-3 and 17 months with 7-3-7; P = 0.04) with the 7-3-7 regimen. Hematologic toxicity was similar for both regimens during induction. but significantly more severe for 7-3-7 during consolidation therapy. Etoposide is active in ANLL and prolongs remission when used in induction therapy.
High-dose etoposide and marrow transplantation, Etoposide underwent conventional Phase I testing in the 1970s. The dose-limiting toxicity in these studies was mild myelosuppression; other toxicities were infrequent. If a greater degree of myelosuppression is accepted. higher than standard doses could be given. This approach takes advantage of the steep dose-response relationship for most chemotherapeutic agents. including etoposide. as shown in early in vitro and clinical studies. Thus. etoposide was considered an ideal agent for further dose-escalation studies. given its wide range of clinical antitumor activity at standard doses. steep dose-response curve. mild bone marrow suppression. and few nonmyeloid side effects. The high-dose etoposide studies that followed used improved and more intensive hematologic supportive care. including. in some trials. autologous marrow transplantation. When etoposide was used as a single agent in these high-dose trials. mucositis. and. to a lesser degree. hepatic dysfunction were dose-limiting. The maximum tolerated dose (MTD) in this setting was 2.4 to 3.0 g/m2. Multi-agent Phase I trials with etoposide and cyclophosphamide. total body irradiation. carmustine. or carboplatin also resulted in dose-limiting mucosal toxicity. with liver and lung problems appearing more often than with high-dose etoposide alone. The toxicity and MTD can be influenced markedly by the schedule of administration. Etoposide as a continuous intravenous infusion can be given at doses of 4.2 g/m2 (with 200 mg/kg cyclophosphamide) with similar toxicity. but without marrow support. The antitumor results in the lymphomas set the stage for treatment of solid tumors. where treatment of patients with "sensitive" relapses had the best outcome. Lymphoma patients had an 80% response rate; overall. long-term (greater than 2 years) disease-free survival was approximately 40%. Germ cell tumors were also responsive. and the same pattern of sensitive relapses and improvement in responding patients was seen (50% to 75% of patients greater than 1 year). In breast cancer and small cell lung cancer (SCLC). high-dose etoposide-containing regimens were used to intensify standard therapy. The results in these settings were not quite as good (breast cancer. 30% disease-free survival at 2 years; SCLC. 10% at 2 years).
The pharmacology of intravenous and oral etoposide, The epipodophyllotoxin derivative etoposide (VP-16) has been in widespread use both alone and in combination chemotherapy for the past decade. It has phase-specific cytotoxicity that acts in the last S and G2 phases of the cell cycle. Although its mode of action is not certain. it appears to act by causing breaks in DNA by interaction with DNA-topoisomerase II or by the formation of free radicals. Most studies show biexponential decay after the intravenous (IV) administration of etoposide. Approximately 30% to 70% of administered etoposide is excreted. with approximately 45% present in the urine. Etoposide is available in oral and IV preparations. It is highly schedule-dependent. with once-daily doses (e.g.. for 5 to 8 days every 21 days) giving results superior to intermittent administration. The bioavailability of oral etoposide is approximately 50%. but its absorption is not linear with increasing dose (e.g.. greater than 200 mg/d. bioavailability decreases). Factors influencing the bioavailability of oral etoposide include patient status. concurrent medications. hepatic and renal function. and nausea and vomiting. In numerous clinical trials. etoposide has demonstrated excellent activity against a range of tumors. including small cell lung cancer (SCLC). malignant lymphomas. gestational trophoblastic tumors. Ewing's and soft tissue sarcomas. and germ cell tumors. with more modest activity in other tumors (e.g.. non-SCLC). Although few comparative studies have been carried out. available data suggest that oral etoposide administered daily during 5 to 8 days is similar to the IV preparation in range of activity. In a study of 53 elderly patients with SCLC treated with etoposide (200 mg/d for five times). there was a response rate of 79% and a median survival of 9.5 months. These results were similar to those achieved with more intensive IV regimens. Several studies of chronic oral etoposide (50 mg/m2/d for 21 times) have been reported recently. Responses were observed in SCLC and germ cell tumors among patients who had relapsed after standard etoposide-containing regimens. These data suggest that etoposide may be a "new" drug when given in this schedule. The high response rates with oral etoposide suggest that oral administration may be substituted for IV administration. This substitution may allow for greater flexibility in chemotherapeutic administration. less hospitalization. and more acceptable toxicity.
Chronic oral etoposide, Etoposide is an important drug that has been recently incorporated with other agents in the curative treatment of patients with advanced neoplasms. including germ cell tumors. non-Hodgkin's lymphomas (NHL). and small cell lung cancer (SCLC). Etoposide demonstrates remarkable schedule dependency. A randomized comparison has shown an impressive survival difference for patients with extensive SCLC receiving a 5-day course versus those receiving a 1-day course. Because of these and previous clinical and laboratory data. etoposide is now given intravenously or orally in a 3-day to 5-day schedule. It is generally accepted that approximately 50% of the orally administered drug is absorbed. The authors have initiated several etoposide studies using an extended administration schedule. believing that a prolonged schedule may be superior to the standard 3-day to 5-day schedule. This was initially tested in a Phase I study. Results showed that etoposide (50 mg/m2/d) given over 21 days was feasible and was associated with only moderate toxicity. Several Phase II studies have been completed or are nearing completion. including studies in patients with SCLC. NHL. germ cell tumors. soft tissue sarcoma. renal carcinoma. and ovarian carcinoma. Responses have been seen in all of these groups. particularly in patients with SCLC. lymphoma. and germ cell tumors. In these groups we saw responses in patients who were clearly resistant to etoposide plus cisplatin given in a standard schedule or in some patients who were resistant to high-dose etoposide with bone marrow transplantation. Investigators at Indiana University Medical Center who studied oral etoposide in a similar fashion in patients with advanced germ cell tumors and SCLC achieved results similar to those reported here. The authors have initiated a number of combination chemotherapy programs using the chronic oral form of etoposide. These include patients with SCLC. non-small cell lung cancer. and elderly patients with high-grade and intermediate forms of NHL. In addition. chronic intravenous oral etoposide is being used in salvage approaches for patients with acute myelocytic leukemia and recurrent resistant intermediate-grade and high-grade NHL. Preliminary pharmacokinetic data suggest that a 50-mg/m2 oral dose is highly bioavailable (91% to 96%). Therefore. during a prolonged oral course at 50 mg/m2. many patients maintain a minimum plasma concentration of 1 microgram/ml. Further studies of multiple dose or continuous infusion etoposide to maintain a potentially critical plasma level are in progress. Etoposide administered in this way could represent a "new" drug because many of its features are different. and its activity spectrum may be broader.
Future directions for etoposide therapy, Etoposide is an important chemotherapeutic agent in the treatment of selected patients with germ cell tumors. lymphomas. and small cell lung cancer (SCLC). Its optimal use is continuing to evolve. It is clear that schedule dependency is of critical importance. Recently. preliminary studies have suggested that a prolonged schedule of etoposide administration (21 days) may be more effective than the standard 3- to 5-day schedule. Results of several Phase II studies show chronic oral etoposide administration induces occasional responses in resistant tumors and higher-than-expected response rates in patients with germ cell tumors and SCLC. Preliminary data show nearly 90% etoposide absorption when given in a low-dose schedule (50 mg/m2/d) for 21 days. These observations indicate that etoposide may be a "new drug" when given in the chronic schedule. Further exploration of the schedule dependency of etoposide is indicated. Etoposide has recently been proven useful in selected patients with gastric. ovarian. and poorly differentiated carcinoma of unknown primary site. Several other drugs are either synergistic or additive and will be explored in combination chemotherapy. The possibility of adding topoisomerase I inhibitors and modulating etoposide's activity by inhibiting drug resistance is now within the realm of human testing.
The clinical pharmacology of etoposide, Etoposide. a semisynthetic derivative of podophyllotoxin. is increasingly used to treat cancer. Etoposide is a phase-specific. cytotoxic drug acting in the late S and early G2 phases of the cell cycle. It appears to cause breaks in DNA by either an interaction with DNA-topoisomerase II or the formation of free radicals. Most studies show a biexponential decay after the intravenous (IV) administration of etoposide. The peak plasma concentrations of drug and the area under the concentration versus time curve (AUC) are linearly related to the IV dose. Considerable interpatient variability of pharmacokinetic variables exists after IV etoposide. Various metabolites of etoposide have been identified. but their detection and quantitation are disputed. Approximately 30% to 70% of an etoposide dose is excreted. The bioavailability of oral etoposide is approximately 50%. but its absorption is not linear with increasing doses within the range in clinical use. Considerable interpatient and intrapatient variability exists in the pharmacokinetics of oral etoposide. There is no evidence of etoposide accumulation after multiple consecutive doses by either the IV or oral route. The exact roles of the liver and kidney in metabolism and excretion of etoposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This. together with the phase-specific action of etoposide and its increasingly widespread use in treating cancer. makes the clinical pharmacology of this drug of great clinical importance.
Role of basic fibroblast growth factor in vascular lesion formation, In the present study we investigated whether basic fibroblast growth factor (bFGF) plays a role in the proliferative response of smooth muscle cells (SMCs) to denuding injury. Rat carotid smooth muscle was found to express the mRNA for bFGF. and bFGF protein was found to be present in rat aorta by immunoblot analysis. Systemically administered bFGF was a potent mitogen for vascular SMCs in arteries denuded with a balloon catheter. increasing replication from 11.5% in controls to 54.8%. Denudation with a device (filament loop). which causes only minimal damage to medial SMCs. showed a similar increase in replication (1.3% versus 43.3%) after bFGF infusion. In unmanipulated vessels. however. SMCs were unresponsive to infused bFGF. Infusion of a "mitotoxin" (bFGF conjugated to saporin) caused a greater than 50% decrease in the number of viable SMCs in the arterial wall after balloon injury. Prolonged administration of bFGF (12 micrograms/day for 2 weeks) after balloon injury caused an approximately twofold increase in intimal thickening. These results show that bFGF. which is synthesized by the arterial wall. could be a potent mitogen for SMCs in vivo and suggest that any release of endogenous bFGF may be capable of stimulating SMC proliferation. which may subsequently lead to intimal lesion formation.
Myocardial capillary permeability after regional ischemia and reperfusion in the in vivo canine heart. Effect of superoxide dismutase, This study assesses the effect of the superoxide anion scavenger superoxide dismutase on myocardial capillary permeability-surface area (PS) products for small hydrophilic molecules after ischemia and reperfusion. Open-chest dogs underwent a 20-minute occlusion of the left anterior descending coronary artery followed by 1 hour of reperfusion. Myocardial plasma flow rate and capillary extraction of chromium 51-labeled EDTA or technetium 99m-labeled diethylenetriaminepentaacetic acid were measured by the single-injection. residue-detection method before ischemia and 5 and 60 minutes after the start of reperfusion. In 13 dogs. no scavenger treatment was given (nonprotected control group). whereas eight dogs were treated systemically with 15.000 units/kg superoxide dismutase during 1 hour. starting 20 minutes before ischemia. In the control group. three dogs developed reperfusion ventricular fibrillation in contrast to none in the superoxide dismutase group. Before ischemia. plasma flow rate. myocardial capillary extraction fraction. and PS values were similar in the two groups. Five minutes after the start of reperfusion. plasma flow rate increased significantly (p less than 0.01) in both groups. In the control group. capillary extraction fraction increased by 12% (p = NS) in spite of the higher plasma flow; these increases in capillary extraction fraction and plasma flow induced a 69% increase in PS (p less than 0.01). In the superoxide dismutase-treated group. capillary extraction fraction decreased by 32% (p less than 0.05) in accordance with the increased plasma flow rate. resulting in an unchanged PS (p = NS). Sixty minutes after reperfusion. plasma flow rate. capillary extraction fraction. and PS returned to preocclusion values in both groups (p = NS). The increased capillary extraction fraction and PS values seen in the control group suggest an increased capillary permeability after ischemia and reperfusion. Superoxide anions seem to participate. directly or indirectly. in this response.
Mechanism of early ischemic contractile failure. Inexcitability, metabolite accumulation, or vascular collapse, The basis of early ischemic contractile failure was investigated in perfused ferret hearts at 27 degrees C. Isovolumic left ventricular developed pressure fell by more than 50% within 30 seconds of the onset of total global ischemia and reached zero by 5 minutes. Monophasic action potential recordings revealed no decrease in excitability during this period. Phosphorus nuclear magnetic resonance spectra obtained at 30-second resolution showed no significant changes in inorganic phosphate or phosphocreatine during the first 30 seconds of ischemia. Intracellular pH (pHi) and ATP changed even more slowly; therefore. none of these metabolites could account for the rapid fall in force. To gauge the contribution of intravascular pressure. we compared ordinary aortic flow occlusion with tissue-level ischemia induced by massive coronary microembolization at the level of the precapillary arterioles. Functional depression developed significantly more slowly in the microembolized hearts. despite accumulation of inorganic phosphate and protons comparable with that in ordinary ischemia. After microembolization. the time course of functional depression reflected much more closely the concomitant inorganic phosphate and pHi changes. Thus. our results provide novel evidence supporting the importance of vascular collapse in the mechanism of early ischemic contractile failure.
Endothelin and increased contractility in adult rat ventricular myocytes. Role of intracellular alkalosis induced by activation of the protein kinase C-dependent Na(+)-H+ exchanger, Endothelin. a 21-amino acid vasoactive peptide. is among the most potent positively inotropic agents yet described in mammalian heart. Having demonstrated that endothelin's inotropic effect is due. in part. to an apparent sensitization of cardiac myofilaments to intracellular calcium. we determined whether this could be due to a rise in intracellular pH (pHi). In isolated adult rat ventricular cells loaded with the H(+)-selective fluorescent probe BCECF. 100 pM endothelin increased contractile amplitude to 190 +/- 26% of baseline and pHi by 0.08 +/- 0.02 (n = 8). whereas 1 nM endothelin increased pHi by 0.13 +/- 0.03 with little further increase in contractility. Amiloride (10(-4)M) prevented the increase in pHi in response to endothelin and reduced the inotropic response by 45%. although the inotropic effect could be readily restored by subsequent NH4Cl-induced alkalinization. Similarly. inhibitors of protein kinase C (H-7 and sphingosine) diminished or abolished the rise in pHi after endothelin superfusion while causing a decline in its inotropic effect comparable with that observed with amiloride. Pretreatment with pertussis toxin. which we have demonstrated results in complete ADP-ribosylation of the alpha-subunits of Go and Gi GTP-binding proteins and abolition of endothelin's positive inotropic effect. only partially reduced the intracellular alkalinization induced by the peptide. suggesting a complex signal transduction mechanism. Thus. the positive inotropic action of endothelin is due in part to stimulation of the sarcolemmal Na(+)-H+ exchanger by a protein kinase C-mediated pathway. resulting in a rise in pHi and sensitization of cardiac myofilaments to intracellular Ca2+.
Mathematical models of myosin heterodimer formation in the rat heart during thyroid hormone alterations, To characterize the mechanisms involved in the formation of the myosin heavy chain (MHC) heterodimer V2 (alpha beta-MHC) and the homodimers V3 (beta beta-MHC) and V1 (alpha alpha-MHC). 82 5-week-old normotensive rats with homogeneous V1 were made hypothyroid with propylthiouracil (0.8%. drinking water). and the proportion of V2. V3. and V1 was determined by pyrophosphate gel electrophoresis in multicellular specimens of the left and right ventricles. After the switch from alpha-MHC to beta-MHC. the beta-MHC occurred initially in the form of the heterodimer. After 4 and 6 days. V2 was greater (p less than 0.05) than V3. At day 8. V2 was smaller than V3. and at day 10. V2 was not statistically different from V3. From day 12 onward. V2 was smaller than V3. After 21 days. the propylthiouracil treatment was stopped. and the remaining 34 hypothyroid rats were injected with a daily dose of thyroxine (average. 0.1 mg/kg body wt). resulting in a switch from beta-MHC to alpha-MHC. After 1 day. V2 still was greater than V1; however. already from day 3 onward. V2 was smaller than V1. This characteristic but unexplained heterodimeric and homodimeric organization of the thick filament was analyzed by mathematical models involving probability calculations. Two principally different models were established that assume either the exchange of MHC dimers or of single MHC in the thick filament. The parameters of the models were estimated by minimization routines using the squared discrepancies between the experimental and predicted isoenzyme populations. Based on goodness of fit and crucial model parameters. we concluded that the characteristic organization of the thick filament can be accounted for by an exchange involving predominantly MHC dimers and not single MHC. The fact that V2 was lower than expected if formation of heterodimers and homodimers were random was attributed to the preferred homodimerization of 35% of the newly synthesized MHC.
Disparate effects of colchicine on thyroxine-induced cardiac hypertrophy and adrenoceptor changes, Short-term (5 days) administration of L-thyroxine (0.1 mg/kg i.p. daily) to adult Sprague-Dawley rats induces a modest degree of cardiac hypertrophy (22% increase in heart weight/body weight ratios) and directionally opposite changes in cardiac adrenoceptors (24% increase in beta-adrenoceptors and 20% decline in alpha 1-adrenoceptors). Pretreatment with colchicine did not affect the ability of L-thyroxine to induce cardiac hypertrophy but prevented its effects on both beta- and alpha 1-adrenoceptors. These results suggest a selective involvement of microtubules in the action of thyroid hormones on the expression of cardiac adrenoceptor genes.
Significance of the number of stimuli to initiate ouabain-induced arrhythmias in the intact heart, Ouabain-induced arrhythmias are a well-known model used to study triggered activity resulting from delayed afterdepolarizations. In the intact heart. initiation of these arrhythmias is promoted by pacing. especially at fast rates. However. the relevance of the number of stimuli is unknown. In conscious dogs with formalin-induced atrioventricular block. we investigated the effect of variations in pacing mode on 1) the behavior of nonsustained triggered rhythms at progressive levels of ouabain intoxication. and 2) the induction of sustained ventricular tachycardia (VT). Twenty experiments were analyzed. Ouabain was administered as a bolus of 40 micrograms/kg followed by continuous infusion. Every 15 minutes the pacing protocol was repeated. with a maximum of 10. until completion or induction of VT. When VT could not be initiated. the experiment was repeated at least 1 week later. adding 5-10 micrograms/kg ouabain to the bolus and increasing the infusion rate correspondingly. This was repeated until VT could be induced. Four interstimulus intervals (200. 400. 600. and 800 msec) and seven numbers of stimuli (5. 10. 20. 35. 50. 100. and 150) were given in two pacing protocols. The effect of these protocols on 1) the number of induced beats per stimulation train. 2) their first postpacing interval. and 3) induction of VT were studied. Initiation of VT occurred after 75 +/- 42 minutes. The bolus of ouabain needed to induce VT was inversely related to the body weight of the animals. Progression of ouabain intoxication resulted in 1) a significant increase in the number of induced beats per stimulation train and 2) a significant shortening of the first postpacing interval. Stimulation at a faster rate and/or more stimuli resulted in 1) a significantly pronounced increase in the number of induced beats at the higher levels and 2) a significantly shorter first postpacing interval at successive levels of ouabain intoxication.
[Ca2+]i transients in the cardiomyopathic hamster heart, Intracellular [Ca2+] transients were studied in isolated hearts of healthy and cardiomyopathic hamsters in late failure perfused with glucose or pyruvate. Hearts of healthy hamsters developed similar pressures when perfused with either glucose or pyruvate. and [Ca2+]i transients were comparable in amplitude when perfused with either substrate. On the other hand. hearts of cardiomyopathic hamsters in late failure developed normal pressure when perfused with pyruvate but developed depressed pressure (50%) when perfused with glucose. The amplitude of [Ca2+]i transients fell severely and was associated with a high diastolic [Ca2+]i in cardiomyopathic hamster hearts when the perfusate was switched from pyruvate to glucose. The high phosphomonoester sugars as evidenced by 31P nuclear magnetic resonance studies and the depressed oxygen consumption in the cardiomyopathic hamster hearts perfused with glucose reflect an inhibition in glycolysis and a subsequent decrease in mitochondrial activity. Without an adequate delivery of substrate to the mitochondria in the cardiomyopathic hamster. the myocardium is no longer capable of maintaining its [Ca2+]i homeostasis.
Effect of preconditioning ischemia on reperfusion arrhythmias after coronary artery occlusion and reperfusion in the rat, Severe arrhythmias occur predictably on reperfusion after 5 minutes of coronary occlusion in the rat. There is little data available on whether ischemic preconditioning (PC) of hearts can reduce the incidence of such arrhythmias. The effect of PC (three cycles of 2 minutes of coronary occlusion and 5 minutes of reperfusion) on development of arrhythmias after a subsequent 5-minute coronary artery occlusion and reperfusion was studied. Rats (n = 16 each group) underwent 5-minute occlusion and reperfusion alone or preceded by PC; arrhythmias were monitored during ischemia and for 10 minutes of reperfusion. and biopsies were taken for creatine phosphate and adenosine triphosphate in ischemic and nonischemic zones of the left ventricle. PC reduced the incidence of ventricular tachycardia (VT) during occlusion (81% control versus 13% PC. p less than 0.001). On subsequent reperfusion. ventricular fibrillation (VF) developed in zero PC animals versus 13 (81%) of controls (p less than 0.001). and irreversible VF in zero of PC versus seven (44%) of controls (p = 0.007). VT occurred in four (25%) of PC versus all (100%) of controls (p less than 0.001). PC reduced mean duration of VT plus VF from 320 +/- 54 to 5 +/- 1 seconds (p less than 0.001) and delayed arrhythmia onset from 8 +/- 2 to 85 +/- 35 seconds after reperfusion. There was no difference in creatine phosphate levels in the ischemic zone at the end of reperfusion in PC animals compared with controls without irreversible VF (16.2 +/- 4.1 versus 15.5 +/- 3.9 nmol/mg protein. p = NS).
Mechanical alternans during acidosis in ferret heart muscle, Acidosis leads to mechanical alternans (i.e.. alternation of large and small contractions) in ferret papillary muscles. This alternation in the size of the contraction is paralleled by alternation in the size of the intracellular Ca2+ transient (monitored using the photoprotein aequorin). In isolated myocytes. the large contraction is accompanied by a prolonged action potential. Mechanical alternans also can be induced by acidosis in isolated myocytes during a train of voltage-clamp pulses. Thus. it appears unlikely that the mechanical alternans is secondary to changes in action potential duration; it is more likely that the observed changes in action potential duration are secondary to changes in the size of the Ca2+ transient. The observation that a Ca2(+)-activated inward current also shows alternation during mechanical alternans provides a possible mechanism for the link between Ca2+ and action potential duration. The alternation in the size of the Ca2+ transient may be secondary to the slowed mechanical restitution observed in papillary muscles during acidosis. This also could explain the observation that decreasing stimulation rate can abolish the alternans.
Passive smoking and heart disease. Epidemiology, physiology, and biochemistry, The evidence that ETS increases risk of death from heart disease is similar to that which existed in 1986 when the US Surgeon General concluded that ETS caused lung cancer in healthy nonsmokers. There are 10 epidemiological studies. conducted in a variety of locations. that reflect about a 30% increase in risk of death from ischemic heart disease or myocardial infarction among nonsmokers living with smokers. The larger studies also demonstrate a significant dose-response effect. with greater exposure to ETS associated with greater risk of death from heart disease. These epidemiological studies are complemented by a variety of physiological and biochemical data that show that ETS adversely affects platelet function and damages arterial endothelium in a way that increases the risk of heart disease. Moreover. ETS. in realistic exposures. also exerts significant adverse effects on exercise capability of both healthy people and those with heart disease by reducing the body's ability to deliver and utilize oxygen. In animal experiments. ETS also depresses cellular respiration at the level of mitochondria. The polycyclic aromatic hydrocarbons in ETS also accelerate. and may initiate. the development of atherosclerotic plaque. Of note. the cardiovascular effects of ETS appear to be different in nonsmokers and smokers. Nonsmokers appear to be more sensitive to ETS than do smokers. perhaps because some of the affected physiological systems are sensitive to low doses of the compounds in ETS. then saturate. and also perhaps because of physiological adaptions smokers undergo as a result of long-term exposure to the toxins in cigarette smoke. In any event. these findings indicate that. for cardiovascular disease. it is incorrect to compute "cigarette equivalents" for passive exposure to ETS and then to extrapolate the effects of this exposure on nonsmokers from the effects of direct smoking on smokers. These results suggest that heart disease is an important consequence of exposure to ETS. The combination of epidemiological studies with demonstration of physiological changes with exposure to ETS. together with biochemical evidence that elements of ETS have significant adverse effects on the cardiovascular system. leads to the conclusion that ETS causes heart disease. This increase in risk translates into about 10 times as many deaths from ETS-induced heart disease as lung cancer; these deaths contribute greatly to the estimated 53.000 deaths annually from passive smoking. This toll makes passive smoking the third leading preventable cause of death in the United States today. behind active smoking and alcohol.
Multicenter patency trial of intravenous anistreplase compared with streptokinase in acute myocardial infarction. The TEAM-2 Study Investigators, Thrombolytic therapy has been shown to improve clinical outcome when administered early after the onset of symptoms of acute myocardial infarction; the mechanism of benefit is believed to be reestablishment and maintenance of coronary artery patency. Anistreplase is a second generation thrombolytic agent that is easily administered and has a long duration of action. To compare anistreplase (30 units/2-5 min) and therapy with the Food and Drug Administration-approved regimen of intravenous streptokinase (1.5 million units/60 min). a randomized. double-blind. multicenter patency trial was undertaken in 370 patients less than 76 years of age with electrocardiographic ST segment elevation who could be treated within 4 hours of symptom onset. Coronary patency was determined by reading. in a blinded fashion. angiograms obtained early (90-240 minutes; mean. 140 minutes) and later (18-48 hours; mean. 28 hours) after beginning therapy. Early total patency (defined as Thrombolysis in Myocardial Infarction grade 2 or 3 perfusion) was high after both anistreplase (132/183 = 72%) and streptokinase (129/176 = 73%) therapy. and overall patency patterns were similar. although patent arteries showed "complete" (grade 3) perfusion more often after anistreplase (83%) than streptokinase (72%) (p = 0.03). Similarly. residual coronary stenosis. determined quantitatively by a validated computer-assisted method. was slightly less in patent arteries early after anistreplase (mean stenosis diameter. 74.0%) than streptokinase (77.2%. p = 0.02). In patients with patent arteries without other early interventions. reocclusion risk within 1-2 days was defined angiographically and found to be very low (anistreplase = 1/96. streptokinase = 2/94). Average coronary perfusion grade was greater. and percent residual stenosis was less. at follow-up than on initial evaluation and did not differ between treatment groups. Enzymatic and electrocardiographic evolution was not significantly different in the two groups. Despite rapid injection. anistreplase was associated with only a small (4-5 mm Hg). transient (at 5-10 minutes) mean differential fall in blood pressure. In-hospital mortality rates were comparable for anistreplase and streptokinase (5.9%. 7.1%). Stroke occurred in one (0.5%) and three (1.6%) patients. respectively; one stroke was hemorrhagic. Other serious bleeding events and adverse experiences occurred uncommonly and with similar frequency in the two groups. Thus. for the end points of our study (patency. safety). anistreplase and streptokinase showed overall favorable and relatively comparable outcomes. with a few differences.(ABSTRACT TRUNCATED AT 400 WORDS).
Detection of patients at risk for paroxysmal atrial fibrillation during sinus rhythm by P wave-triggered signal-averaged electrocardiogram, To determine whether patients at risk for paroxysmal atrial fibrillation could be detected while in sinus rhythm. the signal-averaged electrocardiogram triggered by P waves was recorded in 42 patients with paroxysmal atrial fibrillation (Paf group) and in 50 control patients. The root mean square voltages (LP10. LP20. and LP30) for the last 10. 20. and 30 msec and the duration (Ad) of filtered (40-300 Hz) P wave of the spatial magnitude were measured. LP10 and LP20 were significantly lower in the Paf than in the control group (LP10. 1.92 +/- 0.58 versus 2.49 +/- 0.78 microV. p less than 0.001; LP20. 2.47 +/- 0.78 versus 3.46 +/- 1.20 microV. p less than 0.0001). although no significant difference in LP30 was found between groups. Ad was also significantly longer in the Paf than in the control group (137.0 +/- 14.3 versus 118.6 +/- 11.3 msec. p less than 0.001). These differences between the Paf and control groups remained significant even after dividing by the presence or absence of organic heart diseases. The criteria of "LP20 = 3.5 microV or less" and "Ad greater than 120 msec" as defining "atrial late potential" gave a sensitivity of 91% and a specificity of 76%. These findings suggest that patients at risk for paroxysmal atrial fibrillation could be detected while in sinus rhythm by using the P wave-triggered signal-averaged electrocardiogram.
In vivo technetium-99m S12 antibody imaging of platelet alpha-granules in rabbit endothelial neointimal proliferation after angioplasty, To examine the specificity of technetium-99m monoclonal antibody (S12) imaging for identifying activated platelets at interventional injury sites in atherosclerotic rabbit arteries. subgroups of unheparinized rabbits (n = 39) underwent serial percutaneous transluminal aortic angioplasty (PTA) procedures (with or without intravascular stent placement) followed by in vivo and then ex vivo gamma camera imaging. scanning. and immunoelectron microscopy to determine the intravascular loci of S12 Fab' antibody binding. Despite angiographic vessel patency. image-derived ratios of in vivo S12 binding in injured versus uninjured vascular segments were significantly increased (p less than 0.05) after one PTA (1.3 +/- 0.17. n = 7). PTA twice at 6-week intervals (1.4 +/- 0.22. n = 7). and PTA plus stent placement (1.6 +/- 0.28. n = 7) compared with control experiments (1.1 +/- 0.13. n = 7). Ex vivo imaging of blood-free excised aortas confirmed S12 localization at PTA (2 +/- 0.4. n = 3) and PTA plus stent placement (5 +/- 3.8. n = 7) sites (both p less than 0.05 versus controls). S12 antibody uptake decreased significantly (p less than 0.05) at 1 week after PTA plus stent placement in vivo (1.1 +/- 0.10. n = 4) and ex vivo (1.6 +/- 0.7. n = 3). Electron microscopic studies confirmed dense platelet. fibrin. and red blood cell deposition in regions of acute injury. with endothelial neointimal proliferation at 1 week after PTA. Immunoelectron microscopic studies confirmed specific in vivo S12 binding (22:1 versus nonrelevant IgG) at sites of alpha-granule GMP-140 expression in activated platelets. Therefore. S12 studies may be useful to localize sites of platelet-derived mitogen release at arterial PTA injury sites.
Reduction of myocardial reperfusion injury by intravenous adenosine administered during the early reperfusion period, Adenosine influences the function of several cell types thought to be involved in the pathogenesis of myocardial reperfusion injury. We have previously demonstrated that intracoronary administration of adenosine enhances myocardial salvage 24 hours after reperfusion. To determine if these beneficial effects could be obtained during a prolonged period of reperfusion using an intravenous route of administration. 22 closed-chest dogs were subjected to 90 minutes of proximal left anterior descending coronary artery occlusion and 72 hours of reperfusion. Animals randomly received either intravenous adenosine (0.15 mg/kg/min) or an equal volume of Ringer's lactate during the first 150 minutes of reperfusion. The area at risk was defined in vivo with Monastral blue. and infarct size was measured histologically with Mallory's trichrome stain. Serial global and regional ventricular function were determined with contrast ventriculography and analyzed using a computerized radial shortening method. Biopsies were obtained from the central ischemic zone to assess endothelial ultrastructure and capillary obstruction. No significant effects in heart rate or blood pressure were noted during adenosine infusion. Transmural collateral blood flow during ischemia was similar in the groups. Infarct size expressed as a percentage of the anatomical area at risk was significantly less in the adenosine-treated group (35.3 +/- 4.3% in controls versus 17.1 +/- 4.3% in treated animals. p less than 0.01). A progressive decrease in transmural blood flow was noted in control animals during reperfusion. resulting in a significant reduction at 3 hours compared with the preocclusion value (0.69 +/- 0.11 ml/min/g [at baseline versus 0.45 +/- 0.10 ml/min/g at 3 hours. p less than 0.05]). In contrast. flow in adenosine animals at 3 hours was similar to baseline values (0.91 +/- 0.15 ml/min/g at baseline versus 0.98 +/- 0.14 ml/min/g at 3 hours. p = NS) and was significantly higher (p less than 0.05) than the control group. Radial shortening in the ischemic zone was significantly improved at 3 (-2.6 +/- 2.8% in controls versus 11.6 +/- 3.3% in treated animals. p less than 0.01) and 72 hours (5.5 +/- 2.0% in controls versus 17.3 +/- 3.5% in treated animals. p less than 0.01) after reperfusion in treated animals. Electron microscopy showed reduced neutrophil and erythrocyte plugging of capillaries with relative preservation of endothelial cell structure in the adenosine group.(ABSTRACT TRUNCATED AT 400 WORDS).
Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction. Comparison of thallium scintigraphy with reinjection and PET imaging with 18F-fluorodeoxyglucose, In patients with chronic coronary artery disease and left ventricular dysfunction. the distinction between ventricular dysfunction arising from myocardial fibrosis and ischemic. but viable. myocardium has important clinical implications. By positron emission tomography (PET). enhanced fluorine-18-labeled fluorodeoxyglucose (FDG) uptake in myocardial segments with impaired function and reduced blood flow is evidence of myocardial viability. Reinjection of thallium-201 at rest immediately after stress-redistribution imaging may also provide evidence of myocardial viability by demonstrating thallium uptake in regions with apparently "irreversible" defects. To compare these two methods. we studied 16 patients with chronic coronary artery disease and left ventricular dysfunction (ejection fraction. 27 +/- 9%). all of whom had irreversible defects on standard exercise-redistribution thallium single-photon emission computed tomography (SPECT) imaging. Thallium was reinjected immediately after the redistribution study. and SPECT images were reacquired. The patients also underwent PET imaging with FDG and oxygen-15-labeled water. A total of 432 myocardial segments were analyzed from comparable transaxial tomograms. of which 166 (38%) had irreversible thallium defects on redistribution images before reinjection. FDG uptake was demonstrated in 121 (73%) of these irreversible defects. Irreversible defects were then subgrouped according to the degree of thallium activity. relative to peak activity in normal regions. Irreversible defects with only mild (60-85% of peak activity) or moderate (50-59% of peak) reduction in thallium activity were considered viable on the basis of FDG uptake in 91% and 84% of these segments. respectively. In contrast. in irreversible defects with severe reduction in thallium activity (less than 50% of peak). FDG uptake was present in 51% of segments. In such severe defects. an identical number of segments (51%) demonstrated enhanced uptake of thallium after reinjection. In these severe "irreversible" defects. data on myocardial viability were concordant by the two techniques in 88% of segments. with 45% identified as viable and 43% identified as scar on both PET and thallium reinjection studies. These observations suggest that thallium imaging can be used to identify viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction. Most irreversible defects with only mild or moderate reduction in thallium activity represent viable myocardium as confirmed by FDG uptake.(ABSTRACT TRUNCATED AT 400 WORDS).
Analysis of baroreflex control of heart rate in conscious dogs with pacing-induced heart failure, The autonomic components of the baroreflex control of heart rate were evaluated in conscious mongrel dogs before and after 4-6 weeks of ventricular pacing (250 beats/min). Arterial baroreflex sensitivity (BRS) was determined by the slopes of linear regression of pulse interval versus the preceding systolic arterial pressure in response to bolus injections of either phenylephrine or nitroglycerin. BRS was significantly depressed in the heart failure state [nitroglycerin slope. 5.0 +/- 2.7 (mean +/- SD) versus 16.6 +/- 5.1 msec/mm Hg. p less than 0.005; phenylephrine slope. 15.0 +/- 14.8 versus 32.0 +/- 26.7 msec/mm Hg. p less than 0.005]. There was no depression in BRS in dogs that were used as time controls or were acutely paced for 30 minutes. After beta 1-adrenergic blockade with metoprolol. the resting heart rate in the heart failure state was depressed more than in the normal state (-17.0 +/- 5.0% versus -3.2 +/- 3.4%. p less than 0.001). Atropine significantly increased resting heart rate more in the normal state than in the heart failure state (115.8 +/- 36.7% versus 25.4 +/- 14.5%. p less than 0.005). Thus. dogs in the heart failure state appear to have high resting cardiac sympathetic tone and low resting vagal tone. For nitroglycerin administration. metoprolol depressed BRS by 47.6 +/- 26.3% in the normal state and by 63.6 +/- 58.5% in the heart failure state. Atropine decreased the BRS by 86.7 +/- 7.8% in the normal state and by 39.5 +/- 30.2% in the heart failure state.
Reentrant ventricular arrhythmias in the late myocardial infarction period: mechanism by which a short-long-short cardiac sequence facilitates the induction of reentry, The electrophysiological mechanism by which a short-long-short stimulated cardiac sequence facilitates the induction of ventricular tachyarrhythmia was investigated in dogs 4 days after ligation of the left anterior descending coronary artery. In these dogs. reentry develops in the surviving electrophysiologically abnormal epicardial layer that overlies the infarct zone when premature stimulation results in a critically long arc of functional conduction block. The activation wavefront circulates around both ends of the arc. coalesces. and conducts slowly distal to the arc before reactivating sites proximal to the arc to initiate a figure-eight reentrant circuit. Epicardial isochronal activation maps and effective refractory periods (ERPs) were determined during three different stimulation protocols: A. a basic train of eight beats at a cycle length of 300 msec followed by a single premature stimulus (S2); B. a basic train of eight beats at a cycle length of 300 msec with abrupt lengthening of the last cycle of the train before S2 to 600 msec; C. a basic train of eight beats at a cycle length of 600 msec followed by S2. Protocol B was found to result in a differential lengthening of ERP at adjacent sites within the border of the epicardial ischemic zone. whereas protocols A and C induced. respectively. comparable shortening and lengthening of ERPs at the same sites. The differential lengthening of ERPs at adjacent sites resulted in an increased dispersion of refractoriness so that a premature stimulus induced functional conduction block between those sites. The development of a longer arc of conduction block and. hence. a longer reentrant pathway as well as slower conduction of the circulating wavefront during protocol B allowed more time for refractoriness to expire proximal to the arc and for the circulating wavefront to reexcite those sites to initiate reentry. The lengthening of ERP. associated with a single long cycle (protocol B). ranged from 44% to 79% of the total increase in ERP after a series of eight long cycles (protocol C). Epicardial sites with longer ERPs located close to the center of the ischemic zone showed more lengthening of refractoriness during protocol B compared with more normal sites near the border of the ischemic zone. This strongly suggests that the increased dispersion of refractoriness during protocol B is caused by the shorter memory of ischemic myocardium to the cumulative effects of preceding cycle lengths.
Ischemic heart disease and platelet aggregation. The Caerphilly Collaborative Heart Disease Study, The Caerphilly Collaborative Heart Disease Study is based on a large cohort of men (2.398) aged 49-66 years at the time of study. Platelet aggregation induced by collagen. thrombin. and ADP was measured in fasting blood samples and was related to prevalent angina. past myocardial infarction. and electrocardiographic evidence of ischemic heart disease. A number of subjects had taken aspirin. other nonsteroidal anti-inflammatory drugs. or other drugs affecting platelet aggregation 7 days before blood sample collection; after the exclusion of these subjects. data were available for 1.811 men. No relations were demonstrated with angina. but significant relations were shown between past myocardial infarctions and electrocardiographic evidence of ischemia and ADP-induced aggregation (both primary and secondary) and between electrocardiographic evidence of ischemia and thrombin-induced aggregation. The strongest relation indicated more than a twofold increase in the odds of a past myocardial infarction in subjects of the highest fifth of ADP-induced primary platelet aggregation compared with the lowest fifth. No significant relations were detected with collagen-induced aggregation. Accounting for a number of possible confounding factors had a relatively small impact on the relations between platelet aggregation and ischemic heart disease. Other evidence. including the well-established effect of aspirin on reducing the incidence of ischemic heart disease. indicates that the relations we describe are unlikely to be simply an effect of IHD on platelets.
Myocardial infarction in Mexican-Americans and non-Hispanic whites. The San Antonio Heart Study, Mexican-American men experience reduced cardiovascular mortality compared with non-Hispanic white men. There is no corresponding ethnic difference in cardiovascular mortality in women. The difference in men could result either from a lower incidence of cardiovascular disease or a lower case fatality rate among Mexican-Americans. Although the incidence of cardiovascular disease in Mexican-Americans is unknown. we have collected data on prevalence of myocardial infarction in 5.148 individuals examined in the San Antonio Heart Study. a population-based survey of cardiovascular disease conducted between 1979 and 1988 in Mexican-Americans and non-Hispanic whites aged 25-64 years. Myocardial infarction was assessed by Minnesota-coded electrocardiograms and by a self-reported history of a physician-diagnosed heart attack. For both end points. the age-adjusted prevalence of myocardial infarction was lower in Mexican-American men than in non-Hispanic white men. After adjustment for age and diabetes status (present/absent). the odds of a myocardial infarction. as defined by either criterion. was approximately one third lower in Mexican-American men than in non-Hispanic white men (p = 0.06). In women. the prevalence of both myocardial infarction end points was slightly higher in Mexican-Americans than in non-Hispanic whites. although neither of these differences was significant. Although the ethnic differences in prevalence in this study were not statistically significant. their pattern parallels the pattern in the mortality due to cardiovascular diseases. Therefore. the results support the hypothesis that the reduced cardiovascular mortality rate observed in Mexican-American men reflects a lower incidence of myocardial infarction rather than a reduced case fatality rate because the latter would result in a higher prevalence.
Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group, The Multicenter Diltiazem Postinfarction Trial (MDPIT) reported no consistent diltiazem effect on new or worsened congestive heart failure (CHF) during 12-52 months' follow-up after acute myocardial infarction. This was puzzling in light of the observation that patients with findings suggesting left ventricular dysfunction (LVD) at baseline on diltiazem had more cardiac events (cardiac mortality or recurrent nonfatal infarction) than such patients on placebo. We hypothesized that diltiazem increased the frequency of late CHF as well as of cardiac events. but only in patients predisposed by LVD. Using the same characterizing variables as the primary MDPIT analysis. we found that patients with pulmonary congestion. anterolateral Q wave infarction. or reduced ejection fraction (EF) at baseline were more likely to have CHF during follow-up than those without these markers of LVD. CHF was particularly frequent in the patients with LVD who were randomized to diltiazem. Among those with a baseline EF of less than 0.40. late CHF appeared in 12% (39/326) receiving placebo and 21% (61/297) receiving diltiazem (p = 0.004). Life table analysis in patients with an EF of less than 0.40 confirmed more frequent late CHF in those taking diltiazem (p = 0.0017). In addition. the diltiazem-associated rise in the frequency of late CHF was progressively greater with increasingly severe decrements in baseline EF. This diltiazem effect was absent in patients with pulmonary congestion at baseline but an EF of 0.40 or more. suggesting a unique association between diltiazem-related late CHF and systolic LVD.
Transesophageal Doppler echocardiography evaluation of coronary blood flow velocity in baseline conditions and during dipyridamole-induced coronary vasodilation, Transesophageal echocardiography allows the evaluation of proximal coronary artery anatomy and coronary blood flow velocity (CBFV). To assess the potential of transesophageal echocardiography in evaluating CBFV and its variations induced by coronary-active drugs. we studied 15 patients by high-quality pulsed wave Doppler recordings of CBFV. In these patients. transesophageal Doppler evaluation of CBFV was performed before. 2 minutes after cessation of dipyridamole infusion (0.56 mg/kg in 4 minutes). and 2 minutes after aminophylline infusion (240 mg injected 4 minutes after cessation of dipyridamole infusion). The following CBFV parameters were evaluated at each of the three steps of the study protocol: maximal and mean diastolic velocities and maximal and mean systolic velocities. Furthermore. the following indexes of coronary flow reserve were evaluated: the ratio between maximal diastolic velocity recorded after and before dipyridamole administration and the ratio between mean diastolic velocity recorded after and before dipyridamole administration. Nine of the 15 patients had a normal left anterior descending coronary artery (group A). whereas the remaining six had significant (less than or equal to 75%) stenosis (group B). In group A patients. all CBFV parameters increased significantly during dipyridamole infusion and returned to near baseline values after aminophylline infusion. In group B patients. on the other hand. none of the CBFV parameters increased after dipyridamole infusion. Dipyridamole/baseline maximal diastolic velocity and mean diastolic velocity ratios were. respectively. 3.22 +/- 0.96 and 3.04 +/- 0.88 in group A and 1.46 +/- 0.45 (p less than 0.01 versus group A) and 1.48 +/- 0.49 (p less than 0.01 versus group A) in group B patients.
Regurgitant jet size by transesophageal compared with transthoracic Doppler color flow imaging, Combined echocardiography and Doppler color flow mapping from transthoracic imaging windows has become the standard method for the noninvasive assessment of valvular regurgitation. This study compared regurgitant jet areas by Doppler color flow imaging derived from the newer transesophageal approach with measurements obtained from conventional transthoracic apical views. Maximal regurgitant jet area determinations and an overall visual estimate of lesion severity were obtained from 42 patients who underwent color flow examination by both techniques. Seventy-three regurgitant lesions were visualized by transesophageal flow imaging: 34 mitral. 22 aortic. and 17 tricuspid jets. Transthoracic studies in the same patients revealed fewer regurgitant lesions for each valve; 20 mitral. 16 aortic. and 12 tricuspid (p = 0.0009). A comparison of maximal jet areas determined by transesophageal and transthoracic studies showed a good overall correlation (r = 0.85. SEE = 2.8 cm2) and a systematic overestimation by the transesophageal technique (TEE = 0.96 TTX + 2.7). For the subgroup with mitral insufficiency. valve lesions visualized by both techniques were larger by the transesophageal approach (n = 18. 6.0 versus 3.6 cm2. p = 0.008). Semiquantitative visual grading of individual valve lesions by two independent observers revealed a higher grade of regurgitation with more jets classified as mild (38 versus 25). moderate (18 versus 13). and severe (17 versus 10) by esophageal imaging than by transthoracic imaging. Thus. transesophageal color flow mapping techniques yield a higher prevalence of valvular regurgitation than do transthoracic techniques in the same patients. Jet area and the overall estimate of regurgitant lesion severity were also greater by transesophageal color Doppler imaging compared with standard transthoracic imaging.
Limb-salvage surgery in the treatment of osteosarcoma in skeletally immature individuals, Sacrifice of major growth plates during resection and fixed-length reconstruction of a limb in a skeletally immature child with osteosarcoma may result in a significant limb-length inequality as growth progresses. A limb-length discrepancy in the humerus may cause minor cosmetic problems but does not generally result in a significant functional deficit. In the lower extremity. tumors about the knee. including the distal femur and proximal tibia. usually present the dilemma of whether limb salvage by arthrodesis. osteoarticular allograft. or endoprosthetic replacement would result in a significant limb-length inequality and whether amputation of the extremity is a preferable procedure. The techniques of rotationplasty and an expandable endoprosthesis have been successfully used for treating skeletally immature patients with osteosarcoma of the distal femur. With regard to survival and function. the results obtained with these innovative methods are favorable compared with those of a high above-knee amputation.
Osteolytic monostotic Paget's disease of the fifth lumbar vertebra. A case report, Osteolytic monostotic Paget's disease or osteitis deformans of the fifth lumbar vertebra occurred in a 55-year-old woman. An isolated lytic process involving the entire vertebral body and posterior elements and an open biopsy showed extensive remodeling with cement lines. myelofibrosis. and osteoclastic resorption typical of Paget's disease.
The cellular biology of bone tumors, New knowledge in cell and molecular biology has begun to expand the understanding of the biology of osteosarcoma and Ewing's sarcoma. Studies on osteosarcomas have revealed abnormalities in the growth-inhibiting retinoblastoma gene. which may release cells from normal growth control. Abnormalities in growth factor production or response tend to inappropriately activate cell growth. Tumor cell DNA content and cytogenetics may affect the diagnosis and prognostic grouping of osteosarcomas. In Ewing's sarcomas. a characteristic translocation between Chromosomes 11 and 22 has been identified; this translocation is also found in malignant neuroepitheliomas. A variety of studies point to both neuroectodermal and mesenchymal origins for Ewing's sarcomas. Applications of new biologic knowledge and technology to clinical problems will lead to significant changes in the diagnosis. and perhaps in the treatment. of these tumors in the coming years. Collaborations between community and referral center physicians and scientists are critical for continued progress.
Scapular allografts. A report of two cases, Some malignant tumors of the scapula can be adequately treated by limb-sparing. partial. or total scapulectomy. However. resection of the glenoid portion of the scapula and total scapulectomy result in an unsightly shoulder. In an attempt to minimize the functional impairment and restore stability and cosmesis. scapular glenoid allografts offer a reasonably good biologic replacement. This report describes the cases of a 45-year-old woman and a 32-year-old man in whom massive osteoarticular allografts were used. In one patient. good stability. cosmesis. and function were restored after resection of the glenoid portion. In the other patient. shoulder stability. cosmesis. and limited function were restored after total scapulectomy. No reports of scapular allografts seem to have been previously published in the literature.
Osteoid osteoma of the scapula. A case report and review of the literature, The scapula is a rare location for osteoid osteoma. which in most cases does not involve the flat bones. The en bloc excision in this uncommon location can be problematic since the surgical exposure is difficult. and shoulder joint function can be affected if the lesion is subchondral. In an 18-year-old man. an osteoid osteoma was located in the subchondral area of the glenoid. A guided needle biopsy of the nidus resulted in complete healing. This mode of treatment. with proper follow-up examination. is acceptable for a benign lesion situated in a problematic location.
Ultrasound in the diagnosis of congenital dysplasia and dislocation of the hip joints in children older than two years, To evaluate the use of ultrasound in the diagnosis to congenital dysplasia and dislocation of the hip (CDH) in children older than two years of age. 64 patients with normal hip joints and 47 patients with present or previous CDH were examined. Lateral and anterior ultrasound scanning was employed. and the coverage of the femoral head by the acetabular roof was assessed. The ultrasound measurements were compared with standard roentgenography. and a good accordance between the methods was found. A lateral projection of the femoral head in relation to the bony acetabular rim of more than 8 mm in children younger than ten years of age indicated subluxation and more than 15 mm at age two to four years indicated dislocation. Reliable images were obtained by ultrasound at any age between two and 18 years. Ultrasound is recommended as the primary imaging technique in the evaluation of hip joints. even in older children. and ultrasound should replace roentgenography in most of the follow-up examinations of children with previous CDH.
Somatosensory-evoked potential monitored during total hip arthroplasty, One hundred consecutive patients were monitored using somatosensory-evoked potential (SEP) monitoring to detect intraoperative sciatic nerve compromise during total hip arthroplasty. The peroneal nerve was stimulated using the contralateral extremity to rule out systemic influences on the SEP tracings. Loss of amplitude or an increase in latency of greater than 10% was considered significant. Of the 18 patients who exhibited changes that met these criteria. 16 were female. Two patients had loss of amplitude of the tracings at the time of closure. and both of these patients exhibited postoperative sciatic nerve palsies. There were no false negatives. Femoral reaming and reduction are the surgical events most commonly associated with nerve reactions. Patients who have had prior hip procedures appear to be at higher risk. There was no correlation with intraoperative SEP changes and age. weight. surgical approach. or leg lengthening. Compared with unmonitored patients. there was no reduction in the incidence of sciatic palsy.
Bilateral femoral retroversion associated with acetabular dysplasia. A case report, Retroversion of the proximal femur is associated with a number of acquired conditions but is unusual in a congenital form. It is even more unusual to be associated with acetabular dysplasia. A 38-year-old woman with bilateral hip pain had roentgenographic evidence of acetabular dysplasia with valgus neck-shaft angles. Physical findings were consistent with femoral retroversion. and computed tomography demonstrated 28 degrees of retroversion on both sides. Symptomatic relief was obtained with bilateral varus internal rotation osteotomies of the proximal femur. To date. a case of retroverted femora associated with acetabular dysplasia seems not to have been reported in the literature.
Simple bone cysts. The effects of methylprednisolone on synovial cells in culture, Ten years ago. a protocol using Depo-Medrol injections was developed for the treatment of unicameral bone cysts. This concept. designed by tumor surgeons and based on theory. has been cautiously approached. However. reproducible results have gradually increased clinical acceptance. Understanding the healing process has been restricted because of the lack of an experimental model. In an attempt to elucidate this mechanism of healing. a cell culture model was used to investigate the effects of methylprednisolone on synovial cells. Initially. three doses of the drug were tested and maximal changes were noted with the concentration of 40 mg/ml. Changes were then quantified by morphology. DNA assay. cell protein analysis. and electron microscopy. Results suggest that methylprednisolone may have a direct effect on the cellular component of unicameral bone cysts.
Cryosurgery and acrylic cementation as surgical adjuncts in the treatment of aggressive (benign) bone tumors. Analysis of 25 patients below the age of 21, This article reviews the clinical experience with cryosurgery (use of liquid nitrogen) and acrylic cementation (polymethylmethacrylate; PMMA) in the treatment of aggressive. benign bone sarcomas and the biologic basis of this technique. The results of 25 patients below the age of 21 treated by cryosurgery. with an average follow-up period of 60.8 months. are reported. Three approaches to surgical reconstruction were used: Group 1 (four patients) had cryosurgery with no reconstruction. Group 2 (13 patients) had bone graft reconstruction alone. and Group 3 (eight patients) had composite osteosynthesis with internal fixation. bone graft. and/or PMMA. The overall control rate was 96% (one recurrence). The tumor types were giant-cell tumor. chondroblastoma. aneurysmal bone cyst. and malignant giant-cell tumor. Nineteen lesions involved the lower extremity. and six lesions were located in the upper extremity. There were two secondary fractures (8%). one local flap necrosis. and one synovial fistula. There were no infections. Two epiphyseodeses were performed. The functional results were excellent (83%). good (13%). and fair (4%). The technique of composite osteosynthesis is recommended for all large tumors of the lower extremity. Cryosurgical results compare favorably with those obtained by en bloc resection and demonstrate the ability of cryosurgery to eradicate tumors while avoiding the need for extensive resections and reconstructive procedures.
Limb reconstruction with vascularized fibular grafts after bone tumor resection, Limb-salvage operations are being used with increasing frequency for patients with malignant bone tumors. For children. when a biologic reconstruction is desired. the choice is often between conventional and vascularized fibular grafts. An experimental study was performed in dogs to compare the two types of fibular grafts for bridging segmental defects in the radius and ulna. Twenty-six adult dogs were divided into two groups and studied at intervals of two. three. four. six. and 12 months after transplantation. The conventional grafts healed by creeping substitution i.e.. they were first partially resorbed before new bone was laid down. In contrast. the vascularized fibulae maintained their normal structure and hypertrophied by subperiosteal new bone formation. The conventional fibulae eventually hypertrophied but much later than the vascularized grafts. The vascularized grafts were stronger at four and six months. Between six and 12 months. both grafts remodeled to resemble the size and shape of the forearm bones they were replacing. These experimental results have influenced the treatment of patients. Vascularized fibular grafts are ideal for diaphyseal defects greater than 10 cm long. especially in very young children. a poorly vascularized bed. or when bone healing is delayed by chemotherapeutic agents. To maximize hypertrophy. an external fixator is used to immobilize the graft rather than a plate. which acts as a stress shield.
Modified Van Nes rotationplasty in the treatment of malignant neoplasms in the lower extremities of children, A technique of modified Van Nes rotationplasty has been used since 1981 for limb salvage surgery in children and adolescents with malignant sarcoma of the lower extremity. The original procedure for lesions of the distal femur was further modified and adopted for selected lesions of the proximal femur and tibia. Sixteen skeletally immature children form the base of this report. The tumors were located in the distal femur in ten children. the proximal tibia in five and the proximal femur in one. There were no intraoperative complications and postoperative complications included one infection requiring debridement and three minor healing delays. There were no local recurrences. neurovascular compromises. late derotations. or psychologic decompensations. One patient died of metastatic disease and another died of a second malignancy (leukemia). The remaining patients are good. functional. below-knee prosthesis users who participate in a number of sporting and athletic activities. The procedure is safe. has a relatively low complication rate. allows for the functional demands of an active. growing child. and accommodates for the future growth of extremities.
Ewing's sarcoma. Prognostic factors, disease control, and the reemerging role of surgical treatment, Advances in the treatment of Ewing's sarcoma have been dramatic. Present treatment protocols control local disease by radiotherapy. surgery. or both; systemic spread is limited by aggressive multiagent chemotherapy. In patients with localized osseous Ewing's sarcoma. five-year survival rates now range from 54% to an estimated 74%. With late relapse not uncommon. control of the primary lesion is critical to long-term survival. Several studies now show improved local control and possibly improved survival of patients with surgical treatment of primary osseous Ewing's sarcoma.
The effect of chemotherapy on growth in the skeletally immature individual, One hundred twenty-two children with nonmetastatic osteogenic or Ewing's sarcoma were studied to assess the effect of multiagent adjuvant chemotherapy on skeletal growth and final stature. No deviations from the height distributions of a normal population were noted at diagnosis. There was a marked retardation of linear growth during the year of intensive chemotherapy. Only 15% of the patients grew at the expected rate during that year. The distribution of nutritional status scores was significantly different at the end of the first year than at baseline. The distribution of ultimate height scores was significantly different than the baseline distribution. The overall final distribution was also significantly different from the normal population expectation. Any absolute difference in height. however. is likely to be small. The subgroups that were observed to full adult stature showed mean heights of 162 cm for girls and 176 cm for boys.
Elevated pulmonary artery pressure. An independent predictor of mortality, Analyses in this study were based on hemodynamic and angiographic data obtained in a cohort of 1.371 predominantly black patients during right and left heart catheterization. All patients were followed up prospectively for a mean of 117 weeks. and 103 fatal events were recorded. In Cox survival analysis. three variables were found to be independently related to survival: pulmonary artery mean pressure (PAMP). number of stenosed vessels. and left ventricular (LV) ejection fraction (p less than 0.01); in multivariate stepwise analysis. PAMP entered the model first with the largest chi 2 value of the three prognostic variables (chi 2 = 33.4; p less than 0.0001). The PAMP was 32 percent higher in decedents compared with survivors (25 + 11 mm Hg vs 19 + 8 mm Hg. p less than 0.01 [mean. SD]) and a 10 mm Hg increase in PAMP was associated with a more than fourfold increase in the relative risk of dying; this finding was independent of pulmonary vascular resistance and therefore could not be attributed to primary pulmonary vascular or parenchymal disease. In both the subgroup of 1.118 patients with a normal LV ejection fraction (greater than 50 percent) and the 253 patients with a reduced ejection fraction (less than 50 percent). PAMP emerged as an independent predictor of mortality (p less than 0.0001 and 0.01. respectively). and is therefore a marker of cardiac disease beyond impairment of systolic contractile function. Among patients without obstructive coronary artery disease. PAMP alone provided prognostic information in the multivariate survival analysis.
The effects of smoking on the signal-averaged electrocardiogram in normal subjects, Tobacco smoking increases the risk of sudden cardiac death. possibly by altering the substrate for propagation or sustainment of ventricular tachyarrhythmias. To test this hypothesis. 15 long-term smokers without known coronary artery disease abstained from tobacco smoking for 12 h. after which they underwent SAECG before. 15 min after and 30 min after smoking two cigarettes. Other than minor lengthening of filtered QRS duration. no significant change in time-domain SAECG parameters was noted. We conclude that late potentials are not produced by cigarette smoking and that ventricular arrhythmia substrate as measured by SAECG variables is not worsened in long-term smokers without evidence of coronary artery disease.
Target-flow inspiratory muscle training during pulmonary rehabilitation in patients with COPD, The effects of additional target-flow inspiratory muscle training (TF-IMT) on the performance of the inspiratory muscles. on general exercise capacity. and on psychologic parameters during a pulmonary rehabilitation program (PR) were studied in 40 patients with COPD selected for ventilatory limitation during exercise. The mean age of the patients was 59 years. and the mean FEV1 was approximately 50 percent of predicted. All patients participated in a ten-week PR program. They were randomized to receive either additional TF-IMT (PR + IMT) or not (PR). The TF-IMT was performed by means of a target-flow resistive device; the generated mouth pressure and the duration of inspiration and of the respiratory cycle were imposed. After the training period. maximal inspiratory mouth pressure and EMG-fatigability of the diaphragm were significantly better in the PR + IMT group than in the PR group. Maximal work load and psychologic symptoms increased to the same extent in both groups. The 12-minute walking distance also increased in both groups. but it increased significantly more in the PR + IMT group than in the PR group. We believe that additional TF-IMT during PR in a selected group of patients with COPD who have ventilatory limitation has an extra beneficial effect on the performance of the inspiratory muscles and on exercise performance.
An outbreak of pneumococcal pneumonia in two men's shelters, We report a retrospective study of 39 homeless men hospitalized for acute pneumonia from April 1988 to March 1989. All of them had recently stayed in one of two shelters. A Streptococcus pneumoniae serotype 1. resistant to cotrimoxazole. was isolated in 29 patients (74 percent). Blood cultures were positive in 24 (61 percent). The patients were relatively young; none was over 70 years old. Thirty-five (90 percent) were heavy smokers; 32 (82 percent) were alcoholics. The radiologic pattern was atypical in 14 cases (36 percent). The only fatal case was linked to the adult respiratory distress syndrome. It is likely that the rate of outbreaks of pneumococcal pneumonia is underestimated. The homeless are at high risk for pneumococcal pneumonia. In addition. the closeness existing in shelters favors the occurrence of outbreaks. Consequently. we suggest that shelter residents would benefit from pneumococcal vaccination.
Behavior of the pulmonary circulation at rest and during exercise in miliary tuberculosis, We studied the hemodynamic behavior of the pulmonary circulation at rest and during exercise in six patients with MTB. As a group. in contrast to advanced fibrocaseous tuberculosis. these patients exhibited normal pulmonary hemodynamics at rest and during exercise. Only minor abnormalities in pulmonary vascular resistance at exercise (increased PAd-PWP gradient) were noted in two of the patients. The increase in Rp during exercise does not appear to be related to acute hypoxic vasoconstruction but rather to functional changes (compliance or recruitment or both) of the pulmonary microvasculature. In the genesis of these functional changes. chronic alveolar hypoxia and the inflammatory-fibrotic process might be interacting.
Pulmonary atresia with ventricular septal defect. Selection of patients for systemic-to-pulmonary artery shunt based on echocardiography, From January 1987 to December 1988. in 22 infants with PAVSD. the diagnostic results obtained with echocardiography (two-dimensional. Doppler. and color) were prospectively compared to the angiocardiographic findings. We classified into group 1 patients with confluent and good-sized pulmonary (greater than or equal to 3 mm) arteries. single ductus arteriosus. and normal pulmonary venous connections ("favorable pattern"). The other patients with PAVSD were classified into group 2 ("unfavorable pattern"). The intracardiac anatomy. the morphology of the pulmonary arteries. and the pattern of pulmonary blood supply and pulmonary venous connection were correctly identified with echocardiography in all but one patient. who was erroneously considered to be in group 2. No false-positive of the "favorable pattern" (group 1) was detected. Echocardiography is an effective tool in infants with PAVSD. in order to discriminate cases with "favorable" and "unfavorable" patterns of pulmonary arteries. pulmonary blood supply. and pulmonary veins. The first group with the "favorable pattern" may be considered for systemic-to-pulmonary shunt surgery without angiocardiography. Based on this experience from January to December 1989. four patients with this "favorable pattern" underwent a successful systemic-to-pulmonary artery shunt with an echocardiographic diagnosis alone.
Combined thermodilution and two-dimensional echocardiographic evaluation of right ventricular function during respiratory support with PEEP, In ten patients requiring respiratory support for an episode of acute respiratory failure (ARF). the best therapeutic level of PEEP was determined by measurement of changes in lung and chest wall compliance (CT) during a PEEP challenge from 0 to 20 cm H2O. During this challenge. hemodynamic monitoring combined with thermodilution measurement of right ventricular (RV) ejection fraction (EF) and two-dimensional echocardiographic measurement of RV size permitted assessment of the effects of increasing levels of PEEP on RV function. RV preload. as reflected by RV end-diastolic volume (EDV) and two-dimensional RV end-diastolic area (EDA). remained unchanged and RV diastolic compliance progressively decreased. On the other hand. RV systolic function. as assessed by RVEF and two-dimensional RV fractional area contraction (FAC). was progressively depressed. Substantial deleterious effects of PEEP were noted at high levels of PEEP including reduced CT and augmented pulmonary vascular resistance. Inadequate increase in RV preload to compensate for increased RV afterload resulted in depressed RV systolic function and contributed to the reduction in cardiac output. Finally. two-dimensional echocardiography proved to be more sensitive than fast-response thermodilution to evaluate change in RV function.
Rabbit skeletal muscle PO2 during hypodynamic sepsis, We measured skeletal muscle tissue PO2 (PtO2) in anesthetized rabbits (n = 7) following infusion of an intravenous bolus of E coli endotoxin. An array of surface PO2 microelectrodes was placed over the hindlimb biceps femoris muscle and sufficient readings were obtained to construct a PtO2 histogram. Changes in the histogram standard deviation were used to characterize micro-circulatory maldistribution. Systemic O2 consumption (VO2) was measured by the expired gas method. Cardiac output (Q) and systemic O2 transport (TO2) were calculated. Samples of arterial. right atrial (ra). and hindlimb venous blood. from a catheter placed in the infrarenal portion of the vena cava. were simultaneously obtained for measurement of blood gases and saturations. Following the administration of endotoxin. there were decreases in Q and TO2 of approximately 50 percent. The VO2 initially decreased 23 percent. but returned to baseline levels 30 minutes after endotoxin administration. Systemic O2 extraction ratio (ERO2 = VO2/TO2) increased from 0.32 +/- .03 to 0.54 +/- .07 (p less than 0.01). whereas hindlimb ERO2 increased from 0.42 +/- .03 to 0.60 +/- .02 (p less than 0.01). The arithmetic mean of the PtO2 histograms decreased after endotoxin infusion (43 +/- 4 to 7 +/- 2 mm Hg; p less than 0.01). but PLO2 remained at baseline levels (35 +/- 2 vs. 33 +/- 2 mm Hg; p = NS). The standard deviation of the PtO2 histograms remained constant during the experiment. This finding supports the notion that skeletal muscle microcirculatory heterogeneity does not increase during endotoxin induced hypodynamic sepsis.
Natural killer cell activity in a rat model of amiodarone-induced interstitial lung disease, The role of lymphocytes in the pathogenesis of amiodarone-induced lung disease is controversial. Increases in the percentages of lymphocytes in bronchoalveolar fluid of both patients and animals with amiodarone pulmonary toxicity have been reported. To assess whether these lymphocytes are functionally activated. we measured natural killer cell activity in the lungs and blood of rats with amiodarone-induced pulmonary toxicity. Amiodarone treated rats exhibited pathologic evidence of amiodarone-induced lung disease after one week of treatment and this injury was sustained and more extensive during the remainder of the study period. Control rats had histologically normal lungs. Blood NK activity was equally present in both amiodarone-treated and control groups and was not significantly different over the course of the study (16 +/- 3 percent and 13 +/- 2 percent. respectively; p greater than 0.05). Thus. NK cells were activated only in the lungs of rats treated with amiodarone. suggesting a local immune response in the lung. These data support the concept that lymphocytes play an important role in the pathogenesis of amiodarone-induced lung disease.
Renal vein thrombosis. Initial manifestation of Goodpasture's syndrome, We report a patient who presented with renal vein thrombosis and nephrosis that progressed to alveolar hemorrhage and renal failure. Renal biopsy immunofluorescence and serum antiglomerular basement membrane antibody titer studies confirmed the diagnosis of Goodpasture's syndrome. To our knowledge. this is the first report of renal vein thrombosis as the initial presentation of Goodpasture's syndrome.
Di George anomaly with atrioventricular canal, We report the first case of Di George anomaly associated with atrioventricular canal. This combination of anomalies may represent a chance occurrence of two situations happening in the same patient or. alternatively. the result of a single unknown embriogenetic mechanism.
Fiberoptic bronchoscopy for refractory cough, Fiberoptic bronchoscopy (FB) has a low yield in the diagnosis of chronic cough (greater than 3 weeks) in unselected patients. We assessed the yield of FB for cough during a four-year period in patients with nonlocalizing chest roentgenograms who were refractory to diagnostic efforts and empiric bronchodilator or antitussive therapy. Seven (28 percent) of 25 patients undergoing FB for cough (of greater than 1.500 bronchoscopies) had diagnostic findings (broncholithiasis. two; tracheobronchopathia osteochondroplastica. two; and tuberculous bronchostenosis. laryngeal dyskinesia. and arytenoid polyp. one each). No tracheobronchial neoplasms were detected. Age greater than 50 years and female sex independently predicted positive results (p = 0.02 Fisher's exact test). while duration of cough (two to 240 months). airflow. and smoking status did not. When patients with prior pulmonary or extrathoracic neoplasms were excluded. seven (35 percent) of 20 studies were diagnostic. Diagnoses potentially could have been made by thoracic computed tomographic scanning in four patients and indirect laryngoscopy in two. Fiberoptic bronchoscopy has a respectable yield for diagnosis of refractory chronic cough and is a reasonable procedure in carefully selected patients.
Snoring (I). Daytime sleepiness in regular heavy snorers, Fifteen men. mean (means) age 44 years. were investigated. Their means body mass index was 21.9 kg/m2. and all of them had a respiratory disturbance index below 5 and had good nocturnal oxygen saturation. The subjects were monitored several nights both with and without the following devices: a tight-fitting facial mask. a pneumotachometer. and an esophageal balloon. They were also monitored with and without nasal continuous positive airway pressure. The Multiple Sleep Latency Test was administered after three of the experimental nights (after the baseline nights and after the second nasal CPAP night). Determination of short EEG arousals during nocturnal sleep. which lasted 2 to 10 s. was performed. The relationship between short EEG arousals. the esophageal pressure nadir. and airflow decrease was investigated. We also determined the relationship between clinical reporting of decrease in daytime alertness and MSLT results. and the relationship between MSLT results and the frequency of EEG arousals. The monitoring indicated that heavy snorers may present significant increase in Pes nadir with abrupt decrease in flow leading to EEG arousals. The frequency at which EEG arousals occur has an impact on MSLT scores. Nasal CPAP improves MSLT scores and eliminates these respiration-related EEG arousals. Some heavy snorers without obstructive sleep apnea syndrome may be at risk of having a decrease in daytime alertness.
Pharyngeal volume in asymptomatic snorers compared with nonsnoring volunteers, STUDY OBJECTIVE: to determine if asymptomatic snorers have smaller pharyngeal volumes than age- and height-matched nonsnorers. DESIGN: we recruited asymptomatic heavy snorers and nonsnorers for a study. Each snorer was matched by age (+/- 3 years) and height (+/- 2 inches) with a nonsnorer. The nonsnorers were required to be near ideal body weight. All volunteers underwent overnight polysomnography. pulmonary function testing. and magnetic resonance imaging of the pharynx while awake. The volume of the pharynx was determined by a computer with data input from a digitizing instrument. SETTING: Veterans Administration Hospital and University of Florida Teaching Hospital PARTICIPANTS: Nine volunteers were recruited for both the snorer and nonsnorer groups. Each participant was paid $50. There were no interventions. MEASUREMENTS and RESULTS: There were no differences in sleep variables between the two groups. There was also no significant difference between pharyngeal volumes for the two groups. CONCLUSIONS: The volume of the pharynx in asymptomatic snorers is similar to the volume in age- and height-matched nonsnorers.
Safety and efficacy of thrombolytic therapy for superior vena cava syndrome, The experience at the Cleveland Clinic from 1982 to 1990 using thrombolytic therapy for superior vena cava (SVC) syndrome was retrospectively reviewed. Sixteen patients. 11 of whom had indwelling central venous catheters. were treated with either urokinase (n = 11) or streptokinase (n = 5). Either urokinase (4.400 U/kg bolus followed by 4.400 U/kg/h) or streptokinase (250.000 U bolus followed by 100.000 U/h) was used. and venograms were performed before and after. Overall. 56 percent of patients had complete clot lysis and relief of symptoms. Thrombolytic therapy was effective in eight (73 percent) of 11 patients receiving urokinase and one (20 percent) of five patients receiving streptokinase. Of those with a central venous catheter. eight (73 percent) of 11 patients were successfully lysed. whereas only one (20 percent) of five patients was successfully lysed if no catheter was present. If thrombolytic therapy was performed less than or equal to five days of symptom onset. seven (88 percent) of eight patients were successful. if thrombolytic therapy was performed greater than five days after symptom onset. two (25 percent) of eight patients were successful. Symptoms were relieved and the catheter was preserved in patients in whom thrombolytic therapy was effective. Factors predicting success were as follows: (1) the use of urokinase compared with streptokinase; (2) the presence of a central venous catheter; and (3) a duration of symptoms less than or equal to five days.
Comparison of incentive spirometry and intermittent positive pressure breathing after coronary artery bypass graft, Fifty-two patients were randomized to receive either incentive spirometry (IS) or intermittent positive pressure breathing (IPPB) in addition to conventional chest physical therapy following coronary artery bypass grafting. Slow vital capacity and peak expiratory flow readings decreased rapidly and to an equal extent in both groups after surgery. and partly recovered by the sixth postoperative day (POP). Arterial PO2 values were similar for the groups on the first three POPs. On the POPs 2. 3. and 6. the number of chest films showing atelectases as well as the number of individual patients having atelectases revealed no statistically significant differences between the two groups. Based on the three variables studied. we consider both devices equal in efficiency after coronary surgery.
Longitudinal study of near fatal asthma, The effect of careful follow-up and treatment modification for 45 patients with an admission for NFA has been studied. In 24 of 45. inciting events were recognized. BDP was used by 14 patients pre-NFA. In the mean follow-up of 863 days. there have been no deaths and seven patients have been readmitted with asthma. Six of the 45 patients have attained normal FEV1 and PC20H. Blunted perception of breathlessness. change in VAS ratio/change in FEV1. was found when first measured. but normalized to be no different than that of other asthmatic subjects as airway responsiveness became milder. The CO2 ventilatory responses did not differentiate individual NFA patients from non-NFA asthmatic or normal subjects. Comparison of the NFA cohort with the 1985 asthma admission cohort showed that an asthma admission within the last five years was a risk factor for a NFA episode.
Primary cytomegalovirus infection and gastric ulcers in normal host, A 42-year-old woman presented with epigastric pain and vomiting. Upper gastrointestinal endoscopy revealed three gastric ulcers. Histologic examination of biopsies from the ulcers showed cytomegalovirus inclusion bodies. The appearance of IgM antibodies to cytomegalovirus indicated a recent and primary infection. Stored serum from her last pregnancy 17 months previously contained no cytomegalovirus antibodies. A thorough evaluation of her immune system revealed no abnormality. We are aware of only two other cases where seroconversion was documented in normal hosts. Cytomegalovirus infections in the gastrointestinal tract of normal hosts are very unusual but a common cause of morbidity in immunocompromised hosts. We believe that cytomegalovirus may have a role in the pathogenesis of gastrointestinal lesions in nonimmunocompromised patients.
Enhancement of antibiotic concentrations in gastric mucosa by H2-receptor antagonist. Implications for treatment of Helicobacter pylori infections, We measured the effects of cimetidine on antibiotic concentrations in the luminal portion of gastric mucosa. Guinea pigs were premedicated with cimetidine 4 mg/kg intramuscularly. Clindamycin. an antibiotic previously characterized under physiologic pH conditions. was administered intramuscularly and levels measured in serum and tissue using a high-pressure liquid chromatography (HPLC) technique. The luminal mucosa concentration of clindamycin at 1 hr (pH 5.9) was fivefold greater compared to the concentrations seen under physiologic (pH 2.0) conditions (81.5 micrograms/g vs 15.9 micrograms/g; P less than 0.05) and 10-fold greater at 2 hr (82.7 micrograms/g vs 8.09 micrograms/g; P less than 0.05). There was no difference in peak serum levels between the groups. The finding that an antibiotic with characteristics of a base is thus affected by a nonconservative acid inhibitor such as cimetidine supports the presence of an acidic storage pool as proposed by other investigators. H2-receptor antagonists may be useful therapeutic adjuncts in H. pylori infections by virtue of increasing gastric concentrations of antibiotics that behave as weak bases.
Noninvasive measurement of portal venous blood flow in patients with cirrhosis: effects of physiological and pharmacological stimuli, The present study aims to evaluate the usefulness of combined pulse Doppler-real-time ultrasonography as a noninvasive method for the measurement of portal blood flow in man. This measurement technique was performed on 12 healthy subjects and 20 patients with portal hypertension. Ten patients (group 1) were evaluated prior to and after ingestion of a standard meal (Ensure Plus) or placebo. In the remaining 10 patients (group 2). the effects of isosorbide dinitrate (5 mg/SL) administration or placebo were studied. In group 1. food intake caused a significant increase of portal blood flow (from 1038 +/- 539 to 1572 +/- 759 ml/min. P less than 0.02); this effect was due to a significant rise in mean blood velocity (from 18.5 +/- 3.7 to 23.9 +/- 3.9 cm/sec. P less than 0.02). In group 2. isosorbide dinitrate significantly reduced portal blood flow (from 985 +/- 491 to 625 +/- 355 ml/min. P less than 0.05); a significant decline of mean blood velocity (from 18.8 +/- 4.5 to 14.5 +/- 2.5 cm/sec. P less than 0.02) was observed. Placebo administration had no significant hemodynamic effects in either group. Our results suggest that Doppler measurements gave accurate noninvasive estimations of portal blood flow and that this technique may be used to monitor physiological and pharmological stimuli in patients with portal hypertension.
Treatment of fulminant hepatic failure with insulin and glucagon. A randomized, controlled trial, Insulin and glucagon are among the therapeutic modalities that have been investigated in the treatment of fulminant hepatic failure (FHF). We have completed a randomized. controlled trial of insulin and glucagon in 38 patients with FHF from either viral or toxin exposure. The control and treatment groups consisted of 21 and 17 patients. respectively. and did not differ significantly in etiology or admission laboratory values. Mortality was not significantly different between control and treatment groups and was 67% and 82%. respectively. Time from randomization to death or discharge was not significantly different between the two groups. Peak levels of alpha-fetoprotein were statistically higher in survivors than in nonsurvivors (P less than 0.01). We conclude that even though a type-2 error may exist. the combination of insulin and glucagon is not useful in the treatment of FHF.
Ulcerative proctitis in central Sweden 1965-1983. A population-based epidemiological study, Ulcerative proctitis has by tradition been regarded as a subgroup of ulcerative colitis. Population-based epidemiological studies of ulcerative proctitis are. however. virtually nonexistent. In an epidemiological study of inflammatory bowel disease in the Uppsala Health Care Region. 1065 cases of ulcerative proctitis were diagnosed from 1965 through 1983. Males predominated. with the male to female ratio 1.4:1. Annual incidence rates were higher in urban than in rural areas. The annual incidence rates increased threefold from 2.8 per 10(5) to 6.6 per 10(5) during the period. affecting all age groups over 14 years of age. in both urban and rural areas and in both sexes. Differences in temporal trends and certain other epidemiological characteristics between ulcerative proctitis and extensive ulcerative colitis suggest that ulcerative proctitis is a specific disease whose etiology differs from that of extensive ulcerative colitis.
Effect of captopril on glucose concentration. Possible role of augmented postprandial forearm blood flow, The goal of this study was to evaluate the effects of captopril on plasma glucose concentration. The daily profiles of the plasma glucose levels were determined in 12 non-insulin-dependent diabetic normotensive subjects. treated with or without captopril at a dose of 25 mg 3 times/day. Forearm blood flow was also measured by strain-gauge plethysmography. Administration of captopril improved the daily profile of the plasma glucose level. Postprandial forearm blood flow was also augmented 2 h after a meal. These results suggest that angiotensin-converting enzyme inhibitors may improve glucose metabolism in diabetic subjects. possibly through enhancement of blood flow to skeletal muscle.
Self-care predictors of metabolic control in NIDDM patients, The objective of this study was to evaluate whether the relationship between self-care behavior and metabolic control is comparable in patients with non-insulin-dependent diabetes mellitus (NIDDM) on insulin and not on insulin. We studied 84 NIDDM patients hospitalized for an elective admission in Washington University's Model Demonstration Unit. At admission. patients reported the frequency of exercise. blood glucose monitoring. and meal skipping for the previous 2 wk. Metabolic control over the previous 8-12 wk was determined from glycosylated hemoglobin assays. In cross-sectional analysis controlling for patient sociodemographic and health characteristics. glycosylated hemoglobin levels were positively related to meal skipping (P = 0.0008) and negatively related to the frequency of blood glucose monitoring (P = 0.0025). Self-care behaviors explained 26% of the variance in glycosylated hemoglobin levels in NIDDM patients. Multivariate modeling demonstrated no significant interaction effects between insulin treatment and self-care on metabolic control. In conclusion. these findings support the clinical significance of self-care activities for metabolic control in NIDDM patients. particularly meal skipping and blood glucose monitoring.
Theoretical and baseline considerations for diet and weight control of diabetes among blacks, This article outlines theoretical considerations for diet and weight control of non-insulin-dependent diabetes mellitus (NIDDM) and identifies factors that may be of particular importance in influencing the success of diet and weight control of NIDDM in the Black population. Long-term adherence to dietary or weight-control regimens requires that the patient evaluate and restructure established eating and physical activity patterns. With the use of the social action theory as a conceptual framework. this complex behavioral change task can be understood as a function of the interplay of various self-regulatory mechanisms. These mechanisms are influenced by the person's capabilities for making changes. his/her physical condition and general health status. the physical and social environmental context. and the person's material and social resources. Many of these factors may differ for Blacks and Whites in a direction that suggests a lesser potential for effective diet and weight-loss therapy among Black NIDDM patients. For example. compared with Whites. Blacks are more likely to have limited incomes. low educational attainment. ambivalence about weight control. multiple health problems. and high-fat high-sodium low-fiber diets or food preferences. However. some evidence suggests that state-of-the-art counseling approaches can be as effective for Blacks as for Whites. The challenge is to adapt the types of approaches suggested by the social action theory for culturally appropriate and cost-effective delivery in Black community health-care settings.
Exercise in therapy and prevention of type II diabetes. Implications for blacks, The rationale for the use of exercise in the treatment of type II (non-insulin-dependent) diabetes and its special implications for Blacks are reviewed herein. When performed on a regular basis. exercise may improve glycemic control and improve several risk factors for coronary heart disease including hypertriglyceridemia. hypertension. and hyperinsulinemia. In addition. it may be a useful adjunct to diet in producing weight loss. The metabolic benefits of exercise in part appear to be related to its ability to enhance insulin sensitivity. Benefits are short lived after discontinuing exercise. Because of problems with compliance and concurrent medical problems. many patients with type II diabetes are not good candidates for an exercise-diet program. For this reason. the optimum target population may be people at risk for type II diabetes and premature atherosclerosis. Such a population might include the offspring of patients with these disorders and individuals with impaired glucose tolerance. hyperinsulinemia. gestational diabetes. and/or an android pattern of fat distribution. Type II diabetes is more common in Blacks than in the general population. In most instances. it is associated with cardiovascular risk factors benefited by exercise. Despite this. there are no available studies regarding the effects of regular exercise in Blacks with type II diabetes or those at risk for it.
Chronic diabetic complications and tissue glycosylation. Relevant concern for diabetes-prone black population, A significant segment of the Black population is affected by chronic diabetes. and most of them are subjected to severe cardiovascular. renal. and neurological complications that shorten survival and diminish quality of life. One of the important pathogenetic mechanisms under intensive investigation is advanced tissue glycosylation. Tissue and cell surface proteins modified nonenzymatically by glucose are shown to be highly active in protein cross-linking and have been implicated in tissue damage. Such protein-glucose interactions. called advanced glycosylation end products (AGEs). are processed by macrophages through a high-affinity receptor. Coupling of AGE proteins to their AGE receptors results in their degradation and removal and. simultaneously. in synthesis and secretion of pluripotential cytokines such as tumor necrosis factor and interleukin 1. This suggests that AGE may act normally as a signal for growth-promoting factor secretion in a coordinated replacement process during tissue remodeling. In chronic diabetes. however. where accelerated accumulation of tissue AGE occurs. a disturbance of this balance may lead to several pathological. lytic. and/or proliferative responses like those in the vasculopathy of diabetes. Progress has been made with the discovery of aminoguanidine HCl. an AGE inhibitor. which has prevented significant pathology in short-term diabetic animal studies.
Cross-sectional analysis of renal function in black Americans with NIDDM, Our objective was to define glomerular filtration rate (GFR) and renal plasma flow (RPF) in Black Americans with non-insulin-dependent diabetes mellitus (NIDDM). This was a cross-sectional study of 71 Black NIDDM patients with diagnosed diabetes duration from 1 mo to 21 yr. Hyperglycemia was regulated and stabilized before patients were entered into the study. GFR and RPF were determined by the clearance of [125I]iothalamate and 131I-labeled hippuran. respectively. with a constant-infusion technique and four urine collection periods. Hyperfiltration. as defined by a GFR of greater than 140 ml.min-1.1.73 m-2. was found in 7 of 20 patients (35%) with newly diagnosed (less than 2 yr duration) NIDDM. The percentage of patients with hyperfiltration decreased with increasing duration of diagnosed diabetes. Decreasing GFR and RPF occurred with increasing duration of diagnosed diabetes. In conclusion. renal hemodynamic changes in Black Americans with NIDDM are similar to those known to occur in White populations with IDDM.
Risk factors for gestational diabetes in black population, In a long-term longitudinal study of gestational diabetes mellitus in Black women. risk factors that were identified were age. obesity. a family history of diabetes. and the presence of hypertension. Poor predictors were a history of a previous large-for-date infant. parity. and age at first pregnancy. The prevalence of smooth muscle and nuclear autoantibodies was higher in gestational diabetic subjects. Gestational diabetic subjects who required insulin for glycemic control were more obese. had a lower frequency of the Bf-F phenotype and a higher frequency of the Bf-F1 phenotype. and had a lower frequency of the type 2 allele at the polymorphic locus adjacent to the insulin gene. Restriction-fragment-length polymorphisms flanking the insulin and apolipoprotein A-I and C-III genes. although not associated with gestational diabetes mellitus. may be associated with hyperlipidemia and subsequent atherosclerosis.
Relationships with AIDS patients: clinical metaphors and preventive bioethics, AIDS. more than most diseases. evokes compelling and tragic stories. The AIDS epidemic is "The Plague." We seek the optimally therapeutic relationship. embodied in the metaphor of the covenant. There is a fundamental human possibility of healing through dying. "Death teaches us to live." We advocate asking AIDS patients the explicit question. "How do you want me to work with you?" This can generate conversations that facilitate congruence in relationships. A reluctance to talk about uncertainties and limits is a major source of preventable ethical conflict and a major obstacle to fulfillment of the therapeutic possibilities of the doctor-patient relationship. The Durable Power of Attorney for Health Care (DPA) can be helpful in facilitating discussions with patients and their families. Successful "preventive bioethics" is communication that opens for the patient and doctor the broadest possibilities of hearing. understanding. and expressing. The doctor as parent. fighter. technician. teacher. and covenanter may be important roles at appropriate moments with a given patient who may be experiencing the disease variably as infectious chaos. brutal enemy. spiritual challenge. or opportunity for growth. The context of such communication is a real relationship that includes love. respect. humor. hope. and genuine interest in how this other person lives.
Polyamines and ornithine decarboxylase during repair of duodenal mucosa after stress in rats, This investigation shows whether polyamines and ornithine decarboxylase have a role in duodenal mucosal repair following stress-induced microscopic damage. Rats were fasted for 22 hours. placed in restraint cages. and immersed in water to the xiphoid process for 6 hours. Animals were killed either immediately after the period of stress or at 2-hour intervals up to 24 hours thereafter. Duodenal mucosa was examined histologically. and ornithine decarboxylase and polyamine levels were measured. Ornithine decarboxylase activity was increased significantly up to 6 hours following stress. peaking at 4 hours at a level 10 times the prestress control. By 8 hours. enzyme activity had returned to near normal. Increases in mucosal putrescine. spermidine. and spermine content paralleled the changes in ornithine decarboxylase activity and peaked 4 hours after stress. Stress resulted in microscopic damage evidenced by a nearly complete absence of villi. Significant macroscopic lesions were not present following stress. Mucosal repair was evident 12 hours after stress and almost complete by 24 hours. although the restituted villi were short and blunted. The decreases in mucosal DNA. RNA. and protein content caused by stress were restored and reached near-normal levels 12 hours after the period of stress. In animals given the specific inhibitor of ornithine decarboxylase. alpha-difluoromethylornithine. increases in duodenal mucosal ornithine decarboxylase activity and polyamine levels were inhibited and mucosal repair was almost completely prevented following stress. alpha-Difluoromethylornithine also prevented the recovery of DNA. RNA. and protein content of the duodenal mucosa. These results indicate that duodenal mucosal damage following stress is repaired rapidly; the repair process is accompanied by significant increases in ornithine decarboxylase activity and polyamine levels; and the increases in ornithine decarboxylase and polyamines are absolutely required for the normal repair of the mucosa.
The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden, Previous population-based incidence studies of inflammatory bowel disease are limited by small numbers. short duration. or inadequate case-finding. To address these problems. we identified all persons with confirmed ulcerative colitis (n = 2509) or Crohn's disease (n = 1469) in the Uppsala Health Care Region from 1965 to 1983. Age-specific incidence rates by sex were slightly greater for males with ulcerative colitis and females with Crohn's disease. Incidence rates for ulcerative colitis and Crohn's disease were higher in urban than rural areas. The annual incidence rate of ulcerative colitis increased from less than 7 per 100.000 to more than 12 per 100.000 during the study period. while the rate for Crohn's disease remained between 5 and 7 per 100.000. The increase in the incidence of ulcerative colitis was the result of a marked increase in the number of patients with ulcerative proctitis. Analyses by 5-year birth cohorts suggest that those born from 1945 through 1954 were at higher risk for ulcerative colitis and Crohn's disease. and that this effect was accounted for by those born in the first half of the year. The seasonality in the cohort effect. combined with the urban preponderance of disease. suggests that environmental causes may be involved in ulcerative colitis and Crohn's disease.
Induction of pS2 and hSP genes as markers of mucosal ulceration of the digestive tract, The recently discovered pS2 protein is expressed under estrogen control in a subset of estrogen receptor-positive breast cancers and in an estrogen-independent manner in normal stomach mucosa. The pS2 gene belongs to a family of genes encoding peptides that contain a conserved 5-cysteine domain. the P domains. Although the function of the pS2 protein is unknown. it has been suggested that it may have cell growth stimulatory activity. We report here that expression of the pS2 gene in the digestive tract. which is normally restricted to the stomach. is strongly induced by mucosal ulcerations elsewhere in the tract. most notably in Crohn's disease. pS2 gene expression is restricted to the mucosal layers adjacent to the ulcerations. in a region where a novel epidermal growth factor-secreting cell lineage was shown to be induced by mucosal ulceration. The human hSP gene. which contains a tandem duplication of the pS2 gene P domain and is coexpressed with the pS2 gene in normal stomach mucosa but not in breast cancers. is also expressed in Crohn's disease. We suggest that pS2 gene expression may provide a useful marker for mucosal ulcerations of the digestive tract.
Diarrhea in ciguatera fish poisoning: preliminary evaluation of pathophysiological mechanisms, Ciguatera fish poisoning is a clinical syndrome consisting of a combination of gastrointestinal and neurological symptoms occurring after eating toxin-containing tropical reef fish; it is a major cause of morbidity in Hawaii. the South Pacific. Australia. and the Caribbean. In an effort to define pathophysiological mechanisms responsible for the diarrheal component of the illness. we examined the effect of crude and fractionated toxin preparations on isolated rabbit ileal tissue in a Ussing chamber model. Both the crude toxin preparation (prepared from toxic Ctenochaetus strigosus) and 10% and 50% methanol-chloroform toxin fraction (prepared from a pool of toxic fish samples) gave a striking increase in transepithelial electrical potential difference and short-circuit current. Enterotoxic activity seemed to be mediated by calcium. When examined by light microscopy. the intestinal mucosa was not damaged by the toxin preparations used. Our data demonstrate that toxins involved in ciguatera fish poisoning directly stimulate intestinal fluid secretion without accompanying tissue damage and suggest that calcium is the "second messenger" mediating the process.
Localization of calcitonin gene-related peptide in human esophageal Langerhans cells, Previously undescribed calcitonin gene-related peptide-immunoreactive intraepithelial cells were seen in specimens of esophageal mucosa obtained by biopsy or surgical resection from 14 individuals. These calcitonin gene-related peptide-immunoreactive cells were sparsely seen in normal mucosa but increased markedly in esophagitis. They were inaccessible to routine histological stains. but osmication showed them as dendritic forms resembling Langerhans cells of the skin. Their cytological identity was determined with immunocytochemical tests for human antigenic markers such as Ia. HLA-DR. and OKT6 for Langerhans cells. Leu-M5 and Leu-M3 for intraepithelial macrophages. CD3 and TCR-1 for T-lymphocytes. Leu-14 for B-lymphocytes. S-100 for Merkel cells. and chromogranin for amine precursor uptake and decarboxylation cells. Double localization showed that calcitonin gene-related peptide immunoreactivity colocalized with Ia. HLA-DR. and OKT6 but not with the other markers. These studies show that intraepithelial Langerhans cells in the esophageal mucosa contain calcitonin gene-related peptide. which may serve as an immunomodulator.
Cirrhosis and portal hypertension in a patient with adult Niemann-Pick disease, A woman with known Niemann-Pick disease. type B. presented at age 33 with upper gastrointestinal bleeding. ascites. and peripheral edema. Evaluation showed massive hepatosplenomegaly. infiltration of the liver with Niemann-Pick cells. cirrhosis. and evidence of portal hypertension. Chronic gastrointestinal bleeding. thrombocyctopenia. and platelet dysfunction were treated successfully by splenectomy. Cirrhosis and portal hypertension have not been reported previously in adult Niemann-Pick disease in the absence of some other cause.
Calcium channel blockers in geriatric hypertension, Though the calcium channel blockers have been used to treat angina pectoris for almost a decade. the long-acting forms of these agents that have become available in the last few years have made them practical for use as antihypertensive agents as well. They are becoming increasingly popular in this role. especially to treat elderly hypertensive patients. Because they are vasodilators with a mild diuretic action. they are logical treatment choices for the majority of hypertensive patients who have increased peripheral vascular resistance. They offer the advantage of a dual benefit for hypertensive patients with angina. and they have no effect on carbohydrate or lipid metabolism. Disadvantages include cost and a side effect profile that includes headaches. palpitations. ankle edema. and constipation.
Congestive heart failure: a current overview, Congestive heart failure (CHF). a disease seen primarily in the older patient. can be due to either systolic or diastolic dysfunction. Management is quite different if the heart failure is due to a filling abnormality as compared to poor ventricular systole. The disorder also poses many diagnostic pitfalls in the elderly. Current understanding of CHF and its influence on diagnosis and management is the focus of this review.
Managing lung disease in late life: a new approach, Advanced pulmonary disease (APD). a progressive. incurable condition. ultimately leading to death. is associated with significant. distressing symptoms. This paper reviews how the hospice approach to care. with its emphasis on treating those symptoms causing the patient the most distress. might be used by physicians in the outpatient setting to improve the patient's quality of life. Important aspects of care include management of hypoxia. malnutrition. osteoporosis. adverse drug reactions. and. especially. the symptomatic relief of dyspnea. Relief of emotional symptoms (depression. anxiety. panic) is also discussed.
Analgesic use: a study of treatments used by patients for migraine prior to attending the City of London Migraine Clinic, Eighty-three unselected patients attending the City of London Migraine Clinic for the first time were asked about their drug intake and use of alternative treatment. Thirty-one of those questioned took regular daily doses of medication. Fifteen were taking a combination of drugs bought 'over the counter' (OTC) and drugs prescribed by their GP; eleven took OTC drugs only; and 5 took prescription drugs only. It was noticeable that those taking drugs prescribed both by the GP and obtainable over the counter were more likely than the other groups to be taking several drugs rather than a single type. Thirty five of the 83 (42.2%) had tried alternative treatments for their attacks.
Vasospasm contributes to monosodium glutamate-induced headache, Consumption of monosodium glutamate has long been considered to precipitate headaches in susceptible patients. In this study the direct effects of glutamate and its metabolite. glutamine. on arterial contractility were examined using rings of rabbit aorta. In a high concentration glutamate caused significant concentration-dependent contractions (EC50. 10(-1)M; maximum tension. 188.4 +/- 33.3 mg wt tension/mg tissue). Agonists and antagonists for alpha-adrenergic. histaminergic. serotonergic. cholinergic. and GABA-nergic receptors as well as inhibition of prostaglandin synthesis failed to influence glutamate contractions. At high concentrations (10(-5)M) the calcium channel blocker. verapamil. inhibited the glutamate response. Glutamate and glutamine both exhibited concentration dependent relaxation of norepinephrine (NE). phenylephrine (PE). histamine. serotonin (5-HT). and prostaglandin F2 alpha (PGF2 alpha)-induced contractions. Kainic acid (10(-4)M). an agonist of one subpopulation of central glutamate receptor. potentiated glutamate-induced vasoconstriction; a higher concentration (10(-3)M) produced an irreversible inhibition of glutamate contractility. Only the central glutamate receptor antagonist. ketamine (10(-4)-10(-2)M). induced a reversible. concentration dependent inhibition of glutamate-induced contractions. Glutamate contractility was not dependent on extracellular calcium. an intact endothelium or neuronal function. These results demonstrate a direct effect of glutamate on peripheral arterial tone. Dietary consumption of large quantities of MSG may represent a serious health hazard to certain individuals with pre-existing vascular disease.
The blink reflex in cluster headache, To investigate the involvement of the trigeminal system in cluster headache. in twelve subjects the electrically-elicited blink reflex during a symptomatic period was examined. In eleven cases. the amplitude of the contralateral R2 response on the symptomatic side was significantly lower. at the same stimulus intensity. than on the asymptomatic side (p = 0.005). The blink reflex can be useful to evaluate biological and drug-induced phenomena in cluster headache.
Assessment and treatment of children's headaches from a developmental perspective, Childhood headache is a common pediatric problem. Clinical researchers have evaluated several behavioral treatment. such as biofeedback and relaxation training. that may be viable interventions. Adding a developmental perspective to the evaluation and treatment of childhood headache is a likely way to increase the effectiveness of these strategies. This paper presents developmental issues related to the assessment and treatment of childhood headache. Three major areas of development are examined and the impact of these areas on the treatment and assessment of headache are discussed. The three major areas are cognitive development. self-regulation and psychosocial development. Provided are practical suggestions for the application of child development principles to assessment and intervention practices that may be more developmentally appropriate.
Health status in patients with tension headache treated with acupuncture or physiotherapy, Sixty-two female patients with chronic tension headache were randomly divided into two treatment groups--acupuncture and physiotherapy. Their overall function (Sickness Impact Profile). and mental well-being (Mood Adjective Check List) and the intensity and frequency of headache were assessed before and after treatment. Before treatment the patients showed significantly more dysfunction and less positive mental well-being than a general population sample. Both treatment groups improved in overall function. the physiotherapy group somewhat more. The mental well-being increased only in the physiotherapy group. The intensity and frequency of headache was significantly reduced in both the physiotherapy group and the acupuncture group. The intensity of headache was significantly more improved in the physiotherapy group. The improvement of headache intensity persisted unchanged 7-12 months after treatment.
Nocturnal sleep recording with cassette EEG in chronic headaches, Many headache patients complain of poor sleep. and sleep disturbance has been shown to play a role in chronic pain. We recorded nocturnal sleep with a 4-channel cassette EEG monitoring device in 10 common migraine patients. 10 individuals with muscle contraction (tension) headache. and 10 chronic tension-vascular headache sufferers. Migraine patients had essentially normal sleep. although rapid eye movement (REM) sleep and REM latency were increased. Patients with tension headache had reduced sleep time and sleep efficiency. decreased sleep latency but frequent awakenings. increased nocturnal movements. and marked reduction in slow wave sleep. without change in REM sleep or latency. Mixed-element headaches with both tension and vascular features were associated with reduced sleep. increased awakening. diminished slow wave sleep. and REM sleep that was decreased in amount and reduced in latency. The findings suggest that patients with intermittent migraine may have minimal sleep disturbance. while chronic headache may be worsened by chronically poor sleep. Muscle contraction headache may be associated with frequent awakenings and decreased slow wave sleep similar to the sleep changes of fibrositis. while chronic tension-vascular headache may have a depressive substrate. Four-channel sleep recording may miss contributory sleep apnea. but nonetheless cassette EEG may facilitate outpatient evaluation of refractory headaches.
Contingent Negative Variation in migraine, The Contingent Negative Variation (CNV) is an event-related slow potential. It was recorded in healthy volunteers (n = 8) and in patients suffering from migraine without (n = 12) or with (n = 5) aura. during one (CNV1) and three second (CNV3) foreperiods in a forewarned reaction time task. CNV1 was recorded at the vertex while CNV3 was recorded at multiple electrode sites to assess topographical differences. Seven out of twelve migraine patients without aura had increased CNV1 amplitudes. CNV3 amplitudes were increased as well. but only at electrode positions C3 and C4 and not at Fz. CNV3. which allows for analysis of both an early and a late CNV component. could improve the discrimination of migraine without aura beyond that of CNV1. In migraine with aura all CNV parameters were at control levels. confirming previous results. The data obtained are discussed in terms of arousal. activation and stress and the "biobehavioral model of migraine" (Welch. 1986).
Almitrine mimics hypoxia in fetal sheep with lateral pontine lesions, Almitrine bimesylate is a potent and long-lasting respiratory stimulant in adult species. It acts by stimulating the peripheral chemoreceptors. where it has been shown to accumulate specifically. although its exact mechanism of action is uncertain. In the fetal lamb. however. it produces a profound inhibition of breathing even after denervation of the peripheral chemoreceptors. In this respect its action is similar to hypoxia. To investigate whether almitrine is hypoxia mimetic. we examined the effect of almitrine in nine fetal lambs of 120-130 days gestation. Five had lesions in the lateral pons that changed the fetal depressive response to hypoxia to one of stimulation. In the remaining four fetuses. the lesions did not bilaterally encompass the appropriate area of the pons; thus they still showed the normal fetal depressive response to hypoxia and so acted as controls. Almitrine (10 mg iv) caused a pronounced stimulation of breathing that lasted 406 +/- 26 min in all five fetuses with lesions that caused a stimulatory response to hypoxia. However. in the remaining four fetuses. in which the response to hypoxia was inhibitory. almitrine caused an inhibition of breathing that lasted 184 +/- 28 min. We conclude that the action of almitrine is like that of hypoxia and that. because it acts specifically on the chemoreceptors. it may prove to be a useful tool in the study of possible central chemoreceptor mechanisms.
Effect of exercise and obesity on skeletal muscle amino acid uptake, The genetically obese Zucker rat has a reduced capacity to deposit dietary protein in skeletal muscle. To determine whether amino acid uptake by muscle of obese Zucker rats is impaired. soleus strip (SOL) and epitrochlearis (EPI) muscles from 10-wk-old lean and obese Zucker rats were studied in vitro by use of [14C]alpha-aminoisobutyric acid (AIB). Muscles from fasted rats were incubated under basal conditions at rest or after a 1-h treadmill run at 8% grade. To equate total work completed. lean and obese rats ran at 27 and 20 m/min. respectively. Muscles were pinned at resting length. preincubated for 30 min at 37 degrees C in Krebs-Ringer bicarbonate buffer containing 5 mM glucose under 95% O2-5% CO2. and then incubated up to 3 h in Krebs-Ringer bicarbonate with 0.5 mM AIB. [14C]AIB. and [3H]inulin as a marker of extracellular fluid. Basal AIB uptake in EPI and SOL from obese rats was significantly reduced by 40 and 30% (P less than 0.01). respectively. compared with lean rats. For both lean and obese rats. exercise increased (P less than 0.05) basal AIB uptake in EPI and SOL. but the relative increases were greater in the obese rats (EPI 54% and SOL 71% vs. EPI 32% and SOL 37%). These results demonstrate that genetically obese Zucker rats have reduced basal skeletal muscle amino acid uptake and suggest that physical inactivity may partially contribute to this defect.
Training increases muscle blood flow in rats with peripheral arterial insufficiency, This study investigated the effect of physical training on muscle blood flow (BF) in rats with peripheral arterial insufficiency during treadmill running. Bilateral stenosis of the femoral artery of adult rats (300-350 g) was performed to reduce exercise hyperemia in the hindlimb but not limit resting muscle BF. Rats were divided into normal sedentary. acute stenosed (stenosed 3 days before the experiment). stenosed sedentary (limited to cage activity). and stenosed trained (run on a treadmill by a progressively intense program. up to 50-60 min/day. 5 days/wk for 6-8 wk). Hindlimb BF was determined with 85Sr- and 141Ce-labeled microspheres at a low (20 m/min) and high treadmill speed (30-40 m/min depending on ability). Maximal hindlimb BF was reduced to approximately 50% normal in the acute stenosed group. Total hindlimb BF (81 +/- 5 ml.min-1.100 g-1) did not change in stenosed sedentary animals with 6-8 wk of cage activity. but a redistribution of BF occurred within the hindlimb. Two factors contributed to a higher BF to the distal limb muscle of the trained animals. A redistribution BF within the hindlimb occurred in stenosed trained animals; distal limb BF increased to approximately 80% (P less than 0.001) of the proximal tissue. In addition. an increase in total hindlimb BF with training indicates that collateral BF has been enhanced (P less than 0.025). The associated increase in oxygen delivery to the relatively ischemic muscle probably contributed to the markedly improved exercise tolerance evident in the trained animals.
Respiratory input impedance in anesthetized paralyzed patients, Respiratory impedance (Zrs) was measured between 0.25 and 32 Hz in seven anesthetized and paralyzed patients by applying forced oscillation of low amplitude at the inlet of the endotracheal tube. Effective respiratory resistance (Rrs; in cmH2O.l-1.s) fell sharply from 6.2 +/- 2.1 (SD) at 0.25 Hz to 2.3 +/- 0.6 at 2 Hz. From then on. Rrs decreased slightly with frequency down to 1.5 +/- 0.5 at 32 Hz. Respiratory reactance (Xrs; in cmH2O.l-1.s) was -22.2 +/- 5.9 at 0.25 Hz and reached zero at approximately 14 Hz and 2.3 +/- 0.8 at 32 Hz. Effective respiratory elastance (Ers = -2pi x frequency x Xrs; in cmH2O/1) was 34.8 +/- 9.2 at 0.25 Hz and increased markedly with frequency up to 44.2 +/- 8.6 at 2 Hz. We interpreted Zrs data in terms of a T network mechanical model. We represented the proximal branch by central airway resistance and inertance. The shunt pathway accounted for bronchial distensibility and alveolar gas compressibility. The distal branch included a Newtonian resistance component for tissues and peripheral airways and a viscoelastic component for tissues. When the viscoelastic component was represented by a Kelvin body as in the model of Bates et al. (J. Appl. Physiol. 61: 873-880. 1986). a good fit was obtained over the entire frequency range. and reasonable values of parameters were estimated. The strong frequency dependence of Rrs and Ers observed below 2 Hz in our anesthetized paralyzed patients could be mainly interpreted in terms of tissue viscoelasticity. Nevertheless. the high Ers we found with low volume excursions suggests that tissues also exhibit plasticlike properties.
Compensation of respiratory alkalosis induced after acclimation to simulated altitude, Conscious intact rats previously acclimated for 3 wk to barometric pressure of 370-380 Torr (3WHx) were made alkalotic for 3 h by a decrease in inspired O2 fraction from 0.10 to 0.075 at ambient barometric pressure (730-740 Torr). Controls were normoxic littermates (Nx) in which inspired O2 fraction was lowered from approximately 0.21 to 0.10 for 3 h. Arterial PCO2 decreased progressively and similarly in both groups (65-70% of control at 15 min). Initially. arterial pH increased less in 3WHx (0.09 +/- 0.004 vs. 0.15 +/- 0.008). As hypocapnia continued. delta[HCO3-]/delta pH (mmol.l-1.pH) became more negative in Nx. from -15.2 +/- 2.5 at 15 min to -37.0 +/- 2.9 at 3 h. indicating nonrespiratory compensation of alkalosis. In 3WHx. delta[HCO3-]/delta pH did not change during alkalosis. Cumulative renal excretion of base (mueq/100 g) during alkalosis increased by 73.2 +/- 11.1 in Nx and 25.4 +/- 7.3 in 3WHx. This difference was mainly due to a larger increase in HCO3- excretion in Nx. The data suggest that the smaller compensation of hypocapnic alkalosis in 3WHx is partly due to the smaller increase in renal base excretion. Because base availability limits renal base excretion. the smaller renal response of 3WHx may be secondary to the low plasma HCO3- concentration that accompanies altitude acclimation.
Centrifugal intensity and duration as countermeasures to soleus muscle atrophy, Mechanical acceleration is a countermeasure that may be employed to prevent atrophy of slow-twitch muscle during non-weight bearing. In the present study. daily centrifugation of rats for different durations (1 or 2 h) and at different gravitational intensities (1.5 or 2.6 G) was used to test whether mechanical acceleration could ameliorate the atrophy of the soleus muscle induced by non-weight bearing (tail-traction model). The soleus muscle atrophied 32% during 7 days of non-weight bearing without countermeasures. Centrifugation treatment did not completely prevent atrophy relative to precontrol wet weight of the soleus muscle. Non-weight-bearing groups receiving 2-h daily treatments of 1. 1.5. or 2.6 G had 48. 56. and 65%. respectively. of the atrophy observed in the non-weight-bearing-only group compared with the precontrol group. No evidence was obtained that centrifugation at 2.6 G was more effective than exposure to 1 or 1.5 G as a countermeasure to non-weight-bearing-induced atrophy of the soleus muscle.
Theophylline minimally alters contractile properties of canine diaphragm in vitro, We examined the effects of theophylline on contractile properties and high-frequency fatigue of canine diaphragm in vitro. Eighteen diaphragm muscle bundles were obtained from 10 anesthetized dogs and equilibrated in oxygenated Krebs solution to 100. 200. or 300 mg/l theophylline. These bundles were compared with 18 matched control bundles from the contralateral hemidiaphragm. No statistically significant differences in twitch tension. tetanic tension. twitch-to-tetanus ratio. time to peak tension. or half-relaxation time were observed. Concentrations of 300 mg/l theophylline. however. significantly (P less than 0.05) increased force production at 10 Hz by 32%. A similar tendency was present at lower concentrations and exhibited a clear dose-response behavior. High-frequency fatigue was similar in control and theophylline-treated bundles. We conclude that supratherapeutic in vitro concentrations of theophylline do not increase maximal tetanic tension and do not protect against muscle fatigue but potentiate relative force production at low stimulation frequencies. This relatively small effect cannot be explained by poor diffusion of the drug in the muscle bundle. because theophylline concentrations in the muscle bath and in the muscle bundle were virtually identical. Moreover. it remains unclear whether this potentially beneficial effect can be achieved at in vivo attainable serum concentrations.
Effects of carotid denervation and decerebration on ventilatory response to CO, To clarify the mechanisms involved in the ventilatory response to the inhalation of low concentrations of CO (0.18-0.22% in air). the roles of the arterial chemoreceptors and the forebrain structures have been investigated in unanesthetized adult cats. The ventilatory response was observed in conscious animals intact. after carotid denervation (CD). and after midcollicular decerebration. The results show that the initial small ventilatory depression was unaffected by CD but that the subsequent characteristic tachypnea was blunted after CD even after more prolonged exposure to CO. The CO tachypnea was not observed after decerebration. but a residual hyperventilation was noted with the higher concentration used. It may be concluded that carotid chemoreceptors do not mediate the CO tachypnea. which may then originate in suprapontine structures as shown by comparison of intact and decerebrate animals. The blunting of the tachypnea after CD may be caused by the relative hypercapnia observed in CD animals. The residual hyperventilation observed in decerebrate animals may be caused by central acidosis and/or some peripheral potentiation of chemoreceptor activity resulting from the decrease in arterial blood pressure that accompanied CO inhalation in decerebrate animals.
Ventilatory effect of acute pulmonary hypothermia, The isolated effect of cooling the pulmonary circulation on ventilation was quantified in nine anesthetized dogs. The right pulmonary artery (RPA) was cannulated within the pericardium. and systemic blood was pumped from the left atrium to the RPA between. but not during. periods of cooling. Cooled blood boluses were injected into the RPA under conditions in which either bolus temperature (5-35 degrees C) or volume (0-1.5 ml/kg body wt) varied. Inspiratory time (TI). expiratory time (TE). breath duration (TT). and peak integrated activity (PEAK) were determined from diaphragm EMG. Results for five postinjection breaths were converted to a percent of the values from five preinjection breaths. There was a linear relationship between bolus temperature and TI [r = 0.61. slope (x) = 0.59%/degrees C. P less than 0.001). TE (r = 0.73. x = 1.43%/degrees C. P less than 0.001] as well as TT (r = 0.74. x = 1.10%/degrees C. P less than 0.001). whereas PEAK was unaffected (n = 9). When injection temperature was 5 degrees C. an inverse linear relationship existed between bolus volume and TI (r = 0.75. x = -15.2%.ml-1.kg-1. P less than 0.001) and TE (r = 0.78. x = -23.4%.ml-1.kg-1. P less than 0.001) (n = 4). In two dogs tested the effect of bolus injection was minimal at residual volume and progressively increased with lung volume. The effect of cold bolus injection was eliminated after right vagotomy in three dogs. Results indicate that cooling of some vagal receptor in the lung increases breathing frequency primarily by shortening TE.
Effects of ligation and embolization on Kf and multiple tracer measurements in dog lungs, In isolated blood-perfused dog lungs. the capillary filtration coefficient (Kf) and the permeability-surface area product of urea (PS) were measured to determine their responses to two different methods of altering filtration area: lobe ligation (LL. n = 5) and glass bead embolization (GBE. n = 4) during constant perfusion rates (700 +/- 45 ml/min). When two of three lobes were ligated. Kf decreased (1.36 +/- 0.13 to 0.58 +/- 0.23 g.min-1.cmH2O-1; P less than 0.05). but PS did not change (2.02 +/- 0.4 to 1.71 +/- 0.3 ml/s). Kf per gram of perfused blood-free dry lung weight was unchanged by LL (0.051 +/- 0.17 to 0.052 +/- 0.18 g.min-1.cmH2O-1). indicating that surface area per gram measured by Kf remained the same. However. PS per gram dry lung doubled (0.07 +/- 0.016 to 0.146 +/- 0.06 ml/s; P less than 0.05) after LL. suggesting that recruitment occurred in the remaining lobe. When three lobes were embolized with 200-microns glass beads (0.48 +/- 0.01 g beads/kg body wt). PS decreased (2.1 +/- 0.22 to 0.94 +/- 0.09 ml/s; P less than 0.05). but Kf was not altered (1.01 +/- 0.17 to 1.04 +/- 0.18 g.min-1.cmH2O-1). The constancy of Kf after GBE implies that the vascular pressure increase during the Kf measurement was transmitted to both blocked and flowing vessels and thereby measured the same filtration area before and after GBE. PS decreased significantly after GBE because of a loss of perfused surface area by the beads blocking flow in small arterial vessels.
Time course of changes in lung permeability and edema in the rat exposed to 100% oxygen, Rats were exposed to 100% oxygen for up to 60 h to determine early changes in lung permeability leading to the development of pulmonary edema. The time course of development of increased solute flux was assessed by the clearance of 99mTc-labeled diethylenetriamine pentaacetate (99mTc-DTPA) from the lung and the accumulation of 125I-labeled albumin (125I-albumin) in the lung. These end points were related to the development of pulmonary edema by the measurement of the wet-to-dry weight ratio of the lung and the weight of fluid in the pleural cavity. No significant changes occurred until 48 h of hyperoxia. when sharp increases in both indexes of lung permeability and wet-to-dry weight ratio occurred. By 60 h of exposure. pleural effusions had developed. The volume of this effusion was significantly correlated to both 99mTc-DTPA clearance and 125I-albumin flux.
Paradoxical embolism: an underestimated entity. A plea for comprehensive work-up, Forty-one cases of arterial embolism were reviewed. The work-up included M + 2D echocardiography in 29 patients (71%). arteriography in 22 (54%). both echocardiography and arteriography in 19 (46%). and abdominal aortic ultrasound in 18 (43%). The sources of emboli were probable cardiac (8 = 20%)--mural cardiac thrombus detected by echocardiogram; possible cardiac (12 = 29%)--arrhythmias or other cardiac pathology detected without mural thrombus; probable arterio-arterial (7 = 17%)--proximal arterial thrombus detected; probable paradoxical embolism (2 = 5%)--fulfills the Johnson criteria with cardiac defect and right-to-left shunt detected by contrast echo in one patient and cardiac catheterization in the other; possible paradoxical embolism (3 = 7%)--meets two of three Johnson criteria without evidence of other source; and unknown source (9 = 22%)--conventional work-up negative or incomplete. Five of nine patients (56%) less than 50 years old had probable or possible paradoxical embolism. while in two patients (22%). the origin was unknown. Conclusion: (1) A significant proportion of patients with an arterial embolus are discharged with the source of emboli unknown. (2) paradoxical embolism must be considered and contrast saline or transesophageal echocardiogram should be done in patients under 50 years old.
Splenorenal arterial shunt in the treatment of renovascular hypertension. Approach by a lumbar-retroperitoneal incision, In a period of 16 years. 29 consecutive patients were operated on for a splenorenal arterial shunt through a lumbotomy incision and a retroperitoneal approach. There were 18 males and 11 females with a medium age of 42 years. All cases had uncontrollable and severe hypertension for an average medium time of 48 months. 11 patients had variable degrees of renal insufficiency. The diagnosis was made utilizing standard methods including in all cases angiography of the abdominal aorta. celiac axis and renal arteries. One patient died after the operation due to intestinal infarction. the remaining have been followed for a medium time of 50 months. All patients improved or cured their renal insufficiency. The hypertension was cured in 23. improved in 4 and failed in 1. this latter patient was successfully autotransplanted. A precise exposition of the surgical technique is presented with comments about their advantages and indications. A review of the literature in surgical experience with the technique of splenorenal arterial anastomosis has been done.
The validity of canine platelet aggregometry in predicting vascular graft patency, Several laboratories have found canine platelet aggregometry predictive of thrombotic potential in vascular grafts. Adenosine diphosphate (ADP) is a frequently used agonist. often at unspecified or differing concentrations. This study was designed to evaluate the predictive value of ADP-induced platelet aggregometry and the validity of the methodology. Platelet aggregometry in response to 2 x 10(-5) M ADP was assayed in 70 dogs. Twenty-six percent were aggregators. 51% were non-aggregators. and 20% were indeterminant. All dogs were then treated with aspirin and dipyridamole. Vascular prostheses were implanted bilaterally (aorto-iliac) and anti-platelet therapy continued for two weeks. Dose-response to ADP was studied at three concentrations in 20 dogs. At 2 x 10(-5) 1/20 aggregated. at 4 x 10(-5) 3/19 aggregated and at 2 x 10(-4) 15/20 aggregated. Time between samples and study was evaluated in 11 dogs. with 2/11 changing from non-aggregator to aggregator at two or three hours. Daily reproducibility was studied in 70 dogs. 14 of which changed aggregation status between days. Patency was 58/68 (85%) for non-aggregators. 23/34 (68%) for aggregators (p = 0.038). Platelet aggregometry has significant predictive value for graft patency but methodology must be specified and standardized.
Ultrastructural evidence of the effects of shear stress variation on intimal thickening in dogs with arterially transplanted autologous vein grafts, Based on our findings that changes in wall shear stress. not the rate of blood flow. were the main hemodynamic factor related to intimal hyperplasia of autologous vein grafts. we further investigated the effect of wall shear stress variation on sequential ultrastructural changes in the intimal hyperplasia of arterially transplanted autovein grafts. using canine models. As noted. wall shear stress variation (tau-variation) could be defined by the variation in wall shear stress within a cardiac cycle. using a desktop flow waveform analyzer. In Group I. which had a high flow rate of 78.4 +/- 4.6 ml/min and low tau-variation of 36.1 +/- 2.2 dynes/cm2. intimal hyperplasia was significant. Ultrastructurally. there was a marked transformation of intimal smooth muscle cells to secretory cells 2 to 4 weeks after implantation. The surface of the intima was lined with modified smooth muscle cells at 2 weeks after implantation. In Group II. which had a low flow rate of 5.6 +/- 2.2 ml/min and normal tau-variation value (174.6 +/- 13.0 dynes/cm2). intimal hyperplasia was minimal. and there were several layers of contractile type smooth muscle cells. with characteristic myofibrillae. The surface of the intima was lined with endothelial cells at 2 weeks after implantation. These findings suggest that. in regions of low wall shear stress variation. intimal smooth muscle cells of autovein grafts may well become secretory cells. and enhanced platelet adherence could occur during early intimal repair. causing intimal hyperplasia to develop.
Clinical results of femoropopliteal bypass using externally supported (EXS) Dacron grafts: with a comparison of above- and below-knee anastomosis, As of the end of September 1989. 52 EXS Dacron grafts had been implanted for femoropopliteal bypass operations. The distal ends of 27 grafts were anastomosed to above-knee popliteal arteries and those of 25 grafts to below-knee popliteal arteries. The cumulative patency rate of above-knee grafts was 71.3% at 54 months. and that of below-knee grafts was 78.8% at 48 months (n.s.). Kinking and stenosis of the arteriosclerotic proximal and/or mid popliteal artery when the knee was bent were angiographically remarkable. These changes may explain why some femoropopliteal grafts occlude with time and why the late results of above-knee grafts are not much better than those of below-knee grafts.
Crural artery bypass with adjunctive arteriovenous fistula. A modification in distal anastomosis, We carried out crural artery bypass with an adjunctive arteriovenous fistula in 8 lower extremities of 7 patients with severe ischemic symptoms and poor distal run-off. Mean blood flow rates in the implanted grafts ranged from 43 to 340 ml/min and those of the reconstructed crural arteries from 20 to 100 ml/min. A stenotic lesion was noted on postoperative angiogram in one patient and stasis symptoms caused by downward blood flow into the distal veins in another. The other patients have remained well with good function of the grafts 1-5 years after surgery. We modified the distal corner of the anastomosis as follows: three additional interrupted simple sutures were made on the anterior wall of the concomitant arteriotomy and venotomy incisions after making the common posterior wall of the vessel incisions. A vascular pocket formed at the distal corner of the anastomosis prevents stricture at the anastomosis. The vein is finally ligated just distal to the fistula to intercept downward blood flow into the distal veins. This modification in technique is recommended to prevent stricture of the distal anastomosis and postoperative stasis symptoms.
Clip repair of peripheral side-to-side arteriovenous fistulas. Evaluation of a method in dogs and preliminary results in humans, A simple technique for repair of peripheral arteriovenous fistula by clip application is presented. This procedure is rapid and effective. it minimizes the extent of dissection. and it eliminates the need for application of vascular clamps on the vessels and for anticoagulation. The safety of the procedure was confirmed in dog experiments and clinically applied successfully in four patients. It is suitable for simple. uncomplicated side-to-side fistulas amenable to this procedure.
Preoperative evaluation and surgical treatment for tricuspid regurgitation associated with acquired valvular heart disease. The Kay-Boyd method vs the Carpentier-Edwards ring method, This study compared the results of annuloplastic repair of tricuspid regurgitation (TR) using Doppler echocardiography. Sixty-three patients who underwent tricuspid annuloplasty were studied. Thirty-four patients received Kay-Boyd annuloplasty and 29 Carpentier-Edwards ring annuloplasty. A new classification of TR based on the direction and area of regurgitation flow on Doppler echocardiogram was applied preoperatively. In the Kay-Boyd group. 10 cases showed massive TR and 24 cases showed localized TR preoperatively. Localized TR was well controlled in all cases. but 8 of 9 cases of massive TR showed grade III residual TR. In the C-E group. 21 cases showed massive TR and 8 cases showed localized TR. All cases were well controlled postoperatively. We conclude that (1) although the Kay-Boyd method is acceptable for localized TR. the C-E method should be employed for massive TR; (2) analyzing the regurgitant pattern of TR by Doppler echocardiogram is useful in selecting an appropriate surgical technique.
New quantitative method for evaluating tricuspid regurgitation, A new quantitative method for evaluating regurgitation (TR) is proposed in order to select the most suitable treatment for functional TR associated with acquired valvular heart disease. The regurgitant volume per beat (VTR) is calculated using two-dimensional color Doppler and continuous-wave Doppler echocardiographies. In a study of 48 patients. preoperative VTR showed a significant correlation with tricuspid annular diameter at end-diastole. right atrial mean pressure and right ventricular end-diastolic pressure. Patients were classified into 3 groups according to preoperative VTR: Group I. VTR less than 10 cc (no. 18); Group II. VTR = 10-20 cc (no. 18); Group III. VTR greater than or equal to 20 cc (no. 12). This classification correlated well with the intraoperative findings of TR. In all Group I patients. VTR decreased without any tricuspid valve repair. In Group II. 17 of 18 patients underwent tricuspid annuloplasty. and showed a decrease in VTR to below 10 cc after surgery. In Group III. 10 underwent tricuspid annuloplasty and 2 tricuspid valve replacement. Three of the 10 with tricuspid annuloplasty showed a significant degree of postoperative VTR (10-20 cc). These 3 patients as well as the 2 with tricuspid valve replacement showed a preoperative peak-to-peak pressure difference across the tricuspid valve during the ejection phase (RVsp-TAv) of less than or equal to 20 mmHg and tricuspid annular diameter at end-diastole of greater than or equal to 50 mm. In conclusion. no tricuspid valve repair was required in Group I (TR I). For group II (TR II) patients. tricuspid annuloplasty was necessary and adequate for TR correction. For Group II (TR III) patients. a more substantial procedure like tricuspid valve replacement should be performed. especially when the preoperative RVsp-RAv is less than or equal to 20 mmHg and tricuspid annular diameter at end-diastole is greater than or equal to 50 mm.
Surgical indication for aortic arch hypoplasia in infants, To determine the surgical indications for aortic arch hypoplasia. the distal arch outer diameter. distal arch index (ratio of the distal arch diameter to the normal aortic ring diameter). and postoperative pressure gradient across the aortic arch were studied in 23 patients under 6 months of age who underwent surgery for coarctation and/or aortic arch hypoplasia. The ratio of the pressure gradient across the arch to the right radial artery was used to evaluate the postoperative level of stenosis. The maximum ratio of the pressure gradient that could be tolerated after surgery was considered to be 0.15 from the operative results. Negative correlations were found between the distal arch outer diameter and postoperative pressure gradient ratio (r = 0.80). and the distal arch index and postoperative pressure gradient ratio (r = 0.80). These correlations proved that in order to obtain a postoperative pressure gradient ratio of 0.15 or less. a distal arch outer diameter of 3.9 mm or more and a distal arch index of 0.63 or more were necessary. Consequently. a distal arch outer diameter of 3.9 mm or a distal arch index of 0.63 is considered to indicate that aortic arch hypoplasia is in need of repair.
Annulo-aortic ectasia with DeBakey type II dissecting aneurysm in Gaucher's disease, Annulo-aortic ectasia is an extremely rare complication of Gaucher's disease. We report successful surgery in a patient with Gaucher's disease complicated by annulo-aortic ectasia and aortic dissection. Cabrol's operation was accomplished without bleeding or sternal adaptation problems.
Repair of coarctation with persistent fifth arterial arch and atresia of the fourth aortic arch, Coarctation of the aorta with persistent fifth arterial arch and atresia of the fourth aortic arch between the left common carotid and left subclavian arteries was treated surgically in a two-month-old boy with transposition of the great arteries and double-outlet right ventricle. The aortic arch was repaired using side-to-side anastomosis of the left common carotid and left subclavian arteries. patch repair of the coarctated segment at the origin of the left subclavian artery. and ligation of the patent ductus arteriosus. Pulmonary arterial banding and balloon atrioseptostomy were performed for associated anomalies.
The use of PTFE graft to correct anomalous drainage of persistent left superior vena cava, A new technique to correct persistent left superior vena cava (LSVC) drainage into the left atrium is described in a 14-year-old patient with situs inversus. left atrial isomerism common atrium. and mitral valve regurgitation. During surgery. occlusion of the LSVC markedly increased the venous pressure. precluding its ligation. Because of the malposition of the heart and the unusual atrial anatomy. correction with an intra-atrial baffle was not attempted. After correcting the intra-cardiac anomaly. the LSVC was divided and anastomosed to the "right" atrial appendage using a segment of PTFE graft. The postoperative course was uneventful and an angiogram demonstrated excellent performance of the graft.
A mathematical model of the volume, pH, and ion content regulation in reticulocytes. Application to the pathophysiology of sickle cell dehydration, We developed a mathematical model of the reticulocyte. seeking to explain how a cell with similar volume but much higher ionic traffic than the mature red cell (RBC) regulates its volume. pH. and ion content in physiological and abnormal conditions. Analysis of the fluxbalance required by reticulocytes to conserve volume and composition predicted the existence of previously unsuspected Na(+)-dependent Cl- entry mechanisms. Unlike mature RBCs. reticulocytes did not tend to return to their original state after brief perturbations. The model predicted hysteresis and drift in cell pH. volume. and ion contents after transient alterations in membrane permeability or medium composition; irreversible cell dehydration could thus occur by brief K+ permeabilization. transient medium acidification. or the replacement of external Na+ with an impermeant cation. Both the hysteresis and drift after perturbations were shown to depend on the pHi dependence of the K:Cl cotransport. a major reticulocyte transporter. This behavior suggested a novel mechanism for the generation of irreversibly sickled cells directly from reticulocytes. rather than in a stepwise. progressive manner from discocytes. Experimental tests of the model's predictions and the hypothesis are described in the following paper.
Evidence for a direct reticulocyte origin of dense red cells in sickle cell anemia, To explore our hypothesis of a direct reticulocyte origin of irreversibly sickled cells (ISCs). we fractionated light. reticulocyte-rich. and discocyte-rich sickle anemia red cells on Stractan gradients. and examined the effects of deoxygenation-induced sickling. external Ca2+. acidification. and replacing external Na+ by impermeant N-methyl-D-glucamine (NMG+). Sickling permeabilized light reticulocyte-rich cells to cations (Na+. K+. and Ca2+) more than discocytes; without external Ca2+. Na+ influx matched K+ efflux. with stable cell volume; with Ca2+. many light. low hemoglobin (Hb) F reticulocytes dehydrated rapidly (preventable by quinine. a Ca2(+)-dependent K+ channel inhibitor). Acidification of oxygenated discocytes (high mean Hb F) and reticulocyte-rich fractions yielded denser. reticulocyte-enriched cells with lower Hb F (as in light reticulocyte or dense ISC-rich fractions). Light cells shrank when NMG+ replaced Na+. supporting predictions of a Na(+)-dependent volume control system. Demonstration of sickling-induced. Ca2(+)-dependent dehydration of Hb F-free reticulocytes. and conservation of acid-stimulated K:Cl cotransport among low Hb F. reticulocyte-enriched cells in discocyte fractions support the hypothesis. Ancillary new findings included heparin stimulation of sickling-induced Na+ and K+ permeabilizations. and Ca2+ inhibition of the Na+ leak.
Rapid expression of heat shock protein in the rabbit after brief cardiac ischemia, The effect of brief myocardial ischemia on the expression of heat shock protein (HSP 70) was examined in an in vivo rabbit model of myocardial ischemia using Northern blotting. Functional studies were carried out in the open-chested anesthetized rabbit. The large marginal branch of the left circumflex was occluded four times for 5 min. Using piezoelectric crystals implanted midwall in the ischemic zone. end-diastolic length. end-systolic length. and percent segmental shortening were assessed. Expression of HSP 70 was measured by Northern blotting. A single 5-min coronary occlusion doubled the expression of HSP 70 whereas four cycles of 5 min of ischemia/5 min of reperfusion resulted in a threefold increase in HSP 70 mRNA (P less than 0.001). Measurements with the piezoelectric crystals showed mild myocardial dysfunction concomitant with the increase in HSP 70. This increase in HSP 70 mRNA after repetitive brief ischemia was transient. occurring as early as 1 h and returning to baseline by 24 h after ischemia. Western blot analysis with a monoclonal antibody to HSP 70 was used to compare sham and postischemic myocardial HSP 70 levels. Changes in the amount of HSP 70 were evident as early as 2 h and were even more striking at 24 h.
Stimulation of rat endothelial cell transforming growth factor-beta production by bleomycin, This study examines the hypothesis that mediators from lung endothelial cells could promote lung collagen synthesis in pulmonary fibrosis. Since bleomycin induces pulmonary fibrosis in humans and animals. the effects of this drug on endothelial cells were examined. Endothelial cell conditioned media were prepared in the presence of various doses of bleomycin. and tested for their ability to stimulate lung fibroblast collagen synthesis. The results show a dose-dependent stimulation of endothelial cell secretion of collagen synthesis stimulatory activity by bleomycin. which peaked at a dose greater than or equal to 100 ng/ml. Stimulation was selective for collagenous protein synthesis. Gel filtration analysis showed most of the activity to reside in fractions with an estimated molecular mass range of 10-27 kD. The activity was inhibited by anti-transforming growth factor-beta (TGF-beta)antibody. but not by nonimmune control IgG. The presence of TGF-beta was confirmed using the mink lung epithelial cell assay. Northern blotting revealed significant increases in TGF-beta mRNA in bleomycin-stimulated endothelial cells. Thus in vitro stimulation of endothelial cells by bleomycin upregulates TGF-beta production. presumably by increased transcription. In view of the chemotactic and matrix synthesis stimulatory properties of this cytokine. such an increase in TGF-beta production may play an important role in bleomycin-induced pulmonary fibrosis.
Purification and characterization of a major human Pneumocystis carinii surface antigen, Previous studies of Pneumocystis carinii have identified the major surface antigen of rat and human isolates as proteins of 116.000 and 95.000 mol wt. respectively. that are antigenically not identical. In this study both rat and human P. carinii proteins were purified by solubilization with zymolyase followed by molecular sieve and ion exchange chromatography. The native proteins had an apparent mol wt of 290.000 or greater. based on molecular sieve studies as well as cross-linking studies. Both proteins were glycoproteins; treatment with endoglycosidase H resulted in a 9% decrease in mol wt. The carbohydrate composition of the rat P. carinii glycoprotein was distinct from the human isolate; glucose. mannose. galactose. and glucosamine occurred in approximately equimolar ratios in the human P. carinii protein. whereas glucose and mannose were the predominant sugars of the rat P. carinii protein. To evaluate humoral immune responses to the human P. carinii protein. an enzyme-linked immunosorbent assay using purified protein was developed. Some. but not all. patients who subsequently developed P. carinii pneumonia demonstrated a serum antibody response to the surface antigen. Nearly all subjects without a history of P. carinii pneumonia had no detectable antibodies. Purified P. carinii proteins will greatly facilitate the investigation of host-P. carinii interactions.
Regulation of forearm lipolysis in different types of obesity. In vivo evidence for adipocyte heterogeneity, Forearm and systemic adipose tissue free fatty acid (FFA) release was measured in eight nonobese. six lower-body obese. and eight upper-body obese women under basal. hyperinsulinemic. and hypoinsulinemic conditions to determine whether forearm fat is regulated in a similar manner as whole body fat. Results: Adipose tissue palmitate release was greater from forearm than whole body (5.97 +/- 0.75 vs. 3.84 +/- 0.34 mumol.kg fat-1.min-1. respectively. P less than 0.005. n = 22 subjects). Systemic palmitate release. relative to fat mass. was significantly (P less than 0.01) greater in nonobese than upper-body obese. and upper-body obese than lower-body obese women. and forearm adipose tissue palmitate release followed the same pattern. Hyperinsulinemia suppressed systemic and forearm lipolysis to similar degrees. however. hypoinsulinemia consistently increased systemic palmitate flux without increasing forearm palmitate release. These results confirm the heterogeneity of adipose tissue in an in vivo model and emphasize the need to consider which adipose tissue depots are responsible for the differences in systemic FFA flux in obese and nonobese humans.
Apolipoprotein (apo) E inhibits the capacity of monosodium urate crystals to stimulate neutrophils. Characterization of intraarticular apo E and demonstration of apo E binding to urate crystals in vivo, Factors that modulate the ability of monosodium urate crystals to stimulate leukocytes could regulate gouty inflammation. Lipoproteins that bear apo B-100 and apo E bind to urate crystals and suppress crystal-neutrophil interaction. In this study. we observed that urate crystals. coated with apo E of monocyte origin. had a diminished ability to stimulate neutrophils. Apo E was also detected on the surface of urate crystals recovered from gout patients. Thus. we analyzed apo E in noninflammatory synovial fluid. and found it to be associated with particles of heterogeneous size and of predominantly alpha and pre-beta electrophoretic mobility. Local articular synthesis of at least a portion of synovial fluid apo E was suggested because (a) the synovial fluid/plasma concentration ratio of apo E was significantly higher than that for both apo B and apo A-I. which are not widely synthesized by extrahepatic tissues. (b) cultured rheumatoid synovial cells in first passage secreted apo E. (c) a portion of synovial fluid apo E was heavily sialylated. We conclude that synovial fluids contain apo E that appears partly of local origin. Apo E binds to urate crystals and could modulate gouty inflammation.
Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism, Our aim was to define mechanisms whereby conjugated estrogens (Premarin. exogenous estrogen; Ayerst Laboratories. New York) increase the risk of developing cholesterol gallstones and to determine the role. if any. of dietary cholesterol. We studied gallbladder motor function. biliary lipid composition and secretion. cholesterol absorption. cholesterol synthesis and esterification by peripheral blood mononuclear cells. the clearance of chylomicron remnants. and bile acid kinetics in 29 anovulatory women. 13 were studied on both a low (443 +/- 119 mumol/d) and high (2.021 +/- 262 mumol/d) cholesterol diet. Premarin increased the lithogenic index of bile (P less than 0.05). increased biliary cholesterol secretion (P less than 0.005). lowered chenodeoxycholate (CDCA) pool (P less than 0.001) and synthesis (P less than 0.05). altered biliary bile acid composition [( CA + DCA]/CDCA increases. P less than 0.005). stimulated cholesterol esterification (P less than 0.03). and enhanced the clearance of chylomicron remnants (P = 0.07). Increases in dietary cholesterol stimulated the biliary secretion of cholesterol (P = 0.07). bile acid (P less than 0.05). phospholipid (P = 0.07). and as a result. did not alter lithogenic index. The reduction in CDCA pool and synthesis by Premarin was reversed by increasing dietary cholesterol. Off Premarin. only 24% of the increase in cholesterol entering the body in the diet was recovered as biliary cholesterol or newly synthesized bile acid. On Premarin. 68% of this increase in cholesterol was recovered as these biliary lipids. We conclude that Premarin increases biliary cholesterol by enhancing hepatic lipoprotein uptake and inhibiting bile acid synthesis. These actions of Premarin divert dietary cholesterol into bile.
On the mechanism of impaired insulin secretion in chronic renal failure, It has been suggested that a sustained rise in resting levels of cytosolic calcium [Ca2+]i of pancreatic islets is responsible for impaired insulin secretion in chronic renal failure (CRF). Evidence for such an event is lacking and the mechanisms through which it may affect insulin secretion are not known. Studies were conducted in normal. CRF. and normocalcemic. parathyroidectomized (PTX) CRF rats to answer these questions. Resting levels of [Ca2+]i of islets from CRF rats were higher (P less than 0.01) than in control of CRF-PTX rats. [3H]2-deoxyglucose uptake and cAMP production by islets were not different in the three groups. Insulin content of. and glucose-induced insulin secretion by islets from CRF rats was lower (P less than 0.01) than in control and CRF-PTX rats. In contrast. glyceraldehyde-induced insulin release by CRF islets was normal. Basal ATP content. both glucose-stimulated ATP content and ATP/ADP ratio. net lactic acid output. Vmax of phosphofructokinase-1. and Ca2+ ATPase of islets from CRF rats were lower (P less than 0.02-less than 0.01) than in normal or CRF-PTX animals. Data show that: (a) Glucose but not glyceraldehyde-induced insulin secretion is impaired in CRF; (b) the impairment in glucose-induced insulin release in CRF is due to a defect in the metabolism of glucose; (c) this latter defect is due to reduced ATP content induced partly by high [Ca2+]i of islets; and (d) the high [Ca2+]i in islets of CRF rats is due to augmented PTH-induced calcium entry into cells and decreased calcium extrusion from the islets secondary to reduced activity of the Ca2+ ATPase.
The growth inhibition of human breast cancer cells by a novel synthetic progestin involves the induction of transforming growth factor beta, Recent experimental work has identified a novel intracellular binding site for the synthetic progestin. Gestodene. that appears to be uniquely expressed in human breast cancer cells. Gestodene is shown here to inhibit the growth of human breast cancer cells in a dose-dependent fashion. but has no effect on endocrine-responsive human endometrial cancer cells. Gestodene induced a 90-fold increase in the secretion of transforming growth factor-beta (TGF-beta) by T47D human breast cancer cells. Other synthetic progestins had no effect. indicating that this induction is mediated by the novel Gestodene binding site and not by the conventional progesterone receptor. Furthermore. in four breast cancer cell lines. the extent of induction of TGF-beta correlated with intracellular levels of Gestodene binding site. No induction of TGF-beta was observed with the endometrial cancer line. HECl-B. which lacks the Gestodene binding site. but which expresses high levels of progesterone receptor. The inhibition of growth of T47D cells by Gestodene is partly reversible by a polyclonal antiserum to TGF-beta. These data indicate that the growth-inhibitory action of Gestodene may be mediated in part by an autocrine induction of TGF-beta.
Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels, The present experiments were undertaken to examine the hypothesis that glucose-induced increased de novo synthesis of 1.2-diacyl-sn-glycerol (which has been observed in a number of different tissues. including retinal capillary endothelial cells exposed to elevated glucose levels in vitro) and associated activation of protein kinase C may play a role in mediating glucose-induced vascular functional changes. We report here that twice daily instillation of 30 mM glucose over 10 d in a rat skin chamber granulation tissue model induces approximately a 2.7-fold increase in diacylglycerol (DAG) levels (versus tissues exposed to 5 mM glucose) in association with marked increases in vascular clearance of albumin and blood flow. The glucose-induced increase in DAG levels as well as the vascular functional changes are prevented by addition of 3 mM pyruvate. Pharmacological activation of protein kinase C with the phorbol ester TPA in the presence of 5 mM glucose increases microvascular albumin clearance and blood flow. and similar effects are observed with 1-monoolein (MOG). a pharmacological inhibitor of the catabolism of endogenous DAG. A pharmacological inhibitor of protein kinase C (staurosporine) greatly attenuates the rise in microvascular albumin clearance (but not the rise in blood flow) induced by glucose or by MOG. These findings are compatible with the hypothesis that elevated concentrations of glucose increase tissue DAG content via de novo synthesis. resulting in protein kinase C activation. and that these biochemical events are among the factors that generate the increased microvascular albumin clearance.
Neutrophil nicotinamide adenine dinucleotide phosphate oxidase assembly. Translocation of p47-phox and p67-phox requires interaction between p47-phox and cytochrome b558, Two of the cytosolic NADPH oxidase components. p47-phox and p67-phox. translocate to the plasma membrane in normal neutrophils stimulated with phorbol myristate acetate (PMA). We have now studied the translocation process in neutrophils of patients with chronic granulomatous disease (CGD). an inherited syndrome in which the oxidase system fails to produce superoxide due to lesions affecting any one of its four known components: the gp91-phox and p22-phox subunits of cytochrome b558 (the membrane-bound terminal electron transporter of the oxidase). p47-phox. and p67-phox. In contrast to normal cells. neither p47-phox nor p67-phox translocated to the membrane in PMA-stimulated CGD neutrophils which lack cytochrome b558. In one patient with a rare X-linked form of CGD caused by a Pro----His substitution in gp91-phox. but whose neutrophils have normal levels of this mutant cytochrome b558. translocation was normal. In two patients with p47-phox deficiency. p67-phox failed to translocate. whereas p47-phox was detected in the particulate fraction of PMA-stimulated neutrophils from two patients deficient in p67-phox. Our data suggest that cytochrome b558 or a closely linked factor provides an essential membrane docking site for the cytosolic oxidase components and that it is p47-phox that mediates the assembly of these components on the membrane.
Cartilage expression of a type II collagen mutation in an inherited form of osteoarthritis associated with a mild chondrodysplasia, In a family who expressed severe dominantly inherited osteoarthritis. the underlying mutation was traced by genomic sequencing to a single base change which predicts an amino acid substitution of cysteine for arginine at residue 519 of the triple-helical domain of the type II collagen molecule (Ala-Kokko. L.. C. T. Baldwin. R. W. Moskowitz. and D. J. Prockop. 1990. Proc. Natl. Acad. Sci. USA. 87:6565-6568). In the present study we examined whether this predicted protein phenotype was evident in articular cartilage obtained from an affected family member who underwent hip surgery. The cartilage collagen was solubilized by CNBr digestion. Cysteine residues were labeled by reduction and alkylation with 14C-iodoacetate. Collagen CNBr-peptides were fractionated by ion exchange and reverse phase column chromatography. One peptide from the alpha 1(II) chain. alpha 1(II) CB8. was found to be radiolabeled. Tryptic peptides were prepared from it and identified by microsequence analysis. The results show that approximately one-quarter of the alpha 1(II) chains present in the polymeric extracellular collagen of the patient's cartilage contained the Arg519-to-Cys substitution. The protein exhibited other abnormal properties including disulfide-bonded alpha 1(II)-dimers and signs of posttranslational overmodification. The premature cartilage failure and osteoarthritis are presumably a result of the abnormal type II collagen being expressed in the cartilage matrix.
Anderson's disease: genetic exclusion of the apolipoprotein-B gene in two families, Anderson's disease is a recessive disorder characterized by intestinal fat malabsorption. absence of postprandial chylomicrons. and reduced levels of cholesterol. triglycerides. and apoproteins B. AI. and C. We have studied two families with. respectively. three and two children with Anderson's disease. Intestinal apo-B and apo-AIV mRNAs from two Anderson's patients were normal in size but their concentration was decreased fivefold compared with controls. After DNA digestion with seven restriction enzymes. restriction fragment length polymorphisms of apo-B gene did not show conclusive information except for Xba1. which revealed a lack of cosegregation between the restriction fragment length polymorphism and the Anderson's phenotype. Linkage analysis was performed using the polymorphism of the apo-B gene 3'minisatellite. Genomic DNA from parents and children was amplified by polymerase chain reaction using oligonucleotide primers flanking the apo-B gene 3'hypervariable locus. In both families each child inherited different apo-B alleles from at least one parent. According to the recessive mode of transmission of the disease. our results are incompatible with the involvement of the apo-B gene. More likely a posttranslational defect or a mutation in another gene encoding a protein essential for lipoprotein assembly or secretion may be involved.
Preferential expression of human Fc gamma RIIIPMN (CD16) in paroxysmal nocturnal hemoglobinuria. Discordant expression of glycosyl phosphatidylinositol-linked proteins, The isoform of Fc gamma RIII (CD16) expressed on PMN has a GPI membrane anchor. and in paroxysmal nocturnal hemoglobinuria (PNH) there is a deficiency in Fc gamma RIII expression on PMN. Contrary to expectation. however. CD16 expression is preserved (albeit at reduced levels) in all affected PNH PMN that completely lack the GPI-anchored proteins DAF (CD55) and CD59. Fc gamma RIII negative PMN are not observed in any of the six PNH patients examined in this study. Analysis of the molecular weight of both glycosylated and deglycosylated Fc gamma RIII from PMN with reduced Fc gamma RIII expression indicates no variations in size relative to normal donor Fc gamma RIIIPMN. Indeed. the Fc gamma RIII expressed at intermediate levels is phosphatidylinositol-specific phospholipase C (PI-PLC)-sensitive. Thus. there is no evidence suggestive of expression of a transmembrane isoform and all data indicate that Fc gamma RIIIPMN on affected cells in PNH is a GPI-linked isoform. With Fc gamma RIIIPMN expression preserved at reduced levels on affected cells in PNH. PMN from PNH patients retain the capacity to internalize the Fc gamma RIIIPMN-specific probe E-ConA (at reduced levels) as well as IgG-opsonized erythrocytes. Reduced expression of GPI-anchored molecules on PNH PMN is not restricted to Fc gamma RIIIPMN since intermediate levels of CD59 were observed in the PNH PMN that were decay-accelerating factor (DAF)-negative and Fc gamma RIIIPMN intermediate. In addition. discordant expression of GPI-linked molecules in individual cells is not restricted to PMN since DAF+/CD14- monocytes were observed in one PNH patient. These data suggest that. when analyzed on an individual cell level. the GPI anchor defect in PNH is not absolute and must involve either a hierarchy of access of different protein molecules to available GPI anchors. distinct anchor biochemistries for the different proteins. or differential regulation of protein-anchor assembly.
Coexpression of two fibronectin receptors, VLA-4 and VLA-5, by immature human erythroblastic precursor cells, Human erythroblastic precursor cells adhere to fibronectin (Fn) but the exact nature of the receptors mediating this interaction has not been characterized. In this study. we report data showing that immature human erythroblasts express the integrins VLA-4 and VLA-5 and that both these molecules act as fibronectin receptors on these cells. We have recently demonstrated that adhesion to Fn of purified human CFU-E and their immediate progeny preproerythroblasts was inhibited by antibodies directed against the human fibronectin receptor (VLA-5). Here we have extended those results and characterized by immunoprecipitation with specific antibodies the integrins expressed on surface-labeled normal human immature erythroblasts. A polyclonal antibody recognizing the common VLA beta 1 subunit yielded two polypeptides of 120 and 160 kD. Our data further demonstrate that the polypeptide of 160 kD contains alpha subunits corresponding to both alpha 4 and alpha 5. Thus. erythroblast lysates prepared in 0.3% CHAPS and immunoprecipitated with antibodies which specifically recognize the alpha 4 subunit showed a heterodimer with peptides of 120 (beta 1) and 160 kD (alpha 4) and the additional peptides of 70 and 80 kD which usually coprecipitate with the alpha 4 chain. On the other hand. specific anti-alpha 5 antibodies immunoprecipitated an alpha 5/beta 1 complex with peptides of 120 and 160 kD which under reducing conditions migrated as a single band of 130 kD. Similar experiments performed with an erythroleukemic cell line (KU 812) showed that these cells also coexpress both the VLA-4 and VLA-5 members of the integrin family. Furthermore. monoclonal antibodies recognizing the VLA alpha 4 chain blocked the adhesion of immature erythroblasts to Fn-coated surfaces. thus demonstrating that. as VLA-5. VLA-4 is also a functional Fn receptor on these cells.
Spherical connective tissue inclusions in epithelial hyperplasia of the breast ("collagenous spherulosis"), Partial myoepithelial differentiation is common in simple epithelial hyperplasia (epitheliosis) of the breast but functional myoepithelial differentiation with basement membrane production is exceedingly rare. A peculiar change of hyaline globules within benign epithelial hyperplasia has been recognised before as "collagenous spherulosis" and type IV collagen has been shown by immunohistochemistry. Another seven cases are described which show the presence of laminin and collagens IV and III within the proliferation. Electron microscopy examination of two cases using material retrieved from the wax block showed varying degrees of myoepithelial differentiation of the cells immediately surrounding the spherules and basal lamina material. including mature collagen fibrils in one case. The degree of myoepithelial differentiation of the cells surrounding the spherules seemed to correlate with the differing types and amounts of extracellular matrix in the spherule. Histopathologists should be aware of this rare change as it may be misinterpreted as in situ carcinoma.
Measurement techniques for melanoma: a statistical comparison, Inter- and intra-observer variation in measuring the depth of invasion of malignant melanomas was assessed using three different techniques: eye-piece graticule. stage Vernier. and projection image analysis. Significant variation was found for all methods but was least pronounced with the stage Vernier. It is recommended that this should be the preferred technique for routine use.
Erythroid colony growth from peripheral blood and bone marrow in polycythaemia, Erythroid colony growth in the presence and absence of erythropoietin was compared in 23 patients with primary proliferative polycythaemia (PPP). nine with idiopathic erythrocytosis. 10 with secondary polycythaemia. 15 with pseudopolycythaemia and in 76 normal subjects. Erythroid colonies growing without erythropoietin stimulation (endogenous erythroid colonies) from peripheral blood (BFU-E) were found in 20 of 22 patients with PPP and in two of seven with idiopathic erythrocytosis. None was found in secondary polycythaemia. pseudopolycythaemia. or in normal subjects. Small numbers of endogenous colony forming units-erythroid (CFU-E) (though not BFU-E) were cultured from the bone marrow of three of 24 normal subjects. suggesting that peripheral blood cultures provide a more specific indicator of clonal erythropoiesis. Peripheral blood endogenous erythroid colony growth is an effective and convenient means of distinguishing patients with clonal erythrocytosis and may be of particular value when iron deficiency obscures the diagnosis of PPP on conventional criteria.
Non-specific reactions in enzyme linked immunosorbent assays for serum antibody to entamoeba histolytica and Giardia lamblia in non-endemic areas, Serum samples from 20 Indian children with diarrhoea were compared with those from 20 children resident in the United Kingdom who had been diagnosed as having ulcerative colitis. or Crohn's disease. or indeterminate colitis using enzyme linked immunosorbent assays specific for Entamoeba histolytica and Giardia lamblia. More than 50% of the United Kingdom patients had high IgG responses in ELISAs for E histolytica and G lamblia. A confirmatory ELISA showed that the British sera reacted specifically to bovine serum proteins rather than to protozoal antigens. Prior incubation of sera with 5% bovine serum prohibited this reaction. Bovine serum is an integral part of the crude soluble antigen used in most ELISAs for E histolytica and G lamblia and needs to be replaced with purified antigen preparations. The British sera also reacted to other commonly used blocking agents such as bovine serum albumin. casein. and normal sheep serum. These reactions were attributed to uptake of dietary antigens or an enhanced immunological response to these antigens in patients with inflammatory bowel disease.
Cartilage removal prior to skin grafting in the triangular fossa, antihelix, and concha of the ear, Skin grafting onto a large area of exposed ear cartilage with irregular contours poses an increased risk of inadequate re-establishment of circulation. Removal of cartilage not needed for structural support before grafting following Mohs surgery on the triangular fossa. antihelix. and concha of the ear decreases the risk of recurrence of the carcinoma. and increases the chances for survival of the graft.
The transverse anatomy of androgenic alopecia, Twenty-five biopsy specimens from the balding frontal scalp of five patients were studied. Processing included vertical and transverse (horizontal) sectioning. toluidine blue and hematoxylin and eosin staining. and fixed and frozen sectioning. Findings included decreased hair density. increased numbers of vellus hairs. and alteration of the normal follicular architecture. Transverse frozen sectioning with toluidine blue staining appeared to be a rapid and reliable tool for studying androgenic alopecia.
Fine-needle aspiration for diagnosis of intranodal squamous-cell carcinoma metastatic from the skin, Fine-needle aspiration is a useful way to determine the presence of squamous-cell carcinoma in enlarged lymph nodes of patients at high risk for metastases. Advantages include a high degree of accuracy. outpatient as well as inpatient availability. and negligible potential for seeding of malignant cells. Cutaneous oncologists should consider using this technique in patients with lymphadenopathy and a previous history of cutaneous squamous cell carcinoma.
Interleukin-1 is released at sites of human cutaneous allergic reactions, Interleukin-1 (IL-1) promotes cell recruitment and influences allergic mediator release. We analyzed histamine. prostaglandin D2. IL-1. and leukocytes accumulating hourly for 12 hours at skin-chamber sites after local ragweed challenge in eight allergic subjects with cutaneous late-phase reactions. Ragweed induced a peak of histamine at 1 hour (p less than 0.02). which diminished. and then steadily increased (p less than 0.02). Prostaglandin D2 levels peaked by the second hour (p less than 0.02) and then decreased. approaching prechallenge levels by 12 hours. Leukocyte infiltration (predominantly neutrophils) was detectable 3 to 4 hours after challenge. although selective enrichment of mononuclear cells. eosinophils. and basophils ws observed at later hours (p less than 0.02). IL-1 bioactivity was detected in fluids 10 to 12 hours after challenge but not at control sites (p less than 0.05). Analysis of IL-1 beta levels by RIA revealed an initial peak at 1 hour of 0.90 ng/ml (p less than 0.02) and a second elevation of up to 0.75 ng/ml during the later hours (p less than 0.04). Ragweed challenge of three nonatopic subjects did not change levels of the above-mentioned mediators or cells. Bioactivity in chamber fluids from antigen-challenged sites of atopic subjects was significantly neutralized by an anti-IL-1 beta antiserum. although treatment with anti-IL-1 alpha and anti-IL-1 beta was needed for complete neutralization. IL-1 released locally during cutaneous allergic reactions may contribute to IgE-dependent cutaneous inflammation.
Alpha- and beta-adrenergic-receptor systems in bronchial asthma and in subjects without asthma: reduced mononuclear cell beta-receptors in bronchial asthma, We assessed the adrenergic-receptor system in individuals with bronchial hyperreactivity. beta-Adrenergic receptors on mononuclear cell membranes. alpha-adrenergic receptors on platelet membranes. and the cAMP response in these cell types to different stimuli. including platelet-activating factor (PAF). were determined. Studies were assessed in 10 subjects with mild asthma. six methacholine-sensitive subjects without asthma. and 10 normal subjects. The density and affinity of beta-receptors and alpha-receptors were determined by Scatchard analysis. Our findings were that (1) subjects with asthma had a significantly lower density of beta-receptors compared to normal subjects. (2) subjects with asthma had a significantly lower cAMP response to isoproterenol stimulation compared to the two other groups. (3) in subjects without asthma. PAF decreased the basal cAMP level and significantly inhibited the response to isoproterenol stimulation. (4) there was no difference in density and affinity of platelet alpha-receptors or in platelet cAMP responses to stimulation by alpha-agonists among these three groups. and (5) neither cAMP response or beta-receptor density on mononuclear cells were significantly correlated with pulmonary-function tests (FEV/FVC times 100). sensitivity to methacholine. or cold-air inhalation. These results suggest that patients with asthma may have a lower isoproterenol cAMP response and decreased density of beta-adrenergic receptors on mononuclear cells in the absence of beta-agonist therapy. It is speculated that release of PAF and other mediators secondary to allergen exposure. even in the absence of overt attacks of asthma. may inhibit the response to endogenous or exogenous beta-adrenergic agonists.
Relationship between the early, late, and rechallenge reaction to nasal challenge with antigen: observations on the role of inflammatory mediators and cells, We challenge each of 55 consecutive ragweed (RW)-allergic patients with hay fever and with graded increasing doses of ragweed extract to investigate the frequency and relationship between the early (ER). late (LPR). and rechallenge reactions (RCRs) to nasal challenge. We evaluated the nasal response by measuring the levels of histamine. TAME-esterase activity. and kinins in the nasal lavage fluid and by grading symptoms. Fifty-one subjects (92.7%) had an ER consisting of a dose-dependent. concommitant increase in both mediators and symptoms. The total amount of TAME-esterase activity and kinins generated during ER correlated significantly with specific serum IgE (ssIgE). intradermal skin test (ST) sensitivity. and basophil histamine release (BHR) to antigen E (p less than 0.01 for each). Twenty-four (47%) subjects developed a late increase in mediators and 23 (45%) subjects in symptoms. None of the four subjects without an ER developed an LPR. The levels of the late-appearing mediators were not predicted by ST. ssIgE. or BHR. There was a significant but weak association between the intensity of ER and LPR. but there was no significant difference in the IgE antibodies. ST. BHR. and intensity or threshold of ER between dual and early only reactors. The number of eosinophils and neutrophils in the LPR lavages increased over the prechallenge baseline. and their numbers correlated (p less than 0.05) with ER kinins (r = 0.46. and 0.37. respectively). ER TAME-esterase activity (r = 0.28 and 0.24. respectively). and in the case of eosinophils. ER histamine (r = 0.29).
1,25-Dihydroxyvitamin D3 potentiates the decreased response of lymphocytes from atopic subjects to agents that increase intracellular cyclic adenosine monophosphate, The inhibitory effect of prostaglandin E2. histamine. isobutylmethylxanthine. and 1.25-dihydroxyvitamin D3 (1.25-[OH]2D3) on the mitogenic stimulation of peripheral blood lymphocytes from normal and atopic subjects was studied. We found that lymphocytes from atopic patients were less susceptible to inhibition by the three agents that elevate intracellular cyclic adenosine monophosphate (cAMP) concentrations and by the active metabolite of vitamin D (inhibition of 27%. 14%. 12%. and 36% for the atopic patients as compared with 40%. 20%. 22%. and 46% for the normal donors. by the four agents. respectively; p less than 0.02). The inhibitory effect of the cAMP-elevating agents was potentiated by the addition of 1.25-(OH)2D3 to the lymphocyte cultures. The potentiation was more pronounced on lymphocytes from the atopic donors. increasing their responsiveness to levels comparable to levels of lymphocytes from normal donors. The synthetic corticosteroid. dexamethasone. had a similar potentiating effect on the inhibitory action of prostaglandin E2. In view of the beneficial action of beta-agonists. phosphodiesterase inhibitors. and corticosteroids in the treatment of allergy. the potentiating effect of 1.25-(OH)2D3 on the action of cAMP-elevating agents may be of therapeutic interest.
Comparison of the effect of loratadine on the airway and skin responses to histamine, methacholine, and allergen in subjects with asthma, Loratadine is a highly selective. long-acting. H1-receptor antagonist. In a randomized. double-blind. crossover study. we evaluated the effects of loratadine. 10 and 20 mg. and placebo administered once daily for 3 days on the skin-wheal responses to histamine. the airway responses to inhaled histamine and methacholine. and the skin-wheal and airway responses to allergen in 12 subjects with asthma. There was no evidence of a bronchodilator action 3 hours after a third oral dose. In the airways. the geometric mean of the provocative concentration of histamine causing a 20% fall in FEV1 after placebo or loratadine. 10 and 20 mg. was 0.68 mg/ml. 2.71 mg/ml (p. not significant). and 5.96 mg/ml (p less than 0.05). respectively. The concentration ratios (value after active treatment/value after placebo) for loratadine. 10 and 20 mg. were 5.1 (p less than 0.05) and 13.4 (p less than 0.05). Neither dose of loratadine had any significant effect on the methacholine dose-response relationship. In the skin. loratadine also displaced the histamine log-concentration response curves to the right with concentration ratios of 4.7 and 6.7. respectively. Loratadine. 10 and 20 mg. had no protective effect on the early or late-phase bronchoconstrictor responses to inhaled allergen. In the skin. loratadine. 20 mg. significantly inhibited the mean wheal area to allergen. Thus. in the dose regimens studied. although loratadine is a moderately potent and selective H1 antagonist in the skin and airways. it failed to attenuate the early and late airway responses to inhaled allergen.
Altered production of histamine-releasing factor (HRF) activity and responsiveness to HRF after immunotherapy in children with asthma, To delineate the working mechanisms of immunotherapy (IT) (hyposensitization). the production of. and responsiveness to. histamine-releasing factor (HRF) was studied in four groups. These groups consisted of 32 newly diagnosed children with asthma. 40 good responders and 18 poor responders to IT (older than 2 years). and 15 healthy subjects. The results demonstrated (1) peripheral blood mononuclear cells of new patients produced a much greater HRF activity. either spontaneously or after stimulation. than did those of normal subjects. (2) the spontaneous HRF activity decreased significantly in good responders. whereas that of poor responders increased. (3) both the allergen (mite)- and mitogen (phytohemagglutinin [PHA])-stimulated HRF activity was decreased. although decrease was not significant. in good responders. but the activity was not changed in poor responders. (4) the granulocytes of new patients responded to HRF much more vigorously than did granulocytes of normal subjects. The responsiveness diminished significantly in both good and poor responders. although the magnitude of decrease was slightly greater in the former. (5) there was a positive correlation between PHA- and mite-stimulated HRF activity. mite-stimulated HRF activity and responsiveness to HRF. and plasma histamine level and responsiveness to HRF in the new patients. and (6) there was an inverse correlation between PHA-stimulated HRF production and responsiveness to HRF in good responders. but the correlation was positive in poor responders. Thus. IT is able to suppress the HRF activity. particularly the type of spontaneous synthesis. and responsiveness to HRF in clinically benefitted children with asthma. and this effect may be used to explain. partly. the efficacy of IT in a proportion of allergic patients.
Allergy to different fish species in cod-allergic children: in vivo and in vitro studies, The presence of a positive clinical history and skin test (ST) results for 17 fish species (anchovy. bass. carp. dogfish. eel. gilthead. mackerel. mullet. perch. red mullet. salmon. sardine. sole. tench. toothed gilthead. trout. and tuna) were investigated in 20 children with cod-positive clinical history. ST. and RAST. and in 40 children positive to one or more foods different from cod (cow's milk. chicken egg white. peanut. and tomato). In cod-positive children. positive clinical history (60%) and ST (85%) to fish species were more frequent than in cod-negative children (7.5% and 10% respectively). In cod-positive children. a high frequency of positive STs to eel (85%) and to bass. dentex. sole. and tuna (55%) was observed. Positivity to dogfish (10%) was the least frequent. RAST-inhibition experiments suggested the presence of cross-reacting antigen(s) in cod. bass. dentex. eel. sole. and tuna. Results of this study demonstrate that cod allergy might be. on the whole. a reliable index of fish allergy. but cod-positive children may perhaps tolerate some other species. which will have to be tested for possible inclusion in their diet.
A double-blind comparison of intranasal budesonide with placebo for nasal polyposis, Intranasal budesonide. 400 micrograms two times a day. was evaluated in 36 patients referred for treatment of nasal polyposis. The age range was 20 to 68 years. Polypectomy was done 5.6 (mean) times previously. After a 5-week. treatment-free. baseline period. patients were treated in a double-blind fashion with either budesonide or placebo during 4 weeks. After this treatment period. placebo-treated patients started receiving budesonide in an open trial for an additional 4 weeks. The patients rated their nasal symptoms daily. Nasal examinations and nasal inspiratory flow rate (IFR) measurements were done at clinic visits. After 3 and 4 weeks of treatment. the response to budesonide was significantly greater than response to placebo. The greater reduction in nasal blockage caused by polyps. observed on physical examination. p = 0.005. was mirrored by an increase in nasal IFR (p = 0.0001). Patient rating of the severity and frequency of nasal blockage were reduced more by budesonide than by placebo (p less than or equal to 0.0005). Switching placebo-treated patients to budesonide treatment resulted in a reduction of nasal blockage (p less than 0.001) and an increase in nasal IFR (p less than 0.001). The results demonstrate that topical nasal budesonide. 400 micrograms two times a day. is an effective treatment of nasal polyps.
Selective desensitization to seminal plasma protein fractions after immunotherapy for postcoital anaphylaxis, A 24-year-old white woman reported sexual intercourse-related pruritus. hives. wheezing. and dyspnea within 5 minutes after ejaculation. Systemic reactions (SRs) were prevented by use of condoms. Prick testing confirmed sensitization to five Sephadex G-100-separated fractions of her husband's seminal plasma. The intradermal end point threshold concentrations (ETC) were 10(-4) and 10(-1) micrograms of protein per milliliter to fractions 2 and 3. respectively. Leukocyte histamine release studies exhibited 100% release to fraction 2 and 37% release to fraction 3. A 2-day protocol of rapid immunotherapy (IT) was performed with subcutaneous incremental doses of human seminal plasma (HuSePl) fractions 2 and 3. The patient experienced an SR after receiving a cumulative dose of 38.55 micrograms of fraction 2 on day 1. On day 2. rapid IT with fraction 2 was administered until the patient experienced a mild SR after having received a cumulative dose of 102.8 micrograms. There was a one-log10 increase in the intradermal ETC to both fractions 2 and 3 at the end of day 2. IT was continued three times weekly for 4 months until the patient tolerated 100 micrograms doses of both fractions 2 and 3. At 4 months. coitus was resumed without SRs. and HuSePl IT was stopped. The intradermal ETC to fractions 1. 3. 4. and 5 was increased 6 months after cessation of HuSePl injections. but there was a one-log decrease in the ETC to fraction 2. Our experience demonstrated that systemic tolerance can be achieved by parenteral administration of selected HuSePl fractions. Partial immunologic desensitization of patients with anaphylactic sensitivity can be achieved.
Urticaria: clinical efficacy of cetirizine in comparison with hydroxyzine and placebo, Chronic urticaria is a problem for both physician and patient. In an effort to avoid the risks associated with corticosteroid treatment. many first-generation H1-receptor antagonists have been tried and found to induce undesirable levels of sedation when given in amounts sufficient to control urticaria. Cetirizine. a pharmacologically active oxidized metabolite of hydroxyzine. was developed to provide selective H1-receptor inhibition without depression of the central nervous system. In a 4-week. multicenter. double-blind. placebo-controlled safety and efficacy study. cetirizine. in a once-a-day dose (5 to 20 mg). was equivalent in efficacy to hydroxyzine in divided doses (25 to 75 mg/day). The incidence of somnolence in the cetirizine group was not significantly different from that of the placebo group. However. in the hydroxyzine group. the incidence of somnolence was significantly higher than that in the placebo group (p = 0.001). The results of this study demonstrate that cetirizine has a greater safety margin over the older parent drug hydroxyzine.
Cetirizine: antiallergic therapy beyond traditional H1 antihistamines, For three decades. traditional H1 antihistamines have been used in the treatment of allergic diseases. They are effective in reducing histamine-related symptoms. but the use of such agents has been limited by sedation and anticholinergic side effects. These adverse effects are fewer with the recently introduced H1 antihistamines. One of these. cetirizine. a human metabolite of hydroxyzine. is characterized by its high selectivity for the H1 receptor site and its reliable and consistent inhibition of histamine-induced allergic reactions. It also blocks eosinophil infiltration to the site of allergen-induced cutaneous reactions. Cetirizine has proved effective in the treatment of seasonal and perennial allergic rhinitis and urticaria. It is excreted primarily by renal mechanisms. It is well tolerated by elderly patients. Cetirizine has a low rate of penetration of the blood-brain barrier. and it has minimal central nervous system impairment. Furthermore. it can be given once a day. Cetirizine's low incidence of sedation and anticholinergic side effects contribute to its high profile of safety. In this article the characteristics. pharmacology. pharmacokinetics. and mode of action of cetirizine are reviewed.
Payment mechanism and patterns of use of medical services: the example of hypertension, This study explores the relationship between the use of medical services by hypertensive patients and mechanisms for payment within a single primary care practice. Three payment mechanisms were explored: public assistance. a capitated health maintenance organization (HMO). and fee-for-service. Patterns were examined across reimbursement type for the following variables: age. sex. visit reason. number of visits. medications. tests ordered. referrals made. and recommendations for follow-up visits. Illness severity was controlled in two ways: (1) by the study being focused on one diagnosis--mild to moderate hypertension. and (2) by concurrent chronic illnesses being enumerated and included in the analysis. Medical visits to the physician were examined over a 2-year period for 25 to 30 patients randomly sampled from each of the three payment mechanisms. Statistically significant differences were found for patient behaviors (total number of patient visits) and physician behaviors (number of medications and recommendations for revisits). The highest visit frequency was found for those on public assistance. followed closely by those covered by an HMO. and more distantly by those choosing fee-for-service. In a climate of cost consciousness. further study is needed to explore the impact of reimbursement mechanisms on the use of health care services.
AIDS: family physicians' attitudes and experiences, A study was developed to examine the current experiences and opinions of a national sample of family physicians with regard to acquired immunodeficiency syndrome (AIDS). The survey response rate was 72.5% (757 questionnaires were returned out of a sample of 1044). Approximately 47% of respondents have cared for an HIV-infected patients. This percentage varied from a low of 31.4% in the Midwest to as high as 56.1% on the East Coast. Thirty-two percent of family physicians practicing in communities of fewer than 2500 have dealt with this illness. while 60% of those in communities of greater than 100.000 have done so. Seventy-seven percent of respondents are willing to provide care to HIV-infected individuals; 62.9% believe that physicians have a right to refuse to care for a patient because he or she is infected with the AIDS virus. Forty percent believe that they would lose patients if it were known that they were caring for an AIDS patient in their office. Finally. the vast majority of those surveyed favor required partner notification and would inform the sexual partner of an HIV-positive patient if the patient refused to do so.
Computer-generated physician and patient reminders. Tools to improve population adherence to selected preventive services, Despite an emerging consensus on appropriate preventive services. a minority of patients receive them. A study was undertaken to assess the impact of computer-generated reminders to adult patients. their physicians. or both patients and physicians on adherence to five recommended preventive services: cholesterol measurements. fecal occult blood testing. mammography. Papanicolaou smears. and tetanus immunization. During the academic year 1988-1989. all 7397 adult patients and their 49 physicians in a university family medicine clinical practice were randomized by practice group into one of four study groups: control. physician reminders. patient reminders. and both physician and patient reminders. Adherence was defined in community-oriented terms: the percentage of patients within each group who had received the preventive service in the recommended interval. During the study period. adherence to four of the five preventive services increased significantly. with the largest increases in the physician and patient reminder group: cholesterol measurements increased from 19.5% to 38.1%. fecal occult blood testing 9.3% to 27.0%. mammography 11.4% to 27.1%. and tetanus immunization 23.4% to 35.4% (for each increase. P less than .0001. McNemar's chi-square test). In general. increases were greater in blacks and in patients with any form of insurance coverage. Computer-based physician and patient reminder systems have great promise of improving adherence to preventive services in primary care settings.
Trajectory reconstructions. I: Trace evidence in flight, This paper reviews the use of trace evidence recovered from spent bullets in helping to establish trajectories. The use of information derived from such trace evidence combined with that from geometrical techniques of trajectory reconstruction and other data is discussed. Five cases are reviewed in which the analysis of trace evidential materials adhering to bullets was used to help reconstruct the event.
Fluorometric determination of pseudocholinesterase activity in postmortem blood samples, A fluorometric assay using 3-(p-hydroxyphenyl) propionic acid (HPPA) was conducted to determine the activity of pseudocholinesterase (ChE) [Enzyme Commission (EC) No. 3.1.1.8] in postmortem blood samples so as to test for organophosphate poisoning. By the enzymatic reaction of ChE. its substrate. benzoylcholine. produces choline. which is oxidized by choline oxidase to generate hydrogen peroxide. HPPA is oxidized by hydrogen peroxide and peroxidase to become the fluorogenic dimer whose concentration is measured fluorometrically at an excitation emission wavelength of 320 nm and an elimination emission wavelength of 404 nm. The selectivity and sensitivity of the present method were found to be superior to those of conventional pH and spectrophotometric methods.
An application of probability theory to a group of breath-alcohol and blood-alcohol data, Many jurisdictions have "per se" driving-while-intoxicated (DWI) status expressed in terms of a blood-alcohol concentration (BAC) standard (in grams per 100 mL or the equivalent). Since breath-alcohol (BrAC) analysis is typically employed to determine BAC. there is often challenge to the use of an assumed 2100:1 conversion ratio. This concern may be relevant in light of considerable data that show a low percentage of cases in which BrAC greater than BAC. and this concern increases when the BrAC is used to predict BAC in the context of "per se" legislation. Probability theory provides a basis for estimating the likelihood of an individual having a BrAC greater than or equal to g/210 L with a corresponding BAC less than 0.10 g/100 mL. Actual field data from the state of Wisconsin (n = 404) were evaluated to determine the probability of this occurrence. The probability for this occurrence involves the multiplication law for independent events. The computed probability from the data was 0.018. The actual number of occurrences where BrAC greater than or equal to 0.10 g/210 L and BAC less than 0.10 g/100 mL was 5. resulting in a probability of 0.012. The concern of having BrAC greater than BAC at the critical "per se" level has a very low probability of occurrence. which thus supports the reasonableness of "per se" DWI legislation based upon a blood-alcohol standard determined by breath-alcohol analysis.
The usefulness of lung surfactant phospholipids (LSPs) in the diagnosis of drowning, The authors have studied the usefulness of some lung surfactant phospholipids (LSPs) isolated from lung tissues as markers of drowning. Two different groups of rabbits were sacrificed by drowning in fresh and salt water. and their phospholipid compositions were compared with those of a non-drowned control series. For the phospholipids studied in lung lavages (phosphatidyl choline. phosphatidyl ethanolamine. and phosphatidyl glycerol) the proportions differed between the control group and the drowned group. and between the fresh-water and salt-water drowned animals. According to these results. the lipids we have analyzed can be employed as markers in forensic autopsies. where it is necessary to differentiate between death by drowning and postmortem immersion and between fresh-water and salt-water drowning. In lung tissue. only phosphatidyl choline and phosphatidyl inositol showed significative differences. These results also confirm that LSPs are strongly affected in drowning.
Brain markers and suicide: can a relationship be found, Recent work suggests that some persons who commit suicide have altered neurochemistry in their brains. It remains unclear which of the many reported abnormalities are most reliably present and whether they reflect a specific psychiatric disorder or a disposition to violent impulsivity. A number of technical and interpretive problems must be clarified. but a postmortem test indicating that a subject was at high risk for suicide may eventually emerge. This approach would not be useful for ruling out suicide. since altered neurochemistry is not likely to be involved in every case.
Sudden cardiac death during exercise in a weight lifter using anabolic androgenic steroids: pathological and toxicological findings, A 21-year-old. previously healthy weight lifter collapsed during a bench press workout. He had taken anabolic androgenic steroids parenterally for the previous several months. Pertinent autopsy findings included marked cardiac and renal hypertrophy and hepatosplenomegaly. with regional myocardial fibrosis and focal myocardial necrosis. Nandrolone (19-nor-testosterone) metabolites were identified in postmortem urine. The possible etiologies of the cardiac findings are discussed.
A death resulting from trichlorotrifluoroethane poisoning, Fatalities due to accidental exposure to chlorinated hydrocarbon in an industrial setting have been infrequently reported. The deaths in these cases have occurred within poorly ventilated. enclosed compartments or areas. A case is presented of a 16-year-old male who died as a result of exposure to trichlorotrifluoroethane while working in an open pit. Chromatographic results and tissue concentrations are presented.
The tubular "cookie cutter" bullet: a unique projectile, Recently marketed PMC (Pan Metal Corporation) Ultramag tubular hollow point ammunition is uniquely constructed with a two-part projectile composed of a tubular copper bullet and a Teflon wad. A fatal gunshot wound with this ammunition is described. A unique radiographic pattern and the results of test firing are also presented.
The use of human skin in the fabrication of a bite mark template: two case reports, Comparison of a suspected biter's dental arches with the patterned injury of a bite mark is especially difficult when the bite occurs in an anatomic location with a small radius of curvature or with complex or compound curves. The authors present two case reports in which human skin was used as a template for the reproduction of a bite. In one case the victim's skin was used; in the other. the skin of a anatomically similar person was used. The use of inked dental casts. photography. and transparent overlays significantly reduced the errors common to analysis of bite marks in these highly curved areas.
Florid refractory schizophrenias that turn out to be treatable variants of HLA-associated narcolepsy, Narcolepsy in which the hallucinatory component is unusually prominent may lead to the development of an illness indistinguishable from the schizophrenic syndrome. Psychotic symptoms dominate the symptomatology. so that the primary illness is obscured. Five patients are described for whom conventional antipsychotic drugs were ineffectual. but for whom treatment with stimulants produced substantial improvement. The diagnosis of narcolepsy was confirmed by Human Leukocyte Antigen typing and sleep laboratory testing. These results support the "REM intrusion" hypothesis of the causation of schizophrenia in as many as 7% of a series of schizophrenic patients. Implications for diagnosis and treatment are discussed.
Combat-related PTSD and psychosocial adjustment problems among substance abusing veterans, The purpose of this study were the following: a) to determine the prevalence of combat-related posttraumatic stress disorder (PTSD) symptoms among veterans seeking assistance at a Veterans Administration medical center substance abuse treatment facility. b) to examine the relative contribution of Vietnam war zone variables to PTSD symptom development. and c) to study psychosocial adjustment problems associated with Vietnam combat exposure and with PTSD symptoms among help-seeking substance abusing men. Of 489 male veterans presenting for treatment. 10.7% had significant Vietnam combat-related PTSD symptoms as measured by the Mississippi Scale for Combat-Related PTSD. Clinically significant PTSD symptoms occurred among 46% of the subsample of combat-exposed Vietnam veterans with substance abuse problems. Degree of combat exposure was the most important military stressor that distinguished Vietnam veterans with PTSD from those without PTSD. but the groups also differed on age of war zone duty. duration of war zone duty. and whether they were wounded. Veterans who served in Vietnam did not differ from veterans who had no war zone duty on various parameters of psychosocial adjustment. However. the subgroup of Vietnam veterans with PTSD symptoms reported significantly greater psychosocial adjustment problems than their counterparts who did not have PTSD. The deleterious effects associated with combat-related PTSD appeared to be confined to adjunctive psychiatric difficulties and unemployment and did not increase risk of arrests for antisocial conduct beyond that found for veterans without PTSD. Methodological and clinical implications of these findings are discussed.
Psychological absorption. Affect investment in marijuana intoxication, Absorption (a trait capacity for total attentional involvement) was reported to increase during episodes of marijuana intoxication. Several subsets of the absorption scale items specifically characterized marijuana intoxication. and groups of users and nonusers showed differential affective involvement with these experiences. Additionally. within the drug-using group. a positive correlation between frequency of marijuana use and affective ratings of these experiences was found. The findings support the hypothesis that a specific type of alteration in consciousness that enhances capacity for total attentional involvement (absorption) characterizes marijuana intoxication. and that this enhancement may act as a reinforcer. possibly influencing future use.
Association between post-dexamethasone cortisol level and blood pressure in depressed inpatients, We examined the clinical data for 230 depressed inpatients who had completed a dexamethasone suppression test (DST) to determine whether those with an elevated post-DST serum cortisol level exhibited any of the classic physiological stigmata of Cushing's syndrome. Hypertension was significantly more frequent among DST nonsuppressors (21.2%) than among normal suppressors (11.3%). Percent blood lymphocyte count was significantly lower among nonsuppressors. Confounders such as gender. age. body weight. and use of antihypertensives did not account for the findings. Implications for morbidity and mortality rates among patients with affective disorder are discussed.
Free and peptide-bound amino acids as indicators of ischemic damage of the rabbit spinal cord, The concentrations of free and peptide-bound amino acids aspartate (Asp). glutamate (Glu). glycine (Gly) and gamma-aminobutyric acid (GABA) were studied following ischemia and recirculation in the ventral and dorsal gray matter of the rabbit spinal cord. No changes in the concentration of amino acids following ten minutes (min) of ischemia and four days of recovery were found. The most significant change after 20 min. and especially 40 min. of ischemia was a decrease in free Asp and GABA levels in both parts of the gray matter. The relatively greater decrease in the concentration of free amino acids in the ventral horns corresponds with the greater morphological damage to this part of spinal cord following ischemia. Following 40 min of ischemia and recirculation decrease in peptide-bound Glu in the ventral horns and Asp and Glu in the dorsal horns was found.
HiC-COM: a 2-month intensive chemotherapy regimen for children with stage III and IV Burkitt's lymphoma and B-cell acute lymphoblastic leukemia, We designed a protocol that included 2 months of intensive Cytoxan (cyclophosphamide; Bristol-Myers Co. Evansville. IN). high-dose methotrexate (MTX). high-dose cytarabine (ara-C). and vincristine (HiC-COM) to improve event-free survival (EFS) for patients with advanced-stage Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (ALL). We also wished to test the feasibility of rapidly cycling Cytoxan and high-dose ara-C based on signs of early marrow recovery. Twenty patients including 12 with stage III Burkitt's lymphoma and eight with stage IV Burkitt's lymphoma or B-cell ALL were entered onto this pilot study. The rate of complete remission was 95%. Four patients have relapsed. The 2-year actuarial EFS was 75% (median follow-up. 37 months). Two of the initial five patients developed transverse myelitis. which we believe may have been secondary to the concomitant administration of intrathecal (IT) and high-dose systemic ara-C. We conclude that this short but intensive regimen is highly effective for patients with advanced Burkitt's lymphoma and B-cell ALL. EFS has improved over previous less intensive regimens. and is comparable to regimens of longer duration.
High-dose chemoradiotherapy supported by marrow infusions for advanced neuroblastoma: a Pediatric Oncology Group study [published erratum appears in J Clin Oncol 1991 Jun;9(6):1094, We conducted a pilot protocol at seven Pediatric Oncology Group (POG) institutions to examine the feasibility. toxicity. and efficacy of using a common regimen of high-dose chemoradiotherapy (HD CT/RT) supported by autologous or allogeneic marrow infusions in children with metastatic neuroblastoma (NBL) in first or second remission. During a 57-month period. we accrued 101 patients. We report here results for the 81 who completed treatment at least 2 years ago. The HD CT/RT regimen consisted of melphalan 60 mg/m2/d for three doses. and total body irradiation (TBI) either 1.5 Gy (n = 27) or 2.0 Gy (n = 54) twice daily for six doses. Twenty-three patients also received irradiation consisting of 1.2 Gy twice daily for 10 doses to persisting disease sites. Seventy-four were given autologous and seven allogeneic marrow. 64 autologous marrows being purged immunomagnetically. Fifty-four children were in first complete (CR) or partial (PR) remission and 27 in second CR or PR. As of October 1. 1990. follow-up was from 32 to 72 months. Forty-seven of these 81 children relapsed. 10 died of complications. one of unknown cause. and 23 continue in remission. including 21 of the 54 treated in first remission. and 16 who completed treatment more than 3 years ago. The 2-year actuarial event-free survival (EFS) probabilities are first CR (CR1) 32% (SE 10%). first PR (PR1) 43% (SE 9%). second CR (CR2) 33% (SE 27%). and second PR (PR2) 5% (SE 5%). Probability of EFS correlated with remission number (first better than second. P less than .001). with interval from diagnosis to HD CT/RT (greater than 9 months better than less than 9 months. P = .055). and with TBI dose (12 Gy better than 9 Gy. P = .031). These encouraging results may partly reflect selection for this treatment of patients with NBL who have a slower disease pace.
Relationship of tumor-cell ploidy to histologic subtype and treatment outcome in children and adolescents with unresectable rhabdomyosarcoma [published erratum appears in J Clin Oncol 1991 May;9(5):893, Clinical and histopathologic features are often inadequate for accurate prediction of relapse or survival of individual patients with rhabdomyosarcoma (RMS). We therefore studied the cellular DNA content (ploidy) of RMS cells in relation to histology and response to therapy in 37 patients with unresectable tumors. Using flow cytometric techniques. we found that about one third of patients had diploid tumor stem lines. regardless of the histologic subtype. In the group with abnormal ploidy. a hyperdiploid classification (1.10 to 1.80 times the DNA content of normal diploid cells) was exclusively associated with embryonal histology (P = .001). By contrast. near-tetraploidy (1.80 to 2.60 times the DNA content of normal cells) was strongly associated with alveolar histology (P = .001). Thus. in these histologic subtypes of RMS. abnormal ploidy appears to arise through different mechanisms. Tumor-cell ploidy had a significant impact on survival that was especially apparent in patients with unresectable. nonmetastatic (group III) tumors. In this subgroup. hyperdiploidy conferred the best prognosis and diploidy the worst (P less than .0001). None of the eight patients with diploid tumors survived for more than 18 months. Tumor-cell ploidy was the best predictor of treatment outcome for patients with either embryonal (P less than .001; relative risk. 25.5) or alveolar (P = .073; relative risk 7.1) RMS and contributed significantly after adjustment for disease stage and anatomic site. Patients with unresectable diploid RMS have an unacceptably high risk of treatment failure. justifying new therapeutic approaches for this distinct subgroup.
P-glycoprotein expression in malignant lymphoma and reversal of clinical drug resistance with chemotherapy plus high-dose verapamil, P-glycoprotein is a transmembrane protein thought to function as an efflux pump to detoxify cells. It is associated with multidrug resistance in laboratory systems and has recently been found in human tumors associated with in vitro and clinical drug resistance. We used an immunohistochemical method employing two monoclonal antibodies. JSB-1 and C-219. to detect expression of P-glycoprotein in lymphoma patients. One of 42 newly diagnosed and untreated lymphoma patients (2%) and seven of 11 previously treated and drug-resistant patients (64%) had detectable levels of P-glycoprotein (P less than .001). Based on prior reports suggesting that verapamil sensitizes drug-resistant cancer cells to chemotherapy by competitive inhibition of the P-glycoprotein. we tested the efficacy of verapamil as a chemosensitizer in 18 patients with drug-refractory disease. All patients had previously failed or relapsed within 3 months of a doxorubicin-vincristine-containing drug regimen. Patients received day-1 cyclophosphamide. and 4-day continuous infusion doxorubicin and vincristine and oral dexamethasone (CVAD). CVAD was combined with 5-day continuous infusion verapamil given at maximally tolerated dose. Overall. 13 of 18 patients (72%) responded to treatment including five complete remissions (CRs; 28%). The median duration of response was 200 days and median survival was 242 days. The dose-limiting toxicity of the verapamil infusion was temporary cardiac dysfunction including hypotension. congestive heart failure. and cardiac arrhythmia. We conclude that the P-glycoprotein is uncommonly expressed in untreated lymphomas and frequently expressed in clinically drug-resistant disease. and that chemotherapy using CVAD plus maximally tolerated doses of verapamil results in a high response rate in patients carefully selected for clinical drug resistance.
Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies, Fludarabine phosphate is the 2-fluoro. 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies. particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease. mycosis fungoides. and macroglobulinemia. although suggestive. needs to be further defined and clinical trials are warranted in hairy cell leukemia. prolymphocytic leukemia. and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression. nausea and vomiting. diarrhea. somnolence/fatigue. and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate. even with repeated administration. are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability. the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.
Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial [published erratum appears in J Clin Oncol 1991 Apr;9(4):710, One hundred ninety-three patients with stage II. III. or IV follicular large-cell. diffuse large-cell. diffuse mixed. immunoblastic. or diffuse small noncleaved-cell (non-Burkitt's) lymphoma were randomized to receive either cyclophosphamide 650 mg/m2 intravenously (IV). doxorubicin 25 mg/m2 IV. etoposide 120 mg/m2 IV on day 1. mechlorethamine 6 mg/m2 IV. vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV on day 8. prednisone 60 mg/m2 orally daily days 1 through 14. procarbazine 100 mg/m2 orally daily days 8 through 14. and methotrexate 500 mg/m2 IV on day 15 with leucovorin 50 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate with cycles repeated every 28 days (ProMACE-MOPP) or same day-1 treatment as ProMACE-MOPP plus cytarabine 300 mg/m2 IV. bleomycin 5 U/m2 IV. vincristine 1.4 mg/m2 (no cap at 2 mg total dose) IV. and methotrexate 120 mg/m2 IV on day 8. leucovorin 25 mg/m2 orally every 6 hours for four doses beginning 24 hours after methotrexate. and prednisone 60 mg/m2 orally daily days 1 through 14 with cycles repeated every 21 days (ProMACE-CytaBOM). Co-trimoxazole two double-strength tablets orally twice daily throughout the period of treatment was added to the ProMACE-CytaBOM regimen when an increased risk of Pneumocystis carinii pneumonia was found in the first 35 patients receiving this combination. Median follow-up is 5 years. Among the 99 patients treated with ProMACE-MOPP. 73 achieved a complete remission (CR) (74%). 30 complete responders have relapsed (41%). and 45 patients have died (45%). including two (2%) of treatment-related causes. Among the 94 patients treated with ProMACE-CytaBOM. 81 achieved a CR (86%). 22 complete responders have relapsed (27%). and 31 patients have died (33%). The complete response rate (P2 = .048) and survival (P2 = .046) were significantly higher for patients treated with ProMACE-CytaBOM. The mortality of ProMACE-CytaBOM treatment overall was six of 94 patients (6.4%). There was no treatment-related mortality among patients treated with prophylactic co-trimoxazole (n = 59). ProMACE-CytaBOM combination chemotherapy with co-trimoxazole prophylaxis is a safe and effective treatment for patients with aggressive histology malignant lymphoma and is superior to ProMACE-MOPP.
How American oncologists treat breast cancer: an assessment of the influence of clinical trials, The present study was designed to assess the preferred methods of treatment of breast cancer by American oncologists. and the impact of clinical trials on their practice. We mailed 465 questionnaires to surgical. radiation. or medical oncologists. The questionnaire described five hypothetic patients with breast cancer. and respondents were asked to select their preferred treatment for each patient. For primary breast cancer. most physicians would offer the choice of local excision followed by radiation therapy or modified radical mastectomy. About 80% of physicians would prescribe adjuvant chemotherapy for a premenopausal woman with estrogen receptor-negative. axillary node negative breast cancer. and for a postmenopausal woman with estrogen receptor-negative. node-positive disease. This policy was favored by male and female physicians of each specialty. Almost all respondents would treat a young woman with inflammatory breast cancer with initial chemotherapy followed by radiation and/or surgery. and about 60% would recommend chemotherapy to a postmenopausal patient with estrogen receptor-negative disease and minimally symptomatic bone metastases. Clinical trials have compared treatment strategies that could be applied to patients described in our questionnaire. Preferred treatments for primary breast cancer. and for inflammatory breast cancer are supported by the results of clinical trials. Recommendation of adjuvant chemotherapy for node-negative breast cancer is not based on a consistent demonstration of improvement in survival. although randomized trials with short follow-up have shown delay to recurrence. Recommendation of adjuvant chemotherapy for a postmenopausal woman with node-positive breast cancer is contrary to the results of large randomized controlled trials (and to a meta-analysis). which have shown that this policy does not lead to improved survival. Our report suggests that even large randomized clinical trials may have a minimal impact on practice if their results run counter to belief in the value of the treatment.
4-Hydroperoxycyclophosphamide purging of breast cancer from the mononuclear cell fraction of bone marrow in patients receiving high-dose chemotherapy and autologous marrow support: a phase I trial, We designed an ex vivo bone marrow treatment for breast cancer patients receiving high-dose chemotherapy and autologous bone marrow support (ABMS). using 4-hydroperoxycyclophosphamide (4-HC). an active derivative of cyclophosphamide with known activity against breast cancer. This phase I bone marrow purging trial used ficoll-separated mononuclear cells (MNC) (devoid of granulocytes and RBCs). as opposed to the buffy coat. Twenty-five patients with metastatic breast cancer were studied. Patients received three cycles of the Adriamycin (doxorubicin; Adria Laboratories. Columbus. OH). fluorouracil. and methotrexate (Duke AFM) regimen. followed by marrow harvest. An MNC fraction of marrow was prepared and treated with 4-HC in concentrations of 20 micrograms/mL (four patients). 40 micrograms/mL (four patients). 60 micrograms/mL (nine patients). or 80 micrograms/mL (eight patients) and cryopreserved. Patients then received high-dose systemic cyclophosphamide. cisplatin. and carmustine. followed by infusion of the purged marrow. The study end point was marrow engraftment. defined as WBC count greater than 1.000 cells per microliter. At the first three dose levels (20. 40. and 60 micrograms/mL 4-HC). there was no significant delay in time to engraftment (19. 20. and 23 days. respectively) compared with the unpurged historical controls (17 days). At 80 micrograms/mL. engraftment was significantly delayed compared with the lower concentrations (P = .027). and further escalation of 4-HC was not attempted. A significant correlation was observed between the time of leukocyte engraftment and the 4-HC concentration (P = .017). With a methylcellulose-based tissue culture assay. we demonstrated a statistically significant correlation between the colony-forming unit-granulocyte-macrophage (CFU-GM) content in the purged marrow and the days to engraftment. Ninety-five percent of patients responded clinically to the entire program. 55% of them completely. Longer follow-up is required to assess the ultimate benefit of intensive therapy on long-term survival.
Phase I clinical trial with floxuridine and high-dose continuous infusion of leucovorin calcium, Sixty-two patients with metastatic disease were treated with continuous infusion folinic acid (leucovorin calcium; Lv) and 2-deoxy-5-fluorouridine (floxuridine; FUDR). Lv was given by constant intravenous (IV) infusion at 500 mg/m2/d. days 1 to 6. while FUDR was given by IV push. days 2 to 6. at 3:00 PM daily with doses ranging from 294 to 1.214 mg/m2/d. This program was well tolerated with dose-limiting toxicities of diarrhea and stomatitis. while hematologic toxicity was minimal. Eighty-two percent of the assessable patients (46 of 56) had failed at least one chemotherapy regimen. One complete remission lasting 9 months and 10 partial remissions ranging from 5 to 10 months were observed in this heavily pretreated patient population for an overall response rate of 20%. These data suggest that the combination therapy with Lv and FUDR may have clinical use. Because of differing patient sensitivity to this drug combination. the recommended dose of FUDR for the initial therapy cycle is 500 mg/m2/d. days 2 to 6. with subsequent escalation to 900 mg/m2/d in those patients without extreme sensitivity. Phase II studies are now in progress with these doses.
Adrenal hormones and the anorectic response and adaptation of rats to amino acid imbalance, The role of adrenal function in the anorectic response and adaptation of rats to a diet with an isoleucine (Ile) imbalance was investigated. In the first of four experiments. rats were fed a mildly Ile-imbalanced diet after treatment with metyrapone. and inhibitor of glucocorticoid synthesis. In two separate experiments. rats were presented with either a mildly or severely Ile-imbalanced diet (4.93 and 9.86% imbalanced amino acid mixture. respectively) after bilateral adrenalectomy. Finally. the effects of ICS 205-930. a serotonin-3 receptor antagonist. on the intake of mildly Ile-imbalanced diet were tested in adrenalectomized animals. In each experiment a 2 X 2 factorial design was used. Neither metyrapone nor adrenalectomy altered the initial depression in the intake of an imbalanced diet. The adaptation phase in the response of adrenalectomized rats fed a mildly Ile-imbalanced diet was not different from that of controls. but adrenalectomized rats fed severely Ile-imbalanced diets were unable to adapt. Adrenalectomy did not alter the anti-anoretic activity of ICS 205-930 in this model. These results suggest that adrenal hormones are not necessary for the initial anoretic response or adaptation of rats to an Ile-imbalanced diet. nor are they implicated in the anti-anorectic effect of serotonin-3 blockade.
Lag screw fixation of anterior mandibular fractures, A technique of applying lag screws for treating fractures of the anterior mandible is presented. A review of 41 patients who had lag screws placed to treat such fractures showed that it is a successful method of providing rigid internal fixation. The advantages of this technique over bone-plate fixation are discussed.
Maintenance of condyle-proximal segment position in orthognathic surgery, Twenty patients underwent bilateral sagittal ramus osteotomy for the correction of mandibular retrognathia. A condylar positioning device (CPD) was used intraoperatively in 10 patients to maintain preoperative condyle-proximal segment position. while the CPD was not used in the other 10 patients. Postoperatively. the condyle-proximal segment positions in both groups were compared and evaluated for vertical. horizontal. and rotational changes. A significant improvement (P less than .05) was observed in the vertical and horizontal condylar position in the group in which the CPD was used. However. there was no significant difference in proximal segment rotation.
The Gillies method for fractured zygomas: an analysis of 105 cases, This prospective study analyzed 105 cases treated using the Gillies temporal approach for fractures of the zygoma. In 97 cases (92%) this was sufficient. Only eight cases required open reduction. It is suggested that the Gillies method be used more frequently. because it is associated with minimal morbidity and a short duration of general anesthesia.
Extraoral application of osseointegrated implants, The use of osseointegrated implants to provide support for craniofacial prostheses has provided the clinician with another approach to the treatment of complex craniofacial reconstructive problems. The surgical technique is reviewed and the Mayo Clinic experience is presented.
Care of the asthmatic oral and maxillofacial surgery patient, It is estimated that asthma affects 6 to 9 million people in the United States. The nature of this disease makes it a special concern to the oral and maxillofacial surgeon. Appropriate management of the asthmatic patient with regard to anesthesia and surgical procedures of the oral and maxillofacial region is discussed.
Selective vasopressin inhibition in rats with heart failure decreases afterload and results in venodilatation, The hemodynamic effects of selective inhibition of arginine vasopressin (AVP) with a V1 antagonist. (CH2)5yreAVPa CL-1-4A. were studied in normal rats (n = 17) and in rats 4 weeks after coronary artery ligation with large myocardial infarctions and elevated left ventricular end-diastolic pressures (n = 22). In normal rats AVP inhibition with a 35-micrograms/kg bolus of AVP V1 antagonist did not change heart rate. right atrial. left ventricular systolic. left ventricular end-diastolic or aortic pressures. There were also no changes in mean circulatory filling pressure. unstressed vascular volume. blood volume or venous compliance. In rats with infarction and elevated left ventricular end-diastolic pressures. AVP inhibition did not change heart rate. right atrial pressure. mean circulatory filling pressure or blood volume. but mean aortic pressure decreased from 103 +/- 3 to 88 +/- 2 mm Hg (P less than .001). venous compliance increased (P less than .001) from 2.17 +/- 0.07 to 3.04 +/- 0.11 ml/mm Hg/kg and unstressed vascular volume decreased from 42.3 +/- 3.1 to 34.7 +/- 2.6 ml/kg (P less than .05). We conclude that inhibition of AVP with a specific V1 antagonist had no effect on the venous or arterial circulations in normal rats. but in rats with left ventricular dysfunction and heart failure after chronic myocardial infarction. AVP inhibition decreased arterial pressure and caused venodilatation.
Antisecretory and antilesional effect of a new histamine H2-receptor antagonist, IT-066, in rats, The effects of a new histamine H2-receptor antagonist. IT-066 (3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis-2-++ +butenylamino]- 3-cyclobutene-1.2-dione hydrochloride). were investigated on the secretagogue-induced acid secretion in vivo and in vitro. and on experimental gastric and duodenal lesion in rats. IT-066 (10-60 micrograms/kg) given i.v. inhibited histamine-stimulated acid secretion dose-dependently in gastric lumen-perfused rats. and the inhibitory effect was observed for about 12 hr. Famotidine (FMD) (10-60 micrograms/kg i.v.) also had an antisecretory effect. but the acid secretion recovered to the control level 4 hr after the administration. Cold stress plus indomethacin-induced lesion was significantly inhibited by IT-066 and FMD given i.v. 30 min before the cold stress plus indomethacin treatment. IT-066 given 7 hr before the cold stress plus indomethacin treatment also inhibited lesion formation significantly. but such antilesional effect was not observed with FMD. In the rat isolated gastric mucosal sheet. IT-066 inhibited histamine-stimulated acid secretion dose-dependently and noncompetitively; its action was produced via a unique mechanism. The inhibitory effect of IT-066 remained after washing of the mucosa. and became more potent time-dependently. The inhibitory effects of FMD and cimetidine were not observed after washing the mucosa. These data suggest that IT-066 has a potent and long lasting antisecretory effect in vivo and in vitro. and that these properties are responsible for the long lasting antilesional action.
Neurotoxic action of veratridine in rat brain neuronal cultures: mechanism of neuroprotection by Ca++ antagonists nonselective for slow Ca++ channels, The effect of various Ca++ antagonists and local anesthetics on neuronal cell degeneration induced by veratridine was studied in primary rat brain neuronal cultures. Cell death was quantified by measuring lactate dehydrogenase (LDH) released in the culture medium. The neuronal cell degeneration was Ca+(+)-dependent because. in the absence of extracellular Ca++. 16 hr of exposure to 30 microM veratridine failed to produce release of LDH. Ca++ antagonists. nonselective for slow Ca++ channels (flunarizine. cinnarizine. lidoflazine. prenylamine and bepridil) inhibited veratridine-induced release of LDH with IC50 values between 0.11 and 0.47 microM. Ca++ antagonists selective for slow Ca++ channels were less potent and inhibited veratridine-induced release of LDH at concentrations in the following order of potency: nicardipine greater than gallopamil and verapamil greater than niludipine greater than nitrendipine greater than nifedipine greater than nimodipine greater than diltiazem. Tested local anesthetics were incomplete inhibitors of veratridine-induced release of LDH. A good correlation was found between the potency of the drugs to inhibit released LDH induced by 30 microM veratridine in neuronal cultures and their binding affinity for the batrachotoxin binding site of Na+ channels in rat cortex synaptosomal preparation. It is concluded that protection against veratridine-induced neurotoxicity can be mediated by blocking a veratridine-sensitive Na+ channel. It is a property of certain nonselective Ca++ antagonists. There is apparently no direct relationship with Ca++ antagonistic activity. The effect is unrelated to local anesthetic activity.
Low-dose caffeine physical dependence in humans, This study investigated the effects of terminating low dose levels of caffeine (100 mg/day) in 7 normal humans. Substitution of placebo capsules for caffeine capsules occurred under double-blind conditions while subjects rated various dimensions of their mood and behavior. In the first phase of the study. substitution of placebo for 12 consecutive days resulted in an orderly withdrawal syndrome in 4 subjects which peaked on days 1 or 2 and progressively decreased toward prewithdrawal levels over about 1 week. Data from the remaining three subjects provided no evidence of withdrawal. In the second phase of the study. the generality of the withdrawal effect was examined by repeatedly substituting placebo for 100 mg/day of caffeine for 1-day periods separated by an average of 9 days. Despite differences within and across subjects with respect to the presence. nature and magnitude of symptoms. each of the seven subjects demonstrated a statistically significant withdrawal effect. Although the phenomenon of caffeine withdrawal has been described previously. the present report documents that the incidence of caffeine withdrawal is higher (100% of subjects). the daily dose level at which withdrawal occurs is lower (roughly equivalent to the amount of caffeine in a single cup of strong brewed coffee or 3 cans of caffeinated soft drink) and the range of symptoms experienced is broader (including headache. fatigue and other dysphoric mood changes. muscle pain/stiffness. flu-like feelings. nausea/vomiting and craving for caffeine) than heretofore recognized.
Central adenosinergic system involvement in ethanol-induced motor incoordination in mice, To clarify if the behavioral interaction between ethanol and adenosine reported previously occur centrally or due to a peripheral hemodynamic change. the effect of i.c.v. adenosine agonists. N6-(R-phenylisopropyl)adenosine (R-PIA). N6-(S-phenylisopropyl)adenosine. 5'-(N-cyclopropyl)-carboxamidoadenosine. antagonists. theophylline and 8-p-(sulfophenyl)theophylline as well as enprofylline on ethanol-(i.p.)-induced motor incoordination was evaluated by rotorod. Adenosine agonists and antagonists dose dependently accentuated and attenuated. respectively. ethanol-induced motor incoordination. thereby suggesting a central mechanism of adenosine modulation of this effect of ethanol and confirmed our previous reports in which adenosine agonists and antagonists were given i.p. Enprofylline. a weak adenosine antagonist but potent inhibitor of cyclic AMP phosphodiesterase. did not alter ethanol's motor incoordination. further supporting involvement of brain adenosine receptor mechanism(s) in ethanol-adenosine interactions. Results from R-PIA and N6-(S-phenylisopropyl)adenosine experiments showed nearly a 40-fold greater potency of R-vs. S-diastereoisomer. suggesting predominance of adenosine A1 subtype. However. 5'-(N-cyclopropyl)-carboxamidoadenosine data indicate complexity of the mechanism(s) and point toward an additional involvement of a yet unknown subtype of adenosine A2. No effect of ethanol on blood or brain levels of [3H]R-PIA was noted and sufficient amount of the latter entered the brain to suggest adenosine receptor activation adequate to produce behavioral interaction with ethanol. There was no escape of i.c.v.-administered [3H]R-PIA from brain to the peripheral circulation ruling out a peripheral and supporting a central mechanism of ethanol-adenosine interaction.
Potent selective inhibition of 7-O-methyl UCN-01 against protein kinase C, UCN-01 is a staurosporine-related compound that was isolated from the culture broth of Streptomyces sp. and shows potent and selective inhibitory activity against protein kinase C. Cellular inhibitory activity of UCN-01 against protein kinase C and cytotoxicity of UCN-01 were compared with those of staurosporine. When the mechanism of inhibitory activity was investigated in vitro. UCN-01 as well as staurosporine inhibited the activity of the catalytic domain of protein kinase C. In spite of direct inhibition against the catalytic domain of protein kinase C. cytotoxicity of UCN-01 was much lower than that of staurosporine. In addition. UCN-01 showed more selective inhibitory activity against protein kinase C than did staurosporine because of the sole structural difference at C-7. Therefore. a series of 7-O-alkyl derivatives of UCN-01 was synthesized and investigated. Interestingly. one of the compounds. the beta-methoxy derivative. showed 3-fold greater potency and 17-fold more selective inhibitory activity against protein kinase C than did UCN-01.
Interactions between N-methyl-D-aspartate and CGS 19755 administered intramuscularly and intracerebroventricularly in pigeons, Behavioral effects of N-methyl-D-aspartate (NMDA) and the competitive NMDA antagonist cis-4-phosphonomethyl-2-piperidine-carboxylic acid (CGS 19755) were studied in pigeons. NMDA decreased responding under a fixed-ratio schedule of food presentation and was 8000 times more potent administered intracerebroventricularly (i.c.v.) as compared to intramuscularly (i.m.). CGS 19755 was 870 times more potent in producing catalepsy when administered i.c.v.; however. the duration of catalepsy was similar by the two routes of administration. Administered i.m. CGS 19755 decreased response rates only at doses that also produced catalepsy; administered i.c.v. some doses of CGS 19755 decreased responding without producing other behavioral effects. Rate-decreasing effects of i.m. NMDA were attenuated by i.m. CGS 19755; however. when CGS 19755 was administered i.c.v.. there was little or no antagonism of NMDA. Rate-decreasing effects of i.c.v. NMDA were not attenuated by i.m. or i.c.v. CGS 19755 up to doses that produced catalepsy or eliminated responding. The large difference in potency between i.m. and i.c.v. administration for NMDA and for CGS 19755. as well as the slower onset of catalepsy when CGS 19755 was administered i.m.. suggests these compounds do not readily cross the blood-brain barrier when administered parenterally. The inability of CGS 19755 to attenuate the rate-decreasing effects of NMDA when CGS 19755 or NMDA was administered i.c.v. suggests NMDA might decrease responding by different mechanisms when administered i.m. or i.c.v. in pigeons. Together these results indicate antagonism of NMDA in this study. and perhaps in other studies. when both NMDA and CGS 19755 were administered parenterally. might result from a peripherally mediated interaction. Moreover. this agonist-antagonist interaction is not a simple. competitive antagonism.
Pharmacological characterization of LY233053: a structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action, This study reports the activity of a structurally novel excitatory amino acid receptor antagonist. LY233053 [cis-(+-)-4-[(2H-tetrazol-5-yl)methyl]piperidine-2-carboxylic acid]. the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of [3H] CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or [3H]kainate binding assays was observed (IC50 values greater than 10.000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats. LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons. LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However. a dose of 160 mg/kg. i.m.. was required to produce phencyclidine-like catalepsy in pigeons. In mice. LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary. the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity. The relatively short duration of action of LY233053 may make this compound particularly advantageous as a neuroprotective agent in the treatment of acute conditions such as cerebral ischemia.
Stimulatory effects of maitotoxin on insulin release in insulinoma HIT cells: role of calcium uptake and phosphoinositide breakdown, In hamster insulinoma (HIT) cells. maitotoxin (MTX) induces a time-dependent and concentration-dependent release of insulin that requires the presence of extracellular calcium. The response is nearly completely blocked by cinnarizine and cadmium. but is not inhibited by the L-type calcium channel blocker nifedipine or by manganese. MTX induces 45Ca+ uptake in these cells in a dose-dependent mode. and the uptake is blocked with cinnarizine. nifedipine and cadmium. and is partially inhibited by manganese. MTX induces phosphoinositide breakdown in HIT cells. and the response is partially blocked by cadmium. but is not affected by nifedipine. cinnarizine or manganese. High concentrations of potassium ions also induce insulin release and calcium uptake in HIT cells. Both effects of potassium are blocked partially by nifedipine. cadmium and cinnarizine. High concentrations of potassium do not induce phosphoinositide breakdown in HIT cells. The results suggest that MTX-elicited release of insulin is attained by two mechanisms: 1) a nifedipine-sensitive action. which results from MTX-induced activation of L-type calcium channels. which can be mimicked with high potassium concentrations; and 2) a nifedipine-insensitive action. which may be initiated by the activation of phosphoinositide breakdown by MTX. Such an activation of phospholipase C would result in the formation of 1.4.5-inositol trisphosphate. a release of intracellular calcium and then release of insulin to the extracellular space. Cinnarizine is proposed to block both MTX-elicited mechanisms. the first by blockade of calcium channels and the second by blocking 1.4.5-inositol trisphosphate-induced release of internal calcium. Either mechanism alone appears capable of eliciting release of insulin.
Biphasic modulation of acetaminophen bioactivation and hepatotoxicity by pretreatment with the interferon inducer polyinosinic-polycytidylic acid, Interferons and interferon induction can inhibit cytochromes P-450 and reduce the bioactivation and hepatotoxicity of acetaminophen. However. since P-450 inhibition often is followed by P-450 induction. which would enhance acetaminophen hepatotoxicity. the possibility of a biphasic modulation of acetaminophen hepatotoxicity by interferons was investigated. Outbred male CD-1 mice of various ages. and young inbred male C57BL/6 mice were given the interferon inducer. polyinosinic-polycytidylic acid (Poly I-C). 10 mg/kg intraperitoneally. followed 1 to 48 days later by a single dose of acetaminophen. 300 to 450 mg/kg intraperitoneally. Hepatotoxicity was assessed by the peak plasma concentration of alanine aminotransferase (ALT) occurring between 0 and 48 hr after acetaminophen treatment. Poly I-C inhibited the hepatotoxicity of acetaminophen given within 8 days. with maximal inhibition between 1 and 4 days. Conversely. a maximal 7-fold enhancement of ALT concentration was observed in CD-1 mice when 300 mg/kg of acetaminophen was given 32 days after Poly I-C (P less than 0.05). In the C57BL/6 strain. Poly I-C inhibited the hepatotoxicity of acetaminophen when given within 16 days. whereas a maximal 20-fold enhancement of ALT concentration was observed when 300 mg/kg of acetaminophen was given 24 days after Poly I-C (P less than 0.05). The mechanism of toxicologic enhancement was examined in male C57BL/6 mice using the same treatment regimen. Biochemical assessment of hepatotoxicity was confirmed by detailed histologic evaluation. Plasma concentrations of acetaminophen and metabolites were determined by high-performance liquid chromatography. Acetaminophen bioactivation was quantified by production of the glutathione-derived cysteine and mercapturic acid conjugates of acetaminophen. Poly I-C pretreatment produced a 5-fold increase in acetaminophen-induced ALT release (P less than 0.05). which correlated with histologic evidence of centrilobular necrosis. Poly I-C pretreatment produced respective 3-fold and 1.3-fold increases in the production of cysteine and mercapturic acid conjugates (P less than 0.05). which correlated with peak ALT concentrations (cysteine. r = 0.92. P less than 0.001; mercapturic acid. r = 0.75. P = 0.006). Thus. the hepatotoxicity of acetaminophen can be inhibited when given within days after interferon induction. and conversely enhanced when given after several weeks. The toxicologic enhancement appears to be due to increased P-450-catalyzed bioactivation of acetaminophen.
Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol, Acetaminophen (500 mg/kg i.p.) induced hepatotoxicity in fasted ICR mice in vivo. Acetaminophen also caused a long-lasting 50% reduction of the hepatic ATP content. an irreversible loss of hepatic xanthine dehydrogenase activity and a transient increase of the xanthine oxidase activity. All effects occurred before parenchymal cell damage. i.e.. the release of cellular enzymes. The hepatic content of GSH and GSSG was initially depleted by acetaminophen without affecting the GSSG:GSH ratio (1:200). however. during the recovery phase of the hepatic GSH levels the GSSG content increased faster than GSH. resulting in a GSSG:GSH ratio of 1:18 24 h after acetaminophen administration. The mitochondrial GSSG content increased from 2% in controls to greater than 20% in acetaminophen-treated mice. The extremely elevated tissue GSSG levels were accompanied by a 4-fold increase of the plasma GSSG concentrations but not by an enhanced biliary efflux. although hepatic GSSG formation and biliary excretion were not affected by acetaminophen. Allopurinol protected dose-dependently against acetaminophen-induced cell injury. the loss of ATP and the increase of the GSSG content in the total liver and in the mitochondrial compartment without inhibiting reactive metabolite formation. High. protective as well as low. nonprotective doses of allopurinol almost completely inhibited hepatic xanthine oxidase and dehydrogenase activity. but only high doses prevented the increase of the mitochondrial GSSG content. The data indicate a long-lasting. primarily intracellular oxidant stress during the progression phase of acetaminophen-induced cell necrosis. The protective effect of allopurinol is unlikely to involve the inhibition of reactive oxygen formation by xanthine oxidase but could be the result of its antioxidant property.
Pharmacologic activity of bepafant (WEB 2170), a new and selective hetrazepinoic antagonist of platelet activating factor, The hetrazepine WEB 2170 (international nonproprietary name: bepafant). a thieno-triazolodiazepine that is structurally related to the recently described platelet activating factor (PAF) antagonist WEB 2086. is a potent and selective PAF antagonist both in vitro and in vivo. WEB 2170 inhibited PAF-induced human platelet and neutrophil aggregation in vitro (IC50 values: 0.3 and 0.83 microM. respectively) but had little or no inhibitory action against aggregation induced by other agonists. The potency in vitro was comparable to that described recently for WEB 2086 (Casals-Stenzel. J.. Muacevic. G. and Weber. K.H.: J. Pharmacol. Exp. Ther. 241: 974-981. 1987). When guinea pigs were given i.v. infusions of PAF at 30 ng x kg-1 x min-1. oral (0.005-0.5 mg/kg) as well as intravenous (0.005-0.05 mg/kg) treatment with WEB 2170 abrogated the intrathoracic accumulation of 111In-labeled platelets. the bronchoconstriction and the hypotension as well as the finally occurring death in a dose-dependent fashion. Oral (0.01-1 mg/kg) and intravenous (0.005-0.1 mg/kg) WEB 2170 shared with the beta 2 agonist fenoterol and the steroid dexamethasone the property of protecting elderly NMRI mice from the lethal effect of PAF. In anesthetized rats. intravenous (0.001-0.1 mg/kg) and oral (0.05-1 mg/kg) WEB 2170 inhibited PAF-induced hypotension in a dose-related manner. Coadministration of WEB 2170 inhibited PAF-induced increase of vascular permeability in rat skin very effectively. The half-time of duration of action in the rat was estimated to be about 5 to 6 h after oral administration and about 1.1 to 2.3 h after intravenous application. In conclusion. the hetrazepine WEB 2170 is a strong and selective PAF antagonist. which is in vitro more or less equipotent to WEB 2086. In contrast. in vivo oral WEB 2170 is--depending on the species and considered parameter--about 5 to 40 times more potent against exogenous PAF-induced alterations than the recently described hetrazepine WEB 2086. Particularly in mice and rats. oral WEB 2170 is by far superior to WEB 2086.
New biological properties of pyrroloquinoline quinone and its related compounds: inhibition of chemiluminescence, lipid peroxidation and rat paw edema, Pyrroloquinoline quinone (PQQ) inhibited the chemiluminescence (CL) from mouse peritoneal cells initiated by zymosan. carrageenin and N-formyl-methionyl-leucyl-phenylalanine and CL generated by the xanthine-xanthine oxidase reaction and the lipid peroxidation in the rat brain homogenate. The inhibitory activity of PQQ was more potent than that of idebenone. alpha-tocopherol and ascorbic acid in all the three assay systems. In the xanthine-xanthine oxidase reaction. PQQ had no effect on the formation of uric acid at the concentration of CL inhibition. These results suggest that PQQ might have a radical scavenger-like activity. Structure-activity relationship of PQQ and its six related compounds showed that the 7- and 9-carboxyl groups of PQQ as well as the orthoquinone structure are responsible for the radical scavenger-like activity. In addition. the -NH group in the pyrrole ring of PQQ seemed to be essential for the antilipid peroxidative activity in the rat brain homogenate. When administered i.p.. PQQ inhibited the development of 0.1% carrageenin-induced paw edema in rats. These results suggest that PQQ might have therapeutic effects on various diseases. of which development or exacerbation has been known to be associated with radical oxygens.
Mechanical restraint use among residents of skilled nursing facilities. Prevalence, patterns, and predictors, The patterns of and risk factors for mechanical restraint use were determined in 12 skilled nursing facilities. Restraints were being used for 59% of residents at the beginning of the study; 31% of remaining residents were restrained during the follow-up year. No facility characteristic was associated with restraint use. The resident characteristics independently associated with initiation of restraints were older age. disorientation. dependence in dressing. greater participation in social activities. and nonuse of antidepressants. Unsteadiness (72%). disruptive behavior such as agitation (41%). and wandering (20%) were the most frequently cited reasons for initiation of restraints.
A report of fluorosis in the United States secondary to drinking well water, A 54-year-old female resident of Wellston. Okla. was found to have osteosclerosis on a routine chest roentgenogram. Subsequent investigation disclosed the cause of her osteosclerosis to be fluorosis secondary to the ingestion of well water containing 429 mumol/L of fluoride (recommended levels. 11 to 58 mumol/L). Water samples were also obtained from the 12 wells on properties adjacent to the index case. In three other wells. all at similar depths as the well of the index case. the fluoride concentration of the water was greater than 212 mumol/L. Urine samples from members of the four households who obtain their drinking water from these wells contained elevated urinary fluoride levels. Thus. fluorosis may develop in certain areas of the United States as a result of the natural occurrence of fluoride in the groundwater. Consequently. in known endemic areas. it would appear reasonable to measure the fluoride concentration of the well water at the time of drilling.
Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene, The relation between risk of angina pectoris and plasma concentrations of vitamins A. C. and E and carotene was examined in a population case-control study of 110 cases of angina. identified by the Chest Pain Questionnaire. and 394 controls selected from a sample of 6000 men aged 35-54. Plasma concentrations of vitamins C and E and carotene were significantly inversely related to the risk of angina. There was no significant relation with vitamin A. Smoking was a confounding factor. The inverse relation between angina and low plasma carotene disappeared and that with plasma vitamin C was substantially reduced after adjustment for smoking. Vitamin E remained independently and inversely related to the risk of angina after adjustment for age. smoking habit. blood pressure. lipids. and relative weight. The adjusted odds ratio for angina between the lowest and highest quintiles of vitamin E concentrations was 2.68 (95% confidence interval 1.07-6.70; p = 0.02). These findings suggest that some populations with a high incidence of coronary heart disease may benefit from eating diets rich in natural antioxidants. particularly vitamin E.
Tuftsin deficiency in AIDS, Tuftsin is an endogenous tetrapeptide that stimulates phagocytosis and is released from the Fc fragment of IgG by a splenic endocarboxypeptidase. Tuftsin activity and splenic function were measured in 21 patients with AIDS. 7 patients with AIDS-related complex (ARC). 22 patients who had undergone splenectomy. and 37 healthy volunteers. There was a significant inverse correlation between tuftsin activity and splenic function in all subjects. Tuftsin activity was significantly lower in patients with AIDS. ARC. and in those who had undergone splenectomy compared with healthy volunteers. Tuftsin deficiency may contribute to the risk of bacterial infection in symptomatic HIV-positive individuals.
Person-to-person transmission of Brucella melitensis, Human brucellosis is primarily an occupational hazard in the USA; in the Middle East and Africa ingestion of contaminated dairy products is an important route of infection. Whether human beings can become infected via person-to-person spread is uncertain. During an investigation of a commonsource. laboratory-associated outbreak due to Brucella melitensis. biotype 3. the wife of a microbiologist with serologically proven brucellosis became infected. Her blood isolate was indistinguishable from the epidemic strain. In the absence of other risk factors. we suggest that sexual intercourse is a possible means of transmission.
Experimental reduction of portal hypertension by mechanical increase of liver portal flow, Studies on the isolated perfused rat liver demonstrated that an increase in portal pressure is associated with an increase in the portal blood flow in normal and in cirrhotic livers. In two pigs with portal hypertension mesenteric portal pressure was lowered by mechanically increasing the liver portal blood flow by means of a balloon pump around the portal vein.
Response to treatment with antihistamines in a family with myotonia congenita, In a family in which myotonia congenita was found in five generations. both great-grandparents of the index case were affected. In subsequent generations mild and severely affected cases were clearly segregated down parallel lines of this family. The grandmother of the index case had noted improvement with an antihistamine. When the index case was prescribed trimeprazine. she showed a striking reduction in severity of symptoms. Antihistamines seem to deserve further evaluation as a safe and effective treatment for myotonia congenita.
Helping a child to understand her own testicular feminisation, Children do not think as adults do. They would therefore be less worried than adults are about a diagnosis with serious or ominous implications. yet they are commonly left uninformed until someone judges that they are old enough to understand. For most. this means delivery of painful information during the very vulnerable teenage years. A better approach is to unfold the truth stage by stage. matching simple statements to the child's conceptual growth until the personal implications are finally realised as part of a maturing process. Use of this approach for a child with testicular feminisation is described.
Leishmania donovani chagasi: new clinical variant of cutaneous leishmaniasis in Honduras, During surveillance for endemic visceral leishmaniasis on an island off the Pacific coast of Honduras. an unusual form of cutaneous leishmaniasis was encountered. By clinical and laboratory criteria. 17 cases were identified over 5 months; children aged 4 to 15 years were primarily affected. Lesions were generally few in number. small. always papular. and non-ulcerative. even when present for several years. Patients with skin lesions seemed otherwise healthy and were well nourished. Montenegro skin tests with Leishmania mexicana and L major antigens were positive in 10 of 17 patients tested. and lesions from 9 patients were positive by culture. Since the summer of 1988. cases of atypical cutaneous leishmaniasis continue to occur on the island (8) as well as on the mainland of southern Honduras (23). A total of 9 parasite isolates from skin lesions. 4 from bone marrow of patients with kala-azar. and 2 from sandflies were identified as L donovani chagasi and were indistinguishable from one another by isoenzyme analysis.
Application of pulsed and continuous wave 1.32 and 1.06 microns wavelengths of the Nd:YAG laser in the canine tracheobronchial tree: a comparative study, Previous investigations have shown good clinical potential for the use of the 1.32 microns wavelength Nd:YAG laser because its soft tissue absorption is better than that of the 1.06 microns wavelength Nd:YAG laser. The 1.32 microns wavelength Nd:YAG laser has an absorption coefficient in water that is 10 times higher than the 1.06 microns wavelength Nd:YAG laser. A comparative in vivo study of laser soft tissue effects was performed by using the 1.32 microns wavelength and the 1.06 microns wavelength Nd:YAG lasers in a pulsed wave (PW) mode and continuous wave (CW) mode using a non-contact endoscopic delivery system. A standard 5 mm mucosal lesion was made in the canine tracheobronchial tree down to the level of the perichondrium. Soft tissue and cartilage effects were examined by light and scanning electron microscopy. acutely. 1 week and 2 weeks after operation. and a comparison was made between the different laser modalities. To create similar lesions. higher energy was required when using the 1.06 microns wavelength Nd:YAG laser. Soft tissue injury was greater with the 1.06 microns wavelength in CW mode. and no cartilage damage occurred in the PW mode. Soft tissue and cartilage repair after 1 and 2 weeks was better with the 1.32 microns wavelength laser. In comparison. the CO2 laser and the contact Nd:YAG laser proved to be more precise cutting tools than the 1.32 microns wavelength or the 1.06 microns wavelength Nd:YAG lasers. Both Nd:YAG laser wavelengths were useful for coagulation and vaporization of tissues and blood vessels. More studies are needed to determine the effect of the new 1.32 microns wavelengths on endotracheal tumors.
Trans-scleral application of a semiconductor diode laser, We used a diode laser with an output power of 1 W through a fiberoptic light pipe (200 microns diameter) to deliver laser energy through the sclera of pigmented rabbits. Ciliary body destruction occurred with energy levels of 300-400 mW and exposure time of 0.5 sec. Retinal photocoagulation was achieved with energy levels of 200-500 mW in 0.5 sec. Histologic examination of acute lesions demonstrated thermal destruction of ciliary body processes and retina. Chorioretinal scar formation was observed clinically and histologically within 2-3 weeks. Our data indicate that the transscleral diode laser may be used for destruction of the ciliary body processes or peripheral retinal coagulation in pigmented eyes.
Molecular surgery of the basement membrane by the argon laser, Although the argon laser is used successfully to weld a number of different tissues. the underlying chemical and cellular mechanisms for this process are not precisely defined. Consequently. a biochemical model has been developed in vitro using the well-defined extracellular matrix from the murine Engelbreth-Holm-Swarm (EHS) sarcoma. Control and experimental samples of EHS basement membranes were irradiated with a Trimedyne argon laser at 500-3.000 Joules/cm2 at 0 degrees C. The samples were diluted into cold phosphate-buffered saline and allowed to gel at 35 degrees C. The time course of the gelation reaction was followed in a spectrophotometer at 360 nm. Irradiation reduced the absorbance 7.5-15% compared to controls and was independent of the dilution over a 10-fold range. Gelation was also measured by determining the amount of protein by the Bradford assay that could be collected by centrifugation at 10.000g for 10 minutes. Argon-irradiated samples had 30-40% less protein in the precipitate than the controls. The addition of 5 mM beta-mercaptoethanol to the EHS extract blocked the effect of the laser on the gelation reaction. In addition. when gelation was carried out in the absence of calcium and magnesium. there were no differences between laser-treated samples and controls. The basement membrane proteins were separated by electrophoresis through polyacrylamide gels under denaturing plus reducing or denaturing and non-reducing conditions. No differences in the polypeptide composition were noted between irradiated and control samples using either Coomassie- or silver-staining techniques.
CO2-welded venous anastomosis: enhancement of weld strength with heterologous fibrin glue, The milliwatt CO2 laser was used to perform end-to-end anastomoses in canine jugular veins. There was a high disruption rate (50%) in laser-welded veins (n = 10). Fibrin glue (n = 17). formed from human fresh-frozen plasma. enhanced the weld strength decreasing the disruption rate (18%). resulting in an 82% patency which nearly equaled the contralateral sutured vein patency (93%). The bursting strength was improved with fibrin glue. Transmural necrosis was present initially in all groups but extended for a longer distance in the vessel wall in laser-welded anastomoses. Sutured anastomoses exhibited a greater inflammatory response. In laser-welded anastomoses endothelial cells were not as confluent as in sutured anastomoses by six weeks. Carbon dioxide laser-welded end-to-end vein anastomoses appear to be impractical because they disrupt too easily. However. the addition of heterologous fibrin glue to the weld results in a reasonably strong anastomosis with histologic properties that may be beneficial in vein bypass grafts.
Unexplained rabies in three immigrants in the United States. A virologic investigation, BACKGROUND. Extensive investigation of three patients who died of rabies in the United States failed to reveal any source of exposure to the disease. The three patients had immigrated to the United States from areas in Laos. the Philippines. and Mexico where rabies is endemic. METHODS. We studied rabies viruses isolated from the three patients. other patients with a known source of exposure. and animals in the United States. Thailand (as a proxy for Laos). the Philippines. and Mexico. The viruses were characterized by indirect immunofluorescence and neutralization tests according to their reactions to panels of monoclonal antibodies. Transcribed complementary DNA from these isolates was amplified by the polymerase chain reaction; the DNA product was then analyzed by differential digestion with restriction enzymes. RESULTS. The viral isolate from each of the three patients was a rabies variant with distinctive antigenic or genetic characteristics. For each of the three isolates. identical variants were found in specimens from rabid animals obtained from or near the country in which the patient lived before immigrating to the United States. None of these variants were found among the isolates collected from rabid animals in the United States. CONCLUSIONS. Rabies infection in these three patients did not originate in the United States but resulted from exposures in Laos. the Philippines. and Mexico. Since the three patients had lived in the United States for 4 years. 6 years. and 11 months. our findings suggest that the onset of the clinical manifestations of rabies occurred after long incubation periods.
Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin, BACKGROUND. In both animal and epidemiologic studies. exposure to dioxin (2.3.7.8-tetrachlorodibenzo-p-dioxin. or TCDD) has been associated with an increased risk of cancer. METHODS. We conducted a retrospective cohort study of mortality among the 5172 workers at 12 plants in the United States that produced chemicals contaminated with TCDD. Occupational exposure was documented by reviewing job descriptions and by measuring TCDD in serum from a sample of 253 workers. Causes of death were taken from death certificates. RESULTS. Mortality from several cancers previously associated with TCDD (stomach. liver. and nasal cancers. Hodgkin's disease. and non-Hodgkin's lymphoma) was not significantly elevated in this cohort. Mortality from soft-tissue sarcoma was increased. but not significantly (4 deaths; standardized mortality ratio [SMR]. 338; 95 percent confidence interval. 92 to 865). In the subcohort of 1520 workers with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency. however. mortality was significantly increased for soft-tissue sarcoma (3 deaths; SMR. 922; 95 percent confidence interval. 190 to 2695) and for cancers of the respiratory system (SMR. 142; 95 percent confidence interval. 103 to 192). Mortality from all cancers combined was slightly but significantly elevated in the overall cohort (SMR. 115; 95 percent confidence interval. 102 to 130) and was higher in the subcohort with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency (SMR. 146; 95 percent confidence interval. 121 to 176). CONCLUSIONS. This study of mortality among workers with occupational exposure to TCDD does not confirm the high relative risks reported for many cancers in previous studies. Conclusions about an increase in the risk of soft-tissue sarcoma are limited by small numbers and misclassification on death certificates. Excess mortality from all cancers combined. cancers of the respiratory tract. and soft-tissue sarcoma may result from exposure to TCDD. although we cannot exclude the possible contribution of factors such as smoking and occupational exposure to other chemicals.
Decreased osmotic stability of dystrophin-less muscle cells from the mdx mouse, Human X-linked Duchenne and Becker muscular dystrophies are due to defects in dystrophin. the product of an exceptionally large gene. Although dystrophin has been characterized as a spectrin-like submembranous cytoskeletal protein. there is no experimental evidence for its function in the structural maintenance of muscle. Current hypotheses attribute necrosis of dystrophin-less fibres in situ to mechanical weakening of the outer membrane. to an excessive influx of Ca2+ ions. or to a combination of these two mechanism. possibly mediated by stretch-sensitive ion channels. Using hypo-osmotic shock to determine stress resistance and a mouse model (mdx) for the human disease. we show that functional dystrophin contributes to the stability of both cultured myotubes and isolated mature muscle fibres.
The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus, T-associated maternal effect (Tme) is the only known maternal-effect mutation in the mouse. The defect is nuclear-encoded and embryos that inherit a deletion of the Tme locus from their mother die at day 15 of gestation. There are many genomically imprinted regions known in the mouse genome but so far no imprinted genes have been cloned. The Tme locus is absent in two chromosome-17 deletion mutants. Thp and the tLub2. and its position has been localized using these deletions to a 1-cM region. We report here that the genes for insulin-like growth factor type-2 receptor (Igf2r) and mitochondrial superoxide dismutase-2 (Sod-2) are absent from both deletions. Probes for these genes and for plasminogen (Plg) and T-complex peptide 1 (Tcp-1) were used in pulsed-field gel mapping to show that Tme must lie within a region of 800-1.100 kb. We also demonstrate that embryos express Igf2r only from the maternal chromosome. and that Tcp-1. Plg and Sod-2 are expressed from both chromosomes. Therefore Igf2r is imprinted and closely linked or identical to Tme.
Transcranial Doppler in acute hemispheric brain infarction, We studied cerebrovascular anatomy using intra-arterial digital angiography. and blood flow velocity in the middle cerebral artery (MCA) using transcranial Doppler (TCD) ultrasonography in 42 patients with acute hemispheric ischemic brain infarction. We compared angiography with TCD and the clinical findings within 6 hours of the onset of symptoms. The location and extent of the chronic ischemic brain damage was assessed by CT performed 1 to 3 months after the ictus. Abnormal TCD. as manifested by either an unobtainable MCA flow signal or a significantly depressed MCA flow velocity. was highly associated with proximal MCA occlusions demonstrated by angiography. Abnormal TCD predicted both larger chronic CT lesions and more extensive ischemic change within the MCA territory. These data demonstrate that early TCD conveys useful information concerning cerebral tissue prognosis following hemispheric ischemia.
In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondrial disease, We have investigated the sensitivity and specificity of a rapid phosphorus magnetic resonance spectroscopy (MRS) protocol for detecting metabolic abnormalities in vivo in skeletal muscle of patients with mitochondrial disease. We examined 17 patients with mitochondrial myopathies. Sixteen had only mild or minimal myopathic signs and symptoms. Phosphorus magnetic resonance spectra from the resting gastrocnemius muscles showed an abnormal intracellular energy state (marked by an increased intracellular inorganic phosphate concentration) in 14/17. In 3/17. this was associated with a decreased phosphocreatine concentration. We also studied 20 patients with other diseases of muscle (inflammatory myopathies. metabolic myopathies. muscular dystrophies. and myasthenia gravis) that can present with similar clinical features. Spectra showed increased intracellular inorganic phosphate concentrations in 6/20. All of these muscle diseases were associated with evidence of muscle fiber necrosis. Abnormalities in the muscle energy state in these cases may be due to secondary mitochondrial dysfunction. Except for cases of polymyositis and dermatomyositis. these 6 other myopathies could be readily distinguished from the mitochondrial myopathies on the basis of the clinical examination and blood tests. We conclude that phosphorus MRS of resting muscle is practical in a clinical setting and has a useful sensitivity and specificity for mitochondrial myopathies when used in conjunction with standard noninvasive tests.
"Pseudospasticity" in Guillain-Barre syndrome, We report a woman with Guillain-Barre syndrome who developed a flexion posture of the right arm and hand resembling upper motor neuron dysfunction. EMG demonstrated that involuntary peripherally generated continuous motor unit discharges caused the posture.
Centronuclear myopathy heterogeneity: distinction of clinical types by myosin isoform patterns, We studied muscles from 3 patients with centronuclear myopathy (CNM) by immunocytochemistry using myosin heavy chain (MHC)-specific monoclonal antibodies to determine whether subtypes of CNM express prenatal MHC and to assess if there is an arrest in development of these muscles. Muscle from a woman with childhood-onset CNM did not express prenatal MHC. yet this prenatal MHC was strongly expressed in the muscle fibers of 2 brothers with X-linked CNM. This finding represents the 1st immunocytochemical evidence of the expression of a prenatal myosin isoform in nonregenerating postnatal human muscle and suggests that the X-linked form of CNM differs from the other types because of a true arrest in maturation of the muscle.
Suppression of carbamazepine-induced rash with prednisone, We report our experience with 20 patients who developed a rash shortly after the introduction of carbamazepine and were treated with prednisone and an antihistamine. Sixteen patients were successfully continued on carbamazepine while 4 had to discontinue the drug.
Handcuff neuropathies, Compressive neuropathy due to tight application of handcuffs occurred in 5 patients. The superficial radial nerve was affected in 8 hands and the median nerve in two. Neurologic deficits persisted as long as 3 years after handcuffing. Nerve conduction studies helped to exclude malingering and other diagnoses. All patients had been intoxicated when handcuffed or had been arrested with force. The handcuff mechanism. which allows accidental overtightening after application. is an unrecognized factor in these neuropathies.
Mesencephalic cholinergic nuclei in progressive supranuclear palsy, Using an antibody against choline acetyltransferase (ChAT). mesencephalic cholinergic cell nuclei were studied in autopsy material from 3 cases of progressive supranuclear palsy (PSP) and 4 controls. ChAT-immunoreactive neurons were quantified in sections that spanned the rostrocaudal extent of each nucleus. In PSP. there was a significant decrease in the number of neurons with detectable immunoreactivity for ChAT in and adjacent to the central gray substance in the following nuclei: the nucleus of Edinger-Westphal (69%); the rostral interstitial nucleus of the medial longitudinal fasciculus (97%); the interstitial nucleus of Cajal (78%). A cell loss was also evident in a group of neurons found in the deep layers of the superior colliculus (93%). In contrast. the estimated number of ChAT-immunoreactive cell bodies in cranial nerves III and IV. in the mesencephalic reticular formation. and in the parabigeminal nucleus was not different from that of controls. The results are compatible with the notion that. in PSP. there is a regionally selective destruction of cholinergic neurons.
Absence of highly homologous sequence to HTLV-I in Japanese multiple sclerosis, We tried to detect HTLV-I-related sequences in Japanese patients with multiple sclerosis with a highly sensitive method that employs the polymerase chain reaction (PCR) of genomic DNA followed by Southern blot hybridization analysis. To amplify HTLV-I sequences. we used primers for LTR. pol. gag. and env coding regions. Fourteen patients with definite MS. 14 disease controls. 12 normal controls. and 3 patients with HTLV-I-associated myelopathy (HAM) were investigated. Results of particle aggregation assay for HTLV-I antibodies were negative in serum from all subjects except for the 3 HAM patients. Neither the 14 MS patients nor the 26 controls showed the presence of any highly homologous sequences to HTLV-I. We did observe faint signals for gag. pol. and env coding regions only at low stringent hybridization in some MS patients as well as some normal controls. The nucleotide sequence analysis of the faint bands was more homologous to major histocompatibility complex molecules than the HTLV-I genome.
Central nervous system involvement in Von Hippel-Lindau disease, Fifty individuals with Von Hippel-Lindau disease (VHL) were studied with gadolinium-enhanced magnetic resonance imaging (MRI) to determine the frequency and distribution of CNS lesions. The associated clinical features were also reviewed. Thirty-six (72%) of the 50 had 1 or more CNS tumors. The most frequently affected sites in the CNS excluding the retina were the cerebellum (52%). spinal cord (44%). and brainstem (18%). New regional predilections for the craniocervical junction and conus medullaris were demonstrated by this study. Forty-one percent of all VHL patients with CNS tumors were neurologically asymptomatic: cerebellar tumors (50%). spinal cord tumors (50%). and brainstem tumors (44%) were often without clinical signs or symptoms. Multiple lesions were common. The mean age of all VHL patients (34.5 years) was similar to the mean age of all CNS VHL patients (34.4 years). suggesting a lack of age association. CNS lesions commonly occurred in the 2nd decade of life. All patients at risk for VHL should be evaluated using gadolinium-enhanced MRI after 10 years of age. although ophthalmic examination should be initiated within the 1st 2 years of life. Enhanced MRI is particularly useful in the detection of CNS tumors in patients with the VHL gene.
Comparison of myelography with CT follow-up versus gadolinium MRI for subarachnoid metastatic disease in children, We evaluated 17 children with primary intracranial neoplasms for subarachnoid metastatic disease (SAMD) using myelography with computed tomographic follow-up (Myelo + CT) and cerebrospinal fluid (CSF) histopathologic examination. as well as magnetic resonance imaging with gadolinium DTPA (MRI + Gd). between December 1988 and December 1989. There were 12 boys. and the median age was 5.7 years (range. 0.8 to 21.8 years). Tumor histology included 8 primitive neuroectodermal tumors (PNETs). 3 ependymomas. 2 low-grade astrocytomas. 1 anaplastic astrocytoma. 1 glioblastoma multiforme. 1 atypical rhabdoid tumor. and 1 malignant fibrous histiocytoma. Thirteen tumors originated in the posterior fossa. 2 were supratentorial. and 2 were in the spinal cord. The median interval between the 2 diagnostic tests was 2 days. MRI + Gd was positive in 11 (65%). Myelo + CT in 8 (47%). and CSF in 5 (29%) cases. MRI + Gd was superior in delineating spinal cord nodules and "sugar coating" whereas Myelo + CT more readily revealed nerve root sleeve filling defects. There was no case in which Myelo + CT was positive that MRI + Gd did not reveal SAMD. MRI + Gd is a safe. noninvasive test that should be used as the initial imaging modality for the presence of SAMD.
Quantification of magnetic resonance scans for hippocampal and parahippocampal atrophy in Alzheimer's disease, The brains of patients with Alzheimer's disease (AD) invariably exhibit neuropathology in the hippocampus and entorhinal cortex when examined postmortem. Magnetic resonance imaging (MRI) offers a noninvasive. high-resolution method for quantifying volumetric changes in the AD brain antemortem. Eight patients diagnosed with probable AD and 7 age-matched controls had MRI scans and were tested on a battery of cognitive and olfactory tests. The hippocampus and entorhinal cortex (parahippocampal gyrus) showed significant atrophy. with over 40% reduction in size. Areas of the brain that are not highly involved in the degenerative state of AD. such as the striatum. did not show significant volumetric changes. Hippocampal and parahippocampal gyrus volumes had the highest correlation with scores on the Mini-Mental State Examination (r = 0.89). with lower correlations for a smell identification test (r = 0.65). odor match-to-sample test (r = 0.72). and a visual match-to-sample test (r = 0.26).
Clinical evaluation of the ITI (F-type) hollow cylinder implant, In 1976 the hollow cylinder implant was introduced. A number of articles have been published about the ITI implant system. In this article. short-term results of 102 ITI F-type implants in 40 patients are reported. The results showed this one-stage implant to be at least comparable to other well-known implant systems.
Massive osteolysis of the maxillofacial bones. Report of two cases, Two cases of massive osteolysis were encountered. one affecting the mandible and the other the maxilla and mandible. Only 13 cases have been reported so far in the existing literature for massive osteolysis of the mandible. It is indeed a rare disease. Our two cases were surgically treated and were clinically and histopathologically assessed.
Salivary flow rates in patients with head and neck cancer 0.5 to 25 years after radiotherapy, In this clinical study at the University of Texas M. D. Anderson Cancer Center. unstimulated and stimulated salivary flow rates were obtained from 47 patients with head and neck cancer who had received mantle. unilateral facial. or bilateral facial field radiotherapy from 0.5 to 25 years earlier. The magnitude of salivary flow rate reduction compared with a healthy control group was primarily related to the radiation dosage and the amount of salivary gland tissue included in the irradiated fields. Flow rates were lower for women in all groups. but these differences were not statistically significant.
Blood pressure measurements during dental checkups representative of 26-hour registration, The effect of dental checkups on blood pressure was investigated. In 27 normotensive patients (13 men and 14 women) aged 22 to 64 years (mean 39.75 +/- 10.5 years). a 26-hour continuous. noninvasive blood pressure registration was carried out. Of each patient at least 175 blood pressure measurements were registered during these 26 hours. giving a total amount of 4725 blood pressure measurements. A dental checkup appointment with the family dentist was included. Blood pressure values displayed the well-known diurnal variation. but the visit to the dental surgeon was not accompanied by a rise in blood pressure. There was no significant difference between the blood pressure values during the 26-hour period and those during the checkup period. During a rest period after the dental checkup. neither the systolic nor the diastolic pressure fell to any degree in relation to the 26-hour values or the visit to the surgeon.
Recurrent peripheral facial nerve palsy after dental procedures, Peripheral facial palsy is an uncommon complication of dental procedures. Most cases begin immediately after dental anesthesia and resolve within 12 hours. No report of recurrent facial palsy with dental manipulations has previously been described. We report a patient with two episodes of peripheral facial palsy. 2 years apart. developing within 24 hours of dental procedures. A third episode of contralateral facial weakness developed 3 years after the second event. This event was not related to dental manipulations. Although the exact mechanism is not known. dental manipulations may rarely result in precipitation of recurrent Bell's palsy.
African Burkitt's lymphoma: case report and light and electron microscopic findings, An African Burkitt's lymphoma occurred in a 9-year-old American boy who had jaw tumors. proptosis. and abdominal masses. Histologically. the tumor consisted of a monotonous overgrowth of undifferentiated lymphocytes with a "starry sky" appearance. The differential diagnosis of African versus American form and Burkitt's lymphoma versus non-Burkitt's lymphoma is discussed.
Intramuscular hemangioma in the oral region: report of three cases, The occurrence of intramuscular hemangioma in an intraoral or perioral localization is rare. and a thorough knowledge of these tumors is necessary for adequate diagnosis and treatment. Three cases are presented with discussion. and their histopathology and differential diagnosis are discussed. An adequate primary excision is necessary to avoid recurrence.
The potential of periodontal pocket formation associated with untreated accessory root canals, Teeth that were to be extracted because of periodontic-endodontic involvement. in six patients. were treated by hemisection or root amputation. The roots were processed histologically. All cases showed the presence of accessory root canals with remnants of pulpal tissue. bacteria. and necrotic debris. It was demonstrated in the cases studied that residual necrotic tissue in untreated root canals can result in periradicular pathosis. We may speculate that if the inflammatory process persists and drainage results via the sulcus. in time. plaque and then concretions may develop.
A retrospective clinical study of endodontically treated mandibular incisors in a selected Chinese population, Clinical studies of incidences of the number of canals in human teeth should correlate with the percentages obtained in laboratory samples. In this study the incidence of two canals in the mandibular incisors was compared with figures obtained from in vitro extracted teeth. as well as from one clinical study. A very low percentage was obtained from the examination of clinical records. and this could be due to racial differences in the samples examined.
Cross-sectional tomography. A diagnostic technique for determining the buccolingual relationship of impacted mandibular third molars and the inferior alveolar neurovascular bundle, Twenty-two patients with 31 impacted mandibular third molars were examined with a new. precise. cross-sectional tomographic technique to assess the radiographic size. shape. branching pattern. location. and degree of cortication of the mandibular canal. and the inclination of impacted mandibular third molars in the buccolingual plane. The mandibular canal. including bifid canals. was accurately identified in 30 cases (96.8%). The cross-sectional appearance of the canal was an uncorticated. or partially corticated. radiolucent oval that measured on average (+/- SD) 2.9 +/- 0.7 x 2.5 +/- 0.6 mm in diameter. It was located more frequently (45.2%) on the buccal aspect of the impacted mandibular third molar. About 60% of the mandibular canals notched the inner cortical plate of the mandible or the third molar root surface. Cystic expansion and quantification of cortical bone destruction were readily assessed by this technique. It was concluded that diagnostic information obtained from cross-sectional tomograms significantly aids the oral and maxillofacial surgeon during the preoperative diagnostic workup and that the radiation risks are comparable to those of other accepted localization techniques.
Beta-2-microglobulin concentrations in pediatric human immunodeficiency virus infection, Serum concentrations of beta-2-microglobulin (B2-M) were correlated with disease outcome in 40 children infected by the human immunodeficiency virus. Serum B2-M serum concentrations below 3.0 mg/100 ml or decreasing concentrations were indicative of a stable disease course but were also noted preterminally in lymphopenic children. Of 20 patients with B2-M concentrations above 3.0 mg/liter. 12 had a progressive disease course and 8 remained stable. In the latter 8 patients the B2-M values decreased with time. Elevated B2-M concentrations were also noted in infants younger than 1 year of age and denoted active human immunodeficiency virus infection. B2-M serum concentrations are a useful prognostic marker in human immunodeficiency virus-infected children.
Utility of collecting blood cultures through newly inserted intravenous catheters, We prospectively examined the utility of obtaining blood cultures through newly inserted intravenous catheters in 99 children who required both a blood culture and placement of an intravenous catheter. Two blood cultures were collected from each patient. one through a freshly inserted intravenous catheter and another through a butterfly needle at a separate venipuncture site. A standardized technique of skin preparation with povidone-iodine was used. The rate of contamination was 1.0% (95% confidence intervals. 0 to 3.0%) for each method. Ten patients had blood cultures yielding true pathogens; in five of these bacteremic children. only one of two sets of blood cultures was positive. We conclude that blood cultures can be collected through freshly placed intravenous catheters without increasing the risk of contamination. These results also raise the possibility that obtaining two blood cultures instead of a single culture may improve the detection of bacteremia in children.
Syphilis. A new visit from an old enemy, Syphilis has a number of stages. including a latent one. and may be overlooked or misdiagnosed if the possibility is not kept in mind. Adequate treatment during the primary stage results in a very high cure rate. The latent stage may last for years. during which time a woman may still give birth to an infected child. Symptomatic neurosyphilis occurs more often in men than women. Penicillin G is preferred to treat all stages of the disease; other antibiotics can be used for patients sensitive to penicillin.
Hyperbaric oxygen therapy for acute smoke inhalation injuries, Hyperbaric oxygen therapy is an important adjunct in the management of respiratory injuries secondary to smoke inhalation. especially when injury is complicated by inhalation of a toxic chemical such as carbon monoxide or cyanide. For carbon monoxide poisoning. such therapy has become a standard of practice. As more information becomes available concerning the ability of hyperbaric oxygen to reduce reperfusion injuries. we anticipate that this therapy will become a standard of practice for managing smoke inhalation injuries and cyanide poisoning as well.
Assessment of stable ischemic heart disease. Which tests are best for which patients, An understanding of the importance of various risk factors. the pathogenesis of myocardial ischemia. and the appropriate use of various noninvasive and invasive tests is essential for management of patients with known or suspected coronary artery disease (CAD). Although coronary angiography remains the "gold standard" for diagnosis of CAD. much of the data obtained from risk factor assessment. medical history. and various noninvasive tests provides information that may be even more important than cardiac catheterization data alone for defining prognosis and directing management.
Treating serum lipid abnormalities in high-priority patients, Normalization of serum lipid levels should be initiated as soon as possible in patients with myocardial. cerebrovascular. or peripheral vascular disease. Clinical trials indicate that coronary artery disease and overall mortality rates can be reduced and atherosclerosis stabilized or reversed by lipid-lowering therapy. Treatment should lower low-density lipoprotein cholesterol levels to 130 mg/dL or less and total triglyceride levels to 150 mg/dL or less and increase high-density lipoprotein cholesterol levels to at least 52 mg/dL in men and 66 mg/dL in women. Nonlipid coronary risk factors should be eliminated when possible. Lipid-lowering therapy may consist of dietary modification and drug treatment with colestipol hydrochloride (Colestid). cholestyramine (Cholybar. Questran). lovastatin (Mevacor). gemfibrozil (Lopid). and nicotinic acid (Nicolar).
Physiological induction and reversal of focus formation and tumorigenicity in NIH 3T3 cells [published erratum appears in Proc Natl Acad Sci U S A 1991 Apr 15;88(8):3510, NIH 3T3 cells undergo morphological transformation in response to conditions of constrained growth. such as occur in low serum concentrations or at confluence. Transformation is expressed in a small fraction of the cells by the appearance of discrete foci of multiplying cells on a confluent monolayer of quiescent cells. We isolated and expanded cell populations from three dense and three light foci. Cells from each of these populations efficiently reproduced foci of the same morphotype when grown on a background of nontransformed NIH 3T3 cells. Using cultures derived from one of the dense foci (subline D/2). we found that the number of focus-forming units was stable and the cells remained tumorigenic when they were subjected to repeated thrice-weekly passage in 2% calf serum. However. equivalent passage in 10% calf serum eventually rendered the cells incapable of both focus production and tumor formation. The results show that the capacity to produce tumors as well as morphological transformation are produced as a response to physiological constraints of growth and/or metabolism in the absence of carcinogens and that both properties can be reversed by lifting the constraints. This behavior is typical of an adaptational response and. taken together with other supporting evidence. shows that tumorigenesis does not require conventional genetic alteration.
Cation-dependent mannose 6-phosphate receptor contains two internalization signals in its cytoplasmic domain [published erratum appears in Proc Natl Acad Sci U S A 1991 Feb 15;88(4):1591, The signals required for rapid internalization of the bovine cation-dependent mannose 6-phosphate receptor have been localized to two distinct regions of the 67-amino acid cytoplasmic domain. One signal includes phenylalanine 13 and phenylalanine 18. while the other involves tyrosine 45. The former signal is more potent than the latter. but both must be present for the maximal rate of receptor internalization. Each signal shares similarities with the known internalization signals of other recycling receptors.
Primary combined immunodeficiency resulting from defective transcription of multiple T-cell lymphokine genes, The circulating T lymphocytes of a female child with recurrent opportunistic infections were normal in number and phenotype but exhibited poor proliferation and decreased synthesis of the T-cell growth factor interleukin (IL) 2 in response to mitogens. Recombinant IL-2 fully restored the proliferative responses of her T cells. suggesting that her poor immune function was related to IL-2 deficiency. Northern blot analysis of total cellular RNA from the patient's T cells revealed markedly decreased levels of IL-2 mRNA of normal size. In addition. mRNA levels of other lymphokines selectively expressed by T cells. which include IL-3. IL-4. and IL-5. were either severely depressed or absent. The levels of interferon gamma mRNA were moderately decreased. while those of granulocyte-macrophage colony stimulating factor. a lymphokine the production of which is not restricted to T cells. were unaffected. The decreased level of lymphokine mRNA in the patient's T lymphocytes was not from enhanced catabolism but resulted from a diminution in the transcription rate of the affected lymphokine genes. Normal transduction via the T-cell receptor/CD3 complex of biochemical signals necessary for the initiation of lymphokine gene transcription indicated that the defect was distal to the membrane signal-transducing apparatus. The defect is hypothesized to involve a T-cell-specific trans-acting regulatory factor required for transcription of the affected lymphokine genes.
Analysis of interleukin 2 and various effector cell populations in adoptive immunotherapy of 9L rat gliosarcoma: allogeneic cytotoxic T lymphocytes prevent tumor take, Recombinant interleukin 2 (rIL-2) and various effector cell populations were used for adoptive immunotherapy in the Fischer strain 9L rat gliosarcoma model. The in vivo cytotoxicities of nonspecifically activated lymphocytes and specifically activated cytotoxic T lymphocytes (CTLs) were assessed in a modified in vivo neutralization (Winn) assay. Effector cells (10(6)) and 9L tumor cells (10(5] were combined with 10(4) units of rIL-2 and stereotactically implanted into the right frontal centrum semiovale of the Fischer (F344) rat. At 7 and 14 days. additional effector cells (10(6] and rIL-2 (10(4) units) were administered through the same burr hole. Nonspecifically activated splenocytes were lymphokine-activated killer (LAK) cells. both plastic-adherent and nonadherent. whereas specifically activated CTLs were either syngeneic (genetically identical) or allogeneic (genetically dissimilar). Syngeneic CTLs were T lymphocytes from Fischer rats primed in vivo with 9L cells and restimulated in vitro. Allogeneic CTLs were generated by exposing DA rat lymphocytes either to irradiated Fischer lymph node cells or to 9L Fisher tumor cells in vitro. Control groups included rats bearing 9L tumor who were untreated. those who received peripheral (i.p. or s.c.) administration of rIL-2. or those who received syngeneic unstimulated T lymphocytes and rIL-2. For a set of animals given the same inoculum of 9L tumor. significantly improved survival was shown for groups treated with nonadherent or adherent LAK cells (P less than or equal to 0.0003). syngeneic CTLs (P = 0.0327). or allogeneic CTLs (P = 0.0025) over untreated control animals by using Mantel-Haenzel nonparametric logrank equations. Only treatment with allogeneic CTLs prevented tumor take.
A long terminal repeat-containing retrotransposon is mobilized during hybrid dysgenesis in Drosophila virilis, A hybrid dysgenesis syndrome similar to those described in Drosophila melanogaster occurs in Drosophila virilis when a laboratory stock is crossed to a wild strain collected in the Batumi region of Georgia (U.S.S.R). Mutations in various loci obtained during these crosses are presumably induced by the insertion of DNA sequences. We have cloned an induced white mutation and characterized the insertion sequence responsible for the mutant phenotype. This sequence is a 10.6-kilobase (kb) transposable element we have named Ulysses. This element is flanked by unusually large 2.1-kb long terminal repeats. Ulysses also contains other landmarks characteristic of the retrotransposon family. such as a tRNA-binding site adjacent to the 5' long terminal repeat and open reading frames encoding putative products with homology to the reverse transcriptase. protease. and integrase domains typical of proteins encoded by vertebrate retroviruses. Some of the mutations obtained do not contain a copy of the Ulysses element at the mutant locus. suggesting that a different transposable element may be responsible for the mutation. Therefore. Ulysses may not be the primary cause of the entire dysgenic syndrome. and its mobilization may be the result of activation by an independent mobile element.
Autoimmune preganglionic sympathectomy induced by acetylcholinesterase antibodies, Systemic injection of monoclonal antibodies to neural acetylcholinesterase in adult rats caused a syndrome with permanent. complement-mediated destruction of presynaptic fibers in sympathetic ganglia and adrenal medulla. Ptosis. hypotension. bradycardia. and postural syncope ensued. In sympathetic ganglia. acetylcholinesterase activity disappeared from neuropil but not from nerve cell bodies. Choline acetyltransferase activity and ultrastructurally defined synapses were also lost. Electrical stimulation of presynaptic fibers to the superior cervical ganglion ceased to evoke end-organ responses. On the other hand. direct ganglionic stimulation remained effective. and the postganglionic adrenergic system appeared intact. Motor performance and the choline acetyltransferase content of skeletal muscle were preserved. as was parasympathetic (vagal) function. This model of selective cholinergic autoimmunity represents another tool for autonomic physiology and may be relevant to the pathogenesis of human dysautonomias.
Activation of early events of the mitogenic response by a P2Y purinoceptor with covalently bound 3'-O-(4-benzoyl)-benzoyladenosine 5'-triphosphate, 3'-O-(4-Benzoyl)benzoyl-ATP (BzATP). a photoaffinity analog of ATP. was used as a ligand for a P2Y purinoceptor (adenine nucleotide receptor) present in intact Swiss 3T3 and 3T6 cells and A-431 epidermoid carcinoma cells. Photolysis of serum-starved cells in the presence of 10-50 microM BzATP. followed by extensive washing to remove unincorporated BzATP. induced the release of arachidonic acid. A trace (less than 0.01%) of photoincorporated BzATP was as effective as when 50 microM BzATP or ATP was contained in the incubation medium during the assay. Photoincorporated BzATP also stimulated the production of prostaglandin E2 and the accumulation of cyclic AMP. In previous studies. we demonstrated that these three events are obligatory early steps in a pathway leading to DNA synthesis in the above cell lines. The evidence indicated that the purinoceptor activated by extracellular ATP or BzATP was linked to a pertussis toxin-sensitive GTP-binding protein. Consistent with these observations. we now find that pertussis toxin inhibits the effect of photoincorporated BzATP on arachidonic acid release. These results indicate that BzATP is an effective agonist for the P2Y purinoceptor concerned with stimulation of DNA synthesis in 3T3. 3T6. and A-431 cells. Furthermore. after photolysis it becomes irreversibly associated with intact cells and promotes the activation of early events required for DNA synthesis.
Boron neutron capture therapy of intracerebral rat gliosarcomas, The efficacy of boron neutron capture therapy (BNCT) for the treatment of intracerebrally implanted rat gliosarcomas was tested. Preferential accumulation of 10B in tumors was achieved by continuous infusion of the sulfhydryl borane dimer. Na4(10)B24H22S2. at a rate of 45-50 micrograms of 10B per g of body weight per day from day 11 to day 14 after tumor initiation (day 0). This infusion schedule resulted in average blood 10B concentrations of 35 micrograms/ml in a group of 12 gliosarcoma-bearing rats and 45 micrograms/ml in a group of 10 similar gliosarcoma-bearing rats treated by BNCT. Estimated tumor 10B levels in these two groups were 26 and 34 micrograms/g. respectively. On day 14. boron-treated and non-boron-treated rats were exposed to 5.0 or 7.5 MW.min of radiation from the Brookhaven Medical Research Reactor that yielded thermal neutron fluences of approximately 2.0 x 10(12) or approximately 3.0 x 10(12) n/cm2. respectively. in the tumors. Untreated rats had a median postinitiation survival time of 21 days. Reactor radiation alone increased median postinitiation survival time to 26 (5.0 MW.min) or 28 (7.5 MW.min) days. The 12 rats that received 5 MW.min of BNCT had a median postinitiation survival time of 60 days. Two of these animals survived greater than 15 months. In the 7.5 MW.min group. the median survival time is not calculable since 6 of the 10 animals remain alive greater than 10 months after BNCT. The estimated radiation doses to tumors in the two BNCT groups were 14.2 and 25.6 Gy equivalents. respectively. Similar gliosarcoma-bearing rats treated with 15.0 or 22.5 Gy of 250-kilovolt peak x-rays had median survival times of only 26 or 31 days. respectively. after tumor initiation.
A myo-inositol pool utilized for phosphatidylinositol synthesis is depleted in sciatic nerve from rats with streptozotocin-induced diabetes, Peripheral nerve from experimentally diabetic rats exhibits lowered levels of myo-inositol (MI) and decreased incorporation of [3H]MI into phosphatidylinositol (PI). There are indications that diminished PI turnover may be causally related to reduced Na+.K(+)-ATPase activity in diabetic nerve. We have investigated whether a metabolic compartment of MI that is essential for PI synthesis is decreased in this tissue. Sciatic nerve segments from streptozotocin-induced diabetic and age-matched normal rats were incubated in vitro with either 32Pi or [3H]cytidine in the presence of propranolol. This cationic amphiphilic agent redirected nerve phospholipid metabolism to produce enhanced 32P incorporation into PI and decreased labeling of phosphatidylcholine and phosphatidyl-ethanolamine. The accumulation of phosphatidyl CMP (CMP-PA) was also demonstrated by chromatographic and enzymatic means. The incorporation of [3H]cytidine into CMP-PA in normal nerve increased up to 15-fold when 0.6 mM propranolol was present. In diabetic nerve. the liponucleotide incorporated 2- to 3-fold more isotope and was more readily labeled at lower drug concentrations as compared to normal nerve. The buildup of [3H]CMP-PA was reduced in a dose-dependent manner in the presence of MI in the incubation medium at concentrations up to 3 mM. However. if MI was added after liponucleotide accumulation. preformed CMP-PA could not be utilized for PI synthesis. The difference in liponucleotide labeling between normal and diabetic nerve was nearly abolished at 0.3 mM medium MI. a concentration much less than the level of cyclitol in the tissue. These results strongly suggest the presence in nerve of a pool of MI that is not in equilibrium with the bulk of nerve MI and that is preferentially used for PI synthesis. This metabolic compartment is depleted in diabetic nerve but can be readily replenished by exogenous MI and may correspond to the MI pool that has been proposed to be required for the turnover of a portion of tissue PI involved in maintenance of normal Na+.K(+)-ATPase activity.
Identification of transforming growth factor beta family members present in bone-inductive protein purified from bovine bone, Characterization of the polypeptides present in bone-inductive protein extracts from bovine bone has led to the cloning of seven regulatory molecules. six of which are distantly related to transforming growth factor beta. The three human bone morphogenetic proteins (BMPs) we describe herein. BMP-5. BMP-6. and BMP-7. show extensive sequence similarity to BMP-2. a molecule that by itself is sufficient to induce de novo bone formation in vivo. The additive or synergistic contribution of these BMP-2-related molecules to the osteogenic activity associated with demineralized bone is strongly implicated by the presence of these growth factors in the most active fractions of highly purified bone extract.
Adenovirus 12S E1A gene represses differentiation of F9 teratocarcinoma cells, The F9 teratocarcinoma cell line differentiates in vitro after treatment with retinoic acid and cAMP and has been a widely used model system for the study of the molecular events that are responsible for cellular commitment and differentiation during early development. Previous experiments have suggested intriguing parallels between the control of gene expression during F9 cell differentiation and the regulation of gene expression by adenovirus E1A. Transfection of a 12S E1A-expressing plasmid into terminally differentiated. nonproliferating F9 cells generates. at high frequency. colonies of dividing cells. each of which expresses E1A. Cell lines established from these colonies proliferate in the presence of retinoic acid and have lost the fully differentiated phenotype as characterized by the absence of expression of a series of differentiation-specific genes. We conclude that expression of the viral 12S E1A gene product interferes with retinoic acid-induced F9 cell differentiation. Moreover. the results suggest that the differentiation process. as defined by markers of terminal differentiation. may not be a permanent event but can be reversed by E1A expression.
Repair of O6-ethylguanine in DNA protects rat 208F cells from tumorigenic conversion by N-ethyl-N-nitrosourea, O6-Ethylguanine (O6-EtGua) is one of about a dozen different alkylation products formed in the DNA of cells exposed to the alkylating N-nitroso carcinogen N-ethyl-N-nitrosourea (EtNU). We have evaluated selectively the relative capacity of cells for the specific enzymatic repair of O6-EtGua as a determinant for the probability of malignant conversion. Eleven O6-EtGua-repair-proficient (R+) variant subclones were isolated from the O6-EtGua-repair-deficient (R-) clonal rat fibroblast line 208F by selection for resistance to 1.3-bis-(2-chloroethyl)-1-nitrosourea (frequency. approximately equal to 10(-5). Contrary to the 208F wild-type cells. all variants expressed O6-methylguanine-DNA methyltransferase activity. while both kinds of cells were deficient for repair of the DNA ethylation products O2- and O4-ethylthymine. After exposure to EtNU (less than or equal to 500 micrograms/ml; 20 min). cells were analyzed for the formation of piled-up foci in monolayer culture and of anchorage-independent colonies in semisolid agar medium. Depending on the EtNU concentration. the frequencies of piled-up foci and agar colonies. respectively. in the R+ variants were as low as 1/28th and 1/56th of those in the R- wild type. Contrasting with the cells from R+ variant-derived agar colonies. cells from 208F (R-) agar colonies gave rise to highly malignant tumors when implanted subcutaneously into syngeneic rats. No significant differences in the frequencies of piled-up foci were found between wild-type and variant cells after exposure to the major reactive metabolite of benzo[a]pyrene. (+)-7 beta. 8 alpha-dihydroxy-9.10 alpha-epoxy-7.8.9.10 alpha-tetrahydrobenzo[a] pyrene. for which stable binding to guanine O6 in cellular DNA has not been observed. The relative capacity of cells for repair of O6-alkylguanine is. therefore. a critical determinant for their risk of malignant conversion by N-nitroso carcinogens.
Characterization of a splicing mutation in group A xeroderma pigmentosum, The molecular basis of group A xeroderma pigmentosum (XP) was investigated by comparison of the nucleotide sequences of multiple clones of the XP group A complementing gene (XPAC) from a patient with group A XP with that of a normal gene. The clones showed a G----C substitution at the 3' splice acceptor site of intron 3. which altered the obligatory AG acceptor dinucleotide to AC. Nucleotide sequencing of cDNAs amplified by the polymerase chain reaction revealed that this single base substitution abolishes the canonical 3' splice site. thus creating two abnormally spliced mRNA forms. The larger form is identical with normal mRNA except for a dinucleotide deletion at the 5' end of exon 4. This deletion results in a frameshift with premature translation termination in exon 4. The smaller form has a deletion of the entire exon 3 and the dinucleotide at the 5' end of exon 4. The result of a transfection study provided additional evidence that this single base substitution is the disease-causing mutation. This single base substitution creates a new cleavage site for the restriction nuclease AlwNI. Analysis of AlwNI restriction fragment length polymorphism showed a high frequency of this mutation in Japanese patients with group A XP: 16 of 21 unrelated Japanese patients were homozygous and 4 were heterozygous for this mutation. However. 11 Caucasians and 2 Blacks with group A XP did not have this mutant allele. The polymorphic AlwNI restriction fragments are concluded to be useful for diagnosis of group A XP in Japanese subjects. including prenatal cases and carriers.
Expression of neurophysin-related precursor in cell membranes of a small-cell lung carcinoma, A monoclonal antibody (mAb L6) to a small-cell lung carcinoma surface antigen recognizes a common epitope of vasopressin-neurophysin and oxytocin-neurophysin in hypothalamic nuclei. We now report on the identification of a neurophysin-like precursor in human lung carcinoma (LX-1) cell membrane. mAb L6 immunoaffinity chromatography of solubilized membranes resulted in a single band of approximately 45 kDa. Western blot analysis demonstrated immunoreactivity of this band with mAb L6. anti-vasopressin. and an antibody to the vasopressin precursor. pro-pressophysin. N-terminal sequencing of this band demonstrated a 21-amino acid homology with the N terminus of human pro-pressophysin. and substitution of a Cys33 residue in the tumor antigen with Arg33. Absence of immunoreactivity with the antibodies described above in cytosolic extracts and culture medium suggests nonsecretion of processed or intact pro-pressophysin-like peptide. Northern analysis of LX-1 mRNA with a 30-mer to the C terminus of rat pro-pressophysin resulted in a band of approximately 1000 base pairs. 250 base pairs larger than hypothalamic message. In situ hybridization of LX-1 tumor-bearing nude rat brain with the same probe demonstrated specific hybridization in rat hypothalamus and xenografted tumor. These findings suggest expression of a pro-pressophysin-like protein in this tumor cell line that is preferentially targeted to the cell membrane.
Evolution of sequences encoding the principal neutralization epitope of human immunodeficiency virus 1 is host dependent, rapid, and continuous, The principal neutralization epitope of human immunodeficiency virus 1 is localized in the third variable (V3) domain of the external envelope and has been shown to bind isolate-specific antibodies. Therefore. the extent of variation within the nucleic acid sequence encoding this epitope was studied in DNA directly obtained from peripheral blood mononuclear cells of six children and their plasma donor. This revealed that the quasi-species distribution of sequences obtained after cloning varied from recipient to recipient and that the distance from the donor sequences increased over time. V3 nucleotide evolution rates averaged 9.5 x 10(-3) per site per year for silent sites and 11.4 x 10(-3) per site per year for nonsilent sites (vs. 9.7 and 9.8 x 10(-3) per site per year for a control region 5' adjacent to the V3 region) and. although individual differences were observed. did not correlate with the serum antigen levels or disease progression. Sequences of both the epitope coding region itself (V3) and the control region upstream diverted more from the donor sequence among children not progressing to AIDS than among children progressing to AIDS. The evolution of V3 sequences is apparently host dependent. rapid. and independent of the level of antigen expression.
Evidence that down-regulation of beta-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia, Non-insulin-dependent diabetes mellitus (NIDDM) is attributed to a failure of pancreatic beta cells to maintain insulin secretion at a level sufficient to compensate for underlying insulin resistance. In the ZDF rat. a model of NIDDM that closely resembles the human syndrome. we have previously reported profound underexpression of GLUT-2. the high-Km facilitative glucose transporter expressed by beta cells of normal animals. Here we report that islets of diabetic rats exhibit a marked decrease in the volume of GLUT-2-positive beta cells and a reduction at the electron-microscopic level in the number of GLUT-2-immunoreactive sites per unit of beta-cell plasma membrane. The deficiency of GLUT-2 cannot be induced in normal beta cells by in vivo or in vitro exposure to high levels of glucose nor can it be prevented in beta cells of prediabetic ZDF rats by elimination of hyperglycemia. We conclude that this dearth of immunodetectable GLUT-2 in NIDDM is not secondary to hyperglycemia and therefore that it may well play a causal role in the development of hyperglycemia.
Frequent mutation of the p53 gene in human esophageal cancer, Sequence alterations in the p53 gene have been detected in human tumors of the brain. breast. lung. and colon. and it has been proposed that p53 mutations spanning a major portion of the coding region inactivate the tumor suppressor function of this gene. To our knowledge. neither transforming mutations in oncogenes nor mutations in tumor suppressor genes have been reported in human esophageal tumors. We examined four human esophageal carcinoma cell lines and 14 human esophageal squamous cell carcinomas by polymerase chain reaction amplification and direct sequencing for the presence of p53 mutations in exons 5. 6. 7. 8. and 9. Two cell lines and five of the tumor specimens contained a mutated allele (one frameshift and six missense mutations). All missense mutations detected occurred at G.C base pairs in codons at or adjacent to mutations previously reported in other cancers. The identification of aberrant p53 gene alleles in one-third of the tumors we tested suggests that mutations at this locus are common genetic events in the pathogenesis of squamous cell carcinomas of the esophagus.
Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene, The leukemogenic membrane glycoprotein (gp55) encoded by Friend spleen focus-forming virus appears to bind to erythropoietin receptors (EpoR) sto stimulate erythroblastosis [Li. J.-P.. D'Andrea. A.D.. Lodish. H.F. & Baltimore. D. (1990) Nature (London) 343. 762-764]. To directly compare the effects of gp55 with erythropoietin (Epo). we produced retrovirions that encode either gp55. Epo. or EpoR. After infection with EpoR virus. interleukin 3-dependent DA-3 cells bound 125I-labeled Epo and grew without interleukin 3 in the presence of Epo. These latter cells. but not parental DA-3 cells. became factor-independent after superinfection either with Epo virus or with Friend spleen focus-forming virus. In addition. Epo virus caused a disease in mice that mimicked Friend erythroleukemia. Although Fv-2r homozygotes are susceptible to all other retroviral diseases. they are resistant to both Epo viral and Friend viral erythroleukemias. These results indicate that both gp55 and Epo stimulate EpoR and that the Fv-2 gene encodes a protein that controls response to these ligands. However. the Fv-2 protein is not EpoR because the corresponding genes map to opposite ends of mouse chromosome 9. These results have important implications for understanding signal transduction by EpoR and the role of host genetic variation in controlling susceptibility to an oncogenic protein.
Biomechanics of fracture risk prediction of the hip and spine by quantitative computed tomography, In this review. we have made use of some simple engineering concepts to summarize current efforts relating QCT measures to bone density and strength. From a variety of in vitro experiments on cadaveric vertebrae and femora. it is evident that both apparent and ash densities are strong linear functions of QCT measures. with coefficients of determination ranging from 0.49 to 0.90 and relative errors from 44.9% to 7.1%. QCT data also can be used (with somewhat less confidence) to determine the compressive modulus (R2s from 0.36 to 0.68. relative errors from 45.0% to 35.5%) and compressive strength (R2s from 0.58 to 0.70. relative errors from 56.5% to 39.9%) of trabecular bone from the proximal femur and vertebral body. In cortical bone. material properties are only correlated weakly with QCT measures. Experiments designed to relate QCT data to failure loads for the proximal femur and vertebral body have been remarkably successful. Coefficients of determination have ranged from 0.32 to 0.93. with relative errors from 31.1% to 13.9%. However. when the in vitro failure loads determined in these experiments are compared against available estimates of in vivo loads on the spine and hip. it is apparent. at least in the elderly. that in vivo loads are relatively close to those that cause fracture in vitro. To assess the possibility of developing QCT-based clinical predictors of fracture risk for individual patients. we have introduced the concept factor of risk often used in engineering design to account for uncertainties in estimates of service loads and component strength. The factor of risk for a particular loading condition is defined as the ratio of expected service loads to the known failure loads. To extend this concept to densitometric fracture risk prediction in vivo. it is important to recognize that densitometric data must not only be used to predict the ultimate load carrying capacity of the region of interest. but that this ultimate load must then be compared to the forces expected in vivo under comparable loading conditions. One difficulty with this approach is that little is known about the in vivo forces that are associated with atraumatic age-related fractures of the hip and vertebrae and even less about the forces applied to the hip and spine during traumatic events such as falls. However. from available estimates of in vivo loads during bending and lifting. it is apparent that in the elderly. factors of risk for the spine can easily approach 1.(ABSTRACT TRUNCATED AT 400 WORDS).
Inherited diseases of bone density in children, In this article the radiographic manifestations of various genetic diseases predominately affecting bone mineralization are considered. Osteogenesis imperfecta and other diseases of diffuse osteopenia. hereditary rickets and rachiticlike conditions. and osteopetrosis and other diseases of increased bone density are emphasized. Recognition of the radiographic manifestations allows accurate diagnosis. therapeutic intervention when possible. and determination of recurrence risk for genetic counseling.
Metabolic bone disease. Morphometry, The history of the development of radiologic morphometric techniques is traced. emphasizing their pathophysiologic background and relevance to possible therapies. The techniques are described and longitudinal and comparative studies assessed. Technical limitations of the various methods are presented.
The pathology of metabolic bone disease, The skeletal manifestations of the diverse group of metabolic bone diseases are mediated through the altered function of osteoblasts and osteoclasts and abnormal rates of mineralization. Appropriate understanding of their pathologic conditions requires familiarity with the normal anatomy and physiology of the skeleton. The accurate identification of metabolic bone disease frequently demands histologic confirmation and sophisticated analysis of undecalcified bone specimens labeled with tetracycline by histomorphometric techniques. These procedures allow the assessment of many morphologic features that characterize specific disease states. The most common types of metabolic bone diseases are acquired disorders; nonetheless. rare forms frequently are genetically based and cause intrinsic alterations in the bone-cell populations.
Radiographic appearance of osteopenia, The radiographic appearance of bone is the result of two physiologic processes: the resorption of bone and the remodeling of bone in response to the stresses applied to it. The relative rates of these two processes will determine the structural and. therefore. the radiographic appearance of the affected bone.
Osteoporosis. Current techniques and recent developments in quantitative bone densitometry, Knowledge about the proper use and interpretation of bone densitometry studies and an understanding of appropriate medical interventions are not universal among physicians. nor are instrumentation and technical performance of bone density studies of uniformly high quality. Indeed. this deficiency of medical and technical expertise is the principal deterrent to widespread implementation of our recommended clinical applications at this time. Nonetheless. given the current impetus to disseminate information about osteoporosis. to make newer instrumentation more readily available. and to limit the cost of these techniques. we anticipate that our recommendations may soon become standard medical practice.
Osteoporosis, Osteoporosis. a condition of decreased bone tissue that increases the likelihood of fracture. places a significant burden on our society in terms of health cost and morbidity. The most common type of osteoporosis is involutional. and two subtypes are recognized: type 1 and type 2. Type 1. or postmenopausal. osteoporosis is most commonly seen in perimenopausal and postmenopausal women from ages 51 to 75. Estrogen deficiency is the most dominant factor in the pathogenesis of this disorder. Type 2. or aging related. osteoporosis is seen in elderly women and men aged 70 or more. Bone loss in this group is related to aging. estrogen deficiency. negative calcium balance. and a variety of environmental and genetic factors. The best approach to the management of osteoporosis is to develop a lifelong strategy that maximizes peak bone mass and minimizes aging-related and postmenopausal bone loss. Estrogen is the only medication approved for the prevention of bone loss that is in general use. Other strategies to prevent bone loss (and maximize peak bone mass) include adequate calcium intake. adequate exercise. and avoidance of excess alcohol. tobacco. and caffeine use.
Functional stability of the canine cervical spine after injury. A three-month in vivo study, Although clinical instability is an in vivo problem. most spinal instability criteria are either subjective or are based on in vitro experiments. The authors performed an in vivo experiment using a canine model to study the natural history of spinal instability as a function of healing time up to 12 weeks. Three injuries were produced surgically: sham; laminectomy at C4; and bilateral facetectomy at C4-C5. Three 1.5-mm steel balls were implanted into C3 to C6 vertebrae at the time of surgery. Standardized functional flexion-extension stereoradiographs of the cervical spine were obtained before injury. immediately after injury and at 0.5. 1. 1.5. 2. 3. 4. 5. 6. 7.5. 9. and 12 weeks postinjury and immediately after killing the animals. In general. the authors found decreased ranges of motion (ROM) at the C4-C5 level. compared with the pre-injury values. for all injuries. but most significantly for the facetectomy. The maximum decrease occurred between 0 and 0.5 weeks postinjury. Between 2 and 12 weeks. there was recovery in the ROM. especially for the two less severe injuries. The changes in the ROM at each spinal level were explained by simultaneous presence of a destabilizing factor. caused by the three different injuries with the sham as the least and the facetectomy as the most destabilizing injury. and a stabilizing mechanism of muscle spasm in the beginning and of healing and other adaptive responses in the late phase after injury. Because of the significant differences between the canine model and the human cervical spine. the present findings should be extrapolated to the human situation with caution.
Prognosticating study for cervical myelopathy using evoked spinal cord potentials, One hundred twenty-three cases of cervical spondylotic and ossification of the posterior longitudinal ligament (OPLL) myelopathy cases with long tract signs subjected to surgical treatment were studied to identify the most important factors having an influence on postoperative outcome using evoked spinal cord potentials (ESCP). Disappearance and positive wave changes of these potentials at the level of responsible lesions and slow conduction velocity under 40 m indicated an unsatisfactory outcome. Localized-lesion cases diagnosed by ESCPs had excellent results. significantly more so than extensive-lesion cases. regardless of operative methods. In 123 cases. 76% were found to have localized lesions. while the other 24% showed extensive lesions. Concerning the difference between CSM and OPLL. 54% of OPLL and only 14% of CSM demonstrated extensive lesions.
Immediate closed reduction of cervical spine dislocations using traction, Cervical facet dislocations may be reduced rapidly and effectively using axial traction with weights applied at over the traditional 45-pound limit. Fifty-three sequential patients with cervical facet dislocations were reviewed. Thirty-nine patients required more than 50 pounds of traction to achieve rapid reduction. Sixty-eight percent of the entire series showed significant improvement in neurologic function. There were no cases of significant loss of function. A cadaver study confirmed that the cranial tongs could support over 100 pounds of traction. Careful application of up to 100 pounds seems to be associated with a low risk of neurologic compromise or tong failure. but results in effective reduction of dislocations.
Ligamentous laxity across C0-C1-C2 complex. Axial torque-rotation characteristics until failure, The axial torque until failure of the ligamentous occipito-atlanto-axial complex (C0-C1-C2) subjected to axial angular rotation (theta) was characterized using a biaxial MTS system. A special fixture and gearbox that permitted right axial rotation of the specimen until failure without imposing any additional constraints were designed to obtain the data. The average values for the axial rotation and torque at the point of maximum resistance were. respectively. 68.1 degrees and 13.6 N-m. The specimens offered minimal resistance (approximately 0.5 N-m). up to an average axial rotation of 21 degrees across the complex. The torque-angular rotation (T-theta) curve can be divided into four regions: regions of least and steadily increasing resistances. a transition zone that connects these two regions. and the increasing resistance region to the point of maximum resistance. The regions of least and steadily increasing resistances may be represented by two straight lines with average slopes of 0.028 and 0.383 N-m/degree. respectively. Post-test dissection of the specimens disclosed the following. The point of maximum resistance corresponded roughly to the value of axial rotation at which complete bilateral rotary dislocation of the C1-C2 facets occurred. The types of injuries observed were related to the magnitude of axial rotation imposed on a specimen during testing. Soft-tissue injuries alone (like stretch/rupture of the capsular ligaments. subluxation of the C1-C2 facets. etc.) were confined to specimens rotated up to or close to the point of maximum resistance. The specimens that were subjected to rotations up to the point of maximum resistance of the curve spontaneously reduced completely on removal from the testing apparatus. Spontaneous reduction was not possible for specimens tested slightly beyond their points of maximum resistance.
Adenocarcinoma of the colon and rectum in patients less than 40 years of age, From 1962 to 1988. 50 of 801 patients with adenocarcinoma of the colon and rectum treated at the National Naval Medical Center were less than 40 years old. Symptoms were present in 47 of the younger patients at presentation. The mean duration of time from the onset of symptoms to diagnosis in this group was 4.9 months. Risk factors for carcinoma of the colon and rectum were identified in 14 of 50 patients less than 40 years old. A significantly greater proportion of patients less than 40 years old had Stage C disease compared with the older group of patients (42 versus 22 per cent. p = 0.014). Stage B disease was more common in patients more than 40 years of age (44.8 versus 26.0 per cent. p = 0.014). The proportion of patients with Stages A and D disease was similar in both age groups. The cumulative survival rate in this group at five and ten years was 43 and 34 per cent. respectively. The five year survival rate in patients less than 40 years old with Stage B disease was 76 per cent and with Stage C disease. 37 per cent. All young patients with Stage D disease were dead at 28 months. Synchronous and metachronous carcinomas of the colon and rectum were uncommon in patients less than 40 years old. Patients less than 40 years of age with carcinoma of the colon and rectum are usually symptomatic and have advanced disease at the time of presentation. Survival time for these patients for each stage of disease is similar to the over-all population of patients with carcinoma of the colon and rectum.
Prevalence of hemodynamically significant stenosis of the carotid artery in an asymptomatic veteran population, The results of previous studies have suggested that significant stenosis of the carotid artery occurs in less than 6 per cent of asymptomatic patients. However. some populations studied were not representative of those seen by most vascular surgeons. Accordingly. we examined two cohorts of patients at the Veterans Administration Medical Center using Duplex scanning. There were 153 volunteers in group 1. all more than 50 years of age. who were being treated at our outpatient department for nonvascular problems. There were 116 patients of similar age in group 2 but who were known to have significant arterial occlusive disease of the lower extremity. The majority of patients were men with a mean age of 64.4 years. Risk factors in the total population included hypertension. diabetes mellitus. coronary arterial disease. peripheral vascular disease and smoking. Over-all. significant (greater than 50 per cent diameter) stenosis of the carotid artery was discovered in 25 of 269 patients. The prevalence for those in group 1 was 6.5 per cent versus 12.9 per cent for those in group 2 (p = 0.058). The prevalence in patients with cardiac disease was 15.2 per cent compared with 6.8 per cent in those without cardiac disease (p = 0.032). Smoking was associated with a 10.6 per cent rate of significant disease compared with a 2.3 per cent rate in nonsmokers (p = 0.065). Hypertension and diabetes were not significant risk factors. Significant stenosis of the carotid artery was found in seven of 40 patients in whom coronary arterial disease. peripheral vascular disease and smoking were all present.
The oncologic risks of skin preservation at mastectomy when combined with immediate reconstruction of the breast, Most oncologic surgeons agree that removal of the nipple. the areola and any recent scar at the site of the biopsy is necessary during a mastectomy for treatment of carcinoma of the breast. There is less agreement about what should be done with the remaining uninvolved mammary skin. Its preservation facilitates the performance of immediate reconstruction of the breast and can lead to improved aesthetic results. but many oncologists fear that this practice could lead to an increased incidence of local tumor recurrence. To determine if that fear was justified. 87 patients who had undergone unilateral or bilateral mastectomy with immediate reconstruction for treatment of early carcinoma of the breast were studied. Preservation of uninvolved skin was used in all instances. All patients had a documented follow-up study of 12 months or more; the average follow-up time was 23.1 months. One peripheral local recurrence was observed. This 1.2 per cent rate of early local recurrence is lower than that reported from several series using modified radical mastectomy without skin preservation or immediate reconstruction. and suggests that skin preservation does not confer additional risks of local recurrence of carcinoma of the breast in properly selected patients.
Cholecystokinin enhanced hepatobiliary scanning with ejection fraction calculation as an indicator of disease of the gallbladder, Chronic acalculous cholecystitis represents 5 to 20 per cent of electively treated diseases of the gallbladder. A 70 per cent success rate in relieving these patients of chronic pain was reported when surgical treatment was recommended based on symptoms alone. The cholecystokinin ejection fraction. which is a quantitative measure of emptying of the gallbladder. was 95 per cent accurate in predicting which patients would be relieved of symptoms by surgical treatment. In this study. we report our consecutive experience during a 20 month period with 83 patients.
Gastric lymphoma, From 1976 to 1988. 35 patients were treated for Stage IE and Stage IIE primary gastric lymphoma (non-Hodgkin's). Pain and weight loss were the predominant symptoms. physical findings were usually absent and 20 per cent of the patients were anemic. The results of gastrointestinal contrast studies suggested a malignant condition in 75 per cent. but findings were not specific for lymphoma. Endoscopic findings suggested a malignant process in 85 per cent. but the yield for biopsy was only 60 per cent. Of 28 patients undergoing operative exploration. 75 per cent were resectable. Nine patients received postresectional adjuvant therapy. Five had chemotherapy; three. radiotherapy. and one patient. a combination of the two. Primary nonsurgical treatment consisted of chemotherapy in 11. radiotherapy in two and combined therapy in one instance. Three of five recurrences were successfully treated. The five year survival rate was 65 per cent without significant differences between surgical and nonsurgical regimens. Those with tumors smaller than 7 centimeters had a five year survival rate of 100 per cent versus 50 per cent for larger neoplasms. Patients more than 60 years of age appeared to have a more favorable course after surgical therapy compared with those who had nonsurgical treatment. We concluded that endoscopy is a most useful. although limited diagnostic study and since no treatment program is obviously superior. the choice of therapy can be individualized accordingly.
Strategies for trauma resuscitation, Victims of penetrating trauma often arrive at a trauma center within minutes of sustaining their injury but nevertheless are in a state of deep circulatory shock. Such patients require extensive resuscitative efforts; in particular. some benefit from rapid. massive normothermic fluid resuscitation. During an initial one year period. 153 of 730 patients required immediate operation and. of these. 33 required rapid infusion defined as greater than 5 liters per hour during the first hour. The over-all survival rate of those operated upon was 79 per cent. Encouraged by these data. the rapid infusor (Level 1 H-500) (Level 1. Technologies. Inc.) was modified to further increase normothermic fluid delivery to 500 milliliters per minute. Eleven of the subsequent 205 patients required rapid infusion. There was a statistically significant improvement in clinical flow rates. decrement in resuscitation times and unexpected survival. In particular. the latter group (nine survivors) included four who were clinically dead in the field or on arrival at the trauma center. or both. Rapid infusion of normothermic fluids may be of benefit not only in penetrating trauma but also more generally in the management of massive hemorrhage.
The syndrome of bilateral hemispheric border zone ischemia, Symptoms compatible with vertebrobasilar ischemia have been reported in patients with unilateral or bilateral carotid occlusive disease. Intracranial steal phenomena have been proposed to explain the symptoms. In a review of 54 patients with angiographically documented severe bilateral carotid stenosis (less than or equal to 2 mm residual lumen) or occlusion. eight had symptoms suggesting vertebrobasilar insufficiency. Five patients were identified retrospectively. and the other three were evaluated prospectively. Symptoms included various combinations of hemodynamically mediated. transient bilateral motor. sensory. or visual impairment. Dysarthria. dysphagia. and diplopia were generally absent. Each patient also described additional symptoms compatible with transient hemispheric or retinal ischemia. The anatomic regions subserving the bilateral vertebrobasilar-like symptoms could be correlated with angiographically estimated arterial border zones in both hemispheres and may thus represent bilateral hemispheric border zone ischemia rather than brain stem ischemia. An intracranial steal need not be invoked.
Cerebral blood flow and oxygen metabolism in patients with vascular dementia of the Binswanger type, We performed clinical and neuroradiologic studies. including positron emission tomography. in five patients with vascular dementia of the Binswanger type. The clinical features of these cases consisted of slowly progressive dementia. together with vascular risk factors such as hypertension and often a history of minor stroke. and characteristic white matter lesions on brain computed tomograms or magnetic resonance images. Digital subtraction angiography of the cervical and intracranial arteries demonstrated no occlusive lesion in any patient. Both cerebral blood flow and the cerebral metabolic rate for oxygen were markedly reduced in the white matter (54-77% of control values). and both were decreased in the parietal (73% of control). frontal (74-80%). and temporal (74-83%) cortices. where no abnormalities were detected by brain computed tomography or magnetic resonance imaging. We conclude that vascular dementia of the Binswanger type may be caused by disconnection between the cerebral cortex and subcortical structures due to ischemic damage in the white matter.
Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion, Using in vivo brain microdialysis. we studied amino acid release in the striatum and cortex of eight rats following permanent middle cerebral artery occlusion. We then processed all brains for histopathologic assessment of the volume of ischemic damage 4 hours after occlusion. Ischemic damage was varied by occlusion of the middle cerebral artery at a point either proximal (n = 4) or distal (n = 4) to the lenticulostriate vessels. Proximal occlusion elevated the dialysate contents of all amino acids. The largest increases occurred for the potentially neurotoxic amino acids aspartate and glutamate and for taurine (800-2.800% of basal efflux). We observed smaller increases for the "metabolic" amino acids (280-580% of basal efflux). Distal occlusion did not affect amino acid efflux in the striatum. and release in the cortex was significantly lower than that following proximal occlusion. We compared release data with acute histopathologic outcome. Proximal occlusion resulted in a large volume of ischemic damage in the cortex and striatum (25-48% of hemispheric volume). A smaller volume of ischemic damage was noted following distal occlusion (0-21% of hemispheric volume). The volume of ischemic damage and the amount of amino acid release were significantly correlated (p less than 0.05).
Fetal hemoglobin, sickling, and sickle cell disease, Increased numbers of F cells and large amounts of Hb F/F cell appear to produce clinical benefit in rare variants of sickle cell disease and probably in more commonly encountered patients. Fetal hemoglobin interferes with polymerization of Hb S in vitro. but laboratory studies carried out with homogeneous hemoglobin solutions are inadequate models of events in vivo. because RBCs are heterogeneous in their MCHC and Hb F content. Studies of hemoglobin switching in sheep. in tissue culture. and then in baboons led to use of 5-azacytidine for induction of increased Hb F synthesis in SS patients. Drug trials were successful but the theory that led to them was not. An alternate theory. not without flaws. led to the use of hydroxyurea. Chronic administration of the drug can lead to very impressive increases in Hb F synthesis and apparent clinical benefit. It is not clear that such clinical benefit is real rather than a placebo effect. Nor is it entirely clear that all of the effect of hydroxyurea can be related to increased production of F cells and increased F/F cell. Controlled clinical trials and studies of the properties of RBCs from treated patients may answer those questions. It is also likely that they will not only raise still other questions but probably show that our current understanding of the biology and treatment of sickle cell disease is far from complete.
Vitamin E and neurologic deficits, Over the past decade it has become apparent that vitamin E is an essential nutrient for maintaining the structural and functional integrity of the developing human nervous system. skeletal muscle. and the retina. The clinical and histologic resemblance of the human neuromuscular disorder associated with chronic fat and vitamin E malabsorption to that observed in experimental vitamin E-deficient animal models is striking. Because of chronic malabsorption of vitamin E. children with CF. chronic cholestasis. abetalipoproteinemia. and short bowel syndrome are at risk for the development of neurologic deficits caused by vitamin E deficiency. Correction of the vitamin E deficiency state prevents. reverses. or. at least. stabilizes the neurologic dysfunction in susceptible individuals. Advances in stable isotope technology permit study of the hepatic discrimination among the various stereoisomers and forms of vitamin E. Investigations into the cause of the primary form of vitamin E deficiency. the isolated vitamin E deficiency syndrome. promise to delineate the normal physiologic processes involved in absorption. transport. and tissue delivery of vitamin E. Studies in progress are addressing the optimal route and form of vitamin E therapy to be used in each predisposing condition. One major task remaining is to better define the mechanism by which vitamin E deficiency leads to neurologic injury.
Perinatal grief and mourning, The grief and mourning that parents experience following a perinatal loss is as devastating as the loss of an older loved one. The pattern of mourning can be anticipated and interventions can be implemented. With proper help. the parents can pass through this catastrophic time in their lives with a minimum of scars. If the physician stops. reaches out. listens. and supports the parents. he or she can have a dramatic effect on the lives of these parents. In the same manner in which we started this paper. we close with a quotation from another parent who suffered a loss: Daughters may die. But why? For even daughters can't live with half a heart. Three days isn't much a life. But long enough to remember thin blue lips. uneven gasps in incubators. Racking breaths that cause a pain to those who watched. Long enough to remember I never held her Or felt her softness Or counted her toes. I didn't even know the color of her eyes. Dead paled hands not quite covered by the gown she Was to go home in. Moist earth smell. One small casket. And the tears. You see. I hold in my hand but souvenirs of an occasion. A sheet of paper filled with statistics. A certificate with smudged footprints. A tiny bracelet engraved "Girl. Smith." You say that you are sorry That you know how I feel. But you can't know because I don't feel. Not yet.
Angiographic contrast media interference with laser-induced fluorescence excitation and detection in atherosclerotic human coronary arteries, Laser-induced fluorescence has been used in conjunction with angiography for laser angioplasty guidance. The effect of radiopaque contrast media on the excitation and detection of arterial fluorescence has not been previously reported. Accordingly. fluorescence emission spectra from human coronary artery necropsy specimens (n = 7) during excitation with pulsed excimer laser excitation (308 nm) was examined before and after the addition of three different contrast media. sodium and meglumine diatrizoate. sodium and meglumine ioxaglate. and iopamidol. A decrease in overall fluorescence intensity was observed at all wavelengths for each contrast agent examined. The decrease in intensity of fluorescence emission was more marked at wavelengths less than 410 nm than at wavelengths above 425 nm. Similar effects were observed for contrast media diluted with whole blood. Absorption spectra for all three contrast media demonstrated absorption in the ultraviolet centered around 240 nm. We conclude that preferential absorption in the ultraviolet range by contrast media interferes with the excitation and detection of laser-induced fluorescence; use of visible light excitation may obviate interference with laser-induced fluorescence analysis of plaque.
Normalization of Doppler indices of diastolic dysfunction during pacing is a sign of ischemic mitral regurgitation, Twenty-three patients with angina who were undergoing diagnostic cardiac catheterization underwent cardiac pacing with simultaneous hemodynamic and Doppler echocardiographic evaluation to assess the effects of pacing-induced ischemic on mitral valve velocity. Seventeen patients had significant coronary artery disease. and six patients had normal coronary arteries. Doppler and hemodynamic measurements were performed at rest and immediately after pacing was discontinued to 91% +/- 7% of maximal predicted heart rate. Seven patients experienced new or significant increases in severity of mitral regurgitation after pacing as revealed by Doppler examination. This group had a significant increase (p = 0.007) in early but not in late peak filling velocities immediately after pacing was discontinued. with a resultant decrease in late to early ratios. which decreased from 1.01% +/- 0.12 to 0.70% +/- 0.19 (p = 0.006). Left ventricular end-diastolic pressure increased significantly from 16.7% +/- 6.8 mm Hg to 29.4% +/- 5.3 mm Hg after cardiac pacing (p less than 0.001). Patients with coronary disease who did not develop mitral regurgitation also had significant increases in left ventricular end-diastolic pressure from 18.7% +/- 5.8 mm Hg to 24.3% +/- 8.6 mm Hg (p less than 0.05). There were no changes in late or early wave amplitude. late to early ratio. or other Doppler measurements in any of the other groups. We conclude that mitral regurgitation caused by pacing-induced myocardial ischemia normalizes Doppler indices of mitral inflow. which in turn. may mask persistent or worsened left ventricular diastolic dysfunction.
Pulse rate, coronary heart disease, and death: the NHANES I Epidemiologic Follow-up Study, To determine whether associations of elevated resting pulse rate with CHD incidence or death in white men are independent of other risk factors and whether such associations exist for women and blacks. data were examined from the NHANES I Epidemiologic Follow-up Study. Over a follow-up period of 6 to 13 years. elevated RR for CHD incidence were found for older white men with baseline pulse greater than 84 beats/min compared with less than 74 beats/min after controlling multiple risk factors (RR = 1.37. 95% CL 1.02. 1.84). Risks of death from all causes. cardiovascular diseases. and noncardiovascular diseases were also elevated for white men with elevated pulse rate independent of other risk factors. CHD incidence was increased in white women with elevated pulse rate. Risks of death from all causes. cardiovascular diseases. and noncardiovascular diseases. were also elevated for white men with elevated pulse rate independent of other risk factors. CHD incidence was increased in white women with elevated pulse rate. Risk of death from all causes and cardiovascular diseases was elevated in black men and women with elevated pulse rate. Risk of death from noncardiovascular disease was elevated in black men with elevated pulse rate. The association with cardiovascular death was particularly striking in black women. even after adjusting for baseline risk factors (RR 3.03. 95% CL 1.46. 6.28). Further studies are needed to assess associations of pulse rate with CHD in blacks and to elucidate mechanisms in all groups.
The utility of echocardiography in the diagnostic strategy of postinfarction ventricular septal rupture: a comparison of two-dimensional echocardiography versus Doppler color flow imaging, The diagnostic accuracy of Doppler color flow imaging in the diagnosis of postinfarction ventricular septal defects has not been established. In this study. 43 patients with unexplained hypotension or a new murmur in the periinfarct period were evaluated with conventional two-dimensional echocardiography and Doppler color flow imaging. The presence of a ventricular septal defect was confirmed by oximetry. ventriculography. operative repair. or autopsy in each case. Both two-dimensional and Doppler color flow imaging were 100% specific in excluding a ventricular septal defect. Doppler color flow imaging correctly identified the 12 confirmed ventricular septal defects in this study (100% sensitivity). whereas any combination of two-dimensional criteria only correctly identified seven (58% sensitive) (p less than 0.05). Doppler color flow imaging is superior to conventional two-dimensional imaging in the diagnosis of a postinfarction ventricular septal defect. In addition. Doppler color flow imaging localized the septal defect. and thus guided therapy and technique for repair. Carefully performed Doppler color flow examination can exclude or result in the rapid diagnosis of a ventricular septal defect. which eliminates the need for further time-consuming confirmatory testing.
Dipyridamole perfusion scintigraphy: the experience with its application in one hundred seventy patients with known or suspected unstable angina, We evaluated the safety. accuracy. and potential clinical utility of intravenous dipyridamole perfusion scintigraphy with thallium-201 in 170 patients. 78 with suspected and 92 with known unstable angina. All had coronary angiography. Noncardiac side effects (26%). induced chest discomfort (44%). and ST segment changes (12%) were similar in the two groups. No significant arrhythmias occurred. Two patients had prolonged chest pain. both with extensive reversible image abnormalities and associated creatinine kinase-MB release. Both had elective bypass surgery. Twenty-eight patients had normal coronary arteries. and 35 had single-vessel disease. Scintigraphic per patient sensitivity and specificity were 91% and 79% with a per vessel sensitivity of 74% and a per vessel specificity of 78% without between-group differences. During a brief follow-up period. 62 patients with image abnormalities had coronary revascularization. and there were seven deaths without intergroup differences. In a similar patient group that did not have angiography. scintigraphic defects were less frequent and less extensive. revascularization was not performed. and subsequent deaths occurred less often. Dipyridamole perfusion scintigraphy is an accurate alternative to exercise testing in the evaluation of patients with unstable angina pectoris. Although not without risk. the method appears relatively safe and should be considered as a guide to diagnosis. and probably to prognosis and management.
Myocardial metabolic and hemodynamic effects of a sustained intravenous infusion of nifedipine with and without metoprolol in patients with unstable angina, We tested the usefulness of a sustained intravenous infusion of nifedipine and a combination of nifedipine and metoprolol in the early management of 14 patients with unstable angina pectoris. After a 24-hour run-in period. nifedipine was titrated in a stepwise fashion (mean dose 27 +/- 7 micrograms/min). After nifedipine treatment coronary blood flow increased from 150 +/- 66 to 183 +/- 74 ml/min (p less than 0.05). whereas double product. myocardial oxygen consumption. and both arterial and coronary sinus (nor)epinephrine levels were unchanged. Myocardial lactate uptake increased from 3.4 +/- 26.1 to 31.3 +/- 26.6 mumol/min (p less than 0.005) and free fatty acid uptake from 7.2 +/- 22.1 to 34.5 +/- 33.7 mumol/min (p less than 0.05). A small nonsignificant improvement in amino acid metabolism was observed. Metoprolol was added in seven patients and led to a decrease in double product (-2.2 +/- 1.6 x 10(3); p less than 0.01) and myocardial oxygen consumption (-3.2 +/- 3.8 ml/min; p less than 0.05). The lactate uptake/oxygen uptake ratio increased by 18% after metoprolol (p = NS). The number of episodes of chest pain decreased from 2.4 +/- 1.1/24 hours to 0.1 +/- 0.2 in the nifedipine group and from 2.9 +/- 1.1/24 hours to 0.3 +/- 0.5 in the nifedipine plus metoprolol group (both p less than 0.01). We conclude that in the acute phase of unstable angina. intravenous nifedipine can be carefully titrated to improve coronary blood flow and oxidative metabolism. The addition of metoprolol is also associated with a reduction in myocardial oxygen demand. This treatment results in significant hemodynamic stability.
Study on the genesis of the double potential recorded in the high right atrium in atrial flutter and its role in the reentry circuit of atrial flutter, To investigate the genesis of the double potential (DP). which is two separate waves. and its role in the reentry circuit of atrial flutter (AF). we performed overdrive pacing (ODP) from the high right atrium (HRA) in six cases of spontaneous AF in which the DP was recorded in the HRA. In four of the six cases. when the DP was arbitrarily designated D1 and D2. D1 and D2 showed progressive fusion during ODP. In addition. the D1 return cycle. immediately after the termination of ODP. corresponded to the AF cycle. and the D2 return cycle corresponded to the pacing cycle. This may indicate that the DP is caused by the collision of two directional waves. Furthermore. it is suggested that the HRA plays an important role in preventing a possible shortcutting of reentry waves and in stabilizing the reentry circuit of AF.
Fragmented atrial activity in patients with transient atrial fibrillation, Prediction of atrial fibrillation (AF) is very important in patients with Wolff-Parkinson-White syndrome or in the selection of pacemaker therapeutic modality. In 25 patients with transient AF. the response of the atrial activity width to extrastimuli was examined in comparison with 25 patients without AF to see if the results could be used as an index of subsequent occurrence of AF. Programmed electrical stimulation using eight basic stimuli followed by single or double extrastimuli (P1P2 or P1P2P3) were delivered to the high right atrium. and the atrial activities were examined. The prolongation of the atrial activity caused by extrastimuli was termed fragmentation (Frg). and it was defined as the prolongation of more than 150% of the basic stimuli. Frg zone was defined as the zone of coupling intervals of the extrastimuli (P1P2 or P2P3) that caused Frg. and delta max Frg was defined as the difference between the widest Frg and the atrial wave width during basic stimuli. Fragmentation was reproducibly induced by extrastimuli. and there was an inverse relationship between Frg duration and the coupling interval of the extrastimuli (P1P2 or P2P3). Frg zone and delta max Frg were wider and longer in patients with transient AF in comparison with the control group for both single and double extrastimuli (p less than 0.001). AF inducibility using double extrastimuli was significantly high in patients with AF.
Management of multiple risk factors for coronary heart disease in patients with hypertension, Hypertension intervention trials. which have involved mainly the use of diuretics and beta-blockers. have demonstrated a disappointing benefit in terms of reduction of coronary heart disease (CHD). Rather than suggesting that elevated blood pressure and CHD are not causally related. these data suggest that the antihypertensive agents used were not optimal for the management of hypertension and a review of the currently recommended therapies is needed. Major risk factors for CHD. which include increased blood pressure. elevated serum cholesterol levels. and smoking. are highly prevalent in the general population and appear to cluster in patients with hypertension. Therefore the treatment of hypertension demands a multifactorial approach. one that takes into consideration all the risk factors for CHD. Diuretics and beta-blockers adversely affect the serum lipid profile. and this could negate some of the CHD benefit afforded by blood pressure reduction.
Effects of doxazosin on serum lipids: a review of the clinical data and molecular basis for altered lipid metabolism, The goal of antihypertensive treatment must be not only the reduction of high blood pressure. but also the effective management of elevated cholesterol levels and other risk factors of coronary heart disease (CHD). In controlled clinical trials. doxazosin has been shown to have antihypertensive efficacy comparable with other classes of antihypertensive agents and to lower the levels of total cholesterol. low-density lipoprotein (LDL) cholesterol. and triglycerides while increasing the levels of high-density lipoprotein cholesterol. Doxazosin appears to inhibit the development of CHD on two fronts. First. doxazosin binds to the alpha 1-adrenoreceptor and inhibits the receptor-mediated responses to epinephrine and norepinephrine. Second. doxazosin has direct and indirect effects on lipid metabolism by increasing LDL receptor activity. decreasing intracellular LDL synthesis. reducing the synthesis and secretion of very low-density lipoprotein cholesterol. and stimulating lipoprotein lipase activity. Doxazosin may also inhibit platelet aggregation. Long-term studies will determine how these actions translate into reductions in the morbidity and mortality rates of CHD. First-year results from the Treatment of Mild Hypertension Study (TOMHS) have demonstrated expected reductions in blood pressure for all antihypertensive agents studied. The lipid changes have varied with the type of antihypertensive treatment and have been favorable for doxazosin.
Preliminary results of the Norwegian doxazosin postmarketing surveillance study: a twelve-week experience, The study was designed to investigate the safety and efficacy of doxazosin in the control of blood pressure in general medical practice; the results presented concern the first 748 patients evaluated over a 12-week period. Blood pressure was significantly reduced after treatment with doxazosin (-13/-9 mm Hg). and heart rate was not significantly altered. In addition. doxazosin significantly reduced total cholesterol levels (-6.7%). reduced triglyceride levels (-19.8%). increased high-density lipoprotein cholesterol levels (+2.5%). and the high-density lipoprotein:total cholesterol ratio (+9.7%). The calculated risk of coronary heart disease was reduced by 20.5% over a 12-week period. Thirty-five percent of patients reported at least one side effect. and the number of patients experiencing severe adverse reactions was small. Twenty patients (2.7%) discontinued treatment because of adverse events. and 2.7% had the dose of doxazosin reduced.
Doxazosin: a study in a cohort of patients with hypertension in general practice--an interim report, The objective of this study was to assess the safety and efficacy of doxazosin in a substantial cohort of hypertensive patients drawn from general practice. A total of 4027 patients entered the study. 1472 of whom (36.6%) were untreated hypertensive patients. Patients were not advised to change diet. smoking habit. or life-style during the study. Twenty-one percent were cigarette smokers. and concurrent diabetes was present in 2.3%. Baseline blood cholesterol exceeded 200 mg/dl (5.2 mmol/L) in 90% and 250 mg/dl (6.5 mmol/L) in 56% of patients. The mean decrease in blood pressure produced by doxazosin was 22/15 mm Hg after 10 weeks of therapy; there was a mean decrease in heart rate of 1 beat/min. The mean maintenance dose for all patients was 3.1 mg/day. Side effects considered related or possibly related to treatment were reported in 705 patients. Treatment was discontinued in 233 patients (5.8%) because of adverse events related or possibly related to treatment with doxazosin. Doxazosin produced a significant (p less than 0.001) decrease in total cholesterol. low-density lipoprotein cholesterol. and triglyceride levels and a significant increase in high-density lipoprotein cholesterol and the ratio of high-density lipoprotein:total cholesterol. The potential reduction in 10-year coronary heart disease risk (according to the Framingham equation) was calculated to be 20.4%.
An open, noncomparative study of doxazosin in essential hypertension: experience in general practice in The Netherlands, The antihypertensive efficacy. safety. and lipid effects of doxazosin. a selective alpha 1-inhibitor. were assessed in a general practice setting. Three hundred twenty-six patients were entered into the study. which involved three phases: (1) a 2-week baseline period. (2) an 8-week period in which patients received 1 to 8 mg of doxazosin once daily. and (3) a 4-week maintenance period. After 12 weeks. 78.8% of efficacy-evaluable patients were considered therapy successes (sitting diastolic blood pressure either less than or equal to 90 mm Hg with greater than or equal to 5 mm Hg reduction from baseline or greater than or equal to 10 mm Hg reduction from baseline). The mean daily dose in patients considered a therapy success was 2.8 mg. By the final visit. sitting systolic/diastolic blood pressures of these patients were reduced by 16.4/13.5 mm Hg from a mean baseline of 170/106 mm Hg. The investigators' global assessment of efficacy of once-daily doxazosin therapy was excellent or good for 70% of patients. Of the 326 patients. 30.7% reported a total of 160 side effects; 78% of the side effects were mild or moderate in severity. and 24 patients (7.4%) discontinued treatment because of adverse experiences. The investigators' global assessment of toleration was excellent or good for 87% of patients. Doxazosin produced a significant decrease in total cholesterol (p = 0.02) and triglyceride (p less than 0.001) levels. From baseline to final visit there was also a highly significant reduction of 17% (p less than 0.001) in calculated risk score for coronary heart disease on the basis of the Framingham Heart Study risk equation.
Doxazosin and atenolol as monotherapy in mild and moderate hypertension: a randomized, parallel study with a three-year follow-up, The efficacy and safety of doxazosin (n = 83) and atenolol (n = 81) have been compared during a 3-year period. Doxazosin (mean dose at 3 years. 5.2 mg/day) and atenolol (mean dose. 66.4 mg/day) produced a sustained and overall similar reduction in blood pressure. with no evidence of tolerance. Doxazosin decreased mean blood pressure from 158/104 mm Hg to 146/90 mm Hg; with atenolol the decrease was from 160/103 mm Hg to 144/88 mm Hg. Whereas the reduction in blood pressure with atenolol was paralleled by a significant (p less than 0.05) decrease in heart rate (from a mean of 74 to 60 beats/min). doxazosin produced no clinically meaningful changes in heart rate. In contrast to atenolol. doxazosin reduced triglyceride levels by -5.9% (atenolol +22.5%). increased high-density lipoprotein cholesterol levels by +3.7% (atenolol. -11.2%). and increased the high-density lipoprotein/total cholesterol ratio by +5.9% (atenolol. -10.3%); all of these values were significantly (p less than 0.001) different from those of atenolol-treated patients. Doxazosin also reduced the calculated low-density lipoprotein cholesterol levels by -3.3% (atenolol. unchanged). The adverse effect of atenolol on lipid levels apparently negated any beneficial effect of blood pressure reduction. because the calculated coronary heart disease (CHD) risk actually increased significantly. In contrast. the reduction in calculated CHD risk in the doxazosin group was statistically significant at all points during the study. The safety profile of the drugs was similar. With the added potential of the reduction in the calculated risk of CHD among hypertensive patients.doxazosin represents an appropriate first-line drug for the treatment of essential hypertension.
Cardiovascular disease risk profiles, This article presents prediction equations for several cardiovascular disease endpoints. which are based on measurements of several known risk factors. Subjects (n = 5573) were original and offspring subjects in the Framingham Heart Study. aged 30 to 74 years. and initially free of cardiovascular disease. Equations to predict risk for the following were developed: myocardial infarction. coronary heart disease (CHD). death from CHD. stroke. cardiovascular disease. and death from cardiovascular disease. The equations demonstrated the potential importance of controlling multiple risk factors (blood pressure. total cholesterol. high-density lipoprotein cholesterol. smoking. glucose intolerance. and left ventricular hypertrophy) as opposed to focusing on one single risk factor. The parametric model used was seen to have several advantages over existing standard regression models. Unlike logistic regression. it can provide predictions for different lengths of time. and probabilities can be expressed in a more straightforward way than the Cox proportional hazards model.
Double-blind comparison of doxazosin and enalapril in patients with mild or moderate essential hypertension, The antihypertensive efficacy and safety of doxazosin and enalapril were compared in the general practice setting (n = 54). Both agents produced comparable. statistically significant (p less than 0.05) reductions in mean blood pressure with no clinically relevant changes in heart rate. Side effects in the two groups were mild or moderate and disappeared or were tolerated with continued treatment. Doxazosin. in contrast to enalapril. produced a significant (p less than 0.05) reduction in the total serum cholesterol concentration. a reduction in the level of triglycerides. and a favorable increase in the high-density lipoprotein/total cholesterol ratio. The reduction in calculated coronary heart disease risk produced by doxazosin (-27.58%) was highly significant (p less than 0.0002) and greater than that produced by enalapril (-18.49% p less than 0.02).
A double-blind comparative study of doxazosin and prazosin when administered with beta-blockers or diuretics, The antihypertensive efficacy and safety of doxazosin (once daily) and prazosin (twice daily) were compared in patients with mild or moderate essential hypertension (diastolic blood pressure [DBP] 95 to 114 mm Hg) not adequately controlled by diuretics and beta-blockers. Doxazosin produced significantly greater mean reductions in standing (p = 0.01) and supine (p = 0.04) DBP than did prazosin; there were no significant between-group differences in either mean systolic blood pressure or heart rate. The overall mean daily doses for efficacy-evaluable patients were 4.7 mg of doxazosin and 6.7 mg of prazosin. Sixteen patients (84.2%) treated with doxazosin and 13 patients (56.5%) treated with prazosin were considered therapeutic successes (decrease in standing DBP greater than or equal to 10 mm Hg or to less than or equal to 90 mm Hg with greater than or equal to 5 mm Hg reduction from baseline). Of the 19 efficacy-evaluable patients treated with doxazosin. 15 (78.9%) showed improvement in the severity category of hypertension; an improvement in severity was reported in 14 patients (60.9%) treated with prazosin. Doxazosin produced a more favorable effect on serum lipid levels than did prazosin. although no statistically significant within- or between-group differences were observed. Most side effects experienced with either doxazosin or prazosin were mild or moderate and were tolerated or disappeared with continued treatment. The overall evaluation of toleration was excellent or good for 18 (90%) doxazosin- and 21 (91%) prazosin-treated patients. Clinical efficacy was rated as excellent or good for 16 patients (80%) treated with doxazosin and 15 patients (68%) treated with prazosin.
The addition of doxazosin to the treatment regimen of patients with hypertension not adequately controlled by beta-blockers, When doxazosin was given to patients with hypertension not adequately controlled by beta-blockade. blood pressure was normalized in 94% of the 34 patients (blood pressure less than or equal to 140/85 mm Hg). This reduction in blood pressure was obtained with doxazosin in combination with metoprolol or oxprenolol at a mean final daily dose of 1.3 mg or pindolol or atenolol at 2.0 mg/day. Exercise-induced increase in systolic and diastolic blood pressure was also lower with combined beta-blocker and doxazosin therapy than with beta-blocker alone. After 12 weeks of treatment. the combination of doxazosin and beta-blocker significantly reduced total serum cholesterol and triglyceride levels. All side effects were mild and only one patient was withdrawn from therapy.
A double-blind comparative study of doxazosin and prazosin in the treatment of essential hypertension, Two hundred sixty-six patients took part in a multicenter comparative study of doxazosin and prazosin. Both drugs produced a significant reduction (p less than 0.001) in blood pressure and no increase in heart rate. Blood pressure was considered "markedly decreased" or "decreased" in 70.8% of patients treated with doxazosin and 70.0% of patients treated with prazosin. No statistically significant between-group differences in antihypertensive efficacy were observed. Both doxazosin and prazosin were well tolerated; seven patients (5.6%) in each group had the therapy withdrawn.
Clinical experience with doxazosin in general medical practice in New Zealand, This study investigated the safety and efficacy of doxazosin treatment in a large population of patients (n = 336) with essential hypertension and assessed the effect of doxazosin on the serum lipid profile and the calculated risk of developing coronary heart disease. Patients were assigned to two groups: those with a baseline diastolic blood pressure greater than or equal to 95 mm Hg (group 1) and those with a baseline diastolic blood pressure less than 95 mm Hg (group 2) that was controlled by previous antihypertensive therapy. Doxazosin treatment (monotherapy in 76.2% of patients) significantly (p less than 0.05) reduced the blood pressure of patients in group 1 (-23/-17 mm Hg) after 10 weeks and maintained the control of blood pressure for patients in group 2. Heart rate was essentially unchanged in both groups. Mean final daily doses of 3.6 and 3.2 mg were achieved in groups 1 and 2. respectively. Treatment with doxazosin improved the severity category of hypertension for 88.4% of patients in group 1; 87.3% of patients were considered a therapy success. Doxazosin had a favorable effect on the serum lipid profile in both groups of patients. The majority of lipid changes achieved statistical significance and resulted in a significant 27% decrease in the calculated risk of developing coronary heart disease. Doxazosin was well tolerated; only 24.1% of patients had side effects that were related or possibly related to treatment. In nine (2.7%) patients the dose of doxazosin was reduced and 26 (7.7%) patients withdrew from doxazosin therapy because of side effects.
Doxazosin in the treatment of essential hypertension in general medical practice in Latin America, This Latin American study assessed in the general practice setting the efficacy and tolerance of once-daily doxazosin in the treatment of mild or moderate essential hypertension (sitting diastolic blood pressure. 95 to 115 mm Hg). Patients (n = 220) were treated with doxazosin for 12 weeks as monotherapy or in combination with other antihypertensive agents. At the final visit. doxazosin produced a mean change in sitting systolic/diastolic blood pressure of -18.4/-14.4 mm Hg. at a mean daily dose of 4.3 mg. One hundred sixty-three (77.6%) of the 210 evaluable patients were considered a therapeutic success. Lipid analyses identified a statistically significant (p = 0.02) reduction in total serum cholesterol (4.85%) and an overall decrease in triglyceride levels (5.12%). According to the Framingham Heart Study equation. doxazosin produced a highly significant (p less than 0.001) 20% reduction in the calculated probability of developing coronary heart disease in 10 years. Of the 220 patients evaluated. 54 (24.5%) reported side effects that were considered related to treatment. Ten (4.5%) patients reported side effects unrelated to treatment and 37 (16.8%) reported events of unknown relationship. Most side effects were mild or moderate and were tolerated or disappeared with continued treatment. Nine patients (4.1%) were discontinued from therapy and in 13 (5.9%) the dose was reduced. The most prevalent side effects were headache and dizziness. The investigator's overall assessment of antihypertensive efficacy was excellent or good for 176 patients (80.4%); tolerance was considered excellent or good in 193 patients (88.5%).
A multicenter study of doxazosin in the treatment of essential hypertension in France, This study was designed to assess the efficacy and tolerance of doxazosin in patients with mild. moderate. or severe essential hypertension in a general practice setting. Ninety-six adults of a mean age of 55 1/2 years took part in the 14-week study. consisting of a placebo phase (2 weeks). a dose-adjustment phase with doxazosin (8 weeks). and a maintenance phase (4 weeks). Doxazosin. at a final mean daily dose of 3.4 mg. produced a significant (p less than 0.05) reduction in blood pressure at all points of measurement during the study. The mean change in sitting blood pressure at the end of treatment was -15.4/-15.8 mm Hg. Of the 85 patients who could be categorized as a success or failure. 78 (92%) were considered a therapeutic success; 78 (89%) of the 88 efficacy-evaluable patients demonstrated an improvement in the severity category of their hypertension. Treatment with doxazosin produced a reduction in serum cholesterol (-3.1%) and triglyceride (-3.8%) levels. although these changes did not attain statistical significance. The calculated probability of developing coronary heart disease in 10 years (according to the Framingham equation) was significantly (p less than 0.001) reduced by 22%. from 16.7 chances per 100 (baseline) to 14.3 chances per 100 (final visit). Twenty-six patients (27.1%) reported side effects that were possibly related to treatment. the most prevalent of which were vertigo (7.3%) and headache (6.3%). In four (4.2%) patients the dose of doxazosin was reduced and two (2.1%) were withdrawn prematurely. The investigator's assessments of tolerance was reduced and two (2.1%) were considered to be excellent or good in 85 (88%) patients.
Clinical experience with doxazosin in general medical practice in The Netherlands, This study was designed to investigate the efficacy and toleration of once-daily doxazosin in the treatment of essential hypertension (sitting diastolic blood pressure 95 to 115 mm Hg) in a general medical practice. Fifty-three patients with mild or moderate essential hypertension entered a study of 14 weeks' duration. This consisted of a baseline run-in period of 2 weeks. a dose-adjustment phase with doxazosin (8 weeks). and a maintenance phase of 4 weeks. Doxazosin was initiated at 1 mg/day. and every 2 weeks the dose was doubled unless blood pressure was normalized (sitting diastolic blood pressure less than or equal to 90 mm Hg with greater than or equal to 5 mm Hg reduction from baseline) or significant side effects emerged. The maximum daily dose administered was 8 mg. Doxazosin produced a significant (p less than 0.05) final mean change in sitting blood pressure of -17.4/-12.2 mm Hg at a final mean daily dose of 4.1 mg. Heart rate was not significantly altered. A nonsignificant decrease in total cholesterol concentration (-2.66%. p = 0.06) and triglycerides (-8.80%. p = 0.09) was also observed. The effect of doxazosin on blood pressure and serum cholesterol resulted in a significant (p less than 0.001) reduction of 19% in calculated risk of coronary heart disease. The investigators' assessment of patient toleration of doxazosin was excellent or good in 86.8% of patients.
A long-term study of doxazosin in the treatment of mild or moderate essential hypertension in general medical practice, This study assessed the long-term (54 weeks) antihypertensive efficacy and safety of doxazosin in the treatment of mild or moderate essential hypertension. defined as sitting and standing diastolic blood pressure of 95 to 114 mm Hg. Of the 153 patients who successfully completed an initial 14-week trial. 61 continued uninterrupted into a 40-week extension study. Optimal antihypertensive efficacy was achieved by week 12 and maintained in all patients for the duration of 1 year. The final mean sitting blood pressure was 148/84 mm Hg and was reduced from a mean baseline level of 173/102 mm Hg. Occasional decreases in heart rate were observed. but these were not considered to be clinically relevant (1 to 3 beats/min). The mean final dose of doxazosin for patients evaluable for efficacy was 2.4 mg/day; 91.7% of patients were taking less than or equal to 4 mg/day. No increase in daily maintenance dose was observed from the initial phase to the long-term extension study. After 1 year of treatment. 93.3% of patients were considered a therapeutic success (sitting diastolic blood pressure greater than or equal to 10 mm Hg reduction from baseline or less than or equal to 90 mm Hg with greater than or equal to 5 mm Hg reduction). In no patients was there a worsening in the severity category of the hypertension. Total serum cholesterol concentrations were reduced significantly (6.6% p = 0.03) at the end of week 14. Reductions in total serum cholesterol levels persisted throughout the extension study. with a final reduction of 5.4%.
Doxazosin in the treatment of mild or moderate essential hypertension: an echocardiographic study, Sixteen patients with mild or moderate essential hypertension received 1 to 8 mg/day of doxazosin (mean daily dose. 2.7 mg). Blood pressure reduction (supine and standing) was highly significant (p less than 0.001). and no significant changes in heart rate were observed. A significant reduction (p less than 0.01) in left ventricular mass was seen without a change in left ventricular systolic function. All side effects were mild. and only one patient withdrew from the study.
Echocardiographic assessment of doxazosin on left ventricular mass in patients with essential hypertension, A single daily dose of doxazosin taken during a 12-week period produced a significant reduction in blood pressure and left ventricular mass index in patients with mild or moderate hypertension. The systolic shortening coefficient was also increased and a trend in the improvement of ejection fraction. rate of circumferential fiber shortening. systolic contraction time. and preejective/ejective ratio was observed. No change in heart rate was recorded and no patients had side effects. The serum lipid profile was modified favorably. particularly with regard to the low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio. By producing a reduction in blood pressure and left ventricular mass while favorably modifying the serum lipid profile. doxazosin produced a beneficial change in the overall coronary heart disease risk profile.
Efficacy and safety of doxazosin in the treatment of patients with mild or moderate essential hypertension and elevated levels of cholesterol, In hypertensive patients. elevated serum cholesterol is a frequent and sinister additional coronary risk factor. Selective alpha 1-adrenoreceptor inhibitors appear to have the unique ability to control both risk factors. Forty-two patients. ages 42 to 65 years. including 21 men with sustained hypertension and elevated serum cholesterol levels. were included in a trial of monotherapy with doxazosin administered once daily (range. 1 to 16 mg). The influence of the drug on high blood pressure and elevated serum cholesterol was evaluated over a 28-week period. which consisted of a 4-week. single-blind placebo lead-in period. an open 10-week dose-adjustment period. and finally a 14-week maintenance period. Of the 39 efficacy-evaluable patients. 25 (64%) achieved adequate blood pressure control (diastolic blood pressure less than 90 mm Hg or a decrease in diastolic blood pressure greater than 10 mm Hg) at a mean daily dose of 2 mg of doxazosin. No persistent changes occurred in heart rate. In the 32 patients with evaluable lipid data. there were nonsignificant trends to an increase in high-density lipoprotein cholesterol and a reduction in total cholesterol. together with a significant reduction in serum triglyceride concentration. The combined changes in blood pressure and blood lipid levels resulted in a reduction of 36% in the calculated risk of coronary heart disease. Eleven patients reported side effects and four were withdrawn from therapy. These results confirm the antihypertensive and anticholesterolemic efficacy of once-daily treatment with doxazosin.
A multicenter study of doxazosin in the treatment of patients with mild or moderate essential hypertension and concomitant intermittent claudication, This study assessed the efficacy and safety of once-daily doxazosin in the treatment of patients (n = 19) with mild or moderate essential hypertension (sitting diastolic blood pressure [DBP] 95 to 114 mm Hg) and concomitant intermittent claudication (Doppler ankle/arm ratio of less than 0.80 and walking tolerance of less than 700 m on the treadmill). After 14 weeks of treatment with doxazosin. a significant (p less than 0.05) reduction in systolic blood pressure and DBP was observed. Mean blood pressures were reduced from 170/100 mm Hg at baseline to 161/93 mm Hg at the end of treatment. Minor changes in heart rate occurred. which with continued treatment were not statistically significant from baseline. In 12 of 16 (75.0%) efficacy-evaluable patients blood pressure was normalized (DBP to less than or equal to 90 mm Hg with an greater than or equal to 5 mm Hg reduction from baseline) with a mean daily dose of 7.6 mg/day. Doxazosin improved the hypertension severity category in 13 of 16 (81.3%) patients. The blood pressure ratios between both the thighs and arms and ankles and arms showed no statistically significant changes after treatment with doxazosin. Thigh blood flow at rest and the reactive hyperemia after 3 minutes of arterial occlusion did not change statistically. There was a tendency for pain-free distance to improve. Laboratory data were not significantly changed after treatment with doxazosin. Of the 19 patients studied. 5 reported mild or moderate side effects that were either tolerated or disappeared with continued treatment. No patient had therapy withdrawn and no patient required a dose reduction.
Doxazosin for the treatment of chronic congestive heart failure: results of a randomized double-blind and placebo-controlled study, In this study we evaluated the effects of once-daily administration of oral doxazosin in patients with chronic congestive heart failure (CHF). After a stabilization period of at least 2 weeks with digitalis and diuretics. 73 patients with chronic CHF were randomized to receive additionally either doxazosin or placebo in double-blind fashion. Patients underwent weekly dose adjustments with increasing doses of doxazosin (1. 2. 4. 8. and 16 mg daily) or placebo for 5 weeks. and 67 were evaluated for 12 additional weeks on maximally tolerated doses of blinded study drugs. Treatment groups were evaluated with respect to symptoms of heart failure. indexes of quality of life and left ventricular function. frequency and type of arrhythmia. adverse events. and mortality rates. Doxazosin (11.9 +/- 0.9 mg) given once daily produced a favorable trend in the investigators' and patients' assessments of symptomatic change. Doxazosin was associated with a significantly higher level of voluntary submaximal exercise and a favorable trend on left ventricular ejection fraction (increase of 9.8% of the baseline value vs 2.7% with placebo; p = NS). During the 3-month steady-dosing period. patients treated with doxazosin had a significant (p less than 0.004) reduction in ventricular arrhythmias and significantly fewer morbid and mortal cardiac events (including episodes of worsening heart failure severe enough to prompt discontinuation of the study. myocardial infarction. and death). Doxazosin was well tolerated. producing no major side effects and only a slightly higher frequency of minor treatment-related side effects compared with placebo (p = NS).
An evaluation of the efficacy and safety of doxazosin in hypertension associated with renal dysfunction. The Japanese Doxazosin Study Group, Doxazosin was administered once daily to 26 patients with renal hypertension or hypertension associated with renal dysfunction. Doxazosin produced a significant reduction in blood pressure that was stable throughout the treatment period. A significant change was not observed in heart rate. Blood pressure was "markedly decreased" or "decreased" in 80% of patients receiving doxazosin monotherapy. 78.6% of patients receiving combined therapy. and 79.2% of all the patients. The cumulative efficacy ratio according to final daily dose was 62.5% with 1 to 4 mg/day and 75.0% to 79.2% with 8 to 16 mg/day. Side effects were observed in three patients (12.0%). none of them severe. and all side effects disappeared with continued administration of doxazosin. Abnormal laboratory values in six items were observed in four patients. Serum creatinine and blood urea nitrogen values. which were regarded as renal function parameters. did not show significant changes. and no negative influence was observed with respect to doxazosin therapy. Overall clinical usefulness was considered "very useful" or "useful" in 80% of patients receiving doxazosin monotherapy. 78.6% of patients receiving combination therapy. and 79.2% of all patients. In conclusion. once-daily administration of doxazosin was considered a useful antihypertensive therapy for renal hypertension and hypertension associated with renal dysfunction.
The effect of doxazosin on platelet aggregation in normotensive subjects and patients with hypertension: an in vitro study, An in vitro assay was used to investigate the effects of doxazosin on the platelet aggregation induced by epinephrine. collagen. and adenosine diphosphate. Platelet-rich plasma from normotensive subjects and patients with hypertension was compared. Doxazosin produced a concentration-dependent inhibition of platelet aggregation in both groups. but significantly lower concentrations were required to inhibit platelet aggregation in plasma taken from patients with hypertension. The concentrations of doxazosin that inhibited platelet aggregation in vitro were similar to those that are used clinically to control blood pressure in patients with hypertension.
Evidence of an antiplatelet aggregation action of doxazosin in patients with hypertension: an ex vivo study, Eighteen patients with a mean age of 54.7 years were included in the study. All patients had a diagnosis of mild or moderate essential hypertension (sitting diastolic blood pressure of 96 to 114 mm Hg). The study design was single blind and in two phases: phase I. placebo (4 weeks). and phase II. the active treatment (8 weeks) with increasing doses. if needed. of doxazosin every 2 weeks (1. 2. 4. and 8 mg/day). Results show that doxazosin has an antihypertensive effect that is dose dependent. Systolic. diastolic. and mean blood pressures were decreased significantly. and no effect on heart rate was observed. Doxazosin significantly inhibited the platelet aggregation induced by epinephrine. adenosine diphosphate. and collagen in a dose-dependent manner. In addition. treatment with doxazosin lowered total serum cholesterol and triglyceride levels. without changing other standard biochemical parameters. This indicates that doxazosin could offer a distinct therapeutic advantage in the modulation of atherogenic and thromboembolic factors associated with coronary heart disease.
Role of oxygen free radicals in ischemic and reperfused myocardium, In recent years there has been considerable interest concerning the role of oxygen radicals in myocardial ischemia and reperfusion injury. The sequential univalent reduction of oxygen gives rise to very reactive intermediate products. Normally. the tissue concentration of these intermediate products of oxygen is limited and the aerobic myocardium survives because of the existence of a delicate balance between the generation of the various oxidants and the maintenance of the antioxidant defense mechanism. Several possible sources have been identified for the production of active oxygen species after ischemia and reperfusion and these sources may be mutually interactive. The ability of scavengers of oxygen free radicals. including vitamin E. to improve mechanical. mitochondrial. and sarcoplasmic reticulum function in animal models of ischemic-reperfusion injury also suggests that oxygen free radicals are partly responsible for myocardial damage in these models. although caution in the interpretation of these data is necessary.
Nutritional approach to cancer prevention with emphasis on vitamins, antioxidants, and carotenoids, The main human cancers are associated with complex life-style related causative. enhancing. and inhibiting factors. Tobacco smoking or chewing exposes humans to genotoxic carcinogens and to promoting substances. Likewise. Western dietary traditions involve certain carcinogens and promoters. whereas Oriental traditions implicate other carcinogens and promoters. Importantly. in virtually all situations regular intake of fruits and vegetables appreciably lowers the risk of cancer. This paper reviews the causes of the main human cancers and analyzes the mechanisms of the protective effects of fruits and vegetables. Prevention of human cancer requires the definition of optimal levels of recommended daily allowances of micronutrients.
Vegetables, fruits, and carotenoids and the risk of cancer, Low intake of vegetables. fruits. and carotenoids is consistently associated with increased risk of lung cancer in both prospective and retrospective studies. In addition. low levels of beta-carotene in serum or plasma are consistently associated with the subsequent development of lung cancer. The simplest explanation is that beta-carotene is protective. Since retinol (preformed vitamin A) is not related in a similar manner to lung cancer risk. beta-carotene appears to function through a mechanism that does not require conversion into vitamin A. However. the importance of other carotenoids and other constituents of vegetables and fruit has not been adequately explored. Both prospective and retrospective studies suggest that vegetable and fruit intake may reduce the risk of cancers of the mouth. pharynx. larynx. esophagus. stomach. colon. rectum. bladder. and cervix. But because of fewer studies and less consistency among studies. the epidemiologic evidence is at present less persuasive than for lung cancer.
Prediagnostic serum levels of carotenoids and vitamin E as related to subsequent cancer in Washington County, Maryland, In 1974 and 1975. serum specimens were collected from 25.802 volunteers in Washington County. Maryland. The serum was kept frozen at -73 degrees C until the time of assay. Prediagnostic samples from 436 cancer cases and 765 matched control subjects have been assayed. Nine sites have been studied: colon. rectum. pancreas. lung. melanoma. basal cell of skin. breast. prostate. and bladder. Serum beta-carotene levels showed a strong protective association with lung cancer. suggestive protective associations with melanoma and bladder cancer. and a suggestive but nonprotective association with rectal cancer. Serum vitamin E levels had a protective association with lung cancer; none of the other sites showed impressive associations. Low levels of serum lycopene were strongly associated with pancreatic cancer and less strongly associated with cancer of the bladder and rectum.
Vitamin C and cancer prevention: the epidemiologic evidence, Epidemiologic evidence of a protective effect of vitamin C for non-hormone-dependent cancers is strong. Of the 46 such studies in which a dietary vitamin C index was calculated. 33 found statistically significant protection. with high intake conferring approximately a twofold protective effect compared with low intake. Of 29 additional studies that assessed fruit intake. 21 found significant protection. For cancers of the esophagus. larynx. oral cavity. and pancreas. evidence for a protective effect of vitamin C or some component in fruit is strong and consistent. For cancers of the stomach. rectum. breast. and cervix there is also strong evidence. Several recent lung cancer studies found significant protective effects of vitamin C or of foods that are better sources of vitamin C than of beta-carotene. It is likely that ascorbic acid. carotenoids. and other factors in fruits and vegetables act jointly. Increased consumption of fruits and vegetables in general should be encouraged.
Vitamin E and cancer prevention, Some animal experiments and human studies suggest that vitamin E may protect against cancer. Serum alpha-tocopherol concentration was studied for its prediction of cancer in a cohort of 36.265 adults in Finland. During a mean follow-up of 8 y. cancer was diagnosed in 766 persons. The levels of serum alpha-tocopherol were determined from stored serum samples (at -20 degrees C) taken from these cancer patients and from 1419 matched control subjects. Individuals with a low level of alpha-tocopherol had about a 1.5-fold risk of cancer compared with those with a higher level. The strength of the association between serum alpha-tocopherol level and cancer risk varied for different cancer sites and was strongest for some gastrointestinal cancers and for the combined group of cancers unrelated to smoking. The association was strongest among nonsmoking men and among women with low levels of serum selenium. The findings agree with the hypothesis that dietary vitamin E in some circumstances protects against cancer.
Gastric juice ascorbic acid: effects of disease and implications for gastric carcinogenesis, N-nitroso compounds (NOC) are strongly implicated in the causation of cancer of the stomach and it has been suggested that ascorbic acid might reduce the risk of gastric cancer by preventing their formation within gastric juice. However. until recently there have been no measurements of gastric juice ascorbic acid concentrations. We have measured both gastric juice ascorbic and total vitamin C (ascorbic acid and dehydroascorbic acid). Our findings suggest that ascorbic acid is secreted into the gastric lumen so that gastric juice concentrations are often greater than those in plasma. Gastric pathology affects this secretion. leading to values in gastric juice that are lower than plasma levels. Stimulation of gastric secretion does not raise vitamin C concentrations in individuals whose values are initially low. The role of ascorbic acid in preventing formation of NOC and protecting against gastric cancer is discussed in the light of these findings.
Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology, Essential antioxidants were determined in plasma of middle-aged men representing 16 European study populations. which differed sixfold in age-specific mortality from ischemic heart disease (IHD). In 12 populations with "common" plasma cholesterol (5.7-6.2 mmol/L) and blood pressure. both classical risk factors lacked significant correlations to IHD mortality. whereas absolute levels of vitamin E (alpha-tocopherol) showed a strong inverse correlation (r2 = 0.63. P = 0.002). Evaluating all populations. cholesterol and diastolic blood pressure were moderately associated. but their correlation was inferior to that of vitamin E. In stepwise regression and multiple regression analysis. mortality was predictable to 62% by lipid-standardized vitamin E. to 79% by vitamin E and cholesterol. to 83% after inclusion of lipid-standardized vitamin A (retinol). and to 87% by all the above parameters plus blood pressure. Thus. in the present study the cross-cultural differences of IDH mortality are primarily attributable to plasma status of vitamin E. which might have protective functions.
Scientific basis for medical therapy of cataracts by antioxidants, Cataract is one of the major causes of age-dependent visual impairment and blindness. The geographic distribution of cataract is known to be associated with the intensity and duration of sunlight--especially of the ultraviolet frequency--at particular places. Exposure of animals and humans to oxygen has also been known to result in cataract formation. Studies described in this communication indicate that the ocular lens is physiologically damaged when exposed to an environment of active species of oxygen. commonly referred to as oxyradicals. Several photochemical and nonphotochemical models have been described. The results suggest that an intraocular generation of active oxygen may constitute a significant risk factor in the overall pathogenesis of senile cataracts. The cataractogenic effect of oxyradicals. however. can be thwarted by nutritional and metabolic antioxidants such as ascorbate. vitamin E. and pyruvate. These agents. therefore. may be useful for prophylaxis or therapy against cataracts.
A possible role for vitamins C and E in cataract prevention, Biochemical evidence suggests that oxidative stress caused by accumulation of free radicals is involved in the pathogenesis of senile cataracts. If so. appropriate amounts of the antioxidant vitamins C and E might be expected to prevent or retard the process. Such activity has been observed in several in vitro and in vivo studies of experimentally-induced cataracts. A recent epidemiologic study found that cataract patients tended to have lower serum levels of vitamins C. E. or carotenoids than did control subjects. The present investigation. which compared the self-reported consumption of supplementary vitamins by 175 cataract patients with that of 175 individually matched. cataract-free subjects. revealed that the latter group used significantly more supplementary vitamins C and E (P = 0.01 and 0.004. respectively). Because the results suggested a reduction in the risk of cataracts of at least 50%. a randomized. controlled trial of vitamin supplementation in cataract prevention may be warranted.
Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention, The relationship between antioxidant nutrient status and senile cataract was examined in 77 subjects with cataracts and 35 control subjects with clear lenses. Subjects with low (below the 20th percentile) and moderate (20th-80th percentiles) plasma nutrient and nutrient intake levels of vitamin C. vitamin E. and carotenoids were compared with subjects with high levels (above the 80th percentile). The odds ratio (OR) of cortical (CX) cataract among subjects with low plasma carotenoid levels was 7.2 (P less than 0.05) and the OR of posterior subcapsular (PSC) cataract for persons with low plasma vitamin C was 11.3 (P less than 0.10). Low vitamin C intake was associated with an increased risk of CX (OR = 3.7. P less than 0.10) and PSC (OR = 11.0. P less than 0.05) cataract. Subjects who consumed fewer than 3.5 servings of fruit or vegetables per day had an increased risk of both CX (OR = 5.0. P less than 0.05) and PSC cataract (OR = 12.9. P less than 0.01).
An open trial of high-dosage antioxidants in early Parkinson's disease, High dosages of tocopherol and ascorbate were administered to patients with early Parkinson's disease as a preliminary open-labeled trial for the eventual controlled double-blind study evaluating antioxidants as a test of the endogenous toxin hypothesis of the etiology of Parkinson's disease. The primary endpoint of the trial was the need to treat patients with levodopa. The time when levodopa became necessary in the treated patients was compared with another group of patients followed elsewhere and not taking antioxidants. The time when levodopa became necessary was extended by 2.5 y in the group taking antioxidants. The results of this pilot study suggest that the progression of Parkinson's disease may be slowed by the administration of these antioxidants. A large multicenter. controlled clinical trial currently underway in North America evaluating tocopherol and deprenyl has the potential to confirm these results.
Elevated plasma norepinephrine levels in infants of substance-abusing mothers, Infants of substance-abusing mothers (ISAM) have significant growth and neurodevelopmental abnormalities. The origin of these abnormalities is unknown. We postulated that ISAM have increased sympathetic nervous system tone and altered catecholamine levels. Therefore. we measured plasma norepinephrine. epinephrine. and dopamine levels and the number and receptor affinity of beta-adrenoreceptor binding sites on lymphocytes and alpha-adrenoreceptor binding sites on thrombocytes in 22 otherwise healthy ISAM (age. 2.1 +/- 0.5 months; mean +/- SD) and 15 healthy controls (age. 2.5 +/- 0.8 months). Norepinephrine levels in venous blood were 1.8-fold higher in ISAM than in control infants (6.30 +/- 3.85 nmol/L vs 3.55 +/- 2.45 nmol/L). There were no differences in plasma epinephrine or dopamine levels. There were no differences in the number of binding sites or receptor affinity for beta- and alpha-adrenoreceptors. We conclude that ISAM have elevated circulating norepinephrine levels compared with controls. We speculate that this is associated with increased sympathetic nervous system tone in ISAM and that the absence of adrenoreceptor down-regulation may create catecholamine suprasensitivity.
Four chromosomal breakpoints and four new probes mark out a 10-cM region encompassing the fragile-X locus (FRAXA), We report the validation and use of a cell hybrid panel which allowed us a rapid physical localization of new DNA probes in the vicinity of the fragile-X locus (FRAXA). Seven regions are defined by this panel. two of which lie between DXS369 and DXS296. until now the closest genetic markers that flank FRAXA. Of those two interesting regions. one is just distal to DXS369 and defined by probe 2-71 (DXS476). which is not polymorphic. The next one contains probes St677 (DXS463) and 2-34 (DXS477). which are within 130 kb and both detect TaqI RFLPs. The combined informativeness of these two probes is 30%. We cloned from an irradiation-reduced hybrid line another new polymorphic probe. Do33 (DXS465; 42% heterozygosity). This probe maps to the DXS296 region. proximal to a chromosomal breakpoint that corresponds to the Hunter syndrome locus (IDS). The physical order is thus Cen-DXS369-DXS476-(DXS463.DXS477)-(DXS296. DXS465)-IDS-DXS304-tel. We performed a linkage analysis for five of these markers in both the Centre d'Etude du Polymorphisme Humain families and in a large set of fragile-X families. This establishes that DXS296 is distal to FRAXA. The relative position of DXS463 and DXS477 with respect to FRAXA remains uncertain. but our results place them genetically halfway between DXS369 and DXS304. Thus the DXS463-DXS477 cluster defines presently either the closest proximal or the closest distal polymorphic marker with respect to FRAXA. The three new polymorphic probes described here have a combined heterozygosity of 60% and represent a major improvement for genetic analysis of fragile-X families. in particular for diagnostic applications.
Identification of a highly polymorphic microsatellite VNTR within the argininosuccinate synthetase locus: exclusion of the dystonia gene on 9q32-34 as the cause of dopa-responsive dystonia in a large kindred, Dopa-responsive dystonia is a clinical variant of idiopathic torsion dystonia that is distinguished from other forms of dystonia by the frequent occurrence of parkinsonism. diurnal fluctuation of symptoms. and its dramatic therapeutic response to L-dopa. Linkage of a gene causing classic dystonia in a large non-Jewish kindred (DYT1) and in a group of Ashkenazi Jewish families. to the gelsolin (GSN) and arginino-succinate synthetase (ASS) loci on chromosome 9q32-34. respectively. was recently determined. Here we report the discovery of a highly informative (GT)n repeat VNTR polymorphism within the ASS locus. Analysis of a large kindred with dopa-responsive dystonia. using this new polymorphism and conventional RFLPs for the 9q32-34 region. excludes loci in this region as a cause of this form of dystonia. This provides proof of genetic heterogeneity between classic idiopathic torsion dystonia and dopa-responsive dystonia.
Mothers' postcounseling beliefs about the causes of their children's genetic disorders, Mothers' postcounseling beliefs about the causes of their children's genetic disorders were investigated by means of a Q-sort consisting of 54 statements of possible beliefs that were sorted into nine groups of six items each on the basis of congruence with the subject's beliefs. The subjects were well educated. knowledgeable about the genetics of their child's disorder. and indicated a high level of belief in genetic causes. Differences in beliefs were associated with differences in genetic etiology. indicating that beliefs were affected by the specific information provided in genetic counseling. Factor analysis identified a cluster of Q-sort items characterized by a highly personal relationship to the cause of the disorder (e.g.. personal attributes. being selected and blessed. and God's actions). Subjects who rated these items low had a belief pattern. designated impersonal. that was consistent with a scientific worldview and that indicated psychological distancing from the cause of the child's disorder. Subjects who rated these items high. the personal belief pattern. had a mixture of scientific and nonscientific beliefs that indicated a sense of personal involvement in the cause of the child's disorder. Subjects with the two belief patterns were equally knowledgeable about the genetics of the disorder. Thus. the personal belief pattern did not appear to interfere with acceptance or understanding of the information provided in genetic counseling.
On the inheritance of abdominal aortic aneurysm, To determine the mode of inheritance of abdominal aortic aneurysm. data on first-degree relatives of 91 probands were collected. Results of segregation analysis performed on these data are reported. Many models. including nongenetic and genetic models. were compared using likelihood methods. The nongenetic model was rejected; statistically significant evidence in favor of a genetic model was found. Among the many genetic models compared. the most parsimonious genetic model was that susceptibility to abdominal aortic aneurysm is determined by a recessive gene at an autosomal diallelic major locus. A multifactorial component in addition to the major locus does not increase the likelihood of the data significantly.
Localization of the Aland Island eye disease locus to the pericentromeric region of the X chromosome by linkage analysis, Aland Island eye disease (AIED) is an X-chromosomal disorder characterized by reduced visual acuity. progressive axial myopia. regular astigmatism. latent nystagmus. foveal hypoplasia. defective dark adaptation. and fundus hypopigmentation. The syndrome was originally reported in 1964 in a family on the Aland Islands. To determine the localization of the AIED gene. linkage studies were performed in this family. total of 37 polymorphisms. covering loci on the entire X chromosome. were used. By two-point analysis the strongest evidence for linkage was obtained between AIED and DXS255 (maximum lod score [Zmax] 4.92 at maximum recombination fraction [theta max] .00). Marker loci DXS106. DXS159. and DXS1 also showed no recombination with AIED. Other positive lod scores at theta max .00 were obtained with markers localized in the XY homologous region in Xq13-q21. but the numbers of informative meioses were small. Multilocus linkage analysis indicated that the most probable location of AIED is in the pericentromeric region between DXS7 and DXS72. These results rule out localizations of AIED more distal on Xp that have been proposed by others. Our data do not exclude the possibility that AIED and incomplete congenital stationary night blindness are caused by mutations in the same gene. This question should be resolved by careful clinical comparison of the disorders and ultimately by the molecular dissection of the genes themselves.
Waardenburg syndrome (WS): the analysis of a single family with a WS1 mutation showing linkage to RFLP markers on human chromosome 2q, Waardenburg syndrome type I (WS1; MIM 19350) is caused by a pleiotropic. autosomal dominant mutation with variable penetrance and expressivity. Of individuals with this mutation. 20%-25% are hearing impaired. A multilocus linkage analysis of RFLP data from a single WS1 family with 11 affected individuals indicates that the WS1 mutation in this family is linked to the following four marker loci located on the long arm of chromosome 2: ALPP (alkaline phosphatase. placental). FN1 (fibronectin 1). D2S3 (a unique-copy DNA segment). and COL6A3 (collagen VI. alpha 3). For the RFLP marker loci. a multilocus linkage analysis using MLINK produced a peak lod (Z) of 3.23 for the following linkage relationships and recombination fractions (theta i): (ALPP----.000----FN1)----.122----D2S3----.267----CO L6A3. A similar analysis produced a Z of 6.67 for the following linkage relationships and theta i values among the markers and WS1: (FN1----.000----WS1----.000----ALPP)----.123----D2S 3----.246----COL6A3. The data confirm the conclusion of Foy et al. that at least some WS1 mutations map to chromosome 2q.
Analysis of the chondroitin sulfate proteoglycan core protein (CSPGCP) gene in achondroplasia and pseudoachondroplasia, Achondroplasia and pseudoachondroplasia are autosomal dominant skeletal dysplasias resulting in short-limbed dwarfism. Histologic and ultrastructural studies of the cartilage in pseudoachondroplasia and in homozygous achondroplasia have suggested a structural abnormality in chondroitin sulfate proteoglycan (CSPG). a major structural protein in the extra-cellular matrix. The gene encoding CSPG core protein (CSPGCP) is thus a logical "candidate gene" for analysis in these conditions. cDNA probes encoding CSPGCP were used to identify restriction fragment length polymorphisms (RFLPs) in DNA from a panel of control individuals. No gross alterations at the CSPGCP locus were noted in DNA from 37 individuals with achondroplasia and 5 individuals with pseudoachondroplasia. In addition. allelic frequencies of the RFLPs were not significantly different among controls and patients with either condition. In one three-generation family with achondroplasia. close linkage of the CSPGCP locus and the skeletal dysplasia was excluded using a Bgl II polymorphism. Similarly. in a three-generation family with pseudoachondroplasia. the CSPGCP gene was not tightly linked to the disease phenotype. These results indicate that mutations at the chondroitin sulfate proteoglycan core protein locus do not cause achondroplasia or pseudoachondroplasia in these families.
Erythrocyte membrane protein deficiencies in paroxysmal nocturnal hemoglobinuria, Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by intermittent hemolytic anemia. Membrane abnormalities of blood cells from patients with PNH are the reason for the unusual sensitivity to lysis by autologous plasma complement. A patient with typical clinical disease consistent with PNH is described together with a few strategies and pitfalls for treatment. Commonly used in vitro assays are discussed that document the complement-mediated lysis of aberrant PNH erythrocytes. Membrane-associated proteins that are abnormal in PNH cells. the characteristics of these proteins. and their mechanism(s) of action are described; these include the decay accelerating factor that inhibits the C3/C5 convertases of both complement pathways on cell surfaces. the C8 binding protein that modulates a step in terminal complement lysis. and other proteins that regulate complement-mediated lysis at early or late steps of the complement cascade.
Chloramphenicol toxicity: 25 years of research, Significant progress has been made in recent years in the understanding of the pathogenesis of the two types of hematologic toxicity from chloramphenicol. The common. dose-dependent. reversible bone marrow suppression from chloramphenicol is a consequence of mitochondrial injury. The greater erythroid susceptibility to chloramphenicol appears to be a function of the endogenous mitochondrial amino acid pools. The pathogenesis of aplastic anemia from chloramphenicol treatment remains uncertain. A large body of indirect evidence favors a complex mechanism involving metabolic transformation of the p-NO2 group of chloramphenicol by the predisposed subject. leading to the production of a toxic intermediate causing stem cell damage. A concept is presented wherein metabolites of chloramphenicol generated by intestinal bacteria undergo further metabolic transformation in the bone marrow with in situ production of toxic intermediate. This concept of the marrow being both the metabolic site for the offending agent as well as the target for its toxic metabolites will likely apply to other potential myelotoxins.
Danazol, Danazol is a synthetic attenuated androgen that can interfere with normal interactions between the pituitary-hypothalamic axis and the gonads. These effects are mediated by complex mechanisms. including those in which danazol can compete with natural steroids in binding to androgen receptors or to sex hormone-binding globulin. possibly displacing natural steroids from this protein. and in binding to reactive sites of enzymes required for synthesis of natural steroids. thereby depressing synthesis. Because of danazol's impairment of the pituitary-hypothalamic interactions with gonads. it is an effective therapeutic agent for treatment of endometriosis and cystic disease of the breast. It is effective in the treatment of hereditary angioneurotic edema. but the mechanism of this therapeutic success is unclear. Danazol has been used. without universal success. in the treatment of other gynecologic and certain hematologic disorders.
Glomerular structures and lipids in progressive renal disease, In the last few years. remarkable advances have been made in the understanding of lipoprotein metabolism in the pathogenesis of renal disease in animal models and in vitro cell culture. Central to this work is the problem of the progression of renal disease in humans. This review recapitulates the theory (Lancet 1982; II: 1309-1312) that the progression of disease depends in part on the damage inflicted on the glomerulus by lipoproteins. The glomerular environment of high or low pressure. basement membrane damage. and destruction or damage of the mesangial and epithelial cells permits the filtration of protein. the consequence of which is hyperlipidemia. Whatever the therapeutic measures employed. if proteinuria persists. hyperlipidemia will follow. This suggest that lipoprotein toxicity may contribute to the final common path of renal damage in progressive renal disease. "Lipoprotein toxicity" in arteries is called atherosclerosis. but this term ignores the complexity of the glomerulus and the possible tubular damage that might be caused by filtered lipoprotein. It is clear there is insufficient knowledge of the metabolism of the damaged kidney to confidently attribute the pathology of progression of disease to any single process.
Similarities between glomerular sclerosis and atherosclerosis in human renal biopsy specimens: a role for lipoprotein glomerulopathy, Much recent work has focused on the progressive nature of renal injury. and hemodynamic alterations have been implicated in the pathogenesis of the predominant lesion. focal glomerulosclerosis. Despite the well-documented atherogenic toxicity of lipids in cardiovascular morbidity. little is known about lipid-associated renal injury. However. lipids are toxic to endothelium. and the glomerulus is a vascular bundle. Several authors participating in this symposium have presented evidence for an association between hyperlipidemia and glomerulosclerosis in animal models. This association is particularly significant given the expanded therapeutic armamentarium now available to treat hyperlipidemia. In fact. glomerular injury may be moderated by pharmacologic treatment of hyperlipidemia in a rat renal ablation model. Very little evidence exists. however. for a similar association in human renal disease. We have. in the course of clinical practice. made certain observations in renal biopsy specimens that may for the first time link atherogenesis and lipid deposition to human glomerular injury.
Serum lipids in patients with chronic renal failure on long-term, protein-restricted diets, Disordered lipid metabolism is believed to play an important role in accelerating the progression of chronic renal disease toward uremia. We examine this hypothetic role of lipids in a large population of patients on long-term dietary protein restriction. In our experience. there is no conclusive evidence that lipids may accelerate the progression of functional deterioration in patients with reduced renal function. Hyperlipidemia seems to be only one among the many factors affecting the prognosis of primary renal disease. Dietary protein restriction is effective in maintaining normal or only slightly elevated serum lipid levels in patients with early renal failure. Moreover. patients with renal failure maintained on this diet. which provides an elevated ratio of polyunsaturated to saturated fatty acids. have a more favorable lipid composition of erythrocyte membrane (low percentage of saturated fatty acids and high percentage of polyunsaturated fatty acids) when compared with patients on an unrestricted diet.
Hyperlipidemia after organ transplantation, Hyperlipidemia. long recognized as a difficult and common problem following organ transplantation. may be the underlying cause of the accelerated atherosclerosis observed in heart transplant recipients and children with renal transplants. In addition. hyperlipidemia may play a role in late renal graft loss. The cause of post-transplant hyperlipidemia is unclear. In patients treated with azathioprine and prednisone. hypertriglyceridemia is the commonest finding and probably results from an increased consumption of calories from carbohydrate and fat following resolution of uremia. in conjunction with glucose intolerance secondary to steroid administration. In patients treated with cyclosporine. hypercholesterolemia is the most common form of hyperlipidemia. Cyclosporine is a lipophilic drug that is transported in the plasma. largely in association with lipoproteins. and may require the low-density lipoprotein (LDL) receptor for internalization into cells. Hypercholesterolemia may result from interference with the basic cholesterol feedback mechanism via the LDL receptor. In addition. cyclosporine affects bile acid synthesis and worsens glucose tolerance. both factors that may promote hyperlipidemia. The first therapeutic approach to hyperlipidemia in the transplant recipient is dietary calorie-fat restriction and supplementation with soluble fiber. Ongoing clinical trials of the available pharmacologic lipid-lowering agents are addressing the safety and efficacy of these agents in the setting of immunosuppression; until that time. they should be used cautiously and in low doses.
Aggressive non-Hodgkin's lymphomas in AIDS: the University of Colorado experience, The authors performed this retrospective study to further investigate the relationship between non-Hodgkin's lymphoma (NHL) and the Acquired Immunodeficiency Syndrome (AIDS). From January 1984 through December 1987 all cases of AIDS and NHL diagnosed at the University of Colorado affiliated hospitals were identified and submitted to chart review. Twenty-five patients fulfilled criteria for the diagnosis of AIDS and 24 had biopsy-proven NHL. an additional patient met criteria for the diagnosis of primary central nervous system lymphoma and was included in the analysis. All patients had known risk factors for the development of AIDS. Of the biopsy proven tumors. 23 were categorized as high grade. Most patients (68%) presented with stage IV disease and 92% with extra nodal involvement. Median survival was 5 months and the cause of death was most often progressive lymphoma and/or opportunistic infections. These data are similar to previously published series. Clinical trials to evaluate effective treatment are warranted.
Interaction of chloramphenicol and metabolites with colony stimulating factors: possible role in chloramphenicol-induced bone marrow injury, We have recently demonstrated that two chloramphenicol (CAP) metabolites known to be produced by intestinal bacteria. dehydro-CAP (DH-CAP) and nitrophenylaminopropane (NPAP). are much more cytotoxic to bone marrow in vitro than CAP itself. Since colony stimulating factors (CSFs) play an essential role in hematopoietic cell growth. toxicity from CAP metabolites could also involve interaction with CSF or CSF-producing cells. In the present study. we found that increasing concentrations of rhGM-CSF or rhG-CSF completely reversed the inhibitory effect of CAP (2 x 10(-4) M) on human CFU-GM growth and on the growth of KG-1 cells. GM-CSF also reversed the inhibitory effect of CAP on HL-60 cells. Inhibition by DH-CAP (50% at 5 x 10(-7) M). nitroso-CAP (NO-CAP) (60% at 5 x 10(-6) M) and NPAP (35% at 10(-5) M) was not affected by either CSF. In addition to their inhibitory effect on cell growth. DH-CAP (5 x 10(-6) M) and NO-CAP (5 x 10(-6) M) inhibited CSF production by buffy coat cells 50-70% without affecting cell viability. Neither CAP nor NPAP inhibited CSF production. It is suggested that the dual toxic-inhibitory effect of some intestinal metabolites of CAP such as DH-CAP on hematopoietic cell growth on the one hand. and on CSF production on the other. renders them very potent as potential mediators of CAP induced aplastic anemia.
Chronic therapy for congestive heart failure with benazepril HCl, a new angiotensin converting enzyme inhibitor, Benazepril HCl is an orally effective angiotensin converting enzyme (ACE) inhibitor previously shown to have significant acute hemodynamic benefits in patients with congestive heart failure. In this study. 21 patients with New York Heart Association Class III or IV congestive heart failure were treated with 2 to 15 mg of benazepril HCl as a single daily oral dose for 28 days to determine the clinical and hemodynamic value of chronic therapy. Each patient underwent clinical evaluation during the 28-day period. as well as invasive hemodynamic studies on the first two and last two days of the trial. Plasma ACE activity and aldosterone levels fell significantly and renin levels rose after therapy. Benazepril HCl produced significant (p less than 0.01) reductions in arterial pressure and systemic vascular resistance. with corresponding increases in cardiac output and decreases in pulmonary artery wedge pressure. Responses after 28 days of therapy were equivalent to those after the initial doses. Clinical effects included reduced rest. exertional and paroxysmal nocturnal dyspnea. as well as reduced peripheral edema. Only one patient developed symptomatic orthostatic hypotension. Thus. benazepril HCl. given once daily. is an effective and well tolerated oral agent for the chronic treatment of advanced congestive heart failure.
Nitrogen metabolism in sickle cell anemia: free amino acids in plasma and urine, Twenty-four hour urinary levels and fasting plasma concentrations of free amino acids (AA) were evaluated in adult sickle cell anemia (HbSS) and age-matched HbAA subjects with comparable daily energy (E) and protein (N) intake. HbSS elicited significant reduction in the sum of plasma indispensable (EAA) with no change in the dispensable (NAA) amino acids. resulting in a prominent (P less than 0.01) reduction in the EAA/NAA ratio from 71% to 55%. Arg (-38%). Leu (-32%). Val (-28%) and His (-32%) were among the AA most severely affected. Despite a twofold increase in 24-hour urine volume in HbSS compared with HbAA subjects. total urinary losses of EAA and NAA were markedly reduced in the former group. with Arg (-53%) and Gly (-56%) levels most prominently affected. Compared with HbAA controls. HbSS subjects showed a three-fourfold increase in 24-hour urinary orotate excretion that had no relationship to amount of N intake. The results indicated that adult subjects with HbSS. who consumed adequate N and E as per the RDA for healthy individuals. behaved like normal HbAA controls on a low protein diet. There was evidence that the HbSS subject might be in a precarious state with respect to sufficiency of several amino acids. particularly L-Arg. which is now classified as conditionally indispensable for the human.
Desmopressin-induced improvement in bleeding times in chronic renal failure patients correlates with platelet serotonin uptake and ATP release, Hemostatic defects resulting in life-threatening hemorrhagic episodes are a common occurrence in the chronic renal failure patient. Hemorrhagic tendencies correlate best with laboratory tests of bleeding times. The identification of a specific hemostatic defect and its role in bleeding dyscrasias has yet to be elucidated. Our studies demonstrate that factor VIII coagulant activity and factor VIII related antigen (vWF:Ag) are normal or greatly elevated in uremic renal failure patients with greatly prolonged bleeding times. The multimeric state of the von Willebrand factor is also normal in these patients. The bleeding times were normalized in all 15 patients. 90 minutes post-infusion with desmopressin (DDAVP). No significant changes in factor VIII/vWF associated properties. blood cell counts. or coagulation factors were observed post-DDAVP treatment. However. a significant increase in platelet serotonin uptake (p less than .025) and ATP release (p less than .025) was detected after DDAVP treatment. These results indicate that DDAVP acts on the platelet membrane. This is further substantiated by the ability of DDAVP to block vasopressin-induced platelet aggregation in a dose- and time-dependent fashion. Perturbations in the movement and storage of serotonin and the release of adenosine 5'-triphosphate (ATP) in the platelets of uremic individuals are proposed to play a critical role in regulating bleeding times.
Kaposi's sarcoma involvement of the bone marrow, Kaposi's sarcoma (KS) is a predominantly cutaneous malignancy with several clinical variants. Extracutaneous sites of involvement are uncommon in all disease variants except epidemic KS (human immunodeficiency virus related) and the African lymphadenopathic variant. Extracutaneous KS usually involves the lymph nodes. gastrointestinal tract. and respiratory tract. The authors report the first description of a patient with classic KS to have bone marrow involvement. Two additional patients with KS variants and bone marrow involvement have been described. Bone marrow tumor invasion should be considered in patients with KS and hematologic abnormalities.
Schizophrenia and fatal self-induced water intoxication with appropriately-diluted urine, A 31-year-old woman with untreated chronic schizophrenia developed extreme polydipsia which rapidly led to coma and death due to cerebral edema. Hyponatremia (120 mEq/liter) and serum hypo-osmolality (260 mOsm/kg) were associated with marked polyuria (up to 1850 ml/hour) and appropriately low urinary osmolality (90 mOsm/kg) which responded to treatment. This case and few qualifying previous reports which are reviewed support the possibility that pure self-induced water intoxication with no major contribution of inadequate release of antidiuretic hormone may occur. and that extreme polydipsia can sometimes overwhelm normal renal diluting capacity in psychotic patients.
Can the rate of progression of chronic renal failure be altered, The cost of renal replacement therapy for end-stage renal disease in the United States exceeds three billion dollars per year. Nonimmunologic mechanisms may contribute to progressive renal injury in renal failure of diverse etiologies. Based on the potential adverse renal effects of these processes. a number of dietary and pharmacologic interventions have been proposed as being potentially beneficial in slowing the rate of progression of chronic renal failure to end-stage renal disease. This article reviews current evidence in animal models and humans supporting the efficacy of each of the proposed interventions.
Hyperosmolar states, The composition of the extracellular fluid (ECF) must remain stable for cells to function properly. In normal individuals vasopressin and thirst zealously maintain the total ECF concentration. or osmolality. within a narrow range. Disruption of these regulatory mechanisms or rapid addition of solute to the ECF can lead to hyperosmolality. The serious neurologic symptoms that accompany many forms of hyperosmolality can be explained by understanding the physiologic response of cells to the osmotic stress. This review describes the physiology. pathophysiology. differential diagnosis. and therapy of hyperosmolar states.
Prevalence of lattice degeneration and its relation to axial length in severe myopia, We studied 436 eyes of 218 patients with myopia of -6.00 diopters or more in both eyes. Of 218 patients. 72 (33.0%) had lattice degeneration of the retina. Among these 72 patients. lattice lesions were uniocular in 39 (54.2%) and binocular in 33 (45.8%). Of 105 males. 33 (31.4%) had lattice degeneration; of 113 females. 39 (34.5%) had lattice degeneration. Contrary to previously published data. we found an inverse relationship between axial length and the prevalence of lattice degeneration in severely myopic eyes. The greatest prevalence of lattice degeneration (63 of 154 eyes. 40.9%) was found in eyes with an axial length of 26.0 to 26.9 mm (-6.00 to -8.70 diopters). and the least prevalence of lattice degeneration (five of 71 eyes. 7.0%) was found in eyes with an axial length of 32.0 mm (-24.00 diopters) or greater. This may explain the observation that retinal detachment after cataract surgery has been noted more commonly among patients with moderate than severe myopia.
Ocular clinicopathologic study of gyrate atrophy, We performed a histopathologic study of whole globes obtained post mortem from a patient with well-documented. vitamin B6-responsive gyrate atrophy. The retina in the posterior pole had focal areas of photoreceptor atrophy with adjacent retinal pigment epithelial hyperplasia. An abrupt transition from the near normal retina to a zone of near total atrophy of the retina. retinal pigment epithelium. and choroid was present in the fundus midperiphery. Electron microscopic examination disclosed abnormalities of the mitochondria of the corneal endothelium and the non-pigmented ciliary epithelium. Similar. but less severe. mitochondrial abnormalities were present in the photoreceptors.
Photic retinal injury from endoillumination during vitrectomy, We treated a patient who developed a paramacular area of light-induced retinal damage after endoscopic epimacular membrane removal. Postoperative color photographs showed complete absence of the membrane. but fluorescein angiography demonstrated a previously absent superior paramacular lesion consistent with a photic injury. Operative microscope illumination had been eliminated by corneal shielding. which implicated endoillumination as the source of injury. We recommend the following procedures to avoid this complication: careful planning of vitreous surgery for epimacular membrane removal; using filters; minimizing the length of surgery; keeping the light output low; maintaining maximal light pipe distance from the retina; eccentric orientation of the light pipe; and use of intermittent and variable site illumination techniques.
Light damage in detached retina, We injected homologous fibroblasts over the retinal vascular wing in five rabbits to induce a tractional retinal detachment. Eleven days later. a focal area of detachment was exposed to 30 minutes of visible light by an intraocular fiberoptic probe. Histologic damage to the detached retina exposed to light was demonstrated. The outer retina was affected most severely.
Correlation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma, Fifty-five patients with primary open-angle glaucoma and early glaucomatous damage who had medical therapy and laser trabeculoplasty were followed up for four to 11 years or until progressive glaucomatous damage was documented. Factors associated with the stability or progression of glaucoma were evaluated. Eyes with mean intraocular pressure higher than 21 mm Hg during the follow-up period uniformly had progressive glaucomatous changes. Conversely. eyes with mean intraocular pressure less than 17 mm Hg remained stable. and approximately half of the eyes with mean intraocular pressure between 17 and 21 mm Hg had progressive glaucomatous changes. Patients who remained stable were slightly younger than those with progressive glaucomatous changes (P less than .05). but initial optic nerve head appearance. initial visual field findings. number of medicines used. medical history. and patient gender or race were not statistically associated with stability or progression of the glaucoma. These findings reinforce the importance of intraocular pressure control in primary open-angle glaucoma and the need to identify other markers that help determine the proper level of intraocular pressure for individual patients.
Increased intraocular pressure in severely burned patients, Six eyes of three patients with severe body burns had intraocular pressure ranging from 37.2 to 81.7 mm Hg. Because of extreme orbital congestion. lateral canthotomies were performed. which caused abrupt decrease in intraocular pressure (range. 17.6 to 49.0 mm Hg). None of the patients had a history of glaucoma. narrow angles. or any precondition for a pupillary block mechanism. Two patients survived and neither had optic nerve damage or increased intraocular pressure after hospital discharge. Tonometry should be performed in patients with severe burns and orbital congestion. especially in those patients receiving large amounts of intravenous fluids. Lateral canthotomies may be of benefit to relieve potentially damaging high intraocular pressure.
A new method for documenting lens opacities, We tested an anterior segment camera and digital analyzer on 32 eyes of 22 patients to determine whether its measurement of lens opacities correlated with measurements obtained by a standardized clinical grading system. The lenses were graded clinically for nuclear opacity. nuclear color. cortical opacity. and posterior subcapsular opacity. The lenses were then photographed and analyzed with this new device. and the results were compared. The camera system showed good reproducibility. Its results correlated well with the clinical gradings for nuclear capacity (P = .001) and cortical opacity (P = .001) but less well with posterior subcapsular opacity (P = .3). although there were only seven eyes with posterior subcapsular opacities. This camera system could help document and follow up lens opacity with more accuracy and reproducibility than has been previously possible.
Echographic diagnosis of dural carotid-cavernous sinus fistulas, I used standardized ophthalmic echography to identify specific abnormalities in four patients with low-pressure. low-flow dural arteriovenous malformations. In all of the patients. B-scan ultrasonography showed engorgement of the ipsilateral vertical vein. A-scan ultrasonography dynamically imaged rapid blood flow through the superior ophthalmic vein and enlargement of the culpable ocular muscles in patients with restrictive ophthalmopathy. The 30-degree test distinguished between venous engorgement of the optic nerve sheath and apical compression of the optic nerve by enlarged ocular muscles.
Causes of failure after initial vitreoretinal surgery for severe proliferative vitreoretinopathy, We performed initial vitreoretinal surgery on 81 eyes with rhegmatogenous retinal detachments complicated by severe proliferative vitreoretinopathy. Of 81 eyes. 68 (84%) had undergone previous scleral buckling. We performed vitreous base dissection on all 18 eyes (22%) that had anterior proliferative vitreoretinopathy. With one vitreoretinal operation. 66 of 81 eyes (81%) remained totally reattached. The main cause of initial anatomic failure and reoperation was either new or recurrent proliferation at the vitreous base. With additional vitreoretinal surgery and after a mean follow-up period of 19 months. 73 of 81 retinas (90%) were totally reattached. The final causes of anatomic failure were anterior proliferative vitreoretinopathy and proliferation from relaxing retinotomies. Of the 73 successfully reattached eyes. 62 (85%) had postoperative visual acuity of 5/200 or better.
Attention deficits in children exposed to alcohol prenatally, Twenty children with fetal alcohol syndrome or fetal alcohol effect (FAS/FAE) were compared with 20 attention deficit disorder (ADD) children and 20 normal controls on three experimental tasks designed to isolate four different components of attention. Parents completed three questionnaires regarding their child's activity level and overall functioning. and the children completed a short form of an IQ test. The children in each group ranged from 5 to 12 years. Results indicate that although the children with FAS/FAE are significantly more impaired intellectually. their attentional deficits and behavioral problems are similar to those of children with ADD. These findings imply that the treatments known to facilitate learning in children with ADD may also benefit children with FAS/FAE.
The long-term behavioral effects of prenatal alcohol exposure in rats, Prenatal exposure to alcohol can cause a variety of behavioral disturbances later in life. Many of the reports in animals of the behavioral teratogenic effects of alcohol have focused on assessing younger animals. The purpose of this paper is to review some of the longer lasting behavioral consequences of gestational alcohol exposure in animals. It is not meant as a comprehensive review. but rather focuses on selected studies. It is concluded that prenatal alcohol exposure does have long lasting effects. although some of these might only occur under challenging or stressful circumstances. It is hypothesized that as the animal matures compensatory mechanisms or strategies develop to compensate for these dysfunctions. Thus. behavioral problems may only be detected when these compensatory systems break down. either as a result of stress. because of complex testing procedures. or old age.
Neuroanatomic and neurochemical abnormalities in nonhuman primate infants exposed to weekly doses of ethanol during gestation, Ethanol was orally administered once per week to 54 gravid pigtailed macaques (Macaca nemestrina) in doses of 0.0. 0.3. 0.6. 1.2. 1.8. 2.5 or 4.1 gm/kg from the 1st week in gestation or in doses of 2.5. 3.3 or 4.1 gm/kg from the 5th week. Mean maternal peak plasma ethanol concentrations (MPPEC's) ranged from 24 +/- 6 mg/dl at the 0.3 g/kg dose to 549 +/- 71 mg/dl at the 4.1 g/kg dose. Thirty-three live born infants were assessed for abnormalities of physical and behavioral development. Ocular pathology. neuropathologic and neurochemical assessements were done on 31 animals at 6 months postnatal age. Microphthalmia was noted in three of the 26 animals exposed to ethanol. Retinal ganglion cell loss was significantly associated with intra-uterine ethanol exposure. Microphthalmia and retinal ganglion cell loss was observed in both the delayed and full-gestational exposed animals. No structural anomalies were found in the brains via gross inspection or light microscopy. Chemical abnormalities in the striatal nuclei were identified. Striatal dopamine concentrations increased with increasing MPPEC exposure (0-249 mg/dl) among animals exposed weekly to ethanol throughout gestation. Striatal dopamine concentrations decreased with increasing MPPEC exposure (260-540 mg/dl) among animals whose weekly exposure to ethanol was delayed until the 5th week of gestation. The same pattern of association was also noted between MPPEC and ultrastructural alterations in the caudate nucleus. The extent of ultrastructural alterations increased with increasing MPPEC among the full-gestational exposed animals and decreased with increasing MPPEC among the delayed-dose animals.
Utility of the Self-Administered Alcoholism Screening Test (SAAST) in schizophrenic patients, The utility of the Self-Administered Alcoholism Screening Test (SAAST) in determining alcohol abuse and alcoholism was assessed in a preliminary study of 21 schizophrenic patients during their hospitalization in an acute care psychiatric unit; on admission all met DSM-III-R criteria for schizophrenia and none were detected to have any alcohol-related diagnosis. SAAST scores ranged from 2 to 26 with a mean score of 10.8. Forty-eight percent (10/21) had SAAST scores greater than or equal to 10. indicating "probable alcoholism"; 62% (13/21) scored 8 or higher. Every patient with a SAAST score of 8 or higher also met DSM-III-R criteria for alcohol abuse or dependence on the basis of patient interview. independent chart reviews. and interviews of significant others. In contrast. only half (5/10) of the high SAAST scorers would actually admit to a problem with drinking during the extensive study interviews. Six SAAST items were found to be highly predictive of abuse or alcoholism; the SAAST had greater sensitivity than the interviews. Sixty-two percent (8 of 13) of the schizophrenic patients who met the DSM-III-R criteria for alcohol abuse reported a first degree relative with an alcohol-related problem. in contrast to only 25% of the "nonalcoholic" patients. The patterns of the alcoholic schizophrenic patients' responses on the different SAAST items revealed even greater denial and lack of insight than those of nonschizophrenic alcoholic subjects.
Ethanol causes accelerated G1 arrest in differentiating HL-60 cells, The effects of clinically relevant ethanol concentrations on myeloid differentiation in the HL-60 cell promyelocytic leukemia line have been studied. The exposure of noninduced stem cells to 60 mM ethanol results in an increase in G1 cells. but there is no increase in superoxide production or expression of the Mo1 antigen. When HL-60 cells are induced to differentiate along the myeloid line with dimethylsulfoxide (DMSO) or retinoic acid (RA). there is a shift to smaller cell size. an increase in G1 cells and acquisition of the ability to produce superoxide as reported previously by several authors. When ethanol is present during differentiation. there are further increases in G1 cells. and increases in the percentage of cells which produce superoxide and express Mo1. and decreases in mean cell size and total growth during the incubation period. Regrowth experiments after periods of differentiation indicate that the increased G1 arrest seen in the presence of ethanol represents terminal commitment if inducer is present. but in the absence of inducer the increased G1 percentage is readily reversible. Examination of RNA content by flow cytometry reveals a decrease in both the peak and mean G1 RNA content during DMSO or RA induced differentiation. These decreases are accentuated by the presence of ethanol. resulting in a higher G1A/G1B ratio than in nonexposed cells. These findings indicate that ethanol enhances G1 growth arrest in HL-60 cells exposed to myeloid inducers. Partial differentiation occurs during this process. resulting in terminally arrested cells. some of which have undergone fewer postinduction cell divisions than normal and may not be fully competent.
Alcohol and secobarbital effects as a function of familial alcoholism: acute psychophysiological effects, Previous research has demonstrated response differences following administration of alcohol between adult males with a positive (FHP) versus negative (FHN) family history of alcoholism. These response differences are thought to reflect differences in vulnerability to dependence on alcohol. Thus. the role of positive family alcoholism history in increasing risk of addiction to a variety of drug classes might be studied by determining whether FHP subjects show different responses to drug classes other than alcohol. This was done in the present study by determining dose-effect functions for a variety of physiological (heart rate. skin conductance. skin temperature). subjective (analog mood and drug effect. Subjective High Assessment Scale). and psychomotor measures (hand tremor. body sway. Digit Symbol Substitution Test. eye-hand coordination. and numeric recall) in FHP and FHN college-aged males for secobarbital (0. 100. 200 mg by mouth) and ethanol (1 g/kg). FHP and FHN subjects were matched on light-to-moderate drinking patterns. anthropometric dimensions. age. years of schooling. and drug use. At equivalent blood alcohol levels family-history positive subjects reported greater effects of ethanol than did family-history negative subjects on almost all subjective measures. Following the high dose of secobarbital. FHP but not FHN subjects showed elevated subjective effects; these effects were substantially less and were evident in fewer measures than following ethanol. In contrast to effects on the subjective measures. ethanol and secobarbital produced comparable impairment in both groups of subjects for most psychomotor responses. Group differences were not obtained on any physiological measures.
Sons of alcoholics report greater hangover symptoms than sons of nonalcoholics: a pilot study, We investigated alcohol-induced hangovers among college men at high and low risk for alcoholism. Thirteen sons of alcoholics reported significantly (p less than 0.001) greater hangover symptoms in the past year than 25 sons of nonalcoholics. The two groups reported comparable quantity-frequency of recent drinking. To the extent that hangover represents an acute withdrawal syndrome to alcohol. this raises the question of whether sons of alcoholics are "dependence-prone.".
Taste reactivity in alcohol preferring and nonpreferring rats, Taste reactivity tests were used to examine the orofacial responses of alcohol preferring (P) rats and alcohol nonpreferring (NP) rats to the taste of alcohol. In the initial exposure. naive rats were tested for reactivity to five concentrations of alcohol (5%. 10%. 20%. 30%. and 40% v/v). water. and one solution each of sucrose and quinine. A two-bottle consumption test was then given for a 3-week period to allow the rats access to 10% alcohol. After the preference test. a second taste reactivity test was done using the same solutions as in the initial reactivity test. The results indicated no significant differences in taste reactivity between P rats and NP rats on the initial exposure. except that NP rats made significantly more mouth movements. During the two-bottle tests. consumption of alcohol by P rats was consistently higher than that of NP rats across all test days. On the second taste reactivity test. P rats showed an increase in the number of ingestive responses and a decrease in the number of aversive responses to alcohol. NP rats' taste reactivity to alcohol remained unchanged from Exposure 1 to Exposure 2. P rats' and NP rats' responses to sucrose and quinine did not change from Exposure 1 to Exposure 2. It was concluded that there were no innate taste response differences between P and NP rats to alcohol but that following alcohol experience. P rats showed a significant increase in ingestive responses and a concomitant decrease in aversive responses to the taste of alcohol.
Subject selection bias in alcoholics volunteering for a treatment study, Baseline differences in alcoholism problem severity were compared between alcoholics who did and did not volunteer to participate in a treatment effectiveness study. A positive relationship was found between self-reports of alcohol-related problems and the degree of research participation. Group differences were also revealed in the rate of treatment completion. Possible explanations and solutions for this volunteer bias are discussed.
Alcohol abuse among grandsons of alcoholics: some preliminary findings, Drawing upon self-reports of family history for alcoholism. the present study compared the level of alcohol abuse among grandsons of alcoholic maternal and paternal grandfathers. Although based on a small sample of grandsons (N = 29). the results indicated a significantly higher level of alcohol abuse among maternal compared with paternal grandsons.
Effects of ethanol on hexose uptake by cultured rat brain cells, The effects of ethanol on hexose uptake by glial cells was investigated using primary cultures prepared from term rat fetuses. Specific 3H 2-deoxy-D-glucose (2DG) uptake was significantly reduced by a 4-hr exposure to ethanol at concentrations of 25. 50. and 100 mM. but not 200 or 300 mM. The inhibitory effect of 50 mM ethanol increased with the duration of exposure. with 2DG uptake inhibited by 36% after 18 hr. Astrocytes cultured from the brains of term fetuses of rats fed ethanol during pregnancy showed essentially the same 2DG uptake response to in vitro ethanol treatment. Kinetics of 2DG uptake showed a significant decrease of Vmax in the presence of ethanol. No interaction was found between ethanol and insulin. which stimulated 2DG uptake and protein content of the cultures. The data suggest that ethanol can modulate hexose uptake by astrocytes cultured from fetal rat brain. However. insulin actions on glial cells were not affected by ethanol.
Relationships between neuropsychological test performance and event-related potentials in alcoholic and nonalcoholic samples, Are event-related potentials and nonconcurrently measured neuropsychological test performance correlated? Sober male and female middle-aged alcoholics and peer controls were administered an "oddball" event-related potential (ERP) task and several hours later. a battery of neuropsychological (NP) tests. Alcoholics performed significantly poorer than controls on NP tests. Male alcoholics had significantly altered ERP responses (N1. NdA. and P3 amplitudes) but female alcoholics did not differ on any ERP variables from controls. A number of significant correlations between ERP and NP measures were present. The most consistent findings were positive correlations between perceptual-motor (PM) tests and the P3 amplitude at Pz in both male and female alcoholics and in male alcoholics. a negative correlation between PM tests and P3 latency at Pz. findings similar to those seen in Parkinson patients. Significant correlations were most numerous in family history positive alcoholics. The results lead to two conclusions: first. Grant's postulation that sober alcoholics may manifest an intermediate duration organic mental disorder is supported; second. given the lack of ERP differences in the females. ERP measures should not be considered as being causally related to NP performance.
Comparison of the Self-Administered Alcoholism Screening Test (SAAST) and the Khavari Alcohol Test (KAT): results from an alcoholic population and their collaterals, This study examined the reports of patients and their collaterals on drinking practices. as measured by the summary scale of the Khavari Alcohol Test (the annual absolute alcohol intake. AAAI) and alcohol related behavioral patterns. as assessed by the Self-Administered Alcoholism Screening Test (SAAST). In- and outpatients from two Milwaukee area substance abuse treatment hospitals. and a number of their collaterals. participated in this study. Patients' and collaterals' responses on the AAAI and the SAAST were compared through the use of a paired t test. Results indicated no significant differences between patients' self-reports compared with collateral reports. and demonstrated a direct relationship on the AAAI (two tailed p less than 0.001) and SAAST (two-tailed p less than 0.001). Self-reports of patients who volunteered collaterals compared with self-reports of patients who did not volunteer collaterals also showed no significant differences on the AAAI or the SAAST. demonstrating consistency of reporting whether the patients believed their reports would be compared with information provided by a collateral or not. The AAAI and the SAAST corroborated in their diagnoses of patients as suffering from alcoholism (r = 0.515. p less than 0.001). Multivariate analysis revealed no significant effect of demographic variables on either the AAAI or the SAAST. This study shows: (a) impressive concordance between patient and collateral reports; (2) apparent intactness of memory. and little evidence of denial. as measured by the instruments; and (3) the efficacy of measures such as the AAAI and the SAAST. two vastly different scales measuring dimensions of alcoholism.
Formation of the 37KD protein-acetaldehyde adduct in liver during alcohol treatment is dependent on alcohol dehydrogenase activity, Protein-acetaldehyde adducts (protein-AAs) are formed in vivo during chronic alcohol ingestion. These protein-AAs reported thus far include a 37KD protein-AA in liver cytosol. cytP450IIE 1-AA in hepatic microsomes. hemoglobin-AA. and serum protein-AAs. It has been postulated that acetaldehyde or perhaps a reactive acetaldehyde radical generated by the microsomal ethanol oxidizing system (MEOS or cytP450IIE1) explains the formation of the cytP450IIE1-AA. The source of acetaldehyde responsible for the formation of the cytosolic 37KD protein-AA has not been determined. In this report. we have examined the effects of pyrazole (an ADH inhibitor) and cyanamide (an aldehyde dehydrogenase inhibitor) on the formation of the 37KD liver protein-AA in vivo and in vitro. It was found that feeding rats with an alcohol-containing liquid diet supplemented with cyanamide enhanced while a diet supplemented with pyrazole completely abolished the formation of the 37KD liver protein-AA. The liver of rats fed the pyrazole supplemented alcohol-containing diet showed significantly higher content of cytP450IIE1 than that of rats fed the diet containing alcohol alone. On the other hand. feeding the cyanamide supplemented alcohol-containing liquid diet did not further enhance the content of cytP450IIE1. Similarly. adding cyanamide to the culture medium enhanced while adding 4-methylpyrazole inhibited the production of the 37KD protein-AA by cultured hepatocytes even though the combination of alcohol and 4-methylpyrazole increased the content of cytP450IIE1 2-fold over that in control cells. These results demonstrate that the formation of the 37KD liver Protein-AA is dependent on ADH and not on MEOS.
Acute alcohol ingestion reduces fatty acid extraction of the heart, liver, and small intestine, Ethanol may have profound effects on both the distribution of perfusion and substrate utilization by the liver and heart due to its vasodilating properties and the generation of high levels of circulating acetate and lactate. Since fatty acids are highly extracted by the heart and liver under normal circumstances. changes in the relationship of perfusion/fatty acid uptake may be a sensitive indicator of both altered perfusion and changes in metabolic substrate availability. To test this hypothesis. studies were performed in rats fed 3.1. 6.2. and 9.3 g/kg doses of ethanol. Fatty acid uptake was estimated with a 3-methyl substituted reagent with a chain length equivalent to 17 carbons. The methyl group in the three position prevented beta oxidation and prolonged the residence of fatty acids in the tissue. Eighteen hours after acute alcohol administration. fatty acid uptake was reduced in the heart and the small intestine; in the liver uptake was increased or unchanged. Acute ethanol administration also resulted in increased perfusion. as indicated by enhanced uptake of 201thallium by the heart. liver. and small intestine. The fatty acid extraction of the heart. liver. and small intestine. defined as the concentration of fatty acid divided by the concentration of 201thallium. was markedly decreased by alcohol ingestion. These alcohol effects were dose-dependent and temporally related. The data suggest that ethanol ingestion could potentially alter heart function during exercise or following a prolonged fast. when the heart relies primarily upon fatty acids extracted from the circulation to generated adenosine triphosphate (ATP).
Leukotriene synthesis inhibition and receptor blockade do not inhibit hypoxic pulmonary vasoconstriction in sheep, Several lines of evidence suggest that leukotrienes may be mediators of hypoxic pulmonary vasoconstriction (HPV). However. the effect of leukotriene inhibition on HPV remains controversial. The present study investigated the effect of leukotriene synthesis inhibition and receptor blockade on HPV in the halothane-anesthetized sheep. After initial baseline measurements. the pulmonary pressor response to 15 min of global hypoxia (FIO2 = 0.13) was measured. A second set of baseline measurements was obtained and the sheep then received the combined cyclooxygenase/lipoxygenase inhibitor BW755C. the selective lipoxygenase inhibitor U60257. or the leukotriene receptor antagonist LY171883. Hemodynamic measurements were obtained after drug administration and during a subsequent hypoxic challenge (FIO2 = 0.13). Initial hypoxic challenge increased pulmonary artery pressure 68% and increased pulmonary vascular resistance 104%. Pulmonary hemodynamics after recovery from hypoxia were similar to initial baseline values. Drug administration had no significant hemodynamic effect. Hypoxic challenge after drug administration resulted in a pulmonary pressor response identical to the initial hypoxic challenge. Because leukotriene synthesis inhibition and receptor blockade did not alter the response to hypoxia. we conclude that leukotrienes are not obligatory mediators of HPV. A critical review of the literature supports a modulatory rather than an obligatory role for leukotrienes in HPV.
Effects of neuroleptic agents on rat skeletal muscle contracture in vitro, The purpose of this investigation was to examine and compare the effects of both in vivo pretreatment and in vitro treatment with the neuroleptic agents droperidol. haloperidol. and trifluoperazine on skeletal muscle contracture using an in vitro model. Strips of normal rat diaphragm were challenged with succinylcholine and halothane (halothane: 1% and 3%) subsequent to either in vitro administration (10-100 microM) or in vivo pretreatment (0.35-2.80 mg/kg) with droperidol. haloperidol. or trifluoperazine. After equilibration. maximum increases in tension were recorded and mean data analyzed by analysis of variance (P less than 0.05). When either droperidol or trifluoperazine was administered in vivo. contracture values after exposure to succinylcholine and halothane were significantly decreased. After in vivo pretreatment with haloperidol or in vitro administration of droperidol. succinylcholine-induced contractures were significantly reduced; contractures subsequently induced by halothane did not significantly differ from that of controls. In vitro treatment with haloperidol and trifluoperazine. however. produced significant increases in tension in muscles exposed to succinylcholine and halothane. This study provides evidence that droperidol may be considered a safe anesthetic adjunct in malignant hyperthermia-susceptible patients. and. additionally. that caution should be exercised when interpreting results from studies in which contracture testing is performed on muscle from patients treated with neuroleptic agents.
Cardiorespiratory effects of antagonism of diazepam sedation with flumazenil in patients with cardiac disease, The specific benzodiazepine antagonist flumazenil is currently under intense study. Despite much clinical experience. no detailed invasive hemodynamic studies of its use in cardiac patients have been published. In the present study. hemodynamic and respiratory variables were measured in 10 cardiac patients undergoing catheterization of the right and left sides of the heart. before and after sedation with intravenous diazepam. and after reversal of sedation with flumazenil. A sleep dose of diazepam (12.2 +/- 5.1 mg. mean +/- SD) caused only slight decreases in mean arterial pressure (103 +/- 12 to 98 +/- 14 mm Hg; P less than 0.05). pulmonary capillary wedge pressure (13.2 +/- 6.3 to 11.7 +/- 6.6 mm Hg; P less than 0.05). and left ventricular end-diastolic pressure (20.8 +/- 7.5 to 17.3 +/- 10.0 mm Hg; P less than 0.05). with no significant changes in respiratory gas homeostasis. Intravenous flumazenil (0.22 +/- 0.07 mg) resulted in spontaneous awakening and return to full orientation. yet caused no significant alteration in either hemodynamic or respiratory variables measured. Reversal of diazepam-induced sedation by flumazenil in cardiac patients appears safe and effective.
Hypokalemia before induction of anesthesia and prevention by beta 2 adrenoceptor antagonism, We have observed that serum potassium levels measured immediately before induction of anesthesia ("preinduction K+") are often lower than those measured 1-3 days preoperatively ("preoperative K+"). The purpose of this investigation was to determine. in two studies. the magnitude of this difference and to elucidate the mechanism by which this occurs. In the first study. preinduction K+ (3.6 +/- 0.4 mEq/L. mean +/- SD) was significantly lower than K+ levels measured during routine preoperative testing (4.4 +/- 0.4 mEq/L. n = 47. P less than 0.001). Twenty-three patients (49%) had preinduction K+ levels that were considered hypokalemic (less than or equal to 3.5 mEq/L). but 22 of these 23 patients had normal preoperative K+ levels. The second study tested the hypothesis that preinduction decreases in serum K+ are mediated by beta 2-adrenergic receptors. Preinduction K+ changes were determined in patients given a single preoperative dose of propranolol (beta 1/beta 2-antagonist). atenolol (beta 1-antagonist). or no beta-blocker (control). The difference between preoperative and preinduction serum K+ in patients receiving propranolol (0.1 +/- 0.4 mEq/L) was significantly attenuated (P less than 0.02) compared with the difference in control subjects (0.5 +/- 0.4 mEq/L). but was not significantly different from controls in patients pretreated with atenolol (0.3 +/- 0.4 mEq/L). These results demonstrate that serum K+ levels measured intraoperatively just before anesthetic induction are consistently and significantly less than those measured 1-3 days preoperatively. The ability of propranolol but not atenolol to block this change suggests that the acute decrease in K+ levels was due to beta 2-adrenergic receptor stimulation.
Simultaneous superior oblique sheathectomy and inferior oblique tuck in congenital Brown's syndrome, Since Harold Brown. in 1950. described the superior oblique tendon sheath syndrome. numerous surgical techniques have been explored to treat this condition. Tenectomy of the homolateral superior oblique. alone or in combination with a weakening procedure on the homolateral inferior oblique. has been the technique most advocated. However. good functional results are rarely achieved in a single procedure. and delayed complications are frequent. Taking advantage of the improved dissection and reduced trauma afforded by the use of a surgical microscope. one of the techniques first recommended and later abandoned by Brown was reappraised. The technique consists of dissection of the sheath and attachments of the superior oblique. while preserving its tendon. combined with a 10mm tuck of the homolateral inferior oblique. Both a typical and a severe atypical congenital case. according to the classification of Brown. were treated in this fashion. Full correction was achieved in both.
Aphakic visual fields by automated perimetry, Accurate testing of the visual field of aphakic patients is demanding due to the optical distortion induced by high plus corrective lenses. This testing procedure can be improved by using an aspheric contact lens instead of a full-aperture loose trial lens. We found that the contact lens enhances the ability of the pattern-deviation printout of the Statpac analysis to identify glaucomatous visual field abnormalities in program 30-2 of the Humphrey Visual Field Analyzer.
Effects of hyaluronic acid fractions in the rabbit eye, Two fractions of hyaluronic acid with different molecular weight (Ial. molecular weight 500.000-730.000 and Healon. molecular weight 750.000) were injected intracamerally or intravitreously in the rabbit eye. Although the fraction with higher molecular weight caused an increase in intraocular pressure. no change of this parameter was found after administration of the fraction with the lower molecular weight. Furthermore. various inflammatory reactions in ocular tissues were observed during slit-lamp biomicroscopy after administration of Healon but not of Ial. No inflammatory reaction was found after subchronic instillation of the compounds.
The predictability of infant visual-evoked response testing on future visual acuity, We reviewed the records of 27 infants with abnormal eye examinations and visual-evoked response (VER) testing (mean age. 10.5 months) who subsequently underwent a long-term follow-up ophthalmology examination (mean duration. 41 months). The infants were initially diagnosed with various ocular disorders including cortical blindness (eight). optic nerve hypoplasia (six). congenital cataract (two). and retinopathy of prematurity (one). Standard optotype visual-acuity determinations were available in the follow-up records of 11 children (21 eyes). and fixation behavior was obtained in the remaining 16 children (32 eyes). Results revealed that pattern-reversal VER P1 latency was predictive (87%) of whether visual acuity was equal to (or better than) or worse than 20/100 and whether a patient would have good fixation behavior (fix and follow. FF) or poor fixation (no FF) (86%) (P less than .001). Although flash VER P1 latency was also predictive of later visual acuity or good fixation (73%). it was not statistically significant. Pattern VER P1 amplitude and flash VER P1 amplitude were not predictive of later visual function. The predictive power of pattern VER P1 latency for later visual function probably relates to its reflection of macular function and low variability. An analysis of the variability of each of the four VER factors in normal infants (n = 50) indicated that pattern VER P1 latency was the least variable. and consequently most sensitive. VER factor for detecting and quantifying pathology. Overall. the results of this retrospective study suggest that pattern VER P1 latency may have important predictive power for later visual function in infants with an initially abnormal ophthalmologic examination.
Laryngeal changes during exercise and exercise-induced asthma, Exercise-induced asthma is defined as bronchospasm within the distal airways initiated by exercise. Whether the larynx responds to produce an exacerbation or alleviation of symptoms during an attack has never been evaluated. Thirty subjects were tested. including 15 normals and 15 with exercise-induced asthma. Laryngeal response to exercise was determined by measuring the area of the glottic aperture before. during. and after exercise. The glottis was visualized with a flexible laryngoscope and video images were recorded during monitoring of respirations. Asthma was induced in subjects by having them exercise on an ergometer for 10 minutes while breathing dry air at 10 degrees C. Measurements were subsequently made from recorded images and relative glottic areas were compared between groups. Our data quantify the normal physiologic response of the larynx to exercise and demonstrate a substantial laryngeal contribution to asthma induced by exercise.
Magnetic resonance imaging and computed tomography in pediatric head and neck masses, Fifty-three magnetic resonance imaging (MRI) and 25 computed tomography (CT) studies of 53 head and neck masses in pediatric patients were reviewed retrospectively. All lesions had pathologic proof except for 2 metastatic and 2 recurrent lesions. which only had prior pathologic confirmation at their primary sites. These included 12 malignant tumors. 23 benign tumors. 6 inflammatory masses. and 12 congenital lesions. The MRI performance ranged predominantly from good to excellent in detection of the lesion and the extent of involvement and in contrast to the surrounding tissue; when CT comparison was available. MRI proved to be equal to or better than it in detection of these factors and in preoperative diagnosis. Our results suggest that MRI should be the method of choice for the initial evaluation of the pediatric head and neck region. especially in those patients requiring multiple examinations. However. CT and MRI should be used conjunctively in complicated cases. especially those possibly involving lesions with calcifications or bony involvement.
Hemangioma of the temporalis muscle, A rare case of an intramuscular hemangioma of the temporalis muscle is reported. The clinical examination. carotid arteriogram. computed tomographic scan. and aspiration cytology suggested the vascular nature of the tumor. but an exact diagnosis could only be made after histopathologic examination. Temporary occlusion of the ipsilateral external carotid artery and subperiosteal dissection permitted complete. wide excision without much bleeding.
Computerized identification of pathologic duodenogastric reflux using 24-hour gastric pH monitoring, Duodenogastric reflux is a naturally occurring sporadic event. the incidence. occurrence. and detrimental effects of which have been difficult to assess. The reliability of 24-hour gastric pH monitoring to detect duodenogastric reflux was studied. Central to the use of pH monitoring for this purpose is confidence in its ability to measure and display pH data in a way that reflects changes in the gastric pH environment with sufficient sensitivity. To test this the gastric pH of 10 dogs was measured in the fasting state. after feeding. and after pentagastrin stimulation. The antrum was more alkaline in the fasting state (p less than 0.01) and the display of data by frequency distribution graph was sensitive enough to reflect induced pH changes. To test the consistency of gastric pH at a given position. simultaneous 24-hour gastric monitoring was performed in 12 normal subjects with two probes placed at either 5 or 10 cm below the lower esophageal sphincter. Only at the 5-cm position did the two probes read within 1 pH unit of each other more than 90% of the time. Based on these principles. gastric pH monitoring was performed 5 cm below the lower esophageal sphincter in 30 normal subjects and 11 patients. fulfilling Ritchie's clinical criteria for pathologic duodenogastric reflux. The data obtained was arranged into 71 variables and subjected to discriminant analysis. Sixteen variables were identified. each with a corresponding coefficient to be used as a multiplier to derive a score. A score of more than +2.2 indicated a high probability of pathologic duodenogastric reflux. The test was applied to a validation population consisting of 10 additional normal subjects and 10 patients meeting Ritchie's criteria. All normal subjects had a normal score and all but one (90%) of the patients had an abnormal score. When compared to O-diisopropyl iminodiacetic acid (DISIDA) scintigraphy in another group of 22 normal subjects and 60 patients. 24-hour gastric pH monitoring was superior in the detection of pathologic duodenogastric reflux. The study shows how the application of computer technology can be used to diagnose pathologic duodenogastric reflux in patients with complex foregut complaints.
Metabolic changes in patients severely affected by tetanus, Metabolic changes in six severely affected tetanus patients suffering from characteristic labile hypertension (maximum systolic blood pressure greater than 200 mmHG. maximum diurnal change in systolic pressure greater than 100 mmHg) were investigated. Daily urinary excretion of urea nitrogen increased gradually from the onset of opisthotonus. reached a peak value (10.4 to 15.4 g/m2) in 8 to 20 days. and decreased subsequently. Average cumulative excretion in 30 days reached 239.6 +/- 32.7 g/m2. Urine catecholamine excretion was elevated in each patient and remained elevated during this period. Plasma cortisol and glucagon concentrations were not increased markedly except in a case complicated other systemic bacterial infection. Increased protein catabolism in these patients could not be explained by the metabolic effects of 'stressed hormones' alone. and neurologic factors must be considered.
Synthesis of type I collagen in healing wounds in humans, To quantify wound healing in surgical patients. samples of wound fluid were collected through a silicone rubber tube for 7 postoperative days and their concentrations of the carboxyterminal propeptide of type I procollagen (PICP) and the aminoterminal propeptide of type III procollagen (PIIINP) were measured with specific radioimmunoassays. The mean concentration of PICP in would fluid on day 1 was 207 +/- 92 (SD) micrograms/L. and on day 2 908 +/- 469 micrograms/L (p less than 0.001. signed rank test). On day 7. the mean concentration reached was 380 times higher than that of day 1 (79.330 +/- 54.151 micrograms/L). Only one peak of PICP antigenicity. corresponding to the intact propeptide as set free during synthesis of type I procollagen. was detected on Sephacryl S-300 gel filtration analysis of wound fluid samples. The mean concentration of PIIINP was 70 +/- 61 micrograms/L on day 1. 86 +/- 88 micrograms/L on day 2. and 180 +/- 129 micrograms/L on day 3 (p less than 0.001 when compared with day 1). Finally on day 7. a 250-fold concentration (17.812 +/- 9839 micrograms/L). compared with day 1. was reached. Methods described in the present paper allow separate and repetitive quantification of the synthesis of both type I and type III procollagen during human wound healing.
Surgical repair of Wolff-Parkinson-White syndrome complicated with myocardial bridging, Myocardial bridging causes myocardial ischemia during supraventricular tachycardia. We present a case of Wolff-Parkinson-White syndrome combined with myocardial bridging. The patient complained of angina pectoris during paroxysmal supraventricular tachycardia because of severe constriction of the left anterior descending coronary artery during systole. A myocardial scintigram revealed myocardial ischemia in the anteroseptal wall during paroxysmal supraventricular tachycardia. Myotomy to prevent myocardial bridging and interruption of the accessory conduction pathway was successfully accomplished in a one-stage operation.
Rectus abdominis muscle flap with microvascular anastomoses for repair of recurrent sarcoma, After radical resection of a recurrent leiomyosarcoma. the thoracic wall was stabilized with a Gore-Tex graft. The skin and soft tissue defect was repaired with a large rectus abdominis flap in which the circulation was secured by end-to-end microvascular anastomosis of the inferior epigastric artery to the internal mammary artery. which had to be cut during tumor removal.
Pleural anesthetics given through an epidural catheter secured inside a chest tube, Pain management after thoracic surgical procedures is a difficult clinical problem. A variety of pain management methods are used with variable efficacy. This paper presents an effective method of pleural anesthetic administration using a pleural catheter inserted through a chest tube.
Intraoperative coronary angiography using fluorescein, Intraoperative coronary angiography using fluorescein was applied to evaluate the patency of saphenous vein grafts just after completion of the distal anastomosis. By this technique. the area of the revascularized myocardium was well estimated in real time. This intraoperative direct-vision examination gives us more timely and precise information during coronary artery bypass grafting.
Alternative technique for repair of sinus venosus atrial septal defect, A technique is described for closure of a sinus venosus atrial septal defect using a single patch held in place by sutures placed from outside the right atrium and underneath the superior vena cava. The superior vena cava does not require enlargement and potential damage to the artery to the sinoatrial node is avoided.
Delayed chest wall pain due to sternal wire sutures, This report describes 18 patients with disabling chest wall pain due to one or more sternal wire sutures. The pain occurred from 2 to 84 months after a median sternotomy. The pain was described either as sharp and stabbing or as a deep-seated ache. The involved wires had an exaggerated fibrous tissue reaction surrounding the twisted portion. The adjacent noninvolved wires had minimal reaction. In the last 7 patients. serial sections of the fibrous tissue revealed entrapment of one or more sensory nerve fibers. In 6 of the 7 electrical potentials were measured and found to be elevated. indicating wire damage during twisting. Ferroxyl tests confirmed the collection of iron ions at this anodic point as a result of corrosion. Removal of the involved wires and the fibrous tissue surrounding this anodic point relieved the symptoms of pain and tenderness resulting from entrapped sensory nerves.
Comparison of supraannular and subannular pledgeted sutures in mitral valve replacement, Ten fresh canine hearts were used to compare the peak left ventricular pressure required to disrupt prosthetic mitral valves sutured in place with horizontal mattress sutures with either subannular or supraannular pledgets. Each group consisted of 5 animals. A 29-mm Medtronic mitral valve was secured in the mitral position with ten pledgeted sutures. The aorta was cannulated and normal saline solution was infused into the left ventricle until valvar disruption occurred. The peak pressure and the location and mechanism of disruption were then noted. At the peak left ventricular pressure required for valvar disruption. no individual sutures were broken. Instead. in all specimens a subannular myocardial rupture occurred in the posterior portion of the mitral annulus along the extent of the atrioventricular groove. In addition. the posterior wall of the left atrium dissected upward subsequently. Significantly greater pressures were required in the group with subannular suture placement as compared with the supraannular group (354 +/- 37 versus 236 +/- 33 mm Hg; p less than 0.0007). These data suggest that placement of horizontal mattress sutures with pledgets in the subannular position is superior to the currently recommended method of supraannular suture placement in mechanical valves.
Staged repair of pulmonary atresia with ventricular septal defect and major systemic to pulmonary artery collaterals, Fifty-eight consecutive patients with pulmonary atresia. ventricular septal defect. hypoplastic pulmonary arteries with arborization defects. and major aortopulmonary collaterals were entered into a program for staged surgical repair between January 1979 and July 1989. Prerepair preparatory procedures were designed to (1) encourage native pulmonary artery growth by increasing blood flow and (2) unifocalize pulmonary blood supply by transplanting or ligating major collaterals. A total of 121 staging procedures were performed with an overall mortality of 10.3%. One hundred thirty-four major collaterals were either ligated or transplanted. Thirty patients eventually underwent hemodynamic repair with an early mortality of 3.3% and late mortality of 10.0%. Twenty-six current survivors of repair remain clinically well after a mean follow-up of 3.6 years. Ten patients are currently in various stages of preparation. Twelve patients (20.7%) failed to achieve minimum requirements for repair after staging and await further palliation or heart-lung transplantation. The principles of management have evolved over the years and are discussed.
Altered cellular immune function in the atelectatic lung, Pulmonary atelectasis is common and may predispose the lung to infection. We have previously shown that atelectasis impairs alveolar macrophage antibacterial function. This study examines the effect of atelectasis on the cytotoxic function of lymphocytes harvested from the bronchoalveolar space of atelectatic lung segments by bronchoalveolar lavage. Specifically. we studied natural killer and lectin-dependent cell-mediated cytotoxicity in peripheral blood and bronchoalveolar lavage lymphocytes from the atelectatic lower lobes and contralateral normal lobes in a group of 8 dogs. We observed a decline of natural killer and lectin-dependent cell-mediated cytotoxicity to 62.7% and 61.5%. respectively. of preatelectasis control values in the affected lung lobes (p less than 0.01). Simultaneous measurements of cytotoxic activity of bronchoalveolar lavage lymphocytes harvested from the unaffected contralateral normal lungs were comparable with control values. On the other hand. natural killer and lectin-dependent cell-mediated cytotoxicity activities in peripheral blood lymphocytes were significantly increased in animals having right lower lobe atelectasis (166.7% and 154.7% of pretreated normal control. respectively. p less than 0.01). Atelectasis was also associated with an influx of polymorphonuclear leukocytes into the bronchoalveolar compartment. These findings confirm the presence of natural killer cells and cytotoxic lymphocytes in the bronchoalveolar compartment and demonstrate an atelectasis-induced impairment of local bronchoalveolar lymphocyte function. Such a dysfunction of local lung cellular host defenses may render the atelectatic lung susceptible to infection.
Might free arterial grafts fail due to spasm, The rat femoral artery was used as a free graft and was studied after 2. 7. 14. 30. and 60 days. The patency of the grafts was 100% (2 days. n = 6). 78% (7 days. n = 9). 63% (14 days. n = 8). 33% (30 days. n = 12). and 18% (60 days. n = 11). Histology showed an intimal thickening after 14 days and the media. which in the controls consisted of eight to ten layers of myocytes. was reduced to six to eight cell layers. During the first 2 weeks the graft segments had an impaired contraction when exposed to Krebs solution with 124 mmol/L K+. whereas after 1 month and later the graft segments approached the controls or had even higher contractile force. The thromboxane mimic U-46619 elicited full contractile force at all times whereas the potency was significantly lower during the first 14 days. Noradrenaline was unable to induce contraction in the graft segments during the first 14 days. but at 30 and 60 days it had regained full contractile force and was significantly more potent (approximately 60 times) in the graft segments compared with the controls. This study suggests that intimal thickening and hypercontractility might be a problem in free muscular arterial grafts.
Does cholesterol screening result in negative labeling effects? Results of the Massachusetts Model Systems for Blood Cholesterol Screening Project, Several previous studies that looked at the effects of labeling individuals as hypertensive found increases in psychosocial distress. diminished feelings of well-being. or absenteeism. Other studies found no such effects. Thus far. similar studies relating to labeling for high blood cholesterol levels have not been published. The Massachusetts Model Systems for Blood Cholesterol Screening Project investigated whether labeling effects occurred as a result of the community-based screening. education. and referral programs it conducted in Worcester and Lowell. Nine questions concerning perceptions of physical and psychological well-being were asked on a questionnaire given to screening participants. The same questions were asked as part of a follow-up questionnaire given to all individuals identified as having high blood cholesterol levels at one of the screenings. Comparison of the baseline and follow-up results did not demonstrate significant overall negative effects among any age. sex. racial. income. or educational groups. On the contrary. responses to many of the questions revealed small but statistically significant improvements in perceptions of physical and psychological well-being. The absence of negative labeling effects may be attributable to the positive. supportive approach to participant counseling taken by the project.
Primary care patients who refuse specialized mental health services, The charts of 65 patients who completed mental health care referrals were compared with those of 65 patients who failed to complete such referrals. In the year before referral. the noncompliant patients made 37% more medical visits than the compliant patients. As compared with the compliant patients. a significantly greater proportion of the noncompliant patients' medical visits were for difficult-to-explain somatic symptoms. Mental health referrals from some physicians were much more successful than referrals from other physicians. By attending to their patients' pattern of health care utilization. primary care physicians may be able to identify patients at high risk for noncompliance with mental health referrals.
Suicide attempts by the old and the very old, Attempted suicide by the elderly is a major psychiatric problem. Ninety-five patients between 60 and 90 years of age were evaluated by a psychiatric consultation service after a suicide attempt. Characteristics of this group included (1) a high degree of premeditation. (2) a tendency toward firearm use and wounds to the head. (3) male sex. (4) coexisting medical problems. (5) serious intent that increased by decade. (6) solitary living arrangements. (7) presence or history of a major psychiatric illness. and (8) ill health reported as a precipitant to suicidality. Major depression was the most common psychiatric diagnosis. with congestive heart failure and chronic obstructive pulmonary disease the most frequently noted physical ailments. This elderly population of attempters resembled older persons who actually completed suicide and differed significantly from 1630 persons aged 16 to 59 years who attempted suicide. Heightened investigation of depressive features. treatment of alcohol abuse. early referral for psychiatric care. limited access to firearms. and strategies aimed at decreasing social isolation are recommended to decrease the likelihood of completed suicide in the elderly.
Low serum thyrotropin (thyroid-stimulating hormone) in older persons without hyperthyroidism, We studied a large population (n = 2575) of unselected ambulatory persons older than 60 years to determine the prevalence of a low serum thyroid-stimulating hormone (TSH) level. ie. of less than 0.1 mU/L using a sensitive assay. a level suggestive of hyperthyroidism in younger adults. One hundred one persons (3.9%) had a low serum TSH level. About half of them (51/101) were taking thyroid hormone. Of the remainder. 44 were not hyperthyroid did not become so during up to 4 years of follow-up. Forty-one of the 44 euthyroid persons had a serum thyroxine level of less than 129 nmol/L; repeated testing showed a serum TSH level of more than 0.1 mU/L in the three euthyroid persons with a serum thyroxine level of more than 129 nmol/L. Only six were hyperthyroid or became so during the follow-up period; all had a serum thyroxine level of more than 129 nmol/L. Routine clinical examination was not a sensitive indicator of hyperthyroidism and did not permit discrimination from euthyroidism. A low value of serum TSH alone. while it had high sensitivity and specificity for hyperthyroidism. had a low positive predictive value (12%) for this diagnosis; addition of the thyroxine assay raised the predictive value fivefold to 67%. A low value of serum TSH is far more common in older persons than is hyperthyroidism. Low values in euthyroid persons are accompanied by a clearly normal serum T4 concentration (less than 129 nmol/L) or by a serum TSH level of more than 0.1 mU/L on repeated testing. We recommend measurement of the serum TSH thyroid concentration. using a sensitive assay. as the initial step in testing any older person for possible hyperthyroidism. Measurement of the serum T4 concentration or the free T4 index on the same sample would be needed only in the approximately 2% with a serum TSH level of less than 0.1 mU/L; alternatively. the TSH assay in these could be repeated at a later time.
Hemoptysis. Indications for bronchoscopy, Indications for bronchoscopy in patients with hemoptysis and a normal or nonlocalizing chest roentgenogram continue to be controversial. We reviewed the records for 119 bronchoscopies performed for hemoptysis in patients with a normal (n = 75) or nonlocalizing (n = 44) chest roentgenogram. Bronchogenic carcinoma was identified in 2.5% of the bronchoscopies. Additional neoplasms were found in another 2.5%. The presence of nonlocalizing abnormalities was not associated with an increase in either the rate of bronchogenic carcinoma or in the diagnostic yield (specific anatomic diagnosis or bleeding site identified) at bronchoscopy when compared with patients with normal chest roentgenograms. The factors of male sex. age more than 40 years. and a more than 40 pack-year smoking history appear useful in identifying patients in whom the yield of bronchoscopy is likely to be high.
The impact of physician compliance on screening mammography for older women, Screening mammography is underutilized. even for women older than 50 years for whom there is a general consensus that regular annual screening is appropriate and necessary. To evaluate reasons for this underutilization. we studied a random sample of 517 women in Los Angeles. Calif who were older than 50 years. All women were found to be underscreened. especially women older than 65 years. For example. approximately 35% of women 50 to 64 years old and 47% of women aged 65 years and older never had had even one mammogram. Analyses revealed that the most important factor that predicted whether a women ever had had a mammogram was whether her physician had talked to her about mammography. Women were between four and 12 times more likely. depending on their age group. to have had a mammogram at some time if their physicians discussed it with them. The discussions did not need to be lengthy or complex. These results indicate that physicians need to know that discussing screening mammography with their patients has a major impact on breast cancer screening behaviors.
The relationship of Papanicolaou testing and contacts with the medical care system to stage at diagnosis of cervical cancer, The relationship of Papanicolaou (Pap) testing and physician visits to stage at diagnosis of cervical cancer was assessed by interviews with 149 women with invasive cervical cancer and 214 women with in situ cervical cancer. A significantly smaller percent of study subjects with invasive disease than in situ disease had at least one Pap test in the 3 years prior to diagnosis (age- and race-adjusted odds ratio: 3.38). The two groups did not differ in visits to a physician for other reasons during this period. Pap testing decreased with increasing age for both groups. but not physician visits. While 65% percent of the subjects with invasive disease aged between 65 and 79 years had never had a Pap test until diagnosis. 88% had seen a physician in the preceding 3 years. Women with regional or distant invasive disease were least likely to have had Pap tests. and. within this group. those aged between 35 and 64 years were also least likely to have seen a physician. Strategies for early detection must reflect missed opportunities and the need to bring those not receiving care into the system.
Decreased mortality in users of estrogen replacement therapy, In a prospective study of 8881 postmenopausal female residents of a retirement community in southern California. we evaluated in detail the relationship between estrogen use and overall mortality. After 7 1/2 years of follow-up. there had been 1447 deaths. Women with a history of estrogen use had 20% lower age-adjusted. all-cause mortality than lifetime nonusers (95% confidence interval. 0.70 to 0.87). Mortality decreased with increasing duration of use and was lower among current users than among women who used estrogens only in the distant past. Current users with more than 15 years of estrogen use had a 40% reduction in their overall mortality. Among oral estrogen users. relative risks of death could not be distinguished by specific dosages of the oral estrogen taken for the longest time. Women who had used estrogen replacement therapy had a reduced mortality from all categories of acute and chronic arteriosclerotic disease and cerebrovascular disease. This group of women had a reduced mortality from cancer. although this reduction was not statistically significant. The mortality from all remaining causes combined was the same in estrogen users and lifetime nonusers.
The relationship between hypochondriasis and medical illness, Forty-one Diagnostic and Statistical Manual of Mental Disorders-III-Revised hypochondriacs were accrued from a primary care practice. Seventy-five control subjects were selected at random from among the remainder of the patients in the same clinic. All subjects completed a structured diagnostic interview and standardized self-report questionnaires. Medical morbidity was assessed with a medical record audit and with primary physicians' ratings. The hypochondriacal and comparison samples did not differ in aggregate medical morbidity. although the hypochondriacal sample had more undiagnosed complaints and nonspecific findings in their medical records. Within the comparison sample. higher levels of medical morbidity were associated with higher levels of hypochondriacal symptoms. This occurred primarily because the most serious medical disorders were associated with more bodily preoccupation. disease conviction. and somatization. Within the hypochondriacal sample. no correlation was found between the degree of hypochondriasis and the extent of medical morbidity.
Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery, We performed a case-control study to estimate the relative risk of reoperation for bleeding in coronary artery bypass graft patients who had taken aspirin within the 7 days preceding surgery. Comparison of 90 cases of reoperation with 180 matched control subjects gave an estimated odds ratio for reoperation of 1.82 (95% confidence interval. 1.23 to 3.32). Although their preoperative coagulation values were similar. cases used significantly more whole blood (cases. 9.5 +/- 5.2 units; control subjects. 3.0 +/- 2.0 units; median +/- interquartile range). packed red blood cells (cases. 2.1 +/- 4.0 units; control subjects. 0.9 +/- 2.0 units). and platelets (cases. 12.2 +/- 12.0 units; control subjects. 2.9 +/- 4.0 units) than control subjects. Cases had intensive care unit stays of 4.7 +/- 5.7 days (mean +/- SD) vs 2.1 +/- 1.9 days for control subjects and postoperative hospitalizations of 10.9 +/- 8.2 days vs 7.0 +/- 3.2 days for control subjects. We conclude that aspirin exposure within 7 days before coronary bypass surgery is associated with an increased rate of reoperation for bleeding and that reoperation is associated with large increases in transfusion requirements and intensive care unit and hospital stays.
Weight gain at the time of menopause, We studied prospectively the weight change and the effect of weight change on changes in coronary heart disease risk factors in a population-based sample of 485 middle-aged women. All women were studied first in 1983 to 1984. when they were premenopausal and aged 42 to 50 years. and then restudied in 1987. Women gained an average of 2.25 +/- 4.19 kg during this 3-year period; 20% of women gained 4.5 kg or more. and only 3% lost 4.5 kg or more. There were no significant differences in weight gain of women who remained premenopausal and those who had a natural menopause (+2.07 kg vs +1.35 kg). Weight gain was significantly associated with increases in blood pressure and levels of total cholesterol. low-density lipoprotein cholesterol. triglycerides. and fasting insulin. Weight gain is thus a common occurrence for women at the time of menopause and is related to the changes in coronary heart disease risk factors observed during this period. Efforts to lose weight or to prevent weight gain may help to mitigate the worsening in coronary heart disease risk factors in middle-aged women.
Muscle conditioning in late poliomyelitis, To study the adaptability of postpolio muscles. 12 subjects (mean age 54 years) participated in a high-intensity resistance exercise program. Seventy-five percent met the criteria for postpolio syndrome. Isometric and isokinetic strength and muscle endurance were measured. Polio-affected muscles were identified in muscle biopsies. The biopsies were also used for measurements of enzymatic activities and for histochemical and histopathologic analyses. Pretraining strength values were less than half those of healthy controls. mean fiber areas were twice those of healthy controls. and oxidative enzyme activity was low. After training. a significant increase in isometric (mean 29%) and isokinetic (mean 24%) strength was observed and maintained for some time. This demonstrates remaining adaptability in muscles already compensated from long-standing polio.
Corticosteroid injections in adhesive capsulitis: investigation of their value and site, Forty-eight patients with frozen shoulder for less than six months were assigned at random to receive three shoulder injections into the subacromial bursa or glenohumeral joint at weekly intervals. The treatment groups were (1) intra-articular methylprednisolone and lidocaine. (2) intrabursal methylprednisolone and lidocaine. (3) intra-articular lidocaine. (4) intrabursal lidocaine. The same physical therapy program was carried out for all patients. Assessments of pain and range of motion were performed by a physical therapist who was uninformed about the nature of the injection therapy. There was no significant difference in outcome between intrabursal injection and intra-articular injection. Injection of steroid with lidocaine had no advantage over lidocaine alone in restoring shoulder motion. but partial. transient pain relief occurred in two thirds of the steroid-treated patients.
A tongue force measurement system for the assessment of oral-phase swallowing disorders, A computer-aided measuring system using a highly sensitive beam transducer has been developed to provide a quantitative. reliable measure of tongue strength. This tool has application in both the diagnosis and treatment of dysphagic patients with oral-stage dysfunction. The device is customized to comfortably adapt to each individual. Audiovisual feedback is used to enhance subject interest and motivation. The device has proven reliable in measurements of upward and side tongue thrust in six able-bodied subjects measured during five separate sessions. It has also been used with two dysphagic patients.
Combined hepatic and vena caval resection with autogenous caval graft replacement, Right-sided and caudate hepatic lobectomy with resection of the retrohepatic vena cava were performed in a 34-year-old woman with recurrent adrenal carcinoma. The vena cava was replaced with a graft constructed from autogenous superficial femoral vein. Included herein is a review of the literature detailing the three previously reported cases of combined hepatic and caval resection; to our knowledge. there are no prior reports of the use of an autogenous vein graft in this setting. With surgical and anesthetic techniques. including total vascular exclusion of the liver and venovenous bypass. methods that were developed in large part through experience in liver transplantation. this type of surgery can be performed with a high rate of success.
Photodynamic therapy to treat tumors of the extrahepatic biliary ducts. A case report, The poor survival rate of patients with extrahepatic bile duct tumors is well documented. Over the course of 4 years. we treated a white woman with diabetes diagnosed with histologically proven adenocarcinoma of the common bile duct with six injections of dihematoporphyrin ether followed by seven photodynamic therapy treatments to the biliary duct. As of July 1989. the patient was still alive. was not jaundiced. and had a Karnofsky performance status of 70. No changes occurred in any blood chemistry value from the time of injection to the time of photodynamic therapy. Of the transient elevations of some blood chemistry values and the white blood cell count. which occurred within 24 to 48 hours after photodynamic therapy. only those of alanine aminotransferase. aspartate aminotransferase. and amylase were significant.
Indications for surgical debridement in 125 human bites to the hand, Indications for operative intervention following human bites to the hand were determined based on physical examination and time elapsed since injury. One hundred twenty-four patients admitted to Charity Hospital of New Orleans. La. were stratified according to time elapsed from injury to treatment (early. less than 24 hours; delayed. 1 to 7 days; and late. greater than 7 days). Patients in the early group were mainly treated with conservative wound care. consisting of local wound exploration and irrigation in the emergency department. while those in the late group underwent surgical debridement. Patients in the delayed group either received conservative wound care or underwent debridement in the operating room. The early and late groups recovered excellent hand function while results within the delayed group were variable with improved results depending on rapid surgical debridement or drainage.
Effects of granulocyte-macrophage colony-stimulating factor in burn patients, We studied the effects of granulocyte-macrophage colony-stimulating factor in burn patients. Serial measurements of granulocyte oxidative function were obtained in treated patients and in a group of controls matched for age and total burn size. The administration of granulocyte-macrophage colony-stimulating factor resulted in a 50% increase in mean leukocyte counts. Both groups showed significant baseline increases in granulocytic cytosolic oxidative function. Treated patients showed normal stimulated cytosolic oxidative function. which was significantly depressed compared with that of untreated patients. Myeloperoxidase activity was increased in treated patients during the first postburn week but then declined to normal levels. Untreated patients had a significant increase in myeloperoxidase activity for the first 3 weeks following injury. Untreated patients exhibited a significant decrease in superoxide activity during the second 3 weeks following injury. Treated patients demonstrated normal superoxide activity.
Universal precautions are not universally followed, Adherence to universal blood and body fluid precautions was studied in surgical patient care areas of a university hospital in an effort to identify potentially hazardous health care personnel practices. Surgical teams of an 18-unit operating room. three surgical ward patient care teams. and patient care personnel in a 16-bed surgical intensive care unit were observed during routine patient care activities before (study 1) and after (study 2) specific educational programs were held to improve universal precaution compliance. Overall. infractions occurred in 57% of 549 observed procedures in study 1 and in 58% of 616 observed procedures in study 2. In study 1. infractions occurred in 75% of operating room procedures. 30% of surgical ward procedures. and 75% of surgical intensive care unit procedures. Study 2 procedure infraction rates were 81%. 32%. and 40%. respectively. Only surgical intensive care unit compliance significantly improved. Noncompliance with universal precautions occurs frequently during the care of patients who have undergone surgery. with the type of infraction and specific offender varying according to patient locale. These violations appear unamenable to one-time educational efforts. Substantial overall improvement may arise from ongoing educational programs directed at specific personnel who care for patients who have undergone surgery.
Intussusception and the diagnostic value of testing stool for occult blood, A retrospective review was performed to determine the diagnostic value of testing for occult blood in stool of children suspect for intussusception. Ninety-six children had barium enema studies for suspected intussusception. Of the 57 children who had barium enema confirmed intussusception. 29 did not have history or physical findings of gross blood per rectum. Stool was tested for occult blood in 16 of these 29 patients. and 12 (75%) were positive. In comparison. three (20%) of the children who did not have intussusception had stool positive for occult blood. Stool with occult blood was significantly associated with intussusception (P less than .002). The only other clinical factor significantly associated with intussusception was abdominal mass (P less than .02). Vomiting. episodic irritability. poor feeding. abdominal pain and lethargy were not significantly different in the two groups. In conclusion. the authors suggest stool testing for occult blood when evaluating children who present with nonspecific signs and symptoms supportive of intussusception.
Seatbelt effectiveness and cost of noncompliance among drivers admitted to a trauma center, Enactment of seatbelt legislation in Maryland presented the opportunity to compare seatbelt compliance among seriously injured drivers admitted to a Level I trauma center and to establish levels of severity. length of stay. and hospital cost differences among the study population. Fifty-five randomly selected drivers were examined from a total surgical population of 689. Seatbelt compliance rate was 41.8%. reflecting the rate in the community. Seatbelts reduced the total number of injuries by 34%. major injuries by 57%. and minor injuries by 20%. No deaths occurred among the belted group. The unbelted group had a mean Injury Severity Score two times as great as the belted group and were hospitalized 1.6 times longer at double the cost. Major injuries to the face. chest. and pelvic regions were prevented by the seatbelt. Among the belted group. severe injuries did occur to the head. neck. and abdominal regions. It is recommended that both air bags and automatic restraining devices be required for all drivers if the trauma occurring daily on highways is to be eliminated and acute hospital cost minimized.
Carbidopa-levodopa overdose, A 57-year-old woman ingested 15 to 17 tablets of carbidopa-levodopa 10/100 tablets (carbidopa 150 mg and levodopa 1.500 mg) along with ibuprofen. carisoprodol. hydrocodone. and acetaminophen. The patient developed choreiform movements that persisted despite obtundation and attempts to extinguish them with naloxone. morphine. and diazepam. When the patient developed a rising level of creatine phosphokinase and myoglobinuria. she was treated with ventilatory support and pancuronium. She required paralysis for 60 hours. when her chorea resolved.
Sudden cervical pain: spontaneous cervical epidural hematoma, Three cases of cervical epidural hematoma are reported. Acute neck pain usually associated with a mild effort. closely followed by radicular pain and a neurologic deficit below the lesion is the typical presentation of this extremely rare and difficult diagnosis. As prognosis depends on preoperative neurologic state. the authors emphasize the importance of prompt identification of this lesion. The diagnosis is confirmed by computed tomography. and emergency neurosurgical laminectomy is mandatory.
The Three Rivers Regatta accident: an EMS perspective, The Three Rivers Regatta accident occurred on August 7. 1988 when a Formula I racing craft collided with shore. injuring 24 spectators. The authors retrospectively examined the prehospital-based response for this multiple-casualty incident that used emergency medical service (EMS) physicians and 32 paramedics stationed at water and land-based posts to triage and evacuate 24 patients in 32 minutes. Patients were transported to 5 hospitals including 4 Level I trauma centers; this was accomplished in 53 minutes. The EMS response was unique in a number of respects. This was a prehospital-based rescue with the entire triage and stabilization phase accomplished by River Rescue units that transported paramedic divers. EMS physicians. and trauma supplies for 30 patients. Also of significance was the inordinate proportion of pediatric patients that accounted for 50% (12/24) of the cases. Successful medical care was the result of planning based on "Daily Routine Doctrine" or escalation of existing treatment protocol; adequate supplies. personnel and transport adapted to local geography and patient population; communications. including all services--EMS. police. and fire; and prehospital physician input to ensure correct triage order and patient disposition.
Comparison of median and posterior tibial nerve somatosensory evoked potentials in ambulatory patients with definite multiple sclerosis, Somatosensory evoked potentials (SEPs) were recorded for stimulation of both median nerves and both posterior tibial nerves in control subjects and in subjects with multiple sclerosis (MS) of several years' duration. who were ambulatory and not experiencing exacerbation. Documentation of peripheral nerve conduction revealed no abnormalities in any of the subjects. Centrally. abnormal responses to median and posterior tibial nerve stimulation were found at the spinal level and/or the scalp in nearly all MS patients. Using the latency of the initial negativity of scalp SEPs. posterior tibial SEPs were abnormal significantly more often than median SEPs. Calculations suggested a significant increase in spinal conduction time. The high incidence of abnormal SEPs does not support any substantial physiological recovery in this group of MS patients.
Antibodies to HIV-1 nef(p27): prevalence, significance, and relationship to seroconversion, A sensitive and specific enzyme-linked immunoassay for antibodies to the human immunodeficiency virus type 1 (HIV-1) nef gene product. p27. has been developed using recombinant Escherichia coli-derived protein from the LAV-1-Bru sequence. Of 92 HIV-1 infected hemophiliacs. 72 (78%) produced anti-nef antibodies in this assay; the early appearance of anti-nef prior to full seroconversion was a rare event in this population. occurring in only one subject (approximately 1%). Anti-nef antibodies were not detected in any of 500 sera from 98 repeatedly HIV seronegative subjects who had been exposed to sexually transmitted modes of HIV infection (45 subjects) or through blood products (53 subjects). There was no significant association of titer or anti-nef antibody with protection from disease in HIV infection (p = 0.1). Although the nef protein is relatively immunogenic in natural infection. this study cannot confirm the previously reported high prevalence of anti-nef antibodies prior to seroconversion. nor the finding of anti-nef antibodies in HIV seronegative but exposed subjects.
Measurement of end-expiratory pressure during transtracheal high frequency jet ventilation for laryngoscopy, An anaesthetic technique using high frequency jet ventilation has been proposed for direct laryngoscopy. but this may expose the patients to the risk of barotrauma. In order to assess this risk. we have measured end-expiratory airway pressure (EEP) through the injector using two three-way solenoid valves mounted in series. At the end of insufflation the first valve was switched off and the apparatus deadspace connected to atmosphere through a large exit port during an adjustable time (decompression time). Then the second valve was switched off and the injection line connected to a transducer. allowing measurement of EEP through the injector. The accuracy of this measurement was tested against airway pressure measured directly in the trachea (Pt) in a lung model. Provided that the decompression time was long enough (70 ms) and the apparatus deadspace was small (6 ml). the difference between EEP and Pt was less than 1 cm H2O for frequencies up to 5 Hz. A clinical evaluation was performed in 64 patients under general anaesthesia before laryngoscopy. EEP correlated with end-expiratory pulmonary volume above apnoeic FRC inferred from abdominal and thoracic displacements. At jet frequencies up to 5 Hz. the correlations between these two variables were satisfactory (r greater than 0.88). suggesting that EEP is a good indicator of pulmonary overdistension.
Ultrasound assessment of the position of the tongue during induction of anaesthesia, Tongue position was assessed in 15 female patients at induction of anaesthesia with either thiopentone or propofol. A video recording of a midline sagittal section of the tongue was made using an ultrasound transducer placed below the chin. and representative figures analysed by an observer who was not aware of the patient's state. In 11 satisfactory recordings. the tongue movement was inconsistent in direction and not more than 8 mm in the anterior tongue and 6 mm in the posterior tongue. The movements detected did not suggest that the tongue is likely to be an important cause of airway obstruction on induction of anaesthesia.
The role of alpha 1-adrenoceptors in adrenaline-induced hyperkalaemia, The hyperkalaemic action of adrenaline was investigated in 44 anaesthetized domestic pigs. Plasma and epicardial concentrations of K+ were measured. in the latter case with an ion-selective electrode. Adrenaline 10 micrograms kg-1 caused a rapid increase in the plasma concentration of K+ from 4.2 to 5.9 mmol litre-1. The magnitude and the time course of epicardial concentration of K+ were similar. Alpha-adrenoceptor block with either phentolamine 5 mg kg-1 (non-selective block) or prazosin 0.1 mg kg-1 (selective alpha 1-adrenoceptor block) abolished the hyperkalaemic effect of adrenaline in the plasma and on the epicardium. The alpha 1-adrenoceptor agonist phenylephrine increased the K+ concentration. but the alpha 2-adrenoceptor agonist UK 14.304 did not cause any change in concentration. These results suggest that the hyperkalaemia induced by adrenaline occurs in the interstitial fluid of the myocardium and is mediated by alpha 1-adrenoceptors. These findings may be important in patients at risk of hyperkalaemia. with implications. for example. in the use of suxamethonium during induction of anaesthesia.
Use of the calcium agonist BAY K 8644 for in vitro diagnosis of susceptibility to malignant hyperthermia, We have studied the effects of the calcium agonist BAY K 8644 on the in vitro halothane test in 10 malignant hyperthermia-susceptible (MHS). 12 MH "equivocal" to halothane (MHEh). 30 MH non-susceptible (MHN) and 10 control patients. BAY K 8644 potentiated the halothane-induced contracture in muscle strips from both MHS and MHEh patients. The drug produced a more obvious difference in contracture responses between the MHEh group compared with the MHN and control groups.
Factor analysis in difficult tracheal intubation: laryngoscopy-induced airway obstruction, We have studied eight patients with a history of difficult tracheal intubation. using x-ray laryngoscopy and local anaesthesia. a curved Macintosh blade and a standard intubating position. The view obtained was better than recorded previously during general anaesthesia in two patients. and in a third the x-ray showed that positioning the blade tip beneath the epiglottis would have improved vision. suggesting that reproducibility of the assessment may not be consistent. The "ease of intubation" and "complementary" angles may be helpful in the assessment of such patients. A "peardrop" effect is described whereby during laryngoscopy. the epiglottis became pressed against the posterior pharyngeal wall as a result of tongue compression. In the absence of muscle paralysis. removal of the blade caused immediate correction. However. during anaesthesia with neuromuscular block it is suggested that this not only occurs more readily but. may not correct when the blade is removed. Iatrogenic airway obstruction during moderately difficult tracheal intubation may be common and should be anticipated.
Factor analysis in patients with a history of failed tracheal intubation during pregnancy, Eight patients with a history of failed tracheal intubation during pregnancy were investigated by x-ray laryngoscopy after delivery. Partial elevation of the epiglottis with no view of glottic structures was found in five patients who were therefore considered to still present difficulty. In each of these five patients the blade tip failed to make contact with the hyoid and in four this was explained by the tongue being compressed into a pear shape such that it prevented sight of the larynx. Relatively few abnormal anatomical indices were seen in these patients and this was in keeping with the level of difficulty encountered. An angular measure of jaw protrusion from a line joining the upper incisors and a point just above and anterior to the vocal cords. to the mid-point on the inner surface of the mandible was useful: the lower angle of this triangle was as important as the angle at the incisors.
Unconsciousness associated with midazolam and erythromycin, An 8-yr-old boy suffering from an asymptomatic ventricular septal defect was given erythromycin for antibiotic prophylaxis before adenoidectomy. Sixty minutes after premedication with oral midazolam 0.5 mg kg-1 and oral atropine 0.03 mg kg-1. an infusion of erythromycin 400 mg was started. When 200 mg of erythromycin had been infused. the patient lost consciousness. but other vital functions remained normal. After 45 min. he awakened spontaneously. At the time the plasma concentration of midazolam was 134 ng ml-1. In order to investigate possible interactions between midazolam and erythromycin. we studied the pharmacokinetics of midazolam in six children of the same age undergoing minor otolaryngological surgery. The plasma concentration of midazolam in the patient who lost consciousness was significantly greater than in six other children without concomitant administration of erythromycin. The altered pharmacokinetics of midazolam may result from reduced hepatic clearance of midazolam caused by an enzyme inhibiting drug. erythromycin.
Langerhans cells but not monocytes are capable of antigen presentation in vitro in corticosteroid contact hypersensitivity, Corticosteroids suppress delayed-type hypersensitivity (DTH) reactions in vivo and impair lymphoid cell functions in vitro. In contact hypersensitivity (CHS) to corticosteroids. however. the corticosteroids are capable of inducing DTH responses in vivo. The present study examined the capacity of corticosteroids to induce in vitro proliferation of T lymphocytes from patients with CHS to corticosteroids. With peripheral blood mononuclear adherent cells as antigen-presenting cells (APC) and hydrocortisone-17-butyrate (H-17-B) as hapten. no proliferation responses were detected of T lymphocytes from patients with CHS to H-17-B. However. when epidermal Langerhans cells (LC) were used as APC. weak proliferation responses were observed.
Validation of Sickness Impact Profile and Psoriasis Disability Index in Psoriasis, A prospective cross-sectional questionnaire study of 32 patients with psoriasis was carried out in order to validate the use of the Sickness Impact Profile (SIP) in psoriasis and compare its sensitivity with the Psoriasis Disability Index (PDI). Overall PDI scores. but not overall SIP scores. correlated well with PASI scores (P less than 0.05). There was good correlation between the PDI and overall SIP scores (P less than 0.01). Psychosocial factors are more severely impaired than physical activities in patients with psoriasis. It is now possible to directly compare the disability experienced by psoriatic patients with that experienced by patients suffering from other systemic diseases. using the SIP. The PDI is an appropriate method to give a rapid overall measure of psoriasis disability.
Pigmented spindle cell naevus, We report 22 cases of pigmented spindle cell naevus (PSCN). The usual appearance of these naevi is that of a heavily pigmented papule found mostly on the legs of young patients. Histologically. PSCN was characterized by symmetrical proliferation of spindle-shaped pigmented melanocytes grouped in large junctional nests. Pagetoid spread of single cells in the overlying epidermis was frequently found. In our opinion. PSCN is a distinctive benign acquired melanocytic naevus that in the past has been frequently misdiagnosed as atypical Spitz naevi or malignant melanoma.
Clear ultraviolet blocking lenses for use by PUVA patients, It is well recognized that patients receiving photochemotherapy (PUVA) need to wear UV-blocking sunglasses on the day of ingestion of 8-methoxypsoralen. For many patients the wearing of tinted sun-glasses causes difficulties because they interfere with colour perception. reduce definition in conditions of low background light and often because they are considered 'cosmetically unacceptable'. In this study the UV-blocking properties of a number of lenses with little or no tint were assessed. The following lenses or lens coatings were found to be suitable for use by PUVA patients: Orcolite UV 400. Orma UVX. Rodenstock Lambda 400. Sola UV Gard 400 and Polaroid polarizing lenses.
Factor XIIIa in nodular malignant melanoma and Spitz naevi, The distribution of factor XIIIa-positive dermal dendritic cells was studied in a series of nodular malignant melanomas and compared with that seen in Spitz naevi. Two patterns of distribution were recognizable: (a) diffusely spread through the tumour and (b) located mainly at the periphery of the tumour. These did not correlate with the diagnosis of melanoma or Spitz naevus and the distribution appeared to be a function of growth pattern of the tumour. The diffuse pattern was the most common regardless of diagnosis and the distribution of factor XIIIa-positive cells is the same in malignant melanoma and Spitz naevi.
Lack of evidence for infection of or effect on growth of hematopoietic progenitor cells after in vivo or in vitro exposure to human immunodeficiency virus, The pathogenesis of the hematologic abnormalities commonly observed in patients with acquired immunodeficiency syndrome (AIDS) is incompletely understood. We report here that in vitro growth of myeloid (CFU-GM) and erythroid (BFU-E) progenitor cells from six patients with AIDS was not significantly different from that of normal human immunodeficiency virus (HIV) seronegative donors: 25.3 +/- 5 CFU-GM per 5 x 10(4) low density marrow cells and 33.5 +/- 5 BFU-E were observed in AIDS patients versus 32.7 +/- 5 CFU-GM and 42.1 +/- 5 BFU-E in controls. Furthermore. no HIV-DNA in individual colonies (CFU-GM and BFU-E) could be detected using the polymerase chain reaction (PCR) technique. although HIV-1 DNA was detected in peripheral blood mononuclear cells from the same patients. Similarly. normal bone marrow cells exposed in vitro to different isolates of HIV or recombinant purified HIV-1 envelope glycoprotein (gp) 120 did not exhibit any difference in growth of CFU-GM or BFU-E as compared with mock exposed bone marrow cells. HIV-1 DNA could not be detected by the PCR technique in individual colonies derived from HIV exposed marrow. This study suggests that committed myeloid and erythroid progenitors from AIDS patients are responsive to hematopoietic growth factors in vitro and do not appear to contain HIV-1 DNA. Also. HIV or its envelope gp did not alter the growth of hematopoietic progenitor cells in vitro. No evidence of HIV infection of progenitor cells could be demonstrated. Impaired hematopoiesis in patients with AIDS may not be related to direct effects of HIV on committed progenitor cells.
Free protein S levels are elevated in familial C4b-binding protein deficiency, In plasma. 40% of the protein S is free and functions as a cofactor for the anticoagulant effects of activated protein C. The remaining 60% of protein S is complexed to C4b-binding protein and is functionally inactive. A family with hereditary C4b binding protein deficiency has been identified with C4b-binding protein levels in an affected father and daughter of 37 micrograms/mL and 23 micrograms/mL. respectively; these values are significantly below the normal range for this protein of 180 micrograms/mL +/- 44 micrograms/mL (mean +/- 2 SD). The total protein S (free + bound) is normal in these individuals (23.2 micrograms/mL and 17.8 micrograms/mL. respectively; normal 19.1 micrograms/mL +/- 6.0 micrograms/mL). The free protein S levels are markedly increased at 22.5 micrograms/mL and 17.4 micrograms/mL. respectively (normal 5.9 micrograms/mL +/- 2.4 micrograms/mL). This experiment of nature shows that total protein S levels in plasma are not affected by the absence of C4b-binding protein and that chronic elevation of free protein S is not associated with increased hemorrhagic tendencies.
Surreptitious ingestion of a long-acting vitamin K antagonist/rodenticide, brodifacoum: clinical and metabolic studies of three cases, The vitamin K metabolism of three patients with factitious purpura due to brodifacoum ingestion was studied. These patients. who presented with bleeding disorders due to deficiency of the vitamin K-dependent blood clotting proteins. were refractory to vitamin K1 at standard doses and required fresh frozen plasma to control bleeding until large doses of vitamin K1 were used. Metabolic studies demonstrated a blockade in vitamin K utilization. consistent with the presence of a vitamin K antagonist. but the patients denied use of anticoagulants. Warfarin assays were negative. We show that the factitious purpura in each patient was due to the surreptitious ingestion of brodifacoum. a potent second generation long-acting vitamin K antagonist used as a rodenticide. The coagulopathies responded to long-term therapy with large doses of vitamin K1. The serum elimination half-time for brodifacoum ranged from 16 to 36 days in these patients. The anticoagulant effect is of long duration. requiring chronic vitamin K treatment. With increasing availability of new rodenticides. factitious purpura due to surreptitious ingestion of these potent vitamin K antagonists is emerging as a new problem. previously associated with warfarin. with important implications for diagnosis and treatment.
Regulatory control of the terminal complement proteins at the surface of human endothelial cells: neutralization of a C5b-9 inhibitor by antibody to CD59, Functionally inhibitory antibody to the plasma membrane complement inhibitor CD59 has been used to investigate control of the terminal complement proteins at the endothelial cell surface. Antibodies against purified human erythrocyte CD59 (polyclonal anti-CD59 and monoclonal antibodies [MoAbs] 1F1 and 1F5) were found to bind specifically to monolayers of cultured human umbilical vein endothelial cells. and by Western blotting to recognize an 18- to 21-Kd endothelial protein. When bound to the endothelial monolayer. anti-CD59 (immunoglobulin G or Fab fragment) potentiated membrane pore formation induced upon C9 binding to C5b-8. and augmented the C5b-9-induced cellular responses. including stimulated secretion of von Willebrand factor and expression of catalytic surface for the prothrombinase enzyme complex. Although potentiating endothelial responses to the terminal complement proteins. anti-CD59 had no effect on the response of these cells to stimulation by histamine. Taken together. these data suggest that human endothelial cells express the CD59 cell surface inhibitor of the terminal complement proteins. which serves to protect these cells from pore-forming and cell-stimulatory effects of the C5b-9 complex. These data also suggest that the inactivation or deletion of this cell surface regulatory molecule would increase the likelihood for procoagulant changes in endothelium exposed to complement activation in plasma.
Granulocyte-macrophage colony-stimulating factor synergizes with interleukin-6 in supporting the proliferation of human myeloma cells, The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the growth of multiple myeloma (MM) was investigated in 21 patients with MM. In 17 patients with proliferating myeloma cells in vivo. recombinant GM-CSF significantly increased the endogenous-IL-6-mediated spontaneous myeloma cell proliferation occurring in 5-day cultures of tumor cells in vitro (P less than .01). Furthermore. GM-CSF was detected in 5-day culture supernatants of myeloma bone marrow cells. This endogenous GM-CSF was produced by the myeloma bone marrow microenvironment but not by myeloma cells and contributed to the spontaneous myeloma-cell proliferation observed in 5-day cultures. In fact. this proliferation was partially blocked (67%) by anti-GM-CSF monoclonal antibodies. The stimulatory effect of rGM-CSF was mediated through IL-6 because it was abrogated by anti-IL-6 monoclonal antibodies. rGM-CSF did not reproducibly increase the endogenous IL-6 production in short-term cultures of bone marrow cells of MM patients. Using an IL-6-dependent myeloma cell line (XG-1 cell line). rGM-CSF was shown to act directly on myeloma cells stimulating by twofold their IL-6 responsiveness. rGM-CSF did not induce any IL-6 production in XG-1 cells. nor was it able to sustain their growth alone. Although no detectable GM-CSF levels were found in the peripheral or bone marrow blood of MM patients. it is possible that GM-CSF. produced locally by the tumoral environment. enhances the IL-6 responsiveness of myeloma cells in vivo in a way similar to that reported here in vitro.
Immunochemical and electrophoretic analyses of phosphorylated native and recombinant neutrophil oxidase component p47-phox, Human polymorphonuclear neutrophils (PMNs) possess a potent oxygen-dependent microbicidal system that depends on the activity of a stimulus-activated multicomponent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Patients with chronic granulomatous disease (CGD) lack activity of this oxidase and consequently suffer severe and frequent infections. Components of the oxidase include both membrane-bound factors (most notably. cytochrome b559. which is absent in the X-linked form of CGD) and at least two cytosolic factors. one or the other of which is absent in autosomal CGD. Patients with CGD. particularly the autosomal type. have defective phosphorylation of proteins in the 44 to 48 Kd range. A polyclonal antiserum (B-1) that recognizes cytosolic oxidase components of 47 and 67 Kd was used to identify phosphoproteins in a cell-free oxidase system. Two-dimensional gel electrophoresis showed the identity of the 47-Kd cytosolic protein (p47-phox) recognized by B-1 and the cationic 47-Kd protein that is phosphorylated in normal but not p47-phox-deficient CGD cytosol during activation of the NADPH-dependent oxidase. All full-length and C-terminal recombinant p47-phox proteins augmented the superoxide-generating capacity of the cell-free system and were phosphorylated when added to cytosol from normal subjects or from a patient with p47-deficient autosomal CGD. These studies provide compelling evidence that the 47-Kd cationic protein that is a substrate for phosphorylation during the activation of PMNs is. in fact. p47-phox. a cytosolic protein previously shown to be critical for normal activity of the NADPH-dependent oxidase of PMNs.
Molecular basis for alpha-thalassemia associated with the structural mutant hemoglobin Suan-Dok (alpha 2 109leu----arg) [published erratum appears in Blood 1991 Mar 15;77(6):1404], Hemoglobin (Hb) Suan-Dok (alpha 109Arg) is a rare alpha-globin structural mutation that is linked to an alpha-thalassemia (alpha-thal) determinant. When inherited in trans to an alpha-thal-1 mutation (-). it results in Hb H disease associated with low levels (9%) of the Suan-Dok Hb. The nature of the thalassemic defect associated with the alpha SD mutation has been investigated by structural and functional studies. Sequence analysis of the cloned Suan-Dok allele showed a missense mutation (T----G) at codon 109 in an otherwise normal alpha 2-globin gene. When the alpha 2SD-globin gene was introduced into mouse erythroleukemia cells. the steady state alpha-globin messenger RNA (mRNA) level was equivalent to the alpha A-globin gene control. Although in vitro translation of a synthetic alpha 2SD-globin mRNA generated levels of alpha globin equivalent to alpha 2A-globin mRNA at early time points. the ratio of alpha SD to alpha A globin decreased markedly at later time points. These data suggest that the thalassemic defect associated with the Suan-Dok mutation results from a significant instability of the alpha SD globin.
Regulatory elements of the erythropoietin gene, Because the human hepatoma cell line Hep3B produces erythropoietin (Epo) in a regulated fashion. it can be used to investigate the cis-acting regulatory elements of the Epo gene. Comparison of primate and mouse sequences shows strong homology not only in the coding sequence but also within the 5' flanking region. the first intron. and the 3' flanking region. These portions of the Epo gene were inserted 5' and 3' to a reporter gene. human growth hormone (GH). 5A is a 1.192-base pair (bp) HindIII-Xbal fragment that extends from 378 bp 5' to the cap site through the first intron. To obviate the problem of false initiation of translation from the Epo ATG start codon. this site was changed to TAG by site-directed mutagenesis. 3A is a 255-bp Accl-BglII fragment that extends 67 bp upstream from the Epo termination codon and covers most of the 3' noncoding region of homology. The plasmid DNAs were transfected by electroporation into Hep3B cells with RSVCAT as an internal standard to correct for transfection efficiency. One aliquot of cells was exposed to 50 mumol/L CoCl2 or to 1% O2. At the end of the incubations. GH and Epo were measured in the cell media and the cell pellet was assayed for CAT. Production of GH was stimulated 1.7-fold by cobalt or hypoxia. Furthermore. addition of 3A to the GH gene. irrespective of orientation. stimulated GH production 2.6-fold with CoCl2 and 2.3-fold with hypoxia. Stable cell lines were produced by cotransfection of the above constructions. along with the selectable marker pSV-Neo. In two clones. exposure to hypoxia resulted in much more marked (16-fold) induction of GH. Stimulus of both GH and Epo production by hypoxia was partially abrogated by carbon monoxide. These results demonstrate the presence of promoter and enhancer elements within the human Epo gene that are appropriately responsive to hypoxia and cobalt.
Retroviral transformation of cerebral microvascular endothelial cells: macrophage-like and microvascular endothelial cell properties, We report that L-cell-conditioned medium (LCM) transforms porcine cerebral microvascular (PCMV) endothelial cells into cells with macrophage-like properties. LCM is known to contain both cytokine(s) and the L-cell virus. a murine retrovirus found in the L929 cell and LCM. Our evidence suggests that both LCM cytokine(s) and the L-cell virus are involved in this PCMV endothelial cell transformation. Criteria for transformation include focus formation. decreased serum requirements for growth. changes in morphology including nonadherence. propagation in suspension culture. and a decreased growth response to stimulation with a known endothelial cell mitogen. Macrophage-like characteristics of this transformed cell. designated as RVTE. include pinocytosis of low-density lipoprotein. Fc receptor-mediated phagocytosis. phagocytosis of bacteria and zymosan. the expression of macrophage enzyme markers. and constitutive production of colony-stimulating factor 1. However. the transformed cell retains several properties of the nontransformed cell including the expression of FVIII:RAg and in vitro self-organization into capillary-like structures. Cloning of RVTE cells clearly shows that both macrophage-like and cerebral microvascular endothelial cell properties are present in the same cell. During self-organization. nontransformed cells express morphologic and functional characteristics classically associated with the macrophage. These findings suggest that some brain capillary pathophysiologies could involve macrophage-like cerebral microvascular endothelial cells. Furthermore. the "reticuloendothelial" phenotypic repertoire expressed by this transformed cerebral microvascular endothelial cell may show that the cerebral capillary endothelial cell in vivo is derived from a hematopoietic and/or phagocytic precursor.
Molecular defect in coagulation factor XFriuli results from a substitution of serine for proline at position 343, Our previous findings suggested that coagulation factor XFriuli could be functionally defective owing to a point mutation in the portion of the factor X gene coding for the fully activated heavy chain. To verify the existence of this postulated change. we analyzed all eight exons of the normal and Friuli factor X gene. Each exon was amplified from genomic DNA using the polymerase chain reaction and cloned into the plasmid pUC19. The amplified DNA inserts were subjected to direct sequencing by the dideoxy chain termination method with forward and reverse oligonucleotide sequencing primers. A point mutation (C to T transition at nucleotide position 19.297) that results in coding for serine (TCC) in place of proline (CCC) at amino acid position 343 was found. This substitution involves a highly conserved proline residue oriented spatially close to both the cleavage site of the zymogen and the active site of the enzyme and explains the previous observations of discrete biochemical and functional differences between factor XFriuli and normal factor X. The mutation abolished an HgiCI restriction site present in the normal factor X gene. and this change constitutes the basis for a convenient method for screening individuals carrying this molecular defect. Proline343 is in conserved region 5 of the serine protease superfamily to which factor X belongs and is part of a 14-residue L*****P******C motif that occurs in at least 16 other enzymes. Computer analysis suggests that the motif may be an essential aspect of conformational features important to functional properties of factor X as well as other serine proteases.
Consistent involvement of the bcr gene by 9;22 breakpoints in pediatric acute leukemias, To investigate the relationship of bcr-abl fusion mRNAs with childhood acute lymphoblastic leukemias (ALL). we examined 27 pediatric Philadelphia chromosome (Ph1)-positive acute leukemias using a reverse polymerase chain reaction (PCR) procedure. In cells from 24 leukemias. single bcr-abl PCR products were detected that corresponded to breakpoints in the minor breakpoint cluster region (mbcr in intron 1 of the bcr gene) associated with production of the P190 fusion protein. Cells from the three remaining leukemias contained breakpoints in the major breakpoint cluster region (Mbcr) as shown by PCR and Southern blot analyses. These three leukemias also contained low levels of the mbcr PCR product that may have resulted from alternative splicing of the bcr-abl precursor RNA. A screen of 35 additional leukemias from patients who failed therapy before day 180 (induction failures or early relapses) found one case with unsuccessful cytogenetics to express Mbcr-abl RNA. All four children with Mbcr breakpoints had white blood cell levels in excess of 250.000 at presentation (compared with 2 of 24 with mbcr breakpoints) and two had hematologic and clinical features suggestive of chronic myelogenous leukemias (CML) in lymphoid blast crisis. Our results indicate that in Ph1-positive pediatric leukemias. all 9;22 breakpoints occur in one of the two known breakpoint cluster regions in the bcr gene on chromosome 22. The reverse PCR reliably detected all patients with cytogenetic t(9;22) and is capable of detecting additional Ph1-positive leukemias that are missed by standard cytogenetics. Furthermore. the Mbcr-type breakpoint. associated with production of p210. can be seen in childhood leukemias presenting either as clinical ALL or as apparent lymphoid blast crisis of CML. suggesting that t(9;22) breakpoint locations do not exclusively determine the biologic and clinical features of pediatric Ph1-positive ALL.
Retinoic acid receptors in myeloid leukemia: characterization of receptors in retinoic acid-resistant K-562 cells, Although mRNA for the retinoic acid receptor alpha (RAR-alpha) is expressed in many different myeloid leukemias. most of these leukemia cells exhibit little if any phenotypic response when exposed to retinoic acid (RA). To determine whether such RA resistance is related to altered RA receptor structure or function. we performed a detailed analysis of nuclear RA receptors in RA-resistant K-562 cells. These cells exhibit RA receptors of the same approximate molecular weight and similar kd as those exhibited by the RA-sensitive HL-60 leukemia cell line. but the number of RA receptors in the RA-resistant K-562 cells (80 per cell) is significantly lower than that exhibited by RA-sensitive HL-60 cells (550 per cell). Retroviral-mediated transduction of RAR-alpha cDNA into K-562 significantly increased the number of RA receptors to 2.000 per cell. These RAR-alpha-transduced K-562 cells. when incubated with RA. exhibit diminished cell proliferation associated with decreased c-myc expression and an accumulation of cells in G0/G1. In addition. these RA-treated cells exhibit downregulation of the CD15 surface antigen and a slight increase in hemoglobin production but manifest no other evidence of significant erythroid. megakaryocytic. or myeloid differentiation. These results indicate that an elevated number of nuclear RA receptors can be involved in altering proliferation but not necessarily the differentiation of certain RA-treated myeloid leukemia cells.
Synergistic inhibition by verapamil and quinine of P-glycoprotein-mediated multidrug resistance in a human myeloma cell line model, In an effort to develop a clinically useful approach to overcoming P-glycoprotein-mediated multidrug resistance (MDR1). we evaluated combined chemosensitization with verapamil and quinine in a multidrug-resistant (MDR) human myeloma cell line model. In clonogenic assay. verapamil was used at concentrations from 0.1 to 1.0 micrograms/mL. bracketing the plasma levels achieved by oral administration and high-dose intravenous (IV) infusion. respectively. The dose of quinine was held constant at 1.0 micrograms/mL. a plasma concentration readily achieved by oral administration. At each dose level of verapamil tested. the combination with quinine proved more effective than either drug individually in reversing resistance to doxorubicin and vinblastine and synergistic chemosensitizing interaction was observed. Verapamil at 0.1 microgram/mL combined with quinine was capable of restoring sensitivity to doxorubicin fully and reduced resistance to vinblastine as effectively as verapamil alone at 1.0 micrograms/mL. Furthermore. the combination of 1.0 mumol verapamil with 10 mumols quinine increased accumulation and retention of anthracycline in the resistant cells to a greater extent than did either drug individually (P less than .001) and inhibited drug efflux as effectively as verapamil alone at 10 mumols. Our findings suggest that combined chemosensitization with verapamil and quinine may prove useful for overcoming MDR1 in patients with drug-refractory B-cell neoplasms such as multiple myeloma or non-Hodgkin's lymphomas.
Anti-CD33 monoclonal antibody and etoposide/cytosine arabinoside combinations for the ex vivo purification of bone marrow in acute nonlymphocytic leukemia, Pharmacologic and immunologic methods of ex-vivo bone marrow (BM) purging for acute nonlymphocytic leukemia (ANLL) were combined to augment the effect of either method alone. Etoposide (VP16; 20 to 30 micrograms/mL) with or without cytosine arabinoside (Ara C; 10 mg/mL) was used in tandem with the anti-CD33 monoclonal antibody (MoAb). MY9. chosen because CD33 is found on the stem cell pool in the majority of patients with ANLL. The agents were tested singly or sequentially. with a 1-hour incubation of the drugs preceding complement-mediated lysis using MY9. VP16 combined with Ara C killed up to 3.9 +/- 0.3 and 5.11 +/- 0.4 logs of the human ANLL cell lines HL60 and K562 at drug concentrations that killed only 1.2 +/- 0.1 logs of normal committed granulocyte/macrophage stem cells (CFU-GM). Adding a single exposure of the MY9 and complement (C') to the drug-treated cells. greater than 5.4 logs of HL60 were killed. Similar to other pharmacologic agents. no differential kill for clonagenic leukemic cells (colony-forming unit-leukemia; CFU-L) from patients with ANLL was seen for drug only treated blasts versus normal CFU-granulocyte-macrophage (CFU-GM). with less than 1 log CFU-L kill at drug concentrations that spared 1 log of CFU-GM. Similarly. only 1.1 +/- 0.3 logs of ANLL CFU-L were eliminated using MY9 and C'. However. with the sequential VP16/Ara C----MY9 + C' treatment. synergy was demonstrated and 2.6 +/- 0.3 logs of CFU-L were eliminated. Because CD33 is also found on the normal CFU-GM pool. two-stage long-term BM cultures were performed to determine pluripotent stem cell elimination by the drug/MoAb purging combination. No difference of CFU-GM or BFU-E production at 4 to 6 weeks of culture for VP16/Ara C. MY9 + C'. or VP16/AraC----My9 + C' treated cells was seen compared with untreated controls indicating sparing of early progenitor cells. Sequential ex vivo treatment of human ANLL CFU-L with VP16/Ara C followed by complement-mediated lysis using MY9 synergistically kills CFU-L while sparing early normal hematopoietic progenitor cells. and thus may be a more effective way to purge BM than either alone.
Hemoglobin Cagliari (beta 60 [E4] Val----Glu): a novel unstable thalassemic hemoglobinopathy, This report describes a patient with thalassemia intermedia-like phenotype born to normal parents in whom globin gene sequencing detected a novel abnormal hemoglobin (Hb) due to a T to A substitution at codon 60 of the beta-globin gene arising as a de novo mutation. Normal sequences were detected at the homologous beta-globin locus. This mutation results in the substitution of a polar (glutamic acid) for a nonpolar (valine) residue near the corner of the heme pocket of the beta-globin chain. The novel variant has been designated Hb Cagliari. from the place of birth of the propositus. Kinetics of globin synthesis performed following splenectomy suggest that this new Hb variant is synthesized at a near normal rate but undergoes rapid breakdown. The extreme lability of the variant explains the clinical and hematologic picture characterized by marked ineffective erythropoiesis. thalassemia-like bone changes. iron overload. high proportion of Hb F in the peripheral blood. reduced beta/alpha-globin chain synthesis ratio in peripheral blood reticulocytes. and absence of the abnormal Hb in peripheral blood at extensive protein structural analysis before splenectomy. This case indicates that a thalassemic hemoglobinopathy should be suspected in the presence of a patient with a thalassemia intermedia-like phenotype born to normal parents. even when protein structural analysis fails to detect an abnormal Hb. DNA sequencing may allow to define the mutation. thus making the proper diagnosis.
Flow cytometry for clinical estimation of circulating hematopoietic progenitors for autologous transplantation in cancer patients, Optimum methods of harvesting circulating hematopoietic progenitors for autologous transplantation to support myeloablative cancer therapy are still uncertain. mostly because of the lack of an assay for marrow-repopulating stem cells. The CFU-GM assay. the commonly used indirect indicator of the quality of the graft. is poorly standardized and provides results evaluable only retrospectively. Based on the knowledge that hematopoietic progenitors express CD34 and CD33 differentiation antigens. we developed a dual-color direct immunofluorescence flow cytometry assay with the aim of replacing the CFU-GM assay advantageously. For this purpose. we applied both assays to 157 blood samples obtained daily throughout 20 different recoveries from pancytopenia induced by high-dose cyclophosphamide or etoposide cancer therapy with or without recombinant human GM colony-stimulating factor (rhGM-CSF). The appearance of CD34+ cells in the circulation indicated that hematopoietic progenitors had increased to more than 500 CFU-GM/mL. a level clinically adequate for large-scale harvest by leukapheresis. Total CD34+ cells correlated well with CFU-GM (r = .89). and data could be fitted by a linear regression line described by the equation y = 388.3 + 64.0x. where y = CFU-GM/mL and x = CD34+ cells per microliter. Moreover. in a series of six patients treated with myeloablative chemoradiotherapy. early hematopoietic recovery of marrow functions was predicted more accurately by the number of transplanted CD34+/CD33+ cells than by either total nucleated cells. CFU-GM. CD34+/CD33- cells. or CD34-/CD33+ cells. Data presented in this article favor clinical use of the CD34/CD33 flow cytometry assay to guide harvesting of circulating hematopoietic progenitors for autologous transplantation and contribute to better understanding of the role played by circulating hematopoietic progenitor cell subsets in marrow recovery after myeloablative cancer therapy.
Excretion of urinary protein induced by extracorporeal piezoelectric lithotripsy, An investigation was carried out into renal injury caused by extracorporeal piezoelectric lithotripsy (EPL) using an EDAP lithotriptor. Four urinary proteins. with a molecular weight range of 160000-14500. immunoglobulin G (IgG). N-acetyl-beta-glucosaminidase (NAG). albumin and lysozyme. were monitored in 27 patients 1 day before and 1. 7. 30. 90 and 180 days after unilateral EPL treatment. All patients had non-obstructive renal stones. previously untreated. Apart from 5 patients with stablised hypertension and 6 with persistent urinary infections due to the infected stones. all patients appeared healthy. as confirmed by clinical. haematological and biochemical investigations. Only albumin levels increased significantly 1 day after treatment; statistically nonsignificant increases and decreases were recorded in the levels of NAG and lysozome respectively. IgG was beyond the limit of detection (less than 0.5 mg%) in all patients. The albumin level returned to normal 7 days after treatment. The EPL-induced increase in albumin was recorded in 88% of patients. compared with increased levels of NAG in 46% and lysozyme in 64%. mainly in those with infected stones. These findings indicated a transient glomerular injury after EPL treatment.
Do stone formers have lower urinary fibrinolytic activity than controls, A comparison of urinary fibrinolytic activity between 31 stone formers and 50 controls failed to demonstrate any significant difference and so failed to confirm an earlier independent observation. This may be due to methodological and design differences between the 2 studies. but does suggest reservations about the significance of lowered urinary fibrinolytic activity as a risk factor for renal stone disease. Dietary information from those taking part in the study suggests that a reduction of meat intake by stone formers might be associated with increased urinary fibrinolytic activity. This might account for the discrepancy between the 2 studies. in which case this observation could be of significance.
Small cell carcinoma of the urinary tract, Small cell carcinomas of the urinary tract are rare. but lethal. We report 3 cases of primary small cell carcinoma of the kidney. urinary bladder and prostate with light microscopic. immunohistochemical and electron microscopic findings. One patient with small cell carcinoma of the prostate died of disseminated disease 2 years after diagnosis and another patient with small cell carcinoma of the urinary bladder was free of tumour after 6 months. A partial remission was induced in the third patient with distant metastases of small cell carcinoma of the kidney by using chemotherapy protocols similar to the drug regimens for small cell carcinomas of the lung; the patient survived for 5 months. Immunohistochemical studies revealed the absence of argyrophilic immunostaining of tumour cells in all 3 cases. positive staining for keratin in 2 and staining for neuron-specific enolase in all 3. In the third patient. reactivity for prostate-specific antigen was negative. Dense-core. membrane-bound granules were identified in the cytoplasm of 2 patients. The paraneoplastic syndrome was not found. indicating that in considering the occurrence of ectopic hormones. specific cytoplasmic granules of origin need not be implicated. Recognition of this distinct entity requires full consideration of morphological. immunohistological. ultrastructural and biological features. In order to define the origin of this tumour more clearly and to evaluate the effectiveness of chemotherapy. larger series of patients are needed.
The effect of verapamil on the anti-tumour action of mitozantrone and doxorubicin against renal carcinoma cells in vitro, Ten renal carcinomas were established in culture and their sensitivity to mitozantrone +/- verapamil. as measured by (75Se) selenomethionine incorporation. was studied. The 5 tumours with spread beyond the kidney were those in which sensitivity to mitozantrone was enhanced by verapamil. With 4 of the 10 tumours and 1 further carcinoma. similar experiments were performed using doxorubicin. This drug was more active. its anti-tumour action being related to concentration. Verapamil was more effective in potentiation of doxorubicin and this action increased in proportion to the concentration of verapamil added.
Caffeine: does it affect your bladder, Patients with symptoms of frequency and urgency often complain that their symptoms are exacerbated by tea or coffee. A series of 20 women with confirmed detrusor instability and 10 asymptomatic women were given 200 mg of caffeine citrate and urodynamic studies were performed. In the group with detrusor instability there was a statistically significant increase in detrusor pressure on bladder filling following administration of caffeine. but no difference in volume at first contraction. height of contraction or bladder capacity. Normal women had no abnormality on cystometry.
Experience with a simplified technique for the treatment of female stress urinary incontinence, Over a 9-year period a simple procedure for the correction of stress urinary incontinence was performed in 86 consecutive patients. 31 of whom had failed a previous anti-incontinence procedure. Success was achieved in 81 cases (94%). Of the 5 failures. 2 were successfully treated with a repeat procedure. Operative time ranged from 14 to 49 min (median 27). The average hospital stay was 2 days. Because of its simplicity and reliability. this technique is recommended for the surgical correction of female stress urinary incontinence.
Does ethamsylate reduce haemorrhage in transurethral prostatectomy, A double-blind. randomised trial of 44 consecutive patients undergoing transurethral prostatectomy demonstrated that ethamsylate (Dicynene) did not reduce blood loss during either the operative or the post- operative periods.
Treatment of benign prostatic hyperplasia with phytosterols, In a randomised. double-blind study. the preparation Curbicin. obtained from pumpkin seeds and dwarf palm plants (Cucurbita pepo L. and Sabal serrulata). was compared with a placebo in the treatment of symptoms caused by prostatic hyperplasia; 53 patients took part in the study. which was carried out over a 3-month period. Urinary flow. micturition time. residual urine. frequency of micturition and a subjective assessment of the effect of treatment were all significantly improved in the treatment group. No untoward side effects were noted.
Semen analysis in patients operated on for impalpable testes, Semen analysis was performed on 48 men who had undergone orchiopexy. 40 for unilateral impalpable testes and 8 for bilateral impalpable testes. Patients with unilateral impalpable testes had varying sperm analysis; 18 (86%) of the 23 patients with unilateral impalpable canalicular testes had normal sperm analysis. All patients with bilateral impalpable testes were azoospermic. The subsequent quality of the semen is dependent upon the original anatomical positions of the undescended testes.
Comparison of urethral reaction to full silicone, hydrogen-coated and siliconised latex catheters, Indwelling urinary catheter may induce an inflammatory reaction or even stricture of the urethra. Catheter encrustation and urinary infection are other disadvantages associated with long-term catheterisation. In the present study. 77 male patients were catheterised randomly as part of their normal treatment with 1 of 3 different types of catheter: 22 siliconised latex. 28 hydrogel-coated latex and 27 full silicone catheters. The mean duration of catheterisation was 2.2 days. The urethral inflammatory reaction was assessed from cytological urethral swab specimens. Catheter encrustation was studied using scanning electron microscopic (SEM) analysis. The full silicone catheters induced the mildest degree of inflammation in the urethra. the percentage mean of inflammatory cells in smears being 20%. In both latex catheter groups the value was 36%. Neither the age of the patients nor the duration of catheterisation had any effect on the inflammatory reaction. which was more marked in patients with haemodynamic abnormalities. The hydrogel coating effectively prevented encrustation. while siliconised latex catheters were the least resistant to encrustation. The inflammatory reaction was variable in all patients. The use of urethral catheters should be restricted and suprapubic tubes should be used instead. particularly in patients with shock-like circulatory changes. By developing the biocompatibility and physical properties of urinary catheters. more compatible devices may be manufactured.
Variability in DNA measurements in multiple tumor samples of human colonic carcinoma, The DNA ploidy and cell-cycle distribution of three separate fresh tissue samples of 60 colorectal adenocarcinomas were analyzed by flow cytometry. DNA ploidy was concordant among the three samples in 38 cases (63.3%). In the remaining 22 cases (36.6%). the DNA histograms of two of the three multiple samples were similar; however. the ploidy of the third sample was discordant. No relationship was observed between Dukes' stage and histologic grade with concordance or discordance among samples. Thus. in about one third of the colonic carcinomas. a single sample showing either a diploid or diploid-cycling DNA histogram would not detect aneuploid DNA patterns. Comparison of scrapes and fine-needle aspirates of tumors as alternative sampling methods of tumors for DNA ploidy analysis indicated a strong association with the tumor ploidy (84% and 96%. respectively) only when the ploidy of the multiple samples was concordant. In about 25% of the cases. tumor scrapes and fine-needle aspirates did not correlate with the "most abnormal" ploidy observed in one of the three tissue samples. The data suggest that single or even double tissue samples may not show aneuploid DNA patterns in a substantial proportion of colorectal cancers.
Usefulness of serum glycoconjugates in precancerous and cancerous diseases of the oral cavity, Sera from 47 healthy controls. 18 normal individuals with the habit of tobacco chewing. 43 patients with oral precancerous (PC) conditions. and 40 patients with oral cancer (OC) were studied for the levels of total sialic acid (TSA). lipid-bound sialic acid (LSA). mucoid proteins. and protein-bound hexoses (PBH) (galactose and mannose). The changes in the glycoconjugate levels were insignificant between the controls and the normal tobacco chewers. All four parameters were significantly elevated in oral PC patients compared with controls. The levels of PBH and LSA showed significant increase in the oral PC patients compared with the normal tobacco chewers. A significant increase was observed in the levels of TSA. LSA. mucoid proteins. and PBH in OC patients compared with controls. normal tobacco chewers. and patients with oral PC. Increasing levels of all the biomarkers were found with progression of the malignant disease. Elevations in the levels of TSA and LSA were statistically significant in Stage IV patients compared with Stage III patients. The patients with metastases had higher levels of the biomarkers than the patients with primary OC. However. elevations only in LSA levels were statistically significant. These results suggest that evaluations of the serum glycoconjugate levels may be useful in diagnosis of the patients with oral PC or OC. In addition to their value in early detection. they can also help in staging of the disease.
A prospective randomized comparison of protracted infusional 5-fluorouracil with or without weekly bolus cisplatin in metastatic colorectal carcinoma. A Mid-Atlantic Oncology Program study, One hundred eighty-four patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5-fluorouracil (5-FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI]. 25% to 46%) compared with 33% (28 of 85; 95% CI. 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.
Prognostic value of histopathology in Ewing's sarcoma. Long-term follow-up of distal extremity primary tumors, The pathologic material from 56 patients diagnosed initially as Ewing's sarcoma of the distal extremity and treated on National Cancer Institute protocols between 1968 and 1984 was reviewed and correlated with clinical outcome. Histologically. the tumors were categorized. based on recent pathologic criteria. into three diagnostic groups: (1) typical Ewing's sarcoma. (2) atypical Ewing's sarcoma. and (3) other (predominantly peripheral neuroepithelioma [PN]). Thirty-two patients (57%) had typical Ewing's. 13 (23%) were atypical. and 11 (20%) were in the "other" diagnostic category (seven [13%] PN. two primitive rhabdomyosarcoma. one primitive sarcoma of bone. and one synovial cell sarcoma). No cases of metastatic neuroblastoma. osteosarcoma. or lymphoma were found. Forty-five patients had localized disease at diagnosis; 11 had metastases. Patients with typical Ewing's sarcoma were less likely to have metastatic disease at the time of diagnosis. Only two of 32 patients with typical Ewing's sarcoma had metastases compared with nine of 24 patients in the two other groups. The pattern of relapse was also different in these other groups compared with typical Ewing's patients; five patients developed lymph node metastases and two patients developed brain metastases. Although the presence of metastatic disease at diagnosis was a strong negative prognostic factor. our histologic grouping was independently prognostic of clinical outcome in patients with localized disease. Patients with typical osseous Ewing's sarcoma had an improved overall survival (P2 = 0.03) and patients with other tumors (neither typical nor atypical Ewing's sarcoma) had a poorer disease-free survival (P2 = 0.02). Since no generally accepted histopathologic prognostic criteria exist for Ewing's sarcoma. the potential value of our proposed classification should be evaluated in a larger retrospective and a prospective study.
Prognostic factors in yolk sac tumors of the ovary. A clinicopathologic analysis of 29 cases, Twenty-nine ovarian cancer patients with yolk sac tumors and germ cell tumors with yolk sac tissue as a component of their disease (16 endodermal sinus tumor. 11 mixed germ cell tumors. one embryonal carcinoma. and one polyembryoma) were treated with cytoreductive surgery and combination chemotherapy. Prognostic factors were investigated in this group. Patients with Stage I disease had a more favorable prognosis (P less than 0.003) than those with Stages II and IV disease. The difference in prognosis was significant in cases where residual tumor was absent (P less than 0.003) and in cases where ascites was either absent or less than 100 ml in volume (P less than 0.05). Endodermal sinus tumor with either an intestinal (P less than 0.05) or microcystic pattern (P less than 0.01) was more common in survivors than in those who died. The age. preoperative serum alpha-fetoprotein level. maximum tumor size. and tumor weight had no significant correlation with prognosis. In advanced cases. chemotherapy regimens including cisplatin gave better results than those containing vincristine. dactinomycin. and cyclophosphamide (P less than 0.05). The optimal treatment of yolk sac tumors or tumors with yolk sac tissue as a component of the ovary is discussed in light of these results.
Bone sarcomas as second malignant neoplasms following childhood cancer, This study explores the relationship between histologic variants of bone sarcomas and previous therapy in patients in whom an unrelated malignant neoplasm had been diagnosed during childhood. Sarcomas of bone were the most common second malignant neoplasm (SMN) reported to the Late Effects Study Group. a 13-institution consortium consisting of pediatric oncology centers from western Europe. Canada. and the United States. The authors attempted to relate the histologic subtypes of the 91 bone tumors to clinical factors such as previous therapy and genetic predisposition because morphologic variants have been shown to have biologic significance in other tumors and may have etiologic import. The literature concerning the subtypes of bone tumors. clinical and experimental. is also reviewed. The authors also investigated the effect of several factors on the time interval from the first diagnosis to the SMN (i.e.. the bone sarcoma). Anthracyclines significantly shortened the interval by about 3 years. The primary diagnosis also significantly affected the interval. with leukemia/lymphomas having the shortest interval and retinoblastoma the longest. The authors could not demonstrate any significant relationship between morphologic characteristics of the osteosarcoma and predisposing conditions. However. lesions diagnosed as chondrosarcoma and malignant fibrous histiocytoma occurred almost exclusively in patients who had received radiation therapy to the site in which the SMN developed.
A Southwest Oncology Group study on the use of a human tumor cloning assay for predicting response in patients with ovarian cancer, A total of 211 patients with epithelial ovarian cancer (168 with tumors refractory to prior chemotherapy and 43 with no prior chemotherapy) from 33 different Southwest Oncology Group institutions had their tumors sampled and specimens shipped to two central laboratories for drug-sensitivity testing in a human tumor cloning assay. The 168 patients with a prior history of chemotherapy failure (median of four prior chemotherapeutic agents) were treated with the most effective agent(s) found in the cloning assay (23 patients). and those patients whose tumors did not form colonies in vitro or did not manifest any sensitivity to agent(s) were treated with a clinician's choice of agent(s) (101 patients). The remaining 44 of the 168 patients were not treated with chemotherapy because of deteriorating performance status or early death. The complete and partial response rate in patients treated according to assay results was 28% versus 11% for the patients treated according to clinician's choice (P = 0.03). There was no statistically significant difference in survival between the two options (6.25 versus 7 months. respectively). The 43 patients with no history of prior chemotherapy were all treated with standard combination chemotherapy. and their clinical response was compared with their in vitro sensitivity to the same agents. Overall there was a 100% true-positive rate and 100% true-negative rate for the seven evaluable patients. From these data the authors conclude that use of the human tumor cloning assay may increase the response rate but not the survival for selected patients with advanced chemotherapy-refractory ovarian cancer. The study is weakened. however. by the many steps of patient selection necessitated by inadequate tumor colony formation in vitro and the inability to treat all patients (because of early death or a rapid decline in performance status). The assay does appear to be worthy of additional study for predicting response to combination chemotherapy in patients without a prior history of chemotherapy. Finally the use of central chemosensitivity testing laboratories is feasible for testing in vitro predictive assays in a cooperative group setting.
Achievement of life goals by adult survivors of modern treatment for childhood cancer, To assess the impact of the diagnosis and modern treatment of childhood cancer on achievement of adult goals. the authors evaluated employment. health and life insurance coverage. marriage. divorce. and reproduction in 227 former pediatric cancer patients. Each area was evaluated in relation to a common set of disease and demographic factors that included age at follow-up. age at diagnosis. gender. marital status. history of disease recurrence. and diagnosis. Patients were younger than 20 years of age at diagnosis. and their diagnoses were made between January 1. 1960. and December 31. 1984. The median age at diagnosis was 11.4 years. and the median age at follow-up was 26.6 years. The percentage of unemployed male respondents did not differ from population norms. The percentage of unemployed female respondents. however. was slightly higher than that of the United States population. Approximately 11% of the survivors reported some form of employment-related discrimination. a level significantly lower than that of prior reports. Company-offered health insurance was provided to 92.4% of full-time and 90.0% of part-time employed respondents. Life insurance was purchased by 60% of full-time employed men and 55% of women. These percentages were lower than those reported for the United States population. Twenty-four percent of those with life insurance had difficulty obtaining it. Fifty-eight percent of the subjects were married or lived as married. The percentages of married men and women were significantly lower than United States norms. Twenty percent of those who were married or lived as married have divorced or separated or no longer live as married. Women aged 20 to 24 years were less likely to marry. and women aged 35 to 44 years had a significantly higher frequency of divorce than similarly aged United States women. In general. the history of childhood cancer did not influence the decision to marry or live as married but was occasionally (20%) important in the decision to dissolve a marital relationship. Many former patients indicated that their diagnosis and treatment for childhood cancer influenced their decision to have children. The current study suggests that most former pediatric cancer patients achieve adult life goals. Additional research is necessary to define those populations at greatest risk of failure to achieve these goals.
Prolonged response to carboplatin in an infant with brain stem glioma, Adults and children with brain stem gliomas have a mean survival time of 15 months after radiation therapy (XRT). Infants with this tumor present additional complexities for treatment because of possible neurotoxicity of the radiation to the developing brain. We report a 15-month-old child with biopsy-proven brain stem glioma with clinical and radiographic evidence of disease progression. She was treated with 24 monthly courses of carboplatin without radiation therapy and has had a 39+ month response. The clinical response started after 3 months and the radiographic evidence was documented at 10 months by magnetic resonance imaging. The toxicity was minimal. Longitudinal neuropsychological assessment demonstrated continued improvement at 36 months post diagnosis but with some motor functioning below expected age levels. Cervico-medullary astrocytoma in a young patient may be the appropriate clinical setting for future trials of chemotherapy without XRT.
Postoperative follow-up of patients with early breast cancer. Patterns of care among clinical oncologists and a review of the literature, Eighty clinical oncologists in the southeastern United States were surveyed to determine their strategies for follow-up care after primary treatment of early-stage breast cancer. The frequency of use of the history and physical examination. complete blood count. liver function tests. carcinoembryonic antigen levels. chest x-ray. skeletal survey. bone scan. liver scan. and mammogram for observing hypothetical low- and high-risk patients was assessed. Yearly mammograms were recommended by more than 95% of respondents. History and physical examination were the modalities used most often. whereas periodic bone and liver scans were used only in a minority of patients. A review of the literature supported the strategy of the respondents in this survey and further underscored the cost-effectiveness of the history and physical examination in detecting recurrence during follow-up. Based on this survey and supporting literature. recommendations for reasonable yet cost-conscious follow-up are presented.
Imaging of a parapharyngeal hemangiopericytoma. Radioimmunoscintigraphy (SPECT) with indium-111-labeled anti-CEA antibody, and comparison to digital subtraction angiography, computed tomography, and immunohistochemistry, A 27-year-old male patient with a parapharyngeal hemangiopericytoma was investigated radiologically with orthopantomography. computed tomography. and digital subtraction angiography before the operation. Because a malignancy was suspected. the patient was imaged with gamma camera using radiolabeled monoclonal anticarcinoembryonal antigen antibody including single photon emission computed tomography. The radioantibody accumulated strongly into the neoplasm. Tumor to background ratio was 2.2. Samples of the excised tumor were stained immunohistochemically for desmin. vimentin. muscle actin. cytokeratin. CEA (carcinoembryonic antigen). and factor VIII. They showed that the antibody uptake was of unspecific nature and not due to CEA expression in the tumor.
Results of treating ductal carcinoma in situ of the breast with conservative surgery and radiation therapy, To determine the frequency. pattern. and time course of tumor recurrence in the breast. the outcome of 38 women with ductal carcinoma in situ (DCIS) treated with conservative surgery and radiation therapy between 1976 and 1985 was studied. Surgery typically consisted of local excision without evaluation of the microscopic margins of resection. The median radiation dose to the tumor site was 6400 cGy. With a median follow-up time of 81 months. eight patients (21%) have experienced a recurrence in the breast. The time course to recurrence was protracted in some cases. with failures occurring at 17. 27. 43. 63. 71. 83. 92. and 104 months. The 5-year and 8-year actuarial rates of tumor recurrence in the breast were 8% and 27%. respectively. Seven patients had a recurrence at or near the primary tumor site. four with invasive carcinoma. and one had an invasive recurrence at a site elsewhere in the breast. No clinical or pathologic factor was significantly associated with an increased risk of recurrence. but the number of patients in the study population was small. The authors reached the following conclusions for patients with DCIS treated with conservative surgery and radiation therapy without careful mammographic and pathologic evaluation: (1) recurrence in the breast may be seen in at least one fifth of the patients; (2) recurrence typically occurs at or near the primary site; and (3) recurrence can occur long after treatment. Careful mammographic and pathologic assessment may be useful in reducing the local recurrence rate and should be considered essential if patients are considered for conservative surgery and radiation therapy.
Diagnostic sensitivity of different techniques in the diagnosis of lung tumors with the flexible fiberoptic bronchoscope. Comparison of brush biopsy, imprint cytology of forceps biopsy, and histology of forceps biopsy, Brush and forceps biopsies were done consecutively in 186 cases of pulmonary neoplasia with a flexible fiberoptic bronchoscope guided by x-ray television fluoroscopy. Imprint and histologic sections were prepared from all forceps biopsy specimens. The three techniques were compared for their diagnostic sensitivity. As a result 84.9% of all imprints. 80.6% of brush biopsy specimens. and 62.9% of histologic sections were positive for malignancy. The sensitivity of brush biopsy specimens was independent of the location and morphology of the tumors. but the sensitivity of forceps biopsy specimens was lower in neoplasms unidentified by bronchoscopy. The sensitivity of the diagnostic accuracy when all three methods were used jointly was 97.3%. and the specificity was 100%. Agreement in the final morphologic tumor type was found in 130 of 150 cases (86.7%) by positive brush biopsy specimens. in 136 of 158 cases (86.1%) by positive imprint cytology. and in 104 of 117 cases (88.9%) by positive histology from forceps biopsy specimens. For routine bronchoscopy. all three methods should be used in combination to obtain the highest diagnostic yield.
The interferon system in carcinoma of the cervix. Effect of radiation and chemotherapy, Thirteen patients with advanced carcinoma of the cervix were studied for parameters of the interferon system compared with 40 age-matched and sex-matched controls. All patients had measurable serum interferon levels; controls did not. All patients had non-antibody-type interferon-inhibitory activity. and controls had none. Interferon-synthesizing potential was higher in controls than in patients. After successful radiation and chemotherapy. these parameters normalized in the patients. No change was seen in one patient who did not respond to therapy.
Immunohistologic detection of the epidermal growth factor receptor in human esophageal squamous cell carcinoma, Epidermal growth factor receptor (EGF-R) expression was studied immunohistologically in 38 patients with esophageal squamous cell carcinoma. The EGF-R was faintly expressed in basal and parabasal layers of normal esophageal epithelia and in cancer nests of 20 patients; it was strongly expressed in all areas of dysplastic epithelia and in cancer nests of 18 patients. The patients with strongly expressed EGF-R had lymph node metastases more frequently. and their prognosis was poorer than those with faintly expressed EGF-R. The EGF-R expression showed a mosaic pattern in 17 patients and a diffuse pattern in 21 patients. The patients with a mosaic pattern had lymph node metastases more frequently and a worse prognosis than those with a diffuse pattern. Expression of EGF-R in metastatic lymph nodes was similar to that in strongly expressing areas of primary cancers with a mosaic pattern. Thus EGF-R expression may be an important indicator for malignancies of esophageal squamous cell carcinomas because primary cancer cells with strongly expressed EGF-R metastasize to lymph nodes more frequently.
The value of immunohistochemistry for collagen IV expression in colorectal carcinomas, The Dukes' classification has well-established prognostic value in colorectal cancer patients. Yet. in each Dukes' class. the survival of individual patients may vary considerably. Recent studies show prognostic significance of genetic alterations in colorectal carcinoma. However. the importance of tumor stromal components noted in the surrounding tissue may have been overlooked by the methods used. Therefore. in a longitudinal study of 154 patients with colorectal cancer operated on between 1967 and 1974. the authors determined the influence on prognosis of lymphocytic infiltration and expression of collagen type IV in tumor stroma. Also. age. sex. Dukes' classification. grade of tumor differentiation. vasoinvasion. and the number of positive lymph nodes were analyzed. Follow-up was at least 15 years. Lymphocytic infiltration and collagen IV expression were scored as mild. moderate. or severe. Survival was analyzed by a Cox proportional-hazards model. The density of lymphocytic invasion showed no significant influence on survival. Collagen IV expression analyzed as a single variable was significantly (P = 0.038) related to better prognosis in colorectal cancer patients. By multi-variate analysis collagen IV expression showed a trend toward better prognosis that was not statistically significant (P = 0.12). Dukes' classification (P less than 0.001). the presence of vasoinvasion (P = 0.009). and lymph node status (P = 0.04) significantly influenced survival. In conclusion immunohistochemistry for collagen IV is an important additional staining technique with prognostic value. In addition. collagen IV immunostaining facilitates recognition of vascular invasion by highlighting the basement membrane of vessels.
Radiosurgery of acoustic neurinomas, Eighty-five patients with acoustic neurinomas underwent stereotactic radiosurgery with the gamma unit at the University of Pittsburgh (Pittsburgh. PA) during its first 30 months of operation. Neuroimaging studies performed in 40 patients with more than 1 year follow-up showed that tumors were smaller in 22 (55%). unchanged in 17 (43%). and larger in one (2%). The 2-year actuarial rates for preservation of useful hearing and any hearing were 46% and 62%. respectively. Previously undetected neuropathies of the trigeminal (n = 12) and facial nerves (n = 14) occurred 1 week to 1 year after radiosurgery (median. 7 and 6 months. respectively). and improved at median intervals of 13 and 8 months. respectively. after onset. Hearing loss was significantly associated with increasing average tumor diameter (P = 0.04). No deterioration of any cranial nerve function has yet developed in seven patients with average tumor diameters less than 10 mm. Radiosurgery is an important treatment alternative for selected acoustic neurinoma patients.
A phase II trial of carboplatin and vinblastine in the treatment of advanced squamous cell carcinoma of the esophagus, Cisplatin-containing regimens are active in the treatment of esophageal cancer. with response rates of 25% to 35% in advanced disease. Carboplatin is less toxic than cisplatin; as a single agent. several responses were seen against esophageal tumors. To better define the role of carboplatin in esophageal cancer. the authors treated 19 chemotherapy-naive patients with advanced squamous cell carcinoma of the esophagus with carboplatin and vinblastine. Carboplatin (450 mg/m2 intravenously [IV] on days 1. 29. 57. and every 6 weeks thereafter) was given with vinblastine (5 mg/m2 IV on day 1 and then every 2 weeks). No major responses were seen. No significant renal toxicity and only mild gastrointestinal toxicity (emesis. diarrhea) were observed. Hematologic toxicity was more severe in patients with prior radiation therapy (RT). with three of six patients with prior RT exhibiting Grade 4 hematologic toxicity. Although generally less toxic than cisplatin-containing regimens. carboplatin and vinblastine is also less active in the treatment of squamous cell carcinoma of the esophagus. Hematologic toxicity with this regimen was severe in patients who had received prior RT.
Prolonged venous infusion of cisplatin and concurrent radiation therapy for lung carcinoma. A feasibility study, Fifty patients with non resectable and/or inoperable bronchogenic carcinoma were entered into a feasibility study of cisplatin (CDDP) given in continuous infusion with concurrent radiation therapy. The radiation therapy regimen consisted of 2 Gy given 5 days a week in the first 3 and last 2 weeks of a 7-week split course (50 Gy of total dose). The CDDP (daily dose of 4 to 6 mg/m2) was administered to cover the days of radiation treatment by means of a central venous catheter and a portable pump. Less than 1% of predicted duration of infusion was lost due to complications related to venous access and pump. Toxicity was moderate. The overall probability of a locoregional major response (complete + partial) within 1 month after treatment completion was 86%. Twenty-three patients underwent resection. The 1-year actuarial probability of survival was 64%. The high response and survival rates warrant further studies on concurrent CDDP continuous infusion and radiation therapy in inoperable lung carcinoma.
A phase II multi-institutional trial of low-dose N-(phosphonacetyl)-L-aspartate and high-dose 5-fluorouracil as a short-term infusion in the treatment of adenocarcinoma of the pancreas. A Southwest Oncology Group study, Adenocarcinoma of the pancreas is a highly lethal malignancy and chemotherapy has had little impact on the natural history of this disease. PALA. used to potentiate 5-fluorouracil (5-FU). has been shown to have synergy in vivo and in vitro. Twenty-seven patients were treated with an intravenous push dose of PALA (250 mg/m2) followed 24 hours later with a 24-hour infusion of 5-FU (2600 mg/m2). This regimen was repeated weekly. There was one partial response of 21 eligible patients with an estimated response rate of 5%. Toxicity was severe with one toxic death and four patients experiencing Grade 4 toxicity. 5-Fluorouracil and PALA. given in the schedule described. do not appear to be effective against adenocarcinoma of the pancreas.
A dose-intensive regimen of 5-fluorouracil for the treatment of metastatic colorectal carcinoma, 5-Fluorouracil (5-FU) was delivered in a dose-intensive schedule to 23 patients with metastatic or unresectable colorectal carcinoma. The schedule consisted of bolus single-dose 5-FU therapy 400 to 500 mg followed by 4-day infusion of 5-FU. 600 to 800 mg/m2/day. followed by a 17-day to 24-day infusion of 200 to 250 mg/m2/day. Partial remissions were seen in 22% of all eligible patients. Significant toxicity. including mucositis. diarrhea. and hand-foot syndrome. necessitated dose reductions in most patients. The authors conclude that 5-FU given in this moderately intensive schedule is associated with a moderate level of response. as easily achieved with more conventional schedules or with 5-FU-leucovorin combinations. Tumor responsiveness to dose intensive 5-FU regimens may be limited.
Neoadjuvant chemotherapy and radical surgery in locally advanced cervical cancer. Prognostic factors for response and survival, Between January 1986 and September 1988. 75 patients with locally advanced cervical carcinoma (International Federation of Gynecology and Obstetrics [FIGO] Stages IB-III) received three courses of neoadjuvant chemotherapy (NAC). including cisplatin. bleomycin. and methotrexate (PBM). Fifteen percent of patients achieved a complete response (CR) and 68% a partial response (PR). Pretreatment characteristics were analyzed for response to NAC. Significantly lower response rates were found in patients with tumor size more than 5 cm in diameter and bilateral parametrial involvement to the pelvic side wall. None of the biological parameters studied was related to chemoresponsiveness. Patients achieving CR or PR had a significantly improved 3-year survival rate compared with those who did not respond. After NAC. radical surgery was possible in all responding patients. The median number of lymph nodes removed was 60. A lower than expected incidence of lymph node metastases was detected. None of the clinical and pathologic features considered was significantly correlated with the lymph node status. Twelve of the 62 operated patients had disease recurrence. Pathologic parametrial involvement and cervical infiltration equal to or deeper than 5 mm were found to be significant prognostic factors for recurrence. A 3-year. disease-free survival of 89%. 73%. and 43% for Stage IB-IIA. IIB. and III. respectively. was found. Among the operated patients these rates increased to 100%. 81%. and 66% for Stage IB-IIA. IIB. and III. respectively. A prospective randomized trial comparing NAC and surgery with radiotherapy alone is in progress.
Prognostic factors in the treatment of hepatocellular carcinoma with transcatheter arterial embolization and arterial infusion, From January 1986 to December 1988. a prospective trial of transcatheter arterial treatment was carried out for hepatocellular carcinoma (HCC). Two hundred seventy-five patients were included. Okuda's staging system was employed. Patients with Stage I and II HCC were treated by transcatheter arterial embolization (TAE) with a gelatin sponge containing an anti-cancer agent (protocol 1a); a gelatin sponge and iodized oil mixed with an anti-cancer agent (protocol 1b); or iodized oil mixed with an anti-cancer agent (protocol 2). Patients with Stage III HCC were treated with iodized oil with anti-cancer agent (protocol 2). As an exception. patients with an unsuccessful superselective catheterization into the proper hepatic artery by Seldinger technique or obstruction of the main trunk of the portal vein were treated with percutaneous transcatheter arterial infusion into the common hepatic artery regardless of stage (protocol 3). Tumor type and extension. area of tumor involvement. portal vein involvement. method of treatment. and presence of ascites and icterus were found to be the significant factors for an initial response to therapy. Treatment method was the most important factor. Respective survival rates at 1 and 2 years were 70.9% and 55.3% for protocol 1a; 62.3% and 43.8% for protocol 1b; 37.8% and 18.3% for protocol 2; and 16.5% and 0% for protocol 3. Many factors proved to significantly influenced prognosis; however. tumor type had the most important prognostic significance followed by AFP value. ascites. treatment protocol. and area of tumor involvement.
Second cancer after radiation therapy for cancer of the uterine cervix, Radiation-induced cancers after radiation therapy for cancer of the uterine cervix were investigated on 11.855 patients including 5725 patients treated with radiation therapy alone. 1969 postoperative radiation therapy and 4161 surgery alone. The observed-to-expected ratios of the second primary cancer was 0.933 for the patients with radiation therapy alone and 1.074 for the patients with postoperative radiation therapy. respectively. No significant increase was observed in the risk of second primary cancers when all sites were combined. However. assessing on site by site basis. significant excess was noted for the rectum cancer. leukemia. and bladder cancer for the radiation therapy group but not for the surgery group. A significant excess of lung cancer was observed in both radiation therapy and surgery groups. which was attributed to some other causative factors. Radiation-induced cancers were suggested to develop apparently in organs involved in the irradiated field.
Evaluation of a simple line width test involving magnetic resonance spectroscopy of plasma in carcinoma of the ovary, Magnetic resonance spectroscopic (MRS) measurement of human plasma has been reported as a generally applicable marker for malignancy: patients with malignancy had a MRS line width significantly different from patients with benign diseases or healthy controls. The authors investigated the value of this test in 213 women with ovarian carcinoma. benign pelvic masses. benign nongynecologic diseases. and healthy controls. The MRS measurements were performed on plasma samples at 21 degrees C or 27 degrees C. The line width parameters were obtained by averaging the width at half the height of the methyl and methylene peaks on the resonance spectra. At 27 degrees C using 33 Hz as the threshold for an abnormal result. there was a significant correlation between the result of the test and the presence or absence of malignancy. However. the study demonstrates that the specificity (0.44) and positive predictive value (0.42) are too low for the test to be useful in the management of patients with carcinoma of the ovary. At 21 degrees C no correlation between the results of the test and the clinical status of women with carcinoma of the ovary were observed. In 47 patients the test did not predict preoperatively the benign or malignant nature of a pelvic mass.
Ki-67 immunostaining in human breast tumors and its relationship to prognosis, Ki-67 labeling was quantified in 37 nonmalignant breast tissues and in 63 breast carcinomas by counting ten random high-power fields each in three section planes (RC) or by evaluation of the area with the highest labeling density (HDC). Both procedures proved to be highly correlated (rs = 0.94). Ki-67-positive fractions of the nonmalignant tissues (mean. 2.1% for RC and 4.1% for HDC) were significantly lower as compared with the carcinomas (mean. 14.5% for RC and 17.5% for HDC). In carcinomas the Ki-67 labeling was significantly associated with pT stage. axillary lymph node status. and tumor grading and inversely related to progesterone receptor status. Using the medians of both counting methods (12% for RC and 17% for HDC) as cutoff points. significantly different curves for overall and disease-free survival (median follow-up. 37 months) were obtained. However. Cox multivariate analysis failed to demonstrate an independent effect of Ki-67 labeling. In contrast. Ki-67 reactivity seems to be of independent prognostic value if a higher cutoff level was selected.
A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan, In Japan. hepatocellular carcinoma (HCC) is one of the most prevalent cancers. with a reported fatality rate showing a consistent and significant increase in the last decade. At most. only 25% of HCC cases are positive for the hepatitis B surface antigen (HBsAg). To investigate a potential role for hepatitis C virus (HCV) in the development of HCC. sera from 105 HBsAg-negative HCC patients were collected from five districts of Japan and assayed for antibody to HCV antigen (HCVAb). A large number of these patients (76.2%) were found to be positive for the HCVAb in comparison with the reported prevalence in sera from blood donors (1.1%). A history of blood transfusion was found in 39.6% of the cases positive for HCVAb. which was significantly different to the lower rate (4.7%) observed in HCC patients who were both positive for HBsAg and negative for HCVAb (P less than 0.001).
Non-Hodgkin's lymphoma of the brain after Hodgkin's disease. An immunohistochemical study, Non-Hodgkin's lymphoma (NHL) of the central nervous system (CNS) is a rarely reported complication of Hodgkin's disease (HD). Two patients with NHL of the brain after HD were studied by histologic and immunohistochemical methods. Both patients were in the second decade. had been treated with radiation and chemotherapy. had experienced a relapse of HD before development of NHL. had no evidence of HD at the time of diagnosis of NHL. and died within 1 year of diagnosis. Both brain neoplasms were large cell immunoblastic lymphomas of B-cell lineage. Patients with HD appear to be at increased risk for NHL of the CNS. which may have a poor prognosis.
DNA and RNA flow cytometric study in multiple myeloma. Clinical correlations, Flow cytometric studies of cellular DNA and RNA content using the acridine-orange technique were conducted in 81 patients with multiple myeloma (MM). All patients were treated with the M-2 protocol and clinical response was evaluated according to the criteria of the Chronic Leukemia-Myeloma Task Force. Aneuploid DNA stemlines were found in 38.2% of untreated patients with a median DNA index (DNA-I) of 1.15 in marrow aspirates and 1.22 in biopsy specimens. The median percentage of cells with abnormal DNA content was 31.5 (aspirates) and 35 (biopsy specimens) and a positive correlation with the percentage of bone marrow plasma cells was observed. Significantly higher proliferation (S-phase) was found in marrow biopsy specimens as compared with marrow aspirates. Significantly higher RNA content (RNA index [RNA-I]) was observed in aneuploid versus diploid patients in biopsy material. There was no difference in response to the Memorial Hospital M-2 protocol between diploid and aneuploid patients. In patients with DNA-I greater than 1.15 remission duration was shorter as compared with DNA-I less than or equal to 1.15. Furthermore. no difference in cellular RNA content was noted between responders and nonresponders. This study demonstrates no correlation between cellular RNA content and response. as previously described for patients treated with vincristine. Adriamycin. and dexamethasone (VAD). but DNA aneuploidy appears to be an adverse prognostic factor in MM patients treated with the M-2 protocol. It also demonstrates that prognostic models for MM are not universal but depend on the chemotherapeutic regimen used.
An immunohistochemical evaluation of progesterone receptor in frozen sections, paraffin sections, and cytologic imprints of breast carcinomas, Two monoclonal antibodies to progesterone receptor (PR). JZB39 and KD68. were used for the immunocytochemical visualization of PR in different kinds of breast cancer specimens including (1) cryostat sections of tumors frozen at -80 degrees C; (2) paraffin sections of tumors fixed in formalin or in Bouin's fixative for varying periods of time at room temperature or at 4 degrees C; and (3) imprints and cryostat sections prepared from the tissue used for frozen section diagnosis and stored at -80 degrees C after fixation in Zamboni's solution. Sections of conventionally frozen specimens as well as imprints and cryostat sections stored for varying periods of time were stained with the peroxidase-antiperoxidase technique. whereas the avidin-biotin technique was used for paraffin sections. In all types of specimens the PR immunostaining was localized to the nuclei of carcinoma cells and displayed considerable heterogeneity both in intensity and in distribution of positive cells. Close correspondence was found between the different immunohistochemical techniques as well as between immunostaining and steroid-binding assays. PR staining was more frequently positive in well-differentiated than in moderately or poorly differentiated carcinomas. whereas no meaningful correlation was found between PR staining and extent of the disease. Similar results were obtained with the immunostaining of estrogen receptor in the same material using monoclonal antibodies H222 and D75P3 gamma. Thus. by choosing the technique that best suits the type of specimen available. it is possible to obtain valid information on the receptor status of any breast carcinoma. regardless of its size and clinical presentation.
A comparative study of histopathology, hormone receptors, peanut lectin binding, Ki-67 immunostaining, and nucleolar organizer region-associated proteins in human breast cancer, The current study was performed on 71 cases of human female breast cancer and compares the results of five morphologic methods developed for the detection of estrogen receptors (ER). progesterone receptors (PgR). lectin Peanut agglutinin (PNA) binding sites. monoclonal antibody Ki-67 immunoreactivity. and the mean number of argyrophilic nucleolar organizer regions (Ag-NOR). All the parameters were evaluated on serial cryostat sections representative of a closely related. if not identical. neoplastic population. A significant positive correlation was found between the occurrence of estrogen. progesterone. and peanut receptors and between Ki-67 immunoreactivity. mean number of NOR. and mitotic index. Furthermore. ER. PgR. and PNA receptors showed a significant. inverse correlation with Ki-67 immunoreactivity. mitotic index. and mean number of Ag-NOR. These results provide further data that support the hypothesis that (1) progesterone and PNA receptors are estrogen-induced and indicate a metabolic response of the target cells to functioning estrogen receptors; (2) the mean number of NOR reflects the cell kinetics of the tumor; and (3) metabolic differentiation of neoplastic cells is inversely correlated to the proliferation index.
Nucleolar organizer regions in precancerous and cancerous lesions of the bronchus, Using a silver staining technique. nucleolar organizer region-associated proteins (Ag-NOR) were studied in paraffin sections of five specimens of normal bronchial epithelium. eight of atypical squamous metaplasia. five of carcinoma in situ. and seven of microinvasive squamous cell carcinoma. The mean number of Ag-NOR in the nucleus were normal epithelium 1.2 +/- 0.1 (mean +/- SD). atypical squamous metaplasia (borderline lesion) 2.2 +/- 0.5. carcinoma in situ 3.8 +/- 0.6. and microinvasive squamous cell carcinoma 4.8 +/- 1.1. There was a highly significant difference between the Ag-NOR numbers in the atypical squamous metaplasia and those in the carcinoma in situ (P less than 0.01). The Ag-NOR staining is a useful technique for the differential diagnosis of difficult borderline lesions in the bronchial epithelium.
Plasma thrombin-antithrombin III complexes in the diagnosis of primary hepatocellular carcinoma complicating liver cirrhosis, Detection of hypercoagulable state might be helpful in the diagnosis of primary hepatocellular carcinoma (HCC) complicating liver cirrhosis (LC). Plasma levels of thrombin-antithrombin III complex (TAT) were determined in 50 patients of LC with or without HCC. The levels were above 2 ng/ml in 80% of 25 HCC patients. but only in 12% of 25 non-HCC patients (P less than 0.01). The levels over 2 ng/ml occurred even in five of six HCC patients whose serum alpha-fetoprotein levels were below 20 ng/ml as well as in two of three patients with HCC less than 2 cm in diameter. Those levels in HCC patients were significantly decreased within 8 days after treatment with transcatheter arterial embolization or infusion of antitumor agents. without affecting plasma antithrombin III levels. These results suggest that plasma TAT levels may be useful in the diagnosis of HCC complicating LC.
Insulin secretion and action in patients with pancreatic cancer, The authors investigated insulin secretory capacity and insulin action in 11 preoperative patients with pancreatic carcinoma and 15 age-matched and weight-matched healthy subjects (C). Five patients were classified as diabetic (D). two as impaired glucose tolerant (IGT). and four as nondiabetic (ND). Postabsorptive serum insulin levels (mean +/- SE. in uU/ml) in D (12 +/- 2). IGT (17 +/- 7). and ND (10 +/- 2) were comparable. After administration of 100 g of oral glucose. peak insulin achieved in D (60 +/- 11) was lower than in IGT (101 +/- 26) and ND (83 +/- 20). whereas peak insulin levels in IGT and ND were significantly (P less than 0.05) higher than in C (45 +/- 6). Comparable insulin response to nonglucose stimuli was documented in all subjects using the slow arginine infusion test with mean serum insulin of 27 +/- 4 in D. 28 +/- 6 in IGT. 34 +/- 10 in ND. and 32 +/- 5 in C. In six patients (P) and six controls. insulin action was assessed by the euglycemic hyperinsulinemic clamp technique. with glucose turnover rates estimated by [3-3H]glucose infusion. Steady-state plasma glucose concentrations were maintained at 92 +/- 3 (P) and 91 +/- 1 mg/dl (C). After insulin infusion at the rate of 1.0 mU/kg/min. comparable high physiologic insulin levels were observed in P (73 to 104 uU/ml) and in C (81 to 103 uU/ml). Postabsorptive rates of endogenous glucose appearance (Ra) were higher in P (2.86 to 3.02 mg/kg/min) than in C (1.50 to 2.80 mg/kg/min). At high physiologic insulin concentrations. negative Ra values were documented in all subjects. and complete suppression of Ra was assumed. Total body glucose use (M) was consistently lower in P (3.90 to 6.40 mg/kg/min) than in C (6.98 to 10.40 mg/kg/min). consistent with a state of insulin resistance. Patients with pancreatic cancer manifest insulin resistance by virtue of a decrease in total body glucose use (M) and decreased insulin response to glucose due to either inherent beta cell dysfunction or decreased islet cell mass. The latter is not identifiable by histologic morphology.
Pancreatic mucinous cystadenocarcinoma with pseudosarcomatous mural nodules. A report of a case with immunohistochemical study, A case of pancreatic mucinous cystadenocarcinoma (PMC) with two pseudosarcomatous mural nodules (PMN) is described. These nodules have not been previously described in this type of tumor. In ovarian mucinous tumors (OMT). similar nodules have been reported. the nature of which has been discussed in detail. Here the similarity between the tumor described here and ovarian tumors is stressed. The immunohistochemical study carried out disclosed in the nodules strong positive staining for vimentin and moderate positivity for keratin and epithelial membrane antigen. These findings. along with histologic details. favor the epithelial nature of the nodules. It was concluded that the nodules are foci of anaplastic carcinoma with high proliferative cell rate. which could explain the coexpression of vimentin and keratin.
Life-threatening airway obstruction at the presentation of Hodgkin's disease, Mediastinal involvement from Hodgkin's disease is common. Significant symptoms resulting from disease at this site are less common and only rarely does severe airway obstruction occur. The authors report six cases of Hodgkin's disease in which life-threatening airway obstruction was a major feature of the clinical presentation and early clinical course. The literature describing this complication is reviewed. General anesthesia with endobronchial intubation should be avoided if at all possible in patients with airway obstruction and alternative methods of diagnosis and management are discussed.
Long-term survival in Ki-1 lymphoma, Three patients with histologic and immunologic features of Ki-1-positive large cell lymphoma. who experienced long-term survival. are presented. These three patients at 2. 28. and 49 years of age had adenopathy; all cases had been initially misdiagnosed as metastatic carcinoma or malignant histiocytosis. On subsequent review. they had sinusal and diffuse growth of large pleomorphic cells that were Ber-H2 (Ki-1; CD 30) positive. One case marked as a T-cell lymphoma with UCHL1. one case expressed T-cell and B-cell markers. and one case was negative for both T-cell and B-cell markers. All patients received chemotherapy. and two received local radiation. One patient was not treated until 9 years after initial diagnosis. Two patients had several recurrences. but there has been no evidence of lymphoma in any of the three patients for 63 to 301 months; overall survival time has ranged from 14 to 25 years. These cases are the longest reported survivors with Ki-1 lymphoma; 5 years was the longest survival time previously reported. It also is noteworthy that Ber-H2 and other lymphoid-associated antigens appear to be preserved in formalin-fixed. paraffin-embedded tissues for prolonged periods. This may allow retrospective studies to evaluate the natural history of Ki-1 lymphomas. as well as their spontaneous or treatment-induced regression.
Prognostic implications of tumor diameter in carcinoma of the head of the pancreas, Two hundred twenty patients with a carcinoma in the head of the pancreas were divided into three tumor diameter groups: group 1. 0.5 to 4.4 cm (n = 72); group 2. 4.5 to 6.0 cm (n = 77); and group 3. 6.1 to 15.0 cm (n = 71). For these tumor diameter groups a six-fold eliminatory curability analysis was performed. Of the patients with liver metastases in group 1 the last patient had died at 10 months and in groups 2 and 3 no patients were alive at 18 months after the start of complaints. Patients with extrahepatic metastases did not survive 12 months in group 1. 16 months in group 2. and 25 months in group 3. The 6% actuarial survival rate for inoperable patients was reached in group 1 after 17 months. in group 2 after 36 months. and in group 3 after 27 months after the start of complaints. For groups 1 through 3 in curable. but not curatively operated patients. the respective 0% actuarial survival rate was reached at 24 months. 23 months. and 14 months. The 0% actuarial survival rate in patients with irresectable vessel invasion was reached in group 1 at 33 months. in group 2 at 23 months. and in group 3 at 25 months. The 0% actuarial survival rate in patients with an irresectable tumor was reached at 33 months. 31 months. and 27 months after the start of complaints in groups 1. 2. and 3. respectively. The 0% actuarial survival rate in curatively operated patients was reached in group 3 after 26 months and in group 2 after 29 months. In group 1 25% of the patients were alive at 36 months after the start of complaints. Small tumors were associated with the greatest chance of curative operation and on average had the longest survival. However. small tumors with liver or other metastases carried a worse prognosis than large tumors with liver or other metastases. If tumors were found not to be resectable at the time of operation. the size of the tumor did not appear to affect survival.
Black tobacco, mate, and bladder cancer. A case-control study from Uruguay, A case-control study of bladder cancer involving interviews with 111 incident cases and 222 controls was carried out in Montevideo. Uruguay. The analysis was conducted separately for each sex. Point estimates of relative risk associated with smoking variables. ingestion of infusions of the herb Ilex paraguariensis (mate). and selected dietary items were obtained by stratified and logistic regression analysis. Among men. smokers of black tobacco showed a relative risk (RR) 2.7 higher than blond tobacco smokers and mate exposure showed a significant dose-response. after adjustment for age. residence. social class. hospital. type of tobacco. smoking intensity. smoking duration. and vegetable consumption. with a seven-fold increase in risk for heavy consumers. Joint exposure to type of tobacco and mate consumption showed a multiplicative effect. Women showed a similar increase in risk with mate consumption. The results suggest that the high mortality rates of bladder cancer observed in Uruguay could be explained by the combined effect of black tobacco smoking and mate ingestion.
Response rates in relapsed Wilms' tumor. A need for new effective agents, Three hundred eighty-one children with Wilms' tumor were treated in the United Kingdom Children's Cancer Study Group WT1 Study (1982 to 1986). Seventy-one patients had relapses during or after treatment with surgery and chemotherapy. and radiation therapy. depending on stage and histologic characteristics. Forty-nine patients were evaluable for disease response to second-line chemotherapy alone. Evaluation of response to chemotherapy was impossible in the remaining patients because either surgery or radiation therapy was used at the time of relapse. With second-line combination chemotherapy (which included ifosfamide. etoposide/VM26. cisplatin/carboplatin. bleomycin. melphalan. and Thiotepa [Lederle Laboratories. Pearl River. NY]). there were five complete responses and 12 partial responses. In patients with favorable histologic findings. six of nine with Stage I. five of ten with Stage II. none of 11 with Stage III. three of 16 with Stage IV. and one of five with Stage V disease survived. Two survivors were treated with chemotherapy alone; the others received combined treatment with chemotherapy. radiation therapy. and/or surgery. For those with unfavorable histologic findings of any stage. only two of 20 survived. The authors conclude that. even for patients with localized disease with favorable histologic findings. the "salvage" rate is little more than 50%. and for all other stages and histologic findings the likelihood of cure after relapse is remote. There is clearly a need for additional effective chemotherapeutic agents for these patients.
Primary treatment of large and massive adult sarcomas with iododeoxyuridine and aggressive hyperfractionated irradiation, For a decade. the authors have experimented with treatment for unresectable adult soft tissue and bony sarcomas. Over the last 6 years. they have combined hyperfractionated radiation therapy and intravenous iododeoxyuridine as a radiosensitizer. in regimens designed to minimize toxicity and permit delivery of aggressive radiation therapy. Patients with solitary lesions and those with metastasis (38%) were treated in the hope of both potential cure in some and durable palliation in others. The most formidable of these cancers have been those that are large or massive. often requiring five or more fields and extensive treatment planning. The authors report results from 36 patients with large unresectable sarcomas (tumors ranging from 5 to 35 cm; average 14 cm) treated with hyperfractionated radiation therapy. with a minimum follow-up of 1 year. follow-up of 4 or more years (in 50%). or follow-up until death. Overall local control has been 60%. with control of 66% of lesions from 5 to 9 cm. 63% of those from 10 to 14 cm. 63% of those from 15 to 19 cm. and 57% of those greater than 20 to 40 cm. Morbidity has been modest. This experience compares favorably with the authors' earlier trials with misonidazole. and toxicity has been reduced considerably.
Ultrasound and ultrasound-guided fine needle aspiration biopsy of supraclavicular lymph nodes in patients with esophageal carcinoma, The use of ultrasound combined with ultrasound-guided fine-needle aspiration biopsy (UGFAB) of supraclavicular lymph nodes in the pretreatment staging of 37 patients with squamous cell carcinoma of the esophagus is described. All patients underwent computed tomography (CT) scans of the chest and the abdomen and ultrasound of the abdomen and supraclavicular regions. Supraclavicular lymph node metastases (Stage IV disease according to the tumor nodes metastasis [TNM] classification) were cytologically diagnosed in seven (18.9%) of the 37 patients. In two of these patients. no other metastases were found. In the other five patients. UGFAB replaced more invasive diagnostic procedures. Due to their superficial location. ultrasound and UGFAB of the supraclavicular lymph nodes was relatively simple to perform. and contributed to an improved staging of squamous cell carcinoma of the esophagus.
Altered protein tyrosine kinase levels in human colon carcinoma, To further understand the molecular mechanisms and the biological indicators of colonic tumorigenesis. the authors examined tyrosine kinase activity in the cytosol and in the particulate fraction of the homogenates of specimens from 20 human colonic carcinomas and compared them with the adjacent normal mucosal tissues. Total protein tyrosine kinase activity could be precisely detected using miniphosphocellulose column purification and a synthetic peptide. Glu-asparagine (Asp)-alanine (Ala)-Glu-tyrosine (Tyr)-Ala-Ala-arginine (Arg)-Arg-Arg-glycine (Gly) (E11-G1). as an artificial substrate. Tyrosine kinase activity of colonic carcinoma and normal mucosa was reduced in the cytosol fraction whereas activity in the particulate fraction was elevated with respect to protein concentration. The average specific activity ratios were 1.95 +/- 0.27 (normal cytosolic/carcinoma cytosolic) and 0.57 +/- 0.01 (normal particulate/carcinoma particulate) for tyrosine kinase activity. Cellular distribution (% cytosol) of tyrosine kinase activity in normal mucosa and in carcinoma varied from 21.0% to 91.2% and from 7.0% to 61.4%. respectively. In nearly all cases the percentage of cytosolic tyrosine kinase activity in carcinoma tissues was lower than in normal tissues. There was no difference due to histologic type or the presence of adenomatous components. A significant decrease of cytosolic tyrosine kinases was correlated with Dukes' Stage A. With advancing Dukes' stage. the average specific activity ratios (normal cytosol/carcinoma cytosol) were decreased. This study indicates that colonic carcinogenesis might be associated with alterations in cellular levels of tyrosine kinase activity and that the average specific activity ratio (normal cytosol/carcinoma cytosol) had a possible correlation with colonic tumor growth.
Watch and wait after careful surgical treatment and staging in well-differentiated early ovarian cancer, Patients with well-differentiated epithelial ovarian cancer Stages Ia. Ib. Ic. and IIa (FIGO 1976) were observed after surgical treatment without adjuvant therapy. Careful surgical staging was required. and the extent of the staging procedure was assessed in each individual patient. There were 107 patients entered in the study by nine Dutch oncology centers. Of these 107. 21 did not fulfill all of the inlet criteria of the study and were excluded. Central pathologic review was performed in the remaining 86 cases. revealing that there was borderline tumor in seven patients. moderately or poorly differentiated tumor in nine patients. and tumor of nonepithelial histologic cell type in one patient. In two cases. no material for histologic review was available. After exclusion of these 19 cases. 67 patients were further analyzed. None of these 67 patients was lost during the follow-up period that ranged from 19 to 99 months (mean. 50 months). Tumor recurrence was found in four patients after 11. 25. 34. and 34 months of follow-up. all of whom died shortly after diagnosis of the recurrence without satisfactory response to secondary treatment. For the patients who underwent the most extensive staging procedure. disease-free 5-year survival was 100%. For the patients who were inaccurately staged. disease-free 5-year survival was 88%. It was concluded that well-differentiated early stage (Ia-IIa) ovarian cancer carries an excellent prognosis after surgical treatment and complete surgical staging. with the possible exception of patients with Stage Ic disease with malignant peritoneal washings. Furthermore. it was considered that the application of more objective and consistent ways of assessing tumor grade should be encouraged. Surgical staging should be regarded as the golden standard in defining subsets of low-risk patients and should be included and clearly defined in future trials on early ovarian cancer.
Loss of expression of blood group antigen H is associated with cellular invasion and spread of oral squamous cell carcinomas, Membrane-bound carbohydrates may influence the metastatic behavior of cancer cells. Forty-two squamous cell carcinomas (SCC) of the buccal and maxillary alveolar mucosa were studied retrospectively using a monoclonal antibody (BE2) that reacts with blood group H (type 2 chain) structure. H-antigen staining within the entire tumor did not correlate with the stage of the tumor. i.e.. spread of the tumors. However. loss of staining within the most invasive sites of the tumors correlated significantly with the stage of tumor development and histologic grade of malignancy. These findings support the view that features relating to the cells of deeper parts of the carcinomas are very important for the clinical behavior of the tumors. and that loss of H-antigen expression is related to the stage of tumor and invasion of carcinoma cells.
Ras gene mutations in intraductal papillary neoplasms of the pancreas. Analysis in five cases, Five intraductal papillary neoplasms of the pancreas were analyzed for the presence of the Ras gene mutations. Three (60%) of the five neoplasms showed point mutations at K-ras codon 12. This incidence of the mutations was rather low compared with that found with ordinary pancreatic adenocarcinoma. The presence of the mutations did not correlate with the severity of cellular atypia. but was apparently related to the size of the tumor. The two neoplasms that had no mutations were smaller than the others that had mutations. The analysis suggested that Ras gene mutation is not the first genetic alteration of tumor progression. but that it occurs during the development of neoplasms of the pancreas.
Osteosarcoma in young children, The clinicopathologic features of osteosarcoma in 12 children younger than 16 years of age treated at The Children's Hospital and Dana-Farber Cancer Institute. Boston. during a 70-year time period are presented. Only one of six children treated before 1972 is a long-term survivor. Four of six children (67%) treated after 1972 are disease-free with an average follow-up of 8.8 years. The year 1972 marked the onset of use of effective chemotherapy in osteosarcoma. namely. high-dose methotrexate and leucovorin rescue. It would appear that the pathologic features and behavior of osteosarcoma in young children is similar to that of osteosarcoma in older children and adolescents. A combination of complete (wide) surgical resection or amputation and aggressive chemotherapy offers the best chance of long-term survival.
Fine-needle aspiration in hepatocellular carcinoma. Combined cytologic and histologic approach, Cytologic features of fine-needle aspiration (FNA) of hepatocellular carcinoma (HCC) have not been well documented. Most previous reports described only the the morphologic features of the tumor cells without considering the sinusoidal stroma. Cytohistologic correlation on tissue from the same aspirate has rarely been done. This report describes the cytologic patterns of 50 cases of HCC in terms of histologic pattern observed in cell blocks prepared from the same aspiration specimen and classified according to the World Health Organization (WHO) classification. Tumors were classified according to the predominant pattern. Thirty-two cases gave the trabecular pattern. Smears could be subdivided into a central-sinusoidal pattern (23 cases) and a peripheral-sinusoidal pattern (nine cases). One case gave the pseudoglandular pattern. Seventeen cases gave the compact pattern with inconspicuous sinusoids. In all cases sinusoids were easily recognized in cell block sections. Other cytologic features such as intranuclear cytoplasmic inclusions. eosinophilic globules. and bile secretion could be seen in both smears and cell blocks. Mallory's hyalin and ground glass inclusions were only recognized in cell blocks. More attention should be paid to the sinusoidal stroma for diagnosis of HCC in FNA; cell blocks should be more widely utilized to this effect; cytologic patterns could be classified according to the WHO histologic classification.
Clinical presentation, treatment, and outcome of trilateral retinoblastoma, In this report. three new cases of trilateral retinoblastoma are presented. The clinical presentation. treatment. and outcome of the patients are described and compared with those of 32 cases that have been previously reported in the literature. A positive family history was obtained in 68% of the patients. The mean age at diagnosis of bilateral retinoblastoma was 7.2 months. The mean age at diagnosis of trilateral disease was 39.7 months. resulting in a mean latent interval of 32.6 months. The mean time from diagnosis of trilateral retinoblastoma to death was 6.6 months. and all patients died with spinal metastases. The patients who received no therapy survived an average of 1.3 months after the diagnosis of trilateral disease. The patients who received any form of definitive therapy survived 9.7 months. Five patients who had complete or dramatic response to therapy by computed tomography scans had local intracranial tumor present at autopsy. Therefore. more aggressive local therapy may be warranted.
Factors related to and consequences of weight loss in patients with stomach cancer. The Norwegian Multicenter experience. Norwegian Stomach Cancer Trial, Of 1165 patients with stomach cancer included in a national. prospective multicenter study with 51 surgical units participating. information about weight loss before diagnosis was available for 855 patients (73%). Median weight loss was 5 kg; 259 patients (31%) experienced no weight loss. By logistic regression analysis the authors found that weight loss increased with age and advancing stages of disease (TNM Stage I-IV). with decreasing Karnofsky index. in Lauren's diffuse versus intestinal tumor type. and with tumors located at the cardia/esophagus. Increasing weight loss reduced the resectability rate significantly. but no association between weight loss and postoperative complication rate was found. The odds ratio for postoperative mortality was 2.5 to 1 for the weight loss group 5 to 10kg versus 0 kg. In conclusion. weight loss reflects a less favorable tumor status. Weight loss did not increase postoperative morbidity but did lead Weight to a higher death rate after surgery.
Zinc and copper in breast cancer. A joint study in northern Italy and southern France, The relationship between breast cancer and two trace elements. zinc (Zn) and copper (Cu). was investigated by means of an hospital based case-control study at Milan (Italy) and Montpellier (France). Variables concerning dietary intake of Zn and Cu (in Milan) and their blood levels (both in Milan and Montpellier) were measured. Dietary intake. evaluated through a questionnaire of the dietary history type. and blood levels of Zn and Cu were measured in 261 cases and 261 controls. Cu blood level showed a contradictory tendency in the two samples (higher in controls in Milan. higher in cases in Montpellier). which tended to lessen after adjustment for related variables. No odds ratios (OR) in the different quantiles. nor X2 for trend reached statistical significance. A sharp difference was evidenced on the opposite with regard to Zn blood values in cases and controls. In both samples Zn mean values are significantly higher in cases than in controls. and the difference remains significant in the two samples even after adjustment for related variables. The pooled OR computed from the two samples. after adjustment for known risk factors and related variables. reaches in the fourth quartile a value of 9.5 (CI: 4.9-18.2). Dietary intake of the two minerals (measured only in Milan sample) showed no difference between cases and controls. but a stronger relationship between dietary and blood Zn was evidenced in cases with respect to controls. The authors suggest that the higher Zn level in cases might be related with an higher incorporation of Zn in cancer cases and that the same mineral might play a possible role in tumor growth promotion.
The history and classification of knee braces, There has been a great deal of concern within the orthopedic community regarding the lack of objective data available on the multitude of knee braces flooding the marketplace. This article hopes to fill that void by presenting an overview of the history and classification of knee braces.
Choosing functional knee braces, Choosing a functional brace for knee injury is a complex issue complicated by a lack of quantitative research on the subject and an increasing number of braces currently on the market. The correct brace decision will be facilitated by a better understanding of knee injury biomechanics and by a thorough understanding of the choices available. The ultimate selection of a brace should be based on sound mechanical criteria and individualized for each patient. The brace must be mechanically effectual and one the patient likes. has confidence in. and will tolerate. In combination with aggressive rehabilitation. the functional brace can make a significant contribution to returning individuals to functional activity.
Functional analysis of anterior cruciate ligament braces, Whether or not anterior cruciate ligament (ACL) braces work has been the subject of some debate. Research efforts undertaken to understand these braces have been divided into two fronts: static and functional analysis. This article explores those issues surrounding the functional analysis of ACL braces.
The use of knee braces during rehabilitation, This article has profiled the use of knee braces as an augmentation to the overall rehabilitation program following knee injury. It has also outlined other aspects of rehabilitation. the use of continuous passive motion devices. and other forms of exercises and training that. together with bracing. may enhance patient recovery. Continuous passive motion devices have been used for many different orthopedic problems with good success. Understanding the mechanics of how these devices move the knee and the forces that can be applied to the knee is helpful in deciding on their use after ligamentous reconstructions. Rehabilitation of the knee following surgery requires a good understanding of the effects that each exercise has on the knee and the reconstruction. Gradual progression of exercises to the knee following knee ligament reconstruction will not overstress healing tissues. Many different types of knee braces exist. and careful evaluation of them may enhance patient recovery.
Bracing for patellar instability, Knee pain secondary to problems with patellar tracking is common. The initial treatment for these problems is conservative. Patellar orthotics have been used extensively to treat a variety of extensor mechanism problems. Millions of health care dollars are spent annually on the use of these braces. There are many different patellar orthotics on the market today. The use and design of most of these devices are unclear and often lack a solid biomechanical foundation. The practical mechanical function of these braces is to reduce the lateral displacement of abnormal patellofemoral tracking. Orthotics that are designed and tested using practical biomechanical principles for applying a medially directed force to the patella seem to have a role in treating patients with knee pain secondary to patellar malalignment and instability. Well-defined and controlled clinical studies of the use of patellar braces are lacking.
The effect of bracing on the collateral ligaments of the knee, Disruption of the ligamentous structures of the knee is commonly seen in competitive sports. The role of prophylactic and functional bracing is controversial. Currently. prophylactic bracing has not been shown. conclusively. to be protective. Functional braces appear to have a capacity to provide some protective effect.
Clinical significance and evaluation of prophylactic knee brace studies in football, A review of nine studies of prophylactic knee braces in American tackle football found some support for the use of double-hinge braces in high school but little support for their use at the collegiate level. Problems with bias and confounding make it necessary that caution be exercised in the interpretation of the results of these studies. however.. To which groups these results might apply must also be considered. The two studies that assigned braces randomly found lower injury rates among high school and high-school-sized players for knee injuries and knee ligament injuries. Conversely a large. multiteam collegiate study found a significantly higher rate of knee injuries among brace users. a difference that remained when controlled for position. skill. and previous injury.
Management of smooth-blunt gastric foreign bodies in asymptomatic patients, Guidelines for management in the asymptomatic patient with a smooth-blunt gastric foreign body are not well established in the pediatric literature. Questionnaires were sent to pediatricians. family practitioners. pediatric gastroenterologists and pediatric surgeons with an over-all response rate of 62.2%. There was no agreement in regard to how long one should observe such patients before recommending intervention. There was no correlation of years of clinical experience and length of observation recommended either. Review of the pre-endoscopic literature revealed spontaneous evacuation in 93-99% of all types of foreign bodies in 1477 pediatric patients. An observation period of at least eight weeks should be strongly considered in an asymptomatic patient with a smooth-blunt gastric foreign body. Exceptions would include an anatomic abnormality of the gastric outlet. previous gastric outlet surgery as well as a possibly toxic object.
Effects of discontinuation of phenytoin, carbamazepine, and valproate on concomitant antiepileptic medication, We report a prospective. controlled study of the effects of the reduction and discontinuation of phenytoin (PHT) (22 patients). carbamazepine (CBZ) (23 patients). and valproate (VPA) (25 patients) with concomitant antiepileptic drugs (AEDs). The principal changes in the serum concentrations of concomitant AEDs were (a) phenobarbital (PB) concentrations decreased by a mean of 30% on discontinuation of PHT; (b) total CBZ concentrations increased by a mean of 48% and free CBZ concentrations increased by a mean of 30% on discontinuation of PHT. with no change in CBZ-10. 11-epoxide (CBZ-E) concentrations; (c) VPA concentrations increased by a mean of 19% on discontinuation of PHT; (d) VPA concentrations increased by a mean of 42% on discontinuation of CBZ; (e) ethosuximide (ESM) concentrations increased by a mean of 48% on discontinuation of CBZ; (f) PHT concentrations decreased by a mean of 26% on discontinuation of CBZ; (g) PHT free fraction decreased from a mean of 0.11 to 0.07 on discontinuation of VPA; and (h) the mean concentrations of total and free CBZ increased by a mean of 10 and 16%. respectively. on VPA discontinuation. with a concomitant mean 24% decrease in total CBZ-E and a 22% decrease in free CBZ-E. Apart from the decrease in PB concentrations on PHT discontinuation. all significant changes had occurred by 1 week after the end of AED discontinuation. The implication for clinical practice is that a serum AED concentration at this time reflects the new steady state. Free concentrations did not add any clinically useful information to that gained from analysis of total serum concentrations.
Cognitive function and time-of-day variation in serum carbamazepine concentration in epileptic patients treated with monotherapy, Different parameters of antiepileptic drug (AED) treatment have been shown to affect cognitive function. The drug. dose. and duration of treatment have been studied. The present study assessed cognitive function in relation to time-of-day variation in serum carbamazepine (CBZ) concentration in epileptic patients treated with monotherapy. We studied 10 males and 12 females with a mean age of 36 years and a mean duration of CBZ-therapy of 4.4 years. Patients had been seizure-free for at least 1 month and took two daily CBZ doses. The test battery included tests of motor speed. reaction time. attention. and memory. In the experimental design. the subjects were tested twice at times close to expected daily maximum and minimum serum CBZ concentration. They were studied in two balanced blocks (block 1 tested at 8 a.m. and noon. block 2 tested at noon and 8 p.m.). Blood samples were collected every 2 hr from 8 a.m. to 8 p.m. The subjects showed significant differences in serum CBZ concentration between testing times. with suggested maximum concentration between 10 a.m. and noon. The test battery showed no consistent differences between performance at times of high versus low serum concentration. A supplementary analysis of correlations between mean performance level on cognitive tests and variables related to CBZ treatment did not show consistent trends.
Immunologic aspects of carbamazepine treatment in epileptic patients, Immune abnormalities have been found in epileptic patients receiving antiepileptic drugs (AEDs). Phenytoin (PHT) produces a decrease in serum IgA and IgM levels and a decrease in blastic transformation of circulating lymphocytes stimulated with phytohemoagglutinin (PHA). The effects of carbamazepine (CBZ) on the immune response are still conflicting. To elucidate the effects of CBZ on some immunologic parameters. serum concentrations of IgA. IgG. IgM. the phagocytosis and killing properties of polymorphonuclear leukocytes (PMNs). the cytotoxic activity of natural killer cells and the response of lymphocytes to mitogenic agents were studied. Forty healthy individuals and 39 epileptic patients treated with carbamazepine (CBZ) monotherapy (age range 18-40 years) entered the study. Student's t test was used to evaluate the data. CBZ had no effect on the serum immunoglobulin concentrations or on lymphocytic reactivity to phytohemoagglutinin (PHA) mitogen. CBZ produced a significant enhancement of phagocytosis and killing properties of PMNs and an increase in natural killer (NK) cell activity. Therefore. a negative effect of CBZ therapy on the immune system was not observed in this study.
Effect of felbamate on plasma levels of carbamazepine and its metabolites, Felbamate (FBM) is a novel antiepileptic drug (AED) currently undergoing clinical evaluation in the United States. During a controlled clinical trial conducted at the National Institutes of Health Clinical Center. FBM was added to constant carbamazepine (CBZ) monotherapy. CBZ total concentrations were reduced during active FBM treatment (mean reduction 25%. range 10-42%. p less than 0.001). The effect was evident after the first week of treatment and reached a plateau in 2-4 weeks. To clarify the interaction mechanism. free and total concentrations of CBZ and its plasma metabolites were determined by high-performance liquid chromatography (HPLC) and ultrafiltration in four patients. In these patients. FBM treatment reduced CBZ concentrations and increased CBZ-epoxide (CBZ-E) concentrations (p less than 0.01). Free fractions of all compounds were unmodified. FBM appears to be capable of inducing CBZ metabolism. CBZ-FBM interaction may be clinically relevant.
Double-blind, placebo-controlled, cross-over trial of progabide as add-on therapy in epileptic patients, In a double-blind. cross-over trial. progabide (PGB) and placebo were compared as add-on therapy in 59 patients with moderate to severe epilepsy. Eight patients did not complete the study. 4 because of adverse drug reactions (elevation of liver transaminases. 2; gastritis. 1; and acute psychosis. 1) and 4 because of administrative reasons. Among the remaining 51 patients. seizure frequency was reduced greater than 50% in 18 patients with PGB treatment and in 8 patients with placebo (p less than 0.05). The number of days with seizures was significantly (p = 0.034) reduced during PGB treatment. Both patients' and physicians' preferences at the end of the trial were in favor (p less than 0.01) of PGB. Mild clinical side effects were present in 54.7% of the patients treated with PGB and in 37.7% with placebo. Increase in liver transaminases was observed in 2 patients during the double-blind study and in 1 during the follow-up period. Our data show that PGB. as previously reported. is useful in 30-40% of patients who are not responding completely to other antiepileptic drugs (AEDs). The compound is well tolerated. but liver function must be monitored.
Development and reversal of contingent inefficacy and tolerance to the anticonvulsant effects of carbamazepine, The relationship of the timing of drug administration to anticonvulsant efficacy against amygdala kindled seizures was studied. During kindling development. rats received carbamazepine (CBZ. 15mg/kg) before (CBZ-before) or after each amygdala stimulation (CBZ-after). After kindling to full seizures. when all animals were given CBZ before the stimulation. only the CBZ-after group showed a good anticonvulsant response. The rats that had received CBZ before (during development of kindled seizures) remained unresponsive to CBZ treatment (contingent inefficacy). When drug-naive or CBZ-after animals repeatedly received CBZ before electrical stimulation. they developed tolerance to its anticonvulsant effects (contingent tolerance). The tolerance could be reversed by a period of treatment with CBZ-after or by kindling the animal drug-free. but not by CBZ administration alone or by time off from both drug and seizures. These findings suggest that inefficacy and tolerance to CBZ may be affected by the temporal contingencies of drug administration and that responsiveness can be reinstated by altering these contingencies.
Kindling susceptibility and genetic seizure predisposition in inbred mice, Olfactory bulb kindling rates were studied in two inbred strains of genetically seizure-prone mice (DBA/2 and El) and in three non-epileptic inbred strains [C57BL/6 (B6). ddY. and C3H/He (C3H)]. None of the DBA/2 mice had been stimulated to seizure before or during the kindling and all mice were studied at 4-6 weeks of age. before development of spontaneous or movement-induced seizure activity in the El strain. The audiogenically seizure-susceptible DBA/2 mice required the fewest number of stimulations to reach stage 5 seizure (mean +/- SE = 4.0 +/- 0.6). The nonepileptic C3H mice required the most stimulations to reach stage 5 seizures (22.6 +/- 1.4). Kindling rates for B6 (9.6 +/- 0.6). El (14.8 +/- 1.1). and ddY (18.5 +/- 1.0) strains were intermediate. and the kindling rate for each strain was significantly different from that of the other strains. These findings show that the seizure-susceptible El mouse kindles more rapidly than the genetically similar but nonepileptic ddY control and suggest that an inherited seizure susceptibility accelerates the kindling rate. Nonepileptic B6 mice kindled more rapidly than El mice. however. suggesting that genetic factors other than those that influence seizure susceptibility are of primary importance in the determination of the kindling rate.
Changes of hippocampal glucose utilization subsequent to amygdaloid-kindled generalized seizures, Local changes in cerebral glucose utilization during the postictal phase of amygdaloid-kindled generalized seizures were studied with the quantitative autoradiographic 2-[14C]deoxyglucose method in conscious rats. Measurement was initiated either just after termination of a behavioral seizure (GS-I) or 30 s after seizure termination (GS-II) to determine dynamic metabolic changes in the postictal phase. Although glucose utilization of the neocortex was remarkably depressed in both GS-I and GS-II. that of the hippocampus significantly increased in GS-I and then decreased in GS-II as compared with control. These changes of hippocampal glucose utilization were observed in all sectors of the pyramidal cell layer (CA 1-4) and in the molecular layer. Because metabolic changes associated with development of amygdaloid-kindled seizures begin in the limbic structures including the hippocampus. the transient increase in hippocampal glucose utilization observed in the early postictal phase indicates that the hippocampus is one of the key structures not only for initiating and maintaining but also for terminating kindled seizures.
Panic disorder in seizure patients: a diagnostic pitfall, Panic disorder is a psychiatric diagnosis whose main feature is paroxysmal attacks of anxiety that strike suddenly without apparent provocation. Physicians explain the attacks as an ictal phenomenon in patients with known seizures because of their similarities to complex partial seizures. We report eight patients with seizures and panic disorder. Recognition of a second diagnostic entity resulted in a beneficial change in treatment in six of the eight. We did not find an increased incidence of panic disorder in our seizure clinic population as compared with the general population.
Effect of epilepsy and sleep deprivation on the rate of benign epileptiform transients of sleep, Seventy-eight individuals with EEG records containing benign epileptiform transients of sleep (BETS) were identified among 7.400 records reviewed in our laboratory in a 6-year period. The records contained no other abnormality in 51 patients (65%). Genuine epileptiform discharges were found in the records of 19 patients; 14 had a history of epilepsy. Thirty-five patients (45%) had a proven history of epilepsy with antiepileptic drug (AED) therapy. In the records of these patients. the mean number of BETS per unit of time was significantly higher (11.88 +/- 2) than in the record of the rest of the laboratory population with BETS (6.89 +/- 0.9) (p less than 0.02). Among five conventional surface montages. ipsilateral ear referential montage (IERM) showed a significantly higher number of BETS per unit of time than did any other surface montage used in the study. Thirty-nine records (50%) were performed after sleep deprivation (SD). When only IERM was considered. SD records showed a significantly higher number of BETS per unit of time (7.36 +/- 1.1) than did non-SD records (3.89 +/- 0.69) (p less than 0.01). Our findings support the general consensus that individual BETS may be normal variants. but a high occurrence of BETS in the record should raise suspicion of underlying epilepsy.
Dreams and epilepsy, The relationship between dreams and epilepsy is illustrated by two patients whose awake epileptic seizures and recurrent dreams during night sleep had similar content. In both of our cases the EEG showed right anterior temporal spike discharge. suggesting a role for the temporal lobe in the association between dreams and seizures.
Epilepsy with continuous spike-waves during slow sleep and its treatment, Five children with epilepsy with "continuous spike-waves during slow sleep" (CSWS) are reported. The main clinical features of CSWS include (a) onset between 5 and 7 years of age. (b) the occurrence of several types of seizure (i.e.. partial motor. generalized motor. and atypical absence). and (c) the presence of language disturbances and abnormal behavior based on emotional impairment. The EEG findings were characterized by sleep tracings showing almost continuous (greater than 95%). diffuse slow spike and wave activity. After treatment with valproate (VPA) (or ethosuximide. ESM) and clonazepam (CZP). the spike and wave complex status disappeared. Symptoms and signs of the CSWS also decreased. We suggest that combined treatment is an appropriate treatment for CSWS.
Sexual behavior of a sample of females with epilepsy, A sample of 700 female epileptic outpatients was examined between 1985 and 1987. The incidence of psychosexual disorders was 18%. Epileptic females with psychosexual disorders were compared with epileptic females without sexual disorders and with normal female controls on selected clinical and EEG parameters. Epileptic females with sexual disorders showed: lower marriage rates. a longer duration of illness. sexually colored prodromata. predominance of partial complex seizures (83%) and a higher incidence of menstrual abnormalities. Hyposexuality and exhibitionism were the psychosexual disorders most frequently noted. Temporal lobe EEG abnormalities were significantly higher.
Attitudes of major employers toward the employment of people with epilepsy: a 30-year study, Beginning in 1956. major San Francisco Bay area employers were sampled at 10-year intervals for a 30-year period to assess attitudes toward the employment of epileptic workers. In this time. we documented a trend of sustained positive change that appears to validate the efforts of organizations that have focused on raising public awareness of this disorder.
Antiepileptic drug monitoring at the epilepsy clinic: a prospective evaluation, To assess the value of on site therapeutic drug monitoring at the epilepsy clinic. management decisions were recorded before and immediately after antiepileptic drug (AED) concentrations became available. In the first year of this prospective study. 632 [277 carbamazepine (CBZ). 170 phenytoin (PHT). 113 valproate (VPA). and 72 phenobarbital (PB)] assays were performed during 488 clinic attendances in 182 actively managed epileptic patients. The results of drug analysis led to alterations in management at 114 patients visits. i.e.. 23% of those monitored. Dosage was increased in response to the circulating AED concentration in 12% of consultations and decreased in another 7.5%. Unsuspected poor compliance was uncovered in eight patients. and in three others an AED was added or discontinued on the basis of the assay result. The time of the next appointment was rearranged in 58 attendances. Only 50% of results were in the "therapeutic" ranges for the four major AEDs. Dosage was adjusted (50 up. 16 down) after 54% of low results. "Therapeutic" levels were followed by a change in AED dose (52 up. 31 down) in 26%. Only 29% of concentrations above the "therapeutic" range persuaded the doctor to alter the dosage regimen. and in 20% of these an increase in dose was recommended. On-site AED monitoring had an immediate impact on clinical decision-making in greater than 23% of consultations but in a form more subtle than the simple quest for a therapeutic result.
Appraisal of gut lavage in the study of intestinal humoral immunity, Direct investigation of intestinal humoral immunity requires collection of intestinal secretions or mucosal biopsy specimens. or both. A non-invasive technique of gut lavage. with a polyethyleneglycol electrolyte lavage solution as a means of collecting intestinal secretions for immunoglobulin and antibody studies. was evaluated. Fifty patients were studied--25 immunologically normal patients or volunteers. 15 patients with untreated coeliac disease. and 10 patients with active Crohn's disease. Protease inhibitors were added promptly to samples to prevent proteolysis of immunoglobulin content. Treated lavage samples were assayed by enzyme linked immunosorbent assay for immunoglobulin and antibody content. Studies of serial lavage specimens showed that early. faecally contaminated specimens contained negligible quantities of immunoglobulin. but once the specimens became clear a steady state was reached. with little variation in immunoglobulin content between serial specimens and with a uniform dilution (around 20%) of the ingested polyethyleneglycol. Gut lavage fluid IgA was predominantly secretory. comprising 92%. 81.6%. and 76.7% respectively of the total IgA gut lavage fluid content in the control. coeliac. and Crohn's groups. High values of total IgM and IgA and IgM antigliadin antibodies were detected in the coeliac group. and high values of IgG in the Crohn's disease group. This method of gut lavage is not only an effective bowel cleanser. but also a noninvasive means of obtaining intestinal secretions for the study of humoral immunity in gastrointestinal disease.
Jejunal immunoglobulin and antigliadin antibody secretion in adult coeliac disease, We compared the local intestinal immunoglobulin (Ig) secretion in six adult patients with coeliac disease and nine control subjects by perfusion of a small bowel segment under an occluding balloon and analysis of the perfusion fluid for the content of Ig and secretory component. The results were compared to the number of Ig-containing plasma cells in the test segment. There was. respectively. a two-fold and a fivefold increase in jejunal secretion rates of IgA (both monomeric and polymeric) and IgM in patients with coeliac disease compared with control subjects. The high IgA and IgM secretion rates parallel the increase of Ig-containing plasma cells in the lamina propria. In contrast. the IgG plasma cell density increase was barely significant in patients with coeliac disease and did not result in a high IgG secretion rate. The jejunal secretion rate of secretory component was significantly increased in patients with coeliac disease and no free dimeric IgA was present in the jejunal fluid. Antigliadin-IgA was detected in the serum and jejunal fluid of the six patients with coeliac disease. Antigliadin-IgA. however. was almost entirely polymeric IgA linked to secretory component in jejunal fluid. whereas 61% was dimeric IgA not linked to secretory component in serum. This result. combined with a raised secretory component secretion rate with no evidence of secretory component saturation. suggests that serum and intestinal antigliadin IgA might be of different origins in coeliac disease.
Inflammatory bowel disease and tobacco smoke--a case-control study, A case-control study was carried out in Stockholm. Sweden between 1984 and 1987 to evaluate the association of cigarette smoking and exposure to environmental tobacco smoke during childhood and the subsequent development of inflammatory bowel disease. Information on smoking was obtained by a postal questionnaire. The relative risk of Crohn's disease in current smokers compared with those who had never smoked was 1.33 (95% confidence limits 0.7; 2.6) in men and 4.99 (2.7; 9.2) in women; the corresponding results for ulcerative colitis were 0.96 (0.5; 1.8) and 0.72 (0.4; 1.4). The relative risk of ulcerative colitis in recent exsmokers compared with those who had never smoked was 2.18 (0.9; 5.0). Furthermore. an increase in the risk of Crohn's disease was found in those who were exposed to environmental tobacco smoke during childhood. the relative risk being 1.50 (1.0; 2.3). The corresponding relative risk of ulcerative colitis was 0.98 (0.6; 1.5).
Mortality and causes of death in Crohn's disease. Review of 50 years' experience in Leiden University Hospital, Six hundred and seventy one patients (52.5% women) with Crohn's disease seen at Leiden University Hospital between 1934 and 1984 were identified. Follow up was 98.2% complete. Sixty four (9.7%) of the 659 patients died. The cause of death was related to Crohn's disease in 34 patients. probably related to the disease in four. and unrelated. from incidental causes. in 25. The cause of death could not be identified in one patient. There was a significant decrease of deaths related to the disease after 1973. Causes of death such as amyloidosis and malnutrition have disappeared and postoperative deaths have decreased. The standardised mortality ratio showed an excess mortality of 2.23 for all patients. It was higher for women (3.30) than for men (1.76). A comparison of two recent 10 year periods showed a significant decrease in standardised mortality ratio in men but not in women. Patients whose disease started before the age of 20 years had an excess mortality compared with older patients. This study supports the view that the prognosis of Crohn's disease has improved in general but high quality medical and surgical management is important particularly for younger patients.
Efficacy of biofeedback training in improving faecal incontinence and anorectal physiologic function, The efficacy of biofeedback treatment on faecal incontinence and anorectal function was evaluated in eight patients with faecal incontinence treated with biofeedback training and medical therapy. Outcome and anorectal function were compared with nine faecal incontinent patients who received medical therapy alone. Three month follow up showed that 50% of patients in the biofeedback plus conventional treatment group and 56% of those treated conventionally only had improved. One year follow up showed that 13% in the biofeedback group were free of soiling and an additional 25% had improved. The results were similar in the conventionally treated group--11% were free of soiling and an additional 44% improved. Anal pressures at rest and squeeze. the rectal distension volume that induced sustained inhibition of both the external and internal anal sphincter. and continence to rectally infused saline were significantly reduced in both groups of patients compared with controls (p less than 0.05). Biofeedback treatment had no effect on these abnormal anorectal functions in either patients who improved or those who did not. The improvement in faecal incontinence was probably due to medical intervention or regression of symptoms with time. or both. and not the result of biofeedback training.
Effects of lactulose and lactitol on protein digestion and metabolism in conventional and germ free animal models: relevance of the results to their use in the treatment of portosystemic encephalopathy, Protein digestion and metabolism have been studied in laboratory rats and miniature pigs to investigate the mechanisms of action of lactulose and lactitol when used in the treatment of patients with portosystemic encephalopathy. Lactulose (beta-D-galactopyranosyl-(1----4)-beta-D-fructofuranose) and lactitol (beta-D-galactopyranosyl-(1----4)-D-glucitol) increased the excretion of nitrogenous material in the faeces and decreased nitrogen excretion in the urine in a similar degree to that reported for human patients. In studies with germ free rats given lactulose no such effect was observed. suggesting that. for lactulose at least. these effects are mediated by the gut flora. Measurement of the alpha-. epsilon-diaminopimelic acid content of the faeces confirmed that the enhancement of faecal nitrogen was due to an increased contribution from bacteria. The similarity in the results for lactulose and lactitol suggests that. from the perspective of protein metabolism. lactitol acts in a similar way to lactulose in the treatment of portosystemic encephalopathy.
Comparison of gall bladder bile and endoscopically obtained duodenal bile, In 10 patients with gall stone disease (eight women. two men; mean (SD) age 47.4 (13) years). bile was obtained by endoscopic aspiration after stimulation of the gall bladder with ceruletid and also by fine needle puncture of the gall bladder under local anaesthetic. The total lipid concentration of the puncture bile samples was mean (SD) 11.9 (4.7) g/dl. significantly higher than the endoscopic bile samples (3.9 (3.3) g/dl. p less than 0.001). Total bile acids. phospholipids. and biliary cholesterol (expressed in mol%) and cholesterol saturation index showed no significant differences between the two types of samples. The glycocholic acid concentration in the endoscopically obtained bile (27.7 (6.6) mol% v 23.3 (5.4) mol%; p less than 0.01) was significantly higher than the puncture bile samples. Puncture bile exhibited a significantly shorter nucleation time (3.5 (3.3) days v 19.6 (11.9) days; p less than 0.001). For determination of the nucleation time. endoscopic bile aspiration after gall bladder stimulation with ceruletid led to adequately concentrated samples in 50% of the study subjects. Cholesterol monohydrate crystal formation in native bile was observed in six samples of puncture bile and in three samples of the endoscopically obtained bile. The presence of cholesterol crystals and the determination of nucleation time in the puncture bile were the best discriminants between cholesterol and pigment gall stones and correlated well with computed tomogram analysis.
Isolated lipase and colipase deficiency in two brothers, Two brothers of Arab origin. aged 15 and 10 years. with isolated congenital lipase and colipase deficiency are described. Both were normally developed with a history of passing greasy stools since early infancy. Both have remarkable steatorrhoea and low serum carotene and vitamin E concentrations. After exocrine pancreatic stimulation. lipase and colipase activities in the duodenal fluid were almost completely absent. while amylase trypsin. bile salt. and pH values were normal. No other aetiology for exocrine pancreatic insufficiency was found. This is the first report of congenital combined lipase and colipase deficiency in two brothers.
The clinical value of magnetic resonance imaging in the evaluation of meniscal disorders, This prospective double-blind study was designed to evaluate the capability of magnetic resonance imaging to serve as a diagnostic tool in patients who have a clinically suspected disorder of the meniscus. The imaging studies provided a diagnostic accuracy of 72 per cent. a sensitivity of 88 per cent. and a specificity of 57 per cent. The positive and negative predictive values were 66 and 83 per cent. The diagnostic sensitivity was 94 per cent for lesions of the medial meniscus; this value differed significantly from that of 78 per cent for lesions of the lateral meniscus (p less than 0.05). The 37 per cent specificity for lesions of the medial meniscus was extremely low compared with the rate of 69 per cent for lesions of the lateral meniscus (p less than 0.01). In the intermediate part of the meniscus. the diagnostic sensitivity was 37 per cent on the medial side and 23 per cent on the lateral side; these values were significantly less than the average of 74 per cent for the other meniscal segments (p less than 0.001). The imaging studies provided an over-all accuracy of 67 per cent in the detection of degeneration of the meniscus. 78 per cent in the identification of meniscal tears. and 82 per cent in the delineation of postoperative lesions.
Magnetic resonance imaging of the shoulder. Sensitivity, specificity, and predictive value, The sensitivity. specificity. and predictive value of magnetic resonance imaging in the diagnosis of lesions of the rotator cuff. glenohumeral capsule. and glenoid labrum were evaluated in ninety-one patients and fifteen asymptomatic volunteers. Magnetic resonance imaging demonstrated 100 per cent sensitivity and 95 per cent specificity in the diagnosis of complete tears. and it consistently predicted the size of the tear of the rotator cuff. There was a definite correlation between atrophy of the supraspinatus muscle and the size of a complete. chronic tear of the rotator cuff. The sensitivity and specificity of magnetic resonance imaging in the differentiation of tendinitis from degeneration of the cuff were 82 and 85 per cent. and in the differentiation of a normal tendon from one affected by tendinitis with signs of impingement the sensitivity and specificity were 93 and 87 per cent. The formation of spurs around the acromion and acromiocalvicular joint correlated highly with increased age of the patient and with chronic disease of the rotator cuff. The sensitivity and specificity of magnetic resonance imaging in the diagnosis of labral tears associated with glenohumeral instability were 88 and 93 per cent. The study showed that high-resolution magnetic-resonance imaging is an excellent non-invasive tool in the diagnosis of lesions of the rotator cuff and glenohumeral instability.
Accuracy of diagnoses from magnetic resonance imaging of the knee. A multi-center analysis of one thousand and fourteen patients, Magnetic resonance images of the knee were made for 1014 patients. and the diagnosis was subsequently confirmed arthroscopically. The accuracy of the diagnoses from the imaging was 89 per cent for the medial meniscus. 88 per cent for the lateral meniscus. 93 per cent for the anterior cruciate ligament. and 99 per cent for the posterior cruciate ligament. The magnetic resonance examinations were done at several centers. and the results varied substantially among centers. The accuracy ranged from 64 to 95 per cent for the medial meniscus. from 83 to 94 per cent for the lateral meniscus. and from 78 to 97 per cent for the anterior cruciate ligament. The results from different magnetic-resonance units were also compared. and the findings suggested increased accuracy for the units that had a stronger magnetic field. Of the menisci for which the magnetic resonance signal was reported to be Grade II (a linear intrameniscal signal not extending to the superior or inferior meniscal surface). 17 per cent were found to be torn at arthroscopy.
Tests for posterolateral instability of the knee in normal subjects. Results of examination under anesthesia, An apparently normal knee was examined in each of 100 subjects while they were under general or epidural anesthesia for an unrelated operation. The Lachman. anterior drawer. posterior drawer. and pivot-shift tests were negative in all knees. All knees were stable to varus and valgus stress at both 0 and 30 degrees of flexion. The external-rotation recurvatum test also was negative in all knees. A positive reversed pivot-shift sign was present in 35 per cent of the knees. suggesting that it may not signify abnormality. at least not without a negative test on the contralateral knee. The results of the posterolateral drawer test were variable. difficult to quantify. and did not always have a firm end-point. The amount of maximum external rotation of the tibia. measured from the reference line of the medial border of the foot. was extremely variable at both 30 and 90 degrees of flexion of the knee. External rotation. as determined by this reference. was slightly greater (averaging 9 degrees) at 90 than at 30 degrees of flexion. The normal range of maximum external rotation of the foot was 10 to 45 degrees at 30 degrees of flexion of the knee and 15 to 70 degrees at 90 degrees of flexion. The presence of a large angle of external rotation and a positive reversed pivot-shift sign correlated strongly with increased ligamentous laxity and mild varus alignment of the knee.
Carpometacarpal dislocations. Long-term follow-up, Twenty patients who had a dislocation of one or all of the medial four carpometacarpal joints were followed for an average of 6.5 years (range. 1.5 to 20.5 years). Fifteen patients were treated with open reduction and internal fixation during the first three weeks after injury and the long-term result was excellent in thirteen of them. Three of the four unsatisfactory results were in patients who had injuries to the normally rigid second and third carpometacarpal joints or had a concomitant ulnar-nerve injury.
Healing of digital flexor tendons: importance of the interval from injury to repair. A biomechanical, biochemical, and morphological study in dogs, The effect of an elapsed interval of time between injury and operative repair of the flexor tendons was investigated in a canine model. Transected intrasynovial flexor tendons were repaired either immediately or after a delay of seven or twenty-one days. The biomechanical. biochemical. and morphological characteristics were compared at three and six weeks. The values for angular rotation. linear excursion. ultimate load. and linear slope were determined; concentrations of collagen and reducible collagen cross-links. an index of newly synthesized collagen. were measured; and the ultrastructural morphology of the tendons was examined by high-voltage electron microscopy. For the tendons that were repaired immediately. the values for angular rotation were 9.4 +/- 3.2 and 13.0 +/- 3.7 degrees at three and six weeks; for those that were repaired at seven days. 4.1 +/- 1.3 and 2.5 +/- 1.4 degrees; and for those that were repaired at twenty-one days. 2.7 +/- 0.8 and 4.7 +/- 0.7 degrees. There was a significant effect of the delay until repair on the angular rotation and linear excursion in all three groups (p less than 0.005 for both). Tensile testing of the bone-tendon complex revealed no significant effect of the delay on the values for ultimate load (p greater than 0.05). There were no significant differences in total concentration of collagen at the sites of repair or in the levels of reducible Schiff-base cross-links (indicators of newly synthesized cross-links) in tendons from the three groups.
Nature of altered growth hormone secretion in hyperthyroidism, Hyperthyroidism is accompanied by various neuroendocrine regulatory disturbances that affect not only the thyrotropic. but also the gonadotropic. corticotropic. and somatotropic axes. To examine the nature of alterations in neuroendocrine control mechanisms that direct the somatotropic axis in hyperthyroidism. we have applied a novel deconvolution technique designed to estimate the number. amplitude. and mass of significant underlying GH secretory events after the influence of GH metabolic clearance has been removed mathematically. To this end. blood was sampled at 10-min intervals for 24 h in seven hyperthyroid and seven age-matched euthyroid men. The subsequent GH time series were assayed by immunoradiometric assay (sensitivity. 0.08 ng/mL) and submitted to quantitative deconvolution analysis. We found that hyperthyroid compared to euthyroid men 1) had significantly more GH secretory bursts per 24 h (viz. 15 +/- 1.0 vs. 10 +/- 1.1; P = 0.017); 2) secreted 3 times as much GH per burst (3.7 +/- 0.80 vs. 1.3 +/- 0.42 ng/mL distribution vol; P = 0.013); 3) achieved a maximal rate of GH secretion in each burst 2.3-fold higher than that in control men (0.14 +/- 0.028 vs. 0.060 +/- 0.015 ng/mL.min; P = 0.017); and 4) had 3.7-fold higher 24-h endogenous GH production rates (P less than 0.01). Neither hyperthyroid nor euthyroid men had significant interburst (tonic) GH secretion. We conclude that the somatotropic axis in hyperthyroid men is marked by a higher frequency of spontaneous GH secretory bursts. a higher rate of maximal GH secretion attained per burst. and a larger mass of GH released per burst. These neuroregulatory disturbances result in a nearly 4-fold increase in the 24-h production rate of GH in thyrotoxicosis.
Stimulation of glucagon secretion by gastric inhibitory polypeptide in patients with hepatic cirrhosis and hyperglucagonemia, Porcine gastric inhibitory polypeptide (GIP) was infused iv (120 micrograms in 60 min) in seven patients with biopsy-proven hepatic cirrhosis who had surgical porta-caval anastomoses and hyperglucagonemia in the postabsorptive state. The infusions resulted in elevation of blood levels of immunoreactive GIP into the upper range of those observed after ingestion of large mixed meals. This was accompanied by significant increments in immunoreactive glucagon (IRG) in the plasma. Similar infusions in two cirrhotic patients with surgical porta-caval anastomoses who had normal plasma IRG levels in the postabsorptive state had no effect on the plasma IRG level. Ingestion of triglyceride (60 g) in hyperglucagonemic cirrhotic patients with porta-caval anastomoses also resulted in elevation of plasma immunoreactive GIP. and this was again associated with significant elevation of the plasma IRG level. Chromatography studies showed that the increments in plasma IRG after the administration of GIP or triglyceride were largely accounted for by increases in pancreatic-type glucagon. There were no significant effects of administration of GIP or triglyceride on the blood levels of glucose or immunoreactive insulin. It is concluded that porcine GIP is glucagonotropic in patients with cirrhosis of the liver who show elevated levels of IRG in the plasma in the postabsorptive state. This effect is not due to diversion of portal blood to the systemic circulation and may be attributable to hypersensitivity of the alpha-cells to stimulation by GIP.
Acceleration of luteinizing hormone pulse frequency in functional hypothalamic amenorrhea by dopaminergic blockade, A constellation of neuroendocrine secretory aberrations. including reduced LH pulse frequency and PRL concentrations. has been documented in women with functional hypothalamic amenorrhea (FHA). As pituitary function was preserved. these aberrations were attributed to an alteration in hypothalamic neuromodulation. To investigate the participation of the dopaminergic system in the genesis of the reduced LH pulse frequency and suppressed PRL levels in FHA. we studied six women with FHA and six cyclic women in the early follicular phase by obtaining blood samples at 15-min intervals for 48 h during sequential 24-h infusions of saline and a dopamine receptor blocker. metoclopramide (MCP). A hypothalamic vs. pituitary site of action was inferred from the pulsatility characteristics. MCP consistently elicited an increase in the LH pulse frequency in the women with FHA [7.3 +/- 1.2 (+/- SE) to 10.5 +/- 1.3 pulses/24 h; P less than 0.005]. In contrast. the eumenorrheic women did not show a significant change in LH pulse frequency in response to MCP (15.2 +/- 1.0 to 14.3 +/- 0.9 pulses/24 h). While the PRL concentrations were significantly lower in the FHA group during the infusion of saline (P less than 0.001) and MCP (P less than 0.005). the relative increases in PRL during MCP were similar in both groups. The acceleration of LH pulse frequency by blockade of dopamine receptors implies that there is increased hypothalamic dopaminergic inhibition of GnRH pulse frequency in women with FHA.
Extrarenal production of calcitriol in normal and uremic humans, We have previously reported low serum levels of 1.25-dihydroxyvitamin D3 [1.25-(OH)2D3] and increased 1.25-(OH)2D3 production after the administration of 25-hydryoxyvitamin D (25OHD) to anephric humans. Since normal alveolar macrophages are known to synthesize 1.25-(OH)2D3 when stimulated with gamma-interferon or lipopolysaccharide. we determined whether macrophages derived from peripheral blood monocytes could be an extrarenal source of 1.25-(OH)2D3. Our results demonstrated that macrophages from normal individuals synthesize 1.25-(OH)2D3. The apparent Km for 25OHD3 was 6.6 +/- 0.5 nM and the maximum velocity was 47.4 +/- 13.7 fmol 1.25-(OH)2D3/h.microgram DNA. The activity of this enzyme was reduced 37.2 +/- 3.1% by physiological concentrations (96 pmol/L) of 1.25-(OH)2D3 in the incubation medium. Normal macrophages further hydroxylated 1.25-(OH)2D3 to more polar metabolites. and this catabolic activity was significantly enhanced by physiological concentrations of 1.25-(OH)2D3. In chronic renal failure. peripheral macrophages exhibited an enhanced 1 alpha-hydroxylase activity (8.2 +/- 0.8 vs. 4.2 +/- 0.5 fmol 1.25-(OH)2D3/microgram DNA.h in controls) and a decreased capacity to degrade 1.25-(OH)2D3. Exogenous 1.25-(OH)2D3. in physiological concentrations. reduced 1.25-(OH)2D3 synthesis to a degree (23.6 +/- 8.5%) comparable to that observed in normal cells. 1.25-(OH)2D3 production by macrophages did not correlate with the severity of hyperparathyroidism. Moreover. human PTH-(1-34) in supraphysiological concentrations (20.000 and 100.000 ng/L) did not stimulate the 1 alpha-hydroxylase activity of macrophages from either normal or uremic subjects. These results demonstrate that 1) normal peripheral macrophages metabolize 25OHD3 and 1.25-(OH)2D3; 2) macrophages in uremia display higher rates of 1.25-(OH)2D3 synthesis and lower rates of catabolism than normal macrophages; and 3) 1.25-(OH)2D3 deficiency. but not hyperparathyroidism. may play a role in the stimulation of 1.25-(OH)2D3 production by macrophages in chronic renal failure.
A simple stress test for the evaluation of hypothalamic-pituitary-adrenal axis during the first 6 months of life, In 33 normal infants. divided into 3 age groups (less than 1 month. 1-3 months. and 3-6 months) plasma cortisol was measured at 2230. 2300. and 2330 h. Baseline plasma cortisol at 2230 h. was. as expected. low in all infants. with mean +/- SEM values of 41 +/- 5. 72 +/- 14. and 97 +/- 17 nmol/L in each group. respectively. Thirty and 60 min after the painful stimulus of the venipuncture. plasma cortisol increased significantly (P less than 0.0005). reaching a maximum increase up to 458 +/- 50. 392 +/- 66. and 455 +/- 97 nmol/L in each age group. respectively. We conclude that in these infants the hypothalamic-pituitary-adrenal axis was functionally intact and responded to the painful stimulus of the venipuncture by a significant increase in plasma cortisol. This test may be used as a simple procedure for the evaluation of the integrity of the hypothalamic-pituitary-adrenal axis without the administration of pharmacological agents. Its usefulness. however. should be validated with patients having a disorder of the system.
Falsely elevated serum parathyroid hormone levels due to immunoglobulin G in a patient with idiopathic hypoparathyroidism, A 73-yr-old patient with idiopathic hypoparathyroidism was admitted to our hospital in May 1981. The immunoreactive PTH (iPTH) level determined by RIA using antiserum specific for the C-terminal region of PTH-(65-69) was in the upper normal range (0.6 ng/mL) and over the next 7 yr increased gradually to 6 ng/mL. Since iPTH levels determined using other commercial RIA kits remained constantly decreased or in the undetectable range. we studied the mechanism of false elevation of iPTH in this patient. The patient's serum contained no binding protein to the tracer ([125I]) [Tyr45] human PTH-(46-84)). nor was any heterophilic antibody to the first [guinea pig immunoglobulin G (IgG)] or the second antibody (goat IgG) detected. Consistent with these findings. the dilution curve of the serum was parallel with that of standard bovine PTH-(1-84). Gel filtration analysis revealed that the iPTH-like substance was eluted in the void volume (apparent mol wt. greater than 70.000). Almost all of the iPTH-like substance was adsorbod by a protein-A-Sepharose column. When the IgG fraction purified by protein-A-Sepharose affinity chromatography was applied to an antihuman IgG lambda-Sepharose column. 72% of the iPTH-like substance was detected in the IgG lambda. These results suggest that the falsely elevated iPTH in the patient's serum was due to IgGs (mainly IgG lambda). which were cross-reactive with the antiserum highly specific for the C-terminal region of human PTH-(65-69).
Effect of a single infusion of aminohydroxypropylidene on calcium and bone metabolism in healthy volunteers monitored during 2 months, Recently. bisphosphonates have been used to prevent postmenopausal bone loss. As the effects of bisphosphonates on normal bone metabolism are unknown. 3-amino-1-hydroxypropylidene-1.1-diphosphonate (APD) was studied in healthy subjects. The effects of a single 20-mg APD infusion on biochemical parameters of calcium and bone metabolism were investigated during 2 months in 10 healthy male volunteers. This single moderate dose of APD reduced biochemical parameters of bone resorption during the time of follow-up. After 2 months. urinary hydroxyproline excretion was still below the basal level. The decreased serum calcium levels did not return to basal values. Biochemical parameters of bone formation. serum alkaline phosphatase and osteocalcin. showed a slight increase during the first month after stimulation of the parathyroids and a corresponding increase in serum 1.25-dihydroxyvitamin D. These formation parameters decreased thereafter. probably representing coupling between bone resorption and bone formation.
3 alpha-Androstanediol glucuronide in premature and normal pubarche, To investigate the role of adrenal androgens in 3 alpha-androstanediol glucuronide (3AG) production in childhood. we compared serum 3AG and androgen levels [dehydroepiandrosterone (DHEA). DHEA sulfate (DS). androstenedione (delta 4-A). and testosterone (T)] in 32 children with premature pubarche due to idiopathic premature adrenarche (IPA; n = 26). partial 21-hydroxylase deficiency (n = 2). or 3 beta-hydroxysteroid dehydrogenase deficiency (n = 4) with those in 36 normal prepubertal (18 males and 18 females) and 22 normal pubertal Tanner II-III subjects (10 males and 12 females). Serum 3AG (2.7 +/- 2.0 nmol/L) and all androgen concentrations in children with IPA were significantly higher (P less than 0.05-0.001) than those in normal prepubertal children (3AG. 0.8 +/- 0.5 nmol/L). Serum 3AG and androgen levels. except T. in all children with premature pubarche due to 21-hydroxylase deficiency or 3 beta-hydroxysteroid dehydrogenase deficiency were higher than those in the normal prepubertal children. Serum 3AG and all androgen levels in normal Tanner II-III male (3AG. 3.8 +/- 1.7 nmol/L) or female (3AG. 1.74 +/- 0.52 nmol/L) subjects were also significantly higher (P less than 0.05-0.001) than those in prepubertal children. Serum 3AG. DHEA. DS. and delta 4-A levels in children with IPA were similar to those in normal Tanner II-III females or males. but serum T in children with IPA (0.37 +/- 0.2 nmol/L) was significantly lower (P less than 0.05-0.001) than that in normal pubertal females (0.71 +/- 0.37 nmol/L) or males (4.5 +/- 2.6 nmol/L). In the combined group (n = 88). 3AG levels correlated better with serum DS (r = 0.7). DHEA (r = 0.6). and delta 4-A (r = 0.52). than with T (r = 0.31) levels. These data suggest that the weak adrenal androgens DS. DHEA. and delta 4-A contribute substantially to 3AG production in premature and normal pubarche.
Dual defects in pulsatile growth hormone secretion and clearance subserve the hyposomatotropism of obesity in man, We have examined the mechanisms underlying reduced circulating GH concentrations in the obese human. Computer-assisted (deconvolution) analysis was used to determine endogenous GH secretory and clearance rates quantitatively from entire 24-h plasma GH concentration profiles. These analyses revealed that the half-life (t 1/2) of endogenous GH was significantly shorter in obese (11.7 +/- 1.6 min) than in normal weight subjects (15.5 +/- 0.81 min; P less than 0.01). The accelerated blood disposal rate of GH was not due to decreased circulating concentrations of GH-binding protein. since the latter were similar in obese (25 +/- 1.0%) and normal weight (24 +/- 2.3%) men. However. obese men had significantly fewer GH secretory bursts (3.2 +/- 0.53 vs. 9.7 +/- 0.67/day; P less than 0.01). Among the rare GH secretory bursts that occurred in obese subjects. there were significantly prolonged mean intersecretory burst intervals (282 +/- 65 vs. 131 +/- 11 min; P less than 0.05). The resultant daily GH production rate in obese men was reduced to one fourth that in normal weight individuals. Both GH secretion rate and burst frequency were negatively correlated with the degree of obesity (ponderal index). The decreases in GH burst frequency and half-life were specific. since GH secretory pulse amplitude (maximal rate of GH release). the mass of GH released per burst. and the duration of computer-resolved GH secretory bursts were not different in obese and normal weight men. We conclude that obese men harbor a double defect in GH dynamics involving both GH secretion and clearance. and that the severity of the GH secretory deficiency is proportionate to the degree of obesity.
Pulsatile thyrotropin release and thyroid function in acromegalics before and during subcutaneous octreotide infusion, The pulsatile secretion of TSH was studied in eight patients with active acromegaly before treatment and after 1 month of therapy consisting of the sc infusion of 300 micrograms octreotide/day. Mean GH levels decreased from 37.1 +/- 7.2 to 5.2 +/- 1.4 mU/L (P = 0.002). Insulin-like growth factor-I levels decreased from 82.9 +/- 8.8 to 37.8 +/- 9.8 nmol/L (P less than 0.01) and normalized in five of the eight patients. In one patient TSH levels were undetectable before and during octreotide therapy. In the other seven patients. Cluster analysis revealed 11.9 +/- 0.8 pulses/24 h. with a mean pulse width of 81 +/- 4.6 min. a mean pulse height of 1.33 +/- 0.42 mU/L. and a mean pulse increment of 0.36 +/- 0.12 mU/L. During octreotide therapy these pulse parameters remained unchanged. Pulse height and amplitude increased significantly during the night (i.e. from 2000-0800 h) in both untreated and treated patients. The acrophase was unchanged by therapy. During therapy T3 levels decreased from 2.05 +/- 0.17 nmol/L to 1.44 +/- 0.08 nmol/L (P = 0.001). while rT3 levels increased from 0.14 +/- 0.02 nmol/L to 0.19 +/- 0.03 nmol/L (P less than 0.05). Plasma T4 levels remained unchanged. From these studies we conclude that the TSH pulse generator is unchanged in active acromegaly and apparently unaffected by chronic octreotide infusions.
Type II oestrogen binding sites in human colorectal carcinoma, Seven cases of colorectal adenocarcinomas were investigated for the presence of oestrogen receptors and progesterone receptors. The tumours specifically bound oestradiol. This binding almost exclusively resulted from the presence of high numbers of type II oestrogen binding sites. Oestrogen receptors were absent or present at very low concentrations. Immunohistochemical investigation of nuclear oestrogen receptors gave negative results. This indicates that antioestrogen receptor antibodies recognise oestrogen receptors but not type II oestrogen binding sites. The presence of specific type II oestrogen binding sites and progesterone binding offers further evidence for a potential role for these steroids and their receptors in colorectal carcinoma.
Abnormal fucosylation of ileal mucus in cystic fibrosis: I. A histochemical study using peroxidase labelled lectins, Peroxidase conjugated lectins were used to analyse the glycoproteins of small intestinal mucins in normal infants and those with cystic fibrosis to ascertain whether there are any detectable histochemical differences in saccharide composition. A significant decrease in Lotus tetragonolobus (LTG) binding fucose was shown in normal small intestinal mucin starting around 36 weeks' gestation with total absence of staining at term and beyond. In contrast. the age matched patients with cystic fibrosis showed persistent and intense LTG binding of fucose. These results provide the first clear histochemical evidence that cystic fibrosis mucin is abnormal and confirm the findings of previous biochemical studies.
Abnormal fucosylation of-ileal mucus in cystic fibrosis: II. A histochemical study using monoclonal antibodies to fucosyl oligosaccharides, Abnormal fucosylation of cystic fibrosis mucin was previously shown using peroxidase conjugated lectins on ileal tissue sections. These abnormally fucosylated glycoproteins were investigated further using monoclonal antibodies to fucosyl oligosaccharides based on type 1 and type 2 blood group precursor chains. The results of this study. using monoclonal antibodies to blood group glycoproteins in cystic fibrosis. were negative. yet abnormal fucosylation had been found using lectin histochemistry. Using monoclonal antibodies. lectins. and appropriate enzymes. such as glycosyl hydrolases. it should be possible to delineate further the abnormality found in glycoproteins in cystic fibrosis on appropriately fixed ileal sections. obtained from infants at term presenting with meconium ileus.
Improved silver staining of nucleolar organiser regions in paraffin wax sections using an inverted incubation technique [published erratum appears in J Clin Pathol 1991 Jun;44(6):528, A new simple modification to the silver staining of nucleolar organiser regions (AgNORs) was devised which. by performing the incubation with the slide inverted. results in minimal undesirable background staining. a persistent problem. Inverted incubation is facilitated by the use of a commercially available plastic coverplate. This technique has several additional advantages over other published staining protocols. In particular. the method is straightforward. fast. and maintains a high degree of contrast between the background and the AgNORs.
Comparison of two preparatory techniques for urine cytology, Two methods of preparation of urine for cytology were compared retrospectively. In method 1 cells in the urine were fixed after the preparation of the smear; in method 2 the cells were fixed before smear preparation. Urine cytology reports were correlated with subsequent histological analysis. The specificities of urine cytology using both methods were high (99%). The sensitivity using method 1 was 87%; using method 2 it was 65%. This difference was significant. The cell preparation technique therefore significantly changes the sensitivity of urine cytology. Cellular fixation after smear preparation is preferable to smear preparation after fixation.
Thyroid function in a healthy elderly population: implications for clinical evaluation, Evaluation of thyroid function in elderly people is complex and has generated some controversy about what is normal. This study analyzed thyroid function assays in an identified healthy elderly population of 216 subjects. Thyroxine. free thyroxine. triiodothyronine. T3 uptake. "supersensitive" thyrotropin. and thyroid antibody titers were performed. Histories of treatment for thyroid conditions were present in 13.9% (n = 30) of the population. and test results for an additional 4.3% (n = 8) revealed some hypothyroidism. These subjects were excluded from statistical analysis. Test results revealed significant differences from younger controls as well as skewed distributions for T4. FT4. and TSH. There were no significant correlations with increasing age or gender within the elderly population. 11.8% (n = 21) of the population exhibited elevated TSF levels with normal T4 values. and 23.0% (n = 41) exhibited a titer of one or both thyroid antibodies. Current reference ranges for thyroid tests are broad enough to include the range of values seen in the healthy elderly. but some cautions are discussed.
An assessment of salivary function in healthy premenopausal and postmenopausal females, The elderly represent the most rapidly growing segment of the U.S. population. and the majority of this group are females. The average woman can anticipate living about a third of her life beyond menopause. and many U.S. women undergo hormonal replacement in an attempt to relieve menopausal symptoms. Little is understood about the relationship between menopause. hormonal replacement therapy. and the oral structures. although oral discomfort. xerostomia. and salivary hypofunction have been associated with postmenopausal women. The effects of menopausal status and estrogen therapy on subjective reports of oral dryness and discomfort and objective measurements of major salivary gland output were assessed in 43 healthy premenopausal and postmenopausal females. No complaints of xerostomia or burning mouth and no alterations in the quantity of saliva occurred in this population. This study suggests that among healthy women salivary gland function is not significantly influenced by menopause or hormonal replacement therapy.
Influence of thiamin supplementation on the health and general well-being of an elderly Irish population with marginal thiamin deficiency [published erratum appears in J Gerontol 1991 Sep;46(5):M180, The effect of thiamin supplementation on the health and general well-being of 80 randomly selected healthy elderly Irish women. from a population with marginal thiamin deficiency. was studied. Key variables affecting thiamin status were controlled. Weekly dietary intakes. subjective feelings. and activity assessments were measured during a 4-week baseline and 6-week double blind treatment period. Clinical assessments were performed during the last week of each period. For treatment. subjects were randomly assigned to either thiamin (10 mg daily) or placebo groups. Compared to baseline and placebo supplemented values. thiamin-supplemented women experienced significantly increased appetite. energy intake. body weight and general well-being. and decreased fatigue. Thiamin supplementation also tended to reduce daytime sleep time. improve sleep patterns. and increase activity. These data suggest that evaluation of thiamin status is indicated when nonspecific conditions such as anorexia. weight loss. fatigue. depression. and sleep disorders are present in elderly persons.
Abnormal arginine vasopressin response to cigarette smoking and metoclopramide (but not to insulin-induced hypoglycemia) in elderly subjects, Aging is known to reduce arginine vasopressin (AVP) response to volumetric stimulations and to increase AVP responses to osmotic stimuli and to administration of metoclopramide (MCP). In order to gain a better insight into the effect of age on AVP secretion. we evaluated AVP responses to cigarette smoking. MCP. and insulin-induced hypoglycemia in 30 male subjects aged 22-81 and divided into 3 groups by age. Basal AVP concentrations were similar in all groups. The AVP response during the insulin tolerance test had a similar pattern and magnitude (2.5-fold increase) in all groups. AVP responses to MCP and cigarette smoking were similar in the two younger groups. with plasma AVP levels increased 2 times by MCP and 2.5 times by cigarette smoking. In contrast. both MCP- and cigarette smoking-induced AVP rises were significantly higher in the oldest group. where plasma AVP concentrations increased 2.5 times after MCP and 3.25 times after smoking. When data of the MCP and cigarette smoking tests were combined. regression analyses showed a significant positive correlation between AVP peak responses to MCP and cigarette smoking in the oldest subjects. These data show that elderly humans have increased AVP responses not only to MCP but also to cigarette smoking. suggesting a common disorder for both alterations. In contrast. the lack of age-related changes in AVP response during the insulin tolerance test demonstrates that the mechanism underlying the AVP response to hypoglycemia is not affected by aging.
The relation of pain to depression among institutionalized aged, Nursing home and congregate apartment residents (N = 598) were classified on the basis of a DSM-IIIR symptom checklist as suffering possible major. minor. or no depression; they also completed the Geriatric Depression Scale (GDS) and the Profile of Mood States (POMS). Possible major depressives reported more intense pain and a greater number of localized pain complaints than did minor depressives; nondepressed individuals reported the least intense pain and fewest localized complaints. The effect remained strong even when functional disability and health status were controlled statistically. Both pain intensity and number of localized complaints were correlated with GDS and POMS factor scores. but strength and direction of associations varied with level of depression. Item-by-item examination of localized complaints again indicated that more depressed individuals were more likely to report pain. particularly where physicians had identified a physical problem that might account for the pain. Results are compared with previous research on pain among younger individuals. Implications for treatment of depressed elderly are discussed.
How stressful is retirement? Findings from the Normative Aging Study, The stressfulness of retirement both as a transitional event experienced during the past year and as a life stage was investigated. Transitional stress was assessed using a life events approach. and stage stress using a "hassles" approach. Respondents were 1.516 male participants in the Normative Aging Study. 45% of whom were retired. Among those retiring in the past year. respondents' own and spouse's retirement were rated the least stressful from a list of 31 possible events. Only 30% found retirement stressful. Retirement hassles were also less frequently reported and were rated less stressful than the work hassles of men still in the labor force. The only consistent predictors of both transitional and stage retirement stress were poor health and family finances; personality did not predict retirement stress.
Living arrangements and sources of caregiving, This study examined both the prevalence of different types of caregivers (in terms of the relation to the individual). and whether living with someone is more important for caregiving than the relation of an elder to an individual. Caregiving is examined in terms of IADL and emotional support. Analyses are conducted using three separate random samples of those who are married and living with a spouse. those who live alone. and those who live with nonspousal others in Winnipeg. Manitoba. Canada. The results confirm previous research pointing out that married people tend to receive assistance from their spouse. Among nonmarrieds. children are named most frequently as the primary caregiver. After children. however. those who live alone tend to receive assistance from friends. and those who live with nonspousal others receive assistance from siblings. The data further document the importance of the structural characteristic of living with someone. rather than marital status. for assistance with IADL.
Social networks, health, and emotional well-being among the oldest old in London, A survey of the health and social circumstances of 662 people aged 85 and over. living at home in inner London. was conducted in 1987. A primary aim was to analyze the structure of social support networks of the sample in relation to respondents' emotional well-being and met and unmet needs for practical help. The conceptual and methodological framework that was applied to the study was derived from the theory of social networks. In confirmation of the common assumption that people aged 85+ are different from younger elderly people. as they are the "survivors." high levels of social support and informal help were given to most respondents. Although associations were found between social network variables and the provision of informal help. multifactorial analysis showed that health status explained more of the variation in emotional well-being.
Treatment of duodenitis with cimetidine: a clinical, endoscopic, and histologic study, We studied the effectiveness of cimetidine in the treatment of endoscopically diagnosed duodenitis. Sixty-nine patients with the solitary endoscopic finding of duodenitis (6% of 1.200 patients who underwent fiberoptic endoscopy of the upper gastrointestinal tract in our unit over 3 years) were studied retrospectively: a good clinical response was apparent in 45 of 69 patients treated with cimetidine (65%). and a fair response in another four (6%). In a controlled. randomized prospective study. we evaluated the effectiveness of cimetidine in duodenitis. Statistically significant improvement for the clinical and endoscopic scores was found in 10 patients treated with cimetidine (p less than 0.01). Improvement in the histologic score did not reach statistical significance. No such improvement was demonstrated in seven placebo-treated patients. We believe that duodenitis is a "peptic syndrome." has a good response to cimetidine treatment. and behaves much like duodenal ulcer disease.
Colonic volvulus as a complication of celiac sprue, Colonic volvulus has been a rarely reported complication of celiac sprue. We describe two patients with long-standing celiac sprue. one in whom a recurrent sigmoid volvulus developed. and in the other. a cecal volvulus. Following surgery. both are now asymptomatic on a gluten-free diet. The association between celiac sprue and colonic volvulus was first reported in 1953. There have been only a few isolated cases documented. surprisingly so because the two major predisposing conditions for colonic volvulus are often seen in patients with celiac sprue. Colonic bacterial fermentation of malabsorbed carbohydrate (in celiac sprue) leads to excess gas production. Flaccid bowel loops with sigmoid redundancy. a long mesentery. or cecal hypermobility are not uncommon. A motility disorder in celiac sprue has also been proposed. Thus these factors together would suggest that the likelihood of development of colonic volvulus in celiac sprue would be relatively great. The possibility of underlying celiac sprue should be considered in patients with colonic volvulus who have a background history of recurrent abdominal distention or malabsorptive symptoms.
Six physicians with inflammatory bowel disease, This essay tells the stories of six physicians with inflammatory bowel disease (IBD) to emphasize how important denial and control become when a physician is a patient. Guilt at the supposed psychosomatic "origin" of IBD suggests that we as physicians should never blame our patients for getting sick.
Erythrocyte sedimentation as a measure of Crohn's disease activity: opposite trends in ileitis versus colitis, To test our hypothesis that the erythrocytic sedimentation rate (ESR) correlates well with clinical activity in inflammatory disease of the colon. but not of the small bowel. we stratified 49 Crohn's disease patients according to their anatomic involvement and then measured the correlations between ESR and clinical activity within each of these anatomical subgroups. For 18 patients with Crohn's disease involving primarily the colon. there was a trend toward a direct correlation between clinical score and ESR (p = 0.15). In the 14 patients with Crohn's disease limited to the colon. this direct correlation was even more pronounced and statistically significant (p less than 0.02). By contrast. an opposite trend was observed for patients with small bowel disease. For the 26 patients with disease involving predominantly the small bowel. as well as for the 22 with disease limited to small bowel. there were statistically significant inverse correlations between clinical score and ESR (p less than 0.04). This difference between the directions of the correlations for Crohn's colitis versus ileitis was statistically significant (p less than 0.05). This study provides further evidence for the importance of analyzing putative indications of disease activity separately for each of the protean forms in which Crohn's disease occurs.
Biliary sludge: a critical update, Biliary sludge has been for many years a poorly defined entity. usually with low amplitude. nonshadowing echoes within the most dependent part of the gallbladder. which shift under the influence of postural changes. From a sonographic point of view. the detection of sludge implies the coexistence of small-sized. solid components and of a gel-like embedding material. The chemical nature of biliary sludge has recently been recognized to be predominantly composed of a coaggregate of cholesterol monohydrate crystals and liquid crystalline droplets. and in some cases. such as obstructive jaundice or symptomatic liver diseases. by bilirubin granules. all embedded in a gel matrix of mucous glycoproteins. From a pathogenic point of view. biliary sludge is often associated with biliary stasis. or with conditions characterized by impaired gallbladder contraction. such as prolonged total parenteral nutrition. fasting. and pregnancy. Other causes include mucus hypersecretion. which may favor cholesterol nucleation and crystal growth. and bile infection. Sludge may be an intermediate step in the formation of different types of stones. From an epidemiological point of view. sludge is quite rare in the asymptomatic. free-living population. but may be common in selected series of symptomatic patients. From a clinical point of view. sludge often has a fluctuating course. including frequent disappearances and reappearances. suggesting that the early stages of gallstone formation are reversible.
Thoracic succussion splash: a new symptom and sign of achalasia, A patient with a "thoracic succussion splash" due to achalasia is described. She noted a splashing or sloshing sensation in her chest related to jogging and bending. On examination a splashing sound could be heard over the mid sternum and the posterior chest when the patient was rocked vigorously back and forth.
Coumadin-induced gastrointestinal hemorrhage associated with an ileal duplication, A 31-year-old man had recurrent gastrointestinal hemorrhage after aortic valve replacement and initiation of anticoagulation therapy with coumadin. Radionuclide bleeding scan and subsequent contrast angiogram demonstrated a site of hemorrhage in the distal ileum. and at surgery a 1.8-cm spherical duplication was found. On histologic examination. the duplication was lined with normal ileal mucosa. and near the mouth of the duplication an inflammatory ulceration proved to be the site of hemorrhage. In a young patient with anticoagulation-associated gastrointestinal hemorrhage. alimentary tract duplication should be considered.
Neuromesenchymal hamartoma of the small bowel, We present the case of a long small bowel stricture with pathological features similar to those described as "neuromuscular and vascular hamartoma." showing in addition extensive fatty submucosal infiltration and fibrous intramural nodules. In the controversy about the nature of this disorder. we consider it a separate entity. Taking into account that other mesenchymal tissues than the originally described can participate. we propose the alternative term of "neuromesenchymal hamartoma" of the small bowel.
Quelprud's nodule: a post-auricular cartilaginous nodule, A number of minor variations to the configuration of the external ear are well recognized. This paper brings attention to one entity which is characterized by a small cartilaginous nodule or prominence arising from the posterior surface of the pinna and which we have named Quelprud's nodule. A prospective clinical survey of 208 patients attending an ENT clinic revealed that nearly one-third of the population studied possess this nodule. There was an equal sex incidence. The Quelprud's nodule was identified within families in a distribution which suggests an autosomal dominant inheritance with variable expressivity.
Oestrogen and progesterone receptors in acoustic neuroma, Tissue samples from fourteen consecutive (8 male: 6 female) acoustic neuromas were assayed for hormone receptors using either a monoclonal antibody (MA). dextran coated charcoal (DCC) or isoelectric focusing (IEF) technique. In this series there were no unequivocally positive results. a finding at variance with previously published results.
Conservative management of epistaxis, A retrospective study to assess the clinical usefulness of non-surgical management of epistaxis was performed on 340 patients requiring hospitalisation at the ENT Department of La Paz Hospital (Madrid). The previous history. type of management. hospitalisation time. and volume of transfusion were considered. Nasal packing was employed in 94.1 per cent of the patients. Most patients (82.9 per cent) were hospitalised less than seven days. and 84.1 per cent of the patients required no transfusion. There was one death. This study supports the clinical usefulness of conservative management in the treatment of patients with epistaxis.
Vocal fold sulcus, Vocal fold sulcus is a cause of dysphonia which has not been recognized until recently. Awareness of its existence combined with use of laryngostroboscopy would enhance the management of this group of patients. Five such cases were treated initially by voice therapy and subsequently combined with microlaryngeal Teflon injections of the vocal cord. Representative photomicrographs and the end results of treatment are presented. A good voice. subjectively and objectively. was obtained in three patients. with satisfactory improvement in the other two.
Tracheostomy closure in restrictive respiratory insufficiency, A retrospective study is presented of 31 patients who required ventilatory support via a tracheostomy for periods of one month to 27 years whilst in a tertiary referral centre for the care of patients with restrictive respiratory insufficiency. All patients underwent closure of a long-standing tracheostomy. Post-operative follow-up periods of up to 16 years are documented. The indications for and the complications of tracheostomy closure in patients with severe chronic restrictive respiratory insufficiency requiring long-term respiratory support are discussed. It is concluded that the benefits of operative tracheostomy closure outweigh the disadvantages in this unusual type of patient.
Pharyngeal adenocarcinoma with intestinal features, A high grade adenocarcinoma arising primarily in the pharynx of a 67-year-old man is presented. A CT-scan revealed a tumour mass growing in the pharynx. largely affecting parapharyngeal soft tissues. Lymph node metastases were found at clinical presentation. Both morphological and immunohistochemical studies displayed similar features to those of intestinal origin. To our knowledge. no previous examples of such neoplasm have been reported at this site. Its possible histogenetical origin is discussed.
Cystic hygroma: massive recurrence in adult life, Cystic hygroma is considered a disease of childhood. It may appear for the first time in adult life but recurrence by that stage is rare and may present difficulties in diagnosis due to previous treatment. The authors present a case where early pharmacological intervention may have prevented a potentially life threatening situation. The world literature is also reviewed.
Papillary adenocarcinoma of the middle ear, A case of papillary adenocarcinoma of the middle ear is presented. The patient had an unusually short history of otalgia. aural discharge and facial palsy. and. at presentation the tumour was too large for surgical resection to be a feasible option. The management of this rare tumour is discussed and the relevant literature reviewed.
Fat distribution and steroid hormones in women with alcohol abuse, Anthropometric. hormonal and liver function parameters were examined in 18 premenopausal women with a history of early alcohol abuse. and compared with the data for randomly selected controls of the same age. The alcoholic women showed slightly elevated levels of transaminases. but no clinical or laboratory signs of advanced liver damage. These women were characterized by an increased waist-to-hip ratio. due to enlarged waist circumference. Several endocrine abnormalities were found. including irregular or absent menses as well as low oestrogen. progesterone and delta-4-androstendione levels. The concentration of free testosterone was high and that of sex-hormone-binding globulin was low. These data suggest abdominal distribution of body fat. as well as hyperandrogenicity in alcoholic. premenopausal women. It is postulated that the endocrine abnormalities might be responsible for the abdominal fat distribution.
Lipoprotein-related coronary risk factors in patients with angiographically defined coronary artery disease: relation to number of stenosed arteries, To determine whether an index estimating antagonism between low density lipoprotein (LDL) and high density lipoprotein (HDL) would improve separation between groups with and without coronary artherosclerosis. patients undergoing coronary catheterization (35 women and 99 men) were analysed for total cholesterol (TC). HDL cholesterol (HDLc). apolipoprotein A (apo A) and apolipoprotein B (apo B). The subjects were categorized as groups 0. 1. 2 or 3 according to the number of stenosed arteries (greater than 75% areal stenosis). Thirty of the patients showed no significant coronary atherosclerosis (group 0). Serum apo B and TC concentrations were directly related to the number of stenosed vessels. whereas the concentrations of apo A and HDLc were negatively correlated with the number of stenosed arteries. An 'atherogenic Index' (ATH index) calculated as the product of serum concentrations of apo B. and TC minus HDLc divided by the product of apo A and HDLc. proved more satisfactory than individual lipoprotein components for discrimination between subjects with and without stenosis. Accordingly. identification of coronary groups may be improved by using the ATH index.
Effects of long-term treatment with metoprolol and hydrochlorothiazide on plasma lipids and lipoproteins, In order to evaluate the effects of one-year antihypertensive treatment on plasma lipids and lipoproteins. 65 patients whose diastolic blood pressure was in the range 95-120 mmHg were randomly allocated to groups that received either hydrochlorothiazide or metoprolol. or both drugs when the response to one of them was insufficient to control blood pressure. Blood pressure was effectively reduced in all groups. Patients on hydrochlorothiazide showed a significant increase (P less than 0.01) in low-density lipoprotein cholesterol (LDL-C) after 3 months of treatment. A significant increase in triglycerides was observed after 6 and 12 months. together with a decrease in high-density lipoprotein cholesterol (HDL-C) after 12 months (P less than 0.05) of treatment in patients on metoprolol. In patients treated with both hydrochlorothiazide and metoprolol. total cholesterol increased after 3 (P less than 0.001) and 6 months (P less than 0.05). triglycerides increased after 6 (P less than 0.01) and 12 months (P less than 0.01). and LDL-C increased after 3 (P less than 0.05). 6 (P less than 0.001) and 12 months (P less than 0.01) of treatment. respectively. In 61% of the patients. three or more lipid parameters were affected during the study period. We conclude that long-term antihypertensive treatment with hydrochlorothiazide. metoprolol. and particularly with both drugs. can induce lipid effects that deserve recognition. because in some cases these might counteract the possible benefit of a reduction in blood pressure on the prevention of coronary heart disease.
Wives of coronary high-risk men--are they also at higher risk? The Tromso Heart Study, Blood lipids. blood pressure. body mass index (BMI). smoking. dietary and exercise habits were studied in 911 wives of men with high risk for coronary heart disease (CHD). Following the 1979/80 Tromso Survey. 1373 men. aged 30-54 years. were identified as having high risk for CHD (HDL-cholesterol/total cholesterol less than or equal to 17.6% and/or total cholesterol greater than or equal to 7.86 mmol l-1). Of the 1373 men. 911 individuals had wives who also attended the screening. These wives were compared to age-matched. married women in the general population. A significantly higher total cholesterol level (5.98 mmol l-1 vs. 5.78 mmol l-1). lower HDL-cholesterol/total cholesterol (30.01% vs. 31.58%). higher BMI and higher coronary risk score (4.55 vs. 3.82) was found among the wives of the high-risk men. Furthermore. a higher proportion of these individuals were daily cigarette smokers (47.3% vs. 42.1%). and had received fewer years of education. They also had more dietary habits associated with increased risk of CHD than other married women in the general population. Our findings support the hypothesis that members of the same household as a person with increased risk for CHD also have increased risk. This is most probably due to shared lifestyle.
Verapamil increases serum alkaline phosphatase in hypertensive patients, In rats. verapamil decreases intestinal absorption of calcium. increases serum parathyroid hormone (PTH). and induces osteopenia. In this prospective study. verapamil 80-120 mg three times daily was given for 2 months to 20 patients with hypertension. and the effects on calcium homeostasis were recorded. This dose of verapamil significantly reduced supine systolic and diastolic blood pressure (+/- SD) from 158/100 +/- 9/8 mmHg to 146/89 +/- 14/8 mmHg (P = 0.001). Serum alkaline phosphatase (ALP) increased significantly from 2.77 +/- 1.06 mu kat l-1 to 3.19 +/- 1.22 mu kat l-1 (P = 0.004). and isoenzymes of ALP of skeletal origin appeared after verapamil treatment. The excretion of sodium in the urine increased (Na/creatinine ratio 8.95 +/- 6.01 before and 13.16 +/- 8.26 after verapamil; P = 0.04). while the excretion of calcium. phosphate and potassium was not changed. PTH was slightly increased at the end of verapamil treatment (1.09 +/- 0.54 vs. 0.98 +/- 0.74 microgram l-1; P = 0.07). and s-1.25(OH)2D3 was also somewhat increased (22.3 +/- 14.4 vs. 17.6 +/- 4.9 ng l-1; P = 0.26). Serum Ca was not affected by verapamil (before verapamil 2.43 +/- 0.11 mmol l-1. after verapamil 2.40 +/- 0.12 mmol l-1; P = 0.28). The increase in serum ALP demonstrates that verapamil affects bone cell metabolism in man. This effect could be secondary to the enhancement of PTH secretion.
Trimethoprim-sulphamethoxazole-associated blood dyscrasias. Ten years' experience of the Swedish spontaneous reporting system, During the 10-year period 1976-1985. a total of 154 cases of blood dyscrasia were reported in Sweden which were evaluated as having a probable or possible causal relationship with trimethoprim-sulphamethoxazole (T-SM). There were 61 cases of leucopenia (of which 16 had agranulocytosis). 28 cases of thrombocytopenia. and two of non-haemolytic anaemia. There were also 32 cases of bicytopenia and 31 cases of tricytopenia. The median age varied from 38 years in the leucopenia group to 81 years in those with tricytopenia. The overall fatality rate was 17%. ranging from 2% in the group with mild leucopenia to 52% in the group with tricytopenia. In relation to sales and prescription data. the overall incidence of reported T-SM blood dyscrasias was 5.3 per million defined daily doses. and among out-patients the incidence was one case per 18.000 prescriptions. Thus the overall incidence of any blood reaction to T-SM appears to be low. In relation to prescription data. elderly people were overrepresented among the serious reactions.
The relationship between clinically confirmed cobalamin deficiency and serum methylmalonic acid, Over a 1-year period. we examined 42 consecutive patients with low serum cobalamin levels detected by primary screening test (S-protein binder. RIA). In 31 patients (74%) clinical cobalamin deficiency was confirmed. whereas the remaining 11 patients (26%) were characterized clinically as non-cobalamin deficient. The serum methylmalonic acid level was higher than 0.34 mumol l-1 (3 SD above the mean in normal controls) in 30 of the 31 clinically characterized cobalamin-deficient subjects. and below this level in 10 of the 11 non-deficient patients. We conclude that the serum methylmalonic acid assay provides an appropriate means of discrimination between cobalamin deficiency and non-cobalamin deficiency (efficiency = 0.95). and we recommend that the assay be adopted as the standard test for diagnosis of tissue cobalamin deficiency.
Drug related admissions to a cardiology department; frequency and avoidability, Three hundred and sixty-six consecutive patients admitted to a department of cardiology were evaluated for drug events as a cause of admission. The drug events considered were adverse drug reactions (ADR) and dose-related therapeutic failures (DTF). 'Definite' or 'probable' drug events accounted for 15 admissions (4.1%. 95% confidence limits 2.3-6.7%). of which eleven were ADR and four were DTF. With the inclusion of six 'possible' drug events. the rate of drug-related hospitalizations (DRH) was 5.7%. DRHs were characterized by a preponderance of acute admissions and elderly patients. Hypokalaemia (less than 3.5 mM) was observed in 27 (16%) patients receiving diuretics. and could be related to four cases of arrhythmias (two 'probable' and two 'possible' ADR). The average serum potassium level was similar in diuretic treated patients with or without drugs to counteract hypokalaemia. irrespective of the drugs chosen. Among the 15 'definite'/'probable' DRHs. five were considered to be due to an error in prescription. and a further five cases were judged to have been avoidable had appropriate measures been taken by prescribing physicians. A DRH educational intervention programme should primarily deal with non-compliance or with prescription of diuretics or digoxin. since these problems constitute the majority of cases of DRH. No specific group of doctors could be targeted as responsible for DRH. avoidable or not.
Effect of nicardipine on somatosensory evoked potentials in patients with acute cerebral infarction, We evaluated the effect of nicardipine. a calcium channel blocker. on somatosensory evoked potentials (SEP) in 26 patients with acute cerebral infarction. Post treatment. 58% (15/26) of the N20 and P25 latencies were prolonged in the affected hemispheres; 8% (2/26) were shortened; and 35% (9/26) did not change. The mean N20 and P25 latencies were significantly prolonged two hours post treatment in the affected hemisphere (N20. P less than 0.01. P25 P less than 0.01). Nicardipine (Ni) had no effect on SEP components in the intact hemispheres. Seventy five per cent of the 12 patients with hypertension had a decrease in blood pressure (BP) after taking nicardipine. but there were no undesirable side effects or worsening of neurological signs. Our study demonstrates that nicardipine prolongs the latencies of short-latency components of SEP in the affected hemisphere after acute ischaemic stroke and also decreases BP. These observations suggest that nicardipine therapy might impair neuronal function in the ischaemic zone.
Platelet monoamine oxidase B activity in parkinsonian patients, Monoamine oxidase B (MAO B) plays a pivotal role in N-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) induced Parkinsonism. An increased MAO B activity in platelets of patients with idiopathic Parkinson's disease (PD) is reported in this study. The possibility that high MAO B activity may represent a trait of vulnerability for PD by enhancing the neurotoxic effects of environmental compounds is discussed.
Specificity of affective and autonomic symptoms of depression in Parkinson's disease, Previous investigators have suggested that numerous symptoms used to diagnose depression. such as sleep or appetite disturbance. are non-specific in medically ill patients. and alternative diagnostic criteria should be developed. In the study this hypothesis was tested in Parkinson's disease (PD) by comparing patients with PD who reported a depressive mood with patients having PD but without a depressive mood. Depressed patients showed a significantly higher frequency of both autonomic and affective symptoms of depression. Depressed patients with PD reported a significantly higher frequency of worrying. brooding. loss of interest. hopelessness. suicidal tendencies. social withdrawal. self-depreciation. ideas of reference. anxiety symptoms. loss of appetite. initial and middle insomnia. and loss of libido when compared with non-depressed patients. No significant between-group differences. however. were observed in the frequency of anergia. motor retardation. and early morning awakening.
Neurophysiological observations on corticospinal projections to the upper limb in subjects with Rett syndrome, The aim of the present study was to investigate the excitability of corticospinal neurons and the integrity of their projections to the alpha motor neurons through the corticospinal tract in subjects of different ages with Rett syndrome. Electromagnetic stimulation of the motor cortex and cervical motor roots was used to evoke motor action potentials in the biceps brachii and hypothenar muscles. The phasic stretch reflex in the biceps brachii was also recorded to study the excitability of spinal alpha motor neurons. Motor cortex stimulation evoked motor action potentials at low threshold and with abnormally short latencies and prolonged durations. In contrast cervical motor root stimulation resulted in responses of normal latency and duration. The phasic stretch reflex had a low threshold. short latency and prolonged duration. It is concluded that in Rett syndrome the corticospinal pathway is intact. The results suggest disordered synaptic control of the Betz cell of the motor cortex and/or the spinal alpha motor neuron. although the involvement of the latter might be a consequence of dysfunction in supraspinal descending motor pathways.
A clinico-pathological and follow up study of 10 cases of essential type II cryoglobulinaemic neuropathy, Ten patients with essential cryoglobulinaemia type II were examined for peripheral nerve damage. In six cases distal symmetrical nerve involvement was present. while in three other cases abnormalities restricted to single nerves were found. Electrophysiological and morphological data were consistent with axonal damage. the larger myelinated fibres being most affected. Although active signs of vasculitis and immunoperoxidase staining for immunoglobulins were not present. endoneurial vessels were widely damaged. with abnormally thick endothelial cells and redundant basal membranes. These findings. together with a patchy distribution of myelinated fibre loss. suggest ischaemia as a cause of peripheral neuropathy during essential cryoglobulinaemia type II. A follow up examination. performed one year after haematologial remission. revealed that no further peripheral nerve damage had occurred.
Multiple sclerosis in Australia and New Zealand: are the determinants genetic or environmental?, The prevalence of multiple sclerosis (MS) has been recently reported from nine regions of Australia and New Zealand. There is a marked variation of prevalence with latitude. MS is seven times more common in southern New Zealand than in tropical Queensland. On current evidence. it is suggested that in both countries this variation is predominantly due to environmental rather than genetic factors.
Multiple sclerosis among United Kingdom-born children of immigrants from the Indian subcontinent, Africa and the West Indies, Multiple sclerosis (MS) is very uncommon among ethnic Asians in the Indian subcontinent. among Asians and Africans resident in the New Commonwealth countries of Africa and in the West Indies. It is also very uncommon among those who have migrated to England from those countries. In contrast. the children born in the United Kingdom of Asian. African and West Indian immigrants have. in the age groups available for study. a high prevalence of MS of a similar order to that occurring in the general population of England.
Assessment of pupillary light reflex latency and darkness adapted pupil size in control subjects and in diabetic patients with and without cardiovascular autonomic neuropathy, Increased pupillary light reflex latencies were found more often than a reduced darkness pupil size in diabetic patients with and without abnormal cardiovascular reflexes. This finding suggests that parasympathetic pupillary dysfunction precedes sympathetic pupillary denervation in diabetic autonomic neuropathy.
Lower extremity arterial disease in elderly subjects with systolic hypertension, The ratio of ankle-to-arm systolic blood pressure (ankle/arm index or AAI) appears to be a non-invasive indicator of flow-significant atherosclerosis and may be a useful measure of burden of disease in a high risk population. The prevalence of lower extremity arterial disease (LEAD) was assessed by this method in the Systolic Hypertension in the Elderly Program (SHEP). Subjects were aged 60 and older with systolic blood pressure greater than 160 mmHg upon entry to the study. An AAI of 0.90 or less was considered indicative of flow-significant LEAD. The prevalence of LEAD by this method was 26.7% (50/187). while the prevalence of intermittent claudication (IC) was only 6.4% (12/187). Of those with IC. 66.7% (8/12) had confirmed LEAD. The prevalence of LEAD as measured by AAI increased with age in women and was associated with a history of current smoking and lower levels of high density lipoproteins. In this study population with systolic hypertension. LEAD. as measured by the AAI. is more prevalent than previously described in elderly populations and is associated with other risk factors for atherosclerosis.
Stroke rehabilitation: Australian patient profile and functional outcome, A prospective. multi-institutional. population based study identified 1274 non-surgical stroke admissions to all hospitals in a major Australian city during 1984. The demographic and diagnostic profile and the nature of functional recovery of all 258 first stroke survivors who were referred for inpatient rehabilitation are presented. The median duration of rehabilitation stay was 49 days. The mean functional independence score. as measured on a modified Barthel Index at admission was 44. compared with 78 on discharge. a mean improvement of 34. Stair climbing had the lowest mean value on admission (12). while bowel control had the lowest residual deficit on discharge (95). The stroke study group was representative of the unimpaired aged population in all respects except ethnicity. where differences are attributed to age. The variables identified as significant are; side and severity of paralysis. age and sex. marital status and ethnicity. Stroke rehabilitation outcome was not influenced by etiology. site of lesion. arterial distribution. occupation or education.
Trends in female breast cancer in Connecticut and the United States, Trends for female breast cancer were examined by age. period and cohort for the years 1950-1984 in U.S. mortality. Connecticut mortality and Connecticut incidence. Birth cohort patterns were evident for all three sets of data. The results confirm a continuing increase in invasive breast cancer by providing evidence of a strong birth cohort pattern. over a time series of 90 years of birth cohorts. This trend appears to be real for the most part because of the cohort patterns and because there is minimal underdetection in data obtained by autopsy and blind biopsy. Secondly. when cohort modeling is applied to breast cancer mortality. there is an indication of a modest decline in recent breast cancer mortality (in the face of an apparent long-term increase). which suggests that control of breast cancer mortality may have developed in recent decades. perhaps through earlier detection and improved treatment. Finally. in contrast with a prior report. there is little evidence for a clinically important difference in time trend between pre- and postmenopausal breast cancer.
Progression of renal insufficiency in analgesic nephropathy: impact of continuous drug abuse, Twenty-three patients with analgesic nephropathy and apparent cessation of drug abuse were tested for blood acetaminophen and salicylate on the occasion of routine renal control examinations. In 12 patients (mean creatinine level 2.74 +/- 1.09 mg/dl) no deterioration of renal function was noted within a 1-year observation period (Group 1). In 11 patients a significant progression of renal insufficiency was observed (mean creatinine level rose from 3.86 +/- 1.06 to 6.40 +/- 3.18 mg/dl within the same observation period; Group 2). Blood tests for acetaminophen and salicylate were positive in 2 patients of Group 1 and in 9 patients of Group 2 (chi 2 = 7.326). p less than 0.01). Our data emphasize the importance of a continuous analgesic abuse hidden from the medical staff with regard to the progression of renal insufficiency in analgesic nephropathy.
Recent life change and large bowel cancer. Data from the Melbourne Colorectal Cancer Study, In a large. population based. epidemiological study of colorectal cancer. The Melbourne Colorectal Cancer Study. several etiological factors were investigated. Persons' recent life changes. as well as the degree of upset they experienced as a result of these changes. were included. Interviews with 715 histologically confirmed new cases of colorectal cancer occurring over a 12-month period in Melbourne. Australia. and with 727 age and sex matched community controls were conducted. As one of the methods of assessing any effect of recall bias. 179 hospital controls were also investigated. Major illness or death of a family member. major family problems and major work problems were found to be significantly more common for cases over the 5 years preceding diagnosis compared to controls. Cases also reported being significantly more upset with their recent life changes than did controls. No significant differences in results were found between males and females. or between colon cancer and rectal cancer patients. Although the possibility of recall bias. was not completely controlled for in this study. it was probably not an important factor in explaining case-control differences. Recent life changes. and their perceptions. may have significance in the development of large bowel cancer.
Functional status and quality of life: predictors of early mortality among patients entering treatment for end stage renal disease, We investigated the association between functional status and quality of life in newly-entered dialysis patients and the subsequent risk of mortality. We enrolled the patients from 37 dialysis facilities in two southeastern states (n = 294). Functional status was assessed by the Karnofsky Performance Scale (KPS) and quality of life by the Spitzer Quality of Life Index (SQLI). During a mean (SE) follow-up of 479.6 (109.4) days 49 patients (16.4%) of the cohort died. The mean KPS score (SE) for survivors was 7.31 (0.11) and for non-survivors was 5.89 (0.26). P less than 0.0001. The mean SQLI score (SE) for survivors was 6.74 (0.15) and non-survivors was 4.95 (0.28). P less than 0.0001. Strong gradients of the risk of mortality were found for both measurements. After controlling for other covariates including age. race. sex. primary cause of renal failure and the presence of comorbidity. both the KPS and SQLI scores were independently correlated with risk of mortality. We conclude that functional status and quality of life are strong independent risk factors for subsequent mortality in new dialysis patients. These are easily measured indicators which may serve to predict subsequent risk of mortality or adjust case-mix estimates for comparisons between dialysis populations.
A prospective comparison of rubidium-82 PET and thallium-201 SPECT myocardial perfusion imaging utilizing a single dipyridamole stress in the diagnosis of coronary artery disease, The purpose of the present study is to prospectively compare myocardial perfusion imaging with rubidium-82 (82Rb) by positron emission tomography (PET) with thallium-201 (201Tl) imaging by single-photon emission tomography (SPECT) by recording both studies with a single dipyridamole handgrip stress. and reading both sets of images with the same display technique. In a series of 202 patients with previous coronary arteriography. the sensitivity. specificity. and accuracy of 82Rb PET were 93%. 78%. and 90% and for 201Tl SPECT 76%. 80%. and 77%. respectively. When 70 patients with previous therapeutic interventions were excluded. the remaining 132 patients showed a sensitivity. specificity. and accuracy of 95%. 82% and 92% for 82Rb PET and 79%. 76%. and 78% for 201Tl SPECT. The improved contrast resolution of PET resulted in markedly superior images and a more confident identification of defects.
Recognition of distinctive patterns of gallium-67 distribution in sarcoidosis, Assessment of gallium-67 (67Ga) uptake in the salivary and lacrimal glands and intrathoracic lymph nodes was made in 605 consecutive patients including 65 with sarcoidosis. A distinctive intrathoracic lymph node 67Ga uptake pattern. resembling the Greek letter lambda. was observed only in sarcoidosis (72%). Symmetrical lacrimal gland and parotid gland 67Ga uptake (panda appearance) was noted in 79% of sarcoidosis patients. A simultaneous lambda and panda pattern (62%) or a panda appearance with radiographic bilateral. symmetrical. hilar lymphadenopathy (6%) was present only in sarcoidosis patients. The presence of either of these patterns was particularly prevalent in roentgen Stages I (80%) or II (74%). We conclude that simultaneous (a) lambda and panda images. or (b) a panda image with bilateral symmetrical hilar lymphadenopathy on chest X-ray represent distinctive patterns which are highly specific for sarcoidosis. and may obviate the need for invasive diagnostic procedures.
Gallbladder perforation: correlation of cholescintigraphic and sonographic findings with the Niemeier classification, We retrospectively analyzed the cholescintigrams and sonograms of 36 consecutive patients with gallbladder perforation to (a) determine the sensitivity of each for the preoperative detection of gallbladder perforation and (b) correlate the findings with the modified Niemeier classification. Cholescintigraphic criteria of perforation (free spill. pericholecystic hepatic activity. and scintigraphic gallstone ileus sign) were detected in 14 of 28 (50%) cases. while sonographic criteria of perforation (pericholecystic fluid or pneumobilia with gallstones) were present in 18% (4 of 22) of patients (p less than 0.05). Cholescintigraphic patterns of perforation associated with the Niemeier classification were: Type I (acute free perforation). 3 of 7 scans demonstrated free spill; Type II (subacute pericholecystic abscess). 9 of 19 scans showed pericholecystic activity; and Type III (chronic cholecystoenteric fistula). 1 of 3 scans showed a scintigraphic gallstone ileus. Thus. although cholescintigraphy appears superior to sonography. both modalities are relatively insensitive for the detection of gallbladder perforation.
Differential diagnosis of lung tumor with positron emission tomography: a prospective study, To predict the nature of non-calcifying lung tumors. we performed a prospective study of 46 cases with L-[methyl 11C]methionine (MET. 24 cases) and 18F-fluorodeoxyglucose (FDG. 22 cases) using positron emission tomography (PET). Mean tumor/muscle radioactivity ratios are 5.3 +/- 2.0 (n = 14) for malignant and 1.9 +/- 0.9 (n = 10) for benign with MET (p less than 0.001). and 4.4 +/- 2.2 (n = 12) and 1.5 +/- 0.3 (n = 10). respectively. with FDG (p less than 0.001). The ratios indicate that malignant tumors have higher metabolic demand than benign lesions. Tumors less than 1 cm in diameter were difficult to accurately evaluate due to PET resolution. Compared to the diagnosis at pathology. the MET study showed a sensitivity of 93% (13/14). a specificity of 60% (6/10). and an accuracy of 79% (19/24). The FDG study showed 83% (10/12). 90% (9/10). 86% (19/22). respectively. No significant differences were observed between the two tracers. This study suggests that PET studies using either MET or FDG may be very useful for the differential diagnosis of lung tumors.
Indium-111-antimyosin scintigraphy after doxorubicin therapy in patients with advanced breast cancer, Indium-111-antimyosin (111In-antimyosin) scans were performed in 20 women with advanced breast cancer after 10 cycles of chemotherapy consisting of cyclophosphamide. 5-fluorouracil and doxorubicin (total cumulative dose of doxorubicin of 500 mg/m2). Antimyosin uptake in the myocardium was quantified by means of a heart-to-lung ratio (HLR). Antimyosin uptake in the myocardium was observed in 17/20 (85%) patients. and HLR after chemotherapy was 1.86 +/- 0.25. Left ventricular ejection fraction (EF) was determined before and after chemotherapy. Patients with decreased EF (8/20. 40%) presented with more intense antimyosin uptake (HLR of 2.11 +/- 0.10 versus 1.70 +/- 0.16 (p = 0.01]. HLR values correlated with EF values after chemotherapy (r = -0.47. p less than 0.05). Positive antimyosin studies after chemotherapy including doxorubicin. indicate the presence of myocardial damage in these patients. Antimyosin studies are a sensitive method to detect myocyte damage in patients after doxorubicin therapy.
Indium-labeled anti-colorectal carcinoma monoclonal antibody accumulation in non-tumored tissue in patients with colorectal carcinoma, Indium-111- (111In) labeled murine monoclonal antibodies ZCE 025 (against carcinoembryonic antigen) and CYT-103 MAb B72.3 (against tumor-associated glycoprotein - 72) have been used to image patients with colorectal cancers with encouraging results. The objectives of this study were to assess the frequency and causes of 111In MAb localization in tumor-free. benign tissues. Thus. scans of 75 patients who have undergone exploratory surgery following radioimmunoscintigraphy with 111In-ZCE 025 (n = 37) or 111In-CYT-103 (n = 38) were reviewed in conjunction with operative and histopathology reports. Localization in non-tumored tissues was seen in 10.8% and 13.1%. respectively. of patients receiving ZCE 025 and CYT-103. The most common sites involved were: degenerative joint disease. abdominal aneurysms. postoperative bowel adhesions. and local inflammatory changes secondary to surgery or external irradiation. Review of patients' medical history and results of concurrent diagnostic modalities is likely to lessen the false-positive rate of 111In-labeled MAb scan interpretation.
6-[18F]fluoro-L-fucose: a possible tracer for assessing glycoconjugate synthesis in tumors with positron emission tomography, The potential of 6-[18F]fluoro-L-fucose (6-[18F]FFuc) for assessing glycoconjugate synthesis in tumors with positron emission tomography (PET) was investigated. Using the tissue sampling method with five tumor models. different time-radioactivity profiles were found: a nearly constant level in Lewis lung carcinoma (3LL) and different clearance patterns in others. Rapid clearance in normal tissues resulted in preferable uptake ratios for tumor imaging of brain and pancreas. Metabolic studies and the L-fucose loading effects on the tissue uptake proved the tracer to be a biochemically active L-fucose analog. Imaging of the intracranial rat glioma and 3LL in lungs or hepatomas in mice by autoradiography (ARG) and intramuscular VX-2 carcinoma in rabbits by PET was demonstrated. Using double-radionuclide ARG. similar distribution images of 6-[18F]FFuc and 14C-L-fucose but different tumor-to-liver uptake ratios were found. A metastasis model seemed to show a higher uptake of both tracers as compared to a primary tumor model.
Technetium-99m-human polyclonal IgG radiolabeled via the hydrazino nicotinamide derivative for imaging focal sites of infection in rats, The biologic behavior of human polyclonal immunoglobulin (IgG) radiolabeled with technetium-99m (99mTc) by a novel method. via a nicotinyl hydrazine derivative. was evaluated in rats. Technetium-99m- and indium-111-IgG were co-administered to normal rats and biodistribution was determined at 2. 6. and 16 hr. The inflammation imaging properties of the two reagents were compared in rats with deep-thigh infection due to Escherichia coli. Blood clearance of both antibody preparations was well described by a bi-exponential function: (99mTc-IgG: t1/2 = 3.82 +/- 0.89 and 57.52 +/- 1.70 hr. 111In-IgG: 3.93 +/- 0.117 and 40.71 +/- 1.26 hr). Biodistributions in the solid organs were similar. however. small but statistically significant differences were detected: 99mTc-IgG greater than 111In-IgG in lung. liver. and spleen; 99mTc-IgG less than 111In-IgG in kidney and skeletal muscle (p less than 0.01). At all three imaging times. target-to-background ratio and percent residual activity for the two compounds were remarkably similar. These studies establish that human polyclonal IgG labeled with 99mTc via a nicotinyl hydrazine modified intermediate is equivalent to 111In-IgG for imaging focal sites of infection in experimental animals.
Large telangiectatic focal nodular hyperplasia presenting with normal radionuclide studies: case report, A 9 cm-lesion of telangiectatic focal nodular hyperplasia was incidentally identified in a 31-yr-old female. Despite a typical appearance by X-ray computed tomography and ultrasonography. scintigraphy with technetium-99m-(99mTc) colloid. 99mTc-diethyliminodiacetic acid. and 99mTc-labeled red cells failed to demonstrate any abnormalities. These findings are felt to reflect the relative lack of architectural disruption that histologically characterizes this particular lesion. The present report described the imaging characteristics of the telangiectatic form of focal nodular hyperplasia.
SPECT imaging of pediatric brain tumor with hexakis (methoxyisobutylisonitrile) technetium (I), Technetium-99m-Hexamibi [Hexakis (methoxyisobutylisonitrile) technetium (i)] was developed as a myocardial perfusion agent with biologic properties similar to those of thallium-201 (201TI). As 201TI has recently been observed to be of value for the diagnosis of brain tumors when used in conjunction with single-photon emission computed tomography (SPECT) imaging technology. the possibility that the biologic similarity of the two radiopharmaceuticals extended to their affinity for tumors was tested. A 5-yr-old female patient with a brain stem astrocytoma showed marked focal uptake of 99mTc-Hexamibi at the site of tumor recurrence as defined by biopsy and prior 201TI/SPECT study. Tumor-to-normal cortex radioactivity ratios for the 99mTc-Hexamibi/SPECT study were 132:1 and the spatial resolution of the 99mTc-Hexamibi images was high. This observation suggests that 99mTc-Hexamibi merits further study as a potential agent for SPECT imaging of human brain tumors.
Beta camera for static and dynamic imaging of charged-particle emitting radionuclides in biologic samples, A detection system based on microchannel plates has been constructed to image charged particles emitted by radionuclides in biomedical samples. This technique has significant advantages over conventional film autoradiography for investigating the distribution of radiolabeled compounds: shorter acquisition times due to the high sensitivity. easier sample handling. direct quantification and the ability to perform dynamic studies. The detector performance shows a spatial resolution of 0.9 mm for carbon-14 (14C) (0.156 MeV). good linearity and homogeneity. The noise level is below 50/(cm2.sec). Successful imaging with this system has been performed with beta-emitters 14C. sulfur-35 (35S). iodine-131 (131I). yttrium-90 (90Y). and positron emitters gallium-68 (68Ga). and fluorine-18 (18F). Dynamic studies of axonal transport of 35S-methionine in a nerve. and static images of 90Y-labeled monoclonal antibodies in slices of tumors are presented. The system shows promise for rapid quantitative imaging of charged-particle emitting radionuclides in small biologic samples.
Lowering the cost of lowering the cholesterol: a formulary policy for lovastatin, OBJECTIVES: To describe a medical center policy designed to contain the cost of using the lipid-lowering drug lovastatin in a primary care setting. to examine the effect of the policy on cost containment. and to examine physician acceptance of the policy. SETTING: A Veterans Affairs medical center. INTERVENTIONS: The policy made lovastatin available to physicians when failure of therapy with diet and two first-line drugs was documented on an order form. The form also contained educational information including prices and recommended niacin as the drug treatment of first choice for most patients. DESIGN: To evaluate the effect of the policy. lipid-lowering drug use at the medical center was compared with that at a similar center that did not restrict lovastatin use. and with lipid-lowering drug use in the United States as a whole. A written questionnaire was used to survey physician reaction to the policy. RESULTS: The use of lovastatin as a percentage of total lipid-lowering drug use at the center with the lovastatin policy was one-fourth that at the other center or nationwide. and the use of niacin was four times greater (p less than 0.0001). The estimated savings in drug costs to the center with the lovastatin policy due to these differences was more than $30.000 per year. In the survey of physicians affected by the policy (n = 78. response rate = 100%). less than one-fourth viewed it unfavorably. and 90% favored this policy over restricting the drug to a subspecialty clinic. CONCLUSION: The authors' experience indicates that a formulary policy that permits limited use of an expensive drug in a primary care setting can contain costs in a way that is acceptable to physicians. A policy of this type could be useful to the increasing number of health care provider organizations that cover the cost of outpatient medications.
Estrogen and progestin therapy to prevent osteoporosis: attitudes and practices of general internists and gynecologists, STUDY OBJECTIVE: To assess combined hormone therapy (CHT) prescribing patterns. possible impediments to CHT prescribing. and use of endometrial biopsy to monitor therapy. DESIGN: Mailed questionnaire survey. SUBJECTS: Gynecologists and general internists at two Boston teaching hospitals. MEASUREMENTS AND MAIN RESULTS: Based on a 71% response rate. 72% of internists and 100% of gynecologists reported ever having prescribed CHT. Almost 60% of internists. compared with 8% of gynecologists. reported that over half of their female patients were older than 50 years of age. By logistic regression analysis of the internists' data. female gender of physician (odds ratio 11.0). belief that CHT decreases myocardial infarction risk (odds ratio 3.4). and knowledge of CHT's benefits and risks (odds ratio 2.8) were associated with prescribing. Endometrial biopsy was performed by a majority of physicians only when unexpected vaginal bleeding occurred and in cases of unclear menopausal transition. Physicians who were concerned about litigation were seven times more likely to perform baseline endometrial biopsy. CONCLUSIONS: In the authors' sample. as well as nationally. internists are more likely to provide care for menopausal women. Among internists. gender and knowledge are strongly associated with CHT prescribing. These findings have important educational implications if internists are to routinely provide information and counseling to women about osteoporosis and CHT.
Reducing unnecessary coronary care unit admissions: a comparison of three decision aids, OBJECTIVE: To determine whether published decision rules for ischemic heart disease have practical value in reducing unnecessary admissions to coronary care units. DESIGN: Prospective cohort study. SETTING: A community hospital emergency room. PATIENTS: 235 consecutive patients presenting to an emergency room with a chief complaint of chest pain. MEASUREMENTS: Clinical information. including observations needed to use previously published decision aids. was collected on special forms at the time of the emergency room visit. Follow-up information was obtained from the medical records of patients who were admitted and by telephone interviews with patients who were discharged. The authors compared the residents' actual decisions with the predictions of the decision aids regarding their ability to predict complications (that is. to identify patients who needed admission or intensive care). MAIN RESULTS AND CONCLUSIONS: None of the decision aids could reduce unnecessary admissions without seriously increasing the rate of inappropriate discharges. However. within the clinically relevant subgroup of patients for whom the decision to admit or discharge was not obvious on clinical grounds (those without complications on presentation whom the residents chose not to discharge). the decision aids examined. used in combination to verify the need for admission. might have safely averted some unnecessary admissions.
Association of self-reported injury and alcohol consumption in medical outpatients, OBJECTIVE: This study was designed to examine the association between minor injury and level of alcohol consumption among adult outpatients. DESIGN: Self-administered survey of alcohol use and level of injury in prior month. SETTING: Adult outpatients attending a university-based general internal medicine private practice. PATIENTS/PARTICIPANTS: During a four-month period. 1.011 patients aged 18-65 years were asked to complete questionnaires while waiting to see a physician. The 791 who completed all forms appropriately are included in this study. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The total number of drinks and the total number of injuries reported during the preceding month were calculated. Nondrinkers reported an average of 0.51 (SD = 1.18) injuries in the prior month; and drinkers. 0.92 (SD = 1.70) injuries. Minor injuries were reported more frequently by heavier alcohol consumers only among younger patients (RR = 1.88). There was no association between reported injury and alcohol consumption among patients over 50 years of age (RR = 0.90). CONCLUSIONS: Minor injury is associated with heavier alcohol consumption in younger patients attending a general medical practice. but not among older patients. Further research is needed to establish a causal relationship between alcohol drinking and minor injury.
The use of formal prior directives among patients with HIV-related diseases, OBJECTIVE: To examine the knowledge of. counseling about. and use of prior directives among patients with HIV-related disease. DESIGN: Cross-sectional survey with personal interviews that was part of the evaluation of a multi-site AIDS Health Services Program. SETTING: Outpatient clinics and AIDS community-based organizations. PATIENTS/PARTICIPANTS: To be eligible for the survey. subjects had to be at least 18 years of age and enrolled in the AIDS Health Services Program for at least one month. 1.031 clients were interviewed in nine communities. MEASUREMENTS AND MAIN RESULTS: Of those surveyed. 61% had thought a moderate or great amount about naming a proxy for health care decisions. The majority (68%) of the patients knew about prior directives. yet only 35% had been counseled and only 28% had a prior directive. Of those counseled. physicians had counseled only 11% (38/359). Gay/bisexual men were more likely to have been counseled and to have executed a prior directive than were others. Counseling was associated with having obtained a prior directive. Counseled subjects were 3.5 times more likely to have obtained a prior directive than were those not counseled. CONCLUSIONS: A gap exists between subjects' knowledge and implementation of prior directives. To help bridge this gap. the authors recommend that physicians not only attend to the technical aspects of patient care. but also determine patient values concerning life-sustaining therapy and counsel patients on prior directives.
Supportive evidence for the validity of the epidemiologic necropsy for gallstones, OBJECTIVE: The epidemiologic necropsy measures the occurrence of unsuspected disease through the examination of necropsy records of patients who died for other reasons. The estimates of unsuspected disease derived from the epidemiologic necropsy should approximate what actually occurs in the living population. DESIGN/SETTING: To test this hypothesis. all necropsy records of adult patients at the University of Kansas Medical Center from 1950 to 1984 were examined for the presence of gallstones. Patients with previous cholecystectomy or whose gallstones were diagnosed during life were excluded. The data were stratified by age and race and compared with those of a screening survey from Canada. a surgical series from New York. two screening surveys from Italy. and one from Denmark. The crude necropsy detection rates and the rates from the screening surveys were standardized to the 1970 federal census for Kansas City. RESULTS/CONCLUSIONS: The standardized occurrence rates were similar and suggest that the epidemiologic necropsy accurately assesses the occurrence of asymptomatic gallstones in the living population. thus strengthening its validity as a research tool.
Status of cochlear implantation in children. American Academy of Otolaryngology-Head and Neck Surgery Subcommittee on Cochlear implants, The cochlear implant is a medical device. part of which is placed surgically. that uses electrical stimulation to provide hearing. For almost a decade. investigational studies have been ongoing to define its safety and efficacy in profoundly deaf children. During this period. more than 500 children aged 2 through 17 years have been implanted with either a single-electrode or multielectrode device. Extensive auditory. speech. educational. and psychologic testing has been performed before and after implantation. Results show that the cochlear implant provides auditory detection over much of the speech signal. Compared with the preimplant period. there is significant improvement in auditory discrimination and speech production skills. Limited open-set word and sentence recognition is possible for at least some children. Complications with the device have been minimal. The cochlear implant can provide sound to deaf children unable to benefit from hearing aids. The complex assessment. rehabilitation. and parent counseling should be performed by centers with the multidisciplinary staffs necessary to provide effective care for patients with this specialized auditory prosthesis.
Effectiveness of an antihistamine-decongestant combination for young children with the common cold: a randomized, controlled clinical trial, We tested the hypothesis that antihistamine-decongestant combinations cause no clinically significant relief of the symptoms of upper respiratory tract infections in young children by randomly assigning 96 children to one of three treatment groups: antihistamine-decongestant. placebo. and no treatment. There were no differences among the three study groups in the proportion of children considered "better" overall by the parent 48 hours after the initial assessment (drug. 67%; placebo. 71%; no treatment. 57%; p = 0.53). There were no differences among groups in individual or composite symptom score changes. Two thirds of parents whose children were eligible for the drug trial believed that their child needed medicine for cold symptoms. In the proportion of parents believing that their child needed medicine. there was no difference between those who consented to participate and those who refused. Parents who wanted medicine at the initial visit reported more improvement at follow-up. regardless of whether the child received drug. placebo. or no treatment. We conclude that there is no clinically significant improvement in symptoms of upper respiratory tract infection. including no significant placebo effect. in young children for whom an antihistamine-decongestant is prescribed.
Lovastatin therapy for cholesterol ester storage disease in two sisters, We administered lovastatin to two sisters. aged 4 and 17 years. who had cholesterol ester storage disease. an autosomal recessive disorder manifested by hypercholesterolemia and hypertriglyceridemia. The drug. a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. was taken orally for 6 months. Serum lipid concentrations were determined monthly. Computed tomography of the liver was performed before and during therapy to evaluate liver fat content. The younger sister had liver biopsies before and after 6 months of lovastatin therapy to assess hepatic cholesterol stores. Both patients had marked decreases in serum levels of cholesterol. triglycerides. and low-density lipoprotein-cholesterol; high-density lipoprotein-cholesterol levels increased. Computed tomography during treatment demonstrated a significant increase in linear attenuation. suggesting a decreased liver fat content. Liver tissue obtained 6 months after lovastatin therapy was initiated had 13% less esterified cholesterol than the liver sample obtained before treatment. We conclude that lovastatin may be effective in treating children with cholesterol ester storage disease.
Estimates of metabolic rate in obese and nonobese adolescents, To evaluate the validity of equations for the calculation of basal metabolic rate. we compared measured metabolic rates in a population that included obese and nonobese adolescents with metabolic rates calculated from five equations commonly used to estimate metabolic rate. Of the available options. neither the Mayo Clinic nomogram nor the Food and Agriculture Organization/World Health Organization/United Nations University (FAO/WHO/UNU) equations produced estimates that differed significantly from measured values. In a second cohort of severely obese adolescent girls. the FAO/WHO/UNU equation that included both height and weight provided the most accurate estimate of metabolic rate. Because of their simplicity. we recommend use of the FAO/WHO/UNU equations to estimate metabolic rate in adolescent populations (boys: BMR = 17.5 weight (kg) + 651; girls: BMR = 12.2 weight (kg) + 746). However. when obese cohorts are studied. the FAO/WHO/UNU equation that includes both weight and height predicts metabolic rate most accurately (boys: BMR = 16.6 weight (kg) + 77 height (m) + 572; girls: BMR = 7.4 weight (kg) + 482 height (m) + 217).
Cardiovascular abnormalities in infants prenatally exposed to cocaine, This study utilized a historical cohort to examine the relationship between maternal cocaine use during pregnancy and the occurrence of congenital cardiovascular abnormalities. All neonatal drug screens performed at Boston City Hospital during an 18-month period were reviewed (n = 554); for 214 (39%) screened high-risk neonates. results of toxicologic screens were positive for cocaine. and 340 (61%) neonates had no detectable cocaine. We compared the occurrence of cardiovascular malformations and electrocardiographic abnormalities in these two groups. Matches were sought between these 554 infants and our pediatric cardiology data base. which consisted of inpatient consultation. outpatient consultation. and electrocardiography. Forty-nine patients had drug screens and were also entered into our cardiology data base: 25 had both consultations and electrocardiograms. and 24 had electrocardiograms only. The rate of cardiac anomalies among the cocaine-positive infants was significantly higher (relative risk = 3.7; 95% confidence interval: (1.4. 9.4)) than the rate of these anomalies among the cocaine-negative comparison group (65/100 vs 18/1000); the rate for cocaine-positive infants was also significantly higher than published rates for general populations of infants. Several electrocardiographic abnormalities. high-grade ventricular ectopy. and cardiorespiratory arrests were also noted in our study population. We conclude that cocaine exposure during prenatal life appears to predispose infants to structural cardiovascular malformations. electrocardiographic abnormalities. and. possibly. cardiopulmonary autonomic dysfunction.
Phenotypic variability in glutaric aciduria type I: Report of fourteen cases in five Canadian Indian kindreds, We describe 14 patients with glutaric aciduria type 1 in five Canadian Indian kindreds living in Manitoba and northwest Ontario. The patients had marked clinical variability of the disease. even within families. Eight followed the typical clinical course of normal early growth and development until the onset of neurologic abnormalities. often precipitated by infection. between 6 weeks and 7 1/2 months of age. Five patients had early developmental delay; one was thought to be normal until 8 years of age. Three patients died. seven are severely mentally and physically handicapped. and four have only mild mental retardation or incoordination. Six patients had macrocephaly in the neonatal period. Computed tomography was done for 12 patients. and findings were abnormal in 11. Glutaric acid and 3-hydroxyglutaric acid were detected in increased amounts in the urine of all patients. but the concentrations were much lower than those in most other reported patients. Glutaryl coenzyme A dehydrogenase activity in skin fibroblasts. interleukin-2-dependent lymphocytes. or both. ranged from 0% to 13% of control values. There was no correlation between clinical severity and urine glutaric acid concentration or level of residual enzyme activity. We recommend that organic acid analysis of the urine be done in patients with unexplained cerebral palsy-like disorders. especially if the computed tomographic scan is abnormal. If there is suspicion of glutaric aciduria. glutaryl-coenzyme A dehydrogenase should be measured in fibroblasts or lymphocytes even if glutaric acid is not increased in the urine.
Massive transfusion: outcome in blunt trauma patients, Over a 54-month period 6.142 patients were consecutively admitted to our Level I trauma center. Ninety-two blunt trauma patients required massive transfusion (MT) of 20 or more units of packed red blood cells (range. 20-126). Eighty-two per cent of all transfused blood was given within 24 hours of admission. Forty-eight patients (52%) were long-term survivors. Twenty-six patients died (28%) within 24 hours and 21 of these exsanguinated. Eighteen patients died greater than 24 hours: nine (50%) died from multiple organ failure. and nine (50%) died from severe closed head injury (CHI). Clinical predictors of increased mortality were: shock on admission. closed head injury. and age. Forty-three survivors were followed for a mean of 2.5 years (range. 1-5 years). No patient died during followup. All patients were home at 1 year; only four patients required continued medical assistance. Thirty-two patients (74%) returned to work. We conclude that: 1) blunt and penetrating trauma patients receiving MT have similar survival rates of 50%; 2) shock. closed head injury. and age predict increased mortality but do not preclude survival; 3) long-term outcome in blunt patients requiring MT is excellent. Post-discharge death is rare and 3/4 of the survivors return to work. justifying the high cost of acute care.
How to save fuel and reduce injuries in automobiles, Increased fuel economy and reduced injuries have been portrayed as incompatible goals. based on the false assumption that vehicle weight is the determining factor in both. Physics predicts that size and velocity. not weight. are the primary factors affecting crash forces. while increased weight or increased velocity consumes more fuel. Analysis of fatal injury rates. injury costs. and fuel use relation to vehicle weight. vehicle size. and engine horsepower confirms that weight is of minimal importance in injury severity compared to the other two factors. Fuel use is a function of weight and horsepower. Injuries and fuel use can be reduced by reducing vehicle horsepower without changing vehicle size.
High-pressure injection injuries of the hand, The majority of high-pressure injection injuries can produce serious damage to the hand. Nevertheless. the injury may follow a relatively benign course if the injected substance possesses a less harmful nature. Treatment for these injuries requires immediate and aggressive surgery in most circumstances. but conservative treatment may be justified in certain instances. During a 4-year period. eight cases of high-pressure injection injury were encountered. The types of injected material were: four from paint. and one each from grease. water. benzene. and hydraulic oil. Time is an important factor regarding the results. while the types of injected material modify the clinical courses. It is advisable that the etiology of high-pressure injection injury should be established initially. and this factor be taken into consideration in choosing treatment options.
Traumatic rupture of the interventricular septum and tricuspid valve: case report, Cardiac injury following blunt trauma is an important cause of morbidity and mortality and is often unsuspected. Isolated chamber rupture and valvular injury are infrequent but recognized consequences of nonpenetrating trauma. This report describes a patient who developed a perimembranous ventricular septal defect and disruption of the septal leaflet of the tricuspid valve as a consequence of blunt trauma. Diagnosis and management of traumatic ventricular septal rupture are discussed.
Bullet fragment venous embolus to the heart: case report, This report describes a case of bullet fragment embolus to the heart following a small-caliber gunshot wound to the mouth. Skull and C-spine films appeared to account for the projectile; however. chest X-ray followed by fluoroscopy and two-dimensional echocardiography demonstrated a venous missile embolus in the right heart. The bullet was palpated. trapped in the right ventricle. and easily extruded.
Penetrating injury of a duplicated ureter: case report, Duplications of the genitourinary tract are uncommon and may be a source of confusion in the early diagnosis of ureteral trauma when their presence is not suspected. We present a case of delayed diagnosis of a penetrating injury to a duplicated ureter and its management.
Traumatic scapulothoracic dissociation: case report, A 23-year-old man suffered traumatic scapulothoracic dissociation (TSD) in a car-vs.-bicyclist accident. TSD is a devastating forequarter injury characterized by brachial plexus damage. major upper extremity musculoskeletal disruption. and exsanguinating hemorrhage: our patient survived a hematocrit of 7. Prompt recognition and aggressive management of TSD's multiple injuries are crucial.
The management of mid-face fractures with intracranial injury, Recent advances have radically changed the management of facial fractures. CT scanning. extensive exposure. and rigid plate fixation in the setting of the trauma center have permitted early operation with improved results. A subset of patients with facial fractures will also have intracranial injuries (ICI). We sought to identify parameters associated with an increased risk for ICI. We also sought to examine the safety and limits of early craniofacial repair in patients with intracranial injuries. Of 114 mid-face fractures treated over a 1-year period. 43 (38%) had a concomitant ICI. The majority. 36 (84%). were from motor vehicle accidents (MVA). Frontal sinus and orbitoethmoid fractures were at the highest risk for ICI. although orbitozygomatic fractures caused by MVAs also had a surprisingly high incidence of ICI. Our results show that early craniofacial repair can be performed safely with appropriate general surgical and neurosurgical support.
Improved outcome with early fixation of skeletally unstable pelvic fractures, Thirty-seven consecutive patients with unstable pelvic fractures were divided into two groups: Group 1 (July 1981 to December 1984; n = 18). when early fixation was not routinely used. and Group 2 (January 1985 to March 1988; n = 19). when early fixation was performed unless contraindicated. Hospital stay decreased by 37.8% in Group 2 (p = 0.04). Of Group 1 patients. 60% were disabled for at least 6 months versus 15.7% in Group 2 (p = 0.001). and 45% were discharged to a rehabilitation facility versus 26.4% in Group 2. Group 1 had more complications. 1.3 per patient. versus 1.0. Patients in Group 2 (undergoing early fixation) required 27.2% fewer units of blood than those in Group 1 in whom fracture surgery was delayed. Survival was better in Group 2. 100% versus 83.3% (p = 0.06). Early pelvic fracture fixation reduces hospital stay. long-term disability. and may result in fewer complications. decreased blood loss. and better survival.
Early measurement of systemic lipid peroxidation products in the plasma of major blunt trauma patients, We sought evidence of oxidant-induced biological membrane damage in 43 resuscitated blunt trauma patients (average ISS. 36.9) within 2-6 hours of injury and before anaesthesia and surgery. The plasma levels of the lipid peroxidation products (conjugated dienes. CDs A 233 nm) and malondialdehyde (MDA. nMol/ml) and the oxidant-inducing effect of the trauma plasma on normal FMLP-stimulated neutrophils were compared to those of control subjects. No differences were observed in the plasma levels of MDA (1.73 +/- 2.15 vs. 1.45 +/- 0.70 nMol/ml) and CDs (2.07 +/- 2.16 vs. 1.28 +/- 0.60 A 233nm). or on stimulated neutrophil superoxide production (26.4 +/- 6.9 vs. 29.0 +/- 6.2 nMol O2-/2 x 10(6) PMNs). These observations persisted when the patients were analyzed based on injury severity. the presence of long bone fractures. and the class of shock at presentation. We conclude that there is no evidence of oxidant-induced membrane damage manifested by increased plasma levels of CDs or MDA within 2 to 6 hours of blunt injury.
Spine trauma and associated injuries, A longitudinal. prospectively gathered data base of spine trauma has been developed. A review of 508 consecutive hospital admissions identified the presence of associated injuries in 240 (47%) individuals. most frequently involving head (26%). chest (24%). or long bones (23%). Twenty-two per cent had one associated injury. 15% had two. and 10% had three or more. Most spine fractures involved the lower cervical (29%) or thoracolumbar junction (21%). Comparisons of presence or absence of associated injuries and spine fracture level showed significant differences (p less than 0.001). Eighty-two per cent of thoracic fractures and 72% of lumbar fractures had associated injuries compared to 28% of lower cervical spine fractures. While there was no significant relationship between type of associated injury and spine fracture level. those with associated injuries were less likely to have a neural deficit (p less than 0.05). After hospital admission. there were seven deaths. Early assessment and transport of spine trauma victims must be carried out with appropriate management of associated injuries. Conversely. multiple trauma victims must be handled with due regard for a possible spine fracture. The value of spinal units with specially trained personnel is emphasized.
The epidemiology of seatbelt-associated injuries, This study examined the frequency of spine and abdominal injuries to motor vehicle occupant crash victims. the relationship between the two types of injuries. and the association with restraint use. There were 303 motor vehicle occupants treated at a regional trauma center for spine and/or abdominal injuries over a 5-year period. Patients with Chance-type fractures of the lumbar spine were much more likely to be rear seat passengers and to be using a lap belt than were patients with other types of spinal injuries. Similarly. patients with hollow viscus injuries were more likely to be rear seat passengers and to be lap belted than were patients with injuries to the spleen. liver. pancreas. or kidneys. Nearly two thirds of the lumbar Chance-type fractures were associated with hollow viscus injuries. including six of seven children. This increased risk of Chance-type fractures and hollow viscus injuries was associated with increased use of lap-belt seat restraints in the population.
Fibrinogen degradation product-D, fibrinogen, and serum change polymorphonuclear granulocyte activity--possibly important post-trauma, Severe trauma favors the susceptibility of patients to infection. It has been shown that proteins or protein fragments are responsible for an endogenous immunodepression. After trauma a coagulopathy accompanied by increased serum levels of fibrinogen degradation products (FDP) is often found. Therefore. we examined whether FDP-D can influence the activity of polymorphonuclear neutrophils (PMN). PMN-activation was measured by two different superoxide-specific methods (Cytochrome-C-test. INT-test). With both methods we found a decrease of PMN activity by FDP-D compared to fibrinogen. Albumin. which was used as a control protein. only influenced PMN activity in unphysiologically high concentrations. The third method used to quantify PMN activity was chemiluminescence. which is a more unspecific method since it is developed not only by oxygen radical species but also by activating the lipoxygenase pathway. In contrast to the superoxide specific tests we found an inhibitory effect of fibrinogen and also serum compared to FDP-D using chemiluminescence.
Techniques of emergency ventilation: a model to evaluate tidal volume, airway pressure, and gastric insufflation, We designed a model to evaluate the effectiveness of various noninvasive methods of ventilation. The upper airway was simulated with the head of a Resusci-Annie which was attached to a test lung. The esophagus and stomach were simulated with a Penrose drain connected to a rolling seal spirometer via a PEEP valve. Fifteen paramedic volunteers ventilated the model utilizing mouth-to-mouth. mouth-to-mask. bag-valve-mask. or portable field ventilator (Impact or HARV). Recording of tidal volume. gastric volume. and proximal and distal airway pressure was completed at three different levels of compliance. At normal compliance. all methods except the HARV met or exceeded American Heart Association standards. As compliance decreased. tidal volume fell and gastric insufflation increased. At a compliance of 0.02 L/cm H2O all methods failed to meet AHA standards and gastric insufflation volume equalled delivered tidal volumes for mouth-to-mouth and mouth-to-mask techniques. Mouth-to-mouth and mouth-to-mask techniques generated the largest tidal volumes but also created the largest volume of gastric insufflation. The Impact ventilator provided an acceptable tidal volume with minimal gastric insufflation. Our results suggest that mouth-to-mask ventilation with supplemental oxygen enrichment is the most efficient technique for non-invasive airway management.
Delayed union of fibular fractures accompanying fractures of the tibial shaft, Among 440 adult patients with tibial shaft fracture and accompanying fibular fracture there were eight cases with radiographically ununited fibulae 4 months after the injury. each with uneventful tibial union. Fractures with severe soft-tissue injuries were excluded from this study. In 293 patients the treatment method of the tibial fracture was conservative. comprising closed reduction and immobilization by long plaster cast. In 147 patients it was intramedullary Kuntscher nailing. and all the eight cases with delayed fibular union occurred among these. the frequency being 5.4%. The typical accompanying fibular fracture to develop delayed union was a comminuted one in the middle or distal third of the bone. At a followup examination 5 to 8 years after the original injury four of the eight fractures were found to have ultimately spontaneously united. while three showed a radiographically indisputable nonunion. One patient had undergone segmental fibular ostectomy because of persistent local pain but in the remaining patients the subjective symptoms were negligible. The occurrence of delayed fibular union in association with rigid intramedullary nailing of concomitant tibial shaft fracture is a phenomenon of which trauma surgeons should be aware even if the natural course of the condition often seems to be benign.
Nephron site responsible for the reduced kaliuretic response to mineralocorticoids during hypokalemia in rats, Rats with hypokalemia induced by eating a low-K diet have a diminished kaliuretic response to mineralocorticoids. The purpose of this study was to determine if this was the due to a lower rate of net secretion of K in the cortical collecting duct (CCD) and/or an enhanced rate of reabsorption of K in the medullary collecting duct (MCD). Secondary active secretion of K in the CCD raises the [K] in the lumen as compared to the plasma [TF/P)K). If the (TF/P)K is greater than 1. there was secondary active secretion of K in this nephron segment. The (TF/P)K in the CCD was measured by microcatheterization of the collecting duct. Three groups of rats were studied: rats on a low-K diet with and without the acute administration of DOCA. and rats on a normal-K diet treated with DOCA on a chronic basis. Rats on the low-K diet had a (TF/P)K of 0.8 +/- 0.11; this value did not rise to values significantly greater than 1 after the acute administration of DOCA (1.4 +/- 0.35). In contrast. chronic administration of DOCA to rats fed a normal-K diet did result in a (TF/P)K which was significantly greater than unity (3.1 +/- 0.39). The degree of hypokalemia was not significantly different in these rats. The absolute and fractional reabsorption of K in the MCD was not different in the rats on the low-K diet with or without DOCA. We conclude that the nephron segment which is responsible for the reduced kaliuretic response to mineralocorticoids is the CCD.
Arginine vasopressin gene expression in chronic cardiac failure in rats, Arginine vasopressin (AVP) is known to be increased in patients and experimental animals with chronic cardiac failure (CCF). The importance of an increase in biosynthesis of AVP in the hypothalamus has. however. not heretofore been investigated and is the purpose of the present study. CCF secondary to infarction of myocardial tissue was induced by ligation of the left anterior descending coronary artery and sham operated animals served as controls. Four weeks later hypothalamic AVP mRNA was determined by solution hybridization using sense and anti-sense strand RNA. The blood pressure was lower in CCF than sham animals (131.2 +/- 3.1 vs. 112.8 +/- 4.0 mm Hg. P less than 0.05) and the total heart. and right and left ventricle weights were significantly higher in CCF rats. Plasma AVP was higher in CCF (sham 6.78 +/- 0.30; CCF 11.46 +/- 0.64 pg/ml. P less than 0.001) and plasma atrial natriuretic peptide was also higher in CCF than sham animals (205 +/- 36 vs. 554 +/- 56 pg/ml. P less than 0.001). The AVP mRNA in hypothalamus was significantly higher in CCF than sham animals (55.5 +/- 3.7 vs. 95.9 +/- 4.0 pg/micrograms total RNA. P less than 0.001). There was no difference in beta-actin mRNA in the hypothalamus of sham and CCF rats. indicating that the AVP-mRNA increase was specific in CCF. These results therefore demonstrate that increased AVP biosynthesis in the hypothalamus. in addition to release of the hormone from the posterior pituitary. may occur in CCF.
Effects of probucol on renal function in rats with bilateral ureteral obstruction, To ascertain the potential role of reactive oxygen metabolites in the pathophysiology of obstructive uropathy. we examined the effect of probucol. an antioxidant agent. on renal function in normal rats and rats with unilateral release of bilateral ureteral obstruction (BUO) of 24 hours duration. Rats were fed either a standard diet or a standard diet containing one percent probucol for two weeks prior to study. Probucol lowered serum cholesterol in both normal and BUO rats. Probucol did not significantly affect renal function in normal rats. BUO rats given probucol had greater inulin and PAH clearances at three to five hours and three days following release of BUO than rats with BUO not given probucol. Kidneys from obstructed rats had higher levels of malondialdehyde. an index of lipid peroxidation. a greater number of leukocytes in the cortex. decreased levels of reduced glutathione and increased levels of oxidized glutathione. Renal cortex from obstructed rats treated with probucol had significantly higher levels of reduced glutathione than kidneys of obstructed rats not given probucol. A decrease in cholesterol. using another lipid-lowering agent. lovastatin. did not modify renal function in rats with BUO. The data can be interpreted to indicate a role for reactive oxygen species in the pathophysiology of obstructive nephropathy. The improved renal function seen in probucol-treated rats with BUO may be due to an effect of this agent in affecting accumulation of reactive oxygen metabolites and/or decreasing the number of leukocytes infiltrating the renal cortex.
Three-dimensional morphometric analysis of segmental glomerulosclerosis in the rat, In idiopathic nephrotic syndrome. and in experimental models of nephrosis. changes of visceral epithelial cells involve the entire glomerular population while segmental sclerotic changes are reported to affect only a certain number of glomeruli. Because conventional determination of the percentage of glomeruli affected by sclerotic lesions is usually based on the examination of randomly selected sections. we wondered whether glomeruli appearing normal in a given section could be affected by sclerosis in other regions of the capillary tuft (CT). To assess the real incidence and the spatial extension of sclerotic changes at the level of single glomerulus. we used serial-section morphological analysis to measure the volume of the glomerulus and that of sclerosis lesions. In glomeruli from control rats and in glomeruli from adriamycin (ADR) treated rats surface area of Bowman's capsule (BC). CT and sclerotic regions were measured using stereology techniques in all the consecutive sections containing each individual glomerulus. and corresponding volumes were then calculated. Mean volume of BC and CT were not significantly different between control and ADR rats (0.71 +/- 0.03 and 0.53 +/- 0.03 vs. 0.76 +/- 0.04 and 0.53 +/- 0.02 microns 3 x 10(-6). respectively). The distribution of glomerular volume parameters in the ADR rats were more spread out than in control animals. indicating that some glomeruli became smaller while other became larger. No sclerotic changes were found in control rats. while in the three ADR rats 94. 90 and 92% of glomeruli. respectively. were affected by sclerotic lesions.
Fosinopril prevents hyperfiltration and decreases proteinuria in post-transplant hypertensives, Hypertension and renal mass reduction induce glomerular hypertension (GH). hyperfiltration (HF) and renal injury. GH may contribute to allograft loss in post-transplant hypertensive patients (PT x HT). HF and GH may be evaluated by renal response to acute protein intake (API). Since ACE inhibition may prevent GH. the effects of fosinopril (Fos) were evaluated in 10 PT X HT on azathioprine and prednisone. Patients received 5 to 40 mg/day of Fos during 12 months. Baseline MAP (111.1 +/- 2.9 mm Hg) was significantly reduced by 10 to 12 mm Hg. rising to 114.7 +/- 2.7 mm Hg after Fos was administered. GFR (63.7 +/- 5.9 ml/min) decreased after 4 (48.1 +/- 4.6. P less than 0.05) and 12 months (50.7 +/- 4.6. P less than 0.05). rising to 59.4 +/- 5.6 after Fos was given. There was no GFR response to API before and after one month of Fos. however. a clear response became apparent at 4 (+ 27% P less than 0.05). and 12 months (+ 18%. P less than 0.05). disappearing after Fos discontinuation. Proteinuria (918.8 +/- 710.6 mg/d) decreased after 4 (72.3 +/- 21.6 mg/d. P less than 0.05) and 12 months. rising to 297.8 +/- 172.3 mg/day after therapy. GFR response to API in 22 controls and 17 uninephrectomized donors was 13 and 11%. respectively. Lack of response to API in PT x HT suggests HF and GH. Reduction of GFR. restoration of response to API and reduction of proteinuria. indicate that ACE inhibition with fosinopril ameliorates HF and GH. This effect may be beneficial in preventing hemodynamic-mediated allograft injury.
Congenital hepatic fibrosis in autosomal-dominant polycystic kidney disease, Congenital hepatic fibrosis was found in four families with autosomal-dominant polycystic kidney disease. Congenital hepatic fibrosis is commonly though to be characteristic for autosomal-recessive polycystic kidney disease. but the reported families. show that it can also complicate autosomal-dominant polycystic kidney disease. In three families close linkage between the mutation causing the disease and DNA markers on chromosome 16 was demonstrated. The clinical course of the congenital hepatic fibrosis differed considerably; in one family the children with congenital hepatic fibrosis died soon after birth. in the three other families an approximately 20 years follow-up showed no detectable progression of the liver disease.
L-lactate high-efficiency hemodialysis: hemodynamics, blood gas changes, potassium/phosphorus, and symptoms, Hemodynamic changes were measured during high-efficiency hemodialysis (HEHD) using three dialysis solutions: L-lactate (46 mM). bicarbonate (35 mM + 4 mM acetate). and acetate (39 mM). Cardiac output was determined by changes in thoracic electrical bioimpedance. Although there appeared to be subtle differences in hemodynamic response to L-lactate versus bicarbonate. the blood pressure. cardiac output. and total peripheral resistance were affected less with either of these solutions than with acetate. In particular. neither L-lactate nor bicarbonate HEHD were associated with a change in cardiac output. whereas with acetate HEHD a marked (22%) increase in cardiac output was seen concurrently with a moderate fall in blood pressure and TPR. Both acetate and L-lactate HEHD were associated with hypoxemia. whereas with bicarbonate HEHD the PO2 did not change. With L-lactate HEHD. correction of pH and plasma HCO3 concentrations was delayed but these values were not significantly different from those obtained with bicarbonate HEHD by one hour after dialysis. Potassium removal was comparable with the three dialysis solutions. Phosphorus removal with L-lactate tended to be slightly less than with bicarbonate. but not less than with acetate. Our results suggest that L-lactate (46 mM) dialysis solution may be a suitable alternative to acetate for HEHD. being associated with a hemodynamic profile that is similar to that of bicarbonate and better than that of acetate. Our results further suggest that the hypoxemia associated with the use of acetate dialysis solution is not intrinsic to acetate. but is due either to a low dialysis solution PCO2 level or to accelerated consumption of oxygen during substrate metabolism.
Multicenter trial of L-carnitine in maintenance hemodialysis patients. I. Carnitine concentrations and lipid effects, Previous studies have reported conflicting results of carnitine supplementation on plasma lipids in patients with chronic renal failure. We therefore performed a four center. double-blind placebo controlled trial to evaluate the effects of post-hemodialysis intravenous injection of L-carnitine in ESRD patients on maintenance hemodialysis. Thirty-eight patients received up to six months of L-carnitine infusions (20 mg/kg) post-dialysis and 44 patients received placebo infusions. In both groups of patients. baseline pre-dialysis plasma and red blood cell total carnitine levels were normal. but pre-dialysis plasma-free carnitine concentrations and free/total ratios were subnormal. and plasma acyl levels were elevated. Post-dialysis plasma free and total carnitine concentrations were also subnormal. Plasma and red blood cell total carnitine levels rose eightfold in carnitine recipients. but were unchanged from baseline in those receiving placebo. There were no significant changes observed in plasma triglycerides. HDL-cholesterol or other lipoprotein parameters in either the carnitine or placebo treated groups. We conclude that carnitine metabolism is altered in uremia. Furthermore. in a randomly-selected hemodialysis population. L-carnitine injection at the dose of 20 mg/kg results in significant increases in blood (and perhaps tissue) carnitine levels. but this is not associated with any major effects on lipid profiles.
Gene mapping in Alport families with different basement membrane antigenic phenotypes, The present study was undertaken to determine whether differences among Alport kindreds in the antigenic phenotypes of their basement membranes result from defects at distinct genetic loci or from allelic mutations at a single locus. We analyzed linkage of the Alport gene to polymorphic loci on the X chromosome in three families with Alport syndrome. In two of the families. epidermal basement membranes of affected members showed altered immunohistologic reactivity with a discriminating antibody (FNS1) that identified a 26 kD peptide in the NCl domain of basement membrane collagen. In the third family epidermal basement membranes of affected individuals reacted normally with the antibody. The disease gene mapped to the Xq21-q22 region of the long arm of the X chromosome in the two families with altered basement membrane antigenicity and in the family with normal basement membrane antigens. We conclude that Alport syndrome in each of these kindreds arose from allelic mutations at a single genetic locus. although we cannot at this time exclude the possibility that two or more tightly linked genes are involved. As the genes for the known chains of type IV collagen are on chromosome 13. our findings suggest that the Alport gene may encode a new basement membrane collagen chain.
Influence of calcium acetate or calcium citrate on intestinal aluminum absorption, The risk of aluminum (Al) accumulation in patients with chronic renal failure has led to use of non-Al phosphate binders. Frequently. Al and non-Al phosphate binders are co-administered. Unfortunately. calcium citrate (Ca citr). when given with Al-gel. markedly enhances Al absorption. To determine whether calcium acetate (Ca acetate) also augments Al absorption. 10 normal volunteers were each given orally. three-day courses of the following drug combinations dosed four times daily: 1) aluminum hydroxide gel (Al[OH]3) (5 ml) alone; 2) Al[OH]3 (5 ml) plus Ca acetate (1330 mg); 3) Al[OH]3 (5 ml) plus Ca citr (950 mg). A nine day wash-out occurred between each course. Al levels were measured using flameless atomic absorption spectrophotometry. Daily urine Al excretion was measured during a two-day baseline before each course and during each three-day drug course. Plasma Al was obtained during each baseline and drug course. Mean 24-hour Al excretion (micrograms/g creatinine/day) at baseline versus treatment for each combination was: 1) 5.9 +/- 3.2 versus 42.0 +/- 40.7 (mean +/- SD); 2) 5.7 +/- 3.0 versus 40.3 +/- 28.6: 3) 6.3 +/- 3.4 versus 175.8 +/- 103.3. Al excretion was significantly greater with combination 3 than with either 1 or 2 (P less than 0.05). The difference between 1 and 2 was not significant. Plasma Al (micrograms/liter) at baseline versus treatment for each combination was: 1) 5.3 +/- 4.2 versus 8.1 +/- 2.5 (mean +/- SD); 2) 3.1 +/- 2.2 versus 7.3 +/- 2.9; 3) 3.0 +/- 2.3 versus 12.0 +/- 6.1.
Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin, The development of a 24 hour radioimmunoassay for erythropoietin (EPO) using EPO derived from recombinant DNA as both immunogen and ligand is described in the present paper. Mixed breed rabbits immunized with 10 micrograms/kg of EPO derived from a stably transfected cell line (Elanex Pharmaceuticals Inc.. Bothel. Washington. USA. through McDonnell Douglas Corp.. St. Louis. Missouri. USA; "MD") produced antibodies to EPO with high titer (up to 1:896.000 final dilution in the tube). high affinity (8.4 x 10(11) liter/M). and good specificity. Purified EPO from the above source or from AmGen Biologicals (Thousand Oaks. California. USA; "AG") were successfully radioiodinated with the chloramine-T method and used as ligand in the radioimmunoassay. Standard dose-response curves prepared with EPO from both commercial sources were not significantly different and showed a sensitivity of 0.75 to 0.96 mU/tube. The dose-response curves in both systems also showed parallelism with serially diluted serum from a patient with aplastic anemia. Within-assay and between-assay precision were determined by assaying multiple replicates of a serum pool. Recovery of exogenous EPO added to a serum pool averaged 97% for both systems. The range of normal human serum EPO was determined by assaying the sera of 153 hematologically-normal adult subjects and was found to be 1.1 to 27.3 mU/ml for MD EPO and 0.5 to 16.7 mU/ml for AG EPO. Sera from several patients with hematologic abnormalities were also assayed. including those of 36 patients with anemia of end-stage renal disease (mean +/- SEM. 29.5 +/- 4.0 mU/ml; P less than 0.01). In conclusion. this new. more rapid and sensitive radioimmunoassay system can be used to measure EPO levels in sera from normal human subjects and patients with several types of anemia. and should also be very useful in therapeutic drug monitoring of patients receiving EPO from various commercial sources.
Parathyroid autotransplantation during thyroid surgery, Permanent hypoparathyroidism is one of the most distressing complications of thyroid surgery. The incidence of this iatrogenic complication varies between 3 and 25 percent among patients undergoing total thyroidectomy. Parathyroid injury may be caused by inadvertent removal of the parathyroids. ligation of the blood supply. or destruction secondary to capsular hematoma. Attention to such technical details as identification of the parathyroids. dissection close to the thyroid gland. preservation of the blood supply to the parathyroids. and avoiding manipulation of parathyroids reduces the incidence of temporary and permanent hypoparathyrodism. However. if the parathyroids are injured. the best method of preserving their function is by autotransplantation. Over the past 7 years we have performed 250 thyroidectomies. An attempt was made to identify and preserve parathyroid gland in each case. Even during lobectomy procedures. the ipsilateral parathyroids were identified and preserved. Whenever any of the parathyroids was devascularized or separated from the surrounding structures. it was autotransplanted into the sternomastoid muscle. The sternomastoid was chosen for autotransplantation rather than forearm muscles to avoid an added incision and because selective measurement of parathormone is not essential in this group of patients. Prior to autotransplantation. confirmation of the nature of the tissue was made by frozen section of a small portion of the parathyroid gland. Parathyroid autotransplantation was performed in 15 instances. even when only one parathyroid was injured. Only one member of this group of 15 patients developed temporary hypoparathyroidism. which disappeared after 4 weeks of calcium supplementation. The remaining patients had an uncomplicated recovery. Autotransplantation of the parathyroid glands should be performed whenever the parathyroid is devascularized or damaged by retraction or hematoma. It is essential for every thyroid surgeon to be familiar with the technique of parathyroid autotransplantation.
Modified anterior compartment resection, In the majority of patients with soft tissue sarcomas of the anterior compartment of the thigh. it is possible to preserve a small portion of the quadriceps with intact nerve supply without compromising on the radicality of the procedure or the local control rate. The distal one-third of the vastus medialis can usually be spared with a long. slender branch providing its innervation. Dissection of the femoral nerve below the inguinal ligament and its branch(es) to an uninvolved area of the quadricepts the farthest from the location of the tumor is essential. This modified anterior compartment resection improves dramatically the function of the extremity.
Two prostate carcinoma cell lines demonstrate abnormalities in tumor suppressor genes, Two prostate carcinoma cell lines. DU-145 and PC-3. were examined for abnormalities in the retinoblastoma (Rb) and the p53 putative tumor suppressor genes. We found an abnormal Rb gene product in DU-145 using Western blot analysis. Polymerase chain reaction amplification followed by direct DNA sequencing demonstrated a base substitution mutation that generates a stop codon in exon 21. On Northern. Southern. and Western blot analysis. the p53 gene and its product appear to be normal in DU-145. PC-3. however. failed to demonstrate expression of either the p53 transcript on Northern blot analysis or the p53 protein on Western blot analysis. while the Rb gene products appeared to be normal on both Northern and Western blot analysis. This work extends the correlation between abnormal expression of putative tumor suppressor genes and human malignancies.
Granular cell neoplasm of the extrahepatic biliary tree: morphological, ultrastructural, and immunohistochemical study and review of the literature, A recent case of a biliary granular cell tumor of the cystic duct prompted a literature review and an extensive pathological examination of the tumor in question. A total of 44 cases have been described mostly in black females. Most cases present with biliary symptoms. and simple surgical resection allows complete control of this benign condition. Granular cell tumors are most likely derived from neural crest cells.
Bilateral malignant phyllodes tumours, We report a rare example of bilateral primary malignant phyllodes tumours. The diagnosis was supported by the identification of a benign epithelial element in each lesion. The case illustrates the typical dimorphic features of malignant phyllodes tumours. A contralateral tumour should not be regarded as metastatic without histological confirmation.
Prostaglandin F1 alpha levels during and after neonatal extracorporeal membrane oxygenation, Infants receiving extracorporeal membrane oxygenation therapy undergo long-term cardiopulmonary bypass. are systemically heparinized. and frequently receive platelet transfusions. Prostacyclin is a powerful inhibitor of platelet aggregation as well as a potent vasodilator. The levels of its stable metabolite prostaglandin F1 alpha increase significantly in children undergoing cardiopulmonary bypass during heart operations but decrease to preoperative levels after bypass. To determine the effect of long-term bypass on prostacyclin levels. multiple plasma samples were analyzed in 10 human neonates both during extracorporeal membrane oxygenation therapy and within 24 hours after extracorporeal membrane oxygenation. Prostaglandin F1 alpha. the stable metabolite of prostacyclin. was quantitated by radioimmunoassay in picograms per milliliter. Prostaglandin F1 alpha levels were elevated while the patients received extracorporeal membrane oxygenation therapy but decreased with duration of extracorporeal membrane oxygenation. In most infants. prostaglandin F1 alpha levels rose again during weaning from extracorporeal membrane oxygenation and remained elevated for 24 hours after extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation course influenced circulating prostaglandin F1 alpha levels. Fluctuating prostaglandin F1 alpha levels are of clinical significance in the management of vasomotor tone and platelet function. common problems in the care and the prevention of hemorrhage in these critically ill infants.
A reevaluation of heparin requirements for cardiopulmonary bypass, We wished to determine if reduction in the standard heparin administration for cardiopulmonary bypass could be accomplished safely with the use of membrane oxygenators. An experimental study was designed to evaluate two different heparin administration protocols for cardiopulmonary bypass with hollow-fiber membrane oxygenators. Two groups of six pigs were submitted to hypothermic cardiopulmonary bypass (28 degrees C) for 3 hours. then rewarmed. decannulated. and reassessed after 1 hour. In group I (control) heparin was administered to maintain the activated clotting time in excess of 450 seconds; in group II activated clotting time was maintained between 250 and 300 seconds. The mean total heparin administered was 41.000 units in group I and 25.000 units in group II. Concentration of coagulation factors II. V. and VIII. fibrinogen. and platelet count were determined before. during. and 1 hour after bypass. No significant difference in any of these coagulation parameters was observed between the groups. The performance of the oxygenators was similar in both groups. with no evidence of thrombosis. Thus reduced heparin administration. enough to keep activated clotting time between 250 and 300 seconds. was not related either to major coagulation factors and platelet consumption or to derangements in the oxygenator's performance.
Studies of myocardial protection in the immature heart. V. Safety of prolonged aortic clamping with hypocalcemic glutamate/aspartate blood cardioplegia, This study tests the hypothesis that multidose. hypocalcemic aspartate/glutamate-enriched blood cardioplegia provides safe and effective protection during prolonged aortic clamping of immature hearts. Of 17 puppies (6 to 8 weeks of age. 3 to 5 kg) placed on vented cardiopulmonary bypass. five were subjected to 60 minutes of 37 degrees C global ischemia without cardioplegic protection and seven underwent 120 minutes of aortic clamping with 4 degrees C multidose aspartate/glutamate-enriched blood cardioplegia ([Ca++] = 0.2 mmol/L). preceded and followed by 37 degrees C blood cardioplegic induction and reperfusion. Five puppies underwent blood cardioplegic perfusion for 10 minutes without intervening ischemia to assess the effect of the cardioplegic solution and the delivery techniques. Left ventricular performance was assessed 30 minutes after bypass was discontinued (Starling function curves). Hearts were studied for high-energy phosphates and tissue amino acids. One hour of normothermic ischemia resulted in profound functional depression. with peak stroke work index only 43% of control (0.7 +/- 0.1 versus 1.7 +/- 0.2 gm x m/kg. p less than 0.05). There was 70% depletion of adenosine triphosphate (7.6 +/- 1 versus control 20.3 +/- 1 mumol/gm dry weight. p less than 0.05) and 75% glutamate loss (6.6 +/- 1 versus control 26.4 +/- 3 mumol/gm. p less than 0.05). In contrast. after 2 hours of aortic clamping with multidose blood cardioplegia preceded and followed by 37 degrees C blood cardioplegia. there was complete recovery of left ventricular function (peak stroke work index 1.6 +/- 0.2 gm x m/kg) and maintenance of adenosine triphosphates. glutamate. and aspartate levels at or above control levels adenosine triphosphate 18 +/- 2 mumol/gm. aspartate 21 +/- 1 versus control 2 mumol/gm. and glutamate 25.4 +/- 2 mumol/gm). Puppy hearts receiving blood cardioplegic perfusion without ischemia had complete recovery of control stroke work index. We conclude that methods of myocardial protection used in adults. with amino acid-enriched. reduced-calcium blood cardioplegia. can be applied safely to the neonatal heart and allow for complete functional and metabolic recovery after prolonged aortic clamping.
Analysis of the Medtronic Intact bioprosthetic valve. Effects of "zero-pressure" fixation, The long-term performance of current-design porcine xenograft valves has not been satisfactory. These valves are generally fixed at "low pressures" of about 3 to 5 mm Hg. The Medtronic Intact (Medtronic. Inc.. Minneapolis. Minn.) valve is fixed at "zero pressure" and is proposed as a better alternative to existing xenograft valves. A mechanical analysis of this valve has been carried out to determine if the Intact valve differs significantly from the low-pressure fixed xenograft. Twelve circumferential strips of tissue 5 mm wide were cut from the leaflets of four clinical-grade Intact valves. Their stress/strain. stress relaxation. and flexural behavior were examined mechanically and histologically. The Intact valve was more extensible than the low-pressure fixed xenograft (22% versus 12% strain. p less than 0.001). relaxed faster (p less than 0.001). and was more pliable than the xenograft (p less than 0.05). It did not. however. buckle less than did the low-pressure fixed xenograft during enforced bending. and it buckled significantly more than did fresh porcine aortic valve tissue (p less than 0.001). The Intact valve also relaxed significantly more slowly than did the fresh tissue (p less than 0.05). Its bending stiffness had a stronger dependence on leaflet thickness than the bending thickness of fresh tissue had (p less than 0.001) but a weaker dependence than the bending thickness of the low-pressure fixed xenograft material had (p less than 0.001). The Intact valve demonstrated a very large variability in extensibility. bending stiffness. and buckling behavior. with little correlation between these parameters. Some valves appeared to have wrinkled leaflets; others were likely fixed at different pressures. The shrinkage of the leaflet material at these low fixation pressures is likely important. since it can modify the elastic behavior of the valve cusps. Overall. the Intact valve had a more "natural" elastic behavior than had low-pressure fixed xenograft. and it should therefore experience lower stresses during normal valve function. It can be concluded that zero-pressure fixation does preserve many of the desirable stress-reducing properties of aortic valve tissue.
Migration stimulating activity in serum of breast cancer patients, An assay to measure the ability to stimulate migration of fibroblasts into collagen gel was carried out on serum from treated and untreated breast cancer patients and from healthy controls. Migration stimulating activity was found in the serum of 10 (83%) of 12 untreated breast cancer patients immediately before surgical resection of the primary tumour and in 9 (75%) of them 4 days after resection; in 13 (93%) of 14 patients 1-13 years after tumour resection who had received adjuvant treatment; and in 2 (10%) of 20 healthy women matched for age. The migration stimulating activity in cancer patients' serum was indistinguishable from the migration stimulating factor produced in vitro by fetal and cancer patient skin fibroblasts in its behaviour in various biochemical fractionation procedures. The presence of this activity in the serum of treated breast cancer patients clearly distinguishes it from other oncofetal proteins. which all seem to be produced by tumours.
Feasibility of reversing benzodiazepine tolerance with flumazenil, To examine whether the benzodiazepine antagonist flumazenil can reverse tolerance to benzodiazepines but without precipitating withdrawal seizures. the antiepileptic effect of flumazenil itself and its ability to reverse tolerance at a dose that would leave sufficient receptors free for the binding of benzodiazepines were investigated. Electroencephalographic studies in 6 patients with partial and 6 with generalised seizures showed that flumazenil had a short (20 min) non-dose-dependent suppressant effect on epileptic discharges in those with partial seizures. Receptor occupancy studies in 12 patients showed that 1.5 mg flumazenil given intravenously occupied 55% receptors. whereas 15 mg occupied nearly all receptors. When 3 patients with partial seizures who had become tolerant to clonazepam were given 1.5 mg flumazenil. they were seizure-free for 6-21 days after the injection. The value of intermittent therapy with a benzodiazepine antagonist for preventing or reversing tolerance to benzodiazepine agonists ought to be investigated further.
Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid, With the aim of improving early diagnosis of herpes simplex encephalitis a polymerase chain reaction (PCR) assay with two "nested" primer pairs was developed for the amplification of herpes simplex virus DNA in cerebrospinal fluid (CSF). Southern blotting was used to confirm the specificity of the amplification. The assay was applied to 151 CSF samples from 43 consecutive patients with herpes simplex encephalitis verified by the finding of herpes simplex virus/viral antigen in a brain biopsy sample or at necropsy (13) and/or intrathecal production of IgG antibody to the virus (40). As controls. 87 CSF samples from 60 patients with acute febrile focal encephalopathy (initially suspected to be herpes simplex encephalitis but excluded by the absence of intrathecal antibody synthesis) were tested. PCR detected herpes simplex virus DNA in 42 of the 43 patients with proven herpes simplex encephalitis; all but 1 were positive in the first CSF sample taken. The 1 PCR-negative patient had been treated with acyclovir from 20 h after the onset of symptoms. All the control subjects were PCR negative. as were 270 internal contamination controls. The PCR result remained positive in samples drawn up to 27 days after the onset of neurological symptoms. This method is a rapid and non-invasive means to diagnose herpes simplex encephalitis; it is highly sensitive and specific.
Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris [published erratum appears in Lancet 1991 Apr 20;337(8747):988], The therapeutic efficacy and tolerability of calcipotriol ointment and betamethasone valerate ointment in psoriasis were compared in a multicentre. prospective. randomised. double-blind. right/left trial. 345 inpatients and outpatients with psoriasis vulgaris of symmetrical distribution were treated twice daily for 6 weeks with calcipotriol ointment 50 micrograms/g and betamethasone ointment 0.1% randomly assigned to opposite sides of the body. The main outcome measures--the psoriasis area and severity index (PASI). the investigators' assessments of erythema. thickness. and scaling. and the patients' own assessments of the overall response to treatment--were sought at weeks 2. 4. and 6. Both treatments significantly reduced the PASI scores and the investigator's assessment scores. but at each visit the PASI score was significantly (p less than 0.001) lower with calcipotriol than with betamethasone. At 6 weeks the mean PASI reduction was 68.8% with calcipotriol and 61.4% with betamethasone (95% confidence interval for difference 5.1-9.8. p less than 0.001). The scores for erythema. thickness. and scaling were significantly (p less than 0.001) lower with calcipotriol than with betamethasone at the end of treatment. The patients considered that 82.1% of calcipotriol-treated sides and 69.3% of betamethasone-treated sides had improved greatly or cleared up by the end of treatment (p less than 0.001). 57 adverse events were reported by 52 patients (15.1%). The most common adverse event. lesional/perilesional skin irritation. was slightly but not significantly (p = 0.12) more common with calcipotriol treatment. 15 (4.3%) patients were withdrawn from the study. 3 because of local adverse events. There were no changes in serum calcium during the study. Thus. calcipotriol ointment was superior to betamethasone valerate ointment in psoriasis vulgaris. Though long-term results are not yet available. calcipotriol holds great promise as an antipsoriatic agent.
Rapid diagnosis of malaria by fluorescence microscopy with light microscope and interference filter, Fluorochrome staining to detect malaria parasites in bloodfilms is more sensitive. is easier to do. and is less time-consuming than Giemsa staining. However. standard epi-illuminated. mercury vapour. fluorescence microscopes are expensive. especially for tropical countries where malaria is endemic. Fluorescence microscopy with a standard light microscope and a new interference filter specially designed for the fluorochrome stain. acridine orange. was used to detect malaria parasites in thick and thin bloodfilms. In this system two fluorescence colours. green (nuclei) and red (cytoplasm). were emitted from stained parasites. Thick and thin bloodfilms from patients with malaria were examined with this system. Bloodfilms had been fixed and stored for 1-5 years. Rapid scanning of both thick and thin bloodfilms was possible at a magnification of x200 with standard lenses. indicating that this may be a useful economic system for rapid diagnosis of malarias.
Keratinocytes as initiators of inflammation, Environmental stimuli responsible for inducing cutaneous inflammation include contact allergens and ultraviolet light. We postulate that these diverse stimuli trigger a cutaneous inflammatory response by directly inducing epidermal keratinocytes to elaborate specific pro-inflammatory cytokines and adhesion molecules. The consequences are activation of dermal microvascular endothelial cells and selective accumulation of specific mononuclear cells in the dermis and epidermis. Thus. keratinocytes may act as "signal transducers". capable of converting exogenous stimuli into the production of cytokines. adhesion molecules. and chemotactic factors (acting in an autocrine and paracrine fashion) responsible for initiation of "antigen-independent" cutaneous inflammation. The initiation phase may facilitate or promote an amplification phase with additional production of tumour-necrosis factor alpha and interferon gamma via an "antigen-dependent" pathway. and keratinocyte/T cell/antigen-presenting dendritic cellular associations. The direct activation of keratinocytes. with their ability to produce the complete repertoire of pro-inflammatory cytokines. can profoundly influence endogenous and recruited immunocompetent cells. thereby providing the critical trigger responsible for the swift and clinically dramatic alterations that occur following contact between the epidermis and a host of "noxious" agents.
The axilla: not a no-go zone, Many surgeons. particularly in the UK. give inadequate primary treatment to patients with operable breast cancer. For spurious reasons they regard axillary clearance as unnecessarily extensive surgery and rely instead upon total mastectomy or tumour excision and node sampling. with or without postoperative radiotherapy. But it is now clear that relapse-free and overall survival can be improved by appropriate adjuvant therapy. Thus inadequate exploration of the axilla is doubly unjustified. Not only is there the obvious risk of failure to remove nodes that contain metastases--so that some patients are deprived of cure by primary treatment--but the extent of tumour spread will be inadequately assessed in many more patients. with the risk that they may not receive appropriate adjuvant treatment.
Schwartz-Jampel syndrome with dominant inheritance, The Schwartz-Jampel syndrome (SJS) is a rare congenital multisystem disorder of unknown pathogenesis which is characterized by distinct faces. skeletal deformities. joint contractures. short stature. muscle hypertrophy. clinical myotonia. and continuous muscle fiber activity. The inheritance pattern of SJS has been assumed to be autosomal recessive. We report the occurrence of the classic SJS syndrome in both a father and son in a non-consanguineous family. suggesting that SJS has the potential for a dominant pattern of inheritance.
Carpal tunnel syndrome: correlations between pressure measurement and intraoperative electrophysiological nerve study, In 19 carpal tunnel syndrome (CTS) patients and 4 control subjects a catheter was introduced into the carpal tunnel and slowly retracted in 5 mm steps. Pressure was measured with the continuous infusion technique. In the same group of patients and controls. median nerve antidromic sensory action potential (aSAP) was detected intraoperatively stimulating proximally (S1). in the center (S2). and distally (S3) to the carpal tunnel and recording from the third finger (R). Sensory conduction velocity (SCV) and aSAP amplitude were considered in S1-S2. S2-S3 and S3-R segments. The intracarpal tunnel pressure was significantly higher in CTS patients than in controls. with the highest values located between 25 and 35 mm distal to the proximal border of the flexor retinaculum. SCV and aSAP amplitude were also decreased most often in the distal part (S2-S3) of the carpal tunnel.
Randomized, double-blind trial of mazindol in Duchenne dystrophy, There is evidence that growth hormone may be related to the progression of weakness in Duchenne dystrophy. We conducted a 12-month controlled trial of mazindol. a putative growth hormone secretion inhibitor. in 83 boys with Duchenne dystrophy. Muscle strength. contractures. functional ability and pulmonary function were tested at baseline. and 6 and 12 months after treatment with mazindol (3 mg/d) or placebo. The study was designed to have a power of greater than 0.90 to detect a slowing to 25% of the expected rate of progression of weakness at P less than 0.05. Mazindol did not benefit strength at any point in the study. Side effects attributable to mazindol included decreased appetite (36%). dry mouth (10%). behavioral change (22%). and gastrointestinal symptoms (18%); mazindol dosage was reduced in 43% of patients. The effect of mazindol on GH secretion was estimated indirectly by comparing the postabsorptive IGF-I levels obtained following 3. 6. 9. and 12 months in the mazindol treated to those in the placebo groups. Although mazindol-treated patients gained less weight and height than placebo-treated patients. no significant effect on IGF-I levels was observed. Mazindol doses not slow the progression of weakness in Duchenne dystrophy.
Vector short-latency somatosensory-evoked potentials after median nerve stimulation, A new method has been developed for recording short-latency somatosensory-evoked potentials after median nerve stimulation. Negative electrical forces recorded with three orthodiagonal bipolar electrodes in the neck had a direction opposite to that of impulse conduction in the proximal peripheral and cervical somatosensory pathway. Sequential tracings of vectors opposite the electrical forces were made in three-dimensional display. thus reproducing the actual time sequence of electrical events in those structures. Fixed generators such as the subcortical nuclei were also analyzed with this technique. and multiple generators of N13 potential (N13a and N13b) were visualized. This technique may be useful in the functional evaluation of the somatosensory pathway in the cervical cord.
Neutrophil influx into an inflammatory site inhibited by a soluble homing receptor-IgG chimaera, Neutrophil-mediated inflammation is involved in a number of human clinical manifestations. including the adult respiratory distress syndrome. multi-organ failure and reperfusion injury. One way of inhibiting this type of inflammatory response would be to block competitively the adhesive interactions between neutrophils and the endothelium adjacent to the inflamed region. The lectin-containing murine adhesion molecule gp90MEL. the homing receptor. is found on all leukocytic cells. including neutrophils. MEL 14. a monoclonal antibody directed against this adhesion molecule. blocks lymphocyte traffic to lymph nodes and extravasation of neutrophils from blood to inflammatory sites. Here we show that administration to mice of a soluble immunoglobulin chimaera containing the murine homing receptor extracellular domain significantly decreases the number of neutrophils that migrate to the peritoneum in response to the inflammatory irritant thioglycollate. These results indicate that soluble forms of a single type of adhesion molecule. the homing receptor. could be clinically effective compounds for the inhibition of neutrophil-mediated inflammation.
The Ams (altered mRNA stability) protein and ribonuclease E are encoded by the same structural gene of Escherichia coli, The in vitro and in vivo analysis of the ribonuclease E-deficient (rne-) and the altered mRNA stability protein-deficient (ams-) strains of Escherichia coli has demonstrated that they carry mutations in the same structural gene. Strains encoding either thermolabile RNase E (rne-3071) or Ams protein (ams-1) are defective in both rRNA processing and mRNA turnover. Immediately after a shift to the nonpermissive temperature. the chemical decay rate of bulk mRNA is slowed 2- to 3-fold. and within 70 min. precursors to 5S rRNA begin to accumulate. In addition. all of the phenotypes associated with either the rne-3071 or the ams-1 alleles were complemented by a recombinant plasmid carrying ams+. When taken together with previous genetic studies. these results suggest that the role of ribonuclease E in mRNA turnover involves endonucleolytic cleavages at the proposed ACAG(A/U)AUUUG consensus sequence.
Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis [published erratum appears in Proc Natl Acad Sci U S A 1991 Apr 1;88(7):2967, The gene coding for plasminogen has been compared with several abnormal genes from Japanese patients by the polymerase chain reaction and DNA sequence analysis. Two types of abnormal genes coding for plasminogen were identified in these patients. In the type I mutation. a guanosine in GCT coding for Ala-601 near the active-site histidine was replaced by an adenosine resulting in ACT coding for threonine. This mutation was also shown by the loss of a cleavage site for Fnu4HI endonuclease. a restriction enzyme that recognizes GCTGC but not ACTGC. In the type II mutation. a guanosine in GTC coding for Val-355 was replaced by a thymidine resulting in TTC coding for phenylalanine. This change was readily shown by digestion with Ava II endonuclease. a restriction enzyme that recognizes GGTCC and not GTTCC. The type I mutation has been found to be identical to a plasminogen variant identified in Japanese patients by amino acid sequence analysis and also detected by isoelectric focusing. whereas the type II mutation is a unique amino acid substitution in the connecting region between the third and fourth kringles in plasminogen. DNA sequence analysis also revealed that the abnormal genes carry several silent nucleotide substitutions located primarily within introns and 5' and 3' flanking regions.
Nerve growth factor binding domain of the nerve growth factor receptor, A structural analysis of the rat low-affinity nerve growth factor (NGF) receptor was undertaken to define the NGF binding domain. Mutant NGF receptor DNA constructs were expressed in mouse fibroblasts or COS cells. and the ability of the mutant receptor to bind NGF was assayed. In the first mutant. all but 16 amino acid residues of the intracellular domain of the receptor were removed. This receptor bound NGF with a Kd comparable to that of the wild-type receptor. A second mutant contained only the four cysteine-rich sequences from the extracellular portion of the protein. This mutant was expressed in COS cells and the resultant protein was a secreted soluble form of the receptor that was able to bind NGF. Two N-terminal deletions. in which either the first cysteine-rich sequence of the first and part of the second cysteine-rich sequences were removed. bound NGF. However. a mutant lacking all four cysteine-rich sequences was unable to bind NGF. These results show that the four cysteine-rich sequences of the NGF receptor contain the NGF binding domain.
Genetic disease detection and DNA amplification using cloned thermostable ligase, Polymerase chain reaction. using thermostable DNA polymerase. has revolutionized DNA diagnostics. Another thermostable enzyme. DNA ligase. is harnessed in the assay reported here that both amplifies DNA and discriminates a single-base substitution. This cloned enzyme specifically links two adjacent oligonucleotides when hybridized at 65 degrees C to a complementary target only when the nucleotides are perfectly base-paired at the junction. Oligonucleotide products are exponentially amplified by thermal cycling of the ligation reaction in the presence of a second set of adjacent oligonucleotides. complementary to the first set and the target. A single-base mismatch prevents ligation/amplification and is thus distinguished. This method was exploited to detect 200 target molecules as well as to discriminate between normal beta A- and sickle beta S- globin genotypes from 10-microliters blood samples.
Prothymosin alpha antisense oligomers inhibit myeloma cell division, The function of prothymosin alpha has been investigated by using four different antisense oligodeoxyribonucleotides directed at selected regions of its mRNA. In every case. when synchronized human myeloma cells were released from stationary phase by incubation in fresh medium containing antisense oligomers. cell division was prevented or inhibited; sense oligomers and random antisense oligomers had no effect. A detailed analysis of synchronized cell populations indicated that sense-treated and untreated cells divided approximately 17 hr after growth initiation. whereas cells incubated with antisense oligomer 183. a 16-mer targeted 5 bases downstream of the initiation codon. entered mitosis approximately one cell division late. The failure to divide correlated directly with a deficit in prothymosin alpha and with the continued presence of intact intracellular antisense oligomers over a period of at least 24 hr. Because antisense oligomers had no effect either on the timing of the induction of prothymosin alpha mRNA upon growth stimulation or on mRNA levels seen throughout the cell cycle. we concluded that antisense DNA caused specific hybrid arrest of translation. Our data suggest that prothymosin alpha is required for cell division. However. there is no evidence that prothymosin alpha directly regulates mitosis.
Molecular evolution of inversions in Drosophila pseudoobscura: the amylase gene region, The amylase region of the third chromosome of Drosophila pseudoobscura has been cloned and localized to cytological band 73A. It is contained within a series of highly polymorphic inversions and serves as a convenient tool for a molecular evolutionary analysis of the inverted gene arrangements. Amylase in D. pseudoobscura is a family of three genes. and some chromosomes have deletions for one or two of them. Two overlapping clones covering 26 kilobases were isolated and used as probes to survey DNA restriction map polymorphism among 28 lines. representing five of the major inversion types found in natural populations. as well as single chromosomes from the closely related species Drosophila persimilis and Drosophila miranda. Restriction-site differences are considerably greater among the various gene arrangements than among chromosomes with the same gene arrangement. Clustering the restriction map haplotypes yielded a dendrogram concordant with the phylogeny generated independently from cytogenetic considerations. The inversion polymorphism is estimated to be about 2 million years old.
Evolution of a genetic disease in an ethnic isolate: beta-thalassemia in the Jews of Kurdistan, beta-Thalassemia is a hereditary disease caused by any of 90 different point mutations in the beta-globin gene. Specific populations generally carry a small number of mutations. the most common of which are those that are widely distributed regionally. The present study constitutes an extensive molecular characterization of this disease in a small. highly inbred ethnic group with a high incidence of beta-thalassemia--the Jews of Kurdistan. An unusual mutational diversity was observed. In 42 sibships 13 different mutations were identified. of which 3 are newly discovered: a C----A transversion at -88 to the cap site. a frameshift in codon 36/37. and an A----G transition in the polyadenylylation signal. Four of the mutations are unique to Kurdish Jews and have not been discovered in any other population. A fifth was found outside Kurdish Jews only in an Iranian from Khuzistan. a region bordering Kurdistan. Two-thirds of the mutant chromosomes carry the mutations unique to Kurdish Jews. We traced the origin of the mutations to specific geographic regions within Kurdistan. This information. supported by haplotype analysis. suggests that thalassemia in central Kurdistan (northern Iraq) has evolved primarily from multiple mutational events. In Turkish Kurdistan. the primary mechanism is genetic admixture with the local population. In Iranian Kurdistan. a founder effect appears to be partly responsible. We conclude that several evolutionary mechanisms contributed to the evolution of beta-thalassemia in this small ethnic isolate.
Sequence and functional expression in Xenopus oocytes of a human insulinoma and islet potassium channel, Regulation of insulin secretion involves the coordinated control of ion channels in the beta-cell membrane. We have isolated and characterized cDNA and genomic clones encoding a voltage-dependent K+ channel isoform expressed in human islets and in a human insulinoma. This K+ channel isoform. designated hPCN1. with a deduced amino acid sequence of 613 residues (Mr = 67.097). is related to the Shaker family of Drosophila K+ channels. hPCN1 is homologous to two other human K+ channel isoforms we have isolated. hPCN2 and hPCN3. with 55% and 65% amino acid sequence identity. respectively. The electrophysiological characteristics of hPCN1 were determined after microinjection of synthetic RNA into Xenopus oocytes. Two-microelectrode voltage-clamp recordings of oocytes injected with hPCN1 RNA revealed a voltage-dependent outward K+ current that inactivated slowly with time. Outward currents were inhibited by 4-aminopyridine with a Ki less than 0.10 mM and were relatively insensitive to tetraethylammonium ion or Ba2+. A delayed rectifier K+ channel such as hPCN1 could restore the resting membrane potential of beta cells after depolarization and thereby contribute to the regulation of insulin secretion.
Platelet-derived growth factor receptor alpha-subunit gene (Pdgfra) is deleted in the mouse patch (Ph) mutation, Platelet-derived growth factor receptors are composed of two subunits (alpha and beta) that associate with one another to form three functionally active dimeric receptor species. The two subunits are encoded by separate loci in humans and other species. In this study. we used conventional interspecific backcross mapping and an analysis of a deletional mutation to establish close linkage between the alpha-subunit gene (Pdgfra) and the dominant spotting (W) locus on mouse chromosome 5. Further. by analyzing the restriction fragment length polymorphisms in interspecific F1 hybrids. we were able to demonstrate that the closely associated patch (Ph) locus carries a deletion in Pdgfra. This observation was confirmed by both DNA and RNA analysis of 10.5-day fetuses produced from crosses between Ph heterozygotes. Out of 16 fetuses analyzed. Pdgfra genomic sequences were absent and no mRNA for the receptor was detected in 6 fetuses that were developmentally abnormal (the presumptive Ph homozygotes). We also determined that the deletion associated with the Ph mutation does not extend into the coding sequences of the adjacent Kit gene. by analysis of the genomic DNA from both the interspecific F1 hybrids and the presumptive Ph homozygotes. The absence of Pdgfra genomic sequences and the lack of detectable message associated with the Ph mutation should make this mutant a valuable asset for understanding the role of the receptor alpha subunit during mammalian development.
Dimerization of mammalian progesterone receptors occurs in the absence of DNA and is related to the release of the 90-kDa heat shock protein, In this study we have demonstrated that dimerization of mammalian progesterone receptors (PR) occurs in the absence of DNA. A specific immune coisolation assay was performed on extracts of T-47D human breast cancer cells with a monoclonal antibody specific for the full-length B form of progesterone receptor (PR-B). This resulted in coisolation of significant amounts of truncated form-A receptors (PR-A). indicating the presence of stable PR-A.PR-B dimers in solution. A positive correlation was observed between the ability of different receptor forms to oligomerize in solution and their ability to bind to specific DNA sequences. The ability to form stable PR-A.PR-B oligomers in the absence of DNA was also found to correlate with release of 90-kDa heat shock protein (hsp90) from the unactivated PR complex. These results support the hypothesis that dimerization in the absence of DNA is an important mechanism controlling receptor DNA-binding function and that hsp90 release may be a key step regulating dimerization. This suggests that hsp90 may function to repress DNA-binding activity indirectly by blocking receptor dimerization.
Pancreatic tumor pathogenesis reflects the causative genetic lesion, Transgenic mice in which c-myc expression is targeted to pancreatic acinar cells develop mixed acinar/ductal pancreatic adenocarcinomas between 2 and 7 months of age. This contrasts with the effect on pancreas of the simian virus 40 tumor antigen or activated ras. which in adult mice causes lesions composed exclusively of acinar-like cells. Furthermore. during an early stage of myc-induced pathology. transformed acinar-derived cells appear within islets. suggesting that islet hormones may influence the progression of these exocrine pancreatic tumors. These findings demonstrate that the initial oncogenic alteration can influence the pattern of subsequent tumor pathogenesis and. given that human exocrine pancreatic tumors are predominantly ductal adenocarcinomas. support the suggestion that transformed acinar cells may contribute to the genesis of this serious disease in man.
Modern chemotherapy for brucellosis in humans, The most effective. least toxic chemotherapy for human brucellosis is still undecided. In vitro. the antibiotics most active against Brucella include the tetracyclines. the aminoglycosides. the aminopenicillins. some cephalosporins. trimethoprim-sulfamethoxazole. erythromycin. rifampin. and some new fluorinated quinolones. Because Brucella species are facultative intracellular parasites. the penetration of drugs into and within phagocytes and phagosomes can be problematic and can best be studied in experimental animals or tissue cultures. In humans. the effectiveness of various regimens of chemotherapy has been compared best in acute bacteremic infections by assessment of the control of symptoms. bacteremia. complications. and relapses. The standard therapy against which all other therapies have been judged is a combination of tetracycline and streptomycin. which is almost universally effective but fails to prevent relapse in 10% of cases. A combination of oral doxycycline and rifampin is convenient and currently popular; it is highly effective. with an average relapse rate of only 8.4%. Trimethoprim-sulfamethoxazole is less effective in controlling bacteremia and other manifestations: in collected series. 5.7% of cases did not respond and 12% relapsed. Drug-resistant Brucella strains are rarely a cause of therapy failure. Localized brucellosis poses special problems. often requiring surgery in addition to prolonged combined chemotherapy.
Exchange transfusion as an adjunct to the treatment of severe falciparum malaria: case report and review, Malaria associated with complications or a fatal outcome is almost always caused by Plasmodium falciparum. The mortality due to this disease parallels the degree of parasitemia. Successful use of exchange blood transfusion as a therapeutic adjunct for this infection was first reported in 1974. although the efficacy of this procedure has not been established by randomized. controlled trials. The rationale for this form of therapy is based on: (1) rapid reduction in the parasite load by direct removal; (2) decreased risk of severe intravascular hemolysis and its consequences (disseminated intravascular coagulation and renal dysfunction); (3) improved rheology with transfused blood and reduced microcirculatory sludging; and (4) improved oxygen-carrying capacity with transfused erythrocytes. We describe a case of severe falciparum malaria and review the literature describing the use of exchange transfusion for treatment of this infection.
Antibiotic-associated hypoprothrombinemia: a review of prospective studies, 1966-1988, Many antimicrobial agents have been associated with hypoprothrombinemia. The precise mechanisms are unknown. but alteration in vitamin K status or utilization is involved. The two postulated mechanisms implicate either direct inhibition of biosynthesis of the vitamin K-dependent clotting factors by the N-methylthiotetrazole (NMTT) moiety found in certain antimicrobial agents or eradication of vitamin K-producing intestinal microflora in patients with reduced oral intake of vitamin K. An English-language review of all prospective studies reported between 1966 and 1988 in which serial prothrombin times were monitored in adult patients revealed that the incidence of hypoprothrombinemia varied from 3.7% to 64% with NMTT-containing regimens and from 0% to 24% with non-NMTT-containing regimens. Detailed evaluation of these and other studies suggests that certain risk factors. including malnutrition. hepatic and renal dysfunction. older age. and severity of illness. may be the major determinants of hypoprothrombinemia. The hypothesis that the NMTT side chain is primarily responsible for hypoprothrombinemia may not be justified. We conclude that patients at high risk for coagulopathy should be carefully monitored and that serious consideration should be given to the use of prophylactic vitamin K in such cases.
Alcohol and cocaine use among first-year college students, We surveyed 1528 first-year students at the University of Virginia. 1 month after their arrival on campus. who had used alcohol at some time in their lives. Our survey was designed to identify alcohol and cocaine use. and related psychosocial patterns. Men drank more and more often than women. Our data suggest that body weight should be considered in defining those who drink heavily and often. We define 'frequent heavy drinking' as five or more drinks in a row each week for men and three to four drinks or more in a row each week for women. Frequent heavy drinkers. cocaine users. and students with psychosocial problems appeared disproportionately among students planning to join fraternities and sororities. Although first-year students used cocaine infrequently. its users followed the patterns of frequent heavy drinkers. We believe efforts to correct alcohol and cocaine misuse by college students should be directed. in part. at social organizations such as Greek-letter societies. Also. we must attend to psychosocial features that predispose to alcohol and cocaine misuse.
Pharmacokinetic dosing of phenobarbital in the treatment of alcohol withdrawal syndrome, We used a pharmacokinetically derived phenobarbital dosing protocol to treat alcohol withdrawal syndrome in patients admitted to a family medicine inpatient service. We describe the protocol and include two case reports documenting its efficacy. Although benzodiazepine agents are considered by many to be the primary agents of choice. based upon our experience and its ease of administration. relative safety. therapeutic efficacy. and lower cost. phenobarbital should be reconsidered as a promising alternative. Comparative trials between these two therapeutic classes will clarify their roles in the treatment of alcohol withdrawal syndrome.
Williams' vulvovaginoplasty after supralevator total pelvic exenteration, Seven patients had delayed Williams' vulvovaginoplasty after supralevator total pelvic exenteration. Of the three patients who died of carcinoma of the cervix (at 2. 5. and 15 months after vulvovaginoplasty). the first died before having a chance to attempt intercourse. but the other two had reported intercourse on at least two occasions after the reconstruction. One of the patients described the experiences as neither pleasant nor unpleasant but stated that her husband seemed satisfied. The other patient described the experience as satisfactory to both herself and her husband. The remaining four patients are alive with no evidence of recurrent disease at 28. 42. 56. and 106 months after operation. Two of these patients have reported entirely satisfactory sexual relations approximating pre-exenteration frequency. but the remaining two have not had sexual relations since surgery. Both give the main reason for this as lack of opportunity. The Williams' vulvovaginoplasty appears to be a reasonable alternative for vaginal reconstruction in patients who will have and especially who have had exenteration. To improve results. other methods of vaginal reconstruction should continue to be evaluated.
Obstetric complications in young teenagers, We compared pregnancy outcome in 286 teenaged primigravidas (less than or equal to 16 years old) and 267 adult primigravidas (21 to 25 years old) who had similar prenatal care. socioeconomic status. and racial balance. The incidence of preterm labor and delivery of a low birthweight infant was significantly higher in the teenagers. The incidence of preeclampsia was significantly higher in the adults. Cesarean delivery was not done more frequently in teenagers. nor was there a higher incidence of infants small for gestational age. anemia. and abnormal presentation in labor. The birthweight of infants of black teenagers was significantly lower than the birthweight of those of white teenagers. and overall birthweight was significantly lower in infants of teenagers than those of adults. Although prenatal care. socioeconomic factors. and racial balance were comparable for young teenagers and adults. teenagers were still at a significantly greater risk for delivery of smaller infants. preterm labor. and low birthweight infants.
Roentgenographic evaluation of the augmented breast, We performed a retrospective study to determine the sensitivity of mammography in detecting breast cancer arising in women with augmented breasts. Of eight women with breast implants in whom breast cancer developed. six had mammograms before biopsy. Only two of the six cancers were identified mammographically (sensitivity = 33%). and one of these two was seen only in retrospect. In both cases. the mammographic findings suggested a benign rather than a malignant process. All eight women had a palpable mass and early disease. and all are clinically disease-free at present. The sensitivity of mammography in detecting palpable cancers in a control group of women without implants was 92% (118 of 128). For tumors of 2 cm or less. the sensitivity was 88% (58 of 66). These results suggest that the sensitivity of mammography in detecting breast cancer is decreased when implants are present. Further investigations are needed to determine the effects of prostheses on mammographic evaluations.
A survey of drinking patterns during medical school, Several studies have documented the common use of alcohol among medical students and the significant fraction of students (7% to 17%) who show a pattern of alcohol abuse. Many authors have pointed out the implications of physician impairment due to alcoholism. presently estimated at about 10%. We surveyed 263 junior and senior medical students. and our data support earlier surveys of the prevalence of alcohol abuse and indicate that students tend to drink less heavily and less frequently after entering medical school. The clinically proven CAGE questions used in the survey showed statistically significant associations between heavy or frequent drinking before and during medical school. but only 4.2% of respondents indicated that school officials had asked whether they had a drinking or drug abuse problem. Given these findings. we suggest the routine administration of screening instruments to medical students. using education and minimal intervention strategies with individuals at risk.
A histopathologic study of spinal cord ischemia using an isohistogenic rat upper-half-body transplantation model, To study the histopathologic changes of spinal cords exposed to long-duration complete ischemia. the authors developed an upper-half-body transplantation model of inbred rat. In this model. an infant Lewis rat is transplanted to the inguinal region of another adult Lewis rat using microsurgical vascular anastomosis. Even when 2-week-old donor rats were exposed to complete ischemia for 90 minutes. functions of the spinal cord were comparatively preserved. In histopathologic observations. degeneration proportional to complete ischemia duration was noted. In the 60-minute ischemia group of 2-week-old donor rats. however. no substantial differences from normal spinal cord were observed. Under conditions of equal ischemia duration. it appeared the younger animal had the greater ischemic tolerance.
Scoring system for the preoperative evaluation of metastatic spine tumor prognosis, An assessment system for the prognosis of metastatic spine tumors was evaluated for 64 cases who had undergone surgery. Six parameters were employed in the assessment system: 1) the general condition. 2) the number of extraspinal bone metastases. 3) the number of metastases in the vertebral body. 4) metastases to the major internal organs (lungs. liver. kidneys. and brain). 5) the primary site of the cancer. and 6) the severity of spinal cord palsy. Each parameter ranged from 0 to 2 points. The total score obtained for each patient can be correlated with the prognosis. while being valuable in predicting it. However. the prognosis could not be predicted from a single parameter. In conclusion. an excisional operation should be performed on those cases who scored above 9 points. while a palliative operation is indicated for those who scored under 5 points.
Identification of alpha-motor nerve fiber potentials in lumbar epidural space and its clinical significance, The alpha-efferent component of spinal root potentials (SRPs) was recorded in the lumbar epidural space stimulating the tibial and peroneal nerves for clinical diagnosis and clinical treatment. Five normal volunteers and 15 clinical cases with lumbar disc herniation (LDH) were examined. The SRP by the tibial nerve stimulation in the normal control group consisted of two kinds of potentials with different latency. Simultaneous electromyogram (EMG) recording from the stimulated muscles indicated that the shortest latency potential (first potential) was the ascending volley. including orthodromic afferent and antidromic alpha-efferent volleys; and that the long latency potential (second potential) was the descending volley of reflexively evoked alpha-efferents by the Group Ia afferents. The component of alpha-efferent fiber potential was recorded in the following two methods by changing the intensity of stimulation: 1) identifying alpha-efferent components in the first potential and 2) recording the second potential. Conduction blockage of spinal roots in 15 clinical cases was demonstrated as abnormal positivity and prolonged duration of the potentials. New methods were introduced to estimate two parameters quantitatively. The present study showed either of these signs in all patients tested. The examination was helpful to determine the level(s) of lumbar motor radiculopathies. and the extent of pathologic neuropathy.
The role of the iliolumbar ligament in the lumbosacral junction, The biomechanical function of the iliolumbar ligament in the human lumbosacral junction was investigated by analyzing the three-dimensional movements of the whole lumbar and lumbo-sacral-ilium specimens. The experiment was repeated in the following three conditions: 1) intact iliolumbar ligament. 2) right iliolumbar ligament transected. and 3) bilateral iliolumbar ligaments transected. The representative values of the increased motions. compared with intact. after transection of the bilateral iliolumbar ligaments were 1.7 degrees (23%) in flexion. 1.1 degrees (20%) in extension. 0.3 degrees (18%) in axial rotation. and 1.2 degrees (29%) in lateral bending. The most restricted motion governed by the iliolumbar ligament in the lumbosacral junction was lateral bending. The bilateral iliolumbar ligament specimen could restrict flexion and extension of the lumbosacral junction. but the unilateral iliolumbar ligament preparation alone could not restrict these motions. The iliolumbar ligament also had the function of restricting the rotational movement of the lumbosacral junction.
Biomechanical evaluation of lumbar spinal stability after graded facetectomies, In an in vitro experiment using fresh human lumbar functional spinal units. the effects of the division of the posterior ligaments (consisting of the supraspinous/interspinous ligaments) and graded facetectomies were investigated. The graded facetectomies consisted of unilateral and bilateral medial facetectomies. and unilateral and bilateral total facetectomies. Six kinds of moments were applied and ranges of motion (ROM) and neutral zones (NZ) were determined three-dimensionally by stereophotogrammetric methods. Range of motion was not affected by the division of the supraspinous/interspinous ligaments for all load modes. In flexion. ROM increased slightly after unilateral medial facetectomy. In right axial rotation. ROM increased after left unilateral total facetectomy. Range of motion was not affected. even by bilateral total facetectomies. in extension and lateral bendings. This study suggested that medial facetectomy does not affect lumbar spinal stability. and conversely. total facetectomy. even created unilaterally. makes the lumbar spine unstable.
Magnetic resonance imaging of lumbar disc herniation. Comparison with myelography, Fifty-three patients with surgically confirmed lumbar disc herniation at 55 levels were studied retrospectively to compare the diagnostic accuracy of high-field strength surface coil magnetic resonance imaging (MRI) with that of myelography. Disc herniation was classified into three groups according to MRI findings. namely. unilateral single-disc herniation. central single-disc herniation. and multilevel disc herniation. Magnetic resonance imaging diagnosis of unilateral single-disc herniation was extremely reliable. so myelography was considered to be unnecessary. Conversely. MRI findings of central single-disc herniation and multilevel disc herniation were less definite. in that myelography was necessary in locating the disc causing symptoms.
Ultrasonic level diagnosis of lumbar disc herniation, Although the use of diagnostic ultrasound to measure the spinal canal has been proposed. the value of ultrasound for lumbar disc herniation has not been yet fully assessed. The purpose of this investigation was to evaluate the effectiveness of ultrasound in the level diagnosis of herniated nucleus pulposus. Prospective ultrasound examinations were performed on 80 consecutive patients with clinically suspected lumbar disc herniation. In 41 discs of those 40 patients with surgically confirmed lumbar disc herniation. there were 32 discs (78%) with true-positive ultrasound diagnoses. 37 discs (90%) with true-positive myelographic diagnoses. and 20 patients (50%) with true-positive neurologic diagnoses. Conversely. ultrasound diagnoses showed positive echogram in 24 (60%) of 40 nonoperative patients. These results suggest that ultrasound is of value as an aid for diagnosing the level of lumbar disc herniation.
The system and procedures of percutaneous intradiscal laser nucleotomy, Since 1986. percutaneous intradiscal laser nucleotomy (PILN) has been studied in the authors' laser laboratory. The purpose of this report is to develop PILN as an alternative to chemonucleolysis and percutaneous discectomy. which are currently applied. and to establish a safe. easy. accurate and short-time therapy method for lumbar disc herniation. After laser irradiation. intradiscal pressures (IDP) decreased and the nucleus pulposus was gradually replaced with cartilaginous fibrous tissue. The evaluation of heat distribution with thermocouples and thermography was done to determine safe optimum irradiating conditions and to develop a new double-lumen needle and a bare quartz fiber. Neodymium-yttrium-aluminum-garnet (Nd-YAG) laser devices have been improved for easy and safe use. and a new tip type pressure transducer has been made for improved therapeutic results using this new method.
Unstable lumbar spine without hypermobility in postlaminectomy cases. Mechanism of symptoms and effect of spinal fusion with and without spinal instrumentation, The morbid conditions of unstable lumbar spine that are not associated with hypermobility in postlaminectomy cases were studied. The dura and the nerve roots with adhesion could be affected by minimal movement of the spine. which seemed to be the mechanism of symptoms of instability without hypermobility. The effects of spinal instrumentation on this particular instability were studied. The spinal instrumentation provides instantaneous rigid fixation. and maintains it until fusion is obtained. which might prevent adhesion. new bone formation. and re-stenosis. Spinal instrumentation seemed to be the effective treatment for this particular instability.
Lumbar trapezoid plate for lumbar spondylolisthesis. A clinical study on preoperative and postoperative instability, The authors studied the effects of a "lumbar trapezoid plate" (spinal plate and pedicle screwing). performed for lumbar spondylolisthesis. observing the effect on the remaining adjacent discs with regard to preoperative and postoperative instability. The authors examined changes in preoperative and postoperative lumbar ROM (range of motion). displacement of motor unit levels. and occurrence of instability in the remaining discs. such as horizontal and rotational displacement. in 26 patients who were followed up for a mean of 29 postoperative months; 13 patients had spondylolytic spondylolisthesis and 13 patients degenerative spondylolisthesis. The authors studied the effects of the fused vertebral angle and reduction of spondylolisthesis on the remaining upper and lower adjacent discs and the preoperative and postoperative fused disc heights. Intervertebral fusion must affect the remaining adjacent discs. but compensatory function of the remaining motor unit level was more influenced by the fused intervertebral angle than by repositioning of the spondylolisthesis. Fusion at a physiologically lordotic position is quite necessary. For this purpose. it is considered important to prevent grafted bones of the posterior lumbar interbody fusion (PLIF) from collapse and to maintain the achieved alignment of the lumbar spine.
Natural history of degenerative spondylolisthesis. Pathogenesis and natural course of the slippage, To clarify the natural course of degenerative spondylolisthesis. the mechanism and progression of disk slippage were studied clinically and radiographically in 40 patients. Progressive slippage was observed in 12 patients (30%). No progression of slippage was noted in patients who showed narrowing of the intervertebral disk. spur formation. subcartilaginous sclerosis. or ossification of ligaments. These suggest that the mechanisms of spinal restabilization prevent progression of the disease. General joint laxity was observed in many patients (65%). and this was believed to be involved in the pathogenic mechanism of this disease. There was no correlation between the clinical symptoms and progression of slippage. These findings suggest that careful consideration of the natural mechanisms of spinal restabilization as well as the natural course of the disease is important.
Long-term results of anterior interbody fusion for treatment of degenerative spondylolisthesis, Thirty-nine patients. 34 women and five men. underwent anterior decompression and interbody fusion for degenerative spondylolisthesis between February 1958 and August 1988. Their average age at surgery was 51 years (range. 34-74 years). and their average follow-up period was 12 years 7 months (range. 6 months to 30 years). Clinical evaluation was done by the score rating system of the Japanese Orthopaedic Association (JOA Score). Patients with JOA scores of 25 points or more were rated as "satisfactory." Survivorship was analyzed by the method of Kaplan and Meier to determine the cumulative percentage of patients with satisfactory results. The following results were obtained: Seventy-six percent of the patients had satisfactory results for 10 years after the anterior interbody fusion. 60% for 20 years. and 52% for 30 years. Irrespective of their age at surgery. the patients generally maintained satisfactory results up to 65 years of age.
Clinical study on stability of combined distraction and compression rod instrumentation with posterolateral fusion for unstable degenerative spondylolisthesis, The authors examined the stability of combined distraction and compression rod instrumentation with posterolateral fusion in 40 consecutive patients with unstable degenerative spondylolisthesis. All operations were performed by floating fusion of L3-4 or L4-5 after decompression procedures. Mobility at the fused level was checked every 4 weeks after operation by the disc space angle on the functional radiographic films without brace. The average period of postoperative follow-up was 26 months. In 30 patients. no mobility was found at any time. In six patients. any mobility disappeared within 24 weeks. and in three patients. within 1 year. Pseudoarthrosis was found in one patient. The solid fusion rate was 97.5%. The values of percent slippage and slip angle were slightly improved. Lumbar lordosis was in the normal range at follow-up.
Total sacrectomy and reconstruction for huge sacral tumors, The authors carried out successful total sacrectomy in three cases. two with giant cell tumors and one with a chordoma. The anterior and posterior approach is feasible for resecting huge sacral tumors en bloc. but it is important to reconstruct the continuity between the pelvic ring and spinal column using spinal instrumentation and sacral rods or AO plates. As total sacrectomy is a large-scale. time-consuming. and collaborative operation. two or three teams should be used in relays. Both pelvic and spinal surgical techniques are required. Post-operatively the patient can stand within 3 to 6 months and well-planned rehabilitation allows ambulation. In spite of the serious structural and neurologic damage caused. total sacrectomy can be rewarding procedure in terms of improved morbidity and mortality.
Risk of human immunodeficiency virus (HIV) transmission by blood transfusions before the implementation of HIV-1 antibody screening. The Transfusion Safety Study Group, Little information is available regarding the risk of human immunodeficiency virus type 1 (HIV-1) infection for patients transfused before routine anti-HIV-1 screening of blood donors was instituted in March 1985. A model was developed for estimating both the proportion and the number of transfusion recipients in the San Francisco Bay area who were infected by HIV-1 during each of the 7 years preceding routine donor screening for anti-HIV-1. The model is based on analysis of 1) donation histories of HIV-1-infected donors identified at the regional blood center; 2) HIV-1 seroprevalence estimates for homosexual and bisexual men in San Francisco; and 3) HIV-1 infection and survival rates for recipients traced by the Transfusion Safety Study and Irwin Memorial Blood Centers' Look Back Program. The incidence of transfusion-associated HIV-1 infection is estimated to have risen rapidly from the first occurrence in 1978 to a peak in late 1982 of approximately 1.1 percent per transfused unit. The decrease after 1982 coincided with the implementation of high-risk donor deferral measures. It is estimated that. overall. approximately 2135 transfusion recipients were infected with HIV-1 in the San Francisco region alone. This number suggests a higher prevalence of transfusion-associated HIV-1 infection than has been generally recognized and indicates the need for continued tracing of potentially exposed recipients. The data also strongly support the effectiveness of early donor education and self-exclusion measures and emphasize the importance of continued research and development in this area.
Red cell antibodies arising from solid organ transplants, RBC antibodies arising from transplanted organs and directed against recipient RBCs represent a well-established immunohematologic complication of solid organ transplantation. In ABO-unmatched organs. the frequency and severity of graft antibodies and hemolysis generally increase with the size (lymphoid content) of the organ. from kidney to liver to heart-lung transplants. In the cases reviewed here. the frequency of hemolysis increased in cyclosporine-treated kidney transplant recipients and O-to-A liver transplant recipients and decreased in group AB liver transplant recipients and kidney transplant recipients receiving azathioprine or low-dose postoperative graft irradiation. Available data cannot otherwise distinguish which cyclosporine-treated recipients of ABO-unmatched kidneys and livers (30-40% of total) will develop graft antibody. There has been no conclusive effect to date of the age. race. or gender of the donor or the recipient. of cadaver versus living kidney donors. or of patients' A2 or secretor status. In a few cases of living-donor kidney grafts. the donor was the patient's mother or wife who had been exposed to the recipient's RBC antigens via pregnancy. The ABO antibodies are typically IgG. appear 7 to 10 days after transplantation. and last for about a month. If immediate-spin crossmatching is done routinely. DATs are recommended in compatibility testing after ABO-unmatched transplants. Changes in the immunosuppressive regimen. such as a change from cyclosporine therapy. have not affected the duration of these antibodies. Most patients require only transfusions for this self-limited process. but six cases of hemolysis-induced acute renal failure have been reported. and one death was attributed to complications of hemolysis. RBC or plasma exchange has been performed in a few fulminant cases. RBCs of the donor's blood type are given when antibody appears. Some workers recommend such transfusion as prophylaxis at the time of surgery. although in liver transplants. the plasma accompanying a large amount of group O RBCs given perioperatively might be problematic. In several other centers. ABO-unmatched liver transplants have equivalent overall graft survivals. but the Pittsburgh adult patients with hemolysis have had reduced early graft survival. In the cases reviewed here. nine IgG Rh antibodies from kidney grafts directed against recipient RBCs have been observed. usually beginning 2 to 3 weeks after a cyclosporine-treated transplant. lasting for 2 to 6 months after operation. and causing mild hemolysis. One case represented a primary immune response from a previously unsensitized donor.(ABSTRACT TRUNCATED AT 400 WORDS).
Effect of ileal conduit on patients' activities following radical cystectomy, Over the last twenty months. 110 patients who have undergone a radical cystectomy for bladder cancer at The University of Texas M. D. Anderson Cancer Center were surveyed to assess the effect of an ileal conduit urinary diversion on postoperative activity. Postoperatively. 47.3 percent of the patients were very active. 34.5 percent were moderately active. and 18.2 percent were sedentary. Chemotherapy and the patient's gender were found to have a statistically significant effect on postoperative activity level. Chemotherapy resulted in a decrease of very active patients from 55.6 percent to 27.9 percent and an increase in sedentary patients from 11.2 percent to 30.2 percent (P = 0.005). No difference in activity levels was seen in 73.9 percent of the nonchemotherapy patients. Fifty-one percent of the men were very active as compared with only 19.1 percent of the women. whereas 20 percent more women than men were moderately active and 13 percent more were sedentary. Our experience indicates that the ileal conduit had no significant negative effect on activity if the effects of chemotherapy are controlled: 82.6 percent of the patients not receiving chemotherapy experienced either no change or an increase in their activity.
Cecal tubularization: lengthening technique for creation of catheterizable conduit, The creation of a continent. catherizable stoma is an integral component of successful continent urinary diversion. A technique is described which allows lengthening of a continent appendicovesicostomy. This technique extends the applications for the Mitrofanoff principle of urinary tract reconstruction.
Use of biofeedback in treatment of psychogenic voiding dysfunction, A young man with psychologic problems and a long history of social inadequacy presented with voiding dysfunction. Videocystometrography revealed a normal filling phase and normal initiation of voiding interrupted by considerable straining by the patient and marked sphincter electromyographic (EMG) activity. Temporary amelioration was achieved by infiltration of the sphincter with lignocaine hydrochloride and by biofeedback therapy. In such cases optimal results are expected from long-term behavioral therapy.
Treatment of renal transplant stones by extracorporeal shock-wave lithotripsy in the prone position, Two patients with renal transplant lithiasis were successfully treated with extracorporeal shock-wave lithotripsy (ESWL) in the prone position. Pathogenesis and treatment of transplant lithiasis are discussed. Performing ESWL on renal transplant patients in the prone position has advantages over standard positioning techniques.
Study of antireflux nipple valves of Kock ileal urinary reservoir. Experimental investigation in dogs, To better assess the construction. maintenance. and function of the Kock ileal urinary reservoir with its continent antirefluxing nipple valves. laboratory investigations in dogs were done simultaneously with clinical trials in humans in 1983. Fifteen dogs underwent creation of hemi-Kock ileal reservoirs (without the efferent valve and limb) that were anastomosed to their bladders as enterocystoplasties. The afferent antirefluxing nipple valves were intussuscepted after 7 cm of underlying mesentery had been removed. The nipples were further stabilized with metal and absorbable (Polysorb) staples and Marlex collars. The right ureters were anastomosed to the afferent limb of the reservoirs with the contralateral systems left intact as controls. Ten dogs were able to be followed at the vivaria for twelve to thirty-six months and then studied. All nipple valves remained intact. viable. and nonrefluxing without revision. All kidneys remained histologically normal except those in dogs with dilated ureters secondary to ureteroileal stenosis with concurrent calculi formation. Calculi formed on exposed metal staples and Marlex. The absorbable staples were found to promote appropriate healing and were never the nidus for stone formation. It appears that the intussuscepted nipple valve (with its mesentery removed) is reproducible and functionally reliable in preventing reflux. It also appears these valves can histologically preserve diverted kidneys if the upper urinary tract drainage is normal and calculi are minimized. The proper placement of staples and the elimination of Marlex-anchoring collars are indicated to minimize calculi.
The painful shoulder: Part I. Extrinsic disorders, Shoulder disorders are most commonly manifested by pain and limited function. Careful history and examination help the physician localize the problem to the shoulder joint. the surrounding tissues or adjacent sites that can cause referred pain to the shoulder. Common extrinsic causes of shoulder pain include postural problems and cervical spine disorders.
The radiographic spectrum of renal osteodystrophy, Chronic renal failure often results in bone changes. collectively known as renal osteodystrophy. These changes include osteitis fibrosa. osteosclerosis. soft tissue calcifications. osteomalacia (in adults) and rickets (in children). Early recognition of renal osteodystrophy allows more aggressive clinical control of serum calcium and phosphate levels. Intervention may spare the patient late complications such as fractures. pain and loss of skeletal function.
Antiviral drug therapy, Major advances in molecular virology have led to the development of new antiviral compounds. These drugs include ribavirin. used in the treatment of severe respiratory syncytial virus infection in children; amantadine. used in the prophylaxis and treatment of influenza A infection; acyclovir. used in a variety of herpesvirus infections. including primary gingivostomatitis. genital herpes and herpes zoster; ganciclovir. used in the treatment of retinitis due to cytomegalovirus. and zidovudine. used in the prophylaxis and treatment of human immunodeficiency virus infection.
Severity of single-vessel coronary arterial stenosis and duration of angina as determinants of recruitable collateral vessels during balloon angioplasty occlusion, To determine the factors that influence the presence of collateral vessels during coronary occlusion. we performed standardized contrast injection of the contralateral coronary artery in 58 consecutive patients. without previous myocardial infarction. undergoing percutaneous transluminal coronary angioplasty for 1-vessel disease (left anterior descending artery in 45. right coronary artery: in 10 and left circumflex artery in 3). The presence of collateral vessels during coronary occlusion. defined as partial or complete epicardial opacification by collateral vessels of the vessel dilated. was related to clinical. angiographic and electrocardiographic parameters. The angiographic appearance of collateral vessels during balloon inflation showed a weak. although statistically significant. correlation to the percent diameter stenosis before angioplasty (r = 0.28; p = 0.03) and the duration of angina (r = 0.37; p = 0.004). By combining lesion severity with the duration of angina. collateral vessels during coronary occlusion were particularly related to a lesion severity greater than or equal to 70% and duration of angina greater than or equal to 3 months (p less than 0.001). Furthermore. the presence of collateral vessels was associated with an absence of ST-segment shift (greater than or equal to 1 mm) during 1 minute of coronary occlusion (p less than 0.001).
Characteristics of black patients admitted to coronary care units in metropolitan Seattle: results from the Myocardial Infarction Triage and Intervention Registry (MITI), Since 1988. 641 black and 11.892 white patients with chest pain of presumed cardiac origin have been admitted to coronary care units in 19 hospitals in metropolitan Seattle. Black men and women were younger (58 vs 66. p less than 0.0001). more often admitted to central city hospitals (p less than 0.0001). and developed evidence of acute myocardial infarction (AMI) less often (19 vs 23%. p = 0.01). In the subset of 2.870 AMI patients. blacks (n = 121) were younger (59 vs 67. p less than 0.0001) and had less prior coronary artery bypass graft surgery (2 vs 10%. p = 0.005) and more prior hypertension (67 vs 46%. p less than 0.0001). During hospitalization. whites (n = 2.749) had higher rates of coronary angioplasty (18 vs 10%. p = 0.03) and coronary artery bypass graft surgery (10 vs 4%. p = 0.04). although thrombolytic therapy and cardiac catheterization were used equally in the 2 groups. Hospital mortality was 7.4% for black and 13.1% for white patients (p = 0.07). However. after adjustment for key demographic and clinical variables by logistic regression. this difference was not as apparent (p = 0.38). Questions about the premature onset of coronary artery disease. excess systemic hypertension. and the differential use of interventions in black persons have been raised by other investigators. Despite differences in age. referral patterns and the use of coronary angioplasty and bypass surgery. black and white patients with AMI in metropolitan Seattle had similar outcomes.
Late results of 200 repeat coronary artery bypass operations, To determine the clinical outcome and the long-term results of a second coronary artery bypass operation. we studied preoperative clinical status and catheterization data in 200 consecutive patients over a 9-year period (1979 to 1987) (mean follow up time 34 months. maximum 120). The study group included 169 men and 31 women (mean age 58.4 years [7% greater than 70 years]). Sixty-four percent of patients had severe angina (New York Heart Association class IV). 70% had 3-vessel coronary artery disease and 21% had poor left ventricular function. Reoperation was performed after a mean interval of 58 months after the first procedure. A mean of 3.3 distal anastomoses was placed. The operative mortality rate (30 days) was 7.5%. with additional cardiac morbidity (myocardial infarction. heart failure) in 11.5% of patients. Multivariate analysis showed an increased risk in women (risk ratio 3.6) and in patients with poor left ventricular function (risk ratio 3.1). The cumulative 5-year survival rate was estimated at 84%. with a rate of 77% for patients with poor left ventricular function (difference not significant). The probability of remaining free of a cardiac-related event (myocardial infarction. angioplasty. third operation. cardiac death) was 64% for 5 years. At the end of follow-up. 79% of the surviving patients were in New York Heart Association class I or II and nearly 50% of patients in the fifth year after the reoperation had good functional status. It is concluded that a reoperation is effective but carries an increased. immediate. operative risk.
Cardiovascular risk factor clustering and ratio of total cholesterol to high-density lipoprotein cholesterol in angiographically documented coronary artery disease, High levels of cardiac risk factors tend to cluster together and act synergistically. To develop a suitable and practical marker for clustering. we evaluated 380 consecutive patients at the time of coronary angiography. Analyses of lipid. rheologic. clinical and arteriographic profiles indicated a variety of interwoven relations. Because the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol (total/HDL cholesterol) was closely related to both the presence and extent of greater than or equal to 50% diameter reduction of greater than or equal to 1 coronary arteries. it was used to divide patients into quartiles. Clustering of high- and low-level risk factors was demonstrated in the highest and lowest quartiles of total/HDL cholesterol. respectively (p less than 0.001). The highest quartile may be characterized by an only moderately elevated total cholesterol level but patients in this quartile may have a very low HDL cholesterol level. high triglycerides. a tendency toward high hemoglobin and fibrinogen levels. a history of smoking. previous myocardial infarction and multivessel disease. These results suggest that total/HDL cholesterol serves as a marker not only for obstructive coronary disease but also for a cluster of potentially modifiable risk factors.
Ventricular tachycardia and accelerated ventricular rhythm presenting in the first month of life, Fourteen infants aged less than 1 month presented to our institution during the last 22 years with ventricular tachycardia (VT) or accelerated ventricular rhythm and a structurally normal heart. In 2. VT was associated with long QT syndrome. Both are alive on beta-blocker therapy. 1 with an implanted pacemaker. Twelve infants had accelerated ventricular rhythm. and 2 of these died in the first 2 months of life of unrelated conditions. The other 10 are alive at a median age of 4 years (range 2 months to 11 years). and none were lost to follow-up. Hemodynamic compromise did not occur with accelerated ventricular rhythm. The ventricular rate was very close to the sinus rate in all 12. less than 12% above the sinus rate. The mean QRS duration during accelerated ventricular rhythm was 92.5 ms. and averaged twice the QRS duration during sinus rhythm. Fusion beats were seen in all 12. and there was atrioventricular dissociation with capture beats in 10. In 2. ventriculoatrial conduction was present. Treatment was attempted in 5 of the 10 survivors with accelerated ventricular rhythm. and was thought to be successful in 4. Treatment was later successfully withdrawn in all 5. so that all 10 survivors were free of accelerated ventricular rhythm and were not receiving antiarrhythmic medications at last follow-up. Because of the excellent long-term outcome and the lack of hemodynamic compromise during the rhythm. it seems reasonable to withhold antiarrhythmic therapy in infants with accelerated ventricular rhythm and await resolution of the rhythm.
Characterization of spontaneous termination of sustained ventricular tachycardia associated with coronary artery disease, To characterize the change in cycle length and QRS morphology before spontaneous termination of sustained ventricular tachycardia (VT). electrocardiograms were recorded and VT cycle length measured for the periods 31 to 21 and 11 to 1 beats before termination in 55 episodes from 28 patients with coronary artery disease. Beats 31 to 21 were designated as a period of stable arrhythmia and served as a reference for changes occurring just before termination. Forty-four episodes of VT occurred in the setting of antiarrhythmic drug therapy; 11 episodes occurred in patients not treated with antiarrhythmic drugs. Variability in cycle length was indexed by the standard deviation of the mean cycle length and by the percentage of consecutive cycles varying by greater than or equal to 40 ms (% greater than or equal to 40 ms). There was greater variability just before termination (standard deviation of the mean cycle length. 25.8 ms; % greater than or equal to 40 ms. 16.7%) than during the stable period (standard deviation of the mean cycle length. 8.5 ms; % greater than or equal to 40 ms. 5.4%; p less than 0.001 for both). This was true irrespective of antiarrhythmic drug use. although the differences in the standard deviation of the mean cycle length for beats 11 to 1 and for beats 31 to 21 were greater for the antiarrhythmic drug group (29.6 vs 8.9 ms. p less than 0.001) than for the group not receiving antiarrhythmic drugs (11.0 vs 6.7 ms. difference not significant). No specific patterns of cycle length variability characteristic of VT termination were found.
Comparison of lisinopril versus atenolol for mild to moderate essential hypertension, The antihypertensive effects and safety profiles of lisinopril (10 to 40 mg) and atenolol (50 to 100 mg) were compared in a randomized. double-blind. parallel group trial in 144 patients with essential hypertension. After 8 weeks of therapy. seated blood pressure (BP) decreased by 26/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. Lisinopril produced a greater reduction (p less than 0.05) in sitting systolic BP than did atenolol. Standing BP decreased by 25/15 mm Hg with lisinopril and by 19/14 mm Hg with atenolol. No important changes in hematologic and biochemical profiles were seen with either drug. Eleven patients. 7 receiving lisinopril and 4 receiving atenolol. were withdrawn because of adverse experiences; another 3 patients defaulted during treatment. 1 in the lisinopril group and 2 in the atenolol group. Both drugs were well-tolerated and are therefore suitable for first-line therapy in essential hypertension.
Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure, Previous efforts to block the renin-angiotensin system in patients with chronic congestive heart failure (CHF) have focused on 2 distal sites in the system. the angiotensin-converting enzyme and the angiotensin II receptor. Recent work. however. has led to the development of agents that directly inhibit renin. the proximal step in the cascade. In this study. we investigated the hemodynamic effects of renin inhibition in 9 patients with chronic CHF by using enalkiren. a primate-selective. dipeptide renin inhibitor. which has been previously shown to suppress plasma renin activity and to lower blood pressure in hypertensive patients. The acute intravenous administration of enalkiren (1.0 mg/kg) produced increases in cardiac index (2.0 +/- 0.3 to 2.3 +/- 0.1 liter/min/m2) and stroke volume index (26 +/- 3 to 34 +/- 4 ml/m2) and decreases in left ventricular filling pressure (31 +/- 3 to 25 +/- 3 mm Hg). mean right atrial pressure (15 +/- 1 to 13 +/- 2 mm Hg). heart rate (78 +/- 5 to 72 +/- 6 beats/min) and systemic vascular resistance (2.199 +/- 594 to 1.339 +/- 230 dynes.s.cm-5) (all p less than 0.01 to 0.05). These observations indicate that renin inhibition produces hemodynamic benefits in patients with chronic CHF and could potentially provide a novel approach to interfering with the renin-angiotensin system in patients with this disorder.
Effects of bucindolol on neurohormonal activation in congestive heart failure, To examine the effects of beta-adrenergic blockade on neurohormonal activation in patients with congestive heart failure. 15 men had assessments of hemodynamics and supine peripheral renin and norepinephrine levels before and after 3 months of oral therapy with bucindolol. a nonselective beta antagonist. At baseline. plasma renin activity did not correlate with any hemodynamic parameter. However. norepinephrine levels had a weak correlation with left ventricular end-diastolic pressure (r = 0.74. p less than 0.01). stroke volume index (r = 0.61. p less than 0.02) and pulmonary vascular resistance (r = 0.54. p less than 0.05). Plasma renin decreased with bucindolol therapy. from 11.6 +/- 13.4 to 4.3 +/- 4.1 ng/ml/hour (mean +/- standard deviation; p less than 0.05). whereas plasma norepinephrine was unchanged. from 403 +/- 231 to 408 +/- 217 pg/ml. A wide diversity of the norepinephrine response to bucindolol was observed with reduction of levels in some patients and elevation in others. Although plasma norepinephrine did not decrease. heart rate tended to decrease (from 82 +/- 20 vs 73 +/- 11 min-1. p = 0.059) with beta-adrenergic blockade. suggesting neurohormonal antagonism at the receptor level. No changes in I-123 metaiodobenzylguanidine uptake occurred after bucindolol therapy. suggesting unchanged adrenergic uptake of norepinephrine with beta-blocker therapy. Despite reductions in plasma renin activity and the presence of beta blockade. the response of renin or norepinephrine levels to long-term bucindolol therapy did not predict which patients had improved in hemodynamic status (chi-square = 0.37 for renin. 0.82 for norepinephrine).
Outcomes of direct coronary angioplasty for acute myocardial infarction in candidates and non-candidates for thrombolytic therapy, Coronary angioplasty without prior thrombolytic therapy was performed in 383 patients with acute myocardial infarction (AMI). Patients were divided into 2 groups depending on whether they were candidates or non-candidates for thrombolytic therapy. Patients were not considered thrombolytic candidates if they: (1) presented in cardiogenic shock. (2) were greater than or equal to 75 years of age. (3) had had coronary artery bypass surgery or. (4) had a reperfusion time of greater than 6 hours. Thrombolytic and nonthrombolytic candidates had similar rates of reperfusion (92 vs 88%). nonfatal reinfarction (6.0 vs 5.9%) and recurrent myocardial ischemia (1.8 vs 0%). Thrombolytic candidates had a lower mortality rate (3.9 vs 24%. p less than 0.0001) and a lower incidence of bleeding (4.6 vs 10.9%. p less than 0.05). Improvement in left ventricular ejection fraction at follow-up angiography was 4.4% in thrombolytic and 10.5% in nonthrombolytic candidates (p less than 0.002). Ejection fraction improved most in patients with anterior wall AMI (7.7% in thrombolytic candidates. 15.1% in nonthrombolytic candidates) and in patients with reperfusion times greater than 6 hours (14.2%). These outcomes suggest that direct coronary angioplasty is a viable alternative method of reperfusion in patients with AMI who are candidates for thrombolytic therapy. Nonthrombolytic candidates are a high-risk group of patients. Direct coronary angioplasty may be beneficial in certain subgroups. especially for patients in cardiogenic shock and for patients presenting greater than 6 hours after the onset of chest pain with evidence of ongoing ischemia.
Sequential esophageal motility studies after endoscopic injection sclerotherapy: a prospective investigation, To assess prospectively the effects of endoscopic intravariceal sclerosis (EIS) on esophageal function. we performed esophageal manometry on 13 cirrhotic patients before EIS. 24 h after the second session and 4 wk after the fourth session. EIS had no impact on lower esophageal sphincter pressure. However. a significant decrease in the amplitude of peristaltic waves was observed immediately post-EIS in the lower two-thirds of the esophagus. There was no modification of duration or velocity of progression of peristaltic waves. A four-fold increase in simultaneous contractions was observed early after EIS. These changes were reversible. as assessed by late esophageal testing after EIS. No correlations were demonstrated between esophageal motor parameters and doses of sclerosant. We conclude that sclerosant injection into the esophageal wall acutely impairs esophageal motility. but motor function is partially restored 4 wk after completion of EIS. suggesting that dysmotility is reversible.
Reduction in hepatic venous pressure gradient as a consequence of volume contraction due to chronic administration of spironolactone in patients with cirrhosis and no ascites, The effect of plasma volume contraction induced by a 4-wk administration of spironolactone or furosemide on the hepatic venous pressure gradient was evaluated in consecutively allocated patients with cirrhosis and no ascites. In the spironolactone group (n = 15). the hepatic venous pressure gradient decreased significantly (p less than 0.005). by 21.8%. with a significant contraction of circulating plasma volume (p less than 0.01). Although there were no statistically significant correlations between the change in hepatic venous pressure gradient and changes in circulating plasma volume or in simultaneously determined systemic hemodynamics. a significant negative correlation (r = -0.74. p less than 0.01. n = 12) between the hepatic venous pressure gradient change and the post-treatment plasma aldosterone levels was found. However. in the furosemide group (n = 10). the hepatic venous pressure gradient and circulating plasma volume did not significantly decrease. Our data demonstrated a significant reduction in the hepatic venous pressure gradient on a chronic administration of spironolactone. which may have been due to volume contractions in patients with cirrhosis and no ascites.
The combination of prednisone and colchicine in patients with primary sclerosing cholangitis, Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of the biliary tract. The cause of the disease is unknown. and no effective medical treatment exists. In this study. 12 patients received a combination of low-dose prednisone (10 mg/day) and colchicine (0.6 mg bid). Their course was compared with that of a group of concurrent historical controls. At 6 and 12 months. there was significantly more improvement in liver test results over baseline values in patients receiving prednisone and colchicine than in the untreated controls. At 24 months. however. no significant differences in biochemical tests were appreciated between treated and untreated patients. Analysis of serial liver biopsies showed no differences in histologic change in the two groups. During the 2 yr of follow-up. there were two deaths in the control group but none in the treated group. Four untreated patients developed ascites; gastrointestinal bleeding developed in three untreated patients. one of whom developed ascites. In contrast. in the treated group. ascites and bleeding developed in only one patient. We conclude that the combination of colchicine and prednisone does not retard histologic progression or progression of standard liver tests after 2 yr of therapy. There is a trend toward less clinical deterioration and improved survival after 2 yr of treatment. On the basis of these findings. we would not advocate empiric use of these drugs for patients with primary sclerosing cholangitis. but suggest that. if they are to be used at all in PSC. they be evaluated in a controlled clinical trial as treatment for this as yet incurable disease.
Modified Kraske approach for disease of the mid-rectum, A modification of Dr. Paul Kraske's approach for removal of mid-rectal lesions has been used in 11 patients from 1977 to 1988 by the senior authors. Patients ranged in age from 56 to 89 yr. with an average of 67 yr. There were seven male and four female patients. Indications for surgery were as follows: villous adenoma (seven). carcinoid (one). recurrent dysplasia in a previous endoscopic polypectomy site (one). positive distal margin for neoplasm following low anterior sigmoid resection (one). and adenocarcinoma in one elderly poor-risk patient. All lesions were in the middle rectum (7-11 cm from the anal verge. average 9 cm). The postoperative stay ranged from 6 to 12 days with a mean of 8 days. The average follow-up for the 11 patients is 3 1/2 yr (1 month to 7 yr). with only one patient having a local recurrent lesion. There was no morbidity or mortality. We conclude that this modification of the Kraske approach offers a good alternative for excision of mid-rectal lesions in terms of technical ease. efficacy. safety. and patient tolerance. The modified Kraske approach is indicated in certain situations and should be a part of the surgeon's armamentarium.
The effect of angiotensin-converting enzyme inhibition and dietary protein restriction in the treatment of proteinuria, Both angiotensin-converting enzyme inhibitors and dietary protein restriction have been reported to reduce urinary protein losses in patients with chronic glomerular diseases. We evaluated these two therapies in 12 such patients ingesting a constant metabolic diet containing 1.6 g protein/kg body weight per day. After a steady-state was achieved during a 3-week baseline period. patients were randomly assigned to either enalapril. titrated to reduce mean arterial pressure by 10 mm Hg. or an isocaloric 0.8 g/kg protein diet. Five patients in each group completed 3 additional weeks of observation during the treatment period. Enalapril resulted in an average reduction in urinary protein and albumin losses of 26% and 33%. respectively. without reducing creatinine clearance. Albumin synthesis was unchanged and nitrogen balance increased slightly (+142.8 +/- 85.7 mmol/d [+2.0 +/- 1.2 g/d]. P = 0.075). Dietary protein restriction had no consistent effect on proteinuria or albuminuria. whereas albumin synthesis (25.9 +/- 3.4 v 21.5 +/- 2.9 g/d/1.73 m2. P less than 0.05) and nitrogen balance (-135.6 +/- 92.8 mmol/d [-1.9 +/- 1.3 g/d]. P = 0.10) decreased. Both therapies resulted in a modest increase in plasma potassium concentration. Whether the maintenance of albumin synthesis in the presence of a reduction in urinary protein losses will convey a long-term advantage to treatment of proteinuric patients with angiotensin-converting enzyme inhibitors remains to be determined.
Preservation of renal reserve in chronic renal disease, Protein-induced increases in glomerular filtration rate (GFR). termed renal reserve. is said to be abrogated with the onset of renal disease. However. this notion is inconsistent with the results from animal studies which suggest that alterations in protein intake modulate the glomerular hemodynamics in experimental renal disease. Accordingly. 12 normal subjects and 15 patients with renal disease received a protein meal providing 1 g/kg body weight protein. The subjects were pretreated with either placebo or an angiotensin I converting enzyme inhibitor. enalapril. A significant (P less than 0.05) increase in inulin and para-aminohippurate (PAH) clearance was noted in normal subjects as well as in patients with renal disease. The increase in GFR over basal values in normal subjects (28 +/- 9%). patients with moderate renal failure (20 +/- 13%). and advanced renal failure (21 +/- 14%) was not different. Plasma renin activity was unchanged following protein meal in the placebo studies although it increased following enalapril administration. Enalapril pretreatment did not alter the glomerular vasodilation and hyperfiltration following protein meal. We conclude that protein meal induces glomerular hyperfiltration in renal disease and that this protein-induced hyperfiltration is not mediated by angiotensin II. Because glomerular hyperfiltration is implicated in the progression of renal disease. these data suggest that even in patients who have advanced renal failure. high-protein diets may exert a detrimental effect on the kidney.
Survival in patients with end-stage renal disease, Based on age and medical condition at the time of treatment. 138 patients beginning dialysis for treatment of chronic renal failure between January 1. 1984 and December 31. 1988. were classified into low. average. and high risk of death. The survival in these three groups was shown to be significantly different after as little as 6 months. The classification scheme is simple. and can be performed at the bedside. Efforts to monitor quality assurance in the dialysis unit must account for the significant differences in expected survival that reflect the case-mix observed in a particular unit.
Effect of a calcium-entry blocker, nicardipine, on intrarenal hemodynamics in essential hypertension, The effects of a calcium-entry blocker. nicardipine. on intrarenal hemodynamics were studied in essential hypertension. A 4-week study was performed in eight patients with essential hypertension who were given a regular sodium diet in the first and third weeks. and a sodium-restricted diet in the second and fourth weeks. Nicardipine. 60 mg/d. was administered in the third and fourth weeks. The urinary sodium excretion rate (UNaV) was plotted on the y-axis against the mean arterial pressure (MAP) on the x-axis before and after the administration of nicardipine. Assuming the difference between MAP and the x-intercept of this renal function curve represents the effective filtration pressure across the glomerular capillaries. the intrarenal hemodynamics such as afferent arteriolar resistance (RA) and efferent arteriolar resistances (RE). glomerular pressure (PG). and gross filtration coefficient (KFG) were calculated. Although the MAP on regular salt diet was lowered from 125 +/- 3 to 109 +/- 2 mm Hg by nicardipine. neither the renal blood flow rate (RBF) (670 +/- 40 mL/min) nor the glomerular filtration rate (GFR) (79 +/- 2 mL/min) was altered. The RA was estimated to be reduced from 9.300 +/- 900 to 7.400 +/- 700 dyne.s.cm-5 (P less than 0.01). while no changes were noted in RE (4.900 +/- 400 dyne.s.cm-5). PG (50 +/- 1 mm Hg). or KFG (0.180 +/- 0.041 [mL/s]/mm Hg). Essential hypertension has been characterized by a prominent increase in RA. resulting in maintenance of normal PG. This Ca-entry blocker worked to normalize intrarenal hemodynamics in essential hypertension by dilating afferent arterioles alone.
Chemical peritonitis secondary to intraperitoneal vancomycin, Although previously reported in the literature. the existence of chemical peritonitis due to vancomycin in patients on peritoneal dialysis remains controversial. We report four similar episodes of sterile peritonitis in three patients receiving intraperitoneal (IP) vancomycin. The prior report implicated a change in the brand of vancomycin preparation. from Vancocin to Vancoled. as a contributing factor. We noted the occurrence of such episodes following a switch from Vancocin to a generic preparation from Abbott Laboratories. High-performance liquid chromatographic (HPLC) profiles of the three preparations show Vancocin to have a lower level of impurities than the other two; the presence of certain contaminants in the other brands may be contributing to the clinical difference observed. We conclude that chemical peritonitis due to IP vancomycin administration does occur. and that increased awareness of this entity could allow other cases to be identified.
Twelve-year incidence of coronary heart disease in middle-aged adults during the era of hypertensive therapy: the Framingham offspring study [published erratum appears in Am J Med 1991 Apr;90(4):537, PURPOSE: To provide information on the incidence of coronary heart disease (CHD) in the offspring of the original cohort from the Framingham Heart Study. PATIENTS AND METHODS: From 1972 to 1974. offspring of the original participants in the Framingham Heart Study underwent a baseline examination for standard cardiovascular risk factors. At entry into the study. these offspring were 30 to 59 years old and free of CHD. They were followed for 12 years. during which time 156 of 1.663 men and 55 of 1.714 women developed CHD. RESULTS: In a multivariate proportional hazards model. CHD was significantly associated with age. lower high-density lipoprotein cholesterol (HDL-C) levels. and number of cigarettes smoked. Fasting glucose levels and low-density lipoprotein cholesterol (LDL-C) were highly associated with CHD in men. but borderline in women. while triglycerides and very-low-density lipoprotein cholesterol were not significantly associated with CHD after adjustment for HDL-C and glucose. Blood pressure medication was used in half of the hypertensive individuals. and systolic pressure was associated with CHD in women only. CONCLUSIONS: This study confirms the importance of the common CHD risk factors of cigarette smoking and LDL-C. and extends the prognostic role of HDL-C in a middle-aged cohort. The impact of blood pressure. with or without use of hypertensive medications. was reduced in this study. and the data suggest that this attenuation was due to successful treatment.
Infiltration of the lower respiratory tract by helper/inducer T lymphocytes in HTLV-1-associated adult T-cell leukemia/lymphoma, The human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL). a disorder in which peripheral blood and multiple organs are infiltrated by malignantly transformed T lymphocytes. We investigated the nature of pulmonary disease in a patient with serologic evidence of HTLV-1 infection. In this case. endobronchial biopsy specimens showed infiltration of the bronchial mucosa by pleomorphic cells exhibiting a high degree of nuclear irregularity. These cells were morphologically identical in appearance to malignant cells found in peripheral blood and infiltrating the dermis. expressed the OKT4/Leu3 phenotype and the receptor for interleukin 2. and. by analogy to gene rearrangement studies on leukemic blood cells. were monoclonal in origin. However. in situ hybridization of endobronchial biopsy specimens with full-length HTLV-1 probes failed to detect retroviral RNA or proviral DNA. These studies indicate that T lymphocytic involvement of the lower respiratory tract in HTLV-1-associated ATLL is characterized by expression of a malignant phenotype despite the inability to document actual cellular infection with this retrovirus by a molecular hybridization technique.
Furosemide-131I-hippuran renography after angiotensin-converting enzyme inhibition for the diagnosis of renovascular hypertension, PURPOSE: We have previously demonstrated the greater sensitivity of 131I-hippuran renography than 99mTC-DTPA scintigraphy to diagnose renovascular hypertension (RVH). This study assesses the predictive diagnostic value of furosemide-131I-hippuran renography after angiotensin-converting enzyme (ACE) inhibition in patients with and without RVH. PATIENTS AND METHODS: All patients were investigated at the University of Miami/Jackson Memorial Medical Center. Twenty-eight patients had RVH and 22 did not. Twenty-eight patients had normal or minimally decreased renal function (serum creatinine level 1.5 mg/dL or less) and 22 had renal insufficiency (serum creatinine level 1.8 mg/dL or more). Renography was performed 60 minutes after oral administration of 50 mg captopril or 10 minutes after intravenous injection of 40 micrograms/kg enalaprilat. Forty milligrams of furosemide were administered intravenously 2 minutes after injection of 131I-hippuran. The residual cortical activity (RCA) of 131I-hippuran was measured at 20 minutes. RESULTS: RVH was unlikely when RCA after ACE inhibition was less than 30% of peak cortical activity. Conversely. RVH was present when 131I-hippuran cortical activity steadily increased throughout the test to reach 100% at 20 minutes. In azotemic patients with RCA between 31% and 100%. RVH was differentiated from intrinsic renal disease by obtaining a baseline renogram without ACE inhibition and comparing RCA in that study and RCA after ACE inhibition. If RCA increased (indicating worsening renal function) after ACE inhibition. RVH was likely; whereas. intrinsic renal disease was more likely if RCA remained unchanged or decreased (indicating improved renal function) with ACE inhibition. The test had a specificity of 95% and a sensitivity of 96% in this population. There was a direct correlation between the results of angioplasty or surgery on high blood pressure and the changes in RCA before and after intervention (n = 20). CONCLUSION: Furosemide-131I-hippuran renography with ACE inhibition is highly predictive in identifying patients with RVH.
Infusion of a stable prostacyclin analogue, iloprost, to patients with peripheral vascular disease: lack of antiplatelet effect but risk of thromboembolism, PURPOSE: Prostacyclin. a potent inhibitor of platelet function and vasodilator. has been used to treat peripheral vascular disease. The aim of this study was to monitor the thrombotic status of patients treated by infusion of a stable prostacyclin analogue. iloprost. PATIENTS AND METHODS: Thirteen patients with peripheral vascular disease underwent iloprost infusion for 3 days (8 hours each day) in a dose ranging from 0.5 to 2 ng/kg/minute. Variable parameters of thrombosis such as platelet reactivity (shear-induced hemostatic plug formation and thrombus formation on a collagen fiber). coagulation. and spontaneous thrombolysis (dislodgment of hemostatic plugs) were measured from non-anticoagulated blood samples by hemostatometry immediately before and 1 hour after the infusion and on the last day. 4 hours after initiation of the infusion. RESULTS: Analysis of data from all patients 1 hour after the infusion showed no changes in platelet reactivity and spontaneous thrombolysis. but coagulation was significantly enhanced. In four patients. significant platelet hyperreactivity was observed after the infusion. Four of the five patients tested while undergoing iloprost infusion showed an enhanced thrombotic reaction and markedly enhanced coagulation. Iloprost employed in vitro in a concentration that corresponds to the therapeutic peak blood level caused no inhibition of platelet function but significantly enhanced coagulation. The threshold in vitro iloprost concentration at which anti-platelet effect and increased spontaneous thrombolysis were observed was twice that of the therapeutic blood level. CONCLUSIONS: These findings challenge the view that antagonism of platelet function is an important factor of iloprost therapy. Furthermore. platelet hyperreactivity in some patients and markedly enhanced coagulation during and after infusion of iloprost in general. represent a risk of thromboembolism. especially as patients are already in a prethrombotic condition.
Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus, PURPOSE: The goal of this study was to determine whether elevated serum levels of antibodies to ribosomal P proteins (anti-P antibodies) are associated with neuropsychiatric manifestations in patients with systemic lupus erythematosus (SLE). Additional experiments examined characteristics of these antibodies that might be associated with pathogenicity. PATIENTS AND METHODS: A large number of serum samples were collected from patients with SLE. control subjects with other rheumatic diseases. and normal individuals. At the time serum samples were obtained. patients with SLE were categorized according to the presence of psychosis. depression. and other manifestations of central nervous system (CNS) involvement. Serum anti-P antibody activity was quantitated by an enzyme-linked immunosorbent assay utilizing a synthetic peptide corresponding to the major P protein epitope. RESULTS: In a group of 79 normal individuals. mean (+/- SE) IgG anti-P activity was 0.01 +/- 0.003 and no individuals had values greater than 3 SD above the mean. Similar results were obtained measuring IgM anti-P activity. Normal levels were found in all sera from 21 patients with rheumatoid arthritis. Of 119 patients demonstrating various patterns of antinuclear and anticytoplasmic antibody activity. elevated anti-P levels were found only in patients with SLE. Overall. 19% of 269 patients with SLE demonstrated elevated levels of IgG or IgM anti-P antibodies. including 14% of 187 patients without and 29% of 82 patients with neuropsychiatric manifestations. The frequency of positive test results varied greatly depending on the nature of the CNS involvement. The frequency in patients with severe depression (n = 8) and psychosis (n = 29) was 88% and 45%. respectively. compared with only 9% in patients with nonpsychiatric neurologic disease (n = 45). For the entire SLE group. the odds ratio for the association of anti-P antibodies and severe psychiatric manifestations was 7.63 with a 95% confidence interval of 3.61 to 16.14. In a review of 187 patients with SLE originally classified as not having severe psychiatric disease. seven of 10 patients being treated with antidepressant medications had elevated levels of anti-P antibodies. In serial studies. the serum level of anti-P antibodies appeared to correlate with the activity of psychiatric disease and did not correlate with the activity of other manifestations of SLE. Anti-P antibodies in nearly all patients were IgG and directed primarily to the C-terminal 11 amino acids of the P protein. No difference in these characteristics was observed when patients with and without psychiatric manifestations were compared. Paired serum and cerebrospinal fluid (CSF) samples were also obtained from eight patients with active neuropsychiatric disease. Even when expressed as a fraction of the total IgG present. anti-P activity was markedly lower in CSF than in serum. CONCLUSIONS: Elevated levels of autoantibodies to the C-terminal region of ribosomal P proteins appear to be a specific marker for SLE. and are associated with both severe depression and psychosis in this disease. This assay is easily reproducible and may help distinguish SLE-induced psychiatric disease from that caused by other processes.
X-linked hypophosphatemia: skeletal mass in adults assessed by histomorphometry, computed tomography, and absorptiometry, PURPOSE AND PATIENTS AND METHODS: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets. yet its influence on skeletal mass in adulthood is controversial and incompletely characterized. Accordingly. we measured bone mass at several skeletal sites using histomorphometric and radiographic techniques in 19 adults (four men) with XLH (age range 20 to 66 years). Most subjects had not received medical therapy for XLH since puberty. RESULTS: Eight of 14 subjects who underwent transiliac bone biopsy had an elevated cancellous bone volume (osteoid and calcified bone). and the group's mean value was supranormal (p less than 0.01). Mineralized bone volume. however. was above normal in only three subjects (NS). Another measure of trabecular bone density. vertebral mineral density by computed tomography. was elevated in three of 13 subjects. and the mean value of the group was increased (p = 0.05). Integral spine bone mineral density (BMD) assessed by dual photon absorptiometry (DPA) was elevated in six of 16 subjects. and the mean was also above normal (p less than 0.01). However. total body calcium. total body BMD (both by DPA). and forearm bone mineral content assessed by single photon absorptiometry (predominantly cortical bone) were normal in almost all subjects. as were the group means for these parameters. Mean regional BMD (by DPA) was below normal in the upper and lower limbs (p less than 0.001) and above normal in the spine (p less than 0.005) and ribs (p less than 0.01). There was no relationship between these indices of bone mass and either biochemical or clinical parameters of disease severity. although men tended to have higher z-scores for axial bone density than premenopausal women whose values. in turn. tended to be higher than those in postmenopausal women (NS). CONCLUSION: We conclude that axial bone mass tends to be increased in adults with XLH. sometimes dramatically so. and this is only partially attributable to hyperosteoidosis. Peripheral bone mass. however. tends to be diminished. Despite these group trends. most adults with untreated XLH have normal indices of bone mass as assessed by a variety of techniques at the commonly used measurement sites. These findings suggest that "osteoporotic" fractures are unlikely to develop as a late complication of XLH in adults.
Effects of chronic alcohol intake on carbohydrate and lipid metabolism in subjects with type II (non-insulin-dependent) diabetes, PURPOSE: To study the effects of chronic alcohol intake on carbohydrate and lipid metabolism in subjects with non-insulin-dependent (type II) diabetes (NIDDM). To also evaluate the effect of alcohol withdrawal on metabolic control. PATIENTS AND METHODS: The study group consisted of 46 alcohol-consuming patients with NIDDM (NIDDM-B group). 35 non-alcohol-consuming patients with NIDDM (NIDDM group). and 40 normal control subjects. All patients were admitted to the hospital. Carbohydrate and lipid metabolism was assessed in these individuals immediately on admission to the hospital and during the following days. RESULTS: In the NIDDM-B group. blood alcohol (ethyl alcohol) concentration was very low. However. chronic alcohol intake was associated with higher fasting and postprandial glucose concentrations and higher hemoglobin A1c. No significant differences were found in C-peptide levels. Moreover. higher concentrations of 3-hydroxybutyrate and free fatty acids were observed in the NIDDM-B group than in the NIDDM group. No differences were found in triglyceride concentrations. acid-base patterns. or electrolyte levels. The metabolic effects of alcohol completely waned after 3 days of complete withdrawal. CONCLUSION: Chronic alcohol intake causes deterioration in metabolic control of persons with NIDDM. The effects induced by alcohol are completely reversed after a few days of withdrawal. Strict metabolic assessment is necessary when alcohol is an important constituent of the diet.
Association between hypothermia and mortality rate of premature infants--revisited, The incidence of hypothermia (axillary temperature less than 35 degrees C) on admission of an infant to a neonatal intensive care unit was retrospectively analyzed in 559 very-low-birth-weight (less than 1500 gm) newborn infants. The smaller infants were at greater risk of hypothermia. Only in the larger neonates was mortality related to hypothermia. which suggests that this known association bears little cause-effect relationship.
The accuracy of clinical findings and laparoscopy in pelvic inflammatory disease, The accuracy of clinical diagnosis for pelvic inflammatory disease was determined in 95 women who presented with pelvic pain to primary care physicians and then were referred to gynecologists. Laparoscopy or laparotomy with endometrial biopsy and fimbrial minibiopsy revealed that prevalence of pelvic inflammatory was 46% (44/95) and positive and negative predictive values of gynecologists were 74% (23/31) and 67% (43/64) (p = 0.0002). If histopathologic diagnosis was the standard. clinical accuracies of the gynecologists were no better than chance (p = 0.43). suggesting an expectation bias for visual diagnosis. Laparoscopy had a sensitivity of 50% (12/24) and a specificity of 80% (40/50) for salpingitis if the standard was fimbrial histopathologic diagnosis (p = 0.01). These results support the routine use of laparoscopy. supplemented when negative by endometrial and fimbrial minibiopsy. to accurately diagnose pelvic inflammatory disease.
Tables for estimation of individual risks of fetal neural tube and ventral wall defects, incorporating prior probability, maternal serum alpha-fetoprotein levels, and ultrasonographic examination results, Tables are provided for estimation of the risk of open spina bifida in patients who have elevated maternal serum alpha-fetoprotein levels but normal results on detailed anatomy ultrasonographic scan. Risks are provided for various prior population risks. for various levels of elevated maternal serum alpha-fetoprotein. and for various assumptions about the sensitivity of ultrasonographic examination. The formula used is based on sequential multiplication of odds with the use of Bayes' theorem. but an arbitrary reduction (to the power of 0.5) in the degree to which ultrasonographic information modifies the odds has been made to allow for the nonindependence of ultrasonography and maternal serum alpha-fetoprotein tests. The wide range of resulting risks shows that the decision to offer amniocentesis after a negative scan should be individualized.
Heterotopic pregnancies after in vitro fertilization and embryo transfer, Seventeen cases of heterotopic pregnancies are reported among 1648 clinical pregnancies after in vitro fertilization. The high prevalence of tubal damage among IVF patients and the use of superovulation and multiple embryo transfer might predispose patients to the condition. Nine patients reported abdominal pain and vaginal bleeding. five patients did not have symptoms. and three had acute abdominal emergencies. Transvaginal ultrasonography was superior to transabdominal ultrasonography in the diagnosis of extrauterine pregnancies. The presence of an intrauterine gestation sac in a patient without symptoms should not exclude the diagnosis of a concomitant extrauterine pregnancy until the pelvis is carefully visualized. Early diagnoses of viable ectopic pregnancies before rupture abolishes mortality and morbidity and offers the chance of patient selection for conservative treatment. In two patients the extrauterine gestation sac was treated by transvaginal aspiration and injection of potassium chloride under ultrasonographic guidance. The outcome of the intrauterine pregnancy was favorable regardless of the method of treatment of the ectopic pregnancy.
Forskolin and methotrexate induce an intermediate trophoblast phenotype in cultured human choriocarcinoma cells, The human placenta and its associated membranes are vital to the maintenance. nutrition. and protection of the developing fetus. During placental development some cytotrophoblasts give rise to the chorionic membrane whereas others fuse to form a differentiated syncytium of cells that are responsible for placental protein and steroid hormone production. The mechanisms involved in the differentiation of the trophoblasts are unknown; however. an intermediate stage with a characteristic phenotype has been documented in vivo. We have observed that chemically dissimilar xenobiotic agents induced BeWo choriocarcinoma cells to change their usual cytotrophoblastic phenotype and acquire morphologic and functional characteristics typical of intermediate trophoblast. Incubation of BeWo cell cultures in the presence of 1 mumol/L methotrexate for 48 hours stimulated human chorionic gonadotropin secretion (2.3-fold) and aromatase activity (4.9-fold). Morphologic findings associated with these hormonal changes. including increased nuclear size and cytoplasmic expansion. were also observed. With the use of a computer-interfaced image analyzer. planimetric morphometry of the nuclear area of the cells revealed a 1.8-fold increase after incubation with methotrexate. The effect of forskolin. a direct activator of adenylyl cyclase. was also evaluated by means of this model of cytotrophoblast differentiation. The addition of 10 mumol/L forskolin to BeWo cultures also resulted in dramatic changes in trophoblast cell phenotype. Increases in human chorionic gonadotropin synthesis (7.3-fold). aromatase activity (13.5-fold). and nuclear area (3.0-fold) were induced over those of untreated cells. In addition. increases in [3H]thymidine incorporation (1.7-fold) were afforded by both treatments. These results suggest that biochemical and cytologic changes associated with human trophoblast differentiation can be induced in vitro via activation of the adenylyl cyclase pathway by forskolin and through unknown and apparently independent signals by methotrexate.
Venous Doppler ultrasonography in the fetus with nonimmune hydrops, Eighteen pregnancies with nonimmune hydrops fetalis were referred for fetal echocardiography to rule out congenital heart disease. In 14 of these cases. pulsating blood velocities were recorded in the umbilical vein. which in a normal population had a nonpulsatile blood velocity pattern. The four cases without pulsations in the umbilical vein were found to have intrauterine viral infections. In the last 10 cases examined. the umbilical venous pulsations were found to reflect abnormal central venous pulsations during atrial systole suggesting increased fetal central venous pressure. Right ventricular shortening fraction was significantly decreased in the group with umbilical venous pulsations compared with those without (0.18 versus 0.32. p less than 0.05). All the fetuses without venous pulsations survived. but only four of the 14 with pulsations survived (p less than 0.05). The results suggest that blood velocity recordings in the umbilical and central veins of the fetus can give valuable clinical information with regard to the presence of fetal congestive heart failure and differentiate between this physiologic state and other causes of nonimmune hydrops fetalis. This may have implications for fetal diagnostic work-up and prognosis.
Endometrial thickness as measured by endovaginal ultrasonography for identifying endometrial abnormality, Diagnostic curettage has for many years been the method of choice to diagnose endometrial cancer in women with postmenopausal bleeding. The costs for curettage performed today are huge. and approximately only 10% in this group of women will be diagnosed with endometrial cancer. Thus less expansive techniques to obtain endometrial samples have been evaluated. but all of them are invasive. The value of endovaginal ultrasonography for identifying endometrial abnormality in this group of women has not been evaluated until now. This study used endometrial thickness as measured by endovaginal ultrasonography as an indicator of endometrial abnormality. It was demonstrated in 205 women with postmenopausal bleeding that if the endometrium was less than 9 mm thick. no endometrial cancer was found at curettage. The mean endometrial thickness in those women with endometrial cancer was 18.2 +/- 6.2 mm as compared with 3.4 +/- 1.2 mm in those women with atrophic endometrium. If the cutoff limit for endometrial abnormality was 5 mm. the positive predictive value for identifying endometrial abnormality was 87.3%. If this limit had been used in this study. 70% of the curettage procedures could have been avoided.
Fetal urine output does not influence residual amniotic fluid volume after premature rupture of membranes, Fetal urine production in 12 women with premature rupture of membranes did not differ from that of a control group. and there was no correlation between fetal urine output and residual amniotic fluid volume. Residual amniotic fluid volume after premature rupture of membranes does not appear to depend on or alter fetal renal function.
The diagnosis of ovarian cancer by pathologists: how often do diagnoses by contributing pathologists agree with a panel of gynecologic pathologists, The Cancer and Steroid Hormone Study. a multicenter. population-based. case-control study of ovarian. breast. and endometrial cancer in women 20 to 54 years of age. permitted the diagnoses of contributing pathologists to be compared with those of a panel of three gynecologic pathologists. A diagnosis of ovarian cancer was made by contributing pathologists on 477 subjects. Agreement between the two groups of pathologists was 97% for primary epithelial ovarian cancer and 89% for primary nonepithelial ovarian malignancies. Agreement on diagnosis of major cellular subtypes of ovarian malignancy ranged between 73% for endometrioid cancer and 100% for clear cell carcinomas. We conclude that the diagnosis of pathologic features of primary ovarian cancer is highly predictable. Nonetheless. diagnosis by histologic type varies sufficiently that a review process should be considered for clinical or investigative decisions involving specific histologic diagnoses of ovarian cancer.
Dissection of the cardinal ligament in radical hysterectomy for cervical cancer with emphasis on the lateral ligament, Surgical experience with carcinomas of the uterus and rectum has provided new insights into the surgical anatomy of a lamina. which separates the paravesical space from the pararectal space. It has been proved that each of the lamina consists of the cardinal and lateral ligaments and pelvic splanchnic nerves. descending in the following order. The cardinal and lateral ligaments. as a connective stalk. insert into the lateral walls of the uterus and rectum extending from the inner aspect of the pelvic wall. Clarification of this structural relationship led to the development of a new procedure for the dissection of the cardinal ligament in radical hysterectomy. while still preserving the lateral ligament. This facilitated systematic dissection of the cardinal and uterosacral ligaments with posterior manipulation. leading to a reduction in blood loss and to prevention of brisk bleeding from the venous plexuses.
Relationship of laparoscopic findings to self-report of pelvic pain, An assessment battery including standardized measures of behavioral and psychosocial factors associated with other chronic pain conditions was administered to 102 women scheduled for laparoscopic surgery. Surgeons who were blinded to the patient's self-reported pain data completed the American Fertility Society classification for endometriosis and adhesions on the basis of observed physical disease. Although American Fertility Society classification scores were significantly related to self-assignment into pain or no-pain groups. the extent of physical disease evaluated by this procedure was not significantly correlated with ratings of pain levels or a number of indexes of impairment. The group of patients with laparoscopically diagnosed pathologic conditions reported higher pain levels and greater interference than the group who reported pain and had negative laparoscopic results; however. some women with observable pathologic conditions reported no pain symptoms.
The clinical implications of subchorionic placental lucencies, Forty-six patients were identified at a perinatal diagnostic referral center as having subchorionic placental lucencies. These lucencies varied from simple to multicystic and covered up to 50% of the subchorionic placental surface. Clinical follow-up of 40 patients demonstrated no increase in the incidence of adverse pregnancy outcome. We conclude that these pregnancies are not at higher risk when the subchorionic placental lucencies are not associated with other intraplacental or fetal anomalies.
Leishmania mexicana complex: human infections in the Republic of Panama, Parasites of the genus Leishmania responsible for human cutaneous leishmaniasis in the New World form 2 major taxonomic divisions: the Leishmania braziliensis and the L. mexicana complexes. We report the isolation and characterization of the L. mexicana complex among humans in the Republic of Panama. Characterization was based on parasite morphology. pathogenesis in infected golden hamsters. cellulose acetate isoenzyme electrophoretic mobilities. and membrane-specific monoclonal antibodies using the radioimmune binding assay technique.
Infectivity of the subspecies of the Leishmania braziliensis complex in vivo and in vitro, The infectivity of Leishmania braziliensis ssp. in relation to their growth kinetics in Senekjie's medium was determined using the human macrophage cell line U937 and inbred hamsters. In both systems. infectivity was shown to be distinctive for each subspecies. While L. b. panamensis promastigotes from 6-day-old cultures (early stationary phase) were more infective than parasites from any other culture day. L. b. guyanensis and L. b. braziliensis reached maximum infectivity on days 8-10 and day 10 (late stationary phase of growth). respectively. Although maximum infectivity occurred during stationary growth. strict growth phase dependency was not observed. The populations of parasites on these culture days were composed mostly of small. highly motile promastigotes with flagella 2-3 times the length of their cell bodies. These promastigotes resembled the infective forms transmitted by the sand fly vector. A distinct pathological picture characterized the disease caused by the different WHO reference strains for these subspecies in hamsters: L. b. guyanensis developed the most severe lesions. while moderate and inconspicuous lesions were observed when L. b. panamensis and L. b. braziliensis. respectively. constituted the inocula.
An improved serodiagnostic procedure for visceral leishmaniasis, The enzyme-linked immunosorbent assay (ELISA) is a sensitive and specific serodiagnostic method for leishmaniasis. In this report. we describe how this versatile assay can be improved by the use of protein A or protein G conjugates for the specific detection of Leishmania antibody in the sera of patients with visceral leishmaniasis. In direct comparisons with anti-immunoglobulin conjugate. enzyme-linked protein A gave significantly higher absorbance values for positive sera without a corresponding increase in absorbance values for sera from normal individuals or from patients with other diseases known to cross-react with leishmaniasis. The effect was to increase the distance between positive and negative values. which aided in the interpretation of the results. This also permitted visual distinction between positive sera and negative or weakly reactive sera. The assay was effective using either blood or serum as the source of primary antibody. A further advantage of protein A over anti-Ig conjugate was its ability to detect specific antibody in dog as well as human sera. Finally. we demonstrated the usefulness of the protein A ELISA with a recombinant leishmania antigen. gp63.
Effects of multiple monthly doses of ivermectin on adult Onchocerca volvulus, This paper assesses the effects on adult Onchocerca volvulus of monthly doses of ivermectin (150 micrograms/kg) given over 4. 8. and 12 months to patients in Guatemala. Nodules were removed 4 months after the last dose; the adult O. volvulus were extracted by collagenase digestion. studied by histological techniques. and compared with worms from untreated patients. Twelve monthly doses killed a proportion of the adult worms (12% of males and 22% of females). leaving the remainder relatively unaffected and the females slowly resuming embryogenesis. After 8 and 12 doses. a number of female worms had resumed embryogenesis in 1 genital tract only. and in 1 female a total degeneration of 1 ovary was seen. Ivermectin also led to a marked drop in the number of male worms in nodules. No serious adverse reactions occurred and the treatment was well accepted.
Transmission of Rift Valley fever virus by adult mosquitoes after ingestion of virus as larvae [published erratum appears in Am J Trop Med Hyg 1991 Jun;44(6):580, We studied the ability of Culex pipiens. Aedes circumluteolus. and Ae. mcintoshi. exposed as larvae to liver tissue from a Rift Valley fever (RVF) virus-infected hamster. to become infected and transstadially transmit virus to the adult and for the adults to transmit virus by bite to hamsters. After exposure as larvae. 9% (5/54) of adult Cx. pipiens and 8% (38/505) of the adult Ae. (Neomelaniconion) species were infected. All of the infected Cx. pipiens and about half of the infected Ae. circumluteolus and Ae. mcintoshi tested transmitted RVF virus by bite to hamsters. Transmission rates for mosquitoes orally infected as larvae were higher than those for mosquitoes orally infected as adults. Animals infected with RVF virus may abort or die in the vicinity of mosquito larvae breeding habitats and infected tissue from these animals may contaminate the water.
Myocardial epinephrine sensitization with subanesthetic concentrations of halothane in dogs, The authors investigated myocardial epinephrine sensitization by subanesthetic concentrations of halothane. The dose-response relationship for the action of halothane was examined with etomidate plus varying subanesthetic concentrations of halothane in dogs. The arrhythmogenic threshold of epinephrine was decreased in a dose-dependent manner at end-tidal concentrations of halothane between 0.1 and 0.3%. At end-tidal halothane is greater than 0.3%. and no further reduction of arrhythmogenic threshold of epinephrine occurred. The plasma concentrations of epinephrine producing four or more premature ventricular contractions in 15 s were 201.3 +/- 34.3. 98.1 +/- 13.9. 60.3 +/- 8.63. 57.9 +/- 12.8. 54.5 +/- 8.61. and 53.9 +/- 4.86 ng/ml (mean +/- SEM). at 0. 0.1. 0.3. 0.5. 1.0. and 1.5% of halothane at end-tidal concentrations. respectively. The results suggest that in the presence of etomidate. halothane produces myocardial sensitization to epinephrine at subanesthetic concentrations as low as 0.1%. Increasing halothane to 0.3% produces a further reduction in the arrhythmogenic dose of epinephrine.
Protamine-heparin-induced pulmonary hypertension in pigs: effects of treatment with a thromboxane receptor antagonist on hemodynamics and coagulation, Adverse hemodynamic reactions after protamine neutralization of heparin are an infrequent but important clinical problem. Pre-treatment of swine with a thromboxane A2 receptor antagonist has been reported to prevent the pulmonary hypertensive response occasionally seen after protamine reversal of heparin anticoagulation. In the current study. a control group of pigs (n = 9) received intravenous heparin (300 IU/kg). followed after 10 min by a neutralizing dose of protamine (3 mg/kg). A treatment group of pigs (n = 11) was treated identically. except that the thromboxane A2 receptor antagonist L-670596 (2 mg/kg) was infused intravenously 2 min after the protamine infusion. Hemodynamic and coagulation profiles were monitored during these procedures. Pulmonary hypertension developed and reached a peak within 2 min of protamine administration. often at the same time that L-670596 was administered in the treatment group. There was no statistical difference between control and treatment groups' peak pulmonary arterial pressure and peak pulmonary vascular resistance. However. the interval for return of mean pulmonary artery pressure from peak to baseline values was 11.6 +/- 3.1 versus 5.5 +/- 1.9 min (mean +/- SD) for control and treatment groups. respectively (P less than 0.01). Thromboxane B2 plasma concentrations increased in both groups and were correlated with the pulmonary hypertensive response (r = 0.86. P less than 0.01). Platelet aggregation to collagen was inhibited by the thromboxane A2 receptor antagonist (P less than 0.05). Bleeding time was prolonged beyond normal range in 50% of L-670596-treated pigs. All other coagulation tests in both groups returned to baseline after reversal of heparin with protamine and were unaffected by L-670596.
Acute tolerance in morphine analgesia: continuous infusion and single injection in rats, This study aimed to determine whether the decline of the analgesic effect of morphine with a continuous infusion or that after a single injection correlates with the changes in brain concentration of morphine. The analgesic effect of morphine and its brain and serum concentrations were determined with a continuous 8-h infusion at a constant rate and after a single subcutaneous injection of the agent. The analgesic effect was determined by measuring the threshold of motor response to noxious stimulation. Brain and serum concentrations of morphine were detected by radioimmunoassay with the use of 125I-labeled morphine. With the constant-rate (4 mg.kg-1.h-1. intravenous) morphine infusion. the peak of analgesia could not be maintained: the increase in the pain threshold at 2 h was 1.003 g and at 8h was 286 g (a decrease in analgesia by 72%. P less than 0.0002). At the same time. the brain morphine concentration tended to increase. to 278 ng/g at 2 h and 329 ng/g at 8 h. After the single morphine injection (6 mg/kg. subcutaneous). recovery from analgesia occurred at a much faster rate than did the decrease in morphine brain concentration; the decrease in pain threshold was 79% at 90 vs. 30 min after the injection (P less than 0.0001). and the corresponding decrease in brain concentration was 28% (NS). The absence of correlation between analgesia and morphine brain concentration both with the constant-rate morphine infusion and after the single injection suggests the development of acute tolerance. which is pharmacodynamic in nature.
Double-blind comparison of oral transmucosal fentanyl citrate with oral meperidine, diazepam, and atropine as preanesthetic medication in children with congenital heart disease, The effectiveness of oral transmucosal fentanyl citrate (OTFC) as preanesthetic medication was compared with oral meperidine. diazepam. and atropine (MDA) in 40 pediatric patients scheduled to undergo repair of congenital heart defects. In a double-blinded manner. patients received a fentanyl lollipop (20-25 micrograms/kg) and a placebo oral solution (0.4 ml/kg) (n = 20) or a placebo lollipop and an oral solution (0.4 ml/kg) of meperidine (1.5 mg/kg). diazepam (0.2 mg/kg). and atropine (0.02 mg/kg) (n = 20). The patient's vital signs. systolic and diastolic blood pressures. heart rate. respiratory rate. and oxyhemoglobin saturation (SpO2). as well as activity and apprehension scores were evaluated and recorded at baseline and at 10-min intervals. The patient's emotional status at the time of parental separation and at induction of anesthesia were also assessed. Side effects and onset of action were observed. After OTFC. onset of sedation was significantly faster than with the oral solution of meperidine. diazepam. and atropine. In both groups there was no significant change in heart rate. Although systolic blood pressure. diastolic blood pressure. and respiratory rate showed statistically significant decreases. these changes were not clinically significant. The child's emotional status at the time of separation from the parents and during induction was similar in both groups. Side effects with OTFC were more frequent: nose itching occurred in 65%. body itching in 10%. and vomiting in 30%. Two patients (10%) in the OTFC-treated group became hypoxemic (SpO2 less than 90) and required supplemental oxygen. In the group receiving oral meperidine. diazepam. and atropine. 10% had mild facial pruritus and 5% complained of a dry mouth.
Effect of systemic medetomidine, an alpha 2 adrenoceptor agonist, on experimental pain in humans, The effect of systemic (intravenous) medetomidine. an alpha-2 adrenoceptor agonist. on pain thresholds was studied in healthy human subjects (n = 6). Medetomidine produced a dose-dependent (cumulative doses: 25 and 50 micrograms) sedative effect evaluated by visual analog scale. Also. a dose-dependent decrease of blood pressure but not of heart rate was seen after administration of medetomidine. Pain threshold to electric stimulation of the tooth pulp and cutaneous heat pain threshold were uninfluenced by medetomidine. An index of cutaneous thermal sensitivity to innocuous stimuli. the width of the thermoneutral zone. also was uninfluenced by medetomidine. Medetomidine produced a significant attenuation of the affective-motivational component (unpleasantness) of tourniquet-induced ischemic pain. whereas the sensory-discriminative component (pain magnitude estimate) of the ischemic pain was not attenuated. The results suggest that systemic medetomidine alone at subanesthetic but sedative and hypotensive doses does not significantly influence the intensity and thresholds of experimental pain. whereas the affective-motivational component of pain can be attenuated.
Coronary and left ventricular hemodynamic responses following reversal of flunitrazepam-induced sedation with flumazenil in patients with coronary artery disease, The effects of reversal of flunitrazepam-induced sedation with flumazenil on coronary hemodynamics. myocardial oxygen consumption (MVO2). and left ventricular (LV) performance were investigated. in a double-blind trial. in 12 patients with stable coronary artery disease undergoing cardiac catheterization. Coronary sinus blood flow was measured by continuous thermodilution. Arterial and coronary sinus blood were analyzed for oxygen and lactate contents. The determinants of LV performance were obtained from the cardiac output measured by thermodilution and from left heart catheterization data. To reverse flunitrazepam-induced sedation. patients were randomly allocated to receive placebo or flumazenil (by increment. up to 1 mg) at the end of procedure. In the placebo group. no significant hemodynamic changes were observed. In the flumazenil group. heart rate. cardiac index. maximum velocity of shortening. and relaxation time constant were not significantly altered. By contrast. mean aortic pressure and LV end-diastolic pressure (baselines: 90 +/- 5 and 7.3 +/- 4.1 mmHg. respectively) increased (9%. P less than 0.05 and 67%. P less than 0.05. respectively) after flumazenil administration. but these changes represented mainly a return toward presedation values. MVO2 and coronary resistance were not significantly altered. whereas CSBF increased slightly (baseline: 119 +/- 20 ml/min; increase 10%. P less than 0.05). No electrocardiographic evidence of myocardial ischemia was observed during the study. These data show that reversal of benzodiazepine effects with flumazenil is not associated with a major alteration of LV systolic function. relaxation. or coronary hemodynamics in patients with coronary artery disease. Nevertheless. it should be cautiously used when LV end-diastolic pressure is increased at the time of its administration.
The effect of inhaled corticosteroids on the maximal degree of airway narrowing to methacholine in asthmatic subjects, Airway hyperresponsiveness in asthma is characterized by an increase in sensitivity and in maximal response to airway-narrowing stimuli. Long-term therapy with inhaled corticosteroids is known to reduce airway hypersensitivity in asthmatic patients. To investigate whether these drugs also reduce the maximal degree of airway narrowing we studied the effects of inhaled budesonide on the maximal response plateau of the dose-response curve to inhaled methacholine in mildly asthmatic patients in whom a raised plateau could be measured. Sixteen atopic patients with mild asthma were placed randomly into two parallel treatment groups to receive double-blindly either budesonide (400 micrograms twice daily) or placebo. inhaled via a Turbuhaler. for 4 wk. Before treatment. after 2 and 4 wk of treatment. and after 2 and 4 wk of wash-out. complete dose-response curves to methacholine were obtained using a standardized 2-min tidal breathing method. The response was measured by FEV1. expressed in % fall from baseline. A plateau on the log dose-response curve was considered if three or more data points fell within a 5% response range. The maximal response was obtained by averaging the values on the plateau (MFEV1). and the sensitivity was calculated from the provocative concentration of methacholine. causing a 20% fall in FEV1 (PC20). After 4 wk of budesonide treatment. mean MFEV1 decreased from 41.6 to 33.7% fall (p = 0.0004). The changes in MFEV1 were significantly different between placebo and budesonide (p = 0.03). The geometric mean PC20 increased from 3.4 to 6.3 mg/ml (p = 0.02). but the changes in PC20 were not different between the two groups (p = 0.23).
Morphometry of the airways during late responses to antigen challenge in the rat, To quantitate the structural changes in the airways that contribute to the late bronchial response (LR) to antigen challenge we killed six Brown-Norway rats. sensitized to ovalbumin (OA) and challenged by aerosol. during the LR and compared the dimensions of the intraparenchymal airways with those of six control animals. Lungs were rapidly frozen with liquid nitrogen and fixed in Carnoy's solution. Paraffin sections were stained with hematoxylin-phloxine-saffron. At the time of the LR (382 +/- 39 min after OA challenge). RL increased from the baseline value (0.067 +/- 0.034 cm H2O.ml-1.s) by 0.107 +/- 0.03 cm H2O.ml-1.s (p less than 0.05). RL did not change significantly in the control rats. The lumen size and the wall area of all membranous airways were measured and were corrected for airway size by dividing by the basement membrane length squared (BM2). There was no increase in airway wall area in OA-challenged animals. However. the lumen of large airways (BM: 2.0 to 2.99 mm) was significantly less for the OA-challenged animals (0.039 +/- 0.0055 mm2) than for the control animals (0.058 +/- 0.0063 mm2; p less than 0.05). In six additional rats. the distribution of mast cells (MC) in the bronchial tree was determined. Tissues were fixed with Carnoy's solution and stained with a modified May-Grunwald-Giemsa stain. There were significantly more MC in the large airways than in medial or small airways. We conclude that smooth muscle constriction of large airways and not airway wall edema accounts for the LR in the rat. The distribution of the mast cells corresponds closely to the site of bronchoconstriction.
Morphometry of the subepithelial circulation in sheep airways. Effect of vascular congestion, In order to quantitate the subepithelial microvascular volume and its relation to the airway lumen. we conducted a morphometric analysis of the vascular compartment in the wall of the trachea (within a 55-microns depth from the epithelial basement membrane) and of 1.0 and 0.5-mm bronchioles of sheep. The lungs were fixed by bronchial and pulmonary artery perfusion with glutaraldehyde under three experimental conditions: (1) bronchial artery pressure. 100 mm Hg pulmonary artery pressure. 20 mm Hg (control); (2) bronchial artery pressure. 100 mm Hg. pulmonary artery pressure. 40 mm Hg (pulmonary hypertension. PH); (3) bronchial artery pressure. 100 mm Hg. pulmonary artery pressure. 40 mm Hg (pharmacologic vasodilation with sodium nitroprusside. PH + V). Venous pressures were atmospheric. Under control conditions. the microvascular volume fraction comprised 12. 16. and 15% of the subepithelial tissue in the trachea and 1-mm and 0.5-mm bronchioles. respectively. PH increased the microvascular volume fraction in the bronchioles (p less than 0.05). but it had no effect on the microvasculature in the trachea. PH + V approximately doubled the microvascular volume fraction in the trachea and the bronchioles. PH increased the mean wall thickness. and PH and PH + V decreased the airway cross-sectional area in the 1-mm bronchioles. These observations demonstrate that the microvasculature constitutes a considerable volume fraction of the subepithelial airway tissue and that vascular congestion can narrow the bronchiolar lumen.
Methotrexate-induced asthma, A patient with rheumatoid arthritis developed pulmonary symptoms and function test abnormalities consistent with asthma during methotrexate therapy. Assessments of airway responsiveness to methacholine during therapy revealed airway hyperreactivity that reverted to normal when the methotrexate was stopped. An extension of the methotrexate dosage interval from 7 to 10 days resulted in an abolition of the asthma. which remained in remission despite a return to a weekly cycle after a 3-month period of 10-day cycles.
Prognosis of idiopathic pulmonary fibrosis in patients with mucous hypersecretion, In order to determine the prognosis of patients with chronic idiopathic pulmonary fibrosis (IPF). we evaluated clinical. laboratory. and bronchoalveolar lavage (BAL) data at the onset of IPF in 25 patients who survived beyond 1 yr (nine women and 16 men. 59 +/- 3 yr of age. mean +/- SE). When the patients were divided into two groups according to whether they had or did not have mucous hypersecretion. 11 patients with hypersecretion (Group A) had a poorer survival rate (6 yr) than did 14 patients without hypersecretion (Group B) (10 yr) (p less than 0.01). Further. there was a significant negative correlation between sputum volume and the duration of survival in 25 patients (r = -0.55. p less than 0.01). Before glucocorticoid treatment. we also found significantly larger numbers of neutrophils (17%) and eosinophils (5%) in differential cell counts of bronchoalveolar lavage fluid (BALF) in Group A than in Group B (neutrophils. 1%; eosinophils. 0.6%) (p less than 0.05 each). Chest radiographic findings and other laboratory data including pulmonary function tests did not correlate with the survival rate. These findings suggest that mucous hypersecretion as well as neutrophils and eosinophils in BALF are among the determinants of prognosis in patients with chronic IPF.
Estimating left ventricular filling pressure during positive end-expiratory pressure in humans, In the critically ill. accurate measurements of left ventricular (LV) filling pressure using pulmonary artery occlusion pressure (Ppao) are important for diagnostic and therapeutic purposes. In patients receiving positive end-expiratory pressure (PEEP). Ppao may not reflect LV filling pressure because of elevated pericardial pressure (Ppc). It has been proposed that in humans. Ppc and right atrial pressure (PRA) are equal. so that referencing Ppao to PRA may improve the assessment of LV filling pressure when Ppc is elevated. Similarly. it has also been shown in the dog that nadir Ppao immediately after airway disconnection from PEEP (nadir Ppao). accurately reflects LV filling pressure when LV filling pressure is greater than or equal to 10 mm Hg. We examined methods of estimating LV filling pressure using Ppao measurements under conditions in which increases in Ppc were the primary determinants of differences in the two measurements. Using left atrial pressure (PLA) relative to Ppc. called transmural PLA (PLAtm). as LV filling pressure. we compared the accuracy of Ppao. nadir Ppao. and Ppao relative to PRA to reflect PLAtm in 15 postoperative cardiac surgery patients in whom an air-filled pericardial balloon catheter and a left atrial catheter were inserted during surgery. PEEP was sequentially increased from zero to 15 cm H2O. We found that PRA always exceeded Ppc (p less than 0.01) and increased less with PEEP than did Ppc (p less than 0.05). At less than or equal to 5 cm H2O PEEP. both Ppao and nadir Ppao were similar to each other and to PLAtm.
Endothelium-derived relaxing factor inhibits hypoxic pulmonary vasoconstriction in rats, The hypothesis that endothelium-derived relaxing factor (EDRF) modulates hypoxic pulmonary vasoconstriction (HPV) was tested in isolated. blood-perfused rat lungs ventilated with gas mixtures of 21% O2-5% CO2-74% N2 (normoxia) or of 3% O2-5% CO2-92% N2 (hypoxia); 30 microM NG-monomethyl-L-arginine (L-NMMA). an inhibitor of EDRF production. caused a reduction in the endothelium-dependent relaxant response to acetylcholine (ACh) from 62 +/- 7. 88 +/- 4. and 100 +/- 4% to 26 +/- 8. 49 +/- 12. and 75 +/- 7% at ACh concentrations of 1. 10. and 100 microM. respectively (p less than 0.05 at all concentrations). indicating that L-NMMA acts via the inhibition of EDRF production. L-NMMA induced a concentration-related augmentation in HPV of 20 +/- 5. 32 +/- 8. and 34 +/- 8% at concentrations of 30. 300. and 1.000 microM (p less than 0.05. compared with a vehicle control group at all concentrations). The pressor response to a dose of angiotensin II (A-II). which produced the same increase in pulmonary artery pressure as that induced by hypoxia. was also significantly augmented (2 +/- 0.6%). but to a lesser extent. The augmentation of HPV by 30 microM L-NMMA was completely reversed by 1 mM L-arginine (a precursor of EDRF). but not by D-arginine (an isomer of L-arginine). One and 6 mM L-arginine. but not 6 mM D-arginine caused a significant inhibition of HPV by 20 +/- 2 and 47 +/- 12% (p less than 0.05. compared with the vehicle control group) and a small but not significant reduction in A-II-mediated contraction.
Serum and lavage lactate dehydrogenase isoenzymes in pulmonary alveolar proteinosis, Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of lipoproteinaceous material in the alveolar space. Serum lactate dehydrogenase (LDH) has been noted to be elevated in patients with PAP in previous studies. We sought to extend this observation in a series of patients with PAP by looking at total serum LDH concentrations and LDH isoenzyme fractions measured before and after whole lung lavage. Total LDH and LDH isoenzymes were also determined in the lavage effluent. Total serum LDH was elevated before lavage in 10 of 16 patients. Prelavage serum LDH and prelavage alveolar-arterial O2 gradient showed a significant correlation (r = 0.62. p less than 0.05). A decrease in serum LDH was found after lavage in all patients in whom postlavage data was available (paired t test. p less than 0.01. n = 11). although the magnitude of this decrease varied considerably. The isoenzyme pattern before lavage was isomorphic. and this pattern was unchanged after whole lung lavage. This was in marked contrast to the LDH isoenzyme pattern observed in the lavage effluent. which showed a lower percent LDH1 and LDH2 and a higher percent LDH3. LDH4. and LDH5 when compared with the corresponding prelavage isoenzyme percentages for serum (unpaired t test. p less than 0.001). There was no correlation between the total serum LDH concentration and the total lavage LDH concentration. These data confirm that elevated serum LDH is a common finding in PAP. Furthermore. the LDH elevation found consistently in the alveolar fluid points to this as the source of the serum LDH.
Comparison of lung alveolar and tissue cells in silica-induced inflammation, The silicon dioxide mineral. cristobalite (CRS) induces inflammation involving both alveolar cells and connective tissue compartments. In this study. we compared lung cells recovered by whole lung lavage and by digestion of lung tissue from rats at varying times after 8 days of exposure to aerosolized CRS. Control and exposed rats were examined between 2 and 36 wk after exposure. Lavaged cells were obtained by bronchoalveolar lavage with phosphate-buffered saline. Lung wall cells were prepared via collagenase digestion of lung tissue slices. Cells from lavage and lung wall were separated by Percoll density centrifugation. The three upper fractions. containing mostly macrophages. were cultured. and the conditioned medium was assayed for effect on lung fibroblast growth and for activity of the lysosomal enzyme. N-acetyl-beta-D-glucosaminidase. Results demonstrated that the cells separated from the lung walls exhibited different reaction patterns compared with those cells recovered by lavage. The lung wall cells exhibited a progressive increase in the number of macrophages and lymphocytes compared with a steady state in cells of the lung lavage. This increase in macrophages apparently was due to low density cells. which showed features of silica exposure. Secretion of a fibroblast-stimulating factor was consistently high by lung wall macrophages. whereas lung lavage macrophages showed inconsistent variations. The secretion of NAG was increased in lung lavage macrophages. but decreased at most observation times in lung wall macrophages. No differences were found among cells in the different density fractions regarding fibroblast stimulation and enzyme secretion.
Prevalence of Mycobacterium avium complex in respiratory specimens from AIDS and non-AIDS patients in a San Francisco hospital, Over the past several years there has been a large increase in the recovery of Mycobacterium avium complex (MAC) isolates from respiratory specimens submitted to the clinical laboratory at San Francisco General Hospital (SFGH). This increase in MAC recovery correlates with an increase in the number of cases of acquired immunodeficiency syndrome (AIDS) in the community. Although it is well known that MAC is often isolated from patients with AIDS. the isolation of MAC from respiratory specimens is often attributed to contamination of the specimen with MAC organisms present in the environment. To determine whether the increase in MAC isolates recovered at SFGH was due to an increase in environmental contamination of specimens or to the increase in our AIDS patient population. we conducted a study of the prevalence of MAC in respiratory specimens from AIDS versus non-AIDS patients. Results of specimens submitted to the clinical laboratory at SFGH for culture of mycobacteria were reviewed over a 12-yr period. from 1977 through 1988. The prevalence of MAC in respiratory specimens from AIDS and non-AIDS patients was determined for 4 yr during this period: the pre-AIDS year 1977; the first year AIDS was reported in San Francisco. 1981; 1984; and 1987. In 1977 and 1981 the prevalence of MAC in respiratory specimens was less than or equal to 0.5%. and all MAC isolates were recovered from non-AIDS patients. In 1984 the prevalence of MAC in respiratory specimens for AIDS and non-AIDS patients was 6.5 and 0.3%. respectively. and in 1987. 8.8 and 0.3%. respectively.
Inspiratory muscle performance and pulmonary function changes in insulin-dependent diabetes mellitus, The study examined pulmonary function parameters of 36 patients with insulin-dependent diabetes mellitus and analyzed their inspiratory muscle performance. The control group consisted of 40 healthy reference persons of a sex ratio. age. height. and weight distribution similar to those of the patients. The pulmonary function test included the measurement of the lung volumes and the maximal expiratory flow-volume curves. The values of maximal sniff esophageal (Pes) and transdiaphragmatic pressures (Pdi) were used as parameters for global inspiratory muscle strength and diaphragm strength. respectively. The 12-s maximum voluntary ventilation (MVV) test supplied the parameter of inspiratory muscle endurance. The diabetic patients showed a highly significant decreased value for their inspiratory vital capacity (VCin) compared with that of the control subjects (4.75 +/- 0.84 versus 5.36 +/- 1.37 L; p less than 0.01). Inspiratory muscle performance in the diabetic patients was also restricted. Sniff Pes was significantly lower in the diabetic group (p less than 0.05); sniff Pdi (p less than 0.01) and MVV (p less than 0.05) were also low. The results did not correlate with either the duration of diabetes or the quality of metabolic control measured by glycosylated hemoglobin concentration. The reduction of VCin in diabetic patients may have been caused partly by the reduced capacity of the inspiratory muscles.
The elusive colonic malignancy. A need for definitive preoperative localization, Colonoscopy with biopsy is the standard of practice for the diagnosis of colonic malignancies. Unfortunately. the inability of endoscopy to obtain precise distance measurements from the anal verge can make localization of lesions at operation difficult. For this reason. preoperative barium enema or intraoperative colonoscopy have been advocated to further pinpoint the sites of those lesions not thought to be easily located at operation. Five patients are presented in whom malignant lesions of the colon were diagnosed and verified histologically. but were later undetectable at operation or subsequent colonoscopic examinations. Four of these patients underwent laparotomy and three received colon resections. None of these patients' tumors were identified during intraoperative colonoscopy. in the resected bowel on pathologic examination. or on follow-up colonoscopy. A fifth patient is presented who spontaneously passed a polyp containing invasive adenocarcinoma. but multiple colonoscopic examinations have failed to identify the site of the lesion. To date. none of these tumors have recurred with periods of follow-up ranging from 6 months to 2 years. These patients demonstrate a poorly documented and little understood aspect of the behavior of colonic malignancies. i.e.. the ability to spontaneously regress or slough from the bowel wall. Based on these instances. localization of potentially malignant colon lesions is recommended with submucosal dye injections at initial endoscopy or with colonoscopy in the operating room immediately prior to operation.
Emergency center laboratory evaluation of pediatric trauma victims, Emergency center (ER) trauma evaluations often include leukocyte count (LC). serum amylase (SA). electrolytes (EL). and urine analysis. We reviewed records of 100 pediatric ER patients to determine utility of these tests in management of blunt injury. SA was evaluated in 65 patients and ranged from 30-146 U/L (mean 50.6 U/L); 14 patients with normal CT scans had SA from 30-68 U/L (mean 49.1 U/L). Six patients with intraabdominal or retroperitoneal injuries had SA from 30-130 U/L (mean 64.0 U/L). P = NS. LC was determined in 76 patients and ranged 2.3-28.3 k/ml (mean 13.8 k/ml). Patients with normal abdominal CT (12) had mean LC 14.8 k/ml (range 7.2-19.6 k/ml). Eight patients with injuries on CT had mean LC 14.4 k/ml (range 3.5-27.1 k/ml). ER. SA. and LC did not alter patient management. Thirty-four patients had serum sodium. 36 potassium. and 33 chloride and bicarbonate determinations. Sodium. potassium. and chloride levels were uniformly normal; bicarbonate and leukocyte counts were uniformly abnormal in initial evaluations. These changes are expected in response to severe injury and their determinations did not alter patient care. Combined laboratory urinarlysis (LA) and urine dipstick (DA) analysis for hematuria had sensitivity 75.0 per cent (specificity 81.6%). LA predicted injury with sensitivity 75.0 per cent (specificity 81.6%). DA predicted injury with sensitivity 60.0 per cent (specificity 79.2%). DA accurately represented LA results (sensitivity 100%. specificity of 94.5%). DA is a rapid and effective replacement of LA in evaluation of trauma patients in the emergency center.
The pathology of nonpalpable breast cancer, A principal goal of mammographic screening is the early detection of breast cancer. We reviewed records of 125 women who were referred because of nonpalpable. suspicious abnormalities on mammogram. which subsequently proved to be cancer. requiring mammographic localization biopsy and subsequent surgery for therapy. We found that 72 (57.6%) had invasive tumors. 15 (12%) showed evidence of microinvasion and 38 (30.4%) were noninvasive. A total of 115 patients had lymphadenectomy as part of their definitive surgery. Nine (12.7%) of the patients with infiltrating tumors had between one and 10 malignant nodes on histologic section. None of the patients with noninvasive or microinvasive tumors were found to have involved nodes. The mammographic abnormalities which led to biopsy in our series were: calcifications in 74 (59.2%) patients. mass lesions in 39 (31.2%). mass lesions with calcifications in 11 (8.8%). and asymmetry in one (0.8%). Of the nine patients with nodal metastases. seven (77.8%) had a mass with or without calcifications as the indication for biopsy. Increasing tumor size was found to correlate with invasive tumors on histopathologic examination and the incidence of lymph node metastases. Thirty-seven (54.4%) of the patients with infiltrating tumors had a tumor size greater than 1 cm. Further. seven (77.8%) of the nine lymph node positive patients had tumors between 1 and 3 cm in size. Of note. however. is that two (22.2%) patients with microscopic tumors had involved nodes. The 4-year actuarial survival in patients with infiltrating tumors was 85.2 per cent. while that for patients with noninvasive or microinvasive tumors was 100 per cent (median follow-up of 20 months).
The importance of intraoperative cholangiography during laparoscopic cholecystectomy, Laparoscopic cholecystectomy (LC) using electrocoagulation was successfully performed in 56 out of 58 selected patients. Cholangiography was performed in 53 patients. Six patients had common duct stones; five were unsuspected preoperatively. After the gallbladder was removed. three patients underwent open common duct exploration. In another five cases. anatomical anomalies were discovered. Cholangiography performed via the cystic duct before any structures are divided can prevent the most serious complication--common duct injury. Cholangiography should be attempted on all patients undergoing LC.
Inguinal hernia complicating flexible sigmoidoscopy, Flexible sigmoidoscopy has become part of routine preoperative workup for patients over the age of fifty who present with an inguinal hernia. A recent experience with two patients with a left inguinal hernia allowing sigmoid colon to herniate into the scrotum bring awareness of the possibility for an increased risk of perforation of the sigmoid colon during flexible sigmoidoscopy. or possible iatrogenic incarceration of the hernia. These cases are presented so this clinical entity can be recognized and the complications prevented.
Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption, The intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor to three patients with leukemia who were receiving marrow aplasia-inducing chemotherapy resulted in the development of wide-spread erythematous macules and papules. The course of the eruption paralleled the time of infusion of the granulocyte-macrophage colony-stimulating factor. Skin biopsy specimens taken from two of the eruptions displayed characteristic changes consisting of a variable mixture of granulocytes and lymphocytes. increased number and size of dermal macrophages. mild to moderate epidermal exocytosis. intercellular edema. and rare dyskeratotic keratinocytes. Immunophenotypic analysis of one specimen was notable for keratinocyte intercellular adhesion molecule-1 expression. Administration of the recombinant human cytokine in pharmacologic doses is postulated to induce changes in the immunologic status of the skin. resulting in the expression of a cutaneous eruption.
Intraepithelial anchoring fibril components, Cultured human keratinocytes and cultured human cervical carcinoma cells (ME-180) contained intracellular pools of antigens that reacted with the anchoring fibril antibodies AF1 and AF2. In keratinocytes. these antigens formed a basement membrane-like structure near the apical portions of the cells. Using flow cytometric techniques. pretreatment of the ME-180 cells with acetone revealed large intracellular pools of antigen. The intracellular epitope was calcium sensitive. Some forms of recessive dystrophic epidermolysis bullosa have retention of intracellular portions of the anchoring fibril suggesting a relation of the intracellular anchoring fibril antigens to that disease.
Ultrastructural localization of calcium in psoriatic and normal human epidermis, With ion capture cytochemistry. we previously demonstrated the distribution of calcium ions in murine epidermis. a pattern consistent with a role for this ion in the regulation of epidermal differentiation. Because of the known proliferation and differentiation defects in psoriasis. we compared the calcium distribution of involved vs uninvolved psoriatic lesions and normal human epidermis. Whereas normal human and uninvolved psoriatic epidermis revealed increased calcium-containing precipitates in the uppermost stratum granulosum. in contrast the basal layer of psoriatic lesions contained less extracellular calcium. a condition that favored enhanced proliferation. Moreover. all psoriatic suprabasal cell layers displayed heavier than normal concentrations of calcium. indicating loss of the normal calcium gradient that programs terminal differentiation. This abnormal profile may account for the differentiation defects (eg. parakeratosis) that occur in psoriasis. Finally. psoriatic lesions displayed retained ionic Ca in intercellular domains of the upper stratum granulosum with absence of normal intercellular bilayers. findings that may underlie the abnormal desquamation and permeability barrier in psoriasis.
Fibrin- and fibrinogen-related antigens in patients with venous disease and venous ulceration, Abnormalities in systemic fibrinolysis have been implicated in the pathogenesis of venous ulceration. Patients with venous disease have a prolonged euglobulin lysis time and elevated plasma fibrinogen levels. yet little is known about the metabolism of fibrinogen and fibrin in such patients. In this study. we have used a technique that involves electrophoresis and densitometric analysis of captured fibrin-related antigens to measure the concentration and proportions of the individual fibrin and fibrinogen degradation products in patients with venous disease of the lower extremity. As a group. patients with venous disease had markedly elevated levels of total fibrin-related antigen and D-dimer. the terminal degradation product of cross-linked fibrin. Levels of D-monomer. the breakdown product of fibrinogen and non-cross-linked fibrin monomer. and a measure of fibrinogenolysis were normal in all patients. In patients with ulcers. the levels of D-dimer were disproportionately higher than expected from fibrin monomer levels. On an individual basis. significant elevations of D-dimer were present in six (55%) of the 11 patients with venous disease with ulcers and in three (43%) of the seven patients with venous disease without ulcers. We conclude that patients with venous disease have uniform evidence for enhanced fibrin formation. as evidenced by elevated levels of total fibrin-related antigen and D-dimer. This is regardless of whether the venous disease is accompanied by ulceration.
Familial multiple desmoplastic trichoepitheliomas, A kindred with familial multiple desmoplastic trichoepitheliomas is described. Desmoplastic trichoepitheliomas should be added to the group of lesions that indicate an inherited pattern when they occur as multiple primary tumors. The implications for nosologic status and treatment of desmoplastic trichoepitheliomas are considered.
Papuloerythroderma. Another case of a new disease, We describe a case of papuloerythroderma. This is a distinctive clinical entity characterized by pruritus. red-brown flat-topped papules exhibiting the "deck-chair" sign. eosinophilia. and lymphopenia. We propose that the Langerhans cell may have a central role in the pathogenesis of papuloerthroderma and we describe an excellent response to photochemotherapy.
In vivo ultraviolet irradiation of human skin results in profound perturbation of the immune system. Relevance to ultraviolet-induced skin cancer [published erratum appears in Arch Dermatol 1991 Sep;127(9):1368, Ultraviolet exposure of human skin deletes the function of antigen-presenting Langerhans cells normally resident within the epidermis. Langerhans cells are capable of activating T-lymphocytes by presenting antigens (such as nickel or tumor antigens) to T-lymphocytes. Such activated T-lymphocytes may be involved in the development of contact dermatitis and the immune surveillance of immunogenic skin cancers. Deletion of the function of Langerhans cells does not result in abrogated epidermal antigen presentation since ultraviolet irradiation simultaneously induces the appearance of another epidermal antigen-presenting cell population that is distinct from the Langerhans cell population and seems to induce suppression of the immune response. Suppression of the immune response following ultraviolet irradiation in murine models is critical for growth of immunogenic ultraviolet-induced skin neoplasm. Thus. ultraviolet irradiation of human skin may facilitate the growth of human neoplasms. and the spreading of skin-associated infections due to induction of suppressor T cells.
Pupil-sparing oculomotor nerve palsy due to midbrain infarction, Vasculopathic oculomotor nerve palsies with pupillary sparing are thought to be due to ischemic damage to the nerve in the subarachnoid space or the cavernous sinus. We present two cases of patients with isolated pupil-sparing oculomotor nerve palsies due to midbrain infarcts. Focal ischemic midbrain lesions should be considered in cases of pupil-sparing oculomotor nerve palsies.
The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis, Accumulating evidence indicates that a complement-mediated microvasculopathy may play a pathogenic role in dermatomyositis. In a previous study. we demonstrated neoantigens of the C5b-9 complement membrane attack complex in the muscle microvasculature of childhood and adult cases of dermatomyositis. To further characterize the relationship between the vascular complement deposits and histologic changes. quantitative histopathologic analyses were performed on 39 dermatomyositis biopsy specimens (26 adult. 13 children). There was a significant correlation between the percentage of fascicles with fibers having focal myofibrillar loss. a change seen early in the evolution of ischemic muscle fiber damage. and the percentage of fascicles having capillary deposits of membrane attack complex. Conversely. in biopsy specimens with a higher percentage of fascicles with perifascicular atrophy. membrane attack complex deposits were significantly less common. A fascicle-by-fascicle analysis supported these observations. Patients whose biopsy specimens were negative for microvascular membrane attack complex had clinical weakness for a significantly longer time than those patients with vascular complement deposits. These data support the hypothesis that the complement-mediated vasculopathy is a primary immunopathogenic event in the evolution of muscle lesions in dermatomyositis.
Initial therapy of patients with Wilson's disease with tetrathiomolybdate, Patients with Wilson's disease who present with acute neurological symptoms often become clinically worse when initially treated with penicillamine. Other available anticopper drug therapies do not appear to offer a solution to this treatment problem. We are developing and evaluating a new drug. ammonium tetrathiomolybdate for this purpose. Theoretically. tetrathiomolybdate has optimal properties. including an immediate blockade of copper absorption and the property of forming complexes with copper in the blood. rendering the copper nontoxic. In this article. we present results from six patients treated with tetrathiomolybdate for up to 8 weeks as initial therapy. None of the five patients who had presented with acute neurological symptoms worsened. Also presented are methods of assay. preliminary stability studies. and methods of evaluating therapeutic end points with respect to copper metabolism.
The neural substrate of memory impairment demonstrated by the intracarotid amobarbital procedure, The intracarotid amobarbital sodium (Amytal) procedure (IAP) was performed for 46 patients with temporal lobe epilepsy (21 with left seizure foci; 25 with right seizure foci). After anteromedial temporal lobectomy. neuronal densities were established for hippocampal subfields CA1. CA2. and CA3; the hilum; and the dentate granule cell layer. Intracarotid amobarbital procedure memory results were related to CA3 neuronal loss only. Patients who did not demonstrate memory after injection contralateral to the seizure focus had significantly fewer cells in CA3 than patients who did. Additionally. a significant correlation was observed between the intracarotid amobarbital procedure memory examination raw score after injection contralateral to the seizure focus and CA3 cell density. Using chi 2 analysis. significant differences were documented in the frequency with which memory was demonstrated after injection contralateral to the seizure focus for groups of patients classified by degree of CA3 neuronal loss. This finding supports prior research showing subfield specificity in some memory processes.
Memory complaints in older adults. Fact or fiction, Complaints of poor memory by patients may be an early symptom of a pathologic process like Alzheimer's disease. It is therefore important to determine if patients' complaints of memory impairments are an accurate reflection of real memory disturbance. The relationship between memory complaints (metamemory) and objective memory performance. mood. age. verbal intelligence. and sex was examined in a group of 199 healthy. community dwelling adults (39 to 89 years old). Memory complaints demonstrated a stronger association with depressed mood than with performance on memory tests. Increasing reports of depressive symptoms were associated with more overall memory complaints. Verbal intelligence. age. and sex also contributed to memory complaints. Patients with higher verbal intelligence reported fewer complaints and placed less emphasis on forgetting. Older individuals reported greater frequency of forgetting and greater frequency of using memory techniques. Specific types of memory complaints. seriousness of forgetting. and types of memory aids employed are also described. These results showed that self-rating of memory disturbance by older adults may be related more to depressed mood than to poor performance on memory tests.
Absence of bacteremia during nasal septoplasty, Episodes of staphylococcal bacteremia resulting in metastatic infection have occurred in association with nasal septoplasty. and this has suggested the possible need for antimicrobial prophylaxis. In a study designed to measure the actual frequency with which transient staphylococcal bacteremia occurs during nasal septoplasty. 50 healthy patients had blood cultures drawn immediately prior to and during the procedure. Although 46% of the 50 patients studied had their nasal mucosa colonized with Staphylococcus aureus. some of the blood cultures obtained from the 50 patients showed bacterial growth. The authors conclude that staphylococcal bacteremia during nasal septoplasty is a rare occurrence. and that antimicrobial prophylaxis is unnecessary.
Drug response of head and neck tumors in native-state histoculture, We describe a chemosensitivity testing of head and neck tumors. in which a native-state histoculture. ie. a three-dimensional culture system that maintains important in vivo properties. including tissue architecture. was used. Fifteen specimens of head and neck tumors were evaluated for sensitivity to the following drugs: cisplatin (DDP) at concentrations of 1.5. 15. and 37.5 micrograms/mL; fluorouracil at concentrations of 4.0. 40. and 100 micrograms/mL; and combinations of cisplatin and fluorouracil in corresponding doses. Growth and measurement of drug responses were successfully completed in 10 specimens (five others were contaminated. four of them prior to instituting rigorous antibiotic washes). The results indicated cisplatin sensitivity in five of 10 patients; fluorouracil sensitivity in four of 10 patients; and fluorouracil-cisplatin sensitivity in seven of eight patients. Our preliminary results indicate that the native-state histoculture technique is feasible to test chemosensitivity of head and neck tumors.
Combined use of fine-needle aspiration cytologic examination and tuberculin skin test in the diagnosis of cervical tuberculous lymphadenitis. A prospective study, A prospective study to evaluate the efficacy of combined use of fine-needle aspiration (FNA) cytologic examination and Mantoux test in the diagnosis of cervical tuberculous lymphadenitis was carried out. Tuberculin reactions were determined in 59 control subjects. Preoperative FNA cytologic examinations and Mantoux tests were performed on 74 patients with cervical lymphadenopathy. The lymph nodes were then excised and examined histologically and cultured for mycobacteria. Forty-eight. 22. and 4 patients had histologically confirmed tuberculous. non-specific. and malignant lymphadenopathy. Fine-needle aspiration cytologic examination alone could detect cervical tuberculous lymphadenitis in 37 patients (77%). The predictive value of a strong tuberculin reaction for mycobacterial infection was 100%. The combined use of a Mantoux test and FNA cytologic examination was able to diagnose 43 (90%) of 48 cases of tuberculous lymphadenitis cervical preoperatively. Combined use of FNA cytologic examination and Mantoux test was efficient in the diagnosis of tuberculous lymphadenitis.
Clinical choices for circulatory assist devices, Approximately 1.0% of open heart surgery patients become unweanable from cardiac bypass during the surgical procedure. In addition. nearly 20% of patients accepted for cardiac transplantation die while waiting for a donor heart. Pulsatile pneumatic ventricular assist devices (VADs) provide a realistic solution to these dilemmas. Currently. there are five manufacturers who are competing for the major market share in the clinical use of these devices. Novacor. Thermetics. Thoratec. Symbion. and Abiomed all have competitive VAD systems. Because no one system is optimal for all patients. the limitations. similarities. and strengths of each system should be known to enhance the patient's outcome when using these devices. Successful use of VAD systems. either as a bridge to transplantation or to ventricular recovery. is best approached by adherence to strict patient selection. Once instituted. VAD management centers on detailed attention to anticoagulation and prompt diagnosis and treatment of various complications.
Correlation of gross and microscopic appearance of skin buttons in total artificial heart animals, Pneumatic artificial hearts are powered by compressed air that is delivered through percutaneous tubes. A stress relief device. termed a skin button. surrounds these tubes as they exit from the recipient's tissues. The skin button is designed to protect the tissues from damage and provide a secure material-tissue interface. Prevention of superficial and invasive infection is the primary goal of the skin button. Eight calves were studied prospectively to identify gross or microscopic infection with the skin button. All animals who survived more than sixty days (62-136) had both gross and microscopic evidence of infection. All animals surviving less than 60 days (13-43) had no gross evidence of infection but one had subcutaneous microscopic abscess formation. No animal died secondary to a skin button infection. Skin buttons cannot prevent infection but they can contain the pathologic process in the superficial tissues with no evidence of systemic effects.
Evaluation of albumin loss during low-density lipoprotein apheresis, Because the reduced plasma oncotic pressure from hypoproteinemia causes hyperlipidemia. serum albumin levels should be maintained during low-density lipoprotein (LDL) apheresis. The amount of albumin loss was evaluated in seven patients with familial hypercholesterolemia during LDL apheresis in which columns packed with dextran sulfate-cellulose beads were used as a selective adsorbent of LDL. Serum albumin level significantly decreased from 4.3 +/- 0.3 (mean +/- SD) g/dl to 3.6 +/- 0.2 g/dl. The albumin loss was assessed by two different methods: 1) radioimmunoassay of microalbumin content in the discarded fluid. and 2) measurement of changes in plasma albumin reserve. The albumin losses during one apheresis session were 3.7 +/- 2.9 g and 8.3 +/- 5.7 g. respectively. depending upon which of two different methods was used. There was a significant correlation between these two methods (r = 0.84. p less than 0.02). The amount of albumin loss during apheresis was estimated to be between 4.1% and 9.1% of total plasma albumin reserve. and more than half of the decreased serum albumin level appeared to be attributable to dilution due to the electrolyte solution used for priming of the extracorporeal circuit.
Deterioration following delay in performing femoral angioplasty, It is not uncommon for a delay to occur between assessment arteriography and angioplasty attempt. We reviewed retrospectively the arteriograms of 61 patients where such a delay occurred to assess progression of superficial femoral artery (SFA) disease in this interval. A mean delay of 14.6 days (range 2-60 days) occurred between arteriogram and angioplasty attempt. Arteriographic deterioration was found in six of 61 patients (9.8%) and in three this precluded angioplasty. Of the six patients four had initial arteriography via the same side as the SFA disease whilst two had arteriography via the contralateral femoral approach. We discuss the aetiology of this phenomenon and suggestions are made to reduce its incidence.
Real-time digital contrast enhancement and magnification in the assessment of scaphoid and other wrist injuries, A study on the value of a commercially available desk-top digital magnifier-contrast enhancer (DETECT System) was made in a series of 550 patients presenting with an acute wrist injury. Four radiologists. of varying experience. independently reviewed the radiographs on a conventional lightbox and later with the digitizer. In the scaphoid series (350 cases). the performance of the two more experienced radiologists was marginally better with the digitizer. whereas the less experienced radiologists performed slightly worse. Overall the digitizer improved the confidence of the radiologists in diagnosing correctly the presence of a scaphoid fracture but. for the less experienced radiologists. this was at the expense of identifying normality. In the wrist series (200 cases). the use of the digitizer resulted in a minor increase in the true positive and decrease in the false negative observations. but this was offset by a concomitant minor increase in the false positive and decrease in the true negative categories. Evaluation of the soft-tissue planes around the wrist joint showed a limited value in the identification of a scaphoid fracture with an overall positive predictive value of 0.26. Correlation of soft-tissue changes and the presence or absence of a scaphoid fracture was slightly worse with the digitizer. Possible causes for the apparently poorer performance of the digitizer are discussed. as well as the relative merits and potential value of the unit.
The prognostic significance of radiologically detected knee joint effusions in the absence of associated fracture, The significance of radiologically detected knee joint effusion as a marker of soft tissue injury following trauma is uncertain. In this study 100 patients presenting to the casualty department following acute injury. with effusions but no fracture. were assessed. Of those available for follow-up. 20% required further investigation and 11% proceeded to surgery for significant soft tissue injury. It is concluded that radiologically detected knee joint effusions are a useful marker for underlying soft tissue injury.
Magnetic resonance imaging of primary skeletal muscle diseases: patterns of distribution and severity of involvement, Magnetic resonance imaging of the lower extremities was performed with a low field system in 51 patients representing three different categories of biopsy-proven primary skeletal muscle disease; muscular dystrophies. congenital myopathies and polymyositis. The intermuscular distribution of abnormal signal intensity and the grade of involvement of individual muscles were assessed. Large differences in the degree of pathological signal intensity between individual muscles were found in all categories. In the muscular dystrophy and polymyositis patients. the overall involvement was significantly more severe than in patients with congenital myopathy. Definite patterns of selective involvement were seen. Statistical evidence of selective muscle sparing was found; the gracilis muscle was significantly less affected than the other muscles in all three disease groups. Other muscles with significant sparing include the rectus femoris and sartorius muscles of the thigh and the tibialis posterior muscle of the leg. Common anatomical and functional characteristics of muscles may be related to the distribution of muscular disease.
Cognitive and behavioural impairment among elderly people in institutions providing different levels of care, OBJECTIVE: To compare the prevalence and degree of cognitive and behavioural impairment in elderly patients in institutions providing different levels of care. DESIGN: Prevalence study. SETTING: A nursing home. a home for the aged and psychogeriatric wards in a provincial psychiatric hospital. PATIENTS: Only subjects 65 years of age or older were eligible for inclusion. A random sample was selected comprising 25% of the residents in the nursing home and the home for the aged; of the 119 asked to participate 95 agreed (44 in the nursing home and 51 in the home for the aged). All 50 on the psychogeriatric wards agreed to participate. MAIN OUTCOME MEASURES: The Mini-Mental State Examination (MMSE) and the Kingston Dementia Rating Scale (KDRS). RESULTS: An MMSE score of less than 24 (cognitive impairment) was given to 37 (84%) of the residents in the nursing home. 43 (84%) of those in the home for the aged and 48 (96%) of the patients in the psychiatric hospital; the corresponding numbers for a KDRS score of more than 0 (cognitive impairment) were 41 (93%). 48 (94%) and 50 (100%). The seven patients receiving the highest level of care at the home for the aged (special care) had more behavioural problems than those in the psychiatric hospital did (p less than 0.001). CONCLUSIONS: Cognitive and behavioural impairment was widespread in the three institutions regardless of the level of care. When planning services and allocating resources government funding agencies should consider the degree and prevalence of such impairment among elderly people in institutions.
Progress and challenges in psychosocial and behavioral research in cancer in the twentieth century, Research in the psychosocial and behavioral aspects of cancer has shown steady growth since the 1950s. and its course of development has paralleled the history of medical techniques in treating cancer. Table 1 outlines this parallel evolution from the 1850s to the 1960s. The roles of the American Cancer Society and the National Cancer Institute (NCI) in spearheading and nurturing research in this area are documented. Interest in psychooncologic questions can be traced back for centuries to the search for etiologic factors and psychologic variables that would explain individual vulnerability to cancer. The first psychologic studies of cancer patients were reported in 1951 and 1952 from the Massachusetts General Hospital and Memorial Sloan-Kettering Cancer Center. respectively. The 1970s saw new interest in psychosocial and behavioral research with many issues being addressed for the first time: better care of the terminally ill through more humanistic approaches including better means of pain control; ethical concerns related to patient rights and their status as subjects in experimental protocols; trying to measure quality of life for cancer patients on protocols; seeing the need for multidisciplinary collaborative groups to make up for the absence of formal training in this area; and the need to design valid. accurate measuring scales specific to the symptomology of patients with cancer. Table 4 outlines how the 1980s gave increasing recognition and support to the psychosocial dimensions of cancer. This period produced a series of key conferences that examined a broad research and education perspective and produced recommendations that remain a benchmark in regard to instrumentation. conceptual models. pitfalls of psychosocial research. training. and education. and the organization of research efforts. New precision has been added to the field in the past 6 years: studies measuring concurrent psychologic. endocrine. and immune function; use of statistical modeling to incorporate quality of life data as a correction factor in survival data (TWiST and QALY); and broadened definitions of medical outcome to include functional status. thus allowing advances in psychiatric measurements to help answer questions in cancer. The challenges for the 1990s are identified in a summary in Table 9. Especially noteworthy is the observation that the comprehensive research needed today cannot be carried out by any one discipline alone. New approaches call for areas of the social sciences formerly inactive in cancer research (e.g.. anthropology) to contribute the tools and expertise required to address the problems.
Social environment and social support, Research on the relevance of social support to cancer has been plentiful since the first American Cancer Society workshop on methodological issues in behavioral and psychosocial science. Nonetheless. critical shortcomings continue to characterize the attempt empirically to establish such things as the extent to which social support predicts adjustment to cancer diagnosis and treatment. Prominent among these is the failure to adequately address large elements of the social structure. such as social class and urbanization. and to investigate how they shape the well being of persons with or at risk for cancer and their caregivers. We recommend that more psychosocial research on the link between social support and cancer be conducted within populations beset by poverty and without adequate access to health care. Funding is needed for the training and maintenance of multidisciplinary and multicultural teams of researchers working within community-based organizations and hospitals serving the underserved.
Social support and the cancer patient. Implications for future research and clinical care, This review assesses past progress. current practices. and future needs in research and clinical practice involving the social support needs of cancer patients. A review is given of the various conceptualizations of the social support/stress paradigm and of the state of the art of measuring social support. Then the current work in the field of social support and cancer is considered and an argument is made for the use of social support measures. which are relevant to the experiences of the cancer patient. Potential adaptations of an existing instrument (the Duke-UNC Functional Social Support Scale) are demonstrated. and a taxonomy of stages of cancer that would require additional types of social support measures and interventions is outlined. Interventions are discussed in terms of the traditional support groups as well as interventions by the oncologist and primary care physician. An argument is made for the inclusion of quality of life or functional measures as outcomes in clinical trials and the care of the cancer patient. Finally. the need to address the existential. philosophic. or religious issues surrounding cancer and its treatment is discussed.
Needs and recommendations for behavior research in the prevention and early detection of cancer, Because life-style patterns affect many cancer risks. research on health-risk behavior and behavior change is critical to cancer prevention. This report recommends priorities for the next decade of psychosocial research on cancer prevention and detection. The leading priority for future research is to fill gaps in basic knowledge left by the rush to intervention and outcome studies. Such research must be theoretically driven and should aim to develop broad principles applicable to diverse health behaviors. Studies that include relevant process data on various stages of behavior change are considered more desirable than simple outcome studies. Epidemiologic investigations should be expanded to include measures of relevant behaviors. so that their impact on clinical outcomes might be established. More research is needed on lay perception of health risks and on individual and health-system barriers to effective cancer prevention and detection. Studies that address the needs of minority and underprivileged populations are crucial. Funding agencies' narrow categorical mandates impede interdisciplinary research on multiple risk factors and their interactions; these boundaries must be relaxed to promote such approaches. Funding agencies should also consider basic research as a long-term investment towards the development of effective interventions.
Epidemiologic perspectives on life-style modification and health promotion in cancer research, The clinical. patient-oriented focus of medicine and psychology is contrasted with the epidemiologic (public health) approach in assessing the role of life-style factors and health promotion in cancer research. The unifying host-agent-environment epidemiologic paradigm is applied to contemporary cancer prevention issues. principally smoking cessation and dietary modification. to demonstrate differences in inferences. prevention strategies. and research opportunities. An integration of population-based approaches with the dynamics of patient behavior and risks for cancer is especially salient when considering the role of psychosocial stress and personal and social resources. The social epidemiologic perspective. the study of the psychosocial determinants of physical health status. offers one approach for resolving the outlined differences in perspectives and is particularly relevant for understanding the etiology of life-style behaviors and how they might be altered.
Psychoneuroimmunology. Implications for oncology, Accumulating evidence indicates that the central nervous system (CNS) may regulate the activity of the immune system. Although the overall significance of the immune system in cancer remains controversial. psychosocial influences on immune function could potentially provide a mechanism to account for some of the reports of an association between psychosocial factors and cancer prognosis.
Scientific inquiry in childhood cancer psychosocial research. Theoretical, conceptual, and methodologic issues in the investigation and behavioral treatment of procedure-related distress, This paper discusses the current status of scientific inquiry in childhood cancer psychosocial research. The investigation and behavioral treatment of procedure-related distress serves as a model for illustrating and outlining some of the theoretical. conceptual. and methodologic issues and problems that exist in the area of childhood cancer psychosocial research. Specifically. issues related to the process of scientific inquiry. theoretical/conceptual modeling. measurement and assessment. and behavioral treatment strategies are discussed. Examples of how these issues have been addressed in our investigations of procedure-related distress are presented and recommendations for facilitating growth and development in the field of childhood cancer psychosocial research are offered.
Quality of life research in oncology. Past achievements and future priorities, The status of quality of life research in oncology is assessed. and priorities for future research with regard to conceptual and theoretical developments. focus and content of research. research designs and practical strategies for research implementation. and transferring information to clinical practice and medical policy decision-making are identified. There is general agreement that quality of life is a subjective and multidimensional construct. yet comprehensive theoretical models have not been developed and applied fully. We recommend that future research be based on conceptual models that explicate the interrelationships among quality of life domains throughout the stages of cancer care. These models. and the longitudinal research that follows from them. should attend specifically to cross-class and cross-cultural issues to avoid overgeneralization from theory and research that are based largely on the views of the majority culture. We encourage the inclusion of this theory-based quality of life assessment as a standard component of clinical trials. Success in this endeavor will require additional standardization of quality of life measures for use across a range of cancer patient populations. including the development of age-specific norms and instruments designed to assess the entire family system.
Methodologic issues in assessing the quality of life of cancer patients, Although quality of life assessments have been employed successfully in descriptive and evaluative studies in oncology. their use in cancer clinical trials has. to date. been limited. A range of issues have impeded the conduct of clinical trial-based quality of life investigations. These include: the absence of theoretical models to guide the development of quality of life measures; over-reliance on ad hoc approaches to quality of life assessment; and insufficient attention to the practical constraints operating in clinical research settings. Of primary importance is the need to develop multidimensional quality of life instruments that are brief and psychometrically robust. It is suggested that future work on instrument development focus on refining currently available generic or cancer-specific measures. and on developing new diagnostic-specific questionnaire modules. This psychometric work should be guided by appropriate theoretical models of the relationship among health-related quality of life domains. Although it is widely accepted that the patient represents the most appropriate source of quality of life data. it is suggested that efforts also be directed toward improving the validity and reliability of physician-generated assessments of patients' performance status and of treatment toxicities. and toward determining the feasibility of employing family members as proxy raters of the psychologic and social health status of patients who are unwilling or unable to provide such information. Additional attention should be paid to the many logistical problems that arise in clinical trial-based quality of life investigations. In particular. research designs and data collection procedures should be selected that minimize patient. medical staff. and institutional burden.
Quality-of-life-adjusted survival for comparing cancer treatments. A commentary on TWiST and Q-TWiST, In chronic disease situations where treatment comparisons favor no particular therapy. or where definitive outcome requires a considerable follow-up period. it is useful to have additional and perhaps intermediate endpoints of relevant clinical significance to compare treatments. One such endpoint is Time Without Symptoms and Toxicity (TWiST) which. together with Q-TWiST. attempts to address the quality of life of patients receiving the competing regimens. This paper provides a commentary on these techniques with an emphasis on the problems inherent in implementing Q-TWiST. a measure that attempts to incorporate patient value preferences into TWiST. It is argued that while Q-TWiST is intuitively appealing in the clinical setting. there are formidable design and psychometric hurdles that must be overcome to fully operationalize the concept.
Progress in psychosocial and behavioral cancer research. The need for enabling strategies, A major component of the Second Workshop on Methodology in Behavioral and Psychosocial Cancer Research was a discussion of enabling strategies. that is. strategies by which future goals and needs in the area of psychosocial and behavioral oncology might be accomplished. This report describes and comments on the discussion that took place at a special plenary session at which representatives from four funding agencies. the American Cancer Society. National Cancer Institute. National Institute of Mental Health. and National Science Foundation. presented their views and their agencies' programs for promoting research in psychosocial and behavioral oncology. It is concluded that much progress has been made in the field and that strategies are in place for ensuring continued progress. However. suggestions are also made for new strategies that might accelerate and broaden that progress.
Behavioral and psychosocial cancer research. Building on the past, preparing for the future, This report identifies five general conclusions that emerged from the Second Workshop on Methodology in Behavioral and Psychosocial Cancer Research. These conclusions address diverse topics. including a focus on areas other than methodology; an emphasis on the transfer of technology and knowledge to applied settings; a recognition of the role of basic behavioral research in answering clinical questions; the need to recognize and strengthen ties between the field of behavioral and psychosocial oncology and the basic behavioral and social science fields from which it emerged; and the importance of additional research on minorities and other special populations. It is suggested that meeting the challenges posed in each of these five areas is critical to continued progress in the field.
Interstitial cellular infiltration detected by fine-needle aspiration biopsy in nephritis, Fine-needle aspiration biopsy (FNAB) was used to detect renal mononuclear interstitial inflammation in 56 patients with various types of nephritis (20 IgA nephropathy. 8 focal necrotizing glomerulonephritis. 7 interstitial nephritis. 6 non-classifiable chronic glomerulonephritis. 5 mesangial proliferative (non-IgA) chronic glomerulonephritis. 4 focal glomerulosclerosis. 6 normal histology. who were examined for microscopic hematuria. and 7 controls). Regular renal biopsies for histological and immunofluorescence studies were simultaneously obtained. and available for comparative analysis (not controls). Differential counts of mononuclear infiltration and subtyping of T-cell infiltration into T-helper (T-h) and T-suppressor-cytotoxic (T-s-c) cells. as detected by immunoperoxidase stains from FNAB. were correlated to clinical manifestations and renal function tests. Generally. our results indicated increased mononuclear cell infiltration (monocytes. lymphocytes. and/or activated lymphocytes) in FNAB of patients with IgA nephropathy. interstitial nephritis or focal necrotizing glomerulonephritis (especially monocytes in IgA nephropathy and interstitial nephritis. p less than 0.05 compared with controls. lymphocytes in focal necrotizing glomerulonephritis. and non-classifiable glomerulonephritis. p less than 0.02 and 0.05. respectively). The number of infiltrating activated lymphocytes was significantly increased in focal necrotizing glomerulonephritis. interstitial nephritis and focal glomerulosclerosis. p less than 0.05. less than 0.01 and less than 0.01. respectively. FNAB was at least as sensitive as histological examination for the quantification of interstitial cellular infiltration. and it allowed for cytological differential counts. Patients had decreased T-h and increased T-s-c cell counts. which were accentuated in FNAB compared with peripheral blood. although there were strong positive correlations between local and peripheral counts (p less than 0.0001).
Fertility-sparing treatment of patients with ovarian cancer, The variety of malignant neoplasms produced by the ovary are legion. Each must be considered individually in the young woman with early disease who wishes to preserve her childbearing capability. The risks of conservative surgery are often low. and the patient can be so advised. Careful monitoring of this group of patients is essential regardless of the approach.
Breathing circuit respiratory work in infants recovering from respiratory failure, OBJECTIVE: To compare cardiopulmonary function during spontaneous breathing with three continuous-flow breathing circuits. The major difference between these circuits was the degree of flow resistance offered by the exhalation valve. DESIGN: Randomized crossover trial. PATIENTS: Twelve infants less than 12 months of age recovering from respiratory failure of variable etiology. Only patients weighing 3 to 10 kg were studied. INTERVENTIONS: The patients were connected to each respiratory circuit in a random sequence. with 15 min allowed for equilibration before assessment of cardiopulmonary function. Airway pressure (Paw) and FIO2 were maintained unchanged. MEASUREMENTS AND MAIN RESULTS: Ventilation. gas exchange. or circulatory function were not altered significantly by changing the breathing circuit. However. Paw and esophageal pressure fluctuations were altered and were largest during breathing with the circuit that had an exhalation valve with high-flow resistance. The Paw fluctuation recorded while the patient was breathing with the flow-resistor circuit increased with weight and exceeded 2 cm H2O in all patients weighing greater than 4.5 kg. Paw fluctuation could be decreased by greater than 2 cm H2O in ten of 12 patients by using the threshold-resistor circuit. CONCLUSIONS: The results indicate a need for evaluating the characteristics of respiratory circuits used for spontaneous breathing in infants and children. to avoid unnecessary equipment-related increase in respiratory work.
Evolution of energy expenditure and nitrogen excretion in severe head-injured patients, OBJECTIVE: The aim of the study was to estimate the influence of therapeutic changes on the level of energy expenditure (EE) and N excretion in a homogeneous group of patients usually considered hypermetabolic. DESIGN: EE and N excretion of head-injured patients were measured simultaneously at phases 1 and 2 (patients treated 4 +/- 3 and 18 +/- 8 days after injury. respectively). SETTING: Acute care hospital. PATIENTS: Eight severe head-injured patients. mean weight 63.1 +/- 6.1 (SD) kg. mean age 21 +/- 3.8 (SD) yr. INTERVENTIONS: At phase 1. all patients were sedated with fentanyl (6.7 +/- 1.9 micrograms/kg.hr) plus flunitrazepam (9.1 +/- 4.8 micrograms/kg.hr) and were mechanically ventilated. All patients received continuous total parenteral nutrition. The nonprotein caloric intake averaged 1092 +/- 200 kcal/day. including 77% glucose and 23% fat (Intralipid 20%). The total N intake averaged 7 +/- 5 g/day. consisting of crystalline amino acids. At phase 2. no patient received any sedative and all were breathing spontaneously via tracheostomy. All patients received parenteral and/or enteral nutrition. The nonprotein caloric intake averaged 1929 +/- 200 kcal/day consisting of 65% carbohydrates and 35% fat. The total N intake averaged 13 +/- 2 g/day. MEASUREMENTS AND MAIN RESULTS: The EE was significantly higher at phase 2 than at phase 1 (2121 vs. 1737 kcal). but the interindividual variability was low at both phases. N excretion was high at the two periods of the study and not correlated to the level of EE. The RQ was 0.75 at both periods. indicating predominant fat oxidation. CONCLUSIONS: We could not demonstrate any parallelism in the evolution of EE and protein catabolism in head-injured patients. The therapeutics (mechanical ventilation. sedation. and nutrition) have a major effect on EE but little on N excretion.
Hemodynamic profiles of prostaglandin E1, isoproterenol, prostacyclin, and nifedipine in experimental porcine pulmonary hypertension, BACKGROUND AND METHODS: We compared the hemodynamic effects of four vasodilators in experimental embolic pulmonary hypertension in a randomized controlled trial. using nine pigs weighing 16 to 23 kg. After anesthesia induction and cannulation with arterial. central venous. and thermodilution output pulmonary artery catheters. animals were repetitively embolized with glass beads (60 to 160 mu) in order to establish pulmonary hypertension (pulmonary artery pressure [PAP] doubled from baseline). Prostaglandin E1 (PGE1). isoproterenol. prostacyclin (PGI2). and nifedipine were compared at doses producing equivalent reduction in systemic BP. RESULTS: Only PGE1 and PGI2 decreased both PAP and pulmonary vascular resistance (PVR). PGE1 decreased PAP from 39 +/- 1 to 33 +/- 1 mm Hg; prostacyclin decreased PAP from 38 +/- 1 to 31 +/- 1 mm Hg and produced the largest increase in cardiac output (Qt). Isoproterenol did not change PAP. markedly increased heart rate (162 +/- 8 to 216 +/- 11 beats/min). and resulted in significant arrhythmias. Nifedipine increased PVR from 1044 +/- 113 to 1125 +/- 100 dyne.sec.cm-5 and decreased Qt. CONCLUSIONS: Vasodilators demonstrate unique hemodynamic drug profiles. Isoproterenol infusion is characterized by tachycardia and arrhythmias. Both PGE1 and PGI2 effectively decrease PAP and PVR. Nifedipine depressed Qt significantly in this glass-bead embolization model of acute pulmonary hypertension.
Effects of milrinone on pulmonary vasculature in normal dogs and in dogs with pulmonary hypertension, OBJECTIVE: To study the effects of milrinone on pulmonary vasculature. BACKGROUND: It has been suggested that bipyridines or their derivatives may have a selective pulmonary vasodilation effect. METHODS: Preliminary study: milrinone administration to 12 normal dogs (low dose [bolus 75 micrograms/kg for 5 min followed by a continuous infusion at 0.75 micrograms/kg.min. n = 6]; high dose [bolus 150 micrograms/kg for 5 min followed by continuous infusion at 1.5 micrograms/kg.min. n = 6]). Main study: milrinone administration to 18 dogs with pulmonary hypertension due to pulmonary embolism induced by a massive injection of autologous muscle cubes. The pulmonary hypertension dogs were divided into three groups: a) group E (n = 6) received embolization only. as control; b) group L (n = 6) received low-dose milrinone; and c) group H (n = 6) received high-dose milrinone. equivalent to the preliminary study group. Hemodynamic measurements and blood samplings were obtained at baseline and at 15. 30. and 60 min after start of milrinone infusion. RESULTS: Milrinone did not change mean pulmonary artery pressure (MPAP) in normal dogs. Milrinone decreased MPAP significantly in dogs with pulmonary hypertension. Pulmonary vascular resistance index remained at an almost constant level in normal dogs. but decreased significantly in dogs with pulmonary hypertension. Mean arterial pressure was maintained at a constant level in all groups. High-dose milrinone administration decreased systemic vascular resistance index (SVRI) significantly; low-dose milrinone administration decreased SVRI slightly. CONCLUSIONS: Milrinone may have a selective pulmonary vasodilatory effect only in dogs with pulmonary hypertension. The mechanism that produced a selectivity on pulmonary vasculature in dogs with pulmonary hypertension is unknown. However. an inhibition of platelet aggregation may decrease the MPAP resulting from an increase in cAMP caused by milrinone. Further studies are needed to resolve the pulmonary vasodilatory effect of milrinone in dogs with pulmonary hypertension.
Acute renal failure in critically ill patients: prognosis for recovery of kidney function after prolonged dialysis support, OBJECTIVE: To clarify the prognosis for eventual recovery of kidney function in patients who experience prolonged dialysis dependence after acute renal failure (ARF). DESIGN: Retrospective. chart review. SETTING: Inpatients of a large. referral-based hospital. PATIENTS: Twenty-six consecutive survivors of ARF who required greater than 4 wk of dialysis support. RESULTS: All 26 patients were critically ill and developed ARF during treatment in an ICU. The clinical course of these patients was characterized by multiple episodes of renal ischemia or nephrotoxin exposure during dialysis dependence. However. despite multiple renal insults and prolonged dialysis support (mean duration 8.4 +/- 0.7 wk). 23 (88%) of the 26 patients recovered sufficient kidney function to discontinue dialysis. Preexisting renal impairment was associated with a greater risk of irreversible renal failure. and. in patients able to discontinue dialysis. renal recovery was often incomplete. CONCLUSIONS: Despite some renal damage. most critically ill patients who survive ARF requiring prolonged dialysis support recover life-sustaining kidney function.
Noninvasive cerebral optical spectroscopy for monitoring cerebral oxygen delivery and hemodynamics, OBJECTIVE: To present an algorithm for noninvasive measurement of cerebral oxygen saturation (cerebral oximetry) and cerebral hemodynamics with near infrared spectroscopy. DESIGN: In vitro correlation of oximetry measurements with reference measurements; illustrative cases of hemodynamic and oximetric recordings. SETTING: Tertiary care neuroscience ICU. PATIENTS: Brain-injured patients with a prolonged. decreased level of consciousness chosen as illustrative examples. INTERVENTIONS: Two-channel multiple wavelength diffuse infrared transmission spectroscopy was interfaced with the scalp using adhesive. Transmission data were collected with gross superficial-to-deep spatial resolution. Saturation calculation based on the deep signal was observed longitudinally in the patient. With the same technology. arterial input and cerebral response functions. generated by iv tracer bolus. were deconvoluted to measure mean cerebral transit time. MEASUREMENTS AND MAIN RESULTS: A positive linear regression fit between diffuse transmission oximetry and measured blood oxygen saturation over the range 23% to 99% (r2 = .98. p less than .001) was noted. CONCLUSIONS: The approach used overcomes previously identified difficulties with cerebral oximetry. and demonstrates excellent in vitro correlation. The technique can be performed clinically without difficulty. A simultaneous measure of mean cortical transit time is possible.
The deoxyribonucleic acid regions involved in the hormonal regulation of thyroglobulin gene expression, Transcription of the thyroglobulin (TG) gene is stimulated by TSH via cAMP. We have characterized the sequence elements responsible for the hormone-dependent expression of TG gene in rat thyroid FRTL-5 cells using internal deletion and linker-scanning mutants of the minimal TG promoter (-170 basepairs) fused with the bacterial chloramphenicol acetyltransferase reporter gene. The TG gene is regulated by at least two regions located between -165 and -140 bp (TG-III) and between -95 and -65 bp (TG-I) from the transcription initiation site. The intervening region can be deleted without significant effect on the promoter activity. Either of the two regions alone does not promote hormone-dependent transcription. A DNase footprinting assay showed that TG-I and TG-III are the principal protein-binding sites and that the proteins interacting with these two regions are induced by TSH or cAMP. These results suggest that the hormone-dependent expression of TG gene may be achieved by cooperative interaction of the proteins bound to TG-I and TG-III.
Epidermal growth factor induces the functional expression of dopamine receptors in the GH3 cell line, GH3 cells are a clonal strain from a rat pituitary tumor that synthesizes and secretes both PRL and GH. The peculiarity of these cells is that they do not express receptors for dopamine; thus the hormone release is insensitive to the inhibitory effect of dopamine and D2 receptor agonists. Exposure of GH3 cells to epidermal growth factor for 4 consecutive days markedly altered the cell morphology. from a spherical appearance to an elongated flattened shape. and increased the cell size. These morphological changes were accompanied by the functional expression of D2 dopamine receptors as shown by the presence of a specific. saturable. and stereoselective high affinity binding for [3H]spiroperidol in epidermal growth factor-treated cells and by the fact that the selective D2 agonist quinpirole recovered the property to inhibit PRL secretion in the cell cultures exposed to the neurotrophic factor. The effect of EGF on the functional expression of D2 receptors was dose dependent (EC50 = 8 pM) and reversible. These data suggest that EGF elicits major effects on the expression of specific genes leading to the differentiation of GH3 cells into lactotroph-like cells endowed with dopamine D2 receptors.
The effect of surgical stress on the in vitro metabolism of thyroxine by rat liver, kidney, and brain, In man. acute stress. like extensive surgery. leads to a rapid and prolonged decrease in serum T3 concentrations. The present study was carried out to investigate the mechanisms that underly the abrupt decrease in T3-neogenesis that occurs in response to acute surgical stress. Male Sprague-Dawley rats. surgically thyroidectomized. and treated with 1.2 micrograms T4/100 g BW/day. underwent wide vertical and horizontal incisions extending into the abdominal cavity while receiving light ether anesthesia. Different dietary manipulations were performed to investigate the superimposed influence of reduced carbohydrate and caloric intake on T3-neogenesis. The metabolism of 125I T4 labeled in its outer (phenolic) ring was investigated in liver. kidney. and brain homogenates of animals killed 48 h after surgery. In liver. values for the proportion of T4 degraded and the percent generation of T3 and iodide were unaffected by laparotomy. The percent T3 generation in experiments with 25 nM T4 concentration was 3.7 +/- 1.24% (mean +/- SD) in fed control animals given free access to 5% glucose. 3.4 +/- 0.67% in unoperated controls given a restricted amount of chow and 5% glucose. and 3.8 +/- 0.67% in operated animals given free access to chow and 5% glucose. As expected. T3 neogenesis in livers from unoperated animals was significantly reduced in rats fasted for 48 h and this reduction was similar in laparotomized rats fasted for 48 h after surgery. As in the liver. no effect of laparotomy on T4 metabolism in kidney and brain homogenates was observed. Finally. serum total T4 and T3 concentrations were not affected by surgery. It is concluded that acute surgical stress in thyroidectomized T4 replaced rats does not influence T4 metabolism in liver. kidney. and brain homogenates or affect the serum T4 and T3 concentrations. Since thyroid secretion of T4 (and T3) was eliminated and careful attention was paid to caloric intake in this rat model. previously reported abnormalities in serum thyroid hormone concentrations and T3-neogenesis in various states of nonthyroidal illness in man and rat. including surgery. are probably contributed to by thyroid secretion of T4 (and T3) and caloric deprivation. especially carbohydrate.
Chromogranin A: posttranslational modifications in secretory granules, The primary structure of chromogranin A indicates multiple domains which might be subject to posttranslational modification. We explored chromogranin A's proteolytic cleavage. glycosylation. and possible intermolecular disulfide links. using biochemical and cell biological approaches. Anti-chromogranin A region-specific immunoblots on chromaffin granules suggested bidirectional endoproteolytic cleavage of chromogranin A; control experiments ruled out artifactual cleavage during granule isolation or lysis. Isolation of chromogranin A-derived peptides by gel filtration chromatography or sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). followed by N-terminal amino acid sequencing. established several cleavage sites. including at least two at dibasic sites. Secretion of chromogranin A from bovine chromaffin cells did not initiate further cleavage. nor did prolonged exposure of secreted chromogranins to the secretory cells. The chromogranin A cleavage pattern was qualitatively similar in other neuroendocrine tissues. though cleavage was more complete in adrenal medullary than in anterior pituitary hormone storage vesicles. and N-terminal fragments of 45 and 55 kilodaltons were more prominent in the hypothalamus. A similar cleavage pattern was seen in human pheochromocytoma granules. as judged by chromogranin A region-specific immunoblots. fragment isolation by SDS-PAGE. and microsequencing. The presence of full-length chromogranin A as the core protein of a chromaffin granule soluble proteoglycan was suggested in bovine (but not human) chromaffin granules by glycoprotein staining. chondroitinase ABC digestion. chemical deglycosylation. and region-specific immunoblotting. Human (but not bovine) chromogranin A displayed intermolecular disulfide crosslinks on SDS-PAGE gels and immunoblotting. These results document diverse structural paths that the chromogranin A molecule may take in endocrine secretory cells after its translation.
Comparison of FRTL-5 cell growth in vitro with that of xenotransplanted cells and the thyroid of the recipient mouse, The present work was designed to compare in vitro cell growth kinetics with in vivo growth under conditions as similar as possible using labeling with [3H]thymidine. To this purpose. FRTL-5 cells were cultured as monolayers and as three-dimensional spheroids embedded in collagen gels and transplanted simultaneously into nude mice treated with perchlorate and a low iodine diet. The growth of the transplants was compared to that of the thyroids in host mice. In the intact thyroid. the fraction of [3H]thymidine-labeled follicular cells (FLC; 24-h labeling) increased sluggishly to a maximum of 10% after 3 weeks of goitrogen exposure. with a subsequent autoregulatory decrease to 3% at 7 weeks. A 4-fold higher FLC was found in six adenomas. indicating focal failure of growth-restraining mechanisms. In nonconfluent monolayer cultures the FLC was as high as 90%. even within large individual clusters where cells are in tight mutual contact. Solid. highly cellular grafts growing from transplanted monodispersed cells showed an average FLC of 20%. which is 5 times higher than the FLC in the identically stimulated mouse thyroid. In collagen-embedded cells. forming three-dimensional spheroids. the mean FLC decreased from 70% at 1 week in vitro (40% in vivo) to 20% at 3 weeks both in vitro and in vivo. suggesting effective auto-regulation of excessive growth in both conditions. However. these FLC were again much higher than the 3% FLC in simultaneously assessed host thyroids. The difference remained throughout the 45-day period studied. We conclude that FRTL-5 cells growing as monolayers and as three-dimensional spheroids in vitro or after xenotransplantation in vivo invariably show much higher proliferation rates under comparable environmental conditions than the normal follicular epithelium in the thyroids of host mice. The one exception is the confluent monolayer with near-zero growth. while densely packed three-dimensional transplants still grow intensively. Although growth-retarding cell to cell interactions are also clearly operative in growing FRTL-5 cells. they are less effective than those dampening the replication rate of the thyrocytes within the monolayer hull of normal follicles. A local failure of these mechanisms. allowing growth rates comparable to those of grafted FRTL-5 cells results in adenoma formation in normal thyroids. These observations call for caution in the transfer of in vitro growth studies with FRTL-5 cells to in vivo conditions prevailing in the normal thyroid.
Regulation of pancreastatin release from a human pancreatic carcinoid cell line in vitro, The objective of these experiments was to investigate the influence of activation of three second messenger systems (protein kinase-C. adenylate cyclase-cAMP. and calcium mobilization) on the secretion of pancreastatin (PST) and chromogranin-A (CGA) by a human pancreatic carcinoid cell line (BON) in tissue culture. Stimulation of protein kinase-C by a phorbol ester (0.025-7.5 microM) caused a significant dose-related release of PST (186 +/- 22-4271 +/- 228% over controls). Treatment of BON cells with graded doses of 8-bromo-cAMP (0.14-3.0 mM) and isobutylmethylxanthine (IBMX; 0.01-1.0 mM) also stimulated a dose-related release of PST (107 +/- 22-284 +/- 28 and 16 +/- 12-1076 +/- 100% over controls. respectively). Incubation of BON cells with ionomycin (0.134-13.4 microM) increased the release of PST (102 +/- 15-554 +/- 21% over controls) in a dose-related manner. A combination of IBMX and ionomycin resulted in an additive effect. whereas treatment with a phorbol ester plus IBMX resulted in a synergistic effect on PST release. Pretreatment of BON cells with monensin. an agent that prevents processing of precursors to smaller peptides. significantly decreased PST. but not CGA. secretion in response to phorbol ester or ionomycin. These findings indicate that protein kinase-C. cAMP. and Ca2+ mobilization participate in CGA and PST secretion. Although the observation that secretions of PST and CGA in response to theophylline are quantitatively associated. the absence of a quantitative relationship in the release patterns of PST and CGA in response to phorbol ester and ionomycin do not support a simple precursor-product relationship between CGA and PST. The monensin experiments are consistent with the notion that PST is derived from CGA in BON cells.
Identification of osteoclast precursors in multilineage hemopoietic colonies, The osteoclast is known to be derived from the hemopoietic stem cell. but its lineage and the mechanisms by which its differentiation is regulated are largely unknown. There is evidence that osteoclastic differentiation is induced through a contact-dependent interaction between bone marrow stromal cells and hemopoietic precursors. To analyze osteoclastic lineage. colonies were generated in semi-solid medium from mouse spleen cells in the presence of erythropoietin with either Wehi 3B-conditioned medium or interleukin 3 (IL3). After 7 days. individual colonies were picked. Half of each colony was phenotyped by the morphology of cells in cytospin preparations; the second half of each was incubated for 7 days with a bone marrow-derived cell line (ts8) that induces osteoclastic differentiation from hemopoietic cells. on bone slices in the presence of 1.25-dihydroxyvitamin D3. After incubation. bone resorption was assessed by scanning electron microscopy. No resorption was induced in cells derived from single-lineage colonies. but resorptive cells differentiated in 17% of granulocyte-macrophage (GM) colonies and 38% of multilineage colonies. Since only a minority of GM colonies contained osteoclastic precursors. this suggests that the GM colonies that contained osteoclasts were not typical GM colonies but may have been a form of multilineage colony analagous to other multilineage colonies that contain granulocytes. macrophages. and a third cell type. No resorptive cells were formed when IL3-derived colonies were incubated on bone slices without ts8 cells. The results suggest that osteoclasts are derived from a multilineage precursor. upon which IL3 acts to generate cells capable of osteoclastic differentiation. which form resorptive cells upon incubation with bone marrow stromal cells in the presence of 1.25-dihydroxyvitamin D3.
Diabetes-associated impairment of hepatic insulin receptor tyrosine kinase activity: a study of mechanisms, Insulin receptor tyrosine kinase activity solubilized from liver of control and streptozotocin diabetic rats was studied using histone H2b and poly-Glu-Tyr (4:1) as phosphoacceptors. Both substrates inhibited autophosphorylation and exogenous kinase activity when added before. but not after. receptor activation with ATP. When H2b was added before ATP. insulin stimulated exogenous kinase activity of diabetic-derived receptors was significantly higher (approximately 50%) than control values at low H2b concentrations. but significantly lower (approximately 50%) than control values at high H2b concentrations. suggesting a decrease in the apparent Km and maximal velocity of the diabetic receptor tyrosine kinase toward H2b. When receptors were allowed to maximally autophosphorylate before the addition of H2b. the maximal H2b kinase activity of diabetic-derived receptors was only approximately 25% lower than that of controls. These effects were not attributable to altered ATP kinetics. Insulin receptor kinase activity toward the substrate poly-Glu-Tyr (4:1) was unaltered by insulinopenic diabetes. Insulin receptor alpha-beta dimers were not detectable in either control or diabetic-derived preparations. We conclude that the impairment of hepatic insulin receptor kinase activity associated with insulinopenic diabetes reflects a decreased ability to maximally activate. which is enhanced when the receptor is activated in the presence of some substrates. e.g. H2b. Impaired signalling by the diabetic-derived receptor appears to be dependent on the type of substrate and its concentration.
Regulation of the truncation of luteinizing hormone receptors at the plasma membrane is different in rat and mouse Leydig cells, Regulation of the truncation of LH receptors was investigated in two types of mouse tumor Leydig cells (MA10 and MLTC-1). rat testis Leydig cells (RTL). and a rat tumor Leydig cell (R2C). Receptor numbers were measured by binding [125I]hCG to the cells cultured in monolayers. Addition of 3.3 nM LH for 2 h at 34 C had no detectable effect on binding sites in RTL or R2C cells. but in MA10 and MLTC-1 cells it caused a loss in binding sites. The effect on MA10 and MLTC-1 cells could be mimicked by inhibiting receptor internalization with 5 mM NaN3 and prevented by the addition of protease inhibitors. Incubating RTL and R2C cells with protease inhibitors caused a 2- to 3-fold increase in binding sites and a 2- to 3-fold increase in LH (0.033 and 0.33 nM)-stimulated cAMP production. When RTL and MA10 cells were incubated in the presence of [125I]hCG. a radioactive protein complex with an approximate mol wt of 80.000-90.000 was released into the incubation medium. We conclude that LH receptors are regulated by proteolysis at the plasma membrane in both mouse and rat Leydig cells. Furthermore. truncation of the LH receptor in the mouse Leydig cells is involved in down-regulation. whereas in the rat it is a continuous process.
Evidence that human chorionic gonadotropin/luteinizing hormone receptor down-regulation involves decreased levels of receptor messenger ribonucleic acid, Injection of pseudopregnant rats with pharmacological doses of hCG leads to a characteristic decrease in LH/hCG binding by the isolated luteal cells. The steady state levels of LH/hCG receptor mRNA were determined in rat ovaries during hCG-induced down-regulation of the receptor. Northern blots were performed using a 20-mer probe corresponding to a guanine cytosine-rich carboxyl-terminal untranslated region of the LH/hCG receptor cDNA. The hybridization of the probe to LH/hCG receptor mRNA was highly specific. since the probe hybridized only to rat luteal cell RNA fraction. with no signal detected in nontarget tissues. The LH/hCG receptor level was quantitated by [125I]hCG binding to the isolated membrane fractions from the corresponding treatment and control groups. Examination of mRNA levels of the receptor during hCG-induced down-regulation showed a steady decrease from 0-24 h. followed by a gradual increase to control levels from 24-72 h corresponding to days 8-9 of pseudopregnancy. The [125I]hCG-binding activity during down-regulation paralleled the mRNA profile in both the experimental and control groups. Examination of the levels of mRNA for alpha-actin showed no change during this period. suggesting that the loss of LH/hCG receptor mRNA at 24 h was not due to a general loss of mRNA in luteal cells. These results suggest that hCG-induced down-regulation of the LH/hCG receptor in luteal cells involves regulation of the receptors at the message level.
The rat glucagon gene is regulated by a protein kinase A-dependent pathway in pancreatic islet cells, A cAMP response element (CRE) has been identified in the proximal 5'-flanking region of the rat glucagon gene. and activation of the cAMP-dependent pathway in fetal rat intestinal cells leads to an increase in the levels of glucagon mRNA transcripts. In contrast. the human glucagon gene does not contain a similar CRE. and the results of studies using immortalized rat and hamster islet cell lines have suggested that glucagon gene expression may not be regulated by cAMP. To reconcile these observations. we have studied the control of glucagon gene expression. Incubation of primary rat islet cell cultures with forskolin in the presence of low (0.5 g/liter) or high (2.0 g/L) glucose resulted in a 2- to 3-fold increase in the levels of glucagon mRNA transcripts. Forskolin also stimulated the secretion and synthesis of immunoreactive glucagon. The importance of the protein kinase-A-dependent pathway in the regulation of glucagon gene expression was also examined in hamster islet InR1-G9 cells. Cotransfection of a glucagon-chloramphenicol acetyltransferase (CAT) fusion gene containing the glucagon CRE and a cDNA encoding the catalytic subunit of protein kinase-A resulted in stimulation of glucagon-CAT activity in hamster islet cells. Catalytic subunit cotransfection also activated somatostatin-CAT. but no activation of RSVCAT was detected. The results of these experiments suggest that the rat glucagon gene is regulated by a protein kinase-A-dependent pathway in the endocrine pancreas.
Retinoic acid stimulates placental hormone secretion by choriocarcinoma cell lines in vitro, Retinoic acid (RA). an active metabolite of vitamin A. is an important mediator of cellular differentiation and has been shown to stimulate human CG (hCG) secretion by JEG-3 choriocarcinoma cells in vitro. In order to determine whether RA stimulates the hCG secretion by other trophoblastic cell lines. we evaluated the effect of RA on hCG. hCG-alpha subunit (hCG-alpha). and progesterone secretion in three choriocarcinoma cell lines: JEG-3. JAR. and BeWo. RA stimulated hCG and hCG-alpha secretion in a dose-dependent fashion by each of the three cell lines. The time required to give a statistically significant increment of hCG and hCG-alpha over control cells was 48 h. The addition RA to cholera toxin (10 micrograms/ml) resulted in an additive or synergistic stimulation of hCG and hCG-alpha secretion by the three cell lines. Cycloheximide (1 microM) abolished the effect of RA on hCG and hCG-alpha secretion in the BeWo cell line. Progesterone secretion in response to RA was inconsistent. Progesterone secretion by both JEG-3 and BeWo cell lines were stimulated at high concentrations of RA (1 x 10(-6]. whereas progesterone secretion by JAR cells was not stimulated. Intracellular levels of cAMP were not affected by RA treatment in the JEG and JAR cells. In the dosages used. RA did not significantly alter cell number in any of the cell lines. RA in physiologic concentrations stimulates hCG and hCG-alpha secretion by three choriocarcinoma cell lines in vitro. Whether RA is a physiologic mediator of placental hormone production is unknown.
High concentrations of 17 beta-estradiol stimulate trabecular bone formation in adult female rats, Although the effects of low concentrations of 17 beta-estradiol (E2) on bone formation and resorption are well described. little is known of the effects of E2 on bone at concentrations that circulate during pregnancy. We. therefore. investigated the effects of administration of high dose E2 to 3-month-old female Wistar rats on biochemical and histomorphometric indices of bone formation and resorption. Animals receiving exogenous E2 (4 mg/kg.day for 17 days; n = 9) showed a mean serum E2 concentration of 17.5 +/- 2.9 nM. compared with 0.6 +/- 0.2 nM in those receiving vehicle alone (n = 10). The bone formation rate. measured at the proximal tibial metaphysis after the administration of double fluorochrome labels. was greatly increased in the E2 group (13.6 +/- 2.0 x 10(-2) microns3/microns2.day) compared to controls (3.9 +/- 0.9). as was serum alkaline phosphatase (E2. 133.6 +/- 10.1 IU; controls. 87.5 +/- 5.5). This increase in the rate of bone formation was associated with a significant increase in trabecular bone volume. E2 treatment did not affect urinary hydroxyproline excretion or histomorphometric indices of bone resorption. These findings suggest that high concentrations of E2 strongly stimulate the formation of trabecular bone. This may represent an important mechanism by which calcium stores are accumulated during pregnancy in rats. in anticipation of the mineral requirements of lactation.
Thyroid hormones and 5'-deiodinase in the rat fetus late in gestation: effects of maternal hypothyroidism, Having previously observed that T4 and T3 levels in fetal rat brain and brown adipose tissue are clearly higher than expected from their low circulating levels. we have now studied thyroid hormone concentrations and 5'-deiodinase activities (5'D) in several other rat fetal tissues during the last 6 days of gestation (dg). namely 17-22 dg. This period comprises the onset of fetal thyroid activity. Total thyroidal T4 and T3 contents increased 100- and 400-fold. respectively; T4 concentrations increased 8- to 10-fold in plasma. carcass. lung. and liver. and T3 increased 4.5- to 9-fold. except in plasma and liver. where T3 levels increased less than 2-fold in plasma and 3-fold in liver. During this developmental period 5'D activity increased 5- and 10-fold in fetal liver and lung. respectively. In fetuses from hypothyroid [thyroidectomized (T)] dams. body weight was lower than in fetuses from normal dams. Total thyroidal T4 and T3 contents were initially the same. but decreased markedly in fetuses from T dams by the end of gestation. At the earliest fetal ages studied (17-18 dg) T4 and T3 concentrations were lower in carcass. liver. lung. and brain. although near term there were no consistent differences between the fetal tissues from T and control dams. probably because of compensatory stimulation of thyroidal secretion. Liver 5'D was decreased by 50% throughout gestation. and lung 5'D activities were lower by the end of gestation. Thyroid hormones in placentas from T dams were very low. but increased by the end of gestation because of the contribution by the fetal thyroid. Present results describe the ontogenic profiles for thyroid hormone concentrations and 5'D activities during late fetal development; active regulatory mechanisms are already present at this age. It has been frequently stated that rat fetuses near term are deficient in thyroid hormones. and that their thyroid hormone economy is independent of maternal thyroid status. but present results show that near term. T4 and T3 concentrations in several tissues reach levels that are 50% or more of those described for adult animals. and that fetal thyroid function is influenced by maternal hypothyroidism.
The hypothalamic-pituitary axis of streptozotocin-induced diabetic female rats is not normalized by estradiol replacement, Studies in diabetic rats have found abnormalities at the hypothalamic. pituitary. and/or ovarian level but have not controlled for changes in estrogen levels induced by diabetes. The purpose of this investigation was to study the effect of diabetes on the hypothalamic-pituitary axis in ovariectomized rats treated with estradiol (E2). Ovariectomized 60 day old female rats were assigned to control (C. n = 42). diabetic (D. n = 47) or insulin-treated diabetic (DI. n = 16) groups. Diabetes was induced with an injection of streptozotocin in the D and DI groups. In the C. D. and DI groups. estrogen was replaced by implanting blank. 5 micrograms or 20 micrograms E2 pellets sc. Pituitary LH responsiveness to GnRH was assessed in C and D animals. Anterior hypothalamic and midhypothalamic concentrations of proGnRH and GnRH. pituitary LH and FSH and serum levels of LH. and E2 were measured by RIA. Anterior hypothalamic proGnRH concentrations were decreased in diabetic rats treated with 5 micrograms E2 compared to 5 micrograms E2 control animals (P less than 0.05). Midhypothalamic GnRH concentrations were also reduced in D vs. C animals despite comparable estrogen therapy (P less than 0.004). GnRH-stimulated LH levels were greater in E2-treated diabetic females than in similarly treated control rats (P less than 0.001). D and DI animals were more sensitive than controls to the inhibitory effect of estrogen on basal LH levels. Pituitary LH and FSH content was lower in 20 micrograms E2-replaced animals but was not influenced by the diabetic state. These data demonstrate a diabetes-induced decrease in hypothalamic proGnRH and GnRH concentration which is not corrected with E2 replacement. The hyper-responsiveness of the diabetic rat pituitary to GnRH also suggests a chronic lack of GnRH stimulation from the hypothalamus but a continued ability of the pituitary to respond to GnRH.
Expression of the genes for insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins-1 and -2 in fetal rat under conditions of intrauterine growth retardation caused by maternal fasting, Evidence suggests that insulin-like growth factors-I and -II (IGF-I and II) play a role in regulating fetal growth and development. In the fetus. IGF-I and -II are complexed with two specific binding proteins (IGFBP-1 and -2). which are thought to modulate the actions of the IGFs in target tissues. We examined regulation of the genes for IGF-I. IGF-II. IGFBP-1. and IGFBP-2 in fetal rat liver in an experimental model for intrauterine growth retardation caused by maternal fasting on days 17-21 of gestation. The mean weight of fetuses from the fasted dams was 27-32% lower than the mean weight of fetuses from the fed dams. The concentration of immunoreactive IGF-I was decreased by 71% in serum of fetuses from the fasting dams. The concentration of immunoreactive IGF-II was slightly decreased (by 12%) in serum of fetuses from the fasting dams. whereas the concentration of immunoreactive pro-IGF-II E-domain peptide was decreased by 31%. The abundance of hepatic IGF-I mRNA was decreased by 55% in fetuses from the fasting dams. In contrast. the abundance of IGF-II mRNA in fetal liver was not significantly decreased by maternal fasting. Maternal fasting caused a 2-fold increase in the abundance of IGFBP-1 mRNA in fetal liver. whereas it did not change the abundance of IGFBP-2 mRNA. The induction of IGFBP-1 mRNA in liver of the growth-retarded fetuses is similar to the induction that occurs in liver of fasting adults. while the lack of regulation of IGFBP-2 mRNA differs from the strong induction of IGFBP-2 mRNA that occurs in liver of fasting adults. In summary. these results indicate that maternal fasting causes a decrease in fetal IGF-I gene expression. a decrease in fetal serum IGF-I. and a slight decrease in fetal serum IGF-II and pro-IGF-II E-domain peptide concentrations. Maternal fasting also causes an increase in fetal IGFBP-1 gene expression. Changes in fetal insulin and glucose may be related to changes in expression of the IGF-I and IGFBP-1 genes in the growth-retarded fetuses. The decreased expression of IGF-I and -II and increased expression of the IGFBP-1 gene may contribute to the fetal growth retardation observed in this model system.
In vitro fertilization-embryo transfer (IVF-ET) in the United States: 1989 results from the IVF-ET Registry. Medical Research International, Society for Assisted Reproductive Technology, The American Fertility Society, This is the fourth annual report of the United States Registry of in vitro fertilization-embryo transfer (IVF-ET) and related practices. The present report describes the 1989 experiences of 163 United States member clinics with respect to treatments and outcomes. During 1989. the clinics reported performing 24.183 ovarian stimulation cycles. From all treatments. including frozen ET and IVF with donor oocytes. there were with 4.598 clinical pregnancies and 3.472 live deliveries. Ninety-eight percent of the clinics had at least one delivery. and overall a total of 4.736 babies were born. The overall live delivery rates were 14% for IVF (based on 15.392 retrievals). 23% for gamete intrafallopian transfer (GIFT) (based on 3.652 retrievals). 26% for IVF and GIFT in combination (based on 452 retrievals). and 17% for zygote intrafallopian transfer (ZIFT) and related practices (based on 908 retrievals). In addition to these treatments. results are presented for frozen ETs and IVF of donated oocytes.
Handling of tubal infertility after introduction of in vitro fertilization: changes and consequences, This study aimed at quantifying some important social and economic consequences of the altered handling of tubal infertility after the establishment of IVF treatment. The number of tubal operations was reduced by 50%. This had most important and positive implications on the availability of the operating theater for other elective operations. on the availability of hospital beds for other patient groups. and on the total duration of the certificate of illness. The calculated costs per live birth were $17.000 after tubal surgery. compared with $12.000 after IVF treatment. Life table analyses demonstrated a highly significant increased rate of deliveries after a complete IVF treatment (72.3% per patient) compared with tubal surgery (23.7%. P less than 0.001).
Study of bilateral histology and meiotic analysis in men undergoing varicocele ligation, Fifty men underwent testicular biopsy at the time of varicocele ligation. The biopsies were scored and also a portion from each biopsy was subjected to meiotic analysis. All men were followed up (mean follow-up 19.3 months). There were no consistent histologic or meiotic abnormalities. and there was no evidence that the varicocele side was more defective than the contralateral side. Thirteen pregnancies were recorded. and these occurred only when the mean Johnsen score from one or other testis was greater than 6.0.
The effects of three serotypes of Ureaplasma urealyticum on spermatozoal motility and penetration in vitro [published erratum appears in Fertil Steril 1991 Jun;55(6):1214, The effects of incubation of spermatozoa with three serotypes of Ureaplasma urealyticum on spermatozoal motility and penetration in vitro were investigated. Using computer-assisted video microscopy. three parameters of motility were determined: individual path lengths. individual vectorial distances. and percentage motility. Polyacrylamide gels were used as a medium for assessment of spermatozoal penetration. Ureaplasma-infected spermatozoa did have significantly greater path lengths and individual distances than did uninfected controls. but ureaplasma infection had no significant effect on percentage motility. Overall. there were no significant differences in penetration distances between ureaplasma-infected spermatozoa and their corresponding uninfected controls. Our conclusion is that the ureaplasmas did not adversely affect motility or penetration when spermatozoa were incubated with ureaplasmas for 45 minutes at ureaplasma:sperm ratios as high as 100:1.
Fertility before and after surgery for primary ovarian pregnancy, Primary ovarian pregnancy usually occurs in parous fertile women. It is an accidental event probably related to the presence of the IUD affecting implantation rather than an indicator of altered fertility. Reproductive performance postoperatively remains unmodified.
The concentrations of transferrin, beta 2-microglobulin, and albumin in seminal plasma in relation to sperm count, A number of studies have shown a relationship between transferrin levels in seminal plasma and sperm count. In the present study. the levels of transferrin. beta 2-microglobulin and albumin were measured in 171 samples of seminal plasma (50 subjects with normal sperm count; 32 with azoospermia; 49 with oligozoospermia; 10 with polyzoospermia; and 31 vasectomized). All three proteins were related to sperm count. It is concluded that there is a general relationship between seminal plasma proteins and sperm numbers and that some products of the sperm themselves must control the entry of plasma proteins into seminal plasma.
Oocyte and pre-embryo donation to women with ovarian failure: an extended clinical trial, The outcome of a series of pre-embryo transfers to 31 women with ovarian failure is described. Twenty six fertile women functioned as nonanonymous donors. providing oocytes for in vitro fertilization after undergoing controlled ovarian hyperstimulation and transvaginal ultrasound directed oocyte aspiration. Recipients. 24 to 44 years of age. received hormone replacement therapy before pre-embryo transfer (ET). A mean of 13.7 +/- 1.1 oocytes were obtained per aspiration resulting in the transfer of 4.5 +/- 0.2 pre-embryos to each recipient couple. Twenty-five of 47 ET resulted in pregnancy (53.2% per ET); 5 preclinical. and 20 clinical. of which 18 are ongoing or delivered. The overall implantation rate per individual transferred fresh pre-embryo was 21.1%. We conclude that oocyte donation is a safe and highly efficient means of achieving pregnancy for women with ovarian failure.
Treatment of tubal ectopic pregnancy by salpingotomy with or without tubal suturing and salpingectomy [published erratum appears in Fertil Steril 1991 Jun;55(6):1213-4, Thirty-four women with unruptured tubal ectopic pregnancy (EP) were randomly assigned to undergo salpingotomy without tubal suturing (n = 15) or salpingotomy with tubal suturing (n = 19). The reproductive performance of these patients was compared with 24 patients who underwent salpingectomy for their EP (historical control). Using life table analysis. the cumulative probability of intrauterine pregnancy (IUP) at 12 and 24 months was 45% and 45% after salpingotomy without tubal suturing and 21% and 47% after salpingotomy with tubal suturing. respectively. The cumulative probability of IUP after salpingectomy (21% and 26% at 12 and 24 months. respectively) was significantly lower than after salpingotomy with or without tubal suturing. There was no difference in the cumulative probability of EP after salpingotomy with or without tubal suturing. but it was significantly higher than after salpingectomy. In 18 women who subsequently underwent laparoscopy or laparotomy. no significant difference was found between the degree of adhesions after salpingotomy with or without tubal suturing. These findings suggest that IUP after conservative treatment is higher than after salpingectomy. but recurrent EP is also higher. Intrauterine pregnancy occurs earlier after salpingotomy without tubal suturing than after salpingotomy with tubal suturing. This might be because of rapid return of tubal function after healing by secondary intention.
Ovarian hyperandrogenism: the role of and sensitivity to gonadotropins, To determine if ovarian hyperandrogenism represents enhanced gonadotropic stimulation. augmented ovarian sensitivity to gonadotropins. or both. we have undertaken to evaluate (1) the 24-hour integrated concentrations of serum total testosterone (T) and luteinizing hormone (LH) and (2) the ovarian response of T to exogenous gonadotropic stimulation. To this end. two groups of women. hyperandrogenic anovulatory (n = 4) and early follicular phase (n = 4) normally-cycling controls. were subjected to continuous blood withdrawal over 24 hours with a portable Cormed pump (Cormed Inc.. Middleport. NY) and to exogenous stimulation with human chorionic gonadotropin. Our current observations support the notion that ovarian hyperandrogenism represents the combined impact of an overall increase in gonadotropic support coupled with augmented ovarian sensitivity to gonadotropic stimulation.
Endometrial antibodies versus CA-125 for the detection of endometriosis, Detection of endometrial antibodies using an indirect immunofluorescence method along with a well-established human endometrial carcinoma cell line was evaluated and compared with CA-125 for detecting endometriosis. Two hundred two patient sera from the infertility. gynecological. and gynecological oncology services were evaluated. The sensitivity for antibody testing was 83.1% with a specificity of 78.8%. in contrast to a sensitivity of 27.3% and a specificity of 82.6% for CA-125. These preliminary findings offer promise that antibody detection methods may be a useful adjunct in the diagnosis of endometriosis.
Maturation of immature oocytes by coculture with granulosa cells, To increase the number of embryos available for transfer. immature human oocytes were cocultured with granulosa cells from preovulatory follicles. Greater numbers of immature oocytes incubated with granulosa cells had dispersion of the cumulus and corona cells compared with immature oocytes cultured in media alone. Fifty-four percent of immature oocytes were fertilized after coculture with granulosa cells compared with 20% fertilization of immature oocytes cultured without granulosa cells. There were no cases in which only embryos developed from immature oocytes were transferred. and thus we could not determine if the immature oocytes could contribute to a pregnancy.
A prospective study of sodium-lithium countertransport and hypertension in Utah, A 7-year prospective study of a cohort of 1.458 normotensive adults from Utah pedigrees. screened from 1980 to 1985. was done to determine whether baseline levels of sodium-lithium countertransport were associated with an increased risk of future hypertension. Subsequent new hypertension (n = 39) was ascertained in 1989 from detailed follow-up medical questionnaires (67% response). Previous segregation analyses on a subset of these pedigree members who responded (n = 342) using family relationships in addition to countertransport levels have shown statistically inferred major gene segregation of sodium-lithium countertransport levels. In the normotensive adults inferred by segregation analysis to carry the recessive major gene for high sodium-lithium countertransport. new-onset hypertension occurred in 18.8% (3 of 16) compared with 3.7% (12 of 326) in the low sodium-lithium countertransport genotype group (relative risk. 4.6 [1.6. 13.9]; p = 0.03). However. an elevated baseline sodium-lithium countertransport level without genotype information from segregation analysis did not increase the risk of future hypertension in the complete cohort of adult pedigree members (relative risk. 1.02 [0.85. 1.22]). Adjustment for other risk factors reduced the relative risk to 0.90 (0.72. 1.11). We conclude that the presence of a major gene for sodium-lithium countertransport or another closely linked gene. rather than the actual level of sodium-lithium countertransport. may increase the risk of hypertension onset. High sodium-lithium countertransport levels do not increase the risk of future hypertension for individuals in whom only polygenic and environmental effects determine sodium-lithium countertransport level.
High-normal blood pressure progression to hypertension in the Framingham Heart Study, This study sought to determine if individuals with high-normal blood pressure (diastolic blood pressure of 85-89 mm Hg) progress to hypertension more frequently than those with normal blood pressure (diastolic blood pressure less than 85 mm Hg). thus advancing to a higher cardiovascular risk category. Individuals from the Framingham Heart Study were placed in normal and high-normal blood pressure categories and followed for 26 years for the development of hypertension. With hypertension defined as a diastolic blood pressure of 95 mm Hg or greater or the initiation of antihypertensive therapy. 23.6% of men and 36.2% of women with normal blood pressure developed hypertension compared with 54.2% of men and 60.6% of women with high-normal blood pressure. The relative risk for the development of hypertension associated with high-normal blood pressure was 2.25 for men (95% confidence interval [CI]. 1.8-2.8; p less than 0.0001) and 1.89 for women (95% CI. 1.5-2.3; p less than 0.0001). The age-adjusted relative risks estimated by the proportional hazards model were 3.36 for men and 3.37 for women (p less than 0.001). Among those risk factors examined. baseline systolic and diastolic blood pressure. Metropolitan relative weight. and change in weight over time were significant predictors of future hypertension in men and women whose initial blood pressure was normal. For men with high-normal blood pressure. systolic blood pressure and change in weight were identified as risk factors for future hypertension. These results indicate that the probability of individuals with blood pressure in the high-normal range developing hypertension is twofold to threefold higher than in those with normal blood pressure.
Sympathetic neural adjustments to stress in physically trained and untrained humans, The purpose of this study was to determine if the state of physical training influences sympathetic neural activation during acute stress in humans. We recorded muscle sympathetic nerve activity (microneurography of the peroneal nerve). arterial blood pressure. and heart rate in 12 highly trained. endurance athletes (25 +/- 1 years. mean +/- SEM) and 12 untrained subjects (27 +/- 1 years) before (supine rest control) and during: 1) lower body negative pressure at -5. -10. -15. and -20 mm Hg (orthostatic stress); 2) isometric handgrip at 30% of maximum (exercise stress); and 3) hand immersion in ice water. that is. the cold pressor test (thermal stress). Body weight was not different in the two groups. but the athletes had a lower body fat content (8.9 +/- 1.3% versus 16.1 +/- 2.0%. p less than 0.05). During supine rest. muscle sympathetic nerve burst frequency (24 +/- 3 versus 24 +/- 2 bursts/min. athletes versus untrained subjects) and burst incidence (36 +/- 3 versus 44 +/- 4 bursts/100 heart beats) and arterial blood pressure were not different in the two groups. but heart rate was lower in the athletes (54 +/- 2 versus 67 +/- 3 beats/min. p less than 0.05).
Renal manifestations of NaCl sensitivity in borderline hypertensive rats, Compared with the normotensive Wistar-Kyoto rat. the spontaneously hypertensive rat exhibits exaggerated alterations in renal sympathetic nerve activity and excretory function during volume expansion (exaggerated natriuresis) and environmental stress (antinatriuresis). The borderline hypertensive rat is the first filial offspring of the spontaneously hypertensive rat and the Wistar-Kyoto rat and develops hypertension with increased dietary NaCl intake. The present investigation sought to determine whether the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. Borderline hypertensive rats fed a 1% NaCl diet remained normotensive and exhibited renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress that were similar to those of their Wistar-Kyoto parent. Borderline hypertensive rats fed an 8% NaCl diet developed hypertension and exhibited responses that were similar to those of their spontaneously hypertensive parent. Thus. the dietary NaCl intake-induced transition from the normotensive state of the Wistar-Kyoto parent to the hypertensive state of the spontaneously hypertensive parent in the borderline hypertensive rat was accompanied by a similar transition of the renal sympathetic nerve activity and excretory responses to volume expansion and environmental stress. The results suggest that increased dietary NaCl intake is able to induce or unmask the capabilities for these responses. which are genetically conveyed to the borderline hypertensive rat by the spontaneously hypertensive rat parent in latent forms.
Rapid baroreceptor resetting in chronic hypertension. Implications for normalization of arterial pressure, The purpose of this study was to examine the ability of baroreceptors of renal hypertensive rabbits to reset rapidly during acute changes in arterial pressure. The carotid sinus (CS) was vascularly isolated and baroreceptor activity was recorded during slow ramp increases in CS pressure in hypertensive (one-kidney. one wrap; 127 +/- 3 mm Hg) and normotensive (one-kidney. no wrap; 85 +/- 3 mm Hg) rabbits anesthetized with chloralose. Control measurements were made after holding pressure for 10-15 minutes at the level of arterial pressure recorded before each experiment. Baroreceptor threshold pressure (Pth) was higher in hypertensives (78 +/- 4 mm Hg) compared with normotensives (55 +/- 3 mm Hg. p less than 0.05). and nerve activity was less in hypertensives over a wide range of pressure. CS distensibility (sonomicrometers) was not significantly different in the two groups. After increasing holding pressure from control by 30 and 60 mm Hg for 10-15 minutes. the extent of baroreceptor resetting (delta Pth/delta holding pressure x 100%) in normotensives was 39 +/- 6% and 33 +/- 2%. respectively. but only 14 +/- 5% and 9 +/- 3% in hypertensives (p less than 0.05). After decreasing holding pressure by 30 and 60 mm Hg. resetting was similar in normotensives (32 +/- 6% and 28 +/- 3%) and hypertensives (34 +/- 3% and 30 +/- 4%). In hypertensive rabbits. acute (10-15 minutes) exposure of baroreceptors to normotension (71 +/- 4 mm Hg) decreased Pth to 62 +/- 4 mm Hg and increased nerve activity to levels not significantly different from those of normotensive animals without altering CS distensibility.
Exclusion of the Na(+)-H+ antiporter as a candidate gene in human essential hypertension, The primary abnormalities that contribute to the pathogenesis of human essential hypertension are unknown. The known genetic contribution to this disorder suggests the possible use of genetic linkage analysis to test whether specific candidate genes contribute to the pathogenesis of either essential hypertension or intermediate phenotypes. Among such phenotypes. elevated erythrocyte Na(+)-Li+ countertransport (SLC) is the best known. supporting major gene inheritance by pedigree analysis. Striking similarities between SLC and Na(+)-H+ exchange suggest that mutations at the Na(+)-H+ antiporter gene locus (APNH) might result in elevated SLC and contribute to the subsequent pathogenesis of hypertension. We have tested these hypotheses by genetic linkage analysis. with APNH as a candidate gene. By determining genotypes at APNH and flanking loci in pedigrees that support major gene segregation of elevated SLC. we have excluded linkage of APNH and the major SLC locus with a LOD score of -5.91. an odds ratio of almost 1.000.000:1 against linkage. In the analysis of 93 hypertensive sibling pairs. we have further demonstrated that APNH explains none of the variance in SLC in hypertensive individuals (r2 = 6 x 10(-7). p greater than 0.99). Finally. we have directly tested for linkage of APNH to genes predisposing toward hypertension by linkage in hypertensive sibling pairs. Mean allele sharing at APNH is not greater than expected from random assortment in hypertensive siblings (0.92 versus 1.0. p greater than 0.80). and the upper 95% confidence limit of this value (1.04) indicates that mutations at APNH rarely if ever contribute to the pathogenesis of hypertension in this population.
Methodology of sodium sensitivity assessment. The example of age and sex, This article addresses the methodology of sodium sensitivity assessment. There have been reports to suggest that a high sodium intake is a cause of elevated blood pressure and trials to indicate that a reduction in sodium intake may reduce blood pressure that is already high; the implications of these findings are discussed. Many studies on sodium sensitivity suffer from what could be called the "normal probability fallacy"; without appropriate control conditions. an intervention such as sodium restriction may incorrectly be assigned to a more pronounced response in a subgroup of the study population. As an example. findings are reviewed of age and sex as determinants of a response of blood pressure to variations in sodium intake. The limited data available suggest that subjects that are older and have higher blood pressure levels seem to benefit more from a reduction in sodium intake. In addition. elderly subjects at a high dietary sodium intake may have a higher risk of developing hypertension. Findings in both nonexperimental and experimental studies tend to support this view. Findings on sex differences are less consistent. A systematic approach to the assessment of factors and mechanisms responsible for sodium sensitivity in some subjects is needed to determine who might benefit most. Until more data are available. there is little basis to discriminate sodium-sensitive from sodium-resistant hypertensive subjects.
Racial and ethnic modifiers of the salt-blood pressure response, The relation between sodium and blood pressure is a centuries-old question. A substantial body of epidemiological and experimental data has accumulated that strongly implicates NaCl as having a causal role in the genesis of arterial hypertension. Prospective studies that have been performed in diverse populations that have manipulated NaCl exposure by diet or infusion have repeatedly documented an NaCl pressor effect. Further. similar studies in biracial populations have also demonstrated a greater prevalence of "salt sensitivity" in blacks compared with whites. The reasons for this observation are not entirely clear; however. intrinsic or hypertension-induced renal abnormalities that limit natriuretic capacity. reduced Na+.K(+)-ATPase pump activity. other membrane ion transport disturbances. differential exposure to psychological stressors. greater insulin resistance. and dietary factors (reduced Ca+ and K+ intake) have all been suggested as possibly playing a role. Salt sensitivity appears to be a widespread phenomenon. However. it is critically important to determine what factors account for racial differences in salt sensitivity. Moreover. the prevalence of salt sensitivity in the general population is unknown. Current definitions of salt sensitivity are varied and unidirectional. In comparison with bidirectional criteria (blood pressure increase with salt loading and blood pressure decrease with salt restriction). they are probably inadequate to identify salt-sensitive individuals who manifest less extreme blood pressure change after dietary sodium or plasma volume manipulations. More sensitive criteria for diagnosing salt sensitivity will facilitate a better understanding of racial and ethnic differences in the prevalence of salt sensitivity.
Biohistory of slavery and blood pressure differences in blacks today. A hypothesis, Genetic factors are known to play an important role in the variations in blood pressure levels. However. genetic factors that explain the higher average blood pressure levels of western hemisphere blacks when compared with African blacks have not been seriously considered. Because the genetic makeup of a population is largely determined by biological and ecological forces in the past. an examination of the biohistory of blacks. specifically the slavery era. was conducted. An overview of the salient findings of that investigation is included in this article. The published historical evidence on the transatlantic slave trade and New World slavery (from the 16th century to the 19th century) reveals that conditions existed for "natural selection." and therefore. genetic changes were virtually inevitable in the slave populations. During this period of history. mortality was extremely high. and fertility (or reproductive success) was so low among the survivors that most plantation societies in the western hemisphere depended on a constant importation of captives (over 12 million) from Africa for the viability of the plantation communities. Because the major causes of death were salt-depletive diseases such as diarrhea. fevers. and vomiting. it is argued that individuals with an enhanced genetic-based ability to conserve salt had a distinct survival advantage over others and were. therefore. more likely to bequeath their genotype to subsequent generations of Western hemisphere blacks. Thus. it is predicted that blacks in the Americas have a greater frequency of individuals with an enhanced genetic-based ability to conserve salt than African blacks.
Sodium-potassium interaction in hypertension and hypertensive cardiovascular disease, Epidemiological evidence suggests that low potassium intake is associated with the probability of occurrence of hypertension and stroke. The short-term response to increased potassium intake is increased sodium excretion as well as increased potassium excretion; the short-term response to increased sodium intake is increased potassium excretion as well as increased sodium excretion. In some experimental studies. increased amounts of potassium have been able to block the noxious influences of sodium. Sodium and potassium must be concomitantly considered in the investigation of the association of either of these cations with hypertension and cardiovascular disease. The chloride ion is also important for sodium's effects; its importance in potassium's effects has not been extensively explored.
A consensus approach to electrolytes and blood pressure. Could we all be right, This commentary sets forth the hypothesis that the putative beneficial or detrimental effects of specific electrolytes on blood pressure regulation in fact reflect highly integrated responses to interactions among these cationic and anionic species. In this paradigm. the impact of any given intake of an electrolyte on arterial pressure will be influenced by the concurrent consumption of other electrolytes. Thus. the heterogeneous blood pressure response in humans to isolated manipulations of nutrients such as sodium. calcium. and potassium may be determined. in part. by the adequacy of the dietary intake of other mineral elements. If this hypothesis is validated by continued research in this area. we would have new strategies available to improve blood pressure control in humans. For example. treatment of "NaCl sensitivity" in some humans might be more effectively approached by correcting dietary deficiencies of either potassium or calcium than by restricting dietary NaCl.
Dietary sodium reduction for hypertension prevention and treatment, Nutritional-nonpharmacological approaches for the treatment and prevention of hypertension are of great interest. Sodium reduction is one of the primary methods recommended for these purposes. The general public is interested in the reduction of dietary sodium intake and has responded with a decrease in table salt use. the purchase of lowered sodium food products. and the use of food labels to help guide food purchases. Countervailing trends in the use of convenience foods and dining out increase the difficulty for individuals to lower sodium intake. Clinical trials that have used sodium reduction alone or in combination with other lifestyle therapies have demonstrated the feasibility of reducing dietary sodium intake from 30% to 50% for up to 4 years. in a variety of populations. Trials that used lifestyle and weight loss interventions have also achieved significant reductions in body weight and alcohol consumption and increases in physical activity. A variety of studies indicate that long-term sodium reduction is feasible and that it is acceptable to patients. No negative consequences of these interventions have been observed. and in some cases improvement in the intake of other nutrients has occurred. Nonpharmacological interventions have resulted in hypertension control in significant proportions of the trial populations. These studies demonstrate that the foregoing types of interventions can significantly contribute to hypertension treatment and prevention.
A perspective on reducing salt intake, Epidemiological. clinical. and experimental evidence links excessive salt consumption to hypertension; there appears to be no evidence that it is beneficial. I conclude that it should be public policy to advise and help Americans to reduce their salt intake. Because even mild hypertension increases risk. the overall problem does not appear to be amenable to treatment. although treatment for those with clinical hypertension will always be needed. There appears to be little likelihood that identification of those "at risk" will be successful. nor does it appear that we have the capacity at this time to conduct successful preventive field trials. It is difficult for the individual to modify his diet alone. The successful strategy is to modify the food supply by changing public demand. The public responds to dietary advice if acceptable and identifiable products are available. Because most of the salt is in commercially prepared foods and because their consumption will increase in the future. the major responsibility for lowering salt consumption will fall on the food manufacturers. They are beginning to respond. and there appears to be ample opportunity for them to reduce the salt content of foods markedly. Our temporary objectives. however. should be modest. because unrealistic objectives only discourage those who attempt to follow them.
An overview of randomized trials of sodium reduction and blood pressure, To test for effects on systolic and diastolic blood pressure and to provide precise estimates of their magnitude. we conducted an overview of randomized clinical trials that aimed to reduce the intake of sodium in human subjects. We excluded from pooled analyses trials with confounded designs. those that compared intake levels beyond the usual range in the population. and those without published reports. Two reviewers abstracted information in duplicate and differences were reconciled. Twenty-three trials with outcome data from an aggregate of 1.536 subjects were included. Data were pooled both separately for hypertensive and normotensive subjects and for all trials combined. With the use of sample size weighting. blood pressure reductions (net of controls) were 4.9 +/- 1.3/2.6 +/- 0.8 mm Hg (systolic and diastolic. respectively. with 95% confidence limits) in hypertensive subjects and 1.7 +/- 1.0/1.0 +/- 0.7 mm Hg in normotensive subjects. The combined blood pressure reductions were 2.9 +/- 0.8/1.6 +/- 0.5 mm Hg. These changes were associated with mean reduction of urinary sodium excretion ranging from 16 to 171 mmol/24 hr for individual trials. A dose-response relation across trials was found. both in normotensive and in hypertensive subjects. These results indicate that sodium reduction lowers mean blood pressure in both hypertensive and normotensive individuals for periods of at least several months. The findings are highly consistent with results of observational epidemiological studies and have implications for preventive strategies of blood pressure control.
Neurovascular mechanisms and sodium balance in the pathogenesis of hypertension, Physiological studies have clarified the role that the brain has in the interplay between salt balance and hypertension. Neural mechanisms and endocrine secretions play a pivotal role in the adaptation of mammals to changes in the intake and excretion of sodium. Maneuvers that alter the concentration of sodium in the plasma modify the sensitivity of baroreceptor reflexes and alter vascular reactivity. These changes may be mediated in part by the release of vasopressin. The research also suggests that the brain indirectly modulates the ability of the vascular endothelium to release vasoactive factors. Collectively. these studies illustrate the multiple effects of the sodium ion on the peripheral neural and central endocrine mechanisms that participate in the regulation of arterial pressure.
Genetic traits related to hypertension and electrolyte metabolism, The genetic and cultural heritability and intercorrelation of traits related to hypertension have been carried out in 98 Utah pedigrees (2.500 person) and 58 sibships with two or more hypertensive persons (131 hypertensive persons). Although none of these traits has been established as a marker for "sodium-sensitive hypertension." many of them are related at least indirectly to both electrolyte metabolism and risk of hypertension. Significant recessive monogenic effects and high total heritability (52-84%) were found for urinary kallikrein. high fat pattern index. intraerythrocytic sodium. Na-Li countertransport. and ouabain binding sites. Familial correlations more strongly attributable to shared environment than to genetic effects were found for Na.K-ATPase pump activity. intraerythrocytic magnesium. plasma digoxin-like factor. plasma renin activity. and plasma sodium concentration. All anthropometric variables tested showed highly significant genetic heritability with low and insignificant shared family environmental effects. Several of the genetically determined cellular cation tests also correlated with other genetic traits including plasma lipids. anthropometric measurements. and other cellular cation tests. Among hypertensive individuals with familial dyslipidemic hypertension. plasma insulin levels correlated with obesity and lipid abnormalities and with several cellular cation flux tests associated with hypertension.
Sympathetic neural contribution to salt-induced hypertension in Dahl rats, The Dahl strain provides a model for examining mechanisms involved in the genetic sensitivity or resistance to salt-induced hypertension. Dahl salt-sensitive rats develop hypertension when fed a high salt diet; Dahl salt-resistant rats remain normotensive. Based on early experiments. it was thought that hypertension in Dahl salt-sensitive rats epitomized the overriding importance of renal and humoral mechanisms in salt-induced hypertension. but studies in the past 15 years have demonstrated that alterations in sympathetic neural mechanisms also participate critically in the genetic predisposition to salt-induced hypertension in Dahl salt-sensitive rats. This article briefly reviews sympathetic neural mechanisms in Dahl rats. including evidence for a role of afferent baroreceptor as well as central neural and peripheral adrenergic mechanisms in salt-induced hypertension in Dahl salt-sensitive rats.
Relation between sodium intake, renal function, and the regulation of arterial pressure, The long-term regulation of arterial pressure requires the maintenance of a balance between sodium and water intake and sodium and water excretion. Normal salt and water balance leads to stable body fluid volumes and the maintenance of normal renal function is critical to establishing extracellular fluid volume homeostasis. This review focuses on the role of the kidney in the long-term control of salt and water balance with particular emphasis on the relations between sodium intake. the renin-angiotensin-aldosterone system. renal sympathetic nerve activity. and the regulation of arterial pressure via renal sodium and water excretion. The accumulation of evidence in recent years demonstrates that low level elevation of renin release. circulating angiotensin II or aldosterone. or activation of renal sympathetic outflow may alter renal function such that normal natriuretic and diuretic responses to arterial pressure are significantly impeded. Under these circumstances. the maintenance of normal sodium and water excretion requires a significant elevation of arterial pressure. Thus. compromised renal function leads to elevation of arterial pressure to maintain adequate sodium and water balance during periods of increased sodium intake. The resultant chronic elevation of arterial pressure then becomes a compromise that is used by the kidneys to maintain normal extracellular body fluid volumes.
Dietary salt and blood pressure. A perspective, Although dietary salt restriction is often valuable as sole or adjunctive therapy of hypertensive disorders. it is abundantly clear that hypertensive patients comprise a heterogeneous group with regard to salt sensitivity of blood pressure. This is apparent despite the many methodological obstacles to defining salt sensitivity in an individual patient. Currently. dietary trial is the only sure means of defining a given patient as responsive to salt restriction. Easily definable markers of salt sensitivity would allow appropriate targeting of this rather ponderous therapy. Promising leads include the assessment of membrane ion transporters such as sodium-lithium exchange and of the activity of the renin-angiotensin system. including the phenomenon of "non-modulating" hypertension and other volume regulatory hormones such as atrial natriuretic factor. Although less intensively studied than in hypertensive patients. the blood pressure response of normal subjects to salt restriction is also marked by great variability. Given the possibility of deleterious consequences of population-wide salt restriction for at least some people in a setting such as the United States. it seems imprudent to recommend such a policy before its proven worth has been demonstrated by clinical trial. Pending such evidence and the development of markers. salt restriction should be reserved for those in whom it is of demonstrated efficacy.
Avoiding interpretive pitfalls when assessing arrhythmia suppression after myocardial infarction: insights from the long-term observations of the placebo-treated patients in the Cardiac Arrhythmia Pilot Study (CAPS), The Cardiac Arrhythmia Pilot Study (CAPS) was a 1 year trial that analyzed the safety and effectiveness of arrhythmia suppression in 502 patients surviving acute myocardial infarction who had greater than or equal to 10 ventricular premature depolarizations/h or greater than or equal to 5 runs of ventricular tachycardia on a Holter recording obtained 6 to 60 days after the acute infarction. Because 100 of these patients received placebo in a double-blind fashion for 1 year. a comprehensive objective analysis was performed of spontaneous arrhythmia changes based on real data rather than statistical estimates. In the CAPS placebo group. 19% developed some serious clinical event in 1 year (death. heart failure. proarrhythmia) that could likely be attributable to antiarrhythmic drug toxicity. A significant reduction in the frequency of ventricular premature depolarizations (p = 0.004) occurred in the first few weeks of "therapy" with a further significant (p less than 0.04) decrease between 3 to 12 months. After initiation of placebo antiarrhythmic therapy. 27% had "apparent ventricular premature depolarization suppression" (greater than or equal to 70% reduction) after one Holter recording evaluation and nearly half (48%) after six Holter recordings to assess suppression were performed.
Evaluation of preload reserve during isometric exercise testing in patients with old myocardial infarction: Doppler echocardiographic study, To estimate the preload reserve in response to an increase in afterload in patients with old myocardial infarction. the relation between the Doppler echocardiographic inflow velocity pattern and left ventricular end-diastolic pressure was investigated during isometric handgrip exercise testing. The study population consisted of 16 normal subjects and 40 patients with old myocardial infarction. The 40 patients were subdivided into two groups according to left ventricular end-diastolic pressure at rest: group I (22 patients). less than 18 mm Hg; group II (18 patients). 18 mm Hg or more. At rest. the ratio of peak velocity in atrial contraction phase to peak velocity in early diastolic filling phase (A/E) was significantly higher in the patients with old myocardial infarction than in normal subjects; values in the two subgroups of myocardial infarction did not differ significantly. The A/E ratio and left ventricular end-diastolic pressure increased significantly during exercise in group I. Conversely. the change in left ventricular end-diastolic pressure during exercise in group II was significantly greater than that in group I. and was associated with a decrease in the A/E ratio. Thus. an atrial compensatory mechanism operated effectively in response to the increase in afterload in patients with a normal left ventricular filling pressure. whereas this compensatory mechanism deteriorated in patients with elevated left ventricular filling pressure due to a limited preload reserve.
Noninvasive assessment of intrinsic ventricular load dynamics in dilated cardiomyopathy, On the basis of hemodynamic theory. a new noninvasive method is developed to provide improved insights into the significance of depressed Doppler left ventricular ejection variables in patients with dilated cardiomyopathy. The net force (F) associated with intraventricular flow throughout ejection can be written as: F = A.dv/dt + B.v2. where v is the ejection velocity and A and B are variables related to the geometry of the ventricle and its outflow tract. Instantaneous levels of this force were calculated in 9 normal subjects and 10 patients with dilated cardiomyopathy using Doppler. M-mode and two-dimensional echocardiography. The maximal ejection force (Fmax) was 47.5 +/- 8.5 kdyn in normal subjects and 25.5 +/- 6.2 kdyn in those with dilated cardiomyopathy (p = 0.0001). Peak local acceleration and outflow velocity were severely depressed in those with cardiomyopathy compared with normal subjects (1.260 +/- 129 versus 2.671 +/- 430 cm/s2 and 71 +/- 14 versus 109 +/- 7 cm/s. respectively; p = 0.0001). Maximal ejection force was attained very early in ejection. A significant linear correlation was found between peak outflow acceleration and maximal ejection force (n = 19; r = 0.91. p = 0.0001). At the time of peak ejection velocity. the net force had decreased to 64% of its peak value in those with cardiomyopathy. whereas in normal subjects. it had decreased to only 84% of its peak value (p = 0.008). In normal subjects. the ejection force was positive during the first 75% of ejection. but in those with cardiomyopathy. it was positive only during the first 54% (p = 0.0003). Once its peak value was attained. total left ventricular systolic wall stress declined rapidly during ejection in normal subjects (to 33% of its peak value by end-ejection). whereas it remained elevated throughout ejection in patients with cardiomyopathy (at 60% of its peak value by end-ejection. p = 0.0001 versus normal). The maximal ejection force corresponded to a calculated intraventricular peak pressure gradient of 9.8 +/- 1.6 mm Hg in normal subjects and 6 +/- 1.2 mm Hg in those with cardiomyopathy (p = 0.0001). The average contribution of the intrinsic component of the left ventricular systolic load (that is. wall stress associated with the ventricular to aortic pressure gradient) to the total myocardial load was 9.1% (range 7.3% to 11.2%) in normal subjects and 6.2% (range 3.9% to 7.5%) in those with cardiomyopathy (p = 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS).
Immediate reproducibility of electrically induced sustained monomorphic ventricular tachycardia before and during antiarrhythmic therapy, The immediate reproducibility of sustained ventricular tachycardia induction was evaluated prospectively during 106 studies performed in 53 patients with clinical sustained monomorphic ventricular tachycardia. Programmed electrical stimulation was performed twice. using the same protocol during 53 drug-free studies and 53 subsequent studies on antiarrhythmic therapy. Sustained monomorphic ventricular tachycardia was reproduced in 104 (98%) of the 106 studies. There was no significant difference in the incidence of reproducible tachycardia in the drug-free state compared with that observed during treatment with different classes of antiarrhythmic drugs. An increase in the number of extrastimuli was required to reinitiate the tachycardia in 9 (11%) of 83 studies in which single or double extrastimuli were initially required to induce the tachycardia. In 39 (37%) of 104 studies with reproducible tachycardia induction. the two tachycardias significantly differed in electrocardiographic (ECG) configuration and cycle length. These observations suggest that the overall reproducibility of ventricular tachycardia induction is sufficiently high to provide a reliable marker for evaluating the efficacy of therapeutic interventions. However. specific tachycardia characteristics such as cycle length and ECG configuration are more variable even within the same study and may be less useful in assessing the effects of subsequent interventions.
Differences in QRS configuration during unipolar pacing from adjacent sites: implications for the spatial resolution of pace-mapping, To examine the spatial resolution of unipolar pace-mapping. 12 lead electrocardiograms (ECGs) recorded during pacing from each of the poles of a quadripolar catheter (5 mm interelectrode distance) were examined. Unipolar pacing was performed from each of the poles at late diastolic threshold. twice threshold and 10 mA at a cycle length of 500 ms. In 15 patients. pacing was performed at the right ventricular apex and in 14 at various left ventricular sites. Pacing from the distal catheter pole at threshold (index ECG) was used to simulate the site of origin of ventricular tachycardia. and all other ECGs were compared with the index ECG. Electrocardiograms were evaluated by two independent observers for 1) minor configuration differences (notch. new small component. change in the amplitude of individual components or change in QRS shape); 2) major differences in configuration (new large component. marked change in the amplitude of an existing component or two minor changes); and 3) peak to peak changes in amplitude. Minor differences in configuration were seen in a mean 2.4 +/- 1.9. 4.6 +/- 2.4 and 4.4 +/- 2.9 leads during pacing at 5. 10 and 15 mm from the distal electrode (index site). Major differences in configuration were seen in a mean of 0.3 +/- 0.5. 2.1 +/- 2.1 and 3.7 +/- 2.3 leads during pacing at 5. 10 and 15 mm from the index site. Differences in amplitude were seen in a mean of 3.1 +/- 2.2. 5.6 +/- 2.5 and 6.8 +/- 3.0 leads per ECG during pacing at 5. 10 and 15 mm from the index ECG pacing site. respectively.
Longitudinal dissociation of atrioventricular accessory pathways, Unusual properties of atrioventricular (AV) accessory pathways were found during electrophysiologic investigations in four patients (three men and one woman). Anterograde longitudinal dissociation of the accessory pathway was observed in two patients and retrograde longitudinal dissociation in two others. Two patients had an accessory pathway with a slow conduction time. one in anterograde direction and one in retrograde direction. These observations further expand our knowledge of the spectrum of electrophysiologic properties of accessory AV pathways.
Electrophysiologic findings after Fontan repair of functional single ventricle, Cardiac arrhythmias are well recognized sequelae of the Fontan operation for complex congenital anomalies. In this study the electrophysiologic effects of the Fontan procedure were evaluated in 30 patients who underwent cardiac catheterization with electrophysiologic study 1.9 +/- 1.3 years (mean +/- SD) after modified Fontan repair for functional single ventricle. Abnormalities of sinus node or ectopic pacemaker automaticity were detected in 50% (15 patients) by determination of a prolonged corrected sinus node or pacemaker recovery time. Total sinoatrial conduction time was prolonged in 50% of the patients with normal sinus rhythm. Sinus node or ectopic atrial pacemaker function was entirely normal in only 43% of patients. The predominant atrial rhythm was normal sinus in 70% and ectopic atrial or junctional in 30%. Abnormalities of atrial effective and functional refractory periods were noted in 43% of patients and were most pronounced at faster paced cycle lengths. Atrial endocardial catheter mapping revealed intraatrial conduction delays between adjacent sites in 76% of the patients tested and in eight of nine patients with inducible intraatrial reentry. Programmed atrial stimulation induced nonsustained supraventricular arrhythmias in 10% of the 30 patients and sustained arrhythmias in 27%. Intraatrial reentry was the most common inducible arrhythmia and was present in seven of the eight patients with sustained and two of the three patients with nonsustained atrial arrhythmias. Atrioventricular conduction abnormalities were noted in 10% (three patients). No patient had inducible ventricular arrhythmias with programmed ventricular stimulation. The electrophysiologic findings after Fontan repair include abnormal sinus node function. prolonged atrial refractoriness. delayed intraatrial conduction and inducible atrial arrhythmias.
Late noninvasive evaluation of cardiac performance in mildly symptomatic older patients with Ebstein's anomaly of tricuspid valve: role of radionuclide imaging, Ten patients 8 to 54 years of age with isolated Ebstein's anomaly of the tricuspid valve were evaluated by electrocardiography. maximal exercise treadmill testing. 24 h electrocardiographic (ECG) monitoring. echocardiography and rest radionuclide imaging of the left ventricle. The patients presented after the 1st year of life and had not undergone surgical intervention. All except one were in functional class II. No patient had preexcitation on the surface ECG. but abnormal tachyarrhythmias or bradyarrhythmias were seen in five patients on 24 h ECG monitoring. Subnormal exercise performance was observed in five patients. Echocardiography demonstrated typical variable tricuspid valve displacement and paradoxic interventricular septal motion. Left ventricular end-diastolic dimensions were normal in all patients. but posterior wall motion was reduced in two. Moderate to severe tricuspid regurgitation with a Doppler jet velocity less than 2.5 m/s was demonstrated in eight patients. Left ventricular radionuclide scintigraphy revealed a subnormal ejection fraction (less than 50%) in 5 of 10 patients; these 5 had previously shown suboptimal exercise performance. The two youngest patients (less than 15 years) had no arrhythmia. normal exercise performance and normal left ventricular ejection fraction. There was no correlation between the degree of tricuspid valve displacement or regurgitation and the presence of rhythm disturbance. exercise performance or radionuclide left ventricular function. Late evaluation of patients with Ebstein's anomaly may demonstrate significant unsuspected abnormalities in cardiac rhythm. exercise performance and left ventricular function. Radionuclide scintigraphy is a useful noninvasive technique for assessing left ventricular dysfunction in these patients.
In-hospital mortality after balloon aortic valvuloplasty: frequency and associated factors, Percutaneous balloon aortic valvuloplasty has been accompanied by significant early periprocedural morbidity and mortality. Identification of factors associated with increased mortality might allow for improved selection of patients. The Mansfield Scientific Balloon Aortic Valvuloplasty Registry was analyzed to identify the frequency of in-hospital death and the factors associated with it. Of 492 patients undergoing the procedure. 37 (7.5%) died during the hospital stay in which valvuloplasty was performed. Twenty-four of these patients died within the first 24 h and the remainder died within 7 days after the procedure. There were significant differences in baseline clinical and hemodynamic characteristics as well as procedural and postprocedural variables between patients dying and those surviving the in-hospital period. Multivariate analysis identified four factors associated with increased mortality: 1) the occurrence of a procedure-related complication. 2) a lower initial left ventricular systolic pressure. 3) a smaller final aortic valve area. and 4) a lower baseline cardiac output. Thus. baseline hemodynamic. procedural and postprocedural variables and complications can be identified that are associated with increased mortality.
Predictors of long-term survival after percutaneous aortic valvuloplasty: report of the Mansfield Scientific Balloon Aortic Valvuloplasty Registry, Percutaneous balloon aortic valvuloplasty was used to prospectively treat 492 elderly. symptomatic. nonsurgical patients suffering from severe aortic stenosis in 27 centers in North America and Europe. At 1 year the overall survival rate was 64% and the event-free survival rate (survival free of valve replacement or repeat valvuloplasty) was 43%. Clinical. catheterization and procedural variables were assessed to define prognostic variables. Univariate analysis revealed that patients who survived had a lesser frequency of previous myocardial infarction (2% versus 6%. p less than 0.005). lower incidence of severe ventricular dysfunction (22% versus 48%. p less than 0.001) and lower incidence of symptoms of heart failure (60% versus 75%. p less than 0.02). History of angina (56% versus 45%. p = NS) and syncope (23% versus 16%. p = NS) were similar for both groups. Values obtained at cardiac catheterization that differed in survivors and nonsurvivors included lower pulmonary artery systolic pressure (43 +/- 1 versus 54 +/- 2 mm Hg. p less than 0.001). lower mean pulmonary artery pressure (28 +/- 1.0 versus 36 +/- 1.0 mm Hg. p less than 0.001) and larger initial valve area (0.52 +/- 0.01 versus 0.47 +/- 0.02 cm2. p = 0.006). Discriminate function analysis was performed to identify variables that independently predicted improved probability of survival. Eight variables were significantly and independently predictive. These included age. initial cardiac output. initial left ventricular systolic pressures. initial left ventricular end-diastolic pressures. presence of coronary artery disease. New York Heart Association dyspnea classification. number of balloon inflations and final valve area.
Ventricular load optimization by unloading therapy in patients with heart failure, The effects of unloading a depressed heart were assessed in terms of optimal coupling between the ventricle and arterial system. To assess the effects of preload on ventricular load coupling. preload was reduced with a lower body negative pressure of -20 mm Hg. Nitroprusside was used to evaluate the effects of afterload on the coupling under the condition that preload reduction was comparable to that with lower body negative pressure. In 13 patients with heart failure (ejection fraction 32 +/- 3%. mean +/- SE). direct arterial pressure was simultaneously recorded with the left ventricular echocardiogram as the pressure was elevated by phenylephrine. Left ventricular contractile properties were defined by the slope (Ees) of the end-systolic pressure-volume relation. The effective arterial elastance (Ea) was expressed by the slope of the end-systolic pressure-stroke volume relation. Left ventricular external work. end-systolic potential energy and work efficiency. defined as external work per pressure volume area (external work + potential energy). were determined. Baseline ventricular load coupling in these patients was characterized by an increase in the ratio of arterial elastance to ventricular elastance (Ea/Ees) (1.96 +/- 0.31). This ratio decreased significantly. to 1.45 +/- 0.22. with nitroprusside. and increased to 2.37 +/- 0.34 with lower body negative pressure. Therefore. end-systolic potential energy was decreased by nitroprusside but was unaltered by lower body negative pressure while external work was comparably decreased by both manipulations. indicating that work efficiency was significantly augmented with nitroprusside but declined with lower body negative pressure.
Cardiovascular and hormonal effects of calcitonin gene-related peptide in congestive heart failure, The effects of infusing human alpha-calcitonin gene-related peptide were studied in eight patients with congestive heart failure. five normal rabbits and five rabbits with adriamycin-induced cardiomyopathy. In patients with heart failure. calcitonin gene-related peptide caused a dose-dependent increase in cardiac output and decrease in pulmonary and systemic vascular resistance and pulmonary artery pressure. The systemic blood pressure and right atrial and pulmonary wedge pressures decreased only at the highest infusion rate (16 ng/kg per min). Heart rate remained unchanged. Plasma epinephrine increased (p less than 0.05). whereas aldosterone. atrial natriuretic peptide and prolactin concentrations decreased (p less than 0.05). Plasma norepinephrine. renin activity. cortisol and growth hormone concentrations remained unchanged. In both groups of rabbits. the drug decreased blood pressure and increased cardiac output and heart rate. There was a significant increase in renal blood flow (p less than 0.05). The peptide did not affect the contraction amplitude of human and rabbit ventricular myocytes. These findings suggest that calcitonin gene-related peptide is a vasodilator in the rabbit and humans with little direct effect on ventricular myocardium. This peptide may be useful in some forms of heart failure.
Experimental pericardial effusion: relation of abnormal respiratory variation in mitral flow velocity to hemodynamics and diastolic right heart collapse, Pericardial effusion is associated with an abnormal increase in respiratory variation in mitral flow velocity. However. the relation of the changes in flow velocity to pericardial pressure. hemodynamics and two-dimensional echocardiographic findings is not established. Therefore. 11 sedated dogs with extensive hemodynamic instrumentation were studied with two-dimensional and Doppler echocardiography during four stages of progressively larger pericardial effusion. During all stages of effusion. respiratory variation in peak mitral flow velocity in early diastole and left ventricular isovolumetric relaxation time was increased compared with baseline (p less than 0.05). This increase was seen at the earliest stage of effusion (mean pericardial pressure 4.2 +/- 1.4 versus -0.8 +/- 0.9 mm Hg at baseline. p less than 0.05). and preceded the appearance of unequivocal diastolic right heart collapse in every dog. Maximal respiratory variation coincided with the appearance of right atrial collapse (mean pericardial pressure 7.1 +/- 2.4 mm Hg; mean inspiratory decrease in aortic pressure 9.5 +/- 2.6 mm Hg; mean aortic pressure 88.2 +/- 15.2 versus 102.2 +/- 11.2 mm Hg at baseline. p less than 0.05; and cardiac output 3.8 +/- 1.2 versus 5.5 +/- 1.3 liters/min at baseline. p less than 0.05). but did not increase at stages associated with more severe hemodynamic compromise. In addition. the respiratory changes in peak mitral flow velocity in early diastole were associated with simultaneous changes in the diastolic transmitral pressure gradient. It is concluded that in this model of acute pericardial effusion 1) increased respiratory variation in early diastolic mitral flow velocity. peak mitral flow velocity in early diastole and left ventricular isovolumetric relaxation time occurs almost immediately as pericardial pressure increases and persists at all stages of increasing pericardial effusion; 2) the abnormal respiratory variation occurs before equalization of intracardiac pressures and before the onset of unequivocal right heart collapse; 3) the respiratory variation occurs as a result of changes in the diastolic transmitral pressure gradient; and 4) the magnitude of the respiratory change is not necessarily predictive of pericardial pressure or severity of hemodynamic compromise. especially at the more severe stages of pericardial effusion.
Spontaneous alterations in coronary blood flow velocity before and after coronary angioplasty in patients with severe angina, Cyclic coronary artery flow variations with a spontaneous decline in coronary blood flow to very low levels have been documented in stenosed canine coronary arteries with endothelial injury. These flow variations are associated with transient platelet aggregation and dislodgment and the release of selected mediators. including thromboxane A2 and serotonin. However. cyclic or spontaneous flow variations have not been demonstrated in stenosed coronary arteries in humans. In this study. the hypothesis was tested that spontaneous coronary blood flow velocity variations occur in some patients with stenosed coronary arteries before or after coronary artery angioplasty. Thus. 13 patients with severe and limiting angina underwent intracoronary pulsed Doppler velocimetry of their dilated artery immediately before and after percutaneous transluminal coronary angioplasty. whereas 9 control patients underwent velocimetry of an angiographically normal coronary artery. A 3F catheter with a 20 MHz Doppler crystal was positioned to achieve a maximal stable signal. and the flow velocity signal was recorded continuously for 20 min. Spontaneous flow velocity variations (greater than or equal to 38% change in Doppler frequency shift with wide morphologic changes) were present in 3 of the 13 patients tested. Spontaneous flow velocity variations occurred before angioplasty in one patient. after angioplasty in another and both before and after angioplasty in a third. In addition. 2 of the 13 patients. 1 with spontaneous coronary artery flow velocity variations before angioplasty. had frank vasospasm in an adjacent area just distal to the area of coronary dilation immediately after balloon inflation. These data establish that spontaneous coronary artery flow velocity variations occur in some patients with severe and limiting angina before and after coronary angioplasty. These variations may be related to platelet aggregation or coronary vasoconstriction. or both. at sites of endothelial injury resulting from plaque fissuring or ulceration and endothelial and medial injury occurring during coronary angioplasty.
Elevated plasma beta-endorphin levels in patients with congestive heart failure, Recent experimental studies show that the opioid system is important to the pathophysiology of cardiovascular impairment in congestive heart failure. Plasma beta-endorphin levels were measured in 37 patients with congestive heart failure and compared with those of 21 age- and gender-matched normal subjects. The relation of plasma beta-endorphin levels and cardiac function at rest and exercise capacity was assessed in 17 of the patients with dilated cardiomyopathy. Exercise capacity was determined by symptom-limited maximal treadmill exercise with expired gas analysis. Plasma beta-endorphin levels were elevated and correlated with the patients' New York Heart Association functional cardiac status (control: 14.0 +/- 4.4 pg/ml; class II: 17.9 +/- 3.6 pg/ml; class III: 28.3 +/- 8.8 pg/ml; class IV: 46.7 +/- 14.6 pg/ml. mean +/- SD). No relation was found between plasma beta-endorphin levels and left ventricular systolic performance as assessed by M-mode and Doppler echocardiography. Plasma beta-endorphin levels were negatively correlated with cardiac output determined by Doppler echocardiography and positively correlated with systemic vascular resistance (r = -0.733. r = 0.747. respectively. both p less than 0.001). but not correlated with calf blood flow as measured by a plethysmography. A good correlation was found between plasma beta-endorphin levels at rest and exercise capacity. The correlations with peak oxygen consumption. anaerobic threshold. and peak rate-pressure product were r = -0.721. -0.672. and -0.674. respectively (p less than 0.01). The data show that plasma beta-endorphin levels are elevated in patients with congestive heart failure and reflect. to some degree. the severity of the disease.
Implications of echocardiographically assisted diagnosis of pericardial tamponade in contemporary medical patients: detection before hemodynamic embarrassment, Identification of suspected pericardial tamponade and the decision to perform invasive drainage of the pericardial space have historically been based on classic bedside findings. Two-dimensional echocardiography has improved detection of pericardial effusion. but it may be excessively sensitive in evaluation of patients for hemodynamic embarrassment. Therefore. 50 consecutive medical patients were examined who were identified by echocardiography to have probable tamponade (defined as the presence of right heart chamber collapse in the presence of a pericardial effusion) and who underwent combined right-sided cardiac catheterization and percutaneous pericardiocentesis. All patients had elevated pericardial pressure. However. many had minimal evidence of hemodynamic compromise (94% had systolic blood pressure greater than or equal to 100 mm Hg and 58% had a cardiac index greater than or equal to 2.3 liters/min per m2). Pericardiocentesis resulted in hemodynamic improvement. but frequently did not alleviate dyspnea or correct tachycardia. Patients with malignancy as the cause of tamponade had a high mortality rate (the cumulative probability of survival in such patients was only 17% at 1 year). Echocardiographically assisted diagnosis of pericardial tamponade in medical patients results in the identification of a substantial subset of patients with only subtle evidence of hemodynamic compromise. This subset of patients differs sharply from medical patients described in previous reports with classic tamponade. Although the patients can be managed by invasive catheter pericardiocentesis with few complications. the natural history and the optimal management strategy for this group are not resolved.
Recognition and embolic potential of intraaortic atherosclerotic debris, Atherosclerotic disease of the thoracic aorta is common in the elderly and patients with clinical coronary artery disease. Although embolization can occur from atherosclerotic debris within the thoracic aorta. it is not commonly considered in the differential diagnosis of the source of a systemic embolism. In the current study. the prevalence. clinical significance and embolic potential of intraaortic atherosclerotic debris as detected by transesophageal echocardiography was determined. Intraaortic atherosclerotic debris was identified in 38 (7%) of 556 patients undergoing transesophageal echocardiography. An embolic event occurred among 11 (31%) of the 36 study patients with intraaortic atherosclerotic debris. The incidence of an embolic event was higher when the debris was pedunculated and highly mobile (8 [73%] of 11 patients) than when it was layered and immobile (3 [12%] of 25 patients) (p less than 0.002). Among 15 patients undergoing an invasive procedure of the aorta. the incidence of embolism was 27%. In conclusion. in a patient with an embolic event. the thoracic aorta should be considered as a potential source. Transesophageal echocardiography can reliably detect intraaortic atherosclerotic debris. and when it is identified. an invasive aortic procedure should be avoided if possible.
Coronary arterial remodeling studied by high-frequency epicardial echocardiography: an early compensatory mechanism in patients with obstructive coronary atherosclerosis, Coronary arterial remodeling is a compensatory mechanism that may limit the adverse effects of coronary obstructive lesions by expansion of the entire vascular segment. To determine if this compensatory anatomic change occurs in patients. high-frequency epicardial echocardiography using a 12 MHz transducer was performed during open heart surgery in 33 patients (10 with normal coronary arteries undergoing valvular surgery and 23 with coronary atherosclerosis). From stop-frame videotape high-frequency epicardial echocardiographic images. cross-sectional measurements of luminal area and total arterial area (lumen. intima. media and dense adventitia) were made in the patients with atherosclerosis at the site of arterial lesions and from the most proximal portion of the same artery. Remodeling was defined as enlargement of the total arterial area. In normal arteries measurements were made from proximal and midarterial locations. In the patients with normal coronary arteries. total arterial area. as determined by high-frequency echocardiography. decreased from the proximal site to the midportion of the artery (from 10.4 +/- 0.9 to 8.4 +/- 1.0 mm2. p less than 0.05); luminal area also decreased (from 6.0 +/- 0.6 to 4.5 +/- 0.7 mm2. p less than 0.05). In patients with coronary arterial lesions. luminal area also decreased from the proximal site to the arterial lesion site (from 5.3 +/- 0.6 to 2.3 +/- 0.3 mm2. p less than 0.05). but total arterial area increased (from 11.6 +/- 1.0 to 13.0 +/- 1.0 mm2. p less than 0.05). Of the 25 coronary arteries evaluated. only 4 had angiographic evidence of coronary collateral formation. These data indicate that coronary arterial remodeling is an important compensatory mechanism in obstructive coronary disease.
Detection of coronary blood flow associated with left main coronary artery stenosis by transesophageal Doppler color flow echocardiography, Demonstration of disordered blood flow in a coronary artery may be helpful in anticipating the presence of stenosis. To examine the possibility of disordered coronary blood flow associated with left main coronary stenosis. left main coronary flow was visualized by transesophageal Doppler color flow echocardiography in 52 patients undergoing coronary angiography. Twenty patients had significant left main coronary stenosis (Group 1) and 32 patients did not (Group 2). Adequate two-dimensional echocardiographic images of the left main coronary artery were obtained in 17 patients in Group 1 and 30 patients in Group 2. Sixteen patients in Group 1. including five patients in whom the stenosis could not clearly be defined by two-dimensional echocardiography. exhibited the aliased reddish-yellowish elements producing the mosaic pattern at the stenotic or poststenotic segments. or both. In contrast. nonaliased bluish jets. suggesting laminar flow away from the transducer. were seen in echocardiograms from 27 patients in Group 2. This group included four patients with stenosis-like images on two-dimensional echocardiography. The aliased mosaic pattern was found in only three patients in Group 2 (p less than 0.01). Thus. sensitivity to detect the stenosis was improved when Doppler color flow imaging was applied. Flow velocity was significantly higher at the site of stenosis in patients in Group 1 (116 +/- 28 cm/s. n = 10. mean +/- SD) than in Group 2 (29 +/- 12 cm/s. n = 21. p less than 0.01). suggesting that the augmentation of flow velocity with or without turbulence due to the stenosis contributed to the appearance of the mosaic flow images.
Patients in a persistent vegetative state attitudes and reactions of family members, Patients in a persistent vegetative state (PVS) constituted approximately 3% of the population in four Milwaukee nursing homes. In order to understand family members' attitudes and reactions toward such patients. 33 (92%) of 36 family members of patients in PVS contacted were studied. The age of the patients ranged from 19 to 95 with a mean age of 73.4 +/- 17.2 years. and family members' ages ranged from 41 to 89 with a mean age of 61.8 +/- 3.3 years. The etiology of the PVS varied from dementia to cerebral trauma. The mean duration of the PVS was 54 +/- 8.4 months (range 12 to 204). Family members reported that they visited patients 260 times during the first year following the onset of the PVS and were still visiting at a rate of 209 visits yearly at the time of the interview. There was no significant correlation between the frequency of the family members visits and the duration of the PVS. the patient's or family member's age. or the family member's relationship to the patient. Ninety percent of patients were considered by family members to have some awareness of pain. light or darkness. environment. taste. verbal conversation. or the family member's presence. Most family members thought they understood the patient's medical condition. and the majority did not expect the patient to improve. Nevertheless. the majority of family members wanted the patient to undergo therapeutic interventions. including transfer to the acute hospital and surgery.
Breast cancer screening in older women: practices and barriers reported by primary care physicians, Annual mammography. in combination with clinical breast examinations. can reduce mortality from breast cancer. However. surveys of both patients and physicians suggest that mammography is underutilized. This study examined whether physicians' reported breast cancer screening practices and barriers to mammography varied with patients' age. Data from 576 primary care physicians (internal medicine. family/general practice. and obstetrics/gynecology) who participated in a mailed statewide survey were analyzed. Physicians reported screening elderly women significantly less often than younger women. regardless of family history of breast cancer. With the exception of medical specialty. physicians' demographic and practice characteristics were not associated with reported screening practices. However. physicians' knowledge and beliefs about breast cancer in older women were associated with reported screening practices. When analyzing barriers to ordering mammography. cost to the patient was viewed as a barrier for women of all ages. and pain was viewed as a greater barrier for younger women; otherwise. physicians consistently believed that their elderly patients faced considerably more barriers compared with younger women. Further investigation is required to examine why primary care physicians report age-related differences in both breast screening and barriers to mammography.
Forearm blood flow response to posture change in the very old: non-invasive measurement by venous occlusion plethysmography, Little is known about the peripheral vascular response to posture change in very elderly people who are vulnerable to the development of orthostatic hypotension. This is due. in part. to the risks of currently utilized invasive vascular monitoring techniques in the elderly population. We studied the forearm vascular response to active standing in 18 healthy young. 10 healthy old. and 19 impaired elderly subjects. using the non-invasive technique of venous occlusion plethysmography. In six subjects this technique was compared to duplex doppler ultrasonography for the measurement of postural changes in forearm blood flow. Forearm blood flow changes determined by venous occlusion plethysmography were 11% larger than doppler measurements. but the two methods strongly correlated (r = 0.90. P less than .001). Mean forearm vascular resistance increased to a significantly greater extent at 1 minute of standing in young subjects than in both groups of old. although the response was quite variable in all groups. Two healthy elderly (20%) and eight impaired elderly (40%) subjects had unexpected forearm vasodilatation at 1 minute of standing. By 3 minutes. forearm vascular resistance had increased by similar amounts in all three groups of subjects. Five impaired elderly and no healthy young or healthy old subjects had orthostatic hypotension. defined as greater than or equal to 10 mm Hg decline in mean arterial blood pressure at 1 or 3 minutes of standing. Forearm vascular resistance changes did not correlate with blood pressure response to standing. Thus. forearm vascular response to 1 minute of active standing is attenuated in many elderly subjects. This abnormality may impair adaptation to orthostatic stress in advanced age.
Ostium secundum atrial septal defect in the elderly, Atrial septal defect (ASD) is one of the most common congenital cardiac anomalies in adults. Life expectancy is shortened. and almost 90% of patients die by the age of 60 years. The progression of this congenital disease to congestive heart failure has been related to several factors such as the onset of pulmonary hypertension. arrhythmias. bronchopulmonary infections. or the development of other cardiovascular disease. We describe three cases of very old patients with significant ASDs and late development of symptoms. Given the higher risks and poorer long-term results of surgical closure of the defect in advanced age. the indications for such an intervention in elderly patients should be carefully evaluated.
Separation and characterization of saponins with adjuvant activity from Quillaja saponaria Molina cortex, Saponins were purified from Quillaja saponaria Molina bark by silica and reverse phase chromatography. The resulting purified saponins were tested for adjuvant activity in mice. Several distinct saponins. designated QS-7. QS-17. QS-18. and QS-21. were demonstrated to boost antibody levels by 100-fold or more when used in mouse immunizations with the Ag BSA and beef liver cytochrome b5. These purified saponins increased titers in all major IgG subclasses. To determine optimal dose in mice for adjuvant response. QS-7 and QS-21 were tested in a dose-response study in intradermal immunization with BSA in mice; for both of these purified saponins. adjuvant response (determined by stimulation of ELISA titers to BSA) neared maximum at doses of 5 micrograms and was shown to plateau up to the highest dose tested. 80 micrograms. These purified saponins vary considerably in their toxicity. as assessed by lethality in mice; the main component. QS-18. being the most toxic. Saponins QS-7 and QS-21 showed no or very low toxicity in mice. respectively. None of these saponins stimulated production of reaginic antibodies. The monosaccharide composition of these saponins showed similar but distinct compositions with all four containing fucose. xylose. galactose and glucuronic acid. Predominant differences were observed in the quantities of rhamnose. arabinose. and glucose. Monomer m.w. (determined by size exclusion HPLC) were determined to range from 1800 to 2200.
Delayed-type hypersensitivity initiation by early-acting cells that are antigen mismatched or MHC incompatible with late-acting, delayed-type hypersensitivity effector T cells, The elicitation of delayed-type hypersensitivity (DTH) responses in mice is mediated by the sequential activities of two different Ag-specific. Thy-1+ cells. A required early phase of elicitation is due to DTH-initiating Thy-1+ cells that are CD3- and sIg- and produce Ag-specific factors that act like IgE antibodies in that they sensitize the tissues. so that after local challenge with Ag there is release of the vasoactive amine serotonin. Released serotonin locally recruits and activates CD4+ Th-1 classical DTH effector T cells that secrete lymphokines that attract and activate a nonspecific perivascular infiltrate of circulating. bone marrow-derived leukocytes. The current study used isolated subpopulations of DTH-initiating and DTH-effector T cells to determine whether the two phases of the elicitation of DTH were entirely separate. The contact sensitivity model of DTH was used. Early-acting DTH-initiating cells. and late-acting DTH-effector T cells were either from oxazolone (OX)-immune or picryl chloride (PCl)-immune CBA or BALB/c donors and were transferred to CBA or BALB/c recipients. The results showed that DTH-initiation could be mediated by polyclonal DTH-initiating cells that were Ag mismatched or MHC incompatible with late-acting DTH effector T cells. In fact DTH-initiating cells could be both Ag mismatched and MHC incompatible with late-acting T cells. In addition. potential interactions between different cell populations were ruled out by showing that DTH-initiation could be mediated by a DTH-initiating clone that was Ag or MHC mismatched with the late-acting DTH-effector T cells. Thus. the OX-specific BALB/c clone could initiate DTH for PCl-specific CBA cells in CBA recipients if the recipients were challenged with both OX and PCl. but not when they were challenged with OX or PCl alone. We suggest. at least for the elicitation of DTH reactions in mice. that a more comprehensive description of these responses should accommodate the fact that there are early and late phase responses that each begin with Ag specificity and end with non-specific humoral factors. Inasmuch as the two Thy-1+ cells of DTH can be of different Ag specificity. this suggests that some forms of delayed and chronic inflammation. might be initiated by an immediate hypersensitivity-like immune reactivity to one set of Ag. and could be prolonged and perpetuated by delayed reactivity to another set of Ag.
Ultraviolet B radiation converts Langerhans cells from immunogenic to tolerogenic antigen-presenting cells. Induction of specific clonal anergy in CD4+ T helper 1 cells, We have recently demonstrated that a single dose (200 J/m2) of UVB radiation abrogates the capacity of mouse epidermal Langerhans cells (LC) or splenic adherent cells (SAC) to present keyhole limpet hemocyanin (KLH) to Ag-specific. MHC-restricted CD4+ Th1 cells. In the present study we determined whether such Th1 unresponsiveness represented long-lasting immunologic tolerance. To address this question. Th1 were preincubated with KLH-pulsed UVB-LC or UVB-SAC. then isolated and restimulated with unirradiated APC (LC or SAC) plus KLH or with exogenous rIL-2 in the absence of APC. Preincubation with KLH and UVB-LC or UVB-SAC rendered Th1 unresponsive to subsequent restimulation with APC and KLH. In addition. such Th1 were defective in their autocrine IL-2 production. but could respond normally to exogenous rIL-2. indicating that unresponsiveness was due to functional inactivation and not to cell death. Th1 unresponsiveness was Ag-specific. MHC-restricted. and long lasting (greater than 16 days). In addition. it appears that Th1 unresponsiveness is not due to the release of soluble suppressor factors from UVB-LC or UVB-SAC because supernatants from such cells had no effect on Th1 proliferation. Addition of unirradiated allogeneic SAC during preincubation prevented the induction of unresponsiveness by UVB-LC or UVB-SAC. suggesting that UVB interferes with the capacity of LC or SAC to deliver a costimulatory signal(s) that can be provided by allogeneic SAC. We conclude that UVB can convert LC or SAC from immunogenic to tolerogenic APC.
Newly identified U4/U6 snRNP-binding proteins by serum autoantibodies from a patient with systemic sclerosis, We found serum autoantibodies directed against the proteins binding exclusively to U4/U6 of Sm small nuclear ribonucleoprotein particle (snRNP) in serum from a patient (MaS) with systemic sclerosis. Their specificity. called anti-MaS. is distinct from that of known antibodies against U snRNP. The U4 and U6 small nuclear RNA from a 32P-labeled HeLa cell extract and five proteins with Mr 150.000. 120.000. 80.000. 36.000. and 34.000. in addition to Sm core proteins (B. B'. D. E. F. and G) from an [35S] methionine-labeled extract. were immunoprecipitated by anti-MaS in isotonic solution. However. the Sm core proteins and U4 and U6 small nuclear RNA were separated from the protein-A-Sepharose facilitated MaS immunoprecipitate by incubation in a solution containing 500 mM NaCl. In immunoblots. anti-MaS antibodies reacted with one protein of Mr 150.000 from a HeLa cell nuclear extract that was fractionated by SDS-PAGE and transferred to a nitrocellulose sheet. The monospecific immunoaffinity purified antibody eluted from the immunoblot band immunoprecipitated U4 and U6 small nuclear RNA and reblotted the protein with Mr 150.000. These data indicate that anti-MaS antibodies recognize at least one antigenic protein that binds exclusively to the U4/U6 snRNP.
Parental MHC molecule haplotype expression in (SJL/J x SWR)F1 mice with acute experimental allergic encephalomyelitis induced with two different synthetic peptides of myelin proteolipid protein, To determine if the Ag that induces an autoimmune disease influences parental MHC haplotype molecule expression in situ in MHC heterozygotes. acute experimental allergic encephalomyelitis (EAE) was induced with different encephalitogenic peptides in (SJL/J x SWR)F1 mice. The mice were sensitized with either a synthetic peptide corresponding to mouse myelin proteolipid protein (PLP) residues 103-116 YKTTICGKGLSATV which induces EAE in SWR (H-2q). but not SJL/J (H-2s) mice or a synthetic peptide corresponding to PLP residues 139-151 HCLGKWLGHPDKF which is encephalitogenic in SJL/J but not SWR mice. Mice were killed when they were moribund or at 30 days after sensitization. Twelve of 18 F1 mice given PLP peptide 103-116 and 12 of 17 mice given PLP peptide 139-151 developed EAE within 2 to 3 wk after sensitization. Cryostat sections of brain samples from F1 and parental mice were immunostained with a panel of mAb identifying H-2s and H-2q class I and II MHC molecules. In brains of controls. class I MHC molecules were expressed on choroid plexus. endothelial cells. and microglia whereas class II MHC molecules were absent. In EAE lesions. class I and II MHC molecules were present on inflammatory and parenchymal cells. but the degree of parental haplotype molecule expression did not vary with the different peptide Ag tested. Thus. in (SJL/J x SWR)F1 mice. myelin PLP peptides 103-116 and 139-151 are co-dominant Ag with respect to clinical and histologic disease and parental haplotype MHC molecule expression. We propose a unifying hypothesis consistent with these results and previous observations of differential Ia expression in (responder x non-responder)F1 guinea pigs. We suggest that MHC molecules may bind locally derived peptide Ag in inflammatory sites and that these interactions influence levels of MHC haplotype molecules on APC.
IL-6 production by human T lymphocytes. Expression in HTLV-1-infected but not in normal T cells, IL-6 is an important regulator of humoral and cellular immunity. Although this cytokine is produced by diverse cell types. it is not known whether it is produced by T lymphocytes under physiologic conditions or which agents can induce T cell expression of IL-6. We analyzed the production of IL-6 by human peripheral blood T cells. human thymocytes. and human T cell lines. In pure populations of these cells. stimulated with different combinations of various mitogens and cytokines. IL-6 activity could not be detected. Analysis of purified T-alpha beta and T-gamma delta cells showed that neither T cell subset produced IL-6. Similarly. IL-6 mRNA was not detected in T cell or thymocyte populations for up to 48 h after stimulation. With the use of a PCR assay. IL-6 mRNA in T cells was found to be virtually negligible. and did not change after T cell activation. By in situ hybridization it was shown that the cells expressing IL-6 mRNA after mitogen activation of PBMC do not belong to the T cell lineage. To analyze whether human T cells express IL-6 in vivo. we examined lymphoid tissues by in situ hybridization. In normal human thymus there was no detectable signal for IL-6. Tonsils showed only few positive cells within the parenchyma. but strong expression of IL-6 by epithelial cells in crypts. In contrast to normal lymph node. which contained only rare cells positive for IL-6. a lymph node from a patient with Castleman's disease showed IL-6 expression in cells occupying the marginal sinus and interfollicular areas. Screening of various human T cell lines showed that all cell lines infected with HTLV-1 secrete IL-6 activity and express IL-6 mRNA. In addition. in vitro infection of peripheral blood T cells with HTLV-1 induced de novo synthesis and secretion of IL-6. Furthermore. IL-6 expression in HTLV-1-infected cells was enhanced by stimulation with IL-1 beta or TNF-alpha. In contrast. IL-6 was not detectable in non-infected T cell lines. These studies indicate that IL-6 may not be a physiologic product of human T lymphocytes and that infection of T cells with HTLV-1 results in aberrant expression of this cytokine.
Effects of site-specific mutations on biologic activities of recombinant human IL-6, To examine structure-activity relationships of human IL-6. we have determined the effects of specific mutations on the biologic activity of a human rIL-6 expressed in bacteria. Three types of mutants were examined: 1) a variant that contains serines in place of the four naturally occurring cysteines; 2) a series of cysteine-containing deletion mutants. each having a single internal 20 amino acid deletion; and 3) a cysteine-free variant containing a single 20 amino acid deletion. The mutants of the second type constitute a set of nonoverlapping. adjacent deletions spanning amino acids 4 through 183 of the 184 amino acids in natural human IL-6. All of the mutants were expressed. along with the full length. cysteine-containing analogue. in Escherichia coli as fusion proteins. joined to beta-galactosidase through a collagen linker. This system allows microgram quantities of the rIL-6 variants to be partially purified from small bacterial cultures without chromatographic or refolding steps. Each of the rIL-6 variants was released from the beta-galactosidase fusion protein with collagenase. and the recovered rIL-6 was quantitated by laser densitometry of Coomassie-stained. SDS polyacrylamide gels. The sp. ac. of each of the rIL-6 variants was determined using four assays: induction of IgM secretion from an EBV transformed human B cell line. induction of fibrinogen secretion from a human hepatoma cell line. induction of fibrinogen secretion from a rat hepatoma cell line. and induction of proliferation of a murine hybridoma cell line. Replacement of cysteines with serines reduced activity relative to cysteine-containing rIL-6 to about 20% in the rat hepatoma assay and about 3% in the mouse hybridoma assay. whereas activity in both of the human cell lines was reduced to less than 0.1%. These data suggest that the murine and rat cell lines are less selective than the human cell lines in their requirements for recognition of biologically active IL-6. Each of the deletions. except that of amino acids 4 through 23. resulted in loss of activity in all four assays. These results suggest that the information necessary for activity is not contained within any one portion of the IL-6 molecule. but rather that multiple segments of the protein are required for each of the biologic activities that we tested.
Tumor necrosis factor-independent IL-6 production during murine listeriosis, We report that TNF. IL-6. and IFN-alpha/beta are produced by mice during either sublethal or lethal Listeria monocytogenes infections. The quantities of these cytokines in infected spleens increase and decrease in concordance with bacterial numbers in these organs. While all of these cytokines were present in Listeria-infected spleens. only IL-6 and IFN-alpha/beta were found in the peripheral circulation. Inasmuch as TNF has been reported to be responsible for the production of IL-6 in vivo following the inoculation of a lethal dose of the Gram-negative bacterium. Escherichia coli (Fong et al.. 1989. J. Exp. Med. 170: 1627). experiments were undertaken to determine whether IL-6 production elicited by the Gram-positive bacterium. L. monocytogenes. was also TNF-dependent. It was found that the passive immunization of mice with neutralizing antibodies specific for TNF shortly before i.v. injection of a lethal or sublethal Listeria inoculum resulted in the complete neutralization of endogenously produced TNF. and in the progressive multiplication of bacteria in infected organs. It was also found that the anti-TNF IgG treatment resulted in a progressive increase in the amounts of Listeria-induced IL-6 present in spleen and blood. until the death of the host. These findings indicate that Listeria-induced IL-6 production in mice occurs primarily through a TNF-independent pathway. and correlates directly with the severity of the infection.
The role of tumor-derived cytokines on the immune system of mice bearing a mammary adenocarcinoma. I. Induction of regulatory macrophages in normal mice by the in vivo administration of rGM-CSF, Using a dimethylbenzanthracene-induced immunogenic nonmetastatic murine mammary adenocarcinoma in BALB/c mice. our previous work has shown that splenocytes from tumor bearers have reduced responses to both mitogens and Ag including tumor-associated Ag. NK and cytotoxic T cell activities are also reduced in splenocytes of tumor bearers. Mac-1+2+ macrophages induced in mammary tumor bearers are capable of down-regulating lymphocyte responses to mitogens and tumor-associated Ag by cell to cell contact interaction and increased PGE2 production. We have found that the tumor constitutively releases a granulocyte-macrophage (GM)-CSF-like factor in vivo and in vitro. which may be responsible for the systemic increase in cells of the macrophage lineage in tumor-bearing mice. A tumor cell line established from the in vivo tumor expresses and releases GM-CSF as shown by Northern and Western blot analyses. Daily i.p. injections for 3 wk of 10.000 U of rGM-CSF into normal mice induces hemopoietic and immunologic alterations similar to those observed in tumor bearers. Mac-1+ and/or Mac-2+ macrophages can also be detected in the spleens and bone marrow of the mice treated with rGM-CSF. Additionally. splenocytes from rGM-CSF-treated mice have reduced responses to mitogens and their peritoneal exudate cells can cause in vitro down-regulation of proliferative responses of lymphocytes from normal mice. The suppression can be partially reversed by the addition of indomethacin to the cultures suggesting that PGE2 may contribute to the effect. rGM-CSF enhances the in vitro release of PGE2 by the spleen. bone marrow. and peritoneal cells of normal mice. These data indicate that the high levels of GM-CSF constitutively produced by the tumor may be responsible for the hemopoietic changes and immunologic alterations observed in tumor-bearing mice.
Abnormalities in epidermal lipid metabolism in patients with atopic dermatitis, Atopic dermatitis is an inflammatory skin disease characterized by dryness and itch of the skin. In this study. we measured the phospholipid content and the fatty acid pattern of lesional and lesion-free epidermal keratome biopsies on 15 patients. For comparison. epidermal biopsies were obtained from healthy individuals undergoing plastic surgery. The phospholipid content of atopic epidermis was nearly twice as high as in healthy epidermis. Monounsaturated fatty acids in the phosphoglycerides were significantly increased (p less than 0.001) and n-6 fatty acids were significantly decreased (p less than 0.001) in lesional atopic epidermis compared to lesion-free epidermis. The content of esterified arachidonic acid in phosphatidylcholine from lesional epidermis was only 49% of that found in healthy epidermis (p less than 0.001). The content of free arachidonic acid was 47% higher (p less than 0.05). whereas the content of free long-chain saturated fatty acids was decreased by 29% (p less than 0.01). in lesional compared to lesion-free atopic epidermis. The disease severity. calculated as an arbitrary index. correlated inversely with the n-6 fatty acid content of lesion-free atopic epidermis (r = -0.89. p less than 0.001). Our findings suggest that atopic epidermis is characterized by an increased activity of phospholipase A2 and an incomplete transformation of phospholipids into other lipid classes.
Insulin-like growth factors are mitogenic for human keratinocytes and a squamous cell carcinoma, Normal adult human keratinocytes in monolayer culture and SCL-1. a skin-derived squamous-cell carcinoma cell line. were investigated for the expression of receptors for insulin-like growth factors (IGF) and insulin. As demonstrated by affinity crosslinking. radiolabeled IGF-1. IGF-2. and insulin bound specifically to both cell types. Each cell expressed type I IGF receptors. with affinity for IGF-1 greater than IGF-2 much greater than insulin. Insulin receptors. with highest affinity for insulin. were also present on both cells. However. keratinocytes and SCL-1 cells differed in 125I-IGF-2 binding. 125I-IGF-2-bound to both type I and type II IGF receptors in normal keratinocytes. but bound predominantly to membrane-associated IGF binding proteins in SCL-1. IGF-1 was slightly more potent than IGF-2 in stimulating growth of both keratinocytes and SCL-1 cells. In keratinocytes. concentrations of IGF-1 ranging from 5-100 ng/ml. and of IGF-2 from 50-100 ng/ml. resulted in a significant increase in cell number. At the maximum dose of 100 ng/ml. either IGF-1 or IGF-2 caused a 2.3-times increase in cell number. In SCL-1 cells. IGF-1 was more potent than IGF-2 or insulin at lower concentrations. but either IGF-1 or IGF-2 at the maximal concentration of 333 ng/ml stimulated a 4.7-times increase in thymidine incorporation. The stimulatory effect of insulin in SCL-1 was 10-50 times less potent than that of the IGF. The effect of either IGF on SCL-1 was completely inhibited by the type I IGF receptor antibody alpha IR-3. suggesting that both IGFs are mitogenic through the type I IGF receptor. Insulin action was partially blocked by alpha IR-3. suggesting that insulin can act through both the insulin and type I IGF receptors. It thus appears that IGF-1 and IGF-2 are mitogens for normal and transformed human keratinocytes and that their actions are primarily mediated through the type I IGF receptor. whereas insulin is a mitogen through both the IGF-1 receptor and the insulin receptor.
Effect of retinoic acid on platelet-derived growth factor (PDGF) bioactivity and type-B PDGF receptors in normal and psoriatic human fibroblasts, Psoriasis is a common skin disease in which retinoids have beneficial effects. It offers a model for the study of benign hyperproliferation with abnormal differentiation. The dermis has a prominent role in the appearance of epidermal lesions. It is therefore of interest to study the factors that modulate dermal cell proliferation. In this study. the role of retinoids in modulating platelet-derived growth factor (PDGF) bioactivity was studied in normal (six subjects) and psoriatic fibroblasts from involved and uninvolved tissues (six patients). Retinoic acid treatment (for 4 d at 10(-6) M) of psoriatic fibroblasts significantly increased the chemotactic effect of PDGF in these cells (p less than 0.01 and p less than 0.05. respectively. in involved and uninvolved skin at 20 ng/ml of platelet-derived growth factor as measured in a modified Boyden Chamber Assay). In the same way. retinoic acid treatment of psoriatic fibroblasts increased the mitogenicity of platelet-derived growth factor in these cells. Retinoic acid treatment has no significant effect on the mitogenic and chemotactic activity of PDGF in normal fibroblasts. The binding of the homodimer BB PDGF to its type-B receptor. which mediates the mitogenic and chemotactic effect of PDGF. was not modified by retinoic acid treatment either in psoriatic and/or normal fibroblasts. These results suggest that retinoic acid may modulate the PDGF bioactivity in psoriatic fibroblasts not by affecting the binding of this ligand to these cells but by influencing a post-receptor event.
Inositol phosphate formation in the human squamous cell carcinoma line SCC-12 F: studies with bradykinin, the calcium ionophore A23187, and sodium fluoride, The phospholipase C (PLC)-mediated hydrolysis of membrane phosphoinositides is an important signal transduction pathway coupled to the cell-surface receptors for several hormones and growth factors. In addition. PLC activity can be modulated by changes in intracellular calcium and activation of GTP binding proteins. In this report. differential activation of PLC in the human keratinocyte cell line SCC-12F was studied as judged by specific patterns of inositol phosphate formation. Several hormones and growth factors previously shown to stimulate PLC in a variety of cell types were screened for activity in SCC-12F cells. Only bradykinin was active. stimulating the PLC-dependent generation of inositol (1.4.5) triphosphate (Ins(1.4.5)P3). Ins(1.4.5)P3 was rapidly metabolized to inositol(1.4)biphosphate (Ins(1.4)P2) and inositol(1.3.4.5)tetrakisphosphate (Ins(1.3.4.5)P4). and subsequently degraded to inositol monophosphates. The response elicited by bradykinin was concentration dependent (EC50 value of 50 nM). suggesting involvement of a specific bradykinin receptor. Treatment of these cells with the calcium ionophore A23187 appeared to result in the direct formation of Ins(1.4)P2 without Ins(1.4.5)P3 as precursor. Treatment of the cells with AIF4-. a putative activator of GTP binding proteins. resulted in the generation of inositol monophosphates as the major metabolites in the absence of detectable Ins(1.4.5)P3 formation. Taken together. these observations suggest that the PLC complex present in SCC-12F cells can be differentially activated to yield either Ins(1.4.5)P3. Ins(1.4)P2. or InsP. The observed effects may be due to a direct PLC-dependent hydrolysis of the appropriate membrane phosphoinositide.
Characterization of 230-kD bullous pemphigoid antigen associated with the detergent-insoluble fraction of cultured keratinocytes, The 230-kD protein identified by antibodies from patients with bullous pemphigoid (BP) has a dual location in cultured normal human epidermal keratinocytes: part in a high-speed supernatant of homogenized cells and part in a particulate fraction. where it is resistant to extraction by non-ionic detergent or mild base. Antibodies were affinity purified from the particulate 230-kD BP antigen. which can be extracted in the presence of urea. The affinity-purified antibodies bind not only the cytosolic 230-kD protein. showing that it is related. if not identical. to the particulate form. but also produce a discontinuous granular pattern by indirect immunofluorescence in the basement membrane zone of rabbit esophagus. In stratifying epidermal cultures. expression of the 230-kD BP antigen is limited to basal cells. These data are consistent with 230-kD BP antigen involvement in keratinocyte basal cell interaction with extracellular matrix and indicate that the cultured cell may provide a useful model for analysis of 230-kD BP antigen function.
The calcium-sensitive epitope of pemphigus foliaceus antigen is present on a murine tryptic fragment and constitutes a major antigenic region for human autoantibodies, Recent findings indicate that the pemphigus foliaceus (PF) antigen is involved in epidermal cell adhesion and that characteristic PF lesions result from loss of this function as a consequence of autoantibody binding. In the present communication we present data on the epitopes involved in the human autoantibody binding to an immunologically reactive murine tryptic fragment of the PF antigen (tf-PF). Immunoprecipitation experiments showed that 39 PF sera. obtained from North American. Colombian. and Brazilian patients recognized only calcium-sensitive epitope(s) on the tf-PF. Immunofluorescence blocking experiments showed that preincubation with tf-PF completely blocked the immunofluorescence of 80% of the sera when tested on human skin substrate. and 86% of the sera when tested on murine skin substrate. These results show that the calcium-sensitive epitope(s) originally recognized on human PF complex. is (are) present on the murine tf-PF and constitute(s) a major antigenic region for the human PF autoantibodies. They also implicate this region of the PF antigen in the pathogenesis of PF as well as in epidermal cell adhesion.
Reduced neutrophil LTB4 release in atopic dermatitis patients despite normal fatty acid composition, Propositions about an abnormal fatty acid metabolism in atopic dermatitis patients prompted us to compare the phospholipid fatty acid composition and LTB4 release of neutrophils from 15 atopic dermatitis patients. as well as the adipose tissue triglyceride fatty acid composition. to that of 15 healthy controls matched by age. gender. and smoking habits. We found no differences in the tissue fatty acid composition between the two groups. The release of leukotriene B4 from Ca-ionophore-stimulated neutrophils in patients was on the average only 42% (p less than 0.001) of that measured in the control group. despite the very similar arachidonic acid contents of these cells. Our study does not support the assumption of an abnormal fatty acid desaturation in atopic dermatitis patients. Rather. the capacity to release and/or convert arachidonic acid into leukotrienes in neutrophils appears to be affected by this disease.
Localization of neutrophil-activating peptide-1/interleukin-8-immunoreactivity in normal and psoriatic skin, Various cytokines have in the past been detected in human skin. Among these. the neutrophil-activating peptide NAP-1/IL-8 is a potent 8-kD proinflammatory peptide that has been purified from psoriatic scales. Its chemotactic activity on human neutrophils. as well as its presence in psoriatic scales. may relate to a role in this disease. In the present study. the tissue distribution of the peptide was examined immunohistochemically using two monoclonal antibodies (52E8. 46E5) recently produced and characterized in our laboratory. Immunoreactivity was detected in both normal and psoriatic skin. resulting in uniform suprabasal keratinocyte staining in normal skin with 52E8 and of all keratinocytes with 46E5. Immunoreactivity in psoriasis correlated to the inflammatory tissue reaction. varying from uniform absence in highly active psoriasis to focally weak staining in plaque type psoriasis. Cells of the acrosyringium and hair follicles were always positive and were unaffected by the inflammatory activity. Epidermal immunoreactivity detected in this study may be associated with closely related peptides of the IL8 family or with truncated or extended forms of NAP-1/IL-8.
Characterization of skin-infiltrating lymphocytes in patients with psoriasis, In this study. skin-infiltrating cells in psoriasis patients were characterized in biopsies from both involved and uninvolved skin. Histologic examination of biopsies showed the presence of both CD4+ and CD8+ T cells and the lack of B lymphocytes. Skin biopsies were also placed in tissue culture medium supplemented with human serum. interleukin-2 (IL-2). and irradiated autologous blood lymphocytes. T lymphocytes grew from both plaques and univolved skin biopsies and consisted of a heterogeneous population of T-cell subsets. The immunophenotypic analysis of cultured cells was comparable to the histologic examination on frozen section. i.e.. there was a greater number of CD4/CDw29+ cells than CD8+/CD45+ cells. Cultures were tested in the primed lymphocyte test (PLT) and cell-mediated lympholysis (CML) assays. All cultures tested demonstrated secondary proliferative but not cytolytic reactivity. The PLT results indicate that the cell cultures generated are autoreactive. This autoreactivity was found to be directed against non-human leukocyte antigens (HLA). i.e.. minor HLA with some restriction to major HLA antigens.
IgA-binding structures in dermatitis herpetiformis skin are independent of elastic-microfibrillar bundles, Dermatitis herpetiformis (DH) is characterized in part by the presence of granular deposits of IgA in the papillary dermis just beneath the dermal-epidermal junction. The nature of the structures to which IgA binds in DH skin. however. has not been clearly demonstrated. Previous immunoelectron-microscopy studies using the peroxidase-antiperoxidase technique have concluded that the IgA may bind to abnormal elastic microfibrillar bundles. Recently. antibodies have been developed against a major component of the elastic microfibril bundles. fibrillin. In addition. another dermal matrix protein. hexabrachion. has been characterized and found in normal human skin in a distribution similar to the IgA deposits of DH. Utilizing antibodies against fibrillin. hexabrachion. and human IgA and immunoelectronmicroscopy with immunogold staining techniques. we have examined the skin from patients with DH in order to localize the IgA deposits. Normal-appearing skin from five patients with DH exhibited electron-dense patches within the dermis. which were not seen in skin from normal subjects. These structures were sometimes adjacent to the basement membrane zone. but appeared amorphous and without a well-defined fibrillar structure. The electron-dense patches were labeled with anti-human IgA. but not with antibodies to fibrillin or hexabrachion. The anti-IgA antibody did not label the normal basement membrane. These studies confirm the presence of abnormal electron-dense. amorphous structures in the skin of patients with DH. Due to this lack of association with the elastic microfibril bundles and the lack of labeling with antibodies against fibrillin. we suggest that these deposits are distinct from the microfibrillar bundles of elastic tissue and may represent IgA bound to degraded basement membrane or isolated dermal deposits of IgA.
Expression of basement membrane proteins and interstitial collagens in dermal papillae of human hair follicles, The expression of basement membrane molecules and interstitial collagens in human hair follicle mesenchyme was studied by immunohistochemical staining of tissue sections and of cells cultured from dermal papillae. Type I and type III collagens were found in the dermal sheath and in the dermal papilla throughout the hair cycle. Laminin and type IV collagen were expressed at the outer root sheath basement membrane and in the extracellular matrix of the dermal papilla of anagen and catagen follicles. In telogen follicles. where the volume of the dermal papilla extracellular matrix is much reduced. outline staining of dermal papilla cells for laminin and type IV collagen was still apparent. Staining for bullous pemphigoid antigen was also seen at the outer root sheath basement membrane extending to the lower tip of the hair bulb. In anagen follicles. there was no staining for bullous pemphigoid antigen at the interface between hair bulb epithelium and the dermal papilla and no staining within the dermal papilla. However. linear staining for bullous pemphigoid antigen became continuous around hair follicle epithelium during catagen and telogen. Cells cultured from human dermal papillae also stained for interstitial collagens. type IV collagen and laminin. However. similar results were obtained when cultured dermal fibroblasts were stained with the same antibodies. The expression of basement membrane proteins in human dermal papillae resembles that seen in follicles from other mammalian species and suggests that this is relevant to dermal papilla function. Cultured dermal papilla cells express a similar pattern of interstitial collagens and basement membrane proteins to those seen in tissue sections but this finding is not specific to dermal papilla cells.
Chronic hypomagnesemia caused by cisplatin: effect of calcitriol, A group of six patients with hypomagnesemia (serum magnesium less than or equal to 0.5 mmol/L). previously given treatment with cisplatin for ovarian or testicular cancer. received calcitriol at a dose of 0.5 to 1.0 microgram/day for a period of 4 weeks to determine whether treatment with this vitamin D metabolite could improve their hypomagnesemia. In response to treatment. the serum magnesium concentration fell progressively in association with a rise in serum and urinary calcium levels and a decrease in parathyroid hormone level. In a single previous report. active vitamin D metabolites markedly improved renal magnesium wasting. However. in the present study. increases in serum and urinary calcium levels and suppression of parathyroid hormone. factors known to decrease magnesium reabsorption. presumably overwhelmed any direct effect calcitriol may have had to enhance magnesium reabsorption. so that the net effect was a marked exacerbation of the renal magnesium wasting.
Morphology of sickle cells produced in solutions of varying osmolarities, The effect of varying osmolarities (0.6% to 1.5% NaCl solutions. 213 to 492 mOsm/kg H2O) on the morphology of deoxygenated sickle cells was studied quantitatively with a computer-assisted image analysis system. Discocyte-rich. less dense fractions of sickle cells (density less than or equal to 1.11) were suspended in buffered NaCl solutions (pH 7.4) of various osmolarities. deoxygenated at room temperature for up to 5 hours. and stained by Wright's solution. Microscopic images were analyzed by circular shape factor (CSF = 4 pi x [area]/[perimeter]2) and elliptical shape factor (ESF = [short axis]/[long axis]). Since these two parameters yield different values for elongated cells and for cells of other shapes. such as maple-leaf- or star-shaped cells. the morphologic changes of sickle cells can be analyzed numerically. We found that both the rate and the degree of deformation depended highly on the osmotic pressure of the media in which the cells were suspended. In hypertonic solution. most sickle cells assumed a maple-leaf shape. The deformation occurred quickly. but the degree of deformation (circular shape factor and elliptical shape factor) was lower than that found in isotonic and slightly hypotonic solutions. Although elongated cells were formed in hypotonic and isotonic solutions. deformation was slower in these solutions than in hypertonic solutions. These results indicate that the shape and the degree of deformation of deoxygenated sickle cells are highly dependent on the osmolarity of the suspending medium and that the rate of deformation is inversely related to osmolarity. The relationship between morphology of deoxygenated sickle cells and osmotic pressure of the suspending media is discussed.
Plasma glucagon concentration in cirrhosis is related to liver function but not to portal-systemic shunting, systemic vascular resistance, or urinary sodium excretion, We tested the hypothesis that increased plasma glucagon concentration resulting from portal-systemic shunting or liver dysfunction causes arterial vasodilation and thereby stimulates sodium retention in cirrhosis. Twenty-seven studies were performed in patients with alcoholic liver disease. 11 of whom had ascites. Liver function was quantitated as the elimination rate of antipyrine. caffeine. and stable isotopes of cholic acid administered both orally (2.2.4.4-2H) and intravenously (24-13C). Portal-systemic shunt fraction was calculated as the ratio of the intravenous and oral clearances of the isotopes of cholic acid. Cardiac output was measured by using Doppler echocardiography. Plasma glucagon concentration was increased in patients with ascites when compared with that in patients without ascites (474 +/- 180 pg/ml vs 245 +/- 120 pg/ml. p = 0.0007) but was unrelated to urinary sodium excretion. heart rate. mean arterial pressure. cardiac output. and systemic vascular resistance (r = -0.48. 0.35. -0.13. 0.18. and 0.22. respectively). Plasma glucagon concentration correlated with the half-lives of all model compounds (r = 0.58. p = 0.002; r = 0.62. p = 0.0008; r = 0.62. p = 0.001; and r = 0.64. p = 0.0005; for caffeine. antipyrine. oral and intravenous cholic acid. respectively) but not with shunt fraction (r = 0.14). Increased plasma glucagon concentration in cirrhosis is probably a result of diminished hepatic clearance. However. increased plasma concentration of glucagon does not appear to cause a hyperdynamic circulatory state or sodium retention.
Fibrinolysis, thrombocytopenia, and coagulation abnormalities complicating high-dose interleukin-2 immunotherapy, High-dose interleukin-2 (IL-2) immunotherapy can cause hypotension. respiratory distress. interstitial edema. and thrombocytopenia. similar to endotoxic shock. We have observed that IL-2 has no direct effect on coagulation factors in vitro. but it has been observed to alter the coagulant properties of vascular endothelium. Accordingly. we investigated the possibility that IL-2 infusions initiate plasma fibrinolysis and disseminated intravascular coagulation (DIC). We studied the clinical course. platelet count. and coagulation profile in response to IL-2 infusion in seven patients. two with metastatic melanoma and five with metastatic renal cell carcinoma. Every patient experienced hemodynamic instability and thrombocytopenia. and one patient suffered an unusual complication. mesenteric thrombosis. No patient had appreciable changes in the prothrombin time or the partial thromboplastin time. nor did factors V or VIII decline in the two patients observed. In four patients examined. we found decreased titers of Hageman factor (factor XII). high molecular weight kininogen. prekallikrein. and plasma thromboplastin antecedent. as if these had been consumed by reactions of the intrinsic pathway of thrombin formation. Circulating D-dimer fragments were found in the plasma of every patient at some point during each infusion cycle. and we observed decreased titers of plasminogen in the four patients just mentioned. suggesting that IL-2 infusions initiated fibrinolysis. Taken together. the clotting factor derangements and related toxicity phenomena cannot be ascribed firmly to DIC. Activation of the intrinsic (contact) system of coagulation. however. may provide one link between the vascular endothelial surface alterations caused by IL-2 infusions and the development of the systemic toxicity that resembles septic shock.
Plasma adenosine deaminase2: a marker for human immunodeficiency virus infection, Plasma concentrations of the two isoenzymes of adenosine deaminase (ADA. E.C. 3.5.4.4). adenosine deaminase1 (ADA1) and adenosine deaminase2 (ADA2). were measured in a cohort of ambulatory patients infected with the human immunodeficiency virus (HIV) and controls. A sensitive isoenzyme-specific radioisotopic assay system was developed for these studies. Among 22 HIV-infected patients. plasma ADA2 was significantly elevated as compared with 16 control subjects (p less than 0.01) and 6 uninfected subjects having a risk factor for HIV infection (p less than 0.01). Plasma ADA2 was not associated with the stage of disease as defined by clinical status (p greater than 0.05) or helper (CD4) lymphocyte count (p greater than 0.05). Available evidence suggests that elevated plasma ADA2 could be a useful surrogate marker for HIV infection that occurs early in the disease process.
Detection of salivary HIV-1-specific IgG antibodies in high-risk populations in Zaire, Saliva and blood samples were tested for human immunodeficiency virus-1 (HIV-1) antibodies in two high-risk populations in Kinshasa. Zaire. In a seroprevalence study of 458 sexually transmitted disease (STD) clinic attendees. 142 of 145 seropositive individuals had enzyme-linked immunosorbent assay (ELISA)-positive saliva samples (97.9% sensitivity). All saliva samples from seronegative patients were ELISA-negative (100% specificity). Of the 142 ELISA-positive saliva specimens. 137 were also Western blot-positive (94.5% sensitivity). In a subsequent seroincidence study of 315 initially seronegative female prostitutes followed during 183 woman-years of observation. 9 of 14 women who seroconverted (7.7% seroincidence) had ELISA-positive saliva samples at the time seroconversion was detected. Only three of these saliva specimens could be confirmed by Western blot. Although salivary testing for HIV-1 antibodies using conventional assays was not sensitive in detecting recent seroconversions. screening of salivary samples for HIV-1 antibody provides a convenient alternative method for conducting seroprevalence surveys in populations in whom venipuncture is not possible or convenient.
The costs of AIDS in Los Angeles, This article reports on the findings of a study of medical and non-medical expenditures of persons with acquired immune deficiency syndrome (AIDS) in Los Angeles in 1987 and 1988. Sociodemographic and clinical data as well as information on medical and nonmedical expenditures on 36 persons with AIDS were obtained through patient interviews and review of medical bills. Persons with AIDS required a mean of 1.6 hospitalizations per year and 17 days of in-hospital care. Mean charges for the first 12 months after diagnosis of AIDS were $22.272 for inpatient medical care and $22.850 for outpatient medical care. Overall. medical costs averaged $45.122 per patient per year with almost one-third of these costs devoted to outpatient pharmaceuticals. such as AZT and aerosolized pentamidine. Mean nonmedical costs of care for volunteer services. counselling. and in-kind assistance were $9.276. These results were similar to recently published estimates of medical costs of persons with AIDS. However. our data support changing problems of care for PWAs with increased use of outpatient medical care and pharmaceuticals and decreased use of in-hospital resources.
Assessment of efficacy of activated charcoal for treatment of acute T-2 toxin poisoning, "Superactive" charcoal was assessed for efficacy in decreasing the lethality of both oral and parenteral exposure to T-2 toxin. a fungal metabolite which can cause death or illness upon ingestion. In vitro binding studies. analyzed using the Langmuir adsorption isotherm. showed that activated charcoal had a maximal binding capacity of 0.48 mg toxin/mg charcoal and a dissociation constant of 0.078 mg charcoal/l. In vivo. orally administered. activated charcoal was assessed for treatment of acute oral or parenteral exposure to T-2 toxin in mice. Following oral toxin administration (5 mg/kg). untreated mice showed only 6% survival after 72 hr. Charcoal treatment (7 g/kg.po) either immediately or 1 hr after toxin exposure resulted in significant improvement in survival with values of 100% and 75%. respectively. Following parenteral toxin exposure (2.8 mg/kg. sc). untreated and charcoal-treated (7 g/kg. po) mice showed 50% and 90% survival. respectively. after 72 hr. LD50 value for T-2 toxin. determined at 96 hr after intoxication. increased significantly from 2 mg/kg for untreated controls to 4.5 mg/kg for activated charcoal treatment.
Antiplatelet drugs in femoropopliteal vein bypasses: a multicenter trial, To evaluate the influence of antiplatelet drugs on patency in femoropopliteal vein bypasses. 48 vascular surgeons recruited 549 patients to a randomized double-blind trial of aspirin (300 mg) + dipyridamole (150 mg) or placebo twice daily starting 2 days before surgery and continuing indefinitely. Graft occlusion measured objectively by independent coordinators and cardiovascular events (myocardial infarction or stroke) were studied. expressed by life table. and analyzed statistically by log rank and confidence intervals (95% CI). Randomization achieved comparable groups with 60% of grafts inserted for rest pain or gangrene. Operative complications on aspirin plus dipyridamole included 18 reoperations for bleeding and 12 hematomas compared with 9 and 14. respectively. on placebo (NS). Most of the 172 graft failures occurred early with failure rates of 43/1000 patient-months in the first 3 months. reducing to 17/1000 at 6 to 12 months. and under 10/1000 in subsequent years. Cumulative graft patency on placebo was 72%. 62%. and 60% at 1. 2. and 3 years. respectively. compared with 78%. 70%. and 61% on aspirin plus dipyridamole. The difference in patency of 6.1% (95% CI. -3% to 15.5%) at 1 year and 8.0% (95% CI. -5% to 21%) at 2 years failed to achieve significance (p = 0.43). On mean follow-up of 34 months. 53 (132/1000 patient-years) cardiovascular events (myocardial infarction or cerebrovascular accident) occurred in patients on placebo compared with only 35 (73/1000) on aspirin plus dipyridamole. a significant difference of 59/1000 (p = 0.004). Antiplatelet therapy had little influence on femoropopliteal vein patency. but subsequent myocardial infarction and stroke was reduced in these patients with peripheral vascular disease.
Prospective, randomized comparison of ringed and nonringed polytetrafluoroethylene femoropopliteal bypass grafts: a preliminary report, Kinking and compression with knee flexion are thought to be one cause of failure of below-knee polytetrafluoroethylene femoropopliteal bypass. To prevent this problem polytetrafluoroethylene grafts externally supported with rigid rings have been developed. The present randomized. prospective study compared ringed and nonringed polytetrafluoroethylene grafts in 122 patients who underwent femoropopliteal bypass for severe limb ischemia. Patients were well matched for surgical indications and risk factors. There was no significant difference in the 3-year graft patency rate of ringed versus nonringed polytetrafluoroethylene femoropopliteal bypasses (74% vs 68%. p = 0.5). Similarly. no significant differences were found in the 3-year graft patency rates of ringed versus non-ringed above-knee (82% vs 74%. p = 0.5) or below-knee polytetrafluoroethylene femoropopliteal bypasses (68% vs 59%. p = 0.5). The 3-year graft patency rate of all above-knee polytetrafluoroethylene femoropopliteal bypasses was slightly greater than that of below-knee polytetrafluoroethylene femoropopliteal bypasses (76% vs 62%). but this difference was not statistically significant (p = 0.25). The 3-year limb salvage rate with ringed polytetrafluoroethylene grafts was 92% compared with 79% for nonringed polytetrafluoroethylene grafts. but this difference was not statistically significant (p = 0.25). Data to date from this study fail to support the recommendation that ringed polytetrafluoroethylene grafts be used preferentially over conventional polytetrafluoroethylene grafts in patients who require femoropopliteal bypass with a synthetic graft.
Arterial aneurysms in children: clinicopathologic classification, Thirty-one arterial macroaneurysms in 23 pediatric-aged patients (16 boys and 7 girls) were treated at the University of Michigan. The average age at time of diagnosis was 10.2 years (range 6 months to 18 years). Vessels involved the aorta (4). as well as hepatic (1). splenic (2). gastroepiploic (1). renal (12). iliac (1). superficial femoral (4). popliteal (1). brachial (1). radial (2). and ulnar (2) arteries. Twelve children exhibited overt clinical manifestations including presence of a mass (7). local pain (3). hematemesis (1). and painless obstructive jaundice (1). Eleven children had asymptomatic lesions. Aneurysm existence was confirmed by arteriography or operation. All but one child underwent surgical therapy. with 20 long-term survivors (mean follow-up 3.5 years). One operative death occurred and one death occurred 6 years after surgery. This experience and a review of previously reported cases served as a basis for categorization of childhood aneurysmal disease as true aneurysms associated with (I) arterial infection. (II) giant-cell aortoarteritis. (III) autoimmune connective tissue disease. (IV) Kawasaki's disease. (V) Ehlers-Danlos syndrome or Marfan's syndrome. (VI) other forms of noninflammatory medial degeneration. (VII) arterial dysplasias. (VIII) congenital-idiopathic factors. as well as (IX) false aneurysms associated with extravascular events causing vessel wall injury or disruption. Knowledge of the varied clinicopathologic characteristics of arterial aneurysms in children is important in treating these patients.
The role of duplex scanning in the selection of patients for transluminal angioplasty, As part of our initial evaluation to determine whether patients with lower extremity ischemia are candidates for intervention. arterial duplex examinations are performed in the noninvasive vascular laboratory. Patients with isolated short stenoses on the duplex examination are referred for transluminal angioplasty. One hundred thirty-four arteriograms were performed for ischemic peripheral vascular disease in 122 patients between July 1987 and March 1990. One hundred ten (82%) of the arteriograms were preceded by a lower extremity arterial duplex evaluation. Fifty cases (45%) were scheduled for transluminal angioplasty based on the findings of the duplex examination. Transluminal angioplasty was performed in 47 of 50 cases (94%). No significant differences in age. sex. or diabetes were found between the patients who were referred for transluminal angioplasty and those who were not. These data demonstrate that duplex scanning of the lower extremities allows the detection of lesions that will be amenable to transluminal angioplasty. We think that duplex scanning should become the standard screening tool for detection of treatable lower extremity lesions.
Penile duplex sonography in the diagnosis of venogenic impotence, This study tested the hypothesis that measurements of cavernous arterial diastolic velocity and resistance index could provide a quantitative but noninvasive measure of penile corporal venous leakage. Seventy-four men were studied with duplex ultrasonography after intracavernosal injection of 60 mg of papaverine. Fourteen men had normal erection and served as controls. Sixty men had a 1-year history of transient fading or incomplete erections. In all subjects the peak systolic velocity and end-diastolic velocity were measured. and the resistance index was calculated (peak systolic velocity--end-diastolic velocity/peak systolic velocity). Men with normal erections had peak systolic velocities greater than 35 cm/sec and end-diastolic velocities less than 4.5 cm/sec (group 1). Patients with incomplete erections (group II) could be classified into three subgroups. Twenty-three patients with end-diastolic velocities greater than 4.5 cm/sec and normal peak systolic velocities greater than 35 cm/sec were suspected to have corporal venous leakage (group A). Eighteen patients had normal end-diastolic velocities less than 4.5 cm/sec. Twelve of this group had peak systolic velocities less than 35 cm/sec. and six had peak systolic velocities ranging from 37 to 44 cm/sec. These patients were suspected of having arterial insufficiency (group B). Fifteen patients with end-diastolic velocities greater than 4.5 cm and peak systolic velocities less than 35 cm were suspected of having both venous leakage and arterial insufficiency (group C). Twenty-one patients with abnormal diastolic flow underwent infusion pharmacocavernosometry to determine the saline maintenance infusion rate necessary to maintain an intracavernosal pressure of 90 to 100 mm Hg or a full erectile response.
Ultrasound screening of first-degree relatives of patients with an abdominal aortic aneurysm, The pedigrees were constructed of 43 patients (probands) who underwent resection of an abdominal aortic aneurysm. Seven probands (16.2%) had a first-degree relative (parent. sibling. child) known to have had an abdominal aortic aneurysm (multiplex family). To determine the prevalence of undiagnosed abdominal aortic aneurysm. ultrasound screening of first-degree relatives over age 40 years was undertaken. Of 202 eligible relatives. 103 (51.0%) were screened. An occult abdominal aortic aneurysm was defined as an infrarenal aortic diameter greater than 3.0 cm or an infrarenal/suprarenal aortic diameter ratio of greater than 1.5. An incipient abdominal aortic aneurysm was defined as a clear focal bulge of the infrarenal aorta. which was less than 3.0 cm in greatest diameter. Four of 103 relatives (3.9%) were found to have an occult abdominal aortic aneurysm (age/sex: 57M. 60M. 62F. 65M). and three (2.9%) were found with an incipient abdominal aortic aneurysm (age/sex: 56M. 60M. 67F). These smaller abdominal aortic aneurysms were in patients younger than the operated probands (average age men. 67 years; women. 69 years). Six of seven individuals were in families previously considered simplex. increasing the actual multiplex family frequency from 16.2% to 27.9%. All seven new abdominal aortic aneurysms were found in the 49 siblings age 55 years or older. There were no abdominal aortic aneurysms found in the 39 relatives under age 55 years. in 14 children ages 50 to 59 years or in one parent. Therefore of the siblings age 55 years or older. 5/20 men (25.0%) and 2/29 women (6.9%) were found to have a previously undiagnosed abdominal aortic aneurysm.
The influence of elastic compression stockings on deep venous hemodynamics, To determine the effect of elastic compression stockings on deep venous hemodynamics we measured ambulatory venous pressure. venous refill time. maximum venous pressure with exercise. amplitude of venous pressure excursion. and duplex-derived common femoral and popliteal vein diameter and peak flow velocities with and without stockings in 10 healthy subjects and 16 patients with chronic deep venous insufficiency. The effects of below-knee and above-knee 30 to 40 torr and 40 to 50 torr gradient stockings were studied. Despite documentation of substantial stocking compressive effects by skin pressure measurements. neither below-knee or above-knee elastic compression stockings significantly improved ambulatory venous pressure. venous refill time. maximum venous pressure with exercise. or the amplitude of venous pressure excursion in healthy patients or in patients with deep venous insufficiency (p greater than 0.05). In patients with deep venous insufficiency stockings modestly increased popliteal vein diameter and flow velocity in the upright resting position (p less than 0.02). After tiptoe exercise without stockings deep venous peak flow velocity increased in healthy patients and in patients with deep venous insufficiency by a mean of 103% in the popliteal vein and 46% in the common femoral vein (p less than 0.01). With the application of elastic compression stockings only modest augmentation of deep venous flow velocity occurred in both groups above that seen in the bare leg after exercise. Thus elastic compression stockings did not improve deep venous hemodynamic measurements in patients with deep venous insufficiency. The beneficial effects of stockings in the treatment of deep venous insufficiency must relate to effects other than changes in deep venous hemodynamics.
The association of skin color with blood pressure in US blacks with low socioeconomic status, To determine the association of skin color. measured by a reflectometer. with blood pressure in US blacks. we studied a community sample of 457 blacks from three US cities. Persons taking antihypertensive medications were excluded. Both systolic and diastolic blood pressure were higher in darker persons and increased by 2 mm Hg for every 1-SD increase in skin darkness. However. the association was dependent on socioeconomic status. whether measured by education or an index consisting of education. occupation. and ethnicity. being present only in person with lower levels of either indicator. Using multiple linear regression. both systolic and diastolic blood pressure remained significantly associated with darker skin color in the lower levels of socioeconomic status. independent of age. body mass index. and concentrations of blood glucose. serum urea nitrogen. serum uric acid. and urinary sodium and potassium. The association of skin color with blood pressure only in low socioeconomic strata may be due to the lesser ability of such groups to deal with the psychosocial stress associated with darker skin color. However. these findings also are consistent with an interaction between an environmental factor associated with low socioeconomic status and a susceptible gene that has a higher prevalence in persons with darker skin color.
The occupational risk of cytomegalovirus infection among day-care providers, We prospectively studied day-care providers at six day-care centers in south-eastern Iowa to determine their occupational risk for primary cytomegalovirus infection and to define epidemiologic risk factors. Ninety-six (38%) of 252 day-care providers were seropositive for cytomegalovirus by latex agglutination at entry into the study. Among 82 seronegative providers available for follow-up. seven seroconversions occurred at only two of the six participating centers. yielding an annualized seroconversion rate of 7.9%. Median time to seroconversion among these providers was 13 months. Using Kaplan-Meier estimates of risk. we determined that the overall risk of seroconversion among providers at various centers ranged from 0% to 22% by 12 months and from 0% to 40% by 16 months. Risk of cytomegalovirus acquisition by providers was independent of race. age. education. the presence of a child at home. or caring for children younger than 2 or 3 years in the day-care center. However. the risk of seroconversion among day-care providers appeared to parallel rates of cytomegalovirus excretion and acquisition among children at each center.
Efficacy of bladder training in older women with urinary incontinence, The efficacy of bladder training was evaluated in a randomized clinical trial involving 123 noninstitutionalized women 55 years and older with urinary incontinence. Subjects were urodynamically categorized as those with urethral sphincteric incompetence (N = 88) and those with detrusor instability with or without concomitant sphincteric incompetence (N = 35). Bladder training reduced the number of incontinent episodes by 57%; the effect was similar for both urodynamic diagnostic groups. The quantity of fluid loss was reduced by 54%. This was greater for patients with detrusor instability than for those without it. Diurnal and nocturnal voluntary micturitions were also reduced. The effect on nocturnal micturition. however. was not observed in subjects with unstable detrusor function. It is recommended that bladder training be considered as an initial step in treatment of women with urinary incontinence. Provided prior comprehensive clinical evaluation is done. it can be prescribed without the need for urodynamic characterization.
Multiple alcohol-related problems in the United States: on the rise, Are drinking problems on the rise in the U.S. general population? Surveys of drinking practices and problems conducted in the United States in 1967. 1969. 1979 and 1984 included numerous questions on alcohol-related problems that were identical or nearly identical in wording. Using data from these surveys. we tested for ordered increases over time in the prevalence of an indicator of multiple problems. considered on both a current (1-year) and lifetime basis. We studied prevalence in men and women between the ages of 22 and 59 in all four surveys. Prevalence of the multiple problem indicator was rare. especially when considered on a current basis. However. relative increases in prevalence ranging from 53% to over 200% were found from 1967 to 1984 in the multiple problem indicator for men and women. for lifetime as well as current problems. With the exception of current problems in women (a very rare condition even in the 1984 survey). these changes were all statistically significant or showed a trend toward significance. When respondents were subgrouped by age. all subgroups still showed increases since 1967. although sample sizes decreased and significance tests of ordered increases over time were not so consistent.
Alcohol-predictive cues enhance tolerance to and precipitate "craving" for alcohol in social drinkers, This study attempts to show that tolerance to alcohol is in large part a "learned" response. precipitated by contextual cues predictive of the unconditional drug effect. It also aims to show that the contextual cues integral to such "environment-dependent" tolerance function to increase motivational desire to drink alcohol. Male students (N = 40). drinking on average 10-20 units of alcohol per week. were randomly assigned to one of four groups. Two groups ingested 1.2ml/kg alcohol: one (AL-EXPT) with exteroceptive contextual cues typically associated with alcohol use. and the other (AL-UNEXPT) in a context not normally associated with alcohol. A third group (placebo) believed that they were drinking alcohol but. in fact. consumed a nonalcoholic beverage in the alcohol-expected context. The fourth group drank juice in the alcohol-unexpected context. As predicted. tolerance to the deleterious effects of alcohol on cognition and motor-performance. and subjective desire to consume alcohol. were influenced by the alcohol-predictive contextual cues. A physiological index (pulse rate) also tended to confirm that these cues elicited a conditioned compensatory response to alcohol. The implications of these findings for tolerance to and motivation to drink alcohol in a nonpathological population are discussed.
Some boundary conditions for effective use of alcohol placebos, The present research assessed the conditions under which subjects who consume alcohol and those who consume a placebo beverage. and who report consuming alcohol on a manipulation check question. are equivalent with respect to subjective responses to alcohol. Male subjects were told that they were drinking alcohol and consumed one of four beverages: alcoholic beer. nonalcoholic beer. vodka and tonic with lime. or tonic with lime. Measures of subjective intoxication. body sensations and breath alcohol were taken at different times during and after beverage consumption. Subjective intoxication ratings were higher for subjects who received alcohol. compared to subjects who received a placebo and reported consuming alcohol. when alcohol subjects achieved blood alcohol concentrations at and above .04%. These two groups did not differ in subjective intoxication ratings when alcohol subjects achieved blood alcohol concentrations below .04%. These data suggest that the orthogonal manipulation of alcohol consumption and expectancy effects is problematic at and above blood alcohol concentrations of .04%.
Diagnostic validity of the MAST and the alcohol dependence scale in the assessment of DSM-III alcohol disorders, The comparative validity of the Michigan Alcoholism Screening Test (MAST) and the Alcohol Dependence Scale (ADS) in screening for current DSM-III alcohol abuse/dependence disorders is evaluated. These scales were administered to 501 patients presenting for treatment of alcohol or drug problems. DSM-III alcohol disorders are diagnosed using the Diagnostic Interview Schedule. Receiver Operating Characteristic (ROC) analysis is used to determine optimum threshold scores for the MAST and ADS and to compare the screening ability of the two instruments. Optimum cut points for the MAST and the ADS are 12/13 and 8/9. respectively. The overall accuracy of classification for both instruments using these threshold scores is 88%. The areas under the ROC curves are .91 and .90 (SD = .02) and there are no significant differences between the MAST and the ADS in their ability to screen for alcohol abuse or dependence in this population. The MAST and the ADS correlate highly with each other (.79). The results reported in our study should be applicable to the revised DSM-III since a field trial found a high level of agreement on alcohol disorders between the diagnostic systems. Categorical versus dimensional approaches to the assessment of alcoholism are discussed.
Recent trends in the development of alcohol and drug treatment services in Ontario, This article summarizes the major trends in the development of alcohol and drug treatment services in Ontario since 1979. These trends are contrasted to the objectives of a province-wide Addiction Research Foundation (ARF) community development program designed to establish or expand addiction services within this same time period. Data were obtained from all treatment services in the province by surveys undertaken in 1980. 1983 and 1986. Across the period of analysis. there have been rapid increases in the number of addiction programs. their total cost and the total treatment caseload. Some specific changes have been quite consistent with ARF objectives: a stabilization in the use of hospital beds for addictions treatment. an increase in community-based versus hospital-based treatment resources. an increase in the province-wide capacity for comprehensive client assessment and a larger representation of women in addictions programs. Other ARF objectives have yet to be achieved. In particular. a major increase in nonresidential treatment alternatives and an increase in the proportion of treated cases from special populations such as youth or the elderly are still required. Suggestions are made concerning future program development.
Prediction of adults' drinking patterns from the drinking of their parents, While studies have shown relationships between adolescent and parental drinking patterns. it is not known if these parental influences are maintained when the children are adults and further removed from early influences. A representative general population sample of 6.364 adults living in New York State were interviewed regarding their current drinking as well as about their family structure and the drinking patterns of their parents while they were growing up. A logit modeling analysis revealed that natural father's drinking while growing up. natural mother's drinking while growing up. family structure (father present or not) and sex of the respondent were all significant predictors of current heavy drinking of adults even while controlling for all of the other variables in the model. It is concluded that early family influences may have long-term consequences on drinking behaviors.
Drinking in college: consumption patterns, problems, sex differences and legal drinking age, Data from 606 (75.8%) undergraduate respondents drawn from a random sample (N = 800) at Rutgers University demonstrate that. although fewer college students may be drinking when compared to some previous estimates. there is still a large number of heavy drinkers. In addition. traditional demographic variables continue to predict alcohol consumption levels. Students also report a similar variety of drinking related problems as in previous college drinking studies. Women constitute half as many heavy drinkers as men. but report an equal amount of alcohol-related problems in this sample. When controlling for race. it appears that white students continue to drink the most. and show heavy drinking rates comparable to a previous large college sample in the northeast. Students who live on campus drink more than their commuting counterparts. and the drinking age has little effect on consumption levels or total reported alcohol-related problems. although it alters the context of drinking somewhat. Findings are generally compared to previous as well as more recent college drinking data. Sex differences and similarities are discussed. as well as the findings concerning legal drinking status. Implications for prevention efforts are suggested.
Family background of alcohol abuse and its relationship to alcohol consumption among college students: an unexpected finding, The purpose of this study was to determine the possible association between positive family background of alcohol abuse (having a parent or grandparent who sometimes or often drank too much) and the amount of alcohol consumed per week among college students. It was additionally to determine the possible differences between students with positive. compared to students with negative. family backgrounds of alcohol abuse in regards to drinking patterns. using a survey instrument that indirectly measures family background for alcohol abuse. For this cross-sectional study. a quota sample of 971 college students from all four regions of the United States was selected. Results revealed no association between family history and mean amount of alcohol consumed per week for the total sample (r = .007). or for men (r = .04) or women (r = .02). Curve analysis indicated a slightly positively skewed curve for the total group and also for male and female students. A t test and chi-square analysis found no significant difference between positive and negative family backgrounds and mean amount of alcohol consumed or drinking patterns. Among those with positive family backgrounds there was no clustering on a scatter plot for either heavy or light amounts of alcohol consumed. The results showed remarkable similarity in alcohol consumption and drinking patterns between students who were classified as having a positive. as opposed to negative. family background. It was concluded that having a positive family background for heavy drinking was not associated with either light or heavy alcohol consumption among this national sample of college students.
Drinking styles of adolescents and young adults, Drinking among adolescents and young adults has received more attention during the recent past. but little research has focused on the drinking styles that might characterize younger people. A typology of drinking behavior has special relevance for this group. since the adolescent years and young adult years are formative in the development of drinking habits. This study used a model that had been applied to "normal" drinking behaviors of adults. However. the set of drinking variables was expanded to cover a wider range of activities. and a second set of behaviors. intended to reflect potential "problem" drinking. were derived from the National Council on Alcoholism criteria for the diagnosis of alcoholism. The set of 55 "normal" drinking behaviors was factor analyzed. yielding a six-factor structure. The first four factors were quite similar to previous work on adult drinking styles. and the remaining two factors clearly related to the drinking of younger people. The "problem" drinking variables yielded a two-factor structure. one set consisting of serious but uncommon experiences and the second set consisting of less serious and more common experiences. Several of the "normal" drinking factors were significant predictors of the "problem" drinking scores. suggesting that certain styles of drinking are more likely than others to lead to later problems.
Iodine and thyroid disease, Iodine is a requisite substrate for the synthesis of the thyroid hormones. the minimum daily requirement being about 50 micrograms. An autoregulatory mechanism within the thyroid serves as the first line of defense against fluctuations in the supply of iodine and also permits escape from the inhibition of hormone synthesis that a very large quantity of iodine induces (Wolff-Chaikoff effect and escape therefrom). Environmental iodine deficiency continues to be a significant public health problem worldwide. compounded in some geographic regions by the presence of other goitrogens in some staple foods. The pathologic consequences of severe iodine deficiency include endemic goiter. endemic cretinism. increased fetal and infant mortality. and an increased prevalence in the community of cognitive and neuromotor disabilities. The implementation of an iodization program prevents endemic cretinism and reduces the frequency of the other pathologic consequences of iodine deficiency. Iodine excess results principally from the use of iodine-containing medicinal preparations or radiographic contrast media. The pathologic consequences of iodine excess will ensue only when thyroid autoregulation is defective. in that escape from the Wolff-Chaikoff effect cannot occur. or when autoregulation is absent. Defective autoregulation characterizes the fetal and neonatal thyroid. Hashimoto's thyroiditis. radioiodine or surgically treated Graves' hyperthyroidism. the thyroid of patients with cystic fibrosis. and the thyroid that has been exposed to weak inhibitors of the organic binding of iodine. In these circumstances. the provision of excess iodine may lead to iodide goiter with or without hypothyroidism. Absent autoregulation may be a feature of longstanding multinodular goiter. and the provision of excess iodine in this circumstance may induce thyrotoxicosis (Jod-Basedow disease). The pathologic consequences of iodine excess will resolve when the source of iodine has been dissipated. In addition to its role in reversing iodine deficiency. iodine is used as adjunctive therapy for hyperthyroidism. By inhibiting the proteolytic release of iodothyronines from thyroglobulin. it induces a prompt slowing of thyroid hormone secretion. This effect is exploited in the treatment of thyrotoxic crisis or severe thyrocardiac disease. Iodine also reduces thyroid cellularity and vascularity and therefore is used in the preparation of the patient for thyroidectomy. Finally. by exploiting the failure of escape from the Wolff-Chaikoff effect. iodine may also be used in the early management of radioiodine-treated Graves' hyperthyroidism.
The problem of the nodular goiter, Nodular goiter is a worldwide problem involving millions of persons. Endemic goiter. and associated cretinism. is totally preventable by ensuring an adequate dietary iodine intake and eliminating malnutrition and dietary goitrogens. Therapy. on the other hand. is difficult in that the goiters often do not regress and the cretinoid changes are irreversible. Nonendemic goiter due to autoimmune thyroid disease. genetic defects in thyroid hormone biosynthesis. and environmental goitrogens or neoplasia is not usually preventable. The usual therapy. involving TSH suppression by administration of L-thyroxine orally. will frequently bring about regression of early. diffuse goiters but is often ineffective in bringing about regression of large. multinodular goiters. In these patients. surgical removal of the goiter may be necessary for alleviation of obstructive symptoms. Further research is needed to elucidate the factors involved in the development of these multinodular goiters and to control the autocrine and paracrine factors involved in nodule growth.
Thyroid cancer, There have been important recent advances in our understanding of the biologic nature of thyroid cancer and in the early diagnosis of the disease. Despite these advances. there is still considerable controversy over the management of thyroid cancer. including the extent of surgery. the indications for the use of iodine-131. the effectiveness of thyroid-stimulating hormone suppression. and the prediction of outcome. In this review. the current status of the diagnosis and management of the various types of thyroid cancer are carefully reviewed and extensively documented.
Graves' disease. Current concepts, Graves' disease is an organ-specific autoimmune disorder. There is no universal agreement on the mechanism of Graves' disease. but the over-activity of the thyroid is due to an antibody capable of attaching to and activating the TSH receptor of follicular cells. There are other extrathyroidal features that are not caused either by this antibody or by hyperthyroidism. The clinical diagnosis is generally straightforward and can be confirmed by in vitro measurement of thyroid hormones and TSH. A measurement of radioiodine uptake is also valuable. Treatment is not specific for the immunologic defect. but its purpose is to lower the thyroid hormone levels to normal. This can be achieved with antithyroid medication. radioiodine iodine-131. or thyroidectomy. In most clinical situations. a strong argument can be made for iodine-131 therapy. which is safe and definitive. although posttreatment hypothyroidism and the need for lifelong thyroxine are to be expected.
The ophthalmopathy of Graves' disease, Fortunately. most patients with thyroid-related eye disease have mild ocular involvement that spontaneously involutes. Less than 5% of patients with hyperthyroidism will develop sufficiently severe ocular abnormalities that will require surgical intervention. Most patients with thyroid eye findings should be symptomatically managed. Some will require use of either topical drops or oral steroids to alleviate their eye problems. In approximately one half of those patients who present acutely with severe thyroid orbital finding. nonsurgical therapies will be sufficient to control their eye disease. In the other half. eventually multiple surgical procedures may be required. and as discussed previously. the timing and sequence of those procedures are crucial to achieve optimal results.
The erythrocyte sedimentation rate in congestive heart failure, BACKGROUND AND METHODS. Physicians have long believed that the erythrocyte sedimentation rate is low in patients with congestive heart failure. but this concept is based on a misinterpretation of the results in a single report published in 1936. To reevaluate this concept in the modern era. we measured the sedimentation rate in 242 patients who were referred for treatment of chronic heart failure. RESULTS. The sedimentation rate was low (less than 5 mm per hour) in only 24 patients (10 percent) but was increased (above 25 mm per hour) in 50 percent. Patients with low or normal sedimentation rates (less than or equal to 25 mm per hour) had more severe hemodynamic abnormalities than patients with elevated rates: lower cardiac index (mean +/- SEM. 1.7 +/- 0.1 vs. 2.0 +/- 0.1 liters per minute per square meter of body-surface area) and higher mean right atrial pressure (mean +/- SEM. 12 +/- 1 vs. 9 +/- 1 mm Hg) (both P less than 0.0001). New York Heart Association functional class IV symptoms were present in 66 percent of the patients with a low or normal sedimentation rate. as compared with 42 percent of those with elevated rates (P less than 0.0001). After one to three months of therapy. patients whose sedimentation rates decreased showed little hemodynamic or clinical response to treatment. whereas both cardiac performance and functional status improved in patients whose rates increased (P less than 0.02 for the comparison between groups). The sedimentation rate was correlated with the plasma fibrinogen level (r = 0.64. P = 0.0025). and changes in the sedimentation rate during treatment were correlated inversely with changes in mean right atrial pressure (r = -0.57. P = 0.0002). During long-term follow-up. patients with low or normal sedimentation rates had a worse one-year survival than patients with elevated rates (41 vs. 66 percent. P = 0.01). CONCLUSIONS. These data indicate that the erythrocyte sedimentation rate is correlated with the severity of illness in patients with chronic heart failure. Because of its lack of discriminatory power. however. the test is of limited value in the clinical management of this disorder.
Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency, BACKGROUND. The exercise capacity of patients with muscle phosphofructokinase deficiency is low and fluctuates from day to day. The basis of this variable exercise tolerance is unknown. but our patients with this disorder report that fatigue of active muscles is more rapid after a high-carbohydrate meal. METHODS AND RESULTS. To determine the effect of carbohydrate on exercise performance. we asked four patients with muscle phosphofructokinase deficiency to perform cycle exercise under conditions of differing availability of substrate--i.e.. after an overnight fast. and during an infusion of glucose or triglyceride (with 10 U of heparin per kilogram of body weight) after an overnight fast. As compared with fasting and the infusion of triglyceride with heparin. the glucose infusion lowered plasma levels of free fatty acids and ketones. reduced maximal work capacity by 60 to 70 percent. and lowered maximal oxygen consumption by 30 to 40 percent. Glucose also increased the relative intensity of submaximal exercise. as indicated by a higher heart rate at a given workload during exercise. The maximal cardiac output (i.e.. oxygen delivery) was not affected by varying substrate availability. but the maximal systemic arteriovenous oxygen difference was significantly lower during glucose infusion (mean +/- SE. 5.5 +/- 0.3 ml per deciliter) than after fasting (7.6 +/- 0.4 ml per deciliter. P less than 0.05) or during the infusion of triglyceride with heparin (8.9 +/- 1.3 ml per deciliter. P less than 0.05). CONCLUSIONS. In muscle phosphofructokinase deficiency. the oxidative capacity of muscle and the capacity for aerobic exercise vary according to the availability of blood-borne fuels. We believe that glucose infusion lowers exercise tolerance by inhibiting lipolysis and thus depriving muscle of oxidative substrate (plasma free fatty acids and ketones); this impairs the capacity of working muscle to extract oxygen and lowers maximal oxygen consumption.
Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I, BACKGROUND. As part of an interdisciplinary study of medical injury and malpractice litigation. we estimated the incidence of adverse events. defined as injuries caused by medical management. and of the subgroup of such injuries that resulted from negligent or substandard care. METHODS. We reviewed 30.121 randomly selected records from 51 randomly selected acute care. nonpsychiatric hospitals in New York State in 1984. We then developed population estimates of injuries and computed rates according to the age and sex of the patients as well as the specialties of the physicians. RESULTS. Adverse events occurred in 3.7 percent of the hospitalizations (95 percent confidence interval. 3.2 to 4.2). and 27.6 percent of the adverse events were due to negligence (95 percent confidence interval. 22.5 to 32.6). Although 70.5 percent of the adverse events gave rise to disability lasting less than six months. 2.6 percent caused permanently disabling injuries and 13.6 percent led to death. The percentage of adverse events attributable to negligence increased in the categories of more severe injuries (Wald test chi 2 = 21.04. P less than 0.0001). Using weighted totals. we estimated that among the 2.671.863 patients discharged from New York hospitals in 1984 there were 98.609 adverse events and 27.179 adverse events involving negligence. Rates of adverse events rose with age (P less than 0.0001). The percentage of adverse events due to negligence was markedly higher among the elderly (P less than 0.01). There were significant differences in rates of adverse events among categories of clinical specialties (P less than 0.0001). but no differences in the percentage due to negligence. CONCLUSIONS. There is a substantial amount of injury to patients from medical management. and many injuries are the result of substandard care.
Control of the sperm-oocyte switch in Caenorhabditis elegans hermaphrodites by the fem-3 3' untranslated region, In the Caenorhabditis elegans hermaphrodite germ line. sperm and then oocytes are made from a common pool of germ-cell precursors. The decision to differentiate as a sperm or an oocyte is regulated by the sex-determining gene. fem-3. Expression of fem-3 in the hermaphrodite germ line directs spermatogenesis and must be negatively regulated to allow the switch to oogenesis. In adult hermaphrodites (which are producing oocytes). most fem-3 RNA is found in the germ line. consistent with both the requirement for fem-3 in hermaphrodite spermatogenesis and the maternal effects of fem-3 on embryonic sex determination. Whereas loss-of-function mutants in fem-3 produce only oocytes. hermaphrodites carrying any of nine fem-3 gain-of-function (gf) mutations make none; instead sperm are produced continuously and in vast excess over wild-type amounts. Genetic analyses suggest that fem-3(gf) mutations have escaped a negative control required for the switch to oogenesis. Here we report that all nine fem-3(gf) mutants carry sequence alterations in the fem-3 3' untranslated region (3' UTR). There is no increase in the steady-state level of fem-3(gf) RNA over wild-type. but there is an increase in the polyadenylation of fem-3(gf) RNA that is coincident with the unregulated fem-3 activity. Results of a titration experiment support the hypothesis that a regulatory factor may bind the fem-3 3' UTR. We speculate that fem-3 RNA is regulated through its 3' UTR by binding a factor that inhibits translation. and discuss the idea that this control may be part of a more general regulation of maternal RNAs.
Cyclocryotherapy in selected cases of congenital glaucoma, We investigated the efficacy of cyclocryotherapy. a procedure which destroys the ciliary epithelium. thereby decreasing the production of aqueous humor. by retrospectively studying 109 eyes with advanced primary congenital glaucoma that had undergone the procedure. The eyes were divided into two groups: group I comprised 75 eyes (69%) that had undergone conventional surgical procedures for congenital glaucoma prior to cyclocryotherapy; group II. 34 eyes (31%) that had not undergone any such previous procedures. All eyes were followed for at least 12 months after the last cyclocryotherapy. With "success" defined as "having an IOP greater than or equal to 8 mmHg. greater than or equal to 19 mmHg with or without medication." the success rate in all eyes was 30%. with no significant difference between the success rates in groups I and II (P greater than .05). Chronic hypotony (IOP less than 8 mmHg) was found in seven eyes (6%). Six eyes (6%) developed cataract during the course of treatment with cyclocryotherapy. Cyclocryotherapy appears to be a reasonable addition to the treatment of eyes with advanced. uncontrolled. primary congenital glaucoma.
Epidemiology of pediatric HIV infection, Perinatal transmission of human immunodeficiency virus (HIV) continues to increase. In 1989 alone. it is estimated that 1750 infected children were born in the United States. Although transmission is spreading to areas outside the cities originally most affected. these cities continue to bear the greatest toll. Adolescents may be particularly vulnerable to HIV infection; education and counseling are critical for controlling the epidemic in this age group.
AIDS in the transfusion recipient, In summary. the HIV virus was transmitted to approximately 90% of recipients by infectious blood and blood products transfused prior to donor and product testing begun in March 1985. Self-elimination of at-risk donors several years prior to testing donor blood helped to reduce the number of infected donations. Virtually all contaminated donors are now eliminated. The multiply transfused patient developed a stimulated dysregulated immune system due to the numerous antigens and the iron in red cells and plasma. This dysregulated immune system has resulted in a variable response to the added exposure of the HIV virus. The incubation period and progression to disease have been prolonged and variable. Although a small number of patients have progressed as rapidly as other at-risk groups. many continue to do well without therapeutic intervention. Natural history of the disease needs continual monitoring to determine the ultimate outcome of these transfusion recipients.
Antiviral therapy for human immunodeficiency virus infection in children, Antiretroviral therapy for children is still at an early stage. although progress is being made slowly. Zidovudine administered at 180 mg/m2/dose every 6 hours is the current standard therapy for symptomatic children and those with low CD4 counts. This standard is likely to evolve as further testing clarifies the optimal dosage for ZDV in different populations. Children on ZDV need to be monitored very closely (at least monthly) for hematologic side effects. which are most common in the more seriously ill children. The role of some of the newer antiretrovirals. like ddI and ddC. which are likely to be licensed. has yet to be established. They have a different toxicity profile than ZDV and thus may work well in combination with it. The issue of peripheral neuropathy and the lack of an easy test to measure it makes using ddC or ddI in young. preverbal children a daunting proposition. As with ZDV. the optimum dosage and timing have yet to be fixed for ddC or ddI alone. and even less available are regimens for combination therapy. Antiretroviral drugs other than the dideoxynucleosides are less well developed. Some. like high-titer antiviral immunoglobulin. involve technology that is already available and thus will be relatively easy to study. Others. like the antisense oligomers. are such a new technology that there are many hurdles to be overcome as the agents move from the laboratory to the clinic. The goal of agents that work on sites other than reverse transcriptase is a reasonable one. but the work in perfecting such new categories of drug is difficult and slow. In the meantime. children with HIV should be symptomatically supported and offered the most effective antiretroviral regimens available.
Psychosocial aspects of AIDS in children and adolescents [published erratum appears in Pediatr Clin North Am 1991 Jun;38(3):viii, The first part of this article addresses the neuropsychiatric aspects of human immunodeficiency virus (HIV) infection in children and adolescents. including developmental delay. depression. and dementia. The specific clinical issues of disclosure of diagnosis and discussion of death with a child are examined. The second part presents aspects of the impact of AIDS on families. approaches to HIV antibody testing. and therapeutic interventions for the family.
Laboratory diagnosis of HIV infection, Laboratory diagnosis of human immunodeficiency virus (HIV) infection is complicated by absence of data on sensitivity. specificity and predictive value of the various tests as they apply to children. The presence of maternal anti-HIV passively transmitted across the placenta also confounds diagnosis. The authors review currently available data on the detection of HIV. HIV genome. and HIV gene products. as well as the diagnostic value of detecting serologic and cellular responses to HIV in infants and children.
Host defense abnormalities associated with HIV infection, Infection with human immunodeficiency virus (HIV) impairs immune function. Most abnormalities in host defense associated with HIV infection are due to helper T-cell dysfunction. Studies defining these abnormalities in the HIV-infected patient have largely been done in adults. A more complete understanding of the immunodeficiency that occurs in infants and young children congenitally infected with HIV awaits further study of their immune function and the effect this virus has on the developing immune system.
Elevated plasma aluminum levels in normal infants receiving antacids containing aluminum, Aluminum toxicity is a documented cause of encephalopathy. anemia. and osteomalacia. Excretion is primarily renal; therefore. patients with renal insufficiency are at risk for aluminum accumulation and toxicity. This has been demonstrated in uremic children treated with aluminum-containing antacids. The purpose of this study was to determine whether plasma aluminum levels were elevated in infants with normal renal function during prolonged aluminum-containing antacid use. Ten study infants (mean age = 5.8 months). who had been receiving antacids for at least 1 week. were compared with 16 control infants (mean age = 9.8 months) not receiving antacids. The study patients consumed 123 +/- 16 mg/kg per day (mean +/- SEM) of elemental aluminum for an average of 4.7 weeks. Their plasma aluminum level (37.2 +/- 7.13 micrograms/L) was significantly greater than that of the control group (4.13 +/- 0.66 micrograms/L) (P less than .005). It is concluded that plasma aluminum levels may become elevated in infants with normal renal function who are consuming high doses of aluminum-containing antacids. The safety of antacids containing aluminum should not be assumed and they should be used judiciously in infants. with careful monitoring of the aluminum dose and plasma level.
Clinical manifestations of primary herpes simplex virus type 1 infection in a closed community, The clinical features and the molecular epidemiology of primary herpes simplex virus type 1 (HSV-1) infection among children younger than 3 years of age were investigated in day-care nursery. Serial sera were assayed for anti-HSV-1 glycoprotein B antibody by enzyme-linked immunosorbent assay. Serologic examinations revealed 55 cases of primary HSV infection during the observation period. Fifty-one of them (93%) had typical herpetic gingivostomatitis. showing a high rate of clinically overt infection. Four outbreaks of herpetic gingivostomatitis were observed during the observation period. Forty-one children were infected with HSV-1 in the outbreaks. The rates of infection in the susceptible children were 81%. 73%. 78%. and 100%. respectively. in the four outbreaks. Restriction endonuclease analysis of DNA of isolated HSV revealed that only one strain of HSV-1 had been transmitted among children for a long period.
Individual differences in children's response to pain: role of temperament and parental characteristics, Sixty-five families were enlisted in a study exploring factors associated with distress behavior in 5-year-old children receiving diphtheria-tetanus-pertussis immunizations. At a home visit 1 month before the immunization. the following measures were obtained: (1) the Behavioral Style Questionnaire. a measure of temperament: (2) parental self-reports of medically related attributes (eg. "good patient"); (3) parental attitudes toward pain in children and responsiveness to their child's pain; and (4) parental prediction of distress at upcoming immunization. The child's distress behavior during the immunization was evaluated using a modification of the Procedure Rating Scale-Revised and. after the procedure. the child's assessment of his or her pain was elicited using the Oucher. Children's mean Procedure Rating Scale-Revised score was 2.57 of a possible 11. Thirty-one (48%) had low (less than or equal to 1) and 7 (11%) had high distress scores (greater than or equal to 2 SD above the mean). Factors positively correlated with distressed behavior included more "difficult child" cluster characteristics. the individual temperamental dimension of adaptability. but few parental attitudes and attributes. Parent's predictions of distress were the strongest correlates. These findings document the variation that children demonstrate in response to pain and offer some insight into associated innate and environmental factors. These results imply that treatment strategies derived from parental knowledge and tailored to individual characteristics of the child may be most effective in alleviating pain-related distress in medical settings.
Factors associated with delay in diagnosis of childhood amblyopia, The prevention of permanent visual impairment from amblyopia is an important goal of pediatric vision screening. Unfortunately. many cases of amblyopia are not diagnosed until the child is too old to benefit maximally from treatment. A review of patient records from the practice of a private pediatric ophthalmologist confirmed that late detection is a frequent occurrence among children with amblyopia who have had good access to health care. A case-control study was then used to identify factors associated with delayed diagnosis. in which children with an adverse outcome (diagnosed at or after 5 years of age) were compared with those with an optimal outcome (diagnosed before 5 years of age). The chart review identified 161 children with amblyopia who participated in this study; 75 had late diagnoses (case patients) and 86 served as control patients. Children with early diagnoses more often had the following characteristics: a positive family history of strabismus. greater degrees of strabismus (when strabismus was present). higher maternal educational level. greater parental suspicion that an eye problem existed. and an increased chance that the parents requested the eye examination that led to the diagnosis. The parents of children with late diagnoses expressed less concern over the seriousness of amblyopia but were more likely to report that their children had suffered adverse consequences of amblyopia. When diagnosed early. amblyopia was more often detected by the child's primary health care provider. Physicians of the children with early diagnoses more often reported compliance with both the American Academy of Pediatrics guidelines for vision screening in infancy and referral for vision problems.
Methsuximide for intractable childhood seizures, Methsuximide was added to the therapeutic regimens of 25 children with intractable epilepsy. In 15 patients the drug was well tolerated and resulted in a 50% or greater reduction in seizure frequency. No serious or irreversible adverse effects were seen. Methsuximide is frequently overlooked and may be an effective adjunctive antiepileptic for children with intractable seizures.
Allergenicity of orally administered immunoglobulin preparations in food-allergic children, Passive immunization by the oral administration of immunoglobulin preparations derived from bovine milk. chicken egg. and human sera has been proposed as a method for the prevention and treatment of enteric diseases. However. the allergenic potential of these proteins may be a factor limiting their widespread use for disease prevention. An in vitro study with sera from milk- and egg-allergic children was performed to determine whether these immunoglobulin preparations have allergenic potential. Protein extracts of milk. bovine immunoglobulin. egg white. human immune globulin. and five egg yolk antiviral immunoglobulin preparations were bound to nitrocellulose paper. These preparations were probed for specific IgE binding with sera from milk- and egg-allergic patients. Of 22 milk-hypersensitive patients. 16 had specific IgE binding against the bovine immunoglobulin preparation. Of 28 egg-allergic patients 15 had specific IgE binding against one or more of the egg yolk-derived antiviral chicken immunoglobulins. Control sera were negative against the milk and egg preparations. Western blot analysis confirmed that milk- and egg-allergic patients had IgE-specific antibodies for bovine and chicken immunoglobulin molecules. Therefore. the removal of contaminating proteins from milk and egg antibody preparations would be unlikely to eliminate their allergenic potential. In contrast. sera from milk- and egg-allergic patients displayed no detectable IgE binding to human immunoglobulin preparations. These data indicate that the administration of antibody preparations derived from bovine and chicken sources may lead to severe allergic reactions in milk- or egg-sensitized patients and to sensitization in some nonallergic individuals.
Sucrose as an analgesic for newborn infants, The effectiveness of sucrose as an analgesic agent for newborn infants was assessed during two standard painful hospital procedures: blood collection via heel lance and circumcision. Infants who drank 2 mL of a 12% sucrose solution prior to blood collection cried 50% less during the blood collection procedure than did control infants who had received 2 mL of sterile water. Crying of infants who ingested sucrose returned to baseline levels within 30 to 60 seconds after blood collection whereas control infants required 2.5 to 3.0 minutes to return to baseline. Like findings were obtained for infants who received sucrose on a pacifier prior to and during circumcision. Specifically. control infants who underwent a standard circumcision procedure without intervention cried 67% of the time. A water-moistened pacifier reduced crying to 49% (P less than .01). Crying was reduced further to 31% (P less than .05) by providing infants with a sucrose-flavored pacifier to suck. These findings. which parallel results obtained in studies of pain in infant rats. provide a potent yet simple. benign intervention to help alleviate stress and pain routinely experienced by human infants.
Low-level lead exposure and children's cognitive function in the preschool years, In a cohort of 170 middle and upper-middle class children participating in a prospective study of child development and low-level lead exposure. higher blood lead levels at age 24 months were associated with lower scores at age 57 months on the McCarthy Scales of Children's Abilities. The mean blood lead level at age 24 months was 6.8 micrograms/dL (SD = 6.3; 75th. 90th. and 99th percentiles: 8.8. 13.7. 23.6. respectively) and for all but 1 child was less than 25 micrograms/dL. the current definition of an "elevated" level. After adjustment for confounding. scores on the General Cognitive Index decreased approximately 3 points (SE = 1.4) for each natural log unit increase in 24-month blood lead level. The inverse association between lead level and performance was especially prominent for visual-spatial and visual-motor integration skills. Higher prenatal exposures were not associated with lower scores at 57 months except in the subgroup of children with "high" concurrent blood lead levels (ie. greater than or equal to 10 micrograms/dL). The concentration of lead in the dentine of shed deciduous teeth was not significantly associated with children's performance after adjustment for confounding.
The reliability of magnitude estimation for dyspnea measurement, The reliability of magnitude estimation with an open scale was evaluated in a physiologically stable population of adults with chronic respiratory disease who experienced chronic dyspnea. Magnitude estimation was used to measure one dimension of dyspnea. perceptual sensitivity. The relationship between external inspiratory resistive loads (stimuli) and numbers that reflected the perceived intensity of the breathing effort (response) as expressed by a power function was measured on three visits 3 to 5 days apart. The correlations of the exponent of the power function between visits were high and stable.
Circadian rhythms in blood pressure in school-age children of normotensive and hypertensive parents, The purpose of this study was to describe the characteristics of blood pressure rhythms in school-age children and to compare the circadian mesors and amplitudes between children of normotensive parents and children of hypertensive parents. The sample consisted of 40 healthy children between 8 and 10 years old; 20 children had a parental history of hypertension and 20 did not. Blood pressure was measured every 2 hours during the day and every 90 minutes during the night for one 24-hour cycle using a Dinamap monitor equipped with an automatic printer. Cosinor analyses revealed statistically significant circadian rhythms for systolic and diastolic blood pressures in 12 of the 40 subjects. The acrophases for systolic and diastolic pressures occurred between 1200-1800 hours. The mean systolic mesor was 108.50 while the mean diastolic mesor was 61.41. The mean amplitudes were 8.85 for systolic pressure and 7.44 for diastolic pressure. No statistically significant differences in circadian mesors and amplitudes between children of normotensive parents and children of hypertensive parents were found.
Psychometric and descriptive perspectives of illness impact over the life span, This article describes the development of an instrument that quantifies illness over the course of life. The sample was comprised of 308 women. aged 50 to 70. who were alumnae of a master's program in nursing. Each submitted information concerning illness experienced during each decade of life. Each time period was then rated multidimensionally (Duration. Discomfort. Interference. Threat to Life) to reflect the impact of the various conditions and the means by decade (Decade Impact) were computed. In general. after the first two decades. magnitude of ratings increased with age. indicating greater disease impact. Interrater reliability and internal consistency reliability of the scale were high. Evidence for construct validity included substantial differences between those with and without specific illness conditions. as well as correlations with hospitalization history and health self-ratings. In cluster analysis of patterns across decades. five distinct patterns emerged into which subjects were grouped.
Benign biliary strictures: treatment with percutaneous cholangioplasty, Results of percutaneous balloon cholangioplasty of 17 patients with 28 benign biliary strictures were compared with those of published radiologic and surgical series to determine whether stricture location was related to therapeutic success and whether a patient should undergo percutaneous or surgical therapy. Treatment was considered successful if there was no anatomic evidence of recurrent stricture or need for surgery (mean follow-up. 32 months). Treatment was successful in all nine (100%) intrahepatic (zone 1) strictures. 11 of 12 (92%) extrahepatic-extrapancreatic (zone 2) strictures. one of three (33%) intrapancreatic (zone 3) strictures. and three of four (75%) bilienteric anastomotic (zone 4) strictures. Restenosis occurred in five patients; cholangioplasty was ultimately successful in two of those patients after redilation and stent placement. On the basis of these results and those of published radiologic and surgical series. the authors believe that cholangioplasty is the treatment of choice for zone 1 strictures and is as effective as surgery for zone 2 and 4 strictures. Patients with zone 2 and 4 strictures with concomitant portal hypertension or a history of multiple previous biliary surgical procedures should be considered good candidates for cholangioplasty. Zone 3 strictures may be better treated surgically than percutaneously.
Lung abscess: CT-guided drainage, Lung abscesses were drained by means of catheters guided by computed tomography (CT) in 19 patients who still had sepsis despite standard medical therapy; all patients had received antibiotics for at least 5 days. and 11 of the 19 patients had undergone bronchoscopy. The abscess was cured (by clinical and radiographic criteria) in all 19 patients (100%). and surgery was avoided in 16 of the 19 patients (84%). Three patients underwent surgery for removal of organized tissue or decortication after the lung abscess was evacuated. Complications included a hemothorax that required a chest tube in one patient and three minor complications (a clogged catheter in two patients and transient elevation of intracerebral pressure in one patient). The hemothorax occurred in one of two patients in whom the catheter traversed normal lung. The percutaneous drainage catheters traversed juxtaposed abnormal pleura on route to the abscess in 17 of the patients. CT-guided drainage of lung abscess is an effective method to treat lung abscesses that are refractory to conventional therapy; the procedure should obviate major operation in most patients. A catheter route through abscess-pleural syndesis is preferable. and CT is useful for planning this route.
Cineangiography of the heart in a single breath hold with a segmented turboFLASH sequence, Six healthy volunteers and three patients with cardiac anomalies were studied in a comparison of segmented turboFLASH (fast low-angle shot) cine. a method of magnetic resonance imaging that permits an entire series of high-resolution cine images to be obtained in one breath hold. with standard cine. Segmented turboFLASH uses a gradient-echo sequence designed for short imaging times in combination with a segmented data acquisition method. Presaturation pulses were applied to eliminate the blood pool signal; the signal-to-noise ratio was assessed with a phantom. Standard hardware and image reconstruction methods were used. The breath-hold images consistently showed reduced ghosting and blurring from respiration. Because a very short echo time was used. segmented turboFLASH was relatively insensitive to dephasing caused by local field disturbances or flow. The authors conclude that. by reducing imaging times and eliminating respiratory artifact. segmented turboFLASH can be useful for performing cine studies of the heart and great vessels.
Fatal reactions to intravenous nonionic contrast material, Three cases of fatality related to the use of low-osmolality contrast material (LOCM) are presented. LOCM definitely reduces unpleasant side effects and serious reactions. but data are currently insufficient to determine whether the death rate is any different from that associated with high-osmolality contrast agents. If the present trend toward universal conversion to LOCM continues. an enormous cost for little. if any. lifesaving benefit may be incurred.
Prediction of severe adverse reactions to ionic and nonionic contrast media in Japan: evaluation of pretesting. A report from the Japanese Committee on the Safety of Contrast Media, In a nationwide prospective study of adverse reactions to intravenous contrast media (CM). the Japanese Committee on the Safety of Contrast Media compared high-osmolar ionic CM with low-osmolar nonionic CM. A total of 337.647 cases were analyzed. The reliability of pretesting with an intravenous injection of a small amount of CM as a means of predicting severe or fatal reactions was also evaluated. The predictive values of the pretest were 1.2% for ionic and 0.0% for nonionic CM. and the sensitivity values were 3.7% and 0.0%. respectively. Such low values render this test meaningless for predicting which patients are at risk of a severe adverse reaction. A comparison of the incidence of severe adverse reactions between the nonpretested and pretested patients. as well as between the nonpretested and pretested patients with negative results. disclosed no statistically significant differences. Also. no beneficial effects of premedication in patients with a positive pretest were proved. The authors therefore conclude that pretesting with an intravenous injection of a small amount of CM is not useful in predicting severe reactions to ionic or nonionic CM.
Gastric emptying in infants and children: limited utility of 1-hour measurement, Gastric emptying measurements were performed in infants and children at 1 and 2 hours after a liquid feeding. The 1-hour measurements were predictive of only 58% of the variability in the 2-hour measurements. indicating that the 1-hour measurement was not a good predictor of the 2-hour measurement. Gastric emptying measurements in children should be continued until 2 hours after feeding unless rapid emptying is observed during the 1st hour of the study.
Simple renal cysts in children: diagnosis and follow-up with US, To assess the sonographic frequency of simple renal cysts in children. the authors retrospectively reviewed the results of abdominal sonographic studies of 16.102 children performed over a 5-year period between January 1. 1985. and December 31. 1989. Patients with abnormal renal function. dysplastic kidneys. or a family history of polycystic kidney disease were excluded from the study. The authors' review of the sonograms revealed 37 simple cysts in 35 patients (0.22%); the cysts were evenly distributed by age and sex and measured from 0.3 to 7.0 cm in maximum diameter. Sixteen cysts (43%) were in the upper pole of the right kidney. Follow-up sonographic studies of 23 cysts in 22 patients for up to 5 years showed no change in size in 17 cysts (74%). The largest cyst was drained percutaneously; all other cysts were managed conservatively. No patient showed deterioration of renal function. Therefore. the authors concluded that in a pediatric patient demonstrating normal renal function. no further intervention is necessary when a simple renal cyst is identified at sonography.
Gallstone lithotripsy: relevant physical principles and technical issues, A basic understanding of shock wave generation is essential for the radiologist who performs gallstone lithotripsy. Shock waves differ from ordinary acoustic waves in that they have a rapid rise time. a positive pressure component that gives rise to compressive forces approaching 1.000 atm. and a low-amplitude sustained negative pressure (rarefactive) component. Shock waves are created by means of three different types of shock wave generators: spark-gap. electromagnetic. and piezoelectric. The authors describe and compare these three types of shock wave generators with regard to equipment selection. Regardless of how shock waves are generated. they share common interactions with tissue. These interactions are reviewed along with the proposed mechanisms of stone fragmentation.
Early asbestosis: evaluation with high-resolution CT, To determine the earliest stage at which lesions in asbestosis can be diagnosed and to assess their progression. 23 asbestos-exposed patients with minimal or no abnormalities at plain radiography were examined with high-resolution computed tomography (HRCT) twice. with an interval of 12-37 months between examinations. In 21 of the patients. parenchymal abnormalities were found. Major parenchymal features seen at CT included thickened intralobular and interlobular lines. subpleural curvilinear lines. pleural-based nodular irregularities. hazy patches of increased attenuation. small cystic spaces. and small areas of low attenuation. At paired serial CT. subpleural isolated dots or branching structures connected with the most peripheral branch of the pulmonary artery started to appear in lower subpleural zones and then became confluent to create pleural-based nodular irregularities. CT-pathologic correlation led to the conclusion that the confluence of subpleural peribronchiolar fibrosis creates subpleural fibrosis.
Differentiation of detached retina and vitreous membrane with color flow Doppler, The sonographic criteria for diagnosis of retinal detachment and vitreous membranes are well established. and in most cases a diagnosis can be made. However. in difficult cases. differentiation between the two may be difficult. In this study the use of high-resolution color flow Doppler was evaluated for differentiating between retinal detachments and vitreous membranes. Sonographic evaluation. including color flow Doppler. was performed in 25 symptomatic eyes. Seven eyes had areas of retinal detachment. all of which had detectable blood flow within at least a portion of the detached retina. Fifteen eyes had vitreous hemorrhages or membranes in which no flow was detected. Two diabetic patients with vitreous membranes and no retinal detachment did have flow detectable within the neovascular membranes. Another patient. who had a complete choroid detachment after surgery. demonstrated good flow within the area of detachment. It is concluded that in difficult cases high-resolution color flow Doppler can enable differentiation of an area of retinal detachment from a vitreous membrane in a patient without diabetes.
Multiple sclerosis: specificity of MR for diagnosis, The specificity of magnetic resonance (MR) imaging in the diagnosis of multiple sclerosis (MS) has not been measured systematically. Conventional MR head images with sagittal localizer and axial multiple-echo sequences with long repetition times were obtained in 92 patients with clinically verified MS (Schumacher criteria). 100 healthy volunteers. 60 subjects with hypertension. and eight patients with dementia. Two readers. without the aid of any clinical or demographic information. classified each of the 260 studies as MS or not MS. The readers classified the studies again after being supplied with the subjects' ages and sex. True-negative and true-positive diagnoses of MS were tabulated. The specificity of the MR diagnosis of MS (true-negative results in proportion to all non-MS studies) was 95%-99% with all the control groups included. There is a small risk of misinterpreting incidental periventricular white matter foci as plaques of MS in MR studies.
Cerebral venography with MR, The authors describe a two-dimensional time-of-flight magnetic resonance (MR) angiography technique to create projection venograms of the head. The technique was applied to 27 healthy volunteers and 39 patients. The superior sagittal and straight sinuses. the internal cerebral veins. and the Galen vein were visualized in all the volunteers. Other veins were seen in a high percentage of subjects. Systematic comparison of digital subtraction angiography (DSA) after intraarterial contrast medium injection and MR venography in patients showed good correlation between the two techniques. MR venography proved helpful in identifying thrombosis or patency of cerebral veins and sinuses and showed collateral venous drainage and venous drainage from arteriovenous malformations. There was good correlation between conventional contrast angiography and MR venography. In conclusion. MR venography is considered reliable for showing the cerebral venous system and provides information additional to that of conventional spin-echo imaging.
Marked cerebrospinal fluid void: indicator of successful shunt in patients with suspected normal-pressure hydrocephalus, The authors blindly reviewed the charts of 20 patients with normal-pressure hydrocephalus (a disease of unknown cause characterized radiologically as chronic communicating hydrocephalus and clinically by gait apraxia. dementia. and incontinence) who had undergone creation of a ventriculoperitoneal shunt. The initial clinical response to surgery was graded excellent. good. fair. or poor; 5-year follow-up was available in 55% of cases. The magnetic resonance (MR) images obtained in these patients were also blindly reviewed for the magnitude of cerebrospinal fluid (CSF) flow void (graded on the basis of extent rather than degree of signal loss) in the cerebral aqueduct. A significant (P less than .003) correlation existed between good or excellent response to surgery and an increased CSF flow void. The presence of associated deep white matter infarction on MR images did not correlate with a poor response to surgery. On the basis of these findings. it is suggested that patients who fulfill the clinical criteria of NPH and have an increased CSF flow void undergo creation of a shunt.
Splenic trauma: can CT grading systems enable prediction of successful nonsurgical treatment, The capability of computed tomographic (CT) grading systems to enable prediction of successful nonsurgical treatment of splenic trauma in children and adults was evaluated. Fifty-six patients with documented splenic injury were examined with CT by use of standard trauma protocols. Each CT scan was graded according to two recently proposed grading systems. The charts of these patients were then reviewed. and correlations between the CT grade and clinical outcome were determined with each grading system. Forty patients underwent successful nonsurgical treatment; three of these patients (8%) underwent delayed celiotomy for splenic rupture after failure of nonsurgical treatment. Two of these three had grades that indicated nonsurgical treatment was viable. In each of these three patients. splenectomy was necessary. In the 16 patients who underwent surgery. eight cases (50%) of CT grading errors were documented with surgery. In four cases. the extent of the injury was underscored with CT. and in another four cases the injury was overscored. It is still not clear whether the severity of splenic injury as defined with CT correlates with clinical outcome.
Air in the fissure for the ligamentum teres: new sign of intraperitoneal air on plain radiographs, In each of four patients in whom an acute spontaneous pneumoperitoneum developed. a vertically directed area of hyperlucency in the right upper quadrant was seen on radiographs of the abdomen obtained with the patient supine. This finding. which appeared in the absence of other characteristic signs of free air on plain radiographs and which. to the authors' knowledge. has not been previously recognized. represented intraperitoneal gas confined to the fissure for the ligamentum teres (FLT). The location of the hyperlucent area was confirmed with computed tomography or laparotomy in each patient. The distinctive configuration of air in the FLT is a subtle but reliable indicator of pneumoperitoneum.
Hepatic dynamic sequential CT: section enhancement profiles with a bolus of ionic and nonionic contrast agents, The enhancement characteristics in different portions of the liver during dynamic sequential bolus computed tomography (CT) with iodinated contrast material (DSBCT) were prospectively evaluated in 75 patients by using iothalamate meglumine. iopamidol. and iohexol (25 patients received each agent). After baseline noncontrast CT was performed. DSBCT was performed with a 180-mL intravenous bolus administered at 2 mL/sec. Scanning was started 25 seconds after the bolus was initiated. by using a 3-second scan time and rapid cephalocaudal table incrementation. yielding contiguous 8-mm-thick sections at a rate of nine sections per minute. On postcontrast images. peak enhancement was 115% for iopamidol and 117% for iohexol. both of which were superior to iothalamate meglumine at 95% (P less than .05). After peaking. enhancement then decreased for all three contrast agents. although the decline was more precipitous for iothalamate meglumine. Enhancement on the more caudal sections with both iopamidol and iohexol was superior to that with iothalamate meglumine (P less than .05). The data suggest that the enhancement characteristics for the two nonionic agents may be more optimal for detection of focal hepatic lesions than the ionic agent.
Liver cirrhosis: changes of Doppler waveform of hepatic veins [published erratum appears in Radiology 1991 Aug;100(2):586, The authors compared the Doppler ultrasonographic pattern of hepatic veins (HVs) in a group of 60 patients affected by liver cirrhosis and in 65 healthy subjects comparable for sex and age to (a) detect possible differences in HV waveform in the two groups and (b) investigate the relationship of these differences with the severity of the disease (according to Child-Pugh classification) and the modifications of systemic hemodynamics. The waveform of HVs was arbitrarily classified into three patterns: HV0. a normal waveform; HV1. lower oscillations without the reversed phase; and HV2. completely flat waveform. The resistivity index of the superior mesenteric artery. reflecting the peripheral splanchnic impedance and the hyperdynamic circulation. was also measured in a subgroup of 45 cirrhotic patients. The waveform of HVs in all healthy subjects corresponded to the HV0 pattern. Among cirrhotic patients. HV0 was found in 30 (50%). HV1 in 19 (31.7%). and HV2 in 11 (81.3%). The severity of functional impairment was greatest in the HV2 group and least in the HV0 group. This was significantly correlated with the decrease of the resistivity index in the superior mesenteric artery in the subgroup of 45 patients. Changes in the normal HV waveform could be considered a useful adjunctive tool for the noninvasive evaluation of liver disease. The pathophysiology of these changes in HV blood flow is still unclear. The significant correlation with the severity of the disease and with the decrease of splanchnic resistances indicates that these changes in the HV waveform occur in the presence of marked rearrangements of liver tissue and of hyperdynamic systemic circulation.
Nonpalpable prostate cancer: detection with MR imaging, The pathologic specimens and magnetic resonance (MR) images of 53 patients with clinically palpable prostate cancer confined to one lobe were studied to evaluate the ability of MR imaging to depict clinically nonpalpable prostate cancer. All patients had undergone imaging with a 1.5-T imager with T1- and T2-weighted sequences in both axial and sagittal planes before undergoing radical retropubic prostatectomy. At pathologic examination. only the palpable tumor was present in 30 of the 53 patients (57%). and 33 unsuspected tumors were present in an area distinct from the palpable tumor in 23 of the patients (43%). MR imaging successfully depicted 51 palpable tumors for a sensitivity of 96% and 19 of the 33 unsuspected tumors for a sensitivity of 58%. The sensitivity of MR imaging in the detection of nonpalpable. posteriorly located tumors was greater than for those located anteriorly (85% vs 15%). MR imaging was false-positive for nonpalpable tumor in 17 of 30 patients for a specificity of 43%. On the basis of these data. MR imaging has greater sensitivity in the depiction of posteriorly located cancer and is limited by a high false-positive rate in the depiction of nonpalpable tumors.
Determination of prostate volume with transrectal US for cancer screening. Part I. Comparison with prostate-specific antigen assays, To investigate whether radiologists can objectively define a high-risk group for prostate cancer. the researchers measured gland volume and compared it with results of a screening blood test. prostate-specific antigen (PSA) assay. A total of 768 men. aged 55-71 years. were self-referred to two prostate cancer screening programs using transrectal ultrasound (US) and digital rectal examination. In patients with no evidence of cancer. statistically significant increases in mean PSA values were noted with increasing gland volume ranges (P less than .05). PSA values in patients with cancer were more likely to exceed the volume-adjusted 95th percentile (mean + [1.65.standard deviation]) than those in patients with negative biopsy results (P less than .005). Patients with PSA values above the volume-adjusted 95th percentile have an estimated risk for prostate cancer up to nine times that of the general screening population. The researchers conclude that knowledge of transrectal US gland volume and prostate-specific antigen assay type are important objective variables for future prostate cancer screening programs. The volume-adjusted 95th percentiles presented may help guide cost-effective management of current early detection efforts.
Gynecologic vascular abnormalities: diagnosis with Doppler US, The authors describe the use of duplex and/or color Doppler ultrasonography of the pelvis in three women to demonstrate the presence of venous malformations. One patient with a pulsatile vaginal mass was shown to have an arteriovenous malformation of the vaginal wall. The second patient was shown to have an unsuspected venous angioma in the endometrial cavity. The third patient was shown to have adnexal varices that closely mimicked hydrosalpinx. In the latter two cases. the duplex and color flow capabilities of an endovaginal probe were especially important.
Bullet identification with radiography, The authors provide a simple radiographic method for estimating bullet weight and caliber of both deformed and undeformed bullets that enables accurate determination of caliber for the gamut of bullet shapes. with known degrees of confidence. The weight-determination procedure is based on the correlation between bullet cross-sectional area. as derived from three orthogonal radiographs. and bullet weight. as determined from a data base of the properties of 48 bullets removed from humans. Different equations were developed for bullets weighing 5.8 g or less. or more than 5.8 g. For relatively undeformed bullets an additional method calculated caliber directly from the diameter of the bullet body on radiographs. Both methods enabled correct prediction of the weight and caliber of the bullets; if one method could not be used. results of the other were reliable. Testimony based on these results has been accepted in a local police case and may meet requirements for testimony in U.S. court cases involving gunshots.
Respiratory rate greater than 50 per minute as a clinical indicator of pneumonia in Filipino children with cough, The diagnosis and epidemiology of acute respiratory tract infection (ARI) in 199 children less than 5 years old were investigated in Manila. As part of this study. children who were treated at one of two outpatient clinics for cough of less than 3 weeks' duration were studied to test the validity of the use of a respiratory rate (RR) of greater than 50/minute for identifying ARI of a severity necessitating treatment with antibiotics. In the first population. in which 69% of the children had radiologically confirmed pneumonia. the sensitivity of a RR of greater than 50/minute was 54%. the specificity was 84%. the false-positive rate was 16%. and the false-negative rate was 46%. In the second population. in which 29% of the children had pneumonia. the sensitivity and positive predictive values were low. The validity of a RR of greater than 50/minute may vary in populations with different prevalences of ARI.
Linkage of early-onset familial breast cancer to chromosome 17q21, Human breast cancer is usually caused by genetic alterations of somatic cells of the breast. but occasionally. susceptibility to the disease is inherited. Mapping the genes responsible for inherited breast cancer may also allow the identification of early lesions that are critical for the development of breast cancer in the general population. Chromosome 17q21 appears to be the locale of a gene for inherited susceptibility to breast cancer in families with early-onset disease. Genetic analysis yields a lod score (logarithm of the likelihood ratio for linkage) of 5.98 for linkage of breast cancer susceptibility to D17S74 in early-onset families and negative lod scores in families with late-onset disease. Likelihood ratios in favor of linkage heterogeneity among families ranged between 2000:1 and greater than 10(6):1 on the basis of multipoint analysis of four loci in the region.
Dominant negative regulation of the mouse alpha-fetoprotein gene in adult liver, Transcription of the mouse alpha-fetoprotein gene is activated in the developing fetal liver and gut and repressed in both tissues shortly after birth. With germline transformation in mice. a cis-acting element was identified upstream of the transcription initiation site of the alpha-fetoprotein gene that was responsible for repression of the gene in adult liver. This negative element acts as a repressor in a position-dependent manner.
Hot spots for growth hormone gene deletions in homologous regions outside of Alu repeats, Familial growth hormone deficiency type 1A is an autosomal recessive disease caused by deletion of both growth hormone-1 (GH1) alleles. Ten patients from heterogeneous geographic origins showed differences in restriction fragment length polymorphism haplotypes in nondeleted regions that flanked GH1. suggesting that these deletions arose from independent unequal recombination events. Deoxyribonucleic acid (DNA) samples from nine of ten patients showed that crossovers occurred within 99% homologous. 594-base pair (bp) segments that flanked GH1. A DNA sample from one patient indicated that the crossover occurred within 454-bp segments that flanked GH1 and contained 274-bp repeats that are 98% homologous. Although Alu repeats. which are frequent sites of recombination. are adjacent to GH1. they were not involved in any of the recombination events studied. These results suggest that length and degree of DNA sequence homology are important in defining recombination sites that resulted in GH1 deletions.
Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region, The function of the c-Myc oncoprotein and its role in cell growth control is unclear. A basic region of c-Myc is structurally related to the basic motifs of helix-loop-helix (HLH) and leucine zipper proteins. which provide sequence-specific DNA binding function. The c-Myc basic region was tested for its ability to bind DNA by attaching it to the HLH dimerization interface of the E12 enhancer binding factor. Dimers of the chimeric protein. termed E6. specifically bound an E box element (GGCCACGTGACC) recognized by other HLH proteins in a manner dependent on the integrity of the c-Myc basic motif. Methylation of the core CpG in the E box recognition site specifically inhibited binding by E6. but not by two other HLH proteins. Expression of E6 (but not an E6 DNA binding mutant) suppressed the ability of c-myc to cooperate with H-ras in a rat embryo fibroblast transformation assay. suggesting that the DNA recognition specificity of E6 is related to that of c-Myc in vivo.
Vaccination for disease, Recombinant virus vaccines that express a limited number of epitopes are currently being developed to prevent disease by changing the relative balance between viral spread and the immune response. Some circumstances. however. were found in infections with a noncytopathic virus in which vaccination caused disease; sensitive parameters included the genetic background of the host. the time or dose of infection. and the constituents of the vaccine. Thus. immunopathologic damage by T cells may be an unwanted consequence of vaccination with the new types of peptide or recombinant vaccines that are being investigated for the human immunodeficiency viruses and other pathogens.
The effect of anti-neoplastic drugs on murine acquired immunodeficiency syndrome, The murine acquired immunodeficiency syndrome (MAIDS) is associated with proliferation of target cells that have been infected by a defective retrovirus. To control the growth of this primary neoplasia. virus-inoculated mice were treated with anti-neoplastic drugs. Paradoxically. cyclophosphamide. which is also immunosuppressive. was very effective in preventing the appearance and progression of the disease. in restoring a normal T cell function. and in depleting the number of infected target cells. This result suggests that the proliferating infected target cells were responsible for the immunodeficiency.
Death and functional outcome after spontaneous intracerebral hemorrhage. A prospective study of 166 cases using multivariate analysis, Using death and functional status as end points. we prospectively analyzed the outcome 6 months after spontaneous intracerebral hemorrhage in 166 patients admitted to an acute-care stroke unit on the first day of their stroke. Seventy-one patients (43%) died. 69 (42%) had a satisfactory outcome. and 26 (16%) had a poor functional outcome. Early (30-day) survival was correlated with morphologic parameters on the initial computed tomogram (hemorrhage size. midline shift. and intraventricular spread of the hemorrhage). while later (6-month) survival was correlated with age. Using logistic regression. we found five independent predictors of satisfactory outcome at 6 months: age. hemorrhage size. intraventricular spread of the hemorrhage. limb paresis. and communication disorders. Of these. age was the most important predictor by far.
Functional outcome measures in stroke rehabilitation, I examine statistical considerations in the analysis of functional outcome following stroke and discuss the mathematical relation between improvement in function and discharge functional score. I demonstrate mathematically that the predictor variables of improvement and discharge functional score are the same and that the regression coefficients for improvement and discharge functional score will be equal. except for the admission functional score. for which a mathematically defined relation exists. I argue that the relation between admission functional score and discharge functional score must be positive and strong and that the relation between admission functional score and improvement must be negative for the stroke population. I believe that an ignorance of statistical concepts. especially confounding. and of the differences between raw correlations. partial correlations. and predictors have led to much confusion in functional outcome research.
Platelet volume, aggregation, and adenosine triphosphate release in cerebral thrombosis, We compared whole blood platelet aggregation. adenosine triphosphate release. platelet count. platelet crit (percentage volume of platelets). and mean platelet volume during the acute. subacute. and chronic periods of cerebral thrombosis in 22 patients with value in 29 controls. During the acute and subacute periods. platelet aggregation. platelet count. platelet crit. and mean platelet volume were significantly less in the patients than in the controls (p less than 0.05-0.01) while the adenosine triphosphate release rate per volume of platelets was significantly greater (p less than 0.05). During the acute period. infarct size showed a significant positive correlation with platelet aggregation (r = 0.59. p less than 0.01) and adenosine triphosphate release rate (r = 0.70. p less than 0.001) but a negative correlation with platelet count (r = -0.44. p less than 0.05). Our results suggest that platelet aggregation is reduced during the acute period due to the consumption of platelets during thrombogenesis but that the remaining individual platelets are hyperactive. Platelet consumption during the acute period increases with infarct size. During the chronic period. platelet crit and mean platelet volume were significantly less in the patients than in the controls (p less than 0.01) while the adenosine triphosphate release rate was significantly greater (p less than 0.01). suggesting sustained platelet consumption and chronically enhanced secretion of individual platelets.
Middle cerebral artery blood velocity and cerebral blood flow in sickle cell disease, To understand better the relationship between blood velocity measured by transcranial Doppler and cerebral blood flow measured by the 133Xe inhalation method. we examined 23 patients undergoing evaluation in the Comprehensive Sickle Cell Center at Columbia University. Blood velocity in the middle cerebral artery was directly related to cerebral flow (r = 0.77; p less than 0.05). A multivariate analysis in this sample made it possible to improve this correlation to account for more than 90% of the variability in cerebral blood flow by the use of transcranial Doppler measures of velocity and pulsatility along with the patient's age and hematocrit (r = 0.95; p less than 0.001). It is likely that the combination of Doppler and clinical or demographic variables in other diseases will similarly improve the quantitative estimation of cerebral blood flow.
Noninvasive assessment of cerebral collateral blood supply through the ophthalmic artery, We assessed the potential of 2-MHz pulsed-wave transorbital Doppler ultrasonography to delineate the role of the ophthalmic artery as a source of collateral cerebral blood supply by comparing oculopneumoplethysmography. transorbital Doppler ultrasonography. periorbital continuous-wave Doppler ultrasonography. and transcranial Doppler ultrasonography in 25 patients with unilateral internal carotid artery occlusion and five controls with 10 normal internal carotid arteries. Systolic ophthalmic artery blood velocity was reduced ipsilateral to an internal carotid artery occlusion (38.2 +/- 10.2 cm/sec) compared with the contralateral and control velocities (46.0 +/- 10.3 and 47.5 +/- 6.8 cm/sec. respectively; p less than 0.05). Ophthalmic systolic pressure measured by oculopneumoplethysmography was 94.7 +/- 13.2 mm Hg ipsilateral to an internal carotid artery occlusion compared with 108.4 +/- 15.3 mm Hg on the contralateral side (p less than 0.01). Transorbital and periorbital Doppler ultrasonography detected reversed ophthalmic artery blood flow ipsilateral to an internal carotid artery occlusion in 44.0% and 40.0% of the patients. respectively. Systolic middle cerebral artery blood velocity was 55.2 +/- 22.3 cm/sec ipsilateral to an internal carotid artery occlusion compared with 79.4 +/- 23.5 cm/sec on the contralateral side (p less than 0.05) and 101.2 +/- 18.9 cm/sec in the controls (p less than 0.05). Reversed ophthalmic artery blood flow was associated with a low middle cerebral artery blood velocity and lack of major intracerebral collaterals. Transorbital Doppler ultrasonography permits noninvasive evaluation of the ophthalmic artery.
Mild hypothermic intervention after graded ischemic stress in rats, We investigated the effect of mild (34 degrees C) postischemic hypothermia on hippocampal neuronal damage in 43 rats as a function of the duration of forebrain ischemia. Two temperatures and two durations were investigated. In two normothermic groups ischemia lasted 8 (n = 15) and 12 (n = 10) minutes. respectively. In two hypothermic groups ischemia lasted 8 (n = 9) and 12 (n = 9) minutes. respectively. and was followed immediately by the lowering and maintenance of rectal temperature to 34 degrees C for 2 hours. Seven days after the ischemic insult. the rats were sacrificed and the brains were prepared for histologic analysis; the percentage of necrotic neurons among the total neuronal population in selected CA1/2 sectors of the hippocampus was determined. There was a significant decrease in the percentage of necrotic neurons in the central (77.5% versus 55.5%. p = 0.006) and lateral (62.5% versus 38.9%. p=0.005) areas and in the overall CA1/2 sector of the hippocampus (71.8% versus 52.2%. p = 0.008) for the 8-minute hypothermic group compared with the 8-minute normothermic group. In contrast. no differences were detected in any area of the hippocampus between the 12-minute normothermic and the 12-minute hypothermic groups (p = 0.29-0.49). Our data indicate that mild postischemic whole-body hypothermia ameliorates neuronal survival when ischemia lasts 8 minutes but not 12 minutes.
A novel treatment for ischemic intracranial hypertension in cats, There is no accepted efficacious treatment for ischemic cerebral edema. We show in a cat model of focal cerebral ischemia that infarct volume can be reduced (p less than 0.05) by ventriculocisternal perfusion with an oxygenated fluorochemical emulsion (bis-perfluorobutylethylene). An accompanying effect of such ventriculocisternal perfusion is a reduction in intracranial pressure. At 18 hours following the start of the perfusion. there was a significant (p less than 0.05) difference in intracranial pressure between nonperfused controls (mean 11.4 [range 2.3-23.0] torr. n = 6) and cats perfused with an oxygenated nutrient solution not containing fluorochemical (mean 11.3 [range 3.0-29.0] torr. n = 8) or animals perfused with the oxygenated fluorochemical emulsion (mean 2.21 [range 0-3.5] torr. n = 7). Perfusion with this oxygenated fluorochemical emulsion warrants further study as a treatment for elevated intracranial pressure.
Aspiration pneumonitis: risk factors and management of the critically ill patient, Pulmonary aspiration of gastric contents is a significant source of patient morbidity. mortality. and increased healthcare costs. Prevention by identifying patients at risk for aspiration and initiating prophylaxis is the most effective method of reducing complications associated with aspiration pneumonitis. H2-receptor antagonists are among the best prophylactic agents because of their efficacy in reducing gastric acidity and their convenience of administration.
Assessing the nutritional needs of the critically ill patient, Because critical illness often creates a vigorous metabolic response to permit the repair of injured tissues. nutritional considerations are essential in the medical management of the critically ill patient. Individuals with seemingly adequate endogenous nutritional reserves may rapidly develop complications of starvation. Nutritional supplementation is essential; however. critically ill patients may not readily tolerate nutritional support. Calories may need to be withheld until the patient is able to tolerate and utilize nutritional support. Once the decision to initiate nutritional support is made. nutritional status. level of stress. metabolic condition. and vital organ function influence the patient's nutritional requirements. An assessment of the patient's metabolic condition provides data useful in determining the need for supplemental electrolytes or macronutrients. These data also provide information regarding vital organ function. which is necessary for utilization of the fuel and substrate. Aggressive monitoring and judicious nutritional supplementation will afford the critically ill patient the best chance of recovery.
Sclerotherapy for esophageal varices, Endoscopic injection sclerotherapy (EIS) frequently is used for patients with esophageal varices. both for controlling acute hemorrhage and for prophylaxis. An old technique. interest in EIS increased when other methods did not improve patient outcomes. Clinical trials of EIS for acute hemorrhage demonstrated efficacy and improved outcome. although some researchers disagree with these findings. Recent data on prophylaxis with EIS fail to support the value of EIS for this indication. Ethanolamine oleate compares favorably with other sclerosing agents. and is the only one currently approved for EIS. The intravariceal method is used more frequently than the paravariceal method because it has better efficacy and can be performed more rapidly. The percentage of patients developing significant complications from EIS may be as high as 15 percent; common complications include retrosternal pain. pyrexia. and sepsis. EIS is currently an important clinical tool in the management of esophageal varices.
Interpreting results of exercise studies after acute myocardial infarction altered by thrombolytic therapy, coronary angioplasty or bypass, Numerous studies have assessed the ability of exercise modalities to predict patient outcome after acute myocardial infarction (AMI). Implicit in the use of these prior data to assess the prognosis of patients currently undergoing exercise studies is the assumption that patients selected for exercise assessment are similar over time and that the data generated in the past are therefore applicable to the current patient populations. This study retrospectively assessed the clinical. exercise. and rest and exercise radionuclide angiographic data in 791 consecutive patients referred for exercise radionuclide angiography within 1 month after AMI during a 5-year period to determine if the clinical and exercise characteristics of patients referred for exercise evaluation after infarction have changed significantly over time. Most parameters examined demonstrated significant increasing trends. including thrombolytic therapy at the time of AMI. revascularization procedure between AMI and exercise assessment. age. beta-blocker usage. Q-wave AMI. inferior infarction. exercise double product. exercise capacity. significant ST-segment depression with exercise. peak ejection fraction. and change in ejection fraction with exercise. These data indicate that the characteristics of patients selected to undergo exercise after AMI in a large referral center have changed significantly over time. If these data are applicable to other referral centers and to other exercise testing modalities. previously published results regarding exercise assessment after AMI will need to be reconfirmed in patients currently selected for testing. since these results may no longer be applicable in this current era of aggressive medical and interventional management.
Effect of nifedipine on total ischemic activity and circadian distribution of myocardial ischemic episodes in angina pectoris, A randomized. double-blind. crossover study was conducted in 10 patients to assess the effect of nifedipine versus placebo on total ischemic activity and circadian distribution of ischemic episodes. After baseline exercise treadmill testing and 48-hour ambulatory electrocardiographic ST-segment monitoring. patients received either nifedipine (mean dose. 80 mg/day) or placebo administered 4 times per day. with the initial dose taken immediately upon arising in the morning. Patients were maintained on a stable dose of each study drug for 7 days. after which they underwent repeat exercise treadmill testing and 48-hour ambulatory electrocardiography. During exercise treadmill testing. greater exercise duration was achieved by patients receiving nifedipine than by those receiving placebo (421 +/- 121 vs 353 +/- 155 seconds. respectively; p less than 0.05). Time to greater than or equal to 1 mm ST depression was significantly greater with nifedipine (282 +/- 146 seconds) than at baseline (130 +/- 72 seconds. p less than 0.003) and with placebo (150 +/- 98 seconds. p less than 0.0005). During ambulatory electrocardiographic monitoring. nifedipine reduced both the total number of ischemic episodes (18 vs 54 at baseline and 63 with placebo; p less than 0.02 for both) and the total duration of ischemia (260 vs 874 at baseline and 927 minutes with placebo; p less than 0.02 for both). The surge of ischemia between 06:00 and 12:00 noted at baseline and during placebo therapy was nearly abolished during nifedipine treatment. Nifedipine at this dosage. administered in this manner. is effective in reducing total ischemic activity and may prevent morning surges of ischemic episodes.
Ablation of the atrioventricular junction with radiofrequency energy using a new electrode catheter, Percutaneous catheter ablation using radiofrequency energy can be used to interrupt atrioventricular (AV) conduction in patients with supraventricular tachycardia refractory to drugs. Results of radiofrequency ablation of the AV junction using a custom-designed catheter with a large. 3-mm-long distal electrode. 2-mm interelectrode spacing. and a shaft with increased torsional rigidity were compared with those using a standard quadripolar electrode catheter (Bard EP). An electrocoagulator (Microvasive Bicap 4005) supplied unmodulated radiofrequency current at 550 kHz. which was applied between the distal electrode of the ablation catheter and a large skin electrode. With use of the modified catheter. 12 of 13 patients (92%) had persistent complete AV block induced with 7 +/- 5 applications of 18 +/- 6 W of radiofrequency power. In contrast. complete AV block was produced in only 9 of 18 (50%) historical control patients treated with the standard catheter. despite a similar number of applications (7 +/- 5) and power output (16 +/- 4 W). A rise in impedance. due to desiccation of tissue and coagulum formation. occurred earlier (28 +/- 18 vs 52 +/- 24 seconds. p less than 0.001) and more frequently (54 vs 40% of applications. p = 0.047) in patients treated with the standard catheter than in patients treated with the modified catheter. The use of a catheter designed to increase the surface area of electrode-tissue contact allows more radiofrequency energy to be delivered before a rise in impedance occurs and appears to increase the effectiveness of radiofrequency ablation of the AV junction.
Relative importance of activation sequence compared to atrioventricular synchrony in left ventricular function, This study evaluated the relative hemodynamic importance of a normal left ventricular (LV) activation sequence compared to atrioventricular (AV) synchrony with respect to systolic and diastolic function. Twelve patients with intact AV conduction and AV sequential pacemakers underwent radionuclide studies at rest and Doppler echocardiographic studies at rest and during submaximal exercise. comparing atrial demand pacing (AAI) to sequential AV sensing pacing (DDD) and ventricular demand pacing (VVI). Studies at rest were performed at a constant heart rate between pacing modes. and the exercise study was performed at a constant heart rate and work load. Cardiac output was higher during AAI than during both DDD and VVI (6.2 +/- 1 vs 5.6 +/- 1 and 5.3 +/- 1 liters/min. p less than 0.05). LV ejection fraction was likewise higher during AAI (55 +/- 12 vs 49 +/- 11 vs 51 +/- 13. p less than 0.05). VVI with or without AV synchrony was associated with a paradoxical septal motion pattern. resulting in a 25% impairment of regional septal ejection fraction. In addition. LV contraction duration was more homogenous during AAI. Peak filling rate during AAI and VVI was higher than during DDD (2.86 +/- 1 and 2.95 +/- 1 vs 2.25 +/- 1 end-diastolic volume/s; p less than 0.05). During VVI. the time to peak filling was significantly shorter than during both AAI and DDD (165 +/- 34 vs 239 +/- 99 and 224 +/- 99 ms; p less than 0.05).
Effects of doxazosin on blood pressure, renin-angiotensin-aldosterone and urinary kallikrein, Doxazosin. a new quinazoline-derivative postsynaptic alpha 1-adrenoceptor antagonist. was studied in this randomized. double-blind. placebo-controlled 12-week study. Its effects on blood pressure (BP). heart rate. metabolic functions and renal hormones were analyzed after administration of a single oral morning dose in a 3-phase fashion when administered to 17 patients (11 women. 6 men. 21 to 59 years) with mild to moderate uncomplicated essential hypertension. After titrating the antihypertensive effective dose biweekly from 1 to 8 mg/day and a mean end titration-point dose of 4.14 +/- 0.1 mg (mean +/- standard error of the mean) at week 8 of treatment. it was adjusted to maintain diastolic BP at levels less than or equal to 90 mm Hg for up to 12 weeks of treatment when. at a final mean dose of 4.35 +/- 0.2 mg/day. BP decreased in all patients by a mean 31 +/- 3/17 +/- 2 (supine) and 39 +/- 3/15 +/- 3 (standing) mm Hg (p less than 0.005) with no increase in heart rate and no "first-dose phenomenon." Neither the renin-aldosterone system nor electrolyte excretion was significantly affected. Renal function and metabolic parameters also remained unchanged. Urinary kallikrein excretion was augmented 2.47-fold (p less than 0.002). There was good tolerance; 1 patient discontinued the study because of dry nose. These results suggest that long-term monotherapy with doxazosin is an effective and safe antihypertensive agent for mild to moderate essential hypertension that stimulates urinary kallikrein excretion.
Effect of mitral regurgitation and volume loading on pressure half-time before and after balloon valvotomy in mitral stenosis, Doppler pressure half-time (PHT) is frequently used to assess mitral valve area (MVA). but the reliability of PHT has recently been challenged. specifically in the setting of balloon mitral valvotomy when hemodynamics have been abruptly altered. The effect of volume loading both before and after balloon mitral valvotomy on computation of MVA by Gorlin and by PHT in 18 patients with high-fidelity micromanometer measurements of left atrial and left ventricular pressure was therefore examined. Echocardiographic MVA increased from 0.91 +/- 0.15 to 1.97 +/- 0.42 cm2 after valvotomy. Volume loading produced significant increases in left atrial pressure (16 to 23 before and 12 to 20 mm Hg after valvotomy). in cardiac output (3.7 to 4.1 before and 3.9 to 4.6 liters/min after valvotomy). and in mitral valve gradient (11 to 14 before and 5 to 7 mm Hg after valvotomy). These hemodynamic changes were associated with modest but significant decreases in PHT and increases in MVA estimated by 220/PHT (0.66 to 0.81 before and 1.64 to 1.96 cm2 after valvotomy). whereas the MVA by Gorlin was not affected in a consistent fashion by volume loading (0.85 to 0.89 before and 1.66 to 1.69 cm2 after valvotomy). The correlation between Gorlin MVA and 220/PHT was only fair (r = 0.73. p less than 0.001) and was significantly poorer among patients with greater than 1+ mitral regurgitation (r = 0.72) than among those with less or no regurgitation (r = 0.79) (p = 0.001 by analysis of covariance for mitral regurgitation effect).
Rarity of preclinical alcoholic cardiomyopathy in chronic alcoholics less than 40 years of age, Preclinical alcoholic cardiomyopathy. myocardial damage in the absence of overt congestive heart failure in chronic alcoholics. is well characterized at necropsy. but attempts to identify such a clinical entity before death have produced conflicting results. Studying subjects only at rest. the inclusion of older alcoholics and limitations of noninvasive techniques may explain some of the disagreement. To determine if preclinical alcoholic cardiomyopathy could be identified independent of the aforementioned limitations. 25 asymptomatic chronic alcoholics aged less than 40 years (mean 34). each of whom had consumed a minimum of 1 pint of whiskey or one 6-pack of beer greater than or equal to 5 days per week for greater than or equal to 5 years. underwent radionuclide ventriculography for measurements of systolic and diastolic function at rest. peak supine exercise and during recovery. and echocardiography for assessment of chamber size. wall thickness and left ventricular mass. Red blood cell levels of selenium and thiamine were measured to determine whether abnormalities were present in these 2 potential mediators of alcoholic cardiomyopathy. For comparison. an age-matched group of healthy control subjects was also studied. For alcoholics and control subjects at rest. mean ejection fraction (67 +/- 7% vs 71 +/- 6%) and diastolic peak filling rate (3.4 +/- 0.6 vs 3.3 +/- 0.6 end-diastolic volumes per second [EDV/s]) were similar.
Prognostic value of thallium-201 perfusion defects in idiopathic dilated cardiomyopathy, To assess the prognostic significance of thallium-201 perfusion defects in patients with idiopathic dilated cardiomyopathy (IDC). 43 patients underwent thallium scintigraphy in addition to clinical. echocardiographic. angiographic and hemodynamic evaluation. Eleven patients had no significant thallium perfusion abnormality. 19 had multiple small defects and 13 had a large defect. During 3.2 +/- 2.2 years. 14 patients had disease-related mortality. The patients who died had a higher incidence of ventricular tachycardia (71 vs 31%; p less than 0.02). increased cardiothoracic ratio (60 +/- 6 vs 54 +/- 6; p = 0.005). decreased fractional shortening (11 +/- 6 vs 15 +/- 5; p less than 0.05). increased pulmonary wedge pressure (15 +/- 7 vs 10 +/- 6 mm Hg; p = 0.05). increased left ventricular end-diastolic pressure (21 +/- 8 vs 14 +/- 6 mm Hg; p = 0.02) and abnormal thallium perfusion defects (13 of 14 vs 16 of 26; p less than 0.05) compared with survivors. Age. gender. left ventricular end-systolic and end-diastolic dimensions. cardiac index and ejection fraction were not statistically different in the survivors versus the patients who died. Kaplan-Meier survival estimates at 1. 3 and 5 years were 100% in patients without significant perfusion abnormality; 89. 77 and 64%. respectively. in patients with multiple small defects; and 84. 76 and 30%. respectively. in patients with a large defect (p less than 0.025 by log rank test).
Primary signet-ring cell carcinoma of the urinary bladder, Primary signet-ring cell carcinoma is an uncommon malignancy arising in the urinary bladder. The authors report 12 cases collected at their institution. Median age for the ten men and two women was 58 years; the most frequent presentation was hematuria. In two of nine cases no mucosal lesion was cystoscopically visible. Eleven tumors were of nonurachal origin and one of urachal. At diagnosis. one tumor was stage B. two stage C. seven stage D. and two stages unknown. Nine of 12 patients were dead of disease (range. 1-16 months; median. 9 months). 1 alive with metastatic disease. 1 alive and well. and 1 dead of an unrelated cause. From a literature review. the authors accepted 35 cases that met their criteria and combined them with their 12 cases for statistical analysis. Prognosis was worse with a pure diffuse versus a mixed tumor (P = 0.004) and for nonurachal versus urachal origin (P = 0.005). The difference in five-year survival rates between stages B and D disease (P less than 0.05) was also statistically significant.
Detection of Ki-67 proliferation rate in breast cancer. Correlation with clinical and pathologic features, In situ determination of proliferative activity was performed on 203 breast cancers by use of Ki-67 monoclonal antibody and immunohistochemical methods. Tumor proliferation rate was analyzed and correlated to tumor size and nodal status. The relationship between Ki-67 proliferative activity and nuclear estrogen receptor content was also investigated on adjacent tissue sections. Ki-67 values ranged from 1 to 75%. with a median value of 10%. Premenopausal patients had greater Ki-67 values (median value. 14.1%) than postmenopausal ones (median value. 9.8%). The authors observed no correlation with lymph nodal involvement. whereas a statistically significant relationship with tumor size was found (P less than 0.01). An inverse correlation (Spearman's coefficient = -0.56; P less than 0.001) was seen between Ki-67 values and nuclear estrogen receptor content. These results. similar to those reported for other kinetic measurements. suggest that in situ detection of Ki-67 proliferation rate is a useful method for obtaining cell cycle information. Follow-up studies will be needed to assess an eventual prognostic relevance.
Fluorescent cytochemical detection of estrogen and progesterone receptors in breast fine-needle aspirates, Estrogen and progesterone receptors were studied in fine-needle aspiration biopsy specimens of 56 patients with primary. recurrent. or metastatic breast carcinoma. The ligands. 17 B-estradiol-6-carboxymethyloxine-bovine serum albumin fluorescein isothiocyanate (FITC-BSA estradiol) and hydroxyprogesterone hemisuccinate bovine serum albumin tetramethyl rhodamine isothiocyanate (TMRITC-BSA progesterone). were used in the fluorescent cytochemical method. The findings obtained from the aspirated cells with the use of the fluorescent cytochemical technique were compared with results obtained from the cell population of the same tumor after removal with the use of both the fluorescent cytochemical technique and the biochemical dextran-coated charcoal (DCC) assay. For the needle aspirates. there was 89% concordance for estrogen receptor and 86% concordance for progesterone receptor between biochemical and cytochemical results. A high degree of correlation was also demonstrated between fine-needle aspirates and imprint preparations with the use of the cytochemical technique. This study suggests that the fluorescent cytochemical technique is an effective tool in assessment of estrogen and progesterone receptor content in fine-needle aspirates of primary and metastatic breast cancer. The fluorescent cytochemical technique can be performed easily at community hospitals and is well suited for specimens of insufficient size for biochemical assay.
Evaluation of in vitro bromodeoxyuridine labeling of breast carcinomas with the use of a commercial kit, The prognostic significance of S-phase fraction analyses of breast carcinomas has been reported by several investigators. The Cell Proliferation Kit (Amersham Corporation. Arlington Heights. IL). which uses in vitro bromodeoxyuridine (BRDU) labeling to evaluate cell cycle kinetics without a flow cytometer or radioisotopes. simplifies this assay for the clinical-based laboratory by providing standardized reagents and recommended methods. This study was performed to determine whether data derived from its use were comparable to published S-phase data from the use of thymidine labeling. BRDU. or other methods on breast carcinomas. Primary infiltrating ductal carcinomas (n = 142) and primary lobular carcinomas (n = 6) showed mean and median BRDU labeling of 4.63% and 3%. 1.3% and 1%. respectively. with a range of 0-28%. Benign lesions always had less than 3% BRDU uptake (n = 21). Estrogen receptor (ER) and progesterone receptor (PR) status correlated with BRDU labeling (P less than 0.05). with the highest S-phase fractions in ER- and PR-negative tumors. Correlations between BRDU uptake and histologic tumor type or size were observed. Significant correlations between BRDU uptake and lymph node status. patient age. or histologic tumor grade were not observed. S-phase studies of breast carcinomas using other techniques have shown similar data. therefore. the Cell Proliferation Kit appears to be a practical and useful method for in vitro S-phase analysis that allows concomitant histologic examination of the same tumor tissue sample.
An unusual venous anomaly of the placenta, The authors present an unusual vascular anomaly of the placenta. The placenta was very large. weighing 1.490 g. On the fetal surface. numerous dilated and tortuous vessels were observed on and under the chorionic membrane. of which three branches arose from a vein that was connected to the umbilical vein. One of them had a 5 x 2.5 cm aneurysmal dilatation. where three secondary branches arose. These venous channels were dilated and tortuous. The longest secondary branch was 133 cm in length and 1.2 cm in mean diameter and led into the placenta. Multiple. severely coiled or straight small branches arising from these vessels were also observed as vascular tangles. Some of these smaller vessels also led into the placenta. All abnormal vessels were veins. The umbilical cord was also normal except for a membranous insertion. and the placenta was unremarkable except for its large size.
Platelet aggregation in platelet-rich plasma and whole blood in 120 patients with myeloproliferative disorders, In vitro platelet aggregation in platelet-rich plasma (PRP) and in whole blood (WB) was assessed in 31 patients with idiopathic myelofibrosis. 32 with essential thrombocytosis. 23 with polycythemia vera. and 34 with chronic myelogenous leukemia. In PRP most subjects showed normal or reduced platelet aggregation. whereas in WB the majority of patients showed increased platelet function. Spontaneous platelet aggregation (SPA) was observed frequently in WB. whereas it was seldom observed in PRP. SPA in WB was inhibited by in vitro addition of aspirin and apyrase. and SPA was only partially dependent on high platelet count because it also occurred in samples with normal platelet content (at variance with 13 subjects with reactive thrombocytosis. in which SPA was observed only in samples with high platelet concentration). Platelets from patients with idiopathic myelofibrosis had the highest tendency to undergo SPA.
Expression of blood group antigens H-2, Le(y), and sialylated-Le(a) in human colorectal carcinoma. An immunohistochemical study using double-labeling techniques, In this study. double-labeling immunohistochemistry was used to gain insight into the coexpression or interrelationship between blood group antigens (BGA) that are differentiation antigens in the normal colon. and BGA that are sequential moieties in the same synthetic pathway. Paired-wise Sialylated-Le(a)/Le(y) and H-2/Le(y) was studied. The Sialylated-Le(a) and Le(y) are synthesized from type 1 and type 2 backbones. respectively. In the normal colon. the Le(y) and Sialylated-Le(a) are expressed by cells at the base and surface of the crypt. respectively. representing undifferentiated and differentiated enterocytes. The H-2 is considered oncofetal in nature. and is considered to be the immediate precursor in the synthesis of Le(y). In individual cancers. Sialylated-Lea and Le(y) were detected in different cancer cells within the same malignant glands. separately in different glands. and in different subcellular compartments of the same cell. Both H-2 and Le(y) were coexpressed in the same individual cells in 92% of cancers expressing both these BGA. In 50% of the cancers. the H-2 and Le(y) also were expressed separately in different malignant glands within individual tumors. These findings indicate that. in colorectal cancers. differentiation antigens (Sialylated Le(a) and Le(y)) are expressed by different individual cells within the same malignant gland somewhat. recapitulating the normal colon crypt. Antigens of different backbones occasionally may be expressed in the same cells but within different subcellular compartments. Precursor accumulation is common in cancers. and antigens in the same synthetic pathway are coexpressed in the same cell. The expression of H-2 and Le(y) in different glands (lack of coexpression) may be explained possibly by aberrant synthesis of Le(y) by an alternate pathway.
Cellular localization of interleukin-8 and its inducer, tumor necrosis factor-alpha in psoriasis, The importance of immunologic mechanisms in psoriasis has been deduced from the ability of immunosuppressive therapies to ameliorate this common and chronic skin disease. Certainly the histology of psoriatic lesions suggests a dialogue between the hyperplastic keratinocytes and infiltrating T lymphocytes and macrophages. To begin dissecting the cytokine network involved in the pathophysiology of psoriasis. the location. in both epidermal and dermal compartments. of tumor necrosis factor-alpha. interleukin-8. intercellular adhesion molecule-1. and transforming growth factor-alpha at the protein and/or mRNA levels were identified. Tumor necrosis factor-alpha was selected as a potentially key regulatory cytokine. first because it induces cultured keratinocyte interleukin-8. intercellular adhesion molecule-1. and transforming growth factor-alpha production. and second because intercellular adhesion molecule-1 expression by keratinocytes in psoriatic epidermis had been identified previously. Using immunohistochemical localization. tumor necrosis factor-alpha was identified in 12 psoriatic lesions as intense and diffuse expression by dermal dendrocytes (macrophages) in the papillary dermis (without significant staining of endothelial cells. mast cells. or dermal Langerhans cells). and focally by keratinocytes and intraepidermal Langerhans cells. Functional interaction between the dermal dendrocytes and keratinocytes was suggested by the presence of interleukin-8 expression of suprabasal keratinocytes immediately above the tumor necrosis factor-alpha-positive dermal dendrocytes. Interleukin-8 mRNA and transforming growth factor-alpha mRNA were detectable in the epidermal roof of psoriatic lesions. but neither was detectable at the protein or mRNA levels in any normal skin specimens. Treatment of cultured human keratinocytes with phorbol ester (which experimentally produces psoriasiform changes on mouse skin) or tumor necrosis factor-alpha also increased interleukin-8 and transforming growth factor-alpha mRNAs. Further elucidation of the cellular and molecular basis for the genesis and evolution of psoriasis will provide the framework for a better evaluation of the cause and treatment of this skin disease.
AIDS-related lymphoma. Histopathology, immunophenotype, and association with Epstein-Barr virus as demonstrated by in situ nucleic acid hybridization, To investigate the range of pathology shown by acquired immune deficiency syndrome (AIDS)-related lymphomas arising in an epidemiologically well-defined group of patients. all cases of lymphoma recognized in Danish human immunodeficiency virus (HIV)-infected individuals up to the end of 1988 were studied. Twenty-seven cases (26 high-grade non-Hodgkin's lymphoma [NHL]. 1 Hodgkin's disease) were found. to give a cumulative incidence rate of 8% among Danish AIDS patients. Morphologically most NHL patients were classified into two groups: 1) high-grade tumors with a predominant population of immunoblasts. either monomorphic or more often polymorphic with plasmacytic differentiation; 2) Burkitt-type. Of 26 NHLs. 22 had a B-cell paraffin-section immunophenotype and 4 were non-B. non-T. Epstein-Barr virus (EBV) DNA was demonstrated in tumor cells of 12 of 24 cases (50%) using in situ nucleic acid hybridization with a 35S-labeled probe in paraffin sections. Epstein-Barr virus DNA was found in 65% of group 1 and 20% of group 2 tumors. This study suggests the existence of two main groups of AIDS-related lymphoma with different pathogeneses. First there are immunoblast-rich lesions. which usually are associated with EBV and morphologically resemble lymphomas described in immunosuppressed organ-transplantation patients. Second there are Burkitt-type tumors in which EBV sequences are less common and that may be pathogenetically analogous to sporadic Burkitt's lymphoma.
Monoclonal antibodies detect monocyte/macrophage activation and differentiation antigens and identify functionally distinct subpopulations of human rheumatoid synovial tissue macrophages, Monoclonal antibodies (MAbs) to functionally heterogeneous populations of human rheumatoid arthritis (RA) synovial tissue macrophages and lipopolysaccharide (LPS)-activated U937 cells were generated. These MAbs were used to characterize macrophages in situ in the synovial pannus and to study relative antigen expression on the surface of cells isolated from the synovium and from normal peripheral blood. Monoclonal antibody 3D8. an anti-CD13 MAb. reacts with an antigen expressed on the surface of blood monocytes and is a monocyte activation-related antigen that is upregulated by exposure of monocytes to interferon-gamma (IFN-gamma) and LPS. The expression of the 3D8 antigen increases in parallel with MHC class II antigen expression and also is upregulated in culture as monocytes mature to macrophages. 3D8 antigen is expressed strongly on RA synovial tissue lining cells. which are thought to be composed of macrophages. 8D7 antigen expression. detected by MAb 8D7. increases on blood monocytes on cellular activation with LPS and interferon-gamma. but in contrast to the 3D8 antigen. does not increase with monocyte maturation in vitro. The 8D7 antigen is expressed differentially on density-defined macrophage subpopulations isolated from RA synovial tissue and is expressed more strongly on macrophages that are nonangiogenic than those that are angiogenic.
Dystrophin is required for normal thin filament-membrane associations at myotendinous junctions, Dystrophin. the deficient gene product in Duchenne muscular dystrophy. is located subjacent to the muscle cell membrane at myotendinous junctions. as well as along the entire muscle cell. Myotendinous junctions are sites at which thin filaments normally are linked to one another and to the cell membrane. by both lateral and end-on associations between the thin filaments and membrane. The cell membrane at these sites in normal muscle is folded extensively. Dystrophic junctions display normal contacts between the ends of thin filaments and subsarcolemmal densities. However dystrophic junctions are deficient in lateral associations between thin filaments and the membrane and display less membrane folding than controls. These structural defects would result in stress concentrations at sites of thin filament attachment to the membrane. which can cause membrane tearing during muscle activation. especially in large-diameter and mature muscle cells. This deficiency in dystrophic myotendinous junction structure may contribute to our understanding of previously unaccountable aspects of the etiology of Duchenne muscular dystrophy.
Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells, Vascular permeability factor (VPF). a tumor-secreted heparin-binding protein (Mr approximately 38.000). is responsible for increased vessel permeability and fluid accumulation associated with tumor growth. Vascular permeability factor also promotes the growth of human umbilical vein endothelial cells (EC) and bovine pulmonary ECs in vitro. It is shown for the first time that guinea pig VPF (half-maximal and maximal dose approximately 0.4 and 22 pmol/l (picomolar). respectively). as well as human VPF. are potent stimuli for human ECs resulting in [Ca2+]i increases (maximal three- to fourfold) and inositol triphosphate (IP3) formation. Unlike the maximal responses to thrombin and histamine. the [Ca2+]i response to a maximal VPF dose was preceded by a characteristic 10- to 15-second delay. Guinea pig VPF also selectively increased [Ca2+]i in cultured aortic and pulmonary artery ECs. but not aortic smooth muscle cells. human fibroblasts. or neutrophils. Affinity-purified rabbit antibody (raised to a synthetic peptide representing VPF N-terminal amino acids 1 to 24) adsorbed all vessel permeability-increasing activity. EC growth-promoting activity. and specifically all activity responsible for increasing EC [Ca2+]i. Similar to other mediators that increase [Ca2+]i in cultured ECs. VPF also induced a 200% increase in von Willebrand factor release. Together these data indicate that VPF acts directly on ECs and that rapid cellular events in its in vivo/in vitro actions are likely to involve phospholipase C activation. [Ca2+]i increase. and von Willebrand factor release.
Transforming growth factor-beta production in anti-glomerular basement membrane disease in the rabbit, The purpose of this study was to assay for the presence of collagen synthesis stimulatory activity in the kidney during immune-induced renal injury that results in severe fibrosis in both glomerular and interstitial compartments. A model of antiglomerular basement (anti-GBM) disease in the rabbit was induced on day 0 by the injection of anti-GBM antibody and renal cortex tissues were then sampled at various time points. Only conditioned media prepared from diseased renal cortical samples showed collagen synthesis stimulatory activity when tested on rabbit mesangial cells. The activity had an estimated molecular weight range of 16 to 25 kd and was neutralized by antibody to transforming growth factor-beta (TGF-beta). A standard assay for TGF-beta using a mink lung epithelial cell line confirmed the increase in TGF-beta activity in conditioned media of diseased cortex from day 7 and day 14 animals. which was not significantly activated by previous acidification. This suggests that most of the TGF-beta present in renal conditioned media was in the active form. The increase in renal cortical secretion of active TGF-beta was accompanied by increases in renal cortical TGF-beta mRNA content on days 4 and 7 after induction. with subsequent return to control levels. A similar increase in TGF-beta activity was present in nonacidified conditioned media of purified glomeruli from diseased days 7 and 14 animals. which was also accompanied by significant increases in TGF-beta mRNA. However with acidification no significant differences were noted between control and diseased samples. suggesting the presence of substantial latent TGF-beta activity in control glomerular conditioned media. These same control-conditioned media contained inhibitor activity for added exogenous TGF-beta. These results support the conclusion that the association between increased TGF-beta secretion and increased renal cortical collagen synthesis in this model is consistent with a role for this cytokine in directing fibrogenesis in the kidney.
Increased microvascular permeability in vivo in response to intradermal injection of neutrophil-activating protein (NAP-2) in rabbit skin, Neutrophil-activating protein-2 (NAP-2). an NH2-terminally processed form of the platelet-release product beta thromboglobulin (beta TG). was purified to homogeneity from stimulated human blood leukocytes. In the presence of a vasodilator substance (PGE2. CGRP) picomolar (pmol/l) amounts of NAP-2 induced neutrophil accumulation and plasma leakage on intradermal injection in rabbit skin. whereas the longer forms. beta TG itself and connective tissue-activating peptide III (CTAP-III). had no such effect. NAP-2-induced increased in microvascular permeability was neutrophil dependent and fast in onset. with a half-life of 65 to 75 minutes. comparable to that previously reported for the structural-related neutrophil-activating protein-1/interleukin-8 (NAP-1/IL-8). However NAP-2 showed a lower potency in that more protein was needed to provoke skin reactivity. Nevertheless the finding that a platelet release product can elicit neutrophil-mediated inflammation further narrows the gap between thrombotic events and inflammatory disorders.
Immunoreactivity and receptor expression of insulinlike growth factor I and insulin in human adrenal tumors. An immunohistochemical study of 94 cases, Using immunoperoxidase methods. 94 human adrenal tumors were examined for evidence of immunoreactivity and receptor expression of insulinlike growth factor I (IGF-I) and insulin. The frequency of IGF-I in adrenocortical carcinomas was significantly higher than that in adenomas of the adrenal glands. The adrenocortical carcinomas showed strong intensity of staining for IGF-I. IGF-I receptors. and insulin receptors. A significant correlation between immunoreactivity and receptor expression of both IGF-I and insulin was found only in the adrenocortical carcinomas. The adrenocortical adenomas with Cushing's syndrome and pheochromocytomas. more than adrenocortical adenomas with Conn's syndrome. also stained strongly for insulin receptors. Thus the IGF-I and insulin probably play a role in the growth of adrenocortical carcinoma tissues. possibly through autocrine mechanisms. The expression of insulin receptors in adrenocortical adenomas in the presence of Cushing's syndrome and pheochromocytomas may be associated with functions.
Fibroblast growth factor gene expression in AIDS-Kaposi's sarcoma detected by in situ hybridization, Biopsy samples from five acquired immune deficiency syndrome (AIDS)-Kaposi's sarcomas and one non-AIDS-associated Kaposi's sarcoma were assayed by in situ RNA hybridization onto paraformaldehyde-fixed. paraffin-embedded skin sections for the presence of two fibroblast growth factor gene transcripts. FGFB and FGF5. FGF5 gene expression was detected in the characteristic Kaposi's sarcoma spindle-shaped cells in the five samples from human immunodeficiency-positive (HIV+) patients. FGFB transcripts were detected in Kaposi's sarcoma cells as well as in epidermis of HIV- and HIV+ patients. These results complement the observations about growth factor gene expression done on Kaposi's sarcoma-derived cell lines. which thus appear to be representative of what happens in vivo. Furthermore. they demonstrate a contrasting expression pattern of FGF5 and FGFB genes. both involved in the growth factor pathogenic cascade leading to Kaposi's sarcoma.
Persistence and remission of depressive symptoms in late life, OBJECTIVE: The relation of poor health to the onset of depression symptoms in late life is well recognized. but little attention has been given to characteristics that might predict persistence or remission of depressive symptoms. In previous analyses the authors found that increasing disability and declining health preceded the emergence of depressive symptoms in older community residents and accounted for 70% of the variance explained by discriminant analyses. The aim of the present analysis was to examine the relevance of changes in health and disability to the persistence of depressive symptoms. METHOD: A representative sample of 1.855 adults aged 65 or older were assessed with the Center for Epidemiologic Studies Depression Scale at baseline. Twenty-four months later. 1.577 individuals were available for a second assessment of depressive symptoms. The characteristics of the 97 community residents whose depressive symptoms persisted over 24 months were compared to those of the 114 whose symptoms remitted. RESULTS: Changes in health. differences in age. sleep disturbance. and added formal support services accounted for more than 30% of the variance between the persistently depressed and remission groups. Advanced age and worsening health were associated with persistent symptoms. improved health with remission. CONCLUSIONS: Previous studies have indicated that untoward changes in health and disability play a major role in the onset of depressive symptoms. These findings show a substantial contribution to chronicity as well.
Familial alcoholism in primary unipolar major depressive disorder, OBJECTIVE: Some studies have suggested relationships between depression in probands and alcoholism in relatives. Other studies have not. but some of these have used inappropriate control groups or failed to divide probands by sex. METHOD: The present study controlled for sex of probands and used several comparison groups to further explore the familial relationship between depression and alcoholism. Diagnoses for 723 directly interviewed relatives of 326 probands with primary unipolar depression were compared to diagnoses in 469 control subjects chosen by an acquaintanceship method to demographically resemble the relatives of affective disorder probands. Diagnoses in the uninterviewed relatives of both control and depressed subjects were used for comparisons as well. RESULTS: Results indicated higher rates of alcoholism in the families of depressed women but not in the families of depressed men. CONCLUSIONS: This familial association between alcoholism and depression may be the result of either genetic or environmental factors or an interaction between the two.
Less frequent lithium administration and lower urine volume, OBJECTIVE: This study was designed to determine whether patients maintained on a regimen of lithium on a once-per-day schedule have lower urine volumes than do patients receiving multiple doses per day. METHOD: This was a cross-sectional study of 85 patients from a lithium clinic who received different dose schedules. Patients were admitted to the hospital for measurement of lithium level. creatinine clearance. urine volume. and maximum osmolality. RESULTS: Multiple daily doses of lithium were associated with higher urine volumes. The dosing schedule. duration of lithium treatment. and daily dose of lithium did not affect maximum osmolality or creatinine clearance. CONCLUSIONS: Urine volume can be reduced by giving lithium once daily and/or by lowering the total daily dose. Lithium-induced polyuria seems to be related to extrarenal as well as to renal effects.
The effect of financial management on alcohol-related hospitalization, OBJECTIVE: Treatment-unresponsive alcoholics in New Zealand who are unable to care for themselves tend to be hospitalized for lengthy periods of time. The author examined the effect of adding financial management to the therapeutic management of such patients. The null hypothesis was that this would have no effect on the duration of alcohol-related hospitalization. METHOD: All 61 alcoholic patients registered with an alcohol outpatient clinic who received financial management over a period of 6 years were included in the study. Their alcohol-related disabilities were so severe that they had resulted or were likely to result in lengthy or frequent periods of hospitalization. The financial management involved putting each patient's income into a checking account for which a budget advisory officer was cosignatory for withdrawals. The advisor saw to it that patients' basic living requirements were being met and that expenditure on alcohol was not having a detrimental effect. Participation was voluntary for voluntary patients and involuntary for committed patients. The durations of each patient's alcohol-related hospitalizations were compared for two equal periods of time before and after financial management was instituted. RESULTS: The null hypothesis was not supported. The duration of alcohol-related hospitalizations after financial management was instituted was 86% less than it was before such management. CONCLUSIONS: For the patient who is struggling in the face of excessive drinking to cope with the tasks of daily living. including the provision of adequate shelter and nutrition. the benefits of adding financial management to other therapeutic strategies should be considered.
Drug abuse in schizophrenic patients: clinical correlates and reasons for use, OBJECTIVE: This study aimed to 1) determine substance abuse prevalence and preference in a diverse sample of schizophrenic. schizoaffective. and schizophreniform inpatients. 2) compare drug-abusing and non-drug-abusing patients on demographic and clinical variables during the acute and stabilization phases of their hospital course. and 3) obtain data from patients on reasons for drug abuse and on acute state-related changes during periods of intoxication. METHOD: Eighty-three psychotic inpatients consecutively admitted to a New York City teaching hospital were evaluated. Sixty-eight had schizophrenia. 12 had schizoaffective disorder. and three had schizophreniform disorder diagnosed according to the Structured Clinical Interview for DSM-III-R. Each patient received ratings on the Brief Psychiatric Rating Scale. the Global Assessment Scale. and the Scale for the Assessment of Negative Symptoms at admission and at discharge. an evaluation of premorbid adjustment. and an extensive interview on drug and alcohol use. RESULTS: Forty (48%) of the patients received diagnoses of drug or alcohol abuse or dependence. The drug-abusing patients primarily used cannabis (N = 26). alcohol (N = 21). and cocaine (N = 14) and reported that they abused drugs to get "high." to relieve depression. and to relax. They had significantly fewer positive and negative symptoms at discharge. better sexual adjustment and worse school performance during adolescence. and more family histories of drug abuse than the non-drug-abusing patients. CONCLUSIONS: Schizophrenic patients who abuse drugs may represent a subgroup of patients with better prognoses and less severe clinical characteristics of schizophrenia. but their drug abuse may adversely affect global outcome.
A critical analysis of the largest reported mass fecal occult blood screening program in the United States, Fecal occult blood testing for the detection of colon cancer remains controversial. We performed a mass screening program from January 24. 1988. to February 19. 1988. with intensive media promotion. including 121 minutes of televised air time. A total of 5.000 primary practitioners were notified by mail. Hemoccult-II tests were distributed to 156.000 individuals; 55.051 (35%) were returned. Ninety-five percent of the respondents were informed of the program by television. A total of 3.375 persons (6%) tested positive for fecal occult blood; of these. 2.469 (73%) informed the center that they saw their physician to initiate a work-up. Information from physicians regarding work-ups was returned on only 1.356 (55%) patients. Diagnostic tests numbered 2.227 (1.6 tests per patient). However. 5% had no testing. 16% had a repeat Hemoccult only. and 35% had neither a barium enema nor colonoscopy performed. Thirty-six colorectal cancers and 212 polyps were identified. The predictive value (i.e.. number of cancers per number of patients who tested positive) increased directly by decade. Thirty-three of 36 patients (92%) with cancer underwent either a barium enema or colonoscopy versus only 185 of 438 (42%) patients with a "negative" work-up. Cancers found were carcinoma in situ in 10 patients (29%). Dukes A in 12 (35%). Dukes B in 4 (12%). and Dukes C in 8 (24%); distant metastases were not found in any participant. Thirty-six percent of the tumors were located in either the right or transverse colon. We conclude that: (1) Screening identified early cancers. All were potentially curable and 64% were limited to the bowel wall. (2) Massive Hemoccult distribution was possible over a short interval. but patient and physician compliance was disturbingly low. (3) Total colonic evaluation is mandatory. since at least 36% of tumors were beyond the reach of the flexible sigmoidoscope. (4) Many work-ups were unnecessary (repeat Hemoccults) or inadequate. indicating a need for physician education.
Somatostatin analogue treatment inhibits post-resectional adaptation of the small bowel in rats, Post-resectional hyperplasia is the phenomenon in which residual small bowel increases in size and absorptive capacity after segmental enterectomy. This experiment studied the effect of somatostatin analogue therapy on the development of two structural parameters of post-resectional hyperplasia in rats subjected to 40% proximal small bowel resection. Octreotide acetate-treated rats failed to develop increased villus height (902 +/- 50 microns) relative to saline-treated rats (1.103 +/- 98 microns). Augmentation of residual intestinal weight was also significantly impaired in analogue-treated rats (92 +/- 3 versus 118 +/- 5 mg/cm). We conclude that somatostatin analogue treatment during the early postoperative period does impair the growth of residual bowel in rats. These findings raise concern regarding the use of this drug for postoperative patients who have undergone massive small bowel resection in whom the process of post-resectional adaptation may be critical to allow sustenance with enteral nutrition.
Factors influencing survival after pancreaticoduodenectomy for pancreatic cancer, Eighty-nine patients with carcinoma of the head of the pancreas underwent pancreaticoduodenectomies. The actuarial 5-year survival for all 89 patients was 19%. with a median survival of 11.9 months. The 81 hospital survivors were analyzed in an effort to determine factors influencing long-term survival. Negative lymph nodes and the absence of blood vessel invasion both favored long-term survival. The strongest predictive factor was negative lymph node status with a median survival of 55.8 months. compared with 11 months with lymph nodes involved with tumor (p less than 0.05). Blood transfusions were also predictive. with patients receiving two or fewer units having a median survival of 24.7 months. compared with 10.2 months for those receiving three or more units (p less than 0.05). The most important determinant of long-term survival after pancreaticoduodenectomy for pancreatic cancer is biology of the tumor (lymph node status. blood vessel invasion). However. performance of the resection (units of blood transfused) also appears to be an important factor influencing survival.
Prospective, randomized trial of the biofragmentable anastomosis ring. The BAR Investigational Group, A randomized trial was undertaken to compare the biofragmental anastomotic ring (BAR) with conventional intraperitoneal colorectal anastomotic techniques. Patients were randomized into one of two schemes: BAR versus sutured or BAR versus stapled anastomosis. There were 782 patients entered into the study and 283 patients (36%) had a sutured anastomosis. 104 patients (13%) had a stapled anastomosis. and 395 (51%) had the BAR. Comparison of the BAR with combined suture and stapled controls revealed no significant differences in wound complication. abscess rate. bleeding. anastomotic leaks. ileus. obstruction. or deaths. There were no differences in return of bowel function. return to normal diet. or hospital stay. Intraoperative difficulties occurred in 46 BAR patients (17%). and this was significantly higher (p less than 0.001) than for sutured (3%) but not for stapled anastomoses (11%). The occurrence of these problems did not adversely effect the outcome. The data suggest that the BAR is a safe. satisfactory alternative to sutured or stapled colorectal anastomoses.
Glucose intolerance and hyperinsulinemia of cirrhosis are not results of spontaneous or surgical portosystemic shunting, To assess if spontaneous portosystemic shunting from collaterals contributes to the hyperinsulinemia of cirrhosis. 12 patients with alcoholic cirrhosis underwent a 5-hour oral glucose tolerance test 1 day before and 10 days after an elective side-to-side portacaval shunt. The glucose. insulin. and C peptide responses to oral glucose post-shunt were exaggerated but comparable to preoperative values. Compared with preoperative values. the fasting molar ratio of C peptide to insulin postoperatively had increased 40% (6.0 +/- 1.2 versus 8.4 +/- 0.7). indicating improved hepatic function. These results suggest that extrahepatic portosystemic shunting secondary to spontaneous splanchnic collaterals plays little or no role in the hyperinsulinemia of cirrhosis. It appears that decreased hepatic degradation of insulin in these patients is secondary to hepatocellular dysfunction rather than a result of shunting of portal blood around the liver.
Long-term studies of mental health after the Greenville gastric bypass operation for morbid obesity, From February 1. 1980. to May 1. 1989. 462 patients underwent the Greenville gastric bypass at the East Carolina University School of Medicine. The operation effectively maintained satisfactory weight loss after 9 years (mean weight preoperatively. 293 lbs; at 24 months. 179 lbs; at 96 months. 194 lbs). The gastric bypass favorably affected non-insulin-dependent diabetes. hypertension. and physical and role functioning. In the most recent 157 patients. our studies were extended to study the effects of the gastric bypass on mental health. The significant improvements in mental health indices that were observed 6 and 12 months after surgery eroded by the end of 2 years. This return of the mental health indices to the preoperative status. plus the late occurrence of 3 suicides and 2 deaths from alcohol abuse among the total 462 patients. suggest that long-term follow-up and continued emotional support are essential ingredients for successful bariatric surgery.
Why does somatostatin cause gallstones, Long-term administration of the somatostatin analogue. octreotide. is complicated by gallstone formation. Somatostatin is known to inhibit hepatic bile secretion and gallbladder emptying. However. the effect of octreotide on gallbladder bile composition remains unknown. Therefore. we tested the hypothesis that octretide would alter hepatic bile composition and cause gallbladder stasis. thereby increasing gallbladder bile solute concentrations. Fourteen control prairie dogs received daily saline injections. whereas 10 animals received 1 micrograms of octreotide subcutaneously three times per day for 5 days. Cholecystectomy and common bile duct cannulation were then performed. Octreotide increased hepatic bile concentrations of bilirubin monoglucuronide (p less than 0.05). total bilirubin (p less than 0.05). and total protein (p less than 0.01). Rsa. an index of gallbladder stasis. was decreased (p less than 0.01) in the octreotide group. Gallbladder bile total calcium (p less than 0.05). bilirubin monoglucuronide (p less than 0.05). total bilirubin (p less than 0.01). total protein (p less than 0.05). and total lipids (p less than 0.05) were increased in the octreotide group. Animals receiving octreotide also had decreased hepatic (p less than 0.05) and gallbladder (p less than 0.001) bile pH. No differences in cholesterol saturation index were observed. These data suggest that in the prairie dog. octreotide (1) alters hepatic bile composition. (2) causes gallbladder stasis. and (3) increases gallbladder bile calcium. bilirubin. protein. lipid. and hydrogen ion concentrations. We conclude that octreotide causes alterations in gallbladder bile composition that increase the likelihood of cholesterol and calcium bilirubinate precipitation.
Implications of peritoneal cytology for staging of early pancreatic cancer, Cytologic examination of peritoneal washings was performed in 40 patients with pancreatic ductal adenocarcinoma (35 head. 5 body) whose tumors had been selected as potentially resectable by computed tomographic (CT) findings. Saline (100 mL) was instilled and aspirated at laparoscopy in 27 patients and at laparotomy in 13. Malignant cells were found in the peritoneal washings in 12 of 40 patients (30%): 29% in cancers of the pancreatic head versus 40% in the body; 33% at laparoscopy versus 23% at laparotomy; and in 4 of 8 patients with ascites versus 8 of 32 without ascites. The cytology was positive in 6 of 8 patients (75%) who had a prior percutaneous needle biopsy versus 6 of 32 (19%) of those who did not (p less than 0.01). Liver metastases were found in six patients. all with negative cytology. One of 10 pancreatic head cancers with positive cytology was resectable versus 13 of 25 with negative cytology (p less than 0.05). Survival was significantly longer in patients with negative cytology. We conclude that (1) pancreatic cancer sheds malignant cells into the peritoneum early and commonly; (2) laparoscopic lavage is an effective means of cytologic study; (3) ascites is not a precondition for cytologic study. nor does its presence necessarily imply carcinomatosis; (4) intraperitoneal spread of cancer cells may be promoted by tumor biopsy; (5) cytologic findings provide an additional index of resectability; and (6) cytologic findings appear to correlate with duration of survival. This study shows that even "localized" pancreatic cancer is often not contained and suggests caution with biopsy of potentially curable lesions.
Laparoscopic guided cholecystectomy, Cholecystectomy remains the most effective form of therapy for patients with symptomatic cholelithiasis. An alternative method of gallbladder removal. laparoscopic guided cholecystectomy. was attempted in 100 patients. Five patients required conversion of the laparoscopic procedure to an open laparotomy for the following reasons: discovery of a pancreatic malignancy in one patient. extensive adhesions in one. presence of an aberrant accessory right hepatic duct in one. common hepatic duct injury in one. and avulsion of the cystic duct in one. Both ductal injuries occurred during the early phase of the clinical program. In those patients undergoing laparoscopic cholecystectomy. 93 were discharged within 24 hours of surgery and 94 returned to normal activity within 1 week. Laparoscopic guided cholecystectomy appears to offer a number of advantages in patient care as well as a significant reduction in health care expenses for gallbladder disease. Appropriate training in laparoscopic surgery is necessary in order to avoid operative complications.
A 27-year experience with splenectomy for Gaucher's disease, Gaucher's disease is an inherited metabolic disorder caused by the defective activity of acid beta-glucosidase and the resultant accumulation of glucosyl ceramide-laden macrophages in the liver. bone. and spleen. Splenectomy is the preferred treatment for patients with Gaucher's disease who develop massive splenomegaly with accompanying hypersplenism and/or mechanical pressure symptoms. The charts of 48 patients with Gaucher's disease undergoing splenectomy at our institution between January 1963 and December 1989 were analyzed to determine the short- and long-term results of this procedure. Thirty-five (73%) patients had total splenectomy. whereas 13 (27%) patients had partial splenectomy. There was one postoperative death (after total splenectomy). and 13 patients (27%) had postoperative complications. Eleven patients (23%) presented with accelerated bone disease after total splenectomy (mean follow-up: 96 months). No patients having partial splenectomy (mean follow-up: 25 months) developed progressive bone disease. Eight patients have died since surgery. All four deaths due to malignant disease occurred in patients after total splenectomy. The results of this largest-ever reported series of splenectomy for Gaucher's disease confirm that while either total or partial splenectomy can be performed with minimal morbidity and mortality. total splenectomy is accompanied by more aggressive bone disease and a predisposition to malignancy. Prospective. randomized trials are needed to substantiate whether partial splenectomy is indeed the treatment of choice for splenomegaly associated with Gaucher's disease.
Cyclic anaphylaxis associated with menstruation, A middle-aged woman developed recurrent episodes of severe life-threatening anaphylaxis. All episodes were strikingly associated with the first day of menstrual bleeding. Temporary relief was achieved with indomethacin therapy. The patient fully recovered following abdominal hysterectomy and salpingoophorectomy. The possible role of sex hormones and prostaglandin F2 alpha in the pathogenesis of this problem is discussed.
Emergency room care of asthmatics: a comparison between Auckland and Toronto, We compared emergency room visits for the treatment of asthma in two large downtown teaching hospitals: one in Auckland. New Zealand and one in Toronto. Canada. We wished to determine whether the differences in asthma mortality between New Zealand and Canada were reflected in different patterns of emergency room use or physician management. Emergency room use during the past decade was enumerated in both hospitals. and charts containing the sole diagnosis of asthma were reviewed in detail for a defined study period in 1986. In both Toronto and Auckland. the number of emergency visits for asthma had increased significantly in the past decade (P less than .015 but the rate of rise was significantly higher in Auckland (P less than .05). In Auckland. 27% of asthmatics were admitted whereas in Toronto significantly fewer (16%) were admitted (P less than .0005). Objective measures of pulmonary function were documented more frequently by emergency room physicians in New Zealand than in Canada (90% versus 48%; P less than .0005). Pulmonary function measurement was primarily by peak flow meter in Auckland and most commonly by spirometer in Toronto so that pulmonary function measurements could not be compared directly between centers. In both centers. however. admitted patients had significantly lower pulmonary function indices than discharged patients. In New Zealand. mean peak flow was 38% of the predicted value among all asthmatics assessed; in Toronto. mean FEV1 was 47% of predicted. In Toronto. pulmonary function measurements were most likely to be missing among presumably healthier discharged patients. Pulse rate. respiratory rate. and pulsus paradoxus were documented more consistently in Auckland than in Toronto.
Lymphoproliferative responses to Borrelia burgdorferi in Lyme disease, OBJECTIVE: To compare lymphocyte proliferative responses to Borrelia burgdorferi in healthy controls and patients with Lyme disease. PATIENTS: Twelve patients fulfilling case-definition criteria for Lyme disease. Twelve healthy volunteers and two newborns served as controls. MEASUREMENTS: Antibodies to B. burgdorferi were measured by enzyme-linked immunosorbent assay (ELISA). Proliferation of peripheral blood lymphocytes cultured for 5 days with B. burgdorferi. recall antigens. or pokeweed mitogen was measured by radioactive thymidine uptake. RESULTS: Lymphocytes from 11 patients with Lyme disease. 8 healthy seronegative controls. and two newborns showed elevated responses when stimulated with B. burgdorferi. When a patient and a control were studied on the same day. the patient's lymphocyte response to B. burgdorferi exceeded the control's in only 5 of 12 cases. Lymphocytes from both patients and controls responded to B. burgdorferi isolates from three different sources. CONCLUSIONS: Heightened lymphocyte responses to B. burgdorferi are found in patients with Lyme disease but elevated responses also frequently occur in healthy controls. At present. the interpretation of a positive lymphocyte response to B. burgdorferi would be difficult in ambiguous clinical situations.
The Munich Gallbladder Lithotripsy Study. Results of the first 5 years with 711 patients, OBJECTIVE: To evaluate the long-term results of three types of shock wave treatment in patients with radiolucent gallbladder stones. DESIGN: Cohort study. SETTING: Single-center trial. PATIENTS: Of 5824 patients with gallstones. 19% were eligible; 711 patients were treated. INTERVENTIONS: Patients received extracorporeal shock wave lithotripsy as well as adjuvant therapy with bile acids. RESULTS: Lithotripsy was done in three ways. using a water-tank lithotriptor (group A). a water-cushion lithotriptor at low energy levels (group B). and a water-cushion lithotriptor at high energy levels (group C). The rate of complete fragment clearance 9 to 12 months after lithotripsy was done differed significantly among the three groups: Among patients with single stones of 20 mm or less in diameter. the rate of fragment clearance for group A was 76%; for group B. it was 60%; and for group C. it was 83% (P = 0.03). Among patients with single stones of 21 to 30 mm. the rate of fragment clearance for group A was 63%; for group B. it was 32%; and for group C. it was 58% (P less than 0.005). Among patients with two or three stones. the rate of fragment clearance for group A was 38%; for group B. it was 16%; and for group C. it was 46% (P = 0.01). Patients with fragments of 3 mm or less 24 hours after lithotripsy was done showed a higher probability of fragment disappearance than did those with larger fragments (P less than 0.001). The clearance rate was higher in patients who were compliant than in those who were noncompliant with bile acid therapy (P less than 0.001). Adverse effects included liver hematoma in 1 patients. biliary pain attacks in 253 patients (36%). mild biliary pancreatitis in 13 patients (2%). and cholestasis in 7 patients (1%). Elective cholecystectomy was done in 16 patients (2%). and endoscopic sphincterotomy was done in 4 patients (1%). CONCLUSIONS: The rate of complete disappearance of stones after shock wave therapy depends on the size and the number of the initial stones. the diameter of the largest fragment. and the mode of shock wave treatment. Adjuvant therapy with bile acids appears to be important for complete fragment clearance.
Nonsteroidal anti-inflammatory drugs and peptic ulcer disease, Evidence has accumulated that nonsteroidal anti-inflammatory drugs (NSAIDs) cause clinically important gastroduodenal ulcers. The pathogenesis. which involves the impairment of mucosal resistance to injury in an acid-peptic environment. is multifactorial and controversial. Ulcers caused by NSAIDs can occur either in mucosa inflamed because of infection with Helicobacter pylori or in histologically normal mucosa. The use of these drugs has been linked to an unexpectedly high incidence of ulcer complications. and a history of peptic ulcer disease is common in such cases. Nonsteroidal anti-inflammatory drugs thus appear both to exacerbate an underlying peptic diathesis and to cause de novo ulcers. The association between the use of these drugs and ulcer complications is supported by ulcer prevalence data from cross-sectional studies. and by data from case-controlled and cohort studies. and from randomized. experimental trials. Drug-induced gastric ulcers have been prevented by misoprostol. but not by H2 blocker therapy. Several therapies have been reported to promote ulcer healing despite continued use of NSAIDs. but adequate controlled trials have not been done. Small gastric and duodenal ulcers readily heal. whereas larger gastric ulcers require vigorous and prolonged therapy. The relative efficacies of various therapies in preventing ulcers. healing ulcers. or preventing complications remain to be established.
HIV-1 infection in a cohort of haemophilic patients, The course of HIV infection in 53 haemophilic patients aged 5-20 years was evaluated by clinical examination and laboratory tests. During the evaluation time (median 30 months) two patients died of AIDS and 32 patients (60%) deteriorated when assessed by the Brodt-Helm classification. Nineteen patients (37%) had decreased absolute helper cell counts (less than 500 CD4 positive cells/microliters). and 45 patients (87%) had reduced helper cell to lymphocyte ratios (less than 0.35). HIV-1 was isolated from peripheral lymphocytes in 29 of 46 patients. As the disease progressed the number of positive viral cultures increased. Considerable progression of the HIV infection was seen in haemophilic children and adolescents during the median evaluation period of 30 months. The transition from symptomless HIV infection to immunodeficiency was easily recognised. A lowered ratio of helper cells to lymphocytes seems to be a useful marker of the beginning of the deterioration of the immune system.
Growth velocity before sudden infant death, Weight velocities of 136 infants who died from sudden infant death syndrome (SIDS) were compared with those of 136 controls matched for sex. birth weight. and type of feeding. It was found that the SIDS infants gained weight more slowly overall and that the differences were significantly different for infants who were not breast fed in the last two weeks in which it was possible to estimate their growth velocity. Breast fed infants had more periods of growth below the 25th centile than expected. These differences are unlikely to be useful in the prediction of which babies are likely to die from SIDS as there are frequent episodes of poor growth in infants who do not die.
Long term outcome of ventilated asthmatics, Over a 25 year period. 31 asthmatic children received artificial ventilation for acute asthma at Alder Hey Children's Hospital on 48 occasions. Altogether 47 episodes occurred from 1971-89. with no decline in the number of episodes per year (mean 2.5) over this period. Eight children died during intermittent positive pressure ventilation (IPPV). and of the 23 survivors. three further children had subsequently died from asthma. Seventeen children were followed up for more than a year after IPPV. Sixteen still had symptoms of asthma and over half had symptoms every day. Ten cooperated with pulmonary function tests: mean forced expiratory volume in one second was 83% of predicted and geometric mean provocative histamine concentration (PC20) was 2.1 mg/ml. Since the follow up study a fourth patient had died from asthma. IPPV continues to be required for a small number of asthmatic children each year. The survivors remain a high risk group with significant continuing morbidity and mortality.
Cerebral palsy: why we must plan for survival, The survival of children in the South East Thames region. born between 1970 and 1979 and diagnosed as having some form of cerebral palsy was investigated. Of the 732 children studied. 651 (90%) are still alive. and hence cerebral palsy must be regarded as a condition with which people live rather than a condition of which they die. Survival varies considerably among the different diagnostic groups: those suffering from spasic quadriplegia. dyskinetic and 'mixed' cerebral palsy are most severely affected. Our evidence suggests that. though immobility and severe mental subnormality are the strongest predictors of mortality in children with cerebral palsy. the majority of even the most severely affected patients survive to adulthood. It is therefore appropriate to plan for their survival by funding and evaluating programmes to maximise health. independence. and quality of life.
Human isophane or lente insulin? A double blind crossover trial in insulin dependent diabetes mellitus, Fifty two children with insulin dependent diabetes mellitus were randomised to receive human isophane or lente insulin preparations in combination with soluble insulin in a double blind trial. Patients were seen every two months. and crossed over after four months of treatment. Control assessed by glycated haemoglobin was significantly lower in children on human isophane insulin. but fasting blood glucose and fructosamine concentrations and the number of episodes of hypoglycaemia were similar on both regimens. In five children on twice daily insulin regimens. insulin profiles throughout a 24 hour period demonstrated greater variability on lente compared with isophane insulin despite identically administered insulin doses. A questionnaire completed at the end of the study showed that two thirds of the children and/or their parents preferred the isophane insulin. and they gave perceived improvement of metabolic control as the major reason for their choice.
Are measurements of height made by health visitors sufficiently accurate for routine screening of growth, To find out whether measurements of height made by health visitors are sufficiently accurate for use in routine screening of children we carried out an interobserver and intraobserver reliability study. Height measurements were made on a group of 10 children aged 3 years old and 10 aged 4.5 years old by two sets of four health visitors. They used a Microtoise or wall chart and the measurements were compared with those made by a trained auxologist with a Harpenden stadiometer. For a single assessment of height both pieces of equipment gave reasonably accurate results. In a child aged 3 years. with height measured on the Microtoise as 100 cm. the true height could be expected--with 95% probability--to lie between 99.2 cm-101.8 cm. At the age of 4.5 years. if the measurement was 110 cm. the child's true height could be expected to lie between 108.9 cm and 111.9 cm. The narrowest confidence interval for the growth rate from 3 to 4.5 years was achieved with the Microtoise. taking the mean of three measurements. We conclude that measurements made by health visitors are sufficiently accurate for routine screening of height. and the use of such measurements for the calculation of height velocity could be improved by more structured training.
Diagnosis of Pneumocystis carinii pneumonia from non-invasive sampling of respiratory secretions, An infant infected with HIV presented with fever. tachypnoea. hypoxia. and radiological evidence of bilateral pneumonitis. Fluorescent antibody technique identified Pneumocystis carinii within 24 hours from secretions obtained by nasopharyngeal aspiration. This rapid. non-invasive method should be the first line investigation of suspected P carinii pneumonia in immunocompromised patients.
Nocturnal faecal soiling and anal masturbation, Two cases of late onset faecal soiling as a result of anal masturbation in children who were neither mentally handicapped nor psychotic were studied. The role of soiling in aiding the young person and his family to avoid separating and maturing is highlighted. We suggest that the association of anal masturbation and resistant nocturnal soiling may be unrecognised.
Air pollution and fatal lung disease in three Utah counties, A unique situation found in two Utah counties has made it possible to estimate the fraction of respiratory cancer and nonmalignant respiratory disease (NMRD) deaths. which are attributable to community air pollution (CAP) in one county. The two counties were very similar in many ways. including low smoking rates. until a steel mill constructed during WW II caused substantial CAP in one of them. Subsequent differences in mortality rates from both respiratory cancer and NMRD are striking. A third county. similar to many counties outside Utah. was included in the analysis for comparison. In one county. 30-40% of the respiratory cancer and NMRD deaths were attributable to CAP. In this county. NMRD deaths (but not respiratory cancer deaths) were slightly more frequent than in Salt Lake County where smoking rates were twice as high.
X-ray fluorescence measurements of lead burden in subjects with low-level community lead exposure, A k-x-ray fluorescence (K-XRF) instrument that can measure in vivo bone lead at low levels was used on a population of 34 adults with no known history of excessive lead exposure. A questionnaire that gathered information relevant to occupational and environmental lead exposure was administered prior to the measurement. A 30-min measurement that produced an average estimated uncertainty of 6 mcg lead/g bone mineral was taken at the mid-tibial diaphysis for each subject. Eighteen subjects had bone lead levels below the measurement uncertainty. The remainder had bone lead levels ranging up to 21 mcg lead/g bone mineral. Bone lead levels were greater among older subjects. Among young adult subjects. bone lead levels greater than the measurement uncertainty were confined entirely to subjects who had grown up in housing that was estimated to have been build prior to 1955. Such a childhood environment is at high risk of fostering exposure to biologically absorbable lead through ingestion of lead paint-contaminated dust and lead pipe-contaminated water. We conclude that the K-XRF technique has the potential to distinguish between low levels of lead burden in epidemiologic studies.
Health effects of volcanic ash: a repeat study, The Mount Sakurajima volcano in Kyushu. Japan. is proximal to a large residential area. and it emits an enormous amount of volcanic ash during frequent eruptions. In our previous study. we investigated. for the first time. respiratory effects of chronic exposure to volcanic ash. The study demonstrated a low prevalence of respiratory symptoms. even in the area of highest exposure; only a slight excess prevalence of symptoms appeared to be associated with exposure to volcanic ash. To confirm the findings of our previous study. the prevalence study of chronic respiratory symptoms for residents was repeated in Kanoya and Tashiro. which are located 25 and 50 km. respectively. from the crater of Mt. Sakurajima. The concentration of suspended particulate matter in Kanoya frequently exceeded the national environmental quality standards and. during summer and winter. was 2-3 times higher than that found in Tashiro. Women who were 30-59 y of age and who had resided in Kanoya or Tashiro for more than 3 y completed a modified ATS-DLD questionnaire. The prevalence of nonspecific respiratory disease was low. i.e.. 6.5% in Kanoya and 6.2% in Tashiro; similar prevalences were found in women who had never smoked. When we restricted the analysis to individuals without a history of occupational exposure to dusts and who had no exposure to passive smoking. there was a slightly higher prevalence of nonspecific respiratory disease in Kanoya than Tashiro. but the difference was not significant. Eye symptoms were equally prevalent in the two areas.
Histopathologic features of high-grade non-Hodgkin's lymphomas in acquired immunodeficiency syndrome. The French Study Group of Pathology for Human Immunodeficiency Virus-Associated Tumors, High-grade B-cell non-Hodgkin's lymphomas are observed in 5% to 10% of patients with acquired immunodeficiency syndrome. To describe their histologic subtypes. a group of pathologists was formed. One hundred thirteen cases were reviewed and classified according to the Working Formulation. the updated Kiel classification. and a recent description of morphologic variants of high-grade B-cell non-Hodgkin's lymphoma. Three major types of intermediate- or high-grade lymphomas were observed: (1) large-cell or centroblastic mainly polymorphic lymphomas with a component of immunoblasts (35 cases); (2) immunoblastic lymphomas with plasmablastic and plasmacytic features in most cases (33 cases); and (3) small non-cleaved cell Burkitt's or non-Burkitt's lymphoma (41 cases). with 15 cases fitting typical criteria of Burkitt's lymphoma and 26 heterogeneous cases in which the size and shape of the cells and the presence of plasmablastic features varied. The most frequent pathologic sites of involvement at presentation were the lymph nodes. gastrointestinal tract. bone marrow. brain. oral cavity. and muscles. A comparison between the histologic type and the site of involvement showed that most cases involving lymph nodes. bone marrow. or muscles were small noncleaved cell Burkitt's or non-Burkitt's lymphomas. while those that affected the gastrointestinal tract. brain. and oral cavity were centroblastic or immunoblastic lymphomas with consistent plasmacytic differentiation. In 10 cases. previous persistent generalized lymphadenopathy syndrome was present. In 13 cases. the lymphomatous proliferation was associated with follicular or diffuse hyperplasia seen on the same lymph node biopsy specimen or in another lymph node.
Interpretive criteria of the Western blot assay for serodiagnosis of human immunodeficiency virus type 1 infection [published erratum appears in Arch Pathol Lab Med 1991 Aug;115(8):783, This project was designed to evaluate different criteria used in the interpretation of the human immunodeficiency virus type 1 (HIV-1) Western blot assay on a group of serum samples blinded to the examiner that were collected from individuals attending three different public health departments in central North Carolina. Each individual also completed an anonymous linked questionnaire regarding sociodemographics and risk factors for blood-borne infections. All of the Western blot assays for human immunodeficiency virus type 1 were interpreted according to the criteria established at the University of North Carolina Hospitals. Chapel Hill. the Centers for Disease Control. Atlanta. Ga. in association with the Association of State. Territorial. and Public Health Laboratory Directors. Iowa City. Iowa. the American Red Cross. Washington. DC. the Consortium for Retrovirus Serology Standardization. Davis. Calif. and the Food and Drug Administration. Washington. DC. The results obtained were grouped as positive. negative. and indeterminate according to each organization's criteria and analyzed in the context of the associated risk factors. The results indicate that institutions performing human immunodeficiency virus type 1 Western blot confirmatory testing should adopt the criteria of the Centers for Disease Control and the State. Territorial. and Public Health Laboratory Directors.
Enhancement of immunoreactivity among lymphoid malignant neoplasms in paraffin-embedded tissues by refixation in zinc sulfate-formalin, It has been previously demonstrated that improved cytomorphologic detail can be obtained from tissue blocks initially fixed in 4% formaldehyde solution by means of a "run-back" procedure to an aqueous phase of solution. allowing refixation with a protein-precipitating agent. such as zinc sulfate-4% formaldehyde solution. Because anecdotal experience with immunostaining such reprocessed tissues had suggested improved results. we performed a prospective trial involving 13 cases to compare the intensity of immunoreactivity before and after such reprocessing. In 10 of 13 cases studied with a variety of antibody reagents. we noted a definite improvement of staining. preferentially among those with the weakest original immunoreactivity.
Dipstick analysis of urinary protein. A comparison of Chemstrip-9 and Multistix-10SG, The Boehringer-Mannheim Chemstrip-9 and Ames Multistix-10SG urine dipstick assays for the detection of proteinuria were evaluated. Chemstrip-9 was more precise than Multistix-10SG (13 inconsistencies vs 32 among duplicate pairs). Precision was poorest with the group of inexperienced technologists using Multistix-10SG (Chemstrip-9 yielded two inconsistencies vs 15 for Multistix-10SG) with the use of urine supplemented with protein standard. In the evaluation of both protein-supplemented and consecutively acquired patient specimens. Multistix-10SG and Chemstrip-9 performed in a statistically similar fashion regarding sensitivity and predictive value of a negative test result: supplemented sample sensitivity. patient sample sensitivity. and a predictive value of a negative test result of 90.3%. 46.8%. and 68.6%. respectively. for Multistix-10SG compared with 80.6%. 31.5%. and 63.5%. respectively. for Chemstrip-9. We conclude that neither test is sufficiently sensitive for the detection of low levels of proteinuria (1+ range) to function as a screening test for renal disease.
Expression of ABH blood group antigens, Ulex europaeus agglutinin I, and type IV collagen in the sinusoids of hepatocellular carcinoma, The expression of blood group antigens (A. B. H. Lewis(a) and Lewis(b)). Ulex europaeus agglutinin I (UEA-I). factor VIII-related antigen. and type IV collagen on the sinusoids was examined immunohistochemically in 15 cases of hepatocellular carcinomas (HCC). 11 cases of cirrhosis. 12 cases of chronic active hepatitis. and in a control sample of 16 normal livers. Sinusoidal endothelial cells of HCC characteristically showed a diffuse and strong immunoreactivity to ABH blood group antigens in the specimen with a comparable ABO blood group. The sinusoidal endothelial cells were also diffusely and strongly positive for UEA-I receptors. In contrast. in cirrhosis and chronic active hepatitis a few sinusoidal endothelial cells were positive for ABH blood group antigens and UEA-I receptors. In normal livers. only a few sinusoidal endothelial cells were positive for ABH blood group antigens and UEA-1 receptors. Tests for factor VIII-related antigen and Lewis blood group antigens were almost negative on sinusoidal endothelial cells. Although type IV collagen was distributed diffusely in the space of Disse in these four groups. its expression was strongest in HCC. Blood vessels of portal tracts and fibrous septa were positive for ABH blood group antigens. UEA-1 receptors. factor VIII-related antigen. and type IV collagen. but negative for Lewis blood group antigens. These findings suggest that some sinusoidal endothelial cells undergo "capillarization" in cirrhosis and chronic active hepatitis. and that the majority of sinusoidal endothelial cells of HCC have phenotypic characteristics of capillaries.
A clinical pathologic study of four adult cases of acute mercury inhalation toxicity, We report four cases of fatal mercury vapor inhalation. a rare occurrence. The mercury vapor was released at a private home. where one of the occupants was smelting silver from dental amalgam containing an unknown amount of mercury. Within 24 hours of the incident. all occupants began having shortness of breath necessitating hospital admission. The clinical courses are briefly detailed; however. all included rapid deterioration with respiratory failure. Chest roentgenograms in all four cases were consistent with adult respiratory distress syndrome. All patients were treated with dimercaprol. a mercury chelator. but all died. with survival varying from 9 to 23 days postexposure. Autopsies were performed on all four patients. The lungs in all cases were heavy. firm. and airless. Histologic examination revealed severe diffuse alveolar damage. with variable amounts of fibrosis. conforming with acute lung injury in various stages of organization. Additional postmortem findings included acute proximal renal tubular necrosis. vacuolar hepatoxicity. and a spectrum of central nervous system alterations including multifocal ischemic necrosis. gliosis. and vasculitis.
Pleomorphic (anaplastic) neuroblastoma in nude mice, Two pleomorphic (anaplastic) neuroblastomas. from two children aged 1 and 6 years. were transplanted into nude mice. Two noteworthy observations were made. In one case. the transplanted tumor gave rise to a soft-tissue sarcoma. Moreover. in both cases hepatic metastases were associated with a striking modification of murine hepatocytes. resulting in hyperchromatic and dysplastic nuclei. The latter finding was particularly evident in the hepatic areas surrounding all metastases of pleomorphic (anaplastic) neuroblastoma cells.
Glomus tumor of the coccyx. A curable cause of coccygodynia, A 30-year-old woman presented with recurrent severe coccygodynia. She underwent exploration for a possible pilonidal sinus and was found to have a precoccygeal glomus tumor that also involved bony trabeculae of the coccyx. To our knowledge. a glomus tumor involving the coccygeal bone has not been previously documented. In view of the relief of this patient's pain following the surgical excision of coccyx and tumor. a causal role is suggested.
Systemic idiopathic fibrosis with T-cell receptor gene rearrangement, A case of systemic idiopathic fibrosis was analyzed by Southern blotting with probes to the immunoglobulin heavy chain and T-cell receptor genes. A 45-year-old man presented with bilateral neck swelling. He later developed lower back pain. and findings on a computed tomographic scan were consistent with idiopathic retroperitoneal fibrosis. A biopsy specimen of a neck lesion showed morphologic characteristics typical of idiopathic fibrosing cervicitis. Immunophenotyping of the lesion revealed a polymorphic lymphoid population. Molecular analysis with the use of probes to the immunoglobulin and T-cell receptor genes disclosed a germline DNA pattern for the immunoglobulin gene and a rearranged pattern for the T-cell receptor gene.
Malignant mixed tumor (malignant ameloblastoma and fibrosarcoma) of the maxilla, We present a rare case of carcinosarcoma (malignant ameloblastoma and fibrosarcoma) of the left maxilla that developed in a 63-year-old Japanese man. The tumor recurred repeatedly despite multiple surgical removals. radiotherapy. and chemotherapy and led to progressive cachexia; the patient died after 3.8 years of hospitalization. Histopathologic examination revealed that the recurrent tumor was carcinosarcoma. which had progressed from malignant ameloblastoma with fibroma. An autopsy confirmed the diagnosis of malignant mixed tumor with lung metastasis of malignant ameloblastoma and fibrosarcoma.
Acepromazine. Effects on intraocular pressure, We investigated the effects of the topical application of acepromazine maleate on the intraocular pressure (IOP) in 27 adult rhesus monkeys. The monkeys were divided into two groups: group 1 (16 monkeys) had both eyes normal. and group 2 (11 monkeys) had experimental chronic glaucoma in one eye and a normal fellow eye. One drop of 1% acepromazine maleate solution was instilled in one eye of monkeys in group 1 and in the glaucomatous eye of monkeys in group 2; the other eye served as the control. The IOP was measured before drug administration and 1. 4. 8. 24. and 32 hours after. with detailed slit-lamp examination of the anterior segment. Acepromazine produced no change in IOP in eyes in group 1. but it produced a fall in pressure in all eyes with high IOP in group 2. evident 1 hour after instillation. maximal between 4 and 8 hours. and still remaining after 32 hours. The pupil showed no change in size. but a transient ptosis was observed in the treated eye in all monkeys.
Conjunctival retraction suture for fornix adjustable strabismus surgery, The fornix approach to strabismus surgery is advantageous because the incision is made under the eyelid. there is no need for conjunctival sutures. it is comfortable for the patient. and there is minimal postoperative scarring. The major disadvantage of the fornix approach for the adjustable suture technique has been poor exposure to the muscle-suture apparatus and poor postoperative knot exposure. We describe herein the use of a subconjunctival retraction suture for adjustable suture surgery with the fornix approach. This suture retracts the conjunctiva. exposing the adjustable muscle-suture apparatus while simultaneously fixating the globe. A novel way of tying the noose around the pole sutures and preventing noose slippage is also presented. This technique provides excellent exposure. fixation of the globe. and complete coverage of the knot with conjunctiva after adjustment.
Multiple-dose, dose-response relationship for the topical carbonic anhydrase inhibitor MK-927, The multiple-dose. dose-response curve of MK-927 was studied in a five-center. double-masked. randomized. placebo-controlled. parallel study of 2%. 1%. and 0.5% MK-927 in 76 patients with bilateral primary open angle glaucoma or ocular hypertension and intraocular pressure greater than 24 mm Hg following washout of ocular hypotensive medications. Patients received doses at 8 AM and 8 PM for 14 days. and parallel 12-hour intraocular pressure curves were performed prestudy and on day 14. with 4-hour curves on days 1 and 4. There was a significant dose-response relationship. with 0.5% MK-927 twice daily being a minimal-effect dose. Both 1% and 2% MK-927 were active through 12 hours postdose. and peak mean percent decrease in pressure at 2 hours postdose was 18.6% and 20.6%. respectively.
Multiple-dose efficacy comparison of the two topical carbonic anhydrase inhibitors sezolamide and MK-927, The multiple-dose twice-daily efficacy of the topical carbonic anhydrase inhibitor MK-927. a racemic compound. was compared with that of its pharmacologically more active S-enantiomer in a four-center. double-masked. randomized. placebo-controlled. parallel study of 1.8% sezolamide hydrochloride (MK-417). 2% MK-927. and placebo. given twice daily to 48 patients with bilateral primary open angle glaucoma or ocular hypertension and morning intraocular pressure greater than 24 mm Hg in both eyes following washout of ocular hypotensive medications. Parallel 10-hour modified diurnal curves were performed before the study and on day 14. with 4-hour curves on days 1 and 4. Both compounds demonstrated significant lowering of intraocular pressure at 8 AM. 12 hours following the evening dose. and through 10 and 6 hours following the 8 AM dose for sezolamide and MK-927. respectively. Morning trough (evening) activity as measured by mean percent change in intraocular pressure from prestudy was -9.2% for sezolamide and -11.1% for MK-927 (-13.5% and -9.6%); peak effect occurred 2 hours after dose administration and was -19.4% and -19.2% for sezolamide and MK-927. respectively. From 2 hours after dose administration. sezolamide consistently demonstrated a slightly greater decrease in intraocular pressure than MK-927; however. these differences were not statistically significant.
The relationship of visual acuity, refractive error, and pupil size after radial keratotomy, To better define the relationship between residual refractive error. uncorrected visual acuity. and pupil diameter. we compared 42 eyes that had an eight-incision radial keratotomy according to the Prospective Evaluation of Radial Keratotomy Study protocol with 42 matched control eyes. The parameters measured were best corrected visual acuity. uncorrected visual acuity. and the change in cycloplegic refraction with enlarging pupil diameter. The best corrected visual acuity was 20/16 in both the radial keratotomy and control groups. but the variability (SD) was higher in the radial keratotomy group. The average uncorrected visual acuity was 0.35 (35%) better in the radial keratotomy group. but the variability was 1.77 times higher. Change in refraction with dilation occurred in 9% of the controls and 36% of the radial keratotomy patients. indicating a significant difference (P = .002). The change in refraction with dilation in the eyes with radial keratotomy was almost equally split between a hyperopic change (17%) and a myopic change (18%). which was much different than in the control eyes. only 2% of which changed in a hyperopic direction and 7% in a myopic direction. The radial keratotomy patients with a myopic change had the best uncorrected visual acuity. indicating that positive spherical aberration yielded the best aspherical surface for uncorrected visual acuity.
Clinically detectable nerve fiber atrophy precedes the onset of glaucomatous field loss, Standardized perimetry and nerve fiber layer and color fundus photography were performed annually on 1344 eyes with elevated intraocular pressures. In 83 eyes. glaucomatous field defects developed that met rigid criteria on manual kinetic and suprathreshold static perimetry. Individual nerve fiber layer photographs were read by two masked observers. The more sensitive of the two identified nerve fiber layer defects in 88% of readable photographs at the time field loss first occurred; 60% (6/10) of eyes already had nerve fiber layer defects 6 years before field loss. In contrast. the nerve fiber layer was considered abnormal in only 11% (3/27) of normal eyes and 26% (84/327) of hypertensive eyes. The location of nerve fiber layer and field defects closely corresponded. but nerve fiber layer loss was generally more widespread. Examiner experience and severity of optic nerve damage influenced results. Mild focal defects were more readily recognized than more severe diffuse atrophy. Nerve fiber layer defects expanded with time. often by the development and coalescence of adjacent areas of damage.
Autosomal dominant sectoral retinitis pigmentosa. Two families with transversion mutation in codon 23 of rhodopsin, A cytosine-to-adenine transversion in codon 23 of rhodopsin. the rod visual pigment gene. was reported recently by Dryja et al in 17 of 148 unrelated patients with autosomal dominant retinitis pigmentosa. but the clinical findings associated with this deletion have not been reported in detail. In screening our patients with autosomal dominant retinitis pigmentosa for the codon 23 transversion. we found positive results in four affected individuals from two families with sectoral retinitis pigmentosa. while 12 patients with sectoral retinitis pigmentosa from different families had negative results. suggesting that other gene sites or locations may give this same phenotypic change. From our patients' history of light exposure and the location of degeneration in the retina. we hypothesize that light phototoxicity may be playing an expressive role in this point mutation of the rhodopsin gene. This is the first report in which a type of retinitis pigmentosa has been associated with a specific molecular gene defect. although the actual pathophysiologic mechanism currently is unknown.
Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro-23-His), Ocular findings are presented from 17 unrelated patients with a form of autosomal dominant retinitis pigmentosa and the same cytosine-to-adenine transversion in codon 23 of the rhodopsin gene corresponding to a substitution of histidine for proline in the 23rd amino acid of rhodopsin (designated rhodopsin. Pro-23-His). On average. these patients (mean age. 37 years) had significantly better visual acuity and larger electroretinographic amplitudes than 131 unrelated patients (mean age. 32 years) with autosomal dominant retinitis pigmentosa without this mutation. However. these 17 patients from separate families. as well as 12 relatives with the mutation from four of these families. showed interfamilial and intrafamilial variability with respect to severity of their ocular disease. suggesting that some factor(s) other than this gene defect itself is involved in the expression of their condition. This form of retinitis pigmentosa can now be detected by testing leukocyte DNA from peripheral blood. Some mechanisms by which this mutation in the rhodopsin gene could lead to rod photoreceptor cell death are suggested.
A systemic non-lytic state and local thrombolytic failure of anistreplase (anisoylated plasminogen streptokinase activator complex, APSAC) in acute myocardial infarction, The relation between coronary thrombolysis and coagulation variables after administration of anistreplase (anisoylated plasminogen streptokinase activator complex. APSAC) was studied in patients with an acute myocardial infarction. Fifty eight consecutive patients with acute myocardial infarction were given 30 U of anistreplase intravenously within 4 hours of the onset of symptoms. A fall in the plasma concentration fibrinogen to less than 1.0 g/l 90 minutes after administration of anistreplase was considered to reflect a systemic lytic state. Coronary angiography was performed 48 hours after thrombolytic treatment. The overall patency rate was 74% (43/58). Patency rates were significantly different in patients with a systemic lytic (83% (43/52)) and a systemic non-lytic state (0% (0/6)). The absence of a systemic lytic state after anistreplase administration seemed to be highly predictive of the failure of coronary thrombolysis. Coagulation studies showed evidence of inhibition of anistreplase induced fibrinolytic activity which may explain the failure of thrombolytic treatment in patients with evidence of a systemic non-lytic state.
Dipyridamole magnetic resonance imaging: a comparison with thallium-201 emission tomography, Limitation of space and motion artefact make magnetic resonance imaging during dynamic exercise difficult. Pharmacological stress with dipyridamole can be used as an alternative to exercise for thallium scanning. Forty patients with a history of angina and an abnormal exercise electrocardiogram were studied by dipyridamole thallium myocardial perfusion tomography and dipyridamole magnetic resonance wall motion imaging with a cine gradient refocused sequence. Images for both scans were obtained in the oblique horizontal and vertical long axis and short axis planes before and after pharmacological stress with dipyridamole. The myocardium was divided into nine segments for direct comparison of perfusion with wall motion. Segments were assessed visually into grades--normal. hypokinesis or reduced perfusion. and akinesis or very reduced perfusion. After dipyridamole there were reversible wall motion abnormalities in 24 (62%) of 39 patients with coronary artery disease and 24 (67%) of 36 patients with reversible thallium defects. The site of wall motion deterioration was always the site of a reversible thallium defect. Thallium defects affecting more than two segments were always associated with wall motion deterioration but most single segment thallium defects were undetected by magnetic resonance imaging. There was a significant correlation between detection of wall motion abnormality. the angiographic severity of coronary artery disease. and the induction of chest pain by dipyridamole. There were no significant differences in ventricular volume or ejection fraction changes after dipyridamole between the groups with and without detectable reversible wall motion changes but the normalised magnetic resonance signal intensity of the abnormally moving segments was significantly less than the signal intensity of the normal segments.
A controlled trial of community based coronary rehabilitation, Two hundred patients who had suffered an acute myocardial infarction 4-6 weeks before entered a randomised controlled trial of exercise treatment at a community sports centre supervised by a general practitioner. Eighty one per cent of the treatment group continued to exercise until they returned to work and 73% completed three months' exercise. There were no serious complications of the exercise course. The prevalence of angina pectoris fell by 10% in the treatment group but rose by 60% in the control group. The perceived energy level rose by significantly more in the treatment group than in the controls. The rise in predicted maximum oxygen uptake was significantly greater in the treatment group than in the control group as was the reduction in the double product (a reflection of myocardial workload) at peak exercise. Coronary rehabilitation in the community can be both safe and effective.
Anomalous subaortic position of the brachiocephalic vein (innominate vein): an echocardiographic study, In 24 (0.98%) of 2457 patients with congenital heart disease the brachiocephalic vein was in an anomalous position below the aortic arch. This is a much higher proportion of such cases than reported so far. This high frequency may arise from differences in the study population and the method of diagnosis. This venous anomaly was more common in patients with tetralogy of Fallot or ventricular septal defect with pulmonary atresia. Patients with the venous anomaly were more likely to have a right aortic arch. The anomalous course of the brachiocephalic vein from the neck to the junction of the superior vena cava was shown by cross sectional echocardiography. In doubtful cases. Doppler study usually clarified the anatomical arrangement.
Circadian variation of heart rate is affected by environment: a study of continuous electrocardiographic monitoring in members of a symphony orchestra, Twenty four hour ambulatory ST segment monitoring was performed on 48 members (43 players and five members of the management/technical team) of the British Broadcasting Corporation (BBC) symphony orchestra without a history of cardiac disease. This period included final rehearsals and live performances (for audience and radio) of music by Richard Strauss and Mozart at the Royal Festival Hall (n = 36) and Rachmaninov and Tchaikovsky at the Barbican Arts Centre (n = 21). During the period of monitoring one person (2%) had transient ST segment changes. Mean heart rates were significantly higher during the live performances than during the rehearsals. Mean heart rates during the live performance of Rachmaninov and Tchaikovsky were significantly higher than during Strauss and Mozart in those (n = 6) who were monitored on both occasions. Mean heart rates in the management and technical team were higher than those of the players. The recognised circadian pattern of heart rate. with a peak in the morning waking hours. was altered similarly during both concert days. with a primary peak occurring in the evening hours and a lesser peak in the morning for both musicians and management/technical staff. This study showed that environmental factors are of primary importance in defining the circadian pattern of heart rate. This has important implications when identifying peak periods of cardiovascular stress and tailoring drug treatment for patients with angina pectoris.
A new method of haemodynamic assessment of mitral stenosis in atrial fibrillation: construction of a nomogram, Accurate haemodynamic assessment of mitral stenosis by hydraulic formulas requires measurement of the mean valve gradient and the cardiac output. The calculation is laborious. particularly in the presence of atrial fibrillation when averaged values obtained from multiple beat-to-beat determinations must be used. The relations between valve area. end diastolic gradient. and heart rate in 20 patients with mitral stenosis and atrial fibrillation were examined. In each patient the end diastolic pressure gradient for each cardiac cycle was related linearly to the RR interval of that cycle. and this relation was unchanged on exercise. The slope (S) and intercept (I) of this relation correlated with the degree of mitral stenosis as measured by the Gorlin valve area. The regression equations describing these relations were then used to construct a nomogram relating end diastolic pressure gradient to mitral valve area at different heart rates. When the nomogram was applied to catheterisation data from a further 30 patients the results correlated well with direct calculation of valve area by the Gorlin formula. The nomogram is simple to use. does not require measurement of cardiac output. and is independent of heart rate so that it is unnecessary for the patient to exercise during catheterisation.
Glossopharyngeal neuralgia associated with cardiac syncope: long term treatment with permanent pacing and carbamazepine, Glossopharyngeal neuralgia associated with cardiac syncope developed in a 53 year old man. Symptoms were controlled with temporary and permanent transvenous pacing and carbamazepine.
Comparison of non-mydriatic retinal photography with ophthalmoscopy in 2159 patients: mobile retinal camera study, OBJECTIVE--To determine whether non-mydriatic Polaroid retinal photography was comparable to ophthalmoscopy with mydriasis in routine clinic screening for early. treatable diabetic retinopathy. DESIGN--Prospective study of ophthalmoscopic findings according to retinal camera screening and ophthalmoscopy and outcome of referral to ophthalmologist. SETTING--Outpatient diabetic clinics of three teaching hospitals and three district general hospitals. PATIENTS--2159 Adults selected randomly from the diabetic clinics. excluding only those registered as blind or those in wheelchairs and unable to enter the screening vehicle. MAIN OUTCOME MEASURES--Numbers of patients and eyes correctly identified by each technique as requiring referral with potentially treatable retinopathy (new vessel formation and maculopathy) and congruence in numbers of microaneurysms. haemorrhages. and exudates reported. RESULTS--Camera screening missed two cases of new vessel formation and did not identify a further 12 but indicated a need for referral. Ophthalmoscopy missed five cases of new vessel formation and indicated a need for referral in another four for other reasons. Maculopathy was reported in 147 eyes with camera screening alone and 95 eyes by ophthalmoscopy only (chi 2 = 11.2; p less than 0.001). in 66 and 29 of which respectively maculopathy was subsequently confirmed. Overall. 38 eyes received laser treatment for maculopathy after detection by camera screening compared with 17 after ophthalmoscopic detection (chi 2 = 8.0; p less than 0.01). Camera screening underestimated numbers of microaneurysms (chi 2 = 12.9; p less than 0.001) and haemorrhages (chi 2 = 7.4; p less than 0.01) and ophthalmoscopy underestimated hard exudates (chi 2 = 48.2; p less than 0.001). CONCLUSIONS--Non-mydriatic Polaroid retinal photography is at least as good as ophthalmoscopy with mydriasis in routine diabetic clinics in identifying new vessel formation and absence of retinopathy and is significantly better in detecting exudative maculopathy.
Lipoprotein (a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men, OBJECTIVE--To examine the association between the serum lipoprotein (a) concentration and subsequent coronary heart disease. DESIGN--Prospective case-control study based on a six year follow up of a general population sample of men aged 50 at baseline in 1983-4. Serum samples were frozen at the time of the baseline examination and kept at -70 degrees C for six years. after which the lipoprotein (a) concentrations in the samples were measured in cases and controls. SETTING--City of Gothenburg. Sweden. SUBJECTS--26 Men. from a general population sample of 776 men. who had sustained a myocardial infarction or died of coronary heart disease during the six years and 109 randomly selected controls from the same sample who had remained free of myocardial infarction. In neither cases nor controls was there a history of myocardial infarction at baseline. MAIN OUTCOME MEASURES--Proportion of myocardial infarction or deaths from coronary heart disease. or both. in relation to the serum lipoprotein (a) concentration. RESULTS--Men who suffered coronary heart disease had significantly higher serum lipoprotein (a) concentrations than controls (mean difference 105 mg/l; 95% confidence interval 18 to 192 mg/l). Men with the highest fifth of serum lipoprotein (a) concentrations (cut off point 365 mg/l) suffered a coronary heart disease rate which was more than twice that of men with the lowest four fifths of concentrations. Logistic regression analysis showed the serum lipoprotein (a) concentration to be significantly associated with coronary heart disease independently of other risk factors. CONCLUSION--The serum lipoprotein (a) concentration in middle aged men is an independent risk factor for subsequent myocardial infarction or death from coronary heart disease.
Response by women aged 65-79 to invitation for screening for breast cancer by mammography: a pilot study [published erratum appears in BMJ 1991 Jul 27;303(6796):234], OBJECTIVE--To determine whether there is sufficient benefit to be gained by offering screening for breast cancer with mammography to women aged 65-79. who are not normally invited for screening. DESIGN--Pilot study of women eligible for screening but not for personal invitation. The results of this study were compared with the results of routinely screened younger women (aged 50-64) from the same general practice. SETTING--One group general practice in south Manchester. PATIENTS--The 631 women aged 65-79 on the practice list. A total of 42 (7%) were excluded by the general practitioner. and 22 (4%) invitation letters were returned by the post office. MAIN OUTCOME MEASURES--Response rates to invitation for screening assessed by three indices: crude population coverage ratio. crude invited population coverage ratio. and corrected invited population coverage ratio. RESULTS--344 Patients aged 65-79 (61% of those invited. excluding those who could not be traced) were screened compared with 77% of women aged 50-64. The three response indices were higher for younger women than older: crude population coverage ratio = 66.5%. crude invited population coverage ratio = 69.3%. corrected invited population coverage ratio = 76.8% for women aged 50-64. compared with 54.5%. 58.4%. and 60.7% respectively for women aged 65-79. All four biopsies done in the older women gave positive results. giving a cancer detection rate of 11.6/1000 compared with 4.1/1000 among younger women. CONCLUSIONS--These results show that there is a potential for high attendance at routine screening by older women if they are invited in the same way as younger women. If these results are found elsewhere the costs and benefits of screening older women should be reassessed.
Evaluation of peak flow and symptoms only self management plans for control of asthma in general practice, OBJECTIVE--To compare a peak flow self management plan for asthma with a symptoms only plan. DESIGN--Randomisation to one of the self management plans and follow up for a year. SETTING--Four partner. rural training practice in Norfolk. SUBJECTS--115 Patients (46 children and 69 adults) with asthma who were having prophylactic treatment for asthma and attending a nurse run asthma clinic. MAIN OUTCOME MEASURES--The number of doctor consultations. courses of oral steroids. and short term nebulised salbutamol treatments and the number of patients who required doctor consultations. courses of oral steroids. and short term nebulised salbutamol. RESULTS--Both self management plans produced significant reductions in the outcome measures but there were no significant differences in the degree of improvement between the groups. The results were similar for children and adults. The proportions of patients requiring a doctor consultation fell from 98% (50/51) to 66% (34/51) in the peak flow group and from 97% (62/64) to 53% (34/64) in the symptoms only group and the proportions requiring oral steroids from 73% (34/46) to 47% (21/46) and 52% (31/60) to 12% (7/60). The median number of doctor consultations was reduced from 8.0 to 2.0 in the peak flow group and from 4.5 to 1.0 in the symptoms only group. CONCLUSIONS--The peak flow meter was not the crucial ingredient in the improved illness of the two groups. Teaching patients the importance of their symptoms and the appropriate action to take when their asthma deteriorates is the key to effective management of asthma. Simply prescribing peak flow meters without a system of self management and regular review will be unlikely to improve patient care.
Abuse of elderly people by their carers, OBJECTIVE--To assess the prevalence of abuse of elderly people by their carers and the characteristics of abusers and the abused. DESIGN--Information on abuse and risk factors was collected over six months from carers and patients. Risk factors were identified in the abused group and compared with those in a non-abused control group. SETTING--Carers were interviewed at home; patients were examined in the wards of Putney and Barnes geriatric hospitals. London. SUBJECTS--All patients referred from any source for respite care to the geriatric services over a six month period and their carers. MAIN OUTCOME MEASURES--Amount of physical and verbal abuse or neglect. Quantification of risk factors and correlation with the presence or absence of abuse. RESULTS--45% Of carers openly admitted to some form of abuse. Few patients admitted abuse. The most significant risk factor for physical abuse was alcohol consumption by the carer (p less than 0.001). Other significant risk factors were a poor pre-morbid relationship and previous abuse over many years. Abuse was often reciprocated and was associated with social dysfunction in many patients. Service delivery. respite care. and level of mental and physical disability were not significantly associated with abuse. CONCLUSION--The high level of abuse found in elderly patients in respite care was particularly associated with alcohol abuse and long term relationships of poor quality. which are difficult to change. Even with increased provision of services. care in the community may not be the best solution for these people.
Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions, Delayed hypersensitivity reactions are among the most severe adverse effects of the sulfonamides in current clinical use. These reactions appear to occur because of differences in the metabolism and detoxification of reactive metabolites of the sulfonamides. N-Acetylation is a major metabolic pathway for the sulfonamides. Slow acetylation phenotype might be a risk factor for the development of these reactions. We determined the acetylation phenotype of 21 patients who had suffered hypersensitivity reactions to the sulfonamides. There were 11 females and 10 males in the group. with a mean age of 15 years (age range. 1.8 to 50 years). Their acetylator phenotype was determined by determining the ratio of urinary caffeine metabolites (1-methylxanthine to 5-amino-6-formylmethyluracil after an oral dose of 50 mg caffeine). Nineteen (90%) of the patients were slow acetylators compared to a 55% incidence of slow acetylators in a race-matched control population (p less than 0.008). This suggests that a slow acetylator phenotype is a risk factor for the development of sulfonamide hypersensitivity reactions and provides further support for the role of imbalances in genetically determined pathways of metabolism and detoxification of the sulfonamides in the pathogenesis of these reactions.
Primary defect in alpha-adrenergic responsiveness in patients with varicose veins, Responsiveness of superficial hand veins to local infusions of noradrenaline was compared in patients with primary varicose veins and in healthy volunteers by use of the dorsal hand vein technique. Patients with varicose veins required significantly higher doses of noradrenaline for half-maximal venoconstriction than the dose required by control subjects (geometric mean. 11.6 ng/min in patients compared with 4.8 ng/min in control subjects; p = 0.006). Noradrenaline responsiveness in varicose veins was not significantly different from hand vein responsiveness in the same patients. Our findings indicate a constitutional decrease in venous alpha-adrenergic receptor responsiveness in patients with varicosities. Dilation of varicose veins does not further affect noradrenaline-induced venoconstriction.
Plasma histamine, epinephrine, cortisol, and leukocyte beta-adrenergic receptors in nocturnal asthma, Plasma histamine. cortisol. epinephrine. cyclic adenosine monophosphate (cAMP). and leukocyte beta-adrenergic receptors were measured in asthmatic patients with (n = 7) and without (n = 10) nocturnal asthma at 4 PM and 4 AM and compared with those of normal subjects (n = 10). A twofold higher plasma histamine concentration was observed at 4 AM compared with 4 PM in all groups. with no change in plasma cortisol. epinephrine. and cAMP concentrations. At 4 AM compared with 4 PM. only patients with nocturnal asthma had a significant 33% decrease (p less than 0.05) in mononuclear and polymorphonuclear leukocyte beta-adrenergic receptor density. with no difference in binding affinity in all three groups. Polymorphonuclear leukocytes from patients with nocturnal asthma had significantly impaired response to isoproterenol at 4 AM (17% +/- 7.3% SEM increase in cAMP; p less than 0.05) compared with those of patients without nocturnal asthma (69.4% +/- 13.7%) and normal (80.2% +/- 21.3%) subjects. A significant change in beta-adrenergic receptor density and function occurs at night in patients with nocturnal asthma.
Effect of steroids on cerebrospinal fluid penetration of antituberculous drugs in tuberculous meningitis, Sixteen patients with oral isoniazid. pyrazinamide. rifampin. and intramuscular streptomycin for tuberculous meningitis were studied. The concentrations of isoniazid. pyrazinamide. rifampin. and streptomycin in cerebrospinal fluid (CSF) obtained 3 hours after administration were 2.40. 34.78. 0.29. and 3.78 micrograms/ml. respectively. The CSF concentrations of isoniazid and pyrazinamide were well above the minimum inhibitory concentration for Mycobacterium tuberculosis. Concentrations of rifampin and streptomycin were above the minimal inhibitory concentration initially but declined below the minimal inhibitory concentration at later times. The CSF penetration of isoniazid. pyrazinamide. rifampin. and streptomycin was about 89%. 91%. 5%. and 20%. respectively. In eight patients who received antituberculous drugs in combination with steroids. the mean CSF and serum concentrations. as well as CSF/serum ratios at various intervals of treatment. were not statistically different (p greater than 0.05) from those of the eight patients who did not receive steroids.
Calcium entry blockade and adrenergic vascular reactivity in hypertensives: differences between nicardipine and diltiazem, The interference of nicardipine and diltiazem infused into the brachial artery at systemically ineffective rates. with the forearm vascular response to graded exogenous norepinephrine. was evaluated in hypertensive patients. Nicardipine (1 and 3 micrograms/dl forearm tissue/min in both absence and presence of propranolol) increased forearm blood flow (venous plethysmography) and antagonized dose dependently the vasoconstrictor effect of norepinephrine. suggesting that functional alpha-antagonism may participate in the vasodilating and possibly the antihypertensive effect of the drug. On the contrary. no antagonism but rather potentiation of the responses to norepinephrine occurred after diltiazem (0.5 and 1 microgram/dl forearm tissue/min). Because intra-arterial propranolol abolished that potentiating action of the drug. whereas the local vasodilation to isoproterenol was clearly reduced. diltiazem probably interfered with beta-adrenergic receptor-mediated vasorelaxing mechanisms in human forearm arterioles. The data further stress the heterogeneity of calcium entry blockers in humans.
Skeletal muscle metabolism in heart failure: a 31P nuclear magnetic resonance spectroscopy study of leg muscle, 1. The gastrocnemius muscle of seven patients with mild to moderate chronic heart failure and of five healthy control subjects was studied using 31P nuclear magnetic resonance spectroscopy. Spectra were collected at rest and during an incremental. symptom-limited. exercise protocol. Blood flow was measured in the same study during brief interruptions to exercise. 2. The phosphocreatine/(phosphocreatine plus inorganic phosphate) ratio was lower in patients with heart failure than in control subjects at an exercise rate of 1.5 W. although intracellular pH and blood flow were similar. 3. The cytosolic free adenosine 5'-diphosphate concentration was markedly increased in patients with heart failure exercising at 1.5 W compared with control subjects exercising at the same workload. 4. Although the maximum workload achieved by patients with heart failure was less than half of that reached by control subjects. the pH and the phosphocreatine/(phosphocreatine plus inorganic phosphate) ratio were lower in patients with heart failure at maximal load. Blood flow was less at maximal exercise in patients with heart failure than in control subjects in keeping with the reduced work load. 5. The phosphocreatine depletion induced in the gastrocnemius muscle by exercise was more severe than previously described in the forearm of patients with heart failure. 6. Metabolic abnormalities in skeletal muscle may contribute to exercise intolerance in heart failure. particularly during submaximal exercise.
Effect of polycations on the function of the isolated perfused rat kidney, 1. In minimal change nephrotic syndrome the occurrence of heavy proteinuria can be explained on the basis of a reduction in charge selectivity of the glomerular filtration barrier. and it has been proposed that this might be caused by the neutralization of anionic groups by a circulating polycationic factor. 2. The effects of two polycations. protamine and poly-L-lysine. on the function of the isolated perfused rat kidney have been examined. 3. Poly-L-lysine polymers of relatively high molecular weight (8800 and 17.800) induced heavy proteinuria. while simultaneously causing a marked increase in renal vascular resistance and a fall in filtration rate. Protamine (approximate molecular weight 7000) at relatively high concentration induced modest proteinuria in the absence of effects on vascular resistance or filtration rate. 4. A poly-L-lysine polymer of lower molecular weight (3800) did not induce proteinuria. Protamine at a concentration of 40 micrograms/ml and below did not affect protein excretion either. Both provoked substantial natriuresis. This appeared to be largely due to an effect on the tubular handling of sodium since the filtration rate remained steady while fractional sodium excretion rose markedly. 5. The natriuretic effect of protamine was blocked by heparin. but not by indomethacin or verapamil. suggesting that the mechanism of natriuresis did not depend upon either prostaglandin production or entry of calcium through verapamil-sensitive channels.
Dynamic association between artery shear flow condition and platelet cytosolic free Ca2+ concentration in human hypertension, 1. Blood cells and vascular endothelial cells are subjected to a wide range of haemodynamically generated shear stress forces. In vitro. membrane stretching or shear stress have been observed to activate ion channels and cell metabolism and to facilitate erythrocyte and platelet aggregation. 2. The present study was designed to evaluate the participation of shear stresses in the control of apparent platelet cytosolic free Ca2+ concentration in hypertensive patients. 3. Shear conditions and platelet cytosolic free Ca2+ concentration in vitro were studied after a dynamic perturbation induced by 3 months of double-blind treatment with one of two beta-antagonists. carteolol and atenolol. Brachial artery wall shear rate and stress were estimated by means of a pulsed Doppler velocimeter. and blood viscosity was measured by a co-axial viscometer at a shear rate of 96 s-1. Platelet cytosolic free Ca2+ concentration was simultaneously measured by using the Quin-2 fluorescent chelator. The direct effect of atenolol and carteolol on platelet cytosolic free Ca2+ concentration in vitro was also measured after addition of the beta-blockers to platelet-rich plasma. 4. Atenolol and carteolol decreased blood pressure similarly but their effects on shear rate (P less than 0.02). shear stress (P less than 0.01) and platelet cytosolic free Ca2+ concentration (P less than 0.05) differed after 3 months of therapy. In contrast. neither of the drugs significantly altered platelet cytosolic free Ca2+ concentration. in vitro per se. 5. In the overall population. strong positive correlations existed not only between changes in platelet cytosolic free Ca2+ concentration and those in shear rate (r = 0.81. P less than 0.001) and shear stress (r = 0.83. P less than 0.001). but also between their absolute values. suggesting a possible haemodynamic shear-dependent modulation of transmembrane Ca2+ transport.
Endothelin immunoreactivity in mice with gram-negative bacteraemia: relationship to tumour necrosis factor-alpha, 1. To investigate the role of endothelin in Gram-negative bacteraemia and the possible involvement of tumour necrosis factor-alpha in its pathophysiology. we measured plasma and tissue (lung. kidney and spleen) immunoreactive endothelin levels in Gram-negative bacteraemic mice. with and without passive immunization by anti-(tumour necrosis factor-alpha) antibody. 2. Plasma immunoreactive endothelin levels were greatly increased after the Escherichia coli injection. Pretreatment with anti-(tumour necrosis factor-alpha) antibody did not suppress elevated plasma immunoreactive endothelin levels (P greater than 0.1). 3. Lung tissue immunoreactive endothelin levels in mice were increased 16 h after the E. coli injection and were not affected by prior passive immunization with anti-(tumour necrosis factor-alpha) antibody. Immunoreactive endothelin in spleen and kidney was undetectable (less than 34 fmol/g wet weight). 4. Injection of rMu tumour necrosis factor-alpha into mice did not increase plasma immunoreactive endothelin levels. 5. Antibody to endothelin given 30 min after a 90% lethal dose challenge with E. coli did not affect mortality. 6. We conclude that the rise in plasma and tissue endothelin that occurs in Gram-negative bacteraemia is independent of tumour necrosis factor-alpha.
Non-invasive assessment of the cardiovascular eicosanoids, thromboxane A2 and prostacyclin, in randomly sampled males, with special reference to the influence of inheritance and environmental factors, 1. We studied. in a random sample of 385 nonsmoking men born in 1968-1969 and 31 men born in 1913 or 1923. whether inheritance and environmental factors influenced platelet activity and vessel wall prostacyclin formation. as reflected non-invasively by the urinary excretion of the 2.3-dinor-metabolites of thromboxane A2 (2.3-dinor-thromboxane B2. Tx-M) and prostacyclin (2.3-dinor-6-keto-prostaglandin F1 alpha. PGI-M). respectively. 2. Fathers of young men with high platelet activity did not excrete more Tx-M than fathers of young men with low platelet activity. Men born in 1913 or 1923 displayed higher Tx-M (563 versus 128 pg/mg of creatinine. P less than 0.001) and PGI-M (163 versus 130 pg/mg of creatinine. P less than 0.01) excretion than those born in 1968-1969. Excretion of both Tx-M and PGI-M was correlated to the urinary output of noradrenaline and adrenaline. 3. Well-trained subjects did not differ in their excretion of Tx-M or PGI-M from those who did not exercise regularly. A recent acute infection was also unrelated to the excretion of Tx-M or PGI-M. PGI-M excretion was. however. significantly correlated to Tx-M excretion (r = 0.51. P less than 0.001). 4. This study provides the first non-invasive evidence that advancing age and sympathoadrenal tone are positively correlated to platelet activity in randomly sampled men. and that paternal inheritance. physical fitness and recent infection lack correlation to platelet activity.
Classifications of acute myeloid leukemia, A detailed description of the various subtypes of the acute myeloid leukemias is provided. The importance of cytochemistry and monoclonal antibodies is discussed.
Immunophenotyping of acute myeloid leukemia cells, This article considers the expression of myeloid cell-associated antigens on both normal and malignant myeloid cells. Progress in the use of monoclonal antibodies to myeloid cell surface antigens for the diagnosis. subclassification. and treatment of acute myeloid leukemia is discussed. The results of bone marrow purging with monoclonal antibodies to remove leukemia cells for the purpose of autologous bone-marrow transplantation are promising.
Polycythemia vera and other polycythemic states, The diagnosis of polycythemia requires an accurate and independent assessment of both plasma volume and red blood cell mass. Patients with an increased red cell mass (absolute polycythemia) may be hypoxic or have an erythropoietin-secreting tumor or space-occupying lesion compressing the kidney. Those with a reduced plasma volume (relative polycythemia) most often are tobacco smokers. are taking diuretic or cardiac medications. or ingest increased quantities of caffeine-containing beverages. On the other hand. polycythemia vera is a systemic disease with multiple complications. which is best diagnosed through a complex of findings as outlined by the Polycythemia Vera Study Group.
Platelet abnormalities in myeloproliferative disorders, A large number of various platelet abnormalities are described in patients with MPD. These abnormalities serve diagnostic purposes only. They appear to have little or no predictive value regarding the clinical manifestations of the patients or the progress of the disease. Those platelet characteristics most consistently reported to be defective include a decrease in the platelet content of serotonin and adenine nucleotides. decreased platelet density. an abnormal ultrastructure characterized by paucity of granules and hypertrophy of the surface connecting canicular system. an altered membrane glycoprotein profile that includes reduced levels of GPIb. and reduced lipoxygenase activity and aggregation response with epinephrine. These abnormalities may originate at the megakaryocyte level. Furthermore. the released abnormal platelets may undergo modification of their functional and biochemical characteristics as a result of episodes of intravascular thrombosis or aging in circulation or as a result of the progression and treatment of the disease. thus creating the paradoxic and often conflicting relationship between the thrombotic and hemorrhagic events and the results of platelet functional tests as observed in this disorder.
Granulocytic sarcoma, Granulocytic sarcoma is a variant presentation of acute myeloblastic leukemia. occurring in extramedullary locations. It is uncommon. but it may occur at any site and at any age. which necessitates its inclusion in the differential diagnosis of all undifferentiated tumors. Histology. touch-imprint cytology. cytochemistry. immunocytochemistry. electron microscopy. and molecular studies all contribute to the diagnosis.
Stationary vs. mapping manometry in evaluating dysphagia, Two methods are used to assess esophageal motility. The mapping technique uses catheter withdrawal at 1 cm steps until the entire esophagus is evaluated. A simpler method is commonly used that involves keeping the catheter stationary for the entire evaluation. We compared these 2 techniques in 30 patients referred for the evaluation of dysphagia. Emphasis was placed on the distal 10 cm of the esophagus because this is the primary location of esophageal motility disorders. There was excellent correlation between techniques for mean distal amplitude (r = 0.945). mean distal duration (r = 0.942). and percentage of non-peristaltic contractions (r = 0.967). The overall manometry diagnosis was similar by both methods in 27 (90%) patients. Three patients had different manometry diagnoses resulting from use of the two techniques. However. the change in diagnosis was only clinically important in one patient in whom the mapping technique identified a segmental motility disorder that had been missed by the stationary technique. Stationary manometry had a 94% sensitivity and 93% specificity rate for identifying motility disorders compared to mapping manometry. We conclude that stationary manometry is a simple and accurate method for evaluating esophageal pressures and distal disorders. Only those patients with normal results of stationary studies may benefit by further mapping to identify rare segmental motility disorders.
Radiographic techniques and efficacy in evaluating esophageal dysphagia, The radiographic examination of the esophagus to determine structural and/or functional causes of dysphagia is best performed with multiple techniques. These include full-column studies to produce distended films with or without the use of a solid bolus. mucosal relief films to identify mucosal defects such as esophagitis or the presence of varices. double-contrast films. and motion recording (fluoroscopy). The efficacy of each technique depends on the quality of the study and the specific disorder to be detected. Esophageal lesions producing dysphagia are classified into extrinsic structural lesions. intrinsic structural lesions. and esophageal motility disorders. Radiographic studies are the preferred screening techniques for patients with dysphagia. Although not as sensitive for the evaluation of mucosal lesions. radiographic studies are superior to endoscopy for the detection of abnormal motility. esophageal rings. and strictures.
Symptoms of achalasia in young women mistaken as indicating primary anorexia nervosa, The case of a young women with dysphagia. regurgitation. and weight loss. who was diagnosed as having anorexia nervosa but in whom reevaluation showed that achalasia was causing the symptoms. is presented together with related observations. Misinterpretation of esophageal symptoms may occur not only as a consequence of inadequate history taking and of being biased by a patient's emaciation. age. and gender. which leads to view certain aspects of the patient's history and behavior as suggesting a pathologic attitude towards eating and body weight. but also as a consequence of a misinterpretation of the symptoms as indicative of an eating disorder by the patients themselves. In some cases a disordered attitude toward eating and body weight may develop together or coexist with achalasia. The clinical evaluation of patients with symptoms suggestive of anorexia nervosa but also of bulimia nervosa should include the taking of a thorough history regarding swallowing and vomiting in order to recognize a possible esophageal motor disorder.
Persistence of chronic constipation in children after biofeedback treatment, We investigated the efficacy of biofeedback treatment and evaluated anorectal factors that might be responsible for persistence of chronic constipation with or without encopresis in a group of 38 children with abnormal contraction of the pelvic floor during straining and persistence of chronic constipation with encopresis after conventional treatment. Nine children were unsuccessful in learning to relax the pelvic floor during straining with biofeedback treatment. and one patient had contraction of the pelvic floor on follow-up despite successful biofeedback treatment; none recovered. Twenty-eight children were able to relax the pelvic floor on follow-up; 14 recovered and 14 did not recover from chronic constipation. Nonrecovered patients who learned to relax the pelvic floor had significantly decreased rectal and anal responsiveness to rectal distension as compared to recovered patients during the initial and follow-up anorectal manometric study. Psychological factors such as social competence and behavior problems did not appear to be responsible for recovery or nonrecovery from chronic constipation and encopresis.
Clinical and physiological study of anal sphincter and ileal J pouch before preileostomy closure and 6 and 12 months after closure of loop ileostomy, Spontaneous evolution of pouch and anal function. and absorption features has been assessed in 15 patients who underwent proctocolectomy with J ileal pouch anastomosis without conservation of a rectal muscular cuff. All the patients were studied before preileostomy closure and six and 12 months after the closure of the protection loop ileostomy. Stool frequency was identical at six and 12 months (mean +/- SEM: 5.0 +/- 0.4 and 5.3 +/- 0.5/day. respectively). Sixty-six percent of patients at six months and 40% of patients at 12 months need to defecate at least one time during night. Stool weight as well as steatorrhea decreased significantly six months after the closure of loop ileostomy (P less than 0.05). Mean resting anal pressure remained unchanged six and 12 months after closure of the loop ileostomy (41 +/- 6 and 45 +/- 5 cm H2O. respectively). Maximum squeeze anal pressures increased significantly at six (P less than 0.05) and 12 months (P less than 0.05). The rectoanal inhibitory reflex was always absent at the same period. The maximum pouch capacity increased significantly during the first six months (P less than 0.01) from 142 +/- 17 to 279 +/- 27 ml. The maximum infused volume during a saline continence test was not significantly different at six and 12 months; the percentage of evacuation of the reservoir and the volume at which the first ileal contraction appeared in the reservoir increased significantly (P less than 0.05) at six and 12 months. In conclusion. in patients with ileoanal anastomosis and pouch reservoir. the closure of the loop ileostomy is associated with spontaneous modifications of the anal and pouch parameters.
Modulation of mediator release from human intestinal mast cells by sulfasalazine and 5-aminosalicylic acid, Intestinal mast cells are thought to contribute to the mucosal inflammation in ulcerative colitis and Crohn's disease through release of inflammatory mediators. Since sulfasalazine and its metabolite 5-aminosalicylic acid are effective therapeutic agents in inflammatory bowel disease and have been shown to inhibit generation of inflammatory products in other cells. we examined the effect of these agents in vitro on human intestinal mast cell mediator release. Sulfasalazine (5 x 10(-4)-10(-3) M) was found to significantly enhance goat anti-human IgE-induced histamine release from intestinal mast cells. which is the same response as seen in human blood basophils. whereas its metabolite 5-aminosalicylic acid was an effective inhibitor of stimulated histamine release in both mast cells and basophils. 5-Aminosalicylic acid also inhibited production of prostaglandin D2 by the stimulated intestinal mast cells. Sulfasalazine alone. without immunologic stimulation. did not induce histamine release from mast cells or basophils. but the enhancement of ongoing mast cell activation by sulfasalazine may explain some cases of adverse reactions to the drug. The inhibition of mast cell histamine release and prostaglandin generation by 5-aminosalicylic acid demonstrates a potential therapeutic modality of this agent.
Rectal irrigation with short-chain fatty acids for distal ulcerative colitis. Preliminary report, Colon cells from patients with ulcerative colitis utilize short-chain fatty acids inefficiently and may be exposed to decreased concentrations of these compounds. To test whether irrigation of the inflamed mucosa with short-chain fatty acids is useful. we conducted a six-week preliminary trial in 12 patients with distal colitis. Each patient used twice daily rectal irrigations with 100 ml of a solution containing acetate (80 mM). propionate (30 mM). and butyrate (40 mM). Two patients stopped at three weeks. one because of no improvement and the other because of complete resolution of symptoms. Of the 10 who completed the trial. nine were judged to be at least much improved and showed a change in a mean disease activity index score from 7.9 +/- 0.3 (SE) to 1.8 +/- 0.6 (SE) (P less than or equal to 0.002) and in a mucosal histology score from 7.7 +/- 0.7 (SE) to 2.6 +/- 0.7 (SE) (P less than or equal to 0.002). Thus. ulcerative colitis patients appear to benefit from increased contact with or higher than usual levels of these critical energy substrates.
D-xylose absorption test. Urine or blood, The D-xylose absorption test has been used during the last four decades for evaluation of malabsorption in the small intestine. However. some disagreement still exists about the recommended method of performing this test: the 1-hr blood test. the 5-hr urine test. or both. We evaluated the test by performing 125 combined blood and urine tests in 111 patients. Normal xylose absorption was recorded in both blood and urine in 71 tests (group A. 56.8%). Abnormal test results in both blood and urine were recorded in 29 patients (group B. 23.2%). Only one patient had a pathological blood value and normal xylose excretion in the urine. Twenty-four patients (group D. 19.2%) had normal 1-hr blood xylose (greater than 25 mg/100 ml) with abnormal 5-hr urine xylose (less than 4.5 g/5 hr). Fat and/or bile salt malabsorption were documented in 21 patients (87.5%) of this group using stool fat analysis and the [14C]cholylglycine breath test. These data suggest that in adults the 5-hr urine collection more accurately reflects intestinal absorption in comparison with the 1-hr blood value.
Gallstone dissolution with methyl tert-butyl ether in 120 patients--efficacy and safety, Of 612 patients with cholesterol gallbladder stones. 120 were eligible for percutaneous transhepatic litholysis with methyl tert-butyl ether (MTBE). Puncture of the gallbladder was successful in 117/120 (97.5%). In 113/117 (96.6%) the stones dissolved. With solitary stones. treatment lasted for an average of 4 hr. with multiple stones 10 hr. Mean hospitalization was 3.6 days. In 3/117 (2.6%) patients a bile leakage developed; 33% reported mild complaints. After the end of treatment 34% had some residue in the gallbladder; two of these patients developed recurrent stones. MTBE is exhaled. is distributed in fatty tissue. and is excreted renally together with its metabolite tert-butanol. Methanol was found only in traces. Gallbladder histology of six patients showed chronic cholecystitis. Since these findings were independent of treatment time and the interval between treatment end and operation. they are most consistent with stone-related changes rather than caused by MTBE.
Medical dissolution of gallstones. Clinical experience of d-limonene as a simple, safe, and effective solvent, Retained gallstones in the bile ducts account for 60-70% of all the cases of postcholecystectomy syndromes. A solvent d-limonene preparation was injected directly to the biliary system of 200 patients to dissolve or disintegrate the retained gallstones. The outcomes were: retained stones completely disappeared in 96 cases (48%); partial dissolution in 29 (14.5%); chelating agent was also used with partial dissolution in 16 (8%); ineffective in 59 (24.5%). To make this method more effective. several guidelines should be observed including an in vitro trial dissolution test. Cautious observation for possible side effects and frequent hepatic and pancreatic function tests during the treatment with this preparation also should be performed.
Evaluation of portal-systemic shunting in rats from mesenteric and splenic beds, In rats with partial portal vein ligation. 95 +/- 0.9% of the splenic blood flow is shunted from the portal to the systemic circulation when an intrasplenic injection of microspheres is used to determine the degree of shunting. Despite this magnitude of portal-systemic shunting. several biochemical and endocrine consequences of portal-systemic shunting occur at levels below what is expected for the degree of shunting found. In an effort to resolve these discordant findings. shunting from both the splenic and the mesenteric bed was studied in anesthetized portal hypertensive rats with various degrees and/or duration of portal vein stenosis. The shunting from the mesenteric bed averaged 66.7 +/- 29.9% (range 5.1-99.1%) and was influenced both by the degree and duration of portal vein stenosis. In contrast. shunting from the splenic bed averaged 97.3 +/- 4.0% (range 79-99.9%) and demonstrated no variation between groups determined by the degree of portal vein stenosis. The shunting from the splenic bed was consistently greater than that found from the mesenteric bed. Mesenteric but not splenic shunting correlated with serum bile acid levels. Mesenteric shunting was related inversely to the weight-adjusted liver mass and to serum testosterone levels. Based upon these data obtained in portal hypertensive rats. it is concluded that splenic injections of microspheres overestimate portal-systemic shunting. In contrast. mesenteric injections of microspheres yield values for shunting that correlate well with independently determined biochemical and endocrine consequences of shunting. These observations support the validity of the mesenteric shunting measurements obtained.
Distribution of cholesterol between vesicles and micelles in human gallbladder bile: influence of treatment with chenodeoxycholic acid and ursodeoxycholic acid, The present study aimed at determining the relative distribution of cholesterol between the vesicular and micellar phases in gallbladder bile of gallstone patients (n = 23) and gallstone-free subjects (n = 7). Nine of the gallstone patients were treated with chenodeoxycholic acid and seven were treated with ursodeoxycholic acid. 15 mg/kg/day. for 3 wk before cholecystectomy. The vesicular and micellar fractions in bile were separated by sucrose density gradient ultracentrifugation. and a clear separation between the two phases was obtained. The vesicles were further identified by quasielastic light scattering spectroscopy and appeared to be of a uniform size with a mean hydrodynamic radius of 760 A. The proportion of cholesterol in the vesicular fraction was significantly higher in the untreated gallstone group (40% +/- 4%) compared with the gallstone-free (28% +/- 3%). ursodeoxycholic acid (28% +/- 3%) and chenodeoxycholic acid (18% +/- 4%) groups. Despite a low cholesterol saturation of bile in the latter three groups (88% +/- 12%. 51% +/- 9% and 65% +/- 5%. respectively). a considerable part of the biliary cholesterol was carried in the vesicular fraction. The cholesterol/phospholipid ratio in the vesicular fraction averaged between 0.49 and 0.58 in the gallstone. gallstone-free and chenodeoxycholic acid groups. whereas the ursodeoxycholic acid group had a significantly lower ratio of 0.24. The nucleation time of bile from the gallstone group was short (2 +/- 1 days) compared with the gallstone-free. chenodeoxycholic acid and ursodeoxycholic acid groups (23 +/- 3. 24 +/- 6 and 14 +/- 3 days. respectively.
Prophylactic sclerotherapy for esophageal varices: long-term results of a single-center trial, Survival after prophylactic sclerotherapy was assessed in a single-center study involving 99 cirrhotic (41 alcoholic) patients enrolled over 8-yr. The wedged hepatic vein pressure gradient was measured; those with pressure greater than or equal to 12 mm Hg were randomized to receive sclerotherapy or no treatment. The rest were not randomized. Patients in all three groups who bled were treated with emergency endoscopy and sclerotherapy. Stratification according to presence of ascites was also undertaken. Median follow-up was 61 mo (range = 14 to 107 mo). Survival among unrandomized patients was significantly longer than among randomized patients (p less than 0.006). but there was no significant difference between those treated by sclerotherapy and the controls (p = 0.27). Alcoholic cirrhotic patients undergoing sclerotherapy had better 2-yr survival than did the controls (80% vs. 43%; p = 0.09). but this benefit was not sustained at 5 yr. Survival in the nonalcoholic patient groups was identical. Only 10 of 50 deaths were caused by variceal bleeding. Forty-eight percent of patients with large varices bled. compared with 20% of patients with small varices. Wedged hepatic vein pressure less than 12 mm Hg accurately identified alcoholic patients at low risk of variceal bleeding but not nonalcoholic patients. Only four episodes of variceal bleeding were attributable to elective sclerotherapy. We conclude that in our population. prophylactic sclerotherapy alone does not improve survival. The discrepancy in survival between alcoholic and nonalcoholic cirrhotic patients suggests that factors other than variceal hemorrhage may be responsible for the difference.
Dual association of HLA DR2 and DR3 with primary sclerosing cholangitis, Human leukocyte antigen typing was performed in 81 patients with primary sclerosing cholangitis to investigate reported associations between human leukocyte antigen type and this disease. The results showed a significant increase in the frequency of the antigens B8 and DR3 compared with controls (53% vs. 23%. p less than 0.0005. and 56% vs. 21%. p less than 0.0005). This was caused by a significant rise in the frequency of the human leukocyte antigen A1 B8 DR3 haplotype (32 of 81 patients. 40% vs. 12 of 100 patients. 12%. p less than 0.0005). By contrast. a significant reduction was seen in the frequency of the antigens B44 and DR4 (12% vs. 31%. p less than 0.005. and 12% vs. 34%. p less than 0.001. pc less than 0.011) because of the complete absence of the B44 DR4 haplotype in the patient group (p = 0.027. Fisher's exact test). When all the DR3-positive individuals (including the DR2/DR3 heterozygotes) were eliminated. a significant secondary association with DR2 was noted. 25 (69%) of 36 remaining patients being DR2-positive compared with 27 (34%) of 79 DR3 negative controls (p less than 0.0005. pc less than 0.006). Only 9% of the patients were DR2-positive and DR3-positive. Kaplan-Meier analysis demonstrated that survival was not influenced by the presence of either haplotype nor by the individual antigens. Patients who were DR3-positive were first seen at a significantly younger age than those who were DR2-positive (mean ages = 33 yr and 44 yr. respectively. p less than 0.002. Student's t test).
Significance of natural polymerized albumin and its receptor in hepatitis B infection of hepatocytes, Lack of information regarding the presence of native albumin polymer in serum and its structural similarity to the one produced by glutaraldehyde treatment casts doubt on the postulate that hepatitis B virus attachment to hepatocytes is mediated through polymerized albumin. We used a sandwich enzyme-linked immunosorbent assay with murine monoclonal antibodies raised against glutaraldehyde-polymerized albumin to detect native albumin polymer in human serum and its cross-reactivity with other albumin polymers. Presence of polymerized albumin receptor on the HepG2 cell was studied by radioreceptor assay. Purified hepatitis B virus and synthetic peptide analogous to part of pre-S2 sequence (120-145) were used to study polymerized albumin-dependent attachment of the virus to HepG2 cells. Antibodies raised against pre-S2 peptide were used to inhibit the pre-S2 and hepatitis B virus attachment to HepG2 cells. Glutaraldehyde-treated polymerized albumin was found to be immunologically cross-reactive with native albumin polymer. Its levels were found to be significantly raised in sera of patients with liver diseases. Polymerized albumin has specific saturable receptor on HepG2 cells with two classes of binding sites of different equilibrium dissociation constant (Kd1 = (16 +/- 9.6)pmol/L and Kd2 = (1.019 +/- 172)pmol/L. Albumin monomer was unable to compete for the polymerized albumin receptor sites on HepG2 cells. Anti-pre-S2 antibodies inhibit hepatitis B virus and pre-S2 binding to hepatocyte by 40% and 70%. respectively. Added extraneous polymerized albumin and the antibody against it did not interfere with virus attachment to HepG2 cells.
Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to pre-S- and S-encoded viral surface antigens, The polymerase chain reaction was evaluated as a diagnostic tool in 72 chronic hepatitis B virus carriers. Hepatitis B virus DNA was detectable in the serum of HBsAg-positive virus carriers using aliquots as small as 100 al. The detection limit for cloned hepatitis B virus DNA was 100 ag. Primer pairs for different regions of the HBV genome resulted in different sensitivity. Detection of the amplified hepatitis B virus DNA by Southern blotting and subsequent scintillation counting or densitometry allowed a semiquantitative assay. Using several primer pairs in parallel for optimal detection. all HBeAg-positive HBsAg carriers. 80% of HBe antibody-positive symptomatic HBsAg carriers and 57% of asymptomatic HBe antibody-positive HBsAg carriers were found to have hepatitis B virus DNA in the serum. During antiviral therapy hepatitis B virus DNA disappeared by the polymerase chain reaction assay in patients who became HBeAg negative. but polymerase chain reaction detected a relapse earlier than did the conventional dot blot. Pre-S antigens were assayed in serum and liver samples from most chronic carriers by enzyme-linked immunosorbent assay and/or immunoblot. Although most viremic carriers were strongly positive for pre-S1 and pre-S2 antigens. some hepatitis B virus DNA-positive HBsAg carriers did not have detectable pre-S antigens. and vice versa. Our data show that assay of hepatitis B virus DNA in the serum by polymerase chain reaction is by far more proficient than by dot blot and that it cannot be replaced by serological assays of HBeAg or pre-S antigen.
Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion, Reperfusion injury characterized by loss of endothelial cell viability occurs after cold ischemic storage of livers for transplantation surgery. Here. ultrastructural changes in stored rat livers were examined by scanning and transmission electron microscopy. With increasing times of storage in Euro-Collins solution (4 to 24 hr) followed by 15 min of reperfusion at 37 degrees C. a sequence of structural alterations was observed involving endothelial and Kupffer cells. Widening of endothelial fenestrations occurred after 4 hr and progressed over 8 to 24 hr to retraction of cellular processes. ball-like rounding. sinusoidal denudation and ultrastructural derangements consistent with loss of cell viability. Kupffer cells exhibited progressive rounding. ruffling of the cell surface. polarization. appearance of wormlike densities. vacuolization and degranulation over a similar time course. By contrast. the structures of parenchymal and fat-storing cells were relatively undisturbed by cold storage and reperfusion. Alterations to endothelial and Kupffer cells were also studied as a function of time of reperfusion. After 24 hr of storage. endothelial cells showed retraction of cytoplasm before reperfusion that progressed quickly to loss of viability and denudation during reperfusion. Kupffer cell activation (ruffling. degranulation) during reperfusion was slower and occurred after deterioration of endothelial cells. Livers stored in Euro-Collins solution were also compared with livers stored in University of Wisconsin cold storage solution. an improved preservation medium for transplantation. University of Wisconsin solution provided better preservation of endothelial structure and markedly reduced parenchymal cell blebbing and swelling before reperfusion. University of Wisconsin solution also reduced Kupffer cell activation and release of lysosomal enzymes. In conclusion. endothelial cell deterioration followed by Kupffer cell activation occurred after increasing times of cold ischemic storage and reperfusion of rat livers. Both changes may contribute to the pathophysiology of graft failure caused by reperfusion-mediated storage injury.
Role of influenza B virus in hepatic steatosis and mitochondrial abnormalities in a mouse model of Reye syndrome, The hepatic steatosis observed in the influenza B virus mouse model of Reye syndrome has been attributed to infectious virus or. alternately. to decreased food intake in the virus-treated mice or impurities in the virus preparation. To resolve this issue. 4- to 6-wk-old male Balb C mice were given. by intravenous injection. 12.800 hemagglutination units of influenza B Lee/40 virus in phosphate buffered saline/1% bovine serum albumin using virus prepared by ultra-centrifugation from infected allantoic fluid. by sucrose density-gradient purification of virus prepared by ultracentrifugation from infected allantoic fluid or by irradiation of virus prepared by ultracentrifugation from infected allantoic fluid to inactivate virus. The infectivity titer of virus prepared by ultracentrifugation from infected allantoic fluid was much higher than that of sucrose density-gradient purified virus prepared from infected allantoic fluid: 50% egg infectious dose for virus prepared by ultracentrifugation from infected allantoic fluid was 3.9 x 10(4)/hemagglutination unit vs. 8.7 50% egg infectious dose/hemagglutination unit for sucrose density-gradient purified virus prepared from infected allantoic fluid. Control mice received phosphate-buffered saline/1% bovine serum albumin or uninfected allantoic fluid diluted in phosphate-buffered saline/1% bovine serum albumin. Mice were fasted to eliminate dietary variation. and livers were obtained 36 hr after virus administration. Of the above treatments. only virus prepared by ultracentrifugation from infected allantoic fluid caused clinical illness and increased hepatic triglycerides (p less than 0.02) compared with controls. Hepatic triglycerides in virus prepared by ultracentrifugation from infected allantoic fluid correlated with histopathological vacuolization scores (r = 0.5773; p less than 0.03).
99mTc HM-PAO SPECT in pediatric migraine, 99mTC HM-PAO SPECT brain imaging was performed during the headache-free period in 19 young migraineurs. affected by common migraine (CM. 10 cases). classic migraine (CLM. 6 cases) and hemiplegic migraine (HM. 3 cases). SPECT findings were negative in all 10 patients with CM. in 3 cases of CLM and in 2 cases of HM. Positive findings in the remaining 4 patients (3 cases of CLM and 1 of HM) showed a decreased tracer distribution in the temporo-occipital regions (2 cases) and parietal regions (2 cases): the two with decreased temporo-occipital perfusion reported prodromal symptoms exclusively contralateral to the areas of hypoperfusion. An impaired regional cerebral vascular autoregulation may exist even during headache-free intervals in patients suffering from classic and hemiplegic migraine.
Cerebral vein thrombosis shown by MRI, A 46 year old man with a short history of left facial pain and numbness. and subsequently headaches. had a normal physical examination and a normal CT scan of head. Lumbar puncture yielded normal CSF under increased pressure. MRI showed thrombosis of the superior sagittal sinus. subsequently confirmed by angiography. MRI is a sensitive test for detecting intracranial venous thrombosis. and may be the investigation of choice when this disorder is suspected.
The cluster diathesis, We present further evidence for a sympathetic defect of vasomotor control of the anterior cerebral artery (ACA) on the side of the headache during cluster periods. In 119 cluster headache patients. utilizing transcranial Doppler. we measured CO2 reactivity of the major intracranial vessels. in and out of cluster. Reactivity was significantly lower during the cluster period. but only in the ACA on the side of the headache. Nineteen patients followed sequentially for a full cycle (ie/both in and out of a cluster period) showed the same changes. In 3 out of 6 patients in an active cluster period. we describe a lesion on Gallium single-photon emission computerized tomography (SPECT) in the region of the cavernous sinus which fades as the patient moves out of cluster. It is felt that this lesion may represent the cavernous sinus plexus lesion postulated as the central lesion in cluster. Changes in the sympathetic outflow at this point could explain the changes we have described in ACA CO2 reactivity during cluster.
Relaxation training in school classes does not reduce headache complaints, The effect of teacher-presented Progressive Relaxation Training (PRT) on headaches. fear of failure and school problems was studied in school students. During ten physical education lessons. students received either PRT (n = 110) or placebo training (n = 92). The effect of the training was investigated in students who indicated the presence of headaches in a pre-training diary. No significant differences were found between both training groups regarding headache frequency. duration and intensity and the psychological variables. On the basis of these and previous findings. it is recommended to present PRT to fairly small groups of self-selected subjects instead of complete classes.
Pharmacokinetics of tiaprofenic acid after oral administration in fasting patients during and between migraine attacks, This study examined the pharmacokinetics of 300 mg of tiaprofenic acid. a NSAID belonging to the 2-arylpropionic class. as a single oral dose. in 10 migraine patients during and out of migraine attacks. Plasma concentration of tiaprofenic acid was determined by HPLC analysis. Drug absorption appeared to be the same during and out of migraine attacks (absorption half life: during attack. 0.249 +/- 0.122 hr; out of attack. 0.249 +/- 0.105 hr; maximum plasma concentration: during attack. 37.8 +/- 9.8 ug/ml; out of attack. 40.1 +/- 13.2 ug/ml). The other pharmacokinetic parameters evaluated were not affected by headache attacks as well. We conclude that tiaprofenic acid absorption and metabolism are not affected by migraine attacks. Also. our data suggest that tiaprofenic acid might be useful in the treatment of migraine.
Myocardial infarction prognostic scoring system, A myocardial infarction prognostic scoring system for patients treated in a coronary care unit is described. The prognostic significance of 22 variables. all which were available on admission. were analyzed. A prognostic index was then constructed by a modified stepwise logistic regressional analysis technique. The variables that were used in the scoring system were Killip hemodynamic class. infarct location. and the maximal ST segment elevation in a single lead. The scoring system was validated in an independent group of patients. including a group of patients treated with intravenous streptokinase. The scoring system may prove to be useful for individual patient prognostication and management strategies. and for the quantification of infarct severity for use in clinical studies.
Wellness motivation in cardiac rehabilitation, Lack of patient adherence to prescribed regimens is a fundamental problem in cardiac rehabilitation programs. A causative factor in lack of patient adherence may be related to failure to address differences in individual health behavior motivation in cardiac rehabilitation. A group of 52 patients who had had myocardial infarction were sampled to test the relationship between social support systems. health locus of control. health value orientations. and wellness motivation. Pearson correlation coefficients indicated significant positive correlations between health locus of control variables. health value orientation variations. and wellness motivation. Health locus of control and health value orientation variables entered into a multiple regression equation to explain 32% of the variation in wellness motivation. Awareness of individual motivational responses that influence health behaviors in cardiac rehabilitation may enable nurses to develop intervention strategies for patients with cardiovascular disease who would benefit from modifying their risk-producing life-styles.
Interpleural analgesia [published erratum appears in Heart Lung 1991 Jul;20(4):413, Postoperative pain relief is necessary not only for patient comfort. but also to facilitate ventilation and ambulation. The use of opioid analgesia. either intravenously. intramuscularly. or intraspinally. may be ineffective and can cause respiratory depression. The administration of local anesthetics into the pleural space is a technique of providing analgesia of rapid onset and long duration. This analgesia is accomplished without causing the respiratory depression or sedation associated with the use of opioids. Because innovative analgesic methods are often selected for critically ill patients presenting after surgery in the intensive care setting. critical care nurses may encounter patients receiving local anesthetics administered via interpleural catheter.
Development of a special care unit for chronically critically ill patients, Intensive care units (ICUs) are recognized as one of the most expensive services provided by hospitals. Within these ICUs are a growing population of patients whose stays are extensively prolonged because of complications or underlying chronic health conditions that are exacerbated by a critical illness. These patients can be described as "chronically critically ill" and are costly to hospitals both in terms of actual dollars and in terms of the burden of care to nurses and physicians. This article describes the creation of a special care unit (SCU) designed specifically to meet the needs of chronically critically ill patients. The SCU environment is composed of a physical design that accommodates limited technology and care aimed at family involvement and rehabilitation. a case management practice model. and a shared governance management model. This structure is in contrast to traditional ICU environments. which include physical layouts that allow for high technology and close monitoring of patients. a primary nursing delivery system. and a bureaucratic management model. A research project to compare the effects of the SCU with the effects of the traditional ICUs on nurse and patient outcomes is described.
Treatment strategies in shock: use of oxygen transport measurements, Shock has traditionally been categorized according to its cause. Shock can result from hemorrhage. primary cardiac failure. central nervous system failure. trauma. or sepsis. Therapeutic principles have been developed for each etiologic type. End points for such therapy have included optimization of pulmonary capillary wedge pressure. cardiac output. blood pressure. and urine output. Recent investigators agree that the common denominator in each of the shock syndromes is a reduction in the amount of oxygen consumed by the cell. The logical therapeutic approach would be to increase oxygen delivery to support the increased metabolic demand of the cells. The end point of resuscitation should be optimization of oxygen delivery and oxygen consumption. These variables are easily calculated by using data obtained from pulmonary artery catheter and laboratory measurements. The physician or nurse caring for critical ill patients should have a thorough understanding of the rationale for the use of oxygen transport calculations and the methods of manipulating oxygen delivery. A simple explanation of these principles including the importance of hemoglobin. cardiac index. and percent saturation of hemoglobin and suggested treatment strategies are presented.
Malassezia furfur fungemia associated with central venous catheter lipid emulsion infusion, Malassezia furfur has been associated with fungemias in infants after prolonged intravenous lipid emulsion alimentation. Most cases of M. furfur fungemia reported in the literature involved neonates and required catheter removal for cure. M. furfur is probably an underreported problem in neonates as well as adults with central venous catheters. receiving lipid emulsions. because the organism requires selective enrichment media for growth. for example. Sabouraud's dextrose agar with sterile olive oil overlay. This case report of M. furfur fungemia in a neonates is unique because the neonate recovered on discontinuation of the lipid emulsion. without removal of the central venous catheter.
Is phase 2 cardiac rehabilitation necessary for early recovery of patients with cardiac disease? A randomized, controlled study, In this study the effects of rehabilitation teaching plus exercise testing on perceived self-efficacy for and performance of daily activities were compared with and without exercise training. Subjects were patients who had had myocardial infarction or cardiac surgery (mean age 57.7 +/- 11.3 years) and who had already received inpatient rehabilitation services. Subjects were randomly assigned to one of three groups. Treatment group 1 (n = 11) received teaching. treadmill exercise testing. and exercise training (three times weekly for 5 weeks). Treatment group 2 (n = 15) received only teaching and exercise testing. The control group (n = 14) received only routine care without supervised exercise or teaching. Measurements of self-efficacy and activity performance were made at hospital discharge and at 4 and 9 weeks after the cardiac event. Repeated-measures analysis of variance showed an increase in self-efficacy scores (p less than 0.001) and performance of physical activity (p less than 0.001) for all groups. Both treatment groups. especially the training group. obtained the highest scores. but differences between groups were nonsignificant (p greater than 0.05). These results indicate that in a sample of uncomplicated. motivated patients who had participated in a phase 1 inpatient rehabilitation program. substantial improvements in self-efficacy and performance of daily activities were made early in recovery. before the onset of phase 2. formalized outpatient therapy.
Myocardial infarction in the young adult, CAD in young male adults below the age of 40 years has generally been found to be associated with the usual risk factors associated with CAD. In a lesser number of young adults. MIs may be related to cocaine use. Sympathomimetic effects and increase in myocardial oxygen demand are factors considered responsible for acute MI in cocaine-abusing patients. In young adults who are asymptomatic following an acute MI and who are able to pass treadmill exercise stress tests at levels of Bruce stage 4 have been shown to have normal coronary arteriograms. Thus this subset should not require routine coronary angiograms following an acute MI.
Interaction of chemical and high vascular pressure injury in isolated canine lung [published erratum appears in J Appl Physiol 1991 Mar;70(3):964, Because both chemical and mechanical insults to the lung may occur concomitantly with trauma. we hypothesized that the pressure threshold for vascular pressure-induced (mechanical) injury would be decreased after a chemical insult to the lung. Normal isolated canine lung lobes (N. n = 14) and those injured with either airway acid instillation (AAI. n = 18) or intravascular oleic acid (OA. n = 25) were exposed to short (5-min) periods of elevated venous pressure (HiPv) ranging from 19 to 130 cmH2O. Before the HiPv stress. the capillary filtration coefficient (Kf.c) was 0.12 +/- 0.01. 0.27 +/- 0.03. and 0.31 +/- 0.02 ml.min-1.cmH2O-1 x 100 g-1 and the isogravimetric capillary pressure (Pc.i) was 9.2 +/- 0.3. 6.8 +/- 0.5. and 6.5 +/- 0.3 cmH2O in N. AAI. and OA lungs. respectively. However. the pattern of response to HiPv was similar in all groups: Kf.c was no different from the pre-HiPv value when the peak venous pressure (Pv) remained less than 55 cmH2O. but it increased reversibly when peak Pv exceeded 55 cmH2O (P less than 0.05). The reflection coefficient (sigma) for total proteins measured after pressure exposure averaged 0.60 +/- 0.03. 0.32 +/- 0.04. and 0.37 +/- 0.09 for N. AAI. and OA lobes respectively. However. in contrast to the result expected if pore stretching had occurred at high pressure. in all groups the sigma measured during the HiPv stress when Pv exceeded 55 cmH2O was significantly larger than that measured during the recovery period.
Cough-enhanced mucus clearance in the normal lung, We studied the effectiveness of cough for clearing mucus in 12 nonsmoking subjects with normal lung function. On 2 separate study days. each subject breathed 6-microns Mass Median Aerodynamic Diameter 99mTc-labeled iron oxide particles under controlled breathing conditions while they were seated in front of a gamma camera. Retention (R) of lung activity was measured over the initial 2 h and again at 24 h after particle inhalation. On the control day the subject sat quietly in front of the camera. while on the cough day each subject performed 60 controlled coughs during the 1st h of retention measurements. By paired analysis. retentions at both 1 and 2 h (R1 and R2. respectively) for the cough measurements were significantly less than control (mean control R1 = 85% vs. mean cough R1 = 72%. P less than 0.002; mean control R2 = 75% vs. mean cough R2 = 65%. P less than 0.02). Retention at 24 h (R24) was not significantly different between cough and control measurements (mean cough R24 = 35% and mean control R24 = 32%). Thus coughing increased the rate at which the radiolabeled particles were cleared from the bronchial airways in these individuals. Follow-up experiments with subjects performing rapid inhalations rather than cough showed similar enhanced particle clearance to that seen with cough. These results suggest that the observed enhancement of mucus clearance by cough (and rapid inhalation) in the normal lung may be due to a stimulation of the mucociliary apparatus rather than via a two-phase gas-liquid flow mechanism.
Proton magnetic resonance of exercise-induced water changes in gastrocnemius muscle, Exercise-induced water concentration changes have been determined in the medial gastrocnemius muscle noninvasively with image-guided in vivo proton magnetic resonance spectroscopy (MRS). These measurements were performed on seven normal male volunteers during and after isometric and ischemic-isometric exercise at 5. 10. and 20% maximum voluntary contraction (MVC). The observed water flux changes during different phases of exercise have been interpreted in terms of fluid transfer between the vasculature and exercising muscle. Good correlation between individual MVC and changes in water fluxes and the decay of water content was observed after 20% MVC exercise level. MRS results have been found to be consistent with those reported in the literature based on invasive biopsy techniques.
Intrapulmonary distribution of bronchial blood flow after moderate smoke inhalation, The systemic blood flow to the airways of the left lung was determined by the radioactive microsphere technique before and 17 h after smoke inhalation in six conscious sheep (smoke group) and six sheep insufflated with air alone (sham group). Smoke inhalation caused a sixfold increase in systemic blood flow to the lower trachea (baseline 10.6 +/- 1.7 vs. injury 60.9 +/- 16.1 ml.min-1.100 g-1) and an 11- to 14-fold increase to the intrapulmonary central airways (baseline range 9.5 +/- 1.9 to 13.5 +/- 3.7 ml.min-1.100 g-1 vs. injury 104.6 +/- 32.2 to 187.3 +/- 83.6 ml.min-1.100 g-1). There was a trend for this hyperemic response to be greater as airway diameter decreased from the trachea to 2-mm-diam central airways. In airways smaller than 2 mm. the hyperemic response appeared to diminish. The total systemic blood flow to whole lung is predominantly to small peripheral airways and showed no significant increase from its baseline level of 17.5 +/- 3.7 ml.min-1.100 g-1 in the lung homogenate. Occlusion of the bronchoesophageal artery decreased central airway blood flow 60-80% and peripheral airway blood flow 40-60% in both the sham and the smoke groups.
Flow-volume characteristics in the pulmonary circulation, Isolated ferret and canine lungs were used to validate a method for assessing determinants of vascular volume in the pulmonary circulation. With left atrial pressure (Pla) constant at 5 mmHg. flow (Q) was raised in steps over a physiological range. Changes in vascular volume (delta V) with each increment in Q were determined as the opposite of changes in perfusion system reservoir weight or from the increase in lung weight. At each level of Q. the pulmonary arterial and left atrial cannulas were simultaneously occluded. allowing all vascular pressures to equilibrate at the same static pressure (Ps). which was equal to the compliance-weighted average pressure in the circulation before occlusion. Hypoxia (inspired PO2 25 Torr) in ferret lungs. which causes intense constriction in arterial extra-alveolar vessels. had no effect on the slope of the Ps-Q relationship. interpreted to represent the resistance downstream from compliance (control 0.025 +/- 0.006 mmHg.ml-1.min. hypoxia 0.030 +/- 0.013). The Ps-axis intercept increased from 8.94 +/- 0.50 to 13.43 +/- 1.52 mmHg. indicating a modest increase in the effective back-pressure to flow downstream from compliant regions. The compliance of the circulation. obtained from the slope of the relationship between delta V and Ps. was unaffected by hypoxia (control 0.52 +/- 0.08 ml/mmHg. hypoxia 0.56 +/- 0.08). In contrast. histamine in canine lungs. which causes constriction in veins. caused the slope of the Ps-Q relationship to increase from 0.013 +/- 0.007 to 0.032 +/- 0.006 mmHg.ml-1.min (P less than 0.05) and the compliance to decrease from 3.51 +/- 0.56 to 1.68 +/- 0.37 ml/mmHg (P less than 0.05).
Regional H2O2 concentration in rat brain after hyperoxic convulsions, O2 toxicity of the central nervous system (CNS) may be a result of enhanced generation of reactive O2 species such as superoxide and H2O2 at high PO2. In this study. we measured H2O2 production in six regions of the rat brain before and after convulsions induced by hyperbaric hyperoxia (HBO). H2O2 concentration was determined ex vivo using a method based on the H2O2-dependent decline in catalase activity in the presence of the irreversible inhibitor of compound I. 3-amino-1.2.4-triazole. Regional catalase activity in the brain ranged from 0.029 +/- 0.004 to 0.055 +/- 0.004 mumol O2.min-1.micrograms DNA-1 in cerebellum and medulla-pons. respectively. In the presence of aminotriazole. catalase activity declined after HBO-induced convulsions to 26-45% of normoxic values. The rates of inactivation of catalase were used to predict average steady-state values for H2O2 concentration in different brain structures. Estimated H2O2 concentrations during HBO varied from 31 to 51 pM in cerebellum and posterior subcortex and represented increases of 2.2-7.3 times normoxic values. These findings suggest that H2O2 is an important mediator of selective neuronal vulnerability to CNS O2 toxicity.
Toxic epidermal necrolysis (Lyell syndrome), Toxic epidermal necrolysis is perhaps the most formidable disease encountered by dermatologists. Uncommon but not rare. toxic epidermal necrolysis occurs in 60 to 70 persons per year in France. It remains as puzzling a disorder as it was 34 years ago. when described by Lyell. Whether or not toxic epidermal necrolysis is the most severe form of erythema multiforme is still the subject of discussion. The physiopathologic events that lead to this rapidly extensive necrosis of the epidermis are not understood. Indirect evidence suggests a hypersensitivity reaction. but the search for potential immunologic mechanisms has resulted in little data to support this hypothesis. Accumulated clinical evidence points to drugs as the most important. if not the only. cause of toxic epidermal necrolysis. Sulfonamides. especially long-acting forms. anticonvulsants. nonsteroidal anti-inflammatory agents. and certain antibiotics are associated with most cases of toxic epidermal necrolysis. Many other drugs have been implicated in isolated case reports. All organs may be involved either by the same process of destruction of the epithelium as observed in the epidermis or by the same systemic consequences of "acute skin failure" as seen in patients with widespread burns. Sepsis is the most important complication and cause of death. Approximately 20% to 30% of all patients with toxic epidermal necrolysis die. Elderly patients and patients with extensive lesions have a higher mortality rate. Surviving patients completely heal in 3 to 4 weeks. but up to 50% will have residual. potentially disabling ocular lesions. The prognosis is improved by adequate therapy. as provided in burn units. that is. aggressive fluid replacement. nutritional support. and a coherent antibacterial policy. Corticosteroids. advocated by some in high doses to halt the "hypersensitivity" process. have been shown in several studies to be detrimental and should be avoided.
Recreational sun exposure in Puerto Rico: trends and cancer risk awareness, Persons who sunbathe or engage in other activities at the beach are exposed to large amounts of UV radiation. Four hundred seven adults who visited the beaches of Puerto Rico were surveyed to determine their knowledge about the risks of sun exposure and to evaluate sunscreen use. The group consisted of 195 year-round Puerto Rican residents and 212 tourists. Ninety-five percent believed that the sun can cause skin cancer. although only half of the subset who lived all year in Puerto Rico believed that they personally received enough exposure to be at risk. The majority of the group (83%) understood the meaning of the sun protection factor numbers. although 35% used either nothing or a nonscreening oil. Half of Puerto Rican residents rarely or never used sunscreen protection while sunbathing. When sunscreen was used. the most important factor sought was given as sun protection factor (64%). followed by a perceived ability to aid in tanning (26%).
Cutaneous angiolipoleiomyoma, We describe eight cases of cutaneous angiolipoleiomyoma. a rare tumor previously reported only once under the term cutaneous angiomyolipoma. Clinically. the tumors were acquired. solitary. asymptomatic nodules that were always acral in location. Patients' ages ranged from 33 to 77 years (median 52.6 years); the male/female ratio was 7:1. Signs of tuberous sclerosis or renal angiomyolipoma were absent in all cases. Histologically. the tumors were subcutaneous. well circumscribed. and composed of smooth muscle. vascular spaces. connective tissue. and mature fat. In some tumors the fat was the predominant component. and in others smooth muscle predominated. Elastic tissue stains revealed that some blood vessels had developed an elastic lamina whereas other blood vessels lacked it. Additional histologic features occasionally observed included vascular thrombi. glomus bodies. and focal mucin deposition.
The risk of developing subsequent nonmelanoma skin cancers, Data from the Southeast Arizona Skin Cancer Registry collected during 1985 through June 1988 were used in this study. Patients who had a nonmelanoma skin cancer (basal cell or squamous cell carcinoma) removed in 1985 were observed until subsequent nonmelanoma skin cancers developed or until June 30. 1988. Twelve categories of nonmelanoma skin cancers were developed on the basis of the type of first nonmelanoma skin cancer and type of second. third. and fourth nonmelanoma skin cancers. Analyses showed the highest risk of a subsequent nonmelanoma skin cancer developing was within 1 year (36.39%). the rate of developing another nonmelanoma skin cancer depended on type (squamous cell carcinoma. 100%; basal cell carcinoma. 44.23% to 83.65%). and total risk decreased during the 1277 days of the study.
Histologic pattern analysis of basal cell carcinoma. Study of a series of 1039 consecutive neoplasms, This study attempts to define histologic patterns in 1039 consecutive cases of basal cell carcinoma and to correlate these patterns with adequacy of margins of surgical excision. Five major histologic patterns were identified: nodular. 218 cases (21%); superficial. 181 cases (17%); micronodular. 151 cases (15%); infiltrative. 77 cases (7%); and morpheic. 11 cases (1%). A mixed pattern (two or more major histologic patterns) was present in 401 cases (38.5%). Our study indicates that nodular and superficial basal cell carcinomas can be completely removed by simple surgical excision in a high percentage of cases (93.6% and 96.4%. respectively) whereas the micronodular. infiltrative. and morpheic basal cell carcinomas have a higher incidence of positive tumor margins (18.6%. 26.5%. and 33.3%. respectively) after excision. Mixed patterns that consisted of combinations of the nodular. micronodular. or infiltrative types exhibited a behavior similar to the pattern that resulted in a greater chance of incomplete surgical removal.
Treatment of brittle fingernails and onychoschizia with biotin: scanning electron microscopy, Pathologic hoof changes in horses and swine can be normalized by administration of biotin. This vitamin has been given orally to women with brittle fingernails or onychoschizia. The aim of the study was to test whether the favorable clinical results could be corroborated by scanning electron microscopy. We investigated the distal ends of the fingernails from 32 persons. They were placed into three groups: group A consisted of 10 control subjects with normal nails. group B comprised eight patients with brittle nails studied before and after biotin treatment. and group C was 14 patients with brittle nails in whom the administration of biotin did not coincide exactly with the initial and terminal clipping of the nails. The thickness of the nails in group B increased significantly by 25%. In group C. the increase was 7%. Splitting of the nails were reduced in groups B and C and the irregular cellular arrangement of the dorsal surface of brittle nails became more regular in all nails of group B and in 8 of 11 nails of group C.
Scabies in nursing homes: an eradication program with permethrin 5% cream, Permethrin 5% cream was used to treat scabies in three large nursing homes under a compassionate-plea protocol for chronic. therapy-resistant infestations. All residents. staff. and frequent visitors were treated whether or not symptomatic. Family members of these groups were treated either when symptomatic or directly exposed to scabies. Nine hundred ninety-five persons were treated. 202 of whom were diagnosed with scabies. Approximately 35% (111 of 313) of nursing home residents were diagnosed with scabies. These were patients in whom multiple treatments with other scabicides were unsuccessful. At the completion of the study. 195 patients were examined for efficacy of treatment. Of these. 91 (46.7%) had clearing of lesions with one medication application. 77 (39.5%) with two treatments. and 23 (11.8%) with three or more treatments. The overall cure rate was 98%. Adverse experiences occurred in 2.4% of cases and were mild (i.e.. pruritus and rash).
Lymphocytic infiltrates of the skin in association with cyclosporine therapy, Three patients. one of whom has been previously reported. had erythematous papules and nodules of the face and upper part of the chest during cyclosporine therapy for inflammatory skin diseases. Histologic examination and DNA analysis (performed in two cases) revealed benign dermal lymphocytic infiltrates. In two cases proliferation of only T cells occurred. In the third case. both T and B cell populations were expanded and there was vacuolar degeneration of the basal layer of the epidermis and IgG. IgM. and C3 deposition along the dermoepidermal junction. These findings may be the result of cyclosporine-induced immune dysregulation. The lesions resolved in all patients after therapy was stopped.
Treatment of port-wine stains during childhood with the flashlamp-pumped pulsed dye laser, Seventy-three patients between the ages of 3 months to 14 years (average age 6 years 2 months) with port-wine stains were treated with the flashlamp-pumped pulsed dye laser. More than 75% lightening was achieved with an average of 2.5 treatments in 33 patients (45%). 50% to 74% lightening after an average of 1.7 treatments in 31 (42%). 26% to 49% lightening after 2 treatments in 5 (7%). and less than 25% lightening after 1 treatment in 4 (5%). The overall average lightening after one treatment was 53%. The percentage of lightening increased as the number of treatments increased. Three patients had 100% clearance of the port-wine stain. Patients aged between 3 months and 6 years (44 patients) had a better response after the first treatment (55% lightening) than did patients aged between 7 and 14 years (29 patients with a 48% lightening; p = 0.027). Complications included cutaneous depressions in four patients. hyperpigmentation in 16 patients. and hypopigmentation in three patients. All complications were transient and disappeared completely.
Monoclonal, but not polyclonal, antibodies protect against Plasmodium yoelii sporozoites, One of the primary strategies for malaria vaccine development has been to design subunit vaccines that induce protective levels of antibodies against the circumsporozoite (CS) protein of malaria sporozoites. In the Plasmodium yoelii mouse model system such vaccines have been uniformly unsuccessful in protecting against sporozoite-induced malaria. To demonstrate that antibodies to P. yoelii CS protein could provide protection we established a passive transfer model. Passive transfer of Navy yoelii sporozoite 1 (NYS1). an IgG3 mAb against the P. yoelii CS protein. protected 100% of mice against challenge with 5000 P. yoelii sporozoites. Binding of NYS1 to sporozoites was inhibited by incubation with (QGPGAP)2. a synthetic peptide derived from the repeat region of the P. yoelii CS protein. indicating that the epitope on sporozoites recognized by this mAb was included within this peptide. The levels of antibodies to (QGPGAP)2 by ELISA. and to sporozoites by indirect fluorescent antibody test and CS precipitation reaction were similar in sera from mice that received NYS1 in passive transfer and were protected against challenge with 5000 sporozoites. and from mice that had been immunized with subunit vaccines containing (QGPGAP)2 but were not protected against challenge with 40-200 sporozoites. To determine if antibody avidity. not absolute concentration could explain the striking differences in protection. we established a thiocyanate elution assay. The results suggest that NYS1. the protective mAb. has a lower avidity for (QGPGAP)2 and for sporozoites than do the vaccine-induced antibodies. Although the results of the conventional antibody assays did not correlate with protection. sera from the protected animals inhibited sporozoite development in mouse hepatocyte cultures significantly more than did the sera from the unprotected. subunit vaccine-immunized animals. correlating with protection. The data clearly demonstrate that antibodies to the CS protein can protect against intense sporozoite infection. Improved understanding of the differences between protective mAb and nonprotective polyclonal antibodies will be important in the further development of malaria vaccines.
Induction of DNA fragmentation in chronic B-lymphocytic leukemia cells, Chronic lymphocytic leukemia of B cell type (B-CLL) is a neoplastic disorder characterized by the accumulation of small resting lymphocytes in the periphery. The phenotype of these cells suggests that they are "frozen" at an early stage of maturation. Glucocorticoid hormones are commonly used to treat patients with B-CLL. resulting in a reduction in the peripheral lymphocyte count by an undefined mechanism. Here we report that glucocorticoids stimulate DNA fragmentation characteristic of a suicide process known as apoptosis or programmed cell death (PCD) in suspensions of cells from patients with B-CLL. The effects can be mimicked by Ca2+ ionophore and involve a sustained increase in the cytosolic Ca2+ concentration. Specific antibodies binding to membrane-associated IgM on the leukemic cells can also induce PCD by a similar mechanism. Phorbol esters block DNA fragmentation and cell killing in response to all of the agents. suggesting that activation of protein kinase C desensitizes the cells to PCD. Targeting the B-CLL cells with antibodies that induce an unbalanced. sustained Ca2+ increase may therefore represent a rational strategy for the destruction of leukemic cells.
Transforming growth factor-beta-induced inhibition of T cell function. Susceptibility difference in T cells of various phenotypes and functions and its relevance to immunosuppression in the tumor-bearing state, The present study investigates the nature of humoral component(s) generated in tumor-bearing hosts to induce immune dysfunction of T cells. Cell-free ascitic fluid and culture supernatant (SN) were obtained from the ascites and cultures allowing MH134 hepatoma cells to grow. These ascites and SN samples were tested for their abilities to influence the generation of CTL responses to TNP and alloantigens. The generation of the anti-TNP CTL responses that require self H-2-restricted CD4+ Th cells was markedly suppressed by addition of the ascites or SN under conditions in which these samples did not inhibit anti-allo CTL responses capable of using alternate pathways of allo-restricted CD4+ and CD8+ Th. The activation of CD8+ CTL precursors and CTL activity were also resistant to the ascites or SN. The ascites- or SN-induced suppressive effect to which CD4+ Th were most susceptible was found to be mediated by transforming growth factor-beta (TGF-beta) activity. because: 1) the TGF-beta activity was detected in the MH134 ascites and culture SN; 2) the suppression of CD4+ Th function required for anti-TNP CTL responses was almost completely prevented by addition of anti-TGF-beta antibody to cultures and; 3) rTGF-beta also induced similar patterns of immunosuppression to those observed by ascites or SN. These results indicate that TGF-beta produced by tumor cells induces deleterious effects on T cell. especially on the CD4+ Th subset. and provide an explanation for the molecular mechanism underlying the previously observed CD4+ Th-selective suppression in the tumor-bearing state.
Growth regulation of a human mature B cell line, B104, by anti-IgM and anti-IgD antibodies, An EBNA- human B lymphoma cell line. B104. was established. B104 cells express IgD as well as IgM on their surface. which is thought to be a basic characteristic of mature B cells. The growth of B104 cells was inhibited by treatment with a panel of anti-IgM antibodies. Cell cycle analyses revealed that the transition of B104 cells from the G2/M to the G0/G1 phase of the cell cycle was markedly inhibited by treatment with anti-IgM antibodies. Progression of B104 cells to the M phase of the cell cycle was found to be suppressed in the presence of anti-IgM antibodies. In contrast. both the entrance of G0/G1 phase cells into the S phase and the progression of S phase cells to the G2/M phase of the cell cycle did not seem to be inhibited significantly by treatment with anti-IgM antibodies. These results indicate that the mechanism of the inhibition of growth of B104 cells by anti-IgM antibodies is blockage of the transition from the G2 to the M phase of the cell cycle. In contrast to anti-IgM antibodies. anti-IgD antibodies could not cause growth inhibition of B104 cells at all. B cell growth factors such as IL-4 and IL-6 had no effect on the inhibition of growth of B104 cells by anti-IgM antibody. IFN-alpha and -beta. which have no B cell growth factor activity. did increase the number of cells that survived the treatment with anti-IgM antibodies. B104 is an excellent experimental model for the study of the mechanism of signal transduction through sIg as well as the functional difference between sIgM and sIgD.
Hyperphosphorylation of CD20 in hairy cells. Alteration by low molecular weight B cell growth factor and IFN-alpha, Hairy cell leukemia (HCL) is a B cell tumor affecting the pre-plasma stage of B cell differentiation. Hairy cells produce B cell growth factor (BCGF)-related growth factor(s) and we have previously shown that low mol wt (LMW)-BCGF-induced proliferation of hairy cells is inhibited in vitro and in vivo by IFN-alpha. We therefore suggested that this effect might contribute to the exquisite sensitivity of HCL to IFN-alpha therapy. To elucidate the mechanism involved in the therapeutic effect of IFN-alpha. we have analyzed the pattern of phosphorylated proteins in hairy cells. We detected the presence of a hyperphosphorylated protein with a molecular mass of about 35 kDa. This protein was identified as the CD20 molecule (B1). which is a structurally unique phosphoprotein exclusively detected on B cells and expressed during most stages of B cell development. Incubation of hairy cells with mitogenic concentrations of LMW-BCGF induces an additional increase in CD20 protein phosphorylation. In contrast. preincubation of cells with IFN-alpha. but not IFN-gamma. decreases both basal and LMW-BCGF-induced CD20 phosphorylation. CD20 phosphorylation in hairy cells is also reduced after in vivo IFN-alpha administration. In contrast. in one case of a patient unresponsive to IFN-alpha therapy. CD20 phosphorylation is not altered by in vitro IFN-alpha treatment. whereas LMW-BCGF still elicits CD20 phosphorylation stimulation. Our results suggest that IFN-alpha may act in HCL. at least in part. by inhibiting leukemic cell proliferation via regulation of phosphorylation. since CD20 phosphorylation is thought to be associated with cellular proliferation. A model involving dysregulation of CD20 is discussed.
Synergistic action of monoclonal antibodies directed at p55 and p75 chains of the human IL-2-receptor, TU27. a mouse IgG1 mAb directed at the p75 chain of the human IL-2R. was analyzed for its ability to interact with IL-2 binding on isolated p75 chains (YT-2C2 cells) and high affinity p55/p75 receptors (human alloreactive T cell clone 4AS). to inhibit IL-2-induced proliferation (4AS cells) and to cooperate with an anti-p55 chain mAb (33B3.1) for inhibiting IL-2 binding and proliferation. TU27 and IL-2 bound to the isolated p75 chain expressed by YT-2C2 cells with respective dissociation constants (Kd) of 1.3 and 1 nM. They cross-inhibited each other for binding with inhibition constants (Ki) in agreement with their respective Kd values. The nature of the interaction was. however. not purely competitive and suggested nonidentical epitopes for the two ligands on the p75 chain. On 4AS cells. IL-2 bound with high affinity (Kd = 50 pM) and TU27 with an affinity similar to that found on YT-2C2 cells. The binding of TU27 and IL-2 were also mutually exclusive on 4AS cells. However. the mechanism of interaction of TU27 with IL-2 was complex since the inhibitory potency of the antibody depended on temperature. antibody preincubation and time of assay. Data obtained at 4 degrees C in the presence of suboptimal. tracer-like concentrations of IL-2 indicated that the intrinsic affinity of TU27 for the high affinity configuration was 15-fold lower than for the isolated p75 chain and argued in favor of the affinity-conversion model (as opposed to the preformed complex model) in which p55 and p75 are dissociated in the absence of IL-2. At 37 degrees C. TU27 inhibited IL-2 binding only on short time assays (6 min). Longer time (30 min) of IL-2 binding resulted in an almost complete disappearance of the effect of TU27. suggesting that internalization of the high affinity p55/p75/IL2 complex enables the cells to escape from the inhibitory effect of TU27. In the presence of the 33B3.1 mAb. the interaction of TU27 with IL-2 resembled the one observed on YT-2C2 cells. suggesting that 33B3.1 is able to inhibit the IL-2-induced association of p55 and p75. Both antibody were found to synergize on 4AS cells. as a result of a cooperative mechanism in which 33B3.1 blocks the formation of the high affinity complex hence allowing TU27 to bind with higher affinity. and TU27 blocks IL-2 binding to the p75 chain. Proliferation studies corroborated the binding experiments.(ABSTRACT TRUNCATED AT 400 WORDS).
Expression of VHIII-associated cross-reactive idiotype on human B lymphocytes. Association with staphylococcal protein A binding and Staphylococcus aureus Cowan I stimulation, It has been demonstrated that staphylococcal protein A (SPA) has an "alternative" binding site with specificity for human Ig H chain V region of the VHIII subgroup. Because the major mitogenic component of Staphylococcus aureus Cowan I (SAC) is SPA. it is possible that SAC stimulates a subpopulation of B cells expressing Ig of the VHIII H chain subgroup. In the present study. we have investigated further the relationship between SPA binding and the expression of VHI- or VHIII-associated cross-reactive idiotype (CRI) on the surface of tonsillar B lymphocytes enriched for the expression or nonexpression of the CRI. and we examined the Ig secreted by cell lines established from these populations of B cells by EBV transformation. The VHIII CRI (D12)-enriched population yielded 21 cell lines. with 67% of them secreting SPA-reactive Ig; in contrast. only 6% (1 of 16) of VHI CRI-expressing lines secreted SPA-reactive Ig. The CRI-negative B cell population yielded 54 cell lines. of which 20% secreted SPA-reactive Ig. as might be anticipated because a majority of VHIII Ig+ B cells will be CRI-. SAC stimulation of CRI+ and CRI- populations showed preferential stimulation of the D12 population. These data support the proposal that SAC stimulation of human B cells is mediated through binding of SPA by its alternative binding site to IgV regions of the VHIII subgroup.
Paratope- and framework-related cross-reactive idiotopes on anti-acetylcholine receptor antibodies, Cross-reactive idiotopes are a possible target for therapeutical interventions in autoimmune diseases. To investigate their role in the pathogenesis of experimental autoimmune myasthenia gravis (EAMG) we analyzed the Id of rat anti-AChR mAb 6. 35. 61. 65 and a control myeloma protein IR27. Anti-Id 6. 35. 61. 65 bound in a direct binding assay with various affinity to all rat anti-AChR mAb that were tested. Anti-Id IR27 recognized none of the anti-AChR mAb. The specificity of these crossreactions was confirmed by inhibition studies with anti-AChR mAb and two control rat myeloma proteins (IR27 and IR241). In addition. the Id expression on mAb D6. a mouse anti-human AChR mAb was recognized by anti-Id 6. 35. and 65. Anti-Id. except anti-Id IR27. bound to affinity purified IgG from the sera of rats with EAMG. but not to preimmune Lewis IgG. These results suggest extensive sharing of idiotopes among anti-AChR mAb. which are also present in EAMG serum. Anti-AChR mAb against the main immunogenic region (6. 35. 65) from different rat strains. shared at least one paratope-related cross-reactive idiotopes. In the view of the fact that anti-main immunogenic region antibodies might form a predominant fraction of the polyclonal response against AChR. it is conceivable that an anti-Id recognizing these antibodies could have therapeutical applications as for example a selective immune absorbent or in immunotoxin therapy.
Epidemiologic patterns of wild-type hepatitis A virus determined by genetic variation, Hepatitis A virus (HAV) isolates from different parts of the world are a single serotype. However. genetic analysis of the VP1 genome region of published HAV sequences suggested that distinct genotypes of HAV could be defined based upon the geographic source of the original isolates. To circumvent the process of cell culture adaptation or animal passage. a 247-bp segment within the VP1 genome region of wild-type HAV was amplified by reverse transcription followed by polymerase chain reaction amplification in the presence of negative- and positive-sense primers. From the sequences obtained from 22 epidemiologically distinct HAV isolates. three genetic groups of HAV could be delineated. Two of the groups differed by 10%. while the third group differed from other isolates by approximately 20%. These investigations indicate that HAV isolates from different parts of the world can be differentiated genetically. which will facilitate studies of epidemiologic transmission.
Genome analysis of adenovirus type 31 strains from immunocompromised and immunocompetent patients, Adenovirus type 31 (Ad31) was isolated from 15 immunocompromised patients in 12 of whom seroconversion was also recorded. Ad31 infection has a substantial clinical relevance since 8 of 10 with lower respiratory tract infection and 4 of 4 with hepatitis died. Therefore. Ad31 isolates from immunocompetent and immunodeficient hosts were compared by restriction endonuclease analysis. Nine genome types were identified among the 79 Ad31 isolates. Pairwise comparison of comigrating restriction fragments indicated that the genome types could be divided into three genomic clusters. Several Ad31 genome types were isolated from immunocompromised patients. but no highly virulent genome type could be found. A genome type was identified in a child with severe combined immunodeficiency who originally was infected with another genome type. This observation is suggested to have evolutionary implications.
Comparison of heterotypic protection against influenza A/Taiwan/86 (H1N1) by attenuated and inactivated vaccines to A/Chile/83-like viruses, Children (n = 192) aged 3-19 years from 98 families completed this double-blind. placebo-controlled study comparing the efficacy of a bivalent attenuated (CR) vaccine with trivalent inactivated (TI) vaccine. Both vaccines contained A/Chile/83 (H1N1)-like antigens. After vaccination the geometric mean titer to A/Taiwan/86 (H1N1) was 1:36 in the CR group. 1:92 in the TI group. and 1:5 in the placebo group. During the influenza A/Taiwan/86 (H1N1) epidemic. 21.4% of CR recipients. 16.7% of TI recipients. and 43.9% of placebo recipients were infected with influenza A/Taiwan. TI vaccine provided better heterotypic protection than did CR vaccine for children aged 10-18 years (infection rate. 0 vs. 24%. respectively; P less than .025); in contrast. in the younger children (3-9 years). CR vaccine tended to be more protective (19% vs. 26% for TI).
Comparison of functional activities between IgG1 and IgM class-switched human monoclonal antibodies reactive with group B streptococci or Escherichia coli K1, The influence of valence and heavy chain on antibody activity was investigated using transfectoma-derived. class-switched IgG1 and IgM human monoclonal antibodies (MAbs) reactive with the bacterial pathogens Escherichia coli K1 and group B Streptococcus species. IgG-IgM pairs were compared in vitro for antigen binding and opsonic activities and in vivo for protective efficacy in neonatal rats. For the anti-E. coli pair. the IgM MAb was 1000-fold more potent in all assay formats. Importantly. the 50% protection dose (PD50) of the IgM MAb was 10-20 ng/rat. while 100 micrograms of the IgG MAb was only minimally protective. For the group B streptococcal MAbs. the IgM was 100- and 4500-fold more potent in binding and opsonization assays. respectively. However. while 20 micrograms of IgM protected neonatal rats. 100 micrograms of IgG MAb was partly protective. These experiments demonstrate the utility of recombinant DNA technology for creating a panel of antibodies that may aid in selecting potential immunotherapeutic candidates.
Macrophage- and oxidant-mediated inhibition of the ability of live Blastomyces dermatitidis conidia to transform to the pathogenic yeast phase: implications for the pathogenesis of dimorphic fungal infections, Conidia. produced by the mycelial phase of dimorphic fungi. are thought to represent the infectious form of the organism but must complete a transition to the tissue-invasive. yeast-like phase for infection to ensue. Preventing such transition should effectively eliminate pathogenicity. Using Blastomyces dermatitidis as a target. murine bronchoalveolar macrophages preferentially blocked phase transition after 4 h of incubation with conidia. relatively sparing the ability of conidia to produce hyphae. H2O2. in relatively high concentrations. demonstrated the same activity. The effects of H2O2 seem irreversible. since H2O2-treated conidia that germinated at 48 h at 25 degrees C were still unable to produce yeasts over the next 5 days when incubated at 37 degrees C. Catalase could not reverse the macrophage-induced inhibition of phase transition. suggesting that nonoxidative defense mechanisms may be operative in vivo. Since conidia do not form mycelia at temperatures found in mammalian hosts. these effects may represent a novel host defense mechanism against dimorphic fungal pathogens.
A comparison of 6-, 12-, and 24-monthly dosing with ivermectin for treatment of onchocerciasis, This study was designed to examine the optimal dose and interval of administration of ivermectin. the now-accepted drug of choice for onchocerciasis. Two hundred Liberians with Onchocerca volvulus infection received 100. 150. or 200 micrograms/kg ivermectin or placebo and were followed for 36 months. The reaction after the second dose of ivermectin was significantly less than after the initial dose. although it was still significant in the 200-micrograms/kg group. The skin microfilaria counts in the group treated 6-monthly with 150 micrograms/kg was significantly less than in the group treated yearly (12 and 24 months after initial therapy). Prevalence of microfilariae in the anterior chamber and punctate corneal opacities decreased progressively in all groups over 3 years. There appears to be a slight advantage. in terms of antiparasitic effect over the first 2 years. of therapy given 6-monthly compared with yearly.
Community-based treatment of onchocerciasis with ivermectin: safety, efficacy, and acceptability of yearly treatment, The safety. acceptability. and efficacy of ivermectin during community-based mass treatment of onchocerciasis was assessed. Ivermectin was distributed three times. 1 year apart. to the population of a rubber plantation (14.000 people) in Liberia where greater than 80% of adults have Onchocerca volvulus infection. In a sample of adults. the microfilarial density was reduced by 84% after 2 years of treatment. Acceptance was as high as 98% during the third year. Adverse reactions occurred in 6-13 in 1000 people after first treatment and in only 3-4 in 1000 receiving their second or third annual dose of ivermectin; severe adverse reactions were not seen. These data show that community-based treatment with ivermectin is safe. well accepted. and effective in reducing microfilarial loads and suggest that ivermectin is the first practical drug suitable for mass treatment campaigns to control human onchocerciasis.
Antiidiotypic responses to immunization with anti-Leu 3a in human immunodeficiency virus-seropositive individuals, Anti-idiotypic antibodies to anti-CD4 monoclonal antibodies (MAbs) have been reported to bind to the human immunodeficiency virus (HIV) envelope glycoprotein gp120. To establish whether HIV-infected patients can mount an anti-idiotypic response to murine MAb. four individuals with symptoms of AIDS-related complex (ARC) were immunized over 10 weeks with six intramuscular injections of anti-Leu 3a (1 mg). Despite their immunocompromised state. all patients made anti-constant region and anti-idiotypic antibodies. although the amplitude of the responses varied between individuals. No significant toxic or allergic reactions were seen. and there were no changes in clinical status during the 6 months after immunization. No increase in serum HIV-neutralization titers was seen. and purified anti-idiotypic antibodies did not bind gp120.
Detection of hepatitis B virus DNA by polymerase chain reaction in plasma of volunteer blood donors negative for hepatitis B surface antigen, Plasma samples from 206 volunteer blood donors were tested for hepatitis B virus (HBV) DNA by dot blot hybridization and polymerase chain reaction (PCR). All donors were negative for hepatitis B surface antigen (HBsAg) and had normal serum alanine aminotransferase levels. None of the 206 plasma samples was positive for HBV DNA by dot blot hybridization assay. However. nine samples were positive for HBV DNA by PCR using two primer pairs specific for surface and core regions. Nine persons received the HBV-DNA-positive plasma. and one developed posttransfusion non-A. non-B hepatitis; the others remained well 6 months later. Therefore. approximately 4% of blood donors in Taiwan have low titers of HBV DNA. and a more sensitive method to screen donors may be needed in the future. although the current serologic test remains the most practical at present.
Three new serovars of Chlamydia trachomatis: Da, Ia, and L2a, Three new Chlamydia trachomatis serovars were identified by several monoclonal antibodies in the microimmunofluorescence test and are proposed to be called Da. Ia. and L2a. Each was clearly distinguishable from the related serovars D. I. and L2. To date. 7. 41. and 4 isolates of the respective serovars have been identified. Each appears to be distributed worldwide. The findings meet previously established criteria for establishment of new serovars.
Molecular epidemiologic techniques in analysis of epidemic and endemic Shigella dysenteriae type 1 strains, During 1988 the number of Shigella dysenteriae type 1 infections reported in the United States increased fivefold. To determine if recent isolates from Mexico were related to those that caused epidemics of dysentery worldwide. Southern hybridization analysis was done with Shiga toxin and ribosomal RNA gene probes. Western hemisphere and Eastern Hemisphere strains differed by the size of a single EcoRI fragment carrying the Shiga toxin genes. Three ribosomal DNA (rDNA) patterns were observed. which correlated with the strain's continental origin for 81 of 83 isolates tested. Together the Shiga toxin and rDNA probe results indicated that recent Mexican isolates were chromosomally similar to earlier Central American isolates and distinct from Asian and African strains. This suggests there has been no significant exchange of organisms between continents in recent decades and that the 1988 outbreak in Mexico was caused by strains present in Central America since at least 1962.
Combined use of released proteins and lipopolysaccharide in enzyme-linked immunosorbent assay for serologic screening of Yersinia infections, An ELISA for the screening of serum antibodies to Yersinia species was developed using plasmid-encoded released proteins of Yersinia enterocolitica O:8 and lipopolysaccharide of Y. enterocolitica O:3 as a combined antigen. Of 43 sera from patients infected with one of six different Yersinia serotypes. 40 (93%) were positive in this assay. When tested using six serotype-specific ELISAs with the corresponding Yersinia bacteria as antigens. 38 (88%) were positive. This screening ELISA detects antibodies to all virulent yersiniae in one assay and offers the possibility for diagnosis of infections caused by Yersinia serotypes seen only occasionally and not usually included in the serotype-specific ELISAs. Thus. this ELISA offers a substantial advantage by saving time and money in routine laboratory work.
Transfection and stable transformation of adult mouse Schwann cells with SV-40 large T antigen gene, Cultured Schwann cells derived from adult mouse dorsal root ganglia and peripheral nerves were transfected with a plasmid containing SV-40 large T antigen gene. and 25 colonies of stable transformants were obtained. one of which was expanded and recloned. This transfected cell line. designated MS1. expressed SV-40 large T antigen and showed continuous cell growth with a doubling time of 27 hours. The MS1 cells had distinct Schwann cell phenotypes such as S-100 protein. laminin. 2'.3'-cyclic nucleotide 3'-phosphodiesterase and P0 protein. as shown by immunofluorescence microscopy. When MS1 cells were exposed to dibutyryl cyclic adenosine-3'.5'-monophosphate (dbc AMP). they extended long bipolar processes two- to ten-fold longer than those of untreated MS1 cells and frequently formed whorl-like alignments similar to palisade formations or organoid patterns observed in human Schwannomas and neurofibromas. These results suggest that transformed Schwann cells can be a useful model for analyzing regulatory mechanisms of Schwann cells. neuron-Schwann cell interactions and experimental Schwann cell neoplasms in vitro.
Acute experimental allergic encephalomyelitis in SJL/J mice induced by a synthetic peptide of myelin proteolipid protein, Clinical. histologic. and ultrastructural characteristics of acute experimental allergic encephalomyelitis (EAE) induced by sensitization with a synthetic peptide corresponding to mouse myelin proteolipid protein (PLP) residues 139-151 HCLGKWLGHPDKF were studied in SJL/J mice. Groups of mice were immunized with 20. 50. or 100 nmol of the peptide and were killed from seven to 28 days after sensitization or when they were moribund. Beginning on Day 9. the mice showed signs of EAE and the disease progressed rapidly to paralysis. Central nervous system (CNS) inflammation. edema. gliosis. and demyelination were found in all mice killed between Days 10 and 28 and white matter lesion areas correlated with clinical score at the time the mice were killed. Peripheral nerve roots and the cauda equina did not have lesions. Within the range studied. the severity of clinical or histologic disease was the same regardless of the PLP peptide dose. Two of ten mice immunized with 100 nmol and none of 14 mice given smaller doses of a synthetic peptide of mouse myelin basic protein (MBP) showed clinical EAE. These mice had small numbers of CNS lesions that were indistinguishable from those in PLP peptide-sensitized mice. These findings demonstrate that immunization of SJL/J mice with PLP peptide 139-151 produces a disease with the clinical and morphologic features of CNS tissue-. whole PLP-. whole MBP-. and MBP peptide-induced acute EAE. Thus. PLP is a major encephalitogen and immune reactions to epitopes of different myelin proteins may induce identical patterns of injury in the CNS.
Encephalitogenicity for rats of myelin basic protein without the aid of water-in-oil emulsions, The induction of experimental allergic encephalomyelitis (EAE) with purified myelin basic protein (MBP) has. heretofore. required its incorporation in a water-in-oil emulsion or adsorption on particulate adjuvants. In the present work. the absorption of a saline solution of MBP from the peritoneal cavity into the mediastinal lymph nodes was increased by giving repeated inoculations or by pretreating rats with a peritoneal irritant. Under these conditions. the only adjuvant needed for production of EAE was aqueous pertussis vaccine which was injected separately a few hours or one day after the MBP. Pertussis vaccine was also necessary for production of EAE with intradermal injection of aqueous MBP. By injecting the aqueous MBP directly into pre-enlarged popliteal lymph nodes. it was possible to produce EAE without the pertussis vaccine. Thus. EAE can be induced in rats using MBP without the addition of Freund's adjuvant or pertussis vaccine.
Skin and epidural recording of spinal somatosensory evoked potentials following median nerve stimulation: correlation between the absence of spinal N13 and impaired pain sense, A clinical lesion study and intraoperative epidural recordings were made to test the origin and clinical significance of the spinal N13 and P13 of somatosensory evoked potentials (SEP) that follow median nerve stimulation. Intraoperatively. the respective peak latencies of spinal P13 and N13 coincided with those of the N1 component of the dorsal cord potential and its phase reversed positivity. On both the ventral and dorsal sides of the cervical epidural space. maximal amplitude was at the C5 vertebral level to which nerve input from the C6 dermatome is the main contributor. The modality of sensory impairment in the hand dermatome was examined in selected patients with cervical lesions. who showed such normal conventional SEP components as Erb N9. far-field P9. P11. P14. N18 and cortical N20. with or without loss of spinal N13. Statistically. the loss of spinal N13 was associated with decrease of pain sensation in the C6 dermatome. This was interpreted as being due to damage to the central grey matter of the cord. including the dorsal horn. Our results suggest the spinal N13 and P13 originate from the same source in the C6 spinal cord segment and that they are good indicators for the detection of centromedullary cervical cord damage.
The development of infratentorial atrophy in patients with idiopathic cerebellar ataxia of late onset: a CT study, The development of infratentorial atrophy in six patients suffering from idiopathic cerebellar ataxia of late onset was studied by a retrospective evaluation of consecutive computed tomography (CT) scans. Four patients had evidence of olivopontocerebellar atrophy (OPCA) both on clinical testing and magnetic resonance imaging (MRI). In these four patients. atrophy of the cerebellum and brain stem became visible at the same time and progressed in a roughly parallel manner. whereas in the remaining two the brain stem was left intact. In all patients with OPCA. definite brain-stem atrophy was visible earlier than the appearance of non-cerebellar clinical symptoms. The present data suggest that CT investigations at regular intervals may be of prognostic value in cerebellar ataxias.
Sarcoidosis of the cauda equina: a report of three cases, Three cases of sarcoidosis of the cauda equina are presented. In two there was no previous history suggestive of sarcoidosis and the presentation was one of a painful flaccid paralysis; in these the diagnosis was made after myelography and laminectomy with subsequent histology. The third patient had a previous diagnosis of lupus pernio and magnetic resonance imaging (MRI) was used to aid diagnosis. Only two previous cases have been reported of sarcoidosis presenting in the cauda equina with no other systemic manifestations. This is the first report of the use of MRI in sarcoidosis of the lower meninges.
Reliability of the clinical and electromyographic examination of tendon reflexes, The reliability of clinical examination of the tendon reflexes was examined by studying inter-observer agreement. Twenty patients were examined by three neurologists. The briskness of the tendon reflexes in arms and legs was scored on a nine-point scale. In 28% of the 160 examined reflexes the observations disagreed 2 scale units or more. Disagreement on the presence of asymmetry occurred in 45% of the 80 reflex pairs. In 15% one observer judged a reflex pair to be symmetrical while another observer found asymmetry of at least 2 scale units. In a second experiment clinical observation of apparently asymmetrical quadriceps reflexes was compared with measurement by surface electromyography. A significant. semi-logarithmic relationship was found between clinical scores and measured reflex amplitudes. Measured reflex asymmetry always agreed with clinical asymmetry. and the magnitudes of right-left amplitude differences were correlated with the magnitude of clinically observed asymmetry. The bedside examination of tendon reflexes is subject to considerable inter-observer disagreement.
Impairment of vertical motion detection and downgaze palsy due to rostral midbrain infarction, We present two cases with acute onset of vertical gaze palsy. mainly consisting of impaired downgaze and apraxia of downward head movements. together with neuropsychological deficits (hypersomnia. impaired attention and disorders of memory and affective control). CT and MRI revealed bilateral post-ischaemic lesions in the dorsomedial thalamus and the mesodiencephalic junction. dorsomedial to the red nucleus. thus being restricted to the territory of the posterior thalamosubthalamic paramedian artery. which includes the region of the rostral interstitial nucleus of the medial longitudinal fascicle as the main premotor nucleus for the generation of vertical saccades. In our patients. oculographic examination with electro-oculography and magnetic search coil recording showed severe impairment of downward more than upward saccades and only minor deficits of vertical pursuit and the vestibulo-ocular reflex. Visual functions were normal. with one exception: a psychophysical test of motion perception revealed a significant deficit in the detection of vertical movements. This could be due to a central adaptive mechanism which. in order to minimize oscillopsia. might elevate thresholds for vertical motion perception in cases of vertical gaze palsy. As an alternative explanation. lesions within the midbrain tegmentum could have damaged subcortical visual pathways involved in motion perception.
HLA and multiple sclerosis in Italy: a review of the literature, HLA antigens of locus A. C. B. DR and DQ were typed in 104 Italian multiple sclerosis patients and in 905 healthy controls; the results have been compared with those published in the Italian literature. The Italian studies have been reviewed regarding the ethnic origin of the typed population and the corresponding prevalence of the disease. The data suggest a lack of association between A3 and B7 antigens and Italian multiple sclerosis and a relevance of other DR locus antigens (mainly DR4 and DR5). in addition to DR2. in the susceptibility to the disease.
Wernicke's encephalopathy in two patients with acquired immunodeficiency syndrome, Two non-alcoholic homosexual patients with acquired immunodeficiency syndrome (AIDS) are reported who developed acute Wernicke's encephalopathy in the terminal stage of their illness. The first patient presented with vascular congestion. minute haemorrhages. proliferation of microglia and of the vessel walls at the predilection sites of the Wernicke-Korsakoff process. In the second patient only the mamillary bodies were involved. Besides Wernicke's encephalopathy. a primary cerebral immunoblastoma and cerebral toxoplasmosis were found in the first patient. whereas the second showed severe encephalitis with numerous microglial and multinucleated giant cells reacting positively with anti-HIV antibody. Just as in the development of Wernicke's encephalopathy in malignant diseases. the catabolic trend of the metabolism of the immunodeficient patients with consecutive thiamine deficiency must be considered the principal pathogenetic mechanism.
Intraperitoneal cisplatin and cytarabine in the treatment of refractory or recurrent ovarian carcinoma, Preclinical evaluation has suggested impressive concentration-dependent cytotoxic synergy between cisplatin and cytarabine in ovarian carcinoma. To further evaluate the clinical relevance of these observations. 39 patients with refractory or recurrent ovarian carcinoma were entered onto a phase II trial of intraperitoneal (IP) cisplatin (100 to 105 mg/m2 per course) plus cytarabine (600 to 900 mg per course). Treatment was administered over 2 or 3 days for a maximum of five monthly courses. followed by surgical reevaluation in patients without clinical evidence of disease. The 3-day regimen was discontinued secondary to the development of severe thrombocytopenia (five of 12 courses platelets decreased to less than 50.000/mm3). Additional toxicities included abdominal pain (moderate to severe at some time during therapy in 46% of patients). fever without evidence of infection (44%). and bacterial peritonitis (10%). Three patients declined surgical reassessment. Fourteen of 36 (39%; 95% confidence interval [CI]. 23% to 55%) assessable patients demonstrated surgically defined responses. including 12 of 23 (52%; 95% CI. 32% to 72%) patients with tumor nodules less than 1 cm in diameter and only two of 13 (15%; 95% CI. 0% to 34%) patients with any lesion greater than 1 cm. There were seven (30%; 95% CI. 11% to 49%) surgically defined complete responses (CRs) in patients with less than 1 cm disease and none in patients with larger tumor nodules. IP cisplatin/cytarabine results in a high surgically defined response rate in patients with minimal residual ovarian carcinoma. but activity is low in patients with bulky intraabdominal disease.
Prognostic factors in aggressive malignant lymphomas: description and validation of a prognostic index that could identify patients requiring a more intensive therapy. The Groupe d'Etudes des Lymphomes Agressifs, The objectives of this study were to determine prognostic factors for response to treatment. freedom-from-relapse (FFR) survival. and overall survival of 737 aggressive malignant lymphoma patients treated with the doxorubicin. cyclophosphamide. vindesine. bleomycin. methylprednisolone. methotrexate with leucovorin. ifosfamide. etoposide. asparaginase. and cytarabine (LNH-84) regimen; to construct a prognostic index with factors isolated by multivariate analyses; and to validate this prognostic index with another set of patients. Complete response (CR) was reached in 75% of LNH-84 patients. and 30% of them relapsed. With a median follow-up of 36 months. median FFR survival and median overall survival were not reached. Low serum albumin level. high tumoral mass. weight loss. bone marrow involvement. greater than or equal to 2 extranodal sites. and increased lactic dehydrogenase (LDH) level were associated with a low response rate. Advanced stage. increased LDH level. and nonlarge-cell histologic subtypes (diffuse mixed. lymphoblastic. and small non-cleaved) were statistically associated with a high relapse rate and short FFR survival. Increased LDH level. low serum albumin level. tumoral mass larger than 10 cm. greater than or equal to 2 extranodal sites. advanced stage. and age older than 65 years were statistically associated with short overall survival. Four of these parameters. namely. LDH level. stage. number of extranodal sites. and tumoral mass. were put together to construct a prognostic index. This index partitioned LNH-84 patients into three subgroups of good. intermediate. and poor prognosis (P less than .00001): CR rates of 93%. 83%. and 61%; relapse rates of 12%. 25%. and 45%; 3-year FFR survival of 87%. 73%. and 53%. and 3-year survival of 88%. 71%. and 41%. respectively. This prognostic index was applied to a test set of patients: 155 patients treated on protocols of the Nebraska Lymphoma Study Group. Using this index. these patients had 3-year FFR survival of 70%. 40%. and 22% (P = .0002) and 3-year survival of 79%. 52%. and 31% (P = .005). In patients with aggressive lymphomas. this simple prognostic index could distinguish between patients requiring intensive treatment such as autologous bone marrow transplantation in first complete remission and those who could be treated with standard regimens.
Treatment of advanced-stage massive mediastinal Hodgkin's disease: the case for combined modality treatment, In the initial series of 198 patients treated at the National Cancer Institute (NCI) with mechlorethamine. vincristine. procarbazine. and prednisone (MOPP) chemotherapy for Hodgkin's disease. a review of presenting chest radiographs available on 192 of these patients showed 49 patients with mediastinal masses greater than one third the greatest posteroanterior chest diameter. Five patients had stage IIB disease. and 44 had stage III or IV disease. Thirty-five (71%) patients achieved a complete remission with MOPP chemotherapy. Fourteen (40%) of the complete responders relapsed. but four of these achieved durable remissions in response to subsequent therapy. Thirty (61%) patients have died (14 induction failures. nine relapsed patients. seven complete responders in remission). Thus. with a median follow-up of 20 years (range. 15 to 23). the overall survival for the group is 39%. and the disease-free survival for the complete responders is 60%. A subset of 10 patients received mantle radiation therapy after maximal response to MOPP. One of these patients failed to achieve complete remission. but among the nine complete responders only one has relapsed. In contrast. 13 of 26 (50%) patients achieving a complete response to MOPP alone have relapsed (P2 = .0536). Although MOPP alone was not prospectively compared with MOPP plus radiation therapy in the treatment of advanced-stage massive mediastinal Hodgkin's disease in this series. the retrospective analysis shows a nearly significant difference in disease-free survival favoring combined modality treatment. The difference in tumor mortality between MOPP-treated (44%) and combined modality-treated patients (80%) was also nearly significant (P2 = .055). However. overall survival differences between patients treated with MOPP alone and those treated with combined modality therapy were not significantly different (P2 = 0.23) because of the mortality related to late complications of combined modality treatment.
Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer, A weekly. intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2. alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8. for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%. and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD. 58 weeks; ED. 42 weeks). Hematologic toxicity was predictable. without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all. one quarter of treatment courses were delayed. most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.
Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial, Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Pleurodesis with tetracycline or other sclerosing agents is the usual treatment for malignant pleural effusions. In contrast to this approach. intrapleural chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the effusion. Intracavitary cisplatin-based chemotherapy. which is cytotoxic rather than sclerosing. has proven safe and effective via the intraperitoneal route in ovarian cancer and malignant mesothelioma. There has been little previous experience. however. with intrapleural cisplatin-based chemotherapy. As part of a planned series of trials in malignant mesothelioma. the Lung Cancer Study Group first evaluated intrapleural cisplatin and cytarabine in patients with malignant pleural effusions from a variety of solid tumors. From April 1986 to November 1987. 46 patients with cytologically proven. symptomatic. and previously untreated malignant pleural effusions were entered on study. A single dose of cisplatin 100 mg/m2 plus cytarabine 1.200 mg was instilled into the pleural space via a chest tube. which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1. 2. and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity. four patients had grade 3 hematologic toxicity. and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma.
Sex or survival: trade-offs between quality and quantity of life, Patients with localized prostate cancer may be treated with either surgery (radical prostatectomy) or radiotherapy. Although controversial. many physicians believe that surgery offers a higher survival rate. However. the surgical treatment may also produce a higher rate of sexual impotency. Our study assessed how men value survival and sexual potency when asked to trade off one for the other. Using the treatment-choice technique. we interviewed 50 men aged 45 to 70 years without known prostate cancer. At hypothetical rates of survival (90% at 5 years for surgery) and impotency (90% for surgery and 40% for radiotherapy) representing published estimates. 32% of respondents were unwilling to trade off any survival. but 68% were willing to trade off a 10% or greater advantage in 5-year survival (by choosing radiotherapy) to maintain sexual potency. The median 5-year survival traded off was 10% (range. 0% to 80%). Willingness to trade off survival for sexual potency was significantly related to level of education. but not to age. interest in sex. frequency of sexual intercourse. or ability to achieve erection. We conclude that some men may choose treatment with lower long-term survival to increase their chance of remaining sexually potent. Because these men may be difficult to identify in clinical practice. physicians should thoroughly discuss both surgery and radiotherapy options with patients who have localized prostate cancer.
The role of dose intensity in determining outcome in intermediate-grade non-Hodgkin's lymphoma, To determine whether the dose intensity of chemotherapeutic regimens correlates with the complete remission rate in adult patients with advanced-stage intermediate-grade lymphoma. reports of comparative trials of therapy were reviewed. Reports were identified using MEDLINE. through references from review articles. and through review of selected abstracts. Twenty-two studies including 14 randomized and eight cohort trials were analyzed to assess projected dose intensity. Four other studies were analyzed to assess the role of received dose intensity. Dose intensities were calculated using described methods and correlated with complete remission rates. Individual trials were assessed using "levels of evidence." A metaanalysis of randomized trials and a cross-trial analysis of all comparative trials using a weighted least squares linear regression were performed. Using levels of evidence. support was obtained for the hypothesis that dose intensity correlates with the remission rate from two trials in which dose intensity was "indirectly" tested. As these studies did not "directly" test dose intensity. confounding variables. including those arising from the assumptions made in calculating dose intensity. cannot be excluded. Metaanalysis showed a relative probability of achieving complete remission of 1.34 (95% confidence interval. 1.13 to 1.58) favoring the pooled arm of high dose intensity. Cross-trial analysis showed a relatively weak association between dose intensity and remission rate (r = .49. P = .0001). Two of four reports retrospectively assessing received dose intensity suggested that increased dose intensity is associated with superior remission rates. These analyses suggest that dose intensity may correlate with the remission rate in advanced-stage intermediate-grade lymphoma. However. properly designed trials directly testing dose intensity have not been performed and are needed to confirm this hypothesis.
When is a prognostic factor useful? A guide for the perplexed, Traditionally. a number of variables have been used to predict outcome in patients with early-stage breast cancer. These tests are simple to perform and relatively inexpensive. Recently. a number of new factors. eg. tumor proliferative index. nuclear DNA content. and amplification or overexpression of growth-promoting genes or oncogenes have been identified as potential predictors of outcome in patients with breast cancer. There is now increasing pressure to introduce such tests into routine clinical practice. How does a clinical practitioner identify which test. or group of tests. best predicts adverse outcome and whether any more clinically useful information is provided than with the use of more traditional factors alone? The aim of a prognostic test in breast cancer is to predict which patients are destined to develop a recurrence of cancer and those who are not. The prognostic usefulness of a test can be expressed in terms of relative risk (RR). which is the ratio of the risk of breast cancer recurrence in patients who test positive to the risk in those who test negative. Methodologic guidelines that should be satisfied by a study evaluating the predictive ability of a test include the following: (1) Was an inception cohort assembled? (2) Was the referral pattern described? (3) Were laboratory and clinical outcomes assessed in a blinded fashion? (4) Was complete follow-up achieved? (5) Was adjustment for extraneous prognostic factors carried out? (6) Were appropriate statistical methods used? An approach is suggested to help the clinician choose the test. or combination of tests. likely to discriminate between "high-" and "low-risk" patients in his/her own practice. The decision regarding what particular threshold value (risk) defined by a prognostic test (or series of tests) warrants adjuvant therapy for an individual patient is a complex one but should be based on a clear presentation of the risks and benefits to the patient.
Cerebral palsy and rhizotomy. A 3-year follow-up evaluation with gait analysis, A recent increase in the popularity of selective rhizotomy for reduction of spasticity in cerebral palsy has led to a demand for more objective studies of outcome and long-term follow-up results. The authors present the results of gait analysis on 14 children with spastic cerebral palsy. who underwent selective posterior rhizotomy in 1985. Sagittal plane gait patterns were studied before surgery and at 1 and 3 years after surgery using a digital camera system. The parameters measured included the range of motion at the knee and thigh. stride length. speed of walking. and cadence. The range of motion at the knee was significantly increased at 1 year after surgery and further improved to a nearly normal range at 3 years after surgery. In contrast. postoperative measurements of thigh range exceeded normal values at 1 year. but decreased toward normal range at 3 years. While improvements in range of motion continued between Years 1 and 3. the children developed a more extended thigh and knee position. which indicated a more upright walking posture. Stride length and speed of walking also improved. while cadence remained essentially unchanged. This 3-year follow-up study. the first to examine rhizotomy using an objective approach. has provided some encouraging results regarding early functional outcome.
A variant of arteriovenous fistulas within the wall of dural sinuses. Results of combined surgical and endovascular therapy, Dural arteriovenous (AV) fistulas are thought to be acquired lesions that form in an area of thrombosis within a sinus. If the sinus remains completely thrombosed. venous drainage from these lesions occurs through cortical veins. or. if the sinus is open. venous drainage is usually into the involved sinus. Among 105 patients with dural AV fistulas evaluated over the the past 5 years. seven had a unique type of dural AV fistula in the superior sagittal. transverse. or straight sinus in which only cortical venous drainage occurred despite a patent involved sinus; the fistula was located within the wall of a patent dural sinus. but outflow was not into the involved sinus. This variant of dural AV fistulas puts the patient at serious risk for hemorrhage or neurological dysfunction caused by venous hypertension. Three patients presented with hemorrhage. one with progressive neurological dysfunction. one with seizures. and two with bruit and headaches. A combination of surgical and endovascular techniques was used to close the fistula while preserving flow through the sinus.
Management of hemorrhagic complications from preoperative embolization of arteriovenous malformations, Endovascular embolization procedures have undergone dramatic evolution and improvement in recent years. Despite these advances. controversy remains regarding the optimal role of these procedures in treating cerebral arteriovenous malformations (AVM's) and whether their purpose should be as a presurgical adjunct or as primary therapy. This controversy risks fragmentation between disciplines in the broader efforts to improve management of cerebrovascular disorders. The authors report seven cases of life-threatening hemorrhages that occurred during staged invasive therapy for AVM's which illustrate the value of a unified team approach to optimize patient care. Each patient underwent at least one embolization procedure using polyvinyl alcohol particles. followed in two cases by the occlusion of proximal feeding vessels by platinum microcoils and in one case by the attempted detachment of an endovascular balloon. In three patients. catheter penetration into the subarachnoid space resulted in subarachnoid hemorrhage. One patient suffered rupture of a large feeding vessel during balloon inflation. The final three patients sustained intracranial hemorrhage 2 hours. 8 hours. and 5 days. respectively. following embolization. All but two patients underwent emergency craniotomy at the time of the complication. These cases underscore the advantages of interdisciplinary management optimizing decision-making and providing expeditious care when life-threatening complications develop.
Dorsal root ganglionectomy for failed back surgery syndrome: a 5-year follow-up study, Dorsal root ganglionectomy has been suggested as a method for the treatment of chronic intractable radicular pain. with theoretical advantages over dorsal rhizotomy. which does not interrupt ventral root afferents. The indications for these procedures in patients with persistent pain following lumbosacral spine surgery are not well established. Long-term results have been reported infrequently. and no published series has a mean follow-up period of more than 30 months. The authors have reviewed their experience with a series of 13 patients with failed back surgery syndrome. in whom dorsal root ganglionectomy was performed. Patients were selected on the basis of clinical presentation and diagnostic root blocks suggesting a monoradicular pain syndrome. Follow-up data were obtained at a mean of 5.5 years following dorsal root ganglionectomy. Follow-up interviews to assess outcome were conducted by a disinterested third party. Treatment "success" (at least 50% sustained relief of pain and patient satisfaction with the result) was recorded in two patients at 2 years after surgery and in none at 5.5 years. Equivocal success (at least 50% relief. without clearcut patient satisfaction) was recorded in one patient at 2 and at 5.5 years postoperatively. Improvements in activities of daily living were recorded in a minority of patients. Loss of sensory and motor function was reported frequently by patients. A minority of patients had reduced or eliminated analgesic intake. These results suggest that dorsal root ganglionectomy has a limited role in the management of failed back surgery syndrome. and that methods to select patients to receive this procedure should be refined or alternative approaches should be considered.
Intraoperative monitoring of the facial nerve during decompressive surgery for hemifacial spasm, In 11 consecutive patients. intraoperative electromyographic (EMG) recordings were made from the facial muscles during microvascular decompression for hemifacial spasm. In one patient. recordings could not be obtained for technical reasons. and two patients had no abnormality. In the remaining eight patients. the abnormal response resolved before decompression in two. resolved immediately at the time of decompression in five. and failed to resolve in one. All patients were relieved of their hemifacial spasm. In the five patients whose abnormalities resolved at the time of decompression. there was a precise intraoperative correlation between decompression of the nerve and disappearance of the abnormal EMG response. In three cases. this was a useful guide to the need to decompress more than one vessel. These results confirm the findings of Moller and Jannetta. support the use of this technique for intraoperative monitoring of facial nerve decompression procedures. and provide strong circumstantial evidence that vascular cross-compression is an important etiological factor in hemifacial spasm.
The effects of etomidate on cerebral metabolism and blood flow in a canine model for hypoperfusion, The effects of etomidate. a nonbarbiturate cerebral metabolic depressant. on cerebral metabolism and blood flow were studied in 29 dogs during cerebral hypoperfusion. Three groups of animals were studied during a 45-minute normotensive and a 30-minute hypotensive period: 10 control animals without etomidate. 11 animals receiving a 0.1-mg/kg etomidate bolus followed by an infusion of 0.05 mg/kg/min etomidate (low-dose group). and eight animals receiving doses of etomidate sufficient to suppress electroencephalographic bursts (high-dose group). The mean arterial pressure fell to similar levels (p less than 0.05) during hypotension in all three groups (40 +/- 5. 38 +/- 3. and 27 +/- 6 mm Hg. respectively). The mean cerebral oxygen extraction fraction rose (p less than 0.05) from 0.23 +/- 0.02 to 0.55 +/- 0.08 in the five control animals tested and from 0.33 +/- 0.02 to 0.53 +/- 0.02 in the seven animals tested in the low-dose group. but did not increase (p greater than 0.05) in the four animals tested in the high-dose group (0.24 +/- 0.03 to 0.23 +/- 0.05). Mean cerebral blood flow levels decreased in all groups during hypotension (p less than 0.05): 42 +/- 3 to 21 +/- 4 ml/100 gm/min (52% +/- 12% decrease) in the five animals tested in the control group. 60 +/- 8 to 24 +/- 6 ml/100 gm/min (56% +/- 13% decrease) in the four animals tested in the low-dose group. and 55 +/- 8 to 22 +/- 3 ml/100 gm/min (60% +/- 4% decrease) in the four animals tested in the high-dose group. In summary. the cerebral oxygen extraction fraction increased in the control animals and low-dose recipients during hypotension. suggesting the presence of threatened cerebral tissue. In contrast. the cerebral oxygen extraction did not change during hypotension when high-dose etomidate was administered. It is concluded that high-dose etomidate may preserve the cerebral metabolic state during hypotension in the present model.
Spontaneous decompression of syringomyelia: magnetic resonance imaging findings. Case report, The case of a 30-year-old woman with Chiari I malformation and a cervicothoracic syrinx is presented. The patient was followed clinically over a 2 1/2-year period. Spontaneous and complete resolution of the syrinx. as documented by serial magnetic resonance studies. was accompanied by only a minimal change in objective symptomatology.
Myocardial metabolism of fluorodeoxyglucose compared to cell membrane integrity for the potassium analogue rubidium-82 for assessing infarct size in man by PET, Potassium loss from damaged myocardial cells is linearly related to CPK enzyme loss reflecting extent of necrosis. The potassium analog. rubidium-82 (82Rb). is extracted after i.v. injection and retained in viable myocardium but is not trapped or washed out of necrotic regions. To compare myocardial cell metabolism with membrane dysfunction as indicators of necrosis/viability. 43 patients with evolving myocardial infarction and coronary arteriography had positron emission tomography using fluorodeoxyglucose (FDG) and the potassium analog 82Rb. Percent of heart showing FDG defects and 82Rb washout on sequential images indicating failure to retain the potassium analogue were visually assessed and quantified by automated software. Infarct size based on rubidium kinetics correlated closely with size and location on FDG images (visual r = 0.93. automated r = 0.82). suggesting that loss of cell membrane integrity for trapping the potassium analog 82Rb parallels loss of intracellular glucose metabolism. both comparable quantitative markers of myocardial necrosis/viability.
Comparison of shunt fraction estimation using transcolonic iodine-123-iodoamphetamine and technetium-99m-pertechnetate in a group of dogs with experimentally-induced chronic biliary cirrhosis, Portosystemic shunt fraction estimation using transcolonic iodine-123-iodoamphetamine (IMP) has been previously validated relative to portal vein macroaggregated albumin injections using an experimental model of cirrhosis. Transcolonic technetium-99m-pertechnetate (TcO4-) has been proposed as an alternative tracer to IMP to study portal circulation in cirrhotic patients. We compared shunt fraction estimates from paired transcolonic IMP and TcO4- studies performed on a group of dogs before and after common bile duct ligation surgery. Pertechnetate over-estimated shunt fraction in 6/7 postoperative studies relative to IMP. A good correlation between the two methods was demonstrated. however. the slope of the regression line was substantially less than 1.0 with TcO4- values reaching 100% at IMP shunt values of approximately 60%. This apparent inability to accurately assess high shunt flows may limit the quantitative aspects of TcO4- studies on patients with severe portosystemic shunting.
Indium-111-labeled leukocyte scan in detection of synthetic vascular graft infection: the effect of antibiotic treatment, To determine the sensitivity and specificity of the indium-111-(111In) labeled leukocyte scan for prosthetic vascular graft infection in patients treated with antibiotic therapy. a retrospective study was performed. Of 41 consecutive 111In-labeled leukocyte scans performed to evaluate possible vascular graft infection. 23 scans were performed in patients treated with antibiotics. The average duration of antibiotic therapy was 21 days. Twelve positive and 11 negative scans for graft infection were found. By surgical and autopsy correlation of all positive cases. and clinical correlation (of all negative cases). there were 10 true-positive. 11 true-negative. 2 false-positive. and no false-negative scans for graft infections. for an overall sensitivity of 100% and specificity of 85%.
L-methionine uptake by human cerebral cortex: maturation from infancy to old age, Age-associated changes in amino acid transport from blood to normal frontal cortex were studied using positron emission tomography (PET). Seventeen patients. 1.8-71 yr. were injected intravenously with tracer doses of [11C] L-methionine and a baseline PET scan was obtained. To assess competitive inhibition of [11C]L-methionine uptake. patients received either oral L-phenylalanine or an i.v. infusion of amino acids 1 hr before a second PET study. Uptake of [11C]L-methionine by frontal cortex decreased seven-fold between 1.8 and 71 yr (r = -0.71; p less than 0.05). Blood-to-brain transfer of [11C]L-methionine. at 4.5 yr. exceeded mean adult values by more than five-fold. Competitive inhibition reduced L-methionine uptake in all patients older than 4.6 yr. These developmental changes parallel findings in animals. The neutral amino acid transport system may modulate human brain amino acid levels to meet changing developmental metabolic needs.
Radiation safety considerations for post-iodine-131 hyperthyroid therapy, The purpose of this study was to develop guidelines based on patient measurements as to when iodine-131- (131I) treated hyperthyroid patients may resume close personal contact. External exposure rates were measured on 59 patients using an ionization survey meter in the upright position. The initial measurement was recorded within 20 min post-dose administration at one meter. Exposure rates were measured 2-11 days post-dose administration at 1. 0.6. and 0.3 meters from the patient's thyroid. In the administered dose range of 3 to less than 12 mCi of 131I. all 40 patients measured less than or equal to 2.0 mR/hr at one meter on Day 0. and 25 patients (25/29) were less than or equal to 2.0 mR/hr at 0.6 meter on Days 2-4. Guidelines can be prepared based on the administered dose that are rational and in conformity with existing radiologic health standards.
Clinical validation of a miniature nuclear probe system for continuous on-line monitoring of cardiac function and ST-segment, A new. miniature cesium iodide/photodiode nuclear probe (the "Cardioscint") has been developed for continuous on-line measurement of left ventricular function and the ST-segment. Ejection fraction (EF) measurements in 77 patients were compared with gated equilibrium radionuclide ventriculograms. The probe was positioned over the left ventricle by first using a blind positioning algorithm and then by using the gamma camera. Background was measured both manually and automatically. There was good correlation between probe (positioned blind) and gamma camera EF with both manual (r = 0.80. n = 65) and automatic (r = 0.78. n = 66) backgrounds. Use of the gamma camera did not significantly alter the results. Correlation between the probe stroke counts and thermodilution-derived stroke index during atrial pacing in six subjects was also satisfactory (r = 0.69. n = 102). Thus. the Cardioscint is able to provide a reliable estimate of EF and can track rapid changes in cardiac volumes.
Quantification of hepatobiliary function as an integral part of imaging with technetium-99m-mebrofenin in health and disease, A study was undertaken to check the feasibility of measuring the hepatic extraction fraction (HEF) and excretion T-1/2 values as an integral part of hepatobiliary imaging with technetium-99m-mebrofenin in health and disease. In 18 controls subjects. the HEF was 100% and the T-1/2 excretion mean +/- s.e. value was 15.23 +/- 1.4 min. The mean appearance times of the common bile duct (CBD). gallbladder (GB). and small intestine were 15.8 +/- 1.52. 20.2 +/- 2.7. and 23.8 +/- 3.08 min. respectively. Rising serum bilirubin in patients decreased HEF and increased T-1/2 excretion value resulting in delayed appearance of CBD. GB. and small intestine. In control subjects and patients with bilirubin less than 5 mg%. T-1/2 excretion values at 30. 40. and 50 min were similar to those values calculated using the entire 60 min of data. suggesting that the hepatic phase study time could be reduced to 30-40 min and still use the normal reference values established for 60 min. In patients with bilirubin greater than 5 mg%. the data collection duration should be continued for 60 min.
UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells, UK-68.798 increased the duration and effective refractory period of cardiac action potentials recorded in vitro from canine ventricular muscle and Purkinje fibers in a concentration dependent manner from 5 nM to 1 microM. The resting membrane potential. amplitude and maximum upstroke velocity of action potentials were unaffected by UK-68.798. indicating the selective class III antiarrhythmic properties of this agent. UK-68.798 (5 nM-1 microM) increased the effective refractory period of isolated guinea pig papillary muscles at stimulation frequencies of 1 Hz and 5 Hz without influencing the conduction velocity. further confirming that UK-68.798 is devoid of class I antiarrhythmic activity including block of the sodium channel. Studies using single voltage clamped guinea pig ventricular myocytes indicated that UK-68.798 at concentrations of 50 nM and 2 microM blocks a time-dependent K+ current. with no appreciable effects on the time-independent K+ current or the inward calcium current. UK-68.798 is therefore a highly selective K+ channel blocking agent with class III antiarrhythmic properties. a profile that holds considerable promise for the therapy of life-threatening cardiac arrhythmias.
BMY 30047: a novel topically active retinoid with low local and systemic toxicity, In the treatment of various dermatological disorders. topically applied retinoids have potential therapeutic use with the advantage of improved localized activity and lower toxicity over systemically administered retinoids. However. most retinoids cause a significant degree of local irritation. In the present study. the ability to produce local activity with low local irritation potential was evaluated with a novel retinoic acid derivative. BMY 30047 (11-cis. 13-cis-12-hydroxymethylretinoic acid delta-lactone) is one of a series of retinoic acid derivatives in which the carboxyl function of the polar end was modified with the aim of achieving reduced local irritation and systemic toxicity while retaining the local therapeutic effect. BMY 30047 was evaluated and compared with all-trans retinoic acid for topical retinoid activity in several preclinical assay systems. including the utricle reduction assay in rhino mice. 12-o-tetradecanoylphorbol 13-acetate ester-stimulated ornithine decarboxylase induction in hairless mice and the UV light-induced photodamaged skin model in hairless mice. BMY 30047 was assessed for retinoid-type side effects by evaluating the skin irritation potential in rabbits after repeated topical application. and hypervitaminosis A-inducing potential in mice after i.p. injection. BMY 30047 demonstrated significant topical retinoid activity in several in vivo models with less skin irritation potential relative to the most used clinical concentrations of all-trans retinoic acid. BMY 30047 also showed very little systemic activity and did not produce any evidence of hypervitaminosis A syndrome at systemic doses 20 times greater than the no-effect dose of all-trans retinoic acid.
Carbon monoxide-induced delayed amnesia, delayed neuronal death and change in acetylcholine concentration in mice, We investigated the interrelationship of delayed amnesia. delayed neuronal death and changes in acetylcholine concentration induced by carbon monoxide (CO)-exposure in mice. In the test for retention of the passive avoidance task. amnesia was observed 5 and 7 days after CO-exposure when the mice were exposed to CO 1 day after training; in the case when the mice were exposed to CO 5 and 7 days before training. amnesia was also observed in a retention test given 1 day after training. The number of pyramidal cells in the hippocampal CA1 subfield was lower than that of the control 3. 5 and 7 days after CO-exposure. But the neurodegeneration in the parietal cortex. area 1. was not observed until 7 days after CO-exposure. The findings indicated that the amnesia and the neuronal death were produced after a delay when the mice were exposed to CO. In addition. the delayed amnesia was closely related to the delayed neuronal death in the hippocampal CA1 subfield. Moreover. [3H]glutamate and [3H]glycine binding sites did not change after CO-exposure but. 7 days after CO-exposure. the concentration of acetylcholine and the binding of [3H]quinuclidinyl benzilate in the frontal cortex and the striatum were found to have significantly changed. but those in the hippocampus did not show significant change. Therefore. we suggest that delayed amnesia induced by CO-exposure may result from delayed neuronal death in the hippocampal CA1 subfield and dysfunction in the acetylcholinergic neurons. in the frontal cortex. the striatum and/or the hippocampus.
Protective behavior of captopril on Hg(++)-induced toxicity on kidney mitochondria. In vivo and in vitro experiments, Mercurials are known to induce morphological and functional modifications in kidney mitochondria. In this work we studied in vitro and in vivo the protective effect of captopril on the deleterious effect of Hg(++)-induced nonspecific membrane permeability changes to Ca++ and membrane de-energization. In vivo the administration of captopril prevented the toxic effects of mercury poisoning on membrane permeability. oxidative phosphorylation and Ca++ homeostasis. Moreover. captopril preserves kidney tissue morphology from Hg(++)-induced damage. The protective effect of captopril is most likely related to the existence of a sulfhydryl group in the drug.
Characterization of LY233569 on 5-lipoxygenase and reperfusion injury of ischemic myocardium, LY233569 produced concentration-dependent inhibition of isolated guinea pig 5-lipoxygenase (5-LPO) and 5-LPO activity of human polymorphonuclear leukocytes in vitro; IC50 values were 0.4 and 0.1 microM. respectively. LY233569 also inhibited (IC50 approximately 1.8 microM) zymosan-stimulated production of leukotriene B4 in canine whole blood but had little or no concomitant effect on the production of thromboxane B2. Concentrations of LY233569 as high as 10 microM did not inhibit production or scavenge superoxide from activated human neutrophils. In normal anesthetized dogs. infusion of LY233569 (0.11 mg/kg/min. i.v.) for 6 hr produced persistent inhibition (approximately 80%) of leukotriene B4 production in blood challenged ex vivo with zymosan; the plasma concentration (approximately 4 microM) of LY233569 was consistent with in vitro data illustrating selective and maximal inhibition of 5-LPO. In subsequent experiments. myocardial infarct size was measured after 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion. Continuous infusion of LY233569 (0.11 mg/kg/min. i.v.) had little or no effect on base-line systolic arterial pressure. cardiac rate and the pressure rate product when compared with time-related changes observed in control dogs. LY233569 infusion also did not alter the degree of ST-segment deviation or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant myocardial infarct sizes were 45 +/- 5% of the left ventricle placed at risk in control dogs and 43 +/- 4% in dogs given LY233569. Myeloperoxidase activity of infarcted myocardium did not differ between groups.
Antibodies to synthetic peptides from Epstein-Barr nuclear antigen-1 in sera of patients with early rheumatoid arthritis and in preillness sera, We studied IgG antibody levels to synthetic peptides (p62. E11 and E3) from Epstein-Barr nuclear antigen-1 (EBNA-1) protein sequence in sera of patients with rheumatoid arthritis (RA). in pre-RA and in rheumatoid factor (RF) positive non-RA sera from Finland. Anti-E11 and anti-E3 antibody levels were significantly elevated in RA sera. compared with both RF negative and RF positive nonrheumatoid controls. The concentrations of anti-E11 and anti-E3 antibodies in the preillness sera were lower than those in RA sera. Eight-year followup samples of patients with RA had slightly decreased levels of anti-E3 and anti-E11 antibodies compared with samples taken within 6 months of the disease onset. Anti-p62 antibody levels did not differ significantly between any of the groups studied. Thus. elevated levels of antibodies to 2 of the glycine containing EBNA-1 peptides were associated with clinical RA.
Epidermal growth factor receptor of fibroblasts from patients with scleroderma, Epidermal growth factor receptor (EGF-R) of fibroblasts from 3 patients with scleroderma (progressive systemic sclerosis. PSS) was studied by radioiodinated-EGF binding assay. The binding was 60.9 +/- 4.0% of normal fibroblasts. and the Scatchard plots showed a decrease in the affinity for EGF. not in the number of EGF-R. PSS fibroblasts expressed higher levels (1.15-2.45-fold) of RNA for the v-erbB (EGF-R gene). All-transretinoic acid (retinoid) had little effect on EGF-R. v-erbB gene expression and the proliferation of PSS fibroblasts. These data concerning the abnormality in the EGF-R may all constitute a feature of PSS fibroblasts.
A self-administered hand symptom diagram for the diagnosis and epidemiologic study of carpal tunnel syndrome, Noninvasive tests for carpal tunnel syndrome (CTS) are of limited diagnostic value. A self-administered hand symptom diagram has been developed for use in the diagnosis and epidemiologic study of CTS. Diagrams are rated classic CTS. probable. possible or unlikely. Diagram ratings were compared with nerve conduction diagnoses in 110 patients with upper extremity complaints. A hand diagram rating of classic or probable CTS had sensitivity of 0.64. specificity of 0.73 and positive predictive value of 0.58. The negative predictive value of an unlikely diagram was 0.91. We conclude that the diagram is a useful diagnostic tool and may be valuable for occupational and population screening.
Differential diagnosis between osteitis condensans ilii and sacroiliitis [published erratum appears in J Rheumatol 1991 May;18(5):790, Sacroiliitis of seronegative spondyloarthropathy may sometimes show on pelvis plain films findings indistinguishable from those of osteitis condensans ilii. Computed tomography (CT) can differentiate earlier than plain radiography between the 2 conditions; furthermore. it should also be possible to make this differentiation clinically. The aim of our study was to verify whether the criteria recently proposed by the European Spondylarthropathy Study Group (EESG) for the classification of spondyloarthropathy are useful. CT scans through the synovial part of the sacroiliac joints of 7 consecutive patients meeting the ESSG criteria and showing typical findings of osteitis condensans ilii on plain films were mixed with those of 15 consecutive patients with osteitis condensans ilii not meeting the ESSG criteria. Scans were examined for joint space and surface abnormalities blindly and independently by 2 observers. Six patients in the spondyloarthropathy group and one in the osteiitis condensans ilii group showed clear erosions and/or joint space narrowing of less than 2 mm in at least one joint. The difference was statistically significant (p less than 0.001). Our results suggest that by using criteria valid for the whole group of seronegative spondyloarthropathies. it is possible to differentiate clinically between seronegative spondyloarthropathies with sacroiliitis mimicking osteitis condensans ilii and "true" osteitis condensans ilii.
Miller Fisher syndrome in systemic lupus erythematosus, We describe the first case of Miller Fisher syndrome. a Guillain Barre variant. complicating systemic lupus erythematosus. The symptoms and signs mimicked a brainstem syndrome. Despite treatment with high dose gamma globulin. our patient worsened and required mechanical ventilation. After plasma exchange. the patient improved.
Clinical relevance of immunohistochemical detection of multidrug resistance P-glycoprotein in breast carcinoma, In 20 women with breast carcinoma. 17 of whom had locally advanced cancer and 3 of whom had confirmed metastases. the expression of P-glycoprotein was evaluated before the start of a chemotherapy regimen that included multidrug resistance-related drugs. With the use of the C494 monoclonal antibody in an avidin-biotin-immunoperoxidase technique. P-glycoprotein was detected in 17 of 20 tumor samples. Results were expressed in a semiquantitative manner. taking into account the number of positive tumor cells (N index) and the specific staining intensity (I index). The 17 patients with nonmetastatic cancer were followed from the first cycle of chemotherapy to cancer recurrence; subsequent to six cycles of chemotherapy. all of these patients except one were rendered clinically disease-free through surgery and/or radiation. The end point was defined as either local/regional recurrence or metastasis. Strong P-glycoprotein-positive staining in a majority of tumor cells (the N+/I+ phenotype) was significantly correlated with no initial response to chemotherapy (P less than .02) and with a shorter progression-free survival (P less than .02). Thus. the pretreatment evaluation of P-glycoprotein expression may be of prognostic value in patients with locally advanced breast cancer.
Effects of in vitro electrical stimulation on enhancement and suppression of malignant lymphoma cell proliferation, The suppression and enhancement of proliferation of mouse EL4 lymphoma cells varied significantly when the cells were electrically stimulated within a narrow range of low-level direct current. With the use of platinum electrodes. the suppression characteristics were observed over a narrow range. or window. of direct currents centered at approximately 17 microA. Enhancement characteristics were observed over a broad range of low-level direct currents (approximately 0.1 to 10 microA). These results indicate that the proliferation of certain eukaryotic cells may be directly controlled by stimulation with low-level direct current.
Phase I clinical and pharmacokinetic trial of flavone acetic acid, Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m2. At doses less than or equal to 3.9 g/m2. the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m2. the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m2. Pharmacokinetic studies revealed linear behavior in the eight patients studied. beginning at 3.9 g/m2. Peak plasma levels ranged from 125 to 630 micrograms/mL. with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m2. A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient. this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m2. Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended.
Tumor suppressor genes: new prospects for cancer research, Cancer is thought to arise from the accumulation of several genetic mutations in a single cell. Until recently. the only tumorigenic mutations that have been studied in detail are those that activate oncogenes. The discovery of tumor suppressor genes. for which inactivating mutations elicit tumorigenesis. has added a new dimension to our understanding of neoplasia. The retinoblastoma susceptibility gene RB is the prototype tumor suppressor gene and has been shown to suppress the transformed phenotype for several different cancers. Additional studies have revealed other tumor suppressor genes that may operate in a variety of tissues through a variety of mechanisms. These mechanisms may regulate the choice between cellular proliferation and differentiation and appear to involve such processes as the initiation of DNA replication. regulation of expression of certain genes. intercellular communication and adhesion. and the transduction of external signals to intracellular effectors. The elucidation of these mechanisms will enhance our understanding of both oncogenesis and the fundamental operations of the cell.
Stress response protein (srp-27) determination in primary human breast carcinomas: clinical, histologic, and prognostic correlations, Expression of an estrogen-regulated protein known as the 27.000-d heat-shock or stress-response protein (srp-27) was evaluated in human breast carcinomas and established breast cancer cell lines. Results obtained by Northern and Western blot analyses and immunohistochemical methods were concordant. Immunohistochemical assessment of srp-27 expression in 300 breast carcinomas (with median patient follow-up of 8 years) was performed. Twenty-six percent of lymph node-negative and 45% of lymph node-positive tumors were overexpressors. Univariate analysis demonstrated significant correlations between srp-27 overexpression and estrogen receptor (ER) content. pS2 protein expression. nodal metastases. advanced T stage. lymphatic/vascular invasion. and a shorter disease-free survival period (but not a shorter overall survival) for the study population as a whole. Regression tree analysis showed that srp-27 expression was an independent prognostic indicator for disease-free survival only in patients with one to three positive lymph nodes. The Cox proportional hazards model confirmed the independent prognostic significance of nodal involvement. T stage. and ER content but failed to recognize srp-27 overexpression as a significant independent parameter predictive of patient outcome in the patient population as a whole. The observed associations between srp-27 overexpression and more aggressive tumors suggest a biologic role for srp-27 in human breast carcinomas.
Therapeutic advantage of hypoxic cells in tumors: a theoretical study, The presence of hypoxic cells in solid tumors has long been considered a problem in cancer treatment. particularly for radiation therapy but also for treatment with some anticancer drugs. Three general strategies are being actively explored to overcome the problem: oxygenating the tumor. sensitizing the hypoxic cells to radiation (or chemotherapy). or killing the hypoxic cells (with a hypoxic cell cytotoxin). In the present study. we have examined the impact of each of these three strategies on a standard radiation therapy regimen (30 doses of 2 Gy). using either of two major assumptions: full reoxygenation or no reoxygenation of the tumor cells. We demonstrate that a hypoxic cell cytotoxin can produce a level of tumor cell killing higher (by several orders of magnitude) than that produced by full oxygenation of a tumor or by use of an optimum hypoxic cell radiosensitizer. provided the cytotoxin kills more than approximately 50% of the hypoxic cells each time it is given. The only assumption that makes a difference is whether reoxygenation occurs: In the worst case (ie. no reoxygenation). the hypoxic cell cytotoxin performs only as well as an optimum radiosensitizer. The analysis shows that hypoxic cells in tumors can be a major therapeutic advantage. Therefore. we recommend that research efforts be concentrated on development of superior hypoxic cell cytotoxins rather than improved hypoxic cell radiosensitizers and that. in parallel. emphasis be placed on development of agents to increase hypoxia.
Diffusion and binding of monoclonal antibody TNT-1 in multicellular tumor spheroids, Tumor spheroids of HT-29 human colon adenocarcinoma and A375 melanoma were established to investigate the uptake and clearance kinetics of TNT-1. a monoclonal antibody that targets necrotic cells of tumors. Our data reveal that there was rapid uptake of TNT-1 and its F(ab')2 fragment in both spheroid models. whereas an antibody of irrelevant specificity. Lym-1. and its F(ab')2 fragment bound poorly to the spheroids. Unlike previously reported monoclonal antibodies to tumor cell-surface antigens. TNT-1 showed 1) a linear uptake that increased over time without saturation in tumor spheroids and 2) an unexpected uptake by a subpopulation of cells in the viable outer rim of the spheroids. These preclinical studies provide important information concerning the therapeutic potential of TNT monoclonal antibodies for the treatment of cancer and micrometastases.
Post-transplant renal artery stenosis: a possible immunological phenomenon, A retrospective review of 110 consecutive kidney transplants performed during 4 years revealed the development of renal artery stenosis in 9 patients (8.18%). A comparison of this group with a control group similar in patient age and interval elapsed since transplantation revealed no significant differences in donor and recipient ages. degree of HLA compatibility or serum creatinine levels. However. there was a significant difference in the number of acute rejection episodes. In our series only male patients were affected. A sizable proportion of the patients (50%) had no detectable murmur over the graft area despite high blood pressure and increased creatinine levels. The absence of surgical injury during extraction and implantation of the grafts. together with the anatomical site of the stenosis and correlation with the degree of immunological intolerance suggest an immunological factor as the underlying cause in post-transplant renal artery stenosis.
Acute changes in renal function following extracorporeal shock wave lithotripsy in patients with a solitary functioning kidney, Twelve consecutive patients with a solitary functioning kidney were treated for renal stone by extracorporeal shock wave lithotripsy (ESWL*) with the modified Dornier HM3 lithotriptor and studied for 3 days after treatment. Urinary excretion of electrolytes. N-acetyl-beta-glucosaminidase (NAG). alkaline phosphatase. kallikrein. glycosaminoglycans. albumin and beta 2-microglobulin. and clearances of creatinine. inulin and para-aminohippuric acid were determined. as were serum levels of creatinine. urea. beta 2-microglobulin and aldosterone. and plasma renin activity. Urinary flow rate. free water clearance. and urinary excretion of NAG. kallikrein and beta 2-microglobulin were significantly increased 0 to 24 hours after ESWL. The urinary excretions of alkaline phosphatase. albumin and glycosaminoglycans were unchanged. Glomerular filtration rate was significantly decreased and effective renal plasma flow was unchanged. Filtration fraction was stable. Serum lactic dehydrogenase increased significantly after ESWL and remained high through the period of observation. Serum levels of creatinine. beta 2-microglobulin and aldosterone were unaltered. A decrease in plasma renin activity immediately after treatment is explained by the water immersion and the extracellular volume expansion during treatment.
Ureteral calculi: natural history and treatment in an era of advanced technology, Patients with ureteral stones may be managed expectantly. or treated with a variety of invasive and noninvasive techniques depending on stone composition. size and location. expectations of the patient and experience of the surgeon. Of 378 patients with documented ureteral calculi 60% passed the stones spontaneously. Passage rates from the proximal. middle and distal ureter were 22. 46 and 71%. respectively. Basketing under fluoroscopic control of distal stones was successful in 79% of the attempts and for those in whom this approach failed ureteroscopy was performed. with a success rate of 90%. When ureteroscopy was used as the initial treatment of distal stones removal was achieved in 81% of the patients. These statistics serve as a reminder that traditional therapy of ureteral stones has not lost its role in contemporary practice.
Management of upper tract calculi in patients with tubularized urinary diversions, In a retrospective review of patients with urinary diversion who presented to our stone center during a 3.5-year period 9 underwent 20 procedures for suspected stone episodes. Eventual outcome was excellent in all but 1 patient. In particular. all attempts at retrograde trans-stomal manipulation were successful. We present our cases. and note the technical considerations and management principles. Frequently. these patients are best served by a combination of percutaneous antegrade. trans-stomal retrograde and/or extracorporeal shock wave lithotripsy.
Metabolic alterations following continent urinary diversion through colonic segments, This study examined acid-base metabolism in patients with continent colonic urinary diversions and compared them to a control population. Diverted patients demonstrated mild acidosis and a urinary acidification defect. Ammonium chloride loading failed to demonstrate any major differences in the ability of these patients to handle an acute acid challenge. Continent colonic urinary diversions do not appear to create significant acid-base changes in patients with normal hepatic and renal function.
Vacuum tumescence devices: the role of papaverine in the selection of patients, We conducted a prospective study to determine the positive predictive value of papaverine testing to select patients in whom a vacuum constriction device would be a successful alternative to operative management of impotence. A total of 30 men presenting to an impotence clinic was evaluated with a series of papaverine dosages up to 60 mg. These patients then received a physician-administered trial of a vacuum constriction device. followed by 3 months of home use and a repeat objective evaluation. Initial responses to the device were poor. with 46% of the patients (14) achieving a rigid erection. However. after 3 months of home use 83% of the patients (25) achieved a rigid erection. The positive predictive value of a good response to the papaverine trial was 94%.
Intracavernous self-injection of vasoactive drugs in the treatment of impotence: 8-year experience with 615 cases, Of 615 patients with impotence of varying etiologies who were followed from 12 to 96 months after the institution of intracavernous self-injection therapy with vasoactive drugs (papaverine alone. papaverine and alpha-blockers. and Ceritine. a new multilevel acting drug) 87% (533 patients) returned for followup visits or were regularly contacted. Of these patients sexual activity was restored in 91%. The dropout rate was 11.25%. The 114 episodes of prolonged erections among 51 patients (4.57%) represented less than 3 per 1.000 of the 34.875 recorded injections. All patients were treated without complications. The percentage of patients suffering from nodules or permanent deformations was 2.8%. There were no cases of intracavernous fibrosis. The percentage of satisfied patients (satisfaction index 7 or greater) was 84.8%. Improvement in spontaneous erections during sexual intercourse was obtained in 65% of the cases: 15% no longer needed self-injections and 50% only used them occasionally while 35% remained entirely dependent.
Interstitial temperature measurements during transurethral microwave hyperthermia, Microwave hyperthermia is presently being investigated as a treatment for alleviating the symptoms of urinary outlet obstruction associated with benign prostatic hyperplasia. Two clinical techniques using intracavitary microwave applicators are being evaluated for safety and efficacy at various institutions. The transrectal technique uses a directional microwave radiator that is inserted into the rectum adjacent to the prostate. The transurethral approach uses a symmetrically radiating applicator located within the prostatic urethra. Transrectal prostatic heating techniques require surface cooling to prevent hazardous temperatures in the intervening rectal mucosa. Since transurethral applicators radiate from within the prostatic urethra. heating is confined to the obstructive tissue immediately surrounding the applicator. Concern has been expressed regarding the possibility of thermal injury to the prostate and adjacent rectum during transurethral hyperthermia treatment. In this report we present interstitial temperature measurements of prostatic and rectal temperatures in 5 patients. Temperature was observed to decrease at a rate of about 6C/cm. outward from the applicator. No clinically significant temperature increase was observed beyond 1 cm. outside the prostatic capsule or in the rectal mucosa.
Treatment of benign prostatic hypertrophy by a long-acting gonadotropin-releasing hormone analogue: 1-year experience, Benign prostatic hypertrophy. a common ailment among elderly men. usually is treated by surgery. Since androgens enhance prostatic hypertrophy. their withdrawal seems a logical way to treat this condition. Recently gonadotropin-releasing hormone analogues. known to produce "chemical castration." have been tried in cases of benign prostatic hypertrophy. We report our experience with 20 men treated by a monthly injection of gonadotropin-releasing hormone for prolonged periods. In 17 men treated for 6 months the prostatic volume decreased to an average of 63% of the initial volume; however. this did not correlate with clinical objective improvement. Only 6 men attained normal flow rates. Residual urine volume remained unaltered. Ten patients experienced subjective amelioration. while only 7 (40%) reported objective and subjective improvement. Maximal decrease in prostatic volumes was reached at 9 months of treatment and further treatment did not cause additional shrinkage. At 3 months after discontinuation of treatment prostatic volumes returned to 95 +/- 10.5% of pre-treatment values. A similar decrease in flow rates also was noted. Symptoms remained improved for longer periods. We conclude that this mode of treatment offers little to the majority of men with benign prostatic hypertrophy. Proper patient selection. based perhaps on serum prostate specific antigen. might augment positive results. This therapy should be restricted to patients considered high risk for any surgical and anesthetic intervention. and then it will have to be continued indefinitely.
Bioavailability of potassium and magnesium, and citraturic response from potassium-magnesium citrate, The bioavailability of potassium and magnesium. and the citraturic response were determined for the new compound. potassium-magnesium citrate. in 14 normal volunteers. Results were compared to those of potassium citrate and magnesium citrate. Each subject participated in 4 phases of study: potassium-magnesium citrate. potassium citrate. magnesium citrate and potassium chloride. After stabilization on a metabolic diet. each subject ingested a single load of a test medication followed by timed urine collections for the next 24 hours. Test loads included potassium-magnesium citrate (49 mEq. potassium. 24.5 mEq. magnesium and 73.5 mEq. citrate). potassium citrate (50 mEq.). potassium chloride (50 mEq.) and magnesium citrate (25 mEq.) Urinary potassium. magnesium and citrate were measured for each collection period. Potassium-magnesium citrate provided an equivalent potassium bioavailability as potassium citrate and potassium chloride. and a comparable magnesium bioavailability as magnesium citrate. However. it gave the highest citraturic response. since the cumulative increment in urinary citrate post-load was 129 mg. daily for potassium-magnesium citrate. 105 mg. daily for potassium citrate and 35 mg. daily for magnesium citrate. Thus. potassium-magnesium citrate gave an optimum citraturic response in addition to providing absorbable potassium and magnesium.
Laser treatment of obstruction from incrusted ureteral catheter, Incrustations may develop on ureteral catheters and cause obstruction. We report a case in which obstruction was relieved by laser lithotripsy inside the lumen of the catheter. This completely noninvasive technique may prove to be useful in selected cases.
The no-scalpel vasectomy, A refined method of delivering the vas deferens for vasectomy has been developed and used in China since 1974. This method eliminates the scalpel. results in fewer hematomas and infections. and leaves a smaller wound than conventional techniques. An extracutaneous fixation ring clamp encircles and firmly secures the vas without penetrating the skin. A sharp curved hemostat punctures and dilates the scrotal skin and vas sheath. The vas is delivered. cleaned and occluded by the surgeon's preferred technique. The contralateral vas is delivered through the same opening. The puncture wound contracts to about 2 mm.. is not visible to the man and requires no sutures for closure. The reported incidence of hematoma in 179.741 men followed in China was 0.09%. No hematomas or infections were identified in the first 273 procedures performed by a surgeon in the United States. The operating time in China and for the last 50 United States procedures has ranged from 5 to 11 minutes. The disadvantage of the technique is the hand-on training and number of cases necessary to gain proficiency. However. the advantages for surgeons and patients should enhance the popularity of vasectomy.
Endopyelotomy for secondary ureteropelvic junction obstruction in children, Percutaneous endopyelotomy has been shown to be successful in treating ureteropelvic junction obstruction in adults. Little data have been published regarding this procedure in children. We describe 4 patients 6.5 weeks to 5.5 years old who underwent percutaneous endopyelotomy to treat ureteropelvic junction obstruction following failed open dismembered pyeloplasty. Preoperative obstruction was demonstrated by a nephrostogram. diuretic renogram and/or ultrasonography. Percutaneous endopyelotomy was successful in relieving the obstruction in all 4 patients. although 2 required secondary endoscopic procedures. One patient had persistent obstruction 40 days after endopyelotomy at the ureteropelvic junction and. subsequently. required percutaneous resection of a persistent flap of obstructing tissue. In another patient a ureterovesical stricture was noted at the time of stent removal. which was treated by endoscopic incision. All patients have been followed from 1.5 to 3 years postoperatively. Followup diuretic renograms. ultrasound and/or excretory urography demonstrated a patent ureteropelvic junction in all patients and all have remained asymptomatic. Endopyelotomy appears to be safe and effective in treating secondary ureteropelvic junction obstruction in children.
Polyorchidism: case report and review of literature, Polyorchidism is a rare anomaly with approximately 70 cases reported in the literature. It may result from transverse division of the urogenital ridge. a hypothesis that best explains the anatomical features of the supernumerary testicle. The primary accompanying disorders and anomalies include maldescended testis. inguinal hernia and torsion. Malignancy has been reported in 3 cases. In the absence of any concomitant disorder and if testicular tumor can be ruled out by magnetic resonance imaging and ultrasonography. surgical exploration with biopsy is unnecessary.
Cavernous nerve grafts restore erectile function in denervated rats, Although potency can be preserved in most men following radical prostatectomy. in some patients one or both cavernous nerves must be sacrificed in order to excise all tumor. For these patients we have considered nerve reconstruction at the time of surgery using an interposition nerve graft. This possibility has been tested in a rat model. Animals were divided into three groups. In the sham control group. a pelvic exploration was conducted without division of the cavernous nerves. In the nerve ablation group. a five mm. segment of cavernous nerve was excised. In the graft group. five mm. of cavernous nerve was excised bilaterally and replaced with an interposition graft of genito-femoral nerve. At one month intervals postoperatively animals from each group underwent mating tests to determine potency; the ratio of vaginal intromission to unsuccessful mounts (I/M ratio) was determined. Following the mating tests the animals were re-explored and attempts were made to stimulate erections electrically via the pelvic nerve. Results at two months show the I/M ratio of the rats with grafts (0.05) and the nerve ablations (0.14) are low compared with the sham operated animals (1.0). By month four the graft group (0.89) has approached the sham group (0.91) while the ablation group (0.18) remains unchanged (p less than .05). Electrical stimulation at month two produced no erections in the nerve ablated or the grafted rats and 100% erections in the sham-operated animals. At month four. 50% of the rats with grafts. 10% of the nerve ablated animals. and 100% of the intact animals produced erections upon electrical stimulation (p less than .05). These results suggest that cavernous nerve grafting in rats can be successful in restoring potency after surgical injury. Application of these techniques to man may be indicated.
Obstruction and recanalization of the ureter during embryonic development, Major controversies still exist regarding the terminology. the etiology and the pathogenesis of congenital obstructive diseases of the ureter. To try to provide some additional information to this controversial subject. a comparative study of ureteral development in rat and human embryos. using light and electron microscopy. has been performed. During fetal development we observed and demonstrated the existence of obstructive phenomena. both at the level of the ureterovesical junction (Chwalla's membrane) and along the ureter. At the end of the embryonic period. the ureter undergoes a physiologic recanalization process.
Urinary bladder function 6 months after the onset of diabetes in the spontaneously diabetic BB rat, Urinary bladder function was examined in the spontaneously diabetic BB rat six months after the onset of diabetes. Diabetes caused significant decreases in rat weight and increases in bladder body weights and in vivo bladder capacities compared to age-matched controls. but no changes in the weights of bladder bases. The absolute contractile responses of urinary bladder body and base strips to nerve stimulation. carbachol. 5-hydroxytryptamine. ATP. phenylephrine. and KCl were unaltered by diabetes. However. when the data were corrected for tissue mass. there were slight but not significant decreases in contractile responses of strips from diabetic rats. There were increases in total muscarinic receptor numbers and calcium channel binding sites in bladder bodies from BB rats as a result of the increases in tissue mass. The data indicate that the six month-diabetic BB rat differs from the streptozotocin-diabetic rat in the sensitivity of the urinary bladder to the complications of diabetes. probably as a result of the insulin treatment required to keep BB rats alive.
Color Doppler ultrasound compared to a radionuclide scanning of spermatic cord torsion in a canine model, High resolution color doppler ultrasound can simultaneously display blood flow superimposed on detailed gray scale anatomic images. Using a single-blind study design. nine adult male dogs underwent intravaginal spermatic cord torsion and subsequent evaluation with technetium 99M-pertechnetate radionuclide. and color doppler ultrasound imaging techniques. Torsions of 90 to 720 degrees were created surgically. followed by examination with each modality at one hour (four animals). and four hours (five animals) following the procedure. Testicular torsion was diagnosed if perfusion was absent or markedly diminished on color doppler imaging or radionuclide scan. In all cases of 360 degrees or greater. torsion was diagnosed by either modality at both one and four hour time delays. If observers did not diagnose torsion. they were asked to assess the relative testicular perfusion. Color doppler ultrasound and radionuclide scanning were without error in correctly detecting a relative decrease in perfusion in each of these instances. Furthermore. color doppler imaging with spectral analysis was able to detect an enhancement of the diastolic component of the arterial signal at 180 degrees of torsion. This spectral pattern coupled with a relative decrease in blood flow allowed presumptive diagnosis at one hour of partial torsion that was subsequently apparent as absent perfusion only after 4 hours on radionuclide and repeat color doppler ultrasound. Color doppler ultrasound proved to be superior to radionuclide scanning in detecting diminished perfusion in this experiment. The detailed information provided by spectral and anatomic display with color doppler ultrasound recommends it for the evaluation of acute scrotal pathology of uncertain etiology.
Energy balance in elderly patients after surgery for a femoral neck fracture, To study energy and protein balances in elderly patients after surgery. spontaneous energy and protein intake and resting energy expenditure (REE) were measured in 20 elderly female patients with a femoral neck fracture (mean age 81 +/- 4. SD. range 74-87 years; weight 53 +/- 8. range 42-68 kg) during a 5-6 day period following surgery. REE. measured over 20-40 min by indirect calorimetry using a ventilated canopy. averaged 0.98 +/- 0.15 kcal/min on day 3 and decreased to 0.93 +/- 0.15 kcal/min on day 8-9 postsurgery (p less than 0.02). REE was positively correlated with body weight (r = 0.69. p less than 0.005). Mean REE extrapolated to 24 hr (24-REE) was 1283 +/- 194 kcal/day. Mean daily food energy intake measured over the 5-day follow-up period was 1097 +/- 333 kcal/day and was positively correlated with 24-REE (r = 0.50. p less than 0.05). Daily energy balance was -235 +/- 351 kcal/day on day 3 (p less than 0.01 vs zero) and -13 +/- 392 kcal/day on day 8-9 postsurgery (NS vs zero) with a mean over the study period of -185 +/- 289 kcal/day (p less than 0.01 vs zero). When an extra 100 kcal/day was allowed for the energy cost of physical activity. mean daily energy balance over the 5-day study period was calculated to be -285 +/- 289 kcal/day (p less than 0.01 vs zero). Measurements of total 24-hr urinary nitrogen (N) excretion were obtained in a subgroup of 14 patients.
Use of human growth hormone combined with nutritional support in a critical care unit, The administration of growth factors may potentially accelerate recovery during critical illness by reducing body protein catabolism. enhancing wound healing. and improving skeletal muscle function. The purpose of this phase 1 study was to evaluate the safety and initial efficacy of a recombinant growth factor. human growth hormone (GH). combined with nutritional support in a critical care unit. Following an initial control week. 11 individuals received GH (10 mg/day) daily for 1-6 consecutive weeks. Near constant nutrient intake was provided via parenteral and/or enteral feedings throughout the study period. Vital signs and other clinical parameters. blood values. and nutrient excretion were monitored daily. GH administration was not associated with clinically significant adverse effects. During the first 2 weeks of study. nitrogen excretion decreased from 1356 +/- 157 mmol/day (19.0 +/- 2.2 g/day) during control to 899 +/- 107 mmol/day (12.6 +/- 1.4 g/day) with growth hormone (p less than 0.002) in association with markedly reduced urea generation. Significant reductions in potassium excretion (control 100 +/- 11 mmol/day vs 69 +/- 6 with GH; p less than 0.01) and phosphorus excretion (31 +/- 5 mmol/day vs 18 +/- 3; p less than 0.025) also occurred during GH. The protein-conserving effects of GH were sustained during several weeks of treatment. Growth hormone enhanced the efficiency of administered protein and facilitated nitrogen retention without clinically significant adverse effects in this small patient group. Controlled trials are indicated to determine whether use of this anabolic hormone reduces hospitalization time and improves other clinical outcomes in severely injured patients when combined with appropriate nutritional support.
Factors contributing to increased energy expenditure in thermal injury: a review of studies employing indirect calorimetry, In summary. a remarkably close agreement exists for the mean MEE measured in 28 studies of severe burn trauma. This is especially surprising given the variability in sample sizes. measurement techniques. study designs. and DPBs studied. The mean MEE calculated from the data published in these reports is listed in the final column of Table I. For more than 450 cases. an unweighted MEE is 2750 +/- 85 kcal/day. For those studies prior to 1980. the mean MEE exceeds 3000 kcal/day in eight of 14 reports vs only two of 14 published after 1980. Even so. the mean MEE for the pre-1980 reports differs by only 200 kcal/day (2960 +/- 120. n = 14). The accepted notion that the degree of elevation in MEE is in proportion to the % BSAB up to about 60% BSAB is useful in a general sense but must be applied with caution. The recent studies. which include proportionately more burns exceeding 80% BSAB. suggest an elevation in MEE in these cases. Nevertheless. a physiologic plateau apparently exists at or slightly below 2 x normal RMR at the peak of MEE. The magnitude of the MEE response results from an undefined interaction among several factors of which some have been examined while others such as inflammatory mediators are only beginning to receive study. The contributions to reduction in MEE from interventions to control cardiac output and peripheral cooling. core temperature. evaporative water (heat) loss. and substrate cycling have been reviewed. The importance of indirect calorimetry in patient care is highlighted by the large variability in similarly injured individuals and in the unexplained component of regression analyses.
Intestinal obstruction by distension of a Foley jejunostomy catheter, Jejunostomies can be effective in permitting postoperative nutritional support. particularly in the patient with complicated gastrointestinal disease. In the case presented. however. distension of the Foley balloon catheter. used as the jejunostomy tube. led to intestinal obstruction which was not initially detected. Following radiographic identification of the problem. removal of the air from the Foley balloon allowed the patient to complete his convalescence from surgery. The possibility of obstruction from the Foley jejunostomy catheter should be recognized as a potential problem in the postoperative period.
Hemoglobin Columbia Missouri or alpha 2[88 (F9) Ala----Val]beta 2: a new high-oxygen-affinity hemoglobin that causes erythrocytosis, A previously undescribed hemoglobin variant. hemoglobin Columbia Missouri. alpha 88 (F9) Ala----Val. was detected in a 22-year-old white man who was undergoing assessment for erythrocytosis. This new hemoglobin variant does not separate from hemoglobin A by electrophoresis in conventional media. by isoelectric focusing. or by electrophoresis of purified globin chains in 8 M urea. It exhibits a high oxygen affinity. with a P50 (oxygen tension at 50% saturation) of 19.3 torr for the patient's whole blood. The substitution of hemoglobin Columbia Missouri is an internal residue near the end of the F helix of the alpha chain. Hemoglobin Okazaki has an arginyl residue substitution for a cysteinyl residue at F9 (beta 93) in the beta chain. In comparison with hemoglobin Okazaki. the substitution in hemoglobin Columbia Missouri has a more pronounced effect on oxygen affinity. Consequently. hemoglobin Columbia Missouri is associated with erythrocytosis. whereas hemoglobin Okazaki is not.
Motor neuron disease (amyotrophic lateral sclerosis), Amyotrophic lateral sclerosis is an insidiously developing. adult-onset. progressive anterior horn cell degeneration with associated degeneration of descending motor pathways. It has been recognized as an important clinical syndrome since the middle of the 19th century. Despite increasing clinical and research interest in this condition. its cause remains obscure. even in the broadest terms. Epidemiologic characteristics of the disease have been interpreted as evidence of both genetic and environmental causes. A major change in the view of this disease is the widely developing perception that it is a disease of elderly persons more than of middle-aged adults as was previously taught. Etiologic hypotheses encompass a broad range of postulated pathophysiologic mechanisms. and we review these in detail. The clinical limits of the disease can now be better defined by using modern diagnostic techniques. Although interest in supportive symptomatic therapy is growing. no intervention has yet been shown to modify the biologically determined motor system degeneration.
Common variable immunodeficiency: the disorder and treatment, A case of common variable immunodeficiency. a relatively rare disorder. is presented. This case was complicated by the presence of an anti-IgA antibody in the patient's serum and a history of a possible anaphylactic reaction to a prior intravenous infusion of gamma-globulin. Common variable immunodeficiency is actually a heterogeneous group of demonstrable immunoglobulin deficiencies that have in common low levels of most immunoglobulin isotypes. the inability to form antibodies to antigen. an absence of gross defects in cell-mediated immunity. and the presence of recurrent bacterial infections. The history of immunoglobulin deficiency and its treatment is reviewed. Although the primary therapy for common variable immunodeficiency is gamma-globulin replacement. ancillary measures such as early treatment of infections with antibiotics are also important. Intravenous gamma-globulin replacement therapy is preferred to intramuscular replacement therapy in these patients because intramuscular doses must be limited in volume to minimize local pain and take 2 to 14 days to achieve maximal blood levels. during which time in situ degradation of up to 50% of the administered dose can occur. Five intravenous gamma-globulin preparations are currently available in the United States. The potential adverse effects of intravenous gamma-globulin infusion and the precautions currently taken to ensure safety during administration of this product are discussed.
Longitudinal study of women with negative cervical smears according to endocervical status, A longitudinal study of 20.222 women who received negative cervical smear reports in 1987 showed that the incidence of definite or equivocal cervical intraepithelial neoplasia (CIN) was not significantly different between those whose first smear lacked an endocervical component and those whose smear included an endocervical component. The incidence of definite cytological evidence of CIN was significantly lower in women whose first smear did not include an endocervical component. It is concluded that women whose smears are reported as negative but lack an endocervical component should not be rescreened any earlier than women with negative smears that include an endocervical component.
Interaction of citrus juices with felodipine and nifedipine, Six men with borderline hypertension took felodipine 5 mg with water. grapefruit juice. or orange juice. The mean felodipine bioavailability with grapefruit juice was 284 (range 164-469)% of that with water. The dehydrofelodipine/felodipine AUC ratio was lower. diastolic blood pressure lower. and heart rate higher with grapefruit juice than with water. Vasodilatation-related side-effects were more frequent. Orange juice had no such effects. Six healthy men took nifedipine 10 mg with water or grapefruit juice; the bioavailability with grapefruit juice was 134 (108-169)% of that with water.
Transfusion requirements and effects in patients with thalassaemia major. Cooleycare Programme, Analysis of data available in 1985 on 3468 Italian and Greek patients registered in Cooleycare. an international cooperative programme of quality assessment of treatment delivery in thalassaemia. gave the following picture of treatment requirements and effects. The proportion of patients undergoing splenectomy has progressively decreased. and age at splenectomy has increased with time over the past 20 years. Age at first transfusion exceeds 4 years in a small but important group of patients. which indicates that a milder form of thalassaemia exists in this group. Children receiving modern treatment remain of near-normal stature until age 11 but later tend to be stunted. The mean blood requirement is 35% higher in non-splenectomised than in splenectomised patients. Differences in transfusion interval of 2 to 4 weeks have no measurable effect on blood requirement. Mean blood requirement rises gradually with mean haemoglobin concentration. possibly in a non-linear fashion. The prevalence of red cell alloimmunisation rises with delay in start on transfusion. Transfusion reactions were reported in 1% of transfusions (90% of which were leucocyte-depleted). from 17% of patients.
Tourette syndrome and other tic disorders. Diagnosis, pathophysiology, and treatment, In this report. we discuss the definition. characteristics. pathophysiology. and treatment of tic disorders with a major emphasis on Tourette syndrome. Although the diagnosis of a tic disorder depends on the presence of motor and/or phonic tic(s). patients with these problems also have a variety of co-morbid features including obsessive-compulsive symptoms. attention-deficit hyperactivity disorder. behavioral difficulties. and learning disabilities. Conservative estimates for Tourette syndrome suggest a prevalence rate of 0.1-1.0 per 1000. This syndrome is inherited in a sex-influenced autosomal dominant pattern with either chronic multiple tic disorder or obsessive-compulsive disorder as alternative phenotypes of the putative gene. Current evidence continues to support a pathophysiologic mechanism involving synaptic neurotransmission. with the dopaminergic system as a primary candidate. Therapeutically. it is essential to clarify whether a patient's problems are related to tics or associated behavioral difficulties. Pharmacotherapy for motor and phonic tics is strictly symptomatic and should be reserved for those with functionally disabling symptoms. A comprehensive individualized treatment program is often required in the care of individuals with tic disorders.
Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma, Chromogranin A. co-stored and co-released with catecholamines from adrenal medullary and sympathetic neuronal vesicles. is elevated in the plasma of patients with pheochromocytoma. The usefulness of the hormone in the differential diagnosis of hypertension is examined. An elevated level of chromogranin A had comparable diagnostic sensitivity (83%. 24/29) to. but greater diagnostic specificity (96%. 86/90) than the level of plasma catecholamines when subjects with pheochromocytoma (n = 29) were evaluated in comparison to several reference groups. including normotensive controls (n = 49). subjects with essential hypertension (n = 28). subjects with renovascular hypertension (n = 5). and subjects with primary aldosteronism (n = 3). Subjects with signs or symptoms suggesting pheochromocytoma. but in whom the diagnosis was ultimately ruled out (n = 5) had normal plasma levels of chromogranin A. A modest rise in chromogranin A in those with essential hypertension. and correlation of chromogranin A with diastolic blood pressure in normotensive patients and patients with essential hypertension did not impair the diagnostic usefulness of chromogranin A for pheochromocytoma. Renal failure was associated with an elevated plasma chromogranin A independently of blood pressure. Plasma chromogranin A correlated with tumor mass. tumor chromogranin A content. tumor norepinephrine content. and urinary vanillylmandelic acid excretion; it did not correlate with plasma or urinary catecholamines. nor with blood pressure in patients with pheochromocytoma. Plasma chromogranin A levels did not differ in subjects with pheochromocytoma when stratified by age. sex. tumor location. or tumor pathology. Several drugs used in the diagnosis or treatment of pheochromocytoma (clonidine. metoprolol. phentolamine. and tyramine) had little effect on plasma chromogranin A concentration. Within the pheochromocytoma. chromogranin A was localized along with catecholamines to the soluble core of chromaffin granules. where it accounted for 18 +/- 5% of vesicle soluble protein. We conclude that 1) chromogranin A emerges along with catecholamines from pheochromocytoma chromaffin granules; 2) plasma chromogranin A is a sensitive and specific diagnostic tool in evaluation of actual or suspected pheochromocytoma; 3) plasma chromogranin A predicts pheochromocytoma tumor size and overall catecholamine production; and 4) drugs commonly employed in the diagnosis or treatment of pheochromocytoma have little effect on plasma chromogranin A level. preserving the usefulness of chromogranin A in evaluating pheochromocytoma. Thus. measurement of chromogranin A provides a useful adjunct to the diagnosis of pheochromocytoma.
A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience, Pheochromocytoma is an unusual but potentially devastating tumor. Although a high index of suspicion is necessary. the likelihood of a pheochromocytoma is lower in the absence of the typical symptoms and findings. Nonetheless. screening must be broadened to include patients with a lower risk of the disease. such as those with resistant or labile hypertension who are minimally symptomatic. Extensive diagnostic evaluations should be reserved for those whose clinical or laboratory findings are more suggestive. Symptoms in a group of patients in whom a pheochromocytoma was seriously considered but excluded overlap symptoms in patients with a pheochromocytoma. Certain symptoms are useful: flushing to suggest a non-pheochromocytoma illness; visual symptoms. flank pain. and pallor to suggest that a pheochromocytoma is more likely. Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache. palpitations. and diaphoresis were present in the majority of pheochromocytoma patients. but in a smaller number of non-pheochromocytoma patients. The presence of the entire triad is more specific. but less sensitive. New hypertension. or hypertension associated with unexplained orthostatic hypotension. are suggestive of an underlying pheochromocytoma. Twenty-four-hour urine studies are consistently abnormal in patients with a pheochromocytoma. but are also elevated in a significant proportion of non-pheochromocytoma patients. Values greater then 1.5-2-fold above the upper limit of normal are very suggestive that a pheochromocytoma is present. and warrant a more intensive subsequent evaluation. Imaging studies are reliable in the diagnosis of pheochromocytoma. and can help to confirm or exclude the disease. Patients with a higher clinical likelihood and any elevated urinary testing. or with a lower clinical likelihood and persistently and/or significantly elevated urinary testing. should have imaging studies performed. This combination of clinical screening. 24-hour urinary testing. and imaging studies is a useful and reliable approach to patients suspected of harboring a pheochromocytoma.
Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group, BACKGROUND. HA-1A is a human monoclonal IgM antibody that binds specifically to the lipid A domain of endotoxin and prevents death in laboratory animals with gram-negative bacteremia and endotoxemia. METHODS. To evaluate the efficacy and safety of HA-1A. we conducted a randomized. double-blind trial in patients with sepsis and a presumed diagnosis of gram-negative infection. The patients received either a single 100-mg intravenous dose of HA-1A (in 3.5 g of albumin) or placebo (3.5 g of albumin). Other interventions. including the administration of antibiotics and fluids. were not affected by the study protocol. RESULTS. Of 543 patients with sepsis who were treated. 200 (37 percent) had gram-negative bacteremia as proved by blood culture. For the patients with gram-negative bacteremia followed to death or day 28. there were 45 deaths among the 92 recipients of placebo (49 percent) and 32 deaths among the 105 recipients of HA-1A (30 percent; P = 0.014). For the patients with gram-negative bacteremia and shock at entry. there were 27 deaths among the 47 recipients of placebo (57 percent) and 18 deaths among the 54 recipients of HA-1A (33 percent; P = 0.017). Analyses that stratified according to the severity of illness at entry showed improved survival with HA-1A treatment in both severely ill and less severely ill patients. Of the 196 patients with gram-negative bacteremia who were followed to hospital discharge or death. 45 of the 93 given placebo (48 percent) were discharged alive. as compared with 65 of the 103 treated with HA-1A (63 percent; P = 0.038). No benefit of treatment with HA-1A was demonstrated in the 343 patients with sepsis who did not prove to have gram-negative bacteremia. For all 543 patients with sepsis who were treated. the mortality rate was 43 percent among the recipients of placebo and 39 percent among those given HA-1A (P = 0.24). All patients tolerated HA-1A well. and no anti-HA-1A antibodies were detected. CONCLUSIONS. HA-1A is safe and effective for the treatment of patients with sepsis and gram-negative bacteremia.
Elevation of the petrous bone caused by hyperplasia of the occipital bone presenting as hemifacial spasm: diagnostic values of magnetic resonance imaging and three-dimensional computed tomographic images in a bone anomaly, A case of elevation of the petrous bone due to hyperplasia of the occipital bone presenting as hemifacial spasm is reported. A 44-year-old man sought treatment for twitching of the buccal muscles on the right side that progressed rapidly in severity within 2 weeks of the onset. The anatomical details of the petrous and occipital bones were delineated clearly by computed tomographic scans of a bone window level. Details of the brain stem were shown by magnetic resonance images. The bone anomaly was displayed more realistically by three-dimensional computed tomographic reconstructions. The faithful representation of structures with these radiological studies should be mandatory. to prepare the surgical planning of such a complicated bone anomaly.
Biomechanics of lumbar pedicle screw/plate fixation in trauma, This investigation was conducted to determine alterations in the biomechanical strength and stiffness characteristics of the lumbar spine fixated with Steffee instrumentation. Comparative studies of these parameters were conducted using seven lumbar columns from fresh human cadavers. Three runs were conducted on each T12-L5 column: control. injured. and fixated. The specimens were loaded under the compression-flexion mode until failure (control run) and then reloaded (injury run) to the failure deformation determined in the control run. Screw/plates were then inserted one level proximal and distal to injury. and the specimens were reloaded (fixation run). Radiographs were taken before and after each trial. Data on deformation and force histories were gathered. The load-deflection response of the injured and fixated specimens were bimodal with two representative stiffnesses. Control failure loads and stiffnesses were higher than those for the injured (P less than 0.001) or fixated (P less than 0.01) spine. Initial stiffness was significantly higher for the fixated than for injured columns (P less than 0.001). but the final stiffnesses were similar. The increase in the initial stiffness in the fixated specimen compared to the injured specimen indicates the strength added to the posterior region of the spine. The relatively smaller alteration in the final stiffness between the fixated and the injured columns. corresponding to the load shared by the anterior column. may suggest that. above a critical strain level. the anterior column absorbs a higher portion of the external load and posterior fixation may be inadequate as sole treatment in trauma.
Saccular aneurysms of the distal anterior cerebral artery, We report a series of 42 consecutive patients with aneurysms of the distal anterior cerebral artery (ACA). Of these. 36 patients had one aneurysm. 5 had two aneurysms. and one had three aneurysms. Thirty patients had a ruptured distal ACA aneurysm; among these patients. the size of the aneurysm was less than 5 mm in diameter in 20. 6 to 10 mm in 7. and larger than 11 mm in 3. Eighteen patients (42.9%) had multiple aneurysms. and distal ACA aneurysms were responsible for a subarachnoid hemorrhage in 10. Thirty-four patients underwent direct surgery. and 30 of these had excellent outcomes 3 months after surgery. The treatment of patients with distal ACA aneurysms is often technically difficult. because of their broad neck configuration and the coexistence of other aneurysms. Nevertheless. the present study emphasizes that distal ACA aneurysms tend to bleed. irrespective of their size. and that excellent outcomes are obtainable by direct surgery.
Effect of hydrocephalus on prostaglandins and thromboxane B2 in ventricular cerebrospinal fluid, The concentrations of prostaglandin F2 alpha. prostaglandin E2. 6-ketoprostaglandin F1 alpha (prostacyclin metabolite). and thromboxane B2 were assayed in ventricular cerebrospinal fluid obtained from 28 patients with hydrocephalus (17 obstructive. 11 communicating). Seven patients received dexamethasone or hydrocortisone on the day of sampling. No patient received nonsteroidal anti-inflammatory compounds for 48 hours before sampling. The median values did not differ significantly between the two types of hydrocephalus or from the concentrations in lumbar cerebrospinal fluid obtained from patients without intracranial pathology during lumbar myelography for possible lumbar disc disease. Hence. there is no evidence that eicosanoids accumulate in the ventricles in hydrocephalus. and it is unlikely that they have a significant role in its symptomatology.
Myeloma manifesting as a large jugular tumor: case report, The authors report a case of cranial plasmacytoma with multiple myelomas and palsy of the lower cranial nerves. The osteolytic lesion adjacent to the jugular foramen was demonstrated by an angiogram to be exceedingly hypervascular. with arteriovenous shunting resembling that seen in paragangliomas. Forty-five cases of cranial and intracranial plasmacytoma from the literature were reviewed. The findings indicate that a cranial plasmacytoma commonly appears to be a hypervascular tumor. whereas most dural tumors or intraparenchymal tumors have poor vascularity.
Comparison of the accuracy of glucose reflectance meters in pregnant insulin-dependent diabetics, Home monitoring of blood glucose by reflectance meters has been shown to be accurate in the nonpregnant diabetic and is currently used for outpatient glucose control in the pregnant diabetic as well. Beckman ASTRA glucose results from samples collected into sodium fluoride were used as the standard for this study. Comparisons were then made to four glucose reflectance meters: Accu-Check II. One Touch. DiaScan S. and ExacTech. Although the reflectance meters appeared to be useful for assessing blood glucose trends in the pregnant diabetic. the results obtained from these meters would be unacceptable in the laboratory setting. Unfortunately. because of the erratic combination of proportional and constant bias. correction factors are not easily ascertained. Laboratories and physicians should reconsider the use of these reflectance meters for inpatient evaluation and general population screening of pregnant women.
The effect of lateral tilt on maternal and fetal hemodynamic variables, We measured maternal blood pressure and heart rate. fetal heart rate. and umbilical artery velocity waveforms in 25 healthy women placed in the supine and in both right and left 5 degrees and 10 degrees lateral tilt positions. Although we found no significant difference among these variables in the various maternal positions. two of 25 women became hypotensive and symptomatic in the supine and 5 degrees tilt positions. Because we could not predict which women would become symptomatic. we recommend lateral tilt of all pregnant women during operative procedures beyond 20 weeks' gestation. including those in the lithotomy position for vaginal delivery.
A comparison of Doppler flow velocity waveforms, amniotic fluid columns, and the nonstress test as a means of monitoring post-dates pregnancies, Five hundred thirty-four pregnancies exceeding 294 days were monitored by weekly sonographic estimations of amniotic fluid columns. daily maternal recordings of fetal movements. and thrice-weekly nonstress tests. In addition. each woman received twice-weekly studies of the uteroplacental and umbilical circulations by means of Doppler ultrasound. There were no fetal deaths in the study. Of the individual methods of fetal surveillance. absence of end-diastolic frequencies in the umbilical artery was the most sensitive. predicting 91% of fetuses who developed fetal distress in the first stage. Combining the test with sonographic estimation of amniotic fluid columns improved the prediction to 100%. with only a minimal fall in the specificity. These results strongly suggest that a combination of umbilical artery Doppler waveforms and amniotic fluid determinations is an adequate method of monitoring the post-dates pregnancy.
Low incidence of positive amnionic fluid cultures in preterm labor at 27-32 weeks in the absence of clinical evidence of chorioamnionitis, In order to determine the utility of amniocentesis for detecting subclinical chorioamnionitis in asymptomatic afebrile women in preterm labor with intact membranes. we enrolled 47 women between 27-32 weeks' gestation in a prospective study. After enrollment. 38 women fulfilled all clinical and laboratory criteria for the study; nine women were excluded because they had a leukocyte count exceeding 15.000/microL. None of the 38 asymptomatic afebrile women had a positive culture from the amnionic fluid for bacteria. fungi. Mycoplasma hominis. Ureaplasma urealyticum. Chlamydia trachomatis. or any viruses. Sepsis was not proved in any of the 38 infants delivered to these patients. There was a clear relationship between histologic evidence of chorioamnionitis and failure of tocolytic therapy. Fetal lung profiles were mature in 29% of the amnionic fluid samples from 30-32 weeks' gestation. but in none of the amnionic fluid samples before 30 weeks. Amniocentesis does not seem useful to detect chorioamnionitis in asymptomatic afebrile women with preterm labor and intact membranes at 27-32 weeks' gestation. and should be reserved for those cases in which information about fetal lung maturity would be helpful.
Comparison of continuous versus sequential estrogen and progestin therapy in postmenopausal women, A pilot study was performed comparing the efficacy and safety of continuous versus sequential schedules of the two most commonly prescribed medications for ovarian hormone replacement. conjugated equine estrogens and medroxyprogesterone acetate. Bleeding patterns. endometrial histology. and metabolic parameters were studied in 48 postmenopausal women prospectively randomized to a continuous schedule (daily estrogen and progestin) or a sequential schedule (conjugated estrogen on days 1-25. medroxyprogesterone acetate on days 16-25). Doses studied were 0.625 and 1.25 mg of conjugated estrogens and 10 mg of medroxyprogesterone acetate. Significantly greater bleeding was observed with the 1.25-mg dosage of conjugated estrogens. Bleeding patterns were similar between schedules. with the exception that amenorrhea was more prevalent in the women using the 1.25-mg dosage of estrogen and the continuous progestin schedule. More frequent endometrial atrophy was observed with the continuous schedule. supporting the concept that prolonged use of this schedule may promote amenorrhea in most patients. Both doses and schedules were associated with modest and insignificant increases in high-density lipoprotein cholesterol. Sequential therapy did not prevent the estrogen-induced decrease of low-density lipoprotein cholesterol. whereas the continuous schedule did. particularly with 0.625-mg dosage of conjugated estrogens. Significant increases of triglycerides were also seen with the continuous but not with the sequential schedule. Because of reports that the continuous schedule using the 2.5-mg dosage of medroxyprogesterone acetate does not elicit these actions on circulating lipids. attention should be directed toward examining the long-term effects of this lower dosage given continuously.
Endotoxin in vaginal fluid of women with bacterial vaginosis, The concentration of endotoxin in vaginal fluid was measured in 19 women with bacterial vaginosis and in nine controls with normal vaginal flora. The vaginal fluid of the women with bacterial vaginosis contained significantly greater amounts of endotoxin: 0.308 +/- 0.396 versus 0.008 +/- 0.002 endotoxin units/mg vaginal fluid. Endotoxin in vaginal fluid may contribute to the activation of the prostaglandin system. which could provoke premature labor.
Persistent tubal pregnancy, Persistent tubal pregnancy may be manifest by either acute symptoms or a persistent or rising beta-hCG titer following conservative surgery. This condition is a relatively new complication. related to the recent practice of conservative surgical management of tubal pregnancy. Much has been written on the identification and possible therapy for this condition but little is known about its pathophysiology. Eight cases of persistence were studied. as well as three cases of failed conservative procedures. In nine instances. the surgeon had concentrated appropriately on the maximally dilated portion of the tube. which contained the blood clot and aborted products of conception. Unfortunately. the implantation site was located medially. toward the uterus. Ways of avoiding this complication include medial exploration or possibly the use of mesosalpingeal injection of vasopressin. An understanding of the natural history of the pathologic process might also be valuable in the management of cases of "persistence" identified solely by a continuing beta-hCG titer.
Prognostic factors in stage IB squamous cervical cancer patients with low risk for recurrence, About one-half of cervical cancer patients whose tumors recur after radical surgery have negative lymph nodes and clear resection margins. We evaluated 95 patients with squamous cell tumors who underwent radical hysterectomy and pelvic lymphadenectomy between January 1975 and December 1985 and who were thought to be at low risk for recurrence to see whether other clinical or histopathologic factors were predictive of tumor recurrence. Detailed retrospective record review and complete pathology review were accomplished for each case. The 5-year actuarial survival rate was 89%. Nine patients developed recurrent disease (9.5%). of whom eight died. Several clinical features were evaluated as possible prognostic factors: patient age (P = .26). patient race (P = .60). cervical diameter (P = .24). extent of gross cervical involvement (P = .36). and presence of contact bleeding (P = .82). Histopathologic features were examined: depth of invasion (P = .31). number of mitoses (P = .42). character of the tumor-stromal border (P = .15). histologic differentiation (P = .02). lymph-vascular space invasion (P = .56). and width of tumor (P = .23). Depth of invasion did correlate with increasing tumor width (P less than .001). Once node- and margin-positive patients are excluded. differentiation may be the only feature useful in identifying patients at risk for recurrence. Because almost one-half of our patients had poorly differentiated tumors. sole use of this feature as a criterion for adjuvant therapy would have resulted in overtreatment of low-risk patients.
Familial ovarian cancer in Israeli Jewish women, Among 310 women with ovarian cancer of epithelial origin. eight ovarian cancer-prone families were identified. accounting for 24 cases. Five first-degree relatives underwent prophylactic oophorectomy. and early ovarian carcinoma was diagnosed in one of them. Familial aggregation of ovarian cancer occurs in the Israeli Jewish population.
Bladder training in older women with urinary incontinence: relationship between outcome and changes in urodynamic observations, The purpose of this study was to clarify the mechanism by which bladder training affects urinary incontinence. Urodynamic data and specific urodynamic diagnoses of 108 women with urinary incontinence were compared before and 6 months after treatment with bladder training. Before treatment. 76 women had sphincteric incompetence. 11 had detrusor instability. and 16 had both. After treatment. 33 women no longer fulfilled the urodynamic diagnostic criteria for either sphincter or detrusor dysfunction. Controlling for severity before treatment. the number of incontinent episodes post-treatment was not associated with change in urodynamic diagnosis. Only the first sensation to void. voided volume. compliance. functional urethral length. and flow time showed any significant changes between pre- and post-treatment evaluations; however. none were correlated with change in the number of incontinent episodes. Bladder training does not appear to affect lower tract urodynamic variables or specific urodynamic diagnosis. and it is likely that its mechanism of action reflects adaptive behavioral changes. Physiologic changes not detected with techniques and/or criteria used in this study may still occur.
Peritoneal closure or non-closure at cesarean, The value of peritoneal closure at the time of cesarean birth was evaluated prospectively. Two hundred forty-eight women undergoing low transverse cesarean through a Pfannenstiel skin incision were assigned to one of two groups: peritoneum open (N = 127) or peritoneum closed (N = 121). The mean (+/- SEM) surgical time in the open group (48.1 +/- 1.2 minutes) was significantly less than for the closed group (53.2 +/- 1.4 minutes) (P less than .005). There were no postoperative differences between the groups in the incidence of wound infection. dehiscence. endometritis. ileus. and length of hospital stay. Our study suggests that leaving the parietal peritoneum unsutured is an acceptable way to manage patients at cesarean delivery.
At the water's edge: where obstetrics and anesthesia meet, Conflict exists between satisfying the parturient's desire for oral intake and traditional restrictive standards of obstetric and anesthesia departments. Surveys of institutions providing obstetric services reveal greatly varying oral intake policy. There is neither evidence of benefit in withholding fluids nor evidence of risk in allowing them. Prolonged fasting has potential liabilities. Maternal mortality is rare. and anesthesia-related causes are not among the common etiologies. Aspiration is not a significant factor in the modern era. Higher risk for anesthesia morbidity is associated with general anesthesia. particularly difficult intubation. Instead of implicating oral intake as a risk factor for pulmonary aspiration. the literature consistently emphasizes the critical role of properly trained and dedicated obstetric anesthesia personnel. Unless parturients are not candidates for regional anesthesia. a nonparticulate diet should be allowed. Liberal use of regional anesthesia as well as antacid prophylaxis is recommended.
Cone cerclage in pregnancy, We report a technique of cone cerclage and the results and outcome in 17 patients who required a diagnostic cone biopsy in pregnancy. The mean age of the patients was 30.6 years (range 21-41). The mean gestational age was 18.8 weeks (range 10-32) at the time of the procedure. There were no major complications and hemorrhage was not a significant problem. There were no second-trimester abortions. Two patients required beta-sympathomimetics to suppress uterine activity for longer than 24 hours after the procedure. Six patients had invasive carcinoma. nine had cervical intraepithelial neoplasia (CIN) III. and two had CIN II. In 14 cases. the endocervical and ectocervical margins were negative; two patients with CIN and one with multifocal microinvasion had positive margins. Cone cerclage is a safe and easy method for performing diagnostic cervical conization during pregnancy.
Evaluation of two rapid group B streptococcal antigen tests in labor and delivery patients, Two rapid group B streptococcal antigen tests were compared with nonselective blood agar culture in 1062 unselected patients admitted to labor and delivery. Vaginal specimens taken from each patient on admission were used to perform each of two rapid tests and corresponding cultures. The rapid tests were the Streptex latex agglutination assay and the Equate Strep B test. which uses a solid-phase immunoassay. Overall. 105 patients (9.9%) had at least one positive culture. The sensitivities for the rapid tests were 15.1% for Streptex and 21.5% for Equate. Specificities were 99.3 and 98.7%. respectively. Sensitivity was minimally increased in the setting of ruptured membranes for both tests. Likewise. use of separate swabs for streaking the culture plate and performing the rapid test increased the sensitivity. but this was not significant for either test. In control experiments. the limit of sensitivity of both rapid tests was 5 x 10(6) colony-forming units. We conclude that at present. these tests are not sensitive enough for routine use in this type of clinical setting.
Queuine, a tRNA anticodon wobble base, maintains the proliferative and pluripotent potential of HL-60 cells in the presence of the differentiating agent 6-thioguanine, 6-Thioguanine (6-TG)-induced differentiation of hypoxanthine phosphoribosyltransferase (IMP: pyrophosphate phosphoribosyltransferase. EC 2.4.2.8)-deficient HL-60 cells is characterized by 2 days of growth. after which morphological differentiation proceeds. Addition of the tRNA wobble base queuine. in the presence of 6-TG. maintains the proliferative capability of the cells. The ability of 6-TG to induce differentiation correlates with c-myc mRNA down-regulation. but queuine has no effect on this parameter. Treatment with 6-TG for 2-3 days commits HL-60 cells to granulocytic differentiation. and. once committed. these cells do not respond to the monocytic inducer phorbol 12-myristate 13-acetate. Nonetheless. when cells are treated with queuine and 6-TG. they maintain the promyelocytic morphology and are capable of being induced down the monocytic pathway by phorbol 12-myristate 13-acetate as indicated by stabilization of c-fms mRNA and cell adherence. In the absence of queuine. phorbol 12-myristate 13-acetate is incapable of inducing monocytic markers in the 6-TG-treated cells. The data presented indicate that 6-TG-induced differentiation of HL-60 cells is a tRNA-facilitated event and that the tRNA wobble base queuine is capable of maintaining both the proliferative and pluripotent potential of the cells.
Calmodulins with deletions in the central helix functionally replace the native protein in yeast cells, Deletion of Glu-84. Glu-83 and Glu-84. or Ser-Glu-Glu-Glu (residues 81-84) from the central helix of mammalian calmodulin is known to result in a 5-7 times decrease in its apparent in vitro affinities for three calmodulin-dependent enzymes. However. based on in vitro experiments. it is difficult to estimate how these deletions might affect in vivo cellular function. The yeast Saccharomyces cerevisiae. which requires calmodulin for growth. provides an excellent system to evaluate these deletion proteins in vivo. Based on its ability to restore normal growth characteristics to yeast cells. mammalian calmodulin is functionally identical to the yeast protein; herein we evaluate the effect of deleting residues 84. 83 and 84. or 81-84 from the central helix. Sequences encoding the deletion proteins and an unaltered control sequence were introduced by means of a yeast shuttle vector and were expressed under control of the yeast calmodulin promoter. The deletion and control calmodulins are produced at levels similar to that observed for the yeast protein. and they completely restore normal growth characteristics. This result suggests that the regions deleted from the central helix are not critical for activation of any yeast calmodulin target normally required for cell growth or division. It is likely that there are twisting and shortening motions associated with the deletions from the central helix that alter significantly the spatial relationship between the two lobes of calmodulin. The abilities of the deletion calmodulins to restore completely normal growth characteristics to yeast cells suggest that the lobes of all the deletion proteins can still be appropriately positioned in calmodulin-target complexes. This is consistent with the hypothesis that the central helix of calmodulin is analogous to a flexible tether rather than to a rigid connector between the two lobes of the molecule.
The noncatalytic src homology region 2 segment of abl tyrosine kinase binds to tyrosine-phosphorylated cellular proteins with high affinity, Several proteins implicated in the regulation of cell proliferation contain a common noncatalytic domain. src homology region 2 (SH2). We have used the bacterially expressed SH2 domain of abl protein-tyrosine kinase to evaluate the ability of this domain to bind to cellular proteins. ablSH2 specifically bound to a number of tyrosine-phosphorylated proteins from cells transformed by tyrosine kinase oncogenes in a filter-binding assay and to a subset of those proteins in solution. The SH2 probe bound almost exclusively to tyrosine-phosphorylated proteins. and binding was eliminated by dephosphorylation of cell proteins. Free phosphotyrosine could partially disrupt SH2 binding. suggesting that phosphotyrosine is directly involved in the binding interaction. These results demonstrate that an SH2 domain is sufficient to confer direct. high-affinity phosphotyrosine-dependent binding to proteins and suggest a general role for SH2 domains in cellular signaling pathways.
Treatment of exophthalmos, Current procedures for Graves' exophthalmos fail to achieve complete correction. The standard orbital decompressions were therefore modified to maximize the degree of volumetric increase behind the axis of the globe. In 15 orbits. the preoperative exophthalmos averaged 9.5 mm. whereas the postoperative exophthalmos was 4.1 mm. Postoperative CT study demonstrated that the remaining posterior orbital wall. combined with the persistently increased intraocular muscle volume. blocked retrodisplacement of the globe. despite adequate total volumetric increase. The increased muscle volume varied from 2 to 5 cc. Despite this residual exophthalmos. the modified four-wall expansion provides excellent aesthetic results with visual improvement and resolution of chemosis and exposure keratitis.
Nasal augmentation with split calvarial grafts in Orientals, This study reports on my experience with autogenous split calvarial grafts in nasal augmentation in 62 Orientals. In 78 percent of patients. the procedure was performed under local anesthesia in an outpatient setting. Total operating time for harvesting of split calvarial grafts ranged from 20 to 55 minutes. with a mean of 32 minutes. Patients ranged in age from 16 to 48 years. with a mean of 27 years. Follow-up was from 6 months to 8 years. with an average of 3.1 years. Intraoperative discomfort was uniformly low and well tolerated when local anesthesia was used. The complication rate was 8.0 percent. with three cases of minor seroma-hematoma formation at the bone-graft donor site. These were treated with aspiration. There were two recipient-site complications. with one case of complete bone resorption that occurred in a densely fibrotic nose with preexisting septal perforation and a case of overcorrection that was successfully rasped 1 year later. Because of their easy accessibility beneath the scalp. split calvarial grafts to the nose are useful in various types of nasal augmentation. and the technique is offered as a practical alternative to the use of alloplastic materials.
Free vascularized thin corticoperiosteal graft, This paper describes a new thin corticoperiosteal graft harvested from the medial condylar and supracondylar areas of the femur. It is based on the articular branch of the descending genicular artery and vein and consists of periosteum with a thin (0.5 to 1.0 mm) layer of outer cortical bone. By retaining the cortex. the cambium layer is preserved. and this is thought to have a better osteogenic capacity than vascularized periosteal grafts. This graft was used to treat six patients with fracture nonunion of the upper extremity in which conventional treatment had failed. Uneventful bony union was achieved in all patients within 10 weeks.
Metastatic melanoma to the facial nerve, Isolated metastatic malignant melanoma to the facial nerve has never been reported. This presentation illustrates a primary melanoma of the helix of the ear that was treated by excisional biopsy and then wedge resection in 1983. The primary melanoma was Clark's level IV and 1.3 mm in thickness. In 1985. a facial paresis slowly developed. There was no gross evidence of recurrent melanoma in the ear or neck. but CT scan showed a mass in the region of the stylo mastoid foramen. A reoperation of the primary site revealed metastatic melanoma in the facial nerve. expanding it to approximately 10 times its normal size. A composite resection was done for the melanoma. and the paralyzed face was immediately rehabilitated by a masseter muscle transfer. The patient received 6000 rads to this area postoperatively and has remained free of disease to date. having returned to his profession as a dentist. A detailed study of all the specimens indicated that this represented a primary metastasis to the facial nerve.
Simultaneous bilateral forearm revascularization, A successful simultaneous bilateral forearm revascularization was performed on a 17-year-old boy. Functional recovery of both forearms was evaluated 42 months after injury. The patient can use both hands for the activities of daily living. So far. he has been employed and has no significant psychological problems. Temporary intraluminal silicone shunts are extremely helpful for reducing ischemic damage to the injured limb. The sufficient skeletal shortening of the upper limb replantation is crucially important. The wounds must be managed by aggressive and repeated debridement. Accurate primary nerve repair is essential. and the early postoperative rehabilitation is also important to achieve a satisfactory functional return. The functional replanted or revascularized upper extremity is superior to an amputation or prosthesis. especially in the cases of bilateral upper extremity amputation or devascularization.
Trigger finger secondary to anomalous lumbrical insertion: a case report and review of the literature, Trigger finger is a relatively common clinical entity. most frequently caused by stenosing tenosynovitis. Several other conditions not related to tenosynovitis also have been described as a cause of triggering. and these have been reviewed. We present a rare anomaly of the fourth lumbrical muscle insertion as a cause of triggering of the right little finger. This was completely relieved following excision of the anomalous muscle. This rare anatomic variant should be added to the list of potential causes of trigger finger.
Reflex sympathetic dystrophy syndrome: consensus report of an ad hoc committee of the American Association for Hand Surgery on the definition of reflex sympathetic dystrophy syndrome, This report proposes that reflex sympathetic dystrophy be defined as a pain syndrome in which the pain is accompanied by loss of function and evidence of autonomic dysfunction. In the clinical setting. this diagnosis is usually associated with other anatomic and psychological diagnoses and may be associated with a variety of systemic illnesses and medicolegal factors. All components should be assessed before a treatment plan is established. Priorities should go to emergency care. acute injuries. and systemic illness. psychiatric problems. and chronic anatomic problems. in that order. Early. accurate diagnosis improves prognosis.
An evaluation of the distinction of ectopic and pituitary ACTH dependent Cushing's syndrome by clinical features, biochemical tests and radiological findings, The efficiency of various laboratory and radiological investigations in the differentiation of ectopic from pituitary dependent Cushing's syndrome was studied. based on findings in 23 patients with verified Cushing's disease and seven patients with the ectopic ACTH syndrome. Clinical features strongly favouring the ectopic type were male sex and history for less than 18 months. Basal biochemical features strongly indicating the ectopic syndrome included plasma K+ less than 3.0 mmol/l and HCO3 greater than 30 mmol/l; serum cortisol at 9 a.m. or midnight of greater than 800 nmol/l; urine free cortisol greater than 1300 nmol/24 hours; plasma ACTH greater than 100 ng/l. In the high-dose dexamethasone suppression test. suppression by less than 50 per cent of 9 a.m. serum cortisol. urine free cortisol or 17-oxogenic steroids was usually indicative of an ectopic source of ACTH. A mean suppressed value of greater than 450 nmol/l for the 9 a.m. and midnight cortisol combined occurred in all of those with the ectopic syndrome. but in none of the 23 patients with Cushing's disease. For urine free cortisol. a mean suppressed value of less than 1000 nmol/24 hours was found in all patients with Cushing's disease. but in none of those in the ectopic group. In the metyrapone test. there was an increase of less than or equal to 3-fold in 11-deoxycortisol at 24 hours in patients with ectopic ACTH; the increase was greater than 3-fold in all but one of the patients with Cushing's disease. Failure to respond to either dexamethasone or metyrapone was found in only one of the patients with Cushing's disease (Patient 16); in the ectopic group. all patients except Patient D failed to respond to either test. It is concluded that patients presenting with clinically obvious Cushing's syndrome along with measurable plasma ACTH can be reliably divided by conventional tests into those that are driven from the pituitary and those driven by ectopic ACTH.
Lung scanning for pulmonary embolism: clinical and pulmonary angiographic correlations, A group of 78 patients with suspected pulmonary embolism was studied by both ventilation perfusion lung scanning and pulmonary angiography. Symptoms and clinical signs were analysed using Bayesian techniques to produce pre-test odds for pulmonary embolism in individual patients. While. as a group. those with embolism could be discriminated from those without on this basis. major overlap existed between the groups. invalidating the use of this approach for individual patients. Strict diagnostic criteria for interpretation of lung scans were accurate using pulmonary angiography as the 'gold standard'. but at the expense of a significant number of patients (38 per cent) in the indeterminate (non-diagnostic) group. In the 48 patients in whom the test yielded a diagnostic result. there was a sensitivity of 100 per cent (15/15) and a specificity of 97 per cent (32/33). In the series as a whole. the likelihood of lung scanning correctly diagnosing pulmonary embolism was 55 per cent (15/27) and of correctly excluding embolism. 63 per cent (32/51). By the use of strict criteria for interpretation of lung scanning. reliable information can be obtained on the presence or absence of pulmonary embolism in a large proportion of patients suspected of having the condition. Such information is more discriminating than clinical signs and symptoms.
Donor seropositivity and prednisolone therapy as risk factors for cytomegalovirus infection and disease in cyclosporin-treated renal allograft recipients, We attempted to assess the importance of blood transfusion. donor seropositivity. and prednisolone therapy as risk factors for cytomegalovirus infection in cyclosporin-treated renal allograft recipients. Primary infection was diagnosed in 27 of 86 patients (31 per cent) and recurrent infection in 27 of 79 patients (34 per cent). Receipt of banked blood from unselected donors after transplantation did not increase the incidence of primary infection in the few transfused patients. Kidney donor seropositivity and maintenance prednisolone in addition to cyclosporin were associated with increases in the incidence of primary or recurrent infection. respectively. Cytomegalovirus infection was clinically mild. Presumed bacterial pneumonias occurred in three patients with recurrent cytomegalovirus infection. The absence of severe cytomegalovirus disease probably reflected the minimal use of prednisolone. Matching of seronegative donors with seronegative recipients seemed unjustifiable in cyclosporin-treated renal transplant patients.
Genetic mechanisms of tumor suppression by the human p53 gene, Mutations of the gene encoding p53. a 53-kilodalton cellular protein. are found frequently in human tumor cells. suggesting a crucial role for this gene in human oncogenesis. To model the stepwise mutation or loss of both p53 alleles during tumorigenesis. a human osteosarcoma cell line. Saos-2. was used that completely lacked endogenous p53. Single copies of exogenous p53 genes were then introduced by infecting cells with recombinant retroviruses containing either point-mutated or wild-type versions of the p53 cDNA sequence. Expression of wild-type p53 suppressed the neoplastic phenotype of Saos-2 cells. whereas expression of mutated p53 conferred a limited growth advantage to cells in the absence of wild-type p53. Wild-type p53 was phenotypically dominant to mutated p53 in a two-allele configuration. These results suggest that. as with the retinoblastoma gene. mutation of both alleles of the p53 gene is essential for its role in oncogenesis.
Norwalk virus genome cloning and characterization, Major epidemic outbreaks of acute gastroenteritis result from infections with Norwalk or Norwalk-like viruses. Virus purified from stool specimens of volunteers experimentally infected with Norwalk virus was used to construct recombinant complementary DNA (cDNA) and derive clones representing most of the viral genome. The specificity of the clones was shown by their hybridization with post- (but not pre-) infection stool samples from volunteers infected with Norwalk virus and with purified Norwalk virus. A correlation was observed between the appearance of hybridization signals in stool samples and clinical symptoms of acute gastroenteritis in volunteers. Hybridization assays between overlapping clones. restriction enzyme analyses. and partial nucleotide sequence information of the clones indicated that Norwalk virus contains a single-stranded RNA genome of positive sense. with a polyadenylated tail at the 3' end and a size of at least 7.5 kilobases. A consensus amino acid sequence motif typical of viral RNA-dependent RNA polymerases was identified in one of the Norwalk virus clones. The availability of Norwalk-specific cDNA and the new sequence information of the viral genome should permit the development of sensitive diagnostic assays and studies of the molecular biology of the virus.
Broadly neutralizing antibodies elicited by the hypervariable neutralizing determinant of HIV-1 [published erratum appears in Science 1991 Jan 4;251(4989):13, The principal neutralizing determinant (PND) of human immunodeficiency virus (HIV)-1 resides within the V3 loop of the envelope protein. Antibodies elicited by peptides of this region were able to neutralize diverse isolates. Serum from one of three animals immunized with the human T cell lymphoma virus (HTLV)-IIIMN PND peptide. RP142. neutralized MN and the sequence-divergent HTLV-IIIB isolate. Serum from one of three animals immunized with a 13-amino acid IIIB PND peptide (RP337) also neutralized both of these isolates. Characterization of these sera revealed that the cross-neutralizing antibodies bound the amino acid sequence GlyProGlyArgAlaPhe (GPGRAF) that is present in both isolates. This sequence is frequently found in the PNDs analyzed in randomly selected HIV-1 isolates. Sera from two rabbits immunized with a peptide containing only the GPGRAF residues neutralized divergent isolates. including IIIB and MN.
Abdominal wall considerations and complications in reoperative surgery, The abdominal wall is the source of significant problems for patients undergoing multiple abdominal operations. The orientation of sequential incisions must be carefully considered to avoid compromise of the abdominal wall blood supply. which may result in either acute (dehiscence) or delayed (ventral hernia) complications. Infections are the most serious problems of the multiply operated on abdominal wall. These complications may range from simple wound infection to necrotizing fasciitis. Management may require only simple drainage of the infection or may entail extensive debridement for the necrotizing processes. Regardless of the cause. the multiply operated on abdominal wall may require reconstruction because of lost fascia. Polypropylene mesh can be employed safely and effectively for this purpose.
Reoperation for biliary strictures, Benign bile duct strictures most often follow intraoperative injury not recognized until later. The ideal reconstruction entails a mucosa-to-mucosa anastomosis without tension. usually with a stent tube to maintain patency in the immediate postoperative period. The mortality rate for reoperation and bile duct reconstruction in patients who are not cirrhotic is approximately 2%. and success rates average 85%. Prevention of operative injuries by the use of cholangiography. careful dissection. and removal of the gallbladder from the fundus downward is the best treatment.
Reoperation for intra-abdominal abscess, Reoperative procedures for patients with abscess and other septic complications remain among the most difficult management problems in general surgery. The diagnosis of intra-abdominal septic complications has been greatly enhanced within the last 10 years but remains imperfect and requires clinical judgment that transcends objective methods. Surgical drainage remains the mainstay of care for patients with postoperative intraabdominal abscess.
Reoperation for colorectal carcinoma, In the management of the patient with intra-abdominal recurrence of colorectal carcinoma. surgery remains the primary mode of therapy when cure or significant palliation is anticipated. Appreciation of the importance of close follow-up after primary resection coupled with improved diagnostic modalities has allowed the surgeon not only to detect earlier recurrence but also to select the patients most likely to benefit from resection of recurrent disease. Improved surgical techniques with resultant decreases in the rates of morbidity and mortality have allowed safe hepatic resection of metastatic disease. In selected patients. this procedure produces 5-year survival rates approaching 50%. Although a clear consensus has not been reached. most studies agree that positive prognostic indicators include absence of extrahepatic disease. a small number of intrahepatic lesions. a low CEA level. and a better Dukes stage of the primary. Likewise. in the patient with recurrent disease locally. surgery provides the only means of cure and also plays a significant role in palliation. Aggressive resection with generous surgical margins in patients with contained disease may yield 5-year survival rates approaching 35%. In patients with unresectable disease and even in those with carcinomatosis. palliation can be obtained by surgical therapy. Judgment is necessary in treating these patients both preoperatively and intraoperatively. Surgical intervention for obstruction. perforation. or other anatomic or physiological compromise is often indicated and can improve the quality of life of the patient with intra-abdominal recurrence.
Surgical options in postgastrectomy syndromes, The various operations performed for the treatment of peptic ulcer disease can lead to a variety of iatrogenic disorders collectively referred to as the "postgastrectomy syndromes." Although the etiology of most of these disorders remains unclear. loss of vagal innervation and bypass. ablation. or destruction of the pylorus clearly are involved in the pathogenesis of most. if not all. of these disorders. Unfortunately. there often is also a poorly understood psychological element involved in the pathogenesis. Of all ulcer operations. proximal gastric vagotomy results in the fewest physiologic abnormalities and the mildest postoperative symptoms. The continued popularity of this operation should effect a marked reduction in the incidence of disabling postgastrectomy syndromes. Fortunately. symptoms severe enough to necessitate remedial operation are uncommon. and conservative medical management is always indicated and usually suffices. When disabling symptoms are refractory. a thorough evaluation of the patient and an accurate classification of the syndrome are essential to guarantee a satisfactory result from surgical intervention. Although numerous surgical procedures have been developed to deal with the different syndromes. with varied results. the Roux-en-Y procedure has emerged as the operation of choice for most. if not all. postgastrectomy syndromes. However. the Roux-en-Y procedure has not been universally successful. and this operation can itself lead to the recently recognized postgastrectomy state of Roux-en-Y stasis syndrome. Prevention therefore remains the best form of therapy. and remedial operation should not be undertaken until adequate time has elapsed since the original operation and all forms of conservative treatment have failed.
Reoperation versus alternatives in retained biliary calculi, Retained common bile duct stones can be treated by operation. dissolution. extraction. fragmentation. papillotomy. and reoperation. Each approach requires some expertise. and the likelihood of success of most depends on the composition and size of the stones. Good results often can be obtained nonoperatively. especially with a multidisciplinary team. Reoperation is rarely necessary.
Performance of cesarean section using absorbable staples, Although stapling techniques have gained wide acceptance in general surgery. they are still not commonly used in obstetrics. U.S. Surgical Corporation has introduced a stapling device suitable for use in cesarean sections. The copolymer staples (a blend of polylactic and polyglycolic acids) maintain their tensile strength until healing occurs and absorb without producing granulation tissue. The benefits include minimal trauma to tissue and reduced operating time. blood loss and postoperative morbidity. From July 1988 to February 1989. all patients undergoing low transverse cervical cesarean sections were randomized to either group 1 with the uterine incision performed in a routine manner or group 2 with the uterine incision cut and stapled using the Stapler. The preoperative management. intraoperative technique and postoperative surveillance were similar for both groups. The uterine incision was assessed by pelvic sonography during the postpartum period. Statistical analysis was performed using Fisher's exact test and chi-square analysis. Both groups were comparable for age. race. parity. gestational age and primary diagnosis. The length of the operative procedure was significantly shorter (p less than 0.05) in the stapled group. These patients also had a statistically significantly decreased incidence of uterine incisions and lacerations. All other parameters were not significantly different in the two groups. The stapled uterine incisions were visible by ultrasonography in more patients in the stapled group throughout the postpartum period than in the sutured group. Thus. stapling of the uterine incision was an acceptable alternative to traditional suturing techniques and it was possible to visualize clearly these incisions during the postpartum period.
Mechanical sutures in perforation of the thoracic esophagus as a safe procedure in patients seen late, Between 1976 and 1988. we treated 13 perforations of the thoracic esophagus. excluding ruptured carcinoma and intraoperative wounds. by mechanical sutures without exclusion. The delay between perforation and treatment ranged from eight to 168 hours. more than 24 hours in 11. The length of perforation was 0.5 to 15.0 centimeters. Suture was covered with a flap in ten instances; an antireflux procedure was associated with five instances. No digestive ostomies were performed. There was one death; a patient who was comatose upon arrival. The results of this small series suggest that myotomy exposing the mucosa and a flap are two essential elements of the technique; perforations of less than 6 centimeters. even when seen late. may be treated by primary surgical closure.
Theodor Kocher and the Scientific Foundation of Wound Ballistics, The systemic and rational approach used by Kocher. coupled with his interest in research of wound ballistics for more than 40 years. resulted in a clear elucidation of the principles that form the basic scientific foundation of modern wound ballistics. The validity of his work has been proved repeatedly on the battlefields of the world for more than a century. Presently. more than ever before. the sound scientific precepts revealed by Kocher are essential to keep technologic investigation within the framework of good judgment.
Correlation of APACHE II score, drainage technique and outcome in postoperative intra-abdominal abscess, The APACHE II Score was used to stratify retrospectively severity of illness in 91 patients postoperatively undergoing drainage of intra-abdominal abscesses. The method of initial abscess drainage (percutaneous or operative) was selected by the attending physician. The two groups of patients. those whose initial drainage was performed percutaneously versus operatively were similar with respect to age. sex. abscess location and. most importantly. severity of illness as assessed by the APACHE II score calculated on the day of their abscess drainage. Over-all. the mortality rate was 29 per cent (26 of 91 patients). Only 1.7 per cent of the patients with an APACHE II score of less than 15 died compared with 78 per cent when APACHE II was equal to or more than 15 (p less than 0.0001). Only 8 per cent of patients with APACHE II equal to or more than 15 undergoing percutaneous drainage survived compared with 30 per cent of patients who underwent surgical drainage procedures. While chi-square analysis demonstrated independence between outcome and drainage technique. outcome was dependent upon severity of illness (p less than 0.0005). Paradoxically. despite the attractiveness of a percutaneous technique for abscess drainage in the most ill patients. in this series. a better. although not statistically improved. chance for survival was noted with surgical treatment. We recommend that an objective severity scoring system be used whenever assessing results of treatment of intraabdominal infection and that surgical treatment not be avoided because the patient is considered to be too ill.
The Merkel cell and associated neoplasms in the eyelids and periocular region, Merkel cells are clear oval cells in the epidermis and outer root sheaths of hair follicles. which are probably of epithelial origin. share ultrastructural features with neuroendocrine cells. and are found in association with touch receptors. In the eyelid. they occur singly in the epidermis and external root sheaths of hairs and eyelashes. and in specialized touch spots alternating with eyelashes. Their typical electron microscopical and antigenic features include dense-core granules. intranuclear rodlets. spinous processes. and a positive reaction for specific cytokeratins. epithelial membrane antigen. neuron-specific enolase. chromogranin and synaptophysin. Merkel cell carcinoma probably develops from precursor cells which give rise to keratinocytes and Merkel cells. and nearly one out of ten Merkel cell carcinomas occur in the eyelid and periocular region. They tend to be bulging lesions near the lid margin of elderly patients. reddish in color. and erythematous with telangiectatic vessels. The diagnosis is based on the frequent presence of neurofilaments and paranuclear aggregates of intermediate filaments in addition to features typical of normal Merkel cells. The tumor often mimics lymphoma or undifferentiated carcinoma and frequently invades lymphatic vessels. One third of Merkel cell carcinomas recur. almost two thirds give rise to regional node metastases. and up to one half metastasize widely and result in death. Initial treatment should be prompt and aggressive. with wide resection and routine postoperative irradiation. Although metastatic lesions often respond to radiation therapy and cytostatic drugs. these treatments are mainly of palliative value.
Systemic drug interactions with topical glaucoma medications, Topically administered ophthalmic medications are capable of attaining clinically important serum concentrations. as evidenced by the variety of systemic side effects they can produce. These drugs are therefore also capable of interacting with other drugs administered orally and intravenously. This is especially important when medications are administered to an elderly population. who are often receiving multiple medications. The Physician's Desk Reference and the United States Pharmacopeia Drug Information directory contain numerous warnings of potential interactions between topical glaucoma medications and systemically administered drugs. Unfortunately. literature supporting such interactions is limited. both in quantity and quality. being anecdotal in many cases. This report summarizes available information regarding the nonocular interactions between topical ophthalmic glaucoma medications and other systemically administered medications. Clinical evidence of these interactions is lacking in many cases.
Fifty years in ophthalmology, This renowned glaucoma expert began his residency just as gonioscopy came into existence. to be followed shortly by tonography. In this memoir. Dr. Shaffer shares anecdotes and insights gained over a half century of ophthalmology practice.
The "natural history" of the transplanted lung: rates of pulmonary functional change in long-term survivors of heart-lung transplantation, Long-term pulmonary function in HLT is well preserved with no evidence of functional decline as a result of transplant "aging." providing the allografts remain free of complications. Long-term survivors with OB appear to be able to maintain adequate oxygenation despite the marked alterations of pulmonary function. The ability to preserve gas exchange at reasonable levels of oxygenation may be the factors permitting extended survival with OB for mean periods of 36.0 months or greater. Preliminary studies suggest that a declining FEF50/FVC. at a time when pulmonary function is normal. may be an index of impending airway disease. Physiologically. from a long-term point of view. HLT remains a viable option for selected patients with end-stage cardiopulmonary disease.
Single-lung transplantation for pulmonary vascular disease, Six patients with end-stage pulmonary vascular disease received right SLTs. Though patients generally had difficult early postoperative courses. four of the six have survived from 3 to 23 months and have achieved good recovery of right ventricular function and good functional results. SLT is a viable option in selected patients with severe pulmonary hypertension even when right ventricular function is severely impaired.
Pharmacokinetics of ranitidine in morbidly obese women, The pharmacokinetics of a single dose of ranitidine 50 mg iv were determined in ten normal-weight and ten morbidly obese (greater than 90 percent ideal body weight) age-matched female subjects. No significant difference between normal and obese subjects was found in ranitidine peak serum concentration. volume of distribution. clearance. and elimination rate constant. Ranitidine volume of distribution and clearance were significantly smaller in the obese subjects per kilogram of total body weight (1.45 vs. 0.80 L/kg and 0.59 vs. 0.33 L/h/kg. respectively; p less than 0.001) but not when normalized to ideal body weight (1.65 vs. 1.45 L/kg and 0.68 vs. 0.59 L/h/kg). We conclude that obese patients receiving ranitidine therapy should be treated with standard dosages or dosages based on ideal body weight.
Reports of erythematous macular skin eruptions associated with diltiazem therapy, Diltiazem is a commonly prescribed calcium-channel antagonist for hypertension and ischemic heart disease. The incidence of rash associated with diltiazem therapy is reported to be 1.3 percent. We describe two patients who developed erythematous. macular skin eruptions. approximately two weeks following institution of diltiazem. The skin eruptions resolved after symptomatic treatment and the patients received further therapy with another calcium-channel antagonist. Diltiazem-associated skin eruptions are a rare adverse effect; however. the incidence of rash may occur more frequently than reported in postmarketing surveillance studies.
Fluosol: an oxygen-delivery fluid for use in percutaneous transluminal coronary angioplasty, Fluosol (20% intravascular perfluorochemical emulsion) is an oxygen-carrying emulsion used to deliver oxygen to ischemic myocardium during percutaneous transluminal coronary angioplasty (PTCA). Fluosol is composed of two perfluorochemicals. perfluorodecalin and perfluorotripropylamine. It has a high capacity for oxygen solubility. a low viscosity. and a small particle size. Following administration. the perfluorochemicals in fluosol are not metabolized. Rather. most are expired as gaseous particles through the lungs; the remainder are taken up by the organs of the reticuloendothelial system and later expired. When administered during balloon inflation in PTCA. fluosol preserves ventricular wall motion and global left ventricular ejection fraction. In addition. it minimizes ST segment changes and preserves cardiac output. Fluosol may be especially useful in patients who have poor contractile reserve. multivessel disease. or serious underlying illness. Other uses under investigation include limitation of myocardial infarct size and chemosensitization or radiosensitization of malignant tumors. Adverse effects secondary to the use of fluosol include ventricular arrhythmias. pruritus. bradycardia. chest pain. dyspnea. and increased respiratory rate. Fluosol must be thawed. admixed. warmed to body temperature. and oxygenated prior to intracoronary administration. The usual administration rate is 60 mL/min during each balloon inflation.
Improving compliance and increasing control of hypertension: needs of special hypertensive populations, Approximately 60 million people in the United States have hypertension. More than half are either untreated or treated without blood pressure control. despite the well-known risks of hypertension and the established benefits of treatment. The major reason for inadequate control of hypertension is poor adherence to treatment. Approximately 50% of patients with hypertension fail to keep follow-up appointments. and only 60% take their medications as prescribed. Barriers to effective therapeutic adherence include poor doctor-patient communication. cost of antihypertensive therapy. and side effects of the drugs. To increase control of hypertension. compliance with therapy must be improved. Physicians and patients must be mutually committed to achieving control of blood pressure. Physicians should communicate instructions clearly and prescribe therapies that are effective. affordable. and have minimal or no adverse effects on patient quality of life or overall cardiac risk profile. The needs of special hypertensive populations (i.e.. elderly. black. and young patients) must also be recognized and addressed. Patients must follow recommendations and alert their physicians to any problems with their medications--particularly those relating to side effects and cost. When selecting drug therapy it should be noted that older patients are sensitive to volume depletion and sympathetic inhibition. In this group of patients. initial drug doses should be low and increments smaller and more gradual than in younger patients. Black patients with hypertension show an accentuated response to diuretics and blunted responses to beta-blockers and angiotensin-converting enzyme (ACE) inhibitors as monotherapy. However. when used with a diuretic. there are no racial differences in the blood pressure lowering effects of beta-blockers and ACE inhibitors.
Preclinical pharmacology of celiprolol: a cardioselective beta-adrenergic antagonist and mild vasodilator, Celiprolol is a new antihypertensive agent that represents a new generation of beta-blockers. It combines cardioselective beta-adrenergic antagonism (beta 1) with a mild vasodilation via vasoselective beta-adrenergic agonism (beta 2). Results of animal studies show that celiprolol has beta 1-antagonist potency similar to that of propranolol and atenolol. and cardioselectivity slightly greater than that of atenolol. Celiprolol does not produce bronchoconstriction but has mild propranolol-resistant bronchodilatory properties in cats. The compound also relaxes vascular smooth muscle in a propranolol-sensitive fashion. suggesting a mechanism of beta 2-agonism. The beta 2-agonism results in a selective downregulation in beta 2-receptor number and response in tissue culture. as well as in peripheral tissue from celiprolol-treated volunteers. The decreases in beta 2-receptors are blocked by concomitant treatment with propranolol. Celiprolol is devoid of cardiac depressant activity and in fact has mild cardiostimulatory actions. The cardiostimulation is not via beta 1-stimulation. since it is not abolished by beta-blocking doses of propranolol. In a model of severe myocardial ischemia. celiprolol attenuates the ischemia-induced myocardial acidosis and improves the regional segment function. These results are suggestive of myocardial protection. In summary. celiprolol distinguishes itself from other beta-blockers by virtue of its cardioselectivity. vasorelaxation via beta 2-agonism. and the lack of bronchoconstriction and cardiodepression. These properties observed in animal studies have also been documented in clinical trials.
Clinical safety and efficacy of celiprolol, The management of essential hypertension requires therapeutic selections that are not only effective in reducing diastolic blood pressure but are also tailored to the individual patient. with minimal effect on patient demographics. concurrent illnesses. and cardiovascular risk factors. Celiprolol hydrochloride is a new highly cardioselective vasodilating beta-adrenoceptor antagonist that has been proven effective and safe for the treatment of essential hypertension. It is comparable to other therapies in blood pressure control while demonstrating an excellent safety profile. favorable hemodynamic activity. and minimal effects on other cardiovascular risk factors. Celiprolol may offer the physician a unique therapeutic alternative.
Metabolic considerations in the choice of therapy for the patient with hypertension, The objective of treating patients with hypertension is not simply to reduce blood pressure but rather to prevent the associated morbidity and mortality. Recent assessments of clinical trials have shown that while the risk of stroke is consistently lower with antihypertensive therapy. the same degree of success has not been demonstrated for coronary artery disease (CAD). Although there are many explanations of why we have not done as well in preventing CAD. one possibility is that the therapy used in clinical trials. primarily thiazide diuretics and beta-adrenoreceptor blockers. has increased the patient's risk of developing coronary atherosclerosis or lethal arrhythmias. Four classes of antihypertensive agents are recommended for initial therapy--thiazide diuretics. beta-adrenoreceptor blockers. angiotensin-converting enzyme (ACE) inhibitors. and calcium entry blockers. The metabolic effects of thiazide diuretics include electrolyte disturbances (hypokalemia. hypomagnesemia. and hyponatremia). dyslipidemia (increased triglycerides). abnormalities of glucose metabolism (hyperglycemia. hyperinsulinemia. and peripheral insulin resistance). and hyperuricemia. beta-Adrenoreceptor blockers have many of the same metabolic adverse reactions. beta-Adrenoreceptor blockers without intrinsic sympathomimetic activity (ISA) also cause dyslipidemias (lowered high-density lipoprotein cholesterol and increased triglycerides) and abnormalities of glucose metabolism (hyperglycemia. hyperinsulinemia. and peripheral insulin resistance). beta-Adrenoreceptor blockers with ISA and third-generation beta-blockers with selective partial agonist activity (celiprolol and dilevalol) do not cause dyslipidemia and to date do not appear to induce abnormalities in glucose metabolism. ACE inhibitors may decrease triglycerides and increase high-density lipoprotein cholesterol. and captopril may improve insulin sensitivity. Calcium entry blockers are metabolically neutral.
Body composition by bioelectrical-impedance analysis compared with deuterium dilution and skinfold anthropometry in patients with chronic obstructive pulmonary disease, Body composition is an important measure of nutritional status in patients with chronic obstructive pulmonary disease (COPD). We generated a regression model for bioelectrical impedance (BI) by using deuterium dilution (2H2O) as a reference method in 32 COPD patients. aged 63 +/- 9 y (mean +/- SD). in stable pulmonary and cardiac condition. Height squared divided by resistance (Ht2/Res) correlated well with total body water (TBW) as measured by 2H2O (r = 0.93. P less than 0.001. SEE = 1.9 L). The best-fitting regression equation to predict TBW comprised Ht2/Res and body weight (r2 = 0.89. SEE = 1.8 L. P less than 0.001). BI-predicted TBW was used to estimate BI-fat-free mass (FFM) that was compared with skinfold-thickness-based FFM predictions (Anthr-FFM). Relative to BI-FFM a significant overestimation of 4.4 +/- 0.8 kg was found by Anthr-FFM. Our results suggest that BI is a useful measure of body composition in patients with severe COPD.
Adipose tissue fatty acid composition and its relations to diet and plasma lipid concentrations in hemodialysis patients, Adipose tissue fatty acid composition. serum lipid profile. and dietary intake of 37 patients on maintenance hemodialysis were studied. In August 1982. 1984. and 1986. analyses were carried out in 15 normotriglyceridemic (NTG) and 22 hypertriglyceridemic (HTG; type IV hyperlipidemia) patients. No correlations were found between dietary intake of polyunsaturated fatty acids (PUFAs). ratio of polyunsaturated to saturated fatty acids (P-S ratio). and carbohydrate content on the one hand and serum lipid concentrations on the other in the two groups. Adipose tissue linolenic acid correlated negatively with serum cholesterol in both groups. Strong correlations were found between dietary intake of PUFAs and adipose tissue linoleic acid content. between PUFAs and the double-bond index. between P-S ratio and adipose tissue linoleic acid content. and between P-S ratio and the double-bond index. No significant differences in dietary intake or adipose tissue fatty acid composition were observed between NTG and HTG patients. Thus. no evidence was found for exogenous dietary influences on serum lipid concentrations. The adipose tissue linoleic acid content did reflect the dietary intake of PUFAs.
Correlation of isomeric fatty acids in human adipose tissue with clinical risk factors for cardiovascular disease, The relationships between the adipose tissue concentrations of 19 geometric and positional fatty acid isomers and 10 cardiovascular disease risk factors were determined in 76 free-living adult males. The percentages for trans isomers (total mean +/- SD 4.14 +/- 0.97%) and cis isomers (total mean +/- SD 2.91 +/- 0.34%) in adipose tissue generally agreed with dietary estimates based on the consumption of hydrogenated oils. A major exception was the percentage of 11c-18:1. which was twofold higher in adipose tissue. The total level of fatty acid isomers in adipose tissue or a factor (derived by factor analysis) that was representative of isomers of dietary origin was not significantly correlated with the cardiovascular risk factors. Only three trans isomers (11t-18:1. 12t-18:1. and 5t-14:1) and three cis isomers (11c-18:1. 13c-18:1. and 7c-16:1) were weakly correlated either positively or negatively with age. body mass index. plasma and lipoprotein cholesterol. and/or blood pressure (P less than 0.05. r greater than 0.231).
Plasma lecithin-cholesterol acyltransferase activity and plasma lipoprotein composition and concentrations in kwashiorkor [published erratum appears in Am J Clin Nutr 1991 Sep;54(3):590, Plasma lecithin-cholesterol acyltransferase (LCAT) activity. lipoprotein composition. and lipoprotein concentrations were measured in 21 children with kwashiorkor before (day 1). during (day 10). and after treatment (day 30). Day 1 LCAT activity (78.2 mumol.L-1.h-1) was decreased with respect to day 10 (139.2 mumol.L-1.h-1. P less than 0.001) and day 30 (108.0 mumol.L-1.h-1. P = 0.08). Plasma total cholesterol (TC). cholesterol ester (CE). and lipoprotein CEs (VLDL. IDL. LDL. and HDL) were reduced relative to days 10 and 30 (P less than 0.001). Before treatment HDL composition was abnormal. On days 1. 10. and 30. the respective mean HDL-apolipoprotein A-I (apo A-I) concentrations were 23.33. 39.66. and 36.08 mumol/L. LDL-apo B concentrations were 0.40. 0.68. and 0.56 mumol/L (P less than 0.01. days 10 and 30 vs day 1). LDL particles on day 1 were decreased in number. depleted of CE. and laden with triacylglycerol and surface lipids. LCAT activity on day 1 correlated with LDL-CE linoleate (P less than 0.05. r = 0.48). Reduced plasma LCAT activity is an important factor related to abnormalities in lipoprotein composition and concentrations.
Preprandial blood glucose values and glycemic responses in insulin-dependent diabetes mellitus at constant insulinemia, The influence of preprandial blood glucose (PPBG) concentration on glycemic responses was studied in seven subjects with insulin-dependent diabetes who. by means of the artificial pancreas. had achieved PPBG concentrations of 6. 9. and 17 mmol/L. A test meal of 50 g parboiled rice was given at the three different occasions and a constant insulin infusion was provided during the observation periods. The mean postprandial-blood-glucose-response area (above basal) differed significantly at the three blood glucose concentrations of 6. 9. and 17 mmol/L. reaching 1371. 621. and 179 mmol/L x 240 min. respectively (P less than 0.01). A negative correlation between the PPBG concentrations and the glycemic responses to the test meal was found (r = 0.94; P less than 0.001). The fasting insulin concentration at a PPBG concentration of 17 mmol/L was lower than at a PPBG concentration of 6 and 9 mmol/L. In conclusion. the glycemic responses to a carbohydrate meal are inversely correlated to the PPBG concentration in insulin-dependent diabetic subjects.
Blood pressure lowering in elderly subjects: a double-blind crossover study of omega-3 and omega-6 fatty acids, In 46 elderly (aged greater than or equal to 60 y) hypertensive subjects with entry systolic blood pressure (SBP) greater than or equal to 160 or diastolic blood pressure (DBP) greater than or equal to 90 mm Hg. our specific aim in a randomized. double-blind. crossover study (two 8-wk treatment periods separated by a 3-wk washout) was to compare blood pressure-lowering effects of 9 g fish oil/d [omega-3 (n-3) fatty acid] vs 9 g corn oil/d [omega-6 (n-6) fatty acid]. After a 4-wk baseline period. 22 subjects were randomly assigned to receive fish oil and 24 to receive corn oil. For both 8-wk treatments there were no between-group differences in the change in blood pressure. There was a treatment difference for standing DBP when baseline values were compared with those after treatment 2; DBP decreased by 5.1 mm Hg in the fish-oil group vs 0.72 mm Hg in the corn-oil group (P = 0.024). Within groups during the first treatment. both fish oil and corn oil lowered all four blood pressure measures (P less than 0.05); blood pressures were not further lowered during the second treatment compared with the washout period. There were no significant between-group differences in laboratory safety tests or categorical side effects. Fish oil lowered triglycerides by 0.47 mmol/L (P less than 0.001). In elderly subjects. diet plus both omega-3 and omega-6 supplements (9 g/d) safely and effectively lower SBP and DBP.
Nail-gun suicide, Two cases are reported of young men who committed suicide using a nail gun. One shot himself through the heart and left lung. The other shot himself in the head. No cases of completed suicide by nail gun have previously been reported in the English literature. These cases are reported because of their uncommon nature and because they represent a potentially fatal use of a relatively common industrial implement.
Suicides by starter's pistols and air guns, We report the case of a 25-year-old depressed woman who committed suicide with a starter's pistol loaded with CS tear-gas ammunition. The propellant gases of the contact shot entered her chest through the left sixth intercostal space. Exsanguination was caused by perforations of the pericardium and apex of the heart. Autopsy did not reveal any metallic or other foreign bodies that might have originated from the propellant. the cartridge. or any bulletlike material. Her injuries were thus caused by the propellant alone. 0.5 mg L-1 of the CS degradation product cyanide was detected in the cardiac blood. We also report the case of a 54-year-old man. suffering from depressive psychosis. who committed suicide with an air rifle. The lead-pointed Diabolo bullet entered his brain through the right large wing of the sphenoid bone. traversed the right temporal brain pole. damaged the right middle cerebral artery and the right optic tract. and finally lodged in the left central ganglia. There was extensive basal subdural hemorrhage and tamponade of all cerebral ventricles. Death was attributed to cerebral failure. We furthermore list another 26 cases of suicide by rarely used weapons from 1947 to 1989.
Death by smothering and its investigation, This case report provides details from an extensive death investigation. the results of which led to the certification of suicidal manner of death by means of smothering in a pillow. without additional assistance from other persons or mechanical devices. This was the death of a chronically mentally ill person who was under currently approved professional treatment. Major investigative aspects of this case were the death-scene observations of the body. elimination of the possibility of homicide. and the study and analysis of the subject's psychiatric illness. Reasons for the uncommonness of reported deaths in this category are discussed.
Forensic photography. Ultraviolet imaging of wounds on skin, The use of ultraviolet light (UVL) to study and document patterned injuries on human skin has opened a new frontier for law enforcement. This article discusses the photographic techniques involved in reflective and fluorescent UVL. Documentation of skin wounds via still photography and dynamic video photographic techniques. which utilize various methods of UV illumination. are covered. Techniques important for courtroom presentation of evidence gathered from lacerations. contusions. abrasions. and bite marks are presented through case studies and controlled experiments. Such injuries are common sequelae in the crimes of child abuse. rape. and assault.
A suicide by thiopentone infusion, A suicide by intravenous thiopentone infusion is described. A search of the literature revealed only four cases. but this paucity is possibly due to under-reporting. as these suicides occur amongst medical personnel.
Homicide-suicide by stabbing, It is rare that an assailant kills someone and afterward commits suicide by stabbing himself on the scene. This report describes how a young soldier killed his young girlfriend and then killed himself.
Wrist slashing in a detention center. Case report and review of the literature, Suicides that occur in custody are rare and thus require extensive forensic analysis. Asphyxia by hanging is the most common means of suicide: at least 87.5% of successful suicides are committed in this way. A unique case of suicide in custody is presented in which a prisoner slashed his wrist with an eyeglass lens. The evidence and proceedings that led to this suicide are reviewed and the data are compared with known behavioral patterns. The world literature concerning suicide while incarcerated is reviewed.
Suicide by chloroform ingestion following self-mutilation, A case of suicide is described that combined elements of psychotic self-mutilation. both chronic and terminal. and poisoning with ingested chloroform. This illustrates the need to consider unusual methods when investigating the deaths of people with patterns of bizarre behavior and access to unusual. fatal materials.
Death notification, Family notification in sudden. unexpected. and violent death is a major responsibility of law enforcement. medical examiner. and coroner offices. This report reviews and discusses the process and procedures utilized in death notification and provides suggestions to accomplish this difficult task more effectively.
Long-term results of Ionescu-Shiley valve in the tricuspid position, A retrospective analysis of the long-term results of using the Ionescu-Shiley pericardial bioprosthesis in the tricuspid position was carried out on 73 patients (8 men. 65 women). Of these procedures. ten were tricuspid valve replacement alone and the remainder were in combination with other valve procedures. The mean follow-up was 9.6 years (range. 4 to 18 years). The mean age of the patients was 53 years (range. 27 to 78 years). Seventy-one of the patients suffered tricuspid valve dysfunction from rheumatic heart disease. There were 13 postoperative deaths (within 30 days). giving a mortality rate of 17.8%. The actuarial survival at 10 years was 71% +/- 4.2%. Of the survivors. 49 (79.6%) were in functional class I or II. Primary tissue valve failure in the tricuspid position occurred in 1 patient 12 years after implantation and required reoperation. In another patient bioprosthetic tricuspid valve endocarditis developed. There was no incidence of thromboembolic complications. We conclude that the Ionescu-Shiley pericardial bioprosthesis was a satisfactory prosthesis in the tricuspid position in patients with acquired valvar dysfunction.
Pulmonary embolectomy: a 20-year experience at one center, Between 1968 and 1988. 96 consecutive patients with acute massive pulmonary embolism underwent pulmonary embolectomy under cardiopulmonary bypass. The operative mortality rate was 37.5%. We analyzed 12 clinical and hemodynamic variables by univariate and multivariate analyses to assess the predictive factors of postoperative outcome. Multivariate analysis disclosed that cardiac arrest and associated cardiopulmonary disease were independent predictors of operative death. Long-term follow-up (range. 2 to 144 months; mean. 56 months) information was available for 55 of the 60 discharged patients: 6 had died. and 5 complained of persistent mild or severe exertional dyspnea (New York Heart Association class II). These results help assess the preoperative risk in patients undergoing pulmonary embolectomy. They also show that. in the few patients who do not benefit from optimal medical therapy. pulmonary embolectomy remains an acceptable procedure in view of the long-term results.
When do cerebral emboli appear during open heart operations? A transcranial Doppler study, The transcranial Doppler technique enabled the detection of cerebral air emboli in 10 of 10 patients during open-heart valve operations despite standard deairing procedures. With this technique. the occurrence of emboli in the right middle cerebral artery was followed continuously in patients undergoing aortic or mitral valve replacement. Membrane oxygenators were used. Scattered emboli were observed during the insertion of the aortic cannula. at the start of cardiopulmonary bypass. and after the declamping of the aorta with the heart beating while empty. During the period of aortic cross-clamping. no emboli were detected. Despite careful deairing procedures. the recordings indicated a large amount of emboli during filling of the empty beating heart in all 10 patients. Thus. this study indicates that cerebral emboli in open heart procedures are most likely to occur during the redistribution of blood from the heart-lung machine to the patient when the heart is beginning to eject actively. despite careful standard deairing procedures. Meticulous deairing before declamping the aorta is strongly advocated. In addition. a short period of filling of the beating heart before final closure of the aortic incision or vent may decrease the incidence of cerebral emboli. A concomitant reduction in cerebral blood flow by hyperventilation or anesthetics or both during filling of the empty beating heart may also be beneficial.
Retrograde continuous warm blood cardioplegia: a new concept in myocardial protection, This report presents the results in our first clinical series of patients receiving continuous warm blood cardioplegia through the coronary sinus. Warm oxygenated blood cardioplegia has certain theoretical advantages. such as continuously supplying oxygen and substrates to the arrested heart while avoiding the side effects of hypothermia. Retrograde infusion of cardioplegia also offers certain advantages (eg. in valve operations and in patients with severe coronary artery disease) that are complementary to warm blood cardioplegia. Retrograde warm blood cardioplegia was used in 113 consecutive patients (85 men and 28 women with a mean age of 61 years) undergoing various procedures. Three percent of the patients died. 7% needed transient intraaortic balloon pump support. 6% had evidence of perioperative myocardial infarction. and 96% had spontaneous return of rhythm. There were no coronary sinus injuries. This new technique of retrograde continuous warm blood cardioplegia is a simple. safe. and reliable method of myocardial protection that may change the way we currently protect the heart intraoperatively.
Dopamine and high-dose insulin infusion (glucose-insulin-potassium) after a cardiac operation: effects on myocardial metabolism, Myocardial insulin resistance. in association with surgical stress. restricts the availability of carbohydrates and increases the load of free fatty acids (FFAs) on the heart. On theoretical grounds adrenergic drugs may be expected to aggravate this situation. whereas the opposite is expected from insulin. The influence of dopamine and a combination of dopamine (7 micrograms/kg body weight/min) and high-dose insulin (7 IU/kg) on myocardial energy metabolism was studied in 19 patients 4 to 6 hours after a coronary operation. Infusion of dopamine (7 micrograms/kg body weight/min) induced metabolic changes that may be unfavorable to the strained myocardium. There was an increase of the myocardial FFA load and a rise in myocardial oxygen expenditure by 60% to 70%. There changes were. however. not matched by an increase in myocardial substrate uptake. "Oxygen wastage" of FFA metabolism at high circulating catecholamine levels is suggested. There were also signs suggesting an amplified systemic trauma response: systemic oxygen consumption increased by 15%. and an increase in the arterial levels of FFAs. glucose. and ketones was observed. Divergent metabolic effects of dopamine and insulin were demonstrated. The most prominent metabolic effects of adding high-dose insulin to dopamine were a marked reduction of arterial FFA levels and a shift toward myocardial carbohydrate utilization at the expense of FFAs. Myocardial uptake of FFAs ceased. Myocardial insulin resistance may thus to a significant extent be overcome by supraphysiological doses of insulin. even during infusion of adrenergic drugs.
Transesophageal echocardiography in acute aortic transection, Confirming the diagnosis of acute transection of the descending aorta can be problematic. Unnecessary patient movement and time delay are often associated with conventional investigations. We describe a patient in whom such an injury was clearly and quickly defined at the bedside by transesophageal echocardiography.
Improved technique for inserting a T tube in patients with subglottic stenosis, An improved method for inserting a silicone T tube through a tracheostomy stoma in patients with subglottic stenosis is presented. A silicone T tube is pulled into the trachea with a catheter that is inserted into the tracheostomy stoma. advanced through the stenotic subglottic space. and pulled out the mouth. A cone-shaped dilator is placed beforehand at the proximal end of the vertical limb of the T tube to facilitate the passage of that end through the stenotic subglottic space. This method was used in 4 patients with good results. We suggest this technique be tried when attempts to insert a T tube by the usual method fail. as it can be performed under local anesthesia without special instruments and is technically easy.
Apical aortic cannulation: application of an old method with new paraphernalia, An instrument assembly consisting of a special aortic cross-clamp and double-lumen perfusion cannula is presented. The application of these instruments allows occlusion of the ascending aorta traversed by the perfusion cannula inserted directly or through the apex of the heart as well as simultaneous left ventricular venting.
Depression, distress, lymphocyte subsets, and human immunodeficiency virus symptoms on two occasions in HIV-positive homosexual men, We evaluated the extent to which depressive disorders. psychiatric distress. and psychosocial stressors are related to three measures of human immunodeficiency virus (HIV) illness. both cross-sectionally and during a 6-month period. in a community sample of 124 HIV-positive homosexual men. The dependent variables are immune status measured by CD4 and CD8 cell subsets. number of signs and symptoms commonly associated with HIV infection. and a cumulative index of HIV illness stage. We chose to focus on CD4 cell count because it is the immune marker most closely linked to the clinical consequences of HIV infection. We found no relationships between the independent variables and immune status or illness stage. The HIV-positive men who were depressed or distressed or who reported more life stressors had no greater immunosuppression or more advanced illness stage than did the others. either concurrently or across occasions. We did find a suggestive pattern of association between depressive disorders. distress. and stressors and the number of HIV-related symptoms. which warrants further study.
Multidisciplinary baseline assessment of homosexual men with and without human immunodeficiency virus infection. I. Overview of study design, Although much is known about the virus believed by most experts to be the cause of the acquired immunodeficiency syndrome and about its pathogenic actions. major areas of ignorance remain. Among these are the reasons for the varying time between infection with human immunodeficiency virus and development of acquired immunodeficiency syndrome. the relationship between neurologic and medical aspects of the disease. the time course of neuropsychological findings. and the prevalence of psychiatric morbidity. We assessed 124 homosexual men who were positive for human immunodeficiency virus and 84 who were negative for the virus. In this article we describe the study design. method of recruitment. and medical and demographic characteristics of the cohort. which will be followed up for 5 years.
Effectiveness of psychoeducational interventions in reducing emotional distress after human immunodeficiency virus antibody testing, To examine the effectiveness of three psychoeducational interventions in reducing emotional distress after voluntary serologic testing for human immunodeficiency virus-1.307 physically asymptomatic adults were randomly assigned to standard counseling. counseling plus a three-session interactive video program. or counseling plus six individual sessions of stress prevention training. Subjects were evaluated using five standardized distress measures at entry and 3 months later. Among the 204 human immunodeficiency virus-seronegative subjects. mean distress measures decreased significantly after all three interventions without differential treatment effects. Among the 103 human immunodeficiency virus-seropositive subjects. mean distress measures decreased significantly after the stress prevention training and did not significantly increase in the other two interventions. We conclude that stress prevention training is particularly helpful after notification of human immunodeficiency virus seropositivity.
Dosage of haloperidol for schizophrenia, Eighty-seven newly admitted inpatients with schizophrenia were randomized to receive 10. 30. or 80 mg/d of oral haloperidol. They were treated under double-blind conditions for 6 weeks. less if their acute symptoms remitted sooner. Survival analysis showed no differences among the three treatments. Side effects were minimal in all three treatment groups. and there were no differences in side effects among the groups. These results suggest that dosages higher than 10 mg/d of haloperidol for most patients have no additional beneficial effect in the treatment of acute or exacerbated schizophrenia.
When is it safe to stop patching, Prior reports indicate that about half of amblyopia patients successfully treated with occlusion subsequently require maintenance patching. This retrospective study was designed to discover what clinical characteristics might be associated with a stable outcome following primary occlusion. Included were 188 patients who: (1) had amblyopia related to strabismus. anisometropia or media opacity; and (2) were followed up for at least one year after successful primary occlusion. Patients who did not comply with treatment or who did not achieve equal vision were excluded. Their ages ranged from 2 to 119 months (mean 29 months). Eighty-eight patients (47%) who required no further occlusion were designated the clinically stable group (CSG). The remaining 100 (53%). who subsequently needed patching because of unequal acuities. constituted the maintenance patching group (MPG). CSG patients were older at the beginning (mean 33 months) and at the end (mean 40 months) of primary occlusion than were MPG patients (means 26 and 31 months). Primary occlusion was more likely to have been discontinued because of equal recognition acuities in CSG patients. while equal fixation behaviour or preferential looking was more likely in MPG patients. Distribution of diagnoses. severity of amblyopia at presentation. and length of follow-up were similar in the two groups. Visual outcomes at last follow-up were slightly better in the CSG (p = 0.002). We conclude that. in general. patching can be safely discontinued after the third birthday. Although follow-up after primary occlusion is important to ensure stable results in all patients. preverbal children are more likely to require maintenance patching.
Peripheral contrast sensitivity in glaucoma and ocular hypertension, Contrast sensitivity has been measured in patients with glaucoma and ocular hypertension. the latter graded into high. medium. and low risk clinical groups. Measurements were made centrally and peripherally at 10 degrees. 15 degrees. 20 degrees. and 25 degrees off-axis at each of the four meridians 45 degrees. 135 degrees. 225 degrees. and 315 degrees. A sine wave grating of 1.9 cycles/degree. reversing at 1 Hz was used. It was displayed on a 100-Hz refresh rate monitor. Normal values were established to compare those from 41 eyes from patients with either primary open angle glaucoma (POAG) with minimal field loss detectable on a Humphrey perimeter. or raised IOP and/or disc changes but no field loss (OH). Those with POAG had normal central contrast sensitivity. but at 20 degrees and 25 degrees eccentricity the values were greater than 2 standard deviations above the normal mean. This was also the case for high risk OH. but not for low risk patients. All the high risk patients except one who had abnormal peripheral contrast sensitivity had possible field defects (threshold elevation at one or more points more than 5 but less than 10 dB above normal mean). Only one of those with normal peripheral contrast sensitivity had such 'suspect points'. The results are assessed in terms of screening of glaucoma suspects.
Precapsular film on the aging human lens: precursor of pseudoexfoliation, In many older patients we observed a layer of subtle opacification on the anterior lens capsule. appearing as a ground glass film biomicroscopically. This precapsular film (PCF) could be uniform but often had radial grey lines in the mid zone. holes in the paracentral region. and was occasionally rolled up in strings. Lens capsular material obtained at cataract extraction was studied in patients with and without the film. By scanning electron microscopy the PCF appeared as a friable. incomplete fibrillar layer. with rolling of the edges suggesting loose attachment. Ultrastructurally its component fibrils were from 3-6 nm in diameter. similar to the finer fibrils in pseudoexfoliation (PSX) material. Life PSX material the layer stained positively for the elastic microfibril-associated protein. fibrillin. in a lens with radial striations. These similarities suggested that the two conditions have some relationship and that the PCF may be a precursor of PSX. Finding patches of the fibrillar network in some control patients implies that the PCF is common in patients of cataract age. though seldom detected clinically.
Diode laser trabeculoplasty (DLT) for primary open-angle glaucoma and ocular hypertension, A pilot study has been carried out to examine the efficacy of diode laser trabeculoplasty in the treatment of primary open-angle glaucoma and ocular hypertension. The device used was portable and could be attached to a standard slit-lamp microscope. Powers of 0.8-1.2 W were used. with a spot size of 100 microns and a pulse of 0.20 second. Laser trabeculoplasty carried out on 20 eyes for glaucoma resulted in a mean ocular hypotensive effect of 10.2 mmHG at two weeks after treatment and of 9.55 mmHg at 6 months. It is concluded that diode laser trabeculoplasty is an effective mode of treatment for eyes with open-angle glaucoma or with ocular hypertension.
Stercoral perforation of the colon, Stercoral perforation of the colon is rare. The 64 reported cases are reviewed to define the syndrome of stercoral perforation. and to facilitate accurate diagnosis and treatment. Features of localized or generalized peritonitis were universal; however. only 11 per cent were correctly diagnosed before operation. Recognition that the disease involves a segment of colon rather than only the focal point of perforation is essential to adequate surgical treatment. It is postulated that this is the reason for the higher postoperative mortality following closure of the perforation and proximal colostomy (57 per cent) or exteriorization alone (43 per cent). compared with resection of the diseased segment and exteriorization (32 per cent). Resection and exteriorization is therefore the treatment of choice is most situations.
Surgical strategy for early gastric cancer, The diagnostic and therapeutic options in early gastric cancer are reviewed. In Japan. the rate of detection of early gastric cancers has increased so that minute gastric cancers can now be identified as a result of advances in diagnostic methods. The results of histopathological staging of a large number of resected specimens have led to three surgical options based on size and depth of the primary lesion. namely classical R2 resection. radical resection with limited lymphadenectomy and endoscopic surgery.
Adrenergic control of the internal anal sphincter is abnormal in patients with idiopathic faecal incontinence, There is histological and functional evidence that the internal anal sphincter is abnormal in patients with idiopathic faecal incontinence. The in vitro responsiveness of the internal anal sphincter to noradrenaline (an important sympathetic neurotransmitter) and electrical field stimulation (known to stimulate the intrinsic innervation) has been studied. Muscle strips from eight patients with incontinence undergoing postanal repair and five controls undergoing resection for low rectal carcinoma were studied. The contraction-response curves for noradrenaline were significantly different. and the EC50. the concentration required to produce 50 per cent of maximum contraction. was higher in incontinent patients (P less than 0.001). Electrical field stimulation produced initial contractions in four of the control group which were blocked by phentolamine. This contraction was not present in the incontinent patients (P less than 0.01). These results indicate an abnormality in the adrenergic innervation of the internal anal sphincter in patients with idiopathic faecal incontinence.
Adjuvant chemotherapy with 5-fluorouracil, vincristine and CCNU for patients with Dukes' C colorectal cancer. The Swedish Gastrointestinal Tumour Adjuvant Therapy Group, A prospective controlled randomized trial testing adjuvant postoperative combination chemotherapy (5-fluorouracil. lomustine (CCNU) and vincristine) versus no adjuvant therapy in patients operated on for Dukes' C colorectal cancer is reported. In total 334 patients aged less than 70 years were recruited: 205 patients with colonic and 99 with rectal cancer. but there were three protocol violations and these cases are excluded from further consideration. Twenty-seven patients had a limited resection of their cancer. After 5 years' follow-up there was no significant difference in the tumour-free survival rate or in the survival rate between the treated and control groups. Twenty-nine of the 147 patients who started chemotherapy discontinued this treatment because of side-effects. mainly from the gastrointestinal tract. In 30 patients treatment was discontinued because of recurrent disease. The conclusion is that systemic administration of combination chemotherapy for colorectal cancer after operation is not worthwhile in routine clinical practice.
Value of retesting subjects with a positive Hemoccult in screening for colorectal cancer, Within a prospective randomized screening study for early detection of colorectal cancer with rehydrated Hemoccult II test. the possibility of increasing the specificity of the test by retesting patients with an initially positive Hemoccult II test was investigated. Of those offered the test 3561 (62.6 per cent) returned it and it was positive in 210 cases (5.9 per cent). The repeat test was performed by 184 patients and was positive in 68 (1.9 per cent). All those with a positive initial test had rectosigmoidoscopy to 60 cm and a double contrast enema. A carcinoma was found in one in seven patients with a positive retest but in only one in 100 patients with a negative retest (P less than 0.001). The specificity of the test was. therefore. increased from 95 per cent to 98 per cent and the sensitivity was unchanged. Rescreening was offered at a later date and increased numbers were available: 7147 patients returned the test and 369 (5.2 per cent) were positive. The test was repeated in 360 patients and 118 (1.7 per cent) were positive. A colorectal neoplasm was found in one in three of those with a positive repeat test. compared with one in seven of those with a negative repeat test. In conclusion. screening for early detection of colorectal cancer with a rehydrated Hemoccult II test may be followed by investigation of only those patients with a positive retest. Such a procedure will reduce the work-load by 60 per cent without reducing sensitivity.
Epidermal growth factor receptor expression in colorectal cancer, Epidermal growth factor (EGF) receptor expression was estimated in 50 invasive human colorectal cancers using immunohistochemistry and the degree of expression was quantified from integrated optical density measurements on the stained sections. All tumours stained positively. but Dukes' C tumours exhibited significantly higher levels of receptor than either Dukes' A or B tumours. In addition. histologically high grade cancers expressed receptors more strongly than those of low grade. It is concluded that a high EGF receptor concentration is associated with poor prognostic factors in colorectal malignancy.
Disordered colorectal motility in intractable constipation following hysterectomy, Colorectal and anal sphincter motility and electrophysiology were investigated in 14 women with profound constipation following hysterectomy and compared with an asymptomatic group of control subjects. Twelve patients complained of significant urinary symptoms. No differences in the motor function of the anal sphincters were detectable. The latency of the pudendoanal reflex was unchanged after hysterectomy. Proctometrograms demonstrated significantly increased rectal volumes and compliance in the hysterectomy group together with deficits of rectal sensory function. In the basal state a significant proximal-to-distal sigmoid colon motility gradient existed only in the control group. Following stimulation with Prostigmin. this gradient was enhanced in the control group but paradoxically reversed in the hysterectomized patients. thus constituting a functional obstruction. Denervation supersensitivity was demonstrable in two patients tested with carbachol provocation but not in control subjects. These findings suggest dysfunction in the autonomic innervation of the hindgut in some patients who had undergone hysterectomy. resulting in severe constipation.
Achalasia of the cardia: long-term results of oesophagomyotomy and posterior partial fundoplication, Forty-eight patients with achalasia of the cardia were treated by Heller's myotomy with a posterior fundoplication of approximately 270 degrees. suturing the gastric fundus to the edges of the myotomy. The mean(s.d.) postoperative follow-up period was 5.4(2.8) years. The clinical results were good to excellent in 44 cases (92 per cent) and fair in four cases (8 per cent) (two with residual dysphagia and two with gastrooesophageal reflux). Barium studies showed a decrease in oesophageal diameter and disappearance of distal narrowing but normal oesophageal emptying did not occur. Postoperative manometric studies (29 patients) revealed a significant decrease in lower oesophageal sphincter pressure and a significant increase in the length of the infradiaphragmatic segment. In the oesophageal body a recovery of peristaltic waves in the proximal third was seen in ten of the patients (34 per cent). Twenty-four-hour pH monitoring showed pathological reflux in only three of 25 patients studied. and one of these was asymptomatic. This technique is effective. improving oesophageal symptoms and controlling long-term reflux.
Popliteal aneurysms identified by intra-arterial streptokinase: a changing pattern of presentation, Five patients presenting with chronic or subacute leg ischaemia due to thrombosed popliteal artery aneurysm are described. Only one of these aneurysms was diagnosed before intra-arterial streptokinase infusion. which successfully lysed the thrombus in all cases. One aneurysm had been symptomatic for 5 years and another for 2 years. Popliteal aneurysm may well be underdiagnosed as a cause of chronic leg ischaemia.
Clinical aspects of multiple sclerosis in north-east Scotland with particular reference to its course and prognosis, The prognosis and course of multiple sclerosis (MS) and the factors that affect them were assessed in a group of 1055 patients. representing an unselected (epidemiological) sample observed in the north-east (Grampian region) of Scotland for a period ranging between 1 and 60 yrs. In 7% the disease began before the age of 20 yrs. in 12% after the age of 50 yrs. and in the remainder onset was between the ages of 20 and 50 yrs. The male/female ratio was 1:1.8. Mean disease duration in those observed until death (216 patients) was 24.5 yrs. with no significant difference between the sexes. Prognosis was assessed either by the interval between onset and death or by the degree of disability over a defined period of time. Depending on the length of follow-up. just over one-quarter (26%) to over one-third (36.3%) had a benign course and between 8.0 and 17.7% had a poor prognosis. Nearly a third had a remittent (32.8%) or relapsing cumulative (34%) course and 9% had a progressive course from the start. Several factors were noted to affect the prognosis. Prognosis was significantly better. independent of sex. in those with (1) an early onset (less than 40 yrs of age); (2) retrobulbar neuritis or a brainstem lesion or sensory symptoms alone at onset; (3) short duration of initial symptoms (less than 6 months); (4) a long onset--first relapse interval (greater than 1 yr); (5) a remittent course in the beginning and (6) lack of a family history of MS. The factors which predicted a poor prognosis included: (1) a late onset (greater than 40 yrs of age); (2) progressive course from the start; (3) multiple sites of lesions initially. or a cerebellar or spinal cord lesion at the onset; (4) psychiatric or persistent urinary symptoms at the onset or within 10 yrs; (5) persistent initial symptoms (beyond 1 yr); (6) early first relapse (within 6 months); (7) a family history of MS; (8) social class status IV and V; and (9) bilaterally prolonged visual evoked potential (VEP) P100 latency. Address in childhood and at the onset of the disease. changes in the CSF and CT brain scan were not of predictive value.
Congenital demyelinating motor and sensory neuropathy with focally folded myelin sheaths, Six patients (5 index cases and 1 sib) with a congenital motor and sensory neuropathy are described. The clinical. genetic and electrophysiological features resembled Dejerine-Sottas disease or hereditary motor and sensory neuropathy (HMSN) type III. Sural nerve biopsy of 5 patients revealed segmental demyelination and remyelination with hypertrophic changes. although onion bulbs were not as ubiquitous as in classical HMSN type III. A striking discriminating feature from HMSN type III was an abundance of focal myelin thickenings (tomacula) present in nearly all teased fibres. Possible pathogenic implications are discussed. These cases corroborate the heterogeneity of congenital motor and sensory neuropathies.
Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses, Experiential phenomena that occur in temporal lobe seizures and can be reproduced by electrical stimulation of temporal lobe structures typically encompass perceptual. mnemonic and affective features. either in combination or in isolation. which commonly relate to the patient's individual past experience. These phenomena raise interesting questions concerning brain mechanisms involved in human psychophysiology. The anatomical substrates for the evocation of these phenomena are widely distributed within the temporal lobe and include temporal isocortex and limbic structures (amygdala. hippocampus and parahippocampal gyrus). Arguments are presented which indicate that experiential phenomena are positive expressions of temporal lobe and limbic function and do not result from its ictal paralysis. Recent concepts of parallel distributed processing (Rumelhart and McClelland. 1986) and the importance of parallel distributed cortical networks for higher cognitive functions (Goldman-Rakic. 1988a. b) provide a theoretical framework on which a hypothesis explaining experiential phenomena can be based. In conformity with these concepts the hypothesis assumes that temporal lobe epileptic discharge or electrical stimulation of temporal lobe structures can induce the elaboration of patterns of excitation and inhibition in widely distributed neuronal networks. some of which are capable of forming a specific matrix representing the substrate of a given experience. Neuronal networks engaged in parallel distributed processing (1) have the capacity to recreate the totality of a given experience when only a fragment of the network is activated. and (2) they tolerate a great deal of degradation by random inactivation of its components or by interference through random noise without serious loss of information content. These features are compatible with the assumption that localized epileptic neuronal discharge or electrical stimulation involving some temporal lobe structures could create a matrix representing features of individual experience of the kind activated in the course of temporal lobe seizures. Such an experience could. up to a certain limit. resist the degrading influence of mounting noise which inevitably must attend seizure discharge.
The role of diencephalic pathology in human memory disorder. Evidence from a penetrating paranasal brain injury, A patient (B.J.) is reported who developed severe memory impairment following a penetrating brain injury caused by a snooker cue which entered through his left nostril into the basal regions of the brain. Initially. his memory disorder had the clinical features of a dense amnesic syndrome. with both anterograde and retrograde amnesia. but B.J. subsequently showed significant recovery of memory function. Formal memory testing was carried out 21 months after injury. This demonstrated marked verbal memory impairment. as severe as that seen in patients with the amnesic syndrome. On nonverbal memory tests. his impairment was relatively mild and patchy. His retrograde amnesia had regressed mainly to affect a 6 month period before the injury. On other cognitive tasks. he performed at an average or above average level. and there was no neuropsychological evidence of frontal lobe dysfunction. Neuroradiological investigations at various stages after his injury failed to demonstrate a lesion in any of the thalamic nuclei. Magnetic resonance imaging showed a lesion in the hypothalamus in the region of the mamillary bodies. Our study demonstrates that marked. relatively focal. memory disorder after diencephalic injury can occur without direct pathology to the body of the thalamus. It also indicates that structures in or adjacent to the hypothalamus. such as the mamillary bodies. may play a more important role in human memory functioning than has hitherto been considered.
A century of cerebral achromatopsia, This review is an enquiry into why the early clinical evidence for a colour centre in the cerebral cortex of man was so successfully dismissed for the best part of a century. The imperfection of this evidence cannot be the reason. for the same evidence that was rejected earlier is accepted today. Instead. it was because the prevalent concepts of vision as a function. and of the role of the cerebral cortex in it. dominated facts and prevented acceptance of evidence showing a specialization for colour in the visual cortex. It was only after those concepts were overthrown by the demonstration of functional specialization in the visual cortex of the primate that the evidence for a colour centre in the human brain became acceptable. Today. our new knowledge of the colour areas and pathways in the primate brain allows us to give a more complete account of the pathophysiology of cerebral achromatopsia in man.
Single unit analysis of the human ventral thalamic nuclear group. Activity correlated with movement, During neurosurgical operations for the relief of movement disorders. single thalamic neurons (n = 107) were identified with activity which was related to verbally cued active movements (movement-related cells). The activity of each neuron was examined during different contralateral movements in order to determine the movement which was associated with the most consistent and pronounced change in firing rate (the optimal response). The optimal response was determined by analysis of histograms of neuronal activity which were constructed by using the onset of EMG activity to synchronize successive repetitions of the active movement. Movement-related cells exhibited optimal responses associated with such movements as making a fist. extension or flexion of the wrist. flexing or extending the elbow. pointing with the entire upper extremity. extending the tongue and lifting the leg. Most movement-related cells recorded in a single parasagittal plane in an individual patient had optimal responses related to movements involving the same part of the body. Movement-related cells were classified into those that were activated in response to somatosensory stimulation (combined cells. n = 20) and those which were not (voluntary cells. n = 87). Combined cells were activated in advance of EMG activity during active movement and so could be distinguished from cells responding only to sensory stimulation (sensory cells). Movement-related cells (combined and voluntary cell types) were located anterior to sensory cells and tended to show a mediolateral somatotopic organization parallel to that of sensory cells with cutaneous receptive fields. Combined cells responded to somatosensory stimulation of the same part of the body as that involved in the active movement related to the optimal response of the cell. Combined cells responding to passive movements of a joint always had their optimal response during active movement about the same joint. The activity of combined cells during parkinsonian tremor may clarify the role of sensory feedback in tremor.
Ocular muscle proprioception and visual localization of targets in man, Passive deviation of one eye through 18 degrees. 30 degrees and 42 degrees. achieved by force applied to a sucked-on contact lens. caused the direction of visual targets seen by the other eye to be misjudged in the direction of the passive movement by an amount roughly one-sixth of the angle of passive deviation. The result was the same when the perceived direction was indicated by hand. as when the instant at which a moving target seemed straight ahead was signalled. This result is interpreted by considering that muscular efferents were identical in normal and eye-deviated subjects. The main difference between the two target localization conditions results from the proprioceptor output of the deviated eye. Our data demonstrate that the assessment of the direction of a target seen by an eye that is free to move depends in part on information received by the brain from proprioceptors in the orbit (in our case the contralateral orbit). It would be surprising if the ipsilateral orbit did not contribute as much or more. We therefore consider that this constitutes clear evidence against the pure outflow theory of visual direction judgement (Helmholz. 1867). additional to that provided by the all-or-nothing situation of complete versus incomplete oculomotor paralysis. Two models have previously been proposed to describe the function of the visual localization mechanism. Both assume that the necessary information is derived from the coding of the position of the eye in the orbit. either through a copy of the muscular activation or through eye muscle proprioception. We propose an alternative model in which both afferent and efferent signals from all actively contracted or stretched muscles provide the necessary information to the CNS. The data gathered so far from normal subjects made strabismic with a suction lens. and from a fair proportion of strabismic patients. support our model describing the mechanism of localization of a single punctate target in darkness.
Permanent muscle weakness in familial hypokalaemic periodic paralysis. Clinical, radiological and pathological aspects, Myopathy accompanying familial hypokalaemic periodic paralysis (HPP) is much less well documented than the paralytic attacks from which the disease derives its name. Eleven affected members of a large kinship with HPP were studied clinically and radiologically for the presence of myopathy. In 4 patients muscle biopsies were also performed and in 1 of them the histological findings obtained at autopsy were compared with the CT scans of various muscles. In another patient not previously biopsied. the specimens of both amputated legs were examined histologically. The age of the studied individuals ranged from 33 to 74 yrs. The 4 youngest patients showed no clinical signs of myopathy. However. in 2 of them CT scans demonstrated discrete hypodense lesions in the leg muscles. whereas in the other 2. muscle biopsies showed a vacuolar myopathy. The other 7 patients. all older than 50 yrs. presented both clinical and CT evidence of myopathy of proximal and distal muscles ranging from very mild to very severe. males being slightly more affected than females. In all 11 patients a mean CT grading was made that was based on the abnormalities found in the different muscle groups. The myopathy appeared to be unrelated to the history of paralytic attacks. but a strong correlation was found between age and mean CT grading. It was concluded that HPP is a myopathy with permanent muscle weakness of late onset in all the patients. The expression of the paralytic attacks is variable.
Spongiform encephalopathy transmitted experimentally from Creutzfeldt-Jakob and familial Gerstmann-Straussler-Scheinker diseases, A comparison was made of the effects of experimental intracerebral inoculation into marmosets of brain homogenates from a case of Creutzfeldt-Jakob disease (CJD) and from a member of the Wo. family with cerebral amyloid and spongiform encephalopathy--the Gerstmann-Straussler-Scheinker (GSS) syndrome. All the inoculated marmosets developed spongiform encephalopathy (SE) after incubation times of 20-23 months in the CJD group and 25-32 months in the GSS group. Subsequent passage from 1 affected animal in each group resulted in SE developing after 17 months incubation. In every animal inoculated with CJD or GSS material and in the 2 passage experiments the most severely affected region of the brain was the thalamus which in all cases was almost totally occupied by vacuoles. Other grey matter masses were less severely and less consistently affected. Vacuolation was observed in the cerebellar granule cell layer as well as in the molecular layer and the brain stem was finely vacuolated in all cases. There were only minor and inconsistent differences between the disease transmitted from CJD compared with GSS and some differences between the original transmissions and the SE caused by passaged inocula. Severe astrocytic gliosis accompanied the spongiform changes but no amyloid was identified in any of the marmosets with experimentally transmitted disease. The pathogenesis of the spongiform change in the thalamus was studied in a series of marmosets by light and electron microscopy 3-22 months after the intracerebral inoculation of CJD or GSS homogenates and was compared with controls. Dilated irregularly-shaped cisternae and the large complex vacuoles typical of SE. present in abundance after 18 and 22 months incubation. were considered most probably to be derived from cisternae of neuronal smooth endoplasmic reticulum.
Levamisole and 5-fluorouracil therapy for resected colon cancer: a new indication, OBJECTIVE: To evaluate the benefits and risks of postoperative treatment with levamisole plus 5-fluorouracil (5-FU) in patients with colon cancer. DESIGN: Computerized searches of MEDLINE and CANCERLIT were performed. and the reference list of each retrieved article was checked. Only randomized trials of therapy with levamisole alone or combined with 5-FU for colon cancer without distant metastases were included. The studies were then evaluated with the use of four criteria. RESULTS: We reviewed six randomized trials. of which three satisfied our criteria. Two studies demonstrated a significant improvement in the survival rate with levamisole plus 5-FU among patients with colon cancer and pathologically confirmed metastases to adjacent lymph nodes (Dukes' stage C). A subgroup analysis in another study demonstrated a similar benefit. The toxic effects of the drugs were generally mild. The three other studies showed no difference in survival rates between the treatment groups; however. the samples were too small to detect a clinically or statistically important difference. CONCLUSIONS: Because many patients with colon cancer will suffer a relapse we recommend that they be offered the opportunity to participate in clinical trials of adjuvant therapy. For those with stage C disease not entering a clinical trial levamisole plus 5-FU is appropriate adjuvant therapy.
Estimated burden of diabetes mellitus in Manitoba according to health insurance claims: a pilot study, OBJECTIVE: To estimate the burden of diabetes mellitus in Manitoba from 1980 to 1984. DESIGN: Review of the Manitoba Health Services Commission (MHSC) database. The validity of the MHSC data was established through two substudies: one involved self-reports from a survey of elderly Manitobans. and the other involved people with confirmed diabetes enrolled in the provincial diabetes education program. SUBJECTS: Sample of 100.000 people stratified by age. sex and MHSC health region: 50.000 were aged 25 to 64 years. and 50.000 were aged 65 or more. All MHSC claims containing the ICD-9-CM code for diabetes mellitus or gestational diabetes were identified. MAIN RESULTS: Of the sample 7627 people were found to have a diagnosis of diabetes. the annual prevalence being 0.8% among those 25 to 44 years of age. 3.5% among those 45 to 64 and 7.6% among those 65 or older. The annual incidence rate among those over 25 years of age was 7.8 per 1000. Of the 4556 pregnant women 25 to 44 years old 85 (1.9%) had diabetes; 23 were believed to have gestational diabetes. CONCLUSIONS: The incidence and prevalence rates were similar to those determined on the basis of self-reports in Canadian and US national surveys. The use of an administrative database such as that of the MHSC will provide key information for planning health services for diabetic patients and will permit the monitoring of long-term trends in the incidence and prevalence of the disease.
Influence of low osmolality contrast media on electrophysiology and hemodynamics in coronary angiography: differences between an ionic (ioxaglate) and a nonionic (iohexol) agent, It has recently been suggested that the addition of sodium to low osmolality contrast media may reduce the incidence of ventricular fibrillation and conduction disturbances during coronary angiography. In a randomized. double blind study of 30 patients undergoing coronary angiography we therefore examined the electrophysiological and hemodynamic effects of the two low osmolality contrast media-ioxaglate (with sodium) and iohexol (without sodium). Standard ECG. aortic blood pressure. and His bundle electrocardiogram were recorded. The contrast media were well tolerated and no serious arrhythmias were observed. Both induced a transient decrement in systolic blood pressure and reduction in heart rate 10 s following contrast injection (all P less than 0.01). Ioxaglate prolonged the QT interval at 10 s (P less than 0.01) and also when analysed for the whole observation period (120 s) (P less than 0.05). whereas iohexol did not cause any significant changes in the QT-interval. The AH-interval was prolonged by ioxaglate at 10 s (P less than 0.01). but not altered by iohexol. Thus. other factors than osmolality and sodium content might contribute to QT prolongation. since only the contrast agents with sodium (ioxaglate) induced QT prolongation in this study.
Precertification for percutaneous transluminal coronary angioplasty in Medicare beneficiaries: a melting pot or a need for better national standards, The Health Care Financing Administration has contracted with state peer review organizations (PROs) in its effort to assure the quality of services and eliminate unreasonable and inappropriate care provided Medicare beneficiaries. By law. each state PRO must select 10 procedures for precertification. Coronary angioplasty has been chosen by 45 PROs for precertification and criteria in each state were developed with the advice of local physicians. This report describes the findings of a survey of these precertification criteria in an effort to determine their variability and to compare the PRO criteria to published national criteria created by expert panels. Current precertification criteria of Medicare beneficiaries show significant variability in the priorities and the clinical practice of cardiologists in performing coronary angioplasty. despite established and published guidelines for its safe and efficacious use. It is likely that the establishment of locally based criteria for coronary angioplasty will be geographically uneven and probably have a less than expected impact on the care provided to Medicare beneficiaries.
Rib compression of the coronary arteries, This report describes the finding of coronary artery narrowing caused by compression by an overlying rib in two patients with cardiomegaly. There is probably no clinical significance to this finding. The primary differential diagnostic entity is myocardial bridging.
"Woven" right coronary artery: case report and therapeutic implications, We report an unusual anomaly of the right coronary artery consisting of proximal branching of the artery and subsequent interweaving of the branches. referred to as a "woven" coronary artery. Implications and differential diagnosis are discussed.
Coronary stent implantation in acute vessel closure 48 hours after an unsatisfactory coronary angioplasty, We report the implantation of a balloon-expandable stent in a patient with acute vessel closure in the state of evolving myocardial infarction following 48 hr after unsatisfactory coronary angioplasty. The stent was implanted after successful recanalization of an occluded left anterior descending artery. with repeated unsatisfactory results of balloon angioplasty. Adjunct thrombolytic therapy was contraindicated. No residual stenosis was documented in immediate control angiograms. or after 24 hr. 3 weeks. and 4 months.
Emergent saphenous vein graft stenting for acute occlusion during percutaneous transluminal coronary angioplasty, This report describes the initial use in the United States of emergency intravascular stenting for the treatment of acute coronary occlusion complicating elective saphenous vein graft angioplasty. This case adds further support to the role of the balloon expandable stent as an effective "bail out" device for failed angioplasty.
Implantation of an endoluminal prosthesis at the distal anastomosis of a bypass graft for abrupt closure following balloon angioplasty, A coronary Wallstent was implanted in a 10-year-old saphenous vein bypass graft following a PTCA that was complicated by abrupt closure. Anterograde flow was restored and no myocardial necrosis resulted. One week later. bypass surgery was performed due to a bleeding complication associated with the anticoagulation regimen.
Cardiac sympathetic tone in anaesthetized diabetics, To assess cardiac sympathetic nervous function in diabetics. the heart rates attained following a pharmacological dose of intravenous atropine. 23 micrograms.kg-1. were studied under N2O. isoflurane anaesthesia in diabetics (n = 21) and nondiabetics (n = 30). Atropine-induced heart rate in diabetics was significantly lower than that in nondiabetics (95 +/- 14 (SD) bpm vs 109 +/- 12 bpm. P less than 0.001) and were closely related to preoperative orthostatic diastolic blood pressure change (r = 0.60. P less than 0.01). There was some correlation between the atropine-induced heart rate and preoperative RR-variation in diabetics (r = 0.50. P less than 0.05). The findings suggest that cardiac sympathetic function may also be impaired in diabetics with orthostatic hypotension.
An alternative oxygen delivery system for infants and children in the post-anaesthesia care unit, This randomized controlled trial compared the compliance of a blow-by oxygen method with the standard face mask by children recovering from anaesthesia. The rate at which a face mask was rejected when applied to infants and children in PACU was compared with that of a proposed "hose" method. The efficacy of the "hose" as a method of oxygen supplementation in children at low and high risk for developing postoperative hypoxaemia was also compared with the face mask. Using a Nellcor N-200 pulse oximeter. 66 infants and children (mean age 2.3 yr. range 2 mo-6 yr) were continuously monitored for 30 min upon arrival in the PACU. Patients were randomized to receive oxygen supplementation with either the face mask or the proposed "hose" method. The results showed a greater than 80 per cent rejection of the face mask in contrast to 100 per cent compliance with the "hose" method. The SaO2 measurements following 5. 15 and 30 min of O2 supplementation with the hose were all significantly higher than the SaO2 measurements obtained on room air upon arrival to the PACU. Patients with pre-existing cardiopulmonary disease had a 20 per cent incidence of arterial oxygen desaturation upon arrival to the PACU versus 2.1 per cent of patients with no pre-existing disease. It is concluded that the "hose" is associated with high patient compliance and is effective in the PACU in increasing the SaO2 in children at low or high risk of developing postoperative hypoxaemia.
Alfentanil pharmacokinetics in patients undergoing abdominal aortic surgery, The pharmacokinetics of alfentanil. 300 micrograms.kg-1 IV. were determined in patients undergoing elective abdominal aortic reconstruction. The mean age (+/- SD) of the patients was 64.3 +/- 7.4 yr; their mean weight was 74.7 +/- 13.8 kg. Five patients underwent aneurysm repair and six had aortobifemoral grafting. Serum alfentanil concentrations were measured by gas-liquid chromatography in samples drawn at increasing intervals over a 24-hr period. A three-compartment model was fitted to the concentration versus time data. The volume of the central compartment and the volume of distribution at steady state (Vdss) were 0.44 +/- 0.022 and 0.63 +/- 0.32 L.kg-1. respectively. Total drug clearance was 6.4 = 1.9 ml.min-1.kg-1. The elimination half-time was 3.7 +/- 2.6 hr. Patient age was positively correlated with both Vdss and elimination half-time. There were no significant correlations between the pharmacokinetic variables and the duration of aortic cross-clamping. the duration of surgery. or the rate or total volume of IV fluids infused intraoperatively. In general surgical patients. the elimination half-time of alfentanil has been reported to be 1.2-2.0 hr. Although the elimination half-time of alfentanil was longer in patients undergoing abdominal aortic surgery. alfentanil was eliminated much faster than either fentanyl or sufentanil in this patient population.
Transoesophageal echocardiogram may fail to diagnose perioperative myocardial infarction, We report a case in which a 55-yr-old man undergoing aortocoronary bypass was monitored with electrocardiogram and transoesophageal echocardiogram. Intraoperative electrocardiogram and simultaneous ECG recordings using the Holter monitor showed an ST elevation of greater than 2 mm and new Q wave formation in leads AVF and V5 during skin closure. However. the transoesophageal echocardiogram showed no wall motion abnormalities. No significant haemodynamic abnormalities were observed during the period of intraoperative ECG changes. He was treated with nitroglycerin infusion. Confirmation of a perioperative myocardial infarct was documented by postoperative 12-lead ECG and CPK-MB. A post-operative transthoracic echocardiogram showed a hypokinetic left ventricle with an anteroapical infarct. Thus transoesophageal echocardiography failed to detect an apical wall motion abnormality when the probe was placed at the midpapillary level. This limitation can be overcome by periodically obtaining apical views or by using probes with more than one imaging plane.
Improved outcomes from tertiary center pediatric intensive care: a statewide comparison of tertiary and nontertiary care facilities, OBJECTIVE: To compare outcomes from pediatric intensive care in hospitals with different levels of resources. DESIGN: Prospective. blinded comparison of outcome and care. SETTING: Tertiary (n = 3) and nontertiary (n = 71) hospitals in Oregon and southwestern Washington. PATIENTS: All critically ill children admitted with respiratory failure and head trauma for 6 months. MEASUREMENTS AND MAIN RESULTS: Severity of illness adjusted mortality rates were determined using admission day. physiologic profiles (Pediatric Risk of Mortality score) and care modalities were assessed daily. The crude mortality rate of the tertiary patients was four times higher than for the nontertiary patients (23.4% vs. 6.0%. p less than .0001). In the tertiary patients. the numbers of outcomes were accurately predicted by physiologic profiles (observed: 30 deaths and 98 survivors; predicted: 29.3 deaths and 98.7 survivors. z = -.25. p greater than .4). However. for the nontertiary patients. the number of the deaths were significantly different than predicted (observed: 20 deaths and 315 survivors; predicted: 14.4 deaths and 320.6 survivors. z = -2.08. p less than .05). The odds ratios of dying in a nontertiary vs. a tertiary facility were about 1.1. 2.3. and 8 (p less than .05) for mortality risk groups of less than 5%. 5% to 30%. and greater than 30%. Patients in tertiary facilities received more (p less than .05) invasive (e.g.. arterial catheters) and complex (e.g.. mechanical ventilation) care. whereas patients in nontertiary facilities received more (p less than .05) labor-intensive care (e.g.. hourly vital signs). CONCLUSIONS: Care of the most seriously ill children in tertiary pediatric ICUs could improve their chances of survival.
Use of the Pediatric Risk of Mortality score to predict nosocomial infection in a pediatric intensive care unit, OBJECTIVE: To define infection rates in patients with Pediatric Risk of Mortality (PRISM) scores greater than and less than 10 on admission to the pediatric ICU (PICU). DESIGN: Descriptive. SETTING: An 18-bed PICU admitting patients of all ages except nonsurgical neonates; within a 585-bed tertiary care pediatric hospital. PATIENTS: Patients admitted to the PICU from July 1987 to February 1988 inclusive. Of 685 admitted. 480 were followed for greater than or equal to 72 hr. METHODS: The baseline state of the patients on admission was determined by a designated intensivist using the PRISM score. Other variables included age. length of stay. and hospital day of onset of infection. Infections were identified by a designated intensivist who undertook prospective daily bedside observation. chart. radiographic. and laboratory review. MEASUREMENTS AND MAIN RESULTS: Equal portions of patients had PRISM scores less than and greater than 10. Significantly more infections occurred in the high PRISM population (10.8% vs. 3.4%. p less than .001). This association held through age. service. and length of stay. Sensitivity. specificity. positive and negative predictive values of a PRISM score greater than 10 were 75%. 53%. 11%. and 97%. respectively. Bacteremias accounted for 36% of infections. skin/eye/drain site 22%. respiratory 16%. wound 15%. and urine 9%. The most prevalent organisms were coagulase-negative staphylococci (32%). Pseudomonas aeruginosa (23%). Candida sp. (20%). and S. aureus (9%). CONCLUSIONS: A PRISM score greater than 10 on PICU admission characterizes a population within the PICU at increased risk of infection. However. 93% of patients did not develop infection and thus. a negative predictive value of 97% yields little additional information.
Ineffectiveness of dantrolene sodium in the treatment of heatstroke, STUDY OBJECTIVE: To determine the efficacy of dantrolene sodium in the treatment of heatstroke. DESIGN: Randomized. double-blind. placebo-controlled trial. SETTING: Heatstroke center in Makkah. Saudi Arabia. PATIENTS: Fifty-two adult patients with heatstroke. INTERVENTIONS: Patients were assigned to receive either dantrolene sodium (2 mg/kg body weight iv) or placebo. Conventional cooling therapy was initiated in all. MEASUREMENTS AND MAIN RESULTS: There was no significant difference in the mean cooling times for the treatment and control groups (67.9 vs. 69 min). There was only one death in the control group. Complications were seen in six (23%) patients receiving dantrolene sodium and seven (27%) patients receiving placebo; the difference was not statistically significant. There was no significant difference in the mean number of hospital days (4.7 +/- 2.0 vs. 2.9 +/- 0.9 days). CONCLUSION: Treatment with dantrolene sodium at the dose used. did not prove beneficial to patients with heatstroke.
Systemic and muscle oxygen uptake/delivery after dopexamine infusion in endotoxic dogs, BACKGROUND AND METHODS: This study was designed to test whether dopexamine. a dopaminergic and beta 2-adrenergic agonist. would a) increase systemic oxygen delivery (DO2) in endotoxic dogs. and b) interfere with the ability of resting skeletal muscle to extract oxygen. There were three treatment groups (n = 6 in each group): control. endotoxin alone (E) 4 mg/kg iv. and endotoxin + dopexamine (E + D) 12 micrograms/kg.min. Data were analyzed between and within groups by split-plot analysis of variance with significance of identified differences tested post hoc by Duncan's multiple range test. Donor RBC and dextran were used after endotoxin to maintain adequate perfusion pressures. with Hct kept near 40%. Blood flow to left hindlimb muscles was decreased in controlled steps of 15 min each after stabilization. RESULTS: In E group. cardiac output (Qt). mean arterial pressure (MAP). systemic DO2. and oxygen uptake (VO2) decreased despite blood volume expansion. In E + D group with similar volume expansion. dopexamine maintained Qt. systemic DO2. and VO2 near the control levels. although MAP and systemic vascular resistance were reduced. In comparison with control subjects. endotoxin increased critical DO2 in the isolated limb muscles from 4.6 to 7. mL/kg.min and decreased critical oxygen extraction from 81% to 68%. The pressure/flow relationship in the limb became flattened. indicating loss of vascular reactivity. In the E + D group. there was no further change in the pressure/flow curve nor in the critical oxygen extraction level. CONCLUSIONS: Dopexamine provided hemodynamic support for endotoxic dogs. thereby increasing total DO2 and VO2. while not altering oxygen extraction in the muscle.
Oxygen debt and metabolic acidemia as quantitative predictors of mortality and the severity of the ischemic insult in hemorrhagic shock, BACKGROUND AND METHODS: An experimental canine model of hemorrhagic. hypovolemic shock is described that uses oxygen debt and its metabolic consequences of lactic acidemia and metabolic base deficit as independent variables for the prediction of probability of death. RESULTS: Lactic acidemia and metabolic base deficit are compared with the conventional hemodynamic variables of BP and cardiac output (Qt) as predictors of outcome and are shown to be superior using a modified Kaplan-Meier probability statistic. The LD50 for oxygen debt is shown to be 113.5 mL/kg. 12.9 mmol/L for lactate. and -18.8 mmol/L for base excess (BE). Comparison is made between the ability of Qt. BP. shed blood. BE. and lactate to predict oxygen debt. CONCLUSIONS: Of the single-variable predictors. BE shows the highest explained variability. However. a combined prediction from both lactate and BE appears superior to the use of either alone. Using this regression to compute the oxygen debt. it is possible to estimate accurately the actual level of oxygen debt from the BE and lactate values obtained during hemorrhagic hypovolemia. From serial determinations over time of the increase in these biochemical variables above the oxygen debt baseline. it is possible to estimate the rate of oxygen debt accumulation and the time remaining until the LD50 will be reached as indicators of the severity of the total body ischemia resulting from hemorrhagic shock.
Cardioprotective effects of authentic nitric oxide in myocardial ischemia with reperfusion, BACKGROUND AND METHODS: The purpose of this study was to determine the effects of nitric oxide (NO). believed to be endothelium-derived relaxing factor on reperfusion injury after myocardial ischemia (MI). The effects of NO were investigated in a 6-hr model of MI with reperfusion in open-chest. anesthetized cats. A solution containing NO was infused iv starting 30 min after occlusion of the left anterior descending coronary artery. continuing through reperfusion 1 hr later. and lasting for 5.5 hr. Estimated NO concentration in the circulation was 1 to 2 x 10(-9) M. RESULTS: The areas-at-risk expressed as a percentage of the total left ventricular weights were not significantly different among either of the MI groups. However. the necrotic area (expressed as a percentage of the myocardial area-at-risk) was significantly (p less than .01) lower in the NO-treated MI cats compared with the MI + vehicle group. Cardiac myeloperoxidase activities indicated that significantly (p less than .05) fewer neutrophils were attracted to the necrotic zone of the NO-treated MI cats when compared with MI cats receiving only the vehicle. Sodium nitrate (NaNO2) (pH 7.4). a major breakdown product of NO. failed to exert any protective effect in this same model of MI and reperfusion. CONCLUSIONS: NO appears to provide significant myocardial protection after ischemia and reperfusion. NO may afford cardioprotection by incorporation into circulating blood cells (i.e.. neutrophils. platelets). thereby inhibiting their accumulation and adherence in the ischemic region. or by a direct cardiac cytoprotective effect. Further studies using NO donors rather than NO would be an appropriate clinically relevant mode of treatment in MI.
Inhibition by methylprednisolone of leukocyte-induced pulmonary damage, BACKGROUND AND METHODS: The purpose of this study was twofold: the development of a chronic model of leukocyte-mediated pulmonary injury and the evaluation of the protective effects of methylprednisolone. Rabbits were inoculated ip with zymosan. Blood gases and circulating leukocytes were evaluated. Survivors were killed on day 10 for microscopic studies and for the evaluation of lung lipid peroxidation through the by-product malondialdehyde. RESULTS: Intraperitoneal zymosan resulted in a marked decrease of Pao2 and circulating leukocytes. and increased cellularity of alveolar septa. interstitial edema. and increased lung malondialdehyde. Pulmonary damage was partially prevented when methylprednisolone was administered before zymosan inoculation. but not when methylprednisolone was given 24 hr later. CONCLUSIONS: The authors conclude that a local nonseptic inflammatory stimulus may provoke remote changes to the lungs and that methylprednisolone may counteract the process only if it is administered before or very early after the onset of inflammation.
Long-term postthoracotomy pain, We used a pain questionnaire to evaluate the prevalence and functional significance of long-term postthoracotomy pain. Data on 56 patients who were at least 2 months postsurgery were analyzed. Thirty patients (54 percent) with a median follow-up of 19.5 months had persistent pain; 26 others were pain free at a median of 30.5 months postthoracotomy. Pain was reported in 24 of 44 patients (55 percent) who were more than one year after surgery. 13 of 29 patients (45 percent) more than two years. six of 16 (38 percent) more than three years. and three of ten patients (30 percent) greater than four years postthoracotomy. Pain intensity was low. but 13 patients stated that pain "slightly" or "moderately" interfered with their lives. Five of 56 patients had sufficiently severe chronic pain to require either daily analgesic use. nerve blocks. relaxation therapy. acupuncture. or referral to a pain clinic. We conclude that long-term chest wall pain is common postthoracotomy. It is generally not severe. but a small proportion of patients may experience persistent. moderately disabling pain.
Use of a biotinylated DNA probe specific for the human Y chromosome in the evaluation of the allograft lung, A cloned 3.4 kilobase DNA probe derived from the heterochromatin of the Y chromosome was used to investigate the regeneration and reepithelialization of allograft lungs of nine recipients who received sex mismatched donor organs. Patients were monitored for varying periods of time. up to four years. by transbronchial biopsy. In situ hybridization on paraffin-embedded biopsies utilizing the Y probe revealed that bronchial and alveolar epithelium and arterial and venous endothelium of the peripheral lung retained a donor phenotype. irrespective of episodes of acute or chronic rejection (obliterative bronchiolitis) which are known to injure these cellular subsets. In contrast. migratory cells. lymphocytes and macrophages. gradually. at varying rates. infiltrated the allografted lungs. replacing preexisting donor elements. Cases of active OB were manifested by infiltration of bronchioles by sex-mismatched lymphocytes; however. in some instances. quiescent recipient lymphocytes colonized the allograft and were unassociated with histologic rejection. Macrophages of similar sex seemed to cluster together within air spaces. Use of a DNA probe for the Y chromosome and in situ hybridization techniques allow monitoring of cellular alterations over time in recipients with sex mismatched allografts.
Lymphokine-activated killer cell activity in lung cancer, This study evaluates local pulmonary immune effector cell lytic activity. Purified lymphocyte populations were isolated from BALF obtained from 18 patients with bronchogenic carcinoma. six patients with lung disorders other than cancer. and ten normal control volunteers matched for age and smoking history. These cells were evaluated for NK and LAK cell lytic activity against NK-resistant LAK-sensitive tumor targets (A549 pulmonary tumor and Daudi tumor cells) and an NK-sensitive tumor (K562); LAK activity was detected in BALF from 6 of the 18 patients with cancer. The remaining patients with cancer. the subjects with pulmonary disease other than cancer. and the normal volunteers had no detectable lytic activity. Peripheral blood lymphocytes from all subjects had only NK lytic activity and did not kill the pulmonary tumor target; AMs were not tumoricidal. Interleukin-2. which is required for LAK cell activation. was detected only in BALF recovered from the six patients with pulmonary LAK lytic activity. These results demonstrate that activated LAK cells. capable of killing pulmonary tumor cells. are present in BALF of some patients with bronchogenic carcinoma. This lytic LAK cell population represents a local pulmonary response against the lung cancer in the absence of systemic tumoricidal activity. The functional status of pulmonary immune effector cells. as well as the type and quantities of cytokines in the lung determine local responsiveness to bronchogenic carcinoma and may well control the course of this disease.
Magnetic resonance imaging in the diagnosis of pulmonary infarction, We report for the first time. to our knowledge. MRI features which could differentiate noninvasively pulmonary infarction from pneumonia. Three subjects with angiographically proven pulmonary infarction showed high T1 weighted MRI signals located in the embolic territory. Three patients with pneumonia and one patient with emboli. but without infarction. did not have these T1 weighted images.
Pulmonary function and cardiovascular risk factor relationships in black and in white young men and women. The CARDIA Study, Pulmonary function is known to be related inversely to incidence of coronary heart disease. congestive heart failure. chronic obstructive lung disease. lung cancer. and death from all causes. Reasons for some of these associations are poorly understood. Relationships between cardiovascular disease risk factors and pulmonary function were examined in 5.115 18- to 30-year-old black and white male and female participants in the study of Coronary Artery Risk Development in Young Adults (CARDIA). Forced expiratory volume in 1 s adjusted for height (FEV1/Ht2) was significantly lower in smokers than nonsmokers and in persons who reported shortness of breath; FEV1/Ht2 was correlated positively with a history of strenuous physical activity. duration of exercise on the treadmill. and high-density lipoprotein cholesterol. It was associated negatively with skinfold thicknesses. serum triglycerides. fasting serum insulin. and the Cook Medley scale of hostility. The association between pulmonary function and heart disease risk may reflect associations with physical fitness. vigor. fatness. and lipid profiles. as well as with cigarette smoking.
Hemodynamic effects of nasal CPAP examined by Doppler echocardiography, The effects of incremental application of nasal continuous positive airway pressure (0 to 15 cm H2O) on heart rate. pulmonary artery pressure. and cardiac index were studied noninvasively by Doppler echocardiography. By two-way analysis of variance within two groups (19 normal volunteers and six sleep apnea patients). no significant effects on heart rate. pulmonary artery pressure. ventricular size. or cardiac index could be found with increasing positive intrathoracic pressures and consequent lung hyperinflation. In subjects with normal cardiac function. nasal CPAP is safe from a hemodynamic viewpoint. This simple. repeatable and noninvasive technique may be used to assess the clinical safety and efficacy of prescribed nasal CPAP on cardiac hemodynamics in individual patients.
Respiratory muscle strength and control of ventilation in patients with neuromuscular disease, To assess the relationship between respiratory mechanics and muscle strength and control of ventilation in patients with neuromuscular disease (NMD). we compared PImax and PEmax at RV. FRC and TLC. total respiratory elastance (Ers) with VT. TI. TT. VE. VT/TI. TI/TT. P.01. and P.01/(VT/TI) effective impedance in 21 patients with NMD and 21 healthy control (C) subjects. in seated position breathing room air. Ers in NMD patients was 79 percent higher than in the C subjects. While TI. TT. and VT in NMD were approximately half the corresponding C values. P.01 was 66 percent greater than in the C subjects (both p less than 0.001). NMD PImax and PEmax ranged from 37 to 52 percent of corresponding C values. respectively. Despite significant respiratory muscle weakness. only 7 of 16 patients demonstrated a PaCo2 greater than 45 mm Hg. Ventilatory output in NMD was modulated by respiratory mechanics as indicated by the increased P.01. In spite of muscle weakness. central drive in patients with NMD is not decreased. and in fact. is often increased. VE is not an accurate measure of central drive because of abnormal intrinsic respiratory mechanics and the effects of conscious responses or reflexes.
Amiodarone-induced pulmonary toxicity. Immunoallergologic tests and bronchoalveolar lavage phospholipid content, Amiodarone (A) is a widely-used antiarrhythmic drug. Pulmonary toxicity is the most serious adverse effect with an estimated mortality of 1 to 33 percent. In order to determine an element helpful for diagnosis. we examined four patients with amiodarone-induced pulmonary toxicity. three patients treated with A. without evidence of pulmonary toxicity but with a main underlying pulmonary disease. and four healthy volunteers. Daily and cumulative doses or duration of treatment were similar in the first two groups. Pulmonary function tests (spirometry. CO-diffusing capacity. arterial blood gases). roentgenographic examinations. pulmonary biopsies or immunoallergologic tests (skin reaction. lymphoblastic transformation test and human basophile degranulation test) did not provide any discriminatory element. In APT+. we observed an increased cellularity of the bronchoalveolar lavage. Neither the differential cell count nor the presence of foamy macrophages were distinguishable between APT+ and APT-. The phospholipid composition of BAL fluid showed a decreased total phospholipid and phospholipid/protein ratio in all patients compared to normal subjects. These changes reflect more the severity of pulmonary disease than the specificity of the causative agent. However. we observed that the unique PL which decreases in APT- and remains normal in APT+ is phosphatidyl-serine + phosphatidylinositol (PS + PI). This has to be confirmed and should be evaluated at different stages of the disease to determine an eventual specific element. We conclude that there are no data currently available to establish the diagnosis of APT except perhaps for the analysis of BAL PL content.
Ischemia and reperfusion during intermittent coronary occlusion in man. Studies of electrocardiographic changes and CPK release, The course of 357 balloon inflations performed during 38 angioplasties for single-vessel coronary artery disease was prospectively studied using continuous ECG recording. Ischemic ECG changes appeared during 91 percent of the inflations at a mean of 20 +/- 8 seconds after inflation and resolved in 97 percent of those at a mean of 11 +/- 5 seconds after deflation. Elevation of the plasma CPK level was found in six patients who had ischemic ECG changes for at least 7.8 minutes. The duration of ischemia did not exceed 5.4 minutes in any of the patients without CPK elevation. Resolution of the ischemic changes was delayed in patients with CPK elevation and in last vs initial inflations. We conclude that in patients with noninfarcted myocardium. ECG changes follow coronary occlusion and reflow very rapidly. detecting these coronary events with a high sensitivity. Lack of rapid regression predicts lack of reperfusion. and persistence of ischemia for more than 7.8 minutes is sufficient to cause myocardial necrosis.
Effect of fast vs slow intralipid infusion on gas exchange, pulmonary hemodynamics, and prostaglandin metabolism, Intralipid (20 percent. 500 ml) was infused fast (5 h) or slow (10 h) randomly in patients with lung injury to relate changes in plasma prostaglandin (PG) concentrations to gas exchange and pulmonary hemodynamics. Data were collected at baseline. midpoint of infusion. and 2 h following infusion. Vasodilator and vasoconstrictor PG metabolites. 6-keto-PGF1 alpha. and thromboxane B2. respectively. were measured in radial arterial blood samples. Slow Intralipid infusion increased shunt fraction (QS/QT) without changing mean pulmonary artery pressure (MPAP). whereas fast Intralipid infusion increased MPAP without changing QS/QT. Prostaglandin levels did not change significantly during either infusion. However. in both groups when the PG substrate was removed. hemodynamic and metabolite values decreased in parallel. In conclusion. we were unable to demonstrate a cause and effect relationship between plasma levels of 6-keto-PGF1 alpha and thromboxane B2 and the observed pulmonary hemodynamic response to slow or fast Intralipid infusion.
Effect of cardiac output reduction on rate of desaturation in obstructive apnea, The nadir of SaO2 during an obstructive apnea is dependent upon the apnea's duration and the rate of fall of saturation (dSaO2/dt). We postulated that a low Q. such as in patients with congestive heart failure with sleep apnea. or a reduction in Q. as seen in some humans during obstructive sleep apnea. might steepen dSaO2/dt. The mechanism postulated was lowering of SvO2 with increased pulmonary capillary blood oxygen uptake and faster depletion of alveolar oxygen. This study examines dSaO2/dt following the onset of apnea in eight spontaneously breathing adult baboons. Nonrepetitive obstructive apneas (30. 45. and 60 seconds) were created by clamping an indwelling cuffed endotracheal tube at the end of expiration. Following baseline measurements. the animals were given a bolus of a rapid-acting beta-adrenergic blocker followed by continuous infusion to reduce cardiac output and to limit the cardiovascular response to obstructive asphyxia. Fiberoptic catheters were used for continuous monitoring of SaO2. SvO2. and cardiac output. Esophageal pressure and relative thoracic gas volume (Respitrace) were monitored to insure equivalence of lung volume at the onset of apnea. Beta-adrenergic blockade reduced resting Q by a mean of 25 percent. The blocked vs unblocked dSaO2/dt was 0.73 vs 0.72 percent/s. 0.76 vs 0.73 percent/s. and 0.70 vs 0.71 percent/s for 30-second. 45-second. and 60-second apneas. respectively. Thus. mean dSaO2/dt for all durations of apneas was unaffected by beta-adrenergic blockade. We concluded that dSaO2/dt is not influenced by limited Q preceding or induced by obstructive asphyxia.
Regression of the left main trunk lesion by steroid administration in Takayasu's aortitis, A 62-year-old man with unstable angina due to severe narrowing of the left main trunk (LMT) was examined. Emergency bypass surgery was performed with an internal mammary artery graft. instead of a saphenous vein graft. because of the thickened. edematous ascending aorta. Postoperative coronary angiography showed the lesion of the LMT markedly regressing. Presumably. this stenotic lesion of the LMT was caused by active aortitis and was partially reversible by steroid administration both during and after surgery. Steroid therapy can be added to the list of treatments for cases of LMT disease associated with Takayasu's aortitis. if signs of active inflammation are present.
Treatment of atelectasis with selective bronchial suctioning. Use of a curved-tipped catheter with a guide mark, We applied our technique of selective bronchial suctioning (SBS) for the treatment of atelectasis (AT) of middle and lower lobes; nine patients with refractory ATs were successfully treated. We considered that SBS using a curve-tipped catheter with a guide mark (CTCGM) is the technique of choice for the treatment of refractory AT when conventional respiratory therapy is not effective and a bronchoscopist is not available.
Monitoring the effect of CPAP on left ventricular function using continuous mixed-blood saturation, The hypothetic benefit of CPAP on cardiac performance and on a reduction in VO2 was tested in a patient before heart transplantation after acute myocardial infarction using continuous SvO2 monitoring. The CPAP added to inotropic support (enoximone plus dobutamine) and intraaortic balloon pumping dramatically increased SvO2 in relation to both an increase in cardiac output and a decrease in VO2 secondary to respiratory work reduction. validating the initial hypotheses.
Pseudo pre-excitation with concertina effect in idioventricular tachycardia, The concertina effect is a phenomenon where the QRS complexes reflect alternating phases of gradual widening and narrowing. This is most commonly due to ventricular pre-excitation. and the changes in QRS morphology are due to variability of the ventricular zone that undergoes pre-excitation. This presentation reflects a case where the concertina effect is due to an idioventricular tachycardia at a rate nearly identical to the sinus rate. Variable degrees of ventricular fusion therefore occur. and the concertina effect ensues. in relation to slight variations of the sinus cycle.
Treatment of NIDDM with insulin agonists or substitutes, Non-insulin-dependent diabetes mellitus (NIDDM) is a common disorder occurring in 3-6% of adults in most western populations. In the United States. 29% of patients with diabetes take insulin; of these. 76% have NIDDM. Insulin therapy is usually required at some time in NIDDM. Insulin therapy improves the abnormalities of NIDDM (reduced beta-cell function. increased hepatic glucose production. reduced peripheral glucose disposal. lipid abnormalities). Insulin and sulfonylurea agents have comparable effects on mild forms of NIDDM. but for more severe forms. insulin is usually superior. Combination insulin-sulfonylurea treatment may improve the response to sulfonylureas. although long-term well-controlled trials have not been conducted. Short-term insulin treatment may restore response to sulfonylureas. Other promising treatments (human proinsulin. nasal insulin. somatostatin) have not shown any advantage over conventional insulin therapy. Insulin causes hypoglycemia and peripheral hyperinsulinemia. The hazards of hyperinsulinemia. e.g.. weight gain and hypoglycemia. have been overstated. and questions about its atherogenic effects remain to be resolved. The effect of glycemic control on macro- and microvascular complications has not been established; however. maintaining fasting blood glucose levels of less than 6.7 mM may protect against progression of retinopathy. neuropathy. and nephropathy and reduce the severity of ischemic stroke. Dosage algorithms generally use intermediate- or long-acting insulin to control basal glycemia. with regular insulin added before meals if needed to control postprandial glycemia. Effective therapy depends on the patient being informed. cooperative. and willing to self-monitor blood glucose. Insulin treatment intermittency increases the risk for immune complications (resistance and allergy). Overall. patients with NIDDM can benefit from insulin therapy.
Insulin use in NIDDM, The effects of insulin treatment on the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM) are reviewed herein. Short-term studies indicate variable and partial reduction in excessive hepatic glucose output. decrease in insulin resistance. and enhancement of beta-cell function. These beneficial actions may be due to a decrease in secondary glucose toxicity rather than a direct attack on the primary abnormality. Insulin should be used as initial treatment of new-onset NIDDM in the presence of ketosis. significant diabetes-induced weight loss (despite residual obesity). and severe hyperglycemic symptoms. In diet-failure patients. prospective randomized studies comparing insulin to sulfonylurea treatment show approximately equal glycemic outcomes or a slight advantage to insulin. A key goal of insulin therapy is to normalize the fasting plasma glucose level. In contrast to the conventional use of morning injections of intermediate- and long-acting insulin. preliminary studies suggest potential advantages of administering the same insulins only at bedtime. Obese patients may require several hundred units of insulin daily and still not achieve satisfactory control. In some. addition of a sulfonylurea to insulin may reduce hyperglycemia. the insulin dose. or both. However. long-term benefits from such combination therapy remain to be demonstrated conclusively. Established adverse effects of insulin treatment in NIDDM are hypoglycemia. particularly in the elderly. and weight gain. Self-monitoring of blood glucose can identify patients in whom excessive weight gain is caused by subtle hypoglycemia. Whether insulin causes weight gain by direct effects on appetite or energy utilization remains controversial. A potential adverse effect of insulin has been suggested by epidemiological studies showing associations between hyperinsulinemia or insulin resistance and increased risk for coronary artery disease. stroke. and hypertension. Although potential mechanisms for an atherogenic action of insulin exist. current evidence does not prove cause and effect and does not warrant withholding insulin therapy (or compromising on dosage) when it is needed.
Intensive insulin therapy for treatment of type I diabetes, Intensive insulin therapy is best defined as a comprehensive system of diabetes management with the patient and management team as partners. The system is directed at improvement of glycemia and patient well-being. Glycemic targets should be individually defined. Frequent self-monitoring of blood glucose. probably at least four times per day. is essential for meticulous control. The benefits include improved psychosocial functioning and the potential of lessening the risks of chronic complications of diabetes. The risks relate to problems associated with hypoglycemia. which are increased if meticulous glycemic control is sought. One of the important elements of intensive therapy is a multiple-component insulin program designed to provide effective insulinemia coinciding with each major meal and continuous basal insulinemia throughout the 24-h day. This may be achieved with continuous subcutaneous insulin infusion (CSII) or multiple injections with various insulin regimens. although CSII may offer real advantages in terms of the pharmacokinetics of insulin delivery. Other pharmacokinetic issues to be considered involve selection of injection sites. timing of premeal insulin. and mixing insulins. Many studies have shown that. albeit with effort. excellent glycemic control can be achieved by various intensive insulin-therapy regimens. The implementation of a program of intensive therapy involves patient self-management in terms of altering insulin dosages. food intake. and/or activity in an attempt to achieve the target level of glycemia selected. In motivated patients willing to embark on such a course of therapy. intensive insulin therapy can be worthwhile. It should be considered for all patients with type I (insulin-dependent) diabetes mellitus.
Retinoid modulation of insulin-like growth factor-binding proteins and inhibition of breast carcinoma proliferation, Retinoids induce cellular differentiation and inhibit cellular proliferation. Proliferation of human breast carcinoma cells in vitro is markedly inhibited by these compounds. On the other hand. insulin-like growth factors (IGFs) and their receptors seem to be involved in the growth of certain breast carcinoma cells by autocrine or paracrine effects. Since the effects of both IGF-I and IGF-II may be modulated by specific binding proteins (IGF-BPs) we examined the possibility that one mechanism by which retinoic acid may inhibit cancer growth is by an alteration in these BPs. thereby blocking IGF's growth effect. Retinoic acid (RA; 1 microM) completely blocked the effect of IGF-I (50 ng/ml) on enhancing proliferation of MCF-7 cells in culture. This effect of RA was not associated with any significant change in specific IGF-I-binding sites on these cells. RA induced a 3-fold increase in IGF-binding activity in conditioned medium. measured using a polyethylene glycol-immunoglobulin precipitation assay and a charcoal absorption assay. This increase was associated with the appearance of 42- and 46-kDa IGF-BPs on ligand blotting. The effect of RA on these IGF-BPs was time and concentration dependent. In contrast. during some experiments the 27- and 36-kDa BPs actually decreased. These findings support the hypothesis that RA may inhibit the growth of certain breast carcinoma cells by increasing the secretion of certain IGF-BPs. which could directly modulate the growth effect of IGFs.
Gram-negative infection increases noninsulin-mediated glucose disposal, Peripheral glucose uptake can occur by either insulin- or noninsulin-mediated mechanisms. and the two pathways appear to be regulated independently. Using the euglycemic hyperinsulinemic clamp technique. we have previously demonstrated that sepsis induces whole body insulin resistance. The purpose of the present study was to determine whether infection also alters noninsulin-mediated glucose uptake (NIMGU) and. if so. which tissues are affected. Studies were performed in chronically catheterized conscious rats under either basal (6 mM glucose. 30 microU/ml insulin) or insulinopenic conditions to determine NIMGU. Hypermetabolic sepsis was induced by sc injections of live Escherichia coli. and 24 h later a tracer amount of [U-14C]deoxy-2-glucose was injected for the determination of the in vivo glucose metabolic rate (Rg) in selected tissues. Our results indicate that NIMGU is the predominant route of glucose disposal in both septic and nonseptic rats. accounting for 79-83% of the total rate of glucose disposal. Because the rate of whole body glucose disposal was increased by sepsis. the absolute rate of NIMGU was 46% higher in septic rats than in nonseptic animals. This increase was the result of the elevated Rg in liver. spleen. ileum. and lung. Sepsis also increased whole body insulin-mediated glucose uptake by 88% under basal conditions. and this was due to an enhanced glucose uptake by muscle and skin. In insulinopenic animals in which the plasma glucose concentration was elevated to 17 mM. whole body glucose disposal increased by 107% in nonseptic animals. but by only 32% in septic rats. The hyperglycemic-induced increment in organ Rg was smaller in all tissues examined from septic animals. However. the absolute rate of whole body and tissue glucose utilization was not different between the two groups. These results indicate that gram-negative infection increases whole body NIMGU. which results from an enhanced rate of glucose utilization by tissues rich in mononuclear phagocytes. including the liver. spleen. ileum. and lung. but not by muscle.
Stress-induced adrenocorticotropin secretion: diurnal responses and decreases during stress in the evening are not dependent on corticosterone, To test whether the diurnal rhythm in stress responsiveness is dependent on corticosterone (B)-mediated negative feedback. the responses of intact (SHAM) and adrenalectomized (ADX) rats to restraint for 3-90 minutes or ip injection with saline in the morning (AM) and the evening (PM) were compared. In both SHAM and ADX rats. ACTH responses to restraint stress were larger in the AM. In intact rats. this could have resulted from both fast negative feedback. due to the rate of rise of B during the stress in the PM. and delayed negative feedback. due to the high basal concentrations of B before the stress in the PM. However. this diurnal pattern of stress responsiveness was not dependent on B. as the same relative responses to restraint and ip injection were found in ADX rats. To determine whether the lack of response of ADX rats in the PM to stress was due to a loss of sensitivity to endogenous secretagogues. ADX rats were given CRF + arginine vasopressin (AVP) while anesthetized with ether after 30 min of restraint. In both the AM and the PM. the pituitaries were able to respond to exogenous secretagogues. A second novel finding was that in the PM. but not the AM. plasma ACTH concentrations in the ADX rats decreased substantially during the period of restraint. despite the lack of B-mediated negative feedback. In the AM and the PM. ADX rats were restrained for 30 min and then stressed with ether for 6 min. The ACTH concentrations were not different before and after ether. suggesting that. although the pituitaries of ADX rats are able to respond to exogenous CRF + AVP after stress. an additional stress of ether exposure no longer stimulates endogenous CRF and AVP release after 30 min of restraint at either time of day. After 90 min of restraint in the AM and the PM. the relationship between ACTH and B was positive. not negative. providing no evidence of ongoing B-mediated negative feedback in the SHAM rats. Therefore. the same mechanism responsible for the decrease in ACTH secretion in ADX rats may occur in SHAM rats as well. From these results. we conclude that the diurnal rhythm in stress responsiveness and. in the PM in the ADX rats. the decrease in plasma ACTH during stress. are largely independent of B.
Retinoic acid is able to reinitiate spermatogenesis in vitamin A-deficient rats and high replicate doses support the full development of spermatogenic cells, The effect of various doses of retinoic acid (RA) on the seminiferous epithelium in vitamin A-deficient rats has been studied. Although it was generally thought that RA was not able to reinitiate spermatogenesis in vitamin A-deficient rats. one injection of 5 mg RA strongly stimulated the proliferative activity of A-spermatogonia within 24 h. as evidenced by a 7-fold increase in the number of bromodeoxyuridine-labeled A-spermatogonia. Ten days after RA administration. B-spermatogonia or preleptotene spermatocytes were seen in most of the seminiferous tubules. After 15 days. zygotene spermatocytes were present. Hence. RA is able to induce a massive and synchronized development of A-spermatogonia into spermatocytes. When RA was given once. combined with a RA-containing diet. only few of the zygotene spermatocytes present on day 15 were able to develop into pachytene spermatocytes. which did not develop into spermatids. In subsequent epithelial cycles new B-spermatogonia and spermatocytes were formed. although in lower numbers than during the first cycle after RA injection. When RA was given once a week. the formation of B-spermatogonia and preleptotene spermatocytes continued at a higher level. Also. more pachytene spermatocytes were formed. some of which were able to develop into spermatids. Finally. when RA was injected twice a week. even more pachytene spermatocytes and round spermatids were found after 36 days. and after 49 days elongated spermatids were found in all animals. It is concluded that RA. similar to retinol. is able to induce synchronous proliferation and differentiation of A-spermatogonia. When repeated injections are given. RA is able to support the full development of spermatogenic cells into elongated spermatids.
Binding and action of insulin-like growth factor I in pituitary tumor cells, Insulin-like growth factor I (IGF-I). a target hormone mediating most of the growth effects of GH. suppresses GH gene expression in a feedback regulatory loop. which may be either endocrine or paracrine in nature. Although IGF-I has been shown to directly attenuate GH gene transcription. the relationship of IGF-I binding and action in the somatotroph cell remains unclear. Therefore. IGF-I binding and action were compared in two different pituitary cell lines both secreting GH. Recombinant human IGF-I attenuated GH secretion in GC cells by up to 70% after 48 h in a dose-dependent manner. Surprisingly. IGF-I failed to suppress GH secretion in GH3 cells. a clonally related pituitary cell line. Binding studies showed that although the KD for IGF-I was similar in both cell types. GC cells contain 3-fold more IGF-I binding sites compared to GH3 cells. possibly explaining their resistance to IGF-I action. Nevertheless. both cell lines possessed abundant and similar binding sites for insulin. These results imply that the IGF-I signal for GH gene regulation is receptor-mediated and directly correlated with the number of pituitary IGF-I binding sites. Availability of pituitary IGF-I binding sites may therefore be important in determining the level of GH expression by the somatotroph.
Failure of insulin-like growth factor-I (IGF-I) infusion to promote growth in protein-restricted rats despite normalization of serum IGF-I concentrations, Dietary protein restriction in young rats induces GH resistance characterized by growth arrest and low serum insulin-like growth factor-I (IGF-I) concentrations. To determine whether the low serum IGF-I concentrations are responsible for the stunted growth. we infused 4-week-old protein-restricted rats with recombinant human IGF-I (300 micrograms/day) or rat GH (200 micrograms/100 g body wt/day) by osmotic minipump for 1 week. Despite the normalization of serum IGF-I concentrations by IGF-I infusion. carcass growth was not stimulated. In contrast. growth of the spleen and kidney was enhanced (+45% and +28%. respectively). Serum IGF-binding protein 3 (IGFBP-3). the principal carrier of IGF-I in the serum at this age. is decreased by 34% in protein-restricted animals and restored to normal by IGF-I infusion. Contrary to the selective effects of IGF-I on growth of protein-restricted rats. well nourished hypophysectomized rats infused with 150 micrograms/day recombinant human IGF-I showed a significant growth response. including carcass and organ growth and normalization of IGFBP-3 values. These responses indicate that our IGF-I preparation and mode of delivery were effective. We conclude that: 1) dietary protein restriction causes organ-specific resistance to the growth-promoting properties of exogenous IGF-I; 2) IGF-I mediates the stimulatory effects of growth hormone on IGFBP-3 synthesis; and 3) the absence of carcass growth in the presence of normal serum IGF-I concentrations during infusion of IGF-I suggests that the growth arrest that accompanies protein restriction is mediated in part by resistance to IGF-I.
Sexual dimorphism of pancreatic beta-cell degeneration in transgenic mice expressing an insulin-ras hybrid gene, The human H-ras oncogene induces cell degeneration and diabetes when expressed in pancreatic beta-cells in transgenic mice. The disease develops predominantly in male mice between 5-8 months of age. Most transgenic female mice do not manifest this phenotype. even at much greater ages. However. ovariectomy induces female beta-cell degeneration similar to that in the males. In contrast. castration or the presence of the testicular feminization mutation do not alter the course of the disease in males. Treatment of males and ovariectomized females with estrogen prevents the development of diabetes. These results suggest that testicular androgens and a functional testosterone receptor are not required for the increased susceptibility of male beta-cells to the effects of the Ras oncoprotein. and that the relative resistance of female beta-cells is mediated by estrogen. In addition. a genetic component of female beta-cell resistance to Ras is revealed by crossing the transgenic mice with C3HeB/FeJ mice. which results in a pronounced increase in the incidence of female diabetes.
Pituitary insulin-like growth factor-I content and gene expression in the streptozotocin-diabetic rat: evidence for tissue-specific regulation, Insulinopenic diabetes mellitus in the rat is associated with reduced circulating levels of insulin-like growth factor-I (IGF-I). resulting primarily from decreased IGF-I synthesis in liver and extrahepatic sites. Plasma GH levels in these animals are also suppressed. with loss of episodic secretion and decreased pituitary synthesis. Intrapituitary IGF-I has been postulated to exert local autocrine/paracrine negative feedback regulation on GH synthesis and secretion. The present studies were designed to examine regulation of pituitary IGF-I peptide content and gene expression in insulinopenic streptozotocin (STZ)-diabetic rats compared to that in liver and testis. Serum IGF-I levels were reduced by 86% in STZ-diabetic rats together with reduction of IGF-I content in liver (53%) and testis (74%; all P less than 0.001 vs. control). Concomitantly. liver and testicular IGF-I mRNA levels were reduced by 90% (P less than 0.001 vs. control). Insulin treatment restored IGF-I peptide levels in serum. liver. and testis toward normal. with a partial but significant increase in liver IGF-I mRNA. In contrast. pituitary IFG-I peptide content increased by 69% in STZ-diabetic rats (P less than 0.001 vs. control). with no change in IGF-I gene expression. Insulin treatment completely reversed the rise of pituitary IGF-I peptide content. These results demonstrate a novel discordance in the regulation of IGF-I gene expression and peptide content between pituitary and other tissues in STZ-induced diabetic rats. Elevated IGF-I levels in the pituitaries of these animals may partly explain the suppressed GH synthesis and secretion seen in STZ-diabetic rats and provide further evidence for a potential autocrine or paracrine role of pituitary IGF-I in GH regulation.
Pulsatile luteinizing hormone secretion in normal female mice and in hypogonadal female mice with preoptic area implants, Pulsatile LH secretion is driven by GnRH. the hypothalamic hormone that is lacking in the hypogonadal mutant mouse. Preoptic area grafts containing GnRH neurons correct many reproductive deficits in hypogonadal mice. In this study we evaluated the pattern of LH secretion in hypogonadal female mice with preoptic area grafts (hpg/POA) and in normal female mice. Normal females were ovariectomized at 10 weeks of age. and hpg/POA mice were ovariectomized 4 months after graft surgery. Three weeks later. all mice received intracardial catheters. The next day. sequential blood samples were obtained every 10 min for 4 h from the awake. freely moving mice. At ovariectomy. normal and hpg/POA ovarian weights were 8.6 +/- 0.9 and 7.1 +/- 1.2 mg. respectively. Significant LH pulses were detected in 9 of 10 normal mice and in 9 of 13 hpg/POA mice. Pulse frequency (normal. 0.86 +/- 0.13; hpg/POA. 0.61 +/- 0.13 pulse/h) and interpeak interval (normal. 81.7 +/- 20.3; hpg/POA. 93.2 +/- 24.0 min) were not significantly different (P greater than 0.2). but mean plasma LH levels (normal. 1.07 +/- 0.16 ng/ml; hpg/POA. 0.49 +/- 0.08 ng/ml; P less than 0.005) and mean LH pulse amplitude (normal. 1.92 +/- 0.53; hpg/POA. 0.63 +/- 0.28; P less than 0.05) were significantly lower in the hpg/POA mice. The lower mean LH level and LH pulse amplitude in ovariectomized hpg/POA mice are consistent with the inability of most of these mice to show increased LH secretion after castration. The findings indicate that preoptic area brain grafts are capable of supporting episodic LH release in the hypogonadal mouse and suggest the presence of a functional GnRH pulse generator in the majority of mice with grafts.
Regulation of gene expression in choriocarcinoma by methotrexate and hydroxyurea, Choriocarcinoma. a highly malignant neoplasm of trophoblastic origin. is remarkable for its marked degree of sensitivity to chemotherapeutic agents. We treated two cell lines derived from choriocarcinoma patients with two antineoplastic agents. methotrexate and hydroxyurea (HU). both of which cause nucleotide depletion and have been previously shown to be effective against choriocarcinoma. and found pleiotropic regulation of several genes. Three genes. hCG alpha-subunit. beta-subunit. and placental alkaline phosphatase. were all strongly induced by methotrexate and HU. Expression of c-myc. an oncogene associated with proliferation. was reduced to nearly undetectable levels by the drug treatment. while expression of beta 2-microglobulin. a component of the class 1 major histocompatibility locus. was unchanged. In addition. the mechanism of induction by HU of one of these genes. the hCG alpha-subunit gene. was found to occur at the level of transcription. The similar effects of methotrexate and HU. two mechanistically unrelated antimetabolites. on the induction of specific gene expression in choriocarcinoma cells suggest that these effects are due to nucleotide pool alteration. rather than specific ligand effects. Furthermore. the hCG alpha-subunit promoter contains a transcriptionally regulated HU-responsive element.
Hyperprolactinemia increases and hypoprolactinemia decreases tyrosine hydroxylase messenger ribonucleic acid levels in the arcuate nuclei, but not the substantia nigra or zona incerta, The effects of experimentally produced hypoprolactinemia and hyperprolactinemia on tyrosine hydroxylase (TH) mRNA signal levels were examined in dopaminergic neurons ovariectomized rats. TH mRNA signal levels and relative TH quantity in the arcuate nuclei. zona incerta. and substantia nigra were evaluated by in situ hybridization and immunocytochemistry. respectively. The catalytic activity of TH in the stalk-median eminence (SME) was determined from the in vitro rate of 3.4-dihydroxyphenylalanine (DOPA) accumulation after inhibiting DOPA decarboxylase with brocresine. Chronic administration of bromocriptine (BROMO). a dopamine (DA) agonist. for 3 days reduced circulating rat PRL (rPRL) levels compared to those in the vehicle-treated controls. BROMO treatment decreased TH mRNA signal levels in the arcuate nuclei. the intensity of TH immunostaining in the arcuate-median eminence area. and the rate of DOPA accumulation in the SME. Concomitant administration of ovine PRL (oPRL) reversed the effects of BROMO on TH. resulting in markedly increased TH mRNA signal levels. intensity of TH immunostaining. and rate of DOPA accumulation. Treatment with oPRL by itself for 3 days increased TH mRNA signal levels in the arcuate nuclei and TH activity in the SME. compared to vehicle. Chronic treatment with haloperidol. a DA antagonist. increased circulating levels of endogenous rPRL and increased TH activity in the SME to values similar to those after oPRL treatment. However. in contrast to oPRL. mRNA levels in the arcuate nuclei of haloperidol-treated rats were similar to levels in vehicle-treated animals. To evaluate whether the effect of PRL on TH was species specific. oPRL or rPRL was continuously infused into the jugular vein using an osmotic minipump. TH mRNA levels in the arcuate nuclei were elevated above control levels by either oPRL or rPRL administration. TH mRNA levels in the DA perikarya located in the zona incerta and substantia nigra were not altered by treatment with a DA agonist. a DA antagonist. or PRL. These results indicate that hypoprolactinemia or hyperprolactinemia can selectively reduce or augment. respectively. TH mRNA levels in the tuberoinfundibular dopaminergic neurons. The alterations in TH mRNA content probably contribute to the decrease or increase in TH activity associated with hypoprolactinemia or hyperprolactinemia. respectively.
Humor, aggression, and aging, Humor response to aggressive cartoons was investigated by using ratings of pain and funniness of cartoons by 154 young and elderly men and women. No significant age differences were found; however. sex differences were found. For both young and elderly females. an inverted-U described the relationship between pain and funniness ratings. For young and elderly males. there was no relationship between pain and funniness. This is a preliminary step in exploring age differences in humor but may be relevant for those working with elderly persons.
Cyclosporine in nonpsoriatic dermatoses, This article reviews the indications. efficacy. and possible mechanisms of action of cyclosporine in the treatment of nonpsoriatic dermatoses. These dermatoses can be categorized according to their responsiveness to cyclosporine therapy as excellent. moderate. variable. and nonresponsive. The advantages and disadvantages of cyclosporine are discussed and guidelines are proposed for its use in nonpsoriatic dermatoses.
Management of patients and side effects during cyclosporine therapy for cutaneous disorders, Cyclosporine has been used in the experimental treatment of multiple inflammatory diseases of presumed autoimmune origin. including insulin-dependent diabetes mellitus. uveitis. rheumatoid arthritis. inflammatory bowel diseases. Graves' disease. and myasthenia gravis. In dermatology. the drug has been used successfully as primary therapy for psoriasis and psoriatic arthritis. alopecia areata. pyoderma gangrenosum. Behcet's disease. atopic dermatitis. and lichen planus. At a dose of 3 to 5 mg/kg per day. cyclosporine is well tolerated by most patients. However. because of concerns about its potential short- and long-term side effects. patients who use this drug require close monitoring. This review discusses appropriate clinical and laboratory evaluations. common and unusual side effects and their management. drugs that might alter the pharmacokinetics of cyclosporine metabolism. and criteria for dosage adjustments.
Laboratory monitoring of cyclosporine levels: guidelines for the dermatologist, The following guidelines are recommended for laboratory monitoring of circulating levels of cyclosporine in dermatology patients. Measurements should be determined as trough levels in whole blood. not plasma or serum. The measurements should be performed with an assay that is specific for the parent cyclosporine compound (e.g.. a high-performance liquid chromatography method or a specific monoclonal immunoassay). The results of nonspecific immunoassays that detect cyclosporine as well as its metabolites are difficult to interpret and cannot readily be compared among different studies or laboratories. In psoriasis patients. the circulating concentration of cyclosporine does not correlate reliably with the therapeutic response. Some patients may achieve an excellent response with blood levels in the range of 50 ng/ml; others may show little or no response despite blood levels as high as 200 ng/ml. In patients with a poor clinical response. monitoring of cyclosporine levels may be useful to confirm that the drug has been taken and may provide an estimate of the degree of absorption and metabolism of the parent compound. Because an upper limit of safety for the circulating concentration of cyclosporine has not been clearly defined. one should attempt to achieve a therapeutic response with the lowest possible dose. Clinicians must carefully monitor patients for signs of cyclosporine toxicity. regardless of the circulating concentration of the drug. Whole blood levels exceeding 250 ng/ml should be avoided.
Effects of cyclosporine on renal function in psoriasis patients, Several prospective studies have documented the effectiveness of oral cyclosporine in the treatment of psoriasis. Despite this. the use of cyclosporine has been limited because of concern about the possibility of drug-induced renal dysfunction. We review the effects of cyclosporine on renal function.
Immunity during cyclosporine therapy, Cyclosporine is not cytotoxic but it inhibits the production of immunologic memory-building growth factors by CD4+ T lymphocytes. It also may have inhibitory effects on the effector phase of certain immune reactions. These inhibitory effects are largely reversible and when treatment is stopped. the immune competence of cyclosporine-treated patients returns to normal. In contrast. conventional cytotoxic immunosuppressive agents tend to exterminate the lymphocyte clones that are activated during therapy. and such clonal deletions may cause permanent loss of immunologic memory to those antigens because T lymphocytes are not readily restored in adults with involuted thymus. Most transplant patients have received cyclosporine in combination with various other immunosuppressive agents. and reports suggest that a combination of this drug and conventional immunosuppressive agents may be associated with increased early appearance of non-Hodgkin's lymphoma and. possibly. endocrine-related tumors. An increase in cancers has not been observed in patients treated with cyclosporine alone for such conditions as psoriasis and autoimmune diseases. Treatment of adults with cytotoxic immunosuppressive drugs may permanently delete T-lymphocyte clones that are required for control of latent oncogenic viruses or certain malignant cells. Because of this. when such patients are treated with cyclosporine. further suppression of T-cell function combined with impairment of cytokine-mediated stimulation of natural killer cells and cytotoxic macrophages may facilitate tumor growth. Consequently. it is predicted that if cyclosporine monotherapy is associated with an increased incidence of tumors. it would primarily affect psoriasis patients who are treated with cyclosporine after PUVA or methotrexate therapy. Eventually. comparison of cancer incidence in different categories of patients should resolve this issue.
Interactions of epidermal cells and T cells in inflammatory skin diseases, Multiple cell types and their factors and cytokines are involved in regulating the immune response in inflammatory skin diseases. Stimulatory and inhibitory factors interact to determine whether the immune response is regulated up or down. Normally. stimulatory signals are counteracted by inhibitory signals to prevent an immune reaction from being initiated. However. exogenous antigens and irritants or endogenous factors and altered immunogenic self-peptides can upset this balance. When that occurs. T cells are activated and an inflammatory skin reaction develops. Lymphokines released from such activated T cells can modify the phenotype and function of normal keratinocytes. They can induce the expression of adhesion molecules and receptors involved in antigen presentation. Furthermore. they can also stimulate keratinocyte proliferation. This may be important in development of the hyperplasia seen in inflammatory skin diseases. especially in psoriasis. Cytokines released from the activated keratinocytes can both stimulate and attract T cells to the epidermis and thereby continue the ongoing immune reaction.
Effects of cyclosporine on immunologic mechanisms in psoriasis, A major impetus for further investigation of cellular immunologic mechanisms in psoriasis has been the discovery that cyclosporine. a potent immunosuppressive. is highly effective in the treatment of psoriasis. Cyclosporine has significant inhibitory effects on the ability of T cells to become activated. However. a direct activity of this drug on human keratinocyte signal transduction or growth has been difficult to demonstrate at relevant concentrations. Nevertheless. treatment of psoriasis or of 12-O-tetradecanoyl phorbol-13-acetate-treated murine skin with cyclosporine does reverse many epidermal abnormalities that are common to these two systems. This suggests that the compound exerts an indirect effect on epidermal keratinocytes in vivo. perhaps through immunocyte inhibition. During treatment of psoriasis patients. cyclosporine therapy resulted in selective changes in the numbers and functions of certain antigen-presenting cell subsets (which were distinct from Langerhans cells) and T-cell subsets. These changes were accompanied by indirect evidence of decreased T-cell lymphokine release. Lesional activity of cyclosporine-treated psoriasis patients was closely correlated with the degree of T-cell activation caused by antigen-presenting cells. Cyclosporine inhibition of lymphokine or cytokine release may result in decreased recruitment of non-Langerhans antigen-presenting cells into the epidermis and thus decreased immunoreactivity in the lesion.
Sensitivity restored of Class V abrasion/erosion lesions, The effectiveness of restorative treatment in reducing sensitivity associated with the Class V erosion/abrasion lesion was evaluated and the efficacy of three tooth-colored restorative materials in reducing sensitivity was compared. The 108 lesions were restored with either glass ionomer restorative material. composite resin with a dentin bonding agent. or composite resin with a dentin bonding agent and a glass ionomer liner. Composite resin with glass-ionomer liner restorations significantly reduced sensitivity to air and hot and cold water. Glass ionomer restorations and restorations with composite resin and a dentin bonding agent significantly reduced sensitivity but were also associated with increased sensitivity to air and cold respectively in 20% to 30% of the lesions restored when evaluated at 6 months.
Microleakage at gingival dentin margins of Class V composite restorations lined with light-cured glass ionomer cement, This study compared the microleakage of light-cured and auto-set glass ionomer liners used in Class V composite laminated glass ionomer restorations by determining the amount of microleakage at the gingival cementum/dentin margins. Standardized nonundercut V-shaped Class V cavities with gingival margins below the cementoenamel junction were prepared on the mesial and distal surfaces of 40 molars. establishing a total of 80 cavities. which were randomly divided into four groups. Each was lined with glass ionomers: group 1. Ketac-Bond (ESPE-Premier). which served as the control; group 2. XR-Ionomer (Kerr); group 3. XR-Ionomer with polyacrylic acid (PAA) pretreatment (Kerr); and group 4. Vitrabond (3M). Specimens were thermocycled for 300 cycles in 0.5% aqueous solution of basic fuchsin between 4 and 55 C with a 1-minute dwell time. and individually embedded in an epoxy resin. Statistical analysis indicated no differences among groups using the light-cured glass ionomer (groups 2 to 4). and they showed significantly less leakage than the control (group 1) at P less than 0.00001). Removal of the smear layer using 10% polyacrylic acid solution did not influence microleakage in restorations with light-cured glass ionomer liners.
Effect of endodontic access preparation on resistance to crown-root fracture, This investigation involved the creation of coronal-radicular fractures in vitro and compared the fracture resistance of intact human mandibular molars. with molars after varied tooth preparation. Forty freshly extracted. non-carious. nonrestored human mandibular molars were randomly divided into four treatment groups. The molars were subjected to constantly increasing occlusal load until coronal-radicular fracture occurred. Tooth preparations significantly diminished resistance to coronal-radicular fracture.
Approach to diagnosis of meningitis. Cerebrospinal fluid evaluation, CSF evaluation is the single most important aspect of the laboratory diagnosis of meningitis. Analysis of the CSF abnormalities produced by bacterial. mycobacterial. and fungal infections may greatly facilitate diagnosis and direct initial therapy. Basic studies of CSF that should be performed in all patients with meningitis include measurement of pressure. cell count and white cell differential; determination of glucose and protein levels; Gram's stain; and culture. In bacterial meningitis. Limulus lysate assay and tests to identify bacterial antigens may allow rapid diagnosis. Where there is strong suspicion of tuberculous or fungal meningitis. CSF should also be submitted for acid-fast stain. India ink preparation. and cryptococcal antigen; unless contraindicated by increased intracranial pressure. large volumes (up to 40-50 mL) should be obtained for culture. If a history of residence in the Southwest is elicited. complement-fixing antibodies to Coccidioides immitis should also be ordered. Newer tests based on immunologic methods or gene amplification techniques hold great promise for diagnosis of infections caused by organisms that are difficult to culture or present in small numbers. Despite the great value of lumbar puncture in the diagnosis of meningitis. injudicious use of the procedure may result in death from brain herniation. Lumbar puncture should be avoided if focal neurologic findings suggest concomitant mass lesion. as in brain abscess. and lumbar puncture should be approached with great caution if meningitis is accompanied by evidence of significant intracranial hypertension. Institution of antibiotic therapy for suspected meningitis should not be delayed while neuroradiologic studies are obtained to exclude abscess or while measures are instituted to reduce intracranial pressure.
AIDS in California family medicine. Changing experiences, knowledge, and geographic distribution, Information regarding practice patterns specific to acquired immunodeficiency syndrome (AIDS) was obtained in 1988 from 1774 family physicians in California using a mail survey. Data were analyzed across the following county groupings: Los Angeles County. other counties in standard metropolitan statistical areas. and counties outside standard metropolitan statistical areas. Comparisons were made with the data from a telephone survey conducted in 1986. Differences over time were analyzed. By 1988. the percentage of physicians treating or referring patients for possible AIDS had more than doubled in counties outside standard metropolitan statistical areas. The percentage of physicians reporting one or more diagnosed cases of AIDS had tripled. a finding that suggests the importance of AIDS in family medicine is increasing at a rapid rate. In addition. survey results indicate that a majority of those surveyed still lack the AIDS-related knowledge and competency necessary to effectively deal with AIDS.
Changes in women's mental and physical health from pregnancy through six months postpartum, A longitudinal study was conducted to investigate changes in women's mental and physical health around the time of childbirth. and to determine whether health was related to length of maternity leave. Thirty-seven married. employed first-time mothers completed questionnaires during pregnancy. and again at 6 weeks. 3 months. and 6 months postpartum. Results showed that. from pregnancy to the 6th postpartum month. the number of days that mothers were ill because of infections steadily increased. In addition. depressive symptoms for new mothers rose from pregnancy to the 6th week postpartum. and declined thereafter. For women who did not return to work during the period of the study. a significant decline in depressive symptoms was observed from the prenatal period through the 6th postpartum month. These findings demonstrate significant changes in mental and physical health for this group of first-time mothers.
Should family physicians test for human papillomavirus infection? An opposing view, Recent advances in the field of molecular biology have expanded the knowledge of HPV manifestations. We have attempted to separate those circumstances when HPV testing may be useful in patient management and when it may not. Routine screening for HPV has not yet been shown to be useful. One must weigh informing 10% of patients that they have a potentially oncogenic virus against the ability of a repeat Papanicolaou smear to detect the lesion. On the other hand. HPV detection in the setting of an abnormal Papanicolaou smear and an acetowhite lesion that on biopsy lacks the histologic features of CIL does predict who is at high risk for CIL. HPV typing should not affect clinical management. and we do not recommend it. HPV detection by in situ hybridization is a very useful adjunct to histological analysis in genital tract lesions that are clinically suggestive of an HPV lesion but where the histological analysis is equivocal. This ability to distinguish true HPV lesions from its mimics is often crucial to the patient. given the implications of having a sexually transmitted disease.
The "military family syndrome" revisited: "by the numbers", Because concerns have been raised about high levels of psychopathology in military children. the authors used standardized psychopathology rating scales to survey 213 six-to twelve-year-old children of military parents and their parents. Results from children's symptom self-reports. as well as from teachers' ratings of children. indicated that children's symptom levels were at levels consistent with national norms. In contrast. parents' (especially mothers') ratings of children were significantly higher than national norms. as were parents' ratings of their own symptoms. Also. parents' own symptom reports showed somewhat stronger relationships with life stressors presumably affecting the child than did the children's and teachers' reports. Results suggest that parents' reports of children's symptoms may be mediated by the effects of military life stressors on the parents. but these stressors do not necessarily result in higher symptoms in the children. Overall results do not support the notion that levels of psychopathology are greatly increased in children of military parents. Further studies of military families should address the effects of rank and socioeconomic status. housing. and the current impact of life stressors on the parents as well as the children in order to avoid drawing erroneous conclusions about parts or all of the military community.
Search for retroviral sequences in peripheral blood mononuclear cells and brain tissue of multiple sclerosis patients, DNAs from peripheral blood mononuclear cells (PBMCs) of 21 patients with multiple sclerosis (MS). 1 patient with tropical spastic paraparesis (TSP) as well as DNAs from brain and spinal cord of 5 MS cases and 3 controls were examined for human T-cell lymphotropic virus (HTLV)-related sequences by polymerase chain reaction. The primers used were derived from the HTLV-I gag. env and tax genes. Amplified products were separated on agarose gels. blotted onto nylon membranes and hybridized to specific radiolabelled oligonucleotides. The sensitivity of amplification and hybridization was one copy of target DNA in 10(5) cellular genomes. None of the specimens was positive for HTLV-I sequences except the TSP probe. These negative data are all the more significant because brain material from MS patients was used in these studies. Our studies thus fail to support speculations that HTLV-I is involved in the aetiology of multiple sclerosis.
Traumatic and spontaneous extracranial internal carotid artery dissections, Seventy patients with spontaneous and 21 with traumatic extracranial internal carotid artery dissections were studied clinically and angiographically with mean follow-ups of 64 (spontaneous group) and 40 months (traumatic group). Sixty percent of the patients in the spontaneous group and 71% in the traumatic group also had follow-up angiograms. In traumatic dissections aneurysms were common. significantly fewer aneurysms resolved or became smaller and fewer stenoses resolved or improved. whereas more stenoses progressed to occlusion. Traumatic dissections were more likely to leave the patients with neurological deficits. A significantly higher percentage of the patients with spontaneous dissections were asymptomatic at follow-up compared with the traumatic group. Although both spontaneous and traumatic dissections of extracranial internal carotid arteries mostly carry a good prognosis. the outcome may be somewhat less favorable for the traumatic group.
Fluctuations of interictal brain imaging in repeated 123I-IMP SPECT scans in an epileptic patient, Single photon emission computed tomography (SPECT) brain scans with N-isopropyl-(iodine 123) p-iodoamphetamine (123I-IMP) were performed three times in interictal periods in a 35-year-old man with intractable frontal lobe epilepsy and normal X-ray CT findings. The first scan showed decreased 123I-IMP uptake in the right frontal lobe. This abnormal image was regarded as the primary focus of his epilepsy on the basis of its regional agreement with focal epileptic discharges on EEGs. In the second scan. he showed normal imaging. while the third scan showed the same abnormal image as before. in the right frontal lobe. The frequency of his clinical seizures was almost unchanged during the intervals between scans and further EEGs recorded soon after each scan showed almost no changes in the basic activities and frequency of the epileptic discharges. Such fluctuations in SPECT brain imaging suggest that the severity of functional inactivation underlying the focal hypoperfusion image as an epileptic focus may fluctuate considerably in the interictal state with no relation to the clinical features of epilepsy.
Brain-stem auditory evoked potentials in multiple sclerosis: the relation to VEP, SEP and CSF immunoglobulins, One hundred patients with multiple sclerosis (MS) were analysed retrospectively with respect to investigations of brain-stem auditory evoked potentials (BAEP). pattern reversal visual evoked potentials (VEP). somatosensory evoked potentials (SEP). and cerebrospinal fluid immunoglobulins (CSF-IG). BAEP were abnormal in 42% of those with normal VEP and SEP examinations. and in 38% of patients with normal CSF-IG. The chance of obtaining at least one abnormal EP was lower in patients with normal CSF-IG than in patients with abnormal CSF. When a "dispersion ratio" was included in the criteria for BAEP abnormality. the sensitivity increased compared with conventional BAEP criteria. We recommend that BAEP should still be included in the EP test battery for patients with suspected MS.
Aberrant regeneration in a case of syringobulbia: selective co-activation of abducens and facial nerves during saccades, A patient suffering from syringobulbia and syringomyelia exhibited a phasic contraction of the ipsilateral facial muscles. mainly the levator labii. whenever he looked to the left or right. Facial muscle twitches occurred exclusively with saccades. The selective co-activation of abducens and facial nerves is interpreted as the result of bilateral misrouting of regenerating neurons from the parapontine reticular formation to the facial nerve in the tegmentum pontis.
Familial eating epilepsy, Eating-related seizures affecting 20 individuals among 59 siblings belonging to nine families are presented. The type of epilepsy was partial in all the affected individuals. and the seizures complex in 15 and simple in 5. secondarily generalized in the majority. The onset of epilepsy. in most cases. was in the second decade of life. A remarkable degree of intra-family consistency was observed with regard to age at onset. symptomatology of seizures and timing of eating seizures. The study demonstrates sibling clustering in a partial epilepsy. implicating for the first time genetic susceptibility in the aetiology of eating epilepsy.
Mandibular ramus anatomy as it relates to the medial osteotomy of the sagittal split ramus osteotomy, The sagittal split ramus osteotomy is probably the most frequently used procedure for correction of mandibular skeletal dentofacial deformities. Despite numerous improvements in the technique in the 30 years since the procedure was introduced. a number of troublesome complications still occur. These include unfavorable fracture during surgery. paresthesia. and relapse. The purpose of this study was to determine where fusion of the buccal and lingual cortical plates occurs in the upper mandibular ramus. as it is thought that placement of the horizontal medial osteotomy above the point of fusion (without any intervening medullary bone) may lead to unfavorable fracture during splitting. Forty-nine human mandibles were sectioned vertically at three locations perpendicular to the surface of the ramus and the occlusal plane. Measurements were made to locate vertically the point of fusion of the buccal and lingual cortical plates relative to the lingula and to the depth of the sigmoid notch. The point of fusion occurred between 7.5 and 13.3 mm above the lingula. Only 2% of mandibles had fusion at or below the level of the lingula in the anterior ramus. whereas in the posterior ramus. 6.1% of mandibles were fused at that level. At a level halfway from the lingula to the sigmoid notch. 20% of mandibles were fused in the anterior ramus. whereas in the mid- to posterior ramus. the incidence was as high as 39%. The location of the medial horizontal osteotomy should be at or just above the tip of the lingula. A higher level of cut may be associated with an increased difficulty in splitting or incidence of unfavorable fracture.
Outpatient orthognathic surgery: criteria and a review of cases, Over a 9-year period. 87 orthognathic procedures were performed in an outpatient environment. Procedures performed included horizontal mandibular osteotomies. rapid palatal expansions. bilateral sagittal split osteotomies. posterior and anterior maxillary osteotomies. and Le Fort I osteotomies. Fourteen of these patients were subsequently admitted to a hospital for either observation or full inpatient care. The rates of admission varied for each of the procedures. with length of anesthesia statistically related to the frequency of admission. Patient selection criteria and facilities used are reviewed.
Evaluation of the serum level of immunosuppressive substance in oral cancer patients, The serum level of immunosuppressive substance (IS) was studied in 40 patients with primary oral cancer and in 79 patients without cancer. Its usefulness was evaluated as a parameter for monitoring therapy as well as recurrence of the tumors. Mean values for serum IS in patients with cancer and patients without were 687 +/- 284 micrograms/mL and 464 +/- 153 micrograms/mL. respectively. Normal healthy controls had a mean value of 431 +/- 105 micrograms/mL. with the cutoff value set at 641 micrograms/mL (mean +2 SD). Patients without cancer who had a severe infectious disease showed conspicuously high serum IS levels. and these values were closely correlated with their C-reactive protein values. The positive rate of IS increased in all patients with oral cancer was 58%. The mean level of serum IS in cancer patients was significantly higher than that of the controls (P less than .01). and the level was found to be more elevated as the stage of the disease advanced (stage I to III. 48%; stage IV. 68%). Histologic analysis of the tumor cells in patients with squamous cell carcinoma (SCC) showed that the mean serum IS level of those who had poorly differentiated SCC was much higher (937 +/- 181 micrograms/mL) than that of patients with well-differentiated SCC (616 +/- 159 micrograms/mL). Patients who had recurrent or metastatic cancer. or those who died from the cancer exhibited marked elevation of the serum IS levels. whereas patients who remained free of cancer in the follow-up period showed significantly lower serum IS levels. The rise and fall of the serum IS level was closely correlated with the disease progression and/or remission. These data strongly suggest that serum IS is a useful parameter for monitoring the disease stage as well as the effect of therapy on patients with oral cancer.
Extraoral parotid sialolithotomy, The extraoral approach to duct surgery for the removal of parotid stones can be a simple procedure once the stone is accurately located in relation to the skin surface. The combination of sialography and sonography can provide this information. A case report demonstrates the step-by-step approach to diagnosis. localization. and surgery for the management of such extraglandular sialoliths.
Indications for simultaneous orthognathic and septorhinoplastic surgery, Orthognathic and rhinoplastic surgery can be combined successfully when certain guidelines are understood. Relative indications and contraindications have been established that generally yield predictable results. Tip position (rotation and projection) may be the most difficult aspect to predict and. therefore. is best avoided during simultaneous surgery. Major deformities of the dorsum can be easily corrected in conjunction with maxillary surgery. Three cases demonstrating these guidelines are presented and discussed.
The relationship between the indications for the surgical removal of impacted third molars and the incidence of alveolar osteitis, Six hundred forty-two impacted third molars were surgically removed in 412 patients. Before surgery. each patient was assessed clinically and radiographically. and the reason for the removal of each tooth was specifically recorded. One hundred eighty-two of the impacted teeth were removed for prophylactic reasons and 460 for therapeutic reasons. As much as possible. standardization of the operating procedure and environment. and of the preoperative and postoperative regimens was observed. After surgery. each case was followed to determine the absence or presence of signs and symptoms of alveolar osteitis. It was found that several factors seem to contribute to the development of alveolar osteitis; however. the most significant related finding was that the reason for the extraction. that is. whether the extraction was undertaken for therapeutic or prophylactic reasons.
Internal derangement of the temporomandibular joint: a histochemical study, The purpose of this study was to correlate histologic findings in temporomandibular joint (TMJ) condyles and discs with their macroscopic appearance at surgery. The 24 patients with internal derangement of the joint included 20 women and 4 men (mean age. 37 years; range. 18 to 61 years). The tissue lesions varied in degree from mild soft-tissue fraying and bone remodeling to extensive resorption and new cartilage and bone formation with high phosphatase enzyme activities. and even to loss of articular soft tissue and breakdown of cortical bone. Reactions may arise in the hard tissues before they occur in the articular surface layers.
Endometrial ablation with the roller ball electrode, Endometrial ablation for control of menorrhagia is a safe. effective alternative to hysterectomy in selected patients. Endometrial ablation with a resectoscope equipped with a roller ball electrode was used on 12 patients. The technique appears to be as effective as Nd:YAG laser endometrial ablation and offers gynecologists the advantages of speed. low cost and safety when compared to the laser approach.
Terconazole for the treatment of vulvovaginal candidiasis, A double-blind. randomized trial was conducted to evaluate the efficacy and safety of terconazole for vulvovaginal candidiasis. Treatment consisted of daily intravaginal application of one of the following regimens: 80-mg terconazole suppositories for 3 days. miconazole nitrate suppositories for 7 days or placebo suppositories for 7 days. The terconazole and miconazole nitrate groups had significantly higher therapeutic cure rates than did the placebo group. Evaluation of vaginal secretions with microscopic examination showed no evidence of leukocyte proliferation. Proline aminopeptidase activity. present in patients who have bacterial vaginosis. could not be detected in the vaginal secretions from patients with yeast vulvovaginitis.
The challenge of prophylaxis in cesarean section in the 1990s, Physicians have evaluated the role of antibiotics in the prevention of perioperative infections since these drugs were discovered. but not until it was determined that antibiotics prevented staphylococcal wound infections in the animal model did surgeons consider their use for prophylaxis. In the 1970s. improved techniques in isolating and identifying anaerobic microorganisms and the unacceptably high incidence of infection-related complications convinced obstetricians to study. and ultimately accept. the use of perioperative antibiotic administration to prevent these infections. Recent progress has included refinement of the guidelines for patient selection and drug regimens. Although a single dose of an antibiotic given to the patient undergoing primary cesarean section has been demonstrated to be effective prophylaxis when administered after clamping the umbilical cord. this practice has not been widely accepted. With the discovery of cephamycins the role of these broad-spectrum antibiotics in obstetric and gynecologic surgery was investigated. One of the studies compared the efficacy of cefmetazole with that of cefotetan in preventing post-cesarean section infection. Eighteen patients in each group received a 2-g dose of one of the two drugs when the umbilical cord was clamped. Predetermined elevations in temperature were used to evaluate the presence of ensuing infections. Four subjects in each group developed some type of morbidity. Postoperative complications included wound infection. endometritis. bladder infection and cellulitis. Cefmetazole and cefotetan seemed equally effective in preventing post-cesarean section infections.
Cefmetazole and cefonicid. Comparative efficacy and safety in preventing postoperative infections after vaginal and abdominal hysterectomy, A single 1-g dose of cefmetazole was compared with a single 1-g dose of cefonicid for prophylaxis in vaginal and abdominal hysterectomy to determine their efficacy and safety. The antibiotics were administered intramuscularly 15-90 minutes before the incision was made. Cefmetazole and cefonicid had similar activity against most of the aerobic organisms recovered. but cefmetazole was significantly more active against anaerobic gram-negative microorganisms. The patterns of regrowth of vaginal flora were similar in the two treatment groups. Patient demographic characteristics and surgical procedures were similar in both groups. The difference in primary prophylactic failure (e.g.. cuff cellulitis) with the two study drugs (1 of 53 [1.9%] with cefmetazole and 2 of 28 [7.1%] with cefonicid) did not reach statistical significance. and the results were similar for the two routes of hysterectomy. Cefmetazole. at a dose of 1 g intramuscularly preoperatively. is a safe and effective agent for prophylaxis during hysterectomy.
Prospective randomized multicenter comparison of in situ and reversed vein infrapopliteal bypasses, We have performed a prospective. randomized. multicenter study to compare in situ and reversed vein grafts for long limb salvage bypasses from the proximal thigh to an infrapopliteal artery. Three hundred eighty-four patients required an infrapopliteal bypass for critical lower extremity ischemia. Of these. 259 were excluded because a short vein bypass was performed or because the vein was considered inadequate. The remaining 125 patients had a randomized vein bypass. 63 reversed. 62 in situ. The two groups were similar with regard to risk factors. indications. graft dimensions. and outflow. Secondary patency at 30 months was similar for both techniques: reversed 67% +/- 9% (+/- SE); in situ 69% +/- 8%. For veins less than or equal to 3.0 mm in minimum distended diameter 24-month patency rates were 61% +/- 22% for 12 in situ veins and 37% +/- 29% for 10 reversed veins (p greater than 0.05). Angiographic evaluation of failing grafts revealed lesions similar in type and frequency in both types of grafts. These included focal (in situ. n = 4; reversed. n = 7) and diffuse vein hyperplasia (in situ. n = 2; reversed. n = 1). and inflow and outflow stenoses (in situ. n = 4; reversed. n = 3). The incidence of wound complications and the mortality rate were similar for the two groups. These data show no significant difference in overall patency rates for the two types of vein grafts at 2 1/2 years.
Ruptured abdominal aortic aneurysm: the Harborview experience, During the last decade (1980 to 1989) 186 patients with ruptured abdominal aortic aneurysm were admitted to a single urban hospital. Ninety-six percent of these patients had a prehospital systolic blood pressure less than 90 mm Hg. Management included paramedic field resuscitation and transport. an emergency department diagnostic protocol completed in an average of 12 minutes. rapid transport to a dedicated emergency operating room. aneurysmorrhaphy by general surgery chief residents under the supervision of specialist vascular surgeons. and skilled postoperative intensive care unit care. Nevertheless. 130 (70%) patients died in the first 30 postoperative days--3% in the emergency department. 13% in the operating room. 51% in the intensive care unit. and 3% on the ward or at home. Certain features--age greater than 80 years. female gender. persistent preoperative hypotension despite aggressive crystalloid and blood replacement. admission hematocrit less than 25. transfusion requirements exceeding 15 units--were associated with a greater than 90% likelihood of death. No patient with preoperative cardiac arrest survived more than 24 hours. From this experience we conclude that. although "optimal" prehospital. emergency department. operating room. and postoperative care can improve the outcome of patients with ruptured abdominal aortic aneurysms in shock. most such patients will die. Certain clinical features predict such excessive mortality rates after ruptured abdominal aortic aneurysms that withholding operation may be reasonable. Screening of patients at high risk for abdominal aortic aneurysm. followed by elective aneurysmorrhaphy. is clearly indicated.
Probability of rupture of an abdominal aortic aneurysm after an unrelated operative procedure: a prospective study, It has been assumed by some authors that patients with abdominal aortic aneurysms may be at increased risk of rupture after unrelated operations. From July 1986 to December 1989. 33 patients (29 men. 4 women) with a known abdominal aortic aneurysm underwent 45 operations. Twenty-eight patients had an infrarenal abdominal aortic aneurysm. and five patients had a thoracoabdominal aneurysm. The abdominal aortic aneurysm ranged in transverse diameter from 3.0 to 8.5 cm (average 5.6 cm). Twenty-seven patients underwent a single operation. and six patients had two or more (range of 1 to 6). Operations performed were abdominal (13); cardiothoracic (9); head/neck (2); other vascular (11); urologic (7); amputation (2); breast (1). General anesthesia was used in 29 procedures. spinal/epidural in 6. and regional/local in 10. One postoperative death occurred from cardiopulmonary failure. One patient died of a ruptured abdominal aortic aneurysm at 20 days after coronary artery bypass (1/33 patients [3%]; 1/45 operations [2%]). Fourteen patients had repair of their abdominal aortic aneurysm at a later date. an average of 18 weeks after operation. Four patients had abdominal aortic aneurysm considered too small to warrant resection (average 3.6 cm). Four patients were considered at excessive risk for elective repair. The five thoracoabdominal aneurysm were not repaired. Four patients are awaiting repair. During this same 40-month period. two other patients. not known to have an abdominal aortic aneurysm. died of a ruptured abdominal aortic aneurysm after another operative procedure. at 21 days and 77 days. All three ruptured abdominal aortic aneurysms were 5.0 cm or greater in transverse diameter.
The accuracy of CT scanning in the diagnosis of abdominal and thoracoabdominal aortic aneurysms, As CT scanning has evolved as a reliable clinical tool. the use of angiography in the diagnosis of aortic aneurysmal disease has diminished. Fewer than 25% of patients with aortic aneurysmal disease undergo aortic angiographic evaluation at our institution. A prospective clinical study was undertaken to assess the validity of this policy. One hundred patients with clinical or ultrasonographic evidence of aortic aneurysms were evaluated prospectively during the period July 1987 to December 1989. All patients underwent CT scanning as an initial evaluation. Patients were selected for angiography if they fulfilled any of the following criteria: radiographic evidence of thoracoabdominal or juxtarenal aneurysms. or horseshoe kidney; or clinical suggestion of renal artery stenosis. mesenteric arterial insufficiency. aortoiliac occlusive disease. or lower extremity aneurysmal disease. During this period 19 patients (19%) underwent both CT scanning and angiography. The indications for angiography were thoracoabdominal aneurysms (7). juxtarenal aneurysms (2). clinical evidence of mesenteric insufficiency (1) or renal insufficiency (2). evidence of lower extremity aneurysmal disease (3). or severe aortoiliac occlusive disease (4). Eighty-one patients (81%) underwent CT scanning as the only radiographic evaluation. No patient was adversely affected by elimination of angiographic evaluation. CT scanning revealed inflammatory aneurysms (4). retroaortic renal veins (2). and horseshoe kidney (1). This study suggests that most (81%) patients with aortic aneurysmal disease can be adequately evaluated by CT scanning. and that a very selective policy of angiographic evaluation is indicated.
Mechanisms of vein graft atherosclerosis: LDL metabolism and endothelial actin reorganization, We have explored the effect of arterial hemodynamics on endothelial cell morphology and low-density lipoprotein metabolism in human saphenous vein segments harvested from tissue donors. An arterial pulsatile perfusion system was used to impose physiologic pressures and flows for 20 hours on saphenous vein and companion (control) femoral artery segments. A venous perfusion apparatus was also employed for the perfusion of a second (control) saphenous vein segment for the same period of time. Calculations of fluid shearing and wall tensile stresses were performed and related to induced changes in endothelial cell geometry and cytoskeletal actin organization and the incorporation. degradation. and localization of intact low-density lipoprotein within the vessel wall. Our results indicate that. compared with native arteries and veins. a 20-hour exposure of test saphenous veins to arterial hemodynamics induced (1) a significant increase in endothelial cell luminal surface area and perimeter independent of alignment with flow. (2) disassembly of the dense peripheral band of actin with a concomitant assembly of stress fibers. and (3) a two- to fourfold elevation in the undegraded low-density lipoprotein content. localized primarily within the subendothelial intima. Although the exact mechanisms underlying these results are uncertain. the focal accumulation of intramural low-density lipoprotein may be related to the loss of normal barrier function during endothelial cell enlargement. which is accompanied by transient cytoskeletal reorganization during the adaptation to arterial flow.
Cocaine metabolite detection in homicide victims, We analyzed the blood of homicide victims for the presence of cocaine's major metabolite. benzoylecgonine. During 1989 in Fulton County. Georgia. 81% of 275 homicide victims were tested for benzoylecgonine; 40% tested positive. The proportions of blacks and victims of firearm injuries who tested positive for benzoylecgonine were significantly larger than the respective proportions for whites and victims of injuries not involving firearms. The data show overall proportions of benzoylecgonine positivity much larger than those previously reported in the literature. The relationships between homicide. race. firearms. and cocaine use deserve further study.
Lacunar transient ischaemic attacks: a clinically useful concept, Lacunar ischaemic stroke syndromes are clinically. pathophysiologically. and prognostically distinguishable from cortical ischaemic stroke syndromes. Could cerebrovascular transient ischaemic attacks (TIAs) share similar heterogeneity? 130 patients with TIAs were prospectively studied. 71 of whom underwent carotid angiography. Symptoms were associated with a 50% or greater stenosis of the ipsilateral internal carotid artery in 36 (67%) of 54 patients with presumed cortical TIAs. but in only 1 (6%) of 17 patients with presumed lacunar TIAs (p less than 0.0001). These findings support the view that cortical TIAs are associated with ipsilateral extracranial internal carotid artery atheromatous disease. whereas patients with lacunar TIAs may have absent or insignificant large-vessel disease. and probable intracranial small-vessel disease. Accurate distinction between lacunar and cortical events may have implications for investigation and treatment of patients with TIAs.
Transient ischaemic attacks and small-vessel disease. Dutch TIA Study Group, Histories and computed tomograms of 606 patients with transient cerebral ischaemia were studied. All symptoms and signs had completely resolved within 24 hours. and any episodes suggestive of posterior fossa ischaemia were excluded. Computed tomography. done after the clinical features had resolved. showed 79 relevant infarcts: 46 were small. deep. lacunar infarcts (58%. 95% confidence interval [CI] 47-69%). and 33 were larger cortical infarcts. The histories and the type of infarct in these 79 patients were compared to see whether lacunar infarcts were preceded by a history of unilateral motor or sensory symptoms without features usually attributed to the cerebral cortex. The positive predictive value of such lacunar symptoms was 0.74. with a negative predictive value of 0.61. 11 patients had a cortical infarct despite a history of lacunar TIAs. but only one occurred in the left hemisphere and speech was not affected. Of 527 patients with transient ischaemic attacks without a relevant infarct visible on computed tomography. 335 (64%) had a history suggestive of lacunar ischaemia. whereas in several other studies 20-25% of patients with ischaemic stroke have evidence of lacunar infarcts. Lacunar TIAs may therefore have a better prognosis than cortical TIAs or may often precede cortical infarcts; alternatively. many cortical infarcts may occur without warning.
The role of conditioning and verbal expectancy in the placebo response, Both conditioning and expectancy models have been offered in recent years as explanations for the placebo response. Following our earlier work on conditioning placebo responses in human subjects the current study examined the relative contribution made by conditioning and verbal expectancy. Group 1 received a Combined Expectancy and Conditioning Manipulation; group 2 received Expectancy Alone; group 3. Conditioning Alone; and group 4 was the control group. Subjects' responses were compared with and without a placebo cream. using iontophoretic pain stimulation. The results suggest that conditioning was more powerful than verbal expectancy in creating a placebo response.
Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain, This report examines the relationship of plasma drug concentration to analgesic effect following bolus doses of alfentanil. fentanyl and morphine and assesses individual differences in analgesic response among volunteers. We predicted that the 3 opioids would yield disparate analgesic profiles because their physicochemical and pharmacokinetic characteristics differ. Ten healthy volunteers received intravenous bolus doses of either alfentanil. fentanyl. morphine or normal saline on different days. We stimulated their teeth electrically and measured brain evoked potential (EP) and pain report (PR) repeatedly over 2 h to assess analgesic effect. Concurrently. we drew 18 blood samples to assess opioid plasma concentrations during the test period. The relationship between opioid plasma concentration and analgesic effect was well defined for alfentanil but ambiguous for morphine. Fentanyl exhibited a marked hysteresis. We observed noteworthy individual differences in analgesic response with all 3 drugs but these differences were greatest for morphine and least for alfentanil. Inter- and intrasubject variability in analgesic response across drugs is related to the physicochemical properties of the drugs tested.
Heart rate changes as an autonomic component of the pain response, Autonomic variables have been recommended as measures of the affective-motivational component of the pain response in objective algesimetry. In the present study components of heart rate responses to painful heat stimuli and their relation to stimulus and sensation variables were analyzed. Twelve healthy subjects served. Sixty phasic stimuli of varying temperatures above and below pain threshold were delivered through a Marstock thermode in 1 session. Heart rate. respiration. and subjective stimulus ratings were recorded simultaneously. Phasic heat stimulation above and below pain threshold induced a tonic increase of the heart rate lasting up to more than 20 sec. High intensity stimulation generated steeper rises and greater mean increase than low intensity stimulation. In general. heart rate responses were more closely related to subjective sensation than to stimulus intensity. However. differential temporal analysis demonstrates that. until about 3 sec after stimulation. the autonomic response is determined solely by stimulus temperature. whereas. after approximately 6 sec. it is related only to subjective judgement. Accordingly. the heart rate responses reflect both a brief nocifensive reflex induced by the sensory component and. subsequently. a longer-lasting response which seems to be related to affective and/or cognitive evaluation. This separation of different stages of pain-processing by an autonomic indicator may be useful in clinical algesimetry.
Acoustic reflectometry for assessment of hearing loss in children with middle ear effusion, We sought associations between acoustic reflectometry and hearing loss in ears with and without middle ear effusion in 137 New Zealand children ages 3 to 16 years. Reflectometry was significantly associated with conductive hearing loss. These associations were present in the entire sample; correlation coefficients varied between 0.31 at 2000 Hz (P less than 0.001) and 0.55 for a three frequency pure tone average (P less than 0.001). The associations persisted for the sample of ears deemed to be filled entirely by effusion; correlation coefficients varied between 0.27 at 4000 Hz (P = 0.026) and 0.47 at 500 Hz (P less than 0.001). Using a reflectivity of 6.0 or greater to detect a three frequency pure tone average loss of 30 dB or more. the sensitivity was 88% and the specificity was 44%. The technique of acoustic reflectometry should be explored and extended to permit rational decisions about management of middle ear effusions.
Changes in the differential white blood cell count in screening for group B streptococcal sepsis, We compared several previously defined scoring systems using white blood cell indices as part of a retrospective evaluation of infants with early onset Group B streptococcal (GBS) sepsis. Nineteen newborns were diagnosed with GBS sepsis between January. 1988. and April. 1990. Case controls (n = 33) were selected from patients admitted to the Neonatal Intensive Care Unit for suspected sepsis. Complete blood counts obtained at admission and between 12 and 24 hours of age were reviewed. There was a significant change in the ratio of immature to total neutrophils in the GBS group over time. Scoring systems for neonatal sepsis by Manroe et al.. Rodwell et al. and Spector et al. had poor sensitivity. specificity. positive predictive value and negative predictive value when initial white blood cell count criteria were used. but scoring systems by Manroe and Rodwell were 100% sensitive and had 100% negative predictive value when applied to the repeat white blood cell count. We conclude that a single early complete blood count may not be an adequate screening tool for early onset GBS sepsis and should not be used to rule out infection. Optimal screening for GBS sepsis requires a repeat complete blood count within the first 24 hours of age.
Drugs to lower uric acid levels. How to avoid misuse in gouty arthritis, Several points regarding the use of drugs to lower uric acid levels deserve emphasis. First. these agents are not useful in the management of acute gout. Second. all forms of the drugs should be initiated at low dose with gradual increments to achieve a serum uric acid level between 5 and 6 mg/dL. There are no data to support the widely presumed notion that dropping the uric acid level to a very low range (1 to 3 mg/dL) hastens resorption of tophi or improves joint function. Third. the uricosuric agents probenecid (Benemid) and sulfinpyrazone (Anturane) interact with a number of drugs. and both the patient and physician should be aware of this. Finally. and most important. careful and frequent monitoring is needed during the first several months of therapy with these drugs.
Gallstone pancreatitis. Choosing and timing treatment, Patients with gallstone pancreatitis are often seen initially by primary care physicians. Prompt diagnosis and timely intervention are crucial in reducing morbidity and mortality. Initial management should include supportive medical care and surgical consultation. The timing of surgery is then dictated by serum enzyme levels and liver function test results as well as by the patient's condition. The role of endoscopic intervention is currently evolving. Whether surgery or endoscopic sphincterotomy is preferable as primary therapy for gallstone pancreatitis remains unresolved. However. sphincterotomy with stone extraction is a viable option in selected cases. especially in patients who have severe gallstone pancreatitis.
Degenerative aortic stenosis. One effect of the graying of America, Degenerative calcific aortic stenosis is evolving as a common geriatric problem. Once symptoms develop. it is a highly lethal disease that does not respond well to medical therapy. Aortic balloon valvuloplasty may offer palliation but is unlikely to alter the overall course of the disease. Aortic valve replacement is the therapy of choice. but high perioperative morbidity and mortality rates can be expected in the very elderly. The presence of other appreciable cardiac disorders may contribute to the occurrence of postoperative complications. Patients with asymptomatic aortic stenosis and normal left ventricular function can be treated medically and followed with serial aortic valve area determinations using Doppler echocardiography.
Blistering diseases. Diagnostic help for primary care physicians, At presentation. the differential diagnosis of bullous disease may seem difficult. However. the diagnosis may be clarified by considering such factors as Nikolsky's sign. age of the patient at onset. and pattern and distribution of blisters. Careful review of family. recreational. occupational. and drug histories may also help to identify the cause.
When is pulmonary artery catheterization worth the risks, Bedside pulmonary artery catheterization has proven to be an important addition to the clinical assessment of critically ill patients. Properly used. the procedure may provide hemodynamic information that is not apparent from physical examination or radiography. It may be safely accomplished through various venous routes. but care must be taken to avoid potential complications.
A three-point approach to anemia, Anemia is a sign of underlying disease that is causing blood loss. sequestration of red blood cells (RBCs). impaired RBC production. or primary marrow dysfunction. The most efficient clinical approach to a patient with anemia is to ask the following three questions: Is the anemia microcytic. macrocytic. or normocytic? Is pancytopenia present? Is the marrow response appropriate for the anemia as determined by the reticulocyte count? Answers to these questions focus laboratory evaluation on a logical progression and avoid a costly shotgun approach.
Chronic fatigue syndrome: is it real, Epstein-Barr virus is no longer considered an important cause of chronic fatigue syndrome. Instead. the disease is probably related to an underlying psychiatric disorder. subtle immunologic dysfunction. or an interaction between these two factors. A carefully taken history. physical examination. and simple laboratory testing are usually sufficient to establish the diagnosis. Therapy with antidepressants or nonsteroidal anti-inflammatory drugs may be effective in selected patients. Thorough follow-up conducted with empathy and optimism is important in all cases.
The bed-wetting child. Current management of a frustrating problem, Bed-wetting is a frustrating problem experienced by a significant number of children. It is the role of the physician to exclude serious underlying problems and. at the same time. educate the family concerning treatment options that may be best suited to their child. Once parents and child have a better understanding of the problem and realize that the outlook for nighttime bladder control is excellent. it is easier to start long-term care.
Rheumatoid arthritis. New developments in treatment, If a patient with active rheumatoid arthritis does not obtain significant relief from nonsteroidal anti-inflammatory drugs. prompt institution of disease-modifying antirheumatic drugs (DMARDs) is recommended. If one agent fails. another may be tried. At present. hydroxychloroquine (Plaquenil) sulfate is one of the most widely used and best tolerated. Careful follow-up is essential with all DMARDs. however. because toxic effects may be severe and sometimes unpredictable.
Laboratory tests for rheumatic diseases, A carefully taken history and thorough physical examination remain the most crucial aspects of diagnosing rheumatic disorders. Non-rheumatologic conditions also need to be kept in mind. Laboratory tests should be looked on as mostly supportive or confirmatory. because many of the tests are relatively nonspecific and may lack sensitivity. If their limitations are recognized. however. the tests can be invaluable tools when the clinician confronts the task of differentiating an array of rheumatologic disorders.
Cystic fibrosis transmembrane conductance regulator: nucleotide binding to a synthetic peptide, Multiple mutations in the gene responsible for cystic fibrosis are located within a region predicted to encode a nucleotide-binding fold in the amino terminal half of the cystic fibrosis transmembrane conductance regulator protein. A 67-amino acid peptide (P-67) that corresponds to the central region of this putative nucleotide binding site was chemically synthesized and purified. This peptide bound adenine nucleotides. The apparent dissociation constants (Kd's) for the trinitrophenyl (TNP) adenine nucleotides. TNP-adenosine triphosphate. TNP-adenosine diphosphate. and TNP-adenosine monophosphate. were 300 nanomolar. 200 nanomolar. and greater than 1 micromolar. respectively. The Kd for adenosine triphosphate was 300 micromolar. Circular dichroism spectroscopy was used to show that P-67 assumes a predominantly beta sheet structure in solution. a finding that is consistent with secondary structure predictions. On the basis of this information. the phenylalanine at position 508. which is deleted in approximately 70 percent of individuals with cystic fibrosis. was localized to a beta strand within the nucleotide binding peptide. Deletion of this residue is predicted to induce a significant structural change in the beta strand and altered nucleotide binding.
Senescence of nickel-transformed cells by an X chromosome: possible epigenetic control, Transfer of a normal Chinese hamster X chromosome (carried in a mouse A9 donor cell line) to a nickel-transformed Chinese hamster cell line with an Xq chromosome deletion resulted in senescense of these previously immortal cells. At early passages of the A9/CX donor cells. the hamster X chromosome was highly active. inducing senescence in 100% of the colonies obtained after its transfer into the nickel-transformed cells. However. senescence was reduced to 50% when Chinese hamster X chromosomes were transferred from later passage A9 cells. Full senescing activity of the intact hamster X chromosome was restored by treatment of the donor mouse cells with 5-azacytidine. which induced demethylation of DNA. These results suggest that a senescence gene or genes. which may be located on the Chinese hamster X chromosome. can be regulated by DNA methylation. and that escape from senescence and possibly loss of tumor suppressor gene activity can occur by epigenetic mechanisms.
Predictive value of historical and physical characteristics for the diagnosis of child abuse, Child abuse by burning may be difficult to recognize. especially since the injuries are often small. Historical and physical findings that can be elicited in the initial examination can be helpful in initiating a more in-depth investigation. An injury inconsistent with the history given or a delay in seeking medical treatment were the two most frequent reports that elicited suspicion. As isolated findings. however. they had a low predictive value. The presence of two or more of 13 factors increased the yield in child abuse identification to more than 60%.
Childhood firearms fatalities: the Metropolitan Dade County experience, I reviewed the cases of childhood firearms fatalities in the files of the Medical Examiner Department of Metropolitan Dade County. in Miami. Florida. Comparison of cases during the 5-year period from 1966 through 1970 to those during the 5-year period from 1984 through 1988. noting basic epidemiologic parameters. showed that death due to firearms is increasing among children aged 14 years and younger.
Laparoscopic cholecystectomy: report of 82 cases, In our initial experience with 82 patients. laparoscopic cholecystectomy has shown numerous advantages over open cholecystectomy. Both intraoperative blood loss and postoperative need for pain medication have been minimal. Most patients were discharged within 24 to 36 hours and resumed normal activities within 3 to 5 days. The aesthetic aspect is also an obvious advantage. since the laparoscopic procedure avoids disfiguring abdominal scars. Previous abdominal surgery is not a contraindication to attempting this procedure. Based on our experience. laparoscopic cholecystectomy can be done safely on most patients who are candidates for open cholecystectomy. including the elderly. the obese. and those with acute gangrenous cholecystitis.
Voluntary human immunodeficiency virus testing: acceptance levels and identification of seropositive individuals, Of 4340 clients of a clinic for those with sexually transmitted diseases who were eligible for voluntary. confidential. serologic testing for the human immunodeficiency virus. 4246 (97.8%) consented to testing; 23 (0.5%) were seropositive. Of 94 persons who declined voluntary testing but who were tested in a blinded study. nine (9.6%) were seropositive. Seropositive persons who declined voluntary testing did not conceal their association with a risk group. while only 61% of seropositive individuals who accepted voluntary testing admitted to inclusion in a risk group before the test. Voluntary testing appears to be insufficient. because 28% of the seropositive individuals were not identified as being seropositive; also. there was a significant deficiency associated with identification of risk at pretest counseling among persons agreeing to voluntary testing.
Literacy and laryngectomy: how should one treat head and neck cancer in patients who cannot read or write, The entire population of otolaryngologists and radiation oncologists (N = 192) in active practice in the state of North Carolina were surveyed to assess their level of awareness of illiteracy among adults in the United States and to determine whether these physicians consider illiteracy in the treatment decision process for patients with head and neck cancer. Excluding respondents who did not treat patients with head and neck cancer and physicians practicing outside of the state of North Carolina. the response rate was 115 of 182. or 63%. Only 26% of respondents were able to estimate correctly the prevalence of illiteracy in the US adult population. Forty-one percent of respondents. however. stated that they did consider their patient's ability to read and/or write before making treatment recommendations for head and neck cancer. This survey and accompanying literature review suggest that physicians perceive illiteracy as a problem that may have a significant impact on patients with head and neck cancer. but lack the data needed to enable them to quantify the effect of illiteracy on treatment outcome. The study reported is the first step in examining ways in which illiteracy might negatively affect patient outcomes.
Relationship between blood groups and behavior patterns in men who have had myocardial infarction, Consistent correlations have been found between physical dysfunctional states and blood factors. Some of these disorders have possible psychosomatic components (eg. duodenal ulcer. myocardial infarction). This study focused on the relationship between blood types and various indices of behavior patterns (eg. type A behavior scores. anger ratings) in young patients who had had an initial myocardial infarction. Patients with blood type O scored significantly higher on type A behavior scales and related indices than those having blood type A. Those with blood group B responded on several scales between those with types A and O. We discuss the utility of blood groupings in future research in the prediction of myocardial infarction. methodologic limitations. the relationship of these results to temperament studies. Jenkins Activity Survey subtest patterns. anti-H reactivity pattern. and hypotheses relating blood factors and behavioral traits in patients with psychosomatic disorders.
Endoscopy versus x-ray studies of the gastrointestinal tract: future health care implications, I did esophagogastroduodenoscopy in 147 patients and colonoscopy in 59 patients who had had gastrointestinal x-ray studies. The endoscopic procedure was done within 7 days after the x-ray study and/or while the patient was still symptomatic. The barium swallow findings were confirmed in only 40%; in the other 60%. the x-ray findings could not be confirmed. These unconfirmed x-ray findings were false-positive in 37.4%. false-negative in 16.3%. and suboptimal or nondiagnostic in 6.2%. The barium enema findings were confirmed in 32%. In the other 68%. the x-ray findings were false-positive in 42.3%. false-negative in 22%. and suboptimal in 3.3%. We conclude that in clinical or private practice. relying on x-ray studies alone may be associated with a high margin of diagnostic errors. When all factors are considered. the initial cost advantage of the x-ray studies appears to be lost. In future recommendations on the continuing dilemma of x-ray studies versus endoscopy. consideration should be given to factors other than the initial lower price of the x-ray studies.
Human papillomavirus in prostatic cancer: no evidence found by in situ DNA hybridization, Human papillomavirus has been associated with benign squamous tumors. intraepithelial neoplasia. and invasive squamous cancer. The role of human papillomavirus as the most likely precursor of cervical dysplasia is well studied. We know of no available information as to the possible role of human papillomavirus in prostatic hyperplasia and cancer. We studied formalin-fixed paraffin-embedded tissues of 20 cases of glandular hyperplasia and 20 cases of prostatic cancer by in situ DNA hybridization for human papillomavirus using commercially available biotinylated DNA probes detected by an avidin-biotin peroxidase technique. We found no evidence of DNA hybridization to human papillomavirus-6. -11. -16. -18. -31. -33. or -35 in prostate tissue. Our results show no association between prostatic cancer or hyperplasia and the human papillomavirus genomes that were studied.
Contemporary use of the disease concept: III. A pedantic failure to change behavior regarding the problem of anemia, The frequency with which house staff noticed their patients to be anemic. the frequency with which they tried to find out why the patients were anemic. and the diagnostic accuracy of such endeavors were measured. Next. an intervention was conducted in which the teams were lectured on the subject of anemia. given reading materials on the subject. and given social encouragement to solve the problem. At follow-up no improvement was found in any of the outcome variables.
Anterolateral ankle dislocation without fracture, Dislocation of the tibiotalar joint without associated fracture is rare. We have presented a case of open anterolateral ankle dislocation with complete ligamentous disruption. In contrast to reports that internal fixation is not required to maintain reduction of tibiotalar joint dislocation. we found this dislocation to be grossly unstable. requiring both a syndesmotic screw and a calcaneotalotibial transfixing pin for stabilization.
Paratesticular myxoma: an unusual benign intrascrotal neoplasm, We have presented a case of paratesticular myxoma and have described the clinical history. findings on light microscopy and immunohistochemistry. and possible pathogenesis. Although primary paratesticular myxoma is a rare lesion. it should be considered in the differential diagnosis of intrascrotal mesenchymal tumors.
Giant cell interstitial pneumonia, Giant cell interstitial pneumonia is a distinctive and uncommon form of interstitial pneumonia. It is distinguished by the prominence of large. actively phagocytic alveolar giant cells of histiocytic origin in the presence of chronic interstitial pneumonia. Multinucleated type 2 granular pneumocytes are also identified. The multinucleated cells lack viral intranuclear inclusions of the type seen in measles pneumonia. Giant cell interstitial pneumonia may be idiopathic or it may occur with occupational exposure to hard metals or cobalt. We report this case to give recognition to an uncommon interstitial pneumonia.
Cerebrospinal fluid losses through ventricular catheters leading to hyponatremia in two children, I have presented two cases of patients with hyponatremia due to excessive cerebrospinal fluid losses from ventricular drains. The possibility of such losses exists whether the drain is used to treat hydrocephalus or to monitor intracranial pressure. I find normal saline (sodium concentration = 154 mEq/L) to be an appropriate fluid to replace ongoing losses of cerebrospinal fluid from a ventricular drain and currently start such replacement therapy (mL for mL) when the drain is placed.
Effects of the calcium antagonist nilvadipine on focal cerebral ischemia in spontaneously hypertensive rats, We studied the efficacy of preischemic and postischemic systemic treatment with a new calcium antagonist nilvadipine in a permanent focal cerebral ischemia model of spontaneously hypertensive rats. Rats that underwent microsurgical middle cerebral artery occlusion were blindly assigned to a single intraperitoneal injection of nilvadipine (0.32 mg/kg) or the same amount of polyethylene glycol either 15 minutes before. immediately after. 1 hour after. or 3 hours after occlusion of the left middle cerebral artery. Neurologic conditions of rats were closely examined. and rats were killed 24 hours later. Removed brains were sliced coronally. stained with triphenyltetrazolium chloride. and the size of infarct was determined. Although no neurologic improvements were observed in the treated rats. the area of infarcts was significantly reduced in the groups treated before. immediately after. and 1 hour after occlusion of the middle cerebral artery. Treatment started 3 hours after occlusion was ineffective.
Astroblastoma: electron microscopy and immunohistochemical findings: case report, The clinical. histological. immunohistochemical. and electron microscopic features of a cerebral astroblastoma are reported. The patient is a young woman with a superficial parietal tumor. Macroscopic findings include a well-delineated superficial nodule with a hard central core. Histological study disclosed a predominantly papillary tumor with hyalinized vessels. Tumor cells were scarcely positive with immunohistochemical stain for glial fibrillary acidic protein. extensive and diffusely positive with vimentin and neuron-specific enolase. and intensely positive with S-100 and epithelial membrane antigen in the papillary areas. Ultrastructural study showed abundant intermediate filaments forming bundles in tumoral cytoplasms. membrane junctions. and external laminae when cells were in contact with collagen fibers. Based on immunohistochemical and ultrastructural characteristics. we believe that the filaments seen in tumor cells are mainly vimentin filaments. These peculiar immunohistochemical patterns in a glioma may aid in the histological diagnosis of this rare tumor type.
Intramedullary spinal cord germinoma: case report, A case of intramedullary spinal cord germinoma within the conus medullaris. with lumbago and pain in the lower extremities. is presented. The intramedullary spinal cord germinoma was determined by a biopsy specimen. After local irradiation of 50 Gy. the tumor markedly decreased in size and clinical symptoms disappeared.
A single case of Huntington's disease simultaneously occurring with obstructive hydrocephalus, A case of simultaneously occurring Huntington's disease and obstructive hydrocephalus is presented. Huntington's and other neurodegenerative diseases have been described with normal-pressure hydrocephalus; however. no such description with obstructive hydrocephalus has been reported. The obstructive hydrocephalus displays a familial tendency in its presentation.
Ganglioneuroma of the spinal cord, This report describes a 2-year-old boy who harbored an intramedullary ganglioneuroma involving almost the entire length of the spinal cord. The terminology. pathology. and neurobiological behavior of this tumor is discussed.
Vascularized bone marrow transplantation (VBMT): induction of stable mixed T-cell chimerism and transplantation tolerance in unmodified recipients, In this preliminary report. our model of VBMT across a semiallogeneic barrier consistently brings about antigen-specific host tolerance with absence of GVHD in the majority of recipients. No immunologic or radiologic intervention was utilized. These results emphasized a potentially important mechanism for low-level stable mixed lymphoid chimerism (SMLC) in tolerance induction. independent of immune suppressive effects due to irradiation or immunopharmacologic intervention.
Return of tuberculosis: screening and preventive therapy, Approximately 25 percent of individuals exposed to Mycobacterium tuberculosis become infected. Of those. about 10 percent will develop clinically active tuberculosis at some time in their lives. The tuberculin skin test should be used to screen all patients. especially those at greatest risk of contracting the disease. such as the young and the old. and those with weakened immune systems from poor nutrition. alcohol and drug abuse. chronic illness and human immunodeficiency virus infection. Depending on the characteristics of the local population and individual medical risk factors. a reaction (induration) between 5 and 15 mm (or more) generally represents infection. Isoniazid therapy in persons with positive skin tests will decrease the risk of disease by 60 to 80 percent. Family physicians will play a critical role in efforts to eliminate tuberculosis from the United States by the year 2010.
Tuberous sclerosis, Tuberous sclerosis is an inherited disorder characterized by a triad of signs--mental retardation. seizures and adenoma sebaceum. The hamartomas that commonly affect multiple organ systems can be seen on plain film radiography. Computed tomography and ultrasonography are useful for assessing whether lesions are present in the abdomen. kidneys and brain. The hamartomas tend to bleed. causing symptoms and prompting the need for evaluation.
Alcohol abuse in adolescents, Alcohol abuse among teenagers is an increasing problem with serious physical and social consequences. Early diagnosis of adolescent alcoholism may be delayed for two reasons: the physical indicators of alcohol abuse seen in adults are often not identifiable in teenagers. and alcoholism is generally believed to be an adult problem. If the history is taken carefully. with respect and confidentiality. it can help the family physician determine the extent of a young person's alcohol abuse and begin the process of treatment for both the adolescent patient and the family.
Mammography and early breast cancer detection, Screening mammography has been shown to reduce breast cancer mortality. Both film-screen mammography and xeromammography are highly sensitive and specific. Mammography accreditation programs assure physicians and patients that a facility provides mammography of the highest quality. using the lowest possible radiation dose. Mammographic signs of early cancer include a small mass. calcifications. architectural distortion and a neodensity. Dense tissue may result in a false-negative examination even when a cancer is palpable. with adverse effects if biopsy is delayed.
Comparative clinical pharmacology of calcium channel blockers, Calcium channel blockers are effective antihypertensive agents. both as initial monotherapy and in combination with other antihypertensive agents. These drugs are also effective in the treatment of chronic. stable angina. variant angina and supraventricular arrhythmias. Drugs in this class have different affinities for calcium channels in vascular smooth muscle. cardiac muscle. cardiac sinus and atrioventricular node. They are all useful in hypertension and angina. but only verapamil and diltiazem are also useful in the control of heart rate and supraventricular arrhythmias. Nimodipine may control vascular spasm following subarachnoid hemorrhage. Calcium channel blockers have also been used in the treatment of migraine headache and Raynaud's phenomenon.
Complete left main coronary artery occlusion: angiographic evaluation of collateral vessel patterns and assessment of hemodynamic correlates, An angiographic study of eight patients with total occlusion of the left main coronary artery identified six patients with chronic occlusion and two with acute complete occlusion. In each of six patients. there were two to six different intercoronary collateral pathways. Altogether. a total of 13 specific collateral channels were recognized. One patient had evidence of unique homocollaterals represented by enlarged vasa vasorum. which created a vascular cuff that surrounded a totally obstructed left main artery. The ventricular function and hemodynamic parameters in these patients not only depend on the collateral vessels but may also be affected by the severity of coronary artery disease in the artery that supplies collaterals.
Dilatation of the left ventricular cavity on dipyridamole thallium-201 imaging: a new marker of triple-vessel disease, To investigate the significance and mechanism of dilatation of the left ventricular cavity on dipyridamole thallium-201 imaging. we performed both dipyridamole thallium-201 imaging and dipyridamole radionuclide angiography on 83 patients with known angiograms. The dipyridamole/delayed ratio of the left ventricular dimension from the thallium-201 image was defined as the left ventricular dilatation ratio (LVDR). An LVDR greater than the mean + two standard deviations in patients without coronary artery disease was defined as abnormal. Twenty-two of 83 patients showed an abnormal LVDR. and 18 of the 22 patients (82%) had triple-vessel disease. By defect and washout analysis. the sensitivity and specificity for correctly identifying the patients as having triple-vessel disease was 72% and 76%. respectively. whereas LVDR had a sensitivity of 72% and a specificity of 93%. When LVDR was used in combination with the defect and washout criteria. sensitivity increased to 84% without a loss of specificity. In those 22 patients with abnormal LVDRs. end-diastolic volume measured by radionuclide angiography did not change after dipyridamole infusion. Dilatation of the left ventricular cavity on dipyridamole thallium-201 imaging reflected relative subendocardial hypoperfusion induced by dipyridamole rather than actual chamber enlargement. The LVDR was moderately sensitive and highly specific for triple-vessel disease and provided complementary information to dipyridamole thallium-201 imaging.
Percutaneous balloon valvotomy for patients with mitral stenosis: initial and follow-up results, Percutaneous double balloon mitral valvotomy (PMV) was performed in 25 patients with severe mitral stenosis who were followed for at least 6 months after the procedure. There were 22 women and 3 men. with a mean age of 51 +/- 14 years (range. 27 to 74). Hemodynamic and angiographic findings were evaluated before and after PMV and clinical status was assessed at follow-up. There was a significant decrease in mitral gradient following PMV. from 15.4 +/- 5.1 to 5.0 +/- 2.6 mm Hg (p less than .0001); an increase in cardiac output. from 4.6 +/- 1.1 to 5.2 +/- 1.1 L/min (p less than .01); and an increase in calculated mitral valve area. from 0.9 +/- 0.2 to 2.2 +/- 0.6 cm2 (p less than 0.0001). Mitral regurgitation developed or increased in severity in six patients (24%). At the time of follow-up (mean. 12 +/- 5 months). three patients required elective mitral valve replacement for symptomatic mitral regurgitation and 91% (20 of 22) of the remaining patients had continued improvement in functional class. PMV can safely be performed in properly selected patients with symptomatic mitral stenosis with good immediate and follow-up results.
Value and limitations of Doppler pressure half-time in quantifying mitral stenosis: a comparison with micromanometer catheter recordings, The purpose of this study was to compare the Doppler and catheterization pressure half-time methods of estimating mitral valve area with valve areas obtained by the Gorlin equation in a group of patients with clinically significant mitral stenosis. Data were analyzed from 67 consecutive patients who were undergoing continuous-wave Doppler examination and catheterization with micromanometer catheters. Doppler pressure half-time was calculated as the interval between peak transmitral velocity and velocity divided by the square root of 2. as measured from the outer border of the spectral envelope. Doppler mitral valve area (MVA) was obtained with the equation: MVA = 220 divided by pressure half-time. For catheterization data. the pressure half-time was measured directly from simultaneously recorded left ventricular and left atrial pressure (18 patients) or pulmonary capillary wedge pressure (49 patients). The catheterization half-time was taken as the time required for the peak pressure gradient to fall to one half of the initial value. Calculations of the mitral valve area at catheterization were obtained by the Gorlin equation with pressure gradient and cardiac output determinations. Mitral valve area as determined by the Gorlin equation for all cases ranged from 0.4 to 2.0 (mean = 1.03 +/- 0.37) cm2. Linear regression analysis that compared cardiac catheterization and Doppler half-times yielded r = 0.68. For the subgroup of patients with sinus rhythm. the correlation improved to r = 0.76.
Study of the influence of left bundle branch block on the signal-averaged electrocardiogram: a qualitative and quantitative analysis, To study the influence of left bundle branch block (LBBB) on the signal-averaged electrocardiogram (SAECG). quantitative and qualitative analyses of SAECG parameters were undertaken in 48 patients with electrocardiographic evidence of intrinsic LBBB and in 39 patients with a "normal" surface QRS duration (less than 120 msec) who underwent right ventricular pacing-induced LBBB. We assumed pacing of the right ventricular apex to be a suitable model of this conduction defect. Sustained monomorphic ventricular tachycardia (SMVT) was inducible in 16 of 48 patients with intrinsic LBBB and in 23 of 39 patients with pacing-induced LBBB. Utilizing a filter setting of 25 to 250 Hz. late potentials were defined as a total filtered QRS duration greater than or equal to 120 msec. a root mean square voltage in the terminal 40 msec (RMS 40) of less than or equal to 25 microV. and the duration of signals less than 40 microV (LAS 40) of greater than or equal to 38 msec. Only RMS 40 and LAS 40 criteria were used in patients with LBBB. Prolongation of LAS 40 and fragmentation of signals in the terminal portion of the filtered QRS were characteristic of all patients with LBBB aberration. Of those patients with intrinsic LBBB. the mean total filtered QRS duration. RMS 40. and LAS 40 for inducible and noninducible patients were significantly different (170 +/- 28. 16 +/- 10. 55 +/- 24. and 153 +/- 18 msec. 25 +/- 10 microV. 33 +/- 16.9 msec; p = 0.04. 0.009. and 0.007. respectively). Noninducible patients with a normal QRS duration demonstrated a 60% decrement in the mean RMS 40 value during pacing-induced LBBB. These changes resulted in a 59% false positive incidence of late potentials during pacing-induced LBBB. This correlated with a similarly low mean RMS 40 value in patients with intrinsic LBBB and no inducible SMVT. hence giving rise to a false positive incidence of late potentials of 63%. Since "standard" RMS 40 and LAS 40 criteria resulted in low specificity and positive predictive value. new parameters were selected and analyzed. The combination of RMS 40 less than or equal to 17 microV plus LAS 40 greater than or equal to 55 msec yielded the best overall statistical result. with a sensitivity. specificity. and total predictive accuracy of 69%. 81%. and 77%. respectively. In conclusion: (1) A reduction of RMS 40. prolongation of LAS 40. and fragmentation of signals in the terminal portion of the filtered QRS are characteristics of LBBB.(ABSTRACT TRUNCATED AT 400 WORDS).
Short-term variability of ventricular arrhythmia and rapid assessment of drug efficacy, Statistical criteria for suppression and aggravation of ventricular arrhythmia were defined by means of 50 short-term drug tests performed in 24 patients. Each patient's spontaneous variability (SV) was evaluated by linear regression analysis of hour-to-hour changes in ectopy during 24- to 48-hour Holter monitoring. The response to a single oral dose of disopyramide. 300 mg. flecainide. 200 mg. and propafenone. 450 mg. was measured during a trial lasting 4 hours. Lidocaine was administered intravenously in incremental doses of up to 4 mg/min and was evaluated over 3 hours. Threshold values of ventricular arrhythmia corresponding to 95% confidence limits were calculated from baseline recordings and were used to ascertain the likelihood of a true drug effect. The minimum decrease in hourly ectopy indicating arrhythmia suppression averaged 90.9%. while an increase of at least 947% was required for a proarrhythmic effect. When these efficacy criteria were applied. 16 of 50 short-term tests revealed no drug effect. In contrast. when a 70% threshold derived from studies of daily variability was employed. only 7 of 50 trials were negative. Thus individual determination of hourly arrhythmia variability yields more stringent criteria than extrapolation from day-to-day spontaneous variation.
Flosequinan: a vasodilator with positive inotropic activity, Flosequinan is an oral arterial and venous vasodilator that is currently under investigation for the treatment of congestive heart failure. The effects of flosequinan on ventricular performance and myocardial contractility were studied in 10 patients with severe congestive heart failure during right and left cardiac catheterization. Sixty minutes after a 100 mg oral dose of flosequinan. the peak rate of rise in left ventricular pressure (dP/dt) increased from 940 +/- 180 to 1050 +/- 240 mm Hg/sec (p less than 0.05). while left ventricular end-diastolic pressure decreased from 32 +/- 5 to 26 +/- 8 mm Hg (p less than 0.05). and cardiac index increased (2.1 +/- 0.4 to 2.3 +/- 0.5 L/min/m2. (p less than 0.05). The mean pulmonary artery pressure and vascular resistance decreased from 40 +/- 8 to 33 +/- 12 mm Hg (p less than 0.05) and from 330 +/- 240 to 290 +/- 170 dyne-sec/cm5 (p less than 0.05). respectively. Heart rate. mean aortic pressure. right atrial pressure. systemic vascular resistance. and serum norepinephrine levels did not change significantly. The increase in left ventricular peak dP/dt that was concomitant with a decrease in left ventricular end-diastolic pressure. and no change in systemic arterial pressure or sympathetic tone. argue for a direct positive inotropic effect of flosequinan.
Dietary taurine deficiency and dilated cardiomyopathy in the fox, Taurine deficiency has been implicated as a potential cause of dilated cardiomyopathy. However. the relationship between taurine and myocardial function is presently unclear. The purpose of this study was to determine whether dilated cardiomyopathy in the fox is associated with dietary taurine deficiency. A total of 68 foxes from farms with a history of death caused by dilated cardiomyopathy and 14 foxes from a farm with no history of dilated cardiomyopathy were studied. Dilated cardiomyopathy was diagnosed by echocardiography in 48% of the foxes from one farm with a positive history and in none of the foxes from the control farm. Foxes less than 9 months of age were more commonly affected than older foxes (p = 0.03). Plasma taurine concentrations were significantly less (p less than 0.01) in foxes that had dilated cardiomyopathy (26.8 +/- 16.4 nmol/ml) than in the control foxes (99.3 +/- 60.2 nmol/ml). A significantly higher (p less than 0.01) incidence of dilated cardiomyopathy was present in foxes with a history of a sibling or offspring that died of dilated cardiomyopathy than in foxes without a family history of cardiac death. In one fox with dilated cardiomyopathy that was tested. the myocardial taurine concentration was lower (1.7 mumol/gm wet weight) than that of control foxes (7.3 +/- 1.6 mumol/gm wet weight). Hepatic cysteinesulfinic acid decarboxylase activity was significantly less (p less than 0.001) in foxes with dilated cardiomyopathy (0.97 +/- 0.2 nmol/mm.mg protein) than in control foxes (2.11 +/- 0.07 nmol CO2/mm.mg protein).
Prosthetic valves in children and adolescents, The purpose of this paper is to present the short- and long-term results of prosthetic valve replacement in children. During a 7-year period that ended in April 1985. 186 children. ages 1 to 20 years. underwent valve replacement; there were 55 (30%) aortic valve replacements. 95 (51%) mitral valve replacements. and 36 (19%) multiple valve replacements. Ninety-four percent of the lesions were rheumatic in origin. 4% were congenital. and 2% were infectious. Of 223 valves replaced. 175 (78%) were mechanical valves and 48 (22%) were heterografts; the latter were in the mitral position in all but three patients. Surgical mortality rates were 3.6%. 4.2%. and 19.4% respectively for aortic valve. mitral valve. and multiple valve replacements. Five-year actuarial survival was 91% for aortic valve replacement. 82% for mitral valve replacement and 60% for multiple valve replacement. Major events included reoperation in 34 (with three deaths). progressive myocardial failure that led to death in 10. sudden unexpected death in two. thromboembolic complications in 19 (death in five). subacute bacterial endocarditis in five (two deaths). and bleeding that required transfusion in two patients. Five-year complication-free actuarial survival rates were 83% for aortic valve replacement. 63% for mitral valve replacement. and 57% for multiple valve replacement. The respective five-year complication-free survival rates were 83%. 48%. and 43%. Significant morbidity and mortality rates are associated with valve replacement. Therefore every effort should be made to preserve the native valve by plastic reparative procedures. When prosthetic replacement of mitral valve is contemplated. our data would suggest that heterografts should not be inserted in children 15 years of age or younger. although heterografts may be used in children over 15 years of age with the expectation of valve survival comparable to that of mechanical valves. When complications that are associated with anticoagulant therapy were reviewed. platelet inhibiting drugs seem quite satisfactory in patients with aortic valve replacement; patients with mitral valve replacement seem to require warfarin therapy. and warfarin must be used in patients with multiple valve replacement to reduce the risk of thromboembolic complications.
Beat-to-beat detection of ventricular late potentials with high-resolution electrocardiography, To detect dynamic changes of VLPs we developed a low-noise. HR-ECG with a gain of 10(5)-10(6)X. This system allows the beat-to-beat detection of low-amplitude signals at the bedside in a nonshielded room without any averaging process. Analysis was performed in 39 normal subjects (group A: 27 men. 12 women. mean age. 28 +/- 8 years). in 98 patients with coronary artery disease without documented sustained ventricular tachycardia (group B: 86 men. 12 women. mean age. 59 +/- 10 years) and in 41 patients coronary artery disease with sustained monomorphic ventricular tachycardia (group C: 36 men. 5 women; mean age 63 +/- 9 years). Comparison was made with time-domain signal-averaging (SA-ECG) in all cases at the same electrode position and with identical band-pass filtering. In group A no VLPs were detected; the total filtered QRS duration was 84 +/- 8 msec (mean +/- SD). and the time interval during which the terminal QRS did not exceed 40 microV (I-40) was less than 30 msec in all cases (mean. 17 +/- 6 msec). In group B. VLPs were detected by HR-ECG in 34 of 98 patients (35%); the total QRS duration was 102 +/- 16 msec (mean +/- SD. p less than 0.01 vs group A). and the I-40 was 29 +/- 13 msec (mean +/- SD. p less than 0.01 vs (group A). In group C. VLPs were detected by HR-ECG in 38 of 41 patients (93%); the total QRS duration was 123 +/- 22 msec (mean +/- SD. p less than 0.01 vs group A and group B). and the I-40 was 40 +/- 14 msec (mean +/- SD. p less than 0.01 vs group A and group B). Concordant results between HR-ECG and SA-ECG were observed in 91% of the cases (59 positive and 103 negative results). Late potentials that exhibited dynamic variations were detected by HR-ECG alone in 13 cases. and very low amplitude VLPs were detected by SA-ECG alone in three cases. In conclusion. the present study demonstrates the feasibility of body-surface recording of VLPs on a beat-to-beat basis. without any averaging process. at the bedside in a nonshielded room. This new approach may allow the study of dynamic changes of VLPs during spontaneous ventricular arrhythmias or ischemia.
Risk stratification in survivors of acute myocardial infarction: routine cardiac catheterization and angiography is a reasonable approach in most patients [editorial, Noninvasive risk assessment in survivors of AMI can effectively subdivide patients into groups with differing risk profiles after hospital discharge. but some patients at risk for late death or recurrent AMI may be incorrectly identified; data from cardiac catheterization and angiography provide complementary and generally more powerful prognostic information. Many patients may derive particular benefit from early cardiac catheterization and angiography. including: (1) patients with AMI complicated by recurrent myocardial ischemia. congestive heart failure. and/or complex ventricular arrhythmias; (2) patients with abnormal or inconclusive results of noninvasive testing or those patients unable to perform an exercise test; (3) patients with abnormal left ventricular global systolic function and those with increased left ventricular end-systolic volume; (4) "young" patients (younger than 50 years of age?); (5) older patients (older than 65 to 70 years of age?); (6) patients with non-Q wave AMI; and (7) patients who are receiving thrombolytic therapy. Performance of early cardiac catheterization and angiography in virtually all survivors of AMI. with selective use of appropriate noninvasive tests. may provide a more efficacious means of risk assessment after AMI; if all tests are performed judiciously. the cost of such an approach need not be excessive. A combination of invasive and selected noninvasive tests probably provides optimal information. The risks to the routine performance of diagnostic cardiac catheterization and angiography in all survivors of AMI are: (1) adequate care and attention may not be paid to proper performance of the procedure(s) and to detailed and proper analyses of the data; (2) the need for additional noninvasive testing in selected patients may be ignored; and most importantly. (3) premature or unnecessary revascularization procedures may be performed subsequently. For optimal patient care. the clinician must obtain all necessary data. avoid unnecessary and repetitive tests. know the accuracy of individual tests at his or her own facility. interpret all data in proper context. and then counsel patients objectively about available management strategies. With this approach. all patients who might appropriately benefit from coronary artery revascularization will be correctly identified. and patients who are truly at very low risk (minimal residual coronary artery disease and preserved left ventricular function particularly if associated with a patent infarct-related artery) may be similarly identified and managed appropriately with elimination of unnecessary additional testing and pharmacologic therapy. Finally. whatever approach to risk stratification one chooses for an individual patient. the importance of and the need to correct and/or ameliorate risk factors for coronary artery disease must be recognized and undertaken.
Prognostic importance of delayed Q-wave evolution 3 to 24 hours after initiation of thrombolytic therapy for acute myocardial infarction, The timing of Q-wave evolution and its prognostic significance was studied in 201 patients who received thrombolytic therapy for a first acute myocardial infarction (AMI). One hundred forty-one patients (70%) had evidence of a Q-wave AMI within 3 hours of the initiation of thrombolytic therapy. 31 (16%) developed Q waves after 3 hours but before hospital discharge. and 29 (14%) were discharged with a non-Q-wave AMI. Laboratory indicators of myocardial damage and in-hospital morbidity and mortality were greater among patients with Q-wave AMIs than with non-Q-wave AMIs. When these indexes were examined with respect to the timing of Q-wave evolution. the prognosis of patients with delayed Q-wave development was similar to that of patients with non-Q-wave AMIs. Thus. compared to patients with early (less than or equal to 3 hours) Q-wave evolution. patients with delayed Q-wave evolution or with a non-Q-wave AMI had a smaller creatine kinase peak (mean 661 to 1.081 vs 1.251 to 1.541 IU; p = 0.005). better preservation of left ventricular function as measured by radionuclide ventriculography before discharge (mean +/- standard deviation 54 +/- 11% vs 47 +/- 13%; p less than 0.01). and a lower incidence of congestive heart failure at discharge (3 vs 15%; p = 0.02). In-hospital mortality was lower among patients with delayed Q-wave evolution or with a non-Q-wave AMI (5 of 141 vs 0 of 60; difference not significant).
Immediate and short-term results of a 1988-1989 coronary angioplasty registry, To determine the relevance of recent refinements in angioplasty technology to our particular practice. the records of 507 consecutive patients undergoing a first percutaneous transluminal coronary angioplasty (PTCA) at our center between October 1988 and May 1989 were reviewed. At the time of PTCA. 41% of these patients had class IV angina and 44% were identified as having multivessel disease. Dilatation was attempted in 734 lesions (mean 1.5 per patient). of which 95 (13%) were chronic total occlusions. Overall. 69% of the 734 lesions were judged anatomically complex. and. in dilating these lesions. a rail-type device was used almost exclusively. Successful dilatation was achieved in 659 of the 734 (90%) attempted lesions. There were low incidences of the major complications of death (0.4%). myocardial infarction (1.8%) and emergency bypass surgery (1.8%). Acute rethrombosis occurred in 54 patients (11%). In these patients. initial strategy of repeat dilatation was successful in 38 of 47 patients (81%). Overall. primary clinical success at PTCA was achieved in 480 patients (95%). At a mean follow-up of 7.5 +/- 1.5 months in 497 of the study patients. the event-free rate (freedom from cardiac death. myocardial infarction. repeat PTCA or coronary bypass surgery or recurrence of severe [class III to IV] angina) was 71%. In conclusion. despite the often complex coronary disease in patients currently presenting to our center. a high initial success rate and acceptable short-term outcome of PTCA was achieved.
Sustained reduction in valvular regurgitation and atrial volumes with tailored vasodilator therapy in advanced congestive heart failure secondary to dilated (ischemic or idiopathic) cardiomyopathy, Afterload reduction therapy can acutely improve hemodynamic function in patients with advanced heart failure; however. it is unknown if initial reductions in mitral and tricuspid regurgitation and atrial volumes can be sustained with oral therapy. Atrial volumes and atrioventricular valve regurgitation were measured using 2-dimensional and Doppler echocardiography with color-flow imaging in 14 patients with dilated heart failure (ejection fraction 17 +/- 4%) before and after 3 +/- 1 days of intensive vasodilator and diuretic therapy tailored to hemodynamic goals. Echocardiography was repeated again after 6 +/- 2 months on oral vasodilators and a flexible diuretic regimen. Acute therapy reduced systemic vascular resistance from 1.760 +/- 460 to 1.010 +/- 310 dynes.s.cm-5. pulmonary artery wedge pressure from 30 +/- 5 to 17 +/- 4 mm Hg. and right atrial pressure from 13 +/- 5 to 7 +/- 3 mm Hg. and led to a 61% increase in stroke volume (from 36 +/- 10 to 58 +/- 14 ml) (p less than 0.01). Mitral and tricuspid regurgitation. determined by color-flow fraction. initially decreased from 0.34 +/- 0.17 to 0.20 +/- 0.20 and from 0.33 +/- 0.15 to 0.13 +/- 0.13. respectively (p less than 0.001). This reduction was sustained at 6 months. Significant decreases occurred with acute therapy. with further reductions at 6 months in both mean left atrial volume (from 100 +/- 25 to 80 +/- 19 to 65 +/- 15 cm3) and right atrial volume (from 85 +/- 23 to 64 +/- 23 to 52 +/- 14 cm3) (p less than 0.001).
Frequency and severity of mitral regurgitation one year after balloon mitral valvuloplasty, Mitral regurgitation (MR) was evaluated by Doppler echocardiography in 59 patients with mitral stenosis before. immediately after and 1 year after balloon mitral valvuloplasty (BMV). The severity of MR was graded on a scale from 1+ to 4+. Echocardiographic and hemodynamic variables were analyzed to study the potential factor(s) that might predict the long-term persistence of MR. Echocardiographic variables were mitral valve thickness and motion. subvalvular change. left atrial dimension. commissural calcification and effective balloon/mitral anular diameters. Hemodynamic variables were mitral pressure gradient. pulmonary arterial pressure. ejection fraction. mitral valve area index. age. gender and cardiac rhythm. Mitral valve area index increased from 0.9 +/- 0.5 to 1.5 +/- 0.8 cm2/m2 immediately after BMW. and to 1.4 +/- 0.3 cm2/m2 at 1 year follow-up (p less than 0.01). Immediately after BMV. MR grading did not change in 30 patients (51%). increased by 1+ in 23 patients (39%). by 2+ in 2 patients (3.3%) and by 3+ in 2 patients (3.3%). and decreased by 1+ in 2 others. At 1-year follow-up. only 1 patient with severe MR required valve replacement. Fifty-one patients (88%) had no change in the extent of MR (less than or equal to 1+) and 6 patients (10%) had a 1-grade decrease in their MR; only 1 patient had a 1-grade increase in MR. No clinical or hemodynamic variables or morphologic characteristics of the mitral valve could predict the development of significant MR after BMV. It is concluded that an increment in MR severity less than or equal to 2+ is frequently seen after BMV.
Left ventricular size, mass and function in relation to the duration and quantity of heavy drinking in alcoholics, Left ventricular (LV) hypertrophy and mild dysfunction are frequently observed in alcoholics but little is known about how they relate to the duration and severity of alcohol abuse. LV size. mass and function were studied using echocardiography and systolic time intervals in 78 middle-aged male alcoholics who also gave detailed accounts of the duration of heavy drinking. the quantity of recent ethanol consumption and the duration of abstinence. Compared with 34 healthy nonalcoholics. alcoholics had a higher LV mass index (85 +/- 2 [mean +/- standard error] vs 77 +/- 2 g/m2. p = 0.001). a thicker posterior wall (11 +/- 0.2 vs 10 +/- 0.2 mm. p = 0.02). a longer end-systolic diameter index (18 +/- 0.3 vs 17 +/- 0.3 mm/m2. p = 0.02). and a higher preejection period/ejection time ratio (0.36 +/- 0.01 vs 0.33 +/- 0.01. p = 0.002). In multivariate linear regression models. these abnormalities proved independent of the drinking history. except that posterior wall thickness was weakly related to the duration of heavy drinking (standardized correlation coefficient 0.36. p = 0.01). Univariate analyses suggested that the LV mass index and systolic time interval ratio had. if anything. a curvilinear relation to the total duration of heavy alcohol consumption. It is concluded that the LV hypertrophy and dysfunction found in alcoholics are poorly related to the duration and severity of self-reported alcohol abuse. Together with other data. this suggests that there is no simple linear dose-injury relation in the long-term cardiotoxicity of ethanol. Factors modifying the myocardial effects of ethanol need to be studies more in the future.
Uses and limitations of transthoracic echocardiography in the assessment of atrial septal defect in the adult, Two-dimensional and color Doppler echocardiography accurately detected the presence of an atrial septal defect (ASD) in 47 of 50 adults (mean age 40 years) confirmed by surgery or cardiac catheterization. or both. It correctly categorized all patients with ostium secundum and ostium primum ASD but misdiagnosed 3 of 5 patients with surgically proven sinus venosus ASD. The shunt flow volume across the ASD was calculated with the standard Doppler equation. and assuming the ASD to be circular correlated with shunt flow volume obtained by cardiac catheterization (r = 0.74). The maximum width of the color flow signals moving across the ASD was taken as its diameter. Mean flow velocity was determined either by placing a pulsed Doppler sample volume parallel to the flow across the ASD as visualized by color Doppler or by color M-mode examination. which allowed determination of flow velocities using a previously validated method that incorporates a computer analysis of pixel color intensity. The pulmonary to systemic blood flow ratio obtained by color-guided conventional Doppler interrogation of the left and right ventricular outflow tracts correlated poorly with cardiac catheterization results (r = 0.38). In patients with associated tricuspid regurgitation. the peak systolic pulmonary artery pressure obtained by color Doppler-guided continuous-wave Doppler correlated well with that obtained at cardiac catheterization (r = 0.89). The maximum color Doppler jet width of the flow across the ASD poorly correlated with ASD size estimated at surgery (r = 0.50).
Congestive heart failure, coronary events and atherothrombotic brain infarction in elderly blacks and whites with systemic hypertension and with and without echocardiographic and electrocardiographic evidence of left ventricular hypertrophy, Hypertension was present in 50% of 196 blacks and in 36% of 382 whites (p less than 0.001). A prospective study of 84 elderly blacks (70% women) and 326 elderly whites (73% women) with hypertension correlated echocardiographic and electrocardiographic left ventricular (LV) hypertrophy with incidences of congestive heart failure (CHF). coronary events and atherothrombotic brain infarction (ABI). Echocardiographic LV hypertrophy (p less than 0.02) and concentric LV hypertrophy (p less than 0.001) were more prevalent in hypertensive blacks than in hypertensive whites. Hypertensive blacks were younger (78 +/- 9 years) than hypertensive whites (82 +/- 7 years) (p less than 0.001). Other coronary risk factors were similar. except for higher serum triglycerides in whites than in blacks (p less than 0.02). Follow-up was 37 +/- 18 months in blacks and 43 +/- 18 months in whites (p less than 0.01). Incidences of CHF and coronary events were not significantly different in blacks and whites. ABI incidence was 38% in blacks and 21% in whites (p less than 0.005). Multiple logistic regression analysis showed that prior CHF (p = 0.000). concentric LV hypertrophy (p = 0.018) and echocardiographic LV hypertrophy (p = 0.022) were independent risk factors for CHF. Echocardiographic LV hypertrophy (p = 0.001). serum total cholesterol (p = 0.002). concentric LV hypertrophy (p = 0.005) and prior coronary artery disease (p = 0.042) were independent risk factors for coronary events. Prior ABI (p = 0.001). echocardiographic LV hypertrophy (p = 0.001) and electrocardiographic LV hypertrophy (p = 0.034) were independent risk factors for ABI.
Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with intravenous calcium chloride pretreatment in normal subjects, To evaluate the effects of calcium pretreatment on the disposition and electrocardiographic effects of verapamil. 8 healthy male volunteers received treatment in each of 3 phases in a randomized. double-blind. crossover manner. Phase I denoted 10 ml of 0.9% intravenous sodium chloride followed by 10 mg of intravenous verapamil; phase II denoted 10 ml of 10% intravenous calcium chloride followed by 4 ml of 0.9% intravenous sodium chloride; and phase III denoted 10 ml of 10% intravenous calcium chloride followed by 10 mg of intravenous verapamil. Blood samples for the determination of verapamil concentrations were drawn at 5. 10. 15. 20. 30. 45. 60 and 90 minutes. and at 2. 4. 6. 10 and 24 hours. Blood pressure. heart rate and PR intervals were also measured at these times. Pretreatment of verapamil with intravenous calcium did not alter the disposition of intravenous verapamil. Blood pressure was not significantly altered in any treatment phase. although calcium tended to increase mean arterial pressure and verapamil abolished this effect. Calcium had no significant affect on verapamil-induced PR prolongation (maximum percent change in PR interval: phase I = 19 +/- 11%. phase III = 18 +/- 7%; time to maximal prolongation: phase I = 0.38 +/- 0.21 hours. phase III = 0.37 +/- 0.26 hours; and area under the percent change in PR vs time curve: phase I = 15.5 +/- 10. phase III = 21 +/- 9). Verapamil caused a reflex increase in heart rate of similar magnitude in both phases I and III (24 +/- 10% and 21 +/- 7%. respectively).
Why are autism and the fragile-X syndrome associated? Conceptual and methodological issues, Investigations of the association between autism and the fragile-X syndrome have yielded conflicting results with some studies indicating a strong correlation and others indicating no relation between the disorders. In this paper. we review the relevant research on this controversy and discuss the conceptual and methodological problems involved in such an inquiry. We conclude that autism and fragile X are associated and that this relation will prove fruitful in understanding the role of the X chromosome in a variety of behavior disorders and in unraveling various theoretical accounts on the etiology of autism.
Improved molecular diagnostics for ornithine transcarbamylase deficiency, Since the cloning of the cDNA for X-linked ornithine transcarbamylase (OTC) in 1984. diagnostic accuracy of OTC deficiency for prenatal and carrier detection has been greatly improved by the use of linkage analysis. However. the use of RFLP-based diagnosis is limited in this and in other new mutation diseases. Here we report both the use of direct mutation detection by new PCR-based techniques and our experience with linkage-based diagnosis in 18 families. We have previously reported the use of chemical mismatch cleavage to detect mutations first in amplified mRNA and then in genomic DNA of patients. This technique has now been utilized for prenatal diagnosis. Primers for specific amplification of OTC exons 1. 3. 5. 9. and 10 have been developed and been employed to map deletions of the OTC gene in two families. These primers also have been used to detect alterations in the TaqI sites found in exons 1. 3. 5. and 9. Four novel mutations of the OTC gene leading to abolition of a TaqI site in the OTC cDNA were discovered. One of these mutations is in exon 1; two lie in exon 3; and one is in exon 9. In addition. we have used the PCR products as probes to identify the exon-specific bands seen on Southern blots and to map the polymorphic BamHI and MspI sites. which are commonly used for linkage analysis. This information will facilitate the interpretation of altered band patterns seen in deletion cases and in cases of point mutations affecting restriction sites. Utilization of the appropriate combination of these molecular techniques permitted accurate diagnostic evaluations in 17 of 18 families.
A dimorphic 4-bp repeat in the cystic fibrosis gene is in absolute linkage disequilibrium with the delta F508 mutation: implications for prenatal diagnosis and mutation origin, The gene causing cystic fibrosis (CF) has been recently cloned. and the major mutation (delta F508) accounting for approximately 70% of CF chromosomes has been uncovered. We have identified at the 3' end of intron 6 in the CF gene a 4-bp tandem repeat (GATT) that exhibits interesting features. First. PCR screening of 103 normal individuals revealed that the repeat exists only in two polymorphic allelic forms. either as a hexamer or a heptamer. These two alleles are in Hardy-Weinberg equilibrium and predict a heterozygote frequency of 41% (p[seven repeats] = .71; q [six repeats] = .29). Second. the allele with six repeats was found linked to delta F508 on all 76 CF chromosomes investigated. demonstrating strong linkage disequilibrium and suggesting that delta F508 had originated on the gene bearing six repeats. Third. when the repeat alleles are linked to the DNA markers XV2c and KM19. extended haplotypes are generated. These new haplotypes become informative in situations in which prenatal diagnosis cannot be performed solely with XV2c and KM19. Since this repeat marker is located in the CF gene and would be very less likely to recombine with the gene. it can serve as a valuable DNA marker for haplotype analysis. A possible crossover. however. was identified between XV2c and KM19. transferring delta F508 to a different haplotype.
Two frameshift mutations in the cystic fibrosis gene, Cystic fibrosis (CF) is a recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. We have identified in exon 7 two frameshift mutations. one caused by a two-nucleotide insertion and the other caused by a one-nucleotide deletion; these mutations--CF1154insTC and CF1213delT. respectively. are predicted to shift the reading frame of the protein and to introduce UAA(ochre) termination codons at residues 369 and 368.
Progress in the search for genetic linkage with Tourette syndrome: an exclusion map covering more than 50% of the autosomal genome, Gilles de la Tourette syndrome is a neuropsychiatric disorder with an autosomal dominant mode of inheritance and reduced penetrance at a single genetic locus. Several research groups have genetic linkage studies underway to detect the chromosomal location of the gene that predisposes for this disorder. Strong and clear evidence of linkage has not yet been produced for Tourette syndrome. This paper presents an overview of the methods and progress of the groups centered at Yale University and Erasmus University in excluding linkage from a large portion of the genome. Our labs have screened 228 genetic marker loci for linkage with a gene for this disorder in a series of affected families in the United States. Canada. The Netherlands. and Norway. More than 50% (and perhaps as much as 66%) of the autosomal genome has now been excluded on the assumption that genetic heterogeneity is not an important factor in the Tourette syndrome pedigrees pooled for this summary.
A mutation in the pro alpha 2(I) gene (COL1A2) for type I procollagen in Ehlers-Danlos syndrome type VII: evidence suggesting that skipping of exon 6 in RNA splicing may be a common cause of the phenotype, Fibroblasts from a proband with Ehlers-Danlos syndrome type VII synthesized approximately equal amounts of normal and shortened pro alpha 2(I) chains of type I procollagen. Nuclease S1 probe protection experiments with mRNA demonstrated that the pro alpha 2(I) chains were shortened because of a deletion of most or all of the 54 nucleotides in exon 6. the exon that contains codons for the cleavage site for procollagen N-proteinase. Sequencing of genomic clones revealed a single-base mutation that converted the first nucleotide of intron 6 from G to A. Therefore. the mutation was a change. in the -GT-consensus splice site. that produced efficient exon skipping. Allele-specific oligonucleotide hybridizations demonstrated that the proband's mother. father. and brother did not have the mutation. Therefore. the mutation was a sporadic one. Analysis of potential 5' splice sites in the 5' end of intron 6 indicated that none had favorable values by the two commonly employed techniques for evaluating such sites. The proband is the fourth reported proband with Ehlers-Danlos syndrome VII with a single-base mutation that causes skipping of exon 6 in the splicing of RNA from either the COL1A1 gene or COL1A2 gene. No other mutations in the two type I procollagen genes have been found in the syndrome. Therefore. such mutations may be a common cause of the phenotype. The primers developed should be useful in screening for the same or similar mutations causing the disease.
Molecular genetic basis of maple syrup urine disease in a family with two defective alleles for branched chain acyltransferase and localization of the gene to human chromosome 1, Maple syrup urine disease in humans results from inherited defects in branched chain alpha-ketoacid dehydrogenase. a mitochondrial multienzyme complex. A variety of genetic changes may produce this phenotype by affecting the function of any of the three complex-specific subunits. The varied clinical expression observed in patients may be partially explained by the defects in the involved subunit. Here we report localization of the gene for the branched chain acyltransferase component of the complex to human chromosome 1 and describe a proband who is a compound heterozygote at this locus. One allele. inherited from the father. produces transcripts with 124 nucleotides deleted from the coding region. The deletion is not found in the branched chain acyltransferase gene. implying that the deleted transcripts arise by an error in transcript processing. Cells from the patient's mother contain 50% of the normal amount of mRNA for the subunit. and the proband has inherited this nonexpressing allele from her. As a result. the proband produces no acyltransferase protein and therefore has greatly impaired complex activity. A phenotypically normal sibling is shown to be genetically similar to the mother having inherited the mother's nonexpressing allele and the father's normal allele.
Tay-Sachs disease in Moroccan Jews: deletion of a phenylalanine in the alpha-subunit of beta-hexosaminidase, Tay-Sachs disease is an inherited lysosomal storage disorder caused by defects in the beta-hexosaminidase alpha-subunit gene. The carrier frequency for Tay-Sachs disease is significantly elevated in both the Ashkenazi Jewish and Moroccan Jewish populations but not in other Jewish groups. We have found that the mutations underlying Tay-Sachs disease in Ashkenazi and Moroccan Jews are different. Analysis of a Moroccan Jewish Tay-Sachs patient had revealed an in-frame deletion (delta F) of one of the two adjacent phenylalanine codons that are present at positions 304 and 305 in the alpha-subunit sequence. The mutation impairs the subunit assembly of beta-hexosaminidase A. resulting in an absence of enzyme activity. The Moroccan patient was found also to carry. in the other alpha-subunit allele. a different. and as yet unidentified. mutation which causes a deficit of mRNA. Analysis of obligate carriers from six unrelated Moroccan Jewish families showed that three harbor the delta F mutation. raising the possibility that this defect may be a prevalent mutation in this ethnic group.
HIV risk behavior reduction following intervention with key opinion leaders of population: an experimental analysis, BACKGROUND AND PURPOSE. Peer norms influence the adoption of behavior changes to reduce risk for HIV (human immunodeficiency virus) infection. By experimentally intervening at a community level to modify risk behavior norms. it may be possible to promote generalized reductions in HIV risk practices within a population. METHODS. We trained persons reliably identified as popular opinion leaders among gay men in a small city to serve as behavior change endorsers to their peers. The opinion leaders acquired social skills for making these endorsements and complied in talking frequently with friends and acquaintances. Before and after intervention. we conducted surveys of men patronizing gay clubs in the intervention city and in two matched comparison cities. RESULTS. In the intervention city. the proportion of men who engaged in any unprotected anal intercourse in a two-month period decreased from 36.9 percent to 27.5 percent (-25 percent from baseline). with a reduction from 27.1 percent to 19.0 percent (-30 percent from baseline) for unprotected receptive anal intercourse. Relative to baseline levels. there was a 16 percent increase in condom use during anal intercourse and an 18 percent decrease in the proportion of men with more than one sexual partner. Little or no change was observed among men in the comparison cities over the same period of time. CONCLUSIONS. Interventions that employ peer leaders to endorse change may produce or accelerate population behavior changes to lessen risk for HIV infection.
Motorcycle licensure, ownership, and injury crash involvement, The interrelationships among motorcycle licensure. ownership. and injury crash involvement were investigated in a sample of 2.723 motorcycle drivers severely or fatally injured in California in 1985-86. Owners of motorcycles in such crashes ("driver-owners") were less likely to have valid licenses than a random sample of motorcycle owners who had not been in crashes (42 vs. 57 percent). Thirty-three percent of the crash-involved drivers had valid motorcycle driver's licenses; 39 percent were operating motorcycles they did not own ("driver-nonowners"). Driver-nonowners were less likely to be validly licensed than driver-owners (20 percent vs. 44 percent). The licensing rate of crash-involved driver-nonowners was 15 percent if the owner was also unlicensed. Rates of valid licensure were lowest among the youngest drivers. Virtually no crash-involved driver-nonowners under age 21 were licensed in cases in which the owner was also young and unlicensed.
Alcohol use and abuse in random samples of physicians and medical students, BACKGROUND. This study sought to resolve conflicting views about whether physicians are especially prone to alcohol abuse. METHODS. Using an anonymous. mailed questionnaire on substance use. we surveyed 500 physicians. 510 pharmacists. and 974 of their students. The physicians and pharmacists were selected randomly from the state society's membership lists. and students selected were from local school lists. Follow-up surveys were sent to nonresponders at two-week intervals. RESULTS. The physicians and medical students did not drink especially heavily and were no more vulnerable to alcoholism than were their counterparts in pharmacy and other professions. Physicians differed from pharmacists in their style of drinking (greater frequency. smaller quantity). but not in total amount of alcohol consumed. Drinking habits among physicians were not associated with medical specialty or type of practice. but were positively related to gender (males drank more than females) and to age (older doctors were more apt to qualify as heavy drinkers than were younger doctors). CONCLUSIONS. Physicians were no more likely to abuse substances nonmedically than were other professionals. Any group in which alcohol use is nearly universal incurs a risk of abuse and impairment that cannot be ignored.
Effects on serum lipids of adding instant oats to usual American diets, This study was designed as a test of the serum lipid response and dietary adaptation to recommended daily inclusion of instant oats in an otherwise regular diet. Hypercholesterolemic adults were randomly assigned to a control or intervention group. Participants in the intervention group were given packages of instant oats and requested to eat two servings per day (approximately two ounces dry weight). substituting the oats for other carbohydrate foods in order to maintain baseline calorie intake and keep weight stable. Serum lipids were measured in blood collected by venipuncture at baseline. four weeks. and eight weeks. Baseline mean total cholesterol (TC) levels were 6.56 mmol/L and 6.39 mmol/L for intervention and control groups. respectively. After eight weeks. mean serum total cholesterol of the intervention group was lower by -0.40 mmol/L. and mean net difference in TC between the two groups was 0.32 mmol/L (95% CI: 0.09. 0.54). Low-density lipoprotein-cholesterol was similarly reduced with mean net difference of 0.25 mmol/L (95% CI: 0.02. 0.48) between the two groups. Mean soluble fiber intake increased along with slight self-imposed reductions in mean total fat. saturated fat. and dietary cholesterol intake in the intervention group. Neither group changed mean body weight. Daily inclusion of two ounces of oats appeared to facilitate reduction of serum total cholesterol and LDL-C in these hyperlipidemic individuals.
Behavioral, health and psychosocial factors and risk for HIV infection among sexually active homosexual men: the Multicenter AIDS Cohort Study, We examined whether 644 homosexual men who engaged in receptive anal intercourse were at particularly elevated risk for seroconversion if they also possessed specific behavioral. health or psychosocial vulnerability characteristics. Of 11 potential factors examined. heavy drinking. moderate to heavy drug use. and younger age were significantly related to seroconversion. These variables were also associated with an increased number of sexual partners. anonymous sex. and failure to use condoms.
Responsible alcohol service: a study of server, manager, and environmental impact, A responsible alcohol-service training program was evaluated for its impact on changing beliefs. knowledge. and behavior in 97 servers and 43 managers and on changing establishment policies that encourage safer drinking environments. The training program had a significant impact on changing the beliefs and knowledge of both servers and managers. Observation 4 to 6 weeks after training showed no effects on server behavior. but there was a tendency toward more establishment policies compared with controls.
Increased risk of ectopic pregnancy with maternal cigarette smoking, As part of a case-control study of ectopic pregnancy. we evaluated the potential etiologic role of cigarette smoking. Maternal cigarette smoking at the time of conception was associated with an increased risk of ectopic pregnancy with a dose-response relationship (adjusted odds ratios: 1.30 to 2.49). On the other hand. partner's smoking was not associated with ectopic pregnancy. The study provides a supplementary argument towards a causal effect of smoking in the development of ectopic pregnancy.
Are people more health conscious? A longitudinal study of one community, Secular changes in cardiovascular health awareness. knowledge and behavior were observed in four biennial cross-sectional surveys and a cohort survey in a New England community. These changes are not related to more health promotion activities in the social milieu of respondents. but are more likely due to national mass media health campaigns. the effects of which may influence outcomes of community-based cardiovascular disease prevention studies.
Sexual risk behaviors, AIDS knowledge, and beliefs about AIDS among runaways, Sexual risk behaviors. knowledge of acquired immunodeficiency syndrome (AIDS). and beliefs about AIDS prevention were examined among 126 runaways. In the previous 3 months. 65 percent of youths had been sexually active. Among the sexually active runaways. males reported a median of 2.7 partners and females reported 1.3 partners. and only 18 percent reported consistent condom use. Runaways demonstrated moderately high AIDS knowledge and beliefs endorsing AIDS prevention. Condom use and abstinence were directly related to beliefs about preventing AIDS.
Security measures for AIDS and HIV, This study describes the measures being taken by AIDS surveillance offices across the country to ensure the security of information regarding patients with AIDS and HIV infection. Security measures were evaluated according to the cumulative number of AIDS cases reported. whether partner notification services were provided. and whether HIV seropositive reporting by name was also required. This study showed that public health departments have taken extra steps to ensure the security of AIDS and HIV data.
Carcinoma of the ductus choledochus, A retrospective review of patients treated for carcinoma of the common bile duct has demonstrated improvement in diagnostic capabilities. leading to earlier management by resectional therapy. The ability to resect these tumors is directly translatable to improved long-term survival. Efforts to obtain proof of malignancy prior to resection are often frustrated by the inability to obtain adequate representative tissue for frozen section. Choledochoscopic biopsies and incisional biopsies have given the highest yield of positive diagnoses. In experienced hands. a program of fewer preoperative tests with emphasis on early operation. diagnosis. and definitive treatment may be more cost-effective in the management of patients with common bile duct cancer.
Adult respiratory distress syndrome, Basic scientists and clinicians have written numerous articles on the diverse causes of adult respiratory distress syndrome (ARDS). There is no specific diagnostic test for ARDS; the condition is characterized by interstitial lung edema. reduction in lung compliance. alveolar and small airway closure. decrease in functional residual capacity. and persistent hypoxia with increasing amounts of pulmonary blood flow coursing through nonventilated or poorly ventilated alveoli. Recent studies have emphasized the roles of macrophages and polymorphonuclear neutrophils in lung defense and injury. Advances in understanding the pathophysiology of ARDS have produced little significant change in the clinical management of the syndrome. There is no specific treatment for ARDS. The cornerstone of therapy is the early recognition and elimination of initiating factors such as sepsis. ARDS is not a single disease process. but appears to represent a final common pathway for the manifestation of a variety of lung injuries. The goal of therapy is to eliminate the predisposing condition and support the patient. New modes of ventilatory and pharmacologic therapy are presented.
Neuroendocrine design of the gut, The enteric nervous system (ENS) can be thought of as the third component of the autonomic nervous system. It is a vast network of neurons widely dispersed throughout the gut. The ENS is a dominant regulator of gut function through the action of peptide and non-peptide neurotransmitters. The most intensively studied roles of the ENS have been the regulation of secretory processes. such as gastric acid secretion. and motility. It is clear. however. that the ENS plays a broader role in the regulation of other gut functions. including mucosal defense. the gut immune response. and sphincter function. Alterations in the regulation of gut function by the ENS are likely or suspected in a number of conditions. including achalasia. Hirschsprung's disease. inflammatory bowel disease. Chagas' disease. chronic intestinal pseudoobstruction. biliary dyskinesia. tachygastria. and irritable bowel syndrome. Improved knowledge of the pathophysiology of these troublesome conditions makes effective therapy more likely in the future.
New approaches to the diagnosis, prevention, and treatment of cytomegalovirus infection after transplantation, Infection occurring after solid organ transplantation continues to exert a considerable detrimental effect upon patient and allograft survival. While the search for better targeted immunosuppressive regimens continues. we must seek to improve our ability to both diagnose and treat those infections that do occur after transplantation. Viral infections in general. and cytomegalovirus (CMV) infections in particular. represent an area in which substantial progress is being made. Improvement in diagnostic modalities has allowed more rapid and precise identification of CMV infection and disease. and the use of antiviral agents that possess activity against CMV has allowed both prophylaxis and treatment of this frequently life-threatening disease. The prophylactic use of presently available agents in combination and the development of less toxic. more potent anti-CMV agents should serve to further lessen the impact of CMV disease upon the field of solid organ transplantation.
The Roux operation for postgastrectomy syndromes, The aim of this paper is to describe the technique. indications. and results of the Roux operation as used in the treatment of postgastrectomy syndromes. A Roux gastrojejunostomy with a 40-cm Roux limb is the procedure of choice for alkaline reflux gastritis. because it virtually eliminates reflux of bile and pancreatic juice into the stomach. The slow transit through a Roux limb can also be used to good advantage to slow gastric emptying in patients with dumping. Patients with delayed gastric emptying respond to the combination of near-total gastric resection. which removes the atonic gastric remnant and speeds emptying. and Roux-Y gastrojejunostomy. which prevents reflux esophagitis and provides a reservoir for ingesta in the upper gut. After all Roux operations. however. the Roux limb may slow emptying so much that pain. fullness. nausea. and food vomiting result. the so-called Roux stasis syndrome. Prevention of the Roux stasis syndrome with an "uncut" Roux limb and the treatment of the syndrome by using electrical pacing to suppress the ectopic pacemakers that emerge in the limb offer possible new solutions to this vexing problem.
Cytokines and glucocorticoids in the regulation of the "hepato-skeletal muscle axis" in sepsis, Sepsis results in muscle catabolism and peripheral release of amino acids with a concomitant uptake of amino acids in liver and acute-phase protein synthesis. In addition. there appears to be a cytokine-induced process that blocks muscle amino acid uptake in sepsis. further diverting amino acids from the periphery to the liver. In this article. evidence that cytokines and glucocorticoids play an important role in the regulation of hepatic and muscle protein metabolism during sepsis is presented.
Bacterial overgrowth and intestinal atrophy in the etiology of gut barrier failure in the rat, Bacterial translocation occurs in animal models of shock. trauma. sepsis. and parenteral or elemental enteral alimentation. Bowel atrophy and cecal bacterial overgrowth have both been implicated in the pathophysiology of bacterial translocation in many of these models. To further define the etiology of bacterial translocation resulting from dietary manipulations. rats were fed a elemental/defined-formula diet (DFD) for 2 weeks ad libitum and then randomized to either intestinal decontamination with a nonabsorbable antibiotic (neomycin) or no antibiotic treatment. Neomycin treatment significantly (p less than 0.01) reduced the incidence of bacterial translocation after DFD. in association with a significant reduction in the number of cecal gram-negative bacteria. Neither loss of bowel mass after DFD nor bowel composition was affected by oral neomycin. Bacterial translocation after DFD would thus appear to be the result of cecal bacterial overgrowth rather than a loss of a physical intestinal barrier due to atrophy.
Arterial oxygen saturation during induction of anaesthesia, Three groups of 10 ASA 1 patients were studied to determine the incidence of hypoxaemia (oxygen saturation less than or equal to 90%) using pulse oximetry during induction of 'mask' anaesthesia. and whether simple oxygenation techniques could prevent its occurrence. We also surveyed all anaesthetists in three major hospitals to ascertain their techniques for this method of anaesthesia. Anaesthesia was induced in all patients with thiopentone and maintained with nitrous oxide and isoflurane. The first group received 33% oxygen in nitrous oxide as carrier gases. a second group a few normal breaths of 100% oxygen during thiopentone administration followed by 33% oxygen in nitrous oxide. while a third group received 100% oxygen after loss of eyelash reflex until spontaneous breathing was established. No patient received positive pressure ventilation before spontaneous breathing was established. Six of the 10 patients in the first group became hypoxaemic compared to none in the second group. and three patients became hypoxaemic in the third group. Thirty-seven percent of anaesthetists who responded to the survey either did not apply positive pressure ventilation before establishment of spontaneous breathing. or only did so if apnoea was prolonged. Only one anaesthetist fully pre-oxygenated patients lungs. We conclude that to avoid the likely occurrence of hypoxaemia during induction of mask anaesthesia. a minimum of a few breaths pre-oxygenation is necessary.
The effects of midazolam on cerebral blood flow and oxygen consumption. Interaction with nitrous oxide in patients undergoing craniotomy for supratentorial cerebral tumours, Cerebral blood flow and the cerebral metabolic rate of oxygen were measured in 30 patients during craniotomy for supratentorial cerebral tumours by a modification of the Kety-Schmidt technique using Xenon 133 intravenously. Anaesthesia was induced with midazolam 0.3 mg/kg. fentanyl and pancuronium. and maintained with midazolam as a continuous infusion. fentanyl. pancuronium and nitrous oxide in oxygen or oxygen in air. The concentration of midazolam in the blood of 10 patients was about 300 ng/litre during two measurements; the patients' lungs were ventilated with N2O in oxygen. The concentration of midazolam in the blood of another 10 patients was doubled to about 600 ng/litre during the second flow measurement; the patients' lungs were ventilated with N2O/O2. The concentration of midazolam in the blood of the third group of 10 patients was doubled to 600 ng/litre during the second flow measurement; the patients' lungs were ventilated with oxygen in air. No relationship was found between the dose of midazolam and cerebral blood flow or oxygen consumption. Nitrous oxide in combination with midazolam also had no effect on these variables.
A randomised double-blind study of interpleural analgesia after cholecystectomy, Continuous interpleural analgesia provided by 4 hourly injections of 20 ml bupivacaine 0.5% with adrenaline 5 micrograms/ml was compared with placebo in a randomised. double-blind study after cholecystectomy. All patients self-administered intravenous morphine using a patient-controlled analgesia device. There was a highly significant difference in mean morphine consumption between the groups (72 mg as compared with 22 mg). Visual analogue pain scores tended to be lower in the bupivacaine group throughout and this was significant at 2 hours. Respiratory function measurements were not significantly different between the groups. The mean peak venous plasma bupivacaine concentration after the sixth dose was 3.03 micrograms/ml and no symptoms suggestive of local anaesthetic toxicity occurred. It is concluded that this regimen can provide effective and continuous analgesia after cholecystectomy and that combined administration of interpleural bupivacaine and systemic morphine is more effective than morphine alone in the immediate postoperative period. The doses of bupivacaine required for optimal use of the technique lead to significant total plasma bupivacaine concentrations within 24 hours.
Anaphylactic anaesthetic reactions. The value of paper radioallergosorbent tests for IgE antibodies to muscle relaxants and thiopentone, The three currently available paper radioallergosorbent tests ('suxamethonium'. alcuronium and thiopentone) were evaluated. 'Suxamethonium' radioallergosorbent test (which employs choline conjugated to paper discs) proved to be reliable in the detection of allergy to neuromuscular blockers. which were confirmed as the most common cause of anaphylactic reaction during general anaesthesia. Thiopentone radioallergosorbent test may also be useful. and is recommended in conjunction with 'suxamethonium' radioallergosorbent test in the preliminary investigation of reactions. Patients with positive 'suxamethonium' radioallergosorbent test usually require further testing. including alcuronium radioallergosorbent test. skin testing with a wide range of drug concentrations or leucocyte histamine release test.
Propofol infusion for control of status epilepticus, Two patients with status epilepticus who were resistant to conventional treatment but responded to propofol infusions are reported. An electroencephalogram confirmed the seizures and their successful treatment.
32-gauge spinal catheters through 26-gauge needles, Small diameter intrathecal catheters potentially combine the certainty of intrathecal injection and the advantage of repeatability. without the risk of a high incidence of headache after dural puncture. We report problems placing such catheters.
Patients' expectations of patient-controlled analgesia, Patient-controlled analgesia is an increasingly popular method of postoperative pain relief. However. patients often worry about new therapies. Eighty ASA 1 and 2 patients aged 18-65 years were asked to list the advantages and disadvantages of using patient-controlled analgesia. The most important advantage as perceived by patients was the reduced time spent by nurses in giving medication. but there was concern that direct personal contact would also be lessened. Preservation of self control. autonomy. rapid onset of analgesia. ability to titrate analgesia and lack of injections were seen as an advantage. Addiction and machine faults were seen as minimal problems. Preservation of patient-nurse contact is of great importance to ensure success of postoperative analgesia.
Patient-controlled analgesia in children, We report our experience in introducing patient-controlled analgesia at the Royal Hospital for Sick Children. Glasgow. Twenty-five children used the technique after orthopaedic or general surgery using the Graseby system. The pump was loaded with 1 mg/kg morphine sulphate in 50 ml. A bolus dose of 0.02 mg/kg (1 ml) and a lockout interval of 10 minutes were the initial settings. The dose used. pain and sedation scores. respiratory rate and arterial oxygen saturation were recorded. Ages ranged from 5-15 years (mean 9.6) and the method was used for a mean of 48 hours after operation. Morphine requirements averaged 26 (micrograms/kg)/hour (SD 10.6). Pain control was good and sedation minimal. Adverse effects were few and minor. Education of patients. parents and nurses is essential for its success and safety. The technique is an effective and safe means of providing good quality analgesia in school age children.
Paraesthesia with lumbar epidural catheters. A comparison of air and saline in a loss-of-resistance technique, The epidural space was located in 32 obstetric patients using loss of resistance to air. while in a further 35 saline was used. The incidence of paraesthesia was 56% in the air group and 57% in the saline group. There was no significant difference between the groups in terms of other complications or in the quality of analgesia provided.
Intraoperative detection of patent foramen ovale by transesophageal echocardiography, This study reports the intraoperative use of contrast and Doppler echocardiography techniques to diagnose patent foramen ovale (PFO). Fifty patients without known atrial septal defects undergoing elective cardiovascular surgery were studied. A 5-MHz esophageal echocardiographic probe was used to image the fossa ovalis (FO) and 10 ml agitated saline was injected into the right atrium during apnea. Echocardiographic contrast was then injected during end-inspiration at 20-cmH2O airway pressure. When opacification of the right atrium was complete. the airway pressure was released. During these maneuvers. color and pulsed-wave Doppler interrogation of the atrial septum were also performed. Right-to-left passage of saline contrast across the interatrial septum was seen in 11 of 50 patients (22%). Doppler echocardiography demonstrated a PFO in 2 patients without contrast evidence of shunting. Thus. the combination of contrast and Doppler echocardiography identified a 26% (13 of 50) prevalence of PFO. approximating the previously reported autopsy rate of 25%. These contrast and Doppler techniques may be useful in detecting patients at risk for paradoxical emboli and in identifying candidates for closure of the PFO.
Clinical efficacy of oral-transdermal clonidine combinations during the perioperative period, In an attempt to maintain stable levels of an alpha 2-adrenergic agonist throughout the perioperative period. two different oral-transdermal clonidine dosage regimens were administered according to a randomized. double-blind. placebo-controlled study in patients undergoing abdominal surgery. We determined the clinical efficacy of a high- and a low-dose clonidine regimen on sedation. hemodynamic parameters. anesthesia. and analgesia. The low-dose clonidine group of patients (n = 14) received a 7-cm2 clonidine transdermal patch (Catapres-TTS #2). which was supplemented with oral doses of clonidine approximately 3 micrograms.kg-1 on the evening prior to surgery and on the morning of surgery. The high-dose clonidine group (n = 14) received a 10.5-cm2 clonidine transdermal patch (Catapres-TTS #3) with oral clonidine approximately 4.5 micrograms.kg-1 at bedtime and 6.0 micrograms.kg-1 on the morning of surgery. Placebo-treated (control) patients received the same occlusive patch without active ingredient and oral placebo tablets at bedtime and on the morning of surgery. Preanesthetic medication included midazolam 50 micrograms.kg-1 intramuscularly (im). Anesthesia was induced with alfentanil 30 micrograms.kg-1 intravenously (iv). thiopental 3 mg.kg-1 iv. and vecuronium 0.1 mg.kg-1 iv. and was maintained with 70% nitrous oxide in oxygen and a continuous infusion of alfentanil 0.5 microgram.kg-1.min-1. Isoflurane was added when the blood pressure exceeded 110% of the patient's prestudy value. For pain relief postoperatively. the patients received morphine. 1-2-mg iv boluses. via a patient-controlled analgesia pump. The low-dose clonidine patient group had mean plasma clonidine concentrations that varied from 1.47 ng.ml-1 (preoperative) to 1.32 ng.ml-1 (postoperative day 2).
Beneficial effect of upper thoracic epidural anesthesia in experimental hemorrhagic shock in dogs: influence of circulating catecholamines, The question as to whether reduction of plasma catecholamine concentration contributes to the beneficial effects of upper thoracic epidural anesthesia on survival during hemorrhagic shock was examined. Twenty-six dogs were anesthetized with halothane and nitrous oxide. and blood was withdrawn to reduce the mean arterial blood pressure (MAP) to 40 mmHg. The 12 dogs in group A received both upper thoracic epidural anesthesia before the hemorrhage and intravenous infusion of epinephrine (450 ng.kg-1.min-1) and norepinephrine (150 ng.kg-1.min-1) during hemorrhage. The 14 dogs in group B received none of these. At 20 min after the start of the bleeding. plasma catecholamine concentrations were increased in both groups more than ten-fold. There were no significant intergroup differences with respect to these concentrations at any point during the experimental period. During the 100-min period of hemorrhage. 1 of the 12 animals in group A and 10 of the 14 in group B died. A significant difference in survival was seen between the two groups over the 100-min hypotensive period (P less than 0.01 by the generalized Wilcoxon test). These results suggest that the survival benefit of upper thoracic epidural anesthesia cannot be explained simply by differences in the level of catecholamines in the plasma. and that perhaps differences in the level of catecholamines at the nerve endings or other factors may be more important.
Quantitation of abnormal 67Ga uptake in pulmonary interstitial vascular disease--a new test to detect diffuse lung disease, Gallium 67 has been used as a modality to diagnose and follow the clinical course of diseases such as tumors. infections. inflammatory disorders. and interstitial lung disease. It has been appreciated. however. that mild to moderate changes in scan activity. when these disorders are followed over time. are less than optimal. SPECT (single-photon emission computed tomography) scanning is a new technique designed to obviate this problem. SPECT scanning utilizes computer acquisition to provide three-dimensional scanning and the additional benefit of colorization to aid in discerning differences of uptake. SPECT scanning was performed on 22 patients with interstitial lung disease of various etiologies. Additionally. 7 patients had follow-up SPECT scanning to determine their response to treatment. Two patients are presented as examples.
Active drainage of cardiac lymph in relation to reduction in size of myocardial infarction: an experimental study, Active drainage of cardiac lymph using hyaluronidase was attempted in dogs. The results were satisfactory and the ischemic myocardium was salvaged. The infarct risk area (I/R) ratio decreased after drainage. Regional myocardial ischemia and infarction were provided by means of ligature of the left coronary artery for 120 and 240 minutes respectively. Cardiac lymph was collected by conventional procedures. Enzymes released from the myocardium increased significantly in the cardiac lymph. The volume of cardiac lymph gradually increased after ligature of the coronary artery. Administration of hyaluronidase further increased the cardiac lymph flow and significantly decreased the I/R ratio as determined by triphenyl tetrazolium chloride (TTC) and methylene blue staining. Drainage of the cardiac lymph salvaged the ischemic myocardium. Reduction of interstitial edema and augmentation of cardiac lymph flow with the hyaluronidase prevented the development of the infarction. This is the first documentation of the effect of active drainage of cardiac lymph on the development of infarction through observation of the I/R ratio.
Therapy of ischemic cardiomyopathy with pentoxifylline, Abnormal blood rheology is a known characteristics of coronary artery disease. The authors evaluated the effects of pentoxifylline on the exercise capacity ejection fraction and symptoms of 9 patients with ischemic cardiomyopathy. All patients had signs and symptoms of left ventricular dysfunction. All had at least two major vessels obstructed as determined by coronary angiography. Pentoxifylline 400 mg three times daily was administered for twelve weeks. Seven of 9 patients responded with increases in ejection fraction and exercise tolerance. Exercise tolerance correlated with improvement or lack of improvement in ejection fraction. For all patients at twelve weeks post-therapy mean ejection fraction increased 9.8% over baseline (p = .07). total treadmill time increased 15% (p = .27). and mean double product increased 13% (p = .03). Anginal symptoms were significantly improved over baseline at twelve weeks of therapy (p greater than .001). as well as dyspnea on exertion (p = .03). Pentoxifylline was well tolerated. Pentoxifylline may benefit ischemic cardiomyopathy by improving coronary perfusion owing to favorable alterations in hemorheologic properties.
Microcirculation and hemorheology in NIDDM patients, The authors studied 10 patients with non-insulin-dependent diabetes mellitus and 5 controls matched for age. sex. blood lipids. and smoking habit. The two groups were also comparable for hemorheologic characteristics as evaluated by viscosimetry on whole blood. plasma and serum. erythrocyte filtration and aggregation. The microcirculation was studied in the subjects of both groups by microalbuminuria determination. retinal fluorangiography. and capillaroscopic examination of the bulbar conjunctive and nail folds. None of the patients presented microalbuminuria values higher than the upper limit of normal (20mg/24h). Fluoroangiographic alterations were observed in 4 patients. and all 10 presented capillaroscopic alterations at the bulbar conjunctiva (microaneurysms. erythrocyte aggregates) and nail folds (more frequently of the fingers than toes). Similar alterations were detected in controls. Thus these abnormalities seem independent of hemorheologic values.
The effect of dopexamine HCl upon collateral perfusion of the acutely ischemic myocardium in anesthetized dogs, The effects of low-dose (10(-9) and 3 x 10(-9) mole/kg/min) infusions of dopexamine HCl. a new synthetic catecholamine with beta 2-adrenergic and DA1-dopaminergic agonostic actions. was tested in anesthetized dogs. with and without acute ligation of the left anterior descending coronary artery. The infusions caused diastolic arterial blood pressure to fall by 12 +/- 4 and 23 +/- 5 mmHg. respectively. Microsphere-estimated collateral blood flow to the ischemic myocardium did not change significantly during the drug infusions. The findings suggest that low doses of dopexamine HCl do not cause coronary "steal" from acutely ischemic myocardium.
Aortic dissection with a fistulous communication into the right atrium: a case report, A case of aortic dissection (type 1. De Bakey) with a rent into the right atrium (RA). diagnosed by echocardiography (echo) and confirmed by aortography. is reported. The patient presented with cardiac failure and a continuous murmur in the right second and third intercostal spaces. The patient has survived for two years with medial treatment.
Ventilation and gas exchange during exercise in sickle cell anemia, Adults with sickle cell anemia (SCA) have restrictive lung impairment. increased alveolar dead space. and hypoxemia. These factors. together with increased anaerobic metabolism. are thought to cause exercise hyperventilation. To assess the role of each of these in children. 34 patients with SCA and 16 control subjects performed pulmonary function and exercise tests. Twenty-eight patients with SCA had spirometric values and lung volumes. and all but two patients with SCA had arterial saturation greater than 91% during exercise. Despite a low VO2max (30.07 +/- 6.55 ml/min/kg). the ventilatory anaerobic threshold (VAT) in the patients occurred at a similar %VO2max as in the control subjects (69 +/- 9% versus 63 +/- 12%). The slope of the delta VE/delta VCO2 relationship for sub-VAT work was steeper in the patients (29.4 +/- 6.5 versus 24.7 +/- 5.2. p = 0.01). and the ventilatory equivalent for CO2 (VE/VCO2) in steady-state exercise was greater in the patients than in the control subjects (33.2 +/- 3.5 versus 30.8 +/- 3.5. p = 0.03). End-tidal PCO2 did not differ (38.3 +/- 3.0 versus 39.2 +/- 3.1). indicating equivalent alveolar ventilation. The patients had a higher dead space:tidal volume ratio (VD/VT) than did the control subjects (0.204 +/- 0.033 versus 0.173 +/- 0.024. p = 0.0005). The PaCO2 was significantly lower in those with lower Hb. but there was no difference in pH. In conclusion. children with SCA have an increased exercise ventilatory response caused in part by increased physiologic dead space. and in part by their low Hb. The greater dead space may be the result of sickle cells impairing capillary perfusion to ventilated alveoli.
Cardiac output and oxygen delivery during exercise in sickle cell anemia, Desaturation in patients with sickle cell anemia (SCA) can lead to intravascular sickling and vascular occlusion. The increased metabolic demands of exercise tend to increase oxygen extraction. giving rise to a fall in saturation in the capillary bed that may predispose to sickling. This could be minimized with an increase in cardiac output. The aims of this study were to assess the role of increased stroke volume (SV) in augmenting cardiac output (Q) and to estimate the role of enlarged arteriovenous O2 content difference in maintaining O2 transport in children with SCA. A group of 30 children with SCA (Hb 65 to 133 g/L) and 16 healthy controls of the same racial group and of similar height and weight performed incremental and steady-state exercise at 50% Wmax. Cardiac output (Q) was measured by the indirect (CO2) Fick method during steady state. The slope of delta HR/delta VO2 during incremental exercise was higher in SCA subjects compared with controls (4.01 +/- 1.73 versus 2.80 +/- 0.61 bpm per ml/min/kg VO2. p = 0.001). Q for VO2 was abnormally high in patients. particularly older ones with lower Hb levels. HR (% predicted) was higher in patients than in controls (106 +/- 11 versus 92 +/- 8% predicted. p less than 0.0001). as was SV (113 +/- 16 versus 98 +/- 14% predicted. p = 0.002). Multiple linear regression of Q % predicted and SV % predicted on Hb and age showed a positive correlation with age and a negative correlation with Hb (r = 0.84 for Q and r = 0.76 for SV).
Closure of the ductus arteriosus with indomethacin in ventilated neonates with respiratory distress syndrome. Effects of pulmonary compliance and ventilation, The reported effects of indomethacin on pulmonary compliance are variable depending upon the patient population and on the degree to which indomethacin resulted in successful ductal closure. Eleven fluid-restricted. furosemide-treated premature infants being mechanically ventilated for respiratory distress syndrome (RDS) who also had a significant patent ductus arteriosus (PDA) had pulmonary function testing performed before and after successful closure of the PDA. The diagnosis of a significant PDA was made by clinical and echocardiographic criteria. Indomethacin was administered at a dosage of 0.2 mg/kg/dose every 12 to 18 h for 1 to 3 doses. To control for the 48-h time interval to achieve ductal closure. nine premature infants being ventilated for RDS but who did not have a significant PDA also had pulmonary function evaluations performed before and after the 48 h. Also. to control for the independent effect of fluid restriction and diuretic therapy on pulmonary compliance. eight such premature infants with a PDA had pulmonary function evaluations performed at a 48-h interval. Successful closure of the ductus with indomethacin was associated with an improvement in compliance and ventilation parameters in all infants in the indomethacin-treated infants. In the indomethacin-treated group. the mean percent improvements were noted in the following parameters: CLdyn. 59.2%; CLI. 78.3%; CLE. 63.3%; VT. 63.3%; VE. 54.6%. There were no significant changes in the pulmonary functions in the 48-h RDS or the 48-h PDA fluid-restricted. furosemide-treated control groups. In conclusion. successful closure of the ductus with indomethacin causes a significant improvement in compliance and ventilation parameters in infants being mechanically ventilated for RDS.
An outbreak of tuberculosis in a shelter for homeless men. A description of its evolution and control, An outbreak of tuberculosis at a shelter for homeless men was studied in detail to further the understanding of the epidemiology of tuberculosis in this setting. The shelter provides evening accommodations for men aged 50 yr and older. The capacity is approximately 200 clients. and the client pool is approximately 1.000 men/yr. During a 6-wk period in December 1986 and January 1987. seven cases of tuberculosis were diagnosed in shelter clients. Nine cases were reported in clients during the preceding 12 months. and four cases in the year previous to that. The majority of outbreak cases were pulmonary tuberculosis. sputum smear positive. Drug resistance was rare. Phage typing of 15 Mycobacterium tuberculosis isolates revealed one predominant type and four other types. The goals of the control plan (and the steps taken to achieve them) were to render known infectious cases noninfectious (directly observed therapy); to find undiagnosed infectious cases (repetitive mass screenings); to protect exposed clients (repetitive tuberculin skin testing and isoniazid preventive therapy); and to make the shelter environment safe (exclude infectious. noncompliant clients and improve the shelter's ventilation system). Implementation of this plan rapidly terminated the outbreak; following the first mass screening in January 1987. at which six asymptomatic cases were detected. only five additional cases occurred in shelter clients during a 2-yr period of follow-up. The investigation suggested that the outbreak evolved during 1986 as a result of the presence at the shelter of an increasing number of men with undiagnosed infectious pulmonary tuberculosis.
Immunoglobulin G antineutrophil cytoplasmic antibodies are produced in the respiratory tract of patients with Wegener's granulomatosis, Wegener's granulomatosis (WG) is a small-vessel vasculitis of unknown etiology that usually involves the upper and lower respiratory tract and the kidneys. Recently. an association has been made between the presence of serum antineutrophil cytoplasmic antibodies (ANCA) and WG. Because WG frequently involves the lung. we sought to evaluate bronchoalveolar lavage (BAL) fluids obtained from 14 patients with WG for the presence of ANCA. Immunoglobulin (Ig) G ANCA was found in the BAL with the same staining patterns as observed in the serum. Patients with active disease had the highest serum and BAL IgG ANCA titers. IgA or IgM ANCA was not detected in the serum or BAL of these patients. Protein analysis of BAL fluid revealed that patients with active. untreated WG had approximately a fourfold elevation in total protein (41.3 versus 10.5 mg/dl). with a disproportionately greater increase in the ratio of IgG to albumin (BAL IgG index = 1.49. normal = 0.74; p = 0.027). The increase of the IgG index in patients with active WG suggests that local production of IgG ANCA occurs in the lungs.
Size distribution of human lung elastin-derived peptide antigens generated in vitro and in vivo, The protease-antiprotease hypothesis of emphysema development suggests that degradation of elastin in the lung interstitium may give rise to abnormal quantities of circulating elastin-derived peptides (EDP) during periods of inflammation. Recent studies have shown a relationship between emphysema and high levels of EDP in human plasma. This report characterizes elastin digests on the basis of antigenicity. size. and method of preparation. as well as the size distribution of EDP found in the plasmas of nonsmokers. smokers. and emphysema patients. Gel filtration of elastin digests prepared by hydrolysis of human lung elastin using a low (1:500) ratio of neutrophil elastase to elastin generated a broad protein peak of approximately 70.000 daltons. In contrast. a high (1:25) ratio of neutrophil elastase to human lung elastin gave a broad protein peak. with a size distribution in the 10.000 to 30.000 dalton range. This digest showed distinct immunochemical properties. A polyclonal antibody directed against the low-ratio digest showed a minimum detection of 2 ng/ml for the homologous antigen but required 1.000 ng/ml of the high-ratio digest for detectable inhibition in an indirect ELISA assay. Gel filtration of plasmas from normal nonsmokers and the majority of normal smokers revealed a single immunoreactive EDP fraction of approximately 70.000 daltons. Plasmas from selected normal smokers and emphysema patients with high levels of circulating EDP (greater than 90 ng/ml) fractionated into a complex pattern of peptides in which the 70.000 dalton component represented 50% of the immunoreactive material and several lower molecular weight peptides represented the remaining circulating elastin antigens.
A ten-year follow-up study of cotton textile workers, A follow-up study of respiratory function in cotton textile workers was performed 10 yr after the original cross-sectional study (1975 to 1985). There were 35 nonsmoking female and 31 smoking male textile workers restudied from the original group of 116. The majority of those lost to follow-up had left the industry. The prevalence of byssinosis among the female workers at the time of follow-up was 15/35 (42.9%) compared with 8/35 (22.9%) at the time of the initial study (p = 0.063). For men the byssinosis prevalence at follow-up was 16/31 (51.6%) compared with 8/31 (22.9%) at the time of the initial study (p = 0.03). Similarly. the prevalence of almost all other respiratory symptoms was significantly higher at the follow-up than at the time of the initial study. Significant across-shift decrements in FEV1 and FVC were documented at both surveys. The mean annual decline in ventilatory capacity was greater than expected for both female (FVC: -0.036 +/- 0.005 L/yr; FEV1: -0.059 +/- 0.009 L/yr) and male workers (FVC: -0.059 +/- 0.008 L/yr; FEV1: -0.068 +/- 0.006 L/yr) (Mean +/- SE). The mean total airborne dust concentration measured at the time of the follow-up study was 3.95 mg/m3 with an average respirable dust concentration of 0.97 mg/m3. We conclude that continued exposure to high dust concentrations in the cotton textile industry is associated with an increasing prevalence of respiratory symptoms and progressive impairment of lung function. The increase in respiratory impairment was seen both in smokers and nonsmokers.
Relationship of respiratory symptoms and pulmonary function to tar, nicotine, and carbon monoxide yield of cigarettes, The data from consecutive surveys of the Tucson Epidemiologic Study (1981-1988) were used to evaluate the relationship in cigarette smokers of respiratory symptoms and pulmonary function to tar. nicotine. and carbon monoxide (CO) yields of the cigarette. There were 690 subjects who reported smoking regularly in at least one survey. over age 15. After adjustment for intensity and duration of smoking and for depth of inhalation. the risk of chronic phlegm. cough. and dyspnea were not related to the tar and nicotine yields. In 414 subjects with pulmonary function tested in at least one of the three surveys the spirometric indices used were significantly related to the daily dose of tar. nicotine. and CO (product of the cigarette yield and daily number of cigarettes smoked). The effects were more pronounced for past than for current doses. However. the differentiation of pulmonary function due to various yields of cigarettes was small in comparison to the difference in pulmonary function between smokers and nonsmokers.
Allergen-induced asthmatic responses. Relationship between increases in airway responsiveness and increases in circulating eosinophils, basophils, and their progenitors, The inflammatory response during allergen-induced asthma was assessed using serial measures of peripheral blood eosinophils (Eo). basophils (B). and Eo/B progenitor cells (Eo/B-CFU). A group of 14 stable asthmatic individuals (beta 2-agonists only as needed) had inhalation provocation tests with allergen (18 tests in total) and with diluent. Serial blood samples were taken before and 1 and 24 h after the tests; methylcellulose cultures for Eo/B-CFU and granulocyte-macrophage (GM-CFU) were scored at 14 days. Circulating Eo. B. and Eo/B-CFU were increased at 24 h after allergen inhalation when this resulted in increased histamine airway responsiveness (n = 13). In the 5 subjects with isolated early asthmatic responses the Eo. B. and Eo/B-CFU counts did not change. There was no change in the GM-CFU after allergen. The ratio change in circulating Eo/B-CFU was negatively correlated with baseline histamine airway responsiveness (r = -0.8. p less than 0.05). Four subjects who had an isolated early response and no blood changes to one allergen developed an increase in histamine airway responsiveness and an increase in Eo. B. and Eo/B progenitors after inhalation of a second different allergen. The results indicate that in subjects with an allergen-induced increase in histamine airway responsiveness. an inflammatory response occurs that includes an increase in the number of Eo/B progenitors. This response. possibly mediated by Eo/B growth and differentiation factors. could lead to the accumulation of these cells in the airway and contribute to the airways inflammation present in asthma.
Asthma in the elderly. A comparison between patients with recently acquired and long-standing disease, To characterize asthma in the elderly. 25 consecutive nonsmoking pulmonary clinic patients over the age of 70 who met the American Thoracic Society criteria for asthma were identified. Of these. 12 patients (48%) had developed asthma at an advanced age (greater than 65 yr). This group with late-onset asthma had a mean duration of disease of 5.1 +/- 2.5 yr. The remaining group with early-onset asthma had a mean duration of illness of 31.4 +/- 14.6 yr. On the day of evaluation each patient underwent pulmonary function testing off all medication for at least 12 h. These two groups were indistinguishable by symptoms and medication requirements. Immediate hypersensitivity skin testing to 43 aeroallergens was uniformly negative in all 25 patients but the histamine control was always positive. IgE levels in both groups were not different from those in elderly control subjects. Those with early-onset asthma had a greater likelihood of previous allergic disease (p less than 0.001) and a significantly greater degree of airflow obstruction in pre- and postbronchodilator pulmonary function testing (p less than 0.05). This study suggests that long-standing asthma may lead to chronic persistent airflow obstruction and thereby mimic chronic bronchitis and emphysema (COPD).
Inhalation of an alkaline aerosol by subjects with mild asthma does not result in bronchoconstriction, Although it is recognized that inhalation of acid aerosols by subjects with asthma can cause bronchoconstriction. the effects of the inhalation of an alkaline aerosol are unknown. When supplemental inflatable restraints (automobile air bags) are deployed an alkaline aerosol is released. This aerosol is composed of particles of sodium carbonate and sodium bicarbonate with some sodium hydroxide. The mass median aerodynamic diameter (MMAD) of the aerosol is approximately 1 micron. and the pH of the aerosol is 9.8 to 10.3. A group of 14 volunteer male subjects with mild asthma inhaled increasing concentrations of this aerosol for 20-min periods of mouth-only tidal ventilation. Pulmonary function tests were performed at baseline (preexposure). after inhalation of room air alone (control). and after each period of inhalation of the aerosol. A total of 5 subjects inhaled aerosols at nominal concentrations of 10. 20. and 40 mg/m3. whereas 11 subjects inhaled aerosols concentrations of approximately 30. 60. and 120 mg/m3. The mean changes in FEV1 and specific airways resistance (SRaw) for the 11 subjects who inhaled the higher concentrations (average highest concentration 126.6 +/- 7.5 mg/m3. mean +/- SEM) were -1.4 +/- 1.9 and +17.5 +/- 8.5%. respectively. Neither change in lung function was clinically or statistically significant. We conclude that the inhalation of relatively high concentrations of this alkaline aerosol by subjects with mild asthma does not result in bronchoconstriction.
Protective effect of theophylline on bronchial hyperresponsiveness in patients with allergic rhinitis, Disorders of the upper respiratory tract. particularly allergic rhinitis are commonly associated with bronchial hyperresponsiveness. The latter may be responsible for chronic cough. a common symptom in patients with allergic rhinitis. which. as previously shown. can be the sole presenting manifestation of bronchial hyperresponsiveness. Theophylline is widely used in patients with asthma for its bronchodilator effect. whereas its action on bronchial reactivity is controversial. The aim of this study was to determine the effect of theophylline administration on bronchial hyperresponsiveness in patients with allergic rhinitis complaining of chronic cough. Fourteen patients were studied. All of them were judged atopic on the basis of positive skin tests to common allergens. During control. spirometry. flow-volume curves and specific airway conductance (SGaw) were measured. Bronchial challenges were then performed with increasing concentrations of carbachol. and dose-response curves were constructed. The concentration of carbachol. which decreased SGaw by 35% from baseline (PD35) was determined by interpolating from the dose-response curve. After control measurements patients received in a randomized. double-blind crossover fashion either theophylline 10 mg/kg/day orally or placebo for 30 days. Measurements were then redone. After a washout period of 8 days the measurements were repeated. and patients received theophylline or placebo for a second period of 30 days. Measurements were again performed at the end of this last study period. During control all patients had normal baseline lung function data and showed marked bronchial hyperresponsiveness. PD35 amounting to 26 +/- 7 micrograms of carbachol (normal value greater than 160 micrograms). No significant changes in PD35 were noted after placebo and washout when compared with control values.
Bronchial hyperresponsiveness in normal subjects during attenuated influenza virus infection, Fourteen healthy male subjects with hemagglutination-inhibition antibody titers of 1:8 or less to homologous influenza A virus were studied. Six subjects received live. attenuated influenza virus by nasal drops and by aerosol. Although infection occurred in these six subjects. with the development of 4-fold or greater increases in hemagglutination-inhibition antibody titers. they remained asymptomatic. Eight subjects received placebo via the same route. and did not develop symptoms and showed no increase in antibody titer. Prior to administration of virus or placebo. histamine diphosphate aerosol increased airway resistance only slightly. and there was no difference between the virus and placebo groups. Two days after inoculation. bronchomotor responses in the placebo group were unchanged (p greater than 0.05). but in the virus-infected group. bronchomotor responses were significantly greater than in the preinfected state (p less than 0.01). Isoproterenol hydrochloride reversed and prevented the increase in airway resistance after histamine. suggesting that the bronchoconstriction was caused by smooth muscle contraction. Our findings indicate that transient. asymptomatic respiratory virus infection augments airway smooth muscle responses.
Respiratory membrane permeability and bronchial hyperreactivity in patients with stable asthma. Effects of therapy with inhaled steroids, In patients with stable asthma. we assayed plasma proteins in the bronchoalveolar lavage fluid to obtain information on plasma exudation into the airways. Fourteen nonsmoking patients with asthma who were in a stable period of their disease and eight nonsmoking healthy volunteers were studied. The ratios of the concentrations of albumin. ceruloplasmin (CP). and alpha-2-macroglobulin (A2M) between blood and epithelial lining fluid were calculated (cQalb. cQCP. and cQA2M). The cQalb was increased in the patients (Mann-Whitney U test. p less than 0.05). In 10 patients the bronchial hyperreactivity was assessed with histamine provocation tests. Significant relationships between the cQalb. cQCP. and cQA2M on the one hand and PC15 on the other hand were found (Spearman's rank correlation: r = -0.62. p less than 0.05; r = -0.61. p less than 0.05; r = -0.79. p less than 0.01. respectively). Fourteen patients were treated with two inhalations of 200 micrograms glucocorticosteroids per day in a 3-month prospective study. Three of them were excluded from further study because of an intercurrent exacerbation of asthmatic symptoms during therapy. In the 11 patients with stable asthma. the cQalb and cQA2M decreased after treatment with inhaled steroids (Wilcoxon's matched pairs signed rank test. p less than 0.03). Our results show that in patients with stable asthma. there is an increased plasma exudation into the airways. most likely caused by an increased respiratory membrane permeability. The plasma exudation correlated with the bronchial hyperreactivity to histamine. and it decreased after corticosteroid therapy.
Lymphokine-induced airway hyperresponsiveness in the rat, We evaluated the potential role of the lymphocyte in chronic airway inflammation and responsiveness by repeated administration to rats of interleukin-2 (IL-2). the principal lymphokine responsible for lymphocyte proliferation. Lewis rats (mean weight. 184 +/- 2 g) received either 120.000 units of IL-2 (n = 10) or vehicle (n = 7) subcutaneously twice a day for 4.5 days. Animals were anesthetized with urethane and intubated for measurements of pulmonary resistance (RL) and airway responsiveness to aerosol methacholine (MCh). Lung lavage was performed. the animals were exsanguinated. and the lungs were fixed in 10% formalin. Histologic edema and the extent of infiltration of the bronchi. pulmonary veins. and arteries by cells was scored blindly. IL-2 increased airway responsiveness to MCh; the concentrations of MCh causing a doubling of RL were 0.14 versus 1.39 mg/ml (geometric mean) for the IL-2 and vehicle group. respectively (p = 0.001). IL-2 significantly increased total cellular return and the percentage of lymphocytes. neutrophils. and eosinophils in lavage. IL-2 caused edema and a mixed cellular infiltration of the bronchovascular tree. Lymphocytes predominated around the airways and veins. A correlation (r = 0.50) was present between airway responsiveness and airway inflammation but not with edema or vascular infiltration. Release of IL-2 by lymphocytes in the airways may be an important mediator of airway hyperresponsiveness.
Acute effects of interleukin-2 on lung mechanics and airway responsiveness in rats, We studied the acute effects of interleukin-2 (IL-2). the principal lymphokine responsible for lymphocyte proliferation. on lung mechanics and airway responsiveness to methacholine (MCh) in rats. Lewis (n = 12) and Fisher 344 (n = 13) rats were anesthetized and intubated. and intravenous and intra-arterial lines were inserted. IL-2 (750.000 U/kg) was infused intravenously over 2 to 4 min into seven Lewis and seven Fisher rats. and vehicle alone was administered to five Lewis and six Fisher rats. Blood pressure. heart rate. respiratory frequency (f). tidal volume (VT). minute ventilation (VE). and lung resistance (RL) were measured before and every 5 min for 45 min after the infusion of IL-2. Lung compliance was measured before and 30 min after IL-2. Bronchial provocation testing with MCh was performed 45 min after the infusion of IL-2. Subsequently. the animals were exsanguinated. and the lungs were removed for histologic examination. Infused IL-2 did not alter heart rate or blood pressure. VT. f. VE. and RL increased significantly by 15 min (p less than 0.05). but they returned to baseline by 45 min. Lung compliance decreased significantly in both rat strains. IL-2 increased airway responsiveness only in Lewis rats; the concentration of MCh that caused a doubling of RL (EC200RL) was 0.6 mg/ml and 4.3 mg/ml (p = 0.003) in IL-2-treated and control rats. respectively. The airway responsiveness did not change significantly in Fisher rats; EC200RL was 0.13 and 0.35 mg/ml for IL-2-treated and control rats. respectively (p = 0.09).
Morphometric analysis of the lung in bronchopulmonary dysplasia, We studied lung development in children with or without bronchopulmonary dysplasia (BPD) using light microscopic morphometry and thick lung sections stained for elastic fibers. One lung was obtained at autopsy from each of eight patients with BPD (ages. 2 to 28 months) and six children (ages. 5 days to 51 months) who died without lung disease. Patients with BPD demonstrated severe somatic growth retardation and had reduced lung volumes with abnormal lobar volume proportions. In the central bronchi mean volume proportion of glands and smooth muscle was increased in BPD. Bronchiolar density was also increased. but it tended to normalize with advancing age. Mean bronchiolar diameter was slightly smaller in BPD. and bronchiolar smooth muscle hypertrophy was a constant histologic feature. The most striking change. however. was noted in alveolar structure and development. Total alveolar number was severely decreased in patients with BPD compared with that in control subjects. and there was little evidence of compensatory alveolar development with increasing age. Lung internal surface area was correspondingly reduced. and mean linear intercept was increased. Sections stained for elastic tissue demonstrated in the patients with BPD a simplified acinar structure with thickened. tortuous. and irregularly distributed alveolar elastic fibers. We conclude that in severe. fatal BPD there is marked impairment of lung development with alveolar hypoplasia and reduced internal surface area. In addition. bronchial and bronchiolar smooth muscle hypertrophy and bronchial gland hyperplasia may be important contributing factors to airflow limitation.
Abnormalities in airway smooth muscle in fatal asthma. A comparison between trachea and bronchus, Tracheal smooth muscle from seven cases of fatal asthma demonstrated an increased contractile response to histamine. acetylcholine. and electrical stimulation of intrinsic cholinergic nerves; impaired relaxation to isoproterenol. and possibly theophylline. was also evident (1). Fourth generation bronchial spirals from the same patients were also studied. and these results were compared with those of the trachea and normal bronchi (n = 5). In contrast to trachea. contractile responses in asthmatic bronchi to acetylcholine. histamine. and cholinergic nerve stimulation were similar to those in control bronchi. The potency of isoprenaline (IC50) was reduced 9.4-fold (p less than 0.003). similar to trachea (4.5-fold). whereas theophylline responses were normal. The discrepant results obtained may reflect differences in the disease process. including rates of postmortem change. at the two anatomic sites.
Lack of evidence for beta-2 receptor selectivity: a study of metaproterenol, fenoterol, isoproterenol, and epinephrine in patients with asthma, In order to investigate the pharmacodynamic selectivity of a number of beta-receptor agonists currently used in asthma. we compared the pulmonary and extrapulmonary effects of repeated inhalations of epinephrine. fenoterol. isoproterenol. and metaproterenol in 12 patients with asthma in a randomized double-blind crossover study. The drugs were administered from metered-dose inhalers at 15-min intervals for five doses (total dose. 10 puffs of each compound). Measurements of heart rate. blood pressure. total electromechanical systole (as a measure of inotropic response). QTc interval. plasma potassium. and FEV1 were made 5 min after each dose and 30 min after the final dose. Fenoterol and metaproterenol had significantly greater inotropic. electrocardiographic. chronotropic. and hypokalemic effects than did both isoproterenol and epinephrine. There was no difference in the bronchodilating effect of metaproterenol. fenoterol. or isoproterenol although these agents caused a significantly greater increase in FEV1 than did epinephrine. The concept of increasing beta-2 selectivity for metaproterenol and fenoterol compared with isoproterenol are not supported in the clinical setting.
Urticaria pigmentosa. Systemic evaluation and successful treatment with topical steroids, Nine patients with adult-onset urticaria pigmentosa were studied for the incidence of extracutaneous mast cell involvement and the efficacy of potent topical corticosteroid therapy for cutaneous lesions. Seven of the nine patients had increased mast cells in the marrow biopsy specimens. and five patients had focal aggregates of mast cells. The bone scan was abnormal in one patient. Liver-spleen scans revealed a shift of colloid uptake from liver to spleen in four patients. No abnormal gastrointestinal tract roentgenograms were obtained. Urinary histamine metabolites correlated with nodular bone marrow involvement. but not with other parameters. Results of the psychoneurologic testing revealed significant deviation from the norm with a verbal memory deficit in all nine patients and abnormalities on the Minnesota Multiphasic Personality Inventory in four patients. All nine patients were treated with 0.05% betamethasone dipropionate ointment under occlusion over half of the body nightly for 6 weeks. Seven of nine patients treated responded with almost complete resolution of their lesions. Hypothalamic pituitary adrenal axis suppression was evaluated with intramuscular cosyntropin stimulation and metyrapone administration during treatment. Only two patients. both of whom used the medication improperly. developed transient abnormalities. Slow return of lesions was noted 6 months after completion of therapy. Remissions could be lengthened with single weekly applications of topical steroids. Systemic involvement is frequent in patients with cutaneous mast cell disease and it is best demonstrated by bone marrow biopsy. Mast cell lesions can be safely and effectively treated with topical steroids in motivated patients.
Capillary hemangiomas and treatment with the flash lamp-pumped pulsed dye laser, Strawberry. or capillary. hemangiomas are common vascular neoplasms. with an incidence of approximately 2.6% in neonates. They usually develop in the first few weeks of life. so that between 1 month and 1 year the incidence rises to between 8.7% and 10.1%. These lesions may grow quite large in the first year of life. and they may ulcerate or obstruct a vital organ or function. The great majority will spontaneously regress after the first year of life. Parents are often alarmed at the sight of these hemangiomas and need reassurance that the great majority will regress spontaneously. Treatments such as cryosurgery. irradiation. radium instillation. corticosteroid therapy. or surgical excision are often ineffective or cause significant morbidity. We describe 10 children with capillary hemangiomas treated with the flash lamp-pumped pulsed dye laser. The patients ranged in age from 7 weeks to 5.5 years at the beginning of laser therapy. The patients underwent 3.1 +/- 1 (mean +/- SD) laser treatments. with a mean regression of the lesions of 69.9% +/- 4.5%. All patients demonstrated some diminution in the size and color of their hemangiomas after the treatments. and there were no ill effects. such as ulceration. hemorrhage. infection. or scarring. There was no evidence of hyperpigmentation or hypopigmentation. Pulsed dye laser therapy should be considered as an option in the treatment of capillary hemangiomas. preferably prior to their full evolution. It is also a useful therapeutic approach in those hemangiomas that are slow to regress in older children.
Intercellular IgA dermatosis of childhood. Selective deposition of monomer IgA1 in the intercellular space of the epidermis, We describe a 7-year-old girl with recurrent pruritic vesiculopustular lesions involving the trunk. extremities. face. and oral mucosa. Histopathologic examination revealed intraepidermal bullae containing neutrophils and eosinophils. and direct immunofluorescence test showed the deposition of IgA in the intercellular space of the epidermis. Circulating IgA anti-intercellular antibodies were also detected by indirect immunofluorescence test. Immunofluorescence studies using monoclonal antibodies to human IgA subclasses showed that these IgA antibodies belonged to IgA1. Antisera against J chain and secretory component did not show any specific intercellular staining. Surface IgA(+)-B cells were transiently increased in the peripheral blood during the active stage of the disease. These results indicated the extragut origin of these IgA antibodies. Dapsone therapy was shown to be very effective.
Intralesional bleomycin sulfate therapy for warts. A novel bifurcated needle puncture technique, A multiple puncture technique using a bifurcated vaccination needle to introduce bleomycin sulfate (1 U/mL sterile saline solution) into warts resulted in elimination of 92% of a random series of 258 warts after a single treatment. Recurrence was not observed during a 6-month follow-up period. Six of the 66 patients required two to seven treatments for wart eradication. and four patients requested alternative therapy after initial failure with a single bleomycin treatment.
Telephone use to elicit voice or speech in brain injured subjects, The initiation of speech is often delayed in the early stages of recovery from a serious brain injury. We have found a high percentage of patients with both speech and swallowing problems. This makes bedside assessment of swallowing safety difficult because one cannot listen for the sound of aspirated material on the vocal cords when a patient is at high risk for silent aspiration and is often unable to cooperate with a videofluoroscopic study. The use of the telephone has been described several times for aphasia treatment. but not to elicit speech or assess swallowing safety early after brain injury. This study. therefore. recruited subjects who had brain injuries and (1) were referred early for swallowing and other evaluations. (2) were out of coma and able to follow some commands. and (3) did not initiate voice or speak when asked to. Subjects were asked three questions under two different conditions: face to face and after ringing the telephone from another room. The results were recorded on videotape and analyzed by another investigator for quantifiable differences. Six of the seven subjects responded better with the telephone stimulus than without. This technique may elicit voice or speech early after brain injury in some patients and may be useful in bedside assessment of swallowing safety. It may also serve as an example of appropriate stimulation of brain injured subjects coming out of coma.
The disabled driver: an unmet challenge, A survey was undertaken to determine if driving impairment secondary to a disabling injury is addressed in state licensing laws and training programs. In 35 states drivers submit voluntarily to reevaluation after disabling injuries. but no provision is made for reporting such individuals. Only 15 states authorize physicians to report impaired drivers. and only seven require such reporting. Based on a survey of licensing bureaus in the capital or a major city of every state. clerks (who are likely to be the source of information to injured persons) are generally not aware of reporting requirements and supervisors are only slightly better informed. Of the 100 rehabilitation centers surveyed. only 36 provided on-site training for disabled drivers. Voluntary submission for reevaluation after head injury does not often occur. Despite being asked to do so. none of the 35 head injured patients. followed up to two years post-onset. sought reevaluation. although 21 had resumed regular driving. Two of the 21 were involved in subsequent traffic accidents. Common guidelines need to be established across states to ensure reevaluation of individuals with disabling conditions. delivery of accurate information concerning licensing. and availability of training programs.
Spinal cord injury: prognosis for ambulation based on sensory examination in patients who are initially motor complete, The purpose of this retrospective study was to document that patients with motor complete injury. but preserved pin appreciation. in addition to light touch. below the zone of injury have better prognoses with regard to ambulation than patients with only light touch preserved. Medical records were examined of all spinal cord injury (SCI) patients admitted between 1982 and 1988. Twenty-seven Frankel B patients with upper motor neuron lesions admitted within 72 hours of injury were identified. These patients were divided into two groups (B-1 and B-2). Group B-1 (n = 18) were patients who had touch sensation but no pin appreciation below the zone of injury. Group B-2 (n = 9) were patients who had partial or complete pin appreciation and light touch below the zone of injury. The charts were examined for the patient's ability to walk independently using a reciprocal gait for at least 200 feet. The data were analyzed by the Fisher Exact test. Eight of the nine Group B-2 patients ambulated as compared to two of the 18 Group B-1 patients (p less than .0002). Frankel B SCI patients with only touch preserved below the zone of injury had poor prognoses for ambulation; those with preserved pin appreciation below the zone of injury had excellent prognoses to regain functional ambulation.
Costs of operating a supported work program for traumatically brain-injured individuals, This paper presents a preliminary analysis of costs associated with a return-to-work program emphasizing a supported employment approach for persons who had sustained severe traumatic brain injuries. This analysis spans almost three years. Results indicated that a mean of 237.8 hours of staff intervention time was required to achieve job stabilization. at a cost of +6896. Ongoing follow-along and support services averaged 1.64 hours per week at a cost of +47.56. Over 68% of total staff time and costs were expended in job-site training and advocacy efforts. Application of these findings to state-level and agency-level policies should be weighed against individual characteristics and needs of clients. program design. and outcomes which clients achieve as a result of services.
Reversible nerve conduction block in patients with polyneuropathy after ultrasound thermotherapy at therapeutic dosage, This study investigated the effect of ultrasound on nerve conduction in patients with polyneuropathy. Eight able-bodied controls (Group C) and 16 patients with clinical and physiologic evidence of polyneuropathy were tested. Eight patients (Group NP) had no aching pain symptoms; eight patients (Group P) had severe aching pain. burning sensation. unpleasant tingling. and/or hyperesthesia in the lower extremities. For two minutes. therapeutic ultrasound in doses of 0.5. 1.0. and 1.5W/cm2 were applied over the anterior surface of the leg along the pathway of the deep peroneal nerve. Peroneal nerve conduction studies were performed before. during. and after ultrasound treatment. The compound muscle action potential (CMAP) was recorded from the extensor digitorum brevis muscle. Nerve conduction studies on all eight patients in Group P revealed a significant decrease (41.4% and 44% reduced for doses of 1.0W/cm2 and 1.5W/cm2. respectively; p less than .05) in amplitude of CMAP (from baseline to the first negative peak). and an increase (6.4% and 6.7% increased for doses of 1.0W/cm2 and 1.5W/cm2. respectively; p less than .05) in proximal latency one minute after ultrasound application with a dose of 1.0 or 1.5W/cm2. but not with a dose of 0.5W/cm2 (p greater than 0.1). Changes returned to pretreatment values within five minutes of cessation of ultrasound therapy. In Groups C and NP. there were no significant changes in amplitudes of CMAP or proximal latency before. during. or after ultrasound therapy at a dose of 0.5. 1.0. or 1.5W/cm2. It was concluded that ultrasonic therapy with therapeutic dosage may cause a reversible conduction block on patients with painful polyneuropathy.
Goal attainment scaling and outcome measurement in postacute brain injury rehabilitation, Relationships among two-month and final goal attainment scaling (GAS) scores. preadmission and final Portland Adaptability Inventory (PAI) scores. and work outcome for 16 graduates of a comprehensive. postacute brain injury rehabilitation program were examined. Final GAS scores were higher for program graduates who obtained the most desirable work outcomes. and preadmission and final PAI scores were lower for the successful program graduates. Final GAS scores were significantly correlated with other outcome measures. Preadmission PAI scores predicted work outcome. and two-month GAS scores predicted final GAS scores. Initial PAI scores distinguished between program successes and failures. but not between program successes and dropouts. A brief look at one case illustrates the modified application of GAS in postacute brain injury rehabilitation. Results of this study and case analyses support GAS as a quantifiable. individualized measure that is useful for (1) monitoring patient progress. (2) structuring team conferences. (3) ongoing rehabilitation planning and decision-making. (4) concise. relevant communication to family. referral sources. and funding sources. and (5) overall program evaluation when used in the context of other objective outcome measures. Although our results support the clinical utility of GAS. further study is recommended to assess the psychometric characteristics of GAS in this application.
Factors predicting satisfactory home care after stroke, This study prospectively investigated factors predicting optimal poststroke home care. One hundred and thirty-five first occurrence stroke patients and their primary support persons were evaluated during the initial hospitalization after stroke and again one year poststroke. Discriminant function analysis was used to identify two groups from the baseline data: home care situations which were rated optimal and those which were not. Group membership was predicted and validated with 72.6% accuracy. Patients at risk for less than optimal home care had caregivers who were (1) more likely to be depressed. (2) less likely to be married to the patient. (3) below average in knowledge about stroke care. and (4) reporting more family dysfunction. Our findings suggest that caregiver-related problems can have a collective effect on rehabilitation outcome and that treatment should reduce caregiver depression. minimize family dysfunction. and increase the family's knowledge about stroke care.
Memory retraining to support educational reintegration, A memory retraining package specifically designed to facilitate reintegration of head injured patients into an educational environment is described. Two adolescent patients who had severe head injuries were administered the memory retraining package approximately three months postinjury. A single case study and multiple baseline design was used to evaluate the efficacy of the memory retraining program. The results suggested that this is a promising avenue for improving memory functioning and facilitating educational reintegration. but only where moderate rather than severe memory deficits are involved. Studies involving groups of patients and the collection of data on generalization are required to confirm usefulness.
Visual illusions in a patient with lateral medullary syndrome, The disturbance of visual perception associated with nystagmus is a rare phenomenon. This is a case of a 61-year-old woman who developed progressive right hemisensory deficit. left facial sensory deficit. vertigo. staggering to the left. left ptosis. vertical diplopia. and ataxia of the left upper extremity. She had rotatory nystagmus in primary position. which increased in amplitude with left gaze. The above signs and symptoms were consistent with lateral medullary syndrome. During her rehabilitation. the patient complained of visual disturbances typical of oscillopsia. These disturbances. or illusions. are compensatory mechanisms for nystagmus and its resultant retinal error. The purpose of this case presentation was to study the pathophysiology underlying oscillopsia in patients with nystagmus and to stimulate awareness of such visual disturbances in stroke patients.
Chronologic age, time since injury, and time of measurement: effect on adjustment after spinal cord injury, People are now living longer after spinal cord injury (SCI). yet only limited research has addressed the issue of aging and adjustment after SCI. The purpose of this study was to use a time-sequential design to identify the relationship between adjustment after SCI and three facets of aging; chronologic age. time since injury. and time of measurement. Life Situation Questionnaires were obtained from one sample of participants with SCI in 1974 (n = 256) and from a second sample in 1985 (n = 193). Participants were grouped into five cohorts based on chronologic age. five cohorts based on time since injury. and two groups based on time of measurement (1974. 1985). Two two-way MANOVA's were performed. one between chronologic age and time of measurement. and the other between time since injury and time of measurement. Results indicated that chronologic age and time since injury often worked in opposing directions; as some aspects of adjustment declined with greater chronologic age. but other aspects improved with increasing time since injury. Activity was strongly related to chronologic age. but medical stability was more strongly related to time since injury. Both chronologic age and time since injury were correlated with some aspects of life satisfaction. Comparisons between the two times of measurement (1974. 1985) indicated some limited positive changes in adjustment with time. The results point to the complexity of the relationship between aging and adjustment and the need for rehabilitation professionals to consider multiple aging factors.
Quantitation of DNA ploidy in squamous intraepithelial neoplasia of the laryngeal glottis, The DNA contents in 56 laryngeal glottic biopsy specimens with a spectrum of squamous intraepithelial neoplastic (SIN) changes were evaluated by image analysis. A combination of DNA histogram features were used to define abnormal DNA-containing cell populations that were interpreted as representing intraepithelial neoplastic transformation. Eighteen biopsy specimens were classified as dysplasia/keratosis and graded SIN I. six (33%) of which were aneuploid. Eighteen (78%) of 23 biopsy specimens graded SIN II were aneuploid. and all 15 biopsy specimens graded SIN III had abnormal quantities of nuclear DNA. Twelve biopsy specimens (six of SIN II grade and six of SIN III grade) were considered to represent keratinizing forms of dysplasia. and all 12 (100%) were found to contain increased (aneuploid) quantities of DNA. We conclude that the proposed SIN-grading scheme for laryngeal epithelial abnormalities exhibits strong correlations with nuclear DNA content. In addition. aneuploidy was observed in all SIN II- and SIN III-graded biopsy specimens with prominent keratinization.
Histopathology of metastatic temporal bone tumors, Temporal bone metastasis is now being reported with increasing frequency. To understand the process of temporal bone metastasis. complete histologic evaluation of the temporal bones is essential. In this study. 60 temporal bones from 33 patients were evaluated. Different patterns of temporal bone involvement were noted depending on the mode of spread to the temporal bone. Involvement of the temporal bone usually occurs late in the disease process and is often asymptomatic.
Role of prophylactic antibiotics in uncontaminated neck dissections, The use of perioperative prophylactic antibiotics in uncontaminated head and neck surgery remains controversial. We performed a retrospective analysis of 192 patients undergoing uncontaminated neck dissections from 1976 to 1989. Wound infection developed in 10% (10/99) of patients who did not receive antibiotics. while only three (3.3%) of 93 patients who received antibiotics developed infections. This difference was not statistically significant. We correlated the use of flaps. length of surgery. prior radiation treatment. and postoperative complications with rate of wound infection. The difference was not statistically significant for any of these variables. Our beta error was. however. greater than 0.2. Our data do not demonstrate efficacy of prophylactic antibiotics in uncontaminated neck dissections with statistical significance; however. a trend exists suggesting its possible value.
Effectiveness of radiotherapy with radical neck dissection in cancers of the head and neck, A retrospective analysis of 457 radical neck dissections performed over a 30-year period for cancers of the oral cavity. pharynx. and larynx was carried out. Two hundred thirteen patients underwent radiotherapy to the primary cancer site and/or to the neck. Of these. 164 underwent perioperative adjuvant radiotherapy and 24 underwent definitive radiation for cure and were followed up by salvage surgery. Thus. 188 patients received radiotherapy for nonrecurrent disease. Twenty-five additional patients underwent radiation for surgical failure following radical neck dissection. The goal of the study was to determine whether radiotherapy altered the course or end result of the disease. The T and N stage at onset of disease was similar for the radiotherapy and nonradiotherapy groups. Preoperative radiotherapy was effective in down staging the disease at the primary site and. to a lesser extent. in the lymph nodes. but had limited impact on survival. Failure to control the disease in the neck occurred in 60 (32%) of the 188 patients who received radiotherapy for primary disease; recurrence rates were lower in the combined therapy group than in the surgical group of patients with N2 and N3 stages of disease. The 3-year disease-free survival was 45%; this was no better than the 63% survival rate in patients who did not receive radiotherapy. although survival was better in the combined therapy group for patients with N3 stage of disease. The worst results were in those patients who were irradiated for surgical failure (14% survival); the 24 patients who required salvage radical neck dissection following failure of definitive radiotherapy for cure had a 42% survival.
Scar revision, Different scar revision techniques are compared on similar scars. all on the same patient. Comparison of the final results is unique and interesting and provides insight into choosing the "optimal" technique for these procedures. Historical perspective is provided.
The characteristics of children with epiglottitis who develop the complication of pulmonary edema, A review was performed of 234 consecutive cases of epiglottis that occurred during a 20-year period to delineate the rate of. and clinical characteristics associated with. the complication of pulmonary edema. As a result of the prior utilization of a "dual" management protocol. there were 170 children who received endotracheal intubation. and 64 children managed without placement of an artificial airway. In all. five children (2.1%) of varying ages developed this complication--all experienced severe airway obstruction progressing to respiratory arrest. with evidence of pulmonary edema developing shortly after endotracheal intubation. Two of these five children died due to complications resulting from upper airway obstruction-induced cardiorespiratory arrest. By contrast. no child with milder degrees of airway obstruction managed without an artificial airway exhibited clinical evidence of pulmonary edema. Several possible mechanisms for the development of this complication are described. Pulmonary edema associated with epiglottitis is an uncommon complication that can occur following endotracheal intubation in those patients with marked respiratory insufficiency. An artificial airway should be instituted in all cases of pediatric epiglottitis--the potential complication of pulmonary edema should be anticipated before placement of an artificial airway. especially in those patients with a severe degree of upper airway obstruction.
Riedel's thyroiditis, Invasive fibrous (Riedel's) thyroiditis is a rare thyroid condition of unknown origin that may be associated with inflammatory fibrosclerosing processes elsewhere in the body. Although the condition is benign and self-limiting. its importance lies in its ability to clinically mimic carcinoma almost completely. necessitating performing an open biopsy to establish the correct diagnosis. In a review of over 700 thyroid operations performed at Loma Linda (Calif) University Medical Center in the past 15 years. we encountered only one documented case of Riedel's thyroiditis. Our patient presented with a firm thyroid mass. vocal cord paralysis. and symptoms of esophageal compression. Surgery was performed to obtain a definitive diagnosis and prevent the possibility of subsequent additional tracheal compression with airway compromise. The pathologic findings. as well as the medical and surgical treatment of this condition. are reviewed.
Relation between three-dimensional geometry of the inflow tract to the orifice and the area, shape, and velocity of regurgitant color Doppler jets: an in vitro study, The relation between three-dimensional geometry of the inflow tract to the orifice and the area. shape. and velocity of regurgitant jets was studied in a pulsatile in vitro color Doppler flow model. A 2.5 MHz transducer connected to a diagnostic ultrasound machine was placed in a water tank facing pulsatile jets (duration. 0.5 second) obtained by a calibrated injector. Flow rate from 6 to 52 ml/sec were tested through a 5 mm diameter circular orifice. Four different three-dimensional inflow tract geometries were compared: (A) sharp-edged. (B) Venturi (funnel). (C) converging conical. and (D) diverging conical. Mean velocities of jets were measured by continuous-wave Doppler echocardiography. Driving pressures were also measured by means of a fluid-filled catheter. Two observers independently digitized contours of maximal color jet areas by computer system from two separate sets of experiments. Results are given as the mean values of the four measurements for each parameter. Jet areas were correlated to flow rate. with no difference from A through D. The shape (eccentricity) of jets was different between A and B (p less than 0.05). between B and D (p less than 0.01). and between C and D (p less than 0.01). The shape of jets was correlated with flow rate. continuous-wave velocity. and pressure gradient in B. C. and D but not in A. Measured pressure gradients and estimated gradients by continuous-wave Doppler echocardiography were similarly correlated from A through D.
The reproducibility of intravascular ultrasound imaging in vitro, To determine which factors may affect the image quality when an intravascular ultrasound catheter is used in vivo. the influence of blood. temperature change. and contrast media were evaluated. In addition. to confirm the reproducibility of intravascular ultrasound imaging to measure cross-sectional lumen area. intraobserver and interobserver variability were determined. The findings indicated that ultrasound images in blood are mildly attenuated. that changes from room temperature to body temperature do not have a significant impact on the image quality. that contrast media attenuates the image intensity in a dose-dependent manner. and that the intravascular ultrasound imaging catheter provides a reproducible method for measuring arterial lumen area with excellent intraobserver and interobserver correlation.
The natural history of left ventricular spontaneous contrast, Spontaneous contrast in the left ventricle is an unusual entity. We retrospectively studied 16 patients who were found to have spontaneous contrast present on two-dimensional echocardiograms. specifically noting their clinical characteristics. the reproducibility of this phenomenon. the presence of thrombi and embolic events. and prognostic implications. Diagnoses included ischemic heart disease in nine patients. dilated cardiomyopathy in six patients. and hypertensive cardiomyopathy in one patient. The mean ejection fraction was 17.6%. There were six thromboembolic events in four patients. The spontaneous contrast was reproducible for periods of time up to 39 months. Patients who had improvement in their left ventricular dysfunction or who underwent aneurysmectomy had disappearance of the spontaneous contrast. Those patients who had spontaneous contrast reproduced on subsequent echocardiograms did not seem to have a worse prognosis than patients with similarly depressed ventricular function. but a larger study is necessary to verify this.
Role of ultrasonic tissue characterization to distinguish reversible from irreversible myocardial injury, Tissue characterization reflects structural and functional integrity of tissues. Inasmuch as reversible ischemia causes no structural damage and irreversible ischemia results in persistent structural myocardial damage. we postulated that ultrasonic tissue characterization can distinguish the two types of injuries. Anesthetized open chest dogs underwent 15 minutes (group 1. n = 5) and 90 minutes (group 2. n = 8) of acute total occlusion of the left anterior descending coronary artery. followed by 3 hours of reperfusion. Myocardial ischemia-infarction was confirmed with segment shortening. electronmicroscopic examination. and triphenyl tetrazolium chloride staining. Integrated backscatter Rayleigh 5 (IBR5). a measure of ultrasonic backscatter. and Fourier coefficient of amplitude modulation (FAM). an index of cardiac cycle dependent variation in backscatter. were measured at baseline. during ischemia. and after reperfusion. Group 1 (reversible ischemia) showed an increase in IBR5 from -48 +/- 1.2 dB at control to -45 +/- 1.0 dB (p less than 0.01) during ischemia. which returned to baseline after reperfusion (-47 +/- 1.3 dB). FAM was blunted during ischemia (6.2 +/- 1.0 dB during control versus 1.2 +/- 1.0 dB during ischemia. p less than 0.01) and recovered completely during reperfusion. Segment shortening was abolished during ischemia (18% +/- 3% during control versus -12% +/- 5% during ischemia. p less than 0.01) and recovered partially during reperfusion (4% +/- 5%). The group 2 animals with irreversible myocardial injury showed an increase in IBR5. from -49 +/- 1.2 dB during control to -44 +/- 1.0 dB during ischemia (p less than 0.01) and paradoxical bulging of the ischemic region (17% +/- 3% to -7% +/- 3%. p less than 0.01) during ischemia.
Quantitative echocardiographic analysis of global and regional left ventricular function: a problem revisited, We recorded two-dimensional echocardiograms simultaneously with the respiration measurements of 20 normal subjects and 20 patients with anterior myocardial infarction. The apical long-axis and four-chamber views were quantitatively analyzed. Measurement variability of global ejection fraction and regional ejection fraction of 100 regions was calculated during inspiration and at end-expiration for two observers. To minimize variability. the endocardial contour was redefined and traced with an improved computer-assisted tracing system. Variability (absolute mean difference) between two beats at end-expiration was significantly less than during inspiration (p less than 0.05): for ejection fraction the variability at end-expiration was 3.4% and the variability during inspiration was 6.4% (mean. 54%; SD. 7%); for regional ejection fraction the variability at end-expiration was 11.8% and the variability during inspiration was 21.5% (mean. 56%; SD. 15%). Intraobserver and interobserver variability values of one beat at end-expiration for ejection fraction were 3.1% and 3.8%. respectively. and 9.5% and 12.8%. respectively. for regional ejection fraction. Variability in patients with myocardial infarction was comparable. This method of recording respiration and analyzing left ventricular function at end-expiration. with a new contour definition and tracing system. provides a measurement variability that is considerably less than that reported in previous echocardiographic studies and that is comparable to angiographic methods.
Prenatal detection of foramen ovale obstruction without hydrops fetalis, A case of prenatal echocardiographic diagnosis of obstruction of the foramen ovale is described. Presentation was the ultrasound detection of unexplained marked right atrial and right ventricular dilation without fetal hydrops. It is speculated that fetal outcome depends on the severity and time of onset of foramen ovale obstruction in utero.
Fenestrated atrial septal aneurysm: diagnosis by transesophageal echocardiography, The diagnosis of atrial septal defect by transthoracic echocardiography remains difficult in a small subset of patients because of either suboptimal acoustic windows or unusual anatomy. for example. fenestrated defects. We report the case of a 55-year-old woman with a fenestrated atrial septal aneurysm that was incompletely visualized by transthoracic echocardiography. Subsequent transesophageal echocardiography demonstrated three defects within the atrial septal aneurysm with left-to-right shunting across each defect. Normal pulmonary venous connections were also defined. All echocardiographic findings were confirmed at surgery. This case demonstrates the additional diagnostic accuracy of transesophageal echocardiography for detecting disease of the atrial septum.
Sustained improvement in left ventricular function after successful coronary angioplasty, The short and long term effects of successful percutaneous transluminal coronary angioplasty on left ventricular function. at rest and on exercise were investigated in 49 patients. Thirty-four had had no previous infarction (group 1) and 15 had (group 2). Technetium-99m gated blood pool images were obtained at rest and during exercise before. six weeks after. and a mean of fifteen months after successful angioplasty. Before angioplasty the mean (SD) ejection fraction fell significantly on exercise in both groups from 58 (10)% to 53 (13)% in group 1 and from 48 (10)% to 40 (16)% in group 2. This change was paralleled by a worsening wall motion score (from 0.6 (0.4) to 1.6 (1.2) in group 1 and from 2.3 (1.9) to 3.3 (2.4) in group 2). Six weeks after the procedure there was little change in resting ejection fraction but it increased significantly on exercise (to 62 (11)% in group 1 and to 53 (13)% in group 2). There was a concomitant significant improvement in the exercise wall motion score (to 0.4 (0.6) in group 1 and to 1.8 (1.1) in group 2). This improvement in exercise ejection fraction and wall motion was maintained at later follow up with no significant deterioration in either variable and a clearly sustained improvement in ejection fraction (60 (10)% in group 1 and 51 (10)% in group 2) and wall motion score (0.2 (0.2) in group 1 and 1.3 (0.8) in group 2) compared with values before angioplasty.
Post-extrasystolic potentiation without a compensatory pause in normal and diseased hearts, Variables derived from left ventricular volume were used to study post-extrasystolic potentiation. Left ventriculograms were obtained from 11 healthy individuals and 49 patients with coronary heart disease (30 with a previous myocardial infarction and 19 without any signs of myocardial damage). Post-extrasystolic potentiation was induced by a regularly driven right atrial rhythm that was interrupted by one atrial extrasystole in such a way that the post-extrasystolic RR interval was kept equal to the basic RR interval. The left ventricular end diastolic volumes of the pre-extrasystolic and post-extrasystolic beats were equal. In all groups there was evidence of post-extrasystolic potentiation in one or more of the indices of left ventricular function (ejection fraction. mean normalised systolic ejection rate. and systolic volume. and stroke volume). Potentiation was especially evident in patients with left ventricular damage; this suggests that a compensating mechanism is an intrinsic property of the myocardium. The Frank-Starling mechanism does not contribute to the increased performance of the post-extrasystolic beat in normal individuals or in patients with coronary artery disease.
Streptokinase treatment for femoral artery thrombosis after arterial cardiac catheterisation in infants and children, Data on 205 children who underwent retrograde arterial catheterisation were studied to assess the frequency of femoral artery thrombosis and the safety and efficacy of systemic streptokinase treatment for this complication. In 29 (14%) a transarterial balloon dilatation was performed. In 15 (7.3%) patients impaired arterial perfusion due to vascular spasm with or without thrombus formation was seen in the cannulated leg after catheterisation. Despite heparinisation. signs of impaired arterial circulation persisted in nine patients (4.4% of the total). In these patients femoral artery thrombosis was strongly suspected. Six (53%) of these had undergone a balloon dilatation. Therefore in this study the risk of femoral artery thrombosis developing was 12 times greater after transarterial balloon dilatation than after arterial catheterisation without dilatation (20.6% v 1.7%). Systemic infusion of streptokinase was started in all patients with femoral artery thrombosis. Arterial perfusion became normal in all patients. though in one this was delayed. Haematological monitoring showed lengthening of the thrombin time and a decrease of the fibrinogen concentration during streptokinase treatment. There were no serious complications. Systemic infusion of streptokinase is a safe and useful treatment in children with persistent femoral artery thrombosis after arterial cardiac catheterisation.
Preoperative measurement of pulmonary vascular resistance in complete transposition of the great arteries, Transposition of the great arteries is frequently complicated by the early onset of pulmonary vascular disease. It is difficult to measure pulmonary blood flow by the Fick principle because the pulmonary arteriovenous oxygen content difference is small and bronchial blood flow is increased in this condition. In eight patients (mean age 7.7 years. range 3 months to 29 years) with transposition of the great arteries mass spectrometry was used to measure oxygen uptake and predict pulmonary end capillary blood oxygen content. The effects of the bronchial circulation were studied by computer modelling. There was close agreement between pulmonary end capillary and pulmonary vein blood oxygen contents but the resultant percentage difference in arteriovenous content difference was significant (mean (SE of difference)) (14.5(3.8)%). The effect of the bronchial circulation was to give spuriously high estimates of pulmonary blood flow. The error was greatest when oxygen consumption was low and aortic blood was very desaturated.
Lectin binding sites in normal, scarred, and lattice dystrophy corneas, Normal. scarred. and dystrophic corneas were histochemically probed with a panel of 16 lectins by means of an avidin-biotin revealing system. Normal corneal epithelial cells. keratocytes. and endothelial cells expressed at least two distinct N-linked oligosaccharide subsets. of the non-bisected. biantennary and bisected. bi-/triantennary types. Corneal scars stained variably with the lectin subsets described above. and with Maclura pomifera agglutinin. Lattice dystrophy corneas showed a loss of the oligosaccharide expression observed on the plasma membranes of normal epithelial cells. and there was concurrent deposition of extracellular glycoprotein within the corneal stroma. which was of the same oligosaccharide subsets as were lost from the epithelial cell plasma membranes. This extracellular stromal glycoprotein was far more widely deposited than the amyloid and extended well beyond the stromal scarring. We propose that these observations are related and that in lattice corneal dystrophy a glycoprotein(s) is shed from the plasma membranes of epithelial cells and sequestrated within the corneal stroma. where it subsequently stimulates amyloid deposition.
Audit of an ophthalmology waiting list, The hospital case notes of 209 (98%) of the 213 patients placed on an adult ophthalmic surgical waiting list between mid 1984 and mid 1985 were reviewed. Information on referral sources. previous eye surgery. outpatient visits. and treatment up to the end of 1987 was recorded. The vital status of patients up to the end of 1988 was also ascertained. Waiting list patients (123 women. 86 men) were elderly (73% over 65 years) and most (70%) were listed for cataract surgery. By the end of 1987 (30-42 months after waiting list entry) 64% of all patients (and 56% of cataract patients) had received surgery under the care of the health authority. The remainder had either died (12%). received surgery elsewhere (7%). were still on the waiting list (7%). no longer wanted or were unfit for surgery (6%). or had left the district (4%). By the end of 1988 (42-54 months after waiting list entry) 28% of the original waiting list population had died.
Post-traumatic hyperlipofuscinosis in the human retinal pigment epithelium, Light microscopy (including fluorescence microscopy) and electron microscopy were applied to a study of the photoreceptor-retinal pigment epithelium (RPE) complex in a human eye which had been severely traumatised nine months prior to enucleation. The main feature of interest was a massive accumulation of lipofuscin in the retinal pigment epithelium at the posterior pole. and quantitative fluorescence microscopy provided values three times those obtained in appropriate control tissue. The photoreceptor layer was normal at the posterior pole but became progressively atrophic towards the periphery. The concentration of lipopofuscin was proportional to the degree of preservation of the retinal photoreceptors. By electron microscopy the cells in the RPE were seen to be packed with a mixture of lipofuscin granules and melanolysosomal complexes. but occasional photoreceptor phagosomes were found. Bruch's membrane and the choriocapillaris were normal. We attribute this hitherto unreported abnormality of the RPE after trauma to a dysfunction consequent on an overload of the monolayer by photoreceptor debris at the time of trauma.
Abnormal megakaryocytopoiesis in the Belgrade laboratory rat, The Belgrade laboratory (b/b) rat has a hereditary hypochromic microcytic anemia because of defective transmembrane iron transport into erythroblasts. The present study was prompted by our previous work in which we showed that the b/b rat has hypomegakaryocytic thrombocytopenia associated with increased megakaryocyte size. To define the basic mechanism underlying this abnormality in the b/b rat we have studied both megakaryocytopoiesis and granulopoiesis in anemic b/b rats. chronically transfused b/b rats. iron-treated b/b rats. and controls. We have found decreased concentrations of megakaryocyte and granulocyte progenitors in the marrow of b/b rats. Full correction of the severe anemia by chronic transfusion resulted in normalization of megakaryocyte progenitors. small acetylcholinesterase positive cells. megakaryocyte size. and platelet counts. along with granulocyte progenitors. In contrast. the partial correction of anemia obtained by iron treatment resulted in improvement. but not normalization. of these parameters. These findings indicate that abnormal megakaryocytopoiesis in the b/b rat can be best interpreted as a consequence of hypoxia because of the severe anemia. Because we have recently shown that the number of erythroid progenitors in b/b rats is also low. we propose that abnormal megakaryocytopoiesis in this animal is a reflection of an acquired stem cell disorder induced by the prolonged hypoxia resulting from the severe anemia.
Interleukin-6 and its receptor are expressed by human megakaryocytes: in vitro effects on proliferation and endoreplication, Interleukin-6 (IL-6) is a pleiotropic cytokine that plays an important role in the megakaryocytic differentiation. Recently. we have observed that IL-6 is synthesized by several human cell lines with megakaryocytic features. In this study. we have investigated whether a similar phenomenon occurs during normal megakaryocytic differentiation. Human megakaryocytes (MK) were obtained by culturing normal marrow in liquid culture with aplastic plasma (AP). First. an IL-6 secretion in bone marrow culture enriched in MK as well as in purified MK populations was demonstrated by a biologic assay. Second. IL-6 mRNA was detected in a purified population of MK by the polymerase chain reaction and dot blot analysis. IL-6 mRNA and protein were undetectable in platelets. Third. in situ hybridization procedure demonstrated the presence of IL-6 mRNA in individual immature MK. Fourth. IL-6 protein was detected in MK at the unicellular level by an immunoalkaline phosphatase technique using a monoclonal antibody against IL-6. Furthermore. the presence of IL-6 receptor (IL-6-R) on MK was demonstrated by in situ hybridization using an IL-6-R probe and in situ autoradiography after binding with [125I]-labeled recombinant IL-6. The IL-6 endogenously produced in liquid cultures containing normal human plasma or AP was subsequently neutralized. This resulted in a 50% decrease of the MK growth with a minor shift in the ploidy distribution toward lower values. In semisolid cultures the addition of anti-IL-6 antibodies led to a 42% decrease in colony number in cultures stimulated by IL-3 but not in other conditions of culture. These results suggest that normal human megakaryocytopoiesis might be regulated in part by an IL-6 autocrine loop.
Administration of interleukin-6 stimulates multilineage hematopoiesis and accelerates recovery from radiation-induced hematopoietic depression, Hematopoietic depression and subsequent susceptibility to potentially lethal opportunistic infections are well-documented phenomena following radiotherapy. Methods to therapeutically mitigate radiation-induced myelosuppression could offer great clinical value. In vivo studies in our laboratory have demonstrated that interleukin-6 (IL-6) stimulates pluripotent hematopoietic stem cell (CFU-s). granulocyte-macrophage progenitor cell (GM-CFC). and erythroid progenitor cell (CFU-e) proliferation in normal mice. Based on these results. the ability of IL-6 to stimulate hematopoietic regeneration following radiation-induced hematopoietic injury was also evaluated. C3H/HeN female mice were exposed to 6.5 Gy 60Co radiation and subcutaneously administered either saline or IL-6 (1.000 micrograms/kg) on days 1 through 3 or 1 through 6 postexposure. On days 7. 10. 14. 17. and 22. femoral and splenic CFU-s. GM-CFC. and CFU-e contents and peripheral blood white cell. red cell. and platelet counts were determined. Compared with saline treatment. both 3-day and 6-day IL-6 treatments accelerated hematopoietic recovery; 6-day treatment produced the greater effects. For example. compared with normal control values (N). femoral and splenic CFU-s numbers in IL-6-treated mice 17 days postirradiation were 27% N and 136% N versus 2% N and 10% N in saline-treated mice. At the same time. bone marrow and splenic GM-CFC values were 58% N and 473% N versus 6% N and 196% N in saline-treated mice; bone marrow and splenic CFU-e numbers were 91% N and 250% N versus 31% N and 130% N in saline-treated mice; and peripheral blood white cell. red cell. and platelet values were 210% N. 60% N. and 24% N versus 18% N. 39% N. and 7% N in saline-treated mice. These studies demonstrate that therapeutically administered IL-6 can effectively accelerate multilineage hematopoietic recovery following radiation-induced hematopoietic injury.
IgE-mediated anaphylactic degranulation of isolated human skin mast cells, Isolated human skin mast cells (HSMC) were prepared and cultured overnight before functional and electron microscopic studies. Mast cell suspensions were examined after stimulation with anti-IgE to produce anaphylactic degranulation or examined in buffer-incubated controls. Histamine release was measured in replicate samples. Control. isolated HSMC studied by electron microscopy were well preserved and fully granulated. Although all granule patterns reported for human mast cells were found. crystal granules were the most prevalent. as is true for HSMC in situ. Individual mast cells containing both crystal and scroll granules occurred. Lipid bodies were rare. as in HSMC in situ. Control. isolated mast cells did not express granule changes associated with either piecemeal degranulation or recovery during wound healing in situ; nor were morphologic changes of anaphylactic degranulation present. Spontaneous histamine release was 0% in control samples. Anaphylactic degranulation of isolated HSMC was accompanied by 24% maximum histamine release and characteristically showed extrusion of altered. membrane-free granules through multiple pores in the plasma membrane to the exterior of the cell. Other morphologic aspects of anaphylactic degranulation. as expressed in isolated human lung mast cells. were also present. These events included granule swelling. fusion. alteration of matrix contents. degranulation channel formation. pore formation. and shedding of granules. membranes. and surface processes. The ultrastructural morphology of isolated HSMC and their IgE-mediated degranulation shows some differences from similar studies of isolated human lung mast cells and of human lung and gut mast cells in biopsy samples. These differences include crystal granules as the predominant granule pattern. minor numbers of lipid bodies. and extrusion of granules during anaphylactic degranulation as characteristic for HSMC. By contrast. isolated human lung and gut mast cells have more scroll granules and particle granules. respectively. and more lipid bodies. In isolated human lung mast cells. anaphylactic degranulation is almost exclusively an intracellular fusion event characterized by the formation of complex degranulation channels within which altered granule matrix materials solubilize. In addition to morphologic differences between mast cells of skin. lung. or gut origin. functional differences have also been reported among mast cells of these organs. The ultrastructural morphology of isolated HSMC is identical to that of skin mast cells in biopsy samples. thereby validating the usefulness of this new source of HSMC for correlative functional and morphologic studies.
The effect of N-alkyl modification on the antimalarial activity of 3-hydroxypyridin-4-one oral iron chelators, The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes. and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3-hydroxypyridin-4-ones. a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast. there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20. 38. and 40 failed to suppress malaria. whereas CP51. 94. and 96 had a strong antimalarial effect. similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action. our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.
Molecular characterization of erythrocyte glycophorin C variants, Human erythrocyte glycophorin C plays a functionally important role in maintaining erythrocyte shape and regulating membrane mechanical stability. Immunochemical and serologic studies have identified a number of glycophorin C variants that include the Yus. Gerbich. and Webb phenotypes. We report here the molecular characterization of these variants. Amplification of glycophorin C mRNA from the Yus phenotype. using two oligonucleotide primers that span the coding domain. generated a 338-bp fragment compared with a 395-bp fragment generated by amplification of normal glycophorin C mRNA. Sequencing of the mutant 338-bp fragment identified a 57-bp deletion that corresponds to exon 2 of the glycophorin C gene. Similar analysis showed deletion of 84-bp exon 3 in the Gerbich phenotype. In contrast to the generation of shorter than normal DNA fragments from mRNA amplification in the Yus and Gerbich phenotypes. amplification of mRNA from the Webb phenotype generated a normal-sized fragment. Sequencing of this DNA fragment showed an A----G substitution at nucleotide 23 of the coding sequence. resulting in the substitution of asparagine by serine. This modification accounts for the altered glycosylation of glycophorin C seen in this phenotype. These results have enabled us to characterize glycophorin C variants in three different phenotypes that involve deletions of exons 2 and 3 of the glycophorin C gene. as well as a point mutation in exon 1 that results in altered glycosylation of this protein.
Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation, The existence of an immunologic antileukemia reaction associated with allogeneic bone marrow transplantation (BMT) is well established. However. a similar graft-versus-tumor effect against lymphomas has not been demonstrated. We analyzed the results of BMT in 118 consecutive patients with relapsed Hodgkin's disease or aggressive non-Hodgkin's lymphoma. The 38 patients less than 50 years of age with HLA-matched donors had allogenic marrow transplants. and the other 80 patients received purged autologous grafts. The median age was 26 years in both the allogeneic and the autologous graft recipients. The patient's response to conventional salvage therapy before transplant was the only factor that influenced the event-free survival after BMT (P less than .001). Both the patient's response to salvage therapy before BMT (P less than .001) and the type of graft (P = .02) significantly influenced the probability of relapse after BMT. The actuarial probability of relapse in patients who responded to conventional salvage therapy before BMT was only 18% after allogenic BMT compared with 46% after autologous BMT. However. the actuarial probability of event-free survival at 4 years was the same. 47% versus 41%. for patients with responsive lymphomas who received allogeneic and autologous transplants. respectively (P = .8). The beneficial antitumor effect of allogeneic BMT was offset by its higher transplant-related mortality (P = .01). largely resulting from graft-versus-host disease. Allogeneic BMT appears to induce a clinically significant graft-versus-lymphoma effect. The magnitude of this effect is similar to that reported against leukemias.
Bell ringers' bruises and broken bones: capers and crises in campanology, OBJECTIVE--To determine the incidence. aeriology. and outcome of injuries due to bell ringing. DESIGN--Retrospective review of the last six years' issues of Ringing World. advertisement in Ringing World. and a postal questionnaire sent to 20 active ringing towers. SUBJECTS--Regular bell ringers. RESULTS--Seventy nine injuries were identified both from review and by advertisement in Ringing World. The incidence of injury among 221 ringers identified by postal questionnaire was 1.8% a year. CONCLUSION--Although sonerous. bell ringing can be dangerous and occasionally even fatal. Doctors should be aware of the dangers to which campanologists expose themselves.
Occurrence and repetition of hospital admissions for accidents in preschool children, OBJECTIVES--To examine trends over time in the rates of admission to hospital for accidents of preschool children and to study patterns of repeated admissions for accidents in these children. DESIGN--Analysis of linked. routine abstracts of hospital inpatient records for accidents. SETTING--Six districts in the Oxford Regional Health Authority covered by the Oxford record linkage study. SUBJECTS--Records for 19.427 children aged 5 years and under at the time of first recorded admission to hospital. MAIN OUTCOME MEASURE--Number of admissions to hospital. RESULTS--Records were analysed in three groups: person based annual admission rates were calculated for each calendar year; each child's first recorded admission in 1976-85 was identified. and the child's record was followed up by linkage for one year from that admission; each child's first recorded admission in 1976-81 was identified and followed up for five years. Overall. 19.427 children from an average annual resident population of 163.000 children in 1976-86 had 20.657 admissions for accidents before they were 6 years of age. Of these admissions 13.983 were for injuries. 5717 for poisonings. and 957 for burns. Admission rates declined after 1976 for poisoning. but no substantial changes over time were found in admission rates for injuries or burns. A total of 17.724 children were followed up for one year and 10.889 for five years; 470 (2.6%) of the children who were followed up for one year and 926 (8.5%) of those followed up for five years had at least one further admission for an accident. Of those followed up for one year the 4 and 5 year old children were least likely and those under 1 and 1 year old were most likely to have a further admission for an accident. The number of children who had more than one accident was greater than would be expected if accidents were random occurrences. Those who had a poisoning at first admission were more likely to have another poisoning than an injury or burn; and those who had a burn at first admission were more likely to have another burn. CONCLUSIONS--Hospital admissions for accidents in children are common: on average 1 child in 88 in this population was admitted each year. Multiple admissions are uncommon but none the less occur more often than would be expected by chance.
Familial chondrocalcinosis due to calcium pyrophosphate dihydrate crystal deposition in English families, Familial predisposition to chondrocalcinosis (CC) due to calcium pyrophosphate dihydrate (CPPD) crystal deposition is described in five English kindreds. Two families were characterized by premature-onset polyarticular CC with little associated structural arthropathy. In one of these families. recurrent childhood fits were strongly associated with subsequent development of CC. Affected members of the other three families resembled sporadic disease in showing predominantly late-onset. oligoarticular CC with mild arthritis and destructive change in only one case. Knee synovial fluid levels of inorganic pyrophosphate (PPi) and nucleoside triphosphate pyrophosphate (NTPP) did not differ from those of 59 sporadic cases of CC due to CPPD. although PPi and NTPP levels in both groups were higher than in normal knee synovial fluid (P less than 0.0001). Urinary PPi levels were not different from normal controls. Screening for other metabolic abnormality was negative in all cases. This is the first report of familial CC in the UK. and the first to associate this condition with childhood fits. Absence of overt primary abnormality of PPi metabolism suggests that other factors relating to crystal nucleation/growth may be more relevant to predisposition in these cases.
Transferrin C subtypes in patients with rheumatoid arthritis, Transferrin (Tf) subtypes were investigated in 128 patients with rheumatoid arthritis (RA) and the frequencies of TfC subtypes were compared with the results in normal individuals. The frequencies of the Tf genes: C1. C2. C3. D1. and D2 were 0.4765. 0.3867. 0.0742. 0.0390 and 0.0234. respectively. The frequency of TfC2 gene was significantly higher in these patients (0.3867) compared to the value in the control group (C2 = 0.247). The relative risk of RA in association with TfC1C2 type was 2.0. while it was 0.18 in association with TfC1C1 type and the results were statistically significant. This paper confirms the significant association between TfC2 and RA. Furthermore. it appears from our results that TfC1 homozygous phenotype is protective for the development of RA. The results are discussed in the light of earlier suggestions that the TfC2 subtype confers an increased risk of cellular damage by enhancing hydroxyl radical formation. although it is possible that there exists a genetic linkage of Tf variant to some other locus which is influencing susceptibility to RA.
The prevalence of rheumatoid arthritis in the Sultanate of Oman, One thousand nine hundred and twenty-five Omani adults aged 16 and over were studied in a house-to-house survey in representative areas of Oman. Seven cases (five female) are described who satisfied the 1987 ARA criteria for rheumatoid arthritis (RA). indicating a prevalence of 3.6 per thousand adults. Adjusted for the population structure. the prevalence was 8.4 per thousand adults. Complementary data are also presented on cases of RA ascertained by special screening clinics in rural health centres and by hospital rheumatology clinics. In all parts of the study. cases of RA were less often seropositive than in European populations which may account for the lower prevalence of erosive disease.
Clinical assessment of ankylosing spondylitis: a study of observer variation in spinal measurements, Twenty-two measurements repeated non-sequentially on each of 10 patients by five observers were undertaken to determine their reliability for routine clinical use. Measurements without significant inter-observer variation or with a coefficient of reliability greater than 0.70 were cervical rotation. cervical lateral flexion. tragus to wall distance. fingertip to floor distance on sagittal and lateral flexion. C7 to iliac crest line distraction and modified Schober index. It is concluded that many of the currently used measurements are either statistically unreliable or clinically unhelpful in mild or moderate ankylosing spondylitis. The most clinically useful were cervical rotation using a protractor. cervical lateral flexion using a goniometer. thoracolumbar flexion as the C7 to iliac crest line distraction. thoracolumbar lateral flexion as the fingertip to floor distance and the modified Schober index.
The development and use of Patient Knowledge Questionnaire in rheumatoid arthritis, A multi-choice Patient Knowledge Questionnaire (PKQ) was developed for use with patients with rheumatoid arthritis (RA). Test/re-test was used to test its stability (r = 0.81). and Kuder Richardson formula 20 (r = 0.72) for internal consistency. Seventy randomly selected RA patients then completed the PKQ in a rheumatology out-patient clinic of a large teaching hospital. There was a wide variation in total scores ranging from 3 to 28 out of 30. Total scores correlated with years of general education (P less than 0.05) but not with disease duration or age. Sixty-two per cent of patients knew that the cause of RA is. as yet. unknown but 27% thought it could be caused by injury and 11% by cold damp weather. Fifty-two per cent had no idea why they had blood tests. All but four patients were taking some form of medication but there was widespread confusion about disease-modifying drugs and non-steroidal anti-inflammatory drugs (NSAIDs). Exercise was reasonably well understood but many patients were unable to differentiate between methods of energy conservation and joint protection. This study highlights the need for careful individual knowledge assessment by use of tools such as the PKQ and effective patient education programmes.
Higher incidence of carpal tunnel syndrome in oophorectomized women, To determine whether the hormonal changes of the menopause are related to the onset of carpal tunnel syndrome (CTS). 53 healthy women. younger than 44 years. and subjected to bilateral oophorectomy between 1 and 4 years before the study. were evaluated. Seventy healthy menstruating women matched for age were used as controls. In those complaining of symptoms and presenting signs suggestive of CTS. sensory and motor nerve conduction studies were done. In the oophorectomized group. 17 of 53 (32%) had clinical CTS. while only seven of 70 of the control group (10%) did so (relative risk for the oophorectomized group = 4.25; 95% confidence intervals 1.47 and 12.61). The nerve conduction studies were abnormal in 14 of 16 oophorectomized women (87.5%). and in only one of seven of the control group (14.2%; P less than 0.002). Symptoms tended to be milder in the controls. Symptoms developed in the first year after oophorectomy in 14 of the 17 women with CTS. This suggests that women develop CTS after oophorectomy more frequently than controls.
Cytomorphologic, immunocytochemical, and nucleic acid flow cytometric study of 50 lymph nodes by fine-needle aspiration. Comparison with results obtained by subsequent excisional biopsy, Fifty patients with clinically suspected or previous diagnosis of lymphoma underwent fine-needle aspiration (FNA) and subsequent excisional biopsy of their lymph nodes. Results of cytologic diagnosis made from the direct smears in conjunction with immunocytochemical study of cytospin preparations and nucleic acid flow cytometric study (FCM) were compared with the results obtained from histologic sections. cryostat-immunohistochemical study. and nucleic acid FCM performed on resected lymph nodes. This study demonstrates (1) results of immunocytochemical and DNA-FCM analysis of FNA-derived material are comparable in the majority of cases to those obtained from surgical specimens. (2) immunostaining of cytospin preparations for immunoglobulin (Ig) gives less background staining and in certain cases is easier to interpret than when performed on frozen sections. and (3) monotypia in FNA in conjunction with cytomorphologic study is 100% specific for lymphoma. and polytypic staining for Ig does not exclude HD. T-cell lymphoma. or B-cell malignancy focally involving a lymph node.
Juvenile (embryonal and alveolar) rhabdomyosarcoma of the head and neck in adults. A clinical, pathologic, and immunohistochemical study of 12 cases, Sites in the head and neck region (orbit. nasopharynx. nasal cavity. etc.) are among the most frequent locations for juvenile (embryonal and alveolar) rhabdomyosarcomas in patients younger than 15 years; however. comparable neoplasms in adults are very uncommon. A clinicopathologic and immunohistochemical study of 12 juvenile rhabdomyosarcomas in patients between the ages of 18 and 36 years is presented. There was a female:male ratio of 2:1. The orbit with or without contiguous paranasal sinus involvement. nasal cavity. sphenoid sinus. middle ear. and soft tissues of the neck and preauricular region were the primary sites. Seven tumors involved a parameningeal site and eight cases were alveolar rhabdomyosarcomas which together contributed to the adverse outcome. Only two patients were long-term. disease-free survivors. Six patients have died of tumor and two others are alive with persistent disease. Immunohistochemical study in 11 cases demonstrated reactivity for vimentin and muscle-specific actin (HHF-35) and desmin in ten cases. Juvenile rhabdomyosarcoma rarely presents in the head and neck of adults but should be considered in the differential diagnosis of a small cell neoplasm in patients during the third and fourth decades of life.
A comparative analysis of three different techniques for the detection of breast cancer cells in bone marrow, Three different methods. morphologic. immunocytochemic. and fluorescence activated cell sorter (FC) analysis. were compared with respect to their efficiency in detecting breast cancer cells in bone marrow. In the first series of experiments. the three techniques were compared using bone marrow cells artificially mixed with a known amount of breast cancer cells. whereas in a second series bone marrow from breast cancer patients with bone metastases were used. The following results were obtained: When mixtures of the first series were analyzed. FC analysis detected from 1% to 10% of breast cancer cells in bone marrow (0.2% was a border line value). the morphologic method detected from 0.05% to 10%. and the immunocytochemic method. which was clearly superior. detected breast cancer cells in all mixtures (from 0.00025% to 10%). It was noted that. with both the morphologic and immunocytochemic methods. the percentage of breast cancer cells detected was 2 to 360 times higher than the percentage of added cells. and enrichment was inversely proportional to the percentage of added cells. This result could be a result of different separation of cells during centrifugation due to the different density of breast cancer cells. The superiority of the immunocytochemic method was confirmed in the second series of experiments.
Microinvasive carcinoma of the uterine cervix (International Federation of Gynecology and Obstetrics Stage IA), In 1985 the International Federation of Gynecology and Obstetrics (FIGO) subdivided Stage IA cervical cancer and specified metric criteria to demarcate Stage IA from Stage IB. Early stromal invasion (Stage IA1) denotes the first invasive protrusions of a carcinoma in situ into the stroma. Microcarcinomas (Stage IA2) are small cancers a number of orders of magnitude larger than Stage IA1 lesions and with a maximum depth of invasion of 5 mm and a maximum horizontal spread of 7 mm; larger lesions are classified as Stage IB. This study reviews 486 patients previously classified as having Stage IA disease. This yielded 344 Stage IA1 and 101 Stage IA2 lesions; 41 cancers were reclassified as Stage IB. Three hundred nine. 89. and 38 patients were followed for greater than or equal to 5 years. One (0.3%) patient with Stage IA1 disease re-presented with Stage IIB disease 12 years after conization. Five (5.6%) patients with Stage IA2 lesions developed invasive recurrences; three died. None of the 38 patients reclassified as having a Stage IB lesion. including 16 who were treated conservatively. developed a recurrence. The FIGO classification is not a guideline for treatment. Stage IA1 lesions can be treated conservatively. but treatment in Stage IA2 must be individualized. Risk factors such as vascular space involvement and confluency are of high sensitivity but low specificity.
Leiomyosarcoma of bone. A clinicopathologic, immunohistochemical, and ultrastructural study of five cases, The authors identified five leiomyosarcomas (LMS) in a review of 13 nonmatrix-producing spindle cell sarcomas of bone. Only two were initially recognized as LMS; the others had been diagnosed as malignant fibrous histiocytoma (two) and fibrosarcoma (one). The patients. four of whom were women. ranged in age from 32 to 70 years. Sites included proximal humerus (two). distal femur (two). and rib (one). All tumors presented with clinical and radiographic features consistent with a diagnosis of primary bone neoplasms. although one probably represented a solitary metastasis from a primary uterine LMS. Radiographs showed lytic bone destruction with a moth-eaten appearance. and three cases had soft tissue extension. Histologically. all tumors showed broad. interlacing fascicles of spindle cells with pleomorphic nuclei. frequent mitoses. and necrosis. Two cases had a focal storiform pattern and bizarre multinucleated cells. and two other cases had focally prominent osteoclast-like giant cells. Extensive immunoreactivity for muscle actin was seen in all cases and for desmin in three. In each case. electron microscopy showed definite smooth muscle differentiation including cytoplasmic filaments with densities. At this writing. two patients are free of disease (including the patient with a presumed metastasis). one is alive with locally recurrent disease. and two are dead of disease. Experience suggests that LMS of bone is a distinct clinicopathologic entity that may be more common than previously recognized. Application of immunohistochemistry and electron microscopy to nonmatrix-producing bone sarcomas should facilitate diagnosis of additional cases.
Clinical characteristics and treatment outcome of children with acute lymphocytic leukemia and Down's syndrome. A Pediatric Oncology Group study, Of 2947 children with acute lymphocytic leukemia (ALL). treated during three consecutive studies of the Pediatric Oncology Group (1974-1986). 52 (1.8%) had Down's Syndrome (DS). Comparison of clinical and laboratory characteristics showed no significant differences in leukocyte count. racial distribution. sex ratio. platelet count. incidence of mediastinal mass. lymphadenopathy or hepatosplenomegaly. or percentage of blood or bone marrow blasts for children with ALL with or without Down's Syndrome (DS-ALL or NDS-ALL. respectively). However. children with DS-ALL were slightly older at the time of presentation and had higher hemoglobin values. The relative frequency of each major immunophenotype (early pre-B. pre-B. T. or B) was also comparable for patients with or without DS. For this report. treatment regimens were categorized as either conventional (no consolidation therapy) or intensive. Cox regression analysis revealed that the presence of DS. a higher leukocyte count. black race. or age older than 10 years was independently associated with a poorer event-free survival (EFS) for children treated with conventional chemotherapy. However. for the cohort of children who received intensive chemotherapy. DS was no longer an independent risk factor. In fact. event-free survival (EFS) was markedly improved to a level comparable with that observed in the children diagnosed as having NDS-ALL. On the other hand. serious toxicity. requiring interruption of treatment. was significantly more frequent in the intensively treated children with DS compared with similarly treated patients with NDS-ALL. although deaths resulting from toxicity occurred infrequently.
Psychosocial adjustment in women with breast cancer, There is a plethora of studies investigating psychosocial adjustment in women with breast cancer. its correlates. clinical course. and prognosis. These studies have been conducted with varying degrees of methodologic rigor. An assessment has been made of the quality of this existing evidence to identify from the best evidence the factors which predict the adjustment status of women with breast cancer. Studies have been reviewed. using methodologic standards for the critical appraisal of studies on prognosis. developed by Sackett and colleagues in the Department of Clinical Epidemiology and Biostatistics at McMaster University (Hamilton. Ontario. Canada). Few of the studies investigating psychosocial adjustment of women with breast cancer meet all of the criteria for reviewing studies of clinical course and prognosis. This review focuses the direction and methodologic rigor required in future investigations. In particular. studies are needed that employ prospective designs and that deliberately measure or control for the extraneous prognostic variables that may affect adjustment. Future investigations need to incorporate adequate precision in measurement so that measures of the psychosocial variables are objective. reliable. and valid.
Prognosis of pregnancy-associated breast cancer, The survival of patients with pregnancy-associated (PA) breast cancer is difficult to predict for two reasons: The combination is very rare. and the natural history of breast cancer that is not associated with pregnancy is intricate and varies among individuals. Valid data collection and analysis is problematic given that studies gather patients over many years. The charts of 56 women with Stages I. II. and III breast cancer. who were pregnant or within 1 year postpartum at the time of breast cancer diagnosis between 1960 and 1980. were analyzed. Patients with PA breast cancer were compared to nonpregnant women of comparable ages. who were treated at the same hospital. by the same physicians. and during the same period. Four patients were lost before 5-year follow-up. and one patient before 10-year follow-up. These five patients had distant metastases at the time they were lost to follow-up. and are considered to have died within that time. Across stages. patients with PA breast cancer have survival not significantly different from those patients with non-pregnancy-associated (non-PA) breast cancer.
Combination hormonal therapy with tamoxifen plus fluoxymesterone versus tamoxifen alone in postmenopausal women with metastatic breast cancer. An updated analysis, A randomized trial was performed to determine if therapy with tamoxifen (TAM) plus fluoxymesterone (FLU) was more efficacious than TAM alone for postmenopausal women with metastatic breast cancer. Patients failing TAM could subsequently receive FLU. The dose of both drugs was 10 mg orally twice daily. Objective responses were seen in 50 of 119 (42%) TAM patients and 64 of 119 (54%) TAM plus FLU patients (two-sided P = 0.07). Time to disease progression was better for TAM plus FLU (medians: 11.6 versus 6.5 months; Cox model. P = 0.03). Duration of response and survival were similar in the two treatment arms. Among 97 patients with estrogen receptor (ER) of 10 or greater and 65 years of age or older. there were highly significant advantages for treatment with TAM plus FLU in both response rate and time to progression. Of particular note is that in this patient group TAM plus FLU showed a survival advantage (Cox model. P = 0.05). Although these data require confirmation in a prospective randomized trial. they suggest that there is a substantive therapeutic advantage for TAM plus FLU over TAM alone in elderly women with ER of 10 fmol or greater.
Sphincter preservation in rectal cancer by local excision and postoperative radiation therapy, The authors report the preliminary results of 14 patients with localized. mobile. resectable rectal cancer treated with local excision and postoperative radiation therapy (RT). All had negative surgical resection margins and two received 5-fluorouracil (5-FU). The median follow-up was 29 months (4-43 months). The 3-year actuarial survival was 88%. The incidence of local failure was 7% (only site of failure) and 21% (component of failure). The incidence of local failure increased with T stage (T1. 0/3 [0%]; T2. 1/7 [14%]; and T3. 2/4 [50%]) and tumor size (greater than 3 cm. 33%. versus less than or equal to 3 cm. 0%). Three patients developed local failure at 6. 15. and 21 months. Three underwent a salvage abdominoperineal resection and were locally controlled at 2 and 28 months following salvage surgery. One patient underwent an abdominoperineal resection for a clinically presumed local failure; however. no tumor was found in the specimen. Therefore. the 13 patients who either were initially locally controlled or underwent salvage or nonsalvage surgery had no evidence of disease in the pelvis at the time of last follow-up. Local excision and postoperative RT may be an alternative to standard surgery in selected cases. However. additional follow-up and more experience are needed in order to determine if this approach will ultimately have local control and survival rates similar to those of a low anterior resection or an abdominoperineal resection.
Flow cytometric DNA analysis of hepatocellular carcinoma, The prognostic value of nuclear DNA content was studied retrospectively using flow cytometry in 203 cases of resected hepatocellular carcinoma. The occurrence of DNA aneuploidy. which was detected in 50% of patients. correlated significantly with tumor size and the presence of vascular invasion or intrahepatic metastasis. Overall. patients with DNA aneuploid tumors had a significantly worse prognosis than those with DNA diploid tumors (P less than 0.001) and. also in subdivided groups by tumor size (P less than 0.01). Among DNA aneuploid patients. the survival times were significantly shorter for patients with a low DNA index (less than 1.5) than for those with a high DNA index (greater than or equal to 1.5) (P less than 0.05). In a Cox multivariate analysis. nuclear DNA content provided significant prognostic value (P = 0.008). as did vascular invasion (P = 0.001) and intrahepatic metastasis (P = 0.005). These results indicated that nuclear DNA content has an important prognostic value in hepatocellular carcinoma.
Predictors of physician nonadherence to chemotherapy regimens, Physician nonadherence to cancer treatment regimens may diminish treatment efficacy and compromise clinical research. The influence of clinical. demographic. and psychosocial patient characteristics on physician adherence to breast cancer chemotherapy was investigated. as was the role of the clinician's attitudes concerning the chemotherapy. One hundred seven women recently diagnosed with breast cancer were followed for 26 weeks of treatment. Fifty-six (52%) of the patients experienced unjustified modification for at least one chemotherapeutic agent. Stepwise multiple regression revealed independent contributions of increased patient age. treatment setting (clinic versus academic or community private practice). and stage of disease to physician nonadherence. Regimen complexity. delay in seeking treatment. and presence of psychiatric disorder did not contribute. in general. to unjustified regimen modifications. Patient psychological and psychiatric factors. however. did influence prescribing behavior for vincristine. Physician awareness of factors contributing to unnecessary treatment modifications may reduce the frequency of such behaviors.
Complete remission in refractory anaplastic adult Wilms' tumor treated with cisplatin and etoposide, A 61-year-old woman underwent a left radical nephrectomy for Stage II anaplastic Wilm's tumor. She received no adjuvant therapy. One year later computerized tomography (CT) of the abdomen revealed a mass in the left renal fossa and retroperitoneal adenopathy. A CT-guided needle biopsy was nondiagnostic. The patient had progressive disease after treatment with dactinomycin. doxorubicin. and vincristine. but achieved a complete response after treatment with cisplatin and etoposide. The therapy of Wilms' tumor in adults is discussed.
Expression of class I and II human leukocyte antigens by thyrocytes and lymphocytic infiltration on human thyroid tumors. An immunofluorescence study, Surgical thyroid sections from 30 papillary carcinomas (PC). six medullary carcinomas (MC). three anaplastic carcinomas (AC). two follicular carcinomas (FC). and 16 adenomas (AD) were examined with an indirect immunofluorescence technique employing different monoclonal antibodies to evaluate the expression of human leukocyte antigen (HLA)-A. B. C (Class I) and DR. DP. DQ (Class II) by thyrocytes. together with the phenotype and distribution of inflammatory cells. Ten PC and four FC were also investigated for the presence of intercellular adhesion molecule-1 (ICAM-1). In situ deposits of immunocomplexes and circulating thyroid autoantibodies were also evaluated. An increased expression of Class I antigens was found in all PC and FC. in 33% of MC and AC. and in 31% of AD. An anomalous expression of Class II antigens was observed in 70% of PC. in 50% of FC. in 33% of AC. in 19% of AD. and in none of the MC. Expression of DP or DQ was revealed only in a portion of the DR-positive glands. A reduction of microsomal autoantigen expression was found. No ICAM-1-positive thyrocytes were detected. A moderate T-lymphocytic infiltrate was noticed only in PC. where it was correlated with DR and DP and/or DQ coexpression. B-cells and natural killer cells were virtually absent. The authors speculate that the weak Class II antigens expression. together with the partial or complete loss in microsomal autoantigen and the absence of ICAM-1 by thyrocytes. may account for the limited engagement of immunocompetent cells observed in thyroid tumors.
Advances in medical imaging for cancer diagnosis and treatment, Over the last several decades. significant "new eyes" have been developed that improve the diagnosis. treatment. planning. and monitoring of human cancer: computer tomography (CT). magnetic resonance imaging (MRI) and spectroscopy (MRS). single photon emission computed tomography (SPECT). and positron emission tomography (PET). Innovative advances in both morphologic and functional imaging have led to a dramatic improvement in our ability to diagnose and monitor human cancer. Frequently. anatomic detail can be demonstrated in ways that exceed views at surgery. and functional biochemical imaging is being used to show the metabolic activity and receptor status of normal and pathologic states. In vivo functional and biochemical studies differentiate normal from neoplastic or nonviable tissue. and make it possible to measure progression or regression of the disease. Because physiologic changes often precede morphologic findings in many disease processes. the use of in vivo biochemical probes can demonstrate disease before anatomic abnormalities become evident. Gross changes in anatomy are no longer adequate endpoints for therapy protocols. Today. using physiologic imaging. we can evaluate the response to treatment within hours of administration of therapy. Adjuvant metabolic tumor imaging studies provide complimentary information to morphologic evaluation of human cancers that will ultimately lead to better patient care.
The natural history of colorectal cancer. Opportunities for intervention, There is now a better understanding of the natural history of colorectal cancer. which has provided a basis for intervention to influence outcome. The possible interventions include earlier detection of colorectal cancer. removal of premalignant adenomas. demonstration of the mucosal field defect that precedes neoplasia to evaluate baseline risk and its change with dietary modification. and identification of inherited and dietary risk factors. Five controlled trials evaluating early detection of colorectal cancer with fecal occult blood testing have enrolled more than 309.000 patients. Early stage cancers with improved survival has been observed. but data on mortality reduction have not as yet been reported. Studies of patients with adenomas have demonstrated high synchronous and metachronous rates as a basis for complete colon evaluation initially and a surveillance follow-up program. Hyperproliferation and lack of normal differentiation have been observed as a field defect in the colon preceding neoplasia. Inherited factors have recently been shown to be important in a larger proportion of individuals destined to develop colorectal adenomas and cancer. These observations of the natural history of colorectal cancer have provided new opportunities for the application of radiologic and endoscopic techniques in diagnosis and surveillance; each examination has its merit. Further research is needed to answer many critical questions that have been raised regarding the impact of these interventions.
Imaging techniques in the diagnosis of carcinoma of the colon, The variability in the published results for colonoscopy and barium enema examinations is confusing. With both. optimum results are dependent on meticulous preparation. technical excellence. and operator proficiency. It is a mistake to place colonoscopy and the barium enema in competitive positions; the two methods ideally complement one another in the evaluation of high risk individuals. including those with positive Hemoccult tests. The exclusion of significant pathology by the double-contrast enema can be relied on and is less costly to the patient. Detection of abnormalities by a barium enema should. when necessary. be followed by colonoscopic verification and/or biopsy. When used in this sequence. the procedures provide a cost-effective approach to the early detection and control of cancer; it is estimated that observance of the ACS guidelines can reduce mortality rates by 30%.
Screening for lung cancer. A critique of the Mayo Lung Project, The National Cancer Institute of the United States recently sponsored three large-scale. randomized controlled trials of screening for early lung cancer. The trials were conducted at the Johns Hopkins Medical Institutions. the Memorial Sloan-Kettering Cancer Center. and the Mayo Clinic. Participants were middle-aged and older men who were chronic heavy cigarette smokers and thus at high risk of developing lung cancer. Screening procedures were chest radiography and sputum cytology. the only screening tests of established value for detecting early stage. asymptomatic lung cancer. In the Hopkins and Memorial trials the study population was offered yearly chest radiography plus sputum cytology every 4 months. The control population was offered yearly chest radiography only. In these trials the addition of sputum cytology appeared to confer no lung cancer mortality rate advantage. The Mayo Clinic trial compared offering chest radiography and sputum cytology every 4 months to offering advice that the two tests be obtained once a year. This trial demonstrated significantly increased lung cancer detection. resectability. and survivorship in the group offered screening every 4 months compared with the control group. However. there was no significant difference in lung cancer mortality rate between the two groups. The statistical power of these trials was somewhat limited. Nevertheless. results do not justify recommending large-scale radiologic or cytologic screening for early lung cancer at this time.
The applications of imaging in lung cancer, The applications of imaging to the lung cancer patient have become more focused recently. Screening of high risk patients is not recommended even though intuition and clinical judgment prevail in practice to justify the use of chest radiographs in this patient category. Cross-sectional imaging procedures should be tailored to the staging process in the individual with a large central primary or to confirm an abnormality noted on the chest radiographs. The patient at high risk for thoracotomy is generally also subjected to radiologic staging. The radiologic staging process is reviewed and critiqued. emphasizing our role in identifying the disease sites that would suggest nonrespectability.
Imaging bone tumors in the 1990s, Progress in bone tumor management has occurred as a result of cooperation among surgeons. oncologists. pathologists. and radiologists. During the 1990s radiologists will contribute to care of patients with bone tumors in major ways. Tumor detection and preliminary diagnosis will be accomplished by radiography. Tumor local extent will be assessed by magnetic resonance imaging (MRI) and to a lesser degree by computed tomography (CT). Distant spread of malignancy will be documented by radionuclide scintigraphy (skeleton) and by CT (lungs). The combined estimate of local extent and distant spread will assure adequate staging before definitive management decisions. Preoperative closed percutaneous biopsy for histologic diagnosis will be accomplished on an outpatient basis under fluoroscopic or CT guidance. Arteriography will be employed for delivery of local chemotherapy. Some combination of arteriography. MRI. and MR spectroscopy will be used to evaluate tumor response. After limb-salvage surgery. MRI will sequentially assess the tumor bed; bone scintigraphy and CT will detect skeletal and pulmonary metastases. The radiologist's role will undergo continuous redefinition.
Primary neoplasms of the hollow organs of the gastrointestinal tract. Staging and follow-up, The number of imaging modalities available to stage and follow-up patients with primary neoplasms of the gastrointestinal (GI) tract continues to increase. Magnetic resonance imaging (MRI). computed tomography (CT). and ultrasonography are useful techniques for both staging and follow-up. For staging. CT is most frequently used for the detection of liver metastases and is increasingly used as a substitute for the chest radiograph in the detection of lung metastases. CT is still the imaging test of choice for the preoperative staging of esophageal carcinoma. CT is less helpful in staging the patient with gastric carcinoma or colorectal carcinoma. The current usefulness of MRI in the staging of GI tract malignancies is limited by the lack of an adequate oral intraluminal contrast agent and degradation of images due to motion. Sonography. especially the new technique of endoscopic ultrasound. is promising for the detection of local invasion from GI tract malignancies. CT is used in the follow-up of patients with tumors of the GI tract to detect liver. adrenal. and nodal metastases as well as local recurrence because of the ability of CT to detect extraluminal masses. CT of the pelvis has been recommended as a routine follow-up procedure in patients who have undergone abdominal-peroneal resection. Both CT and MRI can be used to detect local recurrence. but suffer from the inability to differentiate scar from recurrent tumor. The initial hope that MRI would be capable of differentiating postoperative scar tissue from recurrent tumor has not been realized. Therefore. with positive CT or MRI findings. occasionally a percutaneous biopsy will be required to confirm local recurrence.
Liver tumor imaging, Liver tumor imaging is the paradigm of the dilemma of diagnostic decision-making in the current era of abundant high technology. In part. this is a reflection of the multiplicity of imaging techniques now in wide use worldwide. These include ultrasound (US). radionuclide scintigraphy (RNS). computed tomography (CT). magnetic resonance imaging (MRI). and techniques especially designed for staging the extent of known liver cancer. such as computed tomography during arterial portography (CTAP) and intraoperative ultrasound (IOUS). Most authorities concede that CT scanning is the single test most closely fitting the designation "gold standard" for liver tumor imaging. although MRI. a less mature technique. is already preferred by some. Local factors profoundly influence the selection and sequence of imaging studies. including available equipment. radiologic skills. institutional interests. and especially the specific clinical circumstances of the patient. Thus. diagnostic algorithms or decision trees for sequential imaging workup of liver tumor suspects tend to be somewhat institution specific.
Staging and follow-up of breast cancer patients, Staging systems for breast cancer. unlike those of neoplasms in distant or recessed sites. allowed for the early development of clinical staging evaluation. It was established that clinical assessment of the breast lesion was often wrong compared with the pathologic examination (benign vs. malignant); clinical measurement of the tumor in centimeters was often larger than histologic size; and clinical assessment of axillary nodes (clear or metastatic) was incorrect in about 30% of cases. Although both clinical and pathologic staging provide effective discriminants for prognosis of treated patients. prognosis is more accurately determined by the pathologic stage. The single most important prognostic indicator is the axillary nodal status. and when positive. the number of positive nodes. The American Joint Committee on Cancer and the Union International Contra Cancer have agreed on a TNM staging for breast carcinoma. and this is the preferable staging system. Follow-up of treated patients is of most value in detecting local recurrence on the chest wall (after mastectomy) or in the irradiated breast (after lumpectomy). and also in early detection of contralateral breast cancer. Physical examination and periodic mammography are most useful. There is a tendency to overinvestigate asymptomatic patients (with bone scans. blood tests. etc.). but this has been correctly criticized in recent years.
Carcinoma of the female reproductive organs. Value of cross-sectional imaging, Cross-sectional imaging techniques i.e.. computed tomography (CT) and magnetic resonance imaging (MRI). play an integral role in the evaluation of patients with carcinoma of the female reproductive system. Neither CT nor MRI. however. are tissue-specific. and benign and malignant disease cannot be differentiated using these techniques alone. Therefore. the diagnosis is clinical and is based on history. physical examination. and histology. After the diagnosis has been made. CT and MRI are recommended for noninvasive evaluation of tumor extent. often helping in designing optimal therapy. thus facilitating more effective treatment and ultimately influencing patient prognosis. In evaluating tumors of the uterus. including endometrial and cervical carcinomas. CT is limited to the evaluation of more extensive disease. It is believed that the value of CT rises proportionately to the size and extent of disease. Its major limitation is suboptimal tissue contrast resolution. making differentiation between a small tumor and the surrounding normal tissue difficult. MRI renders excellent soft tissue contrast. allowing direct tumor visualization and assessment of tumor volume. depth of penetration. and extension to adjacent tissues. Assessment of these parameters is crucial in deciding on the choice of therapy. whether surgery. radiation. chemotherapy. or their combination. The initial management of ovarian cancer usually includes surgical staging with tumor debulking. CT remains the primary staging technique; its value resides primarily in identification of tumor metastases and in patient follow-up. Despite progress in the use of CT and MRI. second-look laparotomy for ovarian cancer has not been superseded. Technical advances in radiologic cross-sectional imaging have significantly improved the accuracy of noninvasive tumor staging. Although there are still limitations to these techniques. additional technical improvement and better tissue characterization are imminent.
Primary neoplasms of the central nervous system in children, Modern diagnostic imaging techniques are able to detect primary neoplasms of the central nervous system (CNS) in children safely and accurately but with less specificity as to cell type or degree of malignancy. These neoplasms. often peculiar in cell type and size. mediated by hydrocephalus in their clinical presentation. demand careful and often extensive imaging techniques best to evaluate their geography and character. Added to these basic observations. determination of the neoplasm from surrounding edema. detection of possible spread. and evaluation of residual or recurrent neoplasm are prime responsibilities of the pediatric neuroradiologist toward the child. neurosurgeon. and oncologist.
Magnetic resonance imaging in the evaluation of spinal tumors, Magnetic resonance imaging (MRI). which has recently begun to replace myelography. postmyelography computed tomography (CT). and to some extent. bone scans. has become the procedure of choice in the evaluation of spinal tumors; the applications of MRI in this role are reviewed. In the extradural space. MRI is the most sensitive technique for the detection of tumors in the vertebral bodies. At the same time. it provides superb delineation of suspected thecal sac impingement. In the intradural extramedullary space. MRI is generally as accurate as myelography and postmyelography CT while being noninvasive. Finally. in the intramedullary space. MRI is unquestionably the procedure of choice in the evaluation of suspected cord tumors. In general. MRI has become the best initial procedure in the evaluation of suspected tumors of the spine. regardless of the space in which they may lie; frequently. it is the only required examination.
Metastatic tumors of unknown origin, The clinical appearance of metastatic lesions without an obvious primary source for the tumor is a common event. Tumor Registry figures and epidemiologic data grossly understate the actual frequency of unknown primaries. because primary sites are often "assigned" to patients on a best-guess basis without positive proof of a tumor's origin. In the majority of patients whose primary tumors have continued to elude detection. the extensive use of diagnostic imaging studies fails to produce information that alters the patients' clinical course. Rare exceptions will be cited. but these exceptions prove the general rule. Imaging studies should therefore be targeted for selected patients with disseminated malignancies in whom identification of their primary tumors could benefit quality of life or length of survival.
Radioimmunology. Imaging and therapy, Targeting of radioactivity to tumors using antitumor antibodies is evolving from a laboratory curiosity toward a practical diagnostic and therapeutic technique that promises widespread benefits for many common human cancers. The development of the hybridoma technique by Kohler and Milstein for producing monoclonal antibodies is probably the single most important contribution to the development of this field. A large array of monoclonal antibodies against many human tumors have been created and labeled with a variety of radioisotopes; 110 clinical trials have been identified from the literature between the interval of 1978 to the present. These studies are beginning to form the basis for certain conclusions regarding likely benefits for certain combinations of antitumor antibodies and isotopes in specific instances of clinical management in patients with malignant neoplasms. For example. in melanoma. lymphoma. neuroblastoma. and colorectal malignancies. radiolabeled antibodies have demonstrated occult tumors. which could not be disclosed with conventional methodologies. Radioimmunotherapy of malignant lymphoma is achieving durable remissions in patients who have failed conventional forms of therapy. For the most part. these advances have been achieved through intelligent application of known principles of immunochemistry. imaging physics. and tumor immunology. Progress has been slow but steady. In a few instances. the term "magic bullet" is warranted in describing the targeting of a particular radiolabeled antibody to a human tumor. I-131. 3-F8. an IgG3 against the GD2 antigen of neuroblastoma. which was introduced by Cheung. and In-111 T-101. against the CD5 antigen of T-cells. which was developed by Royston. stand out because of the consistency and high concentration of radioactive targeting to human tumors in clinical trials. If certain technical innovations fulfill their initial promise. the future will be bright for radioimmunologic methods of diagnosis and therapy. Genetic engineering will permit the development of "humanized" antibodies with biologic properties that favor tumor localization. New chemical approaches will broaden the range of isotopes available as diagnostic and therapeutic radiolabels. Application of modern imaging methodologies. such as positron emission tomography (PET). will detect more lesions of smaller size and permit quantitative imaging for dosimetry considerations. Greater speed and ease of use of computerized work stations will lead to the broader application of fusion imaging in which radioantibody images will be viewed simultaneously with TCT or MRI for better anatomic correlation of abnormal sites of antigen-reactive tumor deposits.
Single photon emission computed tomography and positron emission tomography in cancer imaging, Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are now being used to improve the information available from radioisotopic imaging of patients with cancer. These nuclear medicine techniques offer the potential for studying regional function and biochemistry by using radiolabeled substrates. The chemical changes of malignancy precede anatomic changes. and PET and/or SPECT may detect these changes before anatomic changes have occurred. The superiority of SPECT compared with planar imaging has been demonstrated for cardiac and brain imaging. Radiopharmaceuticals containing technetium 99 m (99mTc) are best suited for SPECT imaging because large amounts of radioactivity are administered and the collimator-camera systems are optimized for the 140 keV photons of 99mTc. The current interest in imaging cancer with SPECT relates to the use of gallium 67 citrate and monoclonal antibodies labeled with iodine 123 or indium 111. SPECT can image these radioisotopes. but the advantages compared with planar imaging have not been clearly defined. Furthermore. the ability to quantitate the distribution of single photon emitters other than 99mTc has not been demonstrated. New SPECT systems with three heads or rings of detectors offer promise for improved. quantitative imaging. PET has the capability of imaging tracers with the biologically important elements C-11. N-13. O-15. and F-18 used for positron labeling. These radioisotopes have short half-lives and require a cyclotron close to the PET facility. The most prominently used radiopharmaceutical for PET is F-18 fluorodeoxyglucose (FDG). PET studies with FDG in patients with primary brain tumors have demonstrated the ability to determine the degree of malignancy. to differentiate necrosis from recurrent tumor after radiation therapy or chemotherapy. and to predict prognosis. Other metabolic functions of cancer have been studied. including amino acid accumulation. thymidine uptake. oxygen utilization. intermediary metabolism. and receptor status. PET has the potential to make a major impact on the characterization of a malignancy and the effect of therapy.
New directions in medical imaging of cancer. Magnetic resonance methods and single photon emission computed tomography, Magnetic resonance methods and single photon emission computed tomography (SPECT) are developing technologies that provide both functional and anatomic information. Their role in the diagnosis and monitoring of cancer is the subject of current clinical research. Magnetic resonance imaging (MRI) delineates organs and tissue heterogeneities using differences in the relaxation parameters of water and fat protons; both protons and other nuclei can be imaged or studied by magnetic resonance spectroscopy (MRS) to provide information on the state of naturally occurring or infused molecules. SPECT quantifies the distribution of radiolabeled agents in tissues and organs; labeled monoclonal antibodies provide highly specific imaging of tumors. Spatial resolution is the limiting technologic factor. Proton MRI provides the highest current resolution. better than 1 mm in vivo in deep tissues. whereas the resolution of MRS and SPECT is limited to several cubic centimeters. Recent advances in these technologies have significantly increased their specificity and ability to detect small. deep lesions.
Imaging of adult central nervous system primary malignant gliomas. Staging and follow-up, A classification and staging system for primary adult gliomas was proposed. This system uses the high signal intensity found on proton density or T2-weighted magnetic resonance (MR) scans at the site of the tumor and surrounding edema (including infiltrating tumor).
Proliferation and DNA ploidy in malignant breast tumors in relation to early oral contraceptive use and early abortions, In 175 premenopausal breast cancer patients. a history of oral contraceptive (OC) use before 20 years of age was significantly associated with higher tumor cell proliferative activity. as indicated by a higher S-phase fraction (SPF). and a higher fraction of DNA aneuploid tumors. compared with later or never users (P = 0.05 and p = 0.01. respectively). The higher SPF among early OC users was apparent in patients with aneuploid tumors but not in patients with euploid tumors. Abortions (spontaneous or induced) before the first full-term pregnancy also were associated with a higher SPF compared with other young patients with breast cancer (P = 0.03). Adjusting for parity and abortions or OC use. respectively. an early OC use was associated with a 43% higher SPF and early abortions were associated with 49% higher SPF. Younger patients had a higher SPF and a higher frequency of aneuploid tumors. but this was found to be because the users of OC had a lower median age at diagnosis. Among never users. no significant age relationship was seen for SPF or the frequency of aneuploidy. For the DNA analyses there is a selection of patients with breast cancer with larger tumors. and therefore the conclusions drawn in this article may not be generalizable to patients with smaller primary tumors. e.g.. cases diagnosed at breast cancer screening. The higher tumor proliferative activity and frequency of aneuploidy in early OC users are in line with previously reported findings of worse prognostic indicators and a worse survival in early users of OC compared with other young women with breast cancer.
Fludarabine therapy in hairy cell leukemia, This study evaluated the efficacy of fludarabine. a new adenine nucleoside analogue. in typical and variant forms of hairy cell leukemia (HCL). Two patients with HCL and one patient with a variant form of HCL (HCL-variant) with resistant or progressive disease with prior treatments were studied. Fludarabine (30 mg/m2) was administered intravenously over 30 minutes daily for 5 days every month. Two patients (one with HCL and one with HCL-variant) achieved partial responses; the third patient had a minor response. This is the first report of encouraging activity of fludarabine in typical and variant forms of HCL. Further experience with fludarabine in these disorders is indicated.
Treatment of patients with advanced colorectal cancer with cisplatin, 5-fluorouracil, and leucovorin, Based on in vitro studies that have demonstrated synergy between 5-fluorouracil (5-FU). leucovorin (LV). and cisplatin (CDDP) against human colon cancer cell lines. a clinical trial was initiated to determine the effects of this combination in patients with advanced unresectable colorectal carcinoma. Fifty-nine patients were enrolled in the study and 12 of them had received prior conventional 5-FU chemotherapy. Treatment consisted of 4 weekly courses of high-dose LV (200 mg/m2) administered by intravenous (IV) bolus. followed by 5-FU (550 mg/m2) and CDDP (20 mg/m2) each administered as a 2-hour infusion on 4 consecutive days. After a median of 5.5 treatment cycles. objective tumor response was seen in 20 of 59 patients (34%) (this included 3 complete remissions). The response rate in the 47 previously untreated patients was 38% (95% confidence limits. 26% to 53%). Stable disease occurred in 16 (27%) patients. whereas the tumor progressed in 23 (39%) patients. The median survival time was 11.5 months. with 15% of the patients alive at 2 years. The regimen was well tolerated and the primary side effects were mild and reversible gastrointestinal symptoms and myelosuppression. There was no episode of life-threatening toxicity. Eastern Cooperative Oncology Group (ECOG) Grade III adverse reactions that required 25% dose reductions occurred in only 14% of the patients. The results of this trial suggest that 5-FU. LV. and CDDP is an active. safe. and well-tolerated combination regimen in patients with advanced colorectal cancer.
Serum tumor markers and patient allocation to good-risk and poor-risk clinical trials in patients with germ cell tumors, The allocation of patients with advanced germ cell tumors (GCT) to different treatment programs based on clinical characteristics is standard in the design of clinical trials today. Studies have shown that substantial differences exist between entry criteria and that these differences could influence the outcome of clinical trials. The factors contributing to these differences are not clear due to patient selection biases. Two hundred five unselected and consecutive patients allocated to and treated in good-risk and poor-risk treatment programs at Memorial Sloan-Kettering Cancer Center (MSKCC) were reassigned risk status by the Indiana University (IU) Classification. The results were compared with those of the Southeastern Cancer Study Group (SECSG). The results using both criteria indicated substantial agreement in total end results and the identification of good-risk patients. The results in poor-risk patients differed substantially. with 39 patients (19%) classified as poor-risk by MSKCC criteria and 66 (32%) by Indiana criteria. The major discrepancy occurred in IU Stage 7. in which 26 of 32 patients (81%) achieved a complete response. The major factor contributing to this difference in risk assignment was the use of serum tumor markers. Serum tumor markers must be incorporated into risk assignment criteria for GCT clinical trials to minimize the number of good-risk GCT patients in poor-risk trials.
Salvage chemotherapy for patients with germ cell tumors. The Memorial Sloan-Kettering Cancer Center experience (1979-1989), Twenty-eight of 124 (23%) advanced germ cell tumor (GCT) patients who were treated on four successive platin-based induction regimens and who failed to achieve a durable complete response (CR) remain alive (median follow-up. 50 months). An analysis of prognostic factors for response and survival was conducted on the 94 patients who received salvage chemotherapy. Survival and/or response to salvage therapy were significantly enhanced for patients with a prior CR to induction chemotherapy. treatment with a cisplatin-based salvage regimen. a testis primary site. a normal serum human chorionic gonadotropin level. a normal serum lactate dehydrogenase level. one site of metastasis. and an Indiana Class of 6 or less. Patients with a prior incomplete response (IR) had a particularly poor prognosis (P = 0.00007) with only 4 of 52 (9%) patients alive (median follow-up. 37 months) compared with 15 of 42 (36%) patients with a prior best response of a CR (median follow-up. 35 months). The poor survival of patients who fail to achieve a durable CR to induction chemotherapy warrants the continued investigation of new salvage therapy. The identification of prognostic features may direct salvage therapy and aid in the interpretation of clinical trials of salvage regimens.
The prognostic value of image analysis in ovarian cancer, Histologic grading is very important for treatment decisions in ovarian cancer. All grading systems contain a significant subjective component. which could be reduced by including objective measurements into the diagnostic decision. Image analysis was used to determine nuclear area and ploidy distributions in 42 patients with epithelial ovarian cancer. and the results were related to tumor grade and clinical outcome. The mean nuclear area. mean optical density. number of hyperploid cells. and the standard deviation between measurements were significantly higher in Grade 2 and 3 tumors compared with Grade 1 tumors. in rapidly progressive tumors compared with less aggressive malignancies. and in recurrent tumors compared with primary lesions. The number of nuclei with very high DNA content was found to be of prognostic importance. Image analysis thus provides additional prognostic information in epithelial ovarian cancer.
Resection of the primary liver cancer of the hepatic hilus, Primary liver cancer (PLC) of the hepatic hilus was designated as a tumor situated at the main branch of the portal vein or pedicle of the hepatic veins in contact with the intrahepatic vena cava. That is. the main tumor located at segment I. IV. V. or VIII and concentrating on the central part of the liver was called "the central type of PLC." which differed from a tumor located at segment II. III. VI. or VII; the latter was called "the peripheral type of PLC." Surgical treatment of the PLC has been significantly improved in the past two decades. but the resection of the central type of PLC is difficult and hazardous. This institution admitted 903 PLC from January 1970 to April 1988. of which 118 cases were the central type; 65 cases were resected successfully. a resectability of 55.1%. One patient died from sepsis within 1 month of operation (mortality 1.53%). The modes of operation for the different segments are described. and suggestions for improvements are presented. The survival rates were compared with a similar number of patients with the peripheral type of tumor in the same period and treated by the same surgeons. The results show noticeable differences. The one-year. three-year. and five-year survival rates after resection were 70.9%. 43.2%. and 39.2% in the central type of PLC; they were 98.3%. 85.0%. and 76.4% in the peripheral type of PLC (P less than 0.001). Further discussion of improvements in surgical techniques and mental awareness are suggested.
Structural and functional integrity of ovarian tumor tissue obtained by ultrasonic aspiration, For patients with ovarian epithelial cancer. survival increases when residual disease approaches zero after surgical removal of the tumor. A previous study using the Cavitron Ultrasonic Surgical Aspirator (CUSA) (Cavitron Lasersonic Corp.. Stamford. CT) showed the successful removal of ovarian tumors from areas often considered unresectable: the diaphragm. spleen. stomach. and small bowel. However. the CUSA has not yet been approved by the Food and Drug Administration for gynecologic surgery except on an experimental basis. This study was designed to test whether ultrasonic irradiation produced by the CUSA caused alterations in cell structure or physiology of gynecologic tissue in adjacent areas. Paired tumor samples. unirradiated and irradiated. were obtained from ten patients. and portions were sent for pathologic structural evaluation and physiologic tissue culture evaluation. Histologic sections. stained with hematoxylin and eosin. showed that CUSA irradiation produced only minor tissue distortion as observed under the light microscope. A correct diagnosis would have been made in all cases had only tissue fragments obtained from the CUSA specimen trap been stained. For nine of ten patients. initial tumor cell viability was similar in the two specimen types. Flow cytometric DNA analysis confirmed that surgical methods produced matched samples. Cells that survived high-frequency ultrasound appeared functionally intact. For five of eight patients. the cells from the CUSA specimen traps survived and/or divided to a greater extent than those from the knife-dissected tumors. Cells from both surgical routes attained a similar number of passages in culture. It seems reasonable to extrapolate these in vitro observations with pelvic tumor tissues to normal surrounding tissue left in situ. Thus pelvic tissue is believed to be uninjured by CUSA ultrasonic irradiation.
The expression of progesterone receptors coincides with an arrest of DNA synthesis in human breast cancer, Two main models to account for the heterogeneous expression of estrogen receptors (ER) and progesterone receptors (PR) in human breast cancer have been proposed: the clonal model and the stem cell model. The authors previously provided evidence supporting the stem cell model since it was found that most of the proliferating cells in ER-positive (ER+) human breast cancer lack ER and that the ER-negative (ER-) and ER+ subpopulations are interrelated. The authors have analyzed in eighteen ER+/PR+ primary breast tumors the simultaneous expression of ER or PR (by immunohistochemistry) and DNA synthesis (by autoradiography) after 30 minutes of 3H-thymidine incorporation. The authors demonstrated that: (1) the average numbers of ER+ and PR+ cells were similar (36.8 +/- 10.7% and 39.3 +/- 17.6%. respectively); (2) The thymidine-labeling indexes of the ER+. ER-. PR+. and PR- subpopulations were 0.53 +/- 0.69%. 0.74 +/- 0.49%. 0.21 +/- 0.21 and 0.94 +/- 0.54%. respectively; and (3) 75.2% of the DNA-synthesizing cells were ER-. and 88.8% of them were PR-. The authors conclude that the cellular subpopulations expressing ER and PR were not identical. and the expression of PR was associated with a lower rate of cellular proliferation than was ER expression.
Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue, To explore mechanisms of coagulation activation in adenocarcinoma of the prostate. the occurrence and distribution of components of coagulation and fibrinolysis pathways in situ were studied by means of immunohistochemical techniques applied to frozen sections of fresh malignant and benign hyperplastic prostatic tissue obtained at transurethral resection. Fibrinogen was distributed throughout the perivascular and tumor connective tissue in both malignant and benign disease but was not present in adjacent areas of normal prostate. Antibodies specific for fibrin and D-dimer crosslink sites stained vascular endothelium focally in both malignant and benign tissues. Both neoplastic cells and benign hyperplastic glandular epithelial cells stained weakly and in a patchy distribution for tissue factor and focally for low-molecular-weight urokinase-type plasminogen activator. Focal staining of vascular endothelium was also observed for tissue plasminogen activator and plasmin-antiplasmin complex neoantigen. By contrast. no tissue staining was observed for factor VII. factor X. factor XIII "a" subunit. high-molecular-weight urokinase-type plasminogen activator. plasminogen activator inhibitors 1 to 3. protein C. and protein S. Thus. the similarity in findings between benign hyperplastic and neoplastic prostate tissue. the lack of either an intact tumor cell-associated coagulation pathway or fibrin formation. and the presence of fibrin on vascular endothelium are consistent with the concept that coagulation activation in prostatic cancer may not be due to a direct effect of the tumor cells on the clotting mechanism. Rather. such activation may be induced by a soluble tumor product that activates procoagulant activity on certain host (for example. vascular endothelial) cells. These findings. together with the lack of effect of warfarin anticoagulation on the clinical course of patients with prostatic cancer. contrast with findings in certain other tumor types and suggest that coagulation activation may not contribute to progression of adenocarcinoma of the prostate.
Amplification of oncogenes in mammary carcinoma shown by fine-needle biopsy, A procedure that measures the amplification of oncogenes in human cancer cells is described. The cells were obtained by fine-needle biopsy to allow repeated sampling from individual metastases. A drawback was the low number of cells obtained. but this could be overcome by using a slot-blot hybridization technique to measure gene amplification. Two patients with mammary cancer (primary tumors or metastases). analyzed for the levels of amplification of the oncogene erb-B2. are described in detail. This technique is suitable for analyzing alterations occurring during cancer progression and for identifying subgroups of mammary cancer with different characteristics.
Predicting recurrence time of esophageal carcinoma through assessment of histologic factors and DNA ploidy, Cytophotometric analysis of nuclear DNA content was done in 128 patients with squamous cell carcinoma of the esophagus. The relationship among histopathologic features. DNA distribution pattern. and survival time was investigated from the standpoint of recurrence. Of 128 patients. 77 (60.1%) died of recurrence within 2 years after surgery: 16 (12.5%) from 2 to 5 years and two (1.6%) over 5 years. The rate of death of recurrence within 2 years was higher in patients with T4 or N1 than T1. T2. and T3 or N0 (P less than 0.01). Survivors over 5 years more frequently possessed type II DNA pattern than types III and IV (P less than 0.05). The rate of death of recurrence within 2 years was 34.4% in type II. which was lower than the 59.6% rate in type III (P less than 0.05) and the 76.6% rate in type IV (P less than 0.01). Survivors from 2 to 5 years were higher in type III than in type IV (P less than 0.05). and recurrence over 5 years was found only in type II. This inclination was more apparent in those with curative resection. In the patients with type II. careful follow-up may be needed over 5 years for late recurrence. However. in those with type IV. no recurrence over 2 years could be regarded as healed because most of their recurrences occur within 2 years. These findings suggest that the growth rate of esophageal carcinoma should reflect DNA aneuploidy. and the DNA analysis of esophageal carcinoma should be a valuable parameter for postoperative follow-up planning.
Serial immunocytologic analysis of blood for tumor cells in two patients with neuroblastoma, Tumor surveillance tests are used to determine whether malignant cells are responsive or resistant to therapeutic regimens. For patients with neuroblastoma. conventional methods of surveillance are not sensitive enough. Because tumor cells are shed into the circulation. immunocytologic analysis of blood may function as a sensitive monitoring system. In this study. five blood samples were obtained from two patients with disseminated neuroblastoma at diagnosis and during therapy. These samples were analyzed with monoclonal antibodies and immunoperoxidase staining to determine whether circulating neuroblasts were present. In both patients. the presence or absence of circulating neuroblasts yielded information that was more sensitive than that from conventional tests. The authors conclude that immunocytologic analysis of blood should be included with conventional monitoring methods for surveillance of patients with disseminated neuroblastoma.
A recurrent pelvic desmoid tumor successfully treated with tamoxifen, A case of recurrent retroperitoneal desmoid tumor successfully treated with tamoxifen (Nolvadex tablets. ICI Pharma. Division of ICI Americas. Wilmington. DE) is reported. The patient presented late in her second pregnancy with a large retroperitoneal pelvic desmoid tumor that was treated with surgical excision and megestrol acetate. When the tumor recurred 12 months later. it was again treated with surgery. this time followed by radiation therapy. The desmoid tumor quickly recurred. The patient was then treated with tamoxifen. resulting in a complete tumor regression that has remained stable for 27 months. Tamoxifen should be considered as first-line therapy in recurrent desmoid tumors.
Rural-urban differences in stage at diagnosis. Possible relationship to cancer screening, Stage at diagnosis was examined for various malignancies identifiable through screening to determine whether rural-urban differences exist in Georgia. Data were obtained from a population-based cancer registry which registers all incident cancers among residents of metropolitan Atlanta and ten neighboring rural counties. Black and white patients with a first primary invasive malignancy newly diagnosed between 1978 and 1985 were included in this study. Residents of the rural area were twice as likely to have unstaged cancers (18.3%) as were urban residents (9.6%). Among patients with known stage at diagnosis. rural patients tended to have more advanced disease than urban patients. The relative excess of nonlocalized malignancies in rural Georgia was 21% for whites and 37% for blacks. The rural excess of nonlocalized prostate cancer among blacks was especially pronounced. Differences in access to or utilization of early detection methods may contribute to the rural-urban differential in the extent of disease at diagnosis.
Putative mechanisms of the impairment of endothelium-dependent relaxation of the aorta with atheromatous plaque in heritable hyperlipidemic rabbits, Attenuation of acetylcholine-induced endothelium-dependent relaxation of thoracic aortas excised from Watanabe heritable hyperlipidemic (WHHL) rabbits linearly correlated with the percent area coated with atheromatous plaque. To elucidate mechanisms related to this reduced endothelium-dependent relaxation in the presence of atherosclerosis. the acetylcholine-induced release of endothelium-derived relaxing factor (EDRF) was assessed functionally as a percent relaxation of the precontracted detector strips obtained from the tunica media beneath the intact intima or the atheromatous plaque in the same aortic ring preparation. Relaxations of the normal detectors to effluents containing EDRF of thoracic aortas during stimulation by acetylcholine (3 x 10(-6) M) in heterozygous and homozygous WHHL rabbits were 73 +/- 5% and 59 +/- 9% (p less than 0.01) of the phenylephrine-induced precontraction. respectively. Relaxations of the atherosclerotic detectors to effluents (EDRF) through the aortas during stimulation by acetylcholine (3 x 10(-6) M) in heterozygous and homozygous WHHL rabbits were 16 +/- 4% and 14 +/- 5%. respectively--values significantly smaller than those seen in the normal detectors. When superoxide dismutase was added to the perfusate of the donors from homozygous and heterozygous WHHL rabbits. atherosclerotic detectors relaxed by effluents stimulated by acetylcholine to 73% and 65% (p less than 0.01 versus before the addition of superoxide dismutase) of the normal detector. respectively. Relaxations induced by sodium nitroprusside as well as the contractions by acetylcholine. phenylephrine. and KCl (118 mM) were comparable in detector strips from the normal and atherosclerotic portions. Thus. not only is the amount of EDRF released by acetylcholine reduced in the presence of atherosclerosis. the tunica media beneath the atheromatous plaque is also to some extent responsible for the superoxide-induced inactivation of EDRF.
Transmural myocardial deformation in the ischemic canine left ventricle, The myocardium is a complex three-dimensional structure consisting of myocytes interconnected by a dense collagen weave that courses in different directions. Regional ischemia can be expected to produce complex changes in ventricular deformation. In the present study. we examined the effects of ischemia on two- and three-dimensional finite strains during acute transmural myocardial ischemia in 13 open-chest anesthetized dogs. In contrast to systolic deformation observed during the control period in which circumferential shortening exceeded longitudinal shortening. our results indicate that after 5 minutes of acute ischemia. end-systolic in-plane lengthening across the left ventricular wall occurs in approximately equal amounts in the circumferential and longitudinal directions. Along with these changes in extensional strains. there were significant negative transverse shearing deformations during ischemia. Myocardial ischemia also resulted in a loss of the normal end-systolic transmural gradients of shortening and thickening. Three-dimensional end-diastolic strains indicate that the left ventricular wall undergoes a significant passive reconfiguration that varies transmurally with lengthening in the epicardial tangent plane and wall thinning increasing from the epicardium toward the endocardium. The large systolic changes in shearing deformations with ischemia could potentially influence collateral blood flow and certainly indicate that uniaxial measurements of deformation in the ischemic myocardium. which do not account for shearing deformation. are incomplete and must be interpreted with caution. Moreover. normal transmural systolic gradients in deformation. which would be anticipated on geometric grounds. are lost during ischemia. implying that the material properties of ischemic tissue or the loading conditions imposed on the ischemic region by partially impaired adjacent myocardium vary transmurally.
Lack of effect of isoproterenol on unloaded velocity of sarcomere shortening in rat cardiac trabeculae, Several recent reports have indicated that catecholamines may act directly on the crossbridge cycle. independent of intracellular calcium concentration changes. The present study investigated the effect of isoproterenol on peak force during twitches at constant sarcomere length and unloaded velocity of sarcomere shortening in isolated right ventricular trabeculae of hearts with V1 or V3 isomyosin obtained from euthyroid and hypothyroid rats. respectively. Hypothyroidism was induced by treatment of the rats with propylthiouracil for 6 weeks. Electrophoretic analysis showed that the hearts of hypothyroid animals were composed only of V3 isomyosin. whereas the hearts of euthyroid animals were composed predominantly of V1 isomyosin. Force development was measured with a silicon strain gauge and sarcomere length with laser diffraction techniques; the shortening velocity was determined from contractions in which sarcomere length was initially held constant followed by a quick release to zero load and a controlled release at zero load. Both isometric twitch force and unloaded sarcomere shortening velocity were sigmoidal functions of [Ca2+]o and of the concentration of isoproterenol. At optimal [Ca2+]o. unloaded shortening velocity was 40% lower in myocardium of hypothyroid animals than in myocardium of euthyroid animals. Isoproterenol increased the sensitivity of isometric twitch force and unloaded shortening velocity to [Ca2+]o in trabeculae from both euthyroid and hypothyroid animals. Isoproterenol did not increase unloaded shortening velocity at optimal [Ca2+]o. regardless of the thyroid state. From these results we conclude that beta-adrenergic stimulation per se does not accelerate the rate limiting step in the crossbridge cycle that determines unloaded sarcomere shortening velocity in the intact cardiac cell.
Conditioning prepulse of biphasic defibrillator waveforms enhances refractoriness to fibrillation wavefronts, The mechanism of biphasic waveform defibrillation threshold reduction is unknown. We tested the hypothesis that. during refractory period stimulation. sarcolemmal hyperpolarization by the first pulse of biphasic waveforms facilitates excitation channel recovery. which enhances graded responses produced by the second depolarizing pulse. This prolongs cellular refractoriness to fibrillation wavefronts when compared with a monophasic depolarizing stimulus. Monophasic (10 msec. rectangular wave) or symmetrical biphasic (10 msec. each pulse) current injection S2 stimuli at 1.5 and two times S1 threshold were used to scan the S1 action potential refractory period (S1 cycle length. 600 msec) in myocardial cell aggregates. S2 waveforms were delivered with normal and reversed polarity to test the hyperpolarizing action of biphasic waveforms. Responses to an S3 stimulus. which simulated a potential incoming fibrillation wavefront. were also determined. Results showed that biphasic S2 waveforms produced longer graded responses during and immediately after the S1 refractory period than did corresponding monophasic S2 waveforms. The maximum difference in response duration produced by the biphasic and monophasic waveforms was 58.6 +/- 10.0 msec (p less than 0.001). This maximum difference occurred 10 msec before the end of the S1 refractory period. The longer response durations produced by biphasic S2 also produced longer refractoriness to the S3 stimulus. The maximum difference in total refractoriness to S3 of 51.8 +/- 2.8 msec (p less than 0.002) occurred at the same S1S2 coupling interval as the maximum difference in S2 response duration. Prolonged refractoriness may protect ventricular cells from refibrillation wavefronts and act as the cellular basis for greater biphasic waveform defibrillation efficacy.
Protective effect of increased glycolytic substrate against systolic and diastolic dysfunction and increased coronary resistance from prolonged global underperfusion and reperfusion in isolated rabbit hearts perfused with erythrocyte suspensions, Current therapy of myocardial infarction may include early reperfusion. We simulated myocardial perfusion conditions during evolving myocardial infarction in isolated. normothermic. isovolumic rabbit hearts perfused with buffer containing bovine red blood cells (hematocrit of 40%). and we assessed the effects of high levels of glucose and insulin as "therapy" during prolonged (150-minute) severe underperfusion and reperfusion. Protocol 1 consisted of underperfusion at a constant coronary perfusion pressure of 8 mm Hg. The control group (n = 8) received 5.5 mmol/l glucose and 15 microunits/ml insulin; the group treated with high levels of glucose and insulin (G + I) (n = 8) received 19.5 mmol/l glucose and 250 microunits/ml insulin during both underperfusion and reperfusion. Relative to the control group. the G + I group experienced 1) greater developed pressure during underperfusion and increased recovery during reperfusion. 2) preserved diastolic function during underperfusion and reperfusion. 3) lower coronary resistance and greater coronary flow during the underperfusion period. 4) increased glycolytic flux and preserved glycogen stores and high energy phosphate levels. and 5) less loss of myocyte enzymes (creatine kinase and alanine aminotransferase). In protocol 2. coronary flow was kept identical in control (n = 8) and G + I hearts (n = 8) during the underperfusion period. and left ventricular end-diastolic pressure was kept below 10 mm Hg in both groups to minimize subendocardial damage and vascular compression. In this protocol. the effect of the G + I intervention in the prevention of an increase in coronary resistance during the underperfusion period was distinguished from its myocellular metabolic effects; the high G + I substrate had protective effects on mechanical and metabolic function that were less marked than. but similar to. those in protocol 1. indicating that its mechanisms of protection during underperfusion affected both cardiac function and coronary resistance. We conclude that the G + I intervention. in clinically relevant concentrations. markedly protected severely underperfused myocardium for 150 minutes and may be a beneficial intervention in combination with reperfusion therapy in acute myocardial infarction.
Effect of coronary hyperemia on Emax and oxygen consumption in blood-perfused rabbit hearts. Energetic consequences of Gregg's phenomenon, To assess the relation between increases in contractile function and oxygen consumption (VO2) during increased coronary flow (Gregg's phenomenon). we measured the end-systolic pressure-volume relation and the relation between VO2 and left ventricular systolic pressure-volume area (PVA. a measure of total mechanical energy output) in blood-perfused. isovolumically contracting rabbit hearts during control and intracoronary adenosine infusion. During adenosine infusion at a constant perfusion pressure (93 +/- 11 mm Hg). coronary flow increased by 99 +/- 76% (p less than 0.01). and the slope of the end-systolic pressure-volume relation. Emax (ventricular contractility index). increased by 18 +/- 15% (p less than 0.01). When compared at the same left ventricular volume. PVA increased by 20 +/- 14% (p less than 0.01) and VO2 by 19 +/- 15% (p less than 0.01) with adenosine. The VO2-PVA relation was linear under each condition (both median r = 0.98). With increased coronary flow. the VO2-intercept of the VO2-PVA relation (unloaded VO2) increased by 22 +/- 18% (p less than 0.01) without a change in the slope; that is. a parallel upward shift was observed. indicating that the contractile efficiency (energy conversion efficiency of the contractile machinery) remained constant. These increases in Emax and unloaded VO2 were not eliminated by beta-adrenergic blockade with propranolol. We conclude that increased coronary flow with adenosine at a constant perfusion pressure augments both Emax and the nonmechanical energetic cost for excitation-contraction coupling and basal metabolism via nonadrenergic mechanisms. without changing contractile efficiency.
Spontaneous termination of reentry after one cycle or short nonsustained runs. Role of oscillations and excess dispersion of refractoriness, This study describes factors that contribute to spontaneous termination of reentry lasting one to 10 cycles after induction by a single premature stimulus. Reentry was studied in vitro in rings of canine atrial tissue from around the tricuspid valve orifice. Activation was recorded from a circular array of 10 extracellular bipolar electrodes equally spaced around the ring. In some experiments. transmembrane or monophasic action potential recordings were made near critical sites. Termination of reentry within one cycle after induction was recorded 110 times in 11 of 35 experiments. Important factors contributing to termination were 1) an obligatory reversal of the activation sequence that resulted in a long coupling interval in the critical region beyond the site of unidirectional block after the premature stimulus and 2) much longer refractory periods limited to this critical region. which facilitated unidirectional block but contributed to termination when this region was first activated with a short coupling interval at the end of the first reentrant cycle. Termination of nonsustained reentry lasting longer than one cycle resulted from oscillations of conduction and refractoriness initiated by the abrupt shortening of cycle length after initiation of reentry. Oscillations of conduction resulted from interval-dependent conduction of reentrant impulses that encountered partially refractory tissue. For reentry to become sustained. the oscillations after induction of reentry must dampen. Thus. damped cycle length oscillations after induction may identify clinical tachycardias caused by reentry with a partially excitable gap.
Myocardial sulfhydryl pool alterations occur during reperfusion after brief and prolonged myocardial ischemia in vivo, Myocardial sulfhydryl (SH)-containing compounds. including reduced glutathione (GSH). are both defenses against and potential markers of reactive oxygen metabolite injury during ischemia and reperfusion. We examined the alterations in GSH and other myocardial SH pools during reperfusion in anesthetized dogs exposed to brief (15 minutes. n = 7) or prolonged (90 minutes. n = 6) regional ischemia caused by occlusion of the left anterior descending artery. Ninety minutes of ischemia followed by 5 hours of reperfusion. which resulted in myocardial necrosis of 43.9 +/- 4.0% of the area at risk. caused a 22% reduction in total myocardial SH groups (p less than 0.01). a 57% decrease in nonprotein myocardial SH groups (p less than 0.01). a 56% decrease in GSH (p less than 0.01). and a 62% decrease in non-GSH. nonprotein SH groups (p less than 0.02). However. protein SH groups were not significantly reduced (12% decrease. p = NS). Also. myocardial release of GSH and oxidized glutathione (GSSG) into the coronary venous effluent occurred during early reperfusion. In contrast. 15 minutes of ischemia. followed by 30 minutes of reperfusion. did not alter myocardial total SH groups. protein SH groups. or GSH (9% decrease. p = NS); nor was there reperfusion release of GSH or GSSG. However. even with brief ischemia. nonprotein SH groups decreased 23% (p less than 0.05). due mainly to a 59% decrease in the non-GSH. nonprotein SH pool (p less than 0.05). These changes after brief ischemia occurred without alterations in myocardial GSSG or the GSH/GSSG ratio.
Endothelium-dependent responses in long-term human coronary artery bypass grafts, In the present study. responses of long-term human coronary artery bypass grafts (CABGs) to known endothelium-dependent vasodilators. acetylcholine. calcium ionophore A23187. thrombin. and histamine. as well as authentic nitric oxide. the putative endothelium-derived relaxing factor. were studied. Sixteen CAGBs were isolated within 1-2 hours from hearts of 14 patients receiving a cardiac transplant. A total of 109 ring segments were prepared from these CABGs and studied in vitro. The duration of the CABGs ranged from 7 months to 12 years. Addition of acetylcholine (0.01-10 microM). calcium ionophore A23187 (0.01-1.0 microM). thrombin (0.01-1.0 unit/ml). and histamine (0.01-1.0 microM) consistently produced a dose- and endothelium-dependent relaxation. reaching a maximum of -35.3 +/- 3.3%. -45.3 +/- 5.5%. -26.9 +/- 4.8%. and -17.8 +/- 2.5% (mean +/- SEM). respectively. No significant difference was observed among the CABGs with different duration of transplantation. whereas the relaxant responses of different segments along the entire length of a CABG were markedly different. These latter differences in the endothelium-dependent responses appear to correlate inversely with the development of intimal proliferative lesions in these CABGs. Addition of nitric oxide (0.01-10 microM) produced a potent dose- and endothelium-independent relaxation. which was also slightly depressed in CABGs with severe intimal proliferation. These results demonstrate that long-term transplanted human saphenous vein grafts retain their endothelium-dependent responses and that development of severe intimal proliferative lesions. rather than the duration of the grafts. result in marked alterations in the reactivity of these transplanted CABGs.
Accuracy of exercise electrocardiography in detecting physiologically significant coronary arterial lesions, The accuracy of exercise electrocardiography in detecting a physiologically significant coronary artery stenosis has been assessed previously by comparing the exercise test with a coronary arteriogram. The inherent inaccuracy of visually determined percent diameter stenosis measurements might have lead to the conclusion that the exercise electrocardiogram was less accurate than it truly was. To determine the accuracy of the exercise electrocardiography in detecting a physiologically significant coronary stenosis. we studied 40 patients with one-vessel. one-lesion coronary artery disease. a normal resting electrocardiogram. and no hypertrophy or prior infarction. Each patient underwent exercise electrocardiography (Bruce protocol) that was interpreted as abnormal if the ST segment developed 0.1-mV or greater depression 80 msec after the J point. The physiological significance of each coronary stenosis was assessed by measuring of coronary flow reserve (peak divided by resting blood flow velocity) in the stenotic artery using a Doppler catheter and intracoronary papaverine (normal. 3.5 or greater peak/resting velocity). The percent diameter and percent area stenosis produced by each lesion were determined using quantitative angiography (Brown/Dodge method). Of the 17 patients with reduced coronary flow reserve (3.5 or greater peak/resting blood flow velocity) in the stenotic artery. 14 had an abnormal exercise electrocardiogram (sensitivity. 0.82; 95% confidence interval. 0.70-0.94). Conversely. 20 of 23 patients with normal coronary flow reserves had normal exercise tests (specificity. 0.87; 95% confidence interval. 0.77-0.97). The exercise electrocardiogram was abnormal in each of 11 patients with markedly reduced coronary flow reserve (less than 2.5 peak/resting velocity) and in three of six patients with moderately reduced reserve (2.5-3.4 peak/resting velocity). The products of systolic blood pressure and heart rate at peak exercise were significantly correlated with coronary reserve in patients with truly abnormal exercise tests. In comparison. the sensitivity (0.61; 95% confidence interval. 0.46-0.76) and specificity (0.73; 95% confidence interval. 0.60-0.86) of exercise electrocardiography in detecting a 60% or greater diameter stenosis may be significantly lower (p less than 0.05). Exercise electrocardiography. therefore. was a good predictor of the physiological significance (assessed by coronary flow reserve) of a coronary stenosis in patients with a normal resting electrocardiogram and no hypertrophy or prior infarction. Its value in a broader and larger patient population will require further study. These results. however. underscore the importance of a physiological gold standard in assessing the accuracy of noninvasive studies for detecting coronary artery disease.
Secular trends in Q wave and non-Q wave acute myocardial infarction. The Minnesota Heart Survey, The Minnesota Heart Survey examined trends of Q wave and non-Q wave acute myocardial infarction (AMI) using a 50% random sample of all hospital discharges of patients with AMI or another acute coronary disease from 35 of 36 hospitals in 1970 and 30 of 31 hospitals in 1980 in the Minneapolis-St. Paul metropolitan area. A total of 1.901 and 1.864 potential AMI cases were abstracted in 1970 and 1980. respectively. Electrocardiograms were coded according to the Minnesota code. AMIs were validated by computerized algorithm based on chest pain. enzymes. electrocardiograms. and autopsy. This study shows that with the use of a consistent. standard diagnostic algorithm. attack rates for Q wave AMI did not change significantly between 1970 and 1980 and that attack rates for non-Q wave AMI decreased significantly during the same decade. However. when the more sensitive cardiac enzymes creatine phosphokinase and creatine phosphokinase-MB were considered. attack rates of both Q wave and non-Q wave AMIs increased. This research documents four important trends for community AMI rates that are at variance with those reported by others. There was a decline in non-Q wave AMI attack rates from 1970 to 1980; women had outcomes equal to or worse than those for men for both case-fatality and 7-year survival rates; patients with non-Q wave AMIs had worse in-hospital prognoses than those with Q wave AMIs; and 7-year survival rates were worse for Q wave AMI in 1980. These findings demonstrate the need for standard diagnostic criteria for Q wave and non-Q wave AMI if trends are to be monitored. In the future. as new trials of operative and nonoperative therapies of AMI are undertaken. these considerations will increase in importance.
Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy, This study was designed to determine the morphological correlate of chronic heart failure. Myocardial tissue from eight patients undergoing transplantation surgery because of end-stage dilated cardiomyopathy was investigated by electron microscopy and immunocytochemistry using monoclonal antibodies against elements of the cytoskeleton: desmin. tubulin. vinculin. and vimentin. The tissue showed hypertrophy. atrophy of myocytes. and an increased amount of fibrosis. Ultrastructural changes consisted of enlargement and varying shape of nuclei. numerous very small mitochondria. proliferation of T tubules. and accumulation of lipid droplets and glycogen. The most obvious ultrastructural alteration was the decrease of myofilaments. ranging from rarefication to complete absence of sarcomeres in cells filled with unspecified cytoplasm. Immunocytochemistry showed that desmin was localized at the Z lines. In diseased myocardium. the amount of desmin was increased. but it was disorderly arranged. Tubulin formed a fine network throughout the myocytes and was significantly increased in cardiomyopathic hearts. Vinculin. a protein closely associated with the cytoskeleton. occurred not only at the sarcolemma and the intercalated disc but also within the myocardial cells. Ultrastructural changes and alterations of the cytoskeleton were severe in about one third of all cells. About one third of all cells showed moderately severe changes. and the remaining cells were normal. Vimentin was present in the interstitial cells and was increased in relation to the increase of fibrosis. We conclude that the increase of fibrosis. the degeneration of hypertrophied myocardial cells. and the alterations of the cytoskeleton are the morphological correlates of reduced myocardial function in chronic heart failure.
HLA class II (DR and DQ) antigen associations in idiopathic dilated cardiomyopathy. Validation study and meta-analysis of published HLA association studies, We previously reported antigen frequency differences for HLA-DR4 and HLA-DRw6 between idiopathic dilated cardiomyopathy (IDC) patients and healthy controls in a pilot study. To confirm these findings. we undertook an independent study with a prospective hypothesis regarding the frequencies of DR4 and DRw6; typing for a second family of class II antigens (HLA-DQ) was included because of the proximity of the DQ loci to the DR loci and the strong linkage disequilibrium between some of the DR and DQ alleles. Comparing a new consecutive series of IDC patients (n = 41) and healthy blood bank controls (n = 53). we confirmed an increase of DR4 antigen frequency in patients (49% versus 21%. p less than 0.005). A trend toward decreased expression of DRw6 among patients was also noted (10% of patients versus 23% of controls). HLA-DQw4 was significantly elevated in patients compared with controls (27% versus 6%. p less than 0.005; relative risk. 6.1; etiologic fraction. 0.22). We identified the combined DR4-DQw4 haplotype in five of 41 Caucasian IDC patients (12%) and none of 53 controls (p less than 0.007). A comparison of specific antigen frequencies between the preliminary and validation studies did not reveal significant differences; therefore. the data from the two studies were examined in combination. For the combined studies. DR4 was elevated (51% versus 27% in controls. p less than 0.001). and DRw6 was decreased (9% versus 24% in controls. p less than 0.01). The relative risk for DR4 was 2.8. and the etiologic fraction was 0.33.
Acute hemodynamic effects of captopril in children with a congestive or restrictive cardiomyopathy, The acute hemodynamic effects of captopril were evaluated at cardiac catheterization in 16 children (age. 0.3-18 years) with cardiomyopathy. Twelve children had congestive cardiomyopathy. whereas four had restrictive cardiomyopathy. Hemodynamic measurements were obtained 30 and 60 minutes after the oral administration of captopril (0.5 mg/kg). Blood pressures were measured in the aorta. pulmonary artery. right atrium. and pulmonary capillary wedge position; cardiac outputs were measured by the thermodilution technique. Hemodynamic data could not be obtained after the administration of captopril in one child with congestive cardiomyopathy because of an immediate. severe hypotensive response. In 11 of 12 children with congestive cardiomyopathy. cardiac index increased by 22%. from 2.3 to 2.8 l/min/m2 (p less than 0.05). and stroke volume increased by 22%. from 23 to 28 ml/m2 (p less than 0.05). Systemic vascular resistance decreased from 32 to 21 units.m2 (p less than 0.01). but the mean aortic pressure did not change significantly. In contrast. four children with restrictive cardiomyopathy had no change in cardiac output after captopril. but there was a trend toward significant arterial hypotension (mean aortic pressure decreased from 78 to 59 mm Hg). Thus. captopril acutely reduced systemic vascular resistance and increased both cardiac output and stroke volume in children with congestive cardiomyopathy. In children with restrictive cardiomyopathy. however. captopril did not affect cardiac output. but it did decrease aortic pressure. These data indicate that captopril may benefit children with a congestive cardiomyopathy but that captopril probably should not be used in children with restrictive disease.
What is the best method for assessing the long-term outcome of surgery for accessory pathways and atrioventricular junctional reentrant tachycardias, The success of surgery for supraventricular tachycardia (SVT) is evaluated by a variety of methods in different hospitals. Unfortunately. the predictive values of these methods are not known. We therefore compared the various methods in 261 patients undergoing surgery for SVT at Westmead Hospital since 1981. Surgical outcome was assessed by early tests during the first week after surgery (serial 12-lead electrocardiograms. telemetric monitoring of the electrocardiogram. and electrophysiological study performed using epicardial wires); later tests at 6 months after surgery (12-lead electrocardiograms and electrophysiological study); and symptomatic review done by telephone interview at a median of 34 months after surgery. Early tests were obtained in 97%. later tests were obtained in 76%. and symptomatic review was obtained in 98% of patients. All of the examined tests were inaccurate methods of surgical assessment compared with the late electrophysiological study. A large proportion of the patients proven to be surgical failures at the late electrophysiological study were not detected by early tests (83%). by later electrocardiograms (66%). or by symptomatic assessment (41%). Accurate assessment of surgical outcome requires a late electrophysiological study to permit comparison of surgical techniques. Late electrophysiological study also provides accurate information on the current risks and benefits of proposed surgery for communication to patients to enable them to make an informed decision on future treatment. Most patients are willing to have a late electrophysiological study and usually benefit from clarification of their true surgical outcome.
Relation between leisure-time physical activity and blood pressure in older women, Although there is some evidence that physical activity may decrease blood pressure in young and middle-aged women. the physical activity-blood pressure association in older women has rarely been studied. As part of an ongoing community-based study of chronic disease. 641 Caucasian women between the ages of 50 and 89 years had blood pressure measured following the Hypertension Detection and Follow-up Program protocol. They also answered selected Health Interview Survey questions about their leisure-time activity and were classified into categories of light (58%). moderate (24%). heavy (6%). or no physical activity (12%) by the estimated metabolic rate required for each activity. Women who engaged in any physical activity were significantly younger and thinner than sedentary women and had lower fasting and 2-hour postchallenge insulin levels. They did not differ in alcohol consumption. cigarette use. or prevalence of coronary heart disease or diabetes. Rates of systolic and diastolic hypertension were significantly lower in women participating in light. moderate. or heavy physical activity compared with sedentary women. Blood pressure levels decreased with each increase in reported activity intensity (p less than 0.005 for trend). with systolic blood pressure approximately 20 mm Hg lower in the heaviest activity group compared with systolic blood pressure in sedentary women. Intergroup differences remained statistically significant after adjustment for age and body mass index. Although physical activity was associated with lower fasting and 2-hour postchallenge insulin levels (p less than 0.01 for trend). adjustment for insulin levels did not alter blood pressure differences among activity groups.
Mechanisms of reoxygenation injury in cultured ventricular myocytes, To investigate factors contributing to reperfusion and reoxygenation myocardial injury. we exposed layers of cultured chick ventricular myocytes to severe hypoxia for up to 3 hours in the presence of 20 mM 2-deoxyglucose. zero glucose. and 5 mM pyruvate. and then exposed the myocytes to reoxygenation. Lactate dehydrogenase (LDH) release was moderately increased during 3 hours of hypoxia but was increased markedly during reoxygenation. Coincident changes in intracellular calcium concentration ([Ca2+]i) and cell motion were also measured during hypoxia and reoxygenation. During hypoxia. [Ca2+]i increased to more than 1 microM. and with reoxygenation. [Ca2+]i abruptly decreased slightly but remained elevated more than 1 microM. Cells developed a stable rigor after 30 minutes of hypoxia. Reoxygenation caused a marked hypercontracture within 5 minutes. Pretreatment of myocytes with either 2.3-butanedione monoxime. which inhibits Ca2(+)-dependent force development. or cyanide inhibited reoxygenation hypercontracture. LDH release after reoxygenation was also significantly reduced in the presence of 2.3-butanedione monoxime. Treatment of myocytes with superoxide dismutase and catalase during hypoxia also resulted in a decrease in LDH release during reoxygenation. We conclude that an abrupt increase in [Ca2+]i during reoxygenation does not account for reoxygenation injury. However. in the presence of elevated [Ca2+]i. reoxygenation and the resulting probable resynthesis of ATP causes [Ca2+]i-dependent myofilament crossbridge cycling. and the resulting hypercontracture contributes to myocyte damage. The generation of oxygen free radicals after reoxygenation also appears to contribute to cell injury in this system.
A new method for quantification of regurgitant flow rate using color Doppler flow imaging of the flow convergence region proximal to a discrete orifice. An in vitro study, While color Doppler flow mapping has yielded a quick and relatively sensitive method for visualizing the turbulent jets generated in valvular insufficiency. quantification of the degree of valvular insufficiency has been limited by the dependence of visualization of turbulent jets on hemodynamic as well as instrument-related factors. Color Doppler flow imaging. however. does have the capability of reliably showing the spatial relations of laminar flows. An area where flow accelerates proximal to a regurgitant orifice is commonly visualized on the left ventricular side of a mitral regurgitant orifice. especially when imaging is performed with high gain and a low pulse repetition frequency. This area of flow convergence. where the flow stream narrows symmetrically. can be quantified because velocity and the flow cross-sectional area change in inverse proportion along streamlines centered at the orifice. In this study. a gravity-driven constant-flow system with five sharp-edged diaphragm orifices (ranging from 2.9 to 12 mm in diameter) was imaged both parallel and perpendicular to the direction of flow through the orifice. Color Doppler flow images were produced by zero shifting so that the abrupt change in display color occurred at different velocities. This "aliasing boundary" with a known velocity and a measurable radial distance from the center of the orifice was used to determine an isovelocity hemisphere such that flow rate through the orifice was calculated as 2 pi r2 x Vr. where r is the radial distance from the center of the orifice to the color change and Vr is the velocity at which the color change was noted. Using Vr values from 54 to 14 cm/sec obtained with a 3.75-MHz transducer and from 75 to 18 cm/sec obtained with a 2.5-MHz transducer. we calculated flow rates and found them to correlate with measured flow rates (r = 0.94-0.99). The slope of the regression line was closest to unity when the lowest Vr and the correspondingly largest r were used in the calculation. The flow rates estimated from color Doppler flow imaging could also be used in conjunction with continuous-wave Doppler measurements of the maximal velocity of flow through the orifice to calculate orifice areas (r = 0.75-0.96 correlation with measured areas).
Effects of pressure and volume of the receiving chamber on the spatial distribution of regurgitant jets as imaged by color Doppler flow mapping. An in vitro study, Regurgitant jet dimensions imaged by color Doppler flow mapping have been used to evaluate the severity of valvular insufficiency in clinical studies. To study the effect of pressure and volume within the receiving chamber on the magnitude of spatial distribution of regurgitant jets assessed by color Doppler techniques. we designed a simple constant-flow model in which a jet was driven through a known orifice (1.5 mm2) into a compliant receiving chamber by a steady-flow pump. A distal tube at the outflow closed the system and maintained the volume of the chamber constant during pump operation. We varied flow rate from 60 to 270 ml/min into elastic balloons with different static compliances of 1. 2. 4.5. and 9 ml/mm Hg (pressures of 57. 28. 18. and 8 mm Hg. respectively); the balloons served as receiving chambers at the constant volume of 150 ml. We also evaluated the effect of different volumes of a receiving chamber (110. 130. and 150 ml and pressures of 5. 15. and 24 mm Hg) with a static compliance of 2 ml/mm Hg over the same range of flow rates. For each of the different balloons. jet area correlated linearly with the jet velocity across the orifice (r = 0.98. 0.99. 0.98. and 0.97) and also with flow rate (r = 0.97. 0.99. 0.98. and 0.99). At the same flow rate and volume of receiving chamber. however. the jet area imaged by color Doppler decreased as the pressure in the receiving chamber increased. although receiving-chamber volume was constant.
Oral clofilium produces sustained lowering of defibrillation energy requirements in a canine model, The effect of long-term oral administration of antiarrhythmic drugs on defibrillation energy requirements is not well understood. We examined the effect of clofilium. a drug that prolongs cardiac action potential duration without slowing cardiac conduction. on defibrillation energy requirements and ventricular effective refractory periods in a canine model during a 3-week period. Epicardial patch electrodes were implanted in 12 dogs. and baseline testing was conducted under fentanyl anesthesia on day 7. An oral clofilium (100 mg/day) regimen was started on day 8. Six clofilium-treated and six control dogs underwent repeated testing on days 14. 21. and 28 after surgery. Truncated trapezoidal shocks were given repeatedly at various stored energies in random order; delivered current and impedance were measured; and delivered energy was calculated. The energy and current for 50% success in defibrillation (E50 and I50. respectively) were determined. For control animals. E50 increased by a mean 34 +/- 78%. 60 +/- 83%. and 69 +/- 122% compared with baseline (day 7) on days 14. 21. and 28. respectively. In contrast. E50 in clofilium-treated dogs decreased by 39 +/- 62%. 24 +/- 33%. and 32 +/- 15% on days 14. 21. and 28. respectively. Mean current requirements (I50) remained relatively stable compared with baseline in control animals (-7 +/- 39%. +25 +/- 36%. +40 +/- 75% on days 14. 21. and 28. respectively). After clofilium administration I50 decreased by 36 +/- 22%. 32 +/- 17%. and 33 +/- 17% on days 14. 21. and 28. respectively.
Changes in left ventricular volume, mass, and function during the development and regression of supraventricular tachycardia-induced cardiomyopathy. Disparity between recovery of systolic versus diastolic function, Chronic supraventricular tachycardia causes a dilated cardiomyopathy in man. Terminating this tachycardia appears to result in symptomatic improvement; however. its effects on left ventricular (LV) volume. mass. and function have not been fully examined. Accordingly. hemodynamic studies using simultaneous echocardiography and catheterization were performed in three groups of pigs: 1) those subjected to rapid left atrial pacing (240 beats/min) for 3 weeks (SVT. n = 8). 2) those subjected to supraventricular tachycardia for 3 weeks followed by termination of pacing and a 4-week recovery period (PSVT. n = 9). and 3) sham-operated controls (CTR. n = 10). Systolic pump function was assessed using fractional shortening (FS). peak ejection rate [peak (-)dD/dt]. and maximum rate of pressure development [peak (+)dP/dt]. Diastolic function was assessed using the time constant of isovolumic pressure decline (tau). peak early diastolic filling rate [peak (+)dD/dt]. the chamber stiffness constant (Kc). and the myocardial stiffness constant (Km). Supraventricular tachycardia caused LV dilation (end-diastolic dimension [EDD] increased from 3.5 +/- 0.4 cm in CTR to 4.9 +/- 0.5 cm in SVT. p less than 0.05) but no change in LV mass (LV weight-to-body weight ratio [LV/BW]) was 2.58 +/- 0.3 g/kg in CTR and 2.66 +/- 0.4 g/kg in SVT). all indexes of systolic function became abnormal (FS fell from 30 +/- 4% in CTR to 13 +/- 5% in SVT. p less than 0.05). and the indexes of relaxation and filling were slowed (tau increased from 36 +/- 3 msec in CTR to 51 +/- 13 msec in SVT. p less than 0.05). There were no significant changes in Kc or Km. After terminating the supraventricular tachycardia. LV volume fell but remained greater than that in CTR (EDD was 4.2 +/- 0.4 cm in PSVT. p less than 0.05 versus CTR) and substantial LV hypertrophy developed (LV/BW was 3.48 +/- 0.5 g/kg in PSVT. p less than 0.05 versus CTR). Systolic function returned to normal (FS was 31 +/- 5% in PSVT) but diastolic function remained abnormal. In PSVT. tau remained prolonged (49 +/- 12 msec. p less than 0.05 versus CTR). Kc increased from 3.7 +/- 1.0 in CTR to 7.4 +/- 1.2 (p less than 0.05). and Km increased from 4.4 +/- 1.5 in CTR to 13.9 +/- 9.7 (p less than 0.05). Thus. the improvement in systolic function that occurs after the termination of supraventricular tachycardia is associated with the development of LV hypertrophy and persistent diastolic dysfunction.
Load dependence of left ventricular diastolic pressure-volume relations during short-term coronary artery occlusion, We evaluated the effect of altered loading conditions on left ventricular (LV) diastolic pressure-volume relations during acute coronary artery occlusion that was produced by inflation of an intracoronary balloon. Open-chest anesthetized dogs (n = 18) were instrumented so that LV pressure (micromanometer) and LV volume (conductance) could be measured without disturbing the pericardium. The effects of brief periods of occlusion (1-2 minutes) were assessed under steady-state conditions before and after dextran infusion with the pericardium present and absent and during vena caval occlusion. Under steady-state conditions before dextran infusion with the pericardium removed. at an LV end-diastolic pressure (EDP) of 8.4 +/- 1.4 mm Hg. occlusion resulted in a rightward shift in the diastolic portion of the LV pressure-volume loop (delta LVEDP. 2.7 +/- 2.3 mm Hg; delta LVEDV. 6.3 +/- 4.7 ml. both p less than 0.05 versus control). After dextran infusion (LVEDP. 20.9 +/- 6.0 mm Hg). occlusion resulted in a rightward and upward shift in the diastolic portion of the LV pressure-volume loop (delta LVEDP. 5.8 +/- 4.4 mm Hg; delta LVEDV. 4.2 +/- 3.0 ml. both p less than 0.05 versus control). At low cardiac volumes before dextran infusion. the intact pericardium did not affect the response to occlusion. By contrast. after dextran infusion in the presence of an intact pericardium. LVEDP significantly increased (delta. 6.4 +/- 3.6 mm Hg. p less than 0.05) but LVDEV did not (delta. 0.7 +/- 1.5 ml. p = NS). There was a parallel upward shift in the diastolic portion of the LV pressure-volume loop that was eliminated by removal of the pericardium. Thus. the change in LV diastolic pressure and volume during occlusion varied and depended on the baseline cardiac volume and presence of the pericardium. Before dextran infusion with the pericardium present and absent. coronary artery occlusion did not alter the LV diastolic chamber stiffness parameter. which was calculated from the diastolic interval of an averaged steady-state beat (0.040 +/- 0.019 versus 0.036 +/- 0.015 mm Hg/ml. p = NS). After dextran infusion with the pericardium present and absent. coronary artery occlusion increased the LV diastolic chamber stiffness parameter (0.057 +/- 0.034 and 0.074 +/- 0.034 mm Hg/ml. both p less than 0.05 versus controls. respectively). Vena caval occlusion eliminated the shifts in the diastolic portion of the LV pressure-volume loop with the pericardium present and absent.(ABSTRACT TRUNCATED AT 400 WORDS).
Left ventricular diastolic dysfunction limits use of maximum systolic elastance as an index of contractile function, We tested the hypothesis that maximum systolic elastance (Emax) fails to detect a decline in left ventricular (LV) contractile function when diastolic dysfunction is present. Canine hearts were studied in an isolated blood-perfused heart apparatus (isovolumic LV); contractile dysfunction was produced by 60 or 90 minutes of global ischemia. followed by 90 minutes of reperfusion. Nine normal hearts underwent 60 minutes of ischemia. and five underwent 90 minutes of ischemia. After the ischemia-reperfusion sequence. developed pressure. pressure-volume area. and myocardial ATP level were significantly less than those at baseline in all 14 hearts. In the group undergoing 60 minutes of ischemia. LV diastolic pressure did not increase. whereas Emax decreased from 5.2 +/- 2.5 to 2.9 +/- 1.4 mm Hg/ml (p less than 0.05). In the group undergoing 90 minutes of ischemia. diastolic pressure increased (from 10 +/- 2 to 37 +/- 20 mm Hg. p less than 0.05). and Emax did not change significantly (from 5.1 +/- 4.3 to 4.3 +/- 2.5 mm Hg/ml). A second series of experiments was performed in 13 hearts with pressure-overload hypertrophy (aortic-band model with echocardiography and catheterization studies before the ischemia-reperfusion protocol). Five had evidence for pump failure. whereas eight remained compensated. After 60 minutes of ischemia and 90 minutes of reperfusion. developed pressure. pressure-volume area. and myocardial ATP level were significantly less than those at baseline in all 13 hearts. In the group with compensated LV hypertrophy. LV diastolic pressure did not change. whereas Emax decreased from 6.9 +/- 3.0 to 3.1 +/- 2.3 mm Hg/ml (p less than 0.05).
The natural history of peripheral vascular disease. Implications for its management, The durability and the eventual complication rate of endovascular therapy (percutaneous transluminal angioplasty. laser-assisted angioplasty. and atherectomy) are not yet entirely clear. especially with respect to the treatment of atherosclerotic lesions in the femoropopliteal or distal arterial segments. Therefore. the indications for its use have not been firmly established and must take into consideration the natural history of the occlusive disease itself. Although some type of procedural intervention clearly is warranted in the presence of ischemic rest pain or tissue necrosis. intermittent claudication is the only complaint in approximately 70% of patients who present with either aortoiliac or femoropopliteal involvement. Most nondiabetic patients experience substantial symptomatic improvement with a daily exercise program. and their long-term risks for either abrupt deterioration (20-25%) or amputation (less than 10%) are relatively low. In comparison. the 5-year mortality rate ranges from 20-40% even in claudicants. and as many as 40% of those with clinical indications of associated coronary artery disease have been shown angiographically to be candidates for myocardial revascularization. These observations suggest that traditional indications for surgical treatment (truly disabling claudication and/or limb salvage) also should be applied to endovascular therapy until its success is confirmed beyond speculation. and that incidental coronary disease deserves particular attention in patients with lower extremity ischemia.
Impact of nonoperative therapy on the clinical management of peripheral arterial disease, Nonoperative therapy includes conservative noninterventional modalities and the endovascular interventional modalities of percutaneous transluminal angioplasty and a variety of laser systems and atherectomy devices. The role and impact of all nonoperative treatments are considered in the perspectives of the natural history of lower-extremity arteriosclerosis and its present surgical (operative) treatment. Nonoperative treatments may replace and/or facilitate surgical treatment in operative candidates. Nonoperative methods may also justify treatment in patients who cannot or should not be subjected to surgery. Facts and opinions relating to these uses of nonoperative treatments are presented. and the qualifications and credentialing of individuals who should be treating patients with lower-extremity ischemia resulting from peripheral arteriosclerosis are discussed.
Diagnosis and evaluation of renovascular hypertension. Indications for therapy, Renovascular hypertension is caused by two distinct conditions with different causes. fibromuscular dysplasia and atheroma. Diagnosis of the former is both simpler and more rewarding. whereas atheromatous lesions of the renal artery may be secondary to essential hypertension. It is therefore important to establish existence of functional renal ischemia as well as an anatomical lesion. Universal screening of all hypertensive patients is not recommended because of the relatively low prevalence of the disease and insufficient accuracy of available screening tests. When renovascular hypertension is clinically suspected. an oral captopril test is the most reliable office screening test. After this. digital subtraction angiography with renal vein renins or captopril renography are appropriate steps. However. the latter procedure. while promising. requires further evaluation. Duplex scanning of the renal arteries also comes into this category. Arteriography is done last. so that if renal ischemia is indicated. angioplasty can be attempted at the same time as arteriography.
Advances in the treatment of complex cerebrovascular disorders by interventional neurovascular techniques, Treatment of complex cerebrovascular disorders. including intracranial aneurysms. carotid cavernous sinus fistulas. vertebral fistulas. arteriovenous malformations. atherosclerosis of brachiocephalic vessels. and arterial vasospasm. is being performed in selected cases by interventional neurovascular techniques. Recent advances in microballoon technology. permanent solidifying polymers. newer embolic agents. high-resolution digital subtraction angiography with road-mapping technique. and steerable micro-guide wires and catheters have greatly improved access in the distal intracranial circulation and markedly reduced the morbidity associated with these procedures. Interventional neuroradiology is emerging as an important adjunct to neurosurgery for selected cerebrovascular disorders.
Clinical and anatomical considerations for surgery in aortoiliac disease and results of surgical treatment, A variety of surgical procedures are available for the treatment of occlusive disease involving the aorta and iliac arteries. Use of the most appropriate operation in each patient. determined principally by disease location and patient risk. can provide highly effective relief of disabling claudication or limb-threatening ischemia with low morbidity and mortality rates. The excellent. durable results of current surgical practice should serve as the standard with which newer treatment modalities must be compared.
Results and complications of angioplasty in aortoiliac disease, Percutaneous transluminal angioplasty was used to treat 340 aortoiliac lesions in 200 patients who were followed for as long as 90 months (mean. 28.7 months; median. 23 months). The initial success rate was 94.7% for lesions and 93.0% for patients. The indications for percutaneous transluminal angioplasty included claudication in 117 patients (58.5%). rest pain or ischemic night pain in 47 (23.5%). limb salvage in 33 (16.5%). and aiding in wound healing in three (1.5%). In the series. 70% of the patients had two or more cardiovascular risk factors. Angioplasty was initially unsuccessful in 14 patients. and 10 patients were lost to follow-up. Follow-up was obtained in 176 patients. The long-term results were analyzed using the life table method to determine cumulative patency. Fourteen patients were considered failures because of recurrent disease or symptoms. The projected 7.5-year cumulative patency rate was 85%. When the response to redilatation was considered. the projected 7.5-year cumulative patency rate was 92%. The results indicate that percutaneous transluminal angioplasty can successfully correct aortoiliac lesions and provide a long-term benefit for as long as 7.5 years.
Standards for evaluating results of interventional therapy for peripheral vascular disease, Uniform standards for evaluating and reporting the results of therapeutic interventions for peripheral vascular disease are clearly needed. They are already established for vascular surgery. as represented by several reports by SVS/ISCVS committees. but they are not always followed by vascular surgeons and have been largely ignored by other vascular interventionists. In this article. the major problematic reporting practices are discussed and illustrated. and 14 recommendations are advanced to deal with them. They are intended to provide precise definitions. objective criteria of success or failure. standardized severity gradation schemes for peripheral vascular disease and its risk factors. and proper procedures for reporting the outcome of all forms of therapeutic intervention. Until these or some other agreed upon reporting standards are accepted and followed. the literature on peripheral vascular disease and its management will continue to be a source of confusion rather than enlightenment.
Clinical and anatomic considerations for surgery in femoropopliteal disease and the results of surgery, From 1980 to 1988 we performed 288 femoropopliteal bypass operations in 231 patients at the Oregon Health Sciences University. The indication for the procedure was claudication in 31% and the relief of limb-threatening ischemia in 64%. Operative mortality occurred after four of these operations (1.4%). including three deaths from myocardial infarction and one death from stroke. The femoropopliteal bypass patients were divided into groups for patency analysis. including those undergoing bypass surgery with a good quality greater saphenous vein versus alternate bypass conduits and patients undergoing primary limb bypass versus those undergoing repeat bypass after prior bypass failure. Our overall primary graft patency for all femoropopliteal grafts was 79% at 5 years. Patients undergoing bypass with a good quality greater saphenous vein had primary graft patency of 85% at 5 years. Patients undergoing bypass using a conduit other than greater saphenous vein had a 5-year patency of 73%. Patients undergoing repeat bypass after a prior failed bypass had a 5-year patency of 57%.
Femoropopliteal angioplasty. Factors influencing long-term success, Prospective data was recorded on 217 percutaneous transluminal angioplasty (PTA) procedures performed in the superficial femoral and popliteal arteries over an 8-year period. After the initial procedure. patients were followed with serial noninvasive studies and. in 71 patients. repeat angiography. The mean follow-up period was 7 years (range. 2-11 years). Standard life-table survival analysis was used to assess the factors potentially affecting long-term outcome. Excluding an initial technical failure rate of 10%. overall patencies at 1. 3. and 5 years were 81%. 61%. and 58%. respectively. After the first year. the prognosis (i.e.. failure rate) appears to be linear over the long term (i.e.. up to 10 years). Factors negatively influencing long-term patency include the presence of diabetes mellitus. diffuse atherosclerotic cardiovascular disease. or threatened limb loss. Technical factors correlated with failure include lesion length. moderate eccentricity. and a poor post-PTA appearance.
Clinical and anatomic considerations for surgery in tibial disease and the results of surgery, Bypass vein grafts to the infrapopliteal arteries now achieve a 5-year cumulative patency equivalent to that of vein grafts to the popliteal arteries. The technique of in situ vein grafting to the tibial arteries is described and the results are presented. The 5-year cumulative patency for such bypasses and the 5-year limb salvage in the same patients have both been approximately 80%. These results coupled with those reported from other centers that have sizable experience in tibial artery reconstruction suggest that there has been real progress over the past decade in the salvage of lower extremities in patients with far advanced peripheral vascular disease through the use of autogenous venous bypass grafts.
Hot-tip laser. Results and complications, The hot tip laser system for atheroablation has been used since mid-1984 as a device for broadening the indications for and extending the applicability of angioplasty in the management of lower-extremity atherosclerosis. It has been a controversial device. Although the system demonstrates that it can occasionally be useful for the management of occlusive as opposed to stenotic disease of the infrainguinal arteries. a close examination of the published data fails to demonstrate a consistent improvement in either the primary success or long-term patency rates for thermal energy applied to atheroma for recanalization of the lower extremity arteries.
Dose-response relationships for the effects of insulin on glucose and fat metabolism in injured patients and control subjects, 1. Twenty-four patients were studied at around 7 days after musculoskeletal injuries in order to define the nature of the impairment of sensitivity to insulin. Insulin was infused at 6. 35. 200 or 1200 m-units min-1 m-2 for 2 h and the plasma glucose concentration was 'clamped' at 5 mmol/l. Forearm (uninjured) glucose extraction and blood flow were measured. and whole-body substrate oxidation and energy production rates were assessed by indirect calorimetry. The patients were compared with normal control subjects. 2. Plasma insulin concentrations during infusion were similar in patients and control subjects. showing a similar metabolic clearance of insulin. At each infusion rate. the rate of glucose infusion needed to maintain euglycaemia was less in the patients than in the control subjects. The dose-response curve for whole-body glucose infusion rate against plasma insulin concentration showed diminished sensitivity and diminished maximal response in the patients. A similar pattern was seen for forearm glucose uptake. with a marked impairment of both sensitivity to insulin and maximal responsiveness. 3. The resting metabolic rate was increased in the patients compared with the control subjects. but failed to respond to insulin infusion. so that final metabolic rates were similar in patients and control subjects. At the higher insulin infusion rates. the final rate of whole-body oxidation of carbohydrate was significantly less in the patients than in the control subjects. and that of fat was significantly greater.
Changes in electrocardiographic patterns at different stages of Chagas' heart disease in rats, 1. The resting electrocardiogram was obtained from 25 Trypanosoma cruzi-infected rats 30 days after infection (phase I). The resting electrocardiogram was abnormal in 12 (group I) and normal in 13 (group II) animals. Nineteen similar but non-infected animals served as controls. Both the resting electrocardiogram and the ajmaline test were performed 120 and 350 days after infection (phases II and III. respectively). 2. With regard to the resting electrocardiogram of group I animals. left axis deviation was found in 10 of 12 (83%) in phase I. one of 12 (8%) in phase II (P less than 0.05) and in none of phase III (P less than 0.05). An intraventricular conduction delay was found in four of 12 (33%) rats in phase I. two of 12 rats (16%) in phase II (P greater than 0.05) and six of 12 rats (50%) in phase III (P greater than 0.05). The ajmaline test was abnormal in nine of 10 (90%) rats of group I with normal resting electrocardiogram in phase II. and in three of six (50%) animals in phase III (P greater than 0.05). 3. An intraventricular conduction delay was found in the resting electrocardiogram of one of 13 (7%) rats of group II in phase III. The ajmaline test was abnormal in one of 13 (7%) rats in phase II and in one of 12 (8%) rats in phase III. 4. No control rat showed pathological changes.
Differentiation between the intensity of breathlessness and the distress it evokes in normal subjects during exercise, 1. This study was designed to examine whether normal subjects could differentiate between the 'intensity' of their breathlessness and the amount of 'distress' it evoked. by specific wording of the instructions. 2. A preliminary study showed no significant difference between 'distress' score during exercise measured on two separate occasions (P = 0.3). 3. Ten subjects each performed two identical incremental cycle-ergometer exercise tests on separate occasions during which they were asked to quantify either 'intensity' or 'distress' by using modified Borg scales. 4. In all subjects there was a significant correlation (P less than 0.001) between 'intensity' and minute ventilation. In eight subjects there was a significant correlation (P less than 0.05) between 'distress' and minute ventilation. One subject displayed no significant correlation and one registered no distress. 5. Mean 'intensity' was greater than the mean 'distress' (P = 0.0001). The slope of 'intensity'/minute ventilation was greater than the slope of 'distress'/minute ventilation (P = 0.0001). 6. Within individuals there was a significant correlation between 'intensity' and 'distress' (P less than 0.05). There was a wide scatter in the slope of this relationship between subjects and maximum 'intensity' and 'distress' did not correlate. 7. Different elements of the breathlessness sensation could be identified and selectively measured depending on the wording of the instructions given to the subject. 8. There was a wide intersubject variation in the magnitude of both breathlessness 'intensity' and 'distress' estimates. but the differences between subjects in these two components of the sensation did not appear to follow a common pattern.
Functional comparison between double and triple ileal loop pouches, Ileal pouch function in 35 patients operated upon by the same surgeon were compared. Seventeen of the patients had a double loop (J) ileal pouch-anal anastomosis (IPAA) and 18 a triple loop (S) pouch. The patients were examined a mean of 27.9 months and 5.1 months. respectively. after ileostomy closure. Ten of the S-pouch patients were evaluated more than 6 months (S greater than 6 months). mean 9.1 after ileostomy closure. There were no differences in the mean maximum resting pressures or maximum squeeze pressures between the groups. The incidence of daytime and nocturnal leakage was lower in the S-pouch group. 22 and 29 percent. than in the J group 29. and 53 percent. Though the mean maximum tolerated volume (MTV) of the S-pouch group was greater than the J group. the difference was not statistically significant. The difference in the mean compliance between the J- and S-pouch groups and the J and S greater than 6 months group was statistically significant (P less than 0.01) and (P less than 0.008). All the patients could evacuate spontaneously. The difference in the 24-hour frequency of defecation between the S greater than 6 months and J group was significant (P less than 0.05). but not between the S and J groups. The median frequency of nocturnal defecation between the S greater than 6 months and J pouch groups was significant (P less than 0.005). but not between the S and J groups. The triple loop S-pouches were more compliant than the J-pouches and had a better functional result as shown by a lower incidence of nocturnal leakage. and a lower frequency of defecation during the day and night.
Detection by CT during arterial portography of colorectal cancer metastases to liver, A prospective evaluation of the accuracy of real-time ultrasonography (US). computed tomography (CT). infusion hepatic angiography (IHA). and computed tomography during arterial portography (CT-AP) was performed on 65 resected liver metastases of colorectal cancers. The total detection rate was 58.5 percent for US. 56.3 percent for CT. 55.4 percent for IHA. and 86.2 percent for CT-AP. The sensitivity of 29 lesions with diameters of smaller than 1 cm was 65.5 percent for CT-AP. CT found only two. and both US and IHA localized no more than three. The smallest lesions detectable by CT-AP were as small as 0.4 cm in diameter. CT-AP proved most useful in detecting the liver metastases. and the use of this technique is recommended for preoperative planning of hepatectomy on patients with liver metastases.
Rectopexy is an ineffective treatment for obstructed defecation, The symptoms of obstructed defecation have been attributed to rectal intussusception. and thus rectopexy has been advocated in the surgical management. In this study. patients with obstructed defecation underwent manometry and proctography before and after rectopexy. Seventeen patients (16 females and one male. mean age 51.6 years) were studied. Eleven underwent anterior and posterior fixation of the rectum and six had posterior fixation only. Preoperatively five patients demonstrated rectoanal intussusceptions. Fifteen had significant pelvic descent. No significant change in maximum resting pressure. maximum voluntary contraction. pelvic descent. or anorectal angle was seen postoperatively. In the initial follow-up. many patients had significant amelioration of symptoms. However. on longer follow-up (mean 30.8 months) only two had long-term improvement. The remainder had a poor clinical result in spite of complete resolution of rectal intussusception. Many reported a worsening of symptoms as reflected by an increase in tenesmus and stool frequency. In the two cases with a satisfactory result. both could empty the rectum completely and demonstrated rectoanal intussusception on preoperative evacuation proctography. In those with poor results. four had complete emptying and three had rectoanal intussusception. In conclusion rectopexy is an ineffective treatment for obstructive defecation in most patients.
Intraepithelial bodies in colorectal adenomas: Leuchtenberger bodies revisited, The presence of intraepithelial inclusion bodies (Leuchtenberger bodies) was recorded in rectal or colonic specimens from 130 patients. Large to moderate number of intraepithelial bodies were recorded in 81.8 percent of 55 colorectal adenomas from patients with familial adenomatous polyposis (FAP). Conversely. none of the 55 non-FAP adenomas or of the 20 specimens with ulcerative colitis (10 with dysplasia) had similar amounts of intraepithelial granules. Feulgen studies demonstrated that the granules contain DNA and are probably nuclear fragments of destroyed lymphocytes. Although the pathogenesis of this phenomenon remains obscure. it appears that the presence of large to moderate number of intraepithelial bodies in colorectal adenomas should strongly raise the suspicion of FAP.
Subsite distribution and incidence of colorectal cancer in New Zealand, 1974-1983, The purpose of this study was to examine changes in subsite distribution and incidence of colorectal cancer within different age groups. Registration of colorectal cancer by the National Cancer Registry of New Zealand approached 100 percent by 1974. The present study was based on 15.395 individuals aged 25 years and over and registered for colorectal cancer between 1974 and 1983. Subsite distribution (right colon. left colon. rectum) for different age groups (25-49. 50-69. 70+ years) was significantly skewed. with an excess of right colonic cancer in individuals aged 25-49 years and 70+ years. This right colonic excess was accompanied by a relative reduction in left colonic cancer. Age adjusted incidence rates for the periods 1974-78 and 1979-83 were compared and stratified by age group and subsite. Incidence rates increased in all subsites in individuals aged 50+ years. This was particularly evident for right sided cancer in the elderly of both sexes. There was a marked reduction in the incidence of left colonic cancer and rectal cancer in individuals under 50 years. In contrast. the incidence of right colonic cancer remained relatively stable in young individuals. Time trend studies indicate that the skewed subsite distribution of large bowel cancer in different age groups may increase with time and is probably due to varying etiological factors acting on different cohorts.
Colorectal cancer: differences between community and geographically distant patients seen at an urban medical center, Many studies in clinical oncology rely on hospital-derived patients. Hospitals vary in the proportions of patients from the local catchment area vs. those from more distant places. of whom a larger proportion are presumably referrals. To study the differences between these two types of patients. we analyzed 1.245 colorectal cancer patients seen at a large urban medical center over a seven-year period. Three hundred ninety-eight patients were from the local community (32 percent). 489 were from the extended community (39.3 percent). and 358 from more distant communities (28.8 percent). The patients from the local community tended to be older and from minority ethnic groups. In addition. the local community patients were more likely to have advanced disease at the time of presentation. The grade of the tumor and its site distribution within the large bowel were similar for the three groups. After adjusting for age. sex. race. and stage of disease. the survival was somewhat better for the distant community patients as compared with the local and extended communities (P less than 0.02). Overall. in our patient population. the distant patients tended to have more favorable socioeconomic factors and less advanced disease. and these differences may account. in large part. for a better prognosis for these patients. Particularly in large cooperative trials. studies may need to take into account the respective proportions of local community and geographically distant patients in analyzing and generalizing treatment outcomes.
Anal sphincter function after intersphincteric resection and stapled ileal pouch-anal anastomosis, This study was done to determine the effect of the direct ileal pouch-anal anastomosis upon pressure and sensory components of the anal canal and ileal pouch. These findings were related to postoperative continence. Thirty-three patients with ileal pouch-anal anastomosis (25 continent. eight with episodic minor incontinence) were studied 3 +/- 0.3 and 25 +/- 5 months after ileostomy takedown. The maximum resting pressure in the anal canal was significantly lower in patients with an imperfect result (35 +/- 5 mm Hg) than in continent patients (44 +/- 5 mm Hg) (P less than 0.05). Postoperatively the maximum squeeze anal pressure was slightly greater in continent than in incontinent patients (99 +/- 8 mm Hg vs. 87 +/- 7 mm Hg) (P greater than 0.05). The postoperative recto-(ileo-)anal inhibitory reflex was present in 27 percent. The linear correlation between strength of rectal (ileal) distension and depth resp. duration of internal sphincter relaxation as preoperatively observed disappeared postoperatively in every group of patients. Simultaneous measurements of pouch and anal pressure in patients with imperfect results revealed a reduced positive pouch anal pressure gradient compared to the continent group. This low pouch-anal pressure gradient is thought to be responsible for the increased incidence of soiling in some of our patients.
Intra-abdominal desmoid tumors in familial polyposis coli: a case report of tumor regression by prednisolone therapy, A case of intra-abdominal desmoid tumors in familial polyposis coli (FPC). which regressed and disappeared by prednisolone treatment. is reported. A 37-year-old Japanese man with abdominal lumps was admitted to our hospital. He had had proctocolectomy two years before because of FPC with rectal cancer. At laparotomy. tumors were present in the abdominal wall. mesentery. and retroperitoneum. Only a small part of the tumors was resected and diagnosed microscopically to be desmoid tumors. With prednisolone administration (20 to 5 mg/day) subjective symptoms were ameliorated and desmoid tumors slowly regressed. Bilateral hydronephrosis continued and resulted in "retroperitoneal fibrosis." To our knowledge. this case is the first well-documented case of retroperitoneal fibrosis in a patient with FPC. The characteristics of the desmoid tumor in familial polyposis coli or in Gardner's syndrome and the methods for its management are discussed.
Enhancing blood glucose awareness in adolescents and young adults with IDDM, OBJECTIVE: To determine the effectiveness of an intervention program designed to improve blood glucose awareness. RESEARCH DESIGN AND METHODS: Eight young-adult outpatients (mean age 22 yr) and six adolescent inpatients (mean age 14.5 yr) with insulin-dependent diabetes mellitus participated in the intervention program. Nine adolescent inpatients (mean age 13.9 yr) served as an untreated comparison group. One adult outpatient with unreliable data was removed. Before treatment. each patient completed a minimum of 40 blood glucose estimations. blood glucose tests. and symptom-rating checklists. Symptoms of hypo- or hyperglycemia were identified for each patient. The three-session intervention focused on internal (e.g.. personal symptoms) and external (e.g.. timing and amount of insulin. food. and exercise) cues that could be used to enhance blood glucose awareness. At postintervention. patients completed a minimum of 40 additional blood glucose estimates and tests. Comparison subjects completed the pre-postassessments but did not receive the intervention. RESULTS: Blood glucose estimation accuracy was evaluated with error grid analysis. All estimated-actual blood glucose values were plotted into one of five zones: accurate estimates (zone A). benign errors (zone B). and clinically dangerous errors (zones C. D. and E). An overall accuracy index (AI) was calculated by subtracting the summed percentage of clinically dangerous estimates (zones C. D. and E) from the percentage of accurate estimates (zone A). At study entry. the adolescent inpatients' mean AI of 7% was significantly poorer than the 32% mean AI exhibited by the outpatient young-adult sample (P less than 0.02). At postintervention. the adolescents' mean AI improved to 30% (P less than 0.02) and the young adults' mean outpatient AI improved to 45% (P less than 0.06). The treated sample as a whole exhibited increased sensitivity to both hypo- (P less than 0.005) and hyperglycemia (P less than 0.05). Similar improvements did not occur in the untreated comparison sample. CONCLUSIONS: Adolescents may exhibit poorer blood glucose awareness than adults. Although this intervention program improved blood glucose awareness in both adolescent and adult patients. postintervention blood glucose estimation accuracy remained far from ideal.
Racial differences in metabolic control of children and adolescents with type I diabetes mellitus, OBJECTIVE: This study evaluated racial differences in the metabolic control of children and adolescents with insulin-dependent (type I) diabetes mellitus and examined the interactive effects of race with age and sex. RESEARCH DESIGN AND METHODS: Data on several demographic and clinical variables were obtained for 102 black and 108 white children. including the percentage of total HbA1. age. age at diagnosis. duration of diabetes. pubertal status. insulin dose (U.kg-1.day-1). body mass index. number of clinic visits kept and missed. number of hospitalizations for diabetic ketoacidosis (DKA) for the year. and socioeconomic status (SES). RESULTS: Black children had higher insulin dosages (P less than 0.05) and lower SESs (P less than 0.001) than white children. HbA1 was higher in black than white children (P less than 0.01) after statistically adjusting for the effects of insulin dose. diabetes duration. and SES. With HbA1-based criteria. more black than white children were in poor and fewer in good metabolic control (P less than 0.001). Older children (greater than or equal to 13 yr) had higher HbA1 levels than younger (less than 13 yr) children (P less than 0.002). but there were no differences in HbA1 between males and females nor were there interactive effects of race. sex. and age-group. Black children were hospitalized for DKA more frequently than white children (P less than 0.04). More black than white children missed clinic visits (P less than 0.01). but they did not differ in number of visits kept. CONCLUSIONS: Black youths with type I diabetes mellitus are in poorer metabolic control than white youths.
Demonstration of insulin transformation products in insulin vials by high-performance liquid chromatography, OBJECTIVE: To assess the importance of temperature. light. agitation. and regular withdrawal of insulin on the rates of appearance of three groups of insulin transformation products (ITPs) in vials of human and beef soluble insulin. RESEARCH DESIGN AND METHODS: Twelve insulin-treated patients (6 receiving human soluble insulin. 6 receiving beef soluble insulin) participated in the study. Reverse-phase high-performance liquid chromatography was used to measure ITP in serial samples from vials stored in various laboratory environments or issued to patients. Vials in the laboratory were analyzed on nine occasions over 26 wk; those issued to patients were analyzed weekly. RESULTS: Results were expressed as rates of change (% total protein/wk). Except for human insulin stored at 4 degrees C. sampling did not accelerate transformation. Storage at higher temperatures caused more rapid transformation to all ITP groups. and human insulin was more susceptible than beef insulin. Exposure to light accelerated transformation mainly to group 3 ITP. Fibrillation occurred in beef but not human insulin carried in a shirt pocket. Results from patients' vials were consistent with reported storage conditions. CONCLUSIONS: All three ITP groups form in human and beef soluble insulin. Their rate of production is a function of temperature and light exposure. Differences between the two insulins were probably due to differences in formulation. Patients should be discouraged from hoarding vials and storing insulin in direct sunlight. One or more ITPs could contribute to the residual immunogenicity of modern insulin preparations.
International evaluation of cause-specific mortality and IDDM. Diabetes Epidemiology Research International Mortality Study Group, OBJECTIVE: A cross-cultural study was completed to evaluate differences in mortality patterns in four population cohorts in Japan; Israel; Allegheny County. Pennsylvania; and Finland. RESEARCH DESIGN AND METHODS: Cases were diagnosed between 1 January 1965 and 31 December 1979. Mortality was determined as of 1 January 1985. There were 147 deaths occurring in the 8212 insulin-dependent diabetes mellitus (IDDM) patients in the four countries. A standardized protocol for assessing causes of death (cause-specific mortality) was developed; in this article. we report the causes. RESULTS: Major overall mortality differences by country appeared. with IDDM subjects in Japan much more likely to die than in the other countries. In Japan. the elevated mortality was the result of acute diabetes-related complications and kidney disease. For all countries. mortality from acute diabetes-related complications accounted for a surprisingly high percentage of deaths (greater than 25% in each country). A larger percentage of cases in Finland died as a result of suicide than for the other three countries. CONCLUSIONS: The results suggest that there are major cross-country differences in cause-specific mortality and that much of the premature mortality associated with diabetes is potentially preventable.
Superiority of radiobinding assay over ELISA for detection of IAAs in newly diagnosed type I diabetic children, OBJECTIVE: Liquid- or solid-phase assays have been used for insulin autoantibody (IAA) determination. and the method of IAA measurement has not been standardized. RESEARCH DESIGN AND METHODS: IAAs were determined by radiobinding assay (RBA) and enzyme-linked immunosorbent assay (ELISA) in two large age-matched groups of nondiabetic and newly diagnosed insulin-dependent (type I) diabetic children. RESULTS: Positivity for IAA by RBA (greater than or equal to nondiabetic mean + 3SD) was 2 of 178 (1.1%) and 55 of 173 (32%) in nondiabetic and diabetic children. respectively. Prevalence of IAA by RBA was significantly higher in the youngest age-group (63% between 0-4 yr). Positivity for IAA by ELISA was 1 of 178 (0.6%) and 8 of 169 (4.7%) in nondiabetic and diabetic children. respectively. Concordance rates between both assays were 0 of 3 (0%) in control subjects and 5 of 58 (8.6%) in diabetic children. CONCLUSIONS: We conclude that RBA is more appropriate than ELISA for IAA detection at the onset of the disease. In addition. because available data suggest that IAAs detected by RBA only are high-affinity antibodies. it is tempting to speculate that IAAs reflect a mature immune reaction against endogenous insulin.
Vitamin E reduction of protein glycosylation in diabetes. New prospect for prevention of diabetic complications, OBJECTIVE: This study evaluated the possibility of inhibiting protein glycosylation in vivo with vitamin E. RESEARCH DESIGN AND METHODS: Two groups of 10 insulin-requiring diabetic patients. matched for duration of disease and metabolic control. received daily vitamin E supplementation of 1200 and 600 mg. respectively. for 2 mo. A third group of 10 diabetic patients. matched for duration of disease and metabolic control. served as the control group and received placebo. Fasting plasma glucose. mean daily plasma glucose. fasting labile HbA1. and glycosylated proteins were measured in the basal state and after 1 and 2 mo of treatment. In addition. hyperglycemic clamp studies were performed in basal state and after 1 mo of vitamin E administration in all patients. RESULTS: Glycemic indices did not show any significant changes during the study. whereas fasting labile HbA. and glycosylated proteins decreased significantly after 1 and 2 mo in patients on vitamin E administration. Stable HbA1 decreased after 2 mo. Mean glycemic incremental area in the hyperglycemic clamp procedure was similar before and after treatment. whereas a significant reduction in mean labile HbA1 incremental area was found after vitamin E supplementation. A significant difference was also found in both fasting and incremental labile HbA1 levels. stable HbA1. and glycosylated proteins between the two groups of diabetic patients on the two doses of vitamin E; the diabetic patients who received the higher dose of vitamin E showed the greater reduction. No significant changes in these parameters were observed in diabetic patients on placebo administration. CONCLUSIONS: These results demonstrate that vitamin E administration may reduce protein glycosylation in diabetic subjects independently of changes in plasma glucose. an effect that may be due to the inhibition of labile glycosylation. the first step of the Maillard reaction. Long-term studies will help establish the usefulness of vitamin E administration for the prevention of diabetic complications.
Antiepileptic drugs, cognitive function, and behavior in children: evidence from recent studies, The effects of antiepileptic drugs (AEDs) on cognitive function and behavior in children are reviewed on the basis of published studies. Individual AEDs have been shown to differ--the deleterious effects of phenytoin generally contrasting with the relatively minimal effects of valproate and carbamazepine. Some of the differences between results may be attributed to the psychological tests used and to age differences. However. there appears to be a dissociation between AEDs that affect higher cognitive function. e.g.. phenytoin. and those mainly affecting motor function. e.g.. carbamazepine. which appears to increase speed of performance. AEDs should be prescribed with care in children with epilepsy. taking account of their differing effects on cognitive function and behavior.
Computerized neuropsychological assessment of cognitive functioning in children with epilepsy, The value of a range of computer-aided tests in the neuropsychological assessment was investigated in 94-177 children with epilepsy. aged 8-18 years. compared with 68-161 controls in the same age group. Children from the age of 8 years could cope with rather complex tests in a wide range of functions: reaction time measurements. motor speed. information processing. and memory. The speed of performance tended to increase with age in both groups. with differences in information processing becoming apparent from the age of 12 years. The precise control of stimulus and response required to define the mainly minor differences between the epilepsy and control groups can only be fulfilled by computerized testing. which should undergo further refinement including voice and language recognition. followed by artificial intelligence.
Electroencephalographic parameters in assessing the cognitive function of children with epilepsy, Many biological and psychological possibilities have to be considered when attempting to explain cognitive dysfunction in the individual child with epilepsy. Electroencephalographic (EEG) information. which may be particularly relevant in some children. has mainly been studied in relation to the possible direct effects of seizure discharges on learning and behavior. Such discharges can be divided into transient. brief or prolonged. Prolonged seizure discharges includes nonconvulsive status epilepticus during wakefulness and status epilepticus during slow-wave sleep. In addition to the influence of seizure discharges. preliminary findings suggest that some children with epilepsy might have a subtle disorder of arousal mechanisms in sleep. possibly associated with impaired daytime performance.
Discontinuation of antiepileptic drugs in children who have outgrown epilepsy: effects on cognitive function, Cognitive function is frequently impaired in children with epilepsy. compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy. both during and after treatment with antiepileptic drugs. is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy. compared to controls.
Antibiotics: potential hazards to male fertility, Individual agents within each of the major classes of antibiotics have been shown to have significant adverse effects on spermatogenesis or spermatozoal function in mammals. For humans. infertility or significant alterations in semen parameters have been well documented for the nitrofurans and for patients on sulfasalazine. Other commonly used antibiotics. such as minocycline. have been shown to be toxic to sperm at any concentration. Until further information is available. clinicians must keep in mind that treatment with antibiotics may adversely affect the fertility potential of men. It is possible that some classes of antibiotic agents. such as the penicillins or the quinolones. may have minimal effects on male fertility and maintain the clinical efficacy for patients requiring long-term antibiotic suppressive therapy. Further investigation is needed into the relative toxicity of antibiotics and the mechanisms by which antibiotics affect spermatogenesis and spermatozoal function. A background of the current state of knowledge regarding the adverse effects of antibiotics on male fertility is presented in this review.
Laparoscopic cautery in the treatment of endometriosis-related infertility, Life table analysis and the two-parameter exponential method have been applied to pregnancy rates in 72 patients undergoing laparoscopic cautery exclusively. Patients with male factor infertility were excluded. Estimated cure rates for patients with stage I and II disease were 98.2% and 76.6%. respectively (not significantly different). No significant difference was seen when anovulation complicated the endometriosis (68.6%). When greater than one infertility factor was present. a significant difference was observed (50.6%). Patients with stage I disease had an average fecundity of 10.30% with decreasing values observed in stage II (7.59%). anovulation (6.67%). and more than one infertility factor (3.33%). We conclude that laparoscopic cauterization is an effective mode of therapy for the treatment of stage I and II endometriosis associated with infertility.
Life table analysis of fecundity in intravenously gonadotropin-releasing hormone-treated patients with normogonadotropic and hypogonadotropic amenorrhea, The success of pulsatile intravenous (IV) gonadotropin-releasing hormone (GnRH) treatment in patients with normogonadotropic and hypogonadotropic amenorrhea was studied retrospectively using life table analysis. Two hundred forty-four ovulatory cycles in 48 normogonadotropic and hypogonadotropic patients were evaluated. The cumulative conception rate after 12 cycles was 93%. with a mean conception rate of 22.5% per cycle. Comparing cycles 1 to 6 with cycles 7 to 12. no significant difference in conception rate was observed. Subdivisions were made relative to the presence of additional infertility factors. history of weight loss. actual weight. estrogenic status. and primary versus secondary amenorrhea. The life table curves of patients either with or without other infertility factors were significantly different. No statistically significant differences were found in the other subdivisions. It is concluded that IV GnRH therapy is highly successful in patients with normogonadotropic and hypogonadotropic amenorrhea. especially if no other infertility factors are present.
Response of plasma endorphins, corticotropin, cortisol, and luteinizing hormone in the corticotropin-releasing hormone stimulation test in eumenorrheic and amenorrheic athletes, We compared pituitary response in the corticotropin-releasing hormone (CRH) test between 9 eumenorrheic and 10 amenorrheic endurance athletes. The maximal oxygen capacity (VO2max). determined using an exercise test on a bicycle ergometer. was larger in amenorrheic (62.7 +/- 1.0 SE mL/min per kg) than in eumenorrheic (54.7 +/- 2.3 mL/min per kg) athletes. A 100 micrograms bolus of human CRH was administered intravenously. and blood samples were collected at -15. 0. 30. 60. 90. and 120 minutes. The mean basal concentrations of endorphins. adrenocorticotropic hormone (ACTH). and cortisol did not show significant differences between the groups. The cumulative response of ACTH in the CRH test was larger in eumenorrheic (7.7 +/- 1.3 pmol/L) than in amenorrheic (3.6 +/- 0.6 pmol/L) athletes. but the response of endorphins and cortisol did not differ between the groups. A negative correlation was found between the VO2max and the ACTH response during the CRH test in the total group of athletes. These findings indicated changes in the function of hypothalamic-pituitary-adrenal axis in amenorrheic athletes that can be attributed to intensive training.
Polycystic ovary syndrome and bulimia, One hundred fifty-three patients classified as suffering from polycystic ovarian syndrome (PCOS) and 109 patients who were suffering from a clear organic disorder or endocrinopathy received the bulimia investigation test (Edinburgh) (BITE) questionnaire for abnormal eating behaviors. Patients with PCOS showed a significant increase in their mean BITE score for approximately a third had abnormal eating patterns. and 6% have scores suggestive of clinical bulimia compared with only 1% of women in the group with organic endocrinopathies. The work suggests that women with PCOS should be screened for abnormal eating behaviors and raises the possibility that treatment by psychological means should be considered when abnormal eating behaviors are present.
Evaluation and therapy of breakthrough bleeding in women using a triphasic oral contraceptive, This study was designed to investigate the incidence and pattern of breakthrough bleeding (BTB) in 1.259 women who were prescribed for the first time a triphasic oral contraceptive (OC. 7-7-7) and to evaluate a hypothesis of management for BTB persisting after three cycles. The new users were compared with a control group of 696 women who had used various OCs for at least 6 months. The incidence of BTB in the control group was 16.8% and in the new users was 24.9%. 17.5%. and 15.3% in the first 3 months. respectively. Breakthrough bleeding occurred late in the 7-7-7 package in 58% and early or midway through the package in 17% and 25%. respectively. We hypothesized that late-package BTB would improve if the patient was switched to a monophasic pill similar to the relatively estrogenic formulation of the beginning of the package and vice versa for early or midpackage BTB. Seventy women with BTB at 3 months were randomly given 0.5/35 or 1/35 for a further 3 months. Breakthrough bleeding was more likely (P less than 0.05) to improve in women switched to 1/35 compared with 0.5/35 regardless of where in the package BTB occurred.
Endometrial epithelial cells in peritoneal fluid during the early follicular phase, Peritoneal fluid (PF) was obtained during the early follicular phase in 24 women at laparoscopy as part of infertility investigation. The cells present in PF were pelleted and cultured. Developing endometrial epithelial cell colonies were identified in 19 women (79%). Identification of these cell colonies was facilitated using the monoclonal antibody BW 495/36 as specific marker. The number of endometrial epithelial cell colonies showed a large variation (1 to 200 or more PF sample). No significant distinction in incidence and number of cell colonies was found between women with minimal (n = 11) and without endometriosis (n = 12). A significant correlation with number of cell colonies was found in women with infertility and no mechanical and male infertility factors. These data indicate that retrograde transport of viable endometrial cells during menstruation occurs in most women with patent tubes. Implications of the results for the relation between retrograde menstruation. endometriosis. and infertility are discussed.
Detection of a progesterone-induced secretory protein synthesized by the uteri but not the endometriotic implants of rats with induced endometriosis, Steroids modulate the secretory activity of the uterus. but little is known of their effect on ectopic endometrium protein synthesis and secretion. We utilized two-dimensional electrophoresis to visualize proteins produced by the uteri and endometriotic implants of both steroid-treated and reproductively cyclic rats with and without surgically induced endometriosis. Of the greater than 300 proteins visualized. only the uterine cultures from progesterone (P)-stimulated. estrogen-suppressed rats contained a distinctive glycoprotein (P-induced uterine protein-1; molecular weight [Mr] 70.000; isoelectric point [pI] 5.7). This protein was not detected in any of the endometriotic implant cultures. Progesterone-induced uterine protein-1 could play a role in luteal or endometrial physiology and may be valuable in assessing endometrial function. The aberrant secretory behavior of the ectopic endometrium suggests a possible involvement in the reproductive dysfunction associated with endometriosis.
Intraoperative management of ureteral injury during operative laparoscopy, Injury to the ureter from operative laparoscopy is rare. The diagnosis is usually made radiologically. in the postoperative period. when the patient presents with symptoms and signs suggestive of ureteral injury. We report herein a case of ureteral injury resulting from operative laparoscopy for endometriosis. The injury was diagnosed and treated via laparoscopy during the same procedure. The increased utilization of operative laparoscopy to perform more complex procedures increases the potential for operative injury to the ureter. Prior visualization or retroperitoneal dissection of the ureter. in appropriate cases. will help reduce this complication and/or permit a prompt diagnosis in the event of such injury.
Predictive value of the active renin assay for the diagnosis of ectopic pregnancy, The increasing frequency of EP and the need for its early diagnosis have focused our interest on the research of biochemical markers. We have established hormonal values in the plasma of 99 spontaneous ongoing pregnancies between the 4th and 10th weeks of amenorrhea. in 21 EPs. and 20 cases of early abortion. We have examined the predictive values of trophoblastic and CL production in pathological pregnancies. The association of low hCG and low active renin appears to be able to discriminate between ectopic and abortive spontaneous gestations.
Archaeology of NIDDM. Excavation of the "thrifty" genotype, Since the 1940s. numerous cases of non-insulin-dependent diabetes mellitus (NIDDM) have been observed in certain American Indian populations. Extremely high prevalence rates of NIDDM occur most strikingly in several tribes of Paleo-Indians. whose ancestors migrated to North America greater than 11.000 yr ago. Archaeological evidence from that period indicates that certain groups of Paleo-Indians maintained an arctic-like hunter-gatherer life-style in an area in temperate North America ranging from Wyoming to Arizona. This life-style featured a reliance on unpredictable big game species as a major food source. However. at this time. big game species were becoming extinct. It is hypothesized that those Paleo-Indians who relied on big game as a food source developed a "thrifty" genotype that allowed a selective advantage during the periods of fasting that occurred between big game kills. It also is hypothesized that this thrifty genotype in these Indians may contribute to NIDDM when a sedentary life-style is adopted and food sources are constant. Because insulin resistance in muscle is a major feature of NIDDM. it is possible that insulin resistance per se is the phenotypic expression of the thrifty genotype.
Banting lecture 1990. Beta-cells in type II diabetes mellitus, In 1960. immunoassays of insulin first demonstrated significant quantities of circulating hormone in non-insulin-dependent (type II) diabetes and for 30 yr have fostered debate as to whether a beta-cell abnormality plays an etiological role in this syndrome. Early efforts to determine the adequacy of islet beta-cell function showed that obesity and its associated insulin resistance were major confounding variables. Subsequently. it was recognized that glucose not only directly regulated insulin synthesis and secretion but moderated all other islet signals. including other substrates. hormones. and neural factors. When both obesity and glucose are taken into account. it becomes clear that patients with fasting hyperglycemia all have abnormal islet function. Type II diabetes is characterized by a defect in first-phase or acute glucose-induced insulin secretion and a deficiency in the ability of glucose to potentiate other islet nonglucose beta-cell secretagogues. The resulting hyperglycemia compensates for the defective glucose potentiation and maintains nearly normal basal insulin levels and insulin responses to nonglucose secretagogues but does not correct the defect in first-phase glucose-induced insulin release. Before the development of fasting hyperglycemia. only first-phase glucose-induced insulin secretion is obviously defective. This is because progressive islet failure is matched by rising glucose levels to maintain basal and second-phase insulin output. The relationship between islet function and fasting plasma glucose is steeply curvilinear. so that there is a 75% loss of beta-cell function by the time the diagnostic level of 140 mg/dl is exceeded. This new steady state is characterized by glucose overproduction and inefficient utilization. Insulin resistance is also present in most patients and contributes to the hyperglycemia by augmenting the glucose levels needed for compensation. Decompensation and absolute hypoinsulinemia occur when the renal threshold for glucose is exceeded and prevents further elevation of circulating glucose. The etiology of the islet beta-cell lesion is not known. but a hypothesis based on basal hyperproinsulinemia and islet amyloid deposits in the pancreas of type II diabetes is reviewed. The recent discovery of the islet amyloid polypeptide (IAPP) or amylin. which is the major constituent of islet amyloid deposits. is integrated into this hypothesis. It is suggested that pro-IAPP and proinsulin processing and mature peptide secretion normally occur together and that abnormal processing. secondary to or in conjunction with defects in hormone secretion. lead to progressive accumulation of intracellular IAPP and pro-IAPP. which in cats. monkeys. and humans form intracellular fibrils and amyloid deposits with a loss of beta-cell mass.(ABSTRACT TRUNCATED AT 400 WORDS).
Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans, To test the hypothesis that hypoglycemia itself causes reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia. we measured those responses during clamped hypoglycemia (2.8 mM) on consecutive mornings on two occasions. with interval afternoon (1400-1600) hypoglycemia (3 mM) on one occasion and interval afternoon euglycemia (5 mM) on the other. in nine nondiabetic humans. None of the measured responses were reduced by interval euglycemia. In contrast. plasma epinephrine (P less than 0.005). glucagon (P less than 0.005). pancreatic polypeptide (P less than 0.01). cortisol (P less than 0.02). and total (P less than 0.001). neurogenic (P less than 0.001) and neuroglycopenic (P less than 0.05) symptom responses to morning hypoglycemia were reduced after interval afternoon hypoglycemia. Thus. a single episode of hypoglycemia caused a generalized reduction of the neuroendocrine and symptomatic responses to subsequent hypoglycemia. a finding that may be important to the pathogenesis of iatrogenic hypoglycemia in insulin-dependent diabetes mellitus.
Impairment of glycerol phosphate shuttle in islets from rats with diabetes induced by neonatal streptozocin, In islets from adult rats injected with streptozocin during the neonatal period. the oxidative and secretory responses to D-glucose are more severely affected than those evoked by L-leucine. A possible explanation for such a preferential defect was sought by comparing the rate of aerobic glycolysis. taken as the sum of D-[3.4-14C]glucose conversion to labeled CO2. pyruvate. and amino acid. with the total glycolytic flux. as judged from the conversion of D-[5-3H]glucose to 3H2O. A preferential impairment of aerobic relative to total glycolysis was found in islets from diabetic rats incubated at either low or high D-glucose concentration. This coincided in islet mitochondria of diabetic rats with a severe decrease in both the basal (no-Ca2+) generation of 3H2O from L-[2-3H]glycerol-3-phosphate and the Ca2(+)-induced increment in [3H]glycerophosphate detritiation. The mitochondria of diabetic rats were also less efficient than those of control animals in generating 14CO2 from [1-14C]-2-ketoglutarate. The diabetes-induced alteration of 2-ketoglutarate dehydrogenase in islet mitochondria was less marked. however. than that of the FAD-linked glycerophosphate dehydrogenase and was not associated with any change in responsiveness to Ca2+. Sonicated islet mitochondria of diabetic rats displayed normal to slightly elevated glutamate dehydrogenase activity. We propose. therefore. that the preferential impairment of the oxidative and secretory responses of islet cells to D-glucose in this experimental model of diabetes may be at least partly attributable to an altered transfer of reducing equivalents into the mitochondria as mediated by the glycerol phosphate shuttle.
Effects of PP-56 and vitamin E on platelet hyperaggregability, fatty acid abnormalities, and clinical manifestations in streptozocin-induced diabetic rats, The effects of vitamin E and D-myo-inositol 1.2.6-trisphosphate (PP-56) were investigated in long-term studies in streptozocin-induced diabetic rats fed a purified diet with 33% lipids and a polyunsaturated-to -saturated fatty acid ratio of 1. A supplement of vitamin E decreased plasma triglycerides. platelet lipid biosynthesis. some of the delta 6- and delta 5-desaturase abnormalities. and urine ketone bodies but did not affect the response of platelets to aggregation. PP-56 completely normalized the platelet reactivity to ADP and thrombin. This was accompanied by normalization of platelet lipid biosynthesis and diabetes-induced abnormalities in delta 6- and delta 5-desaturases. PP-56 treatment also reduced the mortality rate and to a certain extent urinary ketone bodies. The protective effect of PP-56 on platelet aggregation and mortality rate were dose related. PP-56. a molecule derived from phytic acid. seems to exert potent protective effects on some of the manifestations associated with diabetes in rats.
Insulin-receptor cDNA sequence in NIDDM patient homozygous for insulin-receptor gene RFLP, Resistance to insulin action is a well-established feature of non-insulin-dependent diabetes mellitus (NIDDM) and is believed to contribute to the etiology of this condition. A strong genetic contribution to the etiology of NIDDM exists. and we previously identified an insulin-receptor gene restriction-fragment-length polymorphism (RFLP) associated with the NIDDM phenotype. In an attempt to elucidate whether structural defects in the insulin receptor could be a primary cause of insulin resistance in NIDDM. we analyzed the insulin-receptor cDNA sequence in a subject with NIDDM who is also homozygous for this RFLP. The insulin-receptor cDNA was sequenced with the polymerase chain reaction (PCR). mRNA from transformed lymphocytes was reverse transcribed and amplified with five overlapping sets of primers that span the coding sequence of both alpha- and beta-subunits. No difference was found in the predicted amino acid sequence of the subject's insulin receptor compared with the normal insulin receptor. At nucleotide positions 831 and 2247. the subject is heterozygous for silent nucleotide polymorphisms that do not affect the amino acid sequence. Exon 11 encodes a 12-amino acid insert in the alpha-subunit. which. due to alternate splicing. is not expressed in lymphocyte insulin-receptor mRNA. Consequently. exon 11 was amplified from genomic DNA by PCR; the sequence of exon 11 was found to be normal. In addition. when this patient's transformed lymphocytes were maintained in culture. no abnormalities in insulin binding were observed. We conclude that the insulin resistance seen in this NIDDM subject is not due to a structural alteration in the insulin receptor itself.
Studies on autoimmunity for initiation of beta-cell destruction. VII. Evidence for antigenic changes on beta-cells leading to autoimmune destruction of beta-cells in BB rats, The diabetic syndrome in BioBreeding (BB) rats is believed to result from the destruction of beta-cells by autoimmune responses. However. the initial events that cause the autoimmune destruction of beta-cells remain largely unknown. This investigation was initiated to see whether there are any antigenic changes on the beta-cells from neonatal to adult BB rats that may lead to the autoimmune destruction of beta-cells. Pancreatic grafts from neonatal BB rats remained largely intact without insulitis when transplanted into the renal subcapsular space of acutely diabetic BB rats. Similarly transplanted islet grafts from neonatal BB rats were also not subject to autoimmune destruction. In contrast. islet grafts obtained from adult BB rats. which had been treated with silica to prevent insulitis. were rapidly destroyed in diabetic recipients. These results indicate that beta-cells from neonatal BB rats are different from beta-cells from adult BB rats. at least regarding their recognition by immunologic effectors. Considering our observations and previous information on the initial role of macrophages/dendritic cells in the development of insulitis in BB rats. we suggest that beta-cell-specific antigenic changes that precede insulitis may result in the autoimmune destruction of beta-cells in BB rats.
Production of inhibitor of insulin-receptor tyrosine kinase in fibroblasts from patient with insulin resistance and NIDDM, Although non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in insulin action. the molecular basis of this resistance is unknown. We studied fibroblasts from a markedly insulin-resistant patient with NIDDM but without acanthosis nigricans. Her fibroblasts were resistant to insulin when alpha-aminoisobutyric acid uptake was measured. Fibroblasts from this patient demonstrated normal insulin-receptor content as measured by both insulin-receptor radioimmunoassay and by Scatchard analysis. However. when compared with nondiabetic control subjects. insulin-receptor kinase assays of wheat-germ-purified receptors prepared from her fibroblasts showed very low basal and no insulin-stimulated tyrosine kinase activity. The insulin receptor was then removed from the wheat-germ fraction by monoclonal antibody affinity chromatography. This insulin-receptor-deficient fraction inhibited both basal and insulin-stimulated tyrosine kinase activity of highly purified insulin receptors. When the specificity of this inhibition was tested. less inhibition was seen with insulinlike growth factor I-receptor tyrosine kinase. and even less inhibition was seen with the proto-oncogene p60c-src tyrosine kinase. Thus. these studies indicate that fibroblasts from an insulin-resistant patient with NIDDM produce a relatively specific glycoprotein inhibitor of insulin-receptor tyrosine kinase. Therefore. these studies raise the possibility that this inhibitor may play an important role in the insulin resistance seen in this patient.
Minor papilla cannulation and dorsal ductography in pancreas divisum, Until recently. pancreas divisum represented a major technical barrier to a complete evaluation of pancreatic ductal anatomy. Technical refinements have now made it possible to achieve minor papilla cannulation and dorsal ductography in more than 90% of attempts. In 120 consecutive dorsal ductograms. structural pathology was demonstrated in 36 subjects (30%): chronic pancreatitis in 23. pancreatic stones in 10. pseudocyst(s) in 4. ductal "cut-off" in 7. pancreatic cancer in 3. and partial agenesis in 1 (some patients had more than one finding). For patients in whom alcohol abuse was excluded. ductal pathology was present in 25%. Abnormal ventral ductograms were present in only 8% of cases. demonstrating that dorsal ductography has an appreciable additional diagnostic yield. When the clinical situation indicates the need for pancreatography. minor papilla cannulation should be performed if major papilla cannulation fails or reveals only the ventral pancreatogram of pancreas divisum.
Long-term follow-up in patients who have undergone balloon dilation for gastric outlet obstruction, Although balloon dilation for gastric outlet obstruction has supplanted vagotomy plus drainage or resective therapy in some institutions. there are no long-term data which demonstrate what percentage of patients ultimately requires surgical intervention. Of 23 evaluable patients treated with hydrostatic balloon dilation in our institution. 70% were asymptomatic at a mean follow-up of 2.5 years. Five patients required surgery--one for acute perforation and the other four for symptoms of continued obstruction. despite one to three additional attempts at dilation. Only three of seven patients with previous gastric resection had a satisfactory long-term result. Whereas endoscopic therapy initially cost one tenth to one fifth that of surgical intervention. such figures do not factor for loss of productivity. on the one hand. or potential need for chronic H2 blockade. on the other. Despite instruction to the contrary. only 6 of 15 (40%) active patients continue acid-suppressive therapy. We conclude that balloon dilation remains a viable alternative for selected patients with gastric outlet obstruction.
Endoscopic biopsy has limited accuracy in diagnosis of ampullary tumors, Endoscopic biopsy specimens and surgically resected specimens in a collective series of 78 Japanese patients with ampullary tumor were retrospectively reviewed to investigate the clinical implications of endoscopic biopsy. Endoscopic biopsy specimens were classified into five groups based on the degree of epithelial atypia: group 1 (no atypia). group 2 (mild atypia). group 3 (moderate atypia or adenoma). group 4 (severe atypia or carcinoma in situ). and group 5 (invasive carcinoma). Final diagnosis of the 78 resected ampullary tumors was adenoma in five cases. carcinoma in 27 cases. and both adenoma and carcinoma in 46 cases. Biopsy accuracy of carcinoma (group 4 or 5) was 70% (51 of 73) overall in 73 carcinoma cases. Biopsy accuracy was 50% (7 of 14) in the intramural protruding type. 64% (21 of 33) in the exposed protruding type. and 88% (23 of 26) in the ulcerating type. The diagnostic accuracy of adenoma (group 3) was 80% (4 of 5) in five cases of ampullary adenoma. In 18 (25%) of the 73 carcinoma cases. biopsy diagnosis was adenoma (group 3). whereas carcinoma was found in the deeper layers of surgically resected specimens. Biopsy diagnosis of adenoma does not rule out the possibility of deeper carcinoma in ampullary tumors.
MRI, CT, SPECT, PET: their use in diagnosing dementia, The differential diagnosis of the dementia syndrome may pose a difficult clinical problem. since the most common dementia. Alzheimer's disease (AD). is marked by normal laboratory tests. Neuroimaging has played an important role in evaluating the demented patient. and its uses are growing. Computed tomography (CT) is useful for excluding reversible and treatable causes of dementia. such as subdural hematoma and tumor. More recently. magnetic resonance imaging (MRI) has improved our ability to diagnose vascular disease and may show the presence of cerebral infarcts and white matter disease not visible on CT. Single photon emission computed tomography (SPECT) and positron emission tomography (PET). techniques that visualize such cerebral functions as glucose metabolism and blood flow. may provide positive evidence supportive of the diagnosis of AD.
Pneumonia: update on diagnosis and treatment, Pneumonia is the most common infectious disease necessitating hospitalization of elderly patients. A number of misconceptions exist regarding the clinical and radiological features of pneumonia in elderly patients. Early recognition and appropriate therapy can reduce morbidity and enhance survival. This article explores the manifestations of pneumonia in the elderly. as well as the diagnostic approach and contemporary therapy.
Twelve hour overnight oesophageal pH monitoring in patients with reflux symptoms, Results of continuous 12 hour overnight pH monitoring (duration of pH less than 4) were reviewed in 112 patients with heartburn or regurgitation. or both. and in 56 normal subjects. Patients had more reflux than normal subjects. Medically controlled patients (n = 51) had less acid reflux than patients who subsequently underwent reflux surgery (n = 61). but there was a considerable overlap between those two groups. Surgery was followed by a reduction in acid reflux to a value similar to that in normal subjects. Patients in whom surgery was deemed to have failed had more reflux after the operation than those in whom it was successful. but no difference could be found in the preoperative reflux values of these two subgroups. Monitoring pH is not of value in selecting candidates for surgery since the results are not a good predictor of outcome. but it is useful in the objective evaluation of surgical results.
Evaluation of endosonography in TN staging of oesophageal cancer, Strategies for the treatment of cancer of the oesophagus depend on the tumour stage at the time of diagnosis. Resection. the only curative treatment. is confined to early tumour stages. Tumours with local infiltration are usually unresectable and require palliative treatment. Computed tomography has been widely used for preoperative staging but often fails to define this correctly. Endoscopic ultrasound allows direct visualisation of the parietal wall and may be useful in staging gastrointestinal tumours. In a comparative prospective study. 52 patients with tumours of the oesophagus were investigated preoperatively both by endoscopic ultrasound and computed tomography to determine the stage of tumour infiltration and local lymph node involvement. Thirty seven of these patients underwent operation. resection. or dissection and entered the study. The intraoperative findings or the histopathological assessment. or both. were taken as a reference. For all TN stages of oesophageal tumours. correct preoperative staging was accomplished by endoscopic ultrasound in 89% for T stage and 69% for N stage compared with 51% and 51% respectively by computed tomography (highly significant using Fisher's exact test). This study shows that endoscopic ultrasound is useful in preoperative TN staging of tumours of the oesophagus.
Effect of increasing Helicobacter pylori ammonia production by urea infusion on plasma gastrin concentrations, It has been proposed that the hypergastrinaemia in subjects with Helicobacter pylori infection is caused by the action of the ammonia produced by the organism's urease activity on the antral G cells. To investigate this hypothesis we examined the effect on plasma gastrin of increasing the bacterium's ammonia production by infusing urea intragastrically to eight H pylori positive duodenal ulcer patients. After a 60 minute control intragastric infusion of dextrose solution at 2 ml/minute. a similar infusion containing urea (50 mmol/l) was continued for four hours. During the urea infusion. the median gastric juice urea concentration rose from 1.1 mmol/l (range 0.3-1.6) to 15.5 mmol/l (range 7.9-21.3) and this resulted in an increase in the ammonium concentration from 2.3 mmol/l (range 1.3-5.9) to 6.1 mmol/l (range 4.2-11.9) (p less than 0.01). This appreciable rise in ammonia production did not result in any change in the plasma gastrin concentration. The experiment was repeated one month after eradication of H pylori. at which time the median basal gastrin was 20 ng/l (range 15-25). significantly less than the value before eradication (30 ng/l range 15-60) (p less than 0.05). On this occasion. the gastric juice ammonium concentration was considerably reduced at 0.4 mmol/l (range 0.1-0.9) and the urea infusion did not raise the ammonium concentration or change the plasma gastrin concentration. In conclusion. augmenting H pylori ammonia production does not cause any early change in plasma gastrin.
Helicobacter pylori infection rates in relation to age and social class in a population of Welsh men, The seroprevalence of IgG antibodies to Helicobacter pylori was determined using a standard enzyme linked immunosorbent assay in a population of 749 randomly selected men. aged 30-75 years. from Caerphilly. South Wales. The overall prevalence of H pylori was 56.9%. increasing sharply in middle age from 29.8% in those aged 30-34 to over 59% in those aged 45 or older (p less than 0.0001). Age standardised seroprevalence rates were lowest in combined social class categories I and II (49.2%). intermediate in categories IIIN and M (57.5%). and highest in categories IV and V (62.2%) (p = 0.01). In those aged 30-34 years. the prevalence rate for those in combined social class categories IV and V was 57.9% - double the rate for social class categories IIIM and N (28.3%) and five times the prevalence rate in those in social class categories I and II (11.1%). These differences in the infection patterns of H pylori by social class are consistent with patterns of peptic ulcer disease and gastric cancer.
Dissociation between systemic and mucosal humoral immune responses in coeliac disease, We examined humoral immunity in coeliac disease as expressed in serum (systemic immunity). and in saliva. jejunal aspirate. and whole gut lavage fluid (mucosal immunity). The aims were to define features of the secretory immune response (IgA and IgM concentrations and antibody values to gliadin and other food proteins measured by enzyme linked immunosorbent assay (ELISA)) in active disease and remission. and to establish whether secretions obtained by relatively non-invasive techniques (saliva and gut lavage fluid) can be used for indirect measurements of events in the jejunum. Serum. saliva. and jejunal aspirate from 26 adults with untreated coeliac disease. 22 treated patients. and 28 immunologically normal control subjects were studied. together with intestinal secretions obtained by gut lavage from 15 untreated and 19 treated patients with coeliac disease and 25 control subjects. Jejunal aspirate IgA and IgM and gut lavage fluid IgM concentrations were significantly raised in patients with untreated coeliac disease; the lavage fluid IgM concentration remained higher in patients with treated coeliac disease than in controls. Serum and salivary immunoglobulin concentrations were similar in the three groups. Patients with untreated coeliac disease had higher values of antibodies to gliadin compared with treated patients and control subjects in all body fluids tested; these were predominantly of IgA and IgG classes in serum. and of IgA and IgM classes in jejunal aspirate and gut lavage fluid. Values of salivary IgA antibodies to gliadin were significantly higher in untreated coeliacs. though antibody values were generally low. with a large overlap between coeliac disease patients and control subjects.
Impaired sulphation of phenol by the colonic mucosa in quiescent and active ulcerative colitis, Substantial amounts of phenols are produced in the human colon by bacterial fermentation of protein. In the colonic mucosa of animals. phenols are inactivated predominantly by conjugation with sulphate. The purpose of this study was to confirm sulphation of phenols by isolated colonocytes from man and to evaluate mucosal sulphation in inflammatory bowel disease using the phenol. paracetamol. in rectal dialysis bags. The incubation of paracetamol with colonocytes isolated from resected colon specimens (n = 7) yielded a mean (SE) value of 7.0 (0.9) mumols/g dry weight of paracetamol sulphate after 60 minutes but virtually undetectable values of paracetamol glucuronide. Paracetamol sulphate was detected in rectal dialysates from all control subjects. with a mean (SE) value of 4.2 (0.8) nmol/hour. Sulphation was significantly impaired (p less than 0.01) in 19 patients with active ulcerative colitis (0.6 (0.2) nmol/hour) and in 17 patients with ulcerative colitis in remission (1.1 (0.4) nmol/hour). Sulphation in eight patients with Crohn's colitis (4.3 (2.1) nmol/hour) was similar to that in control subjects. Impairment of the capacity of the mucosa to sulphate phenols in quiescent and active ulcerative colitis may pose a metabolic burden on colonic epithelial cells. which are continuously exposed to endogenous phenols from the colonic lumen.
5-Aminosalicylic acid is a potent inhibitor of interleukin 1 beta production in organ culture of colonic biopsy specimens from patients with inflammatory bowel disease, Interleukin 1 beta in biopsy specimens from inflamed colonic mucosa of patients with active inflammatory bowel disease was studied. Compared with normal colonic mucosal biopsy specimens. a significantly greater amount of interleukin 1 beta was present in rectal mucosa before (median (range) 4.3 (2.0-11.8) v 119.2 (30.1-286.8) pg/mg; p less than 0.01) and produced during organ culture (39.1 (9.4-106.8) v 97.6 (28.2-991.6) pg/mg; p less than 0.01). Values of interleukin 1 beta after culture correlated with concentrations of thromboxane B2. Organ culture of inflamed biopsy specimens in the presence of 5 aminosalicylic acid and dexamethasone reduced the amount of interleukin 1 beta detected. At the doses studied. 5 aminosalicylic acid also reduced the amount of leukotriene B4 detected after culture.
Candidacidal activity of Crohn's disease neutrophils, The ability of normal and Crohn's disease neutrophils to kill Candida albicans has been studied using neutrophils isolated from peripheral blood and suspended in phosphate buffered saline at 5 x 10(6) cells per ml. C albicans was grown to a stationary phase in broth culture and suspended in phosphate buffered saline at 10(7) organisms/ml. Neutrophils and Candida were then incubated together at 37 degrees C in a shaking water bath in the presence of fresh serum. At 30 and 60 minutes samples were withdrawn. neutrophils lysed. and Candida survival assessed by colony counting. Results were compared with control suspensions of Candida incubated with serum alone. After 30 and 60 minutes in the presence of autologous serum normal neutrophils had killed significantly more Candida than Crohn's disease neutrophils (mean (SD) 61.0 (16.7)% v 40.5 (16.2)% at 30 minutes. p less than 0.0001; 83.2 (7)% v 70.8) 16)% at 60 minutes. p less than 0.005). The results did not alter significantly when normal neutrophils were incubated with Candida in the presence of Crohn's disease serum instead of normal serum. When Crohn's disease neutrophils were incubated with Candida in the presence of normal serum instead of autologous serum there was some improvement in candidacidal ability at 30 minutes (48.9 (20.6)% v 40.5 (16.2)%. p less than 0.03) but not at 60 minutes. Phagocytosis. measured using a radiometric assay. was normal. Neutrophils from patients with Crohn's disease have an impaired ability to kill this granuloma provoking organism. It is not due to serum inhibitors or defective phagocytosis.
How bad are the symptoms and bowel dysfunction of patients with the irritable bowel syndrome? A prospective, controlled study with emphasis on stool form, Since it is not known whether the symptoms and bowel function of patients with the irritable bowel syndrome are truly abnormal we used diaries and frequent telephone interviews over a 31 day period to assess symptoms. defecation. and stool types in 26 unselected female hospital patients with the irritable bowel syndrome. 27 women who admitted to recurrent colonic pain but had not consulted a doctor (non-complainers). and 27 healthy control subjects. Unexpectedly. abdominal pain and bloating occurred in most of the control subjects. Pain. however. was six times more frequent in the patients and was more often considered severe. Bloating occurred three times more often. Defecation was more frequent. more erratic in timing and stool form. and more likely to produce stools of extreme forms. indicating rapid fluctuations in intestinal transit time. Urgency was four times more prevalent in patients than control subjects. Straining to finish defecating was nine times more prevalent and was often accompanied by feelings of incomplete evacuation--a combination which could lead to the misdiagnosis of constipation. The normal relation between stool form and the above symptoms was distorted. possibly due to rectal irritability. Non-complainers were intermediate between patients and control subjects in almost every parameter but were closer to control subjects than to patients. Patients with the irritable bowel syndrome have real cause for complaint and their bowel function is truly abnormal.
Steroid hormone abnormalities in women with severe idiopathic constipation, Patients with severe idiopathic constipation are almost exclusively women of reproductive age. To investigate the possibility of a sex hormone abnormality in this condition. we have compared a range of sex hormones during the follicular and luteal phases of the menstrual cycle in 23 healthy women (mean age 33 years) with those in 26 patients with severe idiopathic constipation (mean age 32 years. spontaneous bowel frequency less than one per week). In the patients there was a reduction in the follicular phase of progesterone (4.5 v 4 nmol/l. p = 0.006. median value. controls v patients). 17 hydroxyprogesterone (9.7 v 5.8 nmol/l. p = 0.01). cortisol (387 v 245 nmol/l. p = 0.008). testosterone (2.3 v 1.8 nmol/l. p less than 0.001). androstenedione (10.3 v 8.4 nmol/l. p = 0.02). and dehydroepiandrosterone sulphate (5.1 v 3.0 mumol/l. p = 0.03). In the luteal phase there was a reduction of oestradiol (483 v 350 pmol/l. p = 0.015). cortisol (322 v 242 nmol/l. p = 0.047). and testosterone (2.4 v 1.7 nmol/l. p = 0.003). The concentrations of sex hormone binding globulin. prolactin. luteinising hormone. and follicle stimulating hormone were not significantly different in either phase of the cycle. Women with severe idiopathic constipation have a consistent reduction in steroid hormones.
Provision of gastrointestinal endoscopy and related services for a district general hospital. Working Party of the Clinical Services Committee of the British Society of Gastroenterology, (1) The number of endoscopic examinations performed is rising. Epidemiological data and the workload of well developed units show that annual requirements per head of population are approaching: Upper gastrointestinal 1 in 100 Flexible sigmoidoscopy 1 in 500 Colonoscopy 1 in 500 ERCP 1 in 2000 (2) Open access endoscopy to general practitioners is desirable and increasingly sought. For a district general hospital serving a population of 250.000. this workload entails about 3500 procedures annually. performed during 10 half day routine sessions plus emergency work. (3) High standards of training and experience are needed by all staff. who must work in purpose built accommodation designed to promote efficient and safe practice. (4) The endoscopy unit should be adjacent to day care facilities and near the x ray department. There should be easy access to wards. (5) An endoscopy unit needs at least two endoscopy rooms; a fully ventilated cleaning/disinfection area; rooms for patient reception. preparation. and recovery; and accommodation for administration. storage. and staff amenities. (6) The service should be consultant based. At least 10 clinical sessions are required. made up of six or more consultant sessions and two to four clinical assistant. hospital practitioner. or staff specialist sessions. Each consultant should be expected to commit at least two sessions weekly to endoscopy. Extra consultant sessions may be needed to provide an efficient service. (7) A specially trained nursing sister (grade G or H) and five other endoscopy nurses are needed to care for the patients; their work may be supplemented by care assistants. (8) A new post of endoscopy department assistant (analogous to an operating department assistant) is proposed to maintain and prepare instruments. and to give technical assistance during procedures. (9) A full time secretary should be employed. Records. appointments. and audit should be computer based. (10) ERCP needs the collaboration of an interventional radiologist working with high quality x ray equipment in a specially prepared radiology screening room. This facility may need to serve more than one hospital. (11) A gastrointestinal measurement laboratory can conveniently be combined with the endoscopy unit. In some hospitals one or more gastrointestinal measurement technicians may staff this laboratory. (12) An endoscopy unit is a service department analogous to a radiology department. It needs an annual budget.
Prevention of hypertension and vascular changes by captopril treatment, Treatment of female spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats with captopril was carried out by the addition of the drug in the drinking water throughout pregnancy and lactation and after weaning. At 28 weeks of age. average systolic blood pressure of treated SHR was 113 +/- 3 mm Hg. which was below that of control SHR (188 +/- 3 mm Hg) and WKY rats (124 +/- 3 mm Hg). Body weight and heart rate of the SHR were not affected by the treatment. Tissue level of catecholamines was increased by captopril treatment in the superior cervical ganglia but remained unchanged in the plasma. heart. mesenteric arteries. and the adrenal glands of both SHR and WKY rats. Left ventricular weight. wall thickness. and internal diameter of the left ventricle in the SHR were reduced by the treatment. Morphometric measurements of the mesenteric arteries showed that vascular alterations present in the control SHR were prevented by the treatment. In the superior mesenteric artery and large mesenteric artery. smaller lumen size at maximal relaxation found in the control SHR was normalized to the level of the WKY rats. Hypertrophy of the medial wall in the superior mesenteric. large and small mesenteric arteries. and an increase in the number of smooth muscle cell layers in the large mesenteric artery of the SHR were prevented by the treatment. Perfusion study of the mesenteric vascular bed showed that reactivity of these vessels to norepinephrine was reduced. and sensitivity to norepinephrine (as determined by the effective dose that causes 50% of maximal response) was increased in the SHR by captopril treatment. Sensitivity of the tail artery in response to norepinephrine was not altered by the treatment. We conclude that long-term treatment with captopril of SHR before and after birth prevented the development of hypertension. structural and functional alterations of the mesenteric arteries. and cardiac hypertrophy.
Isolation of preferentially expressed genes in the kidneys of hypertensive rats, By differential hybridization. three complementary DNAs designated as S3. S2. and SA were isolated. and the corresponding messenger RNAs (mRNAs) were differentially expressed between the kidneys of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. S3 is identical to cytochrome P450 IV A2. SA encoded a protein of 546 amino acid residues. and its carboxyl terminal region had a slight homology to luciferase. No homologous sequence has been reported in S2 sequences. S3 mRNA was about four times more abundantly expressed in the kidneys of 28-day-old SHR than in those of age-matched WKY rats. but there was no difference at age 16 weeks. A low NaCl diet positively modulated the expression of the S3 gene. S2 mRNA was almost undetectable in the kidneys of 28-day-old WKY rats but was clearly detected in those of age-matched SHR. The expression level of S2 mRNA in the livers of 16-week-old SHR was about five times higher than that of age-matched WKY rats. The expression of S2 mRNA in the livers was modulated by dietary NaCl and captopril. SA mRNA was more than 10 times more abundantly expressed in the kidneys of SHR than in those of WKY rats from age 4 weeks. With the administration of captopril. the expressions of SA mRNA in the livers of SHR were positively modulated. Because these three genes are not only differentially expressed between SHR and WKY rats but also related to sodium metabolism or blood pressure control. the identification of these genes may provide important probes to examine the mechanisms of hypertension.
Impaired insulin action on skeletal muscle metabolism in essential hypertension, Previous studies have shown that essential hypertension is frequently associated with insulin resistance. The tissues responsible for this metabolic alteration have not been defined. We tested the hypothesis that skeletal muscle is the site of insulin resistance of essential hypertension with the use of the perfused forearm technique. Eight hypertensive (age 42 +/- 3 years. body mass index 27 +/- 1 kg/m2. intra-arterial mean blood pressure 126 +/- 4 mm Hg) and seven normotensive (age 48 +/- 3 years. body mass index 26 +/- 1 kg/m2. mean blood pressure 95 +/- 4 mm Hg) male volunteers were studied. After glucose ingestion (40 g/m2). normal glucose tolerance in the patients was maintained at the expense of a heightened plasma insulin response. suggesting the presence of insulin resistance. During graded. local (intra-arterial) hyperinsulinemia encompassing the physiological range (12-120 milliunits/l). glucose uptake by forearm tissues was significantly (p less than 0.03) reduced in the hypertensive subjects as compared with the controls at each of five insulin steps. by 43% on the average. In addition. forearm lactate and pyruvate release were significantly less stimulated in the hypertensive than in the normotensive group (p less than 0.01 for both). presumably as a consequence of the decreased glucose influx. Forearm exchange of oxygen. carbon dioxide. lipid substrates (free fatty acids. glycerol. and beta-hydroxybutyrate). and potassium were similar in the hypertensive and normotensive groups in the basal state. Insulin had no effect on oxygen consumption. carbon dioxide production. and respiratory quotient in either study group. whereas it stimulated free fatty acids. glycerol. and potassium uptake to the same extent in the hypertensive and normotensive groups.
Nicotine impairs reflex renal nerve and respiratory activity in deoxycorticosterone acetate-salt rats, Smoking exacerbates the increase in arterial pressure in hypertension. The effect of nicotine on the baroreceptor-mediated reflex responses of renal nerve activity (RNA). heart rate. and respiratory activity (minute diaphragmatic activity [MDA]) after bolus injections of phenylephrine was compared in deoxycorticosterone acetate (DOCA)-salt sensitive and normotensive rats. Osmotic minipumps that dispensed either nicotine (2.4 mg/kg/day) or saline were implanted in DOCA and normotensive rats for 18 days. Anesthetized DOCA-nicotine. DOCA-saline. control-nicotine. and control-saline rats had mean arterial pressures (MAP) of 117 +/- 3. 110 +/- 9. 90 +/- 3. and 89 +/- 5 mm Hg. respectively. Nicotine decreased the sensitivity (p less than 0.05) of baroreceptor reflex control of RNA (% delta RNA/delta MAP) in the DOCA-nicotine rats (-0.92 +/- 0.08) compared with the DOCA-saline (-1.44 +/- 0.16). control-nicotine (-1.45 +/- 0.08). or control-saline (-1.45 +/- 0.21) rats. The reflex decrease in respiratory activity (% delta MDA/delta MAP x 100) was impaired (p less than 0.01) in both control-nicotine (-24.5 +/- 3.3) and DOCA-nicotine (-18.2 +/- 4.6) rats compared with control-saline (-59.2 +/- 9.1) and DOCA-saline (-52.5 +/- 9.9) rats. The reflex decrease in heart rate (absolute delta HR/delta MAP) in both DOCA-nicotine (1.56 +/- 0.17) and control-nicotine (1.54 +/- 0.24) rats was augmented compared with DOCA-saline and control-saline rats (0.91 +/- 0.12 and 0.97 +/- 0.14).
Effect of drug and diet treatment of mild hypertension on diastolic blood pressure. The TAIM Research Group, The Trial of Antihypertensive Interventions and Management is a multicenter randomized trial designed to examine the diastolic blood pressure response of various combinations of pharmacological and dietary interventions in the treatment of mild hypertension (diastolic blood pressure 90-100 mm Hg). Eight hundred and seventy-eight participants at 110-160% of ideal weight were randomly allocated to nine drug/diet treatment groups receiving either a placebo. chlorthalidone (25 mg). or atenolol (50 mg). combined with a usual. a weight loss. or a low sodium/high potassium diet. The primary outcome was diastolic blood pressure change from baseline to 6 months. Seven hundred and eighty-seven participants had follow-up data. The mean baseline diastolic blood pressure was 93.8 mm Hg; 55.9% of the participants were male. and the weight loss diet group lost an average of 4.7 kg. Multiple comparisons were accounted for in the analysis. A significantly greater lowering of diastolic blood pressure (12.4 mm Hg) was achieved in the atenolol group compared with either the low sodium/high potassium diet group (7.9 mm Hg. p = 0.001) or weight loss group (8.8 mm Hg. p = 0.006). Adding weight loss to chlorthalidone significantly enhanced blood pressure lowering (15.1 mm Hg) when compared with the diuretic alone (10.8 mm Hg. p = 0.002). but adding a low sodium/high potassium diet (12.2 mm Hg. p = 0.029) did not. In the short-term treatment of mild hypertension where diastolic blood pressure is the sole consideration. drugs outperform diet. and weight loss is beneficial. especially with diuretics.
Characterization of auscultatory gaps with wideband external pulse recording, Three types of auscultatory gaps. called G1. G2. and G3. that occur during blood pressure measurement have been identified by using wideband external pulse recording. We have previously shown that the wideband external pulse recorded during cuff deflation can be separated into three components (K1. K2. and K3). one of which (K2) is closely related to the Korotkoff sound. G1 occurs with cuff pressure just below systolic and is characterized by the presence of K1 and K2 with intermittent disappearance of K2. G1 gaps are related to a phasic decrease of arterial (systolic) pressure and were exhibited by 13 of 60 hypertensive patients. G2 gaps are related to a phasic increase of arterial (diastolic) pressure. occur when cuff pressure is just above diastolic. and are characterized by the presence of K1. K2. and K3 with intermittent disappearance of K2. Seven of 60 hypertensive patients exhibited a G2 gap. G3 gaps occur with cuff pressure between systolic and diastolic and are characterized by an underdeveloped or blunted K2 signal. Three of 60 hypertensive patients exhibited a G3 gap. The identification of auscultatory gaps in relation to the wideband external pulse provides a qualitative measure of their existence. can be of significant value in better understanding aspects of the auscultatory blood pressure measurement technique. and provides an objective basis with which to better understand the mechanisms that cause them.
Treatment of Freiberg's disease. A new operative technique, A method of treating Freiberg's disease of the metatarsal head by shortening the metatarsal bone is described. This operation has been performed in 15 patients (16 feet). Excellent relief of pain was obtained. although most patients had persistent stiffness of the metatarsophalangeal joint.
Percutaneous screw fixation for fractures of the scaphoid, We describe a percutaneous technique for screw fixation of all types of fractures of the scaphoid. During a 15-year period ending in 1984. 280 cases were treated by this method; 198 of them returned for evaluation in 1986 and comprise the material for this report. After a mean postoperative time of 82 months. 89% of the recent fractures had united as well as 81.8% of those with delayed or nonunion and 42.8% of those with sclerotic nonunion.
Fracture-separation of the distal humeral epiphysis, We have reviewed 12 cases of fracture-separation of the distal humeral epiphysis. three of which were initially misdiagnosed as fractures of the lateral condyle and one as an elbow dislocation. Cubitus varus deformity is as common after this fracture-separation as it is following supracondylar fracture. and is most common in children under two years of age. Closed reduction and simple immobilisation is adequate for the older child. but we recommend for those under two years of age that closed reduction should be followed by percutaneous pinning. so that the carrying angle can be assessed immediately after reduction. If the elbow is then in varus the wires should be removed. reduction repeated and treatment by straight lateral traction used to maintain a valgus carrying angle.
Chondrosarcoma of the soft tissues. Two different sub-groups, Chondrosarcomas arising from soft tissues are rare. Two different varieties are described. myxoid and mesenchymal. We have collected nine cases of the tumour. five myxoid and four mesenchymal. from a review of 513 cases of chondrosarcoma seen between 1904 and 1988. We report the principal clinical. radiographical and histological differences between the two varieties and discuss their surgical treatment and prognosis.
Fatigue failure of noncemented porous-coated implants. A retrieval study, The causes of mechanical failure of five noncemented porous-coated components were studied. There were two cobalt-chromium alloy and three titanium alloy implants which fractured after 12 to 48 months. The implants included one acetabular component. and one femoral condylar. one patellar and two tibial components. Examination of the fractured surfaces revealed fatigue to be the mechanism of failure in all cases. The porous coating and the processes required for its fabrication had resulted in weakening and reduction of substrate thickness. Additional factors were stress concentration due to limited. localised bone ingrowth. and some features of the design of the implants.
Correction of coxa vara in childhood. The use of Pauwels' Y-shaped osteotomy, The long-term results following the correction of coxa vara by Pauwels' Y-shaped intertrochanteric osteotomy have been evaluated in 14 children. Ten of the children had unilateral hip disease and were otherwise normal while four had bilateral hip disease due to generalised skeletal dysplasias. In each case. the growth plate was vertical. the femoral head was displaced inferiorly and there were abnormalities in the metaphysis of the femoral neck. The results indicate that this osteotomy provides lasting correction of the deformity. regardless of the cause. as long as the inclination of the growth plate is corrected to 40 degrees or less and adequate support is provided for the metaphyseal defect and the displaced femoral head.
Micromotion of cemented and uncemented femoral components, We evaluated the initial stability of cemented and uncemented femoral components within the femoral canals of cadaver femurs during simulated single limb stance and stair climbing. Both types were very stable in simulated single limb stance (maximum micromotion of 42 microns for cemented and 30 microns for uncemented components). However. in simulated stair climbing. the cemented components were much more stable than the uncemented components (76 microns as against 280 microns). There was also greater variation in the stability of uncemented components in simulated stair climbing. with two of the seven components moving 200 microns or more. Future implant designs should aim to improve the initial stability of cementless femoral components under torsional loads; this should improve the chances of bony ingrowth.
Joint proprioception in normal, osteoarthritic and replaced knees, We measured joint position sense in the knee by a new method which tests the proprioceptive contribution of the joint capsule and ligaments. The leg was supported on a splint. and held in several positions of flexion. The subjects' perception of the position was recorded on a visual analogue model and compared with the actual angle of flexion. Eighty-one normal and 45 osteoarthritic knees were examined. as were 10 knees with semi-constrained and 11 with hinged joint replacements. All were assessed with and without an elastic bandage around the knee. There was a steady decline in joint position sense with age in subjects with normal knees. Those with osteoarthritic knees had impaired joint position sense at all ages (p less than 0.001). Knee replacement improved the joint position sense slightly (p less than 0.02); semi-constrained replacement had a greater effect than hinged replacement. The effect of an elastic bandage in subjects with poor position sense was dramatic. improving accuracy by 40% (p less than 0.001). It is proposed that reduced proprioception in elderly and osteoarthritic subjects may be responsible for initiation or advancement of degeneration of the knee.
Repair of cartilage lesions using biological implants. A comparative histological and biomechanical study in goats, We report the experimental use of three different biological implants to restore articular surface defects: glutaraldehyde-fixed bovine meniscal xenograft. glutaraldehyde-fixed bovine costal cartilage xenograft. and viable osteochondral allografts. The grafts were implanted in the knees of 19 goats who were allowed free-field activity and were studied for up to one year. The natural articular surfaces of meniscal fibrocartilage provided excellent articular surfaces at all times. Equally good articular surfaces were restored by host tissue growth covering costal cartilage grafts at six months. but by 12 months this surface had degenerated. The majority of the allografts survived and integrated with the host at six months. but many showed signs of failure at 12 months. Only three out of seven ungrafted defects healed completely at six months and the healed surfaces were degenerating at 12 months.
Bone structure after removal of internal fixation plates, We used single-photon absorptiometry to assess the forearm bones after the removal of internal fixation plates in 14 patients. We found convincing evidence of cortical atrophy in only one patient. in whom the plates had been removed prematurely after only 16 months. It is suggested that such plates should be retained for at least 21 months. to allow bone density to return to its prefracture level. The recommendations of the AO/ASIF group are supported.
Natural history of nontraumatic avascular necrosis of the femoral head, We studied the natural history of nontraumatic avascular necrosis of the femoral head (ANFH) in 115 hips in 87 patients. 69 steroid-induced. 21 related to misuse of alcohol and 25 idiopathic. The average length of follow-up was over five years. Collapse occurred most often when the focus of bone necrosis occupied the weight-bearing surface of the femoral head. Flatness of the head due to subchondral fracture was an early manifestation of collapse. Classification into six types based upon the radiographic findings provided an accurate prognosis for individual cases of ANFH which is useful in planning treatment and in assessing its outcome.
Femoral head blood flow in femoral neck fractures. An analysis using intra-osseous pressure measurement, We studied 50 patients with fractures of the femoral neck. 33 intracapsular and 17 extracapsular. Intraosseous pressure was measured by a transducer within the bone to quantify blood flow. and intracapsular pressure by a needle introduced into the joint space. The mean intracapsular pressure was lower in the extracapsular fractures. In these. the mean intraosseous pressure in the femoral head was unchanged by aspiration of the joint. However in the intracapsular fractures aspiration produced a significant decrease in intra-osseous pressure and an increase in pulse pressure within the femoral head. The results suggest that aspiration of intracapsular haematoma produced an increase in femoral head blood flow by relieving tamponade.
Successful treatment of severe premenstrual syndrome by combined use of gonadotropin-releasing hormone agonist and estrogen/progestin, Although abolishment of ovarian cyclicity by the use of a long-acting GnRH agonist (GnRH-a) provides effective treatment for premenstrual syndrome (PMS). its use is limited by sequellae of the resultant hypoestrogenism. In this study the effects of estrogen/progestin replacement on the symptomatic improvement afforded by GnRH-a were evaluated in eight women with severe PMS. The 8-month study design included 2 months of control. 2 months of GnRH-a alone. and 4 further months in which the exogenous steroids were replaced in randomized. double blind. placebo-controlled cross-over fashion using 1 month each of 1) conjugated equine estrogen (CEE) on days 1-25. 2) 10 mg medroxyprogesterone acetate (MPA) on days 16-25. 3) CEE (days 1-25) plus MPA (days 16-25). and 4) placebo alone. Mood and physical symptoms were measured daily on a valid and reliable instrument. the Calendar of Premenstrual Experiences. As expected. administration of GnRH-a alone resulted in a 75% improvement in luteal phase symptom scores (17.8 +/- 4.8 vs. 4.2 +/- 1.6; P less than 0.01). Combined sequential administration of CEE and MPA in addition to GnRH-a was effective in maintaining the reduced symptom scores seen after GnRH-a alone and was superior to the addition of CEE alone. MPA alone. or placebo. This combination of CEE and MPA resulted in a 60% improvement (P less than 0.05) compared to the luteal phase of control months in both behavioral (14.1 +/- 3.9 vs. 4.2 +/- 0.8) and total (17.8 +/- 4.8 vs. 6.5 +/- 1.8) symptoms. We conclude that the undesirable consequence of ovarian steroid deficiency in the treatment of PMS by GnRH-a can be overcome by the addition of sequential estrogen and progestogen replacements without significantly reducing the effectiveness of GnRH-a in this disorder.
Low growth hormone levels are related to increased body mass index and do not reflect impaired growth in luteinizing hormone-releasing hormone agonist-treated children with precocious puberty, To test the hypothesis that GH deficiency might explain the low growth velocity of some LHRH agonist (LHRHa)-treated children with central precocious puberty. we measured stimulated (n = 81) and spontaneous (n = 32) GH levels during or after LHRHa treatment. GH stimulation tests in the children who were receiving LHRHa treatment were performed after 2 days of ethinyl estradiol administration. Thirty-one of 81 children (38%) who underwent GH stimulation tests had subnormal responses (less than or equal to 7 micrograms/L) to all tests administered (at least 2 stimuli). including 22 of 67 (33%) who had precocious puberty that was idiopathic or associated with hypothalamic hamartoma. Eleven of 32 children (34%) who underwent measurement of the mean nighttime spontaneous GH level had levels below the normal range for prepubertal children (less than 1.2 microgram/L). Despite the high incidence of subnormal GH levels. there appeared to be no relationship between the GH levels of these children and their growth characteristics. The height. growth velocity. bone maturation rate. predicted height. and insulin-like growth factor-I levels were not different between the children with low GH levels and the children with normal GH levels. Conversely. the GH levels were not different between the children with subnormal growth rates and the children with normal growth rates. Thus. variation in the growth rates of these LHRHa-treated children with central precocious puberty could not be explained by variation in the stimulated or spontaneous secretion of GH. In attempting to understand the high incidence of low GH levels in children with precocious puberty. we examined the relationship between GH level and body mass index (BMI). Both the stimulated (r = -0.33; P less than 0.002) and the spontaneous (r = -0.61; P less than 0.0002) GH levels were inversely related to BMI. Moreover. the children with precocious puberty as a group had significantly elevated BMI [1.2 +/- 0.1 (+/- SE) SD units] compared to normal children of the same age (P less than 0.0001). Thus. increased body mass may explain the high incidence of subnormal GH levels in these patients. and normative GH levels adjusted for body mass are needed before it can be concluded that the apparently subnormal GH levels in LHRHa-treated children with precocious puberty are in fact low.
Effects of glucagon on free fatty acid metabolism in humans, To determine whether physiological changes in plasma glucagon concentrations are important in regulating basal adipose tissue lipolysis. FFA flux ([1-14C]palmitate) was measured in response to increases and decreases in plasma glucagon. Eight volunteers with insulin-dependent diabetes mellitus (IDDM) and nine healthy nondiabetic volunteers were studied using the pancreatic clamp technique to control plasma insulin. GH. and glucagon concentrations at desired levels. Palmitate flux at the chosen euglucagonemic hormone infusion rates was similar to baseline values (1.73 +/- 0.12 vs. 1.75 +/- 0.23 and 1.35 +/- 0.18 vs. 1.35 +/- 0.16 mumol/kg.min. respectively. in IDDM and nondiabetic subjects). No significant changes in palmitate flux occurred in response to glucagon withdrawal or mild (nondiabetic volunteers) or high physiological (IDDM volunteers) hyperglucagonemia. Thus. under conditions of normal FFA availability. changes in plasma glucagon concentrations within the physiological range have little or no effect on adipose tissue lipolysis.
Determination of plasma calcitonin gene-related peptide concentrations by a new immunochemiluminometric assay in normal persons and patients with medullary thyroid carcinoma and other neuroendocrine tumors, There is doubt about concentrations of circulating calcitonin gene-related peptide (CGRP) and the value of plasma CGRP measurements in the detection and follow-up of medullary thyroid carcinoma (MTC). Thus. we developed an immunochemiluminometric sandwich assay for CGRP using antibodies purified from a polyclonal antiserum against human CGRP. The assay was sensitive (limit of detection. 0.4 pmol/L; multiply by 3.7892 to derive nanograms per L) and highly specific [no cross-reaction with human calcitonin (CT)]. Normal plasma CGRP values ranged from less than 0.4 to 4.5 pmol/L (median. 0.8; n = 31). with 61% having detectable levels. Values in samples from patients with MTC were elevated: unoperated patients (n = 10). 4.7-137 pmol/L (median. 7.1); and operated patients with gross persistent or recurrent tumor (n = 14). 4.7-171 pmol/L (median. 23.2). In contrast. CGRP values were normal in 78% of nine postoperative patients with elevated CT. but no detectable tumor (range. less than 0.4 to 6.3 pmol/L; median. 1.6). CGRP levels increased after pentagastrin injection in MTC patients. but less than did CT values. Cultured MTC cells in vitro secreted large amounts of CGRP. and rat nerve root ganglia. human osteoblasts. and microvessel endothelial cells secreted lesser amounts. We conclude that CGRP circulates in normal plasma. but at very low levels. Plasma CGRP concentrations are frequently high in patients with MTC. but primarily in those with gross tumor or metastases. Plasma CT assay is the preferable test for MTC. but CGRP assay deserves prospective study for a possible role in predicting gross metastasis.
Parathyroid function in normocalcemic renal transplant recipients: evaluation by calcium infusion, The extent to which secondary hyperparathyroidism may involute remains poorly defined. Renal transplantation offers a clinical situation in which metabolic stimuli for hyperparathyroidism are removed. To examine whether hyperparathyroidism resolves after transplantation. we evaluated 11 renal transplant recipients who had been normocalcemic 6 or more months after transplantation using a sensitive 2-site immunoradiometric assay for intact serum PTH. Nine of the 11 had PTH concentrations within the normal range. Of these 9. 6 were found to have abnormal parathyroid function when challenged with an iv calcium infusion. The other 2 patients demonstrated significantly elevated basal PTH concentrations and elevated ionized calcium despite normal total serum calcium and albumin concentrations. In both. the PTH response to infused calcium was markedly abnormal. confirming hyperparathyroidism. The estimated renal threshold phosphate concentration was low in 4 of 9 patients with normal basal PTH concentrations and in both with elevated basal PTH. Bone mineral density. measured at the radius by single photon absorptiometry and at the spine by dual energy x-ray absorptiometry. was normal in 8 of the 9 transplant recipients who had normal basal PTH concentrations.
Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links, Pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) are two cross-links of collagen molecules that are present in the extracellular matrix and released during its degradation. In contrast to the wide distribution of collagen. Pyr is present in bone and cartilage. but not in significant amounts in other connective tissues. and D-Pyr appears to be specific for bone tissue. Therefore. the urinary excretion of Pyr and D-Pyr might be a sensitive marker of bone matrix degradation. Using a specific high pressure liquid chromatography assay we have measured Pyr and D-Pyr cross-links in a 24-h and a fasting urine sample in 60 early postmenopausal women and 19 premenopausal women matched for age. Menopause induced a 62% increase in Fu Pyr (49.8 +/- 18.7 vs. 30.8 +/- 8.0 pmol/mumol creatinine; P less than 0.001) and an 82% increase in Fu D-Pyr (8.2 +/- 3.4 vs. 4.5 +/- 1.4 pmol/mumol creatinine; P less than 0.001). In 20 postmenopausal women on hormone replacement therapy. urinary Pyr and D-Pyr returned to premenopausal levels within 6 months. contrasting with unchanged levels during placebo treatment. The 24-h excretion of Pyr and D-Pyr was significantly lower than the fasting excretion. but was similarly decreased after hormone replacement therapy. Pyr and D-Pyr excretion measured in the same urinary sample were highly correlated (r = 0.85 for fasting and 0.83 for 24-h sampling). but correlations between fasting and 24-h values were weak (D-Pyr. r = 0.30; Pyr. r = 0.29; P less than 0.05 for both). Correlations between urinary cross-links and other markers of bone turnover (Fu hydroxyproline/creatinine and plasma osteocalcin) were significant but low (Pyr vs. osteocalcin. r = 0.29. P less than 0.05; Pyr vs. hydroxyproline. r = 0/.34; P less than 0.01; D-Pyr vs. osteocalcin. r = 0.39; P less than 0.01). except for D-Pyr vs. hydroxyproline (r = 0.24; P = 0.07). suggesting that these markers reflect different events of bone metabolism. Finally. a single measurement of the fasting excretion. but not of the 24-h excretion. of cross-links was significantly correlated (Pyr. r = 0.34; P less than 0.05; D-Pyr. r = -0.46; P less than 0.01). with the subsequent spontaneous rate of bone loss assessed by repeated measurements of the radial bone mineral content in 37 postmenopausal women.(ABSTRACT TRUNCATED AT 400 WORDS).
Acute changes in serum osteocalcin during induced hypocalcemia in humans, Although levels of serum osteocalcin are thought to be an indicator of osteoblastic activity and bone formation. there is little information regarding the acute effects of changes in calcium or PTH levels on circulating osteocalcin concentrations. To study the effect of stepwise decreases in ionized calcium (CaI) on osteocalcin levels. we infused six normal subjects with citrate for four 30-min intervals using two different protocols. One protocol (pulse infusion) used alternating rates of infusion and resulted in rapid stepwise decrements in serum CaI. The second protocol (continuous infusion) used constant intermediate rates of citrate infusion and produced slower decrements in CaI. but with similar changes in magnitude. We monitored serum CaI. intact PTH. and osteocalcin concentrations during the course of these infusions. During each step of the pulse infusion the osteocalcin responses to changes in CaI in general were parallel to the changes in PTH (r = 0.462; P = 0.02) and were inversely correlated to CaI (r = -0.562; P = 0.003). The osteocalcin concentrations at the end of each 30-min period were higher than at the beginning of that period; over the total 120 min. osteocalcin levels rose from 3.46 +/- 0.63 to 6.88 +/- 1.08 micrograms/L (P less than 0.05). In contrast. during the first two periods of the continuous infusion. osteocalcin concentrations changed slightly. Only during the last two periods of the continuous infusion did osteocalcin respond in a manner characteristic of that observed with the pulse infusion. These data indicate that osteocalcin concentrations in the circulation may be acutely regulated by calcium and/or PTH.
Nocturnal elevation of glucose levels during fasting in noninsulin-dependent diabetes, To define the spontaneous diurnal variations in glucose regulation during fasting in noninsulin-dependent diabetes (NIDDM). we measured circulating levels of glucose. insulin. C-peptide. GH. cortisol. and glucagon at 15-min intervals in 11 patients with untreated diabetes and 7 matched control subjects studied during a 24-h period. The rates of insulin secretion were derived from the concentrations of C-peptide by deconvolution using a two-compartment mathematical model for C-peptide distribution and metabolism. In both groups of subjects. despite continued fasting. glucose levels stopped declining in the evening and subsequently rose throughout the night to reach a morning maximum. Elevated levels persisted until noon. The morning glucose maximum corresponded to a relative increase of 23.8 +/- 5.5% above the evening nadir in NIDDM patients and 13.2 +/- 4.6% in nondiabetic subjects (P less than 0.05). In NIDDM patients. insulin levels and insulin secretion rates did not parallel the nocturnal glucose changes. In contrast. in control subjects. this nocturnal glucose rise coincided with a similar increase in insulin secretion rates. Cortisol concentrations in patients with NIDDM were higher than those in control subjects throughout the study period (P less than 0.001) and rose earlier in the evening than in control subjects. thus failing to demonstrate the normal nocturnal suppression. In both groups of subjects. the nighttime glucose elevation was temporally and quantitatively correlated with the circadian cortisol rise. GH secretion was increased in the evening and nighttime periods compared to the daytime values. and in NIDDM patients. but not in control subjects. the size of the morning glucose elevation was directly related to the magnitude of this increase in GH secretion (r = 0.88; P less than 0.01). Glucagon concentrations were similar in both groups of subjects and remained essentially constant throughout the study period. We hypothesize that the nocturnal glucose rise that occurs during fasting represents a normal diurnal variation in the set-point of glucose regulation amplified by counterregulatory mechanisms activated by the fasting condition.
Use of m-[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma, The efficacy and safety of m-[131I]iodobenzylguanidine ([131I]MIBG) were assessed in 15 patients with malignant pheochromocytomas in a nonrandomized. single arm trial. in which patients were treated with [131I]MIBG (SA. 740 megabequerel/mg) every 3 months. Seven of these patients had bone and soft tissue metastases. 4 had only soft metastases. and 4 had only bone metastases. The follow-up period ranged from 6-54 months; the number of doses ranged from 2-11. with 2.9 (78.4 mCi) to 9.25 gigabequerel (GBq) (250 mCi)/administration and a cumulative activity from 11.1-85.90 GBq (300-2322 mCi). The absorbed cumulative dose in tumors ranged from 12-155 Gy. A beneficial effect of the treatment was observed in 9 patients (60%). No complete remission of the disease was observed. Seven patients died during the study. among whom 4 never responded to the treatment. Seven had hormonal responses (4 complete and 3 partial). with a duration ranging from 5-48 months. Among these patients. 4 relapsed. and 3 died within 3 months. Five patients had partial tumoral responses mainly located in soft tissues and for a duration ranging from 29-54 months. All patients with a hormonal response had objective improvement in clinical status and blood pressure. There was no clear-cut relationship between the cumulative dose and the responses. The main side-effect observed in 1 patient with widespread bone metastases after three doses (12.9 GBq) was a pancytopenia. which resolved after treatment was discontinued. This study suggests that repeated [131I]MIBG treatment could be effective in patients with advanced malignant pheochromocytoma.
Correlation between serum osteocalcin and 24,25-dihydroxyvitamin D levels in Paget's disease of bone, We have studied the possible correlation between serum 24.25-dihydroxyvitamin D [24.25-(OH)2D] and osteocalcin levels (sBGP) in Paget's disease of bone. We measured serum calcium. phosphate. PTH. 25-hydroxyvitamin D. 1.25-(OH)2D. 24.25-(OH)2D. alkaline phosphatase (sAP). and the urinary hydroxyproline/creatinine ratio (UOH prol/creat) in 19 patients with Paget's disease of bone and 16 age- and sex-matched controls. As expected. sAP. UOH prol/creat. and sBGP levels were significantly elevated. and there was a tendency to a decrease in serum levels of 24.25-(OH)2D in Pagetic patients with respect to the control group. There was no significant difference between patients and controls in serum calcium. phosphate. PTH. 25-hydroxyvitamin D. and 1.25-(OH)2D. The Pagetic patients were subdivided into two subgroups; subgroup A had normal sBGP levels (less than 5 ng/mL). and subgroup B had increased sBGP levels (greater than 5 ng/mL). Serum 24.25-(OH)2D levels in subgroup B were significantly lower than those in controls. while subgroup A showed levels similar to those in the control group. We also found a positive linear correlation between sAP and sBGP and between sAP and UOH prol/creat as well as a negative linear correlation between sBGP and 24.25-(OH)2D and between 24.25-(OH)2D and UOH prol/creat in Pagetic patients. These results point to a possible role of 24.25-(OH)2D in disease activity.
Intranasal administration of neostigmine potentiates both intravenous and intranasal growth hormone (GH)-releasing hormone-induced GH release in short children, Administration of cholinergic agonists increases both basal and GH-releasing hormone (GHRH)-induced GH secretion. probably acting via inhibition of endogenous somatostatin release. The aim of our study was to verify in two groups of children with idiopathic short stature the effect of intranasal administration of neostigmine (inNS; 3 mg). a cholinesterase inhibitor. on basal GH levels as well as on the somatotroph response to GHRH when the peptide was administered either iv (ivGHRH; 1 microgram/kg) or intranasally (inGHRH; 10 micrograms/kg). In group A (n = 6; age. 10.6-16.0 yr) inNS induced a significant GH increase [inNS vs. saline. area under the curve (AUC; mean +/- SEM). 263.7 +/- 60.2 vs. 73.8 +/- 3.1 micrograms/L.h; P less than 0.03] and potentiated the somatotroph response to ivGHRH (inNS with ivGHRH vs. ivGHRH. 1316 +/- 183.0 vs. 644.9 +/- 154.5 micrograms/L.h; P less than 0.03). In group B (n = 6; age. 11.5-15.9 yr) ivGHRH induced a GH rise clearly higher than that induced by inGHRH (604.2 +/- 154.3 vs. 137.1 +/- 28.2 micrograms/L.h; P less than 0.03). Administration of inNS induced a GH rise similar to that occurring after inGHRH (AUC. 239.2 +/- 69.5 micrograms/L.h) and markedly increased the inGHRH-induced GH response (482.4 +/- 103.6 micrograms/L.h; P less than 0.05 and 0.03 vs. inNS and inGHRH. respectively). so that it overlapped with that induced by ivGHRH alone. In conclusion. cholinergic agonists such as neostigmine are able to increase both basal and GHRH-induced GH secretion in short children even when given intranasally. Combined intranasal administration of neostigmine and GHRH (10 micrograms/kg) is able to induce a GH rise similar to that induced by ivGHRH alone (1 microgram/kg). suggesting the potential usefulness of this combination cocktail and route of administration for the treatment of short stature.
Serum osteocalcin in patients taking L-thyroxine who have subclinical hyperthyroidism, Serum osteocalcin. an index of osteoblastic activity. is increased in hyperthyroidism. Serum osteocalcin levels are negatively correlated with bone density in patients with overt hyperthyroidism. Osteocalcin levels are also elevated in patients with multinodular goiter and subclinical hyperthyroidism. We therefore measured serum osteocalcin levels in patients taking T4 to determine if they correlated with the degree of TSH suppression. Despite an upward trend in serum osteocalcin measurements with decreasing TSH concentrations. there was no significant difference in serum osteocalcin among groups of patients with normal (0.5-5.0 mu/L). mildly reduced (0.1-0.5 mU/L). or undetectable serum TSH (less than 0.01 mU/L). However. a weak negative correlation was seen between serum TSH and osteocalcin concentrations (r = 0.29. slope = -0.28. P less than 0.05). Osteocalcin did not correlate with either serum free T4 or free T3 concentrations. Serum PTH concentrations were not different among the three patient groups. Our data suggest that osteocalcin is not a useful clinical marker for increased bone turnover in patients with subclinical hyperthyroidism due to T4 therapy. However. the trend towards higher osteocalcin levels in patients with suppressed serum TSH values. and the weak negative correlation between serum TSH and osteocalcin are consistent with findings of reduced bone density in these patients.
Bone mineral density of the lumbar spine in endometriosis subjects compared to an age-similar control population, The purpose of this study was to compare the lumbar bone mineral density (BMD) between women with endometriosis and age-similar controls. Eighty-five women from nine North American centers (mean age. 30.7 yr) with laparoscopically proven endometriosis (study patients) were enrolled in a study of the efficacy of nafarelin. a GnRH agonist. Fifty-two women (mean age. 32 yr) from the Palo Alto area. with regular menstrual cycles and no major medical problems. served as age-similar controls. Both groups were predominantly (greater than 92%) white. The mean BMD of the lumbar spine was 1.1 g/cm2 in both the study subjects and the controls. Study patients were 104.8% and controls were 104.8% of normal values for age. BMD was not significantly different in the two groups. BMD was not correlated with severity or time from diagnosis of endometriosis. BMD was positively correlated with weight (r = 0.28; P less than 0.05) in both groups. with height (r = 0.30; P less than 0.01) in study patients. and marginally with height (r = 0.26; P less than 0.07) in controls. This study showed no difference in BMD between endometriosis patients and age-similar controls; both groups had normal BMD.
Polycythemia vera blood burst-forming units-erythroid are hypersensitive to interleukin-3, Because polycythemia vera (PV) is a clonal hematopoietic stem cell disease with a trilineage hyperplasia. and interleukin-3 (IL-3) stimulates trilineage hematopoiesis. we have studied the response of highly purified PV blood burst-forming units-erythroid (BFU-E) to recombinant human IL-3 (rIL-3). Whereas the growth of normal blood BFU-E in vitro rapidly declined by 40 and 60% after 24 and 48 h of incubation without 50 U/ml of rIL-3. the growth of PV BFU-E declined by only 10 and 30% under the same conditions. demonstrating a reduced dependence on rIL-3. A reduced dependence of PV BFU-E on recombinant human erythropoietin (rEP) was also present. Dose-response experiments showed a 117-fold increase in PV BFU-E sensitivity to rIL-3. and a 6.5-fold increase in sensitivity to rEP. compared to normal BFU-E. whereas blood BFU-E from patients with secondary polycythemia responded like normal BFU-E. Endogenous erythroid colony (EEC) formation. which is independent of the addition of rEP. was reduced by 50% after erythroid colony-forming cells were generated from PV BFU-E in vitro without rIL-3 for 3 d. whereas rEP-stimulated erythroid colonies were unaffected. These studies demonstrate a striking hypersensitivity of PV blood BFU-E to rIL-3. which may be the major factor in the pathogenesis of increased erythropoiesis without increased EP concentrations.
Proglucagon products in plasma of noninsulin-dependent diabetics and nondiabetic controls in the fasting state and after oral glucose and intravenous arginine, We investigated the major products of proglucagon (PG) processing in plasma in the fasting state. after intravenous arginine and after an oral glucose load in noninsulin-dependent diabetics (NIDDM) and in weight matched controls using specific radioimmunoassays and analytical gel filtration. In the fasting state the glucagonlike peptide-1 (GLP-1) immunoreactivity was significantly elevated in the NIDDM group compared with the control group. Both after intravenous arginine and after an oral glucose load a rise in the plasma concentrations of all immunoreactive moieties measured was seen. All integrated incremental responses after intravenous arginine were identical in the two groups. After oral glucose the insulin concentrations in plasma were lower and the concentrations of all proglucagon products were higher in the NIDDM group compared to the control group. The gel filtration analysis showed that arginine stimulated the secretion of pancreatic glucagon (PG 33-61). major proglucagon fragment (PG 72-158) and probably GLP-1 (PG 72-107 amide) in both groups. whereas oral glucose stimulated the secretion of glicentin (PG 1-69) and intestinal GLP-1 (PG 78-107 amide). an insulinotropic hormone. The elevated levels of immunoreactive GLP-1 in diabetics in the fasting state were mainly due to an increased concentration of major proglucagon fragment.
Advanced glycosylation products quench nitric oxide and mediate defective endothelium-dependent vasodilatation in experimental diabetes, Nitric oxide (an endothelium-derived relaxing factor) induces smooth muscle relaxation and is an important mediator in the regulation of vascular tone. Advanced glycosylation end products. the glucose-derived moieties that form nonenzymatically and accumulate on long-lived tissue proteins. have been implicated in many of the complications of diabetes and normal aging. We demonstrate that advanced glycosylation products quench nitric oxide activity in vitro and in vivo. Acceleration of the advanced glycosylation process in vivo results in a time-dependent impairment in endothelium-dependent relaxation. Inhibition of advanced glycosylation with aminoguanidine prevents nitric oxide quenching. and ameliorates the vasodilatory impairment. These results implicate advanced glycosylation products as important modulators of nitric oxide activity and endothelium-dependent relaxation.
Recruitment of neutrophils during IgE-dependent cutaneous late phase reactions in the mouse is mast cell-dependent. Partial inhibition of the reaction with antiserum against tumor necrosis factor-alpha, Much of the clinically important pathology associated with IgE-dependent disorders is thought to reflect the actions of the blood-borne leukocytes recruited during these responses. To evaluate the extent to which mast cells are responsible for the leukocyte infiltration associated with IgE-dependent cutaneous reactions. we attempted to elicit these responses in normal mice. genetically mast cell-deficient W/Wv mice. and in W/Wv mice selectively repaired of their mast cell deficiency by the intradermal injection of cultured mast cells derived from the congenic normal (+/+) mice. We found that the tissue swelling associated with IgE-dependent passive cutaneous anaphylaxis reactions developed rapidly and diminished markedly from 2 to 4 h after antigen challenge. but remained detectable for at least 24 h after elicitation of the responses. Infiltration of leukocytes (predominantly neutrophils) also occurred at these sites. but reached maximal levels 6-12 h after antigen challenge. persisted at high levels for 24 h. and largely waned by 48 h. Virtually all of the tissue swelling and leukocyte infiltration associated with IgE-dependent cutaneous reactions was mast cell dependent. Intradermal injection of 40 U of recombinant murine TNF-alpha (rmTNF-alpha) elicited neutrophil infiltration similar in magnitude and kinetics to that observed after IgE-dependent mast cell degranulation. A rabbit anti-rmTNF-alpha (R anti-rmTNF-alpha) antiserum. which was able to inhibit 84% of the neutrophil infiltration observed after i.d. injection of rmTNF-alpha. inhibited IgE-. and mast cell-dependent leukocyte infiltration by 47 +/- 7% in three separate experiments. These findings indicate that TNF-alpha contributes to mast cell-dependent recruitment of leukocytes during IgE-dependent cutaneous late phase reactions. but suggest that other mast cell-associated mediators probably also contribute to this response.
Macrophages from nephrotic rats regulate apolipoprotein E biosynthesis and cholesterol content independently, The effects of the nephrotic syndrome in rats on the cholesterol content and the biosynthesis of apolipoprotein E (apoE) by resident peritoneal macrophages have been investigated. Since the nephrotic syndrome has been associated with an increased risk of coronary atherosclerosis. we hypothesized that macrophages from nephrotic rats would accumulate cholesterol and undergo transformation into foam cells. with a concomitant increase in apoE biosynthesis. The nephrotic syndrome was induced in rats with puromycin aminonucleoside. Peritoneal macrophages exposed in vivo for 7-21 d to ascites fluid derived from plasma containing sixfold elevations of lipoproteins did not accumulate unesterified or esterified cholesterol. Nevertheless. immunoprecipitation assays after incubation of the isolated cells with [35S]methionine. or immunoblot analysis of the incubation medium demonstrated a 2.6-fold increase in apoE secretion compared with normal macrophages. This increase was accompanied by 5- to 10-fold increases in cellular apoE messenger RNA as determined by quantitative solution hybridization assay. Peritoneal macrophages cultured from nephrotic rats during the period of hypercholesterolemia also showed distinct and highly reproducible morphologic changes. The dissociation between apoE biosynthesis and macrophage cholesterol content provides new insight into the response of peritoneal macrophages in vivo to endogenous hyperlipemia.
Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation, Generalized resistance to thyroid hormone (GRTH) is a syndrome characterized by impaired tissue responsiveness to thyroid hormone. Two distinct point mutations in the hormone binding domain of the thyroid hormone receptor (TR) beta have recently been identified in two unrelated families with GRTH. One. Mf. involves a replacement of the normal glycine-345 for arginine in exon 7 and another. Mh. replaces the normal proline-453 for histidine in exon 8. To probe for the presence of the Mf and Mh defect in 19 unrelated families with GRTH. we applied separate polymerase chain reactions using allele-specific oligonucleotide primers containing the normal and each of the two mutant nucleotides at the 3'-position. A total of 24 affected subjects and 13 normal family members were studied. The mode of inheritance was dominant in 13 families. was unknown in 5 families. and was clearly recessive in 1 family in which only the consanguineous subjects were affected. Primers containing the substitutions specific for Mf and Mh amplified exons 7 and 8. respectively. only in affected members of each of the two index families. Primers containing the normal sequences amplified exons 7 and 8 of the TR beta gene in all subjects except affected members of one family. In this family with recessively inherited GRTH. neither exon could be amplified using any combinations of primers and DNA blot revealed absence of all coding exons. These results indicate a major deletion of the TR beta gene. including both DNA and hormone binding domains. Since heterozygous members of this family are not affected. the presence of a single normal allele is sufficient for normal function of the TR beta. These data also support the hypothesis that in the dominant mode of GRTH inheritance the presence of an abnormal TR beta interferes with the function of the normal TR beta. Distinct mutations are probably responsible for GRTH in unrelated families.
Human immunodeficiency virus-infected macrophages produce soluble factors that cause histological and neurochemical alterations in cultured human brains, We wanted to establish an in vitro human model for AIDS-associated dementia and pursue the hypothesis that this disease process may be a result of soluble factors produced by HIV-infected macrophages. Human brain aggregates were prepared from nine different brain specimens. and were treated with supernatants from in vitro HIV-infected macrophages (SI). uninfected macrophages (SU). infected T cells. or macrophage-conditioned media from four AIDS patients. Seven of nine treated brains exposed to SI showed peripheral rarefaction after 1 wk of incubation that by ultrastructural analysis showed cytoplasmic vacuolation. Aggregates from two of three brain cultures treated with SI for 3 wk became smaller. an approximately 50% decrease in size. The degree of apparent toxicity in brains exposed to patient-derived macrophage supernatants paralleled the proportion of macrophages found to be expressing HIV p24. Ultrastructural abnormalities were not observed in brains treated with supernatants from HIV-infected T cells. uninfected macrophages. or LPS-activated macrophages. Levels of five neurotransmitter amino acids were decreased in comparison to the structural amino acid leucine. These findings suggest that HIV-infected macrophages. infected both in vitro as well as derived from AIDS patients' peripheral blood. produce factors that cause reproducible histochemical. ultrastructural. and functional abnormalities in human brain aggregates.
Intravenous administration of phosphorylated acid alpha-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice, The lysosomal storage disorder glycogenosis type II is caused by acid alpha-glucosidase deficiency. In this study we have investigated the possible applicability of mannose 6-phosphate receptor-mediated enzyme replacement therapy to correct the enzyme deficiency in the most affected tissues. Bovine testes acid alpha-glucosidase containing phosphorylated mannose residues was intravenously administered to mice and found to be taken up by heart (70% increase of activity) and skeletal muscle (43% increase); the major target organs. The uptake of nonphosphorylated human placenta acid alpha-glucosidase by heart and skeletal muscle appeared to be significantly less efficient. whereas uptake of dephosphorylated bovine testes enzyme was not detectable. The phosphorylated bovine testes acid alpha-glucosidase remained present in mouse skeletal muscle up to 9-15 d after administration. with a half-life of 2-4 d. Besides being measured in skeletal muscle and heart. uptake of phosphorylated bovine testes and nonphosphorylated human placenta acid alpha-glucosidase was measured in several other organs. but not in brain. The increase of acid alpha-glucosidase activity was highest in liver and spleen. We concluded that application of mannose 6-phosphate receptor-mediated enzyme replacement therapy may offer new perspectives for treatment of glycogenesis type II.
Quantitation of G0 and G1 phase cells in primary carcinomas. Antibody to M1 subunit of ribonucleotide reductase shows G1 phase restriction point block, Human cancers have an apparent low growth fraction. the bulk of cells presumed to being out of cycle in a G0 quiescent state due to the inability in the past to distinguish G0 from G1 cells. The allosteric M1 subunit of ribonucleotide reductase (M1-RR) is constitutively expressed by cycling cells (i.e.. G1. S. G2-M). It is acquired during transition from G0 to G1. lost during exit to G0 and thus distinguishes G0 from G1 cells. To estimate the proportion of G0 and G1 cells in primary human breast (n = 5) and colorectal (n = 12) adenocarcinomas. we used both analytical DNA flow cytometry (ADFC) and immunoperoxidase staining of sections with the monoclonal antibody to M1-RR (MAb M1-RR). ADFC of fresh tumors revealed a low percentage of cells in the S phase (4.0 +/- 3.4%) but immunoperoxidase staining for M1-RR revealed an unexpectedly high proportion of positive cells (52.4 +/- 12.7%) in the G1. S. G2-M phases indicating a high G1 content of primary human tumors. Thus. human cancers are blocked in transition in G1 and are not predominantly in a G0 or quiescent differentiated state. This block was interpreted to mean that human cancers are responding to putative regulatory events at a restriction point in the G1 phase. such as relative growth factor deficiency. density inhibition. antiproliferative cytokines. or gene products. Using flow cytometry for both DNA and M1-RR content we found that human colon cancer cell lines arrest in the G1 but not G0 phase upon serum deprivation or density inhibition. Similarly. human breast cancer cell lines are arrested in G1 but not G0 phase by medroxyprogesterone acetate (MPA) or tamoxifen exposure. These findings match our in situ observations. and support the concept of a restriction point block in primary human tumors.
Myocardial protein turnover in patients with coronary artery disease. Effect of branched chain amino acid infusion, The regulation of protein metabolism in the human heart has not previously been studied. In 10 postabsorptive patients with coronary artery disease. heart protein synthesis and degradation were estimated simultaneously from the extraction of intravenously infused L-[ring-2.6-3H]phenylalanine (PHE) and the dilution of its specific activity across the heart at isotopic steady state. We subsequently examined the effect of branched chain amino acid (BCAA) infusion on heart protein turnover and on the myocardial balance of amino acids and branched chain ketoacids (BCKA) in these patients. In the postabsorptive state. there was a net release of phenylalanine (arterial-cardiac venous [PHE] = -1.71 +/- 0.32 nmol/ml. P less than 0.001; balance = -116 +/- 21 nmol PHE/min. P less than 0.001). reflecting protein degradation (142 +/- 40 nmol PHE/min) in excess of synthesis (24 +/- 42 nmol PHE/min) and net myocardial protein catabolism. During BCAA infusion. protein synthesis increased to equal the degradation rate (106 +/- 24 and 106 +/- 28 nmol PHE/min. respectively) and the phenylalanine balance shifted (P = 0.01) from negative to neutral (arterial-cardiac venous [PHE] = 0.07 +/- 0.36 nmol/ml; balance = 2 +/- 25 nmol PHE/min). BCAA infusion stimulated the myocardial uptake of both BCAA (P less than 0.005) and their ketoacid conjugates (P less than 0.001) in proportion to their circulating concentrations. Net uptake of the BCAA greatly exceeded that of other essential amino acids suggesting a role for BCAA and BCKA as metabolic fuels. Plasma insulin levels. cardiac double product. coronary blood flow. and myocardial oxygen consumption were unchanged. These results demonstrate that the myocardium of postabsorptive humans is in negative protein balance and indicate a primary anabolic effect of BCAA on the human heart.
Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression, Evidence is emerging for a direct role of glucose. independent of changes in insulin. in the regulation of cellular glucose transport and glucose utilization in vivo. In this study we investigate potential cellular and molecular mechanisms for this regulatory effect of glucose by determining how normalization of glycemia without insulin therapy in diabetic rats influences 3-O-methylglucose transport and the expression and translocation of two genetically distinct species of glucose transporters (GTs) in adipose cells. These results are compared with alterations in glucose disposal in vivo measured by euglycemic clamp. In rats rendered diabetic by 90% pancreatectomy. insulin-stimulated glucose transport in adipose cells is decreased 50% in parallel with reduced insulin-mediated glucose disposal in vivo. Levels of adipose/muscle GTs measured by immunoblotting are decreased in adipose cell subcellular membrane fractions. as are the corresponding mRNA levels assessed by Northern blotting of total adipose cell RNA. Normalization of blood glucose in diabetic rats with phlorizin. which impairs renal tubular glucose reabsorption and thus enhances glucose excretion. restores insulin-stimulated glucose transport in adipose cells and insulin-mediated glucose disposal in vivo. Importantly. levels of the adipose/muscle GT protein remain 43% reduced in the low-density microsomes in the basal state and 46% reduced in the plasma membranes in the insulin-stimulated state. Adipose/muscle GT mRNA levels remain approximately 50% depressed. Levels of the HepG2/brain GT protein and mRNA are unaltered by diabetes or phlorizin treatment. Thus. changes in ambient glucose independent of changes in ambient insulin can regulate the glucose transport response to insulin in isolated adipose cells and changes in responsiveness parallel alterations in glucose uptake in vivo. Since this effect can occur without alteration in the expression of the two species of glucose transporters present in adipose cells or in their translocation to the plasma membrane in response to insulin. it may result from changes in GT functional activity.
Role of increased cytosolic free calcium in the pathogenesis of rabbit proximal tubule cell injury and protection by glycine or acidosis, To assess the role of increased cytosolic free calcium (Caf) in the pathogenesis of acute proximal tubule cell injury and the protection afforded by exposure to reduced medium pH or treatment with glycine. fura-2-loaded tubules were studied in suspension and singly in a superfusion system. The Ca2+ ionophore. ionomycin. increased Caf to micromolar levels and rapidly produced lethal cell injury as indicated by loss of lactate dehydrogenase to the medium by suspended tubules and accelerated leak of fura and failure to exclude Trypan blue by superfused tubules. Decreasing medium Ca2+ to 100 nM prevented the ionomycin-induced increases of Caf and the injury. Reducing medium pH from 7.4 to 6.9 or adding 2 mM glycine to the medium also prevented the cell death. but did not prevent the increase of Caf to micromolar levels. Cells treated with 1799. an uncoupler of oxidative phosphorylation which produced severe adenosine triphosphate (ATP) depletion. did not develop increases of Caf until just before loss of viability. Preventing these increases of Caf with 100 nM Ca2+ medium did not protect 1799-treated cells. Reduced pH and glycine protected 1799-treated cells without ameliorating the increases of Caf. These data demonstrate the toxic potential of increased Caf in the proximal tubule and show that Caf does sharply increase prior to loss of viability in an ATP depletion model of injury. but this increase does not necessarily contribute to the outcome. The potent protective actions of decreased pH and glycine allow the cells to sustain increases of Caf to micromolar levels in spite of severe. accompanying cellular ATP depletion without developing lethal cell injury.
Murine mast cells synthesize basement membrane components. A potential role in early fibrosis, Mast cells are resident in tissues. particularly in association with endothelial and epithelial cell basement membranes. and increase at sites of inflammation. injury. and fibrosis. Although mast cells are known to both release and generate proinflammatory molecules in response to inflammatory stimuli. little is known about their normal biologic function. Here we demonstrate that IL-3-dependent mouse PT18 mast cells. mouse bone marrow-derived mast cells. and rat basophilic leukemia cells express large amounts of mRNA for collagen IV. laminin. and heparan sulfate proteoglycan. Western blot analysis confirmed that mast cells synthesize and secrete significant amounts collagen IV and laminin B1 and B2 chains. These data suggest that mast cells may contribute to normal tissue repair and/or the early overproduction of basement membrane components seen in a variety of fibrotic conditions.
Insulin-like growth factor II-mediated proliferation of human neuroblastoma, Neuroblastoma is an embryonal tumor that typically arises in cells of the developing adrenal medulla. IGF-II mRNA is expressed at high levels in the adrenal cortex before birth but it is not detectable until after birth in the adrenal medulla. Neuroblastoma cell lines corresponding to early adrenal medullary precursors did not express IGF-II. although all three cell lines we tested were growth stimulated by IGF-II. Cell lines corresponding to more mature adrenal medullary cells expressed IGF-II. and one. SK-N-AS. grows by an IGF-II autocrine mechanism (J. Clin. Invest. 84:829-839) El-Badry. Romanus. Helman. Cooper. Rechler. and Israel. 1989. An examination of human neuroblastoma tumor tissues for IGF-II gene expression using in situ hybridization histochemistry revealed that IGF-II is expressed by tumor cells in only 5 of 21 neuroblastomas. but is detectable in cells of nonmalignant tissues including adrenal cortical cells. stromal fibroblasts. and eosinophils in all 21 tumors. These findings indicate that IGF-II may function as an autocrine growth factor for some neuroblastomas and as a paracrine growth factor for others. They suggest that the growth regulatory pathways utilized by neuroblastoma mimic those used in the precursor cell type from which individual tumors arise.
Limited B cell repertoire in severe combined immunodeficient mice engrafted with peripheral blood mononuclear cells derived from immunodeficient or normal humans, The ability to engraft human PBMC or fetal tissue immune cells in the severe combined immunodeficient (SCID) mouse has created a need for characterization of these systems and their application to disease models. We demonstrate that SCID mice reconstituted with PBMC support the growth and differentiation of a restricted set of B cells. Human IgG levels of 1-2 mg/ml (10-20% of normal human serum levels) were routinely achieved in spite of a serum half life of only 12 d. Ig levels peaked around 50 d and Ig production was maintained for greater than 100 d. The Ig was greater than 85% IgG though some IgM. IgA. IgD. and even IgE could be detected. However. the human IgG produced in hu-PBL-SCID mice was pauci-clonal when analyzed by isoelectric focusing and by kappa/lambda light chain usage. Using a new polymerase chain reaction based analysis capable of monitoring individual VH family utilization. we found that the engrafted B cells showed skewed and restricted human VH subfamily utilization. These parameters were markedly variable among hu-PBL-SCID mice reconstituted from the same donor cell population at both early (21-50 d) and late stages (greater than 100 d). Hu-PBL/CVI-SCID mice constructed with cells from patients with common variable immunodeficiency with an in vitro block in terminal B cell differentiation produced human Ig responses that were quantitatively the same as those produced by hu-PBL-SCID mice from normal donors. The hu-PBL-SCID system using PBMC appears to lead to growth and Ig production by a small number of B cells and results in a restricted B cell repertoire.
Growth factor-induced acceleration of tissue repair through direct and inductive activities in a rabbit dermal ulcer model, The roles of polypeptide growth factors in promoting wound healing and in directing the specificity and sequence of responses of different tissues in wounds are little understood. We investigated the influence of four growth factors on the rates of healing of a novel full thickness dermal ulcer placed on an avascular base in the rabbit ear. The wound model precludes significant wound contraction and requires new granulation tissue and epithelial cells for healing to originate centripetally. 5 micrograms (7-31 pmol/mm2) of platelet-derived growth factor-B chain (PDGF-BB). basic fibroblast growth factor (bFGF). and epidermal growth factor (EGF) applied locally at the time of wounding resulted in a twofold increase in complete reepithelialization of treated wounds (PDGF-BB. P = 0.02 chi square analysis; bFGF. P = 0.04; EGF. P = 0.05); transforming growth factor (TGF)-beta 1 significantly inhibited reepithelialization (P = 0.05). Both PDGF-BB and TGF-beta 1 uniquely increased the depth and area of new granulation tissue (P less than 0.005). the influx of fibroblasts. and the deposition of new matrix into wounds. Explants from 7-d old PDGF-BB-treated wounds remained metabolically far more active than controls. incorporating 473% more [3H]thymidine into DNA (P = 0.05) and significantly more [3H]leucine and [3H]proline into collagenase-sensitive protein (P = 0.04). The results establish that polypeptide growth factors have significant and selective positive influences on healing of full thickness ulcers in the rabbit.
A single base substitution in the coding region for neurophysin II associated with familial central diabetes insipidus, To elucidate the molecular mechanism of familial central diabetes insipidus (FDI). we sequenced the arginine vasopressin-neurophysin II (AVP-NPII) gene in 2 patients belonging to a pedigree that is consistent with an autosomal dominant mode of inheritance. 10 patients with idiopathic central diabetes insipidus (IDI) and 5 normals were also studied. The AVP-NPII gene. locating on chromosome 20. consists of three exons that encode putative signal peptide. AVP. NPII. and glycoprotein. Using polymerase chain reaction. fragments including the promoter region and all coding regions were amplified from genomic DNA and subjected to direct sequencing. Sequences of 10 patients with IDI were identical with those of normals. while in 2 patients with FDI. a single base substitution was detected in one of two alleles of the AVP-NPII gene. indicating they were heterozygotes for this mutation. It was a G----A transition at nucleotide position 1859 in the second exon. resulting in a substitution of Gly for Ser at amino acid position 57 in the NPII moiety. It was speculated that the mutated AVP-NPII precursor or the mutated NPII molecule. through their conformational changes. might be responsible for AVP deficiency.
Identification of two collagen domains within the bullous pemphigoid autoantigen, BP180, Bullous pemphigoid (BP) is an autoimmune disease characterized by subepidermal vesicles and the presence of autoantibodies directed against the epidermal basement membrane zone. Previous studies have identified two protein components of the hemidesmosome. BP180 and BP230. as the primary antigenic targets of BP autoantibodies. We have recently reported the isolation of a 1.0-kb BP180 cDNA. Sequence analysis presented in this report reveals that this partial BP180 cDNA encodes two protein domains which have primary structures that are characteristic of the triple helical domains of collagens. i.e.. glycine appears at every third position and over one-third of the remaining residues are proline. The two collagen domains have lengths of 242 and 30 amino acids and are separated by a noncollagen stretch of 12 amino acids. Collagenase digestion of the BP180 cDNA-encoded fusion protein generated a peptide fragment with a size that was consistent with the predicted locations of the collagenase digestion sites. A possible physiological function for the collagen domains of the BP180 hemidesmosomal protein may be to form stable interactions with constituents of the extracellular matrix of the cutaneous basement membrane zone. Such interactions may provide the molecular framework for the adhesion between the basal keratinocyte and the basal lamina.
Patterns of epidermal growth factor receptors in basal and squamous cell carcinoma, The presence of immunoreactive epidermal growth factor receptors in human skin tumors was investigated using the indirect immunoperoxidase technique. Sixteen basal cell carcinomas and 11 squamous cell carcinomas were evaluated. All of the specimens studied were receptor positive. In 70% of the specimens there was prominent staining of the cell membranes. In 54% of the nodular basal cell carcinoma specimens there was increased staining at the periphery of the tumor cell masses.
Basal cell carcinoma recurring after radiotherapy: a unique, difficult treatment subclass of recurrent basal cell carcinoma, Twenty-seven basal cell carcinomas (BCCs) recurring following radiation therapy alone or in addition to other treatment modalities were treated with Mohs micrographic surgery (MMS) from 1983 to 1989. Mean tumor size was 2.1 cm. Of the tumors. 70.4% arose in the mid-face region. 55.6% had undergone multiple previous treatment modalities. The present recurrence rate is 7.4% (mean follow-up: 25 months). Basal cell carcinoma recurring following radiotherapy deserves special subclassification among recurrent BCC. It is very difficult to eradicate. with high recurrence rates following standard surgical excision or further radiotherapy. Tumors are usually large. aggressive. and invasive. Most arise in the cosmetically crucial mid-face region. where extension into subcutaneous tissue planes is common. Mohs surgery. with its inherent abilities to examine all margins. map tumor extension. and conserve tissue. is uniquely suited to treatment of these difficult tumors.
The abraded punch graft for pitted facial scars, The abraded punch graft procedure is one in which the surrounding scar area and the graft itself are superficially dermabraded before correction of the defect. This alternative procedure has distinct advantages over the standard punch graft and should be considered when contemplating the surgical correction of "ice pick" facial scarring. Following the normal reparative process. the abraded punch graft heals with a pleasing aesthetic appearance.
Incisional slit grafting, Incisional slit grafting. a new and greatly improved technique in hair transplantation. is described. Incisional slit grafting utilizes larger numbers of smaller grafts than does traditional punch grafting. No tissue is removed from the recipient bed. The vascular supply is conserved. resulting in an increased graft yield. The clumping and stalking effect associated with traditional round grafting is eliminated largely. and a more natural frontal hairline is achieved.
Sclerotherapy of varicose and telangiectatic leg veins. Minimal sclerosant concentration of hypertonic saline and its relationship to vessel diameter, The author reports the results of a double-blind. paired-comparison study using saline sclerosant plus or minus heparin additive. The study was designed to elucidate the effects of increasing concentrations of hypertonic saline with regard to vessel diameter. clinical efficacy. complications. and discomfort. Six hundred women with bilaterally symmetrical starburst telangiectasias or varicose veins were entered into the study. Sodium chloride 11.7% appeared to be the minimal sclerosant concentration of saline that produced the most effective vein sclerosis of vessels of less than 8 mm in diameter. while producing the least morbidity. The optimal concentration of the sclerosant may vary with the diameter of the vessels under therapeutic consideration.
The medical necessity of evaluation and treatment of port-wine stains, New lasers and improved laser delivery systems have allowed for the safe and effective treatment of port-wine stains in patients of all ages. The satisfactory results obtained by laser treatment have increased the number of patients seeking consultation regarding their birthmarks. It is imperative that physicians recognize the various medical syndromes and problems associated with port-wine stains. A review of 415 patients with facial port-wine stains has revealed hypertrophy and/or nodularity in 65% of patients by the fifth decade of life. which increases significantly the morbidity of these lesions. It is believed that laser treatment will minimize the medical and psychologic complications that result from the natural evolution of port-wine stains.
Natural history of moderate aortic stenosis, The natural history of severe. symptomatic aortic stenosis has been well documented. However. the natural history of moderate aortic stenosis remains poorly understood. Therefore. a group of 66 patients was identified who had a diagnosis of moderate aortic stenosis at the time of cardiac catheterization (aortic valve area 0.7 to 1.2 cm2) and who did not have surgical therapy during the 1st 180 days after cardiac catheterization. During a mean follow-up period of 35 months. 14 patients died of causes attributed to aortic stenosis and 21 underwent aortic valve replacement. The estimated probability for remaining free of any complication of aortic stenosis at the end of the first 4 years was 59%. Symptomatic patients with decreased ejection fraction or hemodynamic evidence of left ventricular decompensation were at greater risk for these complications. It is concluded that patients with moderate aortic stenosis are at significant risk for the development of complications.
Effect of H1 receptor stimulation on coronary artery diameter in patients with variant angina: comparison with effect of acetylcholine, It has been suggested that histamine is involved in the pathogenesis of coronary spasm but its exact role remains unclear. H1 receptor stimulation of the coronary artery was performed with a selective intracoronary infusion of histamine (2 micrograms/min) in 21 patients with variant angina after blockade of the H2 receptor with cimetidine (25 mg/kg) and its effect on the coronary artery diameter was examined. Intracoronary injection of acetylcholine was also performed in 19 of the 21 patients. Ergonovine (0.2 mg) was intravenously administered in one patient. The coronary artery diameter was measured with cinevideodensitometric analysis. A mean plasma histamine concentration in the coronary sinus increased from 4 x 10(-9) to 7 x 10(-8) M 5 min after histamine infusion into the left coronary artery (n = 18). Coronary spasm was induced in 6 patients (29%) with histamine. in 18 (95%) with acetylcholine and in 1 with ergonovine. The effect of histamine on the luminal diameter was analyzed at the site of spasm in the 26 coronary arteries in which spasm was induced by acetylcholine or ergonovine. Of the 20 coronary arteries with a normal arteriogram or a fixed stenosis less than or equal to 50% of luminal diameter. histamine decreased the diameter in 4. increased it in 14 (70%) and caused no change in 2; of the 6 coronary arteries with a fixed stenosis greater than or equal to 75%. histamine decreased the diameter in 5 and increased it in 1. In the coronary arteries in which spasm was not induced by either acetylcholine or ergonovine. histamine increased the diameter. especially in those without advanced atherosclerosis.
Percutaneous mitral valvuloplasty in surgical high risk patients, Among 126 consecutive patients undergoing percutaneous mitral valvuloplasty. 34 were judged to be at high risk for surgery on the basis of age greater than 70 years (n = 13). New York Heart Association functional class IV (n = 11). ejection fraction less than or equal to 35% (n = 3). severe pulmonary hypertension (n = 7). need for associated coronary bypass (n = 4) or additional valve surgery (n = 20) or severe pulmonary disease (n = 3). Baseline features of the high risk group were substantially worse than those of the other patients: age (65 +/- 11 versus 49 +/- 12 years; p = 0.0001) and echocardiographic score (9.4 +/- 1.8 versus 8.2 +/- 1.5; p = 0.005) were higher. whereas cardiac output (2.9 +/- 0.9 versus 4.1 +/- 1.2 liters/min; p = 0.0001) and mitral valve area (0.9 +/- 0.4 versus 1.1 +/- 0.3 mm2; p = 0.002) were lower. Three high risk patients experienced technical failures and three others had major complications. Among the remaining 28 patients. 18 (65%) had a complete hemodynamic success. 4 (14%) an incomplete success and 6 (21%) hemodynamic failure. Stepwise logistic regression analysis retained echocardiographic score as the only factor independently predictive of success. The percent increase in mitral valve area also correlated with echocardiographic score (r = 0.51. p less than 0.01).
The variable extent of jeopardized myocardium in patients with single vessel coronary artery disease: quantification by thallium-201 single photon emission computed tomography, To assess the extent of jeopardized myocardium in patients with single vessel coronary artery disease of variable severity and location. quantitative exercise thallium-201 single photon emission computed tomography was performed in 158 consecutive patients with angiographically proved single vessel coronary artery disease. The extent of abnormal left ventricular perfusion was quantified from computer-generated polar maps of three-dimensional myocardial radioactivity. Patients with only a moderate (51% to 69%) stenosis tended to have a small perfusion defect irrespective of the coronary artery involved. Whereas a perfusion defect measuring greater than or equal to 10% of the left ventricle was found in 78% of patients with no prior infarction and severe (greater than or equal to 70%) stenosis. this was observed in only 24% of patients with moderate stenosis. Perfusion defect size increased with increasing severity of stenosis for the entire group without infarction and for those with left anterior descending. right and circumflex coronary artery stenosis. However. the correlation between stenosis severity and perfusion defect size was at best only modest (r = 0.38. p = 0.0001). The left anterior descending artery was shown to be the most important of the three coronary arteries for providing left ventricular perfusion. Proximal stenosis of this artery produced a perfusion defect approximately twice as large as that found in patients with a proximal right or circumflex artery stenosis. However. marked heterogeneity in perfusion defect size existed among all three vessels despite comparable stenosis severity. This was most apparent for the left anterior descending coronary artery. where mid vessel stenosis commonly produced a perfusion defect similar in size to that found in proximally stenosed vessels.
Primary angioplasty in myocardial infarction: assessment of improved myocardial perfusion with technetium-99m isonitrile, Technetium-99m-hexakis-2-methoxy-2-isobutyl-isonitrile (technetium-99m isonitrile) is a new radiopharmaceutical compound that reflects myocardial perfusion. Its kinetics. especially its lack of redistribution after intravenous administration. permits the assessment of changes in myocardial perfusion without delay of therapy. Tomographic images at rest were obtained immediately and 6 to 10 days later in 17 consecutive patients undergoing successful primary angioplasty during their first transmural myocardial infarction. Thirteen patients had anterior infarction. The initial (acute) defect size before angioplasty of 48 +/- 17% of the left ventricle decreased significantly (p less than 0.0001) to 29 +/- 19% on the late scans. There was no correlation between the time to therapy and the reduction in defect size. Twelve of the 17 patients. including 7 of the 11 patients treated after 4 h. demonstrated a definite reduction in the initial defect size. Eight patients with angiographically proved persistent coronary occlusion underwent a similar imaging sequence. The initial defect size in this group remained unchanged on the late scans (24 +/- 16% versus 26 +/- 18%. p = NS). Primary angioplasty is an effective approach toward salvaging myocardium; comparison with thrombolytic drug therapy must await the results of controlled clinical trials.
Differentiating cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy utilizing positron emission tomography, To determine if imaging of blood flow (using N-13 ammonia) and glucose metabolism (using F-18 2-deoxyglucose) with positron emission tomography can distinguish cardiomyopathy of coronary artery disease from nonischemic dilated cardiomyopathy. 21 patients with severe left ventricular dysfunction who were evaluated for cardiac transplantation were studied. The origin of left ventricular dysfunction had been previously determined by coronary angiography to be ischemic (11 patients) or nonischemic (10 patients). Images were visually analyzed by three observers on a graded scale in seven left ventricular segments and revealed fewer defects in dilated cardiomyopathy compared with ischemic cardiomyopathy for N-13 ammonia (2.7 +/- 1.6 versus 5 +/- 0.6; p less than 0.03) and F-18 deoxyglucose (2.8 +/- 2.1 versus 4.6 +/- 1.1; p less than 0.03). An index incorporating extent and severity of defects revealed more homogeneity with fewer and less severe defects in subjects with nonischemic than in those with ischemic cardiomyopathy as assessed by imaging of flow (2.8 +/- 1.8 versus 9.2 +/- 3; p less than 0.001) and metabolism (3.8 +/- 3.3 versus 8.5 +/- 3.6; p less than 0.005). Diagnostic accuracy for distinguishing the two subgroups by visual image analysis was 85%. Using previously published circumferential count profile criteria. patients with dilated cardiomyopathy had fewer ischemic segments (0.4 +/- 0.8 versus 2.5 +/- 2 per patient; p less than 0.01) and infarcted segments (0.1 +/- 0.3 versus 2.4 +/- 1.4 per patient; p less than 0.001) than did patients with cardiomyopathy of coronary artery disease. The sensitivity for differentiating the two clinical subgroups using circumferential profile analysis was 100% and the specificity 80%. An index incorporating both number and severity of defects derived from circumferential profile analysis was significantly lower in subjects with dilated cardiomyopathy than in ischemic cardiomyopathy (0.3 +/- 0.8 versus 2.7 +/- 2.4; p less than 0.005). Thus. noninvasive positron emission tomographic imaging with N-13 ammonia and F-18 deoxyglucose is helpful in distinguishing patients with severe left ventricular dysfunction secondary to coronary artery disease from those with nonischemic cardiomyopathy. and a semiquantitative index such as circumferential profile analysis is superior to that of visual analysis alone.
A randomized comparison of the nephrotoxicity of iopamidol and diatrizoate in high risk patients undergoing cardiac angiography, Three hundred seven high risk patients with renal impairment (serum creatinine greater than or equal to 1.5 mg/dl) were randomized in a double-blind manner to either iopamidol (a nonionic. low osmolar radiocontrast agent) or diatrizoate (a conventional radiocontrast agent) at cardiac angiography with subsequent follow-up study of renal function. Baseline clinical and angiographic variables were similar in the iopamidol (n = 155) and diatrizoate (n = 152) groups. Change in renal function after angiography was less pronounced with iopamidol compared with diatrizoate as measured by mean ( +/- SD) increase in 24 h serum creatinine (0.11 +/- 0.2 versus 0.22 +/- 0.26 mg/dl. p less than 0.001). mean maximal increase in serum creatinine (0.2 +/- 0.44 versus 0.38 +/- 0.73 mg/dl. p less than 0.0001) and percent of patients with a maximal increase in serum creatinine greater than 0.5 mg/dl (8% versus 19%. p less than 0.01). Such differences could not be documented in diabetic patients using insulin. There was no significant difference between agents in the number of patients developing clinically severe acute renal dysfunction. It is concluded that iopamidol is less nephrotoxic than diatrizoate in high risk patients at cardiac angiography. However. the difference in nephrotoxicity is small. of no major clinical significance in the majority of high risk patients and could not be documented in insulin-using diabetic patients. Iopamidol may be the preferred agent in certain patients with advanced renal impairment. but further study is warranted.
Comparison of pre- and postoperative conduction patterns in patients surgically cured of atrioventricular node reentrant tachycardia, Patients with atrioventricular (AV) node reentrant tachycardia characteristically have short and constant retrograde His-atrium conduction times (H2A2 intervals) during the introduction of ventricular extrastimuli. It has therefore been suggested that the tachycardia circuit involves retrograde conduction up an accessory pathway located in perinodal tissue. If the mechanism of surgical cure of AV node reentrant tachycardia is interruption of this accessory pathway. postoperative changes in retrograde conduction would be expected. Thirteen patients with drug-refractory AV node reentrant tachycardia underwent surgery. Preoperatively. H2A2 intervals were short and constant. During AV node reentrant tachycardia. earliest atrial activation was seen near the His bundle and was 0 to 25 ms before ventricular activation in all patients except one. Surgery consisted of dissection of right atrial septal and anterior inputs to the AV node and central fibrous body. Postoperatively. the H2A2 interval remained short and constant compared with preoperative values although it was slightly prolonged (74 +/- 18 versus 61 +/- 21 ms. p less than 0.005). Twelve of the 13 patients are free of tachycardia after 28 +/- 13 months and no patient has had evidence of AV node block. Thus. surgical cure of AV node reentrant tachycardia is highly successful; however. there is no reason to postulate an accessory pathway or use of perinodal tissue as part of the tachycardia circuit and the mechanism of surgical success remains obscure.
Prolonged and fractionated right atrial electrograms during sinus rhythm in patients with paroxysmal atrial fibrillation and sick sinus node syndrome, Intraatrial catheter mapping of the right atrium was performed during sinus rhythm in 92 patients: Group I = 43 control patients without paroxysmal atrial fibrillation or sick sinus node syndrome; Group II = 31 patients with paroxysmal atrial fibrillation but without sick sinus node syndrome; and Group III = 18 patients with both paroxysmal atrial fibrillation and sick sinus node syndrome. Atrial electrograms were recorded at 12 sites in the right atrium. The duration and number of fragmented deflections of the atrial electrograms were quantitatively measured. The mean duration and number of fragmented deflections of the 516 atrial electrograms in Group I were 74 +/- 11 ms and 3.9 +/- 1.3. respectively. The criteria for an abnormal atrial electrogram were defined as a duration of greater than or equal to 100 ms or eight or more fragmented deflections. or both. Abnormal atrial electrograms were observed in 10 patients (23.3%) in Group I. 21 patients (67.7%) in Group II and 15 patients (83.3%) in Group III (Group II versus Group I. p less than 0.001; Group III versus Group I. p less than 0.001). The mean number of abnormal electrograms per patient with an abnormal electrogram was 1.3 +/- 0.7 in Group I. 2.5 +/- 1.9 in Group II and 3.5 +/- 2.5 in Group III (Group I versus Group II. p less than 0.01; Group II versus Group III. p less than 0.05). A prolonged and fractionated atrial electrogram characteristic of paroxysmal atrial fibrillation can be closely related to the vulnerability of the atrial muscle.
Spontaneous changes in ventricular tachycardia cycle length, Understanding spontaneous fluctuations in ventricular tachycardia cycle length is required to develop algorithms for ventricular tachycardia detection and termination. Variations in cycle length. time to stable cycle length and the range of RR intervals during ventricular tachycardia were analyzed in 74 episodes of sustained monomorphic ventricular tachycardia induced in patients not taking antiarrhythmic medication. Linear regression demonstrated cycle length variability to decrease over time (41 +/- 24 to 17 +/- 19 ms. p less than 0.001). Slower ventricular tachycardia had more cycle length variability than faster ventricular tachycardia (p less than 0.001). Ventricular tachycardia that was initially more variable tended to remain more variable (p less than 0.001). Fifty-four percent of episodes stabilized within the first 15 beats. 75% by 30 beats and 93% by 50 beats. The number of beats to stable cycle length was independent of ventricular tachycardia rate. The average range in cycle length per episode was 127 +/- 72 ms; 12% of ventricular tachycardia episodes varied by less than 50 ms and 45% by less than 150 ms. The maximal range in RR intervals from a single episode of ventricular tachycardia was 290 ms. Therefore. ventricular tachycardia demonstrates a wide range of cycle lengths and has time-dependent changes in variability and stability. These cycle length changes should be considered in the algorithms for ventricular tachycardia detection and termination by automatic antitachycardia devices.
Echocardiographic evaluation of cardiac structure and function in elderly subjects with isolated systolic hypertension, One hundred four participants in the Systolic Hypertension in the Elderly Program (SHEP) trial (mean age 71 +/- 6 years) were examined by Doppler echocardiography to gain information on the cardiac structural and functional alterations in isolated systolic hypertension. Participants had a systolic blood pressure greater than 160 mm Hg with diastolic blood pressure less than 90 mm Hg and were compared with 55 age-matched normotensive control subjects. Left ventricular mass index was significantly higher in the participants than in the normotensive subjects (103 +/- 28 versus 87 +/- 23 g/m2. p = 0.0014) and 26% of the participants met echocardiographic criteria for left ventricular hypertrophy compared with 10% of normotensive subjects. Left atrial index was also greater in participants than in normotensive subjects (2.26 +/- 0.32 versus 2.11 +/- 0.24 cm/m2. p = 0.005) and 51% of participants had left atrial enlargement. Doppler measures of diastolic filling were significantly different between the two groups. with peak atrial velocity higher (76 +/- 17 versus 69 +/- 17 cm/s. p = 0.02) and ratio of peak early to atrial velocity lower (0.76 +/- 0.23 versus 0.86 +/- 0.22. p = 0.0124) in participants. There was no correlation between left ventricular mass index and Doppler measures of diastolic function. but relative wall thickness correlated significantly with peak atrial velocity (r = 0.22. p = 0.016) and peak early to peak atrial velocity ratio (r = 0.24. p = 0.007). There was no difference in M-mode ejection phase indexes of systolic performance (shortening fraction and peak velocity of circumferential fiber shortening) between the two groups.
Immunosuppressive therapy in the management of acute myocarditis in children: a clinical trial, To assess whether steroid therapy influenced the clinical course of myocarditis in a pediatric population. findings in 13 consecutive infants and children (8 female. 5 male) with biopsy-proved myocarditis were reviewed. The mean age was 5.7 +/- 4.8 years (range 1.1 to 14.8). Congestive heart failure was present in all as were ST-T wave changes. cardiomegaly and pulmonary edema on chest roentgenogram. Echocardiography demonstrated pericardial effusion in five patients and mitral regurgitation in eight. Mean left ventricular ejection fraction was 34 +/- 12%. Prednisone was administered to all patients; one patient also received azathioprine. There was one death. All survivors showed clinical improvement with normalization of ECG changes. heart size and systolic function. No significant side effects occurred. Repeat myocardial biopsy in eight patients demonstrated improvement in all eight and elimination of the inflammatory infiltrate in six. Immunosuppressive therapy in this pediatric population appeared useful in improving the clinical course and cardiac function in acute myocarditis with no adverse side effects.
Effect of atenolol and diltiazem on heart period variability in normal persons, Several time and frequency domain measures of heart period variability are reduced 1 to 2 weeks after myocardial infarction. and a reduced standard deviation of normal RR intervals over a 24 h period (SDNN) is associated with increased mortality. The predictive accuracy of heart period variability may be reduced by drugs used to treat patients after myocardial infarction. Accordingly. a randomized. three period. placebo-controlled. crossover (Latin square) design was used to determine the effect of atenolol and diltiazem on time and frequency measures of heart period variability calculated from 24 h continuous electrocardiographic recordings during treatment with atenolol. diltiazem and placebo in 18 normal volunteers. During atenolol treatment. the 24 h average normal RR (NN) interval increased 24% (p less than 0.001). The three measures of tonic vagal activity were significantly increased (p less than 0.001) during atenolol treatment: percent of successive normal RR intervals greater than 50 ms = 69%. root mean square successive difference of normal RR intervals = 61% and high frequency power in the heart period power spectrum = 84%. Low frequency power also increased 45% (p less than 0.01). indicating that this variable also is an indicator of tonic vagal activity over 24 h. Diltiazem had no significant effect on the 24 h average NN interval or on any measure of heart period variability. The decreased mortality rate after myocardial infarction associated with beta-adrenergic blocker but not calcium channel blocker therapy may be attributed in part to an increase in vagal tone caused by beta-blockers.
Hypertrophy, fibrosis and diastolic dysfunction in early canine experimental hypertension, To examine the relations among hypertrophy. fibrosis and diastolic performance in early experimental hypertension. 18 control dogs and 12 dogs with experimental left ventricular hypertrophy were studied. Diastolic function was impaired in dogs with left ventricular hypertrophy. with decreased Doppler early to atrial inflow velocity ratio (E/A) (1.35 versus 1.72). increased atrial filling fraction (35% versus 29%). decreased sonomicrometric peak rates of wall thinning (-2.01 versus -3.37 liters/s) and filling (4.33 versus 6.64 liters/s) and prolonged time constant of isovolumetric relaxation (tau; 34.3 versus 28.1 ms). Neither chamber stiffness (k; P = AekV) nor passive elastic stiffness (E; E = k sigma. where sigma = stress) was increased. At postmortem examination. the hypertensive left ventricle weighed significantly more than normal (116 versus 80 g; p less than 0.01) and had greater muscle fiber diameter at endocardial and epicardial sampling sites in the apical free wall. basal free wall and septum (mean diameter 50 +/- 8 microns in hypertensive dogs. 37 +/- 8 microns in normal dogs; p less than 0.01). In contrast. neither percent fibrosis (1.2 +/- 0.8 versus 0.9 +/- 0.6 in normal dogs) nor fibrotic volume (1.21 +/- 0.63 versus 0.72 +/- 0.42%/g in normal dogs) was significantly increased. Peak volumetric filling rate was inversely related to fiber diameter (r = -0.74. p less than 0.001). although no variable of left ventricular function was significantly related to percent or volume fibrosis (all r less than 0.60. all p greater than 0.05). Thus. diastolic dysfunction may exist in the setting of hypertrophy without significant fibrosis. Increased myocyte size was associated with early diastolic filling abnormalities characteristic of the hypertensive left ventricle. Fibrosis appears to be a less important determinant of diastolic performance.
Transesophageal echocardiography is superior to transthoracic echocardiography in the diagnosis of sinus venosus atrial septal defect, The purpose of this study was to compare transthoracic and transesophageal echocardiography in the diagnosis of various types of atrial septal defects. Forty-one adult patients with the clinical diagnosis of atrial septal defect were studied by transthoracic and transesophageal echocardiography (30 women. 11 men; 18 to 81 years of age). Transthoracic echocardiography demonstrated the atrial septal defect in 33 patients (secundum type in 28. primum type in 3 and sinus venosus type in 2). Transesophageal echocardiography demonstrated the defect in all 41 patients. Thus. in 8 (20%) of 41 patients the atrial septal defect was demonstrated by transesophageal and not by transthoracic echocardiography. Six of the eight had a sinus venosus type atrial septal defect; the other two patients had a secundum atrial septal defect (one of these two had a technically poor transthoracic echocardiogram and the other had a small atrial septal defect). Transthoracic echocardiography. therefore. failed to demonstrate the sinus venosus defect in six (75%) of eight patients. An anomalous venous connection associated with the sinus venosus defect was visualized by transesophageal echocardiography in seven of the eight patients but was not seen on transthoracic echocardiography in any patient. Sinus venosus type atrial septal defects are frequently not visualized in adults by conventional transthoracic echocardiography. Transesophageal echocardiography is recommended when an atrial septal defect is clinically suspected but cannot be visualized by transthoracic echocardiography.
Mast cell numbers and staining characteristics in the normal and allergic human conjunctiva, In this study we report the numbers and metachromatic dye-staining characteristics of mast cells (MCs) in the conjunctiva of normal subjects and patients with seasonal allergic conjunctivitis caused by pollenosis. In addition. we have used a monoclonal antibody to the MC-specific enzyme. tryptase. to enumerate tryptase-positive cells immunohistochemically. Tarsal conjunctival MCs were found to be present in increased numbers in the allergic compared to the nonallergic subjects. Most of the MCs exhibited staining that was formaldehyde resistant. compatible with their identification as connective tissue MCs or basophils. The high positive staining for tryptase confirmed that the metachromatic cells stained with toluidine blue were MCs and not basophils. both in normal and allergic subjects.
Effect of a thromboxane A2 receptor antagonist (AA-2414) on bronchial hyperresponsiveness to methacholine in subjects with asthma, Bronchial hyperresponsiveness (BHR) to various stimuli is one of the major clinical features of bronchial asthma. In this study. the effect of a thromboxane A2 (TXA2) receptor antagonist. AA-2414. on BHR to methacholine was evaluated in 15 patients with asthma. The methacholine inhalation test was performed before and after oral administration of AA-2414 for 4 days (20 or 40 mg/day). The provocative concentration of methacholine producing a 20% fall in FEV1 (PC20) was measured as an index of BHR. There was a significant increase in PC20 (p less than 0.01) from 0.43 (geometric SEM. 1.42) mg/ml to 0.93 (geometric SEM. 1.43) mg/ml after 40 mg/day of AA-2414. whereas baseline values of FVC and FEV1 were not changed by the treatment. Twenty milligrams per day of AA-2414 did not alter the PC20 value nor the parameter of baseline pulmonary functions. These findings might support our hypothesis that the subthreshold concentration of TXA2 in the bronchial tissues. which has no effect on bronchomotor tone per se. may be involved in BHR in asthma. Further studies with more potent and specific TXA2 receptor antagonists are needed to confirm the conclusion.
Secretion of granule proteins from eosinophils and neutrophils is increased in asthma, The activity of eosinophil and neutrophil granulocytes with respect to secretion of granule proteins was studied in 30 patients with asthma and with varying severity of their disease. Granulocytes were stimulated with serum-opsonized Sephadex particles. and the released amount of eosinophil cationic protein (ECP). eosinophil protein X (EPX). and myeloperoxidase was measured by means of specific radioimmunoassays. Eosinophils from patients with asthma released significantly more (p less than 0.001) ECP and EPX after 20 minutes of incubation than cells from control subjects without asthma. The release of myeloperoxidase from neutrophils was also somewhat higher (p less than 0.03). The serum concentrations of ECP and EPX were also significantly increased (p less than 0.001) in the group with asthma. No significant relationships were found between clinical variables and the secretory activity of either eosinophils or neutrophils. We conclude that eosinophils and. to some extent. neutrophils from subjects with asthma have an increased propensity to release their granule proteins. which we suggest is a consequence of priming of these cells.
Food-dependent, exercise-induced anaphylaxis: a study on 11 Japanese cases, Eleven patients with food-dependent. exercise-induced anaphylaxis were studied. Seven patients experienced anaphylactic symptoms only after eating certain foods. such as shellfish. wheat. and grape before exercise. In the remaining four patients. no specific food could be identified. but the act of eating itself predisposed to anaphylaxis. Their anaphylactic symptoms were all clearly distinguished from cholinergic urticaria by history. Patients who developed anaphylactic symptoms before 20 years of age (N = 7) were atopic themselves or had atopic first-degree relatives. Six patients had increased serum IgE levels. and IgE antibodies against the causative food allergens were detected by the skin prick test or RAST in four cases. In contrast. patients who developed the symptoms after 30 years of age (N = 4) appeared to have a less atopic background. and IgE levels were within normal range except in one case. Three of four patients in the latter group developed symptoms after ingesting food made of wheat followed by exercise. All patients were sensitive to wheat as determined by the skin prick test. In six of 11 patients. a considerable rise in plasma histamine concentration was observed after exercise challenge with treadmill alone. and food intake followed by exercise induced a further increase in one patient.
Modification of the fluorescent allergosorbent test as an inhibition assay for determination of cross-reactivity among aeroallergens, The fluorescent allergosorbent test was adapted as an inhibition assay to determine cross-reactivity between aeroallergens. With this method. similar antigenic determinants were found between short ragweed and giant ragweed. cocklebur. lamb's-quarter. rough pigweed. marsh elder. and goldenrod. Cocklebur and giant ragweed were highly potent in their ability to competitively bind to short ragweed IgE. The other pollens demonstrated lower potency of cross-reacting antigens. The fluorescent allergosorbent test-inhibition assay appears to be a useful method to determine cross-reactivity among aeroallergens.
Physicians' perspectives on cholesterol and heart disease, In early spring of 1988. questionnaires were mailed to 4.000 Midwestern physicians to survey their attitudes and practices regarding elevated serum cholesterol and their use of referrals for nutrition counseling; 633 physicians responded. Sixty-eight percent of the physicians thought that reducing high serum cholesterol levels would substantially affect heart disease; however. physicians attributed considerably less preventive value to reducing the cholesterol level than to reducing blood pressure (80.3%) or ceasing smoking (90.0%). The range of serum cholesterol for which diet therapy was most frequently initiated was 5.70 to 6.20 mmol/L. The most frequent range for initiation of drug therapy was 7.80 to 8.25 mmol/L. The physicians reported that although their medical school training did not prepare them adequately for providing diet counseling. they did feel prepared to provide. and were successful in. counseling on diet modifications for reducing serum cholesterol. Few (10%) of the total sample reported having registered dietitians available for dietary counseling. and most (88.8%) believed that it is the physician's responsibility to provide such counseling. Although the low response rate limits the conclusions of the survey. it is likely that those physicians most interested in the topic responded. We conclude that registered dietitians should explore the need for their special services further. More aggressive marketing of dietetic services could benefit both physicians and patients in the campaign to reduce serum cholesterol.
Nutrition management for individuals with noninsulin-dependent diabetes mellitus in the 1990s: a review by the Diabetes Care and Education dietetic practice group, Noninsulin-dependent diabetes mellitus (NIDDM). or Type II diabetes. is characterized by two primary defects: insulin resistance and insulin secretion. The two major goals of management of NIDDM are to achieve near normal metabolic control and to prevent/delay the microvascular and macrovascular complications of diabetes. Nutrition. exercise. and. if necessary. medication are the three primary treatment modalities used in NIDDM. Treatment regimens need to be individualized and developed with consideration for diabetes management goals and quality-of-life issues. Lean individuals with NIDDM should be encouraged to maintain their body weight and modify food composition and eating pattern to minimize glucose excursions. The primary treatment goal for an obese individual with NIDDM is weight loss. The process of teaching nutrition and meal planning involves developing a cooperative alliance. gathering information. setting realistic goals. intervention. and maintaining change. Nutrition intervention involves providing information in stages. beginning with "survival skill" information and progressing to in-depth information. The dietitian's responsibility is to promote continuity of learning by introducing new ideas and concepts and altering the learning environment. Dietitians can expand their role in the 1990s to that of a diabetes educator taking a leadership role to ensure that the individual with NIDDM receives comprehensive and individualized care.
A dietary education program for hypercholesterolemic children and their parents, A parent-child autotutorial dietary education program for 4- to 10-year-old. hypercholesterolemic children and their families was developed and pilot tested. The 10-lesson program. designed for weekly use at home. uses a "talking-book" approach (audiotapes with accompanying picture booklet) for the child. Parents are provided with information on ways to make recommended dietary changes. along with hands-on activities to do with the children. To help match the instructional approach to the wide developmental range within the children's age span. materials are divided into three program levels that use different story characters and concept presentations. During program development. evaluation by two children (and their parents) for each of the program levels guided the design and refinement of the lessons. A pilot test among 22 hypercholesterolemic children (whose treatment was limited to diet modification) revealed that children within the 4- to 10-year age range liked the "talking-book" approach and identified positively with the story characters. Parents indicated that their materials were clear and helpful. Between the baseline and 3-month follow-up visits. the children exhibited a significant increase in knowledge of heart healthy foods. a decrease in total fat consumption that approached significance. and a significant decrease in plasma low-density-lipoprotein cholesterol values.
Nursing home patients transferred by ambulance to a VA emergency department, Nursing home residents are frequently transferred to hospital emergency departments. Delayed transfer may lead to poor outcomes. However. inappropriate transfer of the frail elderly may cause social and financial problems. We prospectively evaluated 221 consecutive ambulance transfers from community nursing homes to a VA emergency department. The objectives of the study were to describe the process and outcomes of transferred patients and to determine if alternative interventions were feasible. The results indicate that the problems of nearly half the study group could have been treated at the nursing home by a visiting physician with minimal medical equipment. Those admitted to the hospital (52%) were seriously ill. had prolonged lengths of stay (23.6 days). and had a high mortality rate (11%). Complex issues of physician reimbursement. proprietary nursing home budgeting. and day-to-day expediency appear to be involved in decisions to transport patients by ambulance to VA emergency departments.
Is the recommended daily allowance for vitamin D too low for the homebound elderly, A population of sunlight-deprived elderly was studied to determine the daily intake of vitamin D and whether dietary intake was sufficient to maintain a normal vitamin D status. Twenty-two subjects over 65 years old with serum creatinine less than 180 mumols/L and confined indoors for more than 6 months were chosen from the community and a nursing home in Southeast Baltimore. Three-day food records were obtained along with serum levels of 25-hydroxyvitamin D (25-OHD). 1.25-dihydroxyvitamin D (1.25-(OH)2 D). and intact parathyroid hormone (PTH). The mean daily vitamin D intake was over twofold greater than the adult Recommended Daily Allowance (RDA) of 200 IU. The mean 25-OHD level was 40 nmol/L (normal 25-138 nmol/L) with seven patients less than 25 nmol/L. Of these participants with 25-OHD values less than 25 nmol/L. the mean vitamin D intake was 467 IU (range 36-1096 IU). We conclude that the current RDA seems inadequate for many older individuals who do not get sun exposure. This particular population of elderly is at risk to develop vitamin D deficiency and the associated complications.
The timed "Up & Go": a test of basic functional mobility for frail elderly persons, This study evaluated a modified. timed version of the "Get-Up and Go" Test (Mathias et al. 1986) in 60 patients referred to a Geriatric Day Hospital (mean age 79.5 years). The patient is observed and timed while he rises from an arm chair. walks 3 meters. turns. walks back. and sits down again. The results indicate that the time score is (1) reliable (inter-rater and intra-rater); (2) correlates well with log-transformed scores on the Berg Balance Scale (r = -0.81). gait speed (r = -0.61) and Barthel Index of ADL (r = -0.78); and (3) appears to predict the patient's ability to go outside alone safely. These data suggest that the timed "Up & Go" test is a reliable and valid test for quantifying functional mobility that may also be useful in following clinical change over time. The test is quick. requires no special equipment or training. and is easily included as part of the routine medical examination.
Mini-Mental State exam scores vary with education in blacks and whites, Previous studies have suggested that education and race may affect performance on standardized mental status tests. In order to more clearly define these relationships. a prospective longitudinal study was devised to answer two questions: (1) whether race or level of education affects scores on the Mini-Mental State (MMS) exam in non-demented people and (2) what numerical cutpoints maximize the sensitivity and specificity of utilizing the MMS to help diagnose dementia in blacks of varying educational attainment. A total of 100 white and 258 black individuals. recruited from two city hospital primary care geriatric clinics. were evaluated and subsequently followed longitudinally over a 2 1/2 year period in order to assess accurately the presence or absence of dementia. In the non-demented. total MMS scores and performance on each item of the MMS were analyzed. revealing that people with an 8th grade or less education consistently had significantly (P less than .01) worse results than the better educated (9th grade or better) on borough. attention items. recall of table and dog. copying. sentence writing. phrase repeating. and total score. Furthermore. a total of 25% of the lower education group had an MMS score in the 18-23 range. traditionally thought to suggest dementia. There were no consistently significant differences between blacks and whites of equal education. In the better educated groups. using a score of 23 or less to define dementia maximizes the sensitivity and specificity of using the MMS in this diagnosis at 93% and 100%. respectively. In the lower education group. using 17 or less to define dementia maximizes sensitivity and specificity at 81% and 100%. respectively.
Physician practices in the diagnosis of dementing disorders, Because there are both treatable and untreatable causes of dementia. the physician's ability to conduct (or refer a patient for) a differential diagnosis could have a profound effect on health outcomes for patients and on health care costs. This study was undertaken to assess physician practices with regard to the diagnosis of dementing disorders. Data from 53 physicians (a response rate of 48%) in several specialties were obtained from a self-administered mail questionnaire. Results indicate that the majority of physicians provided history taking. physical examination. and neurological examination. Physicians were more likely to refer patients for psychiatric and neuropsychological examinations than to provide these services themselves. The results also point to deficiencies in two key areas: the use of formal. published diagnostic criteria. and the use of mental status and cognitive function tests. Over 75% of physicians surveyed did not use either DSM-III or NINCDS-ADRDA diagnostic criteria. and 42% of physicians did not provide any mental status tests themselves. The need for continuing education to close knowledge gaps is emphasized.
Hyposomatomedinemia in men with post-poliomyelitis syndrome, The age of onset of the post-poliomyelitis syndrome (PPS) coincides with the tendency for declining activity of the growth hormone/somatomedin C (GH/SmC) axis. The normal plasma SmC range in men before the age of 40 is 0.50 to 1.50 units/mL. After age 40 about 30% of men have a plasma SmC level below 0.35 units/mL. signifying no detectable spontaneous GH secretory pulses. Because the GH/SmC axis stimulates DNA. RNA. and protein synthesis in muscle cells and increases their size and number. a deficiency of the GH/SmC axis could theoretically contribute as a secondary factor to the occurrence or severity of the PPS. Accordingly. the authors measured the plasma SmC level in 10 men with PPS. ages 35 to 63. and in 94 healthy men of similar age. In the PPS men. 100% of the values were less than or equal to 0.40 units/mL. and 90% were less than or equal to 0.35 units/mL. The corresponding proportions in the healthy men were 40% and 27%. Analysis of variance including age as a factor showed SmC to be significantly lower in the PPS men than in the healthy men. In an additional comparison. totally immobile nursing home men did not have lowered SmC values. In fact their SmC values were slightly higher than those of healthy men of similar age. The data revealed a new biochemical feature of PPS. hyposomatomedinemia. which might play a contributory role in the pathogenesis of the syndrome.
Retroviral transduction of protein kinase C-gamma into cytotoxic T lymphocyte clones leads to immortalization with retention of specific function, The molecular pathways that are responsible for delivering the proliferative signals from the cell surface to the nucleus in T lymphocytes are still unresolved. but recent data implicates protein kinase C (PKC) involvement in the TCR signaling pathway. To further address the role of PKC in T cell activation. the effects of high level expression of the PKC-gamma isoenzyme in murine CTL clones were examined. Unlike the parental cells that required periodic Ag stimulation for cell activation and growth. cells expressing a retrovirally transduced PKC-gamma gene propagated in culture independent of the need for Ag stimulation. although maintaining identical functional specificity to the parental CTL. Constitutive PKC-gamma expression may therefore mimic physiologic PKC activation. thereby abrogating the requirement for TCR-Ag interaction in T cell activation.
Endothelial cell adhesiveness for human T lymphocytes is inhibited by transforming growth factor-beta 1, Recombinant human transforming growth factor-beta (TGF-beta) was found to inhibit the adhesive phenotype of human umbilical vein endothelial cells for human PBL. purified T lymphocytes. and PHA-activated lymphoblasts. TGF-beta inhibited lymphocyte attachment to resting human umbilical vein endothelial cells and also to endothelial monolayers stimulated with the pro-inflammatory cytokines TNF-alpha and IL-1 beta. Our investigations also show that the ability of endothelial cells to respond to TGF-beta by altering their adhesiveness is lost with prolonged culture of the cells. However. this loss is selective as TGF-beta inhibits cell proliferation in both early and late passage endothelial cells. These results suggest that in vivo TGF-beta may inhibit the adhesive phenotype of endothelial cells and also may limit the immunologic response occurring at the endothelial cell barrier.
Induction of CD4+, human T lymphotropic virus type-1-specific cytotoxic T lymphocytes from patients with HAM/TSP. Recognition of an immunogenic region of the gp46 envelope glycoprotein of human T lymphotropic virus type-1, Although the humoral response to human T lymphotropic virus type-1 (HTLV-I) has been well characterized in patients with HTLV-I-associated neurologic disease (HAM/TSP). little is known about a functional HTLV-I-specific human T cell response. such as CTL. in these patients. To define both the phenotype of the responding CTL and the fine specificity of this response. long term T cell lines were generated from two HAM/TSP patients who were from two different countries. Patient's peripheral blood lymphocytes were repeatedly stimulated in vitro with an HTLV-I expressing autologous T cell line. The resultant long term T cell culture was shown to be CD4+ and cytotoxic for targets expressing HTLV-I Ag. Using a panel of synthetic peptides that span hydrophilic regions of the HTLV-I gp46 envelope glycoprotein. the CTL lines generated from both patients were shown to recognize the same region of the HTLV-I envelope between amino acids 196-209 as defined by the synthetic peptide sp4a1. Interestingly. this sequence overlaps a region of HTLV-I envelope that had also been shown to elicit a strong B cell response in HAM/TSP patients (amino acids 190-203). One CTL line recognized this HTLV-I epitope in the context of HLA DQ5 whereas the other CTL line was restricted by HLA DRw16. The generation of two independent CTL lines from two HAM/TSP patients from different geographic areas that recognize the same region of the HTLV-I envelope glycoprotein highlights the immunogenic nature of this envelope region.
Cytokine release syndrome induced by the 145-2C11 anti-CD3 monoclonal antibody in mice: prevention by high doses of methylprednisolone, The hamster mAb 145-2C11 specific for the CD3 complex of murine T lymphocytes shares many properties with OKT3. including the induction of T cell activation. In vivo. the injection of 145-2C11 entails a variety of pathologic changes in relation to the systemic release of cytokines. We tested the effects on this cytokine release syndrome of different doses of methylprednisolone (m-PDS) given at various intervals of time before the 145-2C11 mAb. The administration of high doses of m-PDS (50 mg/kg) 2 to 3 h before the mAb resulted in an almost complete inhibition of the systemic release of TNF-alpha. IL-2. and IL-6. As far as the pathologic changes are concerned. the hypothermia. the acute renal tubular necrosis. and the fatty infiltration of the liver were completely prevented whereas the hypoglycemia was only partially attenuated. The protective effect of m-PDS on the toxicity of 145-2C11 was confirmed by the reduction of the mortality rate among galactosamine-sensitized mice. The inhibition of the release of cytokines by m-PDS did not affect the immunosuppression triggered by 145-2C11 as assessed by the CTL activity against alloantigens measured 48 h after the injection of the mAb. We conclude that the administration of very high doses of glucocorticoids 2 to 3 h before 145-2C11 prevents the release of cytokines and attenuates the acute toxicity of the mAb. Similar protocols could allow mitigation of the cytokine-release syndrome induced by the OKT3 mAb in man.
Dexamethasone inhibits the induction of monocyte chemotactic-activating factor production by IL-1 or tumor necrosis factor, Recently purified and molecularly cloned monocyte chemotactic and activating factor (MCAF) may play a major role in recruiting and activating monocytes in the inflammatory process. We examined the effects of a potent anti-inflammatory agent. dexamethasone (DXS). on the production of this factor. Over a wide range of concentrations (10(-5) to 10(-8) M). DXS inhibited the production of MCAF at the mRNA and protein level in a human fibrosarcoma cell line. which was stimulated with either IL-1 or TNF-alpha. We examined the turn-over of synthesized MCAF mRNA that showed DXS decreased the stability of MCAF mRNA. Furthermore. the addition of actinomycin D and cycloheximide abolished this effect of DXS. indicating that de novo mRNA and protein synthesis were required for this process. In addition. a nuclear run-off analysis revealed that DXS also inhibited the transcription of IL-1- or TNF-activated MCAF genes. Therefore. both the destabilization of MCAF mRNA and the inhibition of transcription of the gene contribute to the decrease in the MCAF mRNA steady state level by DXS.
Urinary nitrate excretion in relation to murine macrophage activation. Influence of dietary L-arginine and oral NG-monomethyl-L-arginine, Murine macrophage oxidation of L-arginine guanidino nitrogen to nitrite/nitrate yields an intermediate effector. possibly nitric oxide. with antimicrobial activity. Total body nitrogen oxidation metabolism (NOM) was measured in vivo by determining the urinary nitrate excretion of mice ingesting a chemically defined nitrite/nitrate-free diet. As reported previously. mycobacterial infection with bacillus Calmette-Guerin led to a large increase in urinary nitrate excretion. This increase was temporally related to macrophage activation in vivo. The substrate for macrophage nitrogen oxidation metabolism in vitro. L-arginine. was deleted from the diet without ameliorating the urinary nitrate excretion response induced by BCG. This suggested that L-arginine was synthesized endogenously because there are no other known natural substrates for NOM. A competitive inhibitor of NOM. the L-arginine analog. NG-monomethyl-L-arginine was fed to mice in their drinking water. NG-monomethyl-L-arginine ingestion blocked both basal and bacillus Calmette-Guerin-induced urinary nitrate excretion over a 2-4 week time span. These experimental conditions should prove useful for further investigation on the role of macrophage NOM in host defense against intracellular microorganisms.
DNA sequences 3' of the Ig H chain cluster rearrange in mouse B cell lines, A mouse myeloma cell line MPC11 (IgG2b. kappa) and variants derived from it have been used to study DNA rearrangements that occur at the Ig H chain locus. One variant. F5.5. has acquired both VH gene and C epsilon gene rearrangements. Through genomic Southern blot analysis initially directed to mapping the C epsilon gene rearrangement. we observed that the VH region rearrangement was linked. through an inversion event. to sequences that originate 3' of the CH cluster. i.e.. 3' of the C alpha gene. Subsequent studies have shown that DNA rearrangements within the region 3' of the C alpha gene are detected in several other mouse myeloma and hybridoma cell lines and are not associated with the expression of specific isotypes.
Regional variation in the expression of pemphigus foliaceus, pemphigus erythematosus, and pemphigus vulgaris antigens in human skin, The expression of the pemphigus foliaceus (PF). pemphigus erythematosus (PE). and pemphigus vulgaris (PV) antigens in 16 different regions of normal human skin was evaluated by indirect immunofluorescence by using sera with a high titer of PF. PE. and PV antibodies. Regional variations were observed in the expression of all these antigens. The expression of the PF and PE antigens. as measured by endpoint titer of antibody reactivity. was highest in skin specimens obtained from the upper torso. and lowest in those from the buccal mucosa. lower torso. and scalp. This distribution pattern differed from that of PV antigen. whose expression was highest in buccal mucosa and scalp. These patterns correlate with. and may provide a partial explanation for. the different distribution of skin lesions in these different forms of pemphigus.
Glycosaminoglycans production by cultured skin fibroblasts from the Pasini and Cockayne-Touraine forms of dominant dystrophic epidermolysis bullosa, Qualitative and quantitative comparisons of glycosaminoglycans e (GAG) production were made on fibroblast lines cultured from the skin of six patients with the Pasini (albopapuloid) form of dominant dystrophic epidermolysis bullosa. six with the non-albopapuloid form (Cockayne-Touraine). eight lines from patients with simplex or recessive dystrophic epidermolysis bullosa and eight lines from normal individuals. A reasonable match of donor age and gender. site. and passage number was achieved. Contrary to an earlier report. the lines from the Pasini group were unexceptional in the amount of GAG they secreted and the proportions of sulfated and nonsulfated GAG showed no consistent difference from the Cockayne-Touraine or control lines. The Pasini lines secreted 77 +/- 18 (SEM) microgram GAG-uronic acid per 10(7) cells and the Cockayne-Touraine lines 81 +/- 12 micrograms at equivalent cells densities. Sulfated GAG represented averages of 19 +/- 4+ in Pasini lines. 17 +/- 5% in Cockayne-Touraine. and 14 +/- 3% in controls. These findings are consistent with current views of albopapuloid lesions as an unreliable clinical sign in epidermolysis bullosa and bring into question the validity of the Pasini entity.
Examination of HTLV-I integration in the skin lesions of various types of adult T-cell leukemia (ATL): independence of cutaneous-type ATL confirmed by Southern blot analysis, The various clinical features of adult T-cell leukemia/lymphoma (ATL) are frequently accompanied by skin eruptions. Recently. a cutaneous type of ATL has been proposed by clinical studies. We analyzed the viral integration of human T-cell leukemia virus-I (HTLV-I) and monoclonal rearrangement of T-cell receptor (TCR) gene in blood lymphocytes and the cutaneous infiltrated cells of nine ATL patients with various clinical features and skin eruptions. We classified them by the results of Southern blot analysis and propose a cutaneous-type ATL accordingly. In two of them. we could detect the monoclonal integration of HTLV-I and T-cell monoclonality only in the skin but not in the peripheral lymphocytes. We also demonstrated the time course study in one patient. Clinicians should be aware of the HTLV-I positive cutaneous T cell lymphoma that can be named cutaneous-type ATL. Examination of viral integration and T-cell monoclonality in skin lesions is required to make an exact diagnosis of cutaneous ATL.
The lovastatin-treated rodent: a new model of barrier disruption and epidermal hyperplasia, Recent studies have linked epidermal cholesterol synthesis with maintenance of the permeability barrier. To assess directly the importance of cholesterol synthesis. we applied lovastatin. a potent inhibitor of cholesterol synthesis. to hairless mouse skin. Transepidermal water loss (TEWL) began to increase after four to six daily applications. Co-application of cholesterol blocked the expected increase in TEWL. demonstrating the importance of cholesterol for development of the lesion. The histology of lovastatin-treated skin revealed epidermal hyperplasia. accompanied by accelerated DNA synthesis. Whereas cholesterol synthesis initially was reduced in lovastatin-treated epidermis. with further treatment cholesterol synthesis normalized. while fatty acid synthesis accelerated greatly. Although the total free sterol content of lovastatin-treated epidermis remained normal. the fatty acid content increased coincident with barrier disruption. Finally. morphologic abnormalities of both lamellar body structure and their deposited. intercellular contents occurred coincident with the emerging biochemical abnormalities. Thus. the abnormal barrier function in this model can be ascribed to an initial inhibition of epidermal sterol synthesis followed by an alteration in cholesterol and fatty acid synthesis. leading to an imbalance in stratum corneum lipid composition and abnormal membrane bilayer structure.
Immunolocation of TNF-alpha/cachectin in human melanoma cells: studies on co-cultivated malignant melanoma, We have investigated the ability of metastatic cells to produce the macrophage cytokine. TNF-alpha/cachectin. as these cells have macrophage-like properties such as infiltration and migration. We looked for TNF-alpha/cachectin in three tumor cell lines derived from human malignant melanomas and six co-cultivated malignant melanomas derived. in vitro. from these three cell lines plus angioma fibroblasts. Immunohistochemistry with an anti-TNF-alpha/cachectin monoclonal antibody showed that TNF-alpha/cachectin was produced by two of the three parent melanoma cell lines. All the tumor cells in both the co-cultivated malignant melanomas and their in vitro tumorous nodules produced TNF-alpha/cachectin. even those derived from the melanoma cell line. which originally did not. The results clearly show that TNF-alpha/cachectin can be produced by non-hematopoietic tumor cells. A co-cultivated tumor model prepared from other types of human tumor cell lines promises to provide a useful tool for exploring the relationship between TNF-alpha/cachectin and oncogenesis.
Immunohistochemical alterations in basement membrane components of squamous cell carcinoma, To investigate alterations in the basement membrane (BM) in squamous cell carcinoma (SCC). we investigated 20 tumors. Four had the cytologic characteristics of Bowen's disease (SCC-BD) and 16 did not have them (SCC-NB). Tumors were studied immunohistochemically by double immunofluorescent staining by using mouse monoclonal antibodies to the core protein of heparan sulfate proteoglycan (HSPG) and chondroitin 6-sulfate glycosaminoglycan (Ch6S) as well as rabbit antiserum to laminin (LN) and type IV collagen (C-4). In well-differentiated and highly keratinized SCC-NB. LN. C-4. and HSPG could be detected in the tumor nest BM and showed no loss of continuity. but they were largely lost in poorly differentiated and poorly keratinized SCC-NB. This suggests that poorly differentiated SCC-NB cause greater enzymatic degradation of BM components than well-differentiated SCC-NB. Ch6S was detected in parts of the BM of SCC-BD. but it was absent in all SCC-NB examined. It appears that SCC-NB have lost the ability to synthesize Ch6S. and that SCC-BD degrade Ch6S although they continue to produce it. Thus. it appears that in SCC the BM is qualitatively different from that of normal epidermis. and that SCC-BD can be distinguished from SCC-NB by the Ch6S content of the BM.
Secretion of a unique collagen by spontaneously transformed murine keratinocytes (PAM cells) in vitro, A spontaneously transformed murine keratinocyte cell line (PAM cell) was found to secrete two nondisulfide-linked collagenous polypeptides with apparent molecular weight (MW) 190-kd and 120-kd. Pulse-chase experiments indicated that the 190-kd polypeptide was secreted into the culture medium in 2 h and processed to the 120-kd collagen component within 4 h. This process was inhibited by EDTA. The 120-kd polypeptide was sensitive to pepsin. and a 50-kd fragment was produced by a mild pepsin treatment at 4 degrees C. A cyanogen bromide peptide map of the 120-kd polypeptide was distinct from that of types I. II. III. IV. and V collagens. These properties indicate similarities to the type VIII-related collagen produced by human astrocytoma cells. The secretion of the collagen rapidly reached a maximum level on the first day of culture and subsequently declined with cell proliferation. An accelerated processing to the 120-kd polypeptide was observed under culture conditions of high cell density. Similar collagens were also found to be produced by normal human keratinocytes. These results indicate that the 120-kd polypeptide is a potentially functional protein that may participate in the formation of the extracellular matrix of keratinocytes.
Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus, Pemphigus is an autoimmune blistering disease characterized by circulating autoantibodies directed against the keratinocyte cell surface. The two variants. pemphigus foliaceus and pemphigus vulgaris. can be distinguished at the molecular level by immunochemical studies. The large majority of patients with pemphigus develop the disease spontaneously; however. there is a small group of patients who develop pemphigus after treatment with certain medications. of which penicillamine and captopril are the best documented. Most patients with drug-induced pemphigus have circulating and/or tissue bound epidermal cell surface autoantibodies; however. the molecular specificity of these autoantibodies has not been studied. We performed immunoprecipitation studies utilizing extracts of 125I-labeled suction blister epidermis and the sera of three patients with drug-induced pemphigus foliaceus (two due to penicillamine and one due to captopril) and one patient with captopril-induced pemphigus vulgaris. We found that the three patients with drug-induced pemphigus foliaceus had circulating autoantibodies that are directed against the pemphigus foliaceus antigen complex and that the one patient with drug-induced pemphigus vulgaris had circulating autoantibodies that are directed against the pemphigus vulgaris antigen complex. This study demonstrates that autoantibodies from drug-induced pemphigus patients have the same antigenic specificity. on a molecular level. as do autoantibodies from other pemphigus patients.
Identification of a melanoma progression antigen as integrin VLA-2, The expression of the integrin receptors VLA-1. -2. -3. and -6 was studied in normal cultured melanocytes and in five melanoma cell lines. Normal melanocytes synthesized VLA-3. but did not reveal detectable levels of VLA-1. -2. and -6. All melanoma cell lines. however. expressed VLA-2. -3. and -6. VLA-1 was synthesized by two of five melanoma lines. In parallel. we had analyzed the expression of four previously characterized melanoma cell surface antigens. One of them (antigen A.1.43). which is associated with tumor progression of human melanoma. revealed a striking similarity to VLA-2. In sequential immunoprecipitation experiments. we show that A.1.43 is identical with the integrin VLA-2. a cell surface receptor for collagen. laminin. and fibronectin.
Point and period prevalence of otitis media with effusion evaluated by daily tympanometry, Previous studies on daily tympanometric screening using an automatic impedance tympanoscope indicated relatively high incidences of type B tympanograms of one day's duration. which is contrary to our conceptions of the pathogenesis and pathology of otitis media with effusion. We therefore repeated the study in 51 otherwise healthy children (100 ears) attending kindergarten. Tympanometry was performed daily for one month using both the conventional impedance apparatus AZ7 and the automatic impedance tympanoscope ZS 331. The impedance apparatus did not indicate any one-day type B tympanograms and only a few short-lasting episodes occurring either in the beginning or end of the study period. Several ears had type B tympanograms on all days examined. The point prevalence was 15 per cent and the period prevalence 17 per cent. which accord well with findings of previous epidemiological studies of secretory otitis. The impedance tympanoscope indicated 16 cases of B-curves lasting only one day and considerably higher point and period prevalences. which make the impedance tympanoscope unsuited for both scientific and clinical purposes.
Cochlear otosclerosis: statistical analysis of relationship of spiral ligament hyalinization to hearing loss, This paper presents an analysis of the relationship of the amount of hyalinization of the spiral ligament. secondary to cochlear otosclerosis (spongiosis). to the amount of hearing loss. This relationship was previously studied by Parahy and Linthicum. It was found that the larger the amount of hyalinization. the greater the hearing loss. This hyalinization is a measure of the amount of toxic enzymes being excreted into the inner ear fluid. These enzymes are suspected to affect the metabolic function of the hair cells.
Immunopathology of olfactory mucosa following injury to the olfactory bulb, Removal of the olfactory bulb was performed on rats in an attempt to elucidate the processes of olfactory dysfunction following head injury. Degeneration and regeneration of the olfactory mucosa were examined. histopathologically and immunohistochemically. We used antisera to olfactory marker protein (OMP) and neuron specific enolase (NSE) as a marker of the mature olfactory receptor neurons. Following rapid degeneration after bulbectomy. the olfactory receptor neurons regenerated. OMP and NSE containing cells re-appeared 49 days later. However. the cell population of the neuroepithelium did not revert to the numbers observed in the non-operated neuroepithelium. even three months later. The lack of a connection between regenerated axons and the olfactory bulb may result in immature neuronal replacement and reduce the number of olfactory receptor neurons.
Enlarged adenoid and adenoidectomy in adults: endoscopic approach and histopathological study, Adenoid enlargement is uncommon in adults and because examination of the nasopharynx by indirect posterior rhinoscopy is inadequate. many cases of enlarged adenoid in adults are misdiagnosed and accordingly maltreated. This study was conducted on 35 cases of enlarged adenoid aged between 20 and 42 years. The nasal endoscope was utilized to identify the adenoid mass. Adenoidectomy under transnasal endoscopic control was performed and all the excised material was sent for histopathological examination. Adenoidectomy resulted in marked improvement in 94 per cent of cases without major complications. Histopathological examination revealed non-specific inflammatory reaction in 15 cases (43 per cent). pure reactive changes. predominantly follicular hyperplasia. in two cases (6 per cent) and mixed pattern in 18 cases (51 per cent). Endoscopic follow-up for an average 17 months identified recurrence in only two patients. It was concluded that enlarged adenoid tissue in adults has some histopathological differences from that in children and adenoidectomy under transnasal endoscopic control is safe and reliable.
Angiolymphoid hyperplasia with eosinophilia, Angiolymphoid hyperplasia with eosinophilia is a rare condition and is poorly recognized in the otolaryngological literature. The condition is characterized by the appearance of cutaneous nodules within the head and neck region especially around the external ear. Variable lymphadenopathy and peripheral eosinophilia can occur and the condition can mimic neoplasia. It is important to be aware of this disease entity in order to avoid overtreatment. Surgical removal is the treatment of choice; however. this often multilobulated and poorly delineated lesion often precludes initial wide excision and local recurrence is common. We present three cases of this unusual condition and a brief resume of the literature.
Isolated congenital round window absence, An adult with unilateral round window atresia is presented. With care. CT scanning may be used to demonstrate round window occlusion. Cochlear fenestration resulted in only a modest hearing improvement. Previously reported cases are reviewed.
Burkitt's lymphoma of the tonsil, A case of Burkitt's lymphoma involving the tonsil in a 10-year-old Bedouin boy. is presented. The biological behaviour and the clinical presentation of this unusual neoplasm are discussed and the English language literature is reviewed. The diagnosis was made by histological examination. electron microscopy and confirmed by immunohistochemistry. The patient showed an excellent symptomatic response to surgery and chemotherapy.
Alcohol consumption and synthesis of ethyl esters of fatty acids in adipose tissue, Ethyl esters of fatty acids (EEFA) have been found to be formed during ethanol metabolism. Human adipose tissue contains high concentrations of free fatty acids. the substrate for EEFA synthesis. and might therefore be a tissue with great potential for EEFA formation. In order to explore their potential usefulness as markers of alcohol abuse. the EEFA concentration and the activity of EEFA-synthesizing enzyme were therefore determined in adipose tissue from men belonging to the following categories: teetotalers. social drinkers. alcoholics under treatment. or established alcoholics found to have died as a result of alcohol intoxication. In order to estimate the half-life of EEFA and the synthase activity induction. the alcoholics were examined after different time periods of abstinence from alcohol. Comparisons were also made with several established markers of alcohol abuse. EEFA were not found in teetotalers. and were found in low concentrations in some of the social drinkers. EEFA were found in several alcoholics. and the forensic cases had high concentrations. EEFA-synthesizing enzyme activity was found in all subjects. increasing from teetotalers to social drinkers. and being 2-fold higher in alcoholics and 5-fold higher in dead alcoholics. The induction of the enzyme after abstinence appeared to have a half-life of the order of several weeks. Correlations were found between EEFA synthase activity and previously established markers of alcohol abuse known to remain for a long time period after abstinence. such as mean erythrocyte corpuscular volume. This preliminary study suggests the possibility that EEFA synthase induction in adipose tissue might have a longer half-life than previously used markers of alcohol abuse. It is therefore suggested that the induction of EEFA synthase might be a potentially useful new marker for alcohol abuse because of its apparent proportionality to alcohol intake over a prolonged time period. its presumed specificity. and long-term elevation after alcohol abstinence. This potential marker should be analysed further.
Influence of dietary cod liver oil on fatty acid composition of plasma lipids in human male subjects after myocardial infarction, A randomized crossover study was carried out to investigate the fatty acid profile and concentrations of plasma lipids in male patients with myocardial infarction (MI) who supplemented their diet with 20 ml cod liver oil daily for 6 weeks. Subjects were divided into two groups. A and B. Group A received cod liver oil daily for 6 weeks after hospital discharge. but none for the subsequent 6 weeks. Group B did not start taking cod liver oil until 6 weeks after hospital discharge. and they then took cod liver oil for 6 weeks. Diet. medication or smoking habits were kept as constant as possible during the study. During the period of cod liver oil intake. eicosapentaenoic acid (20:5 (n-3). EPA) and docosahexaenoic acid (22:6 (n-3). DHA) increased significantly in phospholipids (PL). triglycerides (TG) and cholesterol esters (CE). whereas linoleic acid (18:2 (n-6). LA). dihomo-gamma-linolenic acid (20:3 (n-6). DHGLA) and arachidonic acid (20:4 (n-6). AA) were significantly decreased in phospholipids. The plasma level of TG was significantly decreased during the cod liver oil intake. Total cholesterol. high density lipoprotein (HDL) cholesterol. and levels of apolipoproteins A1 and B were not affected by cod liver oil in these MI patients.
Atrioventricular plane displacement in severe congestive heart failure following dilated cardiomyopathy or myocardial infarction, Echocardiographic recording of the atrioventricular (AV) plane displacement during the cardiac cycle was used to assess left ventricular (LV) global function in patients with congestive heart failure (CHF). The study population consisted of 70 patients with chronic CHF (NYHA functional groups III and IV) following dilated cardiomyopathy (DCM) or myocardial infarction (MI). and 35 age-matched healthy subjects. The AV plane displacement was recorded from the apical 4- and 2-chamber views at four LV sites located about 90 degrees apart and representing the septal. anterior. lateral and posterior parts of the LV wall. A mean value was calculated from the above sites (AV-mean). Patients with CHF showed a significant generalized reduction of AV plane displacement compared to healthy subjects (5.6 mm vs. 14.5 mm. P less than 0.001). Thirty CHF patients also underwent radionuclide angiography in order to determine the ejection fraction (EF). The correlation between AV-mean and EF was good (r = 0.82. P less than 0.001). The selection of an AV-mean of less than 7 mm to define a severely depressed LV function (EF less than 30%) gave a sensitivity of 92% and a specificity of 67%. It is concluded that the AV plane displacement can be used to estimate LV systolic function in patients with CHF.
Elevation of plasma neuropeptide Y-like immunoreactivity and noradrenaline during myocardial ischaemia in man, Plasma levels of neuropeptide Y-like immunoreactivity (NPY-LI) and noradrenaline were studied for 25 h in 22 patients with acute ischaemic heart disease. On admission. NPY-LI levels were above normal in 16 patients. and 20 patients had increased noradrenaline levels. The initial plasma NPY-LI did not differ between patients with acute myocardial infarction (AMI) and angina pectoris. Initial plasma noradrenaline levels were higher in patients with AMI than in those with angina pectoris. Plasma levels of noradrenaline remained elevated in AMI patients. but decreased towards normal values in patients with angina pectoris. Levels of NPY-LI returned to normal within 25 h in all patients. Tachycardia and left ventricular failure were related to high NPY-LI and noradrenaline levels. A positive correlation was found between noradrenaline and NPY-LI in plasma. It is suggested that neuropeptide Y (NPY). an endogenous vasoconstrictor peptide. should be considered as one of the mediators involved in the cardiovascular response to sympathetic activation induced by myocardial ischaemia.
Unnecessary deaths from valvular aortic stenosis, The annual mortality from aortic valvular stenosis was calculated among potential candidates for surgical replacement of the aortic valve. From the Swedish Central Register of Causes of Death. 70 patients below the age of 80 years who had died from aortic stenosis during a 1-year period in the County of Stockholm (population 1.5 million). were identified. A retrospective analysis of their medical records showed that 37 individuals were suitable candidates for surgery. The presence of aortic stenosis had been verified at autopsy in 31 (84%) patients. The remaining six patients (16%) had their aortic stenosis diagnosis established by a thorough non-invasive investigation performed before death. Although typical signs and symptoms of aortic stenosis were recorded in all 37 patients. only six (16%) of them had been considered by their physicians to be suitable candidates for surgery prior to death. The deceased patients were compared with a group of 68 patients who had undergone aortic valve replacement for aortic stenosis during the same period. There were no significant differences between the two groups with regard to symptoms and clinical findings. except for a higher incidence of syncope in the operated group. It is concluded that. of 105 (68 surgically treated and 37 deceased) eligible patients with aortic stenosis. 37 individuals did not receive surgical care in time. The reason for this was probably insufficient knowledge of the curability of the disease.
High urinary cAMP in hypertensives despite careful drug treatment--an epidemiological study from the Dalby population, The correlation between serum calcium (S-Ca). plasma parathyroid hormone (P-PTH) and hypertension was determined in a population-based. cross-sectional study of carefully treated hypertensives (n = 391; diastolic blood pressure 90.2 mmHg; 57 years) compared with normotensive controls (n = 328; diastolic blood pressure 82.1 mmHg; 57 years). Levels of urinary cyclic-adenosinemonophosphate (U-cAMP). but not of plasma cAMP (P-cAMP). were higher (P less than 0.001) in hypertensives than in controls. This was the case regardless of the type of drug treatment and the blood pressure level that was reached. U-cAMP correlated with adrenaline in multivariate analyses. S-Ca levels were higher (P less than 0.001) and S-Mg levels were lower (P less than 0.001) in hypertensives than in controls. This was not explained by thiazide treatment. Thus. despite 'adequate' blood pressure reduction. substantial differences in S-Ca. S-Mg and U-cAMP still exist between hypertensives and normotensive controls.
Increased whole blood viscosity combined with decreased erythrocyte fluidity in untreated patients with essential hypertension, Erythrocyte fluidity and other haemorheological variables were studied in 22 patients with essential hypertension and compared with age- and sex-matched healthy controls. Hypertensive patients displayed a significantly lower erythrocyte fluidity (P less than 0.001). Similarly. significantly elevated values for haematocrit. plasma and whole blood viscosity. as well as aggregation tendency were observed compared to controls. Although differing in these respects from controls. there were no obvious relationships between these rheological variables and either systolic or diastolic blood pressure. The significantly lower erythrocyte fluidity and other changes in haemorheological variables of red blood cells found in hypertensive patients may be explained by an enlarged metabolic pool of free calcium ions in these red blood cells. It is suggested that the molecular mechanisms underlying the evolution of essential hypertension are multifactorial rather than being based on a single molecular derangement. Primary events resulting in altered physicochemical properties of the red blood cells may work in concert in the development of essential hypertension. in addition to the increased availability of calcium ions and their potential role in smooth muscle contraction.
Modern haemophilia treatment: medical improvements and quality of life, Adequate replacement therapy in haemophilia has been available for two decades. This has led to considerable improvements in the life expectancy and physical status of haemophilia patients. A study was conducted to investigate whether this has also led to improvements in quality of life. With this aim. information was obtained from 935 Dutch haemophiliacs by mailed questionnaires on relationships. marriage. family life and employment. Haemophilia patients were less often married than men in the general population (13% fewer) and had a lower total number of children (30% lower. 17% for those who were married). Twenty-two per cent of the patients were not employed and received an income from the disability funds. While severity of haemophilia. joint damage and age increased the risk of disability. it was noted that home treatment was associated with a 50% reduction in this risk. Remarkably. haemophilia patients did not differ from the general population in their view of the quality of their own health. The results of this study show a positive influence of modern haemophilia treatment on quality of life. At present. AIDS overshadows all optimistic feelings one may have about this field. However. the results described here demonstrate the benefits that can be achieved with adequate replacement therapy. and justify the expectation of further improvements in the near future.
The relationship between symptomatic and biochemical hypoglycaemia in insulin-dependent diabetic patients, The relationship between symptomatic (subjective feelings) and biochemical (blood glucose concentration less than 3 mmol l-1) hypoglycaemia was studied in 66 randomly selected insulin-dependent diabetic out-patients under normal conditions of daily life with conventional insulin injection regimens. The patients (a) collected 7-point diurnal blood glucose profiles at home on three consecutive days and then once weekly for 3 weeks. (b) indicated whether they felt hypoglycaemic at sampling times. and (c) collected extra samples if they felt hypoglycaemic at any time during the study period. The weekly frequencies of symptomatic and biochemical hypoglycaemia were 0.99 and 1.75 per patient. respectively. Biochemical hypoglycaemia was present in 29% of the symptomatic episodes. and symptomatic hypoglycaemia accompanied 16% of the biochemical episodes. Symptomatic hypoglycaemia was experienced at a median blood glucose concentration of 3.4 mmol l-1 (range 1.4-14.9 mmol l-1). Fifty per cent of both symptomatic and biochemical episodes occurred before lunch. while the remainder were evenly distributed throughout the day. The occurrence of biochemical hypoglycaemia. but not of symptomatic hypoglycaemia. was inversely correlated with HbA1c and median blood glucose concentration. Thus symptomatic hypoglycaemia is an unreliable indicator of biochemical hypoglycaemia and of the degree of glycaemic control. Blood glucose measurements are a prerequisite for the diagnosis of hypoglycaemia.
Long-term follow-up after heterotopic splenic autotransplantation for traumatic splenic rupture, The trapping function of the heterotopic splenic autotransplants (HSA) in 13 polytraumatized patients. aged 5-38 yr. was evaluated using heat damaged technetium-99m-labeled autologous red blood cells in early (1-7 mo) and late (3-4.5 yr) period after heterotopic autotransplantation to the omentum. The intensity of tracer accumulation was graded in comparison to the liver uptake. The splenic tissue surface was calculated on anterior projection each time. The shapes of the transplants were compared and new uptake foci suggesting spontaneous splenosis were looked for on both scans. The average surface of HSA was 28.2 (+/- 14.7) cm2 on early and 44.1 (+/- 14.3) cm2 on late examination (p less than 0.003) and the increase in intensity of tracer accumulation on both occasions was significant as well (p less than 0.0001). In three patients. some additional splenotic foci were found on follow-up scans. Howell-Jolly bodies in peripheral blood were detected in six of eight patients in early and remained detectable in lower number in three of eight patients on follow-up. No serious infection was noticed in our group of patients. Our work confirmed the excellent survival rates of HSA with improving trapping function and no important spread from original implantation site on long-term follow-up.
Reproducibility of image interpretation in immunoscintigraphy performed with indium-111- and iodine-131-labeled OC125 F(ab')2 antibody injected into the same patients, An important criterion for the clinical use of a new imaging technique is the correct reproducibility of interpretation. Forty-six paired immunoscintigraphic examinations were performed on 43 patients with suspected ovarian carcinoma recurrence using F(ab')2 fragments of OC125 antibody labeled first with indium-111 and then with iodine-131. Planar scintigraphy (PS) and emission computed tomography (ECT) images were interpreted blindly and separately by three observers. and reproducibility was evaluated by a kappa concordance index. Intra- and interobserver reproducibility were generally satisfactory (kappa values of 0.6 and 0.7. respectively). Binomial analysis of kappa values for ECT showed the superiority of indium-111 for intraobserver (p = 0.035) and interobserver (p = 0.0039) study. However. for PS there was no significant difference in reproducibility with the two radionuclides.
Relationship of uptake of technetium-99m(Sn)-N-pyridoxyl-5-methyltryptophan by hepatocellular carcinoma to prognosis, The relationship of technetium-99m(Sn)-N-pyridoxyl-5-methyltryptophan (99mTc-PMT) uptake by hepatic tumors to survival was studied in 162 cases of hepatocellular carcinoma (HCC). The median survival of 82 patients in whom hepatic tumors showed increased uptake in delayed 99mTc-PMT imaging was 1013 days. which was significantly longer than the survival time of 398.5 days of 80 patients in whom hepatic tumors did not show increased uptake of radioactivity (p less than 0.002). The relationship between the ability of hepatic tumors to take up 99mTc-PMT and survival was also analyzed in patients with HCC showing filling defects in 99mTc-colloid liver images and. in relation to the therapy. serum values of bilirubin and alpha-fetoprotein. Results indicated that the degree of 99mTc-PMT uptake by hepatic tumors is closely correlated with the prognosis of patients with HCC.
Assessment of myocardial perfusion in patients after the arterial switch operation, In 21 patients who had undergone the arterial switch operation. the adequacy of myocardial perfusion was evaluated by thallium-201 computed scintigraphy 2.6 +/- 2 (0.3-7) yr after surgery. Fourteen patients had undergone the arterial switch procedure after pulmonary artery banding and seven as a primary repair. Isoproterenol stress increased the heart rate by at least 55%. Tomographic imaging was performed at peak stress and 3 hr later in the reperfusion phase. Nine patients had perfusion defects. The perfusion defects were located at the left ventricular apex in four (with extension to the inferolateral wall in one). left ventricular anterolateral wall in two. ventricular septum in one. left ventricular inferior wall in one. and right ventricular free wall in one. Some of these defects could be due to myocardial damage at the time of surgery. but these results also raise concern about long-term adequacy of myocardial perfusion following the arterial switch procedure.
Myocardial uptake of carbon-11-acetate as an indirect estimate of regional myocardial blood flow, The rate of clearance of myocardial carbon-11 (11C) activity (after the administration of 11C-acetate) has been shown to correlate closely with myocardial oxygen consumption. In the present study. we hypothesized that regional net myocardial uptake of 11C-acetate. which reflects primarily delivery and extraction of tracer. would be markedly flow-dependent and potentially useful as an indirect index of regional myocardial blood flow. In 22 patients with stable coronary artery disease. the regional distribution of early net uptake of 11C-acetate was correlated with estimates of regional myocardial blood flow assessed with oxygen-15-water. The myocardial images of 11C-acetate uptake were of high quality. The correlation between the two approaches was close (r = 0.88) and not affected by the metabolic state of the tissue. Thus. in patients with stable coronary artery disease. under resting conditions. direct estimates of myocardial oxygen consumption in relation to the level of delivery of tracer to the tissue can now be obtained by PET with use of a single radiopharmaceutical. 11C-acetate. This approach may prove particularly useful in streamlining clinical protocols designed to assess myocardial oxygen consumption.
Comparison of 1073 MBq and 3700 MBq iodine-131 in postoperative ablation of residual thyroid tissue in patients with differentiated thyroid cancer, In a randomized prospective study. we compared the efficacy of low dose (1073 MBq) and high dose (3700 MBq) iodine-131 administration in postoperative ablation of residual functioning thyroid tissue in 63 patients with differentiated thyroid cancer. We were unable to demonstrate any difference between the low- and the high-dose of radioactive iodine in scintigraphic ablation of remnant tissue. In 81% (21/26) of the patients. 1073 MBq ablated after the first dose. 77% (21/26 + 3/5 = 24/31) after the first plus second dose. and 69% (24/31 + 0/4 = 24/35) after the first. second. and third dose. Radioiodine (3700 MBq) ablated in 84%. 73%. and 69% of the patients after respectively 1.. 1. plus 2.. and 1. plus 2. plus 3. dose. Forty percent of the patients ablated with the low dose and 44% ablated with the high dose had elevated thyroglobulin levels at the time of complete scintigraphic ablation. In conclusion. we did not find any difference between 3700 MBq and 1073 MBq iodine-131 as regard to number of doses needed for complete scintigraphic ablation of residual functioning thyroid tissue.
Blood-pool radionuclide angiography in patients with a Novacor left ventricular assist device, Blood-pool radionuclide angiography was used to investigate the left ventricular function in eight patients who received a Novacor assist device as a bridge-to-cardiac transplantation. Studies were performed during maximal and minimal tolerated assist device flows. The left ventricular ejection fraction. volumes. cardiac output. and the pump ejection fraction were computer-assessed. All patients had severe left ventricular dilation and hypokinesis before insertion of the assist device. with a mean ejection fraction of 18% +/- 4% which improved to 44% +/- 18% (p less than 0.01) during maximal assist device flows. but fell to 25% +/- 15% (p less than 0.01) during minimal flows. The ventricular volumes became normal at maximal assist device flow but increased significantly (p less than 0.05) during minimal flow. The pump was well visualized and had an ejection fraction of 82% +/- 7%. These data indicate that this assist device effectively unloads the left ventricle. The deterioration in ejection fraction following decrease in assist device flow is in keeping with the dependency of these patients on the device to sustain adequate hemodynamics.
Early scintigraphic detection of experimental myocardial infarction in dogs with technetium-99m-glucaric acid, Recent data have generated some interest in technetium-99m-(99mTc) glucaric acid as an in vivo viability marker. We studied 99mTc-glucaric acid retention in canine models of myocardial ischemia (20-min occlusion of the LAD/40-min reperfusion). acute myocardial infarction (MI) (90-min LAD occlusion/3-hr reperfusion). and chronic MI (90-min occlusion and either 48-hr or 10-day reperfusion). Regional myocardial blood flow was measured by radiolabeled microspheres. No preferential uptake of glucaric acid was observed in ischemic but viable myocardium. The compound showed high affinity for necrotic myocardial tissue for several days following injury. The preferential uptake in infarcted tissue disappeared by 10 days following injury. This study shows that 99mTc-glucaric acid acts exclusively as a marker of necrosis in canine models of MI. Technetium-99m-glucaric acid may have clinical utility in early cardiac imaging of myocardial infarction and in differentiating recent from old injuries.
Localization of technetium-99m-glucarate in zones of acute cerebral injury, The potential structural similarity of technetium-99m-labeled glucaric acid (99mTc-glucarate) to that of fructose suggests that this agent may enter cells by a sugar transport system. Studies with LLC-PK1 cells demonstrated inhibition of 99mTc-glucarate uptake by fructose. confirming this potential relationship. Since anaerobic metabolism can use either glucose or fructose. we hypothesized that 99mTc-glucarate may concentrate in areas of acute ischemic injury. To test this hypothesis. 63 adult rats with middle cerebral artery (MCA) occlusion followed by reperfusion were injected with 99mTc-glucarate and in vivo and ex vivo images were acquired. Seven animals were also studied with 18FDG and high resolution PET imaging. The radionuclide images were compared to the results of triphenyl tetrazolium chloride (TTC) staining and conventional histopathology. Thirty-five rats had significant accumulation of 99mTc-glucarate and no TTC staining (indicating infarction) in the involved hemisphere. Of the remaining 28 rats with TTC staining (suggesting viability) of the involved hemisphere. 16 (57%) had 99mTc-glucarate accumulation. In the seven rats that were studied with both 99mTc-glucarate and 18FDG. 99mTc-glucarate accumulated at the center of the occluded MCA territory while 18FDG activity was decreased in this region. These results suggest that 99mTc-glucarate is a sensitive marker of acute severe cerebral injury. but its mechanism of localization is probably different from that of 18FDG.
Effect of coronary occlusion and myocardial viability on myocardial activity of technetium-99m-sestamibi, The timing effect of sestamibi administration with respect to the onset of myocardial ischemia and reperfusion was studied in swine. In different groups of animals sestamibi was administered prior to coronary artery occlusion. during occlusion. or 1/2 hour following reperfusion. Sestamibi administered prior to coronary occlusion resulted in an insignificant decrease in 99mTc activity in the ischemic zone. However. infarct zone activity was reduced to 62 +/- 14% of the nonischemic zone. In contrast. administration during coronary occlusion resulted in similar significant reductions of both ischemic and infarct zone activity. Administration of sestamibi during reperfusion resulted in normal ischemic zone activity and markedly reduced activity in the infarct zone. Significantly reduced activity in the infarct zone was found to be independent of the timing of sestamibi administration with respect to the onset of myocardial ischemia and/or reperfusion. Thus. cell viability appears required for uptake and retention of isotope activity.
Extracranial metastatic glioblastoma: appearance on thallium-201-chloride/technetium-99m-HMPAO SPECT images, Sequential thallium-201-chloride and technetium-99m-hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) images were obtained in a patient with extracranial metastatic glioblastoma multiforme. Thallium-201 uptake was high (three times the scalp background) in all pathologically confirmed extracranial metastases and moderate (1.6 times scalp background) intracranially. where most biopsy specimens showed gliosis with scattered atypical astrocytes. Technetium-99m-HMPAO uptake was decreased intracranially in the right frontal and parietal lobes which had been irradiated. It was also decreased in one well-encapsulated scalp lesion and high in another scalp mass with less defined borders. Possible mechanisms of tumor uptake of these agents are reviewed.
Technetium-99m-methylene diphosphonate (MDP) uptake in a sympathetic effusion: an index of malignancy and a review of the literature, We report a patient with a sympathetic pleural effusion secondary to T-cell lymphoma that accumulated the bone imaging agent. Technetium-99m-methylene diphosphonate (99mTc-MDP). This case is significant in that malignant cells were not present on three cytologic examinations of the pleural fluid or multiple pleural biopsies. We also present a review of the published literature on pleural effusions that accumulate bone tracers. We conclude that pleural effusions that accumulate 99mTc-MDP should be considered malignant or secondary to a malignancy and further work-up is essential even if the cytologic exam of the pleural fluid is unremarkable.
Delayed positive gastrointestinal bleeding studies with technetium-99m-red blood cells: utility of a second injection, Two patients studied with technetium-99m-labeled red blood cells (RBCs) for gastrointestinal bleeding had positive findings only on 24-hr delayed images. at which time the site of bleeding could not be ascertained. In each instance. when additional delayed images suggested that active bleeding was occurring. a second aliquot of RBCs was labeled and injected. Sites of active hemorrhage were identified following further imaging in both patients. When delayed GI bleeding images are positive. further views should be obtained to ascertain if the pattern of intraluminal activity changes. If renewed active hemorrhage is suspected. reinjection with a second dose of labeled RBCs may identify the bleeding site.
Modulation by dietary vitamin E of I-compounds (putative indigenous DNA modifications) in rat liver and kidney, I(indigenous)-compounds are age-related. carcinogen adduct-like. putative indigenous DNA modifications detectable by 32P-postlabeling assay in untreated animals. To investigate the origins of these DNA derivatives. we examined the effects of dietary vitamin E. a natural antioxidant. on I-compounds of rat liver and kidney DNA. Weanling female Sprague-Dawley rats were fed Draper's diets containing 0. 100. 1000. or 10.000 mg/kg alpha-tocopheryl acetate for 6 mo. The DNA from four individual rats of each group was analyzed by a nuclease P1-enhanced version of the 32P-postlabeling assay for DNA adducts. The amount of vitamin E in the liver was measured by high performance liquid chromatography. Rats fed vitamin E-deficient diet (0 mg/kg) showed identical profiles and similar levels of I-compounds as those fed the 100 mg/kg diet. Most I-spots were significantly intensified and one tissue-specific extra spot was found in both liver and kidney DNA of rats fed the 1000 or 10.000 mg/kg vitamin E diet. However. one of the five major I-spots detected in the kidney was weaker in the 1000 and 10.000 mg/kg groups than in the 0 and 100 mg/kg groups. These results show that formation of most I-compounds was not affected by vitamin E-deficient diet. and that long-term feeding of diet containing high levels of vitamin E may cause metabolic alterations leading to an increased formation of DNA-reactive (potentially mutagenic or carcinogenic) electrophiles.
MRI-guided stereotaxic brain biopsy in neurologically symptomatic AIDS patients, Two patients with AIDS-related neurologic dysfunction were evaluated with both computed tomographic (CT) brain scans and magnetic resonance imaging (MRI). CT scans were essentially normal in both patients while MRI revealed focal lesions amenable to brain biopsy. Using newly developed instrumentation. MRI-guided stereotaxic brain biopsy was performed without complication. The benefits and impact of this new technology for the care of neurologically symptomatic AIDS patients is discussed.
A multicenter proficiency trial of gene amplification (PCR) for the detection of HIV-1, The sensitivity and specificity of the polymerase chain reaction (PCR) for the detection of HIV-1 proviral DNA was determined in five laboratories with extensive experience in PCR testing. Five panels consisting of 105 HIV-1-seronegative specimens from regularly repeating blood donors with no risk factors for HIV infection and 99 HIV-1-seropositive and culture-positive specimens from a cohort of homosexual/bisexual men were sent under code to each laboratory. Amplification procedures and testing algorithms by which specimens were judged positive. negative. or indeterminate varied between laboratories. The average sensitivity for the five laboratories was 99.0%. with two laboratories achieving 100%. The average specificity was 94.7%. varying between 90.5 and 100%. The overall false-positive rate was 1.8%. the false-negative rate was 0.8%. and the indeterminate rate was 1.9%. Of 1.005 determinations made by the five laboratories. 32 (3.2%) were misclassifications. Most of the classification errors occurred in specimens from uninfected individuals and were distributed among the laboratories in such a way as to indicate laboratory error rather than the inherent reactivity of some samples. This emphasizes the need for standardization of PCR testing and caution in interpreting positive PCR reactions in HIV-1-seronegative persons.
HTLV-I-associated leukemia/lymphoma in south Florida, We report here 10 cases of adult T-cell leukemia/lymphoma (ATL) seen in South Florida between February 1988 and July 1989. All were seropositive for human T-lymphotropic virus type I (HTLV-I) and seronegative for human immunodeficiency virus type 1 (HIV-1). DNA extracted from tumor biopsies/peripheral blood lymphocytes of nine patients was shown by the polymerase chain reaction (PCR) to contain HTLV-I proviral DNA. Blot hybridization of DNA extracted from seven patients with an HTLV-I cDNA probe revealed a monoclonal pattern of proviral integration consistent with a diagnosis of ATL. Eight of the 10 patients were women. Six patients were from Haiti. three from Jamaica. and one from the Bahamas. All patients had very aggressive non-Hodgkin's lymphoma. Two patients presented with sinus and retro-orbital involvement; another had gastric lymphoma that perforated. Nine patients developed hypercalcemia. Eight patients died within 1 year of diagnosis. Two were lost to follow-up. During the course of this study. 66 new cases of non-Hodgkin's lymphoma were diagnosed at this hospital. Ten of these cases were ATL. The prevalence of HTLV-I-related lymphoma in this sample was 15%. Since tissue from all patients was not available for HTLV-I screening. however. it is possible that other cases of ATL went undetected. We conclude from this initial survey that a retroviral etiology should be considered in patients from populations known to be at risk for HTLV-I infection who present with non-Hodgkin's lymphoma.
A landmark case in asbestosis, The first published account of disease attributed to occupational asbestos exposure was that of Nellie Kershaw. who died in 1924. The circumstances relating to that case are described and explanations are given for its not having a greater impact on policy at that time. This case. starting in 1898. is set in the context of missed opportunities for preventing a major public health hazard. The effects of this hazard are still being witnessed today.
The prevalence of gallstone disease in very old institutionalized persons, We present the results of a study that was undertaken at a large geriatric nursing home to assess the prevalence of gallstone disease in very old institutionalized persons. One hundred seventeen residents underwent ultrasound examination of the gallbladder. Two thirds of 82 women and half of 35 men had gallstone disease. When stratified for age. 80% of women and men over the age of 90 years were positive for the disease. In summary. the prevalence of gallstone disease in our very old nursing home population was found to be unexpectedly high.
The management of primary pulmonary hypertension, Primary pulmonary hypertension is a clinical syndrome characterized by pulmonary hypertension in the absence of sufficient underlying cardiac. parenchymal pulmonary. or systemic disease to account for it. The population of patients with primary pulmonary hypertension is a heterogeneous one. both clinically and histologically. As the etiologic mechanisms are unknown. therapy is directed toward the consequences of the pulmonary vascular process. Oxygen supplementation. the use of digoxin and diuretics for symptomatic heart failure. and anticoagulation all may have a role in treating primary pulmonary hypertension. although vasodilator therapy has been the main area of investigation. Screening for vasodilator responsiveness. defining a favorable vasodilator effect. predicting long-term effectiveness. and deciding who to treat have all been controversial. New approaches. such as use of high-dose calcium channel-blocking agents and continuous intravenous infusion of prostacyclin (an investigational agent). have recently been proposed. When medical therapies are exhausted. heart-lung or lung transplantation has increasingly become an option for selected patients.
Nosocomial Pseudomonas pickettii bacteremias traced to narcotic tampering. A case for selective drug screening of health care personnel, Three patients in a university hospital developed nosocomial infusion-related Pseudomonas pickettii bacteremia. Investigation identified six additional patients who had received intravenous fluid contaminated by P pickettii but did not become ill. All nine patients had had surgery. and each of these patients but only nine of 19 operated-on control patients had received intravenous fentanyl citrate in the operating room; the mean dose given to the nine case patients was far greater than that given to control patients. Fentanyl in 20 (40%) of 50 predrawn 30-mL syringes was shown to be contaminated by P pickettii. Contamination was caused by theft of fentanyl from predrawn synringes and replacement by distilled water contaminated by P pickettii. Narcotic theft by health care personnel may cause patients to suffer pain needlessly and can also result in dire unanticipated consequences. such as nosocomial bacteremia. Whereas drug testing in the workplace is highly controversial. we believe that testing of health care personnel is indicated when drug abuse or theft is suspected.
Lovastatin efficacy in reducing low-density lipoprotein cholesterol levels on high- vs low-fat diets, The effectiveness of lovastatin was compared with both a high-fat vs low-fat diet. Hypercholesterolemic subjects were studied under metabolic ward conditions for diet periods of 3 weeks while receiving lovastatin (40 mg/d) or placebo. Multiple lipoprotein levels were measured during the final week of each diet period. Nineteen subjects completed the study on the high-fat (43% of kilojoules) diet and 16 on the low-fat (25% of kilojoules) diet. Lovastatin reduced total cholesterol by 23% and low-density lipoprotein cholesterol by 30%. compared with placebo on both diets. with no significant diet-drug interaction. High-density lipoprotein cholesterol was raised by 7% to 8% on the diet regimens. Addition of lovastatin to the low-fat diet permitted 80% of subjects on this diet. but less than 50% of those on the high-fat diet. to achieve current guidelines. Although lovastatin produces a comparable percentage reduction in lipoprotein profiles on either diet. the accompanying low-fat diet remains advisable for additional reduction of low-density lipoprotein cholesterol levels to specified goals.
Comparison of characteristics of esophageal squamous cell carcinoma associated with head and neck cancer and those with gastric cancer, In ongoing reviews of 339 patients with surgically treated primary squamous cell carcinoma. there were 19 (5.6%) with concurrent gastric cancer and 11 (3.2%) with head and neck cancer. The incidences of intra-esophageal multiple occurrence of esophageal cancer are 27.3% and 26.3% in those with associated head and neck cancer and gastric cancer. respectively. and higher than 7.1% in those without such a concurrent cancer. There was no difference in the clinicopathological characteristics of those with concurrent head and neck and gastric cancers. except for the higher incidence of metachronous occurrence in the former. These findings suggest that. in cases of esophageal cancer associated with concurrent head and neck cancer and gastric cancer. intraesophageal multiplicity of the esophageal carcinoma is frequent and that preoperative serial evaluations is most important to design treatment and estimate the prognosis.
Activation and in vitro expansion of tumor-reactive T lymphocytes from lymph nodes draining human primary breast cancers, The feasibility of in vitro activation of lymphocytes from the draining lymph nodes (DLN) of breast cancer patients was examined. Lymphocytes isolated from 48 DLN from 12 patients were examined for their proliferative responses to rIL-2. autologous tumor cells. or rIL-2 plus tumor cells. Three general patterns of cellular responses were observed. Cells from some DLN (17%) were unresponsive to any stimuli. Lymphocytes from 52% of the DLN responded moderately to rIL-2 alone. The combination of rIL-2 and tumor antigen had a synergistic effect on the proliferation of cells from 31% of the DLN assayed. Phorbol dibutyrate and ionomycin plus rIL-2 stimulated expansion of DLN lymphocytes by up to 850-fold after 35 days. These expanded cell populations. as well as those stimulated with antigen plus rIL-2. were predominantly CD3+ and CD16- cells. varying in proportions of CD4+ and CD8+ subsets. Both populations were cytotoxic against autologous tumor. MCF-7. and K562 target cells.
Neuroendocrine carcinoid tumours of the breast: a variant of carcinoma with neuroendocrine differentiation, Carcinoid tumours most frequently develop in the gastrointestinal tract but have been described in many organs of the body. In 1977 the first cases were reported in the mamma. followed by descriptions of argyrophilic carcinoid-like. neuroendocrine mammary tumours by many investigators who performed immunohistochemical and ultrastructural examinations. The existence of true carcinoids in the mamma is still a controversial issue. Eight mammary neoplasms with monomorphous cytonuclear features. five of the small cell carcinoid-like variety and three composed of larger cells. were examined by immunohistochemical and ultrastructural examination. We believe this kind of tumours are ductal or lobular carcinomas with focal or more extensive neuroendocrine features and are the result of a dual differentiation of neoplastic precursor stem cells along epithelial and endocrine lines. Consequently. we consider that treatment of such cases should not be different from that of the ordinary type of mammary carcinomas.
Characterization and histopathological correlation of cytosol proteins of benign and malignant breast tumors, Significant differences in cytosol protein level exist between normal/benign and cancerous breast tissues. There is a positive correlation between the cytosol protein level and histological grade of carcinoma. Well-differentiated carcinoma have a lower value of cytosol protein than poorly differentiated carcinoma. In slab gel electrophoregrams. the total numbers of bands are almost identical in normal. benign. and malignant conditions. In addition. 37 Kd protein band is consistently present in malignant cases and always absent in normal or benign cases. More extensive biophysical examination of this band may provide further insight into the protein alterations in cancer cells at the molecular level.
Lactation following conservation surgery and radiotherapy for breast cancer, A 38-year-old woman with early stage invasive breast cancer was treated with wide excision of the tumor. axillary lymph node dissection. and breast irradiation. Three years later. she gave birth to a normal baby. She attempted breast feeding and had full lactation from the untreated breast. The irradiated breast underwent only minor changes during pregnancy and postpartum but produced small amounts of colostrum and milk for 2 weeks postpartum. There are only a few reports of lactation after breast irradiation. These cases are reviewed. and possible factors affecting breast function after radiotherapy are discussed. Because of scant information available regarding its safety for the infant. nursing from the irradiated breast is not recommended.
Subrenal capsule assay as a chemosensitivity test for primary esophageal squamous cell carcinoma, The efficiency of the subrenal capsule assay (SRCA) was studied with fresh tissue of esophageal squamous cell carcinoma. The day-to-day changes in 10 carcinoma cases were evaluated for 9 days. The cancer cells continued to proliferate from the 3rd to the 7th day after the implantation and then decreased. The host reaction was recognized histologically from the 3rd or 4th day to the 9th day. However. the immune reaction did not significantly influence the evaluation of SRCA until the 7th day. The immunohistochemical staining with anti-bromodeoxyuridine monoclonal antibody revealed the existence of cancer cells at the DNA synthesizing stage (S stage) in the graft until the 7th day. In chemosensitivity test by SRCA. 21 patients were studied. and all were evaluable. 5-FU administration produced a response in 8/21 cases (38.1%). VDS in 8/21 (38.1%). and CDDP in 3/21 (14.3%). Used in combination. CDDP + VDS was effective in 7/18 cases (38.9%) and CDDP + BLM in 6/18 cases (33.3%).
Squamous carcinoma of the distal esophagus: a survival study, A survival study for squamous carcinomas of the distal esophagus treated by the Southern California Permanente Medical Group in the interval of 1954 to 1988 was undertaken. We found radiation therapy and surgery equally efficacious in terms of cure for patients without distant disease and performance status sufficient to tolerate treatment. We did not find survival benefit for patients treated with palliative surgery. and plan less invasive endoscopic means along with chemotherapy and radiation for palliation. reserving surgery for special circumstances.
Is there ever a role for salvage operations in limited small-cell lung cancer, Combined modality treatment with chemotherapy and radiation produces tumor regression in most patients with small-cell lung cancer. but the impact on survival has been small. and less than 20% of patients with limited disease survive 2 years. Survival time is extremely short after failure to respond or relapse after treatment. Local control remains a problem. with one third of patients having recurrence only at the primary site. In an attempt to prolong survival and perhaps achieve cure. we undertook surgical resection in 28 patients with limited small-cell lung cancer who did not have complete remission with standard treatment or who had only local recurrence after treatment. There were 28 patients. 22 male and six female. median age 61 years (range 41 to 76). All patients had been treated with chemotherapy and 13 had received preoperative radiotherapy to the primary site and mediastinum. Eight patients underwent an operation for relapse after complete remission. Five patients had had no response to treatment. three had had a slight response followed by progression during chemotherapy. and 12 had achieved partial response but had greater than 3 cm residual masses. Twelve patients required pneumonectomy. 15 lobectomy. one patient had unresectable disease. and two had bulky residual masses after the operation. Three others had microscopic residual disease. Pathologic examination showed only small-cell lung cancer in 18 patients. mixed small-cell and non-small-cell in four. and only non-small-cell lung cancer in six. There were only four patients with stage I disease. 10 with stage II. and 14 with stage III. The median survival from the date of diagnosis for the entire group is 105 weeks and from the date of operation. 74 weeks. The projected 5-year survival rate is 23%. The two patients with residual masses died with local progression. and distant metastatic disease developed in 17 others. One patient died at 6 years without recurrent disease. Eight patients are alive 2 to 5 years after diagnosis. Seven of these patients required only a lobectomy. four had stage I disease. two had stage II. and two had stage III disease. Five had pure small-cell lung cancer and three had mixed small-cell and non-small-cell tumors. All of the patients with pathologic stage I disease remain alive compared with one of 10 with stage II disease and two of 14 with stage III. In summary. relapse or failure to respond to chemotherapy may be due to non-small-cell lung cancer or a mixed tumor.(ABSTRACT TRUNCATED AT 400 WORDS).
Meralgia paresthetica after coronary bypass surgery, Meralgia paresthetica is a neurologic disorder characterized by localized paresthesia and numbness on the anterolateral aspect of the thigh and involving the lateral femoral cutaneous nerve. It involves no motor deficits. Meralgia paresthetica. which may result from a variety of causes. has been observed as a rare complication in heart operations. Its cause when associated with such operations is uncertain but may be prolonged relaxed positioning on the operating table and recovery room stretcher. Another possible cause of meralgia paresthetica after heart operations is the "frog-leg" position of the legs during vein harvesting. Patients with this condition should be advised of its untreatable. but benign and self-limiting. nature.
Thromboexclusion of the right ventricle in children with pulmonary atresia and intact ventricular septum, Twelve children with pulmonary atresia and intact ventricular septum underwent closure of the tricuspid valve as a part of a new surgical procedure. In two cases a concomitant Fontan operation was performed. In each patient the right ventricle was very small and right ventricular pressure was higher than systemic pressure. Ventricle-coronary connections provided flow of desaturated blood from the right ventricle into the coronary arteries in 11 of 12 cases. Five of the 12 children did not survive operation and postmortem examination of each revealed severe acute and chronic myocardial ischemic damage and high-grade obstruction or interruption of the proximal left anterior descending coronary artery. Preoperative angiography demonstrated occlusive changes in the coronary arteries. resulting in right ventricular dependent circulation. in all five children who died and in one child who survived operation. Seven children who survived operation are well 4 months to 3.5 years later. Two have undergone subsequent successful Fontan operation and two others are considered suitable candidates for this operation. Tricuspid valve closure is recommended for a carefully selected group of infants with pulmonary atresia and intact ventricular septum provided a right ventricular-dependent coronary circulation can be excluded on the basis of preoperative coronary cineangiography.
Left ventricular mechanics of ejecting, postischemic hearts during left ventricular circulatory assistance, We measured the effects of left ventricular circulatory assistance on ventricular mechanics of ejecting sheep hearts before and after global ischemia. Flows from left atrium to femoral artery ranged between 20 and 100 ml/kg/min during circulatory assistance. In preischemic. ejecting hearts increasing flow through the left ventricular assist device progressively decreased stroke volume. end-diastolic volume. and circumferential systolic wall stress. but only slightly decreased end-systolic volume. In postischemic. ejecting hearts left ventricular assistance progressively and substantially decreased both end-diastolic volume and end-systolic volume; at high flows. end-systolic volume returned to the normal range of preischemic hearts. High flows through the assist device also shifted end-systolic points of pressure-volume loops leftward and increased the stroke work/end-diastolic volume ratio in ejecting postischemic hearts; these observations raise the possibility that left ventricular circulatory assistance acutely improves myocardial contractility of postischemic hearts.
Evolution of human cardiac myocyte dimension during prolonged mechanical support, In animal models using left ventricular assist systems over long time periods. myocardial cellular atrophy has been reported. raising concern that prolonged clinical use of such systems might lead to deterioration in left ventricular function. At the University of Pittsburgh. long-term clinical use of the Novacor (Baxter Healthcare Corp.. Novacor Div.. Oakland. Calif.) left ventricular support system for patients awaiting heart transplants has allowed study of the effects of long-term mechanical support on human subjects. This study determined that cardiac myocyte dimension is initially greater in patients with end-stage cardiac disease who require support rather than in patients with the same disease who do not require such support. Although myocyte dimension does decrease within a few days of the inception of support. this decrease merely brings cell size closer to the values usual in patients with chronic end-stage cardiac disease. and no further shrinkage is observed. Thus the Novacor left ventricular assist system does not appear associated with left ventricular atrophy. and its long-term use may not be detrimental to left ventricular function.
Warm heart surgery, Hypothermia is widely acknowledged to be the fundamental component of myocardial protection during cardiac operations. Although it prolongs the period of ischemic arrest by reducing oxygen demands. hypothermia is associated with a number of major disadvantages. including its detrimental effects on enzymatic function. energy generation. and cellular integrity. We hypothesized that the ideal protected state of the heart would be electromechanically arrested and perfused with blood. that is. aerobic arrest. Under these conditions the fundamental need for hypothermia becomes questionable. We have developed a novel approach to myocardial protection during cardiac operations based on these concepts. in which the chemically arrested heart is perfused continuously with blood and maintained at 37 degrees C. In 121 consecutive coronary bypass procedures we have compared this approach with a historical cohort of 133 consecutive patients treated with hypothermic cardioplegia. Perioperative myocardial infarction was significantly less prevalent (1.7% versus 6.8%; p less than 0.05) in the warm cardioplegic group. as was the use of the intraaortic balloon pump (0.9% versus 9.0%; p less than 0.005) and the prevalence of low output syndrome (13.5% versus 3.3%; p less than 0.005). Cardiac output immediately after bypass was significantly higher than before bypass (3.1 +/- 0.9 versus 4.9 +/- 1.0 L/min; p less than 0.001) only in the warm cardioplegia group. Furthermore. the heartbeat in 99.2% of patients treated with continuous warm cardioplegia converted to normal sinus rhythm spontaneously after removal of the aortic crossclamp compared with only 10.5% of the hypothermic group. The time from removal of the aortic crossclamp to discontinuation of cardiopulmonary bypass (i.e.. reperfusion time) was significantly shorter in the warm cardioplegia group (11 +/- 4.3 versus 27 +/- 5.6 minutes; p less than 0.001). Our results suggest that continuous normothermic blood cardioplegia is safe and effective. Conceptually. this represents a new approach to the problem of maintaining excellent myocardial preservation during cardiac operations.
Studies of controlled reperfusion after ischemia. XX. Reperfusate composition: detrimental effects of initial asanguineous cardioplegic washout after acute coronary occlusion, This study tests whether initial asanguineous washout of potentially toxic substances that accumulate during ischemia improves recovery produced by blood cardioplegic reperfusion and evaluates the role of plasma versus whole blood cardioplegia. METHODS: Twenty-four dogs underwent 2 hours of occlusion of the left anterior descending coronary artery and 20 minutes of blood cardioplegic reperfusion on total vented bypass. In 13 dogs. a 5-minute infusion of either a crystalloid (n = 7) or plasma (n = 6) cardioplegic solution (containing the same pH. calcium potassium. and osmolarity as blood cardioplegia) was given immediately before reoxygenation with blood cardioplegia. Regional oxygen uptake and coronary vascular resistance were measured during controlled reperfusion. and segmental shortening (ultrasonic crystals). tissue water content. and histochemical damage (triphenyltetrazolium chloride stain) were assessed 1 hour after bypass was discontinued. RESULTS: Asanguineous cardioplegic washout before reoxygenation with blood cardioplegic solution resulted in a progressive (+42%) increase in coronary vascular resistances (from 123 to 176 units. p less than 0.05) and low oxygen utilization during 20 minutes of blood cardioplegic reperfusion (29 ml/100 gm. p less than 0.05); coronary vascular resistance remained low throughout blood cardioplegic reperfusion without washout (from 109 to 98 units). and oxygen utilization was 54 ml/100 gm (p less than 0.05). Neither plasma nor crystalloid washout restored substantial regional systolic shortening (3% systolic shortening versus 73% systolic shortening with blood cardioplegia). and asanguineous washout caused more myocardial edema (81.1% +/- 80.9% versus 79.5% water content. p less than 0.05) and produced extensive transmural triphenyltetrazolium chloride damage (48% +/- 41% versus 8% nonstaining in area at risk. p less than 0.05) than initial blood cardioplegic reperfusion. CONCLUSION: Asanguineous cardioplegic washout before blood cardioplegic reperfusion limits oxygen utilization during subsequent controlled reperfusion. restricts early recovery of systolic shortening. allows more myocardial edema. and produces extensive histochemical damage. which may be avoided by initial reoxygenation with blood cardioplegia. The red blood cells appear more important than the plasma components of blood cardioplegia.
Studies of controlled reperfusion after ischemia. XXII. Reperfusate composition: effects of leukocyte depletion of blood and blood cardioplegic reperfusates after acute coronary occlusion, OBJECTIVES: This study evaluates the role of leukocyte depletion during initial reoxygenation with normal blood and blood cardioplegic reperfusates in limiting reperfusion damage. METHODS: Twenty-eight dogs underwent 2 hours of ligation of the left anterior descending coronary artery. The initial reperfusate (37 degrees C) was delivered on total vented bypass to the left anterior descending artery by a calibrated pump via an internal mammary artery graft at 50 mm Hg for 20 minutes. Eight dogs received normal (normokalemic. nonenriched) blood reperfusion (leukocyte count 8000/mm3) and six were reperfused with leukocyte-depleted normal blood (leukocyte count less than 100/mm3). Of 14 dogs reperfused with substrate-enriched (hyperkalemic) blood cardioplegic solution. six received a cardioplegic solution with a leukocyte count less than 100/mm3. RESULTS: Leukocyte depletion of normal blood reduced reperfusion-induced arrhythmias from 63% to 17% (p less than 0.05). Coronary vascular resistance at initial reperfusion was low and remained low during substrate-enriched blood cardioplegic reperfusion with both normal and reduced leukocyte counts. In contrast. coronary vascular resistance rose 63% with normal blood reperfusion. and this increase was avoided by leukocyte depletion (2.6 versus 4.0 mm Hg x ml/min. p less than 0.05). Coronary vascular resistance after 20 minutes was. however. higher than that with blood cardioplegia with normal or decreased leukocyte counts. Negligible functional recovery followed reperfusion with normal blood and leukocyte-depleted blood (12% and 6% of control systolic shortening). In contrast. substantial segmental recovery followed blood cardioplegic reperfusion (73% systolic shortening. p less than 0.05) but was not improved by leukopheresis (81% systolic shortening). Leukocyte depletion of normal blood reperfusate reduced histochemical damage from 53% to 38% (p less than 0.05). but the least histochemical damage followed blood cardioplegic reperfusion with a normal or reduced leukocyte count (8% or 11%. p less than 0.05). CONCLUSIONS: These findings suggest an important role for leukocytes in reperfusion damage. but reperfusate leukocyte filtration alone is inferior to blood cardioplegic reperfusion. Leukocyte depletion of blood cardioplegic solutions seems unnecessary after only 2 hours of ischemia.
Self-management of dietary compliance in coeliac disease by means of ELISA "home test" to detect gluten, To improve compliance with a gluten-free diet in coeliac disease a simple prototype test kit was developed to detect gluten in foods for use at home. The test is based on monoclonal antibodies to heat-stable gluten proteins which crossreact appropriately with barley and rye proteins. It is suitable for use with a wide range of raw or cooked foods. The food is extracted with dilute hydrochloric acid and 1 drop of the extract transferred to an antibody-coated tube; enzyme-labelled gluten detection antibody is added and after 3 min the tube is washed and colour developer is added. The reaction is stopped after 2 min. stabilising the blue colour. The home kit was compared with a quantitative laboratory kit. and the qualitative agreement was very good. The kit could distinguish foods with trace gluten contents (acceptable for a "gluten-free" diet) from those with a slightly higher but unacceptable gluten content. In a trial of the prototype kit by 47 coeliac disease patients of diverse ages and educational backgrounds. 93% of tests correctly identified foods as acceptable or unacceptable.
Serial CD4 lymphocyte counts and development of AIDS, Low CD4 lymphocyte counts are associated with increased risk of progression to AIDS in human immunodeficiency virus (HIV) infection. We investigated the extent to which the timing of progression to AIDS can be explained solely in terms of decline of the CD4 lymphocyte count in 111 haemophiliacs followed for up to 11 years since infection with HIV. A median of 10 CD4 lymphocyte counts were made per patient. By applying a simple linear model for the decline in CD4 lymphocyte counts over time. we estimated the date of development of AIDS in 96 patients who had at least 5 determinations. 84% (81 of 96) of patients were correctly classified as to development of AIDS before Jan 1. 1990 (p less than 0.0001). with this model. The results suggest that differences in the time at which patients with HIV will progress to AIDS can largely be explained by differences in rates of decline of CD4 lymphocyte counts.
Lymphoscintigraphy with 123I-labelled epidermal growth factor, We have used 123I-labelled epidermal growth factor (EGF) scans to study 14 patients with advanced cervical cancer. Abnormal lymph node imaging was seen most clearly 6-8 h after the injection and revealed abnormal uptake by pelvic lymph nodes in 11 patients. 4 of these 11 had abnormal computerised tomographic and ultrasound scans; in the other 7 conventional radiology did not confirm the presence of disease.
Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus, The usefulness of high-frequency stimulation of the ventral intermediate nucleus (Vim) as the first neurosurgical procedure in disabling tremor was assessed in 26 patients with Parkinson's disease and 6 with essential tremor. 7 of these patients had already undergone thalamotomy contralateral to the stimulated side. and 11 others had bilateral Vim stimulation at the same time. Chronic stimulating electrodes connected to a pulse generator were implanted in the Vim. Tremor amplitude at rest. during posture holding. and during action and intention manoeuvres was assessed by means of accelerometry. Of the 43 thalami stimulated. 27 showed complete relief from tremor and 11 major improvement (88%). The improvement was maintained for up to 29 months (mean follow-up 13 [SD 9] months). Adverse effects were mild and could be eradicated by reduction or cessation of stimulation. This reversibility and adaptability. allowing control of side-effects. make thalamic stimulation preferable to thalamotomy. especially when treatment of both sides of the brain is needed.
Radon and health, Radon and its daughter decay products are thought to be the cause of 5% of lung cancer in the UK. This assessment has been made by the National Radiological Protection Board (NRPB) after a national survey of radon levels in homes. when more houses than anticipated were found to have high levels. and after a reappraisal upwards of the effectiveness of radon and its daughter products in causing lung cancer. A review of the scientific evidence reveals no direct evidence to incriminate radon or its decay products at the levels found in our homes in lung cell carcinogenesis. The issue involves different scientific disciplines and is highly complex. Debate between scientists is required and more epidemiological studies of lung cancer and low radon exposure are necessary. Meanwhile the indirect evidence linking low levels of radon exposure to lung cancer is insufficient to warrant the remedial action proposed by the NRPB and accepted by the UK government.
The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. The Canadian Cooperative Multiple Sclerosis Study Group, To find out whether non-specific immunosuppression is beneficial in multiple sclerosis (MS) a randomised. placebo-controlled. single-masked trial was carried out in nine university centres. 168 patients with clinically or laboratory-supported definite MS in progressive phase (deterioration by at least 1.0 on the expanded disability status scale [EDSS] in the previous year) were randomised to receive intravenous cyclophosphamide and oral prednisone (n = 55); daily oral cyclophosphamide. alternate day prednisone (22 weeks). and weekly plasma exchange (20 weeks) (n = 57); or placebo medications and sham plasma exchange (n = 56). All patients were followed for at least 12 months (mean 30.4 months) by a monitoring neurologist. who was aware of treatment allocation. and an evaluating neurologist. who was not. The primary analysis was a comparison of rates of treatment failure (worsening of evaluating neurologist's assessment of EDSS by 1.0 or more on two consecutive 6-monthly assessments). There were no significant differences among the groups in this primary analysis (19 [35%] treatment failures with cyclophosphamide; 18 [32%] with plasma exchange; 16 [29%] with placebo). Nor were there any differences in the proportions improved. stabilised. or worsened at each 6 month assessment or in the mean change in the EDSS at the final assessment (0.81 cyclophosphamide; 0.69 plasma exchange; 0.69 placebo). A slight trend favouring the plasma exchange group at 12-24 months of follow-up was not sustained at the final assessment. This study fails to confirm previous reports that immunosuppressive treatments result in stabilisation or improvement in progressive MS.
Neurofibromatosis type 2: report of a family and review of current evaluation and treatment, Significant advances during the past decade have greatly improved our understanding of neurofibromatosis type 2. a genetic disease which results in bilateral acoustic neuromas. The emergence of gadolinium-enhanced magnetic resonance imaging has allowed early detection of minute intracanalicular eighth-nerve tumors. less than 1 cm in diameter. Recombinant DNA studies have clarified the genetics that underlie neurofibromatosis type 2 and separate it from a variety of related conditions. such as von Recklinghausen's neurofibromatosis. Early diagnosis and surgical removal of these tumors may offer the only hope of preserving hearing and facial nerve function. A report of the evaluation and treatment of a family with multiple affected individuals will exemplify these conclusions.
Imaging modalities in recurrent head and neck tumors, Patients with recurrent neoplasms of the head and neck present perplexing management problems. and accurate preoperative assessment of their disease is crucial. Thirty-eight patients with suspected recurrent neoplasms comprise this study: 30 had computed tomography scans. 4 had magnetic resonance images. and 4 patients underwent both computed tomography and magnetic resonance imaging to assess the anatomical extent of pathology in 34 malignant and 4 benign tumors. Contrast enhancement was essential for detecting disease on computed tomography scan. Differentiation of recurrent tumor was more difficult when the patient had undergone radiation. Magnetic resonance imaging demonstrated superior visibility in recurrent parotid and paranasal sinus neoplasm. but was less helpful in laryngeal and pharyngeal recurrences. Computed tomography demonstration of a mass with infiltration of normal fat or tissue planes or lymphadenopathy correlated highly with recurrent disease. Imaging techniques and fine points for determining recurrent neoplasms are presented.
The use of bromodeoxyuridine cytokinetic studies as a prognostic indicator of cancer of the head and neck, Traditional measures of head and neck tumors often fail to predict patient outcome or clinical course. particularly in nonadvanced disease. This problem of unpredictable tumor behavior has been one focus of cell proliferation studies. Such studies. however. have been limited by difficult methodology. A newer method of quantifying tumor cell proliferation using bromodeoxyuridine is applicable for head and neck squamous cell carcinomas. as shown in the present study. The relative ease with which cell proliferation can be evaluated using this technique will allow large numbers of head and neck tumors to be studied. enabling correlations with tumor behavior to be made.
Diving-related inner ear injuries, Diving-related inner ear barotrauma (IEB) and inner ear decompression sickness (IEDS) most often result in permanent severe cochleovestibular deficits. unless immediate diagnosis is reached and the correct treatment is commenced early. Nine cases of sport-diving-induced inner ear injuries that were referred to the Israeli Naval Hyperbaric Institute between October 1987 and September 1989 are presented with regard to evaluation. treatment. and follow-up. The diagnosis was IEB in five divers and IEDS in four. Explorative tympanotomy was carried out with remarkable results in two patients with IEB. while the remaining three were relieved by bed rest alone. Three of the four IEDS patients were recompressed according to the extended US Navy Table 6 with good short-term results. The role of complete otoneurological evaluation in the decision-making process leading to the correct diagnosis and treatment is emphasized.
The Glasgow Benefit Plot: a new method for reporting benefits from middle ear surgery, Conventionally. the results of middle ear surgery are reported in terms of postoperative closure of the air-bone gap or the improvement in air-conduction thresholds. While these are relevant in that they assess the technical success of the procedure and the lessening of monaural disability. they do not necessarily assess whether the patient has benefited. This is determined by many factors. not least of which is the hearing in the nonoperated ear. In this paper. we suggest that preoperative and postoperative plots of the air-conduction thresholds in both ears be used as an additional method of presenting the results. First. the proportion of patients that fall into each of three main preoperative impairment groups are identified. This is important. as the potential benefits from surgery are not the same in each group. Thereafter. the percentages of patients that achieve various postoperative hearing categories can be calculated. allowing surgeons to audit their results and make comparisons between series.
Three-dimensional computerized tomography in the evaluation of laryngeal injury, A comparison of diagnostic information obtained from the physical examination. conventional two-dimensional axial computerized tomography scanning (2-D CT). and three-dimensional display computerized tomography (3-D CT) was performed in five patients sustaining laryngeal trauma. Four patients had laryngeal fractures and one patient had an incompletely ossified thyroid cartilage (normal variant) simulating a fracture by 2-D CT. Three-dimensional display computerized tomography was found superior to conventional 2-D CT in assessing the presence and nature of the laryngeal injuries while correctly identifying the anatomic variant.
Reversible myeloneuropathy of nitrous oxide abuse: serial electrophysiological studies, Detailed electrophysiological studies were performed in 4 patients with myeloneuropathy induced by abuse of nitrous oxide for 1 to 4 years. All presented with paresthesias. weakness. and Lhermitte's phenomena. and exhibited signs of sensorimotor polyneuropathy. ataxia. and arreflexia. Two had subnormal serum vitamin B12 levels. Baseline electrophysiologic testing revealed reduced motor unit potentials. prolonged F wave latencies. absent H reflexes. denervation potentials. and delays in motor and sensory conduction. Three had peripheral and nuchal delay after median nerve stimulation. All were reevaluated after 3 to 12 months' abstinence and treatment with vitamin B12. and all showed substantial clinical improvement. Parallel improvement in electrophysiologic findings occurred. but residual minor conduction delays. loss of H reflexes. electromyographic evidence of denervation. or abnormalities of posterior tibial SEP were noted. These findings confirm the reversibility of myeloneuropathy of nitrous oxide abuse and describe the profile of electrophysiologic recovery in subjects who abstain from further neurotoxic exposure.
Diaphragmatic fatigue produced by constant or modulated electric currents, In anesthetized rabbits the efficiency of phrenic nerve stimulation with trains of electric current was studied either when ventilation was effected entirely by bilateral nerve stimulation (electrophrenic ventilation) or during unilateral nerve stimulation when animals were ventilated with a pump and open chest. Trains of rectangular electric pulses (RPT) with constant amplitude and frequency or sine waves. both the amplitude and frequency of which were modulated and controlled by a computer (MSWT). were used with each animal. MSWT closely reproduced the physiological shape of transdiaphragmatic pressure waves. Diaphragm fatigue. as determined from the decrease in the maximal relaxation rate of twitches. occurred after 20 minutes of bilateral or unilateral nerve stimulation with RPT. but only after 60 min (unilateral stimulation) or 98 min (bilateral stimulation) with MSWT. These data show the importance of the motor signal pattern in long-lasting nerve stimulation.
Nerve-muscle involvement in a large family with mitochondrial cytopathy: electrophysiological studies, Thirteen patients with mitochondrial cytopathy were investigated. They represent different generations. ages. stages. and severities of the disease. All were assumed to have the same metabolic defect. The disease is a multisystem disorder with a metabolic defect located at complex 1 in the respiratory chain. Clinically. the disorder gives symptoms such as hearing loss. retinal pigmental degeneration. ataxia. cardiomyopathy. muscular fatiguability and neuropathy. The patients were investigated with nerve conduction studies. concentric needle EMG. SFEMG. and macro EMG examinations. Neurophysiologic studies revealed signs of myopathy in both the younger members and in those with slight muscular symptoms. In the more advanced stages. neuropathic changes of the axonal type were seen as well. Macro EMG was interpreted as indicating muscle fiber membrane abnormalities in the early stages. Single fiber EMG studies indicate that this metabolic defect does not disturb neuromuscular transmission.
X-irradiation improves mdx mouse muscle as a model of myofiber loss in DMD, The mdx mouse. although a genetic and biochemical homologue of human Duchenne muscular dystrophy (DMD). presents a comparatively mild histopathological and clinical phenotype. These differences are partially attributable to the greater efficacy of regeneration in the mdx mouse than in DMD muscle. To lessen this disparity. we have used a single dose of X-irradiation (16 Gy) to inhibit regeneration in one leg of mdx mice. The result is an almost complete block of muscle fiber regeneration leading to progressive loss of muscle fibers and their replacement by loose connective tissue. Surviving fibers are mainly peripherally nucleated and. surprisingly. of large diameter. Thus. X-irradiation converts mdx muscle to a model system in which the degenerative process can be studied in isolation from the complicating effect of myofiber regeneration. This system should be of use for testing methods of alleviating the myofiber degeneration which is common to mdx and DMD.
Diagnostic and prognostic value of electrophysiologic tests in meralgia paresthetica, Electrophysiologic diagnosis of unilateral meralgia paresthetica is usually assessed by side-to-side comparison of SNAP amplitudes. SNCVs. and SEP latencies following stimulation of lateral femoral cutaneous nerves. To determine the relevance for diagnosis of these tests and side-to-side comparison. the results were compared in patients with unilateral meralgia paresthetica and normal subjects. The long-term outcome was also considered. in order to determine whether electrophysiologic findings contribute to the prognosis. In our study. SNAP amplitude comparison was found to be more useful for diagnosis than SNCV and SEP latency comparisons. However the value of the SNAP amplitude on the affected side. just as the results of the other tests. was not found to be predictive of the outcome. Also the results of the tests depend on the methods used and on the nerve's route.
Effects of short spaceflights on mechanical characteristics of rat muscles, The aim of this study was to investigate the contractile protein characteristics after 5-day (Cosmos 1514) and 7-day (Cosmos 1667) spaceflights. The experiments were performed on skinned fibers from the soleus. gastrocnemius lateralis. and plantaris muscles isolated from Wistar rats. A reduction in fiber diameter might explain the decrease in the maximal tension in the soleus. whereas this tension was unaltered in the gastrocnemius and the plantaris. Moreover the calcium sensitivity of the myofilament appeared modified in the soleus and in the gastrocnemius: The tension/pCa relationships were shifted toward higher calcium concentrations. indicating a decrease in the apparent calcium binding constant of the troponin C. The tension/pCa relationship appeared unaltered in the plantaris after spaceflight. Finally. the studies of the time to reach a steady tension indicated an increase in the rate of force development in the soleus and. on the contrary. a slowing down in the plantaris. No change in the gastrocnemius was found. The results were analyzed with references to the different muscle functions in disuse atrophy.
Raf-1 protein kinase is required for growth of induced NIH/3T3 cells, Many growth factors regulate the cytoplasmic Raf-1 protein kinase. consistent with its having a central role in transduction of growth signals. The kinase is ubiquitously expressed and can promote proliferation. presumably in a manner dependent on growth-factor receptors and membrane-associated oncogenes. We have now examined the dependence of serum- and TPA (12-O-tetradecanoylphorbol-13-acetate)-regulated NIH/3T3 cell growth on RAF-1 kinase to determine whether Raf-1 is essential for receptor signalling. We inhibited Raf-1 function by expressing c-raf-1 antisense RNA or kinase-defective c-raf-1 mutants. Antisense RNA for c-raf-1 interferes with proliferation of normal NIH/3T3 cells and reverts raf-transformed cells. In revertant cells. DNA replication induced by serum or TPA was eliminated or reduced proportionately to the reduction in Raf protein levels. Expression of a kinase-defective Raf-1 mutant (craf301) or a regulatory domain fragment (HCR) inhibited serum-induced NIH/3T3-cell proliferation and raf transformation even more efficiently. Inhibition by antisense RNA or craf301 blocked proliferation and transformation by Ki- and Ha-ras oncogenes. We conclude that raf functions as an essential signal transducer downstream of serum growth factor receptors. protein kinase C and ras.
Requirement for the replication protein SSB in human DNA excision repair, Replication and repair are essential processes that maintain the continuity of the genetic material. Dissection of simian virus 40 (SV40) DNA replication has resulted in the identification of many eukaryotic replication proteins. but the biochemistry of the multienzyme process of DNA excision repair is less well defined. One protein that is absolutely required for semiconservative replication of SV40 DNA in vitro is human single-stranded DNA-binding protein (SSB. also called RF-A and RP-A). SSB consists of three polypeptides of relative molecular mass 70.000. 34.000 and 13.000. and acts with T antigen and topoisomerases to unwind DNA. allowing the access of other replication proteins. Human SSB can also stimulate the activity of polymerases alpha and delta. suggesting a further role in elongation during DNA replication. We have now found a role for human SSB in DNA excision repair using a cell-free system that can carry out nucleotide excision repair in vitro. Monoclonal antibodies against human SSB caused extensive inhibition of DNA repair in plasmid molecules damaged by ultraviolet light or acetylaminofluorene. Addition of purified SSB reversed this inhibition and further stimulated repair synthesis by increasing the number of repair events. These results show that a mammalian DNA replication protein is also essential for repair.
HTLV-I-associated myelopathy associated with blood transfusion in the United States: epidemiologic and molecular evidence linking donor and recipient, Six months after receiving 58 units of blood components. a 65-year-old white man from New York City. with no other risk factors for human T-lymphotropic virus type I (HTLV-I) infection. developed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Investigation of blood donors identified a 25-year-old white Hispanic woman from Florida whose platelets had been given to the patient and who was seropositive for the virus on a serum specimen obtained 2 years after the donation. She was born in Cuba and had had 2 sexual relationships with men who either had been born in or had resided in the Caribbean. Polymerase chain reaction (PCR) studies of peripheral blood mononuclear cells indicated that both donor and recipient were infected with HTLV-I. Molecular studies of a 595-nucleotide sequence in the 5' envelope region of HTLV-I indicated that the viruses from donor and recipient were identical in each of 32 positions in which published HTLV-I sequences demonstrate molecular heterogeneity; the donor and recipient viruses were also identical in 2 additional positions in which they differed from all published sequences. Transfusion-associated HAM/TSP has occurred in the United States. but additional cases should be prevented by screening blood donations for HTLV-I. Molecular studies of HTLV-I may prove useful in defining the genetic heterogeneity of HTLV-I isolates in the United States and in studying transmission of this virus.
Unusual amyloid polyneuropathy with predominant lumbosacral nerve roots and plexus involvement, We report a 25-year-old patient with a progressive asymmetric peripheral neuropathy of the distal lower limbs. Imaging studies showed enlargement of lumbosacral roots. plexus. and proximal sciatic nerve. Sacral plexus biopsy revealed amyloidosis associated with endoneurial edema. Immunohistochemistry with anti-prealbumin. serum amyloid A. and immunoglobulin light chain antisera failed to label the amyloid.
Patient perception of tics and other movement disorders, To determine the subjective perception patients have of abnormal movements. 170 patients with various hyperkinesias were interviewed with questions directed at the "voluntary" or intentional versus "involuntary" aspects of their symptoms. One hundred and two of 110 patients with non-tic disorders thought that the abnormal movements were entirely involuntary. Forty-one of 60 tic disorder patients stated that all their motor and phonic tics were intentionally produced. Fifteen others had both voluntary and involuntary components. usually with the former predominating. A "voluntary" response could be used to predict the correct diagnostic category (tic versus non-tic) in 8 of 9 patients for whom the referral category was incorrect. These results suggest that a large proportion of the motor and phonic symptoms experienced by tic patients are irresistibly but purposefully executed. more akin to compulsions than to the other "involuntary" hyperkinesias with which they are commonly discussed.
Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study, To identify the symptoms and coexisting medical conditions associated with idiopathic intracranial hypertension (IIH). we administered an 83-item questionnaire at the time of diagnosis to 50 IIH patients and 100 aged-matched controls. Ninety percent of the IIH patients were women; the mean age was 33. Obesity and recent weight gain were much more common among patients than controls. Symptoms most commonly reported by IIH patients were headache (94%). transient visual obscurations (TVO) (68%). and intracranial noises (ICN) (58%). Daily occurrence of these symptoms was much more common among patients than controls. Controls also reported these and other IIH symptoms. but at lower frequencies. Several conditions previously associated with IIH were no more common in patients than controls including iron deficiency anemia. thyroid disease. pregnancy. antibiotic intake. and use of oral contraceptives. We conclude that previous studies of IIH. mostly uncontrolled and retrospective. have underestimated the frequency of symptoms in IIH patients and reported chance and spurious associations with common medical conditions and medications. The profile of a young obese woman with headaches and either TVO or ICN should alert the clinician to the diagnosis of IIH. especially when the symptoms occur daily.
Infarction in the anterior rostral cerebellum (the territory of the lateral branch of the superior cerebellar artery), We report 9 patients with an isolated infarct of the anterior part of the rostral cerebellum. ie. the territory of the lateral branch of the superior cerebellar artery. Clinicoanatomic correlations are based on CT. MRI. or both in 8 patients and on pathologic data in the ninth. The main clinical features were ipsilateral dysmetria and axial lateropulsion. dysarthria. and unsteadiness. In 1 patient. the clinical presentation mimicked a lacunar stroke (dysarthria and clumsy hand syndrome). There were no edematous cerebellar infarcts with signs of brainstem compression. and all patients spontaneously improved without significant sequellae. Angiography in 2 patients and pathologic examination of arteries in 1 patient disclosed no occlusion in the vertebrobasilar system. Six patients had a cardiac source of emboli. In conclusion. infarcts of the anterior part of the rostral cerebellum can be regarded as a benign condition in which there is. frequently. a cardiac source of emboli.
Detection of tuberous sclerosis in parents by magnetic resonance imaging, We performed a detailed physical examination and MRI without gadolinium DTPA contrast in 60 couples with at least 1 child having tuberous sclerosis (TS). Eight parents had TS diagnosed by physical examination. family history. or various diagnostic procedures including MRI. Eight additional subjects and 6 control subjects had nonspecific high-signal white matter changes on MRI. MRI confirmed the diagnosis of TS in only 1 parent without physical findings of the disease. similar to the results of earlier studies using computed cranial tomography. CT may be less sensitive than MRI but is probably more specific for TS. Either CT or MRI may occasionally help substantiate the diagnosis of TS in a parent with few other findings. Both studies may need to be done in some parents to maximize the accuracy of genetic counseling.
Comparison of functional and structural brain disturbances in Wilson's disease, We assessed the functional and structural brain disturbances in Wilson's disease (WD) by evoked potentials (EPs) and magnetic resonance imaging (MRI). All the 25 neurologically symptomatic and 44% of the 16 asymptomatic patients. assessed by both EPs (n = 48) and imaging (n = 41). had at least 1 abnormality of either prolonged EP conduction times. imaging-outlined presence of cerebral lesions. or brain atrophy. Our findings indicate that EPs and MRI are sensitive techniques for the evaluation of brain involvement in WD.
Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy, We examined variations in interictal spiking during sleep and wakefulness to assess differences in reliability for localizing epileptic foci. Forty patients were studied prospectively. Spikes were assessed for rates. field. and appearance of new foci. Final localization was determined by surgery. electrocorticography. and seizure onset. Comparison of interictal EEG foci with final localization was made. In 39 patients. slow-wave sleep activated spiking compared with wakefulness. Most patients showed maximal spiking in sleep stages 3 or 4. Restriction of field in rapid eye movement (REM) sleep and wakefulness. and extension of field in slow-wave sleep occurred. New foci appeared in non-rapid eye movement sleep in 53% of patients. Similar but not identical spiking rates. foci. and field distributions were seen in wakefulness and REM sleep. All REM foci were unilateral. Our findings suggest that localization of the primary epileptogenic area is more reliable in REM sleep than in wakefulness. and in wakefulness more than in slow-wave sleep.
A 21-aminosteroid inhibits stimulated monocyte hydrogen peroxide and chemiluminescence measurements from MS patients and controls, Monocytes are recruited to active sites of multiple sclerosis (MS) demyelination and may promote local tissue injury by generating an inflammatory response. mediated in part by the production of toxic oxygen metabolites. Corticosteroids are frequently and effectively used to ameliorate MS exacerbations. despite inadequate knowledge about the mechanism. We assessed the effects of a 21-aminosteroid. U74500A. a new class of steroid derivatives without glucocorticoid or mineralocorticoid effects. on the production of hydrogen peroxide (H2O2) and chemiluminescence by stimulated monocytes harvested from 8 stable MS patients and age- and sex-matched controls. H2O2 measurements and chemiluminescence were significantly reduced in both groups by U74500A. These results demonstrate that 21-aminosteroids reduce production of toxic oxygen metabolites by monocytes and thus their inflammatory potential. suggesting that these agents may be potentially effective and safe treatment for MS exacerbations.
The effect of flunarizine on essential tremor, We investigated the effect of flunarizine treatment (10 mg/d) in 17 subjects with essential tremor in a double-blind placebo-controlled design. Tremor was assessed by clinical scoring. tremographic recordings. and subjective rating by subjects. Of the 15 subjects who completed the study. 13 showed improvement. We conclude that flunarizine is effective treatment for essential tremor.
Phenytoin toxicity due to interaction with clobazam, The benzodiazepine antiepileptic drug clobazam can be added to existing AED treatment. usually without clinical toxicity. We report 3 patients in whom the addition of clobazam led within several weeks to clinically obvious phenytoin (PHT) intoxication in patients who had been taking maximum tolerable PHT doses. Symptoms and high PHT levels resolved with lowering the PHT dose. Clobazam and norclobazam levels were not elevated. This interaction is probably related to interference with hepatic degradation of PHT. Clinicians should be aware of possible PHT intoxication in patients starting clobazam.
Cerebral air embolism treated by pressure and hyperbaric oxygen, We used pressure and hyperbaric oxygen to treat 2 patients with cerebral air embolism. occurring as the result of invasive medical procedures. and neither suffered any permanent damage detectable by clinical examination and MRI. This outcome contrasts with reports of infarct and disability among untreated victims of air embolism.
A case of myelinoclastic diffuse sclerosis in an adult, We report a case of rapidly progressive cerebral demyelinating disease in a previously healthy 40-year-old woman. This case satisfies the diagnostic criteria for myelinoclastic diffuse sclerosis (MDS). but is unusual in the age of onset. This is the 1st case of MDS in an adult with full documentation of clinical. biochemical. radiographic. and pathologic features.
Nifedipine in the treatment of severe preeclampsia, We conducted a randomized clinical trial in which patients with severe preeclampsia between 26-36 weeks of gestation received either nifedipine (10-30 mg sublingually. then 40-120 mg/day orally; N = 24) or hydralazine (6.25-12.5 mg intravenously. then 80-120 mg/day orally; N = 25). Effective control of blood pressure was achieved with nifedipine in 95.8% of subjects and with hydralazine in 68%. a statistically significant difference (P less than .05). Maternal side effects were minor in both groups. Acute fetal distress developed in one nifedipine subject and in 11 treated with hydralazine. Mean prolongation of gestation was 15.5 +/- 10 days with nifedipine and 9.5 +/- 11 days with hydralazine. a difference that did not reach statistical significance (P less than .07). Infants born to women treated with nifedipine were delivered at more advanced gestational ages (34.6 +/- 2.3 versus 33.6 +/- 2.4 weeks; statistically not significant). weighed more (1826 +/- 456 versus 1580 +/- 499 g; statistically not significant). and tended to have fewer. mainly minor. complications. The average number of days spent in the neonatal intensive care unit was significantly lower in the nifedipine group (15.1 versus 32.7 days; P less than .005). leading to an average 31% reduction in total (maternal and neonatal) hospitalization-related charges for each nifedipine-treated pregnancy. We conclude that nifedipine is an effective. convenient. and low-cost treatment for patients with severe preeclampsia. and is not associated with undesirable side effects.
Etiologies of preterm birth in an indigent population: is prevention a logical expectation, To assess the expectations of preterm birth prevention. we determined the causes of preterm birth in a population of indigent women. We studied 13.119 singleton births in a predominantly black. indigent population occurring between November 1982 and April 1986 to identify the proportion of preterm births that may have been prevented using current treatment modalities. Forty-four percent of the preterm births occurred at 35 to 36 weeks' gestational age. a time when most practitioners do not attempt tocolysis. Of the remainder. 17% occurred before 35 weeks but were indicated for maternal medical or obstetric complications. and another 17% occurred before 35 weeks but followed spontaneous premature rupture of the membranes. Therefore. of the 1445 preterm births. we calculated that only 336 (23.2%) were theoretically preventable. A fourth of these presented at less than 3 cm cervical dilatation and were treated appropriately with tocolytics. but delivered anyway. Therefore. most of the potentially preventable births occurred in the group that presented with cervical dilatation of more than 3 cm. We conclude that improving the preterm birth rate significantly below current levels may be difficult to achieve.
Risk factors for shoulder dystocia: an engineering study of clinician-applied forces, We report on engineering risk factors associated with clinician-applied forces during vaginal delivery of newborns. Specifically. we present and interpret data from a series of experiments using force-sensing devices on 29 randomly selected vaginal births. including two shoulder dystocia deliveries and one birth injury. The results indicate that clinician-applied peak forces are typically about 47 N for routine deliveries. 69 N for difficult deliveries. and 100 N for a shoulder dystocia delivery (P less than .01). The time required to deliver fetal shoulders doubles for nonroutine deliveries (P less than .01). In addition. impulse and rate of application of force distinguish between routine and nonroutine deliveries (P less than .03). We conclude that. if properly perceived. force. force rate. and the duration of force are objective parameters that can be used in recognizing and managing shoulder dystocia and in predicting thresholds for birth injury.
Brain growth among fetuses exposed to cocaine in utero: asymmetrical growth retardation, Fetal growth retardation may be associated with maternal cocaine use during pregnancy. The pattern of fetal growth retardation was analyzed in infants born to 80 women who used cocaine. but not alcohol. during pregnancy. and in two comparison groups: 100 infants born to mothers who used neither alcohol nor cocaine during pregnancy and 67 infants whose mothers used alcohol but not cocaine during pregnancy. There were statistically significant differences in head size between the unexposed and cocaine-exposed infants (P less than .001). Notably. head circumference was reduced proportionately more than birth weight in cocaine-exposed infants. a pattern similar to that observed in alcohol-exposed infants. Alcohol- and cocaine-exposed infants were not statistically different in head circumference. We conclude that brain growth of cocaine-exposed infants is similar to that reported for alcohol-exposed infants. and that cocaine-exposed infants may be characterized as having asymmetrical growth retardation.
A cytogenetic study of spontaneous abortions with direct analysis of chorionic villi, The karyotypes of 144 spontaneous abortuses were determined using direct chromosome preparations from chorionic villi. The frequency of chromosome abnormality was 69.4%. which is considerably higher than figures cited in most previous cytogenetic surveys using the conventional method of cell culturing. Autosomal trisomy was the predominant abnormality (64%). followed by polyploidy (9%). monosomy X (7%). structural rearrangements (6%). mosaicism (6%). double trisomy (4%). and double chromosome anomaly (3%). Direct preparations have advantages in that results can be obtained rapidly. the success rate of karyotyping is satisfactory. and maternal-cell contamination is minimal.
Salpingoscopy: light microscopic and electron microscopic correlations [published erratum appears in Obstet Gynecol 1991 May;77(5):809-10, In order to examine the ability of salpingoscopy to diagnose intratubal pathology. 32 fallopian tubes were evaluated salpingoscopically and histologically. Both flexible and rigid salpingoscopes were used. and observations were documented by intratubal photography. Salpingoscopic criteria were established and each criterion assigned a numerical value. Each tube was evaluated for patency. mucosal fold architecture. erythema. adhesions. and dilatation. Based on these criteria. tubes were graded as normal or as abnormal with mild. moderate. or severe changes. Histologically. each tube was evaluated for patency. epithelial changes. vascularity. dilatation. adhesions. and active inflammation. Six tubes with significant histologic findings and two histologically normal fallopian tubes were also examined by transmission electron microscopy. In five discordant cases. histology revealed epithelial and stromal changes not detected by salpingoscopy. Fallopian tubes with severe disease were diagnosed by both methods. Transmission electron microscopy of histologically abnormal tubes showed flattening of the epithelium with markedly reduced ciliary distribution. degenerating secretory epithelial cells with large intracellular vacuoles. and swollen nuclei containing sparse chromatin. Our results indicate that salpingoscopic observations are consistent with histologic findings when endotubal disease is severe. However. moderate pathologic changes as documented by light microscopy and transmission electron microscopy were frequently not diagnosed salpingoscopically. even with magnification.
Serial endovaginal sonography of ectopic pregnancies treated with methotrexate, Methotrexate therapy is a newly established treatment modality for ectopic pregnancy. We performed this study to determine the time frame for resolution of the sonographically identifiable mass during such therapy and to determine the role of sonography in the management of these patients. Eighteen patients treated with methotrexate for laparoscopically proven ectopic pregnancy consented to long-term follow-up with endovaginal sonography. These 18 patients constitute the study group. The time required for sonographic resolution of the mass was variable. although poor patient compliance with sonographic follow-up affected the conclusions regarding resolution time. One hundred eight days was the longest period accurately known for resolution of a mass. In seven patients. the mass persisted after a negative hCG titer. Enlargement of the adnexal mass during therapy did not necessarily predict treatment failure. as only two of ten such patients required surgery for rupture. Serial sonography did not alter the management of most patients and appears not to be warranted on a routine basis. Follow-up sonography was most useful when complications were suspected. All patients considered for methotrexate therapy should first have an endovaginal sonogram. as cardiac activity remains a relative contraindication to this treatment. We have determined that the mass of an ectopic pregnancy may remain after the hCG is negative. Therefore. a persistent mass should not be interpreted as treatment failure.
Measures of sexual behavior and the risk of pelvic inflammatory disease, A women's sexual behavior affects her risk of acquiring pelvic inflammatory disease. but the risks have not been well characterized. To study the association between pelvic inflammatory disease and sexual behavior. we analyzed data from a multicenter. case-control study involving 712 women hospitalized with an initial episode of pelvic inflammatory disease and 2719 hospitalized control women without a history of pelvic inflammatory disease. Study participants provided information on their frequency of intercourse. number of recent sexual partners. and previous history of gonorrhea. Logistic regression methods were used to adjust for confounding factors. Women who reported having four or more sexual partners were over three times more likely to be hospitalized for pelvic inflammatory disease (relative risk 3.4; 95% confidence interval 2.2-5.3) than were women who reported only one recent sexual partner. To a lesser extent. frequent sexual intercourse and history of gonorrhea also increased a woman's risk of pelvic inflammatory disease. Frequent intercourse was a strong risk factor for pelvic inflammatory disease among a subgroup of women who were at low risk for acquiring a sexually transmitted disease: Married women with one recent sexual partner with intercourse six or more times per week had a risk of pelvic inflammatory disease of 3.2 (1.4-7.2) compared with similar women having intercourse less than once per week. Frequent intercourse. which does not by itself increase the risk of acquiring a sexually transmitted disease. may increase a woman's risk of pelvic inflammatory disease.
First- and second-trimester diagnosis of fetal ocular defects and associated anomalies: report of eight cases, Ocular cataract. hypertelorism. hypotelorism. anophthalmos. and microphthalmos are rare malformations commonly associated with other fetal anomalies. Previously. ocular malformations were detected only after mid-gestation. Transvaginal sonography allows the detection of many structural fetal anomalies. We describe the case reports of eight ocular anomalies among 1600 fetal screenings by transvaginal sonography at 12-18 weeks' gestation. Severe cataract was correctly diagnosed by transvaginal sonography. However. transvaginal sonography failed to detect moderate cataract in a case of repeat cataract in a subsequent gestation. Anophthalmia may sometimes be secondary to a degenerative process in middle and late pregnancy. In five of the eight described cases. the eye malformations were associated with defects of the central nervous system.
Simple standing incremental cystometry as a screening method for detrusor instability, One hundred consecutive neurologically normal women complaining of urinary incontinence underwent standing incremental retrograde medium-fill water cystometrograms on two different days followed by sitting and standing continuous retrograde medium-fill water urethrocystometry on a third visit between November 1987 and February 1989. Studies were done to assess the reproducibility. sensitivity. specificity. and predictive values of a simple cystometer. Standing incremental. retrograde cystometry was found to be relatively inexpensive. simple. reproducible. and sensitive. The two cystometrograms yielded similar results in 84% of the patients. The sensitivities were found to be 84.3 and 90.2% for the first and second cystometrograms. respectively. Using both cystometrograms together. we were able to detect detrusor instability with a sensitivity of 92.3% and to predict its absence with a negative predictive value of 86.7%. Detrusor instability was found in 64% of these patients. Based on these results. it was concluded that when multichannel urodynamics are not available in a high-prevalence population. standing retrograde incremental water cystometry done on two occasions may offer the physician an accurate alternative for the diagnosis of detrusor instability.
Vaginal birth after cesarean: a meta-analysis of morbidity and mortality, The cesarean birth rate has continued to climb despite efforts to counteract it. A major reason for this rise is the practice of elective repeat cesarean. We conducted a meta-analysis that included 31 studies with a total of 11.417 trials of labor to evaluate the association between birth route after a cesarean and morbidity and mortality for the mother and infant. Summary odds ratios were calculated. Maternal febrile morbidity was significantly lower after a trial of labor than after an elective repeat cesarean. The intended birth route made no difference in the rates of uterine dehiscence or rupture. The use of oxytocin. presence of a recurrent indication for the previous cesarean. and presence of an unknown uterine scar were also unassociated with dehiscence or rupture. After excluding antepartum deaths. fetuses weighing less than 750 g. and congenital anomalies incompatible with life. we found no difference in perinatal death rates. The proportion of 5-minute Apgar scores of 6 or lower was higher after a trial of labor. but we were unable to exclude very low birth weight fetuses or those with congenital anomalies from this analysis. Our findings argue for trials of labor for more women after a cesarean birth.
Full-thickness skin graft vaginoplasty for treatment of the stenotic or foreshortened vagina, Vaginal stenosis or foreshortening following surgery or radiation therapy can lead to dyspareunia. This report concerns the successful use of full-thickness skin grafts taken from the flank overlying the iliac crest to treat vaginal stenosis or foreshortening. The operation consists of incising the involved area and creating a space which will become the recipient site. An elliptical piece of full-thickness skin harvested from the area overlying the iliac crest is cleared of underlying fat. trimmed to fit the recipient site. and sutured in place. Vaginal packing is used to keep the graft against the recipient bed. Ten patients have been treated successfully with this technique. without significant complications or sequelae. Follow-up from 6 weeks to 42 months showed excellent postsurgical vaginal capacity in all patients. Similarly. excellent functional results were achieved in eight patients. with distinct improvement in the remaining two. This procedure is a useful addition to the gynecologic surgeon's armamentarium.
Introduction to limb-salvage surgery for sarcomas, This article provides a history of limb-salvage surgery and definitions of terms used to describe aspects of the procedure. Staging is also discussed.
Limb salvage in pediatric surgery. The use of the expandable prosthesis, Limb sparing in growing children has proved to be very effective from an oncologic perspective. with good. long-term acceptance by the patients. As in the adult. when performed by experienced surgeons. limb sparing neither compromises the survival rate nor significantly increases the local recurrence rate. compared with cross-bone amputation. Discussions include patient evaluation. surgical options. materials and methods. and results.
Resection and reconstruction for bone tumors in the proximal tibia, The proximal tibia is a common site for both benign and malignant tumors. This article reviews pertinent anatomy. clinical presentation. and staging methods for tumors of this area. Discussion is given to various methods of resection and reconstruction with useful guidelines for procedure selection. The use of allografts for reconstruction is discussed in depth.
Endoprosthetic reconstruction after bone tumor resections of the proximal tibia, The advent of successful adjuvant chemotherapy and radiation therapy protocols for primary malignant tumors and the development of custom-designed metallic endoprostheses has now made possible a successful limb salvage procedure for malignancies of the proximal tibia. Use of the transposed medial gastrocnemius flap. as proposed by Dr. Jean Duboussett of Paris. has been critical to the soft-tissue reconstruction that routinely permits an excellent active and passive range of motion for these patients. This article describes the operative techniques and technical considerations necessary for a successful proximal tibial endoprosthesis reconstruction.
Resection and reconstruction for soft-tissue sarcomas of the extremity, Soft-tissue sarcomas are uncommon malignant tumors. and when a diagnosis is made early. the patient has up to an 80% chance of surviving. In treating soft-tissue sarcomas. the goal of the surgeon is the prolongation of patient survival. the total eradication of local disease. and the minimization of functional deficits. In addition to treatment. this article discusses evaluation. histology. and staging.
Allograft reconstructions of the shoulder after bone tumor resections, Large skeletal defects resulting from tumor resections about the shoulder create reconstructive challenges for the orthopedic surgeon. Bone allografts offer several advantages compared with other reconstructive techniques. and functional outcomes are generally satisfactory. They may be used either as osteoarticular grafts. intercalated segments to create an arthrodesis. or in combination with standard proximal humerus metallic implants. Patient expectations and specific oncologic factors must be considered when selecting the optimal method of reconstruction.
Resections and reconstructions for tumors of the distal radius, The primary objective in surgical management of the patient with a distal radius tumor is control of the disease. Accurate staging and diagnostic methods applied preoperatively will predict not only the amount of resection necessary to obtain adequate tumor margins. but also the amount of remaining bone and soft tissues to assist reconstruction. With this information. a method of reconstruction can be chosen that provides the patient optimal long-term function and stability with predictable results and the fewest potential complications.
Tumors of the shoulder girdle. Technique of resection and description of a surgical classification, Limb-sparing surgery is safe and reliable for most bone and soft-tissue tumors of the shoulder girdle. Eighty to ninety percent of patients with high-grade sarcomas of the shoulder can be safely treated by the various surgical techniques described. Attention must be paid to appropriate patient selection. preoperative staging. and planning. In addition. careful skeletal and muscular reconstruction of the surgical defect is necessary for a successful outcome. A new. universal. classification schemata (types I-VI) of shoulder girdle resections has been developed. This classification system is based on the bones resected. the status of the abductor mechanism. and the relationship to the glenohumeral joint. This system permits easy description and comparison of the various limb-sparing procedures performed.
Recombinant fusion protein identified by lepromatous sera mimics native Mycobacterium leprae in T-cell responses across the leprosy spectrum, Pooled polyvalent sera from lepromatous leprosy patients were used to screen a lambda gt11 recombinant DNA expression library of Mycobacterium leprae in order to identify the relevant antigens recognized by the human immune response. Of the 300.000 phages screened. 4 clones were identified that coded for fusion proteins of the same molecular mass. The fusion protein from clone LSR2 was tested for immunoreactivity in assays using peripheral blood cells and sera from 11 laboratory personnel and 105 patients across the leprosy spectrum. LSR2 protein appears to be predominantly a T-cell antigen. It evokes similar lymphoproliferative responses as the native bacillus both at the individual level and in the leprosy spectrum as a whole. Though only 50% of patient sera with anti-M. leprae antibodies reacted with the fusion protein. the pattern of reactivity in the antibody responses was also similar for the various clinical types. The coding regions of clones LSR1 and LSR2 are identical. They show no homology with sequences stored in data banks and encode a protein of 89 amino acids with a calculated molecular mass of approximately 10 kDa.
Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse, Retinal degeneration slow (rds) is a retinal disorder of an inbred strain of mice in which the outer segment of the photoreceptor cell fails to develop. A candidate gene has recently been described for the rds defect [Travis. G. H.. Brennan. M. B.. Danielson. P. E.. Kozak. C. & Sutcliffe. J. G. (1989) Nature (London) 338. 70-73]. Neither the identity of the normal gene product nor its intracellular localization had been determined. We report here that the amino acid sequence of the bovine photoreceptor-cell protein peripherin. which was previously localized to the rim region of the photoreceptor disk membrane. is 92.5% identical to the sequence of the mouse protein encoded by the normal rds gene. The differences between the two sequences can be attributed to species variation. Monoclonal antibodies were used with Western blot analysis to localize the wild-type mouse peripherin/rds protein to isolated mouse rod outer segments and to show that it. like bovine peripherin. exists as two subunits linked by one or more disulfide bonds. The relative amounts of peripherin/rds protein and rhodopsin in retinal extracts of normal and rds mutant mice were also compared. Identification of peripherin as the protein encoded by the normal rds gene and its localization to membranes of rod outer segments will serve as a basis for studies directed toward defining the role of this protein in the morphogenesis and maintenance of the outer segment and toward understanding the mechanism by which the rds mutation causes retinal degeneration.
GTPase-activating protein interactions with the viral and cellular Src kinases, GTPase-activating protein (GAP). which regulates the activities of Ras proteins. is implicated in mitogenic signal transduction by growth-factor receptors and oncoproteins with tyrosine kinase activity. Oncogenic viral Src (p60v-src) encoded in Rous sarcoma virus possesses elevated tyrosine kinase activity compared with its nononcogenic normal homolog. cellular Src (p60c-src). To examine molecular interactions between GAP and the two Src kinases. immunoprecipitates of Src or GAP prepared from cell lystates were resolved by gel electrophoresis and analyzed by an immunoblot procedure with antibodies to GAP or Src used as probes. Results suggest that p60c-src is associated with a complex containing GAP in immunoprecipitates from lysates of normal rat and chicken cells. However. GAP is not phosphorylated in p60c-src immunoprecipitates subjected to in vitro kinase reactions. By contrast. GAP undergoes tyrosyl phosphorylation in vitro when immunoprecipitates of p60v-src prepared from transformed cell lysates are incubated with ATP. Our findings suggest that p60v-src and p60c-src associate with complexes containing GAP and provide a biochemical link between both kinases and GAP/Ras signal transduction pathways. These results are consistent with the hypothesis that GAP has a role in mediating normal functions of p60c-src as well as oncogenic activities of p60v-src.
Molecular basis of the activation of the tumorigenic potential of Gag-insulin receptor chimeras, A previous study showed that the human insulin receptor (IR) could be activated by insertion of a 3' portion of the cDNA encoding the beta subunit into a retrovirus genome to form a Gag-IR fusion protein. While capable of transforming cells in culture. this IR cDNA-containing virus. called UIR. was not able to induce tumors in animals. Subsequently. we isolated a spontaneous sarcomagenic variant called UIR19t from the parental UIR. UIR19t was molecularly cloned. sequenced. and found to harbor two mutations. A 44-amino acid deletion immediately upstream from the transmembrane domain of the Gag-IR fusion protein removes all the extracellular sequence of the IR remaining in the original UIR construct. In addition. a single nucleotide deletion at the 3' end results in truncation and replacement of the carboxyl-terminal 12 amino acids by 4 new amino acids. The specific kinase activity of UIR19t is 4- to 5-fold higher than that of the parental UIR. However. no new cellular substrates were detected in UIR19t-transformed cells as compared to UIR cells. Viruses containing either the 5' or the 3' deletion mutation were constructed and assessed for their biological function. Our data indicate that the 5' deletion alone is sufficient to confer tumorigenic ability. We conclude that sequence immediately upstream from the transmembrane domain imposes a negative effect on the transforming and tumorigenic potential of the Gag-IR fusion protein.
cDNA cloning and sequencing of human fibrillarin, a conserved nucleolar protein recognized by autoimmune antisera, We have isolated a 1.1-kilobase cDNA clone that encodes human fibrillarin by screening a hepatoma library in parallel with DNA probes derived from the fibrillarin genes of Saccharomyces cerevisiae (NOP1) and Xenopus laevis. RNA blot analysis indicates that the corresponding mRNA is approximately 1300 nucleotides in length. Human fibrillarin expressed in vitro migrates on SDS gels as a 36-kDa protein that is specifically immunoprecipitated by antisera from humans with scleroderma autoimmune disease. Human fibrillarin contains an amino-terminal repetitive domain approximately 75-80 amino acids in length that is rich in glycine and arginine residues and is similar to amino-terminal domains in the yeast and Xenopus fibrillarins. The occurrence of a putative RNA-binding domain and an RNP consensus sequence within the protein is consistent with the association of fibrillarin with small nucleolar RNAs. Protein sequence alignments show that 67% of amino acids from human fibrillarin are identical to those in yeast fibrillarin and that 81% are identical to those in Xenopus fibrillarin. This identity suggests the evolutionary conservation of an important function early in the pathway for ribosome biosynthesis.
The transcriptional transactivator of human foamy virus maps to the bel 1 genomic region, The human foamy virus (HFV) genome possesses three open reading frames (bel 1. 2. and 3) located between env and the 3' long terminal repeat. By analogy to other human retroviruses this region was selected as the most likely candidate to encode the viral transactivator. Results presented here confirmed this and showed further that a deletion introduced only into the bel 1 open reading frame of a plasmid derived from an infectious molecular clone of HFV abolished transactivation. In contrast. deletions in bel 2 and bel 3 had only minor effects on the ability to transactivate. The role of the bel 1 genomic region as a transactivator was further investigated by eukaryotic expression of a genome fragment of HFV spanning the bel 1 open reading frame. A construct expressing bel 1 under control of a heterologous promoter was found to transactivate the HFV long terminal repeat in a dose-dependent fashion. Furthermore. it is shown that the U3 region of the HFV long terminal repeat is sufficient to respond to the HFV transactivator.
Free radical-derived quinone methide mediates skin tumor promotion by butylated hydroxytoluene hydroperoxide: expanded role for electrophiles in multistage carcinogenesis, Free radical derivatives of peroxides. hydroperoxides. and anthrones are thought to mediate tumor promotion by these compounds. Further. the promoting activity of phorbol esters is attributed. in part. to their ability to stimulate the cellular generation of oxygen radicals. A hydroperoxide metabolite of butylated hydroxytoluene. 2.6-di-tert-butyl-4-hydroperoxyl-4-methyl-2.5-cyclohexadienone (BHTOOH). has previously been shown to be a tumor promoter in mouse skin. BHTOOH is extensively metabolized by murine keratinocytes to several radical species. The primary radical generated from BHTOOH is a phenoxyl radical that can disproportionate to form butylated hydroxytoluene quinone methide. a reactive electrophile. Since electrophilic species have not been previously postulated to mediate tumor promotion. the present study was undertaken to examine the role of this electrophile in the promoting activity of BHTOOH. The biological activities of two chemical analogs of BHTOOH. 4-trideuteromethyl-BHTOOH and 4-tert-butyl-BHTOOH. were compared with that of the parent compound. 4-Trideuteromethyl-BHTOOH and 4-tert-butyl-BHTOOH have a reduced ability or inability. respectively. to form a quinone methide; however. like the parent compound. they both generate a phenoxyl radical when incubated with keratinocyte cytosol. The potency of BHTOOH. 4-trideuteromethyl-BHTOOH. and 4-tert-butyl-BHTOOH as inducers of ornithine decarboxylase. a marker of tumor promotion. was commensurate with their capacity for generating butylated hydroxytoluene quinone methide. These initial results were confirmed in a two-stage tumor promotion protocol in female SENCAR mice. Together. these data indicate that a quinone methide is mediating tumor promotion by BHTOOH. providing direct evidence that an electrophilic intermediate can elicit this stage of carcinogenesis.
Transgenic mice susceptible to poliovirus, Poliovirus-sensitive transgenic mice were produced by introducing the human gene encoding cellular receptors for poliovirus into the mouse genome. Expression of the receptor mRNAs in tissues of the transgenic mice was analyzed by using RNA blot hybridization and the polymerase chain reaction. The human gene is expressed in many tissues of the transgenic mice just as in tissues of humans. The transgenic mice are susceptible to all three poliovirus serotypes. and the mice inoculated with poliovirus show clinical symptoms similar to those observed in humans and monkeys. Rabbit antipoliovirus serum detects the antigens mainly in motor neurons in the anterior horn of the spinal cord and in nerve cells in the medulla oblongata and pons of the paralyzed transgenic mice. Therefore. cell types sensitive to poliovirus in the central nervous system of the transgenic mice appear to be identical to those of humans and monkeys. Furthermore. many more doses of oral poliovirus vaccine strains than of the virulent strains are required to cause paralysis in the transgenic mice. This may reflect the observation that the virulent strain multiplies more efficiently in the central nervous system than the attenuated strain. Thus. the transgenic mice may become an excellent new animal model to study molecular mechanisms of pathogenesis of poliovirus and to assess oral poliovirus vaccines.
Peptide-induced antiviral protection by cytotoxic T cells, A specific antiviral cytotoxic immune response in vivo could be induced by the subcutaneous injection of the T-cell epitope of the lymphocytic choriomeningitis virus (LCMV) nucleoprotein as an unmodified free synthetic peptide (Arg-Pro-Gln-Ala-Ser-Gly-Val-Tyr-Met-Gly-Asn-Leu-Thr-Ala-Gln) emulsified in incomplete Freund's adjuvant. This immunization rendered mice into a LCMV-specific protective state as shown by the inhibition of LCMV replication in spleens of such mice. The protection level of these mice correlated with the ability to respond to the peptide challenge by CD8+ virus-specific cytotoxic T cells. This is a direct demonstration that peptide vaccines can be antivirally protective in vivo. thus encouraging further search for appropriate mixtures of stable peptides that may be used as T-cell vaccines.
Inability of malaria vaccine to induce antibodies to a protective epitope within its sequence, Saimiri monkeys immunized with a recombinant protein containing 20 copies of the nine amino acid repeat of the Plasmodium vivax circumsporozoite (CS) protein developed high concentrations of antibodies to the repeat sequence and to sporozoites. but were not protected against challenge. After intravenous injection of an immunoglobulin G3 monoclonal antibody (NVS3) against irradiated P. vivax sporozoites. four of six monkeys were protected against sporozoite-induced malaria. and the remaining two animals took significantly longer to become parasitemic. Epitope mapping demonstrated that NVS3 recognizes only four (AGDR) of the nine amino acids within the repeat region of the P. vivax CS protein. The monkeys immunized with (DRAADGQPAG)20 did not produce antibodies to the protective epitope AGDR. Thus. determination of the fine specificity of protective immune responses may be critical to the construction of successful subunit vaccines.
Ability of the c-mos product to associate with and phosphorylate tubulin, The mos proto-oncogene product. pp39mos. is a protein kinase and has been equated with cytostatic factor (CSF). an activity in unfertilized eggs that is thought to be responsible for the arrest of meiosis at metaphase II. The biochemical properties and potential substrates of pp39mos were examined in unfertilized eggs and in transformed cells in order to study how the protein functions both as CSF and in transformation. The pp39mos protein associated with polymers under conditions that favor tubulin oligomerization and was present in an approximately 500-kilodalton "core" complex under conditions that favor depolymerization. beta-Tubulin was preferentially coprecipitated in pp39mos immunoprecipitates and was the major phosphorylated product in a pp39mos-dependent immune complex kinase assay. Immunofluorescence analysis of NIH 3T3 cells transformed with Xenopus c-mos showed that pp39mos colocalizes with tubulin in the spindle during metaphase and in the midbody and asters during telophase. Disruption of microtubules with nocodazole affected tubulin and pp39mos organization in the same way. It therefore appears that pp39mos is a tubulin-associated protein kinase and may thus participate in the modification of microtubules and contribute to the formation of the spindle. This activity expressed during interphase in somatic cells may be responsible for the transforming activity of pp39mos.
Cauda equina anatomy. I: Intrathecal nerve root organization, The three-dimensional organization of the human cauda equina has not been described previously. This is partly due to the difficulties of dissecting individual. unfixed nerve roots. By the use of a newly developed in situ fixation and embedding technique on 15 fresh human cadavers. the cross-sectional anatomy of the cauda equina was defined from L2-L3 to L5-S1. A highly consistent cross-sectional pattern was observed in all specimens. The lower sacral (S2-S5) and coccygeal roots were located in the dorsal aspect of the thecal sac. whereas the lumbar and first sacral roots exhibited an oblique. layered pattern as they ascended. The motor bundle was situated anteromedial to its respective sensory bundle within each layer. Invaginations of arachnoid held the nerve roots in a fixed relationship to one another. This previously undescribed three-dimensional anatomy within the thecal sac may aid in the understanding and treatment of trauma. neurocompressive syndromes. and tumors of the cauda equina.
1990 AcroMed Award in basic science. Cauda equina anatomy. II: Extrathecal nerve roots and dorsal root ganglia, Inconsistent data exist regarding the anatomy of the spinal nerve roots lateral to the thecal sac. A newly developed in situ technique was used to precisely define anatomic parameters on 20 fresh human cadavers. The take-off angle of the nerve roots from the thecal sac decreases from a mean of approximately 40 degrees from L1-L5 to 22 degrees at S1. The motor bundles are directly ventral to the sensory fibers within individual roots extrathecally. Dorsal root ganglia size varies with vertebral level. The majority of ganglia lie directly beneath the vertebral pedicles and one third overlie a portion of the lateral intervertebral disc. These previously undescribed relationships may aid in the understanding of lumbosacral neurocompressive disorders and are important to note during pedicle screw insertion. posterolateral decompression for spinal trauma. and paravertebral approaches for lateral disc herniations.
Stimulation of dorsal root ganglia and degradation of rabbit annulus fibrosus, The authors sought to determine whether narrowing of the intervertebral neural foramen. by itself and in association with vibration. would stimulate the mechanosensitive dorsal root ganglia and result in degradation of proteoglycan and collagen of the annulus fibrosus. as proposed in their working model of dorsal root ganglia-neuropeptide-mediated degeneration of the spinal motion segment. Degradation of proteoglycan and collagen of rabbit annulus was observed when there was narrowing of the neural foremen and the degradation process was accelerated by vibration. Vibration alone. in the absence of structural abnormalities of the spinal motion segment. did not induce matrix degradation probably because of a less pronounced stimulation of the dorsal root ganglia. Biological events similar to those postulated here. fomented by a combination of structural abnormalities and environmental factors. could be involved in human disc degeneration.
Coexistence of cervical and lumbar disc disease, A retrospective analysis of 200 patients requiring cervical disc surgery was performed to determine the frequency of coexistent lumbar disc or spine abnormalities. The duration of follow-up ranged from 5 to 25 years. averaging 14 years. Sixty percent were women and 40% were men. their ages ranging from 25-73 years. Antecedent motor vehicle injury had occurred in 49 cases and work injury to the spine in 23. Sixty-four percent had no history of prior back injury. It was found that over 31% had undergone lumbar disc surgery. and a high number of patients demonstrated abnormal lumbar radiographs or myelograms. including 78 with bulging discs. 100 with major root defects. 78 with minor root defects. 8 with spinal stenosis. and 7 with spondylolisthesis. Myelograms were normal in 22 cases. The sites of lumbar abnormalities included L4-5 (110). L5-S1 (90). and multilevel (8). There was a higher incidence of lumbar disc abnormalities associated with multilevel cervical spondylosis. There also was a relationship between residual symptoms and myelographic abnormalities. Two studies in the authors' institution suggest an autoimmune basis for the frequent coexistence of cervical and lumbar disc disease. namely the demonstration of antigenic properties in the nucleus pulposus and high serum immunoglobulins.
Nighttime bracing for adolescent idiopathic scoliosis with the Charleston bending brace. Preliminary report, The authors report their preliminary experience with the Charleston bending brace for the treatment of adolescent idiopathic scoliosis. This brace holds the patient in the position of maximum side bend correction and is worn only at night. Patients in this prospective multicentered study met all the following criteria: skeletal immaturity (Risser 0. 1+. or 2+). curvature greater than 25 degrees before bracing. no prior treatment. and greater than 1-year follow-up since initiation of treatment. There were 191 structural curves in the 139 patients. One hundred fifteen patients (83%) showed improvement or less than 5 degree change in curvature. Twenty-four patients (17%) demonstrated an increase in curvature greater than 5 degrees. Based on these preliminary results. continued use of bending brace treatment at nighttime only is justified for adolescent idiopathic scoliosis. Patients with double curves should be observed closely for increase in compensatory curves.
Analysis of sagittal plane instability of the lumbar spine in vivo, Segmental instability secondary to degenerative disc disease may result in chronic low-back pain. In the sagittal plane. segmental instability can be characterized during lumbar motion from full extension to full flexion. The authors studied this movement using a translational method for the kinematic analysis. implementing a new concept known as the instability factor. Both translational and angular components of motion are evaluated. By computing the incremental motion parameters at different stages of spinal bending. the total amount of translation and angulation is obtained and combined in a ratio termed the instability factor. This factor increases with linear instability and decreases with rotational instability. The authors reviewed 12 control subjects and 36 patients with chronic low-back pain. The diagnoses of patients were categorized into three groups: idiopathic low-back pain. lumbar disc prolapse. and degenerative disc disease. Lateral radiographs of each subject's spine at the L4-5 level were obtained using low dose radiography and were performed serially as the subjects moved from full extension to full flexion. It was found that the group of patients with degenerative disc disease had an average age-corrected instability factor of 37.3 (mm/radian). which was significantly larger than that of normal subjects 25.5 (mm/radian). (P = 0.0065). No significant difference was seen in the instability factor of patients with idiopathic low-back pain or lumbar disc prolapse.
Secondary prevention of low-back pain. A clinical trial, A clinical trial. aimed at secondary prevention of low-back pain. was performed in 142 hospital employees reporting at least three annual episodes of this condition. Participants were randomly assigned to one of three groups: a calisthenics program (CAL) for 3 months with biweekly sessions of flexion exercises. a back school program (5 sessions). and a control group. The effectiveness of the two intervention programs was evaluated over a 1-year period. Baseline preintervention data and evaluation at the end of 3 months of intervention and after an additional 6 months were collected. A monthly surveillance for the whole year showed a mean of 4.5 "painful months" in the CAL group versus 7.3 and 7.4 months in the back school and control groups. respectively (P less than 0.0001). The superiority of the CAL group was achieved partly because of the significant increase in trunk forward flexion and to initial increment in abdominal muscle strength. The increased trunk flexion was associated with the rate of participation in the CAL sessions. Further research is needed to answer the question of "intensity versus type of exercise" by comparing different intervention programs. with similar intensity.
A prospective study of patients with sciatica. A comparison between conservatively treated patients and patients who have undergone operation, Part I: Patient characteristics and differences between groups, Based on a prospective study on 342 sciatica patients examined with rhizography. the aim was to determine which factors others than the rhizography finding and the grade and duration of symptoms were related to the selection of patients to undergo operation. Compared with surgically treated patients. conservatively treated patients who did not undergo operation and who had pathologic rhizography findings had pessimistic attitudes to possible surgery. often expressed a desire to retire. and considered their work as physically stressful. The women in this group were older and had lower pain indices than women who underwent operation. Conservatively treated patients with negative rhizography had more severe occupational handicaps. minor expectations of possible surgery. physically more strenuous jobs requiring difficult physical positions. and lower indices for pain and ADL than did the operated patients. The social and ergonomic background problems are emphasized in sciatica patients conservatively treated after rhizography.
A prospective study of patients with sciatica. A comparison between conservatively treated patients and patients who have undergone operation, Part II: Results after one year follow-up, The prospective study included 122 sciatica patients who had not undergone operation (NOPs) and 220 sciatica patients who had undergone operation (OPs); all had been examined by rhizography. The follow-up study was done on 110 (90%) of the NOPs and 212 (96%) of the OPs. The NOPs were divided into two groups: 30 patients with pathologic rhizography (PR) and 80 patients with negative rhizography (NR). Pain-. ADL-. and occupation-handicap indices showed that after the 1 year follow-up the OP group had the best result and the NR group the lowest result. The PR group had nearly as good a result as the OP group. Thus. sciatica patients are candidates for conservative therapy. even though they have pathologic findings in rhizography. if the symptoms are mild. To improve therapeutic outcome. more accurate diagnostic tools are needed to develop specific therapy especially for those sciatica patients with negative rhizography.
Lumbar isthmic spondylolisthesis in children and adolescents. Radiologic evaluation and results of operative treatment, A clinical and radiologic follow-up study of a group of 75 children and adolescents. comprised of both boys and girls. who underwent spondylodesis for spondylolisthesis between the years 1979 and 1984 is reported. Sagittal rotation. lumbosacral joint angle. lumbar lordosis. wedging of olisthetic vertebrae. and the rounding of the upper sacrum showed considerable statistical correlation to the amount of slipping and accordingly should be noted when estimating the risk of progression of the spondylolisthesis. When the spondylolisthesis was accompanied by scoliosis. it was noted that seriousness of the former was closely correlated to that of the latter. Most patients profited by the operation. and solid fusion was achieved in almost all cases. The posterolateral spondylolysis performed using graft from the iliac crest. the interbody fusion technique. or their combination turned out to be the most reliable surgical methods. The combined technique was especially required in cases with a high degree of slipping.
Knodt rod distraction instrumentation in lumbosacral arthrodesis, Review of 40 patients undergoing lumbosacral fusions over a 4-year period was done to determine the value. efficiency. and safety of Knodt rod distraction instrumentation. The age range was 30-80 years. Mean age was 51 years. Follow-up was 1-4 years. Twenty patients underwent decompression and fusion for spinal stenosis. nine underwent spinal arthrodesis for instability. six underwent the same for spondylolisthesis. and five underwent fusions for other diagnoses. A posterior midline approach was used. Laminal hook sites were prepared. and care was taken to prevent dural compression or tenting. Balanced distraction was done to restore soft tissue tension and stability. No attempt was made to reduce deformity. A posterior and lateral mass fusion augmented with allograft bone was performed on all but three patients. in whom autogenous bone was used. The majority of patients were placed in a custom-molded lumbosacral orthosis for 3-6 months after operation. There were no neurologic complications. dural tears. or pseudomeningoceles. The first sacral laminas were instrumented in 22 patients. Nine of the 40 patients underwent rod removal. Reasons for removal were pain due to loosening in five patients and failure of fusion in two. On rod removal in two patients. no abnormality was found. Insertion within the sacral laminas did not lead to neurologic complications. The major problem appeared to be loosening. which necessitated rod removal in 12% of the patients. Knodt rod distraction instrumentation is a safe and effective method of internal fixation for lumbosacral fusions.
Survival after groin dissection for malignant melanoma, Groin dissection was performed in 158 patients with malignant melanoma (superficial dissection. 76 patients; radical dissection. 82 patients). Of 63 patients with palpable nodes. 57 patients (90%) had histologic involvement. Of 93 patients with nonpalpable nodes. 31 patients (33%) had histologically positive nodes. The 5-year survival rate for patients with histologically negative nodes (n = 69) was 77%; the 5-year survival rate for patients with histologically positive nodes (n = 89) was 43%. The respective 5-year disease-free survival rates were 72% and 34%. Of 57 patients with palpable. positive inguinal nodes. 21 patients (37%) had involvement of the deep nodes. Of 31 patients with nonpalpable. histologic involvement of the inguinal nodes. six patients (19%) had or developed involvement of the deep nodes. One of two patients with uncertain clinical status of the nodes preoperatively had positive deep nodes. In prophylactic node dissection. frozen section of the inguinal group of the nodes does not provide a reliable method. because of sampling errors. in determining microscopic involvement of the nodes and in deciding whether a superficial or radical groin dissection is to be done. For patients with positive nodes the 5-year survival rate was 48% when only the inguinal group was involved and was 28% when both inguinal and deep nodes were involved; the respective 5-year disease-free survival rates were 39% and 20%. Survival after therapeutic groin dissection may partly depend on the thoroughness of the procedure. Patients who have positive. deep nodes and who are undergoing an incontinuity dissection of the inguinal. iliac. and obturator nodes have an appreciable 5-year survival rate.
The role of resection in the management of melanoma metastatic to the adrenal gland, Melanoma metastatic to the adrenal gland diagnosed before death was exceedingly rare before the development of computed tomographic (CT) scanning. The records of 28 patients with melanoma metastatic to the adrenal gland seen since 1975 were reviewed. Eighteen patients were men and 10 were women. Twenty-three patients had unilateral disease. Four patients were diagnosed only at autopsy. leaving 24 for analysis of treatment and survival. Twenty-one patients had received specific active immunotherapy. four had received chemotherapy (dacarbazine. lomustin. bleomycin. and vincristine). and three had received both before the diagnosis of their adrenal disease. Adrenal metastases were diagnosed by CT scanning in 14 patients with symptoms. 10 (91%) of whom had pain. Ten patients were diagnosed by CT before entry into a chemotherapy protocol. Of eight patients who underwent resection of all known disease. five underwent unilateral adrenalectomy. two underwent unilateral adrenalectomy and bowel resection. and one underwent bilateral adrenalectomy. Two patients underwent partial resection of large unilateral tumors. Fourteen patients with adrenal metastases and disease elsewhere were initiated or continued with chemotherapy or were treated symptomatically. Mean survival in the group that underwent resection for cure was 59 months (3 to 112 months). whereas survival in the group with unresectable tumors was 15 months (1.5 to 132 months). Four of eight patients who underwent resection for cure lived more than 5 years after detection of adrenal metastasis. whereas in only one of 14 patients with unresectable tumors was the same true. Patients with metastatic melanoma localized to one or both adrenal glands may benefit from early detection and surgical intervention.
Evaluation of preoperative computed tomography in gastric malignancy, Ninety patients with gastric malignancy underwent computed tomography (CT) before surgery. The CT findings regarding neoplastic invasion of adjacent organs and metastasis or enlarged lymph nodes were compared with the findings at laparotomy (85 cases) or autopsy (5 cases). thus permitting evaluation of the diagnostic accuracy of CT and its usefulness for predicting resectability. When present. neoplastic invasion of adjacent organs was overestimated or underestimated by CT in 21 cases. Invasion of adjacent organs according to CT was false positive in 17 cases and false negative in 11 cases. When liver metastasis or enlarged regional or distant lymph nodes were present. CT overestimated or underestimated their extent in 17 cases. and the diagnosis was false positive in one case and false negative in 33 cases. The positive and negative predictive values of CT concerning resectability of the tumor were 81% and 64%. respectively. Routine preoperative CT in gastric malignancy is concluded to be of limited value and surgical exploration. when feasible. remains the method of choice.
Abdominal aneurysms in childhood: report of a case and review of the literature, Abdominal aneurysms are rare in children and are usually found in association with congenital cardiac or aortic malformations. connective tissue disorders. trauma. or previous arterial catheter placement. A 4-year-old girl who had a common iliac artery aneurysm. who had no history of arterial catheter placement or trauma. and who had no evidence of Marfan's or Ehlers-Danlos syndrome. arteritis. coarctation of the aorta. or other diseases associated with childhood aneurysms is presented. Resection of the aneurysm and arterial reconstruction were performed without the use of prosthetic material or vein graft. Pathologic examination showed no evidence of inflammation or medial degeneration in any of the layers of the arterial wall. This is the fourth report found in the literature of documented idiopathic abdominal aneurysm in a child. The conditions associated with abdominal aneurysms in childhood are discussed. and the literature is reviewed.
Evidence for role of prostacyclin as a systemic hormone in portal hypertension, The possibility that prostacyclin could be a systemic hormone and could mediate the splanchnic hyperemia of chronic portal hypertension was evaluated in rabbits in a normotensive state and in rabbits with chronic partial ligation of the portal vein. In rabbits with portal hypertension (PHT). 6-keto-prostaglandin F1 alpha (PGF1 alpha. a prostacyclin degradation product) was elevated twofold in all vascular beds (systemic arterial. systemic venous. and portal venous) when compared with levels in control animals. In PHT rabbits. exogenous prostacyclin infusion after cyclooxygenase blockade through the systemic arterial. systemic venous. or portal venous route resulted in an equal elevation of 6-keto-PGF1 alpha in the reciprocal vascular beds and restored the original precyclooxygenase blockade hemodynamics. These hemodynamic changes were of equal magnitude irrespective of site of infusion in PHT. In controls there was no significant change in 6-keto-PGF1 alpha or hemodynamics with intraportal infusion. We conclude that prostacyclin achieves systemic levels by escaping hepatic degradation resulting from portosystemic shunting in the animal with chronic portal hypertension.
A preliminary study of dye-enhanced laser photosclerosis, Laser ablation of veins after injection of wavelength-specific dyes to enhance and localize energy absorption could provide a useful adjunct to current treatment options. To enhance the absorption of diode laser energy at 808 nm. ear veins of 41 rabbits were infused with 2 to 3 ml of indocyanine green dye (maximum absorption. 805 nm) and exposed for 2 to 20 seconds. Animals were killed between 0 and 28 days after operation. Discrete time intervals of laser exposure exist during which various-sized vessels can be ablated without significant thermal injury to the overlying tissue. Small vessels (0.2 mm in diameter) blanch after 2 to 3 seconds of exposure. whereas medium-sized vessels (2 mm in diameter) require 8 to 10 seconds. Vessels can be ablated with a power density as low as 11.1 W/cm2. Specimens taken immediately after laser exposure show vessel wall thinning and a reirradiation effect. created as laser energy initially absorbed by dye is reemitted. By the seventh day after operation. a brisk inflammatory response and acanthosis of the overlying epidermal layer develop. The lumen is partially filled by thrombus with cellular invasion. By postoperative day 28. the epidermal thickening and inflammatory reaction have resolved; the vessel walls are fibrotic. The use of low-power. air-cooled diode lasers. in conjunction with wavelength-specific dyes. may provide a simple. viable. and cosmetically appealing alternative to the treatment of superficial varicosities of the extremities.
Effect of 3-hydroxybutyrate on posttraumatic metabolism in man, Of 20 patients suffering trauma. with Injury Severity Scores greater than 20. 11 patients received DL-3-hydroxybutyrate (3-OHB) at a rate of 25 mumol/kg/min for 3 hours. The remaining nine patients received sodium DL-lactate at the same rate as the control subjects. With increased arterial concentrations of ketone bodies. the femoral arteriovenous difference (arterial concentration minus venous concentration) of ketone bodies increased proportionally in the 3-OHB group (R = 0.853. p less than 0.001). Venous concentrations of nonesterified free fatty acids. alanine. glycine. and valine were decreased significantly in the 3-OHB group as compared to the control group. The concentration difference between femoral vein and artery (venous concentration minus arterial concentration) for these substrates also decreased. indicating decreased release from the extremity. A decrease in venous concentration of alanine and difference between femoral vein and artery reached 102.3 +/- 69.3 mumol/L and 32.6 +/- 22.8 mumol/L (mean +/- SD). respectively. after 3-OHB infusion. Decreased alanine release from muscle during 3-OHB infusion in traumatized patients suggests a suppressive effect of ketone body on posttraumatic protein catabolism.
Use of a composite skin graft composed of cultured human keratinocytes and fibroblasts and a collagen-GAG matrix to cover full-thickness wounds on athymic mice, In patients with extensive full-thickness burns. wound coverage may be accelerated if skin can be expanded to produce a skin replacement that reproducibly supplies blood to the wound and has good structural qualities. In addition. development of skin replacements may benefit patients who require reconstruction or replacement of large areas of abnormal skin. We have developed a composite skin replacement composed of cultured human keratinocytes (HK) and fibroblasts. Cultured human fibroblasts are seeded into the interstices. and cultured HKs are applied to the surface of a matrix composed of type I collagen crosslinked with a glycosaminoglycan. which has a defined physical structure. After HKs reach confluence on the matrix surface. the composite grafts are placed on full-thickness wounds on the dorsum of athymic mice. Graft acceptance. confirmed by positive staining with antibodies specific for human HLA-ABC antigens on HKs. is approximately 90%. A defined skin structure is present histologically by day 10 after grafting. with a differentiated epithelium and a subepidermal layer densely populated by fibroblasts and capillaries without evidence of inflammation. Fluorescent light microscopy to identify laminin and type IV collagen and electron microscopy confirm the presence of basement membrane components by 10 days after grafting. Attachment of the graft to the wound is similar with and without the addition of human basic fibroblast growth factor. a potent angiogenic agent. to the skin replacement before graft placement on wounds.
A hepatoblastoma originating in the caudate lobe radically resected with the inferior vena cava, Complete resection of a rare hepatoblastoma in the caudate lobe. involving the inferior vena cava (IVC). is reported. After systemic chemotherapy. a 5-year-old child underwent exploratory laparotomy at another hospital. but resection was not attempted because the tumor in the caudate lobe had extensively invaded the retrohepatic IVC. However. because not only the lack of distant metastases but also the establishment of extrahepatic collaterals were confirmed by imaging. we thought it was possible to radically resect the tumor. We successfully performed an extended left hepatic lobectomy including total excision of the caudate lobe and the involved portion of the IVC. Although we did not reconstruct the IVC. no clinical manifestations arising from caval congestion were seen. The serum alpha-fetoprotein value declined below the normal limit. Our experience with this case has introduced a radical resectability for hepatic malignancy in the caudate lobe. even if it has extended into the IVC.
Treatment of solitary arteriovenous fistulas, Four patients with a solitary arteriovenous fistula were treated by transvascular balloon embolization technique. which resulted in complete fistula closure in three patients and partial closure in one. There were two vertebral arteriovenous fistulas. one peroneal arteriovenous fistula. and one radial arteriovenous fistula. The first two fistulas were spontaneous. the other two were traumatic. The only partial occlusion of the peroneal fistula was. in our opinion. due to a technical failure. the balloon was inflated slightly proximal to the fistular orificium instead of in the orificium itself. There were no complications. and there was no morbidity. In our opinion transvascular balloon embolization technique is the treatment of choice for solitary arteriovenous fistulas.
Relation between respiratory symptoms, type of farming, and lung function disorders in farmers, Respiratory symptoms and function were examined in a random sample of 181 farmers (124 pig farmers and 57 dairy farmers) with a mean age of 43 years. Wheezing and shortness of breath during work in the animal house were significantly associated with pig farming (odds ratio 11.4). current smoking (odds ratio 2.2). bronchial hyperreactivity (odds ratio 3.8). and low FEV1 (odds ratio 3.4). Pig farmers had a slightly lower FEV1 than dairy farmers (101% versus 104% predicted. NS). Symptomatic farmers had significantly lower FEV1 than symptomless farmers (93% versus 106% predicted). A multiple linear regression analysis of the cross sectional values of FEV1 showed that there was a decline in FEV1 associated with pig farming (-12 ml/year of pig farming) and smoking (-23 ml/pack year) in addition to the age related decline of 32 ml/year. A multiple linear regression analysis of PC20 histamine showed that bronchial reactivity increased with age. number of pack years. and number of years in pig farming. Work in closed pig rearing units is a pulmonary health hazard and causes decline in lung function.
Modified muscle sparing posterolateral thoracotomy, A modified posterolateral thoracotomy is described that combines the advantages of complete muscle sparing through a thoracolumbar fascial slide with excellent exposure. The technique is easy to perform. The procedure was associated with relatively little postoperative pain. coughing was effective. and early ambulation was achieved. Experience with this approach in the first 49 patients suggests that it offers an attractive alternative to the standard muscle cutting posterolateral thoracotomy approach for elective procedures.
Inhaled micronised gentamicin powder: a new delivery system, Forty patients undergoing routine bronchoscopy were randomised to receive inhaled micronised gentamicin powder (180 mg) or nebulised gentamicin solution (160 mg) one hour before the procedure. Similar levels of gentamicin were detected in bronchoalveolar lavage fluid in the two groups (micronised powder (n = 20) 9.3 (SD 9.3) mg/l. nebulised solution (n = 20) 8.0 (7.8) mg/l). The micronised gentamicin powder preparation caused cough in half the patients but this did not stop their receiving a full dose. Dry powder gentamicin may be a convenient formulation for long term inhaled treatment if the problem of cough can be overcome.
Use of cyproterone acetate in prostate cancer, Cyproterone acetate is a progestational antiandrogen with potent antigonadotropic activity that results in rapid suppression of serum testosterone. Used as a single agent. cyproterone acetate yields a total androgen blockade. It may be combined with low-dose diethylstilbestrol. orchiectomy. or LHRH agonists to improve. in theory. the results of such therapy. In clinical testing. cyproterone acetate has proved equivalent to diethylstilbestrol with markedly less toxicity. It is useful in conjunction with LHRH agonists. either transiently to block the flare phenomenon. or continuously to block peripheral androgen receptors; the necessity for this latter action has not yet been proved. Cyproterone acetate may afford transient objective improvement in patients not responding to other forms of hormone deprivation. Experience in this role is limited. The drug may be used to suppress the hot flushes associated with orchiectomy or LHRH agonist therapy. Cyproterone acetate induces local tumor regression; owing to its reversible effects. it is useful as neoadjuvant or adjuvant androgen withdrawal therapy in patients with lower-stage disease undergoing radical surgery or radiotherapy. Adverse effects are mostly those related to hormone withdrawal. namely. impotence. infertility. and lassitude. Gynecomastia and breast tenderness occur in less than 18% and cardiovascular complications in approximately 10% of treated men.
Use of suramin in treatment of prostatic carcinoma refractory to conventional hormonal manipulation, Suramin and related compounds. in view of their growth factor and enzyme binding properties. represent in many respects a novel approach to the treatment of cancer. Although in this preliminary analysis of suramin use in the treatment of metastatic prostate cancer. the objective response rate does not appear impressive. much work still needs to be done to optimize suramin's administration to patients and to elucidate its various postulated mechanisms of action. The development of related compounds with more specific enzyme and growth factor antagonist properties is under way.
Advanced prostatic carcinoma. Early versus late endocrine therapy, Since the landmark observations of Huggins and Hodges in 1941. androgen deprivation has been the mainstay of treatment for advanced-stage prostate cancer. Although early. poorly controlled studies suggested enhanced survival with hormonal therapy. this view fell into disfavor as a result of the observations of the first and second VACURG studies. Recently. there has been a proliferation of experimental and clinical data supporting early androgen deprivation. including a reanalysis of the VACURG data. which suggests a survival advantage for younger patients with stage D disease and high-grade tumors who undergo androgen-ablative therapy at the time of diagnosis. The risk-benefit analysis presented in this review is strongly supportive of early hormonal therapy. Finally. long-term survival of patients with metastatic prostate cancer will require the development of novel treatment strategies effective against androgen-resistant tumor cells and their use in concert with early androgen deprivation.
Partial and total penectomy for cancer, Squamous carcinoma of the penis remains an uncommon tumor in the United States. In the properly selected patient. partial or total penectomy performed with an understanding of the salient surgical anatomy results in adequate local control of these cancers with excellent functional and cosmetic results.
Future developments of nonhormonal systemic therapy for prostatic carcinoma, Prostate cancer is the most common type of cancer in men. Despite increased public awareness and new screening methods. a significant proportion of men continue to present with metastatic disease. Most men will respond initially to hormonal intervention; however. given time. the majority will have recurrences of hormonally unresponsive tumor on which present therapies have little impact. Research continues to identify new cellular and molecular aspects of prostate cancer with implications as possible sites of therapeutic intervention.
Total androgen ablation: Canadian experience, A multicenter randomized. double-blind trial comparing total androgen blockade obtained by the use of castration with a pure anti-androgen (nilutamide) with simple castration was begun. One hundred and five patients received the combined treatment and 103 the orchiectomy plus placebo. Several features were used to evaluate the efficacy. Bone pain responded better to combined treatment at 6 months (P = 0.042). The number of favorable responses. as evaluated by the NPCP criteria. was 61% with simple castration and 78% with the combined treatment (P = 0.013). There was no statistically significant difference between the two groups in time to progression (logrank test P = 0.462) or survival (logrank test P = 0.137) despite an increase in median survival of 5.4 months. All other measures showed no difference between the two treatments. With total androgen blockade. 50% of the patients had disease progression at 1 year. and 45% were dead at 2 years. A review of the results of similar reported studies suggests no improvement or very modest improvement with total androgen blockade over testicular androgen ablation alone.
Megestrol acetate plus low-dose estrogen in the management of advanced prostatic carcinoma, Megestrol acetate plus low-dose estrogen may be an effective. low-cost alternative to pharmacologic or surgical castration plus flutamide in the management of patients with advanced prostate cancer. The potential benefit of combined androgen ablation achieved by any means in comparison with conventional hormonal therapy appears to be limited.
Role of 5 alpha-reductase inhibitors in the treatment of advanced prostatic carcinoma, Everything we know about the biology of the prostate supports the concept that DHT is the obligate androgen responsible for normal and hyperplastic growth. Whether this selectivity is maintained during malignant transformation is unknown. The consistent emergence of androgen-insensitive disease highlights the spectrum of biologic evolution this cancer is capable of. If the tumor is dependent only on DHT for neoplastic growth. the unique characteristics of a 5 alpha-reductase inhibitor offer several potential actions that warrant a systematic evaluation.
Use of the nonsteroidal anti-androgen Casodex in advanced prostatic carcinoma, Pure anti-androgens have advantages over steroidal anti-androgens of the cyproterone acetate type in the treatment of patients with advanced prostate cancer because they do not have steroidal side effects or such a marked inhibitory effect on libido. In addition. the long half-life of a pure anti-androgen such as Casodex results in maintenance of high serum anti-androgen concentrations. which allays concern over the clinical significance of any small rise in serum testosterone concentrations. The anti-androgen of choice for the treatment of androgen-responsive diseases has yet to be defined. However. this choice should be based on extensive clinical evaluations of a drug as monotherapy. As always. the clinical efficacy and tolerability of the drug will be important factors in determining the anti-androgen of choice; however. favorable pharmacokinetics should be emphasized in the treatment of a disease in which high and sustained concentrations of antagonist must be present to prevent androgenic stimulation. Casodex. a pure anti-androgen with a relatively long half-life. produces objective and subjective responses similar to those of surgical or pharmacologic castration and is well tolerated. Its profile makes it a strong candidate for consideration as the future anti-androgen of choice in the treatment of advanced prostate cancer.
Use of standard contraceptive diaphragm in management of stress urinary incontinence, The management of stress urinary incontinence (SUI) consists of either surgical intervention and/or pharmacologic manipulation. Twelve patients with SUI were evaluated for management by the use of a fitted standard contraceptive diaphragm. Complete resolution of SUI was achieved in 11 of 12 patients (91%). Two of the 12 patients achieved continence but withdrew from the study because of associated discomfort from the diaphragm. therefore. complete resolution of SUI was achieved in 9 of 12 patients (75%).
Multilocular cysts of kidney. A study of 29 patients and review of literature, Multilocular renal cyst is a distinct renal tumor whose gross external appearance and absence of normal renal tissue within the septa of loculi distinguish it clearly from other renal cystic lesions. Interlocular septa may contain either (1) fibrous tissue alone or (2) embryonic tissue separating adjacent loculi. Of 29 patients with multilocular renal cysts. 24 underwent a renal-sparing procedure. and only 5 had radical nephrectomy. None of the histologic specimens showed evidence of immature renal tissue or neoplasia. Patients were followed from three months to eight years (mean. 39 months). and no evidence of local recurrence or metastatic disease was found. Because it is difficult to distinguish multilocular renal cyst from cystic Wilms tumor and multicystic clear cell carcinoma on the basis of imaging studies alone. surgical intervention is the only effective method to differentiate multilocular renal cyst from a malignant lesion of the kidney.
Mobile epididymis. A new clinicopathologic entity in genesis of male infertility and its treatment by epididymopexy, Mobile epididymis plays an important role in the genesis of male infertility. It constituted 9 percent of a consecutive series of idiopathic infertility. Of 200 patients examined (100 fertile and 100 infertile). mobile epididymis was detected in 9 infertile patients. The clinical picture is characteristic. Epididymis is widely separated from testicle and moves freely from side to side. Its body and tail are ill formed and the epididymovasal angle is obtuse. Azoospermia was persistent in 3 patients and intermittent in 6 patients. Testicular biopsy showed tubular dilatation. Epididymopexy was performed in the 9 patients to fix the epididymis to testicle: 3 patients showed improvement in semen quality with two resultant pregnancies. Failures were due to advanced testicular damage. Infertility in mobile epididymis appears to result from obstruction of efferent ductules. testicular ischemia. and/or interference with sperm maturation. transport. or delivery.
Simple urodynamic evaluation of incontinent elderly female nursing home patients. A descriptive analysis, We present a descriptive analysis of the functional. mental. and urodynamic status of a population of incontinent elderly female nursing home patients. One hundred fifty-five intermediate care female patients with a mean age of 85.5 years were identified as being incontinent of urine at least once daily. After urologic evaluation. each patient was classified into one of four categories: incontinence with normal cystometrogram 68 (44%). detrusor instability (DI) 52 (34%). stress incontinence (SI) 27 (17%). or overflow incontinence (OI) 7 (4%). Thirteen weeks later. patients were again studied using simple water cystometry. At follow-up evaluation. 45 patients (33%) had urodynamic findings which differed from the initial evaluation. Of these women. 10 with DI. 12 with SI. and 2 with OI were found to have normal cystometric parameters at the time of follow-up study. while 19 (14%) who initially had normal cystometric findings had evidence of DI (11) or SI (3). Strong correlation between urinary incontinence in patients with normal cystometric findings and moderate to severe cognitive impairment was present. Simple urodynamic evaluation did identify patients with SI and OI who might benefit from specific therapy. Urodynamic evaluation of incontinent elderly female nursing home patients is indicated and may provide direction for planning treatment strategies.
Pharmacokinetics and metabolism of nilutamide, Data are available on the pharmacokinetics and metabolism of nilutamide in the rat. dog. and human (normal volunteers and patients with advanced prostatic carcinoma). Studies using 14Carbon-nilutamide. radioimmunoassay. and high-performance liquid chromatography (HPLC) are reviewed. In the rat. bioavailability by the oral route was complete. The majority of the plasma radioactivity was unchanged nilutamide up to six hours. t1/2 was seven hours. and clearance was 150 mL/hour/kg body weight. Metabolism studies identified 6 urinary metabolites. The major metabolites result from reduction of the nitro group initially to an hydroxylamine (17%) and then to a primary amino (26%) group. In normal volunteers the compound was rapidly absorbed. displayed linear kinetics over a dose range of 100-300 mg. and declined slowly in plasma with a terminal phase t1/2 of forty-three to forty-nine hours. In studies in 12 patients with advanced (Stage D) prostatic carcinoma. single-dose kinetics after 14C-nilutamide and kinetics with repetitive twice-daily dosing of two to seven weeks were measured. Terminal phase plasma t1/2 of unchanged nilutamide was 56 +/- 19 hours and of total radioactivity 87 +/- 27 hours (mean +/- SD). Area under the curve of plasma radioactivity was 23 to 38 percent unchanged nilutamide. Urinary excretion of radioactivity was slow and incomplete because the collection time was not long enough in regard to t1/2 (mean after 5 days. 62 +/- 10%) and consisted almost entirely of metabolites. Steady-state plasma levels of nilutamide were reached in about two weeks. It can be concluded that in humans. unlike other species. plasma decay of nilutamide is very slow. Elimination is almost exclusively by metabolism. Single-daily dosing is appropriate. Hepatic impairment could be expected to prolong plasma decay; renal impairment is likely to have little effect.
Castration plus nilutamide vs castration plus placebo in advanced prostate cancer. A review, Combination of antiandrogen treatment with surgical or medical castration should improve the efficacy of endocrine treatment of prostatic cancer by blocking the effects of adrenal androgens. A nonsteroidal antiandrogen. nilutamide. has shown promising results in preliminary open studies. In a short-term (29 days) comparison of nilutamide plus buserelin and buserelin plus placebo. nilutamide (300 mg/day). significantly reduced bone pain. and fewer patients experienced worsening pain than in the control group. The initial buserelin-induced increase in prostatic acid phosphatase was prevented by nilutamide. but there was a similar increase in testosterone and gonadotropin concentrations to that seen in the control group. Thus. nilutamide can prevent the tumor flare-up associated with the start of luteinizing hormone-releasing hormone (LH-RH) treatment. even though the endocrine responses are not affected. In three multicenter. randomized. double-blind placebo-controlled trials of castration and nilutamide involving 248 patients. the combination of nilutamide and castration decreased bone pain. improved performance status. and increased the number of patients with objective regression. compared with patients who were castrated but did not receive nilutamide. Nilutamide was generally well tolerated. though visual disorders. gastrointestinal disorders. and alcohol intolerance were reported in patients receiving nilutamide. The results suggest that nilutamide improves the efficacy of castration in patients with prostatic cancer. Current studies are investigating the effects of this treatment on survival and the risk-benefit ratio.
Pharmacology of antiandrogens and value of combining androgen suppression with antiandrogen therapy, Antiandrogens are compounds able to block the effect of androgens directly on their target cells by inhibiting their binding to the androgen receptor (AR). Two chemical classes of antiandrogens are presently on the market or in clinical trials: steroids (cyproterone. megestrol acetates). and nonsteroids (flutamide. nilutamide). Steroid antiandrogens interact not only with AR but also with progestin and glucocorticoid receptors and thus give rise to progestin and glucocorticoid effects. By contrast. nonsteroid antiandrogens interact only with AR and are thus devoid of other hormonal or antihormonal activities. Nilutamide does not need to be transformed into an active metabolite. unlike flutamide. and interacts with dog. rat. and human prostate AR in vitro. Its kinetics lead to a prolonged interaction with AR in vivo after administration to rats. In prostate cancer treatment. it is necessary to combine an antiandrogen to surgical or chemical (estrogens. LH-RH agonists) castration to obtain a complete suppression of androgens. The antiandrogen will block specifically. at the target site. the trophic effect of adrenal androgens left intact by castration. and the secretion of which can only be suppressed by treatments (adrenalectomy. aminoglutethimide. ketoconazole) that also suppress corticoid synthesis. We have shown that nilutamide counteracts the trophic effect. on the prostate of castrated rats. of adrenal androgens administered continuously (minipumps) at circulating levels similar to those recorded in castrated men. Nilutamide will also impede the flare-up effect of the testosterone increase induced by LH-RH agonists at the beginning of treatment. We have shown in the rat treated with buserelin that the increase in prostate weight observed during the initial days of treatment by the LH-RH agonist can be inhibited by a combined treatment with nilutamide. This combined treatment "nilutamide plus castration" has been tested in an experimental androgen-dependent cancer model. the Shionogi tumor. The administration of nilutamide to mice. castrated twenty-four hours before the inoculation of tumor cells. delayed the appearance of tumors and reduced their number. Finally. the absence of androgen effect and the antiandrogen activity of the product were also demonstrated in human tumor cells in culture (T-47 D cells) transfected with the MMTV androgen-dependent promoter coupled with the CAT reporter gene.
Primary hepatic carcinoid tumor. An electron microscopic and immunohistochemical study, A case of primary carcinoid tumor of the liver with striking morphologic and electron microscopic features is reported. Conventional histologic examination showed a prominent paranuclear clear zone in numerous tumor cells. By electron microscopic examination. this clear zone corresponded to a paranuclear mass of intermediate filaments admixed with neurosecretory granules and other cytoplasmic organelles.
Munchausen syndrome by proxy documented by discrepant blood typing, The authors describe a case of Munchausen syndrome by proxy. a form of child abuse. documented by use of routine blood bank serologic procedures. While immunohematologic testing has been used in the legal arena to resolve issues of disputed paternity and to investigate instances of criminal acts. the authors believe this to be the first documented application to this clinical disorder.
Antisperm antibody detection using concurrent cytofluorometry and indirect immunofluorescence microscopy, Anti-sperm antibodies from serum and seminal plasma were detected by concurrent flow cytometry and epifluorescence microscopy using fluorescein-conjugated antihuman immunoglobulins. Experimental conditions were designed. taking advantage of several monoclonal antisperm antibodies. to test aspects of the assay before clinical application. Perturbation of membrane integrity altered both the localization of binding and the number of sperm cells positive for bound antibodies. In specimens from selected infertility patients. 21.6% of the females and 40.8% of the males had significant levels of antisperm antibodies. Differences in the incidence of isoimmunity between female partners of antibody-positive or antibody-negative males and differences in the localization of antigens targeted by serum versus seminal plasma antibodies in men support the idea that. in some cases. immunity to sperm cells may be the result of altered sperm antigens.
Accuracy of portable blood glucose monitoring. Effect of glucose level and prandial state, Glucose was determined on capillary and venous blood samples from 274 adult diabetics by three different methodologies: the Glucoscan 2000 and Accu-Check II portable glucose meters (capillary) and the Kodak Ektachem 700 analyzer (venous). Both glucose meters correlated significantly with the Ektachem results. A significant positive bias was found for the Glucoscan compared with Ektachem. not found with the Accu-Check II. The Accu-Check performed better than the Glucoscan at venous plasma glucose levels less than 1 g/L. The mean error of Glucoscan determinations was significantly greater and biased positive when the measurement was performed within 4 hours of eating. whereas no such effect was seen with Accu-Check error. Multiple regression analysis revealed that the Glucoscan measurement was independently influenced by both venous plasma glucose and prandial state. whereas the Accu-Check II measurement was not dependent on either variable. The within-run precision for both glucose meters were comparable.
Prediction of free phenytoin levels based on [total phenytoin]/[albumin] ratios. Potential errors with hypoalbuminemia, Therapeutic monitoring of the pharmacologically active (free drug) fraction of protein-bound medications (e.g.. phenytoin) represents a major diagnostic challenge in clinical and laboratory medicine. While free drug levels may be beneficial in many clinical situations. current methods for predicting free phenytoin concentrations are unreliable and not recommended for general use. The authors have demonstrated a linear relationship (r2 = 0.98) between serum levels of total and bound phenytoin in 56 patients with seizure disorders. No significant correlations were observed when total phenytoin and albumin levels were compared independently to measured concentrations of free phenytoin or percent free phenytoin. A good correlation (r2 = 0.89) existed between free phenytoin levels and [total phenytoin]/[albumin] ratios in patients with normal or elevated albumin levels. but significantly weaker correlations were found in patients with hypoalbuminemia. Thus. [total phenytoin]/[albumin] ratios may have clinical value in predicting free phenytoin levels in uncomplicated patients without hypoalbuminemia.
The analysis of erythrocyte morphologic characteristics in urine using a hematologic flow cytometer and microscopic methods, Three methods for the examination of erythrocyte morphology in urine are described: phase contrast microscopy. microscopy of cytocentrifuged and stained preparations. and erythrocyte analysis with the Technicon H1. Analysis with the H1 has not been described until now. All methods can be used to discriminate between dysmorphic and isomorphic erythrocytes. The red cell distribution width was the best H1 parameter for this discrimination. The authors have found a good correlation between the microscopic methods. The clinical impact of the three methods was studied with urine samples from patients with a confirmed diagnosis. The discrimination between renal and nonrenal hematuria is similar with phase contrast microscopy and cytocentrifuged preparations. The use of the H1 for this discrimination is not recommended.
Secretin provocation test in the diagnosis of Zollinger-Ellison syndrome, The secretin stimulation test has become the preferred provocative test in suspected cases of Zollinger-Ellison syndrome. A pure secretin preparation. a gastrin-specific radioimmunoassay. and an appropriate sampling sequence are important for the proper interpretation of this test. Gastric acid analysis is necessary in the assessment of hypergastrinemia to confirm acid hypersecretion and exclude achlorhydria. When properly performed and interpreted. the secretin provocation test offers a safe. expeditious. and reliable means of evaluating patients with hypergastrinemia.
Nonpropulsive esophageal contractions and gastroesophageal reflux, Nonpropulsive esophageal contractions radiologically described as tertiary contractions or "corkscrew" esophagus suggest the presence of an underlying motility disorder and may lead to impaired acid clearance. The goals of this study were to determine the prevalence and role of gastroesophageal reflux (GER) in patients with tertiary contractions. Thirty-five consecutive patients with spontaneous. repetitive. nonpropulsive esophageal contractions noted on esophagography were studied with endoscopy. infusion esophageal manometry. and 24-h ambulatory pH monitoring. All patients had esophageal symptoms. mainly dysphagia. heartburn. and chest pain. but only three were found to have esophagitis by endoscopy and biopsy. Nineteen patients had repetitive. nonlumen-obliterating. nonperistaltic (tertiary) contractions. six had corkscrew esophagus. and 10 had forceful. lumen-obliterating simultaneous contractions (rosary bead esophagus). Twenty patients (58%) had GER by pH criteria with mean values: % time pH less than 4. 40.9; %upright pH less than 4. 41; %supine pH less than 4. 44.3%; number of episodes with greater than 5 min of pH less than 4. 12. Esophageal motility revealed "nutcracker" esophagus in eight. low LESP in two. and nonspecific esophageal motility disorder in 10. Symptoms or severity of nonperistaltic contractions did not correlate with GER. Radiologically demonstrable free reflux or the presence of heartburn did not predict GER. We conclude that 1) GER occurs in up to 58% of patients with nonpropulsive (tertiary) esophageal contractions on esophagography. and may play a role in the induction of abnormal peristaltic activity of the esophageal body; 2) GER is usually not associated with endoscopic evidence of esophagitis or characteristic symptoms. and is recognized by 24-h pH monitoring. We speculate that detection and treatment of GER may improve the symptomatic management of patients with nonpropulsive esophageal contractions.
The symptom sensitivity index: a valuable additional parameter in 24-hour esophageal pH recording, Twenty-four-hour esophageal pH monitoring is useful for the quantitative measurement of gastroesophageal reflux and for the demonstration of a temporal relationship between symptoms and reflux. The symptom index. a numerical score. was developed to quantify the association between symptoms and reflux. Because the symptom index primarily assesses the specificity of a patient's reflux symptoms. we propose to refer to this score as the symptom specificity index. Because of certain limitations of this score. we developed and evaluated a new score. the symptom sensitivity index. that quantifies the subject's sensitivity for reflux. Fifty-two consecutive patients. referred to our laboratory for ambulatory 24-h pH recording were studied. Beside the conventional reflux variables. both indexes were calculated. Although a statistically significant correlation between the indexes was found. discordance between the specificity and sensitivity indexes was seen in 17 patients (33%). Based on the findings in this study we advocate that the symptom sensitivity index should be used. in addition to the symptom specificity index. and incorporated in future pH studies to optimalize the interpretation of the results.
Small bowel enteroscopy and intraoperative enteroscopy for obscure gastrointestinal bleeding, Intraoperative endoscopy (IOE) is accepted as the ultimate diagnostic procedure for completely evaluating the small bowel in patients with obscure gastrointestinal (GI) bleeding. Small bowel enteroscopy (SBE) has been reported useful in the nonsurgical evaluation of the small intestine in these patients. but findings may be limited because of incomplete small bowel intubation and a lack of tip deflection. Twenty-three patients underwent 25 SBE exams and subsequently had 25 IOE exams during surgical exploration for continued bleeding. Patients' bleeding histories averaged 2 yr. with an average transfusion requirement of 27 units. Findings on IOE were the same as with SBE in 17/22 (77%) of examinations. We conclude that SBE and IOE are comparable in depth of insertion and ability to detect small vascular ectasias. Both procedures missed pathology due to limited visibility and the evanescent nature of ectasias. Long-term success in abolishing bleeding with these combined techniques can be expected in 55% of these patients. SBE should precede surgery. since the finding of diffuse ectasias precludes any benefit from operative intervention.
Radiographic evaluation of suspected small bowel obstruction, Plain abdominal radiographs and enteroclysis studies were reviewed blindly in 117 consecutive patients undergoing enteroclysis for suspected small bowel obstruction. Plain radiographs were unreliably predictive of the presence of obstruction as determined by enteroclysis and surgery. Among patients with normal or abnormal nonspecific plain radiographs. varying degrees of small bowel obstruction were demonstrated by enteroclysis in 22%. Conversely. of patients with obstruction on plain radiographs. 42% had either normal enteroclysis studies or only minor adhesions. Enteroclysis correctly predicted the presence of obstruction in 100%. the absence of obstruction in 88%. the level (proximal vs distal) of obstruction in 89%. and the etiology of obstruction in 86% of operated patients. Enteroclysis is advocated as the definitive study in patients with clinical uncertainty about the diagnosis of small bowel obstruction.
DNA flow cytometry of colorectal carcinoma: correlation of DNA stemlines with other prognostic indices, DNA flow cytometry (FCM) was performed on paraffin-embedded tissue blocks of 38 surgically resected colorectal carcinomas (CRC). Forty-seven percent of tumors exhibited aneuploidy and 53% were diploid. Seventy-two percent of patients in the aneuploid but only 35% in the diploid group were alive after a mean follow-up of 30.7 and 28.8 months (p = 0.01). and 5-yr survival of 56.7% and 11.7%. respectively (p less than 0.05). The site of tumor location. Dukes' stage. and serum CEA level did not predict a certain DNA stemline. However. irrespective of the ploidy pattern. a serum CEA level greater than 5.0 was associated with a higher mortality and poor 5-yr survival (p less than 0.005). Similarly. advanced Dukes' stage was associated with higher mortality (p less than 0.05). Forty-six percent of the patients with lesions that were Dukes' B2 or advanced stage received adjuvant therapy. Eighty-five percent of this subgroup of patients died; 18% of these patients had aneuploid tumors. The role of FCM in the assessment of prognosis of CRC deserves further clinical evaluation in a randomized control trial.
Extracorporeal piezoelectric lithotripsy for complicated bile duct stones, Today. common bile duct stones are extracted endoscopically. After endoscopic sphincterotomy. nearly 90% of all stones can be removed with a Dormia basket or a mechanical lithotripter. Problems are encountered if there are larger stones or a duct stenosis. New conservative therapies do serve as an alternative to surgical intervention for those few patients in whom endoscopic measures have failed. Stone fragmentation can be achieved by extracorporeal shock wave lithotripsy. and remaining fragments can be removed endoscopically. So far. authors of most reports on the successful disintegration of common bile duct stones used the Dornier lithotripter. Stone localization is thus achieved with x-rays. and the shock waves are generated by an underwater spark discharge. We report on our experiences and results with extracorporeal piezoelectric shock wave lithotripsy (EPL) in 19 patients with complicated bile duct stones. With this lithotripter. stones are visualized by ultrasound. and shock waves are produced by a piezoelectric acoustic generator. Fragmentation was achieved in 84.2%. and complete stone removal in 78.9%. These results show that piezoelectric lithotripsy is also a useful method for the treatment of complicated bile duct stones. as has already been proved for the electrohydraulic- and electromagnetic-generated shock waves systems. However. the renunciation of general anesthesia and the need for analgesia or sedation in only 25% of the treatments render this lithotripter system attractive. especially for elderly and frail patients.
Magnetic resonance imaging of small hepatocellular carcinoma, Thirty-eight patients with small hepatocellular carcinomas (HCCs). size less than 20 mm. initially detected by ultrasound (US) and histologically confirmed. were examined by magnetic resonance (MR) imaging. computed tomographic (CT) scan. and angiography. MR imaging demonstrated HCC nodules in nine (75.0%) of 12 patients with tumors less than 10 mm in diameter and in 22 (84.6%) of 26 patients with tumors 10-20 mm in diameter. In total. HCC nodules were detected in 31 of 38 patients (81.6%) by MR imaging. On the other hand. HCC lesions were found on CT scan in 14 of 26 patients (53.8%) and in 27 of 35 patients (77.1%) by angiography. With MR imaging. HCC nodules were demonstrated in 21 of 31 patients on both T1 and T2 weighted images. and 13 of 21 patients (61.9%) were shown to have low intensity areas or iso intensity areas on T1 weighted image. whereas the other eight patients (38.1%) were shown to have high intensity areas. All 21 patients were shown to have high intensity areas on T2 weighted image. Among 15 resected cases. four patients had a high intensity area on T1 weighted image. and a significant fatty change was noted in HCC nodules by histological study of the resected specimen. We suggest that MR imaging is a useful diagnostic imaging modality. even in small HCC of less than 20 mm.
Annular pancreas as a cause of extrahepatic biliary obstruction, Annular pancreas is a rare congenital abnormality that is increasingly diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) in the adult. In this population. it can present with duodenal or gastric ulceration. duodenal obstruction. pancreatitis. and. rarely. with associated congenital abnormalities. Although it has been suggested that biliary obstruction may result from associated pancreatitis. such cases have not been reported; primary extrahepatic biliary obstruction from a constricting annulus also has not been reported. We report such a case. and describe resolution of symptoms and a return to normal biochemical tests in a patient. The literature and embryology of annular pancreas are reviewed. We suggest that this entity be added to the differential diagnosis of extrahepatic biliary obstruction.
Endoscopic management of postoperative biliary leaks: review of 77 cases and report of two cases with biloma formation, Biliary leaks are uncommon complications of abdominal surgery. Left untreated. they may result in significant morbidity and mortality. The traditional treatment has been surgical. but several authors have reported successful endoscopic management. We review 77 cases of endoscopically managed postoperative biliary leaks reported in the literature over the past 15 yr. Endoscopic treatment was technically successful in 95% of cases. and resulted in biliary leak healing in 82%. Cystic stump leaks had a better prognosis for healing compared with common bile duct or hepatic duct leaks. We also present two additional cases of postoperative biliary leaks with biloma formation successfully treated with endoscopic stent placement. Our experience lends additional support to endoscopic management as the preferred approach to postoperative biliary leaks.
Endoscopic management of retained cystic duct stones, The finding of residual common bile duct stones after cholecystectomy is a relatively frequently encountered problem for which effective nonoperative therapy exists. Retained stones in a cystic duct remnant are very rare. We present a case of multiple retained stones in a long variant cystic duct remnant following cholecystectomy and common duct exploration. which was successfully managed with endoscopic sphincterotomy and balloon extraction.
Intrahepatic lymphatics opacified during hepatic arteriography in a patient with hepatocellular carcinoma, Extrahepatic lymph node metastases are not uncommon in advanced cases of hepatocellular carcinoma (HCC). This is the account of a HCC case in which intrahepatic lymphatics running toward the hepatic hilus were clearly opacified during hepatic arteriography. The patient was treated by hepatic artery embolization followed by selective embolization of the portal branches. but lymph node metastases at the hepatic hilus were later found during follow-up. The clinical course of this case suggests that the communication between the tumor and the lymphatics was responsible for the lymph node metastasis.
Inflammatory pseudotumor of the liver associated with acute myelomonocytic leukemia, A patient with inflammatory pseudotumor of the liver associated with acute myelomonocytic leukemia (M4) is reported. He had spiking fever. epigastralgia. and elevated levels of serum C-reactive protein (CRP) and alkaline phosphatase (ALP). Ultrasonography showed a hypoechoic mass in the liver. and ultrasonically guided fine needle aspiration biopsy of the mass revealed that it was composed of fibrous connective tissue infiltrated with plasma cells. eosinophils. and neutrophils. Accordingly. a diagnosis of inflammatory pseudotumor of the liver was made. Marked reduction in the size of the lesion and a decrease of the levels of the CRP and ALP occurred without specific treatment. We emphasize the importance of ultrasonically guided aspiration biopsy in diagnosis of inflammatory pseudotumor of the liver without the need for surgery.
The effects of reprocessing cuprophane and polysulfone dialyzers on beta 2-microglobulin removal from hemodialysis patients [published erratum appears in Am J Kidney Dis 1991 Jul;18(1):144, To further define the relationship between dialyzer reuse and the removal of beta 2-microglobulin (beta 2M) during dialysis. 26 patients who received hemodialysis were studied. Thirteen patients were dialyzed with conventional cuprophane dialyzers. and thirteen patients were dialyzed with high-flux polysulfone dialyzers. Patients in each group were dialyzed with only new dialyzers during the primary-use phase of the study. and reprocessed dialyzers during the reuse phase. Dialyzers were used six times during the reuse phase. Serum beta 2M levels were measured both predialysis and postdialysis. and adjusted for fluid loss. Dialysis with conventional cuprophane new dialyzers during the primary-use phase of the study resulted in a 3.3% increase in serum beta 2M levels. and a 2.4% increase in serum beta 2M levels during the reuse phase. The difference in the change of the concentration of beta 2M between primary-use and reuse phases was not statistically significant. Dialysis with high-flux polysulfone new dialyzers during the primary-use phase was associated with a decrease of 59.5% in the mean postdialysis concentration of serum beta 2M compared with the predialysis level. A corresponding decrease of 62.6% in serum beta 2M levels was observed after dialysis with high-flux polysulfone reprocessed dialyzers during the reuse phase. These data show no evidence of an adverse effect on the clearance of beta 2M during dialysis from the reuse of dialyzers up to six times. The results confirm previous studies that have reported that high-flux dialysis with polysulfone dialyzers removes substantial amounts of beta 2M. and dialysis with conventional cuprophane dialyzers does not.
Concomitant iron and aluminum mass transfer following deferoxamine infusion during hemofiltration, Variable tissue overloading can alter the removal rate of iron and aluminum from uremics. Owing to its higher affinity to deferoxamine (DFO) and higher plasma concentrations. Fe could impair Al removal in cases of simultaneous body burden. Fe and Al plasma kinetics and mass transfer were therefore studied in 12 uremic patients with different Fe and Al status: six with normal ferritin levels (less than 400 micrograms/L [ng/mL]). and Al 1.4 to 4.7 mumol/L (40 to 131 micrograms/L) (group A); six with increased ferritin (greater than 2.000 micrograms/L). and Al 1.7 to 17 mumol/L (47 to 476 micrograms/L) (group B). DFO (40 and 80 mg/kg in a random sequence) was administered once a week during the first hour of the first hemofiltration (HF). The results show that in both groups and with both DFO doses. maximum Fe and Al mass transfer was achieved in the first and second HF. respectively. The 80-mg/kg dose of DFO significantly raised Al mass transfer in both groups. whereas Fe mass transfer was only slightly affected. Even though plasma Fe levels were almost always higher than Al. Al mass transfer eventually exceeded that of Fe. in both Fe-normal and Fe-overload patients. The bias towards Al in mass transfer was enhanced in both groups in the second HF. and at the higher DFO doses. Thus. DFO once a week reduced Fe loss to less than 30 mumol/wk in patients with normal ferritin levels. In both Fe and Al overloaded patients. Al can be removed. and Al mass transfer may often exceed Fe mass transfer. depending on the degree of tissue burden. the time from DFO infusion. and the DFO dose.
Calcitriol metabolism in patients with chronic renal failure, We studied calcitriol metabolism in white patients with chronic renal failure and in age- and sex-matched normal subjects. The plasma levels of calcitriol (21.9 +/- 1.6 pg/mL. n = 7. v control. 37.4 +/- 2.9 pg/mL. P less than 0.001). metabolic clearance rate (MCR) of calcitriol (0.45 +/- .01 mL/min/kg v control. 0.58 +/- .02 mL/min/kg. P less than 0.001). and production rate (PR) of calcitriol (14.2 +/- 1.0 ng/kg/d v control. 31.8 +/- 3.2 ng/kg/d. P less than 0.001) were significantly lower in patients with moderate renal failure (average creatinine clearance. 0.59 +/- 0.01 mL/s [35.1 +/- 6.1 mL/min]) when compared with the respective values of normal control subjects. The MCR of calcitriol was determined again in patients with renal failure after they received calcitriol. 1 microgram/d. for 1 week. The MCR remained unchanged (0.46 +/- .04 mL/min/kg. n = 7) and plasma levels of calcitriol were increased to 34.6 +/- 2.77 pg/mL. The mechanism by which the MCR of calcitriol decreases in renal failure is partly due to the presence of inhibitory factors of degradation enzymes in uremic plasma. When the ultrafiltrates of uremic plasma obtained from hemodialysis patients were infused to normal Sprague-Dawley rats. the MCRs of calcitriol (0.20 +/- .01 mL/min/kg. n = 6) were markedly suppressed in comparison to those of rats infused with the ultrafiltrates of normal plasma (0.37 +/- .01 mL/min/kg. n = 6. P less than 0.001). The uremic plasma also contained factors that inhibit the synthesis of calcitriol. We conclude that metabolic degradation of calcitriol is decreased in patients with renal failure. and uremic plasma contains inhibitory factors that suppress the synthesis and degradation of calcitriol.
Community-acquired acute renal failure, Acute renal failure usually occurs during hospitalization. but may also be present on admission to the hospital. To define the causes and outcomes of community-acquired acute renal failure. we undertook a prospective study of patients admitted to the hospital with acute elevations in serum creatinine concentrations. Over a 17-month period. all admission serum creatinine determinations were screened for patients with values greater than 177 mumol/L (2 mg/dL). These values were compared with baseline creatinines to select patients with an acute elevation in serum creatinine occurring outside the hospital. One hundred patients were entered into the study. with an overall incidence of 1% of hospital admissions. Seventy percent of the patients had prerenal azotemia. 11% had intrinsic acute renal failure. 17% had obstruction. and 2% could not be classified. Mean peak serum creatinine (318 +/- 18 mumol/L [3.6 +/- 0.2 mg/dL]) and mortality (7%) was lowest in the group with prerenal azotemia. In this group. volume contraction due to vomiting. decreased fluid intake. diarrhea. fever. glucosuria. or diuretics was the most common underlying cause. The group with intrinsic acute renal failure had the most severe renal failure and the highest mortality (55%). Although ischemic acute tubular necrosis is the most common cause of hospital-acquired intrinsic acute renal failure. this etiology was seen in only one patient. Drug-induced nephrotoxicity and infection-related causes were the most common underlying etiologies of intrinsic acute renal failure. Obstructive renal failure had a mortality of 24% and was most commonly due to benign prostatic hypertrophy.
Serial glomerular and tubular dynamics in thyroidectomized rats with remnant kidneys, Serial measurements were performed in Munich-Wistar rats with five-sixths nephrectomy that had undergone prior selective thyroidectomy (Tx group) or thyroidectomy with thyroxine replacement (TxT4 group) to determine the effects of Tx on glomerular and tubular dynamics in relation to Tx attenuation of renal failure progression. At 1 week. inulin clearance rates (Cin) in TxT4 and Tx rats were 0.367 +/- 0.171 and 0.120 +/- 0.036 mL/min. respectively. different at P less than 0.01. Corresponding single-nephron filtration rate (SNGFR). glomerular plasma flow (QA). glomerular transcapillary hydraulic pressure (delta P). and proximal tubular reabsorption (Jv) were all reduced in Tx compared with TxT4 rats (P less than 0.01). Protein excretion (UPROT) was 151 +/- 40 in TxT4 rats. and 9 +/- 5 mg/d in Tx animals. Glomerular mesangial matrix expansion and focal tubulointerstitial changes were more frequent in TxT4 than Tx rats. By 4 weeks. Cin. SNGFR. QA. glomerular ultrafiltration coefficient (Kf) and Jv were similar in Tx and TxT4. Only glomerular capillary pressure (PGC) remained lower in Tx rats (35 +/- 3 v 50 +/- 3 mm Hg in TxT4. P less than 0.001). UPROT was 161 +/- 24 in TxT4 and 17 +/- 12 mg/d in Tx rats. While 7% +/- 4% of glomeruli showed focal sclerosis in TxT4 rats. there was none in the Tx group. Maximal glomerular planar area increased between 1 and 4 weeks in the TxT4 group. but not in the Tx group. However. this measurement was not significantly different between TxT4 and Tx glomeruli at 1 or 4 weeks. Minimal focal tubulointerstitial changes were found in TxT4. but there were not progressive from those observed at 1 week. The reduced PGC at 1 week was the result of a disproportionately greater increase in afferent (RA) than efferent arteriolar resistance (RE) in Tx rats (P less than 0.025); however. at 4 weeks. both RA and RE had decreased to values identical to those in TxT4 animals and the lower PGC in Tx rats was the result of a reduced mean arterial pressure. In conclusion. a reduced PGC was the sole functional correlate of decreased proteinuria and glomerulosclerosis afforded by Tx in this partial nephrectomy model. Suppression of either nephrectomy-related hypertrophy or tubulointerstitial injury by Tx could not be excluded as at least partially protective factors.
Heparin skin necrosis: delayed occurrence in a patient on hemodialysis, A case of skin necrosis in a patient receiving intravenous (IV) heparin during routine intermittent hemodialysis is reported. Multiple erythematous. tender lesions developed over the abdomen and thighs and rapidly became necrotic. Biopsies showed fibrin thrombi in the dermal venules and capillaries. but no cellular infiltrate. The patient was in her third month of regular hemodialysis. Skin necrosis associated with the use of heparin usually occurs within 2 weeks of beginning heparin therapy and has not been reported in patients receiving heparin with hemodialysis. Possible mechanisms. including acquired antithrombin III deficiency leading to heparin-induced skin necrosis. are discussed.
Epidemiologic characteristics of preterm delivery: etiologic heterogeneity, Preterm delivery (less than 37 weeks completed gestation) is known to result from diverse etiologic pathways. which can be grouped into idiopathic preterm labor. preterm premature rupture of the membranes. and medical complications. Data from publications providing sufficient detail to subdivide preterm delivery cases into these groups were tabulated. In spite of inconsistent terminology and incomplete reporting. patterns were identified. Black women have a markedly higher risk of preterm delivery. which is especially pronounced for preterm premature rupture of the membranes. Idiopathic preterm labor is predominant in lower-risk. white populations. These observations encourage consideration of subcategories of preterm delivery in studies of etiology and prevention.
Investigation of placental circulations by color Doppler ultrasonography, The placental circulations of 25 normal and five complicated pregnancies were studied by color Doppler ultrasonography. Flow velocity waveforms were obtained in all 30 pregnancies and could discriminate between fetal and maternal intraplacental blood flow. We believe that color Doppler ultrasonography will improve our understanding of the pathophysiology of various pregnancy disorders that alter the placental circulations and that color ultrasonography is useful for the prenatal differential diagnosis of intrauterine masses.
Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: evidence from a national cohort, A national sample of 1944 white menopausal women greater than or equal to 55 years old from the epidemiologic follow-up of participants in the National Health and Nutrition Examination Survey was reviewed to investigate the role of hormone therapy in altering the risk of death from cardiovascular disease. Women in the study were observed for up to 16 years after the baseline survey in 1971 to 1975. By 1987 631 women had died; 347 of these deaths were due to cardiovascular disease. History of diabetes (relative risk. 2.38; 95% confidence interval 1.73 to 3.26). previous myocardial infarction (relative risk. 2.12; 95% confidence interval 1.56 to 2.86). smoking (relative risk. 2.18; 95% confidence interval. 1.69 to 2.81). and elevated blood pressure (relative risk. 1.49; 95% confidence interval. 1.14 to 1.94) were strong predictors of cardiovascular disease-related death in this cohort. After adjusting for known cardiovascular disease risk factors (smoking. cholesterol. body mass index. blood pressure. previous myocardial infarction. history of diabetes. age) and education. the use of postmenopausal hormones was associated with a reduced risk of death from cardiovascular disease (relative risk. 0.66; 95% confidence interval. 0.48 to 0.90). The same protective effect provided by postmenopausal hormone therapy was seen in women who experienced natural menopause (relative risk. 0.69; 95% confidence interval. 0.45 to 1.06).
Endodermal sinus tumor of the ovary during pregnancy: a case report, Serum alpha-fetoprotein screening led to the detection of an endodermal sinus tumor of the ovary in a 24-year-old female in week 17 of pregnancy. After surgery. chemotherapy was postponed. In week 28 levels of serum alpha-fetoprotein increased. but delivery was delayed until 33 weeks' gestation. After delivery. the patient received four chemotherapy courses (cisplatin. etoposide. and bleomycin). Mother (24 months after last chemotherapy) and child are doing well.
Reproductive factors and risk of endometrial cancer, The role of reproductive factors in endometrial cancer risk has been analyzed in a case-control study conducted since 1983 in the greater Milan area on 568 women (cases) with histologically confirmed endometrial cancer and 1925 women (controls) who were admitted for acute. nonmalignant. hormonal. gynecologic conditions to hospitals that cover a comparable catchment area. Compared with nulliparous women. parous women had a 30% lower risk of endometrial cancer. but there was no evidence of a decline in risk with increasing number of births. The risk of the disease decreased with number of spontaneous or induced abortions; the multivariate relative risk estimates were. compared respectively with no spontaneous or induced abortions. 0.5 for women with two or more spontaneous abortions and 0.3 for women with two or more induced abortions; both trends in risk were statistically significant. When parous women only were considered. no association emerged between endometrial cancer and age at first birth. but the risk decreased with increasing age at last birth: compared with women whose last birth occurred before age 25. the relative risk was 0.5 for women who were greater than or equal to 35 years old at last birth. and the multivariate trend in risk was statistically significant. For most of the reproductive factors that were considered. the risk estimates tended to be greater at younger age or among premenopausal women and to flatten off in subsequent strata of age. An association between endometrial cancer and age at first birth was observed in women who were less than or equal to 49 years old. but not in older groups. The observation that later age at last birth as well as later first birth in younger women decreases the risk of endometrial cancer suggests a short-term protective effect of pregnancy. This finding is consistent with a late-stage (promotional) effect of reproductive factors on endometrial carcinogenesis.
Laparoscopic pelvic lymphadenectomy in the staging of early carcinoma of the cervix, Laparoscopic pelvic lymphadenectomy was performed in 39 patients. An incision of the peritoneum between the round and infundibulo-pelvic ligament on each side gave access to the retroperitoneal space. Subsequently. laparoscopic surgery allowed precise dissection of external and internal iliac vessels. umbilical artery. and obturator nerve. The peritoneum was left open. and the lymph was drained into the peritoneal cavity. No lymphocele was observed. Three to 22 (mean. 8.7) nodes were removed. and there was no significant morbidity. Sensitivity and specificity were 100% in this preliminary experience. It is thus possible to remove the first-line regional lymph nodes of the cervix for pathologic examination. Because "skip" metastases are quite rare in early cervical carcinoma. the risk of missing a positive node is low. Brachytherapy alone. vaginal surgery. or. in microinvasive carcinoma. conization alone can be applied safely without the need of a staging laparotomy in cases with negative nodes.
Pregnancy-related mortality in New York City, 1980 to 1984: causes of death and associated risk factors, To identify causes and risk factors for pregnancy-related mortality in New York City. we analyzed 224 pregnancy-related deaths that occurred from 1980 to 1984. The leading causes of death were ectopic pregnancy complications. embolism. intrapartum cardiac arrest. and hypertension. Mortality ratios were determined by comparing the characteristics of the women whose death was pregnancy-related with those of women who had survived delivery of a live infant in New York City during the same period. Black and Hispanic women had mortality ratios that were respectively 4.2 and 2.0 times higher than those for white. non-Hispanic women. In comparison with women aged 20 to 24. those older than 30 were more than twice as likely to die from pregnancy-related causes. and those older than 40 were five times as likely to do so. Other factors that were associated with an increased risk of pregnancy-related mortality included 9 to 11 years of education. lack of private medical insurance. more than five previous pregnancies. and fewer than five prenatal visits. This study suggests that changes in current maternal-health and family-planning services will be required to achieve further reductions in preventable pregnancy-related mortality.
Estrogen receptors in the external anal sphincter, Inasmuch as anal competence in women is reduced after the age of 50 years. it may be dependent on effects of estrogens. In this study. samples of the external anal sphincter were analyzed for the presence of estrogen receptors and were found to be present at a median concentration of 5.0 fmol per milligram of protein (range. 1.9 to 13) in women (n = 7). and 1.1 fmol per milligram of protein (range. 0 to 3.2) in men (n = 7). These findings are of interest with regard to the treatment of idiopathic anal incontinence.
Postterm infants: too big or too small, Concern over the postterm pregnancy has shifted from that of the difficult delivery of an excessively large fetus to the current concern with death in utero of an undernourished. small-for-date fetus. Studies of postterm pregnancy before the availability of ultrasonography may have included a large proportion of erroneous menstrual dates. The present study of 7000 infants was undertaken to reassess fetal growth in postterm pregnancies in which the expected date of confinement from last normal menstrual period dating was confirmed (+/- 7 days) by early ultrasonography. Results show a gradual shift toward higher birth weight and greater crown-heel length and head circumference between 273 and 300 days of gestational age. No evidence of postterm weight loss or lower weight for length could be demonstrated. Concern in postterm pregnancy should be for fetal macrosomia. not for intrauterine growth retardation.
The value of squamous cell carcinoma antigen in patients with locally advanced cervical cancer undergoing neoadjuvant chemotherapy, Serum levels of squamous cell carcinoma antigen were measured in 688 samples from 119 patients with cervical cancer. Ninety-seven patients had primary tumors and 22 had recurrent disease. Serum samples were obtained before each cycle of chemotherapy. before surgery. at least 4 weeks after surgery. and at 2- to 3-month intervals during follow-up from 78 of the patients with locally advanced cervical cancer who were receiving neoadjuvant chemotherapy. Squamous cell carcinoma antigen serum levels were elevated (greater than 2.5 ng/ml) in 71% of the patients with primary tumors and in 77% of the patients with recurrent carcinomas. The percentage of positivity increased significantly with stage (p = 0.03) and was higher in squamous cell tumors than in adenocarcinomas (p less than 0.001). Pretreatment squamous cell carcinoma antigen levels were not predictive of neoadjuvant chemotherapy response; however. the serial measurement during chemotherapy showed a good correlation with clinical response. In the patients who had surgery. squamous cell carcinoma antigen positivity did not correlate to pathologic findings (lymph node status. cervical and parametrial infiltration). Disease-free survival was significantly longer in patients with squamous cell carcinoma antigen pretreatment values that were lower than 5 ng/ml. compared with patients with marker higher than 5 ng/ml (p less than 0.01). Abnormal squamous cell carcinoma antigen serum levels preceded the clinical detection of recurrence in eight of 11 patients with a median lead time of 5 months.
Toxicities in rats with free versus liposomal encapsulated cisplatin, Wistar rats (five in each group) were given either 1 mg/kg of free cisplatin. 1 or 2 mg/kg of liposomal encapsulated cisplatin. or saline solution intraperitoneally biweekly for 15 injections. Rats in the free drug group showed significantly less weight gain; two rats died during the study. At necropsy. the free cisplatin--treated rats showed gross and microscopic evidence of peritoneal fibrosis that was not detected in any of the remaining groups. The free cisplatin--treated rats showed serum and histologic evidence of renal damage; all five rats had moderate or severe acute tubular necrosis. No renal abnormalities were detected in rats that received 1 mg/kg. and only focal or mild changes were found in rats that received 2 mg/kg of the liposomal preparation. Neurotoxicity. as determined by nerve conduction and inclined plane studies. developed in rats treated with free and liposomal cisplatin. These results are encouraging and warrant further investigation.
Human amniotic fluid modulation of collagenase production in cultured fibroblasts. A model of fetal membrane rupture, The participation of a mechanical factor as the only cause of rupture of fetal membranes during normal labor or premature rupture has been criticized. and the involvement of an enzymatic mechanism has been proposed. In this study we analyzed the effect of human amniotic fluids at different gestational ages on the collagenase synthesis of cultured fibroblasts. Our results show that term amniotic fluids are capable of inducing the synthesis of collagenase and other proteases in fibroblasts. as revealed by selective increases in collagenase activity and in immunoreactive collagenase. Nonterm amniotic fluids failed to do the same. This phenomenon is proposed as a model for studying the collagen degradation of fetal membranes during term gestation.
Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer, Previous studies in breast and bladder cancer have suggested that epidermal growth factor receptor is expressed by only a proportion of cancers and is associated with poor clinical outcome. We used a monoclonal antibody specifically reactive with the extracellular domain of the epidermal growth factor receptor to localize this receptor immunohistochemically in frozen sections of normal ovary and epithelial ovarian cancer. Normal ovarian epithelium was found to express epidermal growth factor receptor in all cases. Among 87 ovarian cancers. however. 23% did not express immunohistochemically detectable receptor. Epidermal growth factor receptor expression was not related to histologic grade or stage. but was associated with poor survival (p less than 0.05). The median length of survival of patients with tumors that did not express epidermal growth factor receptor was 40 months compared with 26 months in patients with tumors that did express epidermal growth factor receptor. As in breast and bladder cancer. expression of epidermal growth factor receptor in ovarian cancer appears to be a poor prognostic factor.
A comparison of penetrating keratoplasty to epikeratoplasty in the surgical management of keratoconus, Of 40 patients intolerant to contact lenses. 47 eyes with keratoconus were surgically corrected with either epikeratoplasty (N = 31) or penetrating keratoplasty (N = 16). The percentage of eyes in both groups that had visual acuity of 20/40 or better with contact lenses at one year were equal (14 of 15 eyes [93.3%] in the penetrating keratoplasty group; 27 of 29 eyes [93.1%] in the epikeratoplasty group); however. the penetrating keratoplasty procedure resulted in a higher percentage of eyes that had visual acuity of 20/20 than the epikeratoplasty group (11 of 15 eyes [73%] compared with seven of 29 eyes [24.1%]. respectively). Both procedures resulted in significant corneal flattening. with the penetrating keratoplasty group producing an average of 3 diopters more keratometric reduction than the epikeratoplasty group one year postoperatively. Although no irreversible graft failures occurred. five of 16 eyes (31%) in the penetrating keratoplasty group had graft reactions. No serious complications were noted in the eyes of the epikeratoplasty group. Both procedures were effective in the surgical management of keratoconus.
Quantitative analysis of lens changes after vitrectomy by fluorophotometry, We measured the amount of autofluorescence in the lens to evaluate quantitatively lens changes after vitrectomy. Thirteen phakic patients. ranging in age from 12 to 75 years. were studied after unilateral vitrectomy. with a follow-up period of more than two years (range. 26 to 55 months). Autofluorescence in the lens was measured at the center along the ocular axis by fluorophotometry. Lens autofluorescence in the eyes that underwent vitrectomy was significantly higher than in the contralateral eyes that were not operated on (P = .0003). The increase of autofluorescence was correlated significantly with the age at time of vitrectomy (P = .0008). There was no correlation between the increase in autofluorescence and the length of postoperative follow-up or the use of air during vitrectomy. Based on these results. we believe that oxidation of lens proteins intraoperatively may be one of the causes of development of nuclear cataract after vitrectomy.
The prevalence of retinal vascular abnormalities in children and adolescents with essential hypertension, We studied 97 children and adolescents with essential hypertension by evaluating photographs of the optic fundus and fluorescein angiography. Photographs were examined for the presence of arteriolar narrowing. tortuosity. and arteriovenous nicking. Intraobserver and interobserver variability in determination of abnormalities was low with agreement of 75% for narrowing. 90% for tortuosity. and 100% for arteriovenous nicking. The prevalence of abnormalities was 41% (95% confidence interval. 31% to 50%) for arteriolar narrowing. 14% (95% confidence interval. 19% to 21%) for tortuosity. and 8% (95% confidence interval. 5% to 11%) for arteriovenous nicking. Of 97 patients. 50 (51%) had one or more abnormality. Retinal abnormalities are relatively common in young patients with essential hypertension.
Acetazolamide in the treatment of abnormal oculovestibular response, We treated seven patients with incapacitating vertigo elicited by walking down a grocery store aisle or driving a car. Results of neurologic. neuro-ophthalmic. and neuroradiologic examinations were normal. Episodic vertigo secondary to an abnormal oculovestibular response was diagnosed. Each patient was given a trial of 250 to 500 mg of acetazolamide daily. Symptoms resolved completely in four patients. two patients had near resolution of symptoms. and one patient had no relief. Carbonic anhydrase activity has been demonstrated in the inner ear. and acetazolamide has been shown to affect the ion balance of the inner ear fluids.
Reproducibility of topographic measurements of the normal and glaucomatous optic nerve head with the laser tomographic scanner, We acquired five independent topographic images of the optic nerve head of eight normal eyes and eight eyes with primary open-angle glaucoma with a laser tomographic scanner. Each image had a field of view of 15 x 15 degrees with a resolution of 256 x 256 pixels. The pixel size was approximately 15 x 15 microns. The value of a pixel of a topographic image represented the height at this position. The mean height and the standard deviation over the five topographic images were calculated for each of the 65.536 pixel positions. The standard deviation of a single height measurement in normal eyes was 38.7 microns (range. 23.4 to 62.2 microns) for areas in the peripapillary retina and 42.6 microns (range. 24.4 to 53.7 microns) for measurements within the optic nerve head area. In glaucomatous eyes. the standard deviation was 41.2 microns (range. 23.2 to 59.6 microns) in the peripapillary retina and 49.4 microns (range. 28.1 to 72.8 microns) within the optic nerve head. There was no significant difference between the standard deviation of a single height measurement in normal and glaucomatous eyes (P = .34 within the optic nerve head area; P = .57 on peripapillary retina). No correlation was found between standard deviation of the measurements and pupil size or age of the subject.
Detection of loss of heterozygosity in formalin-fixed paraffin-embedded tumor specimens by the polymerase chain reaction, A polymerase chain reaction-based procedure was used for the detection of DNA length polymorphisms generated by naturally occurring genetic deletions or insertions of known sequence. This method consists of a simple one-step assay that does not require any restriction enzyme analysis or Southern blot hybridization. allowing identification in ethidium bromide-stained gels. The procedure described here was used to detect loss of heterozygosity at various loci. including the Hbb beta-globin gene cluster. in chemically induced mouse skin tumors. using a variety of tissue preparations. including microdissection of formalin-fixed. paraffin-embedded specimens. short-term cultures. and fluorescence-activated cell sorting of epithelial populations. This approach may be useful in detecting tumor-specific reduction to homozygosity at polymorphic chromosomal loci. allowing the mapping of putative tumor-suppressor loci involved in carcinogenesis.
Platelet-complement interactions in mesangial proliferative nephritis in the rat, Complement has been reported to mediate mesangiolysis and glomerular hypercellularity in the rat in a model of glomerulonephritis (GN) induced with anti-Thy 1 antibody. To investigate the mechanism for the complement-mediated hypercellularity. the authors first determined if the effect of complement depletion was to inhibit cell proliferation or whether the effect was primarily to inhibit leukocyte infiltration. Rats depleted of complement with cobra venom factor (CVF) had 1) significantly less mesangiolysis than controls at day 5 (0.6 +/- 0.1 versus 3.4 +/- 0.4. scale 0-4+. P less than 0.001); 2) less cell proliferation. as assessed by immunostaining for the proliferating cell nuclear antigen (PCNA)/cyclin. a cell-cycle-dependent antigen (0.5 +/- 0.1 versus 2.4 +/- 0.7 cells/glomerular cross-section. P less than 0.01); and 3) less leukocyte infiltration as assessed by immunohistochemical labeling (0.6 +/- 0.1 versus 1.9 +/- 0.3 cells/glomerular cross-section. P less than 0.01). Because it was reported recently that platelets also mediate glomerular cell proliferation in this model. this study examined whether the mechanism for complement-mediated cell proliferation involved an effect on glomerular platelet localization. The glomerular uptake of 111In-labeled platelets was quantitated in normal and CVF-treated rats at 1. 4. 12. and 24 hours after induction of GN. Rats with anti-Thy 1 GN had substantial glomerular accumulation of platelets at all times studied. peaking at 4 hours (608 +/- 171 platelets per glomerulus). Complement depletion profoundly reduced glomerular platelet localization in anti-Thy 1 GN (mean less than 35 platelets per glomerulus at all times studied. P less than 0.05). Thus these studies demonstrate an important role for complement in mediating platelet localization in anti-Thy 1 GN. an effect that may account for the complement-dependent. neutrophil-independent glomerular hypercellularity in this model.
Characterization of preneoplastic and neoplastic lesions in the rat pancreas, Nodules of acinar cells with increased proliferative potential develop in the pancreas of carcinogen-treated rats and in untreated aged rats. Large nodules are classed as adenomas. Phenotypic and genotypic characteristics of nodule cells were compared with normal pancreas and transplantable acinar cell carcinomas by several methods. Nuclei of acinar cells from normal pancreas. adenomas. and three carcinomas in situ had normal diploid DNA content as determined by flow cytometry. One of two primary carcinomas had a hypodiploid DNA content. Two of three transplantable carcinomas were aneuploid with a DNA content in the tetraploid range. Explants from nodules and adenomas failed to grow in soft agar. whereas several carcinomas were positive in this assay. A primary carcinoma was serially transplanted. but transplantation of nodules or adenomas failed. Transfection of DNA from carcinomas in situ yielded a higher frequency of NIH 3T3 transformants than DNA from adenomas. DNAs from the transformants did not contain ras sequences. These studies indicate that cells from nodules and adenomas have low growth potential and lack critical phenotypic and genotypic characteristics of transformed malignant cells that were present in some primary and transplanted carcinomas.
Induction of different morphologic features of malignant melanoma and pigmented lesions after transformation of murine melanocytes with bFGF-cDNA and H-ras, myc, neu, and E1a oncogenes, Malignant melanomas show a remarkable degree of heterogeneity because of different morphologic features. biologic behavior. and prognosis. In this communication. the authors attempted to correlate morphologic heterogeneity of melanomas with transformation by different activated oncogenes; they studied the histologic features of melanocytic lesions induced by murine melanocytes transformed by basic fibroblast growth factor (b-FGF-cDNA) or H-ras. neu. myc. and E1a oncogenes. and the lesions were compared with those observed in human pathology. Tumors formed after grafting onto syngenic mice or subcutaneous injections in nude mice were studied. In syngenic mice. benign melanocytic lesions reminiscent of intradermal nevus were observed with melanocytes transformed with b-FGF-cDNA. and myc and E1a oncogenes. Benign lesions were also formed by neu-transformed melanocytes when they were grafted concomitantly with keratinocytes. whereas malignant tumors were formed by the same cells when grafted alone or together with fibroblasts. In contrast. H-ras melanocytes always formed malignant tumors. In nude mice. b-FGF-transformed melanocytes induced benign lesions. whereas transformed melanocytes by the other oncogenes formed malignant tumors with distinctive and homogeneous morphologic features that depended on the transforming oncogene. Melanomas with either epithelioid cell. spindle cell. small round cell. and anaplastic cell growth patterns could be distinguished after transformation with H-ras. neu. E1a. and myc oncogenes. respectively. These various histologic types are analogous to those that may be observed in human melanomas. even within the same tumor. These studies suggest a possible molecular mechanism for tumor heterogeneity in which distinct oncogenes or oncogenelike activities can be activated in different tumors or discrete parts of the same tumor.
Differential expression of basement membrane collagen chains in diabetic nephropathy, Diabetic nephropathy is characterized by progressive expansion of mesangial matrix and thickening of the glomerular basement membrane (GBM). Kidney tissues from 13 patients with insulin-dependent diabetes mellitus were studied by immunohistochemical techniques for the distribution of three recently described collagen peptides (M28+. M28 [Good-pasture antigen]. and Alport antigen) and various components of classical type IV collagen [alpha 1(IV) noncollagenous (NC) globular domain. alpha 2(IV) NC. 7S. triple helix]. Recently M28 and M28+ were designated as NC monomers of alpha 3(IV) and alpha 4(IV) based on limited amino acid sequencing. During the course of the disease. the distribution of the M28 chains and the Alport peptide segregated completely from that of classical type IV collagen. In diabetic kidneys. antibodies to the M28 and Alport peptides reacted intensely with the thickened GBM but not with the mesangium. In contrast. the reactivity of antibodies to various components of classical type IV collagen was prominent within the expanded mesangial matrix with significant decrease in reactivity in the peripheral capillary wall. In hyalinized glomeruli. components of classical type IV collagen virtually disappeared. whereas the M28 and Alport peptides persisted in the collapsed GBM. These studies support the view that expansion of the mesangial matrix and thickening of the GBM involve separate and distinct collagen components. The differential expression of the M28 and Alport peptides compared with that of classical type IV collagen may be a consequence of differing sites of synthesis (classical type IV collagen from endothelial/mesangial cells and M28 and Alport chains from visceral epithelial cells). independent control mechanisms. and/or differences in degradation.
Human immunodeficiency virus-infected multinucleated histiocytes in oropharyngeal lymphoid tissues from two asymptomatic patients, Human immunodeficiency virus (HIV)-infected multinucleated giant cells previously were detected only in the central nervous system of HIV-positive patients. Reported here are the first cases in which such infected cells were observed outside the central nervous system. in the oropharyngeal lymphoid tissues. Tonsils and adenoids were removed individually from two asymptomatic homosexual men. Follicular hyperplasia and many interfollicular multinucleated giant cells most often in contact with or in close proximity of the mucous membrane were seen. The latter were positive for lysozyme. alpha-1 anti-chymotrypsin. OKM1. and S-100 protein in accordance with a histiocytic origin. In situ hybridization with an HIV envelope-specific RNA probe demonstrated the presence of viral RNA in these multinucleated giant cells. These findings support the role of peripheral histiocytes as a primary virus reservoir early in the disease. They also underline the potential role of oropharyngeal tissue as a primary target in some cases.
Glomerular basement membrane expansion in passive Heymann nephritis. Absence of increased synthesis of type IV collagen, laminin, or fibronectin, The distribution and synthetic rate of glomerular basement membrane components was examined in the Passive Heymann Nephritis model of experimental membranous nephropathy. The extensive tissue injury that developed included subepithelial electron-dense deposits. podocyte foot process effacement. and expansion of the glomerular basement membrane. Levels of mRNA for type IV collagen. laminin. and fibronectin from isolated glomeruli was quantitated by slot-blot analysis and showed no change in experimental animals as compared to controls at either 1 week. 3 weeks. or 3 months after disease induction. Immunoelectron microscopy with gold-labeled anti-laminin IgG revealed no difference in the number of particles bound to the glomerular basement membrane of experimental animals and controls. Immunofluorescence with both type IV collagen antisera and anti-laminin antibody showed no difference in the intensity or pattern of staining. Despite extensive glomerular damage and glomerular basement membrane thickening. no evidence was found for either an increase in the synthetic rate of type IV collagen. laminin. or fibronectin or for an accumulation of basement membrane laminin within the damaged glomeruli. Alternate processes. such as diminished density of matrix components or accumulation of other unmeasured matrix constituents. presumably account for the expansion of the glomerular basement membrane seen in experimental membranous nephropathy.
Early cellular events in evolving cutaneous delayed hypersensitivity in humans, The delayed-type hypersensitivity reaction (DHR) in human skin is prototypic for many inflammatory dermatoses. However the cellular events that precede gross lesion formation are unknown. In this study. inflammatory cell populations and adhesion molecule expression in early phases of DHR elicited by 2.4-dinitrochlorobenzene were evaluated. The first discernible event (at 1 hour) was mast cell degranulation. followed by induction of endothelial leukocyte adhesion molecule (ELAM-1) expression on dermal postcapillary venules at 2 hours. Endothelial leukocyte adhesion molecule expression peaked at 24 hours and declined by 48 hours. In contrast. endothelial expression of intercellular adhesion molecule-1 (ICAM-1) remained at constitutive levels. Intrafollicular T-cell migration occurred independent of ICAM-1 expression and commenced as early as 4 hours after challenge. Mature. activated CD4-positive lymphocytes that expressed a helper-inducer/memory phenotype predominated in early lesions. These results demonstrate in vivo that mast cell degranulation. ELAM-1 expression. and memory T-cell-follicular interactions are key events in subclinical evolutionary stages of cutaneous DHR.
Selective differences in macrophage populations and monokine production in resolving pulmonary granuloma and fibrosis, Alveolar macrophages (AM) and their production of interleukin-1-like activity (IL-1) and macrophage-derived growth factor for fibroblasts (MDGF) were examined during chronic inflammatory reactions leading to either granuloma formation or fibrosis. Groups of five rats each received. respectively. a single transtracheal injection of xonotlite. attapulgite. short chrysotile 4T30. UICC chrysotile B asbestos. or saline. One month later. such treatments induced either no change (xonotlite). granuloma formation (attapulgite and short chrysotile 4T30). or fibrosis (UICC chrysotile B). By 8 months. however. the granulomatous reactions had resolved or greatly diminished. whereas the fibrosis persisted irreversibly. Parallel examination of cell populations obtained by bronchoalveolar lavage revealed that multinucleated giant macrophages (MGC) were present in lavage fluids of animals with resolving granulomatous reactions but absent in those obtained from animals with lung fibrosis. Evaluation of monokine production by inflammatory macrophages also revealed significant differences. Enhanced production of IL-1-like activity was seen in both types of lung injury. although especially during the early stage (1 month) and decreased thereafter (8 months). By contrast. augmentation of MDGF production was observed in animals with lung fibrosis only and persisted up to 9 months. Taken together. these data indicate that production of selected cytokines. as well as AM differentiation along a given pathway. may modulate the outcome of a chronic inflammatory response.
Genetics and psychiatry: an unheralded window on the environment, Two recent reviews in the American Journal of Psychiatry and the British Journal of Psychiatry reported on progress in understanding the genetics of psychiatric disorder. Both reviews focused on this progress as a prelude to psychiatric diagnostics and therapeutics based on molecular biology. Neither review recognized that the latest data in behavioral genetics support environmental causes for abnormal development and psychopathology as much as they support genetic causes. Moreover. these genetic data point clearly to a type of environmental cause with central importance: the environment that is specific or unique to each sibling in a family.
A critical appraisal of mitogen-induced lymphocyte proliferation in depressed patients, OBJECTIVE: The authors' goal was to evaluate the utility of mitogen-induced lymphocyte proliferation assays in clinical research in psychoimmunology. METHOD: They examined 23 depressed patients and 23 matched comparison subjects with this assay. There were no significant differences between these groups. They then combined the results of this study with the results of their previous study of 20 depressed patients and 20 comparison subjects to examine possible determinants of lymphocyte proliferation in depression. RESULTS: Depressed patients with lower proliferative responses than their matched comparison subjects had lower depression subscale. anergia subscale. and total scores on the Brief Psychiatric Rating Scale than did patients with higher proliferative responses than their matched comparison subjects. This finding was unexpected and unexplained. Depressed patients with lower proliferative responses than their matched comparison subjects also had fewer obsessions and compulsions and less psychomotor agitation according to the Schedule for Affective Disorders and Schizophrenia interview than did patients with higher proliferative responses than their matched comparison subjects. Stepwise discriminant analysis and cluster analysis contributed little further understanding of the determinants of in vitro lymphocyte proliferation of cells from depressed patients. CONCLUSIONS: Longitudinal studies using multiple serial determinations of mitogen-induced lymphocyte proliferation are the minimal design needed to make this assay useful in further evaluating any immune system changes in depression.
Depressive symptoms following stroke, OBJECTIVE: The primary purpose of this study was to assess the relation of lesion location to mood and vegetative disturbance following stroke. METHOD: Fifty-two inpatients and outpatients who had had single. unilateral strokes were included. Patients with past CNS or psychiatric disorders were excluded. A modified Visual Analogue Dysphoria Scale was used to allow the inclusion of all but the most impaired aphasic patients. Sleep and eating disturbances were measured by using both self-report and nursing assessments. Location of lesions was determined by CT scan and classified according to three dimensions: right-left. dorsal-ventral. and frontal-nonfrontal. RESULTS: On measures of dysphoric mood and sleep disturbance. results indicated significant three-way interactions among the three lesion dimensions. No differences were found with regard to eating disturbance. Greater dysphoria and sleep disturbance were found in subjects with left parietal/occipital. left inferior frontal. right superior frontal. and right temporal lesions than in subjects with lesions in other locations. Depressive symptoms were not associated with functional impairment as measured by activities of daily living. motor strength. or severity of aphasia. CONCLUSIONS: These results support the hypothesis that lesion location is a valid and significant factor in the mixture of influences which may result in a dysphoric mood state following stroke. The relation between the site of the lesion and subsequent depressive symptoms. however. may be more complex than has been reported previously.
The nature and course of olfactory deficits in Alzheimer's disease, OBJECTIVE: The aim of this study was to determine the specific nature and course of olfactory deficits in Alzheimer's disease. Previous studies had noted impaired odor identification. but there was no unanimity about the presence of odor detection deficits. METHOD: Odor identification was tested in 55 patients with Alzheimer's disease and 57 elderly control subjects by using the University of Pennsylvania Smell Identification Test. Odor detection was assessed in 46 subjects with Alzheimer's disease and 40 control subjects by using a forced-choice threshold test with geraniol as the odorant. RESULTS: Significant deficits in olfactory identification were present in subjects who were in the earliest stages of cognitive impairment. and these deficits increased as Alzheimer's disease progressed. There was some overlap in individual smell identification test scores between cognitively impaired patients and normal elderly subjects. On the other hand. odor detection deficits did not appear until Alzheimer's disease was relatively advanced. Smell identification test scores were correlated with Mini-Mental State scores. but geraniol detection was not. CONCLUSIONS: Odor identification is impaired early in Alzheimer's disease and may be more influenced by cognitive status than is acuity of odor detection. which is not altered until later in the disorder. The pattern of hyposmia in Alzheimer's disease suggests that the disorder may not "begin in the nose." as has been theorized previously. Further refinement of olfactory testing may be useful in the diagnostic evaluation of early dementia.
Nonfearful panic disorder in neurology patients validated by lactate challenge, OBJECTIVE: Nonfearful panic disorder meets the DSM-III-R criteria for panic disorder but is not associated with subjective fear and anxiety. The authors determined its prevalence in a group of neurology patients and assessed its diagnostic validity as a panic disorder subtype by evaluating the response of the patients with nonfearful panic disorder to sodium lactate and antipanic pharmacotherapy. METHOD: The subjects were all neurology patients referred over 1 year to a university hospital's psychiatric consultation service because of negative medical workups for their symptoms (N = 48). Patients who met the DSM-III-R criteria for panic disorder but did not report subjective anxiety or fear during panic episodes were diagnosed as having nonfearful panic disorder. Afterward. each of those patients received a sodium lactate infusion and. 5 hours later. a sodium chloride infusion. They were then treated with antipanic medication and followed for at least 6 months. RESULTS: Of the 48 neurology patients referred for psychiatric evaluation. 11 (23%) met the criteria for panic disorder. and all 11 met the criteria for nonfearful panic disorder. All 11 responded positively to lactate but not to placebo. and they each experienced an at least 75% reduction in symptoms during the 6-month follow-up period. Detailed case reports of three of these patients are presented. CONCLUSIONS: These findings support the construct and predictive diagnostic validity of nonfearful panic disorder as a subtype of panic disorder and suggest that a lack of attention to this group leads to both the underestimation of the prevalence of panic disorder and to the withholding of potentially successful treatments for this group.
Characteristics of 60 adult chronic hair pullers, OBJECTIVE: This study was constructed to detail the demographic and phenomenological features of chronic hair pullers as well as to assess psychiatric comorbidity in a sizable study group. METHOD: Subjects were drawn from an outpatient population of chronic hair pullers who had been referred to a trichotillomania clinic or had responded to a newspaper advertisement announcing a treatment study of adults who pull out their hair. Sixty adult chronic hair pullers completed a semistructured interview that focused on their hair-pulling behavior and demographic characteristics and that incorporated screening questions for DSM-III-R axis I disorders. The data were tabulated to derive a comprehensive picture of this group. RESULTS: The typical subject was a 34-year-old woman who had pulled hair from two or more sites for 21 years. All subjects described either tension before or relief/gratification after pulling hair from the primary site. but 17% (N = 10) failed to describe both of these characteristics and thus failed to fulfill the DMS-III-R criteria for trichotillomania. Forty-nine subjects (82%) qualified for past or current axis I diagnoses other than trichotillomania. Several characteristics of the study group suggested phenomenological differences between obsessive-compulsive disorder and trichotillomania. CONCLUSIONS: Adult trichotillomania is a chronic disorder. frequently involving multiple hair sites. and is associated with high rates of psychiatric comorbidity. Its relation to obsessive-compulsive disorder requires further clarification. The tension-reduction requirement in DSM-III-R for the diagnosis of trichotillomania may be overly restrictive.
Nortriptyline treatment of depressed cardiac transplant recipients, The safety of tricyclic antidepressants in cardiac transplant recipients has not been established. The author used nortriptyline to treat major depressive episodes in eight cardiac transplant recipients. Nortriptyline therapy was associated with increased QRS interval and heart rate but did not significantly affect other hemodynamic or ECG variables or cyclosporine dose requirements. It appears that nortriptyline may be used safely in depressed cardiac transplant patients.
Transdermal nicotine and smoking behavior in psychiatric patients, The authors used a double-blind crossover design to observe the effect of transdermally administered nicotine on the smoking behavior of 13 psychiatric patients who were not trying to stop smoking. The patients smoked significantly fewer cigarettes while receiving nicotine than while receiving placebo. These data suggest that transdermally administered nicotine can be a useful adjunct in treating nicotine-addicted psychiatric patients in a non-smoking environment.
Treatment of angiomas with sclerosing injection of hydroxypolyethoxydodecan, The authors discuss the indications for hydroxypolyethoxydodecan in the sclerosing treatment of angiomas. with particular reference to cavernous. venous. and evolutive angiomas (ie. immature angiomas that fail to involute by eight to ten months). Moreover. the sclerosing agent may be employed. in connection with embolization and subsequent surgery. in arteriovenous angiomas with a relevant cutaneous-subcutaneous development. The authors have successfully used the "interstitial" sclerosing technique. according to Andrews' method. This technique involves interstitial injections to obtain the sclerosis of the thin threads of fibrous tissue stroma between the blood vessels. The sclerosing therapy may cause the complete regression of "low flow" angiomas or. at least. a partial reduction that simplifies the ensuing surgical excision. In the case of partial regression of the angioma obtained with the sclerosing therapy. the surgery of the remaining angioma causes a lesser degree of bleeding (especially in areas that do not particularly lend themselves to surgical exploration. ie. the oral cavity); an increased reliability in the radicality of the intervention (due also to the reduced size of the lesion); and better results from an aesthetic-functional point of view.
Mucoid vasculopathy of unknown etiology, A new vascular disorder with generalized deposition of abnormal amounts of acid mucopolysaccharide (AMPS) material in arteries. veins. and vasanervorum has been observed in a large number of autopsies at the author's institution. It is unlike any of the known vascular diseases and has emerged as a distinct disorder of vascular connective tissue. This has been named "mucoid vasculopathy of unknown etiology." This hitherto unreported entity is described here.
Giant left atrium--a case report, A seventy-seven-year old woman. with mitral stenosis. presented with cardiomegaly evident on her chest roentgenogram. The cardiac enlargement was due to a giant left atrium that distorted the cardiac structures. An echocardiogram and a first-pass nuclear angiogram were able to delineate the huge left atrium.
Sudden appearance of coronary thrombus observed by angiography--a case report, A sudden coronary thrombus formation was documented by chance during cardiac catheterization in a patient with postinfarction angina. The thrombus was successfully treated with intravenous urokinase and heparin infusions. and thereafter. coronary angioplasty was performed without any complication.
Spontaneous cerebral embolism from descending thoracic aortic aneurysm--a case report, A case in which an aneurysm of the proximal descending thoracic aorta was the likely source of retrograde cerebral embolism is described. Atherosclerotic disease of the descending thoracic aorta should be considered as an unusual source of cerebral emboli.
Total occlusion of the left main coronary artery in a young woman with survival: a case report, The total occlusion of the left main coronary artery (LMCA) is rare. and the survival depends on the existence of collateral circulation. The author presents a case of total occlusion of the left main coronary artery with survival in a young woman because he thinks this is a very rare case. owing to the sex and age of the patient.
Axillary subclavian vein thrombosis. Changing patterns of etiology, diagnostic, and therapeutic modalities, Fifty-two patients with axillary-subclavian vein thrombosis were treated in the last 10 years and were available for follow-up for at least 1 year. Eighteen of these were treated in the first 5 years. Group A. and 34 in the last 5 years. Group B. The causes in both Group A and Group B included respectively: effort or spontaneous 28 per cent and 29 per cent. catheter insertion related 17 per cent and 47 per cent. and malignancy or systemic disease 55 per cent and 24 per cent. None of the patients in Group A had noninvasive vascular testing (NIT). However. 27 patients in Group B had IPG/duplex imaging (NIT). All 18 cases in Group A and 27 cases in Group B were treated conventionally (anticoagulants). Seventy-three per cent of these had residual pain on exertion (venous claudication) and/or swelling. Fourteen of these cases had posttreatment NIT/venography. Four of these showed total resolution of the thrombus and all were symptom free. Ten had no resolution. and nine were symptomatic. Seven cases in Group B were treated with thrombolytic therapy. Five of these had total resolution of thrombus and were symptom free (71%). Two had no resolution with residual symptoms (29%) (statistically significant). In conclusion (1) More patients with axillary-subclavian vein thrombosis seen recently are catheter insertion related; 2) Diagnosis should be initiated with duplex imaging; and (3) Thrombolytic therapy significantly decreased residual symptoms and yielded better resolution than anticoagulants.
Splenectomy for the massively enlarged spleen, The experience at the National Cancer Institute from 1955 to 1988 with 46 cases of splenectomy for massive splenomegaly (greater than or equal to 1.500 grams) was reviewed to assess the indications. pathology. operative. and postoperative course for this procedure. The median age was 51 years. Thirty-one splenectomies (67.4%) were performed for malignancy (chronic lymphocytic leukemia. 11; chronic myelogenous leukemia. 10; lymphoma. 9; hairy cell leukemia. 1). 11 for myeloid metaplasia. and four for other nonmalignant conditions. Indications for splenectomy included hypersplenism (32 patients). symptoms (6). diagnosis (3). and splenic rupture (3). A midline incision (30 patients) was most commonly used. Median operative time was 2 hours. 50 minutes. Median operative blood loss was 1.300 ml (range. 100 ml-60 units). The splenic artery was ligated initially in 16 patients (34.8%) but did not correlate with blood loss or operating time. The median splenic weight was 2.030 grams (range. 1500-5320 gm). The postoperative complication rate was 39.1 per cent (21 complications in 18 patients). This included infection in 10 patients. bleeding in six patients. Six patients required reoperation (bleeding. 4; abscess. 1; small bowel obstruction. 1 patient). The 30-day operative mortality was 19.6 per cent (9 patients). Excluding operative deaths. 35 patients were available for follow-up evaluation. Twenty-nine patients had improvement in parameters for which splenectomy was indicated. Six patients had no change in their course after splenectomy. These findings indicate that many patients with massive splenomegaly benefit from splenectomy. however. the procedure is associated with a high risk for postoperative morbidity and mortality.
Diagnostic peritoneal lavage. Limited indications due to evolving concepts in trauma care, This study was undertaken to determine the appropriateness of celiotomy in 100 consecutive patients who underwent celiotomy solely because of positive diagnostic peritoneal lavage (DPL) following blunt (B) or stab (S) abdominal trauma. A total of 32 (32%) patients had positive DPL by laboratory criteria: blunt trauma: greater than 100K RBC/mm3. greater than 500 WBC/mm3; stab trauma: greater than 50K RBC/mm3. greater than 250 WBC/mm3. DPL in 68 patients was positive by gross inspection; 18 of these 68 patients' DPL laboratory results returned after surgery and did not satisfy the laboratory definition of positive DPL. In all 61 per cent underwent therapeutic celiotomy (TC) and 39 per cent underwent nontherapeutic celiotomy (NTC). Grade I and II spleen and/or liver injuries led to 79 per cent of NTCs. Positive DPL. determined by gross inspection or by laboratory testing. has a very poor accuracy rate when evaluated in light of evolving beliefs that promote nonoperative therapy for grade I and II liver and spleen injuries. When positive DPL is the sole indication for celiotomy in patients with blunt or stab abdominal trauma. an unacceptably large number of NTCs will be performed. DPL should have a limited role in the evaluation of patients with abdominal trauma.
Intraoperative pancreatic fine needle aspiration biopsy. Results in 166 patients, Intraoperative fine needle aspiration biopsy (NAB) of undiagnosed pancreatic masses was studied in 166 patients over a 17-year period. The cytologic diagnoses were correlated with histologic specimens. autopsy results. or clinical follow-up (benign disease was documented if the patient was alive without malignancy at least 2 years after laparotomy). Aspirates were interpreted as benign. suspicious. malignant. or unsatisfactory. Malignant disease was the final diagnosis in 109 patients; the cytology was concordant in 101 and was interpreted as suspicious in four. Four patients with benign cytology later proved to have malignant disease--a false-negative rate of 2.5 per cent. A total of 57 patients had benign disease; 51 of these had benign cytology. The remaining patients had "unsatisfactory" cytology reports. A 93 per cent sensitivity. 100 per cent specificity. and 0 per cent complication rate are reported. There were no false-positive cytology reports. Complications are rare and represent case reports. thus. additional sampling is at minimal risk. Intraoperative pancreatic NAB is a safe. easy. more accurate biopsy technique than historical wedge or core needle biopsies. It is the biopsy method of choice for pancreatic masses found at laparotomy.
Relation of left ventricular mass and geometry to morbidity and mortality in uncomplicated essential hypertension, OBJECTIVE: To assess the prognostic significance of left ventricular mass and geometry in initially healthy persons with essential hypertension. DESIGN: An observational study of a prospectively identified cohort. SETTING: University medical center. PATIENTS: Two hundred and eighty patients with essential hypertension and no pre-existing cardiac disease were evaluated using echocardiography between 1976 and 1981. Two hundred and fifty-three subjects or their family members (90%) were contacted for a follow-up interview an average of 10.2 years after the initial echocardiogram was obtained; the survival status of 27 patients lost to follow-up was ascertained using National Death Index data. MEASUREMENTS AND MAIN RESULTS: Left ventricular mass exceeded 125 g/m2 in 69 of 253 patients (27%). Cardiovascular events occurred in a higher proportion of patients with than without left ventricular hypertrophy (26% compared with 12%; P = 0.006). Patients with increased ventricular mass were also at higher risk for cardiovascular death (14% compared with 0.5%; P less than 0.001) and all-cause mortality (16% compared with 2%; P = 0.001). Electrocardiographic left ventricular hypertrophy did not predict risk. Patients with normal left ventricular geometry had the fewest adverse outcomes (no cardiac deaths; morbid events in 11%). and those with concentric hypertrophy had the most (death in 21%; morbid events in 31%). In a multivariate analysis. only age and left ventricular mass--but not gender. blood pressure. or serum cholesterol level--independently predicted all three outcome measures. CONCLUSIONS: Echocardiographically determined left ventricular mass and geometry stratify risk in patients with essential hypertension independently of and more strongly than blood pressure or other potentially reversible risk factors and may help to stratify the need for intensive treatment.
Lack of benefit of methotrexate in severe, steroid-dependent asthma. A double-blind, placebo-controlled study, OBJECTIVE: To determine the effect of low-dose methotrexate in asthmatic patients on steroid use. asthma symptom scores. pulmonary function. airway reactivity. blood cellular components. and immunoglobulin E levels. DESIGN: A randomized. double-blind. parallel. placebo-controlled. 13-week clinical trial with follow-up of patients in an open trial of methotrexate at the conclusion of the double-blind study. SETTING: An asthma care outpatient clinic. PATIENTS: From February 1988 to March 1990. 19 patients with severe. steroid-dependent asthma were enrolled in the study. Two of these patients were excluded from analysis. INTERVENTIONS: Patients were administered methotrexate or placebo intramuscularly. to assure complete absorption. once weekly during the 13-week study. RESULTS: Patients on methotrexate and placebo both significantly decreased their steroid dose by 39.6% (95% CI. 25.1% to 54.1%. P = 0.001) and 40.2% (CI. 17.9% to 67.4%. P = 0.003). respectively. Pulmonary function did not differ significantly between the methotrexate and placebo groups. In addition. airway reactivity and symptom scores were unchanged on methotrexate or placebo. No significant toxicities were seen during the course of the 13-week blinded study. but one patient on methotrexate and prednisone in the follow-up period developed Pneumocystis carinii pneumonia and died. Despite continuing methotrexate for up to 1 year. and increasing methotrexate to 30 mg weekly. no significant benefit of methotrexate on asthma control could be shown. CONCLUSION: Our study does not support the use of methotrexate in the treatment of severe asthma.
Erythrocyte sedimentation rate predicts early relapse and survival in early-stage Hodgkin disease. The EORTC Lymphoma Cooperative Group, OBJECTIVE: To assess the value of an elevated (greater than 30 mm/h) Westergren erythrocyte sedimentation rate (ESR) for predicting early relapse and survival after therapy in patients with clinical stage I or II Hodgkin disease. INTERVENTIONS: We studied 772 patients with early-stage Hodgkin disease who had participated in two separate multicenter clinical trials. Both trials used modern field radiotherapy and. in some patients. multi-agent chemotherapy. MAIN RESULTS: The ESR patterns were based on pretherapy and post-therapy assessments: pattern 1. always normal (n = 261); pattern 2. elevated before therapy but normal immediately after therapy (n = 121); pattern 3. elevated before therapy but normal within 3 months after therapy (n = 89); pattern 4. always elevated (n = 48); pattern 5. normal before therapy but oscillating between normal and elevated after therapy (n = 150); pattern 6. elevated before therapy but oscillating between normal and elevated after therapy (n = 130). By multivariate analysis. independent of whether or not patients received chemotherapy in the initial therapy protocol. ESR patterns 4. 5. and 6 were shown to be the best predictors for early relapse and survival when patients were stratified according to the type of chemotherapy received and the number of involved nodal areas. Patients with ESR pattern 4 had a relative risk for death seven times that of patients with patterns 1. 2. or 3. Early relapse was the second most important factor predicting death. irrespective of ESR; patients with early relapse and ESR patterns 1. 2. or 3 had a relative risk for death of 4.5. and those with early relapse and ESR patterns 4. 5. or 6 had a relative risk for death of 15. Whether or not chemotherapy was given initially did not change the relative risk. which shows that ESR. not initial therapy. was the predictor for early relapse and death due to Hodgkin disease. CONCLUSION: An unexplained elevated ESR after therapy. especially after modern radiotherapy. independent of other factors. strongly suggest the presence of aggressive and resistant Hodgkin disease. An elevated ESR is predictive of early relapse and poor prognosis; its presence justifies early aggressive therapy.
Treatment of intractable aspiration using a laryngeal stent or obturator, Twenty-five patients were treated with a laryngeal stent for potentially reversible chronic aspiration of life-threatening magnitude. The causes of the intractable aspiration were diverse and included chronic neurologic disease. extensive head and neck surgery. and severe gastroesophageal reflux. The advantages of this technique are noted in comparison to those of more invasive procedures. Disadvantages of the laryngeal stent and complications encountered are also covered. The long-term results show that all but one patient had a significant improvement in their chronic aspiration with the stent in place. However. only eight patients achieved adequate oral deglutition without aspiration following stent removal.
Surgical applications of ultrathin flexible bronchoscopes in infants, Ultrathin flexible bronchoscopes with controlled distal angulation allow the conventional diagnostic examination of the lower airways of even the smallest infants. These instruments may be passed through small endotracheal or tracheostomy tubes while ventilation is maintained. It is thus possible. under direct visualization. to control the manipulation of surgical instruments where they could not otherwise be seen. or to study airway dynamics and anatomy intraoperatively without extubating the patient.
Surgical complications with the cochlear multiple-channel intracochlear implant: experience at Hannover and Melbourne, The surgical complications for the first 153 multiple-channel cochlear implant operations carried out at the Medizinische Hochschule in Hannover and the first 100 operations at the University of Melbourne Clinic. The Royal Victorian Eye and Ear Hospital. are presented. In the Hannover experience the major complications were wound breakdown. wound infection. electrode tie erosion through the external auditory canal. electrode slippage. a persistent increase in tinnitus. and facial nerve stimulation. The incidence of wound breakdown requiring removal of the package was 0.6% in Hannover and 1.0% in Melbourne. The complications for the operation at both clinics were at acceptable levels. It was considered that wound breakdown requiring implant removal could be kept to a minimum by making a generous incision and suturing the flap without tension.
Surgical voice restoration with the Blom-Singer prosthesis following laryngopharyngoesophagectomy and pharyngogastric anastomosis, Surgical voice restoration using the Blom-Singer technique is a well-established procedure in patients who have undergone simple laryngectomy. Operations for hypopharyngeal carcinoma are more extensive and require reconstruction using regional skin or myocutaneous flaps. or reanastomosis with colon. jejunum. or stomach. We report the use of the Blom-Singer prosthesis in four patients who had undergone pharyngogastric repair following laryngopharyngoesophagectomy and who had failed to achieve a satisfactory voice. All patients initially developed good speech using the prosthesis. Two patients subsequently had their prostheses removed: one because of recurrent malignant disease and one because the procedure had not significantly altered the quality of the voice. The remaining two patients have continued to use the device at 2 and 5 years after insertion with good voice production.
Radiological abnormalities among sheet-metal workers in the construction industry in the United States and Canada: relationship to asbestos exposure, We investigated the possible adverse health effects to sheet-metal workers who had past exposure to asbestos. A cross-sectional medical examination of 1.330 workers was conducted during 1986 and 1987 in seven cities in the United States and Canada. A total of 1.016 workers had been employed for at least 35 y in the industry. and the mean duration from onset of asbestos exposure was 39.5 y (SD = 7.41 y). Chest x-ray abnormalities were found in more than half of the group. Pleural fibrosis. the most frequently found abnormality. was present in 47.0% of the cases and was the only abnormality found in 27.8% of cases; parenchymal interstitial fibrosis. found in 33.1% of cases. was the only abnormality found in 16.2% of cases. Radiologic abnormalities increased as duration of exposure increased. A positive smoking history was associated with a higher prevalence of radiologically detectable parenchymal abnormalities. a finding confirmed by us and others. Dyspnea on exertion was graded by a Medical Research Council questionnaire. the examinee's self-assessment. and a more detailed 12-point scale questionnaire. Few persons had marked shortness of breath. and approximately one-third had slight dyspnea. Individuals who had radiologic abnormalities experienced more shortness of breath than did those who had no radiologic abnormalities. Cigarette smoking also resulted in a higher prevalence of dyspnea. The results indicate that during the past. construction sheet-metal workers have been significantly exposed to asbestos on the job. Every effort should be made to minimize the anticipated serious health consequences. and further asbestos exposure for those who continue in this trade should be avoided.
Selenium in forage crops and cancer mortality in U.S. counties, The potential protective effect of selenium status on the risk of developing cancer has been examined in animal and epidemiologic studies. This ecological study investigated the association between U.S. county forage selenium status and site- and sex-specific county cancer mortality rates (1950-1969) using weighted least squares regression. Consistent. significant (p less than .01) inverse associations were observed for cancers of the lung. rectum. bladder. esophagus. and cervix in a model limited to rural counties and for cancers of the lung. breast. rectum. bladder. esophagus. and corpus uteri in a model of all counties. No consistent significant positive associations were observed in the rural county models. This remarkable degree of consistency for the inverse associations strengthens the likelihood of a causal relationship between low selenium status and an increased risk of cancer mortality.
Influence of inhaled cadmium on the immune response to influenza virus, Cadmium may exacerbate pulmonary infections. In a previous study. however. cadmium appeared to enhance mouse resistance to influenza pneumonia. We report herein on the influence of cadmium intoxication in mice on different factors of anti-influenza immunity. e.g.. antibody response. local production of interferon. pulmonary cellular response. and the interaction between pulmonary alveolar macrophages and the influenza virus. Cadmium inhalation did not affect production of antibodies or interferon. The protective effect appeared to be related to an enhanced supply to phagocytic cells into the lung.
Rapid analysis of carcinoembryonic antigen levels in gallbladder bile. Identification of patients at high risk of colorectal liver metastasis, Recently it was found that immunoanalysis of carcinoembryonic antigen (CEA) levels in gallbladder bile may be a sensitive method to detect colorectal liver metastases in humans. Methods used in the past for the detection of CEA in various body fluids were cumbersome and time consuming. requiring acid extraction. extensive dialysis. and column purification. Single-step. solid-phase radioimmunoassays. designed specifically for serum CEA analysis. were developed commercially to replace these methods. Parameters and methodology necessary to adapt these kits for Parameters and methodology necessary to adapt these kits for use with gallbladder bile are presented here. A combination of pretreatment procedures for bile. before radioimmunoassay. permit rapid. reproducible. and accurate measurement of CEA levels in gallbladder bile.
Liver transplantation for hepatoblastoma. The American experience, The current role of liver transplantation in treating malignant tumors of the liver is uncertain. except for select histologic types. Pooled data on the results of liver transplantation in 12 children with hepatoblastoma is presented here. One half of the children are alive 24 to 70 (44 +/- 19) months after transplantation with no evidence of recurrence. Three patients (25%) died of tumor recurrence and three (25%) died of other causes. Unifocal and intrahepatic tumors were associated with better prognosis compared to the multifocal tumors and tumors with extrahepatic spread (p = 0.04 and 0.13). Microscopically vascular invasion and the predominance of embryonal and/or anaplastic epithelium were associated with a poor prognosis compared to the tumors with no vascular invasion and with predominantly fetal epithelium (p = 0.08 and 0.1). It is concluded that continued efforts to treat unresectable hepatoblastomas by liver transplantation is justified and the role of adjuvant chemotherapy in improving the results needs to be better defined.
The role of calcium ions and calcium channel entry blockers in experimental ischemia-reperfusion-induced liver injury, Verapamil administered before treatment. but not after treatment. had a beneficial effect on a 90-minute warm ischemia-reperfusion rat liver injury model. The possible activation of proteases converting the xanthine dehydrogenase to xanthine oxidase. the significant mitochondrial calcium loading during the ischemic period. and the potentiation of calcium and oxygen-derived free radicals to promote injury to mitochondria are mechanisms supported by this study. based on both histologic observations and on the pattern of enzyme leak after the acute ischemic event.
Organ procurement in patients with fatal head injuries. The fate of the potential donor, A 46-month. retrospective review of all victims of fatal head injury at a level 1 trauma center was undertaken to estimate donor organ availability. determine causes of procurement failure. and analyze the functional results of organs transplanted from this group of donors. Causes of procurement failure in 126 patients who died principally from their head injuries included failure of initial resuscitation (14%). ineligibility (28%). failure of physiologic support (14%). and denial of consent (20%). Of 73 eligible donors. 29 (41%) were able to donate one or more vascular organs (heart. liver. kidney). In only one instance was an eligible donor not appropriately identified as such. Failure of physiologic support to prevent early death (25%). and denial of consent (34%) were found to be the two major. potentially remediable causes of procurement failure in this series. Based on this data. an estimated 29 patients/million population/year will survive initially and meet all eligibility requirements for organ donation. Data on 47 kidneys transplanted from the donor group demonstrated a 77% overall graft survival rate at a follow-up period averaging 23 months. Prolonged donor hypotension. but not the use of high-dose vasopressors. adversely affected allograft survival. The current limitations of organ procurement in victims of fatal head injury stem from a limited ability to maintain cardiopulmonary function long enough for the procurement process to be completed and a high overall rate (46%) of denial of consent for organ harvest by next of kin.
Splenic trauma. Choice of management, The modern era for splenic surgery for injury began in 1892 when Riegner reported a splenectomy in a 14-year-old construction worker who fell from a height and presented with abdominal pain. distension. tachycardia. and oliguria. This report set the stage for routine splenectomy. which was performed for all splenic injury in the next two generations. Despite early reports by Pearce and by Morris and Bullock that splenectomy in animals caused impaired defenses against infection. little challenge to routine splenectomy was made until King and Schumacker in 1952 reported a syndrome of "overwhelming postsplenectomy infection" (OPSI). Many studies have since demonstrated the importance of the spleen in preventing infections. particularly from the encapsulated organisms. Overwhelming postsplenectomy infection occurs in about 0.6% of children and 0.3% of adults. Intraoperative splenic salvage has become more popular and can be achieved safely in most patients by delivering the spleen with the pancreas to the incision. carefully repairing the spleen under direct vision. and using the many adjuncts to suture repair. including hemostatic agents and splenic wrapping. Intraoperative splenic salvage is not indicated in patients actively bleeding from other organs or in the presence of alcoholic cirrhosis. The role of splenic replantation in those patients requiring operative splenectomy needs further study but may provide significant long-term splenic function. Although nonoperative splenic salvage was first suggested more than 100 years ago by Billroth. this modality did not become popular in children until the 1960s or in adults until the latter 1980s. Patients with intrasplenic hematomas or with splenic fractures that do not extend to the hilum as judged by computed tomography usually can be observed successfully without operative intervention and without blood transfusion. Nonoperative splenic salvage is less likely with fractures that involve the splenic hilum and with the severely shattered spleen; these patients usually are treated best by early operative intervention. Following splenectomy for injury. polyvalent pneumococcal vaccine decreases the likelihood of OPSI and should be used routinely. The role of prophylactic penicillin is uncertain but the use of antibiotics for minor infectious problems is indicated after splenectomy.
The role of calcium channel blockers in the treatment of essential hypertension, Calcium channel blockers. originally developed for the treatment of angina and supraventricular arrhythmias. have been shown to lower elevated blood pressure effectively in hypertensive patients. Verapamil. nifedipine. and diltiazem represent prototype compounds for unique chemical classes with differing pharmacologic properties. These drugs lower elevated blood pressure with efficacy comparable with other commonly used antihypertensives. Combination therapy with other agents usually results in an additive response. Side effects are usually mild and reversible and usually are an extension of the drug's pharmacologic effects. Moreover. adverse metabolic effects on lipid. glucose. or potassium levels are not common. Because of the excellent antihypertensive effects of calcium channel blockers and their potential importance in a variety of other disease states. these agents should be routinely considered for use as a first-line antihypertensive agent in appropriately selected patients with hypertension of any severity as part of a comprehensive plan to minimize cardiovascular risk.
Alanine aminotransferase in clinical practice. A review, Alanine aminotransferase is an enzyme produced mainly in the liver. When serum activity is measured. it provides a marker of hepatic disease. This review explores the biochemistry and laboratory analysis of alanine aminotransferase in terms of its significance in human health and disease. Cut-off levels that define abnormality are rather arbitrary and this decreases the specificity of the test in apparently healthy patients. A small. but important. group of patients with alanine aminotransferase abnormality have underlying liver disease that may be treatable. Most can be diagnosed based on history. physical examination. and biochemical-serological profiles. Liver biopsy can complement the diagnostic process in selected circumstances. Literature pertaining to this is critically reviewed.
Comparative study of a microporous cholestyramine analogue (filicol) and gemfibrozil for treatment of severe primary hypercholesterolemia. Short- and long-term results, The hypolipidemic effect of gemfibrozil in severe hypercholesterolemia is not well established. Fifty patients with primary hypercholesterolemia (including 18 patients with familial hypercholesterolemia) and stable low-density lipoprotein cholesterol levels greater than 3.90 mmol/L (greater than 150 mg/dL) (6.10 +/- 1.30 [SD] mmol/L; 236 +/- 50 mg/dL) while on a hypolipidemic diet were assigned to treatment for 12 weeks with either 9 g/d of filicol. a microporous cholestyramine analogue. or 1.2 g/d of gemfibrozil in a randomized clinical trial. Tolerance was good with both drugs. Filicol and gemfibrozil caused similar decrements of total cholesterol (14% for both). low-density lipoprotein cholesterol (20% and 18%. respectively). and apolipoprotein B (16% and 21%. respectively). Close to 40% of the patients had decreases of greater than 25% in low-density lipoprotein cholesterol levels with both drugs. Gemfibrozil. but not filicol. significantly increased plasma high-density lipoprotein cholesterol (16%) and apolipoprotein A-I (17%) levels and reduced triglyceride levels (35%). No loss of efficacy was observed with either drug in subsets of patients who had a good 12-week response rate and had extended therapy for up to 12 months. This study demonstrates that gemfibrozil may have a beneficial effect on all aspects of the plasma lipid profile in patients with severe hypercholesterolemia. a clinical situation where it can be used with potential advantages over standard doses of anion-exchange resins.
A standard heparin nomogram for the management of heparin therapy, A nomogram for the adjustment of heparin dosage was developed to standardize heparin therapy and to reduce delays in achieving and maintaining a therapeutic activated partial thromboplastin time (APTT) result. Fifty consecutive patients with acute venous thromboembolism had their continuous intravenous heparin therapy adjusted according to this heparin nomogram. The effect of the nomogram on heparin therapy in these patients was compared with data from 53 historical control patients. The proportion of patients in the nomogram group who reached a therapeutic APTT at 24 hours after the start of heparin therapy was 66%. which increased to 81% at 48 hours. In contrast. 37% and 58% of the control patients reached a therapeutic APTT at 24 and 48 hours. respectively. The percentage of therapeutic APTT results of the total number of APTT determinations was greater in the nomogram patients than controls. The use of this heparin nomogram resulted in (1) achieving a therapeutic APTT at 24 and 48 hours in a large proportion of patients and (2) reduced periods of inadequate anticoagulation and overanticoagulation during heparin therapy.
Deleterious effects of criminal victimization on women's health and medical utilization, The long-term consequences of criminal victimization on physical health were examined among 390 adult women (74 nonvictims and 316 victims of crime). Data included health status self-ratings and objective service utilization. Findings indicated that severely victimized women. compared with nonvictims. reported more distress and less well-being. made physician visits twice as frequently in the index year. and had outpatient costs that were 2.5 times greater. Criminal victimization severity was the most powerful predictor of physician visits and outpatient costs. Utilization data across 5 years preceding and following crime were obtained from 15 rape victims. 26 physical assault victims. and 27 noncontact crime victims and were compared with five continuous years of utilization among 26 nonvictims. Victims' physician visits increased 15% to 24% during the year of the crime compared with less than 2% change among nonvictims. We conclude that these long-term deleterious effects suggest that criminally victimized women's needs for medical treatment transcend the traditional focus on emergency care and forensic evaluation.
Ventricular tachycardia during routine treadmill testing. Risk and prognosis, Exercise-induced ventricular tachycardia during exercise testing is considered to increase risk during testing. Moreover. exercise-induced ventricular tachycardia has been considered to confer a poor prognosis although this has not been specifically studied. On a retrospective review of 3351 patients who had undergone routine clinical exercise testing between September 1984 and June 1989. we identified 55 patients with exercise-induced ventricular tachycardia. The mean follow-up was 26 months (range. 2 to 58 months). Fifty patients had nonsustained ventricular tachycardia during exercise testing and one of these patients died due to congestive heart failure during the follow-up period. Five patients had sustained ventricular tachycardia during exercise testing and one died suddenly 7 months after the test. Ventricular tachycardia was reproduced in only two of the 29 patients who underwent repeated exercise testing. Ventricular tachycardia during routine clinical exercise testing occurred rarely (prevalence of 1.5%) and was not associated with complications during testing. The total mortality in the exercise-induced ventricular tachycardia group (3.6%) was not significantly different from the mortality in the entire population (5.1%). Nonsustained ventricular tachycardia occurring during clinical exercise testing is not an independent marker of a poor prognosis.
A population-based study of functional status and social support networks of elderly patients newly diagnosed with cancer, We assessed the functional status and social support networks of 799 men and women aged 65 years or older newly diagnosed with cancer and living in six New Mexico counties. Functional limitations included depending on others for transportation (33%) and mental incompetence or poor recent memory (42%). The percentage of patients with functional limitation increased sharply with increasing age. In a substantial number of patients there was also evidence for poor social support networks; 26.5% of subjects lived alone and 38.9% had no children living in the vicinity. In a multiple logistic regression analysis. the predictors of having a poor social support network included non-Hispanic white ethnicity. advanced age. low income. and being a recent migrant to the area. Subjects with functional limitations were more likely to have poor social support networks than subjects without such limitations. The deleterious combination of impaired functional status and a limited social support network may explain why elderly cancer patients are at increased risk for not receiving appropriate therapy. Given the potential complexities involving the evaluation and appropriate treatment of cancer. care must be taken to adequately assess functional status and support mechanisms of older patients. and to provide adequate support to ensure compliance with treatment.
Ototoxic reaction to erythromycin, We report a case of bilateral hearing loss in a patient treated with intravenous erythromycin lactobionate. The ototoxic reaction occurred despite the patient's having normal renal and hepatic function and the fact that serum erythromycin levels were within the predicted normal range. In addition to hearing loss. a marked labyrinthic hyporreflexia was also observed. Hearing loss improved after the treatment was discontinued. but labyrinthic abnormalities persisted suggesting that erythromycin had caused a permanent vestibular damage.
Recurrent pigmented melanocytic nevus. A benign lesion, not to be mistaken for malignant melanoma, Melanocytic nevi that recur after incomplete removal are pigmented lesions that may clinically and pathologically simulate malignant melanoma in situ. Five examples of recurrent pigmented melanocytic nevus. with emphasis on light microscopic and immunohistochemical findings. are reported herein. Prominent HMB-45 staining in these nevi may cause further confusion in differentiating them from malignant melanoma. The differential diagnosis of recurrent pigmented melanocytic nevi is discussed. with particular emphasis on distinguishing these lesions from malignant melanoma. Our immunohistochemical observations indicate that the recurrences most likely develop as a result of proliferation of melanocytes remaining in the epidermis and/or adnexae following incomplete removal. The approach and management of recurrent nevi are also discussed.
Secretory carcinoma of the breast, Most studies of secretory carcinoma of the breast have been single case reports or separate analyses of the problem in either children or adults. We studied 10 female patients. aged 5 to 87 years. Most patients presented with a palpable mass. often near the areola. Five of six tumors were estrogen receptor negative; three analyzed for progesterone receptor were positive. Histologic patterns present in varying proportions were "classic" secretory carcinoma with microacini. abundant secretion with papillary features. and with prominent solid and papillary apocrine features. The tumors had strong reactivity for alpha-lactalbumin. S100. and carcinoembryonic antigen (polyclonal) and were negative for gross cystic disease fluid protein and anti-carcinoembryonic antigen (monoclonal). Six patients had mastectomy; four had local excision; none had axillary nodal metastases initially. With follow-up of 3 to 72 months (mean. 47 months; median. 48 months). two patients treated by local excision had local recurrences. one patient had axillary nodal metastases. All patients are alive. Comparison of patients under and over 30 years of age revealed one important difference: younger patients had a longer interval between detection and biopsy-30 vs 2 months. Treatment recommendations are initial wide excision or quadrantectomy with low axillary dissection in most cases and. in premenarchal patients. strong effort to preserve the breast bud without jeopardizing local control.
Intraluminal crystalloids in struma ovarii. Immunohistochemical, DNA flow cytometric, and ultrastructural study, We recently encountered a unique case of follicular variant of papillary carcinoma arising in struma ovarii that contained numerous intrafollicular crystalloids. There was no evidence of capsular or vascular invasion or metastases. though the DNA content of the papillary carcinoma was aneuploid. In contrast. diploid DNA was manifested in the histologically benign thyroid tissue. The nature of the crystalloids and the significance of aneuploid DNA content are discussed.
Cold-induced granulocyte agglutination. A cause of pseudoleukopenia, Transient cold agglutination of her granulocytes developed in a 60-year-old woman with a left upper lobe pneumonia during the acute phase of her illness. This phenomenon was manifested by pseudogranulocytopenia. multiple clumps of granulocytes on her peripheral blood smear. and abnormal distribution of granulocytes and monocytes on the white blood cell histogram when measured on an automated hematology analyzer (Coulter S-Plus IV. Coulter Electronics Inc. Hialeah. Fla). The cause is postulated to be an IgM autoantibody directed against components of the granulocyte membranes. Spurious leukopenia is encountered infrequently with automated hematology analyzers. Cold-induced granulocyte agglutination should be recognized as a potential cause of pseudogranulocytopenia so that white blood cell counts can be accurately reported and unnecessary evaluation of patients for leukopenia can be avoided.
The tall cell variant of papillary carcinoma of the thyroid gland. Comparison with the common form of papillary carcinoma by DNA and morphometric analysis, The tall cell variant of papillary carcinoma of the thyroid manifests a more aggressive behavior than the usual form of papillary carcinoma of the thyroid. Morphometric analysis of nuclear features and DNA analysis may yield information predictive of aggressive behavior. Accordingly. the DNA content and morphometric features of the neoplastic cells of the tall cell variant were measured and compared with measurements obtained from neoplastic cells of the usual form of papillary carcinoma. Six of the 11 tall cell neoplasms were aneuploid. as were four of the eight usual papillary neoplasms. Although benign cells were separated from malignant cells in each case. differences between tall and usual papillary carcinoma cells were not observed regarding DNA content. chromatin texture. or nuclear size and shape. Differences in the clinical behavior of these neoplasms will likely need to be explained on the basis of other characteristics.
Squamous cell carcinoma in situ arising in an ovarian mature cystic teratoma. Report of one case with histopathologic, cytogenetic, and flow cytometric DNA content analysis, A squamous cell carcinoma in situ arose in an ovarian mature teratoma (ie. dermoid cyst) in a 62-year-old woman. Flow cytometric DNA content analysis of paraffin-embedded in situ carcinoma showed a normal DNA content with moderate to high proliferative activity (S-phase fraction estimate. 16% to 18%). Cytogenetic analysis of the in situ cancer and the benign cystic portion of the tumor revealed a 46.XX karyotype. In addition. the benign cystic portion of the tumor revealed homozygous chromosomal heteromorphisms. compared with heterozygous markers found in peripheral blood lymphocytes. These results show that this squamous cell carcinoma in situ was euploid and suggest that the mature cystic teratoma was derived from a single germ cell after meiosis I.
Reference ranges for lymphocyte subsets. A comparison of standard vs rapid whole-blood lysis techniques, Reference ranges for lymphocyte subsets may vary with processing techniques. monoclonal reagents. or analytic methods. We compared reference ranges obtained for T- and B-lymphocyte subsets by means of standard manual whole-blood lysis with a wash step vs a rapid. no-wash whole-blood lysis system. Both techniques demonstrated reference ranges similar to those in previous literature reports. The ranges established with standard and rapid lysis were similar when antibodies directed to the same cluster designation were used. Although slight statistical differences in relative percentages of CD2 and CD3 lymphocytes were observed. these differences were probably not clinically significant. These data indicate that the rapid technique provides a standardized method for enumerating T and B lymphocytes in peripheral blood.
Extramammary Paget's disease of the bronchial epithelium, We report the first case. to our knowledge. of extramammary Paget's disease of the bronchial epithelium. The tumor displayed Paget's cells scattered within the bronchial epithelium in most of the lesion. but infiltrating into the bronchial submucosa and pulmonary parenchyma with microglandular and papillary patterns in some area. In addition to the histologic findings of coexistence with adenocarcinomatous components. in situ involvement into bronchial glands and ducts by Paget's cells was observed. suggesting that extramammary Paget's disease of the bronchial epithelium may be a variant of pulmonary adenocarcinoma. which is associated with bronchial glands.
Clinical spectrum of fungal infections after orthotopic liver transplantation, During a 50-month period. we identified 91 episodes of fungal infection in 72 liver transplant recipients (23.8%). Candida species accounted for 83.5% of cases. Clinical patterns of fungal infections included disseminated infection (19). peritonitis (17). pneumonitis (15). multiple sites of colonization (13). fungemia (11). and other sites (16). The diagnosis of fungal infection was usually made in the first 2 months (84.7% of cases). at a mean time of 16 days after transplantation. Risk factors for fungal infections included retransplantation. Risk score. intraoperative transfusion requirement. urgent status. Roux limb biliary reconstruction (in adults). steroid dose. bacterial infections and antibiotic therapy. and vascular complications. Fungal infections were successfully treated with amphotericin B in 63 cases (74.1%) but were associated with diminished patient survival (50% vs 83.5%). Fungal infection is a frequent source of early morbidity and can be related to well-defined risk factors. suggesting the need for effective prophylaxis.
Effect of dietary fish oil on plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha levels in septic rats, Increased mortality from sepsis is associated with high levels of thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha). Linoleic acid. an n-6 essential fatty acid. is the usual precursor of TXB2 and PGF1 alpha. while fish oil is rich in n-3 essential fatty acid. the precursor of less active moieties. Rats were fed chow. an essential fatty acid-deficient diet. or an essential fatty acid-deficient diet supplemented with linoleic acid or fish oil for 2 weeks. The animals then underwent a sham operation or cecal ligation and puncture to induce sepsis. Six hours later. blood was obtained for analysis. The chow and linoleic acid diets produced significant (twofold to fivefold) increases in levels of both TXB2 and PGF1 alpha after sepsis. The essential fatty acid-deficient diet and fish oil diet protected against increases in levels of TXB2 or PGF1 alpha during sepsis. Dietary restriction of linoleic acid or fish oil supplementation may play an important role in altering the inflammatory mediator response to sepsis.
Increased gut permeability following burn trauma, Twenty female Hartley guinea pigs. weighing 350 to 400 g. were given a 30% full-thickness burn injury. Gastrointestinal permeability was assessed before burn and on postburn days 1 through 3. 7. and 14 by administering 5 mL of an isotonic mixture of 8% lactulose and 1.15% L-rhamnose by gavage and measuring the urinary excretion for the next 7 hours. In normal guinea pigs. lactulose (molecular weight. 342d) is mostly absorbed by the paracellular route. whereas L-rhamnose (molecular weight. 164 d) is mostly absorbed by the transcellular route. Gut permeability to L-rhamnose did not increase after burn injury (211 micrograms before burn vs 230. 260. 180. 238. and 221 micrograms on days 1. 2. 3. 7. and 14. respectively. after burn). By contrast. gut permeability to lactulose increased significantly and was greatest in the first 48 hours after burn injury (60 micrograms before burn vs 380. 354. 203. 364. and 279 micrograms on days 1. 2. 3. 7. and 14. respectively. after burn). Gut permeability to low-molecular-weight compounds increases immediately after burn trauma. and this may be by a paracellular rather than transcellular mechanism.
Hepatic extraction of indocyanine green is depressed early in sepsis despite increased hepatic blood flow and cardiac output, Although active hepatocellular function is depressed during sepsis. it is not known whether this occurs in the very early stages of sepsis and whether it is due to depressed cardiac output or hepatic blood flow. To study this. rats were subjected to sepsis by cecal ligation and puncture and hepatocellular function was determined at various intervals thereafter by assessing the ability of the liver to clear different doses of indocyanine green. The indocyanine green concentration was continuously measured in vivo with a fiberoptic catheter and an in vivo hemoreflectometer. Maximal velocity and kinetic constant of the clearance of indocyanine green. hepatic blood flow. and cardiac output were determined in experimental and sham-operated rats. The results demonstrate that hepatic blood flow and cardiac output increased 2 to 10 hours after cecal ligation and puncture. while hepatocellular function (maximum velocity and kinetic constant) was decreased even 2 hours following cecal ligation and puncture. No linear correlation between hepatocellular function and hepatic blood flow or cardiac output was found under such conditions. The extremely early depression in active hepatocellular function. despite the increased hepatic blood flow and cardiac output. may form the basis for cellular dysfunctions leading to multiple organ failure during sepsis.
Effects of high-dose IgG on survival of surgical patients with sepsis scores of 20 or greater, Sixty-two consecutive septic surgical patients receiving standard multimodal intensive care unit treatment who developed a sepsis score of 20 or greater (day 0) were randomized to receive 0.4 g/kg of either intravenous IgG (29 patients) or human albumin (controls; 33 patients). repeated on days +1 and +5. in a prospective. double-blind. multicenter study. The two groups were similar in age. initial sepsis scores. and acute physiology and chronic health evaluation II score. A significantly lower mortality was recorded in the IgG-treated group (38%) than in controls (67%). Septic shock was the cause of death in 7% of IgG-treated patients and in 33% of controls. The results of this study indicate that high-dose IgG improves survival and decreases death from septic shock in surgical patients with a sepsis score of 20 or greater.
Clostridium difficile disease in a department of surgery. The significance of prophylactic antibiotics, A clustering of Clostridium difficile-associated disease in a department of surgery prompted a program of infection control and the evaluation of contributing factors. Fifty patients had diarrhea and positive assays for C difficile cytotoxin during the study period. Twenty-one of the 36 cases that developed among patients admitted to the surgical services occurred on two adjacent general surgery wards that shared attending surgeons and house staff. Perioperative prophylactic antibiotics predated C difficile-associated disease in 20 patients. 12 of whom had short courses (less than 24 hours). Symptoms were typically nonspecific and early diagnosis may be difficult. Incidence remained high. despite infection control measures. until the coincidental closure of two surgical wards. Clostridium difficile-associated disease is a nosocomial infection that can be associated with short courses of prophylactic antibiotics. Recommendations regarding the use of perioperative prophylaxis should recognize C difficile-associated disease as a significant potential complication.
The vagus nerve, gastric secretions, and their relationship to peptic ulcer disease, Although peptic ulcer disease was known to the ancients. the process by which the disease was produced remained a mystery. As advances were made in medicine and science. so too were advances made in the understanding of digestion and gastrointestinal disease. The treatment of peptic ulcer disease improved as our understanding of the digestive process grew. The current surgical treatment for peptic ulcer disease follows the principals articulated by Lester R. Dragstedt. MD. PhD. which he based on his observations in the research laboratory. We present a historical perspective of the role of the vagus nerve in the control of gastric secretions and its relationship to peptic ulcer disease. placing particular emphasis on Dragstedt's contributions.
P300 brain activity in seizure patients preceding temporal lobectomy, Event-related potentials were recorded over occipital and parietal scalp from 20 patients suffering from intractable partial complex seizures prior to undergoing a temporal lobectomy. Subjects were presented with language and nonlanguage visual stimuli using a divided-field. "odd-ball" paradigm. Although behavioral performance (button-press accuracy. reaction time. and running counts) was comparable across all groups (although accuracy was worse for those in the left temporal group). patients showed tremendous variability in both the amplitude and latency of the P300 response. Particularly notable was the observation that more slow wave activity was present among the patients than among the control subjects. and those scheduled for a left temporal resection evinced more amplitude reduction than those scheduled for a right temporal resection. In addition. a number of patients appeared not to show a P300 response at all. These results are discussed in the context of the utility of using noninvasive event-related potential measures to examine both memory impairment and the integrity of the neural structures that mediate memory functioning in certain patient populations.
Age at onset of Alzheimer's disease. Relation to language dysfunction, A later age at onset of Alzheimer's disease (AD) was found to be related to diminished language performance in 86 patients with probable AD. A hierarchical linear model was constructed to assess effects of age at onset and disease duration on the performance of patients with AD on four language tasks (naming. reading. auditory comprehension. and writing to dictation) after controlling for disease severity. Results of univariate analysis. in which the dependent variable was the averaged language task performances. revealed a significant effect for age at onset of AD. but not for disease duration. To assess the possibility that the relationship between the age at onset of AD and language performance reflects effects of normal aging. the language tasks were given to 33 normal subjects of similar ages who scored perfectly on dementia severity measures. A convincing relationship was not found between test score and age.
Anatomic, metabolic, neuropsychological, and molecular genetic studies of three pairs of identical twins discordant for dementia of the Alzheimer's type, Three pairs of twins. each with proved monozygosity. were shown to be discordant for dementia of the Alzheimer's type and to have remained discordant for periods of 8 to 11 years. Dementia of the Alzheimer's type was demonstrated by history; serial clinical examinations; serial measurements of cerebral glucose utilization using positron emission tomography and of cerebral ventricular volumes and of rates of change of volumes using quantitative computed tomography; and by serial neuropsychological tests. The results of each of these measures showed no evidence of clinical abnormality in any unaffected twin. DNA markers from the proximal long arm of chromosome 21 did not distinguish between the affected and the unaffected member of any pair of identical twins. Family pedigrees were negative for Alzheimer's disease. The results suggest that environmental or other nongenetic factors contribute to Alzheimer's disease in discordant monozygotic twins. or that some cases arise by a postzygotic somatic mutation.
The distribution of cerebral muscarinic acetylcholine receptors in vivo in patients with dementia. A controlled study with 123IQNB and single photon emission computed tomography, A high-affinity muscarinic receptor antagonist. 123IQNB (3-quinuclidinyl-4-iodobenzilate labeled with iodine 123). was used with single photon emission computed tomography to image muscarinic acetylcholine receptors in 14 patients with dementia and in 11 healthy controls. High-resolution single photon emission computed tomographic scanning was performed 21 hours after the intravenous administration of approximately 5 mCi of IQNB. In normal subjects. the images of retained ligand showed a consistent regional pattern that correlated with postmortem studies of the relative distribution of muscarinic receptors in the normal human brain. having high radioactivity counts in the basal ganglia. occipital cortex. and insular cortex. low counts in the thalamus. and virtually no counts in the cerebellum. Eight of 12 patients with a clinical diagnosis of Alzheimer's disease had obvious focal cortical defects in either frontal or posterior temporal cortex. Both patients with a clinical diagnosis of Pick's disease had obvious frontal and anterior temporal defects. A region of interest statistical analysis of relative regional activity revealed a significant reduction bilaterally in the posterior temporal cortex of the patients with Alzheimer's disease compared with controls. This study demonstrates the practicability of acetylcholine receptor imaging with 123IQNB and single photon emission computed tomography. The data suggest that focal abnormalities in muscarinic binding in vivo may characterize some patients with Alzheimer's disease and Pick's disease. but further studies are needed to address questions about partial volume artifacts and receptor quantification.
Widespread functional effects of discrete thalamic infarction, In order to investigate functional effects of various thalamic structures on metabolism in remote. morphologically intact cerebral regions. we used positron emission tomography of (18F)-2-fluoro-2-deoxy-D-glucose to study regional cerebral metabolic rates of glucose (rCMRGlu) in 11 patients with chronic unilateral or bilateral infarcts strictly confined to the thalamus. Patients were grouped according to computed tomographic scans showing anterior (three). medial (four). or posterior (four) lesions. Compared with a matched group of 11 healthy subjects (hemispheric CMRGlu 35.2 +/- 3.49 mumol/100 g per minute). glucose metabolism was significantly lower in the hemisphere ipsilateral to the infarction (31.2 +/- 2.97 mumol/100 g per minute). Patients with bilateral infarcts had lower hemispheric CMRGlu (29.9 +/- 2.74 mumol/100 g per minute) than those with unilateral lesions (32.2 +/- 2.97 mumol/100 g per minute). Depending on infarct location within the thalamus. there was differential depression of rCMRGlu. with the largest effects on frontal and occipital areas in medial infarctions. Except for ipsilateral thalamic deactivation. metabolic patterns with anterior thalamic infarcts were close to normal. while posterior infarcts mostly depressed rCMRGlu in the visual and in the inferior limbic cortex. Cerebellar metabolic rates were within normal limits in most cases. These patterns of regional cerebral deactivation may be related to categories of thalamic projections--intrathalamic. to limbic system and basal ganglia. diffuse to most cortical areas. and specific to defined neocortical areas. Even small brain lesions may have widespread functional sequelae. potentially demonstrable by positron emission tomography.
Treatment of multiple sclerosis with hyperbaric oxygen. Results of a national registry, Three hundred twelve patients were entered into a long-term study of effects of hyperbaric oxygen on multiple sclerosis. The protocol called for an initial 20 treatments in either the monoplace or multiplace chamber on a daily basis followed by monthly booster treatments for 2 years. One hundred seventy neurologists and 22 institutions provided data for this study. There was no control group. but the study was based on Schumacher's postulation that a scientifically valid study to test the efficacy of a new therapy was possible by choosing patients who were definitively diagnosed with multiple sclerosis and following them up for 2 years after the imposed treatment. If the overwhelming majority of the subjects failed to get worse over the 2-year observation period. the efficacy of the treatment would be manifest. The expanded Kurtzke Disability Status Scale (EDSS) was used to assess the severity of the disease state. The dropout rate was high with only 76% (237 of 312 patients) finishing the initial 20 treatments. Twenty-two percent (69 of 312) finished 1 year of booster therapy. and 9% (28 of 312) completed 2 years of monthly boosters. The mean deterioration on the Kurtzke EDSS score was 0.93 or almost a full step from the beginning of treatment until the last evaluation. There was no difference in outcome between those who had the shortest and longest periods of time between onset of symptoms and hyperbaric oxygen treatment. Treatment pressure made no difference in outcome. Changes in the Kurtzke EDSS score bore no relationship to the use of booster treatment. Patients who were reasonably well off at the onset of treatment with initial Kurtzke EDSS scores of 1 or 2 (n = 21) deteriorated by an average of 1.7 Kurtzke points. Those patients whose initial Kurtzke EDSS scores were greater than 2 (n = 164) deteriorated on an average of 0.82 points. Of interest was that 19.5% (39 of 200) of the patients reported a temporary improvement in bladder function. but improvement was maintained in only 11 patients (5.5%) at 2-year follow-up. Fifteen patients (7.5%) indicated long-term worsening. There was no significant change in the working status of the patients following hyperbaric oxygen treatment. Although this study treated the patients in accordance with protocols reported to produce a benefit in multiple sclerosis. we were unable to substantiate any useful long-term effect of hyperbaric oxygen therapy.
The effect of sleep on the dyskinetic movements of Parkinson's disease, Gilles de la Tourette syndrome, Huntington's disease, and torsion dystonia, The effect of sleep on the involuntary movements or dyskinesias in Parkinson's disease. Huntington's disease. primary and secondary torsion dystonia. and Gilles de la Tourette syndrome was studied in a total of 52 patients and 10 normal subjects using video electroencephalographic telemetry. Movements typical of the wake pattern were seen occasionally during unequivocal sleep in all but two completed studies. and in each condition reappeared under similar circumstances. The movements were most likely to occur after awakenings or lightenings of sleep. or in stage one sleep. The movements were very rare during the deeper phases of sleep. Those movements that occurred during sleep without awakenings were usually preceded by arousal phenomena and. rarely. by sleep spindles or slow waves. The control group showed normal "semipurposeful" movements under the same conditions during sleep. The rare appearance of the different dyskinesias and normal movements under similar circumstances during sleep could be a result of common effects on the generator systems or changes in the excitability of the final common motor pathway.
Posttraumatic torticollis, We report six cases of torticollis precipitated by neck trauma. The dystonia began 1 to 4 days after the trauma and differed clinically from idiopathic torticollis by marked limitation of range of motion. lack of improvement after sleep ("honeymoon period"). and absence of geste antagonistique. Worsening with action was not present; nor was there improvement with support as seen with idiopathic torticollis. Onset of pain immediately after the trauma and marked spasms of the paracervical muscles were other predominant features. Anticholinergic therapy was without benefit; however. some improvement occurred with botulinum toxin injection. It is concluded that torticollis can be caused by peripheral trauma and that it has unique clinical characteristics.
An early description of slowly progressive aphasia, Slowly progressive aphasia without generalized dementia has become an important issue of present-day neuropsychological research. Historically. credit for the first description is usually given to Pick. Another German-speaking author who has published a vivid description of a pertinent cases is Pick's contemporary. Max Rosenfeld. This author has also observed a patient with slowly progressive spatial disorientation and visual recognition deficit. and he has discussed these patients in a remarkably modern way in the context of partial atrophy of the brain.
Anterior femoral cutaneous nerve injury following femoral artery reconstructive surgery, Two cases are presented exhibiting symptoms and signs of bilateral anterior femoral cutaneous nerve injury. clinically sparing femoral nerve branches to the saphenous nerve and quadriceps muscles. This occurred following surgical dissection in the femoral triangles associated with femoral artery reconstructive surgery. Anterior femoral cutaneous nerve injury should be considered when anterior medial thigh pain and numbness occur following aortofemoral bypass graft surgery and other types of femoral artery reconstructive surgery.
Frontal impairment and hypoperfusion in neuroacanthocytosis, Cerebral blood flow tomography. by xenon 133 inhalation or HMPAO (99mTc-d. l-hexamethyl-propylene amine oxime) technetium Tc 99m injection. revealed a severe hypoperfusion in both frontal lobes of a 40-year-old woman with confirmed neuroacanthocytosis. This finding occurred in conjunction with neuropsychological deficits consistent with selective frontal lobe dysfunction. This observation is the first documentation of this type of dementia in neuroacanthocytosis.
Falls in elderly patients with glaucoma, We analyzed the determinants of serious falls among 489 ambulatory elders aged 65 years and older who received a comprehensive examination at a glaucoma consultation service. For the previous year. at least one fall requiring medical attention or restricted activity was reported by 9.6% (95% confidence interval [CI]. 7.0% to 12.2%) of participants. Using logistic regression to adjust for potential confounding variables. the greatest single risk factor for falls was the use of nonmiotic topical eye medications (odds ratio [OR]. 5.4; 95% Cl. 1.8 to 16.4). Additional risk factors for falls were female sex (OR. 2.3; 95% Cl. 1.1 to 4.7) and use of cardiac medications (OR. 2.5; 95% Cl. 1.1 to 5.6). Three other characteristics were also associated with the risk of falls: use of miotic eye medications (OR. 3.2; 95% Cl. 1.0 to 10.1); visual field impairment of 40% or greater (OR. 3.0; 95% Cl. 0.94 to 9.8); and use of sedatives (OR. 2.4; 95% Cl. 0.89 to 6.7). These findings suggest that ocular and systemic medications are the major predictors of falls even in this elderly population seeking ophthalmologic care for glaucoma. Medications appear to pose a greater risk for falls than even major visual impairment.
Loculated fluid. A previously undescribed fluorescein angiographic finding in choroidal neovascularization associated with macular degeneration. Macular Photocoagulation Study Reading Center, The Foveal Photocoagulation Study. a component of the Macular Photocoagulation Study. is designed to evaluate whether laser treatment can reduce the risk of severe visual loss in eyes with well-defined choroidal neovascular membranes associated with macular degeneration that extend through the foveal center. On one third of the 554 baseline angiograms of study patients enrolled in and whose eyes were graded in the study as of January 31. 1990. the Reading Center staff has noted an unusual pattern of hyperfluorescence in the late-transit frames that has not been described previously. This pattern. which we call "loculated fluid." consists of a well-demarcated area of hyperfluorescence that appears to represent pooling of fluorescein in a compartmentalized space anterior to the choroidal neovascular leakage. Although the loculated fluid may conform to a pattern of typical cystoid macular edema. it can also pool within an area deep to the sensory retina in a shape that does not bear any resemblance to cystoid macular edema. This pattern is important to recognize because it (1) should not be confused with the angiographic pattern or extent of choroidal neovascularization and (2) should be differentiated from a serous detachment or tear of the retinal pigment epithelium.
Low-dose aspirin and risks of cataract in a randomized trial of US physicians, Observational studies have raised the question of a possible benefit of aspirin on the development of cataract. The Physicians' Health Study. a randomized double-masked placebo-controlled trial among 22.071 male physicians. aged 40 to 84 years. provided the opportunity to collect information about whether low-dose aspirin therapy (325 mg on alternate days) affects the development or extraction of cataract. There were 173 age-related cataracts among those physicians assigned to aspirin therapy and 180 among those given placebo (relative risk. 0.95; 95% confidence interval. 0.74 to 1.22). Cataract extractions were less frequent in the aspirin than in the placebo group. but this difference was not statistically significant (relative risk. 0.80; 95% confidence interval. 0.56 to 1.15). Among younger men (aged 40 to 59 years). the relative risks were 0.62 (95% confidence interval. 0.40 to 0.94) for cataract development and 0.67 (95% confidence interval. 0.38 to 1.31) for cataract extraction. These randomized trial data tend to exclude any large benefit of aspirin. While the overall findings concerning cataract development seem to be null. the data on extraction of age-related cataract. while not statistically significant. cannot exclude a possible small to moderate benefit of alternate-day aspirin therapy on the extraction of age-related cataract.
Exposure to phenothiazine drugs and risk of cataract, Clinical reports have indicated an increased risk of ocular opacities in users of phenothiazine drugs. and some recent epidemiologic studies have found an association between cataract and a history of tranquilizer use. To examine the effects of major tranquilizers (phenothiazines and haloperidol) on the risk of cataract extraction. while controlling for suspected risk factors such as diabetes and steroid use. a matched cohort study was performed using information from a large health maintenance organization in Seattle. Wash. The use of either antipsychotic or other phenothiazine drugs increased the risk of cataract extraction by roughly 3.5 times in individuals who were both current users and were exposed some time in the 2 to 5 years prior to their extraction. Risk was also increased in individuals with prior use of antidiabetic agents. systemic steroids. and benzodiazepines. Contrary to some prior reports. there was no elevated risk associated with use of antihypertensives. and there was no protective effect for aspirin. acetaminophen. or ibuprofen.
Effects of antiflammins on endotoxin-induced uveitis in rats, Antiflammins are phospholipase A2-inhibitory. anti-inflammatory. synthetic oligopeptides derived from the region of the highest amino-acid sequence similarity between uteroglobin and lipocortin I. Endotoxin-induced uveitis is a model for anterior uveitis of the eye. which has been suggested to be induced through phospholipase A2 activation. In a preliminary report we demonstrated that topical administration of antiflammins could inhibit endotoxin-induced uveitis in rats. In this study. the anti-inflammatory effects of antiflammins were compared with those of corticosteroids on endotoxin-induced uveitis as measured by phospholipase A2 enzyme activity. inflammatory cell counts in the aqueous humor. and histopathologic features. Antiflammins are as effective as corticosteroids in their ability to suppress endotoxin-induced uveitis.
Autogenous fascial grafts for exposed retinal buckles, Three patients with exposed scleral buckling elements received autogenous fascial grafts as an alternative to buckle removal. All three patients had successful coverage of their scleral buckles. There were no redetachments or infections. One patient had a postoperative ptosis that required repair. Autogenous fascial grafts are useful procedures in patients with exposed retinal buckles who have a significant risk of retinal redetachment with buckle removal.
Prevalence of HIV-1 infection in the Kagera region of Tanzania: a population-based study, A population-based survey was carried out in the Kagera region of the United Republic of Tanzania in 1987 to determine the magnitude of HIV-1 infection and to study associated risk factors. The region was divided into one urban and three rural zones. A multistage cluster sampling technique was adopted. Antibodies to HIV-1 were determined by enzyme-linked immunosorbent assay and confirmed by Western blot analysis. A total of 2.475 adults (aged 15-54 years) and 1.961 children (aged 0-14 years) was studied. The overall prevalence of HIV-1 infection among adults was 9.6%. with a higher prevalence in the urban zone (24.2%) than in the three rural zones (10.0. 4.5 and 0.4%. respectively). The corresponding figures for children were 1.3% overall: 3.9% in the urban area and for the rural areas 1.2. 0.8 and 0.0%. respectively. The age-specific seroprevalence for adults was highest in the age group 25-34 years. The age-standardized sex-specific prevalence was higher among women than men in the urban zone. while it was the same in the rural zones. Change of sexual partners among adults was associated with an increased risk of HIV-1 seropositivity. Travelling outside the region but within the country was also found to be associated with increased risk of HIV-1 infection but only in the rural population.
The evolutionary dynamics of HIV-1 quasispecies and the development of immunodeficiency disease, This paper presents a theory to explain the development of immunodeficiency disease after a long and variable incubation period of infection with HIV-1. Two assumptions are central to the theory: (1) mutation via reverse transcription during viral replication can generate viral strains resistant to neutralization by antibodies specific to earlier mutants in a particular host; (2) the virus can kill the CD4-positive lymphocytes that play a role in mounting an immunological attack directed at the virus. The theory is examined via the development of a mathematical model which reveals that an increasing number of antigenically distinct viral strains may overwhelm the immune system of the host. As the viral diversity increases beyond a certain level the immune system is unable to suppress the population growth of all the strains simultaneously. The intuitive explanation of this pattern of model behaviour lies in the assumption that each virus can kill CD4-positive lymphocytes that are specific to any of the viral strains. but each lymphocyte only directs immunological attack against a single viral strain.
A cohort study of 89 HIV-1-infected adult patients contaminated by blood products: Bordeaux 1981-1989. Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (GECSA) [published erratum appears in AIDS 1991 Mar;5(3):354, A hospital-based surveillance of HIV infection was implemented in the Bordeaux Regional University Hospital (France). This reporting system. initiated by the Groupe d'Epidemiologie Clinique du SIDA en Aquitaine. identified and followed-up 89 adult patients with transfusion-associated HIV-1 infection (7.2% of all reported cases). Contamination occurred between August 1981 and June 1985 and diagnosis was made between 1985 and 1989. By 30 June 1990. 43 patients (48.3%) had full-blown AIDS. and 28 of them had died. The mean follow-up period was 66 months (s.d. 16 months). The mean incubation period. i.e. The time interval between the contaminating transfusion and the development of full-blown AIDS. was 62 months [median 73 months; 95% confidence interval (CI) 66-82 months]. Five years after contamination. the cumulative probability of reaching the AIDS stage was 34.2% (95% CI 20.3-49.3%). and the probability of survival was 81.7% (95% CI 72.5-90.0%). From this surveillance system we estimate that in south-western France at the end of 1989 the cumulative incidence of transfusion-associated HIV-1 infection was at least 126 cases (45.6 per million inhabitants). Although we anticipate an increase in transfusion-associated AIDS cases over the next 5 years. there have been no reports of contamination after 1 August 1985. when systematic screening of HIV antibodies was implemented in French blood banks. This confirms the efficacy of screening in countries like France where the risk of contamination through blood products is now minimal.
Early and specific diagnosis of seropositivity to HIVs by an enzyme-linked immunosorbent assay using env-derived synthetic peptides, We describe and evaluate the sensitivity and specificity of an enzyme-linked immunosorbent assay (ELISA) using a 22-amino-acid peptide corresponding to the carboxy-terminal end of HIV-1 gp120 and two 30-amino-acid long cyclic peptides including the two vicinal cysteines present on HIV-1 gp41 and on HIV-2 gp36. This test was evaluated. Data obtained with the Western blot (WB) and the peptide-based ELISA on a first panel composed of sera from 547 patients attending a specialized outpatient clinic (high-risk population) are in perfect agreement; moreover. 39 samples that had falsely been found positive with a viral lysate-based ELISA were not detected by peptide-based ELISA. The second panel was composed of 309 sera which were difficult to resolve using both WB and viral lysate-based ELISA. Using the peptide-based ELISA. 134 were found clearly positive and 173 clearly negative; only two were falsely positive. Finally. sera from 16 individuals examined at the time of seroconversion gave high absorbancy readings even if they were weakly reactive by WB (weak gp160 band). This test is thus highly sensitive and specific. and capable of detecting early seroconversion. It is also instrumental in clearly defining samples that are found indeterminate in the WB. and consequently it avoids the unnecessary follow-up required when a false-positive result is obtained using viral lysate-based ELISA.
Injecting drug use and female street-working prostitution in Glasgow, There are considerable difficulties associated with calculating the prevalence of covert. illegal and stigmatized activities. This paper outlines new methods we have developed for calculating the prevalence of both drug-injecting street prostitution and non-injecting street prostitution in Glasgow. Our data indicate that Glasgow has a much higher level of injecting drug use than has been reported among prostitutes in other British cities.
An echocardiographic assessment of atrial mechanical behaviour, Relations between movement of the atrioventricular ring and changes in left atrial and ventricular dimensions were studied by echocardiography and compared with apexcardiography and Doppler mitral flow velocity traces in 20 healthy controls and in patients with left ventricular hypertrophy (n = 28) or dilatation (n = 16). During left ventricular systole the atrioventricular ring. a structure common to ventricle and atrium. moved towards the ventricular apex. thus increasing left atrial volume. This action matched pulmonary venous return because it was in phase with the transverse left atrial dimension measured from aortic root to posterior left atrial wall. During early diastole. the mitral ring moved rapidly towards the atrium as transmitral flow accelerated. This requires a force directed from ventricle to atrium. likely to be the result of elastic recoil arising from compression of the ventricular myocardium or stretching of the atrial myocardium during ventricular systole. Two additional mechanisms of ventricular filling with atrial systole were recognised: (a) an increase in ventricular volume as the atrioventricular ring moved upwards and (b) transverse left ventricular expansion by pressure driven transmitral flow. The former is undetectable by Doppler from the apex; it accounted for 10% of ventricular filling in the healthy controls. but for significantly less in those with ventricular dilatation. In left ventricular hypertrophy. left ventricular filling was maintained by both mechanisms compensating for the reduced increase in volume early in diastole. Interactions between the atrium and ventricle are functionally important during ventricular systole. early diastole. and in atrial systole. They are not included in the traditional separation of atrial function into reservoir. conduit. and pump functions.
End diastolic flow velocity just beneath the aortic isthmus assessed by pulsed Doppler echocardiography: a new predictor of the aortic regurgitant fraction, End diastolic flow velocity just beneath the aortic isthmus was measured within 72 hours of cardiac catheterisation by pulsed Doppler echocardiography in 30 controls and 61 patients with aortic regurgitation. The end diastolic flow velocity was determined at the peak R wave on a simultaneously recorded electrocardiogram. In all controls there was no reverse flow at the end diastole beneath the aortic isthmus. In patients with aortic regurgitation the end diastolic flow velocity correlated well with the angiographic grade of regurgitation (r = 0.81) and regurgitant fraction (r = 0.82). The mean (SD) values were 6.3 (5.2). 12.2 (4.3). 22.1 (5.7). and 34.3 (9.3) cm/s for patients with regurgitant fraction of less than 20%. between 20% and 40%. between 41% and 60%. and greater than 60%. respectively. An end diastolic flow velocity of greater than 18 cm/s predicted a regurgitant fraction of greater than or equal to 40% with a sensitivity of 88.5% and a specificity of 96%. The study suggests that the pulsed Doppler derived end diastolic flow velocity is a useful index in the routine non-invasive assessment of the severity of aortic regurgitation.
Interatrial shunt flow profiles in newborn infants: a colour flow and pulsed Doppler echocardiographic study, Interatrial shunt flow profiles in 36 normal term infants were examined serially by colour flow and pulsed Doppler echocardiographic techniques from within an hour of birth to four or five days after birth. Shunt flow across the foramen ovale was detected in 33 normal infants (92%) within an hour of birth (mean 40 minutes). The occurrence of interatrial shunting decreased with age. but a shunt signal was still detected in 17 infants (47%) on the fourth or fifth day of life. by then the ductus arteriosus had already closed in all the normal infants. The direction of interatrial shunt flow was predominantly left-to-right. but in 64% there was a coexistent small right-to-left shunt in diastole within an hour of birth; by four to five days it was found in 19%. In the six patients with persistent fetal circulation the direction of the interatrial shunt flow was predominantly right-to-left with biphasic peaks in diastole and systole at the early stage of the disease. and the period of right-to-left shunt flow during each cardiac cycle was significantly longer than that in normal infants examined within 1 hour of birth. In all patients the ductus closed before the foramen ovale. At the time of ductal closure in all patients with persistent fetal circulation right-to-left shunt flow was seen during diastole and its period was still prolonged. These findings suggest that interatrial shunting. predominantly left-to-right. is common in normal newborn infants.
Distribution of skin-derived antileucoproteases (SKALP) in the marginal zone of the spreading psoriatic lesion, Two new elastase inhibitors (SKALP. skin-derived antileucoproteases) were recently described in the lesional skin in psoriasis. The present study investigated the distribution of SKALP activity in the marginal zone of spreading psoriatic plaques. In a 4-mm zone immediately adjacent to the erythemato-squamous plaques. SKALP activity was slightly increased compared to distant uninvolved skin. Within the lesion the anti-elastase activity was pronounced. but was significantly higher in the central zone of the plaque compared to the periphery. The appearance of SKALP in the psoriatic lesion appears to be a late event compared to endothelial involvement. intraepidermal accumulation of PMNs. epidermal proliferation and abnormal keratinization. This observation lends further support for the hypothesis that the induction of anti-elastase activity is associated with the off-switch of cutaneous inflammation.
Allergic contact and photocontact dermatitis due to psoralens in patients with psoriasis treated with topical PUVA, The incidence and clinical features of allergic contact and/or photocontact dermatitis due to psoralens were examined in 371 patients with psoriasis treated with topical PUVA. The psoralen derivatives used in the study were 8-methoxypsoralen (8MOP). 3-carbethoxypsoralen (3CPs). 4.6.4'-trimethylangelicin (TMA) and 7-methyl pyridopsoralen (MPP). Of 371 patients treated with 8MOP. three (0.8%) developed an acute dermatitis in the PUVA-treated areas. This incidence was significantly lower (P less than 0.01) than that for 3CPs (four of 10 patients) or that for TMA (six of 17 patients). None of the seven patients receiving MPP on PUVA had a reaction. It was confirmed that these dermatitis reactions were due to contact and/or photocontact allergy to psoralens by several methods that include patch and photopatch tests. photopatch test mapping. determination of the minimal erythema dose (MED) and immunohistochemistry.
Induction of lesions of dermatitis herpetiformis by autologous serum, In the present study various factors which contribute to the initiation of lesions in dermatitis herpetiformis (DH) were examined. Thirty-one patients with DH. seven with bullous pemphigoid. two with linear IgA disease and two healthy subjects were studied either before starting treatment or after stopping dapsone for up to 5 days. Intradermal inoculation of freshly prepared autologous serum was followed after 18-24 h by the formation of DH-like lesions in 24/31 DH patients. The lesions were erythematous papules. often with vesicles and microscopically showed papillary tip microabscesses. Serum-induced formation of lesions only occurred in patients with active DH with some spontaneous lesion formation: it did not occur in any of the non-DH controls. The formation of lesions was dose-related. declining proportionately with dilution of the serum down to 1/16. Plasma prepared by various methods of anticoagulation (heparin. citrate. EDTA) caused lesser reactions. while addition of heparin or epsilon-amino caproic acid (EACA). but not citrate. to serum substantially inhibited the formation of lesions. This suggested the responsible factor might be a protease. Other vasoactive agents including histamine (1-4 micrograms) and compound 48/80 (1-5 micrograms) caused normal immediate wealing. DH-like lesions occurred in only one of 13 subjects challenged with histamine and two of nine challenged with 48/80. In all these. autologous serum elicited large vesicular responses. There is a factor(s) in serum in DH which can initiate the formation of lesions. This factor appears to be activated by clotting and can be inhibited by heparin and EACA. suggesting it may be a protease.
An adult with common acute lymphoblastic leukaemia (C-ALL) presenting with skin infiltration, A 22-year-old man presented with multiple raised erythematous skin lesions. pyrexia and epistaxis. A diagnosis of common acute lymphoblastic leukaemia (C-ALL) was made by morphological. cytochemical. immunological and cytogenetic examination of peripheral blood and bone marrow. Biopsy of the skin revealed leukaemic infiltration by similar cells.
Erythema elevatum diutinum mimicking porphyria cutanea tarda, A case of erythema elevatum diutinum (EED) closely resembling porphyria cutanea tarda (PCT) is reported. The initial skin biopsies were suggestive for PCT but porphyrin levels in the urine. stool and plasma were normal. A further biopsy from an early cutaneous lesion showed a leucocytoclastic vasculitis with fibrinoid necrosis of the vessel walls.
Acquired dermal melanocytosis of the face and extremities, Four cases of dermal melanocytosis with symmetrical areas of hyperpigmentation involving the face and extremities are reported. Light and electron microscopic studies showed changes similar to those seen in naevus of Ota.
Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia, Based on in vitro data suggesting that recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating acute myeloid leukemia (AML) blast cells to become more sensitive to cell-cycle-specific drugs we conducted a phase I/II study in de novo AML patients (pts). rhGM-CSF (250 micrograms/m2/d. continuous intravenous infusion) was administered in 18 pts suffering from de novo AML in combination with standard induction chemotherapy (3 + 7 = daunorubicin 45 mg/m2 days 1 through 3. cytosine-arabinoside [Ara-C] 200 mg/m2 continuous infusion days 1 through 7). GM-CSF was started 48 or 24 hours before chemotherapy (prephase) in 14 pts. In four pts with high white blood cell counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction (WBC less than 30.000/mm3). During prephase GM-CSF induced an increase in neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts. respectively. In vivo recruitment of leukemic cells into drug-sensitive phases of the cell cycle could be demonstrated by multiparameter cell-cycle analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On day 14. complete aplasia was evident in 17 of 18 pts. GM-CSF was administered until recovery from chemotherapy-induced myelosuppression (absolute neutrophil counts. [ANC] greater than 500/mm3). Fifteen pts (83%) achieved complete remission. 12 did so with one cycle. A shorter duration of neutropenia was evident in these pts compared with historical controls (n = 39). (ANC greater than 500/mm3. day 22.5 +/- 3.4 v 25.2 +/- 3.7. P less than .05). Three pts achieved complete remission after a second cycle (same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow aplasia because of invasive pulmonary aspergillosis. Clinical side effects possibly related to GM-CSF. mainly fever. diarrhea. and weight gain were mild and tolerable (World Health Organization toxicity grade less than or equal to 2). Together. rhGM-CSF recruits kinetically quiescient AML cells in vivo to enter drug-sensitive phases of the cell cycle and promotes early myeloid recovery from aplasia after exposure to standard induction chemotherapy for AML.
Monoclonal antibody-purged autologous bone marrow transplantation therapy for multiple myeloma, Eleven patients with plasma cell dyscrasias underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MoAb)-treated autologous bone marrow transplantation (ABMT). The majority of patients had advanced Durie-Salmon stage myeloma at diagnosis. all were pretreated with chemotherapy. and six had received prior radiotherapy. At the time of ABMT. all patients demonstrated good performance status with Karnofsky score of 80% or greater and had less than 10% marrow tumor cells. Eight patients had residual monoclonal marrow plasma cells and 10 patients had paraprotein. Following high-dose melphalan and total body irradiation (TBI) there were seven complete responses. three partial responses. and one toxic death. Granulocytes greater than 500/mm3 were noted at a median of 21 (range 12 to 46) days posttransplant (PT) and untransfused platelets greater than 20.000/mm3 were noted at a median of 23 (12 to 53) days PT in 10 of the 11 patients. Natural killer cells and cytotoxic/suppressor T cells predominated early PT. with return of B cells at 3 months PT and normalization of T4:T8 ratio at 1 year PT. Less than 5% polyclonal marrow plasma cells were noted in all patients after transplant. Three of the seven complete responders have had return of paraprotein. two with myeloma. and have subsequently responded to alpha 2 interferon therapy. Eight patients are alive at 18.9 (8.9 to 43.1) months PT and four remain disease-free at 12.3. 17.5. 18.9. and 29 months PT. This preliminary study confirms that high-dose melphalan and TBI can achieve high response rates without unexpected toxicity in patients who have sensitive disease. and that MoAb-based purging techniques do not inhibit engraftment. Although the follow-up is short- and long-term outcome to be determined. relapses post-ABMT in these heavily pretreated patients suggest that ABMT or alternative treatment strategies should be evaluated earlier in the disease course.
Cyclosporine therapy for advanced Langerhans cell histiocytosis, Prompted by evidence that Langerhans cell histiocytosis (LCH) is a nonmalignant disorder of immune regulation. we used cyclosporine (12 mg/kg/d orally) to treat three young children with advanced multisystem LCH. All three patients had partial responses to cyclosporine within 2 months of therapy. as evidenced by complete resolution of organ dysfunction and regression of the majority of lesions. Complete responses were attained by adding relatively nontoxic chemotherapy (ie. prednisone and vinblastine). Toxicity from cyclosporine comprised mild and reversible elevations of the serum creatinine and blood urea nitrogen. These results indicate that further evaluation of cyclosporine for the treatment of patients with advanced LCH is warranted.
Expression of the c-fgr and hck protein-tyrosine kinases in acute myeloid leukemic blasts is associated with early commitment and differentiation events in the monocytic and granulocytic lineages, Two members of the src proto-oncogene family of intracellular tyrosine kinases. c-fgr and hck. are selectively expressed in differentiated myeloid cells. To study the expression of these genes in acute myeloid leukemia (AML) and to determine the specific myeloid lineages and stages of myeloid differentiation at which the expression of these genes is acquired. we used a series of 79 cases of de novo AML as a differentiation model. The levels of c-fgr. hck. and c-fms (encoding the colony-stimulating factor-1 receptor) mRNA transcripts were correlated with the presence of specific cell surface antigens and the morphologic and cytochemical features in these AML blasts. Relatively undifferentiated leukemic myeloblasts with an HLA-DR. CD34. CD33. CD13+/- cell surface immunophenotype (French-American-British [FAB] M1 or M2) were characterized by a lack of c-fms and c-fgr expression. while low levels of c-fms and c-fgr could be detected in undifferentiated myeloblasts (FAB M1 or M2). which also expressed CD14 at low antigen density. The hck transcripts were either undetectable in these cells or were expressed at low levels. In contrast. only hck mRNA transcripts could be identified in blasts with progranulocytic morphology (FAB M3). while c-fms. c-fgr. and hck were all expressed at high levels in blasts with differentiated myelomonocytic or monocytic features (FAB M4 and M5). No c-fms. c-fgr. or hck transcripts were evident in leukemic cells of the erythroid lineage (FAB M6). When undifferentiated leukemic myeloblasts (HLA-DR. CD34. and CD33) were induced to differentiate in vitro to cells with monocytic characteristics. the expression of c-fms. c-fgr. and the CD14 cell surface antigen were induced to high levels. accompanied by the acquisition of hck and CD13 expression. In contrast. when HLA-DR. CD34. and CD33 blasts were induced to differentiate in vitro to cells with granulocytic characteristics. only hck and CD13 expression were induced. Our data suggest that the acquisition of c-fgr and/or hck expression is associated with early commitment and differentiation events in distinct myeloid lineages. Assessment of the expression of these kinases may provide a molecular tool to assign lineage in AML in conjunction with morphology. cytochemistry. and cell surface antigen expression.
Effects of recombinant human macrophage colony-stimulating factor on plasma cholesterol levels, Recombinant human macrophage colony-stimulating factor (rhM-CSF) is a hematopoietic growth factor that stimulates the growth. differentiation. proliferation. and activation of cells of the monocyte/macrophage lineage. rhM-CSF was administered to rabbits and nonhuman primates to evaluate effects on cholesterol homeostasis. Decreases in plasma cholesterol concentrations were observed during rhM-CSF administration. The observed mean (+/- SD) decreases over a range of doses in nonhuman primates receiving rhM-CSF by continuous intravenous infusion (CIVI) or intravenous bolus (IVB) injection were approximately 16% +/- 8% and 43% +/- 10%. respectively. Low-density lipoprotein (LDL) cholesterol levels decreased 55% +/- 9% from pretreatment baseline values in the animals receiving rhM-CSF by IVB. Normocholesterolemic New Zealand white rabbits receiving rhM-CSF over a range of doses by CIVI showed a decrease from baseline in total cholesterol of approximately 28% +/- 17%. with LDL cholesterol levels decreasing by approximately 72% +/- 33%. while high-density lipoprotein levels showed variable changes. including increased values. A decrease of 36% +/- 26% in total plasma cholesterol was observed in Watanabe Heritable Hyperlipidemic rabbits receiving rhM-CSF by CIVI for 7 days. This decrease was attributable almost entirely to decreases in LDL cholesterol. which fell approximately 34% +/- 24% from baseline. Although the mechanism of this cholesterol-lowering effect is unknown. these results strongly suggest that rhM-CSF may provide a novel treatment for hypercholesterolemia and may be useful in investigations into the mechanisms of cholesterol homeostasis and atherogenesis.
Downregulation of the platelet surface glycoprotein Ib-IX complex in whole blood stimulated by thrombin, adenosine diphosphate, or an in vivo wound, In washed platelet systems. thrombin has been demonstrated to downregulate the platelet surface expression of glycoprotein (GP) Ib and GPIX. In the present study. we addressed the question as to whether. in the more physiologic milieu of whole blood. downregulation of platelet surface GPIb and GPIX can be induced by thrombin. adenosine diphosphate (ADP). and/or by an in vivo wound. Thrombin-induced downregulation of GPIb and GPIX on the surface of individual platelets in whole blood was demonstrated by the use of flow cytometry. a panel of monoclonal antibodies (MoAbs) and. to inhibit fibrin polymerization. the peptide glycyl-L-prolyl-L-arginyl-L-proline. Platelets were identified in whole blood by a GPIV-specific MoAb and exclusion of monocytes by light scattering properties. Flow cytometric analysis of whole blood emerging from a standardized bleeding-time wound established that downregulation of platelet surface GPIb and GPIX can occur in vivo. A GPIb-IX complex-specific antibody indicated that the GPIb and GPIX remaining on the surface of platelets activated in vivo or in vitro were fully complexed. Simultaneous analysis of individual platelets by two fluorophores demonstrated that thrombin-induced platelet surface exposure of GMP-140 (degranulation) was nearly complete at the time that downregulation of platelet surface GPIb-IX was initiated. However. degranulation was not a prerequisite because ADP downregulated platelet surface GPIb-IX without exposing GMP-140 on the platelet surface. Inhibitory effects of cytochalasins demonstrated that the activation-induced downregulation of both GPIX and GPIb are dependent on actin polymerization. In summary. downregulation of the platelet surface GPIb-IX complex occurs in whole blood stimulated by thrombin. ADP. or an in vivo wound. and is independent of alpha granule secretion.
Macrophage colony-stimulating factor (CSF-1) gene expression in human T-lymphocyte clones, Macrophage colony stimulating factor (CSF-1) is one of several cytokines that control the differentiation. survival. and proliferation of monocytes and macrophages. A set of 11 human T-cell clones. chosen for their phenotypic diversity. were tested for their ability to express CSF-1 mRNA. After 5 hours of stimulation with phorbol myristate acetate (PMA) + calcium ionophore (Cal). all T-cell clones expressed a major 4-kb transcript. a less abundant 2-kb transcript. and several other minor species. This pattern of expression is typical for CSF-1 mRNAs. Furthermore. of the two alloreactive T-cell clones analyzed. only one showed a definitive message for CSF-1 on specific antigenic stimulation. but with delayed kinetics and less efficiency. Both conditions of stimulation induced the release of CSF-1 protein by T cells in the culture medium. Together. these findings demonstrate for the first time that normal T cells are able to produce CSF-1. previous reports being limited to two cases of tumoral cells of the T-cell lineage.
Loss of interferon antibodies during prolonged continuous interferon-alpha 2a therapy in hairy cell leukemia, Although highly active in hairy cell leukemia (HCL). interferons (IFN) are not curative in this disease; current data indicate that prolonged IFN therapy will be necessary to control disease in the majority of patients. We previously observed acquired IFN resistance in association with neutralizing IFN-alpha 2a antibodies in small numbers of patients with HCL. This finding suggests that the requisite long-term therapy may be compromised if there is an increasing incidence over time of neutralizing antibodies. We performed a follow-up study of IFN antibodies in our patients receiving continuous IFN therapy. All 16 patients who were previously antibody negative remained so. Surprisingly. all nine patients who previously had non-neutralizing IFN antibodies became antibody negative after a median of 14.5 months. Moreover. 3 of 10 patients who had neutralizing antibodies became antibody negative and five had only non-neutralizing antibodies a median of 10 months from the time neutralizing antibody had first been detected. Only two patients had persisting neutralizing antibodies. Inhibition of neopterin synthesis. inhibition of generation of 2'. 5' oligoadenylate synthetase activity. and inability to detect IFN in serum after subcutaneous injection of IFN-alpha 2a was observed only in the one patient tested with neutralizing IFN antibodies confirming that these antibodies have functional significance in vivo. We conclude that. although neutralizing IFN antibodies inhibit the effectiveness of IFN in vivo. these antibodies are produced only transiently during long-term therapy. The long-term effectiveness of this drug will not likely be affected in most patients by neutralizing antibody.
Effect of tamoxifen on cell lines displaying the multidrug-resistant phenotype, We examined the effect of tamoxifen (Tmx). verapamil. and daunorubicin (DNR) in two cell lines that displayed the multidrug-resistant (MDR) phenotype and used laser flow cytometry to quantitate intracellular DNR content. In the vinblastine-resistant human lymphoblastic lymphoma cell line CEM-VBL. simultaneous incubation of DNR with Tmx 10 mumol/L or Tmx 50 mumol/L increased intracellular DNR fluorescence in a dose-dependent manner and demonstrated an uptake pattern similar to that seen with DNR and verapamil. Similar results were obtained in the vincristine-resistant human myeloid leukemia cell line HL-60/RV+. Cellular retention of DNR was also measured in both cell lines and results suggested that continuous exposure of the cells to Tmx resulted in higher intracellular DNR content compared with cells resuspended in fresh medium. No effect of Tmx or verapamil was observed in the drug-sensitive parent cell lines CEM or HL-60. Clonogenic experiments were then performed to determine whether Tmx was itself inhibitory to cell growth or whether Tmx potentiated DNR cytotoxicity. Tmx 10 mumol/L did not significantly inhibit either CEM-VBL or HL-60/RV+ cells after a 3-hour exposure followed by culture in methylcellulose. Tmx 50 mumol/L was significantly more inhibitory in both cell lines. However. cells that had been incubated with DNR and Tmx 10 mumol/L demonstrated a marked increment in growth inhibition compared with cells that had been incubated with DNR alone or Tmx 10 mumol/L alone. Based on the data presented here. we suggest that clinical testing of Tmx and DNR be pursued in the setting where MDR may play a role.
Transmembrane mobility of phospholipids in sickle erythrocytes: effect of deoxygenation on diffusion and asymmetry, We studied the effect of sickling on the transmembrane reorientation and distribution of phospholipids in the red blood cells of patients homozygous for sickle cell anemia (SS). To this purpose. we followed the redistribution kinetics of trace amounts of spin-labeled analogues of natural phospholipids first introduced in the membrane outer leaflet of normal or sickle erythrocytes exposed to air or nitrogen. Deoxygenation had no effect on the lipid redistribution kinetics in normal (AA) cell membranes. At atmospheric pO2. unfractionated SS cells were not different from normal cells. However. on deoxygenation inducing sickling. phosphatidylcholine passive diffusion was accelerated and the rate of the adenosine triphosphate-dependent transport of aminophospholipids was reduced. especially for phosphatidylserine. The stationary distribution of the aminophospholipids between the two leaflets was slightly less asymmetric. a phenomenon more pronounced with phosphatidylethanolamine. These changes were rapidly reversible on reoxygenation. When SS cells were separated by density. both dense and light cells exhibited the properties cited above. However. dense cells exposed to air possessed a lower aminophospholipid transport rate. These data favor the relationship between aminophospholipid translocase activity and phospholipid transmembrane asymmetry. Sickle cell disease is the first case of aminophospholipid translocase pathology.
The beta globin 3' enhancer element confers regulated expression on the human gamma globin gene in the human embryonic-fetal erythroleukemia cell line K562, We have constructed fusion genes comprised of gamma and beta globin elements and globin sequences linked to neomycin resistance (neoR) genes to define the cis acting sequences responsible for developmental stage-specific expression and induction of fetal globin genes in embryonic-fetal erythroleukemia K562 cells. The results indicate that the gamma promoter is required for proper initiation of transcription. However. the accumulation of gamma globin transcripts in response to hemin induction requires the additional presence of either gamma intervening sequence 2 or the 3' enhancer element of the beta globin gene. Thus. the gamma promoter may provide the elements for developmental stage-specific gene expression during fetal life. By contrast. the beta 3' enhancer is erythroid-specific but not developmental stage- or gene-specific.
Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: role of polymerase chain reaction in predicting relapse, We used the polymerase chain reaction (PCR) to detect residual leukemia-specific mRNA in blood and marrow from 37 patients in complete hematologic and cytogenetic remission after allogeneic bone marrow transplant (BMT) for chronic myeloid leukemia (CML). Our two-step PCR method involved the use of "nested primers" in the second step and could detect one K562 cell diluted into 10(5) normal cells. Elaborate measures were taken to exclude false-positive and false-negative results. In nine patients whose blood and marrow were studied simultaneously the results were concordant (two positive and seven negative). Twenty-three patients transplanted in chronic phase (CP) with unmanipulated donor marrow were studied. Blood cells from nine of these patients were studied 3 to 6 months post-BMT and six were PCR positive; three were negative on subsequent studies. Blood cells from 18 patients studied between 8 months and 8 years post-BMT were all PCR negative. Nine patients transplanted in CP with T-cell-depleted marrow cells were studied. Blood from five was positive 3 to 24 months post-BMT; blood from five was negative 3 to 6 years post-BMT. Four patients no longer in first CP were studied after BMT with unmanipulated donor marrow. Blood from all four was positive 5 to 19 months post-BMT. Based on the known clinical results of transplant in these three cohorts we conclude that PCR may be positive within 6 months of BMT in patients who can expect long-lasting remission. whereas PCR positivity later after BMT may indicate that the probability of cure is reduced. Thus. the technique may prove useful for early assessment of new transplant protocols that might inadvertently increase the risk of relapse.
Rapid simultaneous detection of multiple retroviral DNA sequences using the polymerase chain reaction and capillary DNA chromatography, The polymerase chain reaction (PCR) technique is a powerful new tool for amplifying target DNA. thus allowing for sensitive detection of specific nucleic acid sequences. One important potential use of PCR involves screening the donated blood supply for transfusion-transmitted viruses. Realization of this goal has been limited by (1) the requirement for multiple. discrete PCR reactions to amplify and detect target sequences of more than one virus. and (2) the lack of a rapid. nonhazardous means for specific detection of one or more PCR-amplified products. We report the simultaneous amplification of three distinct target sequences without discernable loss in sensitivity toward any single target sequence. We also demonstrate very rapid separation and detection of PCR-amplified viral DNA through the use of automated capillary DNA chromatography. Amplified DNA peaks were initially identified by scanning the capillary effluent at ultraviolet wavelengths. while discrimination of human immunodeficiency virus type 1 and human T-cell leukemic virus type I PCR-amplified DNA was accomplished through use of virus-specific. fluorescently labeled primers and probes. These results indicate progress toward an automated system for screening the blood supply for nucleic acid sequences of multiple pathogens.
Detection of early human T-cell lymphotropic virus type I antibody patterns during seroconversion among transfusion recipients, From a cohort of human T-cell lymphotropic virus type I (HTLV-I) exposed transfusion recipients (N = 71) enrolled in the Jamaican Transfusion Study. 11 were selected for detailed laboratory evaluation. All recipients were followed at monthly intervals for 6 months and then bimonthly up to 1 year for evidence of HTLV-I seroconversion. Without regard to results on screening assays. pretransfusion and posttransfusion samples were tested with two licensed HTLV-1 whole-virus screening enzyme immunoassays (EIAs). recombinant EIAs for antibody against tax (p40x) and p21e envelope. standard whole virus Western blot (WB). WB enhanced with recombinant p21e. and radioimmunoprecipitation assay (RIPA). In the early period posttransfusion. antibody to gag core protein was predominant with anti-p24 generally appearing before anti-p19. Recombinant anti-p21e envelope protein. in EIA and WB format. was frequently the earliest envelope reactivity detected. while anti-gp46 in WB and anti-gp61/68 in RIPA system appeared later. Anti-tax antibodies appeared later in the time course of seroconversion. The whole-virus EIAs were less sensitive than the confirmatory assays. The combination of WB and RIPA or WB enhanced with recombinant p21e appeared equally effective in confirming samples as positive by the Public Health Service two gene group confirmatory algorithm. However. specificity of this assay approach could not be addressed in this study.
Perinatal mortality rates in isolated general practitioner maternity units, OBJECTIVE--To determine the perinatal mortality rate among normally formed. singleton babies with birth weights greater than or equal to 2500 g in Bath health district based on the intended place of delivery at the time of onset of labour or at the time of diagnosis of intrauterine death. DESIGN--The numbers of live births and stillbirths were collected monthly returns from the maternity units concerned. Deaths of infants aged less than or equal to 1 week were collected in the same returns. The intended place of delivery was confirmed at the monthly perinatal mortality meeting. during which maternal and fetal factors were discussed. SETTING--A rural health district of 400.000 population where one third of all deliveries occurred in seven isolated general practitioner maternity units. 8% in the integrated general practitioner unit. and the remainder in the consultant unit. SUBJECTS--All babies of women whose deliveries were booked in the district before the onset of labour or the diagnosis of intrauterine death. excluding twins. babies with lethal congenital malformations. and those less than 2500 g. MAIN OUTCOME MEASURES--Outcome of all deliveries and parity of mothers. RESULTS--14.415 Deliveries were analysed. The perinatal mortality rate was 2.8/1000 births in the consultant unit (7950 deliveries). 4.8 in the isolated general practitioner units (5237 deliveries). and zero in the integrated general practitioner unit (1228 deliveries). Perinatal deaths attributable to asphyxia were more common in the isolated general practitioner units (1.5 per 1000) than the consultant unit (0.6 per 1000). The perinatal mortality rate among babies born to nulliparous women was 3.2/1000 births in the consultant unit and 5.7 in the isolated general practitioner units; for those born to multigravid women it was 2.4 and 4.2 respectively. CONCLUSIONS--The outcome of delivery was not influenced by parity. Both antenatal and intrapartum care were responsible for the higher perinatal mortality rate in the isolated general practitioner units. The integrated unit. which shared midwifery staff with the consultant unit. seemed to work well. Analysis by intended place of delivery at the time of onset of labour or diagnosis of intrauterine death suggested that the care given in isolated units needs to be improved. perhaps by better training of general practitioners and consultant supervision of antenatal care.
Risk of disability and mortality due to overweight in a Finnish population [published erratum appears in BMJ 1990 Nov 3;301(6759):1027, OBJECTIVE--To investigate the effect of overweight on premature mortality and work disability in young and middle aged Finns. DESIGN--Prospective cohort study based on data collected in the multiphasic health examinations by the Social Insurance Institution of Finland from 1966 to 1972 and follow up until 1982. SETTING--34 Communities throughout Finland. SUBJECTS--12.053 Women and 19.076 men who were employed and aged 25-64 at baseline. MAIN OUTCOME MEASURES--Mortality and work disability pensions from all and specified causes. RESULTS--Body mass index was a weak predictor of death but a strong predictor of early work disability. which increased linearly with body mass index. After adjustment for age. geographical region. occupation. and smoking the relative risks of work disability for women and men with a body mass index greater than or equal to 30 kg/m2 were. respectively. 2.0 (95% confidence interval 1.8 to 2.3) and 1.5 (1.3 to 1.7) when compared with those of subjects with body mass index less than 22.5 kg/m2. The increased risks were due to an excess of cardiovascular and musculoskeletal diseases but not of mental diseases. One fourth of all disability pensions from cardiovascular and musculoskeletal causes in women and half as many in men could be attributed to overweight (body mass index greater than 25 kg/m2) alone. CONCLUSIONS--Though modest overweight has little impact on mortality it predicts severe functional impairment. A considerable proportion of work disability pensions could probably be prevented by efficient weight control.
Management of staghorn stones using a combination of lithotripsy, percutaneous nephrolithotomy and Solution R irrigation, The treatment of staghorn and partial staghorn calculi remains complex despite modern methods of stone removal. We describe the results following treatment of 112 stones. Three methods were used: percutaneous nephrolithotomy. extracorporeal shockwave lithotripsy and Solution R irrigation. either alone or in combination; 57 stones (55.8%) were completely cleared. with Solution R irrigation helping to achieve complete clearance in 6 of these. A further 24 stones were not completely cleared (small asymptomatic fragments less than 3 mm remained). A satisfactory outcome (stone-free or asymptomatic fragments less than 3 mm) was achieved in 81 stones (79%).
The impact of extracorporeal piezoelectric lithotripsy on the management of ureteric calculi: an audit, The presentation and management of 153 patients with ureteric calculi requiring active treatment over a 12-month period were reviewed; 74% of patients had primary ureteric calculi and 26% had ureteric calculi composed of fragments resulting from extracorporeal piezoelectric shockwave lithotripsy (EPL) to renal calculi; 32 patients (21%) had more than 1 calculus or a steinstrasse. The primary procedures included were in situ EPL (n = 54). push-bang (44). retrograde ureteroscopy (40). Dormia basket extraction (6). push-pull (1). antegrade ureteroscopy (1) and combinations of these (7). The success of the primary procedure could not be predicted from stone size. site or duration in the ureter. but upper tract dilatation was significantly less (p less than 0.01) in the successful group. The overall success rate for complete stone extraction was 97%. but 54 patients (35%) required more than 1 procedure to achieve this. In situ EPL and push-bang. as either primary or secondary procedures. were successful in treating 79 patients (52%); 2 patients required ureterolithotomy (1.3%). The overall complication rate was 18%. Since EPL is only successful in treating approximately half of ureteric calculi. a range of other treatments should be available to maintain a low rate of open surgery.
Do extracorporeal shock waves affect urinary excretion of glycosaminoglycans, Urinary excretion of glycosaminoglycans (GAGs) was studied in 9 anaesthetised dogs and 10 patients with single kidneys. The animals were studied for 4 to 5 hours after administration of shock waves to 1 kidney. the contralateral organ serving as control. Urinary excretion of GAGs was measured on both sides. The patients were studied 0 to 24 and 32 to 56 h after extracorporeal shock wave lithotripsy (ESWL). In the animals an increased mean urinary excretion of GAGs was observed on both sides; this was more marked in the treated kidney. The increase reflects tissue injury in the exposed kidney induced by the extracorporeal shock waves. No increase in mean urinary excretion of GAGs was observed in the patients.
Night studies for primary diurnal and nocturnal enuresis and preliminary results of the "clam" ileocystoplasty, Modified conventional urodynamic apparatus was used to provide overnight monitoring of bladder and rectal pressure. A group of 26 patients with primary diurnal and nocturnal enuresis underwent both daytime rapid fill cystometry and overnight natural fill cystometry. The overnight study was effective in detecting detrusor instability in 10 patients deemed normal on rapid fill cystometry; 6 of these have now undergone clam ileocystoplasty and 5 are dry; 3 are awaiting this procedure. The clam remains very effective in the management of patients with resistant nocturnal and diurnal enuresis if careful selection is adopted. Overnight cystometry has proved to be an invaluable adjunct to the investigation of patients with primary diurnal and nocturnal enuresis previously felt to be urodynamically normal.
Is voided urine suitable for flow cytometric DNA analysis, Samples of bladder washings are frequently used to provide cellular material for flow cytometric DNA analysis. Since voided urine is a potential source of similar material. the aim of this study was to determine whether voided urine yields satisfactory specimens. We compared the qualitative results of flow cytometric DNA analysis of the cells in 53 specimens of voided urine and 109 samples of bladder washings; 45% (24/53) of urine specimens gave satisfactory DNA histograms compared with 93% (101/109) of bladder washings. This difference was apparent regardless of whether the bladder contained a tumour. It was concluded that bladder washings provide superior material for flow cytometric DNA analysis and that flow cytometric DNA analysis of freshly voided urine may have deficiencies which preclude its use in routine clinical practice.
Radical radiation treatment of invasive and locally advanced bladder carcinoma in elderly patients, A total of 146 patients with invasive or locally advanced carcinoma of the bladder (T2-T4) underwent radiation treatment. A significantly higher complete response rate was observed with doses equal to or above 55 Gy and with doses corresponding to cumulative radiation effect (CRE) values of 1700 radiation effect units (reu) or more. In multivariate analysis. decreasing time from the first diagnosis of bladder carcinoma to radiation treatment and 1 or more transurethral resections was associated with a significant increase in survival; increases in T category and sedimentation rate were negative prognostic factors. Although both radiation dose and CRE levels had a significant effect on survival in univariate analysis. an increase in CRE levels alone was associated with a significant increase in survival in multivariate analysis. However. the most important predictor of survival was whether the patient showed a complete local response or not. This study emphasises the importance of treating patients with an adequate radiation dose over a short period of time in order to achieve the maximum radiobiological effect and thereby increase the possibility of cure.
Activation of complement, kallikrein-kinin, fibrinolysis and coagulation systems by urinary catheters. Effect of time and temperature in biocompatibility studies, Urethral strictures induced by the use of latex catheters and combined silicone/latex catheters following open-heart surgery have been reported. These strictures differ from the post-catheterisation type in affecting a greater length of urethra. Recently it was shown that complement was activated by catheters which cause inflammation. in contrast to clinically silent catheters. The present study was designed to investigate a possible association between catheter-induced inflammation and activation of another mediator of inflammation. the contact system. We also investigated various in vitro conditions to optimise biocompatibility studies. Our data indicate that both the complement and the kallikrein-kinin system are activated by potentially harmful silicone/latex catheters and may be involved in the pathophysiology of catheter-induced urethral strictures. In vitro biocompatibility tests may be performed at both 20 and 37 degrees C. Glass test tubes may be used for in vitro complement but not for kallikrein-kinin investigations.
Haemospermia: a prospective study, A prospective study of 74 men with haemospermia is presented. Most (76%) had experienced 1 or 2 episodes only and 9 (12%) were over 40 years old. Simple investigations led to a diagnosis in all 9 of these men and of those under 40. no pathology could be detected in 48%. A diagnosis was made in 32 of the remaining 34 men by simple investigations. In patients over 40 years of age with haemospermia. a potentially treatable cause will normally be found by routine investigation which should include cystoscopy. In younger men. non-invasive investigation alone should identify any pathology. Invasive investigations should be reserved for those patients in whom the problem is prolonged. excessive or in association with other symptoms.
Iron deficiency anemia in the elderly: the diagnostic process, OBJECTIVE: To determine the effectiveness of physician probability estimates calculated on the basis of findings from history-taking and physical examination in the diagnosis of iron deficiency anemia in elderly patients. DESIGN: Prospective study. SETTING: Two community hospitals offering secondary and tertiary care. PATIENTS: A total of 259 patients over 65 years of age found to have previously undiagnosed anemia. MEASURES: Physician estimates of the likelihood of iron deficiency before (pretest probability) and after (post-test probability) the laboratory test results were available. The hemogram was available to the physicians when they made their pretest probability estimates. Because the serum ferritin level proved to be the most powerful of the laboratory test results studied. the likelihood ratios associated with the post-test estimates were compared with the ratios associated with the serum ferritin level. MAIN RESULTS: The post-test probability estimates were influenced by the serum ferritin level and the pretest estimates. The post-test estimates derived from the findings obtained through history-taking and physical examination and the laboratory test results (including the serum ferritin level) were slightly less accurate in predicting iron deficiency than the serum ferritin level alone. Nevertheless. a model in which the pretest estimates were used in addition to the serum ferritin level to predict iron deficiency proved to be more powerful than the serum ferritin level alone (p = 0.006). This indicated that the limitations of the post-test estimates were due to a misinterpretation of the serum ferritin level and that the findings from history-taking and physical examination added important diagnostic information. CONCLUSIONS: Physicians must be aware of test properties to provide optimal care to their patients. If test results are properly interpreted. pretest probabilities derived from findings obtained through history-taking and physical examination can add useful information that will lead to more accurate diagnoses.
The reliability of palpation in the assessment of tumours, There is now a joint UICC-AJC classification for cervical lymph nodes based mainly on the size of the nodes. There is a recognized error in palpation. not only for detecting the presence of tumour but also its size. This study used an animal tumour model system to compare the ability of 6 independent observers of varying experience to detect and stage superficially transplanted growths. A preclinical medical student was as good as a Consultant ENT Surgeon in predicting the presence of tumour but the ability to stage tumours accurately was related to experience. Whilst the most experienced observers accurately estimated the size of tumours less than 2 cm. they were less accurate for larger (greater than 2 cm) tumours which were constantly understaged. This phenomenon may have important clinical implications particularly related to current nodal staging criteria.
Microdrill versus perforator for stapedotomy, The purpose of this study was to compare the hearing results of performing stapedotomy using either a microdrill or a perforator. Two groups of patients. otherwise similar. were followed up for at least 2 years after the stapedotomy. It was possible to create 0.8 mm fenestra in 91.6% of our patients. There was no significant difference between the two groups in hearing results. The results showed a continuous improvement in the first 6 post-operative months after which the hearing stabilized. In our hands. the microdrill has not proved to be more traumatic than the perforator to the inner ear.
Microscopically assisted posterior lumbar interbody fusion, Microscopically assisted posterior lumbar interbody fusion was performed on 27 patients who had either spondylolisthesis or chronic lower back pain after previous lower back surgery. Overall improved satisfactory results occurred in 22 of 27 patients. Roentgenographic. stable. interbody fusion occurred in 22 of 27 patients. The poorest results and highest rate of pseudarthrosis occurred in patients with double-level fusions. Pseudarthrosis occurred in four of six patients with double-level fusions and unsatisfactory clinical results occurred in five of six patients with double-level fusions. Advantages of the microscopic technique are better examination of the surgical site. less blood loss. and less surgical dissection than other surgical salvage techniques. This procedure should be reserved for single-level pathology in the lumbosacral spine.
The role of the supraspinatus and infraspinatus muscles in glenohumeral kinematics of anterior should instability, To investigate a socket mechanism responsible for controlling the kinematics in the statically positioned glenohumeral joint. a suprascapular nerve block was performed in 13 selected patients. with recurrent anterior instability and defects of the labrum. Kinematics were then documented by roentgenograms in four positions within the horizontal motion plane. Combined paralysis of the supraspinatus and infraspinatus muscles resulted in abnormal anterior translation in only two of 47 roentgenograms. Normal ball-and-socket kinematics were retained in the remaining 45 roentgenograms. The consistent arthroscopic findings were an undamaged glenoid articular surface with a detached or absent labrum. The injury to the labrum reduced the depth of the socket by one-half. The other one-half of the socket provided by the contour of the glenoid remained intact. A balanced muscle envelope was not required to maintain normal kinematics in selected. actively positioned. unstable shoulders. The retained glenoid depth was sufficient to produce the observed ball-and-socket kinematics. Further in vivo study of shoulder kinematics will be needed to clarify the interactive roles of the socket and muscle envelope in maintaining glenohumeral stability during the more demanding stresses during active shoulder motion.
Superior humeral dislocation. A complication following decompression and debridement for rotator cuff tears, Very large rotator cuff tears may be surgically irreparable and under such circumstances debridement of the edges of the cuff and bursal decompression may relieve pain. In this paper. four cases are described of the development of superior migration of the humeral head following a debridement and bural decompression. In all four patients attempts were made to repair the rotator cuff. In each case the repair failed and the humeral head migrated. Two of the patients had the humeral head replaced because of a fracture; in these patients the prosthesis displaced upwards. This serious complication may follow debridement and release of the subacromial bursa when rotator cuff repair cannot be achieved. In the correction of superior humeral migration. reestablishment of the roof of the bursa was carried out in two cases. This procedure appears effective and may be considered in the future for such cases.
The surgical treatment of severe comminuted intraarticular fractures of the distal radius with the small AO external fixation device. A prospective three-and-one-half-year follow-up study, Although fractures of the distal radius are very common. an optimal treatment has not been clearly delineated. This is a prospective study of 40 patients. mainly young and active adults. with comminuted and unstable intraarticular fractures of the distal radius. The end results of closed reduction and rigid fixation with the small AO external fixator includes 36 patients (90%) with excellent and good results. Roentgenograms of 33 of these patients showed accurate alignment of the healed fractures. Four patients (10%) had a fair functional result. with a partial restriction of the range of movement. although roentgenograms demonstrated good alignment of the healed fractures. The small AO external fixator is both a useful and convenient method for the reconstruction and treatment of comminuted intraarticular fractures of the distal radius.
A semiinvasive method for articular Colles' fractures, An external fixation device that allows limited motion of the wrist joint without disruption of the anatomic alignment was used for the articular Colles' fractures in this study. From July 1985 to April 1989 during a 45-month period. 87 patients with 90 articular Colles' fractures (three cases with bilateral involvement) were treated with a modified dynamic external skeletal device after a closed reduction in full supination of the forearm. Excellent anatomic reduction near 91% of the sound wrist as well as satisfactory functional results around 90.5% of the sound wrist were gained during the 24-month follow-up period. Forearm muscles exert compression forces on distal radial metaphyseal fractures throughout the healing period. Any procedure or device that cannot provide constant counterforce to the action of forearm muscles during fracture healing will result in the loss of anatomic reduction. Adequate distraction counter-force was provided by an external fixation device that was superior to other conventional methods because of its simple application. low rate of complications. and excellent anatomic and functional results.
Diagnostic and operative arthroscopy of the wrist, The evaluation and diagnosis of wrist disorders has traditionally been difficult and problematic. Ligamentous wrist sprains and their associated carpal instabilities. triangular fibrocartilage complex disruptions. and cartilage injuries have been virtually impossible to fully assess because of the inadequacy of current diagnostic techniques. Arthroscopy of the wrist allows a thorough evaluation of the soft-tissue structures and cartilaginous surfaces within the radiocarpal and midcarpal joints. In selected cases. wrist arthroscopy can be employed to surgically modify the intraarticular lesions and to assist in the planning of reconstructive operations.
Intercondylar notch measurements with special reference to anterior cruciate ligament surgery, The femoral intercondylar notch width was measured in 93 patients with chronic anterior cruciate ligament (ACL) insufficiency (Group 1). in 62 patients with an acute tear of the ACL (Group 2). and in 38 fresh anatomic specimen knees (Group 3). In six of the specimen knees. further anatomic studies of the intercondylar notch were performed after tissue removal. The average intercondylar distance was 16.1 mm in Group 1. 18.1 mm in Group 2. and 20.4 mm in Group 3. All differences were highly significant. The intercondylar notch was wider in the posterior part and had no crossing bony ridges but had generally concave walls. which provided a functional shelf for the ACL to insert on the lateral side. Significant osteophyte formation and stenosis of the anterior outlet of the intercondylar notch occur early in the ACL-deficient knee. A narrow anterior outlet of the intercondylar notch without osteophytes was also found in knees with an acute ACL rupture. At reconstruction of the ACL. notchplasty should be performed concomitantly.
Anterior-cruciate-insufficient knees treated with physiotherapy. A three-year follow-up study of patients with late diagnosis, To evaluate a functional neuromuscular training program focusing on strength. endurance. postural control. and agility. 26 patients with a rupture of the anterior cruciate ligament (ACL) diagnosed late were examined before starting a training period and then followed for three years. During the study period. four of the patients had an ACL reconstruction. Twenty-two patients treated without surgery were satisfied with the improvement in their knee function and activity level after three to six months of physiotherapy. Compliance with the rehabilitation program was good and the improvement achieved on completion of the training period was maintained for three years in this group of recreational sportsmen and women. Quadriceps strength. functional knee score. activity level. and functional performance were all improved after training and were maintained during the follow-up period.
Dislocation of the knee, The results of treatment for vascular and ligamentous injuries in 17 patients who suffered complete dislocation of the knee were reviewed. Eight patients had 23 associated injuries. All nine patients who had injuries of the popliteal artery had arterial reconstruction with saphenous vein bypass grafts. which were successful in eight (89%). Intraoperative arteriography after vascular repair showed a narrowed anastomosis requiring revision in two (22%) of the nine patients and distal thrombi requiring removal in five (55%) patients. Delay in arterial repair was responsible for the one failure. Eleven patients had satisfactory results after early open ligament repair. The results were less favorable in the patients not treated with early ligament repair.
Varus of the talus in the ankle mortise secondary to calcaneus fracture. A case report, Varus displacement of the talus in the ankle mortise secondary to a calcaneus fracture was observed in a 33-year-old man. Similar to the calcaneus fracture-dislocation. the mechanism involved inferior and medial displacement of the talus into the body of the calcaneus. The patient's ankle deformity was not corrected by a lateral ankle ligament reconstruction. Correction required a distraction subtalar bone block fusion. Successful reconstruction of the hindfoot after calcaneus fractures requires a careful analysis of the pathologic lesion. In this unusual case. correction required restoration of lost hindfoot bone structure.
Epidemiology of primary osteogenic sarcoma in the San Francisco Bay Area of California, This epidemiologic study represents an analysis of all registered new cases of osteogenic sarcoma (OGS) during the 14-year period from January 1973 to December 1986 in five San Francisco Bay counties. Inclusion into the study was limited to patients who were diagnosed in the first three decades of life and who were residents within the Bay Area at the time of diagnosis. To determine epidemiologic characteristics of OGS. records on 96 patients from the Bay Area Resources for Cancer Control with histologically proven OGS were reviewed. The incidence of OGS was influenced by age. gender. and race. but none of the effects were statistically significant. A geographic variation in the incidence of OGS was discovered. although it was not statistically significant. The results are presented in support of a continued search for environmental variables that may someday reveal the etiologic factors of OGS.
Solitary fibromatosis of bone. A rare variant of congenital generalized fibromatosis, Congenital generalized fibromatosis is part of the spectrum of the fibromatoses of infancy and childhood. The lesions are usually multiple and fibrous in nature. They may appear in virtually every organ outside the central nervous system. Congenital generalized fibromatosis can be limited to the skeleton and rarely manifests itself as a solitary bone lesion. Solitary osseous lesions often behave differently than multiple osseous lesions. Solitary lesions often do not regress without treatment and can have a high incidence of recurrence with less than marginal excision. Multiple osseous lesions often regress without treatment.
A histologic and immunohistochemical study of calcium pyrophosphate dihydrate crystal deposition disease, The articular cartilage. synovial membrane. and meniscus from ten patients who had calcium pyrophosphate dihydrate (CPPD) crystal deposition disease showed strong immunoreactivity for dermatan sulfate proteoglycan. Type I collagen. and S-100 protein in hypertrophic chondrocytes around the crystals. their pericellular matrix. and deposits of the crystals. Electron microscopy revealed that small crystals were formed around the hypertrophic chondrocytes. especially in the degenerated matrix containing electron-dense granular materials and cellular debris. Chondrocytes of this kind were never observed in the articular tissue from ten patients who had osteoarthrosis. These hypertrophic chondrocytes with several unique immunohistochemical characteristics may initiate the formation of CPPD crystals.
Phosgene (chlorophenyl)hydrazones, strong sensitizers found in yellow sweaters bleached with sodium hypochlorite, defined as causative allergens for contact dermatitis by an experimental screening method in animals [published erratum appears in Contact Dermatitis 1990 Nov;23(5):383, 12 young men developed allergic contact dermatitis from wearing yellow cotton sweaters. We attempted to identify the causative agents by an experimental screening method in animals. Guinea pigs were sensitized with an acetone extract of the sweater material. by means of the guinea pig maximization test (GPMT). Active ingredients were then separated from the extract. by step-by-step patch test screening of chromatographic fractions in the guinea pigs. and finally analyzed by gas chromatography-mass spectrometry (GC-MS). Although there were 2 allergens with important activity (1 in the fraction eluted from the silica gel column with hexane. and 1 in the methanol fraction). the present study is focussed on the fat-soluble allergens in the hexane fraction. GC-MS analysis revealed that 4 kinds of phosgene (chlorophenyl)hydrazones (PCPHs) were present in the hexane fraction. PCPHs prepared in our laboratory showed strong eliciting activities. not only in the guinea pigs sensitized with the extract. but also in a male volunteer sensitized by exposure to a yellow sweater during irritancy testing. Phosgene (2.5-dichlorophenyl)hydrazone. which was the main component among the PCPHs found in the sweater. sensitized guinea pigs even at the 1 ppm level. From these results. we conclude that PCPHs were one of the allergens responsible for the cases.
Patch and prick test study of 593 healthy subjects, 593 recruits selected by the Military Health Service as being healthy and without a history of present or previous dermatitis. or ocular refraction defects. were patch tested with the GIRDCA (Italian Research Group on Contact and Environmental Dermatitis) standard series. Of these. 336 were also patch tested with substances used in the processing and dyeing of textiles and prick tested with 8 major allergens. 74 (12.5%) reacted to 1 or more substances. The most frequent sensitizers were: thimerosal (28 cases). ammoniated mercury (7 cases). phenol-formaldehyde resin (6 cases). parabens. nickel and Disperse Red 17 (4 cases each). 113 recruits reacted to 1 or more prick test allergens. We have demonstrated the importance of establishing such reference values in healthy groups for the correct evaluation of data collected from selected groups.
Ammoniated mercury ointment: outdated but still in use, Although severe mercury-associated side effects. such as poisoning and high irritant and allergic potential. as well as the weak potency of mercury as an antiseptic or antipsoriatic agent. are well-known. topical mercury preparations are still listed in several pharmacopoeias. including that of the United States. UK and several other European countries. Thus. topical mercurials are still in use. even though more effective and less toxic drugs are now available. We report 2 cases of severe allergic reaction to ammoniated mercury and hope. in agreement with the pertinent literature. to contribute to its removal. and that of most other mercurials. from the therapeutic armamentarium.
Occupational dermatoses from epoxy resin compounds, This study comprises 40 patients with skin disorders from current or previous occupational exposure to epoxy resin compounds (ERC) during 1984-1988. ERCs were the 3rd most common cause (32 of 264 cases: 12.1%) of currently relevant allergic contact dermatitis: 23 cases from epoxy resins based on the diglycidyl ether of bisphenol A (DGEBA-ERs). 5 from reactive diluents. 1 from amine hardeners (DETA). and 3 from epoxy acrylates. 2 cases (0.8%) of irritant contact dermatitis were due to ERCs. Methyl hexahydrophthalic anhydride (MHHPA. an epoxy hardener) caused 1 case of contact urticaria. Previously relevant occupational allergic contact dermatitis from DGEBA-ERs was detected in 5 cases. On patch testing. ERC allergens gave the following positive reactions: epoxy resin of the standard series in 35 cases (4.0% of 870 tested). epoxy reactive diluents in 10 (7.1% of 140). cycloaliphatic epoxy resins in 4 (11.1% of 36). epoxy acrylates in 4 (4.5% of 88). and amine compounds commonly used as epoxy hardeners in 17. Despite extensive patch test series. testing with patients' own ERCs remains important.
Water and electrolyte balance after ileoanal anastomosis, Water and electrolyte balance was studied in 30 patients with ileoanal anastomosis and J pouch. 10 patients with conventional ileostomy. and nine nonoperated patients with quiescent ulcerative colitis. Serum electrolyte concentrations. daily urinary volume. and daily losses of sodium. potassium. and chloride were measured in all patients. Daily fecal weight and daily losses of sodium and potassium were analyzed in patients with ileoanal anastomosis or conventional ileostomy. Serum chloride in patients with ileoanal anastomosis was significantly lower (P less than 0.05) than in those with conventional ileostomy or in nonoperated patients. Daily urinary loss of sodium in nonoperated patients was significantly higher than in patients with ileoanal anastomosis (P less than 0.01) or conventional ileostomy (P less than 0.05). Daily urinary loss of chloride in patients with ileoanal anastomosis was significantly lower (P less than 0.05) than in nonoperated patients. Daily fecal loss of potassium in patients with ileoanal anastomosis was significantly higher (P less than 0.05) than in those with conventional ileostomy. Daily urinary volume and fecal weight did not differ significantly in patients with ileoanal anastomosis or conventional ileostomy. The present study indicates that changes in water and sodium balance after ileoanal anastomosis are similar to those after conventional ileostomy but chloride balance is more altered after ileoanal anastomosis.
Assessment of "squamous cell carcinoma antigen" (SCC) as a marker of epidermoid carcinoma of the anal canal, We measured squamous cell carcinoma antigen (SCC) in epidermoid carcinoma of the anal canal in 66 patients. Samples were taken at diagnosis. before treatment. and during follow-up; 353 samples were analyzed. The positive threshold was taken as 2 ng/ml. At diagnosis. the sensitivity of the marker was 44 percent and its specificity 92 percent. In our series. the pretherapeutic level of SCC does not correlate with T as in Papillons' Clinical Staging System. but it does correlate with nodal invasion (P less than 0.05). It is of no prognostic value at the time of diagnosis. During follow-up. at relapse the level of SCC is 20.3 +/- 43 ng/ml. This increase is significant (P less than 0.01): the sensitivity of the marker is 77 percent. In patients who have relapsed. development of the illness correlates with the level of SCC. which is of prognostic value (P less than 0.01). In conclusion. the level of SCC should be associated with the clinical follow-up of patients with epidermoid carcinoma of the anal canal.
"Mini-perforation" of the colon--not all postpolypectomy perforations require laparotomy, In a 10-year experience with 4.784 consecutive colonoscopic polypectomies. the need for operative intervention in just two of seven perforations indicates that patients with specially defined. limited perforations can usually be treated nonoperatively. This specific complication. which has been termed "mini-perforation." is generally detected within 6-24 hours of polypectomy. and is characterized by local pain and tenderness. without signs of diffuse or spreading peritoneal irritation. Free intra-abdominal or retroperitoneal air on x-ray documents the actual perforation. Complete resolution of symptoms within 24-48 hours confirms the diagnosis of "mini-perforation." Success depends on good bowel preparation for colonoscopy. and early recognition of perforation. with institution of bowel rest and intravenous antibiotics. The "mini-perforation" spontaneously closes. probably by omental adherence. Frequent serial clinical examinations are mandatory so that frank perforation with advancing peritonitis will be promptly recognized and treated surgically. An understanding of the three levels of cautery injury to the colon wall--"serosal burn." "mini-perforation." and "frank perforation" are essential in managing the complications of colonoscopic polypectomy.
Anti-tumor X anti-lymphocyte heteroconjugates augment colon tumor cell lysis in vitro and prevent tumor growth in vivo, Cross-linking an anti-tumor antibody. specific for tumor cell surface antigens. and an anti-lymphocyte antibody. specific for the T lymphocyte receptor complex (TCR/CD3). produces a heteroconjugate that can direct T cells to lyse tumor cells. We tested the ability of anti-tumor X anti-lymphocyte (CD3) heteroconjugates to redirect human peripheral blood lymphocytes (PBLs) to lyse human colon cancer cells in cytotoxicity assays and in a murine colon tumor model. We demonstrated in vitro. that cultured human PBLs alone produced low levels of tumor lysis. but PBLs treated with anti-tumor X anti-CD3 heteroconjugates produced significantly greater tumor cell lysis (P less than 0.0025). Similarly. nude mice injected with LS174T human colon cancer cells and treated with cultured human PBLs and anti-tumor X anti-CD3 heteroconjugates survived significantly longer than saline control mice (P less than 0.01). or mice treated with PBLs alone (P less than 0.01). or heteroconjugates alone (P less than 0.05). F(ab')2 heteroconjugates were equally as effective in prolonging animal survival. but irrelevant heteroconjugates and monoclonal anti-tumor antibodies showed no therapeutic benefit. Anti-tumor X anti-CD3 heteroconjugates may represent an effective approach to tumor-specific cellular immunotherapy.
Polyamine levels in healthy and tumor tissues of patients with colon adenocarcinoma, Tissue polyamine levels were determined in patients with colon adenocarcinoma to try to identify biochemical indicators able to characterize the growth and the metabolism of human solid tumors. Polyamine content was determined in the tumor and in the "healthy" mucosa sampled at different distances within the resection edges. For each patient the polyamine content in the tumor was compared with that in the mucosa. The results demonstrated that the spermidine concentration was higher in the tumor than in the healthy mucosa; the differences were statistically significant. However. spermine in the tumor increased to a lesser degree. No statistically significant differences were observed among these mucosae at different localizations. but the spermine concentration in the mucosa after the tumor showed values very close to those of the neoplasia.
The role of fistulography in fistula-in-ano. Report of five cases, A retrospective review of 27 patients undergoing anal fistulography is presented. The etiology of the 27 fistulas studied are as follows: cryptoglandular infection in 18. IBD in 7 (Crohn's 6. CUC 1). iatrogenic in 1. and foreign body perforation in 1. Twenty-six fistulograms revealed either direct communication with the anus or rectum. or abscess cavities/tracts. or both. Two fistulograms revealed no radiographic evidence of fistula (one patient had two fistulograms). In 13 of the 27 patients (48 percent) information obtained from the fistulograms revealed either unexpected pathology (n = 7) or directly altered surgical management (n = 6). We conclude that anal fistulography in properly selected patients may add useful information for the definitive management of fistula-in-ano.
Incarceration of colonoscope in an inguinal hernia. "Pulley" technique of removal, Because of its relative safety. colonoscopy has become an accepted diagnostic and therapeutic procedure in the evaluation of patients with colorectal disorders. Many unusual complications of colonoscopy have been described. but only anecdotal reports of hernial incarceration have been published. We present a case of a right-sided hernial incarceration of the colonoscope that would not permit reduction of the hernia nor removal of the instrument by conventional means. The mechanism of incarceration. which dictates the size of hernia at risk for incarceration. is explained. The "pulley" technique. which was used to remove the instrument without surgical intervention. is described.
Gender differences in Manning criteria in the irritable bowel syndrome, The objective of this study was to determine if gender differences exist when using the Manning criteria for diagnosis of irritable bowel syndrome. In an outpatient setting. 61 women and 36 men with entry complaints of abdominal pain. altered bowel habits. or both underwent full evaluation by board-certified/eligible gastroenterologists who also systematically rated the presence or absence of the six Manning criteria. Irritable bowel syndrome was defined as the absence of an organic disease explanation for the entry complaints. This determination was made by two other board-certified gastroenterologists after patients had been in the study for 9 months. These raters were independent of the study and rated the transcripts of patients' clinic visits. all other available clinical data from this and other clinics. all laboratory data obtained during the 9-month study period. and the results of a 9-month telephone follow-up to patients and their physicians. Sixty-five percent of the study population had no organic disease explanation for the entry symptoms. thereby representing irritable bowel syndrome for this study. A similar proportion and type of organic disease and irritable bowel syndrome were experienced by men and women. For the total sample of 97 subjects. the correlation of the Manning criteria with irritable bowel syndrome was 0.22 (P less than 0.01). In the 61 women. correlation between the Manning criteria and irritable bowel syndrome was significant (r = 0.47; P less than 0.01). In the 36 men. however. the correlation was in the opposite direction. although it was not significant (r = -0.16). It was concluded that significant gender differences exist when using the Manning criteria for the diagnosis of irritable bowel syndrome and that the Manning criteria were not of diagnostic value in men.
Impairment of esophageal emptying with hiatal hernia, Concurrent videofluoroscopy and manometry were used to analyze esophageal emptying during barium swallows in 22 patients with axial hiatal hernias and in 14 volunteers. Subjects were divided into three groups: (a) volunteers with maximal phrenic ampullary length less than 2 cm (controls); (b) patients or volunteers with maximal ampullary/hiatal hernia length greater than or equal to 2 cm that reduced between swallows (reducing-hernia group); and (c) patients with hernias that did not reduce between swallows. Complete esophageal emptying without retrograde flow was achieved in 86% of test swallows in the controls. 66% in the reducing-hernia group. and 32% in the nonreducing-hernia group (P less than 0.05). Impaired emptying in the reducing-hernia group was attributable to "late retrograde flow." whereby barium squirted retrograde from the hernia during emptying. Impaired emptying in the nonreducing-hernia group was attributable to "early retrograde flow" that occurred immediately after LES relaxation. The nonreducing-hernia group also had longer acid clearance times than the controls (P less than 0.05). We conclude that gastroesophageal junction competence is severely impaired in patients with nonreducing hiatal hernias. suggesting a mechanism whereby this subgroup of hiatal hernia is involved in the pathogenesis of reflux disease.
Small intestinal transit in the portal hypertensive rat, The purpose of this study was to determine the effects of portal hypertension on gastrointestinal transit. Portal hypertension was induced in a group of 15 rats by the staged portal vein ligation technique. A control group of 15 rats underwent a sham operation. Ten days later. a 51Cr-labeled Krebs' buffer solution was instilled into the duodenum and the distribution or radioactivity along the length of the small intestine was determined after 15. 30. and 60 minutes. Portal hypertension was consistently established in the study group; splenic pulp pressure (mm Hg. mean +/- SD. portal hypertensive vs. control) was 20.0 +/- 3.9 vs. 12.7 +/- 3.9. P less than 0.002. Various measures of intestinal transit revealed delayed transit in the portal hypertensive group. Retention of radioactivity in the most proximal quartile of the intestine was greater [percentage retained (portal hypertensive vs. control) was 57.9 +/- 17.3 vs. 31.2 +/- 15.3. P less than 0.02. 49.1 +/- 15.5 vs. 28.3 +/- 4.8. P = 0.03. and 42.4 +/- 17.6 vs. 29.0 +/- 8.8. P = 0.08. at 15. 30. and 60 minutes. respectively] and the geometric mean of transit was located more proximally (P less than 0.02) at each study interval in the portal hypertension group. It was concluded that portal hypertension is associated with delayed intestinal transit. This abnormality could predispose to bacterial overgrowth and contribute to altered digestion and absorption.
Isolation and characterization of normal and neoplastic colonic epithelial cell populations, The aim of the present study was to characterize rat mucosal colonic cells harvested from the crypt continuum during differentiation and dimethylhydrazine-induced neoplasia. The collection of colonocytes was performed using a modified nonenzymatic isolation procedure based on Ca2+ chelation and gentle mechanical dissociation. Light and electron microscopy histomorphological examinations. [3H]thymidine incorporation studies. and activity gradients of alkaline phosphatase. thymidine kinase. and cytoskeleton-associated protein tyrosine kinase indicated that distinct cell populations were harvested from the various crypt regions in a temporal sequence mirroring their zonal and functional distribution in situ. After dimethylhydrazine administration. marked protein tyrosine kinase activity was noted in colonic cells harvested from upper crypt zones. The misplaced and sustained kinase activity preceded the actual polyp or tumor formation. This observation is consistent with the expansion of colonic proliferative compartments beyond allowable boundaries during the preneoplastic period. Companion studies in human colonic epithelial specimens corroborate the findings observed in normal and transformed murine colonocytes. It is believed that the characterization and manipulation of colonocytes using our in vitro model will provide important clues to the molecular events underlying the differentiation program and carcinogenic process in the colonic cell.
Increased uptake of bromodeoxyuridine by hepatocytes from early stage of primary biliary cirrhosis, The relationship between DNA synthesis activities of hepatocytes in biopsied specimens and liver volume was studied in various stages of primary biliary cirrhosis using an in vitro bromodeoxyuridine (a thymidine analogue)-anti-bromodeoxyuridine reaction and computed tomography. The mean bromodeoxyuridine (+/- SE) labeling index for 10 patients in an early histological stage (stage I. 4. and stage II. 6. 3.4% +/- 0.4%) of primary biliary cirrhosis was 17 times that for 6 control subjects (0.2% +/- 0.1%. P less than 0.001). and was significantly higher than that for 19 female patients with chronic aggressive hepatitis (0.9% +/- 0.2%. P less than 0.001). 14 compensated cirrhotic patients of viral origin (all female. 1.1% +/- 0.3%. P less than 0.01). and 5 patients with stage III primary biliary cirrhosis (0.5% +/- 0.1%. P less than 0.001). The mean (+/- SE) liver volume in the early stage of primary biliary cirrhosis (1225 +/- 40 cm3) was about 1.5 times that in control subjects (835 +/- 42 cm3. P less than 0.001). These results suggest that liver volume has already become large in the early stage of primary biliary cirrhosis perhaps because of markedly increased DNA synthesis in hepatocytes.
Glucose and fat metabolism during short-term starvation in cirrhosis, To evaluate the metabolic consequences of short-term (i.e.. less than 24 hours) starvation. glucose and fat metabolism were studied in eight healthy subjects and in eight patients with stable cirrhosis after 16-hour and again after 22-hour starvation by 3-[3H]glucose and [14C]palmitate turnover and by indirect calorimetry. Although patients and controls showed significant increases in free fatty acid concentration (respectively. 48% +/- 12% and 53% +/- 17%) and turnover (55% +/- 14% and 71% +/- 21%) during short-term starvation. the values after 16- and after 22-hour starvation were higher in cirrhosis. Fat oxidation was enhanced in the patients. but did not increase during fasting in contrast to controls (increase 19% +/- 17%. P less than 0.05). Net glucose oxidation was decreased in postabsorptive cirrhotics (P less than 0.05). Although postabsorptive glucose turnover was not different from controls. starvation induced a greater decrease in glucose turnover in the patients (25% +/- 3% vs. 10% +/- 3%. P less than 0.05). This was not reflected in plasma glucose concentrations. In conclusion. the effects of starvation on glucose and fat metabolism are enhanced in cirrhosis; fasting hypoglycemia is prevented by decreased use of glucose. It remains to be established whether these changes are merely explained by defective liver function. per se.
Ascites increases the resting energy expenditure in liver cirrhosis, The purpose of this study was to investigate the effect of ascites on the energy metabolism of patients with liver cirrhosis. The resting energy expenditure was determined in 10 patients with liver cirrhosis and ascites of moderate or large volume. The resting energy expenditure measurement was performed using indirect calorimetry and the resting energy expenditure predictive value was calculated with the Harris-Benedict equation. both before and after removal of ascitic fluid by paracentesis. Metabolic stress factors were absent in all cases. After an interval of 11.2 +/- 7.7 days between measurements. a weight loss of 16.6 +/- 10.3 kg was observed with paracentesis. The resting energy expenditure measured by indirect calorimetry showed a statistically significant decrease from 1682 +/- 291 to 1523 +/- 240 kcal/day (P less than 0.005) after removal of ascites. The repeatability of our indirect calorimetry method only allowed for the analysis of the results in 4 of 10 patients in whom ascites removal produced a consistent decrease in resting energy expenditure. There were no statistically significant differences between the measurements obtained by indirect calorimetry and those provided by the Harris-Benedict equation. but the latter had a moderate reliability in predicting the real resting energy expenditure of every patient. Our results suggest that. far from being an inert volume. ascites may be associated. at least in some patients. with an increased resting energy expenditure and therefore accelerate the appearance of protein energy malnutrition with corresponding complications.
The differential diagnosis of Crigler-Najjar disease, types 1 and 2, by bile pigment analysis, Phenobarbital response. bile pigment composition. and the fractional biliary excretion ratio of bilirubin were studied in nine children with Crigler-Najjar disease. In five children. serum bilirubin levels decreased during phenobarbital treatment by 26% or more and the pigment composition in bile changed with a decrease in the proportion of unconjugated bilirubin from 33% +/- 12% to 13% +/- 1% and an increase in monoconjugates and diconjugates from 57% +/- 14% and 10% +/- 2%. respectively. to 72% +/- 4% and 16% +/- 3%. In four children. serum bilirubin levels did not change significantly during phenobarbital treatment. In these patients. bile pigments comprised 91% +/- 10% unconjugated bilirubin. 9% +/- 11% monoconjugates. and 1% +/- 1% diconjugates. On the basis of these differences. the former group can be classified as having type 2 Crigler-Najjar disease and the latter. type 1. Bile pigment analysis in parents of patients with Crigler-Najjar disease showed an increased proportion of monoconjugates in at least one of the partners in three of four couples tested. despite normal serum bilirubin levels. Serum bilirubin levels were about the same in type 1 and 2 patients and amounted to 236 +/- 62 mumol/L and 214 +/- 82 mumol/L. respectively. In addition the fractional bilirubin excretion ratio. calculated as the ratio ([bilirubin in bile]/[bilirubin in serum])/([bile acid in bile]/[bile acid in serum]) could not differentiate between these two groups. However. there was a 10-fold and 100-fold difference of this ratio between patients with Crigler-Najjar disease and those with Gilbert's syndrome and between patients with Crigler-Najjar disease and controls. The fractional bilirubin excretion ratio proved an excellent tool to differentiate between Gilbert's syndrome and Crigler-Najjar disease. whereas Crigler-Najjar disease types 1 and 2 could be differentiated on the basis of bile pigment analysis.
Incidence of gallstones in a Danish population, Five-year incidence of gallstone disease was assessed by ultrasonography in an age- and sex-stratified random population of Danish origin aged 30. 40. 50. and 60 years. The response rate was 82.8% (2987/3608). Nonrespondents did not differ from respondents regarding variables concerning gallstone disease. The 5-year incidence of gallstone disease in men aged 30. 40. 50. and 60 years was 0.3%. 2.9%. 2.5%. and 3.3%. Corresponding figures in women were 1.4%. 3.6%. 3.1%. and 3.7%. The incidence of gallstones was significantly higher in subjects aged 45 years or more compared with those aged 35 years. The sex difference in gallstone incidence decreased with increasing age. A significantly higher incidence of gallstone disease was found among subjects with former polyps in the gallbladder. Spontaneous disappearance of gallstones was seen in 4.5%.
Extrahepatic portal vein aneurysm associated with a tortuous portal vein, Portal vein aneurysm is rare and its etiology is controversial. A case of extrahepatic portal vein aneurysm associated with an unusually tortuous portal vein is described. Real-time ultrasonography showed anechoic masslike lesions at the porta hepatis communicating with the superior mesenteric vein and intrahepatic portal branches. This suggested the presence of two saccular portal vein aneurysms. 27 x 21 mm and 21 x 13 mm in size. Magnetic resonance imaging and portal venography confirmed the portal vein aneurysms and an unusually tortuous portal vein curving caudally between them. The liver was histologically normal and there was no evidence of portal hypertension. It is speculated that these portal vein aneurysms may have been congenital and that the associated tortuous portal vein might have been secondary to hemodynamic changes in the portal venous system.
Chronic care needs to be a higher priority, Although acute care remains the focus of the U.S. health care delivery system. a shift is taking place toward chronic-illness mortality. Developing effective chronic-disease management processes is tough in the context of today's acute care orientation. according to William F. Henry. president of ForeSight Strategy Associates. St. Paul. MN.
Familial cervical dysplasia, Nine of twelve family members from three generations were affected by an inherited form of cervical vertebral dysplasia. All of the affected people had an abnormality of the first cervical vertebra. Some also had defects of the axis and caudad to it. The mode of transmission of the disorder is autosomal dominant. with apparently complete penetrance and variable expressivity. Two patients had symptoms. One had a passively correctable tilt of the head. with an associated audible clunk and hypoplasia of the left superior facet of the second cervical vertebra. This patient had no local symptoms. neurological involvement. or muscle spasm. In the other patient. suboccipital pain developed. Radiographs revealed an anterior atlanto-occipital dislocation. The symptoms resolved after reduction and arthrodesis. Because of the apparently complete penetrance of this disorder. physicians caring for patients who have this type of congenital malformation of the cervical spine should consider examination of closely related members of the family. Clinical findings such as tilting of the head. torticollis. or limitation of cervical motion suggest that additional evaluation should be done. The examination should include lateral radiographs of the cervical spine in flexion and extension. Three-dimensional computed-tomography reformatting was helpful in demonstrating the complex cervical anatomy in our patients. Patients who have recognized abnormalities should be followed and should be re-examined whenever local or neurological symptoms develop. A magnetic resonance image of the spine in flexion and extension was valuable for identification of the potentially disastrous situation of impending damage to the cord in patients who had instability and evolving symptoms.
Revision total knee arthroplasty for failed unicompartmental replacement, The results in nineteen patients (twenty-one knees) who had a failed unicompartmental knee replacement followed by a revision total knee arthroplasty were evaluated. There were twelve excellent. four good. one fair. and two poor results. The interval between the unicompartmental replacement and the revision total knee arthroplasty ranged from eight months to eight years. At the time of the revision. a major osseous defect was found in sixteen knees (76 per cent). The duration of follow-up after the revision ranged from two to ten years. At the most recent follow-up examination. radiographs revealed at least one radiolucent line in thirteen knees (62 per cent). The technical difficulties associated with the revision operation are evidence that unicondylar arthroplasty is not a conservative procedure that allows a total knee arthroplasty to be done easily later. The results also do not support the argument that a revision performed after failure of a unicondylar arthroplasty is less technically demanding than one performed after a failed primary total knee arthroplasty.
Factors determining improvement in left ventricular function after reperfusion therapy for acute myocardial infarction: primacy of baseline ejection fraction, Improvement in left ventricular ejection fraction is a measure of salvage of ischemic myocardium after reperfusion therapy for acute myocardial infarction. The degree of improvement in left ventricular ejection fraction may be influenced by many factors. Therefore. 137 patients in whom paired radionuclide angiograms were obtained within 24 h of acute infarction and before hospital discharge were retrospectively evaluated to determine which factors most affect improvement in ejection fraction. Only baseline ejection fraction correlated significantly with improvement in ejection fraction by both univariate analysis (ejection fraction as a continuous variable; p less than 0.001; ejection fraction as a categorical variable. less than or equal to 45% versus greater than 45%. p less than 0.0001) and multivariate analysis (p less than 0.0001). Reperfusion status (patent versus occluded infarct artery) and extent of coronary artery disease (one. two or three vessel) were significant factors by multivariate but not by univariate analysis. Location of infarction. treatment modality and time to treatment did not correlate with change in ejection fraction by either statistical technique. Thus. of those factors tested. baseline left ventricular ejection fraction is the most potent predictor of improvement in ventricular function after acute infarction. Knowledge of baseline ejection fraction may be helpful in deciding whether to treat some patients with equivocal indications or contraindications for reperfusion therapy. Clinical trials of reperfusion strategies should stratify patients on the basis of baseline ejection fraction if ejection fraction is to be used as an end point for myocardial salvage.
Incidence and clinical significance of transient creatine kinase elevations and the diagnosis of non-Q wave myocardial infarction associated with coronary angioplasty, To assess the incidence and clinical significance of elevated total plasma creatine kinase (CK) and MB isoenzyme fraction after apparently successful coronary angioplasty. a prospective study of 272 consecutive elective procedures was undertaken. Total CK (normal less than 100 IU/liter) and CK MB isoenzyme (normal less than 4%) were measured immediately after successful completion of the procedure and every 6 h for 24 h. All nonelective procedures and results not fulfilling all American Heart Association/American College of Cardiology Task Force guideline criteria for a successful result were excluded from analysis. Of the 272 elective procedures. 249 (92%) were successfully; abnormally elevated CK or CK MB serum levels. or both. were found in 38 (15%) of the successful outcomes. Three patterns of abnormal enzymes were identified: 15 patients with CK greater than or equal to 200 IU/liter and CK MB greater than or equal to 5% (group 1). 4 patients with CK greater than or equal to 200 IU/litter and CK MB less than or equal to 4% (group 2) and 19 patients with CK less than 200 IU/liter and CK MB greater than or equal to 5% (group 3). The three groups were distinguishable by the nature of the complications causing the enzyme release (in particular. the etiology and clinical manifestations). There were significantly more clinically apparent events in group 1 than in the other groups (13 of 15 versus 11 of 23. p less than 0.01) and more events associated with persistent electrocardiographic changes (p = 0.05) and chest pain (p less than 0.05). However. no clinically important sequelae were recognizable in any group at hospital discharge. Thus. abnormal cardiac serum enzyme release after apparently successful coronary angioplasty is 1) relatively common; 2) has many possible causes. including both minor complications and early reversibility of impending major complications; and 3) results in no permanent clinical sequelae.
Long-term follow-up of medical versus surgical therapy for hypertrophic cardiomyopathy: a retrospective study, In a retrospective analysis 139 patients with hypertrophic cardiomyopathy were followed up for 8.9 years (range 1 to 28 years). Patients were divided into two groups: Group 1 consisted of 60 patients with medical therapy and Group 2 of 79 patients with surgical therapy (septal myectomy). Groups 1 and 2 were subdivided according to the medical treatment. Group 1a received propranolol. 160 mg/day (n = 20); Group 1b verapamil. 360 mg/day (n = 18); and Group 1c. no therapy (n = 22). Group 2a received verapamil. 120 to 360 mg/day. after septal myectomy (n = 17) and Group 2b had no medical therapy after surgery (n = 62). In Group 1. 19 patients died (annual mortality rate 3.6%) and in Group 2. 17 patients died (mortality rate 2.4%. p = NS). Of the patients who died. approximately one half to two thirds in both Groups 1 and 2 died suddenly and the other one half to one third died because of congestive heart failure. The 10 year cumulative survival rate was 67% in Group 1. significantly smaller than that in Group 2 (84%. p less than 0.05). In the subgroups. the 10 year survival rate was 67% in Group 1a. 80% in 1b (p less than 0.05 versus 1a) and 65% in 1c (p less than 0.05 versus 1b). The 10 year survival rate was 100% in Group 2a (p less than 0.05 versus 1a. 1b. 1c) and 78% in Group 2b (p less than 0.05 versus 2a). It is concluded that cumulative survival rate is significantly better in surgically than in medically treated patients.
Prediction of the frequency and duration of ambulatory myocardial ischemia in patients with stable coronary artery disease by determination of the ischemic threshold from exercise testing: importance of the exercise protocol, The relation between ambulatory myocardial ischemia and the results of exercise testing in patients with ischemic heart disease remains undefined. because of the dissimilar results of previous reports. To further investigate this issue and. in particular. to ascertain the importance of the exercise protocol in determining that relation. 70 patients with stable coronary artery disease underwent 48 h ambulatory electrocardiographic (ECG) monitoring and treadmill exercise tests after withdrawal of medications. Patients exercised using two different protocols with slow (National Institutes of Health [NIH] combined protocol) and brisk (Bruce protocol) work load increments. Exercise duration was longer with the NIH combined protocol (14.1 +/- 5 versus 6.8 +/- 2 min; p less than 0.0001). but the maximal work load and peak heart rate achieved were greater with the Bruce protocol (9.8 +/- 2 versus 6.5 +/- 2 METs. and 142 +/- 19 versus 133 +/- 22 beats/min. respectively; p less than 0.0001). A close inverse correlation between exercise testing and the results of ambulatory ECG monitoring was observed using the NIH combined protocol; the strongest correlation was observed between time of exercise at 1 mm of ST segment depression and number of ischemic episodes (r = -0.86; p less than 0.0001). With the Bruce protocol a significantly weaker inverse correlation was found (r = -0.35). The mean heart rate at the onset of ST segment depression was similar during monitoring and during exercise testing with the NIH combined protocol (97.2 +/- 13 versus 101.0 +/- 17 beats/min. respectively) but it was significantly higher (110.4 +/- 13) when using the Bruce protocol (p less than 0.001).
Effects of standing on the induction of paroxysmal supraventricular tachycardia, To evaluate the effects of standing on induction of paroxysmal supraventricular tachycardia. electrophysiologic studies were performed in both the supine and standing positions in 22 patients with atrioventricular (AV) reciprocating tachycardia and in 11 with AV node reentrant tachycardia. AV reciprocating tachycardia was induced in 9 of the 22 patients with AV reciprocating tachycardia when they were in the supine position and in 17 when standing. The effective refractory period of the AV node markedly shortened. from 275 +/- 72 to 203 +/- 30 ms (n = 16. p less than 0.005) after standing. The effective refractory period of the accessory pathway shortened slightly. from 293 +/- 75 to 278 +/- 77 ms (n = 8. p less than 0.005). after standing. AV node reentrant tachycardia was induced in 3 of the 11 patients with AV node reentrant tachycardia when they were in the supine position and in 6 when standing. The effective refractory periods of the slow pathway and fast pathway shortened markedly. from 293 +/- 72 to 216 +/- 40 ms (n = 6. p less than 0.025) and from 416 +/- 85 to 277 +/- 50 ms (n = 10. p less than 0.005). respectively. after standing. Plasma norepinephrine levels increased during standing both in patients with AV reciprocating and in those with AV node reentrant tachycardia (n = 11. p less than 0.005. n = 8. p less than 0.005. respectively). In conclusion. standing. which is associated with increased sympathetic tone. changed the electrophysiologic properties of the reentrant circuits. facilitating induction of AV reciprocating tachycardia and AV node reentrant tachycardia.
Surgery for Ebstein's anomaly: the clinical and echocardiographic evaluation of a new technique, Ten consecutive patients (age range 4 to 44 years. mean 22) underwent surgical repair of Ebstein's anomaly by vertical plication of the right ventricle and reimplantation of the tricuspid valve leaflets. No patient died during or after operation. Intraoperative postbypass echocardiography documented a good result in nine patients but severe tricuspid regurgitation in one patient. who then underwent prosthetic valve replacement during a second period of cardiopulmonary bypass. Two of four patients who had had right ventricular papillary muscle dysfunction in the early postoperative period showed improved papillary muscle function with concomitant reduction of tricuspid regurgitation 6 months later. All patients were evaluated clinically and by echocardiography 2 to 23 months later. All patients showed clinical improvement. seven by one functional class and three by two classes. All were in sinus rhythm. The mean cardiothoracic ratio decreased by 6% (p less than 0.05). On bicycle ergometry performed in six patients. peak oxygen consumption exceeded 20 ml/kg per min in five. Tricuspid regurgitation diminished in eight patients (by three grades in two patients. by two grades in five and by one grade in one patient); it remained unchanged in two. Comparison of preoperative and postoperative pulsed Doppler flow velocities across the pulmonary valve showed an increase in the peak velocity of flow across the valve (mean 83 +/- 14 versus 97 +/- 11 cm/s. p less than 0.005) and a decrease in the time to peak velocity (mean 130 +/- 16 versus 91 +/- 23 ms. p less than 0.05).
The role of chronotropic impairment during exercise after the Mustard operation, To better understand the role of chronotropic impairment on exercise performance after the atrial switch (Mustard) operation. 20 patients who had undergone this operation for uncomplicated d-transposition of the great arteries exercised to maximal volition using a 1 min incremental treadmill protocol. Heart rate. oxygen consumption. carbon dioxide production and minute ventilation were monitored continuously. Two-dimensional echocardiograms were obtained before testing to calculate the right ventricular inflow volume indexed to body surface area. All patients achieved maximal aerobic capacity based on their ventilatory patterns and respiratory exchange ratio. Maximal heart rate was reduced (175 beats/min; 87% of predicted for age) and maximal oxygen consumption was decreased (31 ml/kg per min; 75% of predicted for age and gender). There was no correlation between maximal oxygen consumption and maximal heart rate. Right ventricular volume index. however. had a significant inverse correlation with maximal heart rate (r = -0.62. p less than 0.005). There was no correlation between right ventricular volume index and heart rate at rest. These results suggest that decreased maximal oxygen consumption in patients after the Mustard procedure is not a result of chronotropic impairment. Right ventricular dilation may be a compensatory response to chronotropic impairment.
Effect of captopril, an angiotensin-converting enzyme inhibitor, in patients with angina pectoris and heart failure, The effects of captopril and placebo were compared in 18 patients with chronic heart failure and angina pectoris with use of a double-blind crossover trial design. Symptoms were assessed by patient treatment preference. visual analogue scores and nitroglycerin consumption. Exercise performance was assessed using two different treadmill protocols of different work intensity with simultaneous measurement of oxygen consumption and by supine bicycle exercise and simultaneous radionuclide ventriculography. Arrhythmias were assessed by 48 h ambulatory electrocardiographic monitoring. Patients generally preferred placebo to captopril. and this appeared to be due to an increase in symptoms of angina with captopril. Treadmill exercise time on a high intensity protocol was shorter with captopril than with placebo; on a low intensity protocol. angina became a more frequent limiting symptom even though overall exercise performance was not changed. The heart rate-blood pressure product was reduced. but largely because of a reduction in blood pressure rather than in heart rate. During supine bicycle exercise. no differences in symptoms. exercise performance. ejection fraction or changes in blood pressure were noted and ventricular arrhythmias were reduced. Captopril does not appear to be clinically useful in alleviating angina pectoris in patients with heart failure. and this effect may be related to a decrease in coronary perfusion pressure. Nonetheless. desirable metabolic effects. a reduction in arrhythmias and potential effects on survival require further study of captopril in patients with both angina and heart failure.
Regional myocardial blood flow and left ventricular diastolic properties in pacing-induced ischemia, The relation between left ventricular diastolic abnormalities and myocardial blood flow during ischemia was studied in eight open chest dogs with critical stenoses of the proximal left anterior descending and circumflex coronary arteries. The heart was paced at 1.7 times the heart rate at rest for 3 min. In dogs with coronary stenoses. left ventricular end-diastolic pressure increased from 8 +/- 1 to 14 +/- 2 mm Hg during pacing tachycardia (p less than 0.01) and 16 +/- 3 mm Hg (p less than 0.01) after pacing. with increased end-diastolic and end-systolic segment lengths in the ischemic regions. Left ventricular diastolic pressure-segment length relations for ischemic regions shifted upward during and after pacing tachycardia in dogs with coronary stenoses. indicating decreased regional diastolic distensibility. In dogs without coronary stenoses. the left ventricular diastolic pressure-segment length relation was unaltered. Pacing tachycardia without coronary stenoses induced an increase in anterograde coronary blood flow (assessed by flow meter) in both the left anterior descending and circumflex coronary arteries. and a decrease in regional vascular resistance. In dogs with coronary stenoses. regional vascular resistance before pacing was decreased by 18%; myocardial blood flow (assessed by microspheres) was unchanged in both the left anterior descending and circumflex coronary artery territories. During pacing tachycardia with coronary stenoses. regional coronary vascular resistance did not decrease further; subendocardial myocardial blood flow distal to the left anterior descending coronary artery stenosis decreased (from 1.03 +/- 0.07 to 0.67 +/- 0.12 ml/min per g. p less than 0.01). as did subendocardial to subepicardial blood flow ratio (from 1.04 +/- 0.09 to 0.42 +/- 0.08. p less than 0.01).
Pressure-length loop area: its components analyzed during graded myocardial ischemia, The changes in total pressure-length loop area were compared with changes in effective shortening area. systolic lengthening area and postsystolic shortening area (defined with respect to end-diastolic and end-systolic lengths) of the pressure-length loop during myocardial ischemia in seven anesthetized dogs instrumented for measurement of left ventricular pressure and regional segmental wall motion (sonomicrometry) in the minor axis of the apical region of the left ventricle. Ischemia was induced by gradual tightening of a micrometer-controlled snare around the left anterior descending coronary artery. which supplied the apical myocardium. Data were obtained at normal flow. after critical constriction (loss of pulsatile coronary flow). mild ischemia (ischemia 1: onset of regional dysfunction. i.e.. postsystolic shortening and mild hypokinesia) and moderate ischemia (ischemia 2: marked hypokinesia). At each stage. acute afterloading was performed by partially occluding the descending thoracic aorta. The pressure-length loops were analyzed in terms of four areas: total loop area. effective shortening area. postsystolic shortening area and systolic lengthening area. Total loop area decreased only when marked hypokinesia was present (176 +/- 18.3 mm Hg x mm at ischemia 2 versus 245.1 +/- 26.9 mm Hg x mm at ischemia 1. p less than 0.05). However. effective shortening area (98.2 +/- 0.8% of total loop area at baseline; 93.8 +/- 2.4% at critical constriction; 76.3 +/- 7.2% at ischemia 1; 51.9 +/- 12.2% at ischemia 2) and postsystolic shortening area (1.8 +/- 0.8% of total loop area at baseline; 5.2 +/- 1.9% at critical constriction; 14.3 +/- 3/4% at ischemia 1; 23.8 +/- 5.1% at ischemia 2) changed significantly with each progressive stage of ischemia.
Follow-up of patients with low output, low gradient hemodynamics after percutaneous balloon aortic valvuloplasty: the Mansfield Scientific Aortic Valvuloplasty Registry, Symptomatic patients with a low cardiac output and low aortic valve gradient have a poor prognosis but are at high risk for aortic valve surgery. The outcome of percutaneous balloon aortic valvuloplasty in this subgroup of patients is unclear. Therefore. 67 patients (group 1) underwent percutaneous balloon aortic valvuloplasty between December 1. 1986 and November 1. 1987 who had a low cardiac index (less than 2.5 liters/min per m2) and a low aortic valve gradient (less than or equal to 40 mm Hg) before the procedure. The results were compared with 200 patients (group 2) who had a low cardiac index but not a low aortic valve gradient (greater than 40 mm Hg) before the procedure and who had similar baseline presenting symptoms. After balloon aortic valvuloplasty. there was a greater decrease in aortic valve gradient in patients in group 2 than in patients in group 1 (mean +/- SD -33.0 +/- 16.7 mm Hg and -14.6 +/- 6.9 mm Hg. respectively; p less than 0.001) although there was no significant difference in improvement in estimated aortic valve area (0.31 +/- 0.21 and 0.31 +/- 0.22 cm2. respectively; p = NS). In-hospital mortality was 11.9% for patients in group 1 which was not significantly different from the 7.5% mortality for patients in group 2. However. the actuarial probability of survival at 12 months for patients who survived the initial hospitalization was 46% in group 1 and 64% in group 2 (p less than 0.05). Moreover. at follow-up (mean 8.8 months) 64% of surviving group 1 patients displayed clinical improvement. compared with 70% of surviving group 2 patients.
Lymphocytes and nonlymphoid cells in human nasal polyps, Immunohistochemical stainings were performed on polyp specimens of 48 patients and on mucosal biopsy specimens of the middle and inferior turbinates of 23 and 28 patients. respectively. Significantly more CD8+ (suppressor/cytotoxic) than CD4+ (helper/inducer) cells were found in the polyps. The number of CD2+. CD4+. and CD8+ lymphocytes in nasal polyps were very similar to the number in the macroscopically unaffected mucosa of the middle turbinates. whereas scores in the inferior turbinates were lower. In healthy subjects. the differences were smaller. CD22+ B cells were detected in varying numbers in the polyps in more or less organized clusters. Significantly more HLA-DR+ cells were found in polyps and middle turbinates than in the inferior turbinates. Eosinophils were found in moderate to large numbers in polyps of 77% of the patients. Mast cells and plasma cells were detected in moderate numbers. whereas neutrophils were found in 35% of the patients. In the middle and inferior turbinates varying but small numbers of eosinophils. mast cells. plasma cells. and neutrophils were found. In considering these findings. the role of chronic inflammation with T cell-dependent disturbances is discussed with regard to the pathogenesis of nasal polyps.
Reduction of budesonide after a year of increased use: a randomized controlled trial to evaluate whether improvements in airway responsiveness and clinical asthma are maintained, We have demonstrated recently that 1 year of regular inhaled budesonide use can produce substantial improvements in airway responsiveness accompanied by significant improvements in clinical asthma severity. The present study was designed to evaluate whether these improvements are maintained when the dose of budesonide is reduced. At the end of the original study. 28 subjects with asthma. who had been in the active-treatment arm of the study were randomized either to continue taking the dose of budesonide taken in the original study or to have the dose reduced. Airway responsiveness to methacholine. bronchodilator requirements. symptoms. and spirometry were assessed after 6 weeks and 3 months. During the 3 months. no subject experienced an asthma exacerbation. and there was no evidence of change in airway responsiveness in subjects who had their steroids reduced (provocative concentration causing a 20% drop in FEV1; initial. 2.03 mg/ml; final. 1.91 mg/ml). and this change was not different from change in subjects maintained with a higher dose (initial. 3.02 mg/ml; final. 3.12 mg/ml) (p = 0.39). Similarly. there was no evidence of any change in bronchodilator requirements (p = 0.89). However. after 3 months of reduced steroid use. there was a small decline in spirometry (FEV1 percent predicted: initial. 84.4%; final. 81.5%). and this change was significantly different from change in subjects in whom steroids were not reduced (initial. 90.2%; final. 90.2%) (p = 0.002). At 3 months. symptoms (predominantly sputum production) were also beginning to redevelop in the reduced budesonide group (p = 0.056).
Environmental exposure to cockroach allergens: analysis with monoclonal antibody-based enzyme immunoassays, Quantitative two-site monoclonal antibody (MAb)-based enzyme-linked immunoassays for two cockroach (CR) allergens. Bla g I and Bla g II. have been developed and used to measure allergen levels in house-dust samples. Dust collected from the CR-infested homes of two patients with asthma from Charlottesville. Va.. demonstrated wide variation in the levels of Bla g I. depending on the location of dust collection. Dust from kitchen floors and cabinets contained 50-fold more allergen (mean. 10.755 U/gm of dust) than dust from bedrooms and upholstered furniture (mean. 204 U/gm). One hundred forty-five dust samples were collected from the bedrooms and living rooms of 22 children with asthma and 16 control subjects without asthma living in Atlanta. Ga. Twenty-seven of the 38 homes (17/22 children with asthma; 10/16 control subjects) had detectable Bla g I (4 to 1340 U/gm of dust). Bla g II levels were assayed in 40 kitchen. bedroom. and living room samples from homes in Wilmington. Del. Highest levels of Bla g II were detected in kitchen-floor dust (300 U/gm of dust). Additionally. approximately 20% of homes with no visual evidence of CR infestation had significant levels of Bla g II in at least one dust sample (greater than 4 U/gm of dust). Our results demonstrate that CR may be an occult allergen in homes. The kitchen appears to be the primary site of CR-allergen accumulation. but significant CR-allergen levels can also be found at other sites in the home. The MAb-based assays can be used for quantitation of environmental exposure to CR allergens.
Bronchoalveolar lavage fluid mediator levels 5 minutes after allergen challenge in atopic subjects with asthma: relationship to the development of late asthmatic responses, Inflammatory mediators have been implicated in the pathogenesis of human asthma and have been demonstrated to increase in bronchoalveolar lavage fluid during the time of the immediate asthmatic response (IAR) after allergen instillation in the lungs. However. the relationship of these mediators. measured early to the late asthmatic response (LAR). airway reactivity. and clinical asthma. is unknown. In the present study. we evaluated mediator levels in bronchoalveolar lavage fluid before and 5 minutes after allergen challenge from three subject groups: atopic subjects without asthma (N = 7). atopic subjects with asthma and without LAR [-) LAR) (N = 6). and atopic subjects with asthma and with LAR [+) LAR) (N = 6). Subjects with asthma were differentiated into subjects with and without LARs based on at least a 15% decrease in FEV1 between 3 to 8 hours postallergen inhalation. The mediators. prostaglandin D2 thromboxane B2 leukotriene C4 (LTC4). and histamine. were measured both before and after allergen instillation. Baseline prechallenge levels were similar. except in the case of LTC4. LTC4 was detectable at baseline significantly more frequently in the atopic subjects with asthma with and without LAR when these subjects were compared to the atopic subjects without asthma (nine of 12 detectable versus one of seven detectable). In all groups. significant increases in mediator levels were observed in the groups with asthma postallergen challenge. compared to the atopic subjects without asthma. Atopic subjects with asthma and without LAR had significantly higher levels of all four mediators after challenge than atopic subjects with asthma and with LAR and atopic subjects without asthma.
Airway effects of inhaled bradykinin, substance P, and neurokinin A in sheep, The effects of inhaled bradykinin (BK). substance P (SP). and neurokinin A (NKA) on pulmonary resistance and airway responsiveness to carbachol were studied in conscious allergic sheep. Inhaled BK (20 breaths. 0.1 to 5.0 mg.ml-1) caused dose-dependent increases in pulmonary resistance. Neither inhaled SP nor NKA (20 breaths. 0.1 to 1.0 mg.ml-1) produced significant bronchoconstriction in allergic sheep. However. the response to SP could be enhanced (p less than 0.05) by pretreatment with the neutral endopeptidase inhibitor. thiorphan (40 breaths. 1 mg.ml-1). Sheep that were allergic to Ascaris suum antigen were 5.9 times (p less than 0.05) more sensitive to the constrictor effects of BK than nonallergic sheep. BK-induced bronchoconstriction was blocked in a dose-dependent fashion by the BK beta 2-receptor antagonist. NPC 567 (D-arginine[hydroxyproline3.D-phenylalanine7]BK). Atropine (0.2 mg.kg-1. intravenously) and nedocromil sodium (1 mg.kg-1 in 3 ml of saline. aerosolized) significantly inhibited the BK-induced bronchoconstriction by 97% and 43%. respectively. Chlorpheniramine (2 mg.kg-1. intravenously) had no effect. NKA caused a transient increase in airway responsiveness in allergic sheep. producing a mean 1.9-fold leftward shift in dose-response curves to aerosolized carbachol (p less than 0.05). This hyperresponsiveness was not evident 24 hours after NKA challenge. Neither SP nor BK changed airway responsiveness. Thus. in allergic sheep. inhaled BK caused a more pronounced bronchoconstriction than that observed in nonallergic sheep. The bronchoconstriction was blocked by a BK-receptor antagonist and appeared to be partially mediated via cholinergic reflexes.
Comparison of cockroach allergenic activity in whole body and fecal extracts, Previous studies have established cockroach allergens as important sensitizing agents in the induction/exacerbation of urban asthma. The present investigation compared saline extracts of American cockroach (Periplaneta americana) whole bodies and feces and German cockroach (Blattella germanica) whole bodies and feces as important sources of allergens. All extracts were tested before or after gel filtration on Sephadex G-75 columns (fraction 2) as previously described. Skin test studies of 69 subjects with asthma with extracts of American or German cockroaches demonstrated a significant correlation of reactivity to whole body and fecal extracts for both species. Direct RASTs of 13 sera from cockroach skin test-positive subjects were generally greater to both German whole body extracts (GWBEs) and German fecal extracts (GFEs) as compared to American whole body and fecal extracts. There was a good correlation of RAST reactivity to GWBE with GFE. RAST inhibition demonstrated that GFE contained most of the allergenic activity present in GWBE. These studies demonstrate the allergenic similarities of cockroach whole body and fecal extracts and suggest that cockroach feces are an important sensitizing agent in atopic asthma.
Analyses of microvascular permeability in response to mediators of immediate hypersensitivity, Mediator-induced changes in microvascular permeability were studied in rodent skin. To monitor these changes. Evan's blue dye. iodinated rat albumin and IgG. and tritiated neutral dextran molecules having different molecular radii were used. After intradermal injections of serotonin. histamine. and bradykinin. the degree of radiolabeled tracer efflux was determined by measuring the extent of blueing and the level of radioactivity in skin biopsy specimens. Although the mediators varied in potency on a molar basis (serotonin greater than bradykinin greater than histamine). the efflux resulting from each was similar. Furthermore. kinetic studies revealed that each of these vasoactive agents caused a marked but transient increase in macromolecular permeability that lasted less than 30 minutes. To determine the pore size created and the effect of charge on the transudation of macromolecules into the interstitium. fractions of neutral [3H]dextrans with a known molecular size (average radii. 12 and 4.4 nm. respectively) were infused either singly or in combination with 125I-labeled rat albumin and/or IgG before intradermal injection of serotonin. histamine. bradykinin. or compound 48/80. Regardless of the mediator used. no differences could be demonstrated in macromolecular efflux. as indicated by either the molecular size of the charge of the tracer used. Thus. all mediators of immediate hypersensitivity reactions that were studied produce venular gaps greater than 12 nm in addition to displaying similar vasopermeable characteristics.
A human CD5+ B cell clone that secretes an idiotype-specific high affinity IgM monoclonal antibody, We previously demonstrated the occurrence of a naturally arisen human anti-idiotypic B cell clone. that we transformed with EBV (EBV383). We show evidence that EBV383 not only expresses the CD5 surface Ag. but also contains the 2.7-kb mRNA transcript encoding this protein. In addition. we show the presence of the 3.6-kb mRNA precursor. Most Ig produced by CD5+ B cells are polyreactive natural IgM antibodies encoded by unmutated copies of germline VH genes. However. in this study we present data demonstrating the monoreactive high affinity character of the anti-idiotypic antibody (mAb383) produced by EBV383. These data are in agreement with our previous observations. showing that the VH chain of mAb383 is encoded by an extensive somatically mutated VHV gene in a way that is consistent with an Ag-driven immune response. A possible role for this remarkable anti-idiotypic antibody in the maintenance of B cell memory is discussed.
Administration of IL-7 to mice with cyclophosphamide-induced lymphopenia accelerates lymphocyte repopulation, Lymphopenia was induced in mice by a single injection of cyclophosphamide. IL-7 or a control protein were administered to the mice twice daily and the cellularity and composition of the spleen. lymph node. bone marrow. and thymus were determined at various time points thereafter. In comparison to the control cyclophosphamide-treated mice. animals receiving cyclophosphamide and IL-7 had an accelerated regeneration of splenic and lymph node cellularity. There was no significant difference in the rate of recovery of the bone marrow and thymus of the control and IL-7-treated mice. Assessment of the pre-B cell compartment revealed a dramatic increase in total pre-B cell numbers in the spleen and bone marrow of the IL-7-treated mice as measured by both flow microfluorimetry and a pre-B cell colony-forming assay. This was followed in a few days by a significant increase in surface IgM+B cell numbers to levels above normal values in both the spleen and lymph node. IL-7 administration to cyclophosphamide-treated mice also resulted in an accelerated recovery of peripheral CD4+ and CD8+ cell numbers in the spleen and lymph node. The numbers of CD8+ cells were increased by twofold over normal levels in cyclophosphamide-treated mice receiving IL-7. Myeloid recovery was determined in cyclophosphamide treated mice by assessing the numbers of CFU-granulocyte-macrophage and Mac 1+ cells. There was no significant difference in myeloid recovery between cyclophosphamide-treated mice receiving IL-7 or control protein. These results suggest that administration of IL-7 after chemical-induced lymphopenia may have therapeutic benefits in shortening the period required to achieve normal lymphoid cellularity.
Six epitopes reacting with human cytotoxic CD8+ T cells in the central region of the HIV-1 NEF protein, In order to identify the target epitopes recognized by specific CTL in the NEF protein of HIV-1. 33 peptides derived from the HIV-BRU sequence were tested with NEF-specific CTL generated from HIV-seropositive donors. Six different epitopes were identified and several points were remarkable: 1) They were all located in two regions of the central part of the NEF protein corresponding to residues 73 to 94 and 113 to 147. respectively. 2) The CTL issued from a single donor could recognize several peptides of the NEF protein. 3) Some of these peptides could be recognized in association with at least two or three different HLA class I molecules. 4) Two different overlapping epitopes were present in a relatively short sequence of 15 amino acids. These results suggest that multiple epitopes corresponding to different HLA restrictions could coexist in a relatively small region of the NEF protein. The implications of these results in vaccine strategies using synthetic peptides bearing CTL epitopes are discussed.
Direct identification of the putative surface IgM receptor-associated molecule encoded by murine B cell-specific mb-1 gene, The B cell-specific mb-1 gene was recently reported to encode a putative surface glycoprotein with CD3-like structural properties. Hombach et al. suggested and presented evidence to show that this mb-1 gene encodes the 34-kDa membrane glycoprotein (B34 or IgM-alpha) associated with IgMR molecule. To identify the mb-1 gene product directly in B cells. affinity-purified MB-1-specific antibody was prepared by immunization of rabbits with synthetic MB-1 oligopeptide. Immunoprecipitation in combination with two-dimensional diagonal gel electrophoresis analysis revealed that this antibody detected a B cell-specific surface glycoprotein that is very similar to the IgM-alpha (B34) protein described by Hombach et al. However. MB-1 protein exists usually as the monomeric form on the surface of B cells. in contrast to IgM-alpha. which was detected as the dimeric (IgM-alpha/IgM-alpha or IgM-alpha/Ig-beta) protein. We also found that MB-1 protein is already expressed on the sIgM- pre-B cell lymphoma. which might suggest an alternative functional role of this B cell-specific MB-1 protein in B cell differentiation. The molecular identity of MB-1 protein and IgM-alpha (B34) is discussed.
MHC-restricted recognition of autologous melanoma by tumor-specific cytotoxic T cells. Evidence for restriction by a dominant HLA-A allele, Autologous melanoma-specific CTL recognize a common tumor-associated Ag (TAA) in the context of HLA class I antigens. We have demonstrated that HLA-A2 can be a restricting Ag and. in T cell lines homozygous for HLA-A2. that CTL can be generated by stimulation with HLA-A2 allogeneic melanomas. In the current study. we have investigated T cell lines from patients who are heterozygous at HLA-A region locus. to determine the relative importance of each A-region allele in this MHC-restricted recognition of tumor. We have shown that HLA-A1 can be a restricting Ag. and that allogeneic melanomas expressing HLA-A1 can substitute for the autologous tumor in the generation of HLA-A1-restricted CTL. However. when T cell lines express both HLA-A1 and HLA-A2. the HLA-A2 allele governed restriction of the melanoma TAA. Three autologous-stimulated HLA-A1. A2 CTL lines all demonstrated restriction by the HLA-A2 allele. when examined in cytotoxicity assays. cold-competition assays. and proliferation assays. There was no evidence of restriction by the second HLA-allele. HLA-A1. Although the autologous-stimulated CTL use a single A-region allele for tumor recognition. the autologous HLA-A1. A2 tumors are lysed by both HLA-A1-restricted and HLA-A2-restricted CTL. The dominance of restricting alleles was further demonstrated when HLA-matched allogeneic melanomas were used as the stimulating tumor to generate tumor-specific CTL. Stimulation of the heterozygous (HLA-A1. A2) lymphocytes with HLA-A2-matched allogeneic melanomas resulted in CTL specific for the autologous tumor. and restricted by the HLA-A2 Ag. However. stimulation with an HLA-A1-matched allogeneic melanoma failed to induce tumor-specific CTL restricted by the HLA-A1 Ag. The data suggest there is a dominance of HLA-A region Ag at the level of the T cell. such that only one is restricting in the recognition of the autologous melanoma. At the level of the tumor. however. the TAA is expressed in the context of both HLA-A region alleles. We can generate specific CTL from lymph node cells or PBL and HLA-A region matched allogeneic melanomas; however. because most patients are heterozygous at the HLA-A region locus. an understanding of the dominant restricting alleles must be obtained so that an appropriately matched allogeneic melanoma can be selected.
Cytotoxic T cell clones isolated from ovarian tumor-infiltrating lymphocytes recognize multiple antigenic epitopes on autologous tumor cells, CTL clones were developed from tumor infiltrating lymphocytes (TIL) from the ascites of a patient with ovarian carcinoma by coculture of TIL with autologous tumor cells and subsequent cloning in the presence of autologous tumor cells. These CTL clones expressed preferential cytolytic activity against autologous tumor cells but not against allogeneic ovarian tumor cells and the NK-sensitive cell line K562. The cytolytic activity of these CTL against autologous tumors was inhibited by anti-TCR (WT31 mAb). anti-HLA class I. and anti-CD3 mAb but not by the NK function antibody Leu 11b. Cloning of the autologous tumor cells in vitro revealed that the CTL clones of the ovarian TIL expressed differential abilities to lyse autologous tumor cell clones. The specificity analysis of these autologous tumor specific CTL suggested that they recognize several antigenic determinants present on the ovarian tumor cells. Our results indicate the presence of at least three antigenic epitopes on the tumor cells (designated OVA-1A. OVA-1B. and OVA-1C). one of which (OVA-1C) is unstable. These determinants are present either simultaneously or separately. and six types of ovarian clones can be distinguished on the basis of their expression. These results indicate that CTL of the TIL detect intratumor antigenic heterogeneity. The novel heterogeneity identified within the ovarian tumor cells in this report may be of significance for understanding cellular immunity in ovarian cancer and developing adoptive specific immunotherapeutic approaches in ovarian cancer.
Evidence for the functional binding in vivo of tumor rejection antigens to antigen-presenting cells in tumor-bearing hosts, Spleen cells of BALB/c mice bearing a syngeneic CSA1M fibrosarcoma were treated with anti-Thy-1.2 antibody plus C. yielding a T cell-depleted. APC-containing fraction. The APC-containing fraction was first tested for its capacity to present exogenous modified-self or another tumor (Meth A) Ag after in vitro pulsing. The results showed comparable Ag-presenting capacities to those obtained by APC-containing fraction from normal spleen cells. indicating that APC function is not affected in tumor-bearing mice. We next examined whether APC from CSA1M-bearing mice bind endogenously generated CSA1M tumor Ag onto its surfaces to stimulate tumor-specific T cells. Five rounds of inoculation of APC-containing fraction from CSA1M-bearing mice without further in vitro pulsing resulted in the induction of potent anti-CSA1M immune resistance. The involvement of anti-CSA1M T cells in the induction of anti-CSA1M immunity was excluded by the fact that the in vivo immunity was excluded by the fact that the in vivo immunity was delivered by Thy-1+ cell-depleted. but not by Thy-1+ cell-enriched fractions of spleen cells from CSA1M-bearing mice. Moreover. the failure of Sephadex G10-passed spleen cells to deliver anti-CSA1M resistance demonstrated the absolute requirement of APC for inducing the in vivo immunity. Finally. this in vivo resistance was found to be tumor specific. because APC fractions from CSA1M-bearing and Meth A-bearing BALB/c mice induced immune resistance selective against the corresponding tumor cell challenge. These results indicate that APC from tumor-bearing hosts can not only exert unaffected APC function against exogenous Ag. but also function to present tumor Ag generated endogenously in the tumor-bearing state and to produce tumor-specific immunity in vivo.
Intravascular retention and renal handling of purified natural and intramolecularly cross-linked hemoglobins, Plasma half time of unmodified hemoglobin (UHb) and two intramolecularly cross-linked hemoglobins (alpha alpha XL and beta beta XL) was measured in anesthetized rats after an intravenous bolus of 20 mg.100 gm.-1 To rule out the possibility that differences among plasma half times might be caused by differences in acute effects on renal excretory function. glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured simultaneously with plasma half time. Experiments were also done to determine whether higher doses (60 to 100 mg-1.100 gm-1) of these compounds had a delayed effect (48 hours) on GFR or ERPF. Massive urinary excretion of UHb occurred; however. only 1% of the alpha alpha XL and none of the beta beta XL was excreted. Plasma half time of alpha alpha XL and beta beta XL averaged 3.3 hours. or four times longer than UHb. In no case did a decrease in GFR or ERPF occur. Instead. a transient increase in GFR. ERPF. urine flow. and systemic blood pressure was seen. Similar increases occurred after albumin administration. suggesting expansion of vascular volume as the initiating factor. Renal functions at 48 hours after 60 to 100 mg.100 gm-1 of UHb. alpha alpha XL or beta beta XL were not different from control (albumin). Intratubular hemoglobin casts or intravascular precipitates were not evident in acute or 48-hour studies. At 48 hours Perls' staining material was found in one alpha alpha XL specimen at 3 hours after administration. Perls' staining material was present in renal tubule cells in all but the albumin-treated kidneys.
The prevalence of allergic bronchopulmonary aspergillosis in patients with asthma, determined by serologic and radiologic criteria in patients at risk, Allergic bronchopulmonary aspergillosis. a hitherto uncommon but potentially crippling complication of asthma. occurs at an unknown prevalence in the United States. Using both modern serologic criteria complete with a history of asthma and radiologic findings. we were able to make the diagnosis of allergic bronchopulmonary aspergillosis in 28 of 100 consecutive patients with asthma who had immediate cutaneous reactivity to Aspergillus fumigatus and who were seen in an outpatient setting. Problems associated with use of less comprehensive criteria for this diagnosis are discussed.
Cross-linked hemoglobin solution as a resuscitative fluid after hemorrhage in the rat, Intramolecularly (alpha-alpha) cross-linked hemoglobin has been reported to have oxygen transport properties similar to those of whole blood. The present study evaluated the efficacy of diaspirin alpha-alpha cross-linked hemoglobin solution as a resuscitation fluid. with heart rate. mean arterial pressure. and transcutaneous oxygen tension as the study parameters. Rats were bled and approximately one third of their total blood volume (20 ml/kg) was removed while they were anesthetized; they were then resuscitated with 14% hemoglobin solution. Animals that received either 10 mg/kg (n = 10) or 20 mg/kg (n = 10) of hemoglobin solution responded quickly and positively to the infusions: mean arterial pressure (which had dropped to less than 40% of prehemorrhage levels) returned to baseline within 2 minutes of initiating infusion; by 4 minutes. the mean arterial pressures of the hemoglobin-infused groups were significantly higher (p less than or equal to 0.05) than those in both the autologous shed blood (n = 8) and lactated Ringer's (n = 10) groups. The heart rate and transcutaneous oxygen tension responses in both the half-volume and full-volume replacement hemoglobin groups matched the response to autologous shed blood throughout the hour of observation. The favorable hemodynamic response to infusion of cross-linked hemoglobin solution after hemorrhage suggests that this material is comparable to autologous shed blood and superior to lactated Ringer's solution as a resuscitative fluid as assessed in this model.
Factor XIII and its substrates, fibronectin, fibrinogen, and alpha 2-antiplasmin, in plasma and urine of patients with nephrosis, Plasma and urine concentrations of factor XIII and its circulating substrates (fibronectin. fibrinogen. and alpha 2-antiplasmin) were measured in a group of 36 patients with nephrotic syndrome. The results were compared with those obtained in a group of 32 normal volunteers (control group) and 12 patients with end-stage renal disease (ESRD). A mild but significant reduction in plasma level and an abnormal urinary excretion of alpha 2-antiplasmin was found in the nephrotic group. Plasma concentrations of factor XIII. fibronectin. and fibrinogen were significantly elevated in patients with nephrosis. In contrast. patients with ESRD showed no significant difference in the plasma concentrations of either factor XIII. fibronectin. or alpha 2-antiplasmin and only a modest elevation of fibrinogen when compared with normal controls. No significant correlation was found between serum creatinine concentration and plasma levels of factor XIII and its circulating substrates in the nephrotic group. No measurable quantities of factor XIII and only small quantities of fibronectin were found in the urine of patients with nephrosis. Elevation of plasma factor XIII. fibronectin. and fibrinogen concentrations in the nephrotic group is considered to be the result of a combination of increased synthesis and possibly contracted intravascular distribution of these macromolecular proteins in the face of their negligible urinary losses. The presence of the observed abnormalities in the nephrotic group and their absence in the non-nephrotic ESRD group tends to exclude renal failure as a cause of these abnormalities. Although the clinical significance of these abnormalities is uncertain. they can potentially contribute to the thrombophilic diathesis and platelet hyperaggregability in nephrotic syndrome.
Major histocompatibility gene products and human immunodeficiency virus infection, In the present paper we analyze the role of major histocompatibility gene products. the human leukocyte antigens. in the pathophysiology of the acquired immunodeficiency syndrome. No association has been found between human leukocyte antigen (HLA) frequencies and human immunodeficiency virus type 1 (HIV 1) infection. whereas significant associations have been reported in some populations between some HLA haplotypes and the appearance of either opportunistic infections or secondary cancers. With regard to the human leukocyte class I antigens. their role as restriction elements in presenting HIV 1 to virus-specific cytotoxic T lymphocytes seems to be established. An increase in the serum levels of their soluble forms that correlate with disease stage has also been demonstrated. These circulating molecules could interfere with the immune response to HIV 1 and could contribute to the development of the immunodeficiency. Antigenic similarities have been detected between human leukocyte class II antigens and HIV 1 envelope proteins. These homologies could explain both the presence in some HIV-positive sera of anti-HLA class II antibodies that mediate the lysis of CD4(+)-HLA class II+ T cells and the false-positive reaction of some HIV-negative sera. which contain anti-HLA class II antibodies. in tests for HIV 1 antibodies. Reduced levels of some complement factors (the human leukocyte class III antigens) have been detected in HIV-infected subjects. These defects could play a role in the progression of the disease and affect both the clearance of HIV 1 and complement-mediated antibody responses. The data reported in this review suggest that HLA antigens may be involved in several steps of the immune deficiency of HIV-infected subjects and thus contribute to the pathophysiology of acquired immunodeficiency syndrome.
Multiple spinal epidural metastases; an unexpectedly frequent finding, In a prospective study. patients with known malignant disease who were suspected of having a spinal epidural metastasis. had myelography which was not confined to the clinically suspected site. but included at least the whole lumbar and thoracic spinal canal. Fifty four of the 106 myelograms revealed at least one epidural metastasis. Twelve of these 54 myelograms showed two separate lesions. and four myelograms showed three separate lesions. In all 16 cases with multiple lesions at least one of the lesions was asymptomatic at the time of the diagnosis. It is concluded that multiple spinal epidural metastases are of common occurrence and occur in about one third of the cases. This finding may have important clinical implications. Examination of the spinal canal for epidural metastases should not be confined to the clinically suspected site. but should include as extensive an area as possible of the spinal canal. whatever technique is to be used.
Comparison of motor response to apomorphine and levodopa in Parkinson's disease, The magnitude and pattern of motor responses to single doses of subcutaneous apomorphine and oral levodopa were compared in 14 patients with Parkinson's disease. Although apomorphine produced much shorter motor responses than levodopa. the quality of response to the two drugs was virtually indistinguishable. These clinical observations support the notion that integrity of striatal post-synaptic dopamine receptors is a key determinant of responsiveness to dopaminergic treatment in Parkinson's disease.
Evaluation of vigabatrin as an add-on drug in the management of severe epilepsy, The effects of the addition of Vigabatrin. a new anti-epileptic drug. to the therapy of 128 patients with severe medically refractory epilepsy is reported. Forty two (33%) of patients experienced side effects. which were predominantly neurotropic. In 28 (22%). the drug was withdrawn because of these side effects. The commonest side effects were drowsiness and behavioural change. The remaining 100 patients were followed for a mean of 30 weeks (range 12-75). Forty one of these patients showed a marked improvement in seizure frequency (a 50% or more reduction when compared with the pre-trial period). and nine (7%) were rendered seizure free. Apparent tolerance to the effects of the drug were noted in five patients. An exacerbation of seizures may occur if the drug is withdrawn too quickly. Vigabatrin appears to be a promising new anti-epileptic drug.
Diurnal differences in response to oral levodopa, Diurnal differences in duration and quality of motor response to levodopa are frequently described by patients. The quality and duration of motor responses were objectively assessed to morning and afternoon oral levodopa doses in five patients with Parkinsonian motor fluctuations who complained of diurnal variation in response to their normal levodopa medication. Results suggest that under controlled conditions which eliminated the effects of diet and overlapping levodopa effects the response to levodopa remained unchanged throughout the day. and that the duration of response could be predicted by plasma levodopa levels.
The accuracy of predictions about progress of patients on a stroke unit, The aim of the study was to check the accuracy of predictions about the factors which affect the progress. in physical abilities and activities of daily living. of patients admitted to a stroke unit. A series of 60 patients admitted consecutively to a stroke unit were assessed on tests of motor. functional and cognitive abilities at admission. On the basis of these assessments predictions were made about the abilities of the patients at discharge. Patients were assessed for level of motor abilities and activities of daily living at discharge and the accuracy of the predictions checked. Predictions were found to be significantly correlated with outcome but the relationships were not so close as to be useful for the clinical management of individual patients.
Slowly progressive aphasia: three cases with language, memory, CT and PET data, Three cases of slowly progressive speech and language disturbance were studied at various points post onset (three. five and 15 years respectively). Language. neuropsychological and brain imaging (computer tomography and positron emission tomography) evaluations were completed on all three patients. The data suggest that the syndrome of "progressive aphasia": 1) does not involve a uniform symptom complex; 2) does not necessarily develop into a full blown dementia syndrome; 3) varies greatly in rate of progression from case to case; 4) is associated with normal brain structure (on computer tomography); and 5) is associated with abnormal left temporal lobe metabolism as measured by fluorodeoxyglucose (FDG) positron emission tomography (PET). One patient had histological findings consistent with Alzheimer's disease at necropsy.
Shy-Drager syndrome. Effect of fludrocortisone and L-threo-3,4-dihydroxyphenylserine on the blood pressure and regional cerebral blood flow, In nine cases of Shy-Drager syndrome. the changes in blood pressure and cerebral blood flow on sitting up from a supine position were studied. The influence of fludrocortisone. a synthetic mineralocorticoid. and L-threo-3.4-dihydroxyphenylserine (DOPS). a precursor of norepinephrine. on these changes was examined. On sitting up. the regional cerebral blood flow (rCBF) measured by Xe133 inhalation showed a tendency to decrease. Fludrocortisone reduced the fall of the mean blood pressure significantly. DOPS reduced the fall of both the diastolic blood pressure and rCBF significantly.
Functional outcomes following selective posterior rhizotomy in children with cerebral palsy, The recent increase in popularity of selective posterior rhizotomy demands objective documentation of surgical outcome. For this reason. the authors have analyzed the status of 25 children with spastic cerebral palsy before and after rhizotomy to determine the effects of this therapy on muscle tone. range of movement. and motor function. Postoperative tests showed a reduction in muscle tone compared with preoperative assessments. Range of motion in the lower extremities was significantly increased and improvements in functional gross motor skills were noted. An increase in range of motion in the knees and thighs during gait was detected in 18 ambulatory patients studied with computerized two-dimensional motion analysis. Preliminary findings indicate that selective posterior rhizotomy reduced spasticity. thereby increasing range of motion and contributing to improvements in active functional mobility.
Platelet thromboxane release and delayed cerebral ischemia in patients with subarachnoid hemorrhage, Adenosine diphosphate-induced platelet aggregation and associated thromboxane B2 release were studied in 52 patients with subarachnoid hemorrhage (SAH) in order to detect a possible association between altered platelet function and development of cerebral ischemic complications after SAH. Compared to the values on admission. the patients showed significantly increased platelet aggregability (p less than 0.05) and thromboxane release (p less than 0.001) 1 to 2 weeks after SAH. The highest values of thromboxane release were seen in patients who deteriorated due to delayed cerebral ischemia with a permanent neurological deficit. Thromboxane release was significantly higher (p less than 0.05) before the onset of severe delayed ischemia in six patients with preoperative ischemia compared to the patients without delayed ischemia. In five others. both ischemic deterioration and elevated thromboxane release occurred after operation. These patients had preoperative values similar to the values in those without ischemic symptoms. The observations suggest that increased platelet aggregability and thromboxane release are associated with delayed cerebral ischemia both before and after surgery.
Endovascular occlusion of vertebral arteries in the treatment of unclippable vertebrobasilar aneurysms, Twenty-one patients with aneurysms of the vertebrobasilar circulation underwent unilateral or bilateral endovascular occlusion of the vertebral artery. Six patients presented with subarachnoid hemorrhage (SAH). 10 with mass effect. four with mass effect and SAH. and one with ischemic symptoms. Thirteen patients had good outcomes with complete clinical and angiographic cure. Six patients had partial thrombosis of their aneurysms. There was one death and one treatment failure. One patient suffered transient stroke. It is concluded that endovascular occlusion of the vertebral artery following test occlusion is a safe and effective treatment for proximal aneurysms of the vertebrobasilar circulation.
Gemistocytic astrocytomas: a reappraisal, Although gemistocytic astrocytomas are considered slow-growing astrocytomas. they often behave aggressively. To clarify the biological and clinical behavior of these rare tumors. the authors retrospectively identified 59 patients with gemistocytic astrocytoma whose tumors were diagnosed and treated between June. 1976. and July. 1989. Three patients who were lost to follow-up review were excluded. as were two whose original slides could not be obtained and three whose tumors were diagnosed at recurrence or at autopsy. The pathological material of the remaining 51 patients was reviewed using two sets of histological criteria. Thirteen patients (Group A) had "pure" gemistocytic astrocytoma. defined as a glial tumor with more than 60% gemistocytes/high-power field and a background of fibrillary astrocytes. Fifteen patients (Group B) had "mixed" gemistocytic astrocytoma. defined as a glial tumor with 20% to 60% gemistocytes/high-power field and a background of anaplastic astrocytes. Twenty-three tumors did not meet these criteria and were excluded from analysis. The median age of the patients was 48.5 years in Group A and 38.3 years in Group B (p less than 0.05). In both groups. the median Karnofsky Performance Scale score was greater than 90%. All patients underwent surgical procedures (four total and 19 partial resections. and five biopsies) and postoperative radiation therapy. The majority also had interstitial brachytherapy. chemotherapy. or both. Ten patients had one reoperation for tumor recurrence and one had two reoperations; other treatments for recurrence included brachytherapy. chemotherapy. and repeat irradiation. All four patients who originally underwent gross total resection are still alive; all five who had a biopsy have died. There was no significant difference in median survival times between groups: 136.5 weeks in Group A (range 10 to 310+ weeks) and 135.6 weeks in Group B (range 31 to 460+ weeks). Analysis of all 28 patients showed a better prognosis for patients less than 50 years of age (185 vs. 36 weeks survival time; p less than 0.001). patients with preoperative symptoms lasting for more than 6 months (228.1 vs. 110.2 weeks survival time; p less than 0.05). and patients with seizures as the first symptom (185.7 vs. 80 weeks survival time; p less than 0.01). Survival time did not correlate with the presence of perivascular lymphocytic infiltration. The authors conclude that the presence of at least 20% gemistocytes in a glial neoplasm is a poor prognostic sign. irrespective of the pathological background. It is proposed that gemistocytic astrocytomas be classified with anaplastic astrocytomas and treated accordingly.
Spontaneous neuronal hyperactivity in the medial and intralaminar thalamic nuclei of patients with deafferentation pain, Electrical activity was recorded from single cells in the thalamus of 10 patients with chronic pain associated with deafferentation. Under local anesthesia. these patients underwent either electrode implantation or thalamotomy for treatment of their pain. In eight of the 10 patients. single units were identified as discharging spontaneously in high-frequency. often rhythmic. bursts. The discharges were of two types: short bursts comprised of two to six spikes with a burst frequency of one to four per second; and long trains of 30 to 80 spikes of similar frequency. Reconstruction of electrode trajectories indicated that recordings were made from the region corresponding to the lateral aspect of the mediodorsal thalamic nucleus. the central lateral nucleus. a small part of the central median nucleus. and the parafascicular nucleus. In the eight patients in whom spontaneous neuronal burst activity was exhibited. it was impossible to study activity evoked by natural cutaneous stimulation due to the continuous spontaneous neuronal discharges. Both animal and human studies have suggested that pain related to deafferentation is accompanied by spontaneous hyperactivity in the dorsal horn of the spinal cord and in the ventral posterior thalamic nuclei. The authors present evidence of spontaneous neuronal hyperactivity in the intralaminar thalamic nuclei of patients with pain related to deafferentation. The findings suggest that spontaneous neuronal discharge in patients with pain related to deafferentation is more widespread in the central nervous system than has been previously appreciated. The results have important implications for the surgical treatment of chronic pain.
Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma, Between 1975 and 1989. 108 children with newly diagnosed medulloblastoma/primitive neuroectodermal tumor (MB/PNET) of the posterior fossa were treated at the authors' institution. The patients were managed uniformly. and treatment included aggressive surgical resections. postoperative staging evaluations for extent of disease. and craniospinal radiation therapy with a local boost. Beginning in 1983. children with MB/PNET were prospectively assigned to risk groups; those with "standard-risk" MB/PNET were treated with radiation therapy alone. while those in the "poor-risk" group received similar radiation therapy plus adjuvant chemotherapy with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). vincristine. and cisplatin. The 5-year actuarial disease-free survival rate for all patients treated between 1975 and 1982 was 68%. and 73% when patients who died within 2 weeks after operation were excluded. This survival rate was statistically better for patients treated after 1982 (82%) compared to those treated between 1975 and 1982 (49%) (p less than 0.004). There was no difference in disease-free survival rates over time for children with standard-risk factors; however. there was a significant difference in the 5-year survival rate for poor-risk patients treated prior to 1982 (35%) compared to those treated later (87%) (p less than 0.001). For the group as a whole. a younger age at diagnosis correlated with a poorer survival rate; however. this relationship between age and outcome was significant only for children treated before 1983 (p less than 0.001). These results demonstrated an encouraging survival rate for children with MB/PNET. especially those treated with aggressive surgical resection followed by both radiation therapy and chemotherapy. The results strongly suggest that chemotherapy has a role for some. and possibly all. children with MB/PNET.
Interstitial chemotherapy with drug polymer implants for the treatment of recurrent gliomas, Malignant gliomas have been difficult to treat with chemotherapy. The most effective agent. BCNU (carmustine). has considerable systemic toxicity and a short half-life in serum. To obviate these problems. a method has been developed for the local sustained release of chemotherapeutic agents by their incorporation into biodegradable polymers. Implantation of the drug-impregnated polymer at the tumor site allows prolonged local exposure with minimal systemic exposure. In this Phase I-II study. 21 patients with recurrent malignant glioma were treated with BCNU released interstitially by means of a polyanhydride biodegradable polymer implant. Up to eight polymer wafers were placed in the resection cavity intraoperatively. upon completion of tumor debulking. The polymer releases the therapeutic drug for approximately 3 weeks. Three increasing concentrations of BCNU were studied; the treatment was well tolerated at all three levels. There were no adverse reactions to the BCNU wafer treatment itself. The average survival period after reoperation was 65 weeks for the first dose group. 64 weeks for the second dose group. and 32 weeks for the highest dose group. The overall mean survival time was 48 weeks from reoperation and 94 weeks from the original operation. The overall median survival times were 46 weeks postimplant and 87 weeks from initial surgery. Eighteen (86%) of 21 patients lived more than 1 year from the time of their initial diagnosis and eight (38%) of 21 patients lived more than 1 year after intracranial implantation of the polymer. Frequent hematology. blood chemistry. and urinalysis tests did not reveal any systemic effect from this interstitial chemotherapy. Since the therapy is well tolerated and safe. a placebo-controlled clinical trial has been started. The trial will measure the effect of the second treatment dose on survival of patients with recurrent malignant glioma.
Characterization of astrocytomas, meningiomas, and pituitary adenomas by phosphorus magnetic resonance spectroscopy, Phosphorus magnetic resonance (MR) spectroscopy allows noninvasive measurement of phosphate-containing compounds and pH within brain cells. The authors obtained localized phosphorus MR spectra from 10 normal brains. four low-grade astrocytomas. six glioblastomas. four meningiomas. and three pituitary adenomas and found differences in the spectra of each tumor type. Compared to normal brain. the spectra from low-grade astrocytomas showed a significant reduction of the phosphodiester (PDE) peak. Glioblastomas were characterized by a significant reduction of the PDE peak. elevation of the phosphomonoester (PME) peak. and a relatively alkaline intracellular pH. The spectra from meningiomas and pituitary adenomas were markedly different from the glial tumors. Meningiomas showed significant reductions in phosphocreatine. PDE. and inorganic phosphate. as well as a relatively alkaline pH. Pituitary adenomas resembled meningiomas. but had a much higher PME peak. Although the number of tumors studied was small. there appears to be a characteristic spectrum associated with these different tumor types. The present findings can be useful in the preoperative identification of these tumors and in furthering understanding of their growth and metabolism in vivo.
Effect of 21-aminosteroid U-74006F on lipid peroxidation in subarachnoid clot, The present study was undertaken to investigate the effect of U-74006F on malondialdehyde (a by-product of lipid peroxidation) in subarachnoid clot. Eighteen cynomolgus monkeys were divided into three groups of six each. There were two U-74006F-treated groups. receiving doses of 0.3 or 1.0 mg/kg. and a placebo-treated group. Each monkey underwent baseline cerebral angiography followed by right-sided craniectomy and placement of subarachnoid clot around the middle cerebral artery (MCA). Treatment was administered intravenously every 8 hours for 6 days. Seven days after the experimental subarachnoid hemorrhage (SAH). angiography was repeated and the animals were killed. In the placebo-treated group. significant vasospasm occurred in the MCA on the side of the clot (p less than 0.01). After U-74006F treatment at both dosages. significantly less vasospasm developed in the clot-side MCA (p less than 0.01). The content of malondialdehyde was measured by both the thiobarbituric acid test and high-performance liquid chromatography (HPLC). Comparing the two methods. HPLC proved to be more accurate than the thiobarbituric acid test. especially for measurement of low concentrations of malondialdehyde. In the placebo-treated group. the malondialdehyde content was significantly increased in the Day 7 clot (p less than 0.05). In contrast. malondialdehyde content in freshly prepared clot was very low. In the 0.3-mg/kg U-74006F group. the malondialdehyde content of clot was significantly less at Day 7 compared to clot from the placebo-treated group (p less than 0.05). Although the malondialdehyde content of clot from the 1.0 mg/kg U-74006F-treated group was less than that of placebo. it was not significantly so. Malondialdehyde was not detected in the actual vessel wall of the MCA of any group. These results suggest that lipid peroxidation in subarachnoid clot may play a role in the pathogenesis of vasospasm and that the salutary effects of U-74006F in vasospasm may be mediated by a reduction of lipid peroxidation in SAH.
Relationship between body and brain temperature in traumatically brain-injured rodents, Recent work has shown that mild to moderate levels of hypothermia may profoundly reduce the histological and biochemical sequelae of cerebral ischemic injury. In the present study. the authors examined the effect of fluid-percussion injury on brain temperature in anesthetized rats and the effect of anesthesia on brain temperature in uninjured rats. The relationship between the brain. rectal. and temporalis muscle temperatures during normothermia. hypothermia. and hyperthermia was studied following a moderate magnitude of fluid-percussion brain injury (2.10 to 2.25 atmospheres) in rats. The results showed that mean brain temperature in 10 anesthetized injured rats. in 21 anesthetized uninjured rats. and in 10 unanesthetized uninjured rats was a mean (+/- standard error of the mean) of 36.04 degrees +/- 0.20 degrees C. 36.30 degrees +/- 0.08 degrees C. and 37.95 degrees +/- 0.09 degrees C. respectively. There was no significant difference in temperature under general anesthesia between injured and uninjured rats (p greater than 0.05). In the absence of brain injury. mean brain temperature was significantly lower in anesthetized rats than in unanesthetized rats (p less than 0.001). In anesthetized brain-injured rats. temporalis muscle temperature correlated well with brain temperature over a 30 degrees to 40 degrees C range. even when brain temperature was rapidly changed during induction of hypothermia or hyperthermia (r = 0.9986. p less than 0.0001). In contrast. rectal temperature varied inconsistently from brain temperature. These observations indicated that: 1) brain injury itself does not influence brain temperature in this model; 2) anesthesia alone decreases brain temperature to levels producing cerebral protection in this model; and 3) external monitoring of temporalis muscle temperature can provide a reliable indirect measure of brain temperature in the course of experimental brain injury. The authors believe that it is essential to monitor or control brain temperature in studies of experimental brain injury.
Superior hypophyseal artery aneurysm. Report of two cases, Two cases of saccular intracranial aneurysms arising from the superior hypophyseal artery take-off from the internal carotid artery are presented. The angiographic findings and technical details of the operative approach are discussed. Particular attention is focused on the use of fenestrated angled clips.
Subarachnoid hemorrhage from a dissecting aneurysm of the middle cerebral artery. Case report, A case of subarachnoid hemorrhage (SAH) from a dissecting aneurysm of the inferior limb of the middle cerebral artery is reported. The patient's clinical status and the initial and follow-up angiographic appearance of the aneurysm are presented. Diagnosis and treatment are briefly discussed. It is suggested that. if angiography demonstrates luminal narrowing or vascular occlusion in a patient with unexplained SAH. a dissecting aneurysm of the carotid system should be considered as a cause of the hemorrhage.
Hemangiopericytoma of the sciatic nerve. Case report, The authors report the case of a hemangiopericytoma arising in a sciatic nerve. It was found to be invasive within the epineurium but sparing surrounding tissues. Adequate resection required sacrifice of the nerve. Hemangiopericytomas can be added to the short list of mesodermal peripheral-nerve tumors.
Clinical and immunologic responses to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infants injected at 3, 5, 7, and 18 months of age, The safety and immunogenicity of Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (Hib-TT) were evaluated in 77 healthy infants receiving injections at 3. 5. 7. and 18 months of age. No serious local or systemic reactions were noted. After the first injection the geometric mean Hib antibody level rose to 0.55 micrograms/ml. and each subsequent injection elicited a statistically significant rise in the geometric mean. The percentage of vaccinees with Hib antibody levels greater than 0.15 micrograms/ml serum was 75.5% after the first. 97.4% after the second. and 100% after the third Hib-TT injection. This percentage fell to 90.9% at 18 months of age but rose again to 100% after the fourth injection. Control infants (n = 10) injected with diphtheria-tetanus toxoid-pertussis vaccine only had nondetectable levels after the second injection. Hib-TT elicited increases of Hib antibody in all isotypes: IgG greater than IgM greater than IgA. Among IgG subclasses the highest increases were of IgG1. All vaccinated subjects had greater than 0.01 U/ml of TT antibody (estimated protective level) throughout the study. We conclude that Hib-TT. injected at 3. 5. 7. and 18 months. is safe and induces protective levels of antibodies during the age of highest incidence of meningitis caused by Hib.
Bronchopulmonary dysplasia: improvement in lung function between 7 and 10 years of age, To evaluate the natural history of bronchopulmonary dysplasia. we studied the same 32 patients at a mean age of 7 and 10 years. The group as a whole had normal height and weight percentiles. and each child grew along his or her established somatic growth curve. Although some children had abnormal values. the group maintained a normal mean total lung capacity and functional residual capacity. The mean residual volume and the residual volume/total lung capacity ratios were elevated at both ages. At age 7 years the 19 patients (59%) who had a forced expiratory volume in 1 second (FEV1) of less than 80% had "catch up" improvement by 10 years of age (65 +/- 11% to 72 +/- 16% of predicted value; p less than 0.05). All the children who had a normal FEV1 at 7 years of age continued to have a normal FEV1 at age 10 years. Resting single-breath carbon monoxide uptake by the lung was normal when measured at age 10 years. The majority of patients had a positive methacholine challenge test result at both ages. although there was a low incidence of clinically diagnosed asthma. This study demonstrates that patients with bronchopulmonary dysplasia who have normal lung function at age 7 have had normal lung growth and that those with evidence of mild to moderate lung disease have continued lung growth or repair. or both. during their school years.
Hypomagnesemia and the parathyroid hormone-vitamin D endocrine system in children with insulin-dependent diabetes mellitus: effects of magnesium administration, Because insulin-dependent diabetes mellitus is associated with altered electrolyte metabolism and a derangement of the parathyroid hormone (PTH)-vitamin D endocrine system. we studied 23 children with diabetes (age 9.4 +/- 2.5 years) and found lower serum values for total and ionized calcium. magnesium. intact PTH. calcitriol. and osteocalcin than in age- and sex-matched control subjects. All patients were given magnesium orally (6 mg/kg daily of elemental magnesium) for up to 60 days. During treatment. serum magnesium. total and ionized calcium. intact PTH. calcitriol. and osteocalcin concentrations significantly increased. reaching control values. After a 3-day low-calcium diet. the patients had a significantly reduced delta-increment of PTH and calcitriol in comparison with values obtained during hypomagnesemia. After magnesium repletion. the delta-increments of both PTH and calcitriol. in response to the low-calcium diet. were not significantly different from control values. These data suggest that magnesium deficiency plays a pivotal role in altering mineral homeostasis in insulin-dependent diabetes mellitus.
Dose dependency of time of onset of radiation-induced growth hormone deficiency, Growth hormone (GH) secretion during insulin-induced hypoglycemia was assessed on 133 occasions in 82 survivors of childhood malignant disease. All had received cranial irradiation with a dose range to the hypothalamic-pituitary axis of 27 to 47.5 Gy (estimated by a schedule of 16 fractions over 3 weeks) and had been tested on one or more occasions between 0.2 and 18.9 years after treatment. Results of one third of the GH tests were defined as normal (GH peak response. greater than 15 mU/L) within the first 5 years. in comparison with 16% after 5 years. Stepwise multiple linear regression analysis showed that dose (p = 0.007) and time from irradiation (p = 0.03). but not age at therapy. had a significant influence on peak GH responses. The late incidence of GH deficiency was similar over the whole dose range (4 of 26 GH test results normal for less than 30 Gy and 4 of 25 normal for greater than or equal to 30 Gy after 5 years). but the speed of onset over the first years was dependent on dose. We conclude that the requirement for GH replacement therapy and the timing of its introduction will be influenced by the dose of irradiation received by the hypothalamic-pituitary axis.
Cerebral blood flow, cross-brain oxygen extraction, and fontanelle pressure after hypoxic-ischemic injury in newborn infants, The relationship between mean arterial pressure. intracranial pressure. cerebral blood flow. cross-brain oxygen extraction. cerebral metabolic rate. and outcome was studied during therapy in nine neonates on 3 consecutive days after severe hypoxic-ischemic cerebral injury. Cross-brain oxygen extraction was significantly higher (5.06 +/- 0.5 vs 2.05 +/- 0.8 ml/dl; p = 0.012) in the five neonates who survived with normal neurologic outcome than in the four who died or sustained severe brain damage. In contrast. global cerebral blood flow in the five neonates with normal neurologic outcome was significantly lower (25.6 +/- 8.2 vs 83.2 +/- 44.9 ml/100 gm brain/min; p less than 0.05) during the study period. The differences in cross-brain oxygen extraction and global cerebral blood flow between infants who had neurologic recovery and those who died or sustained brain damage occurred in the presence of acceptable values for intracranial pressure. mean arterial pressure. and cerebral perfusion pressure. Our preliminary data suggest that cross-brain oxygen extraction and possibly global cerebral blood flow may be important variables associated with severe neuronal injury and death after hypoxic-ischemic cerebral injury.
Anticonvulsant and behavioral effects of two novel competitive N-methyl-D-aspartic acid receptor antagonists, CGP 37849 and CGP 39551, in the kindling model of epilepsy. Comparison with MK-801 and carbamazepine, The orally active competitive N-methyl-D-aspartate (NMDA) receptor antagonists CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid) and its ethyl ester CGP 39551 were evaluated in amygdala-kindled rats. a model for complex partial and secondarily generalized seizures. Anticonvulsant and behavioral effects of these novel compounds were compared with those of the noncompetitive NMDA receptor antagonist MK-801 [(+)-5-methyl-10.11-dihydroxy-5H-dibenzo(a.d)cyclohepten-5.10-imin e] and the antiepileptic drug carbamazepine. one of the major drugs for treatment of partial and generalized seizures in humans. For comparative evaluation. the compounds were injected i.p. at the following doses: 1 to 10 mg/kg (CGP 37849 or CGP 39551). 0.05 to 0.3 mg/kg (MK-801) and 20 to 40 mg/kg (carbamazepine). respectively. In contrast to carbamazepine. CGP 37849. CGP 39551 and MK-801 exerted only weak anticonvulsant effects in fully kindled rats and did not increase the focal seizure threshold. The weak anticonvulsant effects of the NMDA receptor antagonists in kindled rats were associated with profound untoward behavioral effects. The behavioral syndrome induced by the NMDA receptor antagonists in kindled rats was characterized by marked ataxia. hyperactivity and. in case of CGP 37849 and MK-801. stereotypies. such as head weaving. The low or absent effectiveness of the novel NMDA receptor antagonists against kindled seizures suggests that these compounds will not be clinically useful antiepileptics against partial and secondarily generalized seizures. Furthermore. in view of the recent clinical findings on psychotomimetic effects of MK-801 in epileptic patients. the similarities in the excitatory effects produced by CGP 39551. CGP 37849 and MK-801 in kindled rats may indicate that competitive NMDA receptor antagonists may also produce psychotomimetic effects in humans.
Prostaglandin E2-induced diarrhea in mice: importance of colonic secretion, The present study has investigated the basis for induction of diarrhea by prostaglandin (PG)E2 in mice. When given i.p.. PGE2 induced a dose- and time-dependent diarrhea; the shortest post-treatment time for diarrhea onset was approximately 7 min. at a PGE2 dose of 200 micrograms/kg. At this dose. PGE2 also produced accumulation of fluid in the small intestine and in the colon (enteropooling). The enteropooling reached its maximum by 9 min and did not decrease until approximately 11 min (i.e.. 2 to 4 min after the mean time for diarrhea onset). PGE2 treatment altered neither gastric emptying nor gastrointestinal propulsion. but strongly enhanced the expulsion of a glass bead from the colon (i.e.. decreased the time to bead expulsion). The shortest time to expulsion of the glass bead was observed at 200 micrograms/kg i.p. The induction of diarrhea by PGE2 was unaffected by cecectomy. or sham-cecectomy. but the dose-response curve for time to onset of diarrhea by i.p. PGE2 was displaced to the right in animals with ligations of the ileo-ceco-colonic (ICC) junctions. The intraluminal fluid accumulation in the colon. evaluated in mice with ICC ligations. was increased by PGE2 administration within 2 min and remained greater than in vehicle-treated animals until the onset of diarrhea. The stimulation of colonic bead expulsion produced by i.p. PGE2 in control mice was not observed in animals with acute ICC ligations. even at i.p. doses up to 800 micrograms/kg.
Enantiomers of oxybutynin: in vitro pharmacological characterization at M1, M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs, The major side effects of racemic oxybutynin (OXY). which is used in the treatment of urinary incontinence are dry mouth (xerostomia) and blurred vision (mydriasis). Highly purified enantiomers of OXY [(R)OXY. (S)OXY] were compared with the racemate both in vitro in functional studies and in vivo in guinea pigs to evaluate their pharmacological action relative to their adverse effects. The affinity of (R)OXY and (S)OXY for different muscarinic receptor subtypes was determined using field stimulated rabbit vas deferens (M1) and guinea pig atria (M2) or bladder (M3) strips. Stereoselective antimuscarinic effects [(R)OXY greater than or equal to (R/S) OXY much greater than (S)OXY] were evident at all three receptor subtypes; the isomeric ratio [(S)OXY/(R)OXY] ranged from 12 to 88. Both (R)OXY and (R/S)OXY were slightly more selective (2-4-fold. P less than .01) for M1 and M3 relative to M2 muscarinic receptors. Stereoselectivity was also evident in vivo for volume-induced urinary bladder contractions as measured by cystometrogram parameters [(S)OXY/(R)OXY approximately 21]. mydriasis [(S)OXY/(R)OXY approximately 136] and salivary gland secretory responses [(S)OXY/(R)OXY approximately 30]. The absolute potencies of (R)OXY or (R/S)OXY for mydriasis and salivation were similar to those for inhibition of intravesical bladder pressure. Also. (R)OXY and (R/S)OXY equipotently antagonized cholinergic-mediated CNS effects in mice. Collectively. the data suggest that the activity of (R/S)OXY resides predominantly in the (R)-enantiomer. However. it appears that (R)OXY may offer no significant pharmacological advantage over (R/S)OXY in terms of its principal therapeutic and side effect profile.
The role of alpha adrenoceptor subtypes in sympathetic control of the acral-cutaneous microcirculation, In pithed and anesthetized rats. laser-Doppler flowmetry was used to evaluate the role of alpha-1 and alpha-2 adrenoceptors in mediating sympathetic responses in acral regions of the cutaneous circulation. The intravenous administration of the selective alpha-1 agonist. phenylephrine. was a more potent vasopressor agent than BH-T 933 (a selective alpha-2 adrenoceptor agonist) in pithed rats. However. BH-T 933 was more potent and more efficacious than phenylephrine in reducing cutaneous microvascular perfusion (CP). BH-T 933 also caused a greater increase in cutaneous microvascular resistance. Neural and humoral sympathetic effects on CP were characterized with selective alpha-1 and alpha-2 adrenoceptor antagonists (prazosin and rauwolscine. respectively). It was found that frequency-related reductions in CP elicited by sciatic nerve stimulation were antagonized by prazosin. but not by rauwolscine. In fact. rauwolscine enhanced neurally evoked reductions in CP at the highest stimulation frequencies. However. both prazosin and rauwolscine antagonized reductions in CP elicited by electrical stimulation of the thoracolumbar outflow (sympathoadrenal activation). Ganglionic stimulation (intravenous 1.1-dimethyl-4-phenylpiperazinium) also caused a profound. transient reduction in CP that was abolished by rauwolscine. but was not significantly altered by prazosin. In contrast. 1.1-dimethyl-4-phenylpiperazinium-induced increases in mean arterial pressure were reduced by prazosin. but not by rauwolscine. In ketamine-anesthetized rats. rauwolscine caused a dose-related increase in CP without altering mean arterial pressure. whereas prazosin lowered mean arterial pressure but did not alter CP. We conclude that acral regions of the cutaneous vasculature are more sensitive to alpha-2 vis-a-vis alpha-1 adrenoceptor-mediated vasoconstriction.
Evidence for intraluminal Ca++ regulatory site defect in sarcoplasmic reticulum from malignant hyperthermia pig muscle, Malignant hyperthermia (MH) is a pharmacogenetic disease of humans and various animal species that predisposes to a life-threatening. anesthetic agent-induced syndrome. MH is thought to be a consequence of abnormal. sustained increases in myoplasmic Ca++ and sarcoplasmic reticulum (SR) membranes from MH muscle have been shown to have a Ca++ release channel defect. In the present study we have tested a hypothesis that the abnormal Ca++ release mechanism in MH can be expressed when Ca++ is loaded in the presence of pyrophosphate. SR membrane vesicles isolated from normal and MH pig muscle were loaded with Ca++ in the presence and absence of pyrophosphate until Ca(++)-induced Ca++ release occurred. Under both circumstances the threshold amount of Ca++ loaded until Ca++ release occurred was lower in the SR from MH pig skeletal muscle. This difference in amount of Ca++ preload is not explained by results obtained comparing rates of Ca++ uptake. number of ryanodine binding sites or the amounts of calsequestrin among SR vesicles from MH and normal muscle. We conclude from this study that use of pyrophosphate for Ca++ loading does not ablate the abnormal Ca++ release in SR from MH muscle. suggesting the study can be done on small amounts of SR from biopsied human muscle. The data also suggest that abnormality in an intraluminal. low affinity Ca++ binding site regulating Ca++ release occurs in the SR membrane of MH pig muscle.
Role of thyroid hormone in the development of beta adrenergic control of ornithine decarboxylase in rat heart and kidney, The role of thyroid status in the ontogeny of beta adrenergic receptor control of ornithine decarboxylase (ODC) activity was assessed in hearts and kidneys of neonatal rats. Hyperthyroidism induced by administration of tri-iodothyronine on postnatal days 1 to 5 caused a reduction in the ability of isoproterenol to stimulate cardiac ODC but subsequently accelerated the onset of the postweaning peak of the response; the latter effect was even more prominent when tri-iodothyronine administration was given on postnatal days 14 to 18. Hypothyroidism induced by propylthiouracil administration led to persistent subsensitivity of the cardiac ODC response to beta receptor stimulation. Kidney ODC. which does not become subject to beta receptor regulation until after weaning. was resistant to hyperthyroid-induced changes in reactivity. but hypothyroidism still resulted in long-term response deficits. These results suggest that thyroid hormone is permissive for normal development of the beta receptor-ODC link. and that the euthyroid state provides the optimal conditions for maturation of this signal transduction mechanism. The relative resistance of kidney ODC responses to alterations by hyperthyroidism further indicates that the effects of excess hormone can only be expressed when the receptor-enzyme link is already competent. Finally. thyroid status had equivalent effects on the abilities of vasopressin or angiotensin to stimulate ODC. suggesting that the site of thyroid hormone action is at a transduction locus common to several different receptor types.
Peripheral alpha-1 and alpha-2 adrenergic receptors in three models of hypertension in rats: an in vitro autoradiography study, In vitro autoradiography was used to compare peripheral alpha-1 and alpha-2 adrenergic receptor binding in various tissues using [3H]prazosin and [3H]rauwolscine. respectively. in three models of experimental hypertension in rats. Models studied included two-kidney. one-clip hypertension. one-kidney. one-clip hypertension. desoxycorticosterone-salt hypertension. and three normotensive control groups: two-kidney control. one-kidney control and salt-loaded control. Blood pressures at death were significantly higher in all three hypertensive groups compared with normotensive controls. but there were no significant differences among the hypertensive or normotensive groups. Plasma norepinephrine levels were significantly elevated in all three hypertensive groups compared with respective controls. with no significant differences among hypertensive or control groups. In all three hypertensive groups. there were significant reductions in binding of aortic and mesenteric vascular alpha-1 receptors. renal tubular alpha-1 and alpha-2 receptors. and adrenal cortical alpha-2 receptors when compared with respective control groups. Reduced binding of cardiac ventricular alpha-1 and alpha-2 receptors was also found in all hypertensive groups. but not to statistically significant levels. No significant differences in intestinal alpha-1 and alpha-2 receptor binding were detected in either hypertensive or normotensive groups. The results suggest increased peripheral sympathetic activity in all three models of experimental hypertension. which is associated with down-regulation of alpha-1 and alpha-2 receptors in a number of peripheral tissues. especially those that control cardiovascular hemodynamics and fluid and salt balance. There is no evidence of an increase in peripheral alpha receptor binding as has often been found in some models of genetic or spontaneous hypertension.
Gonadotropin releasing hormones. Clinical applications in gynecology, Since the identification and synthesis of gonadotropin releasing hormones (GnRH) 19 years ago. over 2.000 GnRH analogs have been synthesized and evaluated for the treatment of a variety of conditions requiring temporary. reversible suppression or stimulation of gonadotropin secretion. Effective stimulation of the gonads requires pulsatile administration of a GnRH agonist. preferably the native decapeptide itself. For gonadal suppression. superagonists have proven to be highly effective. Intensive studies currently under way promise new and more innovative clinical applications of these compounds.
Deep femoral lymphadenectomy with preservation of the fascia lata. Preliminary report on 42 invasive vulvar carcinomas, Forty-two patients with primary invasive vulvar carcinoma were treated with radical vulvectomy and deep femoral lymphadenectomy with preservation of the fascia lata and cribriform fascia. The rationale for using this technique was based on anatomic knowledge of the topographic distribution of groin lymph nodes. which was confirmed by the study of 50 cadavers. The preliminary data show that the number of superficial and deep femoral lymph nodes removed from the 42 patients (mean number of nodes. 20; range. 8-32) was similar to the number reported in anatomy books. In addition. the five-year actuarial survival rate. 70%. was comparable to that in the literature. These preliminary results suggest that the surgical technique used in this study is as radical an oncologic procedure as Way's classic groin lymphadenectomy. which consists of removing the fascia lata and cribriform fascia.
Early diagnosis of vulvar neoplasia as a result of vulvar self-examination, Vulvar self-examination was used to facilitate early diagnosis and treatment of vulvar neoplasia in eight patients. Five of them were found to have invasive squamous cell carcinoma of the vulva. two had carcinoma in situ. and one had a vulva melanoma. All eight patients benefited from early diagnosis. which allowed definitive treatment and vulvar conservation.
Prevalence of marijuana use during pregnancy. A pilot study, We examined the prevalence of marijuana use in a group of pregnant women using a qualitative. rapid urine screen to detect marijuana metabolites. Between July 1. 1987. and Aug 15. 1987. 322 consecutive patients underwent an anonymous urine toxicology screen at the time of admission to the labor-and-delivery unit. Patients were identified only by a consecutive number and by their age. race. marital status. gravidity. parity and obstetric service (clinic vs. private). The prevalence of positive urine toxicologic screens for marijuana was 19.9% among the study population (64 positive tests among 322 women screened). The prevalence was greater among the clinic patients than the private patients (52 of 161. or 32.3%. vs. 12 of 161. or 7.5%. respectively). The distribution of race and marital status among the marijuana-positive and -negative groups were also significantly different. Specifically. the proportions of black and single women were higher among the marijuana-positive group. Our findings suggest that marijuana use is common in our obstetric patients. The possible association between marijuana use during pregnancy and perinatal morbidity. as well as the unreliable nature of patient drug histories. may support the use of rapid. inexpensive screening techniques. especially if general screening is considered.
Early recourse to laparoscopy in the management of suspected ectopic pregnancy. Accuracy and morbidity, Ninety-nine patients with suspected ectopic pregnancy (EP) who were subjected to laparoscopy/laparotomy over an 18-month period at Greenwich District Hospital. London. were audited. A third (32/99) of the cases had an EP. and 67 potentially avoidable laparoscopies were performed. A potentially avoidable laparoscopy was followed by a laparotomy in 27% of cases (18/67). and at least 13 of those laparotomies were unnecessary. In addition. two false-positive diagnoses of EP were made at laparoscopy. resulting in the avoidable loss of part or all of a single remaining fallopian tube. With the use of sensitive pregnancy testing at least 62 laparoscopies. 13 laparotomies and 1 case of pulmonary embolus might have been avoided in these patients and up to 195 days' hospitalization saved.
Breast self-examination in relation to the occurrence of advanced breast cancer, Two hundred nine female enrollees of the Group Health Cooperative of Puget Sound who developed advanced-stage breast cancer during the period 1982-1988 were interviewed about their practice of breast self-examination (BSE). use of other breast cancer screening modalities. and medical and reproductive histories. Each subject's description of how she performed the examination was scored according to her mention of up to 10 recommended BSE techniques. A random sample of 433 women without advanced-stage breast cancer from the same population was interviewed for comparison. Relative to women not practicing BSE. the risk of advanced-stage breast cancer among BSE users was 1.15 (95% confidence interval. 0.73-1.81). Frequency of BSE did not differ between women with advanced-stage breast cancer and control subjects. whether in all subjects or in subgroups defined by age. use of mammography. or frequency of clinical breast examinations. While self-described proficiency in BSE was generally low in both case and control subjects. the small percentage of women reporting more thorough self-examinations. regardless of frequency. had about a 35% decrease in the occurrence of advanced-stage breast cancer compared to women who did not perform BSE. These results suggest that. while carefully performed BSE may avoid the development of some advanced-stage breast cancers. BSE as practiced by most Seattle-area women is of little or no benefit.
Expression of the antimetastatic gene nm23 in human breast cancer: an association with good prognosis, The nm23 gene was identified in murine melanoma cells. in which its expression is associated with the cells' metastatic potential. Expression of nm23 has been detected in human breast tumors by means of hybridization and immunocytochemistry. We measured nm23 mRNA in 71 patients with primary breast cancer and found variable levels of nm23 expression. The nm23 gene was expressed at higher levels in well-differentiated tumors (P less than .02). There was a significant inverse relationship between nm23 expression and nodal status (P less than .02). Expression of nm23 was positively associated with longer disease-free survival and overall survival. and the relationships were significant (P less than .002 and P less than .003. respectively). This study showed that nm23 expression in human breast cancer was associated with good prognosis and a lack of lymph node metastasis and suggests that the nm23 gene product may play an important role in suppressing the metastatic phenotype.
Fluorouracil and recombinant human interferon alfa-2a in the treatment of metastatic chemotherapy-refractory urothelial tumors, Thirty patients with advanced metastatic and chemotherapy-refractory urothelial tumors received a combination of fluorouracil (5-FU) and recombinant human interferon alfa-2a. Thirty-six sites of metastases were present in the 30 study patients. and the median Eastern Cooperative Oncology Group performance status was 3 (range. 1 to 4). All patients had failed to respond to primary combined methotrexate/cisplatin-based chemotherapy. Nine (30%; confidence interval. 15% to 47%) of the patients achieved a partial response. The mean duration of response was more than 5.2 months (median. 6 months; range. 3 to 8 months). Two patients who achieved a partial response of 5 and 7 months' duration. respectively. had control of residual disease (one with radiation and one with surgical excision) and have remained disease-free for an additional period of more than 7 and 13 months. respectively. These data suggest that the combination of 5-FU and recombinant human interferon alfa-2a is synergistic. with clinical significance for the treatment of urothelial tumors. The response rate for this combination of drugs is higher than that anticipated for either of these agents used alone. Additional confirmatory trials are needed to evaluate the significance of these findings.
Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol, RP 56976 (taxotere). a new semisynthetic analogue of taxol. is a potentially important chemotherapeutic agent for the treatment of cancer. We report here that this drug is a potent inhibitor of cell replication and. like taxol. promotes the in vitro assembly of stable microtubules in the absence of guanosine triphosphate and induces microtubule-bundle formation in cells. Compared with taxol. RP 56976 is slightly more active as a promoter of tubulin polymerization. As an inhibitor of cell replication. RP 56976 is 2.5-fold more potent than taxol in J774.2 and P388 cells and at least 5-fold more potent in taxol-resistant cells.
Blunt traumatic rupture of the heart and pericardium: a ten-year experience (1979-1989), Blunt traumatic rupture of the heart and pericardium. rarely diagnosed preoperatively. carries a high mortality rate. From 1979 to 1989. more than 20.000 patients were admitted to a Level I trauma center. A retrospective review identified 59 patients requiring emergency surgery for this condition. Injuries resulted from vehicular accidents (68%). motorcycle crashes (10%). pedestrians being struck by vehicles (7%). falls (5%). crushing (7%). and being struck by a horse (2%) or crane (2%). Seventeen patients (29%) had isolated rupture of the pericardium; 37 (63%) had ruptures of one or more cardiac chambers. All patients had signs of life at the scene or during transportation. but only 29 (49%) had vital signs on admission: 15 with chamber injury. 12 with pericardial rupture. and two with combined injuries. Diagnosis was established by emergency thoracotomy in the 30 patients who arrived in cardiac arrest. In the remaining 29 patients. diagnosis was made by urgent thoracotomy (41%). by subxiphoid pericardial window (34%). during laparotomy (21%). or by chest radiography (3%). The overall mortality rate was 76% (45 patients). but only 52% for those with vital signs on admission. Rapid transportation and expeditious surgical treatment can save many patients with these injuries.
Splenectomy does not influence outcome of pneumococcal septicemia in a porcine model, The existence of the overwhelming postsplenectomy infection syndrome in adults after traumatic splenectomy is controversial. Due to the similarity of the porcine immune system to man we chose the pig to study subsets of peripheral mononuclear cells after splenectomy and resistance to experimental Pneumococcal infection after splenic surgery and specific immunization. Female miniature pigs were assigned to four operative groups: sham operation. splenectomy. splenic resection. and heterotopic splenic autotransplantation. Hematologic and flow cytometric analysis of mononuclear cells and their subsets revealed a marked leukocytosis following splenectomy and autotransplantation but no significant shift in monocyte and B-cell numbers. Response of leukocytes to septicemia. bacterial elimination from peripheral blood. and mortality were not affected by splenectomy or spleen-preserving operations. Mortality of splenectomized animals was 18%. compared to 42% in sham-operated controls (difference not significant). Immunization protected animals from development of leukopenia. and led to an enhanced bacterial elimination. and a significantly decreased mortality of 5%. compared to 48% in nonimmune animals. Thus our data do not show significant effects of splenectomy on subsets of porcine mononuclear cells or on resistance to experimental Pneumococcal septicemia.
Functional outcome of pediatric trauma patients identified as 'non-salvageable survivors', A retrospective study of 305 pediatric trauma patients seen over 17 months was undertaken to evaluate the functional outcome of patients categorized as "non-salvageable survivors" (NSS). Functional outcome was determined by Denver Developmental Screen Tests (DDST) for children less than 5 years of age and Rappaport Severity Rating Scale (RDRS) for those 5 years old and older. Each patient was assigned Abbreviated Injury Scores (AIS). Injury Severity Score (ISS). Glasgow Coma Scale (GCS). and Trauma Score (TS). The total number of patients classified as severe was 65 (21%). and 13 were classified as non-salvageable. with seven non-salvageable survivors and six non-preventable deaths. Our study suggests that current trauma scoring systems tend to overestimate the non-salvageable population. Those identified as non-salvageable and who survived have a high probability of meaningful functional recovery. Current trauma scoring systems are in need of revision to better identify non-salvageable survivors and those children who will not make a meaningful neurologic recovery.
Absorbable mesh splenorrhaphy for severe splenic injuries: functional studies in an animal model and an additional patient series, Polyglycolic acid mesh has been introduced as a method of controlling hemorrhage in severely damaged spleens. This study examines the effect of splenic wrapping on the immune function of the spleen. and also on its ability to control splenic bleeding in trauma patients. Thirty purebred beagle dogs were divided into three groups and subjected to sham operation (Group 1). splenectomy (Group 2). and splenic wrap (Group 3). Immunologic studies showed no difference between the wrapped group (Group 3) and those with their spleens intact (Group 1) in the induction of specific antibody-producing lymphocytes in splenic tissue after the injection of attenuated Pneumococci. All splenic injuries treated at Cook County Hospital between January 1985 and May 1988 were retrospectively analyzed. Of 60 patients with splenic injuries. 14 underwent mesh splenorrhaphy without mortality or serious complications. This study demonstrates that the immune function of spleen is preserved following mesh splenorrhapy. and that this technique can be used in a clinical setting with safe and efficacious results.
Humeral mobility after treatment with hanging cast, A retrospective review of 23 patients after treatment of humeral fractures with hanging cast was performed. The average followup time was 8.59 years (range. 1.0 to 15.5 years). Functional results were good in eight (34.8%) and excellent in 15 patients (65.2%). To assess the flexibility of shoulder and elbow joints 24 parameters were measured on each body side using the neutral-zero method of Debrunner. A cumulative comparison of each parameter revealed decreased flexibilities of the upper limb after treatment with hanging cast: reduced abduction without moving shoulder blade (84.08 +/- 7.53 vs. 77.34 +/- 11.38; p less than 0.05). reduced free abduction (166.09 +/- 14.4 vs. 158.22 +/- 19.28; p less than 0.01). reduced anteelevation (155.26 +/- 10.12 vs. 149.35 +/- 3.22; p less than 0.01). reduced external rotation with hanging arm (48.96 +/- 19.05 vs. 41.18 +/- 16.75; p less than 0.01). increased flexion of the shoulder (25.65 +/- 10.37 vs 27.3 +/- 10.0; p less than 0.05) and reduced extension of the elbow (0.86 +/- 6.92 vs. -2.68 +/- 9.63; p less than 0.05). These findings show that longterm deficiencies of humeral mobility after treatment with hanging casts exist.
Results of operative treatment for intra-articular fractures of the calcaneus, Since 1980 our treatment of displaced intra-articular calcaneal fractures consists of open reduction with distractor. bone grafting. and internal fixation. Thereby no splints are applied and early postoperative movement is possible. For precise preoperative planning a CT scan is required. Proper timing and careful preoperative planning are essential to prevent soft-tissue complications. In a total of 16 fractures good clinical and radiologic results were achieved in 50% of the cases; results were satisfactory in 25% and poor in 25%. The patients returned to work after an average of 5 months. Only three patients (19%) received disability compensations. which compares favorably with nonoperative treatment. We believe that a majority of comminuted intra-articular fractures of the calcaneus profit from open reduction and internal fixation and that more reliable functional results are achieved than with conservative therapy.
Differential regulation of T- and B-lymphocyte activation in severely burned patients, We studied the in vitro expression and regulation of the CD23 and CD25 (Tac) surface antigens by peripheral blood lymphocytes (PBL) from severely burned patients (burn injuries ranging from 25% to 72% TBSA) in order to evaluate T- and B-lymphocyte activation processes after thermal trauma. The spontaneous and cytokine (IL-4. IL-2)-induced expression of CD23 which represents a B-cell activation marker was significantly reduced during the second to fifth week postburn when compared to healthy donors. In contrast. CD25. which is expressed on activated T cells. showed a marked increase both spontaneously. indicating an in vivo activation. and after stimulation with IL-2 or PHA. Concomitantly. T-cell proliferation induced by PHA or Con A was suppressed. However. the number of T and B cells remained unchanged. The data demonstrate the impairment of early events in the lymphocyte program in severely burned patients. The activation of B cells is downregulated. since they become refractory to external helper signals. In addition. T cells are highly activated but fail to proceed to proliferation in response to mitogenic stimuli.
Sonographic screening of mass casualties for abdominal and renal injuries following the 1988 Armenian earthquake, The value of sonography in acute trauma evaluation is generally underestimated. and the opinions are controversial. Sonography was performed as a primary screening procedure in 400 of 750 mass casualty patients with trauma admitted to a large hospital within the first 72 hours after the 1988 Armenian earthquake. Two real-time sector scanners were used in the reception area of the hospital. and the average time spent on one patient was 4 minutes. More than 130 followup sonographic examinations were required. Trauma-associated pathology of the abdomen and retroperitoneal space was detected in 12.8% of the patients. with 1% false negatives and no false positives. The authors believe that sonographic screening of mass casualties is a quick and effective means for detection of abdominal and retroperitoneal injuries. Sonography should be used for this purpose more routinely to gain experience and maintain preparedness of the sonographers for screening of trauma cases in mass casualty situations.
Delayed diagnosis of extremity injuries in patients with multiple injuries, A total of 340 patients treated in the Intensive Care Unit of the Department of Orthopedics and Traumatology at Helsinki University Central Hospital were analyzed in this study. They had in all 1.071 fractures and luxations of the pelvis and extremities. of which the trauma surgeons and radiologists on duty initially missed 45 injuries. i.e.. 4.2%. Taking into account the eventual late symptoms. the most severe delayed diagnoses were of injuries located around the hip and knee joints. The patients with delayed diagnoses were. on the average. the most severely ill: their needs for primary blood transfusions and assisted respiration resembled the needs of patients who later died of their trauma or its complications. The most common causes of the delay in diagnosis were: radiographs not done in 60% of patients. and no notation of visible injury in radiographs in 31%. Inferior quality of radiographs. unnoticed radiologists' reports. a fracture visible at the outermost corner of a radiograph. a fracture hidden by other fractures. or excessive obesity of the patient may also contribute to a delay. The study presents measures for improving diagnostic strategies. but it would appear that delayed diagnoses cannot be totally eradicated.
Successful replantation of both legs in a child--5-year followup: case report, Replantation of lower extremities is an infrequent procedure. and is rarely indicated. due to the usual severity of the primary injury plus the possibility of good prosthetic substitution. We report a case of successful replantation of both legs in an 8-year-old boy (despite Aspergillus flavus septicemia) with followup of 5 years. This case suggests that leg replantation should be considered in young patients. This appears to be the second reported case of successful replantation of both legs.
Spontaneous healing of a traumatic thoracic aortic tear: case report, A patient with deceleration trauma of the thoracic aorta causing significant intimal disruption is described in whom complete angiographic resolution was documented during a period of medical management. Review of the literature. along with our experience. suggests that traumatic aortic disruption constitutes a spectrum of injury rather than an all-or-none phenomenon. Immediate surgery. especially in multiply injured patients. may be delayed or even postponed indefinitely if the injury is relatively limited.
The role of computerized tomography in the diagnosis of an occult femoral neck fracture associated with an ipsilateral femoral shaft fracture: case report, We report a nondisplaced femoral neck and head fracture diagnosed acutely by CT scanning. This case illustrates the potential benefits of an acute femoral neck/head CT scan in obtunded polytrauma patients with high-energy femoral shaft fractures.
Bilateral fracture-dislocation of the sacroiliac joint: a case report, Bilateral fracture-dislocation of the sacroiliac joint with intrapelvic displacement of the sacrum is a rare and extremely severe injury. We treated a patient with bilateral fracture-dislocation of the sacroiliac joint using a nonoperative method and obtained an excellent functional result.
Traumatic renal avulsion into the chest: case report, This is a case report of a patient who survived blunt renal avulsion and herniation of the kidney through a ruptured diaphragm. Symptoms were mild considering the severity of injury. Prompt diagnosis of this unusual combination of injuries was aided by contrast-enhanced computed tomography (CT).
Educational status and drinking patterns: how representative are college students, Using data from a large. nationally representative sample. multiple regressions using sex. ethnicity. age and educational status showed that drinking patterns of college students differed significantly from those of dropouts. high school graduates and former college students. College students were more likely to use alcohol but tended to drink less quantity per drinking day than nonstudents of the same age. Sex differences were smaller among college students than among other groups. especially in proportions of abstainers. While whites were most likely to drink if they were in college. among blacks the college students were the least likely to drink. Age had little association with drinking. Conclusions based on in-school samples may not generalize well to nonschool populations and should be tested. if possible. using more representative databases.
Associations between alcohol and cocaine use in a sample of problem-drinking employees, Increases in cocaine use have created a new and challenging cohort of problem drinkers with dual or multiple addictions. As part of a randomized trial comparing alternative alcoholism treatments at a 10.000-employee industrial plant. we interviewed 224 new alcoholic clients of an employee assistance program (EAP); 40% used cocaine during the 6 months just prior to EAP intake. Compared to employees reporting no recent cocaine use. the cocaine users were younger. less often married and reported heavier drinking and more alcohol-related problems. on the job and off. Even after controlling for demographic and occupational factors. and drinking indicators. cocaine users reported more binges (being drunk 24 hours or more). more blackouts (marginally significant. p = .06). more absenteeism and more warnings about unacceptable job performance. Alcoholic EAP clients who use cocaine appear to engage in riskier drinking and to have more trouble on the job than do those who report no cocaine use. and this seems to be a difference specifically attributable to their use of cocaine.
Sex differences in personality traits and coping styles of hospitalized alcoholics, Forty inpatients on an alcohol detoxication unit of a large municipal hospital were administered a battery of tests consisting of a Coping Styles scale. a Personality Profile scale. a Depression scale and the Brief MAST. A demographically comparable comparison group of 40 outpatients attending the medical screening clinic at the same hospital also completed the battery. The two groups did not differ in terms of age. education or the ratio of men to women. There were significant differences in coping styles and personality characteristics between alcoholics and nonalcoholics and. to a large extent. between men and women within the alcoholic group. Practically no significant differences were found between the men in the two groups. but female alcoholics differed greatly from nonalcoholic women in terms of coping styles. personality variables and also in terms of conflict. These findings indicate that the differences between alcoholic and nonalcoholics in the sample were due largely to patterns uniquely characterizing the female alcoholic group. Results are discussed in terms of cultural expectations.
The effectiveness of alcoholism screening in an ambulatory care setting, Two hundred and eighty subjects in three ambulatory care clinics participated in this study designed to assess the psychometric properties of the SMAST using DSM-III criteria for alcoholism as the diagnostic standard. Eighty-two subjects (30%) who completed the NIMH Diagnostic Interview Schedule met DSM-III criteria for alcohol abuse and/or dependence. The sensitivity of the SMAST. using the generally accepted weighted cut-off score of five or greater. was .56 and the specificity was .83. An unweighted cut-off score of two or greater produced a sensitivity of .72 and a specificity of .64. The results of this study suggest that. when the SMAST is used for screening in an ambulatory care clinic population. the optimum balance of sensitivity and specificity is achieved using an unweighted cut-off score of two or greater. In addition. the alcohol subscale of the Diagnostic Interview Schedule was easy to administer and should be considered for use as the diagnostic standard in clinical settings.
Factors associated with alcohol use in later adolescence, The relative influence of a number of family and individual characteristics on the frequency and intensity of alcohol use in a group of older adolescents was assessed. The sample consisted of 8.661 persons ranging in age from 20 to 21 years obtained from the "High School and Beyond" study. Logistic regression analyses performed on both frequency and intensity of alcohol use indicated that white males from higher socioeconomic backgrounds. living in urban or suburban areas and having an external locus of control and a weak family orientation. tended to drink more frequently and consume a larger quantity of alcohol per drinking episode. Results are explained from a sociocultural perspective.
Development of a measure examining children's roles in alcoholic families, A measure assessing the roles played by children in their alcoholic families is presented. In Study 1. an item pool was generated targeting four distinct roles discussed in the alcohol literature. and the items were reviewed by a panel of experts. The Children's Roles Inventory (CRI) was then administered to 140 adult children of alcoholics and their responses were used to refine the measure. Observed levels of internal consistency seemed adequate (Cronbach's alpha ranged from .89 to .95). In a replication effort (Study 2). the CRI was administered to 142 adult children of alcoholics. Internal consistency remained at acceptable levels. ranging from .90 to .95. Study 3 examined the CRI's convergent and discriminant validity. A sample of 138 adult children of alcoholics as well as a sample of 105 adults from nonalcoholic families completed the CRI. a measure of self-esteem and an index of one's use of social support. Reliability results from Studies 1 and 2 were replicated (in both samples). Likewise. in both samples the CRI subscales were differentially predictive of self-esteem as well as size of and satisfaction with one's social support network.
Children of alcoholic parents in the community, The relationship between parental alcoholism and risk for maladjustment in the offspring was investigated in a community sample. Children of parents who met criteria for DIS/DSM-III alcohol abuse or dependence and children of parents who met criteria for ten other diagnoses were compared to children of "normal" parents. The data were obtained from the merging of the data banks of two major psychiatric epidemiology studies of the adult (17-64) and child (4-16) population of Puerto Rico. Results indicated that parental alcoholism in addition to creating an adverse family environment had an effect on the relative risk for maladjustment in the offspring (as measured by scores on the Child Behavior Checklist). Although previous studies have reported higher levels of externalizing behaviors in children of alcoholics. an increased risk for internalizing symptoms was observed in the children studied. Similar findings were obtained for the children of parents with other psychiatric disorders suggesting that the effects of parental alcoholism in children ages 4 to 16 may not be different from the consequences of parental mental illness per se.
Rediscovering tactile agnosia, Eighty-four patients with damage to various levels of the nervous system. ranging from the peripheral nerves to the cerebral cortex. underwent somesthetic assessment in order to determine the degree to which basic and complex perceptual and motor disorders affect tactile object recognition (TOR) and to determine whether TOR can be impaired in the absence of more basic sensorimotor imperception. The results suggest that (1) basic and intermediate disorders of somesthetic function impair TOR but are commensurately more severe for any given degree of TOR impairment in patients with peripheral lesions than in patients with cortical lesions; (2) neither hemiparesis nor hemianopia alone precludes normal TOR; (3) hemineglect contributes substantially to TOR impairment; (4) impairment of TOR can occur in the absence of more basic somesthetic dysfunction and constitutes tactile agnosia; (5) tactile agnosia is a subtle. nondisabling disorder that should be distinguished from the nonagnosic. severe and disabling disorder. astereognosis; and (6) tactile agnosia results from unilateral damage to parietotemporal cortices. possibly including the second somatosensory cortex. in either hemisphere.
Immunodermatology update: the immunologically mediated vesiculobullous diseases, Before a specific diagnosis of an immunologically mediated blistering disease can be made. the clinical and histologic features and the results of direct and indirect immunofluorescence studies (with use of multiple substrates in some cases) must be assessed. For both subepidermal and intraepidermal groups of blistering diseases. direct immunofluorescence testing of perilesional tissue is critical for diagnosis. For these conditions. indirect immunofluorescence testing of serum is important for diagnosis and has a role in management of selected diseases. In dermatitis herpetiformis. indirect testing of serum for IgA antiendomysial antibodies is useful for both diagnosis and management. Indirect testing of serum for IgG antibodies to intercellular substance is important for diagnosis and. in conjunction with the clinical findings. can be used as a guide for monitoring disease activity in patients with pemphigus. Immunoelectron microscopy. immunoprecipitation. and immunoblotting studies have identified the sites of immune deposits and the specific antigens in most of the immunologically mediated bullous diseases. From a practical standpoint. however. direct and indirect immunofluorescence testing. in conjunction with clinical and histologic evaluations. is a simple. rapid. and relatively inexpensive tool for diagnosis and management.
Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients, BACKGROUND. Studies in animals have shown that serotonin constricts coronary arteries if the endothelium is damaged. but in vitro studies have revealed a vasodilating effect on isolated coronary segments with an intact endothelium. To investigate the effect of serotonin in humans. we studied coronary-artery cross-sectional area and blood flow before and after the infusion of serotonin in seven patients with angiographically normal coronary arteries and in seven with coronary artery disease. METHODS. We measured the cross-sectional area of the coronary artery by quantitative angiography and coronary blood flow with an intracoronary Doppler catheter. Measurements were obtained at base line and during intracoronary infusions of serotonin (0.1. 1. and 10 micrograms per kilogram of body weight per minute. for two minutes). We repeated the measurements after an infusion of ketanserin. an antagonist of serotonin receptors that is thought to block the effect of serotonin on receptors in the arterial wall but not in the endothelium. RESULTS. In patients with normal coronary arteries. the highest dose of serotonin increased cross-sectional area by 52 percent (P less than 0.001) and blood flow by 58 percent (P less than 0.01). The effect was significantly potentiated by administration of ketanserin. In patients with coronary-artery atherosclerosis. serotonin reduced cross-sectional area by 64 percent (P less than 0.001) and blood flow by 59 percent (P less than 0.001). Ketanserin prevented this effect. CONCLUSIONS. Serotonin has a vasodilating effect on normal human coronary arteries; when the endothelium is damaged. as in coronary artery disease. serotonin has a direct. unopposed vasoconstricting effect. When considered with other evidence. these data suggest that platelet-derived factors such as serotonin may have a role in certain acute coronary ischemic syndromes.
Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina, BACKGROUND. Serotonin. a major product of platelet activation. has potent vasoactive effects in animal models. but its role in human coronary artery disease remains largely speculative. METHODS. Using quantitative coronary angiography. we compared the effects of the intracoronary infusion of graded concentrations of serotonin (10(-7) to 10(-4) mol per liter) on coronary vessels in two groups of patients with different clinical presentations of coronary disease (nine with stable angina and five with variant angina). with the effects in a control group of eight subjects with normal vessels on angiography. RESULTS. Normal coronary vessels had a biphasic response to intracoronary serotonin: dilation at concentrations up to 10(-5) mol per liter. but constriction at 10(-4) mol per liter. Vessels in patients with stable angina constricted at all concentrations. with mean (+/- SEM) maximal decreases in diameter of 23.9 +/- 3.6. 33.1 +/- 3.9. and 41.7 +/- 3.1 percent from base line in proximal. middle. and distal segments at a serotonin concentration of 10(-4) mol per liter. Smooth segments constricted more than irregular segments (42.0 +/- 4.6 vs. 21.1 +/- 1.6 percent). Four patients with stable angina had a marked reduction in collateral filling. All the patients with stable angina had angina during the intracoronary infusion of serotonin. and electrocardiographic changes were noted in six. All the patients with variant angina had angina. electrocardiographic changes. and localized occlusive epicardial coronary-artery spasm at concentrations of 10(-6) (n = 2) or 10(-5) (n = 3) mol per liter. CONCLUSIONS. Patients with stable coronary disease do not have the normal vasodilator response to intracoronary serotonin. but rather have progressive constriction. which is particularly intense in small distal and collateral vessels. Patients with variant angina have occlusive coronary-artery spasm at a dose that dilates normal vessels and causes only slight constriction in vessels from patients with stable angina. These findings suggest that serotonin. released after the intracoronary activation of platelets. may contribute to or cause myocardial ischemia in patients with coronary artery disease.
Orbitozygomatic temporopolar approach for a high basilar tip aneurysm associated with a short intracranial internal carotid artery: a new surgical approach, For two cases of a high basilar tip aneurysm accompanied by a short intracranial internal carotid artery. the orbitozygomatic temporopolar approach consisting of an en bloc fronto-orbitozygomatic temporal craniotomy and temporopolar approach was carried out. On angiograms. the height of the bifurcation of an elongated basilar artery and the length of the intracranial internal carotid artery from the interclinoid line between the anterior and posterior clinoid process were 20 mm and 6 mm in Case 1. and 18 mm and 5 mm in Case 2. respectively. The skin flap was separated subfascially to preserve the frontotemporal branch of the facial nerve. The fronto-orbitozygomatic temporal bone flap was made. and a part of the basal bony structures of the orbital roof. the sphenoid ridge. and the temporal bone were removed. The basilar tip aneurysm could be seen and clipped easily by upward and oblique viewing from below through the wide operative space consisting of the less retracted internal carotid and middle cerebral arteries. the oculomotor nerve. the tentorial hiatus. and the emptied anterior temporal fossa obtained by partial division of the temporal bridging veins. The operative procedure is presented in detail and compared with other surgical approaches that have been described previously.
Long-term follow-up of patients with recurrent malignant gliomas treated with adjuvant adoptive immunotherapy, Between August 1986 and October 1987. the Denver Brain Tumor Research Group conducted a clinical trial using autologous human recombinant interleukin-2 (rIL-2)-activated lymphocytes to treat 20 patients with recurrent high-grade gliomas. The trial involved surgical resection and/or decompression followed by intracavitary implantation of lymphokine-activated killer (LAK) cells and autologous stimulated lymphocytes (ASL) along with rIL-2 in a plasma clot. One month later. stimulated lymphocytes and rIL-2 were infused through a Rickham reservoir attached to a catheter directed into the tumor bed. The LAK cells were rIL-2-activated peripheral blood lymphocytes cultured for 4 days; the ASL were lectin- and rIL-2-activated peripheral blood lymphocytes cultured for 10 days. Of the 20 patients treated. 11 were evaluated as a group (mean age. 44 years. range. 15-61 years; mean Karnofsky rating. 69. range. 50-100; mean Decadron dose at entry. 14 mg/d. range. 0-32). The average number of lymphocytes implanted was 7.6 x 10(9) (range. 1.9-27.5 x 10(9]. together with 1 to 4 x 10(6) U of rIL-2. To date. 10 of the 11 patients died. all from recurrent tumor growth. The median overall survival time was 63 weeks (range. 36-201; mean. 86). The median survival time after immunotherapy was 18 weeks (range. 11-151; mean. 39). No significant difference in survival after immunotherapy was found between those patients who had received previous chemotherapy and those who had not. The use of steroids or prior chemotherapy did not influence the in vitro generation of ASL or LAK cells.
Epidural tuberculoma of the spine: case report, Epidural tuberculomas of the spine have been reported only rarely during the past few decades. A case of a surgically treated epidural tuberculoma of the thoracic spine in a 76-year-old women is presented.
Impairment of cerebral autoregulation during the development of chronic cerebral vasospasm after subarachnoid hemorrhage in primates, We studied the impairment of autoregulation of cerebral blood flow (CBF) and its effect on the electrical activity of the brain during the development of chronic cerebral vasospasm after subarachnoid hemorrhage. using a vasospasm model in primates. Fourteen animals were divided into two groups: a clot group (8) and a sham-operated group (6). To induce subarachnoid hemorrhage. all the animals underwent craniectomy. and in the clot group. the autologous blood clot was located around the arteries dissected free from the arachnoid membrane. Cerebral angiography was performed before subarachnoid hemorrhage and 7 days after (Day 7). On Day 7. regional CBF in the parietal lobe--measured by the hydrogen clearance method--and central conduction time were studied during either graded hypertension or hypotension. In the clot group. the mean vessel caliber of the cerebral arteries on the right side (clot side) of the circle of Willis showed significant (P less than 0.01) reduction (more than 40%) as compared with the values on the contralateral. non-clot side. The values for the bilateral parietal CBF in the sham-operated group and the left parietal CBF in the clot group were fairly constant when the mean arterial blood pressure (MABP) was in the range of 60 to 160 mm Hg. In the clot group. right parietal CBF was significantly (P less than 0.05) smaller than that on the left side at an MABP level of 40 to 100 mm Hg. and increased at an MABP level of 180 mm Hg. The right parietal CBF increased as the arterial blood pressure increased. showing impairment of autoregulation.
Monitoring of cortical blood flow during temporary arterial occlusion in aneurysm surgery by the thermal diffusion method, During aneurysm surgery. regional cortical blood flow (CoBF) was continuously monitored in 12 patients with a thermal diffusion flow probe in an attempt to assess the effects of temporary major arterial occlusion on blood flow and outcome. When the CoBF was above 30 ml/100 g/min. the safe period for temporary clipping applied distal to the perforators was 15 minutes. The occlusion time should be shortened when the CoBF is below 30 ml/100 g/min. Two patients suffered basal infarction. which was not detected by CoBF monitoring. Attention should be paid to the blood flow in the deep structures when a temporary clip is applied at a site proximal to the perforating branches. Direct measurement of CoBF may be of value in estimating the time that temporary occlusion of a major vessel can be tolerated.
Cavernous malformations and capillary telangiectasia: a spectrum within a single pathological entity, Cerebral vascular malformations have traditionally been divided into four categories: arteriovenous. venous. cavernous. and capillary telangiectases. A controversy exists about separating the latter two lesions into separate entities. Critics claim the distinction is arbitrary but have been unable to present convincing evidence linking the two types of lesions. We have reviewed the histories of 20 patients with cavernous malformations and have analyzed the clinical. radiographic. and surgical-autopsy data associated with these lesions. In some patients. multiple lesions. including cavernous malformations. capillary telangiectases. and transitional forms between the two. were identified. Based on this analysis. we conclude that capillary telangiectasia and cavernous malformations represent two pathological extremes within the same vascular malformation category and propose grouping them as a single cerebral entity called cerebral capillary malformations.
Chronic headache associated with a functioning shunt: usefulness of pressure monitoring, Chronic headaches in a shunt-dependent patient with small ventricles has long been treated with little or no regard to intracranial pressure. In this study. pressure monitoring on 12 such patients demonstrated that they fell into three distinct categories: 3 had headaches caused by intracranial hypertension. 2 had headaches from hypotension. and 7 showed no relation of symptoms to pressure. As therapeutic procedures for treating these three categories are entirely different and sometimes opposing. it is clear that intracranial pressure monitoring is essential to successful management of this complaint.
Disposition of cerebral metastases from malignant melanoma: implications for radiosurgery, Radiosurgery is becoming more generally available and indications for its use continue to be defined. Cerebral metastases from malignant melanoma are often treated with whole-brain irradiation. but with limited benefit. Innovative treatments. such as radiosurgery. make possible the delivery of doses of radiation that are higher than usual. To determine how many patients might be candidates for radiosurgery. a retrospective analysis of computed tomographic brain scans performed on 41 patients with cerebral metastases from malignant melanoma was undertaken. One-third of these patients were found to have cerebral metastases amenable to a radiosurgical approach. as illustrated radiation dose-volume histograms. Patient and tumor characteristics suggest that this series is represent with cerebral metastases from malignant melanoma. The implications of radiosurgery for normal tissue radiation tolerance and its effects on melanoma are discussed.
Location of abnormalities in panoramic radiographs of edentulous patients, A series of 308 panoramic radiographs of edentulous patients was examined for the presence of pathoses to determine whether any predictive basis could be found for occurrence of abnormalities by sex. age. or location. Radiolucencies. radiopacities. and retained roots and teeth were recorded by size and by anterior or posterior location in edentulous jaws. Radiopacities were the most frequently found abnormality (18% of subjects). followed by retained roots (8%). radiolucencies (3%). and retained teeth (3%). No significant correlation was found by chi-square test between type or location of abnormality and sex of the patient. There was. however. a significant relationship between location and type of abnormality. Radiopaque and radiolucent lesions were more frequently found in the mandible. and unerupted teeth and retained roots were more frequently seen in the posterior maxilla. Selective radiographs to detect retained roots and unerupted teeth in the posterior maxilla may be most productive in terms of prosthodontic treatment outcome. Otherwise. this study finds no basis for selection of intraoral sites for specific intraoral radiographs of asymptomatic edentulous patients.
Enamel pitting: a common symptom of tuberous sclerosis, Dental enamel pitting as a diagnostic sign of tuberous sclerosis is explored. and a protocol for the oral examination of patients and persons at risk is described. In this study 50 patients with tuberous sclerosis and 250 control patients were examined for dental enamel pitting. A simple clinical protocol was established for examination with the use of a dental disclosing solution swabbed on dry teeth. The incidence of enamel pitting in the adult dentition of patients with tuberous sclerosis was 100%. whereas that in the adult dentition of the control group was 7%. The simplicity of the test and the high probability of occurrence in tuberous sclerosis make such an examination useful in the diagnosis of this serious genetic disease.
AIDS and adolescents. How can you help them reduce their risk, AIDS in adolescents (0.4% of all cases) is a problem of increasing importance in the United States. Infection with the human immunodeficiency virus (HIV) exists in high schools and on university campuses. and it presents a real and immediate threat to teenaged Americans who engage in drug abuse and sexual activity. Appropriately targeted educational efforts are needed to limit HIV transmission among adolescents. Most adolescents are aware of the high-risk activities that may lead to HIV transmission. However. only about one third alter their sexual behavior to avoid AIDS. It is important to move beyond imparting knowledge about AIDS transmission and to move toward changing risky behavior. Strategies for AIDS risk reduction in adolescents should be implemented now across the country. Appropriate support and intervention are urgently needed for adolescents at high risk.
Early diagnosis of breast cancer. Universal screening is essential, Breast cancer strikes 1 in 10 women in the United States. Early diagnosis of breast cancer improves chances of survival. With universal screening and expert evaluation of early clinical signs and symptoms of breast cancer. mortality rates can be reduced by 30% to 40%. Physicians can help achieve this goal by taking an active role in patient education and promoting the availability of affordable screening mammography.
Donating a kidney to a family member. How primary care physicians can help prepare potential donors, When a relative needs a kidney to survive. family members often impulsively offer to donate one without stopping to consider the physical. emotional. and financial ramifications. which can be considerable. The family's primary care physician can be very helpful in guiding and educating potential donors and. by arranging for screening to be done in the community. can ease the financial strain. The authors discuss the things a potential kidney donor should consider.
Depression after acute myocardial infarction. The role of primary care physicians in rehabilitation, Depression is a common problem after myocardial infarction. Diagnosis is facilitated by use of the criteria for depression in the Diagnostic and Statistical Manual of Mental Disorders and self-rating questionnaires. Treatment may involve both psychological and pharmacologic interventions. The patient's medical status must be carefully assessed before administration of antidepressant medication. All antidepressants are contraindicated immediately after myocardial infarction. When signs and symptoms of depression are exhibited early in the recovery phase. alprazolam (Xanax) may offer advantages over more traditional antidepressants. Further research is necessary to determine the safety of newer antidepressants.
Enteroclysis and small bowel series: comparison of radiation dose and examination time, Respective radiation doses and total examination and fluoroscopy times were compared for 50 patients; 25 underwent enteroclysis and 25 underwent small bowel series with (n = 17) and without (n = 8) an examination of the upper gastrointestinal (GI) tract. For enteroclysis. the mean skin entry radiation dose (12.3 rad [123 mGy]) and mean fluoroscopy time (18.4 minutes) were almost 1 1/2 times greater than those for the small bowel series with examination of the upper GI tract (8.4 rad [84 mGy]; 11.4 minutes) and almost three times greater than those for the small bowel series without upper GI examination (4.6 rad [46 mGy]; 6.3 minutes). However. the mean total examination completion time for enteroclysis (31.2 minutes) was almost half that of the small bowel series without upper GI examination (57.5 minutes) and almost four times shorter than that of the small bowel series with upper GI examination (114 minutes). The higher radiation dose of enteroclysis should be considered along with the short examination time. the age and clinical condition of the patient. and the reported higher accuracy when deciding on the appropriate radiographic examination of the small bowel.
Intracranial aneurysms: interventional neurovascular treatment with detachable balloons--results in 215 cases, Patients with complex or surgically difficult intracranial aneurysms are being treated with interventional neurovascular techniques. With neuroleptic anesthesia and a transfemoral femoral approach. a silicone micro-balloon can be flow directed through the intracranial circulation. guided directly into the aneurysm. and detached. The aneurysm is thus eliminated from the circulation. and the parent artery is preserved. For broad-based or ectatic aneurysms. test occlusion followed by permanent occlusion of the aneurysm and parent vessel can be performed. Since 1981. 211 patients with 215 aneurysms. including 177 cases involving the anterior and 38 cases involving the posterior circulation. have been treated with this technique. In 127 cases (59.1%). the parent vessel was occluded; in 88 cases (40.9%). primary occlusion of the aneurysm was achieved with preservation of the parent artery. Therapy-related complications included 21 deaths (9.8%) and 16 strokes (7.4%). Follow-up examinations were performed at 1. 3. and 12 months after treatment. and follow-up ranged from 5 months to 9 years. In patients in whom standard surgical therapy fails or for aneurysms in surgically inaccessible anatomic locations. interventional techniques that make use of detachable balloons may be a useful therapeutic alternative.
US-assisted aspiration thrombectomy: in vitro investigations, The authors describe the use of a new ultrasound (US)-aspiration thrombectomy technique. An oscillating US probe was inserted into a thin-walled. large-bore aspiration catheter. Experiments tested the ability of the new device and other catheter combinations to remove clot material from a Petri dish. as well as from small and large vessel models made of silicone and glass tubes. respectively. Results of the experiments demonstrated that an oscillating 1.0-mm US probe inserted into an aspiration catheter (7-9 F in diameter) promoted clot fragmentation and allowed continuous aspiration of thrombi of any size. When compared with simple large-bore catheter aspiration and with mechanical fragmentation by means of a US probe within a catheter that was flushed to cool the probe. US-assisted aspiration thrombectomy demonstrated significantly better results for percutaneous transcatheter removal of fresh thrombi.
Nitinol gooseneck snare for removal of foreign bodies: experimental study and clinical evaluation, The authors describe their use of a new right-angle snare made of nickel-titanium (nitinol) cable for retrieval of foreign bodies and iatrogenically placed devices. The snare loop is at right angles to the cable and comes in five sizes (5. 10. 15. 25. and 35 mm); its radiographic visualization is enhanced by gold-plated tungsten coils. This snare was used to retrieve wire and catheter fragments introduced into the thoracic vasculature of four dogs. Eleven of 13 attempts were successful. Three attempts to retrieve intravascular foreign bodies were successful in two patients; in one of these patients. a 10-mm snare was used to remove a fractured end of a ventriculoatrial shunt tube from the left pulmonary artery. In three other patients. four ureteral stents were successfully removed under fluoroscopic guidance. All retrievals were performed through a vascular sheath and with standard techniques and angiographic equipment. No complications were seen in any of the patients or dogs.
Pulmonary atelectasis: signal patterns with MR imaging, To assess the signal characteristics of different types of pulmonary atelectasis on magnetic resonance (MR) images. the authors studied obstructive atelectasis (OA) in 17 patients and nonobstructive atelectasis (NOA) in 25 patients. All patients underwent electrocardiographically gated MR imaging studies of the thorax with standard spin-echo sequences. No signal differences were observed between either type of atelectasis on T1-weighted images. Conversely. OA and NOA appeared significantly different on spin-density-weighted images (P less than .001) and on T2-weighted studies (P less than .0001). On T2-weighted images. all 17 cases of OA appeared hyperintense. whereas 22 of 25 cases of NOA demonstrated a very low signal intensity. Differences in the pathophysiology of OA and NOA presumably account for this observation. In OA. alveolar air is totally resorbed and secretions accumulate in the obstructed lung. The resulting increase in free fluid prolongs the T2 relaxation times and leads to high signal intensity on T2-weighted images. In NOA. the short T2 relaxation time of lung tissue in the absence of secretions and potential magnetic susceptibility effects due to residual air are likely to be responsible for the low T2 signal pattern.
Apical opacity associated with pulmonary tuberculosis: high-resolution CT findings, To elucidate the nature of the apical opacity that is commonly seen in patients with tuberculosis--usually referred to as an "apical cap" or "apical pleural thickening"--18 patients with upper lobe tuberculosis were studied with high-resolution computed tomography (HRCT). All had a homogeneous apical opacity at least 1 cm thick on chest radiographs. Fifteen of the 18 had a history of pulmonary tuberculosis of more than 5 years duration. and nine showed evidence of ipsilateral pleurisy. HRCT scans at the apex of the thorax in all nine patients scanned at this level showed that extrapleural fat with interspersed vessels accounted for most of the plain radiographic opacity. Scans obtained at a level slightly above visible aerated lung showed extrapleural fat 3-25 mm thick peripherally and atelectatic lung centrally. At more caudal levels. at which both aerated lung and "thickened pleura" were visible on plain radiographs. HRCT showed extrapleural fat (3-20 mm thick). thickened pleura (1-3 mm thick). and atelectatic lung peripherally and areas of emphysematous bullae. bronchiectasis. and atelectatic lung centrally.
Interstitial lung disease: impact of postprocessing in digital storage phosphor imaging, The ability to resolve the fine linear structures of interstitial lung disease is one measure of the limiting performance characteristics of an imaging system. Conventional screen-film radiography was compared with six algorithms of isodose storage phosphor digital radiography (0.2-mm x 10-bit pixel matrix) in the detection of interstitial lung abnormality documented by means of computed tomography in 40 patients with abnormalities and 25 healthy control subjects. Performance was evaluated with an analysis of variance (the Fisher paired comparison test; P less than .05) of the average receiver operating characteristic area of 2.730 observations by six readers. The moderately and the more markedly high-frequency edge-enhanced algorithms of storage phosphor digital radiographs were equivalent in performance to screen-film radiography. The default mode. low- and medium-frequency edge-enhanced algorithms. and gray scale reversed mode of storage phosphor digital radiography were inferior to screen-film radiography. The authors conclude that high-frequency edge-enhanced algorithms can perform as well as screen-film radiography in the detection of interstitial disease.
Primary CT diagnosis of abdominal masses in a PACS environment, Whether the display medium--film versus cathode ray tube (CRT)--affects observer performance during interpretation of computed tomographic (CT) images is an important research issue in these times of implementation and growth of picture archiving and communications systems in radiology. The authors performed a multiobserver receiver operating characteristic (ROC) study to determine the performance of radiologists who read abdominal CT studies displayed on film. as well as on a high-resolution workstation (video monitor) that made use of three different display modes. A total of 166 examinations were evaluated by eight radiologists. who recorded their ordinal confidence ratings of the demonstration of presence or absence of abdominal masses. ROC analysis showed small differences in the confidence ratings assigned by individual readers for the detection and interpretation tasks. Results for the group as a whole showed no significant reduction or improvement in observer performance when ratings for any one of the workstation display modes were analyzed. The results of this study demonstrate that current CRT display technology is adequate for enabling the primary detection of abdominal masses with CT examinations.
Peptic ulcer disease: CT evaluation, The authors retrospectively describe the computed tomographic (CT) findings in 35 patients with peptic ulcer disease. Three of eight patients with gastritis or duodenitis had bowel-wall thickening. Ten of the remaining 27 patients had CT evidence of ulcer perforation (n = 2) or penetration (n = 8). four cases of which were unsuspected clinically. Both patients with acute free perforation had pneumoperitoneum. and one showed free extravasation of orally administered contrast material. The precise site of perforation could not be established in either case with CT. The eight patients with ulcer penetration had CT evidence of bowel-wall thickening (n = 3) and inflammatory changes in adjacent soft tissues and organs (n = 8). including the pancreas (n = 4). liver (n = 1). and lesser omentum (n = 1). Ulcer craters were seen in only two. The CT findings of penetration can mimic other disease processes. CT was not useful in detecting uncomplicated peptic ulcer disease.
Diagnostic fine-needle puncture of the gallbladder with US guidance, From February 1988 to January 1990. 118 fine-needle diagnostic punctures of the gallbladder (DPG) were performed under continuous ultrasound (US) guidance on symptomatic patients with gallstones. The first attempt at gallbladder puncture and aspiration was successful in every patient with use of a 22-gauge needle and continuous US visualization of the needle tip. The aspirated volume varied between 3 and 88 mL (average +/- standard deviation. 25.0 mL +/- 15.3). Biliary analysis revealed an elevation of the cholesterol saturation index in patients with cholesterol gallstones (attenuation at computed tomographic examination of 50 HU or less) relative to that in patients with pigment stones (attenuation more than 50 HU) (1.3 +/- 0.2 vs 1.0 +/- 0.1. P less than .05). The nucleation time was prolonged in patients with pigment stones (19.3 days +/- 3.5 vs 1.8 days +/- 0.8 for patients with cholesterol stones. P less than .001). All patients remained hospitalized for 24 hours after DPG and were reexamined on an outpatient basis at 1 and 3 months thereafter. No complications were detected during either short-term observation or long-term follow-up. The authors conclude that DPG is a safe and valuable technique in the diagnostic work-up of gallstone patients to establish their suitability for nonoperative treatment.
Zollinger-Ellison syndrome: prospective assessment of abdominal US in the localization of gastrinomas, The ability of abdominal ultrasound (US) to help localize gastrinomas was prospectively studied in 79 patients with Zollinger-Ellison syndrome. The results were assessed by means of laparotomy. autopsy. or percutaneous liver biopsy. For hepatic gastrinoma. US had a sensitivity of 63% and a specificity of 100%. with a positive predictive value of 100% and a negative predictive value of 89%. US was slightly less sensitive for detecting gastrinoma in the liver than were computed tomography (CT) (66%) and selective angiography (78%). For detection of extrahepatic gastrinoma. US had a sensitivity of 30%. a specificity of 94%. a positive predictive value of 100%. and a negative predictive value of 25%. US enabled detection of tumor in eight cases not detected with CT and in four not detected with angiography. Specificity for extrahepatic gastrinoma was similar for all three modalities (89%-95%). CT and US were equally effective for the detection of extrahepatic gastrinoma. and angiography was significantly more effective than both US and CT (P less than .01). The authors conclude that US. although of low sensitivity. remains useful as the initial imaging modality in patients with Zollinger-Ellison syndrome.
Asialoglycoprotein receptor function in benign liver disease: evaluation with MR imaging, An arabinogalactan-coated ultrasmall superparamagnetic iron oxide (AG-USPIO) preparation specific for asialoglycoprotein (ASG) receptors on hepatocytes was used as a magnetic resonance (MR) imaging contrast agent in the evaluation of a spectrum of benign liver diseases in animal models. The activity of hepatocyte ASG receptors. which directly reflects liver function. was directly assessed by measuring liver relaxation times in vitro and MR signal intensity in vivo. The following measurements allowed three-dimensional assessment of liver function: (a) liver relaxation time. (b) native MR signal intensities of liver. (c) response of liver to the AG-USPIO probe (percentage decrease of liver signal intensity after intravenous administration of 10 mumol/kg of AG-USPIO: normal liver 55%. fatty liver 57%. acute hepatitis 36%. chronic hepatitis 29%. and cirrhosis 46%). and (d) redistribution of hepatocyte-specific AG-USPIO to the spleen (present in hepatitis and cirrhosis but not in normal liver and fatty liver). The results of this study indicate that cellular hepatic abnormalities can be detected and quantitated with MR receptor imaging.
Percutaneous rotational contact biliary lithotripsy: initial clinical results with the Kensey Nash lithotrite, The percutaneous rotary lithotrite introduces a new concept to fragmentation and percutaneous removal of gallstones. A fluid vortex is generated. pulling calculi into a high-speed blade that fragments stones to predominantly under 500 microns. The results of treating the first 10 patients with this instrument reveal that large stone burdens as well as small stones (2-3 mm) of any composition can be removed if the gallbladder is of sufficient size to accommodate the six-pronged basket. Rotation times of 7-39 minutes were required. Nine of 10 procedures were completed; access was lost in one case. One major complication occurred. At repeat oral cholecystography. the gallbladder was visualized after 3-6 weeks in eight of the nine patients. Ursodeoxycholic acid was administered from 3 to 12 months to five patients with either residual stones or aggregates. The hospital stay ranged from 48 to 72 hours. All patients (except the patient who underwent surgery) resumed light activity in 3-4 days and strenuous activity and full diet within 3 weeks.
Epithelial tumors of the ovary: CT findings and correlation with US, One hundred thirty patients with 170 epithelial ovarian tumors were prospectively studied with computed tomography (CT) before surgery. Ultrasound (US) was performed in 108 patients with 138 tumors. At pathologic examination. 78 tumors (46%) were benign. 14 (8%) borderline. and 78 (46%) malignant. CT results were compared with surgical and pathologic findings in all patients. CT enabled detection of 148 of 170 tumors (87%). and US enabled detection of 118 of 138 tumors (86%). Benign serous cystadenomas (n = 42) were correctly characterized with a sensitivity of 69% at CT and 70% at US. Benign mucinous cystadenomas (n = 21) were correctly characterized with a sensitivity of 62% at CT and 50% at US. Malignancy was suggested in nine of 14 patients (64%) with borderline tumors at CT and in five of 14 (36%) at US. The overall accuracy of characterization of benign versus malignant tumors (including borderline tumors) was 94% with CT and 80% with US. In the 108 patients studied with both CT and US. the sensitivity of CT was significantly superior to that of US (P less than .03). whereas there was no significant difference in specificity (P = .125).
Renal vein renins: inability to predict response to revascularization in patients with hypertension, To determine whether the captopril-stimulated renal vein renin ratio (CSRVRR) could enable identification of patients with hemodynamically significant renovascular lesions who would respond to revascularization. the authors measured CSRVRRs in 143 consecutive patients with hypertension who had been selected because of clinical features suggestive of renovascular hypertension. All patients underwent conventional renal arteriography. Renovascular hypertension was the final diagnosis if revascularization resulted in cure or improvement in blood pressure. Complete data were available for 133 patients. Twenty patients had renovascular hypertension; CSRVRR was greater than 1.5 in 13 of these 20 patients (sensitivity. 65%). However. it was also greater than 1.5 in 54 of the 113 patients without renovascular hypertension (false-positive rate. 47.8%). The positive predictive value of CSRVRR was 18.6%; the negative predictive value. 89.3%. It is concluded that CSRVRR is not sufficiently sensitive to enable prediction of which patients will respond to revascularization and is not specific enough to exclude patients who do not have renovascular hypertension.
Lumbar spinal nerves in the neural foramen: MR appearance, The appearance of the proximal lumbar spinal nerves at magnetic resonance (MR) imaging has not. to the authors' knowledge. been described. MR images and exactly corresponding sections obtained from four cadavers by means of a freezing microtome were correlated to characterize the MR appearance of the proximal spinal nerves. The junction of the dorsal and ventral rami with the dorsal and ventral roots consists of a group of six to 15 fascicles measuring 2-6 mm in length. These fascicles appear in MR images obtained with short repetition times as small foci of lower signal intensity than that of surrounding fat. The proximal spinal nerve and its relationship to the intervertebral disk and osseous margins of the neural foramen can be demonstrated effectively with MR imaging.
Mapping the distribution of amobarbital sodium in the intracarotid Wada test by use of Tc-99m HMPAO with SPECT, The intracarotid amobarbital sodium. or Wada. test has been used to localize speech and memory function prior to surgical treatment of temporal lobe seizures. The authors mixed technetium-99m hexamethyl-propyleneamine oxime (HMPAO) with amobarbital sodium and injected the mixture in 25 patients with epilepsy. Single photon emission computed tomography (SPECT) of the brain was then performed to determine intracerebral distribution of the amobarbital sodium. Results of SPECT were compared with those of conventional and digital subtraction angiography (DSA). The distribution of Tc-99m HMPAO and. presumably. amobarbital sodium varied from patient to patient. SPECT revealed a statistically different distribution from that predicted with conventional angiography. The distribution also often differed from that of DSA. although the difference was not significant. SPECT revealed infrequent delivery to mesial temporal lobe structures. This emphasizes the need for caution in the use of the intracarotid amobarbital sodium test to predict the outcome of removal of these areas.
Tibial collateral ligament bursa: MR imaging, The bursa of the tibial collateral ligament (TCL) may be visualized at magnetic resonance (MR) imaging when it becomes distended with fluid. In the authors' experience. this finding signifies a pathologic condition either in the medial capsuloligamentous complex or in the bursa itself. Such a finding may indicate TCL bursitis. TCL bursitis can be suspected in the setting of isolated pain in the medial joint line in the absence of mechanical symptoms. Prolonged relief of symptoms after injection of steroid into the bursa is supportive of the diagnosis. Seven cases are presented in which a fluid-filled TCL bursa was identified at MR imaging. In five cases. TCL bursitis was suspected. The differential diagnosis for the MR findings is discussed.
Tears of cruciate ligaments and menisci: evaluation with cine MR imaging, A cine magnetic resonance (MR) imaging technique. involving the acquisition of kinematic sagittal images during knee movement. was used to evaluate 52 symptomatic knee joints. Results were compared with those obtained by means of static three-dimensional (3D) MR imaging. Twenty-seven of the 28 anterior cruciate ligament (ACL) tears and 22 of 24 normal ligaments were correctly identified at cine MR imaging for a sensitivity of 96% and a specificity of 92%. Static 3D MR imaging yielded a sensitivity of 71% and a specificity of 88%. All four posterior cruciate ligament tears were identified at cine and 3D MR imaging. For meniscal tears. cine MR imaging yielded a sensitivity of 48% and a specificity of 96%; the sensitivity and specificity for 3D MR imaging were 71% and 96%. respectively. Cine MR imaging proved to be more useful than static MR imaging in assessing the tightness of cruciate ligaments. especially of those that were partially torn. and in assessing the movement of meniscal-free fragments. The increased information obtained with cine MR imaging may warrant continued investigation and clinical application.
Deposition of calcium pyrophosphate dihydrate crystals in the ligamentum flavum: evaluation with MR imaging and CT, Four patients had spinal canal stenosis associated with deposition of calcium pyrophosphate dihydrate within the ligamentum flavum. Radiologic evaluation was performed with magnetic resonance imaging or computed tomography. and surgery was performed on all four patients. Pathologic examination of the surgical specimens demonstrated deposits of calcium pyrophosphate crystals within the ligamentum flavum. Focal enlargement of the ligamentum flavum was present in the cervical spine (n = 1). while a more diffuse. bilateral enlargement was identified in the lumbar spine (n = 3). Enlargement of the ligament either caused or was a component of spinal stenosis that caused neurologic signs or symptoms. Three of the patients had evidence of calcium pyrophosphate deposition elsewhere. Deposition of calcium pyrophosphate dihydrate within the ligamentum flavum causing either focal or diffuse enlargement can be associated with significant spinal stenosis.
Intraoperative I-125 seed implantation for extensive recurrent head and neck carcinomas, From 1978 to 1988. 41 patients with extensive recurrent carcinomas of the head and neck were treated with surgical resection plus intraoperative iodine-125 seed implantation. Surgery was performed to resect the tumors and to expose the tumor beds for implantation. I-125 seeds were implanted intraoperatively. with a spacing of 0.75-1 cm between adjacent seeds. either into the soft tissue in the tumor bed or onto small patches of gelatin sponges to cover the bone. nerve. or blood vessel involved with disease. Reconstructive flaps were used in 18 patients. The average I-125 dose delivered by the implanted seeds was 8.263 cGy. The determinate 5-year actuarial survival rate for the entire group was 40%. The 5-year local disease control rate was 44%. Major complications were transient wound infection (32%). flap necrosis (24%). fistula formation (10%). and carotid blowout (5%). These results indicate that surgical resection plus I-125 seed implantation provides a potentially curative treatment for patients with extensive recurrent head and neck carcinomas that would be considered traditionally unresectable and that would be treated only with palliative therapy.
Patient evaluation for cardiac transplantation, The aim for cardiac transplantation is to improve the quality of life and the survival in patients with end-stage heart failure. Given the scarcity of donor organ availability. the expense of the transplantation process and follow-up care. as well as the tremendous emotional burden the process places on a patient and his/her family. it is essential to carefully screen potential candidates for their symptomatic. functional. hemodynamic. and psychosocial eligibility. and to rule out coexisting hemodynamic or comorbid conditions that would jeopardize successful transplantation and immunosuppression. Comprehensive screening of potential transplant candidates. which is best accomplished by a multidisciplinary team approach working closely with patients and their families. is essential to insure that maximum benefit is derived from this scarce and valuable resource.
The value of symptom directed evaluation in the surveillance for recurrence of carcinoma of the breast, Specific postoperative tests used to diagnose recurrent carcinoma of the breast were evaluated for their ability to have an impact on the over-all course of the disease. Sixty-four patients with recurrent or new contralateral primary disease were divided into two groups based on the method of diagnosis. Those patients with a new complaint at an interval between scheduled follow-up visits and who went on to have tests to document a recurrence were categorized as interval follow-up. Those who were seen at a prearranged regular follow-up period and received tests as recommended by the attending physician or surgeon and had a documented recurrence were classified as routine follow-up. Thirteen patients presented with new contralateral primary disease and 51 with metastatic disease (16. bone; 13. lung; 11. local; three. liver. and eight. multiple). The median time to discovery of recurrence from the primary treatment was 29 and 28 months for the interval and routine groups. respectively. Ninety per cent of the failures occurred by 53 months. The survival time after recurrence was significantly greater in those patients diagnosed routinely (p = 0.003). However. the over-all survival time (from primary therapy to death) was only significantly improved for the routine group when the contralateral new primary diseases were included (p = 0.009). The method of diagnosis of a contralateral primary carcinoma was physical examination and mammogram. Strong recommendations for follow-up testing can be limited to mammogram and physical examination.
Axillary lymphadenectomy for intraductal carcinoma of the breast, During a ten year period. 175 axillary lymph node dissections were done as part of the treatment for intraductal carcinoma of the breast; 98 patients were treated with modified radical mastectomy and 77 were treated by mammary preservation. consisting of excision of the lesion. axillary dissection and radiation therapy. One of 175 axillary node dissections yielded positive nodes. Axillary dissection for intraductal carcinoma of the breast is unlikely to yield involved nodes and is not indicated for use in most instances. It should be reserved for lesions demonstrating microinvasion.
Electrocardiographic subset analysis of diltiazem administration on long-term outcome after acute myocardial infarction. The Multicenter Diltiazem Post-Infarction Trial Research Group, The effect of diltiazem on long-term outcome after acute myocardial infarction (AMI) was assessed in 2.377 patients enrolled in the Multicenter Diltiazem Post-Infarction Trial and subsequently followed for 25 +/- 8 months. The study population included 855 patients (36%) with at least 1 prior AMI before the index infarction and 1.522 patients (64%) with a first AMI. of whom 409 (27%) had a first non-Q-wave AMI. 664 (44%) a first inferior Q-wave AMI. and 449 (30%) a first anterior Q-wave AMI. This post hoc analysis revealed that. among patients with first non-Q-wave and first inferior Q-wave AMI. there were fewer cardiac events during follow-up in the diltiazem than in the placebo group. and that the reverse was true for patients with first anterior Q-wave AMI or prior infarction. The diltiazem:placebo Cox hazard ratio (95% confidence limits) for the trial primary end point (cardiac death or nonfatal reinfarction. whichever occurred first) was: first non-Q-wave AMI-0.48 (0.26. 0.89); first inferior Q-wave AMI-0.66 (0.40. 1.09); first anterior Q-wave AMI-0.82 (0.51. 1.31); and prior AMI-1.11 (0.85. 1.44). Use of cardiac death alone as an end point gave an even more sharply focused treatment difference: first non-Q-wave AMI-0.46 (0.18. 1.21); first inferior Q-wave AMI-0.53 (0.27. 1.06); first anterior Q-wave AMI-1.28 (0.68. 2.40); prior infarction-1.26 (0.90. 1.77). Further analysis revealed that these differences in the effect of diltiazem in large part reflected the different status of the 4 electrocardiographically defined subsets in terms of left ventricular function.
Exercise echocardiography and technetium-99m MIBI single-photon emission computed tomography in the detection of coronary artery disease, To compare the relative diagnostic value of exercise echocardiography with perfusion technetium-99m metoxyisobutylisonitrile single-photon emission computed tomography (SPECT) in detecting coronary artery disease (CAD). 75 patients with suspected CAD but a normal electrocardiogram (ECG) at rest were included in a prospective correlative study. Both the exercise echocardiograms and SPECT studies were performed in conjunction with the same symptom-limited bicycle exercise test. The development of either a new wall motion abnormality or a reversible perfusion defect after exercise. or both. were regarded as a positive test for the exercise echocardiographic and SPECT studies. respectively. The results of these 2 diagnostic tests were compared with coronary arteriography. Exercise echocardiography identified 35 (71%) and SPECT 41 (84%. p = 0.13) of the 49 patients with significant CAD (defined as greater than 50% diameter stenosis). Twenty-five of the 26 patients (96%) without significant coronary stenosis had negative exercise echocardiographic results and 23 of 26 (88%) had negative SPECT results. Exercise-induced new wall motion abnormalities showed a good correlation with reversible perfusion defects. and the results of the 2 methods were concordant in 65 of 75 patients (agreement = 88%. kappa = 0.75 +/- 0.14). Both the diagnostic accuracy of exercise echocardiography and SPECT were significantly higher than the exercise ECG (81 vs 64%. p less than 0.02 and 88 vs 64%. p less than 0.005). The sensitivity and specificity for detecting individual diseased vessels were 60 and 95% for exercise echocardiography and 67 and 94% for SPECT.
Impaired left ventricular filling and regional diastolic asynchrony at rest in coronary artery disease and relation to exercise-induced myocardial ischemia, Impaired left ventricular (LV) diastolic filling at rest is frequently observed in patients with coronary artery disease (CAD) who have normal LV systolic function and no previous infarction. To test the hypothesis that abnormal diastolic function at rest might reflect the functional severity of CAD. as estimated by exercise-induced ischemia. the relation between regional and global LV diastolic function at rest and during exercise-induced ischemia was evaluated in 49 patients with radionuclide angiography. All patients had normal systolic function at rest. Group 1 (n = 26) patients manifested a normal ejection fraction response to exercise and group 2 (n = 23) patients an abnormal response. Data obtained from 22 age-comparable normal volunteers were used for comparison. Although regional and global diastolic function were not different between normal subjects and group 1 patients. peak filling rate was lower in group 2 patients than in normal subjects (2.5 +/- 0.8 vs 3.2 +/- 0.6 end-diastolic counts/s; p less than 0.01). Moreover. regional diastolic asynchrony. as assessed from the radionuclide data by using a regional sector analysis of the LV region of interest. was greater in group 2 patients (46 +/- 44 ms) than in both normal subjects (25 +/- 16 ms; p less than 0.05) and group 1 patients (23 +/- 16 ms; p less than 0.05). Thus. among patients with CAD and with normal LV systolic function at rest. impaired LV filling and regional asynchrony predict a greater degree of exercise-induced ischemia. suggesting a greater extent of jeopardized myocardium.
The Dutch experience in percutaneous transluminal angioplasty of narrowed saphenous veins used for aortocoronary arterial bypass, Of 19.994 percutaneous transluminal coronary angioplasty procedures performed in The Netherlands between April 1980 and January 1989. the long-term follow-up of 454 patients who underwent angioplasty of greater than or equal to 1 saphenous vein bypass graft was reviewed. In 46% of patients single graft angioplasty was attempted. and in 54% of patients sequential graft angioplasty was attempted. The clinical primary success rate was 90%. In-hospital mortality was 0.7%. 2.8% of patients sustained a procedural myocardial infarction. and 1.3% of patients underwent emergency bypass surgery. After a follow-up period of 5 years. 74% of patients were alive. and 26% were alive and event-free (no myocardial infarction. no repeat bypass surgery or repeat angioplasty). In patients in whom the initial angioplasty attempt was unsuccessful. only 3% were event-free at 5 years. versus 27% of successfully dilated patients. The time interval between the angioplasty attempt and previous surgery was a significant predictor for 5-year event-free survival. The event-free survival rates for patients who had bypass surgery 1 year before. between 1 and 5 years. and 5 years before angioplasty. were 45. 25 and 19%. respectively. Less than one-third of patients with previous bypass surgery who had angioplasty of the graft remained event-free after 5 years. In patients needing angioplasty within 1 year after bypass surgery. better long-term results were achieved.
Predictors of cardiac survival after percutaneous transluminal coronary angioplasty in patients with severe left ventricular dysfunction, To assess the outcome of percutaneous transluminal coronary angioplasty (PTCA) in patients with severe left ventricular (LV) dysfunction and to determine the predictors of mortality. 73 patients with LV ejection fraction less than or equal to 40% who underwent initial PTCA were analyzed. The majority of patients had prior (greater than 1 week) myocardial infarction (62 patients. 85%). Congestive heart failure and unstable angina were present in 24 (45%) and 49 (67%) patients. respectively. Multivessel coronary artery disease was present in 60 (83%). The LV ejection fraction ranged from 14 to 40% (mean 34%). Intraaortic balloon pump (15%) and percutaneous cardiopulmonary bypass support (4%) was used infrequently. Angiographic success was obtained in 109 of 128 lesions (85%) attempted. Complete revascularization was obtained in 16 of 60 patients with clinical success. Procedure-related mortality was 5% (4 patients). All patients were followed from greater than or equal to 6 to less than or equal to 71 months (average 26). The estimated survival was 79 +/- 5%. 74 +/- 6%. 66 +/- 7% and 57 +/- 8% at 1. 2. 3 and 4 years. respectively. A Cox regression analysis revealed that the presence of congestive heart failure. a lower LV ejection fraction and a higher myocardial jeopardy score for contractile myocardium were independent predictors of survival after PTCA in patients with LV dysfunction. In conclusion. a high-risk subset can be identified among patients with severe LV dysfunction who undergo PTCA.
Comparison of left ventricular ejection fraction by magnetic resonance imaging and radionuclide ventriculography in idiopathic dilated cardiomyopathy, To assess the validity of gated magnetic resonance imaging (MRI) in determining left ventricular (LV) ejection fraction (EF). MRI (Spin Echo. multislice-multiphase technique on the short-axis plane) was compared with equilibrium radionuclide ventriculography in 32 patients with idiopathic dilated cardiomyopathy. All patients underwent MRI and radionuclide ventriculography. performed consecutively on the same day (mean time interval between the 2 examinations: 40 minutes). Comparison with LVEF showed a high correlation (y = 0.79 X +3.51. r = 0.91; p less than 0.001). Mean difference between radionuclide ventriculography and MRI data was 1.7. with the 95% confidence interval 0.71 to 2.68: MRI slightly underestimated LVEF. MRI interobserver and intrapatient variability (assessed in 15 of 32 patients) showed a high correlation (r = 0.91. r = 0.98). In conclusion. data suggest that MRI. using the short-axis approach and the multislice-multiphase technique. is an accurate. noninvasive. highly reproducible method of evaluating LVEF in patients with idiopathic dilated cardiomyopathy.
Stroke volume during submaximal exercise in endurance-trained normotensive subjects and in untrained hypertensive subjects with beta blockade (propranolol and pindolol), The effect of beta-adrenergic blockade on stroke volume (SV) at increasing submaximal exercise intensities was studied in 12 endurance-trained normotensive and 12 untrained hypertensive (diastolic blood pressure greater than 95 mm Hg) men. aged 18 to 34 years. Subjects were assigned to each of 3 treatments in a double-blind. randomized order: placebo. propranolol (80 mg twice daily) and pindolol (10 mg twice daily) for 10 days. with a period of 48 to 60 hours from the initial dose to the first treadmill test and a 4-day washout period between drugs. Cardiac output was measured using the carbon dioxide rebreathing method and SV was calculated from cardiac output and heart rate as follows: SV = cardiac output/heart rate. Cardiac outputs were estimated at rest and while walking on a treadmill at 25. 45. 60 and 75% of the subject's previously determined maximal oxygen uptake (VO2max). No significant differences were found in cardiac output between either of the drugs and placebo at rest. or at any of the 4 rates of work. Propranolol significantly increased SV above placebo values (p less than 0.05) for both trained and untrained groups at the intensities of 45. 60 and 75%. Significant differences in SV were found between pindolol and placebo only at the intensities of 60 and 75% in the trained group. Contrary to expectations. SV showed no indication of a plateau with propranolol in the trained subjects throughout the 4 different exercise intensities. whereas a plateau was established under placebo conditions by 45% of VO2max in both trained and untrained subjects. These results suggest that both trained and untrained hypertensive persons can exercise with beta-adrenergic blockade at submaximal levels without compromised cardiac function.
Human immunodeficiency virus transmission by child sexual abuse, During 1987-1989. 14 (14.6%) of the 96 children who tested positive for the human immunodeficiency virus (HIV) and were followed up by the Duke University (Durham. NC) pediatric acquired immunodeficiency syndrome team were confirmed to have been sexually abused. Every sexually abused child was evaluated for each of five modes of HIV transmission. and in nine children the pathway was identified. Four of the study children acquired HIV from child sexual abuse and in six. abuse was a possible source. Transmission by child sexual abuse was the most frequent of the proven modes of acquisition of HIV in this population. The other proven modes of acquisition were vertical transmission (n = 3) and HIV-contaminated blood transfusion (n = 2). Twelve males were identified (n = 8) or suspected (n = 4) of being perpetrators. Three knew themselves to have HIV at the time of an assault and eight were aware that the child had HIV at the time of an assault. There was no indication from any child that "safe sex" precautions had been observed. Children with HIV infection had multiple risk factors for abuse or neglect. The sociological descriptors of the lives of the 14 abused children showed multiple known risk factors for sexual abuse that also overlapped with known risk factors for or sequelae of the acquisition of HIV infection. These included drug abuse and alcoholism in the home. prostitution of a parent. lack of parenting. poverty. and chronic illness of the child. Prevention efforts should recognize that children as well as adults are at risk for sexually transmitted HIV infection.
Outpatient assessment of infants with bronchiolitis, Two hundred thirteen infants younger than 13 months with bronchiolitis were prospectively followed up to identify the historical. physical. and laboratory clues at initial emergency department evaluation that would help to predict disease severity. Based on their total course of illness. the patients were classified as having mild (139 patients) or severe (74 patients) disease. and the initial emergency department evaluation findings of these two groups were compared. Six independent clinical and laboratory findings were identified that were strongly associated with more severe illness: (1) "ill" or "toxic" general appearance; (2) oxygen saturation less than 95%. as determined by pulse oximetry; (3) gestational age. younger than 34 weeks; (4) respiratory rate. 70/min or greater; (5) atelectasis on a chest roentgenogram; and (6) age. younger than 3 months. The infant's oxygen saturation as determined by pulse oximetry was the single best objective predictor of more severe disease.
Intraosseous infusion of dobutamine and isoproterenol, Intraosseous infusion has been advocated as an emergency route in sick infants and children when intravenous access is not readily obtainable. Dobutamine hydrochloride and isoproterenol hydrochloride are useful emergency drugs that have not been studied when administered into the bone marrow. In a swine model. we compared the physiologic responses (heart rate. arterial pressure. and cardiac output) of dobutamine and isoproterenol infusions delivered intravenously and intraosseously during 20-minute intervals. We observed statistically significant effects of both dobutamine and isoproterenol delivered by the intraosseous route. In addition. the effects resulting from intraosseous infusion were statistically similar to those resulting from intravenous administration of these drugs. We conclude that the intraosseous infusion of dobutamine and isoproterenol is an effective and useful method for emergency administration of these medications.
Effectiveness of growth-promoting therapies. Comparison among growth hormone, clonidine, and levodopa, The ability of growth hormone. clonidine. and levodopa to stimulate growth was compared in short and slowly growing children randomly assigned to different treatment regimens for 6 months. There were 10 children in each group. and 10 additional subjects served as controls. Growth hormone improved mean height velocity. height velocity SD score. and height SD score. The mean height velocity and height velocity SD score were significantly increased by clonidine. while levodopa only enhanced the mean height velocity SD score of the treated children. Moreover. in nine patients (90%) receiving growth hormone. two (20%) receiving clonidine. and one (10%) receiving levodopa. the height velocity was raised by more than 2 cm/y. The increments in height velocity and height SD score were greatest in the growth hormone group. Clonidine induced an increase in height velocity significantly different from that in control children only. In the control group. there was a significant reduction of height SD score with time.
Skateboarding injuries in children. A second wave, Motivated by a number of skateboard-related injuries seen in an emergency department. we undertook an investigation of skateboarding injuries in the mid-1980s. We studied US Consumer Product Safety Commission injury frequency estimates. which indicated a resurgence of these injuries: 19.182 in 1984 and 37.180 in 1985. Children 10 to 14 years old were injured with greatest frequency. Nontrivial injuries were more common among children younger than 5 years old. reflecting a larger proportion of head and neck injuries. Boys sustained more frequent and more severe skateboard-related injuries. Observed injury patterns (head and neck injuries in younger children. extremity injuries in older children. and more severe head and neck injuries in older children) probably reflect the role of psychomotor development on both risk exposure and biomechanics. Likely prevention strategies include warnings against skateboard use by children younger than 5 years. prohibition of skateboards on streets and highways. and the promotion of use of helmets and other protective gear.
Unsuspected cocaine exposure in young children, OBJECTIVE: To determine the prevalence of cocaine exposure among preschool children with clinically unsuspected signs and/or symptoms. DESIGN: Prevalence study. SETTING: Pediatric emergency department in an inner-city hospital. PARTICIPANTS: 250 children aged 2 weeks to 5 years who underwent urine assays for cocaine prior to discharge from the emergency department. INTERVENTIONS: None. MEASUREMENTS/MAIN RESULTS: Six (2.4%) of the 250 urine assays (95% confidence interval. 0.5% to 4.3%) were positive for benzoylecgonine. the major urinary cocaine metabolite. Four of the positive urine assays were from children younger than 1 year and all children with positive urine assays were younger than 24 months. None of these children presented with a complaint or was identified as having clinical problems currently associated with childhood exposure to cocaine. Possible exposure routes include breastfeeding. intentional administration. accidental ingestion of cocaine or cocaine-contaminated household dust via normal hand-to-mouth activity. and passive inhalation of "crack" vapors. CONCLUSION: Among the inner-city children served by this hospital. significant numbers of infants and young children are being exposed to cocaine. and this exposure occurs in a clinically unsuspected population.
Factors affecting outcome in meningococcal infections, A prognostic score for evaluating meningococcal infections in patients consists of the following five features that indicate a poor prognosis: onset of petechiae within 12 hours of presentation; shock; normal or low peripheral leukocyte count; normal or low erythrocyte sedimentation rate; and absence of meningitis. Based on our experience and some published data. we suspected that the score may no longer be reliable. We reviewed the charts of 73 children with meningococcal infection from December 19. 1979 to December 19. 1987 and applied the prognostic score mentioned previously. Our findings indicate that although a low score is generally associated with a good outcome. a higher score is less predictive of poor outcome than previously suggested. A rash with petechiae or purpura. the presence of shock. and a normal or low peripheral leukocyte count continue to be predictors of poor outcome. Erythrocyte sedimentation rate was not evaluated owing to a limited amount of data. The absence of meningitis did not correlate with a worse outcome in our patients. Most patients who died had evidence of meningeal involvement at the time of presentation. Instead. altered mental status at presentation. particularly obtundation or coma. was an ominous sign. We conclude that absence of meningitis is not a good predictor of outcome. as was previously thought. Altered mental status at the time of presentation may prove to be a stronger indicator of poor outcome.
Antibody responses to four Haemophilus influenzae type b conjugate vaccines, Serum antibody responses to four Haemophilus influenzae type b capsular polysaccharide-protein conjugate vaccines (PRP-D. HbOC. C7p. and PRP-T) were studied and compared in 175 infants. 85 adults and 140 2-year-old children. Antibodies to the H influenzae type b polysaccharide vaccines were determined with a Farr-type radioimmunoassay. The infants received two doses of vaccine at the ages of 4 and 6 months. After the first dose of vaccine. the geometric mean antibody concentration measured at the age of 6 months was 0.09 to 0.10 mg/L. only marginally higher than that measured before immunization in all infants who had received PRP-D. HbOC. or C7p but increased to 0.82 mg/L in those who had received PRP-T. One month after the second dose. the geometric mean antibody concentration was increased in all vaccine groups. No significant differences were noted between recipients of HbOC. C7p. or PRP-T (geometric mean antibody concentrations. 4.32. 3.10. and 6.10 mg/L. respectively). whereas the PRP-D recipients had a significantly lower geometric mean antibody concentration (0.63 mg/L). In contrast. PRP-D. HbOC. C7p. and PRP-T were all highly immunogenic in adults. with no differences noted among them. The 2-year-old children also responded to one dose of these vaccines with a high antibody concentration.
Hypertension, endothelium, and cardiovascular risk factors, The functions of the endothelium and the effects of hypertension. atherosclerosis. and diabetes on the endothelium are reviewed. The endothelium affects vascular tone by releasing vasodilators and modulating the effects of vasoactive substances such as catecholamines. bradykinin. serotonin. and angiotensin II. Relaxation of vascular smooth muscle depends upon a functionally intact endothelium and the release of the endothelium-derived relaxing factor nitric oxide. Endothelial cells also appear to release a hyperpolarizing factor that relaxes smooth muscle through activation of the sodium-potassium pump. and of the endothelium-dependent contracting factors. Similarities are found in the vascular injury resulting from hypertension. atherosclerosis. and diabetes. When these risk factors coexist. they can act synergistically and magnify the vascular injury. The endothelium appears to be one of the major targets for these forms of injury. Future therapeutic strategies will focus on ways to prevent. arrest. or reverse endothelial injury.
Cardiovascular risk reduction: the role of antihypertensive treatment, The effects of antihypertensive drugs on mortality from stroke. coronary artery disease (CAD). and nonvascular causes have been studied in 14 trials involving more than 37.000 patients. In the treated patients. blood pressure was 5 to 6 mm Hg lower than that in placebo-treated patients. and whereas mortality from stroke was reduced by 42%. CAD mortality was reduced by only 14%. A major reason for this lack of effect on CAD mortality is apparently the adverse effects of the primary drugs used in these trials (diuretics and beta blockers) on glucose tolerance. lipid levels. and insulin resistance. The angiotensin-converting enzyme inhibitors favorably influence many CAD risk factors. and their use can be expected to reduce CAD mortality in patients treated for hypertension.
The tangled web of coronary risk factors, Although epidemiologic. genetic. and pathophysiologic studies have shown that low-density lipoproteins (LDLs) are involved in the development of coronary artery disease. the standard measurement of LDL cholesterol comprises a number of separate components that may contribute in different ways to the disease process. Some of these components appear to be of particular pathologic importance. Intermediate-density lipoproteins (IDLs) and lipoprotein (a) are highly atherogenic species that each normally account for up to 10% to 15% total LDL cholesterol but may be disproportionately elevated in pathologic states and may therefore contribute disproportionately to coronary disease risk in certain patients. Recently. another subclass of LDL. characterized by relatively small particle size and increased density. also has been found to be associated with relatively increased risk of coronary disease. Furthermore. levels of this subclass. designated LDL-III. are linked to a number of interrelated hormonal and metabolic factors. each of which have also been associated with risk of coronary artery disease. These include male gender. postmenopause. abdominal adiposity. elevated triglyceride levels. increased levels of apolipoprotein B. and reductions in high-density lipoproteins (HDLs). particularly in the HDL2 subclass. Other studies have demonstrated that many of these factors are also commonly associated with relative insulin resistance and hyperinsulinemia. Thus. a lipoprotein profile characterized by a relative increase in LDL-III and a reduction in HDL2 is indicative of a constellation of metabolic features that defines a high-risk state and that makes it extremely difficult to single out one or more factors that are most directly involved in the disease process. Combinations of genetic and environmental factors acting on this "tangled web" of risk factors may account for much of the variation in coronary disease susceptibility found in the general population.
Regression of atherosclerosis: what does it mean, Angiographic evidence of coronary artery atherosclerosis regression has been demonstrated in controlled clinical trials. The significance of this regression appears to depend in a complex way on the degree of atherosclerosis present when a regression regimen is initiated. Angiographic trials indicate that lesion change is a continuum. with a gradual transition from progression to stability and regression. Divergent lesion change can be seen in the same patient with a progression of some lesions and a regression of others. This makes it necessary to perform a comprehensive survey of all visible coronary segments when evaluating angiograms to determine the outcome of a clinical trial. An important finding in clinical trials is that new lesion formation can be reduced. This indicates that effective control of atherosclerosis may be possible with procedures now available. but noninvasive coronary artery imaging methods need to be refined.
Diabetic retinopathy: can we modify its course, With the exception of panretinal laser photocoagulation. no therapy has been shown to modify the course of diabetic retinopathy. Success in developing new therapies for diabetic retinopathy will depend on how well the disease process is understood and on whether interventions can be identified that ameliorate or circumvent critical stages in the development of the disease. A model of the disease process is presented to serve as a frame-work on which pieces of the puzzle can be placed and new areas of potential interventional therapy can be conceptualized.
Insulin resistance, hyperinsulinemia, and hypertriglyceridemia in the etiology and clinical course of hypertension, Patients with untreated hypertension have been shown to be resistant to insulin-stimulated glucose uptake and are more hyperinsulinemic and hypertriglyceridemic than matched groups of patients with normal blood pressure. In addition. insulin resistance. hyperinsulinemia. and hypertriglyceridemia have been demonstrated in spontaneous hypertensive rats and in Sprague-Dawley rats fed a fructose-enriched diet. The defect in insulin-stimulated glucose uptake in these experimental models can also be shown at the cellular level. Experimental interventions that prevent insulin resistance or hyperinsulinemia from developing in fructose-fed rats also greatly attenuate the increase in blood pressure. Since endogenous hyperinsulinemia and hypertriglyceridemia have been identified as factors that increase the risk of coronary artery disease (CAD). it is likely that they contribute to the increased prevalence of CAD in hypertensive patients. Antihypertensive treatment may have exacerbated these metabolic abnormalities. which could help explain why it has been difficult to show that lowering blood pressure decreases the risk of CAD. These observations raise the possibility that abnormalities of carbohydrate and lipoprotein metabolism may play a role in both the etiology and clinical course of hypertension.
New horizons in the treatment of coronary artery thrombosis, The application of recombinant DNA methodology to clinical medicine offers the clinician a new generation of more potent and specific therapies. Recombinant methods offer great promise in the treatment of coronary artery thrombosis. This review focuses on the characterization of 1) molecules that activate plasminogen locally (in the vicinity of a thrombus) rather than systemically. and 2) molecules that offer new approaches to the inhibition of platelet activation and thrombin activity. We first describe the methods used to uncover these molecules and their characterization at the molecular level. The ways in which this knowledge can lead to the development of agents tailored to clinical needs are then explored.
A history of phlebotomy therapy for hemochromatosis, Hemochromatosis was recognized as an iron-storage disease for 50 years before it was proposed to treat it by removing hemoglobin. Davis and Arrowsmith are credited with the first report that demonstrated its value. Larger series have provided statistically valid evidence of improved quality of life and increased longevity. The earlier the disease is discovered. the less risk of morbidity and mortality. Screening tests (serum iron. total iron-binding capacity. serum ferritin) are recommended for all blood relatives of index cases of this hereditary disease and for all clinics where complications of hemochromatosis may be treated: liver disorder however mild. diabetes mellitus. heart disease. arthropathies. sterility. impotence. premature menopause. and abnormal pigmentation of the skin.
Comparison of stainable liver iron between symptomatic and asymptomatic hemochromatosis homozygotes and their homozygous relatives, The authors compared the amount of hepatic parenchymal cell stainable iron in 159 hemochromatosis homozygotes. They were separated into four groups. Group 1: 59 symptomatic hemochromatosis probands with hemochromatosis (mean age 49 years) who were identified because of symptoms and signs of iron overload. Group 2: 38 asymptomatic probands with hemochromatosis (mean age 29 years) identified during population screening studies or during routine health maintenance evaluation. Group 3: 47 homozygous relatives (mean age 43 years) of Group 1 probands. Group 4: 15 homozygous relatives (mean age 30 years) of Group 2 probands. The symptomatic probands (Group 1) were 20 years older and had much more stainable hepatic iron (p less than 0.0001) than the asymptomatic probands (Group 2). The homozygous relatives (Group 3) of the symptomatic probands also were older and had much more stainable hepatic iron than the homozygous relatives (Group 4) of asymptomatic probands (p less than 0.0002). The results of this study suggest that population screening studies can result in early identification of individuals with hemochromatosis before massive hepatic iron overload occurs and before symptoms of iron overload develop.
The immunogenetics of hereditary hemochromatosis, Hereditary hemochromatosis (HH). an iron overload disease caused by unregulated intestinal iron absorption. is a recessive HLA-linked disease. HH is the most common inherited metabolic disorder with one of every 400 to 500 individuals having both genes and being likely to develop the disease. Thus. although the product of the hemochromatosis gene is unknown. its mode of inheritance allows HLA-genotyping of the proband and his/her siblings to be highly predictive of the genetic propensity to develop the clinical features of HH. In view of the known immunoregulatory properties of iron and its binding proteins. it is important to determine if the high levels of storage iron in HH influence the immunosurveillance network in HH patients and whether that has any clinical relevance. We have defined certain alterations of the effector cells of the cellular arm of the immune system and have studied a patient with HH who had specific immune alterations. including delayed cutaneous-type hypersensitivity anergy. and was diagnosed with poorly differentiated adenocarcinoma of the stomach four years after his HH diagnosis. Those findings are consistent with the interpretation that in certain clinical situations of elevated body iron stores. the immunoregulatory balance or environment may be tipped in favor of growth and development of cancer cells.
The immune system in hereditary hemochromatosis: a quantitative and functional assessment of the cellular arm, The objective of this investigation was to evaluate certain quantitative and functional characteristics of the effector cells of the cellular arm of the immune system in hereditary hemochromatosis (HH) with respect to treatment status. Two observations were consistent with the postulate that the elevated levels of storage iron has in vivo immunoregulatory properties: (1) the absolute number of CD8-positive T cells were significantly elevated in untreated HH patients (n = 7) and reduced in treated patients (n = 7). as compared with controls; and (2) the proliferative response of peripheral blood mononuclear cells from untreated HH patients to mitogens was suboptimal but the response of peripheral blood mononuclear cells (PBM) from treated HH patients was normal. Furthermore. immunoglobulin secretion by PBM from treated HH patients as compared to controls was altered. Finally. one T effector cell abnormality was unrelated to treatment status in that a subset of mature. non-activated T lymphocytes aberrantly formed thermostable erythrocyte-rosettes (TE-R). a lymphoid surface marker usually expressed on thymocytes or activated T cells. Taken together these data define certain immune alterations that are consistent with the interpretation that cellular immunity may be influenced by the high level of storage iron in HH patients.
Expression of beta 1 integrins in normal human keratinocytes, The majority of cell adhesive events to the extracellular matrix are mediated by cell surface receptors. beta 1 integrins. Keratinocytes express at least six different polypeptides of beta 1 integrin class. namely beta 1. alpha 2. alpha 3. alpha 5. and alpha 6 (alpha 6 is mainly associated with beta 4 polypeptide). These epithelial cells use alpha 2 beta 1 as a collagen receptor and alpha 3 beta 1 as a fibronectin receptor. while alpha 6 beta 4 is the major basement membrane receptor. Expression of alpha 5 beta 1 complex is low. Processing of beta 1 integrins is fast in keratinocytes; half-maximal maturation takes only 3 hours. In addition to their function in cell-matrix interactions. beta 1 integrins (alpha 2 beta 1 and alpha 3 beta 1) have also a role in maintaining keratinocyte cell-cell interactions. It is possible that resting basal keratinocytes use beta 1 integrins as cell-cell adhesion receptors. and during activation. like in wound healing. these receptors relocalize to mediate events involving cell-matrix interactions.
The clinical spectrum of thrombocytosis and thrombocythemia, Platelet production is the result of a highly ordered maturation of a developmental hierarchy of megakaryocytic progenitor cells regulated by a variety of cytokines. GM-CSF. II-3 and II-6 have a stimulatory effect and several cytokines (TGF-beta. platelet released glycoprotein. platelet factor 4 and interferons) have inhibitory effects down regulating platelet production perhaps as part of an autocrine control loop. Excess platelet production can be clinically characterized as pseudothrombocytosis. thrombocytosis or thrombocythemia; the clinical features and criteria for each are defined. The term thrombocytosis infers its reactive nature and. in the absence of arterial disease or prolonged immobility. it poses little risk regardless of platelet numbers. By contrast. in thrombocythemia. whether primary or associated with other myeloproliferative lesions. significant thrombohemorrhagic events occur. The natural history. rationale. and approach to platelet reduction and control of clinical sequela are reviewed. Clinical therapeutic options include a new agent. Anagrelide.
Psychosocial factors in maternal phenylketonuria: prevention of unplanned pregnancies, BACKGROUND. Women with phenylketonuria (PKU) not treated prior to conception can have a pregnancy that results in serious fetal damage. In this report. factors associated with preventing unplanned (and hence late treated) pregnancies are described. METHODS. Subjects included 60 phenylketonuric women and two comparison groups composed of female acquaintances and diabetic women. All were interviewed and administered tests of intelligence. general well-being. knowledge. and personality. RESULTS. Thirty-five percent of the sexually active women with PKU used contraception only sporadically. The variables that best predicted reported frequency of birth control use were the extent to which women felt social support to use contraception (r = .64) along with positive attitudes about birth control (r = .66) and knowledge of family planning (r = .43). For the comparison groups. a different pattern of variables predicted contraceptive use. with locus of control figuring most prominently for the diabetics (r = .39) and social support for birth control being most important for the acquaintances (r = .46). CONCLUSIONS. As more girls with PKU enter childbearing ages. there will be an increased need for specific programs that address psychosocial factors in maternal PKU.
Predicting onset and chronicity of women's problem drinking: a five-year longitudinal analysis, BACKGROUND. Longitudinal studies of adult drinking have typically excluded or sampled only small numbers of problem drinking women. and have measured a limited range of influences on women's drinking behavior. METHODS. To study the development of women's problem drinking over time. five-year follow-up interviews were conducted with two groups of respondents from a 1981 national survey of women's drinking: 143 problem drinkers and 157 nonproblem drinkers. Regression analyses examined effects of 1981 predictors on six measures of 1986 problem drinking. for problem drinkers and nonproblem drinkers separately. RESULTS. Among 1981 nonproblem drinkers. predictors of onset of problem drinking indicators by 1986 included younger age. cohabiting. and lifetime use of drugs other than alcohol. The most consistent predictor of persistent (chronic) problem drinking was sexual dysfunction; other predictor included being employed part-time or never married. and experiencing recent depression. Divorce or separation predicted lower levels of subsequent alcohol dependance among problem drinkers. CONCLUSIONS. Findings suggest that different personal and social factors predict the onset of problem drinking as compared with its continuation. and point to nontraditional life-style. sexual dysfunction. and role deprivation as potentially important variables.
A measles outbreak at a college with a prematriculation immunization requirement, BACKGROUND. In early 1988 an outbreak of 84 measles cases occurred at a college in Colorado in which over 98 percent of students had documentation of adequate measles immunity (physician diagnosed measles. receipt of live measles vaccine on or after the first birthday. or serologic evidence of immunity) due to an immunization requirement in effect since 1986. METHODS. To examine potential risk factors for measles vaccine failure. we conducted a retrospective cohort study among students living in campus dormitories using student health service vaccination records. RESULTS. Overall. 70 (83 percent) cases had been vaccinated at greater than or equal to 12 months of age. Students living in campus dormitories were at increased risk for measles compared to students living off-campus (RR = 3.0. 95% CI = 2.0. 4.7). Students vaccinated at 12-14 months of age were at increased risk compared to those vaccinated at greater than or equal to 15 months (RR = 3.1. 95% CI = 1.7. 5.7). Time since vaccination was not a risk factor for vaccine failure. Measles vaccine effectiveness was calculated to be 94% (95% CI = 86. 98) for vaccination at greater than or equal to 15 months. CONCLUSIONS. As in secondary schools. measles outbreaks can occur among highly vaccinated college populations. Implementation of recent recommendations to require two doses of measles vaccine for college entrants should help reduce measles outbreaks in college populations.
Ascertainment of maternal deaths in New York City, Maternal deaths in New York City are defined as deaths from any cause in a woman while pregnant or within six months of pregnancy termination. Pilot studies seeking to improve maternal death ascertainment found that selected medical examiner reports contributed an additional 10.5 percent of the total maternal deaths. vital statistics review contributed 6.3 percent. linkage of death tapes of women of reproductive age to live birth and fetal death tapes contributed 1.0 percent. Medical examiner cases should be incorporated into surveillance data for accurate ascertainment of pregnancy associated deaths.
Using a state cancer registry to increase screening behaviors of sisters and daughters of breast cancer patients, The Pennsylvania Cancer Registry was used to contact breast cancer patients and. through them. their adult sisters and daughters. The sisters and daughters were counseled concerning their higher than average risks for breast cancer and their need for mammography and breast self-examination. Results showed a 9 percent increase in mammography and a 10 percent increase in breast self-examination rates for the counseled over control group. Costs were $49 per counseled sister or daughter indicating a need to increase cost effectiveness before implementation is practical.
Anterior tibial translation during a maximum quadriceps contraction: is it clinically significant, Quadriceps exercises are used sparingly in the early rehabilitation of ACL reconstructions because of concern about prematurely stretching the ACL graft. The aim of this study was to determine if a maximum isometric quadriceps contraction significantly translates the tibia anteriorly at 15 degrees. 30 degrees. 45 degrees. 60 degrees. and 75 degrees of flexion. Secondly. the role of the ACL in knee stability was analyzed by comparing the amount of tibial translation in normal. ACL deficient. and reconstructed knees. Thirdly. the location in the motion arc where a quadriceps contraction produces anterior tibial translation was determined. Anterior tibial translation was measured using an arthrometer (KT-1000) during an 89 N and manual maximum translation applied to the knee at rest. The manual maximum translation test determines the magnitude of anterior tibial translation produced by a high anterior force applied directly to the proximal calf. These translations were compared to the tibial translation intrinsically induced by a quadriceps contraction. Testing was performed in normal (N = 22). ACL deficient (N = 10). and reconstructed (N = 10) knees. Anterior tibial translation produced by a maximum quadriceps contraction was measured at 15 degrees. 30 degrees. 45 degrees. 60 degrees. and 75 degrees of flexion. The extension exercise resulted in less anterior tibial displacement than an 89 N drawer and half the translation produced by a manual maximum translation (P less than 0.001). Instrumented laxity testing produced greater anterior translation of the tibia than a maximum isometric quadriceps contraction. Anterior tibial translation was the same during maximum isometric knee extension in all tested knees.
The contribution of the glenohumeral ligaments to anterior stability of the shoulder joint, The purpose of this study was to investigate the ligamentous stabilizing mechanisms preventing anterior instability in the glenohumeral joint. Six freshly thawed. unembalmed cadaveric shoulders were dissected. preserving the joint capsule and glenohumeral ligaments. the coracohumeral ligament. and the subscapularis tendon. Hall-effect strain transducers were placed on the superior. middle. and inferior glenohumeral ligaments. The humerus and scapula were fixed in a specifically designed mounting apparatus that allowed the glenohumeral joint to be placed in 0 degree. 45 degrees. or 90 degrees of abduction. The mounting apparatus was placed in a model TTC Instron Universal Testing Instrument. which applied an external rotation torque to the humerus. Strain produced in the three glenohumeral ligaments was recorded on a three-channel X-Y chart recorder. At 0 degree of abduction. the superior and middle glenohumeral ligaments developed the most strain. At 45 degrees of abduction. the inferior and middle glenohumeral ligaments developed the most strain. with considerable strain also being developed in the superior glenohumeral ligament. At 90 degrees of abduction. the inferior glenohumeral ligament developed the most strain. with strain also seen in the middle glenohumeral ligament.
On the importance of planned health education. Prevention of ski injury as an example, The planning of health education aimed at preventing sports injuries is often incomplete and not stated explicitly. In most instances. the evaluation is incomplete or nonexistent. We present a theoretical framework for planning and evaluating health education. illustrating the main points by using as an example the health education for downhill skiers. Systematic planning consists of analyzing the magnitude of the problem and the behavioral risk factors. studying behavior determinants. designing an optimal intervention. and implementing the intervention. The evaluation phase deals with the effects on these five levels (implementation. intervention. determinants. behavior. and incidence of injury). Some common pitfalls are mentioned and special attention is given to the study of determinants of behavior and to the design of the intervention. The importance of pretesting health education material and the community approach in educating sports participants is underlined. Health education. together with regulations and facilities. constitutes the health promotion strategy in the prevention of sports injuries. For most sports. there seems to be a strong need for further research on the etiology and determinants of behavior before effective prevention can be realized.
Meniscus repair in the anterior cruciate deficient knee, From 1979 to 1986. isolated repair of a peripheral vascular zone meniscal tear was performed in 22 patients (23 menisci) who had ACL insufficiency. For various reasons none of these patients underwent repair or reconstruction of their ACL. The meniscus repair was done by open arthrotomy in 12 cases and by arthroscopic techniques in 11 cases. The purpose of this study was to evaluate the success rate of a meniscal repair in an anterior cruciate deficient knee. The average age of the patients at the time of surgery was 25 years and the average followup was 56 months. Six patients (26%) had mild occasional pain not requiring medication and one patient had moderate pain requiring nonnarcotic pain medication. Eight patients (26%) had occasional giving way episodes and one of them underwent ACL reconstruction 5 years later because of frequent giving way. One patient required a postoperative manipulation for inadequate range of motion. but there were no neurovascular injuries or infections. There were three patients (13%) who had failed repairs or a retear and required subsequent subtotal meniscectomies. None of the other patients had any clinical symptoms or signs of a meniscal tear. There were no significant differences between the results of open or arthroscopic repair. Even though the failure rate of meniscus repair may be greater in an unstable knee. we conclude that meniscus repair is not contraindicated in an anterior cruciate deficient knee.
The conservative treatment of the anterior cruciate deficient knee, Seventy-nine recreational athletes (average age. 26 years) with complete ACL tears were treated with nonligamentous arthroscopic surgery. monitored rehabilitation. functional bracing. and activity modification. The average followup was 52 months (range. 36 to 102 months). Six (8%) patients ultimately underwent ligament reconstruction and were considered failures of nonreconstructive treatment. The remaining 73 patients were the subject of detailed analysis. There were 9 (11%) excellent. 25 (32%) good. 17 (22%) fair. and 28 (35%) poor results. Although 71 patients (97%) were satisfied with their knee for activities of daily living. only 36 (49%) were satisfied with their knee for sports. Twenty-nine (40%) had significantly modified their athletic activities. Age. sex. interval from injury to treatment. associated meniscal tears (49 or 67%). and articular cartilage damage (21 or 29%) had no apparent effect on the outcome. Poor results were noted in 29 (40%) patients with significant pivot shifts. Multiple repeat injuries. repeat arthroscopy. isokinetic deficits. and increased length of followup were also associated with poor results.
Prevention of common overuse injuries by the use of shock absorbing insoles. A prospective study, Sedentary individuals. particularly new military recruits. who start a physical training program have a substantial risk of developing an overuse injury of the lower limb. In this study we investigated the effect of neoprene insoles on the incidence of overuse injuries during 9 weeks of basic military training. The experimental group consisted of 237 randomly selected new recruits. while 1151 recruits were the control group. Insoles were given to the experimental group and compliance was monitored. A panel of doctors documented and classified all injuries occurring during the 9 week period. A total of 54 (22.8%) and 237 (31.9%) injuries were reported in the experimental and control groups. respectively. In both groups. the majority of injuries were overuse (experimental group. 90.7%; control group. 86.4%). The mean weekly incidence of total overuse injuries and tibial stress syndrome was significantly lower (P less than 0.05) in the experimental group. The mean incidence of stress fractures was lower in the experimental group but not significantly so (0.05 less than P less than 0.1). This study shows that the incidence of total overuse injuries and tibial stress syndrome during 9 weeks of basic military training can be reduced by wearing insoles.
Subscapular elastofibroma in a young pitcher. A case report, Subscapular elastofibromas and scapulothoracic bursitis can cause symptomatic masses in baseball pitchers. Both processes appear to represent reactive soft tissue responses to repetitive stress at the inferior border of the scapula. It is assumed that most masses in the subscapular area represent scapulothoracic bursitis rather than an elastofibroma. However. it is possible that some of the masses treated conservatively as scapulothoracic bursitis may be elastofibromas. A study is currently under way to evaluate the incidence of subscapular masses in college and professional pitchers in the United States. A follow-up report is anticipated when the study has been completed. The author requests information concerning any confirmed cases of elastofibroma in baseball pitchers.
Influence of desflurane on regional distribution of coronary blood flow in a chronically instrumented canine model of multivessel coronary artery obstruction, The influence of desflurane on myocardial perfusion measured by a microsphere technique during a total occlusion of the left anterior descending coronary artery and concomitant moderate or severe stenosis of the left circumflex coronary artery was evaluated in chronically instrumented dogs. Hemodynamics. regional contractile function. and myocardial blood flow were measured during the conscious state and after anesthesia with desflurane (8.2%-9.2% and 12.5%-12.7%) with and without control of arterial pressure. Total left anterior descending occlusion produced in combination with a left circumflex coronary artery stenosis significantly (P less than 0.05) increased heart rate and left ventricular end diastolic pressure in the absence of desflurane anesthesia. Desflurane. administered only in the presence of left anterior descending occlusion and left circumflex stenosis. significantly (P less than 0.05) decreased mean arterial pressure. left ventricular systolic pressure. and left ventricular positive dP/dt50 without change in heart rate. Blood flow to the subendocardium of normal myocardium was reduced during the high concentration of desflurane (P less than 0.05). but perfusion of the subepicardium and midmyocardium was maintained at conscious levels. When the left circumflex stenosis was of moderate severity. only blood flow to the subendocardium distal to the stenosis was reduced by desflurane (P less than 0.05). In the presence of a severe stenosis. perfusion was decreased in the subepicardium. midmyocardium. and subendocardium of the stenotic zone (P less than 0.05). During the reduction in arterial pressure produced by desflurane. collateral blood flow in the left anterior descending region was reduced in dogs with either a moderate or severe left circumflex stenosis (P less than 0.05). When arterial pressure and heart rate conditions observed in the postocclusion conscious state were restored during the high concentration of desflurane. myocardial blood flow in all regions returned to those levels present in the conscious state (P less than 0.05). Ratios of flow between occluded and normal zones were decreased when hypotension produced by desflurane was uncontrolled. but when arterial pressure and heart rate were adjusted to conscious postocclusion levels using partial thoracic aorta occlusion and atrial pacing. the ratio remained at conscious control levels regardless of the degree of left circumflex stenosis severity (P less than 0.05). Results of this investigation indicate that desflurane does not redistribute blood flow away from collateral-dependent myocardium to other regions via a "coronary steal" mechanism in a chronically instrumented canine model of multivessel coronary artery disease.
Role of experience in the response to simulated critical incidents, Eight experienced anesthesiologists (faculty or private practitioners) were presented with the same simulated critical incidents that had previously been presented to 19 anesthesia trainees. The detection and correction times for these incidents were measured. as was compliance with Advanced Cardiac Life Support (ACLS) guidelines during cardiac arrest. and the occurrence of unplanned incidents. Experienced personnel tended to react more rapidly than did trainees. but differences between second-year anesthesia residents (CA2) and experienced anesthesiologists were not statistically significant. There was a high variability in performance between incidents and within each group. Unplanned errors and management flaws still occurred with experience subjects. The response to incidents during anesthesia is a complex process that involves multiple levels of cognitive activity and is vulnerable to error regardless of experience. Most trainees seemed to acquire adequate response routines by the end of the CA2 year. Formal reasoning appeared to play a minor role in responding to intraoperative events. but the exact nature of the anesthesiologist's cognition remains to be thoroughly investigated.
Low-dose bupivacaine does not improve postoperative epidural fentanyl analgesia in orthopedic patients [published erratum appears in Anesth Analg 1991 May;72(5):718, Epidural infusions of 10 micrograms/mL fentanyl combined with low-dose bupivacaine (0.1%) were compared with epidural infusions of fentanyl alone for postoperative analgesia after total knee joint replacement. There were no detectable differences between the two groups in analgesia (visual analogue scale ranging between 15 and 40 mm). infusion rates (which averaged 7-9 mL/h). or serum fentanyl levels (which reached 1-2 ng/mL). The incidence of side effects. including nausea. vomiting. and pruritus. was also similar. Of the patients receiving fentanyl and low-dose bupivacaine. one developed a transient unilateral motor and sensory loss. and one developed significant hypotension and respiratory depression. The addition of low-dose bupivacaine does not improve epidural fentanyl infusion analgesia after knee surgery and may increase morbidity.
Anaphylaxis to annatto dye: a case report, Annatto dye is an orange-yellow food coloring extracted from the seeds of the tree Bixa orellana. It is commonly used in cheeses. snack foods. beverages. and cereals. Previously reported adverse reactions associated with annatto dye have included urticaria and angioedema. We present a patient who developed urticaria. angioedema. and severe hypotension within 20 minutes following ingestion of milk and Fiber One cereal. which contained annatto dye. Subsequent skin tests to milk. wheat. and corn were negative. The patient had a strong positive skin test to annatto dye. while controls had no response. The nondialyzable fraction of annatto dye on SDS-PAGE demonstrated two protein staining bands in the range of 50 kD. Immunoblotting demonstrated patient IgE-specific for one of these bands. while controls showed no binding. Annatto dye may contain contaminating or residual seed proteins to which our patient developed IgE hypersensitivity. Annatto dye is a potential rare cause of anaphylaxis.
Relationships between skin prick test, radioallergosorbent test, and chemiluminescent assays in allergic children, The results of skin prick tests (SPT). radioallergosorbent tests (RAST). and multiple chemiluminescent tests (DHS-CLA) to grass mix. parietaria. D. farinae. and D. pteronyssinus were evaluated in 43 allergic children. All CLA tests had valid positive and negative control threads. Chemiluminescent assays class 4 matched with RAST class 3 and/or 4 and CLA class 3 with RAST class 2. The D. farinae. D. pteronyssinus. and grass results obtained with CLA. RAST. and SPT were investigated by principal components analysis that showed a good association between different methods of measuring allergenicity. The results of the present study confirm that DHS-CLA is an effective "in vitro" method for the detection of IgE-allergen specific antibody.
Clustering of fungal allergen-specific IgE antibody responses in allergic subjects, Statistical analysis of specific IgE immune responses to a panel of nine allergens from 2.094 patients demonstrated significant clustering between Aspergillus fumigatus. Alternaria alternata. and Cladosporium herbarum. not explained by crossreactive elements. This may represent a linked. high responder status to these fungal antigens in the allergic population.
A pilot study of pemirolast in patients with seasonal allergic rhinitis, Pemirolast is a potent. long-acting. orally effective antiallergic agent evaluated for clinical activity in prevention of symptoms of seasonal allergic rhinitis. It was evaluated in a randomized. double-blind. placebo-controlled parallel group in season trials to test its safety. tolerance. and prophylactic activity. Thirty-one patients with a history of fall seasonal allergic rhinitis were treated for 6 weeks with pemirolast. 50 mg bid. or placebo beginning approximately 2 weeks before the onset of the ragweed season in Atlanta. Daily evaluation of symptom scores disclosed statistically significantly less sneezing. rhinorrhea. and stuffy nose during treatment with pemirolast. There was. however. no difference for other evaluated symptoms or for the use of rescue medicines. There were no side effects during this short study. This preliminary study indicates that pemirolast may warrant further evaluation for the treatment of allergic rhinitis.
Inhaled bronchodilator's in asthma: low or high dose, We studied the effect of regular inhalations of low-dose and high-dose fenoterol and low-dose and high-dose combinations of fenoterol and ipratropium bromide in maintenance treatment of 120 adults with moderately severe asthma. We used a double-blind. randomized. parallel group design comparing 12 weeks of treatment with four regimens: fenoterol. 100 micrograms/dose; fenoterol. 200 micrograms/dose; fenoterol. 50 micrograms; and ipratropium. 20 micrograms/dose in a single inhaler (Berodual) and fenoterol. 100 micrograms and ipratropium. 40 micrograms/dose in a single inhaler (Duovent). During the baseline and active treatment period the patients recorded PEFR in the morning and evening. symptoms and use of a rescue inhaler. Changes in twice daily peak expiratory flow rates or asthma symptoms did not show any significant differences among the four treatment regimens during the 12 weeks compared with the baseline period. Use of the rescue inhaler did not differ among the four groups during the active treatment. The patients' assessment of the efficacy of the active treatment favored the low-dose fenoterol and low-dose combination. More side effects were recorded in the high-dose combination group during the first 4 weeks compared with the other groups. We conclude that in maintenance therapy of chronic asthma high doses of fenoterol alone or in combination with ipratropium bromide offer no clinical advantage over low doses. On the contrary. the low-dose fenoterol and the low-dose combination are better accepted and tolerated by the patients.
Sulphasalazine and prednisone compared with sulphasalazine for treating active Crohn disease. A double-blind, randomized, multicenter trial, OBJECTIVE: To determine whether sulphasalazine plus prednisone is more effective than sulphasalazine alone in treating active Crohn disease. DESIGN: Randomized. double-blind. placebo-controlled trial. SETTING: Multicenter trial in one university hospital and nine general hospitals. PATIENTS: Patients with active Crohn disease and a Van Hees Activity Index of 140 or more. Of 71 patients who were randomly assigned. 60 completed treatment and were analyzed. INTERVENTIONS: For 16 weeks. 30 patients received sulphasalazine. 6 g/d (or 4 g/d if adverse effects occurred) and prednisone. 30 mg/d initially. Prednisone therapy was tapered in increments of 5 mg/2 wk to 10 mg/d after 8 weeks. Thirty other patients received sulphasalazine and a placebo. MEASUREMENTS AND MAIN RESULTS: In the first 6 weeks of treatment. the Van Hees Activity Index decreased to a median of 70% (interquartile range. 57% to 81%) of the initial value in patients treated with sulphasalazine and prednisone and to a median of 87% (interquartile range. 70% to 94%) in patients treated with sulphasalazine alone (P = 0.001). In the last 4 weeks of treatment. the corresponding figures were 63% (interquartile range. 40% to 75%) and 70% (interquartile range. 54% to 90%) (P = 0.10). The Crohn's Disease Activity Index decreased in the first 6 weeks to a median of 65% (interquartile range. 57% to 86%) in patients receiving sulphasalazine and prednisone and to a median of 75% (interquartile range. 58% to 101%) in patients receiving sulphasalazine alone (P = 0.13). In the last 4 weeks of treatment. the corresponding figures were 65% (interquartile range. 42% to 90%) and 76% (interquartile range. 49% to 110%) (P = 0.19). CONCLUSIONS: The use of prednisone in addition to sulphasalazine in patients with active Crohn disease results in a significantly faster initial improvement. but not in a significantly better result after 16 weeks of treatment. when disease activity is measured by the Van Hees Activity Index.
Narrow QRS ventricular tachycardia, OBJECTIVE: To determine the frequency and clinical characteristics of narrow QRS ventricular tachycardia (QRS duration less than or equal to 0.11 seconds). DESIGN: Consecutive survey of patients with ventricular tachycardia. SETTING: Tertiary. referral-based arrhythmia service at a university medical center. PATIENTS: Sequential sample of patients with inducible ventricular tachycardia who had a 12-lead electrocardiogram of the tachycardia available for review. MEASUREMENTS AND MAIN RESULTS: Of 106 patients with ventricular tachycardia. 5 (4.7%; 95% CI. 2.1% to 10.6%) had ventricular tachycardia with a QRS duration less than or equal to 0.11 seconds. Three of the five patients were previously incorrectly diagnosed as having supraventricular tachycardia. All five patients had at least two electrocardiographic findings other than QRS duration to suggest ventricular tachycardia. CONCLUSIONS: Narrow QRS ventricular tachycardia should be considered in the differential diagnosis of narrow QRS tachycardias. Electrocardiographic findings other than QRS duration are usually present to suggest the diagnosis.
Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease, OBJECTIVE: To explore the role of endothelin-1. a potent endothelial-derived vasoconstrictor peptide. in pulmonary hypertension. by measuring its concentration in arterial and venous plasma. DESIGN: A survey. case series study. SETTING: University-affiliated hospitals and outpatient clinics. PATIENTS: Twenty-seven patients with pulmonary hypertension: 7 with primary. and 20 with secondary pulmonary hypertension of various causes. The control groups (n = 16) comprised 8 healthy volunteers and 8 patients with coronary artery disease but without evidence of pulmonary hypertension. MEASUREMENTS AND MAIN RESULTS: Pulmonary artery pressure was markedly increased (94/43 +/- 23/13 mm Hg) in the patients with pulmonary hypertension. Venous plasma immunoreactive endothelin-1. measured by a specific radioimmunoassay. was significantly higher in patients with pulmonary hypertension (3.5 +/- 2.5 pg/mL. P less than 0.001) than in normal subjects (1.45 +/- 0.45 pg/mL). or patients with coronary disease (0.75 +/- 0.64 pg/mL). The arterial-to-venous ratio of immunoreactive endothelin-1 was significantly greater than unity in primary pulmonary hypertension (2.21 +/- 0.72. P = 0.01). whereas the patients with secondary pulmonary hypertension had a mean ratio not different from 1 (0.97 +/- 0.42). In contrast. the mean arterial-to-venous ratios were significantly less than unity in both control groups (0.59 +/- 0.35. and 0.54 +/- 0.64; P less than 0.02. for normal subjects and coronary disease patients. respectively). indicating a possible clearance of endothelin-1 across the healthy lung. CONCLUSIONS: Patient with pulmonary hypertension have substantial alterations in plasma immunoreactive endothelin-1. which may reflect changes in net release or clearance of endothelin-1 by the lung. In patients with primary pulmonary hypertension. the high levels in arterial compared with venous plasma suggest pulmonary production of endothelin-1. which may contribute to elevated pulmonary vascular resistance.
Developmental dyslexia in women: neuropathological findings in three patients, Brains from male cases with dyslexia show symmetry of the planum temporale and predominantly left-sided cerebrocortical microdysgenesis. We now report on three women with dyslexia. In all brains. the planum temporale was again symmetrical. Also. in two of the brains. multiple foci of cerebrocortical glial scarring were present. In both women. many of the scars were myelinated. suggesting origination during late intrauterine or early postnatal life. In one. scars were mainly left perisylvian and involved portions of the vascular border zone of the temporal cortex. In the other. scars were more numerous and occurred in the border zone of the anterior. middle. and posterior cerebral arteries symmetrically. All three cases showed to a variable extent brain warts. molecular layer ectopias. and focal architectonic dysplasia identical to those seen in the male cases. Two women had primary brain neoplasms. an oligodendroglioma and a low-grade astrocytoma. respectively. and two women showed small angiomas. Reexamination of previously reported male cases disclosed one with myelinated glial scars. Two control brains with asymmetrical plana temporale showed myelinated glial scars as well. The significance of the anatomical findings is discussed. and possible etiological factors are considered with known effects of autoimmune diseases on the nervous system.
The glucose transporter and blood-brain barrier of human brain tumors, The glucose transporter of the human brain has been localized to endothelial cells expressing the blood-brain barrier. but little is known regarding its mechanism of induction or whether its expression is exclusively linked with restricted vascular permeability. We investigated glucose transporter expression by vessels in human astrocytic tumors and pulmonary metastases to the brain using immunohistochemical techniques. Vessels in 9 of 10 low-grade astrocytomas and 8 of 10 anaplastic astrocytomas were positive for glucose transporter. Glioblastoma vessels were transporter-positive in only 2 of 10 specimens. Vessels in all three metastatic tumors were negative for the glucose transporter. The decrease in transporter expression observed in higher-grade tumors occurred independently of increases in vascular permeability. In low-grade astrocytomas and glioblastomas transporter expression and contrast enhancement were inversely related. but vessels in 6 of 9 anaplastic astrocytomas were transporter-positive despite contrast enhancement. These findings suggest that separate mechanisms induce the glucose transporter and the permeability restrictions of the human blood-brain barrier. They also have potential implications for the therapy and prognosis of astroglial neoplasms.
Timing and topography of cerebral blood flow, aura, and headache during migraine attacks, Ten years of study has resulted in considerable but fragmented knowledge about regional cerebral blood flow in migraine with aura (classic migraine). In the present study. the number of repeatedly studied patients (n = 63) was large enough to determine statistically significant sequences of events and statistically significant spatial relations. The first observable event was a decrease of regional cerebral blood flow posteriorly in one cerebral hemisphere. Further development of this pathological process was accompanied by the aura symptoms. Thereafter headache occurred while regional cerebral blood flow remained decreased. During the headache phase. regional cerebral blood flow gradually changed from abnormally low to abnormally high without apparent change in headache. In some patients headache disappeared while regional cerebral blood flow remained increased. Although regional cerebral blood flow reduction and aura symptoms in the great majority of patients were unilateral. one-third had bilateral headache. Unilateral headache usually localized to the side on which regional cerebral blood flow was reduced and from which the aura symptoms originated (i.e.. aura symptoms were perceived to occur contralaterally but presumably originated in the hypoperfused hemisphere). Our results suggest a simple model for migraine attacks: A pathological disturbance in one cerebral hemisphere causes the aura symptoms and after a time delay. it also causes the headache by stimulating local vascular nociceptors. Bilateral headache caused by a unilateral cerebral disturbance may be explained by recent neuroanatomical and neurophysiological findings.
Effects of treatment on long-term survivors with malignant astrocytomas, We reviewed the records of 160 consecutive patients with glioblastoma and anaplastic astrocytoma to evaluate the long-term consequences of radiation therapy and chemotherapy. We defined long-term survivors as those patients with glioblastoma or anaplastic astrocytoma who lived at least 100% longer than median survival of historical controls. for example. 2 years for patients with glioblastoma and 4 years for patients with anaplastic astrocytoma. There were 9 (5.6%) long-term survivors. Three (30%) became demented and died without evidence of tumor recurrence. One. after survival of 10 years. died of tumor recurrence. Of the remaining survivors. 2 (22%) have significantly impaired short-term memory function and other neurological deficits such as gait apraxia. Three (30%) can function independently. It is likely but cannot be proved that it is radiotherapy and not chemotherapy that is the causal factor of this dismal therapeutic outcome. Our study suggests restraint in the use of radiotherapy for patients with brain tumors that have more favorable prognoses than glioblastomas and anaplastic astrocytomas. such as low-grade astrocytomas and oligodendrogliomas.
Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa, Chemotherapy has only marginal efficacy in adult malignant brain tumors. In contrast. drug therapy is considerably more effective in medulloblastoma/primitive neuroectodermal tumors (MB/PNET) of the posterior fossa. the most common childhood primary central nervous system tumor. At the time of disease recurrence. a variety of different single agents and drug combinations result in tumor shrinkage and increased survival. The addition of chemotherapy to standard radiotherapy improves the rate and length of disease-free survival for those children with MB/PNET who have the most extensive tumors at diagnosis. It remains to be determined which drug or drug combinations are the most effective in MB/PNET. and which patients are most likely to benefit from chemotherapy. Chemotherapy may be useful to reduce or. in selected cases. obviate the need for radiotherapy and reduce treatment-related sequelae.
Ataxia and peripheral neuropathy: a benign variant of peroxisome dysgenesis, A 5-year-old boy with panperoxisomal dysfunction is described. Clinical features included hypotonia. areflexia. and ataxia. Cognition. vision. hearing. and hepatic function were normal. A panel of peroxisomal markers. including very-long-chain fatty acids. phytanic acid. pipecolic acid. and catalase compartmentalization. were abnormal. This is a uniquely benign syndrome of disordered peroxisome biogenesis.
OKT3 encephalopathy, OKT3 therapy for induction immunosuppression in a patient who underwent renal transplantation produced obtundation and quadriparesis associated with computed tomographic scan evidence of brain edema. These findings resolved over 3 days with supportive therapy and OKT3 withdrawal.
Safety and prophylactic efficacy of low-dose rimantadine in adults during an influenza A epidemic, A placebo-controlled. double-blind study to evaluate the safety and prophylactic efficacy of a low dose (100 mg) of rimantadine hydrochloride against naturally occurring influenza in adults was conducted at two sites. After the onset of the influenza season. volunteers (ages. 18 to 55 years) were assigned randomly to receive rimantadine or placebo daily. Subjects were monitored for adverse effects and evidence of influenza virus infection weekly for six weeks. Only 10 (8.7%) of 114 rimantadine recipients and 5 (4.4%) of 114 placebo control recipients reported one or more mild to moderate adverse symptoms. most of which were related to the gastrointestinal or central nervous system. Compared with placebo. low-dose rimantadine was highly effective in the prevention of influenza A virus infection (20 of 110 versus 7 of 112 participants; P less than 0.01) and influenza illness (7 of 110 versus 1 of 112 participants; P = 0.04). Influenza A/Leningrad/87-like (H3N2) virus was recovered from the nasopharynxes of only five placebo recipients. These findings indicate that low-dose rimantadine is well tolerated and highly effective for the prevention of influenza A illness in healthy adults.
Efficacy of short courses of oral novobiocin-rifampin in eradicating carrier state of methicillin-resistant Staphylococcus aureus and in vitro killing studies of clinical isolates, Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial infection problem. Colonization appears to be more common than invasive disease is. Eradication of colonization or the carrier state could limit the spread of MRSA. thus reducing the potential for mortality and morbidity in other patients. The detection of patients with MRSA infection in a rehabilitation ward led to a study of the combination of novobiocin-rifampin in vivo and in vitro. We found that 300 mg of rifampin plus 500 mg of novobiocin orally twice daily for 5 days. in 18 courses of treatment given to 12 patients. resulted in the clearing of MRSA in 79% of the evaluable courses and 81% of the evaluable sites. A second course cleared MRSA from one of the patients with a treatment failure. Side effects were not noted. All 18 pretherapy isolates were susceptible to either drug in vitro. but 1 of 2 posttherapy isolates was rifampin resistant. Timed-kill studies demonstrated that the rate of killing was the same with either drug alone or both drugs together. Pretherapy isolates from treatment successes or failure were killed at the same rate by the drug combination. However. with the rifampin-resistant isolate killing ceased after 48 h. Results of this study suggest that previously untreated patients are likely to have isolates that are susceptible to the combination of drugs and that the combination is commonly effective in eradicating MRSA carriage. Since the regimen is orally administered. and thus convenient. in conjunction with other measures it has the promise of reducing the spread of MRSA in hospitals.
Alpha interferon (2b) in combination with zidovudine for the treatment of presymptomatic feline leukemia virus-induced immunodeficiency syndrome, The therapeutic efficacies of human recombinant alpha interferon (IFN-alpha). IFN-alpha plus zidovudine (AZT). and AZT alone were evaluated in presymptomatic cats with established feline leukemia virus (FeLV)-acquired immunodeficiency syndrome (FAIDS) infection and high levels of persistent antigenemia. Subcutaneous injection of 1.6 x 10(6) U of human recombinant IFN-alpha 2b per kg delivered peak concentrations in plasma of 3.600 U/ml at 2 h postadministration with a half-life of elimination of 2.9 h. This dosage of IFN-alpha could be delivered to cats for up to 12 weeks without significant clinical toxicity. Oral administration of AZT (20 mg/kg three times daily) resulted in peak concentrations in plasma of 3 micrograms/ml at 2 h with a half-life of elimination of approximately 1.60 h. Treatment of FeLV-FAIDS-infected cats with IFN-alpha. either alone or in combination with orally administered AZT. resulted in significant decreases in circulating p27 core antigen beginning 2 weeks after the initiation of therapy. AZT alone had no effect on circulating virus antigen. Depending upon whether high (1.6 x 10(6) U/kg)- or low (1.6 x 10(4) to 1.6 x 10(5) U/kg)-dosage IFN-alpha was used. cats became refractory to therapy 3 or 7 weeks after the beginning of treatment. At these times. IFN-alpha-treated animals developed antibodies to IFN-alpha that were neutralizing. specific for human recombinant IFN-alpha. and dose dependent in magnitude. The results of this study indicate that human recombinant IFN-alpha is effective in reducing circulating virus antigenic load in cats persistently infected with FeLV-FAIDS.
Comparative study of cephradine and amoxicillin-clavulanate in the treatment of recurrent urinary tract infections, Eighty-eight female patients with a history of recurrent urinary tract infections were treated according to a randomization scheme with either 1 g of cephradine every 12 h (47 patients) or 375 mg of amoxicillin-clavulanate every 8 h (41 patients) for 7 days. The treatments were equally effective (cure rates of 89% for cephradine and 88% for amoxicillin-clavulanate) and showed similar relapse rates (cephradine. 14%; amoxicillin-clavulanate. 11%). Adverse effects were similar in both groups (cephradine. 23%; amoxicillin-clavulanate. 22%).
Comparative in vitro activities of newer quinolones against Pseudomonas species and Xanthomonas maltophilia isolated from patients with cancer, The in vitro susceptibilities of three Pseudomonas species (Pseudomonas aeruginosa. Pseudomonas putida. and Pseudomonas fluorescens) and Xanthomonas maltophilia to quinolone antimicrobial agents were determined. Several newer agents. particularly PD117558. PD117596. PD127391. sparfloxacin (AT-4140). A-56620. and temafloxacin. were active against Pseudomonas species. X. maltophilia isolates were generally less susceptible than were Pseudomonas isolates but were inhibited by some of the newer quinolones.
Ampicillin-resistant enterococcal species in an acute-care hospital, A prospective review of all enterococcal isolates for 13 months showed that 9.0% were resistant to ampicillin (MIC. greater than or equal to 16 micrograms/ml; zone diameter. less than 15 mm). as determined by the Vitek system. disk diffusion. microdilution MIC testing. and macrodilution MIC testing. All were beta-lactamase negative. A total of 19 and 3 resistant isolates were from urine and intravascular sites. respectively. Ampicillin-resistant enterococci appear to be a growing clinical problem.
Endogenous colonization by gentamicin-resistant gram-negative bacilli elaborating aminoglycoside (3)-5-acetyltransferase, Members of the family Enterobacteriaceae that elaborate aminoglycoside 3-5-acetyltransferase [AAC(3)-5] caused a nosocomial outbreak at the Vanderbilt University Medical Center and have persisted. To see whether the gene for AAC(3)-5 was present in the community. stool cultures of newly admitted patients and ambulatory persons were examined with a specific gene probe. AAC(3)-5-positive strains were present in the intestinal flora examined.
Increasing resistance of Staphylococcus aureus to ciprofloxacin, We demonstrated the marked emergence of resistance to ciprofloxacin among Staphylococcus arueus strains isolated at the Ann Arbor Veterans Administration Medical Center. All S. aureus isolates tested from 1984 to 1985 were susceptible. whereas 55.1% of methicillin-resistant and 2.5% of methicillin-susceptible strains from 1989 had high-level resistance to ciprofloxacin.
Mineral balance in infantile cortical hyperostosis: effects of corticosteroids, The effects on mineral metabolism of therapeutic doses of corticosteroids were investigated in infantile cortical hyperostosis; in four untreated cases the calcium. phosphorus. and magnesium balances were strongly positive. In one severe case. treatment with prednisolone was associated with an alteration to negative calcium and magnesium balance. and faecal losses of calcium were particularly high. This effect persisted for at least three months after the steroids had been discontinued. and during this period there was pronounced retardation of linear growth. Six months after the treatment had been stopped mineral balance was again positive and there was rapid 'catch up' in growth. In infancy. the negative effect of corticosteroids on calcium. phosphorus. and magnesium metabolism may contribute to inhibition of bone growth and steroid stunting.
Orocaecal transit time in Duchenne muscular dystrophy, Smooth muscle degeneration may occur in Duchenne muscular dystrophy. We measured fasting orocaecal transit time in patients with advanced Duchenne muscular dystrophy and other muscular dystrophies and in healthy controls. No significant differences were found. In contrast to reports of gastric hypomotility in Duchenne muscular dystrophy. we found no evidence of impaired small intestinal motility.
Effects of maternal iodine supplementation during pregnancy, Reduced maternal thyroid hormone concentrations during pregnancy can adversely affect fetal neurological development. In the context of national iodine supplementation programmes. concern has been expressed over the theoretical possibility that iodine supplementation during pregnancy might adversely affect fetal development as a result of maternal thyroid inhibition from the Wolff-Chaikoff effect. In a double blind controlled trial in five villages in Papua New Guinea. several measures of motor and cognitive function showed no significant differences at either age 11 or 15 years between those children whose mothers had received supplementary iodine during pregnancy and the control children whose mothers had received the placebo.
Methaemoglobinaemia after ingestion of amyl nitrite, We report a case of methaemoglobinaemia in a 2 year old girl after ingestion of an 'aphrodisiac' containing nitrite. The availability of these products. their poor labelling. and their intended presence in domestic bedrooms all serve to increase the hazard they pose to young children.
Elemental diet for refractory atopic eczema, A total of 37 children with refractory wide-spread atopic eczema were treated with an antigen avoidance regimen comprising hospitalisation. exclusive feeding with an elemental formula for a median duration of 30 days. and measures to reduce exposure to pet and dust mite antigens at home. After the initial period of food exclusion. food challenges were performed at intervals of seven days. and the patients followed up for at least 12 months. Ten of the children (27%) either failed to respond to the regimen or relapsed within 12 months. Improvement in the eczema was seen in 27/37 (73%) patients. by discharge from hospital their disease severity score had fallen to a median of 27% of the pretreatment figure. and only 3/27 required topical corticosteroids. There were no clinical or laboratory findings which could be used to predict the outcome. Drawbacks to the regimen were prolonged hospitalisation (median 70 days). a fall in body weight and serum albumin concentration. and a risk of anaphylactic shock (4/37 cases). A strict antigen avoidance regimen may be associated with improvement of atopic eczema where conventional treatments have failed.
Treatment of rheumatoid arthritis with an anti-CD4 monoclonal antibody, The effect of treatment with a monoclonal antibody against the CD4 antigen present on T helper cells was studied in 10 patients with severe intractable rheumatoid arthritis. In an open trial. monoclonal antibody 16H5 was infused at a dosage of 0.3 mg/kg of body weight on 7 consecutive days. Studies of the kinetics demonstrated a drastic depletion of CD4+ cells. to as low as 25 cells/microliters. 1 hour after the first infusion. The subsequent recovery of the CD4+ cell numbers 24 hours after infusion did not reach initial levels. and after the full 7-day treatment cycle there was a significant reduction of the number of CD4+ cells (mean +/- SD 51 +/- 28%; P less than 0.02). There was a reduced or even inverse CD4:CD8 ratio. which generally persisted 3-4 weeks. Lymphocyte transformation assays demonstrated significantly reduced reactivity in 5 of the 9 patients who completed the 7-day course. whereas 4 individuals exhibited an unexpected elevation in the T cell response to mitogens and common antigens. Parallel laboratory studies showed a significant decrease in the erythrocyte sedimentation rate (P less than 0.05). rheumatoid factor titer (P less than 0.04). and total immunoglobulin values (P less than 0.01). as well as a reduction in C-reactive protein levels. in 7 of the 9 patients. Clinically. there was a significant reduction in the Ritchie articular index (P less than 0.05) and in the number of swollen joints (P less than 0.04). Adverse effects were urticaria in 2 patients. which led to withdrawal of therapy in 1 of them. and chills with fever. suggestive of a lymphokine release syndrome. in another 2 patients. Only low levels of human anti-mouse immunoglobulin antibodies developed (not exceeding 1.7 mg/liter). It was therefore possible to repeat the treatment cycle. achieving still better efficacy. in 4 of the patients (reductions in the Ritchie index and the number of swollen joints P less than 0.02). Our findings indicate that treatment with monoclonal antibodies against the CD4 antigen leads to immunomodulation which results in clinical benefits. at least during initial observation periods (up to 6 months postinfusion). However. it remains to be determined whether long-term remission can be induced with this therapeutic approach. The use of immunosuppressive therapies or repeated antibody treatments will have to be considered.
Clinical correlations with serum C1q levels in patients with rheumatoid arthritis, Previous studies have suggested that serum C1q levels measured during the first 5 years of rheumatoid arthritis (RA) may be predictive of the extent of subsequent joint damage. To further evaluate the clinical significance of this marker in RA. levels of C1q were measured by radial immunodiffusion in serum samples from 107 well-characterized patients with RA. Mean levels of C1q were higher in patients with a disease duration less than or equal to 5 years (173 micrograms/ml) than in patients with a disease duration greater than 5 years (148 micrograms/ml) (P = 0.032). Serum C1q levels were correlated with total joint counts and activities of daily living scores. but no correlation was observed with erythrocyte sedimentation rates or with radiographic scores. The results suggest that C1q may be a useful early marker of disease activity in patients with RA.
HLA-D region antigens in patients with rheumatoid arthritis, We studied the distribution of HLA-D region antigens in 2 groups of rheumatoid arthritis (RA) patients: those with mild. nonprogressive disease. and those with severe disease. The results demonstrate that DR4 was significantly increased in both RA patient populations. The frequencies of DR1 and DR4-associated DQw7 alleles. however. were different in these 2 groups of patients. DR1 was significantly increased only in patients with mild RA. and DR4-associated DQw7 was significantly increased only in patients with severe disease. The results of the present study. together with previous data from our laboratory and from other investigators on the incidence of HLA-D region antigens in RA. suggest that both DR and DQ (A and B) genes may be important in conferring susceptibility to RA; DR in the mild forms of the disease. and DQ in severe RA.
The effect of nifedipine on myocardial perfusion and metabolism in systemic sclerosis. A positron emission tomographic study, We assessed the effect of nifedipine on myocardial perfusion and metabolism in 9 patients with systemic sclerosis. using positron emission tomography with a perfusion tracer (potassium-38) and a metabolic tracer (18F-fluorodeoxyglucose [18FDG]). Nifedipine. 20 mg 3 times daily for 1 week. induced a significant increase in 38K myocardial uptake. a significant decrease in 18FDG myocardial uptake. and a significant increase in the myocardial 38K: 18FDG ratio. These results indicate that the increase in myocardial perfusion is associated with modifications in myocardial energy metabolism. which probably result from a beneficial anti-ischemic effect of nifedipine in patients with systemic sclerosis.
Evaluation of drug therapy for treatment of hypertensive urgencies in the emergency department, Oral nifedipine (N) and clonidine (C) are often used in the treatment of hypertensive urgencies; however. until recently. there were no comparative studies using the same patient population. The authors reviewed the records of hypertensive patients treated in the emergency department between October 1. 1987 and September 30. 1988. Selected patients had a diastolic blood pressure (DBP) of greater than 115 mm Hg without evidence of acute end organ damage. Patients were stratified into three treatment groups: N. C. and group 3 (G3). G3 received a variety of drug therapies but not exclusively N or C. Systolic blood pressure (SBP). DBP. mean arterial pressure (MAP). percent decrease in MAP (%MAP). time to lower blood pressure. admissions. and discharges were evaluated. Efficacy and safety were defined as reaching a DBP less than 110 mm Hg but %MAP of no greater than either 25% or 40%. respectively. Thirty-five N. 32 C. and 27 G3 patients were identified with no statistical difference between groups in race. gender. pretreatment SBP. DBP. or MAP. N. C. and G3 significantly reduced SBP. DBP. and MAP (P less than .01). Comparing N. C. and G3. no differences were observed in %MAP. admissions. discharges. efficacy. or safety. Time required to decrease blood pressure differed between all three groups (44 +/- 32 N v 77 +/- 57 C v 152 +/- 94 min G3) (p less than .05). These results indicate that N. C. and a variety of drug therapies are equally effective and safe in the treatment of hypertensive urgencies.
Treatment and career attitudes of prehospital care providers associated with potential exposure to HIV/AIDS, Career and treatment attitudes related to potential human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) exposure are reported based on a survey of 1.228 Maryland career and volunteer prehospital care providers trained to provide basic (BLS) and advanced (ALS) life support. Sixty-five percent stated potential exposure to HIV/AIDS was a major occupational stressor. Ninety-two percent stated they would treat HIV/AIDS patients if protected. Given a choice. 38% would avoid providing treatment to HIV/AIDS patients. Eighteen percent considered resigning from emergency medical services (EMS) work. An attitudinal scale (AIDSTRESS) was developed to evaluate overall treatment and career reactions. Respondents with significantly higher (more negative reactions) AIDSTRESS scores were: BLS providers. men. paid providers. personnel with more than 3 years of field experience. those working in urban areas. personnel with no formal education beyond high school. and those who stated that their HIV/AIDS training was inadequate. Implications of the findings for quality of care. career decision making. and inservice education are discussed.
Patient flow in the emergency department: the chest pain patient, Prompt treatment of the chest pain patient in the emergency department (ED) is crucial. To ensure prompt treatment. identification of factors that delay flow of these patients through the department is essential. To identify factors that delay patient flow through the ED. the authors conducted a prospective study of all chest pain patients. using a time-flow analysis. Eighty-eight (36%) of 245 patients required critical unit admissions and had an average department stay of 3 1/2 hours. Flow differences were seen between critical and noncritical care patients. Three primary sources of delay were identified: critical unit bed availability. the registration process. and the role of the unit admitting resident. Additional findings confirmed the efficacy and role of the triage nurse in patient flow. Nursing and medical education and staffing needs were addressed. The use of the community's emergency medical services was examined by analyzing the disposition of patients arriving at the ED by ambulance.
Diagnostic capabilities of magnetic resonance imaging and computed tomography in acute cervical spinal column injury, The present study was conducted to evaluate the imaging capabilities of magnetic resonance imaging (MRI) in evaluating acute cervical spinal column injury and compare these results to that of computed tomographic (CT) imaging. Forty-nine patients undergoing MRI at a Level I and regional spinal cord trauma center to evaluate cervical spinal column injury were studied. Seventy-one injuries were identified by MRI. These injuries were classified as osseous (fracture/dislocation) (n = 21). disc herniation (n = 29). and spinal cord injury (edema/contusion/transection) (n = 21). Diagnostic imaging results in 33 of the 49 patients undergoing both MRI and CT were compared. CT demonstrated 22 fracture/dislocations compared to 10 on MRI. MRI demonstrated 19 disc protrusions compared to 7 on CT. Additionally. MR imaged 13 cord injuries as compared to 0 by CT. MR imaging proved superior in demonstrating spinal cord pathology and intervertebral disc herniation. CT was superior to MRI in demonstrating osseous injury. CT and MRI may be useful together in determining presence and extent of spinal column injury.
The effect of pH buffering on reducing the pain associated with subcutaneous infiltration of bupivicaine [published erratum appears in Am J Emerg Med 1991 Jul;9(4):410, The authors propose that pH buffering of bupivicaine with sodium bicarbonate reduces the pain associated with its local subcutaneous infiltration. In a double-blind. prospective study. 62 healthy adult volunteers received a 0.5 mL subcutaneous infiltration of 0.5% buffered bupivicaine into the dorsum of a randomly chosen hand. The pH was adjusted to 7.0 by adding 0.05 mL of sodium bicarbonate (1 mEq/L [corrected]) to 10 mL vials of commercially available bupivicaine (1:200 dilution). The control hand was injected with the same amount of unbuffered agent. Pain was scored after each infiltration using a nonsegmented visual analogue scale. Student's t-test for paired measurements was used to analyze intergroup pain score differences. Forty-three subjects (69%) reported less pain with buffered bupivicaine and only 17 (27%) noted a modest increase: two subjects (3%) reported no difference. The mean pain score for the buffered agent was 22 mm compared with 30 mm for the control. The mean difference (control-experimental) was 8 mm (t = 4.64. df = 61. P less than .001). The authors conclude that the addition of sodium bicarbonate to bupivicaine reduces the pain associated with its local infiltration.
Experience with esmolol for the treatment of cocaine-associated cardiovascular complications, The authors report their experience using esmolol. an ultra-short acting beta-adrenergic antagonist. for the treatment of seven patients with cocaine-associated cardiovascular complications. No consistent hemodynamic benefit was found with the use of this drug. Although there was a decline in mean heart rate of 23% (range 0% to 35%). they were unable to show a consistent antihypertensive response. Adverse effects occurred in three patients. This included one patient with a marked exacerbation of hypertension and one who became hypotensive. Another patient developed emesis and lethargy during esmolol therapy and required endotracheal intubation. They do not recommend the routine use of esmolol for cocaine cardiotoxicity.
Self-administered intraurethral chlorpromazine: an unusual cause of priapism, Priapism is a prolonged. painful penile erection unaccompanied by sexual desire and not alleviated by ejaculation. The etiologies of priapism are numerous and diverse. Priapism can be a serious adverse effect of psychotropic medications. The case of a 36-year-old man who demonstrated priapism. 48 hours after inserting a crushed chlorpromazine tablet into the urethral meatus of his penis. is reported. Priapism induced by this route of drug administration has not been previously described. The pathophysiology and treatment of priapism are reviewed.
High resolution real-time ultrasound for the diagnosis of venous thrombosis in the rehabilitation setting, Accurate. noninvasive testing for deep venous thrombosis (DVT) by conventional methods is often not possible in the rehabilitation patient. Lower extremity amputation. a cast or bandage. or skin problems present obstacles to standard diagnostic methods. This report describes the use of duplex ultrasound (US) scanning for noninvasive diagnosis of DVT in a seventy-year-old man with a below-knee amputation. on whom Doppler and plethysmography examinations could not be performed. As experience is gained with this technique. the use of venography for diagnosis of DVT becomes more difficult to rationalize.
Research in physical medicine and rehabilitation. XII. Measurement tools with application to brain injury, There are basic principles and techniques of measurement that are relevant across biomedical disciplines. The purpose of this article is to explain some of the most important of these for medical rehabilitation. to illustrate how to use them to choose assessment instruments and to describe the nature of measurement in medical rehabilitation by examples in brain injury rehabilitation. Reliability is basic to any scientific measure. Validity. the ultimate criterion. is closely associated with the purpose of the measure. Content validity. criterion validity and construct validity are explained. Sensitivity to rehabilitative interventions and significance in patients' real lives (ecological validity) are emphasized. Measures of functional outcomes (disability) may show improvement after rehabilitation even when impairment measures do not. An extensive but selected list of measures of coma. global status. disabilities. communicative and cognitive impairments. and handicaps is presented. and their main uses are illustrated. Examples illustrate how to choose measures to study comprehensive program-level outcomes. to study learning-based interventions and to develop a general purpose database. Although there are many measures of activities of daily living and mobility. little published evidence of reliability and validity could be found even for some well-known scales. Ecologically valid and sensitive outcome measures are especially needed. Studies of the clinical utility of measures were also scarce. Many of these gaps can be spanned by clinical researchers with limited resources. Physical medicine and rehabilitation will benefit from formal studies of the reliabilities and validities of both its old and its new measurement instruments and by increased sophistication in choice of measures.
Recovery time of independent function post-stroke, Stroke patients undergoing physical rehabilitation were monitored daily to determine the length of time needed to recover independent function. Of the 93 patients admitted. there were 45 who could not attain the sitting position independently. 75 who could not walk independently and 75 who could not negotiate the stairs independently. By discharge. 25 of 45 patients (55.6%) were able to attain sitting from supine independently. 35 of 75 patients (46.7%) achieved the ability to walk independently but only 25 of 75 patients (33.3%) learned to negotiate stairs independently. The time from admission to achievement of independent function and the time from onset of stroke to achievement of independent function was modeled in relation to explanatory variables: age. sex. side of lesion. comorbidity. the presence of depression and the extent of impairment in perception. cognition. auditory comprehension and verbal expression. Four variables were found to influence recovery time: age influenced the rate of recovery of walking and stair climbing; perceptual impairment influenced the rate of achieving independent sitting and stair climbing; and depression and comprehension influenced walking.
A longitudinal study of children with a family history of strabismus: factors determining the incidence of strabismus, A longitudinal study of ocular refraction. position. and fixation was performed in children with a family history of strabismus. The children were examined at regular intervals between 3 months and 4 years of age. and the results are discussed in terms of changes in refraction between different ages and correlations between refraction and development of strabismus and amblyopia. Six of 34 children (17.6%) developed constant or intermittent esotropia. The strabismus was first noted between 18 and 30 months of age except in one case. All esotropic children were 4 dioptres hypermetropic or more at 6 months. and their hypermetropia remained almost unchanged through the years. Seven additional children were 4 dioptres or more hypermetropic at 6 months but did not develop a squint. In contrast to the squinting children the hypermetropia in these children changed towards emmetropia. This emmetropisation was most pronounced during the first 2 years of age. The implications of these results for an early diagnosis of strabismus amblyopia are discussed.
Retinal arterial macroaneurysms: risk factors and natural history, A case control study was conducted to identify the systemic and ocular risk factors for retinal arterial macroaneurysms. Forty-three patients with 52 photographically confirmed macroaneurysms were located. Forty-three age-matched. race-matched concurrent control patients were also identified. The patients with macroaneurysms had decreased visual acuity (p less than 0.0001) and a higher prevalence of hypertension (p = 0.037). female sex (p = 0.099). and retinal vein occlusions (p = 0.055) than controls. In patients with both a macroaneurysm and venous occlusion there was a 12.0 times higher prevalence of macroaneurysms in the area of retina drained by the occluded vein (p less than 0.05). Common findings associated with macroaneurysms included retinal haemorrhage (81% of patients). retinal exudate (70%). vitreous haemorrhage (30%). macular involvement (30%). and distal arteriolar narrowing (26%). Arteriolar occlusion occurred spontaneously (8%) or after laser photocoagulation (16%).
The association of Fuchs's corneal endothelial dystrophy with axial hypermetropia, shallow anterior chamber, and angle closure glaucoma, A series of 24 patients with Fuchs's dystrophy are presented in whom detailed clinical measurement showed an association with axial hypermetropia and shallow anterior chamber. In 14 of these patients one cornea had developed oedema. of which 11 had required penetrating keratoplasty. Comparison of these eyes with the fellow eyes without corneal oedema revealed that the anomalies in measurement were not due to the process of decompensation. These 14 patients were then compared with the remaining 10 patients without corneal oedema in either eye. and a similar profile of anomalous measurements was observed. The whole group of 24 patients were then compared with three separate control groups. and in each case a significant trend towards hypermetropia. short axial length. and shallow anterior chamber was noted. The mean spherical equivalent refractive error in the patients with Fuchs's dystrophy was +2.48 D compared with -0.31 D for controls; corresponding means for axial length were 22.1 mm compared with 23.4 mm; and for anterior chamber depth were 2.2 mm compared with 2.7 mm. Each of these differences was statistically significant. but there was no significant difference for the keratometry measurements between patients and controls. Five of 24 (21%) of the patients had problems related to shallow anterior chambers of whom 3 (12%) had manifest angle closure glaucoma requiring surgical peripheral iridectomy. The aetiology of Fuchs's dystrophy and of ametropia is discussed and possible modes of association outlined. This previously unrecognised association gives a rational basis for the widely accepted practice of combining penetrating keratoplasty with lens extraction and has several other practical implications which are important in the differential diagnosis and treatment of Fuchs's dystrophy and angle closure glaucoma.
Effect of a beta-blocker on altered body position: induced ocular hypertension, The intraocular pressures (IOP) were measured in both eyes of 25 healthy volunteers in various body positions. One eye was pretreated with levobunolol 0.5% or placebo applied in a masked. randomised fashion. while the other served as control. IOP changes in response to levobunolol and to changes in position were significant (p less than 0.0001). However. pressure rises relative to position were not significantly different in eyes treated with drug vs placebo. Levobunolol did not alter relative changes in IOP from changes in body position. However. the overall lowering effect may offer some protection to patients with glaucoma.
A functional vagotomy induced by unilateral forced right nostril breathing decreases intraocular pressure in open and closed angle glaucoma, There is evidence of the central regulation of intraocular pressure. and it has been suggested that vagal tone might be increased in glaucoma simplex. The nasal cycle. the simultaneous congestion-decongestion response in the nasal cavities. reflects the dynamic lateralisation of the autonomic nervous system. Since this lateralisation presents with sympathetic activity induced by left brain hemisphere stimulation and parasympathetic activity induced by right hemisphere stimulation. it was subsequently demonstrated that forced unilateral nostril breathing induces selective contralateral hemispheric stimulation as measured by relative increases in the electroencephalographic amplitude in the contralateral hemisphere as well as alternating lateralisation of plasma catecholamines. Using this functional vagotomy. we report that left hemispheric stimulation by 20 minutes of forced unilateral right nostril breathing led to a significant bilateral decrease of 4.6 mmHg (25%) in intraocular pressure in 46 patients with open and closed angle glaucoma. However. it significantly increased the IOP in three patients with neovascular. one with juvenile onset. and one with closed angle glaucoma.
Therapeutic outcome of patients suffering from malignant melanomas of the conjunctiva, Eighty-one cases of conjunctival melanoma treated between 1960 and 1988 were studied to determine factors that might affect outcome in patients with such lesions. The therapeutic procedures performed were local excision (16). local excision followed by brachytherapy with Sr-90/Y-90 (32). local excision followed by cryotherapy with liquid nitrogen (16). brachytherapy with Sr-90/Y-90 (12). local excision followed by external beam irradiation (3). and local excision followed by brachytherapy and cryotherapy (2). The median follow-up period was 5.5 years (longest 26. shortest 1 year). Sixty two patients (76.5%) showed a complete regression of the melanoma. 19 (23.5%) developed recurrences. and 15 (18.5%) died from metastases. The melanomas had developed with almost equal frequency from a pre-existing naevus (25.9%). from primary acquired melanosis (25.9%). and 'de novo' (30.9%). Small tumours had a higher chance of regressing (80.6%) than larger ones (68.6%). The cumulative survival rate was 76% after five years and 60% after 10 years from any causes of death and 87.6% after five years and 76.3% after 10 years from deaths caused by metastases. Most deaths from metastases occurred within 5 years. At 88.5%. the cumulative survival rate of patients with small tumours (less than one quadrant of the bulbar conjunctiva and less than 2 mm thickness) was significantly higher than that of patients with larger tumours (more than one quadrant of the bulbar conjunctiva and/or more than 2 mm thickness) with 65% after eight years. Local excision followed by beta ray irradiation (Sr-90/Y-90) or cryotherapy can be recommended as the treatment of choice. Nevertheless the behaviour of conjunctival melanomas remains unpredictable in individual cases.
Injector for highly viscous silicone oil, A syringe device for the injection and evacuation of highly viscous silicone oil was developed. The problem of removing the air interfering with these manoeuvres was solved by providing special outlets in the plunger and handle of a conventional glass syringe. A slightly modified commercial motor perfusor was chosen to power this device. which has proved to be good and fail-safe in more than 100 cases.
Anisometropic and strabismic amblyopia in the age group 2 years and above: a prospective study of the results of treatment, Forty-four children aged 2-9 years with strabismic and anisometropic amblyopia were prospectively followed up during amblyopia treatment. The efficacy of optimised treatment in terms of number of cured children. time to achieve cure. and rate of initial improvement of visual acuity was evaluated in relation to age at start of treatment. type and initial degree of amblyopia. and adherence to treatment regimen. Compliance with treatment was the most critical factor predicting a successful outcome. Among the compliant children 35 out of 36 were cured (visual acuity difference between amblyopic and non-amblyopic eyes not more than one line) within five months regardless of age. treatment regimen. and type or initial degree of amblyopia as compared with none in the group with low compliance. Most of these compliant children were cured within three months. with shorter treatment times on average for the younger children. The initial improvement of visual acuity was also faster at 2 years than at 4 years of age. Anisometropes with moderate amblyopia at the start of treatment were over-represented in the group with low compliance. We conclude that early diagnosis of strabismus in combination with general population screening at the age of 4 to detect amblyopia caused by anisometropia or microstrabismus seems to be efficacious for the cure of most cases. The major factor in treatment failure was found to be inadequate adherence to the treatment regimen.
Postural studies in pulsatile ocular blood flow: I. Ocular hypertension and normotension, Measurements of pulsatile ocular blood flow (POBF) have been recorded in a group of healthy. ocular normotensive volunteers and ocular hypertensive patients recruited from outpatients. Use of a pneumotonometric probe linked to a Langham ocular blood flow system enabled readings of intraocular pressure and its variation with heart rate (ocular pulse) to be taken in erect and supine positions. Pulsatile ocular blood flow was calculated from these values by means of the pressure-volume relationship previously described for living human eyes. Assumption of the supine posture was accompanied by a significant rise in intraocular pressure; in normal eyes (mean. with SEM) (3.1 (0.4) mmHg. p less than 0.0001) and to a greater extent in ocular hypertensive eyes (4.7 (0.6) mmHg. p less than 0.0001). The POBF did not differ significantly between normotensive and ocular hypertensive groups in either the erect or supine postures. In both groups. however. assumption of the supine posture was accompanied by a significant fall in POBF (normals: -121 (21) microliters/min. p less than 0.0001; ocular hypertensives: -75 (16) microliters/min. p less than 0.0002). These reductions in POBF represent decrements of 27.5 (3.0)% and 17.1 (3.8)% respectively. Pulsatile ocular blood flow is reduced in the supine posture. and this may result in tissue hypoxia in subjects at risk of developing glaucoma. A companion paper describes the measurement of POBF in a group of patients with chronic open angle glaucoma treated with topical timolol 0.25%.
Prognostic significance of the pattern visual evoked potential in ocular hypertension, This paper reports a prospective study on 49 ocular hypertensive patients to evaluate the prognostic significance of transient abnormalities in the pattern visual evoked potential (VEP) in the development of glaucoma. Seven of 24 patients with VEP abnormalities at diagnosis of ocular hypertension developed glaucomatous field defects in the follow-up period as compared with none of 25 patients with normal VEPs at diagnosis. We conclude that appropriately designed pattern VEP testing is a valuable complement to careful (preferably computerised. static) perimetry. In addition. our findings support the contention that. in glaucomatous disease of the optic nerve. rudimentary pattern processing mechanisms--that is 'Y'-type units of the magnocellular pathways--may be affected earlier than luminance processing mechanisms.
Hirudin interruption of heparin-resistant arterial thrombus formation in baboons, To determine the role of thrombin in high blood flow. platelet-dependent thrombotic and hemostatic processes we measured the relative antithrombotic and antihemostatic effects in baboons of hirudin. a highly potent and specific antithrombin. and compared the effects of heparin. an antithrombin III-dependent inhibitor of thrombin. Thrombus formation was determined in vivo using three relevant models (homologous endarterectomized aorta. collagen-coated tubing. and Dacron vascular graft) by measuring: (1) platelet deposition. using gamma camera imaging of 111In-platelets; (2) fibrin deposition. as assessed by the incorporation of circulating 125I-fibrinogen; and (3) occlusion. The continuous intravenous infusion of 1. 5. and 20 nmol/kg per minute of recombinant hirudin (desulfatohirudin) maintained constant plasma levels of 0.16 +/- 0.03. 0.79 +/- 0.44. and 3.3 +/- 0.77 mumol/mL. respectively. Hirudin interrupted platelet and fibrin deposition in a dose-dependent manner that was profound at the highest dose for all three thrombogenic surfaces and significant at the lowest dose for thrombus formation on endarterectomized aorta. Thrombotic occlusion was prevented by all doses studied. In contrast. heparin did not inhibit either platelet or fibrin deposition when administered at a dose that maximally prolonged clotting times (100 U/kg) (P greater than .1). and only intermediate effects were produced at 10-fold that dose (1.000 U/kg). Moreover. heparin did not prevent occlusion of the test segments. Hirudin inhibited platelet hemostatic function in concert with its antithrombotic effects (bleeding times were prolonged by the intermediate and higher doses). By comparison. intravenous heparin failed to affect the bleeding time at the 100 U/kg dose (P greater than .5). and only minimally prolonged the bleeding time at the 1.000 U/kg dose (P less than .05). We conclude that platelet-dependent thrombotic and hemostatic processes are thrombin-mediated and that the biologic antithrombin hirudin produces a potent. dose-dependent inhibition of arterial thrombus formation that greatly exceeds the minimal antithrombotic effects produced by heparin.
Identification of functionally distinct domains of human granulocyte-macrophage colony-stimulating factor using monoclonal antibodies, Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein that is required for the survival. growth. and differentiation of hematopoietic progenitor cells. Although the primary structure of GM-CSF is known from cDNA cloning. the relationship between structure and function of GM-CSF is not fully understood. Fifteen different monoclonal antibodies (MoAbs) to human GM-CSF were generated to map immunologically distinct areas of the molecule. Each of the MoAbs was biotinylated and shown by enzyme-linked immunosorbent assay to bind to recombinant GM-CSF that had been affixed to a solid phase. Each of the 15 unconjugated MoAbs was then used to compete with each biotinylated MoAb for binding to GM-CSF. These cross-blocking studies identified eight distinct epitopes of native GM-CSF. Seven of these epitopes were also present in denatured GM-CSF by Western blotting. and four of the epitopes were at least partially conserved on GM-CSF that was reduced in beta-mercaptoethanol. MoAbs to four of eight epitopes neutralized both recombinant (glycosylated and nonglycosylated) and natural human GM-CSF in a GM colony-forming unit (CFU-GM) assay and blocked GM-CSF-induced activation of neutrophils. For most of the antibodies there was a good correlation between neutralizing activity and the capacity to block binding of 125I-GM-CSF to neutrophils or blasts. Non-neutralizing antibodies to one epitope partially blocked binding of 125I-GM-CSF to neutrophils. None of the MoAbs neutralized interleukin-3. G-CSF. or M-CSF. The locations of seven of the epitopes could be partially mapped with regard to the amino acid structure by determining reactivity to GM-CSF synthetic peptides or to human-mouse chimeric GM-CSFs. The neutralizing antibodies were found to map to amino acids 40-77. 78-94. or 110-127. Thus. these MoAbs are useful to identify functional domains of GM-CSF and in identifying regions that are likely to be involved in receptor interaction.
Increased lysis of patient CD10-positive leukemic cells by T cells coated with anti-CD3 Fab' antibody cross-linked to anti-CD10 Fab' antibody, An anti-CD3 Fab' x anti-CD10 Fab' bispecific hybrid F(ab')2 antibody (Ab) was generated. This bispecific Ab had a molecular mass of 100 to 110 Kd. and the capacity to react with both CD3+ T cells and CD10+ acute lymphoblastic leukemia (ALL) cells. We studied whether cytotoxic T lymphocytes (CTLs) could lyse patient CD10+ ALL cells after addition of the bispecific Ab. As effector CTLs. interleukin-2 (IL-2)-stimulated peripheral blood mononuclear cells (PBMCs) and CTL clones were used. When IL-2-stimulated PBMCs were assayed for cytotoxicity to 61Cr-labeled CD10+ ALL cells. their activity was shown to be markedly enhanced by the addition of the bispecific Ab. Most of the CTL clones established lacked cytotoxicity for CD10+ ALL cells. but addition of the bispecific Ab induced a significant level of cytotoxicity. CTLs derived from ALL patients also showed significant cytotoxicity for autologous CD10+ ALL cells after addition of the bispecific Ab. However. this Ab did not affect the cytotoxicity of CTLs when CD10- leukemic cells were used as the targets. These findings suggest that the bispecific Ab can be used for immunotherapy in patients with CD10+ ALL.
Inhibition of hydroxymethylglutaryl coenzyme A reductase activity induces a paradoxical increase in DNA synthesis in myeloid leukemia cells, The effects of competitive inhibition of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase by compactin on the in vitro proliferation of peripheral blood myeloid leukemia cells were studied using the cells from 45 patients with acute myeloid leukemia or chronic myelogenous leukemia in blast phase. The cells from 58% of these patients showed a dose-related inhibition of DNA synthesis when incubated with compactin. Unexpectedly. cells from 18% of the patients were resistant to the inhibitory effects of compactin on DNA synthesis and responded to the HMG CoA reductase inhibition with an actual increase in the incorporation of 14C-labeled thymidine into DNA. Another 18% of the patients studied displayed both inhibition and stimulation of DNA synthesis in a biphasic response depending on the particular concentration of compactin used. The maximum enhanced rates of cellular DNA synthesis were observed with lower compactin concentrations (5 x 10(-7) mol/L) than were required for maximum inhibition of DNA synthesis (10(-5) mol/L). Leukemia cells displaying a stimulated response to compactin had a significantly lower baseline DNA synthetic rate than did cells that showed an inhibitory response of DNA synthesis to compactin. There was no correlation between these cells' varying DNA synthetic response to compactin and measures of baseline HMG CoA reductase activity or acetate conversion to cholesterol. Whereas the observation of cellular DNA synthesis stimulation by HMG CoA reductase inhibition has not been observed in other mammalian cells and seems paradoxical. explanations may emerge in light of our growing knowledge concerning the importance of isoprenylation for the function of certain cell regulatory proteins.
Preliminary studies for an immunotherapeutic approach to the treatment of human myeloma using chimeric anti-CD38 antibody, Multiple myeloma is a disease in which conventional chemotherapy has only limited value. but which may be ideal for treatment with passive antibody against a suitable cell surface antigen on the neoplastic plasma cell. The CD38 antigen is known to be present on the majority of neoplastic plasma cells. and this was confirmed by detailed examination of bone marrow aspirates from three patients. Strong expression of CD38 was confined to cells which. by the criteria of light-scattering profiles and possession of cytoplasmic Ig. were plasma cells. The vast majority of neoplastic plasma cells appeared to be involved. Using a cell line as a model. it was found that the CD38 antigen acts as a target for a chimeric antibody prepared from the antibody OKT10. The chimeric antibody consists of the Fab portion of the mouse monoclonal antibody linked by a stable thioether bond to an Fc molecule derived from human IgG1. thereby forming mouse Fab-human Fc. In contrast to the parent antibody. the chimeric molecule mediates antibody-dependent cellular cytotoxicity (ADCC) very efficiently with human blood mononuclear effector cells. and is effective at low concentration. Also. even though the CD38 antigen is present on natural killer cells. there appears to be little deleterious action of the antibody on effector cell function. The antibody also failed to affect the growth of progenitor cells of the granulocyte/macrophage or erythroid lineages present in normal bone marrows. despite the suspicion that these cells express the antigen. Other advantages of the CD38 molecule are that it is not found in the serum of patients with myeloma. and it does not appear to modulate in vitro. Fourteen patients with florid myeloma and on various chemotherapeutic regimes had an undiminished capacity to mediate ADCC with the chimeric antibody. when compared with normal individuals. The maintenance of ADCC activity. coupled with the known suppression of the antibody response in these patients. augers well for treatment with chimeric antibody.
Epstein-Barr virus infection precedes clonal expansion in Burkitt's and acquired immunodeficiency syndrome-associated lymphoma, The Epstein-Barr virus (EBV) is associated with distinct forms of human lymphoid malignancies. including the endemic (eBL) and sporadic forms of Burkitt's lymphoma (sBL) and acquired immunodeficiency syndrome-associated non-Hodgkin lymphoma (AIDS-NHL). However. whether EBV has a pathogenetic role in these tumors or is a passenger virus has not been conclusively demonstrated. One element to distinguish between these two possibilities is to determine whether EBV infection has preceded and. thus. possibly contributed to clonal expansion. or whether infection has occurred after clonal expansion and thus is unlikely to contribute to pathogenesis. Toward this end we analyzed the structure of the heterogeneous genomic termini of EBV as markers of clonal infection in a panel of eBL (11 cases). sBL (9 cases). and AIDS-NHL (10 cases) biopsies. We show that EBV termini are uniformly clonal in sBL. eBL. and AIDS-NHL. strongly suggesting that EBV infection has preceded and. thus. most likely contributed to clonal expansion in these malignancies.
Preparation and characterization of an intravenous solution of IgG from human immunodeficiency virus-seropositive donors, An intravenous solution of 99% pure globulin (hyperimmune IgG. HIVIG) was obtained from pooled plasma of selected human immunodeficiency virus (HIV-1)-seropositive asymptomatic donors with greater than 400 CD4+/microliters cells per microliter and a high titer of antibody to HIV-1 p24 protein. HIVIG had high titers of antibody to p24. glycoprotein 41 (gp41). and gp120. group-specific neutralizing activity. and binding to the gp120 hypervariable loop region. It inhibited syncytia formation. At low concentration. it enhanced viral production of HIV-1 in infected peripheral blood monocytes but was inhibitory at higher concentration. HIVIG directed group-specific antibody-dependent cellular cytotoxicity against HIV-infected targets. For a period of 6 to 28 months. plasma donors kept stable antibody titers and had a 1.0% decrease in CD4+ cells per month. One gram per kilogram HIVIG injected in two juvenile chimpanzees was well tolerated and did not transmit HIV. as measured by negative cell culture. IgM immune response to HIV proteins. and polymerase chain reaction. The mean half-life of HIV-1 p24 antibody was 15 days. These preliminary data suggest that HIVIG is a safe product suitable for clinical trial in HIV-1-infected individuals.
Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors, Juvenile chronic myelogenous leukemia (JCML) is a good model for the study of myeloproliferation because JCML hematopoietic progenitor cells grow in vitro at very low cell densities without the addition of exogenous stimulus. Previous studies have demonstrated that this proliferation is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF). and that removal of monocytes from the cell population before culture eliminates this "spontaneous" myeloproliferation. suggesting a paracrine role of monocyte stimulation. However. subsequent studies have shown that increased GM-CSF production from the JCML monocytes is not a consistent finding and therefore not a plausible sole mechanism. In examining hematopoietic growth factor dose-response curves. both JCML GM and erythroid nonadherent progenitor cell populations displayed a marked and selective hypersensitivity to GM-CSF. Responses to interleukin-3 and G-CSF were identical to control dose-response curves. This is the first demonstration of a myeloid leukemia in which hypersensitivity to a specific growth factor appears to be involved in the pathogenesis of the disease.
Treatment of aplastic anemia in children with recombinant human granulocyte colony-stimulating factor, Twenty children (aged 1 to 17 years) with severe or moderate aplastic anemia were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) at a dose of 400 micrograms/m2 per day administered as a 30-minute intravenous (IV) infusion daily for 2 weeks. This treatment increased the neutrophil counts (2.7- to 28.0-fold) in 12 of the 20 patients. Increasing doses (800 or 1.200 micrograms/m2 per day) were administered to five patients who had not responded to the initial dose. and three showed an increase in neutrophil count. Differential counts of bone marrow (BM) aspirates showed an increase in the myeloid/erythroid ratio. The response was transient. however. and the neutrophil count returned to baseline within 2 to 10 days of discontinuing treatment. No severe toxicity attributable to rhG-CSF was observed. The results suggest that this agent is effective in stimulating granulopoiesis in children with aplastic anemia. Our study also indicates that rhG-CSF will be particularly useful in managing patients with aplastic anemia complicated by bacterial or fungal infection.
Stages I and II diffuse large cell lymphomas: prognostic factors and long-term results with CHOP-bleo and radiotherapy, One hundred forty-seven patients with Ann Arbor stages I and II diffuse large cell lymphoma (DLCL) were treated with combination chemotherapy consisting of cyclophosphamide. doxyrubicin. prednisone. and low-dose bleomycin (CHOP-Bleo) and involved-field radiation (IF XRT) between 1974 and 1984. A complete remission (CR) was attained by 54 of 57 patients with stage I disease and by 78 of 90 patients with stage II disease. Thirty-five patients had relapsing disease that occurred within 3 years in 31. The overall 10-year survival rate. counting all deaths. for patients with stage I was 72% as compared with 43% for patients with stage II (P less than .01). Determinate survival rates. censoring eight unrelated deaths. were similar to the overall survival rates: 77% and 51%. respectively. A multivariate analysis identified three independent prognostic factors: age. tumor extent. and serum lactic dehydrogenase (LDH) level. When the combined effect of tumor extent and LDH level were taken into consideration in the analysis. three risk groups for survival were identified. The best group. which consists of patients with minimum tumor and normal LDH levels. had a 10-year determinate survival of 79%. Patients with extensive tumors and elevated LDH levels had the poorest survival rate of 44%. An intermediate-risk group with a determinant survival of 62% was composed of patients with either extensive tumors or elevated LDH levels. These differences demonstrate the need to develop different treatment strategies based on risk factors for survival for patients with apparently localized Ann Arbor stages I/II DLCL.
Prevalence of Chlamydia trachomatis infection in women having cervical smear tests, OBJECTIVE--To determine the prevalence of sexually transmitted diseases in patients with normal and abnormal cervical smears. DESIGN--A prospective study of asymptomatic women with normal cervical smears attending their general practitioner and newly referred patients with abnormal smears attending a colposcopy clinic. SETTING--A hospital based colposcopy clinic and an urban general practice (list size 5500) in north west Glasgow. SUBJECTS--197 asymptomatic women attending their general practitioner for cervical smear tests and 101 randomly selected patients attending the colposcopy clinic for investigation of abnormal smears. MAIN OUTCOME MEASURES--Presence of various sexually transmitted infections as determined by culture and serological tests. RESULTS--Of the 101 women with cytological abnormalities. six had current chlamydial infection proved by culture and none had gonococcal infection; of the 197 women with normal smears. 24 (12%) had a chlamydial infection and two had gonorrhoea. Serological studies for Chlamydia trachomatis specific antibody also indicated that a large proportion of patients had been exposed to this agent in both groups. There was no significant difference between the groups in the prevalence of any sexually transmitted disease studied. CONCLUSION--A high prevalence of chlamydial infection is present in women in north west Glasgow irrespective of their cervical cytological state.
Ventilatory function as a predictor of fatal stroke, OBJECTIVE--To investigate the relation between ventilatory function and subsequent mortality due to cerebrovascular disease. DESIGN--Prospective longitudinal study. SUBJECTS--A total of 18.403 male civil servants aged 40-64 years at entry examination for the Whitehall study. MAIN OUTCOME MEASURE--Mortality from cerebrovascular disease (ICD8 430-438) after 18 years of follow up. RESULTS--In all. 262 men with sinus rhythm at entry died due to stroke during the 18 years of follow up. Compared with men with a forced expiratory volume in one second of greater than or equal to 3.5 litres those with a value of less than 3.0 litres were almost twice as likely to die of cerebrovascular disease (rate ratio adjusted for age and systolic blood pressure = 1.88. 95% confidence interval 1.32 to 2.69). This increased risk occurred within each tertile of systolic blood pressure. Nested case-control analyses were used to control precisely for confounding effects of age. height. and smoking (by matching) and employment grade and physiological risk factors (by modelling). The effect of forced expiratory volume in one second was independent of age. height. smoking habits. employment grade. blood pressure. weight. cholesterol concentration. glucose tolerance. electrocardiographic abnormalities. history of chest pain. and history of intermittent claudication. CONCLUSIONS--Measurements of ventilatory function may assist clinical decisions about whether to treat mild hypertension. Impaired ventilatory function and stroke may share common causes.
Suicide during pregnancy and in the first postnatal year, OBJECTIVES--To calculate age adjusted mortality ratios for suicide by women in the first year after childbirth and during pregnancy. and to identify characteristics of postnatal suicide in childbearing women. DESIGN--Retrospective study based on population data for England and Wales from 1973 to 1984. SUBJECTS--Women aged 15-44 who committed suicide in the year after childbirth or during pregnancy. MAIN OUTCOME MEASURES--Observed to expected mortality ratios for the total postnatal sample. for five year age groups. for unmarried mothers. and for suicide after stillbirth; observed to expected mortality ratios for all suicides during pregnancy and for five year age groups; the timing of suicides in relation to delivery; and the frequency of the various methods of suicide. RESULTS--The standardised mortality ratio for postnatal suicide was calculated to be 0.17--that is. the actual total was only one sixth of that expected. The low ratio was not found after stillbirth. which was associated with a rate six times that in all women after childbirth. The low ratio was less pronounced. but still present. in teenage mothers and in unmarried mothers. Women who committed suicide after childbirth most often did so in the first month. and there was a tendency to use violent methods. The standardised mortality ratio for suicide during pregnancy was calculated to be 0.05 of all pregnant women. Teenagers were at substantially increased risk. CONCLUSIONS--Women in the first year after childbirth and during pregnancy have a low risk of suicide despite their high rate of psychiatric morbidity. Underreporting of maternal suicides is unlikely to explain the findings. though it may affect their magnitude. Motherhood seems to protect against suicide. Concern for dependants may be an important focus for suicide prevention in clinical practice.
Serum sialic acid concentration and cardiovascular mortality, OBJECTIVE--To determine whether serum sialic acid concentration may be used to predict short and long term cardiovascular mortality. DESIGN--Prospective study on all men and women who had their serum sialic acid concentration measured as part of a general health survey in 1964 or in 1965. All were followed up for an average of 20.5 years. SETTING--Geographical part of the county of Varmland. Sweden. SUBJECTS--Residents in the area participating in a health check up in 1964-5 (27.065 men and 28.037 women). of whom 372 men (169 with incomplete data and 203 lost to follow up) and 345 women (143 and 202 respectively) were excluded; thus 26.693 men and 27.692 women entered the study. The study sample was restricted to subjects aged 40-74 during any of the 20 years' follow up. MAIN OUTCOME MEASURES--Serum sialic acid concentration. serum cholesterol concentration. diastolic blood pressure. body mass index at the general health survey visit; cardiovascular and non-cardiovascular deaths during three periods of follow up (0-6 years. 7-13 years. and 14-20 years). according to the Swedish mortality register. in subjects aged 45-74. RESULTS--Mean serum sialic acid concentration (mg/100 ml) was 68.8 (SD 8.0) for men and 69.2 (8.0) for women; the average concentration increasing with age in both sexes. A total of 5639 (21%) men and 3307 (12%) women died during the follow up period. in whom death in 3052 (54%) men and 1368 (41%) women was from cardiovascular causes. During short (0-6 years). medium (7-13 years). and long (14-20 years) term follow up the relative risk of death from cardiovascular disease increased with increasing serum sialic acid concentration. The relative risk (95% confidence interval) associated with the highest quartile of sialic acid concentration compared with the lowest quartile was 2.38 (2.01 to 2.83) in men and 2.62 (1.93 to 3.57) in women. Similar results were found for deaths from non-cardiovascular disease with relative risks of 1.50 (1.34 to 2.68) in men and 1.89 (1.57 to 2.28) in women. but these relative risks were significantly lower than those for deaths from cardiovascular disease (p less than 0.001 and p less than 0.005 respectively). In multivariate analysis of total mortality and of cardiovascular mortality with sialic acid concentration. serum cholesterol concentration. diastolic blood pressure. and body mass index as independent variables the impact of sialic acid concentration was virtually the same as in univariate analysis. CONCLUSION--Serum sialic acid concentration is a strong predictor of cardiovascular mortality. A possible explanation of these findings is that the serum sialic acid concentration may reflect the existence or the activity of an atherosclerotic process. and this may warrant further investigation.
Availability of transplantable organs from brain stem dead donors in intensive care units, OBJECTIVE--By audit from January to June 1989 to quantify. separately for hearts. kidneys. liver. lungs and corneas. the possible increases in transplantable organs from brain stem dead potential donors in intensive care units and to compare them with the increases achieved in October-November 1989. during intense. national publicity about transplantation. DESIGN--Prospective audit of all deaths in intensive care units in England from 1 January to 30 June 1989 and subsequent case study of the impact of publicity on offers and donations during October-November 1989. SETTING--15 regional and special health authorities in England. PATIENTS--5803 patients dying in intensive care units. of whom 497 were confirmed as brain stem dead and had no general medical contraindication to organ donation. MAIN OUTCOME MEASURES--Organ specific suitability for transplantation (as reported by intensive care units); consent for donation of specific suitable organs; and procurement of specific organs reported as suitable for transplantation and offered. RESULTS--In the 497 (8.6%) brain stem dead potential donors were estimated the organ specific suitability for heart as 63%. kidneys 95%. liver 70%. lungs 29%. and corneas 91%. Refusal of relatives (30%) accounted for major losses of suitable organs of all types. For kidneys the loss was equivalent to 44% of brain stem dead actual kidney donors. No discussion of organ donation was the second most important reason for missed kidney donors. the loss being equivalent to 10% of brain stem dead actual donors. Non-procurement or difficulties with allocating organs was the second most notable cause of missed suitable liver and lung donors; 29% (55) of the offered total of 189 liver donors and 27% (21) of 78 offered suitable lung donors in six months. Non-procurement of suitable. offered organs was rare for kidneys and modest. of the order of 13% and 10% respectively. for heart and corneas. Corneal donation from brain stem dead potential donors might be improved nearly as much (that is. a 78% increase in brain stem dead actual corneal donors) by specific measures to promote corneal donation when other organs are offered as by reducing the overall refusal rate. Restricted offers. non-procurement. and no discussion of donation accounted for nearly equal numbers of lost donations of hearts (each equivalent to 15% of donated hearts). During October-November 1989 when there was intense. positive publicity about transplantation the rates of refusal and non-discussion fell compared with during January-June (22%. 36/163 v 30%. 138/460; 7%. 33/497 v 2%. 4/167 respectively). Offers of suitable donors increased significantly (p less than 0.02) compared with the first six months of 1989. most notably for heart donors (80 v 60.1 expected) and kidney donors (122 v 102.1 expected) but only for kidneys was there a noticeable 17% increase in actual donors (118 actual audited donors v 100.8 expected donors; p = 0.09). CONCLUSIONS--Four strategies to increase the supply of transplantable organs from brain stem dead potential donors in intensive care units were identified: (a) reducing refusal of relatives (b) avoiding non-procurement of actually suitable organs (by logistical initiatives) and deterioration of initially suitable organs (by donor care initiatives); (c) converting restricted offers to unrestricted offers; and (d) ensuring discussion with families. Early referral to the transplant team or coordinator gives time for discussion about donor care and agreement on medical suitability for donation of specific organs. Solving some of the logistical problems of non-procurement may be a prerequisite for increased offers to be translated into increased donations. The impact of publicity therefore needs to be measured on offers of suitable donors as well as by actual donations.
Comparison of exercise performance in left main and three-vessel coronary artery disease, From a consecutive series of patients who underwent rest and exercise radionuclide angiography over several years. we retrospectively identified 34 patients with left main coronary artery disease and 103 patients with three-vessel coronary artery disease who did not have significant left main disease. The results of gated equilibrium radionuclide angiography were compared in these 2 groups. Multiple exercise hemodynamic. exercise electrocardiographic. and exercise radionuclide angiographic parameters were considered in an attempt to separate the 2 groups. The only parameter that was significantly different between the 2 groups was exercise heart rate. However. no value of the exercise heart rate could meaningfully separate the 2 groups. Despite their known difference in prognosis. patients with left main and three-vessel disease had very similar exercise performance and could not be distinguished from one another by exercise electrocardiography or exercise radionuclide angiography. The inability to distinguish these two groups is a clear limitation of noninvasive exercise modalities.
Atrial septal occlusion improves the accuracy of mitral valve area determination following percutaneous mitral balloon valvotomy, We investigated the impact of the atrial communication on the mitral valve area calculation after percutaneous mitral balloon valvotomy in 17 patients (15 women. 2 men; mean age 56 +/- 4 years). The hemodynamic measurements and mitral valve area calculations were performed with and without balloon occlusion of the atrial septal puncture site. The mitral valve area determined with balloon occlusion was significantly smaller than the mitral valve area determined without occlusion (1.6 +/- 0.1 vs. 1.9 +/- 0.1 cm2. P less than 0.01). and was similar to the echocardiographically determined valve area (1.6 +/- 0.1 cm2). This decrease in the calculated mitral valve area with occlusion was associated with a decrease in the measured cardiac output. without a change in the mitral valve gradient or the diastolic filling period. Occlusion of the atrial septal puncture site may permit more accurate determination of the mitral valve area and thus provide a better reference point for future comparison should the question or restenosis arise.
Preservation of regional myocardial function during coronary angioplasty with an autoperfusion balloon catheter: a case report, Echocardiographic assessment of regional myocardial function was performed during standard balloon coronary angioplasty followed by autoperfusion balloon angioplasty of a proximal left anterior descending artery stenosis. Septal and apical akinesis occurred within 60 seconds of standard balloon inflation. but regional function was well preserved during prolonged autoperfusion balloon inflation.
Successful mitral valvuloplasty using the Inoue balloon in a patient with mitral stenosis associated with subvalvular fibrosis and reduced left ventricular inflow cavity: a case report, Percutaneous transvenous mitral valvuloplasty (PTMV) was performed with two cylindric pigtail balloon catheters in a 52-year-old woman with symptomatic mitral stenosis. The subvalvular apparatus was fibrous with welded chordae and the subvalvular left ventricular space was markedly reduced. As a result of this distorted anatomy. during the inflations. the two balloons constantly slipped back into the left atrium before full inflation was obtained. After the procedure. the mitral valve area (MVA). as estimated by echo-doppler (ED). increased from 1.00 to 1.34 cm2. After 2 months of mild clinical improvement. the patient again became symptomatic and ED examination showed a MVA of 1.25 cm2. A second PTMV was performed with an Inoue balloon. the entire procedure taking less than 1 hour. A stable position of the Inoue balloon and complete dilatation were achieved. ED examination showed a mitral valve area of 2.30 cm2. There was no mitral regurgitation nor atrial septal defect. After 3 months. she has only N.Y.H.A. class I symptoms and MVA. as estimated by ED. was 2.40 cm2.
Percutaneous right brachial artery approach with 5F catheters for studying coronary artery disease, We prospectively studied 60 ischemic patients with 5F catheters (Pigtail and Amplatz) using the percutaneous right brachial artery approach (group I). in order to compare this technique with two groups of 100 patients each randomly studied by the femoral route with either 5F (group II) or 8F (group III) catheters (Pigtail and Judkins). The following parameters were analyzed: need to change the initially elected catheter diameter or/and artery approach; technical difficulty for obtaining LV. LCA. and RCA angiograms; total time of X-ray exposure; quality image of LV. LCA. and RCA angiograms; incidence of arterial puncture related hematomas or total arterial occlusion; and duration of local compression after sheath removal. There were no differences between 5F brachial and femoral approaches except for the arterial compression time (p less than 0.01) and the X-ray exposure time (p = 0.03) which were longer with the brachial approach. Whatever the route used. 5F showed a mild increase difficulty (brachial p = 0.001; femoral p = 0.01) and a mild decreased quality image for LCA (branchial p = 0.006; femoral p less than 0.05). Mild hematomas were more frequent with 8F catheters (p less than 0.05). The procedure could be completed by the elected first artery and type of catheter (5F or 8F) in 57/60 patients in group I. in 95/100 in group II. and in 96/100 in group III (nonsignificant differences). Thus. the percutaneous right brachial artery approach using 5F catheters is similar to the femoral artery approach with the same catheters. Although both of them showed a mild increased technical difficulty and a mild decreased quality image compared to 8F. mainly for LCA angiograms. they allowed complete and reliable angiograms reading and analysis.
Accuracy and reproducibility of quantitative coronary arteriography using 6 and 8 French catheters with cine angiographic acquisition, To determine the suitability of 6 French catheters for quantitative coronary arteriography. the relative accuracy and reproducibility of one type of these catheters was compared to that obtained with standard 8 French catheters in 20 stenoses. Duplicate injections with polyurethane 6 French catheters were obtained using hand and power injection technique with cineangiographic acquisition (four 6 French catheter injections total per stenosis). Measurements of both percent diameter stenosis and absolute dimensions were compared to those obtained with hand injection and cine acquisition using 8 French catheters as a "gold standard." While the reproducibility of dimension determination with the 6 French catheter was generally similar to that obtained with the 8 French catheter (0.27 +/- 0.23 mm for absolute diameter and 8.1 +/- 7.4% for percent diameter stenosis). accuracy was significantly less for the 6 French catheter for measurement of absolute dimensions. Thus. while apparently well suited for serial measurements of the same stenoses. 6 French catheters may not be as accurate in the determination of absolute artery dimensions as 8 French catheters.
Coronary balloon angioplasty through diagnostic 6 French catheters, We investigated the use of ultralow profile balloon catheters (Scimed ACE. USCI Probe. Cordis. Orion) for coronary angioplasty through 6 French diagnostic catheters (Schneider. Cordis). Contrast injection was assisted with a Hercules pump (Cordis) in all cases. During 21 procedures. angioplasty of 27 lesions in 20 selected patients was attempted (1.3 lesion/procedure). Twelve lesions were in the right. 10 in the left anterior descending. and 5 in the left circumflex coronary artery. Balloon size varied between 2.5 and 3.5 mm. Twenty lesions could be successfully dilated (74%) through the 6 French catheter and 7 lesions required an exchange to a 7 French angioplasty guiding catheter. For 5 cases. another balloon was also necessary to complete the procedure. The final overall success rate was 100% per patient and per lesion and there were no major complications. Despite the small internal catheter lumen (1.22 mm) coronary visualization was adequate. and mechanical support was good. Failures of 6 French catheters were attributed to insufficient torque control and excessive friction when the balloon crossed the tapered end of the diagnostic catheter. Coronary angioplasty through a diagnostic 6 French catheter is feasible and may represent a reasonable alternative for simple cases that are done during the same session as the diagnostic angiography. Once available. 6 French high flow angioplasty guiding catheters without a tapered tip should improve success while retaining the advantage of a small femoral puncture site.
Preliminary experience with 5 and 6 French diagnostic catheters as guiding catheters for coronary angioplasty, With the reduction in profile of balloon dilation catheters. until recently. it has been the internal dimensions and performance of the guiding catheter that has mandated the use of 7. 8 or 9 French (F) systems for the performance of percutaneous transluminal coronary angioplasty (PTCA). A new 5F catheter design (Sherwood Medical Co.. St. Louis. MO) provided a large inner lumen (0.4") permitting use of 0.20-0.22" fixed-wire PTCA balloon catheters with good coronary visualization. Potential advantages include reduced coronary artery ostial trauma and catheter induced damping and enhanced patient comfort. We report our initial experience in 14 patients undergoing PTCA with a 5 and 6F guide/fixed-wire system. Mean age was 63 +/- 10 (43-78 years). PTCA indications: Cardiogenic shock (1). post-myocardial infarction angina pectoris (2). grade III angina (5) and unstable angina pectoris (6). Vessel attempted: Left anterior descending (3). circumflex (4). obtuse marginal (2). diagonal (1). right coronary artery (3). and internal thoracic artery (1). Twelve patients had femoral approach; two brachial approach. The USCI Probe (USCI Division. Billerica. MA) was used in 8 lesions and SCIMED ACE (SCIMED Life Systems. Maplegrove. MN) catheter in 7 lesions. Successful 5 or 6F guide/fixed-wire dilations reduced the stenosis (77 +/- 14 to 37 +/- 30%) and were successfully performed in 79% (11/14). One 5F patient required 8F guiding catheter and was dilated with 2.0 fixed-wire balloon. A second failed 5F PTCA could not be dilated with any larger conventional system. A third total occlusion could not be crossed with a guidewire or fixed wire balloon. No patient had a complication.
Application of coronary angioplasty to the septal perforator arteries, Significant coronary artery disease affecting the septal perforator arteries can cause anginal pain. rhythm disturbances. or septal infarction. However. since these vessels are usually inaccessible to coronary bypass surgery. there is a tendency among angiographers and angioplasters to overlook lesions of the septal perforator arteries. Our experience suggests that if medical treatment is not sufficient to treat clinical manifestations resulting from septal perforator disease. then coronary angioplasty can be considered a therapeutic alternative for revascularization. We herein present 11 patients who underwent coronary angioplasty of a major septal artery and discuss angiographic and technical aspects of the procedure.
Immune functions during treatment of growth hormone-deficient children with biosynthetic human growth hormone, Immune functions. including cell surface markers. interleukin-2 receptor levels and responses of lymphocytes to mitogenic stimulation were evaluated in seven growth hormone deficient children ages 4-15 years. during treatment with biosynthetically derived human growth hormone. Treatment resulted in a decrease in % B cells and in % T total cells and also decreases in most individual patients' mitogen responses and interleukin-2 receptor levels. Most of the changes noted were transient and similar to those previously demonstrated during pituitary-derived human growth hormone treatment. Although not resulting in overt clinical manifestations in our patients. we think that potential interactions between growth hormone and immune functions need to be considered by physicians treating children with growth hormone.
Duchenne and Becker muscular dystrophies: genetics, prenatal diagnosis, and future prospects, DMD and BMD are now understood at the genetic. biochemical. and molecular levels. At the genetic level. both disorders result from mutations of the X-linked gene encoding dystrophin. At the biochemical level. DMD results from the deficiency of a large protein called dystrophin. whereas BMD results when dystrophin is present. though abnormal in either amount or molecular structure. To date. thousands of patients have been analyzed for mutations of the dystrophin gene in peripheral blood DNA or alterations of the dystrophin protein in muscle tissue. The severity of the clinical phenotype of these patients has been compared with their dystrophin gene mutations and corresponding dystrophin protein alterations. revealing an unexpectedly high degree of correlation. Thus. information derived from the molecular analysis (DNA or protein) of a particular patient provides a "molecular diagnosis." which is highly predictive of the clinical course that patient can be expected to follow. Because molecular diagnoses are independent of the patient's age. they provide a prognosis for the large majority of muscular dystrophy patients even before clinical symptoms of their disease become apparent. Such prognostic molecular diagnoses have proven particularly valuable when the patient is an isolated case. with no family history for the disorder. Prenatal genetic diagnosis of DMD or BMD may involve use of Southern blot or PCR techniques to search for a deletion in the DNA of at-risk fetuses or more complicated family linkage studies using intragenic and flanking RFLPs. More recently. assay of dystrophin content in fetal skeletal or cardiac muscle from at-risk abortuses has been accomplished. allowing definitive discrimination of affected and normal fetuses in cases in which deletion analyses and family DNA studies were equivocal. In utero fetal skeletal muscle biopsy for dystrophin protein assay has actually been accomplished in at least one at-risk pregnancy in which family DNA studies were uninformative. Dystrophin was present in skeletal muscle from this 20-week-old male fetus. and the pregnancy continued. resulting in the term birth of a healthy male infant. The future holds exciting opportunities for neonatal screening and treatment of these devastating neuromuscular diseases.
Cardiotoxicity of interferon. A review of 44 cases, Cardiovascular complications have occurred in clinical trials of interferon. We review herein experience to date of cardiotoxicity with all types of interferons in cancer patients. The most common presentations of cardiotoxicity were cardiac arrhythmia. dilated cardiomyopathy. and symptoms of ischemic heart disease. including myocardial infarction and sudden death. The cardiac effects were not related to the daily dose. cumulative total dose. or period of therapy. Some of the patients in whom interferon has caused cardiovascular sequelae have had a history of coronary heart disease or have previously been given chemotherapy with drugs known to be cardiotoxic. In most of the patients. cardiac toxicity was reversible following the cessation of the drug therapy.
Individualized aerobic and high intensity training for asthmatic children in an exercise readaptation program. Is training always helpful for better adaptation to exercise, In order to define the role of individualized training intensity in a conditioning program for asthmatic children. we have trained seven asthmatics (age = 11.4 +/- 1.8 years) at their ventilatory threshold (VTh) intensity level for a three-month period (aerobic training) and at maximal intensity also for three months (high intensity training). VTh is the point at which a nonlinear increase of VE occurs. Another group of seven asthmatics (age = 11.4 +/- 1.5) served as control subjects. Cardiopulmonary fitness was determined on a cycle ergometer before and after each training session. This study demonstrated that aerobic training. correctly adapted to the child's physical ability. induces the following: (1) a rapid and marked cardiovascular fitness increase; and (2) a decrease in VE over a given work range so that VTh is increased. This is of great importance because hyperventilation is a major determinant of exercise-induced bronchospasm. In contrast. even if high intensity training is well tolerated in an indoor swimming pool. the long-term effects are unsuitable for asthmatic children because the decrease of VTh will involve an increase of hyperventilation. even when exercise is performed at submaximal intensity.
Oxygen desaturation during fiberoptic bronchoscopy in pediatric patients, STUDY OBJECTIVE: Pulse oximetry was used to measure arterial oxygen saturation and the extent of hypoxemia in pediatric patients undergoing FB. DESIGN: Arterial oxygen saturation was measured (1) prior to the procedure to provide a baseline value. (2) when the bronchoscope was positioned in the nasopharynx. and (3) when the bronchoscope was positioned in the mid-trachea. SETTING: Fiberoptic bronchoscopy was performed in the Pediatric Special Care Unit or in the Pediatric Pulmonary Laboratory using an Olympus BF3C4 fiberoptic bronchoscope with a 3.5-mm outer diameter. PATIENTS OR PARTICIPANTS: Thirty-six children who underwent diagnostic or therapeutic bronchoscopy for a variety of reasons were evaluated. They ranged in age from 6 to 142 months; 20 were male and 16 were female. INTERVENTIONS: There were no interventions. MEASUREMENTS AND RESULTS: Of the 36 patients. 29 experienced a fall in SaO2 levels exceeding 5 percent of baseline values. The youngest age group. 6 to 12 months. showed the greatest drop in saturation as compared with the other groups. Desaturation was significantly increased by midtracheal FB. CONCLUSIONS: A decline in arterial oxygen saturation that may be substantial in infants and children undergoing FB examination was frequently noted. especially in smaller infants and when the bronchoscope was positioned in the mid-trachea. Supplemental oxygen and a brisk procedure time will minimize the risk of dangerous hypoxia.
Systemic to pulmonary bronchial blood flow in mitral stenosis, We measured systemic to pulmonary bronchial blood flow [Qbr(s-p)] during total cardiopulmonary bypass in 15 patients with mitral stenosis and elevated pulmonary venous pressure (group A. mean pulmonary wedge pressure = 22.2 +/- 5.4 mm Hg. mean +/- SD) and in 15 patients with coronary artery diseases and normal pulmonary venous pressure (group B). Qbr(s-p) is the volume of blood accumulating in the left side of the heart in the absence of pulmonary and coronary flows. This blood was vented through a cannula introduced into the left atrium and measured. Qbr(s-p) was 76.3 +/- 13.9 ml/min (2.18 +/- 0.37 percent of extracorporeal circulation pump flow) and 22.3 +/- 2.1 (0.63 +/- 0.15) in group A and B. respectively (p less than 0.01). During total cardiopulmonary bypass. pulmonary venous pressure is approximately atmospheric pressure. and no differences in systemic blood pressure. extracorporeal circulation pump flow. and airways pressure were observed between group A and B. Therefore. vascular resistance through the bronchial vessels draining into the pulmonary circulation is reduced in patients with mitral stenosis and elevated pulmonary venous pressure.
Changes in left ventricular diastolic filling patterns by Doppler echocardiography in cystic fibrosis, The onset of cor pulmonale is a common terminal finding in patients with cystic fibrosis. Since Doppler echocardiography can detect changes in diastolic filling patterns prior to the onset of either systolic dysfunction or clinical symptoms. we utilized this technique to determine whether detectable changes in left ventricular diastolic filling patterns exist in patients with cystic fibrosis. Among 25 patients. the proportion of left ventricular filling attributable to atrial contraction was significantly increased when compared with age-matched control individuals. When filling patterns were compared with severity of pulmonary disease. worsening pulmonary disease was directly correlated to shifts in left ventricular filling patterns. We conclude that changes in left ventricular patterns of relaxation are detectable early in the course of cystic fibrosis and that such changes are probably progressive. Early detection could lead to therapeutic trials designed to improve left ventricular filling and delay the onset of overt cor pulmonale.
Catheter-induced tricuspid regurgitation. Incidence and clinical significance, The incidence and severity of catheter-induced tricuspid regurgitation has not been studied extensively. Given the frequency with which right heart catheters are employed to measure cardiac output. it is important to know whether the severity of catheter-induced tricuspid regurgitation is sufficient to invalidate the measurement of thermodilution cardiac output. Accordingly. the purpose of the present prospective study was to determine the incidence and severity of catheter-induced tricuspid regurgitation in 25 men (mean age. 58.1 +/- 1.4 years) using Doppler ultrasound. The tricuspid valve was interrogated from two orthogonal views using pulsed-wave and color flow Doppler. either in the presence or absence of a 7-French catheter across the tricuspid valve. The severity of catheter-induced tricuspid regurgitation was graded semiquantitatively using a validated scoring system. Pulsed-wave Doppler studies showed that the incidence of catheter-induced tricuspid regurgitation was 48 percent. and that the average tricuspid regurgitation score increased from 0.41 +/- 0.16 to 0.61 +/- 0.17 (p less than 0.01). Color flow Doppler studies showed similar findings. Further. the incidence of catheter-induced tricuspid regurgitation was not related to the patient's underlying hemodynamic status or right ventricular geometry. In conclusion. this study shows for the first time that the quantitative extent of catheter-induced tricuspid regurgitation is small. and is therefore unlikely to be important clinically. particularly with regard to the assessment of thermodilution cardiac output.
Dacron-woven pacemaker pouch. Influence on long-term pacemaker mobility, Pacemaker migration can interfere with correct pacing system function and patient comfort. A Dacron pouch has been developed which may prevent these problems. To assess the efficacy of the pouch. we measured various factors of pacemaker mobility in 100 patients after long-term follow-up. The patients were divided into three groups on the basis of their dictated operative reports: group 1. no pouch or anchoring stitch; group 2. pouch only; group 3. anchoring stitch to pacemaker header or pouch. The average age of the study population was 74.3 +/- 11 years. Total follow-up time was 42 +/- 28 months (group I. 53 +/- 32 months; group 2. 36 +/- 23 months; group 3. 34 +/- 25 months). There were no significant differences when pacemakers were measured for movement in the inferosuperior and lateromedial directions. nor was there any difference in the distance between the incision scar and the pacemaker header in any group. There was a significant difference between group 1 and groups 2 and 3 when the degree of tilt of the pacemaker off the chest wall was compared. This was 46 degrees +/- 34 degrees for group 1 and 27 degrees +/- 26 degrees and 26 degrees +/- 27 degrees for groups 2 and 3. respectively (p less than 0.02 for both). These data suggest that the Dacron pouch does not restrict pacemaker mobility parallel to the chest wall during long-term follow-up but does reduce the angle to which the pacemaker can be tilted relative to the chest wall.
Patterns of resource consumption in medical intensive care, Intensive care is being scrutinized as a major factor in increasing health care costs. We examined 404 consecutive admissions to the medical ICUs at a university medical center to study patterns of consumption of ICU resources and the proportion of resources used by patients admitted for monitoring only. We found a skewed distribution of ICU resource consumption. with the "high-cost" 8 percent using as many ICU resources as the "low-cost" 92 percent. Forty-one percent of admissions did not receive acute ICU treatments. but these admissions consumed less than 10 percent of ICU resources. Reducing the number of patients admitted for monitoring will have a relatively small impact on hospital charges. Since over 70 percent of the high-cost patients died. improved understanding of prognosis and better physician-patient communication may substantially reduce the proportion of critical care resources expended on futile treatment.
Reversible decrease of oxygen consumption by hyperoxia, The hemodynamic and metabolic effects of 90 minutes normobaric hyperoxia were studied in 20 critically ill patients (11 septic. 9 nonseptic) requiring mechanical ventilation with inspired O2 fraction (FIO2) less than 0.40. Thirty minutes after increasing the FIO2 to 1.0. arterial PO2 had increased from about 100 to about 400 mm Hg. and whole body oxygen uptake (VO2) was decreased 10 percent (p less than 0.05) due to an 18 percent decrease in O2 extraction ratio. During the subsequent 60 minutes of hyperoxia. there was no further significant change in VO2. Cardiac index did not change in hyperoxia. but it increased 10 percent (p less than 0.05) in recovery as systemic vascular resistance decreased. VO2 returned to baseline after 30 minutes recovery at original FIO2 due to increased O2 extraction as well as the increased cardiac output. The decrease in VO2 without a decrease in O2 delivery may reflect maldistribution of blood flow and functional O2 shunting to protect tissue from unphysiologically high PO2. While brief oxygenation is advisable before periods of hypoventilation. the present data suggest that hyperoxic ventilation in these patients with already adequate O2 delivery was counterproductive.
Active vs passive rhythms as an explanation of bigeminal rhythm with similar P waves, We describe the criteria for differential diagnosis between 3:2 sinoatrial block from atrial bigeminy due to an ectopic focus in the sinus or parasinus zone. In the 3:2 sinoatrial block the RR interval of the basic rhythm is similar to the short R-R interval of the paired rhythm. In atrial bigeminy. the R-R interval of the basic rhythm is similar to the long R-R interval of the paired rhythm.
Barium sulfate bronchography. Report of a complication, Alveolarization of the barium sulfate and subsequent retention of barium sulfate for years was demonstrated in three patients in whom dilute suspension of barium sulfate in water was used for bronchography. Pathologic examination in one patient showed barium sulfate within macrophages in the alveolar spaces and walls and in the perivascular and peribronchial interstitium. Since the residual barium sulfate interferes with imaging procedures of the lungs. it represents an unwanted event in patients with pulmonary disease. High-resolution computed tomography is the preferred method of evaluating for bronchiectasis. If bronchogram is performed. it should be performed after bronchoscopy using oily propyliodone (Dionosil).
Sleepwalking precipitated by treatment of sleep apnea with nasal CPAP, A 33-year-old man with a long history of snoring. observed apneic episodes. and excessive daytime sleepiness. underwent all-night polysomnography. which demonstrated severe obstructive sleep apnea. During the nasal CPAP trial. two episodes of sleepwalking were observed during a period of delta sleep rebound.
Management of an extensive tracheoesophageal fistula by cervical esophageal exclusion, Giant tracheoesophageal fistulae occurring in ventilator-dependent patients usually result in significant ventilatory embarrassment. Cervical exclusion of the fistula can safely control the fistula and quickly restore adequate ventilation to these critically ill patients.
Venous air embolism. Diagnosis by spontaneous right-sided contrast echocardiography, This report describes the definitive diagnosis of venous air-embolism by documentation of spontaneous echo contrast in the right cardiac chambers following removal of a jugular venous catheter in a patient with hepatic failure. This complication was potentiated by the presence of concurrent hepatic coagulopathy which prejudiced effective hemostasis at the central venous puncture site.
Medical treatment of esophageal achalasia. Double-blind crossover study with oral nifedipine, verapamil, and placebo, Calcium channel blockers have been previously shown to decrease lower esophageal sphincter (LES) pressure and improve symptoms in achalasia. We performed a placebo-controlled. double-blind. crossover study to assess the effects of oral nifedipine and verapamil on LES pressure. amplitude of esophageal body contraction. and clinical symptomatology in eight patients with symptomatic achalasia diagnosed by endoscopy. barium swallow. and manometry. Patients were randomized to receive up to 20 mg nifedipine. 160 mg verapamil. or placebo and underwent esophageal manometry before (baseline) and after four weeks on each drug. Diary cards were kept to record and grade symptoms and drug plasma level determinations were correlated with manometric and clinical findings. Both nifedipine and verapamil caused a statistically significant decrease in mean LES pressure. but only nifedipine caused a significant decrease in the amplitude of contractions of the smooth muscle portion of the esophagus. No statistically significant differences in the overall clinical symptomatology were noted with any of the drugs. although some individual improvements in dysphagia and chest pain were noted. We conclude that. despite the reduction in LES pressure and contraction amplitude of the distal esophageal body. oral nifedipine and verapamil do not significantly alter the clinical symptomatology of patients with achalasia.
Management of dysphagia in suspected esophageal motor disorders, Fifty-three patients suffering from dysphagia because of suspected esophageal motor disorders were treated by pneumatic dilatation using the Rider-Moeller technique. Fifteen had achalasia demonstrated by manometric studies. Forty-nine of them had remarkable clinical improvement after the procedure. During the mean period of follow-up (average 5 years. range 1-11). 75% of the patients needed a new dilatation. with a delay of two years. The results of the dilatation were excellent or good in 80% of the cases. Early complications consisted in two esophageal perforations surgically treated. There was no mortality. We did not observe late complications of the procedure. We conclude that pneumatic dilatation should be the initial procedure in the treatment of dysphagia in suspected esophageal motor disorders.
Reevaluation of manometric criteria for vigorous achalasia. Is this a distinct clinical disorder, Clinical and manometric data from 97 consecutive patients with idiopathic achalasia were analyzed to see if a distinct subset with vigorous achalasia could be identified. Statistical analyses failed to detect a unique group of subjects based on the distribution of contraction wave amplitudes alone. Because of this. patients falling above the 95th percentile (N = 4. mean wave amplitude greater than 100 mm Hg for each) were compared with those having mean amplitudes above the conventional threshold for the diagnosis of vigorous achalasia (mean amplitude 60-100 mm Hg. N = 4). and with the remainder (N = 89. mean amplitude less than 60 mm Hg). Subjects with mean amplitudes less than 60 mm Hg and with mean amplitudes 60-100 mm Hg closely resembled each other in all measured clinical features. whereas subjects with mean amplitudes greater than 100 mm Hg were all male. were older (67 +/- 4 years vs 47 +/- 2 years; P less than 0.01). and appeared to have somewhat longer duration of symptoms when compared with the remainder (82 +/- 41 vs 44 +/- 10 months; P = 0.4). Chest pain and other esophageal symptoms. basal and residual lower sphincter pressures. and response to first treatment did not differ among the three groups. These data indicate that high-fidelity manometry techniques identify a rare subset of achalasia patients with mean contraction amplitudes exceeding 100 mm Hg that. although older and possibly with greater duration of symptoms. presents similarly to others with idiopathic achalasia. Outcome from conventional treatment is also similar for the "vigorous" and "nonvigorous" patients. making the distinction of questionable value.
Ulcerative colitis disease activity as subjectively assessed by patient-completed questionnaires following orthotopic liver transplantation for sclerosing cholangitis, To assess whether or not liver transplantation and subsequent immunosuppression with cyclosporine and prednisone affect ulcerative colitis symptomatology. we surveyed by questionnaire all 23 surviving patients with pretransplant colonoscopy-documented ulcerative colitis who were transplanted for primary sclerosing cholangitis between June 1982 and September 1985. At follow-up [89.8 +/- 7.6 weeks (mean +/- SEM]. all six patients who had had asymptomatic colonoscopy-documented ulcerative colitis reported continued ulcerative colitis quiescence. Among the 17 patients who had had symptomatic colonoscopy-documented ulcerative colitis at time of liver transplantation. 88.2% reported improvement in overall ulcerative colitis severity (P less than 0.001). with significant improvement in the frequency of bowel movements reported by 100%. in crampy abdominal pain by 87.5%. in bowel urgency by 75%. in the occurrence of pus or mucus in stool by 87.5%. in the incidence of ulcerative colitis flares by 81.8%. and in the number of days unable to function normally due to ulcerative colitis symptoms by 78.6% (all at least P less than 0.01). These data demonstrate that ulcerative colitis symptom severity significantly improves following liver transplantation with immunosuppression with cyclosporine and prednisone.
Alzheimer's disease and related disorders in state mental hospitals: data from a nationwide survey, Notwithstanding three decades of transferring of the elderly to nursing homes. geriatric patients continue to reside in state mental hospitals. Many of these patients. perhaps one-third or more. are thought to suffer from Alzheimer's disease and related disorders (ADRD). This study reports data from a nationwide survey of state hospitals that provides an exploratory look at the ADRD patients currently served in state hospitals. Admission trends. reasons for admission. and sources of referral are described. Civil commitment of nursing home patients with dementing illnesses and the place of the state hospital in the continuum of care for ADRD patients are discussed.
Carbon tetrachloride-induced alterations of hepatic calmodulin and free calcium levels in rats pretreated with chlordecone, Calmodulin. a low molecular weight Ca2+ binding protein. regulates a large number of cell activities including cell division. Previous studies from our laboratory indicated excessive accumulation of Ca2+ in hepatocytes succeeded by rapid glycogen breakdown and suppressed cell division in rats receiving CCl4 after previous dietary exposure to 10 ppm chlordecone. Since calmodulin plays a major role in Ca2(+)-regulated events and has been reported to be localized in mitotic apparatus during cell division. we have assessed subcellular distribution of calmodulin and estimated cytosolic phosphorylase a to indicate cytosolic free Ca2+ levels in livers of rats fed 0 ppm or 10 ppm (chlordecone) in the diet for 15 days before CCl4 (100 microliters/kg) administration to understand the role of Ca2(+)-calmodulin in chlordecone + CCl4 toxicity. Hepatotoxicity was assessed by determining serum AST and ALT succeeded by histopathological observations of liver sections. Serum aminotransferases were significantly elevated 6 hr after CCl4 administration to normal rats and returned to control level by 24 hr. However. serum AST and ALT elevations were severalfold higher. and progressive increase was observed starting 4 hr after CCl4 administration to chlordecone rats. Histopathological observations of liver sections for necrotic. swollen and lipid-laden cells provided findings commensurate with the serum enzyme data. These data indicate that normal rats do recover from CCl4 hepatotoxicity. However. the CCl4 hepatotoxicity is progressive in chlordecone rats without recovery. In normal rats. CCl4 administration resulted in a slight increase in phosphorylase a starting at 6 hr.
Expression of laminin and its receptor LBP-32 in human and rat hepatoma cells, Dramatic cellular changes that occur during hepatocarcinogenesis are associated with major alterations in extracellular matrix formation and in the relationships between cells and their microenvironment. We have studied the expression of laminin. the major noncollagenous glycoprotein of basement membrane. and the laminin receptor 32 kD laminin-binding protein in two rat (Faza 967 and HTC) and two human (HepG2 and HBGC2) hepatoma cell lines that express a variety of liver-specific functions. Laminin was found in the rough endoplasmic reticulum of these cells when the indirect immunoperoxidase method and electron microscopic examination were used. Radiolabeled laminin. immunoprecipitated from both media and cell extracts. was resolved by electrophoresis on sodium dodecyl sulfate gel in two major polypeptides that comigrated with the A and B subunits from Engelbreth-Holm-Swarm tumor laminin. Immunoblot analysis showed that the Mr = 400.000 polypeptide did not correspond to the A subunit of laminin. Northern blot analyses demonstrated large amounts of B1 and B2 mRNAs but no A chain mRNA. We conclude that the tumor cells produce the laminin B chains only. In contrast. normal adult hepatocytes from either man or rat lacked laminin mRNAs. whereas in 1-day primary culture. B chain mRNAs became detectable. The steady-state level of 32 kD laminin-binding protein mRNA was 10-fold and threefold higher in rat hepatoma cells than in freshly isolated and 1-day cultured normal rat hepatocytes. respectively. In human hepatocytes. the steady-state levels of 32 kD laminin-binding protein mRNAs varied depending on the donor and never reached the level of the human hepatoma cells.
Cyclosporine enhances the growth of carcinogen-induced enzyme-altered foci in rat liver, Cyclosporine. a powerful immunosuppressant. has been used successfully for organ transplantation. Its efficacy on liver transplants of patients with primary hepatic tumors remains controversial because of a high rate of recurrence of the original tumors in the transplanted livers. In this study. we experimentally tested whether cyclosporine exerts any effects on the growth of carcinogen-initiated liver cells using the short-term assays of rat liver carcinogenesis. Dietary cyclosporine. which maintained sufficient levels of blood cyclosporine and suppressed host immune functions. enhanced the development of the glutathione S-transferase. placental form-positive hepatocyte foci in the liver of male F-344 rats treated with a single weekly dose of diethylnitrosamine (75 mg/kg) for 3 wk. Dietary cyclosporine also accelerated the growth of preformed glutathione S-transferase. placental form-positive foci induced by a single dose of diethylnitrosamine (250 mg/kg) followed by the promoting regimen of a choline-deficient diet. It is possible that the enhancement of the size of hepatocyte foci by cyclosporine could be due to stimulation of growth or inhibition of regression. The mechanisms by which cyclosporine modifies the growth of preneoplastic lesions in the liver are not yet fully understood. Possible involvement of immunologically relevant cells in the liver. Kupffer cells and pit cells in the process is suggested.
Hepatitis B virus integration in hepatitis B virus-related hepatocellular carcinoma in childhood, In Taiwan. hepatocellular carcinoma is one of the major malignancies in children between 5 and 14 yr of age. We studied the status of hepatitis B virus DNA in the hepatocellular carcinoma and nontumorous liver tissues of eight children with positive serum HBsAg and maternal HBsAg. The hepatocellular carcinoma tissues from five of the eight children showed integration of hepatitis B virus DNA into host cellular DNA sequences. A pattern of single-site integration in four children and a multiple-site integration pattern in one child were demonstrated. In the remaining three children. hepatitis B virus DNA could not be demonstrated in the tumor tissues. Using subgenomic fragments of the hepatitis B virus genome as probes. we found that the X gene fragment and the surface antigen gene fragment were the most conserved sequences. The single-site integration of hepatitis B virus DNA in childhood hepatocellular carcinoma may have hit the critical region. resulting in insertional mutagenesis and early development of hepatocellular carcinoma. With a short incubation period and less exposure to environmental carcinogens during early life. childhood hepatocellular carcinoma may provide a good model to study the carcinogenic potential of hepatitis B virus.
The 1990 Everett Idris Evans memorial lecture: the inhalation injury, The most important question that had to be answered from our animal data was whether a significant difference existed between the two groups. It could be observed that the resuscitation with Ringer's lactate did not lead to any increased lymph flow or total transcapillary protein flow in spite of the drop in protein and oncotic pressure in plasma. With Ringer's lactate there was a lower lymph to plasma protein ratio. which might be significant. No negative difference could be observed either in the pulmonary capillary wedge pressure or pulmonary vessel resistance. All animals survived throughout the experiment. and in all experiments no advantages regarding the vital parameters could be ascertained with the administration of albumin; however. several factors must be borne in mind. The inhalation injury was from a heat source alone and no toxic substances were involved. Only inhalation trauma was induced in the absence of a surface burn wound. The duration of the observation was for only 36 hours. Thus some caution must be observed in applying these findings to a clinical situation. In our evaluation of the clinical results. we have seen that no differences could be established in regard to pulmonary capillary wedge pressure and extravascular lung water between the Ringer's lactate and the albumin group. In spite of a 50% drop in oncotic pressure. however. this is only valid for the first 24 to 36 hours. after which one could assume that a further protein drop coupled with a still raised hydrostatic filtration coefficient would lead to interstitial edema.
Persistence of fetal bovine serum proteins in human keratinocytes, Cultured human keratinocytes are used for skin grafts. but their success is limited by late graft loss. Development of antibody to fetal bovine serum (FBS) protein used in culture media for in vitro keratinocyte growth has been identified. The persistence of FBS antigen in skin grafts is important in the induction of the immune response and the susceptibility of the keratinocytes to immune-mediated injury. The magnitude and longevity of FBS protein persistence on human keratinocytes was studied. Secondary passage human keratinocytes were grown in media supplemented with 5% FBS. The media was changed to one supplemented with pooled human AB serum. and the amount of FBS protein incorporated in the tissue was measured over the following 8 days by an ELISA reaction directed against FBS antigen. Incorporated FBS antigen decreased for the first 3 days to 31% of maximum. There was no further significant decrease for 5 days. Keratinocytes grown in alternative serum supplements (NuSerum [Collaborative Research Inc.. Bedford. Mass.] and Serum Plus [Hazelton Research Products Inc.. Lenexa. Kan.]). which contain reduced amounts of FBS. offered no significant reduction in FBS protein incorporation. This duration of antigen persistence would make human keratinocytes susceptible to cell destruction by immune response to FBS and may contribute to delayed loss of human keratinocyte grafts.
Time course of alterations in lung lymph and bronchial blood flows after inhalation injury, The effects of inhalation injury on the pulmonary microvascular fluid flux and bronchial blood flow were examined in a long-term study of sheep (N = 13). They were insufflated with either 48 breaths of cotton smoke (n = 8) or air (n = 5) while they were deeply anesthetized with halothane. After injury. anesthesia was discontinued and the animals were mechanically ventilated throughout the experimental period (24 hours). Bronchial blood flow increased significantly at all time points recorded and reached its peak 20 minutes after the inhalation trauma (11 +/- 1 ml/hr to 106 +/- 18 ml/hr; p less than 0.05). Thereafter. bronchial blood flow decreased to a value that was six to eight times above the baseline measurement for the remainder of the study period. With these changes in blood flow. there was a concomitant increase in lung lymph flow. This variable gradually increased and was 633% of the baseline value (6 +/- 1 ml/hr to 44 +/- 8 ml/hr) 24 hours after the challenge with smoke. The control animals showed little or no change in cardiopulmonary function during the experimental period. There is no correlation between the increase in bronchial blood flow and lung lymph flow patterns after cotton smoke inhalation injury.
Elevated serum aluminum levels in severely burned patients who are receiving large quantities of albumin, Aluminum contaminates various fluids that are used in intravenous therapy. and it is associated with bone disease and encephalopathy. Albumin is highly contaminated with aluminum. which is eliminated primarily by renal excretion. Patients with burns receive large quantities of albumin and have impaired renal function. which puts them at hypothetical risk for aluminum loading. To assess the risk of aluminum loading we analyzed sera from 12 patients with burns for aluminum concentrations. Serum aluminum concentration was elevated in 8 of the 12 patients. and levels were at or near toxicity in 3 of the 8. Serum aluminum and serum creatinine levels directly correlated. r = 0.71 and p less than 0.005. No relation was found between serum aluminum and amount of albumin received. However. patients with the highest serum aluminum levels were the most severely burned and none survived. Thus patients with burns who are receiving albumin are at risk for aluminum loading. Impaired renal function contributes to aluminum retention.
The effect of thromboxane synthetase inhibition on cardiopulmonary function during endotoxemia in sheep, The early pulmonary hypertension seen with endotoxin (lipopolysaccharide) has been reported as resulting from the release of thromboxane A2. We studied the cardiopulmonary response to endotoxin in sheep with and without treatment with a thromboxane synthetase inhibitor. OKY-046. The animals were implanted with instruments for crystallographic dimension analysis of the left ventricle and measurement of left ventricular. aortic. left atrial. and pulmonary arterial pressures and cardiac index. Thirteen sheep received 1.0 micrograms/kg of Escherichia coli endotoxin with (n = 6) and without (n = 7) OKY-046 (10 mg/kg bolus. then 10 micrograms/kg/min). OKY-046 prevented the increase in pulmonary arterial pressure and decrease in cardiac index usually seen during the early phase of endotoxemia. Between 8 and 12 hours after the administration of endotoxin. cardiac index increased from 6.4 +/- 0.8 to 8.4 +/- 0.8 L/min/m2. Concomitantly. the end-systolic pressure/diameter relationship (a sensitive myocardial contractility index) significantly decreased from 14.7 +/- 0.6 to 7.7 +/- 0.7 mm Hg/mm. Another index of the left ventricular contractility. the maximum rate of pressure rise was also reduced. OKY-046 prevented decreases in end-systolic pressure/diameter relationship and maximum rate of pressure rise.
Observations on stability and contraction of composite skin grafts: xenodermis or allodermis with an isograft overlay, Composite skin grafts of xenodermis or allodermis with a thin split-thickness isograft overlay were evaluated for stability and contraction. Male inbred Lewis rats were used as recipients. with Buffalo rats serving as allogeneic dermis donors. Cryopreserved human skin was used for xenodermis grafts. The two components of the composite graft. the xenodermis or allodermis and the isograft overlay. were grafted in one operation to a surgically created wound. Wounds were observed for 1 year. The composite skin grafts took fairly well. although spotty loss of the overlaid isograft was noted. The xenodermis and allodermis remained grossly intact even at 1 year after grafting. However. composite skin grafts in this animal model contracted more than did sheet isografts alone.
Burns from hot oil and grease: a public health hazard, We examined the incidence. etiology. and morbidity of burns due to hot oil and grease. Over a 10-year period from 1976 to 1985. of 1818 patients hospitalized for burns. 85 (4.7%) injuries were due to hot grease or oil. The mean age was 20 years; 34% of patients were less than 8 years old. The mean total body surface areas of second- and third-degree burns was 11.5% (range 0.5% to 40%). and the average length of hospital stay was 19.6 days. Fifty-eight percent of patients required split-thickness skin grafting (n = 49). three required intubation. and one required tracheostomy. Seventy-eight percent of oil burns occurred in the home. The most common circumstances consisted of children who grabbed the handle or electric cord of a frying pan and pulled the hot oil down onto themselves. (Nineteen of the 29 children were less than 8 years old (66%).) Burns due to cooking oil and grease are associated with considerable morbidity. The high boiling point. high viscosity. and potential combustibility of oil increase the potential soft-tissue damage when compared with typical scald injuries from hot water. The dangers of children pulling on the appliance. the dangers of transporting hot oil. the importance of supervision while children are cooking. and the importance of knowledge of the management of grease fires is stressed. Public education is needed to underline the potential seriousness of these burns.
A descriptive summary of New Jersey's 1985 burn population, Data obtained from the New Jersey State Department of Health on the 1985 hospitalized patients with burns and data collected from the National Burn Victim Foundation's standard burn reporting form were analyzed to gather information about the epidemiology of burns. Children (0 to 4 years of age) continue to be the largest percentage of the 0- to 18-year-old age group who sustain burn injuries. and 67% of those injuries are sustained by children under the age of 5. Males accounted for 69% of the total burn population; 58% of admissions were white; 69% of patients were admitted for partial-thickness burns. and 31% were admitted for full-thickness burns; the largest primary payer was third-party payers; and 92% of patients with burns were discharged to home or self-care. Data were also analyzed by examination of selected age groups to determine individual needs of specific groups. An analysis of burn injuries reported to the National Burn Victim Foundation confirmed previous reports that the home is the most likely place for a burn injury to occur and that flame and scald injuries predominate; scald injuries comprise 50% of all sustained burns. Gasoline vapors accounted for 54% of burn injuries caused by flames. The data supported efforts to develop programs that address the needs of the urban child. the 17- to 19-year-old age groups. and the elderly. The information that was collected served to redefine objectives for burn prevention programs.
Cytomegalovirus infection in sexually active adolescents, To determine whether cytomegalovirus (CMV) infection in teenage girls is related to sexual activity. 254 girls 12-18 years old (mean. 15.8) attending a contraceptive counseling clinic were studied. Participants were screened for Chlamydia trachomatis. Neisseria gonorrhoeae. and Trichomonas vaginalis. and serum antibody to CMV was determined. Demographic and sexual history data were collected by interview. The mean number of lifetime sex partners was 2.2; 173 (68%) were seropositive. Race. greater than 3 years of sexual activity. and greater than 2 lifetime sex partners were significant risk factors for CMV infection (odds ratios [OR]. 1.8-4.7; P less than .05). Using logistic regression analysis. a composite sexual activity variable was the most important risk factor for CMV infection (OR. 4.8; P = .003). followed by race (OR. 3.4; P = .004) and a sexually transmitted disease composite variable (OR. 2.4; P = .016). Sexual activity is an important risk factor for CMV infection in adolescent girls.
Pattern of respiratory syncytial virus epidemics in Finland: two-year cycles with alternating prevalence of groups A and B, Time-resolved fluoroimmunoassay with monoclonal antibodies distinguishing between respiratory syncytial virus (RSV) group A and B strains was used to analyze their prevalence in Finland during 1981-1990 among 3285 patients with laboratory diagnosis of RSV. most of them hospitalized. The group typing of antigens in 608 RSV-positive nasopharyngeal aspirates showed a regular alternation of group prevalence. following the cyclic occurrence of the virus. Group A predominated in 73%-90% of specimens from 1981-1982. 1985-1986. and 1989-1990. whereas group B predominated in 70%-100% of specimens from 1983-1984 and 1987-1988. The epidemiologic occurrence of verified reinfections in hospitalized children and the group typing results indicated that children greater than 6 months of age during the first infection were more resistant to severe reinfection with the homologous than with the heterologous group of virus. The study shows that group antigenic variation of RSV has a significant effect on the epidemiology of the virus.
The role of passive immunity in bovine respiratory syncytial virus-infected calves, The role of passive immunity in bovine respiratory syncytial virus (BRSV) infections in neonatal calves was evaluated. Calves were divided into groups as follows: colostrum-deprived. sham-inoculated; colostrum-deprived. BRSV-inoculated; and colostrum-fed. BRSV-inoculated. Calves were inoculated with a low-passage field isolate of BRSV for 4 consecutive days by a combined respiratory tract route and were euthanized 6 days after receiving the last inoculation. Arterial oxygen tension (Pao2) decreased significantly over time in colostrum-deprived. BRSV-inoculated calves (P less than .01) and was significantly different among treatment groups (P less than .05). A significant decrease in arterial oxygen saturation was observed in this same group over time (P less than .01). Mean percentage of pneumonic lung volume (determined by computer data digitalization) was significantly greater in infected. colostrum-deprived calves compared with the other groups (P less than .01). and BRSV antigen was detected in these calves by avidin-biotin immunoperoxidase staining. Thus. passive immunity derived from colostrum feeding decreased the severity of BRSV infections in calves.
Differences in the membrane interaction of scrapie amyloid precursor proteins in normal and scrapie- or Creutzfeldt-Jakob disease-infected brains, The membrane interaction and hydrophobicity of the normal (PrPC) and infectious isoform (PrPSc/CJD) of scrapie and Creutzfeldt-Jakob disease amyloid precursor proteins was studied. The normal isoform of hamster and human scrapie amyloid precursor protein was found on the microsomal/synaptosomal membranes anchored solely by the C-terminal glycolipid. Glycolipid cleavage resulted in dissociation from the membranes and change of behavior from a highly hydrophobic to a hydrophilic protein. susceptible to proteases. In contrast. the PrPSc/CJD isoform was resistant to release by glycolipid-cleaving enzymes. A part of PrPSc/CJD was released from the membranes after prolonged trypsin treatment. yielding a further protease-resistant product of 27-30 kDa. The results demonstrate the proteolytic resistance of the membrane-bound PrPSc/CJD isoform and also indicate the presence of a different. apparently disease-induced mechanism of membrane interaction in the scrapie- and CJD-infected microsomal and synaptosomal membranes.
Immune responses to Bordetella pertussis infection and vaccination, To assess antibody and cellular immune responses. 156 healthy children were immunized at approximately 18 months of age with acellular diphtheria-tetanus-pertussis vaccine. Changes in antibody responses to filamentous hemagglutinin (FHA) and to pertussis toxin (PT) were similar in pattern. and antibody titers reached values equal to those from patients with convalescent-stage pertussis. The FHA-induced DNA synthesis in peripheral blood mononuclear cells was maximum at 4 weeks after the primary series. and these levels were equal to those of patients with pertussis. High amounts of PT-induced DNA synthesis were observed in both immunized and nonimmunized children; thus. PT seemed to act mainly as a nonspecific mitogen. Almost the same responses to several mitogens that activate different subsets of lymphocytes were observed in young infants compared with older children. Furthermore. young infants who had Bordetella pertussis infection responded by FHA stimulation almost as well as older children.
Serologic diagnosis of human ehrlichiosis using two Ehrlichia canis isolates, Ehrlichia canis or a closely related rickettsial organism has been implicated serologically and morphologically as the causative agent of human ehrlichiosis in the United States. Although E. canis has been serially propagated in primary canine monocytes. only a limited quantity of antigen is obtained by this method. A continuous canine macrophage cell line. DH82. supports the growth of a new isolate of E. canis established from the whole blood of a carrier dog in Oklahoma. Serologic comparison of the Oklahoma isolate in the continuous canine cell line with a Florida isolate in commercial antigen slides revealed 100% specificity and 87.5% sensitivity.
Clinical disease, drug susceptibility, and biochemical patterns of the unnamed third biovariant complex of Mycobacterium fortuitum, Previous studies of Mycobacterium fortuitum identified isolates that did not fit its two recognized biovariants. Eighty-five clinical isolates of this group. the "third biovariant complex". were evaluated. They represented 16% of 410 isolates of M. fortuitum submitted to a Texas laboratory and 22% of 45 isolates in Queensland. Australia. Most infections (76%) involved skin. soft tissue. or bone and occurred after metal puncture wounds or open fractures. Isolates differed from biovar fortuitum in resistance to pipemidic acid and use of mannitol and inositol as carbon sources. Two subgroups were present. and examples were deposited in the American Type Culture Collection. Isolates were resistant to doxycycline and one-third were resistant to cefoxitin. All were susceptible to amikacin. ciprofloxacin. sulfamethoxazole. and imipenem. Surgical debridement combined with drug therapy based on in vitro susceptibilities resulted in cures of cutaneous disease or osteomyelitis. DNA homology studies are needed to determine the taxonomic status of these organisms.
Immunoglobulins A, G, and M to cytomegalovirus during recurrent infection in recipients of allogeneic bone marrow transplantation, Occurrence and significance of specific IgA and IgM to cytomegalovirus (CMV) in recurrent CMV infection was evaluated in 21 allogeneic T lymphocyte-depleted bone marrow transplantation (BMT) recipients who had been previously CMV seropositive. Of 17 patients with CMV infection. viruria was detected in 94%. CMV-specific IgA in 88% and IgM in 76%. and a fourfold rise in IgG in 65%. The median time between BMT and detection of viruria was 69 days. of IgA 70. of IgM 62. and of IgG 88 days. The IgM and IgA responses lasted for 14 and 30 days (median time). whereas high IgG titers persisted. Twelve patients developed CMV disease; in these the appearance of viruria. IgA. and IgM preceded the rise of IgG (P less than .02). CMV-specific IgA and IgM are valuable diagnostic tools in BMT recipients with recurrent CMV infection.
Urinary phenolic glycolipid 1 in the diagnosis and management of leprosy, A simplified assay to measure the phenolic glycolipid 1 (PGL-1) of Mycobacterium leprae in the urine was applied to the diagnosis of leprosy and the monitoring of antileprosy chemotherapy. One hundred seventy-nine previously untreated patients and 25 normal controls were tested. The specificity of the assay was 100%. There were no false-positive results. The sensitivity of the assay varied with the type of leprosy from 92% for lepromatous leprosy to 56% for borderline lepromatous and 18% for borderline tuberculoid patients. After the onset of chemotherapy in lepromatous leprosy patients. there was often a transient increase of urinary PGL-1. followed by a steady decline. Within 3 months of multiple drug therapy. urinary PGL-1 levels were reduced by 90%-99% and were often undetectable. This assay appears to have considerable potential for monitoring chemotherapy and detecting treatment failure and relapse in patients with Hansen's disease.
No detection of characteristic fungal protein elongation factor EF-3 in Pneumocystis carinii, The taxonomic status of Pneumocystis carinii is uncertain. and P. carinii has been categorized both as a fungus and as a protozoan. Recent comparisons of RNA sequence homologies between P. carinii and several genera of fungi and protozoa suggest that P. carinii has closer affinities with the ascomycetes than with the protozoa. The translatory systems of the fungi. however. require three soluble protein factors for peptide chain elongation rather than the two necessary in other eukaryotic systems; to date the additional protein elongation factor (EF-3) appears to be unique to fungi. Western blot analysis of cell-free extracts of P. carinii. derived from rat. was done using a polyclonal antibody raised in rabbits to Saccharomyces cerevisiae EF-3. Anti-EF-3 cross-reacting material was detected only in lysates of Candida albicans and S. cerevisiae included as fungal controls; no cross reaction was detected in lysates of P. carinii. P. carinii-infected rat lung. or a protozoan control (Trichomonas vaginalis).
Drugs and femoral neck fracture: a case-control study, Two hundred consecutive patients with femoral neck fractures (FNF) and 200 controls matched by age. sex. nursing home residency and number of admissions within the last 2 years. were interviewed about recent drug use. The matching criteria were chosen to achieve case and control groups that were comparable with regard to overall physical disability. Thus a preliminary study had shown FNF to be strongly associated with nursing home residency and to be correlated with the number of recent hospital admissions. FNF was found to be negatively associated with use of coronary drugs (OR = 0.27; 95% CI = 0.11-0.70) and positively associated with drug use in general (OR = 2.00; 95% CI = 1.04-3.05). The OR for the various classes of psychotropic drugs was consistently greater than 1.. although this was not statistically significant. An inherent problem in interpreting such findings is that underlying disease may predispose the subject to both FNF and drug use. thus creating a non-causal relationship.
Combined zidovudine and interferon-alpha treatment in patients with AIDS-associated Kaposi's sarcoma, The effectiveness of addition of interferon-alpha (IFN-alpha) to zidovudine in patients with AIDS-associated Kaposi's sarcoma was assessed in a non-randomized. phase II clinical trial. Twenty-one patients were treated with oral zidovudine (600 mg daily) and IFN-alpha was increased to 18 MU daily for another 4 weeks. Only one of the 20 evaluable patients achieved a partial response at 8 weeks. that lasted for 3 months. Despite IFN-alpha dose escalation in six patients. no further responses were seen. While myelotoxicity was mild. fatigue was the dose-limiting side-effect that prevented dose escalation in seven eligible patients. The combined treatment did not result in a decrease in HIV-Ag. In summary. our results indicate that the addition of IFN-alpha to zidovudine in patients with AIDS-associated Kaposi's sarcoma is not an efficacious treatment.
A form of familial hypobetalipoproteinaemia not due to a mutation in the apolipoprotein B gene, Familial hypobetalipoproteinaemia (FHBL) is a dominant disorder of lipoprotein metabolism characterized by levels of apolipoprotein B-carrying lipoproteins (VLDL. IDL and LDL) which are 50% of the normal levels in the heterozygotes and almost absent in the homozygotes. Several reports have recently shown that the underlying defect in FHBL involves different mutations in the apo B gene which lead to reduced levels of apo B mRNA or to the production of truncated forms of apo B having either a lower synthetic rate or a higher catabolic rate than normal apo B. We here present a three-generation family with several FHBL members in which the linkage analysis shows absence of co-segregation between apo B gene alleles and the hypocholesterolaemic phenotype. We conclude that a dominantly transmitted mutation in a gene other than that for apo B is responsible for the low plasma cholesterol levels.
A double-blind gastroscopic evaluation of the effects of etodolac and naproxen on the gastrointestinal mucosa of rheumatic patients, The aim of this clinical. endoscopical study was to evaluate the therapeutic efficacy and the gastric tolerability of etodolac. a new anti-inflammatory. non-steroidal drug. compared with naproxen. The study was conducted on 48 patients suffering from rheumatoid arthritis. 44 of whom completed the trial. After an initial oesophagogastroduodenoscopy to exclude the presence of gastric mucosal lesions. patients were randomly allocated to double-blind treatment with either etodolac 200 mg b.i.d. or naproxen 500 mg b.i.d. for a period of 4 weeks. Endoscopic control followed this treatment period. Both drugs proved effective in relieving clinical symptoms. without a statistically significant difference. Gastric mucosal lesions were observed in 15% of etodolac-treated patients and in 46% of patients treated with naproxen (P less than 0.05) (95% CI 0.01-0.60). Painful dyspepsia was observed in 15% of patients treated with etodolac vs. 38% of patients on naproxen therapy. This study demonstrates that etodolac is at least as active as naproxen in relieving rheumatic symptoms. and its administration results in a significantly lower degree of gastric damage.
Pancreatic autoantibodies and pancreatic function in Sjogren's syndrome, Pancreatic autoantibodies were determined in 49 patients with Sjogren's syndrome and related to functional parameters. Pancreatic duct autoantibodies (PDA) were detected in the sera of three patients. and all showed abnormal exocrine pancreatic function. Islet cell antibodies (ICA) were not detected in the sera of the 49 patients. including two individuals with diabetes mellitus. In conclusion. PDA occur in patients with Sjogren's syndrome. and may be associated with exocrine pancreatic dysfunction.
Prophylactic effect of self-administered pump-driven subcutaneous IgG infusion in patients with antibody deficiency: a triple-blind cross-over study comparing P-IgG levels of 3 g l-1 versus 6 g l-1, Eight adult patients with hypoimmunoglobulinaemia were randomly allocated to initiation of low- or high-level IgG-substitution. IgG was administered subcutaneously. at 50 or 150 mg ml-1. 20 ml per infusion. by means of a pocket-portable electric infusion pump. Infusions were given 2 to 4 times weekly for 24 months. with a change of dose regimen after 12 months. The desired plasma IgG levels were reached after a mean lag phase of 3 months (range 1-5 months). The median (and ranges) of the individual mean plasma IgG levels during the ensuing 9-month periods were as follows: high-level period. 6.5 g l-1 (range 6.2-7.8 g l-1); low-level period. 3.2 g l-1 (range 3.0-4.0 g l-1). During the high-level period. compared to the low-level period. there was a significant decrease in the following parameters: 'days in bed at home'. 'days missed work' and 'days with fever'. No serious side-effects were observed. It is concluded that a plasma IgG concentration of 6 g l-1 can readily be achieved by subcutaneous IgG substitution. and the prophylactic effect is superior to that obtained with a plasma IgG concentration of 3 g l-1.
Platelet fatty acids and function in two distinct regions of Belgium: relationship to age and dietary habits, We compared the dietary habits. fatty acid composition of plasma and platelet phospholipids. and platelet function in two groups of healthy Belgian male subjects. known to differ in their mortality rate from coronary heart disease (CHD). In the Walloon subjects. there was a larger intake of saturated and a lower intake of (n-6) polyunsaturated fats. confirmed by the fatty acid composition of plasma and platelet phospholipids. While plasma HDL and total cholesterol were similar in the present samples of the two communities. platelet aggregation to epinephrine was significantly higher in the Walloon subjects. When the two populations were divided into younger (28-54 years) and older (55-73 years) age groups. the older Walloon subjects exhibited platelet hyper-aggregability to most of the agonists. compared to the other three groups. In addition to dietary fats. alcohol and smoking habits. age was an important determinant of platelet phospholipid fatty acids and platelet reactivity. The present results reinforce those of previous studies. indicating that platelet behaviour is significantly affected by the main risk factors for CHD.
Hypoglycaemic episodes during intensified insulin treatment: increased frequency but no effect on cognitive function, Ninety-seven patients with insulin dependent diabetes mellitus (IDDM) were randomized to intensified conventional treatment (ICT. n = 44) or regular treatment (RT. n = 53). The mean HbA1c level (+/- SEM) was reduced from 9.5 +/- 0.2% to 7.4 +/- 0.1% in the ICT group (P less than 0.001). and from 9.4 +/- 0.2% to 9.0 +/- 0.2% (P less than 0.01) in the RT group. The difference between the groups was significant (P less than 0.001). During a period of 3 years. 57% of the ICT patients (95% confidence interval 44-73%) and 23% of the RT patients (95% CI. 11-34%) (P less than 0.001) had at least one episode of serious hypoglycaemia. with the need for third-party assistance or resulting in coma. Eighteen of the 32 ICT patients who initially had adrenergic symptoms during hypoglycaemia changed to predominantly neuroglycopenic symptoms. This was the case with only 8 of 38 RT patients (P less than 0.01). The change in symptoms was related to the increased frequency of serious hypoglycaemia. but neither symptoms nor frequency of hypoglycaemia bor any relationship to insulin dose. body mass index. duration of diabetes or autonomic nerve function. The results of several neuropsychological tests did not differ between the groups at baseline. and did not change during the study. There were no signs of deteriorating cognitive function in the patients with serious hypoglycaemic episodes.
The intrauterine device and pelvic inflammatory disease: the Women's Health Study reanalyzed, The Women's Health Study (WHS) was a large. widely accepted and influential case-control study of the relationship between the use of intrauterine contraceptive devices (IUDs) and pelvic inflammatory disease (PID). The data were collected at 16 hospitals in 9 cities across the U.S.A. from October 1976 through August 1978. The first paper on this research was published in 1981 and concluded that IUDs increase the risk of PID. The report cited an estimated RR (relative risk) of PID for current IUD users vs nonIUD users of 1.6 with a 95% confidence interval of (1.4. 1.9). However. careful examination of the report reveals that the data support conclusions antithetical to those at which the author arrived. When the second report on the WHS was published in 1983. it was anticipated that many of the shortcomings of the first report would be corrected. but they were not. In 1983 we undertook a complete reanalysis of the same WHS data using more appropriate criteria and the results were compared to the first two published reports. The reanalysis revealed an RR of 1.02 (0.86. 1.21) for current IUD users compared to noncontraceptors. The conclusion of the WHS should have been that IUDs do not increase the risk of PID.
Meta-analysis in epidemiology, with special reference to studies of the association between exposure to environmental tobacco smoke and lung cancer: a critique, Meta-analysis. a set of statistical tools for combining and integrating the results of independent studies of a given scientific issue. can be useful when the stringent conditions under which such integration is valid are met. In this report we point out the difficulties in obtaining sound meta-analyses of either controlled clinical trials or epidemiological studies. We demonstrate that hastily or improperly designed meta-analyses can lead to results that may not be scientifically valid. We note that much care is typically taken when meta-analysis is applied to the results of clinical trials. The Food and Drug Administration. for example. requires strict adherence to the principles we discuss in this paper before it allows a drug's sponsor to use a meta-analysis of separate clinical studies in support of a New Drug Application. Such care does not always carry over to epidemiological studies. as demonstrated by the 1986 report of the National Research Council concerning the purported association between exposure to environmental tobacco smoke and the risk of lung cancer. On the basis of a meta-analysis of 13 studies. 10 of which were retrospective and the remaining 3 prospective in nature. the Council concluded that non-smokers who are exposed to environmental tobacco smoke are at greater risk of acquiring lung cancer than non-smokers not so exposed. In our opinion. this conclusion in unwarranted given the poor quality of the studies on which it is based.
The impact of breakthrough clinical trials on survival in population based tumor registries, Three statistical models are developed to study the impact that two breakthrough clinical trials (MOPP for Hodgkin's disease and PVB for disseminated testicular cancer) had on survival in the Connecticut tumor registry and the National Cancer Institute's Surveillance. Epidemiology. and End Results (SEER) registry program. A segmented regression model is used in conjunction with the Cox semi-parametric proportional hazards model. as well as the parametric Weibull and exponential cure models. These models allow us to determine approximately when survival first began to improve dramatically. indicating that improved treatments had become available. and how long it took for survival to level off again indicating that the full population survival impact had been realized. In addition. the degree to which the parametric models fit allows us to determine if the survival improvements occur within a parametric family. Results of the modelling indicate that dissemination took approximately 11 years in Hodgkin's disease while only 3 years in disseminated testicular cancer. In both disease sites survival first broke with prior trends between the time that the breakthrough trial started and its publication. indicating that earlier moderately successful 'precursor' trials with combination chemotherapy may have initiated the improved population survival trends. Reasons for the difference in dissemination time in the two cancer sites are examined in order to understand what factors may be responsible for the speed of dissemination and effective utilization of new therapies.
Low zinc intake affects maintenance of pregnancy in guinea pigs, Zinc deficiency during pregnancy has severe effects in animals. To what extent the effects in animals apply to human pregnancy is not known. Because the pregnant guinea pig shares characteristics with pregnant women that make it a useful model. three experiments were done with guinea pigs in which Zn intake was reduced beginning on the 30th d of gestation. Reduced Zn intake in two of the three experiments resulted in abortion or premature delivery. Zinc-supplemented animals with feed intake restricted to that of Zn-deficient animals also aborted or delivered prematurely. Zinc-supplemented animals fed for ad libitum access delivered living young at term. Fetal/neonatal liver Zn concentration was low in the guinea pigs compared to that reported for other animals and was affected to a lesser extent by low Zn intake by the dam. Zinc concentration of neonatal plasma was also less than that in several other species. Change in activity of angiotensin-converting enzyme with addition of Zn in vitro was greater in the plasma of Zn-deficient guinea pigs than in that of Zn-adequate guinea pigs and may be useful as an indicator of Zn status.
Short-term effects of dehydroepiandrosterone treatment in rats on mitochondrial respiration, Administration of dehydroepiandrosterone (DHEA) to rats results in alterations in liver and serum factors. This study was undertaken to determine the earliest metabolic change(s) associated with DHEA treatment. Serum cholesterol. triacylglycerol. glucose. insulin. glucagon. thyroid hormones and hepatic glucose-6-phosphate dehydrogenase activity were. in general. unaltered in obese Zucker rats after 7 d and 24. 12 and 3 h of DHEA treatment. Malic enzyme. long-chain fatty acyl-coenzyme A hydrolase and catalase activities and peroxisomal beta-oxidation rates were elevated after 7 d and 24 h in DHEA treatment. but not after 12 h. Mitochondrial beta-oxidation was not altered. Hepatic mitochondrial state 3 respiration per g liver with glutamate-malate was elevated after 7 d and 24. 12 and 3 h in DHEA-treated rats and was elevated per mg protein except after 7 d. Succinate-supported state 3 respiration per g liver was also elevated after 7 d and 24 and 12 h of DHEA treatment. Mitochondria from rats treated for 7 d had lower levels of cardiolipin and phosphatidylethanolamine and an increase in phosphatidylcholine. Changes in fatty acid composition of these phospholipids occurred after 7 d and 24 h of DHEA treatment. In an additional study. rats were treated with DHEA or DHEA plus ethidium bromide for 3 d. Ethidium bromide inhibited the increase in mitochondrial protein and respiration associated with DHEA treatment. These findings indicate that mitochondrial respiration is the earliest factor affected by DHEA and may be associated with protein synthesis.
Endotoxin and lipid peroxidation in vivo in selenium- and vitamin E-deficient and -adequate rats, The effect of Salmonella typhimurium endotoxin injected intraperitoneally (0.5 mg/kg body weight) on lipid peroxidation in vivo was assessed. Peroxidation was monitored by measuring ethane production. an autoxidation product of (n-3) unsaturated fatty acids. Weanling rats were fed a selenium- and vitamin E-deficient basal diet or one supplemented with 0.2 mg Se/kg and/or 200 mg vitamin E/kg. After 11 to 13 wk of feeding. ethane production was tripled in LPS-treated Se- and vitamin E-deficient rats compared to saline-treated deficient rats. In both doubly deficient and adequate rats. LPS increased ethane production. but it did so to a greater extent in Se- and vitamin E-deficient rats. Dietary Se or vitamin E supplementation alone significantly reduced ethane production from LPS-treated rats. Vitamin E was more protective than Se against LPS-induced lipid peroxidation. Escherichia coli and Salmonella minnesota LPS also increased ethane production in Se- and vitamin E-deficient rats. These results show that low doses of LPS stimulate lipid peroxidation in vivo in Se- and vitamin E-deficient rats.
Endotoxin and lipid peroxidation in vitro in selenium- and vitamin E-deficient and -adequate rat tissues, The effect of Salmonella typhimurium endotoxin injected intraperitoneally into rats (0.5 mg/kg of body weight) on subsequent lipid peroxidation in vitro was assessed. Peroxidation was monitored by measuring ethane production from tissue slices. as well as thiobarbituric acid-reactive substances and conjugated dienes in tissue homogenates. Weanling rats were fed a selenium- and vitamin E-deficient basal diet or one supplemented with 0.2 mg of Se/kg of diet and 200 mg of vitamin E/kg. After 9 to 16 wk. ethane production and thiobarbituric acid-reactive substances in liver and lung generally were increased by LPS treatment of Se- and vitamin E-deficient rats. Conjugated dienes were increased by LPS treatment in liver of Se- and vitamin E-deficient rats. but paradoxically. were higher in Se- and vitamin E-adequate liver tissue. Daily injections of 1 g of hydroxyurea/kg of body weight. a cell proliferation inhibitor. for 2 d prior to LPS injection significantly decreased the LPS-induced ethane production in Se- and vitamin E-deficient rat liver and lung. These results show that low doses of LPS injected into rats stimulated lipid peroxidation in vitro in Se- and vitamin E-deficient rat liver tissue. Hydroxyurea decreased LPS-induced lipid peroxidation in vitro; this suggests that neutrophils or macrophages are involved in LPS-induced lipid peroxidation.
Bone resorption, stability, and soft-tissue changes following large chin advancements, Large advancement genioplasties were performed in 10 patients (mean advancement. 11.7 mm) by horizontal osteotomy of the inferior border of the mandible. with preservation of a musculoperiosteal pedicle to the advanced genial segment. Preoperative. immediate postoperative. and long-term follow-up lateral cephalometric radiographs were retrospectively analyzed to evaluate the osseous and soft-tissue changes of the chin. After a mean follow-up period of 15 months. 76% of the initial advancement was preserved. representing 24% osseous resorption. The enveloping soft tissues of the chin followed the bony movement in a ratio of 1:0.88. Horizontal osteotomy of the inferior border of the mandible was a relatively stable procedure when used for large chin advancements. The broadcast possible musculoperiosteal pedicle should remain attached to the advanced genial segment to minimize osseous resorption and to achieve more predictable soft-tissue changes.
Creutzfeldt-Jakob disease from allogeneic dura: a review of risks and safety, Surgeons and the lay public have recently expressed concern over the safety of allogeneic dura as it relates to the transmission of Creutzfeldt-Jakob Disease. Indeed. two cases have resulted from use of tissue procured from a commercial agency that did not adhere to criteria accepted by the American Association of Tissue Banks or the Southeast Organ Procurement Foundation. This review discusses the risks and safety of allogeneic dura. The findings should reassure the surgeon of the safety of allogeneic dura when it is properly processed and catalogued by a bona fide. reputable tissue bank. To date. there have been no documented cases reported to the Center for Disease Control in which Creutzfeldt-Jakob Disease was transmitted from allogeneic dura obtained from a registered tissue bank.
Medical and dental implications of cocaine abuse, With the ever-increasing supply of cocaine and use of "crack." the potent and smokeable form of cocaine. the dangers of cocaine abuse. with its high morbidity and mortality. have become recognized. Oral and maxillofacial surgeons may frequently and unknowingly be treating patients who use cocaine. and. therefore. they must be educated about cocaine-related problems and be prepared to deal with the complications. This article discusses the nature of cocaine. its pharmacology. systemic affects. the oral manifestations of cocaine abuse. and recommended clinical management of the patient.
Liposarcoma arising in the cheek: report of a case and review of the literature, The following points can be made about liposarcoma of the oral cavity: 1) it is rare and slow growing; 2) it is often mistaken for a benign lesion; 3) there is a direct correlation of microscopic appearance with biological behavior and prognosis; 4) treatment is primarily surgical. with radiation used for selected cases; and 5) the better-differentiated tumors seem to respond more favorably to radiation.
Controlled drinking, treatment effectiveness, and the disease model of addiction: a commentary on the ideological wishes of Stanton Peele, Despite a long history of extravagant claims followed by sobering discomfirmations. advocates of controlled drinking continue to promote nonabstinent treatment goals and procedures for alcoholics. Recent claims by Stanton Peele in favor of controlled drinking are examined critically in the context of a continuing debate concerning empirical studies of nonabstinent treatment goals. treatment effectiveness. and inpatient versus out-patient treatment of alcoholism. Peele's views concerning "conventional disease-based alcoholism treatment." controlled drinking. and "the disease model" are shown to be based largely on inadequate scholarship. misrepresentations of the literature. inappropriate comparisons. unwarranted generalizations. and straw-man arguments.
Clinical diagnostic considerations on cocaine abuse, Following a review of the research literature on the psychophysiological effects of cocaine. a study is described of a group of 120 cocaine addicts. Of the 120 patients. 10 (8.33%) exhibited fleeting. unformed. organic delusions and hallucinations. Case reports of the 10 cases are presented. The quality of the adverse subjective effects of cocaine is emphasized. and the differential diagnosis between Cocaine Delusional Disorder and Paranoid Schizophrenia is discussed. Guidelines for a more accurate differential diagnosis are provided.
Virola: a promising genus for ethnopharmacological investigation, Data are now available on the antifungal use of Virola from four countries and some 14 different tribes of Indians in these countries who employ the Virola exudate for the same or similar purposes. Three of the five methods of ethnobotanical investigation proposed by Schultes and Swain in 1976 have been employed in this ethnobotanical research. Furthermore. both of the present authors have successfully employed this antifungal treatment themselves. Given that deep fungal infections of the skin are often considered incurable with medications currently in use. further laboratory analysis of Virola resin should be undertaken as soon as possible.
Routine screening for cancer of the prostate, The value of screening for prostate cancer remains unclear. Although digital rectal examination. transrectal ultrasonography. and determination of serum prostate-specific antigen levels may lead to early detection of a malignancy. these procedures have never been shown to reduce disease-specific mortality from prostate cancer. Unfortunately. several potential errors found in uncontrolled trials may suggest benefit from screening where none exists. Only a large. randomized. controlled clinical study demonstrating decreased mortality from prostate cancer can prove that screening is beneficial. Until such a study is performed. patients should be informed of both the potential benefits and the risks of screening and treatment.
A cohort study of fat intake and risk of breast cancer, Between 1982 and 1987. 519 newly incident. histologically confirmed cases of breast cancer were identified in a cohort of 56.837 women enrolled in the Canadian National Breast Screening Study. These women had completed a dietary questionnaire before the occurrence of their breast cancer. and this has been used to estimate their intake of dietary fat and several other nutrients. There is evidence of a positive association between breast cancer and total fat intake. with a relative risk of 1.35 (95% confidence interval. 1.00-1.82) per 77 g per day. and some evidence of a dose-response relationship (P = .052).
A hypothesis: nonsteroidal anti-inflammatory drugs reduce the incidence of large-bowel cancer, Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and tumor growth in the rodent colon. We assessed NSAID use in relation to risk of human large-bowel cancer in a hospital-based. case-control study of 1326 patients with colorectal cancer and 4891 control patients. For regular NSAID use that continued into the year before interview. the multivariate relative risk estimate was 0.5 (95% confidence interval. 0.4 to 0.8); the estimate decreased as the duration of use increased. but the trend was not statistically significant. Similar results were obtained whether cancer or non-cancer controls were used. and the inverse association was apparent for both colon cancer and rectal cancer in men and women and in subjects younger and older than 60 years. Regular NSAID use that had been discontinued at least 1 year previously and non-regular use were not associated with risk. Almost all regular NSAID use was of aspirin-containing drugs. The present data suggest that the sustained use of NSAIDs reduces the incidence of human large-bowel cancer.
Neurobehavioral effects of phenytoin prophylaxis of posttraumatic seizures, In order to determine potential negative neurobehavioral effects of phenytoin given to prevent the development of posttraumatic seizures. 244 subjects were randomized to phenytoin or placebo. They received neurobehavioral assessments at 1 and 12 months postinjury while receiving their assigned drug and at 24 months while receiving no drugs. In the severely injured. phenytoin significantly impaired performance at 1 month. No significant differences were found as a function of phenytoin in the moderately injured patients at 1 month or in either severity group at 1 year. Patients who stopped receiving phenytoin according to protocol between 1 and 2 years improved more than corresponding placebo cases on several measures. We conclude that phenytoin has negative cognitive effects. This. combined with lack of evidence for its effectiveness in preventing posttraumatic seizures beyond the first week. raises questions regarding its use for long-term prophylaxis. Our findings do not negate phenytoin's proven efficacy in controlling established seizures nor do they indicate that its cognitive effects are worse than other anticonvulsant drugs.
Physical and pharmacologic restraint of nursing home patients with dementia. Impact of specialized units, This case-control study of 31 specialized dementia units and 32 traditional units in five states investigated use of physical and pharmacologic restraints among 625 patients with the diagnosis of dementia. Physical restraints were observed in use on 18.1% of dementia unit patients and on 51.6% of comparison unit patients who were out of bed during the day (adjusted odds ratio. 0.283;95% confidence interval. 0.129 to 0.619). Pharmacologic restraints were routinely given to 45.3% of dementia unit patients and 43.4% of comparison unit patients (adjusted odds ratio. 0.950; 95% confidence interval. 0.611 to 1.477). We used multivariate logistic regression to identify residence in a nonspecialized nursing home unit. nonambulatory status. transfer dependency. mental status impairment. hip fracture history. and a high nursing staff-to-patient ratio. which we found to be independent predictors of physical restraint use. Physically abusive behavior. severe mental status impairment. and frequent family visitation were found to be significant predictors of pharmacologic restraint use. while advanced patient age. large nursing home size. and patient nonambulatory status were protective against such use. These results support the conclusion that physical and pharmacologic restraint constitute separate treatment modalities with different risk factors for use. and indicate that specialized dementia units are successful in reducing the use of physical but not pharmacologic restraints.
Rising incidence of adenocarcinoma of the esophagus and gastric cardia, Analyses of cancer incidence data from nine areas of the United States revealed steadily rising rates from 1976 to 1987 of adenocarcinomas of the esophagus and gastric cardia. The increases among men in this period ranged from 4% to 10% per year. and thus exceeded those of any other type of cancer. In contrast. there were relatively stable trends for squamous cell carcinoma of the esophagus and slight declines for adenocarcinoma of more distal portions of the stomach. Adenocarcinomas of the esophagus and gastric cardia disproportionately affected white men and rarely occurred among women. By the mid-1980s. among white men. adenocarcinomas accounted for about one third of all esophageal cancers. while cardia cancers accounted for about one half of all stomach cancers with specified subsites. The rising incidence rates and similar demographic patterns point to the need for investigation into the causes of these poorly understood cancers.
Potential complications of high-dose epinephrine therapy in patients resuscitated from cardiac arrest, Adults resuscitated from nontraumatic cardiac arrest who received intravenous epinephrine in doses chosen by the treating physician and who survived at least 6 hours were studied to determine if high-dose epinephrine produced more complications than standard-dose. A total of 68 patients were enrolled and evaluated for postresuscitation complications attributable to epinephrine. using a two-tailed t test. and contingency analysis. The 33 patients receiving high-dose epinephrine and 35 patients receiving standard-dose epinephrine were similar in demographics and variables known to affect outcome. There was no difference in potential complications between groups except serum calcium. which was 1.97 mmol/L (SD. 0.20) in the high-dose epinephrine group and 2.10 (SD. 0.20) in the standard-dose group. Hospital discharge rates (18% in the high-dose vs 30% in the standard-dose group) and neurological status on discharge were not significantly different. High-dose epinephrine did not produce increased direct complications in this cardiac arrest population compared with standard-dose epinephrine.
Are universal precautions effective in reducing the number of occupational exposures among health care workers? A prospective study of physicians on a medical service, Using a daily questionnaire. we prospectively studied 277 physicians from two hospital medical services for incidents of exposure to blood and body fluids and barrier use before and after the implementation of universal precautions. We found that implementation significantly increased the frequency of barrier use during exposure incidents from 54% before implementation to 73% after implementation of universal precautions. Implementation led to a decrease in the number of exposure incidents that resulted in direct contact with blood and body fluids (actual exposures). from 5.07 to 2.66 exposures per physician per patient care month. and to an increase in averted exposures in which direct contact was prevented by the use of barrier devices. from 3.41 exposures per patient care month before implementation to 5.90 exposures per patient care month after implementation. Implementation affected neither the types of body fluid or procedures involved nor the overall rate of exposure incidents (8.5 per patient care month) but. through an increase in barrier use. it did prevent direct contact with blood and body fluids and thus converted what would have been an actual exposure into an averted one. We conclude that universal precautions were effective in reducing the risk of occupational exposures among physicians on a medical service.
Cardiomyopathy associated with the smoking of crystal methamphetamine, The smoking of crystal methamphetamine. or "ice." is a growing drug abuse problem in the United States. The toxic effects of methamphetamine smoking have not been well described. We describe two patients with cardiovascular toxic effects associated with the smoking of crystal methamphetamine. In our first patient. the use of smokeable methamphetamine was associated with the subsequent development of pulmonary edema and a dilated cardiomyopathy. In our second patient. the smoking of crystal methamphetamine likely produced diffuse vasospasm that resulted in acute myocardial infarction. cardiogenic shock. and death. The recognition of potentially lethal cardiac complications associated with the smoking of crystal methamphetamine is of extreme significance and should be emphasized to potential abusers of this drug.
Catastrophic injuries and fatalities in high school and college sports, fall 1982-spring 1988, Direct and indirect deaths and catastrophic injuries. defined as any injury incurred during participation in a high school/college sponsored sport in which there is permanent severe functional neurological disability (nonfatal) or transient but not permanent functional neurologic disability (serious). are presented for all sports during the period of fall 1982 to spring 1988. Football contributed the greatest numbers of catastrophic injuries but also had the largest number of participants. Ice hockey. gymnastics. and wrestling are the other sports where participants are at greatest risk of catastrophic injury or death. Mechanisms of injury in each sport and corrective actions are identified and discussed. While high school and college catastrophic injuries may never be totally eliminated. they can be dramatically reduced by reliable injury data collection and analysis.
Caloric expenditure, life status, and disease in former male athletes and non-athletes, This study examined the association between aerobic. caloric exercise expenditure and life status (living vs deceased) as well as the prevalence rates of hypertension (HBP) and cardiovascular disease (CVD) in former male athletes (ATH) and non-athletes (N-ATH). The initial survey for this study was done in 1952. Follow-up surveys of respondents were done in 1960. 1968. 1976. and 1984. The present study used all subjects who responded fully to activity and health questions in 1976 and who were reported as either dead or alive (not lost to follow-up) in 1984. A total of 348 subjects (185 ATH. 163 N-ATH) were assessed and caloric expenditure groups were established by kilocalories (kcal) of aerobic exercise per week; 0 kcal (group 1). 1-399 kcal (group 2). 400-899 kcal (group 3). 900-1499 kcal (group 4). 1500-2499 kcal (group 5). and 2500+ kcal (group 6). Only activity considered to be aerobic was used in the establishment of the aerobic categories. Death rate was highest in groups 1 and 2. Subjects in group 1 tended to be the oldest. Year of birth (age) (P less than 0.001) and CVD (P less than 0.05) as reported in 1976 were significantly related to mortality between 1976 and 1984. College athletic status and 1976 exercise level were not significantly related to mortality. Prevalence of CVD and HBP was highest in groups 1 and 6. suggesting a moderate amount of aerobic activity as optimal.
Transient oliguria with renal tubular dysfunction after a 90 km running race, In the course of a 19-d study of renal function in five ultramarathon runners. before. during and after a 90 km race. one runner developed transient oliguria with renal tubular dysfunction and anuria during and immediately after the race. Other features of the renal failure were an 84-fold increase in urine beta 2-microglobulin excretion (from 0.19 to 16.0 micrograms.min-1) and a much smaller increase in urine total protein excretion (from 0.07 to 0.18 mg.min-1) during the post-race period. Post-race creatinine clearance remained below pre-race levels throughout the study. varying between 42.8 and 72.9 ml.min-1. in contrast to the post-race 49% increase in the remaining runners (from 138.1 +/- 12.9 to 205.5 +/- 59.9 ml.min-1). Osmolal clearance also remained low (0.31 to 0.98 ml.min-1) compared with the pre-race values (1.46 +/- 0.02 ml.min-1). as did the urine flow rates (0.11 to 0.18 ml.min-1) compared with the pre-race values (0.34 +/- 0.02 ml.min-1). This renal dysfunction persisted despite the patient receiving 2 l of intravenous fluids immediately after the race and probably resulted from fluid restriction during the race. There was full recovery of renal function 1 yr later when the subject again ran the Comrades Marathon.
Effects of dehydration on gastric emptying and gastrointestinal distress while running, Gastrointestinal distress is commonly reported by athletes after ingestion of a beverage. We speculate that ingestion may be occurring after dehydration has taken place. The high prevalence of GI disorders in marathon runners who have lost greater than or equal to 4% body weight supports this theory. To test this theory. the effects of dehydration. and dehydration in combination with endurance running. on gastric emptying (GE) and frequency of gastrointestinal (GI) complaints were tested in this experiment. A complete cross-over study was designed. Sixteen subjects ingested 8 ml.kg BW-1 of a 7% carbohydrate (296 mOsm.kg-1). solution after a euhydration or dehydration regime. Dehydration (4% BW loss) was produced by 60% maximal speed running at 30 degrees C or by intermittent sauna exposure at 100 degrees C. Euhydration experiments were conducted with a 2 h rest period with water administered at 20 and 40 min. Gastric drink volumes were measured every 10 min for 40 min. Emptying curves were compared using semi-log transformation of the percentage emptying data and simple linear regression. The slope of each line was used as a measure of average GE rate. Dehydration-exercise resulted in slower GE than in all other treatments (P less than 0.05). ANOVA revealed significant effects of dehydration (P less than 0.05) and exercise (P less than 0.05). these two effects being additive in delaying GE. GI complaints were reported by 37.5% of the subjects during dehydration-exercise experiments. No GI disturbance was reported in other tests.
Operation Everest II: ventilatory adaptation during gradual decompression to extreme altitude, To assess the ventilatory adaptation during gradual ascent to extreme altitude. we studied seven healthy males as part of the 40 d simulated ascent of Mt. Everest in a hypobaric chamber. We measured resting ventilation (VE. l.min-1). arterial oxygen saturation (SaO2%). the ventilatory response to oxygen breathing. isocapnic hypoxic ventilatory response (HVR). and hypercapnic ventilatory response (HCVR) at sea level prior to the ascent (760 torr). 14.000 feet (428 torr). 24.000 feet (305 torr). and within 24 h of descent (765 torr). VE increased from 9.3 +/- 1.1 l.min-1 at 760 torr to 23.4 +/- 1.3 l.min-1 at 305 torr and remained elevated at 14.7 +/- 0.7 l.min-1 after descent. Oxygen breathing decreased VE by 9.6 +/- 1.3 l.min-1 at 305 torr. Isocapnic HVR (expressed as a positive slope of VE/SaO2. l.min-1.%SaO2(-1) increased from 0.18 +/- 0.07 at 760 torr to 0.34 +/- 0.11 and 0.38 +/- 0.5 at 428 torr and 305 torr (P less than 0.05) respectively. HVR was elevated further upon return to sea level (0.8 +/- 0.09. P less than 0.05). HCVR (S = VE/PETCO2. l.min-1.torr-1) increased from sea level (S = 4.4 +/- 0.09) to 305 torr (S = 18.7 +/- 3.5. P less than 0.01) and remained elevated upon return to sea level (S = 10.7 +/- 4.6. P less than 0.001). This study is the first to investigate the ventilatory response to such extreme altitude and so soon after descent and shows that hypoxic and hypercapnic responses increase during prolonged progressive hypoxic exposure and remain significantly elevated from pre-ascent levels immediately upon descent.
Single nucleotide primer extension to detect genetic diseases: experimental application to hemophilia B (factor IX) and cystic fibrosis genes, In this report. we describe an approach to detect the presence of abnormal alleles in those genetic diseases in which frequency of occurrence of the same mutation is high (e.g.. cystic fibrosis and sickle cell disease). and in others in which multiple mutations cause the disease and the sequence variation in an affected member of a given family is known (e.g.. hemophilia B). Initially. from each subject. the DNA fragment containing the putative mutation site is amplified by the polymerase chain reaction. For each fragment two reaction mixtures are then prepared. Each contains the amplified fragment. a primer (18-mer or longer) whose sequence is identical to the coding sequence of the normal gene immediately flanking the 5' end of the mutation site. and either an alpha-32P-labeled nucleotide corresponding to the normal coding sequence at the mutation site or an alpha-32P-labeled nucleotide corresponding to the mutant sequence. Single nucleotide primer extensions are then carried out and analyzed by denaturing polyacrylamide gel electrophoresis and autoradiography. As predicted by the Watson-Crick base-pair rule. in the wild type only the normal base. in an affected member only the mutant base. and in carriers both the normal and the mutant base are incorporated into the primer. Thus. an essential feature of the present methodology is that the base immediately 3' to the template-bound primer is one of those altered in the mutant. since in this way an extension of the primer by a single base will give an extended molecule characteristic of either the mutant or the wild type. The method is rapid and should be useful in carrier detection and prenatal diagnosis of every genetic disease with a known sequence variation.
Selective inhibition by a synthetic hirudin peptide of fibrin-dependent thrombosis in baboons, To determine the importance of the thrombin substrate recognition exosite for fibrinogen binding in the formation of both arterial and venous thrombi. we evaluated the antithrombotic effects of the tyrosine-sulfated dodecapeptide from residues 53-64 of hirudin (H peptide) in a nonhuman primate model. This peptide was studied because it inhibits thrombin cleavages of fibrinogen by simple competition without blocking enzyme catalytic-site function. When an exteriorized arteriovenous access shunt model was used in baboons (Papio anubis). thrombus formation was induced by placing a thrombogenic device made of (i) a segment of tubing coated covalently with type I collagen. which generated platelet-rich thrombi under arterial flow conditions. and (ii) two subsequent annular regions of flow expansion that produced fibrin-rich thrombi typically associated with venous valves and veins. Thrombus formation was quantified by measurements of 111In-labeled platelet and 125I-labeled fibrinogen deposition in both arterial-flow and venous-flow portions of the device. Continuous infusion of H peptide (0.5. 15. and 75 mg/kg) proximal to the device for 40 min interrupted. in a dose-response fashion. formation of fibrin-rich thrombus in the regions of disturbed flow and generation of fibrinopeptide A. In contrast. H peptide did not inhibit the capacity of platelets to deposit on the collagen surface (P greater than 0.2 at all doses) or to form hemostatic plugs (as assessed by measurements of bleeding time; P greater than 0.1 at all doses). These findings suggest that. by competitive inhibition of fibrinogen binding to thrombin. fibrin-rich venous-type thrombus formation may be selectively prevented. This strategy may be therapeutically attractive for preserving normal platelet function when conventional anticoagulant therapy is contraindicated.
Seismic communication in a blind subterranean mammal: a major somatosensory mechanism in adaptive evolution underground, Seismic communication. through low-frequency and patterned substrate-borne vibrations that are generated by head thumping. and which travel long distances underground. is important in the nonvisual communication of subterranean mole rats of the Spalax ehrenbergi superspecies (2n = 52. 54. 58. and 60) in Israel. This importance pertains both intraspecifically in adaptation and interspecifically in speciation. Neurophysiologic. behavioral. and anatomic findings in this study suggest that the mechanism of long-distance seismic communication is basically somatosensory and is independent of the auditory mechanism. Seismic communication thus appears to be a channel of communication important in the evolution of subterranean mammals that display major adaptation to life underground.
Retrovirus-induced spongiform myeloencephalopathy in mice: regional distribution of infected target cells and neuronal loss occurring in the absence of viral expression in neurons, The Cas-Br-E murine leukemia virus (MuLV) induces a spongiform myeloencephalopathy resulting in a progressive hindlimb paralysis. We have used in situ hybridization with a Cas-Br-E MuLV-specific probe to study viral expression in the central nervous system. Infected cells were concentrated in regions where spongiform lesions and gliosis are detected (lumbosacral spinal cord. brainstem. deep cerebellar regions). suggesting a causative link between the level of virus expression and the degree of pathological changes in this disease. However. viral expression was not in itself sufficient to cause disease. since significant viral expression was observed in regions that did not exhibit pathological changes (cerebellar cortex. hippocampus. corpus callosum. peripheral nervous system). In both diseased and nondiseased regions. endothelial and glial cells were identified as the main target cells. Neurons in diseased regions did not show viral expression. The regional distribution of the spongiform changes appears to be laid down very early following infection. since expression could be detected at 10 days postinfection in regions that become diseased. These results indicate that nonneuronal cells have distinct properties in various regions of the central nervous system and suggest an indirect mechanism of neuronal loss consequent to viral expression in nonneuronal cells.
Clustered tRNA genes in Schizosaccharomyces pombe centromeric DNA sequence repeats, The centromere-associated B' and B DNA sequence repeats of Schizosaccharomyces pombe chromosomes I and II have been found to contain clusters of tRNA genes. The centromere II region (cen2) includes at least 22 tRNA genes distributed among five copies of the B sequence repeat containing genes specifying tRNA(Ile). tRNA(Ala). and tRNA(Val). Individual B repeats are variously associated with other tRNA genes. including those specifying tRNA(Lys). tRNA(Arg). and tRNA(Glu2). The centromere I region (cen1) contains at least six tRNA genes in two copies of the B' repeated element. including genes specifying tRNA(Ile). tRNA(Ala). and tRNA(Glu3). Multiple tandemly arranged clusters of tRNA genes are presumably conserved due to restricted recombination frequencies in the centromere regions.
scid mutation in mice confers hypersensitivity to ionizing radiation and a deficiency in DNA double-strand break repair, C.B-17 severe combined immunodeficient (scid) mice carry the scid mutation and are severely deficient in both T cell- and B cell-mediated immunity. apparently as a result of defective V(D)J joining of the immunoglobulin and T-cell receptor gene elements. In the present studies. we have defined the tissue. cellular. and molecular basis of another characteristic of these mice: their hypersensitivity to ionizing radiation. Bone marrow stem cells. intestinal crypt cells. and epithelial skin cells from scid mice are 2- to 3-fold more sensitive when irradiated in situ than are congenic BALB/c or C.B-17 controls. Two independently isolated embryo fibroblastic scid mouse cell lines display similar hypersensitivities to gamma-rays. In addition. these cell lines are sensitive to cell killing by bleomycin. which also produces DNA strand breaks. but not by the DNA crosslinking agent mitomycin C or UV irradiation. Measurement of the rejoining of gamma-ray-induced DNA double-strand breaks by pulsed-field gel electrophoresis indicates that these animals are defective in this repair system. This suggests that the gamma-ray sensitivity of the scid mouse fibroblasts could be the result of reduced repair of DNA double-strand breaks. Therefore. a common factor may participate in both the repair of DNA double-strand breaks as well as V(D)J rejoining during lymphocyte development. This murine autosomal recessive mutation should prove extremely useful in fundamental studies of radiation-induced DNA damage and repair.
Influence of chromosomal integration on glucocorticoid-regulated transcription of growth-stimulating papillomavirus genes E6 and E7 in cervical carcinoma cells, In most cervical carcinoma cells the E6 and E7 genes of specific human papillomaviruses are transcribed from viral sequences integrated into host cell chromosomes. Glucocorticoids activate the promoter elements of various human papillomaviruses in transient-expression assays. We have analyzed the effect of dexamethasone on the transcription rate of human papillomavirus 18 E6 and E7 genes integrated at different chromosomal sites in four cervical cancer cell lines. Dexamethasone led to an increase in the transcription rate of the integrated E6-E7 sequences in C4-1 and C4-2 cells but led to a decrease in SW 756 cells and did not affect the transcription rate in HeLa cells. However. when the viral promoter elements derived from HeLa or SW 756 cells. in which dexamethasone does not activate transcription of the integrated E6-E7 sequences. were tested in transient-expression assays within the same cell lines. dexamethasone consistently activated the viral promoter. It thus appears that dominant regulatory mechanisms presumably depending on the chromosomal integration site are able to override the response of the viral promoter to steroid hormones. The growth rate of all dexamethasone-treated cell lines correlated consistently with the expression of the papillomavirus E6 and E7 genes. supporting their role in the maintenance of the proliferative phenotype of cervical carcinoma cells. Since human papillomaviruses are integrated into the host cell genome at variable. presumably randomly selected chromosomal loci. regulatory mechanisms that influence viral gene expression. and hence cell growth. may differ among cancers of independent clonal origin.
Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form, A cDNA clone for human catechol-O-methyltransferase (hCOMT; S-adenosyl-L-methionine:catechol O-methyltransferase; EC 2.1.1.6) was isolated from a human hepatoma cell line (Hep G2) cDNA library by hybridization screening with a porcine cDNA probe. The cDNA clone was sequenced and found to have an insert of 1226 nucleotides. The deduced primary structure of hCOMT is composed of 271 amino acid residues with the predicted molecular mass of 30 kDa. At its N terminus it has a hydrophobic segment of 21 amino acid residues that may be responsible for insertion of hCOMT into the endoplasmic reticulum membrane. The primary structure of hCOMT exhibits high homology to the porcine partial cDNA sequence (93%). The deduced amino acid sequence contains two tryptic peptide sequences (T-22. T-33) found in porcine liver catechol-O-methyltransferase (COMT). The coding region of hCOMT cDNA was placed under the control of the cytomegalovirus promoter to transfect human kidney 293 cells. The endogenous COMT activity. which was approximately 9.98 units per mg of protein in the untransfected cells. increased to 206 units per mg of protein upon transfection with a plasmid containing the COMT cDNA. The COMT activity of recombinant protein was inhibited competitively (IC50 = 700 nM) by the selective COMT inhibitor Ro 40-7592. An anti-COMT monoclonal antibody recognized. on immunoblots. a major polypeptide with apparent molecular mass of 29 kDa. in reasonable agreement with the predicted molecular mass. The recombinant hCOMT was shown by immunoblot analysis to be mainly associated with the membrane fraction. RNA blot analysis revealed one COMT mRNA transcript of 1.4 kilobases in Hep G2 poly(A)+ RNA.
Stimulation of cAMP and phosphomonoester production by melanotropin in melanoma cells: 31P NMR studies, A major part of the present understanding of the molecular basis of signal transduction has been gained from in vitro studies using classical biochemical methods. In this study. we used 31P NMR spectroscopy to investigate the response of live M2R mouse melanoma cells to stimulation by melanocyte-stimulating hormone (MSH; melanotropin). In the presence of 3-isobutyl-1-methylxanthine and a synergistic dose of forskolin (1.67 microM). MSH induced a transient (approximately 60-min) rise in the cellular concentration of 3'.5'-cyclic adenosine monophosphate (cAMP). which coincided in time with an equivalent decrease (approximately 40%) in ATP. However. no detectable change in phosphocreatine concentration was observed. Concomitantly. MSH induced a striking and unexpected increase in the concentration of three phosphomonoester (PME) metabolites (approximately 2-fold increase in total PME signal area); one signal has been assigned to phosphoethanolamine. The levels of the PMEs remained high for 2-4 hr and declined slowly (approximately 10 hr) to basal level. following perfusion with fresh culture medium. The increase in PME was also observed after stimulation with MSH alone. In contrast. stimulation with a high dose of forskolin (50 microM) and isobutylmethylxanthine (0.2 mM). although effective in stimulating the production of cAMP. did not induce the PME response. Evaluation of the cells' energetics indicated that the enhanced production of phosphoethanolamine is probably not due to ethanolamine phosphorylation. Therefore. it is likely to result from hydrolysis of phosphatidylethanolamine by a specific phospholipase C. The response of the PMEs appears to be regulated by a cAMP-independent process. suggesting the existence of an alternative transduction pathway controlled by MSH.
Mononuclear phagocytes: a major population of effector cells responsible for rejection of allografted tumor cells in mice, To understand the in situ mechanism of immunological response of recipient animals to allografted tumor cells. the types of cells that infiltrated into the rejection site were examined. When Meth A cells (H-2d) were given i.p. to an allogeneic [C57BL/6 (H-2b)] strain of mouse. the tumor cells ceased to grow on the 6th day. accompanied by an i.p. infiltration of leukocytes. The tumor cells were totally eliminated from the peritoneal cavity around the 12th day. The highest cytotoxic activity against Meth A cells was obtained with the peritoneal exudate cells harvested on day 8. On this day. the exudate cells consisted of three populations when examined by flow cytometry. and each was isolated by sorting. Each of them appeared to be homogeneous. and they were morphologically identified as lymphocytes; granulocytes; and medium-sized. mononuclear. less-granular cells. The cytotoxic activity was confined exclusively to the last population. The effector cells (H-2b) were cytotoxic against not only Meth A cells (H-2d) but also concanavalin A-stimulated allogeneic spleen cells [C3H/He (H-2k). CBA/N (H-2k). A/J (H-2a). BALB/c (H-2d). and DBA/2 (H-2d) strains of mouse]. The effector cells were totally inert against concanavalin A-activated syngeneic spleen cells [C57BL/6 (H-2b) and C57BL/10 (H-2b) strains of mouse]. The effector cells were phenotypically (Thy-1.2- CD3- Lyt-1- Lyt-2- L3T4- immunoglobulin- asialo GM1-). morphologically. and functionally distinct from cytotoxic T cells. natural killer cells. and lymphokine-activated killer cells but were adherent mononuclear phagocytes.
Very long charge runs in systemic lupus erythematosus-associated autoantigens, Systemic lupus erythematosus and other chronic systemic autoimmune diseases are associated with circulating autoantibodies reactive with a limited set of mostly nuclear proteins. Using rigorous statistical methods we have identified segments of highly significant charge concentration in the majority of the characteristic nuclear and cytoplasmic autoantigens. Extremely long runs of charged residues. including some sequences of greater than 20 consecutive charged residues (purely acidic or mixed basic and acidic). occur in about a third of these proteins. whereas equivalent runs are found in less than 3% of other mammalian proteins. The other sequences have less extreme charge clusters. the type and location of which are often conserved between several otherwise nonsimilar antigens. We propose that supercharged surfaces render the targeted host proteins strongly immunogenic and that antinuclear antibody profiles might result from chronic exposure to intracellular contents. possibly in conjunction with crossreactive viral products. The limited number of potential systemic autoantigens may partly be due to the rarity of requisite charge properties.
AIDS epidemiology: inconsistencies with human immunodeficiency virus and with infectious disease, The newly defined syndrome AIDS includes 25 unrelated parasitic. neoplastic. and noninfectious indicator diseases. Based on epidemiological correlations. the syndrome is thought to be due to a new. sexually or parenterally transmitted retrovirus termed human immunodeficiency virus (HIV). The following epidemiological data conflict with this hypothesis. (i) Noncorrelations exist between HIV and AIDS; for example. the AIDS risks of infected subjects vary greater than 10-fold with their gender or country. Abnormal health risks that are never controlled as independent AIDS causes by AIDS statistics. such as drug addiction and hemophilia. correlate directly with an abnormal incidence of AIDS diseases. Above all. the AIDS diseases occur in all risk groups in the absence of HIV. (ii) American AIDS is incompatible with infectious disease. because it is almost exclusively restricted to males (91%). because if it occurs. then only on average 10 years after transfusion of HIV. because specific AIDS diseases are not transmissible among different risk groups. and because unlike a new infectious disease. AIDS has not spread exponentially since the AIDS test was established and AIDS received its current definition in 1987. (iii) Epidemiological evidence indicates that HIV is a long-established. perinatally transmitted retrovirus. HIV acts as a marker for American AIDS risks. because it is rare and not transmissible by horizontal contacts other than frequent transfusions. intravenous drugs. and repeated or promiscuous sex. It is concluded that American AIDS is not infectious. and suggested that unidentified. mostly noninfectious pathogens cause AIDS.
Photosensitized destruction of human bladder carcinoma cells treated with chlorin e6-conjugated microspheres, A photosensitizer conjugate. chlorin e6 (Ce6) covalently bound to 1-micron-diameter polystyrene microspheres. has been investigated in the photodynamic destruction of MGH-U1 human bladder carcinoma cells in vitro. The microspheres were taken up avidly by the carcinoma cells; confocal laser scanning fluorescence microscopy showed them to be localized in the cytoplasm. apparently within lysosomes. visualized by labeling with acridine orange. In contrast. fluorescence of unconjugated Ce6 was present within most cellular membranes. Use of Ce6-microsphere conjugates led to a 20-fold-higher mean intracellular concentration. compared with unconjugated Ce6. Cells incubated in the presence of Ce6-microsphere conjugates (0.43 microM equivalent) and subsequently irradiated at 659 nm with a dye laser pumped by an argon-ion laser showed dose-dependent phototoxicity. leading to total inhibition of colony formation at a radiant exposure of 5J/cm2; in contrast. cells incubated with either unconjugated Ce6 (0.43 microM) or unconjugated microspheres before laser irradiation were unaffected. Cells pretreated with Ce6-microsphere conjugates and irradiated in the presence of 90% 2H2O showed significantly increased phototoxicity. an effect consistent with an important role for excited-state singlet oxygen in the mechanism of injury. In solution. however. photosensitized generation of singlet oxygen with Ce6-microsphere conjugates was 9 times less efficient than with unconjugated Ce6. The markedly greater phototoxicity of Ce6-microsphere conjugates compared to unconjugated Ce6 was therefore a consequence of the high intracellular Ce6 concentration attained by phagocytosis of the conjugates and their particular sites of intracellular localization. Thus. these conjugates are an efficient system for the delivery of photosensitizing drugs to carcinoma cells.
Quantification of midline shift as a predictor of poor outcome following head injury, A retrospective study of patient outcome. based on admission computed tomography. was carried out in 75 consecutive patients with head injury. Computed tomography data collected included the type and extent of intracranial hemorrhage. the extent of midline shift. and the ratio of midline shift compared with the extent of intracranial hemorrhage. Midline shift was considered to be out of proportion to intracranial hemorrhage when the midline shift of the septum pellucidum exceeded the extent of the hemorrhage as measured radially from the inner table of the skull. When computed tomography data were analyzed by logistic regression. significant predictive factors for poor outcome were intracranial hemorrhage (34%). intracranial hemorrhage with midline shift (61%). and midline shift out of proportion to the extent of intracranial hemorrhage (88%). When patient outcome and mortality rates are considered. our study indicates that midline shift out of proportion to the extent of intracranial hemorrhage is a highly useful predictor of poor patient outcome following head injury.
Intracranial chordoma in a preadolescent. Case report, Chordomas are rare tumors derived from notochord remnants occurring primarily in the sacrum. clivus. and cervical regions. Exceptionally. these tumors occur in children. though usually in the sacrum. Eight cases of clivus chordoma have been described in preteenagers. In this report. a clival chordoma with unusual radiologic features is described in an 11-year-old boy. The literature regarding this entity is reviewed.
Selective in vivo removal of rheumatoid factor by an extracorporeal treatment device in rheumatoid arthritis patients, A prospective phase II trial was conducted to assess the feasibility. tolerance. and efficacy of a device designed for selective removal of rheumatoid factor from the plasma of rheumatoid arthritis patients. The device contained terpolymer hydrogel-coated plates with chemically attached. aggregated human immunoglobulin G. and it operated as an immunoaffinity column. Sixty-one patients aged 25 to 73 underwent weekly plasmapheresis treatments (the primary therapy phase). During the trial. patients continued current rheumatoid arthritis medications without dose adjustments. All patients received two to six treatments (primary therapy). Responding patients were eligible to continue apheresis treatment every 2 to 6 weeks (maintenance therapy). No serious. untoward side effects were noted in the course of this study; of 640 treatments. only 2 (in different patients) were aborted. one because of complaints of dizziness and angioedema and the other because of chest tightness and shortness of breath. Except for a significant (p less than 0.05) decrease in serum iron. no significant changes in complete blood count. serum electrolytes. renal and hepatic function tests. or serum C3 and C4 were noted. Although the trial was not designed to determine clinical efficacy. patients noted less morning stiffness. longer time to onset of fatigue. and improved global pain assessment (p less than 0.004); significant objective improvements were noted in joint pain. tenderness. swelling. and the number of affected joints (p less than 0.001). One-half of the treated patients had at least a 50 percent improvement in objective measures of antirheumatic activity.
Immunochemical studies on the differential binding properties of two monoclonal antibodies reacting with Tn red cells, Two monoclonal antibodies (MoAbs). BRIC 66 (IgM) and BRIC 111 (IgG1). were produced by immunizing mice with ovarian cyst blood group A1 glycoprotein and Tn red cells (RBCs). respectively. Their specificities were determined by inhibitions using Tn sialoglycoproteins (SGPs). mucins (armadillo [ASG] and ovine [OSG] submaxillary glycoproteins). and monosaccharides. BRIC 66 agglutinated both Tn and group A RBCs and reacted immunohistochemically with both the vascular endothelium and tumor cells from a group A adenocarcinoma. BRIC 66 was inhibited by N-acetylgalactosamine (GalNAc). Tn SGPs. and mucins on both hemagglutination inhibition tests and radioimmunoassay. BRIC 111 agglutinated Tn RBCs only. and it specifically stained tumor cells from a group O patient's breast carcinoma and a group A patient's adenocarcinoma. In hemagglutination inhibition tests. BRIC 111 was readily inhibited by Tn SGPs. only partially inhibited by GalNAc. and not inhibited by mucins. In a sensitive radioimmunoassay. BRIC 111 was inhibitable by GalNAc. Tn SGP was 2000-fold more effective as an inhibitor than the mucins (ASG and desialized OSG). which contain a high content of terminal alpha-GalNAc-O-serine (threonine) residues. It is postulated that BRIC 66 is specific for terminal alpha-GalNAc units in carbohydrate chains. The exclusive reaction of BRIC 111 with Tn SGP indicates a combining site larger than GalNAc alpha-1. which probably includes amino acid residues in juxtaposition to GalNAc in Tn SGP. In view of its specific agglutination of Tn RBCs. BRIC 111 is a useful reagent for the examination of polyagglutinable RBCs.
A fatal case of ceftriaxone (Rocephin)-induced hemolytic anemia associated with intravascular immune hemolysis, Fatal hemolytic anemia developed in a 52-year-old woman who was treated with a cephalosporin. ceftriaxone. The patient's red cells (RBCs) were coated with C3. but no RBC-bound IgG. IgA. or IgM was detected. Her serum contained an antibody that did not react with cephalosporin-coated RBCs but reacted strongly with RBCs in vitro when her serum was added to drug and RBCs. This is the first case of immune hemolytic anemia associated with ceftriaxone. the first case of fatal cephalosporin-induced hemolytic anemia. and the second case in which a cephalosporin antibody showed in vitro and in vivo characteristics usually thought to be associated with the so-called immune complex mechanism.
Home blood pressure readings in borderline hypertensive patients, Home blood pressure monitoring can provide valuable information for physicians managing borderline hypertensive patients. This study was conducted to compare office and home blood pressures in 36 borderline hypertensive subjects. and to determine the accuracy of the home monitoring unit used. The patients were very willing to record their home blood pressures for an extended period of time. The home blood pressure monitors were found to be quite accurate. and blood pressures measured at home were significantly lower than readings obtained in the office. In 39% (14 of 36) of the subjects studied. the average home blood pressures were more than 10 mmHg lower than their office readings. These findings support the hypothesis that home blood pressure monitoring can be useful in the management of borderline hypertensive patients.
Collagenous colitis as a cause of chronic diarrhea, When the usual workup for chronic diarrhea fails to provide a diagnosis and the endoscopic findings are normal. alternative etiologies must be considered. This case of collagenous colitis represents such an alternative diagnosis. The patient is a 65-year-old woman who complained of abdominal cramps and watery diarrhea for an 8-month span. The key element to her diagnosis was subepithelial collagen deposits of the mucosa of the colon. Her symptoms were resolved with supportive care. diet. and diphenoxylate. Essential features and treatment of collagenous colitis are reviewed.
Vasodilatory beta-blockers: systemic and regional hemodynamic effects, The systemic and regional hemodynamic alterations in hypertension and of the beta-adrenergic receptor inhibiting agents are reviewed. Hemodynamically. hypertension may be regarded as persistent elevation of arterial pressure associated with increased total peripheral resistance. In early or mild essential hypertension. however. increased total peripheral resistance may not readily be recognized because of the overriding effect of increased cardiac output. Clearly. the hemodynamics of blood pressure control are complex. and the mechanisms of antihypertensive agents must be used appropriately. The early beta-blockers reduced heart rate and cardiac output immediately after intravenous administration without immediately reducing arterial pressure. and calculated total peripheral resistance was increased. With prolonged oral treatment. arterial pressure decreased while maintaining a reduced heart rate and cardiac output. Total peripheral resistance. however. remained elevated. Recent beta-blockers. such as celiprolol. provide an improved physiologic response by instantly reducing arterial pressure and total peripheral resistance without reducing heart rate or cardiac output or expanding intravascular volume.
Angina, ischemia, and effort tolerance with vasodilating beta-blockers, beta-Blockers are known to suppress exercise-induced ischemia but give rise to such problems as fatigue or dyspnea on effort and also bradycardia. In a series of double-blind. placebo-controlled studies of celiprolol (a cardioselective beta 1-blocker with beta 2-agonist and vasodilatory properties) in patients with hypertension and angina and in normal volunteers. it was found that celiprolol did not produce bradycardia when given in combination with verapamil. Celiprolol did reduce exercise-induced ischemia. but there was no reduction in cardiac output at rest or on exercise compared with placebo. Compared with atenolol. celiprolol produced less dyspnea and fatigue at submaximal levels of exercise. It is concluded that celiprolol possesses certain differences. compared with conventional beta-blockers. that may be of direct clinical benefit.
Cardiovascular risk factors and the effects of intervention, Cardiovascular risk factors can be substantially modified by changes in life-style such as diet. exercise. smoking cessation. and moderation of alcohol consumption. In turn. these can reduce blood pressure. heart rate at rest. and blood lipid concentrations. Epidemiologic evidence shows that for every 1% change in serum cholesterol levels. there is a 3% change in the likelihood of developing coronary heart disease. In addition. a long-term (5-year) change of 5 to 6 mm Hg in diastolic blood pressure can reduce the chances of stroke by 35 to 40% and of coronary heart disease by 20 to 25%. The full impact of this broad range of interventions on population health has still to be fully realized in many countries. including the United Kingdom. however it is likely to be considerable. Some of the recent evidence in support of such cardiovascular risk factor modification is selectively reviewed.
Medullary thyroid cancer. An immunohistochemical and humoral study using six separate antigens, The authors investigated the humoral and tissue expression of six antigens associated with medullary thyroid cancer (MTC): calcitonin (CT). calcitonin gene-related peptide (CGRP). carcinoembryonic antigen (CEA). neuron-specific enolase (NSE). somatostatin (SRIF). and thyroglobulin (TG). The antigens were studied in the neoplastic C cells using immunohistochemistry with specific antisera and in the plasma using specific radioimmunoassay. Eighteen patients (8 male and 10 female patients. aged 12-72 years) were studied. Mean follow-up was 70.7 months (range. 2-179 months). Nine patients (50%) died of their disease after a mean follow-up of 47.2 months (range. 2-116 months). By immunostaining. primary tumors expressed CT and CEA in all cases and NSE was positive in 90%. CGRP in 66%. SRIF in 63%. and TG in 58%. Metastatic tissues were positive in all cases of CT staining. 92.8% of CEA. 71.4% of NSE. 73.3% of CGRP. 38.5% of SRIF. and only 13.3% of TG staining. In positive cases the percentage of positive cells and the degree of staining were variable among the different antigens. The expression of an antigen in the neoplastic cells was associated with the hypersecretion of the corresponding antigen in the circulation in the case of CT and CEA. The levels of these antigens were elevated in all patients with metastases and could accurately predict the appearance of new metastases or indicate the effective treatment of previous metastases by surgery. In the case of NSE. CGRP. and SRIF. few patients had increased plasma concentrations of the antigens and these usually occurred during very advanced phases of the disease. Detectable levels of serum TG were never observed. When the outcome of the disease was compared with the expression of CT. CEA. NSE. CGRP. and TG. no correlation could be found. On the contrary. SRIF expression in the primary tumor could differentiate two groups of patients with different survival rates. SRIF-positive patients had survival rates of 100% and 50% at five and seven years. respectively. whereas SRIF-negative patients had survival rates of 40% at five years and 25% at seven years.
Small cell carcinomas of the large intestine, The authors studied the clinical and pathologic features of 38 small cell carcinomas of the large intestine. Most were located in the right colon. Overlying adenomas were present in 45% and squamous differentiation in 21% of tumors. Endocrine differentiation was present in all tumors by at least one method; neuron-specific enolase. dense-core granules. and synaptophysin were present in most cases. Seventy-one percent of tumors metastasized to the liver; 64% of patients were dead at five months follow-up. Twenty-one poorly differentiated adenocarcinomas and undifferentiated carcinomas of the large intestine accessioned during the same period showed less endocrine (7 of 21) and squamous differentiation (1 of 15) and fewer liver metastases (4 of 15) than did small cell carcinomas. Among all 59 tumors studied. small cell histologic characteristics correlated better with liver involvement than did endocrine markers or other histologic features. Small cell carcinomas of the large intestine are aggressive tumors with a propensity for early liver involvement. Although there is a spectrum of squamous. endocrine. and glandular features in large bowel tumors of low degrees of differentiation. the identification of a small cell component appears to be most clinically relevant.
Automated immunohistochemical estrogen receptor in fixed embedded breast carcinomas, The authors immunohistochemically assessed the presence of estrogen receptor (ER) in formalin-fixed. paraffin-embedded tissue sections of 68 breast carcinomas by an automated method using Pronase (CalBiochem. La Jolla. CA) predigestion and alkaline phosphatase detection (Method 1). These results were compared with those obtained by an automated peroxidase-antiperoxidase method with DNAse pretreatment of fixed embedded sections (Method 2). with ER immunostain on frozen sections (Method 3). and with biochemical results (dextran-coated charcoal cytosolic [DCC] assay). Compared with the DCC assay. Methods 1. 2. and 3 gave sensitivities of 54%. 25%. and 89%. respectively. The sensitivity for Method 1 was increased to 74% in those cases with DCC results showing greater than 50 fmol/mg protein. These findings indicate that ER immunohistochemical studies on formalin-fixed paraffin-embedded tissues (as assayed by Method 1) provide useful clinical information when the results are positive. A negative result. especially if surrounding normal elements are not positive. may indicate no receptors. receptor levels less than 50 fmol/mg protein. or improper tissue preservation. In the absence of fresh tissue for ER assay by DCC assay or of frozen sections for immunostaining. and with an understanding of its limitations. this method may be useful.
Ovarian myxoma. A study of two cases with long-term follow-up, Two cases of the so-called ovarian myxoma are reported. One was from a 13-year-old girl who had a 31-year follow-up and no evidence of recurrence. The second case. from a 65-year-old woman. recurred intraperitoneally. 19 years after the surgery. Both tumors were myxoid. with round to stellate cells. Immunohistochemical. electron microscopic (EM). and DNA flow cytometric (FCM) studies were performed on formalin-fixed. paraffin-embedded tissue of the second patient on both the primary tumor and the recurrence. Tumor cells expressed vimentin and were focally positive for desmin and myoglobin. EM findings suggested a fibroblastic differentiation. An aneuploid cell population was present in the recurrent tumor by DNA-FCM studies. Only four other cases of so-called ovarian myxoma were reported to date. and the follow-up does not exceed 18 months. The authors conclude that the presence of aneuploidy and the late recurrence of one of their cases suggest that certain ovarian myxomas might behave like low-grade sarcomas. The histogenesis of this tumor remains unsettled. but similarities were found with myxomas in other locations.
Ceftazidime-induced hemolysis in a patient with drug-dependent antibodies reactive by immune complex and drug adsorption mechanisms, A 35-year-old woman developed acute intravascular hemolysis within five days of beginning a course of ceftazidime. The direct antiglobulin test became strongly positive with both anti-IgG and anticomplement. The serum contained an antibody that. in the presence of ceftazidime. sensitized unmodified reagent cells with IgG and complement (immune-complex type). The serum also agglutinated ceftazidime-pretreated cells at room temperature and 37 degrees C (drug-adsorption type). Retrospective testing disclosed that the drug adsorption antibody. which had been present before the current course of antibiotics. was not demonstrable during the hemolysis. The reactivity of the immune complex antibody. which developed by the second day of ceftazidime. paralleled the degree of hemolysis and the strength of the direct antiglobulin test. The authors believe that this patient had two separate ceftazidime-dependent antibodies and that the antibody reactive by immune complex mechanism mediated an episode of acute intravascular hemolysis.
Issues in cerebrospinal fluid management. CSF Venereal Disease Research Laboratory testing, Three policies for decreasing unnecessary cerebrospinal fluid (CSF) management Venereal Disease Research Laboratory (VDRL) tests were compared. The first policy attempted to educate physicians about the use of serologic tests for diagnosing neurosyphilis but allowed the CSF VDRL to be performed either as a screening test or as a retrospective test. The second policy required that the CSF VDRL be performed as a retrospective test without regard to the patient's serologic status. The third policy required that a patient be seropositive by either rapid plasma reagin (RPR) or fluorescent treponemal antibody absorbance (FTA-ABS) before a CSF VDRL could be performed. Before these policies were instituted. VDRL testing was performed on 18.2% of all CSF samples. The optional and required retrospective policies decreased the CSF VDRL rate to 13.0% and 8.5%. respectively. but the percentages of seropositive patients for whom these procedures were performed were only 7.3% and 12.9%. The third policy decreased the CSF VDRL test rate to 1.8% (P less than 0.001) with seropositivity improving to 90%. To assure serologic tests are obtained in the evaluation of neurosyphilis. requirement for seropositivity must be implemented with the use of retrospective CSF VDRL testing.
Issues in cerebrospinal fluid management. Acid-fast bacillus smear and culture, Meningeal tuberculosis is an uncommon disease in the United States with an annual incidence of fewer than 200 cases. This study evaluates three approaches to improving the use of the cerebrospinal (CSF) acid-fast bacillus (AFB) smear and culture procedure: (1) education alone; (2) optional screening by which physicians can select to have the AFB analysis stopped if the initial CSF findings are unremarkable; and (3) mandatory screening before the performance of all CSF AFB analyses. With education alone. the CSF AFB culture rate decreased from 20.6% of all CSF acquisitions to 15.7% (P less than 0.001); however. the effect may have been related to a decrease in all types of AFB testing. Optional screening had no impact on the AFB testing rate. Mandatory screening significantly decreased the CSF AFB rate to 6.7% (P less than 0.001). unrelated to changes in other types of AFB testing. Laboratories that employ mandatory screening should report the screening results immediately and have a mechanism whereby physicians can bypass the screen. providing CSF AFB analysis on unremarkable fluid from high-risk patients.
Rapid microscopic detection of malaria parasites permanently fluorochrome stained in blood smears with aluminum and morin, Intra- and extracellular Plasmodium parasites in fixed blood smears are easily identifiable by fluorescence microscopy after brief mordanting with aluminum ammonium sulfate and staining with morin (3.5.7.1'.4'-pentahydroxyflavanol). The intensely fluorescent preparations of stained parasites are strongly resistant to photodegradation and remained essentially unimpaired for two years.
Immunotactoid glomerulopathy, During the past 10 years. immunotactoid glomerulopathy has become recognized with increasing frequency. The lesion is characterized histologically by highly organized ultrastructural deposits that appear to be composed of immunoglobulin and complement and are negative for amyloid by Congo red stain. Clinically and/or serologically. patients have no evidence of cryoglobulinemia. amyloidosis. systemic lupus erythematosus. or a paraproteinemia. disorders associated with glomerular deposits. which also have a highly organized tactoidal or fibrillar characteristic. Immunotactoid glomerulopathy does not appear to be a multisystemic disease process and thus may represent a primary glomerulopathy. Patients with immunotactoid glomerulopathy present with proteinuria (nephrotic range in more than 60%) and over half of the patients have hypertension. hematuria. and renal insufficiency. Progression to end stage renal disease has occurred in more than 40% of patients reported to date. The experience in treating this disorder using prednisone and/or immunosuppression is limited and has not been impressive. Four patients have successfully undergone renal transplantation. but proteinuria recurred in two and was associated with the recurrence of immunotactoid glomerulopathy in the renal allograft. Although we have gained insight into the clinical course and histopathology of this disorder over the past few years. we still know little about its pathogenesis. an area for further research.
Prolonged survival with a remnant kidney, Surgical ablation of five-sixths renal mass in Munich-Wistar rats fed a high protein diet leads to focal sclerosis in the remnant kidney and progressive renal failure. Experimental data suggest that this injury results from intraglomerular hypertension and/or chronic glomerular hyperfiltration. Data in humans largely are limited to patients with unilateral renal agenesis or uninephrectomy. either for unilateral renal disease or for kidney transplant donation. Isolated case reports have documented focal sclerosis and progressive renal failure in two patients with a remnant kidney. To obtain data in humans with a remnant kidney. we surveyed more than 800 urologists and nephrologists in the United States and abroad. Criteria for inclusion in the study were (1) surgical resection (in one or more operations) resulting in the presence of a remnant kidney; and (2) an adequate period of follow-up. defined as 5 years or greater. A total of 13 patients were identified (from 13 different centers). Twelve patients had renal cancer and one had tuberculosis. Six patients were observed for 10 or more years postoperatively and all have stable serum creatinine levels of less than 270 mumol/L (3.0 mg/dL); two of these six patients are now more than 25 and 30 years postoperation. The other seven patients. observed for 5 to 7 years. have serum creatinine levels less than 270 mumol/L (3 mg/dL). while one has an increasing serum creatinine level. The two longest surviving patients both have undergone successful pregnancy with no overall change in serum creatinine. These observations demonstrate that it is possible for humans to survive more than 30 years with a stable serum creatinine. despite the presence of only a remnant kidney.
Dialysis-induced alterations in left ventricular filling: mechanisms and clinical significance, Quantitative two-dimensional (2-D) and Doppler echocardiography were used to determine whether hemodialysis results in alterations in left ventricular (LV) diastolic filling that might contribute to dialysis-induced hypotension. as well as to assess whether any hemodynamic variables or indices of diastolic filling might be used to identify which patients were at the greatest risk of becoming hemodynamically unstable during dialysis. Sixteen male patients undergoing routine maintenance hemodialysis for end-stage renal disease were prospectively studied before and after hemodialysis. Following hemodialysis there was a significant prolongation (P less than 0.05) in LV isovolumetric relaxation time (IVRT). as well as a significant reduction in the rate and extent of early rapid ventricular filling (P less than 0.005); in contrast. late atrial-assisted filling did not change significantly. A multiple stepwise linear regression analysis of predialysis hemodynamic parameters and noninvasive indices of LV filling showed that there was a significant independent inverse relationship between the frequency of dialysis-related hypotensive episodes and the duration of early LV filling (r = -0.81; P less than 0.001). These results suggest that hemodialysis results in discrete alterations in early LV filling. with no significant compensatory increase in late atrial-assisted ventricular filling. Further. patients with the shortest early LV filling times appeared to have the greatest predilection for becoming hemodynamically unstable during dialysis.
Evaluation of hemodialysis patients treated with erythropoietin, We evaluated 20 hemodialysis patients who had been treated with erythropoietin (Epo). All patients had hemoglobin levels below 8.5 g/dL. They were randomized to receive either Epo (100 U/kg) or placebo three times per week for 12 weeks. All patients on Epo had a significant (P less than 0.001) elevation of hematocrit levels (19.7% v 35.7%). They also had a significant (P less than 0.05) increase in midweek predialysis blood urea nitrogen (BUN) levels. 27.8 versus 29.6 mmol/L (78 v 83 mg/dL). and serum phosphorus. 1.8 versus 2.1 mm/L (5.7 v 6.6 mg/dL). Protein catabolic rate also increased significantly (P less than 0.05). No changes were seen in the levels of serum creatinine and potassium. but episodes of hyperkalemia were more frequent in patients on Epo. No changes were seen in patients on placebo. When hematocrit increased. the clearance of blood-water for urea decreased 9%. and the clearance of creatinine. potassium. and phosphorus decreased 15%. Patients on Epo increased both their appetite and protein intake. More frequent episodes of hyperkalemia and elevated phosphorus level resulted from a combination of increased intake and decreased dialyzer clearance. We may need blood-water clearance to calculate Kt/V.
Use of the fistula assessment monitor to detect stenoses in access fistulae, Twenty-three unselected hemodialysis patients with functioning access arteriovenous fistulae were studied prospectively to determine the best technique for detecting stenoses within the fistulae. Combined clinical assessment and fistula assessment monitoring were compared with transbrachial angiography. Fistula assessment monitoring was more accurate (96%) than combined clinical assessment (accuracy. 52%) in stenosis detection. Complications of angiography occurred in 17% of patients; there were no complications of fistula assessment monitoring. Fistula assessment monitoring was better than combined clinical assessment in predicting clinical outcome for arteriovenous fistulae over 6 months and was as good as angiography. Routine fistula assessment monitoring could reduce inappropriate angiography and detect clinically significant silent stenoses. It is an ideal method for monitoring arteriovenous access fistulae.
Cyclosporine-induced thrombotic microangiopathy resulting in renal allograft loss and its successful reuse: a report of two cases, Cyclosporine-induced thrombotic microangiopathy is a rare complication of renal transplantation. It commonly leads to graft loss. The mechanism of this entity is unknown. Factors intrinsic to the donor kidney appear to play an important role. We describe two cases of renal transplant patients who lost their first grafts secondary to cyclosporine-induced thrombotic microangiopathy. These patients were successfully retransplanted with an immunosuppressive protocol that included long-term cyclosporine. We conclude that graft loss from this entity is not a contraindication to subsequent successful transplantation with cyclosporine.
Frequency of nonparenteral occupational exposures to blood and body fluids before and after universal precautions training, PURPOSE: During annual periods before and after Universal Precautions training. we compared the frequency of health care workers' self-reported cutaneous exposures to blood and various body substances from any patient and from patients presumed infected with human immunodeficiency virus type 1 (HIV-1). SUBJECTS AND METHODS: Self-reported cutaneous exposures to blood. sputum. urine. feces. and other body substances were evaluated separately in 559 workers during the first survey and 269 workers during the second. RESULTS: Mean annual blood exposures decreased from 35.8 to 18.1. and mean annual exposures to all substances decreased from 77.8 to 40.0 (p less than 0.001 for both determinations). Two matched analyses of a subset of 200 participants who completed both surveys had similar results. Reported exposures to blood. presumably infectious blood. sputum. presumably infectious sputum. and urine were significantly decreased. Participants were tested for antibodies to HIV-1; no participant reporting cutaneous exposures acquired HIV-1 infection. The upper bound for the 95% confidence interval for the risk of HIV-1 infection associated with a single cutaneous exposure was 0.04% for blood presumed to contain HIV-1 and 0.02% for any body substance presumed to contain HIV-1. CONCLUSIONS: These data suggest that Universal Precautions training significantly decreased but did not eliminate cutaneous exposures to blood and body substances. The results further suggest that the risk for HIV-1 infection associated with cutaneous exposures is substantially lower than the risk associated with parenteral exposures.
Unsuspected mitral stenosis, PURPOSE AND PATIENTS AND METHODS: We observed a series of patients in whom the diagnosis of mitral stenosis was first discovered in the echocardiography laboratory. Because of this experience. we examined the records of 152 patients with echocardiographic evidence of rheumatic mitral stenosis to determine the clinical characteristics and course of patients with unsuspected mitral stenosis as well as those factors that may have obscured the diagnosis. RESULTS: Of these 152 patients. 18 had mitral stenosis that was unsuspected clinically until the echocardiogram. These patients were elderly. with a median age of 72 years. They were all referred for echocardiography because of cardiac symptoms. Eight patients were referred for evaluation of congestive heart failure. Five patients were referred for evaluation of aortic valve disease. Three patients were referred because of cerebrovascular accidents and atrial fibrillation. The Doppler-determined mean diastolic mitral gradient ranged from 4 to 15 mm Hg (mean: 7 mm Hg). Mitral stenosis ranged in severity from trivial to very severe. Eight patients had moderate to severe mitral stenosis with estimated mitral valve areas less than or equal to 1.5 cm2. Seven had mild or trivial mitral stenosis with estimated mitral valve areas greater than 1.5 cm2. After further evaluation. two patients underwent mitral valve surgery with improvement of congestive failure. In three patients. warfarin therapy was begun to prevent emboli. Thus. five of 18 patients had a significant immediate change in therapy because of the discovery of mitral stenosis. CONCLUSION: The diagnosis of mitral stenosis may not be suspected in the presence of advanced age. other serious cardiac and medical conditions. or mechanical factors that complicate the physical examination. In these patients. mitral stenosis may be hemodynamically significant and may cause significant symptoms.
Prognostic significance of valvular regurgitation in patients with infective endocarditis, PURPOSE: Doppler ultrasound is a sensitive modality for detecting and quantitating valvular regurgitation in patients with infective endocarditis. Because valvular regurgitation leads to heart failure. we evaluated the prognostic significance of Doppler-detected valvular regurgitation in patients with endocarditis who had not yet developed clinical heart failure. PATIENTS AND METHODS: We reviewed the medical records of 65 patients with a clinical diagnosis of infective endocarditis from May 1985 to March 1990. A total of 49 patients were included in the study: 33 patients with native valve endocarditis and 16 patients with prosthetic valve endocarditis. The initial Doppler echocardiogram was examined in these patients to determine the presence and degree of valvular regurgitation. RESULTS: Significant (moderate to severe) valvular regurgitation was detected in 23 (47%) patients. The presence or absence of significant valvular regurgitation did not predict the development of congestive heart failure. the need for surgery. or death (p = NS). The development of congestive heart failure was significantly associated with the need for surgery (p less than 0.0001) and death (p less than 0.05). CONCLUSION: We conclude that the detection of significant valvular regurgitation in patients with infective endocarditis who have not yet developed heart failure is not predictive of future complications nor does the absence of significant valvular regurgitation identify a group of patients with a more favorable prognosis. In our series. patients who developed congestive heart failure had a significantly higher incidence of surgery and death. Therefore. decisions regarding clinical management in patients with infective endocarditis should not be made solely on the presence or absence of echocardiographically detected valvular regurgitation.
Comparison of labetalol versus enalapril as monotherapy in elderly patients with hypertension: results of 24-hour ambulatory blood pressure monitoring, PURPOSE: This study compared the safety and efficacy of labetalol and enalapril as antihypertensive therapy for elderly patients. PATIENTS AND METHODS: A randomized. open-label. parallel controlled trial was conducted. After completing a 4-week placebo phase. 79 elderly (65 years or older) patients with an average standing diastolic blood pressure (BP) 95 mm Hg or above and 114 mm Hg or less were randomized to receive a 12-week course of either labetalol or enalapril in an open-label design. The patients' BP and heart rate were evaluated biweekly by trained observers unaware of the treatment status. and drug dosage was titrated (up to 400 mg twice a day of labetalol or 40 mg daily of enalapril) to achieve a standing diastolic BP of less than 90 mm Hg and a decrease of 10 mm Hg from baseline. Patients underwent 24-hour ambulatory BP monitoring (ABPM) at the end of the placebo phase and again after 8 weeks of active treatment. RESULTS: The treatment groups were comparable in their reduction of supine diastolic BP. with no significant differences between the two treatments. Labetalol demonstrated a significantly greater reduction (p less than 0.05) in standing diastolic BP at the end of the titration period compared to enalapril. but this difference was not significant by the end of the study period. Based on 24-hour ABPM readings. labetalol reduced mean 24-hour diastolic BP (p less than 0.05) and mean heart rate (p less than 0.05) more than enalapril. The labetalol-treated patients were significantly less often above their diastolic BP goal throughout the 24-hour ABPM period (p less than 0.01). The two treatments were equally well tolerated. CONCLUSIONS: The results indicate that labetalol and enalapril are equally effective in lowering supine diastolic BP in the elderly. but labetalol is more effective in lowering ambulatory BP and heart rate throughout the day.
Local reactions to radioiodine in the treatment of thyroid cancer, PURPOSE: To compare the rate of local complications resulting from radioiodine ablation of thyroid cancer in patients with a residual intact thyroid lobe to that in patients who had more extensive surgical treatment prior to radioiodine administration. PATIENTS AND METHODS: We retrospectively studied 59 patients who had received 131I between 1979 and 1989. The patients were divided into two groups. depending on the extent of their previous surgical thyroid excision. Group 1 comprised 10 patients with a lobectomy or hemithyroidectomy before the ablative radioiodine dose. and Group 2 comprised 49 patients with more extensive thyroid excision (near-total or subtotal thyroidectomy) before the radioiodine treatment. RESULTS: Sixty percent of the 10 patients in Group 1 experienced some degree of neck pain or tenderness following radioiodine ablation of their residual thyroid. In one case. the local reaction was very severe and accompanied by the development of transient hyperthyroidism. There was only a 6% local complication rate in the patients who had undergone more extensive thyroid excision before ablative therapy (p less than 0.001). and none had a severe reaction. CONCLUSIONS: Patients with only unilateral surgical excision before radioiodine therapy have a higher rate of local complications than do patients treated with more extensive surgery prior to radioiodine ablation. If radioiodine is to be employed in such patients. they should be informed of this possible complication. Since evidence supports a dose effect in the pathogenesis of the complications. we recommend using a dose of less than 30 mCi for the initial ablation in these patients even though it may be necessary to repeat this dose to complete thyroid ablation.
A two-step model for development of non-insulin-dependent diabetes, Both insulin resistance and beta-cell dysfunction occur during the development of non-insulin-dependent diabetes mellitus (NIDDM). but controversy exists about which lesion is primary. Based on longitudinal studies in the Pima Indians. a population with the world's highest reported prevalence of NIDDM. a two-step model for development of the disease is proposed. The first step is transition from normal to impaired glucose tolerance. for which insulin resistance is the main determinant. and the second and later step is worsening from impaired glucose tolerance to diabetes. in which beta-cell dysfunction plays a critical role. This hypothesis is consistent with findings from other ethnic groups from many parts of the world.
Elderly patients with congestive heart failure under prepaid care, PURPOSE: Because of concern about the quality of care received by Medicare patients in health maintenance organizations (HMOs). the care of patients with congestive heart failure (CHF) in eight HMOs was compared with the care of fee-for-service (FFS) Medicare cases. PATIENTS AND METHODS: We compared the care of 170 patients with CHF enrolled in one of eight Medicare HMOs with the care of 191 similar FFS patients. Panels of expert physicians developed criteria for evaluating quality of care. and specially trained nurse clinicians abstracted medical records. RESULTS: Outpatient evaluation and management were similar in both settings. although HMO patients were significantly more likely to be advised to restrict salt intake. However. FFS patients with uncontrolled hypertension were more likely to have their medication regimens changed (62% versus 36%. p less than 0.01). Ejection fractions were obtained equally as often. and inpatient management was similar for both groups. Nonetheless. HMO providers scheduled follow-up visits within 1 week of hospital discharge more often (42% versus 27%. p less than 0.01). CONCLUSIONS: This study suggests that financial incentives of prepaid care are not detrimental to most aspects of care for CHF patients. More rapid follow-up after hospital discharge for patients with CHF suggests that HMOs may be more effective in delivering continuity of care for patients with chronic illness.
Artifactual elevation of thyroid-stimulating hormone, A clinically euthyroid patient was found to have a normal serum thyroxine level and an elevated plasma thyrotropin (TSH) level measured by fluoroimmunoassay. Thyroid hormone therapy failed to suppress the TSH level. The TSH level was unresponsive to thyrotropin-releasing hormone (TRH) administration. alpha-subunits of pituitary glycoproteins were undetectable in her plasma. and imaging of the pituitary-hypothalamic region was normal. Measurement of TSH with an assay containing sheep antibody to TSH failed to reveal TSH in the patient's plasma. Addition of mouse IgG to the TSH fluoroimmunoassay reduced the patient's TSH to an undetectable level. These observations are consistent with a spurious elevation of TSH due to the presence of an anti-mouse antibody. Artifactual elevations of TSH have not been identified commonly. but this possibility should be considered when the TSH level is inappropriate for the apparent state of thyroid function.
Detection of Plasmodium falciparum infection with the fluorescent dye, benzothiocarboxypurine, The fluorescent dye benzothiocarboxypurine (BCP) intensely stains nucleic acids. The dye does not penetrate viable white blood cells but does stain these cells following fixation. It has also been found that the dye stains the nucleic acid of viable Plasmodium falciparum. We have subsequently evaluated the staining of P. falciparum by benzothiocarboxypurine within red blood cells and have found that the red blood cell membrane is freely permeable to this dye and consequently P. falciparum is stained within the red blood cell. This finding prompted an in-depth analysis of the dye in the laboratory and in a field study as an alternative to Giemsa-stained blood smears and as a means of enhancing the microscopic diagnosis of malarial infection. In a field study the BCP dye allowed detection of malaria in fresh blood at a level equivalent to the Giemsa method (parasitemia ranged from 0.01% to 30%). The BCP staining procedure could also be used with fixed specimens although the differential staining characteristics were lost following specimen preparation. Of 111 blinded samples obtained in the field 22 were negative by Giemsa-stained thin smear. 16 were negative on thick smear and the same 16 were negative by BCP analysis. We have found that the BCP dye offers many advantages compared with the microscopic diagnosis of P. falciparum infection with standard Giemsa stains. These advantages are especially evident in conditions of low parasitemia. in the speed of staining and evaluation. and the relatively low level of training required to provide consistent results.
Acridine orange fluorescent microscopy and the detection of malaria in populations with low-density parasitemia, Detection of low-density malaria parasites with Giemsa-stained thick smears (G-TS) requires time and experience and becomes impractical with high sample loads. Acridine orange fluorescent microscopy (AO/FM) of capillary centrifuged blood may offer an alternative technique. We compared AO/FM readings with G-TS in 290 specimens from asymptomatic people in Thai villages endemic for malaria. AO/FM specimens were prepared in modified capillary tubes coated with acridine orange (Quantitative Buffy Coat or "QBC tubes") and examined under a fluorescent microscope. Twenty-three (85.2%) of the 27 specimens found positive by G-TS had under 100 parasites/microliters blood (less than 35 parasites/200 microscopic fields). The overall AO/FM sensitivity was 78.9% [range: 66.7% (10/15)-86.7% (13/15)]. For Plasmodium falciparum. regardless of stages. the sensitivities varied from 66.7% (8/12) to 91.7% (11/12). AO/FM performed better for P. falciparum than for Plasmodium vivax and for asexual than for sexual stages of the parasite. However. the species- and stage-specific results must be interpreted with caution because of the small sample sizes and very low parasite densities involved. The test specificity was 96.6% [range: 95.6% (263/275)-97.1% (263/271)]. These levels of accuracy plus the known advantages of AO/FM suggest that the test. supplemented with G-TS to improve species and stage differentiation. is also useful for screening low-density parasitemias.
Plasmodium vivax sporozoite antibodies in individuals exposed during a single malaria outbreak in a non-endemic area, We studied seroreactivity against Plasmodium vivax antigens in 62 individuals living in a small community near Mantena. Minas Gerais. Brazil. an area outside the endemic malaria zone Brazil. Eight months earlier. there had been transmission of P. vivax for a period of 50 days. which was then totally controlled by chemotherapy and insecticides. An anti-sporozoite response. measured by ELISA using a recombinant protein expressed in yeast. was detected in 45% (14 of 31) of individuals eight months after infection and persisted for 20 months in 12%. Eighteen individuals were treated prophylactically for malaria because they lived in houses in which an overt infection had occurred. Seven of these individuals were ELISA positive; of these. 5 had antibodies against the blood stage parasites. Among 13 other individuals in the endemic area who did not have positive smears. had not been ill. and had not received prophylaxis. five were anti-circumsporozoite positive up to a 40-fold serum dilution. They did not develop asexual blood stage antibodies and remained parasite-free for the following 20 months.
Comparison of high dose ivermectin and diethylcarbamazine for activity against bancroftian filariasis in Haiti, This three-phase study was designed to compare high dose ivermectin with a standard diethylcarbamazine (DEC) regimen for patient tolerability. potential to kill adult filaria. and duration of microfilarial suppression in 30 Haitian subjects with Wuchereria bancrofti microfilaremia. All were first given a 1-mg oral dose of ivermectin (phase 1) to reduce microfilaria densities. Participants were randomized into three groups: Group 1 received DEC (6mg/kg per day for 12 days). Group 2 received 200 mcg/kg of ivermectin. and Group 3 received 400 mcg/kg of ivermectin (200 mcg/kg per day for 2 days). All drug regimens were well tolerated with few adverse reactions. Most reactions occurred during phase I and consisted primarily of headache. fever. and myalgia. At the end of phase 1. 27 of 30 (90%) patients were microfilaria negative. During phase 2. four of the six men receiving DEC developed scrotal reactions suggesting killing adult worms; no such reactions were noted in 10 men receiving ivermectin (p less than 0.05). At one-year follow up (phase 3). all treatment groups had less than 10% return to pretreatment microfilaria levels. The mean percent of baseline microfilaria counts were for Group 1. 0.9% (range 0-5%); Group 2. 8.2% (range 0-31%); and Group 3. 3.8% (range 0-25%). Seven individuals in Group 1 were microfilaria-negative. while only one and three individuals were microfilaria-negative in Groups 2 and 3. respectively. These results suggest that DEC causes more damage to the adult worms and greater reduction in microfilaria densities than ivermectin. but that high doses of ivermectin may suppress microfilaremia in lymphatic filariasis for periods much longer than previously reported.
Immunization of owl monkeys with the ring-infected erythrocyte surface antigen of Plasmodium falciparum, Aotus nancymai were immunized with the 4-mer. 8-mer. and 11-mer repeat peptides of the ring-infected erythrocyte surface antigen molecule of Plasmodium falciparum conjugated to diphtheria toxoid with muramyl dipeptide (MDP) as adjuvant. Immunization failed to induce protective immunity against the Uganda Palo Alto strain of P. falciparum as judged by maximum levels of parasitemia of immunized monkeys relative to those of controls. The fused polypeptide FPAg632. when combined with MDP. also failed to induce protective immunity. However. the maximum level of parasitemia and serologic response to the 11-mer peptide were inversely correlated. The safety of the use of MDP was evident.
A spleen is not necessary to resolve infections with Plasmodium yoelii, The role of the spleen in resistance to infections with nonlethal Plasmodium yoelii 17x is dependent upon the genotype of the host. Thus. DBA/2 (D2) mice infected with P. yoelii 17x were not adversely affected by removal of the spleen. while splenectomized C57BL/6 (B6) or Balb/c mice failed to resolve their infections and eventually died. The levels of parasitemia were lower in splenectomized mice compared to intact controls; however. splenectomized mice became as anemic as did spleen-intact controls. Splenectomy resulted in the appearance of large aggregates of mononuclear cells in the livers of infected mice and also altered the liver/body weight ratios. These results indicate that D2 mice have a spleen-independent mechanism of clearing parasites which is lacking in B6 and Balb/c mice.
Computed tomography and ultrasonography of the adrenal glands in paracoccidioidomycosis. Comparison with cortisol and aldosterone responses to ACTH stimulation, Fifteen patients with proven disseminated paracoccidioidomycosis (PCM) had computed tomography (CT) and ultrasonography (US) performed to evaluate the form. shape. density and size of their adrenal glands. Plasma and urinary cortisol were determined and adrenal reserve assessed by measuring the cortisol and aldosterone responses to synthetic ACTH. The adrenal CT showed unilateral lesions in two cases and bilateral in another four. The US study showed more frequent alterations. unilateral in seven and bilateral in three subjects. Combining both methods increased the sensitivity to 85% of the cases. All patients had normal plasma cortisol concentrations and normal or increased urinary cortisol excretion. Plasma aldosterone concentration was also normal except in one patient with hypokalemia. Seven patients showed diminished cortisol responses. five had subnormal aldosterone responses and in five plasma aldosterone concentration increased more than normally after stimulation by ACTH. There was an incidence of limited adrenal reserve in 53% of the patients on ACTH stimulation. No correlation was evident between the disorders in adrenal steroid responses to ACTH and changes in morphology revealed by CT and/or US.
Ketamine as analgesic for total intravenous anaesthesia with propofol, A prospective study of 18 patients who underwent noncardiac surgery was performed to study the use of ketamine as an analgesic during total intravenous anaesthesia with propofol. A comparison was made with the combination propofol/fentanyl. The propofol/ketamine combination resulted in haemodynamically stable anaesthesia without the need for additional analgesics. Postoperative behaviour was normal in all patients and none of the patients reported dreaming during or after the operation. Propofol seems to be effective in eliminating side effects of a subanaesthetic dose of ketamine in humans. We recommend the propofol/ketamine combination for total intravenous anaesthesia for surgery when stable haemodynamics are required.
A comparison of the performance of 20 pulse oximeters under conditions of poor perfusion, The performance of 20 pulse oximeters with finger probes was evaluated by comparison of their readings with directly measured arterial blood oxygen saturations. The samples were taken from patients who had undergone cardiac surgery under hypothermic cardiopulmonary bypass and had poor peripheral perfusion. The mean difference (bias. accuracy). standard deviation (precision) and drop-out rate for each pulse oximeter was determined. An overall ranking of performance of each pulse oximeter was calculated using five criteria (accuracy. precision. number of readings within 3% of standard. percentage of readings given within 3% of standard. expected overread limit in 95% of cases). Two pulse oximeters achieved a combination of accuracy and precision such that 95% of measurements would be expected to be within 4% of the co-oximeter value; these two also had the lowest drop-out rate.
Response to suxamethonium in a myasthenic patient during remission, A cumulative dose followed by an infusion was used to determine the dose response to suxamethonium in a patient with diagnosed myasthenia gravis who was in true remission (asymptomatic while receiving no therapy). The ED50 and ED90 values for suxamethonium were 0.08 mg/kg and 0.20 mg/kg. and an infusion rate of 3.2 mg/kg/hour was required to maintain a 90-95% depression of the single twitch response as monitored by integrated electromyography. These values are within the range for normal patients. and we conclude that myasthenic patients during a true remission may not demonstrate resistance to suxamethonium.
Emery-Dreifuss muscular dystrophy, Emery-Dreifuss syndrome is a rare form of muscular dystrophy associated with cardiac complications that lead to sudden death. The disorder and its potential anaesthetic implications in the management of a patient who presented for orthopaedic surgery is described.
Awareness during caesarean section, Between 1982 and 1989 over 3000 patients were questioned about recall and dreaming after general anaesthesia for Caesarean section. Some 28 (0.9%) patients were able to recall something of their operation and 189 (6.1%) reported dreams. There was uniform adherence to a rigid anaesthetic protocol up to and including 1985. but a much publicized incident reported from the courtroom stimulated a relaxation of this regimen. Consequently the incidence of awareness decreased from 1.3% to 0.4%. and the incidence of dreaming was also reduced. Recollections of surgery were confined to manipulations. noises and voices. None of our patients complained of pain at the time of interview. although one since has. The inadequacies of the initial protocol and an approach to informed consent are discussed.
Coagulation screening before epidural analgesia in pre-eclampsia, A questionnaire survey of current practice at a small cross-section of obstetric units. covering 22% of all United Kingdom deliveries. revealed a marked lack of standard practice regarding requests for coagulation screens on pre-eclamptic patients who require epidural procedures. A retrospective audit was therefore carried out on 434 coagulation screens requested for pre-eclamptic patients in whom epidural analgesia might have been considered. Borderline abnormalities of coagulation were found in only 10 patients (2%). Platelet counts of less than 150 x 10(9)/litre were present in 28% of cases. 'Significant' thrombocytopenia (less than 100 x 10(9)/litre) and all coagulation abnormalities were only encountered in severe pre-eclampsia (diastolic blood pressure of greater than 110 mmHg and proteinuria of + + or greater). Furthermore. coagulation abnormality was always associated with a reduced platelet count (mean. 97 x 10(9)/litre). This study would therefore support anaesthetic practice which restricted any requests for coagulation testing to severe pre-eclamptic patients only. For these patients first line testing could be limited to a platelet count.
Modification of pain on injection of propofol--a comparison between lignocaine and procaine, Pain on injection of propofol was assessed in a controlled. randomised study of 273 patients. They received either lignocaine 10 mg. procaine 10 mg or isotonic saline 0.5 ml. 15 seconds before the injection of propofol into a vein on the back of the hand. The incidence of pain on injection in the control group (51%) was comparable with other studies. Lignocaine and procaine both significantly reduced the pain (35% and 34% respectively. p less than 0.05) but there was no statistical difference between these two groups.
Lidocaine potentiation of cocaine toxicity, STUDY HYPOTHESIS: The toxic effects of cocaine are enhanced in the presence of lidocaine. STUDY POPULATION: Male Sprague-Dawley rats weighing 200 to 300 g. METHODS: Animals received intraperitoneal injections of cocaine (10. 20. 35. or 50 mg/kg). lidocaine (30 or 40 mg/kg). or a combination of all doses of cocaine given simultaneously with 30 or 40 mg/kg lidocaine. The incidence and time to seizure and death were recorded in these groups and compared by chi 2 and analysis of variance analyses. respectively. RESULTS: At doses of 30 or 40 mg/kg. lidocaine does not induce seizures or death. The effect of simultaneous injection of both cocaine and lidocaine was to dramatically increase the incidence of both seizures and death over that of cocaine alone. The incidence of seizures in animals receiving 35 mg/kg cocaine alone was 10%; this increased to 50% and 80% with the addition of 30 and 40 mg/kg lidocaine. respectively (P less than or equal to .05; P less than or equal to .01). Death did not occur in animals receiving 35 mg/kg cocaine alone; the addition of 30 and 40 mg/kg lidocaine resulted in death in 30% and 60% of animals. respectively (P less than or equal to .01 each group). Similarly. in rats receiving 50 mg/kg cocaine. the incidence of death increased from 0% to 60% and 80% with 30 and 40 mg/kg lidocaine. respectively (P less than or equal to .01). CONCLUSION: In the rat. overall toxicity of cocaine is significantly increased with simultaneous exposure to lidocaine.
Use of clinical toxicology resources by emergency physicians and its impact on poison control centers, STUDY OBJECTIVE: The need for clinical toxicology resources by emergency physicians is unclear and may have implications for future training and resource availability. This study was designed to assess current emergency physician use of available resources. DESIGN: Prospective evaluation by mail using a 49-item questionnaire. TYPE OF PARTICIPANTS: All 170 emergency physicians in Utah. INTERVENTIONS: None. RESULTS: The response rate was 75.3% (128 of 170). Resources "outside their own fund of knowledge" were consulted "occasionally" to "frequently" by 98.3%. They used the following resources "occasionally" to "frequently": poison control center (PCC) (93.7%). toxicology textbook (77.6%). "expert colleague" (34.0%). and "in-house POISINDEX" (23.9%). They often contacted the PCC for toxicity information (93.7%) and management recommendations (87.3%) and for acute. symptomatic overdose cases (88.3%). They "almost never" contacted the PCC for adverse drug reactions (76.6%). pill identification (70.2%). consultation with physician toxicologist (68.1%). asymptomatic exposures (62.9%). chronic toxicity (50.4%). or solely to report the case to the American Association of Poison Control Centers data base (90.2%). Those who had access to in-house POISINDEX often did not consult the PCC (82.6%). Of those who did not have in-house POISINDEX. 42.8% contacted the PCC to access it. Providing access to physician toxicologist consultations was thought to be an important role for the PCC by 86.7%. but only 32% of physicians were using this option. CONCLUSION: The vast majority of emergency physicians in Utah consult the PCC only for acute. symptomatic overdoses. They view access to physician toxicologist consultation as an important role for the PCC but seldom use it. The availability of in-house POISINDEX decreases the likelihood of PCC consultations from emergency departments. The frequency of emergency physician consultation with the PCC may decrease as POISINDEX becomes available at more hospitals.
Flumazenil: a new benzodiazepine antagonist, Flumazenil is a recently discovered pharmacologic antagonist of the CNS effects of benzodiazepines. It acts by binding CNS benzodiazepine receptors and competitively blocking benzodiazepine activation of inhibitory GABAergic synapses. Animal studies and some human studies appear to demonstrate that flumazenil has weak intrinsic agonist activity; on the other hand. studies are inconclusive in demonstrating any inverse agonist effects of this agent. Evidence available suggests that flumazenil is well tolerated in human beings over a broad range of doses when given either orally or parenterally and does not produce serious adverse effects. In the setting of isolated benzodiazepine overdose. flumazenil is capable of completely reversing coma within one to two minutes. with this effect lasting between one and five hours. Repeat doses can be given safely to reverse recurrent effects of longer-acting benzodiazepines. Flumazenil is undergoing further evaluation by the Food and Drug Administration; should this drug receive approval. it is likely to be used in emergency departments as well as in a variety of other clinical settings. First. it could be used to effect rapid reversal of benzodiazepine-induced sedation that has been administered to facilitate medical. orthopedic. and surgical procedures. particularly in the event of inadvertent respiratory depression. Second. flumazenil might have a therapeutic role in the management of patients who have taken benzodiazepine overdoses. Although most of these patients can be managed successfully with supportive therapy alone. it is possible that the use of flumazenil may obviate the need for intubation and respiratory support in such patients and eliminate the possible adverse effects of even short-term endotracheal intubation. Finally. flumazenil could have both diagnostic and therapeutic value in patients with acute alterations of mental status of unknown etiology. particularly when possible drug overdose is a consideration. Because flumazenil appears to be specific in its antagonism of benzodiazepine-induced respiratory and CNS depression. it could be used empirically to confirm or exclude a role of benzodiazepines in the generation of mental status changes in the setting of overdose or coma of unknown origin. This in turn might obviate the need for further expensive (eg. computed tomography) and sometimes invasive (eg. lumbar puncture) diagnostic modalities. This might be particularly useful because there is nothing about benzodiazepine-induced coma that clearly distinguishes it from other causes of coma; thus. there are no signs or symptoms that may reasonably allow benzodiazepine overdose to be confirmed or eliminated on clinical grounds. Further studies will continue to define the ultimate use of this new agent.
Cocaine-induced iritis, The case of a 31-year-old man who presented to the emergency department with iritis from intranasal cocaine use is described. This was the second episode of iritis in this patient after casual cocaine use. The differential diagnosis of iritis and a proposed pathophysiologic mechanism are discussed.
Drug-induced supraventricular tachycardia: a case report of fluoxetine, We report the occurrence of supraventricular tachycardia and hypotension in a 54-year-old woman after maintenance therapy with fluoxetine. Although cases of tachycardia and palpitations have been reported. supraventricular tachycardia and hypotension have not been directly attributed to fluoxetine.
Torsades de pointes therapy with phenytoin, We present the case of a woman with myocardial infarction complicated by malignant ventricular arrhythmia and torsades de pointes. The torsades de pointes was refractory to conventional therapy but responsive to phenytoin. This case suggests the clinical usefulness of phenytoin for adjunct therapy of life-threatening ventricular arrhythmias when standard treatment modalities fail.
Plasma concentrations of epinephrine during CPR in the dog, STUDY OBJECTIVE: The purpose of this study was to evaluate whether the marked increase in the plasma concentrations of epinephrine during cardiopulmonary arrest and basic life support (BLS) could be due in part to decreased distribution and/or elimination. DESIGN AND INTERVENTIONS: Dogs were randomly assigned to undergo adrenalectomy or sham-operation. Some adrenalectomized animals received an epinephrine infusion. MEASUREMENTS AND MAIN RESULTS: In the seven sham-operated dogs. the plasma epinephrine concentrations increased markedly during BLS as expected. In the seven adrenalectomized dogs receiving a constant infusion of epinephrine. cardiopulmonary arrest and BLS induced a three to sixfold increase in plasma epinephrine concentrations. with an increase in the mean plasma epinephrine concentrations (calculated from the area under the curve) of 1.21 +/- 0.12 ng/mL (P less than .05). In the seven adrenalectomized dogs receiving a constant epinephrine infusion but not subjected to cardiopulmonary arrest. the plasma epinephrine concentrations remained stable. Finally. in the seven adrenalectomized dogs not receiving an epinephrine infusion. the mean plasma epinephrine concentrations during BLS (calculated from the area under the curve) increased only by 0.05 +/- 0.04 ng/mL. significantly less than in adrenalectomized dogs receiving an epinephrine infusion (P less than .01). CONCLUSION: The increase in plasma epinephrine concentrations during cardiopulmonary arrest and BLS is due in part to an altered disposition of epinephrine.
Management of acute pyelonephritis in an emergency department observation unit, STUDY OBJECTIVES: To determine whether moderately to severely ill patients with acute pyelonephritis can be treated successfully on an outpatient basis. and whether any aspect of history. physical examination. or initial laboratory data predicts failure of outpatient therapy and the need for hospitalization. DESIGN: Retrospective chart review of all patients with a diagnosis of acute pyelonephritis seen during a three-year period. SETTING: Emergency department observation unit of an urban teaching hospital serving residents of the city and county of Denver. TYPE OF PARTICIPANTS: Women between the ages of 15 and 50 with symptoms. physical examination. and initial laboratory data consistent with a diagnosis of pyelonephritis. INTERVENTIONS: Patients received IV antibiotics. rehydration. analgesics. and antiemetics in an observation unit for up to 12 hours. when they were either admitted to the hospital or discharged home on oral antibiotics. MEASUREMENTS AND MAIN RESULTS: Sixty-three of 87 patients (72%) with acute pyelonephritis were managed successfully as outpatients. nine (22%) were hospitalized directly from the observation unit because they were considered to be too ill to go home. and five (6%) returned with persistent symptoms after ED therapy and were hospitalized. No clinical or laboratory variable predicted success or failure of ED observation unit therapy at the time of initial presentation. CONCLUSION: In selected patients. the observation unit may be used to initiate therapy for acute pyelonephritis. Those with an adequate clinical response to initial treatment may be discharged on oral antibiotic therapy with appropriate follow-up.
Treatment of pyelonephritis in an observation unit, STUDY OBJECTIVE: To determine the feasibility of managing patients with acute pyelonephritis as outpatients after initial treatment with IV antibiotics in an emergency department observation unit. DESIGN: Prospective and uncontrolled. SETTING: ED observation unit. TYPE OF PARTICIPANTS: Nonpregnant female patients 14 years old or older without immunocompromise or serious underlying disease and no evidence of septic shock. INTERVENTIONS: All patients received two IV doses of trimethoprim/sulfamethoxazole at a 12-hour dosing interval and promethazine and acetaminophen as needed for nausea and fever. respectively. Baseline laboratory data. urinalysis. and urine and blood cultures were obtained. MEASUREMENTS AND MAIN RESULTS: Patients were observed for signs of septic shock. nausea. vomiting. and the ability to tolerate an oral intake. At the end of the observation period. 43 of 44 patients were discharged on oral trimethoprim/sulfamethoxazole. One additional patient who was doing well clinically was recalled and admitted because of a positive blood culture. CONCLUSION: Patients with acute pyelonephritis. despite significant fever or nausea and vomiting. can be treated effectively as outpatients after a brief period of observation and IV antibiotics.
HIV prevalence in a midwestern emergency department, STUDY OBJECTIVE: To determine the prevalence of human immunodeficiency virus (HIV) seropositivity of patients 15 years of age and older in our emergency department. DESIGN: HIV status was determined anonymously. and the seroprevalence rate was calculated. The 95% confidence intervals also were calculated. Twenty demographic and predictor categorical variable were cross-tabulated with HIV status to determine associations. Only gender and male homosexual preference were significantly associated by Fisher's exact test. TYPE OF PARTICIPANTS: Excess serum samples from 454 randomly selected patients 15 years of age and older who required venipuncture for their ED evaluation were included in the study. MEASUREMENTS AND MAIN RESULTS: Of the 454 serum specimens. six (1.32%) were positive for HIV. The 95% confidence interval was from 0.27% to 2.37%. All six positive patients were men. The only statistically significant risk factors associated with HIV seropositivity were male sex (P = .00112) and male homosexual preference (P = .0000). CONCLUSION: HIV seropositivity occurs in 1.32% of our ED population over the age of 15 years. The only factors that correlate with HIV seropositivity are male homosexual preference and male sex.
Suddenly symptomatic brain tumors at altitude, High-altitude cerebral edema can present with a wide variety of neurologic manifestations; these symptoms resolve with descent. The persistence of neurologic symptoms after descent suggests an intracranial lesion. Brain tumors suddenly becoming symptomatic at altitude have not been reported previously. We report three cases of previously unsuspected brain tumors that suddenly became symptomatic at high altitudes.
Genetic cause of a juvenile form of Tay-Sachs disease in a Lebanese child, Abnormality in the beta-hexosaminidase alpha gene underlying the clinical phenotype of a Lebanese patient with a juvenile form of Tay-Sachs disease has been studied. Clinical features were progressive spasticity. ataxia. and cognitive decline. The protein coding sequence of several beta-hexosaminidase alpha-chain complementary DNAs isolated by polymerase chain reaction was completely normal except for a G-to-A transition at nucleotide position 1511 within exon 13. which resulted in substitution of the normal arginine 504 (CGC) with histidine (CAC). Although the patient was from a first-cousin marriage. she was heterozygous for this mutation. The abnormality in the other allele. which is carried by the father. was not identified. except that it is neither of the two mutations responsible for the infantile Jewish Tay-Sachs disease. Biosynthetic and immunoprecipitation studies in cultured fibroblasts showed synthesis of the alpha-chain precursor. but the mature form of the alpha-subunit was not detected.
Neuroanatomy of fragile X syndrome: the posterior fossa, The occurrence and specificity of posterior fossa abnormalities as measured from magnetic resonance images of the brain were investigated in a group of 14 males with fragile X syndrome and comparison groups consisting of 17 males with other causes of developmental disability and 18 males with normal IQs. The size of the posterior cerebellar vermis was significantly decreased and the fourth ventricle significantly increased in the group of males with fragile X syndrome compared with males in both comparison groups. These neuroanatomical abnormalities appeared to be secondary to hypoplasia rather than atrophy.
Visual dysfunction in Alzheimer's disease: relation to normal aging [published erratum appears in Ann Neurol 1991 Mar;29(3):271, In patients with Alzheimer's disease (AD). compared with age-matched and young healthy control subjects. visual deficits in the following functions were observed: color. stereoacuity. contrast sensitivity. and backward masking (homogeneous and pattern). Critical flicker fusion thresholds were normal. relative to age-matched healthy subjects. For color. the majority of the errors were tritanomalous (blue axis). Color and stereoacuity deficits were unrelated to severity of dementia. in accordance with models of vision that describe these functions as modular rather than diffuse for cortical localization. Although contrast sensitivity was depressed throughout the frequency range in AD. more patients were impaired at low than at high spatial frequencies. contrasting with the observed normal aging pattern of high-frequency loss. Healthy elderly subjects showed depressed critical flicker fusion thresholds and reduced contrast sensitivity at high frequencies. relative to the young group; differences between these groups were not found for the other vision tests. A subset of the AD group received detailed neuro-ophthalmological examination. and no abnormalities were found. This finding. taken together with normal thresholds for critical flicker fusion. suggests that the widespread visual dysfunction reported here is more likely to be related to known pathological changes in primary visual and association cortex in AD than to changes in the retina or optic nerve.
Major differences in the dynamics of primary and secondary progressive multiple sclerosis, In patients with primary and secondary progressive multiple sclerosis (MS). major differences in the pattern and extent of abnormality on cerebral magnetic resonance imaging (MRI) between the two groups have recently been demonstrated. In the present study. 24 patients. matched for age. sex. duration of disease. and disability. had serial gadolinium diethylenetriaminepentaacetic acid-enhanced MRI over a 6-month period. The 12 patients in the secondary progressive group had a total of 109 new lesions over this time (18.2 lesions per patient per year) and 87% of these enhanced. Enhancement also occurred within and at the edge of preexisting lesions. In contrast. only 20 new lesions were seen in the primary progressive group (3.3 lesions per patient per year) and only one of these enhanced. There was no difference in the degree of clinical deterioration between the two groups over the 6-month period. These findings may indicate a difference in the dynamics of disease activity between the two forms of progressive MS. particularly in relation to the inflammatory component of the lesions. and have important implications for the selection of patients and the monitoring of disease activity in therapeutic trials.
Correlation of phasic muscle strength and corticomotoneuron conduction time in multiple sclerosis, Central motor conduction times for the adductor pollicis muscle. the twitch force of that muscle to scalp magnetic motor cortex stimulation. and the maximum force of phasic voluntary contraction of the same muscle were measured in 15 patients with multiple sclerosis. Two tests of manual dexterity of the same hand also were studied: the Purdue pegboard test. and the maximal frequency of a scissors movement of the thumb and index finger. The patients had normal strength or minimal weakness of the intrinsic muscles of the hand on clinical examination. The mean central motor conduction times for the adductor pollicis muscle for the patients were longer than normal. the peak twitch force of the adductor pollicis muscle evoked by cortical stimulation and the maximum force of a phasic voluntary contraction of the adductor pollicis muscle were smaller than normal. There were strong correlations between all these measures. Central motor conduction time in the patients was inversely correlated with voluntary phasic force and the twitch force after cortical stimulation. That is. the longer the central motor conduction time. the weaker the force. Prolonged central motor conduction time is likely to be accompanied by conduction block in corticomotoneuron pathways. The correlation of central motor conduction time with voluntary phasic force and the twitch force most likely reflects the degree of conduction block and temporal dispersion rather than delay in conduction per se. These results indicate that objective assessments of phasic muscle strength may reveal correlations with central motor conduction time that are not evident on conventional clinical examination which assesses tonic muscle contraction strength.
Nerve growth factor prevents toxic neuropathy in mice, Taxol is a promising new antitumor drug with therapeutic use that is limited by a toxic sensory neuropathy. Taxol is also cytotoxic to dorsal root ganglion neurons in vitro. but this effect is prevented by cotreatment with the trophic protein. nerve growth factor. We sought to develop an animal model and then to determine whether nerve growth factor can prevent taxol neuropathy in vivo. Administration of taxol to mice resulted in a profound sensory neuropathy characterized by decreases in dorsal root ganglion content of the peptide neurotransmitter. substance P. elevated threshold to thermally induced pain. and diminished amplitude of the compound action potential in the caudal nerve. Coadministration of nerve growth factor prevented all of these signs of neurotoxicity. These findings suggest that administration of nerve growth factor may prevent certain toxic sensory neuropathies.
Localization of 3H-dihydroergotamine-binding sites in the cat central nervous system: relevance to migraine, Dihydroergotamine (DHE) is the treatment of choice in aborting the acute attack of migraine. Although its efficacy has been known for 40 years. its mechanism of action is still disputed. Data regarding the site of action of dihydroergotamine may provide an insight into its mechanism of action and thus identify a locus of potentially abnormal pathophysiology in migraine. By using in vitro and ex vivo autoradiographic techniques. the localization of specific binding sites for 3H-dihydroergotamine in the cat brain has been examined. Binding was seen in the dorsal horn of the cervical spinal cord. in the medulla. associated with the nucleus of the tractus solitarius. area postrema. and descending spinal trigeminal nucleus. and in the mesencephalon and the cerebral cortex. The highest density of binding sites was found in the dorsal and medial raphe nuclei of the midbrain. Furthermore. these same brain regions were also labeled after intravenous administration of 3H-dihydroergotamine. It is important that the brain areas specifically labeled are key nuclei involved in cranial pain transmission. suggesting that dihydroergotamine may act at these central sites in migraine.
Apparent response of subacute sclerosing panencephalitis to intrathecal interferon alpha, An 8-year-old boy with subacute sclerosing panencephalitis (SSPE) was treated with 1.0 to 3.0 x 10(6) IU human interferon alpha (IFN) by the intrathecal route weekly or fortnightly. Pronounced improvement of clinical and electroencephalographic findings were observed in a dose-dependent manner. Our patient raises hope that IFN can induce sustained remission in patients with SSPE.
Neonatal screening for cystic fibrosis in Wales and the West Midlands: clinical assessment after five years of screening, Screening of the newborn for cystic fibrosis by measurement of immunoreactive trypsin has been undertaken on alternate weeks in Wales and the West Midlands for five years since 1985 to evaluate the possible clinical benefits of early diagnosis. Patients detected by screening and those diagnosed by clinical symptoms alone were assessed annually for differences in clinical. anthropometric. and biochemical variables. Fifty eight infants not considered to be at risk of cystic fibrosis (they did not present with meconium ileus and do not have a sibling with cystic fibrosis) have been detected by screening and they have been compared with 44 children who were diagnosed clinically. This latter group includes nine children whose screening was negative but who were recognised subsequently to have cystic fibrosis. The mean age at diagnosis of the screened group was significantly lower than that of the group diagnosed clinically. Excluding admissions for diagnostic tests for cystic fibrosis. the screened group spent a significantly shorter time in hospital during the first year of life. The results of all other comparisons made between the screened group and those diagnosed clinically were similar up to the age of 4 years.
Controversies in the management of gastroschisis: a study of 40 patients, Forty infants with gastroschisis were referred to two paediatric surgeons during a 13 year period. Overall survival was 90%. Nine patients were transferred in utero and 31 were referred postnatally. Birth weights. gestational ages. and Apgar scores were similar for both groups. Primary closure of the defect was successfully achieved in seven (78%) patients in the prenatally transferred group compared with 17 (55%) in the postnatal group. Significantly less postoperative assisted ventilation. and a trend in favour of early discharge home. were noted after prenatal transfer. Problems arising during postnatal transfer may have contributed to these differences. No major differences resulting from the mode of delivery were identified. Patients treated by primary closure fared significantly better than those undergoing staged repairs with prosthetic material. Prospective randomised studies are required to confirm these findings.
Endotracheal resuscitation of neonates using a rebreathing bag, Thirty asphyxiated neonates were resuscitated endotracheally with an anaesthetic rebreathing bag. The system was not limited either by pressure or by volume and chest movement was used as the criterion for adequate inflation. Inflation pressure and flow were recorded during resuscitation. and flow was integrated to obtain volume. Median mean pressure over the first 10 inflations was 40 cm H2O and this dropped during later resuscitation to 29 cm H2O. The volume delivered did not change significantly. so volume divided by pressure increased from a median of 0.18 to 0.35 ml/kg/cm H2O. Fourteen infants formed part of their functional residual capacity with artificial ventilation and five with spontaneous breaths. Eleven infants showed no evidence of functional residual capacity formation. In the 22 preterm infants there was a strong association between absence of functional residual capacity formation and later hyaline membrane disease that required ventilation. We suggest that pressures of more than than 30 cm H2O may be helpful during initial resuscitation and that there should be further study of devices using positive end expiratory pressure for resuscitation of preterm infants.
National Institute of Mental Health longitudinal study of chronic schizophrenia. Prognosis and predictors of outcome [published erratum appears in Arch Gen Psychiatry 1991 Jul;48(7):642, We performed a longitudinal study of chronic schizophrenic patients who were hospitalized for research purposes at the National Institute of Mental Health (NIMH) Intramural Program in the 1970s and early 1980s. We assessed present course. outcome and predictor data from the initial cohort of 58 young chronic schizophrenic patients who were followed up for 2 to 12 years following their NIMH index hospitalization. At follow-up. the sample showed substantial functional impairment and levels of symptoms with only about 20% of the sample demonstrating a good outcome. In addition. strong intercorrelation was noted among the symptom and functioning indexes at follow-up. Moreover. neuropsychologic tests of frontal cortical functioning were significantly correlated with outcome levels of negative symptoms and social functioning but not with levels of positive symptoms. During the period from the index hospitalization to the follow-up assessment. 78% of the sample suffered a relapse. 38% attempted suicide and 24% had episodes of major affective illness. Furthermore. levels of positive and negative symptoms ascertained when patients received optimal neuroleptic treatment during the index hospitalization significantly predicted outcome levels of symptoms and functioning and time spent hospitalized during the follow-up period. In contrast. levels of index positive and negative symptoms ascertained during the drug-free state did not predict outcome symptoms or functioning. These data suggest that treatment response is a critical predictor variable. We examined the implication of these data for the course of illness in schizophrenics.
Posthospital course and outcome in schizophrenia, To study the early course of schizophrenia. we assessed 79 early phase. young. DSM-III schizophrenic patients at two successive posthospital follow-ups. 2.5 and 5.0 years after index hospitalization. More than 50% of the sample had poor overall outcome. with either severe impairment in functioning and symptoms. or suicide. in the follow-up period. Rehospitalization rates decreased significantly during the course of the two posthospital assessments. despite the sample showing persisting psychosis. Only a small group of schizophrenic patients showed complete remission: 10% at the first follow-up and 17% at the second follow-up. when patients who suicided are excluded from consideration. While progressive deterioration is not common in schizophrenia. our relatively negative findings challenge the conclusions of some other longitudinal studies. Implications of our data on schizophrenic course are discussed.
Acquired methemoglobinemia. The relationship of cause to course of illness [published erratum appears in Am J Dis Child 1991 Feb;145(2):158, To better characterize methemoglobinemia in children. we reviewed the charts of 17 patients who were admitted to a children's hospital over the last 10 years. Two distinct groups were identified: (1) The endogenous group (n = 9) included patients with methemoglobinemia associated with an intercurrent illness. (2) The exogenous group (n = 8) included patients with methemoglobinemia secondary to drug exposure. Despite similar initial methemoglobin levels in the endogenous (mean. 29%) and exogenous (mean. 28%) groups. children in the endogenous group had more acidosis (serum bicarbonate levels of 5.9 vs 19.1 mmol/L and arterial pH of 7.01 vs 7.35). All the children in the exogenous group with methemoglobinemia secondary to an accidental ingestion stayed only 1 day in the hospital. while children in the endogenous group were admitted for an average of 19 days. Children with methemoglobinemia secondary to a drug exposure have a more benign illness with a shorter duration than children with methemoglobinemia associated with an intercurrent illness. It appears that the absolute level of methemoglobin is not as important as the underlying cause in determining both the course and severity of illness.
Risk factors and manifestations of digoxin toxicity in the elderly, The incidence of digoxin toxicity increases with age. largely because the two most common conditions that benefit from use of digoxin. congestive heart failure and atrial fibrillation. are markedly more prevalent in old age. Whether the elderly are more sensitive to the effects of digoxin because of age per se is unclear. However. several other factors render the elderly more susceptible to digoxin toxicity. These include an age-related decline in renal function and a decrease in volume of digoxin distribution. There is also an increase in the number of comorbid conditions. including cardiovascular and chronic obstructive pulmonary disease. which heighten susceptibility to digoxin toxicity. Moreover. treatment of these diseases with such interactive medications as quinidine and calcium channel blockers may increase the serum level of digoxin. Similarly. such electrolyte imbalances as hypokalemia and hypomagnesemia occur more frequently in the elderly as a result of diuretic therapy. However. recent data suggest that manifestations of digoxin toxicity among younger and older patients do not differ. Similar incidences of cardiac toxicity. gastrointestinal toxicity. and altered mental status are found in both patient populations. Treatment of digitalis toxicity in the elderly is the same as for younger patients. Response rates to Digibind are not diminished in the elderly.
Results of multicenter studies of digoxin-specific antibody fragments in managing digitalis intoxication in the pediatric population, Digitalis toxicity continues to be a problem for pediatric patients undergoing therapy with cardiac glycosides for heart failure or arrhythmias. as well as in accidental ingestions. In this article the previous use of digoxin-specific antibody Fab fragments to treat digitalis overdose or intoxication in children is reviewed. The case reports cited in the medical literature and the 57 pediatric cases gathered as a result of the multicenter clinical trial and postmarketing surveillance study reported here indicate that digoxin-specific antibody Fab fragments are effective in ameliorating signs of digitalis poisoning in children. Not only can Fab fragments rapidly eradicate potentially life-threatening arrhythmias and conduction defects. but they are also effective in treating hyperkalemia and other noncardiac manifestations of digitalis toxicity. In the small samples of patients studied to date. complications have been minimal and no allergic reactions to digoxin-specific Fab fragments have been observed. Recommendations for the management of digitalis intoxication in children are outlined.
Recognition and management of digitalis intoxication: implications for emergency medicine, Digitalis intoxication is among the most common serious adverse drug reactions in clinical medicine. While the recent development of a radioimmunoassay to accurately measure serum concentrations of digoxin has been of assistance. digitalis intoxication remains a difficult diagnosis to make with certainty. The difficulty in diagnosing digitalis intoxication arises from the nonspecificity of its associated signs and symptoms. The most common symptoms include fatigue. weakness. nausea. and anorexia. These symptoms can occur with many illnesses other than digitalis intoxication. Similarly. the electrocardiographic disturbances caused by cardiac glycosides may be nondiagnostic. The arrhythmias commonly associated with digitalis toxicity are often nonspecific and can be a reflection of the patient's underlying heart disease. The measurement of serum digoxin levels is useful. but studies have demonstrated overlap of the levels between groups with and without toxicity. Due to the modulation of the cardiac effects of digitalis glycosides by such clinical variables as underlying myocardial or renal disease. electrolyte and acid-base imbalances. and other factors. the correlation of toxicity with particular serum digoxin concentrations may vary. Because of the inherent difficulties in confirming the diagnosis of digitalis intoxication in some cases. digoxin-specific Fab antibodies may play a role as a diagnostic tool. Certainly. digoxin-specific Fab antibodies play a significant part in the treatment of digitalis intoxication. Fab antibodies have been successfully used to reverse the effects of digoxin. digitoxin. and oleander poisoning. These antibodies are useful in the treatment of acute and chronic digitalis intoxication in all age groups. including geriatric and pediatric populations.
Plasma concentrations of bupivacaine and two of its metabolites during continuous interscalene brachial plexus block, An interscalene brachial plexus block was performed via a catheter with 20-28 ml of 0.75% bupivacaine plus adrenaline for surgery of the shoulder region in 12 patients. Constant infusion of 0.25% bupivacaine 0.25 mg kg-1 h-1 was continued for 24 h. During surgery light general anaesthesia. without analgesics. was maintained. Plasma concentrations of total and unbound (free fraction) bupivacaine. desbutylbupivacaine (DBB). 4-hydroxybupivacaine (4-OHB) and alpha 1-acid glycoprotein (AAG) were measured at predetermined intervals during the continuous block. The greatest mean plasma concentrations of bupivacaine were measured at 30 min (1.63 (SD 0.55) micrograms ml-1) and 60 min (1.38 (0.48) micrograms ml-1). There was a small but statistically significant increase in the plasma concentration of bupivacaine between 12 and 24 h of infusion. The mean unbound concentration of bupivacaine in plasma decreased from 0.044 (0.015) microgram ml-1 (3.6 (1.1)% of total bupivacaine concentration) at 3 h to 0.023 (0.011) micrograms ml-1 (2.1 (1.0)%) at 24 h. The AAG concentration in plasma increased by 38% in 24 h. The metabolites DBB and 4-OHB were detectable in plasma from 30 min. with a gradual increase during infusion. At 24 h the mean concentrations of DBB and 4-OHB were 0.33 (0.22) micrograms ml-1 and 0.13 (0.04) micrograms ml-1. respectively. There were no toxic reactions during the blocks.
Pharmacokinetics and clinical experience of 20-h infusions of methohexitone in intensive care patients with postoperative pyrexia, We have studied the pharmacokinetics of 20-h infusions of methohexitone in young patients with postoperative fever undergoing artificial ventilation of the lungs. The infusion rate was adjusted so that patients were unresponsive to vocal stimulation but reacted to tracheal suction. The mean steady state concentration of methohexitone required was 2.6 mg litre-1 (unbound 0.53 mg litre-1). The mean (SD) total clearance of methohexitone was 16.3 (4.2) ml min-1 kg-1. which is greater than that for volunteers or normal surgical patients. The unbound clearance correlated positively with body temperature during the infusion (r = 0.796. P = 0.017). The terminal half-life of methohexitone was 6.3 (3.8) h and that of the 4'-hydroxy metabolite 5.8 (2.1) h. There were no marked haemodynamic effects of the infusion. and no excessive sedation after the infusion. However. the clearance of methohexitone was high and variable. possibly as a direct effect of postoperative fever. Consequently. the need for individual titration of the rate of infusion is emphasized.
Surgical staging of cervical cancer, Noninvasive radiologic methods to detect paraaortic lymph node metastases are reliable when combined with FNA of enlarged lymph nodes. However. the sensitivity is low. and undetected microscopic metastases leads to treatment failure. These patients with paraaortic lymph node metastasis are not treated with extended-field radiation. and they all die within 3 years. The CT scanning is probably the best diagnostic method to evaluate cervical cancer. because it can assess the primary tumor. the urinary tract. gastrointestinal tract. liver parenchyma. and retroperitoneum. It also permits the guidance of FNA and the arrangement of radiation ports. Surgical staging provides the direct assessment of the peritoneal cavity and the retroperitoneal spaces. Metastatic tumor. including enlarged lymph nodes. can be resected. but this is of dubious benefit. The operative morbidity is acceptable. with fewer intestinal complications when the extraperitoneal approach is used. and long-term morbidity is minimal when appropriate paraaortic radiation doses are employed (less than 5.000 cGy). Surgical staging has provided data on the frequency of paraaortic lymph node metastasis by stage of cervical cancer. and thus. treatment strategies can be better developed. Extended-field radiation results in 5-year survival rates of 20-25% in patients with microscopic paraaortic lymph node metastasis. patients who would not survive without the treatment. However. surgical staging has produced only a modest boost in survival rates. because of the high rate of pelvic and systemic failure. When extended-field radiation is used prophylactically or in patients with probable lymph node metastasis seen on radiographic studies. survival rates are similar to patients irradiated after surgical staging finds paraaortic lymph node disease. As our ability to predict. and detect nonsurgically. positive paraaortic node disease improves. extended radiation (or other adjuvant therapy) could be used more frequently without operation in patients who are at high risk for metastatic disease. In a study by Haie et al. prophylactic paraaortic radiation was given to patients at high risk for paraaortic metastasis. In patients with a high probability of local disease control. paraaortic radiation significantly reduced the incidence of paraaortic and distant metastases. Patients with known paraaortic lymph node metastases frequently have occult systemic metastases. In these same patients. pelvic failure is also common. Thus. until effective systemic therapies emerge. a marked improvement in survival is unlikely in patients who have paraaortic lymph node metastasis.(ABSTRACT TRUNCATED AT 400 WORDS).
The new genetics and its relevance to orthopedics, The recent advances in genetics have practical importance for patients with orthopedic problems. Specific genes are being isolated. mapped to chromosomes. and defined. Surgical specimens can be used for genetic studies to define specific genetic abnormalities. Making specific genetic diagnoses is important for appropriate care of the patient and the family.
Application technique of Cotrel-Dubousset instrumentation for scoliosis deformities, Used in over 600 cases. the posterior Cotrel-Dubousset spinal instrumentation device has become the device of choice. This technique allows the most effective correction for all kinds of spinal deformities. It requires lengthy preoperative planning and is a technically demanding surgical procedure; however. because of its versatility it can be adapted to most spinal deformities. The Cotrel- Dubousset technique is a rigid system of immobilization. and. because it does not require any postoperative immobilization. patients are able to resume their normal lives and activities very quickly.
Minor anatomic abnormalities of the hip joint persisting from childhood and their possible relationship to idiopathic osteoarthrosis, A retrospective review was made of roentgenograms from 30 patients with idiopathic osteoarthrosis of the hip. The roentgenograms were taken before the onset or very early in the course of the disease. Nine measurements were made on the anteroposterior and cross-table lateral roentgenograms. These were compared to 54 hips from normal patients. Twenty-nine of 30 patients had abnormal measurements. with as many as seven in a single individual. when compared to normal patients. There were no abnormalities in the control group. The availability of lateral views allowed an additional dimension to be added to previous studies in the literature. This study lends further support to the biomechanical theory of the etiology of idiopathic osteoarthrosis of the hip.
Radiocolloids in the management of hemophilic arthropathy in children and adolescents, Radiocolloids have been used in the treatment of hemophilic arthropathy. Fifty-eight joints of 35 patients were injected with 2-5 mCi of yttrium-90 silicate under local anesthesia. A preinjection arthrogram was performed to ensure correct placement of the needle. Plaster of paris cast immobilization of the joint was used for three days. After a mean follow-up period of seven years (range. two to 12 years). 47 joints were pain free. and 13 joints had not experienced another hemorrhagic episode. The mean hemorrhagic frequency had decreased from four per month to two per year. The radiation risk was far outweighed by the benefits of the procedure. Forty-seven of the 58 joints were rated as improved by the patients. The roentgenographic appearance of the joints had changed little. Only five complications occurred: three needle-track necroses because of extravasation of the radiocolloid. two severely painful joints immediately after injection. and one massive hemorrhagic episode. This form of treatment is suggested for hemophiliacs who have failed to respond to intensive physical and hematologic therapy. and for those patients who have inhibitors.
Changing patterns in the management of fractures in children, Advances in radiographic imagery have greatly facilitated the diagnosis and treatment of pediatric musculoskeletal injuries. In recent years. the indications for operative intervention in the treatment of children's fractures have become more clearly defined.
The management of malignant bone tumors in children and adolescents, A series of 205 pediatric patients affected by osteosarcoma. Ewing's sarcoma. fibrosarcoma. and malignant fibrous histiocytoma of bone were treated from 1978 to 1988. Ninety-eight percent of the patients received chemotherapy and 63% had a surgical resection. Sixty-five percent of all patients were alive at 30 months and were considered disease free. The functional results after surgery were evaluated according to the Musculoskeletal Tumor Society score. In all diaphyseal resections and resections of the upper extremity and pelvis. the results were excellent or good in 60% of the cases. In resections of the proximal femur. distal femur. or proximal tibia and reconstruction with nonexpansible prostheses. the results were excellent or good in 75%. On the other hand. when arthrodeses of the lower extremity were used. only 14% of cases had a good result. This correlates with the resulting lack of articulation and serious limb shortening seen with progression of skeletal growth.
Congenital anomalies of the cervical spine, Congenital anomalies of the cervical spine are uncommon. The majority of afflicted individuals are asymptomatic or have only mild restriction of neck motion. If symptoms develop. they are usually due to cervical instability or degenerative osteoarthrosis. Recent information indicates that patients with upper cervical anomalies such as atlantooccipital fusion. anomalies of the odontoid. or the transverse atlantal ligament have a great propensity to develop early instability and neurologic problems secondary to minor traumatic events. If symptoms occurs in the lower cervical spine. it is usually in adult life and due to degenerative arthritis in the hypermobile articulations adjacent to the area of synostosis. The relatively good prognosis of cervical lesions is overshadowed by the "hidden" or unrecognized associated anomalies. There is a high incidence of significant scoliosis. Sprengel's deformity. renal anomalies. deafness. and neurologic malformations. Early recognition and treatment of these problems may be of substantial benefit. sparing the patient further deformity or serious illness.
Osteoarthrosis retards the development of osteoporosis. Observation of the coexistence of osteoarthrosis and osteoporosis, The clinical. roentgenographic. and biochemical features of the dorsal and lumbar spine were reviewed in 72 postmenopausal women. Nineteen women had both osteoporosis (vertebral collapse) and osteoarthrosis. These patients were compared with 26 patients who had only osteoarthrosis of the spine and 27 who had only vertebral collapse. The patients who had both spinal osteoporosis and osteoarthrosis were older. more advanced in menopause. and physically smaller in stature and body weight than the other groups. They also had higher serum parathyroid hormone level. used nonthiazide diuretics more frequently. and had more nulliparity than the other two groups. These patients had osteoarthrosis of the hip to a lesser degree than patients affected by osteoarthrosis alone. and they had fewer fractures of the forearm and other sites than patients with osteoporosis alone. The incidence of femoral neck fractures in both groups. however. was comparable. These results suggest that osteoarthrosis or a related factor might have a protective effect on the progression of osteoporosis. These results confirm earlier observations that postmenopausal osteoporosis and osteoarthrosis are two distinct diseases and not the result of normal aging.
Analysis of 61 cases of vertebral osteomyelitis, Sixty-one cases of bacterial vertebral osteomyelitis from July 1969 to July 1979 were analyzed. The ages of the 49 men and 12 women ranged from 21 to 66 years. The portal of entry was hematogenous in 58 cases. gunshot wounds in two cases. and and adjacent retroperitoneal abscess in one case. Biopsy was performed in 60 patients. There were 15 complications related to the disease. Gram-negative rods were the predominant bacteria isolated. Blood culture was positive in 13 of the 26 (50%) patients tested. Eleven of the 13 (85%) organisms isolated from the blood cultures correlated with organisms recovered from biopsy specimens. Eleven of the patients had more than one disk level involved. Of the 61 patients. 29 went on to spontaneous fusion. 17 were lost to follow-up study. 11 failed to fuse. three had surgical fusion. and one patient died. Recommendations for diagnosis included the collection of blood cultures and radionuclide bone scans. Management recommendations included systemic antibiotics for at least three weeks and immobilization with either bed rest or spinal orthoses. Surgery was indicated if an abscess was present. neurologic complications occurred. instability became a factor. or the medical treatment failed.
Influences of the protected passive mobilization interval on flexor tendon healing. A prospective randomized clinical study, A prospective multicenter clinical study was carried out to determine whether improved tendon gliding could be achieved with greater durations of daily passive-motion rehabilitation after flexor tendon repair. Fifty-one patients were placed randomly into two controlled passive-motion protocols. Group 1 patients received greater intervals of passive-motion rehabilitation using a continuous passive-motion device. Group 2 patients were treated with a traditional early passive-motion protocol for tendon rehabilitation. For Group 1 patients. the mean interval of controlled motion rehabilitation was 75 hours a week. and the mean number of cycles was 12.000. For Group 2 patients the mean interval of controlled passive motion was four hours a week. and the mean number of cycles was 1000. The minimum follow-up time was six months (mean. 10.8 months). Using Strickland and Glogovac's formula. the mean active motion for digits in Group 1 was 138 degrees +/- 6 degrees. Mean motion for tendons in Group 2 was 119 degrees +/- 8 degrees. The difference between Groups 1 and 2 was statistically significant. The effect of the number of tendons injured per digit within each group was not significant. The data from this experiment indicate that the duration of the daily controlled motion interval is a significant variable insofar as postrepair flexor tendon function is concerned.
Fracture of the index metacarpal base with subluxation of the trapeziometacarpal joint. A case report, A 40-year-old man fell on his outstretched arm and suffered a fracture of the index metacarpal base with subluxation of the thumb basal joint. The small fracture fragment at the base of the index metacarpal was attached to the base of the thumb metacarpal by a strong ligament. as noted at the time of surgery. This pattern of injury. a ligament-reversed Bennett's fracture. seems not to have been previously reported.
Sciatic nerve monitoring during revision total hip arthroplasty, This study presents a simple method of intraoperative sciatic nerve monitoring during revision total hip arthroplasty (THA). utilizing intraoperative. somatosensory evoked potentials. Using this method. the sciatic nerve was protected when surgical correction of shortened limb length was necessary during revision THA. Twenty-three revision THAs were performed using intraoperative sciatic nerve monitoring. No postoperative peripheral nerve complications occurred. with an average increase of 18 mm in leg length. ranging from 6 mm to 43 mm.
Pelvic support osteotomy in an unusual congenital dislocation of the hip. A 52-year follow-up study, Structural changes in the anatomy of the soft tissues as a result of long-standing congenital dislocation of the hip (CDH) are seldom described in the literature. Similarly. the anatomy of a hip 52 years after a pelvic support osteotomy for CDH seems not to have been previously observed. A long-term follow-up autopsy study of bilateral pelvic support osteotomies performed in a 91-year-old autopsy subject showed unexpectedly flattened sciatic nerves.
Closed suction drainage following knee arthroplasty. Effectiveness and risks, A prospective investigation was performed to determine when to remove a suction drain following total knee arthroplasty (TKA). Forty-one TKAs were randomly allocated to closed suction drainage for either 24 or 48 hours. The drain was removed and the tip was cut off and processed by a method giving quantitative cultures. In the 48-hour group. 85% of the total volume was drained during the first 24 hours. During the following 24-hour period. a mean volume of only 50 ml was drained. No organism was isolated from cultures of drain tips sampled at 24 hours. However. at 48 hours. 25% of the drain tips yielded light growths of coagulase-negative staphylococci (four drain tips) and Staphylococcus aureus (one drain tip). Clinical evaluations of wound healing were comparable in the two groups. Clearly. nothing is to be gained by continuing drainage beyond 24 hours. If drainage is maintained for longer periods. there is an increased risk of contamination by bacteria.
Pes anserinus interposition in a proximal tibial physeal fracture. A case report, A ten-year-old girl suffered a Salter-Harris Type II fracture of the proximal tibia. Inspection revealed interposition of the pes anserinus (PA) within the open physis. which prevented reduction. This may be the first case report of PA interposition.
Fractional lengthening of the flexor tendons in clubfoot surgery, Massive scarring of the Z-lengthened flexor digitorum and flexor hallucis longus is a constant finding in clubfoot surgery. A method of fractional lengthening of the tendons is described. This method has been proven effective in preventing this complication.
The occurrence of accessory immunologic cells in bone induction, The differentiating tissues in fracture healing and in demineralized bone-powder-induced (DBP) bone formation were investigated with monoclonal antibodies with respect to the occurrence of Ia-positive cells. macrophages. and lymphocytes with interleukin-2 receptors (IL-2). Ia refers to molecules on the cell surface belonging to Class II of the major histocompatibility complex and is specific for the species and the individual. In both types of granulation tissues (fracture healing and following DBP implantation). the mesenchymal cells from the surrounding musculature were accompanied by large numbers of Ia-positive cells and common macrophages. The occurrence of IL-2 receptors was sparse in fracture healing but rich in DBP induction. probably because of its immunogenic properties. though weak. On Day 7. almost all existing cells in DBP induction were Ia-positive. signifying an immunologic effector phase apparently directed to the remaining still-passive bone powder in the periphery. while the central part of the inserted bone powder was producing cartilaginous cells and matrix. The presence of accessory immunologic cells in fracture healing is perhaps due to a surveillance function (a standard response on injury). but the cell differentiation might also be dependent on the active mediators emitted from Ia-positive cells and macrophages. This investigation strengthens the concept that induced bone development occurs in experimental fracture healing.
Histochemical localization of calcium with potassium pyroantimonate in the articular tissues in calcium pyrophosphate dihydrate crystal deposition disease, The ultrastructural localization of calcium in the articular cartilage. meniscus. and synovium of patients with calcium pyrophosphate dihydrate (CPPD) crystal deposition disease was examined by using potassium pyroantimonate. Focal areas with deposition of CPPD crystals in each tissue showed electron-dense precipitates of the antimony-calcium complex: (1) in the cytoplasm of hypertrophic chondrocytes around CPPD crystals. especially on the margins of intracellular lipid droplets or within electron-dense amorphous material or both; and (2) on the margins of lipid droplets and within electron-dense amorphous material in the degenerated matrix surrounding the hypertrophic chondrocytes. The slender rodlike structures consisting of electron-dense precipitates of the antimony-calcium complex. suggestive of the precursor to rodlike CPPD crystals. were also observed in the degenerated matrix. These findings suggest that the hypertrophic chondrocytes may contribute to the formation of CPPD crystals by intracellular accumulation of calcium and subsequent release of high concentration of calcium into their surrounding matrix.
The stimulating effect of growth hormone on fracture healing is dependent on onset and duration of administration, The effect of onset and duration of growth hormone administration on the biomechanical properties of healing rat tibial fractures was investigated after 40 days of healing. Biosynthetic human growth hormone. 2.7 mg/kg body weight/day. was given in two daily injections to three groups of rats: (1) for the entire healing period; (2) for the first 20 days; and (3) for the last 20 days of healing. Three corresponding groups of control rats were injected with saline. In Group 1. maximum load and stiffness of the healing fractures increased to 165% and 175%. respectively. compared to the control group. In Group 2. maximum load. stiffness. maximum stress. and energy absorption at maximum load increased to 222%. 175%. 171%. and 247%. respectively. compared to the control group. In Group 3. no statistically detectable effects were found. The results show that growth hormone stimulates fracture healing both when given during the first part of the healing period and when given during the entire healing period.
Surgical treatment of brachial plexus birth palsy, Brachial plexus birth palsy remains a challenging condition. In the 1000 infants followed from 1977 to 1988. functional results were much improved over those obtained by observation only. if surgical exploration and repair were performed when no clinical recuperation of biceps function occurred by three months of age. Recovery is slow. and comprehensive follow-up study of reconstructed and conservatively managed children is required to prevent joint contractures. Children who will benefit from palliative procedures such as tendon transfers must also be identified.
A method of assessment of the clubfoot deformity, The literature on clubfeet is inadequate because a common method language for assessing the deformity is lacking. Different severities of clubfoot deformity will give different results for a standard procedure: a less severe deformity can be corrected by limited releases. whereas a severe deformity requires radical procedures. This paper presents a language of assessment that has been used for a number of years. The importance of developing a language of assessment to be able to identify the various types of clubfoot deformity is important if the treatment of this condition is to develop within the field of pediatric orthopedics.
Neurologic status of spina bifida patients and the orthopedic surgeon, The purpose of this paper is to review recent developments in the neurologic assessment of spina bifida patients. Determination of the neurosegmental level of the lesion. recognition of spasticity and progressive paralysis. the potential for deformity. and functional expectations are described. The status of the neurologic deficit remains the most important factor in determining the myelomeningocele patient's ultimate functional abilities. Accurate neurologic assessment will assist in meeting the aims of orthopedic management. which include preventing joint contracture. correcting deformity. preventing skin sores. and obtaining the best possible locomotor function.
Gait analysis in the treatment of the ambulatory child with cerebral palsy, Surgical treatment of children with cerebral palsy has changed from staged. single joint procedures to comprehensive simultaneous bony and soft-tissue corrections. This regimen of treating multiple joint levels and planes of abnormality is subject to error when based solely on the clinical examination. A more scientific evaluation can be provided by the use of clinical gait analysis. Both preoperative and postoperative analyses provide the clinician with information from which neurologic patterns can be determined and surgical protocols can be judged.
A perspective on recent trends for scoliosis correction, The basic principles for scoliosis surgery learned during the Harrington era are still valid today. Experience has confirmed the need for careful selection of the vertebrae to be instrumented. the value of anterior release for rigid curves in imparting convertibility of the deformity. and the importance of careful fusion techniques. During the last decade. further development has occurred because of an increased knowledge of the biomechanical needs for the internally instrumented spine and a three-dimensional appreciation of the scoliotic curve. Biomechanical advances have centered on an understanding of the load-sharing properties afforded by the multiple spinal purchase sites (segmental spinal instrumentation) and the value of two-rod systems linked by couplers. These advances have provided an increased stiffness of the instrumental spine. a reduction in correction loss. improved fatigue properties of the implant. and fewer pseudarthroses. The most important advance of the last decade is an improved awareness of the three-dimensional approach to the scoliotic deformity with the need to preserve or improve sagittal contours. In particular. the importance of the loss of normal thoracic kyphosis or lumbar lordosis has been emphasized. These conceptual gains have led to the development of many new instrument systems to correct deformity. Each is associated with advantages. problems. and risks that must be understood to make intelligent choices for treatment.
Demographic, social and stress correlates of hypertension among the urban poor, The relationship of demographic. social. and psychological variables to the diagnosis of hypertension in a population of urban. poor. predominantly black out-patients is reported. Subjects were 182 patients presenting for health care at Wayne State University Family Practice Clinic. Age. race. marital status. attendance at religious services. education. employment status. income. source of income and interpersonal stress were significantly related to a diagnosis of hypertension in this sample. Of those characteristics found to be significantly related to hypertension. discriminative analysis showed that age. race. education and frequency of church attendance were most important in predicting a diagnosis of hypertension among this out-patient sample of the urban poor. Implications for clinical care and for future research needs are considered.
Diabetes care in a rural primary health care district where patient education is given high priority. Metabolic evaluation, The present population-based study comprises 84% of all known diabetics cared for at a rural primary health care centre. Patient education has been given high priority as an integral part of the treatment provided by a specially trained nurse and dietician under the supervision of the general practitioners. Most of the patients were under good metabolic control. as reflected by HbA1 (diet-treated. n = 119. 7.3 +/- 1.3%; oral agent-treated. n = 127. 7.8% +/- 1.3%; insulin-treated. n = 110. 8.0 +/- 1.3%; reference range 5.3-7.3%). Obvious reasons for any high HbA1 values were found.
Feasibility and effects of a diabetes type II protocol with blood glucose self-monitoring in general practice, A diabetes protocol characterized by self-monitoring of blood glucose was introduced in four general practices with the aim of making the frequency of consultations dependent on the metabolic regulation and emphasizing body weight reduction. The feasibility of the programme was investigated and the results after 1 year were compared with those of conventional care in four control practices. In the experimental practices. 13 patients switched from a medical specialist's to a general practitioner's supervision. 20 remained under supervision of their GP and 33 started self-monitoring. The self-monitoring rate. the consultation frequency according to protocol. the low number of dropouts and inadequate referrals and adherence to the therapeutic scheme showed that the protocol was feasible for both the GPs and the patients. At the initial assessment. the regulation of the diabetes was worse in patients of the experimental group. compared with those of the control group (mean HbA1 9.7% vs 8.9%; p less than 0.05). On average. patients in the experimental group (n = 56) lost 0.4 kg of body weight. whereas those in the control group (n = 73) gained 0.1 kg (n.s.). The mean change in HbA1. adjusted for the initial value. was -0.4% in the experimental and +0.5% in the control group (p less than 0.05). The results of the protocol can be attributed to a combination of greater participation of the patient. the individualized consultation frequency and the prescription of oral hypoglycaemic agents according to body weight development.
Impact of day care on dementia patients--costs, well-being and relatives' views, Forty-seven patients in psychogeriatric day centre were analysed regarding use of resources. costs and well-being. The level of well-being was based on interviews with staff and relatives and related to the economic outcome--a cost utility analysis. A 6 month period prior to day care was compared with the first 6 months in such care. The use of resources at home increased by 20% while the use of institutional care was reduced by 22%. Fifty-three percent of the patients improved in their well-being after participation in day care. When the cost of utility analysis was applied. the cost for a well-year was 4293 pounds.
A simple score for the identification of patients at high risk of organic diseases of the colon in the family doctor consulting room. The Local IBS Study Group, In order to develop a scoring system for selecting patients at high risk of organic diseases of the colon. who would need a colonoscopy or a barium enema. we conducted a study with 14 GPs in the local health care district of Modena. Over one year. 254 consecutive patients who consulted their GP for chronic abdominal pain were asked to answer a guided questionnaire. A checklist of simple parameters suggestive of the presence of organic diseases of the colon was also registered by the GP. For the final diagnosis. the patients underwent either a colonoscopy or a barium enema. Data collected were analysed by means of a stepwise logistic regression analysis to obtain a weighted score for the diagnosis of either irritable bowel syndrome (score less than 0) or organic disease (score greater than 0). Out of the 25 parameters explored. six were significantly more common among patients with organic disease and weighted as positive score (namely ESR greater than 17 mm. first hour. history of blood in the stool. leukocytosis greater than 10.000 cm3. age greater than 45 years. slight fever and presence of neoplastic colonic diseases in first-degree relatives). On the contrary. five parameters were more frequent among patients with irritable bowel syndrome and weighted as negative score (namely visible distension of the abdomen. feeling of distension. presence of irritable bowel syndrome in first degree relatives. flatulence and irregularities of bowel movement). Our scoring system correctly classified 83.5% of the cases. and it was very sensitive (82.4%) for the diagnosis of organic disease.
The importance of the GHQ in general practice, The relationship between General Health Questionnaire (GHQ) score and complaints presented at the general practitioners office was examined. and showed that the correlation between them is not as high as might be expected. Many patients who present psychosocial problems to their GP appear to have a low GHQ score; many patients with a high GHQ score exclusively present somatic complaints. which are also assessed by the GP as being purely somatic. Implications of the results are discussed.
Kinetic modeling of intracellular pH and comparison with 31P NMR experimental values in dialysed uremic patients, Changes in intra-erythrocytic pH values over time. during and after bicarbonate hemodialysis. were studied with 31P Nuclear Magnetic Resonance. Simultaneously. pH values of whole blood were obtained by a gazometric method. A two-compartment model appeared to be the simplest kinetic model to explain the shifts in proton concentrations in extra- and intra-cellular media. Non-linear regression was used to determine exchange constant values. There was a very good correlation between the experimental and calculated proton concentrations. This model can describe all patients but individual experimental constants must be determined. Under these conditions a single blood pH determination before dialysis will permit determination of the initial intra-erythrocytic pH and monitoring of intra-erythrocytic pH during hemodialysis.
Morphological features of blood access stenosis and results of noninvasive angioplasty, We investigated a connection between the results of noninvasive angioplasty for the blood access stenosis and its morphological features in 37 dialysis cases. In 3 cases presenting stenosis in the original artery. the area could not be dilated by noninvasive techniques. In 4 cases with stenosis in the arterialized vein downstream of the needle insertion points for extracorporeal circulation. 3 showed long-term dilatation by the procedures. In 30 cases having stenosis upstream of the points. 16 showed long-term dilatation. In the unsuccessful cases. the angle formed between the axes of the stenosed portion and the normal vessel was over 39 degrees. and the distance between the anastomosis and the stenosed portion was less than 11 mm.
A new cause of female pseudohermaphroditism: placental aromatase deficiency, A description is presented of the first documented case of placental aromatase deficiency. The deficiency caused maternal virilization during pregnancy and pseudohermaphroditism of the female fetus. A 24-yr-old primigravida showed progressive virilization during the third trimester. Urinary excretion of estrogen was less than 14 mumol/day between 35-38 weeks of pregnancy. although nonstress tests showed reactive patterns and serum levels of human placental lactogen were above 460 nmol/L. Maternal serum levels of estrogens were low. and those of androgens were high in the third trimester. A dehydroepiandrosterone sulfate loading test induced a marked increase in maternal serum levels of androgens. whereas no such increase was observed in estrogens. The woman delivered vaginally a live full-term infant who exhibited female pseudohermaphroditism. Cord serum levels of estrogens were extremely low. while those of androgens were high. The aromatase activity of the placenta. determined by the conversion of [7-3H]androstenedione to 17 beta-[7-3H]estradiol and [7-3H]estrone. were less than 0.03 fmol/microgram protein.min (control. 9.6 +/- 2.2 fmol/microgram protein.min). The sulfatase activity of the placenta was 0.63 pmol/microgram protein.min compared to 0.46 +/- 0.16 pmol/microgram protein.min in controls. The rate of aromatization by normal control placentas was the same as that obtained during coincubation of samples of normal placentas and that of the patient. Thus. the presence of aromatase inhibitor in the patient's placenta was excluded.
The influence of simvastatin on adrenal corticosteroid production and urinary mevalonate during adrenocorticotropin stimulation in patients with heterozygous familial hypercholesterolemia, The adrenal gland requires a continuous supply of cholesterol for the biosynthesis of adrenal corticosteroids. which can be supplied by low density lipoprotein receptor-mediated uptake or local synthesis. The present study examined whether hypolipidemic therapy with a potent HMG CoA reductase inhibitor. simvastatin. compromises the adrenal response to ACTH stimulation in adult patients with heterozygous familial hypercholesterolemia. The adrenal response to a 36-h continuous ACTH infusion was determined at baseline and after 2 months of simvastatin treatment (40 mg. twice daily) in eight patients. Simvastatin reduced total and low density lipoprotein cholesterol levels by 36% and 45%. respectively. The time course of the increase in serum cortisol concentrations with continuous ACTH infusion was the same before and during simvastatin therapy. as were the rates of urinary excretion of free cortisol. 17-hydroxycorticosteroids. and 17-ketosteroids. Urinary excretion of mevalonate. which correlates with rates of whole body cholesterol synthesis. decreased from 3.8 +/- 0.42 (+/- SEM) mu.ol/24 h at baseline to 2.75 +/- 0.56 on simvastatin; no significant changes were seen in the urinary mevalonate levels before and after simvastatin therapy during ACTH stimulation. We conclude that the hypolipidemic effects of simvastatin in patients with heterozygous familial hypercholesterolemia are paralleled by a decrease in urinary mevalonate. but that the drug does not adversely affect ACTH-stimulated adrenal corticosteroid production.
Dexamethasone-nonsuppressible cortisol in two cases with aldosterone-producing adenoma, Forty-one patients with aldosterone-producing adenoma (APA) were subjected to a dexamethasone suppression test (DST) before surgery. Serum cortisol and urinary excretion of 17-hydroxycorticosteroids were suppressed by dexamethasone in 39 patients [DST(+)]. In two patients (cases A and B). they were not suppressed [DST(-)]. Clinical manifestations of the two DST(-) patients were similar to those of DST(+) patients. Hypertension. hypokalemia. high serum aldosterone levels. and suppressed PRA were found in all of the patients. The cut surfaces of the adenomas from all of the patients. including cases A and B. were golden yellow. which is typical of APA. However. atrophies of the adjacent normal tissues were evident exclusively in the two DST(-) patients. After removal of the affected adrenals. the serum cortisol level was suppressed by dexamethasone in one of the DST(-) patients (case B). These findings suggested autonomous cortisol production by APA. To evaluate whether cortisol could be produced from the adenoma tissue. the presence of several steroidogenic enzymes was studied by immunohistochemistry and mRNA analysis in the adenomas and the adjacent nonneoplastic adrenals from the 2 DST(-) and 5 DST(+) patients. Immunohistochemical analysis demonstrated that steroidogenic enzymes were expressed in APA tumor tissues from both DST(-) and DST(+) patients. In both groups. mRNAs coding steroidogenic enzymes were present not only in the nonneoplastic but also in the tumor tissues. Quantitative analysis of the mRNA levels revealed that in the adrenals from DST(+) patients. the mRNAs were more abundant in nonneoplastic tissue than in tumor tissue. However. in those from DST(-) cases. the mRNAs were much more abundant in the tumor tissues than in the nonneoplastic tissues. These results indicate that tumor cells of the two DST(-) patients autonomously synthesized not only aldosterone but also cortisol. The diameters of the tumors from the two DST(-) patients exceeded 3 cm. while those from other DST(+) patients were smaller. In patients with large APA. adrenal insufficiency should be anticipated upon removal of the tumor.
Recovery from osteopenia in adolescent girls with anorexia nervosa, Osteopenia is a frequent complication of anorexia nervosa (AN). To determine whether the deficit in bone mineral changes during the course of this illness. we studied 15 adolescent patients prospectively for 12-16 months using dual photon absorptiometry of the spine and whole body. At follow-up. mean weight. height. and body mass index (BMI) had increased significantly. although 6 girls had further weight loss or minimal gain (less than 1.2 kg). Spontaneous menses occurred in 2 girls. and 3 others were given estrogen replacement. Bone mineral density of the lumbar spine did not change significantly (mean +/- SD. 0.836 +/- 0.137 vs. 0.855 +/- 0.096 g/cm2). while whole body bone mineral density increased (0.710 +/- 0.118 vs. 0.773 +/- 0.105; P less than 0.05). Despite gains in bone mineral. 8 patients had osteopenia of the spine and/or whole body. Changes in weight. height. and BMI were significant predictors of change in bone mineral density. Increased bone mass occurred with weight gain before return of menses; conversely. weight loss was associated with further decreases in bone density. In 1 patient who failed to gain weight. estrogen therapy resulted in increased spinal. but not whole body. bone mineral. We also studied a second group of 9 women who had recovered from AN during adolescence. All 9 had normal whole body bone mineral for age. but 3 had osteopenia of the lumbar spine. We conclude that osteopenia in adolescents with AN reflects bone loss. perhaps combined with decreased bone accretion. Weight rehabilitation results in increased bone mineral before the return of menses. Estrogen may have an independent effect on bone mass. The persistence of osteopenia after recovery indicates that deficits in bone mineral acquired during adolescence may not be completely reversible.
Suppression of chromogranin-A release from neuroendocrine sources in man: pharmacological studies, Chromogranin-A (CgA) is an acidic soluble protein with a virtually ubiquitous occurrence in normal human neuroendocrine tissues. Of the many potential tissue sources of CgA immunoreactivity. which contribute to basal (unstimulated) circulating CgA? To explore this question we studied the effects of selective and nonselective suppression of secretion at several sites within the neuroendocrine system. Selective disruption of sympathetic outflow by trimethaphan decreased basal CgA by 25%. suggesting that sympathetic neurons contribute to circulating CgA. Plasma CgA in patients with unilateral and bilateral adrenalectomy fell within the range observed in normal subjects. weighing against the adrenal medulla as a major source of basal circulating CgA. Selective suppression of a variety of anterior and posterior pituitary cell types decreased plasma levels of the usual resident peptide hormones. but left plasma CgA unperturbed. After propranolol treatment. plasma CgA remained unaltered. Secretin suppressed plasma PTH and calcitonin. but did not alter plasma CgA levels. On the other hand. widespread nonselective suppression of a variety of neuroendocrine secretory cells by somatostatin decreased plasma CgA by 48%. Plasma catecholamines were unaltered by somatostatin infusion. suggesting that somatostatin inhibited CgA release from nonsympathoadrenal sources. During the infusion of somatostatin. the plasma epinephrine increment in response to insulin-induced hypoglycemia was maintained. and plasma CgA did not fall. nor did it rise after somatostatin cessation. Taken together. these findings suggest that somatostatin did not inhibit transport of stimulation-released CgA from the adrenal medulla to the circulation. In conclusion. although the adrenal medulla is the major tissue source of CgA immunoreactivity in man. other neuroendocrine sites. including sympathetic axons and multiple endocrine glands. appear to influence the basal circulating concentration of CgA.
Subclinical vitamin D deficiency in postmenopausal women with low vertebral bone mass, To define the potential role of subclinical vitamin D deficiency in postmenopausal bone loss. we analyzed the levels of circulating 25-hydroxyvitamin D (25OHD) in 539 midwestern caucasian women screened for osteoporosis. Low 25OHD (less than 38 nmol/L) was found in 49 subjects (aged 52-77 yr). Women with low 25OHD had a reduced vertebral bone density (VBD). assessed by quantitative computed tomography. compared to age-matched controls (P less than 0.001). They also had significantly lower levels of serum calcium and phosphate. lower urinary calcium. higher serum alkaline phosphatase. and. in most cases. increased immunoreactive PTH (iPTH) concentrations. suggesting secondary hyperparathyroidism. Furthermore. only in the low 25OHD group did VBD correlate directly with 25OHD (r = 0.41; P less than 0.01). and inversely with iPTH (r = -0.47; P less than 0.01). Multivariate analyses revealed that iPTH was the major determinant of the observed decrease in VBD. Seasonal variations of serum 25OHD were noted only in the control population; in this group the 25OHD levels also correlated with sunlight exposure (r = 0.48; P less than 0.01). as assessed by an outdoor score. Thus. vitamin D deficiency develops when both the endogenous and exogenous sources are insufficient and contributes to a reduced bone mass in elderly women.
Reliability of stimulated and spontaneous growth hormone (GH) levels for identifying the child with low GH secretion, The reliability of stimulated and spontaneous GH levels for identifying the child with low GH secretion has been the subject of debate. We compared the ability of GH concentrations after pharmacological stimulation with levodopa and clonidine and of spontaneous peak and 12-h pooled GH concentrations during sleep on a single night to estimate the maximum spontaneous GH secretion from 2 nights in 55 children. aged 5-16 yr. with heights below the 3rd percentile and/or height velocities below the 25th percentile for age. who had two consecutive overnight GH secretory profiles. Maximum stimulated GH concentrations correctly categorized 80% of children who had maximum spontaneous GH concentrations above and below 4 micrograms/L using a double monoclonal immunoradiometric assay for GH (Tandem-R HGH. Hybritech). The remaining 20% of children had stimulated GH concentrations below but spontaneous GH concentrations above 4 micrograms/L. Using this cut-off. the maximum GH concentrations from the first and second nights correctly categorized 98% and 95% of the children. respectively. Night to night variation in GH secretion was low in children who had low spontaneous GH secretion (maximum spontaneous peak and pool GH concentrations. less than 4 and less than or equal to 0.7 micrograms/L. respectively). and pooled GH concentrations from the 2 nights were concordant in 98% of the cases. We conclude that it is not uncommon for stimulated GH concentrations to underestimate spontaneous GH secretion. Even without acclimatization to the hospital setting. measurement of spontaneous GH secretion on a single night was more reliable for identifying the child with low endogenous GH secretion than was GH stimulation testing alone.
The N-terminal sequence of the major erythropoietic factor of an anephric patient is identical to insulin-like growth factor I, The erythropoietic factors present in an anephric patient with nearly normal hematocrit were isolated from plasma by reversed-phase and gel permeation HPLC. The most active fraction was purified and the analysis of its N-terminal sequence was identical to the published sequence of the human insulin-like growth factor I (IGF I). Recombinant human IGF I had identical elution positions as the isolated erythropoietic factor on reversed-phase HPLC and the same molecular weight on gel permeation HPLC. Furthermore. hrIGF I stimulated erythroid colony formation in human bone marrow cultures as was previously shown for the isolated human erythropoietic factor. These results suggest that IGF I may replace erythropoietin as a stimulator of erythropoiesis in some patients with anemia and renal failure.
Endothelial markers in malignant vascular tumours of the liver: superiority of QB-END/10 over von Willebrand factor and Ulex europaeus agglutinin 1, A new monoclonal antibody. QB-END/10. raised against the CD34 antigen in human endothelial cell membranes and haemopoietic progenitor cells. was studied for its usefulness as a marker of neoplastic vascular cells in 21 angiosarcomas and seven malignant haemangioendotheliomas of the liver. QB-END/10 was both more sensitive and more specific than Von Willebrand factor (VWF) and Ulex europaeus 1 agglutinin (UEA-1) in labelling endothelial cells and it did not cross react with epithelia as UEA-1 often does. Staining was uniformly strong and clear in all histological variants of these two tumours. QB-END/10 should prove particularly useful in the differential diagnosis of malignant vascular tumours of the liver.
Breakdown of gastric mucus in presence of Helicobacter pylori, The potential of Helicobacter pylori to degrade gastric mucus was examined. Colonies of H pylori cultured from antral mucosal biopsy specimens of patients with non-autoimmune gastritis were washed with sterile saline. passed through a sterilisation filter. and the filtrate examined for urease. protease. and mucolytic activity. The filtrate failed to hydrolyse bovine serum albumin. or to degrade stable mucus glycoprotein structures of high particle weight that had been separated from human gastric mucus on Sepharose 2B. The high particle weight mucus glycoprotein was. however. extensively degraded when incubated with H pylori filtrate (which possessed urease activity) in the presence of 2 M urea. to release fragments of Mr approximately 2 X 10(6). The high particle weight mucus glycoprotein was also broken down to a comparable extent when incubated with Jack bean urease in the presence of 2 M urea. or 1 M ammonium carbonate. or 40 mM carbonate-bicarbonate buffer (pH 8.7). but not when treated with 4 M urea alone. or Jack bean urease alone. These results indicate that the loss of high particle weight mucus glycoprotein in gastric mucus from patients with gastritis and gastric ulcers is unlikely to be due to the mucolytic action of an extra-cellular protease produced by H pylori. but it may result from the destabilising effects of a carbonate-bicarbonate buffer. generated at the mucosal surface when H pylori urease hydrolyses transuded plasma urea.
Measurement of urinary lipopolysaccharide antibodies by ELISA as a screen for urinary tract infection, Five hundred and twenty two clinical urine specimens submitted for routine microbiological examination were tested in parallel by conventional microscopy and culture and for lipopolysaccharide antibodies by an enzyme linked immunoabsorbent assay (ELISA) to assess the ELISA as a screen for urinary tract infection. When the ELISA alone was compared with routine methods the specificity sensitivity. and predictive value of positive and negative tests was 73.2%. 75.7%. 51.1% and 38.5%. For ELISA with microscopy the same variables were 71.1%. 82.2%. and 92.4% and 94.7%. respectively. The ELISA absorbency increased with increasing bacterial numbers. but results varied widely. Only 65.4% of urines which contained greater than or equal to 10(5) bacteria/ml were positive by ELISA; 36.8% of urines with less than 10(3) bacteria/ml were positive by ELISA; 100% of greater than or equal to 10(5) bacteria/ml cultures of Pseudomonas sp (n = 4). Staphylococcus aureus (n = 3). and Streptococcus faecalis (n = 2) were positive by ELISA but only 71.4% of Proteus sp (n = 7). 61.4% coliforms (n = 70). and 25% of coagulase negative staphylococci (n = 4). It is concluded that further development is required before the ELISA can be used for routine screening for urinary tract infection.
Monoclonal immunofluorescence compared with silver stain for investigating Pneumocystis carinii pneumonia, Two hundred and eighty two specimens from 220 patients positive for HIV with respiratory tract symptoms. or febrile illness. or both. were examined for the presence of Pneumocystis carinii. Specimens were either induced sputum samples or bronchoalveolar lavage fluids. To establish the optimal method for laboratory diagnosis a comparison was made of detection of the organism by use of monoclonal antibody and immunofluorescence with conventional silver staining methods. Three commercially available reagents for immunofluorescence were also compared. Immunofluorescence was significantly more sensitive than the silver stain and the best results for immunofluorescence were obtained using. Northumbria Biologicals Ltd reagents.
HLA antigens in Hungarian patients with idiopathic haemochromatosis, Thirteen unrelated patients with idiopathic haemochromatosis (eight men. five women) were studied. The diagnosis was based on clinical. biological. and histochemical findings. HLA typing was performed in all 13 and in all of their available first degree relatives (n = 31). HLA A3 was present in nine of 13 probands (69.2% compared with 18.8% in the group of 53 healthy blood donors and 22.4% in a selected Hungarian population (n = 1910). HLA B7 was present in five of 13 probands (38.4% compared with 11.3% and 14.6%). An A3B7 antigen association was found in five of 13 patients. The A3B7 haplotype was found in three. A2B12 and A2B38 haplotypes were found twice in 10 genotyped probands. Pedigree studies showed that there was one unaffected homozygote. 24 heterozygotes. and six non-carriers. Extended family and population studies are necessary to establish the prevalence of the gene in Hungary and an association with haplotypes other than A3B7.
Inpatient and post-discharge course of the malnourished patient, A retrospective review of the medical records of 114 malnourished and 106 non-malnourished male veterans assessed the inpatient and 1 year post-discharge dietetic care given for the treatment of malnutrition. The malnourished sample consisted of subjects discharged with a protein-energy or protein malnutrition comorbidity. Subjects in the diagnosis-matched and age-matched control sample were discharged without a malnutrition comorbidity during the same period. Data collected from progress notes included diagnoses. inpatient dietetic feedings and services provided. discharge dietetic care. intervening clinic visits. and rehospitalizations. On initial admission. 79% of the diagnoses for the malnourished group fell into five diagnosis categories: neoplasms; respiratory system diseases; digestive system diseases; endocrine. nutritional. and metabolic diseases; and mental disorders (including alcohol-related disorders). Malnourished subjects received more specialized feedings and dietetic services than did the controls on initial admission. However. the discharge and post-discharge care received by surviving members of both groups was similar. Fewer than half the members of either group received post-discharge care. Fifty-four malnourished and 54 control patients were hospitalized more than once. The findings indicate that levels of inpatient and outpatient dietetic care need to be coordinated to alleviate malnutrition.
Comparison of a food frequency questionnaire using reported vs standard portion sizes for classifying individuals according to nutrient intake, Individual intakes of retinol. carotene. vitamin C. and folacin calculated from a food frequency questionnaire using reported portion size were compared with intakes calculated using standard portion size information. Data from a case-control study to determine the association of nutrient intake and risk of cervical dysplasia were supplemented by standard portion size information from the US Department of Agriculture and reanalyzed. Significant mean differences were found between intake calculated from reported portion size data and that calculated from standard portion size data for all nutrients. Correlation of nutrient intakes obtained by the two methods of data collection ranged from .73 to .92. Calculation of the rho statistic. measuring the consistency of classification of participants into groups of high. medium. and low nutrient intake. led to values ranging from .55 to .71. indicating some misclassification of study participants. To determine the effect misclassification had on the study outcome. odds ratios were calculated using nutrient amounts obtained from both methods of collecting portion size data. Results indicate that replacing reported portion size data with standard portion size data may lead to conflicting outcomes for specific nutrients in research concerning the relationship between diet and disease.
Strain differences in baroreflex inhibition by centrally infused enalapril in old rats, To determine whether inhibition of the brain renin-angiotensin system would affect baroreflexes similarly in old rats of different strains. we compared 24-month-old male Fischer 344 and Sprague-Dawley rats. Baroreflex sensitivity was tested while the rats were awake by recording reflex heart rate responses elicited as blood pressure was elevated with phenylephrine or lowered with sodium nitroprusside. Sprague-Dawley rats had higher blood pressures and lower heart rates initially. Chronic infusion of enalapril. a converting enzyme inhibitor. into a lateral cerebral ventricle (ICV) for two weeks lowered blood pressure in Sprague-Dawley but not in Fischer 344 rats. Furthermore. reflex bradycardia was unaffected in either rat strain. but reflex tachycardia was selectively suppressed in Fischer 344 rats. Thus. although time controls were not done to rule out spontaneous changes during the 14-day infusion period. these results suggest that central cardiovascular regulation does not change similarly with age in these two rat strains. As removal of the brain renin-angiotensin system lowered blood pressure in one strain and inhibited reflex tachycardia in the other. the divergence could mean that the brain renin-angiotensin system acts differently to keep blood pressure elevated in Sprague-Dawley rats and modulate reflex tachycardia in Fischer 344 rats.
Quality of life in elderly, chronically ill outpatients, Quality of life (QL) in elderly outpatients is poorly characterized. We interviewed 258 elderly outpatients from three health care settings to identify the attributes and events that affect self-assessment of QL. These outpatients rated their QL as acceptable. citing medical care. health. interpersonal relationships. financial status. and functional status as affecting their QL. Overall QL ratings were not strongly associated with objective indicators such as demographic characteristics and use of health care services. Subjective indicators. including patient perceptions of health. memory. and financial concerns. were correlated independently with global QL (sigma R2 = .35). We conclude that older. chronically ill patients generally consider their QL to be acceptable and affected by a variety of factors. including their perceptions of their emotional. socioeconomic. intellectual. and physical functioning. Furthermore. QL is poorly associated with objective indicators. Thus. in assessing the QL of elderly. chronically ill outpatients. physicians should elicit information regarding these perceptions.
Value of combined assessment of physical health and functional status in community-dwelling aged: a prospective study in Florence, Italy, A survey of the health and social conditions of a representative sample of 967 persons aged 60 years and older from the city of Florence. Italy. was undertaken in 1980. In 1987. a follow-up survey of this cohort was performed. There were 391 documented deaths. 408 survivors. and 168 individuals who could not be located. Functional ability at baseline was assessed using a World Health Organization 14-item scale. Indicators of physical health status included chronic disease status. number of drugs. physician visits. and days of hospitalization. After adjustment for age and sex. both functional ability and indicators of physical health status were found to be independent. statistically significant predictors of mortality. The results of this study further support the view that biomedical and functional assessment are both necessary for a comprehensive evaluation of the older population.
Relationship of obesity and physical fitness to cardiopulmonary and metabolic function in healthy older men, The relationship of obesity and physical fitness (VO2max) to cardiopulmonary and metabolic function was examined in 132 healthy obese. nonsmoking men age 45-79. Obese men with higher VO2max had lower % body fat and waist-to-hip ratio (WHR) than obese men with low VO2max. The obese subjects with high WHR (upper body fat distribution) had higher systolic blood pressure. hyperinsulinemia and impaired glucose tolerance. lower high density lipoprotein cholesterol (HDL-C). and higher triglyceride (TG). VO2max (ml/kg FFM.min) was lower in the older men (r = -0.54. p less than .001). and 32% of the variation was accounted for by age and the one-second forced expiratory volume. Although pulmonary function was normal. 50% of the variability was predicted by age. height. and VO2max or WHR. Glucose tolerance and insulin correlated better with VO2max and indices of body composition than with age. while plasma TG and HDL-C correlated with body composition. not VO2max or age. Thus. while age affects the cardiopulmonary and metabolic function of obese older men. physical inactivity. obesity. and an abdominal body fat distribution (increased WHR) contributed significantly to their reductions in physiological function.
Decision criteria for pure-tone detection used by two age groups of normal-hearing and hearing-impaired listeners, Response criteria from a yes-no task and detection thresholds from two test procedures were measured for four groups of adults: younger normal-hearing. older normal-hearing. younger hearing-impaired. and older hearing-impaired. The two test procedures were an audiological procedure (which does not control for response bias) and a 21FC adaptive procedure (which does control for bias). The signal was a 500 or 4000 Hz tone presented in quiet. All four groups showed an equally conservative response bias in the yes-no task. In addition. neither age nor hearing loss affected the difference (6.5 dB) between the two threshold measures.
The effects of rate, sequencing, and memory on auditory processing in the elderly, Auditory sequencing. rate. and memory were evaluated in three age groups with a series of subtests that require the identification of tones (Repetition Test; Tallal & Piercy. 1973). The older elderly group (M age = 80). but not the younger elderly group (M age = 70). performed significantly (p less than .05) poorer than the young adult group (M age = 25) when auditory memory of 4 and 5 tones was required and when the interstimulus interval was decreased. Performance was not related to hearing sensitivity. thus suggesting that changes in the auditory mechanism that occur with age may encompass more than a loss of hearing sensitivity. Moreover. performance on the Repetition Test did correlate with memory for digits. which indicates a relationship between auditory processing and higher cortical functions.
Nonorganizational religious participation among elderly black adults, This study investigated rates of participation in nonorganizational religious activities of elderly Black adults. Four indicators of participation were examined: reading religious materials. watching or listening to religious programs. prayer. and requests for prayer. Demographic. religious denomination. and health disability factors influenced participation in these behaviors. The findings were discussed for their implications for the development of a multidimensional conceptualization of religiosity.
Health perceptions and survival: do global evaluations of health status really predict mortality, Self-evaluations of health status have been shown to predict mortality. above and beyond the contribution to prediction made by indices based on the presence of health problems. physical disability. and biological or life-style risk factors. Several possible reasons for this association are discussed: (a) methodological shortcomings of previous studies render the association spurious; (b) other psychosocial influences on mortality are involved and explain the association; and (c) self-evaluations of health status have a direct and independent effect of their own. Four-year follow-up mortality data from the Yale Health and Aging Project (N = 2812) are used to explore these possibilities. The analysis controls for the contribution of numerous indicators of health problems. disability and risk factors. and also makes adjustments of standard errors for the complex sample design. The findings favor the third possibility. an independent effect. to the extent that the particular set of psychosocial factors examined did not explain the basic association. and to the extent that the control variables were an adequately comprehensive set.
Population aging patterns: the expansion of mortality, We used the hypothesis of mortality compression as a framework to examine patterns of mortality from 1962 to 1984. Data from national vital statistics records were used for analysis of the changing age at death for percentiles of the population. Data from the Social Security Administration and the U.S. Census Bureau were used to calculate the force of mortality. The mean age at death for all percentiles. including the oldest groups. has risen during the interval. Examination of the coefficient of variation for the mean age at death suggests that there is a relative increase in the variability of age at death among the oldest old. The available data do not fit a hypothetical sequence of normal density distributions with an increasing mean and declining standard deviation. The force of mortality in those over 85 years appears to be decreasing in a pattern similar to that for those under 85 years. Current mortality patterns suggest an "expansion." rather than compression. of mortality at the oldest ages. Further refinement of these observations. with improved data on mortality among the oldest old. will be helpful in delineating mortality patterns.
Stressful events and life satisfaction among elderly men and women, The purpose of this study was to examine the interrelationships among stressful events. domain-specific assessments of life satisfaction. and global evaluations of life satisfaction. This research was guided by two competing theoretical formulations. According to bottom-up theory. older adults first assess feelings of satisfaction within specific life domains that are based in part on the experiences (i.e.. stressors) they encounter in these areas. The domain-specific views are subsequently synthesized to form an overall sense of satisfaction with life as a whole. In contrast. the top-down theory suggests that a person's ongoing sense of satisfaction with life as a whole predisposes him or her to assess satisfaction with specific domains in ways that are congruent with his or her initial sense of global life satisfaction. Analysis of data provided by older participants in a nationwide survey tends to support the bottom-up perspective.
Prostacyclin production in myocardial infarction in the acute phase and during follow-up, Twenty-five patients with myocardial infarction were monitored in the acute phase and during follow-up with regard to the in vivo production of prostacyclin (PGI2) and thromboxane (TxA2). by measurement of their major urinary metabolites. 2.3-dinor-6-keto-PGF1 alpha and 2.3-dinor-TxB2. respectively. In 22 of these patients PGI2 and TxA2 production were also assessed before. during and after an exercise test performed 6 weeks after discharge. In approximately 24% of patients the in vivo production of prostacyclin did not increase during the acute phase of the infarction process. This inability was usually associated with a decrease in the release of heart muscle enzymes. and was mostly frequently observed in women. During the exercise tolerance test. none of the patients showed any increase in prostacyclin production. in contrast to healthy volunteers. in whom a significant increase was seen. There were no differences between patients with and without an increase in prostacyclin production during the acute phase. At the follow-up 2 years after the myocardial infarction. eight cardiac events had occurred. all of which were noted among patients who exhibited an expected increase in prostacyclin production in association with the infarction. This would seem reasonable. since most of the patients in this group had larger primary infarctions.
Rapid and correct diagnosis of myocardial infarction: standardized case history and clinical examination provide important information for correct referral to monitored beds, The value of thorough examination of the case history as a diagnostic tool on hospitalization of patients with suspected myocardial infarction was investigated in three independent prospective studies. Use of a limited number of pain-related elements (= 'criteria'). that had already been obtained in the emergency room. could improve the decision on whether or not to admit patients to the coronary-care unit. As an example. in one of the studies. use of such criteria would have reduced the number of 'unnecessary' coronary-care-unit admissions from 298 to 162. a 46% reduction (P less than 0.001). In the same patient sample. use of the criteria could have reduced the number of patients with definite acute myocardial infarction. admitted to the general wards. from 47 to 22. a 53% reduction (P less than 0.01). These favourable results were confirmed in the two independent. smaller-scale studies.
Observer variation in the clinical assessment of the thyroid gland, In order to evaluate the reliability of clinical assessment of the thyroid gland. two specialists in endocrinology and two younger doctors independently examined 53 patients twice. and assessed whether they had a diffuse goitre. a multinodular goitre. a solitary nodule or a normal gland. In 30% of the patients all four observers were in agreement. whereas in 47% and 23% of the patients. two and three different diagnoses were given. respectively. Inter-observer variation was determined and kappa values between -0.04 and 0.54 were found. Intra-observer variation was smaller. revealing kappa values between 0.44 and 1.00. The present study suggests that clinical assessment of the thyroid gland may lead to misclassification of the type of thyroid disease. and thereby to a less than optimal choice of therapy.
Serum creatinine: an independent predictor of survival after stroke, We prospectively studied the relationship between serum creatinine and survival among 492 elderly subjects admitted for stroke and monitored for a mean period of 18 months post-stroke. In multivariate proportional hazards models. serum creatinine remained an independent predictor of mortality (P = 0.0001) after accounting for other important predictors such as level of consciousness. Mini-Mental State Score. age. leucocyte count. presence of heart disease. diabetes. heart failure. atrial fibrillation and use of cardiovascular medication. This association between elevated serum creatinine and mortality was also found in patient subgroups with CT-proven infarction and intracerebral haematoma. It is concluded that serum creatinine is an independent predictor of survival after stroke. Further studies are required to confirm this relationship and to elucidate the underlying mechanism.
Pneumothorax in a patient with Wegener's granulomatosis during treatment with immunosuppressive agents, We present the case of a 16-year-old woman with Wegener's granulomatosis. who developed a pneumothorax while receiving treatment with cyclophosphamide and glucocorticoids. The lung was re-expanded by tube drainage. and the patient recovered completely while the immunosuppressive treatment was continued in combination with sulphamethoxazole-trimethoprim. A possible role for this antimicrobial drug in the treatment of Wegener's granulomatosis is briefly discussed.
Gender roles, social support, and postpartum depressive symptomatology. The benefits of caring, Although women are assumed to be particularly vulnerable to depressive symptomatology after childbirth. the extent to which this symptomatology predominates over that found in men at this life cycle stage has not been addressed. This study examined gender differences in postpartum depressive symptomatology and the link between postpartum symptomatology and gender roles and relationships in a sample obtained from childbirth preparation classes. The data show no gender difference in depressive symptomatology at 2 months after childbirth. Women manifested a decrease in depressive symptomatology and men showed a slight increase from the preparenthood point. We partially link women's equivalent rather than higher distress levels to the protective effects of their varied social supports. By contrast. men depended primarily on their spouses. but both genders experienced a decrease in spouse support after childbirth. Female lack of support was more strongly associated with symptomatology in homemakers compared with employed women or women on maternity leave. Within the context of gender role changes. the data highlight benefits of female bonding in contrast to the "costs of caring" depicted by other researchers.
Dependency and eating disorders in female psychiatric inpatients, Research indicates that oral dependent and eating-disordered individuals have similar personality traits. attitudes. and behaviors. suggesting that dependency may be a factor in the dynamics of anorexia and bulimia. To investigate this issue. we compared the proportions of dependent and food-related percepts in the Rorschach protocols of matched samples of eating-disordered (N = 16). obese (N = 18). and non-eating-disordered. normal-weight female psychiatric inpatients (N = 17). Eating-disordered patients reported significantly more dependent Rorschach imagery than did obese or normal-weight control patients. but no difference in the proportion of food-related imagery was found among the three groups. These results support the hypothesis that unresolved dependency issues underlie anorexia and bulimia.
Winning the battle, losing the war? Another editorial about rheumatoid arthritis, Major advances in the therapy of RA will likely require future scientific breakthroughs in the understanding of pathophysiology. That is not to suggest that clinical investigations should be put on hold while the entire focus of research shifts to the laboratory bench. Clinical studies of very early RA. including early treatment interventions. would appear to be of major importance. However. better characterization of the early clinical course and identification of pathologic markers of progressive disease are needed before formal randomized treatment studies of early disease can be initiated. The entire role of aggressive management. particularly with combination chemotherapy. at any stage of RA is in desperate need of answers. In clinical practice it would appear that combination chemotherapy is widely used. often as a last resort in treatment resistant patients who have failed conventional therapies. The published clinical studies would seem to support. but certainly not prove. a valuable potential role for combination chemotherapy in this setting. Moreover. the studies seem to indicate some increased risk of drug toxicities. the limitations of which are not readily apparent for most combinations. Based on the successes observed in these patients that are very difficult to treat. the possibility of a more fundamental role of combination chemotherapy in treatment of the disease has been advocated. These questions need to be resolved by well designed. randomized controlled trials. There is an urgent need to do the trials soon before combination chemotherapy gains an even stronger foothold in therapy.
Seronegative rheumatoid arthritis: a clinical study with HLA typing, We examined both clinically and by determining HLA-A. -B. -C and -DR antigens 50 patients thought to have seronegative erosive polyarticular rheumatoid arthritis (RA) in Finland and the USSR. All the patients fulfilled at least 4 of the 1987 ARA criteria for RA. According to HLA typing and clinical findings. of which a part was collected by followup. the patients fell into 5 groups: HLA-B27 related diseases. putative psoriatic arthritis. putative juvenile chronic polyarthritis. and seropositive and seronegative RA. Our results indicate that most of the patients with seronegative RA had some other disease. In the remaining cases the presence of rheumatoid factors had not been examined adequately. especially at the early phase of disease. The classification of erosive seronegative polyarticular patients is discussed.
Phenotypic markers of lymphocyte and mononuclear phagocyte activation within rheumatoid nodules, We investigated rheumatoid subcutaneous nodules using monoclonal antibodies recognizing functional determinants on mononuclear phagocytes (Mph) and lymphocytes. Mph at the center of rheumatoid nodules showed strong expression of the leukocyte intergrins CR3 and p150.95 which would be consistent with the presence of a central chemotactic stimulus. Mph expression of FcR1. a gamma interferon regulated molecule. was decreased in 5/13 cases despite strong expression of MHC class II. There was a variable unstructured infiltrate of T lymphocytes. a majority of which were CD8 positive. Lymphocytes showed increased MHC class II expression but interleukin 2 receptor expression was low. We discerned no relationship between the number. distribution or phenotype of the T cell infiltrate and the phenotype of the predominant Mph population.
Administration of folinic acid after low dose methotrexate in patients with rheumatoid arthritis, Folinic acid (leucovorin) supplementation has been suggested as a possible means of treating the short term side effects that occur with low dose methotrexate (MTX). However. it has not been established whether leucovorin will abrogate the antiarthritic effect of MTX. We entered 20 patients with rheumatoid arthritis treated with MTX into a 48 week randomized. double blind. crossover trial of folinic acid vs placebo. The dose of folinic acid was equal to the dose of MTX and it was given orally 4 h following the single. weekly MTX administration. Under these conditions. leucovorin did not decrease the therapeutic effect of MTX. While the incidence of stomatitis and gastrointestinal toxicity were lower during leucovorin treatment. our study lacked sufficient power to establish a statistically significant difference.
Systemic lupus erythematosus in Iceland 1975 through 1984. A nationwide epidemiological study in an unselected population, In a nationwide study the 1982 revised ARA criteria were applied for the classification of systemic lupus erythematosus (SLE). This unselected group of patients included all cases diagnosed and managed in hospitals. as well as outside hospitals in Iceland over the 10-year period from 1975 to 1984. Seventy-six new cases were found. with an incidence of 5.9 and 0.8/100.000 for females and males at risk. respectively. The mean age at diagnosis was 46.6 years. Twenty-five percent of the patients would have been missed had the study included hospital patients only. A clinical pattern different from previous studies was found as illustrated by a low incidence of kidney disease; nephritis was found in 20% of patients. Comparison with a former study on SLE in Iceland shows an actual increase in incidence over a period of 10 years. The 5 year survival was 84% and the 10 year survival 78%.
Juvenile systemic lupus erythematosus among Egyptian children, A prospective analysis of 30 Egyptian children with systemic lupus erythematosus (SLE) was conducted throughout a 3 year period. The average followup period was 13 months. The age of onset ranged from 8 to 14 years. Most cases presented with more than one of the classical features of the disease. However. 23.3% presented primarily with major organ involvement. One case presenting with cardiac tamponade is reported in our series. The clinical and laboratory manifestations of the disease are presented. though more complete studies are required to confirm any possible differences in these disease manifestations compared with those found in other populations. Contrary to the frequently held view. our results suggest that childhood onset SLE is not rare in Africa or at least some parts of the continent.
Serological arguments for classifying Raynaud's phenomenon as idiopathic, Twenty-five patients with idiopathic Raynaud's phenomenon were followed prospectively for a mean period of 48 months. Clinical and laboratory assessments were performed on admission and on followup. The sera were analyzed for the presence of autoantibodies (antinuclear. antiskeleton and antiorganelle antibodies). Sixteen patients were antinuclear antibody positive and 2 anticentromere antibody positive. Eight patients produced antivimentin. 5 antimitochondrial. 4 anti-Golgi complex. and 3 anticentriol antibodies. Eleven patients produced antidesmosome antibodies. Only one patient (anti-RNP and antidesmosome antibody positive) developed a systemic disease (mixed connective tissue disease) during followup. The initial screening of sera may help to classify Raynaud's phenomenon as idiopathic more accurately.
Hypophospholipasemia A2 in systemic sclerosis, Phospholipase A2 (PLA2). total and pancreatic. were quantitated in 91 sera of patients with systemic sclerosis (SSc). The mean total PLA2 of 216 +/- 161 U/ml (SD) was significantly lower (p less than 0.001) than in controls (317 +/- 128 U/ml). In 55 of 91 patients (60%) PLA2 was more than 1 SD and in 6 (7%) more than 2 SD below the normal mean. Serum pancreatic PLA2 was also significantly lower in SSc. The prevalence of low serum total PLA2 was significantly greater (p less than 0.001) than in healthy adults. or in patients with rheumatoid arthritis. systemic lupus erythematosus or vasculitis. Repeat assays of PLA2 activity in 10 patients with SSc documented persistence of low PLA2. Among 76 patients with SSc with complete clinical and laboratory assessment. there were 48 with low and 28 with normal (or slightly elevated) PLA2. These 2 groups showed no differences in disease manifestation or therapy. The group with low serum PLA2 had lower erythrocyte sedimentation rates (p less than 0.0005) and lower neutrophil (p less than 0.05) and monocyte counts (p less than 0.025) in the peripheral blood. The finding of low serum PLA2 activity adds to the spectrum of arachidonic acid pathway abnormalities associated with SSc. and may in part be related to the paucity of inflammatory changes observed in this disease.
A prospective double blind dummy placebo controlled study comparing triamcinolone hexacetonide injection with oral diclofenac 50 mg TDS in patients with rotator cuff tendinitis, A prospective double blind placebo controlled study was carried out to compare the effects of subacromial injection of triamcinolone and oral diclofenac in patients with rotator cuff tendinitis over a 4-week period. Both forms of treatment were superior to placebo in reducing pain. improving active abduction and reducing functional limitation. Triamcinolone showed the greatest effect in these respects. and was significantly superior to diclofenac when patients showing improvements in all 3 variables together (responders) were considered.
Growth promoting peptides in osteoarthritis: insulin, insulin-like growth factor-1, growth hormone, Alterations of cartilage and bone. as seen radiographically. are fundamental features of osteoarthritis (OA). Endogenous compounds that regulate bone and cartilage metabolism were quantified by radioimmunoassay in patients with OA and in suitable normotensive controls matched for age. sex. race. height. and weight. Levels of 3 growth promoting compounds were abnormal in OA as demonstrated by low levels of insulin-like growth factor-1 (IGF-1) and elevated levels of insulin and growth hormone (GH) compared to controls. Our findings support a role for these peptides in the pathophysiology of OA.
Chemical dependency in women: a description of its effects and outcome on adequate parenting, The purpose of this article is to define chemical dependency in women as a maladaptive response to inadequate upbringing. A description of the situational and psychological variables that characterize chemically dependent women is offered as well as attributes these women lack that are necessary for effective parenting. The dysfunctional child-rearing patterns and the consequential outcome for the children are also described. Suggestions for clinical intervention are provided.
Individualized care for the treatment of alcoholism, Through a discussion of several case vignettes. the author emphasizes the utilization of an individually tailored treatment approach when working with people experiencing problems related to alcohol consumption. Patients may achieve abstinence without believing in the disease concept of alcoholism. and attending Alcoholics Anonymous meetings need not always be a part of the treatment. Furthermore. for some patients. controlled drinking may be as desirable an outcome as abstinence. The importance of entertaining a multiplicity of perspectives when conducting clinical work with such patients is discussed.
Staffing patterns of American methadone maintenance programs, Methadone maintenance is the most frequently utilized treatment for heroin addiction and also represents one of the best AIDS-prevention tools for the IV drug using population. Despite these important roles. very little has been reported about how methadone maintenance clinics are staffed. Surveys covering various aspects of program operations. including staffing. were sent to all clinics (N = 557) listed in the 1984 National Directory of Drug Abuse and Alcohol Treatment Programs. Using ANOVA. staffing patterns were compared across programs as a function of clinic size. city size. region of the country. and funding resources. While few differences were found based on city or clinic size. staffing patterns varied as a function of regional location as well as the sources of a clinic's funding.
Depression among alcoholics in a Turkish sample, The aim of the present study was to identify the predictor variables of depression among alcoholics in a Turkish mental hospital. A questionnaire and the Beck Depression Inventory (BDI) were utilized to collect data from 71 male alcoholics. A stepwise multiple regression analysis between the BDI scores and demographic and health-related variables resulted in the identification of marital problems and physical problems due to alcohol as the risk factors. The findings are discussed within the context of the findings from Western countries and the similarities are pointed out.
Percutaneous nephrolithotomy for calculi in horseshoe kidneys, Between 1983 and 1988. 15 patients (18 kidneys) underwent percutaneous nephrolithotomy at this unit for calculi in horseshoe kidneys. A standard 1-stage percutaneous access technique with minor modifications was used. In situ disintegration with ultrasound or electrohydraulic lithotripsy was necessary in 15 moieties (83.3%) and nephrostomy drainage was required in 12 (66.7%). Percutaneous access was not a problem and there were minimal perioperative problems. Blood transfusion was required postoperatively in 2 patients. A total of 14 kidneys (77.8%) were rendered free of stone with percutaneous nephrolithotomy alone and 2 kidneys were left with asymptomatic stone fragments of 2 mm. or less. Another 2 kidneys became free of stone after extracorporeal shock wave lithotripsy. thus giving an over-all stone clearance rate of 88.8%. We conclude that percutaneous nephrolithotomy is an acceptable treatment for stones in horseshoe kidneys and it is the treatment of choice for patients in whom imaging is difficult or impossible.
Extracorporeal shock wave lithotripsy of urinary calculi: experience in treatment of 3,278 patients using the Siemens Lithostar and Lithostar Plus, Between March 1986 and June 1989. 3.278 patients with upper urinary tract calculi were treated at our medical center with the Lithostar lithotriptor. The stones were located in the calices in 41.9% of the cases. renal pelvis in 25.7% and ureter in 32.4%. Perirenal hematoma was noted in 0.5% of the patients but this resolved spontaneously within a few days. Auxiliary procedures were performed in 37.3% of the cases. including Double-J stent and ureteral catheter in 26.8%. ureterorenoscopy in 2.1%. percutaneous nephrostomy in 1.6%. Zeiss loop in 4.3% and percutaneous nephrolithotripsy in 3.5%. Of the treatments 83.1% were performed without general or regional anesthesia. Followup after 3 months showed a 63.8% rate free of stone. The Lithostar upgraded with the overhead lithotripsy module is called Lithostar Plus. A total of 25 patients with upper urinary stones underwent treatment with the overhead module. Initial experience revealed fragmentation of stones after the first session in 20 patients. while a second session was necessary in 5. Analgesic sedation was used in 4 patients in whom a Double-J stent was inserted.
Treatment of steinstrasse with repeat extracorporeal shock wave lithotripsy: experience with piezoelectric lithotriptor, Among 958 patients with renal stones who underwent extracorporeal shock wave lithotripsy (ESWL) monotherapy using an EDAP-LT01 piezoelectric lithotriptor steinstrasse developed in 55 (5.7%). Of these 55 cases stone fragments passed spontaneously in 35 (63.6%) and were treated successfully (no residual stone fragment in ureter) with repeat ESWL in 18 (32.8%). Only 2 patients (3.6%) required ureteroscopic management or open ureterolithotomy. Therefore. repeat ESWL is considered a good initial method to treat complicated steinstrasse.
Cystourethrometric findings in patients with detubularized right colonic segment for bladder replacement, Urodynamic evaluation was performed in 13 men 4 to 18 months after cystoprostatectomy and bladder replacement using a detubularized right colonic segment. All patients are continent by day and only 3 are incontinent during the night to a degree that necessitates use of a condom catheter. Two patients awaken every 2 to 3 hours to void and the remainder have nocturia comparable to normal men of their age. The residual volume was 0 to 70 ml. The urethral closure pressure was normal. and in 3 patients studied preoperatively and postoperatively no significant change was observed other than shortening of the profile length. Maximal flow rates were normal although the pattern was intermittent. In 2 patients no cystoplasty contractions were recorded and in all but 2 patients the amplitude of the contractions was less than 40 cm. water. Simultaneous bladder and urethral pressure recordings during bladder filling demonstrated no change in urethral pressure in 10 patients. Although creation of a reservoir with a low pressure and careful preservation of the infraprostatic urethra are important for continence in these patients. we believe that the absence of normal sacral route reflexes after cystoprostatectomy is an important contributing cause to nocturnal incontinence.
The detection of reflux nephropathy in infants by 99mtechnetium dimercaptosuccinic acid studies, Dimercaptosuccinic acid (DMSA) studies were performed in 113 infants less than 1 year old at risk of renal scarring. Of these patients 86 presented with urinary tract infection and 27 were asymptomatic. A voiding cystourethrogram was performed in all cases and excretory urography (IVP) was done in 99. More abnormalities were detected by DMSA study when compared to scars on IVP. When both studies were abnormal there was an excellent correlation on a site by site basis. Fever or systemic disorder was not a reliable sign to determine whether there was upper tract involvement with infection. The incidence of DMSA abnormalities in infants increased with high grade vesicoureteral reflux and decreased with low grade reflux. There was no significant difference in the incidence of abnormal kidneys between the infected and noninfected groups. suggesting that renal scarring may occur with sterile reflux.
Management of auto-emasculation in the psychotic state, We report 2 cases of self-inflicted penile amputations. which offered differing surgical options and contrasting surgical results due to varying time delays. In 1 case repair was done immediately. while repair in the other case was delayed by 3 days due to the psychotic state of the patient. The psychiatric backgrounds of such episodes are discussed. as well as the techniques of repair and reconstruction.
A continuous intravesical drug delivery system for the rat, We describe a self-contained system for the continuous infusion of drugs into the rat urinary bladder. A reversible model of hydronephrosis is used to prepare one renal unit for nephrostomy tube placement. An 0.8 mm. silastic nephrostomy tube is introduced into the hydronephrotic kidney via a 16 gauge angiocath. The nephrostomy tube is then connected to an Alzet mini osmotic pump which is implanted in a subcutaneous location. The ability of this system to deliver a continuous dose of a test agent into the bladder was evaluated. Pumps were filled with a 1% solution of methylene blue in phosphate buffered saline. Following pump implantation. urinary samples were collected on a daily basis and subsequently analyzed for their concentration of methylene blue. At the completion of the experiment. specimens of the kidney. ureter. and bladder were histologically examined. Results demonstrated an average of 102% recovery of the theoretically delivered dose over a 14-day period. Renal histology demonstrated chronic inflammatory changes at the site of nephrostomy tube placement. No upper or lower tract urothelial changes were identified. This model provides a system for the continuous delivery of drugs in the rat urinary tract and results in no histological alteration to the lower urinary tract.
Determination of the coefficient of kinetic friction of urinary catheter materials, The coefficient of kinetic friction plays an important role in the biocompatibility of urinary catheters. A method for determination of the in vivo coefficient of kinetic friction is described that allows the comparison of the catheter-urethral interaction of the various materials used in the production of urinary catheters and the different types of lubricants.
Radio-contrast enhancement of urinary tract stones, Most urologists treating stone disease with any method (ESWL. PCL. URS) have encountered problems of poor stone visualization with fluoroscopy. This difficulty to localize urinary tract (UT) stones or fragments may result in incomplete stone extraction. prolonged surgery and increased risk of recurrence and post-operative complications. We have sought and found means to increase the radioopacity of mineral UT stones by a simple pre-operative perfusion technique. The capacity of radioopacification has first been demonstrated in in vitro incubations of fragments of human mineral stones with aqueous solutions of barium. of the lanthanides and of the two natural actinides. Most of the incubations led to considerable radio-contrast enhancement and heavy metal incorporation. measured by X-ray fluorescence analysis. Dogs with implanted human stone fragments were used as an in vivo model. The UT were perfused through a retrograde pyelic catheter with heavy metal salts solutions. the ensuing radioopacification of the implanted UT-stones was estimated by abdominal radiographies and the metal incorporation was measured on the retrieved stones. Considerable radioopacity enhancement together with heavy metal incorporation was observed for the following elements: Sr. Ba and the lanthanides Gd and Yb. The pathological evaluation of the urothelial linings from animals treated with lanthanide salt showed no toxic effects.
Cytostatic effects of suramin on prostate cancer cells cultured from primary tumors, Suramin is currently undergoing clinical trials as a chemotherapeutic agent for prostate cancer. The effects of suramin on cultured human epithelial cells derived from normal. benign hyperplastic. and malignant prostate tissues were examined. In serum-free medium. suramin inhibited the clonal growth of prostate cells at a half-maximal dose of approximately 10 micrograms/ml. Growth inhibition by suramin was completely reversible even after 24 hours of exposure. In conjunction. suramin did not alter cellular phenotype with regard to expression of keratins and prostate-specific antigens. Although suramin is reportedly an antagonist of growth factor-mediated mitogenesis. ten-fold excesses of growth factors did not appreciably suppress the cytostatic activity of suramin. In comparison to the activities of other possible chemotherapeutic agents. suramin would appear suboptimal because its inhibitory effects are reversible and it does not induce a terminally differentiated cellular phenotype.
Chronic effects of focused electrohydraulic shock waves on renal function and hypertension, The chronic effects of focused electrohydraulic shock waves were studied in a minipig model. Fifteen animals underwent a unilateral nephrectomy and compensatory renal hypertrophy was allowed to take place over a minimum of six months. Baseline studies were then carried out consisting of 1) serum creatinine. blood urea nitrogen. and plasma renin levels 2) intra-arterial blood pressure measurement and 3) 3H-inulin clearance. Ten of the animals then underwent 8 shockwave treatments (2500 shocks per treatment). alternately to the upper and lower pole of the kidney. at two weeks intervals. A total of 20.000 shock waves were administered to each minipig over the four month period. The five control pigs underwent sham procedures. The renal function and blood pressure evaluations were then repeated. No significant decrease in renal function was noted in the experimental animals when compared to the controls. In addition. renin mediated hypertension was not observed despite the excessive number of total shock waves delivered to the kidney.
Renal arterial duplex Doppler ultrasound in dogs with urinary obstruction, Recent clinical studies using duplex Doppler sonography identified an alteration in renal arterial blood flow in obstructed hydronephrotic kidneys that reportedly can be used to distinguish obstructive from nonobstructive collecting system dilatation. We attempted to verify these clinical findings and establish the temporal relationship of the alteration in the Doppler spectrum to the onset of urinary obstruction by evaluating surgically induced urinary obstruction in dogs. We performed laparotomies on 11 dogs. with the left ureter isolated and ligated in five dogs. and left intact in six dogs (control group). Duplex Doppler examination of the left renal arteries performed nine times during the first postoperative month identified a statistically significant difference (p less than .05) in the Doppler resistive index calculation between the two groups on days 1. 2. 4. and week 4. A resistive index discriminatory threshold of 0.7 (greater than 0.7. obstructed; less than 0.7. nonobstructed) produced a test sensitivity of 74% and specificity of 77%. We conclude from our study that renal arterial duplex Doppler sonography can detect a change in renal perfusion as a result of urinary obstruction and that this change can be detected as early as 24 hours after obstruction. However. high false-positive and false-negative rates may limit the ability of this modality to reliably distinguish obstructive from nonobstructive collecting system dilatation.
The effect of radiation therapy and hyperthermia on a human prostatic carcinoma cell line grown in athymic nude mice, The effect of radiation and/or hyperthermia on a human prostatic carcinoma xenograft in athymic nude mice was investigated. A human prostate carcinoma subline (1-LN-PC-3-1A) was inoculated subcutaneously in the thigh of male athymic nude mice. When tumors reached a size of approximately 200 mm.3. they were treated with either radiation (X) or hyperthermia (H) alone. or in combination (X + H). In the combined treatment. hyperthermia was delivered immediately after radiation exposure. Comparison of the time required to reach twice the tumor volume observed at the time of treatment was used to define therapeutic impact on tumor growth. The combined treatment resulted in median tumor volume doubling time of 35.5 days. compared to 18 days and 25.5 days. respectively. for hyperthermia or radiation alone. Analysis of tumor doubling time using a proportional hazards regression indicates that under the conditions of this experiment. the effect of radiation and hyperthermia for 1-LN-PC-3-1A tumors is additive. The impact of this treatment regimen in the management of prostatic cancer requires further investigation.
Image guided localized 31P magnetic resonance spectroscopy of acute urinary tract obstruction, Using 31P magnetic resonance spectroscopy. localized spectroscopy and magnetic resonance imaging we studied effects of acute urinary obstruction in the in vivo pig kidney. Accumulation of urine in the renal pelvis and collecting ducts resulted in the appearance of a new peak in the localized phosphorus spectra originating in the renal papilla. resonating at 3.43 to 4.56 ppm. This was inorganic phosphate with a pH of 5.60 to 6.79 (urine pH). Imaging did not show any dilatation of renal pelvis. There was a significant time dependent fall in renal [ATP] during urinary obstruction followed by a rapid "overshoot" of [ATP] and disappearance of the phosphate peak after release of obstruction. Possible mechanisms for this phenomenon are discussed. We conclude that 31P magnetic resonance spectroscopy provides early evidence of urinary obstruction in vivo and could be of value in clinical diagnosis.
Preliminary experience with the pulsed dye laser for treatment of urolithiasis, We report our initial experience using the pulsed dye laser in 26 patients with urolithiasis. The patients ranged in age from 27 to 82 years; 11 patients were female and 15 were male. Of the 26 patients. 4 stones were in the kidney. 21 were in the ureter. and one was in the bladder. Surgical time ranged from 32 to 130 minutes. All patients were treated under spinal or general anesthesia. The size of ureteral stones ranged from 0.2 to 1.5 cm. and the renal stones 3.0 to 4.0 cm. Chemical analysis of the stones was not available on all patients. but when available. chemical analysis revealed the stones to be calcium monohydrate. calcium dihydrate. or struvite. The use of the Candela miniscope in 11 patients permitted access without ureteral dilation. In 19 patients. ureteral stents were placed. One patient suffered a ureteral perforation. Success was defined as adequate disintegration of the stone for passage of the fragments without the necessity of a secondary procedure. Using this criterion. 22 of 26 patients were successfully treated for an overall success rate of 85%.
Generation of "soft x-rays" by using the free electron laser as a proposed means of diagnosing and treating breast cancer, The diagnosis and treatment of breast lesions may be markedly enhanced by the use of a unique new source of near-monochromatic x-rays. Concentric beams of near-monochromatic x-ray photons may be generated by collision of the free electron laser (FEL) electron beam with the optical beam in an interaction zone that delivers the x-rays to a shirtsleeve environment. The absence of Compton scatter and the photoelectric interaction within tissues improves conspicuity of lesions by two to six times. Increased attenuation of x-rays in malignant vs. normal tissues makes tumors more obvious. K-edge subtraction allows chemical analysis of tumors in vivo--all at radiation doses that are one-tenth to one-fiftieth that delivered by the lowest-dose mammographic x-ray technique available. This allows for an increased sensitivity and specificity and permits prediction of histology. negating necessity for biopsies. Selective bond-breaking at depth in tissues as well as x-ray-activated photodynamic therapy are also being explored.
Resting metabolic rate and energy balance in amenorrheic and eumenorrheic runners, This study investigated metabolic and nutritional factors in association with athletic menstrual dysfunction (AMD). Three groups of women were studied: amenorrheic runners (amenorrheic). eumenorrheic runners (eumenorrheic). and eumenorrheic sedentary controls (sedentary). Amenorrheic and eumenorrheic were similar in age. weight. percent body fat by hydrodensitometry. training pace and mileage. best 10 km race time. years running. and maximal oxygen consumption. When adjusted for body weight or for fat-free mass by analysis of covariance. RMR was significantly lower in amenorrheic than in eumenorrheic and sedentary. The daily caloric intakes of the groups did not differ significantly. but the amenorrheic scored significantly higher than the eumenorrheic and sedentary on a scale of aberrant eating patterns. Amenorrheic high mileage runners seem to have a less adequate diet than eumenorrheic runners but appear to maintain energy balance and stable weight through a reduction in RMR.
Menstrual function and eating behavior in female recreational weight lifters and competitive body builders, A group of 103 female weight lifters (WL) and 92 control (C) women answered a survey concerning eating behavior and attitudes (including the Eating Disorder Inventory) and menstrual function. The incidence of menstrual dysfunction. defined as oligomenorrhea plus amenorrhea. was significantly higher for the WL (30%) than for the C (13%) not on contraceptive pills. Only 2% of the women had amenorrhea. The incidence of dysfunction was highest for the subset of 12 WL who had competed in at least one body building competition (COMP); 86% of the COMP not on birth control pills had menstrual dysfunction (P less than 0.05). More WL than C reported missing at least one menstrual period during the last year (P = 0.06). WL scored significantly higher than C on the Drive for Thinness subscale of the Eating Disorder Inventory (EDI). Fifteen percent of the WL and 9% of the C achieved the criteria on this subscale for being weight preoccupied (P greater than 0.05). Significantly more WL than C responded that they were terrified of becoming fat (WL 56%. C 38%). were obsessed with food (WL 47%. C 30%). used laxatives for weight control (WL 14%. C 1%). and claimed that they had been anorexic in the past (WL 17%. C 5%). Examination of the answers of COMP revealed several items that were significantly different from the remainder of the WL. For example. 42% used to be anorexic. 67% were terrified of becoming fat. and 50% experienced uncontrollable urges to eat.
Skeletal muscle following tonic overload: functional and structural analysis, Functional overloading of skeletal muscle induces a compensatory hypertrophy as an adaptive response to increased functional demand. Overload of the extensor digitorum longus (EDL) muscle (129 ReJ strain male mouse) was induced by unilateral surgical removal of a synergistic muscle. tibialis anterior (TA). Response of the EDL to overload for 7. 21. and 42 d was analyzed for changes in 1) muscle weight. 2) myofiber type distribution. 3) myofiber cross-sectional area by fiber type. 4) speed of contraction and relaxation of the muscle. 5) force of contraction. and 6) myofiber morphologic integrity. The weight of the EDL significantly increased. The overload caused no impairment of muscle contractility and did not have a significant effect on isometric twitch contraction time to peak tension or the time to one-half relaxation of the twitch. Overloaded muscles demonstrated a transient shift in fiber type profile with preferential hypertrophy of Type IIA fibers that occurred in the early phase of overload while type IIB fibers were recruited by 42 d. No significant increase in myofiber number in overloaded muscles occurred. Some morphologic changes in over-loaded muscles parallel those found in patients with neurogenic muscular disorders. However. overloaded muscle did not exhibit a significant occurrence of fiber branching from controls in the midbelly region of the muscle.
Oxygen uptake and heart rate responses during hypoxic exercise in children and adults, Control of ventilation and heart rate during exercise appears to undergo maturation. while aerobic metabolism (VO2) may not. Since we had previously found that hypoxia during exercise produced different ventilatory responses in children (C) compared to adults (A). we hypothesized that VO2 and heart rate kinetics during exercise would show similar maturational responses to hypoxia. To test this hypothesis. we examined the responses during progressive (ramp) and constant work rate tests in children and adults breathing either room air or hypoxic gas (FiO2 = 0.15). When corrected for body weight. children and adults had similar values for lactic acidosis threshold (LAT) (C: 29.1 +/- 5.0 ml.min-1.kg-1; A: 27.9 +/- 4.3) and VO2max (C: 40.7 +/- 8.6 ml.min-1.kg-1; A: 45.2 +/- 6.7) during normoxia. Hypoxia significantly lowered LAT (C: 27.5 +/- 5.4 ml.min-1.kg-1; A: 23.2 +/- 3.8; both P less than 0.05) and VO2max (C: 37.7 +/- 8.3 ml.min-1.kg-1; A: 40.1 +/- 5.3; both P less than 0.05) in both children and adults. Metabolic efficiency (delta VO2/delta work rate) and the VO2-heart rate relationship (delta VO2/delta HR/kg) were similar in the two groups and unaffected by hypoxia. During the constant work rate exercise. VO2 kinetics (time constant during phase 2 of the response (pi 1) and the O2 deficit) were similar between children and adults and were significantly slowed by hypoxia. consistent with current understanding of the control of oxidative metabolism. Finally. heart rate was increased at rest and during exercise with hypoxia. while the time to reach 75% of the end-exercise response was delayed significantly. in both groups.
Effective surgical adjuvant therapy for high-risk rectal carcinoma, BACKGROUND. Radiation therapy as an adjunct to surgery for rectal cancer has been shown to reduce local recurrence but has not improved survival. In a previous study. combined radiation and chemotherapy improved survival significantly as compared with surgery alone. but not as compared with adjuvant radiation. which many regard as standard therapy. We designed a combination regimen to optimize the contribution of chemotherapy. decrease recurrence. and improve survival as compared with adjuvant radiation alone. METHODS. Two hundred four patients with rectal carcinoma that was either deeply invasive or metastatic to regional lymph nodes were randomly assigned to postoperative radiation alone (4500 to 5040 cGy) or to radiation plus fluorouracil. which was both preceded and followed by a cycle of systemic therapy with fluorouracil plus semustine (methyl-CCNU). RESULTS. After a median follow-up of more than seven years. the combined therapy had reduced the recurrence of rectal cancer by 34 percent (P = 0.0016; 95 percent confidence interval. 12 to 50 percent). Initial local recurrence was reduced by 46 percent (P = 0.036; 95 percent confidence interval. 2 to 70 percent). and distant metastasis by 37 percent (P = 0.011; 95 percent confidence interval. 9 to 57 percent). In addition. combined therapy reduced the rate of cancer-related deaths by 36 percent (P = 0.0071; 95 percent confidence interval. 14 to 53 percent) and the overall death rate by 29 percent (P = 0.025; 95 percent confidence interval. 7 to 45 percent). Its acute toxic effects included nausea. vomiting. diarrhea. leukopenia. and thrombocytopenia. These effects were seldom severe. Severe. delayed treatment-related reactions. usually small-bowel obstruction requiring surgery. occurred in 6.7 percent of all patients receiving radiation. and the frequencies of these complications were comparable in both treatment groups. CONCLUSIONS. The combination of postoperative local therapy with radiation plus fluorouracil and systemic therapy with a fluorouracil-based regimen significantly and substantively improves the results of therapy for rectal carcinoma with a poor prognosis. as compared with postoperative radiation alone.
Evidence that histamine is the causative toxin of scombroid-fish poisoning, BACKGROUND. The highest morbidity worldwide from fish poisoning results from the ingestion of spoiled scombroid fish. such as tuna and mackerel. and its cause is not clear. Histamine could be responsible. because spoiled scombroid fish contain large quantities of histamine. Whether histamine is the causative toxin. however. has remained in question. To address this issue. we investigated whether histamine homeostasis is altered in poisoned people. METHODS. The urinary excretion of histamine and its metabolite. N-methylhistamine. was measured in three persons who had scombroid-fish poisoning (scombrotoxism) after the ingestion of marlin. We measured 9 alpha. 11 beta-dihydroxy-15-oxo-2.3.18.19-tetranorprost-5-ene-1.20-dioic acid (PGD-M). the principal metabolite of prostaglandin D2. a mast-cell secretory product. to assess whether mast cells had been activated to release histamine. RESULTS. The fish contained high levels of histamine (842 to 2503 mumol per 100 g of tissue). Symptoms of scombrotoxism--flushing and headache--began 10 to 30 minutes after the ingestion of fish. In urine samples collected one to four hours after fish ingestion. the levels of histamine and N-methylhistamine were 9 to 20 times and 15 to 20 times the normal mean. respectively. During the subsequent 24 hours. the levels fell to 4 to 15 times and 4 to 11 times the normal values. Levels of both were normal 14 days later. PGD-M excretion was not increased at any time. Two persons treated with diphenhydramine had prompt amelioration of symptoms. CONCLUSIONS. Scombroid-fish poisoning is associated with urinary excretion of histamine in quantities far exceeding those required to produce toxicity. The histamine is most likely derived from the spoiled fish. These results identify histamine as the toxin responsible for scombroid-fish poisoning.
Video display terminals and the risk of spontaneous abortion, BACKGROUND. The relation between spontaneous abortion and the use of video display terminals (VDTs) is of great public health concern. Previous investigators of this issue have reported inconsistent findings. METHODS. To determine whether electromagnetic fields emitted by VDTs are associated with an increased risk of spontaneous abortion. a cohort of female telephone operators who used VDTs at work was compared with a cohort of operators who did not use VDTs. To obtain reliable estimates of exposure. we determined the number of hours of VDT use per week from company records and measured electromagnetic fields at VDT workstations and. for purposes of comparison. at workstations without VDTs. Operators who used VDTs had higher abdominal exposure to very-low-frequency (15 kHz) electromagnetic fields (workstations without VDTs did not emit very-low-frequency energy). Abdominal exposure to extremely-low-frequency fields (45 to 60 Hz) was similar for both operators who used VDTs and those who did not. Among 2430 women interviewed. there were 882 pregnancies that met our criteria for inclusion in the study. RESULTS. We found no excess risk of spontaneous abortion among women who used VDTs during the first trimester of pregnancy (odds ratio = 0.93; 95 percent confidence interval. 0.63 to 1.38). and no dose-response relation was apparent when we examined the women's hours of VDT use per week (odds ratio for 1 to 25 hours per week = 1.04; 95 percent confidence interval. 0.61 to 1.79; odds ratio for greater than 25 hours per week = 1.00; 95 percent confidence interval. 0.61 to 1.64). There continued to be no risk associated with the use of VDTs when we accounted for multiple pregnancies. conducted separate analyses of early abortion. late abortion. and all fetal losses. or limited our analyses to spontaneous abortions for which a physician was consulted. CONCLUSIONS. The use of VDTs and exposure to the accompanying electromagnetic fields were not associated with an increased risk of spontaneous abortion in this study.
Clinical importance of myeloid-antigen expression in acute lymphoblastic leukemia of childhood, BACKGROUND. Leukemic cells in 15 to 25 percent of patients with acute lymphoblastic leukemia (ALL) express myeloid antigens as well as lymphoid antigens (the latter reflecting B-cell or T-cell lineage). The relations of myeloid-antigen expression to other features of ALL and to prognosis have been controversial. METHODS. We analyzed clinical and laboratory features present at diagnosis in 236 consecutive cases of ALL in children. Immunophenotyping. including single- and dual-fluorescence analyses. was used to classify leukemic cells as B or T lymphoblasts and also to identify myeloid-antigen expression--the simultaneous expression of lymphoid-associated antigens and at least one of three myeloid-associated antigens (CD33. CD13. and CD14) on cells classified as L1 or L2 according to the French-American-British system. RESULTS. Forty-five of 185 patients with B-lineage ALL had myeloid-antigen expression. as did 8 of 41 patients with T-lineage ALL. In 10 patients. the lineage could not be determined. Myeloid-antigen expression was associated with L2 morphology (P less than 0.05). but it did not correlate with other prognostic features recognized previously. Multivariate analysis showed that myeloid-antigen expression was an important predictor of relapse in childhood ALL and the most significant prognostic factor statistically (P less than 0.0001). A white-cell count greater than or equal to 50 x 10(9) per liter at diagnosis was also an important and highly significant prognostic feature (P less than 0.001). After 40 months. the estimated disease-free survival for patients with ALL was 84 percent for those without myeloid-antigen expression and with a low white-cell count. 57 percent for those without myeloid-antigen expression and with a high white-cell count. 47 percent for those with myeloid-antigen expression and a low white-cell count. and 26 percent for those with myeloid-antigen expression and a high white-cell count (P less than 0.00001). CONCLUSIONS. Myeloid-antigen expression is an important independent predictor of a poor response to chemotherapy in childhood ALL.
Asymptomatic versus symptomatic herniated thoracic discs: their frequency and characteristics as detected by computed tomography after myelography, We retrospectively reviewed the myelograms of 433 patients and identified those who had no symptoms or signs referable to the thoracic cord. roots. or nerves. By post-myelography computed tomographic scan criteria. our frequency of asymptomatic thoracic herniated discs (ATHDs) was calculated. Post-myelography computed tomographic scans of 68 ATHDs were analyzed. Their imaging characteristics were compared with our own series of 5 symptomatic thoracic herniated discs and symptomatic thoracic herniated discs in the literature. We were unable to identify any imaging features that could reliably classify a disc as an ATHD or a symptomatic thoracic herniated disc. Our results call into question the propriety of prophylactic surgery for ATHDs. even when the lesions are radiographically impressive.
Intracranial hypertension in relation to memory functioning during the first year after severe head injury, The relationship between intracranial hypertension and residual memory deficit after closed head injury was evaluated using the 6-month and 1-year neurobehavioral outcome data obtained by the Traumatic Coma Data Bank. Intracranial pressure was analyzed using the percentage of time that it exceeded 20 mm Hg and the maximum value recorded during the first 72 hours after injury. Memory measures included recall of word lists. prose recall. and visual memory for designs that were obtained 6 months (n = 149) and 1 year (n = 132) after injury. Intracranial hypertension occurred in more than half of the Traumatic Coma Data Bank cohort who met the criteria for the neurobehavioral follow-up study. Linear regression analysis disclosed an effect of elevated intracranial pressure on some. but not all. measures of memory at 6 months. whereas the results were negative for the 1-year follow-up examination. We conclude that the elevation of intracranial pressure exerts little if any effect on later memory functioning. and that any effect it does have diminishes over 1 year in survivors of severe head injury.
Interstitial irradiation and hyperthermia for the treatment of recurrent malignant brain tumors, Between June 1987 and June 1989. 29 recurrent malignant gliomas or recurrent solitary brain metastases in 28 patients were treated in a Phase I study of interstitial irradiation and hyperthermia. Patient age ranged from 18 to 65 years. and the Karnofsky Performance Status scores ranged from 40 to 90%. There were 13 glioblastomas. 10 anaplastic astrocytomas. 3 melanomas. and 3 adenocarcinomas. Catheters were implanted stereotactically after computed tomography-based preplanning. Hyperthermia was administered before and after brachytherapy. using one to six 2450- or 915-MHz helical coil microwave antennas and one to three multisensor fiberoptic thermometry probes. The goal was to heat as much of the tumor as possible to 42.5 degrees C for 30 minutes. Within 30 minutes after the first hyperthermia treatment. implant catheters were afterloaded with high-activity iodine-125 seeds delivering tumor doses of 32.6 to 61.0 Gy. Most patients had no sensation of heating. Complications included seizures in 5 patients. reversible neurological changes in 9 patients. a scalp burn in 1. and infections in 3. Of 28 evaluable 2-month follow-up scans. 11 showed definite improvement in the radiological appearance of the tumor. 4 were slightly improved. 7 were stable. and 6 showed tumor progression. Ten patients underwent reoperation for persistent tumor and/or necrosis. Eleven of 28 patients are alive 40 to 97 weeks after treatment. Thirteen patients died of a brain tumor. 2 died of extracranial melanoma metastases. 1 died of new brain melanoma metastases. and 1 died of a pulmonary embolus. The median survival was 55 weeks overall. Median survival has not yet been reached for the anaplastic astrocytoma subgroup. We conclude that interstitial brain hyperthermia using helical coil microwave antennas is technically feasible. The level of toxicity is acceptable. and the computed tomographic response rate is encouraging.
Expression of platelet-derived growth factors, transforming growth factors, and the ros gene in a variety of primary human brain tumors, Ribonucleic acid was isolated from a wide spectrum of central nervous system tumors to examine the expression of platelet-derived growth factors (PDGF) A and B. tumor growth factors (TGF-beta) 1 and 2. and ros messenger ribonucleic acid. Eight glioblastoma cell lines were examined as well as cell cultures from 22 tumor explants. The explants included 6 glioblastomas. 4 anaplastic astrocytomas. 5 astrocytomas. 3 ependymal tumors. 2 meningiomas. 1 medulloblastoma. and 1 ganglioglioma. For comparison. 2 nontumor glial cell cultures were included. The PDGF B-chain was expressed in 5 of 8 glioblastoma cell lines. 2 of 6 glioblastomas. and in 3 of 4 anaplastic astrocytoma explants. There was no PDGF B expression in 4 astrocytomas. 3 ependymomas of varying malignancy. in the remainder of the tumors. or in the nontumor glial cells. The PDGF A-chain was expressed in all of the tumors. with the exception of the malignant ependymoma and in both nontumor glial cell cultures. TGF-beta 1 was expressed in all of the tumors and in nontumor glial cells. The expression of TGF-beta 2 was expressed in many of the benign and malignant tumors and also in both nontumor glial cell cultures. The ros messenger ribonucleic acid was expressed in 1 of 5 glioblastoma cell lines and in 2 of 6 glioblastoma cell explants. but in none of the other tumors or in the nontumor glial cells.
Postoperative computed tomographic evaluation of patients with large pituitary tumors treated with operative decompression and radiation therapy, Thirty consecutive patients who underwent operative decompression and radiation therapy for large sellar and suprasellar pituitary tumors (greater than or equal to 2 cm) were studied in terms of the serial computed tomographic (CT) changes. There were 23 men and 7 women. The mean age was 49.6 +/- 2.5 years. and the mean follow-up was 45.3 +/- 3.9 months. Twenty-eight of the 30 patients had transsphenoidal surgery. and 27 had hormonally inactive tumors. Radiation therapy was begun within 1 month of surgery with a mean dose of 4855 +/- 70 cGy. Postoperative CT scans were obtained within 1 month of surgery and at 6- to 12-month intervals thereafter. Fourteen patients (45%) had no suprasellar tumor visualized in either the early postoperative CT scans or on subsequent scans. Eleven patients (35%) had a persistent suprasellar mass during the early postoperative period that resolved on serial CT evaluation. The mean time for resolution was 10.4 +/- 1.2 months. Six patients (20%) had a persistent suprasellar mass on serial CT evaluation. A persistent postoperative mass that subsequently resolved in many of the patients was thought to be caused by the gradual retraction of the postoperative packing and hematoma. as well as the effect of radiation on any residual tumor.
The influence of the calcium antagonist nimodipine and induced hypertension on the behavior of the cerebral pial arteries, the blood-brain barrier, cerebral edema, and cerebral infarction in cats with one-hour occlusion of the middle cerebral artery, Thirty anesthetized cats were randomly assigned to one of three groups of 10 cats each: nimodipine treatment. nimodipine treatment combined with induced hypertension. or a control group. The behavior of the cerebral pial arteries was measured by means of microscopic observation through a cranial window. The middle cerebral artery of each cat was clipped for 1 hour via the transorbital approach. Five hours after circulation was reestablished in the middle cerebral artery. Evans blue dye was injected intravenously: 30 minutes later. the animal was killed. Administration of nimodipine or saline in the treated or control group was started 5 minutes before the middle cerebral artery was clipped and maintained until the end of the experiment. Induced hypertension was produced by administration of dopamine during the occlusion. Damage to the blood-brain barrier (BBB) was judged by extravasation of Evans blue dye. Cerebral edema and infarction were evaluated from histological findings. They were most prominent in the control group: the extent of hemisphere affected was as follows (mean +/- standard error): extravasation. 40.5 +/- 8.8%; edema. 43.2 +/- 5.7%; infarction. 35.5 +/- 9.6%. On the other hand. the extravasation of Evans blue dye and cerebral edema were significantly more extensive in the group treated with nimodipine and induced hypertension (extravasation. 28.2 +/- 9.6% of the hemisphere; edema. 30.3 +/- 7.1%) than in the group treated with nimodipine alone (extravasation. 18.5 +/- 8.7% of the hemisphere; edema. 19.4 +/- 6.3%). but the infarction size was similar in both groups (16.6 +/- 4.9% of the hemisphere in the former; 17.0 +/- 6.2 in the latter).
Spinal Charcot arthropathy, Charcot joints of the spine are well-documented clinical entities most commonly associated with tabes dorsalis. Spinal neuropathic joints. however. may be produced by other disease processes including syringomyelia. In this review. the authors discuss the cause and treatment of spinal Charcot arthropathy with emphasis on surgical therapy and results.
Kenneth McKenzie, Harvey Cushing, and the early neurosurgical treatment of spasmodic torticollis, In 1923. Dr. Kenneth McKenzie trained at the Peter Bent Brigham Hospital under Dr. Harvey Cushing. At that time. a patient with spasmodic torticollis came to Cushing and was treated with an innovative operation for this disorder with good results. This case sparked an interest in Dr. McKenzie. who published the case 1 year later. In reviewing the surgical histories from the Peter Bent Brigham Hospital. we have found the original records of this well-documented case. The record includes postoperative drawings of the intraoperative field by Dr. Cushing. a sketch by Dr. McKenzie illustrating the postoperative sensory examination. and pre- and postoperative photographs of the patient.
Spinal man after declaration of brain death, Complex spinal automatism in a patient who was declared brain dead is described. These movements tend to appear once cerebrospinal shock has abated. We postulate that these manifestations are a reflection of the physiological potential of the isolated spinal cord. These spinal movements should be included in the revised guidelines for the determination of cerebral death.
Spinal glioblastomas: report of seven cases and review of the literature, Intramedullary glioblastomas are uncommon tumors. They occur chiefly in the cervicothoracic segments. have a slight tendency to occur in the early decades of life. and have a short clinical history before diagnosis. We report seven cases and discuss the salient features of these tumors. particularly the pathological features and treatment. in light of the relevant literature.
Prevention of dry socket: an overview, Dentists. exodontists. oral surgeons. and now oral and maxillofacial surgeons have been plagued with a postextraction complication. commonly known as "dry socket." since the inception of our profession. Other designations that have been attached to this malady over the years include alveolar osteitis. postextraction osteitis. osteomyelitic syndrome. alveolar sicca dolorosa. and. latterly. fibrinolytic alveolitis. Myriad attempts to eliminate this painful condition have been made. to no avail. Nonetheless. significant progress has been made in an endeavor to reduce its incidence. Perhaps it is time to take an inventory of the proven methods that will assist the practitioner in reducing the incidence of this complication in his/her practice. This article presents a review of past investigations that appear to have merit in this regard. with a summary of recommendations at the conclusion of the article.
A comparison of midazolam with and without nalbuphine for intravenous sedation, The introduction of nalbuphine to intravenous sedation with midazolam added little to the quality of sedation for short operative procedures. There was a greater tendency for patients who received nalbuphine and midazolam to sleep in the afternoon after treatment compared with those who received only midazolam. Significantly more patients had nausea and vomiting in the midazolam/nalbuphine group than did patients in the midazolam-only group.
Effects of removing inferior alveolar neurovascular structures on mandibular growth and the eruption of permanent dentition in puppies, Investigation was performed on the effects of removing the inferior alveolar neurovascular structures on the permanent dentition and mandibular growth. Five puppies with erupted deciduous teeth had the inferior alveolar neurovascular structures removed unilaterally. When the test animals were 28 weeks old. examination revealed that the deciduous teeth on the side operated had exfoliated but permanent teeth did not replace them. On the other hand. the permanent teeth on the side not operated on replaced the exfoliated deciduous teeth. After a second period of 28 weeks. the germs of the permanent teeth on the side operated on were still buried in the mandibular bone. and the permanent teeth on the side not operated on erupted normally. Mandibular measurements demonstrated that translative and transformative growth and developmental processes were normal in both the sides operated on and the sides not operated on.
Orofacial odontogenic infections: review of microbiology and current treatment, Orofacial odontogenic infections are common. Current evidence indicates that anaerobes play a major role in these infections and that the most common microbial isolates are Bacteroides. fusobacteria. peptococci. and peptostreptococci as well as some viridans streptococci. Drainage must be established where possible. Penicillin is still the drug of first choice for therapy. with metronidazole a good alternative. Nevertheless. not all clinicians are aware of current views and. therefore. this article is a state-of-the-art review for the practicing clinician of the microbiology and antimicrobial therapy of orofacial odontogenic infections.
A comparison of the signs of temporomandibular joint dysfunction and occlusal discrepancies in a symptom-free population of men and women, To date. there has been no conclusive explanation for the predominance of female patients with temporomandibular joint (TMJ) dysfunction. The purpose of this study was to survey a normal population without symptoms for the presence of certain putative signs of TMJ dysfunction in association with certain signs of occlusal discrepancy and to determine the presence of any gender variation. The subjects (217 men and 217 women) were examined for the presence of three putative signs of TMJ dysfunction: limited mandibular opening (under 37 mm). deviation on opening. and joint sounds. The subjects were also examined for the presence of four signs of occlusal discrepancy: an anterior slide from centric relation (CR) to centric occlusion (CO). lateral slide from CR to CO. nonworking occlusal contacts. and working disclusive contacts distal to the canines. CR is the mandibular position at which the condyles are in their most superior position on the posterior aspect of the articular tubercles. CO is the mandibular position at which the mandibular and maxillary teeth are in maximum intercuspation. There were no significant differences in the prevalence of the putative signs of TMJ dysfunction and occlusal discrepancy between men and women. It was concluded that factors other than the presence of these signs of TMJ dysfunction and occlusal discrepancy are responsible for the high predominance of female patients with TMJ dysfunction.
Oral cancer: a survey of 566 cases from the University of Connecticut Oral Pathology Biopsy Service, 1975-1986, A survey of the University of Connecticut Oral Pathology Biopsy Service was undertaken to analyze cases of oral cancer accessioned during the 12-year period. 1975 through 1986 inclusive. Of 33.429 total specimens accessioned. there were 546 malignant oral neoplasms diagnosed and reported. Sixty-five (11.5%) originated from out of state. Invasive intraoral squamous cell carcinoma was the predominant tumor (69.7% of total). whereas lip cancer constituted only 2.8% of all malignancies. Minor salivary gland adenocarcinomas accounted for 11% of total malignancies whereas verrucous carcinoma. carcinoma in situ. and miscellaneous other forms of oral cancer accounted for the remainder (4.6%. 5.3%. and 6.6%. respectively). Cases of invasive squamous cell carcinoma were further analyzed by year. sex distribution. location subsite. age at diagnosis. and histologic grade. With the exception of histologic grading. we found that the characterization of cases of squamous cell carcinoma within the biopsy service tended to parallel results from a separate but related statewide analysis of both oral cancer and intraoral squamous cell carcinoma from Connecticut over a much longer time span. We concluded that the picture of oral cancer as characterized by cases within the University of Connecticut Oral Pathology Biopsy Service is generally reflective of the disease on a statewide level.
Intracoronal radiolucencies within unerupted teeth. Case report and review of literature, A panoramic radiograph obtained during orthodontic treatment revealed an intracoronal radiolucency within an unerupted permanent second molar. This unusual entity was successfully treated by surgical and endodontic intervention. followed by restorative and orthodontic treatment. These treatments enabled the tooth to maintain pulpal vitality. erupt. complete root formation. and function. This report will review the proposed etiologies for this condition. discuss the need for surgical intervention. and present the details of the case.
A comparison of two temporary restorations: light-cured resin versus a self-polymerizing temporary restoration, Temporary restorative materials are an important component of endodontic therapy. They must both adequately seal the access preparation between visits and protect the obturated canal(s) from microleakage until a permanent restoration can be placed. The efficacy of Cavit and T.E.R.M. (a new light-cured composite product) was compared with the use of a carbon black coronal microleakage protocol. The teeth examined had previously received coronal restorations. After the teeth were accessed. restored with Cavit or T.E.R.M.. and exposed to the dye. they were cleared. Three-dimensional assessment then revealed that Cavit more consistently provided an effective seal. In addition. a great deal of microleakage was observed around the permanent restoration-tooth interface. This indicates that perhaps leaking permanent restorations should be removed in their entirety before initiation of endodontic treatment.
A comparison of three formulations of TAC (tetracaine, adrenalin, cocaine) for anesthesia of minor lacerations in children, A randomized. prospective. double-blind study comparing three formulations of the topical anesthetic solution TAC for laceration repair was undertaken in 250 children. The children's wounds were anesthetized with either TAC I (original formulation--0.5% tetracaine. 1:2000 Adrenalin. 11.8% cocaine). TAC II (1.0% tetracaine. 1:4000 Adrenalin. 7.0% cocaine). or TAC III (1.0% tetracaine. 1:4000 Adrenalin. 4.0% cocaine) prior to repair. The solutions were compared with respect to efficacy. acceptability. wound complications. and side effects. We found comparable efficacy of the three formulations. with similar efficacy to 1% lidocaine infiltration for facial and scalp wounds. Anesthesia for extremity wounds was adequate in only 39.9% of cases. regardless of TAC strength. Wound complications and side effects were within expected and acceptable limits. Our findings support use of TAC for face and scalp lacerations and a change to a less concentrated TAC preparation. such as our "TAC III." which is presumably safer for widespread use.
It may be more significant than you think: BB air rifle injury to a child's head, BB guns of 20 years ago were constructed of coils and springs which generated relatively little force. so that a projectile posed little threat of serious injury. Today. the coil and spring construction has been replaced by pump action pneumatic chambers which allow generation of muzzle velocities near 350 ft/sec. Speeds of 150 ft/sec and 200 ft/sec are required for skin penetration and bone penetration. respectively. We present a seven-year-old boy who suffered intracranial parenchymal injury from an air-powered BB gun projectile while playing with friends. We discuss literature which suggests these once-innocent toys are now harbingers of severe. if not fatal. injury.
Ectatic blood vessels in port-wine stains lack innervation: possible role in pathogenesis, The innervation pattern of port-wine stains was investigated using indirect immunohistochemistry with antibodies to protein gene product 9.5 (PGP 9.5). neuron-specific enolase (NSE). calcitonin gene-related peptide (CGRP). and neurofilament (NF). The pathologically dilated vessels in the middle and deep dermis were found to have defective innervation with only single or no nerve fibers in their vicinity. while other structures in the skin showed a normal density of fibers. NSE- and PGP-like immunoreactive (-LI) nerve fibers were observed innervating vessels with a normal morphology and other structures in the skin. such as sweat glands and hair follicles. as free nerve endings and in nerve bundles. The nerve bundles were often seen to pass the ectatic vessels without giving off any branches. CGRP-LI nerve fibers were detected running toward epidermis. whereas no fibers were found around the ectatic vessels. NF-LI fibers were seen innervating normal vessels in dermis. while in relation to the dilated vessels. no or only occasional fibers were observed. The lack of innervation may be of importance for the development of the disease as a result of decreased tonus of the vessels and/or a loss of neuronal trophic factors.
Early definitive bone and soft-tissue reconstruction of major gunshot wounds of the face, The use of craniofacial surgical techniques. extended open reduction. rigid fixation with plates and screws. and the replacement of severely damaged or missing bone with immediate bone grafting in the treatment of complex facial fractures has been applied to the management of severe gunshot wounds of the face. Early definitive bone and soft-tissue reconstruction has been performed in 37 patients. One-hundred and seventy-seven primary bone grafts were utilized in 33 patients for orbital. nasal. zygomatic. and maxillary reconstruction. Twenty-six patients required mandibular repair with compression or reconstruction plates. Soft-tissue reconstruction was provided by a combination of flaps. Four patients had extensive soft-tissue loss replaced by free vascularized omental flaps. The omentum provided circumferential coverage of the mandibular reconstruction and reconstruction of the floor of the mouth and was then tunneled in a circle through both cheeks into the middle and upper face. The omentum reconstructed deficits in the hard palate and upper buccal sulcus and was then wrapped around all zygomatic. orbital. and midfacial bone grafts and used to fill in dead space in the maxillary. ethmoid. and frontal sinuses. The omentum is not used to provide contour and bulk. but to cover bone grafts and plates and fill in dead space. Carefully shaped bone grafts provide the correct craniofacial scaffold. Early restoration of a midfacial bony scaffold and the prevention of soft-tissue contraction facilitate secondary reconstruction. Four late total nasal reconstructions with tissue-expanded forehead skin wrapped around bone grafts were performed.
The healing of facial bone fractures by the process of secondary union, The mechanism of healing of facial bone fractures was investigated in a rabbit model. Twelve New Zealand white rabbits underwent surgically induced fractures of the right infraorbital rim and fracture ostectomies (4 to 5 mm) of the left infraorbital rim. Animals were sacrificed 2. 4. and 8 weeks postfracture. Bone. including periosteum. obtained from each fracture or fracture osteoctomy site was divided longitudinally for hematoxylin and eosin staining. fluorescent microscopy. microangiography. and microradiography. Sequential fluorochrome labels of oxytetracycline (30 mg/kg). alizarin complexone (30 mg/kg). DCAF (20 mg/kg). and xylenol orange (90 mg/kg) were administered 24 hours preoperatively and at 1. 2. 4. and 8 weeks postfracture. All fracture and fracture ostectomy sites demonstrated vascular ingrowth. mineralization. and woven bone formation by 2 to 4 weeks postoperatively. beginning with a cartilage precursor. Subsequently. the woven bone was replaced with remodeled lamellar bone. resulting in complete bony healing by 8 weeks postoperatively. These steps were substantiated by microscopic. microradiographic. and radiologic examination of the specimens. This study demonstrates that fractures of the facial bones in a rabbit model heal by a process of new bone formation that resembles secondary union in endochondral bones.
Experience with 50 free TRAM flap breast reconstructions, The data from the first 50 patients undergoing free TRAM flap breast reconstruction in two units were examined. Average patient age was 42 years. and average weight was 62 kg. Forty percent of patients were chronic smokers. and 26 percent had low abdominal scars. Twelve percent exercised their abdominal muscles regularly. Eighteen percent had undergone radical mastectomy. whereas 76 percent had undergone modified radical mastectomy and 6 percent had undergone subcutaneous mastectomy. Postoperative radiotherapy had been given in 16 percent of patients. and 54 percent had received postoperative chemotherapy. The average time from mastectomy was 32 months. whereas six breasts were reconstructed immediately. Average operating time was 5.6 hours. and average blood loss was 2.4 units. Average hospital stay was 11.2 days. Complications included three total flap losses (6 percent) and two partial flap losses (4 percent). Abdominal hernia occurred in two patients (4 percent).
Methyl prednisolone in double-lumen gel-saline submuscular mammary prostheses: a double-blind, prospective, controlled clinical trial, At the time of immediate breast reconstruction with submuscular implants. 76 consecutive patients (89 breasts) were randomized into two groups. One received a gel-saline. double-lumen implant with 40 cc of saline added to the outer lumen. while the other received the same implant plus 40 cc of saline and 16 mg methyl prednisolone (40 mg%). Patients were followed for a minimum of 3 years. The groups. which were matched for patient age and implant size. were evaluated at 3. 12. 24. and 36 months for capsular contracture. steroid atrophy. and other complications. With completion of the double-blind study. the patients with submuscular gel-saline implants with only saline added had an overall capsular contracture rate of 38 percent at 3 months. 38 percent at 12 months. and 44 percent at 24 and 36 months. Those with methyl prednisolone had an overall capsular contracture rate of 14 percent at 3 months. and this remained unchanged through the end of the study. The rates of all other complications were comparable. Methyl prednisolone in a dose of 16 mg in 40 cc saline (concentration 40 mg%). when used in the outer lumen of a double-lumen gel-saline implant in a submuscular pocket. is both safe and efficacious in reducing the risk of capsular contracture for a minimum of 3 years in patients undergoing immediate breast reconstruction with submuscular mammary implants.
Analysis of the soft-tissue response to components used in the manufacture of breast implants: rat animal model, The implant-tissue response to the silicone gel mammary prosthesis requires a more thorough evaluation in light of recent concerns related to human connective-tissue diseases. contracture. infection. and neoplasia. The silicone prosthesis is not a homogeneous implant but is a milieu of various silicone chemistries. Silicone polymer precursors and prosthesis components (silicone shells. shells extracted of their low-molecular-weight components. silica-free silicone. silicone oil. fumed silica. and silicone extract) were implanted subcutaneously using a nonhemorrhagic technique into the backs of Lew/SsN rats (n = 90). two implants per rat. for periods of 7. 14. 28. 56. and 90 days for a total of 6 implants per material per time period. Histologic analysis was performed on specimens from the harvested soft tissue. The intensity of the cellular and capsular response was lowest for the silicone oil and increased as the material's molecular weight increased and material compliance decreased. Fumed silica elicited the most highly reactive cellular response. From this study it is apparent that the polymer's molecular weight influences its migration. encapsulation. and intensity of cellular response. Further. the silicone extract distillate elicited a highly intense cellular response with pronounced lymphocyte invasion. The human relevance of this work awaits further correlation with implant retrieval and in vivo performance.
Further experience in rehabilitation of zone II flexor tendon repair with dynamic traction splinting, A review of all flexor tendon repairs in the "no man's land" performed from January of 1985 to June of 1987 was done to evaluate the efficacy of our method of rehabilitation. There were 60 fingers (57 patients) with complete laceration of the flexor digitorum profundus and flexor digitorum superficialis tendons in zone II. Fingers with phalangeal fractures. joint injuries. or significant skin loss were excluded. Follow-up ranged from 12 to 48 months. Rehabilitation consisted of a 12-week protocol using the U.S. military combined regimen of controlled motion. Features from the technique of controlled active extension against rubber band passive flexion as well as those of controlled passive extension and passive flexion were incorporated. The palmar pulley modification of Kleinert's dynamic traction splint was utilized. Strickland's total active motion formula was employed to determine results. The results were classified into the four categories of excellent. good. fair. and poor. Fifty-two fingers (86 percent) were rated excellent. 4 fingers (7 percent) were rated good. 1 finger (2 percent) was rated fair. and 3 fingers (5 percent) were rated poor.
Island flap supplied by the dorsal branch of the ulnar artery, Two cases are reported in which a fasciocutaneous island flap was employed supplied by the ulnaris dorsalis artery after the method proposed by Becker and Gilbert. The original technique has been modified by the authors. and this produces a better venous outflow. The vascular pedicle includes. besides the ascending branch of the artery and the venae comitantes. one of the superficial veins together with its respective subdermal band. A technique is also described that provides an optimal length for the vascular pedicle.
The office laboratory, Few areas of medicine are experiencing such tremendous growth as the office-based laboratory. Recent advances in technology and changes in reimbursement practices have greatly expanded the potential of this segment of patient care. In the 1990s the physician has opportunity to introduce many testing procedures to the office laboratory that were not available 20 years ago. Requirements in the areas of quality assurance and quality control are constantly changing. These regulations vary from state to state and each laboratory should know what is required by their respective certifying agency. In today's market. the physician must choose between the referral laboratory or the resources in the office and consider which option provides the best in care and cost to the patient.
Antibiotics and infectious diseases, Selection of antibiotics in clinical practice has become increasingly complex because more patients have underlying predispositions to infection. a greater variety of microorganisms with varying antibiotic resistance patterns cause these infections. and more antibiotics are available to treat these pathogens. A practical approach to antibiotic decision-making involves comparing the advantages and disadvantages of each group of antibiotics available while remembering the patient population being treated and the common pathogens encountered in one's practice. It is helpful to study the penicillin derivatives in approximately chronologic order of development and the cephalosporins in terms of generations because this puts the use of each individual agent in perspective. Familiarity with commonly encountered adverse antibiotic reactions. dosage guidelines. and special situations (pregnancy. pediatric patients) will help avoid problems associated with antibiotic use. Finally. having one or more useful references at hand will aid in resolving questions about antibiotic use.
Eye infections, This article provides an overview of the diagnosis and treatment of eye infections. The seriousness of eye infections can range from benign and self-limiting to lethal. The primary care physician must determine the seriousness of each particular infection and then. based on that determination. must treat or refer the patient.
Upper respiratory tract infections, Upper respiratory tract infections are among the most common acute infections in humans. This review discusses the clinically important aspects of the epidemiology. etiology. clinical presentation. diagnosis. management. complications. and prevention of the common cold. pharyngitis. otitis media. and sinusitis. Most episodes of the common cold and pharyngitis are of viral origin. and curative therapy is not available. Streptococcal pharyngitis. acute otitis media. and sinusitis are secondary to bacterial infections. and antibiotic therapy is important.
Infectious skin diseases, Descriptions of individual diseases. including impetigo. scarlet fever. and toxic shock syndrome. are presented in the context of the specific organisms that cause them. Pictures are used to show some of the diseases. Testing and treatment information for these diseases are included.
Antibiotics for common infections in the elderly, A decline in host defense mechanisms and concurrent diseases combine to make the elderly patient particularly susceptible to common infections. The bacterial cause and antimicrobial sensitivity patterns may also be different in the elderly. The appropriate selection and dosing of antibiotics for elderly patients with such common infections as pneumonia. bronchitis. urinary tract infections. and skin and soft-tissue infections will optimize the patient's response while minimizing adverse consequences.
Valproate metabolism during hepatotoxicity associated with the drug, Plasma concentrations of valproate and certain of its metabolites and their patterns of excretion in urine are described in three adults who developed hepatotoxicity during treatment of epilepsy with sodium valproate. One patient also developed a degree of reversible renal insufficiency. whilst another may have had associated infectious mononucleosis. All three cases showed evidence of impaired mitochondrial beta-oxidation of valproate. In one the impairment was at the stage catalysed by fatty acyl-CoA dehydrogenase. in another at the stage catalysed by 3-hydroxyacyl-CoA dehydrogenase and in the third at the stage catalysed by enoyl-CoA hydratase and possibly also at the next stage catalysed by 3-hydroxyacyl-CoA dehydrogenase. The impaired beta-oxidation meant that valproate metabolism was diverted into various alternative pathways. Plasma concentrations of the suspected hepatotoxic metabolite 4-en-valproate were normal for the valproate-treated population in all cases. By analogy with certain spontaneous and acquired human disorders of branched chain amino acid metabolism. it is suggested that valproate-associated hepatotoxicity may represent the consequences of a valproate overload on a limited mitochondrial beta-oxidation capacity. causing accumulation of a toxic product of endogenous branched chain amino acid metabolism.
Radiographic manifestations of congenital anomalies of the skull, Congenital anomalies of the pediatric skull are caused by a diverse group of disorders. For the purposes of this discussion. these entities can be classified according to the radiographic appearance of the skull. which may be similar in a variety of different diseases. Enlarged parietal foramina. sinus pericranii. aplasia cutis congenita. anterior fontanelle dermoid. cephaloceles. and craniolacunia are all examples of loceles. and craniolacunia are all examples of calvarial defects. Although there are numerous causes for wormian bones (Table 1). OI. cleidocranial dysplasia. congenital hypothyroidism. and hypophosphatasia are disorders that are commonly associated with defective ossification and the appearance of wormian bones. Osteopetrosis is an important example of rare bony dysplasias that cause sclerosis and hyperostosis of the skull. A partial list of other disorders causing similar radiographic findings is found in Table 2. Craniosynostosis results in an abnormality of skull shape. The suture(s) involved may be predicted by the deformed calvarial configuration. Knowledge of the growth and development of the skull and an understanding of the varied causes of congenital skull anomalies can enable the radiologist to provide the diagnosis or an informed differential diagnosis when confronted with a specific radiographic finding.
Radiographic manifestations of congenital heart disease in the adult patient, Improvements in the preoperative evaluation. surgical treatment. and postoperative care of patients with congenital cardiac disease have allowed a large patient population with congenital cardiac abnormalities to reach adolescence and adulthood. Noninvasive diagnostic imaging procedures (e.g.. plain film radiography. echocardiography. computed tomography. and magnetic resonance imaging) are playing an increasingly important role in the evaluation and management of adults with both treated and untreated congenital cardiac disease. The role of plain film radiology is emphasized.
Radiographic manifestations of congenital anomalies of the spine, Although the foregoing review of embryologic development and congenital anomalies of the spine in infants and children is necessarily brief. the most commonly encountered abnormalities have been reviewed. and when possible. an attempt has been made to cite the stage of embryologic development at which the various abnormalities originate. As noted. congenital abnormalities of the spine are relatively uncommon but may be of profound clinical significance. During the past decade. the most significant developments in the diagnosis and treatment of these abnormalities have been ultrasonography. CT scanning. and MR imaging. In the neonate. the spinal cord and neural outflow can be evaluated by ultrasonography until the osseous elements begin to fuse. Thereafter. MR imaging is the procedure of choice because it permits evaluation of the spine and spinal cord in all planes of imaging and provides detailed evaluation of the effect of osseous abnormalities on neural structures. Finally. plain radiographs of the spine for evaluation of neonates who have any of a spectrum of sacral dimples are rarely helpful. and in the presence of significant cutaneous or subcutaneous abnormalities. ultrasonography is the preferred modality for evaluation.
Angiographic morphology in unstable angina and its relation to transient myocardial ischemia and hospital outcome, Complex stenosis morphology frequently occurs in patients with unstable angina pectoris. However. its relation to transient myocardial ischemia and hospital outcome has not been ascertained. To address this issue. 88 patients with significant (greater than or equal to 50%) coronary artery disease presenting with angina--new onset (n = 38). worsening (n = 20) or at rest (n = 30)-were studied. Patients with left main artery disease. normal coronary arteries or occlusion of the ischemia-related arteries were not included in the study. Continuous electrocardiographic recordings were obtained during the first 24 hours. Angiography was performed within 1 week from admission. Complex morphology was defined as any stenosis with irregular borders. overhanging edges or intracoronary thrombus. Only data referring to the in-hospital outcome were considered in this study. Adverse end points were sudden death. myocardial infarction and emergency revascularization. Analysis of the angiograms revealed a complex morphology in 58 patients (group 1). The remaining 30 patients served as control subjects (group 2). Thirty-two of the 58 group 1 patients had an unfavorable clinical outcome (positive predictive value. 55%). A similar outcome occurred in only 2 of the 30 group 2 patients (negative predictive value. 93%). Of the 32 group 1 patients who had an unfavorable clinical outcome. 29 had a cumulative duration of transient myocardial ischemia of greater than or equal to 60 minutes per 24 hours. A similar duration of ischemia. however. was observed in another 6 group 1 and in 8 group 2 patients.
Anginal symptoms without ischemic electrocardiographic changes during ambulatory monitoring in men with coronary artery disease, Episodes of angina pectoris without electrocardiographic (ECG) signs of myocardial ischemia during 24-hour ambulatory monitoring were studied in 128 patients with a history of stable angina. angiographically proven coronary artery disease and positive exercise test results. In all. 341 episodes of ischemic ECG changes (ST-segment depression greater than 1 mm for greater than 1 minute) and 190 episodes of angina pectoris were observed: 86 episodes consisted of both ECG changes and angina pectoris. 255 episodes consisted only of ECG changes. and 104 episodes only of angina pectoris. Duration and magnitude of ST-segment deviation and heart rate at the onset of ischemia were similar in the 86 symptomatic and the 255 asymptomatic episodes with ECG changes. The 104 episodes of angina pectoris without ECG changes were detected in 44 patients (34%) (group A); 29 of them had only episodes with angina pectoris and 15 patients had both--episodes of angina pectoris with and without ECG changes. In 84 patients (66%) (group B) angina pectoris without ECG changes was not observed; all episodes were accompanied by ischemic ECG changes in these patients. No differences in the angiographic extent of coronary artery disease and in exercise test data were seen in both groups A and B; however. maximal ST-segment depression during exercise testing was significantly greater in group B than in group A patients (2.4 +/- 0.8 mm vs 1.9 +/- 0.9 mm; p less than 0.05).
Dependence of Doppler echocardiographic transmitral early peak velocity on left ventricular systolic function in coronary artery disease, The influence of systolic function on pulsed Doppler echocardiographic transmitral flow velocity patterns was assessed before and after postextrasystolic (PES) potentiation in 12 normal subjects (control group) and in 25 patients with previous healed myocardial infarction (MI) group. Simultaneous high-fidelity left ventricular pressure measurements were performed in all patients. A programmed single-coupled right ventricular extrasystole was induced during echocardiographic and subsequent cineangiocardiographic recordings. Adequate angiograms for volumetric analysis in both baseline and PES beats were obtained in 23 patients (7 in the control group and 16 in the MI group). PES potentiation of contraction was more pronounced in the MI group than in the control group. PES changes in ejection fraction. stroke volume and end-systolic volume were significantly greater in the MI group than in the control group (11 vs 5%. p less than 0.005; 15 vs 5 ml/m2. p less than 0.005; and -13 vs -4 ml/m2. p less than 0.01. respectively). In contrast. PES potentiation prolonged the time constants of left ventricular pressure decline derived from exponential curve fits with a zero (Tw) and non-zero (Tb) asymptote pressure in the MI group to the same extent as in the control group (4 vs 5 ms. difference not significant [NS]. and 9 vs 11 ms. NS. respectively). In the PES beat. peak E velocity remained unaltered (48 vs 49 cm/s. NS) in the control group. whereas it increased significantly (p less than 0.0001) from 47 to 51 cm/s in the MI group.
Relation of serum lipoprotein cholesterol levels to presence and severity of angiographic coronary artery disease, To assess the relation of lipid levels to angiographic coronary artery disease (CAD). lipid profiles were obtained on 125 men and 72 women undergoing diagnostic coronary angiography. CAD. defined as greater than or equal to 25% diameter narrowing in a major coronary artery. was present in 106 men (85%) and 54 women (75%). Multiple regression analyses revealed that only high-density lipoprotein (HDL) cholesterol level in men. and age and total/HDL cholesterol ratio in women. were independently associated with the presence of CAD after adjustment for other risk factors. HDL cholesterol level and age were significantly correlated with both extent (number of diseased vessels) and severity (percent maximum stenosis) of CAD in men. In women. age was the only independent variable related to severity. whereas age and total/HDL cholesterol ratio were related to extent. Of 71 patients with total cholesterol less than 200 mg/dl. 79% had CAD. With multiple regression analyses. HDL cholesterol was the only variable independently related to the presence and severity of CAD in these patients after adjustment for age and gender; extent was significantly associated with age and male gender. and was unrelated to any of the lipid parameters. With use of multiple logistic and linear regression analyses of the group of 197 patients. HDL cholesterol was the most powerful independent variable associated with the presence and severity of CAD after adjustment for age and gender. HDL cholesterol was also an independent predictor of extent. Age was independently associated with each of the end points examined. and was the variable most significantly related to extent. These data add to the growing body of information demonstrating an important association between HDL and CAD.
Edge detection versus densitometry for assessing coronary stenting quantitatively, The optimal method used to analyze quantitatively the immediate angiographic results of coronary stenting in the coronary arteries has not been studied. Accordingly. minimal luminal cross-sectional area was determined by 2 methods. edge detection and densitometry. in 19 patients who underwent percutaneous transluminal coronary angioplasty (PTCA) and then coronary stent implantation for symptomatic coronary stenoses. The correlation coefficient. 0.73 before angioplasty. decreased to 0.59 after coronary angioplasty and then increased to 0.83 after stent implantation. The mean differences between edge detection and densitometric determinations of minimal luminal cross-sectional area were 0.31 +/- 0.51 mm2 before PTCA. -0.38 +/- 1.22 mm2 after angioplasty and 0.35 +/- 0.79 mm2 after coronary stenting. It is concluded that. although the correlation and variability in the measurement of minimal luminal cross-sectional area between edge detection and densitometry deteriorate after PTCA. they are improved after stenting. probably because of smoothing of the vessel contours by the stent and remodeling of the stented segment into a more circular configuration. Therefore. in the stented coronary artery. edge detection and densitometry are equally acceptable methods of analysis.
Frequency of success and complications of coronary angioplasty of a stenosis at the ostium of a branch vessel, The authors of this study hypothesized that percutaneous transluminal coronary angioplasty of a stenosis at the ostium of a branch vessel. whether isolated or associated with a bifurcation stenosis. was associated with reduced procedural success and increased in-hospital complications. One hundred six patients with 119 ostial branch stenoses were compared with 1.168 patients who underwent angioplasty of nonostial branch stenoses. An ostial branch stenosis was defined as a stenosis in the proximal 3 mm of a major branch vessel (diagonal [n = 58]. posterior descending [n = 21]. obtuse marginal [n = 34] and intermediate [n = 6]). The ostial branch stenosis was isolated in 61% of the patients and associated with a bifurcation stenosis in 39%. Despite a balloon to artery ratio of 1.05:1. angiographic success was 74% of ostial branch stenoses versus 91% of nonostial stenoses (p less than 0.01). Furthermore. angioplasty of ostial branch stenoses resulted in a complication rate of 13 versus 5% for angioplasty of nonostial branch stenoses (p less than 0.01). Therefore. angioplasty of ostial branch stenoses results in decreased procedural success and significant residual stenosis despite adequate balloon sizing. suggesting arterial elastic recoil and a significant increase in complications.
Comparison of the efficacy of Questran Light, a new formulation of cholestyramine powder, to regular Questran in maintaining lowered plasma cholesterol levels, Sixty-one men with known hypercholesterolemia (plasma cholesterol greater than 265 mg/dl). most of whom were previous participants in the Coronary Primary Prevention Trial of the U.S. Lipid Research Clinic Program. were chosen to take part in this study to test the effectiveness of a new low-calorie (Questran Light) cholestyramine formulation against the proven effectiveness of the currently marketed formulation Questran in maintaining lowered plasma cholesterol levels. The study recorded changes in fasting plasma lipids. total cholesterol. high-density lipoprotein cholesterol. triglycerides. and calculated low-density lipoprotein cholesterol. After establishing baseline lipid/lipoprotein levels in a 3-week period during which all participants received the currently marketed formulation. the men were randomized into 2 groups. 1 group (n = 31) taking the new Questran Light formulation of 4 g of cholestyramine in 5 g of powder per pack. while the other group (n = 30) continued to take the marketed Questran formulation of 4 g of cholestyramine in 9 g of powder per pack. Each group consumed a total of 24 g/day of cholestyramine in 2 divided doses. At the end of the maintenance phase of the study there were no statistically significant mean changes in percentage from baseline to end-point lipid/lipoprotein levels within either group. nor were there any significant differences between the Questran Light group or the currently marketed Questran formulation group. The new low-calorie cholestyramine formulation appears to be equally as effective in maintaining lowered plasma cholesterol levels as the currently marketed formulation.
Characteristics of accessory pathways exhibiting decremental conduction, The prevalence. electrophysiologic characteristics and functional significance of decremental conduction over an accessory pathway were examined in this retrospective study of 653 patients who had an accessory pathway demonstrated at electrophysiologic study. Decremental conduction was identified in 50 patients (7.6%). In 15 patients with anterograde decremental conduction. the accessory pathway was right parietal or septal in 14 patients and left parietal in 1 patient. In the 40 patients with retrograde decrement. the accessory pathway was left parietal in 19. posteroseptal in 13. right parietal in 2 and right anteroseptal in 6 patients. Anterograde conduction over the accessory pathway was absent in 11 of the 40 patients with retrograde decrement. Retrograde conduction over the accessory pathway was absent in 9 patients with anterograde decrement. There was no significant difference in the accessory pathway effective refractory period. or shortest cycle length with 1:1 conduction over the accessory pathway in anterograde and retrograde directions. The shortest RR interval in atrial fibrillation between 2 preexcited QRS complexes was longer in patients with anterograde decremental conduction than in a control group of patients with anterograde-conducting accessory pathways without decremental properties. These data demonstrate that decremental conduction over accessory pathways is uncommon. Anterograde decremental conduction usually occurs in right-sided or septal pathways that often do not conduct in the retrograde direction.
Usefulness of d, I sotalol for suppression of chronic ventricular arrhythmias, Sotalol is a unique beta-blocking drug. possessing significant class III antiarrhythmic activity. The efficacy and safety of 2 doses of sotalol (320 and 640 mg/day. divided in 2 doses) were compared to placebo in a 6-week randomized. double-blind. multicenter study of 114 patients with chronic ventricular premature complexes (VPCs) at frequencies of greater than or equal to 30/hour. Sotalol significantly reduced VPCs in patients receiving both low (n = 38) and high (n = 39) doses. compared with patients (n = 37) receiving placebo (by 75 and 88%. respectively. vs 10%; p less than 0.001. sotalol vs placebo; p less than 0.05. high vs low dose). The individual efficacy criterion (greater than or equal to 75% VPC reduction) was achieved in 34% of low-dose and 71% of high-dose sotalol versus 6% of placebo-treated patients (p less than 0.003. sotalol vs placebo; p = 0.007. high vs low dose). Repetitive beats were suppressed 25% by placebo (difference not significant). 80% by low-dose (p less than 0.003) and 78% by high-dose sotalol (p less than 0.005). Sotalol decreased heart rate (by 24 to 25%. p less than 0.001) and increased PR (by 4 to 6%. p less than 0.001) and corrected JT intervals (by 12 to 13%. p less than 0.001). but did not change ejection fraction. Proarrhythmia (nonfatal) occurred in 3 sotalol and in 2 placebo patients. Nine discontinued therapy because of adverse effects (1 low dose and 8 high dose. p less than 0.02). In summary. sotalol is an efficacious antiarrhythmic drug for VPC suppression; in lower doses. it is somewhat less effective but better tolerated.
Doppler echocardiographic comparison of the Carpentier and Duran anuloplasty rings versus no ring after mitral valve repair for mitral regurgitation, To compare the hemodynamic results of different anuloplasty techniques of primary valve repair for mitral regurgitation. 122 patients were prospectively studied with Doppler echocardiograms 5 to 10 days after operation. Seventy-seven patients had mitral valve prolapse. 27 had coronary artery disease. 13 patients had rheumatic mitral valve lesions and 5 patients had infective endocarditis. Forty-eight patients received the flexible Duran ring. 46 received the more rigid Carpentier ring and 28 patients received no ring. Doppler echocardiography demonstrated a significant decrease in mitral valve area estimated by the pressure half-time method in patients who received either a Carpentier (2.6 +/- 0.8 cm2) or Duran ring (2.8 +/- 0.8 cm2) when compared with patients who received no ring (3.2 +/- 0.7 cm2) (p = 0.01). No significant differences were observed for peak transmitral diastolic velocity. peak transmitral diastolic gradient. or the grade of mitral regurgitation by color flow Doppler mapping between patients with and without rings. The etiology of mitral disease and concomitant surgical procedures accompanying mitral valve repair did not significantly influence mitral valve area. peak velocity or peak gradient. These data suggest that Carpentier and Duran rings decrease the hemodynamic mitral valve area; however. the decrease in valve area is small and not associated with a clinically important increase in transvalvular gradient.
Colon interposition for esophageal disease: histologic finding of colonic mucosa after a follow-up of 5 months to 15 years, Thirty-six patients. subjected to colon interposition for benign esophageal disease or carcinoma of the esophagus or gastric cardia. were studied by endoscopy for signs of mucosal disease in the interposed colon. Five months to 15 yr (mean 57 months) after the operation. endoscopic finding of the interposed colon was macroscopically normal in 28 patients. Signs of inflammation. including hyperemia or hyperemia and friability. were observed in seven patients. Histologic specimens obtained at endoscopy were examined microscopically. and the findings were compared with those seen in the preoperative graft. In two patients. chronic inflammatory changes were observed in the graft mucosa. consisting of mononuclear cell infiltration of the lamina propria accompanied by crypt dilatation and deformation. In one of these patients. the inflammation was in the proximal third of the graft. and it was also seen at the endoscopy. In the remaining 34 patients. the graft mucosa was microscopically comparable to normal. The alterations were unexpectedly few and mild considering the marked change in the location and function of the colonic segment.
The perception of life events and daily stress in nonulcer dyspepsia, Previous studies on the association of nonulcer dyspepsia with major life events were performed without emphasis on the perception of these events. and have yielded conflicting results. The present study examined the perception of life events and. in addition. the role of daily "hassles" (stressful events) in patients with nonulcer dyspepsia. Thirty-three dyspeptic patients as defined by normal endoscopy and ultrasonogram and 33 controls of comparable sex. age. and social class were recruited for study. Both groups were asked to select from 56 major life events those they had experienced and to give a rating on how they perceived them. They were further asked to select similarly from 117 items of daily stress and to rate the severity of each item. The results demonstrated that the number of positive and negative events and the positive score were similar in both dyspeptic patients and controls. but dyspeptic patients had a higher perceived magnitude of negative events and a higher score of total life change as given by the summation of magnitude of positive and negative events (both p less than 0.05). The "hassles" scores were not significantly different between dyspeptic patients and controls. Analysis of individual life events revealed that dyspeptic patients had significantly (p less than 0.05) higher scores than controls in items of minor law violations. major change in closeness of family members. and major personal illness or injury. We conclude that patients with nonulcer dyspepsia have higher negative perception of major life events. which indicates that psychological factors may play a role in the pathogenesis of nonulcer dyspepsia.
Gluten challenge in patients with celiac disease: evaluation of alpha 1-antitrypsin clearance, Our aim in this study was to monitor changes of the intestinal structure by alpha 1-antitrypsin clearance (alpha 1-ATCL) in order to offer an alternative to the gluten challenge biopsy. In addition. we evaluated the possibility of reducing the time of gluten challenge. Twelve patients had a presumptive diagnosis of celiac disease based on clinical and histological grounds. They were studied when the jejunal histology was normal after gluten-free diet and an alpha 1-ATCL was normal. The gluten was introduced by returning to a normal diet. The challenge lasted 4 wk. We measured alpha 1-ATCL at the end of the 1st and 4th wk. and a new jejunal biopsy was obtained at the end of the 4th wk. By wk 1. alpha 1-ATCL was abnormal in 11 patients but normal in one. By wk 4. alpha 1-ATCL was abnormal in 10 patients and still normal in one. The post-challenge biopsies showed atrophy in 11 and was normal only in the patient with normal alpha 1-ATCL at wk 1 and 4. One patient with abnormal alpha 1-ATCL had to stop the challenge at the first week. The patient with normal clearance at wk 1 and 4 and normal biopsy at wk 4 had abnormal results at 6 months. These data support our hypothesis that alpha 1-ATCL can be used as evidence of gluten toxicity after gluten challenge. and that this test can be abnormal as early as 1 wk after gluten is reintroduced.
Prenatal screening for hemoglobinopathies. I. A prospective regional trial, Prenatal hemoglobinopathy screening was chosen as a model system for the study of patient receptivity to unsolicited genetic information. Providers of prenatal care in Rochester. NY. were offered free testing of all their prenatal patients and genetic counseling of women found positive. The 18.907 prenatal samples tested in a 5-year period represented 35.1% of the pregnancies in the Rochester metropolitan region. A hemoglobinopathy was found in 810 pregnancies (4.3%). Of the 21 different types of hemoglobinopathies detected. the most common were sickle cell trait (59%). hemoglobin C trait (19%). beta-thalassemia trait (11%). and hemoglobin E trait (5%). At the time of phlebotomy. 75% of the pregnancies were of less than 18 wk duration. Sixty-six percent of the pregnancies occurred in patients unaware of their diagnosis. and 80% occurred in patients unaware that they might be at risk for a child with a serious blood disorder. Of the 810 positive pregnancies. 551 (68%) occurred in patients who came for counseling. Of 453 women counseled during their first screened pregnancy. 390 (86%) said they wanted their partners tested and 254 (55%) had their partner tested. In the 77 pregnancies thus found to be at risk. the couple was too late for prenatal diagnosis in 12 cases. and the condition for which the fetus was at risk was too mild in 12 cases. Prenatal diagnosis was offered in the remaining 53 pregnancies and was accepted by 25 couples (47%). These results indicate that unselected patients in the primary care setting in this region. even though pregnant. are receptive to and utilize genetic information.
Prenatal screening for hemoglobinopathies. II. Evaluation of counseling, Learning during genetic counseling is often below expectations. especially in the context of genetic screening. In this report we describe learning as a result of genetic counseling of 298 pregnant women identified as hemoglobinopathy carriers. 234 with sickle cell trait and 64 with beta-thalassemia trait. Counseling was designed to provide the information needed in a simple. clear. and nondirective manner. A special videotape produced for this purpose provided dramatization and a role model illustrating an appropriate response. After viewing the videotape the counselee had an opportunity to question the counselor and to have any misconceptions corrected. Questionnaires revealed significantly increased knowledge as a result of counseling in each of the three hemoglobinopathy subject areas tested-namely. clinical manifestations. genetics. and prenatal diagnosis. Five factors correlated with higher knowledge scores after counseling-namely. a younger patient age. more years of education. knowledge of having trait before this identification. knowledge of the baby's father having trait before counseling. and having no prior children.
Prenatal screening for hemoglobinopathies. III. Applicability of the health belief model, A comprehensive prenatal hemoglobinopathy screening program in Rochester. NY. has been described in a preceding paper in this issue of the Journal. A woman identified as a carrier may face three decisions. The first is whether to accept the offer of counseling. The second is whether to have her partner tested. If her partner also tests positive. then the third decision is whether to accept the offer of prenatal diagnosis. This report analyzes factors affecting her decision. with special attention being given to factors invoked by the Health Belief Model. Factors predicting that a patient who we identified as a carrier would come for counseling included the following: patient had no prior knowledge that she is a carrier (P less than .001). a gestational age less than 18 wk (P less than .01). and Caucasian race (P less than .05). For sickle cell trait counselees and beta-thalassamia trait counselees. factors found to predict patient's intent to have partner tested were the following: a greater postcounseling knowledge of the disease (P less than .009). a lesser perceived burden of intervention (P less than .011). and belief that the partner is also a carrier (P less than .008). Also for sickle cell trait counselees and beta-thalassemia trait counselees. factors predicting that the partner actually will be tested were the following: living with the partner (P less than .001). gestational age at identification less than or equal to 18 wk (P less than .001). a lesser perceived burden of intervention (P less than .002). and a greater perceived seriousness of the disease (P less than .05).
Genetic mapping of new DNA probes at Xq27 defines a strategy for DNA studies in the fragile X syndrome, The fragile X syndrome is the most common cause of familial mental retardation and is characterized by a fragile site at the end of the long arm of the X chromosome. The unusual genetics and cytogenetics of this X-linked condition make genetic counseling difficult. DNA studies were of limited value in genetic counseling. because the nearest polymorphic DNA loci had recombination fractions of 12% or more with the fragile X mutation. FRAXA. Five polymorphic loci have recently been described in this region of the X chromosome. The positions of these loci in relation to FRAXA were defined in a genetic linkage study of 112 affected families. The five loci--DXS369. DXS297. DXS296. IDS. and DXS304--had recombination fractions of 4% or less with FRAXA. The closest locus. DXS296. was distal to FRAXA and had a recombination fraction of 2%. The polymorphisms at these loci can be detected in DNA enzymatically digested with a limited number of restriction endonucleases. A strategy for DNA studies which is based on three restriction endonucleases and on five probes will detect one or more of these polymorphisms in 94% of women. This strategy greatly increases the utility of DNA studies in providing genetic advice to families with the fragile X syndrome.
Mild spondyloepiphyseal dysplasia (Namaqualand type): genetic linkage to the type II collagen gene COL2A1, Namaqualand spondyloepiphyseal dysplasia (NSED) is a mild autosomal dominant form of spondyloepiphyseal dysplasia in which changes are maximal in the femoral capital epiphyses and the vertebral bodies. The condition is present in a large multigeneration South African family. and it is clinically important by virtue of severe progressive degenerative osteoarthropathy of the hip joint. which frequently necessitates prosthetic joint replacement in adulthood. Linkage studies using molecular markers have shown that the loci for the NSED and type II collagen genes are linked (LOD score 7.98 at a recombination fraction of .00).
Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease, Severe methylenetetrahydrofolate reductase (MTHFR) deficiency with less than 2% of normal enzyme activity is characterized by neurological abnormalities. atherosclerotic changes. and thromboembolism. We have discovered a "new" variant of MTHFR deficiency which is characterized by the absence of neurological abnormalities. an enzyme activity of about 50% of the normal value. and distinctive thermolability under specific conditions of heat inactivation. In this study. lymphocyte MTHFR specific activities in the thermolabile variant and control groups were 5.58 +/- 0.91 and 10.33 +/- 2.89 nmol formaldehyde formed/mg protein/h. respectively. The difference was significant (P less than .01). However. there was overlap among the individual values from the two groups. On the other hand. residual MTHFR activity after heat inactivation was 11.2 +/- 1.43% in the thermolabile variant and 36.3 +/- 5.18% in the controls. There was no overlap. Enzyme studies in 10 subjects with thermolabile MTHFR and their family members support the hypothesis that thermolabile MTHFR is inherited as an autosomal recessive trait. To elucidate the association of thermolabile MTHFR with the development of coronary artery disease. we determined the thermostability of lymphocyte MTHFR in 212 patients with proven coronary artery disease and in 202 controls without clinical evidence of atherosclerotic vascular disease. Thermolabile MTHFR was found in 36 (17.0%) cardiac patients and 10 (5.0%) controls. The difference in incidence between the two groups was statistically significant (P less than .01). The average age at onset of clinical coronary artery disease in 36 patients with thermolabile MTHFR was 57.3 +/- 7.6 years (35-72 years). The mean total plasma homocysteine concentration in patients with thermolabile MTHFR was 13.19 +/- 5.32 nmol/ml and was significantly different from the normal mean of 8.50 +/- 2.80 nmol/ml (P less than .05). There was no association between thermolabile MTHFR and other major risk factors. We conclude that thermolabile MTHFR is a variant(s) of MTHFR deficiency which is inherited as an autosomal recessive trait. In addition. it is positively associated with the development of coronary artery disease. Determination of in vitro thermostability of lymphocyte MTHFR is a reliable method for identifying subjects with this abnormality.
Intermediate hyperhomocysteinemia resulting from compound heterozygosity of methylenetetrahydrofolate reductase mutations, Four subjects with thermolabile methylenetetrahydrofolate reductase (MTHFR) were discovered among 16 "obligate" heterozygotes for severe MTHFR deficiency and their family members. All four subjects had less than 25% of normal mean MTHFR specific activity in lymphocyte extracts. Three of them with normal serum folate and cyanocobalamin had intermediate hyperhomocysteinemia. and one with high serum folate and cyanocobalamin had no excessive accumulation of serum homocysteine. The biochemical features in these four subjects are distinguishable from subjects homozygous for the thermolabile MTHFR. whose specific activity is approximately 50% of the normal mean. and from heterozygotes for severe MTHFR deficiency. in whom the enzyme is thermostable and has a specific activity of about 50% of the normal mean. We propose that these four subjects are genetic compounds of the allele for the severe mutation and the allele for thermolabile mutation of the MTHFR gene. It is postulated that subjects with this genetic compound are more susceptible to the development of intermediate hyperhomocysteinemia despite normal folate and B12 levels. Nonetheless. hyperhomocysteinemia due to this compound heterozygosity is correctable by oral folic acid therapy.
Diagnosis of heterozygous states for adenine phosphoribosyltransferase deficiency based on detection of in vivo somatic mutants in blood T cells: application to screening of heterozygotes, An accurate diagnosis of heterozygotes for autosomal recessive disorders with unknown mutations can be difficult. Using a unique phenomenon occurring in vivo. we designed a method for the diagnosis of heterozygotes for adenine phosphoribosyltransferase (APRT) deficiency which makes way for a qualitative distinction between normal and heterozygous subjects. We cultured peripheral blood mononuclear cells with 2.6-diaminopurine. an APRT-dependent cytotoxin. to search for in vivo mutational cells. Fifteen putative heterozygotes examined were found to possess such mutant cells at rather high frequencies; thus. a false negative diagnosis is unlikely. The analysis of genomic DNA in 82 resistant clones from two of the heterozygotes clarified that 64 (78%) had lost the germinally intact alleles. Thirteen members of APRT-deficient families were examined; eight proved to be heterozygotes. Among 425 individuals from two separate residential areas of Japan. two heterozygotes were found. The authenticity of the heterozygosity was validated by two separate methods for the two heterozygotes; hence. a false positive diagnosis can be ruled out. Our data showed a calculated heterozygote frequency of 0.47% (95% confidence limits; 0.05%-1.7%). a value compatible with that (1.2%) calculated from data concerning the incidence of 2.8-dihydroxyadenine urolithiasis. This novel genetic approach for identifying heterozygotes is now being tested to search for other enzyme deficiencies in humans.
Clinical and molecular diagnosis of Miller-Dieker syndrome, We report results of clinical. cytogenetic. and molecular studies in 27 patients with Miller-Dieker syndrome (MDS) from 25 families. All had severe type I lissencephaly with grossly normal cerebellum and a distinctive facial appearance consisting of prominent forehead. bitemporal hollowing. short nose with upturned nares. protuberant upper lip. thin vermilion border. and small jaw. Several other abnormalities. especially growth deficiency. were frequent but not constant. Chromosome analysis showed deletion of band 17p13 in 14 of 25 MDS probands. RFLP and somatic cell hybrid studies using probes from the 17p13.3 region including pYNZ22 (D17S5). pYNH37 (D17S28). and p144-D6 (D17S34) detected deletions in 19 of 25 probands tested including seven in whom chromosome analysis was normal. When the cytogenetic and molecular data are combined. deletions were detected in 21 of 25 probands. Parental origin of de novo deletions was determined in 11 patients. Paternal origin occurred in seven and maternal origin in four. Our demonstration of cytogenetic or molecular deletions in 21 of 25 MDS probands proves that deletion of a "critical region" comprising two or more genetic loci within band 17p13.3 is the cause of the MDS phenotype. We suspect that the remaining patients have smaller deletions involving the proposed critical region which are not detected with currently available probes.
Distribution of three alpha-chain beta-hexosaminidase A mutations among Tay-Sachs carriers, DNA from 176 carriers of the Tay-Sachs gene was tested for the presence of the three mutations most commonly found among Ashkenazi Jews: the so-called insertion. splice junction. and adult mutations. Among 148 Ashkenazi Jews tested. 108 had the insertion mutation. 26 had the splice junction mutation. five had the adult mutation. and nine had none of the three. Among 28 non-Jewish carriers tested. most of whom were obligate carriers. four had the insertion mutation. one had the adult mutation. and the remaining 23 had none of the three.
A mutation in the second nucleotide binding fold of the cystic fibrosis gene, The discovery last year of the deletion of a phenylalanine residue at amino acid position 508 of the cystic fibrosis (CF) gene has meant that approximately 70% of mutant chromosomes associated with CF can be accounted for. We report the finding of a substitution at nucleotide position 4041 of the CF gene. resulting in a change from asparagine to lysine at amino acid position 1303. We believe that this is a disease-causing mutation. as it involves a nonconservative amino acid change and has only been found on CF chromosomes with a consistent haplotype background. The mutation was detected using direct sequencing of PCR-amplified genomic DNA and was confirmed by dot hybridization to both normal and mutant allele-specific oligonucleotides. The mutation was detected on three chromosomes from four individuals but not on any normal chromosome. Its presence in the heterozygous state is not correlated with the clinical status of the individual patients.
Antistaphylococcal activities of teicoplanin and vancomycin in vitro and in an experimental infection, The efficacies of vancomycin and teicoplanin in an experimental Staphylococcus aureus infection in granulocytopenic mice were related to their activities in vitro and their pharmacokinetic profiles. In vitro teicoplanin had a higher intrinsic activity than vancomycin did; and it also had a more favorable pharmacokinetic profile. resulting in higher peak concentrations in plasma. a longer elimination half-life. and a larger area under the concentration-time curve than those of vancomycin. To predict the antibacterial efficacies of the drugs in vivo on the basis of their activities in vitro and pharmacokinetics. a mathematical model was applied. In the model the in vitro effect was expressed as the difference in growth rate between control cultures and those in the presence of the antibiotic (ER). and the in vivo effect was expressed as the difference between numbers of CFU in control and antibiotic-treated animals (EN). The integral of ER against time. ERt. was calculated by using the concentrations found in vivo. A significant linear relationship was found between EN and ERt for different dosages at the same times (4 h) after drug administration as well as for the same doses at consecutive times. although at the lowest doses of teicoplanin the observed effect was less than the predicted effect.
Pharmacokinetics of cefepime in patients with respiratory tract infections, The steady-state pharmacokinetics of cefepime were evaluated in 10 middle-aged and elderly patients with acute lower respiratory tract infections who were receiving 1 g intravenously every 12 h. One preinfusion and 15 postinfusion serum samples and total urine output were collected over one dosing interval between days 3 and 8 of therapy. Cefepime concentrations in serum over time exhibited a multicompartmental profile. Peak and trough concentrations in serum determined by a validated high-performance liquid chromatography method were 71.2 +/- 17.2 (mean +/- standard deviation) and 6.0 +/- 4.9 mg/liter. respectively. The steady-state volume of distribution was 0.22 +/- 0.05 liter/kg. Elimination half-lives ranged from 1.93 to 6.04 h (3.92 +/- 1.28 h). and total body clearances ranged from 36.9 to 102 ml/min per 1.73 m2 (73.0 +/- 19.7 ml/min per 1.73 m2). The disposition of cefepime at steady state in patients was comparable to previous observations in healthy elderly volunteers. The predictive performance of regression equations derived from single-dose studies in volunteers relating creatinine clearance with total body and renal clearances of cefepime exhibited slight biases (mean predictive errors. -9.7 and 2.1 ml/min per 1.73 m2. respectively) and similar precisions. Predicted and observed total body clearances (63.3 +/- 25.1 versus 73.0 +/- 19.7 ml/min per 1.73 m2. respectively) and renal clearances (51.3 +/- 24.4 versus 49.3 +/- 19.6 ml/min per 1.73 m2. respectively) were not significantly different. The pharmacokinetics of cefepime in infected patients appeared to be unaltered by illness. and the steady-state disposition of cefepime was predictable from data derived from single-dose studies in volunteers.
Pharmacokinetics and tissue penetration of a single dose of ornidazole (1,000 milligrams intravenously) for antibiotic prophylaxis in colorectal surgery, Levels in serum and tissue penetration of ornidazole were studied after a single intravenous injection of 1.000 mg given to 14 patients for prophylaxis of surgical infection. They were scheduled for elective colorectal surgery. Adequate levels in blood (greater than or equal to MIC for 90% of Bacteroides fragilis strains tested) were found in all patients throughout the procedure and up to hour 24. Mean-maximal (15 min) and last-determined (24 h) ornidazole levels in serum were 24 +/- 5.2 and 6.3 +/- 1.4 mg/liter. respectively. beta-Phase elimination half-life was 14.1 +/- 2.7 h. and clearance and apparent volume of distribution were 47 +/- 12 ml/min and 0.9 +/- 0.13 liters/kg. respectively. In all patient. adequate levels in tissue were found in the abdominal wall and the epiploic fat at time of incision and in the colonic wall at time of anastomosis. At time of closure. all but one patient had adequate levels in tissue in the abdominal wall and the epiploic fat. No anaerobic nor aerobic infection occurred in the study patients.
Comparative study of the effects of four cephalosporins against Escherichia coli in vitro and in vivo, A thigh muscle infection induced with Escherichia coli in irradiated mice was used as a model to compare the in vivo pharmacodynamics of the antibacterial effect of four cephalosporins (i.e.. cefepime. ceftriaxone. ceftazidime. and cefoperazone) with the in vitro antibacterial pharmacodynamics of these drugs. The following in vitro pharmacodynamic parameters were determined: the maximum effect as a measure for efficacy. the 50% effective concentration as a parameter for potency. and the slope of the concentration-effect relationship. For analysis of the in vivo antibacterial pharmacodynamics. the same parameters were applied for the dose instead of the concentration. For the detection of a relationship between concentration and antibacterial effect in vivo. we determined the pharmacokinetics of the four cephalosporins in the plasma of mice. The results showed that. in general. there is a direct relationship between the in vivo and in vitro pharmacodynamics of these cephalosporins. The maximum effects of cefepime. ceftazidime. and cefoperazone were approximately similar in vivo and in vitro. The sequence of potency of these drugs was. in descending order. cefepime. ceftazidime. and cefoperazone. Ceftriaxone differed from the other three cephalosporins in that it displayed unexpected in vivo pharmacodynamics. Ceftriaxone was just as efficacious as the other three in vitro. but its maximum effect in vivo was much lower. This relatively low maximum effect of ceftriaxone in vivo was not explained by the pharmacokinetic characteristics of the drug. From the present results it can be concluded that the in vitro efficacy of cephalosporins does not necessarily have a predictive value for the in vivo efficacy.
Pharmacokinetics and bioavailability of intravenous-to-oral enoxacin in elderly patients with complicated urinary tract infections, The pharmacokinetics of oral fluoroquinolone antibiotics in normal volunteers have been studied extensively; however. limited patient data exist. Enoxacin steady-state pharmacokinetics and bioavailability were determined following repeated 400-mg intravenous (i.v.) and oral dosing by using compartmental and noncompartmental methods in 10 elderly (mean age. 73.8 years) men with complicated urinary tract infections. Average peak enoxacin concentrations following i.v. and oral dosing were 8.15 and 5.45 mg/liter. respectively. Mean values for major pharmacokinetic parameters (noncompartmental) were similar following i.v. and oral administration. respectively: area under the concentration-time curve from 0 to 12 h. 47.6 and 41.0 mg.h/liter; volume of distribution or volume of distribution/bioavailability. 1.61 and 1.99 liters/kg; total body clearance or total body clearance/bioavailability. 2.58 and 3.01 ml/min per kg; and half-life. 8.2 and 9.1 h. Parameters from analysis of enoxacin plasma concentration data by using a two-compartment pharmacokinetic model also revealed marked similarities between the two administration routes. Enoxacin was highly bioavailable (mean. 86.97%) following oral administration.
Loracarbef concentrations in middle ear fluid, Loracarbef concentrations in plasma and middle ear fluid (MEF) were measured in specimens obtained approximately 2 h after doses of 7.5 or 15 mg/kg. The mean +/- standard deviation concentrations in MEF were 2.0 +/- 2.6 mg/liter (48% of the concentration in plasma) after the smaller dose and 3.9 +/- 2.6 mg/liter (42% of the concentration in plasma) after the larger dose. With the larger dose. the concentrations in MEF were greater than the MIC for 90% of strains of the usual pathogens of acute otitis media tested in 16 of 17 specimens.
A community study of delay in presenting with signs of melanoma to medical practitioners, In the absence of more effective treatment for advanced tumors. early diagnosis and treatment of localized tumors is the most effective way of reducing the burden of illness associated with melanoma. This study examined the following factors: prevalence of signs of melanoma (a mole changing in size. shape. appearance. or color. itching or tingling. bleeding or weeping. becoming raised) in 1344 individuals in a randomly selected sample of 1075 households; the length of delay in seeking medical advice; the factors associated with either going to a medical practitioner or not going/delaying; and the actions of the medical practitioners when first presented with these signs. The results indicate that a large proportion of the sample (11.9%. n = 156) had observed signs of melanoma in the previous 12 months. Of the sample reporting signs that had first appeared in the previous 5 years. only 32% sought medical advice about the signs within the recommended period. Of the sample either not seeking advice at all or delaying. 49% reported that they thought the sign "wasn't serious/would clear up." Furthermore. 30% of the sample either did not known or underrated the importance of early detection and treatment of lesions. These results indicate that there is a deficit in the knowledge of the general public about the signs of melanoma. the severity of the disease. and the possible risks associated with delay.
Epidermolysis bullosa simplex (Koebner) is a keratin disorder. Ultrastructural and immunohistochemical study, A skin biopsy specimen was obtained from a 1-month-old female with epidermolysis bullosa simplex (Koebner). Histologically. an intraepidermal separation was seen and considered to be formed by cytolysis of the epidermal basal cells. Ultrastructurally. the basal cells were lacking in cytoplasmic tonofilaments. and the initial change of the cytolysis seemed to be cleavages of the cytoplasm. Immunohistochemically. a basal cell keratin was expressed in a suprabasal cell layer but not in the basal cell layer. and a panepithelial keratin was not detected in the basal cell layer. These findings suggest that keratin production of the epidermal cells may be delayed. resulting in a weakness of the basal cells against minor trauma to the skin.
Childhood bullous pemphigoid. Clinical and immunologic features, treatment, and prognosis, A 2 1/2-month-old female infant presented with multiple tense bullae on the hands and feet. Analysis of biopsy specimens confirmed our clinical impression of childhood bullous pemphigoid. Confirmatory data included type IV collagen mapping of the basement membrane zone. a readily available technique that helps distinguish childhood bullous pemphigoid from childhood epidermolysis bullosa acquisita. To our knowledge. our patient is the youngest described with childhood bullous pemphigoid. and we use this opportunity to review the literature and examine the clinical and immunologic features. treatment. and prognosis of this rare childhood immunobullous disorder.
Coexistence of pemphigus foliaceus and bullous pemphigoid. Demonstration of autoantibodies that bind to both the pemphigus foliaceus antigen complex and the bullous pemphigoid antigen, Pemphigus and bullous pemphigoid are autoimmune blistering diseases of the skin characterized by circulating autoantibodies directed against the keratinocyte cell surface and the epidermal basement membrane zone. respectively. The coexistence of pemphigus and bullous pemphigoid is very uncommon. We describe a patient with pemphigus foliaceus who later developed bullous pemphigoid and show. by means of immunoprecipitation studies utilizing both cultured keratinocytes and suction blister epidermis. that our patient had circulating autoantibodies directed against both the pemphigus foliaceus antigen complex and the bullous pemphigoid antigen. This report is the first to demonstrate the coexistence of pemphigus foliaceus and bullous pemphigoid at the molecular level.
The spectrum of portal vein thrombosis in liver transplantation, Thrombosis of the portal vein with or without patency of its tributaries used to be a contraindication to orthotopic liver transplantation (OLTX) until quite recently. Rapid progress in the surgical technique of OLTX in the last few years has demonstrated that most patients with portal vein thrombosis can be safely and successfully transplanted. Presented here is a series of 34 patients with portal vein thrombosis transplanted at the University of Pittsburgh since 1984. The various techniques used to treat various forms of thrombosis are described. The survival rate for this series was 67.6% (23 of 34 patients). Survival was best for patients who underwent phlebothrombectomy or placement of a jump graft from the superior mesenteric vein. The survival rate also correlated with the amount of blood required for transfusion during surgery. Overall it is concluded that a vast majority of the patients with thrombosis of the portal system can be technically transplanted and that their survival rate is comparable to that of patients with patent portal vein.
The potential role of postoperative hepatic artery chemotherapy in patients with high-risk hepatomas, The relationship between operative findings of hepatoma and the postoperative prognosis was studied to clarify indications for adjuvant hepatic arterial chemotherapy after hepatectomy. The results of adjuvant hepatic arterial chemotherapy using 0.4 mg/kg of doxorubicin and 0.12 mg/kg of mitomycin C and infusion of 5-fluorouracil were reported. One hundred sixty patients who had undergone hepatectomy for hepatoma were studied. In the operative findings of hepatoma. with a surgical margin of less than 10 mm. intrahepatic metastasis. tumor embolus in the second or more proximal branch of the portal vein. or lack of capsule formation related to the prognosis were the risk factors for recurrence. In 132 patients with these risk factors the survival rate of 19 patients with adjuvant arterial chemotherapy was significantly higher than for the 113 patients without it. Adjuvant hepatic arterial chemotherapy thus may be an effective therapy and should be studied prospectively in patients undergoing hepatectomy for high-risk hepatoma.
Surgical management of 552 carcinomas of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded). Results of the French Surgical Association Survey, Five hundred fifty-two cases of primary carcinoma of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded) collected from 55 surgical centers were reviewed retrospectively. Three hundred seven patients (56%) had upper-third lesions (proximal carcinoma). whereas 71 (13%) and 101 (18%). respectively. had middle-third and lower-third bile duct carcinomas. The remaining patients had diffuse lesions. Resectability rates were 32% for upper-third localization compared to 47% and 51% for middle-third and lower-third localization. respectively. The operative mortality rate for proximal carcinomas was significantly lower with resection (16%) compared with palliative surgery (31%) (p less than 0.05). Overall 1-year survival (operative deaths excluded) was 68% after tumor resection compared to 31% after palliative surgery (p less than 0.001). Long-term results after surgical resection correlated with local and regional extension of the disease. The results of this study show that resection of extrahepatic bile duct carcinomas. particularly in an upper-third localization. often is associated with worthwhile long-term survival.
Blockade of prostaglandin production increases cachectin synthesis and prevents depression of macrophage functions after hemorrhagic shock, Although hemorrhage severely depresses macrophage functions. it is not known whether the increased TNF-alpha or PGE2 production is responsible for it. To study this C3H/HeN mice were bled to mean blood pressure of 35 mmHg for 60 minutes. resuscitated. and treated with either ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage increased plasma prostaglandin E2 (PGE2) levels by 151.7% +/- 40.0% (p less than 0.05) and significantly decreased peritoneal macrophage (pM phi) antigen presentation (AP) by 60.5% +/- 7.3%. Ia expression by 52.3% +/- 7.6%. and interleukin-1 (IL-1) synthesis by 60.5% +/- 12.3% compared to shams. However ibuprofen treatment reduced PGE2 plasma levels by 61.3% +/- 12.1% and significantly increased AP (+237.0% +/- 95.3%). Ia expression (+72.8% +/- 27.5%). IL-1 synthesis (+235.7% +/- 134.7%). and cachectin synthesis (+485.8% +/- 209.0%) compared to vehicle-treated animals. These results indicate that prostaglandins but not cachectin are involved in the suppression of pM phi functions following hemorrhage because blockade of prostaglandin synthesis improved depressed macrophage functions despite enhanced cachectin synthesis.
Bronchoalveolar carcinoma: factors affecting survival, One hundred thirty-four consecutive patients (65 men and 69 women) underwent pulmonary resection for bronchoalveolar carcinoma. Mean age was 65 years. Lobectomy was done in 100 patients. pneumonectomy in 10. segmentectomy in 5. and wedge excision in 19. Only 10 patients had lymph node metastases (7.5%). The neoplasm was solitary in 111 patients (82.8%); 97 were in stage I. 4 were in stage II. 9 were in stage IIIa. and 1 was in stage IIIb. There were two operative deaths (1.5%). Thirty-nine complications occurred in 31 patients. Median follow-up was 5.1 years. Recurrent bronchoalveolar carcinoma developed in 45 patients. Five- and 10-year survival for patients in stage I was 75.2% and 62.0%. respectively. Survival for patients with T1 N0 M0 neoplasms was identical to expected survival and was 90.5% at 5 years. as compared with 55.4% for patients with T2 N0 M0 disease. only 35.9% for patients with multiple bilateral disease. and 0.0% for patients with bilateral disease (p less than 0.0001). Other significant factors adversely affecting survival included the presence of signs and symptoms. diffuse malignant invasion. mucin-producing tumors. and the histological absence of scar. We conclude that bronchoalveolar carcinoma has a unique natural history that is more influenced by local neoplastic processes than by lymph node metastases. Early aggressive pulmonary resection is safe and offers the potential for cure. The presence of bilateral cancer. however. is ominous.
Primary cysts and tumors of the mediastinum, A retrospective analysis was performed on 230 patients with primary cysts and tumors of the mediastinum seen at our institution from January 1944 to April 1989. We divided these patients into two groups. Group 1 was seen before 1970 and group 2 was seen from January 1970 to April 1989. There was a significant increase in the prevalence of malignancy in group 2 (47.2% versus 17.1%; p less than 0.0001) due to an increase in the number of lymphomas (22.6% versus 3.5%; p less than 0.001) and malignant neurogenic tumors (6.8% versus 1.1%; p = 0.0528). There was a significant increase in the number of malignant tumors in the anterior (59.5% versus 30.9%; p = 0.0022) and paravertebral (28.5% versus 2.8%; p = 0.0027) compartments in group 2. More patients with these tumors were symptomatic in group 2 (63.6% versus 5%; p = 0.0422). There was an increase of ancillary diagnostic studies performed to evaluate these tumors (76.0% versus 34.5%; p = 0.0422). Logistic regression analysis identified date of presentation (p less than 0.005). symptoms (p less than 0.01). size (p less than 0.005). and the anterior mediastinal compartment (p less than 0.005) as preoperative predictors of malignancy. The surgical approach to these tumors included more median sternotomy (30.1% versus 10.7%; p = 0.0008). anterior mediastinotomy. and cervical mediastinoscopy in group 2 (1.1% versus 17.5%; p = 0.0002). Long-term results support surgical resection in benign lesions and an aggressive multimodality approach to malignant lesions.
Site of action of continuous extrapleural intercostal nerve block, Continuous extrapleural intercostal nerve block has been shown in a randomized. controlled study to be effective in reducing postoperative pain after thoracotomy and in restoring pulmonary mechanics. To assess the extent of spread of bupivacaine infused through an extrapleurally placed cannula inserted at thoracotomy. iohexol (Omnipaque) was infused at 5 days postoperatively in 5 patients and computed tomography performed. The contrast medium was confined to the paravertebral space covering on average six intercostal spaces. This study demonstrated that anatomically. the site of action of the bupivacaine infused through an extrapleural cannula was primarily in the paravertebral space.
Fibrous skeleton and ventricular outflow tracts in double-outlet right ventricle, Twenty-four hearts in which both great arteries arose from the right ventricle were studied to establish variations present within the fibrous skeleton and infundibular morphologies. Variations were also noted in the location of the ventricular septal defect and measurements were obtained of the outlet septum and the circumferences of the arterial valves. Completely muscular subarterial infundibulums were present in only 9 (37.5%) of the hearts. with varying degrees of fibrous continuity between the leaflets of the arterial and atrioventricular valves in the remainder. The aorta was rightward and posterior in 12 (50%) of the hearts. and subaortic and subpulmonary ventricular septal defects were present in equal numbers in this group. No subaortic defects were present when the aorta was side-by-side and right-sided. No subpulmonary defects were present in hearts with a posterior aorta. The mean ratio of 0.91 +/- 0.36 for the subpulmonary to subaortic length of the outlet septum was significantly less than the value of 1.54 +/- 0.41 noted previously in hearts with tetralogy of Fallot (p less than 0.001).
Superiority of retrograde cardioplegia after acute coronary occlusion, Because antegrade cardioplegia may limit the distribution of cardioplegia beyond a coronary occlusion. this study was undertaken to determine whether retrograde coronary sinus cardioplegia provides superior myocardial protection during revascularization of an acute coronary occlusion. In 20 adult pigs. the second and third diagonal branches were occluded with a snare for 1 1/2 hours. Animals were then placed on cardiopulmonary bypass and underwent 30 minutes of ischemic arrest with multidose. potassium. crystalloid cardioplegia. In 10 animals. the cardioplegia was given antegrade through the aortic root. whereas in 10 others. it was given retrograde through the coronary sinus. After the arrest period. the coronary snares were released and all hearts were reperfused for 3 hours. Postischemic damage in the myocardium beyond the occlusions was assessed by wall motion scores using two-dimensional echocardiography (4 = normal to -1 = dyskinesia). the change in myocardial pH from preischemia. and the area of necrosis/area of risk (histochemical staining). Hearts protected with retrograde coronary sinus cardioplegia had less tissue acidosis (change in pH = 0.08 +/- 0.03 versus 0.41 +/- 0.13; p less than 0.05). higher wall motion scores (2.0 +/- 0.6 versus 1.3 +/- 0.3; not significant). and less myocardial necrosis (43.4% +/- 3.6% versus 73.3% +/- 3.5%; p less than 0.0001). We conclude that retrograde coronary sinus cardioplegia provides more optimal myocardial protection than is possible with antegrade cardioplegia after revascularization of an acute coronary occlusion.
Efficacy of coronary sinus cardioplegia in patients with complete coronary artery occlusions, Myocardial areas distal to complete coronary artery occlusions are poorly protected by antegrade cardioplegia. We assessed the effects of coronary sinus cardioplegia in 30 patients undergoing bypass operations and at high risk of cardioplegic maldistribution because of the following anatomical patterns of coronary artery disease: critical (greater than or equal to 50%) stenosis of the left main trunk with total occlusion of the right coronary artery (16 patients) or critical (greater than or equal to 70%) stenosis of the right coronary artery with total occlusion of the left anterior descending (11 patients) or circumflex artery (3 patients). After induction of arrest through the aorta. coronary sinus cardioplegia was given intermittently during the cross-clamp period at a flow rate of 100 mL/min. Intraoperatively. occluded arteries were consistently found to be filled with the retrogradely infused solution. One patient died early postoperatively of low cardiac output and a second patient died later during his hospital stay. presumably of an arrhythmia. At autopsy. none of them had pathological evidence of inadequate myocardial protection. One patient sustained a myocardial infarction and 3 others required inotropes for more than 24 hours postoperatively. Postoperative values for right and left stroke volume indices were not significantly different from prebypass levels. Overall. these results are consistent with the occurrence of limited intraoperative ischemic damage and. by inference. suggest the efficacy of the coronary sinus route in preserving myocardial areas supplied by completely occluded coronary arteries and. hence. in jeopardy of inadequate cardioplegia delivery.
Thoracoscopic debridement and pleural irrigation in the management of empyema thoracis, As a sequel to a paper reporting good results obtained in 12 patients with empyema thoracis treated by thoracoscopic debridement and irrigation in our department. subsequent experience with a further 18 patients is reported. Drainage of pus and irrigation resulted in resolution of pyrexia with improvement in general condition in all patients. Overall. complete resolution was obtained by this technique alone in 60% (18/30). Of the 12 patients in whom complete resolution was not obtained. secondary surgical measures resulted in resolution of empyema in 8. Four patients died; all were elderly and severely debilitated. 3 with advanced malignancy. Their deaths were not related to the technique. which was well tolerated in all cases. Thoracoscopic debridement and irrigation used routinely as a first-line measure in empyema thoracis is a safe and relatively atraumatic procedure. does not exclude the use of any subsequent surgical measure. and provides valuable time to improve the condition of debilitated patients so that they may tolerate more aggressive surgical procedures.
Computed tomography-guided minithoracotomy for the resection of small peripheral pulmonary nodules, Small peripheral pulmonary nodules ranging in size from 1 mm to 20 mm were excised in 58 patients. Computed tomography was used to mark the skin overlying the nodules to minimize the surgical exposure needed for operative identification. The nodules were 1 cm or less in maximum diameter in 76% of the patients. Twenty-six patients had single nodules and 32 patients had multiple nodules. The preoperative diagnosis was inaccurate in 67% of the patients. In 61% of the patients in whom malignancy was suspected. no tumor was demonstrated. Conversely. of the 20 patients in whom a malignant nodule was excised. the preoperative diagnosis was correct in only 50%. Thirty-one patients required no further treatment apart from their biopsy and 27 required additional intervention. Small peripheral pulmonary nodules require biopsy for diagnosis. When percutaneous needle aspiration biopsy is unsuccessful. or technically difficult. a computed tomography-guided thoracotomy is an effective and minimally invasive surgical alternative.
Strut fixation of an extensive flail chest, The indications for and preferred approaches to operative stabilization of posttraumatic chest wall instability are uncertain. We suggest this simple. rapid. and effective approach to surgical stabilization by Luque rod strutting of the flail segment when operation is required.
Repair of posterior left ventricular aneurysm in a six-year-old boy, Left ventricular aneurysms and diverticula are rarely encountered in the pediatric age group. This paper reports a case of congestive heart failure and mitral regurgitation in a 6-year-old boy with a large posterolateral left ventricular aneurysm. Complete repair was successfully performed by excision of the aneurysm and Dacron patch reconstruction of the left ventricular free wall. The patch extended onto the posterior annulus of the mitral valve. thus restoring the mitral valve to normal geometry and correcting the mitral insufficiency. The surgical literature on congenital cardiac diverticula and acquired aneurysms in children is reviewed and summarized.
Surgical management of carcinoid heart disease, Metastatic carcinoid tumor is often seen with flushing. diarrhea. and cardiac symptoms--the carcinoid syndrome. Cardiac failure is often associated with major morbidity and mortality in carcinoid disease. In this report. a case of successful cardiac valvar surgical intervention has resulted in prolonged alleviation of cardiac symptoms and survival.
Silicone pouch for protection of automatic implantable cardioverter-defibrillator leads, Automatic implantable cardioverter-defibrillator has become routine treatment for recurrent. drug-resistant ventricular tachycardia. Although there is documentation regarding clinical experience and device performance. there is little information on how to avoid complications related to the retrieval of sensing and defibrillation leads from the subcutaneous space. We are reporting our experience with a silicone pouch for protection of automatic implantable cardioverter-defibrillator leads that allows immediate and simple retrieval of the leads in case an automatic implantable cardioverter-defibrillator generator is needed.
Autogenous atrial tunnel for direct cavopulmonary connection in infants and small children, A technique is described for construction of an autogenous right atrial tunnel for direct cavopulmonary connection in infants and small children requiring Fontan operation. Advantages. in this subset of patients. of this method over others previously described using prosthetic or growth-limited materials are suggested.
Muscle rehabilitation in impaired elderly nursing home residents, Based on observations of changes in muscle function associated with aging. and the exacerbation of these changes with frailty. a program of muscle strengthening has been developed to correct specific defects in muscles. This pilot study was undertaken on 18 functionally impaired nursing home residents (age range 60 to 90 years) with markedly deteriorated muscle function (50%) secondary to age. disuse. and multiple chronic illnesses. Fourteen of the subjects completed the six-week program without adverse effects. In 75% of the patients. there was improved muscle function. with endurance. strength. and speed increasing 35%. 15%. and 10%. respectively. After the program. many subjects increased their spontaneous activity and decreased their dependency. The improvements were still evident four months after rehabilitation. These results suggest that it may be possible. through a carefully supervised. short-term program of muscle rehabilitation. for nursing home residents to achieve an enhanced level of physical functioning.
Quantitative gait analysis in unilateral and bilateral total hip replacements, By qualitative and quantitative analysis of gait we evaluated the outcomes in 41 patients after total hip arthroplasty for degenerative arthritis. Patients with unilateral and bilateral degenerative hip disease were evaluated in an effort to characterize preoperative and postoperative gait characteristics. Patients were evaluated using a subjective hip-rating scale and a gait-evaluation mat. Data were compared with those obtained from a control group of 91 patients. All patients showed a marked improvement in both subjective ratings and measured quantitative gait parameters. Patients with unilateral hip disease improved to a greater extent than those with bilateral disease after arthroplasty. We have concluded that total hip arthroplasty can greatly improve the gait characteristics of patients with degenerative arthritis. and that this improvement can be quantified. documented. and followed by using a system of gait evaluation.
Wrist flexion as an adjunct to the diagnosis of carpal tunnel syndrome, The effects of five minutes of wrist flexion on median motor and sensory evoked potential latencies in 87 individuals were studied. Nineteen subjects had carpal tunnel syndrome (CTS) as diagnosed by increased median nerve latencies across the wrist. and 68 had values in the normal range and were assigned to the control group. A slight prolongation of up to 0.5m sec of evoked potential latencies was observed in both groups after flexion. but the differences between the two groups were not significant to establish the value of adding wrist flexion to conventional screening methods.
Detecting lower motor neuron dysfunction of the pharynx and larynx with electromyography, This study assessed the utility of clinical electromyography (EMG) for detecting lower motor neuron (LMN) or upper motor neuron (UMN) dysfunction affecting the intrinsic muscles of the larynx and pharynx. Twenty-nine subjects were examined; their clinical diagnoses included perioperative nerve injury. cerebral infarction. and lateral medullary infarction. Resting activity. motor unit action potential (MUAP) morphology. and MUAP recruitment were evaluated in every case. Medical records (excluding EMG data) were analyzed for clinical evidence of LMN or UMN dysfunction in the intrinsic muscles of the larynx and pharynx. The diagnosis of LMN dysfunction rested on clinical data consistent with cranial nerve injury. poliomyelitis. Wallenberg syndrome. or unilateral bulbar palsy. Criteria for UMN dysfunction included previous cerebral (not brainstem) infarction or mass lesion or the presence of hemiparesis. Electromyographic abnormalities were significantly associated with LMN dysfunction (p less than .05). but they were not significantly associated with UMN dysfunction. Of the parameters tested. MUAP recruitment was the most sensitive (82%) and specific (92%).
Neurobehavioral effects of phenytoin, carbamazepine, and valproic acid: implications for use in traumatic brain injury, Due to the risk of posttraumatic epilepsy. phenytoin. carbamazepine. and valproic acid are often prescribed for patients with traumatic brain injury (TBI). In this review the literature is examined for evidence of neurobehavioral impairment due to carbamazepine. phenytoin. and valproic acid. No comparative studies have been performed in the TBI population. making if difficult to determine if one of these medications is preferable. Direct inference from studies on epilepsy patients to TBI patients is hazardous due to underlying differences in the two populations. Reported findings for epilepsy patients are subtle and not consistent across studies. All three drugs appear to exert some effect on cognitive and motor functions in epileptic patients. and these impairments worsen at increasing serum levels. The varied length of experience with each drug makes it difficult to assign relative weight to the evidence for or against each. A comparative assessment of cognitive and behavioral effects of anticonvulsants should be done in the TBI population.
Electrophysiologic investigation of mandibular nerve injury, Isolated lesions of the mandibular branch of the trigeminal nerve have only rarely been reported. We report the occurrence of an isolated lesion of the mandibular nerve associated with a unilateral mandibular fracture. and its substantiation electrophysiologically. A 65-year-old man was involved in a motor vehicle accident resulting in multiple fractures. including a unilateral mandibular fracture and temporomandibular joint dislocation. No evidence of intracranial pathology by CT scan was noted and the neurologic examination was nonfocal except for dysfunction of the mandibular nerve ipsilateral to the fracture site. Bilateral facial nerve latency and blink reflexes were normal. EMG evaluation of the muscles of facial expression and mastication demonstrated denervation confined to the muscles innervated by the mandibular branch of the trigeminal nerve. In patients complaining of facial sensory dysfunction. malocclusion. or weakness of muscles of mastication after mandibular fracture. an electrophysiologic examination can assist in evaluating cranial nerve integrity.
Dural spinal cord arteriovenous malformation, After multiple hospital admissions and an inpatient rehabilitation stay. a 68-year-old woman was transferred to our rehabilitation facility with a paraparesis of unknown etiology. Previous studies included four CT scans and three MRIs which did not demonstrate the lesion. A myelogram was noncharacteristic. The correct diagnosis. confirmed by selective angiography. was ultimately contingent upon recognition of the clinical features and natural history of dural spinal cord arteriovenous malformations (SCAVM). The unusual combination of this multitude of nondiagnostic imaging studies in the uncommon dural SCAVM served to delay diagnosis and treatment. Such delay may have great functional consequences. This report illustrates the importance of suspecting SCAVM and recognizing its features. Emphasis is placed on the physiatrist's role in assuring proper diagnosis to expedite a timely treatment and to obtain the best functional outcome. A brief review of the classification. clinical features. pathophysiology. diagnosis. and prognosis of SCAVM is presented.
Operative exposure of the abdominal arteries for trauma, Traumatic injuries to the abdominal arteries require operative exposures that allow for flexible repair. Dividing the abdominal arterial tree into four zones. based on exposure. provides expedient and precise repair of all major abdominal arteries.
Why surgeons prefer not to care for trauma patients, A survey of the Washington State Chapter of the American College of Surgeons was undertaken to document the opinions of surgeons on trauma care issues. Thirty-nine percent of the total sample of surgeons who responded would prefer not to treat any trauma patients. These surgeons were more likely to be older. to practice in an urban setting. to feel that trauma call has a negative impact on elective practice. and to believe more strongly that reimbursement from trauma patients is not equal to that of nontrauma patients. They also agreed more strongly with the statements that these patients require a greater time commitment and pose an increased medicolegal risk. The most significant influence on preference not to treat trauma patients was exerted by the perception of a negative impact on practice. older age. and perception of increased medicolegal risk. Reimbursement issues and location of practice were less influential factors. This information can be used to target concerns and barriers to active. willing participation in a trauma care system and to tailor strategies to deal with them effectively.
Simplified hepatic resection with the use of prolonged vascular inflow occlusion, Ten consecutive patients scheduled to undergo liver resection were studied prospectively with the use of a standard protocol. which included routine vascular inflow occlusion to reduce blood loss and blood transfusion requirements. Fibrin sealant was sprayed on the raw liver surface. and abdominal drainage was not performed. No deaths occurred. and the postoperative course was remarkably smooth. The normothermic liver ischemic times of 30 to 122 minutes (mean. 73 minutes) were well tolerated. The amount of blood transfused was reduced to a mean of 2 U (range. 0 to 4 U). The occurrence of infected intraabdominal bile collections in two patients with preexisting biliary tract infection suggested that abdominal drainage should be performed in such patients. Vascular inflow occlusion is recommended for all liver resections.
Inflammatory breast cancer, Historically. the prognosis of inflammatory breast cancer has been poor. We conducted a retrospective review to evaluate the recent Memorial Sloan-Kettering Cancer Center experience. to evaluate the role of combination chemotherapy. and to compare the effect of surgery and radiation on local/regional failure. Fifty-six patients with local/regional inflammatory breast cancer diagnosed between 1975 and 1984 were identified. All were treated with combination chemotherapy. Overall 5-year survival was 45% with a 5-year disease-free survival rate of 37%. Twenty-one patients were treated with induction chemotherapy followed by mastectomy and adjuvant chemotherapy. Survival and disease-free survival rates were similar to those achieved in patients treated with mastectomy followed by chemotherapy. Residual cancer was found in all 21 patients treated with induction chemotherapy. with extensive disease present in 18. including six of seven complete responders. The local/regional failure rate was 34%.
Prognostic significance of carcinoembryonic antigen in colorectal carcinoma. Serum levels before and after resection and before recurrence, The use of carcinoembryonic antigen was evaluated in 425 patients with a mean follow-up of 48 months. The preoperative and postoperative carcinoembryonic antigen levels were predictive of recurrence and survival independent of the tumor stage. In a multivariate regression analysis of age. location. tumor stage. and preoperative and postoperative carcinoembryonic antigen levels. the latter three factors were significant prognostic variables with respect to the adjusted survival. Recurrent disease was found in 42% of patients. excluding patients with stage IV disease. The carcinoembryonic antigen level at recurrence was greater than 5 ng/mL in 79% of the patients and in 89% of the intra-abdominal recurrences. Carcinoembryonic antigen level at recurrence was not predictive of postrecurrence survival except in the subgroup of locoregional disease. The life span in patients with liver and lung metastases was not influenced by carcinoembryonic antigen level at recurrence. Preoperative and postoperative carcinoembryonic antigen levels can indicate a poorer prognostic group of patients with colorectal cancer who may benefit from adjuvant treatment. The carcinoembryonic antigen at recurrence can be used effectively to diagnose intra-abdominal recurrences and project survival after development of local/regional disease.
Prognostic factors in primary retroperitoneal soft-tissue sarcomas, We analyzed independent treatment variables (age. sex. signs and symptoms. site. size. histopathologic findings. grade. and clinical presentation) and treatment-dependent variables (resectability. type of operation. surgical margins. surgical boundaries. microscopic margins. adjuvant radiotherapy. and adjuvant chemotherapy) in 80 patients with primary retroperitoneal soft-tissue sarcomas admitted from 1982 through 1988. Both univariate and multivariate analysis of survival and disease-free survival were performed. The major factor in survival outcome was the ability to completely resect the lesion. When the 62 patients who underwent complete resection were examined. the only independent prognostic factor for both survival and disease-free survival was grade. We conclude that completeness of resection and grade of the lesion are primary determinants of survival. Once all tumor is macroscopically removed. no advantage could be demonstrated by more extensive surgical resection or current adjuvant therapy.
Radioimmunoguided surgery using iodine 125 B72.3 in patients with colorectal cancer, Preliminary data using B72.3 murine monoclonal antibody labeled with iodine 125 suggested that both clinically apparent as well as occult sites of colorectal cancer could be identified intraoperatively using a hand-held gamma detecting probe. We report the preliminary data of a multicenter trial of this approach in patients with primary or recurrent colorectal cancer. One hundred four patients with primary. suspected. or known recurrent colorectal cancer received an intravenous infusion of 1 mg of B72.3 monoclonal antibody radiolabeled with 7.4 x 10 Bq of iodine 125. Twenty-six patients with primary colorectal cancer and 72 patients with recurrent colorectal cancer were examined. Using the gamma detecting probe. 78% of the patients had localization of the antibody in their tumor; this included 75% of primary tumor sites and 63% of all recurrent tumor sites; 9.2% of all tumor sites identified represented occult sites detected only with the gamma detecting probe. The overall sensitivity was 77% and a predictive value of a positive detection was 78%. A total of 30 occult sites in 26 patients were identified. In patients with recurrent cancer. the antibody study provided unique data that precluded resection in 10 patients. and in another eight patients it extended the potentially curative procedure.
Radical resection for carcinoma of the ampulla of Vater, One hundred four consecutive patients who underwent radical resection for ampullary cancer between 1965 and 1989 were retrospectively reviewed. Frequent clinical findings included jaundice (67%). significant (greater than 10%) weight loss (42%). and anemia (27%). Eighty-seven patients (84%) underwent a subtotal pancreatectomy. and 17 patients (16%) underwent a total pancreatectomy. The postoperative mortality was 5.7% (six patients). and reoperation for postoperative complications was required in six patients. The 5- and 10-year survival rates were 34% and 25%. respectively. Eight patients died of tumor recurrence more than 5 years after resection. Patient survival was significantly impaired by microscopic lymphatic invasion. regional nodal metastasis. tumor grade. and the epithelium of origin. In a multivariate analysis. only microscopic lymphatic invasion significantly reduced patient survival. Radical resection for ampullary cancer can be performed with a low morbidity and mortality and should remain the procedure of choice for ampullary carcinoma.
Bilateral iliac vein filtration. An effective alternative to caval filtration in patients with megacava, Greenfield filters were placed bilaterally in the iliac veins in five of 250 patients undergoing percutaneous filter placements. Four of the five patients had megacava (inferior vena cava diameter greater than 28 mm). In all patients. the filters were effective in preventing pulmonary embolism. Follow-up at 9 months in two patients revealed no changes of chronic venous insufficiency or venous stasis. Iliac filtration should be considered in patients in whom a caval filter cannot be placed because of large caval size or because it is technically difficult due to iliac vein tortuosity.
Indomethacin inhibition of middle ear bone resorption, Localized osteoclastic bone resorption is responsible for the pathological changes within the middle and inner ear. which result in hearing loss and vertigo in chronic otitis media and otosclerosis. The local control of osteoclastic bone resorption is incompletely understood. Various small. locally active molecules. cytokines. have been shown to affect resorptive processes. Additionally. prostaglandins and their inhibitors have been shown to modulate the resorptive process in a number of in vitro studies. In this study. indomethacin. a cyclooxygenase inhibitor. was tested in a model of localized bone resorption. the pressurized gerbil bulla. After the experimental period. indomethacin was found to inhibit the number of osteoclasts and the resorptive area on the inner surface of the bulla. Therefore. it is likely that endogenous cyclooxygenase metabolites are intermediates in the sequence of cellular events. which results in localized bone resorption as in some systemic models.
5-year results of cisplatin and fluorouracil infusion in head and neck cancer, As part of the developmental process for the Head and Neck Intergroup trial of adjuvant chemotherapy for advanced resectable head and neck carcinoma. in 1981 the Radiation Therapy Oncology Group. Philadelphia. Pa. conducted two nonrandomized pilot studies using chemotherapy consisting of three courses of cisplatin and fluorouracil infusion. Chemotherapy was administered prior to surgery in 42 patients (induction) and after surgery in an additional 29 patients (sequential). The populations were roughly comparable with respect to tumor site and stage. Twelve of the 42 patients in the induction group and seven of the 29 in the sequential group are alive and with no evidence of disease at the last reported follow-up. The median survival was 31 months in the sequential group vs 20 months in the induction group. Only two of the 26 patients with less than a complete clinical response following induction chemotherapy are still alive. Twenty-seven of the 42 patients who received induction chemotherapy did not undergo surgery as initially planned. Despite the lack of surgery. at 5 years the survival between the two groups was not significantly different (27% for the induction group vs 23% for the sequential group).
Primary parotid malignancies. A clinical and pathologic review, One hundred ninety-four patients with primary malignant tumors of the parotid gland who underwent surgery at the Mayo Clinic (1970 through 1987) are reviewed. Survival patterns were analyzed using the Kaplan-Meier product-limit method that separated histologic results into three significantly different groups. Survival rate was highest for patients with acinic cell. adenoid cystic. and low-grade mucoepidermoid carcinomas; intermediate for patients with high-grade mucoepidermoid carcinomas; and lowest for the remaining six histologic types encountered. Cox multiple linear regression was used to identify patient and tumor characteristics with greatest prognostic significance. In order of decreasing strength. regional metastatic involvement. pain. male gender. grade. stage. and advancing age all demonstrated independent prognostic significance. Fifty-three percent of patients requiring facial nerve sacrifice were asymptomatic at presentation. A high positive correlation was observed between advancing grade and stage.
Noncongenital hereditary hearing loss in children. Prospective documentation, Younger siblings of children with sensorineural hearing loss of possible hereditary cause underwent interval audiologic examination. Seven siblings (in unrelated families) were found to have progressive sensorineural hearing loss despite early audiograms documenting normal hearing levels for age. Continued testing of these children allowed for early identification and intervention. We advocate regular otolaryngologic and audiologic follow-up even after normal audiologic assessments are made for younger siblings of children with documented sensorineural hearing loss. unless a definite nongenetic origin of the hearing loss in the older child is known. Recessive sensorineural hearing loss with onset in infancy or childhood may present with no antecedent family history and with normal behavioral audiograms early in life.
Effective destruction of cervical intraepithelial neoplasia (CIN) 3 at 100 degrees C using the Semm cold coagulator: 14 years experience, A total of 1628 women with CIN 3 treated with the Semm cold coagulator between 1975 and 1989 was followed primarily by cytology. The standard suitability criteria for ablation were adhered to except that patients were treated at their first visit when the colposcopist expected that the diagnosis would be no worse than CIN 3. Overall 97% of the women were treated at their first visit. In 30 women (2%) the histology was glandular or worse than expected. but 22 of these showed no persistent cervical disease subsequently. Follow-up was achieved for 87% at 10 years. In actuarial terms the primary success rate was 95% at 1 year and 92% at 5 years. it was similar for all age groups. Repeat cold-coagulation for persistent/recurrent CIN 3 was less successful and is not advised. The outcome for 226 pregnancies established after treatment is known. The rates for miscarriage. preterm or operative delivery were not increased. Cold-coagulation of CIN 3 at 100 degrees C as performed by us is as effective as any other treatment and calls into question the need for more expensive practices.
Vaginal epithelial abnormalities in patients with CIN: clinical and pathological features and management, Of 4147 women who had CIN treated by laser at the Regional Gynaecological Oncology Centre. Queen Elizabeth Hospital. Gateshead. 103 (2.5%) had co-existing vaginal epithelial abnormalities. CIN 3 was the histological diagnosis most often associated with vaginal lesions. The upper vagina was almost always involved. In 67% the lesion in the cervix appeared to be confluent with that in the vagina. Even when the lesions were confluent. biopsies form the cervical and vaginal components did not always show the same grade of intraepithelial neoplasia and in some biopsies they showed different lesions. Laser treatment appears to be effective for the vaginal lesions and is therefore recommended although. in selected patients. careful follow up alone may suffice.
Babies born before arrival at hospital, OBJECTIVE--To establish the prevalence of babies born before arrival at two local hospitals. To identify women at risk of giving birth before arrival. and the morbidity and mortality associated with such births. DESIGN--A case control study. Each baby born before arrival and its mother were compared with the next born in the hospital (random control). and one matched for gestation and birthweight. together with their mothers. SETTING--Two maternity units serving East Birmingham and Solihull. SUBJECTS--All babies (and their mothers) born before arrival at these hospitals from January 1983 to December 1987. MAIN OUTCOME MEASURES--Perinatal mortality rates. patterns of perinatal morbidity. demographic. social and obstetric features of the mothers. RESULTS--137 (0.44%) of 31.140 consecutive births were before arrival at hospital (BBA group). The perinatal mortality rate in the BBA group was 58.4/1000 (8 deaths) compared with 10.1/1000 for all inborn babies (relative risk 5.8. 95% confidence interval 2.9-11.4). In the BBA group the mean birthweight of 3008 g was 212 g (95% CI 50-374 g) less than that in the random control group; the mean gestation of 266 days was 10 days less (95% CI 5.9-14.1 days) than in the random control group. Hypothermia was the commonest morbidity. Women delivered before arrival tended to be either multigravid inner city Asians living a long way from the hospital or unmarried unbooked younger white Europeans. CONCLUSIONS--The high perinatal mortality was related to immaturity and low birthweight. rather than to birth before arrival itself. Although groups of mothers at risk of delivery before arrival can be identified more information is needed to establish whether additional antenatal care would be beneficial for these women and their babies.
Distal urethral electrical conductance (DUEC)--a preliminary assessment of its role as a quick screening test for incontinent women, Measurement of distal urethral electrical conductance (DUEC) has been used to detect the movement of urine along the distal urethra. DUEC was used as a screening test in 100 women attending the urodynamic clinic with incontinence and in the 33 women who voided over 250 ml. the findings correlated well with subsequent urodynamic diagnosis of urethral sphincter incompetence and detrusor instability.
External cephalic version at term. A randomized controlled trial using tocolysis, OBJECTIVE--To assess the role of external cephalic version (ECV) at term. using tocolysis. DESIGN--A randomized controlled trial over a 12 month period. SETTING--Harare Maternity Hospital. Harare. Zimbabwe. SUBJECTS--208 women with breech presentation at term were recruited after satisfying eligibility criteria. There were 103 women in the study group and 105 in the control group. At the end of the study a further 104 women were recruited for ECV. INTERVENTION--ECV attempted after intravenous injection of 10 micrograms of hexaprenaline. using either forward or backward somersault over a maximum period of 5 min. MAIN OUTCOME MEASURES--Success rate in terms of presentation during labour. need for caesarean section. and various variables related to fetal outcome. RESULTS--ECV reduced the frequency of breech presentation during labour from 83% to 17% and that of caesarean section from 33% to 13%. There were no troublesome complications from the procedure. CONCLUSION--In carefully selected women with breech presentation. ECV at term using tocolysis. safely reduced the rate of breech presentation in labour and also the caesarean section rate. Further research is needed to determine the role of ECV in early labour.
Detecting hypertension: screening versus case finding in Norway, OBJECTIVE--Evaluation of detection of hypertension in adults in the county of Nord-Trondelag. Norway. DESIGN--Cross sectional survey with clinical follow up examinations. SETTING--Health survey by screening teams from the national health screening service. and examinations by all 106 general practitioners in the county. SUBJECTS--During 1984-6. 74.977 persons (88.1% of those aged 20 years and over) participated in the health survey. MAIN OUTCOME MEASURES--Hypertension (when assessed by standardised recording and by questionnaires on drug treatment for hypertension) according to the blood pressure thresholds used in the Norwegian treatment programme. Subjects positive on screening were grouped after clinical examination into treatment groups. RESULTS--In all. 2399 subjects were positive for hypertension. Before screening 6210 (8.3%) patients reported taking antihypertensive drugs and another 3849 (5.1%) had their blood pressure monitored regularly. All who screened positive were referred to their general practitioner and evaluated according to a standard programme. As a result. drug treatment was started in 406 (0.5%) participants screened and blood pressure monitoring in another 1007 (1.3%). Of all patients taking antihypertensive drugs after the screening. 6399 (94.0%) had been diagnosed before screening. and of those whose blood pressure was monitored after the screening. 79.3% had been diagnosed before screening. CONCLUSIONS--At the blood pressure screening thresholds used. and when hypertension is defined by an overall clinical diagnosis. the results indicate that general practitioners can find and diagnose hypertensive patients with the case finding strategy.
Usefulness of immunotherapy in patients with severe summer hay fever uncontrolled by antiallergic drugs, OBJECTIVE--To evaluate the efficacy and safety of immunotherapy (hyposensitisation) in patients with severe summer hay fever. DESIGN--A randomised. double blind. placebo controlled study of a biologically standardised depot grass pollen extract. SETTING--Allergy clinic. Royal Brompton and National Heart Hospital. London. PATIENTS--40 adults (mean age 35 years) with a history of severe grass pollen allergy uncontrolled by standard antiallergic drugs. Patients with perennial asthma were specifically excluded. INTERVENTION--Patients were randomised to receive either an active preparation (Alutard SQ. a grass pollen (Phleum pratense) extract) or placebo at a rate of two subcutaneous injections a week in increasing doses until a maintenance dose was reached. This maintenance dose was given once a month. MAIN OUTCOME MEASURES--Clinical efficacy was evaluated by symptom and drug diary cards. visual analogue scores during the grass pollen season. and a postseasonal assessment by the patients and a doctor. Conjunctival and skin sensitivity to local allergen provocation was measured before and after eight months of treatment. RESULTS--There was a highly significant decrease (median Alutard SQ v median placebo (95% confidence interval for difference between medians] in total symptom scores (p=0.001) in the Alutard SQ treated group (360 v 928 (238 to 825]. Significant differences were also found in total drug use (p=0.002. 129 v 627 (178 to 574]. Visual analogue symptom scores were also reduced in the active group (p=0.02. 2.2 v 5.5 (-4.8 to -0.5]. The postseasonal assessment. by either the doctor or the patients. showed a large improvement (p less than 0.001) in favour of Alutard SQ. Provocation tests showed a greater than 10-fold reduction for the active group in immediate conjunctival allergen sensitivity (p=0.001). a 40% decrease in early phase response (p=0.02). and a 57% decrease in the late phase (p=0.001) cutaneous response after intradermal allergen. A total of 523 active injections were given. There was one systemic reaction at 10 minutes after injection. which was rapidly reversed with intramuscular adrenaline. There was one mild delayed urticarial reaction at 2 1/2 hours. CONCLUSION--Immunotherapy is effective in patients with severe summer hay fever. but immediate anaphylactic reactions limit its use to specialised centres. Patient selection is extremely important. and chronic perennial asthma should be specifically excluded. As serious reactions occur within minutes a two hour wait for all patients after each injection seems unnecessary.
Carcinoma of the breast: measurement and the management of treatment. I. The value of the data, This is the first of a series of papers in which we shall explore some insights into the biological changes which accompany the treatment of human tumours which may be obtained through estimation of volume changes in relation to treatment. We have adopted a working hypothesis that regression slopes reflect the composition of individual tumours and. indirectly. their intrinsic growth rate rather than the effectiveness of treatment. The breast has proved to be a suitable site for measurement and our interpretation of the results has led to the development of a new style of management for carcinoma of the breast: measurement based sequential therapy (MBST). In this paper the method of measurement and detailed statistical evaluation of the quality of the data from 262 patients (263 tumours) is presented. Exponential regression lines have been fitted to describe volume changes in relation to treatment by radiation. chemotherapy and hormones. A simple classification of steepness of slopes is introduced.
Role of phenytoin in healing of large abscess cavities, The promotion of healing of large abscess cavities attained with topical phenytoin was evaluated in controlled studies of clinical and experimental wounds. In the clinical abscess cavities. phenytoin application in 20 patients compared with conventional treatment in 20 patients resulted in earlier separation of slough. decrease in oedema. control of pain and overall enhanced healing. The mean(s.d.) rate of reduction of wound area was 2.02(0.48) cm2/day in the phenytoin group versus 1.58(0.51) cm2/day in controls (P less than 0.05) on day 10. and 1.8(0.32) cm2/day versus 1.19(0.21) cm2/day (P less than 0.01) on day 20. The mean volume reduction rates at both the 10th and 20th day were 0.48(0.01) cm3/day for phenytoin versus 0.32(0.04) cm3/day for controls; (P less than 0.005). By day 20. 17 of the patients treated with phenytoin were rated as having healed completely. compared with only one of the controls. In a standardized guinea-pig model of the clinical abscess cavity. which included inoculation of the wound with Bacillus proteus and Klebsiella pneumoniae. an enhanced healing rate was also observed (at 7 days 0.40(0.05) cm2/day with phenytoin versus 0.21(0.08) cm2/day in controls; P less than 0.005). All eight of the animals treated with phenytoin healed by day 21. compared with one of the eight controls. Biopsies of wounds treated with phenytoin showed less inflammation. no necrosis. and enhanced neovascularization. collagen deposition and fibroblast proliferation compared to controls. Bacterial colonies also decreased more rapidly with the use of phenytoin.
Gastric adaptive relaxation and symptoms after vagotomy, Gastric adaptive relaxation is reported to be impaired after vagotomy. This abnormality has been implicated in the pathogenesis of postvagotomy symptoms. but no association has previously been demonstrated between the two. Gastric adaptive relaxation was measured in 15 healthy volunteers and 33 patients more than 1 year after highly selective vagotomy or truncal vagotomy and drainage. Seventeen patients were asymptomatic. The remainder were symptomatic including seven patients with persistent diarrhoea. Fasted subjects were intubated with a Ryle's tube containing a pressure microtransducer within a flaccid (800 ml) plastic bag. Gastric corpus-fundus pressure was recorded during distension of the bag with air (15 ml/s) over 30 s. Pressure indices were derived from the areas under the pressure curves. Median (range) pressure indices were: healthy volunteers 12.7 (7.5-17.1) cmH2O. highly selective vagotomy 14.0 (9.8-15.9) cmH2O (n.s.). truncal vagotomy and drainage 14.5 (8.6-26.8) cmH2O (P = 0.04). All patients with diarrhoea had abnormally high pressure indices (P less than 0.001). Pressure indices in all other patient groups were within the normal range. We conclude that gastric adaptive relaxation remains abnormal in patients with postvagotomy diarrhoea but not in those who are asymptomatic or who have other symptoms.
Detection of colorectal liver metastases using intraoperative ultrasonography, Intraoperative ultrasonography of the liver has been carried out in 99 patients undergoing surgery for colorectal cancer. Palpation of the liver. preoperative abdominal ultrasonography and computed tomography scanning were also performed in all patients. Metastases were identified in 26 of the 99 patients (26 per cent). Intraoperative ultrasonography diagnosed more metastases than palpation. abdominal ultrasonography or CT scanning. identifying metastases in 24 of the 26 patients. including six patients in whom the metastases were not detected by any other technique. Identification and localization of impalpable liver metastases is therefore possible using intraoperative ultrasonography.
Effect of fibrin sealant on the healing colonic anastomosis in the rat, Fibrin adhesives have been advocated as a protective seal in colonic anastomosis to prevent leakage. In order to assess the effect of fibrin glue sealing we compared the healing of sutured colonic anastomosis in the rat (group 1) with the addition of human-derived fibrin sealant (group 2). As a control for a possible reaction to foreign protein. in group 3 the sutured anastomosis was sealed with specially prepared rat fibrin adhesive. On days 2. 4 and 7. ten animals in each group were killed. Adhesion formation was scored and the in situ bursting pressure was measured. The collagen concentration and degradation were estimated by measuring hydroxyproline. Adhesion formation was significantly increased in groups 2 and 3 compared with the control group. On days 2 and 7 the bursting pressure was not different between the groups. On day 4 the bursting pressure in groups 2 and 3 was significantly lower than in group 1 (P less than 0.001). These findings correspond with the results of collagen measurements. On day 4 the concentration of hydroxyproline was significantly reduced in groups 2 and 3. Histological examination showed infiltration of neutrophilic granulocytes into the sealant on days 2 and 4; on day 7 the sealant had vanished. From these results it is concluded that fibrin sealing of the colonic anastomosis in the rat does not improve healing. as demonstrated by bursting pressure and hydroxyproline concentration. On the contrary. it seems to have a negative influence.
Primary papillary carcinoma of a thyroglossal duct cyst: report of a case and literature review, Thyroglossal duct cysts are the most common anomaly in thyroid development. They are twice as frequent as branchial cleft abnormalities and. in children. are second only to enlarged cervical lymph nodes as the cause of neck mass. Generally. duct cysts are benign. but 1 per cent of cases may be malignant. From the world literature. 114 cases of malignant thyroglossal cysts were available for review. With the addition of our own case. we discuss 115 instances of duct cysts. The different types of neoplasia described included thyroid papillary carcinoma in 81.7 per cent. mixed papillary-follicular carcinoma in 6.9 per cent. squamous cell carcinoma in 5.2 per cent. follicular and adenocarcinoma in 1.7 per cent each. and malignant struma. epidermoid carcinoma and anaplastic carcinoma in 0.9 per cent each. Of the 115 cases surveyed. 35 thyroid glands were examined microscopically; of these. four (11.4 per cent) contained malignant foci. Whether these are primary malignancies of the thyroglossal duct cysts or metastases is discussed.
Neuroacanthocytosis. A clinical, haematological and pathological study of 19 cases, Nineteen cases are described. including 12 cases from three different families and 7 nonfamilial cases. in which multisystem neurological disease was associated with acanthocytosis in peripheral blood and normal plasma lipoproteins. Mild acanthocytosis can easily be overlooked. and scanning electron microscopy may be helpful. Some neurologically asymptomatic relatives with significant acanthocytosis were identified during family screening. including some who were clinically affected. The mean age of onset was 32 (range 8-62) yrs and the clinical course was usually progressive but there was marked phenotypic variation. Cognitive impairment. psychiatric features and organic personality change occurred in over half the cases. and more than one-third had seizures. Orofaciolingual involuntary movements and pseudobulbar disturbance commonly caused dysphagia and dysarthria that was sometimes severe. but biting of the lips or tongue was rarely seen. Chorea was seen in almost all symptomatic cases but dystonia. tics. involuntary vocalizations and akinetic-rigid features also occurred. Two cases had no movement disorder at all. Computerized tomography often demonstrated cerebral atrophy. Caudate atrophy was seen less commonly. and nonspecific focal and symmetric signal abnormalities from the caudate or lentiform nuclei were seen by magnetic resonance imaging in 3 out of 4 cases. Depression or absence of tendon reflexes was noted in 13 cases and neurophysiological abnormalities often indicated an axonal neuropathy. Sural nerve biopsies from 3 cases showed evidence of a chronic axonal neuropathy with prominent regenerative activity. predominantly affecting the large diameter myelinated fibres. Serum creatine kinase activity was increased in 11 cases but without clinical evidence of a myopathy. Postmortem neuropathological examination in 1 case revealed extensive neuronal loss and gliosis affecting the corpus striatum. pallidum. and the substantia nigra. especially the pars reticulata. The cerebral cortex appeared spared and the spinal cord showed no evidence of anterior horn cell loss. Two examples of the McLeod phenotype. an X-linked abnormality of expression of Kell blood group antigens. were identified in a single family and included 1 female. The genetics of neuroacanthocytosis are unclear and probably heterogeneous. but the available pedigree data and the association with the McLeod phenotype suggest that there may be a locus for this disorder on the short arm of the X chromosome.
Idiopathic intracranial hypertension. A prospective study of 50 patients, Management of patients with idiopathic intracranial hypertension (IIH) should be based on the presence and progression of visual loss. To characterize the clinical course of IIH more completely. we monitored the clinical status. especially visual function. in 50 consecutive newly-diagnosed patients over a period of 2 to 39 months (average follow-up 12.4 months). The mean age at onset of symptoms was 31 (range 11-58) yrs; 46 (92%) were women and 47 (94%) were obese (mean weight 90 kg). Common symptoms were headache (92%). transient visual obscurations (72%) and intracranial noises (60%); 13 of the patients (26%) initially had complaints of sustained visual loss. There was visual loss as determined by Goldmann perimetry in 96% and by automated perimetry in 92%. Contrast sensitivity testing was abnormal in 50% and Snellen acuity in 22%. Two patients (4%) became blind in both eyes. The Goldmann visual field grade improved in 60% of patients but visual function deteriorated in 5 (10%). Deterioration of visual field grade was significantly associated only with weight gain during the year before diagnosis. Visual loss in patients with IIH is common and is often reversible. Patients should be evaluated by perimetry using an appropriate strategy and contrast sensitivity testing. along with careful examination of the optic discs.
Dual task performance and processing resources in normal subjects and patients with Parkinson's disease, In recent years. there has been a growing consensus among investigators that the presence or absence of external cues guiding behaviour and attention is an important factor in determining whether or not deficits are found in patients with Parkinson's disease (PD). In an earlier study. the authors suggested that the pattern of impaired and intact performance could be explained in terms of differential resource demands of the tasks. combined with depleted levels of central processing resources in PD patients. Two experiments are reported. both employing dual-task paradigms. The first assessed. in normal subjects. the relative processing demands of a cued and an uncued version of the Stroop task. The results supported the proposal that the noncued task made greater demands on the subject's limited processing resources. Further. performing a resource demanding secondary task concurrently with the Stroop test produced. in normal subjects. the same pattern of impaired performance as that reported previously in PD patients. In the second experiment the same dual-task paradigm was employed with a group of PD patients and normal aged-matched controls. Only the patients showed an increase in reaction time on the Stroop task when performing a resource demanding secondary task. The patients also showed an interfering effect with concurrent foot tapping but not with an articulatory suppression task. The results were taken to support the hypothesis that PD patients have depleted central processing resources. In considering the present data. alternative explanations for the results are considered. in particular the possibility that they represent a deficit in switching processing resources between two tasks as the combined demands outweigh available resources.
The mechanism of spastic muscle hypertonus. Variation in reflex gain over the time course of spasticity, The electromyographic (EMG) response of the initially passive biceps brachii muscle to imposed extension applied at the elbow was studied in 19 hemiparetic and 12 normal subjects. In relaxed normal subjects. the biceps muscle was found to respond only at displacement velocities above 175 deg/s. with a single early burst of activity in the biceps EMG. In contrast. the hemiparetic subjects. in addition to the early EMG activity. also showed considerable late activity. which persisted even with stretch velocities as low as 35 deg/s. This late activity is a stretch reflex. present in fully plegic arms. It was seen in all spastic subjects in whom the tone of the biceps had been clinically assessed to be raised. but was never observed in subjects with normal muscle tone. The mean level of this EMG response was highly correlated with displacement velocity and its duration to the duration of the applied displacement. It is suggested that this reflex EMG activity is the major factor in the genesis of spastic hypertonus in the arm and that it arises not from a reduction in the threshold of the stretch reflexes of the muscle. but from a pathological increase in stretch reflex gain. It is further shown that this activity is at a high level between the first and third months after the onset of spasticity and that the reflex gain is significantly reduced when spasticity is established for a year or more. It is concluded that. while changes in passive mechanical properties may play a role when spasticity has been established for more than a year. the major cause of spastic muscle hypertonus is a pathological increase in stretch reflex activity.
Short-term memory and sentence comprehension. An investigation of a patient with crossed aphasia, The relationship between short-term memory impairment and sentence comprehension is explored in a right-handed patient with a focal temporoparietal lesion of the right hemisphere. The general clinical profile. as well as characteristics of the patient's immediate memory for word lists. suggests the occurrence of a 'mirror image' crossed aphasia. Detailed analysis of the patient's ability to repeat and to comprehend sentences. however. indicates some important differences between this case and previously reported patients with short-term memory impairment. It is suggested that these differences. which may be related to an unusual pattern of neuroanatomical organization of cognitive functions. involve symptom dissociations with implications for models of normal language/memory interactions.
Task-dependent variations in parkinsonian motor impairments, Studies of visually-guided arm movements in patients with Parkinson's disease (PD) have suggested a relationship between slowness of movement and a reduction in the ratio of movement amplitude and peak velocity. Recent studies indicate. however. that PD impairments may be different for well-learned. natural movements performed without visual guidance. or movements associated with sequential motor behaviours such as speech. To address this issue. PD subjects and age/sex-matched controls were compared on the performance of three tasks. all of which required lowering the jaw: (1) single. rapid. visually-guided movements; (2) equivalent movements associated with a single speech syllable (inherently without visual guidance). and (3) well-learned speech movements produced in a natural sequence. PD subjects manifested similar deficits for visually-guided jaw lowering as those previously reported for arm movements. namely reduced velocity/amplitude ratios and increased movement durations. By contrast. analogous jaw movements during the sequential speech tasks were unimpaired on these measures. These results suggest that PD motor impairments are influenced by a variety of factors. including the degree to which tasks are familiar and natural. and the availability of visual information.
Effects of anticonvulsant treatment and low levels of folate and thiamine on amine metabolites in cerebrospinal fluid, A total of 157 epileptic patients were studied with respect to (1) biogenic amine precursors and metabolites in the CSF. (2) levels of folate and thiamine in the blood and CSF. (3) length of treatment with phenytoin (PHT). (4) PHT intoxication. (5) CNS atrophy. Alterations in CSF amine metabolite levels were related primarily to PHT intoxication. and low CSF folate and thiamine levels. but not to length of treatment or CNS atrophy. PHT intoxication increased CSF 5-hydroxyindoleacetic acid (5HIAA). Low folate levels were associated with decreased CSF 5HIAA and homovanillic acid. while low thiamine levels were associated with decreased CSF 5HIAA and 3-methyoxy-4-hydroxyphenylethylene glycol. It remains to be seen to what extent these alterations in biogenic amine metabolism. mediated by low CNS vitamin levels. also lead to deficits in cerebral function.
Human olfactory discrimination after unilateral frontal or temporal lobectomy, Olfactory discrimination and detection was studied in 106 patients with unilateral cerebral excision in the right or left temporal lobe. right or left frontal lobe. left parietal lobe. or right frontal and temporal lobes. and in 20 normal control subjects. Detection thresholds for n-butyl alcohol. measured separately in each nostril. did not differ across subject groups or across nostrils. thus excluding any primary sensory loss. The discrimination task involved monorhinal presentation of repairs of unfamiliar odorants. which the subjects judged as same or different in quality. The results showed a significant deficit in discrimination confined to the nostril ipsilateral to the lesion in patients with temporal lobe removals. Patients with frontal lobe excisions were also impaired and. for patients with right frontal lesions including the orbital cortex. the impairment was found in both nostrils. Patients with left parietal lesions did not demonstrate any significant deficits. Normal subjects showed consistently better performance in the right than in the left nostril. The results are interpreted as reflecting the importance of the orbitofrontal cortex in olfactory discrimination. Temporal lobe lesions may disrupt the input to the orbitofrontal cortex. thereby producing poorer performance. The nostril difference in the normal subjects. together with the birhinal impairment in patients with right orbitofrontal damage. suggest a relative advantage of the right orbital region in olfactory processing.
Muscle performance, voluntary activation, twitch properties and perceived effort in normal subjects and patients with the chronic fatigue syndrome, The decrease in maximal force-generating capacity. the degree of central activation of the muscle. and the subjective perception of effort were measured during prolonged submaximal isometric exercise in 12 male patients suffering from the 'chronic fatigue syndrome' and 13 naive. healthy male subjects. Maximal voluntary isometric torque generated by the elbow flexors was measured before. and at 5 min intervals during an endurance sequence of 45 min of repetitive isometric contractions (6 s duration. 4 s rest interval) producing 30% of the initial maximal voluntary torque. Electrical stimuli were also delivered to the elbow flexors to measure the contractile force in the intervals between voluntary contractions. The degree of central motor activation during maximal voluntary contractions was assessed using a sensitive method of twitch interpolation. In addition. the perceived effort required to achieve the target submaximal contractions was recorded using a standardized self-report scale. A high degree of central activation was achieved in maximal contractions during the endurance sequence both in the patients (mean of maximal force 93.6%; SD 7.8%). and in the control subjects (mean 90.9%; SD 9.5%). The relative torque produced by either voluntary or electrically stimulated contractions was not significantly different between patients and control subjects throughout the test. There was no significant difference in the perceived exertion between the patients and control subjects. These findings support the concept that neither poor motivation. nor muscle contractile failure is important in the pathogenesis of 'fatigue' in patients with the chronic fatigue syndrome.
Sequencing in Parkinson's disease. Abnormalities in programming and controlling movement, Central programming deficits in Parkinson's disease (PD) were studied in two reaction time (RT) experiments. In Experiment 1. PD patients and controls performed sequences of hand postures that varied in length. the number of different postures (repetitive vs heterogeneous). and the delay interval before movement. Before movement. the PD group planned repetitive movements like controls whereas for heterogeneous sequences RT increased less with sequence length for the PD group. implying less preprogramming. The interresponse time (IRT) data from repetitive sequences showed that the PD group had difficulty controlling movement such that IRTs were faster when sequences were longer. thus allowing more time to schedule the termination of the sequence during the course of movement. For heterogeneous sequences. the PD group made more errors and were slower than controls when changing hand postures. suggesting a deficit in switching between different responses. While RT decreased with a longer delay similarly for both groups. IRT1 continued to improve only for the PD group but similarly for both types of sequences. suggesting a deficit specific to programming the first response. In Experiment 2. subjects made decisions about the number of different hand postures contained within a sequence. PD patients' decision times improved more with a longer delay only for heterogeneous sequences. suggesting a problem in identifying the number of different hand postures. The results have implications for levels of motor dysfunction in PD which emphasize the influence of sequence length and complexity.
Effect of educational program and interview on adoption of guidelines for the management of neonatal hyperbilirubinemia, OBJECTIVES: To determine (a) whether physicians are adhering to the guidelines for the management of neonatal hyperbilirubinemia. (b) what influences their decisions to investigate and treat the condition and (c) the effect of an educational program and clinical recall interview on compliance with the guidelines. DESIGN: Retrospective chart audit. SETTING: Urban tertiary care hospital. PARTICIPANTS: All term neonates who received phototherapy but were not admitted to the neonatal intensive care unit. INTERVENTIONS: Educational program and clinical recall interview. MEASURES: Charts were reviewed from March to May 1986 (period I. before publication of the guidelines) and from November 1986 to January 1987 (period II. after publication and after the educational program). The audits were repeated from April to June 1989 (period III. during the interview phase) and from October to December 1989 (period IV. 6 months after the interviews). Two criteria determined the appropriate use of phototherapy: the serum bilirubin level and the postnatal day on which phototherapy was started. RESULTS: The proportion of infants receiving phototherapy for whom there were orders for complete blood counts to investigate hyperbilirubinemia increased from 20% in period I to 37% in period IV. The frequency of orders to determine the proportion of reticulocytes did not change significantly. The number of infants receiving phototherapy decreased over the study periods. The proportion receiving phototherapy in accordance with the criteria for the serum bilirubin level increased from 10% to 17% after the educational program (insignificant difference) and to 31% after the interviews (p = 0.02). Compliance with the guidelines was greater before the infants were 2 days old than when they were 3 days old or more (p = 0.01). Of the 45 physicians who prescribed phototherapy (for 94 infants) during period IV 26 never prescribed in accordance with the guidelines. The other 19 prescribed in accordance with the guidelines for 30 of 52 infants. Decisions to investigate and treat with phototherapy were affected by clinical and parental factors in addition to the guidelines. Two of the 25 physicians interviewed stated that the interview would influence their management of future cases of hyperbilirubinemia. CONCLUSION: A clinical recall interview can have a greater impact on changing physician management practices than factual communication on a group basis.
Serious childhood injuries caused by air guns, OBJECTIVE: To determine the severity of nonfatal injuries to children caused by air guns and pellet guns. DESIGN: Case series (hospital chart review). SETTING: Inpatient wards of the Children's Hospital of Eastern Ontario. PATIENTS: All children under 18 years of age admitted to the hospital from Jan. 1. 1979. to Dec. 31. 1989. under ICD code E917. E922. E955. E965. E970 or E985 who had suffered air gun injuries. MAIN OUTCOME MEASURES: Personal data. circumstances of event and clinical data. RESULTS: The 43 children (37 boys) had a median age of 12 years. The circumstances of the accident were known in 20 cases: 17 children were playing and 3 were cleaning the gun when it went off. Four children thought the gun was unloaded. In five cases the bullet ricocheted into the eye. Nine injuries were self-inflicted. Injury was to the extremities in 21 (49%). the eyes in 15 (35%) and the head and neck in 7 (16%). The median length of hospital stay was 4 days. Six children had long-term disabilities. all the result of eye injuries; two had cataract surgery. and four required enucleation of the eye. CONCLUSIONS: Air guns can cause serious injury to children. Their sale needs to be banned or at least carefully regulated.
Diagnosis of sulfite and aspirin sensitivity, In addition to the well-recognized allergic responses of individuals to high mol wt substances. such as pollens. molds. and animal dander. susceptible asthmatics may also experience adverse reactions to low mol wt substances such as sulfites. ASA. and NSAIDs. The diagnosis of sulfite and aspirin sensitivity can only be made by appropriately conducted provocative challenge. Every precaution should be taken to assure the safety of the patients. since life-threatening reactions can occur. A better understanding of the mechanism or mechanisms involved in the adverse reactions to these substances will not only provide information to better diagnose the reaction. but also improve our understanding of the treatment of asthma.
Using pulmonary function testing in the diagnosis and treatment of asthma, Asthmatics have remarkable changes in their pulmonary function in response to numerous external stimuli and internal controls. Serial pulmonary function testing in the office. hospital. at home. or the work place allows the objective measurement that is necessary to intelligently diagnose and treat these patients. Once the patient and the physician understand how to use the techniques for monitoring the degree of airways obstruction. they become a key in medical management decisions.
Exercise testing in the assessment of pulmonary disease, In this chapter. the different types of exercise tests and the indications for requesting a particular type of test have been discussed. The normal physiological responses to exercise have been reviewed and examples of the abnormal responses seen in a variety of disease states that have been discussed. The relatively small number of these responses limits the specificity of exercise tests in actually establishing a diagnosis. but can be helpful in narrowing the differential diagnosis. Perhaps exercise tests are most valuable in cases where the patient's symptoms are mainly limited to exercise and where investigations done at rest have failed to resolve a diagnostic question. When exercise testing is used under these circumstances. it serves a unique function in the diagnosis and management of pulmonary disease.
Bronchoalveolar lavage, The technique of BAL performed through the fiberoptic bronchoscope has. in two decades. provided clinicians and researchers with the ability to safely sample the inflammatory-immune cell milieu of the human lung. Standardized BAL and processing of the lavage constituents provides assistance in determining the optimal care of patients with a variety of lung diseases. and renders diagnosis in selected cases. It has become indispensable in the diagnosis of pulmonary infiltrates in immunocompromised patients. and plays an important role in improving clinical management. Finally. it continues to yield an ever increasing amount of data for the researchers studying the mechanisms and pathogenesis of lung disease. It is likely that BAL will become an even more valuable tool with increasing relevance to the practice of chest medicine in the 1990s.
Treatment with deferoxamine during ischemia improves functional and metabolic recovery and reduces reperfusion-induced oxygen radical generation in rabbit hearts, BACKGROUND. Iron may play a central role in oxygen radical generation during myocardial ischemia and after reperfusion. Because conditions during ischemia may also liberate iron. we hypothesized that administration of the iron chelator deferoxamine during ischemia would result in improved functional and metabolic recovery after postischemic reperfusion. METHODS AND RESULTS. Isolated. perfused rabbit hearts were studied by phosphorus-31 nuclear magnetic resonance spectroscopy. The hearts received one of three treatments: deferoxamine at the onset of 30 minutes of global ischemia (n = 9). deferoxamine as a bolus followed by a continuous 15-minute infusion begun at reflow (n = 9). or standard perfusate (n = 7). Hearts treated with deferoxamine during ischemia showed better recovery of developed pressure than did control hearts (63.2 +/- 7.5% versus 41.2 +/- 2.9% of baseline) (p = 0.02) and better recovery of myocardial phosphocreatine content (92.4 +/- 10.3% versus 68.2 +/- 4.5% of baseline. p less than 0.05). These functional and metabolic benefits were comparable to those obtained with deferoxamine treatment during early reperfusion. In 15 additional hearts. intraischemic treatment with deferoxamine resulted in no reduction in oxygen radical concentrations as measured on frozen tissue by electron paramagnetic resonance spectroscopy at end ischemia. but the treatment eliminated the reperfusion-induced increase of free radical generation observed in control hearts (2.9 +/- 0.01 versus 7.0 +/- 0.07 microM. p less than 0.001). The magnitude of reduction was similar to that when deferoxamine was given at the onset of reflow (2.4 +/- 0.02 microM. p less than 0.001 versus control). CONCLUSIONS. These results demonstrate improved functional and metabolic recovery of myocardium treated with deferoxamine during ischemia. accompanied by a reduction in reperfusion-induced oxygen free-radical generation to the same degree as reflow treatment. confirming the importance of iron in the pathogenesis of myocardial reperfusion injury.
Myocardial infarct size-limiting effect of ischemic preconditioning was not attenuated by oxygen free-radical scavengers in the rabbit, BACKGROUND. The limiting effect of ischemic preconditioning on infarct size has been reported in canine hearts. which contain considerable amounts of xanthine oxidase. a free radical-producing enzyme. Furthermore. a recent study suggested that free radicals generated during preconditioning may contribute to the cardioprotective effect of preconditioning. The present study examined 1) whether preconditioning limits infarct size in rabbits. which. like humans. lack myocardial xanthine oxidase and 2) whether the cardioprotective effect of PC is mediated by free radicals. METHODS AND RESULTS. A branch of the circumflex coronary artery in rabbits was occluded for 30 minutes and then reperfused for 72 hours. Myocardial infarct size and area at risk were determined by histology and fluorescent particles. respectively. Five groups were studied: an untreated control group. a preconditioned group (PC group). a high-dose superoxide dismutase (SOD)-treated preconditioned group (high-dose SOD-PC group). a low-dose SOD-treated preconditioned group (low-dose SOD-PC group). and a SOD-plus-catalase-treated preconditioned group (SOD/CAT-PC group). Preconditioning was performed with four episodes of 5 minutes of ischemia and 5 minutes of reperfusion. The free radical scavengers (30.000 units/kg SOD for high-dose SOD-PC group. 15.000 units/kg SOD for low-dose SOD-PC group. and 30.000 units/kg SOD plus 55.000 units/kg catalase for SOD/CAT-PC group) were infused intravenously over 60 minutes starting 20 minutes before preconditioning. Infarct size as the percentage of area at risk was 45.1 +/- 3.5% (mean +/- SEM) in the control group (n = 11). 13.3 +/- 3.0% in the PC group (n = 12). 9.7 +/- 1.8% in the high-dose SOD-PC group (n = 8). 11.9 +/- 2.2% in the low-dose SOD-PC group (n = 6). and 9.6 +/- 2.3% in the SOD/CAT-PC group (n = 6) (p less than 0.05 versus control for the last four values). The differences in infarct size as the percent of area at risk among the PC. high-dose SOD-PC. low-dose SOD-PC. and SOD/CAT-PC groups were not significant. CONCLUSION. Ischemic preconditioning delays ischemic myocardial necrosis regardless of myocardial xanthine oxidase content. Free radicals are unlikely to have a major role in the mechanism of the preconditioning in rabbits.
Transvascular intracardiac applications of a miniaturized phased-array ultrasonic endoscope. Initial experience with intracardiac imaging in piglets, BACKGROUND. Recent advances in miniaturization of phased-array and mechanical ultrasound devices have resulted in exploration of alternative approaches to cardiac and vascular imaging in the form of transesophageal or intravascular imaging. Preliminary efforts in adapting phased-array endoscopes designed for transesophageal use to a transvascular approach have used full-sized phased-array devices introduced directly into the right atrium in open-chested animals. The purpose of this study was to assess the feasibility of using a custom-made. very small phased-array endoscope for intracardiac imaging introduced intravascularly through a jugular venous approach in young piglets. METHODS AND RESULTS. Experimental atrial septal defects created in four piglets (3-4 weeks old) had been closed with a buttoned atrial septal defect closure device consisting of an occluder in the left atrium and a counteroccluder in the right atrium. Five to 15 days after atrial septal defect closure. the piglets were returned to the experimental laboratory. where a 6.3-mm. 17-element. 5-MHz phased-array probe mounted on a 4-mm endoscope was introduced through a cutdown incision of the external jugular vein and advanced to the right atrium. From the right atrium all four cardiac chambers. their inflows and outflows. and all four valves were well imaged with minimal superior and inferior rotation. High-resolution imaging of the atrial septum defined with anatomical accuracy. later verified by autopsy. the exact placement of both the occluder and counteroccluder in the left and right sides of the atrial septal defects and the absence of any shunting across the atrial septum in any of the four animals. CONCLUSIONS. Our efforts indicate that transvascular passage of small phased-array probes can be easily accomplished and is a promising technique for detailed visualization of cardiac structures. This approach may provide an alternative to transesophageal echocardiography. particularly for guiding interventional procedures such as placement of transcatheter closure devices in pediatric patients.
Contractility and stiffness of noninfarcted myocardium after coronary ligation in rats. Effects of chronic angiotensin converting enzyme inhibition, BACKGROUND. Previous studies have shown that global left ventricular function is depressed after myocardial infarction. However. little is known about the effects of myocardial infarction on contractility and the passive-elastic properties of residual myocardium. METHODS AND RESULTS. We evaluated isometric function and passive myocardial stiffness in isolated. noninfarcted left ventricular papillary muscle from rats 6 weeks after sham operation or myocardial infarction. Maximal developed tension and peak rate of tension rise (+dT/dt) were significantly decreased in untreated rats with large myocardial infarction compared with controls (3.3 +/- 1.1 versus 4.3 +/- 0.6 g/mm2 and 49.5 +/- 17.5 versus 72.5 +/- 10.5 g/mm2/sec. respectively). Time to peak tension was prolonged (120 +/- 8 versus 102 +/- 4 msec) and myocardial stiffness was increased in untreated myocardial infarction rats compared with controls (35.2 +/- 4.9 versus 24.2 +/- 3.7). Rats with smaller myocardial infarctions differed from controls only with respect to a prolongation of time to peak tension. Papillary muscle myocyte cross-sectional area was increased by 44% (p less than 0.05). and myocardial hydroxyproline content was increased by 160% (p less than 0.05) in rats with large myocardial infarctions compared with controls. To determine whether treatment that improves left ventricular function after myocardial infarction also improves myocardial function. rats were treated with captopril beginning 3 weeks after myocardial infarction and continuing for 3 weeks. Treatment with captopril attenuated the prolongation in time to peak tension in the myocardial infarction rats; however. developed tension. +dT/dt. and muscle stiffness remained abnormal. Compared with untreated myocardial infarction rats. captopril-treated myocardial infarction rats had a 9% decrease in myocyte cross-sectional area (p = 0.1) but a persistent increase in myocardial collagen content. In summary. large myocardial infarction in rats causes contractile dysfunction. increased stiffness. myocyte hypertrophy. and increased collagen content in the residual noninfarcted myocardium. Treatment with captopril alters the process of cardiac remodeling and hypertrophy and improves one parameter of contractility in noninfarcted myocardium; however. myocardial collagen content and myocardial stiffness remain abnormal. CONCLUSIONS. These findings suggest that angiotensin converting enzyme inhibition in the rat infarct model of heart failure improves global cardiac performance via combined effects on myocardial function and the peripheral circulation.
Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta, BACKGROUND. Reduced synthesis of endothelium-derived relaxing factor (EDRF) may explain impaired endothelium-dependent vasodilation in hypercholesterolemia. Accordingly. we designed studies to determine if endothelium-dependent relaxation in hypercholesterolemic rabbits may be restored by supplying L-arginine. the precursor of EDRF. METHODS AND RESULTS. Normal or hypercholesterolemic rabbits received intravenous L-arginine (10 mg/kg/min) or vehicle for 70 minutes. Subsequently. animals were killed. thoracic aortas were harvested. and vascular rings were studied in vitro. Rings were contracted by norepinephrine and relaxed by acetylcholine chloride or sodium nitroprusside. Vasorelaxation was quantified by determining the maximal response (expressed as percent relaxation of the contraction) and the ED50 (dose of drug inducing 50% relaxation; expressed as -log M). In vessels from hypercholesterolemic animals receiving vehicle. there was a fivefold rightward shift in sensitivity to acetylcholine compared with normal animals (p = 0.05. n = 5 in each group). In vessels from hypercholesterolemic animals. L-arginine augmented the maximal response to acetylcholine (83 +/- 16% versus 60 +/- 15%. p = 0.04 versus vehicle) and increased the sensitivity to acetylcholine (ED50 value: 6.7 +/- 0.2 versus 6.2 +/- 0.2. p less than 0.05 versus vehicle). Arginine did not affect maximal and EC50 responses to acetylcholine in vessels from normal animals. Arginine did not potentiate endothelium-independent responses in either group. CONCLUSIONS. We conclude that the endothelium-dependent relaxation is normalized in hypercholesterolemic rabbit thoracic aorta by in vivo exposure to L-arginine. the precursor for EDRF.
Coronary blood flow in dogs with contractile dysfunction due to experimental volume overload, BACKGROUND. Abnormalities in coronary blood flow are responsible for stress-induced reductions in contractile function in pressure overload hypertrophy. Less is known about coronary blood flow in volume overload. In this study. we tested the hypothesis that coronary blood flow abnormalities were responsible for contractile abnormalities in experimental volume overload hypertrophy. METHODS AND RESULTS. We examined coronary blood flow at rest and during pacing in seven dogs with contractile dysfunction secondary to chronic experimental mitral regurgitation (average regurgitant fraction at 3 months. 0.58 +/- 0.05). After 3 months of mitral regurgitation. left ventricular mass had increased from 92 +/- 8 g at baseline to 118 +/- 10 g (p less than 0.002). The slope of the end-ejection stress-volume relation. one of our indexes used to estimate contractile function. had fallen from 5.4 +/- 0.3 at baseline to 3.0 +/- 0.3 at 3 months of mitral regurgitation (p less than 0.001). In the mitral regurgitation dogs. coronary blood flow at rest was similar to that of control dogs (endocardial blood flow: control dogs. 1.33 +/- 0.12 ml/min/g; mitral regurgitation dogs. 1.16 ml/min/g. p = NS; epicardial blood flow at rest: control dogs. 1.30 +/- 0.16 ml/min/g; mitral regurgitation dogs 1.13 +/- 0.2 ml/min/g. p = NS). With pacing-induced stress. coronary blood flow increased appropriately in control and mitral regurgitation dogs. Ultrasonic dimension gauges placed in the endocardium and epicardium demonstrated no further deterioration in ventricular function during pacing in the mitral regurgitation dogs. In a separate group of five control dogs and five dogs with mitral regurgitation and left ventricular dysfunction. coronary blood flow was examined in the conscious closed-chest state at rest. during adenosine infusion. and during rapid atrial pacing (240 beats/min). Blood flow increased similarly in both groups during pacing and adenosine infusion. CONCLUSIONS. We conclude that in dogs with mitral regurgitation that have developed contractile dysfunction. abnormalities in coronary blood flow do not explain the resting contractile dysfunction. Furthermore. studies during pacing-induced stress and coronary vasodilation with adenosine demonstrate that substantial coronary blood flow reserve is present in this type of volume overload hypertrophy.
Myocardial perfusion-contraction matching. Implications for coronary heart disease and hibernation, Experimental studies demonstrate that short-term regional perfusion-contraction matching. in which the energy demands of regional myocardial contraction are reduced to match the diminished myocardial substrate supply. occurs during states of low coronary blood flow under resting conditions and during exercise-induced ischemia. This phenomenon is rapidly reversible and appears to occur in several clinical settings. Sustained perfusion-contraction matching is observed in states of partial experimental ischemia of intermediate duration lasting several hours. This condition might be called short-term hibernation and resembles clinical conditions such as unstable angina pectoris or myocardial infarction with some residual perfusion in which the contractile defect can be improved by reperfusion provided the ischemia is not severe enough to cause transmural necrosis. Such experimental and clinical observations may or may not relate to the setting of regional dysfunction at rest in patients with chronic coronary heart disease. in whom manifestations of acute ischemia may be absent but improvement of wall motion abnormalities occurs after CABG or balloon angioplasty. This condition may constitute the hypothetical state of chronic myocardial hibernation. for which tentative evidence exists from metabolic and perfusion studies using PET. Whether such a condition of prolonged perfusion-contraction matching might be associated with adaptive processes that could allow its persistence for long periods without manifest ischemia remains to be investigated.
Ten-year incidence of myocardial infarction and prognosis after infarction. Department of Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery, BACKGROUND. The 10-year incidence of myocardial infarction (fatal and nonfatal) and the prognosis after infarction were evaluated in 686 patients with stable angina who were randomly assigned to medical or surgical treatment in the Veterans Administration Cooperative Study of Coronary Artery Bypass Surgery. METHODS AND RESULTS. Myocardial infarction was defined by either new Q wave findings or clinical symptoms compatible with myocardial infarction accompanied by serum enzyme elevations with or without electrocardiographic findings. Treatment comparisons were made according to original treatment assignment; 35% of the medical cohort had bypass surgery during the 10-year follow-up period. The overall cumulative infarction rate was somewhat higher in patients assigned to surgery (36%) than in medical patients (31%) (p = 0.13) due to perioperative infarctions (13%) and an accelerated infarction rate after the fifth year of follow-up (average. 2.4%/yr in the surgical group versus 1.4%/yr in the medical group). The 10-year cumulative incidence of death or myocardial infarction was also higher in surgical (54%) than in medical (49%) patients (p = 0.20). According to the Cox model. the estimated risk of death after infarction was 59% lower in surgical than in medical patients (p less than 0.0001). The reduction in postinfarction mortality with surgery was most striking in the first month after the event: 99% in the first month (p less than 0.0001) and 49% subsequently (p less than 0.0001). The estimated risk of death in the absence of infarction was nearly identical regardless of treatment (p = 0.75). Exclusion of perioperative infarctions did not alter the findings. CONCLUSIONS. Although surgery does not reduce the incidence of myocardial infarction overall. it does reduce the risk of mortality after infarction. particularly in the first 30 days after the event (fatal infarctions).
Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure, BACKGROUND. Optimal timing of cardiac transplantation in ambulatory patients with severe left ventricular dysfunction is often difficult. To determine whether measurement of peak oxygen consumption (VO2) during maximal exercise testing can be used to identify patients in whom transplantation can be safely deferred. we prospectively performed exercise testing on all ambulatory patients referred for transplant between October 1986 and December 1989. METHODS AND RESULTS. Patients were assigned into one of three groups on the basis of exercise data: Group 1 (n = 35) comprised patients accepted for transplant (VO2 less than or equal to 14 ml/kg/min); group 2 (n = 52) comprised patients considered too well for transplant (VO2 greater than 14 ml/kg/min); and group 3 (n = 27) comprised patients with low VO2 rejected for transplant due to noncardiac problems. All three groups were comparable in New York Heart Association functional class. ejection fraction. and cardiac index (p = NS). Pulmonary capillary wedge pressure was significantly lower in group 2 than in either group 1 or 3 (p less than 0.05). although there was wide overlap. Patients with preserved exercise capacity (group 2) had cumulative 1- and 2-year survival rates of 94% and 84%. which are equal to survival levels after transplantation. In contrast. patients rejected for transplant (group 3) had survival rates of only 47% at 1 year and 32% at 2 years. whereas patients awaiting transplantation (group 1) had a survival rate of 70% at 1 year (both p less than 0.005 versus patients with VO2 greater than 14 ml/kg/min). All deaths in group 2 were sudden. By univariate and multivariate analyses. peak VO2 was the best predictor of survival. with only pulmonary capillary wedge pressure providing additional prognostic information. CONCLUSIONS. These data suggest that cardiac transplantation can be safely deferred in ambulatory patients with severe left ventricular dysfunction and peak exercise VO2 of more than 14 ml/min/kg.
Catheter modification of the atrioventricular junction with radiofrequency energy for control of atrioventricular nodal reentry tachycardia, BACKGROUND. The utility of transcatheter application of radiofrequency energy to eliminate atrioventricular nodal reentrant tachycardia (AVNRT) was investigated. METHODS AND RESULTS. Thirty-nine patients (mean age. 53 +/- 20 years; range 14-86 years) with medically refractory AVNRT underwent perinodal ablation with radiofrequency energy. A custom-designed 6F catheter with a large (3-mm-long) distal electrode and interelectrode pacing of 2 mm was used in the majority of cases. The catheter used for ablation was initially positioned across the tricuspid anulus to obtain the largest His bundle electrogram. then withdrawn to obtain the largest atrial:ventricular electrogram ratio. with a small His bundle electrogram (less than or equal to 100 microV). Each application of radiofrequency energy (350-550 kHz. 16.2 +/- 5.2 W) was stopped after 60 seconds or if PR prolongation or an impedance rise was noted. The endpoints of the procedure were persistent modification of atrioventricular nodal conduction (either first-degree atrioventricular block or impairment of ventriculoatrial conduction) and noninducibility of AVNRT before and during isoproterenol administration. Radiofrequency energy was applied a mean of 6.8 +/- 3.5 times per session. After a mean follow-up of 8 +/- 3.0 months. 32 of the 39 patients (82%) have been free of AVNRT. and did not have high grade AV block. Three patients (8%) developed complete atrioventricular block and had pacemakers implanted. Two patients had unsuccessful initial procedures. and two patients had initially successful ablations but had recurrences of tachycardia 4-6 weeks later. Elimination of AVNRT appeared to be due to effects on the retrograde fast pathway in most patients. CONCLUSIONS. Radiofrequency ablation of the perinodal right atrium appears to be safe and effective for treatment of typical AVNRT.
Fibrinogen, viscosity, and white blood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative heart disease studies, BACKGROUND. Recent studies have suggested that hemostatic factors and white blood cell count are predictive of ischemic heart disease (IHD). The relations of fibrinogen. viscosity. and white blood cell count to the incidence of IHD in the Caerphilly and Speedwell prospective studies are described. METHODS AND RESULTS. The two studies have a common core protocol and are based on a combined cohort of 4.860 middle-aged men from the general population. The first follow-up was at a nearly constant interval of 5.1 years in Caerphilly and 3.2 years in Speedwell; 251 major IHD events had occurred. Age-adjusted relative odds of IHD for men in the top 20% of the distribution compared with the bottom 20% were 4.1 (95% confidence interval. 2.6-6.5) for fibrinogen. 4.5 (95% confidence interval. 2.8-7.4) for viscosity. and 3.2 (95% confidence interval. 2.0-4.9) for white blood cell count. Associations with IHD were similar in men who had never smoked. exsmokers. and current smokers. and the results suggest that at least part of the effect of smoking on IHD is mediated through fibrinogen. viscosity. and white blood cell count. Multivariate analysis shows that white blood cell count is an independent risk factor for IHD as is either fibrinogen or viscosity. or possibly both. Jointly. these three variables significantly improve the fit of a logistic regression model containing all the main conventional risk factors. Further. a model including age. smoking habits. fibrinogen. viscosity. and white blood cell count predicts IHD as well as one in which the three hemostatic/rheological variables are replaced by total cholesterol. diastolic pressure. and body mass index. CONCLUSION. Jointly. fibrinogen. viscosity. and white blood cell count are important risk factors for IHD.
Upward shift of the lower range of coronary flow autoregulation in hypertensive patients with hypertrophy of the left ventricle, BACKGROUND. At any given perfusion pressure. coronary reserve is expressed by the difference between autoregulated and maximally vasodilated flow. In hypertension the raised coronary resistance reduces the steepness of the pressure-flow relationship at maximal vasodilatation. In the presence of cardiac hypertrophy the line of autoregulated flow becomes higher. For these reasons coronary reserve is reduced and the point at which baseline flow approaches the maximal achievable flow might be shifted to a higher perfusion pressure. Thus. any reduction below this elevated and critical value of pressure would lower the coronary flow. METHODS AND RESULTS. The investigated patients were normotensive (controls. nine) and hypertensive with normal (group I. seven) or augmented LV mass index because of concentric LV hypertrophy (group II. eight). All had effort-induced angina and angiographically normal left epicardial branches. Flow in the great cardiac vein was measured by thermodilution in the baseline and during stepwise (5 mm Hg every 5 minutes) decrease of the coronary perfusion pressure with a titrated nitroprusside i.v. infusion; perfusion pressures of 60 mm Hg in the controls and 70 mm Hg in the hypertensives were taken as end points. Baseline flow averaged 102 ml/min in normotensives. 104 ml/min in hypertensive group I and 148 ml/min in hypertensive group II. At the end points flow was similar to baseline in the controls and group I. In group II coronary flow started to decline and myocardial O2 extraction started to slightly but significantly rise at perfusion pressures of 90-80 mm Hg; at the end point flow was reduced by 26% (p less than 0.01 from baseline). The perfusion patterns did not seem to be related to the changes in tension-time index and heart rate. CONCLUSIONS. The association of high blood pressure (reduced ability of the coronary arterioles to dilate) and hypertrophy of the myocardium (augmented baseline coronary flow) may shift the point of exhaustion of coronary reserve to a higher perfusion pressure and make the myocardium vulnerable to treatment-induced relative hypertension.
Concept of maximal flow ratio for immediate evaluation of percutaneous transluminal coronary angioplasty result by videodensitometry, BACKGROUND. In the setting of percutaneous transluminal coronary angioplasty (PTCA). immediate information about the result of the intervention is important. whereas morphological parameters are often less reliable than in diagnostic coronary arteriography. Recently. a new videodensitometric method was introduced and validated in animal experiments. which allows accurate comparison of maximal myocardial perfusion between situations with different degrees of stenosis. This method uses mean transit time (Tmn) of the contrast agent at maximal hyperemia as a parameter for maximal flow and is strictly in accordance with indicated dilation theory. METHODS AND RESULTS. In 40 patients with angina pectoris. single-vessel disease. and a positive exercise test at the time of acceptance for PTCA. this approach was applied for evaluation of the improvement of maximal flow achieved by the PTCA. Maximal vasodilation was induced immediately before and 15 minutes after PTCA by intracoronary administration of papaverine. and digital angiographic studies were performed. By special breath-holding instruction. almost motionless. triggered image acquisition was possible during 15-20 heartbeats. Excellent subtraction images could be obtained. and reliable determination of Tmn at maximal hyperemia was possible in 33 patients both before and after PTCA. The ratio between maximal flow after and before PTCA. called maximal flow ratio (MFR). was represented by the ratio between Tmn before and after the intervention and compared with the results of exercise testing 24-48 hours before and 7-10 days after the procedure. After correction for pressure changes. MFR was 2.2 +/- 1.5 for the 33 dilated vessels and 1.0 +/- 0.2 for 25 normal vessels serving as a control. In 94% of all patients. an MFR value of more than 1.6 or less than 1.6 discriminated between presence or absence of reversal of exercise test result from positive to negative. If on-line judgment of success was based upon angiographic parameters or measurement of trans-stenotic pressure gradient. the relation with noninvasive functional improvement was present only in 66% and 74% of all patients. respectively. A definite range of what can be called normal Tmn at maximal hyperemia could be distinguished. and post-PTCA values for successfully dilated arteries returned completely to this normal range. CONCLUSIONS. Accurate comparison of maximal myocardial perfusion before and after PTCA is possible in man. improvement of maximal flow is highly related to functional improvement as indicated by exercise test results. and. therefore. this method provides a straightforward way for on-line evaluation of the result of the intervention.
Heart rate adjustment of exercise-induced ST segment depression. Improved risk stratification in the Framingham Offspring Study, BACKGROUND. Simple heart rate adjustment of ST segment depression during exercise (delta ST/HR index) and the pattern of ST depression as a function of heart rate during exercise and recovery (the rate-recovery loop) have been shown to improve the ability of the exercise electrocardiogram to detect the presence of coronary heart disease (CHD). but the performance of these methods for the prediction of future coronary events remains to be examined. METHODS AND RESULTS. We compared the delta ST/HR index and the rate-recovery loop with standard electrocardiographic criteria for prediction of CHD events in 3.168 asymptomatic men and women in the Framingham Offspring Study who underwent treadmill exercise electrocardiography and who. at entry. were free of clinical and electrocardiographic evidence of CHD. After a mean follow-up of 4.3 years. there were 65 new CHD events: four sudden deaths. 24 new myocardial infarctions. and 37 incident cases of angina pectoris. When a Cox proportional hazards model with adjustment for age and sex was used. a positive exercise electrocardiogram by standard criteria (greater than or equal to 0.1 mV horizontal or downsloping ST segment depression) was not predictive of new CHD events (chi 2 = 0.40. p = 0.52). In contrast. stratification according to the presence or absence of a positive delta ST/HR index (greater than or equal to 1.6 microV/beat/min) and a positive (counterclockwise) rate-recovery loop was associated with CHD event risk (chi 2 = 9.45. p less than 0.01) and separated subjects into three groups with varying risks of coronary events: high risk. when both tests were positive (relative risk 3.6; 95% confidence interval. 2.4-5.4); intermediate risk. when either the delta ST/HR index or the rate-recovery loop was positive (relative risk. 1.9; 95% confidence interval. 1.3-2.8); and low risk. when both tests were negative. After multivariate adjustment for age. sex. smoking. total cholesterol level. fasting glucose level. diastolic blood pressure. and electrocardiographic evidence of left ventricular hypertrophy. the combined delta ST/HR index and rate-recovery loop criteria remained predictive of coronary events (chi 2 = 5.45. p = 0.02). CONCLUSIONS. Heart rate adjustment of ST segment depression by the delta ST/HR index and the rate-recovery loop during exercise electrocardiography can improve prediction of future coronary events in asymptomatic men and women.
Electrocardiographic body surface potential mapping in the Wolff-Parkinson-White syndrome. Noninvasive determination of the ventricular insertion sites of accessory atrioventricular connections, BACKGROUND. A reliable. noninvasive procedure to determine the location of accessory atrioventricular connections in patients with Wolff-Parkinson-White syndrome would add an important diagnostic tool to the clinical armamentarium. METHODS AND RESULTS. Body surface potential mapping (BSPM) using 180 electrodes in various-sized vests and displayed as a calibrated color map was used to determine the ventricular insertion site of the accessory atrioventricular (AV) connections in 34 patients with Wolff-Parkinson-White syndrome. Attempts were made to determine the 17 ventricular insertion sites described by Guiraudon et al. All 34 patients had an electrophysiologic study (EPS) at cardiac catheterization. and 18 had surgery so the ventricular insertion sites could be accurately located using EPS at surgery. A number of physiologic observations were also made with BSPM. CONCLUSIONS. The following conclusions were drawn: 1) BSPM using QRS analysis accurately predicts the ventricular insertion site of accessory AV connections in the presence of a delta wave in the electrocardiogram; 2) the ventricular insertion sites of accessory AV connections determined by BSPM and by EPS at surgery were identical or within one mapping site (1.5 cm or less) in all but four of 18 cases; three of the four exceptions had more than one accessory AV connection. and the other had a very broad ventricular insertion; 3) BSPM and EPS locations of the accessory AV connections correlated very well in the 34 cases despite the fact that BSPM determines the ventricular insertion site and EPS determines the atrial insertion site of the accessory AV connection; 4) as suggested by the three cases of multiple accessory AV connections. EPS and BSPM may be complementary since BSPM identified one pathway and EPS identified the other (in the case with a broad ventricular insertion. BSPM and EPS demonstrated different proportions of that insertion); 5) BSPM using ST-T analysis is very much less accurate in predicting the ventricular insertion site of accessory AV connections unless there is marked preexcitation; 6) standard electrocardiography using the Gallagher grid methodology (but with no attempt at stimulating maximal preexcitation) was not as accurate as QRS analysis of BSPM in predicting the ventricular insertion site of the accessory AV connection; however. exact comparison is hampered by the different number and size of the Gallagher and Guiraudon insertion sites; 7) BSPM using QRS analysis appears to be very accurate in predicting right ventricular versus left ventricular posteroseptal accessory AV connections; 8) typical epicardial right ventricular breakthrough. indicative of conduction via the specialized AV conduction system. occurs in all patients with left ventricular free wall accessory AV connections; 9) epicardial right ventricular breakthrough was not observed in cases with right ventricular free wall or anteroseptal accessory AV connections; 10) epicardial right ventricular breakthrough can occur in the presence of posteroseptal accessory AV connections. whether right or left ventricular; and 11) the delay in epicardial right ventricular breakthrough in cases with left ventricular insertion may provide a marker to estimate the degree of ventricular preexcitation.
Diagnostic efficiency of troponin T measurements in acute myocardial infarction, BACKGROUND. The present study was designed to evaluate the efficiency of a newly developed troponin T enzyme immunoassay for the detection of acute myocardial infarction. METHODS AND RESULTS. The study comprised 388 patients admitted with chest pain and suspected myocardial infarction and 101 patients with skeletal muscle damage and additional suspected myocardial cell damage. Troponin T was elevated to more than twice the analytical sensitivity of the assay (0.5 microgram/l) in all patients with non-Q wave (range. 1.2-5 micrograms/l) and Q wave infarction (range. 3-220 micrograms/l). Troponin T appeared in serum as early as 3 hours after onset of pain in 50% of the patients and remained elevated in all patients for more than 130 hours. revealing release kinetics of both free cytosolic and structurally bound molecules. The diagnostic efficiency of troponin T was superior to that of creatine kinase-MB (98% versus 97%) and remained at 98% until 5.5 days after admission. if patients with unstable angina were excluded from analysis. In the 79 patients with unstable angina. troponin T was elevated (range. 0.55-3.1 micrograms/l) in at least one blood sample from each of 37 patients (56%). Circulating troponin T was correlated to the presence of reversible ST segment or T wave changes on the electrocardiogram (p less than 0.005) and to the frequency of in-hospital complications. In the 101 patients with skeletal muscle damage and suspected additional cardiac muscle damage. troponin T was the most useful test; its efficiency was 89% or 94% (depending on the discriminator value used) as compared with 63% for creatine kinase-MB. CONCLUSIONS. Thus. the data of the study indicate that the newly developed troponin T test improves the efficiency of serodiagnostic tools for the detection of myocardial cell necrosis as compared with conventionally used cardiac enzymes.
Intravascular ultrasound imaging of human coronary arteries in vivo. Analysis of tissue characterizations with comparison to in vitro histological specimens, BACKGROUND. Intravascular ultrasound imaging was performed in 27 patients after coronary balloon angioplasty to quantify the lumen and atheroma cross-sectional areas. METHODS AND RESULTS. A 20-MHz ultrasound catheter was inserted through a 1.6-mm plastic introducer sheath across the dilated area to obtain real-time images at 30 times/sec. The ultrasound images distinguished the lumen from atheroma. calcification. and the muscular media. The presence of dissection between the media and the atheroma was well visualized. These observations of tissue characterization were compared with an in vitro study of 20 human atherosclerotic artery segments that correlated the ultrasound images to histological preparations. The results indicate that high-quality intravascular ultrasound images under controlled in vitro conditions can provide accurate microanatomic information about the histological characteristics of atherosclerotic plaques. Similar quality cross-sectional ultrasound images were also obtained in human coronary arteries in vivo. Quantitative analysis of the ultrasound images from the clinical studies revealed that the mean cross-sectional lumen area after balloon angioplasty was 5.0 +/- 2.0 mm2. The mean residual atheroma area at the level of the prior dilatation was 8.7 +/- 3.4 mm2. which corresponded to 63% of the available arterial cross-sectional area. At the segments of the coronary artery that appeared angiographically normal. the ultrasound images demonstrated the presence of atheroma involving 4.7 +/- 3.2 mm2. which was a mean of 35 +/- 23% of the available area bounded by the media. CONCLUSIONS. Intravascular ultrasound appears to be more sensitive than angiography for demonstrating the presence and extent of atherosclerosis and arterial calcification. Intracoronary imaging after balloon angioplasty reveals that a significant amount of atheroma is still present. which may partly explain why the incidence of restenosis is high after percutaneous transluminal coronary angioplasty.
Alterations in left ventricular diastolic twist mechanics during acute human cardiac allograft rejection, BACKGROUND. Contraction of obliquely oriented left ventricular (LV) fibers results in a twisting motion of the left ventricle. The purpose of this study was to assess the effects of acute human cardiac allograft rejection on LV twist pattern and the twist-volume relation. METHODS AND RESULTS. Tantalum markers were implanted into the LV midwall in 15 transplant recipients to measure time-varying. three-dimensional chamber twist using computer-assisted analysis of biplane cinefluoroscopic images. Twist was defined as the mean longitudinal gradient of circumferential rotation about the LV long axis. When plotted against normalized percent ejection fraction (%EF). the resulting twist-normalized %EF relation could be divided into three phases. In systole. LV twist was linearly related to ejection of blood. In contrast. diastolic untwist was characterized by early rapid recoil with little change in LV volume. followed by more gradual untwisting when the bulk of diastolic filling occurred. During 10 acute rejection episodes in 10 patients. maximum twist. peak systolic twist rate. and the slope of the systolic twist-normalized %EF relation did not change. In contrast. the slope of the early (first 15% of filling) diastolic twist-normalized %EF relation (M(early-dia)) decreased significantly (-0.194 +/- 0.062 [prerejection] versus -0.103 +/- 0.054 rad/cm [rejection]. p = 0.0003). resulting in a prolonged tau 1/2 (time required to untwist by 50% [20 +/- 5% versus 28 +/- 5% of diastole]. p = 0.0003) and decrease in percent untwisting at 15% diastolic LV filling (62 +/- 11% versus 36 +/- 13%. p = 0.0003). Therefore. a greater proportion of LV untwisting occurred later in diastole during rejection. as reflected by an increase in the slope (M(mid-dia)) of the middle to late (from 15 to 90% filling) diastolic twist-normalized %EF relation (-0.018 +/- 0.009 versus -0.030 +/- 0.010 rad/cm. p = 0.0015). Peak rate of untwist was not affected. With resolution of rejection. M(early-dia) and percent untwist during early diastole returned to baseline levels (p = NS versus baseline). There was also a trend for M(mid-dia) to return toward prerejection values (p = NS versus baseline). but this change did not reach statistical significance compared with rejection values. CONCLUSION. Acute cardiac allograft rejection is associated with altered diastolic twist mechanics in the absence of any demonstratable systolic abnormalities. During rejection. myocardial edema and other factors may result in intrinsic changes of the elastic properties of the myocardium. thereby leading to modification of recoil forces responsible for the early. rapid unwinding of the deformed ventricle.
Xanthine oxidase inhibition does not limit canine infarct size, BACKGROUND. Evidence supporting the role of xanthine oxidase in myocardial reperfusion injury is based on studies with pharmacological interventions used to inhibit enzyme function. Controversy exists. however. regarding the true role of xanthine oxidase in reperfusion injury. This study was performed to determine whether xanthine oxidase inhibition limits myocardial injury due to coronary artery occlusion and reperfusion. METHODS AND RESULTS. Anesthetized dogs underwent coronary artery occlusion (90 minutes) and reperfusion (6 hours). Oxypurinol (28 mg/kg) or amflutizole (30 mg/kg). chemically unrelated inhibitors of xanthine oxidase. or vehicle was infused intravenously 15 minutes before and 3 hours after reperfusion. Regional myocardial blood flow was determined with radiolabeled microspheres. Infarct size was determined with the tetrazolium method. Myocardial infarct size (percent of risk region) was less in oxypurinol-treated dogs. 32 +/- 16%. compared with that of the control group. 46 +/- 15%. Infarct size for the amflutizole-treated dogs. 40 +/- 21%. was not significantly different from that of the control group. There were no differences in rate-pressure product or collateral blood flow to account for differences in infarct size. Uric acid concentration in the coronary venous plasma increased after reperfusion in the dogs treated with vehicle but not in the drug-treated dogs. Xanthine oxidase inhibition was demonstrated in each of the drug treatment groups. but only oxypurinol limited the extent of myocardial injury. CONCLUSIONS. Previously reported cardioprotective effects of allopurinol. noted to occur only when the drug was administered chronically. may be related to a property of oxypurinol. a major metabolite of allopurinol. The beneficial effect of oxypurinol is unrelated to inhibition of superoxide formation during xanthine oxidase-catalyzed oxidation of xanthine and hypoxanthine.
Adequate resuscitation of burn patients may not be measured by urine output and vital signs, OBJECTIVE: To compare vital sign and urine output monitoring of seriously burned patients with invasive monitoring during early resuscitation. DESIGN: Retrospective review. SETTING: A university hospital burn unit. PATIENTS: Fourteen seriously burned patients who had pulmonary arterial monitoring. Monitoring data were compared at baseline and after fluid challenges. RESULTS: There was no correlation between invasively derived physiologic variables and vital signs and urine output. Vital signs and urine output changed little after fluid challenge. while variables from invasive monitoring demonstrated significant change. In half of the patients. oxygen consumption increased after fluid challenge; vital signs and urine output did not distinguish these patients. CONCLUSIONS: The use of urinary output and vital signs to guide initial burn resuscitation may lead to suboptimal resuscitation. Invasive cardiorespiratory monitoring may be necessary to optimize resuscitation of seriously burned patients.
Outcome following prolonged intensive care unit stay in multiple trauma patients, OBJECTIVE: To describe the hospital course and outcomes of trauma patients requiring ICU stays greater than 30 days and the charges they incur. DESIGN: A retrospective case series analysis of data collected from patient charts and trauma registry. SETTING: A Level I regional trauma center that is part of a statewide trauma system. PATIENTS: Over a 3-yr period. 87 patients (3% of all trauma ICU admissions) had prolonged stays (greater than 30 days) in the ICU; they constitute the study group. Blunt trauma was responsible for 90% of injuries. and the mean Injury Severity Score was 34 +/- 16 SD. RESULTS: Mechanical ventilation was required for 78.5% of the time spent in the ICU. The mean time spent on mechanical ventilators was 47 +/- 23 days; in the ICU. 60 +/- 27 days; and in the hospital. 72 +/- 29 days. Infectious complications occurred in 90% and organ dysfunction was seen in 76% of patients. The overall mortality rate was 17.2% (31% for patients greater than 65 yr). Patients less than 40 yr had lower mortality rates despite a significantly higher Injury Severity Score and lower Glasgow Coma Scale score compared with those greater than 65 yr. More patients greater than 65 yr were discharged to chronic care facilities than those younger (23% vs. 5%). The number of patients followed at 3 and 12 months after discharge was 74% and 54%. respectively. with only two deaths. The mean hospital and professional charges to the patients were $101.000 +/- 61.000 and $35.000 +/- 13.000. respectively. CONCLUSION: Length of ICU stay was most closely associated with the need for mechanical ventilation. The presence of premorbid illness. age greater than 65 yr. and organ dysfunction was associated with increased mortality. Although trauma patients requiring prolonged ICU stays utilize many resources. the ultimate outcome may be fairly good.
Pulmonary effects of ischemic limb reperfusion: evidence for a role for oxygen-derived radicals, OBJECTIVE: To evaluate the lung as a reperfusion target after limb ischemia-reperfusion. and to measure specifically the oxygen radical response to this reperfusion. DESIGN: Paired simple randomized. with continuous interval data in dependent variable and both continuous and nominal independent variables. SUBJECTS AND INTERVENTION: Sprague-Dawley male rats (n = 195) were anesthetized and both hind limbs occluded for 3.75 hr. the overnight LD50. Alveolar lavage was performed on the animals 1 hr after reperfusion or on survivors 20 hr after reperfusion. Groups were either undosed or pretreated with alpha-tocopherol as an antioxidant (50 mg/kg.day) 2 days before ischemia. MEASUREMENTS AND MAIN RESULTS: Luminol-enhanced chemiluminescence was measured in both phorbol myristate acetate-stimulated and unstimulated macrophages. Nanomoles of superoxide radicals per 10(6) alveolar cells/min were also measured using a cytochrome c reduction assay. A significant (p less than .01. Student's t-test). time-dependent increase in response of cells from ischemic-reperfused rats was seen. Pretreatment with antioxidant had no effect at 1 hr. but significant differences were seen in the 20-hr survivors. CONCLUSIONS: These studies show that alveolar lavage cells. 95% macrophages. reflect the reperfusion of ischemic-reperfused hind limbs by a significant increase in oxygen radical activity. an effect partly suppressed in antioxidant-dosed survivors.
Small-volume resuscitation from hemorrhagic shock in dogs: effects on systemic hemodynamics and systemic blood flow, BACKGROUND AND METHODS: This study compared canine systemic hemodynamics and organ blood flow (radioactive microsphere technique) after resuscitation with 0.8% saline (Na+ 137 mEq/L). 7.2% hypertonic saline (Na+ 1233 mEq/L). 20% hydroxyethyl starch in 0.8% saline. or 20% hydroxyethyl starch in 7.2% saline. each in a volume approximating 15% of shed blood volume. Twenty-four endotracheally intubated mongrel dogs (18 to 24 kg) underwent a 30-min period of hemorrhagic shock. from time 0 to 30 min into the shock period. followed by fluid resuscitation. Data were collected at baseline. 15 min into the shock period. immediately after fluid infusion. 5 min after the beginning of resuscitation. and at 60-min intervals for 2 hr. (65 min after the beginning of resuscitation. and 125 min after the beginning of resuscitation). The animals received one of four randomly assigned iv resuscitation fluids: saline (54 mL/kg). hypertonic saline (6.0 mL/kg). hydroxyethel starch (6.0 mL/kg) or hypertonic saline/hydroxyethyl starch (6.0 mL/kg). RESULTS: Mean arterial pressure increased in all groups after resuscitation. Cardiac output increased with resuscitation in all groups. exceeding baseline in the saline and hypertonic saline/hydroxyethyl starch groups (p less than .05 compared with hypertonic saline or hydroxyethyl starch). Sixty-five minutes after the beginning of resuscitation. cardiac output was significantly (p less than .05) greater in either of the two colloid-containing groups than in the hypertonic saline group. After resuscitation. hypertonic saline and hydroxyethyl starch produced minimal improvements in hepatic arterial flow. hypertonic saline/hydroxyethyl starch increased hepatic arterial flow to near baseline levels. and saline markedly increased hepatic arterial flow to levels exceeding baseline (p less than .05. saline vs. hydroxyethyl starch). One hundred twenty-five minutes after the beginning of resuscitation. hepatic arterial flow had decreased in all groups; hepatic arterial flow in the hypertonic saline group had decreased to levels comparable with those during shock. Myocardial. renal. and brain blood flow were not significantly different between groups. CONCLUSIONS: Small-volume resuscitation with the combination of hypertonic saline/hydroxyethyl starch is comparable with much larger volumes of 0.8% saline. and is equal to hypertonic saline or hydroxyethyl starch in the ability to restore and sustain BP and improve organ blood flow after resuscitation from hemorrhagic shock.
Stable and reproducible porcine model of acute lung injury induced by oleic acid, BACKGROUND AND METHODS: Previous studies on acute lung injury induced with oleic acid did not attempt to limit the influence of secondary changes on pulmonary circulation. and cardiopulmonary variable data were only collected and processed intermittently. Our study was designed to continuously monitor the following variables in five swine: systemic and pulmonary pressure; mixed venous oxygen saturation (SVO2) and arterial oxygen saturation (SaO2); minute oxygen consumption and CO2 production before. during. and for 4 hr after the infusion of oleic acid. A personal computer was programmed to produce 20-sec updates of deadspace ratio (VD/VT). venous admixture (Qsp/Qt). pulmonary (PVR) and systemic vascular resistance (SVR). and cardiac output (Qt) from these data. RESULTS: During the oleic acid infusion. there were increases in PVR. SVR. heart rate (HR). mean pulmonary arterial pressure (MPAP). Qsp/Qt. and VD/VT. and a decrease in Qt. SaO2. and SVO2. Thirty minutes after the oleic acid infusion. there was a further increase in HR. Qsp/Qt. and VD/VT. while MPAP. PVR. and SVR gradually decreased to pre-oleic acid infusion levels. No further decrease in SaO2. SVO2. and Qt was observed during that time. After the 30-min period. there was no further change in the cardiopulmonary variables. CONCLUSION: Our method of continuous monitoring was able to demonstrate in swine both the dynamic changes during. and stability after. the oleic acid infusion.
Advantages of a narrow-range, medium molecular weight hydroxyethyl starch for volume maintenance in a porcine model of fecal peritonitis, OBJECTIVE: To compare the effectiveness of two hydroxyethyl starch solutions of different molecular weight ranges for volume maintenance in a porcine model of fecal peritonitis. DESIGN: Randomized prospective trial. SETTING: Laboratory investigation. SUBJECTS: Adolescent female pigs weighing approximately 30 kg. INTERVENTIONS: We compared diafiltered 6% pentastarch with 6% high molecular weight hetastarch for volume maintenance in a porcine model of fecal peritonitis. The number average molecular weight of pentastarch is higher than hetastarch. although the weight average molecular weight is lower. i.e.. a narrow range of medium weight molecules. The infusion rate of each agent was adjusted to maintain baseline arterial Hct for less than or equal to 7 hr after instrumentation and induction of fecal peritonitis. MAIN OUTCOME MEASUREMENTS: The volume of fluid required to maintain arterial Hct was compared along with comparisons of hemodynamic and histologic responses associated with the two agents. RESULTS: Significantly less pentastarch was required to prevent hemoconcentration than hetastarch (109 +/- 22.8 vs. 150 +/- 10.3 mL/kg; p less than .05) while hemodynamics. colloid osmotic pressure. and oxygen transport responses were similar. Capillary patency was greater (21.99 +/- 3.68 vs. 10.09 +/- 1.17%; p less than .05) and mean alveolar capillary barrier thickness was less (2.36 +/- 0.13 vs. 3.06 +/- 0.17 microns; p less than .05) with pentastarch than with hetastarch. as judged by electron microscopy. CONCLUSIONS: These data suggest that pentastarch is better retained in the circulation in capillary leak syndromes compared with hetastarch.
Incontinence and rectal prolapse: a prospective manometric study, A prospective. manometric study has been performed on 23 female patients with rectal prolapse and varying degrees of incontinence. Seven of the 14 incontinent patients regained continence after surgery. and a further two patients improved. Improvement in internal and external sphincter function follows correction of rectal prolapse. Preoperative resting anal pressure was significantly higher in continent patients than in incontinent patients (P less than 0.05). as was the maximum voluntary contraction pressure (P less than 0.027). Postoperatively there was a significant increase in the resting anal pressure (P less than 0.0001) and maximum voluntary contraction pressure (P less than 0.003) in the whole group. The preoperative resting anorectal angle was significantly more acute (P less than 0.028) in continent patients than in incontinent patients. There was no significant change in the resting anorectal angle following prolapse repair. Patients who remained incontinent had a significantly lower preoperative resting anal pressure (P less than 0.01) than patients who improved or regained continence. Similarly. maximum voluntary contraction pressure was lower preoperatively in these patients (P less than 0.02). Preoperative resting anal pressure below 10 mm Hg and maximum voluntary contraction pressure below 50 mm Hg are associated with persisting incontinence after surgery.
The value of radioimmunoguided surgery in first and second look laparotomy for colorectal cancer, Radioimmunoguided surgery (RIGS) using an anti-CEA (A5B7) monoclonal antibody has been assessed in 52 patients (43 primary excisions and nine second look procedures) undergoing surgery for colorectal carcinoma. The antibody localized in 97.8 percent of primary tumours and in 88.8 percent of the principal tumor in second look procedures. Additional information concerning the extent of primary tumor was obtained in 11 of 43 patients (25.5 percent) undergoing excision of primary carcinoma and five of nine patients (55 percent) in the second look series. Incorrect information was obtained about the extent of the primary tumour in six patients (11.3 percent). whereas no incorrect information was obtained during second look procedures. RIGS correctly predicted the subsequent Dukes' staging in 77 percent of first look cases (sensitivity 65 percent. specificity 90 percent). although accurate identification of individual nodes was impossible. The technique influenced the surgical procedure performed in 2 of 43 cases (4.6 percent) in primary surgery and in three of nine patients undergoing second look laparotomy (33 percent). RIGS in primary colorectal carcinoma may provide additional information concerning extent of locally advanced tumors in particular and the principle that the subsequent surgery may be influenced has been established. The technique appears to have a greater role in second look procedures where it may help determine the extent of recurrent tumour. Larger follow-up series are required to define how the additional information provided by this technique may best be exploited.
Vascular responsiveness in obstructed gut, Multiorgan system failure due to hypotension and sepsis is an important cause of death in patients with bowel obstruction. We have investigated the pathophysiology of this entity in an animal model. After 5 days of bowel obstruction. blood flow in the superior mesenteric artery was measured with and without Pitressin and norepinephrine given in separate experiments. In controls. Pitressin in moderate dosages caused a substantial fall in gut blood flow. which was not seen in obstructed animals (blood flow reduction 52 percent vs. 11 percent in sham and obstructed animals respectively. P less than 0.01). Similarly. norepinephrine infusion had less of an effect on gut blood flow in obstructed animals (blood flow reduction 79 percent vs. 58 percent sham vs. obstructed animals (P less than 0.05). Thus. both agents had dose-related effects on gut blood flow. which was maintained at a higher level throughout the drug infusion periods in the bowel of obstructed animals. demonstrating that splanchnic flow is less responsive to vasoactive drug infusion under these experimental conditions. Because splanchnic vasoconstriction is an important feature of normal hemodynamic homeostasis. we suggest that these results may help explain some aspects of the pathophysiology of multiorgan failure caused or worsened by systemic hypotension seen in bowel obstruction.
Nuclear shape as a prognostic discriminant in colorectal carcinoma, In search for a more reliable prognostic discriminant. a retrospective analysis of 100 cases of colorectal carcinoma having undergone curative resection and followed for at least 5 years were assessed by nuclear morphometry. Each case was staged according to the Dukes' classification as well as graded histologically. For all patients in this series. the perimeter. area. and nuclear shape factor of 50 interphase nuclei were determined for each carcinoma. The information was obtained through the use of an image analysis system by tracing the nuclear profiles (magnification 1000x) as digitized on a video screen. The nuclear shape factor was defined as the degree of circularity of the nucleus. a perfect circle recorded as 1.0. A nuclear shape factor greater than 0.84 was associated with poor outcome. Multiple regression models showed that the single nuclear parameter of the shape factor was the most highly significant predictor of survival (P less than 0.0001). This variable remained highly significant even when corrected for sex. age. histologic grade. and Dukes' classification. These findings indicate that a nuclear shape factor greater than or equal to 0.84 as determined by nuclear morphometry is an independent morphometric nuclear variable of great importance in the prognosis of large bowel carcinoma.
Primary de novo adenocarcinoma of the colon measuring 8 mm in diameter with lymph node metastases. Report of a case, Colonic adenocarcinomas measuring less than 10 mm are rare. Herein. we report a carcinoma measuring 8 mm in diameter associated with subserosal extension through a "locus minoris resistentiae" and metastases to lymph nodes. an association not previously reported. No residual adenomatous tissue was found. suggesting a de novo carcinoma.
Regulation of pulsatile luteinizing hormone secretion in experimental uremia, Previous studies have shown that male rats with experimental uremia manifest profound suppression of circulating LH and testosterone levels. yet. paradoxically. after castration gonadotropin levels are elevated greatly above those of nonuremic castrate control rats. To investigate further this phenomenon. we characterized pulsatile LH secretion in experimental uremia. Mature orchidectomized male Wistar rats with subtotal nephrectomy demonstrated a 43% reduction of LH pulse frequency. but a 157% increase in pulse amplitude and a 335% increase in mean LH levels compared with sham-operated controls. All pulse parameters were highly correlated with plasma creatinine (r = 0.53-0.75). To determine the mechanism of the increased pulse amplitude. we tested responsiveness of the postcastration uremic pituitary to exogenous GnRH (0.01-10 micrograms/kg) in a Latin square design. Plasma LH response was linearly related to the logarithm of the GnRH dose in uremic and control rats. but was markedly increased in uremic rats. We conclude that the uremia causes decreased LH pulse frequency independent of testicular feedback. Pituitary hypersensitivity to GnRH magnifies LH pulse amplitude and thereby is the major factor causing the paradoxical LH hyperelevation after castration.
Development and characterization of a new, highly specific antibody to the human chorionic gonadotropin-beta fragment, In addition to high concentrations of hCG. pregnancy urine contains even higher concentrations of a fragment of the hCG beta-subunit. This biologically inactive material complicates immunological measurement of hCG. since it cross-reacts with many polyclonal and monoclonal antibodies to the hCG beta-subunit that are employed for assays of hCG in urine. Although we and others have developed antibodies to this fragment. specific measurement of the fragment in the presence of free hCG beta has remained difficult due to intrinsic cross-reactivity of these antibodies with the intact hCG beta. Rather than attempt to increase specificity by assay optimization. we developed a new. highly specific monoclonal antibody. designated B210. which cross-reacts less than 0.1% with the free hCG beta-subunit in both liquid and solid phase immunoassay formats. We have used this new monoclonal antibody in immunoradiometric assays to measure specifically the hCG beta fragment in urine throughout pregnancy as well as in the sera of two individuals with cancers producing the hCG beta-subunit. We discovered that the hCG beta fragment can bind three monoclonal antibodies simultaneously. indicating that although the epitope for antibody B210 is a new determinant exposed on the hCG beta fragment and not on intact hCG or on free hCG beta-subunit. the hCG beta fragment retains at least two other hCG beta-related epitopes intact. i.e. those that bind monoclonal antibodies B108 and B201.
Human growth hormone-variant is a biologically active somatogen and lactogen, The human GH-variant (hGH-V) gene. a member of the GH-PRL gene family. is expressed by the placenta during the second and third trimesters of gestation. The secreted hGH-V protein differs from pituitary GH (hGH-N) by only 13 amino acids. We have previously demonstrated that hGH-V can bind to both somatogen and lactogen cell surface receptors in vitro. but that the ratio of its somatogen to lactogen receptor-binding affinities is substantially higher than that of hGH-N. We now characterize the somatogen and lactogen bioactivities of hGH-V and contrast them to the bioactivity of hGH-N. Somatogen bioactivity was assayed by stimulation of weight gain in hypophysectomized rats. and lactogen bioactivity was assayed by the mitogenic response of the Nb2 lymphoma cell line. While the average increase in rat body weight in response to a fixed concentration of hormone was comparable using either hGH-V or hGH-N. the mitotic response of the lactogen-inducible Nb2 cells was significantly less for hGH-V. The comparable somatogen. but lower lactogen. bioactivity of hGH-V relative to hGH-N parallels the previously reported receptor binding profiles of the two hormones and suggests that hGH-V has the potential to perform a unique role during human gestation.
Corticotropin-releasing factor modulates the immune response to stress in the rat, We examined the role of CRF. a key mediator of the endocrine response to stress. in modulating immunosuppression during the subacute stress of intermittent electrical shock over 1 h. Administration of shock to intact rats resulted in a 74% decrement in T-lymphocyte proliferation and a 59% decrease in natural killer cytotoxicity. Similar suppression of these two parameters of immune function in response to shock was noted in adrenalectomized rats as well. The immunosuppressive effects of this shock were significantly and comparably blunted when both intact and adrenalectomized animals were pretreated 1) iv with either a highly potent polyclonal CRF antibody or a specific CRF antagonist or 2) intracerebroventricularly with either a high affinity monoclonal antibody to CRF or a specific CRF antagonist. An immunomodulatory role for CRF is further supported by the findings that administration of exogenous CRF. either iv (10 micrograms/animal) or intracerebroventricularly (1 microgram/animal). resulted in significant decrements in lymphocyte proliferation and natural killer cytotoxicity. similar to those seen with the stress paradigm. Our observations indicate that CRF plays a significant role in modulating the immune response to subacute stress. largely by adrenal-independent mechanisms.
Calcium transport by plasma membranes from a glucose-responsive rat insulinoma, Inside-out plasma membrane vesicles from a glucose-responsive rat insulinoma showed an ATP- and Mg2(+)-dependent uptake of Ca2+. The Km (concentration giving half-maximal activity) for Ca2+ was 60 nM. In the presence of 0.4 microM free Ca2+. the Km for ATP was 15 microM. and the Km for Mg2+ was 4 microM. Glucose (30 mM) decreased Ca2+ uptake by 50%. while other insulin secretagogues had no effect. except for glyceraldehyde. which stimulated Ca2+ uptake. Calmodulin increased the uptake of Ca2+. while trifluoperazine and vanadate inhibited the uptake. The Ca2(+)- and Mg2(+)-dependent ATPase from this tumor has a 10- to 20-fold higher requirement for Ca2+. which suggests that this enzyme is not responsible for Ca2+ transport. rather. Ca2+ transport activity represents only a small fraction of the total Ca2(+)-ATPase activity. The physiological importance of Ca2+ transport in insulin secretion is evident from the inhibition of Ca2+ uptake by glucose. which leads to a decrease in Ca2+ efflux from the cell. This inhibition would lead to an increase in intracellular free Ca2+ and insulin release.
The pituitary-adrenocortical system of neonatal rats is responsive to stress throughout development in a time-dependent and stressor-specific fashion, The responsiveness of the neonatal hypothalamus-pituitary-adrenal (HPA) axis to stress has been thought to be impaired or diminished during the first 2 weeks of life. Although we previously found full responsiveness of the hypothalamus-pituitary unit to adrenalectomy in young rats [days (d) 5-10]. we failed to measure a significant increase in ACTH 10 min after ether administration until d14 of age. These studies were. therefore. designed to test the functional activation of the HPA axis after a single or repeated exposures to stress. Both qualitative (time-course. stressor-specific. circadian) and quantitative changes in the ACTH and corticosterone (B) responses to various stressors were tested during the first 10 days of life. Exposure to 3 min of ether vapor increased ACTH and B secretion (P less than 0.05-0.01) in 1-. 5-. and 10-d-old rats. with an increasing amplitude of both ACTH and B responses as a function of age. Peak secretion of ACTH occurred 5 min after the onset of stress (122 +/- 3.8 to 359 +/- 54 pg/ml on d1-10). while the time of maximal B increased as a function of age. Other stressors. such as maternal separation (12 h). cold (4 C; 60 min). or histamine injection (4 mg/kg BW. ip). provoked significant and stressor-specific ACTH and B responses in 10-d old rats. Histamine administration increased ACTH secretion above that of vehicle-injected rats. with a peak of secretion 15 min after drug injection (272 +/- 29 vs. 127 +/- 8 pg/ml; P less than 0.01). Histamine-induced B secretion peaked at 60 min (3.7 +/- 0.5 micrograms/dl). In contrast to early responses observed after ether. separation. or histamine stress. cold stress in 10-d-old pups caused a large ACTH and B release 4 h after the onset of cold compared to that in maternally deprived pups [ACTH: cold. 457 +/- 61 pg/ml; separated. 150 +/- 14 (P less than 0.01); B: cold. 3.3 +/- 0.4 micrograms/dl; separated. 1.8 +/- 0.2 (P less than 0.05)]. We did not detect morning-evening (AM-PM) differences in either the pattern or the magnitude of the ACTH or B response to maternal separation or cold stress. Suppression of cold-induced ACTH release by B injection (1 mg/kg BW) 2 h before stress was observed until 4 h after stress in the AM and PM. whereas when given after cold. B was less effective in the PM than in the AM at preventing the rise in ACTH levels observed at 4 h.(ABSTRACT TRUNCATED AT 400 WORDS).
Transcriptional regulation of ferritin messenger ribonucleic acid levels by insulin in cultured rat glioma cells, Recent data have shown that ferritin. a ubiquitous protein. has a role as a regulator of cellular differentiation. In the present study we have investigated the expression of ferritin mRNAs in cultured C6 cells. a rat glioma cell line. in response to insulin. which has an important role in cellular growth and differentiation. Insulin stimulated steady state levels of both ferritin heavy chain and ferritin light chain mRNAs. An increase in the level of ferritin heavy or light chain mRNA was detected after 2 h of incubation with insulin. and a plateau was reached after 48 h for heavy chain mRNA and after 72 h for light chain mRNA. The responses were dose-dependent and were maximal at 100 nM for both mRNAs. Treatment of cells with actinomycin-D showed that insulin had no effect on the posttranscriptional stability of these mRNAs. Actinomycin-D inhibited insulin-induced accumulation of both mRNAs. suggesting transcriptional stimulation of ferritin genes by insulin. A nuclear run-on assay showed that the insulin-induced increase in ferritin heavy chain mRNA was due to an increase in the rate of gene transcription. We also demonstrated that insulin-like growth factor-I (IGF-I) increased ferritin heavy and light chain mRNA levels in a dose-dependent fashion. and that the maximum effect was obtained at a concentration of 10 nM on both mRNA levels. IGF-I was not only 10-fold more potent. but the absolute level of maximum stimulation was also about 2-fold greater than that for insulin. The combination of insulin (100 nM) and IGF-I (10 nM) showed no additive effect. The results suggested that the ferritin heavy and light chain genes are transcriptionally regulated by insulin and influenced by IGF-I.
Differential regulation of insulin-like growth factor-I (IGF-I) and IGF-II release from cultured neonatal mouse calvaria by parathyroid hormone, transforming growth factor-beta, and 1,25-dihydroxyvitamin D3, In a previous study we found that PTH stimulated bone resorption and release of insulin-like growth factor-I (IGF-I) and IGF-II from cultured neonatal mouse calvaria. Since IGF-I and IGF-II stimulate osteoblast proliferation and collagen synthesis. these results suggested that increased release of IGFs during resorption could mediate in part coupling of bone formation to bone resorption. In the present study two other osteolytic agents. transforming growth factor-beta (TGF beta) and 1.25-dihydroxyvitamin D3 [1.25-(OH)2D3 were examined for effects on IGF release from neonatal mouse calvaria. Like PTH. TGF beta stimulated resorption and increased release of IGF-I and IGF-II. 1.25-(OH)2D3. however. stimulated resorption and IGF-II release comparable to PTH. but inhibited release of IGF-I. 1.25-(OH)2D3 (0.1-100 nM) inhibited basal release of IGF-I. and 10 nM 1.25-(OH)2D3 inhibited release of IGF-I induced by PTH or TGF beta. The effects of 1.25-(OH)2D3 were specific to this vitamin D metabolite and did not occur with 25-hydroxyvitamin D3 or 24.25-(OH)2D3 at the same concentration. Calcitonin (50 mU/ml) decreased 1.25-(OH)2D3 stimulation of resorption. but did not affect 1.25-(OH)2D3 stimulation of IGF-II release and inhibition of IGF-I release. This evidence that effects of 1.25-(OH)2D3 on release of the IGFs were independent of bone resorption supports the conclusion that 1.25-(OH)2D3 modulated the production and secretion of IGF-I and IGF-II in calvarial cells. The results of this and the previous study suggest that PTH. TGF beta. and 1.25-(OH)2D3 differentially regulate mouse calvarial cell IGF-I and IGF-II production.
Comparison of the effects of hypertonic sucrose and intracellular potassium depletion on growth hormone receptor binding kinetics and down-regulation in IM-9 cells: evidence for a sequential block of receptor--mediated endocytosis, To better understand the complex kinetics of human GH (hGH) binding to its receptors. we have further investigated. in IM-9 cultured human lymphocytes. the cellular locus corresponding to the slowly dissociating component of hormone binding. and to the homologous down-regulation of hGH receptors. First. we have detailed the biphasic kinetics of dissociation of bound hormone in control cells at 30 C. When the association at 30 C was extended from 0.5 to 3 h. the time required for half-dissociation of the fast component was slightly decreased (from 30 to 15 min) but that of the slow component increased considerably (from 6 h to 30 h). Concomitantly. the size of the slowly dissociating component increased from 50 to 80% of total. This indicates a maturation of bound hormone. from a rapidly to a slowly dissociating pool and. in the latter. an increase in the apparent affinity that may reflect a molecular rearrangement. Next. we have compared the effect of two procedures reported to inhibit receptor-mediated endocytosis at the level of coated pits. As previously reported. depletion of intracellular K+ abolished the slowly dissociating component and the down-regulation of hGH receptors. In contrast. upon incubation with 0.4 M sucrose. which like K+ depletion virtually abrogated hGH internalization. the dissociation kinetics remained non-first order. and the down-regulation of hGH-receptor was only slightly reduced. Thus. these procedures appear to block receptor-mediated endocytosis at two successive compartments of the cell surface. In conclusion. we propose that some conformational change of hGH-receptor at the cell surface (possibly associated with clustering) may considerably slow down their dissociation and may be sufficient for down-regulation.
Regulation of insulin, epidermal growth factor, and transforming growth factor-alpha levels by growth factor-degrading enzymes, The mechanisms by which growth factors are degraded and the role this process plays in the regulation of cell growth are not well understood. Insulin degradation is believed to be mediated by a specific metalloprotease. insulin-degrading enzyme (IDE). We have previously shown that IDE can also degrade transforming growth factor-alpha (TGF alpha). but not epidermal growth factor (EGF). in vitro. This selectivity was surprising. since TGF alpha and EGF are structurally similar and bind to the same receptor with comparable affinities. Using a spectrum of protease inhibitors. we have now analyzed the degradation of TGF alpha. EGF. and insulin by human hepatoma HepG2 cells. The results suggest that bacitracin-sensitive metalloproteases are involved in the degradation of TGF alpha and EGF as well as insulin. and that the degradation of TGF alpha. but not EGF. is mediated in part by IDE. Inhibiting the activity of these metalloproteases decreased growth factor depletion. suggesting that these enzymes play an important role in the control of extracellular growth factor levels. The existence of separate degradative pathways for EGF and TGF alpha may explain how the two factors exert differential effects in some systems. and degradation of TGF alpha by IDE would provide a possible mechanism for interaction between the insulin and TGF alpha/EGF signalling systems.
Insulin stimulates synthesis and release of human chorionic gonadotropin by choriocarcinoma cell lines, Recent studies have shown that insulin regulates placental lactogen. progesterone. and estrogen production from human trophoblast cells. This study was performed to examine whether insulin also regulates the production of hCG by this type of cell. After 24-36 h of preincubation. JEG-3 and JAR cells (2-3 x 10(5) cells/ml.well) or human term trophoblast cells (1 x 10(6) cells/ml.well) were exposed to the test hormone in serum-free Dulbecco's Modified Eagle's Medium for 24-96 h. Secretion of hCG from JEG-3 cells was stimulated by human insulin. human proinsulin. or porcine insulin in a dose-dependent manner. with lowest effective doses of 6.7. 96. and 53 mg/L. respectively. Time-course studies showed that hCG secretion peaked at 72-96 h with insulin exposure; in contrast. no decernable peak was seen without insulin in serum-free media. Exposure of JEG-3 cells for 24 h to 209 mg/liter insulin stimulated hCG synthesis. with 40 +/- 3% more immunoreactive intracellular hCG (P less than 0.05). Cells grown in the presence of insulin and [35S]methionine had 47 +/- 21% more labeled intracellular hCG and 56 +/- 13% more immunoprecipitable [35S]methionine-hCG secreted into the medium than the control cultures (P less than 0.05). During this time period. human placental lactogen release and total trichloroacetice acid-precipitable [35S]methionine protein were not increased. The insulin-induced stimulation of hCG synthesis was inhibited by cycloheximide. Additionally. insulin did not significantly affect total intracellular protein during 24-96 h of incubation. Insulin also increased hCG release from JAR cells. but not from human term trophoblast cells. A mouse monoclonal antibody to the IGF-I receptor inhibited the stimulation of insulin in JEG-3 cells. We conclude that insulin stimulates the synthesis and secretion of hCG from JEG-3 cells and JAR cells. and that hCG regulation in choriocarcinoma cells differs from that in primary human placental trophoblast cells. The effect of insulin on JEG-3 cells may be mediated in part through the insulin-like growth factor-I receptor.
Cyclosporin-A in vitro decreases bone resorption, osteoclast formation, and the fusion of cells of the monocyte-macrophage lineage, We studied the in vitro effect of cyclosporin-A (CyA) on bone resorption using a fetal rat long bone-resorbing assay. CyA inhibited both PTH-stimulated and unstimulated bone resorption. The inhibitory effect of CyA on basal resorption was dose dependent. and it was more pronounced during the second period (less than or equal to 0.1 microgram/ml) of culture (days 5-7) than during the first period (days 2-4). A cytotoxic effect was ruled out by the absence of decrease in [3H]thymidine incorporation into bones up to a concentration of 5 micrograms/ml CyA. Histomorphometry performed after 4 and 7 days of culture showed that CyA (1 microgram/ml) decreased the number of osteoclasts per bone section after 7 days of culture (23.5 +/- 4.0 vs. 41.7 +/- 2.9 osteoclasts/bone section; P less than 0.05). but not after 4 days (25.6 +/- 3.3 vs. 23.0 +/- 2.5). These data suggested an effect of CyA on osteoclastic differentiation rather than on the function of mature osteoclasts. We further assessed the mechanisms of the inhibitory effect of CyA on osteoclastic differentiation in order to determine 1) the level of this action (proliferation and/or fusion of osteoclast precursors). and 2) if this action is direct or indirect. Autoradiographic studies were performed on bone sections after incubation of bones with [3H]thymidine for the last 48 h of culture. CyA decreased slightly but significantly the percentage of labeled nuclei per osteoclast and the number of osteoclasts containing at least one labeled nucleus (20.2 +/- 0.7 vs. 33.2 +/- 3.5; P less than 0.02). Moreover the number of nuclei per osteoclast was decreased after 7 days in CyA-treated bones (2.4 +/- 0.05 vs. 3.0 +/- 0.1; P less than 0.02). Taken together these results demonstrate that CyA slightly decreased the proliferation of osteoclast precursors. but markedly decreased their fusion. Similar effects were observed in cultures of rat marrow macrophages. CyA (1 microgram/ml) inhibited the fusion of macrophages into multinucleated cells elicited by 1 nM 1.25-dihydroxyvitamin D3. but had only a slight effect on the proliferation of these cells. as assessed by autoradiography. CyA also inhibited the formation of multinucleated cells and the fusion index in long term cultures of human cord blood monocytes. a cellular model for osteoclastic differentiation. By contrast. CyA had no effect on the formation of myotubes by fusion of cultured mononucleated rat myoblasts.(ABSTRACT TRUNCATED AT 400 WORDS).
Defective tolerance to the toxic and metabolic effects of interleukin 1, The effect on food intake. body weight. and survival of mice given recombinant lipopolysaccharide (LPS). tumor necrosis factor/cachectin (TNF). or interleukin 1 (IL-1) (5 micrograms/mouse. ip. twice daily) was studied. All agents induced a rapid reduction of food intake and body weight after 1 day of treatment. Unlike TNF and LPS. IL-1 given as two daily administrations of 5 micrograms was lethal within 3 days. Mice treated with LPS or TNF rapidly developed tolerance to their anorectic effect. whereas tolerance to IL-1 required a longer time to develop and was not complete. We investigated the possible roles of changes in serum corticosterone and glucose in the effects of LPS. TNF and IL-1. A single injection of LPS. TNF. or IL-1 markedly increased serum corticosterone levels after 2 h. After only 2 days of chronic treatment. mice given LPS or TNF were refractory to induction of serum corticosterone by a subsequent injection of LPS or TNF. but mice given IL-1 for 2 days were still fully responsive to IL-1. IL-1. unlike TNF and LPS. induced a marked hypoglycemic response. Repeated administration of IL-1 sensitized to its hypoglycemic effect. This lack of adaptation to the increase of serum corticosterone and hypoglycemia was also observed when IL-1 was given at lower. nonlethal doses (0.25-1.0 microgram) and for a longer period (up to 8 days). The defective tolerance to the metabolic and toxic effects of IL-1 in this experimental model indicates that there are major differences between the in vivo biological responses to IL-1 and TNF.
Is islet amyloid polypeptide a significant factor in pathogenesis or pathophysiology of diabetes, Islet amyloid polypeptide (IAPP) or amylin. a recently discovered minor secretory peptide of the beta-cell related to calcitonin gene-related peptide (CGRP). is a constituent of amyloid deposits in the islets of many non-insulin-dependent (type II) diabetic individuals and some elderly nondiabetic subjects. IAPP is synthesized as a small precursor at a level of approximately 1% that of insulin and is processed. amidated. stored in beta-granules. and released along with insulin and C-peptide. Analysis of its gene (located on chromosome 12) supports an evolutionary relationship to calcitonin and CGRP. peptides with which it shares some biological actions. Like CGRP. IAPP antagonizes the action of insulin mainly at the level of muscle glycogen synthesis. but the levels required for this effect seem to be considerably higher than reported circulating levels. No evidence for overproduction of IAPP in diabetic subjects has been found thus far. but much more work is necessary to define its normal secretory rates and clearance. Other proposed actions of IAPP include serum calcium-lowering effects and smooth muscle relaxation; the latter effect might promote the uptake of insulin into the circulation within the islets. Deposition of amyloid is species selective due to structural differences within the central part of the molecule and may be initiated intracellularly in type II diabetes by several mechanisms. No differences in the structure of IAPP or its precursor have been found in individuals with maturity-onset diabetes of the young or type II diabetes.
Newly identified pancreatic protein islet amyloid polypeptide. What is its relationship to diabetes, Islet amyloid polypeptide (IAPP) or amylin is a newly identified 37-amino acid COOH-terminal-amidated polypeptide that is the major protein constituent of amyloid deposits in insulinomas and amyloid deposits in pancreatic islets of non-insulin-dependent (type II) diabetic humans and adult diabetic cats. IAPP is stored with insulin in beta-cell secretory vesicles and is cosecreted with insulin in response to glucose and several secretagogues. IAPP has been demonstrated in normal pancreatic islets of many species. but IAPP-derived amyloid develops commonly in the islets of only a few species (e.g.. humans and cats). especially in association with age-related diabetes. IAPP from the human and cat inherently contains a short amyloidogenic sequence that is not present in species that do not form islet amyloid. Studies in animals indicate that an aberration in the synthesis or processing of IAPP. leading to a local increase in concentration of IAPP in the islet. is also required to facilitate the conversion of IAPP to amyloid. The formation of islet amyloid may contribute to the development of type II diabetes by causing disruption of islet cells and by replacement of islets. It has also been proposed that an abnormality of IAPP homeostasis underlies the pathogenesis of type II diabetes. A significant causal relationship between IAPP and type II diabetes is based on reports that IAPP inhibits glucose-stimulated insulin release by beta-cells and that IAPP inhibits insulin-stimulated rates of glycogen synthesis and glucose uptake by skeletal muscle cells.
Frequency and effects of apolipoprotein E polymorphism in Mexican-American NIDDM subjects, We typed 254 non-insulin-dependent diabetic (NIDDM) Mexican Americans living in Starr County. Texas. for the three common apolipoprotein E (apoE) alleles. Typing was performed via DNA amplification and Hha I restriction. The allele frequencies (epsilon 2 = 0.041. epsilon 3 = 0.860. epsilon 4 = 0.099) were in Hardy-Weinberg equilibrium (chi 2 = 0.60. df = 3) and did not differ from a random sample from the same population (chi 2 = 0.16. df = 2). Analysis of variance was used to test for mean differences in lipid. lipoprotein. and glucose levels among apoE types. Significant differences among types were detected for low-density lipoprotein cholesterol (LDL-chol; P = 0.042. R2 = 2.6) and beta-lipoprotein cholesterol (P = 0.019. R2 = 3.3) levels. Mean LDL-chol in E2/3 individuals was 2.69 mM. E3/3 was 3.26 mM. and E4/3 was 3.36 mM. Mean beta-lipoprotein cholesterol in E2/3 individuals was 3.05 mM. E3/3 was 3.64 mM. and E4/3 was 3.67 mM. Based on these results. we conclude that the effects of the apoE polymorphism on lipid profiles and glucose levels are the same in NIDDM subjects as in nondiabetic Mexican Americans and other populations. Other studies investigating the role of apoE polymorphism in diabetic subjects have found increased triglyceride levels in individuals possessing an epsilon 2-allele and an increased frequency of the epsilon 2-allele in hyperlipidemic diabetic subjects. We found no significant difference in mean triglyceride levels among genotypes. Possible reasons for this discrepancy are discussed. including DNA- versus protein-typing methods.
Blunted diuretic and natriuretic responses to central administration of clonidine in streptozocin-induced diabetic rats, The purpose of this study was to determine whether diuretic and natriuretic effects are altered in response to intracerebroventricular (ICV) infusion of clonidine in diabetic rats. Diabetes was induced in male Sprague-Dawley rats by 65 mg/kg i.p. injection of streptozocin. and control rats were injected with vehicle 2 wk before the experiment. Blood glucose levels were significantly elevated in the diabetic group (26.3 +/- 1.3 mM) compared with the control group (8.4 +/- 1.6 mM). Before and during ICV infusion of clonidine (2 micrograms.kg-1.min-1 for 45 min). urine flow and sodium excretion were measured from intact and denervated kidneys in anesthetized diabetic and control rats. The ICV infusion of clonidine significantly increased urine flow in both innervated and denervated kidneys from control rats but not from diabetic rats. There was a significant increase in sodium excretion during ICV infusion of clonidine from innervated kidneys of control rats. and denervation abolished this effect. In diabetic rats. clonidine failed to promote natriuresis from intact kidneys. and similar to control rats. did not promote natriuresis in denervated kidneys. This study demonstrates that 1) the diuretic response to the ICV infusion of clonidine is blunted in diabetic rats. and 2) a natriuretic response to the ICV infusion of clonidine is blunted in innervated kidneys of diabetic rats.
Changes in hepatic glutathione metabolism in diabetes, Glutathione is important in the regulation of the redox state. and a decline in its tissue level has often been considered to be indicative of increased oxidative stress in diabetes. In this study of diabetic rats. the level of hepatic glutathione was normal unless food intake was restricted. Thus. the previous report of a reduction in hepatic glutathione in diabetes is likely to be the result of food deprivation rather than diabetes alone. In contrast to changes characteristic of oxidative stress. the efflux of glutathione in bile from diabetic animals was significantly decreased. whereas hepatic mixed disulfides were unchanged. and the hepatic gamma-glutamyltransferase activity was considerably increased. These changes were not reproduced by food deprivation. The decrease in biliary excretion of glutathione in diabetes may reflect an attempt to conserve glutathione by activation of the hepatic gamma-glutamyl cycle. We conclude that the disturbances of glutathione metabolism in diabetes are not typical of those seen in oxidative stress or food restriction.
Lack of evidence for improvement in long-term glycemic control by pulsatile insulin infusion in streptozocin-induced diabetic baboon, To assess the potential therapeutic use of pulsatile intravenous insulin delivery. five streptozocin-induced diabetic baboons were treated with alternate 3- to 6-wk periods of pulsatile and continuous insulin infusion. Time-averaged insulin concentrations were matched during two pulsatile administration periods (P1 and P2) and an intervening period of continuous insulin administration (C). There were no significant differences among the overall means of four daily glucose determinations performed during the three periods (P1. 5.7 +/- 1 mM; C. 5.6 +/- 0.9 mM; P2. 5.3 +/- 0.9 mM); the mean M value. a measure of the stability of glycemic control (P1. 4 +/- 1.7; C. 3.9 +/- 1.8; P2. 3.6 +/- 1.5); the percentage of glucose values less than 2.8 mM (P1. 13 +/- 8.5%; C. 14 +/- 12%; P2. 13 +/- 9.1%); or the glycosylated hemoglobin levels determined at the end of the P1 and C (7.5 +/- 3.4 and 6.5 +/- 1.8%. respectively [all values are means +/- SD]). Fasting hepatic glucose production was suppressed to a similar degree during pulsatile and continuous insulin infusion (P1. 23 +/- 3 mumol.kg-1.min-1; C. 24 +/- 8 mumol.kg-1.min-1). Arterial glucagon levels were similar during pulsatile and continuous insulin infusion. both in the fasting state (84 +/- 29 and 84 +/- 31 ng/L. respectively) and postprandially (30 +/- 14 and 27 +/- 12 ng/L. respectively). Pulsatile insulin infusion failed to entrain a corresponding glucagon secretory rhythm. These data suggest that the metabolic consequences of long-term pulsatile and continuous insulin infusion in an animal model of human non-insulin-dependent diabetes are comparable.
Independent effects of youth and poor diabetes control on responses to hypoglycemia in children, To evaluate the effects of childhood and poorly controlled insulin-dependent diabetes mellitus (IDDM) on counterregulatory hormone and symptomatic responses to hypoglycemia. we studied 16 nondiabetic children (13 +/- 2 yr). 19 nondiabetic adults (26 +/- 3 yr). and 13 children with IDDM (14 +/- 2 yr. HbA. 15.1 +/- 3.3%) during a gradual reduction in plasma glucose with the glucose-clamp technique. Plasma glucose was reduced from approximately 5 to approximately 2.8 mM over 240 min with serial assessment of counterregulatory hormone levels and symptom awareness. The plasma glucose level that triggered a sustained rise in plasma epinephrine was consistently higher in nondiabetic children than in adults (3.9 +/- 0.06 vs. 3.2 +/- 0.06 mM. P less than 0.001). Poorly controlled IDDM further elevated the glucose threshold for epinephrine release to normoglycemic levels (4.9 +/- 0.2 mM. P less than 0.001 vs. both control groups). Age and IDDM also produced an upward shift in the glucose level at which growth hormone release and symptom awareness were initiated. In contrast to the effect on glucose thresholds. maximal epinephrine responses and symptom scores were increased only by age and not IDDM (2-fold higher in children). We conclude that childhood and poor diabetes control independently contribute to an upward shift in glucose thresholds for counterregulatory hormone release and symptom awareness during mild hypoglycemia. Normoglycemic counterregulation may interfere with efforts to control diabetes in young patients.
Use of X-ray diffraction in study of human diabetic and aging collagen, Extensive investigations of the solubility and fluorescence of collagen fibers in diabetes have revealed that there are significant changes in their physical properties. These changes are associated with increased cross-link formation. We used X-ray diffraction to study these changes in human extensor tendons at a molecular level in relation to both aging and diabetes. Our results indicate that diabetes induces significant alterations in the ultrastructure of collagen in the lateral packing of the molecules and the axial structure of the specimen. These changes can be induced in normal tendon by incubation in ribose and glucose-6-phosphate but are different from those associated with the normal process of aging.
Managing geriatric arrhythmias, I: General considerations, Cardiac arrhythmias become increasingly common as people age. but they are not always clinically significant. Sinus node dysfunction. AV conduction disturbances. and ventricular and supraventricular arrhythmias will be found but are not always symptomatic. Treatment of asymptomatic arrhythmias is controversial and probably not indicated. but in symptomatic elderly. therapy is indicated. since even the very elderly have been found to benefit from it as much as younger patients. There are specific guidelines. however. that apply to this age group based on its susceptibility to side effects.
Pain control in the ambulatory elderly, Pain control in the elderly. no matter what the etiology or setting. can be a major clinical challenge. Aging causes unique physiologic changes. eg. a decreased perception of pain and an enhanced sensitivity to opioid analgesics. Principles regarding evaluation of patients with pain are reviewed. including the use of an objective instrument for pain assessment from the viewpoint of both physician and patient. Good pain control can be achieved with the nonopioids. such as acetaminophen and the nonsteroidal anti-inflammatory drugs. the opioid analgesics. and. in some cases. adjuvant agents. Discussed also are the concerns for patient addiction and the WHO Cancer Pain Relief program.
Dry mouth: diagnosing and treating its multiple causes, Dry mouth in the elderly is a common occurrence with multiple etiologies. It is not a normal phenomenon of aging and. therefore. an attempt at elucidating its cause should be made. Sjogren's syndrome may occur. and it is diagnosed by labial biopsy. Medications are also frequently associated with dry mouth. and dosages may need to be adjusted or the drug discontinued if symptoms are severe. Strategies for management of dry mouth are explored.
Effects of hepatitis B virus, alcohol drinking, cigarette smoking and familial tendency on hepatocellular carcinoma, Independent and interactive effects related to the development of hepatocellular carcinoma were assessed using a community-based case-control study for hepatitis B virus. habitual alcohol drinking. cigarette smoking. peanut consumption and history of hepatocellular carcinoma among the immediate family. All 200 male newly diagnosed hepatocellular carcinoma patients were recruited consecutively through the period of study as the case group from two teaching medical centers in northern and southern Taiwan. Healthy community residents matched one-to-one with cases on age. sex. ethnic group and residential area were selected as the control group. The carrier status of HBsAg and HBeAg was determined by blind radioimmunoassays. and other risk factors were obtained through standardized interviews according to a structured questionnaire. Conditional logistic regression analysis showed a significant association between hepatocellular carcinoma and the carrier status of HBsAg and HBeAg with an odds ratio of 16.7 and 56.5. respectively. for carriers of HBsAg alone and for carriers of both HBsAg and HBeAg. There was a dose-response relationship between cigarette smoking and hepatocellular carcinoma with an odds ratio of 1.1. 1.5 and 2.6. respectively. for those who smoked 1 to 10. 11 to 20 and more than 20 cigarettes a day. A significant association with hepatocellular carcinoma was also observed for the habitual alcohol consumer with an odds ratio of 3.4. Those whose immediate family had a history of hepatocellular carcinoma were more likely to have the disease develop. with an odds ratio of 4.6. However. the frequency of peanut consumption was not significantly associated with hepatocellular carcinoma.
Development and application of an in vitro model for screening anti-hepatitis B virus therapeutics, The development of effective anti-hepatitis B virus agents has been hampered by the lack of reliable in vitro systems for the screening of new therapeutics. In an effort to circumvent this problem. we have developed an in vitro system for screening anti-hepatitis B virus drugs using hepatitis B virus DNA-transfected Hep G2 cells. The cell line designated 2.2.15 produces replicative viral DNA intermediates. mature Dane particles and high levels of viral antigens. Subconfluent 2.2.15 cells were treated with a variety of commonly used anti-hepatitis B virus therapeutics. and their efficacy was determined by analyzing changes in the replicative cellular or extracellular hepatitis B virus DNA content by Southern blotting or slot-blot hybridization. The slot-blot method was sensitive. reproducible and rapid and correlated well with Southern blotting. Analysis of the media for hepatitis B virus DNA was indicative of changes in intracellular. replicative hepatitis B virus DNA. permitting sampling of the media. Therefore 2.2.15 cells may provide a valuable method for identifying and monitoring effective anti-hepatitis B virus therapeutics. Using this system to test various agents. we confirm that 2'-deoxyguanosine strongly inhibited viral replication. whereas others tested were less effective. Correlation with in vivo systems is now needed.
Usefulness of pulsed Doppler ultrasound in detection of angiographically evident recurrence of hepatocellular carcinoma after arterial embolization treatment, Because hepatocellular carcinoma treated by transcatheter arterial embolization often regains its size. routine follow-up is necessary. The usefulness of pulsed Doppler ultrasound for detection of this type of recurrence was compared with ultrasonography and computed tomography in 21 such hepatocellular carcinomas. Of 15 hepatocellular carcinomas diagnosed by angiography as showing recurrence. four were detected with ultrasonography and five were detected with computed tomography. Doppler signals were obtained in the peripheral portions corresponding to tumor vessels or stains on angiograms in 14 of these 15 hepatocellular carcinomas. but they were undetectable in six hepatocellular carcinomas with no recurrence. All signals disappeared after transcatheter arterial embolization. One false-negative hepatocellular carcinoma with pulsed Doppler ultrasound showed faint tumor stains on angiograms; these were also negative on ultrasonography and computed tomography. Pulsed Doppler ultrasound may be superior to ultrasonography and computed tomography as a routine procedure to detect the recurrence of hepatocellular carcinoma treated by transcatheter arterial embolization.
Hepatic amino-nitrogen clearance to urea-nitrogen in control subjects and in patients with cirrhosis: a simplified method, The functional hepatic nitrogen clearance during amino acid infusion is a measure of liver cell mass. The clinical feasibility of the test has so far been limited by methodological problems. A simplified procedure was used to measure the urea-nitrogen synthesis rate and functional hepatic nitrogen clearance in nine subjects with normal liver function and in nine patients with cirrhosis. The method was based on only four consecutive 2-hr urine collections and five blood samples. Total body water was calculated from a nomogram based on age and anthropometric data. whereas the gut urea hydrolysis was assigned one fixed fraction of synthesis (0.17 in control subjects and 0.26 in patients with cirrhosis). Finally. a solution of a single amino acid. alanine. was infused as substrate for urea synthesis. Urea-nitrogen synthesis rate increased linearly with increasing alpha-amino-nitrogen concentration. and the slope of the regression (functional hepatic nitrogen clearance) was reduced in cirrhosis from 37.5 +/- 7.0 L/hr to 18.4 +/- 6.7 L/hr; p less than 0.005. The hepatic nitrogen clearance was linearly related to the clinical status (Child-Pugh score). to routine liver function tests and to galactose elimination capacity (r = 0.869). a well-established. quantitative. liver function measure. The simplified method makes the measurement of hepatic nitrogen clearance suitable for routine clinical use. The test might prove useful to study the alterations of nitrogen metabolism in cirrhosis. with special reference to hepatic encephalopathy.
Autoantibodies in primary biliary cirrhosis: analysis of reactivity against eukaryotic and prokaryotic 2-oxo acid dehydrogenase complexes, Six components of the mammalian 2-oxo acid dehydrogenase complexes have previously been identified as M2 autoantigens in primary biliary cirrhosis. In this report. we present data showing that both polypeptide-specific and cross-reacting antibodies are present in patients' sera. Antibodies reacting with E2 of the pyruvate dehydrogenase complex cross-react with protein X but not with any other mammalian antigen. The main immunogenic region on protein X has been localized to within its single lipoyl domain. Polypeptide-specific antibodies bind to E1 alpha and E1 beta of the pyruvate dehydrogenase complex. Antibodies reacting with the E2 polypeptides of the 2-oxoglutarate dehydrogenase complex and branched-chain 2-oxo acid dehydrogenase complex show some cross-reactivity but do not recognize any of the antigens of the pyruvate dehydrogenase complex. Antibodies against the E2 component of the mammalian pyruvate dehydrogenase complex cross-react effectively with the corresponding protein from yeast but not with E2 from Escherichia coli. Antibody titer against mammalian antigens is significantly higher than against the bacterial antigens. arguing against a bacterial origin for primary biliary cirrhosis.
Quantitation of intrinsic drug-metabolizing capacity in human liver biopsy specimens: support for the intact-hepatocyte theory, Hepatic drug metabolism is decreased in patients with severe liver disease. but it is unclear to what extent this is due to altered hepatic blood flow or reduced intrinsic metabolic capacity. In this study we quantitated in needle-biopsy specimens the intrinsic capacity of liver tissue from 67 patients with mild liver disease (n = 36). chronic active hepatitis (n = 16) and cirrhosis (n = 15) to metabolize two model compounds in vitro. Hydroxylation of the low-extraction drug bufuralol resulted in the formation of 251 +/- 25 nmol 1'OH-bufuralol/gm wet wt/hr in mildly diseased liver tissue and was significantly (p less than 0.01) reduced in liver tissue exhibiting chronic active hepatitis (166 +/- 23 nmol/gm wet wt/hr) and cirrhosis (124 +/- 21 nmol/gm wet wt/hr). The formation rates of monoethylglycinexylidide. the main metabolite of the high-extraction drug lidocaine. varied widely and were not significantly different among the three groups. To relate the drug-metabolizing capacity to the hepatocyte content of liver tissue. morphometrical study was performed in the biopsy pieces originally submitted. The metabolic activity of each biopsy piece was then related to the fractional volume of hepatocytes it was calculated to contain. In mildly diseased liver tissue 355 +/- 35 nmol 1'OH-bufuralol/ml hepatocytes x hr or 12.4 +/- 1.0 mumol monoethylglycinexylidide/ml hepatocytes x hr- and in cirrhotic liver tissue 306 +/- 49 nmol 1'OH-bufuralol/ml hepatocytes x hr or 15.3 +/- 3.0 mumol monoethylglycinexylidide/ml hepatocytes x hr--were formed. respectively. and these differences were not significant.
The sensitized liver represents a rich source of endogenous leukotrienes, The ability of livers to produce endogenous leukotrienes after immunological stimulation was tested with organs from rats and guinea pigs. Passive sensitization of rats in vivo with monoclonal murine antidinitrophenol-IgE before antigen challenge in the isolated perfused liver system elicited a rapid hepatic production and biliary excretion of leukotrienes as judged by radioimmunoassay after separation of individual leukotrienes by high-performance liquid chromatography. Within 10 min after antigen infusion. mainly leukotriene C4. but also leukotriene D4 and N-acetyl-leukotriene E4. appeared in the bile. The biliary excretion rate of antigen-induced cysteinyl leukotrienes rose from less than 2 pmol.min-1.(kg body mass)-1 before challenge to about 30 pmol.min-1.(kg body mass)-1 for 20 min before it declined toward prechallenge level. Quantitatively similar hepatic production of cysteinyl leukotrienes was elicited in isolated perfused guinea pig livers challenged with ovalbumin after active sensitization of the animals with ovalbumin plus Al(OH)3. To exclude extrahepatic contributions to the observed leukotriene production. both passive sensitization with anti-dinitrophenol-IgE and subsequent antigen challenge were performed on isolated rat livers perfused with blood-free medium. Such exclusively hepatic sensitization and challenge also resulted in massive production of leukotrienes. The biliary excretion rate of cysteinyl leukotrienes amounted to approximately 20 pmol.min-1.(kg body mass)-1 during the 10 to 20 min period after antigen challenge as compared with less than 1 pmol.min-1.(kg body mass)-1 before challenge.
In micronodular cirrhosis, hepatocytes retain a normal C-25 hydroxylation capacity toward vitamin D3: a study using the rat carbon tetrachloride-induced cirrhotic model, To test further the competence of the cirrhotic liver to metabolize vitamin D3 at C-25. hepatocytes were isolated from controls and from CCl4-induced cirrhotic rat livers. as well as from partially hepatectomized rats. The transformation of D3 into 25-hydroxyvitamin D3 was studied in the presence of 10(7) hepatocytes at D3 concentrations of 20 nmol/L to 15.4 mumol/L. Histologically. micronodular cirrhosis was present in all CCl4-treated rats. whereas controls had normal livers; portal venous pressure (p less than 0.008) and intrahepatic collagen content (p less than 0.0001) were significantly increased in CCl4-treated rats. whereas no difference was found between the two groups in the total and ionized serum calcium. D3 metabolites. ALT. AST and alkaline phosphatase. Cytochrome P-450 was 0.27 +/- 0.02 and 0.25 +/- 0.02 nmol/10(6) hepatocytes in controls and cirrhotic rats (N.S.). and it significantly increased in both groups after phenobarbital or 3-methylcholanthrene administration (p less than 0.0001). 25-Hydroxyvitamin D3 formation was best described by power law equations and varied between 0.02 +/- 0.0004 and 29.57 +/- 2.8 in controls. and 0.024 +/- 0.0004 and 32.0 +/- 7.0 pmol.hr-1.10(6) hepatocytes-1 in cirrhotic rats. No statistically significant difference was found in the slopes of the 25-hydroxyvitamin D3 formation. but the y-axis intercept was found to be lower in cirrhotic rats under basal resting conditions (p less than 0.005). Inducers of the mixed function oxidases significantly increased 25-hydroxyvitamin D3 formation in controls as well as in cirrhotic rats (p less than 0.005). Moreover. both groups were found to respond similarly to the addition of modulators of the enzyme such as the calcium ionophore A23187 and parathyroid hormone. Partial hepatectomy was also without effect on the activation of D3. Furthermore. the cell sequestration of D3 was also found to be unperturbed in hepatocytes obtained from either cirrhotic or partially hepatectomized livers. The data indicate that in well-compensated micronodular cirrhosis. the C-25 hydroxylation of D3 is generally intrinsically normal at the cellular level and that it also remains fully responsive to in vivo and in vitro modulators of its activity.
Rapid induction of hepatic fibrosis in the gerbil after the parenteral administration of iron-dextran complex, The parenteral administration of iron-dextran complex to gerbils caused hepatic hemosiderosis and fibrosis after 6 wk. Type I and III collagen synthesis in the liver developed from perisinusoidal stellate cells that are often referred to as myofibroblasts. Immunohistologically these cells were shown to have large intracellular deposits of ferritin. The hepatic fibrosis appeared to be associated with aggregates of these cells rather than the aggregates of Kupffer cells. which also occur in hemosiderosis in the liver. No appreciable necrosis of hepatocytes to trigger the fibrotic response was found. so that the fibrosis appeared to be related to the accumulation of ferritin in the perisinusoidal stellate cells. In contrast. rats and mice did not accumulate ferritin in their perisinusoidal cells or develop hepatic fibrosis in response to parenterally administered iron. although they accumulated similar or greater amounts of total iron in their livers. The rapid induction of hepatic fibrosis in gerbils in response to parenterally administered iron will provide a model to investigate the mechanism of induction of collagen deposition in response to iron overload and a means of quickly evaluating therapeutic treatments for iron overload-induced fibrosis in vivo using iron-chelating drugs.
Regulation of collagen production in freshly isolated cell populations from normal and cirrhotic rat liver: effect of lactate, Previous work has shown that lactic acid. and to a lesser extent pyruvic acid. is able to increase collagen synthesis significantly in liver slices of CCl4-treated rats but not normal rats. The purpose of this report is to document which cells in the cirrhotic liver are responsible for the lactate-stimulated increase in collagen synthesis. It was found that (a) incorporation of 3H-proline into protein-bound 3H-hydroxyproline is increased threefold to fourfold in hepatocytes from CCl4-treated rats as compared with normal rat hepatocytes; (b) neither the hepatocytes from normal nor those from CCl4-treated rats modify their collagen synthesizing capacity when 30 mmol/L lactic acid was added to the incubation medium; (c) nonparenchymal cells obtained from livers of CCl4-treated rats synthesize much less collagen than hepatocytes. but their synthesis is stimulated twofold by lactic acid; (d) from the different nonparenchymal cells. only fat-storing (Ito) cells increase collagen synthesis when lactic acid is present in the incubation medium. These results suggest that the increased lactic acid levels observed in patients with alcoholic hepatic cirrhosis may play an important role in the development of fibrosis by stimulating collagen production by fat-storing (Ito) cells.
Adrenergic stimulation of renal prostanoids in the Lyon hypertensive rat, Young. genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of norepinephrine and an elevated urinary excretion of thromboxane B2 when compared with normotensive (LN) and low blood pressure (LL) controls. Therefore. the effects of norepinephrine (1.2 x 10(-8) to 9.6 x 10(-7) M) and of phenylephrine (5 x 10(-8) to 1.9 x 10(-6) M) on renal function and the urinary excretion of prostanoids were assessed in isolated perfused kidneys of 8-week-old LH. LN. and LL rats. In addition. the effects of norepinephrine were assessed before and during thromboxane A2/prostaglandin H2 receptor blockade by AH23848 (4 x 10(-6) M). Before drug infusion. LH kidneys differed from those of LN and LL controls by having an elevated renal vascular resistance and a decreased natriuresis and glomerular filtration rate; the urinary output of prostaglandin E2 and F2 alpha. of 6-ketoprostaglandin F1 alpha. and of thromboxane B2 was similar in the three strains. The constrictor effects of norepinephrine and phenylephrine were significantly increased in LH rat kidneys compared with LL but not with LN controls. and their pressure-natriuresis was markedly reduced. Norepinephrine and phenylephrine induced a 10- to 20-fold dose-dependent increase in the synthesis of the four prostanoids. which was more pronounced in LH than in LN and LL rats for thromboxane B2 only. AH23848 infusion significantly reduced the vascular effects of norepinephrine and increased the natriuretic response of LH but not of LN and LL rat kidneys.
Small artery resistance increases during the development of renal hypertension, Vascular pressures were measured in the principal (A1) arteriole and in upstream small arteries of the rat cremaster muscle to investigate vascular resistance changes associated with one-kidney. one clip Goldblatt hypertension. Pressure measurements were made at a proximal and distal site of each vessel using a servonull micropipette system. Vessel diameters were measured using video microscopy. A1 arteriole and external spermatic artery diameters were both decreased after 2 and 4 weeks of hypertension. Mean arterial pressure was elevated after 2 weeks of hypertension (106 +/- 4 mm Hg versus 140 +/- 5 mm Hg). Likewise. vascular pressures were elevated at every site: pudicepigastric artery (36%). external spermatic artery (47%). and A1 arteriole (38%). The pressure drop along the external spermatic artery was increased (87%) after 2 weeks of hypertension. Mean arterial pressure was further elevated from 2-4 weeks of hypertension (105 +/- 4 mm Hg versus 162 +/- 7 mm Hg) but only the proximal pudic-epigastric artery pressure was further elevated during this time from 2 to 4 weeks (131 +/- 5 mm Hg versus 147 +/- 7 mm Hg) of hypertension development. This was associated with an increased pressure drop (87%) along the artery compared with the situation at 2 weeks. These data indicate that small arteries upstream from the microcirculation contribute significantly to the increase in vascular resistance during hypertension. In addition. these data indicate that the increases in small artery resistance do not develop uniformly throughout all vessel branches.
Kinetic abnormalities of the red blood cell sodium-proton exchange in hypertensive patients, The present study was designed to examine the kinetics of Na(+)-H+ exchange in red blood cells of normotensive and hypertensive subjects and its relation to the previously reported abnormalities in Na(+)-Li+ exchange. The Na(+)-H+ antiporter activation kinetics were studied by varying cell pH and measuring net Na+ influx (mmol/l cell x hr = units) driven by an outward H+ gradient. The Na(+)-Li+ exchange was determined at pH 7.4 as sodium-stimulated Li+ efflux. Untreated hypertensive patients (n = 30) had a higher maximal rate of Na(+)-Li+ exchange (0.43 +/- 0.05 versus 0.26 +/- 0.02 units. p less than 0.0003). a higher maximal rate of Na(+)-H+ exchange (62.3 +/- 6.2 versus 47 +/- 4 units; p less than 0.02). but a similar affinity for cell pH compared with normotensive subjects (n = 46). The cell pH activation of the Na(+)-H+ antiporter exhibited a lower Hill coefficient than that of normotensive subjects (1.61 +/- 0.12 versus 2.56 +/- 0.14; p less than 0.0001). This index of occupancy of internal H+ regulatory sites was found reduced in most of the hypertensive patients (73%) whether their hypertension was untreated or treated. Hypertensive patients with Na(+)-Li+ exchange above 0.35 units (0.68 +/- 0.057 units. n = 16) did not exhibit elevated maximal rates of Na(+)-H+ exchange (57.3 +/- 10 units. NS) in comparison with those with Na(+)-Li+ exchange below 0.35 units (66.4 +/- 7.6 units. n = 26). but both groups exhibited reduced Hill coefficients. Hypertensive patients with enhanced Na(+)-H+ exchange activity (more than 90 units) had normal maximal rates of Na(+)-Li+ exchange.
Specific supersensitivity of the mesenteric vascular bed of Dahl salt-sensitive rats, Dahl salt-sensitive (DS) and salt-resistant (DR) rats were maintained on a diet containing normal (0.45%) or high (7%) salt for 5 days. The DS rats had slightly higher systolic blood pressures than DR rats. although a high salt diet failed to significantly elevate pressure in either group when compared with their appropriate (low salt diet) controls. The sensitivity of the isolated. perfused mesenteric vasculature from DS rats fed a high salt diet to nerve stimulation was greater when compared with all other groups in the presence or absence of cocaine (1 microM). A similar difference in sensitivity between high salt DS rats and high salt DR rats to bolus injections of norepinephrine was observed only in the presence of cocaine. The change in sensitivity was characterized by a leftward shift of the dose-response curve without a change in maximum response. No difference in sensitivity between the high salt DS group and any other treatment group was observed in response to the pressor agents KCl. angiotensin II. 5-hydroxytryptamine or the depressor agent acetylcholine. These data indicate that DS rats on a short-term. high salt diet possess a significant and specific elevation in sensitivity to nerve stimulation and norepinephrine in the absence of an increase in blood pressure. Differences in the effectiveness of cocaine among the groups suggest that differences may exist in neuronal uptake (uptake 1).
High NaCl diet enhances arterial baroreceptor reflex in NaCl-sensitive spontaneously hypertensive rats, Previous studies from our laboratory have shown that arterial baroreceptor reflex control of lumbar sympathetic nerve activity is blunted in the NaCl-sensitive spontaneously hypertensive rat (SHR-S) compared with either the NaCl-resistant spontaneously hypertensive rat (SHR-R) or the normotensive Wistar-Kyoto (WKY) rat. In the current study. the effect of dietary NaCl supplementation on arterial baroreceptor reflex control of lumbar sympathetic nerve activity and heart rate was assessed in SHR-S and control SHR-R and WKY rats. Male SHR-S. SHR-R. and WKY rats were fed diets containing either 1% or 8% NaCl beginning at 7 weeks of age and were studied at age 9-10 weeks. Arterial baroreceptor reflex-mediated changes in lumbar sympathetic nerve activity and heart rate were recorded in conscious. unrestrained rats during phenylephrine-induced (15-40 micrograms/kg/min) and nitroprusside-induced (15-300 micrograms/kg/min) changes in mean arterial pressure. SHR-S maintained on a 1% NaCl diet had blunted baroreceptor reflex control of lumbar sympathetic nerve activity during acute increases in MAP compared with SHR-R and WKY rats (p less than 0.05). After ingestion of the 8% NaCl diet. this blunting was absent. indicating enhancement of baroreceptor reflex control of lumbar sympathetic nerve activity. SHR-S maintained on a 1% NaCl diet also had blunted arterial baroreceptor control of lumbar sympathetic nerve activity during nitroprusside-induced decreases in mean arterial pressure compared with WKY rats. but this was not significantly altered during ingestion of the 8% NaCl diet.
Effect of age on coronary circulation after imposition of pressure-overload in rats, We examined the effects of pressure overload on coronary circulation in young adult (7 months old) and old rats (18 months old). Four weeks after the ascending aorta was banded. in vivo left ventricular pressure was measured to estimate the degree of pressure load. In the two age groups. similar increases in peak left ventricular pressure were observed (113 +/- 7 mm Hg in sham-operated rats versus 160 +/- 11 mm Hg in banded rats of the young adult group; 103 +/- 7 mm Hg in sham-operated rats versus 156 +/- 11 mm Hg in banded rats of the old group). After isolating the hearts. they were perfused with Tyrode's solution containing bovine red blood cells and albumin. Resting coronary perfusion pressure-flow relations and reactive hyperemic response after a 40-second ischemia were obtained under beating but nonworking conditions. In young adult banded rats. significant myocardial hypertrophy was observed at the organ level (124% of controls in left ventricular dry weight/body weight ratio; 119% in left ventricular dry weight/tibial length ratio) and at the cell level. Minimal coronary vascular resistance obtained by the perfusion pressure-peak flow relation during reactive hyperemia increased to 150% of controls. and coronary flow reserve decreased significantly. In contrast. myocardial hypertrophy was not observed at the organ or cell level in old banded rats. However. minimal coronary vascular resistance increased. and flow reserve decreased significantly. Thus. pressure overload with coronary arterial hypertension caused abnormalities of the coronary circulation in old subjects even in the absence of myocardial hypertrophy.
Systolic Hypertension of the Elderly Program (SHEP). Part 10: Analysis, The SHEP is a randomized. placebo-controlled trial that will follow standard clinical trial principles in analyzing data relating to its proposed hypotheses. The protocol has stated a priori the main objective as well as the secondary subgroup hypotheses. Sample size calculations for SHEP have accounted for dropins to and drop-outs from active therapy as well as for the risk of nonstroke death. The sample size achieved (4.736 participants) should be adequate to address the proposed questions. Monitoring procedures have been described and established. A data and safety monitoring board that uses these procedures is closely following the data from the trial. The board will periodically examine the data to determine whether termination of the study is warranted.
Arterial mechanical properties in dilated cardiomyopathy. Aging and the response to nitroprusside, The effects of aging on arterial mechanical properties and the response to nitroprusside were examined in 25 patients with dilated cardiomyopathy. High-fidelity pressures were recorded with a multisensor catheter. Pulse wave velocity was determined between two sensors in the thoracic aorta. Arterial compliance was determined by an analysis of the diastolic waveform and cardiac output. At baseline. despite a similar systemic vascular resistance. the pulsatile load (e.g.. arterial compliance) and wave transmission characteristics (e.g.. pulse wave velocity) were altered with aging. Arterial compliance was reduced in older (greater than 50 yr. n = 8) versus younger (less than 35 yr. n = 8) patients (0.51 +/- 0.17 vs. 1.33 +/- 0.63 ml/mmHg. P less than 0.01) and intermediate in those 35-50 yr of age (n = 9. 0.72 +/- 0.40 ml/mmHg). There was a positive correlation between age and pulse wave velocity (r = +0.90). Nitroprusside infusion decreased resistance. increased arterial compliance. and lowered pulse wave velocity in all groups. Yet. advancing age was associated with a greater fall in wave velocity for a given fall in aortic pressure. The slope (K) of the relation between pulse wave velocity and aortic diastolic pressure progressively increased with age (0.01 +/- 0.03. 0.06 +/- 0.02. and 0.09 +/- 0.03 m/s-mmHg). Multiple linear regression analysis revealed a significant relation between K and age. These data demonstrate that in older patients with dilated cardiomyopathy the left ventricle is coupled to an arterial circulation that has a greater pulsatile load. despite a similar steady load. Furthermore. these age-related changes in the arterial system affect the hemodynamic response to pharmacologically-induced vasodilatation.
Transforming growth factor-beta and suppression of humoral immune responses in HIV infection, We reported previously that PBMC from HIV+ patients spontaneously release increased levels of TGF beta 1. contributing to defects in cellular immune responses. This study defines the implications of TGF beta overexpression for humoral immunity in HIV infection. We found that upon Staphylococcus aureus Cowan I (SAC) stimulation of cells from HIV+ donors. B-lymphocyte proliferative responses were decreased. This deficiency correlated closely (r = 0.7. P less than 0.001) with increased TGF beta secretion by PBMC from HIV-infected donors. Conditioned medium from HIV+ PBMC and purified TGF beta 1 had similar inhibitory effects on SAC- or EBV-induced B-cell proliferation. and B cells from HIV-infected donors were as sensitive to inhibition by TGF beta as cells from normal donors. Antibodies to TGF beta 1 neutralized the inhibitory effect of HIV+ culture supernatants on normal B cells and increased low proliferative responses by HIV+ cells. Using PWM as stimulus for B cell differentiation. it was shown that activated TGF beta from HIV+ PBMC is able to significantly reduce the induction of immunoglobulins and this effect was also abrogated by anti-TGF beta. These studies support the concept that in HIV infection. TGF beta is a potent suppressor. not only of the cellular. but of the humoral immune responses as well.
Diastolic dysfunction in hypertrophic cardiomyopathy. Effect on active force generation during systole, We tested the hypothesis that intracellular Ca++ [( Ca++]i) overload underlies the diastolic dysfunction of patients with hypertrophic cardiomyopathy. Myocardial tissue was obtained at the time of surgery or transplantation from patients with hypertrophic cardiomyopathy and was compared with control myocardium obtained from patients without heart disease. The isometric contractions and electrophysiologic properties of all myocardial specimens were recorded by standard techniques and [Ca++]i was measured with the bioluminescent calcium indicator aequorin. In contrast to the controls. action potentials. Ca++ transients. and isometric contraction and relaxation were markedly prolonged in the hypertrophic myocardium. and the Ca++ transients consisted of two distinct components. At 38 degrees C and 1 Hz pacing frequency. a state of relative Ca++ overload appeared develop. which produced a rise in end-diastolic [Ca++]i. incomplete relaxation. and fusion of twitches with a resultant decrease in active tension development. We also found that drugs with increase [Ca++]i. such as digitalis. exacerbated these abnormalities. whereas drugs that lower [Ca++]i. such as verapamil. or agents that increase cyclic AMP. such as forskolin. prevented them. These results may explain why patients with hypertrophic cardiomyopathy tolerate tachycardia poorly. and may have important implications with regard to the pharmacologic treatment of patients with hypertrophic cardiomyopathy.
Risk factors for emphysema. Cigarette smoking is associated with a reduction in the association rate constant of lung alpha 1-antitrypsin for neutrophil elastase, The increased risk of developing emphysema among individuals who smoke cigarettes and who have normal levels of alpha 1-antitrypsin (alpha 1AT) is hypothesized to result from a decrease in the antineutrophil elastase capacity of the lower respiratory tract alpha 1AT of smokers compared with nonsmokers. To evaluate this hypothesis we compared the time-dependent kinetics of the inhibition of neutrophil elastase by lung alpha 1AT from healthy. young cigarette smokers (n = 8) and nonsmokers (n = 12). alpha 1-antitrypsin was purified from lavage fluid using affinity and molecular sieve chromatography. and the association rate constant (k assoc) for neutrophil elastase quantified. The k assoc of smoker plasma alpha 1AT (9.5 +/- 0.5 X 10(6) M-1s-1) was similar to that of nonsmoker plasma (9.3 +/- 0.7 X 10(6) M-1s-1. P greater than 0.5). In marked contrast. the k assoc of smoker lower respiratory tract alpha 1AT was significantly lower than that of nonsmoker alpha 1AT (6.5 +/- 0.4 X 10(6) M-1s-1 vs. 8.1 +/- 0.5 X 10(6) M-1s-1. P less than 0.01). Furthermore. the smoker lower respiratory tract alpha 1AT k assoc was significantly less than that of autologous plasma (P less than 0.01). When considered in the context of the concentration of alpha 1AT in the lower respiratory tract epithelial lining fluid. the inhibition time for neutrophil elastase of smoker lung alpha 1AT was twofold greater than that of nonsmoker lung alpha 1AT (smoker: 0.34 +/- 0.05 s vs. nonsmoker: 0.17 +/- 0.05 s. P less than 0.01). Consequently. for concentrations of alpha 1AT in the lower respiratory tract it takes twice as long for an equivalent amount of neutrophil elastase to be inhibited in the smoker's lung compared with the nonsmoker's lung. These observations support the concept that cigarette smoking is associated with a decrease in the lower respiratory tract neutrophil elastase inhibitory capacity. thus increasing the vulnerability of the lung to elastolytic destruction and thereby increasing the risk for the development of emphysema.
Pretranslational suppression of a glucose transporter protein causes insulin resistance in adipocytes from patients with non-insulin-dependent diabetes mellitus and obesity, A major portion of insulin-mediated glucose uptake occurs via the translocation of GLUT 4 glucose transporter proteins from an intracellular depot to the plasma membrane. We have examined gene expression for the GLUT 4 transporter isoform in subcutaneous adipocytes. a classic insulin target cell. to better understand molecular mechanisms causing insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) and obesity. In subgroups of lean (body mass index [BMI] = 24 +/- 1) and obese (BMI = 32 +/- 2) controls and in obese NIDDM (BMI = 35 +/- 2) patients. the number of GLUT 4 glucose transporters was measured in total postnuclear and subcellular membrane fractions using specific antibodies on Western blots. Relative to lean controls. the cellular content of GLUT 4 was decreased 40% in obesity and 85% in NIDDM in total cellular membranes. In obesity. cellular depletion of GLUT 4 primarily involved low density microsomes (LDM). leaving fewer transporters available for insulin-mediated recruitment to the plasma membrane (PM). In NIDDM. loss of GLUT 4 was profound in all membrane subfractions. PM. LDM. as well as high density microsomes. These observations corresponded with decrements in maximally stimulated glucose transport rates in intact cells. To assess mechanisms responsible for depletion of GLUT 4. we quantitated levels of mRNA specifically hybridizing with human GLUT 4 cDNA on Northern blots. In obesity. GLUT 4 mRNA was decreased 36% compared with lean controls. and the level was well correlated (r = + 0.77) with the cellular content of GLUT 4 protein over a wide spectrum of body weight. GLUT 4 mRNA in adipocytes from NIDDM patients was profoundly reduced by 86% compared with lean controls and by 78% relative to their weight-matched nondiabetic counterparts (whether expressed per RNA. per cell. or for the amount of CHO-B mRNA). Interestingly. GLUT 4 mRNA levels in patients with impaired glucose tolerance (BMI = 34 +/- 4) were decreased to the same level as in overt NIDDM. We conclude that. in obesity. insulin resistance in adipocytes is due to depletion of GLUT 4 glucose transporters. and that the cellular content of GLUT 4 is determined by the level of encoding mRNA over a wide range of body weight. In NIDDM. more profound insulin resistance is caused by a further reduction in GLUT 4 mRNA and protein than is attributable to obesity per se. Suppression of GLUT 4 mRNA is observed in patients with impaired glucose tolerance. and therefore. may occur early in the evolution of diabetes.(ABSTRACT TRUNCATED AT 400 WORDS).
An autocrine role for urokinase in phorbol ester-mediated differentiation of myeloid cell lines, The human myeloid cell line HL60 secretes urokinase-type plasminogen activator (uPA) and expresses its receptor. When stimulated with phorbol myristate acetate (PMA). both secretion of uPA and the expression of its receptor are up-regulated. and these cells differentiate to an adherent phenotype. This adhesive response is markedly reduced in the presence of uPA antibodies. The PMA response is restored by the addition of native uPA. an amino-terminal fragment of uPA (residues 1-143) devoid of proteolytic activity. or a synthetic peptide (residues 12-32) from the uPA growth factor domain known to mediate receptor binding. In contrast. the addition of catalytically active low molecular weight uPA. which is missing the growth factor domain. or a peptide from the catalytic domain (residues 247-266) is ineffective. The influence of uPA antibodies on a second marker of macrophage differentiation. cysteine proteinase activity. was also examined. Cysteine proteinase activity of HL60 cells is increased in PMA-treated cells after 24 h but it fails to increase in the presence of anti-uPA. This increase in cathepsin B-like activity is also restored by exogenous uPA. These experiments indicate that an autocrine interaction of the growth factor domain of uPA with its receptor mediates an essential step in PMA-mediated myeloid cell differentiation.
Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism, In addition to its classical effects on growth. growth hormone (GH) has been shown to have a number of other actions. all of which are initiated by an interaction with specific high affinity receptors present in a variety of tissues. Purification of a rabbit liver protein via its ability to bind GH has allowed the isolation of a cDNA encoding a putative human growth hormone receptor that belongs to a new class of transmembrane receptors. We have previously shown that this putative growth hormone receptor gene is genetically linked to Laron dwarfism. a rare autosomal recessive syndrome caused by target resistance to GH. Nevertheless. the inability to express the corresponding full-length coding sequence and the lack of a test for growth-promoting function have hampered a direct confirmation of its role in growth. We have now identified three nonsense mutations within this growth hormone receptor gene. lying at positions corresponding to the amino terminal extremity and causing a truncation of the molecule. thereby deleting a large portion of both the GH binding domain and the full transmembrane and intracellular domains. Three independent patients with Laron dwarfism born of consanguineous parents were homozygous for these defects. Two defects were identical and consisted of a CG to TG transition. Not only do these results confirm the growth-promoting activity of this receptor but they also suggest that CpG doublets may represent hot spots for mutations in the growth hormone receptor gene that are responsible for hereditary dwarfism.
A mutation in the DNA-binding domain of the androgen receptor gene causes complete testicular feminization in a patient with receptor-positive androgen resistance, Androgen resistance is associated with a wide range of quantitative and qualitative defects in the androgen receptor. However. fibroblast cultures from approximately 10% of patients with the clinical. endocrine. and genetic features characteristic of androgen resistance express normal quantities of apparently normal androgen receptor in cultured genital skin fibroblasts (receptor-positive androgen resistance). We have analyzed the androgen receptor gene of one patient (P321) with receptor-positive. complete testicular feminization and detected a single nucleotide substitution at nucleotide 2006 (G----C) within the second "zinc finger" of the DNA-binding domain that results in the conversion of the arginine residue at position 615 into a proline residue. Introduction of this mutation into the androgen receptor cDNA and transfection of the expression plasmid into eukaryotic cells lead to the synthesis of a receptor protein that displays normal binding kinetics but is inactive in functional assays of receptor activity. We conclude that substitution mutations in the DNA-binding domain of the androgen receptor are one cause of "receptor-positive" androgen resistance.
Differential regulation of adipose tissue glucose transporters in genetic obesity (fatty rat). Selective increase in the adipose cell/muscle glucose transporter (GLUT 4) expression, Adipocytes from young obese Zucker rats exhibit a hyperresponsive insulin-mediated glucose transport. together with a marked increase in cytochalasin B binding as compared with lean rat adipocytes. Here. we examined in these cells the expression of two isoforms of glucose transporter. the erythroid (GLUT 1) and the adipose cell/muscle (GLUT 4) types. in rats aged 16 or 30 d. i.e.. before and after the emergence of hyperinsulinemia. GLUT 1 protein and mRNA levels were identical in the two genotypes at both ages. In contrast. the levels of GLUT 4 protein in obese rat adipocytes were 2.4- and 4.5-fold those of lean littermates at 16 and 30 d of age. respectively. in perfect agreement with the genotype effect on insulin-stimulated glucose transport activity. The levels of GLUT 4 mRNA per fat pad were increased 2.3- and 6.2-fold in obese vs. lean rats 16- and 30-d-old. indicating a pretranslational level of regulation. The obese phenotype was not associated with overexpression of GLUT 4 mRNA in gastrocnemius muscle. This work indicates that the fa gene exerts a differential control on the expression of GLUT 1 and GLUT 4 in adipose tissue and provides evidence that independent of hyperinsulinemia. genotype is a major regulatory factor of GLUT 4 expression in this tissue.
Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation, Studies were undertaken to investigate acquired resistance to cisplatin in human ovarian cancer cells. The cell lines A2780 and A2780/CP70 were studied to assess their respective characteristics of drug accumulation and efflux. cytosolic inactivation of drug. and DNA repair. All experiments were performed using 1-h drug exposures. The A2780/CP70 cell line was 13-fold more resistant to cisplatin than A2780 cells. When studied at their respective IC50 doses. drug accumulation rates were similar for the two cell lines. However. the resistant cell line was twofold more efficient at effluxing drug. which was associated with reduced total drug accumulation for equivalent micromolar drug exposures. At equivalent levels of total cellular drug accumulation. the two cell lines formed the same levels of cisplatin-DNA damage. suggesting that cytosolic inactivation of drug does not contribute to the differential in resistance between these cell lines. Resistant cells were also twofold more efficient at repairing cisplatin-DNA lesions in cellular DNA and in transfected plasmid DNA. We conclude that in these paired cell lines. alterations in drug uptake/efflux and in DNA repair are the major contributing factors to acquired resistance to cisplatin.
Renal nerves modulate renin gene expression in the developing rat kidney with ureteral obstruction, Chronic unilateral ureteral obstruction (UUO) in newborn rats activates renin gene expression in the obstructed kidney. and increases renin distribution along afferent glomerular arterioles in both kidneys. To investigate the role of the renal nerves in this response. 2-d-old Sprague-Dawley rats were subjected to UUO or sham operation. Chemical sympathectomy was performed by injection of guanethidine. whereas. control groups received saline vehicle. At 4-5 wk. renal renin distribution was determined by immunocytochemistry. and renin mRNA levels were determined by Northern blot hybridization. Compared to the saline-treated rats with UUO. renin remained localized to the juxtaglomerular region in both kidneys of rats with UUO receiving guanethidine (P less than 0.05). Moreover. renin mRNA levels were eightfold lower in obstructed kidneys of rats receiving guanethidine than in those receiving saline. Additional groups of rats with UUO were subjected to unilateral mechanical renal denervation: renin gene expression in the obstructed kidney was suppressed by ipsilateral but not by contralateral renal denervation. These findings indicate that either chemical or mechanical denervation suppressed the increase in renin gene expression of the neonatal kidney with ipsilateral UUO. We conclude that the renal sympathetic nerves modulate renin gene expression in the developing kidney with chronic UUO.
Plasticity of integrin expression by nerve-derived connective tissue cells. Human Schwann cells, perineurial cells, and fibroblasts express markedly different patterns of beta 1 integrins during nerve development, neoplasia, and in vitro, Strikingly selective expression patterns of beta 1. alpha 2. alpha 3. and alpha 5 integrin subunits were revealed in endoneurium. perineurium. and epineurium of fetal and adult human peripheral nerve by immunostaining with specific antibodies. The alpha 2 subunit was expressed only on Schwann cells both in fetal and adult nerve. whereas the alpha 3 epitopes were expressed exclusively in the adult tissue and were primarily present on perineurial cells. The alpha 5 epitopes were expressed only on the innermost cell layer of perineurium of fetal and adult nerve. The tumor cells within schwannomas and cutaneous neurofibromas expressed both alpha 2 and alpha 3 subunits. indicating that Schwann cells have the potential to express also the alpha 3 subunit in vivo. Cell cultures established from human fetal nerve and neurofibromas revealed expression of the alpha 2 and alpha 5 epitopes on Schwann cells. perineurial cells. and fibroblasts. whereas only Schwann cells contained the alpha 3 epitopes which were occasionally concentrated on the adjacent Schwann cells at cell-cell contacts. Our findings emphasize that nerve connective tissue cells change their profiles for expression of extracellular matrix receptors under conditions which have different regulatory control signals exerted by. for example. axons. humoral factors. or the extracellular matrix of the peripheral nerve. This plasticity may play an important role during nerve development and in neoplastic processes affecting the connective tissue compartments of peripheral nerve.
Expression of smooth muscle cell phenotype by rat mesangial cells in immune complex nephritis. Alpha-smooth muscle actin is a marker of mesangial cell proliferation, Mesangial cell proliferation is common in glomerulonephritis but it is unclear if proliferation is associated with any in vivo alteration in phenotype. We investigated whether mesangial of mesangial proliferative nephritis induced with antibody to the Thy-1 antigen present on mesangial cells. At day 3 glomeruli displayed de novo immunostaining for alpha-smooth muscle actin in a mesangial pattern. correlating with the onset of proliferation. and persisting until day 14. An increase in desmin and vimentin in mesangial regions was also noted. Immunoelectron microscopy confirmed that the actin-positive cells were mesangial cells. and double immunolabeling demonstrated that the smooth muscle actin-positive cells were actively proliferating. Northern analysis of isolated glomerular RNA confirmed an increase in alpha and beta/gamma actin mRNA at days 3 and 5. Complement depletion or platelet depletion prevented or reduced proliferation. respectively; these maneuvers also prevented smooth muscle actin and actin gene expression. Studies of five other experimental models of nephritis confirmed that smooth muscle actin expression is a marker for mesangial cell injury. Thus. mesangial cell proliferation in glomerulonephritis in the rat is associated with a distinct phenotypic change in which mesangial cell assume smooth muscle cell characteristics.
Apical secretion of lysosomal enzymes in rabbit pancreas occurs via a secretagogue regulated pathway and is increased after pancreatic duct obstruction, Lysosomal hydrolases such as cathepsin B are apically secreted from rabbit pancreatic acinar cells via a regulated as opposed to a constitutive pathway. Intravenous infusion of the cholecystokinin analogue caerulein results in highly correlated apical secretion of digestive and lysosomal enzymes. suggesting that they are discharged from the same presecretory compartment (zymogen granules). Lysosomal enzymes appear to enter that compartment as a result of missorting. After 7 h of duct obstruction is relieved. caerulein-stimulated apical secretion of cathepsin B and amylase is increased. but the ratio of cathepsin B to amylase secretion is not different than that following caerulein stimulation of animals never obstructed. These findings indicate that duct obstruction causes an increased amount of both lysosomal and digestive enzymes to accumulate within the secretagogue releasable compartment but that duct obstruction does not increase the degree of lysosomal enzyme missorting into that compartment. Pancreatic duct obstruction causes lysosomal hydrolases to become colocalized with digestive enzymes in organelles that. in size and distribution. resemble zymogen granules but that are not subject to secretion in response to secretagogue stimulation. These organelles may be of importance in the development of pancreatitis.
Hypoxia induces a specific set of stress proteins in cultured endothelial cells, Vascular endothelial cells (EC) are the initial cells within the vascular wall exposed to decreases in blood ambient oxygen concentration. The mechanisms by which they tolerate low levels of oxygen are unknown. but may parallel the response to other cellular stresses. such as heat shock. After 4-8 h of hypoxia. we found a decrease in total protein synthesis in both cultured bovine aortic and pulmonary arterial EC. SDS-PAGE and autoradiographic analysis of [35S]methionine-labeled proteins demonstrated the concomitant induction of a specific set of proteins (Mr 34. 36. 47. and 56 kD) in both cell types. These hypoxia-associated proteins (HAPs) were cell-associated and up-regulated in a time- and oxygen concentration-dependent manner. Comparison of these proteins with heat shock proteins (HSPs) demonstrated that HAPs were distinct from HSPs. EC maintained chronically in 3% O2 continued to synthesize elevated levels of HAPs. yet further up-regulated these proteins when exposed to 0% O2. The presence of five times the normal media glucose concentration did not alter the appearance of HAPs. Hypoxia sensitive renal tubular epithelial cells up-regulated no proteins corresponding to HAPs and were irreversibly damaged within 8 h of exposure to 0% O2. In vitro translation experiments demonstrated that the steady-state level of several mRNAs was higher in the anoxic EC than in normoxic EC and encoded for proteins of Mr 32. 35. 37. 40. and 48 kD that were different from proteins encoded by HSP mRNAs. The induction of HAPs during acute hypoxia and their continued synthesis in chronic hypoxia suggest that HAPs may be important in the maintenance of endothelial cell integrity under conditions of decreased ambient oxygen.
Differential diagnosis of mut and cbl methylmalonic aciduria by DNA-mediated gene transfer in primary fibroblasts, Methylmalonic aciduria can be caused by mutations in the gene encoding the methylmalonyl coenzyme A mutase apoenzyme (mut) or genes required for the provision of cofactor B12 (cbl). The mut and cbl forms are classically differentiated by somatic cell complementation. We describe a novel method for differential diagnosis of mut and cbl methylmalonic aciduria using DNA-mediated gene transfer of a methylmalonyl CoA mutase cDNA clone. Gene transfer of a functional methylmalonyl CoA mutase cDNA clone into mut fibroblasts reconstitutes holoenzyme activity measured by metabolism of [14C]-propionate in culture. Identical gene transfers into cbl fibroblasts have no effect. This method is used for the differential diagnosis of mut and cbl genotypes in cells from patients with a clinical diagnosis of methylmalonic aciduria and is shown to be a facile. sensitive. and specific method for genetic diagnosis. This work establishes the principle of using DNA-mediated gene transfer to identify the genotype of diseases which can result from mutations at several different genetic loci. This type of differential genotypic diagnosis will be particularly important for establishing the applicability of somatic gene therapy in individual patients.
Decreased content and surface expression of alpha-granule membrane protein GMP-140 in one of two types of platelet alpha delta storage pool deficiency, To determine whether alpha-granule membranes are present in platelets of patients with storage pool deficiencies of both alpha and dense granules (alpha delta-SPD). we examined the content and surface expression of the alpha-granule membrane protein GMP-140 in one patient (J.C.) with a severe alpha-granule deficiency and in three members of a family (family C) with milder alpha-granule deficiencies. Surface expression of GMP-140 in stimulated platelets. assessed by flow cytometric measurements of the binding of two anti-GMP-140 monoclonal antibodies. was 24-38% of normal values in platelets from patient J.C.. vs. 60-95% of normal values in family C. Total platelet content of GMP-140. determined in platelet lysates by antigen-capture ELISA. was 49% of normal in patient J.C.. but normal in the members of family C. Platelets of patient J.C. were found to be heterogeneous with respect to GMP-140 content and surface expression by both flow cytometry and immunogold electron microscopy. Approximately 80% of her platelets expressed little or no GMP-140 after stimulation. whereas the remaining 20% expressed normal amounts of GMP-140 and showed extensive immunogold labeling of typical alpha-granules and clear vacuoles. No such heterogeneity was found in platelets from family C. These findings in the severe alpha delta-SPD patient are in clear contrast to the observations of normal GMP-140 content in the three other alpha delta-SPD patients. and in patients with the gray platelet syndrome. reported previously by others. These results illustrate the phenotypic heterogeneity of alpha-granule deficiencies in human platelets. and suggest that a defect in granule formation in the megakaryocytes may account for the alpha-granule defect in at least one form of alpha delta-SPD.
Biology of basal cell carcinoma (Part I), Basal cell carcinoma is the most common malignancy in humans. Although rarely metastatic. it is capable of significant local destruction and disfigurement. This two-part article reviews the current understanding of basal cell carcinoma biology. Part I examines significant clinical. histologic. and ultrastructural features that relate to invasive potential. Genetic characteristics. including tumor growth rate. chromosomal abnormalities. and oncogene presence. are discussed. and expression of important cell and matrix proteins. including keratin. fibronectin. and HLA antigens. are reviewed. Further topics to be explored in Part II include host immunologic responses. theories of pathogenesis. and valuable second-line therapeutic regimens for treatment of multiple cancers.
Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa. A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry, Inherited epidermolysis bullosa encompasses a number of diseases. with the common finding of blister formation after minor mechanical trauma to the skin. In some forms significant. if not eventually fatal. extracutaneous disease activity may occur. In recent years application of newer technologies has contributed substantially to an overall understanding of this collection of inherited diseases. Concurrently. many new phenotypes have been recognized. in part the result of ongoing prospective patient registries in the United States and abroad. Unfortunately. this has resulted in a massive literature that may appear to be confounded by seemingly excessive or arbitrary subdivision of epidermolysis bullosa variants. With these concerns in mind a subcommittee was established by the National Epidermolysis Bullosa Registry to summarize the current literature and to make recommendations as to the best clinical and laboratory criteria for the practical diagnosis and subclassification of patients with inherited epidermolysis bullosa.
Allergic contact dermatitis to two antioxidants in latex gloves: 4,4'-thiobis(6-tert-butyl-meta-cresol) (Lowinox 44S36) and butylhydroxyanisole. Allergen alternatives for glove-allergic patients, Allergic contact dermatitis developed on the hands and/or face of two patients after exposure to latex examination gloves. Both patients were patch test negative to the usual rubber allergens. but both had a positive patch test reaction to 4.4'-thiobis(6-tert-butyl-m-cresol) (Lowinox 44S36). Patient 2 was also patch test positive to butylhydroxyanisole. The patients were tested with other gloves. to find gloves that they could safely use. Glove manufacturers were queried to ascertain the occurrence of Lowinox 44S36 and butylhydroxyanisole in different brands of latex and vinyl examination gloves. A list of gloves and their associated allergens was generated and is provided to assist dermatologists in helping patients choose gloves free of specific allergens.
Pathogenesis of onychoschizia (lamellar dystrophy), Onychoschizia or lamellar dystrophy of the nails is common. especially in adult women. but little information is available about its cause. Most theories involve environmental factors. but supportive experimental data are scarce. Therefore we studied the in vitro nail changes produced by several organic solvents. detergents. water. other polar materials. and both acidic and basic solutions. Challenged and control fingernail clippings were examined grossly. microscopically. and by scanning electron microscopy at regular intervals. There was a progressive increase in severity with prolonged wetting and drying. By 3 weeks. scanning electron microscopy demonstrated unattached individual cells in empty spaces in which separation was more prominent. Basic solutions caused some softening. but layering (peeling) was seen only after repeated hydration and dehydration. Although other factors may influence onychoschizia. the typical changes can be produced in normal nails after a 21-day challenge of repeated exposure to water followed by dehydration. These findings suggest a probable cause for the condition and a logical approach to management.
Immune sensitization against epidermal antigens in polymorphous light eruption, To get further insight into the pathogenesis of polymorphous light eruption. we studied nine patients with polymorphous light eruption and six healthy persons. Two skin biopsy specimens were obtained from each person. one from previously ultraviolet light-irradiated skin and another one from unirradiated skin. An epidermal cell suspension. skin homogenate. or both were prepared from each specimen. Autologous cultures were made with peripheral blood mononuclear cells combined with irradiated or unirradiated skin homogenate and peripheral blood mononuclear cells combined with irradiated or unirradiated epidermal cell suspension. Cell proliferation was assessed by 3H-thymidine incorporation assay. The response of peripheral blood mononuclear cells to unirradiated epidermal cells or unirradiated skin homogenate was similar in both patients and controls. However. peripheral blood mononuclear cells from patients with polymorphous light eruption showed a significantly increased proliferative response to both irradiated epidermal cells and irradiated skin homogenate. Our results indicate that ultraviolet light increases the stimulatory capability of polymorphous light eruption epidermal cells in a unidirectional mixed culture with autologous peripheral blood mononuclear cells. This suggests that an immune sensitization against autologous ultraviolet light-modified skin antigens occurs in polymorphous light eruption.
Propylene glycol dermatitis, Propylene glycol is a commonly used vehicle for topical preparations. Although it is well suited for this purpose. it is capable of producing both primary irritant skin reactions and allergic sensitization. The literature on propylene glycol is reviewed. with particular attention to the nature of these adverse cutaneous effects. Guidelines for patients sensitive to propylene glycol are discussed.
Persistent light reaction to hexachlorophene, The first patient with what appears to be persistent light reaction caused by hexachlorophene alone is reported. Persistent light reaction may occur in patients with milder degrees of photosensitivity. and appropriate photopatch testing should be performed.
Late metastases of cutaneous melanoma: case report and literature review, The development of delayed metastases. although rare. is well documented in patients with invasive cutaneous melanoma. Only 24 cases. including ours. are clearly documented in the literature. We describe a 56-year-old woman who had an acral lentiginous melanoma of the right hand (thickness 1.2 mm). Thirteen years after excision and postoperative irradiation. a subcutaneous metastasis developed in the right arm. One year later the patient died with disseminated bone metastases. This case. as with most of those with delayed metastases. has typical features: female sex; location at a site other than the back. arm. neck. or scalp; and primary tumor thickness between 1.2 and 2.5 mm.
Hereditary lactate dehydrogenase M-subunit deficiency: lactate dehydrogenase activity in skin lesions and in hair follicles, A 16-year-old Japanese girl had desquamating erythematosquamous lesions mostly on the extensor surface of the extremities. The lesions were worse in summer. The patient also had a mild muscle pain after strenuous exercise. Her paternal and maternal grandfathers are cousins. An analysis of lactic acid dehydrogenase (LDH) isozymes in her serum revealed a single peak of LDH1. Analysis of LDH isozymes of erythrocytes demonstrated a complete lack of LDH M-subunit in the patient and a substantial lack in the parents. The epidermis of the diseased skin and scalp hair follicles of the patient were virtually devoid of LDH activity.
Successful treatment of disseminated cutaneous cytomegalic inclusion disease associated with Hodgkin's disease, A case of disseminated cutaneous cytomegalic inclusion disease associated with Hodgkin's disease is described. The patient had a diffuse eruption of pruritic. erosive erythematous nodules. Histologically. many inclusion bodies were observed in perivascular areas of the skin lesions. Immunohistologically. the inclusion bodies positively stained with both anticytomegalovirus antibody and anti-factor VIII-related antibody. On electron microscopy many virus particles and dense bodies were found in the area where inclusion bodies were observed. Treatment with high-dose intravenous acyclovir and a large amount of immunoglobulin resulted in prompt healing of the skin lesions. Subsequently. the patient's Hodgkin's disease was well controlled on chemotherapy. The patient steadily improved without relapse of skin lesions 1 year after antiviral therapy was administered.
Multiple granular cell tumors associated with giant speckled lentiginous nevus and nevus flammeus in a child, We describe an 11-year-old girl in whom multiple cutaneous granular cell tumors were associated with a giant speckled lentiginous nevus and an extensive nevus flammeus. An association between granular cell tumors and pigmented skin lesions has been reported twice previously and supports a neural origin for these tumors. An abnormality of neural crest development is proposed to explain the coexistence of three uncommon and unusually extensive cutaneous disorders in this patient. This case may represent a further variant of phakomatosis pigmentovascularis.
Abnormal epidermal changes after argon laser treatment, A 26-year-old woman with a congenital port-wine stain on the forehead was treated three times at 2-month intervals with an argon laser. Six months after the last treatment. moderate blanching and mild scaling confined to the treated area was observed. A biopsy specimen of the treated area revealed a significant decrease in ectatic vessels. However. epidermal changes similar to those of actinic keratosis with disorganized cell layers and marked cytologic abnormalities were seen. Analysis of peripheral blood lymphocytes for a defect in DNA repair was negative. Multiple. argon laser-induced photothermal effects may be responsible for the changes observed in our case and may lead to premalignant epidermal transformation.
Hereditary deficiency of C5 in association with discoid lupus erythematosus, A 29-year-old woman with discoid lupus erythematosus had undetectable classic pathway complement activity. Hypocomplementemia was due to selective deficiency of C5. One of her children was also deficient. To our knowledge this is the first documented case of an association between discoid lupus erythematosus and C5 deficiency.
Thrombosis-related markers in unstable angina pectoris, While thrombus formation has been implicated in the pathogenesis of unstable angina. the value of thrombus-related markers for distinguishing unstable from stable angina is not well defined. Fibrin D-dimer and plasminogen activator inhibitor were prospectively analyzed in the peripheral blood of 46 patients (26 with unstable angina and 20 with stable angina or normal coronary arteries). Baseline blood samples were drawn within 24 h after rest pain in patients with unstable angina and in 19 of these 26 patients in less than 6 h. In patients with unstable angina. mean +/- SD (median) values for fibrin D-dimer and plasminogen activator inhibitor values measured 0.09 +/- 0.06 (0.07) microgram/ml and 9.1 +/- 9.6 (5.9) IU. respectively. compared to 0.11 +/- 0.10 (0.05) microgram/ml and 5.5 +/- 1.9 (5.0) IU/ml. in patients in the control group (p = NS for all comparisons between the two groups). Recurrent in-hospital pain. coronary anatomy and need for intervention showed no relation to the levels of these markers. In 19 additional patients (9 with unstable angina and 10 control patients) samples from the coronary sinus and the peripheral blood were also analyzed. Again. in patients with unstable angina all samples were drawn less than 24 h after rest pain; in six of nine patients samples were drawn in less than 6 h. A coronary sinus to peripheral blood gradient for either of these markers could not be demonstrated. The differences between peripheral and coronary sinus D-dimer and plasminogen activator inhibitor concentrations were also similar in patients with unstable angina and control patients.
Coronary vasodilation is impaired in both hypertrophied and nonhypertrophied myocardium of patients with hypertrophic cardiomyopathy: a study with nitrogen-13 ammonia and positron emission tomography, To assess regional coronary reserve in hypertrophic cardiomyopathy. regional myocardial blood flow was measured in 23 patients with hypertrophic cardiomyopathy and 12 control subjects by means of nitrogen-13 ammonia and dynamic positron emission tomography. In patients with hypertrophic cardiomyopathy at baseline study. regional myocardial blood flow was 1.14 +/- 0.43 ml/min per g in the hypertrophied (20 +/- 3 mm) interventricular septum and 0.90 +/- 0.35 ml/min per g (p less than 0.05 versus septal flow) in the nonhypertrophied (10 +/- 2 mm) left ventricular free wall. These were not statistically different from the corresponding values in control subjects (1.04 +/- 0.25 and 0.91 +/- 0.21 ml/min per g. respectively. p = NS). After pharmacologically induced coronary vasodilation (dipyridamole. 0.56 mg/kg intravenously over 4 min). regional myocardial blood flow in patients with hypertrophic cardiomyopathy increased significantly less than in control subjects both in the septum (1.63 +/- 0.58 versus 2.99 +/- 1.06 ml/min per g. p less than 0.001) and in the free wall (1.47 +/- 0.58 versus 2.44 +/- 0.82 ml/min per g. p less than 0.001). In addition. patients with hypertrophic cardiomyopathy who had a history of chest pain had more pronounced impairment of coronary vasodilator reserve than did those without a history of chest pain. After dipyridamole. coronary resistance in the septum decreased by 38% in patients without a history of chest pain. but decreased by only 14% in those with such a history (p less than 0.05). Coronary resistance in the free wall decreased by 45% in patients without and by 27% in those with a history of chest pain (p = 0.06).
Mechanisms for left ventricular systolic dysfunction in aortic regurgitation: importance for predicting the functional response to aortic valve replacement, To test the hypothesis that the combined use of the time-varying elastance concept and conventional circumferential stress-shortening relations would elucidate differential mechanisms for left ventricular systolic dysfunction in severe. chronic aortic regurgitation and therefore predict the functional responses to aortic valve replacement. 31 control patients and 37 patients with aortic regurgitation were studied. The studies included micromanometer left ventricular pressure determinations. biplane contrast cineangiograms under control conditions and radionuclide angiograms under control conditions and during methoxamine or nitroprusside infusions with right atrial pacing. The patients with aortic regurgitation were classified into three groups: Group I had normal Emax and stress-shortening relations. Group II had abnormal Emax but normal stress-shortening relations and Group III had abnormal Emax and stress-shortening relations. The left ventricular end-diastolic and end-systolic volumes showed a progressive increase and the ejection fraction showed a progressive decrease from Group I to III; these values differed from those in the control patients (p less than 0.001). In Group I. there was a decrease in left ventricular volumes (p less than 0.05) but no significant change in ejection fraction (61 +/- 7% versus 63 +/- 4%) after aortic valve replacement. In contrast. in Group II. reduction in left ventricular volumes (p less than 0.01) was associated with an increase in ejection fraction from 50 +/- 8% to 64 +/- 11% (p less than 0.01). Finally. in Group III. reduction in left ventricular volumes (p less than 0.05) was associated with a further decrement in ejection fraction from 35 +/- 13% to 30 +/- 13%. Group I patients had compensated adequately for chronic volume overload. However. Group II had left ventricular dysfunction that was associated with an increase in the left ventricular volume/mass ratio compared with that in the control patients and Group I (p less than 0.05 for both). suggesting inadequate hypertrophy and assumption of spherical geometry. Finally. irreversible myocardial dysfunction had supervened in Group III. In conclusion. a combined analysis of left ventricular chamber performance using the time-varying elastance concept and myocardial performance using conventional circumferential stress-shortening relations provides complementary information that elucidates differential mechanisms for left ventricular systolic dysfunction and therefore predicts the functional response to aortic valve replacement.
Impact of orifice geometry on the shape of jets: an in vitro Doppler color flow study, To investigate the influence of orifice geometry on the three-dimensional shape of jets. an in vitro Doppler color flow study was performed. Jets were formed by discharging blood through round orifices and through orifices with major/minor axis ratios of 2:1. 3:1 and 5:1. These were repeated with orifice areas of 0.1. 0.3 and 0.5 cm2. For turbulent and laminar jets formed by these orifices. Doppler color flow images were obtained from two orthogonal scanning planes aligned with the major and minor orifice axes. Jet width was measured at 1 cm intervals from 0 to 5 cm from the orifice and used to calculate jet eccentricity (ratio of major to minor axis widths) and the rate of divergence of the jet walls. Jets were observed to diverge more rapidly along walls aligned with the orifice minor axis rather than along the major axis. This differential spreading led to the development of circular symmetry at a short distance from the orifice. Jet divergence (theta) occurred more rapidly for turbulent jets and for jets formed by larger orifices: theta (zero) = 0.80 + 6.3.A + 7.0.T + 0.47.E-OR (r = 95. p less than 0.0001. n = 48). where A is orifice area (cm2); T is 0 for laminar jets. 1 for turbulent jets and E-OR combines orifice eccentricity and scanning orientation. ranging from -5 for 5:1 orifices imaged along the major axis. 0 for circular orifices to 5 for 5:1 orifices imaged along the minor axis. Within the jet. eccentricity decayed approximately exponentially with distance from the orifice. more rapidly for turbulent jets. more slowly for the larger and more eccentric orifices.
Patient age and results of balloon aortic valvuloplasty: the Mansfield Scientific Registry experience. The Mansfield Scientific Aortic Valvuloplasty Registry Investigators, Patients enrolled in the Mansfield Scientific Aortic Valvuloplasty Registry were followed up a mean of 7 months after balloon aortic valvuloplasty. Results were compared for patients less than 70. 70 to 79 and greater than or equal to 80 years of age at time of valvuloplasty. As assessed by aortic valve area indexed to body surface area. stenosis was more severe in the older patients and the incidence of congestive heart failure was also greater in those aged greater than or equal to 80 years. The results of valvuloplasty were comparable in all three age groups. and indexed final valve area was not significantly different among the groups. In-hospital mortality ranged from 4.2% to 9.4%. but this and other complications were not significantly different among the groups. Total 7 month mortality was 23%. As performed in this registry study. balloon aortic valvuloplasty produced similar results in older and younger patients. despite initially more severe disease in the older patients.
Drug response at electropharmacologic study in patients with ventricular tachyarrhythmias: the importance of ventricular refractoriness, The clinical and electrophysiologic predictors of successful antiarrhythmic drug therapy for patients with inducible ventricular tachycardia were evaluated in 59 consecutive patients undergoing serial electropharmacologic trials. Structural heart disease was less frequently present in patients for whom effective therapy was found (p less than 0.05). The presence of coronary artery disease and a history of prior myocardial infarction were significantly more frequently present in patients for whom antiarrhythmic drug therapy could not be found (p less than 0.05). The corrected QT interval and ventricular effective refractory period measured at a pacing cycle length of 400 ms were significantly shorter in responders compared with nonresponders (QT interval 428 +/- 52 versus 460 +/- 59 ms; ventricular effective refractory period 237 +/- 28 versus 254 +/- 24 ms; (p less than 0.05). In addition. the interelectrogram coupling interval of the ventricular extrastimulus initiating ventricular tachycardia was significantly shorter in responders compared with nonresponders (223 +/- 37 versus 251 +/- 33 ms; p = 0.003). Logistic regression analysis identified a short ventricular interelectrogram coupling interval (p less than 0.01) and absence of prior myocardial infarction (p less than 0.05) as the only independent predictors of antiarrhythmic drug suppression of the induction of ventricular tachycardia. Greater drug-induced increments in the ventricular effective and functional refractory periods were observed in responders than in nonresponders as was the shortest ventricular interelectrogram coupling interval. Thus. baseline electrophysiologic measurements identify patients with inducible ventricular tachycardia who are likely to respond to antiarrhythmic drug therapy. Furthermore. these patients demonstrate greater drug-induced electrophysiologic changes.
Tricuspid valve dysplasia or displacement in intrauterine life, In 450 cases of structural heart disease diagnosed prenatally. 38 fetuses (8.5%) had either a dysplastic or a displaced tricuspid valve. The tricuspid valve was dysplastic in 22 fetuses. all of which had evidence of tricuspid regurgitation resulting in right atrial dilation and increased cardiothoracic ratio. An associated abnormality of the pulmonary valve occurred in 16 fetuses. The remaining 16 fetuses had Ebstein's malformation. 14 with evidence of tricuspid incompetence at presentation and 10 with an associated abnormality of the pulmonary valve. Of the 38 cases. the pregnancy was interrupted in 17. spontaneous intrauterine fetal death occurred in 8. 11 infants died postnatally and 2 infants are still alive; additional abnormalities were found in 8 cases (chromosomal anomalies in 2. ventricular septal defects in 2. corrected transposition in 2. the Chiari malformation in 2. supraventricular tachycardia in 1 case and coarctation of the aorta in 1). Fetuses with severe abnormalities are selected for fetal echocardiography by the four chamber screening program and a high rate of natural loss both in intrauterine life and immediately after birth was observed in the 21 cases in which pregnancy was continued. This would explain the higher incidence of tricuspid valve disease in our prenatal compared with postnatal series. Although increased cardiothoracic ratio and associated lesions of the right ventricular outflow tract contribute to the poor outcome in the cases detected prenatally. the absence of these features does not always indicate a good prognosis because progression of disease can occur with advancing gestational age. No absolute measurement or single echocardiographic feature emerged as a consistent predictive factor of prognosis.
Anti-ischemic effects of atenolol versus nifedipine in patients with coronary artery disease and ambulatory silent ischemia, The anti-ischemic effects of atenolol and nifedipine were compared in a randomized double-blind crossover manner in 24 patients with stable exertional angina and transient silent ischemia during ambulatory electrocardiographic (ECG) monitoring. Both atenolol and nifedipine were effective (p less than 0.005) in reducing the average number and duration of transient ischemic events. but therapy with atenolol was associated with a significantly greater reduction in the mean number (p less than 0.05) and duration (p less than 0.01) of silent ischemic events. Analyses of the silent ischemic activity during the morning hours revealed that only therapy with atenolol produced a significant reduction in the average duration per patient (139 +/- 54 vs. 1.609 +/- 468 s. p less than 0.01) and in the average duration of silent ischemia per event between 6 AM and 12 noon (62 +/- 21 vs. 208 +/- 24 s. p less than 0.005). There were fewer adverse experiences during therapy with atenolol. These results show that although both atenolol and nifedipine are effective in reducing silent ischemic events. treatment with atenolol is associated with significantly greater efficacy. particularly on the morning surge of silent myocardial ischemia.
Acute biologic response to excimer versus thermal laser angioplasty in experimental atherosclerosis, Vascular injury and platelet accumulation after balloon angioplasty are two potentially important triggers of the process of restenosis that may be minimized by the use of laser energy to ablate atherosclerotic plaque. The type of laser most suitable to achieve these goals remains unknown. Accordingly. angiographic and histologic studies and quantitative platelet deposition analysis were performed on 27 atherosclerotic rabbit iliac arteries randomized to treatment with excimer laser or thermal laser angioplasty. Excimer laser angioplasty was achieved with 35 to 40 mJ/mm2 of 308 nm xenon chloride irradiation delivered through a 4.5F catheter made of 13 concentrically arranged 200 microns fiber optics. at a repetition rate of 25 to 30 Hz and a pulse duration of 135 ns; thermal laser angioplasty was achieved with a 1.7 mm metal probe heated with 10 W of continuous wave argon laser energy. The baseline and post-laser luminal diameters of excimer laser-treated vessels (0.92 +/- 0.28 and 1.56 +/- 0.48 mm. respectively) were similar to those observed in thermal laser-treated vessels (1.05 +/- 0.44 and 1.61 +/- 0.41 mm. respectively). Perforation occurred in 4 (29%) of 14 thermal laser-treated arteries and in 0 of 13 excimer laser-treated arteries (p = 0.04); spasm was observed in only 1 thermal laser-treated vessel. On the basis of a quantitative histologic grading scheme (damage scores of 0 to 4). greater degrees of injury were measured in thermal versus excimer laser-treated vessels (2.4 +/- 1.0 versus 1.3 +/- 0.4. p = 0.009).
Value of ventricular electrogram recordings in the diagnosis of arrhythmias precipitating electrical device shock therapy, An antitachycardia pacemaker-cardioverter-defibrillator that is capable of storing ventricular electrograms before and after delivery of device shock therapy was implanted in 16 patients. Three of the patients experienced out-of-hospital device shock therapy preceded by minimal symptoms. Although limitations of electrogram analysis exist and are discussed. careful analysis and registration of electrograms during all supraventricular and ventricular rhythms observed during in-hospital testing served as an important reference for subsequent arrhythmia diagnosis. By analyzing the electrogram rate and RR interval stability and configuration. a definitive diagnosis was established in all three patients (atrial fibrillation. polymorphic ventricular tachycardia and rate-sensing lead disruption. respectively). Thus. the ability to store ventricular electrograms before shock therapy represents a major advance in the management of patients who receive an electrical device to treat ventricular tachyarrhythmia.
Management of posterior epistaxis with the use of the fibreoptic nasolaryngoscope, Posterior epistaxis is usually treated by repeated nasal packing and in failed situations by ligation of feeding arteries with considerable morbidity and mortality. The most logical approach should be location of the bleeding site and arrest of haemorrhage by local treatment. The exact location of the bleeding area can be identified in actively bleeding noses with the fibreoptic naso-laryngoscope and the bleeding arrested by chemical. or thermal cautery and in failed situations by using small nasal packs confined to the bleeding site. This approach to the management of posterior epistaxis is effective and reduces the duration of hospital stay. It significantly reduces the discomfort to the patient. The current practice of indiscriminate blind nasal packing in the hope of arresting nasal haemorrhage by incidental pressure on the bleeding site should be re-evaluated.
Modifying the translabyrinthine approach to preserve hearing during acoustic tumour surgery, Removing an acoustic schwannoma using the translabyrinthine approach has previously been considered incompatible with hearing preservation. By modifying the approach and preventing the loss of endolymph. we have successfully removed an intracanalicular acoustic schwannoma. which originated from the inferior vestibular nerve. and preserved hearing in the operated ear. This report represents the preliminary findings using this particular technique in the management of an intracanalicular acoustic tumour.
An unusual treatment for a rare dilemma (oesophageal foreign body), Identification of an intramural oesophageal fishbone at operation is difficult. Such a case is discussed with an attempted accurate radiological localization of site pre-operatively. No such case has so far been reported.
Clinical features and associations of 560 cases of motor neuron disease, In 560 cases of motor neuron disease. studied retrospectively from their case notes in three teaching centres. the age at onset ranged from 13 to 87 years (mean 56 years). and the mean duration of illness until death was 2.6 years. In the subgroup of the disease presenting with progressive bulbar palsy presenting after age 59 years. there was a previously unrecognised excess of females sufficient to equalize the sex ratio of incidence of the disease in this age group. No potentially causative clinical associations emerged; no relation was noted between occupational exposure to leather products. trauma or surgical procedures and the disease. There was a trend for patients with motor neuron disease to give a history of abstention from alcohol.
Progressive degeneration of the right temporal lobe studied with positron emission tomography, A 79 year old man with a twelve year progressive history of prosopagnosia and recent naming difficulty. in whom other intellectual skills were preserved. is described. Positron emission tomography (PET) revealed an area of right temporal lobe hypometabolism. with an additional area of less severe hypometabolism at the left temporal pole. This may represent an example of progressive focal cortical degeneration similar to that associated with primary progressive dysphasia. but affecting the right temporal lobe.
Neuronal ceroid-lipofuscinosis: preferential metabolic alterations in thalamus and posterior association cortex demonstrated by PET, Regional brain glucose utilisation was investigated with positron emission tomography (PET) and fluorodeoxyglucose (FDG) in four siblings with neuronal ceroid-lipofuscinosis. A consistent pattern was found. namely a decrease of glucose utilisation in all grey structures but more marked at the level of the thalamus and posterior association cortex. The severity of metabolic anomalies was correlated with the degree of clinical impairment and with disease duration; they were the most severe in the oldest patient. who was also the most affected clinically. intermediate in two others. and minimal in the subject with the shortest period of development of the disease. These observations suggest that PET is useful for the definition of anatomical targets of metabolic diseases and for the investigation of their pathophysiology.
Cyclosporin-associated akinetic mutism and extrapyramidal syndrome after liver transplantation, Three patients developed akinetic mutism on the third day after the introduction of intravenous cyclosporin A. given for immunosuppression after liver transplantation. One patient in addition developed a florid orofacial dyskinesia. which resolved completely. as did the akinetic mutism. after withdrawal of cyclosporin. In these patients the time course of the akinetic mutism and extrapyramidal syndrome. which developed in the absence of any other identifiable cause. suggests cyclosporin A was the precipitating factor. Subsequently. two of the patients showed signs of pseudobulbar palsy with abnormalities in the pons on MRI scanning. suggesting central pontine myelinolysis (CPM). None of the patients had experienced significant fluctuations in serum sodium or other risk factors for central pontine myelinolysis and the exact relationship to the earlier cyclosporin related mutism was not clear.
Grading white matter lesions on CT and MRI: a simple scale, We developed and tested a simple three-point scale for grading white matter lesions in anterior and posterior regions of the brain. Twenty four CT scans and 24 MRI scans were separately judged by 11 and five observers. respectively. on the presence and severity of white matter lesions. The observers were radiologists and neurologists. For CT scans. these periventricular changes were graded according to their extent as absent. or partly involving the white matter. or extending up to the subcortical region. The MRI lesions were graded as no lesion or only a single one. multiple focal lesions. and multiple confluent lesions. The pairwise agreements of all possible combinations of observers for each scan were corrected for chance (kappa statistics; maximal agreement 1.0). The weighted kappa value. for anterior and posterior regions combined. was 0.63 for CT scans. and 0.78 for MRI scans. This three-point scale for two separate regions seems suitable as a basis for cross-sectional or longitudinal studies of large series of patients.
Differential impairment of semantic and episodic memory in Alzheimer's and Huntington's diseases: a controlled prospective study, A controlled prospective study compared the performance of 14 patients with dementia of Alzheimer type (DAT) and 14 patients with Huntington's Disease (HD). who were matched for overall level of dementia. on a battery of semantic and episodic memory tests. The DAT patients were significantly more impaired on measures of delayed verbal and figural episodic memory. and in addition showed a more rapid rate of decline on tests which depend upon the integrity of semantic knowledge (naming. number information. similarities and category fluency). In contrast. the HD patients were significantly worse. and showed a more rapid decline on the letter fluency test. a task especially sensitive to deficiencies in retrieval. The HD patients were also more impaired than DAT patients on a vocabulary test and on copying geometric figures. The observed double dissociations offer compelling evidence that aetiologically distinct forms of dementing illness result in different patterns of cognitive impairment.
Characteristics of respondents and nonrespondents in a prospective study of osteoporosis, During 1981-1982. a cohort of elderly Japanese Americans living in Hawaii was recruited for an epidemiologic study of osteoporosis. The male subjects were simultaneously being examined for an epidemiologic study of heart disease. Baseline data collected from both the men and women at a previous heart disease examination were used to compare responders vs nonresponders. The target population for the osteoporosis study consisted of 1685 men and 1594 women. Of these. 1379 men (81.8%) and 1105 women (72.0%) participated in the initial osteoporosis examination. For each sex. nonrespondents were older and had higher systolic blood pressure levels than did the respondents. Male nonresponders had a higher stroke prevalence and more frequent recent use of vasodilator medicine. Female nonresponders had a less frequent history of having ever taken female hormones than did the responders. The responders and nonresponders were reasonably similar in other respects. as indicated by the comparison of more than 40 other variables. This suggests that nonresponse bias is probably not a major influence in exposure-disease associations in this osteoporosis cohort. We believe this is the first published report dealing with nonresponse characteristics in a cohort study of osteoporosis.
Binary methods for continuous outcomes: a parametric alternative, Often a "disease" or "state of disease" is defined by a subdomain of a continuous outcome variable. For example. the subdomain of diastolic blood pressure greater than 90 mmHg has been used to define hypertension. The classical method of estimating the risk (or prevalence) of such defined disease states is to dichotomize the outcome variable according to the cutoff value. The standard statistical analysis of such risk of disease then exploits methods developed specifically for binary data. usually based on the binomial distribution. We present a method. based on the assumption of a Gaussian (normal) distribution for the continuous outcome. which does not resort to dichotomization. Specifically. the estimation of risk and its variance is presented for the one- and two-sample situations. with the latter focusing on risk differences and ratios. and odds ratios. The binomial approach applied to the dichotomized data is found to be less efficient than the proposed method by 67% or less. The latter is found to be very accurate. even for small sample sizes. although rather sensitive to substitutions of the underlying distribution by thicker tailed distributions. Canadian total cholesterol data are used to illustrate the problem. For the one-sample case. the approach is illustrated using data from a study of the arterial oxygenation of 20 patients during one-lung anesthesia for thoracic surgery. For the two-sample case. data from a prognostic study of the renal function of 87 lupus nephritic patients are used.
Case finding, data quality aspects and comparability of myocardial infarction registers: results of a south German register study, The population-based Augsburg Coronary Event Register (330.000 residents. age 25-74 years) has registered a total of 1012 cases of acute myocardial infarction (AMI) in 1985 and 1021 AMI in 1986 and categorized them on the basis of the current WHO diagnostic algorithm for AMI. The register is designed for longitudinal comparisons of annual AMI risk (incidence. attack rate. death rate). and the risk to the AMI patients themselves (28-day case fatality). The methodology and specific issues encountered during registration and data evaluation are described. With an estimated 95% completeness of case finding. the quality control data review which the register conducts annually shows a consistency of specific data structures which indicate stable case finding and validation procedures. However. local conditions which affect case finding and data completeness per case are responsible for the creation of subsets of AMI which are in turn distinguished by differences in diagnostic category structures. With regard to the study objectives. the differences among subsets appear to have the least effect on rate calculations if DEFINITE and POSSIBLE AMI are combined. The implications of methodological variations and subset differences within and across registers on annual rate calculations and result comparisons are discussed.
Sequential or fixed sample trial design? A case study by stochastic simulation, The properties of Wilcoxon's rank sum test for fixed sample size and a Wilcoxon-type two-sample sequential test have been illustrated and compared by means of stochastic simulation. Data from a real fixed sample trial have been used. both for resampling from the original data. and for construction of an idealized theoretical distribution. The sequential and the fixed sample test obtain equal power. but the sequential test mostly includes considerably fewer patients to reach a conclusion. i.e. the mean and median number of patients included are both much lower than the fixed sample size. Under the hypotheses only a small fraction of the simulation runs exceed the fixed sample size. These findings exemplify results obtained in theoretical analyses and simulation studies covering a wide range of distributions. In our opinion sequential tests have obvious advantages and are in many cases better alternatives than fixed sample tests in clinical trials.
The effect of beta-carotene on the regression and progression of cervical dysplasia: a clinical experiment, In order to gain insight into the causality of the relation between beta-carotene and cancer. we performed a randomized placebo-controlled trial in which the effect of beta-carotene on the regression and progression rates of cervical dysplasia were examined. The experimental group (n = 137) received a supplemental dose of 10 mg of beta-carotene daily for 3 months. The control group (n = 141) received placebo capsules. As the outcome parameter. two definitions of regression and progression were used. which were based on the degree of dysplasia before and after the medication period. The number of patients who showed progression was too small to allow conclusions. No effect of beta-carotene on the regression percentages was observed: OR = 0.68 (95% CI: 0.28-1.60) using the broad definition; and OR = 1.22 (95% CI: 0.43-3.41) with the strict definition. A secondary analysis. in which the effect of the total intake of beta-carotene (diet + medication) on the regression percentages of cervical dysplasia was studied. did not show a positive effect either. The paper discusses to what extent issues in the study design may have masked a potential effect and how our results affect the evidence for a causal relation between beta-carotene and cancer.
Systematic computer-aided search of optimal staging system for colorectal cancer, Two hundred and ninety-eight patients with curatively resected colorectal cancer were classified into 12 categories according to the depth of tumour penetration (T1-T4). and lymph node status (N0-N2). Using a computer. these categories were grouped into 2-12 stages in every possible combination. so a total of 146.975 logical classifications were generated. The optimal model was selected for each group of classifications with equal stage number. thus giving the greatest prognostic information on 5-year survival according to the Akaike criterion. The results showed that (1) 13% of the total classifications. including 85% of the 3-stage classifications. were better than the Dukes system in predicting our patients' outcomes; (2) the T-level was a stage-determinant even more important than the N-level; and (3) major changes in prognosis occurred at more advanced stages than the classical "turning points". We conclude that in order to find an optimal staging of cancer. systematic computer-aided search through all the possible classifications is necessary. using the appropriate database.
The community hospital-based stroke programs in North Carolina, Oregon and New York--V. Stroke diagnosis: factors influencing the diagnostic evaluation of patients following acute stroke, Among the 4129 patients of the Community Hospital-based Stroke Program. 30% had an unspecified stroke diagnosis. Since specific diagnosis and. perhaps. eventual treatment. derives in part from diagnostic testing. we examined the effect of clinical condition. geographic and demographic factors on the incidence of certain diagnostic tests after acute stroke. In this multivariable analysis. race. sex. history of hypertension and history of diabetes did not influence the chance of having any test. but older age strongly reduced the chances of receiving extensive evaluation. When CT scanning was available. the utilization of a CT as well as other diagnostic studies including cerebral angiography. radionuclide brain scan. EEG and EKG was increased. The odds of receiving a CT scan increased if the patient was married. and decreased with a history of previous stroke. A history of previous TIA increased the chance of having a cerebral angiogram while a history of cardiac disease decreased the chance. There were striking regional geographic differences in the use of CT. radionuclide brain scanning and cerebral angiography which may. in part. reflect differences between the availability of these technologies in urban and rural hospitals. These results indicate that evaluation of stroke patients remains heterogenous.
Increased incidence of diabetes mellitus in relation to abdominal adiposity in older women, The relationship between body fat distribution. measured by the ratio of waist-to-hip circumferences (WHR). and the 2 year incidence of diabetes mellitus was examined in a cohort of 41.837 women aged 55-69 years. The 399 women who reported the new onset of diabetes had a significantly greater mean body mass index (kg/m2) and WHR than non-cases. After adjustment for body mass index (BMI). age and education level using multivariate logistic regression. WHR was a significant independent predictor of diabetes in a dose-response fashion. Cases were 4.6 times (95% CI = 3.8. 5.6) more likely than non-cases to be in the upper tertile of WHR and 2.2 times (95% CI = 1.8. 2.7) more likely to be in the middle tertile. Women in the highest tertiles of both WHR and BMI had a 14.4-fold (95% CI = 9.5. 21.9) higher risk of diabetes than women in the lowest tertiles. These results demonstrate that increased abdominal adiposity is a significant independent risk factor for the development of diabetes mellitus in older women.
Usefulness of epidurally evoked cortical potential monitoring during cervicomedullary glioma surgery, This report describes a patient with an intramedullary ependymoma at the region of the cervicomedullary junction in whom there was an abolition of somatosensory evoked potentials following median nerve stimulation. During intraoperative monitoring of cortical potentials elicited by epidural cervical cord stimulation. the tumor was removed. Posterior epidural stimulation appeared to depolarize more ascending fibers than did stimulation of a single peripheral nerve. We recommend that. in cases of operations in this vital area. epidurally evoked cortical potentials be monitored intraoperatively.
A target feedback device for ventilatory muscle training, In a previous study. we successfully used a target feedback device. together with an external resistor. to train the ventilatory muscles of patients with chronic obstructive pulmonary disease. In this article. we describe the details of the design and function of the target feedback device. When used in conjunction with an external resistance. the target feedback device provides timing and pressure targets. together with feedback information. on whether these targets are achieved. The target feedback device consists of readily available electronic components and is relatively simple to construct. Adjustment of an external pressure knob permits setting of pressure targets. Adjustment of internal components is possible and allows control of breathing frequency. inspiratory time. and breathing waveform.
Skin reflectance pulse oximetry: in vivo measurements from the forearm and calf, This study describes the results from a series of human experiments demonstrating the ability to measure arterial hemoglobin oxygen saturation (SaO2) from the forearm and calf using a reflectance pulse oximeter sensor. A special optical reflectance sensor that includes a heating element was interfaced to a temperature controller and a commercial Data-scope ACCUSAT pulse oximeter that was adapted for this study to perform as a reflectance pulse oximeter. The reflectance pulse oximeter sensor was evaluated in a group of 10 healthy adult volunteers during steady-state hypoxia. Hypoxia was induced by gradually lowering the inspired fraction of oxygen in the breathing gas mixture from 100 to 12%. Simultaneous SaO2 measurements obtained from the forearm and calf with two identical reflectance pulse oximeters were compared with SaO2 values measured by a finger sensor that was interfaced to a standard Datascope ACCUSAT transmittance pulse oximeter. The equations for the best-fitted linear regression lines between the percent reflectance. SpO2(r). and transmittance. SpO2(t). values in the range between 73 and 100% were SpO2(r) = -7.06 + 1.09 SpO2(t) for the forearm (n = 91. r = 0.95) and SpO2(r) = 7.78 + 0.93 SpO2(t) for the calf (n = 93. r = 0.88). The regression analysis of the forearm data revealed a mean +/- SD error of 2.47 +/- 1.66% (SaO2 = 90-100%). 2.35 +/- 2.45% (SaO2 = 80-89%). and 2.42 +/- 1.20% (SaO2 = 70-79%). The corresponding regression analysis of the calf data revealed a mean +/- SD error of 3.36 +/- 3.06% (SaO2 = 90-100%). 3.45 +/- 4.12% (SaO2 = 80-89%). and 2.97 +/- 2.75% (SaO2 = 70-79%).
The influence of drug interval on the effect of methotrexate and fluorouracil in the treatment of advanced colorectal cancer, The importance of the interval between methotrexate (MTX) and fluorouracil (5-FU) was studied in 168 patients with previously untreated. measurable. advanced colorectal cancer. They were randomized to receive MTX 200 mg/m2. followed by 5-FU 600 mg/m2 either 24 hours (arm A) or 1 hour (arm B) after MTX. All patients received leucovorin (LV) 24 hours after MTX. 10 mg/m2 orally every 6 hours for six doses. The regimen was repeated every 2 weeks. with 5-FU escalation as tolerated. Arm A was significantly better than arm B with respect to overall response rate (29% v 14.5%. P = .026). time to progression (TTP; median. 9.9 months v 5.9 months. P = .009). and survival (median. 15.3 months v 11.4 months. P = .003). Significant differences between arms were not found in response rate. median TTP. or median survival for the subgroup of patients with rectal primaries who comprised 20% of the patients in each arm. Significant factors prognostic for survival were performance status and number of metastases. as well as treatment. Age did not influence survival. Toxicity was similar in both arms and was primarily gastrointestinal. More mucositis was seen in arm A. There were four toxic deaths secondary to neutropenia and infection (one from arm A and three from arm B) and three other deaths (two from arm A and one from arm B) that were possibly drug-related. The combination of MTX with LV rescue and 5-FU is an active regimen in advanced colorectal cancer; its efficacy is increased in colon. but not rectal cancer. when the interval between MTX and 5-FU is long (24 hours) rather than short (1 hour).
Clonogenic growth in vitro: an independent biologic prognostic factor in ovarian carcinoma, A retrospective analysis was performed to investigate the prognostic value of growth in a human tumor clonogenic assay system for 84 ovarian cancer patients. A significant difference in survival probability (determined by the method of Kaplan-Meier) was found by univariate analysis between patients with ovarian carcinoma whose tumors manifested clonogenic growth (defined as growth of greater than or equal to five colonies per plate) and patients whose tumors did not grow. Clonogenic growth in vitro was associated with worse prognosis (P = .007. log-rank test). A number of generally accepted prognostic factors. International Federation of Gynecology and Obstetrics (FIGO) stage (P = .003). residual tumor mass (P less than .001). and grade (P = .011). were also of prognostic importance in our patient population. Multivariate analysis. based on the Cox regression model. identified clonogenic growth as a significant independent prognostic parameter in ovarian carcinoma (P = .031). in addition to the conventional risk factors. Estimation of survival of individual patients was best accomplished by combining the factors of residual tumor mass (P less than .05). age (P less than .01). and clonogenic growth (P less than .05) (in sequence of decreasing potential of risk).
Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin, In an effort to critically define the incidence and clinical characteristics of secondary responses to cisplatin-based therapy in patients with ovarian cancer previously treated with a cisplatin-based program. a retrospective review was undertaken of patients at the Memorial Sloan-Kettering Cancer Center who received greater than or equal to two cisplatin/carboplatin-based programs. Eighty-two patients were identified who met the entry criteria of having had a cisplatin-free interval (CFI) of more than 4 months between the completion of their first regimen and the institution of a second cisplatin/carboplatin program. Of the 72 assessable patients (10 had no measurable disease. and a laparotomy was not performed to assess response). 31 (43%) responded. including 10 surgically defined complete responses (S-CRs). The overall response rates (and S-CR rate). based on duration of CFI. were 5 to 12 months. 27% (5%); 13 to 24 months. 33% (11%); and more than 24 months. 59% (22%). Twenty-nine patients (35%) received noncisplatin/carboplatin-containing treatments between the cisplatin programs. Patients without any treatment for more than 24 months from the completion of their initial therapy experienced a 77% (17 of 22) response rate and a 32% (seven of 22) S-CR rate. In conclusion. secondary responses to cisplatin/carboplatin-based treatment are common in patients with ovarian cancer who have previously responded to the agents and increase in frequency with greater distance from the initial therapy.
Percutaneous needle biopsy preceding preoperative chemotherapy in the management of massive renal tumors in children, While the National Wilms' Tumor Study (NWTS) Group in the United States puts an emphasis on accurate staging and histology before any therapy is given for Wilms' tumor. the International Society of Pediatric Oncology (SIOP) in Europe focuses on preoperative therapy and safer surgery. Our current approach combines the benefits of both policies in the management of massive renal tumors in children. In seven consecutive patients we first obtained a percutaneous posterior needle biopsy to obtain adequate tissue for histology. and proceeded with preoperative chemotherapy with vincristine and dactinomycin until tumor shrinkage was sufficient. Tumor removals were feasible and uneventful. At the time of operation. two tumors were found to be totally or almost totally necrotic. In the others. which still included viable tumor. the histology corresponded well to the needle biopsy findings. One case with unfavorable histology and one with rhabdoid sarcoma would have been missed and given suboptimal therapy without the primary needle biopsy. As possible biopsy-related complications. subcapsular intratumoral bleeding was recognized in two patients. We conclude that percutaneous posterior needle biopsy is safe and yields definite. detailed histology in massive renal tumors in children. Preoperative chemotherapy facilitates surgery in these patients.
Treatment of relapsed non-Hodgkin's lymphomas with dexamethasone, high-dose cytarabine, and cisplatin before marrow transplantation, Combination chemotherapy is capable of curing many patients with newly diagnosed intermediate- and high-grade non-Hodgkin's lymphomas (NHL). but treatment of relapsed NHL remains problematic. Bone marrow transplantation (BMT) offers the best chance for disease-free survival. but interim chemotherapy is often necessary while awaiting BMT. especially for patients with bulky disease. We report here 39 patients (median age. 44 years) who failed primary therapy with doxorubicin-based regimens and subsequently were treated with one to six cycles of dexamethasone. 40 mg intravenous (IV) every day on days 1 to 4. cisplatin 100 mg/m2 by continuous infusion on day 1. and cytarabine 2 g/m2 IV every 12 hours x two doses on day 2 (DHAP) before the planned BMT. Histologies included 16 diffuse large-cell. six diffuse mixed. five diffuse small-cleaved. four lymphoblastic. and eight other. Twenty-eight patients had stage IV disease. 13 had B symptoms. and 20 had an elevated lactate dehydrogenase (LDH). Patients had been treated with a median of three previous chemotherapy regimens. Sixty-one percent of patients had high tumor burdens according to the MD Anderson criteria. Objective responses to DHAP were seen in 26 patients (67%) including nine complete responses (CRs) (23%) and 17 partial responses (PRs) (44%). and responses lasted a median of 7.5 months. Myelosuppression was the major toxicity. but there were no treatment-related deaths. To date. 17 patients have undergone subsequent BMT with a projected 3-year disease-free survival of 15%. We conclude that the DHAP regimen is effective short-term salvage therapy for relapsed NHL patients. but the long-term prognosis of multiply relapsed patients remains poor.
Second primary cancer following Hodgkin's disease: updated results of an Italian multicentric study, The risk of second primary cancer (SPC) was evaluated in 947 patients treated for Hodgkin's disease (HD) during the period January 1969 to December 1979. The median follow-up of this series was 10.5 years (range. 9 to 19). Treatment categories included radiotherapy (RT) alone (115 patients. 12%). chemotherapy (CHT) alone (161 patients. 17%). combined RT plus CHT (381 patients. 40%). and salvage treatment for resistant or relapsing HD (290 patients. 30.6%). Fifty-six SPCs were observed. occurring between 1 and 17 years from initial treatment. Among these. secondary acute nonlymphoid leukemia (s-ANLL) was the most frequent SPC (23 cases). Secondary non-Hodgkin's lymphoma (s-NHL) occurred in 5 patients. whereas a secondary solid tumor (s-ST) was observed in 28 patients. The calculated actuarial risk (+/- SE) of developing SPC was 5.0% (+/- 0.9%) and 23.1% (+/- 5.8%) at 10 and 19 years. respectively. Concerning treatment modalities and s-ANLL risk. no cases were observed in the radiotherapy group. whereas CHT plus RT and salvage groups showed the highest actuarial risk. This was. in fact. at 10 and 19 years. 3.1% (+/- 0.9%) and 8.1% (+/- 4.0%) in the former group. and 1.8% (+/- 1.0%) and 16% (+/- 9.0%) in the latter. A statistically significant difference was observed when the CHT plus RT group was compared with CHT and RT groups (P = .04). Concerning the relationships with chemotherapeutic regimens. 12 s-ANLL cases occurred in the mechlorethamine. vincristine. procarbazine. and prednisone (MOPP) plus RT group. and only one case in the group receiving doxorubicin. bleomycin. vinblastine. and dacarbazine (ABVD) plus RT. A statistically significant difference of s-ANLL actuarial risk was found comparing patients receiving MOPP plus RT to all other treatment groups (P = .04). With respect to s-ST. the actuarial risk at 10 and 19 years was 2.0% (+/- 0.6%) and 13.0% (+/- 3.8%). respectively. No significant differences were found among groups treated with different modalities. These data were confirmed by a multivariate analysis. which indicated treatment modality and age as independent variables for s-ANLL and s-ST development. respectively. Based on the prolonged follow-up analysis. the actuarial SPC risk at 10 years hereby reported should reflect the real SPC incidence in our series.
The pattern of intrathoracic Hodgkin's disease assessed by computed tomography, Computed tomography (CT) was used to define the sites of intrathoracic abnormality in Hodgkin's disease. determine a pattern of progression of disease in the thorax. and establish the place of this pattern of spread in the differential diagnosis of thoracic abnormalities. One hundred eight patients with newly diagnosed Hodgkin's disease were studied by chest CT. Seventy-seven patients had intrathoracic abnormalities. The pattern seen was one of contiguous spread from the anterior mediastinal/paratracheal area to the other mediastinal lymph node groups (aortopulmonary. subcarinal. posterior mediastinal. and internal mammary). to the hila. and then into the lung by extension or as discrete nodules. Involvement of the pleura. pericardium. or chest wall occurred only after the anterior mediastinal/paratracheal mass had enlarged to greater than 30% of the thoracic diameter. The probability that this pattern of contiguous lymph node spread occurred by chance alone was very small. Hodgkin's disease spreads from the anterior mediastinal/paratracheal area in a contiguous manner. Exceptions are unusual enough that when they occur. diagnoses other than Hodgkin's disease are more likely.
Multiple myeloma: VMCP/VBAP alternating combination chemotherapy is not superior to melphalan and prednisone even in high-risk patients, The efficacy of alternating vincristine. melphalan (M). cyclophosphamide. prednisone/vincristine. carmustine. doxorubicin. and prednisone (VMCP/VBAP) polychemotherapy was compared with the M and prednisone (MP) regimen as induction treatment in multiple myeloma (MM). Three hundred four MM patients entered this study between March 1983 and July 1986; the analysis was performed in December 1989. The treatment groups did not show significant differences with respect to major prognostic factors. Median overall survival was 33.8 months. In the VMCP/VBAP and MP arms. after 12 induction chemotherapy cycles. 59.0% and 47.3% (P less than .068) of the patients achieved an M component reduction greater than 50%. No significant difference was observed in the two treatment arms in terms of remission duration (21.3 v 19.6 months. P less than .66) and survival (31.6 v 37.0 months. P less than .28). Patients younger than 65 years did not show any advantage from the alternating polychemotherapy. At diagnosis. the plasma cell labeling index (LI) and serum beta-2 microglobulin (beta 2-m) were evaluated in 173 and 183 patients. respectively. A significantly reduced survival was observed for patients with LI greater than or equal to 2% (16.4 months) or beta 2-m greater than or equal to 6 mg/L (20.4 months). Even in these poor-risk subgroups. VMCP/VBAP was not superior to MP.
Inhibition of fluorouracil-induced stomatitis by oral cryotherapy, Mucositis is a significant dose-limiting toxicity associated with fluorouracil (5FU). particularly when it is combined with leucovorin. We hypothesized that oral cryotherapy would cause local vasoconstriction and would temporarily decrease blood flow to the oral mucous membranes. If cryotherapy were used during the time of peak serum 5FU levels. then the oral mucous membranes would have less exposure to 5FU and thus develop less mucositis. To test this hypothesis. 95 patients scheduled to receive their first cycle of 5FU plus leucovorin were randomized to have oral cryotherapy at the time of chemotherapy administration or to serve as a control group. Subsequent mucositis was significantly reduced in the group assigned to receive cryotherapy as judged by the attending physicians (P = .0002) and by the patients themselves (P = .0001). We now routinely recommend this cryotherapy procedure for our patients receiving daily bolus 5FU plus leucovorin.
Treatment of limited small-cell lung cancer with concurrent etoposide/cisplatin and radiotherapy followed by intensification with high-dose cyclophosphamide: a Southwest Oncology Group study, Between March 1986 and May 1988. the Southwest Oncology Group enrolled 58 previously untreated patients with limited small-cell lung cancer on a treatment program that administered high-dose cyclophosphamide (150 mg/kg) as late intensification. Treatment consisted of induction chemo-radiotherapy. (weeks 1 to 11). consolidation chemotherapy (weeks 11 to 18). and intensification (week 18). Median age was 61.5 years. Eighty-nine percent of patients had a Southwest Oncology Group (SWOG) performance status of 0-1. Twenty-one patients completed all prescribed treatments. There were seven treatment-related deaths. four as a result of intensification. Fifty-six patients are available for response analysis. Thirty-two patients achieved a complete remission (CR) (57%) and fifteen achieved a partial remission (PR) (26%). Median survival for all patients is 11.1 months. Among the 21 patients who received intensification. nine remain alive in a CR with a median survival of 27 months. This sequence of treatments was not associated with a survival advantage for the group as a whole. possibly because of the toxicity of induction and consolidation treatment and the delayed administration of high-dose cyclophosphamide.
A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide, Ten patients with myeloid leukemias were treated in a phase I trial with escalating doses of mouse monoclonal antibody (mAb) M195. reactive with CD33. a glycoprotein found on myeloid leukemia blasts and early hematopoietic progenitor cells but not on normal stem cells. M195 was trace-labeled with iodine-131 (131I) to allow detailed pharmacokinetic and dosimetric studies by serial sampling of blood and bone marrow and whole-body gamma-camera imaging. Total doses up to 76 mg were administered safely without immediate adverse effects. Absorption of M195 onto targets in vivo was demonstrated by biopsy. pharmacology. flow cytometry. and imaging; saturation of available sites occurred at doses greater than or equal to 5 mg/m2. The entire bone marrow was specifically and clearly imaged beginning within hours after injection; optimal imaging occurred at the lowest dose. Bone marrow biopsies demonstrated significant dose-related uptake of M195 as early as 1 hour after infusion in all patients. with the majority of the dose found in the marrow. Tumor regressions were not observed. An estimated 0.33 to 1.0 rad/mCi 131I was delivered to the whole body. 1.1 to 6.1 rad/mCi was delivered to the plasma. and up to 34 rad/mCi was delivered to the red marrow compartment. 131I-M195 was rapidly modulated. with a majority of the bound immunoglobulin G (IgG) being internalized into target cells in vivo. These data indicate that whole bone marrow ablative doses of 131I-M195 can be expected. The rapid. specific. and quantitative delivery to the bone marrow and the efficient internalization of M195 into target cells in vivo also suggest that the delivery of other isotopes such as auger or alpha emitters. toxins. or other biologically important molecules into either leukemia cells or normal hematopoietic progenitor cells may be feasible.
A phase I clinical, plasma, and cellular pharmacology study of gemcitabine, A novel deoxycytidine analog. gemcitabine (2'.2'-difluorodeoxycytidine [dFdC]). has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1.000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression. with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration. reached after 15 minutes of infusion. was proportional to the total dose administered. Elimination. due mainly to deamination. was rapid (terminal half-life [t1/2]. 8.0 minutes) and dose independent. The deamination product 2'.2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2. 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses. which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1.000 mg/m2). suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.
Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung, To determine if chemotherapy dose intensity (DI) influences treatment outcome. 60 published studies in limited- and extensive-stage small-cell carcinoma of the lung (SCCL) were retrospectively analyzed for relationship between intended DI and response (complete response [CR] or partial response [PR]) or median survival (MS). Agents used in the regimens included cyclophosphamide (C). doxorubicin (A). vincristine (V). etoposide (E). and cisplatin (P). Relative DI (RDI) of each study regimen was calculated against a reference regimen. and weighted regression analysis was used. Additionally. analysis of individual drug RDI within combinations was performed. For CAV. increasing RDI of the regimen showed no correlation with outcome. For the individual drugs. C RDI correlated positively. while A RDI correlated negatively with attainment of CR in limited disease. but both only after unduly influential observations were eliminated. In extensive-stage disease. A RDI correlated positively with CR+. PR but only in randomized trials. and this correlation lost statistical significance after unduly influential observations were eliminated. For CAE and CAVE. the RDI of the regimens correlated positively with MS in extensive-stage disease as did the C RDI. In limited disease. the C RDI correlated negatively with MS. For EP. no significant correlations were seen. We conclude that DI-outcome correlations are not consistent for these chemotherapy regimens in SCCL. Meta-analysis of retrospective data can generate hypotheses for testing in prospective clinical trials. but study sample and method of analysis can appreciably affect conclusions.
Program directors' attitudes towards residents' care of patients who have AIDS, OBJECTIVE: To evaluate the educational strategies and experiences of residency programs regarding the training of primary care providers in the care of patients who have AIDS. DESIGN: Cross-sectional. self-administered questionnaire survey. SETTING: Survey conducted November 1988-April 1989. PARTICIPANTS: All 771 non-military U.S. internal medicine and family medicine program directors were surveyed; 80% responded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: While 91% of the directors felt that primary care of AIDS patients was an important educational experience and 94% reported that their programs usually had AIDS inpatients. only 16% reported that the majority of trainees cared for AIDS patients in their continuity clinics. Even at programs that typically had six or more AIDS inpatients. only 26% of directors reported that most residents had cared for an AIDS patient in their continuity clinics. Among the 57% who did not believe or were unsure whether their residents were adequately trained in AIDS ambulatory care. only 38% reported improving resident education in this area to be a high priority. Among the 39% who did not encourage residents' assumption of primary care. 60% had at least one of the following concerns: AIDS care too stressful for residents (24%). AIDS care too complicated for generalists (31%). or clinic faculty not qualified to supervise residents' caring for AIDS patients (39%). CONCLUSION: Although program directors view education in AIDS ambulatory care as important. most do not believe that residents are adequately trained. many do not encourage residents' assumption of primary care of AIDS patients. and residents usually have not provided such care in their programs. Strategies to augment residents' ambulatory experience in AIDS care are needed.
Inability to demonstrate physiologic correlates of subjective improvement among patients taught the relaxation response, OBJECTIVE: To assess whether the regular elicitation of the relaxation response produces sustained physiologic changes coincident with symptomatic relief or improved psychological state. DESIGN: Prospective. cohort pilot study. SETTING: Clinical research center within a teaching hospital. PATIENTS: Thirteen athletic men. mean age 44.8 years. with borderline or labile hypertension. taking no medication. All 13 completed the study. INTERVENTIONS: Three baseline assessments of psychological state. symptom checklist. and assessment of autonomic response to infusion of beta agonist (isoproterenol). Daily relaxation response exercises for five consecutive weeks followed by repeat assessment of all parameters. Discontinuation of relaxation exercises for subsequent five weeks followed by repeat assessment of all parameters. Measurements and main results: After eliciting the relaxation response. subjects demonstrated significant decreases in anxiety (p less than 0.014) and somatic symptoms (p less than 0.02). Psychological and somatic variables returned toward baseline after the subsequent discontinuation of relaxation exercises. No significant concomitant change in urinary catecholamines. heart rate response to isoproterenol. blood pressure. pulse rate. or serum cholesterol was demonstrated. CONCLUSION: The regular elicitation of the relaxation response can improve psychological performance and reduce symptoms. However. the physiologic mechanism whereby these psychological and symptomatic improvements occur remains poorly understood and warrants further investigation.
Pathogenesis and recent therapeutic approaches to graft-versus-host disease, Effective prophylaxis of acute GVHD should bring about improved patient survival by decreasing severe infections during the first 3 months after transplantation and reducing the incidence of chronic GVHD while not compromising the quality of hematopoietic engraftment or increasing the incidence of leukemic relapse by impairing the graft-versus-leukemia effect. None of the current approaches to prevention of GVHD succeed at meeting these expectations. although postgrafting immunosuppressive therapy comes closest to the ideal. The technique of T cell depletion has been very effective in reducing the incidence of GVHD. but conditioning programs must be developed that will be more successful at eliminating host immune and malignant cells. It is doubtful that this will be achieved with systemic chemotherapy and total body irradiation. Innovative approaches such as the use of monoclonal antibodies. either alone or linked to short-lived radioactive isotopes with short linear energy transfer. promise to result in less toxic but more efficient programs. not only providing better eradication of malignant disease but also ameliorating the problem of graft failure. It is conceivable. however. that it will never be possible to kill all leukemic cells with chemoradiotherapy of any form. and the graft-versus-leukemia effect may be essential. Perhaps in the future it will be possible to distinguish lymphocytes causing the graft-versus-leukemia effect from those causing GVHD. isolate them. and use them in attempts at therapy. In the meantime. postgrafting immunosuppressive drugs are used most frequently to prevent and treat GVHD. and steadily improving survival statistics can be expected.
Interleukin-2: prospects for lymphocyte-mediated destruction of pediatric malignancies, Immunologic therapy of cancer was speculated on at the turn of the century. In animals. in vitro. and most recently in patients. irrefutable evidence has been obtained that lymphocyte responses can have a reproducible and beneficial antitumor effect. These results indicate that "biologic response modification" may truly become a fourth modality for cancer treatment. to be integrated into the standard approaches of radiation. chemotherapy. and surgery. To what extent these immune approaches may enable eradication of microscopic amounts of residual diseases in children who would otherwise have a recurrence of their malignancies remains the critical issue for testing over the next decade. Enthusiasm regarding this approach is abundant. but critical evaluation of all clinical trials is essential to best focus these mechanisms into effective therapy.
Cardiac performance in infants referred for extracorporeal membrane oxygenation, We performed cardiac evaluations in 59 infants referred for severe lung disease to determine whether cardiac performance was impaired in those requiring extracorporeal membrane oxygenation (ECMO). Infants were divided into two groups: group 1 (n = 25) received conventional therapy and group 2 (n = 34) received ECMO therapy after meeting established criteria. Ventilatory and oxygenation indexes and estimates of right ventricular systolic pressure were measured. Load-dependent and load-independent echocardiographic indexes of cardiac performance were also measured. The infants in the two groups had similar diagnoses. age. weight. inotropic support. ventilator and oxygenation indexes on admission. and survival. Heart rate and estimates of preload and afterload were similar in the two groups. Ventricular shortening fraction was 36.1 +/- 7.6% in group 1 and 40.5 +/- 8.8% in group 2 (p value was not significant). Velocity of circumferential fiber shortening (VCF/sec) was 1.41 +/- 0.35 in group 1 and 1.58 +/- 0.39 in group 2 (p value was not significant). The relationship between wall stress and ventricular shortening was similar in the two groups. There were no differences in cardiac output. Pulmonary artery pressure was estimated to be 56 +/- 13 mm Hg in group 1 and 63 +/- 10 mm Hg in group 2 (p = 0.017). Thus no significant differences were found in load-dependent or load-independent measures of cardiac performance in infants with severe lung disease treated with ECMO or conventional therapy. We conclude that cardiac failure is not the primary cause of clinical deterioration in infants with severe lung disease who require ECMO therapy.
Effect of therapeutic plasma concentrations of theophylline on behavior, cognitive processing, and affect in children with asthma [published erratum appears in J Pediatr 1991 Jul;119(1 Pt 1):164, A double-blind. randomized. crossover study assessed the effects of theophylline on behavior. mood. and efficiency of cognitive processing. Thirty-one children aged 8 to 12 years with moderate asthma were randomly assigned to 10-day theophylline followed by placebo or to placebo followed by theophylline experimental conditions separated by 2-day washout periods. Theophylline plasma concentrations and pulmonary function tests were performed throughout the study. Cognitive functioning tests and self-report measures were administered at baseline and after each medication phase. Behavior ratings were obtained from parents and teachers. Parents' and teachers' ratings did not reflect a theophylline effect on attention or activity level; children's self-reports showed no changes in mood. and no statistically significant differences were found on measures of cognitive processing. Large individual differences in sensitivity to theophylline effects were present. Although most of the children tolerated theophylline well. those already having attentional or achievement problems appeared vulnerable to adverse effects. Individual response differences should be a focus of future studies.
Patient-controlled analgesia in children and adolescents: a randomized, prospective comparison with intramuscular administration of morphine for postoperative analgesia, A randomized. prospective trial of patient-controlled analgesia (PCA). that is. a method of analgesia administration involving a computer-driven pump activated by patients to receive small doses within defined limits was performed in 82 children and adolescents after major orthopedic surgery to compare (1) intramuscularly administered morphine. (2) PCA morphine and (3) PCA morphine with a low-dose continuous morphine infusion (PCA-plus). Patients receiving PCA and PCA-plus had lower pain scores and greater satisfaction than patients receiving intramuscularly administered morphine. The three groups used equal amounts of morphine and most measures of recovery were identical in the groups. In particular. PCA and PCA-plus did not increase the incidence of opioid-related complications. and patients receiving PCA-plus were less sedated than patients receiving intramuscular therapy. We conclude that PCA and PCA-plus are safe and effective methods of pain relief in children and adolescents after orthopedic surgery. are better accepted than intramuscular injections. and do not increase perioperative morbidity.
Alternating hepatic intra-arterial floxuridine and fluorouracil: a less toxic regimen for treatment of liver metastases from colorectal cancer, Hepatic intra-arterial (HIA) infusion of floxuridine (FUDR) via an implanted pump has shown promise in the treatment of colorectal cancer metastasized to the liver. However. the potential benefit of this therapy may be offset by the high incidence of treatment-limiting biliary toxicity. Although weekly HIA bolus of fluorouracil (5-FU) is effective against metastatic colorectal cancer to the liver with no biliary toxicity. it is limited by systemic side effects. In December 1986. we began a phase II trial of alternating HIA FUDR and 5-FU via the implanted pump in an attempt to extend the duration of treatment by obviating the limiting biliary (FUDR) and systemic (5-FU) drug toxic effects. Patients received continuous HIA FUDR at 0.1 mg/kg of body weight per day on days 1 through 8 followed by an HIA bolus of 5-FU at 15 mg/kg given via the pump sideport on days 15. 22. and 29. with the cycle repeated every 35 days. Sixty-eight patients were enrolled in this trial. and 64 were fully evaluable. Of the 64 patients. 30 (47%) previously had received chemotherapy. Major response (complete response plus partial response) was observed in 32 (50%) of 64 patients. and the median survival from pump implantation in all patients was 22.4 months. In contrast to the experience with the single-agent HIA FUDR regimen. no patient had treatment terminated because of drug toxicity. Alternating HIA FUDR and 5-FU has efficacy similar to that of HIA FUDR given alone. but when closely monitored and adjusted appropriately. is not associated with toxic effects requiring treatment termination.
Preferential localization of human adherent lymphokine-activated killer cells in tumor microcirculation, The efficacy of adoptive immunotherapy for solid tumors with lymphokine-activated effector cells presumably depends on the ability of these cells to localize adequately in tumor tissues. We present here the first quantitative study of the in vivo movement of fluorescently labeled adherent lymphokine-activated killer (A-LAK) cells. These cells were injected intra-arterially along with low-dose interleukin-2 into normal (mature granulation) tissue and an implant of VX2 carcinoma grown in the rabbit ear chamber. A small proportion of A-LAK cells accumulated preferentially in the tumor microcirculation in vivo because of an increased frequency of long-term adhesive interactions with the tumor vasculature. Stasis of blood flow in the tumor vasculature was observed 1 to 2 days after injection. Subsequent necrosis of the tumors was observed. along with diffuse infiltrates of lymphocytes. monocytes. and granulocytes in the interstitial space within the tumor. Development of necrosis despite low ratios of effector cells to target cells suggests that in addition to direct cytotoxicity. the response to adoptive immunotherapy is mediated via the tumor vasculature. This novel mechanism for adoptive immunotherapy must be taken into account in the development of improved strategies for cancer treatment.
Abdominal aortic aneurysm: results of a family study, Data pertaining to abdominal aortic aneurysm among first-degree relatives of 91 patients with abdominal aortic aneurysm are presented. The percentage of families with at least one affected first-degree relative of the proband (multiplex families) was 15.4%. In 21.4% of multiplex families parent-offspring transmission of abdominal aortic aneurysm was noted; in the remaining families only siblings were affected. The mean age at onset among probands was 67.3 years; that among all affected was 67.4 years. No statistically significant difference in the mean ages at onset between genders was noted. Among affected siblings of probands. the sex ratio. male:female. was 1.33:1. which is not significantly different from 1:1. The relative risk of developing an abdominal aortic aneurysm was 3.97 for fathers. 4.03 for mothers. 9.92 for brothers. and 22.93 for sisters.
Cells derived from omental fat tissue and used for seeding vascular prostheses are not endothelial in origin. A study on the origin of epitheloid cells derived from omentum, The use of microvascular endothelial cells derived from omental tissue has been advocated to seed vascular grafts with autologous endothelial cells in high density. The purpose of our study was to evaluate the precise origin of these cells. Therefore we have compared cellular characteristics of these cells with those of endothelial cells isolated by collagenase treatment of human umbilical veins. The omental cells were isolated from from omental tissue from four different patients by incubation in a collagenase-dispase solution. Part of the material was processed by Percoll density gradient centrifugation in an attempt to purify the isolates. Cellular characteristics of both types of cells were determined by studying the morphologic features of the cells and by determining the presence of von Willebrand factor. antigens EN-4 and PAL-E specific for endothelial cells. cytokeratins 8 and 18. vimentin and desmin. and uptake of diI-acetylated low-density lipoprotein. Epitheloid cells from omental tissue. isolated after collagenase treatment and either purified or nonpurified by Percoll density gradient centrifugation. differed from human umbilical vein endothelial cells with respect to the presence of surface microvilli. the expression of von Willebrand factor. EN-4 and PAL-E. and the presence of cytokeratins 8 and 18 and desmin. von Willebrand factor (in a granular staining pattern) and the presence of EN-4 and PAL-E were only detected in human umbilical vein endothelial cells. Vimentin was present in both cell types. whereas cytokeratins 8 and 18 and desmin were only present in cells derived from omentum. From these data we conclude that the so called microvascular endothelial cells from omentum are not endothelial but mesothelial in nature.
Subclavian artery to innominate vein fistula after insertion of a hemodialysis catheter, Insertion of hemodialysis catheters for temporary use is now preferentially performed by percutaneous infraclavicular subclavian vein catheterization. This method involves passage of a stiff dilator and a peel-away sheath over a guide wire. and is usually carried out without fluoroscopy. For the most part this has proved to be a valuable and safe approach. However. a small incidence of major complications occurs. which needs to be emphasized. Sixteen cases of arteriovenous fistulas between the subclavian artery or its branches and the subclavian vein have been reported so far in the literature. To date only one case of subclavian artery to innominate vein fistula has been reported. We report the second case with this complication and suggest possible preventive measures.
Revascularization of an ischemic limb by use of a muscle pedicle flap: a rabbit model, A rabbit model of hind limb ischemia was designed to demonstrate that new. hemodynamically significant arterial connections will develop between ischemic skeletal muscle and an independently perfused muscle pedicle flap. The right common iliac artery was divided in 15 rabbits. In eight rabbits a muscle flap based on the left deep inferior epigastric artery was transposed to the right thigh (flap group). In seven rabbits a sham operation was performed where the flap was sutured to the abdominal wall (sham group). After 7 days angiography demonstrated arterial connections between the flap and the native limb circulation in all of the flap group animals. The flap increased muscle perfusion in the ischemic limb (2.99 ml/100 gm muscle/minute in the flap group. vs 2.06 ml/100 gm muscle/minute in the sham group. p less than 0.005). Hemodynamically significant vascular connections will develop between a well-perfused muscle flap and an ischemic limb. The augmentation in perfusion provided by these connections can be quantified.
Limitations of magnetic resonance imaging and ultrasound-directed (duplex) scanning in the diagnosis of subclavian vein thrombosis, To investigate the potential role of magnetic resonance imaging and duplex scanning in the diagnosis of catheter-induced subclavian vein thrombosis. we correlated the results of 43 arm phlebograms with duplex scans; 28 of these phlebograms were also correlated with magnetic resonance imaging scans of the thoracic veins. Eighteen of the 43 phlebograms were normal. and all had normal magnetic resonance imaging and duplex studies. Eleven subclavian veins were totally occluded on phlebography; all had duplex scans. and five were also scanned with magnetic resonance imaging. Duplex scans detected 6 of 11 occlusions. whereas magnetic resonance imaging detected 4 of the 5 occlusions scanned. The five occlusions that were not detected by either magnetic resonance imaging or duplex scans were short segmental occlusions of the medial one third of the left subclavian vein. Of 14 nonocclusive thrombi seen on phlebography. duplex scans correctly identified 8. Magnetic resonance imaging was done on eight nonocclusive thrombi but identified only two. All abnormal findings on duplex scanning and magnetic resonance imaging were confirmed by phlebography. Short occlusions of the proximal portion of the left subclavian vein were often undetected by duplex scanning but occasionally seen with magnetic resonance imaging. Neither modality was sensitive to the presence of nonocclusive mural thrombi. Magnetic resonance imaging is highly reliable in ruling out the presence of a thrombotic process in the subclavian vein. but it may on occasion fail to detect the presence of subclavian thrombi. For this reason. in cases with suspected subclavian vein thrombosis magnetic resonance imaging cannot be used as the only diagnostic modality.
Skewflap versus long posterior flap in below-knee amputations: multicenter trial, A multicenter trial of alternative techniques for below-knee amputation is described in which surgeons in 11 centers randomized 191 patients with end-stage occlusive vascular disease to two different methods of stump construction. The skewflap technique was performed in 98 and the long posterior flap was performed in 93. The two groups were well matched in respect to age. sex. smoking. diabetes. and indications for amputation. Early outcome was compared in terms of 30-day mortality rate: skew 11 (11%) deaths versus long posterior flap 16 (17%); the state of the wound at 1 week (primary healing 60% in both groups); the need for surgical revision at the same level 7 (7%) versus 7 (8%). and revision to a higher level 10 (10%) versus 7 (8%). Follow-up information at 6 months was available from records or by mailed questionnaire in 188 (98%) at 6 months. 20 died during that interval. It showed that a prosthetic limb was fitted to 64 (84%) of skew flaps and 50 (77%) of long posterior flaps. Walking. alone or with support. was achieved in 59 (78%) and 46 (71%). respectively. None of these differences reached statistical significance. It is concluded that the skew flap is just as effective as the long posterior flap and is an excellent option for below-knee amputation.
Diagnosis of popliteal artery entrapment syndrome: the role of duplex scanning, The authors present a new diagnostic procedure to quickly and noninvasively diagnose the popliteal artery entrapment syndrome. A large personal experience on the surgical treatment of such a disease (29 cases in 22 patients) allowed us to focus on the optimal diagnostic procedure useful to detect this problem at an early stage. The technique is based on continuous-wave Doppler and duplex scanning studies done both in the resting state and during active contraction of the calf muscles. If compression of the popliteal artery occurs with contraction of the calf muscles. it will be detected by a decrease in flow. This finding will also direct the radiologist to obtain films when the maneuver is repeated. This makes it unlikely that the diagnosis will be missed. Since July 1988 a total of 1212 patients were evaluated with continuous-wave Doppler for suspected chronic ischemia. From this group 41 patients were selected to be studied again with the combined continuous-wave Doppler and duplex scanning method for possible popliteal artery entrapment syndrome. Two cases were discovered and verified by dynamic angiography guided by continuous-wave Doppler and treated surgically.
Suggested standards for reporting on arterial aneurysms. Subcommittee on Reporting Standards for Arterial Aneurysms, Ad Hoc Committee on Reporting Standards, Society for Vascular Surgery and North American Chapter, International Society for Cardiovascular Surgery, The literature on arterial aneurysms is subject to potential misinterpretation because of inconsistencies in reporting standards. The joint councils of the Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery appointed an ad hoc committee to address this issue. This communication. prepared in response to the need for standardized reporting. defines and classifies arterial aneurysms and recommends standards for describing the causes. manifestations. treatment. and outcome criteria that are important when publishing data on aneurysmal disease.
Cancer in populations living near nuclear facilities. A survey of mortality nationwide and incidence in two states, Reports from the United Kingdom have described increases in leukemia and lymphoma among young persons living near certain nuclear installations. Because of concerns raised by these reports. a mortality survey was conducted in populations living near nuclear facilities in the United States. All facilities began service before 1982. Over 900.000 cancer deaths occurred from 1950 through 1984 in 107 counties with or near nuclear installations. Each study county was matched for comparison to three "control counties" in the same region. There were 1.8 million cancer deaths in the 292 control counties during the 35 years studied. Deaths due to leukemia or other cancers were not more frequent in the study counties than in the control counties. For childhood leukemia mortality. the relative risk comparing the study counties with their controls before plant start-up was 1.08. while after start-up it was 1.03. For leukemia mortality at all ages. the relative risks were 1.02 before start-up and 0.98 after. For counties in two states. cancer incidence data were also available. For one facility. the standardized registration ratio for childhood leukemia was increased significantly after start-up. However. the increase also antedated the operation of this facility. The study is limited by the correlational approach and the large size of the geographic areas (counties) used. It does not prove the absence of any effect. If. however. any excess cancer risk was present in US counties with nuclear facilities. it was too small to be detected with the methods employed.
Motor vehicle crash injury patterns and the Virginia seat belt law, Injuries to front seat occupants in tow-away crashes in the Charlottesville. Va. area were compared for 1 year before and 1 year after Virginia's seat belt use law took effect. Vehicle and occupant data were combined to examine crash and injury patterns. Reported seat belt use in crashes increased after the law. and there were substantial decreases in injuries. Front seat occupants were less likely to receive medical treatment following a crash in the postlaw period. The reduction in the number of injuries was greater for passengers in the right front seat than for drivers and for frontal crashes than for other types of crashes. The injury reduction effects occurred primarily through reductions in the number of head and face injuries. particularly those that occur from contact with windshields and instrument panels.
Intrathecal baclofen for spasticity in cerebral palsy, Seventeen patients with congenital spastic cerebral palsy and six patients with other forms of spasticity were injected intrathecally with doses of placebo or baclofen. 25 micrograms. 50 micrograms. or 100 micrograms. in a randomized. double-blind manner. Muscle tone in the upper and lower extremities was assessed by Ashworth scores both before the injections and every 2 hours afterward for 8 hours. Function of the upper extremities was evaluated before the injections and 4 hours afterward. Muscle tone in the lower extremities was significantly decreased within 2 hours after baclofen injection and remained lower than baseline 8 hours afterward. Upper extremity tone and function were not significantly affected by these single doses. Confusion and drowsiness occurred in two of the youngest children in the study after the 50-micrograms dose. but cleared within 2 hours. Our findings indicate that intrathecal baclofen reduces spasticity in children with cerebral palsy. as it does in adults with spasticity of spinal origin.
Follow-up status of patients with angiographically normal coronary arteries and panic disorder, Cardiology patients with normal coronary angiography demonstrate continuing and substantial social. health. and work disability. We hypothesized that the diagnosis of panic disorder would mark those for whom continuing disability is most likely. We interviewed 72 such patients at the time of their normal angiogram. and then again an average of 38 months later. Those with panic disorder (n = 36) demonstrated significantly more disability at follow-up than did the other study patients. We conclude that those patients with normal angiograms who have panic disorder are more disabled than those who do not have panic disorder. Panic disorder in psychiatric samples has been shown to be highly treatable. Therefore. early identification and treatment of panic disorder in this group is likely to minimize the suffering associated with this condition.
Successful treatment of cat-scratch disease with ciprofloxacin, Cat-scratch disease is usually a benign. self-limited disease. Infection may be asymptomatic but is commonly associated with painful regional lymphadenitis. Occasionally. disease may result in systemic symptoms and dissemination. Five adult patients. aged 24 to 57 years. were diagnosed as having cat-scratch disease. based on a positive history of cat scratches followed by typical symptoms including painful regional lymphadenitis. malaise. and positive cat-scratch skin tests. Diagnostic evaluations revealed no other cause for the lymphadenitis. Three patients had not received prior treatment with antibiotics. and two patients had failed to improve on other antibiotics. All five were treated with oral ciprofloxacin. 500 mg by mouth. twice daily. All patients had dramatic improvement in symptoms within a few days and none has relapsed during follow-up. This is the first report of successful treatment of cat-scratch disease with ciprofloxacin. which appears to be an effective therapy for cat-scratch disease in adults.
Antihypertensive therapy. To stop or not to stop, The benefits of continuous antihypertensive therapy have been extensively documented. However. lack of compliance with the prescribed regimen. excessive cost. and troublesome adverse effects of some antihypertensive agents led to the consideration of intermittent therapy or even complete discontinuation of therapy as an effective alternative to lifelong medication. Prospective studies dealing with this subject reported inconsistent results. Nevertheless. they allowed us to identify selection criteria of candidates for step-down or discontinuation of antihypertensive therapy. Such candidates include patients with mild essential hypertension who have one or more of the following characteristics: young age. normal body weight. low salt intake. no alcohol consumption. low pretreatment blood pressure. successful therapy with one drug only. and no or only minimal signs of target organ damage. Stopping antihypertensive therapy without subsequent rise in arterial pressure was shown to be possible in a subset of patients with mild essential hypertension for a period of months to years. This approach appears to be safe. provided that blood pressure is monitored frequently. and may improve compliance. save treatment costs. and reduce adverse effects of certain drugs. although its long-term consequences for morbidity and mortality remain to be determined.
Laparoscopic cholecystectomy, Laparoscopic cholecystectomy is a new endoscopic technique that has diffused throughout the surgical community with great rapidity. Although the DATTA panelists considered the procedure appropriate with respect to both its safety and effectiveness. recognition was made that there are no comparative trials of this technique vs open cholecystectomy and virtually no literature on complication rates. The Society of American Gastrointestinal Endoscopic Surgeons has developed minimal credentialing criteria for determining competence in laparoscopic surgery. This includes completion of an approved residency training in general surgery. training in laparoscopic technique either by a surgeon experienced in this procedure or by completion of an approved course in the technique requiring hands-on laboratory practice. and observation or proctoring of an actual surgical procedure. Many of the DATTA panelists (35 of 40 [87.5%]) reiterated the importance of requiring that the procedure be performed first with animals and that subsequent laparoscopic procedures on patients be done under the supervision of an expert in laparoscopic cholecystectomy.
Surgical treatment for limited small-cell lung cancer. The University of Toronto Lung Oncology Group experience, Since 1977. 119 patients with limited small-cell lung cancer have undergone combined modality therapy including surgery at our institution. Seventy-nine patients (58 male. 21 female; median age 63 years) had surgery first. and 67 of these had adjuvant chemotherapy. Forty (27 male. 13 female; median age 59 years) had chemotherapy first. and 94% had a complete or partial response before the operation. Pretreatment staging revealed 69 stage I. 27 stage II. and 23 stage III tumors. Twenty-six patients required pneumonectomy. 88 lobectomy. and five had no resection. Four patients had gross and six had microscopic residual disease. Postoperative pathologic examination showed small-cell lung cancer only (n = 95). non-small-cell lung cancer (n = 3). mixed (n = 17). and no residual tumor (n = 4). Postoperative staging revealed 35 stage I. 36 stage II. and 48 stage IIIa tumors. The median survival of the entire group is 111 weeks and the projected 5-year survival rate is 39%. No survival difference was seen between patients treated with chemotherapy before the operation and those undergoing an initial operation followed by chemotherapy (p = 0.756). The median survival for patients with pathologic stage I disease has not been reached. and the projected 5-year survival rate is 51%. This is significantly better than for the patients with stage II (median 82 weeks. p = 0.001) or stage III (median 83 weeks. p = 0.001) disease. who have projected 5-year survival rates of 28% and 19%. respectively. Seven of the 12 patients who had no adjuvant chemotherapy remain alive at 6 to 48+ months. Sixty-seven patients have died (11 had no evidence of disease). Only 10 patients had a relapse in the primary site alone. seven at the primary and distant sites. and 39 only in distant sites. In summary. resection improves control at the primary site. and a significant proportion of patients with stage I (N0) disease achieve long-term survival and cure with combined modality therapy including surgery. Stage II and IIIa patients have survival predictions similar to stage IIIa non-small-cell lung carcinoma treated surgically.
The effect of muscle-sparing versus standard posterolateral thoracotomy on pulmonary function, muscle strength, and postoperative pain, Increased interest in alternative approaches to thoracotomy has developed because of the considerable morbidity associated with the standard posterolateral technique. We conducted a prospective. randomized. blinded study of 50 consecutive patients to compare postoperative pain. pulmonary function. shoulder strength. and range of shoulder motion between the standard posterolateral and the muscle sparing thoracotomy techniques. Pulmonary function (forced expiratory volume in 1 second and forced vital capacity). shoulder strength. and range of motion were measured preoperatively and at 1 week and 1 month postoperatively. Pain was quantitated by postoperative narcotic requirements. the visual analogue scale. and the McGill pain questionnaire. Morbidity. mortality. and hospital stay were compared between the standard posterolateral and muscle-sparing techniques. There were no differences in postoperative pulmonary function. shoulder range of motion. extent of lung resection. surgical approach time. mortality. or hospital stay. There was significantly less postoperative pain in the muscle-sparing group. The narcotic requirement was less in the first 24 hours (p = 0.0169). and visual analogue scale scores were significantly lower (p less than 0.05) throughout the first postoperative week. Shoulder girdle strength was decreased at 1 week in the standard incision group whereas the strength was preserved with the muscle-sparing approach. Muscle strength had returned to preoperative levels by 1 month in both groups. Morbidity was identical in the two groups with the exception of postoperative seromas. The prevalence of seroma was 23% in the muscle-sparing group and 0% in the standard incision group (p = 0.0125). We have demonstrated that the muscle-sparing incision may be a reasonable alternative to the standard posterolateral approach.
Comparison of two levels of anticoagulant therapy in patients with substitute heart valves, After cardiac valve replacement patients were blindly randomized into two groups. both receiving aspirin (330 mg) and dipyridamole (75 mg) twice daily and the oral anticoagulant acenocoumarol (Sintrom). An international normalized ratio of 2.0 to 2.99 was assigned to group A and 3.0 to 4.5 to group B; both groups were subsequently analyzed for thromboembolic and hemorrhagic complications. Final evaluation included 51 and 48 patients. respectively. The follow-up was 626 months for group A (12.3 months/patient) and 486 months for group B (10.1 months/patient). The frequency of thromboembolism was equal in both groups: one transient ischemic attack in group A (a rate of 1.92/100 patient-years) and two transient ischemic attacks in group B (a rate of 4.94/100 patient-years). There was. however. a statistical difference in bleeding complications between the two groups (p less than 0.02). Two patients bled in group A. a rate of 3.9% (3.8/100 patient-years). which represents an incidence of one episode each 25.6 years of treatment; 10 patients bled in group B. a rate of 20.8% (24.7/100 patient-years) representing an incidence of one episode each 4 years of treatment. We conclude that an international normalized ratio of 2 to 3 is safer than a ratio of 3 to 4.5 and confers good protection from thromboembolism when oral anticoagulant therapy is used conjointly with platelet function-inhibiting drugs in patients with mechanical substitute heart valves.
Analysis and predictors of pulmonary vascular resistance after cardiac transplantation, Elevated pulmonary vascular resistance is a known risk factor for early death from acute right ventricular failure after orthotopic cardiac transplantation. Patients in whom the elevated pulmonary vascular resistance is due primarily to increased left atrial pressure ("reactive") frequently have normalization of resistance after transplantation. but few studies have detailed the time course and magnitude of these changes. To analyze the response of pulmonary vascular resistance to cardiac transplantation. we analyzed data from 4353 right heart catheterizations on all 182 patients undergoing cardiac transplantation between 1981 and Jan. 1. 1990. Before transplantation 18% of patients had a pulmonary vascular resistance greater than 4 WU. 16% had a pulmonary artery systolic pressure greater than 60 mm Hg. and 16% had a transpulmonary gradient greater than 14 mm Hg. In the overall group of patients. pulmonary vascular resistance (mean value 2.63 WU). transpulmonary gradient (mean value 9.9 mm Hg). and pulmonary artery systolic pressure (mean value 48.0 mm Hg) were normalized within 1 week of cardiac transplantation. In patients with a high preoperative pulmonary vascular resistance (greater than or equal to 4 WU). the resistance fell promptly within 1 week of transplantation but continued to be slightly elevated throughout the period of follow-up. By multiple regression analysis. pulmonary vascular resistance at 1 week and 1 year after transplantation was significantly correlated with the pretransplantation resistance. Pulmonary vascular resistance anytime after transplantation was related to preoperative resistance. body surface area. and pulmonary artery diastolic pressure. Inferences: (1) As a group. cardiac transplant recipients have a normal pulmonary vascular resistance. transpulmonary gradient. and pulmonary artery systolic pressure within 1 week after transplantation with little change thereafter for at least several years. (2) Patients with reversible elevation of pulmonary vascular resistance before cardiac transplantation typically have a reactive and a fixed component. Cardiac transplantation relieves the reactive but not the fixed component. As a result. pulmonary vascular resistance early (within 1 week) and late after transplantation will have fallen but not completely normalized.
The mechanism of heart failure caused by cardiac allograft rejection, Rejection of the cardiac allograft is often associated with reversible myocardial failure. the mechanism of which is not understood. We have examined this phenomenon in a small animal model that provides the opportunity for multimodality study of the rejection process. Heterotopic cardiac transplantation was performed in the Lewis rat with Lewis X Brown-Norway (allografts) or Lewis (isografts) donors. Without immunosuppression. allografts are completely rejected in 6 to 8 days. At 3 days cardiac grafts were explanted and mounted on a modified Langendorff apparatus for functional measurements or submitted for pathologic examination and biochemical determination of high-energy phosphates. Three-day isografts (n = 9) had minimal histologic changes. Pathologic examination of 3-day allografts (n = 13) showed lymphocytic infiltrate and myocyte necrosis. histologic features for which antirejection treatment is usually given clinically. For grafts subjected to functional studies (n = 11). heart rate. cardiac output. coronary flow. and stroke work were determined at baseline and in response to isoproterenol (3 x 10(-8) mol/ml). Three-day allografts (n = 6) and isografts (n = 5) had similar baseline function. The chronotropic response to isoproterenol was similar in allografts and isografts. but allografts had diminished cardiac output and stroke work after isoproterenol. Adenosine triphosphate levels were normal (41.9 nmol/mg) in 3-day allografts (n = 4). We have evaluated functional. biochemical. and pathologic changes associated with myocardial dysfunction during heterotopic cardiac transplant rejection in a small animal. This model reproducibly demonstrates diminished contractile reserve in 3-day allografts with normal baseline function and high-energy stores but histologically significant rejection.
Mitral valve repair by replacement of chordae tendineae with polytetrafluoroethylene sutures, Expanded polytetrafluoroethylene sutures have been used for replacement of diseased chordae tendineae during reconstructive procedures on the mitral valve in 43 patients. There were 28 men and 15 women whose mean age was 55 years. range 21 to 76. Three fourths of the patients were in New York Heart Association class III or IV. Replacement of primary chordae tendineae of the anterior leaflet was performed with 4-0 or 5-0 polytetrafluoroethylene sutures. A double-armed suture was passed twice through the fibrous portion of the papillary muscle head and tied down. Each arm of the suture was brought up to the free margin of the leaflet and passed through the area where the native chorda was attached. After the lengths of the two arms were adjusted. the ends were tied together on the ventricular side of the leaflet. Thirty patients had degenerative disease of the mitral valve; the incompetence was due to prolapse of the anterior leaflet in 14 patients and prolapse of the anterior and posterior leaflets in 16. Eleven patients had rheumatic mitral valve disease: four had stenosis. three had regurgitation. and four had mixed lesions. Two patients had ischemic mitral regurgitation caused by rupture of a papillary muscle head. There were no operative deaths. Patients have been followed up from 5 to 61 months. mean 13. Doppler echocardiographic studies were performed at regular intervals after the operation and revealed normal mitral valve function in most patients There were two failures that necessitated mitral valve replacement: one because of acute mitral regurgitation and the other because of hemolysis. There have been two late deaths. neither one valve related. Replacement of chordae tendineae with polytetrafluoroethylene sutures is simple and allows for reconstruction of the mitral valve in many patients who would otherwise require mitral valve replacement. Because our patients have been followed up for a limited time. the long-term results of this procedure remain unknown.
Alcohol and pyruvate cardioplegia. Twenty-four-hour in situ preservation of hamster hearts, Isolated hamster hearts were first perfused with a normal Krebs-Henseleit medium to demonstrate comparable viability of hearts before perfusing and storing them for 24 hours in one of three solutions. The three solutions were a physiologic saline with pyruvate as the substrate and 4% alcohol to arrest the heart (group 1). a standard cardioplegic solution (group 2). and an alcohol-free physiologic saline with pyruvate as the substrate (group 3). Recovery in terms of rate/pressure product and oxygen consumption after 30 minutes of reperfusion was 81% and 93%. respectively. for group 1. 13% and 32% for group 2. and 70% and 72% for group 3. Percent of physiologic recovery was not related to recovery of adenosine triphosphate. The adenosine triphosphate level returned to approximately 40% control level in all three groups. and in all three groups inorganic phosphate remained approximately 320% over control level after 30 minutes of reperfusion. Phosphocreatine level significantly higher in groups 1 and 3 than in group 2. as a result of improved oxygen consumption. Intracellular pH. determined by phosphorous 31 nuclear magnetic resonance spectroscopy. was physiologic in groups 1 and 3 but alkaline in group 2. This alkalinity may have been caused by leaky membranes. Pyruvate helped preserve mitochondrial function during depressed oxygen delivery. such as was seen during the 24-hour storage period. Four percent alcohol arrested the heart; combined with pyruvate plus alcohol solution were better than a standard cardioplegic solution for maintaining functional capability.
The dynamics of antegrade cardioplegia with simultaneous coronary sinus occlusion. Effects on aortic root infusion pressure, coronary sinus pressure, and myocardial cooling, It has been suggested that antegrade cardioplegia with coronary sinus occlusion improves homogeneous myocardial cooling and reduces myocardial injury in the presence of coronary artery occlusion. Little data are available on the exact relationships among the basic elements or this intervention. including antegrade infusion rate. aortic root pressure. the degree of coronary sinus occlusion. coronary sinus pressure. and myocardial cooling. The purpose of this study was to determine these relationships and to provide some basic guidelines for better understanding of this intervention. Twenty-two sheep were placed on cardiopulmonary bypass. the distal left anterior descending artery was occluded. and the proximal coronary sinus was snared. Sixteen combinations of infusion rate (3. 5. 7. or 9 ml/kg/min) and coronary sinus occlusion (total. subtotal. or moderate occlusion or no occlusion) were adopted for each 2 minutes of antegrade cardioplegia. yielding 96 measurements. Myocardial temperatures in the occluded and nonoccluded regions. aortic root infusion pressure. and coronary sinus pressure were measured during each infusion of cardioplegic solution. Coronary sinus occlusion was then released. and the whole heart was reperfused for 30 minutes for another infusion of cardioplegic solution and measurements. Results showed good degrees of linearity between infusion rate and aortic root infusion pressure for all coronary sinus occlusion and noninfusion groups (p less than 0.01). A positive effect of coronary sinus occlusion on aortic root infusion pressure was observed. The graded increases in infusion rate with various degrees of coronary sinus occlusion were constantly associated with elevation of coronary sinus pressure (p less than 0.01). It was also noted that myocardial temperatures in the region of the occluded left anterior descending artery were significantly lower in coronary sinus occlusion groups than in nonocclusion groups (p less than 0.01 or 0.05). Myocardial temperature in the nonoccluded region decreased significantly with the stepwise increases in infusion rate (p less than 0.01). but not with the increases in coronary sinus occlusion (not significant). Based on this and previous studies. we recommend that the induced coronary sinus pressure be safely maintained in the range of 25 to 35 mm Hg and that further studies be focused on the infusion rate of 5 ml/kg/min with subtotal or total coronary sinus occlusion for the intervention of antegrade cardioplegia plus coronary sinus occlusion.
Esophageal ultrasound and the preoperative staging of carcinoma of the esophagus, Esophageal ultrasound allows the esophageal wall to be viewed as five discrete layers. Lymph nodes are easily identified. and their size. shape. margin. and internal structure can be assessed. This provides an alternative method of preoperative (clinical) evaluation of the primary tumor [T] and the regional lymph nodes [N] of patients with carcinoma of the esophagus. Esophageal ultrasound was attempted in the clinical staging of 28 patients with carcinoma of the esophagus. Six patients (21%) were not assessed because of the inability to pass the esophageal ultrasound probe through the malignant stricture. The staging system for carcinoma of the esophagus developed by the International Union Against Cancer and the American Joint Committee on Cancer was used. Twenty-two patients had the true T determined by pathologic review of the resected esophagus. Esophageal ultrasound correctly identified T in 13 patients (59% accuracy). In four patients (18%) the disease was overstaged by esophageal ultrasound; all these patients had early T1 tumors confined to the submucosa. In five patients (23%) the disease was understaged by esophageal ultrasound; all of these patients had advanced tumors (four T3 and one T4) that invaded beyond the esophageal wall. Seven of the nine incorrect esophageal ultrasound determinations were called T2 (three T1. three T3. one T4). which suggests that the borders of the muscularis propria require careful attention when evaluated by esophageal ultrasound. Twenty patients had the true N determined by pathologic review of the resected specimen. Esophageal ultrasound correctly identified N in 14 patients (70% accuracy). Three patients were falsely identified as having N1 disease and three were falsely identified as having N0 disease. The sensitivity. specificity. positive predictive value. and negative predictive value for N assessment by esophageal ultrasound were 70%. Esophageal ultrasound provides an alternative method of visualization of the esophageal wall and regional lymph nodes. Our early experience shows promise for esophageal ultrasound in the clinical staging of carcinoma of the esophagus.
Freehand allograft aortic valve replacement and aortic root replacement. Utility of intraoperative echocardiography and Doppler color flow mapping, Seventeen consecutive patients undergoing 20 planned aortic valve replacements with allograft valves at Stanford University Medical Center were studied with intraoperative epicardial echocardiography and Doppler color flow mapping before and after cardiopulmonary bypass. Native aortic valves were replaced in 12 of the 20 patients. and eight patients underwent second aortic valve procedures. In 17 of 20 patients allograft selection was guided by prebypass echocardiographic estimates of annular diameter and/or length of allograft aortic root required. Other prebypass findings included unanticipated severe mitral regurgitation in one patient (which precluded allograft aortic valve replacement). left-to-right shunts in five patients. ascending aortic dissection in one. and aortic root disease necessitating coronary reimplantation or bypass in two. Postbypass echocardiography demonstrated acceptable competency of 18 of 19 allograft valves (mild or no aortic insufficiency). Postbypass echocardiography also documented successful repair of four of five shunts and mild mitral regurgitation in 15 of 19 patients (versus 11 of 19 before bypass). Conclusions: Intraoperative echocardiography-Doppler mapping is a useful adjunct for allograft aortic valve or aortic root replacement; it allows confident selection of appropriate tissue size before aortic cross clamping. which minimizes delay from allograft thawing procedures. It also provides helpful information about the extent of aortic root disease and coronary ostial anatomy before bypass. confirms allograft competency after bypass. and detects accompanying valvular and other hemodynamic lesions before and after allograft valve replacement.
No confirmation of visual evoked potential diagnostic test for migraine, We have attempted to replicate the results of studies on a diagnostic test reported to have 90% sensitivity and 89-96% specificity for migraine. The technique is based on peak-to-peak measurements of fast background electroencephalographic activity during a visual evoked potential (VEP) study. VEP latencies and amplitudes did not differ significantly. and showed substantial overlap. between a group of eight migraine patients and ten age-matched healthy controls. We could not recognise previously described fast activity or measure it objectively by peak-to-peak measurements. We cannot confirm that measurement of fast wave activity in the VEP background is useful in diagnosis of migraine.
Maternal age and birth defects: a population study, Since more and more women in developed countries are delaying childbearing to an older age. it is important to find out whether birth defects. other than those resulting from chromosomal anomalies. are related to maternal age. We have studied all 26.859 children with birth defects of unknown aetiology identified among 576.815 consecutive livebirths in British Columbia. All these cases' records were linked with provincial birth records to allow determination of maternal age at birth. We excluded children with chromosomal anomalies and those with other birth defects of known aetiology. Only 3 of the 43 birth defect categories studied showed significant maternal-age-specific trends: there were decreasing linear trends with maternal age for patent ductus arteriosus (chi 2 = 36.65. 1 df. p less than 0.01) and hypertrophic pyloric stenosis (chi 2 = 4.90. 1 df. p less than 0.05) and a bell-shaped curve (risk increasing to maternal age 30 then falling) for congenital dislocatable hip/hip click. The findings from this population-based analysis of no association between the incidence of birth defects of unknown aetiology and advancing maternal age should be reassuring to healthy women who opt to delay childbearing.
Deprivation in infancy or in adult life: which is more important for mortality risk?, Previous ecological studies have suggested that early life factors are important causes of adult cardiovascular and respiratory disease. by showing geographic correlations between past infant mortality rates and present adult mortality rates. However. these studies inadequately take account of the fact that areas which were severely deprived earlier this century remain the most deprived today. Thus the ecological relation between infant and adult mortality rates could simply reflect persistence in the geographic distribution of poor socioeconomic circumstances. To explore this hypothesis further infant mortality rates for 1895-1908 for 43 counties in England and Wales were correlated with cause-specific adult mortality for 1969-73 in people aged 65-74 years. with and without adjustment for present-day social deprivation and social class. The strong simple correlations found between infant mortality in 1895-1908 and adult mortality from various causes in 1969-73 were generally much attenuated or abolished by controlling for indices of present-day socioeconomic circumstances. Our results suggest that previous studies give no strong support for any direct influence of factors acting in early life on adult coronary heart disease mortality risk. Studies which gather data about infancy. childhood. and the full course of adult life are required to clarify this issue.
Safety of and immunological response to a recombinant vaccinia virus vaccine expressing HIV envelope glycoprotein, In a randomised phase I trial of a recombinant vaccina virus vaccine expressing the gp160 envelope gene of the human immunodeficiency virus (HIVAC-1e) 35 healthy. HIV-seronegative males. 31 of whom had a history of smallpox immunisation and 4 of whom were vaccinia naive. were vaccinated and then boosted 8 weeks later with HIVAC-1e or standard NY strain vaccinia virus. The frequency. duration. and titre of virus isolation from the vaccination site and occurrence of local side-effects were similar between the two groups of vaccinees. Vaccinia-naive (vac-n) subjects shed virus from the vaccination site for longer and at a higher titre than did vaccinia-primed (vac-p) individuals (19 vs 7 days and 10(7) vs 10(5) pfu/ml. respectively). In-vitro T-cell proliferative responses to one or more HIV antigen preparations developed in 13 of 16 vaccinia-primed subjects inoculated with HIVAC-1e. T-cell responses were. however. transient and in no subject did antibodies to HIV become detectable. The 2 vaccinia-naive subjects vaccinated with HIVAC-1e showed strong T-cell responses to homologous and heterologous strains of whole virus and to recombinant gp160 protein that remained detectable for over a year; antibodies to HIV envelope also developed in both. Recombinant vaccinia virus vaccines induce T-cell priming to the foreign gene products in most individuals. If used as the sole immunising agent they will be most efficacious in vaccinia-naive individuals.
Surfactant apoprotein-A concentration in sputum for diagnosis of pulmonary alveolar proteinosis, Pulmonary alveolar proteinosis (PAP). a disease characterised by accumulation of surfactant in alveoli. is diagnosed on the basis of invasive biopsy procedures. We have measured apoprotein A (SP-A) concentrations in sputum to see if this is useful for the diagnosis of PAP. Sputum samples from three patients with PAP and twenty patients with other pulmonary disease were assayed using monoclonal antibodies to SP-A. SP-A concentrations were 400 times higher in patients with PAP than in the controls. suggestions that this measurement is useful for the diagnosis of PAP especially where lung biopsy is contraindicated.
Cortisol response to corticotropin and survival in septic shock, Corticotropin stimulation tests were used to assess adrenocortical function in 32 patients with septic shock. 13 patients had a poor cortisol response (rise less than 250 nmol/l) to corticotropin. all of whom died. However. there were only 6 deaths among the 19 patients with adequate responses (p less than 0.001). These results suggest that some patients with septic shock may have relative adrenocortical insufficiency.
Onchocercacidal effects of amocarzine (CGP 6140) in Latin America, An open clinical trial of amocarzine was carried out in onchocerciasis patients in Ecuador and Guatemala. Administration after food was more effective than that during fasting. The most effective and best tolerated regimen. 3 mg/kg twice daily after food for 3 days (in 312 patients). killed 73% of 1477 female worms at nodulectomy 4 months after treatment. The mean microfilarial skin count was greatly reduced within a week (6-11% Of day 0 value on day 8) and it remained low at least 6 months (14-18% on day 180). Follow-up of a higher dose 3 day regimen taken while fasting showed microfilaridermia of 7-9% of the day 0 value 2 years after treatment.
Efficacy of eyepad in corneal healing after corneal foreign body removal, 30 patients with corneal epithelial defect due to removal of corneal foreign bodies were randomly allocated to receive either chloramphenicol with continuous application of an eyepad or chloramphenicol without the eyepad. Almost all corneal defects were healed at 24 h. and all were healed by 48 h. with no statistically significant difference between the two groups. Discomfort at 24 h was greater in the eyepad group than in the control group. An eyepad seems to confer no benefit in healing and is uncomfortable.
Lack of effect of pregnancy on outcome of melanoma. For The World Health Organisation Melanoma Programme, To determine the effect of pregnancy on prognosis in melanoma we investigated 388 women treated for stage 1 primary cutaneous disease during their childbearing years. 85 women had been treated before any pregnancy. 92 during pregnancy. 143 after they had completed all pregnancies. and 68 between pregnancies. Women who had received treatment while pregnant had primary tumours of significantly greater thickness than did those in the other three groups (p = 0.002). Other possible confounding factors (site. age. parity) did not differ between the groups. Once tumour thickness was controlled for. survival rate of women in whom melanoma was diagnosed and treated while they were pregnant did not differ from that in the other three groups. Cox regression analysis showed no differences between the three groups of women who were not pregnant at diagnosis. Women with melanoma should be advised about pregnancy on the basis of thickness and site of tumour and evidence of vascular spread. and not hormonal status.
Randomised prospective study of short-term and long-term initial stay in hospital by children with diabetes mellitus, To assess how an isolated change in the pattern of care influences outcome of care and hospital use. a randomised prospective 2-year study was done in which 31 of 61 consecutive children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) were admitted to hospital at disease onset for about a week and compared with the other 30 children who were admitted for about 4 weeks. Insulin treatment and education about diabetes were similar in the two groups. Duration of initial stay in hospital had no effect on metabolic control during the 2 years but time since diagnosis was significant with respect to effect on haemoglobin A1 (p = 0.001). haemoglobin A1c (p = 0.004). and insulin dose (p less than 0.001). At 2 years. 45% of the children in the short-term group and 29% in the long-term group were C-peptide positive (p = NS); C-peptide positivity correlated with age. A change in the pattern of care of children with IDDM. led to a pronounced decrease in hospital use by this patient group. Irrespective of the length of initial stay in hospital. equally good metabolic control was obtained in both groups for 2 years.
Hospital management of voluntary total fasting among political prisoners, In 1989 20 political detainees. held without trial for up to 32 months. were admitted. on hunger strike. to the Johannesburg Hospital. South Africa. Most were held under the regulations of the State of Emergency (since revoked) and 5 were held incommunicado under section 29 of the Internal Security Act (still in force). Guidelines for ethical management were based on the Declaration of Tokyo. which included the understanding that such detentions constituted mental torture. Conditions of detention in hospital were complicated by police interference in medical and nursing care. and by the chaining of some prisoners to their beds. Doctors are in a unique position to protest against inhuman treatment of prisoners. and should use this authority.
Argon laser stapedotomy, Lasers have been used in otology for 10 years. There have been reports of excellent hearing results using laser energy in surgery for otosclerosis. We used the argon laser in 75 consecutive primary stapedotomy procedures. The postoperative air-bone gap was 10 dB or less in 87% of patients and 20 dB or less in 95%. One ear (1.5%) had no postoperative hearing secondary to a granulomatous reaction. Complications were otherwise uncommon and mild. Most patients were treated on an outpatient basis. Our results compare favorably with other reports of laser surgery for otosclerosis. We conclude that excellent hearing results can be obtained using the argon laser for stapedotomy procedures.
Fine-needle aspiration biopsy of salivary glands, Between January 1. 1973. and December 31. 1988. the authors or their associates performed 552 fine-needle aspiration biopsies on patients with clinically significant masses of the salivary glands. All patients presented at the Medical College of Virginia Hospitals or Clinics of Virginia Commonwealth University; they were followed for periods ranging from 1 to 16 years. When available. the fine-needle aspiration diagnoses were correlated with histologic diagnoses and long-term patient outcomes. The sensitivity for a neoplasm was 93.3%; the specificity for the absence of a neoplasm was 99%. Diagnostic efficiency was 96.4%. and predictive value of a positive aspiration for a neoplasm was 98.3%. With fine-needle aspiration. surgical excision of salivary gland masses is often unnecessary. In patients with primary and metastatic neoplasms involving the salivary glands. fine-needle aspiration aids the surgeon in mapping the extent of the surgical procedure and in preoperatively preparing the patient. The procedure is cost-effective.
Cerebrospinal fluid fistula and endoscopic sinus surgery, Seven cases of cerebrospinal fluid fistulae occurring as a result of endoscopic sinus surgery in a total of 800 ethmoidectomies are discussed. along with 1 case referred for consultation. One cerebrospinal fluid fistula was intrasphenoid. 4 were posterior ethmoid/base of skull. 2 were anterior ethmoid. and 1 was ethmoid cribriform. Six of 8 fistulae were closed endoscopically. The sphenoid sinus cerebrospinal fluid fistula was closed successfully with fibrin glue and Gelfoam. Five cerebrospinal fluid fistulae were closed successfully using fascia. muscle. and Gel-foam. Two cerebrospinal fluid fistulae were treated conservatively. and only 1 stopped. Anatomic and technical aspects related to the occurrence of cerebrospinal fluid fistulae are discussed. Management and treatment of cerebrospinal fluid fistulae occurring during and after endoscopic sinus surgery is emphasized. When identified intraoperatively or delayed. cerebrospinal fluid fistulae can be managed successfully by endoscopic technique.
The response to human rIL-1, rIL-2, and rTNF in the middle ear of guinea pigs, Human recombinant interleukin 1 (rIL-1). interleukin 2 (rIL-2). or tumor necrosis factor (rTNF) were injected transtympanically into the middle ear of normal guinea pigs. Effusion volume and cellular content were determined after sacrifice and rapid dissection of the ear. By 24 hours. rIL-2 (100 U) had produced a cellular effusion (77% to 92% polymorphonuclear neutrophil leukocytes). which cleared by 72 hours. rTNF (10 U) yielded a cellular effusion (12% to 67% lymphocytes) at 24 hours. which cleared by 48 hours. rIL-1 (100 U) did not produce significant effusion when compared to control. rIL-2 and rTNF cause an inflammatory effusion in the middle ear. To the extent they are generated in the middle ear during otitis media. these cytokines have the potential to contribute to the pathogenesis of otitis media with effusion.
Aerobic and anaerobic microbiology of peritonsillar abscess, Thirty-four aspirates of pus from peritonsillar abscesses that were studied for aerobic and anaerobic bacteria showed bacterial growth. A total 107 bacterial isolates (58 anaerobic and 49 aerobic and facultative) were recovered. accounting for 3.1 isolates per specimen (1.7 anaerobic and 1.4 aerobic and facultatives). Anaerobic bacteria only were present in 6 (18%) patients. aerobic and facultatives in 2 (6%). and mixed aerobic and anaerobic flora in 26 (76%). Single bacterial isolates were recovered in 4 infections. 2 of which were Streptococcus pyogenes and 2 were anaerobic bacteria. The predominant bacterial isolates were Staphylococcus aureus (6 isolates). Bacteroides sp (21 isolates. including 15 Bacteroides melaninogenicus group). and Peptostreptococcus sp (16) and S. pyogenes (10). beta-Lactamase-producing organisms were recovered from 13 (52%) of 25 specimens tested. This retrospective study highlights the polymicrobial nature and importance of anaerobic bacteria in peritonsillar abscess.
Origin of nasal polyps, The nasoethmoid complexes from 6 patients with nasal polyps were systematically examined. First. the location and place of the origin of the polyps were recorded and photographed. The polyps and their places of origin were removed. serial sectioned. and examined. In all 6 patients. the polyps originated from the nasal mucosa. Most of the polyps extended laterally from the mucosa into the anterior part of the middle meatus. Several polyps originated from the mucosa near the ethmoid cell ostium or directly from the mucosa lining the edge of the ostium. The ostia themselves were not blocked by the polyps. and there was no indication of polyp formation in the ethmoid cells.
Synchronous positive and negative myoclonus due to pontine hemorrhage, We report a case of synchronous positive and negative myoclonus following pontine hemorrhage. Constant synchronous jerking of the eyes. tongue. face. mandible. larynx. pharynx. and diaphragms persisted during sleep. Jerking of limb muscles occurred during volitional activities. but not at rest. Inability to sustain glottic adduction during phonation contributed to severe dysarthria. Electromyography (EMG) revealed positive myoclonus of the branchial musculature with synchronous negative myoclonus in a generalized distribution. Treatment with trazodone reduced the ocular myoclonus but worsened the dysphagia. We suggest that a single neural rhythm generator may produce both positive and negative myoclonus.
Dystrophin expression in myotubes formed by the fusion of normal and dystrophic myoblasts, Mdx mouse dystrophy is characterized by the absence in the muscle cytoplasmic membrane of a high molecular weight protein called dystrophin. A possible avenue for treatment of muscular dystrophies is to inject normal myoblasts in a dystrophic muscle to form hybrid muscle fibers. Hybrid myotubes were formed in vitro by the fusion of normal rat and dystrophic mouse (mdx) myoblasts. Staining with Hoechst dye 33258 permitted the clear distinction of mouse and rat nuclei. Immunostaining demonstrated that dystrophin was present over the entire membrane of all hybrid myotubes even when nuclei ratio normal/dystrophic was low.
The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration, Three dominant mutations of mec-4. a gene needed for mechanosensation. cause the touch-receptor neurons of Caenorhabditis elegans to degenerate. With deg-1. another C. elegans gene that can mutate to induce neuronal degeneration and that is similar in sequence. mec-4 defines a new gene family. Cross-hybridizing sequences are detectable in other species. raising the possibility that degenerative conditions in other organisms may be caused by mutations in similar genes. All three dominant mec-4 mutations affect the same amino acid. Effects of amino-acid substitutions at this position suggest that steric hindrance may induce the degenerative state.
Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis, Epstein-Barr virus (EBV). a human herpesvirus. establishes a persistent asymptomatic infection of the circulating B-lymphocyte pool. The mechanism of virus persistence is not understood but. given the limited lifespan of most B cells in vivo. it seems most likely that EBV-infected cells must gain access to the long-lived memory B-cell pool. Here we show in an in vitro system that EBV. through expression of the full set of eight virus-coded 'latent' proteins. can protect human B cells from programmed cell death (apoptosis). the deletion mechanism which normally restricts entry into memory. We have found that EBV-positive Burkitt's lymphoma (BL) cell clones retaining the original tumour cell phenotype and expressing only one of the virus latent proteins. the nuclear antigen EBNA 1. are extremely sensitive to apoptosis; in this respect they resemble the tumour's normal cell of origin found in the germinal centres of lymphoid tissue. By contrast. isogenic BL cell clones which have activated expression of all eight EBV latent proteins are resistant to the induction of apoptosis. The EBV latent proteins should therefore be seen not just as activators of B-cell proliferation but. perhaps more importantly. as mediators of enhanced B-cell survival.
Abnormal pattern detected in fragile-X patients by pulsed-field gel electrophoresis, The fragile-X syndrome is the most frequent inherited form of mental retardation. with an incidence of 1 in 1.500 males. It is characterized by the presence of a fragile site at Xq27.3 induced in vitro by folate deprivation or by inhibitors of deoxynucleotide synthesis. Its mode of inheritance is unusual for an X-linked trait. with incomplete penetrance in both males and females. Some phenotypically normal males transmit the mutation to all their daughters who rarely express any symptoms. but penetrance is high in sons and daughters of these carrier women. Genetic and physical mapping of the Xq27-q28 region has confirmed that the disease locus is located at or very near the fragile site. Hypotheses proposed to account for the abnormalities in the inheritance of the disease include sequence rearrangements by meiotic recombination or a mutation that affects reactivation of an inactive X chromosome during differentiation of female germ cells. To detect such rearrangements. or methylation changes that may reflect a locally inactive X chromosome. we used pulsed-field gel analysis of DNA from fragile-X patients with probes close to the fragile-X locus. The probe Do33 (DXS465) detected abnormal patterns in fragile-X patients. but not in normal controls or in non-expressing male transmitters.
Lexical organization of nouns and verbs in the brain, The analysis of neuropsychological disorders of lexical processing has provided important clues about the general organization of the lexical system and the internal structure of the processing components. Reports of patients with selective dysfunction of specific semantic categories such as abstract versus concrete words. living things versus inanimate objects. animals. fruits and vegetables. proper names and so forth. support the hypothesis that the neural organization of the semantic processing component is organized in these categories. There are reports of selective dysfunction of the grammatical categories noun and verb. suggesting that a dimension of lexical organization is the grammatical class of words. But the results reported in these studies have not provided unambiguous evidence concerning two fundamental questions about the nature and the locus of this organization within the lexical system. Is the noun-verb distinction represented in the semantic or in the phonological and orthographic lexicons? Is grammatical-class knowledge represented independently of lexical forms or is it represented separately and redundantly within each modality-specific lexicon? Here we report the performance of two brain-damaged subjects with modality-specific deficits restricted principally (H.W.) or virtually only (S.J.D) to verbs in oral and written production. respectively. The contrasting performance suggests that grammatical-class distinctions are redundantly represented in the phonological and orthographic output lexical components.
Activation of chloride channels in normal and cystic fibrosis airway epithelial cells by multifunctional calcium/calmodulin-dependent protein kinase, Cystic fibrosis is associated with defective regulation of apical membrane chloride channels in airway epithelial cells. These channels in normal cells are activated by cyclic AMP-dependent protein kinase and protein kinase C. In cystic fibrosis these kinases fail to activate otherwise normal Cl- channels. But Cl- flux in cystic fibrosis cells. as in normal cells. can be activated by raising intracellular Ca2+ (refs 5-10). We report here whole-cell patch clamp studies of normal and cystic fibrosis-derived airway epithelial cells showing that Cl- channel activation by Ca2+ is mediated by multifunctional Ca2+/calmodulin-dependent protein kinase. We find that intracellular application of activated kinase and ATP activates a Cl- current similar to that activated by a Ca2+ ionophore. that peptide inhibitors of either the kinase or calmodulin block Ca2(+)-dependent activation of Cl- channels. and that a peptide inhibitor of protein kinase C does not block Ca2(+)-dependent activation. Ca2+/calmodulin activation of Cl- channels presents a pathway with therapeutic potential for circumventing defective regulation of Cl- channels in cystic fibrosis.
Protein synthesis required to anchor a mutant p53 protein which is temperature-sensitive for nuclear transport, The p53 protein is rendered temperature-sensitive by a point mutation. Rat cells transformed by this mutant p53 and an activated ras oncogene grow well at 37 degrees C but cease DNA synthesis and cell division when shifted to 32 degrees C. Immunostaining demonstrates that the mutant p53 protein is in the nucleus of the arrested cells at 32 degrees C but in the cytoplasm of the growing cells at 37 degrees C. This is the first example of a protein which is temperature-sensitive for nuclear transport. The translocation from cytoplasm to nucleus and vice versa occurs 6 h after temperature shift and is coincident with the inhibition of DNA synthesis; transport from cytoplasm to nucleus does not require protein synthesis. Remarkably. inhibition of protein synthesis at 37 degrees C also results in the rapid appearance of mutant p53 in the cell nucleus. These results suggest the presence of a short-lived protein responsible for holding p53 in the cytoplasm at 37 degrees C but not at 32 degrees C. Analysis of a non-temperature-sensitive mutant p53 protein shows that its cytoplasmic location is sensitive to protein synthesis inhibitors but not to temperature.
The nature of opioid responsiveness and its implications for neuropathic pain: new hypotheses derived from studies of opioid infusions, In recent years. the observation that the response of patients to opioid drugs may be influenced by properties inherent in the pain or pain syndrome. such as its pathophysiology. has evolved into the belief that certain types of pain. e.g.. neuropathic pains. may be unresponsive to these drugs. This concept has important implications for both clinical practice and basic understanding of opioid mechanisms. We critically evaluate opioid responsiveness. particularly as it relates to neuropathic pain. and propose a clinically relevant definition and a paradigm for its investigation. The paradigm is illustrated by analgesic responses to opioid infusion in 28 patients with neuropathic pains and by a detailed presentation of the pharmacokinetic and pharmacodynamic relationships in one of these patients. whose central pain responded promptly to an infusion of hydromorphone. From this analysis. we hypothesize that (1) opioid responsiveness in man can be defined by the degree of analgesia achieved during dose escalation to either intolerable side effects or the occurrence of 'complete' or 'adequate' analgesia; (2) opioid responsiveness is a continuum. rather than a quantal phenomenon; (3) opioid responsiveness is determined by a diverse group of patient characteristics and pain-related factors. as well as drug-selective effects; and (4) a neuropathic mechanism may reduce opioid responsiveness. but does not result in an inherent resistance to these drugs. Given the complexity of factors contributing to opioid responsiveness and the observation that outcome cannot be reliably predicted. opioids should not be withheld on the assumption that pain mechanism. or any other factor. precludes a favorable response. Both the clinical use of opioids and paradigms to investigate opioid responsiveness should include dose escalation to maximally tolerated levels and repeated monitoring of analgesia and other effects.
Pain 'memories' in phantom limbs: review and clinical observations, This paper reviews reports of phantom limb sensations which resemble somatosensory events experienced in the limb before amputation. It also presents descriptions of this phenomenon in 68 amputees who took part in a series of clinical studies. These somatosensory memories are predominantly replicas of distressing pre-amputation lesions and pains which were experienced at or near the time of amputation. and are described as having the same qualities of sensation as the pre-amputation pain. The patients who experience these pains emphasize that they are suffering real pain which they can describe in vivid detail. and insist that the experience is not merely a cognitive recollection of an earlier pain. Reports of somatosensory memories are less common when there has been a discontinuity. or a pain-free interval. between the experience of pain and amputation. Among the somatosensory memories reported are cutaneous lesions. deep tissue injuries. bone and joint pain and painful pre-amputation postures. The experience of somatosensory memories does not appear to be related to the duration of pre-amputation pain. time since amputation. age. gender. prosthetic use. level of amputation. number of limbs amputated. or whether the amputation followed an accident or illness. The results suggest that somatosensory inputs of sufficient intensity and duration can produce lasting changes in central neural structures which combine with cognitive-evaluative memories of the pre-amputation pain to give rise to the unified experience of a past pain referred to the phantom limb. Implications for pre- and post-operative pain control are discussed.
Spatially localized magnetic resonance spectroscopy of the brains of normal and asphyxiated newborns, Phase-modulated rotating frame imaging is a modification of magnetic resonance spectroscopy. which uses a linear radiofrequency field gradient to obtain spatially localized biochemical information. Phase-modulated rotating frame imaging was used to study regional cerebral energy metabolism in the brains of 9 normal newborns and 25 newborns after birth asphyxia. Relative concentrations of phosphorus-containing metabolites and intracellular pH were determined for brain tissue at three specified depths below the brain surface for all neonates. Wide variations in metabolite ratios were seen among normal neonates. and considerable metabolic heterogeneity was demonstrated in individual neonates by depth-resolved spectroscopy. Asphyxiated neonates with severe hypoxic-ischemic encephalopathy and a poor neurodevelopmental outcome showed the expected rise in inorganic orthophosphate and fall in phosphocreatine concentrations in both global and spatially localized spectra. Phase-modulated rotating frame imaging showed that metabolic derangement was less in superficial than in deeper brain tissue. The inorganic orthophosphate-adenosine triphosphate ratio from 1 to 2 cm below the brain surface was more accurate than any global metabolite ratio for the identification of neonates with a poor short-term outcome. These data are consistent with the known vulnerability of subcortical brain tissue to hypoxic-ischemic injury in the full-term neonate.
Diphtheria-tetanus-pertussis vaccine and serious neurologic illness: an updated review of the epidemiologic evidence, A widespread impression that DTP vaccine does cause brain damage has been based first on historical precedent--smallpox and rabies vaccines were recognized as sometimes causing devastating neurologic illness; analogy to pertussis--the disease can cause encephalopathy; and more recently on anecdotal evidence. particularly case series. A noncausal relationship--coincidence--could explain the temporal relation between DTP vaccine and neurologic illness. inasmuch as DTP vaccine is given at the age of emergence of idiopathic neurologic disease. The relationship between DTP vaccine and neurologic illness lacks specificity. Case series have had an impact on both physicians' and the lay public's impression of the safety of pertussis vaccine greatly out of proportion to their scientific importance. Case series can be useful for generating hypotheses but cannot provide evidence that pertussis vaccine is causally related to acute neurologic illness or brain damage. Observational studies using cohort and ecologic designs did not find an association between DTP vaccine and serious neurologic illness. but they were not powerful enough to detect an association as rare as that observed by the NCES investigators. The case-control design offers the best chance of providing causal evidence regarding DTP vaccine and serious neurologic illness. The NCES is the only published case-control study of this issue. This study found a rare association between DTP vaccine and some types of acute neurologic illness. Bias and chance are unlikely to account entirely for the association demonstrated by the NCES. However. the association has not yet been replicated by other case-control studies. The NCES does not demonstrate that DTP vaccine causes permanent brain damage.
Hypoxanthine levels in vitreous humor: evidence of hypoxia in most infants who died of sudden infant death syndrome, Postmortem changes of the hypoxanthine in vitreous humor in humans were investigated. Hypoxanthine is formed from hypoxic degradation of adenosine monophosphate. Repeated sampling was performed in 13 deceased adults. Keeping the bodies at +6 degrees C. the increase of the hypoxanthine levels was estimated to 3.5 mumol/L per hour when sampling was started more than 12 hours after death (range 2.8 to 5.6 mumol/L per hour). Results of hypoxanthine measurements from vitreous humor in 73 infants with sudden infant death syndrome. 17 infants and children who died sudden violent deaths. and 6 neonates who died suddenly without hypoxemia prior to death were corrected according to the expected postmortem hypoxanthine increase. The time between death and autopsy was similar in the three groups studied. The corrected median hypoxanthine level in the group with sudden infant death syndrome was 227 mumol/L. which is significantly higher than in the other groups; 22 mumol/L in the group who had violent deaths (P less than .01). and 0 mumol/L in the neonate group (P less than .01). The findings seem to confirm that sudden infant death is preceded by a relatively long period of tissue hypoxia in most cases.
Can clinical judgment detect children with speech-language problems, Pediatricians often rely on clinical judgment derived from observation or parental concern to identify children with developmental problems. The less popular but recommended alternative is to repeatedly administer standardized screening tests. Such tests are time consuming but. unlike clinical judgment. have known detection rates. Preliminary research concerning clinical judgment showed that clusters of parental concerns related to their childrens' performances on screening tests. In the present study. previous research was refined by assessment of the meaning of parents' concerns about their childrens' speech-language development. In this study of 157 families seeking pediatric care. 72% of children whose speech-language screening yielded positive results had parents who were concerned about their speech-language development. Of children with negative screening results. 83% had parents with no concerns about their speech-language development. Although standardized screening tests should be used occasionally in the developmental surveillance process. the findings show that the problems of most children with developmental problems were detected through clinical judgment based on parental concern.
Neuropsychological outcome of pediatric liver transplantation, Children with end-stage liver disease who undergo liver transplantation may have unrecognized neuropsychological and academic deficits. for which remediation programs may be available. Intellectual. academic. and neuropsychological measures of 28 pediatric patients who had received successful liver transplantation at least 1 year previously were compared with those of 18 patients with cystic fibrosis (to control for effects of growth retardation and chronic illness) matched for age. age at diagnosis. physical growth. and parents' socioeconomic status. Liver transplant patients had significantly lower scores on nonverbal intelligence tests (mean +/- SD for liver transplant vs cystic fibrosis patients: 89.1 +/- 19.1 vs 105.8 +/- 17.6). lower academic achievement. and lower zeta scores for age in the areas of learning and memory (-0.68 +/- 1.09 vs 0.19 +/- 1.24). abstraction and concept formation (-1.73 +/- 1.58 vs -0.79 +/- 1.37). visual-spatial function (-0.66 +/- 1.09 vs 0.10 +/- 0.69). and motor function (-0.13 +/- 0.85 vs 0.36 +/- 0.57). No differences were found on tests of verbal intelligence. or in alertness and concentration. perceptual-motor. and sensory-perceptual areas. Cyclosporine levels were found to correlate positively with motor speed (r = .41. P less than .05). Thorough psycho-educational and neuropsychological evaluations should be considered for pediatric patients who receive liver transplantation to allow these children to maximize their potential.
Bovine surfactant replacement therapy in neonates of less than 30 weeks' gestation: a randomized controlled trial of prophylaxis versus treatment, The influence of the timing of surfactant replacement therapy for the treatment of neonatal respiratory distress syndrome was evaluated in a study of 182 neonates of less than 30 weeks' gestation who were randomly assigned prior to delivery to one of three study groups: control (dummy instillation of air given at birth). early surfactant (surfactant given at birth). or late surfactant (surfactant given at less than 6 hours of age). Subjects in the late surfactant group could avoid treatment if they had a clear chest roentgenogram and required no supplemental oxygen at a mean airway pressure of less than 7 cm of water. All treated neonates were eligible to receive up to three additional doses during the first 5 days of life. The three groups were comparable with respect to birth weight. gestational age. and other perinatal parameters with the exception of a lower cord arterial pH and 1-minute Apgar score in the early surfactant group. Of the 60 neonates randomly assigned to late treatment. 29 (48%) were deemed surfactant sufficient and thereby avoided treatment; the other 31 received their first dose at a mean age of 2.9 hours. There was a significant improvement in gas exchange during the first week of life in both surfactant groups compared with the control group. reflected by differences in fraction of inspired oxygen. arterial/alveolar PO2. and ventilation index (peak pressure x rate on the ventilator) (P less than .001). Surfactant therapy also resulted in a lower incidence of pulmonary air leak and severe chronic lung disease (defined as requirement for respiratory support beyond 36 weeks post-conceptional age). There were no differences between early and late surfactant groups in any of these parameters. The only statistically significant difference between the surfactant groups was that the early group had a higher incidence of mild chronic lung disease (respiratory support beyond 28 days of age) than the late treatment group (P less than .005). Neonates in the late treatment group were extubated earlier and had a shorter neonatal intensive care unit stay than control neonates (P less than .05). whereas those in the early group were not significantly different from control neonates in these parameters. It is concluded that replacement therapy with bovine lung surfactant extract in neonates of less than 30 weeks' gestation results in decreased oxygen and ventilatory requirements during the first week of life and a lower incidence of pulmonary air leak and severe chronic lung disease.(ABSTRACT TRUNCATED AT 400 WORDS).
Congenital orthopedic anomalies and their impact on the family, A baby born with a congenital limb deficiency presents a challenge to parents and health care professionals. Lack of information about treatment options can exacerbate the crisis for the family. The treatment modalities available to the family generally depend on the child's specific limb deficiency or deficiencies. Surgery to reconstruct the deficiency is not a workable option for many patients because of abnormal joints and soft tissues. Amputation may be recommended for patients whose deficiency is difficult or impossible to manage prosthetically. Limb lengthening is an option only for patients whose bones are smaller than normal. Prosthetics are the most widely used treatment modality because they immediately equalize limb lengths and improve function. When a baby is born with a congenital limb deficiency. the initial response of the parents is shock and denial. In adjusting to their newborn. they must first mourn the loss of the baby they expected. Once the adjustment process begins. specific information about the limb deficiency and the treatment options should be available. Family adjustment to the child is a continual process. As the child grows. management strategies need to change to adjust to the child's changing needs. With appropriate and timely health care and family intervention. a child with a congenital limb deficiency can be a happy. successful person.
Anterior cruciate ligament injuries. Evaluation, arthroscopic reconstruction, and rehabilitation, The advantages of arthroscopic reconstruction of the anterior cruciate ligament tear over arthrotomy are quite obvious: reduced pain and morbidity. Some arthroscopists are performing these procedures on an outpatient basis. The physician can choose from several graft substitutes for anterior cruciate ligament replacement. Autografts consisting of the iliotibial band. semitendinosus. gracilis. and meniscus have been used as grafts. The most common autograft is the bone-patellar tendon-bone. which has been used since 1930 and has been shown to have a tensile strength near that of the anterior cruciate ligament. The state of the art in surgical alternatives for anterior cruciate ligament tears is arthroscopic reconstruction using the midthird of the patellar tendon. Treatment of anterior cruciate ligament injuries requires prompt and adequate evaluation of the laxity of the ligament as well as other structures in the knee. appropriate treatment options offered to the patient with complete descriptions of knee function after each treatment option. and comprehensive rehabilitation program. Patient compliance is an integral part of the success of this procedure. The nurse must include a description of the injury. preoperative testing. surgical intervention. and rehabilitation program when educating the patient. The successful postoperative anterior cruciate ligament rehabilitation program is multifaceted. In general. there must be specific guidelines applied by a physical therapist who has knowledge of the surgical procedure. understands principles of ligament healing. and has the ability to individualize the program as needed. For any level of athlete or active person. there must be achievement of all goals per phase to a high performance level. In addition. there must always be objective measurements to document progress to the physical therapist and physician but. perhaps most importantly. to reassure the patient that normalcy is being restored.
Stress fractures in athletes, Most stress fractures are preventable. Proper conditioning and preseason training is essential. Selection of the appropriate age-related sport must be taken into consideration. Adequate warm-up and cool-down is important to prevent muscle injuries that may contribute to stress fractures later on. The athlete should be aware of not "over-doing it" because fatigue is a contributing factor to the stress injury rate. Proper dress and equipment are necessary. Using the basic methods of prevention. along with good sportsmanship. safe participation in any sport may be anticipated. Because the demands and expectations of our high-performance athletes are more prevalent. education and rehabilitation of the sports-injured patient have become ever important. With the emergence of sports medicine as a discipline. injured athletes are returned to the playing arenas much more rapidly with newer protocols and techniques. We must be ready rapidly to assess. diagnose. and treat all sports injuries; however. we must be aware and alert to the possibility that it is an injury of "wear and tear" when making any diagnosis and prescribing any treatment regime.
Nursing management of the adolescent with idiopathic scoliosis, Management of the adolescent idiopathic scoliosis patient has many intricate considerations. Whether the patient is braced or surgery is recommended. there is a lot of teaching. assessing. and compassion when dealing with adolescents whose biggest concern is being like their peers. It is important to allow as much independence in decision making as possible. whether it be about bracing or surgical intervention. as long as they clearly understand the consequences. Newer. better surgical instruments. anesthesia. nursing care. and postoperative mobility all have changed the management of the operative scoliosis patient significantly. Nursing assessment of neurologic. respiratory. function. emotional. and developmental needs of the adolescent patient. however. have not changed. If we. as nurses. understand the rationale for assessments. treatments. and restrictions. we can teach our patients and their families.
Common spinal injuries in athletes, Special needs of athletes with spine injuries must be considered when planning for treatment of these patients. The patients wish to return to competition safely but rapidly. Nurses must understand the patients'/athletes' need but put them into perspective with respect to the diagnosis. treatment. and degree of disability. Support. encouragement. and understanding from a knowledgeable health professional are invaluable.
The nursing role in limb salvage surgery, Limb salvage surgery has proven itself as a valuable option for sarcoma patients. The reconstruction options are vast and include metallic implants. allografts. and a combination of both. The nursing implications for these patients are unlimited. The patient needs to be educated and assessed closely for complications such as infections. nonunion of the allograft. and limited mobility. Although the nursing care is more complicated. the rewards with working with these patients are great.
Spinal stenosis. When arthritis is more than arthritis, Spinal stenosis is the result of disc degeneration and narrowing accompanied by facet joint changes culminating in nerve root entrapment. Symptoms of back and leg pain appear gradually usually over a period of years and slowly worsen. Patients are usually in their 50s or older. Most patients are treated initially with nonoperative measures concentrating on pain relief and maintenance of activity. If the symptoms worsen. surgical intervention to relieve pain by decompressing the affected nerve roots is appropriate. Some patients with instability require a fusion. Most patients are satisfied with the results of surgery in relieving preoperative leg pain. Pain relief is often dramatic. allowing most patients to return to normal activity. Elderly patients tolerate this procedure surprisingly well. Old age alone should not be a contra-indication for this surgery. Therefore. the elderly should not be denied the benefits of surgical decompression. Nursing interventions can help these patients learn about spinal stenosis and assist them in pursuing appropriate treatment resulting in improved quality of living.
Pelvic fracture patient care. Reflections on the past, implications for the future, Nursing care of patients with pelvic fractures has changed dramatically in the past two decades. Fracture care that necessitated long periods of immobility and consequent complications has been influenced by new classification systems. the use of external fixation. and the more recent use of internal fixation. The evolution of pelvic fracture patient care has greatly influenced nursing care of these patients.
Pain management in the orthopedic patient, Pain is a familiar phenomenon to all orthopedic nurses. As Dunwoody said. "Few things we do for patients are more fundamental to the quality of life than relieving pain." We as orthopedic nurses are in a position to contribute to the positive management of pain by using a comprehensive approach to pain management that involves the participation of the patient. We need to believe the patient's pain. try new approaches. and help our patients achieve pain relief.
Bone stimulators for fusions and fractures, Even though a complete understanding of electrical responses of bone has not been fully obtained. useful data toward this end have been gathered. The development of devices that use what is known about the bone's electrophysiologic properties has impacted patient care. Many health care professionals remain skeptical about the effects of electrical stimulation in bone healing. Therefore. further research is needed to help the practitioner formulate a more educated opinion on this form of therapy.
Esophageal and gastric endoscopy in critically ill patients. How can it help you, Bleeding from the upper gastrointestinal tract in a critically ill patient is a tough diagnostic situation. Endoscopy can help physicians determine the cause of bleeding and can also provide several therapeutic options. The authors discuss these applications of the current technology.
Emergency resuscitation in children. The role of intraosseous infusion, Intraosseous infusion is a temporary procedure for use in pediatric emergencies when intravenous access is difficult. Multiple drugs and fluids can be safely administered through the intraosseous route. Dosage and rate of infusion are essentially the same as with intravenous infusion.
Abnormal liver enzyme levels. Evaluation in asymptomatic patients, Chronic elevation of serum aminotransferase levels. even in the absence of symptoms. often reflects chronic hepatitis or other significant underlying liver disease. Patients with persistently abnormal alkaline phosphatase levels may have extrahepatic biliary tract disease or a chronic cholestatic disorder. Physicians can discover unsuspected liver disease without undue risk. expense. or inconvenience to the patient by means of the following: a carefully taken history and thorough physical examination. appropriate timing of follow-up blood tests. and timely referral for percutaneous liver biopsy or endoscopic retrograde cholangiopancreatography.
Travel in eastern Europe. Guidelines for patients, Some patients need medical preparation and physician counseling before traveling to eastern European countries. In addition to baseline immunizations. a measles booster. a polio booster. typhoid vaccination. and immune globulin prophylaxis against hepatitis A may be indicated. Advice should also be given regarding air pollution. contaminated food and water. civil unrest. motor vehicle mishaps. and each country's policy on HIV screening. Because the level of healthcare may be poor. contact with American or British embassies or consulates is recommended in an emergency.
Why patients delay seeking care for cancer symptoms. What you can do about it, Patient delay in seeking care for cancer symptoms is common and well documented by research studies. Fear and denial. lack of information about cancer. and financial considerations all contribute to this delay. Patient education may be an important factor in decreasing the length of delay and thereby improving treatment outcome. By making good use of opportunities for patient education. primary care physicians may positively influence the prognosis of several types of cancer. particularly breast cancer and malignant melanoma of the skin.
Raynaud's syndrome. Using a range of therapies to help patients, Raynaud's syndrome is a common medical problem. Approach to diagnosis must involve a search for underlying causes. Treatment includes avoidance of precipitating factors. biofeedback. and possibly pharmacologic therapy. after careful consideration of risks.
Pancreatic pseudocysts. When to drain, when to wait, Acute pain in the upper abdomen in a patient recovering from pancreatitis or abdominal trauma may herald a pancreatic pseudocyst. Although small cysts resolve spontaneously. those larger than 6 cm across usually require treatment to prevent such complications as rupture into adjacent structures and infection. The authors describe operative and nonoperative treatment methods and the success reported with each.
Do you have patients with anorexia or bulimia? Understanding is the first step in helping, Anorexia nervosa and bulimia nervosa have. in recent years. become disorders of major concern. Young women are particularly prone to such eating disorders. and substantial numbers have involved themselves in the practices that identify these problems. Understanding the thinking behind these disorders is helpful in recognizing them and developing a treatment approach. The most effective medication for bulimia reported to date is fluoxetine hydrochloride (Prozac). The concurrent participation of a physician. nutritionist. and family therapist in the care of these patients is ideal.
Help for the hurting elderly. Safe use of drugs to relieve pain, Pharmacologic management of pain in elderly patients is a common and difficult clinical problem. Because of altered drug metabolism and pharmacodynamics in the elderly. the drugs of choice are different than in younger patients and side effects occur more often. However. with judicious use and monitoring for toxicity. oral medications given as part of a multimodality approach can achieve adequate analgesia in most elderly patients.
When to suspect connective tissue disease, When a connective tissue disease is suspected. physical and historical data should be collected to build a case for a clinical syndrome. Negative serologic results may be helpful; positive ones must be used with awareness of their limitations. If a diagnosis is not clinically evident or serologically confirmed. observation may be preferable to overdiagnosis and unnecessary treatment. If the syndrome is atypical. physicians should look for evidence of clinical overlap and reevaluate regularly with an open mind.
Premixed insulins. How do they compare with other insulin preparations, With the availability of premixed insulins. physicians and diabetic patients have a wider choice of therapeutic options. The premixed preparation now available in the United States consists of 70% NPH insulin and 30% regular insulin. The major advantages of premixed insulins are convenience and improved accuracy. They are suitable for patients who are too impaired to mix their own insulin dose and for those whose mixed-dose ratio is similar to that of the 70/30 preparation.
Intensive management of type II diabetes, The goals of intensive treatment of type II diabetes are to restore blood glucose levels to normal; correct hyperlipidemia. hypertension. and other cardiovascular risk factors; and prevent hyperinsulinemia. Treatment should begin with attempts to reduce weight through diet and exercise. In fact. diet and exercise should be stressed as vital components of a diabetic patient's life-style no matter what treatment method is used. Drug treatment may consist of a sulfonylurea to increase insulin secretion and improve insulin resistance or of exogenous insulin to achieve glucose control and avoid the dangers of chronic hyperglycemia. A combination of the two appears attractive but is still under investigation. Control of hypertension is mandatory and may require use of an angiotensin-converting enzyme inhibitor or calcium channel blocker. Normalization of serum lipid levels is also important in these patients. and agents that adversely affect glucose levels must be avoided.
Portable blood glucose meters. Teaching patients how to correctly monitor diabetes, Self-monitoring of blood glucose is an important component of treatment in patients with diabetes. Recent improvements in glucose meters have made patient self-testing more reliable and less dependent on user technique. However. success of the process depends on the training. reassessment. and support of the patient by the healthcare team.
Peptic ulcer disease. How to treat it now, Options for treatment of peptic ulcer disease are becoming more diverse. Most new agents are effective yet offer no real advantage over more traditional therapy. However. omeprazole (Prilosec) may be of benefit owing to its potent inhibition of acid secretion. but it is not yet approved for this purpose. Whether treatment of Helicobacter pylori infection will prove beneficial is not yet known. but the answer should be forthcoming. Finally. as with any disease process. alleviation of risk factors is always important. Appropriate counseling regarding use of nonsteroidal anti-inflammatory drugs and cigarette smoking is a necessity.
Characteristics of erythroleukemia cells selected for vincristine resistance that have accelerated inducer-mediated differentiation, The induction of murine erythroleukemia cells (MELC; DS19/Sc9) to terminal differentiation by hexamethylenebisacetamide (HMBA) is characterized by a latent period of 10-12 hr before onset of commitment to terminal-cell division and increased transcription of globin genes. MELC variants. derived from this parental cell line. selected for resistance to vincristine (VC). can be induced to differentiate with little or no latent period. This study shows that accelerated HMBA-induced commitment is characteristic of MELC with a low level (2- to 5-fold) of VC resistance in four independently derived cell lines. Both resistance to VC and accelerated differentiation are stable phenotypes for at least 50 passages (approximately 5 months) in the absence of VC. Low-level VC-resistant MELC do not display increased levels of P-glycoprotein or mdr1. mdr2. and mdr3 mRNAs. nor do they exhibit cross-resistance to colchicine or doxorubicin. These cells do show (i) increased level of protein kinase C activity. (ii) reduced accumulation of [3H]VC. and (iii) restoration of VC sensitivity in the presence of verapamil. MELC selected for higher levels of VC resistance (approximately 500-fold) do express high levels of P-glycoprotein and the mdr3 gene. During HMBA-induced differentiation. DS19/Sc9 decrease [3H]VC accumulation. but P-glycoprotein content does not change. A VC-transport-associated protein. also critical for the process of induced differentiation. may be constitutively present in VC-resistant MELC. accounting for their enhanced sensitivity to inducer. This protein accumulates by exposure of VC-sensitive cells to HMBA. contributing to their differentiation and decreased level of VC accumulation.
Effects of site-directed mutagenesis at residues cysteine-31 and cysteine-184 on lecithin-cholesterol acyltransferase activity, Native lecithin-cholesterol acyltransferase (LCAT; phosphatidylcholine-sterol acyltransferase; phosphatidylcholine:sterol O-acyltransferase. EC 2.3.1.43) protein. and LCAT in which either or both of the enzyme free cysteines had been replaced with glycine residues by site-directed mutagenesis. has been expressed in cultured Chinese hamster ovary cells stably transfected with the human LCAT gene. The mass of LCAT secreted. determined by immunoassay. did not differ in the native and mutant species. LCAT specific activity was also unchanged in the mutant species. In particular. the cysteine-free double mutant. in which Cys-31 and Cys-184 had both been replaced. was fully active in the synthesis of cholesteryl esters. This result is not consistent with a catalytic role for LCAT free cysteine residues. The classical inhibitor of LCAT activity. 5.5'-dithiobis(2-nitrobenzoic acid) (DTNB). which strongly (89%) inhibited the native enzyme. had partial (45%) inhibitory activity with mutant enzyme species containing a single -SH residue. while the double mutant was not significantly inhibited by DTNB. These data are interpreted to suggest that Cys-31 and Cys-184 are vicinal both to each other and to the "interfacial binding site" at residues 177-182. and that DTNB exerts its effect by steric inhibition.
Interaction of the v-rel protein with an NF-kappa B DNA binding site, The avian reticuloendotheliosis virus T contains within its genome the oncogene rel. The expression of this gene is responsible for the induction of lymphoid tumors in birds. Recently. the rel gene was shown to be related to the p50 DNA binding subunit of the transcription factor complex NF-kappa B. Binding sites for the NF-kappa B complex are found in the enhancer regions of a number of genes. including the immunoglobulin kappa gene and the human immunodeficiency virus long terminal repeat. In this communication we identify an activity from avian reticuloendotheliosis virus T-transformed avian lymphoid cells that binds in an electrophoretic-mobility-shift assay to an NF-kappa B binding site from the kappa enhancer. This activity contains proteins immunologically related to rel. as detected by polyclonal and monoclonal antibodies directed against v-rel. In a DNA affinity precipitation assay using the NF-kappa B site from the human immunodeficiency virus long terminal repeat. v-rel and several other proteins were identified. These data suggest that oncogenic transformation by v-rel is the result of an altered pattern of gene expression.
Nerve growth factor corrects developmental impairments of basal forebrain cholinergic neurons in the trisomy 16 mouse, The trisomy 16 (Ts16) mouse. which shares genetic and phenotypic homologies with Down syndrome. exhibits impaired development of the basal forebrain cholinergic system. Basal forebrains obtained from Ts16 and euploid littermate fetuses at 15 days of gestation were dissociated and cultured in completely defined medium. with cholinergic neurons identified by choline acetyltransferase (ChAT) immunoreactivity. The Ts16 cultures exhibited fewer ChAT-immunoreactive neurons. which were smaller and emitted shorter. smoother. and more simplified neurites than those from euploid littermates. Whereas the addition of beta-nerve growth factor (100 ng/ml) augmented the specific activity of ChAT and neuritic extension for both Ts16 and euploid cholinergic neurons. only Ts16 cultures exhibited an increase in the number and size of ChAT-immunoreactive neurons. Furthermore. Ts16 ChAT-immunoreactive neurites formed varicosities only in the presence of beta-nerve growth factor.
Stage transitions in B-lymphocyte differentiation correlate with limited variations in nuclear proteins, Total nuclear proteins extracted from cell lines representing various stages of differentiation of mouse B lymphocytes were studied by computer analysis of two-dimensional gels. Of the 1438 spots present on the gels. 55 varied significantly in intensity during differentiation. The variations occurred most often in steps correlating with those classically defined for B-cell differentiation. Seventeen spots were not detectable in at least one of the stages (qualitative variations) and could represent switching on or off of genes coding for nuclear proteins. Detailed analysis of the 55 variable spots showed that they fall into small sets characterized by similar expression profiles. which argues for a combinatorial. multistep control mechanism of gene expression. In addition. analysis of the expression of all the nuclear proteins resolved on the gels clearly differentiated B-lineage cells from myeloid cells and suggested that the most important transition in B-cell differentiation occurs between the resting B cell and plasmocyte stages.
Expressional potency of mRNAs encoding receptors and voltage-activated channels in the postmortem rat brain, The stability and integrity of mRNAs encoding neurotransmitter receptors and voltage-activated channels in the postmortem rat brain was investigated by isolating poly(A)+ mRNA. injecting it into Xenopus oocytes. and then examining the expression of functional neurotransmitter receptors and voltage-activated channels in the oocyte membrane by electrophysiological recording. This approach was also used to assess the stability of mRNAs in brains that were incubated in oxygenated mammalian Ringer's solution for various lengths of time and from brains that were freshly frozen and then thawed at room temperature. Oocytes injected with mRNA from up to 21-hr postmortem brains gave large agonist- and voltage-activated responses. indicating that mRNAs encoding neurotransmitter receptors and voltage-activated channels are relatively stable in postmortem brain tissue. In contrast. oocytes injected with mRNA from brains incubated in Ringer's solution exhibited smaller responses. and oocytes injected with mRNA from tissue that was frozen and then thawed displayed very small or undetectable responses. Northern blot analysis using a nucleic acid probe for rat brain Na(+)-channel mRNA indicated that the size of the Na+ currents in injected oocytes reflected the levels of mRNA for Na+ channels in the different mRNA preparations. Thus. the expressional potency of mRNAs encoding neurotransmitter receptors and voltage-activated channels is quite stable in postmortem brains in situ. but it is reduced if the brains are kept in oxygenated saline. and freezing and thawing of tissue results in rapid degeneration of mRNA.
Transfection of C6 glioma cells with connexin 43 cDNA: analysis of expression, intercellular coupling, and cell proliferation, C6 glioma cells express low levels of the gap junction protein connexin 43 and its mRNA and display very weak dye coupling. When implanted into the rat cerebrum. these cells quickly give rise to a large glioma. To investigate the role of gap junctions in the tumor characteristics of these cells. we have used Lipofectin-mediated transfection to introduce a full-length cDNA encoding connexin 43. Several transfected clones were obtained that exhibited various amounts of connexin 43 mRNA transcribed from the inserted cDNA. Immunocytochemical analysis revealed an increase in the amount of connexin 43 immunoreactivity in the transfected cells. being localized at areas of intercellular contact as well as in the cytoplasm. The level of dye coupling was also assessed and found to correlate with the amount of connexin 43 mRNA. When cell proliferation was followed over several days. cells expressing the transfected cDNA grew more slowly than non-transfected cells. These transfected cells will be useful in examining the role of gap junctions in tumorigenesis.
Long-chain (sphingoid) bases inhibit multistage carcinogenesis in mouse C3H/10T1/2 cells treated with radiation and phorbol 12-myristate 13-acetate, Sphingosine and other long-chain (sphingoid) bases inhibit protein kinase C. the putative cellular receptor for the tumor promoter phorbol 12-myristate 13-acetate (PMA). and exert potent effects on diverse cell functions. We tested the ability of long-chain bases to modulate multistage carcinogenesis in mouse C3H/10T1/2 cells exposed to gamma-rays and PMA. Sphingosine and sphinganine completely blocked the enhancement of radiation-induced transformation by PMA (promotion) and partially suppressed transformation by radiation alone. N-Acetylsphingosine. a ceramide analog. did not inhibit transformation. Sphingosine was rapidly taken up by the cells and metabolized; hence. the long-chain bases were added daily to achieve prolonged inhibition. Long-chain bases inhibited protein kinase C activity in C3H/10T1/2 cells and suppressed the down-regulation of this enzyme by PMA. Our results establish that long-chain bases are highly effective inhibitors of carcinogenesis in this model. Our results also indicate that the suppressive effects may be mediated. in part. by inhibition of protein kinase C. The data suggest that sphingosine and other long-chain bases derived from complex sphingolipids may act as cancer-preventative agents.
Molecular characterization of a major nephritogenic domain in the autoantigen of anti-tubular basement membrane disease, Anti-tubular basement membrane (alpha TBM) disease is a form of primary interstitial nephritis mediated by autoimmune T cells and alpha TBM antibodies. In mice and humans the nephritogenic immune response is directed to a glycoprotein (3M-1) found along the proximal tubule of the kidney. We have isolated cDNAs from an expression library that encodes for the common framework domain of the 3M-1 antigen. This common domain was once related evolutionarily to a family of intermediate filament-associated proteins. Northern hybridization revealed that all isoforms of 3M-1 range between 1700 and 1900 base pairs and in situ hybridization studies indicate that transcripts are found in tubular epithelium. Candidate peptide fragments were deduced and synthesized from the sequence encoding this common framework domain. and one of the peptide residues was able to bind a monoclonal 3M-1-reactive alpha TBM antibody. stimulate the growth of 3M-1-reactive helper T cells. and induce nephritogenic effector T cells capable of producing interstitial nephritis. Our results indicate that a unique. immunodominant region of the 3M-1 antigen is an informative participant in the emergence of autoimmune injury to certain basement membranes.
Differentiation of HL-60 leukemia by type I regulatory subunit antisense oligodeoxynucleotide of cAMP-dependent protein kinase, A marked decrease in the type I cAMP-dependent protein kinase regulatory subunit (RI alpha) and an increase in the type II protein kinase regulatory subunit (RII beta) correlate with growth inhibition and differentiation induced in a variety of types of human cancer cells. in vitro and in vivo. by site-selective cAMP analogs. To directly determine whether RI alpha is a growth-inducing protein essential for neoplastic cell growth. human HL-60 promyelocytic leukemia cells were exposed to 21-mer RI alpha antisense oligodeoxynucleotide. and the effects on cell replication and differentiation were examined. The RI alpha antisense oligomer brought about growth inhibition and monocytic differentiation. bypassing the effects of an exogenous cAMP analog. These effects of RI alpha antisense oligodeoxynucleotide correlated with a decrease in RI alpha receptor and an increase in RII beta receptor level. The growth inhibition and differentiation were abolished. however. when these cells were exposed simultaneously to both RI alpha and RII beta antisense oligodeoxynucleotides. The RII beta antisense oligodeoxynucleotide alone has been previously shown to specifically block the differentiation inducible by cAMP analogs. These results provide direct evidence that RI alpha cAMP receptor plays a critical role in neoplastic cell growth and that cAMP receptor isoforms display specific roles in cAMP regulation of cell growth and differentiation.
Age-related balance changes in hearing-impaired children, This study compared balance skills of hearing-impaired children with those of hearing children in order to determine whether a deficit in balance exists in hearing-impaired children and to ascertain whether this deficit is age-related. Twenty-eight hearing-impaired subjects were chosen as a sample of convenience from the Pennsylvania School for the Deaf and placed into one of three age groups. Ten subjects were in the 4.5 to 6.5-year-old age group. 8 in the 8- to 10-year-old age group. and 10 in the 12.5 to 14.5-year-old age group. Selection criteria included bilateral sensorineural hearing loss of greater than or equal to 65 dB and normal intelligence (IQ greater than or equal to 80). Balance was measured by the use of the Balance subtest of the Bruininks-Oseretsky Test of Motor Proficiency. For each age group. a z test was used to compare the subjects' scores with the Balance subtest standard scores. The results showed that for each age group. the mean score for the hearing-impaired children was lower than the standard score. Both older groups had significantly higher scores than the youngest group. but the mean scores of the older groups were not significantly different. No difference between the subjects' balance scores and the Balance subtest standard scores was found among the age groups. suggesting that the balance deficit was not age-related. Gender differences were not found for balance scores.
Movement analysis--an aid to early diagnosis of cerebral palsy, The purpose of this article is to review research related to the use of clinical analysis of movement as an aid to the early diagnosis of cerebral palsy. A historical perspective of clinical techniques used by physicians and physical therapists in the early diagnosis of cerebral palsy will be presented first. including recent research findings on clinical signs that were most predictive of this movement disorder. Predictive neuromotor behaviors common across several recent studies will be highlighted. Future trends in the use of movement analysis. including digitized kinematic analysis of term and preterm infants and fetal ultrasound techniques. will be discussed as well.
Implications of a dynamical systems approach to understanding infant kicking behavior, Implications of the dynamical systems approach to understanding movement dysfunction in infants are discussed. Traditional theories of motor development attribute changes in movement to the hierarchical maturation of the central nervous system. The dynamical systems approach emphasizes that movement self-organizes as the result of the interaction of the participating subsystems in developmental and real time. In this article. I discuss. from the theoretical perspective of the dynamical systems approach. the organization of leg movements in low- and high-risk preterm and full-term infants. developmental changes in movement in low-risk preterm infants from 34 weeks' gestational age to 40 weeks' postgestational age. and differences in movement between low-risk preterm infants at 40 weeks' postgestational age and full-term infants. Preliminary data on high-risk preterm infants are presented. Based on these data. the necessity to review and reinterpret traditional concepts of motor development is explored. Suggestions are offered and questions posed on how the dynamical systems perspective may influence the practice of physical therapy in the evaluation. and treatment of infants at risk for movement dysfunction.
Cognitive strategies during coincident timing tasks, Research findings suggest that experience and cognitive strategies contribute to successful performance during perceptual-motor tasks. This article critically reviews selected literature on the effects of information-processing skills. preferred movement time. experience. and task difficulty on performance during coincident timing tasks. Theoretical information and research findings are discussed. and their applications to clinical practice are considered. Clinical recommendations include assessment of coincident timing skills and use of functional activities that provide opportunities to explore and dynamically interact with the environment.
Measurement and treatment in cerebral palsy: an argument for a new approach, This article describes the need for a shift in our therapeutic strategies for patients with cerebral palsy. Changes in functional abilities must be stressed in therapy. Coincident with this emphasis must be the development of functional assessments to be used when documenting intervention outcomes. Research on functional arm movement using kinematic analysis is described for this patient group.
Dorsal rhizotomy for children with cerebral palsy: support for concepts of motor control, The results from selective dorsal rhizotomy research suggest that therapists need to question some common clinical assumptions about movement dysfunction. The rationale for performing a selective dorsal rhizotomy is based on the clinical assumptions that spasticity is the underlying cause of disordered movement and that reducing or eliminating the spasticity will improve movement. This article reviews the literature related to movement dysfunction. the effects of selective dorsal rhizotomy. and the evidence for disordered motor control in children with spastic cerebral palsy. Selective dorsal rhizotomy appears to reduce spasticity and increase joint range of motion. Abnormal movement patterns. however. persist after the spasticity is reduced. Well-coordinated movement patterns are acquired slowly and appear to be related to an intense period of physical therapy. I argue that these results provide evidence that the presence of spasticity alone is an insufficient explanation for abnormal movement patterns. I propose that physical therapists redirect their efforts from developing methods for reducing spasticity to developing adequate assessment. treatment. and measurement techniques for assessing motor control in children with cerebral palsy. I believe we can maximize the functional potential of children with cerebral palsy by identifying problems related to motor control and applying sound principles of motor learning to treatment.
Heart transplantation in patients with severe pulmonary hypertension and increased pulmonary vascular resistance, Irreversibly increased pulmonary vascular resistance is a contraindication for cardiac transplantation. At our hospital patients referred for recipient evaluation with systolic pulmonary artery pressure greater than 50 mmHg and pulmonary vascular resistance greater than 2 Wood units (Wu) are tested with intravenous sodium nitroprusside for reversibility. In 23 patients whose increased systolic pulmonary artery pressure (67.4 +/- 10.4 mmHg) and resistance (4.8 +/- 2.4 Wu) were reduced by nitroprusside. orthotopic heart transplantation was performed without early mortality. Right heart catheterization after transplantation revealed a significant and persistent fall of the elevated pulmonary artery pressure and pulmonary vascular resistance. We conclude that if severe pulmonary hypertension and elevated pulmonary vascular resistance are reversible with nitroprusside. the patient can safely undergo heart transplantation.
Open-heart surgery in Jehovah's Witnesses, During a 7-year period. 11 adult members of the religious sect Jehovah's Witnesses underwent cardiac surgery with extracorporeal circulation. No homologous blood transfusions were given. Blood-conserving procedures were employed. viz. initial collection of autologous blood. haemofiltration or processing (Cell Saver) of blood collected during extracorporeal circulation and reinfusion of shed mediastinal blood. The total perioperative blood loss averaged 1080 ml (15 ml/kg body weight). equalling 19% of total body blood volume. The mean haemoglobin on discharge from hospital was 11.0 g/100 ml. There was no perioperative mortality. Postoperative pulmonary function was good and there was no serious morbidity. Jehovah's witnesses with serious. surgery-necessitating heart disease can be offered operation comprising recognized blood-conserving procedures.
Effect of dipyridamole (Persantin) on blood flow and patency of aortocoronary vein bypass grafts, The effect of dipyridamole was investigated in 360 patients undergoing coronary bypass surgery. They were randomly allocated to receive dipyridamole (100 mg orally q.i.d. for 2 days preoperatively. 5 mg/kg body weight/24 h i.v. peroperatively and 100 mg orally q.i.d. for 1 year postoperatively) or placebo. Withdrawn from the study were 48 patients on dipyridamole and 57 on placebo. Cardiovascular and/or cerebrovascular events or need for anticoagulant treatment were the reasons for withdrawal in 22 (13%) of the dipyridamole. and 34 (18%) of the placebo group. Logistic regression analysis of risk factors influencing graft patency showed significant relation to peroperatively measured coronary blood flow. A positive trend of treatment was observed (p = 0.08). Vein graft blood flow measured during bypass surgery (245 patients) was significantly greater in the dipyridamole group (p less than 0.01). The occlusion rate was lower in vessels with peroperative blood flow greater than 30 ml/min (vein-marginal p less than 0.01. vein-dexter p less than 0.05. vein-diagonal 0.05 less than p less than 0.1). Dipyridamole increases coronary blood flow and graft patency following coronary bypass surgery.
Pediatric cardiac surgery guided by echocardiography. Established indications and new trends, Cardiac surgery in 602 children was not preceded by cardiac catheterization. the diagnosis being based on clinical findings and two-dimensional and Doppler echocardiography. In the 355 operations without cardiopulmonary bypass there were nine major and seven minor diagnostic errors (2.5% and 2%). Among the 247 cases with open-heart surgery there were no major and eight (3.2%) minor errors. The malformations most suitable for nonbypass surgery without catheterization seem to be those with reduced pulmonary blood flow requiring systemic-pulmonary artery shunt. aortic coarctation and patent ductus arteriosus. For open-heart surgery without invasive investigation. atrial septal defect. partial atrioventricular canal. aortic and pulmonary stenosis. cardiac tumor and isolated valve disorder are 'classic' candidates. Recent experience indicated that selected cases of complete atrioventricular canal. tetralogy of Fallot. truncus arteriosus. total anomalous pulmonary venous connection and transposition of the great arteries may safely undergo primary repair without cardiac catheterization. Because of its diagnostic potentialities. pediatric cardiac surgeons must become familiar with echocardiography.
Ultrastructural changes in rat hearts following cold cardioplegic ischemia of differing duration and differing modes of reperfusion, Morphologic consequences of prolonged global hypothermic (15 degrees C). cardioplegic ischemia and two reperfusion techniques were studied in Langendorff-perfused rat hearts. A 'gentle' reperfusion technique. with gradual rise in perfusate temperature and pressure to physiologic levels over 30 min. was used for 12 hearts following 2-hour or 3 1/2-hour (6 in each group) ischemia. Abrupt reperfusion. with perfusate at 37 degrees C and 70 mmHg. was performed on 13 hearts (6 ischemic for 2 hours and 7 for 3 1/2 hours). Six nonischemic. perfused hearts served as controls. Randomly selected specimens from the left ventricle after 45-60 min reperfusion were prepared for transmission electron microscopy. Volume fractions of myocardial structural components were calculated from stereologic point-counting on the electron micrographs. Two-way analysis of variance revealed that interstitial edema developed with increasing ischemic time and was not influenced by reperfusion technique. The degree of endothelial damage was independent of ischemic time. but was lessened by 'gentle' reperfusion. Both mitochondrial injury and myocyte edema were less when perfusate temperature and pressure were slowly raised after 3 1/2-hour ischemia.
Coronary trapping of a complement activation product (C3a des-Arg) during myocardial reperfusion in open-heart surgery, Accumulation of complement factors has been found to occur in the myocardium after infarction. We studied the possibility that the complement activation product C3a des-Arg is trapped within the coronary circulation during reperfusion of the ischemic myocardium. In 11 patients undergoing routine coronary artery bypass grafting. arterial blood was sampled before. during and after cardiopulmonary bypass. Blood was drawn from the coronary sinus concomitantly with arterial blood sampling 5 and 30 min after release of the aortic cross-clamp (n = 10). From a preoperative value of 92 +/- 13 ng/ml. C3a des-Arg rose during CPB to a maximum of 1816 +/- 393 at the end of CPB. Following reperfusion for 5 min. C3a des-Arg was 1284 +/- 232 ng/ml in arterial and 1106 +/- 100 in coronary sinus blood. a significant difference (p less than 0.05). The amount of C3a des-Arg trapped in the heart at 5-min reperfusion showed positive correlation with its arterial concentration (p less than 0.05). No significant difference was found after 30 min of reperfusion. Complement activation products trapped in the heart in the early reperfusion period may play a pathogenetic role in myocardial ischemia-reperfusion injury.
Perioperative effect of methylprednisolone given during lung surgery on plasma concentrations of C3a and C5a, Methylprednisolone or saline (placebo) solution was infused intravenously in 28 patients undergoing elective lobectomy for lung cancer. The state of the complement system during and after surgery and the effects of methylprednisolone on biologically active products of complement were studied by measurements of plasma C3a and C5a anaphylatoxins and leukocyte counts in peripheral blood perioperatively. In the placebo group plasma concentrations of C3a were significantly increased on postoperative days 1 and 2. whereas C5a had risen significantly 6 hours after surgery and on days 1 and 2. Methylprednisolone infusion during surgery eliminated the postoperative elevation of C3a and C5a. The postoperative leukocyte count in peripheral blood was higher in the methylprednisolone group than in the controls. The observations indicated that methylprednisolone may reduce the influx of leukocytes from peripheral blood into the airways by attenuating production of biologically active complements.
Transdermal clonidine versus chlordiazepoxide in alcohol withdrawal: a randomized, controlled clinical trial, In a prospective. double-blind comparison. we assessed the efficacy of transdermal clonidine with that of chlordiazepoxide in the treatment of moderately severe acute alcohol withdrawal syndrome. While having significant withdrawal symptoms. 50 hospitalized men were randomly assigned to receive either transdermal clonidine or chlordiazepoxide over a 4-day study period. Outcome was evaluated daily. medically and psychiatrically. using both objective and subjective measurements for dependent variables. No patient in either study group had seizures or progression to delirium tremens. The group receiving transdermal clonidine had a more significant response globally for the signs and symptoms of alcohol withdrawal. as measured by the Alcohol Withdrawal Assessment Scale. Also. clonidine more effectively lowered elevated systolic and diastolic blood pressure and heart rate. The core target symptom. anxiety. decreased significantly more in the patients receiving transdermal clonidine when measured by the Hamilton Anxiety Rating Scale and its subscale for somatic anxiety. Cognitive function responded equally in both study populations. Clonidine-treated patients reported less diarrhea. dizziness. headache and fatigue. and the chlordiazepoxide-treated patients reported less nausea and vomiting. We conclude that transdermal clonidine is effective treatment for the acute alcohol withdrawal syndrome.
Titrated intravenous barbiturates in the control of symptoms in patients with terminal cancer, Patients with terminal cancer may have a series of severe and dehumanizing physical and psychologic symptoms. To improve symptom control in the final days and hours of life. we administer intravenous barbiturates continuously to provide heavy sedation or continuous somnolence. Titrated dosage is then reduced to a minimum. after a desired steady-state has been achieved. Improved symptom control is provided. and the patient's dignity is maintained until death.
Pediatric injury surveillance: use of a hospital discharge data base, Mortality data traditionally have been used to describe the epidemiology of childhood injury. Fatal outcomes. however. represent less than 1% of injury events and thus provide a limited characterization of the problem. Future epidemiologic study resulting in injury prevention depends upon the development of morbidity-based injury surveillance systems. "E-coded" hospital discharge data bases (used to indicate external cause of injury) are a valuable source of information for monitoring and controlling serious. nonfatal injuries. An E-coded injury discharge data base was developed and evaluated at The Children's Hospital of Alabama in Birmingham. In addition to patient demographics. length of stay. total charge. and method of payment. E-code and "N-code" (to indicate the anatomic site of injury) data were collected. During the 2-year study period. 1077 discharges from the hospital were documented in children with serious injuries under 15 years of age for an adjusted discharge rate of 78.0 per 10.000 child-years. Injuries accounted for $5.3 million in total charges and 4899 total days of stay. Falls. unintentional poisonings. burns. and bicycle. motor vehicle-passenger. and motor vehicle-pedestrian injuries were the six most common causes of injury. Closed-head trauma accounted for 55.4% of motor vehicle-passenger injuries. 67.6% of bicycle injuries. and 51.8% of falls. Hot water scalds caused 36.4% of burns. and clonidine ingestion accounted for 22.1% of unintentional poisonings.
Fatal incidents involving pickup trucks in Alabama, Death or injury resulting from crashes involving light trucks (ie. pickup trucks) is a significant problem. Data show that fatal crashes and occupant fatalities involving light trucks have steadily increased since 1983. This project describes vehicle crashes involving passengers riding in the beds of pickup trucks. Actual crashes were identified through the Fatal Accident Reporting System (FARS) of the National Highway Traffic Safety Administration. The 40 incidents studied involved 204 pickup truck passengers. Of these. 45 were killed. 107 sustained visible injuries or were carried from the scene. 6 had bruises and abrasions. and 2 had no visible injury but were briefly unconscious or had a documented complaint of pain. The risk of death among pickup truck passengers who were fully ejected from the vehicle was nearly six times that of passengers not fully ejected. Correspondingly. the risk of ejection from the truck was 26.7 times greater among occupants riding in the bed than occupants riding in the cab.
Factitious cyclic hypersomnia: a new variant of factitious disorder, The central goal of patients with factitious disorders is to receive medical care. Unnecessary diagnostic procedures and recurrent hospitalizations often ensue. We saw a 39-year-old man with a novel variation of this disorder: factitious cyclic hypersomnia. or the simulation of recurrent episodes of excessive sleep. This case highlights the observations that patients whose illnesses are simulated may have diverse symptoms. that no syndrome is immune to factitious imitation. and that attempts at treatment. though exceedingly challenging. are always contingent upon appropriate recognition.
Cerebellar degeneration and Meige's syndrome, We have reported a case of Meige's syndrome in a middle-aged man who eventually had a cerebellar degeneration syndrome. The extrapyramidal symptoms preceded cerebellar signs and symptoms by 5 years. Most patients with idiopathic Meige's syndrome show some improvement with high-dose anticholinergic therapy. Our patient's lack of response to such agents and his subsequent cerebellar symptoms are reminiscent of the situation seen with parkinsonian patients who do not respond to medications. indicating a more widespread degenerative disease. The association of extrapyramidal symptoms with some spinocerebellar disorders. and the pathologic changes seen in the one reported autopsy case. should place the group of spinocerebellar disorders high on the differential list.
A case of neonatal tetanus, The morbidity and mortality from neonatal tetanus are preventable. It is largely a disease of developing countries. This single case of neonatal tetanus in southern Florida must serve as an indicator for the need for health care professionals to evaluate the degree of utilization of maternal health services and the impact of immunization programs for those women at risk. in this case. women who have migrated from developing countries.
Management of soft tissue sarcomas of the extremities, The management of soft tissue sarcomas has undergone and continues to undergo important changes. The purpose of this report is to review the presentation. diagnosis. and natural history of soft tissue sarcomas. In so doing. the importance of a careful and rigorous method of evaluation will be emphasized. Furthermore. the results of multidisciplinary treatment. with a goal towards limb salvage. will be reviewed. With appropriate and timely intervention. selected patients with pulmonary metastases may still experience long-term survival. Throughout this review. the importance of early and continuing multidisciplinary treatment and evaluation will be emphasized.
The value of routine preoperative laboratory testing in predicting postoperative complications: a multivariate analysis, The purpose of this study was to evaluate the ability of preoperative laboratory testing to predict postoperative complications. Five hundred twenty patients undergoing elective surgery had their American Society of Anesthesiologists' classification. ponderal index. electrolyte values. glucose levels. blood urea nitrogen/creatinine values. complete blood counts. coagulation studies. total protein/albumin/lymphocyte count. electrocardiogram. chest radiograph. urinalysis. pulmonary function tests. type of anesthesia. and type of operation recorded preoperatively. Patients were followed prospectively after surgery for the development of complications. The data were analyzed by univariate and multivariate methods. Postoperative complications were strongly associated with American Society of Anesthesiologists' classification. type of anesthesia. and type of operation. However. only a few laboratory tests. such as electrocardiogram. chest radiograph. and nutritional status. were associated with postoperative complications. Therefore. in general. preoperative laboratory testing should only be undertaken for specific indications. Recommendations for routine tests are made depending on the age of the patient.
Experience with surgical treatment of Takayasu's disease, We reviewed 28 patients with Takayasu's disease to determine the incidence of stroke and its relationship to the involvement of the thoracic aortic arch and its branches. We describe surgical experiences with 10 of the 28 patients who required 21 vascular surgical procedures for critical thoracic aortic arch arterial stenoses. upper and lower extremity ischemia. and renal artery stenoses. Four of the 28 patients initially had a stroke caused by occlusion of one or more thoracic aortic arch arteries. Six of the 10 patients underwent 7 bypass procedures for critical thoracic arch stenoses. All have remained free of stroke for 5 or more years. Four patients had five anastomotic stenoses or graft occlusions in late follow-up; the development of these stenoses did not relate to disease activity at the time of the operative procedure. All bypass grafts originating from the subclavian axillary artery developed anastomotic stenoses; no anastomotic stenoses occurred in bypass grafts originating from the ascending aorta. In contrast to other reports. no anastomotic false aneurysms occurred. Occlusions of major aortic arch arteries in Takayasu's disease cause stroke. Bypass of critically stenoses aortic arch arteries protects against stroke and is best performed with grafts originating from the ascending aorta. Anastomotic stenoses but not anastomotic aneurysms are common. This study suggests that aggressive surgical treatment can be performed with good results.
Bacteriologic quality of intraoperative autotransfusion, Controversies remain about the bacteriologic aspects of intraoperative blood salvage despite the widespread use of this technique. In this prospective study. intraoperative salvaged blood was cultured in 401 patients. according to a direct plating technique. Bacterial growth was detected in 12.7% of cases. These results were compared with those obtained in control studies with sterile water and blood bank units under the same culture conditions. Most microorganisms were coagulase-negative staphylococci. followed by other skin and environmental contaminants. Quantitative estimates of contaminations showed low counts of colony-forming units (CFU/ml): 82% of positive cultures yielded 1 or 2 CFU/ml and 6% had 5 to 20 CFU/ml. Patients were followed up for a minimum of 3 months to detect septic complications. No statistically significant correlation could be found between bacteriologic results of autotransfused blood and infectious complications. This study suggests that bacteriologic monitoring of patients who have undergone autotransfusion may help in detecting surgical field contamination. It also confirms that intraoperative autotransfusion adds little septic risk to cardiac surgery.
Bacterial translocation from the gut impairs systemic immunity, The goal of this study was to determine the influence of bacterial translocation on systemic immunity. since bacteria and their products play a major role in the development and maintenance of the host's immune system. To test this hypothesis. we measured the blastogenic response of mononuclear cells harvested from the blood. spleen. Peyer's patches. and mesenteric lymph nodes of control and Escherichia coli C25 monoassociated mice to a battery of mitogens. The E. coli C25 monoassociation model was used because this bacterial translocation model is not associated with experimental manipulations that are likely to affect the systemic immune system. The mitogenic response of lymphocytes isolated from the E. coli C25 monoassociated mice was significantly depressed compared to the control groups (p less than 0.01). Since the biologic significance of depressed in vitro mitogen responsiveness is difficult to determine. we assessed the ability of the mice to control a bacterial challenge using an in vivo Staphylococcus aureus abscess model. It appears that the observed changes in mitogen responsiveness may be of biologic significance. since the ability of the E. coli C25 monoassociated mice to control the injected S. aureus was impaired (p less than 0.01). These results suggest that an association exists between bacterial translocation and decreased systemic immune responsiveness.
Isolated subclavian artery dissection after blunt trauma, We present a case report of a patient with an isolated dissection of the subclavian artery after blunt trauma. The patient who was admitted to our center after a motor vehicle accident. complained of chest and neck pain and physical findings of diminished left extremity pulses. Arteriography showed an occluded subclavian artery with the possibility of a dissection. The dissection was confirmed at surgery with the proximal extent originating just distal to the origin of the vertebral artery. The distal extent of the dissection was not determined. Operative repair was performed by a carotid-to-subclavian artery bypass obliterating the false lumen of the dissection with a running vascular anastomosis. The patient. who was discharged 5 days after repair. had normal extremity neurovascular function at 4 months follow-up.
Early detection program for prostate cancer: results and identification of high-risk patient population, Three hundred sixty-two men underwent transrectal ultrasound of the prostate (TRUS). digital rectal examination (DRE). and serum prostate-specific antigen (PSA) determination as part of an early detection program for prostate cancer. Thirty-seven (10%) cancers were detected. DRE had the highest sensitivity and specificity. 89 percent and 84 percent. respectively. TRUS and PSA had comparable sensitivities (84% and 81%) and specificities (82% and 82%). The positive predictive values of DRE. TRUS. and PSA determination were 39 percent. 35 percent. and 33 percent. respectively. We found a cancer detection rate of 16 percent among patients with symptoms of bladder outlet obstruction and 5 percent in patients without these symptoms. The detection rate was 36 percent for physician-referred patients and 3 percent for self-referred patients. This suggests to us that at the present time the best utilization of medical resources to increase prostate cancer detection is to educate men to have annual medical evaluations by primary-care physicians who are encouraged to incorporate risk assessment and screening DRE as part of their routine practice. Any man with either abnormal findings on examination or increased risk should be referred to a urologist for further evaluation.
Incontinence management scale for elderly inpatient men, For many elderly inpatients. urinary incontinence cannot be successfully treated and the management objective is identifying a suitable method for containment of urine loss. In elderly inpatient men. an external catheter is utilized in many cases for incontinence management. The role of the severity of incontinence and the use of an external catheter was investigated in 66 elderly inpatient men. Quantitative incontinence measurements showed incontinent patients having an external catheter had approximately 6.3 (SD = 2.5) episodes per day compared with 3.2 (SD = 2.0) episodes per day in the noncatheter incontinent patients. The clinical management method used in these patients was associated with the measured severity of incontinence.
Predisposing factors in bladder calculi. Review of 100 cases, One hundred patients. aged twenty to ninety-two years. underwent 111 procedures for removal of bladder calculi. Most patients (88) had some type of bladder outlet obstruction. Two types of stones were identified: those that had apparently formed in the upper tract and been trapped in the bladder (17 cases) and those that appeared to have formed in the bladder in the presence of various types of outlet obstruction. Stone analysis revealed uric acid stones in 50 percent. calcium oxalate stones in 19 percent. and stones of mixed composition in 31 percent. Five patients had metabolic abnormalities predisposing to stone formation; in 2 cases. these abnormalities were discovered during the evaluation for stone disease. Treatment depended on stone characteristics. associated pathology. and the general health of the patient. A review of the literature with regard to the morbidity and mortality of combining treatment of vesical calculi and bladder outlet obstruction secondary to prostatic obstruction is included.
Endoscopic treatment of vesicoureteral reflux in children with neurogenic bladders, Endoscopic subureteral injection of Teflon was performed in 12 children (20 ureters) with neurogenic bladders and vesicoureteral reflux (grades III-IV). Follow-up evaluation by ultrasonography and voiding cystourethrogram at three-month intervals up to two years revealed successful correction of the reflux in 70 percent of the ureters.
Pediatric testicular tumors: the Johns Hopkins experience, Testicular neoplasms constitute 1 percent of all childhood malignancies and rank eighth in childhood cancer mortality. From 1970 to 1988. 25 testicular tumors in children eighteen years and under were seen. The majority of the patients were white (88%). Pathologic analysis of the tumors revealed that 68 percent were germinal and 32 percent were nongerminal. Staging was undertaken in all patients with serum markers. chest x-ray film. and computerized tomography scans or lymphangiography. All patients underwent radical orchiectomy. and further therapy was given dependent on tumor type and stage. The survival among this cohort was excellent. with only 3 patients succumbing to their disease. Detailed results of treatment. and approaches to avoid excess treatment morbidity are reviewed.
Causes of post-prostatectomy retention, Forty-eight patients in urinary retention following prostatectomy underwent urodynamic evaluation. Fifteen patients (31%) were found to have persistent residual obstruction. while 14 patients (29%) had detrusor hyporeflexia. In 9 patients (19%) a combination of outflow obstruction and detrusor hyporeflexia was demonstrated. In 6 patients (13%). urinary retention was due to compromised mental status. No abnormality was detected in remaining 4 patients (8%) on urodynamic evaluation. For proper evaluation of unsatisfactory voiding after prostatectomy cystoscopy is of limited value while urodynamic testing is essential.
Application of microwave tissue coagulation in partial nephrectomy, Microwave tissue coagulation was used during partial nephrectomy in 10 mongrel dogs. without clamping the renal artery. There were no major complications. such as retroperitoneal hematoma. abscess formation. or macroscopic infarction of the kidney tissue related to this new procedure. The advantages of microwave coagulation are reduced blood loss. shorter operative time. and minimal risk of vascular injury.
Subacute poisoning with phosalone, an organophosphate insecticide, An illness characterized by weakness. dizziness. and gastrointestinal symtoms was identified among a crew of 30 migrant field-workers employed by a grape grower in Madera County. California. during August 1987. The onset of symptoms occurred between August 24 and August 30 and a median of 9 days from the date of first employment. The first crew member sought medical treatment on August 26. and 10 crew members were admitted to hospital between August 27 and August 30. For most workers. gastrointestinal and constitutional symptoms resolved shortly after admission. but 4 patients had episodes of severe sinus bradycardia persisting for several days. On the day of admission. transient atrioventricular dissociation developed in 2 persons. Interviews with 16 crew members not admitted to the hospital identified only 1 additional worker ill with gastrointestinal symptoms. but all 16 had moderate to severe inhibition of both plasma and red blood cell cholinesterase. Four other workers who were tested but not interviewed also had cholinesterase depression. The crew had had exposure since August 19 to the organophosphate insecticide phosalone. which was last applied to the vineyard on July 21. or 29 days earlier. Although this is the first report unequivocally linking phosalone to field-worker poisoning. the delayed onset and nonspecific nature of the symptoms associated with subacute poisoning may have hindered the recognition of previous similar episodes.
Counseling patients seropositive for human immunodeficiency virus. An approach for medical practice, Persons at risk for infection with the human immunodeficiency virus are being encouraged to learn their serostatus. While such knowledge can help patients seek appropriate medical care. it can also be distressing. We describe an approach. based on crisis counseling. for physicians to use in working with patients infected with HIV. It can help physicians in assisting patients with emotional reactions to the diagnosis as well as in directing patients to manage practical issues of concern. Methods for discussing safer sex or injection practices are also presented.
New developments in cardiopulmonary resuscitation, Since the last revision of the American Heart Association's guidelines in 1985. several new developments of clinical importance have occurred in the field of cardiopulmonary resuscitation. These include enhanced access to and earlier use of defibrillation. the use of high-dose epinephrine when standard doses fail. the assessment of resuscitative efforts with end-tidal CO2 monitoring and the addition of two new drugs. amiodarone (for refractory ventricular fibrillation) and adenosine (for paroxysmal supraventricular tachycardia). Time will determine the ultimate role of these advancements in the management of cardiac arrest.
Giant cell tumor of bone, Giant cell tumor is the second most common benign tumor of bone. Plain radiographs may demonstrate distinctive features but can also be misleading. The diagnosis may be aided by the use of other imaging modalities. such as bone scan. computed tomography and angiography. The recurrence rate is high. but some of the newer treatments seem to be associated with better outcomes.
Selective fallopian tube canalization, Infertility is an increasingly common problem. Occlusion of the fallopian tubes is one of the principal causes. and until recently surgery was the only available treatment. The success rate of surgery is often low. particularly with occlusion of the proximal tube. Selective fallopian tube canalization under fluoroscopic guidance has been successful in alleviating proximal tubal obstruction. This procedure may be performed in the outpatient setting and is a safe. cost-effective alternative to surgery.
PUVA therapy, PUVA is an acronym for psoralen plus ultraviolet-A radiation. This form of photochemical therapy is commonly used in the treatment of psoriasis and vitiligo. but it is also beneficial in other dermatologic diseases. An understanding of psoralen's mechanism of action and the unique properties of the various psoralen preparations is important in ensuring optimal results with this therapy.
Cephalosporins: rationale for clinical use, Cephalosporins. the most widely used class of antibiotics. are more resistant than penicillins to inactivation by beta-lactamases. Based on their spectrum of activity against gram-negative bacteria. cephalosporins are classified into three generations. The generation classification. however. does not correlate with activity against gram-positive bacteria or anaerobes. First-generation cephalosporins have a narrow gram-negative spectrum but are most active against gram-positive bacteria. particularly Staphylococcus aureus. Third-generation compounds have excellent activity against gram-negative bacteria. The cephamycins. a second-generation subgroup that includes cefoxitin. cefotetan and cefmetazole. have the best activity against anaerobes.
Late streptokinase infusion and antithrombotic treatment in myocardial infarction reduce subsequent myocardial ischemia, Of 255 consecutive patients with acute myocardial infarction. 111 were eligible for attempted late thrombolysis. They were randomly assigned to either thrombolytic and antithrombotic treatment (treatment group) or routine treatment (control group). Patients in the treatment group received streptokinase initiated late (mean 32 hours; range 12 to 49) after the onset of symptoms. followed by heparin infusion for at least 5 days and warfarin and dipyridamole for at least 3 months. Patients were examined clinically and by bicycle ergometry on discharge from the hospital and after 3 and 12 months. The two groups did not differ with respect to deaths or reinfarctions. There was a trend toward a lower incidence of angina pectoris in the treatment group. Exercise tolerance in this group was significantly higher than in the control group (at 3 months 124 +/- 39 W vs 107 +/- 41 W; p less than 0.05). The difference was entirely accounted for by patients with no previous history of infarction or angina pectoris (at 3 months 142 +/- 37 W vs 112 +/- 45 W; p = 0.01). ECG signs of myocardial ischemia. silent or symptomatic. occurred at significantly lower levels of exercise among patients in the control group compared with patients in the treatment group. The results support the notion that thrombolytic therapy given as late as 12 to 49 hours after the onset of symptoms may reduce the incidence of residual ischemia during the postinfarction period.
Immediate regional endocardial surface expansion following coronary occlusion in the canine left ventricle: disproportionate effects of anterior versus inferior ischemia, The exact time of onset of functional expansion after acute myocardial infarction/ischemia remains unclear in spite of its potential link to chronic pathologic infarct expansion and its potential implications for therapy. To examine this early change in ventricular morphology. 14 open-chest dogs were studied with two-dimensional echocardiography before and after occlusion (10 minutes) of the left anterior descending coronary artery (LAD. n = 7) or circumflex artery (CIRC. n = 7). The endocardial surface area (ESA) and the area of abnormal wall motion (AWM) were reconstructed from the echocardiographic data using a previously reported technique for quantitatively mapping the ESA and extent of AWM. For the total group (N = 14). the mean ESA before occlusion was 48.9 +/- 9.8 cm2. increasing to 65.7 +/- 18.9 cm2 at 10 minutes occlusion (p less than 0.001). For the LAD subgroup. the mean ESA before occlusion was 50.7 +/- 9.3 cm2. increasing to 79.1 +/- 14.1 cm2 at 10 minutes following occlusion (p less than 0.001). For the CIRC subgroup. the mean ESA before occlusion was 47.1 +/- 10.8 cm2. increasing to 52.3 +/- 12.6 cm2 at 10 minutes after occlusion (p less than 0.001). The ESA increase for the LAD subgroup was significantly larger than that of the CIRC subgroup (LAD range 14.5 to 49.9 cm2 versus CIRC range 1.5 to 9 cm2. p less than 0.0001). Coronary occlusion resulted in similarly sized regions of AWM for both subgroups (LAD. 31.3 +/- 12.2 cm2 versus CIRC. 25.9 +/- 10.3 cm2. p = n.s.). For the LAD group. the largest increase in endocardial circumference occurred within the zone of AWM at the apex (39.9 +/- 12%). The endocardial surface area therefore expands immediately after coronary occlusion and the magnitude of this process is primarily related to the site (anteroapical) rather than to the extent of AWM.
Detection of myocardial infarction in the presence of Wolff-Parkinson-White syndrome by QRST isoarea map in dogs, The possibility of detecting myocardial infarction (MI) in the presence of Wolff-Parkinson-White (WPW) syndrome by means of body surface QRST isoarea maps was studied in eight dogs. Eighty-seven body surface ECGs were recorded simultaneously. Recordings were taken during right atrial (RA) and right atrial and right ventricular (RA + RV) sequential pacing. which simulated WPW syndrome. during control periods and at 1-hour intervals for up to 5 hours after occlusion of the left anterior descending coronary artery. In ECGs during the RA drive. diagnostic findings of MI such as abnormal Q waves were observed but became obscure during the RA + RV drive. On the contrary. the QRST values over the anterior chest during both drives were positive soon after coronary occlusion. decreased gradually as time passed. and became abnormally negative after 5 hours. The QRST isoarea maps during RA and RA + RV pacing showed quite similar patterns and were highly correlated with each other throughout this study (r greater than 0.95). These findings demonstrate that localized abnormalities resulting from MI are evident in QRST isoarea maps even in the presence of preexcitation and fusion.
Acute reduction of mitral valve area after percutaneous balloon mitral valvuloplasty: assessment with Doppler continuity equation method, Mitral valve areas before and after balloon mitral valvuloplasty were serially determined by the Doppler continuity equation method in 16 patients. Ultrasound examinations were performed before and immediately after balloon inflation and 24 hours. 1 week. and 1 month after valvuloplasty. Mitral valve area determined by the Doppler continuity equation method correlated well with that determined at catheterization by the Gorlin formula. not only before but also immediately after balloon inflation (y = 0.87 x + 0.05. standard error of estimate = 0.22 cm2. r = 0.90). Serial calculation of mitral valve area by the Doppler continuity equation method showed a slight but significant decrease in the valve area at 24 hours after balloon mitral valvuloplasty but no change after that. We conclude that the Doppler continuity equation method provides an accurate estimation of mitral valve area before and even after balloon valvuloplasty. Mitral valve area dilated by balloon inflation is decreased slightly within 24 hours after the procedure. which corroborates valve stretch as one mechanism for increasing mitral valve area with balloon valvuloplasty. Estimation of mitral valve area immediately after balloon mitral valvuloplasty may overestimate the long-term efficacy of the procedure.
Acute hemodynamic effects of intravenous diperdipine, a new dihydropyridine derivative, in coronary heart disease, The acute hemodynamic effects of a new dihydropyridine calcium channel blocker. diperdipine. which is suitable for intravenous administration. were studied by right and left cardiac catheterization in 16 patients with coronary heart disease. Diperdipine markedly reduced systemic vascular resistance and improved stroke index and left ventricular ejection fraction. Mean pulmonary artery and wedge pressures were slightly increased as a possible consequence of enhanced venous return. whereas right atrial and left ventricular end-diastolic pressures were not significantly changed. Nevertheless. an increase in preload was clearly indicated by an augmented left ventricular end-diastolic volume index after administration of diperdipine. Left ventricular contractility. which was estimated by the end-systolic pressure-volume ratio and by dP/dt max was not significantly changed. though analysis of individual data suggests a minimally negative inotropic effect. However. such a minor effect on left ventricular contractility was largely counterbalanced by the marked reduction of afterload. which produced a sharp improvement of stroke index. Enhancement of left ventricular ejection fraction and reduction in systemic vascular resistance were inversely and directly correlated to control values. Overall. diperdipine was well tolerated. but one patient had a major untoward reaction that consisted of an ischemic episode that was possibly related to drug administration. In conclusion. intravenous diperdipine appears to be a potent arteriolar dilating agent that does not affect left ventricular contractility.
Ultra short-acting intravenous beta-adrenergic blockade as add-on therapy in acute unstable angina, To assess the efficacy and safety of the ultra short-acting beta-blocking agent. esmolol. in acute unstable angina. we administered esmolol to 21 patients who had persistent angina despite conventional medical therapy. Following a baseline Doppler echocardiographic examination. esmolol was titrated to reduce the rate-pressure product by at least 20%. Once the patients had been receiving a maintenance dosage for 30 minutes. Doppler echocardiographic studies were repeated. Mean esmolol dose at target response was 17 +/- 16 mg/min. with the dosage range of 8 to 24 mg/min. Esmolol was effective in alleviating anginal chest pain in 18 of the 21 patients. Seven patients eventually underwent percutaneous transluminal coronary angioplasty (PTCA) and eight had coronary bypass surgery. The remainder were discharged receiving medical therapy including oral beta-blockade. During esmolol therapy. heart rate and blood pressure decreased significantly (86 +/- 14 to 68 +/- 12 beats/min and 125 +/- 16 to 103 +/- 20 mm Hg. both p less than 0.001). Cardiac output decreased from 5.4 +/- 1.3 to 4.5 +/- 1.1 L/min (p less than 0.001) secondary to a decrease in heart rate as stroke volume remained unchanged. Left ventricular ejection fraction increased from 47 +/- 12 to 49 +/- 13 with esmolol therapy. although this change was not statistically significant. Both the one third filling fraction as well as E/A ratio (ratio of early-to-late diastolic filling velocities) increased with esmolol therapy (35 +/- 8% to 38 +/- 8% and 0.73 +/- 0.2 to 0.85 +/- 0.23. both p less than 0.005). indicating improvement in left ventricular diastolic function.
Improvement of systolic and diastolic left ventricular wall motion by serial echocardiograms in selected patients treated for unstable angina, The purpose of the study was to evaluate the effect of antiischemic treatment on left ventricular function in selected patients with unstable angina pectoris that was due to severe proximal left anterior descending coronary artery narrowing and to identify subgroups liable to an adverse outcome (mean term 2.7 years). Effect of antiischemic treatment on systolic and diastolic left ventricular wall motion was studied in 35 patients who had unstable angina pectoris and an electrocardiogram that indicated severe proximal left anterior descending coronary artery narrowing. Treatment consisted of either a revascularization procedure (17 patients) or antianginal drug therapy (18 patients). All patients underwent a two-dimensional echocardiographic study within 48 hours (mean 20 hours) of entry into the study. This study semiquantitatively analyzed systolic performance of the ischemia-related segments by calculation of a total wall motion score. In 16 patients this investigation was combined with a continuous detailed recording of only the apical interventricular septal wall motion. This detailed study included measurements for regional function by providing a typification of the pattern of systolic and early diastolic excursion of the endocardial border of the apical interventricular septum. A repeat ultrasonic study was performed at least 1 month (median 2 months. 7 days) after admission. Results of the systolic wall motion analyses of all 35 patients showed. in both treatment groups. a significant improvement in systolic wall motion of the anterior and apical segments (mean total wall motion score at early study vs late study: revascularization. 6.9 vs 2.2 and medical therapy. 4.6 vs 1.0).
Identification of the rate-dependent functional refractory period of the atrioventricular node in simulated atrial fibrillation, We continuously observed successive pairs of R-R intervals during atrial fibrillation and hypothesized that the shortest R-R interval for a given preceding R-R interval in a pair represents the functional refractory period of the atrioventricular node at that preceding interval. To test this hypothesis we simulated atrial fibrillation in 28 isolated cross-perfused canine hearts and obtained an R-R interval scatterplot by plotting the R-R intervals as a function of the immediately preceding R-R interval. This scatterplot enabled us to detect a series of the shortest R-R intervals for a wide range of preceding R-R intervals. and this allowed us to estimate the rate-dependent functional refractory period of the atrioventricular node in simulated atrial fibrillation. The estimated functional refractory periods correlated well with those measured by the conventional method (r = 0.93). We conclude that the proposed method makes it possible to estimate the rate-dependent functional refractory periods of the atrioventricular node in atrial fibrillation.
Septal ventricular pacing in the immature canine heart: a new perspective, Cardiac pacing initiated from epicardial or transvenous apical right ventricular electrodes causes asynchronous ventricular contraction. This alters myocardial stress vectors and results in adverse cellular and subcellular changes in the experimental animal. Clinically. such changes may contribute to the adverse hemodynamics reported with long-term ventricular pacing. To determine the feasibility of direct stimulation of the ventricular specialized conduction systems and therefore the potential for maintenance of normalized depolarization patterns. 13 beagle puppies were studied. Baseline ventricular activation and contraction patterns were obtained using intracardiac electrograms and multigated nuclear acquisition (MUGA) imaging. Septal electrode insertion from the aortoatrial groove was accomplished by use of two-dimensional echocardiography and continuous electrocardiographic (ECG) monitoring of the surface ECG during pacemaker implantation in five puppies. Standard right ventricular epicardial electrodes were implanted in five additional animals. with three remaining as age-matched non-paced controls. After 4 months of observation. repeat MUGA imaging and intracardiac electrograms demonstrated nearly normal biventricular activation and contraction patterns among the septal-paced group. Histopathologic examination illustrated normal cellular morphology in the septal-paced animals. This study demonstrates that pacing electrode insertion into the proximal interventricular septum is feasible and results in utilization of the normal ventricular conduction pathway. Such an approach to initiation of ventricular stimulation may attenuate the adverse effects of long-term ventricular pacing.
Effect of nisoldipine on hemodynamic responses to defibrillation, Sequences of ventricular fibrillation-defibrillation cause transient hypertension; we hypothesized that this "adrenergic overshoot" might be blunted by the functional antiadrenergic effect of the calcium channel blocking drug nisoldipine. with a potentially beneficial reduction in myocardial oxygen requirements. However. other calcium channel blocking drugs have been shown to reduce shock success for defibrillation. a deleterious effect. Thus the purposes of this study were to assess the effect of nisoldipine on the hemodynamic responses to the sequences of ventricular fibrillation-defibrillation. and its effect on the energy requirements for defibrillation. In 16 dogs we administered intravenous nisoldipine (1 microgram/kg bolus followed by an infusion of 0.075 to 0.50 microgram/kg/min) to lower mean blood pressure 10% and 20% below baseline. Ventricular fibrillation was induced electrically. and shocks of varying energy levels (30. 50. and 100 joules) were administered to determine defibrillation energy requirements. Heart rates and blood pressures were recorded up to 3 minutes after each shock to determine hemodynamic responses. Measurements were made before nisoldipine administration and again at the two levels of drug-induced blood pressure decline. We found that the usual systolic blood pressure "overshoot" after defibrillation (typically maximum at 15 to 30 seconds after shocks) was significantly blunted after nisoldipine administration (p less than 0.05). Heart rate slowing after defibrillation (a cholinergic response) was not affected. Nisoldipine did not alter shock success rates. which varied from 12 +/- 7%SE at 30 joules to 68 +/- 12% at 100 joules. Thus nisoldipine blunted the "adrenergic overshoot" of systolic blood pressure following defibrillation. a potentially beneficial effect. without altering the energy requirements for transthoracic defibrillation.
Noninvasive estimation of left atrial pressure in patients with congestive heart failure and mitral regurgitation by Doppler echocardiography, A completely noninvasive method for estimating left atrial pressure in patients with congestive heart failure and mitral regurgitation has been devised with the use of continuous-wave Doppler echocardiography and brachial sphygmomanometry. Of 46 patients studied with mitral regurgitation. 35 (76%) had jets with distinct Doppler spectral envelopes recorded. The peak ventriculoatrial gradient was obtained by measuring peak mitral regurgitant velocity in systole and using the modified Bernoulli equation. This gradient was then subtracted from peak brachial systolic blood pressure. an estimate of left ventricular systolic pressure. to yield left atrial pressure (left atrial pressure = systolic blood pressure - mitral regurgitant pressure gradient). Noninvasive estimates of left atrial pressure from 35 patients were plotted against simultaneous recordings of mean pulmonary capillary wedge pressure resulting in the correlation y = 0.88x + 3.3. r = 0.88. standard error of estimate = +/- 4 mm Hg (p less than 0.001). Therefore. continuous-wave Doppler echocardiography and sphygmomanometry may be used in selected patients with congestive heart failure and mitral regurgitation for noninvasive estimation of left atrial pressure.
Myocardial imaging with Tc-99m teboroxime: technique and initial results, This study examined the results of Tc-99m teboroxime imaging in 22 patients aged 59 +/- 9 years and compared the results with those of thallium-201. The exercise and rest teboroxime studies were obtained within 3 hours of each other using a dose of 15 mCi/study. Because of the very short wash-out half-life of teboroxime. imaging was begun within 1 to 2 minutes after injection. Both SPECT and planar images were obtained; the SPECT protocol was modified by changing the number of frames. the time per frame. or the filters used for reconstruction of images. The planar images were obtained in the supine or upright position. Shorter acquisition time for SPECT (10 sec/frame) and the use of a Butterworth filter with a frequency cutoff of 0.3 cycle/cm and a power of 10 yielded best image quality. There was a close agreement with thallium results in identifying an abnormal or normal perfusion pattern in 89% of vascular territories. The scans were abnormal by both techniques in 12 patients. normal in nine patients. and discordant in only one patient. Thus Tc-99m teboroxime myocardial imaging is feasible at rest and during exercise using either SPECT or planar imaging. Shorter acquisition time and appropriate filtering for SPECT imaging and the upright position in planar imaging improve image quality and are convenient for the patient.
Future directions in vasodilator therapy for heart failure, Vasodilator therapy has become a major pharmacologic approach for improving left ventricular function. and consequently. vasodilator drugs are being used increasingly in the treatment of heart failure. Ideally. vasodilator drugs used in the long-term management of heart failure should show clearly defined pharmacodynamic effects. These include reduced impedance to left ventricular ejection. increased venous capacitance. increased left ventricular ejection fraction and reduced heart size. absence of neurohormonal stimulation. and slowed progression of left ventricular dysfunction. The mechanisms of action and sites of activity of the various vasodilator drugs currently available vary considerably. and none as yet has proved ideal for the treatment of heart failure or hypertension. The complexity surrounding the multiple vasoconstrictor mechanisms involved in heart failure has led to a rationale for combined vasodilator therapy and certain combinations are discussed. From a therapeutic standpoint. the development of drugs with multiple mechanisms of action is particularly attractive. Flosequinan is a new vasodilator agent whose cellular mechanism of action remains uncertain. Flosequinan has the advantage of being able to relax both arterial and venous beds and as such may be particularly beneficial in the treatment of heart failure.
Clinical efficacy of flosequinan in heart failure, The effects of the new arterial and venous vasodilator flosequinan have been evaluated in a variety of ways in different groups of patients with chronic heart failure. Flosequinan improved the central hemodynamic effects of heart failure in one group. with benefits still apparent up to 24 hours after a single oral dose. In another group it also improved calf blood flow and. therefore. blood flow to skeletal muscle. Also. using a number of different tests. it improved the exercise performance of the patients. In a further group the improvement in exercise tolerance produced was similar to that of captopril. Flosequinan has the necessary properties of a drug that is likely to be of benefit in the treatment of patients with chronic heart failure.
Early beneficial effect of streptokinase on left ventricular function in acute myocardial infarction, The effect of intravenous streptokinase therapy on the time course of functional recovery was investigated in a controlled study of 64 patients randomized within 3 hours after the onset of acute myocardial infarction (AMI). Contrast ventriculography was performed 1 to 4 days after AMI and repeated 5 weeks later. Wall motion was analyzed by the centerline method in the central infarct. peripheral infarct and noninfarct regions. In patients with ventriculographic data at the early catheterization. streptokinase-treated patients had less severe hypokinesia in the central infarct region than control patients (-2.9 +/- 0.9 [n = 29] vs -3.4 +/- 0.7 standard deviations below normal [n = 21]. p less than 0.05). The benefit of streptokinase was more marked in the peripheral infarct region (-1.5 +/- 0.7 vs -2.1 +/- 0.6. p less than 0.001). As a result. the ejection fraction was slightly higher in treated versus control groups (46 +/- 10 vs 43 +/- 7%. respectively; difference not significant). At 5 weeks. function in the streptokinase and control groups had diverged further because of continued improvement in the streptokinase-treated patients. This study shows that streptokinase benefits left ventricular (LV) function by 1 to 4 days after AMI. earlier than previously reported. The benefit was not limited to the peripheral infarct region. where ischemia might have been less severe. but was also seen in the central infarct region. The implication is that thrombolytic therapy can improve LV function during the period of myocardial stunning. while myocardial function is still recovering.
Effects of nisoldipine on myocardial ischemia during exercise and during daily activity, The antiischemic properties of nisoldipine. a dihydropyridine calcium antagonist. were assessed in a multicenter. double-blind. placebo-controlled trial by repeated exercise testing and 72-hour ambulatory electrocardiographic monitoring in 82 patients with coronary artery disease. Patients with positive treadmill stress test results and greater than or equal to 2 ischemic episodes per 24 hours were included in this study. Administration of all chronic antiischemic medications except beta blockers were discontinued. During the first week all patients received placebo twice daily. During the second and third weeks. 41 patients received nisoldipine 10 mg and 41 patients received placebo twice daily. In the placebo group there were no changes in exercise parameters or in ambulatory electrocardiographic parameters. In the nisoldipine group. exercise duration increased from 403 to 448 seconds (p = 0.0035). time to 1 mm of ST depression increased from 224 to 298 seconds (p = 0.002). time to pain increased from 241 to 321 seconds (p = 0.01). and maximal ST depression was reduced from 2.6 to 2.3 mm (p = 0.002). Among the ambulatory electrocardiographic parameters in the nisoldipine group. only the number of episodes was reduced. from 14.4 to 11.6 (p = 0.0013) per patient. There was no significant reduction in total ischemic time (132 vs 120 minutes per patient). No significant side effects were observed. This is the largest clinical trial to date on the effects of nisoldipine on myocardial ischemia. The results indicate that nisoldipine was effective in improving all exercise parameters and only partially effective in suppressing ischemia during daily activity.
Usefulness of blood lactate as a predictor of shock development in acute myocardial infarction [published erratum appears in Am J Cardiol 1991 Apr 15;67(9):912, Data were obtained and analyzed in 229 patients admitted to the coronary care unit from November 1988 through July 1989. The patients were classified into 2 groups: patients without or with only mild left ventricular failure (Killip class I or II) during their hospital stay (group I). and patients who were in Killip class I or II on admission but developed cardiogenic shock during hospitalization (group II). Discriminant function analysis was performed using the following variables: patients' age. history of previous myocardial infarction. diabetes mellitus. blood lactate. urea. creatinine. creatine kinase. aspartate aminotransferase. lactate dehydrogenase concentrations. and chest x-ray cardiothoracic ratio. Variables that were found to significantly discriminate the 2 groups of patients were age. previous infarction. x-ray cardiothoracic ratio. blood urea and lactate concentrations. The risk index was computed. and blood lactate was the variable with the greatest predictive power for shock development. The sensitivity. specificity and predictive value of the risk index. taking various cutoff points. were calculated. With a cutoff value of 1. sensitivity was 65%. specificity 91%. positive predictive value 36% and negative predictive value 97%. With a cutoff value of 2. sensitivity was 53%. specificity 99%. positive predictive value 82% and negative predictive value 96%.
Capabilities of supine exercise electrocardiography versus exercise radionuclide angiography in predicting coronary events, The ability of supine exercise electrocardiography and exercise radionuclide angiography to predict time to subsequent cardiac events (cardiac death. nonfatal myocardial infarction or late coronary bypass grafting or angioplasty) were compared in 265 patients with normal resting electrocardiograms who were not taking digoxin. All patients had undergone coronary catheterization and were initially treated medically. Follow-up study was performed at a median of 51 months. Separate logistic regression models. which had been previously developed to predict 3-vessel or left main coronary artery disease (CAD). were compared using a Cox regression analysis to predict time to a subsequent cardiac event. The exercise electrocardiography model. consisting of the magnitude of ST depression. exercise heart rate and patient gender. was a powerful predictor (chi-square = 30.8. p less than 0.0001) of subsequent events. The exercise radionuclide angiography model. which included the exercise response of the pressure-volume ratio in addition to the exercise electrocardiography variables. had similar prognostic power (chi-square = 31.8. p less than 0.0001). In a separate analysis considering only cardiac death and nonfatal myocardial infarction. the exercise electrocardiography model remained a significant predictor of events (chi-square = 12.2. p less than 0.001). None of the radionuclide angiography variables added significantly to the prognostic power of the exercise electrocardiography model. Thus. in patients with a normal resting electrocardiogram who are not taking digoxin. the supine exercise electrocardiography model that predicts 3-vessel or left main CAD also predicts future cardiac events. Exercise radionuclide angiography does not provide any additional prognostic information in such patients.
Relation of cardiac output at rest and during exercise to age in essential hypertension, It has been suggested that the decline of cardiac output with age is due to increased prevalence of disease. particularly occult coronary artery disease. Therefore. the relation of cardiac output (direct oxygen Fick method) to age was analyzed in 110 sixteen- to 64-year-old men with World Health Organization stage I or II essential hypertension at the time of the hemodynamic study. who were alive and free of cardiovascular complications 7 years later. At supine and seated rest. during upright bicycle exercise at 50 W and and at peak work load. cardiac output was inversely (p less than 0.01) related to age. These relations were independent of weight and mean intraarterial pressure. Stroke volume decreased with advancing age at supine rest. but not at rest and during exercise in the seated position. Heart rate was not affected by age in the supine position. but was slower in older patients during upright rest and at peak exercise. In conclusion. in patients with essential hypertension who remained free of cardiovascular complications for 7 years. cardiac output was independently and inversely related to age at various levels of activity. These findings suggest that occult cardiovascular disease does not explain the decline in cardiac output with age in patients with essential hypertension.
Comparison of the effects of guanadrel sulfate and propranolol on blood pressure, functional capacity, serum lipoproteins and glucose in systemic hypertension, In a controlled. double-blind. crossover study. the effects of guanadrel sulfate and propranolol on blood pressure (BP) and selected cardiopulmonary and metabolic variables were compared in 15 physically active and moderately hypertensive subjects. Guanadrel sulfate reduced systolic and diastolic BP at rest by -16 and -15 mm Hg. and at maximal exercise by -33 and -13 mm Hg. respectively (p less than 0.005). without affecting submaximal oxygen consumption (VO2). maximal VO2. ventilatory threshold. forced vital capacity. forced expiratory volume in 1 second. or fatigue. as assessed by perceived exertion. In contrast. propranolol significantly decreased diastolic BP at rest (-16 mm Hg) and systolic BP at maximal exercise (-44 mm Hg); however. it significantly decreased submaximal VO2 (-3.9 ml.kg-1.min-1). maximal VO2 (-3.9 ml.kg-1.min-1). ventilatory threshold (-0.3 liters.min-1). minute ventilation at submaximal exercise (-7.3 liters.min-1). forced expiratory volume in 1 second (-0.27 liters). and concomitantly increased the rating of perceived exertion at maximal exercise (1.9 U). Guanadrel sulfate was also associated with significant decreases in mean fasting plasma glucose and total serum cholesterol. whereas propranolol resulted in an increase in serum triglycerides (p less than 0.05). In contrast to propranolol. guanadrel sulfate appears to decrease BP without evoking negative metabolic consequences or impairing exercise tolerance.
Abnormal baroreflex control of heart rate in decompensated congestive heart failure and reversal after compensation, Congestive heart failure (CHF) causes impairment of baroreflex control of heart rate (HR). To determine if this derangement is reversible. the cardiac chronotropic control was assessed in 10 patients with class IV chronic CHF of various etiologies before and after compensation achieved by bed rest. salt restriction. diuretics and vasodilators. Mean time between the 2 studies was 15 +/- 3 days. The management was modified 3 days before the second autonomic evaluation. so as to reestablish the same diet and pharmacologic conditions of the previous study. Compensation led to significant reduction in symptom-based class. body weight. and pulmonary and systemic congestion. Mean +/- standard error of the mean HR responses (beats/min) before and after compensation were. respectively: (1) to atropine (0.04 mg/kg): 10 +/- 2 and 27 +/- 2 (p less than 0.01); (2) to handgrip (30% maximum capacity. 1 minute): 9 +/- 2 and 19 +/- 3 (p less than 0.005); (3) to headup tilt (5 minutes): 4 +/- 3 and 20 +/- 4 (p less than 0.005). Mean +/- standard error of the mean baroreflex sensitivity (ms/mm Hg) of RR responses to phenylephrine and amyl nitrate-induced changes in systolic pressure was. respectively. in each condition: phenylephrine. 0.9 +/- 0.2 and 8 +/- 2.3 (p less than 0.05); amyl nitrate. 0.3 +/- 0.2 and 4.1 +/- 1.1 (p less than 0.05). A significant correlation between improvement in HR responses to atropine and tilt and changes in body weight was obtained. These findings show a reversible component of impaired baroreflex control of HR in severe CHF. possibly due to its congestive effects.
Doppler echocardiographic study of porcine bioprosthetic heart valves in the aortic valve position in patients without evidence of cardiac dysfunction, To study the natural history of the hemodynamic performance of bioprosthetic heart valves. Doppler echocardiograms were recorded in a group of clinically stable patients at 2 and 5 years after replacement of native aortic valves with bioprosthetic valves. Eighteen patients completed a 2-year and 26 patients a 5-year follow-up examination. The effective orifice areas of identical models of bioprosthetic valves (Hancock II) were determined in vitro in a left-sided heart pulse duplicator system. In vivo Doppler-derived effective orifice areas were compared with the in vitro measurements for the same valve size. At both the 2- and 5-year follow-up examinations. the Doppler-derived effective orifice area was significantly less than the in vitro area (p less than 0.0001 at each interval). Ten of 16 valves evaluated serially decreased greater than 0.20 cm2 in the Doppler-derived effective orifice area between studies. The mean decrease in effective orifice area in valves evaluated serially was 0.25 +/- 0.29 cm2 (p less than 0.005). The peak transaortic gradient increased from 21 +/- 6 to 27 +/- 8 mm Hg (p less than 0.01). The mean transaortic gradient increased from 12 +/- 4 to 15 +/- 7 mm Hg (p less than 0.05). It is concluded that serial Doppler echocardiographic studies demonstrate a deterioration in the hemodynamic performance of bioprosthetic valves over time in patients with no symptoms or signs of valvular dysfunction and that Doppler echocardiography may be useful for identifying subclinical bioprosthetic valvular dysfunction.
Postheparin lipolytic activity and plasma lipoprotein response to omega-3 polyunsaturated fatty acids in patients with primary hypertriglyceridemia, The hypotriglyceridemic action of omega-3 (n-3) fatty acids is attributed primarily to reduction in hepatic triglyceride synthesis and reduced secretion of very-low-density lipoproteins (VLDLs). However. increased catabolism of triglyceride-rich lipoproteins was reported and could be due to increased availability of peripheral lipoprotein lipase (LPL) or hepatic lipase (HL). In this study plasma lipoproteins and postheparin activities of LPL and HL were determined in 12 patients with primary hypertriglyceridemia before and during isocaloric substitution of omega-3 fatty acids (10 g/d) for 4 wk. Omega-3 polyunsaturates resulted in 53% and 61% reductions in plasma triglyceride and VLDL-cholesterol concentrations. respectively (P less than 0.0001). However. low-density-lipoprotein (LDL)-cholesterol concentrations increased by 26% (P less than 0.001). Activities of postheparin LPL and HL essentially remained the same. Thus. in patients with primary hypertriglyceridemia. reduction in plasma triglyceride concentrations and increase in LDL-cholesterol concentrations mediated by omega-3 polyunsaturates seem to occur without an increase in LPL or HL activities.
Fat absorption in neonates: comparison of long-chain-fatty-acid and triglyceride compositions of formula, feces, and blood, We studied malabsorption of fat in neonates who were fed either a lard-modified formula (n = 22. gestational age. 33.6 +/- 3.9 wk) or an unmodified formula (n = 14. gestational age. 34.1 +/- 3.7 wk). In both groups fecal lipid consisted almost completely (greater than 90%) of free fatty acids. whose composition was highly correlated with the corresponding formula's fatty acid composition [r = 0.96 (lard modified) and r = 0.99 (standard)]. Both groups had similar relative amounts and compositions of fecal cholesterol esters and triglycerides. Plasma and. to a lesser extent. erythrocyte membrane long-chain-fatty-acid compositions correlated with those of the corresponding formulas. We suggest that the extensive intestinal hydrolysis and limited absorption of dietary lipids is. at least partly. due to lipolysis in the colon. Appearance of triglycerides in the colon may be due to a rapid small-intestinal passage in relation to small-intestinal lipolysis.
Lack of effect of chronic administration of oral beta-carotene on serum cholesterol and triglyceride concentrations, Previous studies suggest that chronic oral administration of retinol and other retinoids causes elevation of plasma triglyceride concentrations. The effects of chronic oral administration of beta-carotene. a carotenoid partially metabolized to retinol. on plasma lipid concentrations have not been well studied; therefore. we studied 61 subjects over 12 mo while they were enrolled in a skin-cancer-prevention study in which patients were randomly assigned to receive either placebo (n = 30) or 50 mg beta-carotene/d orally (n = 31). At study entry and 1 y later. fasting blood samples were obtained for measurement of triglycerides. total cholesterol. HDL cholesterol. retinol. and beta-carotene. Retinol concentrations changed minimally in both groups; beta-carotene concentration increased an average of 12.1 +/- 47 nmol/L in the placebo group and 4279 +/- 657 nmol/L in the active-treatment group. Both groups experienced similar small increases in triglyceride and total cholesterol concentrations and small decreases in HDL cholesterol. Daily oral administration of 50 mg beta-carotene/d did not affect plasma lipid concentrations.
Lactose maldigestion and milk intolerance in healthy Greek schoolchildren, The prevalence of lactose maldigestion in Greek adults is 75% but the age at which the lactase activity starts declining is not known. The prevalences of lactose maldigestion and intolerance were investigated in 150 randomly selected Greek children 5-12 y old by using breath-hydrogen analysis after ingestion of lactose (2 g/kg body wt. maximum 50 g) or 0.240 L of milk. Prevalence of lactose maldigestion increased with age (y = -7.30 + 6.49x. r = 0.88. P = 0.004). being 29.4% and 80.0% at ages 5 and 12 y. respectively. Before testing. the reported prevalences of milk-related symptoms by children with high and low lactose-digestion capacity were 21.1% and 39.7% (chi 2 = 5.96. P = 0.015). respectively. However. the corresponding prevalences of lactose intolerance after ingestion of milk were 7.3% and 8.6% (chi 2 = 0.1. P = 0.72) and only three children had a delta H2 greater than or equal to 20 ppm postprandially. Although intestinal lactase activity declines before age 5 y and many Greek children report milk-related symptoms. true malabsorption and intolerance of lactose after a glass of milk is rarely seen at this age.
Beta-carotene's effects on serum lipoproteins and immunologic indices in humans, Doses of beta-carotene for cancer-prevention trials have been chosen based on epidemiologic data. Mechanisms of the putative antineoplastic effects by beta-carotene are unknown but may involve modulation of the immune system. We measured plasma carotenoid concentrations and selected immunologic indices at baseline and at 2 and 4 wk in 50 healthy humans (5 groups of 10 each) ingesting 0. 15. 45. 180. or 300 mg beta-carotene/d for 1 mo in this randomized placebo-controlled. open-label. parallel study. Plasma beta-carotene concentrations were markedly increased by 2 wk and were correlated with dose. Beta-carotene concentrations plateaued between 2 and 4 wk except for the 300-mg group. Thus. we developed a dose-concentration curve to optimize beta-carotene-dose selection to achieve target plasma concentrations. We were unable to identify any effects of beta-carotene ingestion on the immunologic indices studied. but modest increases in high-density-lipoprotein cholesterol were observed in all beta-carotene-treated groups.
Isotonic high-sodium oral rehydration solution for increasing sodium absorption in patients with short-bowel syndrome, We compared the effect of a standard oral rehydration solution and a high-sodium polymeric-glucose solution on sodium absorption in short-bowel syndrome. Six patients with high jejunostomy were tested in a random order with the standard solution or a solution containing maltodextrins (18 g Glucidex 12/L) enriched with 2.5 g NaCl/L. Solutions were administered via a nasogastric tube at a rate of 2 mL/min. Jejunal effluent was collected during an 8-h period. The net 8-h fluid absorption was not significantly different in the two periods. Glucose absorption was greater than 90% of the administered amount for both solutions. Net sodium absorption was greater for the maltodextrin solution than for the standard solution (56 +/- 12 vs 24 +/- 20 mmol. P less than 0.05). We conclude that replacement of glucose with maltodextrins and addition of sodium in the standard oral rehydration solution results in improved sodium absorption in short-bowel syndrome.
Empiric antibiotic selection by physicians: evaluation of reasoning strategies, The objectives of the study were to evaluate the appropriateness of empiric antibiotic selection by housestaff treating medical patients with bacteremia. The design was a prospective. observational study at a university-affiliated hospital. Seventy-eight patients with bacteremia were evaluated. A clinical grade of acceptable or not acceptable was assigned to each antibiotic prescription by a consensus panel. The consensus panel found that 34.6% of antibiotic prescriptions were unacceptable (clinical grade). At least one flaw in the chain of reasoning was found in 56.4% of the 78 cases evaluated. Assessment of the clinical setting was correct in 94.9% of the cases; the portal of entry was identified in 91%; adequate knowledge of the bacterial flora at the suspected site of infection was found in 69%; the diagnostic workup was appropriate in 81%. and the correct antibiotic susceptibility patterns were given in 72%. A correct chain of reasoning was more likely to result in an acceptable clinical grade than flawed reasoning (p less than 0.005). However. an appropriate antibiotic selection was made by some physicians despite flawed reasoning. and inappropriate antibiotic selection occurred in a few cases despite fautless reasoning. In 3.8% of cases. unexpected organisms appeared in blood culture. Prescription of broad spectrum antibiotics may then be learned response. If so. educational efforts that emphasize narrow. rather than broad spectrum prescribing may be inadequate to change physician prescribing habits.
Brain uptake of glucose in diabetes mellitus: the role of glucose transporters, It is not known if the diabetes-related reduction in blood-brain barrier (BBB) transport of glucose is due to a change in the functional capacity of transporters or to an as yet unidentified mechanism occurring at the plasma membrane or cytoplasm. To increase our understanding of this problem. the cerebral blood flow. the brain uptake index (BUI) of 3-O-methyl glucose and the concentration of 3H-cytochalasin B binding sites were determined in diabetic rats and diabetic rats treated with insulin. The BUI of 3-O-methyl glucose was significantly reduced (less than 0.001) in diabetic rats (32.7 +/- 1.2%) compared to control rats (41.9 +/- 1.0%). This change could not be attributed to an alteration in cerebral blood flow or to a non-specific change in BBB permeability. Normalization of blood glucose with insulin therapy corrected the BUI measurements in diabetic rats (42.2 +/- 1.4%). The level of measurable glucose transporters measured with 3H-cytochalasin B binding assay did not appear to be reduced in the diabetic brain microvessels. The data indicate that the reduced brain uptake of glucose in chronic hyperglycemia can occur in the absence of a change in glucose transporter concentration.
Aplastic anemia associated with antithyroid drugs, Prognosis in aplastic anemia is usually linked to the degree of hypoplasia in the bone marrow and pancytopenia in the blood. The authors were. therefore. intrigued when a patient with methimazole-associated aplastic anemia who satisfied criteria for severe disease recovered rapidly and completely once her drug was withdrawn. Review of the English language literature revealed ten fully documented cases of aplastic anemia associated with use of the antithyroid drugs methimazole. carbimazole. and propylthiouracil. Analysis of the ten and of an eleventh case presented here indicated that the disorder is typically characterized by severe pancytopenia and profound marrow hypoplasia. yet surprisingly good prognosis. ie. minimum survival of more than 70% with partial or complete recovery from symptoms and cytopenias in survivors within 2-5 weeks. The only deaths. both in the 1950s. were from brain hemorrhage in patients who were not transfused with platelets. The discrepancy between the clinical and laboratory severity of antithyroid drug-associated aplasia. on the one hand. and its relatively good prognosis and short term course. on the other. should be kept in mind when considering these patients for bone marrow transplantation or for therapy with antithymocyte globulin.
Hereditary hemorrhagic macular dystrophy, We treated two brothers who had a hemorrhagic macular lesion in one eye; a similar problem affected the fellow eye of both patients within eight months. Generalized fine granularity of the retinal pigment epithelium and peripheral iris transillumination defects were observed in both siblings. A study of the family suggested that the disorder was dominantly inherited and probably was Sorsby's pseudoinflammatory macular dystrophy. The macular lesions in one brother were treated by argon green laser photocoagulation and in the other brother by krypton red laser photocoagulation. Although the brother treated by krypton red laser photocoagulation attained better final visual function. additional differences in treatment methods also may have contributed to the final outcome.
A simple transposition procedure for complicated strabismus, We combined a recession or resection of recti muscles with a vertical or horizontal transposition to correct a complicated paralytic ocular deviation in eight patients. The transposed muscles were reattached to the globe parallel to the spiral of Tillaux and adjacent to the paralyzed muscle. Postoperatively. seven patients demonstrated fusion in the primary position or required a slight head turn to fuse. There were no surgical complications. and no patient developed symptomatic cyclotropia. diplopia. or anterior segment ischemia.
A comparison of total and partial tenonectomy with trabeculectomy, We compared the results of two methods of tenonectomy at the time of trabeculectomy. Of 49 eyes. 23 were randomly assigned to a partial tenonectomy and 26 to a total tenonectomy. There was no statistically significant difference in the success rate between the two surgical groups using an upper limit of intraocular pressure of either 18 or 21 mm Hg as the criterion for success. There was no difference in the need for postoperative medications or further surgical intervention between the two groups. Although certain advantages exist with each technique. these findings suggest that equivalent results can be anticipated with either a total or partial tenonectomy.
Therapeutic ultrasound for the treatment of glaucoma [published erratum appears in Am J Ophthalmol 1991 Jul 15;112(1):105, A multicenter clinical trial of therapeutic ultrasound for the treatment of glaucoma included 20 centers in the United States in which 1.117 treatments were performed on 880 eyes. The study was limited to patients with refractory glaucoma who had not benefited from conventional medical and surgical techniques. Approximately 782 of 1.117 treatments (70%) showed an initial decrease in intraocular pressure from a pretreatment mean of 38.1 mm Hg to 22 mm Hg or less. By Kaplan-Meier survival analysis. the single treatment success rate (intraocular pressure between 6 and 22 mm Hg) was 48.7% at six months posttreatment. When retreatment was used subsequent to failure. the one-year multitreatment success rate was 79.3%. The most common complications were an immediate posttreatment intraocular pressure increase lasting a few hours and mild iritis. Other complications included scleral thinning in 28 of 1.117 treatments (2.5%) and phthisis bulbi in 12 of 1.117 treatments (1.1%).
The intratracheal administration of endotoxin and cytokines. III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin- and IL-1-induced acute inflammation, Endotoxin. a lipopolysaccharide (LPS) component of gram-negative bacteria. induces alveolar macrophages to express interleukin-1 (IL-1). Lipopolysaccharide and IL-1 both cause severe acute neutrophilic inflammation in the lung after intratracheal injection. suggesting that LPS-induced IL-1 expression contributes to the pathogenesis of LPS-induced acute inflammation. In the present study. the role of IL-1 in LPS-induced acute pneumonia was investigated by quantitating the acute inflammation occurring at 6 hours after the intratracheal injection of LPS as compared to the same timepoint after the intratracheal coinjection of LPS and IL-1 receptor antagonist (IL-1ra). The IL-1ra was found to inhibit LPS-induced acute inflammation (P greater than 0.0001) as measured by the number of neutrophils recovered in bronchoalveolar lavage. The LPS-induced emigration of neutrophils was inhibited by as much as 45%. Recombinant IL-1 beta-induced neutrophil emigration into the lung was inhibited by 95% when IL-1ra was coinjected intratracheally with IL-1 beta. Coinjection of recombinant IL-1 beta and LPS increased the neutrophilic exodus as compared to the intratracheal injection of either agent alone. Intratracheal injection of LPS induces a progressive increase in IL-1ra mRNA expression in whole-lung RNA preparations. suggesting that endogenous IL-1ra may play an important role as a negative feedback mechanism to downregulate LPS initiated IL-1-mediated acute inflammation. In conclusion IL-1ra inhibits both LPS- and IL-1-induced neutrophilic inflammation and may therefore prove clinically useful as an anti-inflammatory agent for the therapy of either septic or aseptic IL-1-mediated acute inflammation.
Effects of the phospholipase inhibitor mepacrine on injury in ischemic and metabolically inhibited adult isolated myocytes, The phospholipase inhibitor mepacrine has been shown to delay cell death of metabolically inhibited cultured cardiomyocytes. The present study was initiated to determine if mepacrine also delays cell death and development of osmotic fragility of both metabolically inhibited and ischemic adult rat cardiomyocytes. Isolated myocyte suspensions were incubated with 3 mmol/l (millimolar) iodoacetic acid and 6 mmol/l amytal (inhibited) or were pelleted into a slurry and layered with oil (ischemic) in the presence and absence of 10 or 50 mumol/l (micromolar) mepacrine. Rates of contracture. cell viability as determined by trypan blue permeability. cell viability after osmotic swelling in 170 mOsm media (osmotic fragility). and cell morphology were monitored. Mepacrine had no effects on rates of contracture. but was found to significantly delay cell death during isotonic incubations of both metabolically inhibited and ischemic cells. In contrast. mepacrine had no effect on the development of osmotic fragility. Incubation of metabolically inhibited myocytes in calcium-free media did not delay contracture or cell injury. but did attenuate the protective effects of mepacrine. This study confirms previous reports that mepacrine protects cells from injury. extends the observations of protection to ischemic isolated adult myocytes. but shows that development of osmotic fragility is not inhibited by mepacrine.
Development of intrapancreatic transplantable model of pancreatic duct adenocarcinoma in Syrian golden hamsters, Intrapancreatic and subcutaneous (SC) inoculation of cultured pancreatic cancer cells. derived from an induced primary pancreatic cancer in a Syrian hamster. resulted in tumor take in all recipient hamsters. The intrapancreatic allografts grew rapidly. were invasive. and metastasized into the lymph nodes and liver in 2 of 9 cases. In comparison. SC tumors grew relatively slower and formed a large encapsulated mass without invasion and metastases. Histologically. tumors of both sites showed fairly well-differentiated adenocarcinomas of ductal/ductular type resembling the induced primary cancer. Similar to the primary induced pancreatic cancers. tumor cells of both allografts expressed blood-group-related antigens. including A. B. H. Le(b). Le(y). Le(x). and tumor-associated antigen TAG-72. The tumor cells did not express Le(a). CA 19-9. 17-1A. or DU-PAN-2. The expression of these antigens was retained in the metastases and presented the same patterns of reactivity as the allografts. Thus intrapancreatic transplantation provides a rapid model for production of pancreatic cancer with morphologic similarities to human pancreatic cancer.
Contrasting roles for tumor necrosis factor in the pathogeneses of IgA and IgG immune complex lung injury, Recent studies suggest that development of acute gamma G immunoglobulin (IgG) immune complex lung injury is partially dependent on a tumor necrosis factor (TNF)-dependent mechanisms of neutrophil (PMN) recruitment. The authors have sought to further define the role of intrapulmonary TNF in IgG alveolitis and to examine its role in IgA immune complex alveolitis. a neutrophil-independent model of acute lung injury. IgG immune complex lung injury resulted in a marked rise in intrapulmonary TNF activity accompanied by progressive pulmonary PMN accumulation. Intratracheal instillation of neutralizing concentrations of anti-TNF markedly reduced PMN influx measured at 4 hours but had no effect on PMN recruitment quantitated at 2 hours. IgA immune complex deposition resulted in acute lung injury accompanied by increased numbers of intrapulmonary mononuclear phagocytes but few neutrophils. Lung lavage fluids obtained from IgA immune complex-injured rats contained both neutrophil and monocyte chemotactic activities. albeit at twofold to fourfold lower concentrations than observed in IgG-mediated alveolitis. In contrast to IgG complex-mediated alveolitis. lung lavage fluids from IgA-injured rats contained no TNF activity. Intratracheal administration of anti-TNF antibodies had no effect on the development of IgA lung injury as assessed by morphology and measurements of vascular permeability. In vitro exposure of isolated alveolar macrophages to performed IgG immune complexes resulted in dose-dependent TNF secretion. while exposure to IgA complexes resulted in very low levels of TNF secretion. These data suggest that TNF-mediated pulmonary neutrophil recruitment (in IgG lung injury) is manifest chiefly in the late phase (approximately 4 hours) of developing alveolitis. The virtual absence of intrapulmonary TNF activity in evolving IgA immune complex alveolitis may in part account for the limited PMN recruitment observed in this model.
S-100 protein antibodies do not label normal salivary gland myoepithelium. Histogenetic implications for salivary gland tumors, Neoplastically modified myoepithelial cells have a key role in developing the histologic characteristics of some salivary gland tumors. S-100 protein expressed in certain of these tumors is suggested to support this role. as the principal component in the human salivary gland reported to be S-100 protein-positive is myoepithelium. Confirmation of such an important aspect is required. Immunoperoxidase staining of parotid salivary gland shows considerably different patterns obtained with antibodies to S-100 protein. neuron-specific enolase. and neurofilaments compared with those for muscle-specific actin and cytokeratin 14; many more cells and their processes associated with acini and ducts are evident with the latter two antibodies. Double immunofluorescent staining with antibodies to either S-100 protein or neuron-specific enolase combined with muscle-specific actin does not reveal colocalization of these antigens in myoepithelial cells. The former localize only to nerve fibers adjacent to. but separate from. acini. and the latter only to myoepithelial cells. It is apparent that S-100 protein staining of the rich network of unmyelinated nerves in the interstitial tissues. evident ultrastructurally. has been misinterpreted as myoepithelium. This result has important implications for histogenetic classifications of salivary gland tumors.
Platelet-derived growth factor-BB and transforming growth factor beta 1 selectively modulate glycosaminoglycans, collagen, and myofibroblasts in excisional wounds, Recombinant platelet-derived growth factor (PDGF) and transforming growth factor beta 1 (TGF-beta 1) influence the rate of extracellular matrix formed in treated incisional wounds. Because incisional healing processes are difficult to quantify. a full-thickness excisional wound model in the rabbit ear was developed to permit detailed analyses of growth-factor-mediated tissue repair. In the present studies. quantitative and qualitative differences in acute inflammatory cell influx. glycosaminoglycan (GAG) deposition. collagen formation. and myofibroblast generation in PDGF-BB (BB homodimer)- and TGF-beta 1-treated wounds were detected when analyzed histochemically and ultrastructurally. Although both growth factors significantly augmented extracellular matrix formation and healing in 10-day wounds compared with controls (P less than 0.002). PDGF-BB markedly increased macrophage influx and GAG deposition. whereas TGF-beta 1 selectively induced significantly more mature collagen bundles at the leading edge of new granulation tissue (P = 0.007). Transforming growth factor-beta 1-treated wound fibroblasts demonstrated active collagen fibrillogenesis and accretion of subfibrils at the ultrastructural level. Myofibroblasts. phenotypically modified fibroblasts considered responsible for wound contraction. were observed in control. but were absent in early growth-factor-treated granulating wounds. These results provide important insights into the mechanisms of soft tissue repair and indicate that 1) PDGF-BB induces an inflammatory response and provisional matrix synthesis within wounds that is qualitatively similar but quantitatively increased compared with normal wounds; 2) TGF-beta 1 preferentially triggers synthesis and more rapid maturation of collagen within early wounds; and 3) both growth factors inhibit the differentiation of fibroblasts into myofibroblasts. perhaps because wound contraction is not required. due to increased extracellular matrix synthesis.
Murine retroviral neurovirulence correlates with an enhanced ability ofvirus to infect selectively, replicate in, and activate resident microglial cells [published erratum appears in Am J Pathol 1991 May;138(5):1058, To determine the biologic basis of ts1 MoMuLV neurovirulence in vivo. newborn CFW/D mice were inoculated with neurovirulent ts1 MoMuLV and nonneurovirulent wt MoMuLV and the temporal response to virus infection in the central nervous system (CNS). spleen. and thymus was studied comparatively. Experimental procedures included single and double labeling in situ immunohistochemistry with selective morphometric analyses. and steady state immunoblotting of viral proteins. Cellular targets for virus infection were identical for both ts1 and wt MoMuLV and consisted sequentially of 1) splenic megakaryocytes. 2) splenic and thymic lymphocytes. 3) CNS capillary endothelial cells. and 4) CNS pericytes and microglia. Resident microglial cells served as the major reservor and amplifier of virus infection in the CNS of ts1 MoMuLV-infected mice; a similar but much less significant role was played by microglia in wt MoMuLV-infected mice. The genesis and progression of severe spongiform lesions in ts1 MoMuLV-infected mice were both temporally and spatially correlated with amplified virus infection of microglia. and hyperplasia and hypertrophy of both virus-infected and nonvirus-infected microglial cells. Direct virus infection of neurons was never observed. The development of clinical neurologic disease and spongiform lesions in ts1 MoMuLV-infected mice correlated with the accumulation of both viral gag and env gene products in the CNS; there was no selective accumulation of env precursor polyprotein Pr80env. When compared to wt MoMuLV-infected mice. the neurovirulence of ts1 MoMuLV-infected mice occurred by an enhanced ability to replicate in the CNS and to infect and activate more microglia. rather than by a fundamental change in cellular tropism or topography of virus infection.
Epithelial cells immortalized by human papillomaviruses have premalignant characteristics in organotypic culture, Three HPV-16--and four HPV-18--immortalized human foreskin keratinocyte cell lines were analyzed on organotypic epidermal raft cultures at various passage levels. This culture system allowed normal cultured keratinocytes to stratify and differentiate in a manner similar to normal epidermis. All seven HPV-immortalized cell lines displayed epidermal morphologies on organotypic cultures. which were clearly abnormal and resembled premalignant lesions in vivo. Features of premalignant lesions that were shared by all of the HPV-immortalized cell lines included disorganized tissue architecture. mitotic cells present throughout the living layers of the epidermal sheet. abnormal mitoses. enlarged nuclei. and variable cell size and shape. Most HPV-immortalized cell lines were stable in terms of epidermal morphology with long-term passage in culture. Two of the HPV-18--immortalized cell lines. however. lost all morphologically apparent terminal squamous differentiation potential after long-term passage in monolayer culture. These results strongly support the idea that immortalization of squamous epithelial cells in culture by HPV-transforming genes generates a morphologically premalignant cell.
Hairless micropig skin. A novel model for studies of cutaneous biology, Reported here is the structural and immunohistochemical similarities between the Yucatan hairless micropig (HMP) skin and that of humans. Hairless micropig skin surface was composed of complex intersecting furrows that created geometric patterns remarkably similar to human skin surface glyphics. The dermal--epidermal interface consisted of undulant downgrowths that interdigitated with dermal papillae. Hairless micropig epidermis contained two morphologically distinct populations of basal keratinocytes (serrated and nonserrated). Similar heterogeneity has been seen only in human epidermis and primate palmar epidermis. Immunohistochemistry revealed that the HMP epidermis is reactive with monoclonal and polyclonal antisera to keratin proteins. Melanocytes reactive with antisera to S-100 protein. as in human skin. also were observed in HMP epidermis. Organization of dermal extracellular matrix. including collagen and elastic fibers. and the organization and reactivity of the microvasculature with antisera to factor VIII. were consistent with human skin. The costicosteroid-induced atrophy and subsequent rebound phenomenon after withdrawal of steroid observed in HMP skin was similar with that observed in humans. It is concluded that HMP skin approximates human skin significantly more precisely than most existing species and is an excellent model for studies of cutaneous physiology and pharmacology.
Secondary deposition of beta amyloid within extracellular neurofibrillary tangles in Alzheimer-type dementia, The hippocampal areas of 34 autopsy specimen brains from aged demented and nondemented subjects were examined using double staining of Bodian and beta protein. In 18 cases (75.5 +/- 7.4 years old). none of the extracellular neurofibrillary tangles (E-NFTs) were immunoreactive with beta protein. In 16 cases (82.9 +/- 5.4 years old). the minority of E-NFTs were immunoreactive with beta-protein antiserum. These beta-immunoreactive E-NFTs frequently appeared in the areas having senile plaques. while they were not observed in the area lacking beta-immunoreactive senile plaques. The ultrastructure of beta-immunoreactive E-NFTs revealed that they consisted of extracellular amyloid fibrils. extracellularly located bundles of paired helical filaments. astroglial processes and degenerating neurites. These findings suggest that the beta immunoreactivity of E-NFTs comes from secondary deposition of amyloid fibrils.
Induction of inflammatory cell infiltration and necrosis in normal mouse skin by the combined treatment of tumor necrosis factor and lithium chloride, Previously we reported that lithium chloride (LiCl) potentiates tumor necrosis factor (TNF)-mediated cytotoxicity in vitro and in vivo. Here. using a murine normal skin model. it is shown that a subcutaneous injection of TNF plus LiCl induces acute dermal and subcutaneous inflammation and necrosis. Histology showed a marked initial dermal and subcutaneous neutrophil infiltrate by approximately 2 hours. followed by a predominantly mononuclear infiltrate by 24 hours. which remained present for several days. Tumor necrosis factor or LiCl alone induced negligible inflammation. disappearing after 6 hours; furthermore there was never necrosis or ulceration of the overlying skin in case of single-agent application. In vitro studies showed that the combination of TNF and LiCl. but not either agent alone. was directly cytotoxic to fibroblastic cells of murine skin. No inflammatory infiltration was visible in tumors treated intratumorally or perilesionally with TNF plus LiCl. although the latter treatment resulted in a perilesional leukocyte infiltration. Furthermore the combination of TNF and LiCl had no effect on macrophage cytotoxicity to L929 tumors.
Expression of VLA-alpha 2, VLA-alpha 6, and VLA-beta 1 chains in normal mucosa and adenomas of the colon, and in colon carcinomas and their liver metastases, 'Very late antigen' (VLA) proteins are members of the integrin superfamily with cell-surface receptor function and are involved in the cell-cell matrix interaction. They are heterodimers with a common beta 1 chain and different alpha chains counted through VLA-1 to VLA-6. The VLA-2 complex (alpha 2/beta 1) was found to act as collagen receptor on platelets and the VLA-6 complex (alpha 6/beta 1) as laminin receptor. Using monoclonal antibodies and an indirect immunoperoxidase method. we investigated the expression of VLA-alpha 2. VLA-alpha 6. and VLA-beta 1 chains in 20 normal colonic mucosa samples. in 20 colonic adenomas. and in 96 carcinomas together with 10 accompanying liver metastases. All three proteins were expressed throughout the colonic epithelium. except for VLA-alpha 2. which was present in the cryptic gland but was absent on the mucosal surface in some cases. In general. adenomas were strongly positive for the VLA proteins but 3 of 20 cases showed focal VLA-alpha 2-negative areas. The carcinomas revealed considerable heterogeneity of VLA-alpha 2 expression; ie. 59 tumors were completely positive. 35 tumors revealed a focal loss of antigen. and 2 cases were negative. This reduced antigen expression was statistically associated with Dukes' stage C/D (P = 0.003). VLA-alpha 6 was expressed throughout in all tumors. VLA-beta 1 was found extensively expressed in 77 carcinomas. partially expressed in 17 carcinomas. and was absent in 2 carcinomas. As compared to their primary tumors. liver metastases showed roughly corresponding patterns of antigen expression. The down regulation/loss of VLA proteins in a subset of epithelial colon tumors might cause a disturbed cell-cell/cell-matrix interaction that might augment the invasive property of their cells.
Basal cell-specific and hyperproliferation-related keratins in human breast cancer, In normal breast tissue and in noninvasive breast carcinomas. various keratin-14 antibodies were reactive predominantly with the basal/myoepithelial cell layer. although mainly in terminal and larger ducts luminal cells sometimes also were stained. A similar reaction pattern was found with an antibody directed against keratin 17. although this antibody was more often found negative than keratin 14 in the pre-existing myoepithelial cells in intraductal carcinomas. Furthermore antibodies reactive with hyperproliferation-related keratins 6 and 16 were used. One of these (LL025) was completely negative in normal breast tissue and noninvasive breast carcinomas. However 10% of the invasive carcinomas were diffusely or focally positive with this latter antibody. while in 18 of 115 cases of invasive breast carcinomas studied. a basal cell phenotype was detected. A relatively high concordance was found between the carcinomas immunostaining with the basal cell and the hyperproliferation-related keratins. but not between these markers and the proliferation marker Ki-67. This supports the conclusion that basal cells in breast cancer may show extensive proliferation. and that absence of Ki-67 staining does not mean that (tumor) cells are not proliferating.
Cultured human atherosclerotic plaque smooth muscle cells retain transforming potential and display enhanced expression of the myc protooncogene, The proliferation of vascular smooth muscle cells (SMC) is critical to atherosclerotic plaque formation. The monoclonal hypothesis proposes that the stimulus for this SMC proliferation is a mutational event. Here we describe a procedure for growing human plaque smooth muscle cells (p-SMC) in culture. We show that p-SMCs derived from two patients differ from SMC cultured from normal vascular tissue in expression of the protooncogene myc. One p-SMC strain was extensively characterized; these diploid. karyotypically normal cells have a finite life span in culture. Ultrastructural examination revealed two populations. one with classic contractile SMC appearance. the other. modulated to a synthetic state. Northern blotting showed a 2- to 6-fold and a 6- to 11-fold enhanced expression of myc by p-SMC. compared to SMC derived from healthy human aorta (HA-SMC) and saphenous vein (HV-SMC). respectively. In contrast. the p-SMC and HV-SMC expressed similar levels of message for the genes N-myc. L-myc. Ha-ras. fos. sis. myb. LDL receptor. EGF receptor. IGF I receptor. IGF II. and HMG CoA reductase. Finally. although p-SMCs are not tumorigenic. DNA isolated from these cells is positive in the transfection-nude mouse tumor assay. Myc. however. does not appear to be the transforming gene because no newly introduced human myc gene was detected in the p-SMC-associated nude mouse tumor. Thus human atherosclerotic p-SMCs possess both an activated myc gene and a transforming gene that is retained throughout many cell passages.
Traditional versus laparoscopic cholecystectomy, Laparoscopic cholecystectomy is a minimally invasive procedure whereby the gallbladder is removed using laparoscopic techniques. The indications are similar to those for elective traditional cholecystectomy. but selection of patients is important for success. Contraindications are currently evolving. Patients with advanced cholecystitis. abdominal sepsis. ileus. bleeding disorders. pregnancy. and morbid obesity should not undergo this procedure. The procedure requires good traditional surgical skills. as well as additional laparoscopic (and laser) skills. Operative time is slightly longer than for traditional cholecystectomy. but decreases with experience. Morbidity is low. but there is a concern about bile duct injuries. Mortality is very low (0%) and is comparable to traditional cholecystectomy (0.4%). The major advantages of laparoscopic cholecystectomy are the short hospital stay (average: 2 days) and early return to normal activity (7 days). This results in a reduction in hospital costs. Adequate training and credentialing are important processes to foster good patient outcomes.
Laparoscopic cholecystectomy, With more than 500.000 cholecystectomies performed per year. great interest has developed in laparoscopic cholecystectomy. The procedure offers the patient reduced hospital stay. faster return to work. less pain. and improved cosmetic results. In September 1988. we developed a technique of performing laparoscopic cholecystectomy that we have now performed in more than 800 cases with good results. The technique allows the surgeon to fully evaluate the common duct via operative cholangiography and has allowed us to use a laparoscopic approach in all patients who were candidates for cholecystectomy. The technique offers a minimally invasive alternative to open cholecystectomy.
The Los Angeles experience with laparoscopic cholecystectomy, Surgeons should be competent in diagnostic laparoscopy before performing laparoscopic cholecystectomy (LC). Well-structured and endorsed courses with experienced faculty are important. Within 12 months. 418 LCs were performed in our hospital. The number of open cholecystectomies decreased to one third of all cholecystectomies performed. Cholangiography was attempted routinely and the duct was successfully cannulated in 90%. Inquiries were made at 6 other hospitals within a 5-mile radius where a total of 220 LCs were performed. The following gray areas need to be addressed: patients with slightly increased liver function tests but no jaundice. and unsuspected stones discovered by cholangiography. New projects are in progress to explore the common bile duct via the cystic duct or directly through the common bile duct with insertion of a T tube. The authors recommend proper training as well as caution and sound judgment before commencing with LC.
The European experience with laparoscopic cholecystectomy, A retrospective survey of 7 European centers involving 20 surgeons who undertook 1.236 laparoscopic cholecystectomies was performed. The procedure was completed in 1.191 patients. Conversion to open cholecystectomy was necessary in 45 patients (3.6%) either because of technical difficulty (n = 33). the onset of complications (n = 11). or instrument failure (n = 1). There were no deaths reported. and the total postoperative complication rate was 20 of 1.203 (1.6%). with 9 being serious complications requiring laparotomy. The total incidence of bile duct damage was 4 of 1.203. The median hospital stay was 3 days (range: 1 to 27 days) and the median time to return to full activity after discharge was 11 days (range: 7 to 42 days).
Complications of laparoscopic cholecystectomy, The emergence of laparoscopic cholecystectomy as a viable alternative to traditional cholecystectomy has been greeted with enthusiasm by the surgical community. This new technique is not without complications. both potential and real. The complications associated with diagnostic laparoscopy are well documented. as are those associated with traditional cholecystectomy. All of these may also be seen with laparoscopic cholecystectomy. The incidence of their occurrence. however. may vary. It remains too early to evaluate the complication rates from this new procedure. as reports of large series are just beginning to emerge. Early reports are encouraging but caution that bile duct injury. hemorrhage. and even death may occur. Early enthusiasm for this new method must be tempered with care in its practice if complication rates are to be maintained at an acceptable level and the procedure is to earn a permanent place in the armamentarium of the surgeon.
Interruption of professional and home activity after laparoscopic cholecystectomy among French and American patients, With a laparoscopic approach. patients can undergo cholecystectomy with a shorter hospitalization. minimal pain. and quicker recovery. It has not been demonstrated. however. that patients actually return to work after laparoscopic cholecystectomy faster than the traditional 4- to 6-week absence from work after a standard open procedure. A survey of 104 French and 84 American patients undergoing laparoscopic cholecystectomy revealed that postoperative discomfort was completely resolved in 2 weeks in 73% of French and 93% of American patients. All but 11 French and 5 American patients were back to normal home activities by 2 weeks after the operation. Of the 35 American and 40 French patients who had professional activity outside the home. 63% and 25%. respectively. returned to work within 14 days. Five (14%) of the American patients and 12 (30%) of the French patients returned to work 4 weeks or more after the operation. The amount of physical activity on the job correlated with the period off work. but. interestingly. at least six patients with very hard physical activity at work (including construction workers) were able to return to full work activity within 1 week. These data suggest that early return to work is possible and that pain resolves quickly after laparoscopic cholecystectomy. The economic benefit of having patients back on the job quickly. however. may be less than expected until cultural norms change with regard to leave of absence after major surgery.
Training, credentialling, and granting of clinical privileges for laparoscopic general surgery, Despite the lack of scientific data comparing it with traditional open operations. laparoscopic surgery has gained rapid acceptance and implementation by general surgeons. Individual hospitals. which have the responsibility for developing their own privileging criteria. are searching for guidance as to the amount and type of additional training required to grant clinical privileges in laparoscopic general surgery. Laparoscopic surgery involves techniques different from those learned during general surgery residency training. Therefore. until such techniques are regularly included in general surgery residency programs. additional training for and granting of separate privileges in laparoscopic surgery are appropriate. Adequate training for surgeons already experienced in abdominal and biliary tract surgery can be acquired through a preceptorship in diagnostic laparoscopy. attending a course in laparoscopic surgery that includes both didactic instruction and live animal experience. assisting with the procedures in humans. and being proctored and certified as competent by an experienced general surgeon.
Clinical utility of a position-monitoring catheter in the pulmonary artery, Unsuspected distal migration of the tip of the pulmonary artery catheter may cause life-threatening complications. We prospectively evaluated the clinical utility of the PA Watch Catheter in 25 patients after cardiac surgery by hourly measurements of pulmonary artery (distal lumen). right ventricular (middle lumen). and central venous (proximal lumen) pressures. The catheter was considered to be in the proper position when the middle lumen port. located 10 cm from the tip. transmitted a right ventricular pressure waveform. Satisfactory initial catheter placement was obtained in 24 of 25 patients. During the 28.4 +/- 1.8 h of postoperative monitoring. clinically unsuspected distal catheter migration. indicated by the presence of a pulmonary artery pressure waveform in the middle lumen port. occurred in 12 of the 25 patients (48%). In these patients. 20 episodes occurred and required catheter withdrawal distances of 1.8 +/- 0.3 cm (range 1-6 cm). The PA Watch Catheter proved to be a useful indicator of unsuspected distal catheter migration in the postoperative period. The PA Watch Catheter allows assessment of catheter tip placement in the proximal pulmonary artery and may decrease catheter-induced complications.
Atracurium decay and the formation of laudanosine in humans, Several groups of investigators have reported that the plasma concentrations of laudanosine. a metabolite of atracurium. are high immediately after administration of atracurium and thereafter decline. Such a time profile of a metabolite in plasma is very unusual. The authors describe a model of atracurium decay and laudanosine disposition that satisfactorily explains these data. The model reveals the following: 1) each atracurium molecule is degraded into two of laudanosine; 2) the generation of laudanosine occurs through two processes--a rapid one. involving approximately 31% of the atracurium dose and proceeding with a half-life of 0.25 min. and a slower one. involving the residual 69% and proceeding with a half-life of 51 min; 3) atracurium degradation by Hofmann elimination proceeds in the central and the noncentral compartments; 4) laudanosine formed from atracurium gains access to its central compartment and disappears from plasma in a biexponential pattern; 5) in cirrhotic patients. only 18% of the atracurium dose is degraded rapidly and laudanosine is disposed of more slowly. The authors propose that the rapid degradation of atracurium in plasma proceeds through a nucleophilic substitution reaction. with plasma nucleophiles substituting for the laudanosine moiety in atracurium. Because both laudanosine moieties in atracurium are required to establish and sustain plasma concentrations of laudanosine. excretion of atracurium or its degradation through pathways not generating laudanosine must be small.
The induction dose of propofol in infants 1-6 months of age and in children 10-16 years of age, The propofol dose needed for satisfactory induction of anesthesia was determined in 22 infants 1-6 months of age and 22 children 10-16 yr of age. A single bolus of propofol was given over 10 s. Thirty seconds after injection the lid reflex was tested and the anesthesia mask was applied. The patient was considered to be asleep if there were no gross movements during the next 30 s while the patient breathed O2. The dose required for satisfactory induction in 50% of patients (ED50) (+/- SE) was 3.0 +/- 0.2 mg/kg in infants and 2.4 +/- 0.1 mg/kg in older children (P less than 0.02). Pain on injection occurred in 50% of the infants and 18% of the children.
Enhanced mobilization of intracellular Ca2+ induced by halothane in hepatocytes isolated from swine susceptible to malignant hyperthermia, Halothane. in a dose-dependent manner. induced the release of intracellular Ca2+ in hepatocytes prepared from swine. The magnitude of the release induced by halothane was greater for hepatocytes prepared from animals susceptible to malignant hyperthermia (MH) than for those from normal swine. Two different methods were used to ascertain the release of Ca2+ induced by halothane: 1) the release of 45Ca2+ from nonmitochondrial stores of saponin-permeabilized hepatocytes was measured; and 2) changes in luminescence from intact hepatocytes loaded with the Ca2(+)-sensitive photoprotein aequorin were recorded. It was also observed that. although 1.4.5-inositol trisphosphate (IP3). guanosine-5-triphosphate. and arachidonic acid all induced a significant release of 45Ca2+ from permeabilized swine hepatocytes. only the quantities of 45Ca2+ released by IP3 were significantly greater for the hepatocytes prepared from the animals susceptible to MH. These data indicate an abnormal Ca2+ homeostasis in hepatocytes isolated from swine susceptible to MH. which supports the hypothesis that membrane systems from multiple organs may be affected in this genetic disorder.
The dynamic flexometer: an instrument for the objective evaluation of spasticity, Anesthesiologists may care for patients who have spasticity in the operating room or pain clinic. A number of therapeutic modalities for treatment of spasticity exist. but there are few simple objective methods for evaluating their effect. We describe one instrument. the Dynamic Flexometer. that measures the force required to move the limb passively through its maximum range of motion. The data presented validate the instrument's reliability. Two clinical cases presented here demonstrate the instrument's utility. This device may be of value to anesthesiologists involved in the care of patients with spasticity.
Cellular immunity in current active pulmonary tuberculosis, A group of 10 patients with recently diagnosed pulmonary TB were studied and compared to 10 bacillus Calmette-Guerin (BCG) immunized healthy individuals. Cellular immune mechanisms were explored in vitro utilizing fresh and precultured peripheral blood mononuclear cells exposed to PHA. PPD. and recall antigens (SK/SD and CA). Proliferative assays were also carried out in the presence of either each patient's serum (autologous serum) or cocultured with CD3(+)-depleted adherent cells. Serum measurements of soluble interleukin-2 (IL-2) receptor and synthesis of IL-2 generated by mononuclear cells stimulated with PPD and SK/SD were also performed. Patient sera were able to inhibit autologous as well as allogeneic cell responses. and a significant adherent cell suppressive effect was observed. As a whole the group of patients showed decreased blast transformation to PPD. preserved proliferative responses to other recall antigens. and a low PPD-induced generation of IL-2. Furthermore. as possible evidence of preactivated T cells. these patients demonstrated high soluble IL-2 receptor serum levels. Early compromise of specific cell-mediated immunity. including IL-2 abnormalities. may be of significance in newly diagnosed pulmonary TB.
Respiratory effects of occupational exposure in a general population sample in north Italy, We assessed the effects of occupational exposure in a general population sample living in an unpolluted rural area of North Italy. In the age range of 18 to 64 yr. there were 417 participants who reported any exposure to dusts. chemicals. or gases and 1.218 who reported no exposure. Each subject completed a standardized interviewer-administered questionnaire (CNR-questionnaire). A variable proportion of participants succeeded in performing flow-volume curves. diffusing capacity of carbon monoxide. and slope of alveolar plateau of nitrogen. There was no significant difference for symptom prevalence rates between exposed and nonexposed in men and women who smoke. In nonsmoking women. those exposed showed significantly higher prevalence rates for exertional dyspnea and asthma. Regarding lung function. in exposed male smokers there was a significantly higher slope of the alveolar plateau. In exposed female nonsmokers. FEV1 and forced expiratory flows were significantly lower. Multiple logistic models in the overall group. accounting for age. smoking. and pack-years. showed that work exposure was associated significantly with higher risks for all symptoms in men (e.g.. odds ratio: 2.76 for dyspnea. 2.31 for asthma. 1.69 for cough. and 1.64 for phlegm); in females. the association was significant for dyspnea (OR = 3.74) and asthma (OR = 3.29). Exposed men also had a significantly higher risk for %FEV1 or FEV1/FVC% below 70 (OR = 1.45). Our findings confirm those of the other few epidemiologic surveys in general population samples and contribute to the suggestion of a causal association between occupational exposure and chronic obstructive pulmonary disease.
Dynamic T-cell changes in peripheral blood and bronchoalveolar lavage after antigen bronchoprovocation in asthmatics, We previously demonstrated decrease of peripheral blood CD4+ cells 48 to 72 h after antigen-induced bronchoprovocation in asthmatic subjects. To determine if this was accompanied by reciprocal changes in bronchoalveolar lavage (BAL) fluid. we sampled BAL before and 48 h after antigen administration. Peripheral blood lymphocytes (PBL) and BAL T-cell subset composition were examined in eight extrinsic asthmatics during three different weeks. During control week (CW) BAL was preformed at baseline. and PBL subsets were followed for 3 days. During placebo week (PW) a placebo inhalation was followed by a BAL at 48 h and daily PBL for 3 days. Asthmatic attacks were induced by inhalation of a relevant antigen at the start of antigen week (AW) and followed by examining the BAL at 48 h and PBL daily for 72 h. We found that BAL as a stimulus had no effect on T-cell composition of the PBL after the procedure. After induction of an asthmatic attack there was a reduction of PBL CD4+ cells from a baseline mean of 52.6% to 38.8% at 48 h (p less than 0.05). At the same time BAL CD4+ cells increased from 35.6% at PW to 47.3% in AW (p less than 0.05). These data are compatible with specific recruitment of PBL CD4+ cells into the respiratory system in atopic subjects undergoing antigenic bronchoprovocation.
Cultured peripheral blood mononuclear cells derived from patients with acute severe asthma ("status asthmaticus") spontaneously elaborate a neutrophil chemotactic activity distinct from interleukin-8, Peripheral blood mononuclear cells (PBMC) isolated from patients with acute severe asthma on the day of admission to hospital were cultured in vitro in serum-free medium in the absence of mitogenic stimulants for as long as 72 h. PBMC isolated from control groups (mild asthma. chronic obstructive airway disease. normal subjects) were cultured in a similar fashion. After incubation. the culture supernatants were tested for neutrophil chemotactic activity (NCA) using a modified Boyden chamber technique. PBMC from patients with acute severe asthma elaborated significantly greater amounts of NCA into the culture supernatants as compared with all three control groups (p less than 0.01). The amounts of PBMC-derived NCA from the same patients after 7 days of hospital therapy and clinical improvement were reduced (p less than 0.01). A correlation was observed between the extent of reduction in spontaneous release of NCA by PBMC derived from patients with acute severe asthma and the degree of clinical improvement of their asthma (p less than 0.02). Both monocytes and lymphocytes. when cultured separately. released NCA in amounts sufficient to account for the total activity released by unfractionated PBMC. NCA in PBMC culture supernatants accumulated progressively with time. a process inhibited in a dose-dependent fashion by cycloheximide. The amounts of NCA in culture supernatants did not correlate with the concentrations of histamine in lysates of the PBMC prepared just prior to culture.
Effects of zymosan-activated human granulocytes on isolated human airways, In asthma a temporal association exists between the late allergic reaction (LAR). the influx of granulocytes into the airway wall. and an increase in bronchial responsiveness. We therefore tested the hypothesis that activated human granulocytes constrict isolated human airways and increase their sensitivity to cholinergic stimuli. Bronchial rings were dissected from 23 lung tissue specimens collected at thoracotomy and studied isotonically in organ baths. Airways were incubated with 1. 2. 5. 10. or 20 x 10(6) granulocytes from normal or atopic donors. Activation of the cells with serum-treated zymosan (STZ. 0.2 mg/ml). which itself did not alter baseline airway caliber. resulted in a bronchoconstriction proportional to the number of zymosan-activated granulocytes (ZAG) present (rs = 0.79. p less than 0.001). This contraction was reduced by about 70% with the leukotriene C4/D4 receptor antagonist FPL 55712 (11.5 microM; p less than 0.001) or with the lipoxygenase inhibitor nordihydroguaiaretic acid (10 microM; p less than 0.001). The scavengers of activated oxygen molecules superoxide dismutase (300 U/ml) and bovine catalase (5.000 U/ml). the cyclooxygenase inhibitor indomethacin (10 microM). or the histamine (H1) receptor antagonist mepyramine (2.8 microM) had no effect. Granulocyte suspensions from atopic donors contained more eosinophils (p less than 0.001). and the magnitude of the contraction to 10 x 10(6) ZAG was related to the proportion of eosinophils (rs = 0.66. p less than 0.01). The sensitivity of the airways to methacholine was unchanged in the presence of 1. 2. or 5 x 10(6) ZAG and decreased with 10 or 20 x 10(6) ZAG (p less than 0.05).
Inhaled furosemide prevents both the bronchoconstriction and the increase in neutrophil chemotactic activity induced by ultrasonic "fog" of distilled water in asthmatics, Inhaled furosemide has been shown to prevent bronchoconstriction induced by inhalation of ultrasonic nebulization of distilled water (UNDW) in bronchial asthma. To evaluate whether inhaled furosemide also prevents the increase in serum neutrophil chemotactic activity (NCA) observed during UNDW bronchoconstriction. we measured NCA during UNDW challenge without (control) and immediately after inhalation of furosemide (40 mg) or placebo (saline) in 10 asthmatics responsive to UNDW. in a randomized. double-blind study. NCA was assessed by measuring the maximal distance reached by neutrophils in a filter when challenged with the subject serum in a Boyden chamber ("leading front"). UNDW inhalation produced a significant increase in NCA in each subject. Gel filtration chromatography on S400 column indicated that the NCA released were 600 to 700 kD. Saline had no effect on bronchoconstriction nor on NCA increase induced by UNDW in nine patients. Furosemide did not change baseline FEV1. but it prevented bronchoconstriction and NCA increase in nine patients. In the whole group the maximal decrease in FEV1 after UNDW was -31.1%. SEM 4.7 after saline and -7.5%. SEM 5.2 after furosemide. p less than 0.001. the maximal increase in NCA after UNDW was +52.9%. SEM 9.2 after saline and +3.8%. SEM 3.1 after furosemide. p = 0.001. These results indicate that inhaled furosemide prevents both the bronchoconstriction and the NCA increase induced by UNDW inhalation in most asthmatic patients. This finding adds support to the suggestion that furosemide acts on mast cells.
Increased TNF-alpha secretion by alveolar macrophages from patients with rheumatoid arthritis, Tumor necrosis factor alpha (TNF) and interleukin-1 (IL-1) production by alveolar macrophages (AM) was evaluated in 17 rheumatoid arthritis (RA) patients without interstitial lung disease (ILD. Group 1) and 14 RA patients with clinical ILD (Group 2) in comparison with 10 control subjects. AM after recovery by bronchoalveolar lavage were selected by adherence. and then supernatants were collected after 3 or 24 h of culture. Results showed no modification of IL-1 synthesis in either group of RA patients. Spontaneous TNF production was significantly increased in Group 2 (2.5 +/- 0.5 ng/ml) as well as in Group 1 (2.4 +/- 0.4 ng/ml) compared with control subjects (0.43 +/- 0.1 ng/ml. p less than 0.001). In addition. AM from patients untreated or treated exclusively by nonsteroidal antiinflammatory drugs produced similar levels of TNF. whereas those receiving corticosteroids. second-line drugs (such as sulfasalazine. aurothiomalate. and methotrexate). or the combination of both therapy regimens released significantly less TNF. Interestingly. TNF was not different in both groups. but Group 2 had a markedly increased ratio of local immune complex to albumin in bronchoalveolar lavage fluid (0.47 +/- 0.12 versus 0.07 +/- 0.02 in Group 1; p less than 0.002). TNF thus appears an additional component of RA subclinical alveolitis in RA. but its prognostic value and its precise role in lung damage remain to be determined. Development of ILD requires certainly complex interactions of synergistic factors. possibly including local immune complexes detected in BAL fluids.
Fibrinogen depletion and control of permeability in oleic acid lung injury, To determine if the biphasic pulmonary clearance of aerosolized 99mTc diethylene penta acetate (99mTc-DTPA) observed in oleic acid lung injury represents acute epithelial damage followed by sealing as a result of intra-alveolar fibrin deposition. we examined the effect of fibrinogen depletion. 99mTc-DTPA clearance was assessed in three groups of rabbits: Group 1. normal fibrinogen + oleic acid injury; Group 2. fibrinogen-depleted + oleic acid injury; Group 3. fibrinogen-depleted with no oleic acid injury. In Group 3 animals with no lung injury. the 99mTc-DTPA clearance rate. expressed as k. the percent decrease in thoracic radioactivity. was similar to that previously reported for healthy rabbits (k = 1.16 +/- 0.57%/min. mean +/- SD). Oleic acid administration to Groups 1 and 2 resulted in significantly faster clearance rates. with identical biphasic curves in all animals. irrespective of fibrinogen status. There were no significant differences between either the initial fast phase (k. Group 1 = 5.26 +/- 1.83%/min. Group 2 = 5.70 +/- 1.77%/min) or the subsequent slow phase (k. Group 1 = 1.67 +/- 0.63%/min. Group 2 = 1.57 +/- 0.55%/min. p greater than 0.05). On histologic examination. Groups 1 and 2 showed greater cellular interstitial infiltrate. alveolar edema. and hemorrhage than did Group 3. Fibrinogen depletion plus oleic acid injury resulted in greater alveolar cellular exudate. edema. and hemorrhage than did either oleic acid or fibrinogen depletion alone. We conclude that fibrinogen is not necessary to produce biphasic 99mTc-DTPA clearance in oleic acid lung injury.
Effect of Towne live virus vaccine on cytomegalovirus disease after renal transplant. A controlled trial, OBJECTIVE: To test the efficacy of vaccination with the Towne live attenuated cytomegalovirus vaccine. DESIGN: A double-blind. randomized. placebo-controlled trial in candidates for renal transplantation. The cytomegalovirus serologic status of both recipients and donors were determined. and the recipients were followed for periods of 6 months to 7 years after transplant. SETTING: A university transplant center. PATIENTS: The analyses were made on 237 patients who were given either vaccine or placebo. received renal transplants. and were followed for at least 6 months. INTERVENTION: Subcutaneous inoculation with Towne live attenuated virus or with placebo. MAIN OUTCOME MEASURES: The presence of cytomegalovirus infection was defined by virus isolation and antibody tests. If infection occurred. a prearranged scoring system for cytomegalovirus disease was used to objectify disease severity. RESULTS: The vaccine was well tolerated. and there were no discernible long-term adverse effects. Recipients who were originally seropositive did not clearly benefit from vaccination. Protective efficacy was analyzed in the group at highest risk for cytomegalovirus disease; recipients who were seronegative at the time of vaccination and who received a kidney from a seropositive donor. Compared with placebo recipients. vaccinated patients in this group had significantly less severe cytomegalovirus disease. with a significant reduction in disease scores (P = 0.03) and 85% decrease in the most severe disease (95% CI. 35% to 96%). although infection rates were similar. Graft survival at 36 months was improved in vaccinated recipients of cadaver kidneys (8 of 16) compared with unvaccinated recipients (4 of 16) (P = 0.04). CONCLUSIONS: Previous vaccination of seronegative renal transplant recipients with live cytomegalovirus results in reduction of disease severity mimicking the action of naturally derived immunity.
Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Philadelphia chromosome-positive patients, OBJECTIVES: To evaluate the frequency and the course of complete cytogenetic responses in interferon-alpha (IFN-alpha)-treated patients with chronic myelogenous leukemia. DESIGN: Two prospective trials in consecutive patients. SETTING: A major tertiary cancer center. PATIENTS: Ninety-six consecutive patients with chronic myelogenous leukemia with disease duration of less than 1 year. INTERVENTION: Patients received partially pure IFN-alpha intramuscularly. from 3 to 9 million U/d (51 patients) or recombinant IFN-alpha 2a (Roferon. Hoffmann-LaRoche. Inc.. Nutley. New Jersey). 5 million U/m2 body surface area daily (45 patients). MEASUREMENTS: Hematologic and cytogenetic tests were administered. MAIN RESULTS: Seventy of the patients (73%) achieved hematologic remission (95% CI. 63% to 81%). and 18 (19%) had complete suppression of the Philadelphia chromosome on at least one cytogenetic test. A complete cytogenetic response was induced in 7 of 51 or 14% (CI. 6% to 26%) of the patients treated with the partially pure IFN-alpha and in 11 of 45 or 24% (CI. 13% to 40%) of the patients treated with recombinant IFN-alpha 2a. The difference in complete cytogenetic response between the two groups was 10.7% (CI. - 5% to 26%; P greater than 0.2). Eleven patients had durable. ongoing. complete cytogenetic responses from 6 to more than 45 months (median. more than 30 months). CONCLUSION: This study was the first to show sustained. complete cytogenetic responses in a subset of patients with chronic myelogenous leukemia treated with single-agent therapy. The nature of this remission. that is. whether it depends on continuous therapy. requires further study.
Cross-national changes in the effects of peptic ulcer disease, OBJECTIVE: To describe and to analyze the changing effects of peptic ulcer disease over time. DESIGN: Variables relating to peptic ulcer disease from 1970-1986 were compared. The variables included rates of mortality. hospitalizations. operations. physician visits. and endoscopies. and the amount of disability-related loss of work and early retirement in six countries (Belgium. England and Wales. the Federal Republic of Germany. The Netherlands. Sweden. and the United States). MEASUREMENTS: Nonparametric epidemiologic time-trend analysis. MAIN RESULTS: The historic. slow. declining trend in mortality and hospitalization rates continued. The rate of operations for peptic ulcer disease exhibited a large. one-time reduction. then returned to a parallel declining trend. but at a lower level. The rate of physician visits declined by 50%. The greatest changes were found in the rate of endoscopy use and in disability-related loss of work and early retirement. where increasing trends were quickly followed by decreasing trends. The elderly. especially women. generally did not share many of these benefits. CONCLUSIONS: The effects of new interventions can be understood more fully by examining several variables in many countries over a long time. Contrary to expectations. the effects of the widespread use of histamine H2 antagonists have been more indirect (affecting work loss and disability retirement more) than direct (affecting high-cost medical service use and mortality less).
Improvement of amphotericin B activity during experimental cryptococcosis by incorporation into specific immunoliposomes, Cryptococcosis is an opportunistic infection that is responsible for increased morbidity and mortality in patients with the acquired immunodeficiency syndrome. The high toxicity of the antifungal agent that is mainly used against cryptococcosis. amphotericin B (AMB). accounts for the need for new treatments. especially in patients with the acquired immunodeficiency syndrome because of the high relapse rate of cryptococcosis. Drug targeting may be one of these alternate treatments. Since we have demonstrated that an immunoglobulin G1 (IgG1) anti-Cryptococcus neoformans serotype A monoclonal antibody (E1) was protective during experimental cryptococcosis in mice. we investigated whether specific targeting of AMB with liposomes that bear E1 would improve the therapeutic index of the drug. For that purpose. in vitro and in vivo experiments were designed to compare the specificities and activities of these liposomes with those of control immunoliposomes bearing a nonrelated IgG1 monoclonal antibody (CY34). The immunoliposomes were prepared by covalently linking E1 or CY34 and small unilamellar vesicles. When immunoliposomes were incubated with yeast cells. only E1-bearing liposomes recognized C. neoformans. In vivo. mice that were treated 24 h after infection with one injection of AMB (0.12 mg/kg of body weight) intercalated into E1-bearing liposomes survived significantly longer than did those given the same dose of AMB alone or AMB intercalated into nontargeted liposomes or control immunoliposomes. None of the mice that were given control treatments did statistically better than those that were given AMB. Keeping in mind that this kind of therapy requires knowledge of the antigenic type of the infecting organism. the results suggest that specific targeting of small doses of AMB improve the efficacy of AMB and might be an alternative to the use of larger doses of AMB.
In vitro activity of sparfloxacin (CI-978; AT-4140) for clinical Legionella isolates, pharmacokinetics in guinea pigs, and use to treat guinea pigs with L. pneumophila pneumonia, The activities of sparfloxacin. ciprofloxacin. and erythromycin for 21 clinical Legionella isolates were determined by agar and broth dilution susceptibility testing and by growth inhibition assays in guinea pig alveolar macrophages (sparfloxacin and ciprofloxacin). All three antimicrobial agents had roughly equivalent activities when buffered charcoal yeast extract agar medium supplemented with 0.1% alpha-ketoglutarate was used as the test medium; the MICs for 90% of strains were 1.0 micrograms/ml for erythromycin and sparfloxacin and 0.5 microgram/ml for ciprofloxacin. Buffered charcoal yeast extract medium supplemented with 0.1% alpha-ketoglutarate inhibited the activities of all the antimicrobial agents tested. as judged by the susceptibility of a control Staphylococcus aureus strain. Broth macrodilution MICs for two L. pneumophila strains in buffered yeast extract supplemented with 0.1% alpha-ketoglutarate were less than or equal to 0.03 microgram/ml for sparfloxacin. 0.06 microgram/ml for ciprofloxacin. and 0.25 microgram/ml for erythromycin; only erythromycin was inhibited by this medium. Ciprofloxacin and sparfloxacin (both 0.25 microgram/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 log10 CFU/ml. but regrowth occurred over a 3-day period. Sparfloxacin. but not ciprofloxacin (both 1 microgram/ml). caused a 3- to 4-day postantibiotic effect. Pharmacokinetic and therapy studies of sparfloxacin were performed in guinea pigs with L. pneumophila pneumonia. For the pharmacokinetic study. sparfloxacin was given (10 mg/kg of body weight) to infected guinea pigs by the intraperitoneal route; peak levels in serum and lung were 2.6 micrograms/ml and 1.6 micrograms/g. respectively. at 1 h. with a terminal-phase half-life of elimination from serum of 5 h.
Comparative in vitro and in vivo susceptibilities of the Lyme disease spirochete Borrelia burgdorferi to cefuroxime and other antimicrobial agents, The in vitro and in vivo susceptibilities of the Lyme disease pathogen Borrelia burgdorferi to cefuroxime were compared with those of several other antibiotics commonly used to treat this disease. Cefuroxime demonstrated a higher MBC in vitro (1.0 microgram/ml) than ceftriaxone (0.08 microgram/ml) or erythromycin (0.32 microgram/ml). but the MBC was similar to that of amoxicillin (0.8 microgram/ml) and doxycycline (1.6 micrograms/ml). B. burgdorferi was considerably less susceptible to tetracycline (3.2 micrograms/ml) and penicillin G (6.4 micrograms/ml). Of the three other Borrelia species tested. two (Borrelia turicatae and Borrelia anserina) also demonstrated susceptibility to cefuroxime. while the third (Borrelia hermsii) was less susceptible. Results obtained with four antimicrobial agents in the in vivo hamster model parallel the antibiotic susceptibilities in the in vitro study. The three antibiotics with similar MBCs in vitro. i.e.. cefuroxime. doxycycline. and amoxicillin. demonstrated comparable activities in preventing borreliosis in B. burgdorferi-challenged hamsters (50% curative doses = 28.6. 36.5 and 45.0 mg/kg. respectively). Penicillin G. which demonstrated the highest MBC in vitro. had very weak protective activity in the hamster model system. These results indicate that the in vitro and in vivo activities of cefuroxime against B. burgdorferi are comparable to those of several oral antibiotics currently being used in the treatment of early Lyme disease and suggest that the oral form of this cephalosporin may be an effective alternative therapy for this disease.
Evaluation of the anti-influenza virus activities of 1,3,4-thiadiazol-2-ylcyanamide (LY217896) and its sodium salt, 1.3.4-Thiadiazol-2-ylcyanamide (LY217896) and its sodium salt were shown to be effective against influenza A and B viruses in vitro and in the mouse model. In nondividing confluent MDCK cells. the 50% inhibitory concentration of LY217896 ranged from 0.37 to 1.19 micrograms/ml against various strains of influenza A virus and from 0.75 to 1.54 micrograms/ml against various strains of influenza B virus. with no apparent cytotoxicity. However. at a concentration of 0.31 microgram/ml. LY217896 inhibited the replication of dividing MDCK cells. LY217896 (9 mg/m2 of body surface area per day) administered in the diet. in the drinking water. by oral gavage. by intraperitoneal injection. or by aerosolization was well tolerated and protected CD-1 mice infected with a lethal dose of influenza A or B virus. Effective administration of the compound could be delayed for up to 96 h postinfection. Virus titer was reduced by 1 to 2 log10 units in lungs of mice given LY217896 in the drinking water. Mice treated initially with protective levels of LY217896 were resistant to a subsequent challenge of influenza virus in the absence of the compound. indicating that the animals were able to develop immunity to the initial infection. Administration of LY217896 to uninfected mice did not induce interferon-like activity or interfere with natural killer cell function. In the ferret. LY217896 was effective in preventing fever induced by influenza virus.
Outbreak of ceftazidime resistance caused by extended-spectrum beta-lactamases at a Massachusetts chronic-care facility, During a 4-month period in late 1988. we isolated ceftazidime-resistant strains of Klebsiella pneumoniae and other members of the family Enterobacteriaceae from 29 patients at a chronic-care facility in Massachusetts. Ceftazidime resistance resulted from two distinct extended-spectrum beta-lactamases of the TEM type which efficiently hydrolyzed the cephalosporin: YOU-1 with a pI of 5.57 and YOU-2 with a pI of 5.2. Genes encoding these enzymes were present on different but closely related high-molecular-weight. multiple antibiotic resistance plasmids of the H12 incompatibility group and were transferable by conjugation in vitro. Agarose gel electrophoresis of extracts from clinical isolates indicated that this outbreak arose from plasmid transmission among different strains of the family Enterobacteriaceae rather than from dissemination of a single resistant isolate. Isolation rates of ceftazidime-resistant organisms transiently decreased after use of this drug was restricted. but resistant isolates continued to be recovered 7 months after empiric use of ceftazidime ceased.
Novel plasmid-mediated beta-lactamase (MIR-1) conferring resistance to oxyimino- and alpha-methoxy beta-lactams in clinical isolates of Klebsiella pneumoniae, Klebsiella pneumoniae isolates from 11 patients at the Miriam Hospital were identified as resistant to cefoxitin and ceftibuten as well as to aztreonam. cefotaxime. and ceftazidime. Resistance could be transferred by conjugation or transformation with plasmid DNA into Escherichia coli and was due to the production of a beta-lactamase with an isoelectric point of 8.4 named MIR-1. In E. coli. MIR-1 conferred resistance to aztreonam. cefotaxime. ceftazidime. ceftibuten. ceftriaxone. and such alpha-methoxy beta-lactams as cefmetazole. cefotetan. cefoxitin. and moxalactam. In vitro. MIR-1 hydrolyzed cephalothin and cephaloridine much more rapidly than it did penicillin G. ampicillin. or carbenicillin. Cefotaxime was hydrolyzed at 10% the rate of cephaloridine. Cefoxitin inactivation could only be detected by a microbiological test. The inhibition profile of MIR-1 was similar to that of chromosomally mediated class I beta-lactamases. Potassium clavulanate had little effect on cefoxitin or cefibuten resistance and was a poor inhibitor of MIR-1 activity. Cefoxitin or imipenem did not induce MIR-1. The gene determining MIR-1 was cloned on a 1.4-kb AccI-PstI fragment. Under stringent conditions. probes for TEM-1 and SHV-1 genes and the E. coli ampC gene failed to hybridize with the MIR-1 gene. However. a provisional sequence of 150 bp of the MIR-1 gene proved to be 90% identical to the sequence of ampC from Enterobacter cloacae but only 71% identical to that of E. coli. thus explaining the lack of hybridization to the E. coli ampC probe. Plasmid profiles of the 11 K. pneumoniae clinical isolates were not identical. but each contained a plasmid from 40 to 60 kb that hybridized with the cloned MIR-1 gene. Both transfer-proficient and transfer-deficient MIR-1 plasmids belonged to the N incompatibility group. Thus. the resistance of these K. pneumoniae strains was the result of plasmid acquisition of a class I beta-lactamase. a new resistance determinant that expands the kinds of beta-lactam resistance capable of spread by plasmid dissemination among clinical isolates.
Effects of butenafine hydrochloride, a new benzylamine derivative, on experimental dermatophytosis in guinea pigs, Butenafine hydrochloride. N-4-tert-butylbenzyl-N-methyl-1-naphthalenemethylamine hydrochloride (butenafine). is a novel antifungal agent of the class of benzylamine derivatives. Butenafine was investigated for its activity against guinea pig dermatophytosis caused by Trichophyton mentagrophytes or Microsporum canis in comparison with those of naftifine. tolnaftate. clotrimazole. and bifonazole. Topical butenafine showed excellent efficacy against dermatophytosis when it was applied once daily. and the effect was superior to those of all four reference drugs. When applied once at 24 or 48 h before infection. the drug exhibited excellent prophylactic efficacy against experimental T. mentagrophytes infection. The concentrations of butenafine in animal skin at 24 and 48 h after application of 0.2 ml of a 1% solution were several hundred times higher than those required to kill T. mentagrophytes and M. canis. The good efficacy of butenafine against dermatophytosis may be attributable to its fungicidal activity and long retention in the skin after topical application.
Effects of butenafine hydrochloride, a new benzylamine derivative, on experimental tinea pedis in guinea pigs, Butenafine is a new antifungal benzylamine. The efficacy of butenafine was investigated in an experimental tinea pedis model in guinea pigs. which is pathologically similar to natural infections in humans. Butenafine (0.1 ml) in 0.2 to 1.0% solutions was applied to the site of infection. Treatment was started on day 10 postinfection and was continued for 20 days. Butenafine applied once daily exhibited excellent dose-related therapeutic efficacy. The efficacy of butenafine was significantly superior to those tolnaftate. clotrimazole. and bifonazole.
In vitro activities of new antimicrobial agents against multiresistant Staphylococcus aureus isolated from septicemic patients during a Belgian national survey from 1983 to 1985, The antimicrobial agents most active against bacteremic isolates of oxacillin-resistant Staphylococcus aureus isolated from 1983 to 1985 were new fluoroquinolones. including PD 117.596 and PD 127.391 (MIC for 90% of isolates [MIC90] in agar. in micrograms per milliliter. 0.1) and temafloxacin. pefloxacin. and ofloxacin (MIC90. 0.4). Other active antimicrobial agents included fusidic acid (MIC90. 0.2) and fosfomycin (MIC90. 12.5). Vancomycin was active against all isolates. Mupirocin was very active (MIC90. 0.4).
In vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to seven fluoroquinolones, The in vitro susceptibilities of Bordetella pertussis and Bordetella parapertussis to seven fluoroquinolones were assessed by the agar dilution method. Ciprofloxacin and temafloxacin were the most active compounds (MIC for 90% of isolates tested [MIC90]. 0.06 microgram/ml). while enoxacin and pefloxacin were the least active (MIC90. 0.5 microgram/ml). Fleroxacin. lomefloxacin. and ofloxacin showed intermediate activities (MIC90s. 0.125 to 0.25 microgram/ml). These results suggest a possible role for the fluoroquinolones in the treatment of pertussis. at least in adult patients.
Depot testosterone in boys with anorchia or gonadotrophin deficiency: effect on growth rate and adult height, Eleven teenage boys with bilateral anorchia and 12 with gonadotrophin deficiency were treated by injections of testosterone ester (enanthate) at an initial dose of 100 mg every six to eight weeks. rising to 250 mg every four weeks after three to four years. In the anorchic boys average adult height was 177.1 cm. compared with a mean mid-parental height of 174.4 cm. and mean predicted adult heights of 177.0 cm (Tanner-Whitehouse method) and 178.0 cm (Bayley-Pinneau method). In the patients with gonadotrophin deficiency. mean adult height was 176.9 cm. compared with a mean mid-parental height of 176.1 cm. and mean predicted adults heights of 174.0 cm (Tanner-Whitehouse method) and 177.3 cm (Bayley-Pinneau method). We conclude that this testosterone regimen allows achievement of full growth potential in such patients.
Outcome among surviving very low birthweight infants: a meta-analysis, Because published outcome studies are the only available source of data about the morbidity among surviving very low birthweight infants (VLBW. less than 1500 g) a search was carried out of 1136 references in the English language. A total of 111 outcome studies were found that reported morbidity data in cohorts of VLBW infants born since 1960. The methods used and results obtained in these studies were systematically assessed. No agreement exists about the definition of study populations. descriptive statistics. or measurement of outcome. Follow up ranged from six months to 14 years. In 85 cohorts the incidence of cerebral palsy was recorded. and in 106 that of disability. Studies that followed up infants for longer time periods reported higher incidences of disability. Studies from the United States reported higher incidences of disability than those from other countries. The median incidence of cerebral palsy among all the cohorts studied was 7.7%. and the median incidence of disability was 25.0%. Despite substantial improvements in the mortality of VLBW infants. poor outcomes among survivors are common.
Body water measurement in growth disorders: a comparison of bioelectrical impedance and skinfold thickness techniques with isotope dilution, Total body water was estimated as part of the assessment of body composition in children with growth disorders. using the newly commercially available method of bioelectrical impedance. This was undertaken to compare the precision and accuracy of the results with those derived from skinfold thickness against measurement of stable isotopically labelled water (H2(18)O) dilution as a standard. The comparisons were carried out to see to what extent the impedance method could be applied with confidence to assessment of children with growth disorders. Total body water was derived from impedance (I) using an association with height (Ht2/I). Impedance and skinfold thickness estimates of total body water were equally precise when compared with values obtained from H2(18)O dilution (limits of agreement -1.9 to +1.3 and -1.7 to +2.0 kg respectively). The mean intraobserver coefficient of variation for repeat measurements of impedance was 0.9% compared with 4.6% for skinfold thickness with an interobserver coefficient of variation for impedance of 2.8%. Bioelectrical impedance estimation of body composition is likely to be of value in the growth clinic when expertise in measurement of skinfold thickness is limited or repeated measurements are to be undertaken by different observers.
Congenital parvovirus infection, A case of congenital parvovirus (B19) viraemia with associated thrombocytopenic purpura and platelet antigen incompatibility in an infant is reported. Results of laboratory investigations indicated that the baby was infected in utero.
Rationale and efficacy of conservative therapy for gastroesophageal reflux disease, Major recent advances in the diagnosis and understanding of gastroesophageal reflux disease have afforded the practicing clinician a number of therapeutic options to treat the increasingly recognized affected patient population. With highly effective acid-suppressive therapies available. simple life-style modifications. such as selective food and medicine avoidance. weight loss. smoking cessation. elevation of the head of the bed. and the judicious use of antacids and alginate. have been relegated to a minor. if any. role in the management of these patients. The validity of these recommendations. however. remains consistent with our current understanding of the pathogenesis of gastroesophageal reflux disease. Although few well-designed placebo-controlled trials have been conducted. a review of the medical literature indicates an appreciable efficacy of these interventions. which are founded on well-studied physiologic determinants of gastroesophageal reflux. Most patients with gastroesophageal reflux disease can be managed by reassurance and simple life-style adjustments alone. The therapy for those with chronic or relapsing disease should always include the adjunctive reinforcement of these simple. efficacious. and cost-effective measures.
Bad news: delivery, dialogue, and dilemmas, The narrative from a real patient encounter is used to illustrate the powerful effect that delivering bad news can have on both patient and physician. The meaning of bad news to the patient may be quite different than the medical or the personal meaning to the physician. Differences in perception must be explored and understood before the common ground necessary for joint decision making is established. Initial patient responses can be divided into three categories: (1) basic psychophysiologic (fight-flight or conservation-withdrawal). (2) cognitive. and (3) affective. Responses vary considerably depending on the meaning of the diagnosis to the patient. the degree of immediate threat. and the patient's previous experience with illness. Desired outcomes of the initial meeting include (1) minimizing aloneness and isolation for both patient and physician; (2) achieving a common perception of the problem; (3) giving information tailored to the immediate needs of the patient; (4) addressing immediate medical needs. including the risk of suicide; (5) responding to immediate discomforts; and (6) ensuring a basic plan for follow-up. Though all clinicians deliver bad news. few have had formal training or open exploration of the profound potential impact of the experience.
The association of allergen skin test reactivity and respiratory disease among whites in the US population. Data from the Second National Health and Nutrition Examination Survey, 1976 to 1980, Data collected on 12- to 74-year-old whites (N = 10.854) during the second National Health and Nutrition Examination Survey. 1976 to 1980. a sample of the US population. were used to determine the association between various respiratory symptoms and the degree of allergen skin test reactivity. Prick-puncture testing using eight unstandardized allergens was performed. Allergen skin test reactivity was classified by means of the mean diameter of the erythema reaction at the 20-minute reading. Nonreactors were the comparison group. The prevalence of allergic rhinitis increased as allergen skin test reactivity increased. with the odds ratio exceeding 8 for the group with two or more positive test results. The prevalence of asthma increased with increasing allergen skin test reactivity only in nonsmokers. The odds ratio for allergic rhinitis with allergen skin test reactivity was higher with outdoor than indoor allergens. The association of allergic rhinitis with allergen skin test reactivity was higher when a physician had previously diagnosed allergic rhinitis. Chronic rhinitis was not associated with allergen skin test reactivity.
Leukopenia, neutropenia, and reduced hemoglobin levels in healthy American blacks, Hematologic profiles of 462 persons. mostly active-duty service members. were studied to determine whether hematologic differences between blacks and whites exist in a healthy population. Whites had significantly greater mean concentrations of leukocytes (6.73 vs 5.95 x 10(9)/L). neutrophils (3.96 vs 3.16 x 10(9)/L). and hemoglobin (153 vs 135 g/L for men. 147 vs 125 g/L for women). The mean differences were largely due to relatively symmetric shifts in the frequency distributions for these cell concentrations. No significant correlation was found between neutrophil count and morbidity from infection as measured by a standardized questionnaire. The use of separate hematologic reference values for blacks and whites should be considered.
Physicians' effectiveness in assessing risk for human immunodeficiency virus infection, An American Medical Association committee recently recommended that physicians routinely screen patients for behaviors that put patients at risk for human immunodeficiency virus infection. yet there is evidence that this screening does not occur routinely. Faculty. fellows. and residents at a teaching hospital in a midwestern state with a low prevalence of acquired immunodeficiency syndrome were surveyed regarding their experience in screening for human immunodeficiency virus. their training related to substance abuse and human sexuality. and their confidence and ease in addressing such topics with their patients. Results indicated that only 11% routinely screened patients for high-risk behaviors. While most physicians had received training in human sexuality. most had not received training in substance abuse screening. Those trained felt more confident in addressing substance abuse and human sexuality and felt more comfortable in caring for patients known to be infected with human immunodeficiency virus. A concerted effort to encourage human immunodeficiency virus risk assessment by physicians is needed. This should include training opportunities in screening and counseling patients about sexual activities and substance abuse.
Flavimonas oryzihabitans (Pseudomonas oryzihabitans; CDC group Ve-2) bacteremia in the immunocompromised host, Flavimonas oryzihabitans. known previously as Pseudomonas oryzihabitans. and a member of the Centers for Disease Control group Ve-2. is a gram-negative organism that has rarely been implicated as a human pathogen. Flavimonas oryzihabitans appears to be a soil and saprophytic organism that survives in moist environments and is indigenous to rice paddles. To our knowledge. only seven cases of human infection caused by this organism have been reported; they involved four patients with bacteremia and three patients with peritonitis who were receiving continuous ambulatory peritoneal dialysis. In this report. we describe three immunocompromised patients with catheter-associated bacteremia: a patient with cancer. a patient with acquired immunodeficiency syndrome. and a patient with sickle cell disease. There is emerging clinical evidence that F oryzihabitans should be recognized as an organism that is capable of causing human disease. particularly in immunocompromised patients and with the increased usage of permanent catheters.
Immune complexes in the choroid plexus in liver cirrhosis, A histopathologic and immunofluorescence study of the choroid plexus was performed in 12 cases of liver cirrhosis (cirrhosis group) and in 20 patients who died of diseases with no evidence of liver or brain involvement. and in which renal disease and alcoholism were also excluded (control group). IgA. IgG. IgM. C3. and C1q were investigated by direct immunofluorescence technique. Positive immunofluorescence in the choroid plexus was found in 83.33% of the cirrhosis group. IgA and IgG were the immunoglobulins more frequently found. C3 was also commonly found. Histologic examination of the choroid plexus showed changes in 66.67% of the cirrhosis group characterized. mainly. by subepithelial deposition of a homogeneous. acidophilic. and periodic acid-Schiff-positive substance. with thickening of the epithelial basement membrane. In the control group. the immunofluorescence in the choroid plexus was negative in all cases and only two cases (10%) presented histopathologic changes of the choroid plexus with a pattern similar to that of the cirrhosis group.
Extramedullary hematopoiesis in the liver in sudden infant death syndrome, Liver extramedullary hematopoiesis was examined in 54 victims of sudden infant death syndrome and in 21 infants who died of other causes in an attempt to confirm Naeye's findings of increased extramedullary hematopoiesis in cases of sudden infant death syndrome. Our data showed greater extramedullary hematopoiesis in victims of sudden infant death syndrome (F = 23.52). supporting Naeye's hypothesis that victims of sudden infant death syndrome have suffered a subtle. chronic hypoxemic condition before death.
Tumefactive fibroinflammatory lesion of the extremity. Report of a case and review of the literature, Tumefactive fibroinflammatory lesion is an idiopathic fibroinflammatory process of the head and neck region. Although benign histopathologically. it is invasive. destructive. and locally recurrent. leading to uncertainty regarding its proper management; as the disease is rare. determining optimal treatment is difficult. given the anecdotal nature of reports. We report the first case of a tumefactive fibroinflammatory lesion occurring outside the head and neck region. Our patient was treated with corticosteroids and had a favorable response. supporting this approach as initial treatment. Immunohistochemical studies performed on a pretreatment specimen were consistent with a secondary inflammatory component because no monoclonal nor aberrant phenotypes were detected. The tumefactive fibroinflammatory lesion appears to be indistinguishable from the other known idiopathic fibroinflammatory processes; patients presenting with any one of these should be evaluated for the others.
Primary rhabdomyosarcoma of the ileum in an adult, We report a case of primary rhabdomyosarcoma of the ileum occurring in a 45-year-old man. The rhabdomyoblastic nature was immunohistochemically confirmed by positivity with anti-myoglobin and anti-striated actin antisera. We discuss the differential diagnosis with similar tumors. To our knowledge. ileal rhabdomyosarcomas have not been previously reported in adults.
Hemangiopericytoma of the sternum, Hemangiopericytoma of the chest wall is a rare tumor. We describe a patient with malignant hemangiopericytoma of the sternum who was treated with primary surgical resection and discuss the clinical. radiographic. and histologic features of the case. Surgical resection is the primary mode of therapy. High-dose radiotherapy and chemotherapy with a doxorubicin hydrochloride-containing combination may be warranted in certain cases.
Histocompatibility testing in transplantation, The question of whether or not HLA is important in transplantation can now be answered with a definite yes. The nationwide six-antigen-matching program. in which over 100 US transplantation centers have participated. has shown that a high (88% to 90%) 1-year graft survival rate can be achieved when kidneys are shipped to well-matched recipients. Long-term outcome (measured as half-life) is also markedly improved. from an average of 7 years for cadaveric donor transplants to as much as 19 years in the six-antigen-matched recipients. One of the major factors influencing long-term survival is histocompatibility matching. as shown by the survival differences among HLA-identical siblings (25-year half-life). one-haplotype-mismatched parental donors (12-year half-life). and two-haplotype-mismatched cadaveric donors (7-year half-life). For the past 25 years of kidney transplant experience. cadaveric donor half-life has remained stable at 7 years. despite many improvements in immunosuppression protocols. Histocompatibility matching unquestionably offers the best approach to prevention of chronic rejection.
The role of vascular endothelial cells in transplantation, The interface between an allograft and the recipient's immune system is the endothelium of the allograft vasculature. In this boundary position. endothelial cells may play important roles in the afferent and efferent phases of allograft rejection. in the response of the allograft to pretransplant perfusion and to drug therapy. and in the response to viral infection of the host. The expression by endothelial cells of granule membrane protein-140 (GMP-140) and endothelial leukocyte adhesion molecule-1 (ELAM-1). increased tissue factor activity. increased secretion of plasminogen activator inhibitor. and decreased thrombomodulin may all contribute to hyperacute rejection. Similarly. endothelial cells may actively participate in acute cellular rejection and in the development of transplant-associated arteriopathy as a result of induction of antigen-presenting function (ie. HLA class II expression). upregulation of adhesion molecules for lymphocytes and monocytes. and release of platelet-derived growth factors. Endothelial cell functions. which are important for normal inflammatory responses and vessel behavior. may be pathogenic in the allograft.
Assessing the severity of dementia. Patient and caregiver, In dementia there is cognitive impairment. disability in daily life. and sometimes behavioral disturbance. These changes are a burden for the caregivers of patients with dementia. Few studies are available that examine all these aspects and their interrelationships in a single patient group. In our study we selected detailed methods for assessment of all these aspects. Interrelationships were studied in 30 mild to moderately impaired patients with dementia and their caregivers. Although the relations of cognitive deterioration to disability in daily life and of burden experienced by the caregiver to patient's condition were stronger than often reported. it was impossible to deduce the overall severity of dementia from one single aspect. Thus. for effective management of patients and caregivers. for evaluation of individual treatment or of clinical trials. attention should be paid to all the different aspects of patients' condition and caregivers' burden. Outcome measurements will then be more valid.
Comparison of postmortem magnetic resonance imaging and neuropathologic findings in the cerebral white matter, Two types of high-signal intensity abnormalities are frequently found bilaterally in the cerebral white matter of brains of elderly patients on T2-weighted magnetic resonance imaging (MRI) scans. One is located in the immediate periventricular region; the other. in the deep subcortical white matter (centrum semiovale). The diagnostic implications of this second type continue to be uncertain. To determine the neuropathologic correlates of these lesions. the brains from seven elderly patients were fixed in buffered formaldehyde solution. subjected to MRI scanning. and examined neuropathologically. Variable degrees of bilateral periventricular (subependymal) sharply defined areas of high-signal intensity were found in all the brains. and the larger of these showed corresponding areas of myelin pallor with gliosis and dilated perivascular spaces. Discrete bilateral patches of high-signal intensity were found in the centrum semiovale in five patients. Myelin and axon stains showed varying degrees of diffuse white matter pallor in many areas examined. both with and without these areas of high-signal intensity on MRI scans. Neither the myelin nor the axon stains showed discrete white matter abnormalities that corresponded to the MRI findings. We believe that these changes. so commonly found on MRI scans in the elderly. reflect actual changes in the white matter but that their nature and clinical significance need to be elucidated.
An assessment of disability rating scales used in multiple sclerosis, Twenty patients with clinically definite. stable multiple sclerosis were examined independently by three of us at the same visit and given scores on the Ambulation Index. Expanded Disability Status Scale. and Kurtzke Functional System scales. Observer error accounted for 12% to 55% of the variation observed between individual Kurtzke Functional System scores. 17.1% of the variation observed between the patients' Expanded Disability Status Scale scores. and only 3.9% of the variation between Ambulation Index scores. The implications of these findings for the choice of scales in clinical trials are described.
Lateral deviation of the eyes on forced lid closure in patients with cerebral lesions, We examined 35 patients with unilateral cerebral lesions to determine the incidence of lateral deviation of the eyes under forcefully closed lids and the reliability of this sign in predicting the side of the lesion. Only patients with radiologically confirmed unilateral lesions were studied. Over 70% of patients had contralateral ocular deviation (Cogan's "spasticity of conjugate gaze"). 20% had ipsilateral deviation. and less than 9% of the patients had no deviation. Lateral ocular deviation was as sensitive. but not as specific. as a unilateral Babinski plantar response in determining the side with the lesion. Contralateral deviation was more common with parietotemporal localization. suggesting that the phenomenon reflects an underlying disturbance of attentional mechanisms.
Seizure disorders in Down syndrome, The prevalence. onset. and type of seizure disorders. as well as seizure control. were studied in a large cohort of 405 individuals with Down syndrome (age range. 6 months to 45 years). The evaluation of a questionnaire completed by the subjects' parents and of the patients' medical records indicated that 33 (8.1%) of 405 persons with Down syndrome had seizure disorder. With regard to the onset of seizures. a bimodal distribution was noted: 40% of patients began having seizures before the age of 1 year. and another 40% started with seizure activity in the third decade of life. In the younger age group. primarily infantile spasms and tonic-clonic seizures with myoclonus were observed. and the older patients often had partial simplex or partial complex seizures as well as tonic-clonic seizures.
Horner's syndrome from hypothalamic infarction, We report a case of Horner's syndrome due to ipsilateral posterior hypothalamic infarction. occurring in the absence of other signs of hypothalamic dysfunction. Associated symptoms of contralateral faciobrachial weakness and dysarthria correlated with the extension of the infarct into the posterior limb of the internal capsule seen by magnetic resonance imaging. The likely vascular anatomy of this lesion is discussed.
Value of plasmapheresis in hepatic encephalopathy, Plasmapheresis is used for treating the complications of liver failure. We performed plasmapheresis on 6 children with hepatic encephalopathy resulting from acute hepatic failure and prospectively assessed its effects on neurologic and electrophysiologic (electroencephalography and evoked potentials) function. Clinical improvement was observed in 3 of 6 patients; changes in the serum ammonia value or the results of initial electrophysiologic tests did not predict the patient response. Two patients underwent transplantation after neurologic improvement was produced by plasmapheresis; however. despite plasmapheresis. 4 patients progressed to brain death. Our data demonstrate that plasmapheresis may transiently improve the encephalopathy of acute hepatic failure but is not curative alone. Therefore. plasmapheresis may be a useful adjunct in the treatment of liver failure. potentially improving the pretransplantation status of the patient.
Wide cavum septum pellucidum: a marker of disturbed brain development, A wide cavum septum pellucidum defined as a separation of greater than 1 cm of the leaves occurs uncommonly. Nine children with wide cavum septum pellucidum were studied; 8 were abnormal. Observed abnormalities included cognitive impairment (8). seizures (4). hypoplasia of the corpus callosum (4). optic nerve hypoplasia (2). and growth failure (4). The incidence of intellectual dysfunction. the association with midline anomalies of the brain. and growth failure all suggest that wide cavum septum pellucidum may represent part of a spectrum of midline brain anomalies.
Human interleukin-3 mRNA accumulation is controlled at both the transcriptional and posttranscriptional level, Interleukin-3 (IL-3) is a hematopoietic growth factor that regulates the differentiation of multilineage and committed progenitor cells and the functions of some mature blood cells. The expression of human IL-3 appears to be restricted to stimulated T lymphocytes. We have investigated the kinetics and mechanisms involved in the induction of IL-3 expression in the human T lymphocytic tumor cell line Jurkat. We show that accumulation of IL-3 mRNA is controlled at both the transcriptional and posttranscriptional level. Transcription of the IL-3 gene in these cells appears to be constitutive but no IL-3 mRNA was detected in unstimulated cells. indicating that in resting cells IL-3 mRNA is highly unstable. Treatment with phytohemagglutinin (PHA) induced a small and transient increase in the IL-3 gene transcription rate and led to the production of detectable levels of IL-3 mRNA and protein. Optimal induction of IL-3 expression required a second stimulus. Costimulation of Jurkat cells with both phorbol myristate acetate and PHA caused both a transient increase in IL-3 gene transcription. which is dependent on new protein synthesis. and also a transient increase in mRNA stability.
Blood mononuclear cells from patients with severe congenital neutropenia are capable of producing granulocyte colony-stimulating factor, Severe congenital neutropenia (SCN) is a disorder of myelopoiesis characterized by severe neutropenia or absence of blood neutrophils secondary to a maturational arrest at the level of promyelocytes. We examined peripheral blood mononuclear cells (PBMC) of SCN patients who demonstrated normalization of their blood neutrophil counts in a phase II clinical study with recombinant human granulocyte colony-stimulating factor (rhG-CSF). When stimulated in vitro with bacterial lipopolysaccharides (LPS). PBMC of those SCN patients produced G-CSF activity. as judged by proliferation induction of the murine leukemia cell line. NFS-60. Western and Northern blot analysis showed G-CSF protein and G-CSF-mRNA indistinguishable in size from those of normal controls. We conclude that PBMC of the SCN patients tested are capable of synthesizing and secreting biologically active G-CSF in vitro.
Induction of protein kinase C mRNA in cultured lymphoblastoid T cells by iron-transferrin but not by soluble iron, Iron-transferrin (FeTF) is an essential growth factor required for proliferation of lymphoid cells. FeTF activates protein kinase C (PKC) in the lymphoblastoid T-cell line. CCRF-CEM. We have treated CEM cells with human FeTF. then examined levels of PKC mRNA by hybridization analysis using cDNA probes specific for alpha-. beta-. and gamma-PKC subspecies. CEM cell mRNA hybridized with the beta-subspecies probe but not with probes for alpha- or gamma-subspecies. After exposure to FeTF an increase in PKC-beta mRNA was detectable at 10 minutes. peaked at 12 hours. and was sustained for 72 hours. Nuclear transcription assays demonstrated that rates of PKC-beta mRNA transcription were increased in FeTF-treated cells. By contrast. steady state levels of PKC-beta mRNA did not increase after treatment of cells with apotransferrin or gallium TF. Similarly. treatment with soluble iron as ferric ammonium citrate did not increase steady state levels of PKC-beta mRNA. despite producing a marked increase in cellular ferritin content. Ferritin increased from a baseline value of 63 ng/10(6) cells to 98 and 100 ng/10(6) cells in CEM cells treated for 1 hour with ferric ammonium citrate or FeTF. respectively. FeTF did not increase cytoplasmic-free calcium in CEM cells loaded with fura-2. indicating that binding of FeTF to transferrin receptors did not open membrane Ca2+ channels or release intracellular Ca2+. In addition. pretreatment of cells with desferrioxamine. but not ferrioxamine. blocked the FeTF-induced increase in PKC-beta transcripts. Therefore. iron as FeTF (not soluble iron or nonferric TF) stimulates transcription of the CEM cell PKC-beta gene. Transcriptional rate of the PKC-beta gene does not correlate with cellular iron content as judged by ferritin measurements. Furthermore. the requirement for FeTF does not appear to reflect activation of a classic agonist pathway as judged by stable cellular Ca2+. These data suggest that delivery of iron by FeTF to one or more specific cellular compartments may stimulate PKC-beta gene transcription in CEM cells.
Protection from arabinofuranosylcytosine and n-mustard-induced myelotoxicity using hemoregulatory peptide pGlu-Glu-Asp-Cys-Lys monomer and dimer, We have previously shown that the synthetic peptide pGlu-Glu-Asp-Cys-Lys (pEEDCK monomer) inhibits the cytostatic drug-induced proliferation of hematopoietic stem cells CFU-S. Keeping CFU-S quiescent by pEEDCK treatment renders them insensitive to cycle-specific cytostatic drugs and leads to reduced toxicity. Here we show that pEEDCK application during repeated (twice) administration of clinically relevant (nonlethal) 1-beta-D-arabinofuranosylcytosine (Ara-C) doses reduced the percentage of CFU-S in S-phase from 60%-70% to 25%-30% and led to a sustained stem cell number in the bone marrow (BM). whereas unprotected mice had lost about 75% of their CFU-S population. Owing to its cysteine content. the pEEDCK monomer is easily oxidized. The resulting dimer (pEEDCK)2 is a potent stimulator of hematopoiesis. As we show. it can be used for postchemotherapy acceleration of hematologic recovery. similar to the use of recombinant hematopoietic growth factors. A single injection of 30 micrograms/kg pEEDCK monomer to mice 2 hours before the second Ara-C injection retarded onset of neutropenia (by 2 to 3 days) and improved recovery after depression. The quantitative degree of neutropenia was not changed. Postchemotherapy (Ara-C administered twice. followed by N-mustard) infusion of the stimulatory (pEEDCK)2 dimer (1.4 micrograms/kg/d) produced a 4.6-fold increase of progenitor levels (6.7 CFU-GM/1.000 BM cells v 1.45 CFU-GM/1.000 in normal mice) 2 days after the end of the cytostatic treatment when CFU-GM were not detectable in unprotected mice. This increase was followed after several days by strongly elevated granulocyte counts. which remained high for approximately 1 week. Up to 75% of the peripheral leukocytes were mature polymorphonuclear leukocytes (PMN) during this phase. Ara-C (twice) and monomer treatment as above followed by dimer infusion resulted in the complete protection of hematopoiesis. Mice treated with the protective pEEDCK monomer plus stimulatory dimer did not develop the leukocyte depression noted in unprotected animals. The inhibitory monomer appears to keep the stem cell population numerically and qualitatively intact. thus providing optimum target cell conditions for the subsequent stimulator (dimer) treatment. Our results show that the hemoregulatory peptide monomer and dimer can be used for improving the hematologic status of mice treated with clinically relevant doses of cytostatic drugs (antimetabolite and alkylating. alone and in combination). Combining both peptides can prevent occurrence of neutropenia completely. Both peptides can be obtained easily by chemical synthesis and are also active on human cells. They are thus highly promising candidates for application as multilevel hemoprotectors in cancer chemotherapy.
Vanillin, a potential agent for the treatment of sickle cell anemia, Vanillin. a food additive. has been evaluated as a potential agent to treat sickle cell anemia. Earlier studies indicated that vanillin had moderate antisickling activity when compared with other aldehydes. We have determined by high performance liquid chromatography that vanillin reacts covalently with sickle hemoglobin (HbS) both in solution and in intact red blood cells. Hemoscan oxygen equilibrium curves show a dose-dependent left shift. particularly at low oxygen tensions. Rheologic evaluation (pO2 scan Ektacytometry) of vanillin-reacted HbS erythrocytes shows a dose-dependent inhibition of deoxygenation-induced cell sickling. Ektacytometry also suggests that vanillin may have a direct inhibitory effect on HbS polymer formation. Vanillin has no adverse effects on cell ion or water content. X-ray crystallographic studies with deoxyhemoglobin (HbA)-vanillin demonstrate that vanillin binds near His 103 alpha. Cys 104 alpha. and Gln 131 beta in the central water cavity. A secondary binding site is located between His 116 beta and His 117 beta. His 116 beta has been implicated as a polymer contact residue. Oxygen equilibrium. ektacytometry. and x-ray studies indicate that vanillin may be acting to decrease HbS polymerization by a dual mechanism of action; allosteric modulation to a high-affinity HbS molecule and by stereospecific inhibition of T state HbS polymerization. Because vanillin is a food additive on the GRAS (generally regarded as safe) list. and because it has little or no adverse effects at high dosages in animals. vanillin is a candidate for further evaluation as an agent for the treatment of sickle cell disease.
Molecular defect of a phosphoglycerate kinase variant (PGK-Matsue) associated with hemolytic anemia: Leu----Pro substitution caused by T/A----C/G transition in exon 3, We have identified the mutation in a phosphoglycerate kinase variant (PGK-Matsue) associated with severe enzyme deficiency. congenital nonspherocytic hemolytic anemia. and mental disorders. The mRNA coding for PGK was reverse transcribed and amplified by the polymerase chain reaction. Nucleotide sequencing of the variant cDNA showed a point mutation. a T/A----C/G transition in exon 3 of the variant gene. No other mutation was found in all coding regions of PGK-Matsue. The nucleotide change created an additional NciI cleavage site in the variant gene; thus. the NciI fragment types detected by Southern blot hybridization differ in the variant DNA and normal DNA. The mutation should cause Leu----Pro substitution at the 88th position from the NH2-terminal Ser of PGK. Because the Leu----Pro substitution is expected to induce serious perturbation and instability in the protein structure. the severe enzyme deficiency is mainly caused by more rapid in vivo denaturation and degradation of the variant enzyme.
Rate of deoxygenation and rheologic behavior of blood in sickle cell anemia, To understand the relationship between deoxygenation rate. rheologic behavior. and red blood cell (RBC) morphologic characteristics of blood in sickle (SS) cell anemia. washed oxy SS RBC suspensions (hematocrit. 40%) were subjected to relatively fast and gradual deoxygenation procedures. Relatively fast deoxygenation resulted in 50% decline in percent hemoglobin oxygen saturation (%HbO2) within 1 minute. The SS suspensions following relatively fast deoxygenation showed two distinct phases in viscosity profiles. First. there was a sharp increase in individual viscosities to a peak value at 7 minutes of deoxygenation. Second. prolonged deoxygenation resulted in a 27% to 37% decrease in individual viscosities at 30 minutes as compared with the respective peak values at 7 minutes. Most of the viscosity increase (ie. about fourfold) occurred within the first 3 minutes of relatively fast deoxygenation. Scanning electron microscopy and differential morphologic analysis of deoxy cells showed that at 7 minutes a majority of cells had a granular appearance that was characterized by a bumpy irregular surface and the presence of small spicule-like projections. Prolonged deoxygenation resulted in the appearance of a large percentage of elongated cells that were unlike typical sickle cells. Transmission electron microscopy showed that the elongated shape resulted from the alignment of HbS polymers into long projections. In contrast. gradual deoxygenation over a period of 30 minutes resulted in a progressive increase in viscosity and in the formation of typical sickle shapes and holly leaf cells. The results show that at matching %HbO2. the SS suspensions containing mainly granular shaped cells after 7 minutes of relatively fast deoxygenation are as viscous as the gradually deoxygenated suspensions that contain classic sickle shapes and holly leaf forms. while the suspensions having a large percentage of elongated cells (30 minutes after relatively fast deoxygenation) are the least viscous. The two distinct time-dependent viscosity phases observed after relatively fast deoxygenation probably result from differences in the RBC shape characteristics reflecting physical attributes of the polymer. which could affect cell orientation in the viscometric flow.
Calcium ionophore, A23187, induces commitment to differentiation but inhibits the subsequent expression of erythroid genes in murine erythroleukemia cells, Murine erythroleukemia (MEL) cells are a useful model for studying the processes that regulate erythroid differentiation because exposure of these cells to a variety of chemical inducing agents results in expression of erythroid-specific genes and the resultant loss of cellular immortality. Previously it has been suggested that the calcium ionophore. A23187. has effects on the early cellular events that lead to the commitment of these cells to differentiation. but was not in itself sufficient to induce differentiation. We demonstrate here that A23187. as well as another calcium ionophore. ionomycin. are capable of inducing commitment to differentiation. Unlike other inducing agents. continual exposure to A23187 inhibits transcription of the erythroid-specific genes. beta-globin and Band 3. This effect is not attributable to an increase in cytosolic calcium concentration. because cells induced by ionomycin produce normal amounts of hemoglobin. These effects of A23187 on MEL cells confirm that commitment to differentiation is a distinct event from the subsequent transcriptional activation of erythroid genes. The ability of both ionophores to induce commitment to differentiation suggests that an increase in cytosolic calcium can trigger commitment to differentiation. These agents should prove useful in investigating the cellular processes that are responsible for commitment to differentiation.
Integration of hepatitis B vaccination into rural African primary health care programmes, OBJECTIVE--To determine the efficacy of hepatitis B vaccine when added to the routine expanded programme on immunisation under field conditions in rural Africa. DESIGN--Infants were immunised according to two schedules--an early schedule at birth. 3 months. and 6 months and a later schedule to correspond with routine vaccination in the expanded programme on immunisation at 3 months. 4 1/2 months. and 6 months. SETTING--Venda. northern Transvaal. South Africa. a self governing region of 7460 square kilometers varying from rural villages to small towns. SUBJECTS--The 1989 birth cohort of Venda. MAIN OUTCOME MEASURES--Coverage for hepatitis B vaccine at first. second. and third doses; serological assessment of vaccine efficacy by prevalence of antibodies to hepatitis B surface antigen in infants who had completed the three dose course of immunisation; antibodies to hepatitis B core antigen to determine if natural infection occurred. RESULTS--Vaccine coverage for hepatitis B dropped sharply from 99% to 53% to 39% for the first. second. and third dose respectively. In contrast. vaccine coverage was maintained at 97-99% for the three doses of poliomyelitis vaccine. Serological evaluation of vaccine efficacy showed that only 3.5% of recipients of all three doses failed to develop antibodies to hepatitis B surface antigen. Only 6.6% of vaccine recipients were vaccinated according to either the early or later schedules whereas 93.4% received their doses of vaccine at intervals beyond the limits of either of the planned schedules. There was. however. no significant difference in seroconversion to the surface antigen between the "unscheduled" or scheduled groups of those who were vaccinated according to the early or late schedules. The pattern of prevalence of antibodies to hepatitis B core antigen. which showed a sharp fall in children aged over 7 months. suggested that the antibodies were acquired passively rather than by active infection. CONCLUSIONS--Supplementation of the present expanded programme on immunisation with hepatitis B vaccine in rural Africa is fraught with difficulties. However. the vaccine was effective within a fairly wide spacing of dosage. Adding hepatitis B vaccine to diphtheria. tetanus. and pertussis as a tetravalent vaccine is proposed as a means of effectively integrating it into the expanded programme on immunisation in Third World settings.
Rationale for different chemotherapeutic and radiation therapy strategies in cancer management, The two primary therapeutic strategies in cancer have been to give either chemotherapy and radiation therapy together or give a complete course of one treatment modality before starting the second. Clinical studies show that toxicity has been one of the major deterrents to substantial improvements in cancer management when the two modalities are administered together. On the other hand. the prolonged time necessary to administer all of one modality followed by the other makes it likely that repopulation of the tumor during sequential treatment will diminish therapeutic effectiveness. A third strategy of giving chemotherapy and radiation therapy has been developed. This new regimen was designed to give chemotherapy initially. maintain the chemotherapy schedule to avoid any reduction in its effectiveness. and add radiation therapy as early as possible in between courses of chemotherapy to minimize the development of cross resistance. One of the primary objectives of alternating chemotherapy and radiation therapy is to increase the therapeutic index by reducing toxicity without a significant reduction in therapeutic effectiveness. Recent clinical. experimental. and theoretic results with radiation therapy and chemotherapy for cancer management emphasize the necessity of giving both modalities with the greatest intensity possible in the initial phase of induction therapy. Cancer treatment scheduling determines the toxicity and thereby limits the dose intensity that can be tolerated. Scheduling may also govern the antitumor effect directly; however. normal host tissue makes the determination of the direct effects on the tumor difficult. if not impossible. in clinical studies. Well-defined experimental solid-tumor systems provide the means for determining directly the relationship between toxicity and antitumor effects in relation to tumor burden and total therapeutic dose. In addition. its relationship to dose intensity and scheduling can be determined by the using more sophisticated research techniques. such as response surface methods. Well-defined clinical protocols to determine how to interact chemotherapy with radiation therapy more effectively hold considerable potential for rapid improvement in treatment of radiosensitive and chemosensitive cancers.
13-cis-retinoic acid in the treatment of elderly patients with acute myeloid leukemia. A phase II pilot study of the Eastern Cooperative Oncology Group, The management of acute myeloid leukemia in the elderly (65 years and older) is unsatisfactory because of poor patient tolerance of standard myeloablative chemotherapy. The authors conducted a Phase II study to evaluate the effectiveness and toxicity of 13-cis-retinoic acid (CRA) in the therapy of elderly patients with acute myeloid leukemia (AML). Patients presenting with leukocyte counts less than 20.000/microliters were treated with CRA alone. Those with leukocyte counts of 20.000/microliters or greater were pretreated with hydroxyurea. followed by CRA. Twelve of 18 patients received at least 4 weeks of CRA and were thus considered evaluable for toxicity and response. No objective responses were observed. Cis-retinoic acid administration was well tolerated; only modest dermatologic. musculoskeletal. and gastrointestinal toxicity was observed. Alternative therapeutic strategies should be investigated in this subpopulation of AML patients.
A brief-duration combination chemotherapy for elderly patients with poor-prognosis non-Hodgkin's lymphoma, Curative combination chemotherapy is available for many patients with aggressive non-Hodgkin's lymphoma (NHL); however. treatment of elderly patients with these regimens is difficult due to excessive toxicity. From 1983 to 1988 the authors treated 26 patients 65 years and older with aggressive NHL with a novel 8-week chemotherapy regimen containing bleomycin. etoposide. cyclophosphamide. doxorubicin. methotrexate with leucovorin. and prednisone (BECALM). designed to preserve dose intensity and minimize toxicity. Median age was 75 years. Histologic types included the following: 20 intermediate grade (16 large noncleaved cell; two large cleaved cell; one intermediate grade. unspecified); six high grade (four small noncleaved cell; one immunoblastic sarcoma B-cell; one high grade. unspecified). Twenty-one patients were Stage III or IV. Twenty-two of 26 patients had one or more of the following: tumor greater than 10 cm; multiple extranodal sites; lactate dehydrogenase (LDH) 400 IU/l or greater; small noncleaved cell histologic type. Chemotherapy consisted of bleomycin 20 U intravenously (IV) weeks 1 and 7; etoposide 75 mg/m2 IV every day x 3 days on week 4; cyclophosphamide 600 mg/m2 IV weeks 1. 4. 7; doxorubicin 40 mg/m2 IV weeks 1. 7; methotrexate 50 mg/m2 IV weeks 1. 2. 4. 5. 7. 8 with oral leucovorin rescue; prednisone 60 mg orally for 10 days on weeks 1. 4. 7. Eighteen patients completed the 8-week treatment course. There were 13 complete responses (CR); seven patients remain in continuous CR at a median follow-up of 37.5 months. There have been five relapses. including one late relapse; and one patient died of an intercurrent illness in CR. Overall and actual event-free survivals are 38% and 27%. respectively. The major toxicities were neutropenic fever and mucositis. There were four treatment-related deaths. The authors conclude that BECALM chemotherapy can be administered to elderly patients with aggressive NHL. Although neurotoxicity and cumulative toxicity from bleomycin and anthracycline are avoided. the regimen remains moderately toxic. particularly with respect to myelosuppression. Treatment results compare favorably with other reported regimens in this group of patients with multiple poor prognostic features.
Stage IV neuroblastoma in infants. Long-term survival, Before the advent of multiagent chemotherapy. the prognosis for patients with Stage IV neuroblastoma of all ages was dismal. More recently. marked improvement in infants with Stage IV neuroblastoma has been reported. Twenty-four infants with Stage IV neuroblastoma have been treated at the Dana-Farber Cancer Institute/The Children's Hospital. and the Joint Center For Radiation Therapy. Boston. Massachusetts. between 1970 and 1988. Twenty-three of these patients were treated with multiagent chemotherapy and one with a single drug. In the initial report. ten of 11 patients were alive without evidence of disease after intensive therapy. In this report the authors update their initial series of patients and include 13 additional patients who subsequently presented to our institutions with Stage IV neuroblastoma younger than 1 year of age. The 5-year actuarial event-free survival for the 24 patients is 75%. No patient without bone metastases died from neuroblastoma. and 12 of 16 patients with bone metastases remained disease free. These results confirm that infants with Stage IV neuroblastoma have a very good prognosis when treated with intensive multiagent chemotherapy.
18F-2-deoxy-2-fluoro-D-glucose uptake into human tumor xenografts. Feasibility studies for cancer imaging with positron-emission tomography, The positron-emitting glucose analogue 18F-2-fluoro-2-deoxy-d-glucose (FDG) was evaluated for its accretion into the following subcutaneous human tumor xenografts in nude mice: B-cell lymphoma (Namalwa or Raji). ovarian carcinoma (HTB77). colon cancer (SW948). choriocarcinoma (BEWO). bladder cancer (UM-UC-2). renal cell carcinoma (UM-RC-3). neuroblastoma (Mey). melanoma (HTB63). and small cell lung carcinoma (NCI69). Two hours postinjection. tumor uptakes ranged from 0.027 (colon cancer) to 0.125% kg injected dose/g (melanoma); and was greater than 0.085 in the Namalwa lymphomas and the renal cell carcinomas. Tumor-blood ratios of up to 23:1 were seen 2 hours postinjection (melanoma) with a mean tumor-blood ratio for all tumors of 12.3 +/- 1.8. Uptake in the other tumors was intermediate. When evaluated. tumor uptake was slightly greater at 1 than at 2 hours postinjection. although target-background ratios were generally higher at 2 hours postinjection. This compound. FDG. may have broad applicability as a tracer for positron-emission tomographic imaging of many human malignancies.
Detection of somatic DNA alterations in ovarian cancer by DNA fingerprint analysis, The M13 phage single-strand DNA probe which recognizes highly polymorphic loci was applied to HinfI-digested DNA isolated from tumor tissue and peripheral leukocytes from 20 patients with ovarian cancer. An average of 22 minisatellite-containing DNA fragments were observed per individual. DNA fingerprint analysis revealed a change in restriction-fragment-length patterns in the DNA from 12 of 20 (60%) tumors compared with the patient's constitutional DNA. Deletion of one or more bands from the tumor was recognized by the probe in seven cases. new bands were identified in two. and intensity shift was demonstrated in eight. The authors conclude that the unmapped M13 minisatellite probe is a useful method for identifying cancer-related somatic DNA alterations.
Association of interleukin-2 therapy with staphylococcal bacteremia, The authors prospectively monitored patients undergoing leukapheresis for peripheral stem cell harvesting (PSCH) or lymphokine activated killer (LAK) cell generation for 3 weeks after catheter placement for evidence of local or systemic infections. Over a 1-year period. 16 patients underwent leukapheresis for PSCH in preparation for autologous bone marrow transplantation (ABMT). The original catheters remained in place an average of 20 days without any documented infections. Seventeen patients underwent leukapheresis as part of a low-dose interleukin-2 (IL-2) treatment for LAK cell generation. and their catheters remained in place an average of 20.2 days with three documented episodes of bacteremia (18%). Eight patients treated with high-dose IL-2 also underwent leukapheresis for LAK cell generation and their catheters remained in place an average of 12 days with three documented episodes of bacteremia (38%). In all cases of bacteremia. Staphylococcus species were isolated from the blood. The IL-2 exposure level was associated with the risk of bacteremia (P = 0.01). Other potential risk factors (e.g.. number of pheresis procedures. complement level. serum immunoglobulin levels. absolute neutrophil count) were not related to this risk.
Immunohistologic localization of alpha, mu, and pi class glutathione S-transferases in human tissues, Human alpha. pi. and mu class glutathione S-transferases (GSH S-T) have been localized immunohistologically in a variety of organs. Alpha GSH S-T are found principally in hepatocytes. proximal convoluted tubules of kidney. the deep reticular layer of the adrenal gland. interstitial cells of the testis. and oxyntic cells of the stomach. The pi GSH S-T are present in relative abundance in ductular. as opposed to parenchymal cells in the liver. pancreas. salivary glands. and kidney. The presence of mu GSH S-T in the tissues of certain patients and its absence in the same tissues from other patients has been demonstrated. The pi GSH S-T seems to be most persistently and strongly expressed in tumors but alpha GSH S-T are also found in some neoplasms whereas the mu GSH S-T are occasionally present when the other two transferases are weak or absent.
Lymph nodes in incipient adult T-cell leukemia-lymphoma with Hodgkin's disease-like histologic features, Lymph nodes were examined from four patients with incipient adult T-cell leukemia-lymphoma (ATLL) who had mild lymphadenopathy. fatigue. no or a few atypical lymphocytes in their peripheral blood. and integrated proviral human T-cell lymphotrophic virus type I (HTLV-I) DNA in the nodes. The HTLV-I DNA was detected by southern blot analysis and/or polymerase chain reaction in the lymph nodes of all cases. The nodal architecture was preserved. Some scattered or aggregated highly lobular. cerebriform. or Reed-Sternberg-like giant cells were observed. with occasional mitoses and diffuse infiltration of small to medium-sized lymphocytes. with no or minimal nuclear abnormalities in the enlarged paracortex. The giant cells were usually positive for Ki-1 and also for UCHL-1 and other T-cell markers but negative for Ber-H2. Rearrangement and/or deletion of T-cell receptors were found in three of four patients. All patients died within 2 years. with transformation to overt leukemia-lymphoma occurring in three patients. and pulmonary carcinoma in one. The incipient or prelymphomatous phase of ATLL should be differentiated from Hodgkin's disease because of the distinctly different prognoses of these two diseases.
Correlation between bromodeoxyuridine-labeling indices and patient prognosis in cerebral astrocytic tumors of adults, Bromodeoxyuridine (BUdR). a nonradioactive thymidine analogue. is taken up by cells in S-phase. and the ratio of BUdR-positive nuclei to the total number of cells counted is defined as the labeling index (LI). In this study. BUdR LI and the clinical course of 50 cerebral astrocytic tumors in adults were analyzed. The obtained LI distributed continuously in a broad range from 0% to 19%. The mean LI of 28 glioblastomas. 12 anaplastic astrocytomas. and ten astrocytomas were 8.5%. 4.2%. and 1.2%. respectively. and these differences were statistically significant (P = 0.05). In the analysis of LI and the recurrence-free period (RFP). regardless of the histologic findings. 23 patients with LI more than 5% had a median RFP of 9.0 months; the median RFP of nine patients with LI of 3% to 5% was 14.7 months. Nine of 13 patients with LI less than 3% have not yet recurred after a median follow-up of 36 months. These differences were also statistically significant by the generalized Wilcoxon test (P = 0.05). The proliferative potential reflected by the BUdR LI is a good clinical indicator for predicting the rate of tumor growth in cerebral astrocytic tumors. In combination with histologic diagnosis. BUdR LI could help in determining a patient's prognosis more precisely.
Association between DNA ploidy pattern and cellular atypia in colorectal carcinomas. A new clinical application of DNA flow cytometric study, Fresh tissue specimens from 406 colorectal carcinomas were analyzed by DNA flow cytometric study. and the DNA ploidy pattern was compared with Dukes' stage. histologic grade. and degree of cellular atypia. Sixty-one percent of the carcinomas had a distinct aneuploid DNA pattern. The proportion of aneuploid carcinomas was significantly higher in the advanced Dukes' stages than in the localized ones. A highly significant association was found between DNA ploidy pattern and degree of cellular atypia. whereas no association was demonstrated between DNA ploidy pattern and histologic grade. This finding might indicate that cellular atypia has a stronger prognostic impact than the growth pattern of the tumor. The authors suggest that flow cytometric DNA quantification may replace assessment of cellular atypia in the histologic evaluation. Furthermore. together with earlier findings by others. these results indicate that the degree of cellular atypia may be conserved during the development from adenomas to carcinomas.
Thermography as a predictor of prognosis in cancer of the breast, Although thermography is generally considered to lack sufficient sensitivity to be a useful in diagnosis of cancer of the breast. the association of a thermal abnormality with some breast cancers cannot be discounted. Breast cancers demonstrating such a thermographic abnormality have been reported to be associated with decreased survival when compared with patients with no such change. In a study of 214 patients confirmed to have breast cancer without distant metastases. 121 were found to have a thermographic abnormality. Patients whose tumors were thermographically abnormal had significantly larger primary lesions and a higher proportion of metastatic axillary lymph nodes. However. both the 5-year survival and the 5-year disease-free survival were not significantly different from patients who had no thermographic abnormality.
Depression of serum melatonin in patients with primary breast cancer is not due to an increased peripheral metabolism, Serum melatonin and its main metabolic product 6-sulfatoxymelatonin were determined in 17 patients with breast cancer (BC) with either a fresh primary tumor (nine) or a secondary tumor (eight) as well as in four patients with untreated benign breast disease (controls). Circadian rhythms were detected in all groups with acrophases around 2 AM for melatonin and around 3 AM for 6-sulfatoxymelatonin. The nocturnal melatonin and 6-sulfatoxymelatonin concentrations were significantly depressed in the group of patients with primary breast cancer compared with controls (P less than 0.01. P less than 0.025). The circadian amplitudes of melatonin and 6-sulfatoxymelatonin were also depressed by 81% (P less than 0.01) and 63% (P less than 0.01). In contrast. patients with secondary BC had nocturnal melatonin and 6-sulfatoxymelatonin concentrations and amplitudes similar to controls. These results demonstrate that the depression of circulating melatonin in patients with primary BC is not due to an enhanced degradation to 6-sulfatoxymelatonin in the liver but must be due to a reduced activity of the pineal gland.
The human costs of cancer and the response of the National Cancer Program, The three foundations of the National Cancer Program are basic research. clinical trials (in prevention and treatment). and cancer centers. These foundations have supported a great deal of progress against cancer over the past 20 years. Nevertheless. a number of challenges remain. and continued progress will depend on the speed with which research advances can be translated into practical realities. Poverty is a risk factor for cancer incidence and mortality. Thus. a lack of access to the technologies generated by the National Cancer Program can be a force for bringing about differential burdens of cancer in underserved populations.
Changing cancer care in the 1990s and the cost, Progress in cancer research in the 1980s has led to predictions of a technologic explosion in the 1990s. Yet. with this progress there has been a groundswell of protest at the rapidly escalating costs of health care. More than $600 billion was spent on health care in 1989 and estimates of $1.5 trillion are made for the year 2000. Repeated attempts at cost containment have failed. It has been suggested that only by retarding technologic advances will we be able to control costs. Many observers believe that rationing of health care is the only solution. but new technology not only improves cancer care. it often decreases cost. It is not rational to retard advances that may later reduce costs. nor is it humane to retard advances that improve care. even if they cost more. In identifying priorities we should begin with the principle that treatments be restricted to clinical trials unless they have been demonstrated to prolong survival or improve the quality of life. If the payers reimburse procedures in an investigative setting. they will be on firm ground when they deny support for those same procedures outside an investigative setting. This is both an ethical and a fiscally responsible position for the third parties to take. It will not be easy for the profession or for the payers to deal with these problems. Public education and patient education will be key elements of any solution. Shifting the blame from politician to payer to professional will only make the problems worse.
Forces of change in the health care system. Implications for cancer care in the 1990s, Dramatic changes will occur in the health care system during the 1990s which will profoundly affect the delivery of care for cancer. Perhaps the most important factor is the aging of the population. As the proportion of people who achieve old age increases. the absolute prevalence and incidence of cancer will increase despite improved treatment techniques. This phenomenon will increase health care expenditures despite ongoing efforts to control costs. Second. there will be continuing efforts at cost control and increased emphasis on quality assurance and outcomes by third party payers. Providers will be scrutinized and compared with one another. The large payers of the nation's health care bills will demand proof of outcome and cost leading to bidding by providers and payment only to those who have the best outcome for the least money. Third. there will be an increasing emphasis on prevention and screening. in public health policy. an approach that may conflict with personal freedom. Fourth. there will be increasing deliberations and questions about the ethics of the health care system and treatment decisions. There will be continuing debate about the need for a rationing of health care and the right of individual privacy versus the states' right to preserve life. These changes will impact on all health care professionals whose practice includes patients with cancer.
Legislative influences on cancer care, Deficit reduction politics was a major force in policymaking in the 1980s and a pervasive fact of life in the development of health policy. The Medicare budget was habitually used to find savings for deficit reduction and reforms. such as how to address the problem of 31 to 37 million uninsured Americans. were postponed. The 101st Congress did produce major physician payment reforms and in the spring of 1990. the Pepper Commission issued its recommendations for access to care and long-term care. Less sweeping but significant proposals affecting cancer care were considered by Congress. For example. positive actions were taken on anti-smoking and food labeling proposals. Funding for the National Institutes of Health was increased. and there was a growing awareness of the threat to biomedical research presented by assaults on animal research facilities.
Access to cancer prevention, detection, and treatment, The American Cancer Society Hearings on Cancer and the Poor made visible to the nation the harsh realities and consequences of lack of access to health care among the poor and uninsured in America. Access to care is more than mere availability; it is also financial accessibility. effectiveness. acceptability. appropriateness. and comprehensiveness of care. The problems and consequences of lack of health care access and its impact on the cancer problem among poor Americans are explored. and ways practitioners and public advocates can improve access are suggested. Local communities have risen to action to make health care more accessible. Successful programs have done their research to document access problems; then they have taken their findings to county governments to request additional funding and to health care institutions to request institutional policy and service changes to make health care more available and accessible.
Adjuvant therapy for node-negative breast cancer. The use of prognostic factors in selecting patients, Patients with invasive breast cancer and pathologically negative lymph nodes (NO) have a favorable 10-year survival rate. particularly with small (less than 1 cm) primary tumors. Overall. however. 20% to 35% will experience recurrence with local therapy only. Adjuvant chemotherapy or tamoxifen have prolonged disease-free survival (DFS). but not overall survival (OS). Unanswered questions of optimal end point (DFS or OS) and the risk of treating many to benefit few have prompted clinicians to use prognostic indicators to facilitate treatment recommendations. Currently. the most readily available and accurate information comes from TNM staging. pathologic features. and hormone receptors. Ploidy. S-phase fraction. HER-2-neu amplification or over-expression. and cathepsin-D may be useful prognostic indices. Until a more precise system of weighing several prognostic variables is developed. the decision to recommend adjuvant systemic therapy in this generally good prognosis group will have to be thoughtfully considered by patient and physician. Whenever possible. patients should be encouraged to enter clinical trials.
The role of chemotherapy for node-negative breast cancer, Approximately 25% of women with early stage breast cancer and negative axillary nodes will eventually die of metastatic disease. Some studies have shown a recurrence rate of 40% or more at 10 years in this relatively good prognostic group. The incidence of breast cancer continues to increase approximately 1% per year with a great increase in the frequency of early stage disease (particularly in situ carcinoma). The increased use of mammography and physical examination with appropriate follow-up will increase the frequency of diagnosis of node-negative patients compared with those with more advanced stages. Women with positive axillary nodes who are premenopausal benefit from adjuvant chemotherapy. whereas those who are postmenopausal have shown a clear reduction in mortality when treated with tamoxifen. It is even more reasonable to speculate that women with node-negative disease could have an even greater benefit from adjuvant therapy because they have a lower tumor burden at the time of diagnosis. Compared with earlier clinical adjuvant trials. more recent studies (1981-89) have shown a disease-free survival advantage for node-negative breast cancer patients treated with adjuvant chemotherapy. Hopefully. the differences noticed in disease-free survival will show a similar survival advantage with further observations. The results of these clinical trials suggest that adjuvant chemotherapy may be of benefit to patients with node-negative disease but do not support the contention that all node-negative patients with breast cancer should receive adjuvant chemotherapy. Some prognostic subgroups (tumor size greater than 2 cm) have shown an overall 10-year survival rate of 92% for women who have not received adjuvant therapy. The benefits versus toxicities of adjuvant therapy should be carefully evaluated before the initiation of adjuvant therapy.
Measuring the quality of care for the cancer patient, In recent years. the efforts to better define quality of patient care have focused on attempts to improve on the measurement of quality. These efforts raise three questions: (1) Why attempt to measure quality? (2) What is the best way to measure quality of care of the cancer patient? and (3) What must be done to achieve this? Three main reasons for measuring quality of patient care are to describe the current state. plan strategies for improvement. and implement and monitor improvements. To measure quality. both the definition of quality and the tools available for measurement must be addressed. The difficulty in developing a measurable definition of quality is achieving agreement on the measurable components of quality. The tools to measure quality have evolved to focus on monitoring of key indicators for comparative use. The utility of indicators lies in demonstrating that they have the capacity to identify opportunities for improving care. The Joint Commission is improving measurement tools through the development and testing of oncology indicators for reliability and the capacity to identify opportunities for improving care. The development and teaching of new quality improvement methods to health care professionals also is necessary.
Continuity of cancer care, The importance of providing continuity in the care of all patients with major medical problems. such as cancer. has widespread acceptance in our current health care system. From the perspective of an oncology social work clinician. this article offers a definition of the concept of continuity of care. examines factors influencing its provision in oncology. and reviews key components in continuity of cancer care planning and implementation. It also examines some innovative efforts in practice to improve continuity.
A provider's view of prevention approaches in a prepaid group practice, Kaiser Permanente's health care delivery system and its efforts to integrate public health preventive medicine and curative medicine are described. The author advocates an increased focus on prepaid delivery systems like Kaiser Permanente as the best vehicle to achieve the full promise of health screening. health education. and life-style modification. Because these systems have brought the proper incentives into alignment. prevention and health promotion have become effective tools to achieve cost containment goals. A number of Kaiser Permanente projects are highlighted that demonstrate integration of public health preventive medicine and curative medicine: the Northern California Region's uniform health appraisal examination. which is linked with health education and counseling; the Colorado Region's breast cancer screening program. which is expected to show a higher rate of early breast cancer detection than in the general population; cooperative efforts with two Northern California towns to reduce smoking through a community-wide project; educational theatre programs aimed at early intervention and education of children before high-risk behaviors have become established life-style; and research projects that are possible because of an integrated program. Also. several forces that could endanger integrated systems including cost control practices of employers and insurers. and public policy such as mandating specific benefits. are noted.
Changing demographics in the United States. Implications for health professionals, The coming decade will bring dramatic changes in the composition of the American population. Changes in immigration laws. illegal and legal immigration into this country. and the aging of the "baby boomers" will all result in profound changes in the demographics of this country. These demographic changes will necessitate alterations in all aspects of the health care system. This article focuses on the projected changes that will occur in relation to the elderly. Hispanics. Asian Americans. and the economically disadvantaged. and on the related implications for health care professionals. The cancer incidence and mortality rates for each discussed minority group differ from the rates presently reported for white Americans. Thus. health professionals will have to be aware of the differences among these groups and tailor their primary and secondary prevention efforts accordingly. The future task for all health care providers serving minorities and the elderly will be to familiarize themselves with the special health problems of the population with whom they work and with the ethnocultural barriers that deter proper use and delivery of health services.
Clinical trials. Access and reimbursement, Clinical trials continue to play an extremely important role in clinical oncology. but of the nearly 1 million cancer patients diagnosed in the United States each year. only 2.5% (25.000) participate in such trials. Access to clinical trials has been enhanced by the adoption by the NCI of a promotional campaign that involves seminars. dissemination of information to national and local news media. and assisting in making information about clinical trials available to patients and physicians. Factors that hinder accrual of patients to clinical trials include: (1) physicians' concern about losing contact with patients. (2) physicians who feel that "experimental therapy" is not as good as "standard therapy." and (3) the time it takes to discuss and implement clinical trials. Reimbursement for clinical trials has also become a major concern. Who should pay for clinical research? Many insurance companies have been reluctant to pay for "experimental therapy" but will pay for "standard therapy." If this trend continues. the whole concept and organization of clinical trials. i.e.. Phase I. II. and III trials. will be greatly hindered. Solutions must be found. and third party payers need to realize that an investment in clinical trials today will decrease the long term costs of state-of-the-art care.
Patient perceptions, The cancer patient's perceptions about treatment. prognosis. and long-term care have emerged in the context of interaction with the changing healthcare system. A brief overview of cancer patients' perceptions regarding their disease and subsequent care is provided. The economic. organizational. and technological environment in which this care is provided and the patient's perceptions of that environment are discussed. In addition to economic pressures. the ever-increasing number of cancer patients. prolonged survival. and patients' perceptions have created changes in the healthcare system. These changes are mediated by important socioeconomic. cultural. and demographic characteristics of the cancer patient. Recommendations to address these changes are discussed.
Alternative therapies, 1990. An overview, The availability of alternative therapies for many health problems is a well-documented historical fact. Alternative therapies are generally understood to be those therapies outside of the usually accepted medical therapies for disease processes. such as cancer. arthritis. diabetes. psoriasis. lupus. and AIDS. Some other descriptive terms utilized include questionable. unproven. dubious. unorthodox. and unconventional. These alternative therapies vary from active involvement in promotion of one's own health (exercise. diet) to quackery. In today's society. with emphasis on self-involvement with individual health. metabolic therapies have become the most widely practiced alternative therapy. In an antiestablishment. anti-intellectual climate. with an increasingly mobile. rootless population. alternative therapies are in somewhat of a renaissance. Some confusion exists regarding clinical trials and alternative therapies in the general population and in the noninvolved health profession. Various studies indicate that from 10% to 50% of cancer patients use some alternative therapy. with national expenditures ranging as high as $10 billion annually. Better-educated patients with higher-than-average income are more likely to choose alternative therapies and are frequently supported by a physician in this choice. Most cancer patients continue under a physician's care and continue usual therapy while pursuing alternative methods. Approximately 5% of cancer patients abandon appropriate therapy and pursue potentially harmful alternative methods. A variety of sociomedical questions are brought forth by studies of the use of alternative therapies. A great need for public and professional education regarding this subject is evident.
Facilitating clinical trials. The expanding role of the nurse, Clinical trials are becoming increasingly difficult to carry out in the face of a changing health care delivery system. The reluctance of third party payers to reimburse for experimental therapy and the growing practice of providers to limit resources allocated for the care of cancer patients undergoing such therapies seriously curtail the ability of investigators to test new cancer treatments clinically. In addition. certain beliefs. attitudes. and perceptions held by the public may interfere with patient case accrual. Nurses can help facilitate both accrual to and conduct of clinical research. This article addresses selected consumer- and provider-centered factors that inhibit clinical research. The expanding role of the nurse in the areas of public education. informed consent. direct care. and collaborative research is also described.
Clinical trials. A family physician's perspective, Primary care specialists diagnose and manage a wide variety of problems. Cancer is one relatively small part of the practice of these clinicians. Patients with newly diagnosed cancer usually are referred to surgical specialists. Primary care physicians often determine future events after surgical care. Oncologists may or may not be consulted depending on tumor type and past experiences of the physician. patient. and patient's family. Many primary care physicians think that chemotherapy regimens given empirically have little if any scientific evidence to support their use. Side effects of cancer treatment regimens often cause suffering and profoundly effect quality of life. There is a lack of communication between oncologists and primary care physicians. Dialogue between oncologists and primary care doctors may help solve communication problems. Clinical trials help determine which treatments are effective. Many clinical trials are conducted at the community hospital level. Most primary care physicians support clinical trials once they know about them. Education activities should be directed at promoting patient referral for participation in clinical trials.
An inner city cancer prevention clinic. Design, methods, and early results, An American Cancer Society demonstration pilot project is underway that is designed to provide comprehensive cancer prevention-related services to the underserved community of West Oakland. California. An array of cancer prevention services are being made available through an inner-city clinic (West Oakland Health Center). including cancer risk assessments and education about cancer. physical examinations for cancer. teaching of self-examination procedures. smoking cessation. and nutrition counseling. appointments for Pap smears. sigmoidoscopy. mammography. and other more specialized screening procedures. case management for findings suspicious for cancer. and community education programs. Described is the process of implementing these services. their utilization. and their impact (after 6 months).
Increasing the cancer screening of the medically underserved in south Florida, Diagnosis and treatment of cancers at advanced stages have contributed to a significantly lower survival rate among individuals of low socioeconomic status compared with those in higher brackets. In an effort to increase the accessibility and acceptability of cancer screening among such individuals in Dade County. Florida. the Cancer Control Division of the Sylvester Comprehensive Cancer Center at the University of Miami School of Medicine initiated a pilot early detection program in 1987. The program initially provided breast cancer screening for women. aged 40 and older. who attended ten community health care centers located in low-income neighborhoods. With the selection of Miami by the American Cancer Society as one of three sites for conducting a screening demonstration project for the socioeconomically disadvantaged. this program has recently been expanded to include pelvic screening for women. aged 40 and older. and prostate screening for men. aged 65 and older.
Prevention and changing demographics. The underserved and cancer, This paper illustrates the complexity of the "cancer control in the underserved" problem. especially as it is affected currently. and will be in the future. by the multiple demographic changes in the United States. It does so by extensively quoting from four rather different articles by authors from a variety of backgrounds in health. management. and economics. Another issue is that although the articles quoted refer mainly to secondary and tertiary prevention. they do apply equally to primary prevention and health promotion. Furthermore. the twin issues of priority and ethnic/cultural differences need to be addressed insofar as they affect health risks. risk reduction efforts. early diagnosis. treatment. and rehabilitation/disability reduction. Finally. the point is made that social and structural change of this magnitude cannot occur in the health care system and society at large without the allocation of discrete private and public sector resources.
Cessation of treatment in advanced cancer, A major responsibility for all physicians. but particularly for oncologists. is to recognize the time when active antitumor treatment ceases to have a rational basis. The decision to treat or not to treat at any stage of disease requires an analysis of "the legitimate aims of therapy." We have acquired the ability to cure or prolong survival in an increasing proportion of patients with several types of cancer. For patients who fail to achieve those results and for those with tumors that are rarely amenable to specific therapy. the choice of less surely effective therapy is an option; the patient must participate in the decision. armed with as much information and insight as possible. for conventional and experimental treatment. A distinction must be made between specific antitumor therapy and palliative measures for which cessation is never an option. Happily. cessation of treatment must also be considered when therapy has been so successful that the patient has achieved complete remission. At what point may treatment be discontinued without the danger of relapse? These issues are rarely crisply defined. but primary concern for the patient and careful analysis of the available data can lead to appropriate value judgements.
Primary prevention of cancer. The case for comprehensive school health education, Comprehensive school health education plays an important role in the primary prevention of cancer because so many of the health habits relating to cancer and other diseases have their onset early in life. A comprehensive health education program should begin early in life. Such education must be multifactorial from kindergarten through high school. should involve annual health screening. must be assessed annually. and is most effective when coordinated by a full-time health education teacher. Those concerned about the many problems of health behavior in our society should insist that such programs become mandatory in every state in this nation.
Technetium-99m (v) dimercaptosuccinic acid: a clinical and scintigraphic study in an animal tumour model, Technetium-99m (99mTc) (v) dimercaptosuccinic acid (DMSA) is a new tumour-imaging agent which has been used to image head and neck squamous carcinoma. This study used an established rabbit tumour model to compare palpation versus planar scintigraphy in the detection of superficially transplanted cancers. Palpation detected 83% of tumours measuring less than 2 cm compared with 58% for scintigraphy. Overall. the sensitivity for palpation was 88% (77% specificity) compared with 50% (63% specificity) for scintigraphy.
Intratympanic gentamycin in severe Meniere's disease, From 1982 to 1987. 20 patients with disabling attacks of vertigo and severe hearing loss due to unilateral Meniere's disease were treated with local intratympanic gentamycin. In 18 patients control of vertiginous attacks was achieved. Hearing deteriorated in 8 patients. In spite of complete control of attacks a disabling ablation type of unsteadiness and dizziness affected 7 patients. Two patients required additional treatment after 5-8 months remission. Intratympanic gentamycin seems to be a less useful method of treating severe unilateral Meniere's disease than previously stated. It is. however. a possible alternative to surgical labyrinthectomy with a fair chance of residual hearing preservation.
Immunohistochemical analysis of extracellular components in the glomerular sclerosis of patients with glomerulonephritis, Immunofluorescence and immunoperoxidase staining was carried out to determine correlations between the progression of glomerular sclerosis and changes in the amount or distribution of glomerular extracellular components. including type I. III. IV. and VI collagens. laminin and fibronectin. in patients with IgA nephropathy. membranoproliferative glomerulonephritis and rapidly progressive glomerulonephritis. Staining of type I and III collagens was not observed in glomeruli from normal individuals or patients with mild glomerulonephritis. In the advanced stages of glomerulonephritis. the staining of type IV and VI collagens. laminin and fibronectin was marked in the glomerular mesangium. and the distribution of fibronectin extended to the glomerular capillary walls in the sclerotic lesions of glomeruli. However. the staining intensity of type IV collagen. laminin and fibronectin was gradually decreased during the progression of glomerular sclerosis. On the other hand. the staining of type I and III collagens was observed focally in sclerotic or hyalinotic glomeruli and around such glomeruli in those patients. Light microscopic examination revealed that patients who showed marked staining of type I and III collagens by immunofluorescence had severe damage of Bowman's capsules. These results suggest that the hyperproduction and/or invasion of interstitial collagens. i.e.. types I and III. are closely linked to the progression of glomerular sclerosis and hyalinosis in patients with various types of glomerulonephritis.
Acute effects of paracetamol on prostaglandin synthesis and renal function in normal man and in patients with renal failure, The effects of oral dosing with paracetamol (40 mg/kg/day for 3 days) on serum thromboxane B2 (TXB2). glomerular filtration rate (GFR). sodium homeostasis. urinary excretion of prostaglandin E2 (PGE2) and on some other renal function parameters were investigated in 10 healthy young controls aged 23-26 years. 9 healthy elderly persons with normal renal function aged 66-78 years and 9 patients with chronic stable impaired renal function. Plasma paracetamol concentration was unaffected by age and GFR. whereas the sulphate and glucuronide metabolites of paracetamol accumulated substantially in patients with renal failure. and to a lesser degree in elderly controls. Serum TXB2 was significantly reduced 1 and 4 hours after oral ingestion of a single dose of paracetamol (18 mg/kg). but the values were normalized after 12 hours. Urinary sodium excretion was reduced by 23.4% on the first treatment day in elderly controls. but unchanged in young controls and in patients with renal failure. Urinary excretion of PGE2 was unchanged in young controls. but reduced by 35.9% on the first day on paracetamol treatment in elderly controls and from 22-29% on the 3 days on paracetamol in patients with impaired renal function. Paracetamol was without effect on potassium homeostasis or on the excretion of glandular kallikrein or proteins in urine. Our study indicates that oral treatment with paracetamol in therapeutic doses reversibly reduces serum TXB2 for at least 4 hours after ingestion both in healthy controls and in patients with impaired renal function. Our data also suggest that paracetamol effects renal PGE2 excretion. especially in patients with impaired renal function. Renal glomerular and tubular function parameters were unchanged by paracetamol.
Effect of cardiac catheterization on renal function, Sensitive acute renal clearance methodology was used to investigate the incidence of radiocontrast-induced nephrotoxicity in patients undergoing cardiac catheterization. Patients at the University of Oklahoma Teaching Hospitals scheduled for elective cardiac catheterization had their creatinine clearance measured on the day preceding and the day following their procedure. All patients had a serum creatinine concentration lower than 175 mumol/l. The creatinine clearance was calculated from the mean of four consecutive 30-minute renal clearance periods obtained in the fasted state during water loading. The change in renal function following the catheterization was evaluated. There was no significant change in the creatinine clearance after the cardiac catheterization (Ccr 101.5 +/- 6.4 ml/min before and 111.6 +/- 7.4 ml/min after the procedure). A decrease in Ccr exceeding 25% occurred in 1 of 23 subjects (4.3%. Patient age. presence of diabetes. and volume of contrast agent were not adverse risk factors. The results suggest a low risk of nephrotoxicity in low-risk patients undergoing elective cardiac catheterization. even when very sensitive measures of glomerular filtration rate are utilized.
Platelet thromboxane A2 receptors in type I diabetes, 1. Human platelet thromboxane A2 receptor expression on the membrane surface is possibly dynamically regulated by changes either in the ligand concentration or in membrane fluidity. An increased thromboxane A2 production and a decreased membrane fluidity has been reported in diabetic patients. 2. In the present study the binding characteristics of platelet thromboxane A2 receptors have been investigated in nine diabetic patients (type I) and in 15 healthy control subjects by a radioligand-binding method using 9.11-dimethylmethane-11.12-methane-16-[3-125I-4-hydroxyphenyl]-13. 14- dihydro-13-aza-15-tetranor-thromboxane A2 as the radiolabelled ligand. 3. The maximum concentration of binding sites was 163 (SD 35) fmol/10(8) platelets (n = 15) with 987 (SD 209) receptors/platelet in controls. whereas in diabetic patients the maximum concentration of binding sites was 74.2 (SD 28) fmol/10(8) (n = 9) with 447 (SD 172) receptors/platelet (P less than 0.001). The dissociation constants were 18 (SD 4) nmol/l and 21 (SD 6) nmol/l (not significant) in control subjects and in diabetic patients. respectively. Glycated haemoglobin. which is reported to reduce membrane fluidity. was found to be negatively correlated (r = 0.60. P less than 0.05) with thromboxane A2 receptor number in the diabetic patient group. On the contrary. a positive linear correlation between the equilibrium dissociation constant and glycated haemoglobin was found in diabetic patients (r = 0.75. P less than 0.01).
Abnormal erythrocyte choline transport in patients with chronic renal failure, 1. Erythrocyte choline transport has been studied in nine patients on maintenance haemodialysis for chronic renal failure. six patients on continuous ambulatory peritoneal dialysis. 31 patients with renal transplants and in nine normal control subjects. 2. The mean maximum rate of choline influx (Vmax.. measured at an extracellular choline concentration of 250 mumol/l) was 66.7 (SD 14.1) mumol h-1 l-1 cells in patients on haemodialysis. 87.8 (SD 18.5) mumol h-1 l-1 cells in patients on continuous ambulatory peritoneal dialysis and 30.5 (SD 4.9) mumol h-1 l-1 cells in control subjects. The increase in choline flux in patients on haemodialysis and patients on continuous ambulatory peritoneal dialysis compared with control subjects was highly significant (P less than 0.001). 3. Renal transplant patients showed variable values for the Vmax. of choline influx (range 17.7-71.7 mumol h-1 l-1 cells). The values showed a significant negative correlation with creatinine clearance and this correlation correctly extrapolated to the maximum choline flux in normal subjects and in patients on dialysis. 4. The kinetics of choline transport have been studied in erythrocytes of patients on haemodialysis and control subjects in 'zero-trans' conditions after depletion of intracellular choline. The mean Vmax. in these conditions was 38.4 (SD 4.6) mumol h-1 l-1 cells in patients on haemodialysis compared with 14.2 (SD 3.7) mumol h-1 l-1 cells in control subjects. The mean Km under 'zero-trans' conditions was 19.4 (SD 2.4) mumol/l in patients on haemodialysis and 7.4 (SD 1.4) mumol/l in control subjects. These differences were significant (P less than 0.001).
Indocyanine green elimination in patients with liver disease and in normal subjects, 1. The validity of a two-compartment pharmacokinetic model for the estimation of the hepatic extraction ratio of Indocyanine Green was tested in six patients with cirrhosis of the liver. 2. No agreement was found between the value of the hepatic extraction ratio measured directly and that calculated using the two-compartment model. 3. To investigate the reasons for the failure of the model. an extended sampling period was used to define the time course of Indocyanine Green in plasma in six healthy subjects and in six patients with cirrhosis of the liver after a bolus injection of the dye. 4. Indocyanine Green was measurable in the plasma for up to 10 h after injection in healthy subjects. and up to 48 h after injection in the patients. The plasma elimination curve in both groups was best described by a triexponential function. 5. The clearance of Indocyanine Green calculated using data collected in the first 20 min after injection overestimated that calculated using data collected for as long as Indocyanine Green was measurable in the plasma. In the patients with cirrhosis the mean overestimate was 87%. 6. Thus. a two-compartment pharmacokinetic model was inappropriate for the description of the disposition of Indocyanine Green and estimates of the hepatic extraction ratio obtained using this model in patients with cirrhosis were inaccurate.
Reassessment of the single intravenous injection method with inulin for measurement of the glomerular filtration rate in man, 1. Factors influencing the total body and renal clearances of inulin were investigated in a total of 37 healthy adult volunteers and 10 patients with stable chronic renal failure after the single intravenous injection of a dose of 70 mg/kg given over 5 min. 2. The elimination of inulin was highly concentration-dependent. and in healthy volunteers the renal clearance fell from 103.7 +/- 14.4 ml min-1 1.73 m-2 during the first hour after administration to 49.1 +/- 20.9 ml min-1 1.73 m-2 over the period 6-8 h. In the patients with renal failure the renal clearance fell correspondingly from 39.7 +/- 16.5 to 26.6 +/- 8.6 ml min-1 1.73 m-2. There were no changes in the simultaneously measured clearances of creatinine. 3. The values obtained for the total body clearance of inulin after a single injection depend critically on dose. the number and timing of blood samples. the choice of pharmacokinetic model. the number of data points chosen for estimation of the slope of the terminal elimination phase for analysis by the methods of residuals. and the weighting used for curve fitting by non-linear regression analysis. 4. With standardized conditions of sampling from 0 to 2 h and weighted non-linear regression analysis of the plasma concentration-time data. the total body and renal clearances of inulin were almost identical in subjects with normal renal function at 105.2 +/- 10.2 and 102.9 +/- 13.0 ml min-1 1.73 m-2. In the patients with chronic renal failure sampling was continued for 3 h and the corresponding clearances were 40.4 +/- 15.3 and 38.9 +/- 15.7 ml min-1 1.73 m-2. 5. The 0-2 h total body and renal clearances of inulin were measured by the single injection method and the renal clearance was measured by the standard constant infusion method on different occasions in 10 healthy volunteers. The respective clearances were similar at 101.4 +/- 6.6. 94.9 +/- 11.9 and 88.4 +/- 12.1 ml min-1 1.73 m-2. 6. The reproducibility of the single injection and constant infusion methods was compared by measuring the inulin clearance with both techniques on three occasions in separate groups of eight and nine healthy volunteers. The mean coefficient of variation for the total body clearance with the single injection method was only 3.9% compared with 9.5% for the renal clearance determined the same way and 12.0% for the renal clearance during constant infusion.(ABSTRACT TRUNCATED AT 400 WORDS).
Lymphocytotoxins in sera from highly sensitized multiparous dialysis patients: antibody class, relationship with the HLA and with paternal antigens, 1. Sera from 11 highly sensitized multiparous dialysis patients were studied in order to define the target antigens. antibody class and relationship with paternal HLA class I antigens of the underlying lymphocytotoxic antibodies. All sera contained lymphocytotoxic antibodies to over 70% of a panel of lymphocytes from 24 donors (panel reactivity greater than 70%). 2. Inhibition of cytotoxic activity against paternal lymphocytes by monoclonal antibodies to HLA framework determinants indicated that all 11 sera contained lymphocytotoxic antibodies to paternal class I antigens. In addition. five sera contained lymphocytotoxic antibodies to paternal class II antigens. 3. In order to determine the extent to which lymphocytotoxic antibodies were directed to paternal antigens. the panel reactivity of sera was compared before and after absorption with paternal peripheral blood lymphocytes. Over 50% of panel reactivity was absorbed from eight out of 11 sera. and in three of these 11 over 80% was absorbed. In the majority of patients this change in panel reactivity could be ascribed to binding of lymphocytotoxic antibodies to specific paternal class I antigens. 4. Digestion of sera with dithiothreitol had no significant effect on panel reactivity. indicating that the lymphocytotoxic antibodies were of immunoglobulin G class. 5. No sera reacted with either autologous lymphocytes or K562 cells. indicating an absence of autoantibodies. 6. These studies imply that panel-reactive lymphocytotoxic antibodies in the sera of highly sensitized multiparous patients are those which mediate hyperacute renal allograft rejection. Their development may be related to secondary humoral responses to antigens in blood transfusions from donors who share paternal class I specificities.
The role of interleukin-2 in cancer immunotherapy, The arena of cellular immunotherapy is an emerging field of study. The field has strong foundations in numerous animal tumor models. which provide avenues of research for refinements in human immunotherapy. Experience from a number of research centers can be generalized: LAK cell trials in humans have demonstrated that PBMCs activated with IL-2 possess reproducible antitumor activity in vitro. Exogenous IL-2 administration to patients is required to maintain the biologic activity of the activated cells. although the requirement for LAK cells in tumors like melanoma is not clear-cut. Overall. the response rate to immunotherapy in humans is approximately 30%. The toxicity of immunotherapy. which is related to the dose of systemic IL-2. can be significantly reduced. The next generation of trials of cellular immunotherapy in humans will use TILs. Murine experiments indicate that this population of cells is more powerful and potentially more specific for tumor than LAK cells. Like LAK cells. TILs also require exogenous IL-2 for optimum performance in vivo. The difficulty in reproducible TIL growth can be overcome by the use of monoclonal antibody activation and IL-2. Improvements in TIL therapy are anticipated from the use of TILs combined with hybrid antibodies. the addition of other biologic response modifiers. and the implementation of genetically engineered cells and cell products.
Acute psychosis. Functional versus organic, Acute psychosis is a true emergency and is a manifestation of multiple organic and functional disorders. The emergency medicine physician's role in dealing with the acutely psychotic patient is to control the patient's behavior. to delineate the etiology of the psychosis. and to provide appropriate initial treatment and disposition. When making initial contact with the psychotic patient. behavioral control can be accomplished through supportive. physical. or pharmacologic interventions. Judicious use of rapid tranquilization permits rapid control of these patients when supportive and other nonpharmacologic therapies fail. Initial examination is directed at identifying immediate life-threatening organic disorders and promptly treating them. Historical data. mental status examination. physical examination. and appropriate radiologic and laboratory investigations give information that assist in delineating functional from organic psychosis. Most acute organic psychoses. with the exception of some drug intoxications that clear in the Emergency Department. require medical or surgical admission. Acute functional psychotic patients who are a danger to themselves or others. who are without a reliable social support system. or who present with their first psychotic episode require admission to the psychiatric service for further evaluation and treatment.
The somatic patient, A significant proportion of patients seen in the Emergency Department will present with somatic complaints for which there is no apparent physiologic cause. Such patients may be divided into two broad categories: (1) those with symptoms and signs consciously synthesized by the patient. either for obvious secondary gain (malingering) or as a result of more subtle and complex motivations (factitious disorders); and (2) those patients with symptoms that are the unconscious expression of psychological stress (somatoform disorders). The somatoform disorders include (1) somatization disorder (characterized by a chronic history of numerous and widely divergent somatic complaints). (2) psychogenic pain disorder (somatization expressed in terms of persistent pain). (3) hypochondriasis (a conviction that one is diseased and disabled in conjunction with a well-focused constellation of supporting symptoms). and (4) conversion disorder (a single. usually nonpainful neurologic symptom. often with identifiable coping value for the patient). The first three disorders have been aggregately termed the "common somatization syndrome." Management of the somatically focused patient includes the communication of a caring attitude to the patient in conjunction with a cautious and diligent search for treatable medical or psychiatric illness. Resocialization and development of patient links with ongoing. nurturing nonmedical as well as medical support systems is of benefit.
Drug-induced psychoses, Major causes of drug-induced psychoses include cocaine. amphetamines. phencyclidine. cannabinoids. LSD. mescaline. the so-called designer drugs. anticholinergic compounds. and steroids. Most drug-induced psychoses are managed with general supportive measures. reassurance. minimizing patient stimulation. and benzodiazepines as needed; however. specific antidotes such as physostigmine for anticholinergic poisoning or urinary acidification to enhance excretion of amphetamines or phencyclidine may be indicated in some patients. Any patient with a drug-induced psychosis must be evaluated carefully for evidence of other toxic effects of the drug in question.
Cyclic antidepressants, lithium, and neuroleptic agents. Pharmacology and toxicology, Cyclic antidepressants. lithium. and phenothiazines are frequently prescribed to psychiatric patients. Emergency department physicians must be familiar with these medications. and the pharmacologic and toxicologic characteristics of them are discussed. Cyclic antidepressants are the primary cause of drug-related death in the United States. with sodium bicarbonate recognized as the treatment of choice. Lithium toxicity may be subtle. and treatment is generally supportive in addition to volume replacement with normal saline and hemodialysis for significant intoxications. A neuroleptic overdose is managed primarily with supportive care. Neuroleptic malignant syndrome must be considered in any psychiatric patient presenting to the Emergency Department.
Controlled ovarian hyperstimulation and intrauterine insemination for treatment of infertility, Empirical therapy for subfertility using assisted reproductive technologies recently has gained popularity; however. the cost-effectiveness of these therapies. compared with an untreated control group. has not been established. Similarly. there has been no comparative cost analysis of the utility of controlled ovarian hyperstimulation and IUI in the management of the same condition. Significant PRs in untreated couples with subfertility mandate the design and execution of controlled trials to ascertain the role of controlled ovarian hyperstimulation and IUI in infertility therapy. Various disorders of subfertility have been treated with controlled ovarian hyperstimulation and IUI. The rationale for this therapy is the increase in gamete density at the site of fertilization. as with GIFT and IVF when used for management of the same problems. The live birth rate per initiated cycle and risk of complications are similar to results recently reported for GIFT and IVF. The utility of controlled ovarian hyperstimulation and IUI still remains controversial. When the relatively low direct and indirect costs of controlled ovarian hyperstimulation and IUI are considered. acknowledging the lack of prospective. controlled studies. this procedure appears to be at least as cost-effective as GIFT and IVF.
Combined use of progesterone and human chorionic gonadotropin determinations for differential diagnosis of very early pregnancy, Progesterone (P) level and daily change in human chorionic gonadotropin (hCG) were determined in the serum of 307 patients with suspected ectopic pregnancy (EP). Of the viable intrauterine pregnancies (IUP). 99% had P values above 30 nmol/L. whereas 75% of the EP and 81% of the spontaneous abortions had P values less than 30 nmol/L. Among the viable IUP. 95% had normal hCG increases. whereas 89% of the EP and 99% of the spontaneous abortions had abnormal hCG increases. A P value less than 30 nmol/L combined with an abnormal hCG increase had a positive predictive value for pathological pregnancy of 1.0. Consequently. in such cases. further invasive diagnostic or therapeutic measures can be taken with a low risk of jeopardizing a viable IUP.
Use of a single random serum progesterone value as a diagnostic aid for ectopic pregnancy, We evaluated the usefulness of serum progesterone (P) determinations in differentiating between ectopic pregnancy (EP). normal intrauterine pregnancy (IUP). and abnormal IUP. Values were obtained from 233 samples from 54 patients with IUP. 100 samples from 26 patients with abnormal IUP. and 125 samples from 46 patients with EP. Although mean values from all three groups were significantly different. we could not detect a single value that readily predicted both the presence and absence of EP. Only 2% of patients with EP (excluding those having undergone ovulation induction) had a P greater than 20 ng/mL and only 2% of patients with IUP had a value less than 10 ng/mL. Thirty-one percent of IUP. 23% of abnormal IUP. and 52% of EP had values that fell between 10 and 20 ng/mL. which limits the clinical usefulness of this test.
Detection of premature luteinization with serum progesterone levels at the time of the postcoital test, Poor cervical mucus (CM) may be caused by a number of factors. including premature luteinization. local cervical effects. and inadequate folliculogenesis. In an attempt to distinguish between these causes of poor CM. we obtained progesterone (P) levels at the time of postcoital tests (PCTs) in infertile women during spontaneous or clomiphene citrate (CC)-stimulated cycles. The amount of CM. viscosity. ferning. spinnbarkeit. and cellularity were each scored from 0 to 3 points on the day after detection of the urinary luteinizing hormone surge (luteal day 1). The charts of 46 such patients were retrospectively reviewed. Eleven control patients with good CM scores (greater than 10) had low P levels (less than 2.5 ng/mL). Of the remaining 35 cycles. 19 were marked by low P levels. and 16 were accompanied by P levels of greater than 2.5 ng/mL. Overall. 94.4% of CC-stimulated cycles versus 64.3% of spontaneous cycles had abnormal CM scores (less than 9). On the basis of these inappropriately elevated P levels. premature luteinization can be cited as the cause of poor mucus quality. In fact. premature luteinization may be responsible for some of the purported antiestrogenic effects of CC. Therefore. it is appropriate to draw a P level at the time of a poor PCT. particularly in cycles stimulated by CC.
Bone mineral density of the lumbar spine in women with endometriosis, Young women with endometriosis have reduced cortical and trabecular bone mineral density of the wrist compared with age-matched controls. This conclusion was based on 41 subjects from one geographical location. The purpose of this study was to test this finding in a larger. more geographically diverse population. One hundred women with laparoscopically proven endometriosis were enrolled in this study for the evaluation of the efficacy of nafarelin. a gonadotropin-releasing hormone agonist. Patients were recruited from nine investigators across the United States and Canada. and bone mineral density of the lumbar spine was obtained at baseline. with 6 Hologic QDR (Hologic Inc.. Waltham. MA) and a Lunar DPX (Lunar Radiation Corp.. Madison. WI) instrument. The age of the women was 30.3 +/- 5.8 years (mean +/- SD); 91% were white. Bone mineral density of the lumbar spine was 1.1 +/- 0.11 g/cm2 (n = 85 Hologic QDR) and 1.2 +/- 0.93 g/cm2 (n = 15 Lunar DPX). Hologic bone mineral density was 104.8 +/- 11.0 and Lunar bone mineral density was 103.4% +/- 7.8% of normal values for age. To conclude. in a population based cross-sectional study of patients with endometriosis. we do not observe low bone mineral density of the lumbar spine by techniques that measure a combination of cortical and trabecular bone.
Experience with peritoneal oocyte and sperm transfer as an outpatient-based treatment for infertility, Fifty-nine patients underwent 74 peritoneal oocyte and sperm transfer procedures. Forty-nine had previously failed treatment with inseminated frozen donor sperm and 10 had unexplained infertility. All procedures were carried out under ultrasound direction on an outpatient basis without general anesthetic by the transabdominal or vaginal route. Eighteen (24%) procedures resulted in pregnancy. Of these patients. 16 have delivered live infants (1 set of triplets. 2 twins. and 13 singletons) and 2 miscarried. Peritoneal oocyte and sperm transfer offers an outpatient-based alternative to gamete intrafallopian transfer (GIFT) for in vivo conception. It can also be used in patients scheduled for intrauterine insemination where stimulation is excessive because the number of oocytes replaced can be limited.
Detection of human immunodeficiency virus type 1 in semen from seropositive men using culture and polymerase chain reaction deoxyribonucleic acid amplification techniques, We have demonstrated that the polymerase chain reaction is a valid and sensitive technique for the detection of human immunodeficiency virus type 1 (HIV-1) proviral deoxyribonucleic acid (DNA) in human semen. The combination of extraction. polymerase chain reaction. and liquid hybridization techniques used in this study was sensitive to a level of detection of one HIV-1 infected cell in 100.000 (or 3 infected cells/test sample). In a series of matched peripheral blood mononuclear cells (PBMC) and semen cells from 25 HIV-1 seropositive homosexual men. HIV-1 DNA was detected by polymerase chain reaction in 23 of 25 PBMC samples and 1 of 25 semen samples. By coculture on mitogen-activated peripheral blood leukocyte target cells. 19 of 24 PBMC and 4 of 24 semen samples were positive for infectious HIV-1. Of the four culture-positive semen samples. three were negative for the proviral form of the virus in the polymerase chain reaction assay. These data indicate that HIV-1 infected cells are not as prevalent in semen as in the peripheral blood. Furthermore. they indicate that the classical polymerase chain reaction approach. which only detects HIV-1 proviral DNA (infected cells). is not sufficient for clinical screening programs whose goal is the detection of HIV-1-infected semen samples. Accurate semen analysis by polymerase chain reaction may require enrichment of the infected cell population and/or a reverse transcriptase step to enable detection of the infectious ribonucleic acid form of the virus.
Low human chorionic somatomammotropin fails to predict spontaneous resolution of unruptured ectopic pregnancies, Early diagnosis of EP allows conservative medical and surgical therapy but also commits a proportion of patients whose EP would spontaneously resolve to therapeutic intervention. This prospective study examined the feasibility of not treating those EPs whose hCS level was low. However. three of eight subjects with EP required therapy. Thus. a single hCS alone cannot be used to identify which EPs required no therapy.
The fourth stage of labor: the health of birth mothers and adoptive mothers at six-weeks postpartum, This study was conducted to determine the frequency of various health problems in new adoptive and biological mothers six weeks after they adopted or delivered their infants. Participants included 108 married first-time adoptive mothers. 72 married first-time biological mothers. and 133 controls (married women without children). each of whom completed a mailed questionnaire. Compared to controls. adoptive and biological mothers reported more fatigue. less readiness to work at a job. and less activity with household chores and recreational or social functions. In addition. biological mothers complained of more breast and genitourinary problems than did adoptive mothers or controls. Apart from their fatigue and hesitation to work at a job. adoptive mothers reported relatively good health. with the best mental health outcomes and the fewest acute physical problems of the three groups. These findings suggest that. for both adoptive and birth mothers. some aspects of postpartum recovery may continue up to and beyond the sixth postpartum week.
Chlamydia trachomatis infections in children evaluated for sexual abuse, The purpose of this study was to elucidate the conditions under which children evaluated for sexual abuse should be tested for Chlamydia trachomatis. Children were seen in an outpatient sexual abuse clinic over a nine-month period. Eight patients. ranging from 1.5 to 14.5 years of age. had positive C. trachomatis cultures. The records of these patients were examined for historical information and physical findings suggestive of rectal or vaginal penetration. Neither historical information of abuse nor physical findings were helpful in predicting the C. trachomatis infections. These results suggest that all children being evaluated for sexual abuse should be cultured for C. trachomatis.
Differential effect of streptozotocin-induced diabetes on the innervation of the ileum and distal colon, The effect of short-term and long-term streptozotocin-induced diabetes on the pattern of distribution and tissue content of adrenergic and peptidergic nerves in ileum and distal (descending) colon of the rat was examined using immunohistochemical. biochemical. and immunochemical techniques. The effect of short-term streptozotocin-induced diabetes on the level of noradrenaline compared with weight-restricted (starved) and untreated controls in the celiac (celiac-superior mesenteric ganglia complex) and inferior mesenteric ganglia. which supply the two regions of the intestine. was also compared. The pattern of change in the distribution of dopamine-beta-hydroxylase-. substance P-. calcitonin gene-related peptide-. and vasoactive intestinal polypeptide-like immunoreactive nerve fibres that was observed in the ileum from diabetic rats was not evident in the myenteric plexus of distal colon. In contrast to the ileum. there was no evidence of degenerative change in any of the nerve types investigated in the myenteric plexus of the distal colon. The level of vasoactive intestinal polypeptide in the diabetic rat ileum was significantly increased. whereas the level of noradrenaline was reduced; no such changes were observed in the distal colon. The tissue content of noradrenaline in the celiac ganglion. which projects to the ileum. was increased at 8-week diabetes compared with both weight-restricted and untreated controls. whereas the diabetic state had no effect on the levels of noradrenaline of the inferior mesenteric ganglion. which projects to the distal colon. It is concluded that there is a differential effect of streptozotocin-diabetes on different regions of the rat intestine. The adrenergic and peptidergic innervation of the distal colon were changed little compared with ileum. This may be explainable in terms of the different functional roles of these two regions of the intestine and/or by the difference in origin of the sympathetic nerves supplying the two regions of the intestine.
Adenocarcinomas of the colon and rectum in persons under 40 years old. A population-based study, Data collected by nine population-based tumor registries participating in the Surveillance. Epidemiology. and End Results Program of the National Cancer Institute were analyzed to characterize the epidemiology of noncarcinoid adenocarcinomas of the colon and rectum in young adults. Tumors diagnosed in persons under 40 years old between 1973 and 1984 (n = 1736) were compared with those in persons 40 years and older (n = 106.760). This first large U.S. population-based study of colorectal adenocarcinomas in the young shows a higher incidence in blacks than whites and later detection in black males. It also shows a higher proportion of tumors of mucinous and signet ring histological type than in older age groups. Among the younger group. the average annual age-adjusted incidence rate was 34% higher in black males than in white males (12.6 vs. 9.4 per million persons) and 46% higher in black females than in white females (13.0 vs 8.9 per million persons). The proportion of tumors that were right-sided varied by age: 0-29 years. 30%; 30-39 years. 26%; 40-49 years. 22%; 50-59 years. 21%; 60-69 years. 24%; 70-79 years. 30%; and 80+ years. 35%. Males under age 40 were less likely to present with localized disease (whites. 27%; blacks. 21%) than were those aged 40 and older (whites. 39%; blacks. 36%). The proportion of tumors classified as mucinous decreased with age. from 28% among those aged 0-19 years to 5% among those 40 years and older. A similar trend was observed for signet ring tumors. Although this latter type accounted for 10% of large-bowel tumors among subjects aged 0-19 years. this proportion decreased with age to 0.2% in those 40 years and older.
Hepatic metabolism of cholesterol in Crohn's disease. Effect of partial resection of ileum, To study cholesterol metabolism in Crohn's disease and especially the effect of ileum resection. liver biopsy specimens were obtained from patients undergoing partial ileal resection because of Crohn's disease (n = 17) and patients with Crohn's colitis undergoing colectomy (n = 3). Gallstone-free patients (n = 16) undergoing cholecystectomy because of adenomyomas or polyps of the gallbladder served as controls. The mean levels of cholesterol 7 alpha-hydroxylase activity and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. rate-determining enzymes in bile acid. and cholesterol synthesis. respectively. were twofold to threefold higher in the ileum-resected patients than in the controls. Significant positive correlations were obtained between length of resected ileum and cholesterol 7 alpha-hydroxylase activity. Provided patients who had received total parenteral nutrition preoperatively were excluded from analysis. a significant correlation was also observed between length of resected ileum and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Significant positive correlations were also obtained between length of resected ileum and serum levels of 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) and lathosterol (a marker for cholesterol synthesis). The plasma levels of total and low-density lipoprotein cholesterol were negatively correlated to the length of resected ileum. The expression of hepatic low-density lipoprotein-receptor binding activity was determined in five of the patients and in three of the controls. A significant positive correlation was observed between 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and low-density lipoprotein-receptor binding activity. The results show that malabsorption of bile acids leads to parallel stimulation of cholesterol synthesis. cholesterol degradation. and low-density lipoprotein-receptor expression in human liver. The resulting effect in the present patients was a significant reduction in low-density lipoprotein cholesterol.
Nocturnal intragastric acidity during and after a period of dosing with either ranitidine or omeprazole, The magnitude and duration of changes in nocturnal intragastric acidity caused by 25 days of dosing with the antisecretory drugs ranitidine and omeprazole were investigated in a double-blind study of 22 healthy subjects. Nocturnal intragastric acidity was studied before (twice). during (on day 25). and after (every 3 days for 21 days) dosing with either 300 mg ranitidine at night or 40 mg omeprazole every morning. Three and six days after withdrawal of dosing with ranitidine. median integrated nocturnal intragastric acidity was increased significantly (17% and 14%. P = 0.01 and P = 0.05. respectively) compared with before dosing. Three days after withdrawal of dosing with omeprazole. median integrated nocturnal intragastric acidity was decreased significantly (-23%. P = 0.003). Compared with before dosing. no significant differences were seen in the ranitidine group between days 9 and 21 or the omeprazole group between days 6 and 21 after cessation of dosing. Fasting plasma gastrin concentration was measured on the morning of each study; compared with before treatment. the only significant elevations occurred on the last day of dosing with omeprazole (before. 4 pmol/L; during. 7 pmol/L). It is concluded that rebound intragastric hyperacidity after dosing with 300 mg ranitidine at night or sustained hypoacidity after dosing with 40 mg omeprazole every morning reflect transient disturbances of gastric function that are unlikely to be of clinical importance.
Disturbed gastroduodenal motility in patients with active and healed duodenal ulceration, Disordered gastroduodenal motility may promote duodenal ulceration by allowing prolonged acid contact with the duodenal mucosa. Using a multilumen perfused catheter incorporating 3 pH microelectrodes. antral and duodenal pH and antropyloroduodenal pressure activity were recorded in 36 subjects (10 with healed duodenal ulceration. 11 with active duodenal ulceration. and 15 healthy volunteers) during fasting and after a radiolabeled solid test meal. Correct pH probe/catheter position was continuously verified by recording transmucosal potential difference across the pylorus. Patients with active and healed duodenal ulcer had similarly disordered gastroduodenal motility. The chief abnormalities consisted of an increase in postprandial duodenal retroperistalsis (healed duodenal ulceration. 12 +/- 1 events per hour; active duodenal ulceration. 12 +/- 1; control. 6 +/- 1; mean +/- SEM: healed and active duodenal ulceration vs. control. P = 0.004 and P = 0.03. respectively). a reduction in pressure waves sweeping aborally through the duodenum after the meal (healed duodenal ulceration. 22 +/- 4 events per hour; active duodenal ulceration. 23 +/- 3; control. 34 +/- 4: healed and active duodenal ulceration vs. control. P = 0.04 and P less than 0.05. respectively). and an increased incidence of atypical. complex forms of coordinated duodenal motor activity throughout the study (postprandial data; healed duodenal ulceration. 8 +/- 1 events per hour; active duodenal ulceration. 10 +/- 1; control. 4 +/- 1: healed and active duodenal ulceration vs. control. P = 0.02 and P less than 0.02. respectively). In addition. gastric emptying of the solid test meal was significantly delayed in healed. but not active. duodenal ulceration [half-emptying time. healed duodenal ulceration 185 minutes (117-235); active duodenal ulceration 102 minutes (80-200); control 107 minutes (78-130): healed duodenal ulceration vs. control. P less than 0.009]. Duodenal bulb pH was similar in controls and patients with active duodenal ulceration; however. bulb pH was less than 4 for a significantly greater period of time in healed duodenal ulceration compared with active ulcer patients. particularly after the meal. In conclusion. duodenal ulcer disease is associated with disturbed gastroduodenal motility. even when the ulcer is quiescent and when intraduodenal acidity is low. In healed duodenal ulceration. disturbed motility may promote ulcer relapse by impairing acid clearance from the bulb. However. in active ulceration other factors such as mucosal bicarbonate secretion may have a more influential role in determining intraduodenal pH.
Macrophage engulfment of mucosal mast cells in rats treated with dexamethasone, The effects of corticosteroid treatment on mucosal mast cells in rat jejunal mucosa were examined. Rats previously infected with Nippostrongylus brasiliensis received a single IP injection of 1 mg dexamethasone. Three hours later. one third of mucosal mast cells demonstrated minor granular changes (fusion or peripheral clear zones) by electron microscopy. At 7 hours. by light microscopy. the majority of mucosal mast cells appeared abnormal with clustering of granules. By electron microscopy. 151 of 233 (65%) mucosal mast cells had been engulfed by enlarged macrophages and were in various stages of degeneration inside large phagosomes. By 24 hours. the number of mucosal mast cells had decreased to less than 10% of the initial number with parallel decreases in tissue rat mast cell protease II and histamine levels. Serum levels of rat mast cell protease II did not increase. and intestinal morphology was invariably normal with no evidence of inflammatory changes up to and including 24 hours. Observations were similar in uninfected animals. In contrast. in rats undergoing antigen-induced anaphylaxis. a significant elevation of serum rat mast cell protease II level was evident at 3 and 7 hours. and macrophage engulfment of mucosal mast cells was never seen. although tissue edema. enterocyte loss. and hemorrhage were observed. It is concluded that dexamethasone treatment results in macrophage engulfment and destruction of mucosal mast cells that occurs without granular mediator release and local inflammatory effects.
Role of free radicals and platelet-activating factor in the genesis of intestinal motor disturbances induced by Escherichia coli endotoxins in rats, The effects of IV administration of Escherichia coli endotoxin on intestinal myoelectric activity was investigated in conscious fasted rats chronically implanted with nichrome electrodes in the duodenojejunum. These effects were compared with those of platelet-activating factor and were evaluated in animals pretreated with a specific platelet-activating factor antagonist. BN 52021. indomethacin. a selective prostaglandin E2 antagonist. SC 19220. and several free radical scavengers. Intravenous administration of endotoxin (E. coli S.O111:B4) at a dose of 50 micrograms/kg suppressed the migrating myoelectric complexes. which were replaced by continuous rhythmic clusters of rapidly propagated spike bursts for 114.7 +/- 19.9 minutes. Intraperitoneal platelet-activating factor (25 micrograms/kg) also inhibited the migrating myoelectric complex pattern for 146.1 +/- 24.1 minutes. Previous IV administration of BN 52021 (50 mg/kg-1) abolished the motor alterations induced by platelet-activating factor and significantly reduced to 43.1 +/- 12.2 minutes those induced by endotoxin (P less than 0.01). Indomethacin (10 mg/kg IP). injected before endotoxin or platelet-activating factor. also significantly reduced the duration of migrating myoelectric complex inhibition to 45.6 +/- 7.8 and 47.7 +/- 8.3 minutes. respectively (P less than 0.01). SC 19220 significantly reduced the effects of platelet-activating factor from 151.8 +/- 26.4 to 67.4 +/- 14.7 min (P less than 0.01). Superoxide dismutase (15.000 U/kg IV) injected before either endotoxin or platelet-activating factor shortened the migrating myoelectric complex inhibition to 45.7 +/- 9.9 and 72.9 +/- 10.4 minutes. respectively (P less than 0.01). Allopurinol and dimethylsulfoxide administered orally at 50 mg/kg 1 hour before endotoxin reduced the migrating myoelectric complex inhibition to 42.5 +/- 6.5 and 38.2 +/- 6.4 minutes. respectively (P less than 0.01). They also reduced platelet-activating factor-induced intestinal myoelectric alterations to 68.5 +/- 10.6 and 31.7 +/- 6.1 minutes. respectively (P less than 0.01). It is concluded that endogenous release of platelet-activating factor is partly responsible for the intestinal motor alterations induced by endotoxin. these effects being also mediated through the release of prostaglandins and free radicals. However. prostaglandins. as well as free radicals. appear to be partly involved in the platelet-activating factor-induced action of E. coli endotoxin on intestinal motility.
Mucin and nonmucin secretagogue activity of Entamoeba histolytica and cholera toxin in rat colon, Depletion of colonic mucus occurs before invasion of the colonic mucosa by Entamoeba histolytica trophozoites. It is hypothesized that E. histolytica releases a mucus secretagogue; this was studied in a rat colonic loop model. In colonic loops exposed to live amebae. mucus secretion was quantitated by release of acid-precipitable [3H]glucosamine-labeled luminal glycoprotein and by specific immunoassay. Mucus secretion increased in dose-dependent fashion in response to greater than or equal to 1 X 10(5) trophozoites; cholera toxin (20 micrograms per loop). a known mucus secretagogue. elicited a similar response. Thin-section histological analysis of amebae and cholera toxin-exposed loops showed increased mucus release and streaming from mucosal goblet cells with cellular cavitation compared with control loops. Sepharose-4B chromatography of amebae and cholera toxin-stimulated glycoproteins demonstrated secretion of mucins and an 80%-90% increase in low-molecular-weight proteins. E. histolytica trophozoites and cholera toxin enhanced the secretion of preformed and newly synthesized mucin glycoproteins and stimulated colonic glycoprotein synthesis. The level of mucus secretion elicited by axenic E. histolytica strains correlated with their virulence in vivo and in vitro. The amebic secretagogue was released into the culture medium and was heat stable. Mucus secretagogue activity of E. histolytica may contribute to depletion or alteration of the protective mucus blanket. facilitating pathogenesis of invasive amebiasis.
Irritable bowel syndrome in office-based practice in the United States, United States estimates of the frequency of visits to physicians and patterns of medical care for the diagnosis of the irritable bowel syndrome were derived from the 1975. 1980-1981. and 1985 National Ambulatory Medical Care Surveys. These surveys of office-based physicians allow national estimates of various aspects of ambulatory care. The overall rate of visits with the diagnosis of irritable bowel syndrome in 1980-1981 and 1985 were 10.6 per thousand U.S. population. Women had 2.4 times the rate of visits by men and rates rose in both sexes until middle-age. Irritable bowel syndrome was the leading digestive disease diagnosis among gastroenterologists but only the seventh leading diagnosis among all physicians. Gastrointestinal symptoms. association with mental disorders. prescriptions. and disposition were also examined in patients with visits for irritable bowel syndrome. Among records with digestive tract symptoms and a first listed diagnosis of irritable bowel syndrome. stomach or abdominal pain was listed on only about one half of records and disorders of bowel function were listed on fewer than 40%. In 1975 and 1985. irritable bowel syndrome was noted approximately twice as often as other digestive diseases at visits with mental disorder symptoms and diagnosis. although mental disorder symptoms and diagnoses were noted at fewer than 15% of visits with irritable bowel syndrome. Medications were prescribed at approximately 75% of visits for irritable bowel syndrome; the most common were gastrointestinal medications followed by combination gastrointestinal-psychoactive medications. Subsequent appointments were scheduled following at least 50% of the visits of patients with irritable bowel syndrome.
Noninvasive trigeminal evoked potentials: normative data and application to neuralgia patients, A mild electric shock applied to the lower lip was used to elicit reliable evoked potentials from the trigeminal nerve in 20 normal young adults. The wave forms were morphologically similar to those observed with invasive procedures. No substantial differences for either the right or left side of stimulation. recording electrode. or subject sex were obtained for any of the individual potential amplitudes or latencies. The same procedures were applied to 10 patients who had been treated with retrogasserian glycerol injections for trigeminal neuralgia. Trigeminal evoked potentials were elicited in all patients. although the quality of the individual wave forms was more variable than that observed for the normal subjects. Comparison of the treated with the unaffected face side in the patients demonstrated significantly smaller N2-P2 amplitudes and longer N2 latencies for the affected face side. The results suggest that these procedures produce reliable evoked potential measures of trigeminal nerve function noninvasively which can provide an objective index of treatment efficacy.
Common headaches: type, duration, frequency and implications, Questionnaires completed by 327 preclinical medical and dental students showed that 97.9% had experienced headaches. most frequently attributed to insufficient sleep (38.8%). mental stress (38.8%). alcohol (38.5%). excess heat (36.7%). reading (31.5%). excess noise (29.9%) or light (27.7%). and sleeping too long (23.5%). The frequency and duration of these and other headaches are listed. 8% of the headache group had consulted a doctor. Only 2.1% of all students had never experienced a headache. Two hypotheses are examined: (1) can headaches be normal?--delineated by their disappearing soon after the noxious stimulus has ceased; (2) can pain in the head. as elsewhere in the body. act as a warning and therefore have protective. even survival value?.
Naproxen sodium in menstrual migraine prophylaxis: a double-blind placebo controlled study, In this study. the efficacy of Naproxen sodium (Nxs) in the prophylaxis of Menstrual Migraine (MM) was tested. versus Placebo (PL). Forty women suffering from MM were admitted to a double-blind treatment protocol with Nxs 550 mg twice each day by mouth or Placebo (PL). for 3 months; in the next 3 months all the women were treated with the active drug in an open study. The headache intensity and duration. as well as the number of days of headache and the analgesic consumption. were significantly reduced with Nxs compared to PL. The efficacy of Nxs. shown also in improving premenstrual pain. and its good tolerability. support the use of this drug in the prophylactic therapy of MM.
A comparative study of naproxen sodium, pizotyline and placebo in migraine prophylaxis, 318 patients satisfying the Ad Hoc Committee's criteria for common or classical migraine were entered into an 8 week single-blind placebo recording phase to establish. by diary cards. the frequency and severity of their attacks. 176 patients completed this and had records indicating 4-8 episodes in the 8 week period. with sufficient severity to reduce activity and/or work; these patients were randomized by a predetermined code. into three double-blinded groups: naproxen sodium 550 mg bid (60 patients). pizotyline 0.5 mg tid (59 patients). or placebo (57 patients). The patients were followed at monthly intervals for 12 weeks. with 25 dropping out (3 on naproxen sodium. and 2 each on pizotyline and placebo because of "side effects;" the remaining 18 because of noncompliance or reasons unrelated to therapy). Approximately 25% of patients in each of the 3 groups complained of side effects. Statistical analysis showed that both naproxen sodium and pizotyline were better than placebo. and of overall equivalent (i.e. equal) efficacy in the prophylaxis of migraine. In some respects. naproxen sodium was slightly more effective than pizotyline in the first month of treatment.
Cervicogenic headache: diagnostic criteria, Criteria for the diagnosis of cervicogenic headache are proposed. which include unilateral head pain. symptoms and signs of neck involvement. non-clustering episodic moderate pain originating in the neck then spreading to the head. and response to root or nerve blockade; plus rarer and non-obligatory features such as autonomic disturbances. dizziness. phonophotophobia. monocular visual blurring. and difficulty swallowing.
Angiographic changes suggestive of vasospasm in migraine complicated by stroke, A 30-year-old woman with a history of common migraine developed a permanent left homonymous hemianopia during a typical headache. CT scan demonstrated a right posterior cerebral infarction and angiography showed irregular narrowing of the ipsilateral posterior cerebral artery. suggestive of vasospasm. In the case no risk factors for atherosclerotic stroke were present except for smoking. and no other causes of stroke could be found.
Headaches in dementia, We investigated 288 elderly subjects with various degree of dementia. focusing on headaches. Seventy-three of 288 elderly subjects (25.3%) complained of some headaches. The most common type was the tension-type headache. from which 43 of the 73 subjects with headaches (58.9%) suffered. The degree of cognitive disturbances. evaluated by Hasegawa's intelligence scale. significantly correlated to the prevalence of headaches. and indicated that patients with dementia appeared to have less headaches. The methodological issues and views on headache research in dementia were assessed. and it is concluded that the field is a difficult one. with potential for error.
Double-plating of comminuted, unstable fractures of the distal part of the femur, The cases of nine patients who had a complex fracture of the distal part of the femur and a deficient medial-cortical buttress were reviewed. Stable fixation was not achieved with the lateral condylar buttress plate alone. Collapse of the distal fragment into varus angulation was noted intraoperatively. with the axis of rotation being the junction of the distal screws and the plate. Additional stabilization with a medial plate and a bone graft from the iliac crest was applied in all nine patients: in six. at the time of the index operation and in the remaining three. after the open wound and open fracture were considered clean. At an average duration of follow-up of twenty-six months (range. twenty-one to thirty-four months). all of the fractures had healed. Evaluation of the functional outcome revealed five good and four fair results. In three patients. less than 90 degrees of flexion of the knee was present and in six. the arc of flexion was limited to between 90 and 100 degrees. Additionally. four patients had an extensor lag of 5 degrees.
The joint-contact area of the ankle. The contribution of the posterior malleolus, Eight ankles from fresh cadavera were tested under simulated clinical conditions to determine the effect of increasing the size of the posterior malleolar fracture on the contact area of the ankle joint and on the distribution of joint pressure. The surface area of contact decreased with increased size of the posterior malleolar fragment. However. the documented changes were smaller than expected on the basis of the findings of Ramsey and Hamilton; they reported a 42 per cent reduction in contact area with only a one-millimeter lateral shift of the talus. which clinically would be associated with a similar one-millimeter shift of the distal tibial fragment. In addition. clinical experience has shown a high rate of post-traumatic degenerative arthritis associated with an inadequately reduced one-half-size posterior fragment. There were considerable changes in the load-distribution patterns. with increased confluence and concentration of loads as the size of the fragment was increased. In plantar flexion. many specimens had three separate areas of contact between the tibia and the talus. With increased size of the posterior fragment. the three areas of contact always joined to become one. Similarly. for all positions of the ankle. increased size of the posterior fragment caused decreases in the contact area. The maximum loss of contact area was 35 per cent for specimens with one-half-size fractures that were tested in the neutral position.
Growth disturbance of the proximal part of the femur after treatment for congenital dislocation of the hip, The radiographs of ninety patients in whom treatment of unilateral congenital dislocation of the hip was complicated by disturbance of growth of the proximal part of the femur were studied retrospectively. All patients were followed until closure of the affected proximal femoral physis. We divided the patients into three groups. according to the degree of vascular insufficiency: patients who had mild vascular insufficiency of the hip. which had little effect on growth; those who had moderate vascular insufficiency. which produces partial arrest of growth; and those who had severe vascular insufficiency. which causes complete arrest of growth. Good correlation was found between the initial degree of vascular insufficiency and the radiographic results at the most recent follow-up. The radiographic signs that were used to predict the extent of physeal involvement were a crescent-shaped epiphysis. medial bowing of the femoral neck (a shorter and more concave curve between the lesser trochanter and the proximal femoral metaphysis [the lateral portion of the Shenton line]). lateral tilting of the capital epiphysis. and premature physeal closure. Signs that were diagnostic of existing physeal involvement were elevation of the greater trochanter and shortening of the affected extremity. The presence and severity of these signs correlated well with the degree of vascular insufficiency. Medial bowing was the most reliable prognostic factor for the determination of the fate of the hip joint at maturity.
Spinal narcotics for postoperative analgesia in total joint arthroplasty. A prospective study, Sixty patients who were scheduled to have an elective total hip or knee arthroplasty were randomly assigned to one of three groups of twenty patients each before operation with spinal anesthesia. A double-blind technique was used throughout the study. The patients in Group I (control group) received hyperbaric 1 per cent tetracaine with epinephrine as the subarachnoid spinal anesthetic; the patients in Group II (morphine group). hyperbaric 1 per cent tetracaine with epinephrine and a single subarachnoid dose of Duramorph (morphine sulphate). 0.5 milligram; and those in Group III (Dilaudid group). hyperbaric 1 per cent tetracaine with epinephrine and a single subarachnoid dose of Dilaudid (hydromorphone hydrochloride). 0.002 milligram per kilogram of body weight. During the first twenty-four hours after the operation. the patients in Group II and Group III had significantly less pain compared with those in Group I. This was shown by the use of a visual linear-analog pain scale (p less than 0.05). the patients' ratings of the quality of relief of pain (p less than 0.02). and comparative measurements of the pain-altering medications that were used (p less than 0.05). The patients in Group II and Group III did not have any more complications or side effects than those in Group I. There was no significant difference in the quality and duration of analgesia between Group II and Group III.
Mediastinal widening associated with fractures of the upper thoracic spine, Widening of the mediastinum. when seen on radiographs of the chest in victims of trauma. is usually attributed to injury to the aorta. An aortic injury. when not lethal. often causes paraparesis or paraplegia due to ischemia of the spinal cord. A fracture of the upper thoracic spine can produce similar clinical and radiographic findings. The cases of three patients who had those findings are presented; in all three. the differential diagnosis between the vascular and skeletal injuries was difficult. Fracture of the thoracic spine should be included in the differential diagnosis whenever mediastinal widening is seen on radiographs.
The presence of human papillomavirus type 16 in squamous cell carcinoma of the proximal finger and reconstruction with a bilobed transposition flap, In a 71 year old white female a clinically diagnosed keratoacanthoma on the dorsum of the right third finger was removed using Mohs micrographic surgery and histologically diagnosed as a squamous cell carcinoma. It was shown by dot blot hybridization to have HPV type 16 DNA in the tumor. The wound was reconstructed with a bilobed transposition flap.
Forehead reconstruction, Guidelines for forehead reconstruction include maintaining or re-establishing normal boundaries. preserving nerve function. and maximizing scar camouflage. The interrelationships of anatomy. function. and principles of tissue movement which are critical to optimal reconstructive planning will be presented.
Pediatric mastocytosis, The onset of mastocytosis occurs between birth and 2 years of age in approximately 55% of all cases; an additional 10% develop the disease before the age of 15 years. Mastocytosis in these age groups differs in many respects from mastocytosis that has its onset in adulthood. The typical presentation of pediatric-onset mastocytosis consists of cutaneous manifestations: either a solitary mastocytoma. urticaria pigmentosa. or. less commonly. diffuse cutaneous mastocytosis. Particularly in infants. bullous eruptions may occur. Mastocytosis in infants and children may involve internal organs. including the bone marrow and the gastrointestinal tract. although such manifestations appear to be less common in children than in adults. Plasma histamine levels may be elevated in pediatric-onset mastocytosis. Treatment usually involves the use of H1 and H2 antihistamines to control itching and to control the hypersecretion of gastric acid that may occur. The prognosis for children with mast cell disease is variable; approximately half of the children with urticaria pigmentosa may experience resolution of lesions and symptoms by adolescence.
Biochemical diagnosis of systemic mast cell disorders, Systemic mastocytosis is characterized by an abnormal proliferation of tissue mast cells. Symptoms of mastocytosis are primarily attributed to the release of mast cell mediators during episodes of systemic activation of the excessive numbers of mast cells. Thus. biochemical evidence for the release of increased quantities of mast cell secretory products can suggest or confirm. depending on the clinical situation. a diagnosis of systemic mastocytosis. A major advantage of the biochemical approach to the diagnosis of systemic mast cell disease is that it has allowed the recognition of a class of patients in whom episodes of systemic mastocytes activation can be unequivocally documented biochemically but in whom clear-cut evidence of abnormal mast cell proliferation is lacking by current histologic criteria. Although the release of increased quantities of mast cell mediators can be demonstrated during episodes of mast cell activation in such patients. mediator levels are usually normal at quiescent times. By contrast. patients with proliferative mast cell disease (mastocytosis) usually exhibit chronic overproduction of mast cell mediators. Mast cell secretory products that can be measured in an attempt to obtain biochemical evidence of systemic mast cell activation include histamine. prostaglandin D2. tryptase. and heparin. The analytical approaches to assessing release of those individual mast cell products are evaluated. In general. the diagnosis and investigation of patients with systemic mast cell activation can best be accomplished by concerted use of histologic examination of key tissues together with analysis of chemical markers of the mast cell.
Classification and diagnosis of mastocytosis: current status, Mastocytosis is a disease characterized by an abnormal increase in mast cells. Manifestations of the disease are provoked in large part by the resultant increase in mast cell-derived mediators. which have a variety of local and systemic effects. Mastocytosis is variable in respect to the organ systems involved. clinical manifestations. and association with hematologic diseases. This has suggested the need for an improved classification scheme to allow assessment of prognosis and therapy. The heterogeneity of the disease patterns in mastocytosis strongly suggests that more than one biologic lesion may occur in the developmental sequence that leads to placement of mature mast cells in tissues.
Photoinactivation of T-cell function with psoralen and UVA radiation suppresses the induction of experimental murine graft-versus-host disease across major histocompatibility barriers, Bone marrow transplantation is employed in the treatment of a number of hematologic and malignant diseases. A major complication is the induction of graft-versus-host disease. Whereas removal of T lymphocytes from the donor marrow effectively reduces the incidence of graft-versus-host disease. the incidence of graft failure often increases when T cells are depleted from the transplanted marrow. In the current study. photoinactivation of the donor cells with 8-methoxypsoralen coupled with exposure to long-wavelength ultraviolet radiation (PUVA therapy) was used to inactivate the response of the donor T cells against the host. PUVA therapy suppressed the ability of spleen cells to respond to alloantigen in the in vitro mixed lymphocyte reaction. The induction of acute graft-versus-host disease across complete major histocompatibility barriers in lethally X-irradiated mice was significantly suppressed after bone marrow transplantation with photoinactivated bone marrow cells. Long-term survivors demonstrated allogeneic reconstitution and partial restoration of T-cell function. Because PUVA therapy had no inhibitory effect on hematopoiesis. these data suggest that using phototherapy to inactivate the alloreactivity of T cells may provide an alternative to purging T cells from the donor marrow. thus suppressing both the incidence of graft-versus-host disease and the incidence of graft failure.
Digital cutaneous vascular responses to histamine and neuropeptides in Raynaud's phenomenon, The pathophysiology of Raynaud's phenomenon is not well defined. but active cutaneous microvascular vasoconstriction and emptying must occur to account for the pallor and are reasons for studying the microvasculature. It has been proposed that there may be a defect in a local histamine vasodilator mechanism. The role of the peptidergic nervous system in Raynaud's phenomenon has not been previously investigated. To study the histaminergic and peptidergic axes in Raynaud's phenomenon. we measured the cutaneous microvascular responses of patients with Raynaud's phenomenon to digital intradermal injections of saline. histamine. the histamine-releasing agent. compound 48/80. substance P. and calcitonin gene-related peptide. We compared these results with those obtained in normal subjects. Intradermal cutaneous microvascular blood flow responses were quantified by planimetry and laser Doppler flowmetry. The results show: a) that in primary Raynaud's phenomenon there is no evidence of local deficiency in histamine release or insensitivity to histamine in the cutaneous microvasculature; and b) that patients with Raynaud's phenomenon react normally to the neuropeptides calcitonin gene-related peptide and substance P. providing a rationale for treating Raynaud's phenomenon with vasoactive peptides.
Localization of basic fibroblast growth factor mRNA in melanocytic lesions by in situ hybridization, Basic fibroblast growth factor (bFGF) is a mitogen for normal human melanocytes and keratinocytes in culture. Experiments in vitro suggest that keratinocytes supply bFGF to melanocytes through a paracrine mechanism and that the aberrant expression of bFGF in melanomas confers growth independence from bFGF-producing cells. To determine whether bFGF is expressed in vivo. we examined a series of benign and malignant melanocytic lesions in situ using bFGF riboprobes on tissue sections. and correlated bFGF expression with histologic phenotype. Seventeen melanocytic neoplasms were studied. including four common acquired nevi. four dysplastic nevi. four primary malignant melanomas. and five metastatic melanomas. Nevic cells in benign intradermal nevi showed low signal intensity (1+). whereas compound and dysplastic nevi showed 2+ to 3+ expression in the junctional nevic cell population and 1+ expression in the dermal nevic cell population. Melanocytes in primary melanomas had intermediate (2+) and those in metastatic melanomas had low (1+) levels of bFGF gene transcripts. Fibroblasts expressed high levels (3+) and epidermal and adnexal keratinocytes moderate (2+) levels of bFGF in all cases studied. Basic FGF expression in endothelial cells. known to produce and respond to this growth factor in vitro. was lower than that in the fibroblast and keratinocyte cell population and. in 10 of 17 cases. no bFGF mRNA was detectable. This study shows that bFGF is expressed in nevomelanocytes in vivo in all melanocytic lesions studied and thus cannot be used as a marker for transformation. The presence of bFGF gene transcripts in the various dermal cell types and in keratinocytes suggests that it may act as an autocrine and paracrine growth factor in regulating cellular proliferation in the skin.
The skin in mastocytosis, The most frequent site of organ involvement in patients with any form of mastocytosis is the skin. Cutaneous expressions include urticaria pigmentosa. mastocytoma. diffuse and erythrodermic cutaneous mastocytosis. and telangiectasia macularis eruptiva perstans. The cutaneous lesions tend to appear early in life. Although urticaria pigmentosa has been reported in 12 pairs of twins and one set of triplets. the majority of affected individuals have no familial association. Most patients with systemic mastocytosis have skin lesions; however. an occasional patient will have systemic disease with no other skin features than flushing. In lesional cutaneous sites and in non-lesional skin. there is an increase in the number of mast cells. Electron microscopy shows quantitative differences between lesional skin mast cells from patients with and without systemic disease. The mast cells from adult patients with systemic disease have a larger mean cytoplasmic area. nuclear size. and granule diameter. The granules contain predominantly grating/lattice structures. The cutaneous mast cells contain tryptase and chymase. They retain their functional reactivities to relevant secretory stimuli. such as C3a. morphine sulfate. and calcium ionophore A23187. Lesional skin contains histamine. leukotriene B4. prostaglandin D2. 5-hydroxyeicosatetraenoic acid. platelet-activating factor. and heparin. Treatment of the cutaneous manifestations includes the use of H1 and H2 antihistamines. oral disodium cromoglycate. psoralens plus ultraviolet A photochemotherapy. and potent topical corticosteroid preparations.
Proliferating cells in psoriatic dermis are comprised primarily of T cells, endothelial cells, and factor XIIIa+ perivascular dendritic cells, Determination of the cell types proliferating in the dermis of patients with psoriasis should identify those cells experiencing activation or responding to growth factors in the psoriatic dermal milieu. Toward that end. sections of formalin-fixed biopsies obtained from 3H-deoxyuridine (3H-dU)-injected skin of eight psoriatic patients were immunostained. followed by autoradiography. Proliferating dermal cells exhibit silver grains from tritium emissions. The identity of the proliferating cells could then be determined by simultaneous visualization with antibodies specific for various cell types. UCHL1+ (CD45RO+) T cells (recall antigen-reactive helper T-cell subset) constituted 36.6 +/- 3.1% (mean +/- SEM. n = 6) of the proliferating dermal cells in involved skin. whereas Leu 18+ (CD45RA+) T cells (recall antigen naive T-cell subsets) comprised only 8.7 +/- 1.5% (n = 6). The Factor XIIIa+ dermal perivascular dendritic cell subset (24.9 +/- 1.5% of proliferating dermal cells. n = 6) and Factor VIII+ endothelial cells (23.0 +/- 2.3%. n = 6) represented the two other major proliferating populations in lesional psoriatic dermis. Differentiated tissue macrophages. identified by phase microscopy as melanophages or by immunostaining with antibodies to Leu M1 (CD15) or myeloid histiocyte antigen. comprised less than 5% of the proliferating population in either skin type. In addition to calculating the relative proportions of these cells to each other as percent. we also determined the density of cells. in cells/mm2 of tissue. The density of proliferating cells within these populations was increased in involved versus uninvolved skin: UCHL1+. 9.0 +/- 1.7 cells/mm2 versus 1.8 +/- 0.6 cells/mm2. p less than 0.01; Factor XIIIa+. 6.0 +/- 0.7 cells/mm2 versus 1.5 +/- 0.5 cells/mm2. p less than 0.01; Factor VIII+. 5.5 +/- 1.4 cells/mm2 versus 0.0 cells/mm2. p less than 0.05. The presence of preferential active proliferation of a T-cell subset in lesional dermis suggests that activating signals specific for this subset are contained within the psoriatic dermis in vivo. The activation of recall antigen-reactive T cells may be a driving force behind the dendritic cell and endothelial cell proliferation. Alternatively. the selective proliferation and expansion of these two constitutive cell types (Factor XIIIa+ and Factor VIII+) may result in signals that promote activation of UCHL1+ (CD45RO+) T cells.
Cross-antigenicity between the scabies mite, Sarcoptes scabiei, and the house dust mite, Dermatophagoides pteronyssinus, This study demonstrated that antigens of the parasitic mite Sarcoptes scabiei (SS) cross-react with antigens of the house dust mite Dermatophagoides pteronyssinus (DP). Crossed immunoelectrophoresis (CIE) reaction of SS extract with rabbit anti-DP serum resulted in multiple immunoprecipitates. Reciprocal CIE reactions gave similar results. Immunoprecipitates from both reactions bound IgE in the sera of dust-mite-sensitive patients who had no history of scabies. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis resolved protein/peptide bands of both SS and DP also bound serum IgE from dust-mite-allergic patients following immunoblotting. Non-allergic control sera gave no IgE binding to either SS or DP antigens. These results indicate that patients with atopy to dust mites exhibit circulating antibodies built to DP but that recognize determinants on SS antigens. It is highly probable that scabietic patients build antibodies to SS antigens that also recognize DP antigens. These results raise questions concerning the reported isotypic antibody responses to SS because the sensitivity of scabietic patients to house dust mites has not been previously evaluated. This cross-reactivity may play an important role in the susceptibility to scabies and its clinical manifestations.
Increased number of dendritic cells in draining lymph nodes accompanies the generation of contact photosensitivity, Draining lymph node cells isolated from mice 48 h after topical exposure to tetrachlorosalicylanilide (TCSA) + UVA radiation (TCSA + UVA) demonstrated a two-fivefold increase in the number of dendritic cells (DC) compared with control mice treated with vehicle + UVA. The increase in number of DC was both time and dose dependent. with the peak DC accumulation occurring at 48 h post application and at a TCSA dose of 1.0%. Photospecificity was evident in that mice irradiated prior to treatment with TCSA (UVA/TCSA) demonstrated no significant increase in DC accumulation. The accumulation of DC was followed by a significant increase in total lymph node cellularity. An in situ 3H-thymidine incorporation assay showed a significant increase in proliferative activity of cells isolated from the draining lymph nodes of mice treated with TCSA + UVA as compared to naive. vehicle. or UVA/TCSA-treated mice. Dendritic cells isolated from mice treated 24 h earlier with TCSA + UVA. but not those from naive mice or mice treated with UVA/TCSA. were capable of TCSA-specific antigen presentation. Responder lymphocytes from untreated mice or mice photosensitized with musk ambrette showed a much lower response to DC isolated from TCSA + UVA-treated mice. demonstrating the specificity of the reaction. DC-depleted lymph node cells were unable to stimulate this blastogenesis response. These results suggest that application and photoactivation of TCSA induces cellular and functional changes in the lymph node DC indicative of their involvement in the induction phase of a contact photoallergic reaction.
Cyclosporin A suppresses ICAM-1 expression by papillary endothelium in healing psoriatic plaques, To analyze the mode of action of Cyclosporin A (CsA) in psoriasis. we examined the phenotypic profile of resident and passenger skin cells in seven psoriatic patients before and after 2 weeks of CsA treatment using a large panel of monoclonal antibodies in a three-step immunoperoxidase technique. For comparison. skin biopsies from psoriatic patients receiving psoralen + UVA (PUVA) therapy were examined. Although both treatment protocols were equally effective in inducing resolution of psoriatic lesions. the phenotypic changes induced by CsA differed greatly from those seen after PUVA. In CsA-treated patients there was a dramatic reduction in the ICAM-1 expression by papillary endothelial cells. but density. pattern. and phenotype of infiltrating inflammatory cells remained essentially unchanged. In contrast. PUVA therapy had no visible effect on ICAM-1 expression by papillary endothelial cells. but resulted in a significant reduction of the hemopoietic resident and infiltrating mononuclear cells within the epidermis. These results favor. but do not prove. the assumption that the CsA regimen chosen in this study exerts its anti-psoriatic effect primarily at the level of the keratinocyte. i.e.. by inhibiting events leading to keratinocyte proliferation as well as by interfering with the secretion of mediators responsible for ICAM-1 expression by papillary endothelial cells.
Interleukin-4 promotes the expansion of skin-infiltrating lymphocytes from atopic dermatitis in vitro, Functional studies of lymphocytes in atopic dermatitis (AD) have so far focused on peripheral blood mononuclear cells (PBMC). whereas cells at the involved site. the skin. have not been examined. Accordingly. we have developed methods to generate lymphocyte cultures from biopsies of inflammatory skin areas. Skin-infiltrating lymphocytes (SIL) were isolated from skin biopsies of 6 patients with severe AD and expanded in vitro in the presence of interleukin-2 (IL-2) without additional antigens. After 6-10 d in culture. outgrowth of mononuclear cells from biopsy tissue was observed in all cases. Phenotypic analysis of skin-derived cells revealed the predominance of CD4+ T-helper/inducer phenotype in SIL populations. Parallel cultures of SIL and PBMC showed an increase and expansion of CD8+ T cells in cultured PBMC. whereas the CD4+ phenotype was predominant in SIL cultures. As indicated by their expression of HLA-DR and CD25 antigens. most of the SIL were activated and the cells mainly expressed T-cell receptors (TCR) composed of alpha and beta chains. Different strategies for expansion of SIL in vitro were examined. High levels of IL-4 (1.000 U/ml) in combination with IL-2 (50 U/ml or 1.000 U/ml) preferentially promoted growth of SIL derived from AD and were much more effective than IL-2 alone. No cells expanded in cultures with IL-4 alone. SIL grown with high concentrations of IL-4 contained a significant proportion of double-positive CD4+8+ cells. No other marked differences were observed in the distribution of T cell subsets in cultures propagated under different conditions for 21 d. Our results demonstrate the feasibility of growing infiltrating T lymphocytes from inflammatory skin of AD patients. The use of high concentrations of IL-2 in combination with high levels of IL-4 allows a large expansion of these cells and thus represents a useful strategy to expand cells for further functional and molecular biologic studies.
Genomic, phenotypic, and functional analyses of T cells in patients with psoriasis undergoing systemic cyclosporin A treatment, Recent studies have demonstrated that cyclosporin A (CyA) exerts a beneficial effect on psoriasis. It remains unclear. however. whether T-cell immune responses are definitely impaired in psoriasis and whether the anti-psoriatic effect of CyA is mediated by interference with T-cell activation. To study these questions. 20 patients with severe psoriasis were treated with oral CyA (5 mg/kg/d) for 12 weeks and examined for several phenotypic and functional properties of peripheral blood T cells before and after therapy. The analyses included CD3. CD4. and CD8 phenotypes. IL-2 production and IL-2 receptor expression following Con A stimulation. proliferative responses to PHA. and in vivo responsiveness to a foreign antigen. PPD. When the values of patients before therapy and healthy individuals were compared. no statistically significant differences were detected in any of these analyses. Furthermore. none of these T-cell properties were changed after 12 weeks of treatment. To assess possible minor mutations in T-cell-related genes in psoriasis. the T-cell receptor beta-chain locus was analyzed by Southern hybridization. With a cDNA probe for C beta 1. a polymorphic fragment of congruent to 9 kb was detected in Eco RI digests in one of 20 patients and in four of 10 healthy individuals examined. No polymorphism was detected in Bam HI digests in any individual. These results fail to support the hypothesis that a general or "systemic" alteration in T-cell immunity plays a central role in the pathogenesis of psoriasis and in the action of CyA against this skin disorder.
The liver, spleen, and lymph nodes in mastocytosis, In systemic mastocytosis the liver. spleen. and lymph nodes may be infiltrated by mast cells. with patterns of infiltration specific for each tissue. This may result in hepatosplenomegaly and enlarged lymph nodes. Extensive involvement with mast cells may also be associated with organ dysfunction. Specifically. in the case of liver. mast cell infiltration may result in fibrosis. portal hypertension. and abdominal ascites. Clinically significant involvement of the liver. spleen. and lymph nodes appears to be more common in patients with aggressive forms of mastocytosis. including those with a hematologic disorder.
Hematologic aspects of mastocytosis: I: Bone marrow pathology in adult and pediatric systemic mast cell disease, The typical bone marrow lesions seen in adults with systemic mast cell disease (SMCD) are foci of spindle-shaped mast cells in a fibrotic matrix and are found in up to 90% of adults with SMCD. Lymphocytes and eosinophils frequently are admixed with the mast cells. forming the classic MEL lesion. The mast cell lesions can be found in perivascular. peritrabecular or intertrabecular locations and may on occasion completely replace intratrabecular regions of the marrow. In contrast. the mast cell lesions found in children with cutaneous mast cell disorders are uniformly small and subtle and are most frequently located perivascularly. Lymphocytes. eosinophils. and early myeloid elements may be associated with these lesions. Of perhaps greater specificity for SMCD is the finding of confluent clusters of mast cells on the marrow aspirates; such clusters are noted in up to 30% of patients with SMCD.
Systemic mastocytosis: retrospective review of a decade's clinical experience at the Brigham and Women's Hospital, The clinical experience with a group of 21 patients with systemic mastocytosis followed at our institution is summarized. Cutaneous and gastrointestinal symptoms and findings were the most prominent chronic manifestations; episodic vascular collapse was the most dramatic acute event. All patients had indolent mastocytosis. There was no mortality.
The treatment of mastocytosis: an overview, The treatment of mastocytosis requires a recognition of specific disease patterns of involvement. with consequent institution of appropriate therapy based on the disease pattern manifested in a given patient. Treatment for most forms of mastocytosis is conservative and symptomatic. H1 and H2 antihistamines in combination or alone remain the primary drugs of choice. In specific cases. patients may require aspirin and/or steroids; some must be prepared to self-administer epinephrine for severe anaphylactic episodes. In patients with associated hematologic disorders. the treatment of the disorder will depend on the hematologic findings. In rare cases. and in aggressive forms of mastocytosis only. it may be necessary to consider limited forms of chemotherapy.
The prevalence of osteoporosis risk factors and physician intervention, To determine the prevalence of osteoporosis risk factors and the probability of physician risk recognition and intervention. the medical records of a cohort of 243 women aged 40 to 65 years were reviewed retrospectively. A historical cohort design was used. Risk factors present before the start of the study were identified. Osteoporosis risk recognition (discussion. problem list). osteoporosis specific intervention (counseling about risk. or estrogen or calcium supplementation). or nonspecific intervention (dietary. exercise. smoking. or alcohol counseling) were recorded over a 3-year follow-up period. Seventy-four percent of the women had two or more risk factors. The most common were perimenopausal or postmenopausal status (73%) and absence of estrogen supplementation (ever) (65%). During the period of the study. 46 women (19%) had received an osteoporosis-specific intervention. One hundred eleven women (46%) had received one of the above or a less specific intervention. The medical records of only 25 women (10%) documented an assessment of osteoporosis risk. Only menopausal status predicted osteoporosis intervention. and the probability of intervention decreased as the total number of risk factors increased. The data identify three groups of women who could benefit from increased risk-reduction strategies: premenopausal women. perimenopausal or postmenopausal women who have never previously taken supplemental estrogens. and women with multiple risk factors.
Assessment and counseling of coronary risk factors by family practice residents, A study was undertaken to determine (1) the likelihood that patients seen for episodic health care in a family medical center have been assessed and counseled for coronary heart disease (CHD) risk factors. and (2) the likelihood that patients having an identified risk factor have been assessed and counseled regarding other CHD risk factors. One thousand five hundred twenty-eight medical records were randomly selected from all visits occurring over two periods in 1986 and 1987 to 122 residents in an eight-site family medicine residency network. Patients with cardiovascular disease and those younger than 20 or older than 65 years of age were excluded. Assessments were made of (1) smoking history. blood pressure. weight. physical activity. and dietary content during the previous 12 months; (2) family history of cardiovascular disease during the previous 12 months and in the initial patient history; (3) and blood cholesterol during the prior 5 years. Risk-factor counseling practices were examined for the previous 12 months. Blood pressure was assessed in 96% of patients. smoking in 40%. cholesterol in 26%. and family history in 52%. Ninety-six percent of hypertensive patients were counseled for hypertension. but only 45% of smokers and 20% of patients with hypercholesterolemia were counseled for those risk factors. Of patients having a given risk factor. assessment for any other risk factor occurred in fewer than 60% of cases. Patients having a documented positive family history were only slightly more likely than other patients to be assessed for additional risk factors. There is continued need for enhancing coronary risk-factor assessment and counseling by resident physicians.
Differences in the obstetric practices of obstetricians and family physicians in Washington State, In response to the obstetric malpractice crisis. both obstetrician-gynecologists and family physicians have raised their fees and preferentially selected lower risk patients. In addition. large numbers of general and family physicians have left obstetric practice altogether. The impact of these responses was explored by examining the differences in the demographic and clinical profile of patients served by these two disciplines in the State of Washington. Eighty-five percent (45.540) of all complete records from 1983 births attended by physicians in the State of Washington were matched to physician specialty information. These births represent 67% of the total deliveries in Washington State in 1983. Although twice as many general and family physicians as obstetricians were practicing obstetrics. obstetricians delivered 2.5 times as many infants as did general and family physicians. Obstetricians served an older patient population with more low-birthweight infants. multiple births. and complications of pregnancy than family physicians. General and family physicians were more likely to care for minorities. teenagers. and unmarried and rural mothers. Obstetricians cared for patients with higher medical risks. whereas general and family physicians provided care to more socially vulnerable and geographically isolated populations. To the extent that general and family physicians are differentially abandoning obstetric practice because of the current malpractice crisis. access to care for rural and socially vulnerable groups may deteriorate rapidly.
Multivariate data reduction by principal components, with application to neurological scoring instruments, Principal components analysis is widely used as a practical tool for the analysis of multivariate data. The aim of this analysis is to reduce the dimensionality of a multivariate data set to the smallest number of meaningful and independent dimensions. The analysis can also provide interpretable linear functions of the original measured variables that may serve as valuable indices of variation. A brief introduction to principal components analysis is given herein. followed by an examination of a particular set of multivariate data accruing from a study of acute brain injuries in a pediatric population. in which severity of brain injury had been assessed with the Glasgow Coma Scale (CGS). Principal components analysis reveals that the GCS sum score is a particularly inefficient summarizer of information in this cohort. The determination of an objective weighting of measured variables. as provided through principal components analysis. is essential in the construction of meaningful neurological scoring instruments.
A manifesting carrier of Duchenne muscular dystrophy with severe myocardial symptoms, A 42-year-old so-called manifesting carrier of Duchenne muscular dystrophy (DMD). whose first complaints were severe myocardial symptoms. is described. Immunohistochemical study using anti-dystrophin anti-serum and analysis of cloned segments of X chromosome DNA were performed. Her two sons and one of her brothers appear to have had the same disease. She was admitted to the hospital complaining of dyspnoea. back pain and palpitations and was first diagnosed as having myocardial infarction. However. this diagnosis was excluded. The echocardiogram showed diffuse abnormalities of myocardial function. Serum enzymes were increased. Minimal weakness and decreased deep tendon reflexes were detected in her left lower extremity. Muscle biopsy revealed a small number of necrotic fibres. Immunohistochemical study using anti-dystrophin antiserum showed a mosaic pattern of the surface membrane. Analysis of cloned segments of X chromosome DNA from the patient and her son showed the XmnI(Asp) alleles of pERT 87-15 and the TaqI alleles of pERT 87-8 in both patients.
Intracranial germ-cell tumors in children, All patients with confirmed intracranial germ-cell tumors treated at the Hospital of Sick Children during the period January. 1952. to December. 1989. were reviewed. Of the 51 tumors reviewed. 16 were located in the suprasellar region. 32 in the pineal region. and three in both the pineal and the suprasellar regions. Forty-nine patients underwent surgical resection which was total in seven and partial in 20. and consisted of a biopsy in 22. Two patients were managed on the basis of serum and cerebrospinal fluid markers. Surgical tools such as the operating microscope. the ultrasonic surgical aspirator. and the laser beam allowed safe debulking and removal of the deep-seated tumors in the pineal region. There were no operative deaths in the 36 patients treated since 1972. who included 23 with pineal tumors. Twenty-five patients with germinomas received radiotherapy and had a 5-year survival rate of 85.1%. Thirteen patients with non-germinoma germ-cell tumors received radiotherapy and had a 5-year survival rate of 45.5%. On the basis of this review. the authors recommend resection of pineal and suprasellar germ-cell tumors in order to firmly establish an accurate histological diagnosis to guide the extent of adjuvant therapy. In the case of a pure germinoma without evidence of dissemination. adjuvant therapy consists only of local radiotherapy. On the other hand. for malignant non-germinoma germ-cell tumors. adjuvant therapy must include chemotherapy as well as craniospinal axis radiotherapy.
Language function following anterior temporal lobectomy, The authors report the results of a prospective investigation that evaluated postoperative changes in language function after dominant (29 cases) or nondominant (35 cases) anterior temporal lobectomy for treatment of complex partial seizures. These patients received conservative resection of lateral temporal cortex but aggressive resection of medial temporal cortex. None of the patients underwent functional mapping of cortical language ability. All patients were assessed with a standardized aphasia battery (Multilingual Aphasia Examination) before and 6 months after surgery. Postoperatively. the dominant anterior temporal lobectomy group did not show any significant losses in language function compared to patients who underwent nondominant anterior temporal lobectomy. In addition. the dominant temporal lobectomy group showed significant postoperative improvement in complex receptive language comprehension compared to the nondominant group. These results suggest that patients with complex partial seizures of medial temporal lobe onset can undergo a conservative resection of lateral temporal cortex without language mapping. Such surgery carries little risk to language function and provides an excellent postoperative surgical outcome.
Giant carotid-ophthalmic artery aneurysms: direct clipping utilizing the "trapping-evacuation" technique, The authors have devised a "trapping-evacuation" technique to facilitate direct clipping of giant aneurysms in the paraophthalmic region of the internal carotid artery (ICA). The giant aneurysm is collapsed by first trapping the aneurysm by temporary occlusion of the cervical common carotid and external carotid arteries. along with temporary clipping of the intracranial ICA distal to the aneurysm. Thereafter. intra-aneurysmal blood is simultaneously aspirated through a catheter placed in the cervical ICA. Exposure of the proximal end of the aneurysm neck is mandatory for successful clipping. This is accomplished by extensive unroofing of the optic canal. removal of the anterior clinoid process. opening of the anterior part of the cavernous sinus. and exposure of the most proximal intradural (C2) and genu (C3) portions of the ICA. Four cases of giant aneurysms of the paraophthalmic ICA were successfully treated by this technique and the postoperative outcome was good in all cases. Preoperative magnetic resonance imaging for evaluation of the anatomical details. balloon occlusion test of the ICA. and intraoperative measurement of cortical blood flow were important to the success of the operation. Intraoperative digital subtraction angiography via the catheter placed in the cervical ICA was useful in confirming successful clipping.
Sequential magnetic resonance imaging following stereotactic radiofrequency ventralis lateralis thalamotomy, Serial postoperative magnetic resonance (MR) studies were obtained in 21 patients who underwent somatotopically placed stereotactic radiofrequency (rf) ventralis lateralis thalamotomy for the control of movement disorders. The MR studies were reviewed to determine the MR characteristics of early-phase (less than or equal to 7 days) and late-phase (8 days to 5 months) lesions. Surgery was performed for the control of parkinsonian tremor (14 cases). intention tremor (six cases). and essential tremor (one case). Single rf lesions were made with an electrode (1.6 mm in diameter. 3 mm in tip length) heated to 78 degrees C for 60 seconds. On MR images of the lesions. three distinct concentric zones were identified. described as follows (from the center outward). Zone 1 gives increased signal on long-relaxation time (TR) (T2-weighted) MR images in early- and late-phase lesions and decreased signal on short-TR (T1-weighted) MR images in early-phase lesions only. Zone 2 gives decreased signal on long-TR (T2-weighted) images in early- and late-phase lesions; it gives isointense signal on short-TR (T1-weighted) images in early-phase lesions only. Zone 3 gives increased signal on long-TR (T2-weighted) images in early-phase lesions only and decreased signal on short-TR (T1-weighted) MR images in early-phase lesions only. It is considered that in early-phase lesions. Zone 2. with a mean diameter of 7.3 mm on axial long-TR (T2-weighted) imaging. represents an area of hemorrhagic coagulation necrosis. In late-phase lesions. Zone 2. with a mean diameter of 5.0 mm on axial long-TR (T2-weighted) imaging. represents hemosiderin deposition. Zone 3 likely represents edema. and this zone disappears between the early and late periods. From regression analysis. lesion size began to stabilize at approximately 7 months with a mature lesion diameter of 3.3 mm. Long-term follow-up monitoring (median 16 months) showed good tremor control. Based on clinical and radiological findings. the authors conclude that forms of hemoglobin are suitable markers to assess the size of rf lesions. Serial MR imaging provides a noninvasive means of studying the evolution of rf thalamotomy lesions.
Intracranial pressure and cerebrospinal fluid outflow conductance in healthy subjects, Conductance of cerebrospinal fluid (CSF) outflow (Cout) is an important parameter to be considered in patients with CSF circulation abnormalities. In patients with normal-pressure hydrocephalus it is the single most important parameter in determining if the patient needs CSF shunting. The lower normal limit for Cout has been estimated from the effect of shunting in patients with normal-pressure hydrocephalus. from patients retrospectively reevaluated after recovering from illness. and from patients with known abnormalities in the brain or the CSF system. The true value of Cout in normal individuals. however. has hitherto not been reported. In the present study. Cout has been measured by a lumbar infusion test in eight young volunteers with no suspicion of disease. The mean intracranial pressure (ICP) was 11 mm Hg and a linear relationship was found between CSF absorption and ICP. The mean Cout was 0.11 ml/min/mm Hg and the lower 95% confidence level was 0.10 ml/min/mm Hg. These values are in accordance with those obtained from previous studies.
Lack of neural control and reactivity to vasoactive agents in malignant glioma arteries, Vessels in malignant brain tumors have a defective blood-brain barrier. It is important to know if tumor vessels respond to vasoactive agents. since systemic administration of vasodilatory agents together with chemotherapy could increase the access of these drugs to the tumor. It was found that arteries in human malignant gliomas have no neural control and are totally nonreactive to various vasoactive agents. The vessels lose their reactivity within 1 to 2 mm outside the visible tumor front.
Magnetoencephalographic localization of interictal spike sources. Case report, The reliability of localization of interictal spike sources using magnetoencephalography (MEG) was examined by repeated measurements in a patient with temporal lobe epilepsy. During two preoperative recording sessions. the estimated sources. projected onto magnetic resonance images of the patient's brain. were found to lie less than 1 cm apart within the area subsequently resected. The MEG localization was in close agreement with intraoperative cortical recordings.
Vertical odontoid fracture. Case report, A case of vertical odontoid fracture is presented in which a concomitant fracture of the skull indicated possible pathogenetic mechanisms. The radiological diagnosis and the management of this case are discussed.
Primary central nervous system T-cell lymphoma. Case report, Primary central nervous system (CNS) T-cell lymphoma is extremely rare. The present case report provides immunocytochemical evidence for a cerebellar CNS T-cell lymphoma. The patient underwent surgery followed by radiation therapy and is alive and well 36 months postoperatively. The clinical and pathological features of primary CNS T-cell lymphoma as well as diagnostic measures and treatment options are discussed. together with a compilation of all previous case reports of primary CNS T-cell lymphomas.
Intraoperative protection of cranial nerves and perforating arteries by silicone rubber sheets. Technical note, The authors describe a technique whereby. during microneurosurgery. vital structures are covered or wrapped with small pieces of silicone rubber sheeting to protect them from intraoperative injury. In this way. perforating arteries located behind a large aneurysm can be covered to avoid their inclusion within the blades of the clip. and the cranial nerves coursing around or through a tumor can be wrapped to protect them from injury by a suction or forceps. By insulating nerves and arteries. this silicone rubber sheet has the added advantage of protecting them from injury due to electrical current of bipolar forceps. The silicone rubber sheet described here is smoother. thinner. and lighter than a cotton pattie.
Normal number and kinase activity of insulin receptors in liver of genetically fat chickens, Genetically fat (FL) chickens exhibit an increase in liver lipogenesis and. in the fasting state. insulin sensitivity compared with genetically lean (LL) chickens. Liver insulin receptor number and insulin receptor kinase (IRK) activity were studied at 5 wk. In the fasting (16 h) and fed state. insulin binding to liver membranes and insulin receptor affinity (50% inhibition of tracer binding. range: 5-7 ng/mL at 4 degrees C) were very similar in fat and lean chickens. Insulin degrading activity of membranes was negligible for both genotypes. Following solubilization with Triton X-100. liver receptors were purified either on wheat germ agglutinin (WGA receptors) or on lentil then wheat germ lectins (lentil receptors). Both types of purified receptors exhibited the same binding affinity. independent of the genotype or the nutritional state. Autophosphorylation and IRK activity toward artificial substrate poly(Glu. Tyr)4:1 were not different between genotypes. Basal IRK (i.e.. in the absence of insulin) was decreased by the overnight fast. Fattening of genetically fat chickens cannot be accounted for by an increase in the number or the kinase activity of liver insulin receptors. Steps following the binding or the receptor kinase may be involved.
Opposite effect of cold on energetic efficiency in normal and obese Wistar rats with hypothalamic lesions, Reduced thermogenesis in brown adipose tissue (BAT) may contribute to increased energetic efficiency and obesity in rats with ventromedial hypothalamic (VMH) lesions. Thermogenic activity of BAT is a function of the environmental temperature. If a relationship exists. it follows that the increased energetic efficiency of VMH-lesioned rats likewise should be governed by temperature. We have therefore investigated the energy balance of normal and VMH-lesioned rats housed at 30 degrees C and 10 degrees C. Experiments at differing feeding levels allowed calculation of maintenance energy requirements and the net energetic efficiencies of each group. VMH-lesioned rats at thermoneutrality (30 degrees C) accumulated more body fat at all feeding levels than did normal rats. Maintenance energy requirement was reduced. but the net energetic efficiency did not differ significantly from normal. The reduced maintenance energy requirement of lesioned rats persisted at 10 degrees C. Net energetic efficiency decreased in normal rats acclimated to cold but increased in the lesioned group. The difference was significant (P less than 0.05). The cold-induced increase in interscapular brown adipose tissue (IBAT) oxidative capacity of VMH-lesioned rats was only half that of normal rats. Differences in BAT thermogenesis may be the basis for the differing temperature effects on net energetic efficiency.
Sampling the difficult-to-sample, Difficult-to-sample populations are defined as rare populations or populations that are difficult to locate. enumerate or interview. This definition includes subgroups of the United States population that are at increased risk of adverse health effects associated with malnutrition. Examples include persons who are rare (pregnant women). difficult to locate (migrant farm workers). difficult to enumerate (homeless individuals) or difficult to interview (substance abusers). Probability methods to sample rare and elusive populations are reviewed briefly. Methods include disproportionately allocated sampling. multiplicity sampling and the use of multiple frames. The advantages and disadvantages of nonprobability sampling methods are compared using criteria typically applied to assess alternative probability sampling methods. The cost of data collection alone may prohibit consideration of probability sampling methods. but caution is urged before abandoning this statistically sound approach to sample selection. Considerations for sampling the difficult-to-sample are illustrated for one such population. the homeless.
Treatment of mice with sepsis following irradiation and trauma with antibiotics and synthetic trehalose dicorynomycolate (S-TDCM), Compromise of antimicrobial defenses by irradiation can result in sepsis and death. Additional trauma can further predispose patients to infection and thus increase mortality. We recently showed that injection of synthetic trehalose dicorynomycolate (S-TDCM) significantly augments resistance to infection and increases survival of mice compromised either by whole-body irradiation with gamma radiation or equal mixtures of fission neutron and gamma radiation. In this study. C3H/HeN mice were given a lethal dose of gamma radiation (8.0 Gy) and an open wound (15% total body surface area [TBSA]) 1 hr later while anesthetized. Irradiated/wounded mice became more severely leukopenic and thrombocytopenic than mice exposed to radiation alone. and died from natural wound infection and sepsis within 7 days. S-TDCM given 1 hr postirradiation increased survival of mice exposed to radiation alone. However. this treatment did not increase survival of the irradiated/wounded mice. Systemic antibiotic therapy with gentamicin or ofloxacin for 10 days significantly increased survival time compared with untreated irradiated/wounded mice (p less than 0.01). Combination therapy with topical gentamicin cream and systemic oxacillin increased survival from 0% to 100%. Treatment with S-TDCM combined with the suboptimal treatment of topical and systemic gentamicin increased survival compared with antibiotic treatment alone. These studies demonstrate that post-trauma therapy with S-TDCM and antibiotics augments resistance to infection in immunocompromised mice. The data suggest that therapies which combine stimulation of nonspecific host defense mechanisms with antibiotics may increase survival of irradiated patients inflicted with accidental or surgical trauma.
Clenbuterol decreases catabolism and increases hypermetabolism in burned rats, Following a 30% body surface area full-thickness open-flame burn. rats exhibited hypermetabolism. body weight loss. and muscle catabolism. Twenty-one days of treatment of one group of burned rats with the selective beta 2-adrenergic agonist. clenbuterol. increased resting energy expenditure and normalized body weight gain. muscle mass. and muscle protein content. Conversely. similar treatment of another group of burned rats with the long-acting beta-adrenergic antagonist. nadolol. reduced muscle mass. while having no effect on resting energy expenditure. body weight gain. or muscle protein content. These results demonstrate that hypermetabolism does not invariably result in loss of lean body mass and suggest that clenbuterol may be useful in preserving muscle mass and protein in catabolic diseases.
Post-traumatic basal ganglia hemorrhage: analysis of 52 patients with emphasis on the final outcome, A series of 52 patients suffering post-traumatic basal ganglia hemorrhage (BGH) after closed head injury is reviewed. Post-traumatic BGH was associated with other intracranial lesions in most cases. The outcome in this series is rather good. with 53.8% of patients having a functional survival. Radiologically. the post-traumatic intraventricular hemorrhage (IVH) and brainstem hemorrhage usually coexisted with a poor outcome. Old age (greater than 60). abnormal pupil reaction. impaired oculocephalic response. and abnormal motor response to pain stimuli are reliable clinical hallmarks for poor prognosis.
Class C firework injuries in a pediatric population, Class C fireworks are those which can be readily purchased by the public. Between July 1971 and August 1988. 23 patients were admitted to our institution with firework injuries. Fourteen patients (60.9%) sustained injuries related to Class C fireworks. All patients were males with a mean age of 9.0 +/- 3.6 years. with a total body surface area (TBSA) burn of 18 +/- 20% with 10 +/- 15% being full thickness. Thirteen of the 14 patients required hospitalization. Five patients were admitted acutely and eight patients were referred to our institution at least 3 days postinjury. All patients required operative intervention in order to obtain wound closure. Patients admitted acutely showed a decrease in length of hospital stay and patient morbidity when compared to referral patients. Our data suggest that class C firework injuries. although small in terms of TBSA burned. result in full-thickness wounds that warrant aggressive surgical management.
Pediatric bicycle trauma, Bicycle-related trauma is a serious pediatric problem. Serious injuries and even fatalities can occur. and care must be taken to avoid undertreating these patients. In an effort to further define the problem. 201 consecutive patients admitted for bicycle trauma were reviewed. The patients ranged in age from 3 to 16 years and 76% (153/201) were male. Head trauma was the most common admission diagnosis (99/201; 49%). Fourteen per cent (28/201) were admitted to the Intensive Care Unit and 23% (47/201) required an operative procedure. The average hospital stay was 3 days; however. patients who were admitted at least 24 hours after injury had an average hospital stay of 7 days.
Carotid and vertebral artery injury in survivors of atlanto-occipital dislocation: case reports and literature review, Atlanto-occipital dislocation (AOD) usually results in immediate death from transection of the upper cervical spinal cord near the spinomedullary junction. However. over the last several decades increasing numbers of AOD survivors have been identified. Although many of these patients initially demonstrate profound neurologic deficits. a number who survive have regained most or all neurologic functions. indicating that they did not suffer mechanical disruption of the spinal cord at the time of AOD. In the survivors. a growing body of evidence indicates that many of the initial neurologic deficits are related to vascular injury to the carotid or vertebral arteries and their branches. We recently encountered three AOD survivors with no evidence of mechanical injury to the spinal cord in which angiography demonstrated vascular injury to the internal carotid artery in the form of vasospasm in one case and to the vertebral arteries in the forms of focal stenosis at the site of dural penetration. focal stenosis and distal vasospasm. and focal stenosis with distal intimal flap and dissection in one case each. Autopsy after one of the three died after cardiac arrest demonstrated diffuse infarction of the cerebrum. cerebellum. midbrain. brainstem. and upper cervical spinal cord without evidence of mechanical laceration or transection of the spinal cord. Recovery of neurologic function in two cases following prompt immobilization and angiography suggests that neurologic deficits secondary to vascular injury are potentially reversible.
Traumatic popliteal artery pseudoaneurysms: case report and review of the literature, Traumatic pseudoaneurysms of the popliteal artery are an uncommon late complication of arterial injury. Although reviewed extensively in wartime. they occur less frequently in civilian trauma and have accordingly been less frequently studied. A case report of a traumatic popliteal artery pseudoaneurysm and review of the literature are presented.
Irreducible skin penetration of the ulnar head in Colles fracture--case report, Three cases out of four of skin penetration by the ulnar head associated with Colles fractures were found to be irreducible. On exploration they had identical pathologic anatomy. viz. buttonholing of the ulnar head between the flexor carpi ulnaris. flexor digitorum profundus. pronator quadratus. and the flexor retinaculum. Incising the flexor retinaculum facilitated reduction.
Splenic laceration secondary to closed chest massage: successful recognition and management--case report, Closed chest massage can be a lifesaving act. Performed incorrectly or by untrained individuals it can lead to life-threatening complications. Successful recognition and treatment of a lacerated spleen secondary to cardiopulmonary resuscitation is reported. All patients surviving CPR should be screened for potential complications.
Trends of HIV seroconversion among young adults in the US Army, 1985 to 1989. US Army Retrovirus Research Group, Because soldiers in the US Army are recurrently tested for the presence of antibody to the human immunodeficiency virus (HIV). HIV seroconversion rates can be directly measured. From November 1985 through October 1989. 429 HIV seroconversions were detected among 718.780 soldiers who contributed 1.088.447 person-years of follow-up time (HIV seroconversion rate. 0.39 per 1000 person-years). Period-specific seroconversion rates declined significantly from 0.49 per 1000 person-years (November 1985 through October 1987) to 0.33 per 1000 person-years (November 1987 through October 1988) to 0.29 per 1000 person-years (November 1988 through October 1989). The HIV seroconversion risk among active-duty soldiers was significantly associated with race/ethnic group. age. gender. and marital status. Based on these trends. we estimate that approximately 220 soldiers (95% confidence interval. 160 to 297 soldiers) were infected with HIV during 1989 and 1990. with potentially fewer in future years.
The epidemiology of tuberculosis among North Carolina migrant farm workers [published erratum appears in JAMA 1991 Jul 3;266(1):66], Although tuberculosis (TB) has been recognized as a significant health problem of migrant farm workers. the nature and extent of the problem have been poorly defined. We report the first population-based study of TB in a random sample of farm workers (n = 543) and the first use of recall antigens in an epidemiologic study of TB. Purified protein derivative positivity ranged from 33% in Hispanics to 54% in US-born blacks and 76% in Haitians. Active tubercular disease occurred in 3.6% of US-born blacks and 0.47% of Hispanics. Among US-born blacks. risk factors associated with farm work were most significant. Blacks born in the United States also had the highest prevalence of anergy. The use of recall antigens made possible a better description of the epidemiology of TB by excluding false negatives and clarifying associations between infection and risk factors. We conclude that TB among farm workers represents a serious public health problem with previously unrecognized risk factors. Additional resources for migrant health care. improvements in health care access. and fundamental changes in the system of migrant labor are all necessary to reduce the transmission of TB.
Platelet activating factor receptor blockade ameliorates murine systemic lupus erythematosus, Untreated 16-week-old MRL/MpJ-lpr/lpr (lpr) mice. when compared to congenic MRL/MpJ-+/+ (+/+) mice. are characterized by a systemic lupus erythematosus syndrome. including severe glomerulonephritis. proteinuria and reduction of renal function. We hypothesized that platelet activating factor (PAF). a potent chemotactic and proinflammatory phospholipid mediator synthesized and released by circulating cells. glomerular mesangial and renal medullary interstitial cells. may play a role in the development of renal injury in lupus mice. We assessed renal PAF synthesis in lpr as well as +/+ mice and the effect of treatment with a PAF receptor blocking agent. Treatment with the PAF receptor antagonist L659.989 for four weeks. starting at 12 weeks of age. significantly reduced acute glomerular infiltration and proliferation. and prevented chronic glomerular histological changes; proteinuria and serum creatinine levels were also significantly reduced in treated mice. Renal PAF production was increased in lpr when compared to +/+ mice. and treatment with L659.989 restored renal PAF synthesis to the control levels. Our results support the hypothesis that PAF can be one of the mediators of glomerular injury characteristic of murine lupus nephritis. and indicate the possible therapeutic utility of PAF receptor antagonists in immunologic renal diseases.
Glomeruli synthesize nitrite in experimental nephrotoxic nephritis, Activated macrophages synthesize nitric oxide (NO) from L-arginine. In culture. the major stable end product is nitrite (NO2). Activated macrophages accumulate in glomeruli and are responsible for injury in experimental immune complex glomerulonephritis. We examined NO2- production by isolated glomeruli and urinary NO2- in accelerated nephrotoxic nephritis in the rat. Normal glomeruli did not produce NO2- spontaneously or when stimulated with lipopolysaccharide (LPS) (1 microgram/ml) or A23187 (2 microgram/ml). Cultured mesangial cells at first or seventh passage did not produce NO2- spontaneously or when stimulated. Nephritic glomeruli spontaneously produced NO2 at all times studied; this production was maximal at 24 hours after induction of glomerulonephritis (158.4 +/- 8.4 nmol/48 hr/ml. N = 3). The production of NO2- was inhibited 75 to 100% by NG-monomethyl-L-arginine (L-NMMA). and this inhibition was reversed by L-arginine. indicating NO2- production from L-arginine via NO. The production of NO2- was increased by LPS (1 microgram/ml) at 2. 7 and 21 days. NO2- was undetectable in normal rat urine; however. it was present in urine of rats with glomerulonephritis (Day 0 to 1:8161 +/- 2605 nmol/24 hr. N = 12). The production of NO in nephritic glomeruli may have implications for both the mechanism of glomerular injury and glomerular hemodynamics.
Effects of acute and chronic uremia on active cation transport in rat myocardium, As abnormalities of active cation transport could contribute to the genesis of uremic cardiomyopathy. we investigated myocardial sodium pump function in rats with acute renal failure (ARF) and with a model of experimental chronic renal failure (CRF) that has metabolic similarities to advanced chronic uremia in humans. CRF rats were hypertensive and had left ventricular hypertrophy (33% higher heart:body weight ratio; P less than 0.01) at four weeks compared to pair-fed sham-operated rats. Importantly. both ouabain- and furosemide-sensitive 86Rb uptake rates were unchanged in left ventricular myocardial slices from CRF. and the intracellular sodium concentration was not different from that of control rats even though skeletal muscle sodium was increased. as we found previously (J Clin Invest 81:1197. 1988). Insulin-stimulated. ouabain-sensitive 86Rb influx was also preserved. There also were no abnormalities in myocardium cation transport in rats with ARF. However. [3H]ouabain binding was decreased 45% in CRF rats (P less than 0.01); it was unchanged in acute uremia. Decreased ouabain binding in chronic uremia was due entirely to fewer low affinity [3H]ouabain binding sites (the binding affinity for ouabain was unaffected). We conclude that in chronic. (but not acute) renal failure. sodium pump number is reduced in myocardium but intracellular sodium is unchanged and active cation flux rates are maintained. These results emphasize that in rats with chronic uremia. intracellular sodium homeostasis is preserved in myocardium. despite the presence of marked abnormalities of active cation transport in skeletal muscle that are characteristic of chronic uremia.
Quantitative studies of tubular immune complex formation and clearance in rats, Tubular antibody deposition and clearance was quantitatively studied using affinity-purified rabbit antibodies to rat Tamm-Horsfall protein (TH). a surface membrane glycoprotein of the tubular cells of the thick ascending limb of the loop of Henle. Immune complexes are formed in situ at the base of these cells in rats injected with antisera to TH. The renal binding of I125-anti-TH was determined in pair label studies. Kidneys and other organs were removed from groups of rats for isotope counting at four hours to 14 days after an injection of I125-anti-TH and I131-normal rabbit IgG. The greatest total renal anti-TH binding after injection of 500 micrograms of anti-TH was observed at 24 hours in normal rats (18.55 +/- 1.6 micrograms). During the period of most rapid clearance (day 2 to day 7) the half life of renal anti-TH binding (84.2 hours) and the half life of anti-TH in the serum (68.5 hours) were shorter than that of IgG in the serum (117.8 hours). There was no substantial uptake of anti-TH by other organs. A close relationship between serum levels and renal uptake of anti-TH at 24 hours was also observed in rats given from 50 to 6000 micrograms of anti-TH; renal saturation was evident only at the highest dose. This close relationship was also present during the clearance phase in rats injected with 3700 micrograms of anti-TH; the half life of anti-TH was 96.2 hours in kidneys and 110 hours in serum while the half life of rabbit IgG in serum was 151.8 hours. Markedly increased renal uptake of anti-TH was observed in protein-uric rats with passive Heymann nephritis. In very proteinuric rats. 14.1% of the injected dose was bound to kidneys at 24 hours. In these rats. serum anti-TH levels decreased very rapidly to 4% of control serum levels by five days. Throughout the period of study. the serum levels of anti-TH determined by direct radiometric assay corresponded very closely to those obtained by enzyme-linked immunosorbent assay (ELISA). Urinary excretion was a major mechanism for the clearance of anti-TH in proteinuric rats; more than 10% of the injected I125-anti-TH was recovered intact (that is. protein bound) during the first day after injection. During the clearance phase for renal deposits. urinary clearance of anti-TH exceeded urinary clearance of IgG due to release of renal bound antibody into urine.(ABSTRACT TRUNCATED AT 400 WORDS).
Somatosensory evoked potentials in acute renal failure: effect of parathyroidectomy, Effects of acute renal failure (ARF) on somatosensory evoked potentials (SEP) were studied in rats. Cervical and cortical SEPs were measured both before and after bilateral ureteral ligation. A significant augmentation of amplitudes and an increase in latencies of the cortical SEP were observed in ARF. The peripheral nerve conduction velocities were unchanged. Serum parathyroid hormone (PTH) levels in uremic rats were significantly elevated after the bilateral ureteral ligation. In previously parathyroidectomized rats. the bilateral ureteral ligation had no effects on amplitudes of SEP or serum PTH levels.
Effect of aluminum on bone matrix inductive properties, The effect of aluminum on the bone inductive properties of implanted bone matrix was studied in rats. After decalcification femur sections were placed in either 0.1 or 0.01 M AlCl3 or a solution of similar pH without Al for 24 hours. Following 28 days of implantation in subcutaneous pouches the aluminum content was 3232 +/- 1020 and 51 +/- 6 mg/kg in the matrix pretreated with 0.1 and 0.01 M AlCl3. At the same time period following implantation the matrix calcium content was 794 +/- 539 and 3038 +/- 692 mmol/kg in the 0.1 and 0.01 M AlCl3 pretreated groups versus 4252 +/- 579 mmol/kg in the control group (P less than 0.01). In the control group bone histology showed extensive osteoblastic and osteoclastic remodeling. tetracycline labeling and bone formation. In contrast all of these histological features were virtually absent in aluminum treated matrix. Aluminum-induced resistance of bone matrix to collagenase degradation and restoration of bone inductive properties with chelation suggests that aluminum forms intermolecular cross links between collagen fibrils. Aluminum-induced cross links of collagen fibrils and/or its effects on bone inductive proteins present in bone matrix could explain the mechanism by which aluminum induces osteomalacia.
Glucose-induced insulin secretion in uremia: effects of aminophylline infusion and glucose loads, To explain mechanisms responsible for derangement of insulin release in uremia. we investigated glucose metabolism through three different tests in 14 patients with end-stage chronic renal failure. These tests were: intravenous glucose tolerance test with 0.33 g/kg of glucose solution (IVGTT); IVGTT with 0.5 g/kg of glucose solution (IVGTT2); IVGTT during aminophylline infusion (IVGTT + A). Twelve of the patients had IVGTT repeated after two to four months of thrice-weekly regular hemodialysis (IVGTT3). In each test we measured plasma glucose (G). immunoreactive insulin (IRI) and C-peptide. We also calculated glucose constant decay (K). insulin production (IRI area). insulinogenic index (IGI). and insulin resistance index (RI). Twenty-nine healthy volunteers formed the normal controls for IVGTT. As compared to controls. during IVGTT uremic patients showed significantly lower values in K. IRI area and IGI. and showed a significant RI value increase. During IVGTT2. IRI are values were higher than during IVGTT but IGI and K values were unchanged. During IVGTT + A both IRI area and IGI values were higher than during IVGTT. After hemodialysis treatment (IVGTT3) K. IRI areas and IGI increased significantly as compared to the predialysis period. K increase after hemodialysis correlated directly to IGI increase and inversely to RI changes. IGI increase during IVGTT3 was directly correlated to IGI rise during IVGTT + A. From these data we infer that defective insulin release in uremia is due to a decrease of beta-cell glucose sensitivity rather than to their functional exhaustion. An impaired adenyl cyclase-cAMP system may have an important role in the pathogenesis of this abnormality.
Renal structure and hypertension in autosomal dominant polycystic kidney disease, Hypertension has been reported to occur in 50 to 75 percent of subjects with autosomal dominant polycystic kidney disease (ADPKD) prior to the onset of marked renal insufficiency but concurrent with cystic deformation of the renal parenchyma. The present study was undertaken to examine whether the renal structural abnormalities are greater in hypertensive (HBP) versus normotensive (NBP) male and female patients with ADPKD who were matched within gender groups for age. body surface area. serum creatinine concentration (males HBP 1.2 +/- 0.02 vs. NBP 1.1 +/- 0.03 mg/dl. NS: females HBP 0.9 +/- 0.03 vs. NBP 0.9 +/- 0.02 mg/dl. NS) and creatinine clearance (males HBP 100 +/- 3 vs. NBP 108 +/- 3 ml/min/1.73 m2. NS: females HBP 97 +/- 3 vs. NBP 96 +/- 2 ml/min/1.73 m2. NS). Renal volume was significantly greater in the HBP compared to the NBP group (males HBP 624 +/- 47 vs. NBP 390 +/- 43 cm3. P less than 0.0005; females HBP 446 +/- 32 vs. NBP 338 +/- 24 cm3. P less than 0.002). Since increased renal volume is due to increased cysts. the results indicate that the early high incidence of hypertension in ADPKD correlates with the renal structural abnormalities in this disorder.
Effect of conjugated estrogens on platelet function and prostacyclin generation in CRF, In a double-blind. randomized. placebo-controlled cross-over study. we investigated in seven patients with chronic renal failure the effect of conjugated estrogens (0.6 mg/kg/day for 5 days) on template bleeding time and on thromboxane A2 (TxA2). beta-thromboglobulin (beta-TG) and prostacyclin (PGI2) concentrations in blood emerging from the template bleeding time incisions. Administration of conjugated estrogens resulted in a significant shortening of the bleeding time in six out of seven patients with a maximum effect 7 and/or 14 days following treatment. Both TxA2 (measured as thromboxane B2. TxB2) and beta-TG release in bleeding time blood were significantly higher following administration of conjugated estrogens as compared to placebo administration. No difference was seen in endothelial PGI2 (measured as 6-keto-prostaglandin F1 alpha) formation when patients were treated with conjugated estrogens as compared to placebo administration over the 28 day observation period. We conclude that in patients with chronic renal failure. infusion of conjugated estrogens results in a significant shortening of the bleeding time together with an increase in platelet reactivity. as indicated by an increase of TxA2 and beta-TG concentration in the microvasculature. No effect was seen on PGI2 production. thereby excluding a major effect on vascular prostaglandin metabolism.
Glomerular interleukin 1 production is dependent on macrophage infiltration in anti-GBM glomerulonephritis, Both macrophages and glomerular mesangial cells have the potential to synthesize interleukin 1 (IL-1). however. their respective contributions to IL-1 production in anti-GBM glomerulonephritis (GN) are unknown. To address this problem. IL-1 production by glomeruli from rabbits with macrophage-associated anti-GBM GN (passive autologous anti-GBM GN [PAGBMGN]) and macrophage independent (heterologous phase) anti-GBM GN was studied. Macrophage-infiltrated nephritic glomeruli produced IL-1 bioactivity which was inhibitable by an anti-IL-1 antibody. and had a molecular weight consistent with rabbit IL-1. Glomerular IL-1 production in PAGBMGN was markedly augmented (1.43 +/- 0.79 U/10(3) glomeruli [gloms]/24 hr) compared to normal glomeruli (0.13 +/- 0.06 U/10(3) gloms/24 hr. P less than 0.05) or glomeruli from rabbits with macrophage independent GN (0.11 +/- 0.07 U/10(3) gloms/24 hr. P less than 0.05). IL-1 production by glomeruli from leukocyte depleted rabbits with PAGBMGN (0.16 +/- 0.07 U/10(3) gloms/24 hr) was not significantly elevated compared to normal glomeruli. Glomerular macrophages from rabbits with PAGBMGN produced more IL-1 (3.62 +/- 1.63 U/10(3) cells/24 hr) than blood monocytes (0.51 +/- 0.30 U/10(3) cells/24 hr) or alveolar macrophages (0.24 +/- 0.12 U/10(3) cells/24 hr) from the same animals. These results show that in experimental anti-GBM GN where injury is macrophage dependent. IL-1 production is also macrophage dependent and infiltrating glomerular macrophages are the major source of IL-1. Further. as glomerular IL-1 production was not significantly augmented in GN in the absence of macrophages. glomerular deposition of immunoglobulin and complement alone do not stimulate significant IL-1 production by intrinsic glomerular cells in experimental anti-GBM GN.
Phosphate depletion impairs insulin secretion by pancreatic islets, Phosphate depletion (PD) is associated with resistance to the peripheral action of insulin and with glucose intolerance. However. data on the effect of PD on insulin secretion are not consistent. and were derived indirectly by measurements of blood levels of insulin during intravenous glucose tolerance test (IVGTT) or with hyperglycemic clamp technique. Direct evidence for an effect of PD on insulin secretion by pancreatic islets is not available. and the potential mechanisms through which PD may affect insulin secretion are not known. We performed IVGTT. examined in vitro insulin secretion by pancreatic islets. and evaluated various factors involved in insulin secretion in PD and pair weighed (PW) rats. PD animals had fasting hyperglycemia and normal plasma insulin levels. and displayed abnormal IVGTT as compared to PW rats. Both initial and late phases of D-glucose-induced insulin secretion from islets were markedly and significantly (P less than 0.01) lower than from islets of PW rats. In contrast. D-glyceraldehyde-induced insulin release in PD rats was similar to that of PW rats. [H3]2-deoxyglucose uptake by islets and their cyclic AMP content after exposure to D-glucose. D-glyceraldehyde or forskolin were not different among the two groups of animals. Insulin content in PD islets was modestly but significantly (P less than 0.01) higher than PW islets. In PD islets. ATP content and the ATP/ADP ratio at basal state and after incubation with 16.7 mM D-glucose were significantly (P less than 0.01) lower and resting cytosolic calcium was significantly (P less than 0.01) higher than in PW islets.
Experimental immune complex-mediated glomerulonephritis in the nonhuman primate, This study was undertaken to develop a model of immune complex (IC)-mediated glomerulonephritis (GN) in the nonhuman primate that could be used in subsequent studies to examine critically the role of the erythrocyte complement receptor (E-CR) in the pathogenesis of IC-mediated disease. Cynomolgus monkeys were chosen for study because they constitutively express E-CR levels that are either less than. equal to. or greater than that seen in normal man. After immunization with bovine gamma globulin (BGG). the GN induction protocol was begun in 10 cynomolgus by initiating daily i.v. administration of BGG in amounts sufficient to achieve or exceed antigen/antibody equivalence (assessed by the quantitative precipitin assay) for precipitating antibody present in the plasma volume. We found that within eight weeks of daily BGG administration of all the cynomolgus developed IC-mediated GN. irrespective of the initial E-CR level of the animals. However. the high E-CR cynomolgus tended to receive the higher BGG doses because of higher initial antibody levels to BGG. When the total number of glomerular deposits (determined by morphometric studies) per total BGG dose for each animal was plotted against the initial CR/E of that animal. there was a tendency for the animals with higher CR/E levels to have a lower number of glomerular deposits/BGG dose (r = 0.62. P = 0.06). Also. the total number of glomerular deposits correlated with the severity of the GN. During the early weeks of the GN induction protocol. the IC that formed in vivo (assessed by infusion of 125I-BGG) bound in large amounts to the circulating erythrocytes of the cynomolgus with medium or high E-CR levels. However. when tested after the onset of heavy proteinuria. which occurred between weeks 5 and 8 of daily BGG administration. the IC that formed in the circulation bound only poorly to circulating erythrocytes. By this time the E-CR levels had declined to 43 +/- 9% of initial values (P less than 0.01). This study demonstrates that: 1) A workable model of IC-mediated GN has been developed in the nonhuman primate. 2) During the induction of GN. CR/E and the ability of the erythrocyte to bind IC in vivo are decreased significantly. This suggests that an intact E-CR system could play a role in the protection against IC-mediated disease. However. further study will be needed to test that hypothesis critically. The present model should be useful in such studies.
Effect of chlorpropamide on water and urea transport in the inner medullary collecting duct, The present in vitro microperfusion study examined whether chlorpropamide (CPM) has a direct effect on hydraulic conductivity (Lp x 10(-6) cm/atm.sec) and 14C-urea permeability (Pu x 10(-5) cm/sec) in the middle and distal inner medullary collecting duct (IMCD) obtained from acutely water-loaded Wistar rats and rats homozygous for diabetes insipidus (DI). CPM (10(-4) M) added to the bath fluid increased the Lp in the water-loaded Wistar rats from -0.05 +/- 0.13 to 6.25 +/- 0.74 (p less than 0.01) and in the DI rats from 0.05 +/- 0.01 to 5.95 +/- 0.84 (p less than 0.01). but had no effect when it was added to the perfusate. CPM stimulated Lp in a dose-dependent manner with the threshold effect at 10(-6) M. However. the addition of CPM (10(-4) M) to submaximal concentration of VP in the bath fluid did not increase the Lp. Furthermore. CPM was unable to block the inhibitory action of PGE2 on the vasopressin (VP)-stimulated Lp. On the contrary. PGE2 blocked the CPM-stimulated Lp. CPM (10(-4) M) in the peritubular fluid was able to cause a significant rise of the Pu from 13.5 +/- 0.8 to 17.3 +/- 1.0 reversibly. which represented 16% of maximum stimulated effect produced by 50 microU/ml of VP. Thus. pharmacological doses of CPM added to the peritubular side have a direct effect on terminal IMCD increasing water and urea permeability in the absence of VP. but this drug does not potentiate the VP-stimulated water transport in the IMCD. Our results were unable to confirm the hypothesis that CPM potentiates the VP-antidiuresis by the inhibition of PGE2 action in the rat IMCD.
Localization of clusterin in the epimembranous deposits of passive Heymann nephritis, The membrane attack complex of complement (MAC) plays an important role in the mediation of proteinuria in experimental membranous nephropathy induced by Heymann antiserum. SP-40.40 is a recently described serum protein which appears to inhibit the formation of cytolytic MAC in a manner analogous to S protein/vitronectin. SP-40.40 is homologous to proteins originally isolated from rat and ram seminal fluid (sulfated glycoprotein 2 and clusterin. respectively). By current convention. these proteins are considered clusterin homologues. The objective of this study was to examine the participation of rat clusterin in passive Heymann nephritis. Using an antibody to rat clusterin as an immunofluorescent probe. clusterin deposits were demonstrated along the glomerular capillary wall in an identical pattern to rat C3 and C5b-9. Decomplementation using cobra venom factor prevented proteinuria and intraglomerular MAC formation. The epimembranous clusterin were not detected in the complement-depleted animals. The role of clusterin in the mediation of glomerular injury remains unknown. but it is probably related to in situ formation of the terminal complement cascade where it may play a regulatory role.
Direct vasopressor effect of recombinant human erythropoietin on renal resistance vessels, The contractile properties of recombinant human erythropoietin (rHuEPO) on isolated resistance vessels of renal and mesenteric vascular beds were studied in an in vitro model using a small vessel myograph. Under isometric conditions. rHuEPO caused a contraction of this vasculature in a concentration range between 10 U/ml and 200 U/ml. A maximal active wall tension of 1.52 +/- 0.19 mN/mm was obtained under a rHuEPO dose of 200 U/ml. In Ca2+ free solution. the pressor response to high rHuEPO-concentrations was attenuated. and the response to low rHuEPO concentrations was abolished. In the presence of verapamil. phentolamine and saralasin. rHuEPO-induced contractions were not affected significantly. A dose-dependent vasodilatation of mounted vasculature to acetylcholine (ACh) indicated that endothelium remained intact in our preparations. rHuEPO-induced vessel contraction was not abrogated after an enzymatical removal of endothelium by collagenase. confirming that the described contractile responses are endothelial independent. These findings suggest that a direct vasopressor effect of rHuEPO on proximal resistance vessels may contribute to development of hypertension seen in rHuEPO-treated hemodialysis patients.
Osmoregulation of thirst and vasopressin release in severe chronic renal failure, Subjects with severe chronic renal failure (CRF) have higher plasma concentrations of arginine vasopressin (AVP) than normal subjects. and some develop severe thirst. Eight patients with CRF and seven matched controls underwent hypertonic saline infusion to explore the relationship of thirst and plasma AVP with plasma osmolality. Differences in urea concentration between the two groups were controlled for by correcting measured osmolality to a urea of zero. Linear regression analysis of the relationships between plasma AVP and thirst with plasma osmolality (corrected for urea) was performed. Mean results were: control. pAVP = 0.26 (pOsmc - 283.7) versus CRF. pAVP = 0.72 (pOsmc - 282.0); and control. thirst = 4.0 (pOsmc - 279.4) versus CRF. thirst = 3.5 (pOsmc - 281.8). The apparent sensitivity (slope) of AVP release was greater in severe CRF than in normal controls (P = 0.04). There was no significant difference between the groups in thirst sensitivity. threshold for thirst onset and threshold for AVP release. Osmoregulated thirst was normal in severe CRF. but increasing osmolality leads to higher concentrations of AVP than would be expected.
Urinary excretion of endothelin-1 in normal subjects and patients with renal disease, To elucidate the pathophysiological significance of urinary endothelin-1 (ET-1). we measured urinary excretion of ET-1-like immunoreactivity (L1) in 17 patients with renal disease and 9 normal subjects. Twenty-four hour urinary ET-1-L1 excretion in patients with renal disease (358 +/- 68 ng. mean +/- SE) was significantly (P less than 0.005) greater than that of normal subjects (77 +/- 5 ng). In patients with renal disease. ET-1-L1 clearance (CET) exceeded creatinine clearance (CCR); CET/CCR (305 +/- 81%) was significantly (P less than 0.005) greater than that of normal subjects (43 +/- 13%). The 24-hour urinary excretion of ET-1-L1 in patients with renal disease showed significant correlation with that of N-acetyl-beta-D-glucosaminidase (r = 0.587. P less than 0.05). beta 2-microglobulin (r = 0.614. P less than 0.01) and albumin (r = 0.484. P less than 0.05). Intravenous infusion of saline (500 ml) in seven normal subjects did not affect urinary ET-1 excretion rate. These data suggest that urinary excretion of ET-1 derives mainly from renal tubular secretion at least in patients with renal disease. and that degradation and/or reabsorption of ET-1 at the tubular site may also contribute to the renal handling of ET-1. Therefore. urinary excretion of ET-1 should serve as a potential marker for renal injury.
Phagocytosis in uremic and hemodialysis patients: a prospective and cross sectional study, Leukocyte response to phagocytic challenge was assessed in uremic and hemodialysis patients in a prospective and cross sectional study. Using latex. zymosan and staphylococcus as phagocytic challenge. the utilization of glucose-I-C14 and the generation of reactive oxygen species was measured in these patients. In uremic. non-dialysis dependent patients. the response to phagocytosis was significantly reduced when creatinine exceeded 6 mg/dl and prior to initiation of dialysis (mean serum creatinine 9.3 +/- 0.3 mg/dl) was less than half that of patients with normal renal function (P less than 0.01). In a prospective study of 15 patients initiated on dialysis. the metabolic response of their leukocytes was assessed sequentially. In eight patients. initiation of dialysis with cuprophane (Cu) membrane lead to a further decline (60%) in their metabolic response to phagocytosis at the end of four weeks of dialysis compared to pre-initiation of dialysis (P less than 0.01). whereas in seven other patients. dialysis with non-complement activating membranes did not result in a significant decline. Prospective cross-over studies of chronic hemodialysis patients corroborated these findings; eight patients dialyzed with new CU membranes had a significant decline of their metabolic response to phagocytic challenge acutely at the end of each dialysis and in pre-dialysis samples after two weeks of Cu dialysis. whereas their response returned back to baseline after two weeks of dialysis with non-complement activating membrane. In prospective and cross sectional studies. a decreased response to phagocytic stimulus was a predictor of hospitalization. primarily for infectious reasons.
Seizure-associated speech arrest in elderly patients, Recurrent. brief episodes of speech arrest associated with bifrontal electroencephalographic seizure activity developed in three ill elderly patients. The seizures ceased after the initiation of antiepileptic drug therapy and the correction of metabolic abnormalities. The cause of the seizure activity remains unknown. but a possible mechanism may be a transient epileptogenic cortical dysfunction that predominantly affects the frontal lobes as a result of concomitant metabolic alterations.
Serum lipids and lipoproteins are less powerful predictors of extracranial carotid artery atherosclerosis than are cigarette smoking and hypertension, The effect of serum lipids and lipoproteins on extracranial carotid artery atherosclerosis (CAS) was studied in patients who underwent carotid arteriography. Serum lipid and lipoprotein values along with data on other potential predictors of extracranial CAS were determined in 240 patients who had at least one extracranial carotid artery visualized. In a multiple logistic regression analysis. the independently significant predictors of the presence of extracranial CAS were. in decreasing order of significance. duration of smoking of cigarettes. hypertension. age. and low-density lipoprotein cholesterol. Serum cholesterol. triglycerides. high-density lipoprotein cholesterol. and apolipoprotein A-I did not show an independent effect. Although low-density lipoprotein cholesterol was an independent predictor of the presence of extracranial CAS. its effect as a predictor was far outweighed by the effects of the duration of smoking of cigarettes and a history of hypertension.
Efficacy of percutaneous mitral balloon valvuloplasty with the inoue balloon, Percutaneous mitral balloon valvuloplasty has become an accepted technique for use in selected patients with severe. symptomatic mitral stenosis. Recently. a new balloon catheter with an "hourglass" shape and specially designed guidewires and dilators has become available (Inoue balloon). The design of this balloon provides ease of manipulation and self-stabilization across the mitral valve during inflation. These features should decrease the incidence of complications associated with the procedure. Preliminary results in 12 consecutive patients who underwent percutaneous mitral balloon valvuloplasty with the Inoue balloon are presented. The mitral valve area increased from 0.92 +/- 0.21 cm2 before the procedure to 1.75 +/- 0.40 cm2 after the procedure. No complications occurred from the procedure. including no increase in severity of mitral regurgitation or creation of an atrial septal defect. Further follow-up is necessary to determine the long-term efficacy with this new balloon. Nonetheless. the preliminary results are encouraging.
Effect of the somatostatin analogue octreotide acetate on hemostasis in humans, Octreotide acetate is a somatostatin analogue that has been shown to ameliorate the side effects of excessive secretion of hormone from benign and malignant tumors. The ability of this drug to inhibit the growth of malignant cells and to control gastrointestinal hemorrhage will prompt additional clinical trials. Because some of these patients may have thrombocytopenia. platelet dysfunction. or a coagulopathy. we studied tests of platelet function and blood coagulation in 15 patients before and after 14 days of therapy with octreotide acetate at a dosage of 500 micrograms three times daily. We found no substantial change in the results of these tests. and no patient experienced bleeding or thrombosis. These results suggest that octreotide acetate does not adversely affect platelet function or the coagulation system in humans.
Plastic bronchitis: an old disease revisited, Expectoration of bronchial casts (plastic bronchitis) is an uncommon but ancient problem. Herein we describe a 40-year-old man. with no prior lung disease. who had dyspnea. cough. and expectoration of long branching bronchial casts. No specific cause was delineated. although special stains for eosinophilic granule major basic protein demonstrated occasional foci of eosinophils and small amounts of extracellular major basic protein in the bronchial casts. Various diseases. such as allergic bronchopulmonary aspergillosis. bronchiectasis. and cystic fibrosis. have been associated with the formation of bronchial casts and should be considered in the differential diagnosis. Although most previously reported cases have been associated with some type of pulmonary disease. our patient had no evidence of an underlying pulmonary disorder.
Endothelin immunoreactivity of airway epithelium in asthmatic patients, There is extensive pharmacological and physiological evidence that endothelin-1 influences airway calibre. In mammals. endothelin receptor occur on airway smooth muscle. local storage and release of the peptide have been demonstrated. and inhalation of endothelin-1 induces bronchoconstriction. To investigate the relation between endothelins and asthma the expression of this peptide in endobronchial biopsy specimens was examined immunohistochemically with an antiserum against endothelin-1. Biopsy specimens from 17 asthmatic patients and 11 atopic and non-atopic healthy controls revealed striking differences. with endothelin expression being evident in airways epithelium and vascular endothelium in 11 of the 17 asthmatic patients but in only 1 of 11 controls. These results suggest that endothelins may play a part in the exaggerated bronchomotor tone of asthma.
Correlations between therapeutic response of leukaemias and in-vitro drug-sensitivity assay, To develop the differential staining cytotoxicity (DiSC) assay. an in-vitro drug sensitivity test designed specifically for use with fresh human haematological tumour cells. into a predictive test for response to therapy as well as a tool for identifying new treatment strategies. test results have been correlated with response in patients with haematological malignancies. 22 of 119 tests indicated extreme drug resistance (tumour cell survival greater than 55%) in vitro. None of these patients responded to chemotherapy. The proportion of patients responding to therapy and 50% patient survival rose with in-vitro drug sensitivity. 11 specimens showing extreme drug resistance to the agents prescribed for the patient were subjected to drug sensitivity tests of drugs not prescribed; patients showing some sensitivity to these drugs had better survival than did those with extreme drug resistance to all drugs tested. The DiSC assay can also be used to identify new agents worth testing in clinical trials. and cross resistance profiles of new agents may indicate what combinations might be useful.
Contraceptive effects of extended lactational amenorrhoea: beyond the Bellagio Consensus, We have recorded the duration of lactational anovulation and amenorrhoea in a well-nourished group of Australian women who breastfed their babies throughout the study. The data enabled us to compare the theoretical cumulative probability of conception among breastfeeding women who had unprotected intercourse irrespective of their menstrual status with that of those who had unprotected intercourse only during lactational amenorrhoea. Breastfeeding alone is not an effective form of contraception. since all the women in our study resumed normal ovulation while still breastfeeding. However. among women who have unprotected intercourse only during lactational amenorrhoea but adopt other contraceptive measures when they resume menstruation. only 1.7% would have become pregnant during the first 6 months of amenorrhoea. only 7% after 12 months. and only 13% after 24 months. Thus for our women it would be possible to extend the Bellagio Consensus Conference guidelines which stated that lactational amenorrhoea can only be relied on as a contraceptive for the first 6 months post-partum in women who are fully or almost fully breastfeeding. The lactational amenorrhoea method can be relied on for excellent contraceptive protection in the first 6 months of breastfeeding. irrespective of when supplements are introduced into the baby's diet; for women who continue to breastfeed the method can also give good protection for up to 12 months post partum. Once menstruation has returned. other forms of contraception are essential to prevent pregnancy.
Trends in serum cholesterol levels from 1980 to 1987. The Minnesota Heart Survey, BACKGROUND AND METHODS. We assessed community trends in the awareness. treatment. and control of hypercholesterolemia (defined as a serum cholesterol level greater than 6.21 mmol per liter [240 mg per deciliter]) during the 1980s in the Minneapolis-St. Paul (Twin Cities) metropolitan area. Twin Cities residents 25 to 74 years old participated in independent. cross-sectional. population-based surveys of risk factors for cardiovascular disease in 1980-1982 (n = 3365) and 1985-1987 (n = 4545). RESULTS. Mean serum total cholesterol levels. as adjusted for age. decreased significantly (P less than 0.01) from 1980-1982 to 1985-1987 in men (from 5.30 mmol per liter [205 mg per deciliter] to 5.16 mmol per liter [200 mg per deciliter]) and women (from 5.19 mmol per liter [201 mg per deciliter] to 5.04 mmol per liter [195 mg per deciliter]). The prevalence of hypercholesterolemia as adjusted for age decreased significantly (P less than 0.05) in men (17.8 to 15.1 percent) and women (17.1 to 13.6 percent). The ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol was unchanged during this period. because of a concurrent decline in the level of HDL cholesterol. Participants with hypercholesterolemia in the 1985-1987 survey were more likely than those in the 1980-1982 survey to be aware of their condition (32.6 vs. 25.4 percent). to be treated with lipid-lowering agents (4.3 vs. 1.9 percent). and to have their condition controlled (1.9 vs. 0.3 percent). Among those who reported treatment by a physician for hyperlipidemia. changes were observed in the type of treatment recommended. A significant increase (P less than 0.05) was noted from 1980-1982 to 1985-1987 in the percentage of men being treated for hyperlipidemia with lipid-lowering medication (5.2 vs. 11.6 percent) and with exercise programs (10.3 vs. 20.1 percent). In women being treated for hyperlipidemia. a nonsignificant increase was noted in the use of lipid-lowering medication (8.2 vs. 13.9 percent). and a significant increase (P less than 0.05) was observed in the number of exercise prescriptions (4.1 vs. 12.0 percent). CONCLUSIONS. We found a substantial decline in the prevalence of hypercholesterolemia in the Twin Cities between 1980-1982 and 1985-1987 that may be attributed to changes in lifestyle. such as diet and exercise. and to a lesser extent to more aggressive intervention with lipid-lowering drugs by physicians.
The effect of cesarean delivery on birth outcome in very low birth weight infants. National Institute of Child Health and Human Development Neonatal Research Network, To determine whether cesarean delivery is associated with a better outcome than vaginal delivery for infants weighing less than 1500 g (very low birth weight). we examined neonatal mortality and the incidence of intraventricular hemorrhage (IVH) in 1765 very low birth weight inborn infants admitted to seven neonatal intensive care centers. The cesarean rate was 32.5% for infants weighing 501-750 g and 52.4% for infants weighing 751-1000 g. The neonatal death rate was 53.1% for infants weighing 501-750 g delivered by cesarean. compared with 64.3% for vaginally born infants (P = .046). However. for infants weighing 1001-1250 g. the neonatal death rate for infants delivered by cesarean was 14.4%. compared with 7.8% for infants born vaginally (P = .02). The incidence of IVH was significantly lower in infants born by cesarean than in those born vaginally only in the 1251-1500-g birth weight interval (11.8 versus 18.9%; P = .03). Compared with women delivering vaginally. those delivered by cesarean were more likely to attain a higher mean gestation. to have preeclampsia. and to have a breech presentation. and less likely to be in labor. After adjusting by logistic regression for gestational age. preeclampsia. breech presentation. presence or absence of labor. and for center effects. the odds ratio for neonatal death was 1.00 (95% confidence interval 0.71-1.41); for IVH. the odds ratio was 0.85 (95% confidence interval 0.61-1.19). These data suggest that after accounting for certain maternal and fetal factors. cesarean delivery is not associated with a lower risk of either mortality or IVH.
Toluene abuse during pregnancy: obstetric complications and perinatal outcomes, Toxic vapor abuse during pregnancy was found to be associated with increased maternal and fetal morbidity. Toluene-induced renal tubular acidosis occurred in over half of these women and was clustered among long-duration abusers. The renal acidosis placed the mother at risk for hypokalemia. with associated cardiac dysrhythmias and rhabdomyolysis. Beta-mimetics and intravenous fluid for preterm labor therapy potentially exacerbated the electrolyte abnormalities. Among 21 newborns exposed to toluene in utero. preterm delivery. perinatal death. and growth retardation were significantly increased. Delivery during uncorrected maternal acidosis further compromised these infants. As children. growth retardation and developmental delay were common findings. Recognition of the unique obstetric and medical characteristics of the toluene-abusing woman is needed if complications are to be averted and perinatal outcomes improved.
Calcium excretion in preeclampsia, Recent studies have suggested that preeclampsia is associated with hypocalciuria. We compared 24-hour urine data from 143 obstetric patients: 33 with preeclampsia. 58 normotensives. and 52 patients with gestational hypertension. The mean maternal age. race. and parity of these three groups did not differ significantly. The patients with preeclampsia had significantly less excretion of total calcium (129.7 +/- 18.7 mg/24 hours) (mean +/- SEM) than normotensives (283.9 +/- 12.3) or those with gestational hypertension (233.2 +/- 22.3) (P = .0001). The mean arterial pressure and excretion of total protein were significantly increased in the preeclampsia group (P = .0001). Using the receiver operator curve. a urine calcium threshold of 12 mg/dL was chosen as predictive for the development of preeclampsia. with a sensitivity of 85%. specificity of 91%. and positive and negative predictive values of 85 and 91%. respectively. Urinary calcium levels below 12 mg/dL may help distinguish preeclampsia from other hypertensive disorders of pregnancy.
Endocrine pancreatic function in growth-retarded fetuses, Maternal-fetal glucose gradient and fetal plasma glucose. insulin. and glucagon were measured in 63 fetuses: 34 controls and 29 with growth retardation (nine with and 20 without end-diastolic frequencies in the umbilical artery). Maternal-fetal glucose gradient and fetal glucagon levels were higher in the growth-retarded group than in controls (P less than .001). whereas fetal insulin and glucose concentrations were lower (P less than .001). Although maternal-fetal glucose gradient. fetal glucose. and insulin concentrations were similar among the growth-retarded fetuses. fetuses without end-diastolic frequencies in the umbilical artery had higher fetal glucagon levels (P = .01) than those with end-diastolic frequencies. In growth-retarded fetuses. the increase in fetal glucagon might reflect a compensatory response to hypoglycemia and appears to be a better index of fetal compromise than is glucose or insulin.
Laparoscopic excision of ovarian neoplasms subsequently found to be malignant, One hundred fifty-six members and candidate members of the Society of Gynecologic Oncologists responded to a survey concerning the "laparoscopic management of ovarian neoplasms subsequently found to be malignant." Twenty-nine responders (19%) reported a total of 42 cases of ovarian malignancy. The laparoscopic procedure was aborted or the cyst was aspirated in 38% of the cases. and partial or complete excisions were attempted in 33 and 29%. respectively. The characteristics of the masses were as follows: less than 8 cm 67%. cystic 62%. unilocular 48%. and unilateral 81%. All four "benign" characteristics were present in 31% of the cases found to be malignant. and three of four characteristics were present in 24%. Laparotomy was performed at the time of laparoscopy in 17% of cases. after laparoscopy in 71% with an average interval of 4.8 weeks. and not at all in 12%. Fifty-seven percent of the cases were invasive epithelial malignancies. whereas 29% were tumors of low malignant potential. At least 50% of the patients had stages II-IV. We conclude that attempted laparoscopic excisions of adnexal masses that are subsequently found to be malignant are not uncommon. and that the presence of so-called "benign" characteristics does not preclude malignancy. Attempts at partial or complete excision are common. as are delays in subsequent definitive surgery. The stage of disease is often advanced. and all histologic types of malignancy are encountered. We advocate careful evaluation of this practice. with development of strict guidelines to ensure optimal patient care.
Use of various epithelial tumor markers and a stromal marker in the assessment of cervical carcinoma, The epithelial cell tumor markers squamous cell carcinoma antigen. CA 125. CA 15-3. and TAG 72. and the aminoterminal propeptide of type III procollagen. an indicator of collagen metabolism. were evaluated in 111 cervical carcinoma patients. Squamous cell carcinoma antigen was pathologic in 47%. aminoterminal propeptide of type III procollagen in 40%. CA 125 in 13%. CA 15-3 in 30%. and TAG 72 in 9% of the 91 patients with squamous cell carcinoma. The squamous cell carcinoma antigen. aminoterminal propeptide of type III procollagen. and CA 125 correlated with the clinical stage. The predictive value of a pathologic squamous cell carcinoma antigen was 78% and that of a negative result 68%. Squamous cell carcinoma antigen and aminoterminal propeptide of type III procollagen further increased the detection rate by approximately 20% from that obtained by squamous cell carcinoma antigen alone. In 16 patients with advanced disease. squamous cell carcinoma antigen correlated with the behavior of the disease in eight. aminoterminal propeptide of type III procollagen in nine. and CA 125 in six patients. Pathologic squamous cell carcinoma antigen. CA 125. CA 15-3. TAG 72. and aminoterminal propeptide of type III procollagen appeared in 11. 32. 31. 31. and 47% of 19 patients with adenocarcinoma. respectively. Squamous cell carcinoma antigen is clinically useful in squamous cell carcinoma but poor in adenocarcinoma. for which the other markers are better. Squamous cell carcinoma antigen. CA 125. and aminoterminal propeptide of type III procollagen may be used for monitoring the behavior of advanced squamous cell carcinoma.
Dynamic urethral pressure profilometry pressure transmission ratio: what do the numbers really mean, Sixty-three women with genuine stress urinary incontinence were evaluated urodynamically both before and after modified Burch colposuspension to determine the association between pressure transmission ratio and leakage of urine during dynamic urethral pressure profile and the effect of surgery on pressure transmission ratio. Preoperatively. there was no difference in pressure transmission ratios between urethral pressure profiles associated with leakage of urine and those without urine leakage. Postoperatively. there were differences in pressure transmission ratios between leak and nonleak profiles in the sitting full and supine positions (P less than .001). We could not determine a threshold pressure transmission ratio that was more characteristically associated with leakage of urine. Finally. preoperative pressure transmission ratios were not associated with surgical success. but the higher the postoperative pressure transmission ratio. the more likely the surgery was to be successful (P = .023). In addition. the greater the difference between preoperative and postoperative pressure transmission ratios. the more likely was a cure (P = .011). The pressure transmission ratio may not be helpful in discriminating leak from nonleak dynamic urethral pressure profiles. and there may not be a threshold pressure transmission ratio below which patients characteristically leak urine. However. comparison of preoperative and postoperative pressure transmission ratios is helpful in determining the adequacy of surgical correction of the anatomical defect associated with genuine stress incontinence.
Fetal platelet consumption: a feature of placental insufficiency, The involvement of fetal platelets in placental insufficiency was investigated. Platelet life span and the rate of platelet turnover were measured by a novel technique in fetuses with moderate and severe placental insufficiency and in controls. This procedure involves the measurement of platelet count and concentration of free glycocalicin in plasma. Placental insufficiency was defined by antenatal Doppler ultrasound analysis of the umbilical artery waveform. which was used to categorize the subjects according to whether their systolic-diastolic ratios were normal. moderately raised. or severely raised. Mean platelet life span in fetuses affected by placental insufficiency was only 60% of the normal fetal platelet life span (P less than .001). In addition. affected fetuses had a higher rate of platelet turnover. reflected in an elevated plasma glycocalicin concentration (4.06 +/- 0.19 versus 3.28 +/- 0.15 microgram/mL for severe placental insufficiency and control fetuses. respectively; P less than .01). Platelet life span did not differ between the moderate and severe placental insufficiency groups. We hypothesize that the observed changes in platelet life span and turnover result from increased platelet activation. which plays a role in the development of placental insufficiency.
Treatment of ectopic pregnancy by transvaginal intratubal methotrexate administration, Twelve women with tubal pregnancies were treated with intratubal transvaginal methotrexate injection (1 mg/kg body weight). Serum beta-hCG levels decreased in all patients. and the resolution time from injection to undetectable beta-hCG levels was 14-120 days. In spite of declining serum beta-hCG and unruptured tubal pregnancy. two patients subsequently requested definitive treatment for their ectopic pregnancies and underwent surgery. Four of six women found to have a living embryo in their gestational sacs required a repeat methotrexate injection; one of these also required a local potassium chloride injection. The tubal pregnancies resolved in nine patients treated with methotrexate alone. During resolution. we noted a gradually increasing resistance index of the blood flow in the region of the gestation. but the tube became distended to 4.4 +/- 0.4 cm before gradually decreasing in size. No complications or side effects were encountered. These findings suggest that intratubal transvaginal methotrexate administration can provide a safe alternative to surgical treatment for patients with early unruptured tubal ectopic pregnancy. However. the presence of a living embryo makes the ectopic pregnancy more resistant to methotrexate treatment.
Contribution of pretreatment radiographs to orthodontists' decision making, A study was conducted to determine the amount of diagnostic and treatment planning information gained by orthodontists when pretreatment radiographs are added to a set of orthodontic records. Thirty-nine orthodontists evaluated six test cases and formulated a diagnosis and treatment plan. Information was collected about the participants' certainty with their diagnoses and treatment plans. the impact of the radiographs. the number and type of radiographs that were selected. and the difficulty of each case. Results showed that orthodontists were approximately 75% confident of their diagnosis before reviewing any radiograph. There were 741 radiographs ordered. of which 192 produced changes to the diagnostic process. The lateral cephalometric radiograph was the most productive. Panoramic and full-mouth series were productive but provided largely duplicative information.
A technique for evaluating bony changes in the anterior edentulous maxilla: a modification of a cephalometric analysis, A modification of a cephalometric analysis is presented for evaluating maxillary bone loss in the edentulous maxilla. The analysis involves tracing a lateral cephalometric radiograph of an edentulous maxilla. identifying the new landmarks. and measuring the appropriate vertical and horizontal distances of the maxilla. Comparison of the measurements for the patient's initial or baseline radiographic analysis with those of the patient's follow-up radiographic analysis identifies the amount of bone loss that has occurred between the two examinations.
Geriatric voice and laryngeal dysfunction, Vocal disorders are a common dysfunction associated with aging that can have a significant effect on the quality of life. An appreciation for the many causes of vocal dysfunction in the elderly is a first step to providing better care for the geriatric patient with complaints about voice dysfunction.
Effects of aging on the swallowing mechanism, Normal swallow involves a number of closely coordinated neuromuscular events. Investigators have identified some small temporal changes in the swallow of older adults as compared with young adults. Further research is needed to define completely the primary effects of aging on deglutition. Many medical conditions that commonly affect the elderly can cause dysphagia. These are discussed in terms of their effects on swallow physiology. Diagnosis and treatment of dysphagia in the elderly should be pursued as aggressively as in the younger adult.
The geriatric auditory and vestibular systems, Age-related declines in auditory and vestibular function are becoming more prevalent and better understood. The personal and societal impact of these disorders is impressive. and present techniques of amplification or balance training can be of great benefit. However. many issues await investigation. and continued integration of ever-increasing technologies promises many new answers. and questions. in the future.
Facial fractures and bone healing in the geriatric patient, A discussion of the biology of bone healing serves as the basis for a review of the clinical management of maxillofacial skeletal injury in the geriatric patient. Age-related changes in the facial skeleton and fractures of the edentulous mandible are described in detail.
Reconstructive and rehabilitative aspects of head and neck cancer in the elderly, Age should not be considered a contraindication to adequate head and neck oncologic surgery. Reconstructive efforts should be by the most direct means to attain restoration of form and function in one stage. The next significant breakthroughs in the battle against cancer may well come on the cellular or molecular level. We endorse the plea of Endicott for increased education and research directed at the problem of head and neck cancer and rehabilitation as they relate to the geriatric patient.
Reliability and validity of the work assessment scale for persons with multiple sclerosis, Reliability and validity of the Work Assessment Scale (WAS) was done on a sample of 551 subjects with multiple sclerosis. Work was defined as those activities performed in employment. homemaking and/or personal care. The WAS has two parts consisting of: Work-Impeding (WAS-I) and Work Enhancing (WAS-E) situations and conditions. Varimax rotated factor analysis of the WAS-I resulted in a seven-factor solution containing 33 of the 53 scale items. Theta reliability coefficients for the factors ranged between .73 and .90 and test-retest correlation coefficients (n = 51) ranged between .76 and .91. Varimax rotated factor analysis of the WAS-E resulted in a five-factor solution containing 19 of the 27 scale items. Theta reliability coefficients for the factors ranged between .66 and .81 and test-retest correlation coefficients ranged between .68 and .82. Concurrent validity was shown between WAS and both ADL and Symptom subscales.
An evaluation of three blood pressure methods in a stabilized acute trauma population, Blood pressure values were evaluated in 30 acute adult trauma patients using two indirect methods. the bell and diaphragm components of the stethoscope. and one direct arterial method. K1. K4. and K5 measurements were taken 4 to 72 hours (M = 30) after admission when vital signs had stabilized. Data were collected using a random-zero (RZ) sphygmomanometer for indirect blood pressure and radial intraarterial cannula for direct blood pressure. The sequence of measurement was randomized and variables shown to alter blood pressure values were controlled. There was no overall significant difference in K1. K4. and K5 blood pressures among the three methods. These results suggest that when clinicians monitor variables such as the frequency response of arterial lines and peripheral vascular resistance. indirect blood pressure methods are reliable for use with stabilized trauma patients.
Isolated pulmonary valvular regurgitation: current perspectives, IPVR is a rare clinical entity that was first diagnosed during life in 1955. In the past 35 years. only 69 patients have been reported. With increasing clinical awareness. as well as use of PDE. the confirmation of its clinical diagnosis has become easier and more accurate without having to take recourse to invasive cardiac studies as in the past. For this reason. it is becoming increasingly apparent that IPVR is not so rare as has been suggested in the past. IPVR is more common in men than in women. in whites than blacks. and in the young than the elderly. The mean age of IPVR patients is 27 years (range. 4 to 85). The majority of the patients are asymptomatic and the diagnosis is usually suspected upon the discovery of a crescendo-decrescendo. low-pitched. early to mid diastolic murmur in the second and third left intercostal space. which increases during inspiration. particularly in the presence of a hyperdynamic right ventricle and in the absence of peripheral circulatory phenomenon of aortic regurgitation. The ECG often shows right axis deviation. incomplete right bundle branch block. and rarely. right ventricular hypertrophy and strain. However. a normal ECG does not preclude its diagnosis. Approximately 30% of the IPVR patients have normal 12-lead ECGs. The diagnosis may be further suggested by the posteroanterior chest roentgenogram when dilated and large central pulmonary arteries are noted to pulsate vigorously (hilar dance) on chest fluoroscopy.
Multiple representations of pain in human cerebral cortex, The representation of pain in the cerebral cortex is less well understood than that of any other sensory system. However. with the use of magnetic resonance imaging and positron emission tomography in humans. it has now been demonstrated that painful heat causes significant activation of the contralateral anterior cingulate. secondary somatosensory. and primary somatosensory cortices. This contrasts with the predominant activation of primary somatosensory cortex caused by vibrotactile stimuli in similar experiments. Furthermore. the unilateral cingulate activation indicates that this forebrain area. thought to regulate emotions. contains an unexpectedly specific representation of pain.
An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency, Deficiency of adenosine deaminase (ADA) results in severe combined immunodeficiency (SCID). a candidate genetic disorder for somatic cell gene therapy. Peripheral blood lymphocytes from patients affected by ADA- SCID were transduced with a retroviral vector for human ADA and injected into immunodeficient mice. Long-term survival of vector-transduced human cells was demonstrated in recipient animals. Expression of vector-derived ADA restored immune functions. as indicated by the presence in reconstituted animals of human immunoglobulin and antigen-specific T cells. Retroviral vector gene transfer. therefore. is necessary and sufficient for development of specific immune functions in vivo and has therapeutic potential to correct this lethal immunodeficiency.
A prospective study of work perceptions and psychosocial factors affecting the report of back injury [published erratum appears in Spine 1991 Jun;16(6):688, A longitudinal. prospective study was conducted on 3.020 aircraft employees to identify risk factors for reporting acute back pain at work. The premorbid data included individual physical. psychosocial. and workplace factors. During slightly more than 4 years of follow-up. 279 subjects reported back problems. Other than a history of current or recent back problems. the factors found to be most predictive of subsequent reports in a multivariate model were work perceptions and certain psychosocial responses identified on the Minnesota Multiphasic Personality Inventory (MMPI). Subjects who stated that they "hardly ever" enjoyed their job tasks were 2.5 times more likely to report a back injury (P = 0.0001) than subjects who "almost always" enjoyed their job tasks. The quintile of subjects scoring highest on Scale-3 (Hy) of the MMPI were 2.0 times more likely to report a back injury (P = 0.0001) than subjects with the lowest scores. The multivariate model. including job task enjoyment. MMPI Scale-3. and history of back treatment. revealed that subjects in the highest risk group had 3.3 times the number of reports in the lowest risk group. These findings emphasize the importance of adopting a broader approach to the multifaceted problem of back complaints in industry and help explain why past prevention efforts focusing on purely physical factors have been unsuccessful.
Axial rotation of the lumbar spine and the effect of flexion. An in vitro and in vivo biomechanical study, A series of experiments were performed on eight whole. cadaveric lumbar spines and on eight male volunteers to determine whether axial rotation changed with subjects bending forward compared with being in a neutral posture and whether rotation was affected by articular tropism. Kirschner wires were inserted into the spinous processes of the eight cadaveric lumbar spines. and the axial rotation of the wires was measured while the spine was rotated in a torsion apparatus. Similarly. Steinmann pins were inserted into the spinous processes of L3. L4. and L5 of the eight volunteers. and the axial rotation of the pins was measured while the subjects rotated in a torsion apparatus. Axial rotation was found to be less when combined with forward flexion. and articular tropism did not influence the amplitude of rotation.
Percutaneous nucleotomy. An anatomic study of the risks of root injury, Fifteen cadaveric dissections have been performed to determine the anatomic relationships of nucleotomy guide wires. All the 44 guide wires inserted were found to be in contact with at least one nerve root (eight transfixed a root). Guide wires passing anterior to the nerve roots always passed anterior to the center of the disc. Lateral displacement of the skin entry point made safe entry to the center of the disc impossible. Nerve root transfixion is likely to be a significant complication in percutaneous nucleotomy. Entry to the center of the disc avoiding the nerve roots is simplest if the skin entry is as near to the midline as possible.
Intradiscal invasion of Paget's disease of the spine, A retrospective study of 84 patients with Paget's disease of the spine revealed 9 who developed pagetic intradiscal invasion from the adjacent vertebral bodies. Two patients were asymptomatic. One patient had back pain. one had symptomatic intraforaminal stenosis without back pain. and five had clinical and radiologic spinal stenosis and spine pain; of these five. one demonstrated clinical and radiologic findings indistinguishable from spondylodiscitis. The incidence of intradiscal transgression in Paget's disease of the spine was 10.7%. Spinal pain was present in 67% patients; 22% were asymptomatic. This study shows that disc pathology is not invariably associated with spinal pain.
Postoperative cerebrospinal fluid leakage after lumbar spine operations. Conservative treatment, Cerebrospinal fluid (CSF) leakage from a postoperative wound after lumbar spine operation is an uncommon complication. It may result from excessive traction of the nerve roots. direct trauma. or laceration at the time of operation. causing the dura to be inadvertently opened. Other reasons for this complication are postlaminectomy residual bone spikes. traumatic myelography puncture. and improper suture of dura defects. Eight patients who had postoperative CSF leakage as the only complication after lumbosacral spine operations were examined. They were all treated conservatively with bed rest in the Trendelenburg position. antibiotic coverage. watertight skin suturing. and daily subcutaneous punctures. No patient was operated on for the same type of complication.
Anterior perforations in lumbar discectomies. A report of four cases of vascular complications and a CT study of the prevertebral lumbar anatomy, Four cases of vascular complications to anterior perforations during discectomy prompted a CT study to measure lumbar disc diameters and to evaluate the prevertebral anatomy. Fifty young adults who had been referred for low-back pain and/or sciatica but had not undergone operation were included. In five additional patients. prone versus supine CT examinations were compared. Six typical configurations of the vascular anatomy could be classified to explain the type of vascular complications occurring at the L3-4 and L4-L5 disc levels. The sagittal diameter of the three lowest lumbar discs varied from 33 to 56 mm. indicating the importance of this parameter as an intraoperative guideline for the spine surgeon. Air-filled intestines were observed anterior to the L5-S1 disc predominantly in the prone position. The possible relationship between this finding and postoperative discitis is discussed.
Experimental nerve root compression. A model of acute, graded compression of the porcine cauda equina and an analysis of neural and vascular anatomy, Nerve root compression has been suggested as one important pathogenetic factor in low-back pain syndromes and sciatica. The underlying pathophysiologic mechanisms are. however. incompletely known. partly because of the lack of experimental data on this topic. In the present study. a model for experimental compression of the porcine sacrococcygeal cauda equina is presented. The model consists of surgical exposure of the cauda equina and compression of the cauda equina toward the ventral aspect of the spinal canal by an inflatable balloon fixed to the spine. This compression system was shown to have a high accuracy in pressure transmission from the balloon to the cauda equina. The gross and microscopic neural anatomy and the vascular anatomy of the porcine cauda equina were analyzed with light microscopic and ink-perfusion techniques. The porcine cauda equina showed a close anatomic resemblance to the human lumbosacral cauda equina. The presented model offers unique possibilities for experimental studies on nerve root compression injury because of the easy surgical exposure and the sufficient length of the nerve roots. In separate studies. this model. along with investigations of solute transport to the nerve tissue and of impulse propagation. has been used to analyze the effects of acute. graded compression on blood flow and edema formation in the cauda equina. The porcine cauda equina would also be particularly suitable for chronic compression studies because any neurologic deficit acquired would be restricted to the tail.
The effect of an exercise program on vital capacity and rib mobility in patients with idiopathic scoliosis, All 813 patients with idiopathic scoliosis who completed their first Schroth physiotherapeutic rehabilitation program at the Katharina Schroth Hospital between 1984 and 1987 were reviewed. The patients were divided into four age groups. In Group I (10-13 years. N = 278). vital capacity in patients treated for the first time improved by 18.94% (445 ml). In Group II (14-17 years. N = 264). the average increase in vital capacity after initial treatment was 16.33% (497 ml). In Groups III (18-24 years. N = 123) and IV (greater than 24 years. N = 148). the corresponding increases were 15.11% (501) and 13.77% (394 ml). respectively. In the 256 patients receiving repeat treatment. the increases in vital capacity in the respective age groups amounted to just more than half those in the patients treated for the first time. The average increase in chest expansion was more than 20% in all groups at all measuring points. These findings show that a course of inpatient treatment by the Schroth method can lead to an increase in vital capacity and chest expansion so that. even in adult scoliosis patients. effective treatment of the associated restrictive ventilatory disorder is possible.
Inner-city trauma centers. Financial burdens or community saviors, Trauma systems have proved effective in reducing morbidity and mortality rates. Depending on a center's geographic location and patient mix between penetrating and blunt trauma. participation in a system may be a liability or an asset. In general. inner-city hospitals tend to see more indigent patients and to have sizeable financial losses. At the same time. they provide an invaluable service to any community. and their ability to do so must be preserved. The two important issues of malpractice and uncompensated care threaten to destroy the very concept of trauma care and therefore pose a serious threat to the health care profession. Solutions are possible. but it will take a significant public awareness and education campaign to elicit the support and initiate the programs that will ensure that every injured patient has an opportunity to receive the best of trauma care. Inner-city hospitals are both a financial burden and a community savior.
Principles of ballistics applicable to the treatment of gunshot wounds, Ballistics is the science of the motion of a projectile through the barrel of a firearm (internal ballistics). during its subsequent flight (external ballistics). and during its final complicated motion after it strikes a target (terminal ballistics). Wound ballistics is a special case of terminal ballistics. Although wound ballistics is at best sets of approximations. its principles enter usefully into an evaluation of a gunshot wound and its treatment. A special consideration in these cases is their medicolegal aspects. At a minimum. the medical team receiving the patient should exert care not to destroy the clothing and in particular to cut around and not through bullet holes. to turn over to law enforcement officials any metallic foreign body recovered from the patient. and to describe precisely. or even to photograph. any entrance or exit wounds.
Management of penetrating neck injuries. The controversy surrounding zone II injuries, Penetrating neck injuries present a difficult challenge in management. given the unique anatomy of the neck. Controversy surrounds the approach to zone II injuries; mandatory versus selective exploration. On the basis of an extensive literature review. the authors conclude that neither approach is obviously superior. A selective approach is safe in the asymptomatic and hemodynamically stable patient. provided that accurate invasive diagnostic means are immediately available. The mandatory approach is safe. reliable. and time tested. The greatest problem appears to be the accuracy of detection of cervical esophageal injuries: Radiologic evaluation may be inaccurate. rigid esophagoscopy carries a risk of perforation. and the injury may easily be overlooked during surgical exploration.
Penetrating orthopedic injuries, The treatment of gunshot wounds involving bones or joints remains controversial. Antibiotics and thorough debridement may not be necessary for many of these wounds (stable fractures with minimal soft-tissue damage). However. as in the treatment of open fractures and joint injuries from blunt trauma. the damage to the skin frequently is not a good indicator of the amount of soft tissue to be found underneath.
Extremity replantation, Although the success of replantation and revascularization is in part related to the length of the ischemic interval. it is important to bear in mind that microsurgical intervention must be given appropriate priority relative to the patient's other injuries. Very few patients die as a result of upper extremity trauma. However. the economic. psychologic. and physical debility of a chronic hand injury will be the ultimate handicap in patients who survive multisystem trauma. Therefore. management of the injured extremity has an important place in the overall scheme of trauma care.
Vertical deceleration trauma. Principles of management, A highly complex interaction of several physical and biomechanical factors determines the patterns of injury and probability of survival in free falls. Falls from extreme heights result in massive visceral and vascular injuries. which are usually lethal. Urban falls tend to result in severe lower extremity. spinal. and pelvic fractures. Retroperitoneal hemorrhage is a significant cause of death and is best managed by emergency angiography and embolization. Early fixation of fractures reduces morbidity.
Inhalation injuries and burns in the inner city, Burns in the urban environment present special problems. Although there generally is ready access to appropriate care and short transport times. burn injury remains a serious concern. Inhalation injuries. electrical and chemical burns. and burns as a result of abuse or assault are common problems.
Nautical accidents. Unique injuries, Not much has been written about nautical injuries. although the increasingly popular recreational boating activities and other water sports are becoming a significant source of injury and death. The authors review common and not-so-common nautical injuries and possible preventive measures.
Racial differences in cerebrovascular disease hospitalizations, We studied the relationship of race to incidence of hospitalization for cerebrovascular disease among 74.096 white and 33.041 black persons who took health examinations in a prepaid health care program. Analyses were controlled for age. sex. body mass index. coffee use. smoking. alcohol use. systolic blood pressure. and baseline disease. Blacks were at higher hospitalization risk than whites for hemorrhagic cerebrovascular disease (relative risk = 2.4. 95% confidence interval = 1.3-5.8). cerebral thrombosis (relative risk = 1.9. 95% confidence interval = 1.2-2.9). and nonspecific cerebrovascular disease (relative risk = 1.6. 95% confidence interval = 1.2-2.2) but at lower hospitalization risk for extracranial occlusive disease (relative risk = 0.4. 95% confidence interval = 0.2-0.7). Blood pressure had a similar relation to all types of cerebrovascular disease in both races. but there were disparities in the relations of other atherosclerosis risk factors to different types of cerebrovascular disease. Educational attainment had little relation to hospitalization for extracranial occlusive disease. a finding that reduces the likelihood that selection bias explains the racial disparity. These data show unexplained racial differences in the type and location of cerebrovascular disease. The differences are important in understanding the pathogenesis of cerebrovascular disease and have practical clinical implications.
Probability of stroke: a risk profile from the Framingham Study, A health risk appraisal function has been developed for the prediction of stroke using the Framingham Study cohort. The stroke risk factors included in the profile are age. systolic blood pressure. the use of antihypertensive therapy. diabetes mellitus. cigarette smoking. prior cardiovascular disease (coronary heart disease. cardiac failure. or intermittent claudication). atrial fibrillation. and left ventricular hypertrophy by electrocardiogram. Based on 472 stroke events occurring during 10 years' follow-up from biennial examinations 9 and 14. stroke probabilities were computed using the Cox proportional hazards model for each sex based on a point system. On the basis of the risk factors in the profile. which can be readily determined on routine physical examination in a physician's office. stroke risk can be estimated. An individual's risk can be related to the average risk of stroke for persons of the same age and sex. The information that one's risk of stroke is several times higher than average may provide the impetus for risk factor modification. It may also help to identify persons at substantially increased stroke risk resulting from borderline levels of multiple risk factors such as those with mild or borderline hypertension and facilitate multifactorial risk factor modification.
Correlation of common carotid flow volume measured by ultrasonic quantitative flowmeter with pathological findings, To evaluate the possibility of quantitatively diagnosing carotid and cerebral atherosclerosis noninvasively. we measured common carotid flow volume in 60 sides (30 patients). using an ultrasonic quantitative flowmeter. and then compared these findings to the severity score of carotid and cerebral atherosclerosis as determined at autopsy. Stenosis decreased common carotid flow volume in the carotid and cerebral arteries. Increases in the severity score varied inversely with reduced flow volume. which was high in inverse correlation (r = -0.696). Patients with flow volumes of 8.5 ml/sec or greater did not have stenosis greater than or equal to 75%. whereas all patients with flow volumes of 6.4 ml/sec or less had stenosis greater than or equal to 50%. with 45% of these having stenosis greater than or equal to 75%. These pathological findings confirm that the common carotid flow volume reflects the degree of carotid and cerebral atherosclerosis present and that the lower limit of common carotid flow volume in healthy subjects is 6.5 ml/sec.
Quantitative assessment of cerebral blood volume by single-photon emission computed tomography, We implemented a technique for measuring regional cerebral blood volume using single-photon emission computed tomography and in vivo technetium-99m-labeled red blood cells and then evaluated it in nine normal human volunteers (controls) and seven patients with bilateral occlusion or severe stenosis of the internal carotid artery. We also measured regional cerebral blood flow using single-photon emission computed tomography and intravenous xenon-133 in the same subjects. We studied regional cerebral blood flow. regional cerebral blood volume. and their ratio before and after the intravenous injection of 1 g acetazolamide. Mean +/- SD baseline regional cerebral blood volume was higher in the patients than in the controls (4.1 +/- 0.6 versus 3.2 +/- 0.3 ml/100 g. p less than 0.01). and mean +/- SD baseline regional cerebral blood flow was lower in the patients than in the controls (40.5 +/- 11 versus 55.6 +/- 11 ml/100 g/min. p less than 0.05). Acetazolamide induced similar mean +/- SD increases in regional cerebral blood volume in both the controls and the patients (0.3 +/- 0.1 and 0.3 +/- 0.2 ml/100 g). while the mean +/- SD regional cerebral blood flow reactivity was significantly less in the patients than in the controls (12.6 +/- 7.6 versus 24.5 +/- 9.6 ml/100 g/min. p less than 0.05). Our study shows that single-photon emission computed tomography can provide quantitative estimates of both regional cerebral blood volume and regional cerebral blood flow in humans.
Air embolism of the brain in rabbits pretreated with mechlorethamine, Infusion of 400 microliters air into the left internal carotid artery of five anesthetized rabbits caused transient pial arteriole air embolism. an immediate 41.9 +/- 0.8% dilatation of the embolized vessels. suppression of the cortical somatosensory evoked response to 29.4 +/- 2.7% of baseline. and a progressive decline in ipsilateral cerebral blood flow (measured by hydrogen clearance) to 46 +/- 4.1% of baseline after 2 hours. These values were significantly different from those at baseline and from the responses of 10 control rabbits given equivalent intracarotid saline infusions. Twelve other rabbits were made leukopenic by treatment with 1.5 mg/kg i.v. mechlorethamine 72 hours prior to study. Mean +/- SEM leukocyte count decreased from 6.320 +/- 73/mm3 to 1.890 +/- 66/mm3 without any change in the leukocyte differential or erythrocyte and platelet counts. Intracarotid infusion of saline into seven of the leukopenic rabbits caused no changes. In the other five leukopenic rabbits. infusion of 400 microliters air caused air embolism but did not produce the anticipated declines in cerebral blood flow or the cortical somatosensory evoked response. both of which remained indistinguishable from baseline values and responses in the seven saline-treated leukopenic controls. Similarly. air-embolized arterioles showed nonsignificant dilatation in leukopenic rabbits. Our data suggest that the decreases in both cerebral blood flow and brain function seen after air embolism require the presence of leukocytes.
Postischemic (S)-emopamil therapy ameliorates focal ischemic brain injury in rats, (S)-Emopamil is a calcium channel blocker of the phenylalkylamine class. having potent serotonin S2 antagonistic properties and high blood-brain barrier penetrability. Previous studies have documented cerebroprotective effect in animal models of both focal and global ischemia. The present study was undertaken to define the postischemic "window" of therapeutic efficacy for this agent. Sprague-Dawley rats were subjected to permanent proximal middle cerebral artery occlusion. combined with an initial 30-minute period of halothane-induced hypotension (50 mm Hg). (S)-Emopamil (20 mg/kg) was administered intraperitoneally either 20-30 minutes prior to middle cerebral artery occlusion or 1 hour. 2 hours. or 3 hours following occlusion. Treated groups received a second similar dose 2.5 hours later and twice daily for 2 days thereafter. Brains were perfusion-fixed on the third day. Planimetric analysis of hemotoxylin and eosin-stained coronal brain sections documented a cortical infarct averaging 72.9 +/- 33.3 mm3 (mean +/- SD) in untreated rats. Cortical infarct volume was reduced by 48% (to 37.6 +/- 27.6 mm3) when therapy was initiated 1 hour postischemia (p less than 0.05). When treatment was deferred to 2 hours postichemia. mean cortical infarct volume was reduced by 34%. but this difference did not attain statistical significance. Infarct volume in rats with treatment initiated at 3 hours postischemia was indistinguishable from that in controls. Striatal infarct volume was similar in all groups. These results document a postischemic therapeutic window of cerebroprotection for (S)-emopamil lying between 1 and 2 hours after middle cerebral artery occlusion.
Adventitial red blood cells produce intimal platelet accumulation in cerebral arteries of cats following subarachnoid hemorrhage, After dividing 21 cats into three equal groups. we exposed their right middle cerebral arteries transorbitally and adventitially irrigated them with 2 ml washed red blood cells. blood plasma. or saline. To determine arterial intimal platelet accumulation in each cat. we injected [111In]oxine-labeled platelets intravenously immediately before injecting the various experimental solutions. Animals were sacrificed 2 or 4 hours following the injection of labeled platelets. Irrigation with washed red blood cells produced a significantly greater intraluminal accumulation of platelets than irrigation with saline (p less than 0.05). Plasma tended to have less of an effect on platelet accumulation than washed red blood cells. but this difference was not significant. These data suggest that the adventitial blood fraction responsible for intimal platelet accumulation in cerebral arteries following subarachnoid hemorrhage may be derived mainly from the red blood cell fraction.
Effect of delayed centrifugation or reading on the detection of ABO incompatibility by the immediate-spin crossmatch, The immediate-spin (IS) crossmatch is a method that detects ABO incompatibility. However. under certain circumstances. this test may show unwanted negative or weak results. even though the red cells (RBCs) and serum being tested are ABO incompatible with each other. The present study investigated the potential effect of delayed centrifugation or reading on the IS crossmatch test performance. When the centrifugation step of the IS crossmatch between group O sera and group A1 RBCs was delayed for 2 minutes. 5 of 200 crossmatches showed no agglutination with only trace (n = 2) or moderate (n = 3) hemolysis. and one crossmatch showed only weak. macroscopic agglutination. but moderate hemolysis. All six sera contained A antibodies that were lytic in vitro and. therefore. probably were capable of causing in vivo hemolysis of transfused A1 RBCs. Delaying the reading of the IS crossmatch test for 2 minutes had no apparent effect on test performance. These data demonstrate the importance of technologists' recognition of hemolysis as a positive result on IS crossmatches. especially if the performance of the centrifugation step of the test is delayed. Furthermore. the unwanted negative agglutination results were abolished by suspending the group A1 RBCs in saline containing EDTA. The authors' laboratory has modified its IS crossmatch procedure so that donor RBCs are routinely suspended in saline containing EDTA before testing. This procedural change should increase the safety of the IS crossmatch.
A rational attitude toward serum alanine aminotransferase measurement by blood banks, based on a longitudinal study of a cohort of repeat blood donors, A cohort of 879 blood donors was followed over a 3-year period. Of the 3858 units of blood collected. 112 (2.9%). obtained from 64 donors. had an alanine aminotransferase (ALT) activity over 45 IU per L; of these. 39 had a single ALT elevation. The incidence of ALT increase was 2.01 per 100 units. or 5.1 per 100 donors. per year. The pattern of elevated ALT was followed in 72 donors. 54 of whom were from the 64 cited above. At the second blood donation (BD2). about 5 months later. 62.5 percent had a normal ALT value. and most (91%) retained those values at blood donation 3 (BD3). However. 19 (70.3%) of the 27 whose ALT levels had not returned to normal at BD2 had an increased value at BD3. These results led to the formulation of the following algorithm to improve the management of blood donors; at the first donation. the ALT assay is done after the blood collection. but. at the next donation. the ALT level is measured before donation if the preceding ALT activity had been abnormal. If ALT is elevated. blood is not collected. Three consecutive ALT elevations are a criterion for permanent exclusion of the donor.
Heterogeneity of human red cell autoantibodies assessed by isoelectric focusing, Human red cell (RBC) autoantibodies may be the products of a single lymphocyte clone or of a restricted number of clones. For insight into the clonal distribution of human RBC autoantibodies. serum fractions from 28 individuals with various forms of autoimmune hemolytic anemia (AHA) and two nonanemic individuals with positive direct antiglobulin tests were separated by isoelectric focusing (IEF). and RBC binding in each fraction was quantitated with a solid-phase radioimmunoassay. IEF fractions of serum from normal volunteers and patients with nonimmune hemolytic anemia served as controls. These studies indicate that RBC antibodies are found in a restricted number of IEF fractions in sera from some patients with immune hemolytic anemia. IEF fractions containing RBC-binding activity vary among patients with idiopathic AHA. and distinct patterns of binding activity are found in serum from some patients with AHA associated with alphamethyldopa and procainamide or with B-cell immunoproliferative diseases. These findings suggest that the mechanism leading to autoantibody production may differ among patients with the various forms of immune hemolytic anemia.
The critical role of blood from HLA-homozygous donors in fatal transfusion-associated graft-versus-host disease in immunocompetent patients, Fatal transfusion-associated graft-versus-host disease developed in a 69-year-old woman with colon cancer who underwent elective hemicolectomy. During the perioperative period. she was transfused with 4 units of nonirradiated fresh whole blood less than 6 hours after the blood was donated by family members. She was immunocompetent and was not treated with any immunosuppressive agents such as corticosteroids. chemotherapy. or irradiation therapy. The implicated donor was thought to be her daughter. who was homozygous for an HLA haplotype that was shared with the recipient: A24. Bw52. CBL. DR2. This is the most common haplotype in the Japanese population. This case and others in the Japanese literature indicate that the transfusion of fresh. nonirradiated blood that contains immunocompetent lymphocytes and peripheral hematopoietic precursor cells from HLA-homozygous donors can be lethal to the recipient.
Tissue transplant-transmitted infections, Tissue bankers. as well as those transplanting tissues. have been sensitized to the possibility of transmission of fatal infection via tissue transplants. particularly following recent reports of a few cases of AIDS or HIV infection from bone. semen. and skin grafts. It is beyond the scope of this review to describe the steps taken by tissue banks to enhance the safety of tissue transplants. Of note is the fact that a number of new donor screening tests. such as those for antibody to HIV. HBcAg. hepatitis C virus. and human T cell lymphotropic virus type I. have recently been implemented. In addition. rapid advances in the medical history screening of tissue donors and tissue procurement. processing. and preservation continue. Viral inactivation studies are also being undertaken. All these measures are being introduced to increase the safety of tissue transplants.
Evaluating results of clinical trials in treatment of complicated urinary tract infection, Clinical trials of new drugs should produce results that are not due to chance. inherent differences in groups. or handling of the groups by the investigator. These sources of error may be prevented by having groups of a size that provides sufficient statistical power and thus rules out sample variation. Differences in groups can be prevented by randomization. and double blinding the subjects prevents investigator bias.
Parenteral ofloxacin in treatment of pyelonephritis, The interim findings of two studies of intravenous ofloxacin for the treatment of pyelonephritis are presented. The findings are from one center of a multicenter trial. In the first study intravenous (IV) ofloxacin was given to 34 patients with urine-culture-positive pyelonephritis. After three days of intravenous therapy patients could be switched to oral ofloxacin. Microbiologic eradication occurred in 97 percent and clinical cures in 97 percent of the patients treated with ofloxacin. There were three probable drug-related adverse events. In the second comparative study 38 patients with pyelonephritis were randomized to receive IV ofloxacin with the option of switching to oral ofloxacin after three days. IV ceftazidime was given to 30 patients with pyelonephritis with the option of switching to trimethoprim/sulfamethoxazole (TMP/SMX) after three days. Microbiologic cures were experienced by 97 percent of the ofloxacin patients and by 100 percent of the ceftazidime patients. Probable drug-related adverse reactions were experienced by 3/28 ofloxacin patients and by none of the ceftazidime patients. These interim study findings indicate that the intravenous preparation of ofloxacin is efficacious in the treatment of pyelonephritis and that it is safe. In addition. IV ofloxacin is as efficacious as IV ceftazidime for the treatment of pyelonephritis.
Worldwide clinical experience with ofloxacin in urologic cases, Ofloxacin is a quinolone carboxylic acid with a broad spectrum of activity for gram-negative pathogens that are common causes of urologic infections including cystitis. pyelonephritis. and prostatitis. The data in this publication will review clinical trials in urologic infections as well as the literature which dates from January 1983 through February 1989. The database includes over four hundred reports from nineteen foreign countries and involves data from more than 21.000 patients. The data from the United States were accumulated in clinical trials conducted between 1984 and 1988. Ofloxacin has certain attributes that make it a potentially useful drug in the treatment of urologic infections. These include the high bioavailability from oral administration and the fact that the product is excreted almost entirely by the kidney. primarily as the active parent compound. Urinary levels of ofloxacin two to four hours postadministration can achieve concentrations above 600 micrograms/mL after a single 400-mg dose. Urinary levels twenty-four hours after a single dose are noted to be typically around 50 micrograms/mL. Both of these concentrations are well above the minimum inhibitory concentration (MIC90) for uropathogens. which might be below 1 microgram/mL for many uropathogens. With respect to the prostate. ofloxacin penetrates prostatic tissues well and can achieve concentrations of approximately 4.5 micrograms per gram of prostate tissue as a mean peak level. Prostate levels ten hours postdose will typically be approximately 2.7 micrograms per gram of prostatic tissue. These levels exceed the MIC90 for the majority of prostatic pathogens as well.
Fleischner lecture. Developmental abnormalities in the systemic blood supply to the lungs, Developmental abnormalities in the systemic blood supply to the lungs occur in association with congenital heart disease. congenital lung disease. and rarely with apparently normal heart and lungs. Although most of these anomalies are rare. in the aggregate they are relatively common and of special interest to students of chest and heart disease.
Lymphoma of the lung: CT findings in 31 patients, Lymphomatous involvement of the lungs is often a difficult clinical and radiologic diagnosis to make. yet is often critical in determining treatment. To better define the CT appearance of pulmonary lymphoma. we undertook a retrospective review of 31 patients with recurrent or secondary non-Hodgkin lymphoma or Hodgkin disease and lung parenchymal involvement on CT scans. Diagnoses were confirmed either by lung biopsy or by disease regression or progression with appropriate therapy. The CT scans were evaluated for the following findings: (1) nodules less than 1 cm. (2) a mass or masslike consolidation greater than 1 cm with or without cavitations or bronchograms. (3) alveolar or interstitial infiltrates. (4) masses of pleural origin. (5) peribronchial or perivascular thickening with or without atelectasis. (6) pleural effusions. and (7) hilar or mediastinal lymphadenopathy. The most common CT finding was a mass or masslike consolidation larger than 1 cm. seen in 21 (68%) of the 31 patients. The second most common finding was nodules less than 1 cm (19 patients). Sixty-eight percent of patients had three or more of the CT abnormalities. Lymphoma involving the lung parenchyma causes a variety of CT findings. the most common being a mass or masslike consolidation. Two-thirds of patients have more than one type of CT finding simultaneously.
Diagnosis of pneumoperitoneum on supine abdominal radiographs, A blinded. retrospective study was performed to determine the value of supine abdominal radiographs in diagnosing pneumoperitoneum. Supine films from 44 cases of pneumoperitoneum were randomly interspersed among supine films from 87 control subjects without free air. and the films were reviewed for the presence or absence of various signs of pneumoperitoneum. including Rigler's sign (gas on both sides of the bowel wall). the falciform ligament sign (gas outlining the falciform ligament). the football sign (gas outlining the peritoneal cavity). the inverted-V sign (gas outlining the medial umbilical folds). and the right-upper-quadrant gas sign (localized gas in the right upper quadrant). One or more of these signs were present in 26 cases (59%) of pneumoperitoneum. including the right-upper-quadrant gas sign in 18 cases (41%). Rigler's sign in 14 cases (32%). and the falciform ligament and football signs in one case each (2%). Unfortunately. there were frequent errors in the interpretation of the right-upper-quadrant gas sign and Rigler's sign. with a total of 11 false-positive cases (13%). Further analysis of the true-positive right-upper-quadrant gas signs showed that these gas collections were always triangular or linear with an inferolateral to superomedial orientation and. if triangular. a concave superolateral border. In the true-positive Rigler's signs. the bowel wall thickness ranged from 1 to 8 mm. whereas the false positives all had a bowel wall thickness of 1 mm or less. Proper interpretation of the various signs of pneumoperitoneum on supine films should lead to more accurate diagnosis of this condition.
Imaging the gallbladder: a historical perspective, After Wilhelm Conrad Roentgen's discovery of the X-ray in 1895. it was initially thought that gallstones could not be visualized. Surgeons relied solely on the clinical examination to detect biliary disease. Today. no evaluation of the gallbladder would be complete without the performance of an imaging study. Radiology has gone through several eras in the imaging of gallstones. The plain film era. 1895-1924. was characterized by techniques that improved soft-tissue detail. allowing better detection of radiopaque stones. The contrast media era. 1924-1960. was initiated by the invention of IV cholecystography. In 1925. oral cholecystography was developed. During the era of expanding technology. 1960-1979. percutaneous transhepatic cholangiography. scintigraphy. and sonography came into use. The therapeutic era began in the 1980s.
Carcinoma of the cervix: value of MR imaging in detecting parametrial involvement, In patients with cervical carcinoma. precise knowledge of parametrial tumor extension affects the therapeutic decision between surgery and radiation therapy. The purpose of this prospective study was to determine the efficacy of MR imaging in detecting the presence or absence of parametrial invasion in patients with cervical cancer thought clinically to be confined to the cervix. Twenty-five consecutive patients were included in the study. All patients underwent radical hysterectomy or total abdominal hysterectomy and had detailed histologic evaluation of the parametrium. Ten had pathologic evidence of parametrial invasion; in the remaining 15. no parametrial invasion was identified pathologically. MR findings were compared with pathologic findings in all cases. For determining parametrial involvement. MR imaging had an accuracy of 88%. a sensitivity of 100%. and a specificity of 80%. Our results suggest that MR imaging is a reliable means of assessing parametrial invasion by cervical cancer.
Repair of Achilles tendon ruptures with a polylactic acid implant: assessment with MR imaging, An investigational tendon repair device composed of a polymer of lactic acid (PLA) is currently undergoing multicenter clinical trials for use in repairing rupture of the Achilles tendon. The advantages of the PLA device include high tensile strength and the induction of a rapid proliferative tissue response resulting in a shorter rehabilitation period than with conventional surgical repair. We reviewed 16 MR examinations performed in 10 patients 3-35 months after repair to characterize the MR appearance. All 16 T1-weighted sagittal images revealed a thickened fusiform tendon with streaks of moderate signal within the tendon corresponding to the PLA device and its surrounding collagenogenic response. The double-echo T2-weighted axial images at the mid tendon level demonstrated progressive changes in the signal pattern of the central portion of the tendon that reflected the maturation of the healing tendon. All tendons repaired with PLA implants were uniformly hypertrophied relative to the contralateral normal side because of the induced proliferative collagenogenic ingrowth. Two follow-up MR examinations were performed in six patients and showed mean reductions in tendon caliber of 24% and 30% at the mid and inferior levels. MR imaging of the Achilles tendon repaired with PLA implants shows a diffusely thickened tendon with streaks of signal within the tendon that distinguish it from tendons repaired by conventional techniques.
Extension of growth-plate cartilage into the metaphysis: a sign of healing fracture in abused infants, The present study was carried out to determine if healing metaphyseal injury in abused infants is accompanied by an increase in the thickness of the growth-plate zone of hypertrophic cartilage and if a radiolucent extension from the growth plate into the metaphysis correlates with this histologic indicator of healing fracture. The radiologic studies of 13 infants who died with evidence of inflicted injury were reviewed. Thirteen distal metaphyseal fractures were identified. Histologically. nine of these fractures were noted to be healing and four showed no evidence of healing. The nine healing injuries were accompanied by statistically significant thickening of the zone of hypertrophic cartilage. Seven of these demonstrated localized areas of hypertrophic cartilage extension; in six of these. corresponding radiolucent extensions of the growth plate into the metaphysis were seen. The extensions tended to be single and focal with minimal osseous injury and broad and multiple with extensive injury. No similar extension was visible in the four acute injuries. Because metaphyseal injuries are notoriously difficult to date. the presence of a reliable radiologic indicator of healing metaphyseal fracture can be important in the evaluation of infant abuse. Because the radiologic findings reflect the histologic alterations. extension of the growth-plate cartilage into the metaphysis may have implications for estimating fracture age.
Normal metaphyseal radiologic variants not to be confused with findings of infant abuse, Postmortem high-detail skeletal radiography of 78 infants who died of the sudden infant death syndrome was performed during a 3-year period. Review of the studies reveals a variety of distinct radiologic variants that should not be confused with the metaphyseal injuries caused by infant abuse.
Osteomyelitis of the talus: an unusual cause of limping in childhood, Hematogenous osteomyelitis of the talus is a rare and infrequently considered cause of limping in children. We describe five children younger than 2 years of age with osteomyelitis of the talus who had a limp and a paucity of constitutional symptoms. Conventional radiography and scintigraphy were the imaging techniques used. The usual radiologic features include soft-tissue swelling and an osteolytic defect in the talus without sequestrum formation of periosteal reaction. Bone scans were positive in all cases and led to the localization of the lesion in two patients. Definitive diagnosis was made in all cases only after needle aspiration or open biopsy and curettage. Increased awareness of this unusual lesion and its subtle early radiologic manifestations will allow prompt diagnosis and treatment.
The risks of death and of severe nonfatal reactions with high- vs low-osmolality contrast media: a meta-analysis, Estimates of the risks associated with the use of radiologic contrast agents frequently are based on a subjective review of some of the numerous articles that have been published on the subject. We have chosen instead to synthesize the existing evidence in an objective. quantitative way by statistically combining the data from individual studies through meta-analysis. Although meta-analysis is subject to whatever biases may exist in the underlying data. and may inappropriately pool data from studies with significant differences. the estimates draw proportionately from each original study and. in addition. gain considerable precision owing to the increased amounts of data considered. Using this technique. we analyzed the data from all available original reports appearing since 1980. Crude rates derived from all reports were used to estimate risks with high-osmolality media. Weighted rate differences based on comparative studies only were used in the estimation of the reductions in risk obtainable with low-osmolality media. The risk of death with high-osmolality media was 0.9 per 100.000 uses (95% confidence interval. 0.3-2.6 per 100.000). The difference in risk produced by using low-osmolality media was 0 (95% confidence interval. -1.1 to 1.1 per 100.000). The risk of severe reactions associated with high-osmolality media was 157 per 100.000 uses (95% confidence interval. 144-172 per 100.000). The reduction in risk that can be obtained by the use of low-osmolality media was estimated to be 126 per 100.000 (95% confidence interval. 110-142 per 100.000). This meta-analysis shows that the risk of death is very low with either type of contrast material and that there is no difference between them. Severe nonfatal reactions with high-osmolality media. although more frequent. are still rare; approximately 80% of them can be prevented by using low-osmolality media.
Standardized percentile curves of body-mass index for children and adolescents, Weight-for-height indexes are often used in the clinical assessment of obesity in children and adolescents. The direct measurement of adiposity. using hydrostatic weighing and other techniques. is not feasible in studies involving young children or with large numbers of older subjects. Ratios of weight relative to height. such as the body-mass index (weight/height). may be used as indirect measures of obesity and correlate with more direct measures of adiposity. Using data from the First National Health and Nutrition Examination Study. 1971 to 1974. standardized percentile curves of body-mass index for white children and adolescents were developed. These curves may be used to monitor the body-mass index of white children and adolescents longitudinally and for comparing an individual with others of the same sex and age.
Detection of Epstein-Barr virus DNA by in situ hybridization and polymerase chain reaction in salivary gland biopsy specimens from patients with Sjogren's syndrome, PURPOSE: To determine whether Epstein-Barr virus (EBV) could be involved in the pathogenesis of Sjogren's syndrome (SS). PATIENTS AND METHODS: In situ hybridization using the BamH1-W fragment of EBV DNA was performed using labial salivary gland biopsy specimens from 14 patients with SS (eight with primary SS and six with secondary SS) and 39 control subjects. Furthermore. labial salivary gland biopsy specimens from 12 patients with SS (seven with primary SS and five with secondary SS) and 24 control subjects were submitted to the polymerase chain reaction to detect EBV DNA. RESULTS: In situ hybridization detected EBV DNA in epithelial cells of labial salivary gland biopsy specimens from four of eight (50%) patients with primary SS. zero of six patients with secondary SS. and three of 39 (8%) control subjects. The difference between patients with primary SS and control subjects was statistically significant (p less than 0.02). The polymerase chain reaction detected EBV DNA in six of seven (86%) patients with primary SS. three of five (60%) patients with secondary SS. and seven of 24 (29%) control subjects. The difference between patients with primary SS and control subjects was statistically significant (p less than 0.01). CONCLUSION: Both newly developed techniques showed that the presence of EBV DNA was significantly increased in patients with primary SS in comparison with control subjects. In all the positive SS patients who underwent in situ hybridization. epithelial cells of the labial salivary gland were the target of EBV infection. Our results suggest that this virus may play a role in the pathogenesis of SS. We cannot yet determine whether EBV is directly responsible for the destruction of the gland. or if its presence is a secondary event following gland injury.
Bone mineral density in postmenopausal women treated with L-thyroxine, PURPOSE: To determine if bone mineral density is decreased in postmenopausal women treated with 1-thyroxine. and. if any decrease is observed. whether it is related to overtreatment with thyroid hormone. to deficiency of calcitonin. or to other factors. PATIENTS AND METHODS: The study consisted of 19 postmenopausal women between 50 and 75 years of age treated with 1-thyroxine for 5 years or longer. and 19 matching control subjects with no thyroid disease. Bone mineral density of the spine and hip was measured by dual-photon absorptiometry. Plasma calcitonin concentrations and serum thyroid hormone levels were determined by radioimmunoassays. RESULTS: The 1-thyroxine-treated women had lower bone density in the lumbar spine (1.013 g/cm2 [95% confidence interval. 0.945 to 1.081] versus 1.134 g/cm2 [1.026 to 1.242]. p = 0.043); in the femoral neck (0.736 g/cm2 [0.694 to 0.778] versus 0.809 g/cm2 [0.747 to 0.872]. p = 0.040); in Ward's triangle (0.576 g/cm2 [0.530 to 0.623] versus 0.694 g/cm2 [0.617 to 0.770]. p = 0.011); and in the trochanteric area (0.626 g/cm2 [0.581 to 0.672] versus 0.722 g/cm2 [0.651 to 0.794]. p = 0.027). The maximal increase in calcitonin following calcium infusion was 1.37 ng/L (95% confidence interval. -0.44 to 3.17) in the 1-thyroxine-treated patients versus 18.8 ng/L (95% confidence interval. 10.0 to 27.5) in normal women. p less than 0.001. The average dose of 1-thyroxine was 120 micrograms/day; 16 of the 19 patients had normal serum thyroxine levels. However. TSH levels were low in 13 of the 19. suggesting that 1-thyroxine treatment was supraphysiologic. Seven of the 19 patients had a history of hyperthyroidism in the distant past; these patients. considered separately. had significantly reduced bone density in the hip. The other 12 patients. considered separately. did not have a statistically significant loss of bone density. CONCLUSIONS: Long-term 1-thyroxine therapy is associated with decreased density of the spine and hip. Since subclinical hyperthyroidism. decreased calcitonin responsiveness. and a history of hyperthyroidism were demonstrated in some or all of these patients. these factors must be considered as possible causes of the decreased bone density.
Maternal serum alpha-fetoprotein screening: further consideration of low-volume testing, Unrecognized assay drift that may occur during low-volume (fewer than 500 specimens per week) maternal serum alpha-fetoprotein testing could result in either underestimation or overestimation of the number of pregnant women who are at increased risk of fetal malformations and genetic anomalies. Quality control software programs that incorporate the use of a multirule Shewhart chart are designed to detect assay drift. Careful selection of quality control sera for inclusion in analytic assays and appropriate application of a multirule quality control procedure to values that are obtained on these control materials should detect assay drift. regardless of the volume of patients' specimens in the run.
Posterior colporrhaphy and perineorrhaphy: separate and distinct operations, Posterior vaginal repair is often poorly understood and ineffectively performed. The goals of reconstructive surgery emphasize relief of symptoms and restoration of normal anatomic relationships and of function. A useful method to preoperatively determine posterior vaginal wall weakness is outlined along with a surgical description of important steps in surgical reconstruction.
Antepartum cultures for Ureaplasma urealyticum are not useful in predicting pregnancy outcome. The Vaginal Infections and Prematurity Study Group, To test the hypothesis that genital colonization with Ureaplasma urealyticum would predict adverse pregnancy outcome. 4934 women from five medical centers were evaluated for vaginal colonization with U. urealyticum between 23 and 26 weeks' gestation and followed up to delivery. U. urealyticum colonization was associated with maternal age. parity. racial-ethnic group. martial status. income. education. smoking. number of sexual partners. and colonization with Trichomonas vaginalis. Mycoplasma hominis. and bacterial vaginosis. After adjustment for medical and sociodemographic factors in a multivariate analysis. there was no difference in the mean birth weight or proportion of low-birth-weight infants delivered by women who carried U. urealyticum and those who did not. U. urealyticum colonization at 23 to 26 weeks was not associated with preterm rupture of membranes. preterm labor. or preterm delivery. A positive vaginal culture for U. urealyticum in midgestation does not predict those women at risk for preterm labor. preterm delivery. preterm premature rupture of membranes. or delivery of a low-birth-weight infant.
Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. II. Relationship between receptor expression and response to epidermal growth factor, Previously we have shown that epidermal growth factor acts as a mitogen for some. but not all. ovarian cancer cells in culture. In this study we examined the effect of epidermal growth factor on proliferation of normal human ovarian epithelial cells in monolayer culture. We found that epidermal growth factor stimulated twofold to fourfold increases in proliferation in epithelial cells from each of five normal ovaries (p less than 0.01). In addition. Scatchard analysis of binding of epidermal growth factor tagged with iodine 125 indicated the presence of high-affinity receptors in all of the ovarian epithelial cells and ovarian cancer cell lines. The number and affinity of receptors was similar in the normal epithelium and cancer cell lines. and there was no relationship between epidermal growth factor receptor number and responsiveness to epidermal growth factor. We conclude that human ovarian epithelial cells normally express epidermal growth factor receptors and that epidermal growth factor acts as a mitogen for these cells. Although the mitogenic response to epidermal growth factor often is attenuated in ovarian cancer cell lines. loss of responsiveness to epidermal growth factor does not appear to be due to decreased receptor expression.
Prevention of preterm birth in high-risk patients: the role of education and provider contact versus home uterine monitoring, A total of 394 patients were enrolled in a study to assess the effectiveness of an educational preterm delivery prevention program and to determine whether the addition of home uterine monitoring to the program improved results in patients at high risk of preterm labor. Both the educational program and home uterine monitoring were found to increase the percentage of women with preterm labor who sought care while still favorable for long-term suppression. resulting in a decreased incidence of preterm births and improved outcome when compared with similar high-risk patients who did not participate in these programs. In a randomized. prospective study. addition of home uterine monitoring to the educational program was found to significantly improve outcome in twin gestations but not in singleton gestations. However. the number of singleton pregnancies was too small to rule out possible benefit from home uterine monitoring in that group.
Small-for-gestational-age birth: maternal predictors and comparison with risk factors of spontaneous preterm delivery in the same cohort, Low birth weight. the primary predictor of infant mortality and morbidity. can be a result of shortened gestation (preterm delivery) or fetal growth retardation (small for gestational age). We examined the relationship between maternal characteristics and the risk of delivering a small-for-gestational age infant in 2228 women who participated in the University of California. San Diego Prenatal Nutrition Project between 1978 and 1988. A multivariate analysis indicated that significant risk factors for small for gestational age were cigarette smoking (odds ratio. 3.18). a low rate of maternal weight gain (odds ratio. 2.96). black ethnicity (odds ratio. 2.60). pregravid underweight (odds ratio. 2.36). Asian ethnicity (odds ratio. 1.88). primiparity (odds ratio. 1.85). and low maternal height (odds ratio. 1.63). These findings are contrasted with those previously published on preterm deliveries in the same cohort. We conclude that with the exception of black ethnicity and low maternal weight gain. different maternal characteristics were significantly associated with small-for-gestational-age and preterm birth in this population.
Genotyping of macerated stillborn fetuses, It is generally impossible to collect blood or to culture tissue from a macerated stillborn fetus. Accurate genotyping of such a fetus may. however. be critical for the diagnosis of genetic diseases and appropriate genetic counseling. In the East Flanders Prospective Twin Study. placental tissue of twin and triplet sets. in some of which one or both members were stillborn and macerated. has been stored at -20 degrees C. Of all these fetuses. sex and zygosity could be determined accurately on the placental deoxyribonucleic acid. We tested the possibility of nongenetic changes in deoxyribonucleic acid that result from maceration or tissue degradation over time in storage on placental samples from monochorionic twins in which only one member was stillborn and macerated. The deoxyribonucleic acid variants in these monozygotic twins were identical whether or not either cotwin was macerated. Thus deoxyribonucleic acid variants can be determined accurately on the placental tissue of macerated fetuses. even after prolonged freezing.
Fetal breathing movements after preterm premature rupture of membranes, Forty-three patients with preterm premature rupture of membranes were studied between 24 and 34 weeks' gestation. Intraamniotic infection was excluded by amniocentesis. There were significantly fewer fetal breathing movements for the first 2 weeks of membrane rupture. compared with controls. with a return to near normal by the third week. This reduction in fetal breathing may play a role in the production of pulmonary hypoplasia in some of these patients. Further studies are needed to investigate whether ruptured membranes are associated with a reduction in fetal breathing at earlier gestational ages.
Outpatient sedation: an essential addition to gynecologic care for persons with mental retardation, Routine gynecologic care for persons with mental retardation may be difficult to provide. especially to those women who do not allow a pelvic examination to be performed. Of 275 women referred to a multidisciplinary clinic addressing the reproductive health concerns of mentally retarded women. 61 patients (22%) did not allow a gynecologic examination to be performed. The administration of ketamine alone. midazolam alone. or a combination of midazolam and ketamine allowed for the successful performance of a gynecologic examination in 81% of previously uncooperative women. No adverse effects of the medications were noted. We conclude that sedation of difficult-to-examine. mentally handicapped women can be safely performed in the outpatient setting. thus avoiding the need for general anesthesia and its inherent risks.
Does unexplained second-trimester (15 to 20 weeks' gestation) maternal serum alpha-fetoprotein elevation presage adverse perinatal outcome? Pitfalls and preliminary studies with late second- and third-trimester maternal serum alpha-fetoprotein [published erratum appears in Am J Obstet Gynecol 1991 Jul;165(1):241, Several reports have suggested that persons with an unexplained maternal serum alpha-fetoprotein elevation at 15 to 20 weeks' gestation are at an increased risk for a variety of other pregnancy complications (e.g.. preeclampsia) and adverse perinatal outcomes (e.g.. fetal death. low-birth-weight infants). However. ascertainment biases could explain some of these reported findings. and predictive value of unexplained elevated maternal serum alpha-fetoprotein levels in the prediction of pregnancy complications seems limited. If elevated second-trimester levels were truly predictive of pregnancy complications. we reason that third-trimester levels could prove even more useful. We thus studied late second-trimester and early third-trimester (24 to 36 weeks' gestation) maternal serum alpha-fetoprotein levels with the same enzyme immunoassay we use to evaluate routine second-trimester (15 to 20 weeks' gestation) levels. Values rose up to 32 weeks and fell slightly thereafter. Variance was greater than at 15 to 20 weeks but not so great as to preclude clinical usefulness in the third trimester. Of 279 women with a normal (0.4 to 2.49 multiples of the median) maternal serum alpha-fetoprotein value at 15 to 20 weeks' gestation. 270 (96.8%) showed levels in the same range later in gestation; however. none of six singleton pregnancies with unexplained maternal serum alpha-fetoprotein levels greater than 2.50 multiples of the median at 15 to 20 weeks' gestation showed maternal serum alpha-fetoprotein levels in this range at 24 to 36 weeks' gestation. The relationship between second- and third-trimester maternal serum alpha-fetoprotein levels in abnormal pregnancies remains to be elucidated in a large sample. Thus we are conducting not only cohort but also cross-sectional studies. Preliminary findings suggest that women with preterm premature rupture of membranes or with premature labor show elevated late second-trimester and early third-trimester maternal serum alpha-fetoprotein levels; however. larger sample sizes are necessary.
Cardiac function in fetuses of type I diabetic mothers, Cardiac function was cross-sectionally studied by means of M-mode and Doppler echocardiography in 40 fetuses of mothers with well-controlled insulin-dependent diabetes at 20 to 38 weeks of gestation. These variables were measured: interventricular septal thickness. ratio between the peak velocities during early passive ventricular filling and active atrial filling at the level of the atrioventricular valves. peak velocities. and the time to peak velocity at the level of the ascending aorta and the pulmonary artery. The values obtained were compared with our reference limits for gestation. A significant increase of interventricular septal thickness that was unrelated to maternal glycosylated hemoglobin levels was evidenced. Early passive ventricular filling/active atrial filling ratios were significantly lower in fetuses of diabetic mothers than in control fetuses. These differences were significantly related to interventricular septal thickness. No significant modifications were found in either aortic or pulmonary peak velocities or in time to peak velocity values. These findings suggest that in spite of an adequate metabolic control an interventricular septal hypertrophy that affects cardiac diastolic function develops in fetuses of diabetic mothers.
Mild fetal lateral cerebral ventriculomegaly: clinical course and outcome, The neonatal. pathologic outcome and karyotypic abnormalities are reported for 44 fetuses with mild ventriculomegaly diagnosed antenatally. Seventeen of these 44 fetuses (39%) had other ultrasonographic defects. and five (12%) had abnormal karyotypes. Five pregnancies were electively aborted and three other fetuses died in the neonatal period. Twenty-six (72%) of the remaining 36 live-born neonates are developmentally and clinically normal at 3 to 18 months of age. Twenty-one of these 26 had isolated mild ventriculomegaly as the only ultrasonographic finding. The other 10 live-born infants are developmentally impaired. and five of these 10 had mild ventriculomegaly as the only prenatal ultrasonographic abnormality. In conclusion. these data show that fetuses with mild ventriculomegaly have a lower incidence of associated anomalies and a better outcome than fetuses with more severe ventricular dilatation. as reported in the literature. The majority of fetuses with mild ventriculomegaly as an isolated finding and a normal karyotype are developing normally.
Nonsurgical management of tubal pregnancy. Necessity in view of the changing clinical appearance, The incidence of ectopic pregnancy is definitely increasing. Ectopic pregnancies are diagnosed earlier these days because of the improvement in diagnostic means and the increasing awareness of the condition. It seems that there is a dramatic change in the clinical presentation of this disease; it used to be a grave and life-threatening condition. and now it is a more benign presentation. The vast majority of the diagnosed ectopic pregnancies are unruptured. This has stimulated various investigators to attempt nonsurgical methods of treatment such as systemic administration of methotrexate or RU 486 (mifepristone) or local injection of methotrexate. potassium chloride. or prostaglandins under laparoscopic or ultrasonographic guidance. Most of these conservative. nonsurgical measures proved efficient in 80% to 90% of cases. Expectant management. which was practiced in some cases. proved to be equally successful. We believe that the ideal mode of treatment in early unruptured ectopic pregnancy is still to be determined. The answer probably lies in proper selection.
The effect of volume expansion on placental blood flow in awake hypovolemic rats in late pregnancy, Symptomatic hypovolemia in preeclampsia is often treated by volume expansion. However. the effect of this treatment on placental blood flow is unclear. In the present study the hypothesis was tested that slow volume expansion. imposed on volume-depleted rats. does not compromise placental blood flow. Mild hypovolemia was induced in rats in late pregnancy by 24 hours' thirsting. The resulting gradual dehydration was associated with a 7% reduction in blood volume. These rats were then subjected to blood volume expansion by a continuous infusion with a plasma substitute. Volume expansion increased blood volume by 32% and cardiac output by 73%. The extra cardiac output was distributed to kidneys. carcass. and portal bed. Placental blood flow decreased by 31%. The pattern of response was comparable to the one previously observed in normovolemic rats. However. the magnitude of the changes was larger. probably associated with a delayed or impaired diuretic response. These data suggest that volume expansion therapy in mildly hypovolemic pregnant rats elicits an exaggerated hemodynamic response as compared with normovolemic rats. including placental compromise.
Morbidity and disability in older persons in the years prior to death, BACKGROUND: A large proportion of the disease and disability which affects older persons occurs in the years just prior to death. Little prospective evidence is available which quantifies the burden of morbidity and disability during these years. METHODS: In three community-based cohorts of persons age 65 and older. chronic conditions and disability were evaluated for the three years prior to death in 531 persons who had three annual assessments and then died within one year of the third assessment. Number of chronic conditions. prevalence of disability in activities of daily living (ADLs). and prevalence of disability on a modified Rosow-Breslau scale were determined for these decedents and compared to 8821 members of the cohorts known to have survived. RESULTS: Prevalence rates of disease and disability increased during the follow-up for both decedents and survivors. with decedents generally having higher rates than survivors. Disability rates prior to death. but not the number of diseases. increased with increasing age at death. The odds ratio for disability in ADLs at any of the three assessments for decedents versus survivors ranged from 3.0 to 4.2 in the three communities. In each community the odds ratio for ADL disability was higher in women decedents versus survivors than in men decedents versus survivors. CONCLUSIONS: These results have important implications for disability levels in future older populations in which death is projected to occur at increasingly higher ages.
The yield of cholesterol screening in an urban black community, BACKGROUND: While the distribution of cholesterol levels have been well studied in the general population. little is known about cholesterol and other cardiovascular disease risk factors in screenings held in an urban Black community. This study was designed to determine the yield of cholesterol screening in this community. METHODS: Screening took place in eight community sites. Serum total cholesterol was measured using a rapid capillary technique. Blood pressure was taken according to national guidelines and the average of two to three measurements were used. Standard interviews were used to determine the presence of cardiovascular risk factors by history. RESULTS: Of the 562 individuals screened. 44.9 percent had cholesterol levels requiring referral for follow-up care. Of those with total cholesterol greater than or equal to 6.21 mmol/L. 66.4 percent were previously undetected and more than half also had blood pressure levels greater than or equal to 140/90 mmHg on screening; 45 percent of all participants had blood pressure greater than or equal to 140/90 on screenings. Of those with a history of elevated total cholesterol levels. none had levels below 5.17 mmol/L at the time of screening. CONCLUSIONS: Multiple risk factors are highly prevalent in the urban Black community during cholesterol screening programs. Findings suggest the need for cholesterol programs incorporating blood pressure screening in the urban Black community.
Does increased detection account for the rising incidence of breast cancer, BACKGROUND: The incidence of breast cancer has been increasing over time in the United States. METHODS: To determine the role of screening in this increase. trends in the incidence of in situ and invasive carcinoma of the breast were evaluated using records of the metropolitan Atlanta SEER program between 1979 and 1986. From a sample of records. evidence of symptoms and mammographic screening prior to diagnosis was recorded. RESULTS: The average annual age-adjusted incidence of invasive disease rose 29 percent among Whites and 41 percent among Blacks. Incidence increased in all age groups. A trend towards earlier detection of invasive disease was found. Asymptomatic tumors accounted for only 40 percent of the increased incidence among whites and 25 percent of the increased incidence among blacks. with mammography as the principal contributing procedure. CONCLUSIONS: These data suggest that increased detection accounts for some but not all of the rising incidence of breast cancer in the United States.
The validity of health risk appraisals for coronary heart disease: results from a randomized field trial, BACKGROUND: While health risk appraisals (HRAs) are becoming increasingly popular as tools for health assessment and health education. comparatively little is known about the accuracy of these risk estimates. METHODS: A field trial among 732 randomly selected adults ages 25 to 65 years was conducted to assess the validity of the risk scores produced by four widely used HRAs. RESULTS: Self-reported HRA risk scores for cigarette smoking and relative weight were generally accurate. but correlations between physiological measurements and scores for blood pressure. cholesterol. and physical activity were always lower than .51. Correlations between epidemiologic estimates of the probability of CHD death and HRA total risk scores ranged from .13 to .75; partial correlations adjusting for age. race. and gender ranged from .12 to .47. CONCLUSIONS: The HRAs chosen for the field trial exhibited modest correlations with the CHD mortality risk predicted by the epidemiologic model. Mathematical errors made by respondents completing self-scored instruments and lack of knowledge regarding physiologic status decrease the accuracy of HRA risk estimates.
Clinical and epidemiological features of neurotoxic shellfish poisoning in North Carolina, BACKGROUND: In October 1987. a red tide due to P. brevis affected the North Carolina coast for the first time. The purpose of our study was to describe the clinical and epidemiological features of neurotoxic shellfish poisoning (NSP). an illness caused by eating shellfish contaminated with the neurotoxins of P. brevis. METHODS: Active surveillance was established for cases of NSP. A descriptive study of the NSP cases was then completed. RESULTS: Forty-eight persons. who had eaten oysters at 20 meals. met the case definition. A variety of gastrointestinal tract and neurological symptoms were reported. The illnesses were generally mild and of short duration. and there were no deaths. Forty-one (85 percent) affected persons lived in five communities located within a 70-kilometer area along the coast. Cases occurred from October 27 to December 9; 27 (56 percent) of the cases occurred before the first closure of affected shellfish waters on November 2. There was a significant increase in the illness attack rate with an increase in the number of oysters eaten. CONCLUSIONS: Routine monitoring of coastal waters for P. brevis is needed to facilitate earlier recognition of red tides. closure of affected areas. and education of the public before substantial exposure to contaminated shellfish occurs.
Bone cancer incidence rates in New York State: time trends and fluoridated drinking water, BACKGROUND: Recent animal studies of the potential carcinogenicity of fluoride prompted an examination of bone cancer incidence rates. METHODS: Trends in the incidence of primary bone cancers. including the incidence of osteosarcomas were examined among residents of New York State. exclusive of New York City. Average annual osteosarcoma incidence rates in fluoridated and non-fluoridated areas were also compared. RESULTS: Among persons less than 30 years of age at diagnosis. bone cancer incidence among males demonstrated a significant increase since 1955. while incidence among females has remained unchanged. A significant decrease in bone cancer incidence rates since 1955 was observed among both males and females age 30 years and over at time of diagnosis. Osteosarcoma incidence rates have remained essentially unchanged since 1970. among both younger and older males and females. The average annual age adjusted incidence of osteosarcomas (1976-1987) in areas served by fluoridated water supplies was not found to differ from osteosarcoma incidence rates in non-fluoridated areas. CONCLUSIONS: These data do not support an association between fluoride in drinking water and the occurrence of cancer of the bone.
Capacity of US labs to provide TLI in support of early HIV-1 intervention, We surveyed laboratories to assess their capacity to perform T-lymphocyte immunophenotyping. Of the 1026 respondents. 279 located in 41 states and the District of Columbia performed this type of testing. Most laboratories were located in hospitals. reported a low weekly test volume. and indicated that it took 6-24 weeks for flow cytometer operators to become proficient. Many laboratories appear to have the capacity to perform additional CD4+ cell testing. but training additional operators may be necessary. The paucity of laboratories performing T-lymphocyte immunophenotyping in the public sector may affect referral patterns from that setting.
Response of hospitals, skilled nursing facilities, and home health agencies in Oregon to AIDS: reports of nursing executives, To describe experience and readiness to provide care for persons with acquired immunodeficiency syndrome (AIDS). responses to a mailed survey from 86 percent of chief nursing executives of the 207 hospitals. skilled nursing facilities (SNFs) and home health agencies (HHAs) in Oregon were summarized. As of January 1989. 44 percent reported having provided care; even in low incidence counties. 64 percent of hospitals had provided care. Adequate resources were reported by 79 percent in hospitals. 26 percent in SNFs. and 69 percent in HHAs.
Mass flea outbreak at a child care facility: case report, Cat fleas. Ctenocephalides felis Bouchet. were collected at a Mississippi child care facility after reports of large numbers of adult fleas occurring on children and personnel. One building yielded 161 (99 percent) of the fleas collected. Urticarial lesions due to flea bites occurred on the legs of six children. Flea presence was due to cats occupying the crawl space. Fleas were eradicated by eliminating entry of cats and using residual insecticides throughout the facility.
Black-white differences in cancer prevention knowledge and behavior, Data from the 1987 National Health Interview Survey Cancer Control Supplement were used to estimate multivariate logistic regression models of diet change. mammography utilization. stool blood test utilization. and smoking. Predictor variables included race. sex. age. income. dietary concerns. and four knowledge-related variables: education and three measures of cancer prevention knowledge. When knowledge variables were included in the models. race was not a significant predictor of behavior. with one exception: among women. Blacks were found to smoke less than Whites.
Report of an association between race and thyroid stimulating hormone level, We examined the association between race and thyroid stimulating hormone (TSH) level in 809 consecutive Black or White adults tested for mild suspicion of hypothyroidism with a normal TSH result. The mean TSH level of Blacks was 0.4 (SE .053) mU/L lower than that for Whites after age and sex adjustment. race explaining 6.5 percent of the variation in TSH levels. A validation sample yield similar results. This finding supports the possibility that differences in thyroid function and/or regulation may be associated with race.
Dose-response evaluation of oral labetalol in patients presenting to the emergency department with accelerated hypertension, STUDY OBJECTIVE: Dose-response evaluation of oral labetalol (100. 200. or 300 mg) on heart rate and systemic blood pressure in emergency department patients with hypertensive urgency (diastolic blood pressure. 110 to 140 mm Hg. and no end-organ evidence of hypertensive emergency). METHODS: This acute-treatment. dose-ranging study used a randomized. double-blind. parallel design. Patients with supine diastolic blood pressure of 110 to 140 mm Hg after 30 minutes of bedrest received an oral dose of labetalol. Supine blood pressure and heart rate were measured manually and recorded hourly for four hours after dose. Diastolic blood pressure of 100 mm Hg or less or a 30-mm Hg reduction in diastolic blood pressure was considered a treatment success. RESULTS: Two hundred fifty-five patients were evaluated for inclusion. and 36 patients (19 women and 17 men; mean age. 44 years; age range. 23 to 67 years) were studied. The most frequent reason for exclusion was a spontaneous decrease in diastolic blood pressure to less than 110 mm Hg (31%) with bedrest. There were 12 patients in each treatment group. Compared with baseline. the 100-mg dose significantly (P less than .05) reduced heart rate at three and four hours after dose. and the 300-mg dose significantly (P less than .05) reduced heart rate at one. two. and three hours after dose; the 200-mg dose did not significantly affect heart rate. All doses produced a significant decrease in systolic and diastolic blood pressures at one. two. three. and four hours after dose compared with baseline. There were no statistically significant differences between treatment groups with regard to systolic or diastolic blood pressure or heart rate at baseline or one. two. three. or four hours after dose. At two hours after dose. diastolic blood pressure control was observed in 75%. 58%. and 67% of patients receiving 100. 200. and 300 mg. respectively (P = .903). At four hours after dose. diastolic blood pressure control was observed in 50%. 64%. and 67% of patients receiving 100. 200. and 300 mg. respectively (P = .755). A comparison of treatment success rates between the two time periods showed a waning of response with the 100-mg dose of labetalol at hour 4 compared with hour 2 (P less than .05). No adverse effects were observed. CONCLUSION: Labetalol provides safe and effective treatment for hypertensive urgencies when administered orally in doses of 100 to 300 mg.
Dispatcher-assisted telephone CPR: common delays and time standards for delivery, STUDY OBJECTIVES: To determine the rate of bystander CPR before and after implementation of a telephone CPR program in King County; to determine the reasons for dispatcher delays in identifying patients in cardiac arrest in delivering CPR instructions over the telephone; and to suggest time standards for delivery of the telephone CPR message. DESIGN: An ongoing cardiac arrest surveillance system to calculate the annual bystander CPR rates from 1976 through 1988. Two hundred sixty-seven taped recordings of calls reporting cardiac arrests to nine emergency dispatch centers during 1988 were reviewed and timed. SETTING: King County. Washington. excluding the city of Seattle. PARTICIPANTS: Two hundred sixty-seven persons with out-of-hospital cardiac arrests receiving emergency medical services. Arrests in doctors' offices. clinics. or nursing homes were excluded. INTERVENTIONS: Dispatcher-assisted telephone CPR. MEASUREMENTS AND MAIN RESULTS: The rate of bystander CPR increased from 32% (1976 through 1981) to 54% (1982 through 1988) after implementation of the dispatcher-assisted telephone CPR program. although an increase in survival could not be demonstrated. The median time for dispatchers to identify the problem was 75 seconds; to deliver the early protocols. 19 seconds; to deliver the ventilation instructions. 25 seconds; and to deliver compression instructions. 30 seconds. The total time to deliver the entire CPR message was 2.3 minutes. The most frequent cause for delay was unnecessary questions (57%) with questions about patient age asked most frequently (32%). Other causes included the caller not being near the patient (29%) and deviations from protocol (22%). CONCLUSION: In a metropolitan emergency medical services system. a dispatcher-assisted telephone CPR program was associated with an increase in bystander CPR. Delays in proper delivery of telephone CPR can be minimized through training.
Attack of the sand brier, Corneal foreign bodies represent one of the more common sources of eye-related trauma presenting to emergency and primary care physicians. Presented is the case of a man in whom the diagnosis was overlooked because a magnifying optical device was not used.
Prehospital care: the future of emergency medical services, Most prehospital interventions. both pharmacologic and procedural. have been accepted without clear demonstrations of their abilities to impact patient outcomes or without clear indications that withholding or delaying the intervention pending arrival at a definitive emergency department will adversely affect the patient. Interventions that have the benefit of supportive research have been applied equally to urban and nonurban emergency medical services environments. In selecting interventions. inadequate consideration has been given to the differences in emergency medical services personnel training. frequencies of their exposure to patients. frequencies of skill use. and availabilities of effective continuing education programs in the urban and nonurban environments. These issues are discussed. and the necessary focus of the future of emergency medical services in urban. suburban. and rural environments is predicted.
Neural control of airway vasculature and edema, The tracheobronchial vasculature is controlled by adrenergic. cholinergic. and peptidergic nervous mechanisms. Sympathetic nerves release norepinephrine and neuropeptide Y (NPY). which are both constrictor agents. the latter being long-lasting. Parasympathetic nerves release acetylcholine and usually vasoactive intestinal polypeptide (VIP). both of which are vasodilators. VIP being the longer lasting. These motor nerves are controlled by many reflex inputs. Activation of pulmonary C-fiber receptors by irritants and inflammatory mediators causes a powerful vasodilatation. mainly via sympathetic motor nerves. Cardiac and chemoreceptor reflexes also influence airway vascular tone. Sensory nerves in the airway mucosa are responsible for local axon reflexes in response to irritants and inflammatory mediators. These nerves contain neuropeptides such as substance P (SP). neurokinins A and B (NKA. NKB). and calcitonin gene-related peptide (CGRP). All these neuropeptides are powerful vasodilators. Thus. inflammatory conditions in the lungs such as asthma cause vasodilation by local direct action of mediators. by axon reflexes. and by central nervous reflexes. The vasodilation could lead to mucosal edema. Thus. airway vascular responses have to be added to bronchoconstriction and mucus secretion as part of the mucosal pathology of asthma.
Neuropeptides and asthma, Many neuropeptides have recently been identified in human and animal airways. These peptides have potent effects on airway caliber. blood vessels. and secretions. raising the possibility that they may be involved in airway diseases such as asthma. Vasoactive intestinal peptide and peptide histidine methionine are potent bronchodilators and may be neurotransmitters of nonadrenergic bronchodilator nerves. In asthma. if these peptides are broken down more rapidly by enzymes from inflammatory cells. this might contribute to exaggerated bronchial responsiveness. Neuropeptides that are found in sensory nerves. such as substance P. neurokinin A. and calcitonin gene-related peptide. have inflammatory effects and might also contribute to the pathology of asthma if released from sensory nerve endings by an axon reflex. These findings may have important therapeutic implications for the future.
Effect of inflammatory mediators on airway nerves and muscle, The neuromuscular mechanisms underlying airway hyperresponsiveness have been reviewed on the basis of studies of the changes induced by ozone inhalation in dogs. In vivo. there is increased. nonspecific airway hyperresponsiveness based on studies of the response to inhaled acetylcholine or histamine. The underlying inflammatory mechanism involves release of LTB4 and/or other chemotactic agents from epithelial or lumenal cells. ingress of macrophages. neutrophils. and platelets from the blood vessels between the muscle and epithelium. and migration of mast cells into the epithelium. The hyperresponsiveness seems to depend upon the influx of neutrophils and actions of thromboxane A2 released from the neutrophils. In vitro. there is increased responsiveness to field stimulation of cholinergic nerves and to acetylcholine (not to KCI) in tracheal strips. These effects can be mimicked by a thromboxane A2 analog (U44619). In the sucrose gap. the TxA2 analog does not affect the excitatory junction potential. but in low concentration it increases and prolongs a series of fading membrane oscillations closely related to the contractions. We consider these oscillations to reflect ongoing release and/or action of acetylcholine. In high concentrations the analog causes a small depolarization and a tonic contraction. but it does not enhance the sensitivity to acetylcholine. TxA2 may be acting either presynaptically or postsynaptically or both to produce these effects; however. changes in release of an epithelial-derived relaxing factor do not seem to be involved. We conclude that TxA2 actions probably underlie hyperresponsiveness developed in vivo and in vitro after ozone inhalation.
Airway luminal liquid. Sources and role as an amplifier of bronchoconstriction, The release of mediators from inflammatory cells into the airway lumen can initiate a series of events leading to airway obstruction. particularly smooth muscle contraction and alteration of endothelial and epithelial permeability leading to mucosal edema and subsequent influx of liquid into the airway lumen. In this report we briefly review the effects of several inflammatory mediators. including eicosanoids. platelet-activating factor. and histamine. as well as the effects of plasma proteins and tachykinins that may be secondarily released because of the presence of inflammatory mediators on endothelial and epithelial permeability. We then consider physical mechanisms whereby the resulting airway luminal liquid could amplify the response of an airway previously constricted because of smooth muscle contraction. Specifically. liquid in the interstices between epithelial projections that are formed during muscular contraction could amplify the degree of luminal compromise by (1) further decreasing luminal cross-sectional area by occupying space. and (2) providing an additional source of inward recoil because of the surface tension of the air-liquid interface.
Mast cell/nerve interactions in vitro and in vivo, In this report. we review the evidence for mast cell/nerve interactions. We believe that the morphologic and functional evidence now strongly support a purposeful and biologically significant interaction between these two cell types. This interaction has physiologic consequences and appears to be able to regulate such local events as chloride ion secretion by epithelial cells of the intestinal and respiratory tracts in experimental models. In this way. the mast cell and nerve may be considered as a functional homeostatic regulatory unit. The extent to which this unit may be involved in maintenance of normal integrity of mucous membranes or other structures. in health and in disease. is not clear at the present and will require considerably more investigation and elucidation. However. the concept of such an interaction is an interesting one and may bring new approaches of a therapeutic and diagnostic nature to bear on some old problems. The observations reviewed in this report that psychologic conditioning may itself cause mucosal mast cell degranulation and mediator release in the rat is significant. We consider that this evidence of central nervous system control of mast cell degranulation is an extension of the idea that mast cells and nerves communicate.
PAF antagonism as an approach to the treatment of airway hyperreactivity, Platelet-activating factor (PAF) would seem a good candidate for a mediator of airway hyperreactivity. It has been reported to induce a long-lasting. if modest. increase in hyperreactivity in both experimental animals and humans. Evidence (albeit often indirect) suggests increased levels associated with bronchial hyperreactivity or the related "late-phase reaction" of asthma. In experimental animals. specific inhibitors of PAF can suppress both allergen and PAF-induced hyperreactivity as well as the late-phase reaction to allergen. The mechanism by which PAF induces hyperreactivity is unknown. but the potent effects of PAF on the eosinophil. a cell characteristic of the inflammatory processes often associated with asthma and hyperreactivity. may be important. A number of potent and selective PAF antagonists are now available. The crucial test for the hypothesis that PAF has a role in human airway hyperreactivity will be the testing of substances such as these in appropriate double-blind. placebo-controlled clinical trials.
Bilaminate synthetic dressing for partial thickness burns. Lack of cost reduction for inpatient care, Forty-nine cases of second degree burns initially treated as inpatients from April 1984 through December 1987 are reviewed. Thirty-four patients were treated with bilaminate synthetic dressing (Biobrane) application. while 15 were treated with a topical antimicrobial. usually silver sulfadiazine. The burns ranged from 1 to 25 per cent total body surface area and were comparable in both groups. The mean age in each group was 30 years. Thirty patients were successfully treated with Biobrane. and their average hospital stay was 9.1 +/- 5.4 days compared with 9.2 +/- 8.6 days for the topically treated group. The mean hospital cost for dressings and supplies for the Biobrane group was $360 +/- $90 compared with $310 +/- $190 for the topical group. Four patients (12%) required Biobrane removal during their hospitalization. one due to increasing burn depth and three due to purulent fluid collections beneath the Biobrane. These burns were subsequently treated with topical antimicrobial agents and healed primarily. The mean total hospital stay for this group was 18.0 +/- 11.9 days with the costs being much higher secondary to the initial cost of the Biobrane. the costs associated with topical antibiotic therapy. and extended hospital stay. Although there was a decrease in nursing time and a subjective decrease in patient discomfort associated with using synthetic dressing. no benefit was found in either decreasing hospital stay or total cost of hospitalization and supplies used for inpatients treated at this institution.
Spontaneous pneumoperitoneum. A surgical dilemma, Pneumoperitoneum is usually the result of hollow viscus perforation with associated peritonitis. Nonsurgical spontaneous pneumoperitoneum incidental to intrathoracic. intra-abdominal. gynecologic. iatrogenic. and other miscellaneous causes not associated with perforated viscus have been documented in the literature. Seven cases of spontaneous pneumoperitoneum admitted over 3-year period to Grady Memorial Hospital. Atlanta. Georgia are reported. Six patients with pneumoperitoneum underwent exploratory laparotomy when clinical examination suggested an acute abdomen; no intra-abdominal pathology was documented in any of these patients. A seventh patient. on ventilatory support. was managed conservatively after performing a diagnostic peritoneal lavage that was negative. There were no cases of radiographically misdiagnosed pneumoperitoneum. Pneumoperitoneum. preceded by a reasonable incidental cause in a patient with a adequate abdominal examination. may warrant continued observation thus avoiding an unnecessary laparotomy.
Sonication provides maximal recovery of staphylococcus epidermidis from slime-coated vascular prosthetics, Staphylococcus epidermidis (S. epidermidis) prosthetic vascular graft infections are often difficult to detect. A reliable culture method is needed so that appropriate therapeutic decisions can be initiated in a timely fashion. Sonication of graft material has been proposed as a method of enhancing bacterial recovery. Theoretically. however. this could cause cell lysis and false-negative culture results. Several methods of obtaining bacterial cultures were compared to determine the best method of quantitative bacterial recovery from infected graft material. Polytetrafluoroetehylene (PTFE) and knitted Dacron graft segments (n = 192) were exposed to a slime-producing strain of S. epidermidis or Escherichia coli (E. coli) at four different bacterial concentrations. Recovery of bacteria from the segments was then compared using three different methods to obtain organisms. One-third of the segments were pressed directly onto the agar to transfer bacteria while the other two-thirds were placed in broth and then either sonicated or vortexed prior to plating onto agar. The direct technique was significantly less effective (P less than 0.01) at recovering bacteria than either sonicating or vortexing for both graft materials at bacterial concentrations of 10. 10(2). and 10(4) CFU/ml of S. epidermidis. Sonication was significantly better at recovery from either material at 10(2) and 10(4) CFU/ml of S. epidermidis than vortexing (P less than 0.05). E. coli graft adherence was poor. and significant recovery occurred only at 10(8) CFU/ml. Sonication is necessary to maximally recover S. epidermidis from infected prosthetic grafts.
Effect of desmopressin acetate on hemorrhage without identifiable cause in coronary bypass patients, After early hopeful reports. the ability of desmopressin acetate (DDAVP) to substantially reduce post surgical hemorrhage has been questioned. A total of 74 elective coronary bypass patients (Group A) receiving DDAVP (0.3 micrograms/kg) who. in the opinion of the operating surgeon. did not achieve adequate hemostasis after protamine neutralization of heparin were studied. They were compared with 91 age- and sex-matched controls (Group B). Before surgery there was no difference in hematocrit (40.8% vs. 40.3%); bleeding time (5.3 vs. 4.9 sec); platelet count (267 +/- 8 vs. 309 +/- 13 X 10(3)/mm3); fibrinogen (363 vs. 361 mg/dl); or activated clotting time (ACT) (168 +/- 4 vs. 163 +/- 3 sec). Both groups had the same number of grafts (3.3/pt). use of the mammary artery (72%). and average bypass time (124 min). There were also no differences in postbypass ACT (142 +/- 3 vs. 135 +/- 2 sec); platelet count (97 +/- 10 vs. 120 +/- 24 X 10(3)/mm3); and fibrinogen (157 +/- 35 vs. 207 +/- 40 mg/dl). However. postoperative hemorrhage was strikingly different: 1306 +/- 89 vs. 896 +/- 33 ml (P less than .0001). Fifteen patients in Group A bled more than 1.5 liters compared with 4 in Group B. Red cell transfusion rates were 1.23 +/- 0.26 for Group A and 0.35 +/- 0.8 for Group B (P less than 0.005). Sixteen Group A patients received additional blood products (plasma and platelets). The hemorrhage difference remained significant even when these patients were excluded (1098 +/- 57 vs. 896 +/- 34. P less than 0.003). Three Group A patients were re-explored without a bleeding source located.
Emboli in infective endocarditis: the prognostic value of echocardiography, OBJECTIVE: To determine whether vegetations visualized on two-dimensional echocardiography are an independent risk factor for the development of subsequent emboli in patients with infective endocarditis and to assess the timing of emboli relative to the initiation of antimicrobial therapy. DESIGN: Investigator-blinded. retrospective incidence cohort study. SETTING: Tertiary referral center. PATIENTS: Patients with left-sided native valve infective endocarditis who had two-dimensional echocardiography within 72 hours of beginning antimicrobial therapy. MEASUREMENTS AND MAIN RESULTS: The crude incidence rate of first embolic events in patients receiving antimicrobial therapy was 6.2 per 1000 patient-days (95% CI. 4.2 to 9.2). The rates in patients with and without vegetations were 7.1 and 4.9 per 1000 patient-days. respectively (incidence rate ratio. 1.4; 95% CI. 0.6 to 3.3). The relation between vegetations and risk for emboli was microorganism-dependent: Stratified incidence rate ratios were 6.9 (95% CI. 1.1 to 42.5; P less than 0.05) and 1.0 (95% CI. 0.2 to 3.9) for viridans streptococcal and Staphylococcus aureus endocarditis. respectively. The rate of first embolic events diminished over time (P less than 0.001). falling from 13 per 1000 patient-days during the first week of therapy to less than 1.2 per 1000 patient-days after completion of the second week of therapy. CONCLUSIONS: Overall. the presence of vegetations on echocardiography was not associated with a significantly higher risk for embolus in patients with left-sided native valve infective endocarditis. The relative risk for embolic events associated with echocardiographically visualized vegetations may be microorganism-dependent. with a significantly increased risk seen only in patients with viridans streptococcal infection. The rate of embolic events declines with time after initiation of antimicrobial treatment.
The changing prognosis of classic hemophilia (factor VIII "deficiency"), OBJECTIVE: To estimate relative risk of mortality and median life expectancy for patients with classic hemophilia by a life-table analysis. taking into account deaths that may have occurred in infancy or childhood before the onset of symptoms. DESIGN: Retrospective chart review of clinical series. SETTING: Referral-based university medical center. PATIENTS: Seven hundred one patients with classic hemophilia (hemophilia A; factor VIII "deficiency") were studied for the years from 1900 to 1990; patients were identified in 289 families. MEASUREMENTS AND MAIN RESULTS: Relative risk for mortality and median life expectancy among hemophiliacs were compared with those among normal U.S. males. Overall. mortality (relative to that of contemporaneous U.S. males) was increased about sixfold among severely affected patients. more than twofold among moderately affected patients. and was equivalent to that of U.S. males among mildly affected patients. Median life expectancy at 1 year of age had reached almost 68 years in the decade 1971 to 1980. but declined to only 49 years in the decade 1981 to 1990. CONCLUSIONS: After improvement in survival from 1971-1980 (corresponding to widespread treatment with lyophilized concentrates of antihemophilic factor [factor VIII]). relative mortality is now increasing. especially among severely affected patients. in large measure because of the acquired immunodeficiency syndrome (AIDS).
Comparison of silent and symptomatic ischemia during exercise testing in men, OBJECTIVE: To compare angina and ST-segment depression during exercise testing. as markers for coronary artery disease. DESIGN: Retrospective analysis of exercise test responses and cardiac catheterization results. SETTING: A U.S. Veterans Affairs medical center. PATIENTS: Four hundred and sixteen men who were referred for the evaluation of symptoms. postmyocardial infarction testing. or both. Two hundred patients had no clinical or electrocardiographic evidence of previous myocardial infarction. whereas 216 were survivors of a previous myocardial infarction. INTERVENTIONS: All patients did a standard exercise test and had diagnostic coronary angiography with ventriculography within an average of 32 days (range. 0 to 90 days) of their exercise test. RESULTS: Two hundred patients without a previous myocardial infarction were divided into four groups: the no ischemia group had 80 patients; the angina pectoris only group had 23 patients; the silent ischemia group had 40 patients; and the ST-segment depression and angina pectoris group had 57 patients. In patients without a previous myocardial infarction. exercise-induced ST-segment depression was a better marker than exercise-induced angina for the presence of any coronary artery disease (P less than 0.005). Patients with symptomatic exercise-induced ischemia had a higher prevalence of severe coronary artery disease than did those with only silent ischemia (30% compared with 20%; 95% CI. - 7.3% to 27.0%; P = 0.005). For the 216 survivors of a myocardial infarction. divided into the same four groups. ST-segment depression again was a better marker for the presence of severe coronary artery disease compared with angina alone (P = 0.08). The prevalence rates of severe coronary artery disease in the no ischemia plus myocardial infarction group. the angina pectoris only plus myocardial infarction group. the silent ischemia plus myocardial infarction group. and the ST-segment depression and angina pectoris plus myocardial infarction group were 10%. 9%. 23%. and 32%. respectively (P less than 0.01). CONCLUSIONS: Exercise-induced ST-segment depression is a better marker for coronary artery disease than is exercise-induced angina. Symptomatic ischemia during the exercise test is a better marker for severe coronary artery disease than is silent ischemia.
Psychological and behavioral implications of abnormal mammograms, OBJECTIVE: To evaluate women's psychological responses to abnormal mammograms and the effect on mammography adherence. To identify psychological responses and other factors that predict mammography adherence in women with normal or abnormal mammograms. DESIGN: Survey study with prospective analysis of factors associated with mammography adherence. SETTING: Health Maintenance Organization of Pennsylvania and New Jersey (HMO PA/NJ). PATIENTS: Study patients. members of HMO PA/NJ who were 50 years of age or older. and who had had mammography done 3 months earlier. included women with normal mammograms (n = 121). women with low-suspicion mammograms (n = 119). and women with high-suspicion mammograms (n = 68). but not women with breast cancer. MEASUREMENTS: Psychological responses 3 months after mammography and adherence to subsequent annual mammography were assessed. MAIN RESULTS: Women with high-suspicion mammograms had substantial mammography-related anxiety (47%) and worries about breast cancer (41%). Such worries affected the moods (26%) and daily functioning (17%) of these women. despite diagnostic evaluation excluding malignancy. For each variable. a consistent trend (P greater than 0.05) was seen with degree of mammogram abnormality. Sixty-eight percent of women with normal results. 78% of women with low-suspicion results. and 74% of women with high-suspicion results obtained their subsequent annual mammograms (P greater than 0.05). The number of previous mammograms (odds ratio. 3.2; 95% CI. 1.6 to 6.2) and the effect of the previous results on concerns about breast cancer (odds ratio. 0.5; CI. 0.2 to 1.0) were independent predictors of adherence in logistic regression analyses (P less than 0.05). CONCLUSIONS: A substantial proportion of women with suspicious mammograms have psychological difficulties. even after learning that they do not have cancer. Such sequelae do not appear to interfere with subsequent adherence.
Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention, OBJECTIVE: To review the available information about nitrate tolerance. its potential mechanisms. clinical implications. and strategies for prevention. DATA IDENTIFICATION: A survey of the National Library of Medicine MEDLINE database and bibliographies of the reviewed articles. STUDY SELECTION AND DATA EXTRACTION: Studies were selected from the English language literature with an emphasis on recent studies and. when available. randomized placebo-controlled studies. Old studies were selected on the basis of their historical value and originality. A total of 134 retrieved articles were considered relevant and were reviewed in depth. RESULTS: The available information about the experimental as well as the clinical evidence for tolerance to organic nitrates has been summarized. In addition. information related to potential mechanisms. clinical implications. and possible methods for prevention have been reviewed. CONCLUSIONS: Evidence indicates that prolonged in-vitro exposure to organic nitrates. continuous intravenous or topical administration of nitrates. and frequent in-vivo oral dosing result in the rapid development of tolerance to the peripheral as well as to the coronary vasodilatory effects of the drugs. This phenomenon leads to the rapid attenuation of the hemodynamic and anti-ischemic effects of nitrates in patients with ischemic heart disease or congestive heart failure. or both. Tolerance development seems to be dose- and time-dependent. and its main mechanism seems to be a depletion of sulfhydryl groups at the vascular cell. Although the repletion of sulfhydryl groups with the use of sulfhydryl-containing drugs may help to prevent tolerance. the efficacy and safety of this approach requires further evaluation. Intermittent therapy allowing a sufficiently long. daily nitrate-washout interval seems to be the most effective and the most safe strategy currently available for the prevention of nitrate tolerance.
NIH conference. Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection, An understanding of the immunopathogenic mechanisms of infection with human immunodeficiency virus (HIV) is fundamental in developing successful approaches to designing effective therapeutic and vaccine strategies. In this regard. we have investigated the mechanisms by which HIV inserts itself into the human immune system and uses the elaborate cytokine network to its own replicative advantage. We have also shown that the burden of HIV in CD4+ T cells is directly associated with a decline in this cell population in vivo and a progression to disease. Mononuclear phagocytes may play a role in the pathogenesis of HIV infection by serving as reservoirs of the virus. Of note is the fact that monocytes in the peripheral blood of HIV-infected individuals are rarely infected in vivo. whereas infected-tissue macrophages may play a role in organ-specific HIV-related pathogenesis. The role of HIV-specific humoral and cell-mediated immunity in HIV infection is not well understood. However. fine specificity of responses against HIV have been delineated in some in-vitro systems. It is unclear why these responses. particularly HIV-specific cytolytic T-cell responses. diminish over the course of infection and are unable to contain progression of infection.
Rehabilitation in spinal cord disorders. 1. Epidemiology, prevention, and system of care of spinal cord disorders, This self-directed learning module highlights current concepts of the epidemiology. prevention. and systematic treatment of spinal cord disorders. It is part of the chapter on rehabilitation of spinal cord disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This article contains information regarding the incidence. prevalence. and causes of spinal cord injury. methods of prevention. and the components of a comprehensive system of care for spinal cord injury.
Rehabilitation in spinal cord disorders. 4. Outcomes and issues of aging after spinal cord injury, This self-directed learning module highlights current concepts in outcomes and issues of aging in spinal cord injury. It is part of the chapter on rehabilitation in spinal cord disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This article includes discussion of the measurement of impairment. disability. and handicap. and outcomes with respect to employment. long-term adjustment. aging. life expectancy. and causes of death in spinal cord injury.
Rehabilitation in brain disorders. 1. Basic sciences, This learning module highlights the basic sciences of brain disorders and their relevance to the rehabilitation process. It is part of the chapter on rehabilitation in brain disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. The chapter is composed of four articles. and each builds on principles established in the others. This article contains essential information on the hierarchy and integration of cerebral neural processes. functional anatomy. and neurochemistry. It also highlights newer advances in brain plasticity and response to injury. at a cellular level and with reference to acute and secondary processes. which will likely be at the forefront of medical management and functional "damage control" in the near future. The learner is directed to articles 2. 3. and 4 in this chapter for supporting information.
Rehabilitation in brain disorders. 2. Clinical manifestations and medical issues, This self-directed learning module highlights advances in clinical manifestations of brain disorders. It is part of the chapter on rehabilitation in brain disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. This chapter is composed of four articles. and each builds on principles established in the others. This article covers medical complications. neurobehavioral aspects. and cognitive deficits seen in patients with brain disorders. specifically seizures. hydrocephalus. heterotopic ossification. and cardiovascular/pulmonary. neuroendocrine. gastrointestinal. genitourinary. communication. motoric. and visual/spatial/sensory disorders. Advances that are covered in this section are neuroendocrine complications. seizure prophylaxis. and coma treatment. The learner is directed to articles 1. 3. and 4 in this chapter for supporting information.
Rehabilitation in brain disorders. 3. Intervention strategies, This self-directed learning module highlights advances in the principles of management of brain disorders. It is part of the chapter on rehabilitation in brain disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. The chapter is composed of four articles. and each builds on principles established in the others. This article covers rehabilitation philosophy. management of cognitive remediation. and behavioral management. with attention to communication disorders. social factors. vocational/educational/avocational issues. treatment of motor deficits. dysphagia. sensory dysfunction. sexual dysfunction. and substance abuse. Advances that are covered in this section include pharmacologic and rehabilitative interventions for acute. chronic. and progressive brain injuries and diseases. The learner is directed to articles 1. 2. and 4 in this chapter for supporting information.
Rehabilitation in brain disorders. 4. Specific disorders, This self-directed learning module highlights important aspects of medical rehabilitation of patients with brain disorders. The specific disorders reviewed in this module are traumatic brain injury. stroke. multiple sclerosis. Parkinson's disease. and other degenerative disorders. This module is a section of the chapter on rehabilitation of brain disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. The chapter is composed of four articles. and each builds on principles established in the others. Emphasis is given in this section on key elements of current medical practice. including epidemiology. pathophysiology. prognosis. and outcome. Neurologic assessment and management is highlighted for coma. amnesia. cranial nerve and late intracranial complications. postacute management. and postconcussive syndromes. The learner is directed to articles 1. 2. and 3 in this chapter for supporting information.
Orbital decompression in Graves' disease. The predictability of reduction of proptosis, We studied 42 orbits of 23 patients with Graves' disease who had proptosis secondary to the orbitopathy of their disease and had undergone decompressive operations. The patients were evaluated preoperatively and underwent computed tomography. They were also examined frequently during the first postoperative year and the computed tomography was repeated at 6 months. Three variables correlated well with the reduction in proptosis: the percentage of increase in orbital volume after surgery. the absolute increase in orbital volume. and the degree of orbital "stiffness" as measured preoperatively. The first two variables have an inverse correlation with the third. We refer to the loss of resilience of orbital tissues and the increase in adherence between tissue planes. collectively. as orbital "stiffness." While other factors. such as the size of the anterior opening of the orbit. the resistance of the lid diaphragm. and pressure changes within the orbit. may affect the resultant reduction in proptosis. we did not attempt to measure these factors.
Enhanced ocular hypotensive response to epinephrine with prior dexamethasone treatment, In 12 patients with ocular hypertension and similar pressures in each eye. one eye was randomly selected in a masked manner for pretreatment with three applications of topical 0.01% dexamethasone sodium phosphate drops prepared in artificial tears. The other eye was treated with three applications of drops of artificial tears alone. Both eyes were then treated with 0.1% epinephrine hydrochloride drops. Ocular pressures were measured for the next 2 hours at 20-minute intervals. When compared with eyes treated with epinephrine drops alone. eyes pretreated with dexamethasone drops showed a significantly greater decrease in pressure (mean [+/- SD] maximum difference. 3.1 +/- 2.1 mm Hg). Five patients had a difference of 1.0 to 4.0 mm Hg and five patients had a difference of 4.0 to 6.0 mm Hg. Two patients showed no response. Younger age was associated with the greater response. Adrenergic-glucocorticoid synergism resulting in the lowering of ocular pressure may offer a potential for therapeutic use in ocular hypertension and glaucoma.
Quantitative descriptors of corneal topography. A clinical study, Quantitative descriptors of corneal topography determined by computerized algorithm and designed to augment the information derived from topographic maps were evaluated in a clinical study. The surface regularity index. a measure of central corneal optical quality. was highly correlated with best spectacle-corrected visual acuity (rho = 0.80. P less than .001). The relatively low correlation between the surface asymmetry index. a measure of central corneal asymmetry. and best spectacle-corrected visual acuity (rho = 0.62. P less than .005) suggests that corneal symmetry is a lesser but still important determinant of the optical performance of the anterior corneal surface. There was also a high correlation between factors determined from computer-generated orthogonal simulated keratometer values and clinical keratometry values (mean corneal power. total corneal cylinder. and the location of the steepest corneal meridian). The information derived from these algorithms has both clinical and research applications and can be incorporated into computer-assisted topographic analysis systems.
Association of HLA antigens with Vogt-Koyanagi-Harada syndrome in a Han Chinese population, Vogt-Koyanagi-Harada syndrome. or the uveomeningitis syndrome. is one of the most commonly identified types of endogenous uveitis diagnosed in China. Because its incidence is higher in Orientals than in whites. immunogenetic backround may be an important factor in its incidence. We performed HLA-A. -B. and -DR typing on 25 patients with Vogt-Koyanagi-Harada syndrome and on 65 healthy control subjects from the Han Chinese population. The results showed that HLA-DR4 and -Dw53 were closely associated with Vogt-Koyanagi-Harada syndrome (P less than .001 [relative risk = 16.0] and P less than .001 [relative risk = 34.2]. respectively). This association is similar to that reported in patients with Vogt-Koyanagi-Harada syndrome in Japan. suggesting that DR4 and DRw53 may play important roles in the development of Vogt-Koyanagi-Harada syndrome in Oriental populations.
Pupillary and electroretinographic abnormalities in a family with neuronal intranuclear hyaline inclusion disease, Abnormal pupillary function and a severely depressed electroretinogram were found in four members of a family with neuronal intranuclear hyaline inclusion disease. an idiopathic degenerative disorder that involves the central and peripheral nervous systems. Symptoms were limited to the gastrointestinal system and consisted principally of abdominal pain. constipation. and severe weight loss. The discovery of light-fixed pupils in the propositus led to the first antemortem diagnosis by rectal biopsy in two generations of this family. Abnormalities of gastrointestinal motility and pupillary reactions constituted the only objective evidence of autonomic dysfunction; the abnormal electroretinogram was the only evidence of central nervous system dysfunction.
Histologic features of human orbicularis oculi treated with botulinum A toxin, To evaluate muscle histologic features in humans following therapeutic botulinum toxin injections. we studied orbicularis oculi from 11 patients with blepharospasm; nine had previously received botulinum toxin injections and two had not. All muscles had comparable variability in muscle fiber diameter. with no necrosis. inflammation. denervation. or consistent alterations in muscle fiber internal architecture. Botulinum toxin produces no persistent histologic changes in human muscle fibers.
Botulinum-induced changes in monkey eyelid muscle. Comparison with changes seen in extraocular muscle, Botulin type A was injected into the eyelids of adult monkeys. and structural alterations in the orbicularis oculi muscle were evaluated after survival times of 7 to 84 days. The most profound change seen at both the light- and electron-microscopic levels was nonselective atrophy of virtually all muscle fibers. Moreover. the botulin-induced blockade of neuromuscular transmission was nonspecific in producing alterations in the three orbicularis fiber types. Muscle structural changes appeared to be reversible. with no apparent long-term consequences. While sprouting of preterminal axons was noted in botulin-treated muscle. formation of collateral sprouts did not appear to be widespread. These changes contrast with the fiber type-specific. long-term alterations induced in extraocular muscle by botulin treatment. However. this differential response may be attributed to the very clear differences in fiber type composition and motor control mechanisms between eyelid and extraocular muscle groups. The efficacy of botulin treatments for strabismus and focal dystonia may then be directly related to both the anatomic fiber type composition and the functional properties of motor control systems of the injected muscle.
Inhibition of intraocular fibrin formation following infusion of low-molecular-weight heparin during vitrectomy, We studied the inhibition of intraocular fibrin formation following infusion of 5 IU/mL of low-molecular-weight heparin sodium (Fragmin. KabiVitrum AB. Stockholm. Sweden) during lensectomy. vitrectomy. and retinotomy in the rabbit model. Surgery was performed on 18 eyes. with nine receiving low-molecular-weight heparin and nine serving as controls. Masked postoperative examinations assessed fibrin quantity. corneal clarity. media clarity. and amount of vitreous hemorrhage. Five (56%) of nine eyes receiving low-molecular-weight heparin did not show fibrin exudation development. with the remainder demonstrating a minimal fibrin response. Eight (89%) of nine control eyes demonstrated prominent fibrin exudation. with five (56%) showing development of a fibrin clot that obscured two or more quadrants of the posterior chamber. No significant difference in the degree of vitreous hemorrhage was noted between groups. Corneal clarity was improved in the heparin-treated group.
Synthesis of platelet activating factor by ocular tissue from inflamed eyes, Platelet activating factors (PAFs) are a family of ether lipids with properties that suggest a major role in inflammation. We have previously implicated PAFs in ocular inflammation based on the inhibition of several rabbit models of iritis with a specific PAF receptor antagonist. We have tested ocular tissues for the ability to synthesize PAF. Iris. ciliary body. cornea. and/or retina were carefully dissected from New Zealand white rabbits. and tissue from four eyes was pooled. Tissues were stimulated with calcium ionophore (10 mumol/L). and supernatants were extracted with chloroform-methanol. Platelet-aggregating activity was found in the chloroform phase in 2 of 9. 1 of 8. 0 of 9. and 3 of 9 studies involving iris. retina. ciliary body. or cornea. respectively. Twenty-four hours after the intravitreal injection of 125 ng of endotoxin. aggregating activity was consistently detectable from supernatants of stimulated iris and ciliary body. occasionally present from stimulated retina but not detectable from cornea. The shape of the aggregation curve resembled that produced by 0.5 to 2.0 ng of authentic PAF. Moreover. the aggregation could be completely inhibited by a PAF receptor antagonist and the aggregating activity chromatographed identically on high-performance liquid chromatography to a PAF standard. These studies indicate that PAF-like activity could be detected from several ocular tissues subsequent to inflammation. Iris. ciliary body. retina. vascular endothelium. and/or leukocytes could each contribute to the presence of this inflammatory mediator.
Is basal laminar deposit unique for age-related macular degeneration, The ultrastructural nature and distribution of basal laminar deposit. considered to be a precursor of age-related macular degeneration. were studied in 42 human maculae. Basal laminar deposit was found from age 19 years on. not only between the retinal pigment epithelial cells and their basement membrane but also more often on the choriocapillary side of Bruch's membrane. No direct relationship was found with other aging changes. such as calcifications in Bruch's membrane. accumulation of lipofuscin granules. or drusen in the macular area. Material similar to basal laminar deposit can be found in the trabecular system. in the cornea. and also in many other organs and tissues. On a structural and morphometrical basis. we think that basal laminar deposit is similar to fibrous long-spacing collagen and thus does not seem to be a purely ocular abnormality.
Surgical correction of lower-eyelid tarsal ectropion by reinsertion of the retractors, Lower-eyelid tarsal ectropion is an unusual form of eyelid malposition in which the entire lid is everted. The cause is most likely the disinsertion of the lower-eyelid retractors. In 12 eyelids of six patients. a transconjunctival approach was used to reunite the retractors with the inferior tarsal border. In eight eyelids. a horizontal tightening procedure was also needed. The looping passage of fornix sutures through the full thickness of the eyelid created a vector force that helped rotate the lid margin inward. The subsequent formation of an inflammatory cicatrix induced by the absorbable sutures also contributed to maintain the lid in an upright posture. During follow-up periods ranging from 8 to 36 months. there were no instances of overinversion. recurrent ectropion. or suture abscess.
In vitro regulation of B cell differentiation by interleukin-6 and soluble CD23 in systemic lupus erythematosus B cell subpopulations and antigen-induced normal B cells, Polyreactive systemic lupus erythematosus (SLE) B cells were compared with antigen-induced SLE and normal B cells for their interleukin-6 (IL-6) and soluble CD23 requirements. Unlike normal B cells. secretion of antibody by SLE B cells in serum-free medium was not enhanced by exogenous IL-6. Anti-IL-6 antibodies inhibited immunoglobulin production in cultures of normal and SLE B cells. which suggests that IL-6 is required for B cell differentiation. SLE culture supernatants had elevated levels of IL-6. which explains the poor response of the SLE cells to exogenous IL-6. Soluble CD23 enhanced the responses of cells from normal subjects and SLE patients.
Amelioration of lapine osteoarthritis by treatment with glycosaminoglycan-peptide association complex (Rumalon), The chondroprotective potential of glycosaminoglycan-peptide association complex (GP-C) was examined in the medial meniscectomy model of lapine osteoarthritis (OA). Prophylactic treatment with increasing doses of intramuscular GP-C (0.05-0.5 ml/kg) caused a significant reduction in OA lesion area and histologic scores. and the effect on disease activity appeared to be dose related. The DNA and uronic acid contents of OA tissue were unaffected by prophylactic treatment with GP-C. However. levels of hydroxyproline in OA cartilage increased to near control levels with prophylactic treatment. Cartilage levels of active and total metalloproteinases that digest proteoglycans were elevated in rabbits with OA; prophylactic treatment with low-dose GP-C (0.05 ml/kg) produced a significant reduction in active. but not total. enzyme. Cartilage levels of tissue inhibitor of metalloproteinases in animals with OA were comparable with control levels. but rose with increasing doses of GP-C. We also investigated GP-C as a therapeutic treatment in animals that had already developed OA lesions. Carbon black retention and histologic score returned to near-normal after therapeutic treatment with GP-C. Uronic acid and hydroxyproline levels were decreased in OA cartilage. Therapeutic treatment with GP-C had no statistically significant effect on uronic acid levels. but was associated with increased hydroxyproline content in the cartilage. The changes in metalloproteinase and metalloproteinase inhibitor were similar to those found in the studies of prophylactic treatment. The findings in this animal model may help explain some of the beneficial effects of GP-C in human OA.
A double-blind randomized controlled trial of ketotifen versus placebo in early diffuse scleroderma, To determine the efficacy of the mast cell-stabilizing drug ketotifen in scleroderma. we conducted a 6-month. randomized. prospective. double-blind. placebo-controlled trial in 24 patients. No significant improvement in the clinical parameters. pulmonary function. global assessments. and mast cell releasability was noted. Pruritus tended to improve in the group taking the active drug. Six months of treatment with ketotifen (6 mg/day). therefore. produced no apparent benefit in patients with early scleroderma. We were unable to address the role of mast cells in scleroderma since mast cell suppression was not achieved.
Diagnosis of recent myocardial infarction with quantitative backscatter imaging: preliminary studies, Acute myocardial ischemia and chronic myocardial infarction may be recognized with ultrasound tissue characterization techniques because of myocardial acoustic changes caused by reduced perfusion and/or collagen deposition. Our purpose was to study the acoustic properties of recent myocardial infarction when the predominating pathologic finding was myocardial edema and leukocytic infiltration. We used a new quantitative backscatter imaging system to study 18 patients 9 +/- 5 days after myocardial infarction (eight patients with anteroseptal myocardial infarction and 10 with inferior myocardial infarction) and 20 normal subjects. The cyclic variation of relative integrated backscatter (end-diastolic minus end-systolic) was calculated from on-line measurements. Standard parasternal long- and short-axis and apical four- and two-chamber views were obtained. In the anteroseptal myocardial infarction group. the cyclic variation of relative integrated backscatter was lower in the septum (1.5 +/- 1.6 dB) than in the posteroinferior wall (3.2 +/- 1.2 dB); however. the sample size of only three patients (of eight patients imaged) in the latter group prevented statistical comparison. The cyclic variation of relative integrated backscatter in the infarcted septum was less than the measurement obtained in the septum of the control group (4.3 +/- 2.4 dB. p less than 0.05). In the inferior infarction group. the cyclic variation of integrated backscatter in the posteroinferior wall (1.8 +/- 1.7 dB) was not significantly different from the measurement obtained in the septum (3.7 +/- 3.6 dB); however. the cyclic variation in the posteroinferior wall was significantly less than that obtained in the control group posteroinferior wall (5.7 +/- 1.7 dB. p less than 0.05).
Plaque and structural characteristics of the descending thoracic aorta using transesophageal echocardiography, The in vivo acoustic and structural characteristics of atherosclerosis in the descending thoracic aorta have not been well delineated. We prospectively evaluated the descending thoracic aorta of 147 patients (35 women and 112 men; age. 61 +/- 14 years) who underwent clinically indicated transesophageal echocardiography. Patients with suspected disease of the aorta were excluded. Thirty-eight patients (26%) had protruding plaques (men. 25%; women. 29%). Six patients had mobile intimal densities with the mobile area ranging up to 1 cm2. As expected. aortic lumen area was decreased (plaque-free. 3.53 cm2; plaque. 3.19 cm2; p less than 0.05) and wall area was increased (plaque-free. 1.51 cm2; plaque. 1.92 cm2; p less than 0.05) in the regions of the plaque. However. total arterial area was not increased (plaque-free. 5.04 cm2; plaque. 5.09 cm2; difference not significant) in a compensatory manner as observed in other arterial beds. Plaque gray scale was less than the gray scale of plaque-free wall (plaque-free. 141.2; plaque. 122.7; p less than 0.05) when compared at the same level of the descending thoracic aorta or with a second aortic plaque-free level (plaque-free. 150.4; plaque. 122.7; p less than 0.05). Standard deviation of gray scale level was similar between plaque and normal regions. Unsuspected protruding plaques in the descending thoracic aorta occurred in one quarter of the patients referred for routine transesophageal examination. Plaques tended to have lower echogenicity and were differentiated from plaque-free walls within patients. Plaque formation did not result in increased total arterial area. These data suggest that the degree or character of compensatory atherosclerotic remodeling in the highly elastic descending thoracic aorta may differ from other arterial beds.
Doppler echocardiographic assessment of changes in pulmonary artery pressure associated with vasodilating therapy in patients with congestive heart failure, Transpulmonic pressure gradient and pulmonary artery pressures can be estimated from the Doppler pulmonary regurgitant flow velocities by applying the simplified Bernoulli equation. In this study. continuous-wave Doppler echocardiography was used to assess changes in pulmonary regurgitant flow velocities associated with administration of vasodilators in 10 patients with congestive heart failure. M-Mode echocardiographic parameters such as left ventricular end-systolic and end-diastolic dimension and fractional shortening did not change with administration of vasodilators. Pulmonary regurgitant flow velocity at end diastole decreased from 1.9 +/- 0.6 to 1.3 +/- 0.3 m/sec (p less than 0.01). and Doppler-estimated transpulmonic pressure gradient at end diastole decreased from 16 +/- 11 to 8 +/- 4 mm Hg (p less than 0.01). Doppler-estimated transpulmonic pressure gradient at end diastole was compared with catheterization-determined pulmonary arterial end-diastolic pressure before and after administration of vasodilators in three patients. and there was a good agreement between these measurements. Thus noninvasive and sensitive assessment of the effect of vasodilators on pulmonary arterial end-diastolic pressure in patients with congestive heart failure is possible with continuous-wave Doppler echocardiographic measurement of pulmonary regurgitant flow velocities.
Transesophageal echocardiography in pediatric patients: preliminary results, Transesophageal echocardiography was attempted in 59 pediatric patients with congenital heart disease in the operating room (n = 33) or during heart catheterization or in the intensive care unit (n = 26). Six different commercially available transducers were used with diameters ranging from 7 to 15 mm. Age ranged from 1 day to 16 years. and body weight ranged from 3.7 to 65 kg. Objectives of the study were to determine (1) minimum body weight in which transesophageal echocardiography with various probes is possible. (2) additional diagnostic value. and (3) potential applications. In three cases (one surgical and two nonsurgical) the probe could not be inserted. Minimum body weight was 17 to 20 kg for probes with a diameter of greater than or equal to 13 mm and approximately 12 kg for the 11 mm probes. A 7 mm probe. on the other hand. could be inserted easily in all patients (including a neonate) in whom transesophageal echocardiography was attempted. In 11 of 56 patients. additional diagnostic information was obtained. Thus. transesophageal echocardiography is feasible in the pediatric age group provided that special probes are used in small children. Additional diagnostic information can be obtained. and the technique is of value during cardiac surgery or balloon interventions for evaluation of the efficacy of the procedure and for monitoring ventricular function.
Value and limitations of proximal jet dimensions for the quantitation of valvular regurgitation: an in vitro study using Doppler flow imaging, To evaluate usefulness and limitations of proximal jet dimensions for the quantitation of valvular regurgitation. fluid jets were created in a pulsatile flow model. and proximal jet width and cross-sectional area were measured by means of color Doppler flow imaging. When circular orifices with diameters from 1 to 6 mm were studied. jet width and cross-sectional jet area measured as close as possible to the orifice were directly related to the orifice diameter (r = 0.97; standard error of the estimate. 0.4 mm; y = 0.5 + 0.97x) and the orifice area (r = 0.97; standard error of the estimate. 5.7 mm2; y = 0.22 + 2.47x). respectively. No significant dependence on flow rate or pressure gradient was found for these measurements. Jet width was measured with color M-mode Doppler by use of the smallest sample volume size (1 mm) and was slightly greater than the orifice diameter (4.2 +/- 1.7 mm versus 3.8 +/- 1.7 mm). However. cross-sectional areas were approximately fourfold the orifice areas. on average (52.5 +/- 24.6 mm2 versus 12.3 +/- 9.7 mm2). with a range of twelvefold (smallest orifice) to threefold (largest orifice). When the sample volume size was reduced from 2.4 to 1.0 mm. color areas decreased by 25.6 +/- 6.0%. Slit-shaped orifices were studied with two different orientations of the slit-parallel and perpendicular to the ultrasound beam: Color M-mode measurements were again slightly greater than length and width of the slit. but cross-sectional areas were substantially larger than the orifice areas and increased between 44% and 115% when changing the orientation of the slit from perpendicular to parallel. This. again. reflected problems with lateral resolution. When cross-sectional areas were measured at increasing distances from the orifice. the cross-sectional jet area increased significantly within a few millimeters. This increase was greater with higher gradients and smaller orifice sizes. In case of a small orifice (2 mm) and a high gradient (130 to 160 mm Hg). increase in area was as great as 122% within a distance of only 5 mm. Thus. proximal jet width and cross-sectional area were directly related to the orifice size. which could be a valuable parameter for the evaluation of valvular regurgitation. Measurements of jet width by color M-mode seemed to be most accurate but are limited by the fact that in vivo valvular defects may be irregular rather than of circular shape.(ABSTRACT TRUNCATED AT 400 WORDS).
Quadricuspid aortic valve and aortic regurgitation diagnosed by Doppler echocardiography: report of two cases and review of the literature, Two cases of patients with quadricuspid aortic valve diagnosed by Doppler echocardiography are presented. Aortic regurgitation was detected by pulsed Doppler echocardiography in both patients. Because they were young patients. this aortic regurgitation indicated that aortic regurgitation is not necessarily a late-developing event. as has been thought previously.
Detection and evaluation of intrapulmonary vascular shunt with "contrast Doppler" transesophageal echocardiography, Contrast echocardiography is useful for detecting intrapulmonary right-to-left shunt lesions. In a patient with suspected pulmonary arteriovenous fistula. contrast transesophageal echocardiography was used to demonstrate the presence of a right-to-left shunt. By use of a combination of two-dimensional echocardiography. contrast injection. and pulsed Doppler echocardiography. each pulmonary vein was successfully interrogated for evidence of contrast shunting. This case demonstrates that contrast transesophageal echocardiography is useful for the detection of intrapulmonary fistulas and that it has the potential for localization of the shunt lesion.
Inositol metabolism in mononuclear leucocytes from patients with atopic dermatitis, Elevated activity of cyclic adenosine monophosphate-specific phosphodiesterase (PDE) has been previously documented in the peripheral blood mononuclear leucocytes (MNLs) of patients with atopic dermatitis (AD). Because of the potential interactions of the cyclic nucleotide and inositol secondary messenger systems we sought to determine whether differences exist in the inositol uptake and metabolism between atopic and normal MNLs. We found no difference in the uptake of tritiated inositol by MNL between 19 atopic patients and 16 non-atopic control subjects. However. after stimulation of MNLs by concanavalin A. there was a significantly greater metabolism of inositol to inositol-1-phosphate (IP1) in the controls compared to the atopic MNLs; the mean percentage rise in the IP1 fraction over baseline level was 40% in the atopics. but almost 200% in controls after 2 h. Diminished inositol metabolism in atopic MNLs may explain the reduced cell-mediated immunity that characterizes the atopic state.
The mitogenic effects of sera from psoriatic subjects on normal dermal fibroblasts: an absence of correlation with the clinical activity of psoriasis, Serum was obtained from 21 normal and 22 psoriatic subjects. and the severity of skin disease in the psoriatic patients was recorded using the PASI score. The scores ranged from 1.8 to 51.0. The growth stimulatory effect of the sera on normal dermal fibroblasts in cell culture was assessed by measuring [3H]-thymidine uptake. Each serum was assessed at four concentrations (2.5. 10.20%). The psoriatic sera were more growth stimulatory than normal sera. but this difference was statistically significant (P less than 0.02) only at 20% serum concentration. Eleven of the 22 psoriatic serum samples had a mitogenic effect greater than the mean +/- SEM of all the normal sera; these sera were then from patients with PASI scores of 4.5-51.0. Six of these psoriatic subjects were recalled after 5 months; their PASI scores were reassessed. and the mitogenic effect of new serum samples was compared with that of the initial samples. All of these patients displayed a change in serum mitogenic effect. but this was not consistent with the change in severity of skin disease over the corresponding time period. In one subject. the severity of the psoriasis had increased marginally over the 5 months. while the mitogenic effect of her serum decreased significantly (mean counts of 43808 vs. 32660; P = 0.0029).
Glomus tumours of the skin: an immunohistochemical investigation of the expression of marker proteins, Immunohistochemical studies were carried out on cutaneous glomus tumours from 10 patients. The glomus areas in these tumours reacted strongly with anti-smooth muscle (CGA-7). anti-muscle (HHF-35) and anti-vimentin antibodies. Their neural supply was analysed using several nervous tissue markers (anti-neurone specific enolase. anti-S 100. anti-Leu 7. anti-neurofilaments). The results indicate a sprouting and proliferation rather than entrapment of pre-existing nerve fibres.
Photoelectric quantitative evaluation of argon laser treatment of port wine stains, Sixty patients with port wine stains were treated with the argon laser and graded visually into four subjective categories for changes in skin colour. For objective quantitative evaluation a photoelectric colorimeter was used. Reproducible definition of the lightness of the lesions into numbers was obtained. Differentials in lightness between normal contralateral skin and the port wine stain before and after treatment were quantified for each individual. The objective evaluation revealed a statistically significant difference between the four categories (P less than 0.05). The best clinical therapeutic effect was found to correlate with only 80-90% blanching. The average lightening obtained was 46.5%. Local heating of port wine stains in 12 patients showed no measurable darkening in the colour of the lesions. whereas the normal contralateral skin reacted with marked reddening. Determination of changes in lightness by photoelectric colorimetry provides an objective. quantitative means to evaluate the effects of laser treatment of port wine stains.
Autosomal dominant ichthyosis exfoliativa, An unusual ichthyosiform dermatosis with circumscribed areas of blistering hyperkeratoses as well as scaly areas was observed in five consecutive generations of a German family. Light and electron microscopical studies revealed oedema of the keratinocytes in the upper epidermis but no defects of tonofilaments and keratohyalin granules. We suggest that this type of ichthyosis exfoliativa inherited as an autosomal dominant trait represents a new and distinct entity.
Congenital and maternal cytomegalovirus infections in a London population, OBJECTIVE--To determine if women at risk of having babies infected with cytomegalovirus (CMV) can be identified antenatally. DESIGN--Prospective serological and demographic study of pregnant women and virological study of their newborn infants. SETTING--Teaching hospital in London. SUBJECTS--3315 pregnant women and 2737 of their babies. MAIN OUTCOME MEASURES--Quantitative detection of CMV IgG antibodies; qualitative detection of CMV IgM antibodies; demographic characteristics of mothers; qualitative and quantitative titration of CMV viruria in newborn. RESULTS--Congenital CMV infection was found in nine newborn babies (0.33%) two of whom had symptoms. Serological testing of the nine mothers showed four primary and five recurrent infections; both of the symptomatic children were born in the latter group. Testing for CMV specific IgM antibodies or quantitation of IgG antibodies in early pregnancy sera could not differentiate those women at risk of giving birth to babies infected or damaged by CMV from the rest of the population. Quantitation of viruria confirmed that those babies most at risk of CMV disease have the highest titres of CMV. CONCLUSIONS--(i) Since laboratory tests in pregnant women cannot reliably identify fetuses at risk of disease. screening for asymptomatic maternal infection coupled with termination of pregnancy cannot be recommended. (ii) Since 'immune' women can still give birth to babies affected by CMV. we propose that future CMV vaccines should be used to immunize children with the aim of eradicating CMV infection in preference to selective immunization of sero-susceptible females.
Early postoperative mortality following hysterectomy. A Danish population based study, 1977-1981, The main objective of this cohort study was to analyse the early postoperative mortality after 'simple' hysterectomy for benign indications and to compare it with that of a randomly selected reference group of women matched for age. Registry data covering the entire Danish female population were used. Included in the study were all patients operated in the period 1977-1981. Patients were only included if no cancer was diagnosed and if no major co-surgery was performed (29.192 patients). Cancer patients were also excluded in the reference group (16.182 women). Mortality was studied according to characteristics of patients. their residential area. the surgical approach and operating hospital. Overall 47 patients died within 30 days of admission for hysterectomy (overall mortality 16.1 per 10.000). Only seven deaths were expected on the basis of the population sample. and adjusted for age. the relative risk (RR) for hysterectomy patients was 6.38 (95% CI 4.33-9.39). Early postoperative mortality increased with age. and the risk was elevated among emergency patients (RR = 3.22; 1.72-6.04). Patients with more than one diagnosis at discharge (RR = 4.53; 2.12-9.70) were at high risk. but early postoperative mortality was independent of surgical approach. Causes of death are discussed. Compared to the general population. patients who undergo 'simple' hysterectomy are faced with a sixfold risk of dying within 30 days. but a complete assessment of the risks and benefits of hysterectomy requires prospective studies of survival and morbidity. including quality of life for longer periods of time following operations.
Peritoneal fluid volume and sex steroids in the pre-ovulatory period in mild endometriosis, Twenty infertile women with laparoscopically confirmed mild endometriosis and ten women with tubal infertility underwent diagnostic laparoscopy 32 h after the onset of the endogenous luteinizing hormone (LH) surge during a spontaneous menstrual cycle. All visible peritoneal fluid was aspirated for assessment of volume and sex steroid content. There was no significant difference in peritoneal fluid volume or concentrations of oestradiol. progesterone and androstenedione between the two groups. Furthermore. in the endometriosis group there was no significant difference in peritoneal fluid volume and concentrations of sex steroids between those women who had been treated previously with danazol and those who were left untreated.
Increase in incidence of disease due to diagnostic drift: primary liver cancer in Denmark, 1943-85, OBJECTIVE--To examine the extent to which changes in diagnostic methods and classification are responsible for the striking increase in incidence of primary liver cancer in Denmark since 1943. DESIGN--Analysis of the time trends in sex specific. age standardised incidence of primary liver cancer and unspecified liver cancer (either secondary without known primary cancer or not specified as primary cancer) in the entire population from 1943 to 1985. By review of the 727 notifications from three periods of 5 years (1948-52. 1963-7. and 1978-82) the changes in histological diagnosis and classification were assessed. SETTING--Denmark. SUBJECTS--Notifications of liver cancer to the Danish cancer registry. RESULTS--Concomitant with the increase in primary liver cancer. the incidence of the unspecified liver cancer declined. The proportion of histologically diagnosed primary liver cancer rose from 85% to 98%. whereas the proportion for unspecified liver cancer rose from 12% to 51%. When the proportion of primary versus unspecified liver cancer obtained by histological diagnosis was extrapolated to all cases. the annual incidence of primary liver cancer was 4.4 rather than 1.6 per 100.000 population in 1948-52 and 6.0 rather than 5.5 per 100.000 in 1978-82. CONCLUSION--The increase in the incidence of primary liver cancer may be much smaller than the numbers of registered cases indicate. This example emphasises the need to consider diagnostic drift in time trend studies of disease incidence.
Management of childhood diarrhoea by pharmacists and parents: is Britain lagging behind the Third World?, OBJECTIVE--To investigate the role of community pharmacists in providing advice and treatment for children with diarrhoea; to investigate mothers' responses to diarrhoea in their children. DESIGN--Cross sectional questionnaire study of a random selection of community pharmacists and of mothers attending child health clinics. Pharmacists were interviewed and given a questionnaire and a separate group was visited by a researcher posing as a parent; mothers were interviewed at the clinic. SETTING--Newcastle upon Tyne. SUBJECTS--20 pharmacists were interviewed and visits by a researcher posing as a parent were carried out to 10 different pharmacists; 58 mothers were interviewed. MAIN OUTCOME MEASURES--Advice given by pharmacists was contrasted with standard advice on management of diarrhoea in children. RESULTS--Half of the pharmacists interviewed and 70% of pharmacists visited by a researcher posing as a parent recommended inappropriate treatment of childhood diarrhoea (such as antidiarrhoeal drugs and withholding breast milk). and only 30% at interview stated that they would ask for the age of the child. Mothers' knowledge of home treatment was inadequate. All pharmacists in the posed visits recommended a purchased treatment. CONCLUSION--Pharmacists are widely used by parents for consultation for children's ailments but their advice is not always appropriate; hence they should be given more consistent training in recognising and managing clinical problems. Medical advice on management of diarrhoea is also inconsistent and should be modified to conform to the guidelines of the World Health Organisation.
Incidence of insulin dependent diabetes in children aged under 15 years in the British Isles during 1988, OBJECTIVE--To ascertain the annual incidence rate of insulin dependent diabetes diagnosed in children under the age of 15 years in the British Isles during 1988. and to compare the results with an earlier study carried out in 1973-4. DESIGN--Active monthly reporting of cases by consultant paediatricians. with additional input from diabetologists and all specialist diabetes nurses and health visitors. SETTING--British Isles (England. Wales. Scotland. Northern Ireland. Republic of Ireland) with a total population at risk of 11.819.000 children. PATIENTS--All children diagnosed under the age of 15 years with primary insulin dependent diabetes from 1 January to 31 December 1988 and resident in the British Isles at diagnosis. MAIN OUTCOME MEASURES--National incidence rate of insulin dependent diabetes; differences in incidence rates between regions and between three age groups: 4 and under. 5-9. and 10-14 year olds. RESULTS--1600 children (837 boys and 763 girls) had a confirmed diagnosis of insulin dependent diabetes. giving a national incidence rate of 13.5/100.000/year (95% confidence interval 12.9 to 14.2/100.000/year). This was considerably higher than the incidence rate of 7.7/100.000/year in children under the age of 16 years reported in the British Diabetic Association's study of 1973-4. The age-sex adjusted rates varied between regions. ranging from 6.8/100.000/year (Republic of Ireland) to 19.8/100.000/year (Scotland). There were considerable differences in the numbers of cases diagnosed each month. with the 10-14 year age group showing the most seasonal variation. A quarter of the children (404/1600) were under 5 years old. Case ascertainment was estimated as 90%. CONCLUSIONS--Insulin dependent diabetes in the British Isles does not seem to occur uniformly over time or geographical area. Even allowing for differences in ascertainment between the 1973-4 and 1988 studies. there seems to have been an increase in the incidence rate of insulin dependent diabetes in children under the age of 15 years during the 15 year time period. If diabetes is becoming more common in this age group. possibly by developing earlier in susceptible children. this would be a matter of considerable public health concern.
Audit of diabetes in general practice, OBJECTIVES--To complete a first audit cycle of diabetes care in a general practice and to develop a simple method for continuing the audit cycle. DESIGN--Retrospective examination of the medical records of all diabetic patients in a general practice in 1990. SETTING--A group general practice in a Bristol health centre with roughly 13.200 patients. which since 1983 had had a protocol for care of its diabetic patients. PATIENTS--223 known diabetic patients in the practice. MAIN AUDITED MEASURES--Comparison against previously agreed standards of process and outcome of diabetes care in the practice. including number of patients whose care had been reviewed in accordance with the practice protocol. serum fructosamine and blood glucose concentrations in patients aged under 70. and number of newly diagnosed patients given explicit education and referred for diatetic advice. RESULTS--Defined standards were not met for several criteria--for example. percentages of patients aged below 70 (n = 149) with serum fructosamine concentrations less than 3.5 mmol/l (62% v 90% defined value) and less than 2.8 mmol/l (35% v 70%) and last recorded blood glucose concentrations less than 10 mmol/l in insulin dependent patients (n = 48) (23% v 90%) and less than 8 mmol/l in non-insulin dependent patients (n = 101) (17% v 90%). Of newly identified diabetic patients (n = 32). 59% and 28% respectively were referred to dietitians and given educational material compared with the 100% standard. CONCLUSIONS--The practice has a high prevalence of diabetes (1.7%) but has the resources for their care. The format and implementation of the agreed systematic process of care for diabetic patients needs improvement. IMPLICATIONS--A simple audit suitable for most general practices might record two measures of the process of care--a disease register of all diabetic patients in a practice and an attendance register to determine whether they have regular check ups--and one measure of the outcome of care. such as serum fructosamine concentration (or local equivalent). A practice could establish its own standards for these measures and monitor its performance against them.
Sonographic detection of foreign bodies of the extremities, A prospective study to assess the accuracy of ultrasound in the detection and localization of foreign bodies of the extremities was undertaken. Forty-five patients with clinical suspicion of foreign bodies were included in the study. Among 20 patients with radio-opaque foreign bodies. ultrasonic detection of foreign bodies was achieved in 19 patients. In 25 patients. with no radiographic evidence of foreign body. ultrasonic detection of foreign bodies was made in seven patients and among these foreign bodies were confirmed and removed at surgery in five patients. Accurate pre-operative ultrasonic localization of foreign bodies was carried out in three patients.
Barium meals in the elderly--a quality reassurance, The consecutive double contrast barium meal examinations of 100 elderly patients (aged over 65 years) and a group of 33 younger adult patients were analysed by two observers for technical quality and pathological abnormalities. Technical quality declined with patient age. especially in those over 75 years. but was sufficient to enable diagnosis of abnormalities in 60% of the elderly group. It is concluded that. in the majority of elderly patients. the technical quality of double contrast barium meal examinations is sufficiently high to offer considerable diagnostic utility.
A new phantom for mammography, A new mammography phantom from Du Pont is described. It has a wider range of types of detail than in previous phantoms. including some which closely simulate breast tissues. Experience of its use. and comparisons with an earlier ("Barts") phantom. are reported. The Du Pont phantom appears to have greater sensitivity to changes in tube kV and focal spot size. and better discrimination between different film-screen combinations and between films from different breast screening centres.
Carcinoma of the breast: measurement and the management of treatment. II. The regression of tumours, Regression slopes fitted in 238 new cases of primary breast cancer submitted to a variety of managements are analysed. Contrary to the original hypothesis that slopes would primarily reflect the composition of the tumours. the steepness of resorption slopes is found also to be treatment dependent. Investigation of other factors influencing slopes is confined to radiotherapy where the expectation that the prescribed dose will be delivered is high. A large cumulative radiation effect before the start of shrinkage is associated with steeper slopes. A small correlation between slope and both menopausal status and starting diameter has been found. with premenopausal patients and small tumours producing the steepest slopes. The full range of slopes has been seen in postmenopausal patients. The data has been fitted to a linear model to evaluate the relative importance of these associations. Illustrative cases support the hypothesis that resorption slopes are a product of tumour architecture and histology but we conclude that the maximum possible steepness of slope is not always achieved in the clinic. even when radiation is used. A combination of histological and regression data is therefore required to characterize a tumour for predictive purposes.
Fractionated high dose rate versus low dose rate regimens for intracavitary brachytherapy of the cervix. I. General considerations based on radiobiology, Intracavitary brachytherapy at low dose rate (LDR). often with the addition of external-beam radiotherapy. has long been considered the treatment of choice for carcinoma of the cervix. maximizing acute damage in the treatment volume. whilst minimizing late effects. In recent years. primarily for reasons of convenience and cost. there has been a move towards treatments involving a few fractions at high dose rate (HDR). Using data from cells of human origin cultured in vitro. we make estimates of the doses that. delivered in 2-12 HDR fractions. produce tumour control and early effects equivalent to intracavitary treatments at LDR. We also show that. for situations where the normal-tissue dose responsible for late effects is significantly smaller than the tumour dose. HDR schemes may be devised which. while yielding early killing comparable with that of LDR. should not result in worse late effects. We suggest that this scenario probably applies to treatment of carcinoma of the cervix.
Observation of cerebrospinal fluid flow with echo-planar magnetic resonance imaging, Using echo-planar (EP) magnetic resonance imaging (MRI). cerebrospinal fluid (CSF) flow patterns have been demonstrated in the normal subject and patients with pathological conditions including communicating hydrocephalus. aqueduct stenosis and syringohydromyelia. Snap-shot imaging times of 128 ms allow detailed demonstration of transient intraventricular CSF flow patterns. which is not possible with conventional MRI. The potential of EPI as a method for qualitative and quantitative assessment of CSF dynamics is illustrated.
Sequential renography in acute urinary tract obstruction due to stone disease, A group of 76 patients with urographically proven acute calculus obstruction was studied prospectively using 99mTc-DTPA renography to see if kidneys at risk of irreversible renal damage could be identified. There was a statistically significant relationship between the presence of obstruction on renography and the subsequent requirement for intervention. but not with the degree of obstruction (partial or severe). Stones over 5 mm in size are highly likely to cause obstruction. a drop in relative renal function and require intervention. In all. 14 patients sustained a drop in relative renal function of greater than 7% on renography and 12 of these returned to normal limits when their calculi had been passed or removed. The 2 kidneys whose function remained impaired had fallen below 25% of overall renal function and both patients had received prior treatment for their calculi. No patient who presented de novo suffered any permanent loss of ipsilateral renal function. The results confirm that the criteria for intervention were well founded and emphasise the importance of achieving a stone-free state after primary treatment. Renography is recommended for stones over 5 mm in size. those in the middle and upper ureter and for those patients discharged with a stone in situ.
Histopathological "self control" in transurethral resection of bladder tumours, Between 1979 and 1989. 462 bladder tumours were resected in 319 patients using the differentiated technique. After transurethral resection (TUR) that was considered optically to be complete. histopathological examination of the specimen revealed residual tumour in 35% of cases. The danger of insufficient resection increases in relation to the depth of infiltration (pT) and is closely associated with the growth pattern of the tumour. The differentiated form of TUR is important in determining the depth of infiltration. peripheral expansion of the tumour and the completeness of removal.
Dilatation of the prostatic urethra with 35 mm balloon, A series of 54 men. 25 with acute urinary retention and 29 with cytometrically proven bladder outflow obstruction (BOO). underwent dilatation of the prostatic urethra using a 35 mm fixed diameter. low compliance balloon. In 42 patients this was performed under cystoscopic guidance and in 12 patients under fluoroscopic control. Three months following dilatation. 13/27 patients (48%) with BOO who returned for review were rendered unobstructed and 19/27 (70%) were symptomatically improved. By 6 months only 3 remained unobstructed but 15 remained symptomatically improved. Nine months after dilatation 14 patients retained symptomatic improvement but only 2 remained unobstructed. Of the 25 patients treated for acute retention only 6 voided spontaneously. 1 of these relapsing into retention at 2 months and another at 4 months. No patient was rendered unobstructed but 2 patients (who declined prostatectomy) noted an improvement in their obstructive symptoms at both 3 and 6 months. No patient developed retrograde ejaculation following dilatation. Balloon dilatation to 35 mm has no role in acute urinary retention but may have a role in younger men with BOO who wish to avoid prostatectomy and the risk of retrograde ejaculation. In these patients careful follow-up is required.
The contribution of median nerve SEPs in the functional assessment of the cervical spinal cord in syringomyelia. A study of 24 patients, Since the early study of Halliday and Wakefield (1963) it has generally been agreed that scalp somatosensory evoked potentials (SEPs) are normal in patients with dissociated loss of pain and temperature sensation. Up to now a few patients with abnormal spinal N13 and preserved scalp P14 and N20 have been reported in the literature. but there is no firm evidence. based on group data. that this dissociation can be related to any form of dissociated sensory loss. We studied median nerve SEPs in 24 patients with syringomyelia documented by CT scan or MRI. For the recording of the cervical N13 we used a Cv6 anterior cervical montage. which cancels the potentials generated above the foramen magnum and enhances the amplitude of N13. Scalp far-field and early cortical SEPs were recorded using a noncephalic reference electrode. Since N13 pathological changes are mainly changes in amplitude we measured the N13/P9 amplitude ratio in normal subjects and patients and found that it was a reliable index to quantify the amplitude decrease of N13. Absent or reduced N13 was observed in 40 median nerve SEPs (83%) in conjunction with normal P14 and N20 in 30 SEPs. Thus the dissociated loss of the cervical N13 was identified as the most conspicuous SEP feature in syringomyelia. A significant correlation was found between abnormal N13 and loss of pain and temperature sensations. whereas P14 abnormalities correlated well only with loss of joint and touch sensations. In the median nerve territory. sensation was either normal (6 cases) or lost only for pain and temperature (24 cases) when SEPs showed abnormal N13 and normal P14. Although it does not directly reflect the postsynaptic activity of spinal cells receiving their inputs from A delta and C fibres the N13 potential proved to be a reliable index of spinal cord grey matter dysfunction in syringomyelia.
Congenital mirror movements. Abnormal organization of motor pathways in two patients, We studied 2 patients with congenital mirror movements by means of various neurophysiological and metabolic techniques. including mapping of motor evoked potentials to transcranial electrical and magnetic stimulation. premovement and somatosensory evoked potentials. kinematics of voluntary movements. muscle reflexes. and positron emission tomography (PET). Abnormalities in maps of motor and premovement potentials and in PET scans were consistent with a bilateral representation of hand muscles in the motor cortex. the existence of physiologically active connections capable of conducting fast efferent volleys from the motor cortex to ipsilateral muscles. the presence of mirror EMG activity in either hand with intended voluntary movement of the other hand. the absence of mirrored EMG responses from wrist flexors and extensors to mechanical perturbation of the contralateral wrist. and normal scalp distribution of somatosensory evoked potentials to right and left median nerve stimulation. Our findings are consistent with aberrant organization of motor representation areas and corticospinal pathways with ipsilateral as well as contralateral control of voluntary movement.
Perception and action in 'visual form agnosia', A single case study of a patient with 'visual form agnosia' is presented. A severe visual recognition deficit was accompanied by impairments in discriminating shape. reflectance. and orientation. although visual acuity and colour vision. along with tactile recognition and intelligence. were largely preserved. Neuropsychological and behavioural investigations have indicated that the patient is able to utilize visual pattern information surprisingly well for the control of hand movements during reaching. and can even read many whole words. despite being unable to make simple discriminative judgements of shape or orientation. She seems to have no awareness of shape primitives through Gestalt grouping by similarity. continuity or symmetry. It is proposed that many of these perceptual disorders might be the combined result of (1) a selective loss of the cortical elaboration of the magnocellular visual processing stream. and (2) a selective output disconnection from a central processor of visual boundaries and shape primitives in the occipital cortex.
Modulation of the stretch reflex during volitional sinusoidal tracking in Parkinson's disease, Sinusoidal visually-guided wrist tracking. in normal and parkinsonian subjects. was perturbed by torque transients every 90 degrees throughout the movement. Long-latency stretch reflex and volitional EMG amplitude modulations were assessed as functions of the tracking phase. Reflex modulation during tracking. both in wrist flexor and extensor muscles. was found to differ significantly between parkinsonian and normal subjects. In the parkinsonian group. the abnormality consisted of an increased reflex activity during tracking phases in which the muscle was lengthening. At these phases the reflex generated torque is opposite in direction to the volitionally generated torque and the tracking movement. No differences in the unperturbed volitional EMG modulation were observed between groups for this error constrained tracking paradigm. Significant correlations were found between ratings of bradykinesia and the amount of abnormal reflex modulation in the wrist flexor. These data suggest that a component of bradykinesia results from a defective coordination of supraspinal reflex and volitional control systems.
Microsaccadic flutter, Microsaccadic flutter is a rare symptomatic saccadic oscillation that has been reported only twice previously. Here we describe 5 patients with this disorder. The oscillation is horizontal. has a frequency of 15-30 Hz. an amplitude of 0.1-0.5 degrees. and cannot be seen with the unaided eye. It is usually not associated with any underlying neurological disorder. We hypothesize that microsaccadic flutter is due to malfunction of the brainstem omnipause neurons.
Morphological changes in unmyelinated nerve fibres in the sural nerve with age, Quantitative changes in unmyelinated nerve fibres in sural nerves obtained at autopsy were evaluated in 28 normal adults. The following conclusions were reached. (1) The density of unmyelinated axons showed no significant correlation with age. but the densities of (2) Schwann cell subunits with axons. (3) Schwann cell subunits without axons. (4) single protrusions of Schwann cells and (5) collagen pockets. and (6) the mean number of Schwann cell profiles per axon. all showed positive correlations with age. Additionally. (7) the percentage of subunits containing unmyelinated axons and (8) the mean number of axons in single axon-containing Schwann cell subunits demonstrated negative correlations with age. The density of Schwann cell nuclei related to unmyelinated fibres did not show a significant change with age. The age-dependent changes in unmyelinated nerve fibres thus mainly consist of an increased production of processes by Schwann cells in the absence of cell multiplication. A decrease in unmyelinated nerve fibre density or a compensatory increase of small unmyelinated axons did not occur in these normal adults. In terms of relative sensitivity for the detection of the earliest changes in unmyelinated fibres. the indices (6) and (7) are considered to be useful and superior to the conventional assessment of unmyelinated axon density and diameter distribution. These two indices are not influenced by postmortem swelling of the axons and Schwann cells. Measurements of unmyelinated axon density and size distribution will continue to be useful in the assessment of more advanced pathological conditions.
Subcutaneous lisuride infusion in Parkinson's disease. Response to chronic administration in 34 patients, Thirty-eight parkinsonian patients with motor fluctuations and dyskinesias on chronic levodopa therapy were treated with subcutaneous lisuride infusion (SLI). Thirty-six were discharged from hospital on combined treatment with 24 h lisuride infusion (111.3 +/- 29.5 micrograms/h) and oral levodopa plus a decarboxylase inhibitor (729.6 +/- 452 mg/day); all obtained a marked initial improvement in mobility (mean reduction 'off' hours 87.5%); 34 were followed for a mean of 20.85 (range 6-45) months. Most patients continued to show improvement with respect to baseline assessment during chronic treatment but 23 developed dyskinesias. 'off' periods or both. which were difficult to control by changing the levodopa schedule. lisuride dose or both. In only 5 patients was lisuride treatment stopped because of inefficacy. The high incidence of psychiatric side-effects (18/38) was the major limiting factor for continuing lisuride infusion in this population of severe parkinsonian patients. Many complained about the inconvenience of the pump's technical requirements for long-term utilization. but only 4 patients abandoned SLI for this reason. These results indicate that motor function may be substantially improved in severe parkinsonian patients treated with SLI but increased dyskinesia or psychiatric adverse effects limited the long-term usefulness of this approach. It is suggested that continuous dopaminergic stimulation may be a particularly useful therapeutic strategy when applied in earlier stages of the disease.
Motor reorganization after upper limb amputation in man. A study with focal magnetic stimulation, To evaluate reorganization in motor pathways following amputation. we studied motor evoked potentials (MEPs) to transcranial magnetic stimulation in 7 patients with unilateral upper limb amputations. a patient with congenital absence of a hand. and 10 normal subjects. Electromyographic recordings were made from biceps and deltoid muscles immediately proximal to the stump and the same contralateral muscles. Magnetic stimulation was delivered by a Cadwell MES-10 magnetic stimulator through a 'figure eight' magnetic coil over scalp positions separated by 1-2.5 cm. Maximal M responses were elicited by peripheral nerve stimulation at Erb's point. The amplitude of MEPs was expressed both as absolute values and as a percentage of maximal responses to peripheral nerve stimulation. Threshold for activation of muscles ipsilateral and contralateral to the stump and the region of excitable scalp positions were also determined in 7 patients. Magnetic scalp stimulation induced a sensation of movement in the missing hand or fingers in the patients with acquired amputation. but failed to do so in the patient with congenital absence of a limb. It evoked larger MEPs. recruited a larger percentage of the motoneuron pool. and elicited MEPs at lower intensities of stimulation in muscles ipsilateral to the stump than in contralateral muscles. Muscles ipsilateral to the stump could be activated from a larger area than those contralateral to the stump. These results are compatible with cortical or spinal reorganization in adult human motor pathways targeting muscles proximal to the stump after amputations.
Multiple representations contribute to body knowledge processing. Evidence from a case of autotopagnosia, Body schema disturbances were studied in a 62-yr-old woman with Alzheimer's disease. She was severely impaired in verbal and nonverbal tasks requiring her to localize body parts (on her own body. the examiner's body or a doll's body) even though she correctly named the same parts when pointed at by the examiner. Pointing responses were misdirected mainly to parts contiguous with the target area and. to a lesser extent. to functionally equivalent body parts. We also found that the patient was able to define body part names functionally but not spatially. In another series of tasks. and in contrast to the above results. performances were normal when small objects. attached to the patient's body. served as pointing targets. Furthermore. on subsequent testing she pointed correctly at the remembered position of these objects. The fact that the same point in 'body space' is localized correctly when it corresponds to an external object and erroneously when it corresponds to a body part contradicts the idea of the body schema as a unitary function. Learning the position of objects on the body surface requires access to some form of body-reference system on which this information can be mapped. We argue that such a system can be available in autotopagnosia and is independent from the visuospatial representations of the body structure that are postulated to be damaged or inaccessible in this syndrome. An integrated account of the present results and of those reported by other authors suggests that multiple levels of representation (e.g.. sensorimotor. visuospatial. semantic) are involved in the organization of body knowledge.
Responses of single spinal motoneurons to magnetic brain stimulation in healthy subjects and patients with multiple sclerosis, Magnetic stimuli delivered over the scalp can cause single motor units to discharge in intrinsic hand muscles. The discharge characteristics of 26 tonically active. low threshold single motor units in the first dorsal interosseous muscle of 13 healthy subjects and of 21 motor units in 9 patients with multiple sclerosis (MS) were studied. Up to 500 transcranial magnetic stimuli were delivered at the vertex and were given randomly with respect to. or at a fixed delay after. the previous voluntary discharge. Peristimulus time histograms (PSTHs) of motor unit discharges were constructed. In healthy subjects. two periods of increased firing probability were seen at onset latencies of 20-31 ms and 56-90 ms after the stimulus. These periods have been termed the primary peak and the secondary peak. The primary peak had a mean duration of 4.6 ms and was found to be multimodal in 17 motor units. Subpeaks had intermodal intervals of between 0.6 and 2.4 ms. Subpeaks probably result from a sequence of excitatory postsynaptic potentials (EPSPs) induced at the motoneuron by corticospinal impulses. In patients with MS. the primary peak could be absent. delayed in onset. of increased duration without discernible subpeaks. or showing increased intermodal intervals between subpeaks. In 3 motor units from patients with MS. PSTHs with normal features were found. It is postulated from this study of the corticospinal inputs to single motoneurons that motor impairment in MS can be due to a number of mechanisms including slowed conduction in corticospinal fibres. dispersion of arrival times of corticospinal impulses at spinal motoneurons and conduction block in corticospinal fibres. which may be frequency dependent.
Correlation of SEP abnormalities with brain and cervical cord MRI in multiple sclerosis, In 31 patients with definite or suspected multiple sclerosis (MS) presenting with a cervical cord syndrome. somatosensory evoked potentials (SEPs) were recorded to median and posterior tibial nerve stimulation. using cephalic and noncephalic reference electrodes. Magnetic resonance imaging (MRI) of the brain and cervical spinal cord was performed. the latter in sagittal and axial views. SEPs were abnormal in 67.7% of patients. whereas MRI showed cervical cord lesions in 74.2% and intracranial lesions possibly involving the somatosensory pathways in 64.5% of cases. A significant correlation was found between abnormalities of cervical (N13) and cortical (N20) potentials following median nerve stimulation with Fz reference and MRI abnormalities involving the ipsilateral or posterior half of the cervical cord. but not the contralateral or anterior half. The N13 potential. recorded from the low cervical region to a supraglottal reference. was most frequently abnormal in patients with MRI lesions at C6 or C7. whereas P14. recorded from the scalp to a clavicle reference. was most often affected by lesions at Cl or the cervicomedullary junction. Abnormalities of the cortical P40 to tibial nerve stimulation were less significantly correlated with cervical MRI lesions. The latency of N20 measured from N9 at the clavicle and the absolute latency of P40 were significantly correlated with the length of MRI abnormalities in the ipsilateral cervical cord. No significant correlation was observed between SEP abnormalities and brain MRI lesions. which it was considered might possibly involve the intracranial somatosensory pathways. It was concluded that (1) the morphological lesions seen in MRI of the cervical cord usually give rise to appropriate electrophysiological deficits. but the occasional finding of a widespread MRI lesion with normal SEP suggests that myelin damage is not the only or the major factor responsible for abnormal MRI signal; and (2) 'clinically silent' lesions apparently involving the radiations and other sensory structures of the brain appear not to give rise to detectable SEP abnormalities. using the methods of the present study.
The contribution of routine follow-up mammography to an early detection of asynchronous contralateral breast cancer, The role of routine mammography was assessed in the early detection of asynchronous contralateral breast cancer (ACBC). The breast cancer patient populations of two cities. Nijmegen and Eindhoven. The Netherlands. which were subjected to a well-defined follow-up program. were compared. The program consisted of regular physical examination and annual mammography in Nijmegen and physical examination only in Eindhoven. From 1975 until 1987. 24 ACBC patients were detected within a group of 880 breast cancer patients in Nijmegen (3%) and. from 1971 until 1984. 14 ACBC patients within a group of 411 patients in Eindhoven (3%). In Nijmegen. eight of the 23 evaluable patients (35%) had a contralateral tumor with a histologic size smaller than 10 mm or an in situ carcinoma. compared with one of the 14 of the Eindhoven patients (7%). whereas 18 of the 24 (75%) versus eight of the 14 patients (57%) were node-negative. Thus annual mammography is very likely a contribution in the early detection of contralateral breast cancer as compared with follow-up by regular physical examination only.
Prognosis of node-positive colon cancer, The most recent American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging system subgroups patients into one to three and four or more positive nodes. However. the Gastrointestinal Study Group and the National Surgical Adjuvant Breast and Bowel Project divides node-positive patients into one to four and five or greater. A Cox multi-variate retrospective analysis was done of the overall survival of node-positive colon cancer patients with the specific objective of determining the most appropriate subcategorization. Data on 306 patients with node-positive colon cancer who underwent potentially curative surgery from 1970 to 1984 were analyzed retrospectively. No patient received adjuvant chemotherapy. Also excluded were patients with synchronous resected metastatic disease or those with rectal primaries. The median follow-up was 6 years. and the median survival for the entire group was 8.6 years. By univariate analysis. the following were significant prognostic features: number of positive nodes (P less than 0.0001). degree of differentiation (P less than 0.0001). colon primary site (P = 0.009). tumor stage (P = 0.001). and tumor size (P less than 0.0001). Lymphatic/blood vessel invasion and a mucinous histology were not significant. By Cox multivariate analysis the number of positive lymph nodes remained the best discriminant of survival (P = 0.0001). The number of positive nodes was related inversely to prognosis with the optimal dichotomization between one to three (66% 5-year survival) and four or greater nodes (37% 5-year survival).
The development of neutralizing antibodies in a patient receiving subcutaneous recombinant and natural interleukin-2, Systemic administration of interleukin-2 (IL-2) in humans may induce antibodies specific to IL-2. The case is reported of a patient with metastatic rectal carcinoma who was treated with long-term subcutaneous IL-2 and a combination of subcutaneous IL-2 and interferon-alpha 2b (IFN-alpha 2b). This patient developed nonneutralizing and neutralizing anti-IL-2 antibodies recognizing both the recombinant and natural cytokine. Detectable serum levels of neutralizing antibodies were accompanied by the inhibition of immune responsiveness to systemic IL-2 in vivo.
A multifaced DNA ploidy analysis to determine ovarian carcinoma aggressiveness, A microfluorometric DNA study was conducted on isolated cells from 64 fragments of ovarian epithelial tumors. Data analysis considered the DNA content of the main stemline and the prevalence of cells in the different compartments of the DNA ploidy histogram in relation to the mitotic activity index and the histologic architecture. Main stemlines were found remarkably stable in different parts of the same tumor. Peridiploid (1.8c to 2.2c) stemlines were found both in well-differentiated and in poorly differentiated tumors. However. low aneuploid (2.2c to 3.0c) stemlines were mostly found in nonsolid tumors and high ploidy (3.2 to 5.04 c) stemlines were prevalent in solid tumors. A comparative analysis between DNA ploidy parameters and mitotic activity was useful to evaluate the expanding modalities of neoplastic cell populations. This analysis revealed that several tumors accumulate an excessive amount of heteroploid cells and others an excessive amount of G2 cells. Yet. most neoplastic cell populations vary from slow to rapidly growing patterns without relevant abnormalities in their ploidy graphic profiles. No relationship was found between stemline ploidy and histologic architecture compared with expanding modalities. These findings indicate that multifaced criteria combining features such as main ploidy. graphic profile. mitotic rate. and histologic architecture measured on one or more microsamples of the same tumor may help to objectively estimate the aggressiveness reached by the neoplastic cells at the time of clinical presentation.
An unusual organoid tumor. Alveolar soft part sarcoma or paraganglioma, The histogenesis of alveolar soft part sarcoma (ASPS) is a subject of continued debate. Although many recent reports suggest a muscle origin. others advocate a neuroendocrine derivation. A tumor in the chest wall of a 16-year-old woman was diagnosed and treated as ASPS. The light microscopic. electron microscopic. and immunohistochemical findings showed features of both ASPS and paraganglioma. In addition. this lesion was positive for antibody to glucagon. a characteristic of neither ASPS nor paraganglioma. although seen in a few gangliocytic paragangliomas. This case demonstrates the need for continued inquiry into the histogenesis of ASPS.
Relationship between lung asbestos fiber type and concentration and relative risk of mesothelioma. A case-control study, Lung tissue from 221 definite and probable cases of malignant mesothelioma reported to the Australian Mesothelioma Surveillance Program from January 1980 through December 1985 and from an age-sex frequency matched control series of 359 postmortem cases were examined by light microscopic (LM) and analytical transmission electron microscopic (TEM) analysis and energy dispersive x-ray analysis (EDAX). Concentrations of total fibers (coated and uncoated) (LM). crocidolite. amosite. chrysotile. and unidentified amphibole (TEM) (fibers/g dry lung tissue) were measured. Fiber concentrations less than 10 microns in length and greater than or equal to 10 microns in length were separately quantified. By comparing cases (221) and controls (359 LM. 103 TEM). odds ratios for increasing fiber concentrations compared with less than 15.000 fibers/g (LM) and less than 200.000 fibers/g (TEM) (the respective detection limits) were calculated. Univariate analyses showed statistically significant dose-response relationships between odds ratio and fiber concentration for all fiber concentration measures. The relationship between log(odds ratio) and log(fiber concentration) was linear. Multiple logistic regression analysis showed that a model containing crocidolite greater than or equal to 10 microns. amosite less than 10 microns. and chrysotile less than 10 microns as explanatory variables best described the data. The odds ratios for a X10 increase in fiber concentration (fibers/micrograms) were as follows: crocidolite greater than or equal to 10 microns. 29.4 (95% confidence interval [CI]. 3.6 to 241); chrysotile less than 10 microns. 15.7 (95% CI. 6.1 to 40); amosite less than 10 microns. 2.3 (95% CI. 1.0 to 5.3). An additive risk model gave similar results. In a subgroup of cases and controls with only chrysotile in the lungs. a significant trend in odds ratio with increasing fiber content was found.
Flow cytometric DNA index in the prognosis of colorectal cancer, The authors investigated the relationship between flow cytometric DNA index (DI. defined as the ratio of the DNA content of malignant cells to that of normal cells) and other prognostic factors (grade and stage. anatomical site. age and sex) with the survival of 115 patients with colorectal cancer. Multiple biopsy specimens from 62 patients were taken during colonoscopy before surgery. Additional samples from 53 patients were obtained from paraffin-embedded material. All patients were treated with surgery only. Fresh-frozen material gave higher incidence of DNA aneuploidy than paraffin-embedded material (79% versus 41%). The patients with DNA diploid tumors (DI = 1) had a better overall survival than those with DNA aneuploid tumors (DI = 1). Among DNA aneuploid tumors. those with DI greater than 1.2 (excluding DI = 2) were worse than those with DI = 1.2 (excluding DI = 1) and DI = 2. Cox's regression analysis showed that pathologic stage was more important for prognosis than DNA index. whereas age. sex. histologic grade. and anatomic site were removed from the analysis as not relevant for prognosis. Relative risk of death (RR). in reference to patients with DI = 1 and Stages A + B (RR = 1). were RR = 1.8 for patients with carcinomas with Stage C. RR = 2.7 for patients with carcinomas with DNA near-diploid and DNA tetraploid tumors. RR = 3.5 for those with DI greater than 1.2 (excluding DI = 2). and RR = 8.0 for those with Stage D. These data indicate that flow cytometrically evaluated DI values have a relevant independent power for predicting the clinical outcome of colorectal cancer patients.
Sputum occult blood screening for lung cancer. Stage II screening of 14,431 subjects, Sputum occult blood screening (SOBS) for lung cancer was performed in outpatients with suspected lung cancer. A total of 1011 patients were seen. Among them. 604 patients were found to be negative for SOBS. and 407 were found to be positive. The false-negative rate was 3.97% (24 of 604). and the opposite positive rate was 19.65% (80 of 407). A total of 14.431 normal subjects over 40 years of age were screened by SOBS. In the series. 1942 specimens were found to be positive. Among the 1942 patients. 31 were found to have definite cancer cells.
Status of sex steroid hormone receptors in large bowel cancer, To determine the potential role of sex steroid hormones in the development of colorectal tumors in humans. specific androgen (AR). estrogen (ER). and progesterone (PGR) receptors were investigated in normal mucosa (NM) and in tumor (T) paired biopsy specimens from 94 patients. Androgen receptors were detected in 98% and 96% of NM and T samples. ER in 91% and 83% of NM and T biopsy samples. whereas PGR were detected only in 14% and 10% of NM and T specimens. respectively. These incidences are independent of the sex and age of the patients. They are not related to tumor localization. histologic grade. or stages of Dukes' classification. Scatchard analysis of labeled ligand binding indicated the existence of one single class of high affinity binding sites; the calculated dissociation constant (Kd) was 1.7 +/- 0.6 10(-9) molar concentration (M) for 5 alpha-dihydrotestosterone (DHT) and 0.6 +/- 0.3 10(-9) M for estradiol (E2). These values were identical in NM and T tissue for both AR and ER. The binding capacity for DHT was 148 +/- 67 and 93 +/- 43 fmol/mg of cytosol protein in NM and T tissues. respectively (P less than 0.05). The ER content was lower and similar in NM and T biopsy specimens: 19 +/- 9 and 18 +/- 10 fmol/mg protein. respectively. The PGR content was 10 +/- 4 in NM versus 17.5 +/- 6 fmol/mg protein in T specimens. It is observed that the elevated AR in normal mucosa is not related to any known function for androgens in the digestive tract. The receptor pattern observed in tumors does not support the hypothesis previously raised in the case of chemically induced colonic tumors in rodents.
Attributes and survival patterns of multiple primary cutaneous malignant melanoma, From a series of 1495 patients with primary cutaneous malignant melanoma (PCMM). 26 patients (1.73%) had multiple primary cutaneous malignant melanoma (MPCMM). This report describes the attributes and survival patterns in this small. but important. subgroup of patients with PCMM. Of 26 patients. 23 had two primaries. two had three primaries. and one had six primaries. Five patients had synchronous and 21 patients had metachronous MPCMM. The median interval between the occurrence of the first and subsequent PCMM in these patients was 1.93 years. The estimated 5-year survival rate from the first melanoma was 83.5%; that from the last melanoma was 53.1%. In summary. MPCMM is a distinct biologic phenomenon. A second or subsequent malignant melanoma should be treated like a primary melanoma.
Second cancers following non-Hodgkin's lymphoma, The risk of second malignancies following non-Hodgkin's lymphoma (NHL) was estimated in 29.153 patients diagnosed with NHL between 1973 and 1987 in one of nine areas participating in the National Cancer Institute's Surveillance. Epidemiology. and End Results Program. Compared with the general population. NHL patients were at a significantly increased risk of developing second cancers (observed/expected [O/E] = 1.18; O = 1231). The O/E ratio increased significantly with time to reach 1.77 in 10-year survivors. Significant excesses were noted for acute nonlymphocytic leukemia (O/E = 2.88). cancers of the bladder (O/E = 1.30). kidney (O/E = 1.47). and lung (O/E = 1.57). malignant melanoma (O/E = 2.44). and Hodgkin's disease (O/E = 4.16). Chemotherapy appeared related to subsequent acute nonlymphocytic leukemia (ANLL) and bladder cancer. Radiation therapy was associated with ANLL and possibly cancers of the lung. bladder. and bone. Malignant melanoma was not clearly related to initial NHL treatment.
Mammography and age: are we targeting the wrong women? A community survey of women and physicians, To determine mammography use among women with a broad range of ages. the authors surveyed women aged 30 to 74 years and physicians practicing primary care in two eastern North Carolina counties. Twenty-five percent of women in their 30s had ever had a mammogram. and 34% intended to have one in the coming year. From 45% to 52% of women in their 40s. 50s. and 60s had ever had a mammogram. and 55% to 57% intended to have one in the next year. Thirty-seven percent of women aged 70 to 74 years had ever had a mammogram. and 40% intended to have one in the following year. Nineteen percent of physicians reported screening nearly all women aged 30 to 39 years. and 14% screened few women aged 50 to 74 years. Younger women were more worried about breast cancer than older women and assessed their risk as higher. attitudes that were generally associated with higher mammography utilization. These community surveys suggest that mammography use may be excessive among younger women; older women continue to be underscreened.
Cisplatin and 5-fluorouracil for advanced locoregional and metastatic squamous cell carcinoma of the skin, Seven patients with advanced locoregional or metastatic squamous cell carcinoma of the skin were treated with cis-daimminedichloroplatin (cisplatin) and 5-fluorouracil (5-FU). Responses were seen in six of seven patients (three partial responses [PR] and three complete responses [CR]). One patient is alive and disease-free at 2 years. These results indicate that cisplatin and 5-FU is an effective combination regimen that should be used in future clinical trials in squamous cell carcinoma of the skin.
Magnetic resonance imaging of cardiac rhabdomyosarcoma. Quantifying the response to chemotherapy, This report illustrates the use of cardiac magnetic resonance imaging (MRI) to quantify the initial extent of a cardiac rhabdomyosarcoma and. more importantly. its response to chemotherapy. Image slices spanning the heart and adjacent structures were analyzed using Simpson's rule applied to the image slices to estimate the tumor volume initially. then after 5 weeks. and again after 4 months of chemotherapy. A substantial. progressive reduction in tumor volume during chemotherapy was shown. After chemotherapy was discontinued. an increase in tumor volume was shown. It is suggested that. in addition to being useful in patient care. the technique may be useful in clinical investigations by providing an objective. quantitative measure of tumor response to therapy.
Lymphocyte subset distribution after radiation therapy for cancer of the uterine cervix. Possible prognostic implications and correlation with disease course, An analysis of lymphocyte subpopulations was done in patients with cancer of the uterine cervix before and at different intervals after the commencement of radiation therapy. A common feature was a duration of T-cell and B-cell lymphopenia after therapy. The findings relating to the T-cell subsets were interesting. Although the CD4/CD8 ratio remained unchanged in Stages I/IIA for 24 months after treatment. patients with Stages IIB and III showed a lowering of the ratio immediately after treatment. Distinctive patterns of lymphocyte subset distribution were seen in a comparison between patients who were disease-free and those with recurrent disease. The CD4+ cell counts and CD4/CD8 ratio differed between the two groups. with consistent lowered values during the follow-up associated with recurrent disease. This study demonstrates the effects of radiation therapy in altering lymphocyte subset distribution. resulting in characteristic patterns which could be used as clinical and prognostic indicators.
Factors affecting recurrence in lumpectomy without irradiation for breast cancer, Between 1980 and 1988. 122 women with operable invasive breast cancers underwent wide excision and axillary dissection without subsequent irradiation. During the follow-up period of 1 to 8 years (median. 4 years). recurrences were observed in 23 patients (19%). 22 occurring in the breast and one in the axilla. This is a significant rate of recurrence and supports the need for breast irradiation after conservative surgery. The incidence of recurrence in the breast did not appear to be related to the presence or absence of axillary nodal metastasis. No recurrences were noted in 20 patients whose primary tumors were smaller than 1 cm. The incidence of recurrence was directly correlated to the increasing size of the tumor. but it also appeared to decrease with advancing age. In 31 patients over 70 years of age. only one (3%) recurrence was observed. If these early findings are confirmed. it is likely that patients with tumors smaller than 1 cm or patients over 70 years of age may be spared breast irradiation after wide excision.
Is local recurrence of minor importance for metastases in soft tissue sarcoma, The authors analyzed the relationship between treatment. local recurrence. and metastases in a population-based series of 375 patients with soft tissue sarcoma of the extremities and the trunk wall. Treatment was inadequate (marginal excision alone) in 107 patients. local recurrence occurred in 112. and 128 patients developed metastases. Local recurrence was 3.5 times more common after inadequate treatment than after adequate and 2.5 times more common in patients with metastases than in those without. However. metastases were only 1.2 times more common after inadequate treatment than after adequate. Of the 128 patients who developed metastases. 63 had local recurrence and 65 had not. In these two subgroups the timing of metastases and the distribution of clinicopathologic factors--age. sex. tumor size. localization. depth. histotype. and malignancy grade--were similar. These findings indicate that local recurrence is of minor importance for development of metastases in soft tissue sarcoma. The increased local recurrence rate in metastatic tumors may be an expression of the aggressiveness of the primary tumor; highly malignant tumors combine a potential both for local and distant spread.
Effect of hyperthermia in vitro and in vivo on adenine and pyridine nucleotide pools in human peripheral lymphocytes, Hyperthermia has been shown in vitro and in vivo to potentiate the effects of ionizing irradiation. Previous studies found that hyperthermia alters the metabolism of adenosine diphosphate (ADP)-ribose polymers required for recovery from DNA damage and that poly(ADP-ribose) polymerase activity is very sensitive to cellular nicotinamide-adenine dinucleotide (NAD) levels. Thus. the effect of 41.8 degrees C hyperthermia in vitro and in vivo on NAD and adenosine triphosphate (ATP) levels was studied in human peripheral lymphocytes. In vitro studies showed significant decreases in oxidized NAD (NAD+) and ATP levels after heating that simulated a clinical whole-body hyperthermia (WBH) treatment. This nucleotide depletion could not be attributed to nucleotide leakage or increased enzymatic NAD+ consumption. As the reduction of NAD observed was sufficient to decrease poly(ADP-ribose)polymerase activity by 50%. the studies were extended to clinica cases. Cellular NAD+ and ATP were measured in previously stored lymphocytes obtained from four patients before and after WBH; a statistically significant decrease in NAD+ was observed after WBH which quantitatively agreed with the in vitro results. Based on these results a prospective study was done in three patients; NAD+ was extracted immediately on sample collection. and the kinetics of WBH-induced NAD depletion were studied. These data. which agree quantitatively with the laboratory results. are presented.
Survival of children and adolescents with acute lymphoid leukemia. A study of American Indians and Hispanic and non-Hispanic whites treated in New Mexico (1969 to 1986), During the period 1969 to 1986. 196 American Indian and Hispanic and non-Hispanic white children and adolescents (ages. 0 to 19 years) were treated for acute lymphoid leukemia (ALL) at the University of New Mexico affiliated institutions. There were 28 American Indians (14%). 91 Hispanic whites (46%). and 77 non-Hispanic whites (39%). Median survivals for patients undergoing antileukemic therapy ranged from 8 months for American Indian boys to 140 months for non-Hispanic white girls. American Indian boys had the highest initial median leukocyte count (WBC) at 23.8 X 10(9)/l. Compliance problems occurred most commonly among American Indian children of both genders. Other clinical and pathologic features evaluated in this study were distributed similarly among the ethnic gender groups. Multi-variate analysis revealed that independent prognostic variables for survival included initial WBC. age. and gender. Ethnicity and compliance problems were possible. but confounded. prognostic variables. To the authors' knowledge this represents the most comprehensive study to date of ALL in American Indian patients.
Comparative investigation of c-erbB2/neu expression in head and neck tumors and mammary cancer, Normal tissues. primary tumors. and metastases of mammary and salivary glands and oral/laryngeal mucosa have been analyzed with Northern-blots employing 32P-labeled RNA probes for the expression of the neu oncogene. Neu oncogene expression of a mRNA species of 4.6 kilobases was found in all normal salivary (five) and mammary glands (four) as well as in two normal or inflamed samples of tongue mucosa. This expression was regarded as baseline activity of the neu gene for the respective tissues and was used as standard for the evaluation of benign and malignant tumors. None of 14 squamous cell carcinomas of the oral and laryngeal mucosa showed enhanced neu transcription level. Five fibroadenomas. one benign variant of phylloid tumor. one carcinosarcoma. and one of two proliferative fibrocystic diseases of the breast showed lacking or normal baseline expression of the neu oncogene. as did one monomorphous cystadenolymphoma of the parotid gland. In contrast. four parotid pleomorphic adenomas and one salivary gland adenocarcinoma showed enhanced neu expression. For mammary adenocarcinomas. increased neu oncogene expression concerned ten of 34 cases--all being variants of ductal carcinomas--and all metastases analyzed (six) deriving from three primaries. One adenoid cystic carcinoma also showed enhanced neu expression. Neu overexpression may reflect accidents of genomic reconstitutional events occurring regularly within the differentiation pathway of epithelial/myoepithelial cells. This assumption was supported by further immunohistochemical analysis which showed stainings of myoepithelial and myoepithelia-like cell populations in tumors. especially pleomorphic adenomas and adjacent normal-looking tissues.
Immunochemical and immunohistochemical studies on three aldolase isozymes in human lung cancer, The aldolase isozymes A. B. and C in tumor tissues (63) and sera (104) of patients with lung cancer were determined with an enzyme immunoassay system. compared with normal lung tissues (13). and the sera of normal healthy subjects (100). Tissue aldolase A and C concentrations were enhanced in 83% (52/63) and 51% (32/63) of patients with lung cancer. respectively. regardless of histologic type or stage (P less than 0.01). But aldolase B was not elevated in tissue levels. In the sera of patients with lung cancer. there were no significant elevations of the isozymes. Immunohistochemically aldolase A and C stained more intensely in the cytoplasm of lung cancer cells than those in normal tissues. These results indicate lung cancer cells contain enhanced tissue levels of aldolase A and C.
Adenoid cystic carcinoma of the esophagus. A clinicopathologic study of three cases, In a group of 245 cases of primary carcinoma of the esophagus the authors found three cases of adenoid cystic carcinoma (ACC). Clinical and pathologic data of those patients (one female and two male; age range. 49-74 years) were analyzed. Tumors were localized in the middle third of the esophagus. One patient lived 15 months after surgery. Another is a case of early ACC who has been living 4.5 years after surgery and is without specific symptoms. The third patient had not had surgery and died 13 months after the onset of dysphagia. An autopsy showed only a locally invasive tumor growing into the surroundings of the esophagus. and regional lymph node metastases without distant parenchymal metastases. These findings support pathologic and biologic similarities between ACC of the esophagus and ACC of the salivary glands. There are synchronous tumors of the esophagus and the vital localization which makes the prognosis of ACC of the esophagus worse than ACC of the salivary glands.
Clear cell sarcomas and metastatic soft tissue melanomas. A flow cytometric comparison and prognostic implications, Eleven soft tissue clear cell sarcomas (CCS) were examined flow cytometrically for their DNA content with a correlation of the DNA with the patients' survival. Diploidy was expressed in six sarcomas and it conferred a longer survival (mean. 68.6 months) than aneuploid sarcomas (mean. 8.2 months). For comparison. 13 metastases to soft tissues from cutaneous melanomas were assessed by flow cytometric study. The aneuploid neoplasms of both entities were categorized into low and high degree based on extent of the DNA index (DI). Low degree was defined by a DI of less than or equal to 1.5 and high degree by a DI of greater than 1.5. Significant differences in DNA content between CCS and metastatic melanomas were observed. Melanomas were preponderantly aneuploid (11/13) of high degree (mean DI. 1.7) whereas CCS manifested more diploidy (six of 11) and their aneuploidy was of a low degree (mean DI. 1.2; P = 0.001). Clear cell sarcomas and melanomas were also examined for their immunoreactivity to S-100 protein and HMB-45 antigen. All CCS reacted with S-100 protein and HMB-45. In CCS the reactions were diffuse for both in six tumors. diffuse with HMB-45 and moderate to S-100 protein in three tumors and diffuse with S-100 and moderate with HMB-45 in two tumors. All melanomas reacted diffusely to S-100 protein except for one heavily pigmented tumor which reacted only focally. The reaction to HMB-45 was diffuse in nine and focal in three melanomas. These data suggest that measurements of DNA content in CCS may be valuable in predicting clinical outcome and that there are quantitative differences in DNA content between CCS and metastatic melanoma in soft tissues.
Monoclonal prostate-specific antigen in untreated prostate cancer. Relationship to clinical stage and grade, The authors evaluated 440 men with clinically staged and untreated prostate cancer with a monoclonal prostate-specific antigen (PSA) assay. The serum PSA value correlated significantly with both the stage and grade of disease (P less than 0.00005). The relationships between PSA and consecutive Stages A. B. C. and D2 (alpha = 0.15) and between progressive Gleason's scores 2 to 4. 5 to 7. and 8 to 10 (alpha = 0.15) were statistically significant. Also statistically significant was the correlation between serum PSA level and intracapsular versus extracapsular disease (P less than 0.00005). although no one value can be used to differentiate reliably between patients in these two categories. The probability of clinically detectable metastasis (Stage D2) is 85% if the serum PSA level is greater than 30; however. 12% of patients without clinical evidence of metastases (Stages A. B. and C) have such a serum PSA value. Despite the statistically significant association between PSA and tumor differentiation and volume as reflected by tumor grade and clinical stage. this marker cannot be used to determine either for an individual patient.
Exposure histories in acute nonlymphocytic leukemia patients with a prior preleukemic condition, A subset of patients with acute nonlymphocytic leukemia (ANLL) have evidence of a myelodysplastic syndrome (MDS). low infiltrate leukemia. or other preleukemic condition that may be present for several months before onset of disease. The hypothesis that these conditions act as markers for environmentally induced cancer was examined in 270 ANLL patients. 46 with a preleukemic phase and 224 with an acute onset. Although the effects of previously identified risk factors (male sex. age older than 50 years. prior cytotoxic therapy) were demonstrated. no associations with common environmental conditions (cigarette smoking. alcohol use. occupations with exposure to chemicals or radiation) were present with the exception of hobbies involving potential chemical exposure. odds ratio (OR) and 95% confidence intervals = 4.2 (1.4 to 12.3) and self-reported exposure to pesticides. OR = 10.2 (1.8 to 63.1). These may be chance associations although a previous case-control study of MDS reported similar findings.
Incidence and survival rates of children and young adults with osteogenic sarcoma, Gender-specific and race-specific incidence and survival rates of osteogenic sarcoma over a 14-year period are presented for persons aged 0 to 24 years from eight Surveillance. Epidemiology. and End Results (SEER) registries. They were no significant gender or racial differences in age at diagnosis. There was no significant gender difference in overall incidence. Although incidence rates were slightly higher in blacks compared with whites. the difference was not significant after controlling for multiple comparisons. Females (median. 74 months) survived longer than males (median. 29 months). although this difference weakened after controlling for stage. No racial differences in survival were observed. White females survived the longest (median. 94 months). followed by black females (median. 41 months). black males (median. 34 months). and white males (median. 29 months). This striking difference in survival should be explored more fully.
On the mechanisms for the selective action of vitamin D analogs, A variety of analogs of 1.25-(OH)2D3 with less calcemic activity and lower receptor binding affinity than 1.25-(OH)2D3 have been developed. However. these compounds have equal or greater ability to differentiate leukemia cells and psoriatic fibroblasts and to suppress PTH synthesis and secretion. The mechanism for this selectivity has not been elucidated. Because the lower potency of ergocalciferol compared to cholecalciferol in preventing or curing rickets in chicks was associated with a lower affinity of the avian vitamin D binding protein (DBP) for vitamin D2. we tested five analogs with low calcemic activity including 22-oxa-1.25-(OH)2D3 (OCT). MC903. 1.25-(OH)2-16 ene-23-yne D3. 1.25-(OH)2-26.27 dihomo-22-ene-D3. and 1.25-(OH)2-24-trihomo-22-ene-D3 for their affinity for rat serum DBP. All analogs had a low affinity for DBP. ranging from 50-3000 times less than that of 1.25-(OH)2D3. OCT also bound with low affinity to dog and human serum DBP. We tested with OCT the possible consequences of its low affinity for serum DBP. One of the functions of DBP is to prolong the lifetime of 1.25-(OH)2D3 in circulation. Quantification of the metabolic clearance rate (MCR) of OCT in 8 normal dogs using a single bolus injection technique showed that OCT was cleared at a rate of 48.2 +/- 7.5 ml/min. approximately 6-7 times more rapidly than 1.25-(OH)2D3 (6.8 +/- 0.4 ml/min). The estimated half-life of OCT in the circulation was 2.5 +/- 0.3 h compared to 7.0 +/- 0.6; n = 7 for 1.25-(OH)2D3. As our primary interest is the potential of OCT in treating the secondary hyperparathyroidism of CRF. we also measured the MCR of OCT in 5/6 nephrectomized dogs. Uremia does not affect the rate of clearance of OCT from the circulation (MCR: 56.8 +/- 4.5; t1/2 = 2.1 +/- 0.2 n = 4). Despite its shorter half-life. OCT suppressed PTH secretion in vivo in uremic dogs. The effects of low binding to DBP on the percentage uremic dogs. The effects of low binding to DBP on the percentage of free sterol were determined using an ultrafiltration procedure. We compared the proportion of free (unbound) OCT and 1.25-(OH)2D3 in 0.1% BSA-PBS with concentrations of human serum ranging from 0-25%. The proportion of OCT in the free form was significantly higher than that of 1.25-(OH)2D3 for every serum concentration tested. The physiological relevance of a higher percentage of free OCT was tested in normal human macrophages.(ABSTRACT TRUNCATED AT 400 WORDS).
Increased insulin action in cultured hepatocytes from rats with diabetes induced by neonatal streptozotocin, Previous studies have shown that Wistar rats injected at birth (n0) with STZ (n0-STZ) develop as adults a noninsulin-dependent diabetic state characterized by a lack of insulin response to glucose in vivo. a mild basal hyperglycemia. and an impaired glucose tolerance. Our former in vivo studies using the insulin-glucose clamp technique revealed an increased insulin action upon hepatic glucose production in these animals. We have now cultured hepatocytes from these mildly diabetic rats in parallel with hepatocytes from control rats. to examine more closely basal and insulin-regulated glucose production and glucose incorporation into glycogen. In addition. we extended our investigation to other hepatic functions such as lipid synthesis and amino acid transport. which could not be studied in vivo. Although glucose production from glycogenolysis or gluconeogenesis in absence or presence of glucagon was identical in the two cell populations. glucagon-stimulated glycogenolysis was more sensitive to insulin action in diabetic hepatocytes. Similarly. insulin action on glucose incorporation into glycogen. lipogenesis. and amino acid transport were enhanced in diabetic hepatocytes. The hormone effect was manifested by an increase in the sensitivity and/or in the responsiveness. reflecting the multiplicity of the pathways whereby the insulin signal is transduced through the insulin receptor to multiple postreceptor sites. To gain insight into the possible mechanism of these disturbances. we evaluated the initial insulin receptor interaction and the kinase activity of the receptor beta-subunit. In accordance with our previous study on intact livers. we found no alteration in either of these parameters in n0-STZ rat hepatocytes. Thus. the present study clearly demonstrates that these diabetic rats exhibit a postreceptor hyperresponsiveness to insulin at the cellular level. It strengthens the notion that a beta-cell deficiency with glucose intolerance does not necessarily lead to a hepatic insulin resistance.
Elevated activity of low molecular weight insulin-like growth factor-binding proteins in sera of vitamin C-deficient and fasted guinea pigs, We have previously reported that scorbutic and fasted guinea pig sera contain an insulin-like growth factor-I (IGF-I)-reversible inhibitor of collagen. proteoglycan. and DNA synthesis in cultured cells. Here we report that IGF-binding protein (IGFBP) activity is increased in serum containing the inhibitor [125I]IGF-I or -II bound to these sera was eluted in the 30- to 50-kDa region of an S200 gel column. [125I]IGF-I affinity cross-linking analysis revealed that a 38-kDa cross-linked species increased markedly in fasted and scorbutic sera. with a lesser increase in a 34-kDa species. while scorbutic sera also yielded a 44-kDa species. Gel filtration of unlabeled sera showed a 10-fold increase in the activity of two proteins in the 30- to 50-kDa region from the experimental sera. Their activity correlated with their ability to inhibit binding of [125I]IGF-I to its cellular receptor. suggesting that they have the potential to inhibit IGF-I-dependent functions. Ligand blotting showed that 29 and 35-kDa IGFBPs were almost undetectable in normal serum. but were dramatically induced by scurvy and fasting. so that they accounted for close to 40% of the total circulating BPs. Total IGFBP-3 in the experimental sera was increased about 30%. while there was little effect of scurvy or fasting on the level of BP-3 activity isolated by acid extraction of the high mol wt region of the S200 column. An IGF-I analog with normal affinity for the 30- to 50-kDa BPs from fasted and scorbutic sera. but with reduced affinity for the cell receptor. was equivalent to IGF-I in reversing the inhibition of collagen synthesis by scorbutic guinea pig serum in human fibroblasts. Thus. reversal of inhibition appears to require initial saturation of IGFBPs. The overall results suggest that two circulating IGFBPs with unoccupied binding sites are induced in vitamin C-deficient or fasted guinea pigs and may be responsible for inhibition of IGF-I-dependent functions by sera from these animals.
Deficiency of osteoclasts in osteopetrotic mice is due to a defect in the local microenvironment provided by osteoblastic cells, We have reported that osteoblastic cells are required for differentiation of osteoclast progenitors in splenic tissues into multinucleated osteoclasts. In the present study we examined the pathogenesis of the osteoclast deficiency in osteopetrotic (op/op) mice using a coculture system of spleen cells and osteoblastic cells. When spleen cells obtained from op/op or normal (+/?) littermates of op/+ parent mice were cocultured with osteoblastic cells obtained from calvaria of normal ddy strain mice. numerous tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) were formed in the presence of 1 alpha.25-dihydroxyvitamin D3 [1 alpha.25(OH)2D3]. Most of the TRAP-positive MNCs bound [125I]salmon calcitonin. This suggests that there is no abnormality in the osteoclast progenitors present in the splenic tissues of op/op mice. When osteoblastic cells from +/? littermates were cocultured with normal spleen cells from ddy mice. TRAP-positive MNCs were similarly formed in response to 1 alpha.25(OH)2D3. In contrast. in cocultures of op/op osteoblastic cells with normal spleen cells. no TRAP-positive cells appeared. even in the presence of 1 alpha.25(OH)2D3. The op/op mutation was recently reported to exist in the coding region of the macrophage colony-stimulating factor (M-CSF) gene. Adding M-CSF and 1 alpha.25(OH)2D3 to the coculture with op/op osteoblastic cells induced the appearance of TRAP-positive MNCs with calcitonin receptors. These results clearly indicate that osteoclast deficiency in op/op mice is due to a defect in the local microenvironment in bone. in which M-CSF produced by osteoblastic cells plays a critical role in osteoclast development.
Growth hormone and insulin-like growth factor I treatment increase testicular luteinizing hormone receptors and steroidogenic responsiveness of growth hormone deficient dwarf mice, To test the hypothesis that insulin-like growth factor (IGF-I) is required for the in vivo development of testicular Leydig cell function. either recombinant human GH [(hGH) (1.5 micrograms/g BW) or recombinant IGF-I (1 microgram/g BW) was injected three times daily into immature Snell dwarf mice (dw/dw) and into phenotypically normal control (Dw/-) for 7 days. In dw/dw mice hGH enhanced significantly body. liver. kidney. and testicular weight. In addition. hGH increased testicular LH receptors and the acute steroidogenic response to human CG. but there was no significant effect on basal plasma testosterone or plasma LH levels. The effects of IGF-I in body and kidney weight were less pronounced than those produced by hGH. but its effects on testicular weight and LH receptors. as well as on the acute steroidogenic response to human CG. were similar to that observed after hGH treatment. In Dw/- mice hGH had no effect on either body or organ weight or on testicular function. despite the fact that it induced a significant increase in plasma IGF-I levels. These results indicated that IGF-I is able to induce the maturation of Leydig cell function and that the effects of hGH on the testis are probably mediated by IGF-I. They also suggest that the delayed puberty associated with GH deficiency or resistance is most likely related to an IGF-I deficiency.
Presence of identical mitochondrial proteins in unstimulated constitutive steroid-producing R2C rat Leydig tumor and stimulated nonconstitutive steroid-producing MA-10 mouse Leydig tumor cells, The acute regulation of steroidogenesis in steroidogenic tissues requires de novo protein synthesis. It is believed that these newly synthesized proteins are instrumental in the delivery of the substrate. cholesterol. to the inner mitochondrial membrane where the cholesterol side-chain cleavage complex converts cholesterol to pregnenolone. A number of studies have attempted to characterize the protein(s) synthesized in response to hormone stimulation and. hence. function in the delivery of cholesterol to the cholesterol side-chain cleavage complex. While a number of potential protein candidates have been described. there is at present no unequivocal evidence which indicates that they are involved in steroidogenic regulation. We and others have described proteins that are induced in a variety of steroidogenic tissues in response to hormone stimulation and are localized in the mitochondria of these tissues. In an attempt to determine whether these induced proteins may be involved in steroidogenesis. we compared mitochondrial protein profiles in two separate Leydig tumor cell line. One cell line. the MA-10 mouse Leydig tumor cell line. has a very low basal steroid production. but synthesizes large amounts of progesterone in response to both tropic hormone and cAMP analog. The other cell line. the R2C rat Leydig tumor cell line. produces constitutively large amounts of progesterone. which cannot be increased further with hormone stimulation. Two-dimensional polyacrylamide gel electrophoresis profiles of newly synthesized mitochondrial proteins demonstrated that four 30-kDa proteins are induced in response to hormonal stimulation in MA-10 cells. Further. it was shown that proteins identical to these induced proteins are present constitutively in the mitochondria of R2C cells and cannot be further increased with hormone stimulation. These results strongly suggest that the 30-kDa mitochondrial proteins shown to be induced in several steroidogenic tissues are involved in the acute regulation of steroid production.
Transforming growth factor-alpha and -beta are potent and effective inhibitors of GH4 pituitary tumor cell proliferation, The mechanisms that restrict cell proliferation play an important regulatory role in differentiation and tumorigenesis. The growth of PRL-secreting cells of the anterior pituitary is known to be highly estrogen dependent; however. estrogen may act indirectly via growth regulatory polypeptides. We have used the GH4C1 rat pituitary cell line to investigate the action of two classes of growth regulatory polypeptides. transforming growth factor-alpha (TGF alpha) and TGF beta. TGF alpha and TGF beta each inhibit GH4 cell proliferation. as measured by cell number and [3H]thymidine incorporation. and given together arrest GH4 cell proliferation. The growth inhibitory action of TGF alpha is concentration dependent (IC50 = 100 pM) and saturable. Activin-A. a TGF beta-related polypeptide. also inhibits proliferation. but is less effective than TGF beta. TGF alpha and TGF beta each alter GH4 cell cycle distribution by decreasing in the percentage of S phase cells (74% and 34%. respectively) and increasing proportionally G0-G1 phase cells. The growth inhibitory action of TGF alpha differs from that of TGF beta in that TGF alpha also causes a temporary accumulation of cells in G2-M phases. We next initiated experiments to evaluate the role of protein kinase-C in the growth inhibitory actions of TGF alpha and TGF beta. The alpha- and beta-isoforms of protein kinase-C were down-regulated by pretreatment with 12-O-tetradecanoylphorbol-13-acetate. yet TGF alpha and TGF beta still substantially inhibited GH4 cell proliferation. We next compared the actions of TGF alpha and TGF beta on two other well characterized prolonged GH4 responses. TGF alpha and TGF beta each increased GH4 cell adhesion. but differed in their effects on PRL production. This indicates that TGF alpha and TGF beta activate different signaling pathways in GH4 cells. Activin-A acted like TGF beta by enhancing cell-substratum adhesion and inhibiting PRL production. consistent with an interaction at a common receptor site. Taken together these results identify biological functions for TGF alpha. TGF beta. and activin-A on PRL cells and open the possibility that they may represent the direct in vivo mediators of estrogen action to regulate the growth of PRL cells in the anterior pituitary gland.
Growth hormone-dependent and -independent regulation of cytochrome P-450 isozyme expression in streptozotocin-diabetic rats, The sexually dimorphic GH secretory pattern is thought to be the major factor regulating constitutive expression of hepatic P450IIC11 (P-450h) and P450IIC12 (P-450i). In this study we investigated whether factors other than the diabetes-induced decrease in GH secretion contribute to alterations in P-450 isozyme expression in streptozotocin (STZ)-diabetic rats. In male rats. hepatic P-450h apoprotein and mRNA decreased to 13% and 24% of control male levels. respectively. within 14 days of STZ injection. STZ-diabetes had little effect on expression of P-450i in females. Treatment of diabetic male rats with GH did not reverse the suppression of P-450h. STZ treatment also suppressed P-450h expression in GH-treated hypophysectomized (Hx) male rats. but incompletely. Thus. GH can partially reverse diabetic suppression of P-450h. However. in Hx male rats without GH supplementation. STZ treatment suppressed P-450h apoprotein and mRNA expression to 16% and 6% of nondiabetic Hx male levels. respectively. demonstrating the existence of GH-independent regulation of P-450h expression. In Hx female rats. P-450h apoprotein levels were 40% of those in intact control males and were not significantly decreased by STZ. Concomitantly. STZ produced a greater decrease in serum insulin levels and a greater increase in serum glucagon in Hx male rats than in Hx females. The results provide evidence for the existence of STZ-sensitive GH-independent expression of P-450h and further document the gender differences in STZ sensitivity.
Passive immunization against insulin-like growth factor-I does not inhibit growth hormone-stimulated growth of dwarf rats, Passive immunization against insulin-like growth factor-I (IGF-I) was undertaken in GH-deficient rats in an attempt to elucidate the relative importance of the endocrine vs.autocrine/paracrine actions of IGF-I in stimulating growth. Antiserum against IGF-I was raised in sheep and purified by affinity chromatography. The ability of the purified antibodies to neutralize the actions of IGF-I in vitro and bind IGF-I in vivo were extensively tested using L6 myoblast and cartilage bioassays. Four groups of male rats with isolated GH deficiency were used in the study. At 49 days of age the rats received 100 microliter normal saline given sc each day for 10 days. 2 mg/kg recombinant bovine GH (bGH) given in 100 microliter. sc. each day. 2 mg/kg bGH. sc. and 300 microliter immunoglobulin G purified from normal sheep serum given daily ip. or 2 mg/kg bGH plus 300 microliter anti-IGF-I immunoglobulin G daily. ip (a dose that was able to completely inhibit IGF-I actions on sulfate uptake into cartilage). Treatment with GH significantly increased growth rates (P less than 0.001) in the rats. but there was no difference between any of the three GH-treated groups; passive immunization against IGF-I did not diminish the GH-stimulated growth in these rats. Excess antibody could be detected in the plasma of all anti-IGF-I-treated rats at the conclusion of the experiment. and the antibody was capable of sequestering both free and binding protein-bound IGF-I. The absence of even a slight retardation of GH-stimulated growth in the anti-IGF-I-treated rats suggests that circulating IGF-I may not be important in mediating the growth-promoting actions of GH. although the immunoneutralization probably does not affect GH stimulation of tissue IGF-I production.
Central role of brown adipose tissue thyroxine 5'-deiodinase on thyroid hormone-dependent thermogenic response to cold, As judged by the response of uncoupling protein and key enzymes. brown adipose tissue (BAT) is highly dependent upon the local generation of T3 catalyzed by the tissue type II T4 5'-deiodinase (5'-D-II). In hypothyroid rats treated with T3 or T4. the capacity to withstand cold seems better correlated with the normalization of BAT responses than with the liver thyroid status. 5'D-II is activated by cold via sympathetic nervous system (SNS) stimulation. and the activation generates enough T3 to nearly saturate BAT nuclear T3 receptor (NTR) in euthyroid rats. In hypothyroidism. 5'D-II is highly stimulated by the SNS and hypothyroxinemia. In the present studies we have taken advantage of this situation to test 1) the capacity of 5'D-II to maintain nuclear T3 in rats with various degrees of hypothyroxinemia. and 2) the hypothesis that thyroid hormone-dependent BAT-facultative thermogenesis. rather than the effect of thyroid hormone on obligatory thermogenesis (basal metabolic rate). is the basic mechanism by which thyroid hormone confers protection against acute cold exposure. We treated methimazole-blocked rats (undetectable plasma T4 and T3) for a week with either subreplacement doses of T4 (0.5. 1. 2. and 4 micrograms/kg.day) or replacement doses of T4 or T3 (8 or 3 micrograms/kg.day. respectively). Sources and content of BAT nuclear T3 were studied at 25 C and after 48 h at 4 C by labeling the plasmaborne T3 (T3[T3]) with [131I]T3 and the locally generated T3 (T3[T4]) with [125I]T4. Neither the kinetics of nuclear-plasma exchange of T3[T3]. the time of appearance of T3[T4] in BAT nuclei. nor NTR maximal binding capacity (0.71 ng T3/mg DNA) was affected by hypothyroidism. Kinetic analyses indicated a maximal BAT NTR occupancy of 40% at euthyroid serum T3 concentrations if T4 is not present. Replacement with T4 normalized both serum T4 and T3. while replacement with T3 normalized serum T3; for all other doses of T4. serum T4 and T3 concentrations were predictably related to the dose. 5'D-II activity decreased with increasing doses of T4. but for each dose of T4. this activity was 2-4 times greater at 4 C than at 25 C. BAT NTR occupancy normalized with 2 micrograms T4/kg in rats maintained at 25 C and with 4 micrograms T4/kg in cold-exposed rats. although in neither condition were serum T4 and T3 normalized nor more than 30% of NTR occupied by plasma T3.(ABSTRACT TRUNCATED AT 400 WORDS).
Inhibition of pyroglutamyl peptidase II synthesis by phorbol ester in the Y-79 retinoblastoma cell, Pyroglutamyl peptidase II (EC 3.4.19.-). a highly specific membrane-bound TRH-degrading enzyme. is inactivated in Y-79 human retinoblastoma cells by exposure to 12-O-tetradecanoyl phorbol-13-acetate (TPA) in a biphasic manner. We have previously demonstrated a rapid decrease in pyroglutamyl peptidase II activity to 10% of the control level within 15 min. which returns to 70% of the control level by 1 h. This decrease results from enzyme phosphorylation by TPA-activated protein kinase-C. We now report a second phase of inactivation after longer exposure of cells to TPA. After 1 h. enzymatic activity slowly and progressively declined. By 7 h. only 15% of control activity remained. Cotreatment of cells with H-7. a protein kinase-C inhibitor. prevented this second phase of inactivation. Immunoblot experiments demonstrated a reduction in the amount of pyroglutamyl peptidase II in Y-79 membranes after long term exposure to TPA. Y-79 cells were labeled with [35S]methionine. and pyroglutamyl peptidase II was immunoprecipitated. A decreased incorporation of [35S]methionine paralleled the decrease in enzyme activity. These studies demonstrate that the second phase of inactivation after exposure to TPA is due to an inhibition of enzyme synthesis.
Multiple abnormalities in insulin responses to nonglucose nutrients in neonatally streptozotocin diabetic rats, Insulin responses to nutrient secretagogues were investigated in neonatally streptozotocin-injected (n-STZ) rats. i.e. an animal model of noninsulin-dependent diabetes. In the perfused pancreas 16 mM L-glutamine induced and 10 mM octanoate tended to induce (P less than 0.2) higher responses in n-STZ than in nondiabetic rats. Addition of 3.9 mM glucose potentiated responses to glutamine and octanoate more in n-STZ (3.3- and 3.4-fold) than in nondiabetic rats (1.5- and 1.9-fold). Conversely. the succinate derivative succinate monomethylester (Succ ME) induced lesser response in n-STZ rats (57% of that in nondiabetic rats) and coperfusion with 3.9 mM glucose increased the response less in n-STZ (1.4-fold) than in nondiabetic rats (3.8-fold). Pyruvate (20 mM) mimicked the potency of 3.9 mM glucose. i.e. pyruvate potentiated the response to Succ ME only nonsignificantly (1.2-fold) in n-STZ but markedly (4.9-fold) in nondiabetic rats. Dichloroacetate (20 mM) failed to affect the response to Succ ME together with pyruvate in n-STZ rats. To investigate the role of hyperglycemia for octanoate-induced secretion. nondiabetic rats were made hyperglycemic by 48-h glucose infusions. Octanoate-induced secretion from perfused pancreas was enhanced 3.8-fold after moderate hyperglycemia (13.2 +/- 0.6 mM) and 17-fold after marked hyperglycemia (22.7 +/- 0.6 mM). This positive association between response and degree of hyperglycemia was not found with a nonnutrient secretagogue. 3-isobutyl-1-methylxanthine. Results with glutamine and octanoate indicate that oxidation of nonglucose nutrients which normally do not regulate secretion is enhanced secondary to chronic hyperglycemia. Results with Succ ME and pyruvate suggest that early steps of oxidation of glucose are impaired in n-STZ rats.
Effects of age on seizure susceptibility in genetically epilepsy-prone rats (GEPR-9s), To study the effect of age on seizure latency. intensity. reproducibility. and mortality in genetically epilepsy-prone rats of the severe colony (GEPR-9s). 472 seizure-naive rats. ranging in age from 14 to 65 days. received a series of three audiogenic stimulations. Both the percentage of rats having one or more seizures and the percentage of seizures that were stage 9 generally increased with advancing age of the animal at the time of the first stimulation. Mean latency to seizure onset decreased while seizure intensity increased with increasing age of the animal. Reproducibility of seizure stage also increased with advancing age of the animal. The effects of senescence on seizure susceptibility were also investigated in an additional 18 prepubescent rats (25-35 days) who received three audiogenic stimulations and were tested again between the ages of 480 and 540 days with identical testing procedures. No significant changes occurred with either latency to seizure onset or seizure intensity in rats tested during prepubescence and again at senescence. Although GEPR-9s provide an excellent model of inherited seizures. latency to seizure onset. seizure intensity. and seizure reproducibility is dependent on age of the animal. Once established. however. audiogenic-induced seizures persist throughout life.
Noradrenergic abnormalities in the central nervous system of seizure-naive genetically epilepsy-prone rats, Norepinephrine (NE) concentrations were measured in 15 discrete areas of the central nervous system of two types of genetically epilepsy-prone rats (GEPRs) and in nonepileptic controls. Both moderate-seizure (GEPR-3) and severe-seizure (GEPR-9) animals had extensive abnormalities in brain NE concentration. Deficits of equal magnitude in GEPR-3s and GEPR-9s were found in the spinal cord. midbrain minus the inferior colliculus. inferior colliculus. hypothalamus. amygdala. hippocampus. occipital + parietal cortex. frontal cortex. and olfactory septum. Because both types of GEPRs share these deficits and share seizure susceptibility. we hypothesize that these areas are candidates for regulation of seizure susceptibility in GEPRs. In addition. because GEPR-9s have more severe seizures than GEPR-3s and because GEPR-9s had greater NE deficits in several brain areas (cerebellum. pons-medulla. thalamus. and possibly the temporal cortex and olfactory bulbs). we hypothesize that these areas may be important in regulation of seizure severity in GEPRs. All animals used in these experiments had been protected from seizure-provoking stimuli and were naive to seizures. Because the abnormalities in NE concentration were present in seizure-predisposed animals that were protected from seizures. we conclude that these abnormalities are important components of the seizure-predisposition characteristic of GEPRs and do not result from seizure experience.
Interictal spikes and hippocampal somatostatin levels in temporal lobe epilepsy, We investigated the relationship between somatostatin-like immunoreactivity (SSLI) and interictal spikes (IIS) in human temporal lobe epileptic tissue. IIS counted manually from depth electrode recordings obtained preoperatively were expressed as spike frequency in anterior. middle. and posterior portions of hippocampus. SSLI was determined by radioimmunoassay (RIA). An inverse relationship between SSLI in the entorhinal cortex (EC) and IIS frequency in hippocampus was present (r = -0.55. p = 0.06). No correlation between IIS and SSLI in CA4. CA3. CA1. or the dentate was evident. This finding suggests a role of the EC in generation. regulation. or expression of interictal paroxysmal electrical activity in temporal lobe epilepsy (TLE). for which somatostatin may be a marker.
Correlation of abnormalities of interictal n-isopropyl-p-iodoamphetamine single-photon emission tomography with focus of seizure onset in complex partial seizure disorders, Single-photon emission tomography (SPECT) scanning with n-isopropyl-p-iodoamphetamine (IMP) was performed on 23 patients with complex partial seizures undergoing long-term video electroencephalographic (EEG) seizure monitoring. Twenty-one of the 23 patients had abnormalities on SPECT scanning consisting of areas of decreased activity reflecting diminished cerebral blood flow. In 15 of these 21 patients. there was good correlation between the site of the abnormality on SPECT scan and the site of origin of seizures monitored by EEG. Of the six remaining patients. four had multifocal SPECT abnormalities. with one of the abnormal areas corresponding with an ictal site. The two remaining patients had SPECT abnormalities and major ictal EEG foci in entirely different areas. In contrast to the high proportion of abnormal SPECT scans. only 10 of 23 focal abnormalities were discovered on magnetic resonance imaging (MRI) scans. Three patients who had seizures within 2 h of an initial scan were rescanned 4-5 h after injection. Focal areas of increased blood flow were noted on all three scans. although not always at the ictal site. The SPECT scan appears to be useful in interictal localization of seizure foci. Postictal scans may also be useful. although our numbers are too small to draw conclusions.
Temporal lobectomy and independent bitemporal interictal activity: what degree of lateralization is sufficient, We attempted to determine whether the degree of lateralization of independent bitemporal interictal spikes and sharp waves (ISSW) is correlated with good results after temporal lobectomy. Three observers independently counted ISSW in the scalp EEGs of 59 candidates for temporal lobectomy to determine the degree of lateralization of ISSW. Interobserver correlation in percentage of lateralization was excellent (r = 0.92). Thirty-one candidates were also evaluated with depth EEG (DEEG). Operative success was graded by the number of seizures reported in the second postoperative year. There was a significant progressive decrease in the number of good operative results as the degree of lateralization of ISSW lessened (p = 0.0142). Ninety-two percent of patients with greater than 90% lateralization had a good surgical outcome. whereas only 50% with less than 90% lateralization had a good outcome. Even when all DEEG-recorded seizures emerged from the side of the lobectomy. patients with greater than 90% lateralization appeared to have better outcomes than patients with less than 90% lateralization. We conclude that greater than 90% lateralization of temporal ISSW is associated with good surgical outcome. and DEEG may not be necessary in these patients. Less than 90% lateralization is associated with poor surgical outcome and the additional information provided by DEEG may be especially useful in such patients.
An objective method for the assessment of psychosocial problems in adolescents with epilepsy, Psychosocial problems in adolescents with epilepsy have been of concern for many years. but have been difficult to assess. This article presents the multicenter development of the Adolescent Psychosocial Seizure Inventory (APSI). an empirically based self-report test patterned after the Washington Psychosocial Seizure Inventory. which is used to evaluate psychosocial problems in adults. After pilot work. 120 adolescents with epilepsy from five centers in North America took the APSI and were interviewed by professionals with respect to adequacy of adjustment in eight psychosocial areas. At least one parent or guardian was also interviewed. Interrater reliability of professional ratings in each area was established. Using an item-by-item. empirically based technique. eight psychosocial scales were developed as well as three validity scales. Reliability of the scales was established by both internal consistency and test-retest procedures. Results for each adolescent are presented in profile form. These results give a visual display of the types and extent of problems that likely would be identified in a detailed professional assessment. It is anticipated that the APSI will be of value in a variety of treatment and research contexts.
A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms, The spontaneous remission rate and long-term outcome in 44 patients with infantile spasms not treated with hormonal drugs were studied. The cumulative spontaneous remission rate during the first 12 months after onset of infantile spasms. as determined by retrospective analysis. was as follows: 1 month. 2%; 2 months. 2%; 3 months. 5%; 4 months. 7%; 5 months. 9%; 6 months. 11%; 7 months. 11%; 8 months. 14%; 9 months. 16%; 10 months. 18%; 11 months. 25%; 12 months. 25%. The average age at follow-up was 80 months. Nine percent of patients had normal development or only mild impairment. The remainder showed various degrees of retardation. These data should be useful in the design and interpretation of therapeutic drug trials in patients with infantile spasms.
Comparative pharmacodynamics and brain distribution of E-delta 2-valproate and valproate in rats, The E-isomer of 2-unsaturated valproate (E-delta 2-VPA) is a pharmacologically active metabolite of VPA that is less teratogenic and hepatotoxic than its saturated precursor. To assess potential use of E-delta 2-VPA as an alternate to VPA. a dose-response study comparing the anticonvulsant activity and neurotoxicity of E-delta 2-VPA and VPA was conducted in rats using the intravenous (i.v.) pentylenetetrazol (PTZ)-infusion threshold seizure model. Assay of drug in whole brain and plasma allowed comparison of the drug concentration-effect relationships and the brain distribution characteristics of the two compounds. E-delta 2-VPA was two to three times more potent than VPA in elevating the clonic seizure threshold of PTZ. in reference to either plasma or whole-brain drug concentrations. Furthermore. much steeper response curves were observed with E-delta 2-VPA as compared with VPA. Within the pharmacologic concentration range (defined as EC25 to EC75). E-delta 2-VPA was less neurotoxic than VPA as assessed by behavioral tests. Therefore. E-delta 2-VPA has a much more favorable protective index than VPA. At low doses. the concentration ratios of brain to plasma for both E-delta 2-VPA and VPA increased markedly with increasing plasma drug concentration. E-delta 2-VPA and VPA were previously shown to exhibit saturable binding to rat plasma proteins. If we assume that uptake of drug into the CNS is limited to the equilibrium plasma free fraction in the brain microvasculature. much of the nonlinear brain distribution features of VPA could be accounted for by saturable drug plasma protein binding. On the other hand. more complex kinetics involving simultaneous saturation of plasma protein binding and blood-to-brain transport are proposed to explain the brain distribution of the unsaturated compound. In addition. the brain-to-free drug concentration ratios for both E-delta 2-VPA and VPA were below unity at high drug-concentration range. consistent with the presence of an efficient efflux mechanism of these compounds from brain.
Effects of vigabatrin (gamma-vinyl GABA) on neurotransmission-related amino acids and on GABA and benzodiazepine receptor binding in rats, The effect of 12-day intraperitoneal i.p. administration of vigabatrin (GVG. gamma-vinyl GABA) to rats on the neurotransmission-related amino acids in various brain regions (cortex. hippocampus. cerebellum. and spinal cord). cisternal fluid (CSF) and blood was studied. Results showed that GVG administration increased the levels of GABA in cortical and subcortical regions of the brain and CSF without affecting GABA and benzodiazepine receptors in the cortex. In addition. a dose-dependent decrease was noted in the concentration of glutamate in the hippocampus and in the concentrations of aspartate and glutamine in the cortex. hippocampus. and cerebellum. The changes in the levels of amino acids in the brain. except for that of GABA. were not reflected in the CSF. however. and the levels of amino acids in discrete brain regions did not show any correlation with those in the serum or in the CSF. The results suggest that GVG administration might suppress development and spread of seizures not only by elevating the level of the inhibitory amino acid GABA. but also by decreasing the levels of excitatory amino acids in the brain.
Carbamazepine dose requirements during stiripentol therapy: influence of cytochrome P-450 inhibition by stiripentol, The inhibitory effect of stiripentol (STP) on disposition of carbamazepine (CBZ) and carbamazepine-10.11-epoxide (CBZE) was quantitated to establish CBZ dosage reduction guidelines for future clinical add-on efficacy trials of STP. In seven epileptic patients. STP (1.500-3.000 mg/day for 2 weeks) inhibited CBZ clearance by 50 +/- 16% (p = 0.001) and reduced the CBZE/CBZ plasma ratio by 45 +/- 14% (p = 0.0005). The inhibitory effect was gradually manifested over a period of 7-10 days after initiation of STP therapy. In contrast to inhibition of CBZE formation. STP had no effect (p greater than 0.05) on elimination clearance or half-life (t1/2) of CBZE in six healthy volunteers. STP most likely exerts inhibitory effects through inhibition of cytochrome P-450. This hypothesis was confirmed in the present study by the finding that a therapeutic concentration of STP (7 micrograms/mL) inhibited 10.11-epoxidation of CBZ in human liver microsomes by 40-50%. On the basis of results from this study. we propose that (a) CBZ dosage should be reduced in steps over a period of 7-10 days after initiation of STP. and (b) a CBZ dosage of 4.3 to 8.7 mg/kg/day will maintain therapeutic CBZ plasma levels of 5-10 micrograms/mL.
Negligent hiring and retention: some evidence of hospital vulnerability, Hospital human resource managers were surveyed to determine their understanding of negligent hiring employment law and the tools used in employment screening. This article describes the results. which indicate that hospital human resource managers understand the law but that there are gaps in the use of some employment screening tools. The authors make recommendations for future research.
A technique for improving accuracy of the pulmonary artery diastolic pressure as an estimate of left ventricular end-diastolic pressure, Pulmonary artery diastolic pressure (PAD) is often used to estimate left ventricular end-diastolic pressure (LVEDP) when artifact. respiratory variation. or technical difficulties make the wedge pressure difficult to identify on the waveform. To determine which point on the PAD waveform best estimated LVEDP. we performed studies in 100 adults undergoing routine diagnostic cardiac catheterization. During normal spontaneous respiration. simultaneous recordings of the electrocardiogram. PAD. and LVEDP were obtained. Three end-expiratory measurements of PAD were recorded: at the lowest point on the waveform (PAD). at 0.04 seconds (PAD 0.04). and at 0.08 seconds (PAD 0.08) after the onset of the QRS complex. The PADs were correlated with LVEDP by linear regression. PAD 0.08 correlated best with LVEDP (r = 0.88. standard error of the estimate [SEE] = 3.6 mm Hg) whereas PAD 0.04 and PAD correlated slightly less strongly (r = 0.86. SEE = 4.0 mm Hg; r = 0.82. SEE = 4.4 mm Hg respectively). Therefore. when the wedge pressure is not easily determined. PAD 0.08 may be the best point on the waveform to use when attempting to estimate LVEDP in the clinical setting.
Effects of two chest tube clearance protocols on drainage in patients after myocardial revascularization surgery, The purpose of the study was to determine the effects of two methods of clot clearance on chest tube drainage in patients undergoing myocardial revascularization. Two hundred adult patients immediately after myocardial revascularization were randomly assigned to a specific chest tube manipulation group. The dependent variables were drainage. incidence of cardiac tamponade. incidence of surgical reentry. hemodynamic values. and number of manipulation episodes. Statistical analyses revealed no difference in any of the dependent variables when milking and stripping were used. Of the 200 patients. 78 did not require any manipulation of the chest tubes in the first 8 hours after surgery. One patient had signs of cardiac tamponade and six other patients required surgical reentry. Positioning of the connecting tube in a nondependent position assisted with the removal of drainage from the chest cavity. In conclusion. patients having myocardial revascularization did not need their chest tubes manipulated the first 8 hours after surgery. Visible drainage in the chest tube did not cause a lack of patency.
Sensations during chest tube removal, Nurses prepare patients for chest tube removal. yet little has been written to indicate the sensations to be expected during this routine procedure. The sensations reported by patients and factors that could influence those sensations were examined in this study. The sample consisted of 36 patients after thoracic surgery (24 men and 12 women). all of whom were scheduled to have either a mediastinal or a pleural tube removed. They reported their sensations and the intensity of those sensations (using a 100 mm visual analog scale) within 15 minutes after tube removal. The most frequently reported sensation during chest tube removal was burning. followed by pain and pulling with mean intensities of 64. 62. and 45. respectively. Subjects reported having few sensations after the tube was removed with only five reporting soreness in the chest. The sensations and intensities did not differ for those who did and did not receive analgesia or for those having a pleural tube versus a mediastinal tube removed. The sensations were similar for the old and young subjects with younger subjects reporting higher intensities. Women reported pain more frequently than men. but the intensities of the sensations reported by men and women were not significantly different. The sensations reported during chest tube removal differ from those described in the literature and can be used to prepare patients more appropriately for chest tube removal.
Preoperative pulmonary status and postoperative extubation outcome of patients undergoing elective cardiac surgery, The purpose of this study was to determine whether factors associated with impaired pulmonary function were predictive of postoperative extubation outcome (extubation according to protocol or delayed extubation) in a sample of patients undergoing elective cardiac surgery. Forty-seven patients were assessed before surgery and after postoperative extubation using a noninvasive assessment technique. Positive preoperative affect was the sole factor associated with extubation outcome in this sample of patients undergoing cardiac surgery. Those who were extubated according to hospital protocol had significantly higher positive affect scores (p = 0.02) than did those who were not. Subjects with delayed extubations had a greater incidence of postoperative atelectasis (p = 0.02). They also had significantly longer stays in the surgical intensive care unit (p = 0.01) and the hospital (p = 0.05). Preoperative pulmonary function. age. sex. and history of smoking were not associated with postoperative extubation outcome.
Effects of occupied and unoccupied bed making on myocardial work in healthy subjects, Strict bed rest prescribed after acute myocardial infarction provides rest for the heart in an effort to lessen myocardial work. However. bed rest has been implicated as a threat to physical and psychosocial well-being. Nurses must question whether activities associated with bed rest. such as bed making by hospital personnel while the patient is occupying the bed. actually require less myocardial work than out-of-bed activities. In this study we examined cardiovascular function of 22 healthy individuals. 10 (45.5%) men and 12 (54.5%) women ranging in age from 34 to 69 years (mean 48 years). during occupied (side to side method) and unoccupied (patient up to chair) bed making. Cardiac output. heart rate. stroke volume. systolic blood pressure. diastolic blood pressure. mean arterial pressure. total peripheral resistance. and the ratio of preejection period to left ventricular ejection time were measured by using an impedance cardiograph and vital signs monitor. Although differences between these measurements during the two bed making procedures were statistically significant (p less than 0.001). they were not deemed clinically significant for healthy subjects because they represent transient reflexive responses to posturally induced changes in venous return rather than substantial increases in myocardial work. When the goal is minimal myocardial energy expenditure. making the bed when it is unoccupied may offer a sound alternative to making an occupied bed.
Right ventricular infarction: a clinical case study, In this article we review the specific case of Mrs. F.. a 63-year-old white woman who recently had classical right ventricular infarction associated with left ventricular inferior wall myocardial infarction. The presentation covers her medical history. clinical course pathophysiology of the right ventricular infarction. and goals of the medical modalities used in treatment. Nursing problems are identified specifically related to right ventricular infarcts. and treatment considerations are discussed. A brief conclusion recaps Mrs. F.'s discharge course and reviews some specific problems associated with right ventricular infarcts. of which critical care nurses need to be aware.
Evaluation of animal models for the study of exercise-induced muscle enlargement, Skeletal muscle is known to enlarge in response to high-resistance training programs in humans. Study of the cellular mechanisms of muscle enlargement and the adaptations of muscle to strength-training programs has been difficult because of the need to analyze entire muscles. This precludes the use of human subjects in many experiments of this nature. Several animal models have been developed for the study of muscle enlargement; these models basically fall into three categories: 1) stretch hypertrophy. 2) compensatory hypertrophy. and 3) exercise-induced hypertrophy. This review attempts to analyze these models as models of muscle enlargement produced by strength training in humans. Three areas must be considered when evaluating animal models of human muscle enlargement produced by strength training: 1) response topography. 2) magnitude of enlargement. and 3) muscle fiber adaptations produced as a result of the enlargement. Based on these considerations. it is concluded that none of the animal models currently in use truly represents the human strength-training situation under all conditions. All three models. however. provide valuable information about the plasticity of skeletal muscle in response to a broad spectrum of muscle enlargement.
Effect of increased left atrial pressure on breathing frequency in anesthetized dog, Distension or loading of the isolated canine left heart caused reflex tachypnea in prior studies. The object of the present effort was to explore the possibility that this depended primarily on atrial distension. Cardiopulmonary bypass perfusion and ligation of pulmonary veins were used to isolate the left-heart chambers of anesthetized dogs. Simultaneous distension of the beating left atrium and fibrillating ventricle stimulated breathing frequency (f). whereas isolated ventricular distension did not. At other times. intervals of atrial fibrillation were imposed under two different conditions: 1) while the right heart and lungs were bypassed and systemic perfusion was provided by the left ventricle using blood returned to the left atrium by pump and 2) while the ventricles fibrillated and systemic perfusion was supplied directly by the pump. Atrial fibrillation increased left atrial pressure and stimulated f in condition 1. In condition 2. f increased only if fibrillation was associated with a rise in left atrial pressure. Vagal cooling blocked the effect of fibrillation. I conclude that left atrial distension may initiate reflex tachypnea.
Substrate utilization during acute exercise in obese Zucker rats, The purpose of the present study was to compare the carbohydrate use of insulin-resistant obese Zucker rats with that of their lean littermates during steady-state exercise. Obese and lean rats were randomly assigned to a sedentary group or to a run group in which rats ran at 72-73% of their maximal O2 consumption. with the duration of exercise set to require an energy expenditure of 2.1-2.2 kcal. During the run the respiratory exchange ratio was significantly higher in the obese than in the lean rats [0.94 +/- 0.01 (SE) and 0.86 +/- 0.01. respectively]. which indicate that the obese rats required 54% more carbohydrate than the lean rats. Total muscle glycogen utilization in the soleus. plantaris. and red and white gastrocnemius was not different between groups. Obese rats had total liver glycogen values five times greater than those of lean rats (833.38 +/- 101.4 and 152.8 +/- 37.5 mg. respectively) and utilized twice as much liver glycogen as their lean littermates (193.5 and 90.4 mg. respectively). The obese rats exhibited higher blood glucose and insulin concentrations than the lean rats during the run. These findings indicate that. despite their characteristic insulin resistance. the obese Zucker rats had a greater dependency on carbohydrate as a substrate during exercise than their lean littermates and that the major source of this carbohydrate was liver glycogen.
Thyroarytenoid muscle activity during hypoxia in awake lambs, It is generally accepted that hypoxia in early life results in active laryngeal braking of expiratory airflow via the recruitment of glottic adductor muscles. We examined the electromyogram expiratory activity of the thyroarytenoid muscle in seven 11- to 18-day-old awake nonsedated lambs exposed to an inspired O2 fraction of 0.08 for 18 min. The lambs breathed through a face mask and a pneumotachograph. During baseline prehypoxic breathing. the thyroarytenoid muscle was largely inactive in each awake lamb. Unexpectedly. no recruitment of the thyroarytenoid muscle was recorded during hypoxia in any of the seven lambs; simultaneous examination of the flow-volume curves revealed an absence of expiratory airflow braking. Also unexpectedly. marked expiratory activity of the thyroarytenoid muscle was recorded. with each expiration occurring within less than 10 s after the return to room air. The resulting delay of expiration was apparent in the flow-volume loops. Thus. in awake 11- to 18-day-old lambs. 1) active expiratory glottic adduction is absent during hypoxia and 2) a return from hypoxia to room air results in prolonged expiration as well as active glottic adduction that controls end-expiratory lung volume.
Role of xanthine oxidase and neutrophils in ischemia-reperfusion injury in rabbit lung, This study evaluated the effect of ischemia-reperfusion (I-R) on pulmonary capillary permeability in isolated rabbit lungs and the roles of xanthine oxidase (XO). aldehyde oxidase (AO). and neutrophils (PMN) in producing this lung injury. Effects of XO and AO were studied by inactivation with a tungsten-enriched diet (0.7 g/kg) and inhibition of XO by allopurinol (100 microM) or AO by menadione (3.5 microM). PMN effects were studied by preventing endothelial adhesion with the monoclonal antibody IB4 (10 microM). Vascular permeability was evaluated by determining the capillary filtration coefficient (Kf.c) measured before and after I-R in all experimental conditions. Reperfusion after 2 h of ischemia significantly increased pulmonary capillary permeability (Kf.c changed from 0.096 +/- 0.014 to 0.213 +/- 0.025 ml.min-1. cmH2O-1.100 g-1). and this increase was blocked by the addition of catalase (50.000 U) at reperfusion (baseline Kf.c was 0.125 +/- 0.023 and 0.116 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). XO inactivation with the tungsten-supplemented diet and XO inhibition with allopurinol prevented the Kf.c increase observed after I-R (0.183 +/- 0.030 to 0.185 +/- 0.033 and 0.126 +/- 0.018 to 0.103 +/- 0.005 ml.min-1.cmH2O-1.100 g-1). Inhibition of AO had no effect on I-R injury (Kf.c 0.108 +/- 0.011 to 0.167 +/- 0.014 ml.min-1.cmH2O-1.100 g-1). Preventing PMN adhesion resulted in significant attenuation of the change in Kf.c associated with I-R (0.112 +/- 0.032 to 0.090 +/- 0.065 ml.min-1.cmH2O-1.100 g-1). We conclude that XO and PMN adherence. but not AO. are involved in the increased capillary permeability associated with I-R.
Changes in lung mechanics and reactivity with age after viral bronchiolitis in beagle puppies, We measured changes with growth in lung function and airway reactivity after acute canine parainfluenza virus type 2 (CPI2. n = 5). canine adenovirus type 2 (CAV2. n = 7). and sequential CAV2-CPI2 (n = 6) infections or no infection (controls. n = 6) in beagle puppies (age approximately 79 days). In the CPI2 and CAV2 groups. a lower respiratory illness developed by day 3 postinfection with clinical recovery by day 14. In the CAV2-CPI2 group. puppies were inoculated initially with CAV2 and 12 days later with CPI2. In this group. illness persisted until day 14 after infection with CPI2. Lung resistance (RL). dynamic (Cdyn) and static (Cst) lung compliance. functional residual capacity (FRC). and responsiveness to aerosolized histamine were measured before infection and at periodic intervals until 239 +/- 43 days of age. Lung function data were analyzed using a longitudinal random effects model. In all groups. FRC. Cst. and Cdyn increased with age. In all infected groups. the regression slopes for Cdyn were steeper than in controls. RL decreased linearly with age without group slope differences. Histamine reactivity increased with age. but there were no differences in slope among groups. Lung pathological studies showed areas of obliterative bronchiolitis and chronic small airways inflammation particularly in the CAV2 and CAV2-CPI2 groups. Thus. viral bronchiolitis produces chronic small airways inflammation in beagle puppies and alters the changes in lung function occurring with growth. Histamine reactivity increases with age and is not modified by viral infection.
Cardiovascular-sympathetic adjustments to nonexertional heat stress in mature and senescent Fischer 344 rats, The purpose of this study was to test the hypothesis that the cardiovascular-sympathetic nervous system adjustments during nonexertional heat stress are exaggerated in senescent (S. 24 mo) vs. mature (M. 12 mo) conscious unrestrained Fischer 344 rats. During two separate trials (48 h apart). each animal was exposed to an ambient temperature (Ta) of 42 degrees C until a colonic temperature (Tco) of 41 degrees C was attained and then cooled at a Ta of 26 degrees C until Tco returned to the initial control level. Trial 1: heart rate (HR). mean arterial blood pressure (MAP). and arterial plasma concentrations of norepinephrine (NE). epinephrine (E). and lactate (La) were similar between the S and M groups during the baseline (control) period. The absolute increases in HR. MAP. NE. and E from the control period to the end of heating were of similar magnitudes between groups; however. La increased more in the S than M animals (P less than 0.05). During recovery. the declines toward control levels for all variables were similar or even more rapid in the S vs. M animals (P less than 0.05). Trial 2: the changes in HR and MAP during heating were similar to those observed in trial 1 in both groups. Generally. NE and E control levels were elevated in both groups compared with those in trial 1. The absolute increases in NE during heating were similar to trial 1 in both groups. whereas E increased to a greater extent than in trial 1 in the S animals (P less than 0.05).
Lung injury in a surfactant-deficient lung is modified by indomethacin, Repetitive total lung lavage in adult rabbits leads to a reproducible severe surfactant-deficient lung injury. Hypoxemia requiring mechanical ventilation occurs. accompanied by a substantial pulmonary hypertension. a large intra-alveolar protein leak. peripheral neutropenia. and pathological features of marked neutrophil infiltration with extensive hyaline membrane formation. Pretreatment with indomethacin abolishes postlavage pulmonary hypertension. preserves a slightly better lung function with higher arterial PO2. and prevents the postlavage peripheral neutropenia found in untreated animals. Pretreatment with a thromboxane A2 receptor blocker (L 655.240. Merck Frosst. Canada) also completely attenuated pulmonary hypertension. providing evidence that thromboxane A2 mediates pulmonary arterial hypertension after lung lavage. However. specific thromboxane receptor blockade had no other long-lasting beneficial effects on the ongoing injury in this model.
Persistence of enhanced aerosol deposition in the lung after recovery from carbachol-induced airway obstruction, Time course recovery from induced airway obstruction by carbachol infusion (CI; 0.2 microgram.kg-1.min-1 for 40 min). carbachol aerosol (CA; 10 breaths of 2% solution). and histamine aerosol (HA; 25-50 breaths of 5% solution) challenge was investigated in conscious sheep (n = 6 each). Total lung aerosol deposition and airway caliber as assessed by pulmonary airflow resistance (RL) were measured every 20-30 min up to 4 h after the challenges. Aerosol deposition was measured by monitoring aerosol concentration continuously with a laser aerosol photometer while the sheep rebreathed 1.0-micron-diam inert oil droplets delivered by a 0.25-liter bag-in-box system driven by a respiratory pump at a breathing frequency of 30 breaths/min. Total accumulated deposition at the fifth breath (AD5) as percentage of the initial aerosol concentration was determined and used as an aerosol deposition index. Percent changes in AD5 from baseline were compared with corresponding changes in RL. Both RL and AD5 increased after Cl. CA. and HA: 192-477% for RL and 23-44% for AD5 (P less than 0.05). Mean RL return to baseline values 1 h after CI and HA and 2 h after CA. Mean AD5 returned to baseline at 1 h post-HA. In contrast. mean AD5 remained elevated for 2-4 h after CI and CA (P less than 0.05). and the increased AD5 could not be reversed by a bronchodilator aerosol. The persistence of enhanced aerosol deposition long after the return of RL to baseline suggests that complete recovery of airway conditions after CI and CA takes much longer than predicted by RL.
Beta-adrenergic effects on carbohydrate metabolism in the unweighted rat soleus muscle, The effects of insulin on carbohydrate metabolism in atrophied rat soleus muscle are increased after unweighting by tail-cast suspension. This work has been extended by testing the effect of unweighting on the response of carbohydrate metabolism to isoproterenol. a beta-adrenergic agonist. Isoproterenol promoted glycogen degradation more in the unweighted than in the weight-bearing soleus but showed no differences in the extensor digitorum longus. which is unresponsive to hindlimb unweighting. In soleus muscles depleted of glycogen. to avoid varied inhibitory effects of glycogen on glycogen synthesis. isoproterenol inhibited this process more in the unweighted muscle. Isoproterenol did not have a greater inhibitory effect on net uptake of 2-deoxy-D[1.2-3H]glucose by the unweighted muscle. Measurements of intracellular 2-deoxy-[3H]glucose 6-phosphate and 3-O-methyl-D-[1-3H]glucose. which cannot be phosphorylated. showed that isoproterenol inhibited glucose phosphorylation but not transport. This effect could be explained by an increase of glucose 6-phosphate. an inhibitor of hexokinase. At 100 microU insulin/ml but not at a lower amount (10 microU/ml). isoproterenol inhibited hexose phosphorylation more in the control than in the unweighted muscle. This result may be explained by greater insulin antagonism in the unweighted muscle owing to increased insulin sensitivity. However. insulin antagonism of isoproterenol stimulation of glycogenolysis or inhibition of glycogenesis was not altered by unweighting. Therefore. for some aspects of carbohydrate metabolism. the unweighted muscle has an increased response to beta-adrenergic activation. just as this muscle shows increased responses to insulin.
Hemodynamic effects of synchronous high-frequency jet ventilation in mitral regurgitation, We tested the hypothesis that increases in intrathoracic pressure (ITP). by decreasing the pressure gradient for anterograde left ventricular (LV) ejection. should augment cardiac output in acute mitral regurgitation (MR). In a pentobarbital-anesthetized closed-chest canine model. LV stroke volume (SLLV) was measured by integration from an aortic flow probe signal. MR was induced by a regurgitant ring. ITP was elevated over apnea by means of intermittent positive-pressure ventilation (IPPV). asynchronous (asynch) high-frequency jet ventilation (HFJV). and cardiac cycle-specific (synch) HFJV. IPPV resulted in the greatest increase in ITP. MR caused a fall in SVLV and a rise in LV filling pressure that were not altered by IPPV. Compared with IPPV or apnea. both asynch and synch HFJV increased SVLV and reduced LV filling pressures (P less than 0.05). Systolic synch HFJV induced a greater increase in SVLV (32%) than diastolic synch HFJV (26%) despite similar ventilatory settings. Our data suggest that when LV contractility is normal but MR impairs forward flow. cardiac cycle-specific increases in ITP will augment forward flow.
Transfer function of sound transmission in subglottal human respiratory system at low frequencies, The amplitude of sound transmission from the mouth to a site overlying the extrathoracic trachea and two sites on the posterior chest wall was measured in eight healthy adult male subjects at resting lung volume over the 100- to 600-Hz frequency range. The ratios of the estimated magnitude spectra of transmission of each of the chest wall sites to the tracheal site were determined. with the resulting spectra representing effective transfer functions of transmission in the subglottal system. For the group. the transfer functions exhibited a single peak. which occurred at 143 +/- 13 Hz (mean +/- SD) with a quality factor (Q) of 2.0 +/- 0.2 for the upper chest wall site and at 129 +/- 6 Hz with a Q of 2.2 +/- 0.4 for the lower site. The trend of decreasing spectral energy with increasing frequency was indicated by roll-offs of -10 +/- 4 and -17 +/- 5 dB/octave from 300 to 600 Hz at the two sites. respectively. The fundamental radial mode of a model thoracic cavity. which is a large rigid cylinder filled with lossless lung tissue. provides a good estimate of the observed low-frequency resonance. This agreement suggests that thoracic cavity resonances may have particularly important effects on sound transmission at frequencies below approximately 250 Hz. where the magnitude of parenchymal attenuation appears to be small.
Neurogenic inflammation of the rat trachea: fate of neutrophils that adhere to venules, The goal of this study was to determine whether neutrophils that adhere to the vascular endothelium in association with neurogenic inflammation in the respiratory tract migrate out of the blood vessels or whether they detach and reenter the circulation. We also sought to determine whether the fate of the neutrophils is influenced by neutral endopeptidase (NEP). an enzyme that degrades the tachykinins that produce neurogenic inflammation. Neutrophils in the tracheal mucosa of anesthetized pathogen-free rats were examined 5 min or 4 h after neurogenic inflammation was produced by an injection of capsaicin (100 or 200 micrograms/kg iv). In whole mounts of these tracheae stained histochemically for myeloperoxidase. adherent intravascular neutrophils had a spherical or teardrop (regular) shape and migrating neutrophils had a polarized amoeboid (irregular) shape. The number of regular neutrophils in the tracheae was increased at both times. but the increase at 4 h was only half that present at 5 min. The reduction between 5 min and 4 h was not offset by an appreciable increase in the number of irregular neutrophils. unless NEP was inhibited by phosphoramidon. We interpret these results as indicating that the rapid adherence of neutrophils to the vascular endothelium after an injection of capsaicin is followed by a gradual reentry of the neutrophils into the circulation and comparatively little neutrophil migration. However. when the effect of the stimulus is increased and/or prolonged by inhibition of NEP. some of the adherent neutrophils migrate out of the vessels. Thus the activity of NEP can regulate both the magnitude of the neutrophil adherence and the fate of the adherent cells.
Cystic fibrosis, vasoactive intestinal polypeptide, and active cutaneous vasodilation, The transmitter substance for the active cutaneous vasodilation that accompanies sweating during hyperthermia in humans is unknown. Hokfelt et al. (Nature Lond. 284: 515-521. 180) hypothesized that it is vasoactive intestinal polypeptide (VIP) that is cotransmitted with acetylcholine. Heinz-Erian et al. (Science Wash. DC 229: 1407-1408. 1985) reported that VIP innervation is sparse in the skin of persons with cystic fibrosis (CF). A corresponding attenuation of active vasodilation in these subjects would be evidence that VIP is involved in this effector mechanism of human thermor-regulation. Immunocytochemical analysis of skin biopsies from four men with CF confirmed that VIP innervation was sparse. We also analyzed immunoreactivity for calcitonin gene-related peptide (CGRP; normal). substance P (normal). and neuropeptide Y (low). VIP-immunoreactive Merkel cells were abnormal. Despite sparse VIP-immunoreactive innervation. our CF subjects' cutaneous vascular responses to hyperthermia were normal. Because VIP was not completely absent. this evidence is insufficient to rule out VIP as the vasodilator transmitter. However. the CGRP and substance P innervation we observed could mean that release of one or both of these peptides was the mechanism of the fully developed active cutaneous vasodilation.
Pulmonary arterial and venous constriction during hypoxia in 3- to 5-wk-old and adult ferrets, We have determined the sites of hypoxic vasoconstriction in ferret lungs. Lungs of five 3- to 5-wk-old and five adult ferrets were isolated and perfused with blood. Blood flow was adjusted initially to keep pulmonary arterial pressure at 20 cmH2O and left atrial and airway pressures at 6 and 8 cmH2O. respectively (zone 3). Once adjusted. flow was kept constant throughout the experiment. In each lung. pressures were measured in subpleural 20- to 50-microns-diam arterioles and venules with the micropipette servo-nulling method during normoxia (PO2 approximately 100 Torr) and hypoxia (PO2 less than 50 Torr). In normoxic adult ferret lungs. approximately 40% of total vascular resistance was in arteries. approximately 40% was in microvessels. and approximately 20% was in veins. With hypoxia. the total arteriovenous pressure drop increased by 68%. Arterial and venous pressure drops increased by 92 and 132%. respectively. with no change in microvascular pressure drop. In 3- to 5-wk-old ferret lungs. the vascular pressure profile during normoxia and the response to hypoxia were similar to those in adult lungs. We conclude that. in ferret lungs. arterial and venous resistances increase equally during hypoxia. resulting in increased microvascular pressures for fluid filtration.
Effect of positive airway pressure on capillary transit time in rabbit lung, We used fluorescence videomicroscopy to measure the passage of fluorescent dye through the subpleural microcirculation of the lung. With the rabbit in the left lateral decubitus position. the subpleural microcirculation was viewed either through a transparent parietal pleural window located in the superior part of the chest or directly with the chest open. There was no physical contact with the chest or lung. The rabbit was anesthetized. paralyzed. and mechanically ventilated with 100% O2. The dye was injected into the right ventricle during a 2-min apneic period to eliminate lung movement due to ventilation. The video signal of the passage of the dye was analyzed frame by frame by use of digital image processing to compensate for cardiogenic oscillations of the lung surface. Gray scale levels of an arteriole and adjacent venule were measured every 1/30 s. Capillary transit time was determined from the difference between the concentration-weighted mean time values of the arteriolar and venular dye dilution curves. We studied the effect of airway pressure (0-20 cmH2O) on transit time. Cardiac output was measured at different airway pressures by the thermal dilution technique. Capillary transit time averaged 0.60 s at functional residual capacity. Right ventricular-to-arteriolar transit time was four times as large as the capillary transit time. An increase in airway pressure from 0-5 to 20 cmH2O resulted in a fourfold increase in both capillary and arterial transit times and a threefold decrease in cardiac output.
Cholinergic stimulation of the pons depresses respiration in decerebrate cats, The injection of carbachol into the pontine tegmentum of decerebrate cats evokes a postural motor atonia that has many of the characteristics of the atonia of natural rapid-eye-movement (REM) sleep (Morales et al. J. Neurophysiol. 57: 1118-1129. 1987). We have used the carbachol-injected decerebrate cat to study the changes in respiratory neuronal activity that accompany the atonia. The activities of representative respiratory motor nerves--phrenic. intercostal. and hypoglossal--and that of a motor branch of C4 were recorded in decerebrate. vagotomized. paralyzed. and artificially ventilated cats. After the microinjection of carbachol. there was a profound suppression of activity in all the nerves and a decrease in respiratory rate. This was a consistent stereotyped response in which the magnitude of the suppression of respiratory-related activity was phrenic (to approximately 65% of control) less than inspiratory intercostal (approximately 50%) less than hypoglossal (approximately 10%) less than expiratory intercostal (approximately 5%). The decrease in respiratory rate (to approximately 70% of control) was caused by a prolongation of both inspiratory and expiratory durations. Complete reversal of the carbachol effect was elicited by the microinjection of atropine into the same site as the carbachol injection. This allowed us to produce a second episode of atonia by the injection of carbachol into the contralateral pons. Thus we have demonstrated the existence of neural pathways originating in the cholinoceptive cells of the pons that have the potential to powerfully and differentially depress various respiratory motoneuronal pools and to reduce the respiratory rate. These pathways are likely to be activated along with the atonia of REM sleep.
Tibial torsion measured by ultrasound in children with talipes equinovarus, Previous clinical studies have studied tibiofibular torsion by measuring the angular difference between a proximal (often bicondylar) plane and a distal bimalleolar plane. We measured the angular difference between the proximal and distal posterior tibial planes as defined by ultrasound scans. We found no significant torsional difference between the right and left tibiae of 87 normal children. nor between their different age groups. The mean external torsion of 58 legs with congenital talipes equinovarus was 18 degrees; significantly less than the mean 40 degrees in the normal children and 27 degrees in the clinically normal legs of the 22 patients with unilateral congenital talipes equinovarus. We did not confirm the previously reported increase in external torsion with increasing age. The relative internal tibial torsion we have demonstrated in patients with congenital talipes equinovarus must be differentiated from the posterior displacement of the distal fibula observed by others and which may result from manipulative treatment. The relative internal tibial torsion we found in the clinically normal legs of children with congenital talipes equinovarus is further evidence that in this condition the pathology is not confined to the clinically affected foot.
Free vascularised fibular grafts for congenital pseudarthrosis of the tibia, We describe 11 patients with congenital pseudarthrosis of the tibia treated by a free vascularised fibular graft (FVFG) and followed up from 10 to 64 months (mean 38). Bony union was achieved in nine of the 11 cases: two failures required amputation. The mean time for union in the successful cases was five months. Nine of the 11 patients had had an average of four surgical procedures before the FVFG. so the graft was a salvage procedure for which the only alternative was amputation. FVFG is recommended as a primary procedure for the treatment of congenital pseudarthrosis of the tibia if there is a large tibial defect (over 3 cm) or shortening of more than 5 cm. The primary use of this operation is not advised for cases in which standard orthopaedic procedures are expected to succeed. For a small defect with a favourable prognosis (Boyd and Sage 1958). we recommend conventional bone grafting. intramedullary nailing and electrical stimulation.
Neonatal hip stability and the Barlow test. A study in stillborn babies, Ten normal neonatal hips were examined in stillborn babies. At first. forcible Barlow manoeuvres did not produce subluxation or dislocation. but by repeated examination a previously stable joint could be rendered unstable. Dissection of the hips showed that the vacuum fit between the femur and the acetabulum was an important factor in neonatal hip stability. The posterior capsule was not a strong or. in itself. an important structure. It is postulated that the capsule and the labrum act together as 'O' rings to maintain the vacuum fit; it is possible that repeated examinations. by producing an effusion. could break the seal and allow instability.
Sequential magnetic resonance imaging in Perthes' disease, Forty-eight images using magnetic resonance imaging (MRI) in 16 hips with Perthes' disease were evaluated over a mean period of two years. MRI depicted exactly the infarcted zone in the femoral head before typical radiological changes were evident. Early determination of the extent of the infarcted bone on MRI benefits those patients who require treatment. Follow-up MRI scans at six-monthly intervals. reflected the chronological stages of the repair process in each group classified according to Catterall.
Chiari's osteotomy in the treatment of Perthes' disease, Seventeen patients. with an average age of nine years 11 months. underwent 18 Chiari osteotomies for the treatment of painful subluxation of the hips following Perthes' disease. The average follow-up period was four years three months. The 13 patients reviewed clinically all did well and none complained of pain or instability. The radiographs were examined in all 17 cases. The average centre-edge angle and percentage femoral head cover were definitely improved by the operation. No significant medical displacement of the femoral head was achieved. The clinical success may result from improved femoral head coverage and diminished eccentricity. Chiari's osteotomy is recommended for adolescent patients with painful subluxation of the hip as a consequence of Perthes' disease.
Proximal femoral allografts in revision hip arthroplasty, We followed prospectively 69 patients with 78 proximal femoral allografts performed for revision of total hip arthroplasty for an average of 36 months (range 29 to 68). Large fragment proximal femoral allografts and cortical strut allografts were successful in 85%. Grafts smaller than 3 cm in length (calcar grafts) were clinically successful in 81%. but 50% underwent significant radiographic resorption. We conclude that large proximal femoral allografts and cortical strut allografts provide dependable reconstruction of bone stock deficiencies during revision total hip arthroplasty.
A bioabsorbable delivery system for antibiotic treatment of osteomyelitis. The use of lactic acid oligomer as a carrier, We prepared a composite of D.L-lactic acid oligomer and dideoxykanamycin B for use as a biodegradable antibiotic delivery system with sustained effect. The composite was implanted in the distal portion of the rabbit femur. and the effective concentration of the antibiotic was measured in the cortex. the cancellous bone. and the bone marrow. In all bone tissues around the implant. the concentration of antibiotic exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis for six weeks. Most of the implant material had been absorbed and the bone marrow had been repaired to a nearly normal state within nine weeks of implantation. The implant caused no systemic side effects. and it is likely to prove clinically useful as a drug delivery system for treating chronic osteomyelitis.
The snapping hip. Treatment by Z-plasty, We describe a new method of Z-plasty for the snapping hip caused by a tight band in the iliotibial tract. Eight hips in six patients were treated by this method and at follow-up all had a successful result. with relief of snapping.
Sagittal plane laxity following knee arthroplasty, We measured the sagittal laxity in 70 knee replacements at least six months after surgery. using a KT 1000 arthrometer. With an unconstrained prosthesis (the Oxford meniscal knee) anteroposterior stability was normal in joints known to have intact cruciate ligaments. There was increased laxity in those which lacked an anterior cruciate ligament. In knees with an intact anterior cruciate ligament. sagittal laxity did not increase with time.
Iatrogenic injuries of peripheral nerves, In this study. we discuss 68 cases in which peripheral nerve trunks were inadvertently divided by surgeons. Most of these accidents occurred in the course of planned operations. Delay in diagnosis and in effecting repair was common. We list the nerves particularly at risk and the operations in which special care is needed. We recommend steps to secure prompt diagnosis and early treatment.
Bone weakness after the removal of plates and screws. Cortical atrophy or screw holes, Bone weakness leading to refracture is a recognised complication of the removal of rigid fixation plates. We have used partially demineralised rabbit tibiae to simulate atrophic changes and to determine whether weakness is due to atrophy or to residual screw holes. Partial demineralisation and a screw hole each reduced maximum bending moment. However. energy absorbing capacity was little affected by demineralisation. but was reduced to 50% by a single drill hole. Residual screw holes are a considerably more important cause of bone weakness after plate removal than is cortical atrophy.
Forearm fractures in children. Cast treatment with the elbow extended, Fractures of the proximal forearm in young children may be unstable with the elbow flexed but stable with it in extension. Fifteen such fractures were managed by immobilisation in long-arm casts with the elbow extended. Only one patient had more than 15 degrees angulation at the time of bony union. All obtained normal elbow movement at two weeks and full forearm rotation at follow-up. No casts fell off. The extended elbow cast is awkward but it provides an alternative to internal fixation for some unstable fractures.
External fixation for intra-articular fractures of the distal radius, In a prospective study of 132 patients with an average age of 35 years. unstable intra-articular fractures of the distal radius were treated by external fixator. Only 15 cases required limited open reduction. Follow-up was for a mean of 42 months. There were few complications and 83% of patients had good or excellent results. There was a statistically significant correlation between the severity of the fracture and the clinical outcome. irrespective of radiological restoration. Articular and soft-tissue damage following violent compressive forces may lead to a degree of functional impairment.
Unstable Colles' fractures in elderly patients. A randomised trial of external fixation for redisplacement, We report the results of a prospective randomised controlled trial of the management of 101 Colles' fractures in patients over the age of 55 years. Within two weeks of initial reduction 43 fractures had displaced with either more than 10 degrees dorsal angulation or more than 5 mm radial shortening. These patients were randomly divided into two groups: 21 were remanipulated and held by an external fixator; in the control group of 22 patients. the redisplacement was accepted and conservative treatment was continued. Patients treated with external fixation had a good anatomical result. but their function was no better than that of the control group. We found no correlation between final anatomical and functional outcome. and concluded that the severity of the original soft-tissue injury and its complications are the major determinants of functional end result.
The treatment of Colles' fracture. Immobilisation with the wrist dorsiflexed, In a prospective study. 204 consecutive patients with displaced Colles' fractures had closed reduction then plaster immobilisation. Three different positions of the wrist in plaster were randomly allocated: palmar flexion. neutral and dorsiflexion. The results in the three groups were compared. Fractures immobilised with the wrist in dorsiflexion showed the lowest incidence of redisplacement. especially of dorsal tilt. and had the best early functional results. Immobilisation of the wrist in palmar flexion has a detrimental effect on hand function; it is suggested that it is also one of the main causes for redisplacement of the fracture. This is discussed in relation to the functional anatomy of the wrist and the mechanics of plaster fixation.
Compound tibial fractures with bone loss treated by the Ilizarov technique, We report our experience of the use of the Ilizarov technique to treat nine patients with severe compound tibial fractures. The mean defect in bone was 6.3 cm. and four cases were infected. All nine patients had satisfactory union and function without the use of bone grafts or antibiotics. The Ilizarov technique was very satisfactory; there were no major complications.
Open fractures of the pelvis. Review of 43 cases, We reviewed 43 patients treated from 1984 to 1988 for open fractures of the pelvis. There were four Gustilo type I wounds. seven type II and 32 type III; 22 fractures were stable and 21 unstable. The overall mortality was 30%; the average Injury Severity Score was 30. being 26 in the survivors and 40 in the fetal cases. We analysed the influence of a number of factors on the mortality rate. The most important were the ISS and the age in years. while the presence of a type III wound and instability of the fracture also had an influence. We describe two simple methods of assessment of the prognosis in individual cases. based on these factors.
Coccydynia. Aetiology and treatment, A five-year prospective trial involving 120 patients was undertaken to investigate the aetiology and treatment of coccydynia. The cause lies in some localised musculoskeletal abnormality in the coccygeal region. Lumbosacral disc prolapse is not a significant factor. The condition is genuine and distressing and we found no evidence of neurosis in our patients. Physiotherapy was of little help in treatment but 60% of patients responded to local injections of corticosteroid and local anaesthesia. Manipulation and injection was even more successful and cured about 85%. Coccygectomy was required in almost 20% and had a success rate of over 90%.
Insulin-like growth factor-I receptors in human hyperplastic prostate tissue: characterization, tissue localization, and their modulation by chronic treatment with a gonadotropin-releasing hormone analog, Insulin-like growth factor I (IGF-I) receptors were characterized in membranes obtained from prostate tissue of patients affected by benign prostatic hyperplasia (BPH) before and after treatment with a GnRH agonist analog. Binding of [125I]IGF-I to membranes obtained from untreated patients was specific and time and temperature dependent. Analysis of the binding data yielded two classes of binding sites. one of high affinity (Kd. 10(-11) mol/L) and one of lower affinity (Kd. 10(-9) mol/L). BPH membrane preparations were affinity-cross linked to labeled IGF-I. and then subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Analysis by autoradiography revealed one labeled protein with an apparent Mr = 300K under nonreducing conditions and two labeled protein with Mr = 270K and Mr = 130K under reducing conditions. Excess unlabeled IGF-II reduce both of them. whereas the same excess of IGF-I completely abolished them. In membrane preparations of prostatic tissues from patients affected by BPH and treated for 2 months with a GnRH agonist analog. the binding capacities of both binding sites were significantly higher than those of BPH tissue from untreated patients. whereas binding affinities were unchanged. The IGF-I receptor in BPH prostate tissue of untreated patients was mainly localized in the basal layer of the epithelium. as demonstrated by immunohistochemical staining. whereas in the tissue from treated patients positive staining was found also in the glandular epithelium. These results demonstrate that: 1) specific binding sites for IGF-I are present in prostatic tissue from patients with BPH. 2) androgen deprivation increases their binding capacities and seems to modify their epithelial localization.
Reduced glucose-induced thermogenesis is present in noninsulin-dependent diabetes mellitus without obesity, Decreased glucose-induced thermogenesis has been observed in all forms of obesity. However. some studies implicate insulin resistance rather than obesity per se as the mechanism by which glucose-induced thermogenesis is reduced. To establish the role of insulin resistance in reduced thermogenesis independent of obesity. we compared energy expenditure in 9 nonobese individuals with noninsulin-dependent diabetes mellitus (NIDDM) to 16 nonobese control subjects using indirect calorimetry and the hyperinsulinemic clamp technique. To document the presence of insulin resistance and reduced glucose-induced thermogenesis in nonobese NIDDM. 6 individuals from each group were studied under identical conditions of hyperinsulinemia (120 mU/m2.min) and euglycemia (approximately 5 mmol/l). Both glucose uptake (0.482 +/- 0.042 vs. 0.737 +/- 0.040 g/min) and energy expenditure above basal (0.04 +/- 0.02 vs. 0.10 +/- 0.02 kcal/min) were decreased in nonobese NIDDM compared to control subjects (both P less than 0.05). To determine whether decreased glucose-induced thermogenesis could be overcome by correcting for reduced glucose uptake. the 9 nonobese NIDDM individuals were age and weight-matched to 9 control subjects and clamps were performed at matched rates of glucose uptake. During a 40 mU/m2.min insulin infusion. the nonobese NIDDM individuals were studied at hyperglycemia (17.5 +/- 1.9 mmol/L) and compared to the control subjects at euglycemia (5.1 +/- 0.1 mmol/L; P less than 0.05). Under these conditions. both groups achieved similar rates of glucose uptake (0.698 +/- 0.040 vs. 0.688 +/- 0.038 g/min. NIDDM and control subjects. respectively) and similar rates of energy expenditure above basal (0.08 +/- 0.03 vs. 0.06 +/- 0.02 kcal/min. P = NS). During 600 mU/m2.min clamps performed at hyperglycemia (19.0 +/- 1.2 vs. 14.5 +/- 1.1 mmol/L. NIDDM vs. control subjects. respectively; P less than 0.05). rates of maximal glucose uptake (1.538 +/- 0.093 vs. 1.518 +/- 0.047 g/min) and energy expenditure above basal (0.34 +/- 0.03 vs. 0.31 +/- 0.03 kcal/min) were also similar (P = NS). In conclusion nonobese NIDDM is associated with both decreased rates of glucose uptake and decreased glucose-induced thermogenesis. Decreased glucose substrate availability. due to impaired insulin action. appears to be the critical determinant of glucose-induced thermogenesis in nonobese NIDDM. These data indicate that decreased thermogenesis in NIDDM is a consequence of insulin resistance and can occur independent of obesity.
Sequential cerebrospinal fluid and plasma sampling in humans: 24-hour melatonin measurements in normal subjects and after peripheral sympathectomy, Simultaneous measurements of plasma and cerebrospinal fluid (CSF) melatonin and urinary excretion of 6-hydroxymelatonin were performed in four normal volunteers and one patient before and after upper thoracic sympathectomy for the control of essential hyperhidrosis. For normal individuals. hourly 24-h melatonin concentrations in plasma and CSF exhibited similar profiles. with low levels during the day and high levels at night. Peak plasma levels varied from 122-660 pmol/L. and the peak CSF levels from 94-355 pmol/L. The onset of the nocturnal increase in melatonin did not occur at the same time for each individual. Urinary 6-hydroxymelatonin levels also exhibited a daily rhythm. with peak excretion at night. The individual with the lowest nocturnal levels of circulating melatonin also had the lowest excretion of 6-hydroxymelatonin. In the patient with hyperhidrosis. a prominent melatonin rhythm was observed preoperatively in the CSF and plasma. After bilateral T1-T2 ganglionectomy. however. melatonin levels were markedly reduced. and the diurnal rhythm was abolished. These results provide direct evidence in humans for a diurnal melatonin rhythm in CSF and plasma as well as regulation of this rhythm by sympathetic innervation.
Insulin resistance: an early metabolic defect of Turner's syndrome, To evaluate whether insulin resistance contributes to the increased risk of diabetes in patients with Turner's syndrome. we measured insulin sensitivity (using the euglycemic insulin clamp technique. 40 mU/m2.min) and whole body glucose and lipid oxidation (assessed by indirect calorimetry) in two groups of nondiabetic patients with Turner's syndrome and age-matched normal controls. Group 1 consisted of eight young patients (mean age. 10 +/- 0.8 yr) who had never received hormone therapy. and group 2 consisted of five patients (mean age. 17.6 +/- 1.4 yr) who had been or were on estrogen therapy. In group 2. [3-3H]glucose was also infused during the euglycemic clamp to assess hepatic sensitivity to insulin. During the euglycemic clamp. insulin-stimulated glucose metabolism was decreased in both groups of patients [group 1. 8.4 +/- 1.0 vs. 14.7 +/- 2 mM/m2.min in controls (P less than 0.05); group 2. 9 +/- 0.7 vs. 11.7 +/- 0.9 mM/m2.min in controls (P less than 0.05)]. The impairment of insulin-stimulated glucose metabolism in patients with Turner's syndrome was accounted for by reduced nonoxidative glucose disposal; glucose oxidation rose to a similar extent in Turner patients and normal controls. Insulin-induced suppression of hepatic glucose production (group 2) and plasma FFA and branched chain amino acid levels in Turner patients was also indistinguishable from that in normal controls. Our data suggest that in patients with Turner's syndrome. insulin resistance is a very early metabolic defect that may be restricted to nonoxidative pathways of intracellular glucose metabolism.
Insulin action kinetics in adipocytes from obese and noninsulin-dependent diabetes mellitus subjects: identification of multiple cellular defects in glucose transport, Recent results from in vivo studies have shown that the kinetics of insulin action are impaired in lean and obese noninsulin-dependent diabetes mellitus (NIDDM) subjects as well as in obese nondiabetic subjects. We have measured the onset and loss of insulin action on glucose transport in adipocytes obtained from obese nondiabetic and obese NIDDM subjects to determine the contributions of obesity and diabetes to these cellular defects in insulin action. Basal and maximally insulin-stimulated rates of 3-O-methylglucose transport in adipocytes from obese and obese NIDDM subjects were reduced to 50% of the values in cells from normal subjects (P less than 0.05). The activation of glucose transport by insulin (4.3 nmol/L) was slower in cells from obese NIDDM patients. Half of the maximal insulin effect (A50) was reached by 23.0 +/- 5.0 min compared to 9.4 +/- 1.1 min in normal cells (P less than 0.05). Conversely. the deactivation of insulin-stimulated glucose transport upon removal of insulin was more rapid in adipocytes from the obese and obese NIDDM subjects. Half of the maximal insulin effect (D50) was lost by 12.4 +/- 1.7 min in obese NIDDM cells and by 8.9 +/- 1.9 min in obese subjects compared to 25.3 +/- 1.9 min in adipocytes from normal subjects (P less than 0.01). In conclusion. 1) basal and insulin-stimulated rates of glucose transport are similarly reduced in adipocytes from obese and obese NIDDM subjects; and 2) adipocytes from obese and obese NIDDM subjects display defects in the kinetics of insulin action. slower activation and accelerated deactivation. that mirror the defects measured in vivo. Both impairments in the kinetics of insulin action may contribute to the insulin resistance in these subject groups.
Serum luteinizing hormone concentrations, as measured by a sensitive immunoradiometric assay, in children with normal, precocious or delayed pubertal development, To determine the diagnostic potential of a highly sensitive immunoradiometric assay (IRMA) for LH in children with normal puberty or altered tempo of sexual maturation. we compared serum LH levels by IRMA (LH IRMA) and standard RIA (LH RIA) in children with idiopathic precocious thelarche (IPT; n = 6). idiopathic premature adrenarche (IPA; n = 14). central precocious puberty (CPP; n = 15). and constitutional delay of puberty (DP; n = 15). and 160 control children (79 males and 81 females). Subjects in the latter group were staged. according to their genital or breast development. as early prepubertal (P1E; age. less than 8 yr). late prepubertal (P1L; 8-12 yr). or stage II-V (P2-P5; n = 22-34 for each subgroup). Serum LH IRMA levels in P1E. IPT. and IPA children were either undetectable (95% of subjects less than 0.25 IU/L) or barely detectable (5% of subjects. less than or equal to 0.5 IU/L). Serum LH IRMA levels were greater than 0.5 IU/L in 38% of P1L (mean +/- SD for the group. 1.0 +/- 1.3 IU/L) and 57% of P2 (1.4 +/- 1.3 IU/L); they were greater than 1.0 IU/L in 100% of P3 (2.6 +/- 1.3 IU/L). P4 (3.9 +/- 2 IU/L). and P5 (8.6 +/- 4 IU/L) children. Comparison of serum LH levels between contiguous pubertal stages showed significantly higher LH IRMA concentrations in P3 vs. P1E. P4 vs. P2. P5 vs. P4 (all P less than 0.001). and P3 vs. P1L (P less than 0.05). In contrast. LH RIA values were not significantly different in P1E (2.0 +/- 0.6 IU/L). P1L (2.3 +/- 0.6 IU/L). P2 (2.7 +/- 0.9 IU/L). P3 (3.2 +/- 1.3 IU/L). and P4 (3.7 +/- 2.2 IU/L). although they were higher in P5 (6.8 +/- 4 IU/L) than in P4 (P less than 0.001). From P1E to P5 LH IRMA levels increased 38-fold in females and 21-fold in males. while LH RIA increased 4- and 2.1-fold. respectively. Serum LH IRMA correlated significantly with serum testosterone levels in boys from P1L to P5 (r = 0.76; P less than 0.001). while LH RIA levels did not (r = 0.18). Serum LH IRMA concentrations were above the prepubertal range (greater than 0.5 IU/L) in 67% of children with CPP (group average. 1.8 +/- 1.4 IU/L) and 87% of children with DP (1.6 +/- 1.4 IU/L).(ABSTRACT TRUNCATED AT 400 WORDS).
Sexual dimorphism in insulin sensitivity in adolescents with insulin-dependent diabetes mellitus, Sex-related differences in insulin sensitivity were evaluated in male and female adolescents with insulin-dependent diabetes mellitus (IDDM). They were matched for age. pubertal staging. body mass index. and glycohemoglobin levels. During a 1.7 mU/kg.min hyperinsulinemic-euglycemic clamp. the insulin-mediated glucose disposal rate was lower (26.9 +/- 2.1 vs. 47.1 +/- 3.7 mumol/kg.min; P less than 0.001). and GH levels were higher (6.5 +/- 1.2 vs. 2.9 +/- 0.8 micrograms/L; P = 0.03) in females than in males. Plasma glucagon. cortisol. epinephrine. and norepinephrine levels during the clamp were similar in the two sexes. except for pancreatic polypeptide. which showed a tendency to be higher in females (19 +/- 4 vs. 11 +/- 1 pmol/L; P = 0.07). During insulin-induced hypoglycemia. the rate of drop in plasma glucose was faster (0.16 +/- 0.01 vs. 0.11 +/- 0.01 mmol/L.min; P = 0.001). and the rate of glucose recovery was slower in males than in females (0.04 +/- 0.01 vs. 0.06 +/- 0.01 mmol/L.min; P = 0.05). Plasma glucose concentrations were lower in males than in females (glucose nadir. 2.3 +/- 0.2 vs. 3.3 +/- 0.2 mmol/L; P = 0.002; glucose peak. 3.7 +/- 0.2 vs. 5.3 +/- 0.4 mmol/L; P = 0.002). with similar plasma free insulin concentrations. Despite a greater degree of hypoglycemia. GH responses were lower in males than in females. The remaining counterregulatory hormone responses were similar in both sexes. We conclude that there is a distinct sexual dimorphism in insulin sensitivity in adolescents with IDDM. This is likely to be due to sex-related differences in GH levels. Furthermore. male patients with IDDM are apt to develop greater degrees of hypoglycemia accompanied by lower GH responses.
Fasting hypertriglyceridemia in noninsulin-dependent diabetes mellitus is an important predictor of postprandial lipid and lipoprotein abnormalities, Postprandial lipoprotein metabolism may be important in atherogenesis and has not been studied in detail in noninsulin-dependent diabetes mellitus (NIDDM). We used the vitamin A fat-loading test to label triglyceride-rich lipoprotein particles of intestinal origin after ingestion of a high fat mixed meal containing 60 g fat/m2 and 60.000 U vitamin A/m2 in 12 untreated NIDDM subjects with normotriglyceridemia (NTG; triglycerides. less than 1.7 mmol/L). 7 untreated NIDDM subjects with moderate hypertriglyceridemia (HTG; triglycerides. 1.7-4.7 mmol/L). and 8 age- and weight-matched normotriglyceridemic nondiabetic controls. The postprandial triglyceride increment was greater in NIDDM with HTG (P = 0.0001) and correlated strongly in all groups with the fasting triglyceride concentration (r = 0.83; P = 0.0001). Retinyl palmitate measured in whole plasma. an Sf greater than 1000 chylomicron fraction. and an Sf less than 1000 nonchylomicron fraction was also significantly greater in NIDDM with HTG. but did not differ significantly between NIDDM with NTG and controls. In NIDDM with HTG. chylomicrons appeared to be cleared at a slower rate. as evidenced by the significantly later intersection of the chylomicron and nonchylomicron retinyl palmitate response curves (13.7 h in HTG NIDDM vs. 8.5 h in NTG NIDDM vs. 7.3 h in controls; P less than 0.01). Although fasting FFA levels were similar in all three groups. the HTG diabetic subjects had a late postprandial surge in FFAs that lasted for up to 14 h. The postprandial FFA elevation in all groups correlated with the fasting triglyceride concentration (r = 0.57; P less than 0.002) and postprandial triglyceride increment (r = 0.80; P = 0.0001). The fasting core triglyceride content of the HDL particles in NIDDM with HTG was significantly elevated compared to those in NIDDM with NTG and controls (21.0% vs. 14.0% vs. 14.1% respectively; P less than 0.05). and this increased proportionately in all groups after the meal at the expense of cholesteryl ester. the increase correlating with total plasma postprandial triglyceride increment (r = 0.51; P less than 0.01). We conclude that moderate fasting hypertriglyceridemia in NIDDM is predictive of a constellation of postprandial changes in lipids and lipoproteins that may potentiate the already unfavorable atherogenic fasting lipid profile in these subjects.
Elevated serum diiodotyrosine (DIT) in severe infections and sepsis: DIT, a possible new marker of leukocyte activity, Ether link cleavage (ELC) of T4 yielding diiodotyrosine (DIT) has recently been shown in vitro to be the major pathway of T4 metabolism in phagocytosing leukocytes. To evaluate this pathway in vivo and the possible clinical relevance of DIT measurements in diseases with increased leukocyte activity. radioimmunological studies on serum levels of DIT and other thyroid parameters were performed in 125 critically ill patients classified into 3 groups with bacterial infections according to the severity of infection and 1 group without infections. While the pattern of iodothyronine and TSH levels typical for severe nonthyroidal disorders. i.e. decreased total T3 and elevated rT3. normal or decreased total T4 and TSH. and normal free T4. was found in all four groups of intensive care patients studied. elevated serum DIT was observed only in those patients whose clinical course was complicated by severe bacterial infections. Serial measurements revealed a close temporal connection between the infection phase and increased DIT levels. Median values and 16th to 84th percentile ranges (in parentheses) of serum DIT (normal range. 0.02-0.55 nmol/L) were as follows: sepsis. 1.38 (0.32-5.14); severe nonsystemic infections such as peritonitis and abscesses. 3.84 (0.24-17.2); moderate infections such as pneumonia and tracheobronchitis. 0.44 (0.18-1.16); and critical illness without infections. 0.14 (0.08-0.30) nmol/L. These elevations of circulating DIT could neither be correlated with changes in renal function nor attributed to drug effects. The results of the present study do not allow any definitive conclusions to be made about the mechanisms underlying the phenomenon of increased serum DIT levels in infections. Apart from this open question. DIT appears to be a relatively specific serum parameter for the presence and course of severe bacterial inflammations. Its measurement could provide useful clinical information. particularly for monitoring the time course of deep-seated infections.
A 5-year safety and efficacy evaluation with fibrel in the correction of cutaneous scars following one or two treatments [published erratum appears in J Dermatol Surg Oncol 1991 Aug;17(8):691, In a multicenter clinical trial 300 patients were treated with Fibrel. 4 weeks following a negative skin test. for the correction of cutaneous scars. Fibrel treatment was restricted to one or two implants in a maximum of four scars. The scar corrections were evaluated by the physician. the patient. and also via an objective photogrammetric method. At the end of 1 year the percentage of scars with moderate. marked. or complete correction were 65. 63.3. and 85.8% according to physician. patient. and photogrammetric evaluations. respectively. A cohort of 111 patients were followed for up to 2 years and 87 patients were followed up to 5 years postimplantation. The physician and patient evaluations showed 55.1 and 50.6%. respectively. of the scars in the moderate. marked. or complete correction category at the end of 5 years with only one or two treatments. Safety evaluations included tests for antinuclear antibodies. rheumatoid factor. and presence of antibodies to Fibrel and their crossreactivity to human collagen I and III. These tests did not show any causal relationship to Fibrel treatments and the patients did not have any untoward immunologic symptoms. The data from these patients demonstrate that one or two Fibrel treatments are effective in maintaining greater than 50% correction of depressed cutaneous scars up to 5 years with negligible adverse sequelae and no untoward immunologic symptoms.
Prognosis and treatment of advanced squamous cell carcinoma secondary to epidermodysplasia verruciformis: a worldwide analysis of 11 patients, Data were collected from three medical centers in the USA. Poland. and Japan regarding 11 patients with advanced squamous cell carcinoma (SCC) secondary to epidermodysplasia verruciformis (EV). Analysis was conducted regarding primary tumor location. age at onset of EV. age at diagnosis of SCC. treatment of SCC. history of local tumor recurrence. presence of metastases. and age at death. Three of 11 patients developed both lymph node and visceral metastases and the mean patient age at death was 44 years (N = 6) with no patient to date living past 54 years. Mean patient survival time following metastases was 1.7 years (N = 2). Human papilloma virus typing of nine patients was performed. Current controversies regarding the treatment of patients with advanced SCC in the setting of EV are reviewed.
Slit grafting: the use of serrated island grafts in male and female-pattern alopecia, Successful aesthetic treatment of earlier thinning of scalp hair in men and women has necessitated the development of alternatives to traditional punch grafting. The hair-bearing "serrated island" remaining between two parallel rows of round donor sites can be removed and dissected to yield a large number of "serrated island grafts" and single-hair grafts. These miniature grafts. along with half grafts from bisected plugs. can be placed. in one or several sessions. into dozens to hundreds of small "slits" between the remaining hairs in patients with early or advanced thinning on the crown. vertex. or anterior scalp--hence the name "slit grafting." The versatility of this technique is demonstrated by its value for patients with dark hair and light skin. in repair work. in patients necessitating extensive vertex coverage. or in combination with alopecia reduction and traditional punch grafting. The finely tufted progressive growth from hundreds of these carefully placed slit grafts can thus counteract further hair loss in a variety of different situations.
"Pinch modification" used to repair a large surgical defect on the scalp: other proposed uses, Dr Peng's "pinch modification" of the linear advancement flap. a reconstructive technique used to correct surgical wounds on the nose and suggested as a surgical alternative in other non-hair-bearing skin. was used successfully to correct a surgical defect of 55 mm in diameter located on the occipital area. on hair-bearing skin. Other possible uses for this technique are suggested.
Power drills to fenestrate exposed bone to stimulate wound healing, Power drills can be used to stimulate the formation of granulation tissue over exposed cortical bone. These tools allow for the rapid fenestration and selective abrasion of large areas of exposed bone; fenestration and abrasion create the multiple bleeding points essential for the production of granulation tissue. The granulation tissue thus produced is allowed to grow out through the holes to cover bone. This procedure can be performed in an outpatient setting. usually without the need for either local or general anesthesia; it is particularly useful for patients considered to be poor risks for general anesthesia. Healing by granulation tissue is a somewhat slow process. but it has a high success rate. causes few complications. and produces very good cosmetic results. Two cases illustrate the method of fenestration of exposed cranial bone to stimulate granulation tissue. Specific instructions describe the needed care of exposed bone.
Cryotherapy in the treatment of condylomata acuminata: a controlled study of 64 patients, A clinical controlled study is presented for the treatment of condylomata acuminata with cryotherapy in 64 patients. Condylomata resolved in 83% within 4 weeks and 96% after 6 weeks by using cryotherapy. The results were significantly better compared with the control group of 70 patients (13% and 45% after 4 weeks and 6 weeks. respectively). Other therapeutic modalities are reviewed. Cryotherapy is an elegant and effective method for the treatment of condylomata acuminata without discomfort to the patient.
Alar rim reconstruction utilizing a perinasal transposition flap overlying a hinged "turn-down" flap, Construction of the alar rim is an extremely challenging problem. Utilizing supradefect nasal tissue as a hinged "turn-down" flap combined with perinasal tissue mobilized as an inferiorly-based transposition flap allowed the formation of a thin and properly contoured rim configuration.
A modified rhombic transposition flap and its application in dermatology, A modified rhombic transposition flap based around a circular primary defect is described. We have found it to be a versatile design that produces good cosmetic results with a low incidence of postoperative complications. It has become the most frequently used transposition flap in our dermatologic practice.
Proliferating trichilemmal tumor: report of a case and review of the literature, The authors report a case of proliferating trichilemmal tumor and review the related literature. Although considered biologically benign. malignant proliferating trichilemmal tumor have been reported. The authors emphasize the importance of recognizing that the tumors can occur in individuals in their 20s and 30s. and that the tumors should be excised with a margin of normal tissue. Routine follow-up is recommended.
Invasive squamous cell carcinoma in a patient with epidermodysplasia verruciformis, A patient with epidermodysplasia verruciformis died of intracranial invasion by squamous cell carcinoma (SCC). A biopsy of clinically normal skin had revealed perineural invasion by malignant keratinocytes. Because SCCs arising in patients with epidermodysplasia verruciformis may be biologically aggressive. it is best to excise them with careful control of the surgical tissue margins.
Rehabilitation of a patient with asthma in the outpatient setting, Although traditional rehabilitation medicine approaches are necessary in patients with the most severe asthma. principles of rehabilitation described in this article are useful for almost all patients. These principles are perhaps most useful early in a patient's course when the setting of appropriate expectations is important in minimizing restrictions from both disease and its treatment. Once a patient has developed restrictions. prompt institution of rehabilitation is essential to prevent significant disability. which can be avoided or even reversed. Once rehabilitation has been instituted. progress with rehabilitation goals should be monitored in visits to the physician so that communication with the appropriate health care professional can be established to readjust therapy. Physician interest in the process of rehabilitation can stimulate motivation of the patient.
Allergenic structures in cockroach hypersensitivity, The tissues from which cockroach allergens were derived were identified by use of serum IgE of five patients with allergic rhinitis and bronchial asthma as a result of hypersensitivity to German cockroach. RAST and skin test results demonstrated four of five patients to be positive to cockroach only. and one patient was tested positive to house dust mite as well. Allergen-specific IgE binding to German cockroach was investigated by cryostat sections by means of immunofluorescent test. In all patients with cockroach hypersensitivity. we found IgE bound to the gastrointestinal epithelium and contents of the intestinal tract. In four cases. IgE was also bound to the Malpighian vessels (equivalent in function to kidneys). In three cases. IgE was also bound to the ovarian cells. All cases revealed cytoplasmic staining.
Reassessment of the temporal patterns of bronchial obstruction after exposure to occupational sensitizing agents, Typical asthmatic reactions after exposure to common or occupational allergens have been classified as isolated immediate. early late. late. and dual (Pepys and Hutchcroft. 1975). Atypical reactions can also occur. but their temporal behavior and frequency are unknown. We analyzed 69 bronchospastic reactions after exposure to three types of occupational sensitizers in the laboratory: isocyanates. western red cedar. and IgE sensitizing agents. Graphs of the reactions were presented to three observers in a blind. randomized way. Reactions were defined as follows: (1) typical patterns. that is. isolated immediate. early late. late. and dual. as put forward by Pepys and Hutchcroft. and (2) atypical patterns including progressive (onset. during. or minutes after exposure. progressing to a maximum reaction 5 to 6 hours later) and square waved (similar to a dual reaction but with only partial recovery [less than 10%] between the immediate and late falls in FEV1). Some curves were also analyzed by polynomial regression. The three observers agreed in 59/69 cases (86%). and a consensus was reached after discussion for the remaining subjects. Fifteen of 63 (22%) reactions were atypical. IgE-mediated reactions and reactions to red cedar were. respectively. mainly of the immediate and late types. The distribution of reactions to isocyanates. however. was significantly different (chi-square. 6.1; p = 0.01). the "progressive" pattern occurring in 7/23 instances (30%). There was a satisfactory concordance between visual assessment and polynomial fit analysis in distinguishing dual from square-waved reactions. We conclude that isocyanates frequently cause atypical progressive bronchospastic reactions that are rarely observed after exposure to IgE agents and western red cedar.
Clinical and immunologic evaluations of reactive dye-exposed workers, To evaluate type 1 hypersensitivity to reactive dyes. its prevalence. and its relationship to respiratory dysfunction. we studied clinical and immunologic features. including skin prick tests. RAST. and bronchoprovocation tests. of 309 employees working in a reactive-dye industry. Our survey revealed that 78 (25.2%) employees had work-related lower respiratory symptoms associated with or without nasal. skin. or eye symptoms. Among these employees. 38 (48.7%) had nonspecific bronchial reactivity. Thirteen demonstrated immediate (6). dual (6). or late only (1) asthmatic responses after inhalation of four kinds of reactive-dye solutions. Twenty-five employees demonstrated immediate skin responses to black GR dye. and 21 reacted to orange 3R. Fifty-three employees (17%) had specific serum IgE antibody against black GR and orange 3R-human serum albumin conjugate. Specific IgE was detected more frequently in symptomatic employees (30%) and smokers (100%). No association was found between atopy and specific IgE binding. The RAST-inhibition tests of black GR revealed significant inhibitions by black GR-human serum albumin conjugate and minimal inhibitions by unconjugated black GR. Orange 3R RAST-inhibition tests revealed significant inhibitions by conjugated forms of black GR and orange 3R and some inhibitions by two unconjugated dyes. suggesting an immunologic cross-reactivity between these dyes. These findings suggested that reactive dyes could induce immunologic responses. most likely IgE-mediated.
Occupational allergy to pancreatic powder: characterization of IgE-binding antigens in pancreatic extract by immunoblotting, The IgE response to inhaled dust of pancreatic powder was studied with sera from two employees of a pharmacy. IgE from both sera was directed against both porcine and bovine trypsin preparations. The major IgE-binding structures had an isoelectric point in the pH 8 to 9 range. The molecular weight of the IgE-binding structures was different for both patients. In one patient. most IgE was directed against a 28 to 30 kd structure. whereas the second patient had IgE directed against components with a molecular weight of 35 and 45 kd. respectively.
The release of platelet-activating factor into plasma during allergen-induced bronchoconstriction, Plasma histamine and platelet-activating factor (PAF) were measured in six subjects with mild seasonal asthma before and after allergen-induced bronchoconstriction. and in six other patients with asthma before and after methacholine-induced bronchoconstriction. A significant increase in plasma histamine and PAF levels was found in patients with mild seasonal asthma after allergen-induced bronchoconstriction but not in patients with asthma after bronchoconstriction induced by methacholine. There was a significant correlation between the baseline plasma PAF levels and the degree of bronchial hyperresponsiveness to methacholine. These findings suggests that PAF may be an important mediator in the pathogenesis of asthma and bronchial hyperresponsiveness.
A comparison of cutaneous testing and ELISA testing for assessing reactivity to ethylene oxide-human serum albumin in hemodialysis patients with anaphylactic reactions, In five patients who have experienced anaphylaxis and in 29 patients who have not had such episodes during hemodialysis. we have performed two immunologic studies: cutaneous testing with ethylene oxide-human serum albumin (ETO-HSA) and ELISA for IgE against ETO-HSA. Four of five patients with reactions had positive cutaneous tests. whereas only one nonreactor had a positive skin test (p less than 0.0002). The same four of five patients with reactions also had positive ELISA results. whereas three nonreactors has positive ELISA results (p less than 0.003). In this group of patients. the positive predictive value of cutaneous testing (80%) is somewhat higher than that of ELISA testing (57%). However. the sensitivity. specificity. and negative predictive values are similar. We conclude that cutaneous testing with ETO-HSA probably offers a small advantage over IgE against ETO-HSA as determined by ELISA.
Ultrastructural demonstration of specific IgG and IgE antibodies binding to Aspergillus fumigatus from patients with aspergillosis, Aspergillus-induced diseases usually demonstrate elevated circulating antibodies belonging to different isotypes. The antigens currently used to detect antibodies are crude culture filtrate and mycelial extracts of A. fumigatus (Af). Most Af-associated diseases result from the inhalation of the spores of the organisms present in the environment. However. it is not known whether specific circulating antibodies directed only against spore or mycelia of Af exist in the sera of patients with Af-induced diseases. With colloidal gold we have investigated thin sections of spores and hyphae of Af for their reactivity with Af-specific IgG and IgE antibodies. The results indicate that both spores and hyphae reacted identically with IgG and IgE antibodies from patients. None of the sera from normal control subjects reacted in this system. although low levels of antibodies were detected in the sera by ELISA. Sera from both patients with allergic bronchopulmonary aspergillosis or aspergilloma reacted with cell envelope antigens. whereas sera from patients with invasive aspergillosis also bound to cell sap. This method therefore demonstrates localization of antigens binding to different isotypes in the sera from different clinical forms of aspergillosis and may be useful in purifying specific antigens for immunodiagnosis.
In-hospital sting challenge in insect venom-allergic patients after stopping venom immunotherapy, Immunotherapy (IT) in venom-allergic patients has been demonstrated to provide a highly efficient protection from severe reactions to a re-sting. It is not known whether this protection will persist after IT is stopped in patients with remaining venom sensitivity. In 25 adult patients with a previous severe systemic reaction to a Hymenoptera insect sting. 28 in-hospital sting challenges after stopping IT resulted in no systemic reactions. The mean duration of venom IT was 42.8 months (range. 36 to 83 months). and the mean time interval from the time IT was stopped until sting challenge was. in mean. 25.2 months (range. 12 to 36 months). The mean venom-specific IgE after stopping IT was 2.4 PRU/ml (range. 0 to 16.9 PRU/ml). at the day of sting challenge. 2.7 PRU/ml (range. 0 to 22 PRU/ml). and 2 weeks later. 2.4 PRU/ml (range. 0.02 to 27.8 PRU/ml). These changes in IgE were not significant. Venom-specific IgG concentration when IT was stopped was 64 PU/ml (range. 20 to 144 PU/ml). decreasing significantly to the day of sting challenge to 41.1 PU/ml (range. 13 to 84 PU/ml). and 2 weeks later. a significant increase to a mean of 53.5 PU/ml (range. 12 to 117 PU/ml) was found. Our results suggest that venom IT may be stopped after 3 years. regardless of the level of specific antibodies. To confirm this finding. a larger number of patients should be studied.
Honeybee venom allergy: results of a sting challenge 1 year after stopping successful venom immunotherapy in 86 patients, In 86 patients with a history of severe systemic reactions (SRs) to honeybee stings confirmed by a positive skin test and/or RAST to honeybee venom (HBV). immunotherapy (IT) with HBV was stopped after 3 to 10 years. All patients had tolerated well a honeybee sting during IT and were resubmitted to a sting 1 year after VIT was stopped. At the latter time. 15 patients (17%) developed an SR and 71 did not. There was no difference between the two groups regarding age. sex. IT duration. severity of the SR before treatment. as well as diagnostic tests with HBV (skin tests. RAST. and specific IgG) before the challenge. Patients with a relapse of their allergy had. however. developed allergic SRs to IT injections more frequently than patients with lasting protection (p less than 0.001). SRs to the sting challenge (CH) after IT was stopped occurred more frequently in those patients in whom efficacy of IT had previously been confirmed by lacking responses to a field sting than in patients who had tolerated an intentional CH during the injection period (p less than 0.025). Indeed. the incidence of relapse after venom IT was stopped was only 9.6% in patients who had previously tolerated an intentional CH. It is concluded that well-tolerated HBV IT may be stopped after at least 3 years. provided its efficacy has been documented by a CH without SR.
The effect of dapsone in steroid-dependent asthma, We studied the steroid-sparing effect of dapsone in 10 subjects with chronic asthma in a preliminary open trial. Dapsone was chosen because it inhibits neutrophil function and possesses anti-inflammatory effects in a variety of disorders. The study group consisted of 10 subjects with stable. steroid-dependent asthma. aged 23 to 80 years. with normal glucose-6-phosphate dehydrogenase levels. Average daily baseline prednisone dose ranged from 5 to 60 mg. Dapsone. 100 mg. twice daily. by mouth. was started after a 1-month baseline period. Baseline steroid dose. symptom scores. and daily peak flow rates were compared to the latest available 4-week period of dapsone treatment. Average cumulative monthly prednisone dose was reduced from 428 mg to 82 mg (p less than 0.02). Five of 10 patients stopped steroids by month 6 and two additional patients by month 13. Two additional patients demonstrated a coincidental 74% reduction in steroid dose. and one patient demonstrated no response. Clinical parameters remained stable despite steroid reduction. These preliminary data suggest dapsone may have steroid-sparing effects in chronic asthma.
Local immunotherapy with Dermatophagoides extract in asthma, Local immunotherapy (LIT) with Dermatophagoides extract or placebo were administered to two groups of 11 patients with allergic asthma in a double-blind fashion. All patients received cromolyn sodium (20 mg four times a day) during treatments. Bronchial provocation tests with allergen and methacholine were performed before. 1 week. and 4 weeks after the end of treatments. Symptom score. drug consumption. and peak expiratory flow were monitored daily from 2 weeks before to 4 weeks after treatments. Compared to baseline. early bronchial sensitivity to allergen was significantly reduced both 1 week (p less than 0.0005) and 4 weeks (p less than 0.01) after LIT but not after placebo administration. Late bronchial reaction to allergen occurred similarly after placebo administration and LIT. However. in the group with LIT. the severity of late reaction was unchanged after treatment in spite of the significantly larger doses of allergen administered to provoke the early asthmatic reaction. Neither symptom score. nor drug consumption. nor peak expiratory flow were significantly different in the two groups before and during the treatment period even though both symptom score and drug consumption tended to be reduced after LIT. We conclude that LIT may be an effective and safe alternative to traditional immunotherapy.
Increase of ovalbumin (OVA)-specific B cells in the peripheral blood of egg-allergic patients, Allergen-specific B cells were detected by antigen-coated magnetic beads. The frequency of ovalbumin (OVA)-specific B cells was significantly higher in patients with egg white-allergy than in age-matched nonallergic individuals. These B cells. isolated by the immunomagnetic-beads method. produced anti-OVA antibodies of mostly IgM class when they were transformed by Epstein-Barr virus and cultured for about 2 weeks. Based on a chronologic analysis. the increase of OVA-specific B cells was found to precede the increase of IgG and IgE anti-OVA antibodies in the serum. These observations indicated that OVA-binding B cells in the peripheral blood are already committed to producing IgM antibody and probably are the precursors of antibody-forming cells of the IgG or IgE class.
Clinical and immunologic reactivity of patients allergic to grass pollens and to multiple pollen species. I. Clinical and immunologic characteristics, The heterogeneity of pollen-allergic individuals is well-known but poorly characterized. Twenty-six patients were studied to characterize their immunologic and clinical patterns. Thirteen patients were allergic only to grass pollens. and 13 other patients were allergic to grass-pollen and other pollen species. including Cupressaceae. plane tree. olive. and Parietaria. The IgE response was assessed by the titration of serum total IgE and orchard grass-specific IgE. as well as by IgE immunoblots to orchard-grass pollens. Clinical reactivity was assessed by nasal challenge with orchard-grass pollens before the pollen season and nasal and bronchial symptom-medication scores between April 1 and June 15. Pollen counts were obtained during this period of survey. Polysensitized patients had significantly increased levels of serum total and specific IgE and a greater heterogeneity of IgE immunoblots. suggesting an enhanced qualitative and quantitative IgE immune response. Polysensitized patients had nasal and bronchial symptoms occurring earlier than grass pollen-allergic individuals. confirming the priming effect caused by other plans flowering with an earlier season for both nasal and bronchial mucosa. Alternatively. the early symptoms may be attributable to the tree pollens or might reflect the higher grass-pollen IgE level in the polysensitized group. Bronchial symptoms appeared a few weeks after nasal symptoms. Nasal challenges were similar in both groups. and the severity of nasal symptoms during the season was not significantly different in both groups. suggesting that the intensity of symptoms is not related to the sensitization nor to the IgE immune response of the subjects.
The effect of recombinant human growth hormone on malnourished older individuals, Malnutrition in the elderly is often unrecognized and untreated. Reduced secretion of growth hormone (GH) has been suggested as a cause of decreased muscle and bone mass with aging. This pilot study characterized the nutritional response of elderly malnourished subjects to recombinant human GH (rhGH). Subjects were included if they were over 60 years of age. if weight was more than 20% below average body weight (ABW). and if serum albumin concentration was less than 3.8 g/dL. Subjects were divided into two groups: one received 100 micrograms/kg rhGH (Protropin. Genentech) intramuscularly (IM) daily for 21 days; the other received a daily control injection of normal saline (Controls -C) (0.1 mL/kg IM) for the same period of time. During the 3-week period. mid-arm muscle circumference (MAMC) increased an average of 0.6 cm in GH patients but fell in C subjects. There was a non-significant trend to a decreased caloric intake in the control group. Weight increased an average of 4.95 lbs (2.2 kg) in the GH treated group. and decreased an average of 4.9 lbs (2.2 kg) in C subjects (P less than 0.05). Urinary nitrogen retention occurred only in the growth hormone treated subjects (P less than 0.05). Somatomedin C (IGF-1) rose significantly in those treated with GH (P less than 0.05). while there was no change in the control group. There was a significant association between weight change and IGF 1 concentration (r = 0.837. P less than 0.05). Neither clinical edema nor hyperglycemia was noted. These findings suggest that GH may be an effective way of maintaining and enhancing weight in malnourished older individuals.
The progression of mild idiopathic dementia in a community population, Thirty-one subjects aged 75 years and over who were identified as suffering from mild. idiopathic dementia in a large community survey were reviewed at annual intervals for 2 years. Diagnoses and severity ratings were based on defined criteria following a mental state examination. a medical and psychiatric history. detailed cognitive testing. and an interview with relatives or other key informants. Fourteen subjects became more severely demented within 2 years. The initial cognitive test battery failed to reveal any differences between respondents whose dementia advanced and those whose condition remained unchanged. but. in the former group. subjects' symptoms had been present for longer. and a greater proportion had been recognised as demented. or possibly demented. by their general practitioners. We suggest that subjects whose dementia progressed had actually been more severely disabled at the time of identification.
B complex vitamin patterns in geriatric and young adult inpatients with major depression, This study compared the B complex vitamin status at time of admission of 20 geriatric and 16 young adult non-alcoholic inpatients with major depression. Twenty-eight percent of all subjects were deficient in B2 (riboflavin). B6 (pyridoxine). and/or B12 (cobalamin). but none in B1 (thiamine) or folate. The geriatric sample had significantly higher serum folate levels. Psychotic depressives had lower B12 than did non-psychotic depressives. Poorer blood vitamin status was not associated with higher scores on the Hamilton Depression Rating Scale or lower scores on the Mini-Mental State Examination in either age group. The data support the hypothesis that poorer status in certain B vitamins is present in major depression. but blood measures may not reflect central nervous system vitamin function or severity of affective syndromes as measured by the assays and scales in the present study.
Dementia in institutionalized elderly: relation to sleep apnea, Sleep apnea is characterized by transient hypoxemias which are thought to affect mental functioning. Accordingly. speculation and research have focussed on relationships between sleep apnea and dementia. We studied 235 nursing home (ie institutionalized) patients (152 women with a median age of 83.5; 83 men with a median age of 79.7) with portable sleep recording equipment. The Mattis Dementia Rating Scale and the Geriatric Depression Scale were given to each. Seventy percent of the patients had five or more respiratory disturbances per hour of sleep and 96 percent showed some dementia. Sleep apnea was significantly correlated with all subscales on the dementia rating scale. There were trivial differences in dementia ratings between those with mild-moderate apnea and those with no apnea. There were significant differences. however. between the latter two groups and those with severe apnea. In particular. items reflecting attention. initiation and perseveration. conceptualization. and memory tasks on the DRS distinguished between those with and without severe sleep apnea. Among those patients with no depression. all patients with severe sleep apnea were also severely demented. Our data suggest that there is a strong relationship between dementia and sleep apnea when the sleep apnea and dementia are severe. Although causality cannot be inferred from associations. our hypothesis for study is that sleep apnea causes deficits in brain function. possibly due to global effects rather than any particular cortical or subcortical structure.
Follow-up of mild hypothyroidism in a nursing home, The course of untreated mild hypothyroidism was followed in 67 nursing home residents (mean age 78 years). The diagnosis was based on a normal free thyroxine index (FTI) and elevated thyrotropin concentration (TSH 4.6 to 15.0 microIU/mL. nl less than or equal to 4.5 microIU/mL. FTI and FSH were measured in follow-up 42-378 (mean 161) days after the diagnosis of mild hypothyroidism had been made. In 45 patients initial TSH was less than 6.8 microIU/mL; in 23 of these subjects TSH returned to normal during the observation period. whereas in 22 TSH remained elevated. In all 22 residents whose initial TSH was greater than 6.8 microIU/mL. TSH remained elevated at follow-up. In 4 subjects whose initial TSH concentrations ranged from 5.0 to 9.6 microIU/mL. FTI fell below normal 91-141 days after the diagnosis of mild hypothyroidism was made. Clinical progression of the signs or symptoms of hypothyroidism was not detected in the 4 patients who developed hypothyroxinemia. Three demonstrated positive thyroid antibody titers. and 1 had myasthenia gravis. These observations suggest a need for replacement therapy in debilitated patients with mild hypothyroidism and evidence of thyroid autoimmunity.
Differential effects of the stimulation of complement receptors CR1 (CD35) and CR2 (CD21) on cell proliferation and intracellular Ca2+ mobilization of chronic lymphocytic leukemia B cells, The regulatory role of CR1 and CR2 on B cell activation and proliferation has been investigated by using B cells from patients with chronic lymphocytic leukemia. The chronic lymphocytic leukemia B cells are clonal expansions of B lymphocytes frozen at specific stages of activation. They displayed two patterns of response upon surface Ig (sIg) cross-linking in terms of in vitro proliferation and intracellular free Ca2+ mobilization: cells from patient F (first pattern) proliferated in the presence of mitogenic anti-mu antibodies. whereas cells from patient A (second pattern) did not respond to sIg cross-linking but proliferated in the presence of low m.w. B cell growth factor and IL-2. Coculture of A or F cells with C3b-bearing SRBC led to a two- to four-fold increase in thymidine incorporation in cultures containing low m.w. B cell growth factor but not in cultures containing rIL-2. This enhanced proliferation was inhibited by F(ab')2 polyclonal rabbit antihuman CR1 antibodies. Only cells which proliferated in the presence of anti-mu (cells F) responded to cross-linking of sIg with a rise in intracellular Ca2+. No increase in calcium mobilization was observed after co-cross-linking of CR1 and sIg on A and F cells with mAb or polyclonal anti-CR1 antibodies. Co-cross-linking of CR2 with sIg only led to an enhanced intracellular Ca2+ rise in F cells but not in A cells. The lack of CR2-mediated synergy in Ca2+ rise in A cells indicates that the synergy occurs only if there is a proper coupling of sIg to phospholipase C. CR1-induced proliferation of B cells does not involve the signaling pathways of sIg. These results provide additional evidences for the role of C3 fragments in modulation of human B cell activation.
Cytokine regulation of localized inflammation. Induction of activated B cells and IL-6-mediated polyclonal IgG and IgA synthesis in inflamed human gingiva, It is well established that increased numbers of plasma cells occur in the localized tissues of chronic inflammatory diseases such as adult periodontitis. and enzymatic isolation has shown that most B lineage cells produce IgG-subclass with some IgA-subclass responses. It would be of importance to determine if excess production of cytokines in the localized lesion account for these responses and in the present study we have assessed gingival mononuclear cell (GMC) supernatants for cytokines that activate B cells including IL-6R expression and for levels of IL-6 present. Inasmuch as limited numbers (approximately 1 to 3 x 10(6) cells) of GMC were obtained from surgically removed tissues (approximately 400 mg). we have focused on the analysis of IL-6 production by GMC in this study. Further. initial evidence of additional cytokines that are produced by GMC and induce expression of IL-6R on resting B cells has been obtained. The GMC and PBMC from individual patients were cultured in the presence (or absence) of Con A. Higher levels of IL-6 were produced spontaneously by GMC when compared with Con A-stimulated PBMC. When PBMC cultures were supplemented with GMC supernatants obtained from the same patient. high numbers of spot-forming cells (SFC). mainly of IgG followed by IgA isotype. were seen. The induction of SFC by GMC supernatants was inhibited by incubation with a goat anti-human IL-6 antibody. When the effect of GMC supernatants on subclasses of PBMC SFC was determined. the response was IgG1 greater than IgG2 greater than IgG3 = IgG4 and IgA1 greater than IgA2. a pattern remarkably similar to the distribution of plasma cells in the GMC itself. To assess for cytokines in GMC supernatants that mediated B cell activation. supernatants containing anti-IL-6 were cultured with PBMC or purified B cells for 72 h. This treatment induced small proliferative B cell responses and elevated expression of IL-6R on B cells. but did not induce SFC responses. Further. incubation of B cells with GMC supernatants induced resting B cells (G0/G1) to enter the cell cycle (S and G2/M). Addition of human rIL-6 to these cultures on day 3 restored IgG- and IgA-subclass SFC responses by day 7. Cytokine-induced IL-6R expression also occurred in vivo because freshly isolated GMC expressed high levels of this receptor.(ABSTRACT TRUNCATED AT 400 WORDS).
The naive repertoire of human T helper cells specific for gp120, the envelope glycoprotein of HIV, The envelope glycoprotein of HIV gp120 is a T cell Ag in experimental animals and in humans infected with HIV or deliberately immunized with gp120 in various forms. Inasmuch as T cell responses result from the interaction of Ag processed and presented by APC with the unprimed T cell repertoire. we have investigated the human T cell repertoire specific for gp120 in seronegative. normal individuals. T cell lines and clones specific for HIV gp120 were generated by repeated in vitro stimulation of peripheral blood T lymphocytes with gp120-pulsed APC. followed by IL-2 expansion. We observed that the T cell response to whole gp120 involved single restricted immunodominant epitopes in gp120 that differ between responding individuals. Focusing of the response to limited regions of gp120 when the whole Ag is used for priming suggests that one or more adjacent epitopes are immunodominant and mask responses to "immunorecessive" epitopes. We have been able to generate primary in vitro responses to recessive epitopes by stimulation in vitro with synthetic peptides of gp120. The results indicate that a much broader T repertoire can be detected when individual peptides are used for priming in vitro rather than gp120. This information has important implications for the development of vaccination protocols aimed at eliciting diverse immune responses to "immunorecessive" regions of envelope glycoprotein.
Passive transfer of local immunity to influenza virus infection by IgA antibody, Secretory IgA is presumed to be the mediator of mucosal immunity based on many studies that show a correlation between protection and secretory IgA titers; however. a causal relationship has not yet been established. Classically. passive transfer of antibody has been used to demonstrate causality. but the passive transfer of local immunity with physiologically transported IgA has not been previously reported. In this study mice were injected intravenously with polymeric IgA (pIgA). monomeric IgA (mIgA). or IgG1 mAb specific for the H1 hemaglutinin of PR8 influenza virus. pIgA was shown to be specifically transported into nasal secretions relative to the mIg. The transported pIgA was functional. as evidenced by its ability to bind to virus in an ELISA assay and to protect nonimmune mice against intranasal infection with H1N1 but not H3N2 influenza virus. Intravenous injection of similar virus-neutralizing doses of anti-influenza IgG1 mAb did not protect against nasal viral challenge. IgA-mediated protection could be abrogated by the intranasal administration of antiserum against the alpha chain of IgA. These data demonstrate the passive transfer of local immunity by the i.v. administration of pIgA antibody and show that the IgA in secretions can protect against influenza virus infection. This general approach could provide a model for the evaluation of the role of local IgA in host defense against other pathogens.
T cell recognition of transforming proteins encoded by mutated ras proto-oncogenes, Activated ras proto-oncogenes contribute to the pathogenesis of many animal and human malignancies. ras proto-oncogenes are generally activated by point mutations within codons 12 or 61. which result in the expression of ras protein (p21) bearing characteristic single amino acid substitutions at the corresponding residues. The purpose of the current study was to determine whether the presence of single transforming amino acid substitutions can render normal ras protein immunogenic and. thus. a possible target for T cell-mediated tumor therapy. In initial experiments. C57BL/6 mice were immunized with a synthetic peptide corresponding to residues 5 through 16 of p21 containing the transforming substitution of arginine for normal glycine at residue 12. The results demonstrated that class II MHC-restricted T cells which were specific for the peptide could be elicited. and that the peptide-induced T cells could specifically recognize the corresponding intact p21 ras protein. Recognition of p21 ras protein by peptide-specific T cells implies that C57BL/6 APC can process the activated ras protein in a fashion that allows presentation of digested protein by class II MHC molecules in a configuration similar to the configuration with synthetic peptide. Evaluation of the immunogenicity of peptides containing alternative transforming amino acid substitutions of ras protein demonstrated that some. but not all. were immunogenic in individual strains of mice. Therefore. although ras protein-specific T cells can be elicited by immunization with synthetic peptides. not all of the potential ras mutations commonly associated with malignancy may be recognizable by T cells from all individuals.
Expression of the Blast-1 activation/adhesion molecule and its identification as CD48, We have analyzed the induction and expression of Blast-1 at the mRNA and protein levels and demonstrated its identity with CD48. Blast-1/CD48 is expressed on a wider range of cell types. notably T cells and monocytes. than previously thought. but appears to be restricted to lymphoid and myeloid cells. Resting B and T cells express Blast-1/CD48 molecules at the cell surface; however. they lack the epitope recognized by the 17D6 mAb. Resting B cells express no detectable Blast-1/CD48 mRNA. Induction by EBV infection or stimulation with PMA. IL-4. or PHA results in increased levels of Blast-1/CD48 protein (both 6.28 and 17D6 epitopes) at the cell surface. Detailed analysis of EBV-induced expression revealed that it is due to increased steady-state levels of Blast-1/CD48 mRNA induced by transforming but not nontransforming strains of the virus. Induction by IL-1 beta. ionomycin. or suboptimal levels of PMA plus ionomycin results in increased expression of the 17D6 epitope only. In transfected Cos-7 cells Blast-1/CD48 at the cell surface expresses only the 6.28 epitope. whereas cytoplasmic molecules express both 17D6 and 6.28 epitopes. We suggest that these results are most consistent with the idea that Blast-1/CD48 molecules are complexed at the surface of resting cells and Cos-7 cells. resulting in masking of the 17D6 epitope. Activation causes dissociation of the complex. revealing the 17D6 epitope. The existence of 17D6+6.28- Blast-1/CD48 molecules was demonstrated by immunoprecipitation analysis. which also revealed that. unlike the rest of the molecules. this subset was resistant to digestion with glyosylphosphatidylinositol-specific phospholipase C.
Pituitary hormones regulate c-myc and DNA synthesis in lymphoid tissue, Hypophysectomy of Fischer 344 rats of both sexes led to a rapid involution of the thymus and spleen which was associated with a profound decrease in spontaneous DNA synthesis in these organs. The proportion of B lymphocytes in the spleen. of T cells and their subsets (CD4+/CD8+) in spleen and thymus. and the histological structure of the involuted organs remained normal. Treatment of hypophysectomized animals with growth hormone (GH) or prolactin (PRL) stimulated the expression of the c-myc proto-oncogene and DNA synthesis and reversed the involution in these organs. Replacement doses of adrenocorticotrophic hormone. follicle-stimulating hormone. luteinizing hormone. or thyroid-stimulating hormone had no influence on thymus or spleen size and DNA synthesis. A rapid expression of c-myc was also observed in thymuses and spleens of intact rats after the injection of GH or PRL. In vitro physiological concentrations (2.5 ng/ml) of either ovine or rat PRL or GH stimulated the incorporation of [3H]thymidine by thymus and spleen cells. These results indicate that GH and PRL regulate lymphocyte growth. This regulatory role is likely to serve as the principal mechanism of immunoregulation by these hormones.
Detection of cytotoxic T lymphocytes specific for synthetic peptides of gp160 in HIV-seropositive individuals, Four synthetic peptides corresponding to the IIIB sequence of gp160 of HIV were recently reported to stimulate Th cell function by PBL from HIV-infected. asymptomatic patients. In the present report. we used these same peptides to demonstrate CTL activity in a similar patient population. EBV-transformed B-cell lines from asymptomatic. HIV seropositive and seronegative control donors were pre-incubated with the peptides. Fresh PBL from 19 (76%) of 25 HIV seropositive donors lysed autologous targets pulsed with at least one of the four peptides. Autologous targets pulsed with two non-immunogenic peptides were not lysed. PBL from none of the eight HIV seronegative controls lysed peptide-preincubated autologous targets. The CTL activity was mediated by T cells. was predominantly MHC class I restricted. and was increased by in vitro restimulation of PBL with the peptides. HLA A-2 was identified as a restricting element for all four peptides in different patients. and for three of the peptides in the same donor. HLA-A1 or -B8 may also present some of the peptides. Thus. the same peptides can be recognized by human Th cells and class I MHC-restricted CTL.
Recombinant human acetylcholine receptor alpha-subunit induces chronic experimental autoimmune myasthenia gravis, A synthetic gene encoding the 210 N-terminal residues of the alpha-subunit of the nicotinic acetylcholine receptor (AChR) of human skeletal muscle was cloned into an inducible expression plasmid to produce a fusion protein in high yield in Escherichia coli. Like native human AChR. the recombinant human alpha 1-210 protein induced AChR-binding. AChR-modulating. and AChR-blocking autoantibodies in rats when injected once intradermally as an emulsion in CFA. with Bordetella pertussis vaccine as supplementary adjuvant. The minimum dose of recombinant protein required to induce biochemical signs of experimental autoimmune myasthenia gravis (EAMG) with 100% incidence was 2.2 micrograms. With 6.6 to 22 micrograms. serum levels of autoantibodies were persistent. and clinically apparent EAMG lasted more than a month. Clinical. electrophysiological. and biochemical indices of EAMG induced by doses of 66 micrograms or more were more uniformly severe and persistent. with 33% fatality. Rats receiving a control extract of E. coli containing plasmid without the alpha 1-210 codon insert. with adjuvants. did not develop autoantibodies or signs of EAMG. This highly reproducible new model of EAMG induced by a recombinant human autoantigen should be valuable for testing Ag-specific immunotherapeutic strategies that might be applicable to treating acquired myasthenia gravis in humans.
Autoantibodies to nucleolin in systemic lupus erythematosus and other diseases, The 110-kDa intracellular phosphoprotein (110K) described previously by this laboratory as a common IgM autoantigen in SLE and certain other systemic autoimmune disorders and viral infections is identified as nucleolin in the present investigation. Using rabbit antiserum to rat nucleolin as a probe. IgM autoantibody-reactive 110K co-migrated with human lymphocyte nucleolin in one- and two-dimensional immunoblots. Rabbit anti-nucleolin also specifically depleted autoreactive 110K from detergent lysates of human cells. Because nucleolin shares amino acid sequence similarity and/or forms dynamic particles with other prominent autoantigens. the present observation raises the possibility that the nucleolin/anti-nucleolin system may be of special significance for the development of humoral autoreactivity to nuclear Ag.
Autoantibodies to the centrosome (centriole) react with determinants present in the glycolytic enzyme enolase, Autoantibodies to cellular Ag are found in the sera of patients with systemic rheumatic diseases. Identification and characterization of the reactive autoantigens has helped clinicians to define subsets of rheumatic diseases and has assisted biologists in defining the function within the cell of these molecules. We have studied autoantibodies from patients that react with the centrosome (centriole) region of the cell. We found by immunoblotting techniques that these antibodies react with a 48-kDa protein. Additional immunoblotting and affinity purification studies indicate that the Ag may be the glycolytic enzyme enolase.
trans-Activation of genes encoding activation-associated human T lymphocyte surface proteins by murine retroviral sequences, The mechanisms whereby RNA leukemia viruses cause T lymphocyte leukemias or lymphomas after a long latent period are not understood. We report here that infection of human T lymphocyte lines with a murine leukemia virus results in up-regulation of a number of lymphocyte-specific cell surface Ag. These proteins include CD2. CD3. CD4. the TCR. and MHC class I Ag. The expression of other cell surface proteins. such as LFA-3. are unaffected by the presence of the retrovirus. This up-regulation occurs at the level of the mRNA transcripts encoding these proteins. and is the result of increased transcription of the respective genes. The increases in transcription are the result of a trans-activation process by the leukemia virus. The transient introduction of chimeric genes consisting of MHC class I gene promoter sequences attached to the reporter gene CAT into human T cells containing murine retrovirus produces stimulated transcription of the reporter gene. Subgenomic portions of the murine leukemia virus containing the long terminal repeats and the 5' untranslated region are sufficient to produce transactivation of the same set of T cell genes as the whole leukemia virus. The finding that murine leukemia viruses enhance transcription and expression of a group of T cell surface proteins. all of which have been reported to be capable of transducing an activating signal to the lymphocyte. may be relevant to the pathophysiologic mechanisms whereby these viruses induce leukemias and lymphomas.
Genetic construction and characterization of a fusion protein consisting of a chimeric F(ab') with specificity for carcinomas and human IL-2, A genetic construct was created incorporating gene fragments encoding the H chain V region of the human carcinoma specific antibody L6. the CH1 domain of human IgG1. a linker region. and human IL-2. This construct was cotransfected with a chimeric L6 L chain construct into the murine myeloma cell line Ag8.653 for expression. First round clones produced the fusion protein at an estimated 5 to 10 micrograms/ml based on idiotypic reactivity. Dual binding activity was demonstrated through specific interaction with the L6 Ag on human tumor cells and the IL-2R on activated human T cells. The IL-2 portion of the molecule was shown to support the growth of the IL-2-dependent T cell line CTLL2. and the qualitative nature of the IL-2 signal was found to be the same as rIL-2 with respect to induction of tyrosine-phosphorylation of intracellular protein substrates. Tumor cells coated with the fusion protein were shown to cause T cell proliferation and the presence of the fusion protein was found to enhance cell-mediated destruction of human tumor cells.
Mechanism of nonresponsiveness to AKR/Gross leukemia virus in AKR.H-2b:Fv-1b mice. An analysis of precursor cytotoxic T lymphocyte frequencies in young versus moderately aged mice, As young adult AKR.H-2b:Fv-1b mice reach about 9 wk of age. they begin to develop a nonresponsiveness to AKR/Gross leukemia virus. Unlike young mice that are responders. moderately aged AKR.H-2b:Fv-1b mice. after immunization and secondary in vitro restimulation in bulk culture with AKR/Gross virus induced tumors. can not generate anti-AKR/Gross virus-specific CTL. The mechanism of conversion to nonresponsiveness in moderately aged AKR.H-2b:Fv-1b mice is not understood. but it is correlated with increased expression of endogenous ecotropic viral antigens. Our present investigation focuses on determining the frequency of anti-AKR/Gross virus precursor CTL in AKR.H-2b:Fv-1b mice as a function of age. This was achieved by performing limiting dilution cultures of immune spleen cells obtained from young and moderately aged AKR.H-2b:Fv-1b mice. Although spleen cells obtained from immune moderately aged mice can not differentiate in bulk cultures into anti-AKR/Gross virus-specific CTL. there was no evidence of substantially decreased frequencies of virus-specific precursor CTL. relative to precursor CTL frequencies observed in young responder AKR.H-2b:Fv-1b mice.
Transfallopian tube embryo transfer: successful pregnancy outcome, A case of partial Asherman syndrome and blocked fallopian tube following complication of cesarean section is presented. Two IVF-ET attempts failed where difficulty at uterine embryo transfer was encountered. Transtubal embryos transferred 48 hr after transvaginal oocyte collection and in vitro fertilization resulted in an in utero pregnancy and delivery.
Chromosomal analysis of unfertilized oocytes and morphologically abnormal preimplantation embryos from an in vitro fertilization program, In vitro fertilization cycles yield a low percentage of pregnancies. Eighty-five to ninety percent of the transferred embryos do not implant. and the abortion rate approaches 30%. Aneuploidy is assumed to be responsible for a major portion of this pregnancy wastage. The purpose of this study was to determine if there was any correlation between morphology and chromosomal content of unfertilized oocytes and rejected embryos. To assess the chromosomal content of oocytes and embryos. we used the method described by Tarkowski in 1966. Sixty oocytes fron 28 women. aged between 27 and 41 years. were analyzed. Sixty-seven percent were aneuploid; of these. 23.35% were hyperhaploid. 23.35% were hypohaploid. 8.35% were hyperdiploid. 3.35% were diploid. and 8.35% showed premature chromosome condensation. Of 20 preimplantation embryos analyzed. 80% were aneuploid. 10% were diploid. 5% were haploid. and 5% showed structural anomaly. Correlation was found between maternal age and aneuploidy in oocytes and between morphology and genetic balance in preimplantation embryos.
The incidence of human immunodeficiency virus (HIV) in fetal cord samples utilized as serum supplements for in vitro fertilization, Prior to initiating routine fetal cord serum (FCS) supplementation in our in vitro laboratory. the incidence of HIV in 306 random fetal cord samples obtained at the Labor and Delivery Unit of the Johns Hopkins Hospital from July 1985 to January 1988 was determined from a cross-sectional patient sample. Of 306 samples. 3 (0.98%) were positive for HIV. and confirmed by Western blot analysis. enzyme immunoassay (ELISA). a prevalence significantly higher than a national sample (0.012%). The use of FCS in this setting was determined to be an unacceptable risk to patients undergoing in vitro fertilization. The 90-day quarantine period for verification of HIV seronegativity applied to semen donors may not be applicable to FCS sampling. Patient risk may also increase with pooling of FCS samples prior to HIV testing.
Dipyridamole technetium-99m-2-methoxy isobutyl isonitrile tomoscintigraphic imaging for identifying diseased coronary vessels: comparison with thallium-201 stress-rest study, A same-day double injection protocol employing 99mTc-methoxyisobutyl isonitrile (MIBI) and myocardial single-photon emission computed tomography (SPECT) for detecting coronary artery disease (CAD) was assessed in 30 patients. SPECT was performed 1 hr after a first injection (250 MBq) of 99mTc-MIBI. given after 0.56 mg/kg dipyridamole (DPD) infusion. Patients were then reinjected at rest (750 MBq) and were reimaged 1 hr later. Within 1 wk. all patients underwent a complete stress-rest SPECT thallium study. Of the 330 myocardial segments evaluated. 25 were judged ischemic by both techniques. while persistent defects were demonstrated in 50 and in 47 with 99mTc-MIBI and 201TI. respectively. Six regions were considered for diseased vessels identification. Sensitivity and specificity for CAD were 100% and 75%. respectively. for both 201TI and 99mTc-MIBI. Sensitivity for identification of diseased vessels by 201TI was 68% for LAD. 89% for RCA. and 80% for LCX as opposed to 75%. 89% and 80%. respectively. by 99mTc-MIBI. Specificity was 93% in both cases for LAD. 73% and 63% for RCA. and 53% and 46% for LCX.
rCBF-SPECT in brain infarction: when does it predict outcome, We prospectively studied 26 patients with ischemic stroke within 24 hr. after 2 wk. and after 6 mo with thallium-201-diethyldithiocarbamate single-photon emission computed tomography (SPECT) and neurologic and functional assessments. The admission flow deficits correlated with outcome. The admission and 6-mo scores correlated with clinical conditions at each time. At 2 wk. the flow deficits were smaller and did not correlate with clinical parameters. Nor did the presence or absence of hyperfixation of the radiopharmaceutical. Six months after the infarct. the flow defect had decreased in 9 of 15 patients in whom three serial scans were available. with better clinical improvement than in the remaining six whose flow deficits increased. More patients in the first group had been treated randomly with the calcium-entry blocker flunarizine. SPECT imaging of rCBF within 24 hr after stroke correlates with clinical outcome and condition. whereas rCBF imaging at 2 wk after the stroke shows no clinical correlation.
Thyroglobulin level as a predictive factor of tumoral recurrence in differentiated thyroid cancer, Ninety-eight patients with differentiated thyroid carcinoma were studied. Actuarial methods were used to investigate the 10-yr probability of survival (pS) and disease-free survival (pDFS). Our results show that the pDFS is a function of: (1) clinicopathologic stage: Stages I-II. pDFS = 90.9% +/- 5.0% versus Stages III-IV. pDFS = 55.9% +/- 17.8% (p less than 0.005); (2) age: Age less than 45 yr. pDFS = 87.2% +/- 10.0% versus age greater than or equal to 45 yr. pDFS = 66.6% +/- 12.0% (p less than 0.002); and (3) plasma thyroglobulin (Tg) levels: Tg less than or equal to 23 ng/ml. pDFS = 100% versus Tg greater than 23 ng/ml. pDFS = 68.3% +/- 10.6% (p less than 0.005). Using the multivariate analysis of proportional risk. the regression coefficients obtained (Stage: beta = 0.7615; Age: beta = 1.6398. and Tg: beta = 1.7607) allowed us to establish two different groups of risk of relapse on the basis of a prognostic index.
Combined technetium radioisotope penile plethysmography and xenon washout: a technique for evaluating corpora cavernosal inflow and outflow during early tumescence [published erratum appears in J Nucl Med 1991 Jul;32(7):1374, Combined technetium radioisotope penile plethysmography and xenon washout is a new technique that measures both corporal arterial inflow and venous sinusoidal outflow during early tumescence in patients with erectile dysfunction. Fourteen patients were studied using 99mTc-RBCs to measure inflow and 133Xe or 127Xe in saline to measure outflow. Tumescence was induced by injecting papaverine intracorporally. Peak corporal rates corrected for outflow (r = 0.88) and uncorrected for outflow (r = 0.91) and change in volume over 2 min centered around peak flow [corrected] (r = 0.96) all correlated with angiography. Outflow measurements did not correlate with intracorporal resistance. Thus. outflow rates alone could not be used to predict venous sinusoidal competence. Normal inflow rate is greater than 20 ml/min; probable normal 12-20; indeterminate inflow 7-12; and abnormal inflow less than 7 ml/min. Technetium-99m radioisotope penile plethysmography and xenon washout can be performed together and both provide a method for simultaneously evaluating the relationship between corporal inflow and outflow rates in patients with erectile dysfunction.
Lung thallium-201 uptake during exercise emission computed tomography, To test whether the analysis of lung uptake is worth adding to the interpretation of exercise thallium-201 (201TI) emission computed tomography (ECT). a lung/heart ratio of 201TI uptake was measured from an anterior image during ECT in 25 clinically normal (Group 1). 91 angiographically normal (Group 2). and 265 subjects with coronary artery disease (Group 3). The mean +2 s.d. of ratios in Groups 1 and 2 were the same (0.37). In Group 3. 80 subjects (30%) with increased ratios (greater than 0.37) had higher frequencies of prior infarction and multi-vessel disease. more severe left ventricular dysfunction. and 201TI defects than 185 subjects with normal ratios. Subjects with markedly increased ratios (greater than 0.45) had three-vessel disease more frequently than those with slightly or moderately increased ratios (67% versus 14% or 35%). Thus the measurement of lung/heart ratios may provide information regarding the severity of coronary artery disease and should be added to the routine interpretation of exercise ECT.
Use of technetium-99m-MAG3 for renal scintigraphy after angiotensin-converting enzyme inhibition, Technetium-99m-mercaptoacetyltriglycine (99mTc-MAG3) was tested in 82 hypertensive patients submitted to renal scintigraphy 1 hr after oral premedication with 50 mg of Captopril. Baseline studies were obtained only for those patients showing abnormal findings in the provocative study. All patients underwent renal arteriography. Sensitivity and specificity for the detection of renal artery stenosis (RAS) greater than 50% were 89% and 91%. respectively. After Captopril administration. tracer parenchymal transit time increased significantly in ischemic kidneys (334 +/- 93 sec in baseline conditions versus 468 +/- 96 sec after Captopril. p less than 0.001) but not in kidneys with no RAS or RAS less than 50% (243 +/- 46 sec versus 271 +/- 95 sec. p = ns). False-positive responses were mostly bilateral and associated with a marked decrease in blood pressure. Technetium-99m-MAG3 is an effective compound for detecting RAS greater than or equal to 50% with Captopril renal scintigraphy. Performing the provocative test as a first step considerably reduced the number of scintigraphic studies required.
Relative accuracy of three scintigraphic methods for determination of right ventricular ejection fraction: a correlative study with ultrafast computed tomography, The accuracy of three scintigraphic methods for determination of right ventricular ejection fraction (RVEF) was tested in 29 patients using ultrafast computed tomography (UFCT) as the gold standard. RVEF measurements by the ECG-gated first-pass approach showed excellent correlation with the UFCT results (r = 0.96. y = 0.06 + 0.91x). while both the standard gated acquisition blood-pool imaging (r = 0.71. y = 0.14 + 0.59x) and the nongated first-pass curve approach (r = 0.63. y = 0.18 + 0.37x) significantly underestimated RVEF. The error can be ascribed to partial inclusion of the atrial activity in the region assigned to the right ventricle. The tricuspid valve plane was found to move by a distance equal to 9%-33% (mean = 20%) of the right ventricular long-axis between systole and diastole. This translational motion was more pronounced with higher EFs.
Proposal of a modified scintigraphic method to evaluate duodenogastroesophageal reflux, Hepatobiliary scintigraphy with 99mTc-HIDA offers a noninvasive method to detect duodenogastric reflux. Biliary reflux was graded using the persistence rather than the intensity of the radioactive refluxate: Grade 0 was considered the absence of reflux. minimal reflux. or reflux in the first 10-15 min; Grade 1 was repetitive reflux lasting less than 10 min; Grade 2 was persistent reflux; and Grade 3 was reflux up to the esophagus. Twenty-five patients with foregut symptoms were studied and results were compared to 24-hr gastric pH monitoring. Scintigraphy and pH monitoring agreed in 15 out of 25 patients (60%). but no correlation was found with the endoscopic findings. The rationale for this approach is based on pathophysiologic evidence that damage to gastric and/or esophageal mucosa is mainly related to the prolonged contact time with duodenal contents. This technique seems to allow a complete functional evaluation of the esophagogastroduodenal tract without causing adjunctive irradiation or discomfort to the patient.
Thallium-201 scintigraphy in differentiated thyroid cancer: comparison with radioiodine scintigraphy and serum thyroglobulin determinations, The role of thallium-201 (201TI) scintigraphy in the follow-up evaluation of differentiated thyroid carcinoma (DTC) is controversial. Desirable characteristics of 201TI scintigraphy including the potential for no thyroid hormone withdrawal. immediate imaging postinjection. and low radiation burden relative to iodine-131 (131I) suggests it is logistically superior to 131I scintigraphy. Fifty-two patients with DTC were evaluated with 201TI and 131I neck and chest images. and serum thyroglobulin measurements. In post-thyroidectomy and pre-131I ablation therapy patients. very little 201TI accumulation was noted within the thyroid bed. with discordantly increased 131I activity and normal serum thyroglobulin measurements. Twenty-nine percent of patients evaluated after 131I ablative therapy had elevated serum thyroglobulin levels and localized neck and chest abnormalities on 201TI scan that were not seen on 131I studies. Our data suggest that 201TI is more sensitive than 131I diagnostic (5 mCi) studies for detection of DTC. while 131I is more sensitive in detecting normal residual thyroid tissue postoperatively.
Comparison of myocardial imaging with iodine-123-iodophenyl-9-methyl pentadecanoic acid and thallium-201-chloride for assessment of patients with exercise-induced myocardial ischemia, Iodine-123-iodophenyl-9-methyl-pentadecanoic acid [( 123I]MPDA) and thallium-201 (201Tl) were sequentially injected in 11 patients during exercise-induced myocardial ischemia. Simultaneous dual-energy planar images were obtained at 5 min. 3 and 5 hr. All studies were concordantly either positive (8/11) or negative (3/11) by both radionuclides. Exact agreement for segmental uptake was 93%. 94% and 94% for 5-min. 3- and 5-hr images. respectively. Exact agreement for defect reversibility by 3 and 5 hr were 95% and 92%. The initial defect contrasts and myocardial-to-lung ratios were similar by both agents but myocardial-to-liver ratio was lower by [123I]MPDA at 5 min. which became similar to 201Tl at 5 hr. Normal percent myocardial clearances of both agents were comparable and significantly higher than those in defect zones. Thus [123I]MPDA is suitable for myocardial imaging and correlates closely with 201Tl for initial postexercise myocardial uptake and defect reversibility. Defect reversibility appears to result from differential myocardial clearance from normal and ischemic regions.
Detection of a local staphylococcal infection in mice with technetium-99m-labeled polyclonal human immunoglobulin, The purpose of this study was to investigate both the ability of 99mTc-labeled polyclonal human immunoglobulin (HIG) to localize an infection and the modes of action involved in this process. Mice. infected with Staphylococcus aureus ATCC 25923 in a thigh muscle. received HIG intravenously. Scintigrams were made 1. 4. and 24 hr later; subsequently the mice were killed and the activity in several organs and thighs was determined. The radiopharmaceutical demonstrated a time-dependent accumulation at the site of infection. It was found that vascular permeability or Fc binding alone could not account for the mode of action of HIG. Neither the origin of Ig (human versus murine) nor the total amount of protein (0.01-1.0 mg Ig per mouse) affected the target-to-background (T/B) ratios. Ratios were not different for leukocytopenic animals. A correlation (p less than 0.001) was demonstrated between the number of bacteria at the site of infection and the T/B ratio. This was also found after antibiotic treatment (p less than 0.02).
Imaging focal sites of bacterial infection in rats with indium-111-labeled chemotactic peptide analogs, Four DTPA-derivatized chemotactic peptide analogs: ForNleLFNleYK-DTPA (P1). ForMLFNH(CH2)6NH-DTPA (P2). ForNleLFK(NH2)-DTPA (P3). and ForNleLFK-DTPA (P4). were synthesized and evaluated for in vitro bioactivity and receptor binding. The peptides were radiolabeled with 111In by transchelation and their biodistribution determined in rats at 5. 30. 60 and 120 min after injection. Localization at sites of infection was determined by scintillation camera imaging in animals with deep-thigh infection due to Escherichia coli. Images were recorded from 5 min to 2 hr after injection. All peptides maintained biologic activity (EC50 for O2-production by human PMN's: 3-150 nM) and the ability to bind to the oligopeptide chemoattractant receptor on human PMN's (EC50 for binding: 7.5-50 nM); biologic activity and receptor binding were highly correlated (r = 0.99). For all the peptides. blood clearance was rapid (half-lives: 21.5. 33.1. 31.6. and 28.7 min for P1. P2. P3. and P4. respectively). Biodistributions of the individual peptides were similar with low levels of accumulation in the heart. lung. liver. spleen. and gastrointestinal tract. In the kidney. P1 had much greater accumulation than other organs. All peptides yielded high quality images of the infection sites within 1 hr of injection. This study demonstrates that 111In-labeled chemotactic peptide analogs were effective agents for the external imaging of focal sites of infection.
Cellular internalization, transport, and esterification of iodine-125-NP59 by MA-10 Leydig tumor cells, The present studies were directed toward understanding the cellular processing of the cholesterol analogue. NP59. NP59 readily entered MA-10 Leydig tumor cells. The cholesterol analogue entered the cells by binding to the plasma membrane and becoming internalized along with plasma membrane cholesterol. Internalized NP59 was readily esterified to NP59 ester. Transport of NP59 within the cell was indistinguishable from transport of cholesterol. Cholesterol and NP59 transport were under the control of cAMP. however. only cholesterol entered the mitochondria and was converted into progesterone. Thus. internalized NP59 could not be removed from the cell by conversion into steroid hormones. Esterified NP59 was metabolically inert and could not be converted back to free NP59 and free fatty acid. Since NP59 was not a substrate for the cholesteryl ester hydrolase. it became trapped in the cell as NP59 ester.
Incidental demonstration of pericardial fistula during hepatobiliary scintigraphy, Biliary vomiting developed 16 mo after resection of adenocarcinoma of the esophagus in a patient with a complex postoperative course. A biliary scan revealed an outline of the pericardium. suggesting a fistula. The potential role of radionuclide imaging in this rare and potentially fatal complication is discussed.
Gallium-67 imaging in retroperitoneal fibrosis: significance of a negative result, A patient with retroperitoneal fibrosis and right peritracheal and hilar lymphadenopathy was studied using gallium-67-citrate. No abnormal uptake was seen in the regions of retroperitoneal fibrosis. while there was avid uptake in chest lesions later shown to represent small cell lung carcinoma. Retroperitoneal fibrosis which does not show gallium uptake is most likely mature. with few inflammatory elements. In patients with multiple retroperitoneal and/or mediastinal masses. gallium imaging may be useful in identifying the most active sites of disease for possible biopsy and for subsequent monitoring of response to therapy.
The diagnosis of drug dependence by primary care providers, HIV infection cannot be treated nor can its spread among those who use drugs be contained unless physicians diagnose and treat drug dependence. Recent changes in the DSM-III definitions simplify diagnosis. It is primarily by the presence and extent of the dependence syndrome that decisions are made regarding early HIV counseling and testing. medical management. referral for drug dependence treatment. and the approach to minimizing disease spread by the patient.
Primary care and HIV disease, Nearly one million Americans are infected with the human immunodeficiency virus (HIV). With the advent of increasingly effective therapy. including intervention early in the course of infection. there will be a growing need for physicians technically and attitudinally prepared to provide primary care for HIV-infected individuals. For any disease. however. determination of which physicians provide the bulk of care depends on several factors. including the prevalence and chronicity of the disease. the complexity. rate of change. and toxicity of therapy. and the socioeconomic characteristics of patients with the disease. General internists will clearly constitute a large part of the pool of practitioners caring for HIV-infected patients. especially in the earlier stages of infection. It seems reasonable to expect every general internist to be competent in four aspects of HIV care: counseling about transmission and prevention; the proper administration and interpretation of diagnostic tests; monitoring and care of patients in early stages of infection; and recognition of complications of advanced infection for proper management or referral. Academically based generalists will have a major role in research. teaching. and patient care in the AIDS epidemic. The organization and delivery of primary and specialty care for HIV-infected people in future years will continue to evolve with changes in therapy and in the demography of the epidemic.
Survey of antibiotic prophylaxis for intraoral orthognathic surgery, A survey was sent to 114 oral and maxillofacial surgery residency programs to determine the prophylactic use of antibiotics with intraoral orthognathic procedures. Seventy-four percent of the programs responded. Review of the data showed that all programs used antibiotic prophylaxis for intraoral orthognathic procedures. and that penicillin or a cephalosporin were the drugs most often used. However. there was no consistent protocol for the method or duration of drug administration. A discussion of rationale for antibiotic usage. concentration. and duration is presented.
Use of N2O/O2/enflurane anesthesia for dental treatment of the handicapped, To develop an anesthesia maintenance method that could be expected to maintain a reasonably stable state during dental treatment of the handicapped. three methods (N2O/O2 [0% enflurane (E). n = 12]. N2O/O2/0.6% E [n = 8]. N2O/O2/1.5% E [n = 7]) were evaluated in terms of changes in plasma levels of cortisol. epinephrine (EP). and norepinephrine (NE). During a treatment period of 60 minutes. cortisol levels increased in the 0% E group (from 9.5 +/- 1.8 micrograms/dL to 19.4 +/- 2.4 micrograms/dL. P less than .01). did not change in 0.6% E group. and decreased in 1.5% E group (from 9.3 +/- 1.7 micrograms/dL to 5.8 +/- 1.0 micrograms/dL. P less than .01). Epinephrine and NE levels increased in the 0% E group. but were suppressed in the 0.6% E and 1.5% E groups. It is suggested that N2O/O2 inhalation anesthesia supplemented with low-dose enflurane produces a stable state during dental treatment with respect to cortisol. EP. and NE responses.
Small-vessel pathology and anastomosis following maxillofacial firearm wounds: an experimental study, This experiment was designed to provide a biological basis for early reconstruction of maxillofacial defects caused by firearms using free vascularized flap transfer. The pathologic changes of small-vessel injury. injury mechanism. and the feasibility for early anastomosis of these vessels in the maxillofacial region following high-velocity missile wounds were studied. Dogs' faces were wounded by a steel sphere. weighing 0.7 g and 1.03 g. with an initial velocity of 1.300 m/s or 1.500 m/s. Angiography and high-speed x-ray photography were used to record the effect of injury to blood vessels and other tissues. The pathologic changes in the small blood vessels in the wounds were studied by light microscopy (LM) and electron microscopy (EM). Anastomosis of small vessels in the wound was performed at different times after injury. There were temporary cavity effects and small vascular injury in the wounds. The pathologic changes of the small vessels included microthrombus formation. endothelial loss. breaks in the internal elastic layer. and necrosis. Degeneration of cells was found to end 3 cm from the wound edge. Anastomosis of the vessels performed 3 days after injury provided good short-term patency. These results suggest that the operation for repairing facial defects should be performed 3 days after injury.
Clinical use of ganciclovir for cytomegalovirus infection and the development of drug resistance, Cytomegalovirus (CMV) infection is extremely common in patients with advanced human immunodeficiency virus infection. in whom it can produce a variety of clinical syndromes. Ganciclovir is a guanosine analogue that selectively inhibits CMV DNA polymerase when intracellularly phosphorylated to its active form. In patients with CMV retinitis. induction therapy with ganciclovir results in high rates of clinical and virologic response; maintenance therapy is required to forestall progression of disease. Clinically relevant resistance of CMV to ganciclovir has recently been reported. Decreased phosphorylation of ganciclovir to its active form has been observed in cells infected with resistant strains. suggesting that CMV may encode a ganciclovir-phosphorylating enzyme whose function is deleted by mutation. conferring resistance. Further study is needed to establish the mechanism of resistance and to define the prevalence of resistance in the clinical setting.
Cytomegalovirus as a possible cofactor in HIV disease progression, It has been suggested that cofactors in human immunodeficiency virus (HIV) disease. particularly other viral infections. may accelerate progression to the acquired immune deficiency syndrome (AIDS). We have shown that in a population of 108 HIV-infected hemophiliacs observed for up to 9 years after the first documented HIV seroconversion. coinfection with cytomegalovirus (CMV) adversely influenced the course of the disease; in particular. logistic regression analysis showed that the age-adjusted relative risk of developing AIDS in CMV-seropositive patients was 2.5 times that in CMV seronegatives (p = 0.02). A number of potential mechanisms for the interaction of HIV and CMV have been proposed. Several groups have reported interaction at a molecular level between HIV and other viruses. including CMV. through transactivation of the HIV genome. Mechanisms by which the two viruses might gain entry to the same cell have been identified in vitro; these include Fc receptor-mediated uptake of antibody-coated HIV by CMV-infected fibroblasts. There is also some evidence that coinfection with HIV and CMV can occur in vivo. within brain cells. Interaction between these two viruses might also occur indirectly through the production of cytokines. such as tumor necrosis factor. Identification of cofactors in HIV infection may help in understanding the pathogenesis of AIDS. and may provide an important opportunity for intervention in the progression of the disease. particularly when an infectious agent for which specific therapy is available is identified.
Future directions in the management of cytomegalovirus infections, Ganciclovir currently is the only agent approved for use in the treatment of cytomegalovirus (CMV) retinitis in immunocompromised patients. including those with the acquired immune deficiency syndrome (AIDS). Its effect against CMV in vitro and in vivo suggests its usefulness in other types of CMV infection as well. Investigations of the use of this agent in the treatment of AIDS patients with CMV gastrointestinal disease and in the treatment or prevention of CMV disease in transplant recipients are ongoing. In other studies. issues important to the management of patients receiving ganciclovir therapy are being addressed. Particular objectives include characterizing the scope of ganciclovir resistance in CMV. detailing the prospects for the tolerance of coadministered ganciclovir and zidovudine. and determining the plausibility of enhancing drug delivery through the concomitant use of recombinant human granulocyte-macrophage colony-stimulating factor and through oral administration of the agent.
Involvement of sodium in the protective effect of 5-(N,N-dimethyl)-amiloride on ischemia-reperfusion injury in isolated rat ventricular wall, During reperfusion in the isolated right ventricular wall of the rat after 60 min of ischemia. developed tension and resting tension were 35 +/- 4 and 221 +/- 12%. respectively. of preischemic values. Including 35 microM ouabain in the perfusate before and after ischemia resulted in more severe cardiac dysfunction during reperfusion than in drug-untreated hearts. Introduction of the Na(+)-H+ exchange inhibitor. 5-(N.N-dimethyl)-amiloride (DMA). could effectively protect the right ventricular wall against ischemia-reperfusion dysfunction in the presence or absence of ouabain. The ion content in the right ventricular wall was measured with atomic absorbance spectrophotometry. Before ischemia. Na+.Ca++ and K+ content were 53.4 +/- 6.4. 2.70 +/- 0.22 and 262 +/- 7.7 mumol/g of dry weight tissue. respectively. After 60 min of ischemia and 6 min of reperfusion. Na+.Ca++ and K+ content were 73.4 +/- 7.2. 3.79 +/- 0.31 and 180 +/- 15 mumol/g of dry weight tissue. respectively (P less than .05). Introduction of 20 microM DMA normalized ion content in the muscles which was consistent with the contractile function recovery during reperfusion. The data suggest that a rise in intracellular Na+ in the early stage of reperfusion represents a crucial or primary step for the development of cardiac contractile dysfunction. DMA. which protects against severe reperfusion-induced cardiac contractile dysfunction. appears to act via a normalization of tissue sodium levels. This action is consistent with its proposed role as a blocker of transsarcolemmal Na(+)-H+ exchange.
Protective effects of specific platelet-activating factor receptor antagonists in experimental glomerulonephritis, The present study was undertaken to evaluate the hypothesis that enhanced production of platelet-activating factor (PAF) contributes to the renal hemodynamic alterations and impaired glomerular permselectivity that characterize the heterologous phase of nephrotoxic serum nephritis. Intravenous administration of nephrotoxic gamma globulin to normal rats led to a rapid decline in glomerular filtration rate within 60 min from 1.08 +/- 0.08 to 0.45 +/- 0.12 ml/min/100 g b.wt.. P less than .001. and in effective renal plasma flow rate from 2.56 +/- 0.15 to 1.35 +/- 0.21 ml/min/100 g b.wt.. P less than .02. Concomitantly. the fractional excretion of protein rose from 3.4 +/- 0.6 X 10(-5) to 11.6 +/- 2.3 X 10(-5). P less than .03. Pretreatment with the specific PAF receptor antagonists WEB 2086 or WEB 2170 significantly ameliorated the impairment in glomerular filtration rate and in effective renal plasma flow rate induced by nephrotoxic globulin. Filtration rate declined by 0.63 +/- 0.12 ml/min/100 g b.wt. 60 min after administration of nephrotoxic globulin. but fell only 0.30 +/- 0.14 ml/min/100 g b.wt. in rats pretreated with WEB 2086. P less than .05 and 0.34 +/- 0.11 ml/min/100 g b.wt. in rats pretreated with WEB 2170. P less than .01. The decline in effective renal plasma flow rate 60 min after administration of nephrotoxic globulin was 1.21 +/- 0.30 ml/min/100 g b.wt.. but only 0.86 +/- 0.23 ml/min/100 g b.wt. in rats pretreated with WEB 2086. NS. and 0.52 +/- 0.21 ml/min/100 g b.wt. in rats pretreated with WEB 2170. P less than .003.
Separate neural mechanisms mediate sufentanil-induced pupillary responses in the cat, The pharmacologic characteristics of a highly selective mu receptor agonist. sufentanil. were studied on the cat's pupillary responses (size. light reflex and fluctuations) measured with an infrared video pupillometer. The pupillary effects of sufentanil were also compared with those of morphine and clonidine. known mydriatics in the cat. Sufentanil (0.3-10 micrograms/kg i.v.) dose-dependently increased pupillary size and decreased light reflex and fluctuations. Naltrexone (10 micrograms/kg i.v.) pretreatment shifted the dose-response curve to the right by a factor of 26 for pupillary size. 9.5 for light reflex and 7.2 for fluctuations (nonvalid bioassay). Equivalent mydriatic doses of sufentanil (1 micrograms/kg). morphine (0.5 mg/kg) and clonidine (10 micrograms/kg) produced divergent effects on the light reflex and fluctuations. At these doses. morphine was more effective than sufentanil in inhibiting fluctuations. Clonidine was a more potent inhibitor of fluctuations but significantly enhanced the light reflex. Sufentanil (compared with morphine in a previous study) was 298 times more potent than morphine as a mydriatic. 100 times more potent in inhibiting the light reflex. and only slightly more potent in inhibiting fluctuations. These results indicate that separate neural mechanisms control the three pupillary components and that mu opioid receptors are more involved in mediating opiate-induced mydriasis than in inhibiting the light reflex and fluctuations in the cat.
Antiplatelet and antithrombotic effects of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) inhibition by arginine-glycine-aspartic acid-serine (RGDS) and arginine-glycine-aspartic acid (RGD) (O-me)Y (SC-46749), Arginine-glycine-aspartic acid (RGD) is the minimal sequence in fibrinogen that leads to recognition and binding to the glycoprotein IIb/IIIa platelet receptor during aggregation. Analogs of tetrapeptides containing the RGD sequence have been previously shown to block fibrinogen binding to activated platelets in vitro. SC-46749 is an analog of arginine-glycine-aspartic acid-phenylalanine in which the phenylalanine is replaced by O-methyltyrosine. In this study the biological activities of SC-46749 were examined and its actions compared with the tetrapeptide arginine-glycine-aspartic acid-serine (RGDS). one of the natural sequences on the fibrinogen alpha chain that binds to platelets. In vitro. SC-46749 was more potent than RGDS in inhibiting fibrinogen binding (IC50: SC-46749. 27 microM; RGDS. 47 microM). in preventing ADP-induced aggregation in human platelet-rich plasma (IC50: SC-46749. 32 microM; RGDS. 95 microM) and in inhibiting thrombin-induced aggregation in washed human platelets (IC50: SC-46749. 23 microM; RGDS. 64 microM). In rats. SC-46749 prevented collagen-induced thrombocytopenia with an ED50 of 0.87 mg/kg whereas RGDS did not inhibit the response by 50% at doses up to 10 mg/kg. SC-46749 inhibited thrombus formation in an electrically damaged rat carotid artery in a dose-dependent fashion whereas the effects of RGDS were biphasic. RGDS appeared to delay thrombus formation at lower doses but had no effect at higher doses. When infused in dogs for 15 min. SC-46749 prevented ex vivo collagen-induced aggregation at 4 mg/kg/min. These data demonstrate that SC-46749 is a potent inhibitor of platelet aggregation and platelet-dependent thrombus formation.
Isovolumic hemodilution with dextran 40 in the rat: effect on the development of peripheral edema and various physiologic parameters, Low molecular weight dextran 40 (D40). 40.000 daltons. is a potential therapeutic agent for cerebral ischemia because it increases local cerebral blood flow. However. the evaluation of D40 in the rat has been difficult due to systemic effects. We evaluated the effects of isovolumic hemodilution with D40 on the development of peripheral edema. mean arterial pressure. hematocrit (Hct) and total blood volume in 18 rats. during 30 min or 4 hr i.v. infusions. in animals with and without previous challenge with D40. Reduction of Hct without peripheral edema to a mean of approximately 31% was only achieved in the animals challenged with i.p. D40 24 hr before hemodilution and who received D40 over a period of 4 hr. Infusion of D40 over a period of 30 min was associated with shorter survival time. compared to the 4-hr infusion group (P less than .005). In the pretreated. rapidly infused group. total blood volume per body weight decreased significantly over time (P less than .005) and the mean arterial blood pressure dropped. but not significantly (P less than .07). whereas no change in Hct was detected and there was a trend toward increased peripheral edema. relative to the slowly infused groups. We conclude that reduction of Hct can be achieved successfully with i.p. administration of D40 24 hr before the study combined with infusion of the agent during a 4-hr period. without significant peripheral edema and early hypotension. This procedure should be used to avoid allergic reactions when evaluating hemodilution with D40 in rats.
Effect of alcohols and other hypnotics in mice selected for differential sensitivity to hypothermic actions of ethanol, Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of an acute dose of ethanol were tested twice during the course of genetic selection for their hypothermic response to other alcohols and sedative hypnotics. The drugs administered were ethanol. propanol. n-butanol. t-butanol. pentanol. diazepam. phenobarbital. pentobarbital. methyprylon and ethchlorvynol. all of which have sedative effects on the central nervous system. and hydralazine. a peripheral vasodilator. All drugs decreased body temperature of both HOT and COLD mice. In mice selected for seven to nine generations. COLD mice were more sensitive than HOT mice to all sedative drugs. The longer-chain alcohols were more potent than ethanol in inducing hypothermia. but the magnitude of the response difference between HOT and COLD mice appeared to be smaller. The difference between HOT and COLD mice in hypothermic sensitivity to an acute dose of ethanol was greater after 11-15 generations of selection than after seven generations. Similarly. the differential effect of the other alcohols. phenobarbital. pentobarbital. and methyprylon. on HOT and COLD mice increased with more generations of selection but to a lesser extent than ethanol. These data demonstrate that selecting for sensitivity to acute ethanol hypothermia has produced mice that are also differentially sensitive to other sedative hypnotic agents. They also support the hypothesis that the drugs used in the present study share a common mechanism of action for inducing hypothermia. which may be regulated by a common set of genes.
Effect of neurotransmitter-selective drugs in mice selected for differential sensitivity to the hypothermic actions of ethanol, Mice selectively bred for resistance (HOT) and sensitivity (COLD) to the hypothermic effect of EtOH were tested for their hypothermic response to neurotransmitter-specific drugs and for the effect of such drugs on EtOH induced hypothermia (HT). The drugs administered were the opiate drugs morphine. levorphanol and U50488H. the dopamine agonists apomorphine. LY171535 and SKF38393. the dopamine antagonist chlorpromazine. the alpha adrenergic agonist St587. the cholinergic agonist nicotine and amphetamine. which increases the release of catecholamines. All of the drugs tested. with the exception of SKF38393 and amphetamine. induced a hypothermic response in HOT and COLD mice. SKF38393 had no effect on body temperature or HT produced by EtOH. Amphetamine caused HT at low doses and hyperthermia at high doses. COLD mice were more sensitive than HOT mice to the hypothermic effect of morphine and levorphanol. mu-opiate agonists. and U50488H. a relatively specific kappa agonist. All of the other drugs tested were approximately equally potent in HOT and COLD mice. These results suggest that the differential sensitivity of HOT and COLD mice to EtOH-induced HT may be partially mediated through genetic changes in opiate mechanisms.
Suppression of mouse mammary tumorigenesis by long-term tamoxifen therapy, A sustained release of tamoxifen. which produced decreasing serum levels of this drug (24 to 4 ng/mL) over 6 months. suppressed mammary tumorigenesis in virgin or once pregnant C3H/OUJ female mice. Tamoxifen was consistently more effective than early ovariectomy. which only delayed tumorigenesis. Tamoxifen prevented the stimulatory action of cyclical (alternate-month) progesterone administration on mouse mammary tumorigenesis. However. when tamoxifen treatment (12 months) was stopped. progesterone treatment initiated tumorigenesis. In contrast. when long-term tamoxifen treatment was stopped in mice that had not undergone ovariectomy. and estrous cycle returned. the majority of these mice remained tumor free. A comparison of different durations (3. 6. and 12 months) of tamoxifen treatment of virgin mice. starting at approximately 4 months of age. showed an equivalent effect on mammary tumorigenesis. All virgin mice developed tumors by 18 months of age. whereas 80% of the tamoxifen-treated mice were tumor free. Nevertheless. cyclical progesterone administration caused rapid development of tumors after 3 months of tamoxifen treatment; only 15% of these mice were tumor free at 18 months. Cyclical progesterone administration caused an increase in tumorigenesis after 6 months of tamoxifen treatment; 50% of these mice were tumor free at 18 months of age. These data demonstrate the efficacy of tamoxifen to suppress mouse mammary tumorigenesis and demonstrate that continuous tamoxifen therapy is necessary to prevent the development of tumors by progesterone. a stimulatory hormone.
Excess number of bladder cancers in workers exposed to ortho-toluidine and aniline, A retrospective cohort study of the incidence of bladder cancer was conducted in response to a union request for an evaluation of a possible excess number of cases of bladder cancer at a chemical plant in western New York State. Workers at the plant were exposed to two potential bladder carcinogens--ortho-toluidine (o-toluidine) and aniline. Incidence rates of bladder cancer among workers at the plant were compared with those of the population of New York State (excluding New York City). Among all 1749 workers at the plant. 13 cases of bladder cancer were observed versus 3.61 expected [standardized incidence ratio (SIR) = 3.60; 90% confidence interval (CI) = 2.13-5.73]. Among the 708 workers who worked in areas in which o-toluidine and aniline were used. 7 cases were observed versus 1.08 expected (SIR = 6.48; 90% CI = 3.04-12.2). Among the 288 maintenance. shipping. and janitorial workers thought to have been possibly exposed. 4 cases were observed versus 1.09 expected (SIR = 3.66; 90% CI = 1.25-8.37). Among the remaining 753 workers who were probably not exposed. 2 bladder cancers were observed versus 1.43 expected (SIR = 1.39; 90% CI = 0.25-4.39). Increased risk of bladder cancer was strongly associated with increased duration of employment in the department where o-toluidine and aniline were used (P less than .001). Among workers with 10 or more years of employment in the department. the SIR was 27.2 (90% CI = 11.8-53.7). o-Toluidine is an animal carcinogen more potent than aniline and is known to produce bladder tumors in rats; hence. it is more likely that o-toluidine is responsible for the observed excess number of cases of bladder cancer. although aniline may have played a role.
Socioeconomic factors and cancer incidence among blacks and whites, Findings from previous studies suggest that differences in socioeconomic status may be responsible for some. if not all. of the elevated incidence of cancer among blacks as compared with whites. Using incidence data from the National Cancer Institute's Surveillance. Epidemiology. and End Results (SEER) Program. we tested this hypothesis by correlating black and white cancer incidence rates in three US metropolitan areas between 1978 and 1982 with data from the 1980 census on socioeconomic status within individual census tracts. The study analyzed data on the incidence of cancer at all sites combined (greater than 100 cancer sites) and at seven major sites separately. As in other studies. income and educational levels served as surrogates for socioeconomic status. The present study also used census-tract data on population density as a surrogate factor. Each of these measures of socioeconomic status was analyzed independently. Before correlation with census-tract data. age-adjusted data on cancer incidence showed statistically significant elevated risks among blacks for cancer at all sites combined and at four of the seven separate sites; whites showed an elevated risk for cancer at two sites. Cancer at only one site. the colon. showed no significant association with race. When age-adjusted incidence data were correlated with socioeconomic status. the comparative black-white risks changed: Whites showed an elevated risk of cancer at all sites combined and at three of the seven separate sites; blacks maintained their elevated risk at three sites. These findings suggest that the disproportionate distribution of blacks at lower socioeconomic levels accounts for much of the excess cancer burden among blacks. They also suggest that for both blacks and whites unidentified racial factors. which may be either cultural or genetic and which are not closely linked to socioeconomic status. may play a role in the incidence of some cancers.
Increased DNA synthesis and repair-enzyme expression in lymphocytes from patients with chronic lymphocytic leukemia resistant to nitrogen mustards, Resistance to the nitrogen mustards in patients with chronic lymphocytic leukemia (CLL) correlates with an enhanced removal of melphalan-induced DNA interstrand cross-links. This finding suggests that DNA repair enzymes may be involved in this process. The activity of 3-methyladenine-DNA glycosylase. which can release altered bases. including adducts at the N-7 position of guanine. was increased significantly in lymphocytes from patients with resistant CLL compared with those from untreated CLL patients. Since glycosylase activity varies with cell proliferation. the amount of [3H]thymidine incorporated into DNA was determined and found to be elevated almost threefold in lymphocytes from patients with resistant CLL. The ratio of glycosylase activity to level of thymidine incorporation did not differ between these two groups of patients. Northern blot analysis of ERCC1 gene (a putative DNA repair enzyme involved in nucleotide excision repair) expression in lymphocytes from patients with CLL revealed multiple gene transcripts (1.1. 3.4. and 3.8 kilobases). In addition. analysis of two samples revealed the presence of a 2.6-kilobase transcript. The 2.6-kilobase transcript was recognized by specific RNA probes that hybridize to antisense ERCC1 transcripts. Levels of expression of the 1.1-kilobase protein encoding transcript in lymphocytes from patients with resistant CLL were increased twofold to threefold above those of untreated patients with CLL. These results indicate that increased expression of ERCC1 and increased activity of 3-methyladenine-DNA glycosylase occur with the development of resistance to the nitrogen mustards in patients with CLL. suggesting a role for enhanced DNA repair in this process.
An objective criterion for the cessation of deferoxamine therapy in the acutely iron poisoned patient, The criteria for the cessation of deferoxamine therapy in the acutely iron poisoned patient are vague and imprecise. We have developed a urinary iron assay which is not confounded by the presence of deferoxamine and have established a reference range in non-iron poisoned deferoxamine treated human volunteers. When reported as a urine iron to creatinine ratio the results from isolated urine specimens can be utilized to guide deferoxamine therapy. This method is rapid. simple and inexpensive and utilizes equipment and reagents found in laboratories already providing emergency serum iron concentrations. We have found this assay to be useful as a criterion for the cessation of deferoxamine therapy in the acutely iron poisoned patient and as an objective indicator of a positive deferoxamine chelation challenge.
Isopropanol ingestion: a report of six episodes with isopropanol and acetone serum concentration time data, The disposition of isopropanol and its major metabolite acetone were observed in six isopropanol ingestion episodes among five patients. Serum admission isopropanol and peak acetone concentrations ranged from 16.5 to 220 mg/dL and 141 to 585 mg/dL respectively. Ingestions ranged from 120 to 300 mL of 70% isopropanol with concomitant ethanol ingestion in two episodes. The isopropanol and acetone apparent half-lives ranged from 2.9 to 16.2 hours (h) and 7.6 to 26.2 h respectively. Two episodes of isopropanol ingestion were observed within a 9 month period in patient one. Isopropanol terminal elimination rate constants were 0.043 and 0.085 per hour (per h) with no marked difference in acetone terminal elimination rate constants (0.025 and 0.033 per h). Discrepancy between the two isopropanol elimination rate constants reflected concomitant ethanol abuse with the first ingestion. Reductions in isopropanol and acetone half-lives were also noted among patients requiring ventilatory support.
Hospitalizations due to poisonings in Finland--1978-1984, In the seven year period 1978-1984. 40.847 registered cases of poisonings were treated in hospital wards in Finland. 73.9% of the poisonings were due to drugs and 26.1% were due to technochemical products. The patients were primarily treated in internal medicine wards (65%) and in pediatric wards (16.3%). Seasonal variation was seen for agents such as oils. carbon monoxide. solvents. psychotropics. mushrooms and pesticides. Poisonings due to psychotropic drugs occurred at a steady rate during the period. For example. in 1984 there were 21.3 admissions per 100.000 inhabitants per year. Neuroleptics were the most common psychotropic drugs. Antidepressants caused fewer poisonings than did sleeping pills. which increased steadily to 13.9/100.000 inhabitants. Poisonings due to cardiovascular drugs declined. paralleling a decrease in digoxin prescriptions. During the period studied there were 13 to 14 admissions/100.000 inhabitants/year due to alcohol. The rate of cases of corrosive and solvent intoxication was steady at about 3 admissions/100.000 inhabitants/year.
Demographic and electrocardiographic factors associated with severe tricyclic antidepressant toxicity, This study was designed to evaluate a historic cohort of pure tricyclic antidepressant overdose patients for factors associated with severe toxicity. Hospitalized tricyclic antidepressant overdose patients were identified by computerized discharge diagnosis (ICD-9 codes). Patients with a serum drug screen positive for tricyclic antidepressants and an emergency department 12-lead electrocardiogram were included in the study. Multiple drug overdoses were excluded. Patients were divided into two groups: minor toxicity (n = 41 and major toxicity (n = 65). Criteria for inclusion in the major toxicity group were the occurrence of seizures. endotracheal intubation. coma. arrhythmias requiring treatment. hypotension. or death. The following were found to be associated with increased likelihood of major toxicity (p less than 0.05): ingestion of amitriptyline (odds ratio (OR) 2.57). age greater than or equal to 30 years (OR 2.56). heart rate greater than or equal to 120 bpm (OR 2.86). serum tricyclic antidepressant level greater than or equal to 800 ng/mL (OR 5.20). terminal 40 ms QRS axis (T40-ms axis) greater than or equal to 135 degrees (OR 2.73). QRS interval greater than or equal to 100 ms (OR 2.74). QRS axis greater than 90 degrees (OR 3.68). and QTc interval greater than 480 ms (OR 3.89). The mean T40-ms axis on the initial ECG was more rightward in the major toxicity group (174 +/- 84 vs 125 +/- 91 degrees. p = 0.006). We conclude that patients with severe tricyclic antidepressant toxicity tended to have a more rightward T40-ms axis than those with minor toxicity and that the presence of the above parameters was associated with an increased likelihood of severe toxicity.
Red blood cell and total blood acetylcholinesterase and plasma pseudocholinesterase in humans: observed variances, Although acetylcholinesterase is the target molecule of organophosphate poisoning. it is not always assayed in clinical evaluations which include only the determination of plasma or serum cholinesterase. In this paper we present observations on workers exposed to. or poisoned by. ethylparathion. Acetylcholinesterase decreased earlier and more intensely than cholinesterase. with the suggestion of an initial increase of acetylcholinesterase activity in newly exposed. workers. A simplified standard Ellman assay of total acetylcholinesterase activity of hemolyzed total blood correlated with that of washed erythrocyte acetylcholinesterase. All results were standardized to both red blood cell and hemoglobin concentration. Normal values in a group of unexposed subjects were acetylcholinesterase: 1225 +/- 181 nU x 10/RBC and 39.30 +/- 5.05 U/g Hb for men. 1321 +/- 234 nU x 10/RBC and 42.57 +/- 6.85 U/g Hb for women. Differences between total and erythrocyte acetylcholinesterase were not statistically significant. Plasma cholinesterase appeared to be decreased in pregnancy and increased in anesthesia. liver and kidney disease and neuropathologic conditions attributed to metal poisoning while total acetylcholinesterase was unaffected. The determination of both cholinesterase and acetylcholinesterase assists the evaluation of individuals exposed to or poisoned by organophosphate. the differentiation of other conditions affecting cholinesterase and the recognition of genetically atypical cholinesterase.
Taiwan National Poison Center survey of glyphosate--surfactant herbicide ingestions, Between January. 1986 and September. 1988. the Taiwan National Poison Center recorded 97 telephone consultations (49 male. 48 female) on cases of ingestion of glyphosate-surfactant herbicide concentrate containing the isopropylamine salt of glyphosate (N-phosphonomethyl glycine. CAS 1071-83-6) and a non-ionic tallow amine surfactant. Eleven of the cases resulted in fatalities. all among those attempting suicide. The average amount ingested by survivors was 120 +/- 112 mL and by nonsurvivors was 263 +/- 100 mL (p less than or equal to 0.0001). The average age of survivors was 35 +/- 15 years compared to 54 +/- 11 years for fatalities (p less than or equal to 0.0002). Irritation of the oral mucous membrane and gastrointestinal tract was the most frequently reported effect. Other effects recorded were pulmonary dysfunction. oliguria. metabolic acidosis. hypotension. leukocytosis and fever. Fourteen patients received either atropine or pralidoxime plus atropine despite the fact that glyphosate does not inhibit acetylcholinesterase. Thirteen percent of patients received a urine test for paraquat or treatment customarily used for paraquat ingestion. possibly reflecting similar initial presentations following ingestion of these two herbicides. Laboratory differentiation is essential if any doubt exists about which herbicide was ingested. Patients ingesting large volumes of concentrated glyphosate-surfactant herbicide formulations require close observation and supportive treatment.
Gonadal differentiation: a review of the physiological process and influencing factors based on recent experimental evidence, The sexual differentiation of a gonad is determined in normal embryology by the presence or absence of the TDF gene. a short segment of DNA localized near the tip of the short arm of the Y chromosome. Under the stimulus of this gene. the somatic cells of the genital ridge differentiate into Sertoli cells and secrete anti-mullerian hormone. This hormone inhibits the germ cells from entering meiosis and may well also trigger the formation of the primary sex cords. Once the Sertoli cells are formed. further differentiation of the gonad is independent of the TDF presence. although this gene may further contribute to the normal functioning of the male gonad. In true hermaphroditism the normal regulation of the gonadal differentiation is missing. Gonadal differentiation may revert to a more primitive evolutionary level at which the rate of growth of the gonad determines its sexual direction. When this exceeds a certain threshold a testis may develop despite the absence of the TDF gene.
A report on extracorporeal shock wave lithotripsy results on 1,569 renal units in an outpatient clinic, We report our experience with extracorporeal shock wave lithotripsy (ESWL*) treatment of 1.569 renal units in an outpatient clinic with a small focused piezoelectric lithotriptor. A stone-free rate of 93% was achieved. In 3.6% of the patients. mainly those with a history of surgery and/or anatomical caliceal deformations. fragments smaller than 3 mm. in diameter remained despite multiple ESWL sessions and intensive upside down physiotherapy. Of the cases 3.4%. including those without sufficient data. were considered unsuccessful. We treated 58 renal units in children 14 years old and younger. 55 patients had a single kidney and 7 had a horseshoe kidney.
Extracorporeal shock wave lithotripsy for large renal calculi: the role of ureteral stents. A randomized trial, Ureteral stents reduce complications after extracorporeal shock wave lithotripsy (ESWL*) and contribute to successful stone passage. However. some reports note complications that are attributed to indwelling ureteral stents. We randomized 64 patients with large renal calculi (stone burden more than 200 mm.2) for in situ treatment or treatment with a prophylactically inserted stent. We used a 6Ch round stent with single-coiled ends or a triangular shaped stent with double-coiled ends. Patients were treated with a Siemens Lithostar lithotriptor. After 3 months we evaluated the results of treatment and post-ESWL morbidity. Of the in situ group (23 patients) treatment complications consisted of fever in 3. pyelonephritis in 1 and steinstrasse in 3. After 3 months 8 patients (35%) were free of stones. Of the stented population (41 patients) treatment complications consisted of fever in 7. pyelonephritis in 1. steinstrasse in 6 and bladder discomfort in almost half of the patients. Stent calcification and stent migration were also seen in 7 and 10 patients. respectively. Calcified stents had been in situ longer than noncalcified stents. The round stents migrated and calcified more often than the more rigid triangular stents. After 3 months 18 of the stented patients were stone-free (44%). We conclude that ureteral stents do not reduce post-ESWL complications. They are clearly associated with morbidity and do not improve stone passage markedly. Therefore. patients with a stone burden of more than 200 mm.2 should be treated in situ without auxiliary stenting.
Comparison of endoscopic and radiological residual fragment rate following percutaneous nephrolithotripsy, The stone-free rate after extracorporeal shock wave lithotripsy (ESWL) is primarily determined by a plain abdominal radiograph alone. However. the accuracy of that assessment can be challenged by renal tomography and flexible nephroscopy. We report on 29 patients with large renal calculi treated with a combination of percutaneous nephrolithotripsy and ESWL. Stone-free rates were determined by plain abdominal radiograph. renal tomography and flexible nephroscopy. The plain abdominal radiograph and renal tomography overestimated stone-free rates by 35% and 17%. respectively. compared to flexible nephroscopy. To determine stone-free rates after ESWL renal tomography is superior to a plain abdominal radiograph alone. Also. among patients with large renal calculi the use of the flexible nephroscope markedly improves the stone-free rate.
A comparison of anatrophic nephrolithotomy and percutaneous nephrolithotomy with and without extracorporeal shock wave lithotripsy for management of patients with staghorn calculi, A retrospective study was conducted comparing anatrophic nephrolithotomy (10 cases). percutaneous nephrolithotomy alone (4 cases) or percutaneous nephrolithotomy combined with extracorporeal shock wave lithotripsy (23 cases) for the treatment of large staghorn calculi. A comparison based on collecting system anatomy demonstrated that anatrophic nephrolithotomy resulted in a greater stone-free rate. shorter hospitalization and lower costs while complication rates were similar. Anatrophic nephrolithotomy should still be considered a viable treatment option. especially for patients with large branched calculi in complex collecting systems.
The clinical implications of brushite calculi, The clinical history of 30 patients with a total of 46 proved brushite urinary calculi was reviewed. The patients were active metabolically with 87% having a history of multiple calculi. Of the brushite stones 61% appeared hyperdense on x-ray but they had no consistent shape. Of the patients who were metabolically evaluated 82% had treatable abnormalities. Treatment with percutaneous nephrostolithotomy or ureteroscopy and ureteral lithotripsy was 92% successful in rendering the patient stone-free. whereas. extracorporeal shock wave lithotripsy monotherapy resulted in a stone-free rate of only 11%. Brushite stone patients require aggressive treatment. full metabolic evaluation and close clinical followup.
Endourological treatment of ureteroenteric anastomotic strictures: long-term followup, In 1987 we reported our initial experience with an endosurgical incisional approach to ureteroenteric anastomotic strictures (that is endoureterotomy). We have extended that initial report to encompass 15 patients with 19 ureteroenteric strictures followed for an average of 2.5 years. In all cases an endosurgical approach was well tolerated. blood loss was less than 50 cc and hospital stay averaged 3.5 days. A 16 to 22F external stent was left in place for 4 to 6 weeks postoperatively in 14 strictures. A permanent external 12F catheter was left in 5 strictures due to the presence of metastatic disease (4) and a complete dense stricture (1). The only major complication was a ureteroenteric fistula that healed over a ureteral stent without any open surgical intervention. Among 14 ureteroenteric strictures in which the stent was removed. the ureteroenteric area has remained patent in 8 (57%) with an average followup of 28.6 months (range 9 to 57 months). Failures were associated with metastatic disease in 2 cases. generalized debility in 2 and unexplained in 2. In this series an endosurgical approach to ureteroenteric strictures provided long-term satisfactory management of the problem in the majority of patients with benign and malignant disease. By current standards. only 1 patient (7%) would have been considered a candidate for open surgical repair.
Cigarette smoking: an independent risk factor for atherosclerosis in the hypogastric-cavernous arterial bed of men with arteriogenic impotence, We investigated the relationship between cigarette smoking and atherosclerosis of the hypogastric-cavernous arterial bed by evaluating arteriograms of young impotent men referred for selective pudendal angiography. Those patients with hemodynamically significant atherosclerosis had smoked more pack-years than had patients without arterial disease. These differences were statistically significant (p less than 0.05) for the common penile artery (32.8 pack-years. 40 patients versus 22.3 pack-years 57 patients) and the dorsal artery (31.3 pack-years. 48 patients versus 22.0 pack-years. 49 patients). The effect of cigarette smoking as an independent risk factor for atherosclerotic disease in the hypogastric-cavernous arterial bed was evaluated as well. When controlled for age. trauma history. hypertension and diabetes. cigarette smoking was independently associated with atherosclerosis in the internal pudendal artery (p less than 0.05). The relative risk (and 95% confidence interval) of developing internal pudendal artery atherosclerosis for each 10 pack-years smoked was 1.31 (1.05 to 1.64). A third analysis investigated the potential interactive effects of cigarette smoking and pelvic or perineal trauma. A significantly higher incidence (p less than 0.05) of cavernous artery atherosclerosis was found among smokers with a history of chronic perineal trauma (33 patients) compared to nonsmokers with a similar history (25 patients). The findings of this study indicate that cigarette smoking is an independent risk factor in the development of atherosclerotic lesions in the internal pudendal and common penile arteries of young impotent men. Cigarette smoking appears to predispose these patients to early atherosclerotic lesions in the cavernous artery following chronic perineal trauma.
Infusion pharmacocavernosometry and nocturnal penile tumescence findings in men with erectile dysfunction, Infusion pharmacocavernosometry and nocturnal penile tumescence findings were compared in 50 men with erectile dysfunction of either organic or psychogenic etiology. Of the men 29 had abnormal and 21 had normal nocturnal penile tumescence. Infusion pharmacocavernosometry parameters (equilibrium pressure. maintenance flow rate and 30-second pressure fall) were compared to nocturnal penile tumescence status (normal versus abnormal). When traditional normal values were used for infusion pharmacocavernosometry parameters poor correlation with nocturnal penile tumescence status was found. When new cutpoints for infusion pharmacocavernosometry parameters were chosen a stronger correlation was noted. This study suggests that when vasoactive drugs are injected intracavernously for diagnostic purposes. anxiety and/or the absence of sexual stimulation following the injection may prevent complete cavernous smooth muscle relaxation resulting in falsely abnormal values. Therefore. over reliance on infusion pharmacocavernosometry as a single test for evaluation and treatment decisions concerning erectile dysfunction should be avoided.
Clinical significance of intratesticular arterial anatomy, Testicular atrophy has been reported in 2 to 18% of the patients following orchiopexy for cryptorchidism. A possible cause of this atrophy is interference with the testicular blood supply by placement of a testicular traction suture through the tunica albuginea. Arterial casts of 32 adult human testes were created following placement of a 3-zero silk traction suture through the lower pole of the testis to determine the effects of this suture upon intragonadal arterial circulation. Significant arterial blockage. manifested as failure of the parenchymal branches to fill. was observed in 14% of the casts produced via injection through the internal spermatic artery and in 100% of the casts produced via injection through the deferential artery. The results of this study support discontinuing the routine use of parenchymal testicular traction sutures during orchiopexy.
Detailed anatomy of the internal spermatic vein and the ovarian vein. Human cadaver study and operative spermatic venography: clinical aspects, The exact anatomical course of the spermatic vein and the ovarian vein (gonadal) has not been described in detail previously. To determine the precise anatomy of the gonadal veins an autopsy study of 70 fresh human cadavers (40 men. 10 women. 10 male stillborns and 10 female stillborns) was performed by making a resin cast of both gonadal veins which then was carefully dissected. The study showed absence of valves in the spermatic vein. cross-communications between the right and left spermatic veins. and communication between the spermatic and renal capsular veins. spermatic and ipsilateral ureteral veins. and spermatic ipsilateral colonic veins. For clarification of the presence of valves intraoperative antegrade spermatic venography was done in 6 men with and 5 without varicocele. In both groups valves were not detected. These observations regarding the anatomy of the spermatic vein and the ovarian vein may help to explain related clinical conditions.
Correlation of testicular color Doppler ultrasonography, physical examination and venography in the detection of left varicoceles in men with infertility, High resolution color Doppler ultrasound is a noninvasive means of simultaneously imaging and evaluating the blood flow to the testes. To define the ability of color Doppler ultrasound to detect clinically evident as well as subclinical varicoceles men referred to our urology division with oligospermia and infertility underwent spermatic vein venography of the left testis if there was physical examination and/or color Doppler ultrasound evidence of a varicocele. The detection of valvular incompetence on venography was considered diagnostic for a varicocele. Of 17 study patients physical examination detected 10 of 14 venographically evident varicoceles (71%). whereas color Doppler ultrasound detected 13 of 14 (93%). Of 5 patients with a normal physical examination but with color Doppler ultrasound evidence of a varicocele 4 had a confirmatory venogram. and 1 of 2 patients with a varicocele on physical examination and a normal Doppler ultrasound had a positive venogram. These data suggest that color Doppler ultrasound of the testis may more appropriately direct further invasive testing and therapy of infertile men than physical examination alone.
Subclinical varicocele: the effectiveness of varicocelectomy, To investigate the controversial concept that subclinical varicoceles are detrimental to spermatogenesis. we undertook a prospective study of the effectiveness of surgery in 56 infertile men with clinical and subclinical varicoceles. Our statistical approach specifies improvement as a change from individual baseline level. The over-all variability in sperm counts precluded the demonstration of significant changes in sperm density consequent to surgery. Improvement in sperm motility was seen in both groups. being slightly greater in the subclinical group. The changes were inversely related to baseline levels and increased with time from surgery. Therefore. it appears that the detection of subclinical varicoceles may be warranted in infertile men with abnormal semen parameters.
The absorption of chlortetracycline following transscrotal instillation for the treatment of primary hydrocele testis, We describe the absorption of chlortetracycline from the emptied hydrocele sac. which was instilled to treat a primary hydrocele of the testis. The study included 7 patients and 2 control subjects who were given 500 mg. chlortetracycline. Plasma concentration was determined at 0. 1/2. 1. 2. 4. 6. 12 and 24 hours after instillation. and in 2 patients plasma levels also were determined at 48 and 72 hours. The area under the plasma concentration-time curve (AUC1) was calculated in each case by using the trapezoidal rule. In the control group the plasma level was determined at 0. 1. 2. 4 and 6 hours after instillation. The area under the plasma concentration-time curve (AUC2) was calculated by the formula AUC2 = Co/Kc. The fraction F of absorption can be expressed as F = AUC1/AUC2; median F = 0.67 (range 0.41 to 0.92). We conclude that chlortetracycline passes readily and almost completely through the tunica vaginalis lining the hydrocele sac.
Core biopsy instrument in the diagnosis of prostate cancer: superior accuracy to fine needle aspiration, The recent availability of an automated core biopsy gun has made the performance of core biopsies of the prostate easier and better tolerated. A prospective study was conducted to compare the efficacy of fine needle aspiration to core biopsy with the gun. Among 94 patients subjected to both biopsy techniques at the same visit 30 (32%) had a positive diagnosis of prostate cancer. Core biopsy was positive in these 30 patients (100%). while fine needle aspiration was positive in 21 (70%). This study suggests that core biopsy with the gun is superior to fine needle aspiration in the diagnosis of prostate cancer.
Bladder outlet obstruction versus impaired detrusor contractility: the role of outflow, The uroflow curves of 45 men with either bladder outlet obstruction or impaired detrusor contractility were retrospectively reviewed. The definitive diagnoses were attained by clinical and video-urodynamic studies with simultaneous detrusor pressure and uroflow measurements. Eight parameters were analyzed to determine if uroflow can differentiate obstruction from impaired contractility. There were no differences between the 2 groups in any of the parameters. This finding suggests that uroflowmetry as a single examination cannot distinguish between bladder outlet obstruction and impaired detrusor contractility.
Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: oxybutynin versus propantheline versus placebo, Clinical efficacy and adverse effects of oxybutynin and propantheline in the treatment of symptoms related to detrusor hyperactivity were studied in a randomized. controlled. double-blind multicenter trial. Of 169 patients entered into the study 154 were evaluable for statistical analysis. Mean grade of improvement (visual analogue scale) was significantly higher with oxybutynin (58.2%) versus propantheline (44.7%) and placebo (43.4%). Mean bladder volume at first involuntary cystometric contraction was significantly increased with oxybutynin (+57.0 ml.) versus placebo (-9.7 ml.). Mean maximum cystometric bladder capacity was also significantly increased with oxybutynin (+80.1 ml.) versus placebo (+22.5 ml.). Rate of inquired possible adverse effects was significantly higher for oxybutynin (63%) versus propantheline (44%) and placebo (33%). However. only 5 patients dropped out of the study because of adverse effects (oxybutynin 2 and propantheline 3). No serious or lasting adverse effects were encountered with dryness of the mouth being the major complaint. Oxybutynin has statistically significant effects on subjective symptoms and objective urodynamic parameters in patients with detrusor hyperactivity compared to propantheline.
Osteosarcoma of the spermatic cord, Malignant tumors of the spermatic cord are rare but the vast majority of these tumors are sarcomas. We report on a patient with osteosarcoma arising in the spermatic cord. Left radical orchiectomy with high dissection of the spermatic cord was performed. and the patient remains free of recurrence 2 years postoperatively. We could find no previous discussion or report of this tumor.
Cell proliferation of human bladder tumors determined by BrdUrd and Ki-67 immunostaining, The cell proliferation of bladder tumors was assessed in situ using BrdUrd (bromodeoxyuridine) and Ki-67 immunostaining. BrdUrd is incorporated into S-phase cells. and Ki-67 monoclonal antibody recognizes a nuclear antigen present in proliferating. but not resting cells. The percentage of labeled cells was expressed as the labeling index (LI). The average BrdUrd LI obtained applying this method to normal epithelium and to transitional cell carcinoma were 4.1% and 13.1%. respectively. while the Ki-67 LI had average values of 6.2% and 17.8%. respectively. Labeled cells were distributed throughout both the basal and surface layers of transitional cell carcinoma. In general. the value of the BrdUrd LI was correlated to that of the Ki-67 LI. A relatively large fraction of labeled cells was found in high grade or invasive tumors. Bladder tumors with lymph node involvement had higher LI than those without. In addition. a high frequency of S-phase cells within tumor tissue appeared to indicate a great potential for malignancy and thus a poor prognosis. These findings indicate that immunostaining with BrdUrd and Ki-67 may be useful tools for easy and quick evaluation of proliferating cells in bladder tumors.
The evaluation of urinary protein patterns in a stone-forming animal model using two-dimensional polyacrylamide gel electrophoresis, The exact role of urinary proteins in kidney stone formation remains an area of controversy. Some investigators believe that urinary proteins are selectively incorporated within urinary calculi and as such have an active role in stone formation. Other investigators believe that urinary proteins are nonspecifically adsorbed into urinary crystals and thus have only a passive role in stone formation. In the current investigation a previously described stone-forming animal model (hyperoxaluric rat) was utilized along with an animal model for renal tubular injury (gentamicin nephrotoxicity) in an effort to clarify the role of urinary proteins in kidney stone formation. Urine specimens were collected before and after the induction of stone formation and after the induction of renal tubular injury. The purified proteins from each urine specimen were separated in two dimensions by electrophoresis resulting in a characteristic "map" of protein spots for each urine specimen. All animals in the stone-forming group had pathologic evidence of early stone formation (diffuse intranephronic calculosis). Early stone formation was consistently associated with a reduction in the excretion of low molecular weight urinary proteins (30.000 dalton and less than 20.000 dalton ranges). Alcian blue staining confirmed the presence of matrix within clumps of intranephronic calcium oxalate crystals. Renal tubular injury was associated with an increase in the excretion of low molecular weight proteins (approximate 20.000 dalton range) consistent with classical tubular proteinuria. These results suggest that low molecular weight urinary proteins are selectively incorporated within the crystalline structure of the stone early during its formation.
The hypocholesterolemic effects of beta-glucan in oatmeal and oat bran. A dose-controlled study, Oat cereals rich in the water-soluble fiber beta-glucan have been studied as a dietary therapy for hypercholesterolemia. To determine the hypocholesterolemic response of beta-glucan in the diet. 156 adults with low-density lipoprotein cholesterol (LDL-C) levels above 4.14 mmol/L (160 mg/dL) or between 3.37 and 4.14 mmol/L (130 and 160 mg/dL) with multiple risk factors were randomized to one of seven groups. Six groups received either oatmeal or oat bran at doses (dry weight) of 28 g (1 oz). 56 g (2 oz). and 84 g (3 oz). A seventh group received 28 g of farina (beta-glucan control). At week 6 of treatment. significant differences were found for both total cholesterol and LDL-C levels among the farina control and the treatment groups who were receiving 84 g of oatmeal. 56 g of oat bran. and 84 g of oat bran. with decreases in LDL-C levels of 10.1%. 15.9%. and 11.5%. respectively. Fifty-six grams of oat bran resulted in significantly greater reductions in LDL-C levels than 56 g of oatmeal. Nutrient analysis shows no difference in dietary fat content between these treatment groups; therefore. the higher beta-glucan content of oat bran most likely explains the significantly greater LDL-C reductions. A dose-dependent reduction in LDL-C levels with oat cereals supports the independent hypocholesterolemic effects of beta-glucan.
Possible health care professional-to-patient HIV transmission. Dentists' reactions to a Centers for Disease Control report, On July 27. 1990. the Centers for Disease Control reported possible transmission of the human immunodeficiency virus (HIV) from a dentist to a patient as a result of patient care. We surveyed a random national probability sample of 300 dentists with a 26-item survey in August and September 1990 to assess reactions to the report (response rate. 59%). Respondents tended not to believe the report (mean was 3.2. median 3.0. where 1 indicated "do not believe" and 7 indicated "believe"). Our sample also tended to believe that transmission of HIV from dentists to patients was unlikely in the future (mean was 2.0. median 2.0. where 1 indicated "not at all likely" and 7 indicated "very likely"). Fifty-one percent of our sample recommended that dentists infected with HIV should discontinue practice. while 38% recommended continuing practice with changes in procedures. Seventy-four percent believed patients should be told if their dentist was infected with HIV. In summary. dentists doubted the possibility of dentist-to-patient transmission of HIV and did not believe the Centers for Disease Control case report. but they did believe infected dentists should refrain from clinical work or modify their practice.
Estrogen and coronary heart disease in women, We review herein the evidence that estrogen is protective against the development of cardiovascular disease in women. To our knowledge. no studies in women have looked at endogenous estrogen levels as predictors of cardiovascular disease. Studies of surrogate measures of endogenous estrogen such as parity. age at menarche. and age at menopause have provided inconsistent results. Current use of oral contraceptives increases risk in older women who smoke cigarettes. but most studies of past use show no increased risk. Most. but not all. studies of hormone replacement therapy in postmenopausal women show around a 50% reduction in risk of a coronary event in women using unopposed oral estrogen. These important observations need to be confirmed in a double-blind. randomized clinical trial. since the protection is biologically plausible and the magnitude of the benefit would be quite large if selection factors can be excluded.
Red blood cell magnesium and chronic fatigue syndrome, The hypotheses that patients with chronic fatigue syndrome (CFS) have low red blood cell magnesium and that magnesium treatment would improve the wellbeing of such patients were tested in a case-control study and a randomised. double-blind. placebo-controlled trial. respectively. In the case-control study. 20 patients with CFS had lower red cell magnesium concentrations than did 20 healthy control subjects matched for age. sex. and social class (difference 0.1 mmol/l. 95% confidence interval [CI] 0.05 to 0.15). In the clinical trial. 32 patients with CFS were randomly allocated either to intramuscular magnesium sulphate every week for 6 weeks (15 patients) or to placebo (17). Patients treated with magnesium claimed to have improved energy levels. better emotional state. and less pain. as judged by changes in the Nottingham health profile. 12 of the 15 treated patients said that they had benefited from treatment. and in 7 patients energy score improved from the maximum to the minimum. By contrast. 3 of the 17 patients on placebo said that they felt better (difference 62%. 95% CI 35 to 90). and 1 patient had a better energy score. Red cell magnesium returned to normal in all patients on magnesium but in only 1 patient on placebo. The findings show that magnesium may have a role in CFS.
Hydrocortisone: an important cutaneous allergen, We have found a high incidence (4.8%) of allergy to hydrocortisone in patients with suspected allergic contact dermatitis. In view of this finding we would suggest that. in any condition that does not improve or that deteriorates after administration of hydrocortisone. allergy to this compound should be considered.
Dental enamel defects in first-degree relatives of coeliac disease patients, To find out whether dental changes can be used to screen for coeliac disease among apparently healthy relatives of patients with the disorder. 56 healthy first-degree relatives of such patients were subjected to dental examination and small bowel biopsy. 25 had coeliac-type general permanent-tooth enamel lesions. All 7 who had histological evidence of coeliac disease also had enamel lesions. The finding that enamel defects may occur without small bowel changes must be borne in mind in screening. The coeliac-type enamel changes were strongly associated with HLA-DR3. and most of the DR3 alleles belonged to the extended haplotype A1; B8; DR3 group.
Exercise capability in heart failure: is cardiac output important after all, The exercise capability of 39 patients with severe chronic heart failure was assessed in several ways and compared with measurements of cardiac output. The relation between cardiac index and exercise tolerance measured on a treadmill was poor (r = 0.191. p = 0.245). However. exercise tolerance measured with a series of self-paced corridor walk tests showed moderate correlations with cardiac index (r = -0.404. p = 0.015 to r = -0.516. p = 0.001) and customary activity assessed by step counting correlated better with cardiac index (r = 0.537. p less than 0.001). Cardiac output therefore seems to be a factor determining patients' exercise capability when they choose their own walking speed but not when they undergo formal treadmill tests in the laboratory.
Hyperdynamic circulation in cirrhosis: a role for nitric oxide, Hypotension. low systemic vascular resistance. and a reduced sensitivity to vasoconstrictors are features of cirrhosis. These cardiovascular changes might be the result of increased synthesis of a vasodilator. Nitric oxide (NO). a potent vasodilator. is synthesised in and released from peripheral blood-vessels in man. Studies in animals indicate that bacterial endotoxin and cytokines induce NO synthase expression in vessel walls. with sustained NO release and consequent hypotension. Endotoxaemia is a common feature of cirrhosis; persistent induction of NO synthase may account for the associated haemodynamic changes.
Adult Still's disease: manifestations, disease course, and outcome in 62 patients, Clinical and laboratory manifestations. disease course. outcome. and HLA associations were studied in an inception cohort of 62 subjects with adult Still's disease (ASD) from 5 Canadian universities. Twenty-eight patients (45%) were female and the median age at disease onset was 24 years. In general. the clinical features observed in our patients were identical to those in other published series. However. significantly higher frequencies of sore throat (92%). weight loss (76%). lymphadenopathy (74%). pleuritis (53%). pneumonitis (27%). and abdominal pain (48%) were noted in our patients compared to those in a recent literature review. Liver involvement with hepatomegaly (44%) or abnormal liver function tests (LFTs) (76%) was common and was responsible for the 2 deaths attributed to Still's disease in our series. Severe liver failure always occurred in conjunction with aspirin or NSAID therapy. Therefore. whether or not aspirin or other NSAIDs are used. we recommend close monitoring of LFTs in patients with ASD. especially early in the disease course. Laboratory manifestations were similar to those already reported. Leukocytosis (greater than or equal to 15.000/mm3) was present in 50 patients (81%). a normochromic. normocytic anemia (hemoglobin less than or equal to 10 g/dl) in 42 (68%). and an elevated ESR in all. The mean follow-up of the 62 patients was 70 months (range. 2-163). Twenty-one patients (34%) had a self-limited disease course. 15 (24%) an intermittent course. and 22 (36%) a chronic disease course. Four patients (6%) died. and 2 of these deaths were attributed to Still's disease. For those patients who experienced a recurrence of ASD. the flares were usually of shorter duration and milder in severity than the initial episode. No initiating factor for disease exacerbation was identified in our patients. Although 22 of 62 patients (36%) had a chronic disease course. 52 (90%) were in ARA Functional Class I. and only 4 and 2 patients were in ARA Functional Class II and III. respectively. Patients with Still's disease had higher scores than the controls on the Pain (P less than 0.01) and Physical Disability (P less than 0.05) subscales of Arthritis Impact Measurement Scales health status questionnaire. Joint radiographs performed at the follow-up evaluation disclosed typical carpometacarpal and intercarpal involvement in 16 of 39 patients. In our series. HLA-B17. B18. B35. and DR2 were significantly associated with ASD. Three significant predictors of an unfavorable outcome. either a chronic disease course or a longer time to clinical remission. were identified.(ABSTRACT TRUNCATED AT 400 WORDS).
Epstein-Barr virus lymphoproliferative disease associated with acquired immunodeficiency, Epstein-Barr virus (EBV) lymphoproliferative disease is seen in patients with both congenital and acquired immunodeficiencies. Lymphoproliferative disease has been reported in 1 to 3% of renal transplant recipients. Most patients presented with solid tumor masses. rather than an infectious mononucleosis-like syndrome. About one third of cases had involvement of the renal allograft with tumor; the small intestine or central nervous system was also frequently affected. About half of the patients survived. The most frequent therapy used for survivors was decreasing the dose of immunosuppressive therapy and surgical resection of lymphoproliferative lesions. Compared with fatal cases. survivors more often had evidence of active EBV infection (primary or reactivated). received cyclosporine as the major immunosuppressive agent. had polyclonal lesions. and had B-cell hyperplasia rather than lymphoma. Lymphoproliferative disease has been described in 5 to 13% of heart transplant recipients. In our review. the cardiac allograft was not involved by disease in any patient; however. the lungs were involved in more than half of the cases. The soft tissues were frequent sites of lymphoproliferative disease. All patients had lymphoma or immunoblastic sarcoma on pathology and all had monoclonal lesions. While only 8% of patients survived. about half died from causes unrelated to lymphoproliferative disease. EBV lymphoproliferative disease has been reported in 9% of heart-lung transplant recipients. Most of the patients presented with pulmonary symptoms and the pulmonary allograft was involved in 80% of cases. The large and small intestine were frequently affected. About 60% of patients survived; survivors were treated with acyclovir and decreases in the dose of immunosuppressive drugs. Lymphoproliferative disease has been described in 2% of liver transplant recipients. In our review. the hepatic allograft was involved in one third of cases; the tonsils. kidneys. and small intestine were frequently affected. Half of the patients survived; survivors were most often treated with reduction in immunosuppressive therapy and surgical resection of lesions. Compared with fatal cases. survivors had fewer organs involved and fewer monoclonal lesions. Lymphoproliferative disease has been reported in 1 to 2% of bone marrow transplant recipients. Use of T-cell depleted bone marrow and infusion of anti-T-cell antibodies to prevent graft-versus-host disease increased the risk of EBV lymphoproliferative disease. In our review. the bone marrow was involved by lymphoproliferative disease in one third of cases; the liver. spleen. kidney. and lungs were frequently affected. About 16% of patients survived; 2 survivors were treated with infusions of monoclonal anti-B-cell antibodies and 1 received interferon alpha.(ABSTRACT TRUNCATED AT 400 WORDS).
Lyme disease: clinical features, classification, and epidemiology in the upper midwest, Lyme disease can be classified using the terminology of syphilis. In this series of 95 cases from the upper midwest. early cases. defined as an illness of less than 2 months. were more likely to have lived in or recently visited a highly endemic area. Unlike late cases. early cases presented entirely in the nonwinter months (p less than .001). Early disease was further subdivided into primary and secondary disease. Ninety percent of primary and 43% of secondary cases had erythema migrans. while no late cases had active erythema migrans (p less than .001). Clinical manifestations of nonspecific inflammation. except for arthralgia. were more common in early than late disease (p less than .01). In secondary cases. monoarticular arthritis was slightly more common than polyarticular arthritis. with the reverse occurring in late disease (p less than .05). Indirect fluorescent antibody testing revealed a ratio of IgM to IgG antibodies to be helpful in distinguishing early from late disease. Antibacterial therapy in early. primary cases caused Jarisch-Herxheimer reaction 7% of the time. Despite longer and more frequent parenteral therapy. late Lyme disease frequently required retreatment. owing to poor clinical response (p less than .05).
Noncardiogenic pulmonary edema following upper airway obstruction. 7 cases and a review of the literature, Pulmonary edema is a relatively common problem facing most physicians. Its separation into cardiogenic and noncardiogenic or high-permeability variants is crucial to its proper early management. Our understanding of the disease processes producing noncardiogenic pulmonary edema has greatly expanded in the last 2 decades. Upper airway obstruction (UAO) is one of many recently recognized mechanisms which can produce noncardiogenic pulmonary edema. The UAO may be subtle in some patients. making its association with the subsequent pulmonary edema difficult especially for the physician unaware of this entity and the potential risk factors contributing to it. A high index of suspicion for this diagnosis is required in the right clinical settings. Our clinical results support a noncardiogenic basis for pulmonary edema occurring after UAO. Five of our 7 patients had at least 1 identifiable risk factor for the development of peri-intubation UAO and pulmonary edema. Additionally. the onset of pulmonary edema following UAO and the duration of the pulmonary edema varied considerably in our patients. Individuals with additional risk factors for the development of noncardiogenic pulmonary edema developed a more severe form of pulmonary edema associated with other organ-system disease. However. in most individuals. UAO-associated pulmonary edema appears to be a self-limited reversible process once it is recognized and properly treated.
Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis, Ataxia-telangiectasia is a syndrome with many facets. involving a progressive cerebellar ataxia. immunodeficiency. cancer susceptibility. radiosensitivity. defects in DNA repair/processing. chromosomal breakage and rearrangements. elevated serum alphafetoprotein. and premature aging. Ataxia-telangiectasia is an autosomal recessive disorder. rare in outbred populations; carriers of the ataxia-telangiectasia gene may be as common as 1 in 60 and have subclinical radiosensitivity and cancer susceptibility. One estimate suggests that 8.8% of patients with breast cancer could be carriers of ataxia-telangiectasia. These carriers may be responsible for underestimating normal tolerance doses for radiation therapy by 15% to 20%; thus by preselecting and excluding carriers of ataxia-telangiectasia from cohorts of patients with cancer. conventional radiation doses might be increased so as to improve greatly the efficacy of radiotherapy. The genes for the 3 most common ataxia-telangiectasia complementation groups. which include 97% of tested families. have recently been localized to the long arm of chromosome 11.
National allocation of cadaveric kidneys by HLA matching. Projected effect on outcome and costs, BACKGROUND. Although receiving a cadaveric kidney matched at the HLA-A. B. and DR loci enhances graft survival in cyclosporine-treated patients. the value of a national system of kidney allocation based on HLA matching. with the attendant increased likelihood of better matching. is still questioned. Some fear that the costs of a national system are unjustified when only a small fraction of donors would exactly match any of the 16.000 potential recipients anyway. We estimated the effect on graft survival of the use of HLA matching for all allocations of cadaveric kidneys in the United States. METHODS. The graft-survival rates in five mutually exclusive groups of transplants with increasing numbers of HLA mismatches were estimated by partitioning the data for 22.190 first-time recipients of cadaveric kidneys. Overall graft survival was projected as a weighted average with use of the percentages of transplants in the hierarchical groups in recipient waiting pools of various sizes. We compared the benefits and costs of HLA matching in a national system with those of introducing cyclosporine. which was projected to enhance graft survival by 7 percentage points at 10 years. RESULTS. Sharing kidneys nationally on the basis of hierarchical HLA matching was estimated to enhance graft survival by an additional 5 percentage points at 10 years. The anticipated five-year cost of national allocation of kidneys by HLA matching for 7000 recipients. including consideration of the costs of graft removal and dialysis after transplant rejection. would be +4F6.5 million less than the cost of using cyclosporine alone. CONCLUSIONS. The use of an HLA allocation system will not add to the cost of renal transplantation. but it will improve the long-term results to the same extent as cyclosporine. We propose the initiation of a national kidney-sharing system based on hierarchical levels of HLA matches.
Clonal deletion of V beta 14-bearing T cells in mice transgenic for mammary tumour virus, Autoreactive T lymphocytes are clonally deleted during maturation in the thymus. Deletion of T cells expressing particular receptor V beta elements is controlled by poorly defined autosomal dominant genes. A gene has now been identified by expression of transgenes in mice which causes deletion of V beta 14+ T cells. The gene lies in the open reading frame of the long terminal repeat of the mouse mammary tumour virus.
Multiple sclerosis, retroviruses, and PCR. The HTLV-MS Working Group, Previously reported serologic and polymerase chain reaction (PCR)-based findings have suggested an association between the human retrovirus. HTLV-I. and multiple sclerosis (MS). Due to the inherent ability of PCR to produce false-positive results. we developed a set of physical and procedural safeguards to minimize the possibility of molecular carryover. These were applied as part of a blinded. large-scale. multipopulation. multiplex PCR-based study designed to examine this issue of association. Our results do not support the hypothesis that HTLV-I. which plays a role in the pathogenesis of an encephalomyeloneuropathy. HTLV-II. or closely related agents are associated with MS. A concomitant review of the current literature supports this view.
Volumetric atrophy of the amygdala in Alzheimer's disease: quantitative serial reconstruction, The present study quantitatively assessed volumes of the amygdala and its subnuclei in autopsied cases of advanced Alzheimer's disease (AD) for comparison with age-matched controls. Amygdalar nuclei showed significant atrophy in AD with the exception of the paralaminar portion of the basal nucleus. The magnocellular regions of the amygdala showed proportionately greater size reductions as a fraction of total amygdala volume than did other areas. Computerized reconstruction of the amygdala provided three-dimensional views of a variety of structural alterations accompanying the volumetric declines with AD. The apparent selective vulnerability of the magnocellular amygdalar areas coincides with the loss of large nerve cells in AD.
Polyneuropathy syndromes associated with serum antibodies to sulfatide and myelin-associated glycoprotein, We studied a series of 64 patients with sensory +/- motor peripheral neuropathies by comparing clinical and physiologic features to serum antibody reactivity against compounds containing sulfated carbohydrate moieties. We determined antibody reactivity by an enzyme-linked immunosorbent assay (ELISA) using purified glycolipids and glycoproteins as antigens. and we used high-performance thin-layer chromatography and Western blotting to test the specificity of results. Twelve patients with high titers of IgM antibodies directed against the myelin-associated glycoprotein (MAG) had sensory-motor polyneuropathies with physiologic evidence of demyelination. IgM antibody reactivity to MAG was associated with an IgM serum M protein in five patients. Eight other patients. most with sensory greater than motor polyneuropathies. had high titers of antibody reactivity to sulfatide but not of IgM to MAG. Two had an associated IgM paraprotein. None of the patients with selective serum antisulfatide activity had predominantly demyelinating features on physiologic testing. We conclude that (1) high ELISA titers of antibodies to MAG may be more common than previously suspected in patients with chronic demyelinating sensory-motor neuropathies. and (2) the presence of high titers of antisulfatide antibodies in serum may provide clues to the pathogenesis of otherwise idiopathic. axonal. predominantly sensory neuropathies.
Multicenter long-term safety and efficacy study of vigabatrin for refractory complex partial seizures: an update, We followed 66 patients with refractory complex partial seizures and a favorable initial response to vigabatrin for 5 to 72 (median. 43) months. Thirty-seven patients discontinued vigabatrin for the following reasons: benefit-to-risk evaluation. 8; seizure breakthrough. 6; adverse events. 6; seizure breakthrough and adverse events. 5; moved or lost. 4; no longer eligible for study. 2; non-drug-related death. 2; narcotic abuse. 1; and patient request. three. There were no clinically significant abnormalities in laboratory studies including SMA 12. complete blood count. ECG. EEG. and visual evoked response testing. and no toxicity other than reversible. dose-dependent side effects. Based on this and other long-term data. clinical trials of vigabatrin have resumed in the United States and Canada.
Clozapine-related seizures, Clozapine is an atypical antipsychotic drug with minimal extrapyramidal toxicity recently approved by the Food and Drug Administration for hard-to-treat schizophrenic patients. We reviewed information on 1.418 patients treated with clozapine in the United States between 1972 and 1988. Forty-one of 1.418 (2.8%) patients had generalized tonic-clonic seizures during treatment with clozapine. Life-table analysis predicts a cumulative 10% risk of seizures after 3.8 years of treatment. Clozapine-related seizures appear to be dose-related. High-dose therapy (greater than or equal to 600 mg/day) was associated with a greater risk of seizures (4.4%) than medium (300 to 600 mg/day; 2.7%) or low doses (less than 300 mg/day; 1.0%). Also. rapid upward titration may increase seizure risk. Thirty-one of 41 patients were successfully continued on clozapine despite seizure occurrence. either with reduction of dose or addition of an antiepileptic medication. Recognition and treatment of clozapine-related seizures will become increasingly important as its use grows in the 1990s.
The occurrence of motor fluctuations in parkinsonian patients treated long term with levodopa: role of early treatment and disease progression, The aim of this study is to evaluate what factors influence the risk of occurrence of motor fluctuations in patients with Parkinson's disease (PD) with particular reference to the role of early or delayed introduction of levodopa therapy during the course of the disease. One hundred twenty-five consecutive newly diagnosed patients with PD started levodopa treatment at the time diagnosis and were followed for 2 to 10 years. During follow-up. 60 patients had wearing-off or early morning akinesia. We estimated the cumulative time-dependent risk of motor fluctuation occurrence through a multivariable analysis. The risk was lower for patients with tremor-predominant PD. for those with shorter disease duration prior to levodopa. and for those who were relatively older at levodopa initiation. Our results suggest that. as far as motor fluctuations are concerned. disease prognosis is not influenced by early levodopa treatment. These observation support the introduction of levodopa as soon as there is a subjective need for the patients to maintain their level of social and work performance.
Glucosephosphate isomerase as a CSF marker for leptomeningeal metastasis, Glucosephosphate isomerase (GPI). also known as phosphohexoisomerase. is a glycolytic enzyme whose activity is elevated in serum and CSF of patients with primary and metastatic CNS tumors. To improve the diagnostic accuracy of leptomeningeal metastasis (LM). we measured GPI levels in CSF of 66 patients with CNS or systemic malignancies with suspected LM. We determined GPI kinetically using a coupled enzyme reaction assay. There were 31 males and 35 females. aged 1 to seventy-six. Thirty-one had primary brain tumors. and 35 had systemic cancer with suspected CNS metastasis. We analyzed 95 samples; GPI values ranged from 0.85 to 329.0 U/l (normal. less than 20 U/l). Compared with positive CSF cytology and myelography. GPI sensitivity was 53.5% and specificity 92.1% for the group as a whole. There was a highly significant association between elevated CSF GPI (greater than 20 U/l) and LM. The results were similar for both primary CNS and systemic malignancies. Although not very sensitive. an elevated CSF GPI strongly suggests LM and may aid in early diagnosis of this serious complication of cancer.
Paralysis of saccades and pursuit: clinicopathologic study, We report a 73-year-old patient with an eye movement disorder characterized by paralysis of saccades and pursuit. At autopsy. there were small cortical lesions in the middle frontal gyrus immediately anterior to the precentral gyrus and in the inferior parietal lobule on both sides.
Corticosteroid-responsive dominantly inherited neuropathy in childhood, We describe three children with corticosteroid-responsive inflammatory demyelinating polyneuropathy from families with dominantly inherited neuropathy. There were atypical clinical. electrophysiologic. and pathologic characteristics that suggested a coexistent inflammatory demyelinating neuropathy and that should alert the clinician to the possibility of an associated acquired. potentially treatable disorder.
Neuralgic amyotrophy in association with radiation therapy for Hodgkin's disease, We describe 4 patients with Hodgkin's disease who developed neuralgic amyotrophy in the setting of radiation therapy. In contrast to tumor progression or radiation plexopathy. the symptom onset was abrupt and occurred within days to weeks of receiving radiation treatments. There is an association between Hodgkin's disease. radiation therapy. and neuralgic amyotrophy.
Necrotizing angiopathy presenting with multifocal conduction blocks, We describe conduction block as an unusual electrophysiologic manifestation in a patient with necrotizing angiopathy. The patient developed subacute symptoms over a 1-month period consisting of progressive pain. tingling. and weakness of the lower extremities. Physical examination revealed a pattern consistent with a polyneuropathy. Electrodiagnostic studies provided evidence of a conduction block in the left ulnar nerve. Pathologic studies confirmed the process to be a necrotizing angiopathy. This report establishes the role of conduction block in human nerve ischemia.
Locked-in syndrome with bilateral ventral midbrain infarcts, We report a patient who was quadriplegic and mute. but retained consciousness and communicated by eye movements and blinks. EEG and SEPs were normal. BAEPs showed slight prolongation of latencies for waves IV and V. MRI showed bilateral infarcts only in the middle and lateral portions of the cerebral peduncles.
HTLV-I-associated myelopathy in a Californian: diagnosis by reactivity to a viral recombinant antigen, A male patient developed leg numbness and weakness. and bowel. bladder. and erectile dysfunction. Examination revealed an isolated thoracic myelopathy. with lower-extremity spasticity. decreased vibration and position sense. hyperreflexia. and Babinski's signs. Serum and CSF showed antibody reactivity to human T-cell lymphotropic virus type I or II (HTLV-I/II). suggesting HTLV-I-associated myelopathy. Antibody reactivity to a unique HTLV-I recombinant protein provided definitive diagnosis of HTLV-I infection.
"Frontal lobe" utilization behavior associated with paramedian thalamic infarction, Disinhibited. exaggerated responses to objects and environmental cues (utilization behavior) occur predominantly with frontal lobe damage. We report a striking example associated with paramedian thalamic infarction suggesting a thalamofrontal component to environmental interactions that require inhibition. self-monitoring. and cognitive flexibility.
Newly designed continuous corneal irrigation system for chemical burns, A newly designed continuous irrigation system has been applied in our clinic. Six cases of corneal chemical burns have been treated with this system from September 1988 to February 1989. The present system has been available in any clinics by materials such as a disposable intravenous tube and a scalp vein tube for infants. Compared with the methods previously reported. this system showed good results. simplicity for setting up. good patient tolerance and low cost of the equipment.
Influence of lens opacities on visual field indices, This report presents the results of a study designed to verify the influence of lens opacities on the visual field indices. Four age-matched groups of subjects were considered: healthy volunteers. glaucomatous patients without lens opacities. cataractous patients without glaucoma and glaucomatous patients with lens opacities. The quantification of lens opacities was performed with the Lens Opacity Meter 701 instrument. The visual field indices were obtained automatically from the G1 program of the Octopus system. The statistical analysis of the results (coefficient of correlation) has shown that only the visual field indices that correspond to uniform and diffuse loss of light sensitivity were influenced by the presence of cataract. On the contrary. the visual field indices that indicate local irregularities of the threshold were not significantly influenced by the presence of lens opacities.
Lipid-containing eye drops: a step closer to natural tears, Disturbances of the lipid composition can. like mucin or fluid deficiency. cause 'dry eye'. The substitution of the lipids of the tear fluid has previously been unsatisfactory since eye ointments containing fats can lead to a considerable deterioration of the visual acuity due to the film of ointment resulting from an irregular spreading behavior. We proposed the introduction of physiological lipids that are normally present in tear fluid. such as phospholipids. saturated and unsaturated fatty acids and triglycerides. to provide lipid-containing eye drops. These best correspond to 'natural tears' and. due to the small size of the lipid particles. avoid a disturbance of the spreading behavior of the lipid layer. With lipid-containing eye drops of this kind. we carried out the following examinations: inquiry of patients' symptoms based on a standardized interview; Schirmer test under local anesthesia; break-up time (BUT); biomicroscopic evaluation of the lipid film. and stability tests as pH. gas chromatographic analysis of the fatty acid pattern and thin-layer chromatographic analysis of the lipid pattern. Schirmer test. BUT measurement and questioning about symptoms were undertaken after 1 week and then again after 3 weeks of treatment. All three parameters finally showed an improvement with a high statistical significance (p less than 0.001). The stability tests have shown that pH. lipid particle size. fatty acid and lipid composition of the examined lipid-containing eye drops were nearly unchanged till 4 months after preparation.
Principles of treatment of pediatric solid tumors, Great strides have been made in the treatment of pediatric solid tumors over the last three decades. A multimodality approach involving a combination of surgery. radiation therapy. and chemotherapy is now used in the treatment of these diseases. This article reviews the principles that guide the use of these modalities and the multidisciplinary approach used to integrate them into a coordinated treatment plan. The role of each modality in the control of local and systemic disease is described. Radiation treatment planning. dose fractionation. and toxicity are also discussed.
The genetics of retinoblastoma. Relevance to the patient, The understanding of the molecular biology of human cancer has advanced rapidly in the last decade. in part due to discoveries in the rare. pediatric ocular tumor. retinoblastoma. RB studies have led to recognition of a class of human genes. the tumor suppressor genes. that are critical in the initiation and progression of the malignant process. Mutations in the RB1 gene initiate RB and other specific tumors. They may also contribute to progressive stages of many other malignancies. The protein product of RB1 (p110RB1) is a basic regulator of the cell cycle. In the absence of normal protein. the cell proceeds to the next cell division without the potential to become quiescent. Understanding the genetics of RB has benefited the patients. as the precise identification of the RB1 mutations in families has led to accurate prediction of individuals at risk for RB tumors. It seems unlikely. in the foreseeable future. that direct genetic manipulation of mutant RB1 genes will play a role in therapy. but complete understanding of the function of p110RB1 may eventually allow exploitation of its powerful antiproliferative effect. Other molecular genetic events in addition to RB1 mutations are documented in RB tumors. and may play a critical role in the full malignant phenotype. The oncogene. N-myc. is amplified in some RB tumors and is expressed in normal fetal retina. The cytogenetic abnormality. i(6p). is almost unique to RB tumors. The molecular and tissue-specific roles of these abnormalities are not yet known. Many RB tumors also acquire excessive expression of the cell surface membrane glycoprotein. p170. linked to multidrug resistance. whether or not the RB tumor has been exposed to chemotherapy. We anticipate that ways to avoid or counteract the drug resistance of excessive p170 expression will be developed for other pediatric tumors and eventually will be applied to chemotherapy for RB patients.
Osteosarcoma. Clinical features and evolving surgical and chemotherapeutic strategies, Osteosarcoma is the most common neoplasm of bone in children and adolescents. The first effective therapy became available in the early 1970s. and although controversy existed for several years regarding the relative value of aggressive multiagent chemotherapy. presently about 60% of patients with resectable primary tumors and no metastases at diagnosis will be cured. New imaging methods. including computerized tomography. magnetic resonance imaging. and radionuclide techniques. that are sensitive to changes in local tumor perfusion have improved the ability to define the extent of tumor and the response to chemotherapy. and to plan surgery. Although amputation historically has been the primary method for local tumor control. newer surgical techniques and endoprosthetic devices. coupled with effective preoperative chemotherapy. have offered less radical surgery for 50% to 80% of patients with osteosarcoma. New therapeutic agents. including ifosfamide and the immunosuppressive drug. muramyl tripeptide phosphatidylethanolamine. hold promise for improvement in the cure rate of osteosarcoma.
Rhabdomyosarcoma. From the laboratory to the clinic, The prospect of identifying and developing new agents for treatment of rhabdomyosarcomas is discussed in the light of current prognosis for children with advanced stage disease. Preliminary attempts to identify tumor-specific agents using in vitro cell culture show potential promise. but as yet remain unproven. The more complex system of identifying therapeutically active agents using human tumor xenografts has demonstrated usefulness. The potential problems associated with this system are discussed.
Ewing's sarcoma. Radiotherapy versus surgery for local control, Significant strides in the treatment of Ewing's sarcoma. the second most common bone tumor of childhood. have resulted in cure for approximately 50% of patients. Successful therapy requires systemic chemotherapy for the eradication of microscopic or overt metastatic disease and surgery or irradiation therapy for control of the primary lesion. The article debates the controversy over the extent to which surgical resection should play a role in the local management of this disease.
Tumors of the central nervous system. Improvement in outcome through a multimodality approach, More children with CNS tumors will continue to be cured of their neoplasms as a result of improved surgical. radiotherapeutic. and chemotherapeutic intervention. The complex problems seen in these patients mandate their treatment at academic centers actively involved in therapeutic investigations and capable of providing comprehensive multidisciplinary care.
Treatment of high-risk solid tumors of childhood with intensive therapy and autologous bone marrow transplantation, Autologous bone marrow transplantation (ABMT) allows delivery of intensive. marrow-ablative chemotherapy or chemoradiotherapy to children with high-risk solid tumors. Results from several studies of neuroblastoma suggest that outcome is improved by ABMT; however. relapses can occur months to years after complete clinical remission. Other high-risk tumors including peripheral neuroepithelioma. Ewing's sarcoma. rhabdomyosarcoma. Wilms' tumor. and brain tumors also appear to be responsive to intensive marrow-ablative therapy. although few studies have been reported. For tumors that can metastasize to marrow. a sensitive method is necessary for detecting tumor cell contamination. Immunocytologic analysis with monoclonal antibodies can identify one neuroblastoma cell per 10(5) normal marrow cells; this method also is applicable to other tumors with appropriate antibodies. Ex vivo removal (purging) of tumor cells decreases the probability of infusing tumorigenic cells with the ABMT. There is considerable experience in tumor detection and purging for neuroblastoma. but little has been done for other childhood solid tumors. Future investigations of ABMT will aim to further increase disease-free survival by intensifying induction and marrow-ablative regimens and by developing therapies to be given after ABMT that are directed at minimal residual disease. As pilot investigations mature. the efficacy of ABMT and conventional chemotherapy will be compared in multi-institution randomized studies.
Immunotherapy. Neuroblastoma as a model, Combinations of aggressive therapy and radiotherapy directed at the primary tumor site as well as dose intensive chemotherapy against metastases can effectively induce complete remissions in patients with stage IV neuroblastomas. By virtue of its tumor specificity. the use of immunotherapy at the time when microscopic residual disease is present holds great promise in eradicating the tumors permanently. Monoclonal antibodies can accumulate selectively and at high concentrations in neuroblastomas. They have the potential of initiating complement activation and inflammation at the tumor site. Hematopoietic factors and cytokines can reinforce the body with tumoricidal leukocytes. Ex vivo activation of autologous white cells as well as arming by genetic manipulation can also produce tumor-seeking vehicles that may be therapeutically useful. As the knowledge of tumor and host immunobiology accumulates. the optimal combination of these approaches will become apparent.
Remaining problems in the treatment of patients with Wilms' tumor, Major advances have been made in the treatment of children with Wilms' tumor. Remaining areas of investigation include the role of adriamycin and the treatment of children with stage III and IV disease and the role of whole lung radiation therapy in the treatment of children with pulmonary metastases. Long-term follow up of successfully treated patients will provide valuable insight into the importance of genetic factors in the cause of Wilms' tumor.
The child with recurrent solid tumor, A significant percentage of relapse occurs in children with solid tumors despite advances in treatment. This article discusses reasons for failure of primary therapy. evaluation of the relapsed patient. treatment of the relapsed patient. as well as questionable cancer therapies and therapy cessation.
The survivors of childhood solid tumors, With the improvement in cancer therapy in recent years. the number of cancer survivors is rapidly increasing. Potential late medical and psychosocial sequelae of cancer therapy are reviewed. A practical guide for the primary health care giver is provided.
Incorporation of 12-methoxydodecanoate into the human immunodeficiency virus 1 gag polyprotein precursor inhibits its proteolytic processing and virus production in a chronically infected human lymphoid cell line, Covalent linkage of myristate (tetradecanoate; 14:0) to the NH2-terminal glycine residue of the human immunodeficiency virus 1 (HIV-1) 55-kDa gag polyprotein precursor (Pr55gag) is necessary for its proteolytic processing and viral assembly. We have shown recently that several analogs of myristate in which a methylene group is replaced by a single oxygen or sulfur atom are substrates for Saccharomyces cerevisiae and mammalian myristoyl-CoA:protein N-myristoyltransferase (EC 2.3.1.97; NMT) despite their reduced hydrophobicity. Some inhibit HIV-1 replication in acutely infected CD4+H9 cells without accompanying cellular toxicity. To examine the mechanism of their antiviral effects. we performed labeling studies with two analogs. 12-methoxydodecanoate (13-oxamyristate; 13-OxaMyr) and 5-octyloxypentanoate (6-oxamyristate; 6-OxaMyr). the former being much more effective than the latter in blocking virus production. [3H]Myristate and [3H]13-OxaMyr were incorporated into Pr55gag with comparable efficiency when it was coexpressed with S. cerevisiae NMT in Escherichia coli. [3H]6-OxaMyr was not incorporated. even though its substrate properties in vitro were similar to those of 13-OxaMyr and myristate. [3H]13-OxaMyr. but not [3H]6-OxaMyr. was also efficiently incorporated into HIV-1 Pr55gag and nef (negative factor) in chronically infected H9 cells. Analog incorporation produced a redistribution of Pr55gag from membrane to cytosolic fractions and markedly decreased its proteolytic processing by viral protease. 13-OxaMyr and 3'-azido-3'-deoxythymidine (AZT) act synergistically to reduce virus production in acutely infected H9 cells. Unlike AZT. the analog is able to inhibit virus production (up to 70%) in chronically infected H9 cells. Moreover. the inhibitory effect lasts 6-8 days. These results suggest that (i) its mechanism of action is distinct from that of AZT and involves a late step in virus assembly; (ii) the analog may allow reduction in the dose of AZT required to affect viral replication; and (iii) combinations of analog and HIV-1 protease inhibitors may have synergistic effects on the processing of Pr55gag.
Unexpected, spontaneous conversion of a family of rats, from low-leukemic to high-leukemic inbred line, From a nucleus of Sprague-Dawley rats received in 1960 from the National Institutes of Health. we have raised. by brother-to-sister mating. a colony of these animals. The incidence of leukemia in 313 females and 316 males was 1.6% and 1.2%. respectively. About 3 years ago. we observed a relatively high incidence of leukemia in offspring of a healthy female. no. 1. Among the offspring of this female. observed through 12 successive generations. there were 17 leukemias among 44 females (38.6%) and 21 leukemias among 40 males (52.5%). developing at ages varying from 6 to 11.6 months. The most frequent form of leukemia observed was acute myeloid. with a high count of myeloblasts. promyelocytes. and myelocytes; lymphatic form was relatively rare but was observed occasionally; pronounced anemia was common. In most instances. on autopsy. the pathological picture was that of an enlarged spleen and liver. with the exception of those few animals that developed lymphatic leukemia. with thymic and mesenteric lymphoid tumors. We have no satisfactory explanation for this sudden. unexpected conversion of a part of our Sprague-Dawley rat colony from low-leukemic to high-leukemic inbred line. As a working hypothesis. the possibility of a spontaneous activation of a hypothetical oncogenic virus should be considered. The high leukemic C58 inbred line of mice originated in a similar. unexplained manner [MacDowell. E.C. & Richter. M.N. (1935) Arch. Pathol. 20. 709-724]. However. leukemia developing in mice was subsequently found to be caused by a transmissible virus. whereas. thus far at least. no evidence of a transmissible virus has been found in leukemia developing spontaneously in rats.
The human immunodeficiency virus type 1 polyadenylylation signal: a 3' long terminal repeat element upstream of the AAUAAA necessary for efficient polyadenylylation, Several polyadenylylation (PA) signals containing elements upstream of the AAUAAA have recently been characterized. Similar to PA elements found downstream of the AAUAAA. the upstream elements function to increase efficiency of AAUAAA use as a signal for cleavage and PA. Using deletion and linker scanning mutations we show that the PA signal of human immunodeficiency virus type 1 contains upstream elements transcribed from the U3 region of the 3' long terminal repeat. The element that has the greatest effect on PA site use lies 77 to 94 nucleotides upstream of the AAUAAA. between the TATA element and the transcriptional initiation site. Mutations in the adjacent region. between 59 and 76 nucleotides upstream of the AAUAAA. have a smaller effect on PA efficiency. Mutations in a region further upstream. between 141 and 176 nucleotides upstream of the AAUAAA. also affected PA modestly. Functional similarity between upstream elements was indicated by the ability of the human immunodeficiency virus upstream region to replace the upstream region of the simian virus 40 late PA signal. The sequence of the major upstream element of human immunodeficiency virus is uracil-rich. analogous to many defined downstream PA elements. This fact may imply that upstream and downstream elements have similar mechanisms of action.
Different mRNAs code for dopa decarboxylase in tissues of neuronal and nonneuronal origin, A cDNA clone for dopa decarboxylase (EC 4.1.1.28) has been isolated from a rat pheochromocytoma cDNA library and the cDNA sequence has been determined. It corresponds to an mRNA of 2094 nucleotides. The length of the mRNA was measured by primer-extension of rat pheochromocytoma RNA and the 5' end of the sequence of the mRNA was confirmed by the PCR. A probe spanning the translation initiation site of the mRNA was used to hybridize with mRNAs from various organs of the rat. S1 nuclease digestion of the mRNAs annealed with this probe revealed two classes of mRNAs. The comparison of the cDNA sequence and published sequences for rat liver. human pheochromocytoma. and Drosophila dopa decarboxylase supported the conclusion that two mRNAs are produced: one is specific for tissue of neuronal origin and the other is specific for tissues of nonneuronal (mesodermal or endodermal) origin. The neuronal mRNA contains a 5' untranslated sequence that is highly conserved between human and rat pheochromocytoma including a GA stretch. The coding sequence and the 3' untranslated sequence of mRNAs from rat liver and pheochromocytoma are identical. The rat mRNA differs only in the 5' untranslated region. Thus a unique gene codes for dopa decarboxylase and this gene gives rise to at least two transcripts presumably in response to different signals during development.
Reconstitution of high-affinity opioid agonist binding in brain membranes, In synaptosomal membranes from rat brain cortex. the mu selective agonist [3H]dihydromorphine in the absence of sodium. and the nonselective antagonist [3H]naltrexone in the presence of sodium. bound to two populations of opioid receptor sites with Kd values of 0.69 and 8.7 nM for dihydromorphine. and 0.34 and 5.5 nM for naltrexone. The addition of 5 microM guanosine 5'-[gamma-thio]triphosphate (GTP[gamma S]) strongly reduced high-affinity agonist but not antagonist binding. Exposure of the membranes to high pH reduced the number of GTP[gamma-35S] binding sites by 90% and low Km. opioid-sensitive GTPase activity by 95%. In these membranes. high-affinity agonist binding was abolished and modulation of residual binding by GTP[gamma S] was diminished. High-affinity (Kd. 0.72 nM). guanine nucleotide-sensitive agonist binding was reconstituted by polyethylene glycol-induced fusion of the alkali-treated membranes with (opioid receptor devoid) C6 glioma cell membranes. Also restored was opioid agonist-stimulated. naltrexone-inhibited GTPase activity. In contrast. antagonist binding in the fused membranes was unaltered. Alkali treatment of the glioma cell membranes prior to fusion inhibited most of the low Km GTPase activity and prevented the reconstitution of agonist binding. The results show that high-affinity opioid agonist binding reflects the ligand-occupied receptor-guanine nucleotide binding protein complex.
A retinoic acid response element is part of a pleiotropic domain in the phosphoenolpyruvate carboxykinase gene, Several hormones. including insulin. glucagon. and glucocorticoids. regulate the expression of the rate-limiting gluconeogenic enzyme. phosphoenolpyruvate carboxykinase [GTP: oxaloacetate carboxy-lyase (transphosphorylating); EC 4.1.1.32; PEPCK] in liver. In this report we demonstrate that retinoic acid (RA) also regulates PEPCK expression by inducing a 3-fold increase in the rate of transcription of the PEPCK gene. A RA response element located between -468 and -431 in the PEPCK promoter mediates a 7-fold increase in expression of a chimeric construct containing the basal PEPCK promoter ligated to the chloramphenicol acetyltransferase reporter gene. This element confers RA responsiveness through the heterologous thymidine kinase promoter and functions relatively independent of position and orientation. An 18-base-pair core sequence (-451 to -434) (i) mediates an effect of RA on PEPCK gene expression and contains motifs found in two other RA response elements; (ii) corresponds to AF1. an accessory factor element that is an integral component of the complex glucocorticoid response unit in the PEPCK gene promoter; (iii) is in a region involved in the developmental expression of the PEPCK gene; and (iv) shows homology to elements involved in the tissue-specific regulation of genes. including the hepatic apolipoprotein genes and the alpha 1-antitrypsin gene.
Transforming function of proto-ras genes depends on heterologous promoters and is enhanced by specific point mutations [published erratum appears in Proc Natl Acad Sci U S A 1991 May 1;88(9):4059, Based on transfection into cells in culture or natural transduction into retroviruses. proto-ras genes seem to derive transforming function either from heterologous promoters or from point mutations. Here we ask how such different events could achieve the same results. To identify homologous regulatory elements. about 3 kilobases of rat DNA upstream of the first untranslated proto-Ha-ras exon was sequenced. Surprisingly. the sequence shares at -1858 a homology of 148 nucleotides with Harvey (Ha) sarcoma virus. 5' of viral ras. signaling possibly a second untranslated proto-Ha-ras exon. In addition the sequence contains a perfect repeat of 25 CA dinucleotides at -2655. A retroviral promoter. even from upstream of the poly(CA). conferred transforming function on proto-Ha-ras and increased transcription greater than 100-fold compared with that of unrearranged proto-ras. Point mutations were not necessary for transforming function of rat and human proto-Ha-ras genes with retroviral promoters but did enhance it greater than 10-fold. A unifying hypothesis proposes that proto-ras genes depend on high expression from heterologous promoters or enhancers for transforming function. which is modulated by ras point mutations. The hypothesis makes two testable predictions. (i) Unrearranged proto-ras genes with point mutations. which occur in some cancers. have no transforming function. Indeed. tumors with mutated proto-ras genes. even those that also lack hypothetical tumor-suppressor genes. are indistinguishable from counterparts with normal proto-ras genes. (ii) Proto-ras genes in transfected cells derive transforming function from heterologous promoters or enhancers acquired via illegitimate recombination from vector DNAs and particularly from viral helper genes that must be cotransfected for transformation of primary cells. Indeed. expression of exogenous proto-ras genes in cells transformed by transfection is as high as for viral ras genes and is much higher than in the cells of origin.
Mechanisms associated with the generation of biologically active human immunodeficiency virus type 1 particles from defective proviruses, The human immunodeficiency virus (HIV) is the etiological agent of acquired immunodeficiency syndrome (AIDS). HIV exhibits extensive genetic diversity and it is apparent that an infected individual contains different populations of distinct viral strains. a large proportion of which has been found surprisingly to be defective for replication. A similar phenomenon has also been observed with some cell lines that are known to produce infectious viral particles but harbor defective proviral genomes. Here. we investigated the molecular basis of this phenomenon by cloning proviral genomes of HIV from a cell line that was capable of producing high titers of biologically active HIV particles that readily induced syncytia with CD4+ cell lines and peripheral blood lymphocytes. This cell line was found to contain five proviral genomes. all of which. when tested individually. failed to produce replication-competent viruses upon transfection into human cells. However. when a specific combination of two proviral genomes was used in such transfection studies. it was possible to obtain biologically active. replication-competent viral particles that infected and replicated in CD4+ cell lines and induced syncytia characteristic of HIV. Such a result may be due to homologous recombination between proviral DNAs occurring in cells after transfection and/or complementation of replication-defective proviral DNAs. The diploid nature of the viral RNA genome present in the viral particle may enable the persistence of defective HIV genomes.
The c-fms gene complements the mitogenic defect in mast cells derived from mutant W mice but not mi (microphthalmia) mice, Mutations at three loci in the mouse--W. Steel Sl). and microphthalmia (mi)--can lead to a deficiency in melanocytes and mast cells. As well. W and Sl mutants can be anemic and sterile. whereas mi mice are osteopetrotic due to a monocyte/macrophage defect. Recent data have shown that the c-kit receptor tyrosine kinase is the gene product of the W locus. whereas Sl encodes the ligand for this growth factor receptor. We show here that ectopic expression of c-fms. a gene that encodes a macrophage growth factor receptor that is closely related to the c-kit receptor. complements mutations at the W locus in an in vitro mast cell/fibroblast coculture system but is unable to reverse the inability of mi/mi mast cells to survive under these conditions. Furthermore. mast cells expressing the c-fms receptor survive on a monolayer of fibroblasts homozygous for the Sl mutation. These results suggest that ligand binding to the c-kit or c-fms receptor activates identical or overlapping signal transduction pathways. Furthermore. they suggest that mi encodes a protein necessary for transducing signals mediated by way of either the c-kit or c-fms receptor.
Protamine transcript sharing among postmeiotic spermatids, Sharing of cytoplasmic constituents through intercellular bridges connecting postmeiotic spermatids can allow for functional equivalence of genetically nonequivalent spermatids. The technique of in situ hybridization was used to study postmeiotic distribution of transcripts from the mouse protamine 1 (Prm-1) gene among spermatids of mice with chromosomally unbalanced gametes. The Prm-1 gene is located on chromosome 16 and is expressed exclusively in haploid spermatids. Mice doubly heterozygous for two Robertsonian translocations involving chromosome 16 were used for the study of postmeiotic accumulation of transcripts of the Prm-1 gene in spermatogenic cells. The meiotic segregation pattern of chromosomal homologues in these mice produces some spermatids that are chromosomally unbalanced; some spermatids lack chromosome 16 while others have two. In situ hybridization with a cDNA probe for the Prm-1 gene transcript performed on both whole testis sections and spermatogenic cell suspensions showed that there was no statistical difference in distribution of grains over step-5 to step-10 spermatids from Robertsonian-translocation heterozygous mice and from control mice of normal karyotype. These results are consistent with sharing of transcripts of the Prm-1 gene among spermatids within a syncytium.
A self-assembling protein kinase C inhibitor, Previous studies have described a dicationic anticarcinoma agent that can chemically assemble in situ from monocationic phosphonium salts. The chemical combination of these monocationic precursors in the micromolar concentration range. occurring after their uptake by cells. was probably responsible for their synergistic inhibition of cell growth and for their selective cytotoxicity to Ehrlich ascites murine carcinoma cells relative to untransformed epithelial cells. Here. we report that the dicationic product that forms in this assembly reaction is an in vitro inhibitor of protein kinase C (PKC) alpha and beta 1 isoforms. exhibiting IC50 values of 20.4 microM and 35 microM. respectively. The monocationic precursors proved to be much weaker inhibitors of PKC (IC50 values greater than 200 microM). When PKC is exposed to combinations of the two precursors. the enzymatic activity decreases steadily as a function of time. Using dose-response data and HPLC kinetic studies. we show that when the two precursor compounds are added as a combination to PKC under these conditions. the rate of formation of the inhibitory product follows the observed time course of decline in PKC activity under identical conditions. We discuss the possibility that antiproliferative effects against carcinoma cells of the preformed dication and of the combined monocationic precursors involve inhibition of PKC.
Murine erythroleukemia cell line GM979 contains factors that can activate silent chromosomal human gamma-globin genes, We introduced a normal chromosome 11 into GM979 murine erythroleukemia cells by fusing them with Epstein-Barr virus-transformed lymphocytes from a normal individual. In contrast to previous data obtained with other murine erythroleukemia cells. we detected activation of human chromosomal gamma-globin genes in GM979 cells. GM979. unlike previously used murine erythroleukemia cell lines. expresses murine embryonic globin in addition to adult globin. While all the hybrids expressed gamma- and beta-globin. they displayed a wide range of gamma-globin expression in relation to that of beta-globin. No correlation. however. was found in quantitative expression between murine embryonic globin and human gamma-globin in these hybrids. suggesting that the two globins are regulated independently. at least in this cell line. These data indicate that gamma-globin genes from normal. nonerythroid chromosomes are not irreversibly silenced. and they can be activated by a positive trans factor(s) present in GM979 cells.
Erythropoietin receptors induced by dimethyl sulfoxide exhibit positive cooperativity associated with an amplified biologic response, Erythropoietin triggers the differentiation of erythrocyte progenitors by binding to receptors on their plasma membrane. We report here that pretreatment of erythropoietin-responsive murine erythroleukemia cells with chemical inducers resulted in a striking increase in erythropoietin-specific hemoglobinization. This amplification of the erythropoietin biologic response was accompanied by the induction of a new population of high-density receptors (approximately 20.000 per cell) exhibiting marked positive cooperativity. Erythropoietin binding to new receptors displayed a convex upward Scatchard plot and a Hill coefficient (nH) of 6.75. Measurement of erythropoietin receptor mRNA demonstrated an initial decrease in receptor transcript followed by an approximately 2- to 3-fold increase after 24-48 hr. This increase in receptor message does not appear to account for the magnitude of the receptor up-regulation by dimethyl sulfoxide. We propose that this positive cooperativity reflects the interaction (clustering) of receptors. presumably through the formation of homooligomers or heterooligomers. and that this receptor interaction may amplify the erythropoietin signal transduction pathway.
Corporate-sponsored breast cancer screening at the work site: results of a statewide program, Mobile screening mammography was offered to 3.627 employees of a large corporation in Pennsylvania and Delaware. The examination was available to women employees or employee spouses aged 35 years and older. Women were charged $30 for a standard two-view examination. They also received health education materials on mammography and breast self-examination. The remaining costs of the program were underwritten by the corporation. During this program. 3.627 mammographic studies were performed; 63 biopsies were recommended. Fifty-seven biopsies were performed. and nine cancers were diagnosed. Costs of this program are presented in detail. The authors conclude that mobile screening programs at the work site provide an inexpensive. convenient alternative to more traditional screening programs. The inherent advantages of this program are the low cost. the relative ease with which the examination can be performed. and the positive role that corporate medical personnel assume in encouraging individual and group participation.
Pulmonary artery-bronchus ratios in patients with normal lungs, pulmonary vascular plethora, and congestive heart failure, The pulmonary artery-bronchus ratio (ABR). defined as the external diameter of a pulmonary artery divided by the external diameter of its accompanying bronchus. was measured in the upper and lower lung zones on frontal chest radiographs in the following groups of subjects: erect healthy subjects. erect subjects with pulmonary vascular plethora. erect subjects with clinical evidence of decompensated left-sided congestive heart failure (CHF). supine normal subjects. and supine subjects with clinical evidence of decompensated CHF. Characteristic vascular patterns were found in each group. The positive predictive value of an abnormal vascular pattern determined by means of changes in the ABR on the erect chest radiograph was 100%. with the negative predictive value of a normal pattern being 97%. The erect chest radiograph was 93% accurate in distinguishing between plethora and CHF. The positive predictive value of an abnormal vascular pattern on the supine chest radiograph was 100%. with the negative predictive value of a normal vascular pattern being 97%. Measurements of ABR can be a helpful adjunct to the interpretation of supine and erect chest radiographs.
Supraclavicular lymph node metastases in carcinoma of the esophagus and gastroesophageal junction: assessment with CT, US, and US-guided fine-needle aspiration biopsy, The preoperative assessment of supraclavicular lymph node metastases was prospectively studied in 100 patients with carcinoma of the esophagus and gastroesophageal junction. Findings at computed tomography (CT). ultrasound (US). and palpation were compared. and US-guided fine-needle aspiration biopsy of nodes with a small axis of 5 mm or greater was performed. Supraclavicular metastases were detected on CT scans in 11 of 13 patients (85%) and on US scans in 14 of 16 patients (88%) but were palpable in only three of the 16 patients (19%). The predictive value of a supraclavicular node indicating metastases was .74 at US and .85 at CT. Metastases were diagnosed in 10 of 46 patients with squamous cell carcinoma (22%) and five of 50 patients (10%) with adenocarcinoma. Nodes with metastases had a round configuration. with a statistically significant greater short-axis to long-axis ratio than that of benign nodes (0.89 vs 0.54; P = .05). In four of 16 patients (25%) with supraclavicular metastases proved with cytologic examination. neither CT nor US of the mediastinum and abdomen showed enlarged nodes.
Colorectal carcinoma: preoperative TNM classification with endosonography, Transcolorectal endosonography (TES) with use of both a nonoptic instrument and an echocolonoscope was performed in 91 patients with colorectal carcinomas (61 rectal and 30 colonic). Correlation of results at TES with results of histologic analysis of resected specimens according to the 1987 TNM classification demonstrated that TES allowed accurate staging of all tumors except T2 carcinomas. which were often accompanied by peritumoral inflammation or abscesses. Overall. the accuracy of staging rectal and colonic carcinomas with TES was 81% and 93%. respectively; overstaging occurred in 13% and understaging in 2%. For regional lymph nodes. the accuracy of staging with TES was 70%. the sensitivity was 94%. and the specificity was 55%. Correlations between findings at TES and the Dukes classification were as follows: for rectal carcinoma. 48% for class A. 50% for class B. and 96% for class C; for colonic carcinoma. 67% for class A. 46% for class B. and 91% for class C. Overall accuracy was 67%. With the addition of abdominal computed tomographic or ultrasonographic examinations to evaluate distant metastases. TES should become an important imaging technique for clinical TNM staging of colorectal carcinomas.
Cystic fibrosis: MR imaging of the pancreas, The appearance of the pancreas in 17 adult patients with cystic fibrosis was evaluated with magnetic resonance (MR) imaging. The pancreas was abnormal in 15 patients. Three patterns were observed: (a) lobulated enlarged pancreas with complete replacement by fatty tissue (n = 9). (b) small atrophic pancreas with partial replacement by fat tissue (n = 5). and (c) diffuse atrophy of the pancreas without fatty replacement (n = 1). Replacement of the pancreas by fat tissue was seen on T1-weighted images with. characteristically. a very high signal intensity. The sensitivity of MR imaging in depicting pancreatic abnormality in cystic fibrosis is 94%. which is comparable to that of computed tomography.
Graves ophthalmopathy: role of MR imaging in radiation therapy, Twenty-three patients with Graves ophthalmopathy who underwent radiation therapy were monitored by means of magnetic resonance (MR) imaging. T2 relaxation times of extraocular muscles and orbital fat. areas of extraocular muscles. and degree of exophthalmos were measured by means of MR imaging at the beginning. at the end. and 3 months after completion of radiation therapy. As a result. patients with primarily elevated T2 times of extraocular muscles showed a better therapy response regarding muscle thickening than patients with primarily normal T2 times. Elevated T2 times. which probably represent acute inflammatory changes. were markedly decreased at the end of therapy. Therefore. quantitative MR imaging favors the choice of anti-inflammatory therapy regimens in patients with elevated T2 times of extraocular muscles. However. the clinical response (activity scores) to the low-dose treatment protocol that was used did not correlate well with primarily elevated T2 times. Furthermore. T2 times increased again after cessation of therapy. Whether a higher radiation dose or a different fractionation scheme leads to better results must be clarified by means of further study.
Senile dementia and healthy aging: a longitudinal CT study, Volumetric indexes of cerebral atrophy obtained by using computed tomography (CT) were measured longitudinally in patients with senile dementia of the Alzheimer type (SDAT) and in healthy elderly control subjects. Measurements were made three times over a 51-month period. Of the original 44 patients with SDAT. five were available for CT examination at the last time of assessment (51 months); in contrast. 41 of the original 58 control subjects were still available for study at 51 months. As a group. scans of SDAT subjects showed greater atrophy than those of control subjects in all volumetric indexes at each time of testing and demonstrated greater progression of atrophy during the study period. However. the overlap of indexes between the patients with SDAT and the control subjects indicates that CT data cannot be used alone to predict the presence or progression of dementia in individual cases.
Ischemic brain damage: reduction by sodium-calcium ion channel modulator RS-87476, A novel sodium-calcium ion channel modulator. RS-87476. reduced cerebral infarct size in cats subjected to permanent unilateral occlusion of the middle cerebral artery. Cerebral injury was assessed in vivo with a combination of magnetic resonance (MR) imaging and spectroscopy for 5-12 hours after occlusion and was compared with the area of histochemically ischemic brain tissue. Compared with infarcts in placebo-treated animals. infarcts in cats given RS-87476 were reduced by an average of 70% at the lowest dose. 75% at the intermediate dose. and 88% at the highest dose. Tissue edema. observed as areas of signal hyperintensity on diffusion- and T2-weighted spin-echo images. was confined to small regions of the parietal cortex and basal ganglia in drug-treated animals. Mean plasma levels of RS-87476 at the lowest dose were 13 ng/mL initially. falling to maintenance levels of 3-5 ng/mL; at the intermediate and highest doses. plasma levels of drug were approximately five- and 20-fold greater. The drug was only slightly hypotensive. At least part of the potent cerebroprotective effects of RS-87476 result from its ability to stabilize metabolic energy reserves. reduce lactate formation in ischemic tissues. and attenuate intracerebral edema.
Proliferative retinopathy: absence of white matter lesions at MR imaging, One form of retinopathy associated with diabetes is a proliferative small vessel process thought to be mediated by biochemical. hemodynamic. and endocrinologic factors. The authors conducted a prospective study to determine whether patients with diabetes who had proliferative retinopathy had evidence of intracranial microangiopathy visible at magnetic resonance (MR) imaging. Twenty-five patients under 40 years of age with proliferative retinopathy and insulin-dependent diabetes mellitus and 10 age-matched control subjects were studied with MR imaging. Axial images were reviewed by two neuroradiologists for the presence of white matter foci of high signal intensity. No patients demonstrated evidence of these foci. There was no evidence of ischemic foci in any of the patients (all patients were neurologically asymptomatic). The vasculopathy associated with proliferative retinopathy does not appear to affect the intracranial circulation to the extent detectable with MR imaging. The presence of white matter foci of high signal intensity or ischemic changes in the brains of insulin-dependent diabetic patients under 40 years of age should not be attributed to diabetic vasculopathy. Other causes should be considered.
Wrist arthrography: value of the three-compartment injection method, Arthrography of the wrist was performed on 300 consecutive patients by injecting contrast material separately into the radiocarpal (RCJ). midcarpal (MCJ). and distal radioulnar (DRUJ) joints. The addition of MCJ and DRUJ injections to the standard RCJ injection significantly improved diagnostic yield. In 78 (26%) of the 300 cases. the abnormality was found after MCJ or DRUJ injections alone. Of the 103 triangular fibrocartilage complex (TFCC) abnormalities identified. 27 (26%) could be demonstrated after DRUJ injection alone. Of the 145 abnormal RCJ and MCJ communications. 42 (29%) could be seen after MCJ injection alone. Similarly. 22 (15%) of the 145 abnormal RCJ and MCJ communications were seen after RCJ injection alone and would have been missed if only MCJ injection had been performed. Thus. three separate injections into the RCJ. MCJ. and DRUJ are necessary for complete arthrographic evaluation.
Comparison of STIR and spin-echo MR imaging at 1.5 T in 45 suspected extremity tumors: lesion conspicuity and extent, Short inversion time inversion recovery (STIR) imaging and a double-echo spin-echo (SE) sequence at 1.5 T in 45 sequential patients with suspected extremity tumors were compared to assess the number of lesions detected. subjective conspicuity of lesions. approximate volume of abnormality detected in each lesion. and identification of peritumoral brightening in tissues adjacent to each lesion. STIR sequences enabled detection of all 45 lesions; 44 were detected with the SE sequence. Tumor appeared most conspicuous on STIR images in 35 patients (78%) and was most conspicuous on SE images in 10 patients (22%). Peritumoral brightening. which indicated either peritumoral edema or microscopic tumor infiltration. was detected in 20 patients but was detected only with STIR sequences in nine patients. It is concluded that. although STIR and SE sequences are comparable for lesion detection in the extremities. most lesions appear more conspicuous with STIR. STIR may enable detection of a greater volume of abnormality than SE sequences and may therefore have important implications for local staging and surgical and radiation therapy planning.
Normal and diffusely abnormal myocardium in humans: functional and metabolic characterization with P-31 MR spectroscopy and cine MR imaging, The current study tested the concept that cine magnetic resonance (MR) imaging and phosphorus-31 MR spectroscopy might be used to provide a comprehensive evaluation of the functional and metabolic status of the myocardium in humans. Thirteen patients with congestive cardiomyopathy and eight healthy volunteers were imaged at 1.5 T with the one-dimensional chemical shift imaging technique for localization of P-31 MR spectroscopy and an electrocardiographically referenced gradient refocused sequence for imaging of the heart. Prominent peaks in the PDE and PME regions were observed in cardiomyopathic patients. but only the former peak was measured. The PCr/beta-ATP peak ratio was not significantly lower in cardiomyopathic patients compared with healthy subjects (1.51 +/- 0.08 vs 1.54 +/- 0.04). The ratios of PDE/PCr (0.80 +/- 0.07 vs 0.54 +/- 0.10) (P less than or equal to .01) and PDE/beta-ATP (1.19 +/- 0.10 vs 0.84 +/- 0.08) (P less than or equal to .05) were significantly higher in patients with dilated cardiomyopathy compared with healthy volunteers. Left ventricular systolic wall thickening was significantly lower and left ventricular peak and end-systolic wall stress and mass were significantly higher in cardiomyopathic patients compared with healthy volunteers. Thus. localized. gated P-31 MR spectroscopy combined with cine MR imaging allowed identification of both abnormal myocardial phosphate metabolism and abnormal ventricular function. While this study suggests that increased myocardial PDEs may be a marker for abnormal myocardium. the sensitivity and specificity of this marker need to be further evaluated.
Liver transplantation: MR angiography with surgical validation, Thirty patients (mean age. 45 years) were evaluated with magnetic resonance (MR) angiography before liver transplantation to assess the accuracy of MR angiography. A series of breath-hold. two-dimensional images were acquired and subsequently processed to form three-dimensional projection angiograms. Graphic information on blood flow in the portal vein was acquired by using presaturation bolus tracking. Correlative duplex ultrasound (US) was performed in 28 patients. and surgical or autopsy correlation was available in all cases. MR angiography demonstrated patency of the portal vein in 26 (96%) of 27 patients. made possible the diagnosis of portal venous occlusion in three of three patients. depicted reversed portal flow in one patient. and provided clear delineation of the extent of varices and specific portosystemic collateral vessels. When duplex US was successful. there was full agreement with MR angiographic results in assessing portal vein patency and flow direction. All of the MR findings were corroborated at surgical exploration or autopsy. The authors conclude that MR angiography is very accurate in the portal system and is valuable in preoperative assessment for liver transplantation.
US-guided fine-needle aspiration biopsy of gallbladder masses, Ultrasonically (US) guided fine-needle aspiration biopsy was performed in 88 patients who had gallbladder masses. All masses were less than 4.8 cm in diameter. A 22- or 23-gauge. Teflon-coated needle was placed into the mass with the transhepatic or transperitoneal route. By means of this technique. gallbladder malignancy was confirmed in 69 of the 78 cases of malignancy (88.5%). Ten of 10 benign lesions were properly categorized. One patient developed bile peritonitis following a single needle pass with the transperitoneal approach. Pain. a minor complication of the procedure. was noted in four cases. No instances of hemorrhage or vasovagal reactions occurred. From their experience in this large series. the authors conclude that US-guided fine-needle aspiration biopsy of gallbladder masses is a safe. reliable. and accurate technique for the diagnosis of malignancy.
Palpable masses in the prostate: superior accuracy of US-guided biopsy compared with accuracy of digitally guided biopsy, The accuracies of digitally guided biopsy versus ultrasound (US)-guided biopsy of the prostate were compared in 112 consecutive men with palpable prostatic lesions who had previously undergone conventional digitally guided biopsy and in which the results were negative for carcinoma. US-guided biopsies were performed with either the transperineal (n = 51) or transrectal (n = 61) approach. by means of previously described methods. All US-guided biopsies were performed within 3 months after the most recent conventional biopsy. In 44 patients (39.3%) with negative results of conventional biopsies. the results of US-guided biopsy revealed cancer. The transrectal and transperineal digitally guided biopsies were equally inaccurate. and the transrectal and transperineal US-guided biopsies showed no statistically significant differences in accuracy. The patients accepted and tolerated both US techniques equally well; neither technique was associated with significant complications. It is concluded that all patients with a palpable nodule should undergo US-guided biopsy if the result of conventional digitally guided biopsy is negative for cancer and the diagnostic US scan suggests an abnormality.
Prostatic MR imaging performed with the three-point Dixon technique. Work in progress, The three-point Dixon technique is an enhancement of the original Dixon method for the creation of water- and fat-proton magnetic resonance (MR) images. With the three-point Dixon technique. three measurements of phase shift at 0. pi. and -pi between the fat and water resonances are employed. Compensation for B0 inhomogeneity leads to an error-free decomposition into water- and fat-proton images; an accurate B0 map is also created. The lack of chemical shift artifact in the water- and fat-selective MR images permits the application of narrow receive bandwidth for the creation of T2-weighted images with a high signal-to-noise ratio. The technique was applied in vivo with four healthy subjects. seven patients with prostatic carcinoma. and one patient with benign prostatic hypertrophy and compared with conventional T2-weighted imaging. The three-point technique yielded images with improved definition of normal intraprostatic structures and zonal anatomy and. in some cases of prostatic carcinoma. provided better visualization of extraprostatic spread of tumor.
Therapeutic effect of hysterosalpingography: oil- versus water-soluble contrast media--a randomized prospective study, In a prospective randomized study. the number of pregnancies after hysterosalpingography (HSG) was estimated in 398 patients who had been infertile for longer than 1 year. Iohexol was used in 101 patients. ioxaglate in 102 patients. diatrizoate meglumine in 97 patients. and ethiodized poppy-seed oil in 98 patients. Ten months after HSG. the patient. referring physician. and/or hospital department was consulted for information about pregnancies. Questionnaires were obtained from the patients who became pregnant during the waiting period of 3 months. No differences in demographic parameters. infertility status. or diagnosis made with HSG were detected among the four contrast media groups. Significantly more patients became pregnant after HSG in the ethiodized poppy-seed oil group than in the three water-soluble contrast media groups (P less than .01). When only intrauterine pregnancies resulting in full-term births were considered. significant differences in pregnancy rates between the oil-soluble and the water-soluble contrast media groups became more obvious. In the group that received ethiodized poppy-seed oil. almost one-third of the infertile women had normal pregnancies and childbirths after HSG.
Obstructed uterovaginal anomalies: demonstration with sonography. Part II. Teenagers, The sonograms of 13 patients with obstructed uterovaginal anomalies were reviewed to determine the role of sonography in diagnosis and management. In a retrospective analysis. the authors were able to define the cause of the obstruction and the upper level and length of the obstruction by combining the sonographic findings with those from the physical examination (ie. bulging hymen. blind vaginal pouch. no vaginal depth. normal vagina) or by combining transabdominal sonography with simultaneous digital insertion into the vaginal orifice. When the sonogram demonstrated hematometrocolpos or hematocolpos. the lesion was due to an imperforate hymen (n = 1) or high. middle. or low transverse vaginal septum (n = 7). When the sonogram demonstrated a hematometra. the lesion was due to Mayer-Rokitansky-Kuster-Hauser syndrome with functioning uterine anlage(n) (n = 2). cervical dysgenesis (n = 1). and an obstructed uterine horn (n = 2). The presence and patency or absence of the cervix was established. Since the differentiation between a transverse vaginal septum. Mayer-Rokitansky-Kuster-Hauser syndrome with active anlagen. and cervical dysgenesis with absent vagina cannot be made clinically. sonography provides important presurgical information.
Legg-Calve-Perthes disease: imaging with MR, Magnetic resonance (MR) imaging studies were obtained to evaluate the shape of the cartilaginous femoral head and the adequacy of femoral acetabular containment in 35 children with Legg-Calve-Perthes disease (LCPD). MR results for 24 of the 35 children were compared with results at arthrography. The shape of the cartilaginous femoral head was well identified with MR imaging. but. with arthrography. less information could be obtained about the medial and lateral aspects of the cartilaginous capital epiphyses in nine and three cases. respectively. Thirteen children underwent surgery; remodeling and regained femoroacetabular congruity of the articular surfaces following derotation varus osteotomy was identified in seven of 10 who underwent repeat MR imaging. In addition. MR images and conventional radiographs of the hips were compared. The radiographically identifiable distribution of the bone necrosis of the capital epiphysis correlated well with that demonstrated on MR images. MR imaging is a valuable non-invasive procedure with which to obtain information about the status and treatment of the cartilaginous femoral head in children with LCPD.
Endothelial cell biology, The endothelium is not a passive blood-compatible lining for the containment of blood cells and plasma. but rather it is a metabolically active tissue that subserves a wide range of functions relating to vascular homeostasis. This article reviews the current understanding of endothelial cell biology in terms of the molecules and biochemical pathways involved. These regulate coagulant and thrombotic properties of the vessel wall. vascular tone. and hence blood flow and pressure; changes in solute permeability and leukocyte traffic during the generation of inflammatory and immune responses; and finally the processes of vessel growth and angiogenesis. The review concludes with a consideration of how these functional properties can be disturbed. and their possible consequences. in response to irradiation. intravascular contrast media. or angioplasty.
The toddler's cuboid fracture, The authors describe two proved and two presumed cases of cuboid fractures in toddlers. These children were seen because of their inability to bear weight on the affected foot following a fall. Initial radiographs were normal; however. early scintigraphy revealed focal uptake in the cuboid. Follow-up radiographs demonstrated characteristic sclerosis of the base of the cuboid. Cuboid fractures are another example of a toddler's injury that may be difficult to diagnose at initial physical and radiographic examination.
Assessment of brain death in children by means of P-31 MR spectroscopy: preliminary note. Work in progress, The authors examined the possibility of assessing cerebral damage with phosphorus-31 magnetic resonance (MR) spectroscopy in 24 patients (three infants. four children older than age 5 years. and 17 adults) who met the adult criteria for brain death. In all patients except patient 3 (an infant 8 months old). inorganic phosphate with phosphodiester was observed. and adenosine triphosphate (ATP) and phosphocreatine (PCr). which are detectable in healthy brains. were not detected. In 22 of these 23 patients. cardiac death occurred within 7 days after clinical brain death. and in one infant 14 months old. cardiac death occurred 38 days after clinical brain death. In patient 3. ATP and PCr were detected with P-31 MR spectroscopy. and now. more than 20 months after brain death. cardiac death has not yet occurred. In children younger than age 5 years. P-31 MR spectroscopic findings were predictive of the patient's clinical outcome. These findings may help establish criteria for the diagnosis of brain death in children younger than age 5 years.
Isolation of sequences that span the fragile X and identification of a fragile X-related CpG island [published erratum appears in Science 1991 Apr 26;252(5005):494, Yeast artificial chromosomes (YACs) were obtained from a 550-kilobase region that contains three probes previously mapped as very close to the locus of the fragile X syndrome. These YACs spanned the fragile site in Xq27.3 as shown by fluorescent in situ hybridization. An internal 200-kilobase segment contained four chromosomal breakpoints generated by induction of fragile X expression. A single CpG island was identified in the cloned region between markers DXS463 and DXS465 that appears methylated in mentally retarded fragile X males. but not in nonexpressing male carriers of the mutation nor in normal males. This CpG island may indicate the presence of a gene involved in the clinical phenotype of the syndrome.
Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox, The two mouse genes. En-1 and En-2. that are homologs of the Drosophila segmentation gene engrailed. show overlapping spatially restricted patterns of expression in the neural tube during embryogenesis. suggestive of a role in regional specification. Mice homozygous for a targeted mutation that deletes the homeobox were viable and showed no obvious defects in embryonic development. This may be due to functional redundancy of En-2 and the related En-1 gene product during embryogenesis. Consistent with this hypothesis. the mutant mice showed abnormal foliation in the adult cerebellum. where En-2. and not En-1. is normally expressed.
Babbling in the manual mode: evidence for the ontogeny of language, Infant vocal babbling has been assumed to be a speech-based phenomenon that reflects the maturation of the articulatory apparatus responsible for spoken language production. Manual babbling has now been reported to occur in deaf children exposed to signed languages from birth. The similarities between manual and vocal babbling suggest that babbling is a product of an amodal. brain-based language capacity under maturational control. in which phonetic and syllabic units are produced by the infant as a first step toward building a mature linguistic system. Contrary to prevailing accounts of the neurological basis of babbling in language ontogeny. the speech modality is not critical in babbling. Rather. babbling is tied to the abstract linguistic structure of language and to an expressive capacity capable of processing different types of signals (signed or spoken).
The Greenfield filter as the primary means of therapy in venous thromboembolic disease, During a five year period at Akron City Hospital. 165 Greenfield filters were placed in 165 patients. Of this group. 78 patients were available for long term analysis. and of these. 42 did not receive anticoagulation treatment for venous thromboembolic diseases. either acutely or on an outpatient basis. An analysis of the outcome for these 42 patients who had the Greenfield filter only as the primary mode of therapy for the disease included chart review and asking each person a standard set of questions. Leg swelling was the most common complaint. occurring in 33 per cent of patients. Venous stasis ulceration occurred in two patients and recurrent deep venous thrombosis occurred in one patient. When compared with a historical control group with venous thromboembolic disease that was treated with anticoagulation alone. the incidence of these sequelae in Greenfield-treated patients was not significantly different. Finally. in this review. the Greenfield filter is better than 95 per cent effective in the prevention of pulmonary embolism. This is no less effective than anticoagulation alone. the efficacy of which is 95 to 98 per cent. The placement of a Greenfield filter is a safe procedure that can usually be done after a local anesthetic was administered to the patient with a complication rate of less than 10 per cent. Unfortunately. major complications of anticoagulation (usually hemorrhage) are relatively common at a rate of 2 to 15 per cent. and occur more frequently in the older population. It is for reasons of safety of therapy and of an equal or better efficacy that the Greenfield filter is recommended in a broader range of clinical circumstances. In particular. it is concluded that the Greenfield filter should be used as a primary means of therapy in venous thromboembolic disease. particularly in those patients who are more than 65 years of age. when the risks of anticoagulation are most threatening.
Thigh bleeding time as a valid indicator of hemostatic competency during surgical treatment of patients with advanced renal disease, We compared the usefulness of the modified Ivy bleeding time performed in the forearm (arm bleeding time) with that performed in the thigh (thigh bleeding time) as an indicator of hemostatic competence during surgical treatment in 16 patients with chronic renal failure. In 22 normal adults. the arm bleeding time (mean plus or minus standard deviation. 6.6 +/- 1.4 minutes) was significantly longer than the value in the thigh (mean plus or minus standard deviation. 4.1 +/- 1.3 minutes) (p less than 0.001). and there was no correlation between arm and thigh bleeding time. Preoperatively. the arm bleeding time in patients with renal disease was markedly prolonged (greater than 20 minutes) in 15 patients and slightly prolonged in one patient. There was no abnormal perioperative bleeding in 13 patients whose preoperative thigh bleeding time was seven minutes or less. Prolonged and excessive perioperative bleeding was observed in three patients whose thigh bleeding time was 8.0. 9.5 and 26.5 minutes. These findings suggest that thigh bleeding time is a better indicator of competence of primary hemostasis during the operation than the arm bleeding time in patients with advanced renal failure.
Complications of indwelling central venous catheters in bone marrow transplant recipients, Complications associated with indwelling central venous catheters in patients undergoing bone marrow transplantation are presented. The study group was comprised of 123 patients who underwent transplantation from 1982 to 1988 in whom 139 catheters were placed. One hundred and fifteen of 139 catheters placed had a triple lumen. while 24 had a dual lumen. Percutaneous placement through the subclavian vein was used in 127 of 139 catheters with a low complication rate. Catheters remained in place for 65.0 +/- 55.5 days (mean +/- standard deviation). One hundred and eight catheters remained functional during the course of treatment for these patients and lasted until elective removal or until the patient died. Thirty-one catheters were removed because of a complication. Infection was the most common complication. occurring in 22 catheters. Seven infected catheters were salvaged with antibiotic therapy. Coagulase negative staphylococcus was the most frequent organism identified. Mechanical problems causing catheter malfunction. migration. thrombosis and cuff erosion occurred in 19 catheters; 15 were removed. We concluded that double and triple lumen Silastic (silicone rubber) catheters provide relatively safe and effective access for bone marrow transplant recipients. The triple lumen catheter provides an additional venous access port that facilitates intensive care. The duration of catheter function is sufficient in most patients for therapy during and after bone marrow transplantation. Infection is the most common complication; our results indicate that catheters can be maintained and salvaged in some patients with septicemia. Noninfectious complications are less frequent. although catheters with persistent mechanical problems are less likely to be salvaged.
Choledocholithiasis in Chinese immigrants with cholelithiasis, During the period from January 1987 to December 1989. admissions for biliary tract disease at the New York Infirmary--Beekman Downtown Hospital were split almost evenly between Chinese immigrants from southeast Asia and all other ethnic groups (Caucasian. Hispanic. black. et cetera). However. the incidence of choledocholithiasis in patients undergoing cholecystectomy for cholelithiasis was much higher in the Chinese immigrant population. 37.2 versus 11.8 per cent. a highly significant difference (p = 0.001). In addition. we often found the disease to be of greater severity in Chinese patients. They were more likely to have large numbers of stones in the duct and more likely to have significant ductal enlargement. This increased risk was essentially constant regardless of age. Because of this threefold risk of choledocholithiasis when operating on a Chinese immigrant from southeast Asia for cholelithiasis. intraoperative cholangiography is mandatory. even in those without other indications for common bile duct exploration.
The role of aspiration cytologic examination in the diagnosis of carcinoma of the breast, A study of 2.000 patients who had undergone fine needle aspiration of a solid lump of the breast was conducted to determine the accuracy of this technique. During the period 1982 to 1989. all patients with a solid mammary mass. presenting to a specialized breast unit were initially investigated by fine needle aspiration cytologic examination (FNAC). To date. we present data on 2.000 consecutive aspirations with matching histologic diagnosis on the excised pathologic specimens. In particular. the relationship between tumor histologic factors and the accuracy of cytologic diagnosis was examined. The sensitivity of FNAC in the diagnosis of a malignant growth was 84 per cent; this represents first aspiration results only. The specificity was more than 99 per cent. The rate of acellular or unsatisfactory aspirations was 12 per cent. We had a positive predictive rate for diagnosis in carcinoma of the breast of almost 95 per cent. The diagnosis of lobular and in situ patterns of disease was questioned. with three of three in situ lesions and ten of 23 lobular lesions missed by FNAC. We do not recommend that FNAC replace excision biopsy and frozen section in the diagnosis of carcinoma of the breast.
The two stage tracheostomy as a safe technique in instances of severe coagulopathy, A simple two stage tracheostomy procedure is described for use in respirator-dependent patients in intensive care units. It is useful in patients in whom tracheostomy is indicated. but refractory coagulopathy is a deterrent.
Use of the diaphragm to reinforce anastomosis of the intestines, Use of a diaphragmatic flap to buttress and help secure persistent intestinal fistula is described. The potential for the use of muscle flaps in the management of recurrent intestinal fistula is presented.
In utero intravascular transfusion for treating fetal hemolytic disease, Technologic advances in ultrasound have led to the ability to access the fetal circulation in utero. Precise evaluation and accurate treatment of fetal hemolytic disease is now possible. This technique of in utero intravascular transfusion has several advantages. It uses a closed system that reduces the risk of infection and air embolus. The proximal extension tubing minimizes manipulation of the hub of the needle. which may lead to dislodgement of the needle. and permits a sampling port with minimal dead space between it and the fetal circulation. The HemoCue hemoglobinometer allows for rapid assessment of the concentration of fetal hemoglobin and. therefore. a shorter interval of time in which the needle is in the umbilical cord. This reduces the risks of trauma to the umbilical cord.
The use of Glisson's capsule flap in reduced orthotopic hepatic transplantation, The technique of graft reduction has increased the donor pool for children in need of orthotopic hepatic transplantation. However. this technique has been associated with increased perioperative blood loss. Further refinements. such as covering the cut surface of the donor hepatic duct with a flap of Glisson's capsule. may help reduce this complication.
Disorders of esophageal motility, Patients with esophageal motility disorders usually have dysphagia and many also have chest pain similar to angina. The diagnosis is suggested by the clinical presentation. and supporting evidence is often provided by contrast roentgenography. Esophageal manometry is usually necessary to confirm the diagnosis. Conservative therapy using pharmacologic agents is often useful as an initial trial. although many patients who continue to be symptomatic ultimately require surgical intervention.
Changes in the relative frequency of gastric adenocarcinoma in southern California, The incidence of gastric cancer is decreasing in most counties of the developed world. but at the Los Angeles County-University of Southern California Medical Center. we diagnosed 99.8 cases of gastric adenocarcinoma per 10(5) discharges in the period 1982 to 1986 as opposed to 62.2 per 10(5) discharges in 1972 to 1976 (P less than .0001). This change involved primarily Hispanics younger than 30 years of age with 30 cases per 10(5) vs 4.2 cases per 10(5) (P less than .0001) and whites older than 30 years: 87 cases per 10(5) vs 54 cases per 10(5) (P less than .05) during 1982 to 1986 and 1972 to 1976. respectively. There was no change in the relative frequency rates of gastric adenocarcinoma among African Americans and Asians. Although these changes do not seem important enough to make the detection of gastric cancer a high-priority public health problem. they should alert physicians working in areas with high Hispanic populations of the relative possibility of the occurrence of gastric malignancy even in young patients. Also. we have found that gastric cancer is still prevalent in whites of low socioeconomic class.
Brain tumors, Recent advances in experimental tumor biology are being applied to critical clinical problems of primary brain tumors. The expression of peripheral benzodiazepine receptors. which are sparse in normal brain. is increased as much as 20-fold in brain tumors. Experimental studies show promise in using labeled ligands to these receptors to identify the outer margins of malignant brain tumors. Whereas positron emission tomography has improved the dynamic understanding of tumors. the labeled selective tumor receptors with positron emitters will enhance the ability to specifically diagnose and greatly aid in the pretreatment planning for tumors. Modulation of these receptors will also affect tumor growth and metabolism. Novel methods to deliver antitumor agents to the brain and new approaches using biologic response modifiers also hold promise to further improve the management of brain tumors.
Lovastatin use and muscle damage in healthy volunteers undergoing eccentric muscle exercise, We did a double-blind. placebo-controlled crossover study of 10 healthy young men taking no medications to determine if ingesting lovastatin is associated with more severe muscle damage after exercise. Five men in the first group took 40 mg of lovastatin daily for 30 days while those in the second group took an identical-appearing placebo. Each volunteer then walked downhill on a -14-degree incline on a treadmill at 3 km per hour for an hour. After a 2-week rest. the subjects were crossed over. Serial serum creatine kinase activity was measured immediately before and 8. 24. 48. 72. 120. and 144 hours after each treadmill session. With each subject serving as his own control. peak mean serum creatine kinase activity (/+- SEM) following treadmill after lovastatin therapy was similar to that following placebo (168.4 +/- 25.8 U per liter versus 146.7 +/- 14.7 U per liter. respectively [P = .9]). With an alpha value of .05. we had greater than a 99% chance of detecting a difference in the rise of serum creatine kinase activity of 200 U per liter between groups. Our data suggest that lovastatin is not an independent risk factor for developing exercise-induced muscle damage using this model of exercise in our study population.
Effects of atenolol alone, nifedipine alone and their combination on ambulant myocardial ischemia, The effects of atenolol (100 mg/day) and nifedipine (20 mg 3 times daily) and their combination on ambulant myocardial ischemia were investigated using a randomized. double-blind. placebo-controlled. crossover trial. Eighteen men with symptomatic coronary artery disease. exercise-induced ischemia and minimal symptoms. underwent 4 blinded treatment periods of 2 weeks' duration (2 placebo. 1 atenolol. 1 nifedipine). Those that did not have ischemia eliminated by monotherapy received combination therapy with both drugs. Forty-eight-hour ambulatory electrocardiographic monitoring was used to quantitate ischemic parameters at the end of each period. Both nifedipine and atenolol as monotherapy reduced the number of ischemic episodes and the average duration of each episode compared with placebo (p less than 0.05). Compared with placebo. nifedipine reduced the total duration of ischemia (p less than 0.05) but the effect of atenolol on ischemia duration was of borderline significance (p = 0.066). There were no differences in reduction of ischemic parameters when atenolol was compared with nifedipine (difference not significant). In the 9 patients who continued to have ischemia with monotherapy. combination therapy eliminated it in 2 and reduced the duration by greater than 50% in the remaining patients compared with placebo. In conclusion. monotherapy with nifedipine or atenolol is similarly effective in eliminating or reducing ambulant ischemia. Combination therapy can provide additional benefit in those with continued ischemia.
Spontaneous myocardial ischemia and the signal-averaged electrocardiogram, The effects of transient myocardial ischemia on the signal-averaged electrocardiogram were investigated in 13 patients with coronary artery disease and spontaneous angina undergoing 3-channel ambulatory electrocardiography. Ischemia was seen as ST elevation in 2 patients or ST depression in 11; it was anterior in 5 patients. inferior in 4 and undefined in 4. Signal-averaged electrocardiograms with noise levels less than or equal to 1 microV were obtained from Holter tapes during 54 of 61 ischemic attacks recorded in the study group (88%). and compared with 54 tracings recorded within 60 minutes of the index attacks. Baseline tracings were normal in 8 patients (62%). showed a long QRS duration in 2 (15%). and both a long QRS duration and a late potential in the remaining 3 (23%). Comparison of recordings at baseline and during ischemic attacks revealed no significant changes in signal-averaged electrocardiographic parameters. Absence of significant differences was also noted when analysis was performed according to the type of ischemic attacks (associated with ST elevation [n = 14] or ST depression [n = 40]). their location (anterior [n = 21] or inferior [n = 23]). their duration (greater than 10 minutes [n = 29] or less than or equal to 10 minutes [n = 25]). and their magnitude (greater than 2 mm [n = 18] or less than or equal to 2 mm [n = 36]). It is concluded that spontaneous transient myocardial ischemia. independent of its type. location. duration and magnitude. does not generate a substrate for late potentials on the signal-averaged electrocardiogram.
Right ventricular systolic function during exercise with and without significant coronary artery disease, To evaluate the effects of exercise and coronary artery disease on right ventricular (RV) systolic function. rest and exercise biplane RV angiograms were recorded in 20 patients undergoing diagnostic cardiac catheterization. Thirteen patients had exercise angiograms of sufficient quality to undergo analysis and were classified into 2 groups. Group 1 had no or only mild coronary artery disease; group 2 had significant coronary artery disease as manifested by new. exercise-induced. left ventricular regional wall motion abnormalities. RV systolic pressure increased in both groups during exercise: 33 to 57 mm Hg in group 1 (p = 0.0002) and 33 to 55 mm Hg in group 2 (p = 0.0004). Pulmonary resistance did not change in group 1 during exercise but increased in group 2 (3.2 to 4.8 Wood units. p = 0.04). RV ejection fraction increased slightly. but not significantly. during exercise in group 1. but decreased in group 2 (73 vs 58% with exercise [p = 0.01]). The change in RV ejection fraction from rest to exercise correlated closely with the change in pulmonary resistance from rest to exercise (r = -0.89. p less than 0.0001). RV regional wall motion analysis demonstrated a generalized decline in regional ejection fraction in group 2 during exercise. even in patients without right coronary artery disease. In conclusion. there is a decline in RV ejection fraction during exercise in patients with significant coronary artery disease. The generalized reduction in regional RV ejection fraction coupled with the close correlation with the change in pulmonary resistance suggests that increased afterload. rather than RV ischemia. is the cause.
Coronary collateral circulation in coronary artery disease and systemic hypertension, The extent and functional capacity of coronary collateral circulation in patients with systemic hypertension has not been elucidated. In the present study. 313 patients with coronary artery disease were studied to evaluate coronary collateral circulation in relation to the presence of systemic hypertension and left ventricular hypertrophy. Patients had greater than or equal to 95% diameter luminal obstruction of either the left anterior descending or the right coronary artery. Patients were classified into 2 groups: The hypertensive group consisted of 61 patients. mean age 55 +/- 9 years. with systemic hypertension. and the normotensive group consisted of 252 patients. mean age 53 +/- 8 years. without hypertension. The hypertensive group had more severe angina pectoris and less history of healed myocardial infarction than the normotensive group (p less than 0.001). Left ventricular wall thickness was 1.26 +/- 0.1 cm in the hypertensive and 1.03 +/- 0.06 cm in the normotensive group (p less than 0.001). The hypertensive group had more extensive coronary collateral circulation than the normotensive group (p less than 0.01). There was a positive relation between coronary collateral circulation and left ventricular wall thickness (p less than 0.001). These results indicate that patients with systemic hypertension and coronary artery disease have an increase in coronary collateral circulation corresponding to the degree of left ventricular wall thickness.
Time of onset of supraventricular tachyarrhythmia in relation to alcohol consumption, It is widely believed but has never been proved that idiopathic supraventricular tachyarrhythmias beginning during or after weekends or winter holidays are frequently alcohol-related ("holiday heart" syndrome). The time of arrhythmia onset was therefore studied in relation to self-reported ethanol consumption and results of a screening test for alcoholism (CAGE questionnaire) in 289 patients aged less than 65 years admitted for supraventricular tachyarrhythmias. There were 102 patients having an etiologically idiopathic arrhythmia with a known time of onset. Among them. but not among those with disease-related arrhythmias. patients with arrhythmic episodes beginning on Saturdays or on Sundays were more often chronic alcohol abusers (9 of 19. 47%) than either patients with episodes beginning from Mondays through Fridays (18 of 83. 22%; p = 0.040) or control subjects from the out-of-hospital population (8 of 66. 12%; p = 0.002). In multivariate analysis. the time of arrhythmia onset was related to the CAGE response (G2 = 6.0. p = 0.014) but not to the most recent ethanol use. However. the increased frequency of problem drinkers among patients with weekend-onset idiopathic arrhythmias was only relative. and resulted from a decreased number of abstainers and non-problem drinkers. No conspicuous clustering of alcohol-related arrhythmias was seen after New Year's or May Day. Thus. although the present study confirms an association between heavy drinking and idiopathic arrhythmias beginning during weekends. it shows that the question may be of a relative rather than an absolute overrepresentation. The term holiday heart may also be somewhat misleading since no postholiday accumulation of alcohol-related arrhythmias was found.
Hemodynamic and neurohormonal effects of quinidine in patients with severe left ventricular dysfunction secondary to coronary artery disease or idiopathic dilated cardiomyopathy, Quinidine causes vasodilation directly and by inhibition of adrenergic vasoconstriction. but it also exerts negative inotropic activity. Although this drug is often administered to patients with severe congestive heart failure. the net consequences of these opposing actions have not been evaluated in such patients. The hemodynamic and neurohormonal response to oral quinidine (600 mg) in 19 patients with severe chronic heart failure was therefore determined. Vasodilation was the predominant effect of quinidine. with reductions in mean arterial. left ventricular filling and right atrial pressures of -9% (confidence interval [CI] -5 to -13). -8% (CI -19 to 3). -15% (CI -26 to -4). respectively. The quinidine-induced vasodilation increased plasma norepinephrine and epinephrine concentrations by 44% (CI +17 to +72) and 47% (CI +2 to +91). respectively. No change in cardiac performance was noted. with the cardiac index slightly increased (+10%. CI +2 to +17) and stroke work index unchanged (0%. CI -11 to +11) after quinidine. Although the mean serum quinidine concentration was within the therapeutic range or lower in all patients. the serum quinidine concentration and the change in mean arterial pressure did correlate (r2 = 0.64). In conclusion. vasodilation is the predominant hemodynamic effect of oral quinidine in patients with congestive heart failure. However. potential adverse effects may be caused by consequent neurohormonal activation.
Effects of prolonged infusion of human alpha calcitonin gene-related peptide on hemodynamics, renal blood flow and hormone levels in congestive heart failure, We have previously demonstrated that short-term infusion of calcitonin gene-related peptide (CGRP) has beneficial effects in congestive heart failure. The effects of prolonged infusion of CGRP on hemodynamic functions. plasma hormones and renal blood flow were studied in 9 patients with congestive heart failure (New York Heart Association class III or IV. ejection fraction less than 35%). Hemodynamic variables were measured at 30-minute intervals for 8 hours during CGRP infusion (8 ng/kg/min) and for 2 hours after discontinuation. CGRP caused a decrease in right atrial (28%. p less than 0.05). pulmonary artery (22%. p less than 0.02). pulmonary artery wedge (37%. p less than 0.001) and systemic arterial (18%. p less than 0.05) pressures. Systemic vascular resistance decreased more than pulmonary vascular resistance. Cardiac output (72%. p less than 0.001) and stroke volume (60%. p less than 0.02) increased. Heart rate did not change. There was no evidence of tolerance throughout the infusion. The hemodynamic effects were lost within 30 minutes of stopping CGRP. Renal blood flow (34%. p less than 0.01) and glomerular filtration rate (43%. p less than 0.01) increased. Atrial natriuretic peptide decreased (p less than 0.05). while plasma cortisol (p less than 0.02) increased. Plasma epinephrine. norepinephrine. renin activity. aldosterone and growth hormone were unchanged. It is concluded that in patients with severe congestive heart failure. CGRP has sustained beneficial effects on hemodynamic functions and has no adverse effects on hormones. Unlike many other vasodilators. CGRP also increases renal blood flow and glomerular filtration.
Analysis of survival in patients with pulmonic valve atresia and ventricular septal defect, This study reviews the clinical course of 104 consecutive patients with pulmonic valve atresia and ventricular septal (VSD) defect who were diagnosed in the first year of life and followed for a mean period of 4.95 years (range 2 days to 13.75 years). Specific attention was paid to the nature of the pulmonary blood supply and to its influence on patient outcome. Confluent pulmonary arteries supplied by a single ductus arteriosus were present in 72 patients (69%. group I). whereas 32 patients (31%. group II) had a pulmonary blood supply that was partially or exclusively dependent on systemic collateral arteries. An estimate of the probability of survival for 10 years was 69% in the entire cohort. with no different between patients in group I and group II. Definitive surgical repair was performed in 33 of 72 group I patients (46%). compared with 5 of 32 group II patients (16%). Arborization and distribution abnormalities of the pulmonary arteries as well as intrapulmonary stenoses that were exclusively present in patients with systemic collateral arteries (p less than 0.00001) accounted for the significantly lower probability of undergoing corrective surgery in group II patients.
Pulmonary artery morphology and hemodynamics in pulmonic valve atresia with ventricular septal defect before and after repair, Cardiac catheterization and angiography were performed in 22 patients with pulmonic valve atresia and ventricular septal defect to evaluate pulmonary morphology and hemodynamics before and after repair. In 12 of the 22. pulmonic valve atresia and ventricular septal defect were associated with major aortopulmonary collateral arteries. which were ligated in most. Mean postoperative pulmonary artery pressure (PAP) ranged from 9 to 92 mm Hg (mean 28 +/- 19) and pulmonary vascular resistance ranged from 1.1 to 35.2 U.m2 (mean 6.4 +/- 8.0). These data correlated (r = 0.89. p less than 0.001). The number of pulmonary artery subsegments connected to the central pulmonary arteries was 22 to 42 (mean 38 +/- 6). Univariate analysis revealed that the mean postoperative PAP correlated with the number of pulmonary artery subsegments connected to the central pulmonary arteries (r = -0.81. p less than 0.001). with mean postoperative PAP (r = 0.79. p less than 0.001). with the postoperative pulmonary artery area index of the right and left pulmonary arteries at prebranching (r = -0.76. p less than 0.001). and with the sum of the pulmonary artery areas after branching (r = -0.69. p less than 0.005). Pulmonary vascular resistance correlated with the number of pulmonary artery subsegments connected to the central pulmonary arteries (r = -0.85. p less than 0.001). with the mean preoperative PAP (r = 0.79. p less than 0.001). with the sum of the pulmonary artery areas after branching (r = -0.73. p less than 0.001). and with the postoperative pulmonary artery area index (r = -0.70. p less than 0.001). The incidence of pulmonary vascular resistance being less than 3 U.m2 was significantly higher in patients with greater than 36 pulmonary artery subsegments connected to the central pulmonary arteries and with a preoperative pulmonary artery area index greater than 0.5 (88%) (p less than 0.01).
Assessment of right ventricular oxidative metabolism by positron emission tomography with C-11 acetate in aortic valve disease, Evaluation of right ventricular (RV) oxidative metabolism is limited by the inability to easily determine oxygen extraction by the RV myocardium and the complex morphology of this ventricle. Because left ventricular C-11 clearance rate constants closely correlate with myocardial oxygen consumption. it was postulated that C-11 clearance rate constants for the RV free wall should also reflect its oxygen consumption. Therefore. RV C-11 clearance rate constants were compared with RV loading in 21 patients with aortic valve disease to assess the possible use of this technique for noninvasive evaluation of RV oxidative metabolism. RV free wall C-11 clearance rate constants correlated with the product of systolic pulmonary artery pressure and heart rate for all patients (r = 0.65. p = 0.002). but the relation was stronger if 2 patients with overt RV dysfunction were excluded (r = 0.83. p = 0.001). On the basis of mean pulmonary artery pressures. patients were stratified into subgroups with normal (group I. n = 8) and elevated (group II. n = 13) pulmonary pressures and were compared with 10 normal control subjects. RV C-11 clearance rate constants were significantly higher in group II than in group I and in normal control subjects (p less than 0.05). These data suggest that RV C-11 acetate clearance rate constants can provide noninvasive evaluation of RV oxidative metabolism. This technique may allow serial assessment of RV performance in various cardiac and pulmonary diseases. and particularly of changes associated with therapeutic interventions.
Treatment of hypertension in the elderly: effects on blood pressure, heart rate, and physical fitness, The subjects were 36 hypertensive patients aged 61 to 79 years (mean. 66 years). After a placebo run-in period of one month. each patient was randomly assigned to two months of treatment with 100 mg of metoprolol. 50 mg of captopril. or 25 mg of hydrochlorothiazide plus 2.5 mg of amiloride daily. or placebo. The doses were doubled if diastolic pressure was above 95 mm Hg after one month of treatment. Blood pressure. heart rate. and physical fitness (endurance during a standard cycle ergometer exercise) were measured and side effects assessed after each two-month treatment period. Mean blood pressures were significantly lower after treatment with metoprolol (154/92 mm Hg). captopril (157/92 mm Hg). and hydrochlorothiazide-amiloride (152/91 mm Hg) than after placebo (170/101 mm Hg). Heart rate was significantly lower after treatment with metoprolol (64 beats/minute) than after placebo (77 beats/minute). Exercise endurance was lower after treatment with metoprolol (498 seconds) and hydrochlorothiazide-amiloride (519 seconds) than after placebo (529 seconds) and higher after captopril (541 seconds). More patients reached the target exercise work load after captopril than after the other treatments. No patients withdrew from treatment because of side effects or abnormal laboratory test results. All three active treatments benefited the elderly hypertensive patients and did not lower their physical fitness. Captopril appeared to be more effective than the other two treatments.
Hypertension and the risk of dementia in the elderly, Vascular dementia is the second most common type of dementia in the elderly after the dementia of Alzheimer's disease. Six forms of vascular dementia have been described: multi-infarct dementia. lacunar dementia. Binswanger's subcortical encephalopathy. cerebral amyloid angiopathy. white-matter lesions associated with dementias. and single-infarct dementia. Each is described. Severe dementia is found in 5% of persons over age 65 and in 15% to 20% of persons over age 80 years. Alzheimer's disease accounts for 50% to 60% of cases of severe dementia and vascular dementia for 10% to 20%; 20% of the patients have both disorders. The incidence of vascular dementia. which seems to be declining. is about 7/1.000 persons/year. Hypertension is the most powerful risk factor for all vascular dementias. Vascular dementias can be accurately diagnosed by using clinical and mental state examinations. Diagnostic and Statistical Manual of Mental Disorders criteria. ischemic scores. and computed tomography or magnetic resonance imaging. The most successful treatment of vascular dementia is the prevention of cerebral infarcts. Study of the incidence of vascular dementias and their treatment will be included in the European Trial on Systolic Hypertension in the Elderly (SYST-EUR) of 3.000 elderly hypertensive patients.
Veterans Administration Cooperative Study Group on Hypertensive Agents: effects of age on treatment results, In three double-blind studies of 1.396 hypertensive patients. the age-related effects of hydrochlorothiazide or bendroflumethazide were compared with those of propranolol. nadolol. or captopril. given singly or in combination with a thiazide. Patients in each treatment group were divided into those aged 55 to 69 years and those aged under 55. Whereas no age-related differences were apparent with propranolol. nadolol alone. or captopril alone. in all three studies the blood pressure-reducing effect was found to be greater in the older group of thiazide-treated patients than in the younger thiazide-treated group. The antihypertensive drugs studied are at least as effective in older as in younger hypertensive patients and the antihypertensive response with diuretics is greater in older patients than in younger patients.
Age-related hypotensive effect of placebo and active treatment in patients older than 60 years. European Working Party on High Blood Pressure in the Elderly, Elderly hypertensive patients were randomly assigned to active treatment (n = 365) or placebo (n = 377). The effects of treatment on blood pressure were calculated by subtracting pretreatment blood pressure from the blood pressure at 3 months. In the two treatment groups. the decrease in systolic and diastolic pressures was more pronounced in older patients. However. the slopes of blood pressure change with age were not significantly different in the two treatment groups: systolic. -0.47 and -0.37 mm Hg/year in the active-treated and placebo patients. respectively; diastolic. -0.26 and -0.15 mm Hg/year. respectively. Thus. proving that an observed age-related hypotensive effect is caused by a particular drug requires comparison with a control group on placebo.
Choice of drug treatment for elderly hypertensive patients, It is generally agreed that moderate and severe hypertension in the elderly should be treated. but it is not clear which drug or drugs are most appropriate. Thiazide diuretics are inexpensive and effective. but they are associated with metabolic side effects that are becoming less acceptable as newer agents become available. Beta blockers are effective. but can be associated with central nervous system side effects and are often contraindicated by coexisting disease. Recently. attention has been focused on the newer agents. including calcium antagonists and angiotensin-converting enzyme inhibitors. The advantage of calcium antagonists is that they do not produce metabolic side effects. However. they are expensive and may cause vasodilatory side effects. The angiotensin-converting enzyme inhibitors are effective and relatively free of side effects and may be particularly useful for elderly hypertensive patients with congestive heart failure.
Left ventricular hypertrophy in elderly hypertensive patients: a report from the European Working Party on High Blood Pressure in the Elderly trial, In a double-blind. placebo-controlled trial. 840 elderly hypertensive patients were randomly assigned to treatment with a combination of hydrochlorothiazide and triamterene or placebo; methyldopa or matching placebo was added to the treatment regimen if blood pressures remained high. After adjustment for age. gender. and body mass index. initial electrocardiographic (ECG) voltage measures of RaVL and SV1 + RV5 were significantly related to systolic blood pressure; RaVL was also related to diastolic blood pressure. After one year of treatment. the decrease in RaVL and SV1 + RV5 in the treated patients. adjusted for age and body mass index. were not correlated with the changes in systolic blood pressure. but the decreases in SV1 + RV5 were positively related to the decrease in diastolic blood pressure. After four years of treatment. the decreases in RaVL and SV1 + RV5 were significantly and positively related to the decrease in systolic blood pressure after adjustment for age and changes in body mass index. In a four-year cohort of 222 patients. most of the decreases in ECG voltages in the treated patients and the increases in the placebo patients were found to have occurred during the first year of treatment. The type of treatment (diuretics alone or diuretics plus methyldopa) did not affect ECG voltages during the first year of follow-up. Total and cardiovascular mortality were related to initial amplitude of RaVL. but the significant correlation disappeared after adjustment for age.
Mortality and treated blood pressure in patients of the European Working Party on High Blood Pressure in the Elderly, Elderly hypertensive patients were randomly assigned to treatment with diuretics and methyldopa (n = 352) or placebo (n = 339). and divided into three groups. each according to their blood pressures. after nine months of treatment. Subsequently. 65 placebo patients and 56 treated patients died. A U-shaped relation was seen in treated patients between mortality and systolic blood pressure. and in placebo patients between mortality and diastolic blood pressure. Whereas in treated patients. the highest mortality was seen in patients with the lowest diastolic pressure. the lowest mortality was seen in the group with the highest diastolic pressure. The increased mortality in treated patients with the lowest blood pressure may not be drug-induced. but an expression of deterioration in general health. as indicated by the decreases in body weight and hemoglobin levels found in patients with the lowest blood pressures in previous analyses of these data.
Isolated systolic hypertension in the elderly: an epidemiologic review, Isolated systolic hypertension (ISH) is usually defined as a systolic blood pressure greater than or equal to 160 mm Hg and diastolic blood pressure less than 90 or 95 mm Hg. Systolic blood pressure has been found to increase with age in most populations studied and thus the prevalence of ISH can be expected to increase with age. ISH is more prevalent in elderly women than in elderly men. Estimates of the prevalence of ISH vary according to its definition and the number of blood pressure measurements. There is evidence that the prevalence of ISH is decreasing. Results of a survey of the prevalence of ISH in 11 countries are presented; the estimates among men aged 60 to 69 years ranged from 1% in Israel to 24% in Norway. Only a prospective standardized survey conducted in several countries will reveal the true prevalence of ISH.
Biological correlates of mental activity studied with PET, The development of newer imaging techniques that allow direct investigation of the function of the human brain under normal and pathological conditions has affected the way in which we conceive of the mind/brain relation. In this report the authors use examples from findings obtained with positron emission tomography (PET) to illustrate the highly interactive organization of the brain. Because operations in the brain require the participation of various brain areas. a model that does not require a one-to-one relationship between the physical and mental. but rather allows an association between clusters of physical processes and one or more mental phenomena. may reflect better the relation between physical brain phenomena and mental activities.
An empirical study of diagnostic criteria for delirium, OBJECTIVE: The objective of this study was to determine empirically how many patients are identified as delirious or nondelirious according to DMS-III. DMS-III-R. and ICD-10 criteria. METHOD: Daily. a trained research assistant using a structured instrument to detect the presence of symptoms of delirium evaluated 325 elderly patients who were admitted to a general hospital for acute medical problems. Each patient's symptoms were then compared with these diagnostic criteria sets to determine if the patient met criteria for delirium. RESULTS: DSM-III criteria were the most inclusive: they identified 125 patients as delirious. DSM-III-R identified a somewhat different group of 106 patients as delirious. ICD-10 criteria identified only 30 patients as delirious. CONCLUSIONS: The development of new criteria for delirium (e.g.. DSM-IV) will have to balance the need to define a pure group of patients for research purposes with the need to include cases of clinical interest. Changes in criteria should be based on data such as those presented in this paper.
Neuropsychological performance in medicated and unmedicated patients with Tourette's disorder, OBJECTIVE: To date. there have been no formal investigations of neuropsychological performance in patients with Tourette's disorder who are taking psychotropic medications. The authors conducted this study to provide such information. METHOD: They examined the neuropsychological performance of 96 patients 6-18 years old who met DSM-III-R criteria for Tourette's disorder; 51 of these patients were taking neuroleptic medications and 45 were not. The groups were well matched with regard to age. sex. education. and duration of symptoms. Each group was given a complete neuropsychological test battery as well as instruments rating symptoms of Tourette's disorder. obsessive-compulsive characteristics. and other behavioral disturbances. RESULTS: The patients taking medications did not differ from those not taking medications on any of the neuropsychological. intellectual. or educational measures. In addition. the groups did not differ with regard to level of Tourette's disorder symptoms. CONCLUSIONS: The results of this investigation suggest that patients with Tourette's disorder who do not experience intolerable side effects from neuroleptic medications are able to perform on educational. intellectual. and neuropsychological tests at a level comparable to that of unmedicated patients. These results have positive implications for patients with Tourette's disorder who respond to neuroleptic medications.
Roles of beta 1- and beta 2-adrenoceptors in the mechanism of halothane myocardial sensitization in dogs, The authors investigated the comparative roles of beta 1- and beta 2-adrenoceptors in myocardial sensitization by halothane in dogs. The arrhythmogenic dose (AD) of isoproterenol was determined in the presence of various doses of phenylephrine during halothane anesthesia in dogs. and the influences of 1-metoprolol (beta 1-antagonist) and ICI-118.551 (beta 2-antagonist) on the AD were examined. In the presence of 1-metoprolol. the AD of isoproterenol was significantly greater than the control. but in the presence of ICI-118.551. the AD of isoproterenol was lower. Blood pressure during the arrhythmias was higher in the presence of ICI-118.551 than that in controls. In addition. the AD of ritodrine (beta 2-agonist) was also determined at various doses of phenylephrine. The interaction between phenylephrine and ritodrine in inducing arrhythmias showed hyperbolic isoboles. However. 1-metoprolol completely inhibited the occurrence of arrhythmias induced by ritodrine and phenylephrine. The results suggest that myocardial beta 1-adrenoceptors play an essential role in the genesis of arrhythmias during halothane anesthesia in dogs. whereas beta 2-adrenoceptors do not.
Which drug prevents tachycardia and hypertension associated with tracheal intubation: lidocaine, fentanyl, or esmolol, Eighty patients. ASA physical status II-IV. scheduled for noncardiac surgery. were randomly assigned in a double-blind. placebo-controlled manner to receive a preintubation dose of either placebo. 200 mg lidocaine. 200 micrograms fentanyl. or 150 mg esmolol. Induction of anesthesia was accomplished with 4-6 mg/kg thiopental IV followed immediately by the study drug; 1-1.5 mg/kg succinylcholine was given at minute 1. Laryngoscopy and intubation were performed at minute 2 with anesthesia thereafter maintained with 1 MAC (+/- 10%) isoflurane in 60% nitrous oxide in oxygen at a 5 L/min flow for 10 min. Heart rate was recorded every 15 s and blood pressure every minute from induction until 10 min after intubation. Maximum percent increases in heart rate (mean +/- SE) during and after intubation were similar in the placebo (44% +/- 6%). lidocaine (51% +/- 10%). and fentanyl (37% +/- 5%) groups. but lower in the esmolol (18% +/- 5%) group (P less than 0.05). Maximum systolic blood pressure percent increases were lower in the lidocaine (20% +/- 6%). fentanyl (12% +/- 3%). and esmolol (19% +/- 4%) groups than in the placebo (36% +/- 5%) group (P less than 0.05). but not different from each other (P greater than 0.05). Only esmolol provided consistent and reliable protection against increases in both heart rate and systolic blood pressure accompanying laryngoscopy and intubation.
Continuous infusion of interpleural bupivacaine maintains effective analgesia after cholecystectomy, Twenty-five patients who had undergone elective cholecystectomy were prospectively randomized to receive via an interpleural catheter either a continuous infusion of 0.25% bupivacaine at 0.125 mL.kg-1.h-1 (n = 13) or repeated bolus injections (n = 12) of 0.5% bupivacaine with epinephrine 1:200.000 at 0.4 mL/kg every sixth hour. Adequacy of pain relief was measured by the amount of patient-controlled analgesia morphine required postoperatively and by patient scores on a visual analog scale obtained every sixth hour. Two venous blood samples for measurements of serum bupivacaine levels were obtained from patients in the continuous group at hours 6 and 24; four blood samples were obtained from patients in the bolus group. both immediately before and 30 min after injections at hours 6 and 24. Among the patients receiving the bolus injections. morphine was required 62 +/- 15 (SEM) times over the 24-h study period with total morphine dosage averaging 30 +/- 15 mg. Corresponding values for patients in the continuous groups were 35 +/- 10 times and 23 +/- 5 mg of morphine. The difference was not. however. statistically significant. but when activity during the 2-h time periods immediately before reinjection were examined. patients in the bolus group required and received significantly more morphine than did those in the continuous group (P less than 0.05). Patients in the continuous group had visual analog scale scores that averaged 2.9 +/- 0.6 over the 24-h study period. Patients within the bolus group had visual analog scale scores before and again 30 min after injection that averaged 5.8 +/- 0.8 and 1.8 +/- 0.5. respectively (P less than 0.05).
Comparison of epidurally administered sufentanil, morphine, and sufentanil-morphine combination for postoperative analgesia, Postoperative analgesia provided by epidurally administered sufentanil and/or morphine was evaluated in 45 patients recovering from major gynecologic surgery. At the first complaint of pain in the Postanesthesia Care Unit. patients received a single epidural bolus of 30 micrograms sufentanil (group A). 5 mg morphine (group B). or 30 micrograms sufentanil plus 3 mg morphine (group C) in a randomized blinded fashion. Analgesic efficacy was assessed throughout the 24-h study period with 10-cm visual analog scales. The need for additional postoperative analgesia (patient-controlled analgesia. 1 mg of morphine every 6 min as necessary) and the incidence of adverse effects were also assessed. Patients receiving sufentanil (groups A and C) had significantly faster onset of analgesia than did patients given morphine alone (group B. P less than 0.05). Group B subjects experienced the longest duration of analgesia (B vs A and C. P less than 0.05) and required significantly less patient-controlled analgesia (morphine) than patients in group A (P less than 0.05). No patient developed clinically significant respiratory depression or excessive sedation. and there were no intergroup differences in incidence of pruritus or nausea (P value not significant). The data indicate that a mixture of sufentanil and morphine provides either a more rapid onset of epidural analgesia or reduced patient-controlled analgesia narcotic requirement than respective doses of each agent administered alone.
Effects of H2-receptor blockers on response of cerebral blood flow to normocapnic hypoxia, Cimetidine blunts the increase in cerebral blood flow (CBF) normally observed during hypoxia. It is important. therefore. to know whether other H2-blockers also affect the cerebral circulation adaptation to hypoxia. Cerebral blood flow was measured in 24 awake dogs after an intravenous injection of either saline (control) or one of three H2-blockers: 1 mg/kg ranitidine. 0.4 mg/kg famotidine. or 1 mg/kg roxatidine. These doses are equipotent blockers of H2-gastric receptors. Each dog was studied during normoxia and after 2 and 4 h of normocapnic hypoxia (FIO2. 0.10; FICO2. 0.035). During each set of experimental conditions. a bolus of either saline or one of the anti-H2 drugs was administered. and. 15 min later. radiolabeled microspheres (ruthenium 103. scandium 46. and cerium 141) were injected into the left atrium for measurement of regional CBF. After death by an overdose of thiopental. each dog's brain was excised and fixed in 10% formaldehyde; it was then weighed and dissected by region. with the radioactivity measured in each region using a gamma counter. During hypoxia. PaO2 ranged from 45 to 50 mm Hg. and pH. PaCO2. and hematocrit were within the normal limits. In the control group CBF increased 34% above normoxic baseline levels after 2 h and 31% after 4 h of hypoxia. Ranitidine (1 mg/kg) did not prevent the increase in CBF during hypoxia. but famotidine and roxatidine prevented it. When the dose of ranitidine was doubled (2 mg/kg). it too abolished the increase of CBF induced by hypoxia. In conclusion. H2-receptor blockers could interfere with the adaptation of CBF during hypoxia.
Hemorheologic and coagulative pattern in hypercholesterolemic subjects treated with lipid-lowering drugs, The effects on the coagulative and rheologic pattern of two lipid-lowering drugs. bezafibrate and simvastatin. were studied in 36 hypercholesterolemic subjects. Patients were randomly divided into two groups (18 subjects each) and received bezafibrate R 400 mg/day or simvatatin 10-40 mg/day over a twelve week period. Besides a decrease in plasma fibrinogen and fibrinopeptide A (p less than 0.001 both). bezafibrate induced a reduction of factor VIIc and VIIIc activity (p less than 0.001 both). while antithrombin 3 activity was increased (p less than 0.001) and the hemorheologic pattern was greatly improved (p less than 0.001). Simvastatin caused a slight decrease in factor VIIIc activity and a moderate reduction of beta-thromboglobulin. The efficacy of bezafibrate in reducing the activation of the coagulative cascade and improving the hemorheologic pattern has been confirmed; the peculiar triglycerides- and fibrinogen-lowering effect of the drug. not observed with simvastatin. could be responsible for these modifications.
The effect on skin blood flow of short-term venous hypertension in normal subjects, Plugging of skin capillaries by activated white blood cells is one of the proposed mechanisms by which skin damage may be initiated in chronic venous insufficiency. The aim of this study was to determine whether a microcirculatory deficit was induced in the skin by raising the venous pressure proximally for thirty minutes. Seventeen subjects with no evidence of venous or arterial disease had laser Doppler velocimetry performed in the goiter region of the leg; 8 different subjects had the measurement done on the dorsum of the hand. Peak hyperemic response following three minutes of ischemia was measured before and after a thirty-minute period of sustained venous hypertension applied by a proximal tourniquet inflated to 80 mm Hg. A decrease in the peak flow: baseline flow ratio (median ratio 2.25 before. 1.70 after. p less than 0.02) and an increase in the time taken to reach maximal hyperemia (median time ten seconds before. twenty seconds after. p less than 0.01) were observed after the period of venous hypertension in the lower limb. The second parameter. but not the first. was significantly affected in the upper limb. The authors conclude that a microvascular deficit in the skin is demonstrable after a short period of venous hypertension. This is consistent with the white-cell-trapping theory. but other possible explanations are discussed.
Isoxsuprine in nonproliferative diabetic retinopathy: effect on human retinal circulation assessed by fluorescein angiography--a pilot study, The retinal vessel filling time of 10 patients with early nonproliferative diabetic retinography was measured by fluorescein angiography. Initially. the reproducibility of the authors' standardized fluorescein angiography was assessed by control angiograms on two different dates in each patient. Thereafter. prolonged use (six months) of isoxsuprine sustained release (80 mg/day) led to a nearly 50% reduction of the arterial filling time and a nearly 25% reduction of the arteriovenous filling time. whereas no changes were seen in control patients. This effect of isoxsuprine might be explained by an increase of red cell deformability and. concomitantly. a decrease of platelet adherence in the microcirculation of patients with diabetic mellitus.
Cardiac arrest due to spontaneous coronary artery dissection in a patient with coronary ectasia--a case report, Spontaneous coronary artery dissection is a rare event and only in a few patients has the diagnosis been angiographically confirmed during life. A spontaneous dissection of the right coronary artery was detected as a cause of out-of-hospital cardiac arrest in a patient with coronary artery ectasia.
Transcranial Doppler in reversible migrainous vasospasm causing cerebellar infarction: report of a case, A young woman with a history of classic migraine suffered a large cerebellar infarction. Comprehensive evaluation did not disclose any potential causes for the stroke and she had no other risk factors. Transcranial Doppler (TCD) was useful in identifying vasospasm of the vertebral arteries. Following treatment with propranolol. angiography and repeat TCD revealed resolution of the vasospastic disorder. TCD is a useful noninvasive tool in detecting vasospasm associated with ischemic lesions in certain patients with migraine.
A rheolytic system for percutaneous coronary and peripheral plaque removal, A method for plaque dissolution has been identified that percutaneously delivers a pulsatile high-velocity stream of saline to the site of an atheromatous lesion within a coronary or peripheral artery. In vitro evaluation and in vivo canine and porcine testing were performed using this 'rheolytic' system to determine its feasibility in ablating calcified plaque and soft thrombotic tissue. A prototype rheolytic guidewire capable of providing 30.000 psi of internal pressure was designed to fit within the guidewire lumen of a standard percutaneous transluminal coronary angioplasty catheter. An additional over-the-wire rheolytic catheter was fabricated to follow a standard .014-inch guidewire. The rheolytic devices were tested in vitro with simulated atheromatous and thrombotic lesions to evaluate the size and quantity of the particulate effluent. The particulate was then sterilized. mixed with saline. and introduced percutaneously into the animal kidney and heart for evaluation. The in vitro studies demonstrated that the rheolytic catheter and guidewire were able to follow both a coronary and femoral arterial model and successfully ablate the simulated lesions. The particle size for osseous. muscular. and cartilagenous tissue ranged from 2 to 6 micrometers; for fresh human plaque the particles ranged from 2 to 15 micrometers. Injection of cartilagenous and plaque particles into the animal model caused very slight regions of necrosis but no clinical sequelae. Applications of the rheolytic devices to the animal femoral artery demonstrated that both devices could ablate and cross calified or soft thrombosed lesions without damage to the vessel wall; the rheolytic catheter provided a debulking of the plaque.
Comparison of coronary angiographic features and oral dipyridamole thallium 201 tomography, Coronary angiography and left ventriculography is commonly used to identify those patients with incomplete infarctions and therefore. a need for revascularization. The authors compared coronary angiography and left ventriculography with thallium 201 tomography using oral dipyridamole to identify patients with potential ischemia in the infarct zone indicating viable tissue. Forty-five patients (37 men. 8 women) with acute myocardial infarctions (29 anterior. 16 inferior) who received intravenous thrombolytic therapy were studied. On the basis of the left ventriculograms. only 16 patients were judged to have residual function in the infarct zone. Six of these patients had no thallium redistribution in the infarct zone. indicating lack of residual ischemia. Of the 29 patients with no residual function in the infarct zone. 18 had redistribution in the infarct zone. suggesting residual ischemic myocardium and thus viable tissue. Among the 32 patients with open infarct vessels. 15 had no redistribution in the infarct zone. but of the remaining 13 patients with occluded infarct vessels. 9 had redistribution in the infarct zone indicating residual ischemia and thus viable tissue. The authors' data suggest that neither wall motion analysis by left ventriculography nor the angiographic status of the infarct vessel identifies those patients with residual ischemia as evidenced by thallium tomography using oral dipyridamole.
Adverse cutaneous reactions due to macrolides, Macrolides. which are widely prescribed and seldom produce hypersensitivity reactions. are considered to be safe drugs. We present five patients with generalized skin reactions due to erythromycin and/or spiramycin. proved by oral challenge tests. One patient showed reactions to both erythromycin and spiramycin. All skin prick and patch tests and histamine release tests with both macrolides were negative.
Emergency management of childhood bronchial asthma: a multicenter survey, Bronchial asthma is one of the most common diseases of childhood. This survey was conducted to examine the existing practices in the emergency management of asthma. The questionnaires were sent to 233 Directors of Pediatric Emergency Services in Pediatric Residency Training Programs and 118 (51%) responses were received. The results of this survey demonstrate that clinical scoring systems are not commonly used while pulmonary function tests are frequently obtained on symptomatic patients with bronchial asthma. Sixty-seven of the surveyed institutions do not routinely administer oxygen to all wheezing patients. Despite recent studies showing the effectiveness of inhaled beta adrenergic agents. injectable beta agonists remain the initial intervention of choice in most institutions. Corticosteroids are usually utilized at the time of the patient's disposition and inhaled anticholinergic agents are frequently used.
Theophylline inhibits early and late asthmatic reactions induced by allergens in asthmatic subjects, To determine whether oral slow-release theophylline inhibits asthmatic reactions and the associated increase of airway responsiveness to methacholine induced by allergens. we examined six asthmatic subjects who developed a dual asthmatic reactions after allergen bronchoprovocation with Dermatophagoides pteronyssinus or with grass pollen. We gave oral slow-release theophylline and placebo to each subject for seven days in two series of experiments in a double-blind. randomized. crossover study. The individual daily dose of theophylline (4.7 to 16.6 mg/kg/day. divided into two doses) was calculated for each subject by measuring individual theophylline clearance and optimal daily dosage. During treatment with placebo. the subjects developed dual asthmatic reactions. ie. FEV1 decreased from 4.1 +/- 0.17 L before bronchoprovocation to 3.2 +/- 0.14 L at 15 minutes and to 3.2 +/- 0.19 L at seven hours after allergen bronchoprovocation. By contrast. during active treatment FEV1 decreased from 4.2 +/- 0.28 L to 3.9 +/- 0.26 L at 15 minutes. and to 3.8 +/- 0.13 L at seven hours (both cases. P less than .03 compared with placebo). Mean serum theophylline concentration was 13.2 +/- 0.6 mg/L. Although 1 week's treatment with slow-release theophylline did not modify significantly either prechallenge airway responsiveness to methacholine or its increase after allergen inhalation challenge. in five out of six subjects theophylline significantly inhibited the increase of airway responsiveness to methacholine induced by allergens compared to placebo and control day (P less than .05). These results suggest that slow-release theophylline may inhibit allergen-induced asthmatic reactions and the associated increase of airway responsiveness. suggesting some antiinflammatory effects for this drug.
Double-blind comparison of cetirizine and placebo in the treatment of seasonal rhinitis, The efficacy and safety of cetirizine were evaluated in 419 patients with seasonal allergic rhinitis. Using a 4-way. double-blind randomization schedule. patients were given a 1-week course of once daily cetirizine (5. 10. or 20 mg) or placebo. Patient and physician efficacy ratings corresponded. indicating superiority of cetirizine to placebo (P less than .05) in reducing symptom severity scores for sneezing. rhinorrhea. ocular pruritus. nasal pruritus. watering of the eyes. and redness of the eyes. All cetirizine doses achieved higher efficacy ratings (72.7%. 79.2%. and 75.7%. respectively) than placebo (52.9%; P less than .05) by the physician's global assessment. Cetirizine was well tolerated. with sedation being the most common adverse experience. increasing in frequency at higher doses. A dose-response relationship was evident for selected symptoms. and the once daily 5-mg dose was found to be an effective minimum dose.
Anomalous macular vessels: case report and review of the recent Japanese literature, We examined a 19-year-old woman with large macular vessels who had temporarily impaired visual acuity. The anomalous macular vessels had arteriovenous shunts and were associated with abnormal capillary networks. In a review of the recent Japanese literature. we found another eight patients with anomalous macular vessels who had undergone fluorescein angiography. We prefer the term anomalous macular vessels to describe this condition.
Krypton laser-induced lens opacity as a complication of retinal photocoagulation, Lens opacification is a well-documented complication of argon laser photocoagulation. particularly in eyes with preexisting cataracts. In eyes with media opacity. the krypton laser is frequently used for its superior penetrating qualities. To date. lens opacification from krypton application has not been documented. We report such a case in a cataractous eye with a vitreous hemorrhage undergoing panretinal photocoagulation. Factors previously implicated in the etiology of laser-induced lens damage were not present. The opacities were similar to those produced by the argon laser. We present a mechanism for understanding laser-induced lens damage and speculate on the difference between the interaction of argon versus krypton laser energy with lens constituents.
Histologic evaluation of the larynx in sudden infant death syndrome, Seventy-four larynges removed at death from children who died of sudden infant death syndrome (SIDS) have been studied by serial sectioning in the transverse plane. An increase in subepithelial glandular tissue is seen in many specimens. and the reduction in the available subglottic area has been measured with the Measuremouse Image Intensifying system. This preliminary report confirms that in some of these children with SIDS. particularly around the age of 3 months. there is a potentially lethal reduction in subglottic airway secondary to an increase in mucus-secreting glands. possibly from an associated mild upper respiratory tract infection. Accepting that adequate control infants within this age group who have not had any trauma to the laryngotracheal area are not available. these findings offer a possible explanation for what are always tragic events.
Cholesterol cysts of the temporal bone: diagnosis and treatment, Cholesterol cyst (or granuloma) of the temporal bone. a recognized clinical entity distinct from cholesteatoma. is more common than previously thought. Apparently it is caused by obstruction of previously pneumatized temporal bone air cells. Surgical cure is achieved by drainage and reestablishment of normal pneumatization. This paper reviews 14 cholesterol cysts of the temporal bone. emphasizing the importance of preoperative imaging and surgical approach. Use of magnetic resonance imaging differentiates cholesterol cysts from cholesteatoma or other neoplasms. Computed tomography delineates the location of the lesion and defines temporal bone anatomy essential to surgical approach. The two studies together allow the surgeon to properly plan drainage. as in the case of a cholesterol cyst. versus excision or exteriorization. as in the case of cholesteatoma. The infralabyrinthine approach to a petrous apex cholesterol cyst is the procedure of choice when hearing preservation is desired.
Cochlear implants as a contraindication to magnetic resonance imaging, Magnetic resonance imaging poses little risk to the majority of patients undergoing scanning. However. cochlear implantation should pose a contraindication to this imaging process. This conclusion is based on several findings of in vitro testing of three cochlear implants: the 3M/House and 3M/Vienna designs and the Nucleus device. Specifically. tremendous torques are generated by each of these devices when they are introduced into the coil of a magnetic resonance imager; in addition. the 3M products not only were noted to induce an electrical current. but also were significantly magnetized and rendered afunctional. The clinical implications are discussed.
Italian experience of voice restoration after laryngectomy with tracheoesophageal puncture, This report concerns 102 cases of tracheoesophageal puncture performed as a means of secondary voice restoration after total laryngectomy. in 70 patients proving unable to learn esophageal speech and as a treatment of choice in a further 32 cases. Complications arose in 21 cases but were generally minor and could be overcome. Results were favorable in 45 of 70 and 29 of 32 cases. respectively. The method was considered effective. particularly when supported by the patient's determination to learn a verbal communication method.
Radiographically confirmed cochlear otospongiosis among the Chinese, A high-resolution computed tomography (HRCT) study on 55 patients with surgically confirmed clinical otosclerosis confirms the existence of cochlear otospongiosis among the Chinese. Positive radiographic results of cochlear otospongiosis (13 ears. 12%) were found in patients with mixed-type deafness but in none with conductive hearing loss. Although there is a positive correlation between audiologic and radiographic findings. the HRCT results showed a lower positive rate and less severity than anticipated from the audiologic results. However. compared with the occurrence and extension of radiographic findings in similar studies of white people. it would seem to support our previous contention that the disease is indeed milder in Chinese people. Cochlear otospongiosis with extensive labyrinthine demineralization was found in three young patients with rapidly progressive hearing loss. This is important evidence of the overlooked fact that cochlear otospongiosis may also be one of the causes of sensorineural hearing loss in the Chinese. Thus. a high index of suspicion of the existence of this inner ear disorder is of paramount importance. and in such cases an HRCT study should be performed and sodium fluoride given to prevent further hearing deterioration.
Cutaneous cellulitis, Cellulitis has long been postulated to be the result of antecedent bacterial invasion with subsequent bacterial proliferation. Nonetheless. the difficulty in isolating putative pathogens from cellulitic skin has served to cast doubt on this hypothesis. In this regard. the skin is provided with a unique set of lymphoid and reticular cells with the capacity to secrete lymphokines and cytokines. These substances rapidly reduce the number of viable bacteria from infection by enhancing the infiltration of skin by circulating macrophages and neutrophils. The warmth and erythema associated with cellulitis are most likely produced both by a small number of residual bacteria and by fragmented bacterial remnants. and amplified by the lymphokines that are secreted in response to antigenic challenge. Anti-inflammatory agents may play a significant role in enhancing the resolution of infection by reducing the production of soluble mediators by these intra-epidermal immunocompetent cells.
Treatment of psoriasis with piritrexim, a lipid-soluble folate antagonist, Methotrexate is an effective and convenient treatment for severe psoriasis whose use is limited by the development of hepatic fibrosis and cirrhosis in a small number of patients. The mechanism of hepatotoxicity is unknown. but it is believed to be the result of intracellular polyglutamation and prolonged retention of methotrexate within the cell. Piritrexim isethionate is a lipid-soluble antifolate that has a mechanism of action similar to that of methotrexate. Since it is not polyglutamated. piritrexim could be effective in the treatment of psoriasis without the associated long-term hepatotoxicity. A 12-week phase I/II clinical trial of severe chronic plaque psoriasis assessed the safety and efficacy of oral piritrexim therapy. Based on experience gained from oncologic trials. each patient received a twice-daily dosage for 5 consecutive days every 2 weeks. Dosages ranged from 25 to 100 mg twice a day. Improvement in both lesion scores and percentage of body involvement was significant at a dose of 50 mg or more twice daily. Fifteen of 19 patients who completed 12 weeks of therapy demonstrated greater than 50% improvement in lesion scores. Improvement was limited by recrudescence of lesions over the 9-day rest period. Adverse experiences were minimal and dose related. Piritrexim is efficacious in the treatment of psoriasis.
Normal peroxisomal function and absent skeletal manifestations in Conradi-Hunermann syndrome, We describe a child with the classic cutaneous and ocular manifestations of Conradi-Hunermann syndrome in whom repeated roentgenographic studies during the first 2 years of life revealed no evidence of epiphyseal stippling. The findings in this case and others from the literature suggest that skeletal changes may be absent or show limited expression in patients with this condition and that chondrodysplasia punctata should not be considered an invariable feature of Conradi-Hunermann syndrome. Studies of peroxisomal function in our patient failed to confirm two previous reports of a significant reduction in activity of the peroxisomal enzyme dihydroxyacetone phosphate acyltransferase in this disorder.
Spontaneous regression in Merkel cell (neuroendocrine) carcinoma of the skin, In two Japanese women. 68 and 88 years old. Merkel cell (neuroendocrine) carcinoma of the face developed. Their tumors regressed after biopsy was performed. a rare occurrence. Histological and electron microscopic examination showed apoptosis. cellular necrosis. and an infiltration composed mainly of lymphocytes in the tumors. These changes may have been related to the mechanism of regression. It is interesting that our two patients were women. as was another patient described with Merkel cell carcinoma regression. in light of the fact that the prognosis of this tumor is sex dependent.
Sclerosing panniculitis. A clinicopathologic assessment, Six patients with well-circumscribed. indurated. inflammatory plaques of the lower extremity are described. Incisional biopsy specimens in each patient revealed fat necrosis. sclerosis. and a lobular panniculitis. These patients are similar to those described under the designations hypodermitis sclerodermaformis or lipodermatosclerosis. The name sclerosing panniculitis is proposed to unify these conditions. The pathogenesis is unknown. although a role for venous stasis or previous thrombophlebitis has been proposed. Systemic or local anti-inflammatory therapies have not been clinically effective.
Mortality among aerial pesticide applicators and flight instructors: a reprint [corrected and republished article originally printed in Arch Environ Health 1990 Sep-Oct;45(5):295-302, A cohort mortality study was conducted of male aerial pesticide applicators and flight instructors identified from computerized Federal Aviation Administration medical examination records from 1965-1979. Vital status of 9.677 applicators and 9.727 instructors was determined through January 1. 1980. and standardized mortality ratios (SMRs) were calculated. The overall SMR was 127 for applicators (699 deaths) and 93 for instructors (454 deaths). Fatalities from nonmotor vehicle accidents. mostly aircraft crashes. were in notable excess (SMR = 1.168 among applicators. 630 among instructors). whereas deaths from most chronic diseases. including all cancer. was below expectation (e.g.. for arteriosclerotic heart disease. SMR = 52 among applicators and 50 among instructors). The ability of the study to assess cancer risk among applicators was limited by a relatively brief follow-up period. However. 8 applicators (SMR = 171). but only 1 flight instructor (SMR = 24). died of leukemia. and small. nonsignificant risk elevations for some other cancer sites among applicators were observed and warrant continued follow-up.
Leukemia and non-Hodgkin's lymphoma and residential proximity to industrial plants, The risks of developing leukemia and non-Hodgkin's lymphoma from living near industrial facilities were evaluated among men from Iowa and Minnesota in a population-based. case-control study. We found a statistically significant increase in the risk of developing non-Hodgkin's lymphoma (RR = 1.4) and a slight. nonsignificant excess for leukemia (RR = 1.2) among individuals who lived .8-3.2 km (1/2-2 miles) from a factory. Risks were greater for certain histologic types: follicular lymphoma (RR = 1.5). acute lymphocytic leukemia (RR = 5.4). and acute myelocytic leukemia (RR = 2.2). For non-Hodgkin's lymphoma (but not for leukemia). the relative risks for those living within .8 km (1/2 mile) of a factory were similar or slightly larger than for those living .8-3.2 km (1/2-2 miles) from a factory. Risks did not increase with duration of residence near a factory. The elevated risks of non-Hodgkin's lymphoma were particularly associated with residing near stone. clay. or glass industry facilities. The risk of developing leukemia was greater among persons who resided near chemical and petroleum plants. These preliminary findings raise the possibility that general environmental exposure associated with certain industrial activities may elevate the risk of developing leukemia and non-Hodgkin's lymphoma. Evaluation of data on proximity to industrial plants from studies in other geographic locations is needed to determine whether our results represent a meaningful association.
Respiratory hospital admissions associated with PM10 pollution in Utah, Salt Lake, and Cache Valleys, This study assessed the association between respiratory hospital admissions and PM10 pollution in Utah. Salt Lake. and Cache valleys during April 1985 through March 1989. Utah and Salt Lake valleys had high levels of PM10 pollution that violated both the annual and 24-h standards issued by the Environmental Protection Agency (EPA). Much lower PM10 levels occurred in the Cache Valley. Utah Valley experienced the intermittent operation of its primary source of PM10 pollution: an integrated steel mill. Bronchitis and asthma admissions for preschool-age children were approximately twice as frequent in Utah Valley when the steel mill was operating versus when it was not. Similar differences were not observed in Salt Lake or Cache valleys. Even though Cache Valley had higher smoking rates and lower temperatures in winter than did Utah Valley. per capita bronchitis and asthma admissions for all ages were approximately twice as high in Utah Valley. During the period when the steel mill was closed. differences in per capita admissions between Utah and Cache valleys narrowed considerably. Regression analysis also demonstrated a statistical association between respiratory hospital admissions and PM10 pollution. The results suggest that PM10 pollution plays a role in the incidence and severity of respiratory disease.
Effects of calcium on vascular smooth muscle tone, It is generally acknowledged that calcium plays a major role in the generation of vascular tone. However. in recent years it has become increasingly evident that relatively calcium-insensitive pathways of excitation-contraction coupling also exist in the vascular smooth muscle cell. Possible mechanisms of vascular smooth muscle contraction and their possible role in the pathophysiology of hypertension are reviewed. The rationale for the use of calcium channel blockers in the treatment of hypertension is discussed.
Renal vascular effects of calcium channel blockers in hypertension, Recent evidence suggests that calcium channel blockers have specific effects on renal hemodynamics in patients with hypertension and may also slow the progression of chronic renal failure. When these agents are studied in vitro. their predominant effect is to reverse afferent arteriolar vasoconstriction induced by catecholamines or angiotensin II. Because efferent resistance may remain high. glomerular filtration rate rises while renal blood flow remains low. The effects in vivo are less consistent. In human hypertension. calcium channel blockers lower renal resistance and may raise both renal blood flow and glomerular filtration rate. In experimental models of chronic renal disease. calcium channel blockers slow the progression of renal damage; however. variable effects on renal hemodynamics have been found. Other factors implicated in the progression of renal damage. including compensatory renal hypertrophy. platelet aggregation. and calcium deposition. may also be favorably influenced by these agents. Recent studies suggest that calcium channel blockers may have similar protective effects in patients with hypertension and chronic renal disease.
Sustained calcium channel blockade in the treatment of severe hypertension. A two year experience, Thirty-nine patients with severe hypertension (diastolic blood pressure greater than 120 mm Hg) predominantly drawn from an inner-city population were placed on nifedipine gastrointestinal therapeutic system (GITS) for long-term treatment to achieve a sustained diastolic blood pressure less than 95 mm Hg. Fourteen patients failed to complete 6 months of therapy. For the 25 who remained in treatment for 6 months or more. systolic/diastolic blood pressure reductions were 62 +/- 5/40 +/- 2 mm Hg at 6 months; for those followed more than 12 months (n = 18). 58 +/- 7/37 +/- 3 mm Hg at 12 months; and for those followed more than 18 months (n = 11). 54 +/- 6/37 +/- 3 mm Hg at 18 months. Overall. 75% of these severely hypertensive patients were controlled with nifedipine GITS alone; 80% required 90 mg/day or more. During the two years of observation. no patient had a severe medical event. and 44% of those who entered remain in treatment. Left ventricular hypertrophy. as determined by echocardiography. diminished significantly during the course of treatment. These results indicate nifedipine GITS is well-tolerated and effective as monotherapy in the treatment of severe hypertension.
Nifedipine gastrointestinal therapeutic system in the treatment of hypertension. Results of a multicenter trial. The Modern Approach to the Treatment of Hypertension (MATH) Study Group, Nifedipine. in the gastrointestinal therapeutic system (GITS) formulation. a controlled-release formulation for once-a-day administration. was evaluated in the Modern Approach to the Treatment of Hypertension (MATH) trial. In this study conducted at 127 centers. 1155 patients with mild-to-moderate hypertension representative of the spectrum seen in practice were included in the analyses of effectiveness. After a 2 week placebo period. nifedipine GITS therapy was started at 30 mg/day and was titrated to a maximum dose of 180 mg/day over 6 weeks. Response criteria were a sitting diastolic blood pressure less than 90 mm Hg and a decrease of greater than or equal to 10 mm Hg. After titration. patients were observed for 12 weeks during treatment. At the final visit. nifedipine GITS significantly (P less than .0001) reduced sitting systolic blood pressure 17 +/- 14 mm Hg (mean +/- SD). and sitting diastolic blood pressure 14 +/- 8 mm Hg. Similar highly significant reductions in standing blood pressure were observed. For all subjects. 76% achieved goal blood pressure response during titration. More than 50% were controlled on doses of 30 to 60 mg/day. At the final visit blood pressure reductions in men and women were similar. except for a significantly greater decrease in sitting systolic pressure for women. A similar proportion of blacks responded compared with whites. and reductions in sitting systolic and diastolic blood pressure were also similar in the 2 groups. Nifedipine GITS had no effect on renal function. serum potassium. or total. HDL. or LDL cholesterol. Uric acid was reduced by 0.5 mg/dL (P less than .001).
Antihypertensive effectiveness of nifedipine gastrointestinal therapeutic system in the elderly. The Modern Approach to the Treatment of Hypertension (MATH) Study Group, The Modern Approach to the Treatment of Hypertension (MATH) trial was conducted to determine the therapeutic safety and efficacy of the once-a-day nifedipine gastrointestinal therapeutic system (GITS) formulation in a large and diverse cohort of patients with mild-to-moderate hypertension. One of the goals of the MATH study was to evaluate the clinical utility of nifedipine GITS in elderly hypertensives. This analysis compares the safety and efficacy of nifedipine GITS in elderly patients (greater than or equal to 65 years of age) and nonelderly patients (adults less than 65 years of age). A total of 222 elderly and 933 nonelderly patients from 127 centers were evaluated. Following a 2 week placebo washout phase. patients were titrated over 1 to 6 weeks on nifedipine GITS 30 to 180 mg/day. increasing in 30 mg increments to achieve goal blood pressure. defined as sitting diastolic blood pressure of less than 90 mm Hg and a 10 mm Hg decrease from baseline. Therapy was maintained at the optimal dose for an additional 12 weeks. Hemodynamic and laboratory parameters were assessed at baseline and at the final treatment visit. Baseline parameters were comparable between patient groups except for systolic blood pressure. which was significantly greater in the elderly compared with nonelderly patients (164 +/- 18 v 150 +/- 14 mm Hg. respectively. P less than .0001). After 12 weeks of therapy with nifedipine GITS. sitting and standing systolic and diastolic blood pressure was significantly decreased from baseline for both elderly and nonelderly patients.
Therapeutic considerations in the elderly hypertensive. The role of calcium channel blockers, Hypertension is an extremely common problem in the elderly. The optimum antihypertensive agent to use in this population is not certain. In this paper. the factors influencing the choice of antihypertensive therapy are reviewed. They include efficacy. safety. comorbidity. utility in special populations. drug interaction. dosage schedule. cost. the mechanisms of action of the drug. and the pathophysiology of the patient's hypertension. Calcium channel blockers are effective and safe in the elderly. They improve other conditions frequently seen in that population and. with the exception of cardiac conduction abnormalities associated with some calcium channel blockers. do not adversely affect other comorbid diseases. They work well together with other antihypertensives and as vasodilators. they may be specifically appropriate in elderly hypertensives. whose hypertension is associated with reduced cardiac output and increased peripheral vascular resistance. Once- and twice-a-day preparations are available to foster compliance. but calcium channel blockers are expensive.
Pathophysiology of hypertension in blacks, The pathophysiology of hypertension in the black population differs to some extent from that of the nonblack population. Although black hypertensives exhibit enhanced sodium retention. expanded plasma volume. lower plasma renin activity. and a greater increase in blood pressure in response to high levels of Na+ intake compared with nonblack hypertensives. there is considerable heterogeneity in these studies. Alterations in ion transport mechanisms. such as a decrease in Na+K(+)-ATPase activity and Na+K+ cotransport. have been demonstrated in the black hypertensive population. Those features provide the physiologic basis for the differential response to monotherapy with diuretics and. perhaps. with calcium channel blockers. that is observed in black hypertensives. particularly when compared with responses to beta-blockers or angiotensin converting enzyme inhibitors.
Different plasma ionized calcium correlations with blood pressure in high and low renin normotensive adults in Utah, Plasma ionized calcium levels have been shown to be lower than normotensive control levels in hypertensive patients with low plasma renin activity and higher than control levels in hypertensive patients with high renin activity; they did not differ between high and low plasma renin activity groups of normotensive controls. To see if ionized calcium may have different relationships with blood pressure across renin categories in normotensive individuals. plasma ionized calcium was measured on 875 healthy individuals. ages 3 to 83. who had never been diagnosed as having hypertension. Blood pressures were measured in the sitting. standing. and supine positions. along with pressures measured during two stress maneuvers: isometric handgrip and a 50 degrees tilt from a supine position. There was no linear correlation of blood pressure with plasma ionized calcium in the entire sample of youths or adults. However. after dividing the adults into tertiles based on plasma renin activity. there were significant inverse correlations between ionized calcium and systolic and diastolic blood pressure in the low renin group (r = -0.16 to -0.25. P less than or equal to .05). while the systolic blood pressure correlations were significantly positive in the high renin group (r = 0.14 to 0.22. P less than or equal to .05). Adults with normal renin levels did not have any significant correlations of plasma ionized calcium with blood pressure. These confounding effects of renin were greater for systolic than for diastolic blood pressure. These correlations within renin tertiles occurred even though there were no differences in mean blood pressure. plasma ionized calcium. total plasma protein and plasma sodium across renin categories.
Arterial blood pressure. Correlation with erythrocyte count, hematocrit, and hemoglobin concentration, The relationship between arterial blood pressure and red blood cell variables was investigated in 1013 unselected persons with a blood pressure range of 90 to 225 mm Hg systolic and 50 to 145 mm Hg diastolic. Statistically significant correlations were demonstrated between mean (as well as systolic and diastolic) arterial blood pressure and red blood cell count (r = 0.27; P less than .0001). hematocrit (r = 0.28; P less than .0001). and hemoglobin concentration (r = 0.29; P less than .0001). Average arterial blood pressure was higher in men than in women (133 +/- 16/83 +/- 10 v 124 +/- 16/79 +/- 9 mm Hg. P less than .0001) and this was associated with higher values for erythrocyte count. hemoglobin concentration. and hematocrit in men as compared to women. The significant correlation of blood pressure and hematocrit. which represents one important determinant of blood viscosity. points to a role for rheological factors in the long-term control of blood pressure. Moreover. it might be speculated that the sex difference in blood pressure as observed in the present study may be due. at least in part. to stimulated erythropoiesis in men as compared to women.
Extended release felodipine in essential hypertension. Variations in blood pressure during whole-day continuous ambulatory recording, Intraarterial blood pressure (BP) monitoring during free ambulation (Oxford technique) was carried out in 12 essential mild-to-moderate hypertensive patients undergoing 4 weeks treatment with felodipine. 10 mg given once daily in an extended release formulation. Compared to placebo. felodipine significantly reduced systolic and diastolic blood pressure throughout 24 h. The greatest reduction was observed at 10 AM. 3 h after drug administration (-32 +/- 6/-24 +/- 5 mm Hg for systolic and diastolic BP. respectively. P less than .001). Hourly BP values remained significantly lower up to and including the 24th hour during felodipine extended release treatment (-18 +/- 5/-11 +/- 3 mm Hg. P less than .001). Felodipine extended release also reduced 24 h blood pressure variability. evaluated on the standard deviation of each hourly mean (from 16.3 +/- 0.9/12.6 +/- 0.6 to 13.4 +/- 0.6/10.4 +/- 0.6 mm Hg. P less than .01). Furthermore. absolute BP values dropped significantly at the peaks of dynamic exercise (bicycle ergometer: from 248 +/- 13/123 +/- 11 to 204 +/- 24/102 +/- 13 mm Hg. P less than .001). isometric exercise (hand grip: from 232 +/- 18/133 +/- 16 to 180 +/- 20/101 +/- 16 mm Hg. P less than .001). and cold pressor test (from 229 +/- 20/127 +/- 14 to 178 +/- 22/99 +/- 15 mm Hg. P less than .001). In conclusion. felodipine extended release exerts a good antihypertensive effect which is maintained for 24 h and reduces the level of blood pressure peaks reached under different physical stresses.
Relationship between blood pressure, plasma insulin and triglyceride concentration, and insulin action in spontaneous hypertensive and Wistar-Kyoto rats, Previous results have shown that spontaneously hypertensive rats (SHR) are insulin resistant. hyperinsulinemic. and hypertriglyceridemic as compared to Wistar-Kyoto rats (WKY). Since SHR rats also have higher blood pressures than WKY rats. the current study was initiated in an attempt to evaluate the relationship between the magnitude of blood pressure and the differences in insulin and lipid metabolism seen in SHR and WKY rats. The experimental variables to be compared were determined in three groups of SHR and WKY rats. varying in age: Group I rats were 6 to 7 weeks of age; Group II rats were 8 to 9 weeks old; whereas Group III rats were 12 to 13 weeks of age. Maximal insulin-stimulated glucose transport by adipocytes isolated from SHR rats was significantly lower (P less than .005) than isolated adipocytes from WKY rats in all three groups. whereas plasma insulin and triglyceride concentrations were significantly higher (P less than .005). Blood pressure was also higher in SHR than in WKY rats within each group. Since absolute values for maximal insulin-stimulated glucose uptake did not change statistically as the rats grew older. the magnitude of the decrease in SHR rats was similar in each group. The increase in plasma insulin and triglyceride concentration observed in SHR rats was also the same in each group. but the absolute values increased with age in both SHR and WKY rats. However. blood pressure rose significantly with age in SHR. but not WKY rats. leading to a progressive increase in the degree of hypertension in SHR rats. These results support the view that hypertension. per se. does not lead to insulin resistance. hyperinsulinemia. and hypertriglyceridemia.
Proximal tubular alpha 2-adrenoceptor density in the spontaneously hypertensive rat, In the kidney of the spontaneously hypertensive rat (SHR). alpha 2-adrenoceptors are increased and may be related to hypertension. We measured alpha 2-adrenoceptor density and characteristics in a proximal tubule suspension with the alpha 2-adrenoceptor antagonist. 3H-rauwolscine. SHR had a significantly greater density of alpha 2-adrenoceptors when compared to their normotensive controls. the Wistar-Kyoto (WKY) rats (146 +/- 13 v 58 +/- 7 fmol/mg protein; P less than .001). Competition experiments determined the alpha 2-adrenoceptor to be an alpha 2B-subtype. Agonist competition curves were shallow and exhibited pseudo-Hill slopes of less than 1. indicating that they bind to both high and low affinity receptor sites. In summary. alpha 2-adrenoceptors are increased in the proximal tubule of SHR and appear to be of the alpha 2B-subtype. An increase in alpha 2-adrenoceptors may be related to abnormalities in hypertension.
Inhibition of norepinephrine release from vascular adrenergic neurons by oral administration of beta-blocker in DOCA-salt hypertension, The ability of a beta-blocker to inhibit vascular sympathetic nerve activity associated with hypertension was studied in DOCA-salt hypertension in rats. A seven week treatment of DOCA and salt resulted in a significant increase in the systolic blood pressure of the uninephrectomized rats. The administration of propranolol (40 mg/L and 80 mg/L in drinking water) had little effect on the development of hypertension. After a three week administration of propranolol. perfused mesenteric vasculatures were prepared in vitro. and endogenous norepinephrine release as well as vascular responsiveness were examined. Endogenous norepinephrine and pressor responses during periarterial nerve stimulation were greater in the untreated DOCA-salt hypertensive rats than in the normotensive rats. In the DOCA-salt hypertensive rats treated with propranolol. the stimulation-evoked norepinephrine release and pressor responses were significantly attenuated. at both doses. compared with the untreated DOCA-salt hypertensive rats. These results demonstrate that propranolol inhibited the vascular sympathetic nerve activity in DOCA-salt hypertensive rats. This occurrence suggests a possible role of presynaptic beta-adrenoceptors in the regulation of sympathetic tone in DOCA-salt hypertension.
The effect of Ca and Mg supplementation and the role of the opioidergic system on the development of DOCA-salt hypertension, The effect of calcium and magnesium supplementation and the role of opioidergic system was examined in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. The rats were divided into four groups receiving standard laboratory rat diet (control group; n = 9); a calcium-rich diet with 2% CaCl2 added (Ca-group; n = 12); a magnesium-rich diet with 0.5% MgO added (Mg-group; n = 11); and a calcium and magnesium-rich diet with 2% CaCl2 and 0.5% MgO added (Ca/Mg-group; n = 11); each diet contained 7% NaCl. After four weeks on these diets. the rats were decapitated and blood was obtained for the measurement of plasma electrolytes. intraerythrocyte sodium. potassium and magnesium content (RBC-Na. -K. in mEq/L cells and RBC-Mg. in mg/dL cells) and plasma beta-endorphin concentration (beta-END. in pg/mL). In the control group. systolic blood pressure and RBC-Na were obviously higher than in the other groups. Plasma beta-endorphin concentration was 45.1 +/- 13.4 in the control group. 70.7 +/- 17.4 in the Ca-group (P less than .05 v control group). 58.0 +/- 20.1 in the Mg-group and 83.8 +/- 24.8 in the Ca/Mg-group (P less than .01 v control group). The blood pressure correlated significantly with both RBC-Na (r = 0.416. P less than .01) and beta-END (r = 0.436. P less than .005). A negative correlation was also observed between RBC-Na and beta-END (r = 0.437. P less than .005).
Use of arterial compliance for evaluation of hypertension, Arterial compliance describes a change in the volume of arteries following a change in blood pressure. The physical basis of the compliance concept and experimental procedures in animals both indicate that the relation between arterial compliance and blood pressure pattern is often unclear. Compliance is pressure-dependent because of the biphasic elastin and collagen composition of arteries and. hence. decreases when blood pressure increases. Compliance also determines the pulsatile amplitude of the pressure wave by regulating the buffering function of an artery's face to the cardiac pump and. accordingly. its reduction induces a selective increase in systolic level. The questions are whether these theoretical and experimental phenomena can be extrapolated to human hypertension and whether they can be assessed from indirect measurement of arterial compliance by means of a time-domain analysis of arterial pressure and flow waves via various models of the arterial tree. Whatever the method and site of measurement. arterial compliance was found to be decreased in different forms of hypertension. This low compliance can be considered to have a causal role in elderly patients with isolated systolic hypertension. In contrast. in patients with systolo-diastolic hypertension physiologic and pharmacologic arguments exist against the fact that low arterial compliance may be the pure consequence of mean blood pressure elevation. Moreover. it is suggested that aging acts in concurrence with pressure elevation to decrease arterial compliance. and that in certain hypertensive patients additional factors. perhaps atherosclerotic in nature. contribute to impair the elastic properties of arteries.
Fibrosarcoma of the head and neck. The UCLA experience, Between 1955 and 1987. twenty-nine patients with the diagnosis of fibrosarcoma of the head and neck were seen at the UCLA Medical Center. Follow-up ranged from 15 to 192 months. with a median of 66 months. Absolute 5-year survival was 62% (13/21). Five of 17 patients treated initially with surgery alone achieved local control and long-term survival. All five had low-grade lesions. Five patients received postoperative radiation therapy because of positive surgical margins. Three were rendered disease free. and all had low-grade lesions. Radiation therapy was used as primary treatment in six patients. four of whom received additional chemotherapy. Of these six. two are disease free with longer than 5-year follow-up. Surgery with and without adjuvant therapy successfully salvaged 42% (5/12) of the patients with local recurrence. Eighty percent (12/15) of the patients with low-grade lesions were ultimately rendered disease free vs only 8% (1/12) of the patients with high-grade histologic features. Seventy-two percent (13/18) of the patients with local recurrence were known to have positive surgical margins. Sixty-eight percent (13/19) of the patients with recurrent disease had high-grade lesions and/or tumor size larger than 5 cm. Tumor grade is the most important prognostic factor followed by tumor size and surgical margin status. Patients with low-grade lesions and adequate surgical margins are treated well with surgery alone. Patients with high-grade lesions or positive surgical margins should receive adjuvant treatment.
Ultrasound-guided fine-needle aspiration biopsy of neck nodes, The assessment of nodal involvement in patients with squamous cell carcinoma of the head and neck is still a major diagnostic problem. Although the sensitivity of imaging techniques for detection of neck nodes is gradually improving. the specificity for metastases remains low. Cytologic examination could. theoretically. supply additive information. Computed tomographic-and magnetic resonance-guided aspiration techniques have been described. but these were not efficacious and laborious. In 1984. we developed a technique for ultrasound-guided (UG) fine-needle aspiration biopsy (FNAB). This technique is described herein. and the value of UGFNAB is compared with conventional FNAB. All statistical characteristics of UGFNAB appeared to be superior to conventional FNAB (sensitivity. 98% vs 88%; specificity. 95% vs 82%; positive predictive value. 98% vs 93%; negative predictive value. 95% vs 74%; and accuracy. 97% vs 87%). Furthermore. UGFNAB was characterized by less nondiagnostic aspirations. It is concluded that UGFNAB is a reliable technique for differentiation between benign nodes and cervical lymph node metastases and it may. therefore. contribute to a more accurate assessment of the neck in squamous cell carcinoma of the head and neck.
Thyroidectomy under local anesthesia, Thyroidectomy for benign and malignant disease is most commonly performed with the patient under general anesthesia. although the literature is sprinkled with reports of series of operations performed using local anesthetic techniques. A retrospective review of 43 sequential thyroidectomies compares 21 performed using local anesthesia with 22 performed using general anesthesia. No significant difference was demonstrated in the incidence of major complications. All patients who required a second operation to remove the remaining hemithyroid after the final pathology reports were reviewed elected local anesthesia for their second procedure. attesting to patient satisfaction. Some hemithyroidectomies performed using local anesthesia were outpatient procedures. The indications. guidelines for patient selection. and operative technique of this effective alternative approach to thyroid surgery are presented.
The complete nucleotide sequence of a pathogenic molecular clone of simian immunodeficiency virus, The complete nucleotide sequence of an infectious clone of simian immunodeficiency virus of macaques. SIVmac239. has been determined. Virus produced from this molecular clone causes AIDS in rhesus monkeys in a time frame suitable for laboratory investigation. The proviral genome including both long terminal repeats is 10.279 base pairs in length and contains open reading frames for gag. pol. vif. vpr. vpx. tat. rev. and env. The nef gene contains an in-frame premature stop after the 92nd codon. At the nucleotide level. SIVmac239 is closely related to SIVmac251 (98%) and SIVmac142 (96%). It will not be possible to test which features of the viral sequence are critical molecular determinants for the pathogenesis of AIDS.
Vaccine protection of rhesus macaques against simian immunodeficiency virus infection, Rhesus macaques (Macaca mulatta) immunized with an inactivated whole SIVmac vaccine and muramyl dipeptide (MDP). incomplete Freund's adjuvant (IFA). or aqueous suspension were challenged intravenously with 0.1 TCID50 of cell-free SIVmac. Whereas virus was readily recovered from the peripheral blood lymphocytes of 10 of 10 nonvaccinated controls following this challenge dose. virus was not recovered from the three animals that received the vaccine with MDP nor from one of two animals that received the vaccine with IFA and one of three animals that received the aqueous vaccine. The animals that were protected against challenge were those that had detectable SIV antibody response to the envelop. both the outer glycoprotein (gp120) and the truncated transmembrane glycoprotein (gp31). Protected monkeys tended to have higher titers of syncytial inhibition antibody prior to challenge. An anamnestic response after challenge was observed only in the vaccinated monkeys that became infected. Vaccinated animals that became challenge-infected tended to live longer than infected controls. These results confirm those at two other primate centers and indicate that killed whole SIV vaccines can protect against low challenge doses of SIV and prevent early death in those monkeys that do become infected. The mechanism of this protection remains undetermined. This finding adds optimism to the possibility of an eventual AIDS vaccine.
Human immunodeficiency virus vpr gene encodes a virion-associated protein, The vpr gene of human immunodeficiency virus type 1 (HIV-1) is one of the seven accessory genes that are believed to have roles in the virus replication cycle. We report here the detection of a 13 kD vpr protein in sucrose gradient-purified HIV-1. This protein was not detected in cells infected with a virus having a truncated vpr gene that lacks the potential to encode for 26 C-terminal amino acid residues. These findings raise the possibility that virion-associated vpr proteins may be involved in the early life cycle of HIV-1 replication and suggest that the C-terminal region of the vpr gene is essential for its expression.
Enhancement of soluble CD4-mediated HIV neutralization and gp 120 binding by CD4 autoantibodies and monoclonal antibodies, We have identified 6 sera containing autoantibodies to CD4 in 174 human immunodeficiency virus-type (HIV-1) positive sera tested in an antigen-capture enzyme-linked immunosorbent assay (ELISA) using sCD4. and none in 34 HIV type 2 sera. These autoantibodies do not bind to cellular CD4. but react with sCD4 to increase its binding in ELISA to monoclonal antibodies and the HIV surface glycoprotein gp120. The effect of CD4 autoantibodies is mimicked by monoclonal antibodies to the third and fourth domains of CD4. The enhanced sCD4 binding to gp120 in ELISA is reflected by a reduction in the concentration of sCD4 required to neutralize HIV-1 and HIV-2 infection in tissue culture when CD4 autoantibodies or the relevant monoclonal antibodies were present.
Expression of HTLV-I envelope protein fused to hydrophobic amino-terminal peptide of baculovirus polyhedrin in insect cells and its application for serological assays, The envelope of human T-cell leukemia virus type I (HTLV-I) consists of two glycoproteins gp46 and p20E. Recombinant envelope proteins were produced by using an expression vector derived from insect baculovirus. Bombyx mori nuclear polyhedrosis virus. Polyhedrin fusion proteins C182. N147. and N287 contained whole region p20E. C-terminal half of gp46. and almost whole region gp46. respectively. N147 and N287 were suggested to be processed forms resulting from internal cleavage by cellular enzymes. In cultured cells and the insect larvae. C182 and N147 were produced abundantly enough to be purified to homogeneity; however. N287 was produced poorly and not purified. The purified proteins were recognized by HTLV-I-infected human sera and shown to be highly specific antigens for blood screening systems.
Rapid and quantitative detection of enzymatically amplified HIV-1 DNA using chemiluminescent oligonucleotide probes, A hybridization protection assay (HPA) that uses acridinium ester (AE) labeled oligonucleotide probes which are specific for a conserved gag gene region of human immunodeficiency virus type 1 (HIV-1) was developed to measure the amount of HIV-1 nucleic acid. Hybridization of the single-stranded probes with their target HIV-1 sequences protected the chemiluminescent AE group from subsequent alkaline hydrolysis. The chemiluminescence from the residual AE could be easily quantitated in a luminometer. The entire process comprising template dissociation. hybridization. alkaline hydrolysis. and chemiluminescence measurement can be completed in less than one hour and does not require the separation of hybridized probe from unhybridized probe. We demonstrated that HPA could quantitatively measure the amount of DNA amplified by polymerase chain reaction. A comparative study using amplified DNA from the peripheral blood mononuclear cells (PBMC) of HIV seropositive and seronegative persons showed that HPA was as sensitive as the previous methods using 32P-labeled DNA probes.
Expression of HIV-1 integrase in E. coli: immunological analysis of the recombinant protein, Sequences encoding the human immunodeficiency virus type 1 (HIV-1) integrase gene have been cloned and expressed in Escherichia coli. The expressed protein is a lambda cII fusion protein of 37 kD containing the carboxyl-terminal 27 amino acids of reverse transcriptase fused to the entire integrase sequence and is insoluble. a feature which allows partial purification away from soluble bacterial proteins. As judged by its reactivity with HIV positive sera in Western blot and in enzyme-linked immunosorbent assay (ELISA). the recombinant integrase retains antigenicity similar to native protein. Additionally. ELISA data obtained with the cloned protein indicate that patients infected with HIV-1 who are at different stages of progression to AIDS have antibodies reactive with the cloned integrase. HIV-2 positive human sera are also reactive with the cloned integrase. Rabbit antibodies produced against the recombinant protein react both by ELISA and Western blot with the homologous bacterially expressed protein. recognize both virion HIV-1 integrase and reverse transcriptase in Western blots. and immunoprecipitate an HIV-1 virion protein of 34 kD. Unlike human antisera from patients infected with HIV-1 or HIV-2 which are frequently reactive with both HIV-1 and HIV-2 integrase. the rabbit antibodies are type specific. reacting with HIV-1. but not with HIV-2 integrase by Western blot.
Human immunodeficiency virus (HIV) circulating immune complexes in infected children, Circulating immune complexes (CIC) were studied for the presence of human immunodeficiency virus (HIV) antigens (HIV-Ag) in 55 children infected by the human immunodeficiency virus type 1 (HIV-1). CIC were elevated in 85% of patients. In 33 of 55 patients CIC included at least one HIV-Ag (HIV-Ag-CIC). Sixty percent of patients had p17 antigen. 50% had p24 antigen. and 16% had gp120 associated with CIC. Levels of HIV-Ag-CIC did not correlate with free serum HIV antigens. Patients with high HIV-Ag-CIC had a more severe clinical course and 90% of those with markedly elevated HIV-Ag-CIC (greater than 3+) have died within 6 to 24 months. HIV-Ag-CIC were also present in some patients including neonates and young infants in whom free HIV-Ag was undetectable. Monitoring of HIV-Ag in isolated CIC may be of value for early detection of HIV infection and for monitoring of disease outcome.
Blood lead levels in children and pregnant women living near a lead-reclamation plant, OBJECTIVE: To determine the effect of lead contamination around a lead-reclamation plant on the blood lead levels of children and pregnant women living in the area. DESIGN: Prevalence study. SETTING: Residents living 150 m or less (high-exposure area). 151 to 400 m (intermediate-exposure area) or 401 to 800 m (low-exposure area) southeast from the plant. PARTICIPANTS: All children aged 10 years or less and all pregnant women living in the designated area. OUTCOME MEASURES: Correlation of venous blood lead levels with soil lead concentrations in the areas in which the subjects lived and with sociodemographic and behavioural factors. MAIN RESULTS: Of the estimated 57 pregnant women 38 (67%) participated: 20 were in the high-exposure area and 18 in the other two areas; their geometric mean blood lead levels were low (0.15 and 0.13 mumol/L respectively). Of the 625 eligible children 510 (82%) participated: 169 were in the high-exposure area. 179 in the intermediate-exposure area and 162 in the low-exposure area; their geometric mean lead levels were 0.43. 0.30 and 0.26 mumol/L respectively. Within each age group children in the high-exposure area had the highest levels. The mean levels for children aged 6 months to 5 years were 0.49. 0.35 and 0.28 mumol/L in the three areas respectively. Within each exposure group children aged 1 to 2 years had the highest levels. No potential confounding variables could explain the relation between blood lead level and soil lead concentration. CONCLUSIONS: The pregnant women's blood lead levels did not seem to be affected by exposure level. but the children's levels were primarily related to the soil lead concentration.
The prognostic significance of urinary interleukin 6 in IgA nephropathy, Our previous study has shown that interleukin 6 (IL-6). a multifunctional cytokine. is closely associated with the pathogenesis of mesangial proliferative glomerulonephritis (mesPGN). To investigate whether urinary IL-6 can be used as an indicator in the prognosis of patients with IgA nephropathy. we monitored IL-6 activity in the urine of patients with IgA nephropathy for 10 months and compared IL-6 activity with clinical data as well as the histological changes of the kidneys obtained from the patients. It was found that among the patients who had continuously high urinary IL-6 activity. histological progression of IgA nephropathy was observed. On the other hand. among the patients whose urinary IL-6 became undetectable during the 10-month follow-up. histological improvement of IgA nephropathy was observed. These data suggest that the measurement of urinary IL-6 is a helpful tool for monitoring the progression of IgA nephropathy.
Hemodialysis and heparin. Alternative methods of measuring heparin and of detecting activation of coagulation, A bolus dose of heparin was administered pre-dialysis to patients (n = 6) undergoing regular maintenance hemodialysis with cuprophane flat plate and hollow fiber membranes. Blood samples were withdrawn at hourly internals for measurement of a) heparin and b) activation markers of coagulation. fibrinolysis and platelets. Two assay methods for heparin were employed; amidolytic assay of anti-factor Xa activity in plasma and a simple whole blood clotting time based upon factor Xa inhibition (Heptest). Results from these heparin assays correlated well with each other (r = 0.89) and both showed similar negative correlations (r = -0.72. amidolytic and r = -0.66. Heptest) with levels of a marker of fibrin clot formation. fibrinopeptide A (FPA). Large differences in levels of FPA were observed during dialysis with the two dialyzer types. when similar levels of heparin were present. Heparin levels declined from 1-5-h dialysis and were associated with rises in plasma levels of FPA. thrombin-antithrombin complex (TAT) and beta thromboglobulin (BTG). but not of D-dimer. Regression analysis revealed the best correlation was between FPA and TAT (r = 0.94). followed by FPA and BTG (r = 0.81). FPA and D-dimer exhibited significant. but lower (r = 0.42). correlation. TAT levels. like FPA levels. showed good correlation with heparin (r greater than 0.65). It is concluded that the Heptest assay may be a useful bedside measurement of heparin levels and the TAT assay may be a simplified means of evaluating coagulation system activation during dialysis.
Early identification of hearing loss: listen to parents, Families of 49 hearing-impaired children responded to a questionnaire requesting information about the identification of their child's hearing loss. Parents were the first to suspect the hearing loss in 48 cases but more often than not were told that the child would outgrow it or was too young to test. When professionals agreed with the parents and attended to their concerns. confirmation of the hearing loss occurred significantly more rapidly than when they disagreed with parents and ignored their concerns. A child whose hearing loss is not clearly identified and whose communication is inadequate or nonexistent. causes frustration and stress within the family and prevents the child from receiving the maximum benefit from early language input and amplification. It would benefit both the child and family if professionals would listen to parental concerns regarding their child and assist in the early identification process.
Screening for biotinidase deficiency in children with unexplained neurologic or developmental abnormalities, To test the hypothesis that the frequency of biotinidase deficiency is greater in children with unexplained developmental delay or neurologic abnormalities than in the general population. we studied children seen at a large outpatient clinic over a four-year period who had one or more of these neurologic abnormalities and for whom no specific cause for their abnormalities could be found. The group totaled 274 children (163 boys; 111 girls) whose ages ranged from 2 weeks to 17 years. Characteristics were IQ/DQ. 30 to 70 in the 115 for whom scores were available; 41% had seizures; 15% had sensorineural hearing loss; 54% showed gross motor delay or ataxia; and 27% had decreased muscle tone. One patient with a classical clinical picture of biotinidase deficiency was diagnosed during the study period and was not included in the study. None of the patients with nonclassic findings had a deficiency of biotinidase activity. Our results suggest that biotinidase deficiency does not account for a large proportion of children with unexplained neurologic abnormalities or developmental delay. This does not negate the importance of biotinidase testing in children with clinical patterns specifically suggestive of the deficiency.
Clinical evaluation of a new chest tube used in neonates, We report preliminary experience with a newly designed chest tube (JCT). for evacuation of neonatal pneumothorax. The catheter has a unique pigtail confirguration at the distal end. intended to simplify placement and minimize chest wall and lung trauma by reduced tube size and depth and insertion. Thirty-eight JCTs were placed in neonates with pneumothoraces. Neonates' birth weights ranged from 400 to 3.595 grams. All 38 tubes immediately relieved clinical signs of pneumothoraces. Thirty-five (92%) tubes immediately fully evacuated the pneumothoraces as evidences on chest radiograph. Twelve pneumothoraces partially reoccurred at a mean of 24 hours following JCT placement. These tubes were either irrigated or replaced. This newly configured chest tube functions effectively in the treatment of neonatal pneumothorax.
Furosemide absorption in patients with cirrhosis, Twelve patients with cirrhosis (seven mild and five severe) were administered intravenous and oral furosemide in random order to assess its absorption and disposition. Total serum clearance (113 +/- 49 ml/min). volume of distribution (11.9 +/- 4.5 L). and elimination half-life (166 +/- 149 minutes) were similar to those reported previously in both healthy control subjects and patients with cirrhosis. Bioavailability of 58% +/- 17% (range. 37% to 82%) was comparable to that of previous studies. and there was no difference between patients with mild and those with severe cirrhosis. In 9 of 12 patients the mean absorption time was longer than the mean residence time determined after intravenous administration (mean for all patients. 203 +/- 86 versus 134 +/- 101 minutes; p less than 0.05). indicating that furosemide followed a "flip-flop" model in these patients. In all patients the mean absorption time was prolonged relative to normal subjects irrespective of the presence of edema. As such. the slower absorption of furosemide in edematous states. such as congestive heart failure and cirrhosis. does not appear to be a consequence of edema per se. Moreover. because similar changes occur in patients with congestive heart failure. it seems that diseases with diverse pathophysiology can slow furosemide absorption.
Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis, The pharmacokinetics of cefpiramide. a new cephalosporin. were investigated after a single 1 gm intravenous injection in 11 patients with alcoholic cirrhosis and compared with those of 11 healthy subjects. In patients with cirrhosis the plasma elimination half-life was three times longer than that in normal subjects. The total plasma clearance was decreased significantly (p less than 0.001): 12.3 +/- 6.5 ml/min in patients and 25.6 +/- 4.6 ml/min in healthy volunteers. respectively. The urinary excretion of unchanged drug (percent of intravenous dose) for patients (69.8% +/- 29.9%) was statistically higher (p less than 0.01) than that for subjects (16.2% +/- 3.9%). The renal elimination became increasingly important with hepatic impairment. Protein binding of cefpiramide was reduced significantly in the group with cirrhosis. The average unbound fraction was 10.4% +/- 9.5% in patients with cirrhosis and 1.9% +/- 0.3% in normal subjects (p less than 0.01). Because the rate of elimination from plasma in patients is slower. the dosage regimen of cefpiramide would probably be modified in cirrhosis.
Intraocular pressure increases with fenoldopam, but not nitroprusside, in hypertensive humans, Fenoldopam mesylate stimulates adenyl cyclase in porcine ocular trabecular meshwork and raises intraocular pressure in humans. To clarify whether this results from direct activation of the dopamine-1 receptor or indirectly from baroreflex sympathetic stimulation after blood pressure reduction. intraocular pressure was measured in 14 patients with accelerated/malignant hypertension. randomized between intravenous fenoldopam or sodium nitroprusside. Intraocular pressure was measured with a Perkins tonometer. before and at the twentieth minute of each dose increment. In seven patients with a mean blood pressure of 232/131 mm Hg treated with fenoldopam. intraocular pressure increased in a dose-dependent fashion. from 16 +/- 1 to 20 +/- 2 mm Hg (p less than 0.005). In contrast. seven patients with a mean blood pressure of 225/134 mm Hg treated with sodium nitroprusside exhibited no change in intraocular pressure (15 +/- 1 versus 14 +/- 1 mm Hg) despite similar blood pressure reduction. Increases in heart rate were not significantly different. Rates of urinary excretion of norepinephrine plus epinephrine increased significantly relative to baseline (p less than 0.05) but were not different between groups. These data suggest that the increase in intraocular pressure with fenoldopam results from specific activation of the dopamine-1 receptor and is not caused by baroreflex sympathetic stimulation. Because dopamine-1 receptors may modulate intraocular pressure. dopamine-1 receptor blockers might be useful therapy for glaucoma.
A phase I study including pharmacokinetics of polyethylene glycol conjugated interleukin-2, A more soluble formulation of recombinant interleukin-2 with a prolonged half-life would allow alternate routes or schedules of administration and enhance patient comfort. The covalent attachment of polyethylene glycol to recombinant interleukin-2 provides an analog with preclinical data suggesting those desired characteristics while maintaining biologic activity. This is the report of a phase I study in which we sought to determine the maximum tolerated dose of polyethylene glycol interleukin-2. observe biologic activity. and confirm the prolonged half-life in vivo. Sixty-six patients were entered into the study during 19 months. Polyethylene glycol interleukin-2 was administered intravenously once a week over 15 minutes. The maximum tolerated dose was 20 x 10(6) U/M2. The pattern of toxicity was quite similar to that of the parent compound. Four patients had evidence of tumor regression (three partial remission; one minor response). The pharmacokinetic data confirmed a 10- to 20-fold prolongation in half-life compared with recombinant interleukin-2. No neutralizing antibodies were detected. This study provides sufficient impetus for the ongoing phase II studies of polyethylene glycol interleukin-2.
Prospective pharmacokinetically based development of effective infusion regimens for ACC-9358, a new antiarrhythmic drug, In this study we evaluated the clinical pharmacology of intravenous ACC-9358. a new antiarrhythmic drug derived from a Chinese herbal remedy. In a first-study phase. 0.125 to 1.0 mg/kg during 10 minutes was administered to six patients with chronic nonsustained ventricular arrhythmias. These data were then used to design 3-hour infusions to maintain stable plasma concentrations: these infusions suppressed arrhythmias by 90% or greater for 2 1/2 hours or more at plasma concentrations of 114 to 1010 ng/ml (mean. 400 +/- 421 ng/ml [SD]). and with QRS interval increases of 2.5% to 8.8% (5.1% +/- 2.9%). Mean clearance was 478 +/- 151 ml/min. and elimination half-life was 19.1 +/- 6.1 hours. ACC-9358 did not produce adverse effects in this study. ACC-9358 shows antiarrhythmic activity in humans at concentrations that prolong QRS only slightly and do not alter rate-corrected QT; further studies in other patient populations. at dosages and plasma concentrations defined here. are required to establish a clinical role for ACC-9358. The pharmacokinetically based dose-ranging approach allowed the safe initial evaluation of ACC-9358 in patients.
The effects of benazepril, a new angiotensin-converting enzyme inhibitor, in mild to moderate essential hypertension: a multicenter study, Benazepril hydrochloride is a new angiotensin-converting enzyme inhibitor. In a multicenter study. 206 patients with mild to moderate hypertension were randomized to receive benazepril at a dose of 2. 5. 10. or 20 mg. hydrochlorothiazide. 25 mg. or placebo once daily for 4 weeks. The 20 mg dosage of benazepril lowered blood pressure to a degree equal to that of 25 mg hydrochlorothiazide: -12.2/7.7 mm Hg and -13.4/-7.5 mm Hg. respectively. Hydrochlorothiazide proved to be more effective in black subjects. At lower dosage levels of benazepril (2. 5. and 10 mg). blood pressure reduction was not significantly different from that with placebo. In those patients who failed to achieve goal diastolic blood pressure of less than 90 mm Hg with monotherapy after 4 weeks. the addition of open-label hydrochlorothiazide (25 mg/day) to benazepril. hydrochlorothiazide. or placebo produced a substantial additional decrease in blood pressure over a 2-week period. No definite adverse effects on hematologic measurements. serum biochemistry test results. or urinalyses were noted. Subjective adverse experiences were common in all groups but except in three or possibly four instances were not considered causally related to the study drug.
Risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs: The International Agranulocytosis and Aplastic Anemia Study, The risks of agranulocytosis and aplastic anemia in relation to the use of cardiovascular drugs were estimated in a population-based case-control study conducted in Israel and Europe (total population. 23 million). Cardiovascular drug use in the week before onset of illness was compared between 270 patients hospitalized with agranulocytosis and 1870 hospitalized control subjects. Propranolol (relative risk. 2.5). dipyridamole (3.8). digoxin (2.5). and acetyldigoxin (9.9) were significantly associated with agranulocytosis. The excess risks attributable to these drugs ranged from one to three cases per 10 million persons exposed for up to 1 week. Increased risks were also observed for cinepazide (used by six cases and no control subjects). procainamide (7. 1). and aprindine (5. 1); based on crude relative risk estimates. the excess risks for the latter two drugs were approximately three per million persons exposed for up to 1 week. The use of cardiovascular drugs in a 5-month period ending 1 month before hospital admission was compared between 152 patients with aplastic anemia and 2180 control subjects. Furosemide was the only significantly associated drug (relative risk. 3.1); the excess risk attributable to any exposure in a 5-month interval was 1.7 per million.
Comparison of anterior sphincteroplasty and postanal repair in the treatment of idiopathic fecal incontinence, Both postanal repair and anterior sphincteroplasty with levatorplasty have been advocated in the treatment of idiopathic fecal incontinence. To assess the functional results of these procedures. physiologic and radiologic measurements were carried out prospectively in 33 patients with idiopathic incontinence undergoing operative treatment. and 12 age- and sex-matched controls. Sixteen patients had anterior sphincteroplasty and levatorplasty and 17 had postanal repair. A satisfactory postoperative outcome was defined as perfect continence or incontinence of flatus only. Ten patients in the anterior sphincteroplasty group had satisfactory results (64 percent) and 10 in the postanal repair group (59 percent). Preoperatively. both groups had decreased resting and squeeze pressures. impaired and mucosal electrosensitivity. and marked pelvic descent vs. controls. Postoperatively. significant improvement in sphincter pressures and mucosal electrosensitivity was seen in both groups. No significant change in anorectal angle was demonstrated in the postanal repair group. whereas it was made significantly more obtuse in the anterior sphincteroplasty group. It is likely that the improved continence resulting from either of these two procedures is secondary to better anal sphincter muscle function and improved and sensation. It would appear that the anorectal angle is not crucial in maintaining continence.
The effect of posterior rectopexy on fecal continence. A prospective study, Twenty-three patients with rectal prolapse or intussusception were studied to specifically focus on the effect of posterior rectopexy on fecal continence. anal pressure. and rectal capacity. Before operation. five patients were fully continent (A). 10 were continent for solid stools (B) and eight patients were fully incontinent (C). Group A remained fully continent; continence was regained nine times in group B and in group C. three patients regained full continence. two became continent for solid stools. three patients remained incontinent. Other symptoms such as constipation. false urgency. and a feeling of incomplete evacuation were not beneficially influenced by rectopexy. The patients' continence status was correlated to anorectal manometry and rectal capacity measurement. In group B. incremental pressure (P = squeeze - basal P) increased significantly (P less than 0.02) as well as incremental volume (V = maximum tolerated volume - volume of first sensation) (P less than 0.05). We conclude that. by an increase of incremental anal pressure and incremental rectal volume. posterior rectopexy offers an 83 percent chance of regaining full continence. or a major improvement. and a 17 percent chance of stabilization of fecal incontinence.
Local recurrence following abdominoperineal excision and anterior resection for rectal carcinoma, The aim of this retrospective study is to compare the outcome of abdominoperineal excision (APE) and anterior resection (AR) for rectal cancer in terms of local tumor recurrence. A further comparison has been carried out between hand-sewn and stapled anastomosis; 147 patients have been followed for at least 2 years: 69 after APE and 78 after AR. 40 being stapled. The following variables potentially related to the risk of recurrence were evaluated: age. grading. staging. and site of the tumor. An overall 2-year local recurrence rate of 11 percent after APE and 12 percent after AR was observed. whereas it was 13 and 11 percent following stapled and hand-sewn sutures. respectively. Both differences were not statistically significant. A similar local recurrence rate was noted after APE and AR when the patients were matched for Dukes' stage and grading of the lesion. A trend toward an increased risk of recurrence following AR (P = 0.07) was shown when comparing the two procedures if mid and upper rectal cancers were grouped together. In the patients with anastomotic leaks after AR. no increase of local recurrence was observed. In conclusion. AR is unlikely to be followed by an increased risk of local recurrence and. therefore. when oncologically indicated. may be considered the operation of choice in the treatment of rectal cancer. although the possible risk of its overuse should be taken into account.
Drug-induced colonic pseudo-obstruction. Report of a case, Colonic pseudo-obstruction may have many possible causes. Some of these are well described and pose no diagnostic problems. Drug-related colonic pseudo-obstruction remains underreported. but is of importance in modern society where drugs are endemically abused. This case highlights the importance of drugs in altering colonic motility and emphasizes the nonsurgical management of this condition.
Omeprazole. Overview and opinion, Omeprazole. a substituted benzimidazole. is a specific inhibitor of the enzyme H+/K(+)-ATPase. which is found on the secretory surface of the parietal cell. This enzyme. the "proton pump." catalyzes the final step in acid secretion. Omeprazole is a powerful inhibitor of gastric acid secretion. At the time of writing. omeprazole has been licensed in the United States for the treatment of severe grades of gastroesophageal reflux disease (GERD) as well as GERD unresponsive to treatment with currently available agents. and for the treatment of Zollinger-Ellison syndrome and other gastric hypersecretory states. Most recently. it has been recommended by the FDA advisory committee for approval as first-line therapy in duodenal ulcer disease.
Use of omeprazole in patients with Zollinger-Ellison syndrome, Omeprazole. a substituted benzimidazole. has been shown to be a potent inhibitor of gastric acid secretion in patients with Zollinger-Ellison syndrome (ZES). We review our experience. as well as the published data on 210 patients with ZES who have required omeprazole for control of gastric acid hypersecretion over the past seven years. The dose of omeprazole required in individual patients ranged from 10 to 180 mg/24 hr with 20-60% requiring a split dosage regimen. Omeprazole was effective in approximately 99% of the patients over a period ranging from 0.5 to 54 months. Twenty-four percent of patients required an increase in omeprazole dose. while 26% required a decrease in dose. Adverse effects attributable to omeprazole were reported in 2% of patients. and in all cases. they were mild (ie. rash. constipation. headache). There was no effect of omeprazole on serum gastrin concentration or on gastric endocrine cells in three studies. Although one patient with multiple endocrine neoplasia. type-I syndrome (MEN-I) in this series developed a gastric carcinoid while taking omeprazole. evidence is presented that suggests the presence of MEN-I per se may be important in determining the development of gastric carcinoid in patients with ZES. It is concluded that omeprazole is safe and effective in patients with ZES. and in these patients. it is the drug of choice for the management of gastric acid hypersecretion. However. yearly assessment is indicated to clearly evaluate the long-term risk of gastric carcinoid as well as therapy directed at the gastrinoma itself.
Prevalence of inflammatory bowel disease in family members of Jewish Crohn's disease patients in Israel, A familial study of 189 Jewish Crohn's disease patients was conducted in order to evaluate the risk for inflammatory bowel disease (IBD) in relatives of the patients and to try to understand better the genetic component in the etiology of the disease among Jews. One hundred fifty-seven patients filled out questionnaires that were verified by personal interviews. In 10 families (6.6%). a first-degree relative of the propositus was found to have IBD. seven Crohn's disease and three ulcerative colitis. Among first-degree relatives. siblings were more frequently affected: of 400. five had Crohn's disease and one ulcerative colitis. Among 304 parents. two had Crohn's disease and two ulcerative colitis. while none of the propositi's children had IBD. The prevalence of first-degree relatives with Crohn's disease was similar in the 98 and 45 families of Ashkenazi and non-Ashkenazi origin: 5.1% and 4.4%. respectively. The risk for siblings of the probands to be affected were also similar in the two groups: 1.5% and 1.8%; while parents of the probands were affected only in the group of Ashkenazi Jews.
Mechanisms controlling growth of hepatocytes in primary culture, Mature hepatocytes in primary culture express most of the functions and hormonal responsiveness seen in normal liver studied in vivo. The growth of hepatocytes in culture is regulated by various growth factors. We have identified a hepatocyte growth factor that is isolated from rat platelets. We found that rat platelets also contain a growth inhibitor. transforming growth factor-beta which is secreted as a latent molecule. Its latency is due to its binding with a masking protein. Growth of hepatocytes is also suppressed by interleukin-1 (IL-1) and IL-6. Moreover. the growth and functions of liver cells in culture are regulated reciprocally by cell density: at higher cell density liver-specific functions are expressed and growth is suppressed. whereas the opposite situation is observed at lower cell density. In contrast. neonatal hepatocytes in culture grow autonomously without a requirement for added hormones. This autonomous growth is due to an autocrine mechanism in which the cells secrete one or more growth factors into the culture medium. However. this autonomous growth ceases one week after birth at a time when the cells begin to express differentiated characteristics. Based upon these data. the mechanisms of liver regeneration. differentiation. and hepatocarcinogenesis are discussed.
Characterization of rat hyperplastic bile ductular epithelial cells in culture and in vivo, A novel intrahepatic biliary cell culture/in vivo transplantation system has been developed with an essentially pure population of bile ductular epithelial cells isolated from rat liver 6-12 weeks after bile duct ligation. In primary culture. these cells retain staining strongly for gamma-glutamyltranspeptidase and glutathione S-transferase P. The cytoplasm of cultured bile ductular cells reacts with an anti-laminin antibody. but loses immunoreactivity with a monoclonal anti-cytokeratin 19 antibody. Semiconservative DNA synthesis in the cultured cells was dependent upon the continued presence of 10% fetal calf serum in the medium. Replicating bile ductular cells could be subcultured for a finite number of passages. In addition. freshly isolated bile ductular epithelial cells gave rise to well differentiated bile ductular structures when transplanted into the interscapular fat pads of syngeneic recipient rats.
An assessment and care planning strategy for nursing home residents with dementia, Dementia is extremely common among nursing home patients. and it takes many forms. Accurate assessment by staff is crucial in providing appropriate care to these patients. Equally important is the ability to establish care priorities. Current staging models are so general. however. that their usefulness is limited. Thus. this paper proposes a strategy that. using basic assessment data. categorizes dementia residents according to four key determinants of care needs: activities of daily living status. behavioral problems. communication abilities. and physical transition.
Ritual and dying: a cultural analysis of social support for caregivers, This study examines the role of social support in the process of caring for someone dying at home. Based on data from in-depth ethnographic interviews with 16 caregivers. it employs a cultural analysis to draw parallels with rituals of transition. Ritual provides a broad context of meanings and routines for securing the doubts and unknowns of individual experience. The way social support is provided plays a key role in the caregiver's transition to bereavement.
Burden: a review of measures used among caregivers of individuals with dementia, This paper critiques and discusses 10 measures of burden that have been used with caregivers of individuals with dementia. Current measures target diverse caregiver and care recipient populations. and vary in conceptualization and measurement of burden. Although many measures contain reliability data. relatively few report content validity. convergent/divergent validity. criterion validity. or sensitivity to change. Implications of these limitations for research and clinical practice are discussed.
Biology of basal cell carcinoma (Part II), Host-tumor relationships involve several factors that can enhance or suppress neoplastic growth. This second part of a review of basal cell carcinoma biology examines the role that hormones. cytokines. local and systemic immunity. congenital and genetic syndromes. and environmental factors play in the development of this neoplasm. Theories of etiology and pathogenesis are discussed. and transplantation and cell culture techniques used to study this cancer are explored. Valuable second-line therapies for treatment of multiple tumors are reviewed. and important areas of present and future research are emphasized.
Systemic hydrocortisone/cortisol induces allergic skin reactions in presensitized subjects, To determine whether systemic hydrocortisone can elicit allergic skin reactions in patients with contact hypersensitivity to hydrocortisone. we studied four patients with contact hypersensitivity to hydrocortisone and hydrocortisone-17-butyrate and two patients with contact hypersensitivity to hydrocortisone-17-butyrate but not to hydrocortisone. Open oral provocation with 100 or 250 mg hydrocortisone in patients with hydrocortisone contact hypersensitivity elicited cutaneous reactions at sites of previous allergic dermatitis caused by hydrocortisone in two patients and at sites of earlier allergic patch test reactions caused by hydrocortisone in the other two patients. Provocations in two patients with contact hypersensitivity to hydrocortisone-17-butyrate but not to hydrocortisone remained negative. To determine whether the adrenal cortical hormone cortisol. which is identical to hydrocortisone. could induce similar skin reactions. one patient with hydrocortisone contact hypersensitivity underwent adrenocorticotropic hormone stimulation tests; as a control. one hydrocortisone-sensitive patient underwent analogous provocations with placebo. After an 8-hour infusion with the adrenocorticotropic hormone analog tetracosactide. a similar skin reaction to that seen with oral hydrocortisone was observed. whereas provocations with placebo remained negative. We conclude that both oral hydrocortisone and intrinsic cortisol are able to induce allergic skin reactions in presensitized subjects.
Primary neuroendocrine carcinoma of the skin. Clinicopathologic study of 18 cases, The clinical and pathologic features of primary neuroendocrine carcinoma of the skin in 18 elderly patients are reported. The carcinomas arose in the dermis and subcutaneous tissues. particularly on the head and the upper extremities. One tumor occurred in an irradiated area. Using Gould's clinicopathologic classification. we have found four trabecular types. eleven intermediate cell types. and two small cell types. One tumor could not be classified. Other noteworthy pathologic features were association with invasive squamous cell carcinoma. lentiginous melanocytic hyperplasia. and presence of intratumoral melanocytes. Immunoreactivity for cytokeratins (56 kD). neurofilaments. neuron-specific enolase. and epithelial membrane antigen was observed. The paranuclear globular staining pattern of cytokeratins and neurofilaments was conspicuous. The ultrastructural features revealed paranuclear intermediate filament aggregates (fibrous bodies). neurosecretory granules. and cell junctions. In two metastatic tumors. high levels of catecholamines were found. The trabecular types were characterized by localized disease and a good prognosis. The patients with the small cell types died of distant metastases. Postoperative radiotherapy seemed to reduce the rate of local recurrences.
Spironolactone in dermatologic therapy, In the treatment of androgen-mediated skin disorders spironolactone provides a valuable therapeutic option. This article reviews the use of spironolactone as an antiandrogen in dermatologic therapy. The endocrinologic effects. pharmacology. dermatologic uses. and side effects are discussed. and guidelines for its use are provided.
Treatment of cutaneous T cell lymphoma with a combination of low-dose interferon alfa-2b and retinoids, In a pilot study the therapeutic effect and side effect profile of low-dose interferon alfa-2b in combination with a retinoid for the treatment of cutaneous T cell lymphoma were evaluated. Seven patients (four women. three men) with histologically confirmed cutaneous T cell lymphoma were included. Four patients had received therapy previously. The treatment schedule consisted of 2 million U of interferon alfa-2b administered subcutaneously three times per week and oral 13-cis-retinoic acid. 1 mg/kg/day. with subsequent dose reduction in case of response. The combination therapy produced two complete and two partial remissions. Responses were maintained by continuous therapy for up to 15 months even after dose reduction of both agents by 50%. Side effects were negligible and did not result in discontinuation of treatment in any patient.
Topical metronidazole in the treatment of perioral dermatitis, The twice-daily topical application of 1% metroindazole cream was compared with 250 mg oral tetracycline. taken twice daily. in the treatment of perioral dermatitis in a prospective. double-blind. double-dummy. randomized. multicenter trial. One hundred eight patients were treated for 8 weeks. At the end of this time the median number of papules in the metronidazole-treated group was reduced to 8% of the initial number. and the median number in the group treated with tetracycline was reduced to 0% of the initial number. Although both treatments were effective. oral tetracycline was significantly more effective than topical metronidazole.
Who is being screened for melanoma/skin cancer? Characteristics of persons screened in Massachusetts, We conducted a survey of persons who voluntarily attended melanoma/skin cancer screenings in Massachusetts in 1987. Of 1219 persons asked to fill out a questionnaire. 1116 (92%) completed it. Our study demonstrates that persons attending the melanoma/skin cancer screening program were. for the most part. at risk for the disease and appropriately selected themselves to be screened. Most were women. well educated (with college or advanced degrees). and white. More than 86% had at least one risk factor for melanoma/skin cancer whereas 78% had at least two risk factors. Future studies are necessary to determine whether our experience can be verified. Additional efforts should try to attract those who are at risk but perhaps are less willing to attend screening programs--men and those of lower socioeconomic status. These efforts can help target screening to those at highest risk and maximize the yield of these public health efforts.
Comparison of cardiac catheterization and Doppler echocardiography in the decision to operate in aortic and mitral valve disease, Clinical decisions utilizing either Doppler echocardiographic or cardiac catheterization data were compared in adult patients with isolated or combined aortic and mitral valve disease. A clinical decision to operate. not operate or remain uncertain was made by experienced cardiologists given either Doppler echocardiographic or cardiac catheterization data. A prospective evaluation was performed on 189 consecutive patients (mean age 67 years) with valvular heart disease who were being considered for surgical treatment on the basis of clinical information. All patients underwent cardiac catheterization and detailed Doppler echocardiographic examination. Three sets of two cardiologist decision makers who did not know patient identity were given clinical information in combination with either Doppler echocardiographic or cardiac catheterization data. The combination of Doppler echocardiographic and clinical data was considered inadequate for clinical decision making in 21% of patients with aortic and 5% of patients with mitral valve disease. The combination of cardiac catheterization and clinical data was considered inadequate in 2% of patients with aortic and 2% of patients with mitral valve disease. Among the remaining patients. the cardiologists using echocardiographic or angiographic data were in agreement on the decision to operate or not operate in 113 (76% overall). When the data were analyzed by specific valve lesion. decisions based on Doppler echocardiography or catheterization were in agreement in 92%. 90%. 83% and 69%. respectively. of patients with aortic regurgitation. mitral stenosis. aortic stenosis and mitral regurgitation. Differences in cardiac output determination. estimation of valvular regurgitation and information concerning coronary anatomy were the main reasons for different clinical management decisions. These results suggest that for most adult patients with aortic or mitral valve disease. alone or in combination. Doppler echocardiographic data enable the clinician to make the same decision reached with catheterization data.
Prognostic value of thallium-201 myocardial perfusion imaging in patients with unstable angina who respond to medical treatment [published erratum appears in J Am Coll Cardiol 1991 Sep;18(3):889, Although the prognostic value of thallium-201 imaging is well established. its ability to risk stratify patients who present with unstable angina is unclear. Fifty-two consecutive patients admitted with unstable angina who responded to medical treatment and underwent stress thallium-201 imaging within 1 week of discharge were studied. Patients were followed up for 39 +/- 11 months. Cardiac events included cardiac death (n = 3). nonfatal myocardial infarction (n = 4) and admission for unstable angina or revascularization (n = 17). The ability of thallium-201 data (redistribution. fixed defects. normal) to predict cardiac events was compared with clinical data (age. gender. prior myocardial infarction. anginal syndrome. rest and stress electrocardiogram) and cardiac catheterization data using logistic regression. Thallium-201 redistribution was the only significant predictor of cardiac death or nonfatal myocardial infarction (p less than 0.05). The number of myocardial segments with thallium-201 redistribution (p less than 0.0005) and a history of prior myocardial infarction (p less than 0.05) were the only significant predictors of all cardiac events. Cardiac death or nonfatal myocardial infarction occurred more frequently in patients with thallium-201 redistribution (6 [26%] of 23) than in those without redistribution (1 [3%] of 29. p less than 0.05). Similarly. total cardiac events developed more frequently in patients with thallium-201 redistribution (p less than 0.001). Stress thallium-201 imaging has important prognostic value in patients admitted with unstable angina who respond to medical therapy and can identify subgroups at high versus low risk for future cardiac events.
Comparison of epicardial coronary artery tone and reactivity in Prinzmetal's variant angina and chronic stable angina pectoris, It has been suggested that a generalized coronary vasomotion disorder is present in variant angina and that evaluation of baseline coronary artery tone may be useful for predicting the occurrence of coronary artery spasm. The vasomotor response of angiographically normal proximal and distal coronary artery segments was studied in 9 patients with atypical chest pain and normal coronary arteriograms (control group). 13 patients with active variant angina and 41 patients with chronic stable angina. Ergonovine (intravenous. 100 to 300 micrograms. or intracoronary. 8 to 20 micrograms. was administered to all 22 patients in the control and variant angina groups and to 11 of the 41 patients with chronic stable angina. All patients also received intracoronary isosorbide dinitrate (1 to 2 mg). Computerized coronary artery diameter measurement of angiographically normal segments was carried out before and after ergonovine and nitrate administration. Mean baseline intraluminal diameter of proximal and distal coronary segments was not significantly different in control patients and those with variant angina (nonspastic segments only) or coronary artery disease (proximal 2.89 +/- 0.15. 2.83 +/- 0.14 and 2.82 +/- 0.09 mm; distal 1.60 +/- 0.08. 1.63 +/- 0.07 and 1.62 +/- 0.06 mm. respectively). After ergonovine. proximal segments constricted by 10 +/- 2%. 15 +/- 3% and 11 +/- 4% and distal segments by 11 +/- 3%. 11 +/- 2% and 14 +/- 3% in control. variant angina and coronary artery disease groups. respectively (p = NS).
Exercise intolerance in patients with heart failure and preserved left ventricular systolic function: failure of the Frank-Starling mechanism, Invasive cardiopulmonary exercise testing was performed in 7 patients who presented with congestive heart failure. normal left ventricular ejection fraction and no significant coronary or valvular heart disease and in 10 age-matched normal subjects. Compared with the normal subjects. patients demonstrates severe exercise intolerance with a 48% reduction in peak oxygen consumption (11.6 +/- 4.0 versus 22.7 +/- 6.1 ml/kg per min; p less than 0.001). primarily due to a 41% reduction in peak cardiac index (4.2 +/- 1.4 versus 7.1 +/- 1.1 liters/min per m2; p less than 0.001). In patients compared with normal subjects. peak left ventricular stroke volume index (34 +/- 9 versus 46 +/- 7 ml/min per m2; p less than 0.01) and end-diastolic volume index (56 +/- 14 versus 68 +/- 12 ml/min per m2; p less than 0.08) were reduced. whereas peak ejection fraction and end-systolic volume index were not different. In patients. the change in end-diastolic volume index during exercise correlated strongly with the change in stroke volume index (r = 0.97; p less than 0.0001) and cardiac index (r = 0.80; p less than 0.03). Pulmonary wedge pressure was markedly increased at peak exercise in patients compared with normal subjects (25.7 +/- 9.1 versus 7.1 +/- 4.4 mm Hg; p less than 0.0001). Patients demonstrated a shift of the left ventricular end-diastolic pressure-volume relation upward and to the left at rest. Increases in left ventricular filling pressure during exercise were not accompanied by increases in end-diastolic volume. indicating a limitation to left ventricular filling.
Quantitative assessment of ultrasonic myocardial reflectivity in hypertrophic cardiomyopathy, The purpose of this study was to investigate the relation between acoustic properties of the myocardium and magnitude of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy. An on-line radio frequency analysis system was used to obtain quantitative operator-independent measurements of the integrated backscatter signal of the ventricular septum and posterior free wall in 25 patients with hypertrophic cardiomyopathy and 25 normal age-matched control subjects. The integrated values of the radio frequency signal were normalized for the pericardial interface and expressed in percent. Tissue reflectivity was significantly increased in the hypertrophied ventricular septum. as well as in the nonhypertrophied posterior free wall. in patients with hypertrophic cardiomyopathy (58 +/- 15% and 37 +/- 12%. respectively) compared with values in normal subjects (33 +/- 10% and 18 +/- 5%. respectively; p less than 0.001). Furthermore. measurements of reflectivity of the septum or posterior free wall. or both. were beyond 2 SD of normal values in greater than 90% of the patients and were also abnormal in each of the five study patients who had only mild and localized left ventricular hypertrophy. No correlation was identified between myocardial tissue reflectivity and left ventricular wall thickness in the patients with hypertrophic cardiomyopathy (correlation coefficient r = 0.4; p = NS). These findings demonstrate that myocardial reflectivity is abnormal in most patients with hypertrophic cardiomyopathy and is largely independent of the magnitude of left ventricular hypertrophy. Moreover. quantitative analysis of ultrasonic reflectivity can differentiate patients with hypertrophic cardiomyopathy from normal subjects independently of clinical features and conventional echocardiographic measurements.
Adjacent solid boundaries alter the size of regurgitant jets on Doppler color flow maps, Recent studies have attempted to predict the severity of regurgitant lesions from jet size on Doppler flow maps. Jet size is a function of both regurgitant volume and fluid entrained from the receiving chamber and. for a free jet. is a function of its momentum at the orifice. However. regurgitant jets often approach or attach to cardiac walls. potentially altering their momentum and ability to expand by entrainment. Therefore. this study addressed the hypothesis that adjacent walls influence regurgitant jet size as seen on Doppler flow maps. Steady flow was driven through circular orifices (0.02 to 0.05 cm2) at physiologic velocities of 2 to 5 m/s. At a constant flow rate and orifice velocity. orifice position was varied to produce three jet geometries: free jets. jets adjacent to a horizontal chamber wall lying 1 cm below the orifice and wall jets with the orifice at the level of the wall. Doppler color flow imaging was performed at identical instrument settings for all jets. Two long-axis views of the jet were obtained: a vertical view perpendicular to the wall. resembling that most commonly used in patients to image the length of the jet. and a horizontal view parallel to the chamber wall. Velocities along the jet were also measured by Doppler mapping.
Effect of lesion characteristics on outcome of directional coronary atherectomy, Directional coronary atherectomy. a new transluminal procedure for treatment of obstructive lesions in coronary arteries by excision and removal of tissue. was performed on 447 lesions in 382 procedures. Successful outcome. defined as a reduction of stenosis by greater than or equal to 20% with a less than 50% residual stenosis. was achieved in 89.5% of lesions and mean stenosis was reduced from 75.9 +/- 13.3% to 14.5 +/- 22.1% (p less than 0.001). Complications included vessel occlusion during the procedure. 2.4%; vessel occlusion after the procedure. 1.3%; new lesion. 0.5%; nonobstructive guiding catheter-induced dissection. 0.3%; perforation. 0.8%; distal embolization. 2.1%; Q wave myocardial infarction. 0.8% and non-Q wave myocardial infarction. 4.2%. Twelve patients (3.1%) required coronary artery bypass surgery for these complications. The atherectomy success rate was greater than 80% and the combined atherectomy and angioplasty success rate was greater than 90% for complex morphologic features such as eccentric lesions. lengthy lesions. lesions with abnormal contour. angulated lesions. ostial lesions and lesions with branch involvement. In the presence of calcific deposition. atherectomy success rate was 52% for primary lesions and 83% for restenosed lesions. Among angiographically complex lesions. calcium was the predictor for failed atherectomy (p less than 0.0001). In summary. directional coronary atherectomy is safe and effective for treatment of obstructive lesions in coronary arteries in selected cases. In particular. it achieves a high success rate in lesions with complex morphologic characteristics. such as eccentricity. abnormal contour and ostial involvement.
Comparison of early versus late experience with percutaneous mitral balloon valvuloplasty, The immediate outcome of the first 150 patients (Group 1) and the last 161 patients (Group 2) who underwent percutaneous mitral balloon valvuloplasty was compared. There was no difference between the two groups in age. gender. New York Heart Association functional class. presence of calcification. atrial fibrillation. degree of mitral regurgitation. mean pulmonary artery pressure. left atrial pressure. cardiac output. pulmonary vascular resistance. mitral valve gradient and mitral valve area. Fewer patients in Group 1 than Group 2 had an echocardiographic score less than or equal to 8 (62% versus 69%. respectively. p = 0.02). The atrial septum was dilated with an 8 mm balloon in 74% of patients in Group 1 and with a 5 mm balloon in all patients in Group 2. Ratio of effective balloon dilating area to body surface area was larger in Group 1 than in Group 2 (4.05 +/- 0.07 versus 3.7 +/- 0.03 cm2/m2. p = 0.0001). A good result (mitral valve area greater than or equal to 1.5 cm2) was obtained in 77% and 75% in Groups 1 and 2. respectively (p = NS). After percutaneous mitral valvuloplasty. a greater than or equal to 2 grade increase in mitral regurgitation was noted in 12% of Group 1 and 6% of Group 2 (p = 0.02) and a left to right shunt was detected in 22% of Group 1 and 11% of Group 2 (p = 0.0001). There were three procedure-related deaths in Group 1. but none in Group 2.
Transcardiac release of leukotriene C4 by neutrophils in patients with coronary artery disease, Leukotriene C4 is a potent constrictor of smooth muscle in vitro and may induce coronary vasoconstriction in vivo. To study leukotriene C4 release by neutrophils in patients with coronary artery disease. neutrophils were separated from blood samples taken from the coronary sinus and aorta in 20 patients with stable exertional angina and angiographically documented coronary artery narrowings (group I). Eight patients with normal coronary arteries were also studied (group II). To assess leukotriene C4 generation. neutrophils were incubated with calcium ionophore A 23187 (0.25 microM) and the supernatants obtained after centrifugation were analyzed for leukotriene C4 by radioimmunoassay. Patients in group I had a significantly lower release of leukotriene C4 from neutrophils separated from the coronary sinus blood than from those separated from aortic blood (4.33 +/- 0.69 versus 5.92 +/- 0.54 ng/ml. p less than 0.025). whereas patients in group II had a similar release of leukotriene C4 by the neutrophils separated from coronary sinus blood and from aortic blood (6.0 +/- 0.72 versus 6.4 +/- 0.66 ng/ml. p = NS). Moreover. in group I patients. a significant correlation was found (p less than 0.01) between the extent of coronary artery disease (expressed by the Leaman coronary score) and the percent reduction in leukotriene C4 released from neutrophils separated from coronary sinus blood as compared with leukotriene C4 produced by neutrophils separated from aortic blood. These data show that neutrophils from patients with coronary artery disease have a reduced ability to produce leukotriene C4 after stimulation by calcium ionophore A 23187.
Recovery of retrograde fast pathway excitability in the atrioventricular node reentrant circuit after concealed anterograde impulse penetration, The recovery of the retrograde fast pathway excitability in atrioventricular (AV) node reentry has been difficult to assess with ventricular extrastimulation because of difficulty in achieving sufficiently short intranodal coupling intervals and the potential interposition of "lower common pathway" nodal tissue. To circumvent these methodologic obstacles in 10 patients with inducible AV node reentrant tachycardia. a fixed atrial extrastimulus (A2) coupled to a basic atrial drive (A1) at a cycle length of 500 ms was utilized to reproducibly initiate AV node reentrant echoes. A ventricular extrastimulus (V3) was then introduced after A2 at progressively shorter coupling intervals (A2V3) in an attempt to pre-excite the retrograde fast pathway after concealed anterograde penetration by A2. In six patients. retrograde fast pathway pre-excitation was achieved at critical A2V3 intervals. as evidenced by the appearance of A3 by up to 28 +/- 6 ms in advance of the expected first AV node reentrant echo. In five of the six cases. the V3A3 interval was virtually unaltered (less than or equal to 5 ms decrease) when A2 was omitted. In seven patients. at a critically short A2V3 coupling interval (195 +/- 27 ms ). V3 abruptly failed to elicit A3 and concomitantly abolished all AV node echoes; yet when A2 was omitted. an A3 response returned. with V3A3 identical to previous values.
Hypoplastic left heart syndrome: hemodynamic and angiographic assessment after initial reconstructive surgery and relevance to modified Fontan procedure, After undergoing initial reconstructive surgery for hypoplastic left heart syndrome performed between August 1985 and March 1989. 59 patients (age range 3 to 27 months. mean 13.8 +/- 4.5) underwent elective cardiac catheterization in anticipation of a modified Fontan procedure. Five important hemodynamic and anatomic features considered to be components of successful reconstructive surgery were specifically addressed. 1) Interatrial communication: Only two patients had a measured pressure difference of greater than 4 mm Hg across the atrial septum. 2) Tricuspid valve function: Angiography demonstrated significant tricuspid valve regurgitation in only five patients (moderate in two and severe in three). 3) Aortic arch: Pressure tracings from the right ventricle to the descending aorta revealed a gradient greater than 25 mm Hg in only two patients. 4) Pulmonary vasculature: Ten patients had a calculated pulmonary vascular resistance greater than 4 U.m2; 51 (86%) of the 59 patients had no evidence of distortion (stenosis or hypoplasia) of either the left or the right pulmonary artery. 5) Right ventricular function: Five patients had an end-diastolic pressure in the right ventricle greater than 12 mm Hg and two patients had qualitative assessment of decreased ventricular function. Comparison of catheterization data between survivors and nonsurvivors of the subsequent modified Fontan procedure showed that only significant tricuspid regurgitation is a possible predictor of poor outcome. After first stage reconstructive surgery for hypoplastic left heart syndrome. most survivors have favorable anatomy and hemodynamics at follow-up cardiac catheterization for a subsequent Fontan procedure.
Pathologic spectrum of malformations of the tricuspid valve in prenatal and neonatal life, The morphologic spectrum of malformations of the tricuspid valve in 14 fetal and 5 neonatal heart specimens is described. Echocardiography during fetal life had revealed the valvular malformations along with dilation of the right-sided chambers of the heart and atrioventricular (AV) valve incompetence. This functional impairment reflected either Ebstein's malformation (10 cases) or dysplasia of valve leaflets having a normal junctional attachment (9 cases). The right atrium and right ventricle were markedly enlarged. and heart weight was increased to 181% (median) and 179% (median) in the groups with Ebstein's malformation and valvular dysplasia. respectively. In contrast. lung weight was in the lower range of normal. showing a decrease of 67% (median) in patients with Ebstein's malformation and of 43% (median) in those with valvular dysplasia. One ventricular septal defect and six atrial septal defects were noted in each group. Severe obstruction at the level of the pulmonary valve was seen in 40% of the group with Ebstein's malformation and in 66% of those with valvular dysplasia. The most important factor in the particularly poor prognosis in these patients is the incompetence of the tricuspid valve. leading to right atrial enlargement and subsequent pulmonary hypoplasia. No significant difference was found between the pathologic features of fetal and neonatal hearts and no features that might have prompted the valve to become regurgitant during fetal life were identified.
Balloon valvuloplasty for critical aortic stenosis in the newborn: influence of new catheter technology, Between 1986 and July 1990. balloon valvuloplasty was attempted in eight newborns (less than 28 days of age) with isolated critical aortic valve stenosis. Balloon valvuloplasty could not be successfully accomplished in any of the three infants presenting before 1989. Since March 1989. when improved catheter technology became available. all five neonates presenting with critical aortic stenosis were treated successfully by balloon valvuloplasty. A transumbilical approach was utilized in all four infants in whom umbilical artery access could be obtained. One newborn who was 25 days of age underwent transfemoral balloon valvuloplasty. Balloon valvuloplasty was immediately successful in all five newborns. as evidenced by a decrease in valve gradient and improvement in left ventricular function and cardiac output. Peak systolic gradient was reduced by 64% from 69 +/- 8 to 25 +/- 3 mm Hg (p = 0.005). Left ventricular systolic pressure decreased from 128 +/- 9 to 95 +/- 9 mm Hg (p = 0.02) and left ventricular end-diastolic pressure decreased from 20 +/- 2 to 11 +/- 1 mm Hg (p = 0.02). Moderate (2+) aortic regurgitation was documented in two infants after valvuloplasty. The time from first catheter insertion to valve dilation averaged 57 +/- 14 min (range 26 to 94) and the median length of the hospital stay was 4 days. With the use of recently available catheters. the transumbilical technique of balloon valvuloplasty can be performed quickly. safely and effectively in the newborn with critical aortic stenosis. It does not require general anesthesia. cardiopulmonary bypass or a left ventricular apical incision and it preserves the femoral arteries for future transcatheter intervention should significant aortic stenosis recur.
Immediate and short-term cardiovascular effects of fosinopril, a new angiotensin-converting enzyme inhibitor, in patients with essential hypertension, Immediate and short-term cardiovascular effects of a new angiotensin-converting enzyme inhibitor. fosinopril. were assessed in 10 patients with mild to moderate essential hypertension. Administration of a 10 mg oral dose of fosinopril reduced mean arterial pressure (p less than 0.001) as a result of a 24% fall in total peripheral resistance (p less than 0.001). Short-term therapy (12 weeks) maintained the decrease in mean arterial pressure (p less than 0.05) by decreasing total peripheral resistance (p less than 0.01). without reflexive cardiac stimulation or expanding intravascular volume. Renal vascular resistance decreased (p less than 0.05) while renal blood flow. glomerular filtration rate and filtration fraction remained unchanged. The response pattern to mental. isometric and orthostatic stress was similarly unchanged. Left ventricular mass diminished by 11% (p less than 0.01); myocardial contractility was unaffected. Afterload was reduced (p less than 0.05). and velocity of circumferential fiber shortening and stroke volume increased (p less than 0.05). Thus. arterial pressure reduction produced by fosinopril was associated with improved systemic and renal hemodynamics and reduced left ventricular mass.
Regional diastolic mechanics of ischemic and nonischemic myocardium in the pig heart, To assess the role of segmental dyssynchrony as a determinant of ischemic diastolic dysfunction. systolic and diastolic mechanics of ischemic and nonischemic myocardium were compared in the open chest pig heart (n = 7). Pacing tachycardia (1.8 x heart rate at rest) was imposed for 3 to 5 min in the presence of a single critical stenosis of the left anterior descending artery (demand ischemia. n = 7). After 30 min of recovery. the left anterior descending artery was totally occluded for 1.5 min in the same pigs (primary ischemia. n = 6). Both demand and primary ischemia increased left ventricular end-diastolic pressure and prolonged the time constant of left ventricular pressure decline. Percent systolic shortening of ischemic segments (perfused by the left anterior descending artery) decreased by 32% during demand ischemia and by 120% during primary ischemia. but that of nonischemic segments (perfused by the left circumflex artery) did not change significantly during either type of ischemia. During demand ischemia (but not during primary ischemia). left ventricular diastolic pressure increased relative to segment length so that a higher diastolic pressure was needed to stretch the ischemic segment to the same length (decreased distensibility). In nonischemic areas. diastolic pressure and segment length increased commensurately during both types of ischemia. indicating no change in diastolic distensibility. During demand ischemia. peak early diastolic lengthening rates increased in nonischemic segments but remained unchanged in ischemic segments. Diastolic segmental dyssynchrony developed during both types of ischemia. but was more pronounced during primary ischemia. Therefore. segmental dyssynchrony is unlikely to account for the rise in diastolic pressure relative to segment length seen during demand ischemia.
Standards for analysis of ventricular late potentials using high-resolution or signal-averaged electrocardiography: a statement by a task force committee of the European Society of Cardiology, the American Heart Association, and the American College of Cardiology, Sufficient data are available to recommend the use of the high-resolution or signal-averaged electrocardiogram in patients recovering from myocardial infarction without bundle branch block to help determine their risk for developing sustained ventricular tachyarrhythmias. However. no data are available about the extent to which pharmacological or nonpharmacological interventions in patients with late potentials have an impact on the incidence of sudden cardiac death. Therefore. controlled. prospective studies are required before this issue can be resolved. As refinements in techniques evolve. it is anticipated that the clinical value of high-resolution or signal-averaged electrocardiography will continue to increase.
Is preoperative ultrasound cancer survey necessary in patients with normal liver function tests, Abdominal ultrasound examination is so easy that it may be overused. To reduce medical costs. we investigated whether preoperative ultrasonic abdominal survey was necessary for oncologic patients with normal liver function tests. We used the ultrasound diagnosis as the final standard to test the value of liver function tests for the prediction of liver metastases. Five hundred forty-four patients with various primary malignancies were referred for preoperative ultrasonic survey of the abdomen. The results showed that for a single test. serum albumin was most sensitive (87.2%) but least specific (29.4%). and serum bilirubin was least sensitive (13.0%) but most specific (97.2%). for the prediction of liver metastases. For a combination of five tests or more. the sensitivity was 95.9% and the specificity 29.5%. In patients with normal liver function tests. liver metastases were detected by ultrasound in two of 106 (1.9%) patients. One hundred of 544 (18.4%) patients having major abnormalities that may influence clinical management were also detected during the ultrasound examination. We conclude that ultrasound is convenient. cheap. and without side effects. It can provide additional information affecting patient management. even in the presence of normal liver function tests.
Dysphagia and esophageal motor dysfunction in gastroesophageal reflux are corrected by fundoplication, Abnormalities in esophageal peristaltic function and acid clearance appear to be responsible for prolonged esophageal acid exposure. a major determinant of the reflux esophagitis and esophageal stricture. We evaluated esophageal motility by manometry in 50 healthy controls and in 35 symptomatic reflux patients before. within 6 months. and 1 year after Nissen fundoplication. Preoperative motility was analyzed in relation to the presence or absence of both nonobstructive dysphagia and erosive esophagitis. We found that (a) preoperative dysphagia was related more to peristaltic dysfunction than to esophagitis; (b) peristaltic wave amplitude and duration were significantly lower than control values in patients with reflux. without correlation to degree of esophagitis or lower esophageal sphincter hypotension; (c) dysphagia ceased in most patients after antireflux surgery at the same time that normal motility was restored independently of lower esophageal sphincter pressure increments. These results suggest that motility disturbances are an important cause of dysphagia in reflux disease. and that reflux is the cause of. rather than the consequence of. peristaltic dysfunction.
Crack-related perforated gastropyloric ulcer, Cocaine is a potent topical vasoconstrictor that causes nasal mucosal and dermal ulceration. Use of the purified cocaine derivative "crack" has reached epidemic proportions in large cities. In 18 months we operated on 24 patients with perforated peptic ulcers. Five of the patients were young (27-38 years) male crack users without prior history of gastric symptoms who presented with a perforated gastric ulcer related to smoking crack. Three had had symptoms for only 1-5 days before admission. All five were afebrile. had a rigid abdomen. normal leukocyte count. and free intraabdominal air upon radiography. Five other age-matched. non-crack-using patients served as case controls. Their duration of symptoms was 1-24 months. they had elevated leukocyte counts on admission. and. in contrast to the crack users. four of these patients had duodenal perforations. The clinical presentation of the crack smokers and the unusual localization of the perforations imply different pathogenetic mechanisms than are commonly seen in perforated ulcer disease. With increasing abuse of crack. greater numbers of patients with this new complication may be expected to present to emergency services in urban areas.
The pitted duodenal bulb, The radiologic. endoscopic. and histologic findings in two patients with flaskshaped or collar-button collections of barium in the duodenum are presented. These abnormal mucosal depressions. which may be related to inflammation. were seen endoscopically and identified radiographically and have not been reported previously.
A controlled trial of beclomethasone versus betamethasone enemas in distal ulcerative colitis, Steroid enemas are widely used in distal inflammatory bowel disease (IBD). They are partly absorbed and suppress adrenocortical function. Beclomethasone dipropionate (BD) is a topically active steroid that undergoes rapid first-pass inactivation in the liver and is practically devoid of systemic side effects. We treated 32 consecutive patients with active distal ulcerative colitis (40 attacks) with 0.5 mg BD and/or 5 mg betamethasone phosphate (BP) enemas for 28 days. Clinical. laboratory. sigmoidoscopic. and histologic data were recorded before. during. and after the trial. The clinical efficacy of both treatments was similar. Betamethasone was slightly more effective in relation to the histologic improvement and disappearance of blood from the stools. Clinical signs of steroid overdosage were noted in patients on BP but not in patients on BD. Mean fasting plasma cortisol at the end of the trial was 2.9 micrograms/dl in the BP group and 15.3 micrograms/dl in the BD group. The adrenocorticotropin test was markedly suppressed in the BP group but not in the BD group. The absence of systemic steroid side effects makes BD enemas a useful addition in the therapy of IBD. Its oral administration should also be considered.
Colonoscopy without prior preparation in mild to moderate active ulcerative colitis, We evaluated the effect of different types of preparations on the diagnostic yield of colonoscopy (total or limited) in mild to moderate active ulcerative colitis. Our ability to determine the extent of disease and see the mucosa beyond the inflamed areas was assessed in patients receiving no preparation (group A. 72 examinations) and those receiving diphosphosoda enemas (group B. 181 examinations). There were three failures in group A and 11 in group B. In the majority of patients (71% of group A. 83% of group B) the scope could be passed under optimal viewing conditions at least one segment beyond the involved area. In group A the cecum was reached in 16% of the procedures and in group B in 18%. We conclude that in mild to moderate active ulcerative colitis. colonoscopy can be performed without preparation. and still achieve the same results as with preparatory enemas.
Cimetidine in the treatment of acetaminophen overdose, Acetaminophen overdose is generally treated with oral N-acetylcysteine. While N-acetylcysteine is protective. an additional effective mode of treatment is desirable in large overdoses. A growing body of evidence suggests that cimetidine significantly reduces the hepatotoxicity of an acetaminophen overdose and that its hepatoprotective action may be additive to that of N-acetylcysteine. We report a case of acetaminophen overdose treated with oral N-acetylcysteine in conjunction with cimetidine by continuous i.v. infusion. The 4-h acetaminophen level was 410 micrograms/ml. and the highest measured level of serum glutamic oxaloacetic transaminase was 83 IU/L on day 3. indicating minimal hepatic toxicity.
Prevalence of ulcerative colitis in the Israeli kibbutz population, We carried out an epidemiological study of ulcerative colitis in 279 Israeli kibbutzim (121.403 population). The prevalence on December 31. 1987 was 121.08 per 100.000 population. When the data were stratified according to ethnic groups. the highest point prevalence was found in Israeli-born Jews (220.56 per 100.000 population). more than in Asian-African-born. or European-American-born kibbutz members (139.20 and 78.73 cases per 100.000 population. respectively). There were 68 men and 78 women (ratio of 0.87). The average age of the patients in the year of this survey was 46 years; it was 35 years at the time of diagnosis. Proctitis was found in 57%. left-sided colitis in 12%. and substantial or total colitis in 31%. Relapse at pregnancy was demonstrated in seven patients. and remission in one. Family history of a first-degree relative with inflammatory bowel disease was documented in three patients (2%). Probable complications of ulcerative colitis were observed in 38 (26%). anemia in 13 (9%). One patient (0.7%) with rectal cancer. also had breast cancer. We suggest that the impressive increase in ulcerative colitis prevalence among Israeli and Asian-African-born. in comparison with European-American-born kibbutz members. points toward a role of environmental factors in the etiology of this disease.
Retinoic acid receptor gene expression in human skin, Human skin exhibits a characteristic. pleiotypic response to topical retinoic acid. In attempting to understand this response at the molecular level. we have used fast protein liquid chromatography (FPLC) and RNA blot hybridization to characterize the expression of the nuclear retinoic acid receptor (RAR) alpha. beta. and gamma genes in adult human epidermis. Size exclusion FPLC of 0.6 M NaCl nuclear extracts prepared from keratome biopsies revealed two peaks of specific [3H] retinoic acid (RA) binding at Mr 45 and 18 kDa. in agreement with the expected sizes of RAR and cellular RA binding protein. Blot hybridization analysis of total RNA extracted from keratome biopsies revealed that RAR-gamma was the predominant RAR species expressed in human epidermis. as RAR-alpha transcripts were detectable only at low levels and RAR-beta transcripts were undetectable. RAR transcripts were not induced by topical treatment with 0.1% RA cream under occlusion for 4 h or 4 d. Moreover. there was no significant difference in RAR-gamma transcript levels in normal and psoriatic epidermis. RAR-gamma transcripts were constitutively expressed not only in cultured human keratinocytes. but also in human dermal and lung fibroblasts. RAR-beta was induced by RA in dermal fibroblasts. but not in keratinocytes. RA induced IL-1 beta transcripts in keratinocytes rapidly (2 to 4 h) and at low concentrations (3 x 10(-10) M). consistent with activation of the IL-1 beta gene via RAR. These results demonstrate constitutive expression of RAR-gamma in human epidermis. and suggest that RAR-gamma is a molecular target of RA action in adult human skin.
Neuropeptides in psoriasis: an immunocytochemical and radioimmunoassay study, The present study examines the presence of neuropeptides in the skin and plasma of patients with psoriasis using the techniques of immunocytochemistry and radioimmunoassay. Immunocytochemistry failed to demonstrate differences in the pattern of neuropeptide innervation in psoriatic lesional skin when compared to normal skin. However. radioimmunoassay of skin biopsy extracts. both substance P and vasoactive intestinal polypeptide. were significantly elevated in psoriatic lesional skin when compared with both psoriatic non-lesional and normal control skin (p less than 0.001). There was no significant difference between the plasma levels of neuropeptides in psoriatic patients compared to those of control subjects. and no significant correlation among the plasma levels of neuropeptides with the surface area of involvement with psoriasis. The finding of elevated levels of substance P and vasoactive intestinal polypeptide in lesional psoriatic skin suggests that these peptides may be involved in the pathogenesis or maintenance of the psoriatic skin lesion and the development of safe and stable antagonists of these neuropeptides may have applications in the treatment of psoriasis.
Responsiveness to interleukin 4 and interleukin 2 of peripheral blood mononuclear cells in atopic dermatitis, Although the pathogenesis of atopic dermatitis (AD) is unknown. many immunologic abnormalities such as high levels of serum IgE and increase of IgE Fc receptor-positive lymphocytes have been demonstrated. Recently. interleukin 4 (IL-4) has been shown to induce enormously the production of IgE and to enhance the expression of IgE Fc receptor by B cells. suggesting the possible involvement of IL-4 in the pathogenesis of AD. We examined IL-4 responsiveness or interleukin 2 (IL-2) responsiveness of peripheral blood mononuclear cells of 31 patients with AD. 19 healthy individuals. and seven patients with other skin diseases. We found that IL-4 responsiveness of AD was higher than that of non-AD control. although IL-2 responsiveness of AD showed no significant change. However. the value of the IL-4 responsiveness did not significantly correlate with the clinical severity. personal history of respiratory allergy. serum IgE level. or clinical course of patients with AD. The hyperresponsiveness to IL-4 detected in AD was not likely to be due to the effects of steroids or anti-mast cell drugs because the value of IL-4 responsiveness was significantly low. compared to AD. in patients with other skin diseases who were treated similarly. Because the T-cell-enriched population. but not the B-cell-enriched population. showed significant proliferation in response to exogenous IL-4 or IL-2. T cells were the main population that reacted in our proliferation assay. These results indicate that IL-4-driven proliferative response may be efficiently operative in T cells in patients with AD.
Characterization of cutaneous infiltrates in MRL/lpr mice monitored from onset to the full development of lupus erythematosus-like skin lesions, The skin is a primary site injured in lupus erythematosus (LE). but it is still controversial whether the injury is due to cells of the mononuclear infiltrate and which immunocompetent cells play the major role in the development of cutaneous LE. To better characterize the role of immunocompetent cells. we performed an immunohistochemical examination of these cells in LE-like skin lesions in MRL/Mp-lpr/lpr (MRL/lpr) mice. Skin lesions in 60 female MRL/lpr mice were monitored from onset to full development. Skin specimens from each stage were stained for epidermal Ia+ Langerhans cells (Ia(+)-LC). for Thy-1+ dendritic epidermal cells (Thy-1+DEC). and for the phenotype of the mononuclear cell infiltrates. The numbers of Ia(+)-LC and Thy-1+DEC were decreased markedly in the skin lesions at the later stage. However. the numbers of Ia(+)-LC were increased significantly in the central portion of lesions at an early stage and in the peripheral portion of lesions later. L3T4+ cells were predominant. and the L3T4/Lyt-2 ratio was high in dermal infiltrates at an early stage. With advancing stage. the L3T4/Lyt-2 ratio gradually decreased in dermal infiltrates. whereas the Thy-1.2/Lyt-2 ratio in lymph nodes was reversed. L3T4+ cells were especially predominant in dermal infiltrates under the epidermis with increased numbers of Ia(+)-LC. This immunohistochemical analysis of a mouse model of cutaneous LE revealed changes in immunocompetent cell populations with the evolution of skin lesions. and we conclude that Ia(+)-LC and Thy-1+DEC. as well as L3T4+ and Lyt-2+ cells. may play pathogenic roles in the development of skin lesions.
Selective expression of immune-associated surface antigens by keratinocytes in irritant contact dermatitis, The expression of three immunoregulatory surface antigens by epidermal keratinocytes was studied in irritant contact dermatitis (ICD). in order to assess whether keratinocytes have a modulatory role in the pathogenesis of this disorder. Biopsies were taken from 48-h patch test reactions to six structurally unrelated irritants. and frozen sections immunolabeled with monoclonal antibodies to the major histocompatibility complex class II antigen. HLA-DR. intercellular adhesion molecule-1 (ICAM-1). and the 88-Kd glycoprotein CD36 (OKM5). as well as to the CD3 (T cells) and CD11a (lymphocyte function associated antigen-1. LFA-1) antigens. We found that there was very limited expression of HLA-DR by keratinocytes. with no correlation between the extent of HLA-DR positivity and the degree of T cell infiltration into the epidermis and dermis. suggesting that interferon gamma may not be a significant mediator of ICD at 48 h. In contrast. keratinocytes showed extensive upregulation of ICAM-1. with an excellent spatial association between ICAM-1 expression and LFA-1 positive leucocytes in the epidermis. This indicates that keratinocyte ICAM-1 induction is not restricted to diseases in which antigen presentation is pivotal. but that it has a generalized role in cutaneous inflammatory reactions. promoting the infiltration of leucocytes into the epidermis. Immunolabeling with OKM5 revealed that CD36 is present to a variable degree on keratinocytes in normal skin. Differential changes in the pattern of keratinocyte expression occurred between irritants. in a manner that suggested that the CD36 antigen does not act as an adhesion molecule in ICD. but rather that its expression is related to the proliferative state of the epidermis. The results of this study demonstrate that immune-associated antigens are selectively expressed on the surface of keratinocytes in 48-h ICD biopsies. implying that these cells play an important regulatory role in the development of the inflammatory response to irritant chemicals.
Decreased level of ceramides in stratum corneum of atopic dermatitis: an etiologic factor in atopic dry skin, Stratum corneum lipids are an important determinant for both water-retention function and permeability-barrier function in the stratum corneum. However. their major constituent. ceramides. have not been analyzed in detail in skin diseases such as atopic dermatitis that show defective water-retention and permeability-barrier function. In an attempt to assess the quantity of ceramides per unit mass of the stratum corneum in atopic dermatitis. stratum corneum sheet was removed from the forearm skin by stripping with cyanoacrylate resin and placed in hexane/ethanol extraction to yield stratum corneum lipids. The stratum corneum was dispersed by solubilization of cyanoacrylate resin with dimethylformamide. and after membrane filtration. the weight of the stratum corneum mass was measured. The ceramides were quantified by thin-layer chromatography and evaluated as microgram/mg stratum corneum. In the forearm skin of healthy individuals (n = 65). the total ceramide content significantly declined with increasing age. In atopic dermatitis (n = 32-35). there was a marked reduction in the amount of ceramides in the lesional forearm skin compared with those of healthy individuals of the same age. Interestingly. the non-lesional skin also exhibited a similar and significant decrease of ceramides. Among six ceramide fractions. ceramide 1 was most significantly reduced in both lesional and non-lesional skin. These findings suggest that an insufficiency of ceramides in the stratum corneum is an etiologic factor in atopic dry skin.
Normotensive young men with family histories of hypertension gain weight and decrease their intraerythrocyte sodium content during a 5-year follow-up, Young normotensive men matched for age and body mass index with (n = 16) and without (n = 13) family histories of hypertension were investigated at baseline and after 5 years of follow-up with respect to blood pressure. body weight and intracellular sodium content. Subjects with positive family histories of hypertension increased significantly in body weight (from 81.9 +/- 11.5 kg to 89.5 +/- 11.4 kg. P less than 0.001) compared to subjects with negative family histories of hypertension (from 79.9 +/- 10.8 kg to 80.7 +/- 12.2 kg. NS). Their blood pressure did not differ initially (137 +/- 12/75 +/- 11 mmHg vs. 135 +/- 8/72 +/- 9 mmHg). but was reduced in subjects without family histories of hypertension (to 125 +/- 3/68 +/- 13 mmHg) in the follow-up examination. At follow-up. body mass index showed a positive correlation with blood pressure among subjects with positive family histories of hypertension (r = 0.77. P less than 0.001). At baseline. subjects with hypertensive fathers had significantly higher intraerythrocyte sodium levels than subjects with normotensive parents. At re-examination 5 years later. this difference was no longer present. We conclude that normotensive subjects with positive family histories of hypertension are predisposed to gain weight rather than to show an increase in blood pressure at this age. Normalization of intracellular sodium content. as found in the present study. could be a consequence of this weight gain and the ensuing metabolic adaption.
Determinants of carotid intima-media thickness: a population-based ultrasonography study in eastern Finnish men, We investigated the determinants of maximal intima-media thickness of common carotid arteries in a population-based sample of 1224 Eastern Finnish men aged 42. 48. 54 or 60 years. A high-resolution B-mode ultrasonographic examination was performed as part of the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD). The maximal intima-media thickness (IMT) varied between 0.48 mm and 4.09 mm (mean value +/- SD. 0.94 mm +/- 0.38 mm). Age (standardized partial coefficient. beta = 0.238. P less than 0.0001). ambulatory pulse pressure (beta = 0.130. P less than 0.0001). cigarette-years of smoking (beta = 0.125. P less than 0.0001). serum LDL cholesterol concentration (beta = 0.125. P less than 0.0001). history of ischaemic heart disease (beta = 0.125. P less than 0.0001). pre-exercise systolic blood pressure (beta = 0.070. P = 0.0113) and diabetes (beta = 0.068. P = 0.0072) were most strongly associated with IMT. This study confirms the role of systolic blood pressure. smoking and serum LDL cholesterol levels as major risk factors for increased carotid intima-media thickness.
Atrial fibrillation and left atrial enlargement: cause or effect, In a blinded controlled study. 58 consecutive patients with definite left atrial enlargement (M-mode dimension of at least 45 mm) were followed up after 1-2 years. The aim of the study was to examine the following: (a) the prospective risk of developing atrial fibrillation (AF); and (b) the effect of the heart rhythm on the left atrial size. Of 36 patients in sinus rhythm. one developed paroxysmal AF and one developed persistent AF during a median follow-up period of 20 months. Thus the incidence of new AF was 5% per year. Eighteen patients died before scheduled echocardiographic follow-up. but in the remaining subjects the left atrial dimension did not change significantly: the median increment was 1 mm in 20 patients who sustained sinus rhythm vs 2 mm in 16 patients with chronic AF (P greater than 0.05). Although left atrial dilatation may cause AF and vice versa. this study demonstrated that the incidence of new AF is low. despite the fact that the left atrial dimension is substantially increased. Similarly. AF per se does not appear to have any major impact on the left atrial dimension.
Antibodies to neutrophil granulocyte myeloperoxidase and elastase: autoimmune responses in glomerulonephritis due to hydralazine treatment, Autoantibodies against myeloperoxidase and elastase were found in a study of nine patients who had developed glomerulonephritis after treatment with hydralazine. but not in patients who were treated with hydralazine without side-effects. Circulating IgM isotype antibodies against myeloperoxidase. and IgM and IgG anti-elastase. were mainly present during the initial months after withdrawal of the drug. By contrast. IgG isotype antibodies against myeloperoxidase. initially found in seven patients. had increased in concentration and were present in all patients at follow-up after 4-12 years.
Antacid-induced osteomalacia: a case report with a histomorphometric analysis, The case of a 75-year-old woman with severe osteomalacia secondary to ingestion of large amounts of an aluminum-containing antacid is reported. Biochemical analysis revealed signs of phosphate malabsorption and increased levels of bone markers (S-alkaline phosphatase and U-hydroxyproline). A 99mTc-bone scan revealed multiple areas of increased uptake. The patient was normocalcaemic. with normal serum levels of intact parathyroid hormone and 25-hydroxyvitamin D. Serum 1.25-dihydroxyvitamin D was high normal. A transiliac bone biopsy from the patient showed severe osteomalacia. Symptoms. biochemical parameters. bone scan and bone morphology were all normalized 1 year after stoppage of antacid ingestion and treatment with vitamin D2. calcium phosphate and sodium fluoride because of severe osteopeni. The characteristics of this condition and the role of phosphate depletion and aluminum in the pathogenesis of bone lesions are discussed.
Counterregulatory hormonal response to insulin-induced hypoglycaemia in insulin-dependent diabetic patients: a comparison of equimolar amounts of porcine and semisynthetic human insulin, The aim of the present study was to compare the degree of hypoglycaemia. the hypoglycaemic symptom score and counterregulatory responses to equimolar amounts of intravenously administered porcine and semisynthetic human insulin in a double-blind crossover study in insulin-dependent diabetic patients. After overnight stabilization of blood glucose to approximately 6 mmol l-1. insulin was infused from 06.00 hours at such a rate as to keep the blood glucose concentration constant at 6 mmol l-1. At 09.00 hours hypoglycaemia was induced by increasing the infusion rate to give a blood glucose level of 2 mmol l-1 within about 60 min. The individual infusion rate from the first test was repeated in the second test. 1 week later. Blood glucose minimum levels were 2.1 (range. 1.3-2.9) and 2.1 (1.3-2.8) mmol l-1 for porcine and human insulin. respectively. The insulin concentrations at blood nadirs were 107 (66-180) and 107 (56-184) pmol l-1. respectively. for porcine compared to human insulin (NS). Symptom scores at minimum blood glucose concentrations were 43 and 46. respectively. with a maximal difference in intensity of 1 point in each patient. There were no statistical differences in the counterregulatory responses of glucagon. epinephrine. norepinephrine. cortisol. growth hormone. prolactin. beta-endorphine or in serum-potassium decreases. Patients were unable to discriminate between the two forms of insulin. It is concluded that there are no differences between porcine and semisynthetic insulin with regard to glucose fall. hormonal counterregulation or symptom scores. when the two forms of insulin are administered intravenously in equimolar amounts.
Gunshot entrance wound abrasion ring width as a function of projectile diameter and velocity, The relationships between gunshot entrance wound abrasion ring widths versus projectile diameter and velocity. using foam-backed deer hides as targets. were investigated. At a fixed velocity. abrasion ring width increased with increasing projectile diameter but decreased in proportion to the central defect diameter. For fixed-diameter projectiles. very slow and high velocities produced minimal abrasion width. Maximal abrasion width occurred at intermediate velocities. The authors postulate that abrasion width is a function of the ratio of projectile velocity and the maximum deformation velocity of the target skin. The largest abrasion width occurs when the ratio is one. Using a projectile velocity known to produce maximum abrasion width at an initial warm temperature. then decreasing the target deformation velocity by cooling. produced the expected results of decreasing abrasion width.
A comparison of three computer models for prediction of dose in acute amitriptyline overdose, The pharmacokinetics of amitriptyline in overdose have been reported not to fit conventional compartmental models. In this study. the dose-concentration-time relationships of amitriptyline in overdose were modeled with discriminant analysis. with an evolutionary heuristic search program. and with a decision-tree model based on the entropy of uncertainty of classification. The computer models all used the same data from dogs administered treatment (80 mg/kg). toxic (250 mg/kg). or fatal (500 mg/kg) doses directly into the surgically isolated duodenum. All the models achieved a high degree of success (77 to 93%) in assigning records to the high-. low-. or middle-dose groups. Two of the models gave a probability of the assignment. Results of this analysis suggest that blood amitriptyline and nortriptyline concentrations are most useful in estimating dose in acute amitriptyline overdose.
The toxicological examination of the victims of the British Air Tours Boeing 737 accident at Manchester in 1985, The results of toxicological analyses of the body fluids of the victims from the accident involving the British Air Tours Boeing 737 in August 1985 are presented for carboxyhemoglobin. cyanide. and volatiles. All the victims except one had raised concentrations of carbon monoxide. All the victims had raised concentrations of cyanide. All the victims showed the presence of volatile substances in the blood. Autopsies revealed that all the victims had carbon particles in the trachea and bronchi. Thus. all the victims must have inhaled fire products in the burning aircraft cabin. Six victims had concentrations of carbon monoxide or cyanide in the blood that were neither fatal nor incapacitating; therefore. it is reasonable to suggest that these six victims survived for a comparatively short time and that there may have been other causes. in addition to toxic fumes. for their deaths. The other 48 victims must have survived long enough in the fire to accumulate incapacitating or fatal concentrations of carbon monoxide or cyanide or both. The effects of these substances found in the blood of each of the 48 victims must have combined to produce an insurmountable impediment to escape from the aircraft.
Recognition of cemetery remains in the forensic setting, Cemetery remains exposed through vandalism or natural phenomena are frequently brought to the attention of law enforcement agents or medical examiners. Although it is often difficult to distinguish cemetery remains from those of medicolegal significance. clues to their origin may exist. Characteristics consistent with cemetery remains include physical characteristics associated with the embalming process. Characteristics indicative of cemetery remains include functional or ornamental artifacts associated with the coffin. devices used in embalming the body. and elevated levels of embalming chemicals in the soft tissue.
Sarcosaprophagous fly activity in Maryland, Eighty-six successful rearings of sarcosaprophagous flies characteristic of the first successional insect wave of infestation of a corpse were conducted under field conditions in Maryland. Different species were observed to be active during spring and summer. The development times for the immature stages of each species. with the related temperatures at which the development occurred are reported for both seasons studied.
Radiographic identification by mastoid sinus and arterial pattern, A skull and some incomplete postcranial remains were discovered in two searches over a two-month period near Santa Fe. New Mexico. The discoveries could be demonstrated to be from the same person. and the remains were shown to be consistent with a specific missing person on the basis of anthropological analysis. Further work led to a positive identification on multiple grounds. including agreement of the details of the mastoid sinus and endocranial arterial patterns observed radiographically. These features may be useful for establishing positive identification from skeletal remains when antemortem radiographic studies for comparison are limited to lateral cranial vault studies.
Skeletal muscle as an alternative specimen for alcohol and drug analysis, In a random group of medical examiner cases. muscle tissue. as well as blood and vitreous humor. was analyzed for ethyl alcohol. and the results were compared. When the blood concentration was greater than 0.10 g/dL. the muscle to blood ratio was 1.00 or less (average 0.94). and when the blood concentration was less than 0.10 g/dL. this ratio was greater than 1.00 (average 1.48). The author proposes that this ratio is dependent upon the time course of absorption and distribution. as has been observed for vitreous humor. but with a more rapid equilibration. Muscle tissue was also analyzed in another group of cases found to be positive for one or more drugs in blood. The concentrations of the drugs in muscle varied from none detected to 6.5 times those in blood and seemed to be dependent on the time course between ingestion and death. as well as on the nature of the drug. For most common basic drugs. the ratios were often near unity. Muscle is proposed as a useful alternative specimen to postmortem blood.
Hospitalization and the cognitive deficits of schizophrenia. The influences of age and education, The study investigated the relationship between length of hospitalization and increasing cognitive deficit in schizophrenics. Using Halstead-Reitan Battery data obtained from 245 schizophrenic patients. multiple regression analyses were performed using age. education. and length of hospitalization as independent variables and various summary test indices as dependent variables. These analyses showed that there was not a statistically significant change in percentage of explained variance when length of hospitalization was entered into the multiple regression equations. On the basis of these analyses. it was concluded that the association between increasing deficit and length of hospitalization experienced by schizophrenic patients is no greater than what would be anticipated on the basis of aging.
The use of cognitive behavior therapy with a normalizing rationale in schizophrenia. Preliminary report, Sixty-four consecutively referred patients with schizophrenia were treated with cognitive-behavioral psychotherapy as an adjunct to standard treatment. A destigmatizing rationale to explain symptom emergence was devised and supplemented these techniques. They proved safe to use and appeared acceptable to patients and their relatives. Members of the group are being maintained on low levels of or no medication and have required minimal hospitalization. The techniques used are described in detail.
Discontinuation of neuroleptic medication in older, outpatient schizophrenics. A placebo-controlled, double-blind trial, Thirty-five schizophrenic outpatients over the age of 52 who had been stable on neuroleptic medication were all switched to haloperidol. Ten patients were unable to tolerate the haloperidol and two dropped out of the study. The remaining 23 patients were randomly and blindly assigned to haloperidol or placebo and then followed for 6 months. Five patients did not complete the study due to medical or administrative reasons. Among the patients who completed the study. five of 10 randomized to placebo relapsed compared with only one of eight randomized to haloperidol. However. three of 10 patients randomized to placebo have remained stable without medication for 2.5 years.
Urine screening practices in methadone maintenance clinics. A survey of how the results are used, The urinalysis practices of 324 methadone maintenance clinics were surveyed using a brief self-report questionnaire. Results indicate that there is wide variability in collection practices and clinic responses to positive findings. Virtually all clinics provide counseling and revocation of take-home methadone doses as a response to positive urinalysis results. However. increase in urine screening frequency. methadone dose adjustments. contingency contracting. group therapy. and eventual discharge are interventions also used. The implementation of different interventions varied as a function of clinic size. city size. region of the country. and program funding source.
A retrospective outcome study and review of hypnosis as treatment of adults with sleepwalking and sleep terror, Hypnosis has been described anecdotally to be effective in the treatment of sleepwalking and sleep terror. potentially dangerous parasomnias. The authors report the use of hypnosis in the treatment of 27 adult patients with these disorders. A total of 74% of these individuals reported much or very much improvement when followed over substantial periods after instruction in self-hypnotic exercises that were practiced in the home. Hypnosis. often preferred over pharmacotherapy by patients. required one to six office visits (mean = 1.6). This represents a very cost-effective and noninvasive means of treatment. especially when constrasted with lengthy psychotherapy and pharmacotherapy.
Influence of age and magnesium on calcium metabolism in rats, This study evaluates the effect of dietary magnesium concentration on calcium metabolism in rats of differing ages. Young (3 wk) and old (18 mo) Fischer 344 rats were fed the AIN-76A diet modified to contain either low (218 mg/kg) or adequate (419 mg/kg) Mg for 4 wk. Some rats subsequently underwent a metabolic balance study (12 d duration). Other rats were gavaged with approximately 220 KBq (6 microCi) of 47Ca; daily fecal and urine collections were made and periodic whole body radioactivity determined. Femurs were removed and analyzed. Calcium retention and balance were not affected by Mg in young rats. In old rats low Mg intake increased apparent Ca balance. Young rats retained about 3.25 times more of the original dose of 47Ca than did old rats. Young rats retained more 47Ca in the femur than did old rats; Mg intake had little effect. Aging accelerated Ca turnover rate. and whole body retention data suggest that adequate Mg does not significantly reduce Ca turnover.
Fetal organ response to maternal protein deprivation during pregnancy in swine, To test the hypothesis that maternal protein deprivation in early pregnancy retards body and organ growth of 63-d (midterm) pig fetuses. 16 primiparous domestic four-way crossbred swine were fed a diet adequate in protein (13% protein) (A) or a protein-restricted (0.7% protein) diet (PR) from d 1 to 63 of pregnancy or to parturition. Maternal body weight. plasma protein. hematocrit. and heart and spleen weights were reduced. and indices of body fatness were increased by the PR diet. Fetal body weights were reduced and fetal placental weights were increased at d 63 by protein restriction. Length from crown to rump and weights of liver. kidney. gastrointestinal tract. and cerebrum were lower in PR than in A fetuses. Concentrations of protein. RNA and DNA in liver. cerebrum and longissimus muscle were unaffected by maternal diet. but total amounts of all three constituents in liver and cerebrum were lower in PR than in A. Relative organ weights were similar in A and PR fetuses except that kidneys and gastrointestinal tract were greater in A fetuses. Newborn body weights and absolute organ weights were generally lower in PR than in A. but relative weights were similar. The observed reduction in body and organ weights and amounts of protein. RNA and DNA in 63-d fetuses and newborn progeny of PR swine establishes that the stunting effect of maternal protein restriction can be initiated by midterm. preceding the period of most rapid accretion of body tissues during prenatal life in the pig.
Age-related effects of chronic ethanol intake on vitamin A status in Fisher 344 rats, The present study was designed to investigate the interaction of age and ethanol on vitamin A status in rats. Rats aged 2 and 19 mo were fed a liquid diet containing 36% of total energy as ethanol or pair-fed a diet containing isoenergetic carbohydrate in place of ethanol. After 3 wk older rats had lower serum retinol (P = 0.04) and higher vitamin A concentrations in liver (P = 0.0001). esophagus (P = 0.0001) and the proximal (P = 0.03) and distal (P = 0.0001) colon than younger animals. Hepatic microsomal cytochrome P-450. retinyl ester hydrolase (REH) and cellular retinol-binding protein (cRBP) were significantly reduced; acyl coenzyme A: retinol acyltransferase (ARAT) was increased; and alcohol (retinol) dehydrogenase (ADH) activity was unchanged with age. Ethanol ingestion increased serum retinol as well as esophageal and colonic vitamin A levels in both age groups. Hepatic cRBP decreased further in the older rats with ethanol feeding. but no change was noted in the percentage of hepatic vitamin A as retinol or retinyl esters. Ethanol ingestion decreased REH (P = 0.0001) and ARAT activities (P = 0.02) and increased cytochrome P-450 (P = 0.04) but had no effect on the activity of ADH in either age group. These data indicate that. regardless of age. chronic ethanol ingestion significantly alters the tissue distribution of vitamin A; however. ethanol reduced cRBP levels only in older rats.
Regulation of carnitine acyltransferase synthesis in lean and obese Zucker rats by dehydroepiandrosterone and clofibrate, The effects of dehydroepiandrosterone (DHEA) and clofibrate on mitochondrial and peroxisomal proliferation and carnitine acyltransferases [mitochondrial carnitine palmitoyltransferase (CPT) and peroxisomal carnitine octanoyltransferase (COT)] were measured in lean and obese female Zucker rats. DHEA increased total hepatic mitochondrial protein twofold; clofibrate increased total hepatic peroxisomal protein more than fivefold. Both DHEA and clofibrate administration increased enzyme activities. immunoreactive protein. messenger RNA levels and transcription rates for the carnitine acyltransferases. Transcription rates and messenger RNA concentration for both carnitine acyltransferases correlated with the increases in activity. These data suggest that the hepatic CPT and COT in female Zucker rats are regulated primarily at the transcriptional level by DHEA and clofibrate.
Vitamin A status and the immune response to pneumococcal polysaccharide: effects of age and early stages of retinol deficiency in rats, Production of antibodies to pneumococcal polysaccharide from Streptococcus pneumoniae. type III was determined in young rats at different ages and stages of vitamin A deficiency. At 30. 35 and 45 d of age. serum retinol concentrations of vitamin A-depleted rats were 46. 35 and 9%. respectively. of the serum retinol concentrations of pair-fed controls. Specific antibody production was low at 30 d of age for both vitamin A-depleted rats and control rats. Between 30 and 45 d of age. antibody production increased considerably in normal rats; however. the response of vitamin A-depleted rats was only 22% (P less than or equal to 0.001) that of controls at 35 d of age and 8% that of controls (P less than or equal to 0.001) for 45-d-old rats. Lymphocyte populations were examined by flow cytometry. The numbers of immunoglobulin M- and immunoglobulin D-positive cells changed with age. but not as a result of dietary treatment. The numbers of total T cells or helper and suppressor T cell subsets did not differ with age or with vitamin A status. These studies showed that the normal antibody response to pneumococcal polysaccharide develops rapidly after 30 d of age in the rat. that this antibody response is impaired even during the early stages of vitamin A deficiency. and that impaired antibody production does not seem to be accompanied by quantitative differences in splenic lymphocyte populations.
Effect of dietary calcium on colon carcinogenesis induced by a single injection of 1,2-dimethylhydrazine in rats, The purpose of this study was to determine if high levels of dietary calcium could inhibit the induction of colon tumors in rats injected with a single dose of 1.2-dimethylhydrazine (DMH). Rats were given a single subcutaneous injection of DMH (200 mg/kg body weight) 2 wk before they were fed purified diets containing 5% fat and four different levels of calcium (as calcium gluconate). After 8 mo. the following incidences of colon tumors (total) were seen: 0.2% Ca. 56%; 0.5% Ca [National Academy of Sciences/National Research Council (NAS/NRC) recommended level]. 75%; 1.0% Ca. 61%; 2.0% Ca. 41%. Thus. rats fed calcium at levels above or below the NAS/NRC recommendation had lower tumor incidences. The total tumor incidence and the incidence of adenocarcinomas (with or without invasion) were not significantly affected by calcium. but the incidences of benign adenomatous polyps and of distal colon tumors were significantly affected. Autoradiographic examination of [3H]thymidine-treated rats revealed that the level of calcium did not significantly alter the cell kinetic indices in the distal colon. In the proximal colon. however. the 0.2% Ca group had a significantly larger proliferative zone. with significantly more labeled cells present at the bottom of the colon crypt. Mineral analysis of tibias and serum samples revealed that rats fed higher levels of calcium had lower bone Fe and serum Mg contents. but no significant trends were seen for Ca. P. Zn or Cu. Therefore. increasing or decreasing the calcium content above or below the NAS/NRC recommendation (supplemented to low fat diets) during the promotional phase of colon carcinogenesis altered the tumor incidence. but the effect was confined to the distal colon and to benign adenomatous polyps.
The legal implications of dietary fats: risks of cardiovascular disease and the duty of food manufacturers, The arguments for a warning on foodstuffs open new ground in product liability. Some of the dangers of fat-laden foods have been apparent for many years and are widely known to the public. Other aspects of fat consumption. specifically hidden fats. such as saturated fats. have only recently been explored. and are known to a limited segment of the population at risk. Negligence and warranty theories are too narrow to encompass this situation. wherein the benefits and risks of a product are not well defined and not easily separable. Some warning about the dangers resulting from fat ingestion is necessary. but may be adequately dispensed by ingredient labeling. If consumers are aware of the potential for harm. then they are assuming a substantial portion of the risk. How risk-free can we. or should we. make our society? The marketplace is the appropriate venue for determining the acceptance of saturated-fat-containing products by our society. Clear and open labeling policies will allow consumers to weigh the relative advantages and disadvantages of lower fat intake. Warnings of fat content need not be extreme. but should disclose the possible physiological outcome of the heavy ingestion of saturated fat.
Reevaluation of the ambulatory pediatric patient whose blood culture is positive for Haemophilus influenzae type b, We conducted a retrospective review of 60 patients with Haemophilus influenzae type b bacteremia initially treated as outpatients. to test the hypothesis that a subgroup of these patients is at low risk of continuing invasive infection and thus requires a less comprehensive reevaluation. These patients were 6% of the 975 patients with invasive H. influenzae type b infection identified by active surveillance in Dallas County. Texas. during a 6 1/2-year period. The clinical assessment of "ill" appearance and persistent fever (greater than or equal to 38.0 degrees C) on the return visit were the two most useful variables in identifying patients at risk of continuing infection. Among 25 (42%) patients who were considered "ill" (febrile or afebrile). 20 (80%) had continuing invasive infection and 14 (56%) had a subsequent culture that was positive for H. influenzae type b. Among 8 patients who were considered "well" but who remained febrile. 3 (38%) had continuing infection. including 1 (13%) patient with a second culture that was positive. By contrast. among 27 (45%) patients who were considered "well" and who were afebrile. continuing invasive infection was identified in only 2 (7%) patients. and all repeat cultures were negative. These results suggest that when patients return for reevaluation of H. influenzae type b bacteremia. clinical assessment by an experienced physician. together with the febrile status of the patient. can identify those at high versus low risk of continuing invasive infection and thus guide the extent of diagnostic reevaluation.
Safety of casein hydrolysate formula in children with cow milk allergy, The purpose of this study was to determine whether a new casein hydrolysate infant formula. Alimentum. could be administered safely to children with cow milk hypersensitivity. The formula was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and with a sensitive enzyme-linked inhibition immunoassay. and it was judged to be safe for clinical trials in children allergic to cow milk. Twenty-five such children underwent double-blind placebo-controlled oral food challenges with 10 gm of powdered cow milk and casein hydrolysate formula. All children were highly atopic and had positive skin prick reactions to cow milk. No patient reacted to placebo during a double-blind. placebo-controlled food challenge. Two patients lost their allergy to cow milk and did not react during the challenge; the remaining patients reacted with a variety of cutaneous. respiratory. and gastrointestinal symptoms within 15 to 90 minutes of challenge. All children tolerated the blinded challenge to the casein hydrolysate and were fed the hydrolysate openly without difficulty. We conclude that this casein hydrolysate is generally safe to feed to children with immediate hypersensitivity to cow milk. We recommend that all infant formulas promoted as "hypoallergenic" be tested in milk-allergic patients to assess their allergenic potential. in addition to standard nutritional evaluation and animal testing for antigenicity.
Partial reversibility of cisplatin nephrotoxicity in children, To evaluate the long-term renal toxicity of cisplatin. 40 children who had been without treatment at least 18 months (range 18 months to 7 years) were observed. In all the children. glomerular filtration rate (GFR) was estimated from the plasma clearance of chromium 51-labeled ethylenediaminetetraacetic acid. both at the end of treatment and at a median follow-up of 2 years 6 months after treatment was stopped (range 18 months to 7 years). In 21 children. serum magnesium level was also measured at follow-up. Median age at diagnosis was 15 months (range 13 days to 13 years 8 months). and median cumulative doses of cisplatin was 500 mg/m2 (range 120 to 1860 mg/m2). In 22 of 24 children with an end-of-treatment GFR of less than 80 ml/min per 1.73 m2. the median improvement in GFR at follow-up was 22 ml/min per 1.73 m2 (range 2 to 56 ml/min per 1.73 m2). Hypomagnesemia was found in 6 of 21 children and was independent of GFR. No significant correlation was found between improvement in renal function and total cisplatin dose. age. gender. tumor type. or associated nephrotoxic medication. We conclude that most children have some recovery from cisplatin glomerular toxicity. especially if damage is not severe. but that hypomagnesemia may persist.
Prolonged survival in patients with beta-thalassemia major treated with deferoxamine, To determine whether survival of patients with beta-thalassemia major has been prolonged by management that utilizes hypertransfusion and chelation with deferoxamine. we analyzed longevity by the Kaplan-Meier product-limit method. Group 1 patients (n = 71) followed between 1960 and 1976 with a low-transfusion regimen (pretransfusion hemoglobin level 7 to 8 gm/dl) and no chelation had an estimated median age of survival of 17.4 years. whereas it was 31.0 years for group 2 subjects (n = 80). who began hypertransfusion between 1976 and 1978 (pretransfusion hemoglobin level 10.5 to 11.5 gm/dl) and chelation with deferoxamine (20 to 60 mg/kg per day) (p less than 0.0001). For 70 patients who were treated with hypertransfusion and deferoxamine. we had data to calculate the ratio of total milligrams of transfusional iron to cumulative grams of deferoxamine. The 24 patients who died had a total iron burden of greater than 1.05 gm/kg; the ratio for them exceeded 31. These patients were characterized by poor compliance with chelation or by late start of therapy. with inability to receive enough deferoxamine before death. Death was preceded by arrhythmia requiring therapy in all but one. and by cardiac failure in all. Of 41 similarly iron-loaded survivors. 33 had a ratio of less than 31; only three had an arrhythmia. and five had cardiac failure. We conclude that treatment with deferoxamine. when used in amounts proportional to iron burden. delayed cardiac complications and improved longevity.
Indomethacin-induced changes in renal blood flow velocity waveform in premature infants investigated with color Doppler imaging, Renal dysfunction has been recognized as an adverse effect of indomethacin treatment and is probably secondary to impairment of renal blood flow. We therefore evaluated renal artery blood flow velocity in 15 premature infants with a symptomatic ductus arteriosus before and during the first 12 hours after a single intravenous dose of 0.1 mg/kg of indomethacin. Renal artery blood flow velocity was measured serially by color-Doppler flow imaging and used as a qualitative measure of true renal blood flow. Indomethacin administration led to a sharp decrease in peak systolic flow velocity and temporal mean flow velocity of the renal artery. This effect was maximal at 10 minutes after indomethacin dosing; the flow velocities showed a slow recovery. reaching baseline values again at 2 hours after indomethacin dosing. We conclude that indomethacin can affect renal blood supply in the premature infant for a period of at least 1 hour after indomethacin treatment.
Comparative efficacy of ceftriaxone and ampicillin for treatment of severe shigellosis in children, In a prospective randomized open study. ceftriaxone. 50 mg/kg per day. was compared with ampicillin. 100 mg/kg per day. both given for a period of 5 days. for the treatment of 40 children whose mean (+/- SD) age was 4.5 +/- 3.2 years and who had severe dysentery caused by Shigella organisms. Twenty patients were treated with ceftriaxone and 20 with ampicillin. Both drugs were initially given intravenously for a period of 1 to 2 days and were continued intramuscularly. in the case of ceftriaxone. or orally. in the patients receiving ampicillin. All Shigella organisms isolated were susceptible to ceftriaxone; 28% were resistant to ampicillin. The diarrhea persisted for a mean (+/- SD) period of 2.5 +/- 1.0 days in the ceftriaxone-treated patients versus 6.8 +/- 6.3 days in the ampicillin-treated patients (p less than 0.005). At the end of the 5 days of therapy. stool cultures for Shigella organisms were negative in 12 (60%) of the 20 patients from the ampicillin group and in all the children (100%) from the ceftriaxone group (p less than 0.001). Bacteriologic relapses were observed in eight (40%) of the patients treated with ampicillin but in none of the children treated with ceftriaxone (p less than 0.001). In instances of clinical or bacteriologic failure in the ampicillin group. retreatment was instituted in most of the cases with ceftriaxone; persistent clearing of the Shigella organisms from the stool was finally achieved after a mean (+/- SD) period of 11.75 +/- 9.4 days after therapy was started. as compared with 1.85 +/- 0.6 days in the ceftriaxone-treated patients (p less than 0.001). We conclude that in children with severe shigellosis. treatment with ceftriaxone for 5 days is effective and better than use of ampicillin for clinical cure and eradication of the Shigella organisms from the stool.
Antihypertensive effect and pharmacokinetics of nitrendipine in children, Nitrendipine. a new calcium-channel antagonist. was used to treat 25 children (aged 6 months to 17 years) with severe hypertension. Systolic and diastolic blood pressures (mean +/- SEM) fell from 148 +/- 2/99 +/- 2 mm Hg to 128 +/- 4/77 +/- 3 mm Hg after 24 hours and to 121 +/- 2/75 +/- 2 mm Hg after 2 weeks. No further reductions in systolic or diastolic blood pressure were observed after continued therapy. Transient reflex tachycardia occurred during the first week of therapy. Other adverse effects were uncommon and included headaches. flushing. palpitations. and edema. Pharmacokinetic parameters were estimated at steady state after an oral dose of 0.56 +/- 0.04 mg/kg in 13 children. Although absolute oral bioavailability could not be determined. estimates of the area under the plasma concentration versus time curve. the apparent peak serum concentration. and the apparent time at which the peak serum concentration occurred indicated that both the rate of absorption and oral bioavailability are variable. Coadministration of nitrendipine with food decreased the rate of absorption and may have reduced oral bioavailability. A relationship between age and the apparent plasma elimination half-life of nitrendipine was not observed. Nitrendipine. 0.25 to 0.5 mg/kg per dose administered orally every 6 to 12 hours. appeared to be an effective and safe treatment for resistant hypertension in infants and children.
Vaccines and milk immunoglobulin concentrates for prevention of infectious diarrhea, Considerable progress has been made in the last decade in developing vaccines against the most important enteric infections. Two new. widely licensed vaccines (oral Ty21a and parenteral Vi) are available against typhoid fever. and new attenuated Salmonella typhi strains are ready for testing. An engineered live orally administered cholera vaccine. CVD 103-HgR. is undergoing clinical trials for safety. immunogenicity. and transmissibility in children in areas where cholera is endemic. Multiple candidate vaccines against rotavirus. Shigella. and enterotoxigenic Escherichia coli are in clinical trials. Newly acquired knowledge about pathogenesis and mucosal and cellular immunology. coupled with application of biotechnology. has already resulted in many candidates for vaccines. and more are expected to appear within the next few years.
Estimates of morbidity and mortality rates for diarrheal diseases in American children, Although the importance of diarrhea as a prime cause of morbidity and death in developing countries is well recognized. the disease burden in the United States has never been thoroughly examined. We have prepared national estimates of the annual number of cases of diarrhea in children less than 5 years of age and of the outcome. measured in terms of visits to a physician. hospitalizations. and deaths. The annual number of diarrheal episodes was estimated by reviewing longitudinal studies of childhood diarrhea conducted in the United States and extrapolating these data to the nation. Estimates of physician visits. hospitalizations. and deaths were prepared from a variety of national data sources. We estimate that 16.5 million children less than 5 years of age have between 21 and 37 million episodes of diarrhea annually. Of these. 2.1 to 3.7 million episodes lead to a physician visit. a total of 220.000 patients are hospitalized. and 325 to 425 children die. The major cost of diarrhea lies in the high numbers and cost of hospitalizations. because approximately 10.6% of hospitalizations in this age group are for diarrhea. Diarrheal deaths occur in relatively small numbers. are more common in the South and among black persons. are potentially avoidable. and could represent as much as 10% of the preventable postneonatal infant death in the United States. These estimates underscore the extensive burden of diarrheal illness in children in the United States and suggest that interventions to prevent disease or decrease its severity could be cost-effective.
Improved water and sodium absorption from oral rehydration solutions based on rice syrup in a rat model of osmotic diarrhea, Rice syrup solids. rice protein. and casein hydrolysate were added to experimental oral rehydration solutions in various combinations and tested in a rat intestinal perfusion system. Chronic osmotic diarrhea was induced in juvenile rats by supplying the cathartic agents. magnesium citrate and phenolphthalein. in their drinking water for 1 week. The experimental oral rehydration solutions were compared with standard oral rehydration solutions containing 20 gm/L or 30 gm/L of glucose and with each other to determine if there were significant differences in net water. sodium. or potassium absorption. An oral rehydration solution containing 30 gm/L of rice syrup solids had a net water absorption rate significantly higher than that of the standard 20 gm/L glucose-based oral rehydration solution (2.1 +/- 0.62 versus 1.5 +/- 0.48 microliters/[min x cm]. p less than 0.05). Casein hydrolysate did not significantly affect net water absorption. However. combinations of 30 gm/L rice syrup solids and 5 gm/L casein hydrolysate significantly increased (p less than 0.05) net sodium and potassium absorption compared with the 20 gm/L glucose-based oral rehydration solution but not versus rice syrup solids alone. Oral rehydration solutions containing 30 gm/L rice syrup solids plus 5 gm/L rice protein. and 30 gm/L rice syrup solids plus 5 gm/L casein hydrolysate. had net water absorption rates significantly higher than the rate of a 30 gm/L glucose-based oral rehydration solution (2.5 +/- 0.36 and 2.4 +/- 0.38. respectively. versus 0.87 +/- 0.40 microliters/[min x cm]. p less than 0.05). Rice protein and casein hydrolysate. however. did not significantly affect net water. sodium. or potassium absorption when added to rice protein glucose-based oral rehydration solutions. An inverse correlation between osmolality and net water absorption was observed (r = -0.653. p less than 0.02). The data suggest that substitution of rice syrup solids for glucose in oral rehydration solutions will improve water absorption and that rice syrup solids in combination with protein hydrolysates may. in addition. promote better sodium and potassium uptake.
Glucose polymers as an alternative to glucose in oral rehydration solutions, Several issues involving glucose-based oral rehydration therapy may limit its acceptability and sustained use. Our studies suggest that defined short-chain glucose polymers (2 to 9 glucose units) are hydrolyzed and absorbed faster than isocaloric solutions of D-glucose in the small intestine of the rat. Glucose polymers. primarily from rice-based solutions. have been shown to be as effective as glucose-based solutions. They offer additional advantages in reducing the amount and duration of diarrhea with lesser volumes of solution. thereby reducing the costs of treatment. Rice-based solutions provide high caloric density and increase the absorption of sodium without an osmotic overload. The result is increased net absorption of glucose. sodium. and water. Glucose polymers from rice or other starches in oral rehydration solutions may be effective. inexpensive. easily used. and safe treatments for acute diarrhea.
Cereal-based oral rehydration therapy. I. Clinical studies, Studies of "improved" oral rehydration solutions. in which glucose polymers (starch) derived from rice or other cereals were added to improve cotransport of sodium and to promote sodium and water absorption. have been reported. These solutions were administered to decrease diarrhea volume and duration. reduce vomiting. and replace volume loss in stools. In clinical trials of children and adults with high-output diarrhea. such as in cases of cholera. the use of cereal-based oral rehydration solutions (ORS) compared with glucose-based ORS produced significant (20% to 53%) reductions in stool volumes. In one study the duration of diarrhea was shortened by 30%. In noncholera diarrhea in children. cereal-based ORS was as effective as glucose-based ORS. Although the amino acid transport systems were intact in patients with cholera. the addition of glycine to glucose-based or rice-based ORS did not reduce stool volume or duration of diarrhea. The exception was alanine. which reduced stool output and ORS requirements. More research is needed to determine the optimal mix of starch. amino acids. oligopeptides. and proteins that would utilize the absorptive active transport systems maximally to reduce fluid losses and duration of diarrhea.
Cereal-based oral rehydration therapy. II. Strategic issues for its implementation in national diarrheal disease control programs, Field studies in Bangladesh demonstrated that after proper training. village mothers were able to prepare and use rice-based. salt-enriched oral rehydration solutions containing safe concentrations of sodium. and were capable of achieving significantly fewer treatment failures and a reduction in the duration of diarrhea than with glucose-based oral rehydration solutions (ORS). An additional longitudinal study showed that improved growth and weight gain occurred with the consistent use of ORS; the effect was greater when rice-based ORS were used. In addition. the following possible limitations and benefits of cereal-based oral rehydration therapy. which are relevant to the strategies for its implementation in national diarrheal disease control programs. are discussed: safety. osmolarity. hypernatremia. spoiling. effectiveness. rehydration ability. reduction in diarrhea volume and duration. nutritional effects. effect on food intake. acceptance and usage by care givers. training of health workers. self-reliance of families. effect on other child survival activities. costs. potential problems in changing to cereal-based ORS. and the role of industrial production in packaged cereal-based ORS.
A capture enzyme immunoassay for detection of HIV-2/SIV antigen, An antigen capture enzyme immunoassay was developed for the demonstration of human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus (SIV). The assay (HIV-2 CE) has a sensitivity of approximately 250 pg/ml of HIV-2/SIV antigen. The HIV-2 CE was 4-16 times more sensitive than the Abbott HIV-1 antigen assay for detection of HIV-2/SIV antigen in cell culture supernatant. The sensitivity for detection of HIV-2/SIV antigen in serum or plasma was 98.5% in the HIV-2 CE and 95.5% in the Abbott HIV-1 antigen assay. The specificity of the HIV-2 CE was 99.2% (one false positive among 119 negative sera) whereas the Abbott assay was 100% specific. The HIV-2 CE detected antigen in supernatants from cultures of peripheral blood mononuclear cells of macaque monkeys infected with HIV-2 or SIV about 1 week before a reverse transcriptase (RT) microassay was positive and remained positive for at least 1 week after the RT assay had become negative. Three cultures from persistently infected monkeys were positive only in the HIV-2 CE. reflecting a higher sensitivity compared to the RT microassay. Thus. the HIV-2 CE was more sensitive than the Abbott HIV-1 antigen assay for detection of HIV-2/SIV antigen in culture supernatants as well as in serum/plasma. Furthermore. the HIV-2 CE showed a higher sensitivity than the RT microassay for detection of HIV-2/SIV in cell culture supernatants.
Reciprocal activation of human T-lymphotropic viruses in HTLV-I-transformed cells superinfected with HIV-1, The finding of dual HTLV-I and HIV-1 infection in populations at risk for AIDS raises the possibility that interaction between the two viruses might have clinical significance. It was shown that HTLV-I enhances HIV-1 expression. but whether HIV-1 activates HTLV-I remains to be demonstrated. To study HTLV-I behaviour following HIV-1 infection. we superinfected cells from two HTLV-I transformed cell lines with HIV-1 (strain IIIB). Viral RNA analysis indicated that HTLV-I expression in the doubly infected cells was moderately enhanced. Moreover. CAT assays in HTLV-I transformed cells transiently transfected with HTLV-I LTR-CAT disclosed higher activity in the HIV-1 superinfected cultures. This enhancement was observed only after infection with active HIV-1 virus. but not following exposure to inactivated viral particles or transfection with HIV-1 tat gene.
HIV-2 and HIV-1 AIDS cases in Senegal: clinical patterns and immunological perturbations, The serological and immunological parameters. disease patterns. and social characteristics of 39 human immunodeficiency virus type 2 (HIV-2) seropositive CDCIV cases seen in Dakar. Senegal were studied. These data were compared with those obtained from 48 HIV-1 seropositive CDC stage IV patients. Social characteristics of populations infected with HIV-1 or HIV-2 were clearly different. A patient sex ratio of three men to one woman was found for both viruses. In addition. the immune status of nonsymptomatic HIV-1 and HIV-2 seropositive people was evaluated. The correlation between abnormalities of the immune system and clinical status was similar for the two infections. Clinical symptoms of both diseases were the same. but this cross-sectional study could not address the questions of differences between the two infections in latency and development of disease or specific manifestations of HIV-2 infection. This study suggests that HIV-2 infection may contribute to the present AIDS epidemic in West Africa.
Cerebrospinal fluid anti-cardiolipin antibodies in patients with HIV-1 infection, Both cerebrospinal fluid (CSF) immunologic abnormalities and serum anti-cardiolipin antibodies (aCL) have been reported in patients with HIV-1 infection. The antibody specificity of only a small amount of the total CSF IgG in these patients is known. and is directed against a variety of HIV-1 antigens. The specificity of the remaining CSF IgG is unknown. We report the results of the first study of CSF aCL in an HIV-1-infected population. We measured aCL IgG and IgM in the CSF of 21 HIV-1-infected patients without nervous system symptoms or AIDS. and in four HIV-1-negative controls. Twelve HIV-1-infected patients had an abnormal serum aCL value and CSF immunologic abnormalities and 9 HIV-1-infected patients had either abnormal serum aCL or CSF immunologic abnormalities but not both. or were normal in both regards. There was no difference between any HIV-1-infected patient and controls for CSF aCL IgM. Nine of 12 patients with an abnormal serum aCL and CSF immunologic abnormalities had CSF aCL IgG values that were at least 5 SD above normal control values. whereas none of the remaining patients had abnormal CSF aCL IgG values. All patients with abnormal CSF aCL IgG values had an intact blood-brain barrier as evidenced by an albumin index of less than 9. and all had nonreactive CSF VDRL tests. These data demonstrate that aCL IgG is produced intrathecally in some HIV-1-infected patients.
Human chorionic gonadotropin, its free subunits and gestational trophoblastic disease, Monoclonal antibody-based immunoassays can detect specifically intact human chorionic gonadotropin (hCG). the free alpha-subunit and the free beta-subunit. The differential production of hCG and its free subunits is important in gestational trophoblastic disease. Using well-defined epitope-specific monoclonal antibodies in an immunoradiometric assay format. specific and sensitive assays have been developed. Serum levels of free beta-hCG were abnormally high in patients with gestational trophoblastic disease. In contrast. free alpha-hCG levels in serum were not increased.
Placental site trophoblastic tumor. Diagnosis, clinical behavior and treatment, Placental site trophoblastic tumor is a rare trophoblastic neoplasm with the potential for metastatic disease and death. Difficulty diagnosing these tumors and predicting their biologic behavior has clouded attempts to successfully outline individual treatment plans. This review details current knowledge of the origin and clinical behavior of this rare form of trophoblastic disease. The use of various markers to predict clinically aggressive behavior is reviewed critically. and treatment is recommended on the basis of recently published clinical series.
Flow cytometric analysis of nuclear DNA content in gestational trophoblastic disease, Flow cytometric analysis of nuclear DNA is a quick and accurate method of determining nuclear ploidy. This technique allows a clear distinction to be made between diploid and triploid hydatidiform moles. Additional ploidy aberrations. such as tetraploidy and aneuploidy. have also been reported in flow cytometric studies of hydatidiform moles. Recent investigations have suggested that aneuploidy in complete hydatidiform moles is associated with a high risk of persistent gestational trophoblastic disease. In addition to DNA ploidy analysis. cell cycle activity may be calculated from analysis of the DNA histogram. No significant correlation between clinical course and cell cycle kinetics has been demonstrated to date. By providing valuable DNA ploidy data. flow cytometric studies of hydatidiform moles may be helpful in the identification of patients at high risk of postmolar trophoblastic sequelae.
Evolving concepts of molar pregnancy, Molar pregnancy is composed of two distinct clinical and pathologic entities. complete and partial mole. Knowledge of the cytogenetic origin. natural history and treatment of complete and partial hydatidiform mole is evolving.
Single-agent chemotherapy for nonmetastatic gestational trophoblastic neoplasia. Perspectives for the 21st century after three decades of use, After 30 years of successful chemotherapy for nonmetastatic gestational trophoblastic neoplasia. methotrexate and actinomycin remain the most effective and widely used agents. Though cost effectiveness is a consideration. primary efficacy may be a more important factor in this curable malignant disease. The criteria used for diagnosing neoplasia and for making therapeutic decisions were evaluated critically.
Gestational trophoblastic disease of the fallopian tube, Tubal gestational trophoblastic disease (GTD) was diagnosed in 16 (0.8%) of 2.100 women with GTD managed at the New England Trophoblastic Disease Center. Tubal partial mole. complete mole and choriocarcinoma were present in 5. 5 and 6 patients. respectively. Patients with tubal GTD were not clinically distinguishable from those with traditional tubal pregnancies. While only one patient with tubal mole developed metastases. four patients with tubal choriocarcinoma presented with metastases. All the patients achieved complete. sustained remission.
Sonographic measurements with umbilical and uterine artery Doppler analysis in suspected intrauterine growth retardation, A retrospective analysis was performed to evaluate the role of sonographic measurement with umbilical and uterine artery Doppler studies in cases of suspected intrauterine growth retardation (IUGR). The sonogram was more sensitive (72%). but the umbilical artery Doppler scan was more specific (90%). for the diagnosis of IUGR. Abnormal uterine artery Doppler measurements in cases of IUGR diagnosed with a sonogram and umbilical artery Doppler scan were associated with chronic maternal hypertension. Those fetuses fared worse than those in which the uterine artery Doppler scans were normal. In contrast. small infants from pregnancies in which all three studies were normal performed well overall. Complementary use of these three studies to evaluate suspected IUGR fetuses may help us distinguish the small. troubled fetus from the small but healthy one.
Microtuboplasty as an outpatient procedure, Fifteen cases of microtuboplasty were done as outpatient procedures at low cost and with increased patient convenience. Advances in outpatient surgery at free-standing surgery centers have allowed many new patient care innovations. and microsurgery should now be considered an outpatient procedure for gynecologic patients. Outpatient microtuboplastic surgery is not only feasible but perhaps preferable to that done as an inpatient procedure.
Adenomatous polyp of the fallopian tube. A case report, Benign epithelial lesions of the fallopian tube are rare. An adenomatous polyp of the fallopian tube was discovered incidentally at laparotomy.
A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer [published erratum appears in JAMA 1991 Sep 11;266(10):1362, To quantify the effect of estrogen replacement therapy on breast cancer risk. we combined dose-response slopes of the relative risk of breast cancer against the duration of estrogen use across 16 studies. Using this summary dose-response slope. we calculated the proportional increase in risk of breast cancer for each year of estrogen use. For women who experienced any type of menopause. risk did not appear to increase until after at least 5 years of estrogen use. After 15 years of estrogen use. we found a 30% increase in the risk of breast cancer (relative risk. 1.3; 95% confidence interval [CI]. 1.2 to 1.6). The increase in risk was largely due to results of studies that included premenopausal women or women using estradiol (with or without progestin). studies for which the estimated relative risk was 2.2 (CI. 1.4 to 3.4) after 15 years. Among women with a family history of breast cancer. those who had ever used estrogen replacement had a significantly higher risk (3.4; CI. 2.0 to 6.0) than those who had not (1.5; CI. 1.2 to 1.7).
Nonenzymatic glycosylation of immunoglobulin G impairs complement fixation, Transient hyperglycemia in patients receiving total parenteral nutrition may be associated with impaired immune function. The effects of short-term hyperglycemia on one aspect of antimicrobial immune function. ie. the ability of IgG to fix complement. were investigated. Aliquots of anti-human albumin. anti-horse ferritin. and anti-alkaline phosphatase were incubated for 0. 8. 16. 24. 48. and 96 hr with either 0 or 240 mg of glucose per deciliter of buffer. All samples were analyzed for the degree of glycation using a thiobarbituric acid assay. and for complement fixation ability using a microcomplement fixation assay. Significant increases in glycation over control samples were observed after only 16 hr (31 vs 15 mmol 5-hydroxymethylfurfural/mol IgG. p less than 0.01). Complement fixation was significantly altered after 48 hr of incubation (76 +/- 5% vs 90 +/- 8% total serum complement fixed by albumin/anti-albumin complex. p less than 0.03) when four of the 84 (4.7%) IgG lysine residues were glycated. It is demonstrated that a significant reduction in complement fixation by immunoglobulin occurs with elevated glucose concentrations and that this may play a clinically significant role in transiently hyperglycemic patients.
Prognosticators of second-look laparotomy findings in patients with epithelial ovarian cancer, Prognosticators of outcome at second-look laparotomy (SLL) were evaluated in 49 patients with epithelial ovarian carcinoma undergoing SLL. Residual tumor volume was found to be the most significant prognosticator of outcome. with initial tumor stage being of secondary importance. Grade of tumor played no role in outcome at SLL. The results of the study led us to the conclusion that the second-look procedure may be safely omitted in stage I patients. The importance of optimal cytoreduction during primary surgery was stressed.
Lugol stain for intraoperative determination of the proximal surgical margin of the esophagus, An adequate proximal surgical margin is difficult to determine particularly in cases of esophageal carcinoma with surrounding intraepithelial invasion. We report here readily facilitated intraoperative approaches for detection of the exact margin of carcinomatous invasion of the esophagus. The resected specimen of the esophagus is incised longitudinally and placed in a 1% Lugol bath for 2-3 minutes. The normal squamous epithelium includes glycogen that interacts with the iodine of Lugol's solution and the normal epithelium of the esophagus becomes a uniform greenish-brown. A squamous cell carcinoma does not include glycogen. hence is not stained with this solution and a clear identification is feasible. Thus. a carcinomatous infiltration not recognizable in routine examinations becomes macroscopically visible when Lugol's solution is used.
Analysis of iodine-125 interstitial therapy in the treatment of localized carcinoma of the prostate, Definitive treatment of localized carcinoma of the prostate has included radical surgery. external beam radiation therapy. and interstitial radiation therapy. The interstitial agent most commonly used is Iodine-125. Forty-eight patients were treated with interstitial radiation therapy using Iodine-125 implants with a median follow-up of 55 months. Forty-three percent of the evaluable patients had progressive disease with approximately 50% progressing at 5 years by Kaplan-Meier analysis. Overall actuarial survival in the group was 80% at 5 years. This and several other studies suggest that control of prostate cancer with Iodine-125 seeds may be suboptimal as compared with other treatment modalities. especially the radical retropubic prostatectomy. Analysis of treatment parameters is presented along with a discussion of the current status and future prospects for treatment of localized carcinoma of the prostate with interstitial radiation therapy.
Tumors in undescended testis, We herein report our experience in the management of 21 patients with tumors in undescended testis. The primary tumor was in the abdominal testis in six patients and in the inguinal testis in 15 patients. Seventeen patients had unilateral involvement and four had bilateral. Prior orchiopexy was reported in six (30%) patients. unilateral in three and bilateral in the other three. although tumors occurred in one side of three bilateral orchiopexy patients. Clinical staging showed five as stage I. six at stage IIb. two as stage IIc. seven as stage III. and in one no stage was possible. Microscopy showed seminoma. non-seminoma. and mixed tumors in 12. six. and three patients. respectively. As per protocol. stages I and IIb had either radiotherapy or retroperitoneal node dissection. giving three and five year survival of 11/11 (100%) and 7/7 (100%). All nine patients with stage IIc and stage III received induction chemotherapy (VAB-6) first and showed complete response (CR) in four (45%) and partial response (PR) in five (55%). Three and 5 year survival was 45% and 33%. respectively. Overall. 3 and 5 year survival was 70% and 69% respectively in all patients. Early stage disease (stages I. IIb) had excellent survivals. showing the adequacy of treatment. while patients with advanced tumor can still be salvaged with a combination of surgery. chemotherapy. and radiotherapy.
Endobronchial carcinoid and mucoepidermoid carcinoma in children, Endobronchial neoplastic disease is rarely encountered in patients under 20 years of age. The great majority of these lesions are carcinoids or mucoepidermoid carcinoma. Symptoms are secondary to bronchial irritation and manifest as recurrent pneumonitis. hemoptysis. persistent cough. reactive airway disease. and chest pain. Early bronchoscopy reliably enables identification and may prevent harmful sequelae resulting from delay in diagnosis. Retrospective data from four cases collected from the Tumor Registry in the Southern California Kaiser Permanente Medical Group is presented and a review of the literature is discussed.
The surgical treatment of atrial fibrillation. III. Development of a definitive surgical procedure, On the basis of the known electrophysiologic mechanisms of atrial fibrillation. multiple surgical procedures were designed and tested in dogs to determine the feasibility of developing a surgical cure for human atrial fibrillation. These experimental studies culminated in a surgical approach that effectively creates an electrical maze in the atrium. The atrial incisions prevent atrial reentry and allow sinus impulses to activate the entire atrial myocardium. thereby preserving atrial transport function postoperatively. Since September 1987. this surgical procedure has been applied in seven patients. five with paroxysmal atrial fibrillation of 2 to 9 years' duration and two with chronic atrial fibrillation of 3 and 10 years' duration. All seven patients have been cured of atrial fibrillation and none is receiving any postoperative antiarrhythmic medications.
The surgical treatment of atrial fibrillation. IV. Surgical technique, The operative technique for the current surgical procedure of creating an electrical maze for the treatment of atrial fibrillation is described in a sequential fashion. The accompanying diagrams of the procedure are drawn from the view of the operating surgeon.
Obstructed total anomalous pulmonary venous return. Toward neutralization of a major risk factor, Among 57 neonates undergoing repair of total anomalous pulmonary venous return with severe pulmonary venous obstruction from 1980 through 1989. date of operation (1980 to 1984). preoperative hemodynamic instability. and failure to monitor pulmonary artery pressure postoperatively were risk factors for death. Thus. among the 30 patients having repair between 1985 and 1989. the 55-month survival rate including hospital deaths was 83%.
The importance of acquired diffuse bronchomalacia in heart-lung transplant recipients with obliterative bronchiolitis, The results of heart-lung transplantation are improving with increasing experience in postoperative management. but obliterative bronchiolitis may still develop late postoperatively. We have performed 19 heart-lung transplants. with 1-month. 1-year. and 2-year actuarial survival rates of 95% +/- 5%. 84% +/- 8%. and 69% +/- 16%. respectively. Three early recipients died of bronchiolitis. and four patients who were operated on more than 2 years ago are currently being followed up with bronchiolitis. Since August 1988. 13 surviving recipients have undergone serial postoperative bronchoscopies and transbronchial biopsies with topical analgesia. Diffuse bronchomalacia. involving the main bronchi down to the fifth-order bronchi bilaterally. has developed in four patients with bronchiolitis 9 +/- 2 months after the diagnosis of bronchiolitis was confirmed. Pulmonary function tests have revealed a lower ratio of forced expiratory volume in 1 second to forced vital capacity. lower specific airway conductance. and higher airway resistance in heart-lung recipients with bronchomalacia than in patients with bronchiolitis alone. We conclude that diffuse bronchomalacia occurs frequently in heart-lung transplant recipients who have obliterative bronchiolitis. Bronchomalacia worsens the functional airflow obstruction caused by bronchiolitis and may play an important role clinically in the declining respiratory status of heart-lung transplant recipients.
Treatment of severe peptic esophageal stricture with Roux-en-Y partial gastrectomy, vagotomy, and endoscopic dilation. A follow-up study, Eleven patients with dysphagia caused by severe esophageal stricture (length 2 to 10 cm) resulting from reflux esophagitis were treated with fibroendoscopic dilation (Eder-Puestow) and Roux-en-Y partial gastrectomy with vagotomy during 10 years (1979 to 1988). There was no operative mortality. but complications developed in three patients: One patient had a mediastinal abscess demanding thoracotomy as a result of esophageal perforation after dilatation; one had postoperative pneumonia; and one patient had ileus. After a mean follow-up of 4 years (range 1 to 10 years) esophagitis healed in all cases. as judged by endoscopy. Eight patients were asymptomatic. but three had slight transient dysphagia. Postoperatively one to eight dilations (average three to four) were needed to relieve dysphagia in the first postoperative year. but later the stricture healed in every case. Postoperative pH measurement was performed in six latest patients and showed complete absence of reflux in all cases. It is concluded that Roux-en-Y partial gastrectomy with vagotomy and endoscopic dilation is an effective. simple. and safe procedure in the management of severe peptic esophageal (acid or alkaline esophagitis) stricture. However. occasional postoperative dilations at the outpatient clinic are often needed in severe cases in the first postoperative year.
A clinical trial of allopurinol (Zyloric) for myocardial protection, This study explored myocardial protective effects of allopurinol at various doses. Ninety patients undergoing coronary artery bypass or repair or replacement of cardiac valves were divided into three groups of 30 patients each in accordance with the amount of allopurinol administered to patients in each group. Patients in group I received no allopurinol. those in group II received low-dose allopurinol (total dose 1200 mg). and those in group III received high-dose allopurinol (total dose 2400 mg). Aspartate aminotransferase. cardiac isoenzyme of creatine kinase. and lactic dehydrogenase levels were measured up to 5 days after operation. Concentrations of allopurinol and oxypurinol were also measured before initiation of cardiopulmonary bypass and at the start and at the end of aortic crossclamping. Postoperative aspartate aminotransferase. creatine kinase. and lactate dehydrogenase 1 plus lactate dehydrogenase 2 levels in group III were significantly lower than those in groups I and II. Aspartate aminotransferase. creatine kinase. and lactate dehydrogenase 1 plus lactate dehydrogenase 2 levels in group II were lower than those in group I. without statistically significant differences. Plasma oxypurinol concentrations were significantly higher in group III than in group II. It was concluded that allopurinol had resultant high myocardial protective effects in dose-related fashion. but its effect might be attributed to oxypurinol levels formed by its degradation.
Long-term results after cavopulmonary anastomosis, Brief case histories of three patients who underwent cavopulmonary anastomosis 28. 27. and 26 years ago. respectively. are presented. From this limited sample the following conclusions may be drawn. (1) Long-term survival with good functional results in patients with complex congenital anomalies who undergo cavopulmonary shunting at an early age is possible. (2) Secondary changes in the circulation of the right lung such as underperfusion of the upper lobe and the development of multiple arteriovenous connections in the lower lobe do occur. maybe more often than appreciated. (3) By 15 to 20 years after their initial operation. most of these patients require additional operations such as systemic-pulmonary artery shunt or. if possible. total repair of their underlying anomaly.
Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease, BACKGROUND. Creutzfeldt-Jakob disease is a transmissible neurodegenerative disorder that occurs more than 100 times more frequently among Libyan Jews than in the worldwide population. We examined 11 patients with the disease--10 Libyan Jews from Israel and 1 Libyan Jew from Italy--to determine whether abnormalities of the prion protein could be detected in them. Abnormal forms of this host-encoded protein are the predominant if not sole components of the transmissible agent that causes the disease. METHODS. The prion-protein open-reading frame in peripheral-leukocyte DNA from the Italian patient was amplified with the polymerase chain reaction and sequenced. Allele-specific oligonucleotide hybridization was used to assess a prion-protein codon 200 lysine mutation in the 10 Israeli patients and 37 control subjects. RESULTS. The prion-protein sequence in DNA from the Italian patient revealed a single nucleotide change (G----A) at the first position of codon 200 that resulted in a substitution of lysine for glutamate. This substitution was detected in all 10 Israeli patients. 8 of whom had a positive family history of Creutzfeldt-Jakob disease. One patient was homozygous for the lysine mutation. and her clinical course did not differ from that of the patients heterozygous for the mutation. The lysine mutation was not found in one Moroccan Jew from Israel with Creutzfeldt-Jakob disease. CONCLUSIONS. The codon 200 lysine mutation of the prion-protein gene is consistently present among Libyan Jews with Creutzfeldt-Jakob disease. strongly supporting a genetic pathogenesis of their illness. The similarity of the clinical courses of the patient homozygous for this mutation and the patients heterozygous for it argues that familial Creutzfeldt-Jakob disease is a true dominant disorder.
Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension, BACKGROUND. To test the prognostic value of plasma renin activity prospectively. we determined the pretreatment renin-sodium profile of 1717 subjects with mild-to-moderate hypertension (mean age. 53 years; 36 percent white; 67 percent men) in a systematic work-site treatment program. METHODS. Renin profiles. obtained by plotting plasma renin activity against the urinary excretion of sodium. were classified as high (12 percent of the subjects). normal (56 percent). and low (32 percent). and there were expected variations according to age. sex. and race. Modified stepped-care treatment for hypertension. prescribed without reference to the renin profile. was similar in the three renin groups. RESULTS. Mean (+/- SD) blood pressure at entry was 151 +/- 19/100 +/- 10 mm Hg in the subjects with a high renin profile. 151 +/- 19/97 +/- 10 mm Hg in those with a normal profile. and 151 +/- 20/96 +/- 11 mm Hg in those with a low profile. During 8.3 years of follow-up. there were 27 myocardial infarctions. As adjusted for age. sex. and race. the incidence of myocardial infarction per 1000 person-years was 14.7 among the subjects with a high renin profile. 5.6 among those with a normal profile. and 2.8 among those with a low profile (rate ratio for high vs. low. 5.3; 95 percent confidence interval. 3.4 to 8.3). The rate of mortality from all causes was 9.3 in the high-profile group. 5.3 in the normal-profile group. and 3.9 in the low-profile group. The independent association of a high renin profile with myocardial infarction (but not with stroke or noncardiovascular events) was affirmed by Cox analyses (rate ratio for high vs. normal plus low. 3.2; 95 percent confidence interval. 1.2 to 8.4) after adjustment for race. sex. age at entry. serum cholesterol level. smoking status. electrocardiographic evidence of left ventricular hypertrophy. blood glucose level. body-mass index. history of cardiovascular disease or treatment. blood pressure. and use of beta-blockers. CONCLUSIONS. In the study population. whose blood pressure before and during treatment was in a narrow range. and after other cardiovascular risk factors had been considered. the renin profile before treatment remained independently associated with the subsequent risk of myocardial infarction.
Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter, Glucose/galactose malabsorption (GGM) is an autosomal recessive disease manifesting within the first weeks of life and characterized by a selective failure to absorb dietary glucose and galactose from the intestine. The consequent severe diarrhoea and dehydration are usually fatal unless these sugars are eliminated from the diet. Intestinal biopsies of GGM patients have revealed a specific defect in Na(+)-dependent absorption of glucose in the brush border. Normal glucose absorption is mediated by the Na+/glucose cotransporter in the brush border membrane of the intestinal epithelium. Cellular influx is driven by the transmembrane Na+ electrochemical potential gradient; thereafter the sugar moves to the blood across the basolateral membrane via the facilitated glucose carrier. We have previously cloned and sequenced a Na+/glucose cotransporter from normal human ileum and shown that this gene. SGLT1. resides on the distal q arm of chromosome 22. We have now amplified SGLT1 complementary DNA and genomic DNA from members of a family affected with GGM by the polymerase chain reaction. Sequence analysis of the amplified products has revealed a single missense mutation in SGLT1 which cosegregates with the GGM phenotype and results in a complete loss of Na(+)-dependent glucose transport in Xenopus oocytes injected with this complementary RNA.
Potential of community-wide chemotherapy or immunotherapy to control the spread of HIV-1, Whether zidovudine (3'-azido-3'-deoxythymidine. AZT) should be offered to symptomless individuals infected with human immunodeficiency virus type-1 (HIV-1). in the hope of delaying or even preventing progression to AIDS. has been much debated. The discussion has focused on the efficacy of the drug in delaying progression to disease. the severity of its side-effects. and the likelihood of its prolonged and widespread use resulting in zidovudine-resistant strains of the virus. Little attention has been given to the degree to which treatment reduces the infectiousness of symptomless patients. and to the concomitant implications for the overall transmission rate of HIV-1 in the community. Here we use simple mathematical models to show that community treatment with antiviral drugs or immunotherapies that lengthen the incubation period of AIDS without significantly reducing the infectiousness of treated individuals. can increase the rate at which HIV-1 infection spreads (which is fairly obvious) and can even. under certain circumstances. increase the AIDS-related death rate in the community (which is less obvious).
Fifteen-year argon laser and xenon photocoagulation results of Bascom Palmer Eye Institute's patients participating in the diabetic retinopathy study, Fifteen years after panretinal photocoagulation in the Diabetic Retinopathy Study. 86 (57%) patients had died. 14 (9%) could not be located. and 51 (34%) of 151 patients were examined to determine the long-term treatment effects. Of the eyes randomized to photocoagulation only 1 (5%) of 19 argon-treated and 1 (3%) of 32 xenon-treated eyes had received additional laser treatment. but 8 argon-treated and 7 xenon-treated eyes had had cataract removal. Eleven (58%) of the initially argon-treated and 13 (41%) of the initially xenon-treated eyes had 20/40 or better acuity. and 18 (95%) of the initially argon-treated and 26 (82%) of the initially xenon-treated eyes had 20/200 or better acuity. Of the control eyes 17 (33%) had 20/40 or better. and 30 (58%) had 20/200 or better acuity. Argon and xenon panretinal photocoagulation for diabetic retinopathy provide good results for at least 15 years.
Postkeratoplasty astigmatism control. Single continuous suture adjustment versus selective interrupted suture removal [published erratum appears in Ophthalmology 1991 Jul;98(7):1005-7, Two different suturing techniques performed during keratoplasty were retrospectively evaluated to compare postkeratoplasty astigmatism. number of suture manipulations. and time to optical stability. One group of patients (n = 31) received a combination of continuous 11.0 nylon suture and 12 or 16 interrupted 10.0 nylon sutures (CCIS). which were selectively removed post-operatively to reduce astigmatism. The second group of patients (n = 26) received a single continuous 10.0 nylon suture (SCS) that was adjusted postoperatively at the slit lamp to regulate corneal astigmatism. Compared with the CCIS technique. adjusting the single continuous suture resulted in less postoperative astigmatism (SCS. 1.5 +/- 1.1 diopters [D]; CCIS. 3.2 +/- 1.9 D). fewer suture manipulations per patient (SCS. 0.9 +/- 0.7; CCIS. 3.8 +/- 1.8). and earlier optical stability for visual rehabilitation (SCS. 2.6 +/- 1.5 months; CCIS. 9.6 +/- 4.7 months) (P less than 0.01). No continuous sutures were broken during adjustment. The adjustable single continuous suture may offer an improved method for early control of postkeratoplasty astigmatism.
Specular microscopic observation of human corneal epithelial abnormalities, The diameter of the cone lens of the specular microscope was enlarged from its original size of 3.5 mm to 6.0 mm. This modification enabled the authors to take clear pictures of the corneal epithelium with a specular microscope (SM) contact lens. because tears could be excluded from the photographic field by exerting even pressure on the cornea. The normal corneal epithelium showed three kinds of cells with no abnormally shaped or reflex cells. As spindle-shaped cells were mainly observed in keratoconus patients. post-penetrating keratoplasty patients. and postepikeratophakia patients. this suggests that these cells may be an indicator of wound healing. Large cells were observed in diabetic aphakic patients. aphakic extended-wear soft contact lens wearers. and aphakic patients using 0.5% indomethacin eye drops; thus. the presence of large cells may indicate suppressed metabolism and mitosis. Colonies of small cells were observed in keratoconjunctivitis patients. Cells with nuclei and irregular cell patterns were observed in all diseased conditions. There are several common abnormal patterns in the corneal epithelium that are observable under the specular microscope. Modified specular microscopic observation can detect these subtle alterations at the cellular level.
Modified Schocket implant for refractory glaucoma. Experience of 55 cases, Fifty-five eyes of 51 patients with different forms of refractory glaucoma (15 aphakic. 12 neovascular. 9 postpenetrating keratoplasty. 8 congenital. 5 secondary to uveitis. 4 associated with aniridia. 1 pseudophakic. and 1 traumatic) underwent antiglaucomatous surgery using a modified 90 degrees Schocket implant. In 25 eyes (45.4%). this was the first surgical procedure. Follow-up ranged from 3 to 27 months (mean. 10.3 +/- 5.4 months). The mean preoperative intraocular pressure (IOP) was 39.5 +/- 8.6 mmHg (range. 22 to 66 mmHg). The mean postoperative IOP was 17.8 +/- 7.6 mmHg (range. 4 to 50 mmHg). Intraocular pressure remained less than 21 mmHg in 50 eyes (90.9%) during the follow-up period. In 13 of these eyes (26.0%). IOP remained under control without any medication. Complications were observed in 13 eyes (23.6%) and were successfully treated in 11 of them. Complications included iris-tube block (5.4%). vitreous-tube block (3.6%). early postoperative flat anterior chamber (1.8%). choroidal effusion (3.6%). tube exteriorization from anterior chamber (3.6%). tube displacement from silicone band (1.8%). retinal detachment (1.8%). tube-cornea touch (1.8%). vitreous hemorrhage (1.8%). infectious endophthalmitis (1.8%). and phthisis bulbi (1.8%). Modified 90 degrees Schocket implants are an effective technique in the management of refractory glaucoma.
Internal and transconjunctival neodymium:YAG laser revision of late failing filters, Seven cases of hypofunctioning trabeculectomies or full-thickness filters were treated using the Q-switched neodymium:YAG (Nd:YAG) laser delivered either transconjunctivally. gonioscopically. or by a combination approach. In four eyes. internal laser revision was attempted initially. Internal revision was successful in one case. where the sclerostomy had become occluded by a fibrous membrane. The Nd:YAG laser was then focused transconjunctivally onto the episcleral fibrous tissue within the bleb in the three eyes treated unsuccessfully by the internal approach and used as a primary treatment in three additional cases. Transconjunctival laser treatment was successful in producing an immediate and substantial decrease in intraocular pressure (IOP) (mean IOP reduction of 12 mmHg at 2 hours posttreatment) in all cases. In six of seven cases. there was a persistent reduction of intraocular pressure with an average of 5.7 months of follow-up. Transconjunctival Nd:YAG laser revision of hypofunctioning filters may be effective in restoring filtration in selected cases.
Strabismus presenting after cataract surgery, Strabismus presenting after cataract surgery is etiologically related to a heterogenous group of disorders. Clinical data from 63 patients so affected revealed four broad etiologic categories: 1) pre-existing disorders that preceded the cataract surgery. but were rendered asymptomatic by the occluding cataract (e.g.. thyroid eye disease. cranial nerve palsy. myasthenia); 2) disorders precipitated by prolonged occlusion by a cataract (e.g.. sensory deviations. decompensation of heterophorias. and central disruption of binocular vision); 3) disorders resulting from surgical trauma to extraocular muscles and orbital soft tissues. Traumatic injury to the inferior rectus muscle secondary to retrobulbar anesthesia injection. a specific subset. is postulated to result from a Volkmann's type ischemic contracture. a well-known osseofascial compartment syndrome occurring in peripheral skeletal muscles. 4) Disorders related to resulting aphakia/pseudophakia and associated optical aberrations (e.g.; anisophoria. ocular dominance reversal. and color/brightness disparity). The diagnostic and therapeutic implications of these findings are discussed.
Clinical characteristics and treatment of isolated inferior rectus paralysis, Isolated inferior rectus paralysis without mechanical restriction of the globe has received only scant attention in the literature. The authors report on 21 patients treated during the past 16 years. The etiology was congenital. traumatic. myasthenic. and vascular. Anomalous head posture. diplopia. or a disfiguring hypertropia were presenting symptoms. Diagnosis was made on the basis of the prism and cover test in the diagnostic positions and on examination of ductions and versions. The direction of the head tilt. the Bielschowsky head tilt test. and tests for cyclotropia are only of secondary diagnostic value since they may give paradoxical results. Surgery consisted of resection of the paralyzed muscle. combined with or without recession of its antagonist and/or recession of the contralateral superior oblique. After a mean follow-up of 17 months. 14 patients were cured. 6 had improved. and 1 remained unchanged.
Anisometropic amblyopia, One hundred twenty-four patients with anisometropia of 1 diopter or greater and amblyopia were reviewed as to the type and amount of anisometropia. whether or not they had consulted with an ophthalmologist. visual acuity before and after treatment. and type of treatment. The patient population was divided into five groups according to the type of anisometropia. Eighty-two percent of all patients reached a visual acuity of 20/40 or better. Eighteen percent of all patients reached a visual acuity of 20/20. The best visual acuity obtained was not found to be related to the degree of anisometropia or the age at which treatment was begun. Patients with myopic and compound myopic astigmatism/mixed astigmatism anisometropia had poorer visual outcomes. There was a strong positive correlation between the initial visual acuity and the best visual acuity obtained (P = 0.0001).
Preventing eye injuries. What to tell patients, Primary care physicians can help prevent a large number of eye injuries by giving their patients a few simple safety tips. Eye protectors with polycarbonate plastic lenses are recommended for most athletes. regardless of whether they have normal vision or they wear glasses or contact lenses. Polycarbonate lenses in a sturdy frame also offer protection during common daily. recreational. and avocational activities.
Ogilvie's syndrome. Would you recognize it, Numerous conditions predispose to Ogilvie's syndrome. a process that mimics bowel obstruction. Characteristic radiographic findings of acute pseudo-obstruction include dilatation of the cecum and the remainder of the colon but not the small intestine. Treatment is individualized. Massive cecal dilatation carries the risk of cecal perforation and its attendant high mortality rate. Conservative therapies. such as nasogastric suction. gentle enemas. and use of a rectal tube. may be beneficial. Decompression by colonoscopy or other means may be necessary.
Alcoholism. Are you missing the diagnosis, Early diagnosis of alcoholism requires exploration of the impact of alcohol on the patient's life. The disease cannot be readily detected simply by asking questions about the quantity of alcohol consumed. Few physical findings are present until late in the disease. and laboratory tests for alcoholism are neither sensitive nor specific when used alone. Use of screening questionnaires should be part of routine office practice. Elderly alcoholics are difficult to identify and need special consideration. Effective therapy is available if alcoholism is detected early.
Managing dysphagia. Special problems in patients with neurologic disease, Swallowing is a brief but intricate process. When this process is interrupted. as in patients with neurologic disorders. problems such as aspiration and risk of malnutrition can occur. The authors of this article discuss an individualized approach to evaluation and management of neurogenic oropharyngeal dysphagia. Three cases illustrate the diversity of causes. signs and symptoms. and clinical course.
How efficient is sliding-scale insulin therapy? Problems with a 'cookbook' approach in hospitalized patients, Sliding-scale insulin therapy is seldom the best way to treat hospitalized diabetic patients. In the few clinical situations in which it is appropriate. close attention to details and solidly based scientific principles is absolutely necessary. Well-organized alternative approaches to insulin therapy usually offer greater efficiency and effectiveness.
Newer antihypertensive agents, Three recent additions to the list of antihypertensive agents have been approved for use as monotherapy or in combination with other drugs. Betaxolol hydrochloride (Kerlone) maintains its effect for 24 hours. making it a true once-a-day beta blocker. Penbutolol sulfate (Levatol) is as effective as other beta blockers and diuretics. Doxazosin mesylate (Cardura). a selective alpha 1 blocker. also allows once-a-day dosing and has produced favorable changes in lipid profiles. Two new drug delivery systems. one for verapamil hydrochloride (Verelan) and one for extended-release nifedipine (Procardia XL). allow less frequent dosing and may offer other advantages. such as greater compliance and a more tolerable side-effect profile.
Renovascular hypertension. Difficulties in diagnosis and treatment, Renovascular hypertension is not easily identified clinically. and most tests are not totally reliable in detecting its presence. The condition may be due to fibromuscular dysplasia or congenital anomalies in patients younger than age 30 or to atherosclerosis in patients older than 50. The goal of treatment is to lower blood pressure and improve or maintain renal function. Cure or improvement of hypertension is more likely in patients with fibromuscular dysplasia than in those with atherosclerosis. Interventional procedures include percutaneous transluminal angioplasty. surgical revascularization. and nephrectomy.
Comparison of vastus medialis obliquus: vastus lateralis muscle integrated electromyographic ratios between healthy subjects and patients with patellofemoral pain, The purpose of this study was to compare vastus medialis obliquus:vastus lateralis muscle (VMO:VL) integrated electromyographic (IEMG) ratios of healthy subjects and patients with unilateral patellofemoral pain (PFP) under isotonic and isometric quadriceps femoris muscle contraction conditions. Subjects ranging in age from 18 to 35 years (mean = 28.06. SD = 5.97) were assigned to one of three groups on the basis of type of knee condition. In group 1. which consisted of seven healthy control subjects with no history of knee pathology. both knees were tested. In group 2. which consisted of nine patients with unilateral PFP. only the painful knee was tested. In group 3. which consisted of the same nine patients who comprised group 2. only the nonpainful knee was tested. Nonnormalized and normalized VMO:VL IEMG ratios were computed for ascending stairs. descending stairs. submaximal isometric contraction. and maximal isometric contraction (nonnormalized only). A two-way analysis of variance for repeated measures indicated VMO:VL ratios for isotonic stair-climbing activities were significantly greater than VMO:VL ratios for isometric contractions. Nonnormalized VMO:VL ratios in group 1 were significantly greater than nonnormalized VMO:VL ratios in the other two groups. Patients with PFP may have abnormal VMO:VL activation patterns. and isotonic quadriceps femoris muscle exercise may elicit more favorable muscle activation patterns than isometric exercise for patients with PFP.
Kinematic analysis of lower-limb movement during ergometer pedaling in hemiplegic and nonhemiplegic subjects, The purpose of this descriptive study was to examine bicycle pedaling as a model for studying motor control dysfunction in persons with hemiplegia. Results of a kinematic analysis of the involved lower extremity of 10 hemiplegic patients were compared with the lower-extremity kinematic data of 10 "normal" (nonhemiplegic) subjects. Subjects pedaled at a constant work load at two pedaling rates. Hip. knee. and ankle angular-displacement variables were studied. Statistical comparisons for variables at the hip and knee were not significantly different between groups or between pedaling speeds. Ankle dorsiflexion and total ankle excursion were significantly different across pedaling speeds. but not between groups. Phase-plane analyses of angular-displacement and angular-velocity variables revealed that the most striking difference between the hemiplegic and the normal subjects was the control of ankle displacement and velocity of the lower extremity during pedaling.
The surgical anatomy of the scalp, Cadaveric dissections and surgical observations have led to the description and clarification of the boundaries. blood supply. and nomenclature of the layers of the scalp. Special attention was directed to the layer of "loose connective tissue" that lies beneath the entire galea and above the cranial periosteum centrally. and the temporalis fascia laterally. It has been named the subgaleal fascia (SGF). The subgaleal fascia is a trilaminar structure with unusual potential in reconstructive surgery. Histologic study reveals the subgaleal fascia to be composed of a central dense collagenous layer surrounded by vascularized areolar tissue. It is readily dissected from surrounding galeal and periosteal layers. The subgaleal fascia was probably included in previously described "pericranial flaps." which were often based beyond the periosteum. The blood supply of the subgaleal fascia originates from the proximal portion of the peripheral vessels of the scalp and continues within the areolar lamina. The subgaleal fascia is an exceptionally thin. malleable. and well-vascularized flap useful for facial reconstruction.
The case for early bone grafting in cleft lip and palate: a second report, In 1982. the first long-term study of our early bone-grafting and infant maxillary orthopedic approach to newborn complete clefts of the lip. alveolus. and palate was published. The protocol and sequence of procedures were shown on the first 16 consecutively treated orthodontic patients. with a mean age of 14 years. Cephalometric analysis evaluated anteroposterior and vertical facial growth. This report follows the next 37 consecutively treated individuals in a similar manner and includes not only 20 complete unilateral clefts. but also 17 complete bilateral clefts. Results. when evaluated alone and in comparison with the original series. show once again that there are no adverse growth restraints and that early primary bone grafting in our protocol leads to teeth in better overall occlusion than if it had not been undertaken.
Displaced orbital roof fractures: presentation and treatment, Of 457 patients with facial fractures admitted by the plastic surgery service from 1986 to 1988 at Wayne State University. there were seven displaced orbital roof fractures in five patients. All presented with supraorbital rim fractures. inferior dystopia. limitation of supraduction. upper eyelid ptosis. and diplopia. Proptosis was present in four orbits in three patients. One of these patients had an orbital floor fracture. However. enophthalmos was present in three orbits in two patients with associated zygoma and floor fractures. Two patients had intracranial neurologic injuries. but no ocular injuries were seen. Patients underwent frontal craniotomy and removal of the supraorbital rim for exposure. The orbital roof was reconstructed with outer-table cranial bone grafts. Associated fractures were repaired. Mean follow-up was 21.4 months. In all patients. the inferior dystopia. proptosis or enophthalmos. limitation of supraduction. and diplopia were corrected. In one patient. residual mild eyelid ptosis was seen. No residual neurologic or ocular injury was seen.
Mersilene tip implants in rhinoplasty: a review of 98 cases, Reshaping the nasal tip is the most difficult part of a rhinoplasty. particularly in certain types of nasal tip deformities. such as the recessed tip. the thick-skin tip. the boxy tip. the asymmetrical tip. the thin-skin tip. the bifid tip. the turned-up tip. and the turned-down tip. A new approach is introduced regarding the use of Mersilene tip implants. Guidelines for preoperative evaluation and surgical technique are outlined. The so-called "PEPSI" rule (pocket. experience. positioning. shape and size. and incision) is emphasized. The advantages and disadvantages of the Mersilene tip implant are discussed. The Mersilene implant was used in the tip region in a total of 98 patients. and the results are satisfactory.
Management of the chest-wall deformity in male patients with Poland's syndrome, The chest-wall deformity associated with Poland's syndrome was reconstructed in eight male patients 16 to 38 years old (average age 20 years). Follow-up ranged from 1 to 10 years. Two patients had custom silicone implants placed subcutaneously. In one of these patients. the edge of the implant could be seen. Three patients had transfer of an ipsilateral pedicled latissimus dorsi muscle flap with intact thoracodorsal nerve. All these patients had noticeable atrophy of the flap. and one underwent subsequent implantation of a custom silicone implant beneath the flap. Three other patients had a custom silicone implant covered immediately by a latissimus dorsi muscle flap. All four patients who had a combination of silicone implant and latissimus dorsi muscle flap had satisfactory correction of their deformity.
Noninvasive assessment of implant capsules, The assessment of implant capsular contracture has been imprecise and vulnerable to observer bias. Attempts to measure capsules with instruments that measure implant deformability are influenced by surrounding breast tissue. subcutaneous fat. and skin. Xeromammography. B-mode ultrasound. and CT were employed in an effort to provide a noninvasive and accurate method of capsule assessment. Through two study phases. implants were placed bilaterally in a total of 21 rabbits. At 4 months. animals underwent radiologic assessment and were then sacrificed for direct implant capsule measurements. Mammographic measurements. more than ultrasound-derived measurements. strongly correlated with laboratory measures of capsular dimensions and deformability. Cross-table lateral mammographic views were more informative than traditional views. providing measures of diameter and height that both strongly correlated with laboratory measurements. CT is theoretically the most accurate method to assess contracture. but it is impractical because of expense and time requirements. The results indicate that radiologic assessment. in particular by xeromammography. of implant capsules is accurate. practical. and noninvasive. Mammography strongly correlates with laboratory measures of implant capsular contracture and therefore could be used in the clinical setting to assess capsular contracture.
Penile reconstruction for a victim of electrical injury with bilateral below-elbow amputations, We report on a young man who had complete loss of the penis and bilateral below-elbow amputations following severe electrical injury. Reconstruction of the penis was completed by using a deliberately tailored dorsalis pedis flap to solve the problems encountered by a migrated skin tube. Construction of a neourethra with release of the contracture was done simultaneously and brought about successful results.
Cosmetic treatment of shagreen patches in selected patients with tuberous sclerosis, Patients with mild forms of tuberous sclerosis may request cosmetic treatment of skin hamartomas. Treatment may consist of planning of an elevated shagreen patch with a Reese dermatome and/or laser treatment of facial angiofibromas. These precise patients. i.e.. patients with a forme fruste of tuberous sclerosis. are more likely to have pulmonary involvement than patients with the usual complete disease form. A chest x-ray should be obtained in these patients to rule out pulmonary involvement. Half the patients with pulmonary involvement of tuberous sclerosis die an avoidable death from spontaneous pneumothoraces. Positive-pressure ventilation during anesthesia in these patients should be avoided or monitored closely.
How selective is selective posterior rhizotomy, Although selective posterior rhizotomy has become an increasingly utilized surgical treatment for spasticity. the procedure is unstandardized and is performed differently at various medical centers. Most surgeons use some form of direct dorsal rootlet stimulation with intraoperative multichannel electromyographic response monitoring. Electrophysiological monitoring offers the theoretical advantage of identifying pathologic reflex circuits for interruption while preserving those pathways that are "normal." However. the monitoring technique most commonly used has not been critically evaluated and. therefore. its value remains uncertain. In 22 selective posterior rhizotomy procedures performed for spastic cerebral palsy. the authors were unable to identify a single electromyographic response that could be called normal by presently accepted criteria. Dorsal rootlets were chosen for division on the basis of relative degrees of abnormality. Intraoperative electromyographic monitoring of a nonspastic patient produced tracings suggestive of spasticity by presently accepted criteria. These discrepancies suggest that current electrophysiological monitoring in selective posterior rhizotomy should be reevaluated.
Left alien hand sign and mirror writing after left anterior cerebral artery infarction, A 43-year-old. right-handed man was admitted complaining of peculiar movements of his left hand. Computed tomography scan and magnetic resonance imaging showed an infarct area in the territory of the left anterior cerebral artery. The abnormal movements of the left hand were diagnosed as so-called alien hand sign. This patient also exhibited mirror writing with his left hand. The clinical manifestations and neuroradiological findings of this case are described in detail. and the possible mechanisms of these extremely rare combinations of alien hand sign and mirror writing are discussed.
Protrusion of the first thoracic disk, A case of lateral prolapse of the T-1/T-2 intervertebral disk is presented. The patient complained of pain radiating down the medial aspect of the forearm into the little and ring fingers. This was associated with a subjective sensory loss in the same distribution. intact reflexes. and no long tract signs. Oculosympathetic paralysis was not present. Twelve cases have been mentioned in the literature. only eight of which contain details of the neurological findings. The varied findings in these cases are also reviewed. and it is noted that unless radiological examination includes the upper thoracic spine in cases of brachial neuralgia. these lesions will be missed.
Flow cytometric DNA analysis of hepatocellular carcinoma: preliminary report, Flow cytometric DNA analysis was performed in 50 paraffin-embedded specimens of clinical hepatocellular carcinoma (HCC) after hepatic resections. The DNA distribution pattern was classified in two types. diploid and aneuploid. according to the degree of dispersion on the DNA histogram. The major DNA pattern of HCC in this report proved to be aneuploid (78%). although 22% of tumors revealed a diploid pattern. The serum alpha-fetoprotein level exceeded 40 ng/ml in 86.1% of the aneuploid tumors and in 13.9% of the diploid tumors (p less than 0.05). We found no correlation between DNA distribution and hepatitis B surface antigen positivity. the presence of liver cirrhosis or tumor size. Additionally we noted no significant correlation between the DNA pattern and survival rates in patients with HCC who underwent hepatic resection.
Effect of the glucocorticoid receptor antagonist RU 38486 on muscle protein breakdown in sepsis, The role of glucocorticoids in muscle catabolism during sepsis was tested with the glucocorticoid receptor antagonist RU 38486. Sepsis was induced in male Sprague-Dawley rats (40 to 60 gm) by cecal ligation and puncture (CLP). Other animals underwent sham operation. Two hours before CLP or sham operation. rats received RU 38486 (5 mg/kg) or a corresponding volume of vehicle by gavage. Sixteen hours after CLP or sham operation. protein synthesis rate was determined by measuring incorporation of 14C-phenylalanine into protein in incubated extensor digitorum longus muscles. Total and myofibrillar protein breakdown rates were determined by measuring net release of tyrosine and 3-methylhistidine. respectively. The protein synthesis rate was approximately 30% lower in rats with sepsis than in sham operated rats and was not affected by treatment with RU 38486. The total protein breakdown rate was increased by approximately 70% and myofibrillar protein degradation was increased more than fivefold in muscle from rats with sepsis. Treatment with RU 38486 resulted in a 28% reduction of total and a 44% reduction of myofibrillar protein breakdown in rats with sepsis but did not affect proteolysis in muscle from sham-operated animals. The results support a role of glucocorticoids in accelerated muscle proteolysis during sepsis. It is not clear whether glucocorticoids are the only required mediator or they interact with other substances to induce muscle protein breakdown during sepsis.
Catecholamine regulation of adipocyte lipolysis after surgery, The effect of surgical trauma on the regulation of lipolysis was studied in isolated fat cells obtained before and 24 hours after elective cholecystectomy in 12 patients who were not obese and who were healthy otherwise. Surgery was accompanied by a twofold increase of the basal rate of lipolysis and by a significant 50% elevation of the lipolytic effect of catecholamines. The actions of various agents that selectively stimulate lipolysis at different early or late steps in the cyclic adenosine monophosphate system beyond the adrenoreceptors were also increased about 50% after surgery (p less than 0.01). The properties of the beta-adrenoceptors were not altered by surgery. as assessed by radioligand binding and isoprenaline sensitivity. The antilipolytic properties of catecholamines (mediated by alpha 2-adrenoreceptors) were not influenced by cholecystectomy. Lipolysis was not altered in four subjects who had no surgery and who served as control subjects 24 hours after being given the same type of postoperative nutrition as patients who underwent cholecystectomy. We concluded that moderate surgical trauma is associated with increased lipolytic activity of fat cells. This is secondary to an enhanced ability of catecholamines to stimulate lipolysis because of a modification at the most distal steps in the cyclic adenosine monophosphate system. which may involve the protein kinase/hormone sensitive lipase complex.
Transient inhibition of neutrophil adherence with the anti-CD18 monoclonal antibody 60.3 does not increase mortality rates in abdominal sepsis, Monoclonal antibodies (MAbs) that recognize the neutrophil (PMN) adherence complex CD11/CD18 inhibit PMN adherence to endothelium and attenuate PMN-mediated ischemia-reperfusion injury. One consideration regarding the clinical usefulness of such therapy is whether transient inhibition of PMN adherence or function will impede host defense and increase susceptibility to infection and sepsis. We studied susceptibility to sepsis in New Zealand white rabbits with an appendiceal devascularization model to answer the question: Does inhibition of PMN adherence with the anti-CD18 MAb 60.3 increase morbidity and mortality rates in abdominal sepsis? Four treatment groups of 10 animals each were studied: group 1 (controls) received no treatment. group 2 received MAb 60.3. group 3 was given the antibiotic cefazolin alone. and group 4 received both cefazolin and MAb 60.3. PMN emigration into the peritoneum was inhibited significantly in MAb 60.3-treated animals (groups 2 and 4). There was no difference in weight loss. incidence of infectious complications. or mortality rates when MAb 60.3-treated animals were compared with untreated animals. These results demonstrate that transient inhibition of PMN adherence does not increase morbidity or mortality rates in this model of abdominal sepsis. These results suggest that if MAb 60.3 or similar antibodies are used to prevent PMN-mediated injury. they will not increase susceptibility to sepsis.
The response of retroperitoneal fibrosis to tamoxifen, Although retroperitoneal fibrosis is uncommon and histologically benign. it is a progressive and potentially fatal tumor. As the fibroblasts proliferate. they encase and may obstruct important retroperitoneal structures. Medical therapy in the past has been ineffectual. and since the tumor usually cannot be resected. surgery consists of lysis or bypass of the involved structures. Tamoxifen is effective in the treatment of desmoid tumors. and we report its use in two patients with retroperitoneal fibrosis with excellent results. The simplicity and safety of this treatment make tamoxifen an attractive choice of therapy.
Cerulein-induced pancreatitis in the ex vivo isolated perfused canine pancreas, Infusion of supramaximal doses of the cholecystokinin analog cerulein is well established as an in vivo technique for inducing experimental pancreatitis in small animals. An attempt was made to simulate this model and initiate pancreatitis in the ex vivo isolated perfused canine pancreas. Control preparations gained minimal weight (mean 8.3 +/- 5.1 gm). demonstrated no edema accumulation. and did not develop hyperamylasemia (mean 1342 +/- 790 units) after 4 hours of perfusion. Electron microscopy after 4 hours of perfusion remained normal. Intraarterial cerulein infusion produced significant weight gain (mean 27.6 +/- 12.3 gm; p less than 0.001). edema formation. and marked hyperamylasemia (mean 26.838 +/- 21.341 units; p less than 0.001) after 4 hours of perfusion. During the 4-hour perfusion. electron microscopy of cerulein preparations demonstrated depletion of zymogen granules. condensing vacuole formation. and basolateral exocytosis. Pretreatment of cerulein preparations with the free radical scavengers superoxide dismutase and catalase and the iron chelator deferoxamine did not modify the pancreatitis. Continuous infusion of the nonpeptide cholecystokinin antagonist L364.718 reduced cerulein-induced weight gain (4.3 +/- 3.4 gm; p less than 0.001) and hyperamylasemia (9392 +/- 6718 units; p less than 0.05). We conclude that cerulein pancreatitis in the ex vivo isolated perfused canine pancreatic preparation is identical physiologically. biochemically. and morphologically with that seen in intact animals.
Tissue oxygen tension and other indicators of blood loss or organ perfusion during graded hemorrhage, Currently employed clinical indicators of perfusion provide inadequate warning of developing hazards caused by marginal perfusion in certain vital organs or "peripheral" tissues that are pivotal to postsurgical wound healing. In this study. mean arterial blood pressure. cardiac output. and transcutaneous and subcutaneous oxygen tensions (PtcO2 and PsqO2) were investigated during serial hemorrhage. as indicators of the degree of both hypovolemia and perfusion to specific tissues. Blood was removed in stages (10%. 20%. 30%. 40%. 55%. 60%. and 65% of original volume) from anesthetized dogs. Injections of variously radiolabeled microspheres allowed assessment of blood flow at each stage of hemorrhage in bone. brain. colon. heart. kidney. liver. muscle. pancreas. skin. small intestine. spleen. stomach. and subcutaneous tissue. PsqO2 was correlated more highly with blood volume lost than was PtcO2. Furthermore PsqO2 was more sensitive to blood loss than was either cardiac output or PtcO2 and. also during the early loss (0% to 40%). was more sensitive than mean arterial pressure. Some organs (e.g.. pancreas) appeared to lose considerable blood flow with only small loss of blood volume. but their blood flow then stabilized at a low level despite further hemorrhage. Other organs. notably the kidney. appeared to be relatively unaffected by substantial loss of blood volume (20% to 40%). after which. however. their blood flow quite abruptly became sensitive to further hypovolemia. This explains why blood flow-related performance of the kidney (e.g.. urine volume) may not adequately predict a developing hazard or peripheral perfusion. Some indicators were found to be better indexes of blood flow in some organs than in others (e.g.. cardiac output and PsqO2 correlated more closely with skin. spleen. and intestinal flows [and one another] than with vital organ flows).
Giant benign mesenchymoma of the breast, The term mesenchymoma refers to a group of mixed tumors that are composed of two or more mesenchymal elements. excluding fibrous tissue. not ordinarily found together within the same tumor. Mesenchymomas occur most commonly in the renal and perirenal regions with rare occurrence in the breast. We describe what to our knowledge is the first report of a giant benign mesenchymoma of the breast. The clinical presentation. course. and treatment of a patient with this condition is discussed. Clinicians should be aware that benign mesenchymomas may involve the breast and simulate a malignant breast neoplasm.
Primary solid neoplasms of the greater omentum, Primary solid tumors of the greater omentum are rare. with only 42 reported cases. Malignant hemangiopericytomas constitute only three of these cases. The 40-year-old patient described in this report had abdominal pain. a palpable abdominal mass. early satiety. and weight loss. At laparotomy a large omental hemangiopericytoma was excised. and no other evidence of disease was grossly evident. Eighteen months after initial laparotomy. the patient had widespread progression of the tumor and. despite chemotherapy. died 2 months later. A review of reported cases shows that abdominal discomfort (56%) and mass (35%) are the most common clinical characteristics of a primary omental tumor. Weight loss. ascites. and peritoneal implants usually indicate malignancy. Rare long-term follow-up prevents definitive conclusions regarding therapy and prognosis. At present. surgical excision alone appears to be the treatment of choice. with no demonstrable benefit from either chemotherapy or radiation.
Inflammatory abdominal aortic aneurysm: an indication for the retroperitoneal approach, In three recent cases. one of which is described in this report. we have found the retroperitoneal approach to have the following significant and distinct advantages over the transabdominal repair of inflammatory abdominal aortic aneurysms: (1) The posterolateral aspect of the aorta characteristically is not significantly involved by the inflammatory process. whereas the anterior aspect is. (2) The duodenum does not need to be dissected away from the aorta and. in fact. is not seen. (3) The left renal vein moves up off the neck of the aneurysm with forward mobilization of the kidney. facilitating proximal control. Now that the computerized tomography scan has become the preferred preoperative imaging technique for abdominal aortic aneurysms. the diagnosis of inflammatory abdominal aortic aneurysm can routinely be made before elective operation allowing the retroperitoneal approach to be selected.
Diagnosis and management of phencyclidine intoxication, Because phencyclidine intoxication has both psychiatric and physical manifestations. it continues to present a challenge to physicians. Intoxication may be viewed as occurring in three stages. Mild intoxication. the first and most common stage. is manifested primarily by psychiatric signs and symptoms. In the second stage. patients are stuporous to comatose. but they have intact deep pain responses. In the third stage. patients do not respond to deep pain stimuli. Treatment depends on the stage of intoxication.
Shoulder dystocia, Shoulder entrapment during delivery is a true obstetric emergency that can result in significant maternal and infant trauma. Fetal macrosomia. maternal obesity. maternal diabetes and prolonged second stage of labor are associated risk factors. Infant complications of shoulder dystocia include traumatic brachial plexus injury. humeral fracture. clavicular fracture and severe birth asphyxia. With fetal shoulder entrapment. the mother may have significant hemorrhage. fourth-degree perineal lacerations and endometritis. Maneuvers to release the shoulder include closed-fist suprapubic pressure. downward pressure on the posterior shoulder. rotation of the anterior shoulder to the oblique position. rotation of the posterior shoulder beneath the pubic symphysis. release of the posterior arm and anterior rotation of the fetal body.
COPD: management and rehabilitation, Chronic obstructive pulmonary diseases include emphysema. chronic bronchitis and asthma. Patients with mild disease may remain asymptomatic for many years. In patients with a sedentary lifestyle. 60 percent of lung function may be lost before shortness of breath occurs during daily activity. Spirometry may detect mild to moderate airflow obstruction in asymptomatic patients. Goals of therapy include reduction of airflow obstruction. prevention or treatment of complications. and improvement in quality of life.
Addison's disease, Addison's disease is an uncommon endocrine condition manifested by a variety of nonspecific symptoms. such as malaise. anorexia and nausea. Symptoms usually do not occur until most of the adrenal gland has been destroyed. Autoimmune disease has surpassed tuberculosis as the primary cause of Addison's disease. Nevertheless. tuberculosis still accounts for a significant proportion of cases. The rapid adrenocorticotropic hormone (ACTH) stimulation test is useful for identifying adrenal insufficiency. Maintenance therapy consists of hydrocortisone and fludrocortisone.
Use of antibiotics during pregnancy, Pregnancy is occasionally complicated by infections that necessitate antibiotic therapy. When considering therapeutic options for pregnant women. both the physiologic changes of pregnancy and the prenatal effects of the drug must be weighed. Antibiotics should be selected with regard to the trimester of pregnancy. Some antibiotics are safe for use throughout pregnancy. while others are completely contraindicated. Choosing the proper antibiotic requires balancing the seriousness of the infection with the antibiotic's safety and antimicrobial activity.
Quantification of rate of coronary artery disease progression by a new method of angiographic analysis, To assess the rate and variability of atherostenosis progression in patients with coronary artery disease at baseline angiography. we used a simplified quantitative method of analysis to study single angiograms in 54 patients and paired angiograms in 29 patients. All discrete lesions were identified. then traced and digitized to determine lumen diameter (LD). and summed to give the total LD; the differences in LD for paired angiograms were summed to give total stenosis change (TSC). The following results were obtained: Correlation between LD measured by our method and LD determined by the Brown/Dodge method was excellent (r = 0.99. N = 54). There also was a high correlation between interobserver (r = 0.98. N = 54) and intraobserver (r = 0.99. N = 54) findings. Short-term TSC (N = 9. angiograms paired at less than 1 week) was negligible (0.03 +/- 0.38 mm). Long-term (N = 20. angiograms paired at 0.6 to 4.3 years) total LD differed significantly from baseline total LD (4.1 +/- 2.5 mm vs 6.0 +/- 3 mm; p less than 0.001). and TSC (2.0 +/- 1.3 mm) in long-term patients differed significantly from TSC in short-term patients (p less than 0.001). These results show that true coronary disease progression occurring over 1 to 4 years can be distinguished from intraobserver. interobserver. and interstudy variability by means of a simplified method and provide approximate rates and variability of progression. These results will be useful for power calculations in therapeutic trials aimed at slowing progression. Further prospective studies with the use of this method appear indicated.
Severity of coronary atherosclerosis correlates with the respiratory component of heart rate variability, Decreased vagal activity is frequently observed in coronary artery disease. but the mechanism of this association is unknown. We investigated cardiac autonomic function by relating heart rate spectral components to clinical and angiographic findings in 80 patients who were undergoing coronary angiography. The age- and sex-adjusted magnitude of the respiratory spectral component. which is an index of cardiac vagal tone. showed a significant negative correlation with the extent of coronary atheromatosis (r = -0.43. p less than 0.0001) and a less significant negative correlation with the severity of coronary stenosis (r = -0.30. p = 0.0070). These relationships were independent of previous myocardial infarction and of left ventricular function. Stepwise regression analysis showed that the respiratory spectral component contributed to atheromatosis independently of established coronary risk factors (partial R2 = 9.4%. p = 0.002). but not to stenosis. Our results support the hypothesis that decreased cardiac vagal activity is associated with an increased risk of coronary atherosclerosis.
Segmental wall motion abnormalities in the absence of clinically documented myocardial infarction: clinical significance and evidence of hibernating myocardium, To determine the frequency and significance of left ventricular wall motion abnormalities in patients without clinical evidence of myocardial infarction. we reviewed the two-dimensional echocardiograms of 252 patients who had no history or electrocardiographic evidence of myocardial infarction and who subsequently underwent coronary angiography. Seventy-seven patients (31%) had one or more segmental wall motion abnormalities. Sixty-six of the 77 patients (86%) had significant coronary artery disease (greater than or equal to 50% luminal diameter stenosis). Seventy-four percent of the patients with coronary artery disease had multivessel disease. The left ventricle was divided into anterior and posterior regions. In the 66 patients. there were 77 separate regions with wall motion abnormalities (49 hypokinesis. 22 akinesis. 6 dyskinesis). including 60 regions (78%) supplied by coronary vessels with greater than or equal to 70% stenosis. Thirty-two patients underwent coronary artery bypass surgery or percutaneous transluminal coronary angioplasty. Follow-up echocardiograms were obtained in 19 patients who had wall motion abnormalities involving 22 regions. Twenty of the 22 regions were revascularized. Wall motion improved in 17 of 20 regions (85%) and returned to normal in 15 regions (75%). We conclude that segmental wall motion abnormalities may be detected by echocardiography in up to one third of patients evaluated for suspected coronary artery disease without documented myocardial infarction. These abnormalities are associated with a high likelihood of multivessel disease as well as with significant narrowing of the artery supplying the region demonstrating abnormal wall motion. Improvement in segmental wall motion abnormalities after revascularization suggests that these areas represent regions of hibernating myocardium.
Coronary angiographic patterns in hypertensive compared with normotensive patients, Patients in this study were assessed by coronary angiography because of classic effort angina and a positive exercise test. Of these patients. 320 had untreated primary hypertension and 320. similar in age and gender distribution. were normotensive. In all patients coronary angiography documented that at least one major epicardial branch was restricted by 50% or more. Prevalence of single- and double-vessel disease in the fourth and fifth decades of life was similar in the two populations and in both tended to decline with age. Prevalence of triple-vessel disease was also similar in the two populations in the fourth and fifth decades; in either population it rose with age and reached a peak at the seventh decade of life. The percentages of hypertensive patients in the sixth and seventh decades with triple-vessel disease was significantly (p less than 0.01) greater (40% and 50%. respectively) than the corresponding values in normotensive individuals (25% and 31%. respectively). The left main coronary artery was not significantly more involved in the high blood pressure group. Pressure was moderately and similarly raised at any age in hypertension; serum cholesterol and triglyceride levels. blood glucose. and smoking habits were comparable in the two populations. These results suggest that hypertension does not accelerate the appearance of significant coronary narrowing or multiple vessel involvement. Starting from the sixth decade. the natural age-related evolution of coronary disease seems to be aggravated in hypertensive subjects. as reflected by an augmented number of diseased vessels. This process is probably related to high blood pressure in itself; whether the severity of hypertension might also exert an influence is not deducible from this study.
Relationship of left ventricular mass to impairment of coronary vasodilator reserve in hypertensive heart disease, An impaired coronary vasodilator reserve has been demonstrated in all stages of hypertensive heart disease but is most likely in the setting of hypertrophy. The decrease in coronary flow reserve has. however. not been predictable previously. We postulated that flow reserve depression might be related to a left ventricular mass threshold. Seventy-two patients (82% with hypertension) with suspected ischemic heart disease who were found to be free of significant coronary artery disease at cardiac catheterization were evaluated utilizing the intracoronary Doppler catheter and two-dimensional directed M-mode echocardiography for determination of coronary flow reserve and left ventricular mass. For left ventricular mass indexed (LVMI) by body surface area (BSA) greater than or equal to 50% above normal using established gender-specific norms. American Society of Echocardiography (ASE) and PENN methods (correction of LV mass by regression equation agreeing with necropsy estimates of mass) predicted impairment of flow reserve (p = 0.005 and 0.009. respectively). Unindexed left ventricular mass and LVMI by height were not helpful in this regard. Using the ASE method for LV mass determination. coronary flow reserve was moderately depressed (2.4 +/- 1.0) for those with LVMI greater than or equal to 50% above normal; in comparison. flow reserve was normal (3.5 +/- 1.3) for those with LVMI less than 50% above normal. A rare patient was able to maintain a normal flow reserve when ASE- and Penn-indexed mass estimates were greater than or equal to 50% above normal. but only in the setting of a markedly elevated mean arterial pressure.
Electrocardiographic signs of atrial overload in hypertensive patients: indexes of abnormality of atrial morphology or function, Left atrial electrocardiographic (ECG) abnormalities have been reported as common findings in hypertension; however. their relationships with atrial anatomy are still uncertain. In addition. in arterial hypertension several studies demonstrated an abnormal left ventricular filling. The aim of this study was to investigate the relationships of the ECG signs of left atrial abnormality to atrial anatomy and left ventricular filling as evaluated by pulsed-wave (PW) Doppler in a group of patients with uncomplicated essential hypertension. To this end. 53 untreated essential hypertensive patients (age 44 +/- 8 years; blood pressure 160.5 +/- 21.5/104.7 +/- 13.5 mm Hg) underwent a complete 12-lead ECG and a PW Doppler study of the transmitral flow velocities. The ECG criteria of left atrial abnormality were: P wave wider than 0.12 (or 0.10) second or higher than 0.25 mV in lead II; P wave/PR segment ratio (Macruz index) greater than 1.6 in lead II; and P wave terminal forces in lead V1 equal to or more negative than 0.04. Echocardiographic measurements were made according to American Society of Echocardiography (ASE) convention. Doppler parameters of left ventricular filling were measured as E and A peak velocity. A/E ratio. and the ratio between the velocity-time integral under the E peak and that of the whole diastolic flow. which represents the rapid filling fraction (RFF). At least one ECG sign of atrial abnormality was present in 34 patients (64%); the Macruz index gave the most common ECG index of atrial abnormality (31 patients).
Late potentials in progressive muscular dystrophy of the Duchenne type, This study describes the late potentials (LPs) obtained by signal-averaged electrocardiography (SAECG) in 66 patients with Duchenne's progressive muscular dystrophy (DMD). It also assesses the possible relationships between LPs and the severity of DMD. and the findings of two-dimensional echocardiography. as well as ventricular arrhythmias examined with the Holter system. SAECGs were performed with a Marquette MAC-1 unit. Based on Swinyard-Deaver's system of stages. ranging from the mildest. S1. to the most severe. S8. one patient each could be assigned to S2 and S4. 6 to S5. 20 to S6. 21 to S7. and 17 to S8. LPs were observed in 21 of the 66 patients (32%). including 3 of the 20 assigned to S6 (15%). 10 of the 21 in S7 (48%). and 8 of the 17 in S8 (47%). The total wall motion index evaluated by the method of Hegar was significantly greater in the patients with LPs (8.4 +/- 4.4) than in those without LPs (5.8 +/- 3.1) (p less than 0.05). The incidence of LPs was found to be higher in the dilated cardiomyopathy (DCM) type (8 of 12;67%) than in the normal type (9 of 41;22%) (p less than 0.01). The incidence of ventricular premature complexes (VPCs) was significantly higher in patients with LPs (13 of 21;62%) than in those without LPs (13 of 45;29%) (p less than 0.05). No sustained ventricular tachycardia (VT) was observed. although nonsustained VT was noted in three patients with LPs. The LPs in patients with DMD were thus associated with left ventricular dysfunction. and the presence of LPs might be correlated with the extent of myocardial derangement in DMD.
Dynamic changes in left ventricular outflow tract flow velocities after amyl nitrite inhalation in hypertrophic cardiomyopathy, Doppler echocardiography was performed in 21 patients with hypertrophic cardiomyopathy (HC). in nine patients with no evidence of left ventricular (LV) hypertrophy by two-dimensional echocardiography. and in five patients with systemic hypertension and concentric LV hypertrophy. The LV outflow tract (LVOT) peak velocity was recorded by continuous wave Doppler technique at rest and after amyl nitrite inhalation. The LVOT pressure gradient was calculated by the modified Bernoulli equation. A significant increase in heart rate and a drop in systolic blood pressure were observed in all patients after amyl nitrite inhalation; no adverse effects were encountered. The peak LVOT velocity and pressure gradient increased significantly after provocation in all patients. but the increase was much more pronounced in patients with HC (peak LVOT velocity increased from 2.2 +/- 0.8 to 4.3 +/- 1.0 m/sec and peak gradient increased from 22 +/- 17 to 78 +/- 36 mm Hg). The Doppler spectral signal in patients with HC demonstrated a characteristic contour. with peak velocity occurring in late systole. However. the observed increase in LVOT peak velocity was not statistically different between treated (with beta-blockers and calcium blockers) and untreated patients with HC. We conclude that LVOT peak velocity and pressure gradients in patients with HC can be readily assessed by Doppler echocardiography both at rest and after amyl nitrite inhalation. The dynamic changes in LVOT velocity induced by this provocation have certain characteristic features in obstructive HC but appear to be independent of the medical regimen used. at least in the dosages tested in our study.
Left ventricular remodeling after acute myocardial infarction: clinical course and beneficial effects of angiotensin-converting enzyme inhibition, LV enlargement is an important determinant of survival after AMI. Pathophysiologic mechanisms leading to LV dilatation after an AMI include early thinning and stretching of the infarcted segment (e.g.. infarct expansion) and hypertrophy of the noninfarcted myocardium. Such LV dilatation may adversely affect subsequent cardiac function. leading to heart failure and death. Experimental data in animals and preliminary studies in humans have demonstrated that early administration of captopril. an angiotensin-converting enzyme inhibitor. may limit infarct expansion and will attenuate progressive LV dilatation. This article discussed the clinical importance of the dilated left ventricle and reviewed advances and ongoing research in the use of angiotensin-converting enzyme inhibitors in the chronic phase after AMI.
Doxazosin effects on insulin and glucose in hypertensive patients. The Finnish Multicenter Study Group, This study investigates the effects of prolonged doxazosin treatment on serum lipids. glucose. serum insulin. and blood pressure in hypertensive patients. Following 26 weeks of treatment with doxazosin. supine and standing blood pressures were significantly decreased at a final mean daily dose of 6.4 mg. Blood glucose levels were significantly lower at 26 weeks than after the initial placebo period (p less than 0.05) or after 4 weeks' treatment with doxazosin (p less than 0.001). There was a significant (p less than 0.05) decrease in serum insulin levels following 4 weeks of treatment. and a highly significant (p less than 0.001) decrease after 26 weeks. In addition. doxazosin produced a significant reduction in total cholesterol (p less than 0.05) and low-density lipoprotein (LDL) cholesterol (p less than 0.01) after 26 weeks. although the levels of high-density lipoprotein (HDL) cholesterol. very-low-density lipoprotein (VLDL) cholesterol. and triglycerides showed no significant change. There was a tendency for the ratio of HDL: total cholesterol to increase. The combined changes in blood pressure. blood glucose levels. serum insulin. and serum lipids favorably affect the probability of developing coronary heart disease (CHD).
Physical-activity-assessment measures compared in a biethnic rural population: the San Luis Valley Diabetes Study, We evaluated the consistency of three questionnaire methods of assessing work and leisure activity in the rural biethnic population of the San Luis Valley Diabetes Study. A 7-d physical activity recall (PAR). a ranking of usual activity. and a history of usual participation in vigorous activity were used. Energy expenditure (kJ.kg-1.wk-1) (EE) was estimated from PAR. Subjects were 503 adults [49% non-Hispanic white (NHW). 51% Hispanic]. Physical activity at work rather than leisure-time activity largely determined total energy expenditure. Average EE at work increased with work rank for all subjects combined [mean EE (SEE) for rank 1 (low) = 324.2 (24.4). rank 4 (high) = 874.0 (102.1)] and within sex. ethnic. and occupational subgroups. Leisure EE increased with leisure rank only for NHW men and employed women. Similar patterns were observed in comparisons of PAR data with history of vigorous activity. Further development and validation of instruments appropriate for use across population subgroups are needed.
Energy-metabolism adaptation in obese adults on a very-low-calorie diet, In this study. six obese women received a very-low-calorie diet (VLCD) for 3 wk. At day 0. body composition was assessed with a bioelectric impedance analyzer. The evolution in lean body mass (LBM) during the VLCD was estimated from nitrogen balance. measuring urine and fecal losses and taking into account skin. nitrate. and menstrual losses to avoid underestimation bias that could explain the decreased ratio of resting metabolic rate (RMR) to LBM previously reported. RMR was measured at days 0. 3. 5. and 21. The RMR-LBM ratio declined significantly during the VLCD period and decreased faster during the first week; the day 3. day 5. and day 21 ratio values were 94%. 91%. and 82%. respectively. of the original. The RMR-LBM ratio decrease after 21 d of a VLCD was near that found in chronic undernutrition. Results of previous studies that did not find any drop in the RMR-LBM ratio in obese adults on VLCDs might be explained by their LBM-assessment methods.
Reference data for obesity: 85th and 95th percentiles of body mass index (wt/ht2) and triceps skinfold thickness, Body mass index (BMI) and triceps skinfold thickness (TSF) are commonly used measures of adiposity in clinical and epidemiologic studies. The 85th and 95th percentiles of BMI and TSF are often used operationally to define obesity and superobesity. respectively. Race-specific and population-based 85th and 95th percentiles of BMI and TSF for people aged 6-74 y were generated from anthropometric data gathered in the National Health and Nutrition Examination Survey 1 (NHANES I). The complex sample design of the survey is reflected in the reference values presented. Racial differences in these extremes of the distribution do not emerge until adulthood. Researchers may choose population-based. race-specific. or age-specific criteria for obesity on the basis of assumptions underlying their specific research questions.
Effects of pyruvate and dihydroxyacetone consumption on the growth and metabolic state of obese Zucker rats, Female obese Zucker rats (aged 6 wk) were randomly assigned to one of two control or one of three experimental-diet groups. Experimental diets contained 6% pyruvate (Pyr). 6% dihydroxyacetone (Dha). or 3% each pyruvate and dihydroxyacetone (Pyr-Dha). Control-group 1 was fed a normal diet ad libitum and control-group 2 was pair fed according to the experimental group with the lowest consumption. After 5 wk the rats receiving Pyr (357.5 +/- 12.7 g) were significantly lighter than pair-fed (385.9 +/- 4.9 g) and ad libitum-fed (404.3 +/- 10.1) controls. Resting oxygen consumption (mL.min-1.kg0.65) was significantly higher in Pyr-fed rats than in pair-fed controls and food-conversion efficiency was significantly decreased. Rats fed Pyr had a lower resting respiratory-exchange ratio than did ad libitum- and pair-fed controls (0.81 +/- 0.01 vs 0.88 +/- 0.01 and 0.87 +/- 0.01. respectively). Results suggest that pyruvate consumption reduced the weight gain and food-conversion efficiency of obese Zucker rats. in part by increasing resting metabolic rate and fatty acid oxidation.
Long-term evaluation of cardiac function in obese patients treated with a very-low-calorie diet: a controlled clinical study of patients without underlying cardiac disease, Twenty obese women were randomly assigned to consume (for 16 wk) either a 420-kcal/d liquid diet (n = 12) or a 1200-kcal/d balanced diet (n = 8). Thereafter. patients in both conditions were prescribed a 1200-kcal/d diet for the remainder of treatment (week 45). Six obese nondieters served as control subjects. Ambulatory electrocardiographic (Holter) monitor readings were obtained on all patients at baseline and weeks 3. 9. 13. 17. 19. and 45 of the study and were analyzed for ventricular premature depolarizations (VPDs) per hour. paired forms. and runs of ventricular tachycardia. There were no statistically significant changes in VPDs in any condition during treatment. Similarly. there were no significant changes in the PR. QRS. and corrected QT intervals. The results indicate that under appropriate medical supervision. very-low-calorie diets can be used safely for up to 16 wk by significantly obese patients free of pre-existing cardiac disease.
Parental influence on food selection in young children and its relationships to childhood obesity, This investigation evaluated the impact of parental influences on children's food selections and the impact of childhood obesity on these food choices. Subjects were 53 young children of various weight status. Foods ranging widely in nutritional values were offered to each child for lunch. The children were again offered foods but were told that their mothers would be monitoring their selections. Finally. mothers were allowed to modify their children's last food choices. Results indicated that parental influences have a marked effect on food selection; both the threat of parental monitoring and actual parental monitoring lowered the number of nonnutritious foods chosen and total caloric content of the meal. The obesity status of the mothers and children had no impact on these results. The implication of these results for future intervention efforts are discussed.
Changes in vitamin and mineral intakes and serum concentrations among free-living men on cholesterol-lowering diets: the Dietary Alternatives Study, Nutritional adequacy of diets with 18-30% of calories from fat was investigated in men with elevated serum cholesterol (n = 396) at the end of diet classes and 1 and 2 y later. On 4-d food records. intakes of vitamin A. beta-carotene. folate. vitamin C. magnesium. vitamin B-6. iron. thiamin. and riboflavin increased from baseline whereas niacin. selenium. vitamin E. and zinc decreased. Median zinc intake. 80% of the recommended dietary allowance (RDA) at baseline. decreased to approximately 75% of the RDA. most markedly when intakes of meat. fish. and poultry were limited to 85 g/d. Nutrient densities generally increased. Of the serum nutrients measured. median beta-carotene and vitamin C increased. whereas vitamin B-6. iron. and zinc were unchanged. Below-normal values were fewer for vitamin C and magnesium. Diets similar to the National Cholesterol Education Program Step-Two Diet [less than 7% saturated fatty acids. less than 200 mg cholesterol/d] appeared to provide increased levels of most micronutrients both short and long term to men receiving comprehensive dietary counseling.
Experimental short-bowel syndrome: effect of an elemental diet supplemented with short-chain triglycerides, To determine whether short-chain triglycerides (SCTs. 1:1 triacetin:tributyrin. wt:wt) enhance intestinal adaptation in short-bowel syndrome (SBS). male Sprague-Dawley rats underwent 60% distal small-bowel resection with cecectomy and received either a chemically defined diet (CD) or a CD containing 40% of nonprotein energy as either medium-chain triglycerides (MCTs) or SCTs. After 12 d the SCT group had significantly increased jejunal mucosal weight compared with the MCT and CD groups and had significantly increased segment weight and mucosal protein compared with the CD group. In the colon the SCT group had significantly increased segment and mucosal weights and mucosal protein and DNA compared with both the MCT and CD groups. Body-weight change and measurements of serum ketones. albumin. glucose. and triglycerides revealed no significant differences among groups. SCTs improved jejunal and colonic adaptive growth and maintained comparable nutritional status in SBS when compared with CD alone or CD with MCTs.
Relationships between growth and acute lower-respiratory infections in children aged less than 5 y in a highland population of Papua New Guinea, One hundred fifty-six children in the highlands of Papua New Guinea aged less than 5 y. studied for a total of 7019 child-weeks. had an incidence of 1.3 episodes per child-year of acute lower-respiratory-tract infections (ALRIs). There was a marked age trend with an incidence of almost three times this average for children aged less than 6 mo. Those with low weight-for-age or low height-for-age had a higher ALRI incidence rate. with no evidence of cutoffs above which nutritional status had no effect; there was no association between low weight-for-height and increased risk of ALRI. A slow weight gain was not a significant risk factor in the short term but weight gain was reduced during episodes of ALRI.
Heffalumps, jagulars, and cheshire cats. A commentary on cytokeratins and soft tissue sarcomas, Historically. antibodies to cytokeratin intermediate filaments have been models of target specificity. In most diagnostic settings. the utility of these antibodies was unquestioned; reactivity for cytokeratin was dogmatically equated with epithelial differentiation. Recently. however. the diagnostic importance of these antibodies has been challenged. prompted by the demonstration of cytokeratin reactivity in a variety of "nonepithelial" neoplasms. In this review. the evolving literature on this topic is explored. and the practical implications of these findings are discussed.
Nuclear grading of breast carcinoma by image analysis. Classification by multivariate and neural network analysis, The use of nuclear grade as a prognostic indicator for breast carcinoma has been limited by interobserver variability. Advances in image analysis and automated cell classification offer one approach to this problem. The authors used the CAS-100 (Cell Analysis System. Elmhurst. IL) system to measure and analyze nuclear morphometric and texture features of cytologic preparations from 35 breast carcinomas (well. moderate. and poorly differentiated) as well as benign lesions. Morphometric and Markovian texture feature data from breast cancer nuclei of various grades comprised a training set. which was then used to establish classification criteria by multivariate (Bayesian) analysis and to train a neural network system. Both systems were tested for the ability to classify the nuclear grade of individual nuclei. There was good agreement between computer classification and the grade assigned by human observer to individual nuclei using either Bayesian or neural network analysis. Thirty-one unknown cases. which were assigned an overall grade by an observer. were then analyzed by computer. and an overall grade assigned based on the grade of nucleus most frequently present. Using this method. both classification systems were able to assign a "correct" grade to low-grade lesions (approximately 70% correct) more often than to high-grade tumors (approximately 20%). Difficulty in computer assignment of high-grade tumors was explained by nuclear heterogeneity in these tumors (i.e.. although the percentage of high-grade nuclei was increased compared with that of low-grade tumors. high-grade nuclei frequently did not predominate). The authors present this study to demonstrate the feasibility of using image analysis as an objective means of nuclear grading. Further studies will be needed to establish criteria for assigning overall nuclear grade based on computer analysis of imaging data.
Bartonellosis. An immunodepressive disease and the life of Daniel Alcides Carrion, The history of human Bartonellosis. a unique South American biphasic bacterial disease. is reviewed. The course of this disease and its natural history offer many puzzling problems. Its geographic distribution. its absence of a natural reservoir. the development of transient immunosuppression during the acute hematic phase. and the subsequent development of vascular proliferations are highlighted. These vascular proliferations represent a unique example of tissue reactivity recalling the vascular proliferations of patients with AIDS. In addition. the authors review the life and times of Daniel Alcides Carrion. a Peruvian medical student who in 1885 by self-experimentation linked both phases of the disease and died in doing so. Carrion's life. and the impact of his experiment on the subsequent study of Bartonellosis by Peruvian and international scholars. epitomize the constant struggle of the Peruvian medical profession (past and present) to upgrade domestic biomedical research and to find a national identity.
Molecular pathology and diagnosis of infectious diseases, The authors have reviewed and described molecular methods for the detection of etiologic agents or genetic sequences involved in the pathogenesis of various diseases. Molecular probes are now available for the rapid diagnosis of diseases caused by a large number of viruses. bacteria. fungi. spirochetes. rickettsia. and other infectious agents. Since nucleic acid probes can distinguish minute differences indicative of genetic mutations or alternations. specific probes also can be developed even for those diseases with unknown causative agents or etiologies. Further. using these techniques. specific drug-resistant and pathogenic strains associated with epidemics in widely separated areas of a country or a town have been identified. Thus. the sensitivity and specificity of molecular detection methods using both radioactive and nonradioactive probes are at a point that clinical specimens can be tested for rapid diagnosis and identification of etiologic agent(s) that may be responsible for the pathogenesis of a wide variety of diseases.
Molecular and clinical heterogeneity in primary hyperoxaluria type 1, The autosomal recessive disease primary hyperoxaluria type 1 (PH1) is caused by a functional deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). An analysis of liver samples from 59 PH1 patients showed considerable heterogeneity at the enzymic level. Approximately two thirds of patients had zero AGT catalytic activity. whereas the remaining one third had activities that ranged from 3% to 48% of the mean normal level. Two thirds of patients with zero AGT activity also had zero immunoreactive AGT protein. while the other one third. together with all the patients with detectable AGT catalytic activity. had levels of immunoreactive AGT protein that varied from normal to only a few percent of normal. All patients with AGT catalytic activity had their enzyme in the wrong intracellular compartment (ie. mitochondria). On the other hand. in all but one of the patients with immunoreactive AGT protein. but zero catalytic activity. the inactive AGT was correctly located within the peroxisomes. This enzymic heterogeneity was matched by considerable heterogeneity at the clinical level (eg. age at onset. rate of progression. age at renal failure. etc). No simple relationship was found between the level of hepatic AGT and the severity of the disease. It is suggested that a lack of AGT might be responsible for a broader pathological phenotype than classically associated with PH1. The possibility is advanced that some patients with idiopathic oxalate stone disease might owe their predisposition to stone formation to a functional deficiency of AGT.
Oxalate transport in renal tubular cells from normal and stone-forming animals, To investigate the cellular mechanism(s) underlying kidney stone disease. we examined oxalate uptake in suspensions of renal cortical and papillary cells derived from control and stone-forming animals. In control animals. both cortical and papillary cells exhibited a time-dependent accumulation of oxalate. This uptake was mediated both by passive diffusion and by one or more transport processes sensitive to the anion transport inhibitor. DIDS. Oxalate uptake was also markedly sensitive to extracellular pH. showing increased uptake at acidic pH outside (pHo) (6.0). and reduced uptake at alkaline pHo (8.0). In renal tubular cells from stone-forming animals. oxalate uptake was markedly altered. Uptake was significantly reduced in cortical cells. whereas it was significantly stimulated in papillary cells from the same animals. Since the observed changes in oxalate handling occurred only in stone-forming animals. it is possible that alterations in renal cell oxalate transport contribute to calcium oxalate stone formation.
Cloning and expression of the oxalyl-CoA decarboxylase gene from the bacterium, Oxalobacter formigenes: prospects for gene therapy to control Ca-oxalate kidney stone formation, Evidence suggests that the formation of calcium-oxalate stones in the urine is dependent on the saturation levels of both calcium and oxalate; thus. management of one or both of these ions in individuals susceptible to urolithiasis appears important. Since there are no known naturally occurring enzymes in vertebrates capable of degrading oxalate. we have initiated a study to insert a plant-derived oxalate degrading enzyme gene into human cells as a means of lowering plasma and urinary oxalate concentrations. We present here the cloning of the oxalyl-CoA decarboxylase gene from the bacterium Oxalobacter formigenes and its subsequent expression in a foreign environment. These results provide the basis for eventual transfer of an oxalate decarboxylase gene into mammalian cells.
Hypercalciuria and stones, Hypercalciuria. defined as the urinary excretion of more than 0.1 mmol Ca/kg/d (4 mg/kg/24 h). is observed in approximately 50% of patients with calcium oxalate/apatite nephrolithiasis and is one of the risk factors for stone formation. Urinary Ca excretion rates among such patients are higher than normal. despite comparable ranges of glomerular filtration rate (GFR) and serum ultrafiltrable Ca concentrations. and thus glomerular filtration of Ca. suggesting that hypercalciuria is the result of inhibition of net tubular Ca reabsorption. Although increased dietary NaCl or protein intake and reduced K intake increase urinary Ca excretion rates. urinary Ca excretion rates are higher among hypercalciuric stone formers than among normal subjects in relation to comparable ranges of urinary Na. SO4 (as a reflection of protein intake). or K excretion rates. indicating that these dietary factors are not primarily responsible for hypercalciuria. Hypophosphatemia is observed among a subset of hypercalciuric patients and consequent activation of 1.25-(OH)2-D synthesis increases intestinal Ca absorption and urinary calcium excretion. Other hypercalciuric patients exhibit augmented intestinal Ca absorption without elevated plasma 1.25-(OH)-2-D levels. suggesting that either the capacity of 1.25-(OH)2-D to upregulate its own receptor in the intestine or 1.25-(OH)2-D-independent intestinal Ca transport are responsible for increased Ca absorption and hypercalciuria. Hypercalciuric patients also exhibit accelerated radiocalcium turnover. negative Ca balances. reduced bone density. delayed bone mineralization. fasting hypercalciuria. and increased hydroxyproline excretion. all of which reflect participation of the skeleton and presumably a more generalized acceleration of Ca transport. Hypercalciuria may be familial.
Physical chemical studies of calcium oxalate crystallization, The physical chemical approach to the investigation of the calcium oxalate (CaOx) crystallization and urolith formation is the systematic examination of the various aspects of mineral precipitation and growth in pure solution. in the presence of individual urinary components. and in whole urine media. Recent experimental studies have indicated that while small urinary ions such as citrate. magnesium. and phosphocitrate retard the mineralization rate of CaOx. urinary macromolecules may act either as inhibitors of growth or promoters of nucleation. Some CaOx mineralization inhibitors have also been found to influence the growth mechanism of the phase and its flocculation properties. Therefore. urinary macromolecules that are adsorbed on the mineralizing crystals and incorporated into the developing stone may play a significant role in urolithiasis.
Crystal-cell interactions: crystal binding to rat renal papillary tip collecting duct cells in culture, Retention of stone crystallites by urothelium is clearly one of the prime requisites for urinary stone disease. Studies in the literature as early as 1937 have highlighted that the initiation of renal calculi followed the formation of subepithelial calcified plaques in the renal pelvis. The renal papilla is one of the primary sites for crystal fixation and stone maturation. We have developed an in vitro model system for the study of kidney stone crystal retention to tubular epithelium using rat renal papillary collecting tubule (RPCT) cells in primary culture. We have qualitatively and quantitatively analyzed the binding of preformed calcium oxalate monohydrate (COM). hydroxyapatite (HA). and uric acid (UA) crystals to RPCT cells. Our goal was to determine if three common urinary stone crystals evidenced different crystal-cell binding characteristics. Also. since these crystals are frequently observed admixed in stones. we have studied the inhibitive binding characteristics of these crystals with RPCT cells. The RPCT cells in culture grow both as the typical polygonal cells in monolayer and as clumps of aggregated cells. The cells in the aggregates are viable epithelial cells that have lost their attachment to the basement membrane. resulting in the exposure of surface molecules that would not normally be present unless the cells were damaged or if there was a loss of intercellular tight junctions. COM. HA. and UA crystals all preferentially bound to the aggregated cells and all exhibited similar saturable binding patterns.
Inhibitors within the nephron, Kidney-derived inhibitors of crystal growth and aggregation prevent supersaturations created by water conservation from expressing themselves in pathological soft tissue calcifications and intranephronal crystallizations. These inhibitors include nephrocalcin (NC). an acidic glycoprotein produced in proximal tubules and thick ascending limbs of Henle's loop. and the Tamm-Horsfall glycoprotein (THP). produced only in the thick ascending limb. NC inhibits growth and aggregation of calcium oxalate monohydrate (COM). the major crystalline component of human renal stones. THP inhibits only COM aggregation. Patients who form COM stones produce abnormal NC molecules that lack gamma-carboxyglutamic acid and fail to inhibit COM crystallizations normally.
Significance of glycosaminoglycans for the formation of calcium oxalate stones, Glycosaminoglycans (GAG) are polysaccharide chains composed of repeating disaccharides of identical composition. Little is known about the mechanism of their excretion. but there is no doubt that urinary GAGs are degradation products of high molecular weight proteoglycans. Renal excretion takes place chiefly as glomerular filtration. and tubular reabsorption or secretion has not been demonstrated. Differences in the literature comparing GAG excretion in urolithiasis patients and healthy subjects are mainly attributable to methods of analysis and noncomparability of the investigation conditions. We found no differences between the two groups in several series. It is interesting to note that GAG excretion in men is significantly higher than in women. that a circadian rhythm of GAG concentration and excretion occurs in healthy subjects on a standardized diet. and that values are raised postprandially and at night. Seasonal course of GAG excretion curves is almost synchronous for men and women. irrespective of the absolute values. and GAG excretion in the spring and summer significantly exceeds that in winter months by up to 50%. All crystallization models cited demonstrate that GAG reduce the risk of calcium oxalate stone formation. Inhibitors of crystal growth and aggregation act by blocking the growth sites. Inhibition of calcium oxalate crystallization is also attributed to direct binding of calcium to GAG. In the presence of urate ions. and favorable pH. the ability of chondroitin sulfate C to bind calcium may be impaired by as much as 31%. These measurements support the concept that urate ions interact with GAG in urine.
Citrate and renal calculi: new insights and future directions, Citrate is pathogenetically important in stone formation. because it retards the crystallization of stone-forming calcium salts and because its level in urine is low in many patients with nephrolithiasis. Potassium citrate is useful therapeutically. because it can often restore normal urinary citrate. Hypocitraturia often results from dietary aberrations. including sodium excess. and exaggerated intake of animal proteins. Hypocitraturia is frequently accompanied by a low net gastrointestinal absorption of alkali. New drugs are under development as improvements or refinements of currently available potassium citrate. They are potassium citrate 10-mEq-tablet preparation. effervescent calcium citrate. and potassium-magnesium citrate.
Shock wave physics, Extracorporeal shock wave lithotripsy has significantly altered the management of symptomatic renal and ureteral calculi. Yet in an effort to limit the potentially harmful effects of shock waves. while still maintaining or maximizing stone fragmentation. one must understand basic shock wave physics. This report presents a brief overview of the physical properties of shock waves and describes three different areas of shock wave physics investigation: measurement of shock wave pressures. assessment of stone fragmentation. and development of a stone phantom to allow the comparison of various lithotripsy devices. It is only through additional study of the basic physics of high-energy shock waves that we will be able to further enhance the clinical benefits of extracorporeal shock wave lithotripsy. Further understanding of the individual characteristics of a shock wave pressure field such as peak positive pressure. peak negative pressure. pulse duration. and size/shape of the focal region will allow the subsequent enhancement of stone fragmentation while minimizing the potential for shock wave injury to surrounding tissues.
Shock wave lithotripsy-induced renal injury, Both clinical and experimental reports clearly show that shock wave lithotripsy (SWL) causes acute renal effects in a majority. if not all. treated kidneys. SWL-induced acute renal damage may result in severe injury to the nephron. microvasculature. and the surrounding interstitium. In addition. at least three chronic adverse effects have been identified when shock waves are administered at a therapeutic dose. These include (1) an accelerated rise in arterial blood pressure. (2) a decrease in renal function. and (3) an increased rate of stone recurrence. The clinical and experimental data that document tissue injury as a result of shock wave treatment are compelling. but have not allowed us to determine the factors responsible for the adverse acute side effects or to identify conditions that may predispose a patient to serious long-term health problems. Thus. there is an urgent need for incisive. fundamental experimental studies to establish the safe limits for shock wave delivery. To accomplish this goal. animal experimentation is required so that the time course and severity of acute and chronic alterations can be followed in a model that closely mimics human renal structure and functions. The minipig provides this model.
Strong inference in mechanistic urolithiasis: a tribute to Birdwell Finlayson's biophysical contributions, The career of Birdwell Finlayson was distinguished by his continual efforts at casting problems he encountered in urolithiasis in terms of relevant physical theory. His extensive background in biophysics qualified him uniquely for this task. He employed a process called "strong inference" as much as possible; this process was derived from a 1964 essay by John R. Platt. and it appears repeatedly as a guiding principle in Finlayson's research.
IgA antibodies to dietary antigens and lectin-binding IgA in sera from Italian, Australian, and Japanese IgA nephropathy patients, We studied serum IgA as antibodies to dietary antigens (Ag). as lectin-binding molecules. and as conglutinin-binding immune complexes (IgAIC) in people from geographical areas in which IgA nephropathy (IgAGN) is particularly frequent. Sera from 63 Italian. 21 Australian. and 25 Japanese patients affected by IgAGN and 24 Italian. 20 Australian. and 40 Japanese healthy controls were studied. Increased values of IgAIC were detected in 42.8% of Italian patients. while only in 23.8% and 8% of Australian and Japanese patients. respectively. Mean values were significantly increased only in Italian patients (P less than 0.0001). Positive values of IgA antibodies against dietary Ag had variable prevalences. but again Italian patients showed the highest frequency. from 19% to 28.5% versus 0 to 38% in Australians and 0 to 16% in Japanese. Mean values of these antibodies were not significantly increased in any patient groups in comparison to the corresponding healthy populations. However. patients with elevated values of IgAIC had significantly higher serum concentrations of antibodies to alimentary components and a linear correlation was found between IgAIC and some IgA antibodies to food components. The relationship between these two series of data was particularly evident for Italian and Australian IgAGN patients. Moreover. the patients with positive data tended to have a cluster of increased levels of IgA antibodies against several alimentary Ag at the same time. A linear correlation was evident between values of IgA antibodies to gluten fractions and to heterologous albumins. None of these correlations was evident among healthy controls.
The iliotibial band lateral sling procedure and its effect on the results of anterior cruciate ligament reconstruction, The effect of iliotibial band "lateral sling" augmentation on long-term outcome in ACL reconstruction using free autogenous central-third patellar tendon was evaluated retrospectively. Eighty reconstructions were reviewed; the minimum followup was 2 years and the average was 4 years. Sixty percent of the procedures involved supplementation with a lateral sling. By both clinical evaluation and KT-1000 measurement. there were no differences in the results of patients with lateral sling augmentation and those without it. In addition. 40% of patients had chronic pain and/or swelling related to the lateral sling. We do not currently recommend the routine use of a lateral sling augmentation for ACL reconstruction using central-third patellar tendon.
The stabilizing function of passive shoulder restraints, The static restraints of the scapulohumeral joint provide stability for the humeral head in the glenoid cavity. limit extremes of motion of the glenohumeral joint. and guide positioning of the humerus during normal shoulder movement. Eleven fresh-frozen cadaver shoulders of unknown age were attached to a shoulder motion device that allowed measurement of motion in three planes with an accuracy to 0.5 degrees. Four shoulders underwent motion analysis and seven were used for strain gauge analysis of the static scapulohumeral ligamentous restraints. The results of the motion analysis demonstrated that any attempt at simple motion (flexion. extension. abduction. internal or external rotation) resulted in coupled motion in two additional planes. The strain gauge data. expressed as a percent of total tension for each ligament tested. demonstrated a reciprocal tension-sharing relationship among all ligament components and a transference of tension among these components when original and new joint positions were compared. These data provide an in vitro model of shoulder restraint function to explain primary restraint. tension sharing. and transference of tension functions in the in vivo scapulohumeral joint. Clinical relevance: These principles of shoulder function have application in the treatment of instability and frozen shoulder syndrome. and provide an in vitro model to better understand static restraint function in the throwing mechanism.
Anterior cruciate ligament reconstruction using freeze-dried, ethylene oxide-sterilized, bone-patellar tendon-bone allografts. Two year results in thirty-six patients [published erratum appears in Am J Sports Med 1991 May-Jun;19(3):272, Thirty-six of 44 patients (82%) who underwent ACL reconstruction using freeze-dried. ethylene oxide-sterilized. bone-patellar tendon-bone allografts were evaluated at least 2 years postoperatively. A detailed subjective evaluation using the Lysholm scale was recorded as well as a functional evaluation using the Tegner activity scale. All of the patients received a detailed physical examination that included testing with the KT-1000 ligament arthrometer and the Cybex dynamometer. Complete chart reviews and radiographic evaluations were also obtained. Only 17 patients were considered to be functionally successful and performing at their desired activity level. The average KT-1000 showed a side-to-side difference of 5.9 mm at 30 pounds for the successful group and 7.9 mm for those who had functional failure. The Lysholm scores were 91.6/100 versus 61.1/100 in the failures. Eight patients (22%) at repeat surgery were noted to have complete dissolution of the graft. Large femoral cysts were noted radiographically in all of these patients. It was concluded that freeze-dried. ethylene oxide-sterilized. bone-patellar tendon-bone allografts have a high failure rate and cannot be recommended for ACL reconstruction.
Soccer injuries to the brain. A neuropsychologic study of former soccer players, Thirty-seven former soccer players of the National Football Team of Norway were individually examined with an extensive battery of psychologic tests. The neuropsychologic examination demonstrated mild to severe deficits regarding attention. concentration. memory. and judgment in 81% of the players. This may indicate some degree of permanent organic brain damage. probably the cumulative result of repeated traumas from heading the ball.
Tarsal tunnel syndrome in athletes. Case reports and literature review, Tarsal tunnel syndrome is being seen in increasing frequency in the athletic population. especially in the running athlete. The sports medicine physician must be cognizant of this entity. including proper diagnostic testing and management.
Functional biomechanical deficits in running athletes with plantar fasciitis, Plantar fasciitis is a relatively common injury that occurs in running athletes. The disease entity is a good example of an overloaded process of the plantar fascia at its calcaneal insertion. This study was designed to examine the strength and flexibility findings in the muscles that are put on tensile load during running. and which are responsible for controlling the forces on the foot during stance and pushoff. thus modifying the overload. Three groups of athletes underwent physical examination. including checking ankle range of motion in plantar flexion and dorsiflexion. Cybex peak torque measurements were taken at 60 and 180 deg/sec. The groups were a control group of 45 athletes with no symptoms. a group that included 43 affected feet with symptomatic plantar fasciitis. and a group that included the 43 unaffected contralateral feet. Analysis of data showed dynamic range of motion deficits in 38 of 43 affected feet. static range of motion deficits in 37 of 43 affected feet. deficits in peak torque at 60 deg/sec in 41 of 43 affected feet. and deficits in peak torque at 180 deg/sec in 37 of 43 affected feet. Statistical comparison of range of motion showed that the group with symptomatic plantar fasciitis was significantly restricted compared to both control and unaffected contralateral feet groups. Statistical comparison of peak torque showed that the symptomatic plantar fasciitis group was significantly lower than both other groups at both velocities. This study documents strength and flexibility deficits in the supporting musculature of the posterior calf and foot that are affected by plantar fasciitis.
Isokinetic torque imbalances in the rotator cuff of the elite water polo player, The specific repetitive activity of water polo. like baseball pitching. emphasizes adduction and internal rotation. This study used the Cybex II to evaluate the isokinetic strength of the rotator cuff in elite water polo players and in a group of control subjects. The water polo players were significantly stronger than the controls. Of greater importance was the confirmation of imbalances in the rotator cuff force couples of adduction/abduction and external/internal rotation. These changes are similar to those reported for pitchers. The adductors in the water polo group had gained in relative strength resulting in an increase in the adduction/abduction ratio to about 2:1. The internal rotators had gained in relative strength resulting in a decrease in the external/internal ratio to about 0.6:1. For both force couples the differences are more apparent at a slow speed. Side-to-side differences were not significant.
Physician care for interscholastic athletes in Michigan, Between January 1989 and March 1989 the athletic directors of the 711 high schools in the Michigan High School Athletic Association were surveyed as to what sports and levels of competition each school offered and what level of medical care was available. Fifty-seven percent of the surveyed schools returned properly completed forms. Sixty-one percent of the schools responding reported having a physician available for at least one team at some time during the year. This was almost universally the football team; with 59% of the schools with varsity football reporting a physician present at either a practice or a contest at least once during the year. Only 13% of the schools reported having a physician available for a team other than varsity football. Seventy-four percent of all varsity teams had neither a physician nor an athletic trainer present at any time during the year. Comparison of the results of this study with similar studies performed in Michigan in 1975 and 1979. as well as studies in other states. demonstrates that despite the increased awareness and popularity of sports medicine. there has been no appreciable change in the amount of access interscholastic athletes have to physician care.
Thermal balance and tremor patterns during epidural anesthesia, Five healthy. nonpregnant volunteers were studied before and after induction of lumbar epidural anesthesia to determine the cause of central hypothermia during epidural anesthesia. Cutaneous heat loss was measured from 10 area-weighted sites using thermal flux transducers. Oxygen consumption was measured and converted to heat production in watts (W). After a 2-h control period at approximately 20 degrees C. epidural anesthesia was induced by injection of 30-50 ml 3% chloroprocaine. Additional boluses were given to extend the sensory blockade to at least the T5 dermatome. Tremor during epidural anesthesia was compared with normal shivering induced by rapid central venous infusion of approximately 4 l iced saline in six unanesthetized volunteers. Average skin temperature and cutaneous heat loss decreased during the control period. while tympanic membrane temperature remained stable. During the 1st h of epidural blockade. tympanic membrane temperature decreased 1.1 +/- 0.3 degrees C. and average skin temperature increased 0.9 +/- 0.5 degrees C. Cutaneous heat loss increased 16 +/- 6% (15 +/- 5 W). but metabolic heat production increased even more (and was associated with a shivering-like tremor). Tremor during epidural anesthesia and shivering induced by iced saline infusion had similar synchronous waxing-and-waning patterns. No abnormal EMG patterns were detected during epidural anesthesia. We conclude that central hypothermia during the 1st h of epidural anesthesia does not result from heat loss to the environment in excess of metabolic heat production. but results primarily from redistribution of body heat from central to peripheral tissues. Analysis of the tremor patterns suggests that oscillations recorded during epidural anesthesia in nonpregnant individuals is normal thermoregulatory shivering. Shivering occurred sooner and was more intense during iced saline infusion than during epidural anesthesia. despite comparable central hypothermia. The low intensity of shivering during epidural anesthesia. and in some individuals the delay in onset. may result from blockade of afferent cutaneous cold signals.
Intrathecal morphine 0.2 mg versus epidural bupivacaine 0.125% or their combination: effects on parturients, To compare the efficacy and side effects of 0.2 mg intrathecal (IT) morphine with 0.125% epidural bupivacaine. 62 women in labor were studied. They were randomly divided into three groups: group 1 (n = 20) received IT morphine; group 2 (n = 22) received epidural bupivacaine; and group 3 (n = 20) received a combination of both using a combined spinal-epidural (CSE) technique. According to a visual analogue scale for assessing analgesia. neither IT 0.2 mg morphine nor 10 ml 0.125% epidural bupivacaine was effective in producing adequate pain relief in labor. whereas the combination produced excellent analgesia. The use of IT morphine significantly reduced the dosage requirement of epidural bupivacaine. The incidence of nausea. vomiting. and pruritus was significantly higher when IT morphine had been administered. whereas that of urinary retention did not differ. No serious respiratory depression occurred in any of the patients. When the course of labor was studied. the prior use of IT morphine significantly prolonged the duration of the first stage of labor and the total duration of labor. We conclude that the administration of 0.2 mg IT morphine in combination with epidural administration of 0.125% bupivacaine provides better analgesia than the administration of either drug alone.
Cardiopulmonary effects of an anterior mediastinal mass in dogs anesthetized with halothane, The authors evaluated the cardiac effects of an anterior mediastinal mass to better understand the acute cardiovascular collapse that has been associated with anesthesia and positive-pressure ventilation. An 800-ml-capacity intravenous bag was placed within the anterior mediastinum of 12 dogs to simulate a mediastinal mass. After mediastinal mass inflation. the authors measured cardiac index (CI) during periods of spontaneous ventilation (SV). SV with added continuous positive airway pressure (CPAP). intermittent positive-pressure ventilation (IPPV). and continuous positive-pressure ventilation (CPPV). Similar mediastinal mass volumes resulted in similar decreases in CI during SV (169 +/- 51 to 105 +/- 10 ml.kg-1.min-1); CPAP (175 +/- 48 to 122 +/- 34 ml.kg-1.min-1); IPPV (151 +/- 15 to 93 +/- 24 ml.kg-1.min-1); and CPPV (183 +/- 56 to 117 +/- 46 ml.kg-1.min-1). The authors also found. by linear regression. that the relationship between CI and mass volume was similar during both SV and IPPV. In six dogs. transesophageal echocardiography (TEE) was used to measure ventricular short axis dimensions. The authors found that mass inflation caused left ventricular end-diastolic dimension to decrease significantly by 6 +/- 2 mm and 4 +/- 1 mm during SV or IPPV. respectively. and right ventricle dimensions to increase by 2 +/- 1 mm and 3 +/- 1 mm during SV or IPPV. respectively. The changes in chamber dimensions were similar with either SV or IPPV. These results suggest that the decrease in CI associated with a mediastinal mass results from an increase in right ventricular afterload. causing right ventricular enlargement. Subsequently. there is impingement on the left ventricle volume because of interventricular interdependence.
Evaluation of the potential role of serodiagnosis of tuberculosis in a clinic in Bolivia by decision analysis, Decision analysis was used to examine the potential effect on cost and expected quality of care of the introduction of serodiagnosis by enzyme-linked immunosorbent assay (ELISA) of tuberculosis at the Instituto de Torax in La Paz. Bolivia. Previously published data collected at that facility were used as the basis for this analysis. Decision trees were constructed including test availability. test result. test predictive values. and the consequences of correct or incorrect treatment decisions. Five diagnostic algorithms were assessed. ELISA was found to make a contribution to the diagnosis of tuberculosis similar to that of sputum smear. Chest roentgenography improved the quality of patient care. but it did so at substantially increased cost. While ELISA did not add to the diagnosis when sputum smear was available. it might be of great use where sputum smear is not available.
Lung function and bronchial reactivity in asthmatics during exposure to volatile organic compounds, The purpose of the present study was to investigate whether vapors of organic solvents at low concentrations could exert an adverse effect in the lower airways. Under controlled conditions in a climate chamber. 11 persons with bronchial hyperreactivity to histamine and bronchial asthma were exposed for 90 min to a mixture of organic solvents at levels of zero. 2.5. and 25 mg/m3. During exposure to 25 mg/m3 a decrease in FEV1 to 90.7% of baseline value was measured. This was significantly different from the initial value (p less than 0.05). but not significantly different from the value found after sham exposure (FEV1. 97.4% of initial value). The decline in FEV1 during exposure to 25 mg/m3 was most pronounced in persons with high bronchial sensitivity. No changes were found in histamine reactivity after exposure. and no late reactions were registered. Ratings of discomfort showed different individual patterns ranging from no response to reactions towards both of the concentrations. The ratings indicated development of tolerance during exposure. Volatile organic compounds in concentrations found in both the work and the home environments may influence lung function and are probably of importance as bronchial irritants.
Steroid-induced reduction of histamine release does not alter the clinical nasal response to cold, dry air, In some persons. cold. dry air (CDA) provokes symptoms of rhinitis that are associated with increased levels of histamine and other inflammatory mediators in nasal lavages. Because the patterns of mediators released during the early reaction to antigen and CDA-induced rhinitis are similar. we believe that mast cell activation is part of the reaction to CDA. In view of our previous finding that 1-wk pretreatment with topical steroids reduced symptoms and mediator release in the early nasal response to antigen of allergic subjects. we examined the effect of beclomethasone dipropionate on the response to CDA. Using a double-blind. crossover design. 84 micrograms of beclomethasone or placebo were administered in each nostril twice a day to 13 volunteers for 7 days prior to CDA challenge. The reaction to CDA was monitored by measuring the levels of histamine. N-alpha-p-tosyl-L-arginine methyl ester (TAME)-esterase activity and albumin in nasal lavages before and after provocation. Overall symptom scores. as well as scores for rhinorrhea and congestion. were also obtained. Cold. dry air challenge resulted in elevation over baseline of all parameters after placebo pretreatment. After beclomethasone. a significant reduction in histamine levels. but not in TAME-esterase activity or albumin levels or in number of symptoms. was observed. These results indicate that 1-wk pretreatment with beclomethasone affects mast cells. reducing histamine release after CDA. as it did in antigen-induced rhinitis. They also indicate that histamine may not be essential for the development of the immediate nasal reaction to CDA.
The safety aspects of fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy in asthma, We have documented the physiologic effects of fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and endobronchial biopsy performed under local anesthesia in 20 asthmatic subjects. 8 healthy nonatopic control subjects. and 8 atopic nonasthmatic subjects. Premedication consisted of nebulized albuterol (2.5 mg; except for the study of atopic nonasthmatic subjects). ipratropium bromide (500 micrograms). and intramuscular atropine (0.6 mg). Intravenous midazolam was given for mild sedation. and oxygen was delivered via a nasal cannula. FEV1 was measured before and after premedication. immediately postbronchoscopy. and after 2 h recovery. There was a significant fall in mean (+/- SD) FEV1 immediately postbronchoscopy in both the asthmatic (26.2 +/- 16.7%; p less than 0.001) and normal (9 +/- 4.7%. p less than 0.05) groups. which in the asthmatic subjects correlated inversely with the concentration of methacholine provoking a 20% fall in FEV1 (PC20) measured 5 days prebronchoscopy (r = -0.74. p less than 0.001) but not with symptom scores. albuterol use. or peak expiratory flow (PEF) variation recorded during 2 wk before the investigation. There was significant arterial hemoglobin O2 desaturation during biopsy in the asthmatic subjects (median 3%. range -1 to 17% fall from baseline; p less than 0.01). which was not related to any of the measured indices of asthma severity. PC20. measured 5 days before and 5 days after bronchoscopy in the asthmatic subjects and 2 days before and 1 day after bronchoscopy in the atopic nonasthmatic subjects was not significantly affected by the procedure. We conclude that fiberoptic bronchoscopy with BAL and endobronchial biopsy can be conducted safely in asthmatic subjects. but requires caution in those with very responsive airways.
Changes in Schultz-Dale reaction in sensitized canine tracheal smooth muscle, Tracheal smooth muscles from adult dogs 17 to 20 months of age sensitized with ragweed pollen demonstrated a Schultz-Dale phenomenon in response to specific antigen challenge. Seventy percent of the sensitized tracheal smooth muscles developed a Schultz-Dale reaction that consisted only of a phasic response. and the remaining 30% developed a Schultz-Dale reaction that consisted of a phasic component followed by a discrete tonic component. All the Schultz-Dale reactions were mediated only by histamine. The triggering of presynaptic acetylcholine release by histamine during the Schultz-Dale reaction from tracheal smooth muscles of ragweed-pollen-sensitized puppies 6 to 8 months of age was not detected in sensitized adult dogs. Hyperresponsiveness to acetylcholine was detected in tissues from sensitized puppies but not from sensitized adult dogs. Maximal active tension obtained from the sensitized adult canine trachealis during the Schultz-Dale reaction was lower than that obtained from trachealis from sensitized puppies. Dose-response studies showed that sensitized tissues used in the present studies were hyperresponsive to histamine when compared with their nonsensitized control littermates. These results suggest that the nature of the Schultz-Dale response and the identity of the transmitters is age-dependent.
Alveolar macrophage migration after lung transplantation, Pulmonary infection is a major source of morbidity and mortality in recipients of lung allografts. The alveolar macrophage plays an important role in pulmonary host defense. and to fulfill this role it must have the ability to orient and migrate in the direction of a stimulus. Thus migratory activity was measured in cells recovered from lung transplant recipients by bronchoalveolar lavage. The primary patient group consisted of recipients who had no evidence of infection or rejection at the time of bronchoalveolar lavage. These patients were further subdivided into an early postoperative group (less than 6 wk posttransplant) and a late postoperative group (greater than 6 wk posttransplant). Other categories included patients with chronic rejection and a small group of patients with Pneumocystis carinii pneumonia. Alveolar macrophages recovered by bronchoalveolar lavage were assayed for migratory response to N-formylmethlonylphenylalanine and endotoxin-activated human serum. Stimulated migration of cells from healthy recipients obtained in the late postoperative course was similar to that of normal control subjects. but stimulated migration of cells from healthy recipients in the early postoperative period and those undergoing chronic rejection was greater than expected. Spontaneous migration was similar in all groups except those with P. carinii pneumonia. in whom it was greatly increased. We conclude that alveolar macrophage migration is not impaired in lung allograft recipients without apparent signs of infection or rejection and is in fact increased during periods of possible macrophage activation (shortly after transplantation and during chronic rejection).
Macrophage-T suppressor cell interference in the lungs of steroid-treated sarcoidosis patients, In the bronchoalveolar lavage of sarcoidosis patients the mononuclear cell infiltrate was enumerated on T helper and suppressor lymphocytes as well as macrophages by means of a triple-staining assay on cytospin slides. As was seen on the slides. lymphocytes were often adhered very closely to macrophages. This phenomenon. many times described but not understood. was studied in a group of 13 sarcoidosis patients. of whom 7 received prednisolone treatment. It could be shown that treatment with the corticosteroid was followed by an increase in the percentage of suppressor lymphocytes adhered to macrophages. Second. the number of such alveolar T suppressor lymphocyte-macrophage aggregates was dramatically increased in the prednisolone-treated patients.
Gcglobulin functions as a cochemotaxin in the lower respiratory tract. A potential mechanism for lung neutrophil recruitment in cigarette smokers, Activation of the complement pathway with generation of the potent chemotaxin C5a may play a significant role in the neutrophil accumulation seen in the lungs of patients with smoking-associated diseases. Although C5a is rapidly degraded to the less potent chemotaxin C5a des Arg. binding of this peptide with its cochemotaxin Gcglobulin (GcG) can restore its chemotactic potency. Therefore. modulation of Gcglobulin levels in smoking-induced lung disease could affect the accumulation of neutrophils seen in this disorder. To test this hypothesis GcG was measured by an enzyme-linked immunosorbent assay in bronchoalveolar lavage fluids (BALF) obtained from non-smokers. asymptomatic smokers. and patients with chronic obstructive pulmonary disease (COPD). Antigenic amounts of GcG in BALF were increased in COPD patients and asymptomatic smokers compared with nonsmokers (6.35 +/- 1.02 and 5.15 +/- 1.07 versus 2.82 +/- 0.37 micrograms/mg albumin. p less than 0.05). In addition. we found that BALF enhanced C5a des Arg-mediated chemotaxis (48.3 +/- 5.6 versus 11.2 +/- 1.6 cells/high power field. p less than 0.05). an effect that was not seen in the presence of GcG antibody. Furthermore. BALF GcG was similar to serum GcG using Western blot analysis. and the interaction of GcG with C5a des Arg was not inhibited by cigarette smoke. These data demonstrate that elevation of BALF GcG levels occurs in smoking-associated lung disease and that this protein is biologically active and capable of increasing C5a des Arg-mediated chemotaxis. This suggests that modulation of GcG levels may be important in smoking-associated lung diseases.
Capillary hemangioma of the right main bronchus treated by sleeve resection in infancy, Respiratory distress developed in a 5-month-old female infant with roentgenographic evidence of hyperinflation of the right lung. Bronchoscopy revealed a vascular tumor extending from the medial wall of the right main bronchus leading to a check-valve mechanism. Radionuclide lung scans showed ventilation and perfusion of the right side reduced to 36 and 11% of the total lung ventilation and perfusion. respectively. At the age of 7 months a sleeve of the right main bronchus was resected and a reanastomosis performed. The operation specimen contained a capillary hemangioma measuring 1.2 X 0.6 cm. The postoperative course was uneventful. Perfusion of the right lung had markedly improved 6 months after the operation. and at the age of 2 yr and 9 months it was completely normal. Capillary hemangiomas must be considered a cause of bronchial obstruction in infancy. and surgery can be performed successfully.
Clonidine treatment of Gilles de la Tourette's syndrome, The safety and effectiveness of clonidine hydrochloride (3 to 5 micrograms/kg per day) were evaluated in 47 subjects with Gilles de la Tourette's syndrome. aged 7 to 48 years. Twenty-four subjects were randomly assigned to clonidine treatment and 23 to placebo. Forty subjects (21 given clonidine and 19 placebo) successfully completed the 12-week. double-blind clinical trial. Clinical ratings of tic severity improved for both groups. The magnitude of response was greater in the group receiving clonidine. Clinician-rated measures of motor tic severity. the degree to which the tics are "noticeable to others." motor tic counts from videotaped interviews. and parent-rated measures of impulsivity and hyperactivity were the most responsive to clonidine treatment. These results indicate that clonidine is more effective than placebo in reducing some of the tic and other behavioral symptoms associated with Gilles de la Tourette's syndrome.
Intermittent vs maintenance medication in schizophrenia. Two-year results, This is a 2-year. double-blind. placebo-controlled study of 101 patients. evaluating the relative efficacy of intermittent medication (given only when the patient shows early signs of relapse) compared with moderate doses of maintenance medication for stable schizophrenic outpatients. Patients were dropped from the study if they had three prodromal episodes in 1 year or if an episode lasted more than 9 weeks. Fourteen percent of patients given maintenance treatment were dropped from the study compared with 46% of intermittently treated patients. Relapse rates were 16% for patients given maintenance treatment and 30% for intermittently treated patients. a nonsignificant difference. Intermittently treated patients were receiving significantly less medication. but there were no differences found in drug side effects. There appears to be no advantage in using the intermittent approach. but we found that the use of an early intervention strategy reduced the relapse and rehospitalization rates for these patients.
Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia. II. Two-year effects of a controlled study on relapse and adjustment. Environmental-Personal Indicators in the Course of Schizophrenia (EPICS) Research Group, We demonstrated earlier that a novel family psychoeducational approach and an individual social skills training approach designed for patients living in high-expressed emotion households each reduced schizophrenic relapse by one-half when compared with medication controls in the 1st year after hospital discharge. The combination of treatments resulted in no relapse. Results have now been obtained after 2 years of continuous treatment. By 24 months. a persistent and significant effect of family intervention on forestalling relapse was observed. but the effect of social skills training was lost late in the 2nd year. There was no additive effect on relapse that accrued to the combination of treatments. Beyond 2 years. however. the effect of family intervention was likely compromised as well. Treatment effects on the adjustment of survivors were circumscribed. due. in part. to study design characteristics. Effects generally favored the social skills-alone condition at 1 year and the family condition or combined family/social skills condition at 2 years.
Cervicocephalic kinesthetic sensibility in patients with cervical pain, Head orientation in space makes use of multiple sensory afferents. among which the cervical proprioceptive cues could play a predominant role. To quantify the alteration of neck proprioception in patients with cervical pathology. we proposed a test for the clinical evaluation of the ability to relocate the head on the trunk after an active head movement. for 30 healthy subjects and 30 patients with cervical pain. The data demonstrated that this ability was significantly poorer in the patient group. indicating an alteration in neck proprioception. This test permits a discriminant classification of healthy and sick subjects. justifies proprioceptive rehabilitation programs. and allows a quantitative evaluation of their results.
Rehabilitation of physically disabled dentists: a model for a vocationally specific rehabilitation program, A unique collaborative program whose goal is to facilitate the return of disabled dentists to active dental practice is described. This approach includes comprehensive interdisciplinary evaluation and remediation. and it has succeeded in revealing previously undiagnosed impairments which should be considered in the formulation of a rehabilitation plan. A case report illustrates the process. This program can serve as a model for similar programs addressing the needs of other disabled health care professionals.
Cosmetic, functional, independent: self-help aids, Self-help orthotics have been developed to assist functional activities for high-level spinal cord injured patients. The goal of rehabilitation has been to do this with as little intrusion on independence and cosmesis as possible. This paper describes devices to help a patient with C6 quadriplegia independently place his own utensils and eat with an almost normal appearance. The new self-help aids are made from standard silverware. a rivet. and two one-eighth-inch Kydex loops. The loops are riveted centrally on the utensil. allowing for free rotation. The device was evaluated on a patient with C6. complete quadriplegia. The subject demonstrated independence in donning and doffing the device and in eating with an almost normal appearance.
Radiation therapy for intraductal carcinoma. Is it an equal alternative, Of 213 consecutive patients with intraductal carcinoma. 109 were selectively treated with mastectomy and 104 with radiation therapy. There were eight local recurrences. seven in patients treated with radiation therapy and one in a patient treated with mastectomy. Histologically. there were 110 comedocarcinomas and 103 noncomedocarcinomas. Seven local recurrences occurred in patients with comedocarcinomas and one in a patient with a noncomedo tumor. Three (38%) of eight local recurrences (all comedo) were invasive. The 5-year actuarial survival for all subgroups was 100%. The median follow-up was 51 months. Intraductal carcinoma is unlikely to metastasize to axillary lymph nodes. and routine dissection is unnecessary. Ductal carcinoma in situ of the comedo variety is more aggressive and more likely to recur than its noncomedo counterpart. We currently view conservative therapy for patients with intraductal comedocarcinoma with caution.
A cytotoxic T-lymphocyte clone derived from mice with progressively growing tumors, Tumor-specific T-cell clones were derived from spleen cells of mice bearing a syngeneic PHS-5 tumor (a P815 mastocytoma mutant). Cells were expanded in vitro and characterized and assayed for activity against the relevant tumor in vivo. Clone cells were CD4-. CD8+ T lymphocytes. as determined by fluorescence activated cell sorting analysis and were specifically cytotoxic against P815 tumor cells in vitro. as shown in chromium 51 release assays. These cells require both antigen and interleukin 2 to proliferate; neither alone is sufficient. even with the addition of interleukin 1. In an experimental P815 liver metastasis model. the adoptive transfer of GD11 or GD11.17 clone cells and injection of recombinant interleukin 2 (7500 U intraperitoneally) 3 days after infusion of tumor cells reduced the number of tumor nodules. while the adoptive transfer of lymphokine-activated killer cells was ineffective.
Effect of morphine on growth of metastatic colon cancer in vivo, Control of colon cancer depends. in part. on intact immune defense mechanisms. Since opiates are known to affect some components of immune function. this study was conducted to determine the effect of high-dose subcutaneous morphine sulfate and of low-dose intrathecal morphine on the postoperative growth of metastatic colon cancer. Five groups of 15 Fischer 344 rats were given intraportal injections of colon cancer cells as follows: group 1. control; group 2. daily subcutaneous injections of 20-mg/kg morphine the day before and for 2 days after colon cancer cell inoculation; group 3. daily subcutaneous injections of saline; group 4. daily intrathecal injections of 20 micrograms of morphine; and group 5. daily intrathecal injections of saline. There was a significant decrease in the hepatic tumor burden in group 2 compared with groups 1 and 3 and a significant increase in the hepatic tumor burden in groups 4 and 5 compared with group 1. This study demonstrates that intermittent injections of a narcotic may decrease the growth of tumor cells that gain access to the circulation during a surgical procedure. In addition. the results support the concept that tumor cells entering the circulation during a vulnerable period of postoperative immunosuppression are more likely to survive as metastatic tumor.
Ubiquitin hybrid protein gene expression during human colon cancer progression, Ubiquitin is involved in cell-cycle control and DNA replication through a specific proteolytic pathway. Our previous studies demonstrated selected higher expression of a gene encoding ubiquitin-ribosomal protein S27a in poorly differentiated colon carcinoma cell lines. In this study. we evaluated this ubiquitin hybrid protein gene expression in surgical specimens of colon cancers. Northern blot analysis showed that ubiquitin hybrid protein messenger RNA was overexpressed in primary colon cancers compared with adjacent normal colon mucosae in 17 of 20 patients. Dot blot analysis of RNA of 27 tumor samples revealed significantly greater expression in higher Dukes' stage primary colon tumors and liver metastases. These data imply that protein translation machinery is highly activated during progression and metastasis of colon tumors. and that ubiquitin hybrid protein may be useful as a marker of biological aggressiveness.
Differential effects of sodium butyrate and hexamethylene bisacetamide on growth and secretion of cultured human endocrine tumor cells, Advanced gastrointestinal endocrine tumors respond poorly to conventional chemotherapy. In this study we examined the effects of two agents that promote cellular differentiation. sodium butyrate and hexamethylene bisacetamide. on the in vitro growth and secretory responses of a human pancreatic carcinoid (BON) and human gastrinoma (PT-2 and PT-SM) cell lines that have been established in our laboratory. We found that both sodium butyrate and hexamethylene bisacetamide strongly inhibited growth of BON. PT-2. and PT-SM cells. With continuous exposure of BON cells to sodium butyrate (2 mmol/L). the doubling time was prolonged. from 60 hours in controls to 156 hours. and saturation density was reduced to 28% that of controls. Hexamethylene bisacetamide (4 mmol/L) reduced saturation density to 37% that of controls in BON cells and prolonged the doubling time. from 60 hours to 103 hours. Antiproliferative effects of similar magnitudes were observed in the gastrinoma cell lines. In contrast. differential effects were produced on amine biosynthesis in BON cells; sodium butyrate stimulated levels of 5-hydroxytryptamine in the cells. whereas hexamethylene bisacetamide caused a profound dose-dependent inhibition of amine biosynthesis. The significant antiproliferative activity of sodium butyrate and hexamethylene bisacetamide and the inhibitory effects of hexamethylene bisacetamide on amine biosynthesis warrant evaluation of these agents or analogues for treatment of metastatic carcinoid and gastrinoma.
Lymphokine-activated killer cell suppressor factor in malignant effusions, We examined the possibility that tumor-released products inhibit lymphokine-activated killer cell activation. Lymphokine-activated killer cells from human peripheral blood lymphocytes were activated with recombinant interleukin 2 for 4 days in the presence of malignant effusions or conditioned media from cultured cell lines (10% vol/vol). Eight of 10 malignant effusions/media suppressed the induction of lymphokine-activated killer cell cytotoxicity. as measured in a 4-hour sodium chromate release assay. Seven of 10 effusions/media inhibited lymphokine-activated killer cell proliferation. Suppression was both dose and time dependent. A representative suppressive effusion was fractionated by agarose gel chromatography. treated with detergents disruptive of ionic bonds and lipids. and refractionated using polyacrylamide gel chromatography. Seven suppressive fractions ranging in molecular weight from 1 x 10(5) to 3 x 10(5) d were isolated. It is speculated that this suppressor factor may represent a large multimeric structure with ionic-bonded individual suppressive components.
The importance of anatomic site in prognosis in patients with cutaneous melanoma, To determine the prognostic relevance of the anatomic site of origin of cutaneous melanoma to survival. we retrospectively analyzed a computerized database of 3428 patients with stage I and II cutaneous melanoma. Patients were stratified by the recognized prognostic variables of stage of disease. Clark's level of invasion of the primary lesion. and the nodal involvement at the time of lymphadenectomy. Melanoma arising in skin of the upper part of the back. back of the arms. neck. and scalp (BANS) region occurred more frequently in male than female patients. There were no statistically significant differences in the distribution of Clark's level of invasion of BANS and non-BANS region primary melanomas or in the extent of nodal involvement in patients with stage II disease. The 5-year actuarial survival of patients with stage I BANS region melanomas was 87%; stage I non-BANS. 89%; stage II BANS. 38%; and stage II non-BANS. 69%. The BANS region appears to have prognostic significance in cutaneous melanoma and. particularly. in patients with stage II melanoma.
Touch preparation cytology of breast lumpectomy margins with histologic correlation, Residual microscopic disease after lumpectomy for breast cancer may cause significant local recurrence. We evaluated one hundred fourteen consecutive breast lumpectomy margins in this study by touch preparation cytology. Cytologic preparations were intraoperatively correlated with gross and frozen section results and subsequently with permanent histologic sections of representative margins. Three specimens were cytologically unsatisfactory and 86 yielded benign findings. while material suggestive or diagnostic of malignancy was obtained from 25 specimens. Gross. frozen section. and permanent histologic margins were positive in 10. 17. and 22 cases. respectively. There were three false-positive touch preparation cytologic results. while frozen section specimens were false-negative in five cases. Sensitivity and specificity of touch preparation cytology were 100% and 96.6%. respectively. with a diagnostic accuracy of 97.3%. Touch preparation cytologic examination rapidly and reliably evaluates lumpectomy margins and overcomes sampling errors and artifacts related to frozen section evaluation. This technique currently complements frozen section evaluation of lumpectomy margins as part of a protocol aimed at reducing local recurrence of breast cancer.
Interaction of 1,25-dihydroxyvitamin D and plasma renin activity in high renin essential hypertension, Renin secretion by the kidney is inhibited by an increase in free intracellular calcium concentration. This increase in free intracellular calcium content may be augmented by serum 1.25-dihydroxyvitamin D. In 10 subjects with high renin hypertension. an increase in dietary sodium intake resulted in an increase in urinary calcium excretion (2.5 to 3.4 mmol/L. P = .011) and an increase in serum 1.25-dihydroxyvitamin D (51.2 to 61.0 pmol/L. P = .045). An inverse correlation existed between the change in vitamin D and the change in plasma renin activity (r = -0.765. P = .01). An inverse correlation also existed between the change in plasma renin activity and the change in mean arterial blood pressure (r = -0.757. P = .011). It is postulated that the increase in dietary sodium led to an increase in serum 1.25-dihydroxyvitamin D concentration. which may have contributed to an increase in intracellular calcium concentration. a decrease in renal secretion of renin. and a fall in plasma renin activity. The resultant fall in PRA in part effected the change in blood pressure to the increased sodium intake. Therefore. 1.25-dihydroxyvitamin D may be a mediator in the response of high renin hypertension to increased sodium intake.
Awareness of hypertension increases blood pressure and sympathetic responses to cold pressor test, The present study was aimed at examining the effects of awareness of hypertension on blood pressure and sympathetic responses to the cold pressor test. Nineteen-year-old men with similarly elevated mean blood pressure at a medical screening. but without knowledge of this. were randomized into two groups. The first group (n = 16) was sent a letter saying that their pressure was too high. and the second (n = 13) was sent a neutral letter. Information increased mean blood pressure both after 15 min sitting. by an average of 11.5 mm Hg (P less than .01). and after 30 min supine rest. by an average of 4.5 mm Hg (P less than .05). Changes in heart rate (8.4 +/- 2.4 v 1.9 +/- 1.7 beats/min) and plasma epinephrine (0.11 +/- 0.04 v 0.01 +/- 0.03 nmol/L) during execution of a cold pressor test were significantly greater in the informed group (P less than .05). Plasma dopamine was lower in the informed group (P less than .05). Thus. psychological stress caused by the awareness of hypertension may increase blood pressure and sympathetic responses to a provocative maneuver. Ideally. studies on sympathetic function in essential hypertension should be undertaken on subjects unaware of their blood pressure status.
Increased platelet membrane sodium-proton exchange rate in spontaneously hypertensive rats, It has been proposed that increased Na-H exchange activity is involved in the pathophysiology of genetic hypertension. We studied platelets of spontaneously hypertensive rats (SHR). normotensive Wistar-Kyoto (WKY). and domestic Wistar rats (DWR). since platelets have similarities to smooth muscle cells and have been shown to have potentially related ion metabolism abnormalities. such as increased intracellular calcium activity. We determined the exchange rate by the intracellular acidification-dependent. extracellular sodium-dependent volume increase. The rate of increase during the first 3 min is linear and is shown to be higher in SHR (0.475 X min-1) than in WKY (0.410 X min-1) or DWR (0.389 X min-1). We conclude that the Na-H activity is increased in platelets of SHR. Similar findings in lymphocytes and neutrophils of SHR. and analogous findings in platelets of humans with essential hypertension. suggest that this abnormality is expressed by several cell types. some of which may be involved in the pathophysiology of genetic hypertension in both rats and humans.
Effect of propranolol on endothelin-induced increase in cytosolic free calcium, This study was designed to investigate the effect of propranolol on endothelin (ET)-1-induced increase in cytosolic Ca2+ [( CA2+]i) in cultured vascular smooth muscle cells (VSMCs) obtained from rat aorta. Propranolol (0.01 to 1 mmol/L) reduced the changes in the initial transient and the later sustained phase of [Ca2+]i induced by 100 nmol/L ET-1 as well as 10 mmol/L procaine. The inhibitory action of propranolol on the change in [Ca2+]i induced by ET-1 may be involved in one of the mechanisms of propranolol-induced reduction of vasospasms.
Roles of renal and vascular renin in spontaneous hypertension and switching of the mechanism upon nephrectomy. Lack of hypotensive effects of inhibition of renin, converting enzyme, and angiotensin II receptor blocker after bilateral nephrectomy, Inhibitors of angiotensin converting enzyme. renin. and the angiotensin II (Ang II) receptor lower the blood pressure of spontaneously hypertensive rats (SHR) used as a model of essential hypertension. Since their plasma renin levels were normal or subnormal. renin in the vascular tissue was considered to play a key role in the maintenance of the hypertension. To clarify the source and localization of renin in SHR. antirenin antibodies. the converting enzyme inhibitors delapril. enalapril. and the Ang II receptor antagonist DuP 753 were administered to intact and bilaterally nephrectomized SHR and their normotensive controls. The efficient hypotensive action of the renin antibody indicated that renin of renal origin is a dominant factor. Gradual but complete disappearance of antihypertensive action of these inhibitors of the renin-angiotensin system upon bilateral nephrectomy indicated the importance of membrane-associated renin of the renal origin and angiotensin converting enzyme in the maintenance of the spontaneous hypertension.
A study of the effects of delapril, a new angiotensin converting enzyme inhibitor, on the diurnal variation of arterial pressure in patients with essential hypertension using indirect and direct arterial pressure monitoring methods, In order to investigate the effect of delapril. a new angiotensin converting enzyme inhibitor. on the diurnal variation of arterial pressure in patients with essential hypertension. this study examined 24 h arterial pressure using an indirect or a direct monitoring system. When the effect of twice-a-day administration of delapril at daily doses of 30 to 90 mg was examined using the indirect monitoring system in 12 outpatients. delapril decreased systolic and diastolic arterial pressures significantly only at limited points during the day. However. each of the averaged 24 h daytime and nighttime arterial pressures showed significant reductions. The 24 h intraarterial pressure monitoring demonstrated that delapril decreased systolic and diastolic arterial pressure at most of the measurement points. The arterial pressure reductions during daytime and nighttime were not significantly different. that is. there was no excessive reduction in nighttime arterial pressure. Heart rate and its variability were virtually unaffected by the delapril treatment in either monitoring study. No adverse reactions were observed in the indirect or direct monitoring studies. Thus. it is concluded that twice-a-day administration of delapril at daily doses of 30 to 90 mg brings about a safe and stable antihypertensive effect. without affecting the diurnal variation of arterial pressure.
Comparison of the antihypertensive effects of delapril and enalapril, The angiotensin converting enzyme (ACE) inhibitors delapril and enalapril were compared in a double-blind. randomized. parallel study. The population included 142 patients with essential hypertension who were treated with delapril and 140 treated with enalapril. At the end of a 2 week initial placebo period. the diastolic blood pressure of these patients ranged from 95 to 115 mm Hg in the sitting position. After this placebo period. randomization took place. Patients in the delapril group received 15 mg of the drug twice daily. Treatment with enalapril was started with a daily dose of 10 mg. If the diastolic blood pressure did not fall to less than or equal to 90 mm Hg or at least by 15 mm Hg after 2 weeks of treatment. the doses of the ACE inhibitors were doubled. After another 2 weeks. 25 mg hydrochlorothiazide daily was added if the target level of diastolic blood pressure was not reached. Both drugs caused a similar decrease of systolic and diastolic blood pressure. The antihypertensive effect of both ACE inhibitors was increased by the addition of the diuretic. The frequency and severity of side effects were similar in the two groups of patients. It is concluded from this study that delapril and enalapril do not differ in antihypertensive efficacy nor in safety.
Long-term effects of delapril on renal function and urinary excretion of kallikrein, prostaglandin E2, and thromboxane B2 in hypertensive patients, The effects of delapril. an angiotensin converting enzyme (ACE) inhibitor. on renal function and the renin-angiotensin and kallikrein-prostaglandin systems were investigated in 10 hypertensive patients who were treated for between 4 months and 1 year. There was a significant (P less than .05) increase in renal blood flow (RBF) without affecting glomerular filtration rate. Filtration fraction increased. while renal vascular resistance decreased. There were also significant (P less than .05) increases in urinary kallikrein and prostaglandin excretion. while thromboxane excretion decreased. There was no change in urinary aldosterone excretion. These results suggest that renal hemodynamic changes seen during long-term therapy with delapril are caused. in part. by activation of the kallikrein-prostaglandin system. as well as suppression of the renin-angiotensin system.
The antihypertensive mechanism of delapril, a newly developed converting enzyme inhibitor, is related to the suppression of vascular angiotensin II release in the spontaneously hypertensive rat, Accumulating evidence suggests an important role of vascular renin-angiotensin system (RAS) in the local control of arterial tone. To further gain insight into the significance of vascular RAS in hypertension. we investigated the relationship between the antihypertensive action of delapril. a newly developed converting enzyme inhibitor (CEI). and its effects on vascular angiotensin II (Ang II) release in spontaneously hypertensive rats (SHR). Male SHRs were given delapril or its active metabolite (5-hydroxydelapril diacid; 5-hydroxy-DPD) orally (10 mg/kg/day) for 2 weeks. Isolated hind legs of these rats were perfused with angiotensinogen-free Krebs-Ringer solution. and Ang II released into the perfusate was directly determined by extraction with Sep-Pak C18 cartridges connected to the perfusion system. Both delapril and 5-hydroxy-DPD produced a sustained antihypertensive action. The spontaneous release of Ang II from isolated perfused hind legs of control SHRs was about 50 to 110 pg during the first 30 min of perfusion. and it remained stable up to 3 h. Another active metabolite. delapril diacid (DPD). when added to the perfusion medium (10(-9) to 5 x 10(-5) mol/L). suppressed the Ang II release in a dose-dependent manner. The maximal percent inhibition of Ang II released evoked by DPD (5 x 10(-6) mol/L) was approximately 51%. Oral pretreatment of either delapril or 5-hydroxy-DPD for 2 weeks suppressed the Ang II release by 61% and 73% for delapril and 5-hydroxy-DPD. respectively. These results suggest the presence of a functional RAS in vascular tissues. and that delapril exerts its antihypertensive effect through inhibition of vascular Ang II release in SHRs.
Converting enzyme inhibitors and renal function in essential and renovascular hypertension, Converting enzyme inhibitors (CEI) are useful in the treatment of hypertension. However. acute renal deterioration may occur in some conditions in association with the crucial role of angiotensin in the regulation of glomerular filtration rate (GFR). such as volume depletion. severe stenosis of both renal arteries. and stenosis of a single functioning kidney. CEI-induced acute renal failure can develop in the absence of a fall in systemic pressure. is facilitated by prior sodium depletion. and is reversible upon discontinuation of treatment. In a personal study conducted in 28 patients with CEI-induced renal dysfunction (reversible after discontinuation of CEI). the incidence of stenosis of large renal vessels was 61%. whereas 39% of these subjects had no significant renal artery abnormalities. Although the occurrence of such a complication is not a convincingly accurate predictor of the existence of renovascular hypertension. angiographic detection of renal artery stenosis (bilateral or on a single-functioning kidney) may be justified in some of these patients.
The use of angiotensin converting enzyme inhibitors in combination with other antihypertensive agents, Angiotensin converting enzyme (ACE) inhibitors have additive effects with most other antihypertensive agents. but the mechanisms of these interactions vary. With diuretics the interaction with ACE inhibitors can be explained by their contrasting effects on the renin-angiotensin system. while with calcium antagonists it may be attributed to independent mechanisms of action. With beta-blockers there is a variable additive effect. which has been proposed to be due to more complete blockade of the renin-angiotensin system than can be obtained with either type of agent alone.
Angiotensin converting enzyme inhibitors and quality of life, The term quality of life implies more than adverse effects that make treatment intolerable. It is not new but has only relatively recently become a parameter to be measured in patients treated for cardiovascular disease. Lessons can be learned from other conditions in which the Karnovsky Index and the Arthritis Impact Measurement Scale have been used. Several investigators have used questionnaires to assess quality of life during antihypertensive therapy. However. assessment of the effect of angiotensin converting enzyme (ACE) inhibition on quality of life has only been done recently. The largest and best known study. of 625 white men with mild hypertension. reported that patients given captopril showed a significant improvement after 6 months in general well-being. work performance. and those skills associated with cognitive function. No such improvement was found with methyldopa and there was significant worsening in measures associated with depression. sexual dysfunction. and life satisfaction. The propranolol group. while showing improvement in cognitive functioning and social participation. manifested worsening of sexual function and physical symptoms. Diuretic therapy had a greater negative impact on the quality of life of hypertensive patients than captopril. propranolol. or methyldopa alone. Whether these results will be seen in other patient populations. and the pharmacological basis for these results. remains to be determined. As newer agents become available (eg. beta-blockers with ancillary properties. calcium channel blockers with allegedly more selective actions on various vascular beds). comparative studies between these agents and ACE inhibitors old and new are awaited with interest.
Special considerations for research with pharmacologic agents, As physical medicine and rehabilitation becomes more and more complicated. the medical rehabilitation research teams are often bewildered by the sweeping changes occurring in the application of therapeutic drugs for rehabilitation. Society. through the instrument of governmental regulations. dictates that all new treatments must be efficacious before "release.".
High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults, Seventy consecutive adult patients with acute myelogenous leukemia (AML). median age 44 years. received high-dose cytarabine (3 g/m2 every 12 hours for 12 doses) followed by daunorubicin (45 mg/m2 daily for three doses) for remission induction. A single. identical course was planned for postremission therapy. Complete remission (CR) was achieved in 63 patients (90%. 95% confidence interval [CI] 83% to 97%). 60 after a single course. Eight patients were selected to undergo elective bone marrow transplantation (BMT) during first CR. Of the remaining 55 patients. 40 (73%) underwent planned post-CR therapy; 15 patients did not. owing to early relapse. excessive toxicity from the induction chemotherapy. or refusal. Nineteen patients. including 13 who received planned post-CR therapy. remain in continuous CR at a median follow-up of 5.2 years (range 3.0 to 7.1 years). The 5-year actuarial leukemia-free survival was 30% (95% Cl. 19% to 42%) for all patients achieving CR and 32% (95% Cl. 19% to 47%) for the 40 patients who received the planned post-CR chemotherapy. Analysis of various putative prognostic factors for CR and overall and leukemia-free survival showed significance for a previous history of myelodysplasia. higher initial leukocyte counts. certain French-American-British (FAB) types. and certain abnormal karyotypes. None of these factors was consistently significant regarding the above parameters. although small patient numbers in certain analyses may have obscured significant associations. Myelosuppression was occasionally prolonged after remission induction and especially post-CR therapy. Severe cerebellar toxicity was observed in 13 patients; in 11 cases. this toxicity was fully reversible. Other serious complications were infrequent. Intensive chemotherapy with high-dose cytarabine and daunorubicin has substantial antileukemic activity in adult AML. and may represent an improvement over conventional therapy. Relapses were common. however. even in patients who received planned therapy. and substantial toxicity was observed. The optimum use of this regimen in AML remains to be determined.
Inhibition by 1,25 dihydroxyvitamin D3 of chemically induced erythroid differentiation of K562 leukemia cells, The physiologically active form of vitamin D. 1.25 dihydroxyvitamin D3 [1.25(OH)2D3]. was found to inhibit erythroid differentiation of human leukemic K562 cells. Differentiation was induced by 1 mumol/L arabinocytosine (Ara-C). 40 mumol/L tiazofurin. 1 mumol/L aphidicolin. or 1 mumol/L hydroxyurea. and was monitored daily by the appearance of hemoglobin in an increasing proportion of cells. Pretreatment for 48 hours with 2.4 x 10(-8) mol/L 1.25(OH)2D3. a concentration that is also optimal for induction of monocytic differentiation of HL-60 cells. reproducibly inhibited subsequent induction of erythroid differentiation by all of the above inducers. and modified the morphologic changes that Ara-C produced in these cells. The inhibition of hemoglobinization was approximately 50% irrespective of the degree of differentiation produced by the various inducers. but growth inhibition associated with exposure to the inducers was not affected by 1.25(OH)2D3. Similar inhibition of differentiation by 1.25(OH)2D3 was observed in mouse erythroleukemia cells MEL-D1B treated with 5 mmol/L hexamethylenebisacetamide. The inhibitory effect of 1.25(OH)2D3 on erythroid differentiation of K562 cells was abrogated by cyclohexamide (20 micrograms/mL). an inhibitor of protein synthesis. The mRNA for 1.25(OH)2D3 receptor (VDR) was detected in K562 cells. and was downregulated by a 96-hour exposure to 1.25(OH)2D3 or a 48-hour exposure to Ara-C. The presence of VDR mRNA suggests a physiologic role for 1.25(OH)2D3 in K562 cells that are precursors of erythroid cells. This role is perhaps to shift the pathways of differentiation from the erythroid to the monocytic lineage.
Interleukin-5 is a human basophilopoietin: induction of histamine content and basophilic differentiation of HL-60 cells and of peripheral blood basophil-eosinophil progenitors, Cytokine-induced differentiation of basophils may contribute to various inflammatory processes. We examined the effects of recombinant human interleukin-5 (IL-5) and other human cytokines in vitro on myeloid colony formation in methylcellulose and on alkaline passaged HL-60 basophilic cell differentiation. Myeloid colonies (CFU-C) at day 14. formed in the presence of either IL-3. IL-5. granulocyte-macrophage colony-stimulating factor (GM-CSF). or G-CSF included peripheral blood-derived progenitors of the eosinophil/basophil lineage. IL-5 stimulated a greater proportion of basophil-containing. histamine-positive. eosinophil-type colonies compared with GM-CSF. IL-3. or G-CSF. IL-5 also stimulated dose-dependent increases in histamine content of alkaline-passaged. butyrate cotreated HL-60 cells. The concentration of IL-5 required for half-maximal induction of HL-60 histamine content was similar within twofold to that needed for half-maximal stimulation of the multifactor dependent TF-1 erythroleukemic cell line. Neutralizing rat monoclonal antibodies to human IL-5 were developed and used to demonstrate that each of these IL-5 bioactivities could be specifically blocked. We conclude that in addition to its previously described eosinophil differentiation activity. IL-5 may be considered a basophilopoietin.
T-lymphocytic leukemia expresses complex, branched O-linked oligosaccharides on a major sialoglycoprotein, leukosialin, Leukocytes express a major sialoglycoprotein. leukosialin. of which the apparent molecular weight (mol wt) can be variable according to the differences in O-glycans attached to this molecule. In the present study. we analyzed the structures of O-glycans attached to leukosialin present in various T-lymphocytic leukemia cells. T-lymphoid cells from patients with acute T-lymphocytic leukemia express a large amount of the branched hexasaccharides. NeuNAc alpha 2----3Gal beta 1----3(NeuNAc alpha 2----3Gal beta 1----4GlcNAc beta 1----6)GalNAc. which are also expressed in activated normal T lymphocytes. but that are almost absent in resting normal T lymphocytes. T-lymphoid cells from patients with chronic T-lymphocytic leukemia. on the other hand. mainly express the tetrasaccharides NeuNAc alpha 2----3Gal beta 1----3(NeuNAc alpha 2----6)GalNAc on leukosialin. but they also express a small significant amount of the hexasaccharides. The same hexasaccharides can be detected in thymocytes. The increased amount of the hexasaccharides in acute leukemia is associated with increased activity of beta 1----6 GlcNAc-transferase. a key enzyme in forming the hexasaccharides. Immunoblot analysis of cell lysates showed that monoclonal antibody (MoAb) T-305 reacts preferentially with leukosialin of high mol wt containing the hexasaccharides. These findings indicate that T-lymphocytic leukemia cells reexpress the oligosaccharides present in immature cells.
Cytogenetic analysis of 434 consecutively ascertained specimens of non-Hodgkin's lymphoma: clinical correlations, Cytogenetic and histopathologic data were correlated with clinical parameters from 423 patients with non-Hodgkin's lymphoma (NHL). Clinical correlations were performed on subgroups of 149 patients with low-grade lymphoma (LG) and 205 patients with diffuse lymphoma with a large cell component (DLLC). Correlations were made between clinical outcome and individual recurring cytogenetic aberrations. each of which was noted in greater than 5% of cases belonging to LG NHL and DLLC. and derived measures of karyotypic complexity. comprising modal chromosome number. number of marker chromosomes. and number of translocation breakpoints. No correlations with survival were noted in LG NHL. although median follow-up was only 2 years. Seven patients with t(8;14) LG NHL had an indolent course. Among 104 patients with DLLC and abnormal karyotypes at diagnosis. breaks at 1q21-23 or more than 4 marker chromosomes was associated with a shortened median survival. Using these variables we constructed a proportional hazards model with a good fit to observed data. Breaks at 6q21-25 predicted a decreased probability of achieving remission. Patients with DLLC and breaks at 1q21-23 or 1p32-36 had a shorter duration of complete remission. Of 41 DLLC studied at relapse. the only long-term survivors had t(14;18).
Patterns of chromosomal breakpoint locations in Burkitt's lymphoma: relevance to geography and Epstein-Barr virus association, We have examined. by Southern blotting. the patterns of chromosomal breakpoint locations in 55 cases of Burkitt's lymphoma (BL) with respect to geography and Epstein-Barr virus (EBV) association. We have confirmed the association between chromosome 8 breakpoint and geography: 74% of endemic (eBL) but only 9% of sporadic BL (sBL) had breakpoints outside the HindIII fragment encompassing the c-myc gene (P2 less than .00001). Conversely. not only did 91% of sBL manifest a rearranged HindIII fragment. but at least 56% of these cases. in contrast to 17% of eBL cases. had a breakpoint within the first exon or intron of c-myc (P2 less than .004). Breakpoints outside the switch mu (S mu) region (ie. the HindIII fragment encompassing S mu) on chromosome 14 were twice as common overall (73%) as those within S mu (27%). but in the 15 tumors with S mu breakpoints. 13 (87%) had a rearranged c-myc gene. Breakpoints outside the HindIII fragment encompassing c-myc on chromosome 8 were predominantly associated with non-S mu breakpoints on chromosome 14 (85%) and this was the combination most frequently associated with eBL (65%; 6% of sBL. P2 less than .00001). In sBL. the most frequent breakpoint combination was a rearranged c-myc gene with a non-S mu breakpoint (63%; 13% of eBL). Twenty-eight percent of sBL and 13% of eBL had breakpoints both within c-myc and within S mu. EBV DNA was present in 19 of 20 tumors with breakpoints outside c-myc. in none of 7 with a breakpoint in the immediate 5' region of c-myc. in 4 of 5 tumors with breakpoints in the first exon. and in 7 of 12 tumors with breakpoints in the first intron. These data suggest that the pathogeneses of eBL and sBL differ with regard to the mechanism of c-myc deregulation. and probably also with regard to the state of differentiation of the target cell for malignant transformation. We have formulated a testable hypothesis regarding the potential role of EBV in pathogenesis: that it is required to contribute to the deregulation of c-myc in the presence of some. but not all. types of c-myc damage arising from the chromosomal translocations.
Epstein-Barr virus in benign lymph node biopsies from individuals infected with the human immunodeficiency virus is associated with concurrent or subsequent development of non-Hodgkin's lymphoma, Individuals infected with the human immunodeficiency virus (HIV) have an increased incidence of high-grade B-cell lymphoma. In many instances. these lymphomas contain Epstein-Barr viral (EBV) genomes. To investigate the role of EBV in development of HIV-related lymphoma. benign fixed lymph node biopsies from normal individuals and HIV-infected individuals with persistent generalized lymphadenopathy (PGL) were analyzed for EBV sequences by polymerase chain reaction and in situ DNA hybridization techniques. EBV DNA was not detected in any of 16 benign lymph node biopsies from normal individuals. but could be detected from 13 of 35 PGL biopsies. The EBV-infected cells were present in both follicular and interfollicular areas and in both small and large lymphoid cells. The presence of detectable amounts of EBV DNA in the 13 PGL biopsies was associated with an increased incidence of concurrent lymphoma at another site (n = 3) or development of lymphoma in time (n = 2). In contrast. only 1 of 22 individuals with EBV-negative PGL biopsies developed lymphoma in time (P less than .05). EBV was detected in all five lymphomas in which tissue was available for subsequent analysis. including the lymphoma that developed in the individual without EBV in his previous PGL biopsy. These findings support the hypothesis that EBV plays a role in development of some HIV-related lymphomas. Detectable EBV lymphoproliferations occur in a few PGL biopsies and are associated with a significant risk of EBV DNA-positive non-Hodgkin's lymphoma.
Stages of T-cell receptor protein expression in T-cell acute lymphoblastic leukemia, In this study five monoclonal antibodies (MoAbs) to T-cell receptor (TCR) proteins (WT31. alpha F1. beta F1. TCR delta-1 and delta TCS-1) were used to identify discrete maturative stages in 40 cases of T-cell acute lymphoblastic leukemia (T-ALL). These MoAbs reacted exclusively with CD3+ T cells and did not label B-lineage and myeloid cells. In 17 of the 40 T-ALL cases studied the leukemic blasts lacked membrane and cytoplasmic TCR chains (group I). In 12 cases cells did not have membrane CD3/TCR but expressed cytoplasmic TCR proteins heterogenously: nine cases had cytoplasmic TCR beta chains (beta F1+. alpha F1-; group II). one case had cytoplasmic TCR alpha chains (alpha F1+. beta F1-; group III). and two cases were labeled by both alpha F1 and beta F1 MoAbs (group IV). The remaining 11 cases were mCD3+: nine were TCR alpha beta+ (group Va) and two exhibited TCR gamma delta (TCR delta-1+. delta TCS-1+; group Vb). The analysis of the TCR beta. -gamma. and -delta gene configurations in 23 of the 40 T-ALLs showed that: (1) the lack of TCR protein expression was due to the lack of TCR gene rearrangements only in one of nine cases; (2) five of five TCR beta+. TCR alpha- cases studied had germline TCR alpha genes (ie. no detectable TCR delta gene deletions); (3) seven of eight cases with TCR delta gene deletions expressed TCR alpha proteins. whereas in 12 of 20 of the T-ALLs with TCR beta gene rearrangements the synthesis of the corresponding protein occurred; only 2 of 16 cases with rearranged TCR delta genes expressed TCR delta chains. The T-ALL categories identified with anti-TCR MoAbs did not have additional characteristic phenotypic patterns and may correspond to the normal stages of T-cell development more precisely than those defined by other differentiation antigens.
Oncogene rearrangements in chronic B-cell leukemia, Forty-four B-chronic lymphocytic leukemias (CLL) were studied by Southern blot analysis using probes for the Ig genes and bcl-1. bcl-2 (major. minor and 5' breakpoint region). bcl-3. c-myc. and retinoblastoma (Rb) loci. Eight cases had three or more rearranged JH bands. indicating oligoclonality. clonal evolution. or chromosomal translocation. One case had a rearrangement of the bcl-1 locus and three of the bcl-2 locus. In the first case. comigration of the rearranged bcl-1 and JH sequences indicated a t(11;14)(q13;q32) translocation. which. in contrast to previously described cases. seems to be completely reciprocal. One case with a bcl-2 rearrangement showed comigration of the bcl-2 major breakpoint region and a rearranged JH band. This indicates a t(14;18) (q32;q21). The two other cases showed rearrangements of the bcl-2 5' breakpoint region without apparent comigration. No rearrangements were detected of c-myc and bcl-3. located at chromosome 19. nor was a deletion of Rb found. All but three cases had CD5 expression. The exceptions included the t(11;14) and the t(14;18) cases. Our results confirm recent data on rearrangements at the 5' site of bcl-2 in CLL. Additionally. they corroborate the presumption that CD5-negative chronic B-cell leukemias should be considered apart from classical CLL.
Contribution of the band 3-ankyrin interaction to erythrocyte membrane mechanical stability, In an effort to evaluate the role of the band 3-ankyrin linkage in maintenance of red blood cell membrane integrity. solution conditions were sought that would selectively dissociate the band 3-ankyrin linkage. leaving other membrane skeletal interactions intact. For this purpose erythrocytes were equilibrated overnight in nutrient-containing buffers at a range of elevated pHs and then examined for changes in mechanical stability and membrane skeletal composition. Band 3 was found to be released from interaction with the membrane skeleton over a pH range (8.4 to 9.5) that was observed to dissociate the band 3-ankyrin interaction in vitro. In contrast. all other membrane skeletal associations appeared to remain intact up to pH 9.3. after which they were also seen to dissociate. Whereas hemolysis of mechanically unstressed cells did not begin until approximately pH 9.3. where the membrane skeletons began to disintegrate. enhanced fragmentation of shear stressed membranes was seen to begin near pH 8. where band 3 dissociation was first observed. Furthermore. the shear-induced fragmentation rate was found to reach a maximum at pH 9.4. ie. where band 3 dissociation was essentially complete. Based on these correlations. we hypothesize that the band 3-ankyrin linkage of the membrane skeleton to the lipid bilayer is essential for red blood cell stability in the face of mechanical distortion but not for cellular integrity in the absence of mechanical stress.
Autologous bone marrow transplantation for high-grade lymphoid malignancy using melphalan/irradiation conditioning without marrow purging or cryopreservation. The Northern Regional Bone Marrow Transplant Group, We report the safety and efficacy of 34 consecutive autologous bone marrow transplant (ABMT) procedures performed in adult patients with high-grade lymphoid malignancy after remission induction therapy. Fifteen patients with acute lymphoblastic leukemia (ALL) and six with high-grade non-Hodgkin's lymphoma (NHL) received pretransplant conditioning with intravenous (IV) melphalan and fractionated total body irradiation (TBI). Thirteen other patients with NHL were conditioned with melphalan alone. having previously received local involved field radiotherapy. Unmanipulated noncryopreserved autologous marrow was reinfused within 48 hours of harvesting. Engraftment occurred in all patients with medians of 10 days of neutropenia (neutrophils less than 0.5 x 10(9)/L). 4-day platelet transfusion requirement. 3 U packed RBC transfusion. and 18 days in hospital posttransplant. There were no procedure-related deaths. Actuarial disease-free survival in the 13 patients with ALL receiving autotransplant early in first remission is 48% with a median follow-up of 3 years. Two other ALL patients who had autotransplants after a period of maintenance therapy also remain in complete remission (CR). These results compare favorably with our 34% disease-free survival (DFS) in 15 allogeneic ALL transplant patients and 21% DFS in 19 patients on standard maintenance after a common induction schedule. No relapses have occurred in the 17 NHL patients transplanted in remission (median follow-up 2 years). but the two NHL patients who developed recurrent disease before ABMT died of progressive disease after temporary responses. We conclude that this method of ABMT results in rapid reengraftment with lack of toxicity and that the conditioning treatment used shows good efficacy against disease. It is applicable in high-grade lymphoid malignancy in first remission. and our results call into question the need for marrow purging in ALL and NHL patients transplanted in first remission.
Amplification by the polymerase chain reaction of hypervariable regions of the human genome for evaluation of chimerism after bone marrow transplantation, We combined the polymerase chain reaction (PCR) with oligonucleotide hybridization as a novel and sensitive technique to evaluate posttransplant chimerism. Specific oligonucleotides for hybridization were synthesized homologous to tandemly repetitive core sequences of regions with a variable number of tandem repeats (VNTRs). Polymorphisms at such loci result from allelic differences in the number of repeats. Primers flanking the repeat region of each of the corresponding VNTRs were used for amplification. Recipient and donor pretransplant DNA and recipient posttransplant DNA were amplified. The resultant fragments were analyzed after gel electrophoresis either by hybridization in-gel or after Southern transfer. To confirm our findings. we also performed standard assays of restriction fragment length polymorphisms (RFLPs). Evaluation of 13 selected cases indicated mixed chimerism (4). complete chimerism (5). recurrence of leukemia (2). and endogenous repopulation of hematopoiesis (2) after marrow transplantation. Sensitivity of the method was determined by mixing various proportions of recipient and donor DNA; the limit of detection of the minor component in a mixture was 0.1%. PCR data correlated with RFLP data in all cases except two in which PCR proved more sensitive than RFLP. PCR amplification of VNTRs combined with oligonucleotide hybridization is a novel technique for documenting posttransplant chimerism and has advantages over RFLP analysis: high sensitivity. use of small amounts of DNA (250 ng). ease of preparation of DNA. elimination of need for restriction enzymes. and the ability to complete studies in 2 days.
Report of the Canadian Cardiovascular Society's consensus conference on the Management of the Postmyocardial Infarction Patient, In October 1989. the Canadian Cardiovascular Society announced a program to achieve consensus on important issues in the care of patients with cardiovascular disease. This report on the management of the postmyocardial infarction patient represents the first in a series of these consensus conferences. The process for establishing consensus recommendations involved several steps. A primary panel of 11 experts from various fields was selected to review the available clinical evidence and to make a list of recommendations about management decisions in the postmyocardial infarction period. The initial report was distributed to a secondary panel of 16 reviewers* representing allied health care constituencies from across Canada. On the basis of the critical reviews and feedback from these reviewers. a revised report was distributed to all members (over 800) of the Canadian Cardiovascular Society for further review and feedback. This iterative approach resulted in a penultimate report that was presented at a plenary session of the annual scientific meeting of the Canadian Cardiovascular Society on Oct. 18. 1990. in Halifax. NS. On the basis of discussion and feedback from this symposium. the consensus review was completed.
Essential hypertension: a sign in search of a disease, The concept of disease is of cardinal importance in medical practice. The current definition has developed over more than 200 years. It includes a distinctive natural history and identifiable cellular changes. Pickering proposed a fundamental alteration to the definition when he suggested that essential hypertension is a quantitative disease without causative cellular change distinguishing normal from abnormal. The nature of essential hypertension has been confused from the beginning because of a category error. Injury is conceptually distinguished from disease. Essential hypertension. defined as elevated blood pressure together with its cardiovascular consequences. is found to be neither an injury nor a disease according to current definitions. Instead. essential hypertension refers to a treatment group just as "the fevers" did in an earlier century. One effect on patients of the failure to resolve this diagnostic paradox is the burden of suffering from the label of "disease" rather than from a state that may be substantially due to their own behavior. A theoretical consequence of importance for psychiatric theory is that the disease status of functional disorders can no longer be defended by an appeal to the existence of a quantitative disease of blood pressure.
Hearing loss in elderly patients in a family practice, OBJECTIVE: To investigate hearing loss in elderly patients. DESIGN: Cohort study. SETTING: Family practice. PATIENTS: All ambulatory patients 65 years of age or older who attended the practice from June to August 1989. OUTCOME MEASURES: The Hearing Handicap Inventory for the Elderly--Screening Version (HHIE-S) and the Welch-Allyn Audioscope. Patients who failed one or both of the screening tests were referred to a speech and hearing clinic for audiologic assessment and treatment recommendations. Those with hearing aids were excluded from the main study but were given the opportunity to have them assessed at the clinic. MAIN RESULTS: Of 157 eligible patients 42 were excluded: 16 refused to participate. 13 already had hearing aids. and 13 could not be contacted. Of the remaining 115. 34 failed one or both of the tests (14 failed the HHIE-S. 9 failed the audioscope test. and 11 failed both). Of the 34. 25 completed the audiologic assessment at the clinic. Fifteen were found to have severe hearing impairment; the recommendation was hearing aids for 12. further assessment for 2 and no treatment for 1. Of the remaining 10 patients it was thought that 6 would benefit from hearing aids. Ten of the 11 patients with hearing aids who agreed to undergo testing at the clinic were found to need an adjustment or replacement of their devices. CONCLUSIONS: Hearing loss is a significant problem in elderly patients in primary practice. Further study is required to determine which of the two screening tools is most effective. Most elderly patients with hearing aids may require modification or replacement of their devices.
Rural obstetrics: a 5-year prospective study of the outcomes of all pregnancies in a remote northern community, OBJECTIVE: To determine whether a small. isolated hospital that has no facilities to perform cesarean section and handles fewer than 50 deliveries annually can provide acceptably safe obstetric and perinatal care. DESIGN: Cohort study. SETTING: Southern region of the Queen Charlotte Islands. BC. served by a 21-bed hospital and medical clinic in Queen Charlotte City. The hospital and clinic are staffed by five family practitioners without local obstetric. pediatric. anesthetic or surgical support. PATIENTS: All women beyond 20 weeks' gestation who gave birth from Jan. 1. 1984. to Dec. 31. 1988; 33% were primiparous and 20% native. Of the 286 women 192 (67%) delivered locally. 33 (12%) were transferred after admission because of antepartum or intrapartum complications. and 61 (21%) delivered elsewhere by choice or on their physician's recommendation. OUTCOME MEASURES: Perinatal mortality rate and adverse perinatal outcome (death. birth weight of less than 2500 g. neonatal transfer or Apgar score of less than 7 at 5 minutes). MAIN RESULTS: There were six perinatal deaths. for a perinatal mortality rate of 20.8 (95% confidence interval [CI] 4.4 to 37.2). The hospital-based rate of adverse perinatal outcome was 6.2% (12 of 193 newborns) (95% CI 2.8% to 9.6%). CONCLUSIONS: The perinatal mortality rate is not a meaningful way to assess small populations; about 85 years of data would be required to decrease the 95% CIs from within 16 to within 4. The rate of adverse perinatal outcome in our study was consistent with the rate in other studies. Collaboration of small. rural hospitals is required to increase cohort size so that the correlation between the currently accepted standard. the perinatal mortality rate. and other outcome measures can be determined.
Identification of ischemic and hibernating myocardium: feasibility of post-exercise F-18 deoxyglucose positron emission tomography, The identification of ischemic and hibernating myocardium facilitates the selection of patients most likely to benefit from revascularization. This study examined the feasibility of metabolic imaging. using post-exercise F-18 deoxyglucose positron emission tomography (FDG-PET) for the diagnosis of both ischemia and hibernation in 27 patients with known coronary anatomy. Normal post-exercise FDG uptake was defined in each patient by reference to normal resting perfusion and normal coronary supply. Abnormal elevation of FDG (ischemia or hibernation) was compared in 13 myocardial segments in each patient. with the results of dipyridamole stress perfusion imaging performed by rubidium-82 positron emission tomography (Rb-PET). Myocardial ischemia was diagnosed by either FDG-PET or Rb-PET in 34 segments subtended by significant local coronary stenoses. Increased FDG uptake was present in 32/34 (94%) and a reversible perfusion defect was identified by Rb-PET in 22/34 (65%. p less than .01). In 3 patients. ischemia was identified by metabolic imaging alone. In 16 patients with previous myocardial infarction. perfusion defects were present at rest in 89 regions. 30 of which (34%) demonstrated increased FDG uptake. consistent with the presence of hibernation. Increased post-exercise FDG uptake appears to be a sensitive indicator of ischemia and myocardial hibernation. This test may be useful in selecting post-infarction patients for revascularization.
Coronary artery dilatation requiring high inflation pressure, A patient with rigid coronary lesions refractory to balloon dilatation is described. A Cordis Orion fixed wire balloon able to withstand 20 bar was required for successful dilatation.
Transseptal catheterization technique: a simple safety procedure, The major complication of transseptal catheterization. that of inadvertent perforation of other structures. can best be avoided by maintenance of the correct needle tip position during introduction and maneuvering of the assembly. The addition of a needle-stop to the transseptal needle shaft and a sterile ruler to check its present position assures the maintenance of the needle tip position. freeing the operator's concern for accurate location of landmarks. The method of utilizing and setting the needle-stop is described.
Predictability and prognosis of PTCA-induced coronary artery aneurysms, The natural history of coronary aneurysms. defined as local dilatations exceeding the diameter of the normal adjacent vessel segments by at least 1.5 times. is not significantly different from the natural history of nonaneurysmal coronary disease. However. little is known about the prognosis of percutaneous transluminal coronary angioplasty (PCTA)-induced coronary aneurysms. Therefore. we investigated the occurrence and the medium long-term prognosis of such aneurysms in 728 patients who. after successful PTCA. underwent repeat coronary angiography at mean 4.5 months post-PTCA. A coronary aneurysm at the site of PTCA ws noted in 3.9% of patients (n = 28). Of the potentially predictive factors analyzed. only a coronary dissection at the time of PTCA had statistically significant influence. The long-term prognosis of PTCA-induced coronary aneurysms was excellent. One patient underwent (unrelated) cardiac surgery. all other 27 patients remained eventfree. We conclude that the same benign nature of coronary aneurysmal disease holds true for those aneurysms that develop after PTCA.
Left ventricular mid-cavitary obstruction after balloon dilation in isolated aortic valve stenosis in children, A hyperdynamic left ventricle can lead to post-dilation mid-cavitary obstruction in the absence of any preballoon mid-cavitary obstruction in children with aortic valve stenosis. The purpose of this study was to define the incidence and course of post-dilation mid-cavitary obstruction. We reviewed the catheterization and echocardiographic data of 35 patients. ages 3 days to 18 years (mean = 7.9 years). with isolated aortic valve stenosis who underwent balloon dilation with a fall in aortic valve gradient to less than 20 mm Hg. Post-dilation mid-cavitary obstruction was suspected from post-dilation left ventricular angiogram and was quantitated by echocardiographic and Doppler examinations performed immediately after dilation and in a 1-3 month follow-up period. Continuous wave Doppler directed by color flow Doppler was used for evaluation and differentiation of post-dilation mid-cavitary obstruction and residual aortic valve stenosis. Three children (3/35 [9%]) all under 2 years of age developed post-dilation mid-cavitary obstruction immediately after dilation. The obstruction within the cavity resolved spontaneously in all three patients. Conclusions: 1) Post-dilation left ventricular mid-cavitary obstruction can occur in children under 2 years of age after balloon dilation of severe aortic valve stenosis. and 2) total regression of post-dilation mid-cavitary obstruction occurs spontaneously in all patients.
Determination of the anatomical size of ventricular septal defects on the basis of hemodynamic data and noninvasive assessment of pulmonary to systemic vascular resistance ratio Rp/Rs by Doppler-echocardiography, The pulmonary and systemic flow (Qp/Qs) and resistance ratios (RP/Rs) were determined in children with isolated ventricular septal defects (VSD) to derive an "effective defect resistance" (Rd/Rs) representing the ratios of the resistance of the defect to the systemic vascular resistance. The defect size (expressed as the ratio of the area of the defect to the cross-sectional area of the ascending aorta) was related to the calculated "effective defect resistance." where a significant (non-linear) correlation was found. The effective resistance of the defect is a useful aid for estimation of the anatomical size of a ventricular septal defect. The close correlation between anatomical size and the hemodynamic parameter Rd/Rs allows one to calculate the ratio Rp/Rs with this concept using noninvasive Doppler-ultrasound and echocardiography. This was performed in 21 children with VSD who underwent cardiac catheterisation. The noninvasive calculated flow ratio Qp/Qs and the resistance ratio Rp/Rs showed a close correlation to the values measured at cardiac catheterisation.
Regulation of expression of M, B, and mitochondrial creatine kinase mRNAs in the left ventricle after pressure overload in rats, Pressure overload of the left ventricle induces synthesis of creatine kinase isoenzymes. To determine whether this response is associated with an altered pattern of creatine kinase gene expression. we induced arterial hypertension in rats by suprarenal aortic banding. After 4 days. left ventricular myocardium from hypertensive (n = 7) and normotensive. sham-operated (n = 5) rats was analyzed for isoenzyme activities by chromatography; M and B creatine kinase subunit protein by Western blot; and M. B. and mitochondrial creatine kinase mRNA by Northern blot. Although total creatine kinase activity increased in hypertensive (1.096 +/- 214 IU/g left ventricle) compared with normotensive rats (648 +/- 81 IU/g left ventricle. p less than 0.01). the relative proportions of the cytoplasmic and mitochondrial isoenzymes did not change. The mass of M and B subunits increased 1.9- and 2.7-fold. respectively. in hypertensive compared with control rats. Similarly. the mRNA for M and B subunits as well as mitochondrial creatine kinase increased 2.6-. 1.6-. and 1.8-fold. respectively. in hypertensive rats compared with control rats. Thus. increased energy requirements in acute pressure overload are met by generalized induction of creatine kinase mRNA and subunit protein and not by an isoenzyme switch.
Thromboxane mediates diapedesis after ischemia by activation of neutrophil adhesion receptors interacting with basally expressed intercellular adhesion molecule-1, Ischemic injury is characterized by neutrophil (PMN)--endothelial cell adhesion and diapedesis associated with thromboxane (TX) generation. Neutrophil-endothelial cell interaction is regulated in part by the leukocyte adhesion receptor CD 18 glycoprotein complex and the endothelial intercellular adhesion molecule-1 (ICAM-1). This study tests the role of TX in ischemia-induced diapedesis and evaluates whether the diapedesis is regulated by neutrophil or endothelial adhesion receptors. Plasma derived from rabbit hind limbs made ischemic for 3 hours (n = 6) and reperfused for 10 minutes had increased levels of TXB2 3.450 pg/ml. which was higher than sham rabbit (n = 6) values of 653 pg/ml (p less than 0.05). When introduced into abraded skin chambers placed on the dorsum of other normal rabbits (n = 6). this ischemic plasma induced 1.000 pg/ml of new TX synthesis and diapedesis of 1.235 PMN/mm3. The total TX concentration and PMN accumulations in blister fluid were correlated (r = 0.88. p less than 0.05). In contrast. sham rabbit plasma induced no TX synthesis and diapedesis of only 77 PMN/mm3 (p less than 0.05). Administration of 50 ng/ml of authentic TXB2 into blisters induced an accumulation of 453 PMN/mm3. which was higher than that in saline controls (18 PMN/mm3) (p less than 0.05). Pretreatment of normal rabbits used for the diapedesis assay (n = 4) with the TX synthetase inhibitor OKY 046 (2 mg/kg/hr) limited ischemic plasma and authentic TXB2 induced diapedesis to 142 and 76 PMN/mm3. respectively (both p less than 0.05).
Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the isolated working rat heart, To assess the effects of fasting on recovery of function and exogenous glucose metabolism after 15 minutes of total ischemia. we perfused isolated working rat hearts from fed and fasted animals. Hearts were perfused in a recirculating system with bicarbonate buffer containing glucose (10 mM). Mechanical performance. release of marker proteins for ischemic membrane damage (lactate dehydrogenase. myoglobin. citrate synthase). and the concentrations of lactate and glucose in the perfusion medium were measured serially. Tissue metabolites were also measured. Fasting raised the myocardial glycogen content by 25%. Cardiac performance of perfused hearts from fed and fasted animals was the same during the preischemic and the post-ischemic period. The time of return of function to preischemic values was significantly less in hearts from fasted rats (2.3 versus 7.8 minutes. p less than 0.025). The release of cytosolic and mitochondrial marker proteins was significantly lower in hearts from fasted rats than in hearts from fed rats. Glucose metabolic rates during control and reperfusion were unchanged for hearts from fasted rats. but decreased for hearts from fed rats during reperfusion. The adenine nucleotide content at the end of ischemia was higher in hearts from fasted animals than in hearts from fed animals. We conclude that increasing glycogen levels prior to ischemia improves recovery of function. lessens membrane damage. and prevents loss of adenine nucleotides.
Carnitine palmitoyltransferase in cardiac ischemia. A potential site for altered fatty acid metabolism, The sensitivity of carnitine palmitoyl coenzyme A (CoA) transferase I to inhibition of its activity by malonyl-CoA is progressively reduced in mitochondria isolated from ischemic cardiac cells as blood flow decreases to 30% or less of the preocclusion flow. The activity of carnitine palmitoyl-CoA transferase I in mitochondria isolated from nonischemic cardiac cells demonstrates incomplete inhibition. even at high concentrations of malonyl-CoA. Kinetic analyses of these data gave results most consistent with the expression of two overt enzyme activities: one activity that is sensitive to inhibition by malonyl-CoA and one activity that demonstrates little or no sensitivity to such inhibition. The decrease in malonyl-CoA-sensitive activity associated with ischemia results from a 13% decrease in the activity of the sensitive component and a corresponding 13% increase in the activity of the insensitive component. Decreased sensitivity of ischemic carnitine palmitoyl-CoA transferase I to inhibition by malonyl-CoA. together with potential fluctuations in the content of malonyl-CoA in tissue. would increase the synthesis of palmitoylcarnitine during ischemia and facilitate return to the use of fatty acid as a preferred metabolic fuel on reperfusion. This apparent conversion occurs concomitantly with a decrease in the free protein thiol content of the mitochondrial membranes isolated from ischemic cardiac cells. Treatment of the mitochondria from ischemic cardiac cells with dithiothreitol in vitro partially reverses the loss in sensitivity to malonyl-CoA. suggesting the possible role of thiol oxidation in the altered metabolism of ischemic mitochondria. Western blot analysis of these mitochondria using an antibody against carnitine palmitoyltransferase II purified from beef heart demonstrates a 68-kDa protein. which under ischemic conditions apparently is decreased by 2 kDa. These results are more indicative of a modification in protein folding of carnitine palmitoyltransferase than proteolytic changes during ischemia.
Inhibitory role of the coronary arterial endothelium to alpha-adrenergic stimulation in experimental heart failure, The role of the endothelium in regulating coronary alpha-adrenergic tone was evaluated in isolated coronary arterial rings from dogs with and without pacing-induced congestive heart failure (CHF). The maximal contractile response to methoxamine was attenuated approximately 43% (p less than 0.05) in both intact and denuded CHF rings compared with control. Conversely. norepinephrine-induced contractions were diminished 58% in intact CHF vessels and 39% in denuded CHF vessels (p less than 0.05). Denudation did not alter responses to methoxamine but significantly (p less than 0.05) augmented the tension generated by norepinephrine in both control (1.7-fold) and CHF (2.4-fold) arteries. In both intact control and CHF coronary arteries. norepinephrine elicited rapid. transient relaxations that preceded slow. sustained contractions; the initial relaxation phase was endothelium dependent. because denudation eliminated the response. Relaxations to the selective alpha 2-adrenoceptor agonist BHT 920 were also dependent on the presence of an endothelium. At peak CHF. endothelium-dependent relaxations to norepinephrine and BHT 920 were enhanced. whereas relaxations to nitroglycerin and acetylcholine were unaltered. The data suggest that alpha-adrenergic tone in canine coronary arteries is diminished by pacing-induced CHF because of a decrease in alpha 1-adrenoceptor-mediated constriction and an enhanced capacity of the endothelium to antagonize the direct vascular smooth muscle response of norepinephrine through endothelium-dependent. alpha 2-adrenoceptor-mediated relaxations.
Correlation dimension of heartbeat intervals is reduced in conscious pigs by myocardial ischemia, A reduced standard deviation of RR intervals (SDRR) predicts increased mortality in groups of survivors of myocardial infarction. Like SDRR. the correlation dimension (D2) describes variation within a sampled time series. but uniquely it reveals 1) the epoch's geometric structure and 2) the degrees of freedom of the generator. These unique features may be more sensitive predictors of mortality than SDRR. We developed a new algorithm for estimating D2 (i.e.. the "point-D2"). tested it with known data. and found that it had greater accuracy for finite data than other published algorithms. Analysis of RR intervals from eight conscious pigs undergoing acute occlusion of the left anterior descending coronary artery revealed a drop in the point-D2 from a control mean and standard deviation of 2.50 +/- 0.81 to 1.58 +/- 0.64 during the first minute of ischemia (p less than 0.01) and to 1.07 +/- 0.18 during the last minute preceding ventricular fibrillation (p less than 0.01). Partial occlusions (50-90% reduction of coronary blood flow) evoked point-D2 reductions only 25-30% of control (p less than 0.01). The point-D2 means were correlated between pigs with the magnitude of the respiratory sinus arrhythmia (p less than 0.01). but during ischemia this correlation was replaced by one between the standard deviation of the point-D2s and SDRRs. Because the simultaneous reduction in the mean point-D2 and its standard deviation to 1.07 +/- 0.18 occurred in every case. was unique to the few minutes preceding ventricular fibrillation. and never reached these low values during other conditions in which it was reduced. we conclude that the point-D2 may be an accurate prospective predictor of mortality within the individual subject.
Remodeling of myocyte dimensions in hypertrophic and atrophic rat hearts, Changes in hemodynamic load cause alterations in cardiac myocyte size. with regional variations in myocyte size distribution possible within the ventricular wall. We studied regional changes in cellular dimensions and their distribution in two models of cardiac hypertrophy and in cardiac atrophy in the rat. Combined volume-pressure overload was produced by 3.3'.5-triiodo-L-thyronine (T3) treatment; atrophy was produced by heterotopic isotransplantation. Our previous data from long-term pressure overload after aortic constriction were used for comparison. Isolated ventricular myocytes were obtained after in vitro coronary perfusion with collagenase. Cell volume and its distribution were determined; cell length was directly measured by image analysis. and cross-sectional area was estimated from the cell volume/cell length ratio. assuming a cylindrical model. Myocyte hypertrophy resulting from hyperthyroidism and aortic constriction was primarily due to increased cross-sectional area. In both cases. the relative response was greater in the right ventricle than in the left ventricle. Within the left ventricle. epimyocardial myocytes enlarged the most. Aortic constriction and T3 treatment predominantly increased the size of smaller myocytes. Heterogeneity in myocyte size increased after constriction but remained relatively unaffected after T3 treatment. Atrophy of left ventricular myocytes was due to a proportional decrease in cell length and cross-sectional area. with the greatest decrease in the left ventricular endomyocardium. Atrophy predominantly affected larger myocytes. resulting in a more homogeneous overall population of smaller myocytes. We conclude that various alterations in load lead to diverse remodeling in the myocyte population throughout the ventricular wall. In general. smaller myocytes show the highest growth potential. whereas larger myocytes exhibit the highest potential to atrophy.
Effects of mental stress on myocardial perfusion in patients with ischemic heart disease, The purpose of the present study was to determine whether and to what extent mental stress can reproduce the perfusion defects that are known to be induced by exercise. Twenty-four patients with recent myocardial infarction (New York Heart Association functional class I) and evidence of ischemic response were evaluated by means of SESTAMIBI scintigraphy performed once after exercise and then again within 2 days after mental arithmetic. Baseline. exercise. and mental stress planar scintigrams were divided into 15 segments. and each segment was reviewed and scored on a scale of 0 to 3 by experienced observers using circumferential profile analysis. Conflicting scores were resolved by consensus. Electrocardiographic abnormalities were found in 15 of 24 patients during exercise and in none during mental arithmetic. Chest pain was experienced by five patients during exercise and by none during mental stress. Twenty patients showed reversible perfusion defects during mental stress. Of the 360 pooled scintigram segments. 99 evidenced uptake defects during exercise. and 48 of these showed the same defects during mental stress. Twenty of the remaining 51 of 99 segments were adjacent to segments showing reversible hypoperfusion. suggesting milder hypoperfusion in these segments during mental arithmetic than during exercise. Furthermore. 10 segments showed reversible defects only during mental stress such that seven of these occurred in areas adjacent to those that had shown exercise-induced reversible perfusion defects. two occurred in areas that had shown fixed SESTAMIBI defects during exercise. and one occurred in a segment that had shown completely normal uptake during exercise.
Electrocardiographic markers of ischemia during mental stress testing in postinfarction patients. Role of body surface mapping, In patients with coronary artery disease. radionuclide investigations have documented a high incidence of mental stress-induced myocardial ischemia in the absence of significant electrocardiographic changes and/or angina. To investigate the causes of the low electrocardiographic sensitivity. we recorded body surface maps during mental arithmetic in 22 normal volunteers and 37 postinfarction patients with residual exercise ischemia. Myocardial perfusion was studied with thallium-201 or technetium-99 (SESTAMIBI) planar scans. In 14 patients. body surface maps were also recorded during atrial pacing at the heart rate values achieved during mental stress. While taking the body surface maps. the area from J point to 80 msec after this point (ST-80) was analyzed by integral maps. difference maps. and departure maps (the difference between each patient's difference map and the mean difference map for normal subjects). The body surface mapping criteria for ischemia were a new negative area on the integral maps. a negative potential of more than 2 SD from mean normal values on the difference maps. and a negative departure index of more than 2. Scintigraphy showed asymptomatic myocardial hypoperfusion in 33 patients. Eight patients had significant ST segment depression. The ST-80 integral and difference maps identified 17 ischemic patients. Twenty-four patients presented abnormal departure maps. One patient presented ST depression and abnormal body surface maps without reversible tracer defect. In 14 of 14 patients. atrial pacing did not reproduce the body surface map abnormalities. The analyses of the other electrocardiographic variables showed that in patients with mental stress-induced perfusion defects. only changes of T apex-T offset (aT-eT) interval in Frank leads and changes of maximum negative potential value of aT-eT integral maps significantly differed from those of normal subjects. Our results confirm the low electrocardiographic sensitivity for detecting mental stress-induced myocardial hypoperfusion in postinfarction patients. ST analysis in the body surface map increases the information content of the electrocardiographic signal. T wave analysis appears to offer fewer diagnostic advantages.
Platelet activation by emotional stress in patients with coronary artery disease, We studied the effects of experimentally induced emotional stress (mental arithmetic) on different hemodynamic parameters. catecholamine levels. and serum and platelet function tests in 25 postinfarction patients and in 10 apparently healthy. age-matched control subjects. Mental stress (10 minutes) induced significant increments in heart rate. systolic blood pressure. diastolic blood pressure. double product. and cardiac output. indicating a sympatho-adrenal stimulation that was confirmed by a significant increase in serum epinephrine and norepinephrine levels. All of the effects disappeared at minute 10 of recovery. Concomitantly. the test produced a significant increase in platelet aggregation (induced by 3 microM ADP or 1 microgram/ml collagen). the formation of circulating platelet aggregates. and an increase in thromboxane B2 levels in plasma and serum. These effects were also rapidly reversible. Similar activation of hemodynamic parameters and a similar but less evident increase in platelet function by emotional stress were observed in control subjects. A possible artifact due to factitious platelet activation by catheter sampling was excluded with experiments in which a 40-minute rest was introduced after the baseline period and before mental stress; platelet activation did not occur during baseline or rest periods. only after emotional stress. Furthermore. the antiplatelet drug dipyridamole reduced the stress-induced formation of platelet aggregates in postinfarction patients. These results demonstrate the existence of a direct link between emotional stress and platelet function and offer an explanation of one of the mechanisms through which mental stress may be involved in the development of coronary artery disease.
Ventricular responses to mental stress testing in patients with coronary artery disease. Pathophysiological implications, Recent research examining the effects of mental stress on left ventricular wall motion and/or ejection fraction has used four techniques to measure contractile function: radionuclide ventriculography. a stationary nuclear probe. two-dimensional echocardiography. and an ambulatory radionuclide left ventricular function monitor. This research has consistently revealed that mental stress-induced myocardial ischemia occurs frequently during laboratory stress testing. particularly among patients with exercise-induced ischemia. This ischemia is usually silent. occurs at low heart rate elevations but with significant blood pressure increases compared with exercise-induced ischemia. and is frequently not detected when electrocardiographic markers are used alone. Exploration of factors underlying differences between mental stress- and exercise-induced ischemia has provided a means for studying the complex pathophysiology of myocardial ischemia.
Methodology of mental stress testing in cardiovascular research, Many issues related to the selection. reliability. and validity of mental stress testing in cardiovascular research are discussed. Five categories of mental stress testing are distinguished: problem-solving tasks. information-processing tasks. psychomotor tasks. affective conditions. and aversive or painful conditions. A series of practical and theoretical criteria are outlined for the selection of appropriate tests. and the measurement of a range of dependent variables is emphasized. The temporal stability of cardiovascular responses to mental stress tests is examined through an analysis of test-retest correlations (weighted for sample size) in 28 comparisons with intervals between sessions varying from 1 day to more than 1 year. Heart rate reactions to tasks show an average-weighted Z of 0.732 +/- 0.031 (r = 0.62). with Z = 0.575 +/- 0.034 (r = 0.52) for systolic blood pressure and Z = 0.313 +/- 0.035 (r = 0.30) for diastolic blood pressure. It is argued that the validity of mental stress tests can be judged in relation to several different aspects. specifically. methodological. ecological. diagnostic. prognostic. and therapeutic validities. The nature of these standards is described. and pertinent literature is presented.
Influence of mental stress on ventricular pump function in postinfarction patients. An invasive hemodynamic investigation, To assess the influence of mental stress on ventricular pump function in coronary patients. 88 postinfarction patients (mean age. 53 +/- 10 years) performed mental arithmetic during Swan-Ganz catheterization monitoring a mean of 44 +/- 16 days after myocardial infarction. The test lasted 3 minutes in 66 patients and 10 minutes in 22 patients. Two patients suffered acute pulmonary edema a few minutes after mental arithmetic. but no others complained of symptoms. Mean heart rate increased from 76 +/- 14 to 92 +/- 17 beats/min. mean systolic blood pressure increased from 138 +/- 22 to 160 +/- 27 mm Hg. mean diastolic blood pressure increased from 89 +/- 10 to 101 +/- 15 mm Hg. mean pulmonary wedge pressure increased from 13 +/- 6 to 19 +/- 8 mm Hg (p less than 0.001). and mean stroke volume decreased from 72 +/- 18 to 65 +/- 18 ml (p less than 0.001) during mental arithmetic. The changes in central hemodynamics during mental arithmetic were not predictable from noninvasive parameters. In the 22 patients who performed 10-minute mental arithmetic. the changes persisted throughout mental exercise. Eighty-one patients underwent supine bicycle ergometry after mental arithmetic: Absolute mental arithmetic-pulmonary wedge pressure values correlated with those during exercise at the first stage (25 W) (r = 0.63. p less than 0.001) and at maximal load (77 +/- 29 W) (r = 0.49. p less than 0.001). and pulmonary wedge pressure change between stress values and baseline during mental arithmetic did not correlate with those during the first stage of exercise (r = 0.09. p = NS) or during maximal load (r = 0.11. p = NS). Twenty-nine patients repeated the study 1 year after myocardial infarction. and the same hemodynamic changes were observed during mental arithmetic. In conclusion. it appears that mental stress can cause deteriorations of central hemodynamics that can be independent of changes in heart rate and blood pressure and are not predictable from exercise-induced changes; stress-induced cardiovascular activation can last for at least 10 minutes and is stable over long time periods.
Effects of mental exercise in patients with dilated cardiomyopathy and congestive heart failure. An echocardiographic Doppler study, To assess the effects of mental stress on left ventricular diastolic function in patients with congestive heart failure. nine patients aged 57 +/- 12 years with dilated cardiomyopathy (end-diastolic volume. more than 110 ml/m2; ejection fraction. less than 40%; mean. 28 +/- 8%) and congestive heart failure in New York Heart Association functional class II or III and 14 normal volunteers (mean age. 49 +/- 8 years) were studied during mental arithmetic lasting 10 minutes with echocardiographic Doppler monitoring of transmitral flow velocity. During mental arithmetic. the ratio of peak flow velocity in early versus late diastole (E/A) and deceleration time of early diastole did not change in normal controls. However. E/A increased significantly (from 1.6 +/- 1.5 to 1.9 +/- 1.7; p less than 0.01) and deceleration time markedly decreased (from 156 +/- 49 to 108 +/- 31 msec; p less than 0.001) in patients with congestive heart failure. In 16 postinfarct patients with ejection fraction of less than 40% studied during mental arithmetic with simultaneous hemodynamics and Doppler recordings. good correlations were found between pulmonary wedge pressure and Doppler parameters (wedge pressure versus E/A. r = 0.89; wedge pressure versus deceleration time. r = -0.87). During mental arithmetic. the pulmonary wedge pressure-E/A correlation was weaker (r = 0.67). whereas the correlation between pulmonary wedge pressure and deceleration time was stronger (r = 0.91). The value of 153 msec in deceleration time was the best cutoff point in predicting 12 mm Hg pulmonary wedge pressure. both at rest and during mental arithmetic: the higher the deceleration time. the lower the pulmonary wedge pressure. and vice versa. Among patients with congestive heart failure. five showed normal baseline deceleration time (195 +/- 21 msec; pattern 1). and the remaining four showed a short (less than 153 msec) deceleration time (108 +/- 13 msec; pattern 2). During mental arithmetic. deceleration time markedly decreased to as short as 119 +/- 20 msec in all patients except one with baseline pattern 1. Deceleration time further decreased to 75 +/- 6 msec in all patients with baseline pattern 2. Mental arithmetic induces changes in left ventricular diastolic function in patients with congestive heart failure. Transmitral echocardiographic Doppler provides a simple noninvasive method of estimating and monitoring pulmonary wedge pressure in patients with severe left ventricular dysfunction.
Assessment of ventricular function with an ambulatory left ventricular function monitor, Changes in ventricular function caused by activities of daily living. including standing. walking. stair climbing. and mental stress. were evaluated using a radionuclide device that recorded left ventricular function on a beat-by-beat basis. The ambulatory monitor was positioned over the patient's left ventricle after a gated blood pool scan. Monitoring revealed a 10% increase of left ventricular ejection fraction from baseline to brisk walking. an 18% increase during stair climbing. and a 6% increase with mental stress. In some subjects. however. the increase in ejection fraction during mental stress exceeded that during exercise.
Psychophysiological stress testing in postinfarction patients. Psychological correlates of cardiovascular arousal and abnormal cardiac responses, The psychophysiological responses to two mental stress tests (mental arithmetic and an interactive concentration task) were assessed in 168 unmedicated. male. postinfarction patients 36-69 years old. Patients also completed a standard battery of psychological tests. Psychophysiological responses were generally unrelated to age and education. Comparison of patients scoring high (more than 75%) and low (less than 25%) relative to the normal population on psychological measures indicated that heart rate and blood pressure responses to mental stress tests were significantly greater in those reporting low than in those reporting high neuroticism. The study population was subsequently divided into high. medium. and low cardiovascular responders on the basis of rate-pressure product reactions to the two stress tests. The three cardiovascular response groups did not differ in age. interval between myocardial infarction and stress testing. ejection fraction. incidence of exercise-induced ischemia. or ischemic signs during Holter monitoring. However. the high cardiovascular responders were more likely to manifest possible or definite electrocardiographic signs of ischemia or significant arrhythmia during mental stress testing than were the medium or low cardiovascular responders (50% versus 19.6% and 7%. respectively). High cardiovascular responders also reported lower levels of trait anxiety. neuroticism. psychophysiological symptoms. and depression.
Sympathovagal interaction during mental stress. A study using spectral analysis of heart rate variability in healthy control subjects and patients with a prior myocardial infarction, We tested the hypothesis that psychological stress testing in the clinical laboratory provokes changes in the sympathetic and vagal activities regulating heart rate that can be assessed noninvasively using spectral analysis of RR variability. To account for the effects on respiration produced by talking. this study was performed with two different procedures: the I.K.T. (i.e.. a computer-controlled mental task that is performed in silence and does not entail human confrontation) and a stressful interview. Finally. we assessed whether ischemic heart disease modifies the spectral changes induced by psychological stress by comparing a group of healthy subjects (age. 38 +/- 2 years) with a group of patients (age. 52 +/- 3 years) recovering from 1-month-old myocardial infarctions. The findings indicate that psychological stress induced marked changes in the sympathovagal balance. which moved toward sympathetic predominance. The low-frequency component of RR variability. a marker of sympathetic activity. increased from 58 +/- 5 normalized units (NU) to 68 +/- 3 NU with the I.K.T. and to 76 +/- 3 NU with the interview. This increase was absent in the group of post-myocardial infarction patients. However. arterial pressure increased significantly in both groups of subjects. The possibility of age playing an important role in determining the differences observed was disproved by the findings of a marked increase in low frequency with mental stimuli in an additional group of borderline hypertensive subjects with ages (55 +/- 2 years) comparable to those of post-myocardial infarction patients.
Autonomic nervous system and coronary blood flow changes related to emotional activation and sleep, Experimental models have been developed to investigate the influences of anger. fear. and sleep on coronary blood flow. Studies of anger in dogs with coronary stenosis indicate that the postarousal phase is particularly conducive to myocardial ischemia. Specifically. a delayed coronary vasoconstrictor response has been observed within 1-3 minutes after cessation of behavioral arousal. The response is prevented by bilateral stellectomy and can be elicited in anesthetized animals by electrical stimulation of the right or left stellate ganglion. The latter effect is averted by alpha-adrenergic blockade with prazosin. Although the basis for the protracted nature of the delayed vasoconstriction remains to be clarified. the current hypothesis is that the phenomenon results from a time-dependent imbalance between the vasoconstrictor effects of adrenergic input and the vasodilator influences of coronary pressure and/or cardiac metabolic activity. A behavioral model emulating the fear state has also been developed. When dogs that fail to exhibit anger are placed in a food-access confrontation protocol. the animals demonstrate a fearlike state evidenced by a cowering posture and somatic tremor. There is a distinct plasma catecholamine profile that is characterized by a predominant increase in epinephrine compared with norepinephrine. This is in contrast to the pattern observed during anger. in which a prevalent increase in norepinephrine is observed. Fear results in significant increases in heart rate. arterial blood pressure. and coronary arterial flow. Sleep is also associated with substantial alterations in coronary hemodynamic function.
Coronary dynamics and mental arithmetic stress in humans, Incidence and mechanisms of psychological stress-induced myocardial ischemia were investigated in a population of 63 patients using mental arithmetic. Fifty subjects (group 1) were selected as a consecutive population of ischemic patients with electrocardiographic documentation of ischemia at rest. on effort. or both. Mental arithmetic induced increases in heart rate. blood pressure. and rate-pressure product in all patients. Transient ischemic electrocardiographic changes occurred in 22 patients (44%; positive mental arithmetic). the majority of whom had both resting and exercise angina. In negative mental arithmetic tests. peak rate-pressure product was always lower than that achieved during exercise (mean +/- SD. 11.9 +/- 3 versus 21.3 +/- 5. p less than 0.01). Of the 22 patients with positive mental arithmetic tests. ischemia occurred in only six. at a rate-pressure product equal to or more than the one achieved during exercise (21.1 +/- 5 versus 19.4 +/- 4. p less than 0.01). suggesting an increase in myocardial O2 demand exceeding the limited increase in flow; in the remaining 16 patients. rate-pressure product values were significantly lower (14.8 +/- 3 versus 22.7 +/- 6. p less than 0.01). suggesting a primary reduction in coronary blood flow that is probably related to an increase in coronary tone. To assess the possible site of such a vasoconstriction. the effect of mental arithmetic on large coronary artery diameter was tested in 13 additional unselected patients (group 2) undergoing coronary angiography for a chest pain syndrome.
Disease-modifying agents and experimental treatments of rheumatoid arthritis, The pharmacologic management of the rheumatoid arthritis (RA) patient involves the use of various classes of therapeutic agents to induce symptomatic relief and reduce disease activity. Aspirin and nonsteroidal antiinflammatory drugs are used initially to lessen the degree of pain and swelling associated with the inflammatory disease process. The addition of a heterogeneous class of compounds. "second-line" therapy (previously known as disease-modifying antiinflammatory rheumatic drugs). is advocated to modify the disease course itself. Second-line treatments include antimalarials. gold salts. D-penicillamine. azathioprine. and methotrexate. Randomized placebo-controlled trials ahve demonstrated the efficacy of these compounds in RA. Improvement in standard parameters of disease activity including the number of painful and swollen joints. duration of morning stiffness. and erythrocyte sedimentation rate has been noted with these second-line drugs. Whether they modify roentgenographic progression is under rigorous study. These agents alone or in combination rarely induce complete disease remission. Therefore. newer therapies are under intensive investigation and include sulfasalazine. cyclosporin A. and combination therapy.
Current principles of rehabilitation for patients with rheumatoid arthritis, Rehabilitation is rooted in the comfort and palliation that sufferers of rheumatic symptoms have sought from physical modalities throughout history. In recent decades. several of these empiricisms have been tested scientifically. Furthermore. function has joined comfort as a desirable and measurable outcome. This article highlights some of the more substantive information as it relates to rheumatoid arthritis. It is clear that such information facilitates more effective and efficient programs of intervention. It is equally clear that the therapeutic perspective of rehabilitation for rheumatoid arthritis is more appropriately applied throughout the course of the disease in an ongoing program of habilitation than held in reserve as a form of salvage.
Full-thickness rotator-cuff tear. An analysis of results, A retrospective review is reported on 68 patients with 72 full-thickness rotator-cuff tears treated surgically. Duration of symptoms before surgery averaged 18 months (range. one month to ten years). Tears of the rotator cuff were divided into small (12 shoulders). medium (26 shoulders). large (17 shoulders). and massive (17 shoulders). Rotator-cuff tears were repaired by use of a bony trough in 88% of patients. All patients were treated with decompression acromioplasty. In addition. an acromioclavicular arthroplasty was performed in 29 patients. Forty-seven men and 21 women with an average age of 58 years (range. 31-76 years) were followed for an average of 24 months (range. nine to 57 months). Excellent results are reported in 46 shoulders. good in 20. fair in four. and poor in two. The size of tear and duration of symptoms did not significantly affect results.
Valgus stability of the elbow. A definition of primary and secondary constraints, The stabilizing structures of the elbow that resist valgus stress were studied with a tracking device in a model simulating active motion and muscle activity. By varying the order of serial release of the medial collateral ligament complex and removal of the radial head. each structure's contribution to valgus stability against the effect of gravity was determined. In the otherwise intact elbow. absence of the radial head does not significantly alter the three-dimensional characteristics of motion in the elbow joint. Isolated medial collateral release. on the other hand. causes increases in abduction rotation of about 6 degrees-8 degrees in magnitude. Releasing both structures results in gross abduction laxity and elbow subluxation. This study defines the medial collateral ligament (MCL) as the primary constraint of the elbow joint to valgus stress and the radial head as a secondary constraint. This definition facilitates the proper management of patients with radial head fractures and MCL disruption. The comminuted radial head fracture uncomplicated by MCL insufficiency should be treated by excision without the need for an implant and without concern of altering the normal kinematics of the elbow.
"Ratchet-type" marginal fracture of the radial head with locked anterior dislocation. A case report, Locked anterior dislocation of the superior radioulnar joint occurred in a 26-year-old man. The configuration of the associated radial head fracture maintained the locked position and predisposed to recurrence after open reduction. Radial head excision was necessary to resolve the problem. Both medial ligament repair and a radial head prosthesis were necessary to stabilize the elbow.
Ulnar nerve decompression with medial epicondylectomy for neuropathy at the elbow, Ulnar nerve decompression with medial epicondylectomy was performed in 66 elbows between 1966 and 1986 for compressive ulnar neuropathy at the elbow. This study is an updated review that adds 36 cases to a previously published report on 30 cases. These elbows were graded preoperatively and postoperatively using McGowan's grading system. Eighty-three percent improved one or two grades. and 11% improved subjectively although they showed no objective improvement. 3% noted no change. and 3% were subjectively worse. One early case sustained damage to the ulnar collateral ligament with resultant instability. No other complications occurred. The best results were seen in the Grade I and II lesions. whereas those with Grade III lesions were the least predictable. The procedure is technically uncomplicated with minimal morbidity and reliable results.
Magnetic resonance imaging in acetabular residual dysplasia, Eighteen hips in 15 children showed persistent roentgenographic evidence of congenital acetabular residual dysplasia at four- to eight-year follow-up evaluations. The mean follow-up period was 5.8 years. These hips were subsequently evaluated by magnetic resonance (MR) imaging. MR imaging studies revealed thick unossified chondroepiphyseal cartilage of the acetabular roof adjoining the ilium in all hips. The cartilage in these hips counterbalanced the steep acetabular slope seen on roentgenograms. Initially these hips were regarded as candidates for an acetabular reconstruction. but 11 hips displayed sufficient cartilaginous acetabular coverage on MR images. MR imaging promotes more accurate selection of patients for acetabular reconstruction and aids in the choice of the most appropriate type of acetabular reconstruction.
Traumatic dislocation of the hip, Of 125 patients with traumatic dislocation of the hips treated. 96 were reviewed retrospectively; 80 were males and 16 females with an age range from seven to 81 years (mean. 33.5 years). Motorcycle accidents were the leading cause of traumatic dislocation in this series (40 cases. 42%). Associated injuries were found in 68 cases (70.8%). Seventy-seven hips (80%) were reduced within 24 hours. In follow-up periods ranging from 15 months to 18 years (mean. 7.5 years). 56 patients had excellent or good results (58.3%). Statistical analysis of the clinical results showed that those patients with simple dislocations had better functional recovery. The earlier the reduction. the better the results. Associated injuries affected prognoses. Good results were obtained in patients with early. stable. and accurate reductions by either closed or open methods.
Intraosseous lipoma within the femoral head. A case report, Intraosseous lipoma occurring within the femoral head seems not to have been previously reported. Symptoms associated with the tumor included slowly increasing pain and a cystic lesion shown on roentgenograms. Management was by total hip arthroplasty. Pathologic examination of the specimen showed that the tumor was composed almost entirely of mature adipose tissue in keeping with a diagnosis of Stage 1 intraosseous lipoma. A sclerotic border and osteoid seams were noted. two features that seem not to have been previously reported in early lesions. Recent papers suggest intraosseous lipomas are more common than previously thought. and the femur now accounts for 25% of reported cases.
Epidemiologic aspects of rheumatoid arthritis. Current immunogenetic approach, Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology. Pathologically. RA is characterized by a destructive synovitis in multiple diarthrodial joints and immunologically by the presence in serum and joint fluid of autoantibodies to IgG (rheumatoid factor). The diagnosis remains a clinical one and. as such. RA investigations use epidemiologic methodologies. It is now clear that there is an important genetic contribution to the etiology of RA evidenced by the association of the disease with HLA-DR4. an allele of the major histocompatibility complex located on the short arm of chromosome six. HLA associations with RA occur in several different populations. This genetic epidemiologic approach substantiates the HLA association with disease and lays the foundation for recent molecular genetic discoveries that are reviewed. particularly the MHC structure and function.
Angular remodeling of midshaft forearm fractures in children, Thirty-six children treated for angulated midshaft forearm fractures were roentgenographically reexamined after a median time of four years (range. two to 5.8 years). The angulation of the fractures and epiphyseal plates was measured at the time of healing and at the follow-up examination. In children younger than 11 years of age. there was a significant correlation between fracture correction and change in epiphyseal plate angulation. with the highest degree of correction being 13 degrees. In children older than 11 years. no correlation was found. and the degree of fracture correction was unpredictable. The study points to an important influence of the epiphyseal plate on fracture remodeling. which decreases in late childhood.
Congenital pseudarthrosis of the forearm and fibula. A case report, Congenital pseudoarthrosis of the ulna and contralateral fibula occurred in a seven-year-old boy. Multiple limb involvement is extremely rare and has only been reported involving the tibia and fibula. Congenital pseudarthrosis of the tibia is a well-known entity. with other bones affected much more rarely. A case is reported involving the ulna and the contralateral fibula. This appears to be the first case of congenital pseudarthrosis reported involving an upper and a lower limb.
Healing of a large nonossifying fibroma after grafting with bone matrix and marrow. A case report, Healing of a large tibial nonossifying fibroma in a 12-year-old girl occurred following excision. curettage. and filling of the bony defect with human demineralized bone matrix powder mixed with a small quantity of the patient's bone marrow. The use of this graft composite was successful in the treatment of the lesion and reduced the potential risk and morbidity associated with pediatric orthopedic surgical procedures with autogeneic iliac crest and other bone grafts.
The role of the neutrophil in rheumatoid arthritis, Neutrophils acquire lysosomal granules and assembly systems for producing soluble mediators of inflammation during the process of maturation in the bone marrow. Subsequently. they emigrate from the circulation when they become attracted to joint spaces of rheumatoid arthritis patients by chemoattractants such as the complement split product. C5a. and leukotriene B4. Exposure to immune complexes. rheumatoid factor. and cytokines in the synovial fluid results in neutrophil activation with release of granule contents. toxic oxygen metabolites. and proinflammatory products of the arachidonic acid cascade. This process is analogous to a local Arthus reaction in which activation of the complement system is a central event. Some of the inflammatory materials released by this reaction contribute to the cartilage destruction seen in rheumatoid arthritis. Because others are chemoattractants themselves. they perpetuate intraarticular inflammation and permit the predominance of acute inflammatory cells in lesions maintained by chronic inflammation.
Diagnosis of rheumatoid arthritis. Medical and laboratory aspects, The diagnosis of rheumatoid arthritis (RA) is largely dependent on the existence of a characteristic pattern of clinical symptoms and signs that must be present for at least six weeks. Early morning joint stiffness and symmetric polyarticular inflammation. particularly in the metacarpophalangeal. proximal interphalangeal. wrist. and metatarsophalangeal joints. are typical of the disease. Extraarticular disease. including rheumatoid nodules. is usually associated with severe and well-established arthritis. and occular. pulmonary. cardiac. neurologic. and vasculitic involvement can be a considerable source of morbidity. Serologic testing for rheumatoid factor (RF) is helpful in confirming the diagnosis since 80% of patients are seropositive. but RFs are expressed in many other disease states. Expression of multiple RF isotypes differentiates RA from other populations. Erythrocyte sedimentation rates. C-reactive protein levels. circulating immune complexes. and platelet counts are often elevated in RA and serve as indicators of disease activity.
Advances in imaging of rheumatoid arthritis, Several new imaging modalities have been found useful in clinical evaluation of patients with rheumatoid arthritis (RA). Magnetic resonance (MR) imaging has proven to be an excellent noninvasive method to evaluate the spine. shoulder. hip. and knees; its use for the evaluation of smaller joints is still being investigated. In patients with RA. MR imaging has been used to evaluate cervical spine instability. rotator cuff tear. osteonecrosis. and osteomyelitis. Patients with RA may have advanced osteoporosis. predisposing to insufficiency fractures. This includes fractures associated with increased activity after hip or knee arthroplasty. Newer methods for measuring the degree of osteoporosis include single photon absorptiometry. dual photon absorptiometry. quantitative computed tomography (CT). and dual-energy projection radiography. It has not yet been determined which of these methods will be most widely used in the future. but quantitative CT and dual-energy projection radiography currently show the most promise. Ultrasonography provides an excellent noninvasive method for the diagnosis of popliteal cysts. and color Doppler sonography can differentiate cyst and popliteal aneurysm. As compared to radiography or conventional CT. high-resolution CT provides an improved method to detect the early changes of RA in the lung parenchyma.
Current medicinal approaches to the treatment of rheumatoid arthritis, Aspirin. nonacetylated salicylates. and numerous other nonsteroidal antiinflammatory drugs (NSAIDs) are used in rheumatoid arthritis (RA) patients to decrease joint inflammation and improve function. The choice of medication and its optimum dosage must be individualized because of marked intersubject variations in drug metabolism. excretion. antiinflammatory and analgesic efficacy. and susceptibility to adverse effects. Equivalent doses of aspirin and of nonacetylated salicylates are equally antiinflammatory in RA. although the nonacetylated salicylate is a poor inhibitor of prostaglandin synthesis. Chronopharmacology studies suggest that many patients may have better efficacy and fewer side effects with evening doses than with morning doses of certain NSAIDs; however. the optimum time must be individualized by trial and error because some patients do better with other regimens. The gastric. renal. and platelet adverse effects of NSAIDs are related to their inhibition of prostaglandin synthesis. and tend to be related to dose and intensity of therapy. Various strategies can minimize the impact of these side effects. such as coadministration of gastric protectants or the use of short half-life NSAIDs to decrease the duration of preoperative NSAID withdrawal needed to ensure adequate platelet coagulation during surgery. An intramuscular analgesic NSAID is now available and is reported to be equivalent to morphine sulfate in some painful postsurgical conditions. Although associated with many problems. chronic corticosteroid therapy is. or has been. a major therapeutic component for many RA patients who consequently are unable to respond adequately to the stresses of general anesthesia and surgery because of complete or partial adrenal insufficiency. These patients must be given appropriate supplemental corticosteroid therapy perioperatively.
Growth hormone deficiency in children has psychological and educational co-morbidity, Growth delay caused by growth hormone deficiency (GHD) is a condition presented with increased frequency to pediatricians. Recent evidence suggests these patients should be evaluated developmentally for behavioral and educational problems. Such assessment would assure a comprehensive approach to treatment and increase the likelihood of a satisfactory outcome in young adulthood. This article briefly reviews what is known about the behavioral and educational difficulties experienced by growth hormone deficient patients. Specific recommendations for educational assessment and anticipatory guidance are presented.
Klinefelter syndrome: the need for early identification and treatment, A 14-year-old boy presented with severe academic difficulties. emotional disturbance. borderline mental retardation. tall stature. delayed sexual development. small testes. and gynecomastia. Chromosomal analysis revealed an additional X chromosome compatible with the diagnosis of 47. XXY Klinefelter Syndrome. This case retrospectively follows the progression of learning and behavioral problems occurring in the primary grades prior to the diagnosis of Klinefelter Syndrome and reports the effects of psychiatric treatment. modified educational placement. testosterone supplementation. and corrective surgery in adolescence. The early identification of Klinefelter Syndrome is vital to the XXY male in that many of the developmental. behavioral and emotional problems associated with an additional X chromosome are amenable to treatment.
Neonatology in the 1990's: surfactant replacement therapy becomes a reality, It has been more than 35 years since the lung was discovered to be lined with a layer of surface-active material that is important in lung stability and mechanics of respiration. The absence of this "anti-atelectasis" factor was proposed by Avery and Mead in 1959 to be the cause of hyaline membrane disease of premature infants. An indepth historical review of pulmonary surfactant by Tierney was recently published. In the years since 1959. there has been an exhaustive amount of research aimed at elucidating the structure and function of pulmonary surfactant. the ultimate goal being a safe and effective exogenous surfactant for the treatment of the Respiratory Distress Syndrome (RDS). The days of surfactant research are far from over. but the era of surfactant replacement therapy is now upon us. The practitioner needs to be knowledgeable about surfactant and aware of his or her role in surfactant therapy for premature infants. The following is intended to clarify some of the important issue of surfactant replacement.
Creatine kinase MB elevation in paralytic shellfish poisoning, An outbreak of paralytic shellfish poisoning occurred in southern Taiwan. affecting 116 persons who had consumed purple clams. Two victims died within four hours. Gonyautoxins were identified as causative toxins. During the outbreak. five patients with paralytic shellfish poisoning were seen in our hospital. All recovered following supportive treatments. Serum creatine kinase concentration was elevated in three of the five patients. The levels of the enzyme did not seem to correlate with the severity of poisoning. The most significant finding was the previously unreported observation of elevation of the creatine kinase MB level. In all four patients who had creatine kinase MB value determined. it was elevated.
PEEP and "reverse mismatch". A case where less PEEP is best, A V/Q lung scan was obtained in a patient with LLL collapse who was receiving IPPV and PEEP. This revealed absent ventilation and hyperperfusion to the collapsed lobe. After a reduction in PEEP from 12 to 5 cm H2O. a repeat V/Q scan showed a more even distribution of pulmonary perfusion. Arterial hypoxemia improved.
Failure of long-term digitalization to prevent rapid ventricular response in patients with paroxysmal atrial fibrillation, Digitalis is frequently prescribed to patients with paroxysmal atrial fibrillation to reduce the ventricular rate during subsequent paroxysms. To verify the validity of this assumption. we determined the ventricular rate during paroxysmal atrial fibrillation in 13 patients receiving long-term digoxin therapy (mean plasma digoxin level + 1.28 +/- 0.4 ng/ml) and compared it with that of a group of 14 patients who had not taken digoxin or beta-adrenergic and calcium-blocking agents before the attack. The treated and the untreated groups were similar statistically. The mean ventricular rate of the digitalized patients was 121 +/- 15 beats per minute. while that of the patients in the control group was 118 +/- 16 beats per minute. It is concluded that long-term digoxin therapy is not effective in reducing the ventricular response in patients with paroxysmal atrial fibrillation despite adequate therapeutic levels.
Dilated cardiomyopathy complicated by a pedunculated and mobile left ventricular thrombus on ruptured false tendons, A 68-year-old man was admitted with congestive heart failure. He was treated with diuretics and digitalis; thereafter. the two-dimensional echocardiogram suggested a pedunculated and mobile left ventricular thrombus. He underwent surgical thrombectomy because of the high risk of systemic embolization. To our knowledge. this is the first case of dilated cardiomyopathy with a mobile left ventricular thrombus that was attached to ruptured false tendons.
Proximal aortic dissection with cardiac tamponade. Long-term survival without surgery, Proximal aortic dissection in a 79-year-old woman was complicated by cardiac tamponade. aortic regurgitation. and pleural leak. Following pericardiocentesis and control of her hypertension. she survived without an operation for more than four years.
Primary malignant fibrous histiocytoma of the aorta associated with aortic dissection, We report a unique case of primary aortic malignant fibrous histiocytoma presenting clinically as aortic dissection. To our knowledge. this occurrence is the first ever reported. The magnetic resonance imaging technique may provide superiority in the differential diagnosis between tumor and hematoma of aortic dissection. Aortic tumor. although rare. should be included among the causes of aortic dissection.
Benefits of a multidisciplinary pulmonary rehabilitation program. Improvements are independent of lung function, We evaluated the conditions of 33 patients who completed an outpatient pulmonary rehabilitation program to determine what types of improvements occurred. and whether these changes were related to the baseline degree of ventilatory impairment. to determine whether rehabilitation was beneficial to patients. regardless of the degree of underlying lung dysfunction. Endurance measurements. including sustained submaximal performance on a cycle ergometer and the 12-minute walk distance (1.349 +/- 625 feet to 1.700 +/- 670 feet) increased significantly (p less than 0.01). as did multiple educational and subjective parameters. Maximal exercise performance on a graded cycle test improved very little. with a decline in the ventilatory equivalent for oxygen consumption (VE/VO2) being the only significant change (48.2 +/- 28.3 L/ml to 36.6 +/- 8.7 L/ml). Of the observed changes. only one endurance measurement. the sustained submaximal exercise performance. correlated with FEV1 (r = 0.5. p less than 0.01). but only if it was expressed as an absolute number (liters) and not as percent predicted. Lung function did not correlate with changes in the 12-minute walk distance. in maximal exercise performance on the cycle ergometer or with changes in educational and subjective parameters. We conclude that because the magnitude of change in both physiologic and psychologic parameters was not directly related to lung function. the benefits of rehabilitation can extend to all patients with chronic lung disease. regardless of the severity of preexisting pulmonary dysfunction.
Predictors of improvement in the 12-minute walking distance following a six-week outpatient pulmonary rehabilitation program, We evaluated the relationship of clinical characteristics. pulmonary function. and exercise test data to the degree of improvement in the 12-minute walking distance (12MD) in 50 ambulatory outpatients completing a six-week pulmonary rehabilitation program. The 12MD increased by 27.7 +/- 32.5 percent. or 462 +/- 427 ft. by the end of the program. There were no significant relationships between improvement in the 12MD and age. sex. oxygen requirement. arterial blood gas levels. and pulmonary function; however. patients with a greater ventilatory reserve (1-[VEmax/MVV] x 100) had more improvement in their 12MD. both with respect to distance and percentage of increase over baseline. Additionally. patients with a lower peak oxygen consumption (VO2) and peak oxygen pulse (O2P) showed greater percentage of improvement in their 12MD. The magnitude of the initial 12MD was inversely related to its improvement. both with regard to distance (r = -0.43; r2 = 0.18; p less than 0.003) and percentage of increase (r = -0.71; r2 = 0.51; p less than 0.0001). Using stepwise regression. the combination of smaller initial 12MD and greater FEV1 was significantly predictive of improvement in the 12MD. Patients with poor performance on either a 12MD or maximal exercise test are not necessarily poor candidates for a pulmonary rehabilitation program.
Diagnostic, morphologic, and histopathologic correlates in bronchogenic carcinoma. A review of 1,045 bronchoscopic examinations, Information on the correlation between bronchoscopically visible aspects. histopathologic classification. and diagnostic yield is very scarce. To contribute to the knowledge of the subject. we reviewed the bronchoscopic charts of 1.045 patients with lung cancer who were seen in the years from 1983 to 1989 at the Bronchology Service of the A. Carle Hospital. Tumors were more often located centrally and superiorly. No preference as to side was found. Squamous carcinomas were. by far. the most frequent cell type. Forceps biopsies. brushings. and washings were positive in 79 percent. 38 percent. and 32 percent of the obtained specimens. respectively. Bronchoscopically. squamous and small-cell carcinomas were more often visualized as central tumor-like lesions. which were better diagnosed by forceps biopsies. Adenocarcinomas. on the contrary. were more frequently peripheral and showed infiltrative. compressive. or aspecific findings. In these latter tumors. cytologic studies were more fruitful. Large-cell anaplastic carcinomas had an intermediate behavior. Cell type. endoscopic appearance. and diagnostic success are interrelated features. Visible characteristics at bronchoscopy can therefore anticipate the more likely histotype and guide the diagnostic approach.
Medication adherence patterns in chronic obstructive pulmonary disease, While medical treatment of COPD has advanced. the failure to adhere to regimens for medication poses a significant barrier to effective management. Furthermore. no data are available regarding adherence for patients within the United States. Data from this investigation indicate that 78 outpatients from a medical center in the southeastern region of the United States were prescribed an average of 6.26 medications with both various dosing schedules and different modes of administration. Adherence was poor. with 42 patients (54 percent) underutilizing medications. 39 patients (50 percent) overutilizing medications during periods of respiratory distress. and 24 patients (31 percent) employing ineffective inhaler dosing techniques. Prescription patterns and adherence were not associated with demographic variables; however. adherence was related to classes of medication and situational variables.
The effect of nightly nasal CPAP treatment on underlying obstructive sleep apnea and pharyngeal size, Nasal continuous positive airway pressure (CPAP) is an effective treatment for obstructive sleep apnea (OSA). It is usually prescribed for nightly use; however. recent studies show that patients often do not wear the appliance consistently. Previous studies have also suggested that nasal CPAP may improve a patient's underlying OSA even when the mask is not in place. We investigated 12 men with OSA to see if nasal CPAP used nightly for six weeks would improve their underlying sleep-disordered breathing. We also studied pharyngeal volumes measured using magnetic resonance imaging and a computer-controlled digitizing pad. Patients with more severe OSA had improvement after six weeks; however. they still demonstrated significant OSA. Patients with less severe OSA did not have significant change. We were unable to show a significant difference in any patient's awake pharyngeal volumes. We conclude that patients with OSA should be encouraged to wear their nasal CPAP machines regularly.
Analysis of referrals for lung transplantation. The Washington University Lung Transplantation Group, In the first year of our lung transplantation program. 211 patients with end-stage pulmonary disease were referred for consideration. Over 50 percent of the patients had chronic obstructive pulmonary disease. and almost 20 percent had idiopathic pulmonary fibrosis. The referrals were screened according to predefined criteria of eligibility for single and double lung transplantation. After screening. 46 of the referred patients were admitted for an extensive inpatient evaluation. and 18 of these were accepted as candidates for transplantation. Although interest in lung transplantation is growing in both the medical and lay communities. a significant number of patients with endstage pulmonary disease were ineligible by our current criteria. As experience with these procedures is gained. criteria for selection may become less restrictive. and more patients may be candidates for transplantation.
Effects of PAF antagonist, BN52021, on the PAF-, methacholine-, and allergen-induced bronchoconstriction in asthmatic children, Platelet-activating factor (PAF) is an inflammatory mediator capable of inducing protracted inflammation of the airways and bronchial hyperreactivity. Twenty-one asthmatic children were evenly divided into three groups and each group performed a double-blind. placebo-controlled and crossover study on the effect of aerosolized BN52021. a PAF antagonist. on the bronchoconstriction induced by PAF. methacholine. or specific allergen. respectively. One group of healthy children was included for comparison. Total WBC. neutrophils. and eosinophils were counted before and after PAF challenge. The results showed the following: (1) six of seven asthmatics and one of seven normal subjects gave a positive bronchial provocation with PAF; (2) in asthmatics. prior inhalation of BN52021 could inhibit the bronchoconstriction induced by PAF (6/6) and allergen (3/7). but not by methacholine; and (3) 5 min after inhalation of PAF. there was a marked decrease of peripheral blood eosinophils and neutrophils that could be inhibited by prior inhalation of BN52021 in normal subjects but not in asthmatics. These findings support the idea that PAF may be involved in the pathogenesis of bronchial asthma and PAF antagonist may have a role in the prevention and treatment of this disease.
Is sick sinus syndrome an adenosine-mediated disease? Effects of intravenous aminophylline on sick sinus node function after pharmacologic autonomic blockade, To assess the effects of intravenous aminophylline on the sinus node. 12 patients with clinical and Holter monitor-documented sick sinus syndrome were studied (1) during the control state. (2) after pharmacologic autonomic blockade and (3) 5 min after intravenous administration of aminophylline. The effects of aminophylline on sinus node function were compared with those after pharmacologic autonomic blockade. No significant improvement of sinus node function was found after intravenous aminophylline administration with a mean sinus cycle length and a mean maximum CSRT of 968 +/- 218 and 1832 +/- 1036 ms. respectively. The mean serum theophylline level was 10.9 +/- 1.7 micrograms/ml. Since aminophylline is an adenosine receptor antagonist. these findings suggest that intrinsic adenosine may not play an important role in pathogenesis in patients with chronic and advanced sick sinus syndrome.
Ventricular free-wall rupture after myocardial infarction. Treatment and outcome, Ventricular free-wall rupture remains one of the leading causes of death after myocardial infarction (MI). With increased abilities for diagnosis and resuscitation techniques. surgical correction of free-wall myocardial defects resulting from ischemia and necrosis may become a simple modality of treatment. resulting in improvement of the survival rate. We are reporting our experience with four patients with ventricular free-wall rupture after MI. with emphasis on clinical presentation. diagnosis. and surgical management.
A multivariate analysis of the risk of pulmonary complications after laparotomy, We evaluated the relationship between PPC and various putative risk factors in a prospective longitudinal study of 1.000 patients undergoing abdominal surgery. Transient subclinical events were excluded by defining PPC as positive clinical findings in combination with either positive sputum microbiology. unexplained pyrexia. or positive chest roentgenographic findings. The overall incidence of PPC was 23.2 percent (232/1.000). Multivariate analysis identified seven factors which were associated with PPC: ASA classification greater than 2. upper abdominal surgery. residual intraperitoneal sepsis. age greater than 59 years. BMI greater than 25. preoperative hospital stay greater than 4 days. and colorectal or gastroduodenal surgery (overall F score = 33.5. p less than 0.0001). The ASA classification was the most powerful indicator of risk in both the univariate and the multivariate analyses. The combination of ASA classification greater than 1 and age greater than 59 years identified 88 percent (205 of 232) of the patients who developed PPC. These findings provide clinicians and clinical investigators with a simple means of identifying patients who are at high risk of PPC after abdominal surgery.
Increased airways responsiveness in swine farmers, A respiratory questionnaire. pulmonary function tests. and an examination of airways responsiveness were conducted on 20 swine farmers and 20 control subjects. The swine farmers represented almost the complete work force from 13 Hutterite colonies and had worked in confinement buildings with more than 2.000 swine (3.270 +/- 1.221 swine) for at least four hours (6.6 +/- 1.8 hours) per day for more than two years (10.5 +/- 7.5 years). The control subjects were randomly selected from outdoor city workers from the city of Saskatoon and were matched for gender. age (+/- 2 years). and smoking status. Eleven swine farmers (55 percent) had chronic cough. compared with three (15 percent) of the control subjects (p less than 0.01). Eight (40 percent) of the swine farmers had symptoms of wheezing. compared with three (15 percent) of the control subjects (p less than 0.05). The FEV1 was significantly lower in swine farmers (97.2 +/- 11.5 percent predicted) than in control subjects (106.0 +/- 12.0 percent of predicted) (p less than 0.05). Airways responsiveness was measured by methacholine challenge with doubling concentrations ranging from 0.25 to 256 mg/ml. The provocation concentrations resulting in a reduction of 10 percent (PC10) and 20 percent (PC20) in FEV1 were lower in swine farmers than in control subjects (PC10. 77.2 +/- 78.8 mg/ml vs 180.8 +/- 96.5 mg/ml; p less than 0.01; and PC20. 154.5 +/- 99.9 mg/ml vs 229.6 +/- 66.8 mg/ml; p less than 0.05). Twelve swine farmers (60 percent) had PC20 of less than 256 mg/ml. compared with three (15 percent) of the control workers (p less than 0.01). Fewer swine farmers demonstrated atopy as measured by skin prick tests than did control workers (21 percent vs 56 percent; p less than 0.05). These findings suggested that occupational exposure in swine confinement buildings is associated with mild increases of nonspecific. nonatopic airways responsiveness in swine farmers.
Blood lactate levels are superior to oxygen-derived variables in predicting outcome in human septic shock, Recent reports have shown that oxygen delivery (Do2) and oxygen uptake (Vo2) could be related to outcome of critically ill patients. In this study. we examined measurements of cardiac output. oxygen-derived variables. and blood lactate levels in 48 patients with documented septic shock. There were 27 survivors and 21 nonsurvivors from the shock episode. For all 174 observations. there was a significant linear relationship between Vo2 and Do2 (Vo2 = 79 + 0.17 x Do2. r = 0.64. p less than 0.001). There were no significant differences in Do2 between survivors and nonsurvivors at the onset of septic shock (mean +/- SD. 540 +/- 219 vs 484 +/- 222 ml/min.m2. NS) or in the final phase of septic shock (506 +/- 163 vs 443 +/- 187 ml/min.m2. NS). Also. no significant differences were found in Vo2 and oxygen extraction between survivors and nonsurvivors. However. survivors had significantly lower blood lactate levels both initially (5.1 +/- 2.7 vs 8.2 +/- 5.4 mmol/L. p less than 0.05) and in the final phase of septic shock (2.6 +/- 1.9 vs 7.7 +/- 5.6 mmol/L. p less than 0.001). Only the survivors had a significant decrease in blood lactate levels during the course of septic shock (p less than 0.001). We conclude that the oxygen-derived variables. Do2 and Vo2. cannot be used as prognostic indicators in human septic shock. In contrast. blood lactate levels are closely related to ultimate survival from septic shock. Furthermore. decreases in blood lactate levels during the course of septic shock could indicate a favorable outcome. Therefore. blood lactate levels can serve as a reliable clinical guide to therapy.
Great vein and right atrial thrombosis in critically ill infants and children with central venous lines, We performed a retrospective review of echocardiographic data files of infants and children hospitalized in the Newborn and Pediatric Intensive Care Units. Echocardiograms were examined to detect the presence and evolution of great vein and right atrial thrombosis in patients with central venous lines. Thirty-seven patients were identified over a five-year period. Echocardiograms were performed. not routinely. but in response to specific indications including catheter malfunction. thrombocytopenia. persistent chylothorax. bacterial or fungal sepsis. and superior vena cava syndrome. Fifteen of 37 patients died. 13 of them during the hospitalization in which the thrombus was discovered. Thrombolytic agents and surgery were used to treat selected patients. with mixed results. Two of the 22 survivors have significant disability related to the thrombus or complications arising from it. We conclude that great vein and/or right atrial thrombosis is a common complication of central venous catheterization in small infants and children; moreover. the morbidity and mortality relating to this complication is substantial.
Reversible cardiogenic shock due to chest tube compression of the right ventricle, A 62-year-old woman developed shock immediately after the insertion of a right-sided chest tube. A chest roentgenogram showed the chest tube to be overlying the heart and possibly compressing the right ventricle. An animal model was developed to replicate this clinical situation. Using a domestic goat model pulmonary artery. peripheral arterial catheters were inserted along with a right sided chest tube placed to suction. A second chest tube guided by a flexible fiberoptic bronchoscope placed within its lumen was positioned between the right ventricle and the sternum of the animals. Thirteen paired measurements in three goats (average of 4.3 measurements per animal) of cardiac output. heart rate. and mean arterial blood pressure were made at baseline and after chest tube placement over the right ventricle. The data were analyzed using a paired t test statistic. Compared with baseline measurements. there was a significant decrease in cardiac output (p less than 0.001) and mean arterial pressure (p less than 0.001) as well as an increase in heart rate (p = 0.0056) after placement of the chest tube across the right ventricle. We conclude that a misplaced chest tube compressing the right ventricle can impede cardiac output and lead to a low cardiac output state. Physicians inserting chest tubes in patients should be aware of this potential complication as it is easily treated by withdrawal of the chest tube.
Laboratory parameters to monitor safety and efficacy during thrombolytic therapy, Thrombolytic therapy is being used with increasing frequency in myocardial infarction (MI). pulmonary embolism. deep venous thrombosis (DVT). and peripheral arterial occlusion. Use of these agents. however. is hampered by concerns regarding safety and efficacy. Numerous laboratory parameters have been evaluated for monitoring the risk of bleeding complications. with levels of fibrinogen (and percentage of decrease) and fibrin/fibrinogen degradation products (FDPs) correlating to a variable extent with clinical bleeding. The bleeding time (BT) test has also been proposed as a potential predictor of bleeding during thrombolytic therapy. With respect to efficacy. the D-dimer fragment of FDPs. when corrected for soluble fibrin polymers. has been shown to correlate with clot lysis in venous thromboembolism but not MI. The BT also is being considered as a marker of lysis in patients with DVT. Given the increasing concomitant use of antiplatelet agents during thrombolytic therapy. the BT. as an in vivo test of hemostasis and platelet function. has potential utility as a noninvasive. adjunctive marker of thrombolytic efficacy.
Thrombolysis in acute myocardial infarction, The 1980s has been a critical decade for the management of acute myocardial infarction (MI) because of the concentration in a very short time span of innovative results produced by a new generation of trials. in which thrombolysis has been the preeminent topic. The message coming from the results in the more than 50.000 patients included in the five key trials is simple and clear: thrombolysis. of any type. is the cornerstone of acute treatment of MI. and it works well to produce a very favorable epidemiologic picture. In the GISSI-2 trial. the nationwide adoption of a package of recommended treatments centered on thrombolysis for the overall population of patients with an acute MI has produced a relevant modification of the natural history of the disease. reducing the in-hospital mortality by about 40% in few years (from 13% to 8.8%). In particular. in the great majority of cases (patients aged less than 70 years in Killip class I with a first acute MI). the mortality has gone down to 3%. making a further reduction very hard to obtain with new drugs or strategies. In this context. we will discuss the concept of the relevance for clinical practice of obtaining even greater patency rates with new thrombolytic agents (hopefully more efficient and safe) or with new combinations of traditional agents.
Reperfusion adjunctive therapy, The beneficial effects of coronary thrombolytic therapy may be enhanced by certain adjunctive therapies. Some of these are of proven value. some appear to offer no benefit in spite of theoretical advantages. and some remain to be evaluated in clinical trials. Acetylsalicylic acid markedly enhances the mortality reduction of thrombolytic therapy and should be used routinely. There is a strong theoretical rationale for the use of heparin. but evidence for its benefit exists primarily in small angiographic trials. and convincing clinical benefit has not yet been demonstrated. Early intravenous beta-blockers were shown in the prethrombolysis era to confer modest benefit. but extensive data on their adjuvant use with thrombolysis are available from only one trial. Intravenous nitrates were demonstrated to reduce mortality in the prethrombolysis era. and are soon to be evaluated in trials employing thrombolytic therapy. The calcium channel blockers. in spite of a variety of theoretical benefits. have proved to be of no value acutely. and in the subacute setting. only diltiazem appears to confer benefit in the subgroup of patients with non-O-wave infarction. Angiotensin-converting enzyme inhibitors are likely to be of value in survivors of acute myocardial infarction with left ventricular dysfunction. and benefits observed with acute use in experimental infarction are now being evaluated in clinical trials.
Indications, timing, and optimal technique for diagnostic angiography and angioplasty in acute myocardial infarction, Emergency cardiac catheterization and coronary angioplasty for acute myocardial infarction (MI) have a continuing role in the thrombolytic era. Although thrombolytic therapy has revolutionized the treatment of MI. it has significant shortcomings: about 75% of patients with acute MI cannot be treated with thrombolytic agents. 25% of treated patients will have persistent occlusion of the infarct-related artery. 70% will have a residual stenosis greater than or equal to 70%. and 20% of treated patients will experience reocclusion. Cardiac catheterization identifies the coronary anatomy for mechanical revascularization and allows the unstable patient to receive special therapy. such as intra-aortic balloon pumping. Many large clinical studies have evaluated approaches to coronary angioplasty for acute MI. Deferred angioplasty has indisputable advantages over immediate routine angioplasty. Direct angioplasty without concomitant thrombolytic therapy has acceptable success and complication rates. so that it can be considered the treatment of choice for acute MI in centers with an angioplasty program if thrombolytic therapy is contraindicated. Patients at very low risk may not require cardiac catheterization routinely before discharge. since their good prognosis cannot be improved by invasive evaluation and intervention. Emergency surgical revascularization is indicated in a very small percentage of cases.
Principles of thrombolysis in pulmonary embolism, A canine model of pulmonary embolism. induced by injection of autologous radioactive blood clots. was used to investigate principles of thrombolysis in pulmonary embolism. One study compared recombinant tissue plasminogen activator (rtPA) with heparin in the treatment of pulmonary embolism. This study also compared the efficacy of rtPA (1 mg/kg) given over 15 min (rtPA15) to the same total dose infused over 90 min. Compared with heparin. both rtPA regimens induced marked pulmonary thrombolysis. During drug infusion. the rate of thrombolysis was increased 2-fold with rtPA15. A 2nd canine study investigated the physiologic mechanism of the decrease in pulmonary artery pressure with rtPA. The pattern of hemodynamic improvement with rtPA indicated that pulmonary thrombolysis predominantly occurred in partially. rather than totally. obstructed vascular units. A 3rd canine study compared rtPA and high-dose urokinase (UK) in treatment of pulmonary embolism. Both rtPA regimens were superior to UK in inducing pulmonary thrombolysis and improving pulmonary hemodynamics. Most recently. the effects of flow dynamics on rtPA-induced pulmonary thrombolysis were investigated. and it was demonstrated that an increase in cardiac output markedly enhanced rtPA-induced pulmonary thrombolysis. Most likely. the increase in cardiac output increased thrombolysis by enhancing delivery of rtPA to thrombus in partially obstructed vascular units.
Doppler ultrasound of the deep leg veins. A revolution in the diagnosis of deep vein thrombosis and monitoring of thrombolysis, The diagnosis of lower limb deep vein thrombosis can be made rapidly by compression ultrasound. This noninvasive test has almost completely replaced contrast phlebography in some major hospitals in North America. Compression ultrasound is well suited for making the diagnosis of deep vein thrombosis. measuring its extent. and monitoring the draining veins of the calf for evidence of spread of calf vein thrombosis. The nature of the deep vein thrombus. whether it is obstructing or nonobstructing. can be determined with the additional use of color Doppler mapping. a technique that displays flowing blood as a color overlay to the 2-dimensional real-time ultrasound image. Serial noninvasive determinations of the extent of thrombus in the lower-extremity deep veins is now possible with this combined sonographic imaging approach. Monitoring of possible changes in the extent of the thrombus burden can now be undertaken in patients enrolled in trials assessing the efficacy of different thrombolytic regimens.
Recent advances in the diagnosis and lytic therapy of pulmonary embolism, During the past year. there have been 2 major advances in the management of pulmonary embolism (PE). First. the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) investigators published the results of their comparison of ventilation-perfusion lung scanning and pulmonary angiography. This multimillion-dollar trial sponsored by the National Heart. Lung. and Blood Institute indicated that lung scanning is surprisingly insensitive to the diagnosis of PE. High-probability lung scanning detects fewer than half of the cases of PE that are found at pulmonary angiography. The PIOPED results force us to conclude that increased utilization of both ultrasonography of the deep leg veins and pulmonary angiography is warranted in order to detect the majority of cases of venous thromboembolism. Second. in June 1990. the Food and Drug Administration approved recombinant human tissue-type plasminogen activator (rt-PA) for use in the treatment of acute PE. The dosing regimen is 100 mg of rt-PA as a continuous peripheral intravenous infusion administered over 2 h. The convenience. rapid effect. and relative safety of this therapeutic approach may result in increased use of thrombolysis for management of PE.
The pharmacology of aspirin, heparin, coumarin, and thrombolytic agents. Implications for therapeutic use in cardiopulmonary disease, The modern treatment of cardiopulmonary disease is increasingly predicated on the goal of dissolving the offending clot to establish vascular patency as rapidly as possible and then preventing rethrombosis. The availability of thrombolytic agents has made this therapeutic approach possible and the adjunctive use of heparin. coumarin. and aspirin has increased the efficacy of lytic drugs. The administration of any of these medications is associated with inherent risks. which are enhanced when they are used concomitantly. An understanding of coagulation and an appreciation of the pathophysiologic processes of the thrombotic events occurring in cardiopulmonary disease states are critical to the formulation of innovative therapeutic regimens that maximize efficacy and safety. Furthermore. knowledge of the comparative pharmacology of the various thrombolytic agents is useful in explaining the benefits and complications observed in clinical trials.
Outpatient microsurgical reversal of tubal sterilization by a combined approach of laparoscopy and minilaparotomy, A prospective study of 17 cases of microsurgical reversal of tubal sterilization by a combined approach of laparoscopy and minilaparotomy was performed. Inclusion criteria included age less than 43; weight less than ideal body weight plus 20%; documentation of ovulation; 2 cm of proximal oviduct on hysterosalpingography; and a normal semen analysis or postcoital test. A comparison group of the 5 cases of sterilization reversal performed by a standard inpatient technique during the same period was analyzed. The study technique was performed on an outpatient basis in 15 of the 17 cases. 12 patients (71%) conceived 13 intrauterine pregnancies. one ectopic pregnancy occurred. and total patient costs and time until return to work were significantly less with the study versus standard technique.
Luteinizing hormone responses to gonadotropin-releasing hormone and naloxone in menstruating women with type I diabetes of different duration, Luteinizing hormone (LH) responses to gonadotropin-releasing hormone (GnRH) (100 micrograms injected intravenously (IV)) or naloxone (4 mg injected plus 8 mg infused in 2 hours IV) were evaluated in 29 women with insulin-dependent diabetes mellitus (IDDM) (duration. group I (n = 15): less than 10 years. range 3 to 9 years; group II (n = 14): greater than 10 years. range 11 to 20 years) and in 15 normal controls. on the 22nd days of normal menstrual cycles. Both GnRH- and naloxone-induced LH responses were similar in group I diabetics and normal controls. whereas they were significantly lower in group II than in group I diabetics or normal controls. Positive correlations were found between LH responses to GnRH and naloxone. whereas negative correlations were observed between maximal LH peaks in response to GnRH or naloxone and duration of diabetes. These data indicate that a hypothalamic pituitary disorder affects LH secretion with time after the onset of IDDM.
Treatment of hirsutism by an association of oral cyproterone acetate and transdermal 17 beta-estradiol, Twenty-four hirsute women were treated with an inversal sequential scheme of cyproterone acetate. 50 mg/d by oral route from the 1st to the 15th day of the menstrual cycle. along with 100 micrograms/24 h of 17 beta-estradiol transdermally administered from days 1 to 21. for nine cycles at weekly intervals. The acne and seborrhea as well as hirsutism showed a significant improvement in all subjects studied. The plasma testosterone and dehydroepiandrosterone sulfate decrease from 1.5 +/- 1.3 ng/mL and 6.9 +/- 1.3 micrograms/mL to 0.5 +/- 0.03 ng/mL and 2.7 +/- 1.7 micrograms/mL. respectively. Similar values were observed in subjects with idiopathic hirsutism during the treatment. The metabolic parameters. as well as the plasma levels of sex hormone-binding globulin. appeared unaffected by the therapy. Furthermore. the luteinizing hormone and follicle-stimulating hormone secretion was strongly inhibited from the first cycle of treatment. In conclusion. considering the good clinical results and the avoidance of any hepatic effect. this association should be taken into account in the treatment of hirsutism. especially in case of oral estrogen intolerance.
Conservative management of ectopic pregnancy: prospective randomized clinical trial of methotrexate versus prostaglandin sulprostone by combined transvaginal and systemic administration, In a prospective randomized study. 21 patients with an unruptured tubal pregnancy were treated with local and systemic injection. On the day of diagnosis. methotrexate (MTX) (1 mg/kg) or sulprostone (500 micrograms) were injected into the gestational sac under transvaginal sonographic control. The systemic component consisted of an intramuscular injection of MTX (1 mg/kg) 3. 5. and 7 days after local injection or of sulprostone (500 micrograms) on the 1st 2 postlocal injection days. Methotrexate therapy was successful in 8 of 12 patients and sulprostone therapy in 6 of 9. Laparoscopy was then performed on the 7 unsuccessful patients: 3 of them had pain and hemoperitoneum and 4 of them had rising human choriogonadotropin (hCG) levels. One stomatitis after MTX and one cramping abdominal pain were observed. Thirteen of 14 successfully treated patients had initial hCG levels less than 5.000 mIU/mL. At subsequent hysterosalpinography. 13 of 14 patients had normal tubal configuration and patency. Three of 10 patients who desired another pregnancy had already achieved a normal intrauterine pregnancy. These results suggest that MTX and sulprostone were equally effective. and medical approach for the unruptured ectopic pregnancy may be restricted to patients with hCG less than 5.000 mIU/mL.
The absence and effect of induced menopause by gonadotropin-releasing hormone analogs on lower urinary tract symptoms and urodynamic parameters, The clinical and urodynamic relationship between the onset of menopause and the appearance of lower urinary tract symptoms has been studied in 12 premenopausal urinary symptom-free patients in whom hypoestrogenism was induced by treatment with gonadotropin-releasing hormone analogs. No urodynamic changes in the cystometric. uroflowmetry. and urethral pressure profile measurements were found after 6 months of treatment. Clinically. only one patient had diurnal frequency after treatment. We conclude that estrogen deficiency in the absence of aging and other factors leading to urinary symptoms is probably of minimal significance as a cause of lower urinary tract disability in the immediate menopausal period.
Levels of cholesterol and phospholipids in freshly ejaculated sperm and Percoll-gradient-pelletted sperm from fertile and unexplained infertile men, Cholesterol and phospholipid levels were determined in individual sperm samples obtained from 20 fertile and 20 unexplained infertile men. The determination was performed on both washed freshly ejaculated sperm and Percoll-gradient-pelletted sperm. Although sperm cholesterol levels in unexplained infertile patients were significantly lower. i.e.. 10.6 +/- 1.3 (mean +/- SD) nmol/10(7) freshly ejaculated sperm and 5.4 +/- 0.7 nmol/10(7) Percoll-gradient-pelletted sperm as compared with 19.9 +/- 1.9 nmol/10(7) and 12.6 +/- 1.5 nmol/10(7) for corresponding sperm populations in fertile donors. Motility parameters measured in 10 sperm samples of the two groups of fertile and unexplained infertile men revealed increases in the amplitude of lateral head displacement and decreases in percent of straightness in sperm tracks from unexplained infertile men.
The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer, Our data demonstrate the high incidence of combined pregnancy among patients who have undergone IVF. Close monitoring of pregnancies in IVF programs may prevent a possibly deleterious delay in the treatment of simultaneous ectopic and intrauterine gestation.
Variation in sperm penetration assay related to viral illness, Semen specimens from a single pregnancy-proven fertile donor were evaluated in the SPA on a weekly basis over a 4-month period that included a febrile viral illness. This report documents the time course for recovery of decreased sperm density and decreased egg-penetrating ability of human sperm after a febrile viral illness. Observations from these data suggest that egg penetration ability monitored in the SPA is acquired in the testicle during early to midspermiogenesis. This finding contrasts with the more commonly held belief that fertilization capabilities are acquired during epididymal transit.
Role of oxidative stress in development of complications in diabetes, N epsilon-(carboxymethyl)lysine. N epsilon-(carboxymethyl)hydroxylysine. and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds. termed glycoxidation products. accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations. even in diabetic collagen. studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress. tissue damage. and cell death. leading to increased free radical production and compromised free radical inhibitory and scavenger systems. which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.
Metabolic effects of IGF-I in diabetic rats, Insulinlike growth factor I (IGF-I) stimulates glucose utilization (GU) in nondiabetic rats. We compared the effects of IGF-I and insulin on glucose metabolism in control (fed plasma glucose 7.7 +/- 0.1 mM. n = 30) and partially (90%) pancreatectomized diabetic (plasma glucose 18.4 +/- 0.8 mM. n = 30) awake unstressed rats. IGF-I was infused at 0.65 or 1.96 nmol.kg-1.min-1 and insulin at 22 or 29 pmol.kg-1.min-1 in combination with [3-3H]glucose while euglycemia was maintained by a variable glucose infusion. In controls. GU during the 0.65- and 1.96-nmol.kg-1.min-1 IGF-I infusions (127 +/- 7 and 168 +/- 4 mumol.kg-1.min-1. respectively) was similar to rates observed during the 22- and 29-pmol.kg-1.min-1 insulin infusions (121 +/- 2 and 156 +/- 5 mumol.kg-1.min-1). Whole-body glycolytic rate (3H2O generation) and muscle glycogen synthetic rate were identical during insulin and IGF-I infusions. In diabetic rats. GU was reduced by 30% versus control rats (P less than 0.01) during both the low-dose (88 +/- 7 vs. 121 +/- 7 mumol.kg-1.min-1) and higher-dose (109 +/- 4 vs. 156 +/- 5 mumol.kg-1.min-1) insulin clamps. The defect in insulin action involved both muscle glycogen synthesis and glycolysis. In diabetic rats. IGF-I elicited rates of GU similar to controls (115 +/- 10 and 164 +/- 12 mumol.kg-1.min-1 during the 0.65- and 1.96-nmol.kg-1.min-1 infusions. respectively) and corrected the intracellular defects in glycogen synthesis and glycolysis.
Maternal diabetes and retarded preimplantation development of mice, The streptozocin-induced diabetic (STZ-D) mouse was found to be a suitable model for studying the effects of maternal diabetes on the preimplantation embryo. This study looked at the effects of maternal diabetes on embryonic growth. Female Quakenbush mice were made diabetic (plasma glucose levels greater than 20 mM) by injection of 190 mg/kg i.p. STZ and were superovulated by standard methods. The blastocysts collected on day 4 from diabetic mothers had 8.5% fewer cells and a 35% lower protein synthetic rate than control embryos. Their cellular protein synthetic rate was 19% less than that in controls. Morulae from diabetic mothers also displayed a reduced protein synthetic rate. but this reduction was not seen in the two-cell embryo. Furthermore. blastocysts cultured in vitro from two-cell embryos from diabetic and control mothers displayed similar protein synthetic rates. This infers that the two-cell embryos from diabetic mothers are normal. and the retardation seen in later development in vivo occurs after the two-cell stage while the embryo is still free in the oviductal and uterine environment. Treatment of the diabetic mice with ultralente insulin every 12 h raised the protein synthetic rate of those blastocysts toward control levels. whereas treatment with lente insulin every 8 h recovered the embryo to the same rate as the control embryos. Because insulin has been shown to be mitogenic and stimulates protein synthesis of morulae and blastocysts in vitro. the absence of insulin in the diabetic mothers may be the cause of the retardation observed in their preimplantation embryos.
Effects of polyol-pathway inhibition and dietary myo-inositol on glomerular hemodynamic function in experimental diabetes mellitus in rats, Early functional disturbances in nerve. retina. and lens in diabetes mellitus appear to result from a common mechanism involving increased polyol-pathway activity with an associated effect on tissue myo-inositol metabolism. We tested the role of increased polyol-pathway activity in the early glomerular hemodynamic abnormalities in experimental diabetes in rats with dietary myo-inositol supplementation or the administration of sorbinil. an aldose reductase inhibitor. Each maneuver prevented the glomerular hyperfiltration of early streptozocin-induced diabetes and reversed the hyperfiltration of established diabetes of 10 days' duration. We also found that the abnormal response to captopril in diabetic rats was improved by dietary myo-inositol supplementation or sorbinil administration. Although nonhypotensive doses of captopril lowered glomerular filtration rate (GFR) in diabetic rats on a 0.01% myo-inositol diet. GFR increased substantially after captopril infusion in diabetic rats treated with sorbinil or myo-inositol supplementation. These data suggest that normalization of tissue myo-inositol metabolism restores normal responsiveness to angiotensin II; this may contribute to the reduction in GFR with the two experimental maneuvers. We also tested the interaction between polyol-pathway activation and high dietary protein intake. Aldose reductase inhibition and dietary myo-inositol supplementation had no effect on the component of increased GFR due to 50% dietary protein intake but specifically inhibited the hyperfiltration attributable to diabetes. These results suggest that hyperglycemia acts through increased polyol-pathway activity and its effects on tissue myo-inositol metabolism to play a fundamental role in the pathogenesis of the glomerular hyperfiltration characteristic of early diabetes.
Production of marked prolongation of islet xenograft survival (rat to mouse) by local release of mouse and rat antilymphocyte sera at transplant site, Polymer rods impregnated with lyophilized particles of mouse (M) or rat (R) antilymphocyte serum (ALS) were placed adjacent to rat islet xenografts transplanted beneath the kidney capsule of diabetic mice. Insertion of rods containing only MALS or RALS had no effect on the survival time of the rat islet xenografts. In contrast. the insertion of both MALS and RALS rods with the graft produced a marked prolongation of islet xenograft survival (mean survival time greater than 55.5 +/- 10.9 days) compared with controls (14.7 +/- 2.5 days). One recipient was still normoglycemic at 100 days. and removal of the graft returned the animal to a diabetic state. The islet graft had a normal degree of beta-granulation. and a slight fibrotic reaction was present around the rods. The effect of the rods in prolonging survival of the xenografts resulted from a local slow release of MALS and RALS. because implantation of the MALS and RALS rods in the right kidney and the islets in the left kidney had no effect on prolonging islet xenograft survival. These findings indicate that local immunosuppression produced marked prolongation of rat islet xenograft survival in mice. This raises the possibility of using polymer rods for the local slow release of monoclonal antibodies to lymphokines and other agents for prevention of rejection of islet allografts and xenografts and to determine the effect of lymphokines in vivo on islet function.
Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes, In early 1988. a colony of GK rats was started in Paris with progenitors issued from F35 of the original colony reported by Goto and Kakisaki. When studied longitudinally up to 8 mo. GK rats showed as early as 1 mo (weaning) significantly higher basal plasma glucose (9 mM) and insulin levels (doubled). altered glucose tolerance (intravenous glucose). and a very poor insulin secretory response to glucose in vivo compared with Wistar controls. Males and females were similarly affected. Studies of in vitro pancreatic function were carried out with the isolated perfused pancreas preparation. Compared with nondiabetic Wistar rats. GK rats at 2 mo showed a significantly increased basal insulin release. no insulin response to 16 mM glucose. and hyperresponse to 19 mM arginine. Pancreatic insulin stores were only 50% of that in Wistar rats. Perfusion of GK pancreases for 50 or 90 min with buffer containing no glucose partially improved the insulin response to 16 mM glucose and markedly diminished the response to 19 mM arginine. whereas the responses by Wistar pancreases were unchanged. These findings are similar to those reported in rats with non-insulin-dependent diabetes induced by neonatal streptozocin administration and support the concept that chronic elevation in plasma glucose may be responsible. at least in part. for the beta-cell desensitization to glucose in this model. The GK rat seems to be a valuable model for identifying the etiology of beta-cell desensitization to glucose.
Antidiabetic action of vanadyl in rats independent of in vivo insulin-receptor kinase activity, The effects of oral vanadyl sulfate administration for 9-12 days on carbohydrate and lipid metabolism in the basal state and on glucose dynamics during submaximal hyperinsulinemic clamps were investigated in nondiabetic and streptozocin-induced diabetic rats. Decreases in growth rate and water and food consumption were the only significant alterations noted in control animals receiving vanadyl. Administration of vanadyl to diabetic rats resulted in weight loss; a significant decrease in plasma glucose. triglyceride. and cholesterol levels; and decreases in food and water intake. without a concomitant change in plasma insulin concentrations. Vanadyl treatment did not modify either peripheral glucose utilization or hepatic glucose production in control rats during submaximal insulin clamps. In contrast. vanadyl therapy increased insulin-induced glucose utilization significantly and had a small but nonsignificant effect on insulin-mediated suppression of glucose production in diabetic rats. The tyrosine kinase activity of liver- and muscle-derived insulin receptors from diabetic rats that underwent clamp study. which reflected the in vivo phosphorylation state of insulin receptor. was not altered by vanadyl treatment. In conclusion. these results show that augmentation of peripheral glucose utilization is the major determinant of the antidiabetic action of vanadyl and support the notion that the action of vanadyl is independent of insulin-receptor kinase activity.
Effects of insulin and amino acids on leg protein turnover in IDDM patients, To determine whether the responses of muscle protein metabolism to insulin and amino acids in patients with insulin-dependent diabetes mellitus (IDDM) were different from those in nondiabetic subjects. leg tissue kinetics of [15N]phenylalanine and [1-13C]leucine and its metabolites were measured in eight insulin-withdrawn IDDM patients and eight nondiabetic subjects during basal insulinemia and during infusion of insulin (0.29 nmol.min-1.m-2). The diabetic patients were studied in the absence of amino acids. and both groups were studied during infusion of a mixed-amino acid solution (AA). In the diabetic patients. insulin alone and combined with additional AA reduced leg tissue phenylalanine release by 42 and 41%. respectively (both P less than 0.05). but uptake was unchanged. Leg tissue leucine oxidation was unchanged by insulin alone but was increased (P = 0.012) fourfold during insulin infusion with additional AA. In the nondiabetic subjects. insulin with AA infusion increased leg tissue phenylalanine uptake (45.7 +/- 7.5 to 73.1 +/- 7.3 nmol.min-1.100 g-1. P less than 0.01). Insulin-stimulated glucose uptake in the diabetic patients (1.60 +/- 0.28 mumol.min-1.100 g-1. P = 0.04). These results suggest that. in IDDM patients. 1) infusion of insulin fails to stimulate muscle protein synthesis even when combined with a substantially increased provision of AA. and 2) compared with nondiabetic subjects. muscle protein synthesis as well as glucose uptake exhibit blunted responses to insulin.
Higher insulin and C-peptide concentrations in Hispanic population at high risk for NIDDM. San Luis Valley Diabetes Study, Hyperinsulinemia has been demonstrated in Hispanics with normal glucose tolerance and in other populations at higher risk for non-insulin-dependent diabetes mellitus (NIDDM). We compared fasting and glucose-stimulated insulin and C-peptide levels in a community-based sample of 464 Hispanic and 676 non-Hispanic white adult residents of the San Luis Valley of Colorado. All subjects had normal glucose tolerance as confirmed by oral glucose tolerance testing interpreted with World Health Organization criteria. Mean fasting and 1- and 2-h post-glucose load insulin levels were significantly higher in Hispanics versus non-Hispanic whites (fasting 0.08 vs. 0.07 nM. P = 0.0026; 1 h 0.52 vs. 0.47 nM. P = 0.0129; 2 h 0.36 vs. 0.27 nM. P less than 0.0001). even after adjustment for age. sex. body mass index. waist-hip ratio. family history of diabetes mellitus. concurrent plasma glucose level. and fasting insulin level. Mean fasting and 1- and 2-h glucose-stimulated C-peptide levels in Hispanics also significantly exceeded those in non-Hispanic whites (fasting 0.58 vs. 0.54 nM. P = 0.0119; 1 h 2.72 vs. 2.46 nM. P less than 0.0001; 2 h 2.25 vs. 1.97 nM. P less than 0.0001). The C-peptide-insulin molar ratio was greater in non-Hispanic whites than Hispanics at all times measured. These findings confirm that Hispanics with normal glucose tolerance are hyperinsulinemic and that increased insulin secretion is at least partly responsible for this phenomenon. The lower levels of C-peptide compared with insulin in Hispanics suggest that the hyperinsulinemia seen in this ethnic group may be due in part to decreased hepatic insulin extraction.
Study in Tanzania of impaired glucose tolerance. Methodological myth, During a study of diabetes prevalence in six rural Tanzanian communities. a repeat oral glucose tolerance test (OGTT) was carried out in 514 subjects greater than or equal to 15 yr of age within 1 wk of an initial 75-g OGTT. In 498 subjects. blood glucose was measured 2 h after the glucose load on both occasions. and in 175 subjects. fasting blood glucose measurement was also repeated. Of the 498 subjects. 245 had normal glucose tolerance in the first test and were selected at random for further testing; 223 subjects had impaired glucose tolerance (IGT). and 30 had diabetic values. Diabetes and IGT were diagnosed on the basis of the 2-h blood glucose values. In the second test. 241 (98.4%) of the 245 subjects with normal tolerance continued in this category and 4 (1.6%) showed IGT. Of the 223 with IGT in the first test. 171 (76.2%) reverted to normal on the second test. 7 (3.1%) had diabetic values. and 45 (20.2%) persisted with IGT. Of the 30 subjects diagnosed as diabetic in the first test. 8 (26.7%) remained with diabetic values. 11 (36.7%) had IGT. and 11 (36.7%) were normal. Based on the second test. the population-prevalence rates of diabetes and IGT would have been 0.5 and 3.3% vs. 1 and 7.6% based on the first test. There was a significant downward trend in the mean 2-h blood glucose values in all three diagnostic groups. Regression toward the mean could not account for the downward shift in blood glucose values observed on retesting.
Managing geriatric arrhythmias, II: Drug selection and use [published erratum appears in Geriatrics 1991 Jun;46(6):100, Age-related impairments in antiarrhythmic drug distribution. metabolism. and excretion may result in accumulation of these potent drugs. increasing the risk of adverse drug reactions and drug interactions in the elderly. These risks are minimized by using modest initial dosage with slow dosage titration. Therapeutic drug monitoring is a method which employs antiarrhythmic concentration data and a determination of drug clearance in order to develop an optimal dosing regimen. The pharmacology. indications for use. and adverse effects of currently available antiarrhythmics are reviewed. Dosing guidelines for the geriatric population are provided.
Geriatric endocarditis: avoiding the trend toward mismanagement, The average age of patients with endocarditis is increasing. It is becoming a disease of the elderly. especially related to use of prosthetic heart valves and IV lines or catheters associated with bacteremias. Recognition is the major problem in the elderly patient since many features of the disorder are often attributed to aging. The diagnosis should be considered in the elderly patient with fever or other unexplained findings. Blood cultures are indicated to prevent misdiagnosis.
Orthotopic liver transplantation for patients with hepatitis B virus-related liver disease, Fifty-nine patients with prior hepatitis B virus infection underwent orthotopic liver transplantation. During the first 2 mo. mortality was not significantly different in the hepatitis B virus-infected group (25.5%) vs. a hepatitis B virus-immune control group (21%). Beyond 2 mo. the mortality. rate of graft loss. need for retransplantation and incidence of abnormal liver function were significantly higher in the hepatitis B virus-infected group. Treatment of the hepatitis B virus infection was attempted with passive immunization. combined active and passive immunization. alpha-interferon or nothing. The clinical outcome was not significantly influenced by any of these therapies. However. of the patients who lived more than 60 days. 6 of 22 treated with active plus passive immunization were cleared of HBsAg. something achieved once in 16 patients treated with alpha-interferon. never in 3 patients with passive immunization only and once in 4 patients with no therapy. In patients with recurrent hepatitis B virus infection. the pace of hepatitis development in the graft appeared to be accelerated. and this was particularly striking in patients who underwent multiple retransplantations at progressively shorter intervals. None of the patients who became HBsAg-negative had HBeAg preoperatively.
Expression of insulin-like growth factor II, alpha-fetoprotein and hepatitis B virus transcripts in human primary liver cancer, Insulin-like growth factor II is a fetal growth factor structurally and functionally related to insulin and insulin-like growth factor I. Its mRNA expression is developmentally regulated in human liver. the reexpression of insulin-like growth factor II fetal transcripts being often observed in primary liver cancer. Insulin-like growth factor II and alpha-fetoprotein mRNAs were studied in 16 human primary liver cancers. most of which were highly differentiated. Hepatitis B virus transcripts were also analyzed in the tumors from hepatitis B virus chronic carriers. alpha-Fetoprotein mRNA was detected in only four tumors and in one nontumorous cirrhotic tissue; all these samples also displayed insulin-like growth factor II fetal transcripts. Furthermore. fetal insulin-like growth factor II mRNAs were observed in five tumors and six nontumorous cirrhotic areas not expressing alpha-fetoprotein mRNA. The presence of hepatitis B virus RNA was only observed in tissues not expressing alpha-fetoprotein or fetal insulin-like growth factor II mRNA. In conclusion. fetal insulin-like growth factor II transcripts are more frequently observed than alpha-fetoprotein mRNA in highly differentiated liver cancers and in surrounding cirrhotic areas. The reexpression of fetal insulin-like growth factor II transcripts might then be a marker of early steps of liver cell transformation.
Incidence of parenchymal liver diseases in Denmark, 1981 to 1985: analysis of hospitalization registry data. The Danish Association for the Study of the Liver, The sex-specific and age-specific incidence rates of the major parenchymal liver diseases in a North European population were estimated using a computerized registry of all admissions to somatic hospitals in Denmark. The incidence was calculated by counting all incident cases of these diseases reported to the registry in the 5-yr period 1981 to 1985 and dividing the number of cases by the number of person-years at risk in this period. The incidence rates (per million person-years) were for men and women. respectively: infectious hepatitis. 109 and 71; toxic hepatitis. 19 and 22; chronic hepatitis. 27 and 29; alcoholic cirrhosis. 190 and 85; nonalcoholic nonbiliary cirrhosis. 110 and 82; primary biliary cirrhosis. 4 and 14. The pattern of the age-specific incidence rates was similar in men and women in infectious hepatitis. alcoholic cirrhosis. nonalcoholic nonbiliary cirrhosis and primary biliary cirrhosis. Toxic and chronic hepatitis had a higher incidence in women than in men only in older age groups. The incidence of idiopathic hemochromatosis. Wilson's disease. secondary biliary cirrhosis. portal vein thrombosis and Budd-Chiari's syndrome were less than four in both sexes.
High cholestanol and low campesterol-to-sitosterol ratio in serum of patients with primary biliary cirrhosis before liver transplantation, Serum levels of cholesterol precursors (squalene. delta 8-cholestanol. desmosterol and lathosterol). plant sterols (campesterol and sitosterol). cholestanol and cholestanol/noncholesterol sterol ratios were related to liver damage and liver transplantation indications in healthy controls (n = 26) and in 31 patients with primary biliary cirrhosis divided into group I (S-bilirubin less than 21 mumol/L; n = 14). group II (S-bilirubin 21 to 108 mumol/L; n = 7) and group III (elected for liver transplantation; S-bilirubin 109 to 520 mumol/L; n = 10). The mean serum respective lathosterol levels in controls and in group I were three and two times higher than those in groups II and III. respectively. The plant sterol contents were higher in group II than in groups I and III and the campesterol/sitosterol ratios were lowest in group III. The serum cholestanol levels were high even in group I (i.e.. in patients without icterus) and increased progressively to group III. up to 6 and 13 times those in group I and the control group. respectively. The cholestanol/noncholesterol sterol ratios increased progressively from the controls to groups I. II and III. The serum cholestanol levels were positively related to serum bilirubin levels in all primary biliary cirrhosis patients (n = 31. r = 0.906) and to the plant sterol levels in the control group and group I. but significantly negatively in group III. The cholestanol vs. precursor sterol correlations were negative in most cases.
IgA triggers tumor necrosis factor alpha secretion by monocytes: a study in normal subjects and patients with alcoholic cirrhosis, Under endotoxin-free conditions. peripheral blood mononuclear cells and purified monocytes isolated from healthy control subjects and patients with alcoholic cirrhosis disclose elevated tumor necrosis factor alpha messenger RNA level and produce tumor necrosis factor alpha in response to stimulation by either soluble polymeric IgA or monomeric IgA bound to the surface of culture dishes but not by soluble monomeric IgA. Polymeric IgA induces tumor necrosis factor alpha secretion in a dose-dependent fashion. These results suggest that cross-linking of Fc alpha receptors on human monocytes induces the messenger RNA accumulation and the secretion of the cytotoxic and immunoregulatory cytokine tumor necrosis factor alpha. Furthermore. it is shown that lipopolysaccharide-induced tumor necrosis factor alpha secretion by peripheral blood mononuclear cells is synergistically enhanced in the presence of solid phase monomeric IgA but not in the presence of either soluble monomeric or polymeric IgA. Although increased lipopolysaccharide-induced tumor necrosis factor alpha secretion is observed at baseline in alcoholic cirrhotic patients. this synergism is also expressed in this group of patients. These observations could be of pathophysiological relevance in alcoholic cirrhosis because monomeric IgA deposits along the liver sinusoids and increased serum levels of polymeric IgA are common even in the early stages of this disease.
Characterization of liver-associated natural killer cells in patients with liver tumors, The existence of a marginal lymphocyte population in rat liver sinusoids has already been demonstrated using the sinusoidal lavage method. We used the same technique to study the lymphocyte population in human liver obtained ex vivo after partial hepatectomy for benign or malignant tumors and compared it with peripheral and portal blood lymphocyte populations. Percentages of lymphocyte surface phenotypes were evaluated by flow cytometry. The lymphocyte population obtained from human liver is mainly made up of CD56+ (35%) cells. This percentage is three times greater than that found in peripheral and portal blood. Two-color flow cytometry analysis showed that within the CD56+ liver cell population. at least three distinct subsets could be found: (a) CD3+/CD56+/CD16-; (b) CD3-/CD56+/CD16-; and (c) CD3-/CD56+/CD16+. Although these subsets were also present in peripheral and portal blood. the percentage distribution was completely different because most CD56+ cells in peripheral and portal blood belonged to the CD3-/CD56+/CD16+ subset. These results show the existence of a heterogeneous natural killer cell population in human livers with tumors. The functional significance of this heterogeneity still needs to be explained.
Biliary tract disease in rats with experimental small bowel bacterial overgrowth, Small bowel bacterial overgrowth. which develops in surgically created jejunal self-filling blind loops. is associated with hepatic injury in susceptible rat strains. The histological findings are portal tract inflammation and bile duct proliferation and destruction. In this study. evidence of injury to the extrahepatic and intrahepatic bile ducts in susceptible and resistant inbred rats with self-filling blind loops was determined by bile flow rates. histological appearance of cross-sections of bile ducts and cholangiography. Lewis and Wistar rats with self-filling blind loops had thickening of the cross-sectional area of the extrahepatic bile ducts compared with controls and nonsusceptible Buffalo rats (p less than 0.001). Daily metronidazole therapy significantly reduced thickening of bile ducts in Lewis and Wistar rats with self-filling blind loops. Bile flow was increased in Lewis and Wistar rats with blind loops compared with controls (p less than 0.05). Cholangiograms of Lewis and Wistar rats with self-filling blind loops demonstrated extrahepatic ductal dilatation and ectasia with irregular. beaded. rapidly tapering and tortuous intrahepatic ducts. Blinded cholangiographical scores of susceptible rat strains with self-filling blind loops were higher (score = 5.9 +/- 2.3) than those of controls (1.2 +/- 0.4). rats with blind loops treated with metronidazole (0.8 +/- 1.3) and nonsusceptible Buffalo rats with blind loops (0.6 +/- 0.9) (p less than 0.01). Biliary histological and cholangiographical abnormalities found in this rat model resemble features of primary sclerosing cholangitis. This animal model will be useful in exploring mechanisms of the association of hepatobiliary inflammation with intestinal injury and investigating potential therapeutic agents.
Glutamic acid and gamma-aminobutyric acid neurotransmitters in central control of breathing, We review recent cross-disciplinary experimental and theoretical investigations on metabolism of the amino acid neurotransmitters glutamic acid and gamma-aminobutyric acid (GABA) in the brain during hypoxia and hypercapnia and their possible role in central control of breathing. The roles of classical modifiers of central chemical drive to breathing (H+ and cholinergic mechanisms) are summarized. A brief perspective on the current widespread interest in GABA and glutamate in central control is given. The basic biochemistry of these amino acids and their roles in ammonia and bicarbonate metabolism are discussed. This review further addresses recent work on central respiratory effects of inhibitory GABA and excitatory glutamate. Current understanding of the sites and mechanisms of action of these amino acids on or near the ventral surface of the medulla is reviewed. We focus particularly on tracer kinetic investigations of glutamatergic and GABAergic mechanisms in hypoxia and hypercapnia and their possible role in the ventilatory response to hypoxia. We conclude with some speculative remarks on the critical importance of these investigations and suggest specific directions of research in central mechanisms of respiratory control.
Physical fitness and cardiovascular regulation: mechanisms of orthostatic intolerance, We studied three groups of eight men each--high. mid. and low fit (peak O2 consumption 60.0 +/- 0.8. 48.9 +/- 1.0. and 35.7 +/- 0.9 ml.min-1.kg-1)--to determine the mechanism of orthostatic intolerance in endurance athletes. Tolerance was defined by progressive lower body negative pressure (LBNP) to presyncope. Maximal calf vascular conductance (Gmax) was measured. The carotid baroreflex was characterized using both stepwise R-wave-triggered and sustained (2 min) changes in neck chamber pressure. High-fit subjects tended to have lower LBNP tolerance than mid- and low-fit subjects but similar baroreflex responses. Subjects with poor LBNP tolerance had larger stroke volumes (SV) (120 +/- 6 vs. 103 +/- 3 ml) and greater decline in SV with LBNP to -40 mmHg (40 +/- 2 vs. 26 +/- 4%). Stepwise multiple linear regression analysis revealed that Gmax and steady-state gain of the carotid baroreflex contributed significantly toward explaining interindividual variations in LBNP tolerance. Thus endurance athletes may have decreased LBNP tolerance. but apparently not as a simple linear function of aerobic fitness. Orthostatic tolerance depends on complex interactions among functional characteristics that appear both related (Gmax and SV) and unrelated (baroreflex function) to fitness or exercise training.
Effect of sleep-induced increases in upper airway resistance on respiratory muscle activity, To investigate the response of inspiratory and expiratory muscles to naturally occurring inspiratory resistive loads in the absence of conscious control. five male "snorers" were studied during non-rapid-eye-movement (NREM) sleep with and without continuous positive airway pressure (CPAP). Diaphragm (EMGdi) and scalene (EMGsc) electromyographic activity were monitored with surface electrodes and abdominal EMG activity (EMGab) with wire electrodes. Subjects were studied in the following conditions: 1) awake. 2) stage 2 sleep. 3) stage 3/4 sleep. 4) CPAP during stage 3/4 sleep. 5) CPAP plus end-tidal CO2 pressure (PETCO2) isocapnic to stage 2 sleep. and 6) CPAP plus PETCO2 isocapnic to stage 3/4 sleep. Inspired pulmonary resistance (RL) at peak flow rate and PETCO2 increased in all stages of sleep. Activity of EMGdi. EMGsc. and EMGab increased significantly in stage 3/4 sleep. CPAP reduced RL at peak flow. increased tidal volume and expired ventilation. and reduced PETCO2. EMGdi and EMGsc were reduced. and EMGab was silenced. During CPAP. with CO2 added to make PETCO2 isocapnic to stage 3/4 sleep. EMGsc and EMGab increased. but EMGdi was augmented in only one-half of the trials. EMG activity in this condition. however. was only 75% (EMGsc) and 43% (EMGab) of the activity observed during eupneic breathing in stage 3/4 sleep when PETCO2 was equal but RL was much higher. We conclude that during NREM sleep 1) inspiratory and expiratory muscles respond to internal inspiratory resistive loads and the associated dynamic airway narrowing and turbulent flow developed throughout inspiration. 2) some of the augmentation of respiratory muscle activity is also due to the hypercapnia that accompanies loading. and 3) the abdominal muscles are the most sensitive to load and CO2 and the diaphragm is the least sensitive.
Flow redistribution during progressive hemorrhage is a determinant of critical O2 delivery, O2 consumption (VO2) of anesthetized whole mammals is independent of O2 delivery (DO2) until DO2 declines to a critical value (DO2c). Below this value. VO2 becomes O2 supply dependent. We assessed the influence of whole body DO2 redistribution among organs with respect to the commencement of O2 supply dependency. We measured DO2. VO2. and DO2c of whole body. liver. intestine. kidney. and remaining carcass in eight mongrel dogs during graded progressive hemorrhage. Whole body DO2 was redistributed such that the organ-to-whole body DO2 ratio declined for liver and kidney and increased for carcass. We then created a mathematical model wherein each organ-to-whole body DO2 ratio remained approximately constant at all values of whole body DO2 and assigned organ VO2 to predicted organ DO2 by interpolation and extrapolation of observed VO2-DO2 plots. The model predicted that O2 supply dependency without redistribution would have commenced at a higher value of whole body DO2 for whole body (8.11 +/- 0.89 vs. 6.98 +/- 1.16 ml.kg-1.min-1. P less than 0.05) and carcass (6.83 +/- 1.16 vs. 5.06 +/- 1.15 ml.kg-1.min-1. P less than 0.01) and at a lower value of whole body DO2 for liver (6.33 +/- 1.86 vs. 7.59 +/- 1.95. ml.kg-1.min-1. P less than 0.02) and kidney (1.25 +/- 0.64 vs. 4.54 +/- 1.29 ml.kg-1.min-1. P less than 0.01). We conclude that redistribution of whole body DO2 among organs facilitates whole body O2 regulation.
Hepatic oxygen and lactate extraction during stagnant hypoxia, As O2 delivery falls. tissues must extract increasing amounts of O2 from blood to maintain a normal O2 consumption. Below a critical delivery threshold. increases in O2 extraction cannot compensate for the falling delivery. and O2 uptake falls in a supply-dependent fashion. Numerous studies have identified a critical delivery in whole animals. but the regional contributions to the critical O2 delivery are less fully understood. In the present study. we explored the limits of O2 extraction in the isolated liver. seeking to determine 1) the normal relationship between O2 consumption and delivery in the liver and 2) the relationship of hepatic lactate extraction to the drop in hepatic O2 consumption at low O2 deliveries. To answer these questions. using support dogs as a source for oxygenated metabolically stable blood. we studied eight pump-perfused canine livers. By lowering the blood flow in a model of stagnant hypoxia. we explored the relationship between O2 consumption and delivery over the entire physiological range of O2 delivery. The critical O2 delivery was 28 +/- 5 (SD) ml.kg-1.min-1; the livers extracted 68 +/- 9% of the delivered O2 before reaching supply dependence. This suggests that the liver has an O2 extraction capacity quite similar to the body as a whole and not different from other tissues that have been isolated. At high blood flows. the livers extracted approximately 10% of the lactate delivered by the blood. but the arteriovenous lactate differences were small. At low blood flows. however. the livers changed from lactate consumption to production. The O2 delivery coinciding with the dropoff in lactate extraction did not differ significantly from the critical O2 delivery. We conclude that reductions in lactate uptake by the liver do not precede the transition to O2 supply dependence.
Relationship of fluid filtration to lung vascular pressure during edema, Effect of edema on the relationship between rate of fluid filtration and vascular pressure was studied in ventilated isolated dog lung lobes blood-perfused at constant flow. Constant rate of lobe weight gain (S). representing transvascular fluid flux. was obtained at different venous pressures (Pv) as Pv was increased stepwise from 2 to 40 and then similarly decreased from 40 to 2 Torr (n = 6). In another group (n = 6). edema was maximized by reversing the sequence of Pv change; S was obtained during similar Pv steps as Pv was decreased from 40 to 2 and then returned to 40 Torr. In both groups. delta S was disproportionately greater for delta Pv at higher Pv's. with S vs. Pv fit by an exponential curve (P less than 0.001). The exponential relationship was independent of lung hydration inasmuch as greater edema on the second limb of Pv change did not alter the curve (P greater than 0.05). At 144% weight gain. interstitial compliance was 55.5 +/- 26.8 ml.100 g-1.Torr-1 (n = 10). Interstitial pressure reportedly remains constant. i.e.. fails to increase to further buffer fluid filtration. after transition of the lung interstitium from low to high compliance at approximately 40% lung weight gain. If so. then the exponential S vs. Pv relationship observed in the present study at elevated interstitial compliance does not appear related to tissue pressure-buffering effects.
Effects of treadmill exercise on fuel metabolism in hepatic cirrhosis, We studied whole body and regional fuel metabolism before. during. and after 90 min of treadmill exercise at 50% of maximal aerobic capacity (VO2max) in four subjects with hepatic cirrhosis and in four normal volunteers. Rates of endogenous glucose production (EGP) were measured using D-[6-3H]glucose infusions and fuel oxidation using indirect calorimetry. In the basal state. cirrhotic subjects had similar rates of EGP compared with controls. Forearm release of alanine and lactate was significantly greater in cirrhotic subjects (P less than 0.05). suggesting increased basal rates of gluconeogenesis. During exercise. EGP increased 2- to 2.5-fold in control subjects (P less than 0.01) but did not increase in cirrhotic subjects. Despite lower glucose concentrations in cirrhotic subjects. progressive hypoglycemia did not occur during exercise. probably because cirrhotic subjects demonstrated increased plasma concentrations of fat-derived substrates and derived a greater percentage of total energy requirement from fat oxidation than did controls (P less than 0.05) and because forearm muscle glucose extraction was significantly lower in cirrhotic subjects compared with controls (0.5 vs. 3.6%. respectively; P less than 0.05). During recovery. control subjects demonstrated significant increases in EGP rates compared with both the basal and exercise periods. but cirrhotic subjects showed no increase. In conclusion. cirrhotic subjects failed to demonstrate the normal increase in EGP during and after exercise. Significant hypoglycemia during exercise did not occur. possibly because of the increased availability of fat-derived fuels. which may spare the requirement for circulating glucose as an oxidative fuel for exercising muscle tissues.
Effect of chronic resistive loading on inspiratory muscles in rats, The development of animal models of respiratory muscle training would be useful in studying the physiological effects of training. Hence. we studied the effects of chronic resistive loading (CRL) for 5 wk on mass. composition. and mechanics of inspiratory muscles in laboratory rats. CRL was produced by means of a tracheal cannula (loaded animals) and results were compared with sham-operated controls. Acutely. upper airway obstruction led to a doubling of inspiratory pleural pressure excursion and 25% decrease in respiratory rate. We observed no changes in lung pressure-volume curves. nor in the geometry of the respiratory system in loaded compared with control animals. Muscle mass normalized for body mass increased in the diaphragm (DI) and the wet weight-to-dry weight ratio increased in the sternomastoid (SM) in loaded compared with control animals. Loaded animals demonstrated a decrease in ether extractable (fat) content of the DI and SM muscles but not the gastrocnemius. For the DI there was no change in length at which active tension was maximal (Lo). but there was an increase in maximum tension at lengths close to Lo in loaded compared with control rats. Endurance did not change. although twitch tensions remained higher in loaded compared with control rats. We conclude that 1) alteration of inspiratory muscle structure and function occurs in rats with CRL; 2) the DI and SM demonstrate different adaptive responses to CRL; and 3) although maximum tension increases. endurance does not.
Effect of mild-to-moderate airflow limitation on exercise capacity, To determine the effect of mild-to-moderate airflow limitation on exercise tolerance and end-expiratory lung volume (EELV). we studied 9 control subjects with normal pulmonary function [forced expired volume in 1 s (FEV1) 105% pred; % of forced vital capacity expired in 1 s (FEV1/FVC%) 81] and 12 patients with mild-to-moderate airflow limitation (FEV1 72% pred; FEV1/FVC % 58) during progressive cycle ergometry. Maximal exercise capacity was reduced in patients [69% of pred maximal O2 uptake (VO2max)] compared with controls (104% pred VO2max. P less than 0.01); however. maximal expired minute ventilation-to-maximum voluntary ventilation ratio and maximal heart rate were not significantly different between controls and patients. Overall. there was a close relationship between VO2max and FEV1 (r2 = 0.62). Resting EELV was similar between controls and patients [53% of total lung capacity (TLC)]. but at maximal exercise the controls decreased EELV to 45% of TLC (P less than 0.01). whereas the patients increased EELV to 58% of TLC (P less than 0.05). Overall. EELV was significantly correlated to both VO2max (r = -0.71. P less than 0.001) and FEV1 (r = -0.68. P less than 0.001). This relationship suggests a ventilatory influence on exercise capacity; however. the increased EELV and associated pleural pressures could influence cardiovascular function during exercise. We suggest that the increase in EELV should be considered a response reflective of the effect of airflow limitation on the ventilatory response to exercise.
Role of tachykinins in hyperpnea-induced bronchovascular hyperpermeability in guinea pigs, Isocapnic dry gas hyperpnea causes bronchoconstriction in guinea pigs that is mediated by release of tachykinins from airway sensory nerves. Exogenous neuropeptides can induce microvascular leak. Therefore we tested whether dry gas hyperpnea also elicits bronchovascular hyperpermeability by measuring Evans blue-labeled albumin extravasation along the airways of mechanically ventilated guinea pigs. We found that 1) room temperature dry gas hyperpnea increased Evans blue extravasation in extrapulmonary and intrapulmonary airways as a specific consequence of local airway heat/water losses. 2) capsaicin pretreatment ablated the bronchoconstrictor response to dry gas hyperpnea and reduced bronchovascular leak only in intrapulmonary airways. 3) phosphoramidon given to capsaicin-pretreated animals partially restored dry gas hyperpnea-induced bronchoconstriction and increased the vascular hyperpermeability response to hyperpnea in intrapulmonary airways. and 4) propranolol administration had no important effects on any of these airway responses. We conclude that dry gas hyperpnea causes bronchovascular hyperpermeability in guinea pigs. Tachykinins have a dominant role in this response in the intrapulmonary airways. although another mechanism may also contribute to the microvascular leak in the extrapulmonary airways.
Fetal breathing and pressures in the trachea and amniotic sac during oligohydramnios in sheep, Oligohydramnios commonly leads to fetal lung hypoplasia. but the mechanisms are not fully understood. Our aim was to determine. in fetal sheep. the effects of prolonged oligohydramnios on the incidence and amplitude of tracheal pressure fluctuations associated with fetal breathing movements (FBM). on tracheal flow rate during periods of FBM (VtrFBM) and periods of apnea (Vtrapnea). on tracheal pressure relative to amniotic sac pressure. and on amniotic sac pressure relative to atmospheric pressure. In five sheep. oligohydramnios was induced by draining amniotic and allantoic fluids from 107 to 135 days of gestation (411.8 +/- 24.4 ml/day). resulting in fetal lung hypoplasia. In five control sheep. amniotic fluid volume was 732.3 +/- 94.4 ml. Oligohydramnios increased the incidence of FBM by 14% at 120 and 125 days and the amplitude of FBM by 30-34% at 120-130 days compared with controls. From 120 days onward. VtrFBM was 35-55% lower in experimental fetuses than in controls. Influx of lung liquid during FBM was 87% lower in experimental fetuses than in controls. Vtrapnea. tracheal pressure. and amniotic sac pressure were not significantly altered by oligohydramnios. Our tracheal flow rate data suggest that transient changes in lung liquid volume during periods of FBM and periods of apnea were diminished by oligohydramnios. We conclude that the primary factor in the etiology of oligohydramnios-induced lung hypoplasia is not an inhibition of FBM (as measured by tracheal pressure fluctuations) or a reduction in amniotic fluid pressure.
Myosin heavy chain turnover during cardiac mass changes by glucocorticoids, One aim of this investigation was to determine whether the cardiac enlargement observed with glucocorticoid treatment is temporary or remains a permanent adaptation if steroid treatment is prolonged. A second aim was to study whether myosin heavy chain (MHC) synthesis rates are coordinated with the cardiac mass responses. Female rats received either a vehicle (1% aqueous carboxymethyl cellulose in saline) or hydrocortisone 21-acetate for 1. 3. 7. 11. and 15 days. Peak cardiac enlargement (10-15%) was observed after 7 days of hormone treatment in two separate series of experiments. The enlargement was maintained through 11 days of steroid injections but by 15 days had declined toward control levels. MHC synthesis measurements were performed by constant infusion of [3H]leucine. Leucine specific activities were similar among precursor pools (intracellular. extracellular. and leucyl-tRNA) and did not vary with steroid treatments. Fractional synthesis rates of ventricular MHC (%/day) did not change during the period of increase in ventricular mass but were reduced to 56-59% of controls (-11/19.5) at 7 and 11 days of treatment. when ventricular mass increases were highest. MHC breakdown (%/day) was reduced to approximately 60% (-11.5/18.7) of controls at 7 and 11 days. Changes in total protein synthesis. which was measured in isolated perfused hearts. were similar to the MHC responses and indicated that the alterations in MHC synthesis are synchronized with the hormonal effects on total protein metabolism. These results demonstrate that peak cardiac enlargement is not maintained with long-term glucocorticoid treatment.
Developmental changes in vascular responses to histamine in normoxic and hypoxic lamb lungs, This study of newborn (3-10 day old) and juvenile (6-8 mo old) in situ isolated lamb lungs was undertaken to determine whether 1) histamine receptor blockade accentuates hypoxic pulmonary vasoconstriction more in newborns than in juveniles. 2) histamine infusion causes a decrease in both normoxic pulmonary vascular resistance and hypoxic pulmonary vasoconstriction in newborns. and 3) the H1-mediated dilator response to infused histamine in newborns is due to enhanced dilator prostaglandin release. Pulmonary arterial pressure (Ppa) was determined at baseline and in response to histamine (infusion rates of 0.1-10.0 micrograms.kg-1 min-1) in control. H1-blocked. H2-blocked. combined H1- and H2-blocked. and cyclooxygenase-inhibited H2-blocked lungs under "normoxic" (inspired O2 fraction 0.28) and hypoxic (inspired O2 fraction 0.04) conditions. In newborns. H1-receptor blockade markedly accentuated baseline hypoxic Ppa. and H2-receptor blockade caused an increase in baseline normoxic Ppa. In juveniles. neither H1 nor H2 blockade altered baseline normoxic or hypoxic Ppa. Histamine infusion caused both H1- and H2-mediated decreases in Ppa in normoxic and hypoxic newborn lungs. In juvenile lungs. histamine infusion also caused H2-mediated decreases in Ppa during both normoxia and hypoxia. During normoxia. histamine infusion caused an H1-mediated increase in normoxic Ppa in juveniles as previously seen in mature animals; however. during hypoxia there was an H1-mediated decrease in Ppa at low doses of histamine followed by an increase in Ppa. Combined histamine-receptor blockade markedly reduced both dilator and pressor responses to histamine infusion. Indomethacin failed to alter the H1-mediated dilator response to histamine in newborns.
Evaluation of renal function and fluid homeostasis during recovery from exercise-induced hyponatremia, Renal function including fluid and electrolyte balance was studied during recovery in eight subjects who developed symptomatic hyponatremia (HN; plasma sodium concentration less than 130 mM) during an 88-km ultramarathon footrace and compared with results for normonatremic runners [NN; n = 18. mean postrace plasma sodium concentration. 138.2 +/- 1.2 (SE) mM]. Estimated fluid intake during the race for HN was 12.5 +/- 1.6 (SE) liters over 9 h 41 min (+/- 28 min). HN excreted a net fluid excess of 2.95 +/- 0.56 (range 1.2-5.9) liters compared with a fluid deficit of 2.7 +/- 0.3% body weight in NN. The sodium deficit was 153 +/- 35 mmol in HN and 187 +/- 37 mmol in NN. Despite the fluid overload. plasma volume was decreased by 24.1 +/- 5.0% in HN compared with 8.2 +/- 2.6% in NN. Serum renin activity (5.1 +/- 2.0 ng.ml-1.h-1). aldosterone concentrations (410 +/- 34 ng/l). creatinine clearances (174.8 +/- 28.2 ml/min). and urine output (6.4 +/- 1.0 ml/min) were markedly elevated in HN during recovery. Thus the hyponatremia of exercise results from fluid retention in subjects who ingest abnormally large fluid volumes during prolonged exercise.
Muscle glucose uptake of obese Zucker rats trained at two different intensities, Exercise training reduces the muscle insulin resistance of the obese Zucker rat. The purpose of the present study was to determine whether the magnitude of this training response is exercise intensity specific. Obese Zucker rats were randomly divided into sedentary (SED). low-intensity (LI). and high-intensity (HI) exercise groups. For the LI rats. exercise training consisted of running on a rodent treadmill at 18 m/min up an 8% grade for 90 min. Rats in the HI group ran at 24 m/min up an 8% grade for four 17-min bouts with 3 min between bouts. Both exercise groups performed the same amount of work and trained 5 days/wk for 7 wk. To evaluate muscle insulin resistance. rat hindlimbs were perfused for 30 min with perfusate containing 6 mM glucose (0.15 mu Ci of D-[14C(U)] glucose/ml) and either a maximal (10.0 mU/ml) or a submaximal (0.50 mU/ml) insulin concentration. Perfusions were performed 48-56 h after the last exercise bout and a 12-h fast. In the presence of 0.5 mU/ml insulin. the rate of muscle glucose uptake was found to be significantly faster for the HI (9.56 +/- 0.66 mumol.h-1.g-1) than for the LI (7.72 +/- 0.65 mumol.h-1.g-1) and SED (6.64 +/- 0.44 mumol.h-1.g-1) rats. The difference in glucose uptake between the LI and SED rats was not significant. In the presence of 10.0 mU/ml insulin. the rate of glucose uptake was significantly faster for the HI (16.43 +/- 1.02 mumol.h-1.g-1) than for the LI rats (13.76 +/- 0.84 mumol.h-1.g-1) and significantly faster for the LI than for the SED rats (11.02 +/- 0.35 mumol.h-1.g-1).
Preservation of oscillations in postocclusive reactive hyperemia, Oscillations in skin blood flow (SkBF) during postocclusive reactive hyperemia are believed to be due to locally mediated events in the microcirculation. We characterized the activity of these oscillations in nine healthy young men who underwent 0. 10. and 40 Torr of lower body negative pressure (LBNP). Postocclusive SkBF was estimated in both forearms simultaneously in a stable thermal environment with laser-Doppler velocimetry. Periodic behavior of SkBF was characterized by frequency-domain power spectral analysis. LBNP at 40 Torr increased heart rate. decreased forearm blood flow. and decreased postocclusive SkBF amplitude but did not change the periodicity of SkBF in the frequency response range that is characteristic of postischemic SkBF oscillations (0.11 +/- 0.04 Hz). We observed that LBNP did not alter the frequency response of the postocclusive SkBF as quantified in the periodogram. even though the amplitude of the SkBF was markedly diminished as a part of the general decrease in arm blood flow. We found inferential evidence for a disseminated common pacemaker mechanism that performs similarly at distant sites. We conclude that the LBNP baroreflex-mediated modulation of SkBF reduces the amplitude but does not change the frequency behavior of postocclusive SkBF. We propose on the basis of our findings that the preservation of vasomotion suggests that this phenomenon is an adaptation to the ischemic changes induced by disruption of blood flow.
Multireceptor activation of the pulmonary chemoreflex, Schertel et al. (J. Appl. Physiol. 61: 1237-1240. 1984) reported that pulmonary C fibers initiate the prompt apnea followed by rapid shallow breathing evoked by pulmonary arterial injections of capsaicin. However. doubt has remained as to whether these changes in breathing pattern are induced exclusively by direct stimulation of pulmonary C fibers or whether secondary stimulation of slowly adapting pulmonary stretch receptors by capsaicin-induced reflex bronchoconstriction also contributes to the response. To determine the contribution of this secondary mechanism to changes in breathing pattern. we evoked the pulmonary chemoreflex in spontaneously breathing dogs before and after blockade of muscarinic receptors with atropine. Right atrial injections of capsaicin before the administration of atropine induced a classical pulmonary chemoreflex. i.e.. apnea. hypotension. and bradycardia followed by rapid shallow breathing and bronchoconstriction. After atropine. all components of the pulmonary chemoreflex induced by right atrial injections of capsaicin remained intact except bronchoconstriction. However. the absolute magnitude of the change in each component of the reflex except apnea was significantly attenuated. We conclude that the classic pulmonary chemoreflex is a complex phenomenon initiated primarily by stimulation of pulmonary C fibers but significantly influenced by secondary stimulation of slowly adapting pulmonary stretch receptors.
Influence of bronchial arterial PO2 on pulmonary vascular resistance, In six anesthetized and mechanically ventilated adult sheep. the bronchial artery was perfused with blood from an oxygenator-pump circuit. When the lungs were ventilated with 100% O2 and the bronchial O2 tension (PbrO2) was approximately 600 Torr. the mean of the pulmonary vascular resistances (PVR) measured at the beginning (3.32 +/- 0.29 units) and end (3.17 +/- 0.13 units) of the experiment was 3.24 +/- 0.20 units. When the PbrO2 was changed to 58 +/- 1 Torr. the PVR (2.99 +/- 0.14 units) did not change significantly. However. when the lungs were ventilated with air as PbrO2 was decreased to 91 +/- 4. 77 +/- 3. 56 +/- 2. and 42 +/- 1 Torr. the PVR increased to 3.67 +/- 0.18. 4.03 +/- 0.16. 4.79 +/- 0.19. and 4.71 +/- 0.35 units. respectively. However. when the PbrO2 was decreased further to 26 +/- 1 and 13 +/- 1 Torr. the PVR decreased to 3.77 +/- 0.28 and 3.91 +/- 0.30 units. respectively. In contrast. the bronchial vascular resistance decreased monotonically as PbrO2 decreased. The bronchial circulation supplies vasa vasorum to the walls of all but the smallest pulmonary arteries. and it is therefore suggested that the PO2 of the bronchial circulation is responsible for the bimodal response of the pulmonary vasculature. with stimulation of hypoxic pulmonary vasoconstriction at moderate hypoxemia and of hypoxic pulmonary vasodilation at profound hypoxemia. The physiological and pathophysiological significance of the influence of systemic PO2 on pulmonary vascular tone is discussed.
Protein concentrations have little effect on reabsorption of fluid from isolated rat lungs, A study was conducted to determine whether differences in the concentrations of large molecules between the air space and perfusate solutions altered the rates at which fluid was reabsorbed from isolated fluid-filled perfused rat lungs. Four groups of experiments were conducted: 1) 5 g/dl albumin in the air spaces and perfusate. 2) 15 g/dl albumin in the air space and 5 g/dl albumin in the perfusate. 3) 5 g/dl albumin in the air space and 15 g/dl albumin in the perfusate. and 4) a mixture of 5 g/dl albumin and 7 g/dl Dextran 70 in the air spaces and 5 g/dl albumin in the perfusate. Fluid reabsorption was determined by following the concentration of albumin labeled with Evans blue (T-1824) in the air space and perfusate compartments. Because leakage of protein between the air space and perfusate compartments is very slow. increases in T-1824 concentrations in the air spaces indicated loss of fluid from this compartment. whereas decreases in these concentrations in the perfusate compartment provided evidence of fluid transport into the vasculature. Approximately 30% of the air space fluid was reabsorbed in a 2-h period. and virtually all of this fluid reached the perfusate compartment. Despite oncotic differences that ranged from -65 to 65 Torr. variations in air space or perfusate albumin concentrations did not have a significant effect on this process. A 30% decrease in fluid reabsorption was observed when dextran was in the air space solution. but this decrease did not appear to be due to the oncotic properties of this solution because albumin did not have a measurable effect on reabsorption.
Leakage of macromolecules in ventilated and unventilated segments of preterm lamb lungs, The movement of macromolecules into and out of unventilated lung segments was evaluated in prematurely delivered and ventilated lambs. Seven lambs at 130 days gestational age had a bronchial balloon placed at birth before the first breath to obstruct the left lower lobe. Surfactant and 131I-albumin were instilled into the left lower lobe while surfactant and 125I-albumin were instilled into the remaining lung. and 70.000 molecular weight [3H]dextran was given into the vascular space at birth. Twenty-five percent of the lung by weight was not ventilated. and 24% of the total leak of dextran from the vascular space was recovered in the unventilated lungs at 3 h. An epithelial leak of protein from the two lung regions was documented by the loss of 11.4 and 18.4% of the labeled albumins in the nonventilated and ventilated lung regions. the appearance of 4.9 and 7.5% of the airway-instilled albumin in the vascular space from the nonventilated and ventilated lung regions. and the recovery of the labeled albumins in the carcasses of the lambs. The bidirectional flux of macromolecules was larger in the ventilated than in the nonventilated lung regions. indicating that ventilation can increase the leak of protein in the preterm lung. The lung areas that were never exposed to ventilation or oxygen also demonstrated a large bidirectional flux of macromolecules. a finding not present in the fetus. fullterm newborn. or adult. These findings indicate that ventilation is not solely responsible for the increased protein leak found in preterm lungs.
Effects of glucose on hypoxic vasoconstriction in isolated ferret lungs, To characterize the effects of glucose on the pulmonary vascular response to anoxia and hypoxia. isolated ferret lungs were ventilated with 28% O2 and 5% CO2 and perfused at constant flow (100 ml.kg-1.min-1). Perfusate glucose concentrations were allowed to fall spontaneously to less than 1 mM (low glucose) or were controlled at 5-6 mM (normal glucose) or 12-17 mM (high glucose). At 60. 120. and 180 min of perfusion. the inspired O2 tension (PIO2) was reduced to 0. 10. or 30 Torr for 30 min. and vasomotor responses were quantified by continuous measurement of pulmonary arterial pressure. At PIO2 of 0 Torr. the response consisted of an early phase of transient intense vasoconstriction and a late phase of sustained slight vasoconstriction. High glucose markedly potentiated the magnitude of late-phase vasoconstriction with each successive anoxic exposure. This effect was not reproduced in normal glucose lungs and was not caused by a change in perfusate osmolarity. an action on blood cells. or an altered ability of pulmonary vascular smooth muscle to contract. At PIO2 of 10 Torr. high glucose not only potentiated late-phase vasoconstriction but also slowed the onset of early-phase vasoconstriction. At PIO2 of 30 Torr. high glucose had no effect on vasomotor responses. which were characterized by a slowly developing sustained vasoconstriction. Our results suggest that the vascular response of isolated ferret lungs to severe hypoxia consisted of separate early and late phases of vasoconstriction. This biphasic response may have resulted from two distinct vasoconstrictor mechanisms or from modulation of a single vasoconstrictor mechanism by a secondary vasodilator influence.
Influence of lung volume and left atrial pressure on reverse pulmonary venous blood flow, Infarction of the lung is uncommon even when both the pulmonary and the bronchial blood supplies are interrupted. We studied the possibility that a tidal reverse pulmonary venous flow is driven by the alternating distension and compression of alveolar and extra-alveolar vessels with the lung volume changes of breathing and also that a pulsatile reverse flow is caused by left atrial pressure transients. We infused SF6. a relatively insoluble inert gas. into the left atrium of anesthetized goats in which we had interrupted the left pulmonary artery and the bronchial circulation. SF6 was measured in the left lung exhalate as a reflection of the reverse pulmonary venous flow. No SF6 was exhaled when the pulmonary veins were occluded. SF6 was exhaled in increasing amounts as left atrial pressure. tidal volume. and ventilatory rates rose during mechanical ventilation. SF6 was not excreted when we increased left atrial pressure transients by causing mitral insufficiency in the absence of lung volume changes (continuous flow ventilation). Markers injected into the left atrial blood reached the alveolar capillaries. We conclude that reverse pulmonary venous flow is driven by tidal ventilation but not by left atrial pressure transients. It reaches the alveoli and could nourish the alveolar tissues when there is no inflow of arterial blood.
Mechanisms of blood flow during pneumatic vest cardiopulmonary resuscitation, Mechanisms of blood flow during cardiopulmonary resuscitation (CPR) were studied in a canine model with implanted mitral and aortic flow probes and by use of cineangiography. Intrathoracic pressure (ITP) fluctuations were induced by a circumferential pneumatic vest. with and without simultaneous ventilation. and by use of positive-pressure ventilation alone. Vascular volume and compression rate were altered with each CPR mode. Antegrade mitral flow was interpreted as left ventricular (LV) inflow. and antegrade aortic flow was interpreted as LV outflow. The pneumatic vest was expected to elevate ITP uniformly and thus produce simultaneous LV inflow and LV outflow throughout compression. This pattern. the passive conduit of "thoracic pump" physiology. was unequivocally demonstrated only during ITP elevation with positive-pressure ventilation alone at slow rates. During vest CPR. LV outflow started promptly with the onset of compression. whereas LV inflow was delayed. At compression rates of 50 times/min and normal vascular filling pressures. the delay was sufficiently long that all LV filling occurred with release of compression. This is the pattern that would be expected with direct LV compression or "cardiac pump" physiology. During the early part of the compression phase. catheter tip transducer LV and left atrial pressure measurements demonstrated gradients necessitating mitral valve closure. while cineangiography showed dye droplets moving from the large pulmonary veins retrograde to the small pulmonary veins. When the compression rate was reduced and/or when intravascular pressures were raised with volume infusion. LV inflow was observed at some point during the compressive phase. Thus. under these conditions. features of both thoracic pump and cardiac pump physiology occurred within the same compression. Our findings are not explained by the conventional conceptions of either thoracic pump or cardiac compression CPR mechanisms alone.
Synthesis of 70K stress protein by human leukocytes: effect of exercise in the heat, To determine whether reinduction of 70.000-Da (70K) stress protein synthesis could be used as an assay for thermal history and/or cellular levels of 70K stress protein in hyperthermic humans. leukocytes were obtained before and after 2 h of exercise and then incubated at 37 or 41 degrees C. Five healthy males completed 2 h of treadmill exercise consisting of running at 4-6 km/h for 30-45 min followed by 75-90 min of walking up a 2-10% grade. This exercise bout was performed by two subjects in hot (46 degrees C. 15% relative humidity) and by five subjects in cooler (30 degrees C. 40% relative humidity) environmental conditions. Exercise resulting in rectal temperature (Tre) less than 40 degrees C did not alter the amount of 70K stress protein synthesized by leukocytes incubated at 41 degrees C. In contrast. exercise resulting in Tre greater than 40 degrees C reduced the amount of 70K stress protein synthesized by leukocytes incubated at 41 degrees C. A protein immunoblot. probed with an antibody specific for the inducible 72K stress protein. showed that the reduction of 35S-labeled 70K stress protein in these postexercise leukocyte samples occurred without marked elevations of this protein. In vitro incubation of human leukocytes at 40 degrees C for 15-120 min reduced. in a time-dependent manner. the amount of 70K stress protein synthesized during a subsequent 41 degrees C heat stress. This reduction of 70K stress protein synthesis in 41 degrees C-treated leukocytes was abolished when cycloheximide was present during the 40 degrees C preincubation.
Quantitative relationships between left ventricular ejection and wall thickening and geometry, The quantitative relationships that exist between left ventricular (LV) wall shortening. wall thickening. and geometry during LV ejection are not well defined. We used a mathematical model to measure these parameters in 40 patients with various LV geometries studied by echocardiography. As opposed to wall shortening. the percent contribution of wall thickening to LV ejection (% delta Vh) was 25 +/- 2% in normal subjects; in all the patients. it varied from 18 to 45% and was inversely correlated (r = 0.94) to the midwall radius-to-wall thickness ratio (R/h) of the ventricle at end diastole. On the other hand. the ratio of the quantity of blood ejected per unit of LV wall volume magnitude of delta V/V omega magnitude of varied from 0.20 to 1.20 (normal subjects 0.83 +/- 0.11) and was directly correlated (r = 0.94) to R/h; using independent data in the literature. we also found a similar relationship (r = 0.80) between the ratio of quantity of blood ejected per unit of LV mass (magnitude of delta V/M omega magnitude of) and R/h. Patients with presumably abnormal myocardial function did not satisfy the relationship between magnitude of delta V/V omega magnitude of or magnitude of delta V/M omega magnitude of and R/h.
Diaphragmatic force and substrate response to resistive loaded breathing in the piglet, Inspiratory resistive loaded (IRL) breathing results in hypoventilation and diaphragmatic fatigue in the piglet. We studied the effects of 6 h of IRL on ten 1-mo-old piglets. The load was adjusted to increase spontaneously generated transdiaphragmatic pressure five to six times baseline. Six 1-mo-old piglets acted as controls and were identically instrumented but were not subjected to IRL. Measurements of ventilation. blood gases and pH. diaphragmatic electromyogram. force-frequency curve. blood flow. and end-expiratory lung volume were obtained hourly. Diaphragmatic muscle samples were obtained after 6 h for determination of ATP. phosphocreatine. lactate. and glycogen levels. No changes occurred in the control animals. IRL resulted in a significant decrease in ventilation. an increase in diaphragmatic EMG. onset of abdominal expiratory muscle activity. and a fall in end-expiratory lung volume by 1 h. The force-frequency curve adjusted for lung volume change fell by 20% at all frequencies of stimulation at 1 h and by 40% at 6 h. Blood flow to the costal and crural diaphragm increased by 51 and 141%. respectively. No differences were noted in ATP. phosphocreatine. lactate. or glycogen between control and IRL animals. It is concluded that submaximal spontaneous contractions of the piglet diaphragm over a 6-h period cause a substantial decrease in its maximal force-generating capacity that is not related to substrate depletion.
Regional blood flow to canine parietal pleura and internal intercostal muscle, Transcapillary Starling forces in the parietal pleura and the underlying interstitium may potentially contribute to the exchange of fluid across this barrier. However. the extent of blood flow to the parietal pleura has not been measured. Thus. using standard microsphere techniques. we compared blood flow to the parietal pleura. including the subpleural interstitium. with blood flow to the adjacent internal intercostal muscle. as well as with flows to other serous tissues. including mediastinal pleura. pericardium. and parietal peritoneum. in anesthetized dogs that were either breathing spontaneously (n = 9) or ventilated to control arterial PCO2 (n = 5). Blood flow (ml.min-1.g-1) was measured after 20 min of equilibration in four successive body positions: right lateral decubitus. supine. left lateral decubitus. and prone. Overall. flow to parietal pleura was not different in spontaneous [1.07 +/- 0.14 (SE)] and mechanically ventilated animals (0.74 +/- 0.11). Flow to the internal intercostal muscle was significantly less than pleural blood flow. averaging 0.24 +/- 0.03 and 0.16 +/- 0.03 in the same groups. although again there was no effect of ventilation mode. Blood flow to other serous tissues in the thoracic cavity. specifically the mediastinal pleura (0.67 +/- 0.14) and pericardium (0.88 +/- 0.22). was similar to parietal pleural flow. whereas that to the parietal peritoneum was an order of magnitude lower (0.09 +/- 0.02. P less than 0.05). Changing body position had no effect on blood flow to any of the sampled tissues. Blood flow to the dorsal aspect of the chest wall muscle in spontaneously breathing animals tended to be greater than that to lateral or ventral portions of the chest wall.
A prospective study of aspirin's effect on red blood cell loss in cardiac surgery, The effect of aspirin on red blood cell (RBC) loss and blood transfusions was evaluated prospectively in 100 consecutive patients. with normal bleeding times. undergoing elective coronary artery bypass (CABG) surgery. Patients taking 85-325 mgm of aspirin daily up to or within 48 hours of surgery (the "aspirin" group) were compared to patients not taking aspirin or those who had discontinued aspirin at least 4 days before surgery (the "no-aspirin" group). RBC loss was determined by measuring preoperative and postoperative RBC volume using RISA and 51Cr techniques. There were no significant differences. respectively. between the aspirin and no-aspirin groups for: RBC loss (1158 +/- 67 ml vs 1129 +/- 47 ml. p = 0.737). chest tube drainage (925 +/- 31 ml vs 844 +/- 70 ml. p = 0.553). and gm% discharge Hemoglobin (Hgb) (9.94 +/- 0.32 vs 9.49 +/- 1.4. p = 0.0148). Strict criteria for blood transfusions were employed: (1) intraoperative hematocrit of less than 21%. (2) postoperative Hgb of less than 7 gm% for patients less than 70 years old and (3) postoperative Hgb of less than 8 gm% for patients greater than 70 years old. There were no significant differences. respectively. between the aspirin and no-aspirin groups for units of blood transfused (1.32 +/- vs 1.21 +/- 0.20. p = 0.843) and patients not receiving transfusions during the entire hospitalization (44% vs 50%). Patients taking 85-325 mgm of aspirin with a normal bleeding time undergoing elective CABG did not have increased RBC loss or increased transfusion requirements. These results indicate it is not necessary to delay elective CABG surgery for the purpose of discontinuing aspirin.
Semi-closed, ex-situ, non-reversed or reversed autogenous vein grafting. A technique for femoro-distal arterial bypass, A technique is described for femoro-distal grafting in which vein is removed through very small incisions using the Mayo vein stripper. valves are ablated with the vein "ex-situ". and the graft is inserted non-reversed or reversed according to arbitrary criteria as to its diameter. with the distal anastomosis performed under tourniquet control. Early experience with 35 consecutive vein grafts showed no serious technical problems. satisfactory results and excellent patient acceptance.
Femoro-popliteal and femoro-distal bypass: a comparison between in situ and reversed technique, The present report compares the in situ technique with that using the reversed vein for femoropopliteal bypass. In 1986 the in situ technique was introduced at our clinic as the preferred method for femoropopliteal bypass with the lower anastomosis below the knee or femorodistal bypass. Forty patients operated with the in situ technique were compared with an equal number of patients operated with the reversed technique 1983-1985. The two groups were comparable regarding concomitant cardiovascular and pulmonary disease. preoperative ankle-brachial index and level of distal anastomosis. Patency after 6 months was significantly higher (84%) for the in situ grafts compared to reversed veins (49%). The difference was mainly caused by a significantly higher patency for in situ grafts anastomosed to infrapopliteal arteries. Despite better patency rates in the in situ group limb salvage at 6 months was the same in both groups. Operating time was also similar in both groups. It is concluded that the in situ technique is superior to the reversed technique. at least in infrapopliteal reconstructions. The superior patency rate and the technical advantages without apparent disadvantages are the basis for the recommendation to use the in situ technique for femoropopliteal and femorodistal bypass.
Predictors of postoperative ventricular dysrhythmias: a multivariate study, Postoperative ventricular dysrhythmias were studied to document their incidence after coronary bypass grafting and to identify risk factors for their development with the hope of finding a subgroup of patients who might benefit from postoperative. prophylactic drug therapy. One-hundred-nine patients who were undergoing urgent or elective coronary bypass grafting were studied. prospectively. Twenty-five of 109 patients (23%) developed significant postoperative ventricular dysrhythmias that required counter-shock or drug intervention. Seven of eight instances of sustained ventricular tachycardia. the most serious dysrhythmia. occurred within 36 hours of operation. There was no postoperative mortality related to these dysrhythmias. Serious postoperative complications. such as stroke. hemorrhage. or myocardial infarction. were decreased in patients with ventricular dysrhythmias versus those without (8% versus 16%. p = 0.053 for the Fisher's exact test statistic). Univariate statistical analysis was performed using 15 patient variables and revealed that advanced age (p = 0.008 for the unpaired t test). failure to use an internal mammary artery conduit (p = 0.03 for the two-tailed Fisher's exact test). and development of postoperative atrial dysrhythmias (p = 0.02 for the two-tailed Fisher's exact test) were significantly more common in patients with postoperative ventricular dysrhythmias. Variables such as previous myocardial infarction. ejection fraction less than 50%. prolonged operative time. perioperative myocardial infarction. or fewer number of vessels bypassed were not significantly increased in patients with dysrhythmias (the statistical power for these "negative" results was greater than 0.8).
Secondary femoral-distal bypass, Thirty-nine secondary femoral-distal (femorotibial and femoroperoneal) bypasses were reviewed and compared to 89 primary femoral-distal bypasses (done during the same time period) to investigate the efficacy of secondary femoral-distal bypass. Graft patency at 2 years by life table analysis was similar in both groups (38% primary group vs 36% secondary group). However. limb salvage was significantly less in the secondary group (52% vs 68% at 2 years. p less than 0.05). This decrease was primarily due to poorer limb salvage using composite grafts (prosthetic/vein) compared to vein grafts in patients who underwent secondary femoral-distal bypasses (37% vs 76% at 2 years. p less than 0.05). Postoperative wound infections and mortality were similar in both groups. Thus. femoral-distal bypass after failure of a previous infrainguinal reconstruction offers good long-term limb salvage with acceptable surgical risk when autologous vein is available for use as the arterial conduit.
Occult paravalvular leak in a clinically normal St. Jude's mitral valve presenting with life-threatening microangiopathic hemolytic anemia, A case of microangiopathic hemolytic anemia associated with a St. Jude Medical prosthetic paravalvular valve leak. not detected by echocardiography or cardiac angiography and requiring thoracotomy for diagnosis and therapy is described. The importance of considering the presence of a paravalvular leak in a patient with MAHA and a prosthetic valve even with a negative invasive cardiac work-up is discussed.
The clinical utility of carotid duplex scanning, We retrospectively compared the results of duplex scanning (DS) with contrast angiography (CAN) in the evaluation of 119 patients whose 238 carotid arteries were evaluated by both methods within a four-week period. The results of all patients were then categorized by two different definitions of severity of stenosis. Category A classified 1-29% stenosis as mild. 30-69% stenosis as moderate. and 70-99% diameter reduction as severe stenosis. Category B defined mild stenosis as 1-19% lumen diameter reduction. moderate as 20-49% stenosis. and severe as 50-99% stenosis. The findings by each classification were compared in 60 patients with hemispheric symptoms and in 59 patients with nonspecific symptoms. CAN was our "gold standard". and exhibited greater sensitivity. specificity. accuracy. and predictive values than DS. Carotid arteries with 70% stenosis were identified by DS with greater specificity. accuracy. and predictive values than were arteries with 50% stenoses. Only the sensitivity was comparable in categorizations A and B (80% and 83%). All parameters of measurement were superior in patients with hemispheric symptoms. DS alone cannot substitute for CAN in selecting patients for carotid endarterectomy because its error rate exceeded acceptable rates of complications for carotid artery surgery. The false positive rate of DS was 4%. DS failed to diagnose 7 of 19 carotid artery occlusions. 9 of 11 ulcerated plaques. 7 of 119 instances of aortic arch disease. and 13 cases of severe intracranial artery stenosis.
Surgical treatment of renovascular hypertension and respective late results. A twenty years experience, This paper presents the long term results following operative reconstruction for renovascular hypertension in 115 patients operated upon over a period of 20 years. There were 71 (61.7%) males and 44 (38.3%) females with a median age of 46 years (range 16-67). Renal revascularization was unilateral in 96 (83.4%) cases and bilateral in 19 (16.6%). Dacron knitted bypass grafts. were used in 51 and PTFE in 33 instances. Saphenous vein grafts were used in 11 patients. In 15 cases treatment was by local endarterectomy with concomitant angioplasty (12 unilateral and 3 bilateral). Simultaneous aortorenal reconstruction was undertaken in 38 (33%) patients. There were no deaths in the group with isolated renal artery reconstruction. In the group of aortorenal reconstructions. two deaths were encountered (5.7%). Postoperatively. blood pressure was either normal or improved in 83 (72%) patients at a mean follow-up period of 48.3 months (range 1-195 months). The best results were obtained in younger individuals with segmental renal artery lesions. Linear progression analysis. showed age to be a major determinant in the postoperative response to hypertension. There was a greater degree of long term success in patients with fibromuscular dysplasia. as compared to individuals with atherosclerosis. Crude survival probabilities. were 78% and 61% at 5 and 10 years respectively. Late deaths encountered in the present series. were mostly attributable to myocardial infarction (7.8%). In this series. the best results were obtained in individuals younger than 50 years of age. with segmental renal artery lesions.
Evaluation of the perforating veins of the lower extremity using high resolution duplex imaging, The purpose of this study was to evaluate duplex imaging as a means of assessing perforating veins in patients with longstanding venous stasis ulceration. Thirty patients with nonhealing venous stasis ulcers and twenty normal volunteers serving as controls were evaluated with a standard 8-MHz imaging probe and integrated pulsed Doppler. The internal diameter of perforating veins was measured and perforators were grouped into one of four categories based on functional criteria: competent perforator with venous flow (C); incompetent perforator with venous flow (IC); competent perforator with arteriovenous flow (C-AVC); incompetent perforator with arteriovenous flow (IC-AVC). Sixteen of the patients with ulcers were subsequently studied by ascending venography and in 11 patients. intraoperative identification of perforating veins was made during the Rob procedure. In this subset of patients the vessel was categorized as competent or incompetent regardless of flow signal. There were significant differences in mean perforator diameter between ulcer patients and normal volunteers. Duplex imaging identified 93 perforators and venography a total of 70. In all 16 extremities. duplex imaging made the diagnosis of significant perforating vein incompetence. verified by venography. Intraoperative findings demonstrated an excellent correlation with duplex imaging. We believe duplex imaging to be a promising new modality for evaluation of the perforating veins of the lower extremity.
Reconstructive surgery in chronic venous obstruction of the lower limbs, Forty-one patients with chronic venous insufficiency due to venous trunk obstruction of the lower limbs underwent 43 flow reconstruction procedures consisting of either free veno-venous bypass or venous transposition. The indicating symptoms for these procedures were (1) progressive chronic edema. (2) claudication while walking. or (3) trophic lesions. Doppler ultrasound and plethysmographic techniques were employed in the diagnosis while phlebography was considered the most useful and most essential technique. Iliac vein obstruction was the most common venous obstruction. followed by superficial femoral vein obstruction. Two patients were operated on for combined obstruction at both levels. Free veno-venous bypass was the most frequently used procedure. In two cases of cavo-iliac obstruction. an original technique of femoro-axillary veno-venous bypass yielded good results. Temporary arteriovenous fistulas to improve patency at sites distal to venous bypass were used in the most complex cases. Good results were obtained in 80% of the operated cases. Postoperative follow-up phlebograms were obtained in 30 of 43 operations.
Familial chylomicronemia (type I hyperlipoproteinemia) due to a single missense mutation in the lipoprotein lipase gene, Complete deficiency of lipoprotein lipase (LPL) causes the chylomicronemia syndrome. To understand the molecular basis of LPL deficiency. two siblings with drastically reduced postheparin plasma lipolytic activities were selected for analysis of their LPL gene. We used the polymerase chain reaction to examine the nine coding LPL exons in the two affected siblings and three relatives. DNA sequence analysis revealed a single nucleotide change compared with the normal LPL cDNA: a G----A substitution at nucleotide position 680. This transition caused a replacement of glutamic acid for glycine at amino acid residue 142 of the mature LPL protein. Amino acid sequence comparisons of the region surrounding glycine-142 indicated that it is highly conserved among lipases from different species. suggesting a crucial role of this domain for the LPL structure. Expression studies of the mutant LPL cDNA in COS-7 cells produced normal amounts of enzyme mass. However. the mutated LPL was not catalytically active. nor was it efficiently secreted from the cells. This established that the Gly----Glu substitution at amino acid 142 is sufficient to abolish enzymatic activity and to result in the chylomicronemia syndrome observed in these patients.
Reduced capacity and affinity of skeletal muscle for insulin-mediated glucose uptake in noninsulin-dependent diabetic subjects. Effects of insulin therapy, We have estimated the capacity and affinity of insulin-mediated glucose uptake (IMGU) in whole body and in leg muscle of obese non-insulin-dependent diabetics (NIDDM. n = 6) with severe hyperglycemia. glycohemoglobin (GHb 14.4 +/- 1.2%). lean controls (ln. n = 7) and obese nondiabetic controls (ob. n = 7). Mean +/- SEM weight (kg) was 67 +/- 2 (ln). 100 +/- 7 (ob). and 114 +/- 11 (NIDDM). P = NS between obese groups. NIDDM were also studied after 3 wk of intensive insulin therapy. GHb post therapy was 10.1 +/- 0.9. P less than 0.01 vs. pretherapy. Insulin (120 mu/m2 per min) was infused and the arterial blood glucose (G) sequentially maintained at approximately 4. 7. 12. and 21 mmol/liter utilizing the G clamp technique. Leg glucose uptake (LGU) was calculated as the product of the femoral arteriovenous glucose difference (FAVGd) and leg blood flow measured by thermodilution. Compared to ln. ob and NIDDM had significantly lower rates of whole body IMGU and LGU at all G levels. Compared to ob. the NIDDM exhibited approximately 50% and approximately 40% lower rates of whole body IMGU over the first two G levels (P less than 0.02) but did not differ at the highest G. P = NS. LGU was 83% lower in NIDDM vs. ob. P less than 0.05 at the first G level only. After insulin therapy NIDDM were indistinguishable from ob with respect to whole body IMGU or LGU at all G levels. A significant correlation was noted between the percent GHb and the EG50 (G at which 1/2 maximal FAVGd occurs) r = 0.73. P less than 0.05. Thus. (a) insulin resistance in NIDDM and obese subjects are characterized by similar decreases in capacity for skeletal muscle IMGU. but differs in that poorly controlled NIDDM display a decrease in affinity for skeletal muscle IMGU. and (b) this affinity defect is related to the degree of antecedent glycemic control and is reversible with insulin therapy. suggesting that it is an acquired defect.
Gelsolin-related amyloidosis. Identification of the amyloid protein in Finnish hereditary amyloidosis as a fragment of variant gelsolin, The Finnish type of familial amyloidosis is a systemic disease characterized by progressive cranial neuropathy. corneal lattice dystrophy. and distal sensimotor neuropathy. Amyloid fibrils were isolated from the kidney and heart of a patient with Finnish amyloidosis. After solubilization. the amyloid proteins were fractionated by gel filtration and purified by reverse-phase HPLC. Complete amino acid sequence analyses show that the two amyloid components obtained are fragments of gelsolin. an actin-modulating protein occurring in plasma and the cytoskeleton. The larger component represents residues 173-243 and the minor component residues 173-225. respectively. of mature gelsolin. When compared with the predicted primary structure of human gelsolin a single amino acid substitution is present in amyloid: at position 15 of the amyloid proteins an asparagine is found instead of an aspartic acid residue at the corresponding position (187) in gelsolin. Antibodies to a dodecapeptide of the amyloidogenic region of gelsolin specifically stain the tissue amyloid deposits in Finnish hereditary amyloidosis. The results show that the amyloid subunit protein in Finnish hereditary amyloidosis represents a new type of amyloid that is derived from an actin filament-binding region of a variant gelsolin molecule by limited proteolysis.
The role of von Willebrand factor and fibrinogen in platelet aggregation under varying shear stress, Exposure of platelets to shear stress leads to aggregation in the absence of exogenous agonists. We have now found that different adhesive proteins and platelet membrane glycoproteins are involved in aggregation depending on the shear stress conditions and the concentration of divalent cations in the medium. When blood is collected with trisodium citrate as anticoagulant. which causes a decrease in the levels of external ionized calcium ([Ca2+]o). platelet aggregation can be induced under low shear force (12 dyn/cm2) and is mediated by fibrinogen binding to the glycoprotein IIb-IIIa complex. Aggregates formed under these conditions are not stable. and when shear force is increased to 68 dyn/cm2. disaggregation results. By contrast. platelets from blood collected with hirudin as anticoagulant. wherein [Ca2+]o is within normal plasma levels. do not undergo low shear-induced aggregation; however. after exposure to a shear force above 80 dyn/cm2. aggregation is observed but only when von Willebrand factor is present and can interact with both its platelet binding sites. glycoprotein Ib-IX and glycoprotein IIb-IIIa. Fibrinogen is not involved in high shear-induced aggregation which. in fact. occurs normally in patients with severe afibrinogenemia. Thus. von Willebrand factor in the absence of exogenous agonists can mediate platelet aggregation in experimental conditions that may mimic the hemorheological situation of partially occluded arteries. This pathway of platelet aggregation involving only one adhesive ligand and two membrane adhesion receptors may play a relevant role in thrombogenesis.
Endogenous insulin-like growth factor (IGF) binding proteins cause IGF-1 resistance in cultured fibroblasts from a patient with short stature, The ED50 of insulin-like growth factor (IGF)-I-stimulated alpha-aminoisobutyric acid (AIB) uptake (mean +/- SD) in cultured fibroblasts from a child with short stature that we have reported (1.40 +/- 0.24 nM). is significantly higher than the ED50 of IGF-I-stimulated AIB uptake in fibroblasts from 11 normal subjects (0.42 +/- 0.12 nM) and from 127 short children (0.35 +/- 0.11 nM). Similarly. the ED50 of IGF-I-stimulated thymidine incorporation in fibroblasts from this child is 2.8 times higher than that in fibroblasts from four normal subjects. To minimize potential modulation of IGF-I action by endogenous IGF binding proteins in these assays. fibroblast responsiveness to [Q3.A4.Y15.L16]IGF-I. an IGF-I variant that has a 600-fold reduced affinity for serum IGF binding proteins. has been examined. The biological activity of this variant is comparable in the patient's and normal fibroblasts. suggesting that the resistance to IGF-I action cannot be attributed to a defective IGF-I receptor. To investigate directly the possibility that IGF-I sensitivity in the patient's fibroblasts is reduced by endogenous IGF binding proteins (IGFBP). binding proteins that are secreted into AIB assay buffer during a 3-h collection and that are cell-associated at the end of the collection have been analyzed. Ligand blot analysis of conditioned AIB assay buffer demonstrates that fibroblasts from the patient secrete 1.3-2.2 times more of Mr 46.400/42.900. 32.000. and 26.800 binding proteins than normal fibroblasts. The major difference between fibroblasts from the patient and from normal subjects is a striking 10-fold increase in the amount of a cell surface Mr 32.000 binding protein in the patient's fibroblasts. The Mr 32.000 binding protein is similar in size to IGFB-1 and different from IGFBP-2 and IGFBP-3. but it does not cross-react with an antibody against IGFBP-1. We conclude that the resistance to IGF-I action in the patient's fibroblasts is caused by an abnormal production and/or cell association of IGF binding proteins.
Accelerated cholesteryl ester transfer in plasma of patients with hypercholesterolemia, To discern the mechanism(s) that underlie abnormal cholesteryl ester transfer (CET) in patients with hypercholesterolemia. we have studied this dysfunctional step in reverse cholesterol transport in 13 subjects with genetically heterogeneous forms of hypercholesterolemia (HC). In all HC patients. the mass of CE transferred in whole plasma from HDL to VLDL and LDL increased rapidly initially and was significantly greater than in controls at 1. 2. and 4 h (P less than 0.005). To further characterize this disturbance. we performed a series of recombination experiments. Combining HC d less than 1.063 containing acceptor VLDL + LDL with the d greater than 1.063 fraction from controls containing donor HDL + CE-transfer protein (CETP) and not the converse combination showed the same characteristics of accelerated CET noted with intact HC plasma. indicating that abnormal transfer was associated with the HC acceptor lipoproteins. When HC VLDL and its subfractions and LDL were isolated separately and then combined with control d greater than 1.063 fractions. accelerated CET was only associated with VLDL1. Consistent with an acceleration of the neutral lipid transfer reaction occurring between HDL and VLDL1 in HC in vivo. we found that the triglyceride/CE ratio was decreased in HC VLDL1 (P less than 0.001). and increased in HDL (P less than 0.25). CETP mass was significantly increased in HC plasma (HC 2.3 +/- 4 micrograms/ml vs. control 1.3 +/- 0.3 micrograms/ml; mean +/- SD; P less than 0.025). This series of observations demonstrate that CET is accelerated in the plasma of HC patients. and this disturbance results from dysfunction of the VLDL1 subfraction rather than an elevation of CETP levels. Since an abnormality of this type in vivo can lead to the accumulation of potentially atherogenic CE-enriched apoB-containing lipoproteins in plasma. it may be an additional previously unrecognized factor that increases cardiovascular risk in HC patients.
A plasma protease which is expressed during supramaximal stimulation causes in vitro subcellular redistribution of lysosomal enzymes in rat exocrine pancreas, The complex events by which digestive enzyme zymogens and lysosomal hydrolases are segregated from each other and differentially transported to their respective membrane-bound intracellular organelles in the pancreas have been noted to be disturbed during the early stages of several models of experimental pancreatitis. As a result. lysosomal hydrolases such as cathepsin B are redistributed to the subcellular zymogen granule-rich fraction and lysosomal hydrolases as well as digestive enzyme zymogens are colocalized within large cytoplasmic vacuoles. The current study was designed to create an in vitro system that would reproduce this redistribution phenomenon. Our results indicate that cathepsin B redistribution occurs when rat pancreatic fragments are incubated with a supramaximally stimulating concentration of the cholecystokinin analogue caerulein along with plasma from an animal subjected to in vivo supramaximal caerulein stimulation. Neither the plasma nor a supramaximally stimulating concentration of caerulein. alone. is sufficient to induce in vitro cathepsin B redistribution. The ability of the plasma to induce in vitro cathepsin redistribution is dependent upon its content of a 10.000-30.000-D protein and is lost by exposure to protease inhibitors. In vitro cathepsin B redistribution also occurs when rat pancreatic fragments are incubated with plasma obtained from opossums with hemorrhagic necrotizing pancreatitis caused by bile/pancreatic duct ligation.
L-arginine normalizes endothelial function in cerebral vessels from hypercholesterolemic rabbits, We hypothesized that normal vascular reactivity could be restored in vessels from hypercholesterolemic animals by exposing them to L-arginine. the precursor of endothelium-derived relaxing factor (EDRF). Basilar arteries were harvested from New Zealand white rabbits fed normal chow or that supplemented with 2% cholesterol for 10 wk. Vessels were cannulated for perfusion at physiologic pressure. Changes in vessel diameter were monitored by videomicroscopy. In comparison to normal vessels. those from hypercholesterolemic animals vasoconstricted more to KCl. endothelin (E). and 5-hydroxytryptamine (5-HT). Conversely. vasodilation to acetylcholine (ACh) (but not that to verapamil) was significantly impaired in the hypercholesterolemic animals. In vitro administration of L-arginine (3 mM) for 45 min normalized vasodilation to ACh and vasoconstriction to E. 5-HT. and KCl in the isolated vessels from hypercholesterolemic animals. This effect was stereospecific. since D-arginine had no effect. To conclude. these data confirm that hypercholesterolemia attenuates endothelium-derived relaxation. and enhances the sensitivity of these vessels to vasoconstrictors. In vitro administration of L-arginine normalized vascular reactivity of isolated vessels from hypercholesterolemic animals. Thus. hypercholesterolemia induces a reversible endothelial dysfunction that may be corrected by supplying the precursor of EDRF. L-arginine.
Sialic acid storage diseases. A multiple lysosomal transport defect for acidic monosaccharides, A defective efflux of free sialic acid from the lysosomal compartment has been found in the clinically heterogeneous group of sialic acid storage disorders. Using radiolabeled sialic acid (NeuAc) as a substrate. we have recently detected and characterized a proton-driven carrier for sialic acid in the lysosomal membrane from rat liver. This carrier also recognizes and transports other acidic monosaccharides. among which are uronic acids. If no alternative routes of glucuronic acid transport exist. the disposal of uronic acids can be affected in the sialic acid storage disorders. In this study we excluded the existence of more than one acidic monosaccharide carrier by measuring uptake kinetics of labeled glucuronic acid [( 3H]GlcAc) in rat lysosomal membrane vesicles. [3H]GlcAc uptake was carrier-mediated with an affinity constant of transport (Kt) of 0.3 mM and the transport could be cis-inhibited or trans-stimulated to the same extent by sialic acid or glucuronic acid. Human lysosomal membrane vesicles isolated from cultured fibroblasts showed the existence of a similar proton-driven transporter with the same properties as the rat liver system (Kt of [3H]GlcAc uptake 0.28 mM). Uptake studies with [3H]NeuAc and [3H]GlcAc in resealed lysosome membrane vesicles from cultured fibroblasts of patients with different clinical presentation of sialic acid storage showed defective carrier-mediated transport for both sugars. Further evidence that the defective transport of acidic sugars represents the primary genetic defect in sialic acid storage diseases was provided by the observation of reduced. half-normal transport rates in lymphoblast-derived lysosomal membrane vesicles from five unrelated obligate heterozygotes. This study reports the first observation of a human lysosomal transport defect for multiple physiological compounds.
Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption, Acetaldehyde. the toxic product of ethanol metabolism in the liver. covalently binds to a variety of proteins. Recent studies indicate that such binding can stimulate the production of antibodies against the acetaldehyde adducts. We raised rabbit antibodies which recognized various protein-acetaldehyde conjugates but not the corresponding control proteins. Such antibodies were used in immunohistochemical studies to find out whether acetaldehyde-generated epitopes can be detected from liver specimens of 13 human subjects with different degrees of alcohol consumption. While the specimens obtained from alcohol abusers (n = 4) and alcoholics (n = 3) exhibited marked positive staining for acetaldehyde adducts inside the hepatocytes in a granular uneven pattern. the control samples (n = 6) were almost devoid of immunoreactivity. In the alcohol abusers with an early stage of alcohol-induced liver damage. staining was detected exclusively around the central veins. The data indicate that intracellular acetaldehyde adducts occur in the centrilobular region of the liver of individuals consuming excessive amounts of alcohol. Immunohistochemical detection of such adducts may prove to be of value in the early identification of alcohol abuse and in elucidating the mechanisms of alcohol-induced organ damage.
Urate crystals stimulate production of tumor necrosis factor alpha from human blood monocytes and synovial cells. Cytokine mRNA and protein kinetics, and cellular distribution, Crystals of monosodium urate (MSU) provide a dose-dependent stimulus for the production by human blood monocytes of tumor necrosis factor (TNF). a cytokine with proinflammatory properties; TNF activity was inhibited selectively by monoclonal antibody to TNF alpha. Biologically active cell-associated TNF activity peaked at 3 h and was exceeded at 6 h by extracellular activity. which peaked at 12-18 h. Comparable kinetics were observed with immunoreactive TNF alpha. TNF alpha mRNA accumulation in monocytes stimulated with MSU crystals appeared as a single peak at 2-4 h. kinetics compatible with rapid production of a short half-life transcript. In contrast. crystals of calcium pyrophosphate or of hydroxyapatite did not stimulate significant production of TNF or of message. Fresh tophaceous material from a patient with gout contained significant levels of TNF alpha and cells cultured from the tophus produced TNF alpha in vitro. In rheumatoid synovial cells. spontaneous release of TNF alpha was increased by in vitro exposure to MSU crystals. Taken together with earlier work. these results support an expanded view of gouty inflammation in which the crystal-stimulated production of cytokines provides a crucial link between crystal deposition and many of the clinical and pathological facts of both acute and chronic gouty arthritis.
Thrombospondin-induced adhesion of human platelets, Washed human unactivated platelets attached and spread on thrombospondin (TSP)-coated microtiter plates. Platelet adhesion was promoted by divalent cations Mn2+. Mg2+. and Ca2+ as compared to buffer having all divalent cations complexed with EDTA. TSP-dependent adhesion was inhibited by anti-TSP fab fragments. an anti-TSP monoclonal antibody. an RGD-containing peptide. complex-specific anti-glycoprotein (GP)IIb-IIIa monoclonal antibodies (A2A9 or AP-2) and anti-VLA-2 monoclonal antibodies (6F1 and Gi9). but not by rabbit preimmune fab fragments. mouse IgG. an anti-GPIIIa monoclonal antibody. or monoclonal antibodies against either the human vitronectin receptor. glycocalicin. or GPIV. At saturating concentrations. anti-GPIIb-IIIa inhibited adhesion by 40-60%. Glanzman's thrombasthenic platelets. which lack GPIIb-IIIa. adhered to TSP to the same extent as anti-GPIIb-IIIa-treated normal platelets or 40-60% as well as untreated normal platelets. Antibody 6F1 (5-10 micrograms/ml) inhibited platelet adhesion of both normal and thrombasthenic platelets by 84-100%. Both VLA-2 antibodies also inhibited collagen-induced platelet adhesion. but had no effect on fibronectin-induced adhesion of normal platelets. These data indicate that platelets specifically adhere to TSP and that this adhesion is mediated through GPIIb-IIIa and/or VLA-2.
Effect of nicotinic acid-induced insulin resistance on pancreatic B cell function in normal and streptozocin-treated baboons, To study the interaction between insulin secretion and insulin action in maintaining glucose homeostasis. we induced experimental insulin resistance in eight normal baboons. in six baboons treated with 40 mg/kg streptozocin (STZ-40). and in six baboons treated with 200 mg/kg streptozocin (STZ-200). Insulin resistance was induced by a 20-d continuous intravenous infusion of nicotinic acid (NA). Normal animals showed compensatory increases in several measures of insulin secretion (fasting insulin [FI]. acute insulin response to arginine [AIRarg]. acute insulin response to glucose [AIRgluc]. and glucose potentiation slope [delta AIRarg/delta G]). with no net change in fasting plasma glucose (FPG) or glycosylated hemoglobin (HbAtc). STZ-40 animals showed compensatory increases in FI. AIRarg. and AIRgluc. but delta AIRarg/delta G failed to compensate. Although FPG remained normal in this group during NA infusion. HbA1c rose significantly. STZ-200 animals failed to show compensatory changes in both AIRgluc and delta AIRarg/delta G. with both HbA1c and FPG rising. These animals showed a paradoxical inhibition of insulin secretion in response to intravenous glucose during NA infusion. at a time when they were hyperglycemic. These data indicate that a significant degree of insulin resistance does not cause hyperglycemia in the presence of normal B cell function but. in animals with reduced B cell mass and superimposed insulin resistance. the degree of hyperglycemia is proportional to the degree of pancreatic B cell dysfunction.
Fatty acid distribution in systems modeling the normal and diabetic human circulation. A 13C nuclear magnetic resonance study, A nonperturbing 13C nuclear magnetic resonance (NMR) method was used to monitor the equilibrium distribution of carboxyl 13C-enriched fatty acids (FA) between distinct binding sites on human serum albumin. native human lipoproteins. and/or phospholipid model membranes. under conditions that mimic the normal and diabetic human circulation. Two variables pertinent to the diabetic circulation were examined: FA/albumin mole ratio (as elevated in insulin deficiency and/or nephrosis) and pH (as decreased in acidosis). 13C NMR spectra for samples containing carboxyl 13C-enriched palmitate. human serum albumin. and phospholipid vesicles or native lipoproteins (all samples at pH 7.4. 37 degrees C) exhibited up to six carboxyl NMR resonances corresponding to FA bound to distinct binding sites on albumin and nonalbumin components. When the sample FA/albumin mole ratio was 1. three FA carboxyl resonances were observed (182.2. 181.8. and 181.6 ppm; designated peaks beta. gamma. and beta'. respectively). These resonances corresponded to FA bound to three distinct high-affinity binding sites on human serum albumin. When the sample mole ratio value exceeded 1. additional carboxyl resonances corresponding to FA bound to phospholipid vesicles (179.0 ppm. peak phi). lipoproteins (180.7 ppm. peak sigma). and lower affinity sites on albumin (183.8 ppm. peak alpha; 181.9 ppm. peak gamma'). were observed. The intensity of peaks phi and sigma increased with increasing mole ratio or decreasing pH. Using Lorentzian lineshape analysis. the relative mole quantities of FA bound to albumin and nonalbumin binding sites were determined. Plots of the fraction of FA associated with nonalbumin components as a function of FA/albumin mole ratio were linear and extrapolated to the abscissa at a mole ratio value of 1. This pattern of FA distribution was observed regardless of the type of nonalbumin acceptor used (phospholipid vesicles. human high- or low-density lipoproteins) or the type of FA used (palmitate. oleate. or stearate). and provided evidence for negative cooperativity for human serum albumin upon binding of 1 mol of FA per mole albumin. These in vitro NMR results suggest that the threshold FA/albumin mole ratio value for alterations in FA distributions in the human circulation may be 1. rather than 3. as previously held. The pathophysiological implications of these findings are discussed.
Enteroaggregative Escherichia coli elaborate a heat-stable enterotoxin demonstrable in an in vitro rabbit intestinal model, Enteroaggregative Escherichia coli (EAggEC) have been associated with persistent diarrhea in young children. but little is known about its pathogenesis. We assayed for enterotoxic activity in culture filtrates (CF) of EAggEC strains in Ussing chambers mounted with rabbit ileal mucosa. CF from strain 17-2. a prototype Chilean EAggEC strain. caused a greater rise in potential difference and short circuit current (SCC) than that seen in HB101 control. and this effect was abolished by protease pretreatment and partially stable after heat treatment. Ultrafiltration of 17-2 CF preparations localized the active moiety to the 2-5 kD Mr size range. CF from HB101 transformed with the 17-2 plasmid showed Ussing chamber activity. less than 10-kD CF fractions from five of six other EAggEC strains screened in Ussing chambers gave SCC responses of similar magnitude to 17-2. The 17-2 CF activity was not neutralized after pretreatment with polyclonal anti-STa antibody. Additionally. all of the seven EAggEC strains studied were nonreactive by heat-stable enterotoxin variant STa ELISA. were negative in the suckling mouse assay. and failed to hybridize with heat-stable enterotoxin variant STh and STp DNA probes. In summary. our data indicate that 17-2 produces a low molecular weight. partially heat-stable. protease-sensitive enterotoxin which appears to be plasmid associated. and genetically and immunologically distinct from E. coli STa. Preliminary screening suggests that this tox+ phenotype may be common among EAggEC.
The isolation and characterization of a Norwalk virus-specific cDNA, Norwalk virus. an important cause of epidemic. acute. nonbacterial gastroenteritis in adults and children. has eluded adaptation to tissue culture. the development of an animal model. and molecular cloning. In this study. a portion of the Norwalk viral genome encoding an immunoreactive region was cloned from very small quantities of infected stool using sequence-independent single primer amplification. Six overlapping complementary DNA (cDNA) clones were isolated by immunologic screening. The expressed recombinant protein from a representative clone reacted with six of seven high titer. Norwalk-specific. postinfection sera but not with corresponding preinfection sera. Nucleic acid sequence for all clones defined a single open reading frame contiguous with the lambda gt11-expressed beta-galactosidase protein. Only oligonucleotide probes specific for the positive strand (defined by the open reading frame) hybridized to an RNaseA-sensitive. DNaseI-resistant nucleic acid sequence extracted from Norwalk-infected stool. Furthermore. RNA extracted from serial postinfection. but not preinfection. stools from three of five volunteers hybridized to a Norwalk virus cDNA probe. Clone-specific oligonucleotide probes hybridized with cesium chloride gradient fractions containing purified Norwalk virion. In conclusion. an antigenic. protein-coding region of the Norwalk virus genome has been identified. This epitope has potential utility in future sero- and molecular epidemiologic studies of Norwalk viral gastroenteritis.
Human eosinophil major basic protein induces airway constriction and airway hyperresponsiveness in primates, We have examined the effects of direct intratracheal instillation of purified eosinophil granule proteins on pulmonary function and airway responsiveness in primates. The results of this study show for the first time that installation of major basic protein (MBP) directly into the trachea of primates results in a significant and dose-related increase in airway responsiveness to inhaled methacholine. Furthermore. MBP and eosinophil peroxidase (EPO) induce a transient bronchoconstriction immediately after instillation that resolves by 1 h postinstillation. In contrast. instillation of other eosinophil granule proteins had no effect on airway responsiveness or pulmonary function. These data indicate a direct role of the eosinophil in the pathogenesis of airway hyperresponsiveness. We suggest that the MBP of human eosinophils has an effector role in the pathogenesis of airway hyperresponsiveness which may involve active interaction with resident airway tissue cells. MBP may also mediate altered lung function in various inflammatory lung diseases associated with pulmonary eosinophilia.
Physician response to notification of acute problems in nursing homes, A frequently cited example of physicians' alleged disinterest in nursing home patients is their failure to respond rapidly or appropriately to telephone calls about acute events or important changes in patient status. This study of 45 SNFs and their 15 attached ICFs evaluated the length of time required to reach physicians by phone about significant clinical changes in patients' conditions and the appropriateness and timeliness of action taken by the physicians once contact was made. Calls on administrative matters. updating of orders. and similar routine calls were excluded. Seven hundred and fifty calls were identified from 24-hour nursing reports; the nature of the problem and the time and details of physicians' responses were recorded from patient charts. Judgment on the quality of physicians' responses was made by consensus of the regional UR committee except in the case of infections where decisions were based on detailed criteria developed in a previous study. The most frequent clinical problems were acute infections (32%). trauma (12%). GI tract disorders (11%). cardiorespiratory problems (10%). neurological disorders (7%). and diabetic control (7%). Results were very encouraging: 96% of physicians' call-backs and actions were judged to be timely. and 87% of physicians' actions taken were judged to be appropriate. However. actions taken were judged inappropriate for certain specific clinical problems. ie. in 22% (54/243) of infections. 24% (4/17) of CVA's. and 12% (6/49) of diabetic control problems. Implications for nursing home care and recommendations for improving the response to acute problems are discussed.
The quality of life in women with urinary incontinence as measured by the sickness impact profile, The objectives of this paper were to assess the quality of life of community-living women with urinary incontinence according to age. symptom group. amount of leakage. and duration. by use of the Sickness Impact Profile (SIP). Thirty-six women aged between 40 and 60 years and 40 women aged 70 years or more were randomly selected from the clients attending an incontinence clinic and interviewed using the SIP questionnaire. Urge and stress incontinence subgroups were defined by means of a symptom questionnaire. Total. psychosocial. and physical dysfunctions were moderate (8%. 7%. and 8% respectively) in general. but major differences were found when age and symptom groups were analysed. Urge symptoms were associated with more impairment than symptoms of stress incontinence. The elderly women with symptoms of stress incontinence were relatively little affected. while their younger counterparts were severely affected. especially in the categories of emotional behavior and recreation and pastimes. We conclude that urinary incontinence in women adversely affects quality of life to a significant degree; the extent depends on the nature of incontinence and the age of the person.
Epidemiology of asymptomatic bacteriuria in elderly women, We studied asymptomatic bacteriuria in elderly ambulatory women residents without indwelling catheters in self-contained apartment houses at the Philadelphia Geriatric Center (PGC). in the nursing home at PGC. and in several life-care communities (LCC). Subjects were studied every 6 months from January 1983 through January 1989. and since enrollment was continuous some participated in more surveys than others. PGC residents were middle class and lived either in a self care apartment house (CL) or nursing home (NH); LCC residents were middle or upper class. Antimicrobial therapy for asymptomatic bacteriuria was not given by the study team. The ages of the 865 women studied averaged 80.3. 82.8. and 83.3 years in LCC. CL. and NH. respectively. On each survey about 11% at LCC. 18% at CL. and 25% at NH sites had positive cultures. Turnover was high. The conversion rate from a negative to a positive culture was 5% at LCC. 11% at CL. and 8% at NH. The reversion rate from a positive to a negative culture was 33% at LCC. 34% at CL and 31% at NH (P greater than 0.05). Persistent infection with the same organism was uncommon. Infection risk was associated with residence. which was partially explained by a factor evaluating mobility. but was unrelated to age or scores evaluating activities of daily living or mental status. Besides mobility. other more complex factors play a role in the acquisition of infection.
Multicenter study of strains of respiratory syncytial virus, Two major groups of respiratory syncytial virus (RSV) strains. A and B. have been identified and their patterns of isolation determined in different communities but not simultaneously in multiple communities. In this study. we tested 483 RSV isolates from 14 university laboratories in the United States and Canada for the 1984/1985 and 1985/1986 RSV seasons; 303 (63%) isolates were group A. 114 (24%) were group B. and 66 (14%) could not be grouped. Isolates were subdivided into six subgroups within group A and three within group B; up to six and often four or more different subgroups were isolated in the same laboratory during the same RSV season. The pattern of group and subgroup isolations varied among laboratories during the same year and between years for the same laboratory. These differences suggest that RSV outbreaks are community. possibly regional. but not national phenomena. The ability to identify group and subgroup differences in isolates is a powerful tool for epidemiologic studies of RSV.
Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection, Seventy-two AIDS patients treated with ganciclovir for cytomegalovirus (CMV) disease were prospectively monitored for the development of drug-resistant virus. No resistant strains were found in 31 patients before therapy or among seven culture-positive patients treated for less than or equal to 3 months. Of 13 culture-positive patients treated for greater than or equal to 3 months. 5 excreted virus resistant (ED50. greater than 12 microM. or ED90. greater than 30 microM) to ganciclovir. Thus. 38% of patients and receiving ganciclovir for greater than 3 months and excreting virus or. overall. 7.6% of the patients were excreting CMV resistant to the drug.
Safety and immunogenicity of a live attenuated hepatitis A virus vaccine in seronegative volunteers, Seronegative adults were enrolled in a dose-escalating study of a live attenuated hepatitis A virus (HAV) vaccine that was prepared from the F' variant of HAV strain CR326F. They were injected subcutaneously with 10(4.1). 10(5.2). 10(6.1). or 10(7.3) TCID 50 of HAV vaccine (n = 40) or with placebo (n = 12) and were followed for 6 months. None of the vaccine recipients developed significant systemic reactions or aminotransferase elevations. HAV was not isolated in cell culture from any postvaccination serum or stool specimen tested. Antibody to HAV was detected by modifications of HAV antibody assays (HAVAB or HAVAB-M) in 20%. 40%. 60%. and 100% of the recipients of each vaccine dose. in ascending order. Neutralizing antibody was present in all 10(7.3) TCID50 recipients tested at 3 and 6 months after vaccination. This live attenuated HAV vaccine was well tolerated and highly immunogenic at a dose of 10(7.3) TCID50.
Epidemiology of ocular chlamydial infection in a trachoma-hyperendemic area, The epidemiology of ocular chlamydial infection in a trachoma-hyperendemic area of Tanzania was investigated. Specimens for chlamydial isolation cultures and direct fluorescent antibody cytology were collected from 1085 children aged 1-7 years. Other data included examinations for signs of clinical trachoma and the collection of household data on risk factors. A total of 33% of children had a positive laboratory test for Chlamydia species. The most important factors for predicting chlamydial infection were the presence of a sibling with laboratory evidence of infection. increased number of flies around the house. a household that herded cattle. and practice of a local religion. Younger children and girls were at no increased risk for a positive laboratory test. although these subgroups have more clinical disease. The data are compatible with a model of less frequent episodes of reinfection as children become older.
Epidemiologic studies of group 9 pneumococci in terms of protein type and 9N versus 9V capsular type, The variability among Streptococcus pneumoniae isolates of capsular group 9 was analyzed with a panel of six monoclonal antibodies to pneumococcal proteins. These antibodies differentiated the 104 group 9 isolates into 18 protein types and a group (PO) not typable with the antibody panel was used. Capsular type was determined for 87 isolates: 70% were capsular type 9V. 28% 9N. and 2% 9A. In terms of protein type. the 9V isolates were four times as diverse as the 9N isolates. Significant associations were observed between the protein type. geographic origin. and year of isolation. Statistically significant associations were also observed between different manifestations of pneumococcal disease and protein type of the capsular type 9V isolates. Thus. even within capsular types. pneumococci can be highly diverse; pneumococcal protein types may be useful in epidemiologic studies to distinguish related strains in the environment.
Pathogen-specific humoral response in Treponema pallidum-infected humans, rabbits, and guinea pigs, Molecular analysis of the humoral response to pathogen-specific polypeptides was done using sera from patients at different stages of syphilis and sera from Treponema pallidum-infected rabbits and guinea pigs collected at various times after infection. The sera were examined by ELISA. fluorescent treponemal antibody absorption test (FTA-ABS). and immunoblot before and after sequential adsorption with cyanogen bromide-activated Sepharose 4B coupled individually to five sonicated nonpathogenic treponemes. Guinea pig antisera were also adsorbed with rabbit proteins. After adsorption. sera from all three species reacted neither by ELISA nor by immunoblot with nonpathogenic treponemes. nor did guinea pig sera react with rabbit proteins. Regardless of the species of treponema used for initial adsorption. none by itself could effectively remove all cross-reactivities. Nine pathogen-specific polypeptides (15. 17. 33. 37. 39. 43. 45. 47. 97 kDa). eight (15-47 kDa) known as integral membrane or endoflagellar components. were commonly recognized by the tree species when chancre immunity developed. The substantial reduction in immune reactivity after adsorption suggests that most of these peptides consist of specific and common treponemal epitopes. Throughout the various stages of the human disease. pathogen-specific antibodies were exclusively of the IgG isotype.
Antigenic and genomic diversity within group A respiratory syncytial virus, Antigenic analysis using monoclonal antibodies and genomic analysis using ribonuclease protection was done on 47 isolates of group A respiratory syncytial virus (RSV) recovered from children in St. Louis during four RSV seasons. Antigenic analysis identified four subgroups; of the three that included more than one member. those designated A/2 and A/2V had characteristic ribonuclease protection patterns. A third subgroup. A/4. exhibited more extensive genomic heterogeneity. but all isolates were distinguishable from those in subgroups A/2 and A/2V. Individual RSV epidemic seasons included isolates representing multiple subgroups of group A and multiple intrasubgroup variants. in addition to isolates from group B. Isolates that were indistinguishable by either antigenic or genomic analysis were present in more than one epidemic season. The subgroups may represent parallel evolutionary lineages. whose relevance to RSV immunity and pathogenesis requires further study.
Varicella-zoster virus-specific immunity after herpes zoster, The frequency of varicella-zoster virus (VZV)-specific T lymphocytes was higher in elderly subjects who had herpes zoster infections than in age-matched controls. This increase in T cell response persisted for at least 2 years while antibody levels to VZV returned to control values at this time. There were no differences in T cell or antibody responses to VZV between individuals with and without postherpetic neuralgia. Elderly subjects who had not had herpes zoster had a comparable increase in VZV-specific T responder cell frequency after immunization with Oka strain VZV. The data suggest that the potential for a boost in T cell response to VZV persists in the elderly. and that immunization can elicit a T cell response in this age group.
Monoclonal antibody to the receptor for murine coronavirus MHV-A59 inhibits viral replication in vivo, Because many strains of mouse hepatitis virus (MHV) infect laboratory mice. no effective vaccine has yet been developed. An alternative approach to control MHV disease is the use of a host cell receptor-targeted ligand. To address the potential usefulness of this approach. a monoclonal antibody directed against the host cell receptor for the coronavirus MHV-A59 was administered to infant mice that were then challenged oronasally with 10(4) intracerebral infant mouse median lethal doses of MHV-A59. Antibody treatment of virus-challenged mice resulted in lower proportions of mice with MHV-A59 in target organs and markedly reduced viral titers in these organs compared with mock-treated infected mice. Some antibody-treated infected mice survived for 7 days after viral challenge. whereas no mock-treated. infected mice survived beyond day 3 after viral inoculation. These results support a receptor-targeted approach to intervention in coronavirus disease.
Bioactive and inactive forms of tumor necrosis factor-alpha in spinal fluid from patients with meningitis, Twenty-four patients. including 12 with meningitis. were admitted with meningeal symptoms and fever. Their serum and spinal fluid tumor necrosis factor-alpha (TNF alpha) levels were determined by ELISA. TNF alpha immunoreactivity was found in spinal fluid of 10 meningitis patients and one nonmeningitis patient. whereas 7 sera. 5 from meningitis patients. contained TNF alpha. Levels were significantly higher in spinal fluids than in serum samples. and the TNF alpha bioactivity of spinal fluids and sera was considerably below predictions based on ELISA measurements. Gel filtration chromatography demonstrated the presence of both polymeric (greater than 200 kDa) and oligomeric (10-40 kDa) TNF alpha in spinal fluid. Significant bioactivity was obtained only from samples containing oligomeric cytokine. In agreement with previous in vitro findings. these results strongly indicate that bioactive TNF alpha oligomers form inactive polymers and monomers. which could contribute to the observed in vivo discrepancies between immunoreactive and bioactive protein. Finally. the data support the concept of local central nervous system production of TNF alpha in meningitis.
Biochemical and genetic characterization of autoagglutinating phenotypes of Aeromonas species associated with invasive and noninvasive disease, The genetic characteristics and biochemical and structural properties of a number of autoagglutinating (AA) strains of Aeromonas associated with invasive and noninvasive disease in humans and infections in animals and from environmental sources were investigated. Of 27 strains analyzed by multilocus enzyme typing and DNA hybridization studies. 25 (93%) were confirmed to belong to either hybridization group 1 (phenospecies and genospecies Aeromonas hydrophila) or 8 (phenospecies Aeromonas sobria; genospecies Aeromonas veronii). Further analysis of 19 of these strains indicated that four major groups could be identified on the basis of serologic and surface characteristics. protein and lipopolysaccharide composition. and virulence properties; these groupings held true regardless of the site of isolation or disease process involved. The major AA+ group identified was serogroup O:11. whose strains possessed an S layer. were resistant to the bactericidal activity of normal serum. and were pathogenic in mice. The results suggest a set of useful phenotypic and structural markers for identification of specific subsets of mesophilic Aeromonas involved in a wide range of infections in the animal kingdom.
Increased phagocytic activity of polymorphonuclear leukocytes of chronic granulomatous disease as determined with flow cytometric assay, Using flow cytometry. we compared the phagocytic activity of polymorphonuclear leukocytes (PMNs) from healthy donors with that of PMNs from 10 patients with chronic granulomatous disease (CGD). eight carriers of X-linked CGD. and one patient with myeloperoxidase deficiency. Ingestion of fluorescent bacteria by CGD and myeloperoxidase-deficient PMNs was significantly increased. that is. about 1.5 times that of normal controls. In CGD carriers. two PMN populations were found: one population consisted of PMNs with enhanced phagocytosis. and the other consisted of PMNs with normal phagocytic activity. With a two-dimensional analysis. we also demonstrated in CGD carriers that phagocytosis of the PMNs that failed to generate hydrogen peroxide was significantly elevated. as was phagocytosis of PMNs in patients with CGD. while on the other hand. the PMNs that normally produced hydrogen peroxide exhibited a normal phagocytic activity. When sodium azide. an inhibitor of myeloperoxidase and catalase. was added to control and carrier PMNs. phagocytic activity was significantly increased. p less than 0.01 in both. but not to the level seen with CGD PMNs. Phagocytosis of CGD and myeloperoxidase-deficient PMNs. however. remained unchanged by the azide treatment. On the basis of above findings. we speculate that phagocytosis of CGD PMNs is increased because the H2O2-myeloperoxidase-halide system. which may modulate phagocytic activity of PMNs. fails to operate.
Effects of chronic administration of a vasopressin antagonist with combined antivasopressor and antiantidiuretic activities in rats with left ventricular dysfunction, The present experiments were designed to study the long-term aquaretic effect of [d(CH2)5-D-Tyr(Et)VAVP]. an antagonist to arginine vasopressin (AVP) with combined vascular (V1) and renal (V2) receptor inhibiting properties. in rats with left ventricular dysfunction resulting from myocardial infarction (MI). The continuous intravenous infusion of the AVP antagonist (36 micrograms/12 microliters/day) via osmotic minipumps over 11 days resulted in an increase in urine volume and a decrease in urinary osmolality by approximately 10-fold on the first day. but in subsequent days this response decreased in both the post-MI (n = 7) and normal (n = 6) rats. Nevertheless. the daily urine volume remained significantly higher and the urinary osmolality lower in the post-MI rats than in the normal ones throughout the study (p less than 0.05). In two other groups of post-MI (n = 5) and normal (n = 6) rats. intermittent intraperitoneal injections of the AVP antagonist (100 micrograms/kg) every third day resulted in a profound diuresis that was reproducible by each injection and was again significantly greater in the post-MI rats than in the normal rats (p less than 0.05). The cumulative urinary output over the first 10-day period of each treatment was greater with intermittent injections than with continuous infusion in both the post-MI and normal rats. but the difference was significant only in the post-MI rats (398.82 +/- 12.87 ml vs 309.07 +/- 32.44 ml. intermittent vs continuous. respectively. p less than 0.05). even though the cumulative dose of AVP antagonist given intermittently was only about one third of that given continuously.
Effects of diabetes mellitus on parathyroid hormone-stimulated protein kinase activity, ferredoxin phosphorylation, and renal 1,25-dihydroxyvitamin D production, Impairment in the stimulation of renal production of 1.25-dihydroxyvitamin D[1.25 (OH)2D] by parathyroid hormone (PTH) occurs in diabetes. Renal response to PTH in terms of 25-hydroxyvitamin D-1-hydroxylase (1-OHase) stimulation involves increased cyclic adenosine monophosphate (cAMP) production. increased cAMP-dependent protein kinase activity. and dephosphorylation of renal ferredoxin (renoredoxin). To identify the step where diabetes might impair PTH stimulation of 1-OHase. we studied the effects of PTH on 1.25(OH)2D production. cAMP content. cAMP-dependent protein kinase activity. and the phosphorylation state of renoredoxin by using renal slices from diabetic and nondiabetic rats. PTH and forskolin significantly stimulated 1.25(OH)2D production in renal slices from nondiabetic animals but not from diabetic animals. PTH-stimulated cAMP production and cAMP-dependent protein kinase activity in renal slices were not altered by diabetes. However. diabetes significantly impaired the capacity of PTH to dephosphorylate renoredoxin and to increase the activity of the 1-OHase enzyme complex. These results suggest that the decreased capacity of PTH to stimulate 1-OHase activity in diabetic animals may reflect the decreased capacity of PTH to alter the phosphorylation state of renoredoxin in these animals.
The presence of cartilage matrix glycoprotein in serum as determined by immunolocation analysis is not a sensitive indicator of "early" osteoarthritis of the knee, Widespread effort is being devoted to the search for a serologic "marker" that could aid in the early diagnosis of osteoarthritis and in following the progression of the disease in response to treatment. It is obvious that such a marker would have its greatest utility in patients with mild or early osteoarthritis. CMGP is a disulfide-bonded 550.000 dalton cartilage matrix glycoprotein with a half-life of only 48 to 72 hours that has been found. through immunolocation analysis. in the serum of dogs with experimentally induced osteoarthritis and in the synovial fluid of patients with osteoarthritis but not other types of arthritis. To determine whether detection of CMGP in serum might be of value in identifying patients with "early" osteoarthritis. we examined serum samples from 26 patients with knee pain who had articular cartilage lesions of osteoarthritis at arthroscopy but whose knee radiographs were normal or showed only mild or moderate osteoarthritis. CMGP was identified by immunolocation analysis with specific antibodies. Eleven patients (42%) were seropositive for CMGP. In two. the degenerative cartilage lesions visualized at arthroscopy were mild (grade 2); in the other nine they were more severe (grade 3 or 4). However. 10 of the 15 seronegative patients also had grade 3 or 4 cartilage degeneration. Thus. this serum assay for CMGP was often negative in this group of patients in the presence of well-defined cartilage degeneration.
AIDS in primary care: a report from the Ambulatory Sentinel Practice Network, BACKGROUND. Despite the importance of the epidemic of acquired immune deficiency syndrome (AIDS). little is known about the incidence and prevalence of AIDS in the patient population of primary care physicians. This study was designed as an initial step in evaluating the impact of this disease on primary care practices. METHODS. We conducted a survey to characterize the AIDS cases in the Ambulatory Sentinel Practice Network (ASPN). ASPN is a practice-based primary care research network. In 1987 it was composed of 65 practices and 193 clinicians serving approximately 270.000 patients in the United States and Canada. Clinicians representing each practice were asked to report the number of AIDS patients that their practice cared for between January 1982 and December 1987. They were further asked to characterize relevant data for these patients. RESULTS. Thirty-nine prevalent cases of AIDS were reported in ASPN from January 1982 through December 1987. Seventy-nine percent of the patients were male. 15 to 44 years of age; three patients (7.6%) were female; and all cases had at least one risk factor for AIDS. An expected number of cases for the 194.973 patients of 47 practices was calculated using age-sex register data and nationally based rates from 1986. The projected number. 13. corresponded with the number of AIDS cases. 11 and 15. reported from ASPN practices in 1986 and 1987. respectively. CONCLUSIONS. This survey suggests that AIDS is at least as prevalent in the primary care practices in ASPN as predicted using national estimates. and may. in fact. be more prevalent. Primary care clinicians need to be prepared to assume a major role in addressing the AIDS epidemic.
Patient attitudes and knowledge about HIV infection and AIDS, BACKGROUND. Family physicians are caring for an increasing number of those with human immunodeficiency virus (HIV) infection. those at risk. and those concerned about HIV disease. METHODS. A questionnaire survey of attitudes and knowledge about HIV infection was conducted in 430 patients in three family practices in Monroe County. NY. RESULTS. The majority of those surveyed had worried about catching HIV and had spoken with friends or relatives about HIV. Approximately 7.5% had had the HIV test. Approximately half of all the respondents expressed a desire to discuss HIV-related issues with their family doctor; however. less than 8% had actually done so. The majority of the respondents believed their family doctor was competent to answer questions about HIV disease. Furthermore. the majority were well informed about the modes of transmission of HIV. Many of the respondents were unsure of the lack of risk from casual contact. however. and whether acquired immune deficiency syndrome (AIDS) is incurable at the present time. CONCLUSIONS. Family physicians need to take a more active role in educating and counseling patients about HIV disease.
Incidental blood pressure elevations: a MIRNET project, BACKGROUND. A prospective study was undertaken to determine the prevalence of hypertension in office patients with an incidental diastolic blood pressure greater than or equal to 90 mm Hg. METHODS. During routine screening of 14.890 patients. 174 patients with elevated diastolic blood pressures but no previous diagnosis of hypertension were identified over a 3-month period. Only 115 (64%) returned as requested for two subsequent blood pressure readings. RESULTS. Sixty percent of those returning fit the definition for hypertension using the criteria of the Joint National Committee on Detection. Evaluation. and Treatment of Hypertension. Sixty-nine percent (43/62) of the men and 49% (26/53) of the women were hypertensive. Women under 40 years old were less likely to be hypertensive. but age did not predict hypertension in men. Among those patients with a diastolic pressure reading below 105 mm Hg. progressively higher diastolic readings on the first visit did not predict a higher probability of hypertension. Among those patients with a diastolic pressure reading above 105 mm Hg. however. 90% (9/10) were hypertensive. CONCLUSIONS. Physicians should take incidental elevation of diastolic pressure seriously because of the high prevalence of confirmed hypertension in this group of patients.
Alcohol abuse and alcoholism in primary health care settings, Alcohol problems are common in primary care patients. yet they are often not detected and treated. Methods for improving the detection and diagnosis of alcohol problems in the primary care setting are reviewed in terms of pertinent history. physical examination. and laboratory findings. Screening instruments such as the CAGE questionnaire and the Michigan Alcoholism Screening Test are recommended for routine use by primary care physicians. Such instruments have been shown to have higher sensitivity than laboratory tests alone. Although less is known about intervention and management. earlier intervention with innovative (less costly) management techniques may be both efficacious and acceptable to the patient.
Scales for rating motor impairment in Parkinson's disease: studies of reliability and convergent validity, Study 1 examined the reliability of the ratings assigned to the performance of five sign-and-symptom items drawn from tests of motor impairment in Parkinson's disease. Patients with Parkinson's disease of varying severity performed gait. rising from chair. and hand function items. Video recordings of these performances were rated by a large sample of experienced and inexperienced neurologists and by psychology undergraduates. using a four point scale. Inter-rater reliability was moderately high. being higher for gait than hand function items. Clinical experience proved to have no systematic effect on ratings or their reliability. The idiosyncrasy of particular performances was a major source of unreliable ratings. Study 2 examined the intercorrelation of several standard rating scales. comprised of sign-and-symptom items as well as activities of daily living. The correlation between scales was high. ranging from 0.70 to 0.83. despite considerable differences in item composition. Inter-item correlations showed that the internal cohesion of the tests was high. especially for the self-care scale. Regression analysis showed that the relationship between the scales could be efficiently captured by a small selection of test items. allowing the construction of a much briefer test.
Differential memory and executive functions in demented patients with Parkinson's and Alzheimer's disease, Selected aspects of verbal memory and executive function were compared in 11 demented Parkinson's disease (PD) patients and 11 Alzheimer's disease (AD) patients with equally severe dementia. with 11 healthy controls matched for age and education. Semantic and episodic memory were impared in all patients compared with controls. but to a relatively greater degree in AD patients than in those with PD. In contrast. demented PD patients were relatively more compromised on executive tasks. These findings. taken in the context of the neuropathological and neurochemical overlap between demented PD and AD patients. suggest that differences in neurobehavioural patterns in patients with these diseases are relative. rather than absolute.
The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method, Using an unbiased stereological technique. the total numbers of pigmented and non-pigmented neurons were estimated in the substantia nigra of seven patients with Parkinson's disease and seven control patients. Compared with the controls. in which the average total number of pigmented neurons was 550.000. the number of neurons was reduced by 66% in the patients. The average total number of non-pigmented neurons was 260.000 in controls and reduced by 24% in the patients. A significant correlation (r = 0.81) existed between the total numbers of pigmented and non-pigmented neurons in the controls. whereas a similar correlation (r = 0.72) in the patients fell just short of statistical significance. The stereological estimates made in this study are unbiased. in that they are independent of nerve cell size. section thickness and of dimensional changes in brain tissue induced by histological procedures. The stereological method is considerably more efficient than previous conventional methods.
Extrapyramidal features in advanced Down's syndrome: clinical evaluation and family history, Extrapyramidal. frontal release. and other neurological signs were studied in 54 demented and non-demented patients with Down's syndrome (DS). Fourteen patients were demented and five showed extrapyramidal signs. mainly of the rigid-hypokinetic spectrum and similar to Parkinsonian features in advanced Alzheimer's disease (AD). None of the non-demented patients had Parkinsonian signs. The mean age of the demented DS patients with extrapyramidal signs was significantly higher than that of the patients without. Frontal release signs were present in demented and non-demented patients. A questionnaire showed no increase in either the proportion of early- or senile-onset dementia or Parkinsonism among first- and second-degree relatives of DS patients. Parkinsonian signs appear to be present at a lower frequency in DS than in advanced AD. A speculative hypothesis about a gene dosage effect of Cu/Zn-superoxide dismutase in preventing toxic radical formation in the substantia nigra of DS patients is presented.
Cervico-ocular function in patients with spasmodic torticollis, The cervico-ocular (COR) and active and passive vestibulo-ocular reflexes (VOR) were measured in seven patients with spasmodic torticollis (ST) and six normal controls. The COR was found to be weak or absent in both groups. The VOR gain was similar in the two groups but five patients had a significant asymmetry of the response. There was no evidence of abnormal cervico-vestibular interaction during active head rotation. The study suggests that the VOR asymmetry frequently found in ST cannot be explained on the basis of an abnormal cervical input.
The prevalence of multiple sclerosis in the Southampton and South West Hampshire Health Authority, A first survey of the Southampton and South West Hampshire Health Authority showed an overall prevalence of multiple sclerosis of 99/100.000 in a population of 417.000 on 1 January 1987. This finding is similar to other recent first surveys in the South of the United Kingdom and only repeat surveys will show if case only repeat surveys will show if case ascertainment has been more complete in these than earlier first studies in Scotland.
Acute posterior multifocal placoid pigment epitheliopathy with cerebral involvement, In a patient with angiographically proven cerebral vasculitis five months after acute posterior multifocal placoid pigment epitheliopathy (APMPPE) neurological symptoms promptly responded to steroid treatment. Cerebrospinal fluid (CSF) showed a lymphocytic pleocytosis. Magnetic resonance imaging (MRI) revealed multifocal white matter lesions in the hemispheres and the brain stem suggesting a diffuse subcortical vasculitis.
Extracranial metastases of medulloblastoma in adults: literature review, A consecutive series of 30 cases of extracranial medulloblastoma metastases in adults is analysed. The majority of the patients were males with a 3:1 male/female ratio. Bone was the most frequent site of metastases in adults (77%) and children (78%). followed by lymph nodes (33%) in both children and adults. Lung metastases were more common in adults (17%). but liver metastases occurred more frequently in children (15%). Possible routes of spread and development of metastases are discussed. with special emphasis on the role of shunts in tumour seeding. Distant extracranial metastatic spread of medulloblastoma occurs at the rate of 7.1%. Mean interval between operation of the primary tumour and the discovery of metastases was shorter in children (20 months) than in adults (36 months). Survival after the discovery of metastases was also shorter in children (5 months) than in adults (9.5 months). Shunts were associated with an earlier appearance of metastases and with a poorer prognosis. A detailed review of the literature of 119 cases of medulloblastoma with extracranial metastases is provided.
Medulloblastoma: a population-based study of 532 cases, Five hundred thirty-two cases of medulloblastoma (males n = 327 and females n = 205). aged 0 to 86 years diagnosed between 1973 and 1986 were studied to determine the incidence in different geographic regions of the United States and to evaluate the effect of various factors on survival. The median age was 9 years and average follow-up time was 45 months. The overall incidence rate was 1.8 per one million person-years. Variables that were statistically significant (p less than 0.05) in a multivariate model determining survival in rank order were treatment group. sex. geographic region. year group and age. This observational study found that 1) age and sex were statistically significant factors in describing the incidence rates. whereas year group and geographic region were not; 2) no incidence peak in the third decade of life was observed; 3) a significant improvement in survival was observed in the combined 1978 to 1986 year groups relative to the 1973 to 1977 year group; 4) the overall 5-year survival probability was 45%; and 5) there has been an increase over time in the use of more than two modalities of treatment.
Increased susceptibility of human fetal astrocytes to human T-lymphotropic virus type I in culture, Human T-lymphotropic virus type I (HTLV-I) has been considered as an agent responsible for tropical spastic paraparesis and HTLV-I associated myelopathy. However. the pathogenesis of the diseases remains unclear. In a previous study we demonstrated that HTLV-I could infect adult human astrocytes and oligodendrocytes in vitro. although the rates of infected cells were low. at a rate of 0.1% and 0.01-0.05% respectively. Since mother-to-child transmission has been proposed as one of the major pathways for the prevalence of HTLV-I endemic. in the present study we investigated the susceptibility of human fetal astrocytes to HTLV-I in culture. After two days of co-culturing fetal brain cells with irradiated MT-2 cells (an HTLV-I-producing T-cell line). immunofluorescence staining revealed many positive astrocytes for HTLV-I p19 antigen. Multinucleated giant cells doubly immunoreactive to glial fibrillary acidic protein and HTLV-I antigen were frequently observed and showed a characteristic feature of hairy or fluffy external appearance. The percentage of infected astrocytes became as high as 19.4% at Day 21 of co-culture and then decreased. Electron microscopic examination revealed type C virus-like particles in astrocytes. These results indicate that human fetal astrocytes are more susceptible to HTLV-I infection than adult human astrocytes in tissue culture.
Risk factors for carotid artery stenosis: an epidemiological study of men aged 69 years, Four hundred and seventy-eight men born in 1914 and residing in the city of Malmo. Sweden. underwent ultrasonic Doppler examination of the carotid arteries in 1982/83. The known risk factors for vascular disease--blood pressure. lipids. glucose. hematocrit. alcohol consumption and Body Mass Index were also measured. A moderate stenosis (diameter reduction 30-59%) of the internal carotid artery was found in 95 men (20%); 15 men (3%) had a greater than or equal to 60% stenosis of the internal carotid artery. while 7 (1.5%) had complete unilateral occlusion. Smoking was found to be significantly related to severe carotid artery disease. There was also a significant correlation between maximum flow velocity in the internal carotid artery and triglycerides. Those quitting smoking before the age of 50 had the same incidence of internal carotid artery disease as non-smokers. while those quitting later in life had a slightly higher incidence than life-long smokers.
Self-report of physical activity and patterns of mortality in Seventh-Day Adventist men, The Adventist Mortality Study provides 26-year follow-up through 1985 for 9484 males who completed a lifestyle questionnaire in 1960. The relationship of self-reported physical activity and all cause and disease-specific mortality was examined by survival analysis and with the Cox proportional hazards model. controlling for demographic and lifestyle characteristics. Moderate activity was associated with a protective effect on cardiovascular and all cause mortality in both analyses. In the Cox model. age-specific estimates of relative risk (RR) were obtained for several endpoints due to a significant interaction between level of physical activity and attained age (age at death or end of follow-up). This model permits calculation of the age at which the RR = 1.0. or the age at crossover of risk. For moderate activity. this age was 95.6 years (95% confidence intervals. 81.7-109.4 years) for all cause mortality and 91.5 years (95% confidence intervals. 79.0-104.0 years) for cardiovascular mortality. While the protective effect on mortality associated with moderate activity decreased with increasing age. it remained significant to the verge of the present life span.
Quantifying the potential benefit of CA 125 screening for ovarian cancer, We develop a stochastic model of screening for ovarian cancer with serum levels of the CA 125 radioimmunoassay. a tumor-specific marker. The natural history of the disease is constructed using a four stage model characterized by a multivariate distribution for duration in each stage. Preserving its important features. we simplify the model to a function of two parameters; the average duration in stage I and the coefficient of variation of duration in each stage. A yearly screening program is superimposed using exponential CA 125 growth curves which result in stage-specific sensitivities corresponding to values reported in the literature. By implementing a computer simulation of the stochastic model. we estimate the benefit due to screening. This benefit is expressed as expected years of life saved per case of ovarian cancer. The model incorporates the stochastic nature of the disease process. allows easy analysis of repeated screens. and automatically accounts for correlation between subsequent tests. It provides the basis for planning optimal screening strategies with CA 125 testing.
Errors in reporting cervical screening among public health clinic patients, This study examines women's knowledge of whether or not they had a cervical smear as part of their examination in a public health clinic for sexually transmitted diseases. Usable interviews were completed with a cluster sample of 318 women. Approximately 56% of the women were not able to correctly report if they had a cervical smear; and 90% of the erroneous responses consisted of reporting a cervical smear when none actually was done. Young women and single women were more likely to report incorrectly. Overall. the results suggest considerable error in overreporting cervical screening in this population.
Estimating and testing an index of responsiveness and the relationship of the index to power, Responsiveness has been proposed as a criterion. in addition to reliability and validity. to evaluate instruments that measure quality of life or functional status. The responsiveness index measures the change in a quality of life score due to a treatment relative to the variability of changes in that score within a stable control group. We derive the expected value. variance and distribution of the responsiveness index and give a large sample distribution for comparing the responsiveness of two different instruments. We also give the relationship between the responsiveness index and the power of a test of treatment effect.
The effectiveness of the hair-restorer "Dabao" in males with alopecia androgenetica. A clinical experiment, In a randomized. double-blind trial the effectiveness of 6 months' use of a Chinese herb extract (Dabao) as a hair-restorer was studied on 396 males with alopecia androgenetica. The effect was evaluated by nonvellus hair counts. participants' opinions and a panel's judgement of a photo-report. Twenty-three participants withdrew prematurely from the study. In both the Dabao and placebo groups an increase in the amount of hair was observed; 133 and 109 hairs on a 5 cm2 marked area. a difference of 24 hairs (p = 0.03. one-sided). Participants as well as the panel reached a similar conclusion. Regarding cosmetic effect. 42% of the participants in the Dabao group and 37% in the placebo group reported positive results. The average panel score for the cosmetic result on a scale of -10 to +10 was 0.46 in the Dabao and 0.21 in the placebo group. a difference of 0.24 (p = 0.04. one-sided). It appears from our study that. although the cosmetic effect over 6 months is modest. Dabao does have a certain effect on the growth of nonvellus hair.
Evaluating cervical cone biopsy specimens with frozen sections at hysterectomy, Frozen section evaluations of cervical cone biopsy specimens were performed at the time of hysterectomy to exclude invasive cervical cancer. During a two-year period we prospectively evaluated 43 cone biopsy specimens. We found all the diagnoses made with frozen sections to be accurate when compared with prospective permanent sections. and all patients received appropriate therapy. Thirty-eight cases showed no evidence of invasion. Two patients had invasive squamous cell cervical cancer. one had invasive cervical adenocarcinoma extending to the endometrial cavity. and two had microinvasion. All invasive cancers were diagnosed correctly with frozen sections and confirmed with permanent sections. When hysterectomy immediately followed conization. no complications occurred. and no significant increase in blood loss was noted. We found frozen section evaluation of a cone biopsy specimen at the time of hysterectomy to be a reliable procedure that saves time. eliminates the risk of additional anesthesia and decreases patients' costs.
Seroprevalence of human immunodeficiency virus in women admitted to the hospital with pelvic inflammatory disease, To assess the association of the human immunodeficiency virus (HIV) with other sexually transmitted diseases we undertook an anonymous HIV antibody serosurvey of all women admitted to the hospital with pelvic inflammatory disease. All the patients were given HIV risk reduction information and offered voluntary antibody testing. Thirty-one consecutive patients were evaluated; 30 specimens were suitable for anonymous testing. Five of the 30 (16.7%) were seropositive on both an enzyme-linked immunosorbent assay and Western blot test. The majority of the patients expressed concern about their HIV risk; 23 (74%) requested confidential testing. Of those tested. five (21.7%) were seropositive; three had traditional risk factors (intravenous drug abuse and/or sexual contacts at risk). and two denied traditional risk factors but reported nonintravenous cocaine use and multiple sexual partners. Of the seronegative women. 33% reported nonintravenous cocaine use (many with multiple sexual partners). Preventing the heterosexual spread of HIV into this vulnerable population is a formidable public health challenge.
Prevalence and severity of the premenstrual syndrome. Effects of foods and beverages that are sweet or high in sugar content, The objective of this study was to evaluate whether certain foods and beverages that are high in sugar content or taste sweet are related to the prevalence and severity of the premenstrual syndrome. Specifically. we sought to evaluate whether consumption of "junk foods". chocolate. caffeine-free cola. fruit juices or alcoholic beverages might exert an effect on the premenstrual syndrome apart from any effects of daily consumption of beverages that are high in caffeine (caffeine-containing coffee. tea and colas). The study was based on 853 responses to a questionnaire probing menstrual and premenstrual health and certain daily dietary practices; it was mailed to female university students in Oregon. An analysis of the data revealed that the consumption of chocolate. but not of other junk foods. was related to the prevalence of the premenstrual syndrome among women with more severe premenstrual symptoms. Likewise. the consumption of alcoholic beverages (all alcoholic beverages and beer only) was related to the prevalence of the premenstrual syndrome among women with more severe symptoms. as were both fruit juice and caffeine-free soda. None of the associations was substantially altered when the daily consumption of beverages high in caffeine content was controlled for. Taken together. these data suggest that the consumption of foods and beverages that are high in sugar content or taste sweet is associated with prevalence of the premenstrual syndrome.
The Ball-Burch procedure for stress incontinence with low urethral pressure, Up to a 50% failure rate may be expected when genuine stress incontinence with low urethral pressure is treated with routine urethropexy. A combination of Ball and Burch procedures has been suggested as an acceptable alternative to a sling procedure for the condition. In this study. 18 women undergoing a Burch procedure and 48 undergoing a Ball-Burch procedure were available for follow-up urodynamic evaluation. The one-year objective failure rate of the Burch procedure was 38%. and that of the Ball-Burch procedure was 10%. for a statistically significant difference (P less than .05). The Ball-Burch procedure appears to be an effective means of curing women of genuine stress incontinence with low urethral pressure.
Peptide inhibition of neointimal hyperplasia in vein grafts, Angiopeptin. a novel synthetic octapeptide. was evaluated as a new approach toward the inhibition of neointimal hyperplasia in vein grafts. Male New Zealand white rabbits (n = 22) underwent carotid artery interposition bypass grafting with autologous reversed jugular vein. Nine rabbits were in the treatment group. and 13 were in the control group. The treatment group received angiopeptin 20 micrograms/kg/day by subcutaneous injection beginning 1 day before operation and continuing for 3 weeks until they were killed. At death the vein grafts were fixed in situ with 10% buffered formalyn at 80 mm Hg perfusion pressure. Histologic sections through each vein graft were analyzed by computerized morphometric analysis for area of neointimal hyperplasia (mm2). Neointimal hyperplasia in the control animals was 0.080 + 0.017 mm2 (mean + SEM). whereas neointimal hyperplasia in the group treated with angiopeptin was 0.022 + 0.006 mm2 (mean + SEM) (p = 0.02). This is the first time that peptide inhibition of neointimal hyperplasia has been demonstrated in vein grafts and may have significant implications for future use in vascular surgery.
Effects of ischemia and hemoglobin on vascular function in isolated rabbit aortas, The vascular endothelium is important in the modulation of vascular tone via production of endothelium-derived relaxing and contracting factors. The abdominal aortas of five groups of rabbits were subjected to varying lengths of ischemia (0. 1. 2. 3. or 4 hours). removed. sectioned into transverse rings. and placed in tissue baths containing Krebs' buffer at 37 degrees C and aerated with 95% O2/5% CO2. After equilibration the rings were tested for endothelium-dependent vasodilation with methacholine and nonendothelium-dependent vasodilation with nitroprusside. Endothelium-dependent relaxation as elicited by methacholine was impaired at 3 and 4 hours of ischemia but was not significantly different at 1 and 2 hours as compared to control. whereas endothelium-independent vasodilation remained normal throughout the different periods of ischemia. The addition of 1 x 10(-6) mol/L rabbit hemoglobin reduced the time needed to demonstrate significant impairment of endothelial function to 2 hours. Endothelium-independent vasodilation was not affected by hemoglobin. We conclude that hemoglobin exacerbates ischemia vascular dysfunction in the rabbit aorta.
Endovascular management of arterial intimal defects: an experimental comparison by arteriography, angioscopy, and intravascular ultrasonography, To determine the feasibility of the endovascular management of intimal defects while comparing the accuracy of arteriography with angioscopy and intravascular ultrasonography. we developed an in vivo model of arterial intimal flaps. In 10 superficial femoral arteries of five anesthetized mongrel dogs. intimal flaps were constructed and then imaged by arteriography. angioscopy. and intravascular ultrasound. A flexible microbiopsy forceps was used to remove each intimal flap under angioscopic guidance. Arteriographic lumen diameters were measured and cross-sectional areas calculated. Corresponding measurements by angioscopy and intravascular ultrasound with reduction in luminal area at the flap were obtained by use of computerized planimetry. Uniplanar arteriography identified 60% (6/10) of the intimal flaps. whereas angioscopy and intravascular ultrasound demonstrated 100%. Lumen diameter (in millimeters) measured by arteriography (3.4 +/- 0.6) correlated significantly with measurements by angioscopy (3.5 +/- 0.5. r = 0.77) and intravascular ultrasound (3.5 +/- 0.6. r = 0.96). Similarly. lumen area (square millimeters) by arteriography (9.2 +/- 2.9) correlated with measurements by angioscopy (8.9 +/- 2.2. r = 0.82) and intravascular ultrasound (8.6 +/- 2.7. r = 0.91). Reduction in lumen area by the flap by angioscopy (37 +/- 7%) and intravascular ultrasound (33 +/- 8%) also correlated significantly (r = 0.72). The intimal flaps were removed successfully in all 10 arteries as confirmed by arteriography. angioscopy. and intravascular ultrasound. We conclude that the endovascular management of intimal defects is possible. Additionally. angioscopy and intravascular ultrasound accurately evaluate lumen diameter and area while providing direct assessment of intimal defects.
Rupture of arteriovenous fistula after in situ saphenous vein bypass, Residual saphenous vein tributaries function as arteriovenous fistulas after in-situ lower extremity bypass. Whether or not all of these tributaries need to be ligated at the time of bypass is controversial since many will close spontaneously. Other consequences of retained fistulas range from local skin problems to diminished graft flow and ultimate graft thrombosis. A complication not previously reported is rupture of a retained arteriovenous fistula. This unusual and potentially catastrophic complication should be discoverable at an earlier stage by periodic graft surveillance by means of duplex sonography. The routine policy of selective ligation of saphenous vein tributaries needs to be reexamined.
Successful treatment of infected thoracoabdominal aortic graft by percutaneous catheter drainage, A large perigraft abscess infected with Klebsiella sp. developed around a woven Dacron prosthesis inserted into a patient at high-risk with a leaking thoracoabdominal aortic aneurysm. Percutaneous insertion of a sump drainage catheter under ultrasound guidance accompanied by local and systemic antibiotic therapy was the only reasonable management option. Two years later the patient remains well with no evidence of sepsis on clinical examination. hematologic studies. computerized tomography or indium 111 labeled autologous leucocyte imaging. This technique may be successful in selected high-risk situations.
The need for quality assurance in vascular surgery, The need for quality assurance in vascular surgery can be deduced from the variability in unruptured abdominal aneurysm operative death rates in a group of patients large enough that factors influencing mortality rates other than quality of care can be controlled. Operative mortality rate for 3570 patients undergoing unruptured abdominal aortic aneurysm repair was determined for all non-Veterans Administration surgeons and hospitals in New York State from 1985 to 1987. The average annual number of aneurysm operations per surgeon was 3.6. and per hospital it was 10.2. Unruptured aneurysm repair mortality for surgeons performing 1 to 5 aneurysm operations per year was 10% whereas for surgeons performing more than 26 aneurysm operations per year it was 6% (p less than 0.0001). Unruptured aneurysm repair mortality for hospitals performing 1 to 5 aneurysm operations per year was 14% and for hospitals performing more than 38 aneurysm operations per year it was 5% (p less than 0.0001). Even when these mortality rates were adjusted for differences in patient age. severity of illness. secondary diagnoses and admission status. significant mortality rate differences persisted: 9% versus 4% for low and high volume surgeons. respectively (p less than 0.001). and 12% versus 5% for low and high volume hospitals. respectively (p less than 0.001). Surgeons who performed more than 7 aneurysm operations per year devoted more of their practice to aortic (11%) and vascular operations (52%) than did surgeons who performed 7 or fewer aneurysm operations per year (2% and 19%. respectively).
Carcinoma of the extrahepatic bile ducts, Thirty-seven patients with carcinoma of the extrahepatic bile ducts (EHBD). diagnosed over 14 years from 1974 to 1987. were studied retrospectively. The most common presenting complaint was jaundice. followed by abdominal pain. nausea and vomiting. and weight loss. The majority of EHBD carcinomas were located at the middle third of the bile duct (43.2%). followed by upper third bile duct (37.8%). and lower third bile duct (18.9%). The resectability of the surgically managed group was 44.4%. The most common histologic type was adenocarcinoma. The 30-day postoperative mortality was 30.6%. The mean overall survival of the patients with EHBD carcinoma was 11.2 months. Patients with distal third tumors had the best prognosis with a mean overall survival of 16.0 months. The mean overall survival of patients with upper-third and middle-third tumors were 10.9 months and 9.4 months. A high index of suspicion of the disease as well as earlier. aggressive surgery may improve patient survival.
Prognostic value of DNA flow cytometry in paragangliomas of the carotid body, A carotid body tumor is a paraganglioma of the carotid bifurcation. Histologic appearance does not correlate with the malignant potential of the lesion. and thus a reliable prognostic marker for these tumors is lacking. To determine whether flow cytometric analysis of paraffin block specimens by DNA index and synthetic phase fraction (SPF) would be of prognostic value. a retrospective chart review of 14 patients with carotid body tumors was performed. Three of 14 tumors were aneuploid and were the only tumors with SPF greater than 15%. One of 3 patients (33%) with an aneuploid tumor (SPF = 22%) developed a local recurrence; no patient with a diploid tumor developed a recurrence. Two of 3 (67%) patients with aneuploid tumors (SPF = 18%) but only 1 of 11 (9%) with a diploid tumor were symptomatic preoperatively (P = 0.03). DNA index and SPF may help select a subgroup of patients with more aggressive tumors who are at increased risk for recurrence and therefore require closer follow-up.
Hormonal receptors in locally advanced breast cancer: change with response to neoadjuvant chemotherapy, Twenty-one cancers in 20 patients with locally advanced breast cancer were studied. Incisional biopsy was performed without using electrocautery. Tissue was obtained for histology and estrogen (ER) and progesterone (PR) receptors. Patients received chemotherapy after biopsy. All responded and had radical mastectomy performed. Tissue was removed from the mastectomy specimen to confirm residual tumor and for repeat receptor measurements. Initial receptor levels were negative in 13 cancers. Following chemotherapy. both ER and PR levels were unchanged in 11 cancers. Levels in one cancer changed from ER-PR- to ER+PR- and one changed from ER-PR- to ER+PR+. Six cancers were ER+PR+ at initial examination. Repeat receptor levels after chemotherapy were ER+PR+ in three. One ER+PR+ tumor became ER-PR+. one changed to ER+PR-. and one to ER-PR-. One ER+PR- cancer remained ER+PR- after treatment and an ER-PR+ cancer became ER-PR- after treatment. Chemotherapy dose not significantly alter hormonal levels in breast cancer tissue.
Primary undifferentiated small cell carcinoma of the esophagus: clinicopathological and flow cytometric evaluation of eight cases, We present a clinicopathological and flow cytometric evaluation of eight primary small cell carcinomas of the esophagus representing 1.5% of all esophageal malignancies diagnosed during a 22-year period (1965-1987) in the Tampere University Central Hospital. The mean age of the patients (four male and four female) was 67 years (range 55-75 years). Five cases had distant metastases at the time of diagnosis. Three patients were treated by esophageal resection. one by laser vaporisation. and four by chemotherapy. The median survival time was 4 months (range 9 days to 8 months). A complete local response to chemotherapy in serial esophagogramms was detected in one patient. All four patients given chemotherapy survived longer than those treated with esophageal resection only. Four (67%) of the six carcinomas analyzed by DNA flow cytometry contained DNA-aneuploid stemlines. The median S-phase fraction of these small cell carcinomas was high (16.3%). reflecting rapid cell proliferation rate. which may be related to their responsiveness to chemotherapy.
Serum trace elements and Cu/Zn ratio in breast cancer patients, Serum copper. zinc. and the Cu/Zn ratio were measured in 55 patients with breast disease (20 with benign breast diseases and 35 patients with breast cancer) and 30 controls. The mean serum copper levels were higher in breast cancer than in benign breast diseases (167.3 micrograms/dl vs. 117.6 micrograms/dl) (P less than 0.001) and controls (167.3 micrograms/dl vs. 98.8 micrograms/dl) (P less than 0.001). Patients with advanced breast cancer had higher serum copper levels than did patients with early breast cancer (177.9 micrograms/dl vs. 130.4 micrograms/dl) (P less than 0.001). The mean serum zinc levels were lowered only in patients with advanced breast cancer as compared with controls (88.6 micrograms/dl vs. 115.1 micrograms/dl) (P less than 0.001). Serum zinc levels were not decreased in patients with early breast cancer and benign breast diseases. The Cu/Zn ratio was increased in breast cancer patients (1.91 vs. 0.86) (P less than 0.001) but not in patients with benign breast diseases. The precise mechanisms responsible for the alterations in trace element levels in breast cancer patients are still unclear and require further evaluation. However. the serum copper levels and the Cu/Zn ratio may be used as biochemical markers in these patients.
Correlation between estrogen receptor status and histological malignancy in human breast cancer, Sixty-two breast carcinoma patients underwent mastectomy and were analyzed for correlations between estrogen receptor (ER) status of the tumor and the histological findings of tumor. age. nodal status. and tumor size. An immunocytochemical assay for the detection of ER in breast carcinomas was used to evaluate the staining intensity index (SII) of the ER level of the tumors. which was calculated from the staining intensity of cancer cells and the percentage of ER-positive cancer cells. The histological differentiation of carcinomas showed a strong correlation with the SII. A statistically significant (F = 10.580. P less than 0.0005) negative correlation was found between the grade of malignancy and the SII. Patients under 50 years of age tended to have a lower SII. whereas patients over 49 years of age tended to have a higher SII. The tumor size. and nodal status showed no correlations with the SII in any of the patients. The histological differentiation of the tumor cells showed a strong correlation with the heterogeneity of the distribution of ER-positive cells in breast cancers.
Wound healing complications in soft tissue sarcoma management: comparison of three treatment protocols, A prospective. nonrandomized comparison of three treatment protocols was undertaken in 45 patients with soft tissue sarcoma designated preoperatively as being at high risk of wound healing complications. All patients underwent complete resection of the gross tumour mass (5 with positive and 40 with negative microscopic margins). Fourteen patients received postoperative adjuvant irradiation (group I). 16 preoperative irradiation (group II). and 15 preoperative irradiation and vascularized tissue transfer to the surgical bed after resection (group III). Major wound healing complications (defined as complications requiring at least 1 further surgical procedure) were lower in group III patients (chi-square = 5.57. P less than 0.03). as was the mean postoperative hospital stay (P less than 0.02. analysis of variance). and the mean number of secondary surgical procedures. Multivariate analysis showed that the only variable influencing length of stay was the use of tissue transfer. Careful intraoperative assessment of the adequacy of resection is essential prior to performing vascularized tissue transfer to ensure that tumour contamination of the donor site is avoided. Since this study is a nonrandomized clinical trial using sequential distribution of patients to the treatment groups. the data should be considered as preliminary. rather than definitive. evidence of the efficacy of vascularized tissue transfer.
Significance of surgical adjuvant chemotherapy for gastric cancer, One hundred and twenty-four specimens (72 primaries and 52 metastases) in 107 patients with gastric cancer were tested using the human tumor clonogenic assay (HTCA). Assays for 64 specimens (52%. 33 primaries and 31 metastases) were considered evaluable. The clonogenicity of the primaries was less than that of the metastases (P less than 0.01). In the primary specimens. well-differentiated tumors were more highly clonogenic than poorly differentiated or signet ring cell tumors (P less than 0.05). Viable malignant cells and clonogenic cells were abundant in the primary tumors with mucosal (m) and submucosal (sm) invasion. i.e.. in early gastric cancers by Japanese criteria. and were reduced in numbers as the primary tumors advanced (P less than 0.05). In vitro chemosensitivity corresponded well to the clonogenicity of the primary tumors stratified by the degree of tumor invasion. At the early phase of primary tumor progression and metastasis. clonogenicity and chemosensitivity were high. Aggressive chemotherapy with sensitive drugs after surgery may improve the clinical results for the gastric cancer patients with early phase of metastases.
Mixed mesodermal tumours of the ureter, This report is of a 78 year-old male with a mixed mesodermal tumour of the left ureter. A comparison of all reported patients with such neoplasms has been made in the discussion. in an attempt at characterization of this neoplasm.
Preoperative selection for curable renovascular hypertension, Clinical research has defined the criteria for identifying "curable" renovascular hypertension. The prediction is based on the measurement of plasma renin activity in peripheral veins. renal veins. and the aorta. Renin profiles can be examined with the method of Laragh and coworkers (the so-called incremental method). in which values for plasma renin activity are incorporated into formulas to compute indexed parameters. A score is attributed to each index and the prediction is based on the final score. Because the identification of curable renovascular hypertension is made according to numerical rules. the method is easily transformed into a computer-assisted process. The program is written in BASIC. and it is short enough to run on a personal computer.
Visually evoked potentials and electroretinography in neurologic evaluation, Electrophysiologic testing of the visual system requires primarily the ERG and the VEP. The flash electroretinogram provides information about the outer retina only. The pattern electroretinogram is derived from both the outer retina and the innermost retinal layers including the ganglion cell layer. The VEP is based on electrical information recorded from the visual cortex in response to stimulation of the retina. Thus. the integrity of the entire visual pathway can be tested. Localizing ability of the VEP is limited. Since the visual cortex is heavily weighted by representation of the central retina. peripheral lesions. including those producing peripheral visual field abnormalities that do not impinge upon central fixation. may produce relatively little disturbance of the VEP. As with most tests. electrophysiologic studies of the visual system must be placed in context of the entire examination. including the patient's history and neurologic and especially neuro-ophthalmologic evaluation. Electrophysiologic testing has three main uses in neurology. Pattern-reversal VEPs may be useful in detecting hidden visual loss in multiple sclerosis; VEPs and ERGs can distinguish function from organic visual loss; and VEPs and ERGs can be useful in the diagnosis of visual loss in nonverbal patients. especially in children.
Measurement of prostate-specific antigen in serum as a screening test for prostate cancer, BACKGROUND. Prostate-specific antigen (PSA) is secreted exclusively by prostatic epithelial cells. and its serum concentration is increased in men with prostatic disease. including cancer. We evaluated its usefulness in the detection and staging of prostate cancer. METHODS. We measured serum PSA concentrations in 1653 healthy men 50 or more years old. Those with PSA values greater than or equal to 4.0 micrograms per liter then underwent rectal examination and prostatic ultrasonography. Ultrasound-directed prostatic needle biopsies were performed in the men with abnormal findings on rectal examination. ultrasonography. or both. The results were compared with those in 300 consecutively studied men 50 or more years old who underwent ultrasound-directed biopsy because of symptoms or abnormal findings on rectal examination. RESULTS. Serum PSA levels ranged from 4.0 to 9.9 micrograms per liter in 6.5 percent of the 1653 men (107). Nineteen of the 85 men in this group (22 percent) who had prostatic biopsies had prostate cancer. Serum PSA levels were 10.0 micrograms per liter or higher in 1.8 percent of the 1653 men (30). Eighteen of the 27 men in this group (67 percent) who had prostatic biopsies had cancer. If rectal examination alone had been used to screen the men who had biopsies. 12 of the 37 cancers (32 percent) would have been missed. If ultrasonography alone had been used to screen these men. 16 of the 37 cancers (43 percent) would have been missed. Serum PSA measurement had the lowest error rate of the tests. and PSA measurement plus rectal examination had the lowest error rate of the two-test combinations. CONCLUSIONS. The combination of measurement of the serum PSA concentration and rectal examination. with ultrasonography performed in patients with abnormal findings. provides a better method of detecting prostate cancer than rectal examination alone.
The influence of a family history of asthma and parental smoking on airway responsiveness in early infancy [published erratum appears in N Engl J Med 1991 Sep 5;325(10):747, BACKGROUND. Airway responsiveness to inhaled nonspecific bronchoconstrictive agents has been demonstrated in normal. healthy infants. However. it is unknown whether airway responsiveness is present from birth or if it develops as a result of subsequent insults to the respiratory tract. To investigate this question. we assessed airway responsiveness in 63 normal infants at a mean age of 4 1/2 weeks. METHODS. Respiratory function was measured with use of the partial forced expiratory flow-volume technique to determine the maximal flow at functional residual capacity (VmaxFRC). The infants inhaled nebulized histamine at sequentially doubled concentrations (0.125 to 8.0 g per liter). until a concentration was reached at which the VmaxFRC fell by 40 percent from the base-line value (PC40) or until a concentration of 8.0 g per liter was reached. We also assessed maternal serum levels of IgE. cord-serum levels of IgE. the infants' skin reactivity to several allergens. and the parents' responsiveness to histamine and obtained family histories of asthma and smoking. RESULTS. Airway responsiveness was increased in infants with a family history of asthma (n = 19; median PC40. 0.78 g per liter; 95 percent confidence interval. 0.44 to 1.15; P less than 0.01). parental smoking (n = 13; median PC40. 0.52 g per liter; 95 percent confidence interval. 0.43 to 5.40; P less than 0.05). or both (n = 20; median PC40. 0.69 g per liter; 95 percent confidence interval. 0.37 to 2.10; P less than 0.05). as compared with the infants with no family history of asthma or smoking. The infants with no family history of asthma or smoking had a median PC40 of 2.75 g per liter (95 percent confidence interval. 1.48 to 4.00). No significant relations were detected between the immunologic variables and the PC40 in the infants. CONCLUSIONS. This study indicates that airway responsiveness can be present early in life and suggests that a family history of asthma or parental smoking contributes to elevated levels of airway responsiveness at an early age.
Lack of effect of induced menses on symptoms in women with premenstrual syndrome, BACKGROUND. No physiologic abnormality of the luteal phase has been consistently demonstrated in women with premenstrual syndrome (PMS). Using the progesterone antagonist mifepristone. we truncated the late luteal phase of the menstrual cycle in a blinded fashion to evaluate the relation of the events of the late luteal phase to the symptoms of PMS. METHODS. Fourteen women with PMS were given mifepristone (12.5 or 25 mg per kilogram of body weight) by mouth on the seventh day after the surge of luteinizing hormone. On the sixth through the eighth days after the surge. they also received injections of either placebo or human chorionic gonadotropin (2000 IU). Seven women with PMS received placebo instead of both mifepristone and human chorionic gonadotropin. All the women completed daily questionnaires measuring a variety of mood-related and somatic symptoms. RESULTS. Mifepristone consistently induced menses. The women receiving only mifepristone had plasma progesterone levels like those of the follicular phase (less than 3 nmol per liter) within four days. whereas all the other women had plasma progesterone levels characteristic of the luteal phase (greater than 8 nmol per liter) for at least seven days after treatment. In all three groups. the severity of symptoms was significantly higher after treatment than before. according to an analysis of variance with repeated measures. The level and pattern of the ratings of symptom severity were similar in all treatment groups. CONCLUSIONS. Neither the timing nor the severity of PMS symptoms was altered by mifepristone-induced menses or luteolysis. The temporal association of typical PMS symptoms with an artificially induced follicular phase suggests that endocrine events during the late luteal phase do not directly generate the symptoms of PMS.
Survival and quality of life among patients receiving unproven as compared with conventional cancer therapy, BACKGROUND. Cancer treatments without proved efficacy have achieved new levels of popularity. particularly among well-educated patients. The value of these therapies is vigorously debated. METHODS. We compared the length of survival and quality of life in patients who received treatment at a prominent unorthodox cancer clinic in addition to conventional treatment and in matched control patients from an academic cancer center who received only conventional treatment. All the patients had documented extensive malignant disease associated with a predicted median survival time of less than one year. The study sample consisted of 78 pairs of patients matched according to sex. race. age. diagnosis. and time from the diagnosis of metastatic or recurrent disease. who were enrolled over a period of 3 1/2 years. Periodic follow-up (approximately every two months) continued until death. RESULTS. There was no difference between the two patient groups in length of survival. Median survival for both groups was 15 months (P = 0.22; relative risk. 1.23; 95 percent confidence interval. 0.88 to 1.72). Quality-of-life scores were consistently better among conventionally treated patients from enrollment on. CONCLUSIONS. For this sample of patients with extensive disease and for this particular unorthodox treatment regimen. conventional and unorthodox treatments produced similar results.
Mutational hotspot in the p53 gene in human hepatocellular carcinomas, Human hepatocellular carcinomas (HCC) from patients in Qidong. an area of high incidence in China. in which both hepatitis B virus and aflatoxin B1 are risk factors. were analysed for mutations in p53. a putative tumour-suppressor gene. Eight of the 16 HCC had a point mutation at the third base position of codon 249. The G----T transversion in seven HCC DNA samples and the G----C transversion in the other HCC are consistent with mutations caused by aflatoxin B1 in mutagenesis experiments. No mutations were found in exons 5.6.8 or the remainder of exon 7. These results contrast with p53 mutations previously reported in carcinomas and sarcomas of human lung. colon. oesophagus and breast; these are primarily scattered over four of the five evolutionarily conserved domains. which include codon 249 (refs 4-9). We suggest that the mutant p53 protein may be responsible for a selective clonal expansion of hepatocytes during carcinogenesis.
Association of p60c-src with polyoma virus middle-T antigen abrogating mitosis-specific activation, Polyoma middle-T antigen is required for tumorigenesis in animals and for viral transformation of a variety of cells in culture (reviewed in ref. 1). Middle-T associates with and thereby activates p60c-src. a cellular tyrosine kinase homologous to the oncogene product of Rous sarcoma virus. Activation of p60c-src by middle-T is accompanied both by dephosphorylation of tyrosine 527. a site which negatively regulates src kinase src kinase activity (reviewed in refs 4-6) and by autophosphorylation on tyrosine 416 (refs 7-10). Phosphoprotein p60c-src is subject to cell cycle-specific regulation. It is most active during mitosis and repressed in interphase. Here we report that mitotic p60c-src is dephosphorylated at tyrosine 527. We also show that in cells expressing middle-T. src kinase activity is high both in mitosis and during interphase. An oncogenic mutant src protein. p60c-src(527F). where tyrosine 527 is substituted by phenylalanine. is also highly active in all phases of the cell cycle.
Intracranial tumor in infants: characteristics, management, and outcome of a contemporary series, Since 1980. 22 patients less than 2 years of age have been treated for intracranial tumors at our institution. The most common presentation was elevated intracranial pressure associated with ventriculomegaly (73%). The diagnosis was made by computed tomography or magnetic resonance imaging and confirmed surgically in every case. In 68% of cases. the tumor involved midline structures in the central nervous system. Tumors were infratentorial in 29% of patients less than 1 year of age and in 60% of those more than 1 year of age. Most tumors were either primitive neuroectodermal tumors (41%. 7 of 9 located in midline posterior fossa structures) or astrocytomas (27%. 5 of 6 located in the hypothalamus. chiasm. or optic nerve). Twenty patients had gross or subtotal tumor resection. Surgical mortality and neurological morbidity were 10% and 5%. respectively. Of 5 patients who underwent a second operation for tumor recurrence. 3 demonstrated a change in the pathological features of the tumor from those of the original diagnosis. Of 10 surgical survivors with malignant tumors. 8 received chemotherapy and 5 radiation therapy. Radiation was not administered before 1 year of age. The overall 1-year survival was 70%. and 2-year survival was 58%. Two-year survival for benign and malignant tumors was not significantly different. We think that the interdisciplinary efforts directed toward the treatment of these tumors has improved survival and that all children should be offered entry to a research protocol and aggressive treatment.
The relevance of anatomic and hemodynamic factors to a classification of cerebral arteriovenous malformations, Potential prognostic anatomic and hemodynamic factors were evaluated in 248 patients with cerebral arteriovenous malformations (AVMs). all treated by direct microsurgical removal. The size of each AVM was calculated by its volume. obtained by the multiplication of the three AVM diameters by 0.52. A surgical classification of AVM location (in 11 groups) is proposed. Types of feeders and of drainage were classified as superficial or deep; the extent of the drainage system was classified according to a four-degree scale. The mean flow velocity in the main AVM feeder. detected using transcranial Doppler ultrasonography. was used as an indirect measure of AVM shunt flow in a small number of patients (n = 29). AVM volume was a very important prognostic factor: the incidence of hyperemic complications and the morbidity and mortality rate were significantly higher when the volume of the lesion was greater than 20 cm3 (P less than 0.0001 for hyperemic complications; P less than 0.001 for permanent morbidity and mortality). The incidence of hyperemic complications and the morbidity rate were higher in AVMs in rolandic. inferior limbic. and insular locations than in AVMs in other locations. As for other anatomic factors: a) the presence of deep feeders significantly increased the incidence of hyperemic complications. as well as the morbidity and mortality rate; b) the presence of deep drainage significantly increased permanent morbidity only; c) the extension of the venous system was significantly related to the development of hyperemic complications. and to morbidity and mortality. Transcranial Doppler examination showed that mean flow velocities greater than 120 cm/s in the main feeder were associated with a significantly higher rate of postoperative hematomas and transient deficits. A classification of cerebral AVMs that takes into account AVM volume and location. the type of feeders. the extent of the drainage system. and the main feeder flow velocity is suggested.
Effect of subarachnoid hemorrhage on serotonin uptake and release in the rabbit basilar artery, This study analyzes the changes induced by subarachnoid hemorrhage (SAH) on the serotonin (5-hydroxytryptamine. 5-HT) uptake and release evoked in rabbit basilar arteries by tyramine. Rabbits were injected with 5 ml of autologous arterial blood into the cisterna magna to produce SAH. Tritium accumulation in basilar arteries was measured after 30 minutes of incubation with 10(-7) M [3H]5-HT and a subsequent 120-minute superfusion (1 ml/min) period. The uptake of 5-HT by arteries 1. 2. 3. and 7 days after SAH was found to be 109%. 69%. 57% (P less than 0.05). and 67% (P less than 0.05) (n = 4. 4. 9. and 6; P less than 0.05) of control (n = 13; 16.8 +/- 1.2 X 10(2) dpm/mg tissue). respectively. The neuronal (cocaine-sensitive) uptake of 5-HT in the arteries 3 days after SAH decreased to approximately 38% of control. whereas the extraneuronal (cocaine-insensitive) uptake of both groups had almost the same absolute value (n = 6 and 6; 4.4 +/- 0.4 and 4.8 +/- 0.4 X 10(2) dpm/mg). Autoradiographic study disclosed that dense clusters of silver grains in the adventitia were not observed after treatment with cocaine (3 X 10(-5) M). although a diffuse distribution of grains was present throughout the vascular wall. The labeled arteries were stimulated by superfusion of tyramine. which is known to replace amines in the sympathetic nerve ending. Tyramine (10(-6) and 10(-4) M)-induced 3H efflux was significantly potentiated by SAH (n = 6) and was suppressed by treatment with cocaine.
Surrogate receptor-mediated cellular cytotoxicity against malignant human glioma cells, A method for incorporating palmitate-derivatized antibody molecules into effector cells and the influence of these incorporated antibodies (surrogate receptors) on the lytic potential of peripheral blood lymphocytes is described. This surrogate receptor-mediated cellular cytotoxicity provides a means by which killer cells are directed specifically to the desired target glioma cells. The cytotoxic activity does not require the Fc region of the incorporated antibody molecules and shows more lytic potential than ordinary antibody-dependent cellular cytotoxicity. By complement-mediated cell depletion and Percoll gradient separation. the effector cell populations for surrogate receptor-mediated cellular cytotoxicity are found to be natural killer cells. as in the murine system. This strategy of surrogate receptor incorporation into effector cells may provide not only valuable insights into the mechanism of cell-mediated cytotoxicity. but also a means of generating target-specific effector cells for clinical applications in neurosurgery.
Peritumoral blood flow in intracranial meningiomas, Blood flow was measured in intratumoral tissue. the cerebral hemispheres and particularly in the peritumoral area of 12 patients with intracranial meningiomas using the stable xenon-enhanced computed tomographic scan. Tumor blood flow frequently showed a heterogeneous pattern of enhancement with high flow at the tumor periphery and a central area of hypoperfusion. Blood flow values were on average 28% lower in the peritumoral area than in the ipsilateral cerebral hemisphere. In individual cases. blood flow values in the peritumoral edematous area were very low. These findings suggest that the hypodense area surrounding meningiomas does not solely represent vasogenic edema. but may actually represent tumor pressure ischemia.
Surgical treatment of a rare congenital anomaly of the vertebral artery: case report and review of the literature, A case of an abnormal loop of the vertebral artery compressing both the cervicomedullary junction and the accessory nerve is reported. The embryological development of the vertebrobasilar system may explain this anatomical anomaly. The possibility of an abnormal location of the vertebral artery may complicate the lateral C1-C2 puncture for myelography. Only five similar cases have been reported previously. but none of them presented any clinical symptomatology. and surgical treatment was never required. The present patient was cured by microvascular decompression. The pathogenetic and surgical implications are discussed in light of the literature.
Barbed spear injury to the skull base: case report, A case of a barbed spear injury to the left orbit and skull base is presented. The unusual nature and circumstances of the injury and the management problems related to the proximate neurovascular bundles are discussed.
Association between neuroepithelial tumor and multiple intestinal polyposis (Turcot's syndrome): report of a case and critical analysis of the literature, We report a case of association of a brain tumor with multiple intestinal polyposis (Turcot's syndrome) and offer a critical analysis of the relevant literature with a view to revising the classification of the syndrome in relation to familial multiple polyposis and Gardner's syndrome. For this purpose. we considered only cases of intestinal polyposis associated with a primary neuroepithelial tumor (medulloblastoma. glioma. or glioblastoma) as originally described by Turcot. Differences emerged. depending on the central nervous system tumor type. which suggests that this neoplastic association may be classified as two distinct syndromes.
Cervical spine diastematomyelia in adulthood, Adult cervical diastematomyelia is a rare malformation and is usually associated with posterior element anomalies. A case of isolated cervical diastematomyelia. which was initially thought to be a herniated cervical disc. is described. Diagnosis and surgical management are discussed.
Continuous regional cerebral blood flow monitoring in acute craniocerebral trauma, Regional cortical cerebral blood flow (rCBF) and intracranial pressure (ICP) were monitored continuously with a combined thermal diffusion probe/ICP monitor in 12 patients (8 men and 4 women; mean age. 31 years; range. 7-65 years) with acute head injuries. The mean Glasgow Coma Scale score at admission was 6 (range. 4-12). The rCBF/ICP probes were placed during surgical procedures (n = 11) or in an intensive care unit (n = 1) for subdural hematomas (n = 7). cerebral contusions (n = 4). and an epidural hematoma (n = 1). No probe-related complications occurred. Reduced CBF often occurred and was often inversely proportional to elevations in ICP. Posttraumatic cerebral arterial vasospasm in one patient was detected by rCBF monitoring and confirmed by angiography. In 6 patients who progressed to brain death. rCBF patterns disappeared. which correlated with their clinical and electroencephalographic examinations. Several patients with severe. diffuse brain injuries and high ICP had hyperemic rCBF patterns. In 2 of these patients. increases in rCBF preceded rises in ICP. which implied loss of autoregulation as a mechanism in the development of malignant cerebral edema. This method of CBF monitoring has not yet been established for clinical decision making. The early detection of ischemic or hyperemic responses by continuous CBF monitoring could hasten intervention aimed at restoring adequate tissue perfusion. The technique could also serve as an index of the efficacy of therapeutic interventions and is suitable to gain more insight into the pathophysiology of head injury. especially the relationship of CBF to ICP.
The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease, The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as "definite Alzheimer's disease" (AD). "probable AD." "possible AD." and "normal brain" to indicate levels of diagnostic certainty. reduce subjective interpretation. and assure common language. To pretest the protocol. neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied. the CERAD neuropathology protocol will help to refine diagnostic criteria. assess overlapping pathology. and lead to a better understanding of early subclinical changes of AD and normal aging.
Amyotrophic lateral sclerosis: fasting plasma levels of cysteine and inorganic sulfate are normal, as are brain contents of cysteine, Recent reports suggest that amyotrophic lateral sclerosis (ALS) is caused by one or more unidentified neurotoxins that are poorly metabolized in patients to less toxic and more readily excreted compounds. and that a genetically determined defect in cysteine degradation and in inorganic sulfate production is the mechanism underlying a failure to metabolize xenobiotics normally in ALS. We measured concentrations of total cysteine and of inorganic sulfate in the plasma of age-matched groups of ALS patients and healthy control subjects and found no differences. L-Cysteine. a putative endogenous neurotoxin in ALS. was present in equal concentrations in autopsied brain from ALS patients and controls.
The prognostic value of residual spikes in the postexcision electrocorticogram after temporal lobectomy, We correlated the postresection electrocorticograms (ECoGs) of 80 patients who underwent temporal lobectomy under general anesthesia for treatment of intractable complex partial seizures with surgical results in three groups: seizure/aura free (32 patients). auras only (16 patients). and one or more postoperative seizures (32 patients) at mean follow-up times of 34. 31. and 38 months. respectively. Spontaneous "residual spikes." ie. present after all resections. were present in 47% of patients who had no postoperative seizures or auras. However. they occurred in 72% of patients with any postoperative seizures (p less than 0.05). The location (convexity. mesial. or edge of resections) or the distribution (unifocal versus multifocal) of the residual spikes was not of prognostic value. Quantitative studies in 5-minute epochs of the postexcision ECoGs did not reveal a significant difference in the morphology of the residual spikes. ie. the amplitude or firing pattern (single versus polyspike). in the three groups. The group with postoperative seizures showed a higher number of spikes per epoch (greater than or equal to 50). but it was not significant. Although the study shows that patients with residual spikes may have good prognosis. they are at significantly higher risk for postoperative seizures as compared with those without residual spikes. The possibility that intensity of firing of residual spikes may be an additional predictor of outcome warrants further study.
Driving in Parkinson's disease, Altered motor or mental skills in Parkinson's disease (PD) could adversely affect driving ability. We interviewed 150 patients regarding their driving habits and compared them with 100 controls. Thirty patients had stopped driving because of PD. PD patients had no more lifetime accidents than controls. With increased disability. however. there was a smaller percentage of patients still driving with fewer miles traveled and with proportionately more accidents occurring. Though disability scores did not correlate well with driving ability. there were significantly more accidents in subjects with more severe PD. The presence of cognitive impairment was associated with an increased accident rate. We conclude that driving in PD may be a public health problem and that some PD patients should not drive.
Anticardiolipin antibodies: a study of frequency in TIA and stroke, We undertook a prospective study of consecutive patients to determine the frequency of elevated IgG and IgM anticardiolipin antibodies in transient ischemic attack and ischemic stroke and found elevated IgG antibodies in 8.2% (9 of 110) and IgM in 9.1% (10 of 110). only the former being significantly greater than in a healthy control population. We suggest that anticardiolipin screening be concentrated on the young.
Spinal cord inhibitory mechanisms in Parkinson's disease, We studied two spinal cord inhibitory mechanisms. recurrent (Renshaw) inhibition and reciprocal inhibition. in seven patients with asymmetric Parkinson's disease in order to determine their contribution to the pathogenesis of rigidity. Recurrent inhibition. studied in the leg. did not differ from that found in normal subjects. All three periods of reciprocal inhibition. studied in the forearm. were present but reduced in magnitude compared with those observed in normal subjects. The arms. whether more symptomatic or less symptomatic. gave similar results. The diminution of all three periods of reciprocal inhibition is similar to the findings in patients with dystonia and is apparently indicative of an abnormal supraspinal influence on spinal mechanisms in these two disorders of basal ganglia function.
Increased glucose metabolism in the medulla of patients with palatal myoclonus, Hypertrophic degeneration of the inferior olivary nuclei is the pathologic substrate for palatal myoclonus. but the physiologic correlate of this finding is uncertain. Using the 2-[18F]fluoro-2-deoxy-D-glucose and PET method. we determined the local cerebral metabolic rate of glucose utilization in seven patients with palatal myoclonus (following stroke or infection. or idiopathic). one patient with oculopalatal myoclonus (following a stroke affecting the brainstem). and nine normal subjects. The metabolism of glucose in the medulla of the patients with palatal myoclonus was significantly greater than that of the normal subjects. This may well have been due to increased metabolism of the inferior olivary nuclei. Glucose metabolism in the medulla of the patient with oculopalatal myoclonus was normal. These findings suggest that the inferior olivary nuclei. or a region of the brainstem encompassing the inferior olivary nuclei. are hypermetabolic in palatal myoclonus and may be the generators of the involuntary movements in palatal myoclonus.
The sensitivity of transcranial cortical magnetic stimulation in detecting pyramidal tract lesions in clinically definite multiple sclerosis, We determined central motor conduction time (CMCT) (motor cortex to root C-8 and motor cortex to root S-1) as well as the amplitude of the compound muscle action potentials in the hypothenar and the abductor hallucis muscles on both sides in 44 patients with definite MS. We compared the values with standards obtained from 86 healthy controls and correlated them with the degree of clinical deficit of the limbs examined. Thirty-nine patients (88.6%) showed a prolonged CMCT. By comparison. only 74.4% of patients had abnormal visual evoked potentials.
Interleukin-6 in cerebrospinal fluid of HTLV-I-associated myelopathy, We demonstrated significant titers of interleukin-6 (IL-6) in the CSF from 6 of 11 patients with HTLV-I-associated myelopathy (HAM). The patients positive for IL-6 generally had more severe clinical symptoms and signs than those negative for IL-6. There was no correlation between the value of IL-6 and inflammatory findings in the HAM CSF.
Cortical asymmetry of REM sleep EEG following unilateral pontine hemorrhage, A 24-year-old woman with a left pontine hematoma showed marked asymmetry in the EEG of REM sleep. suggesting that a unilateral pontine lesion is sufficient to disrupt normal REM sleep EEG in the ipsilateral hemisphere. Other REM sleep characteristics (rapid eye movements. muscle atonia) were unaffected by this lesion.
Open reduction and internal rigid fixation of subcondylar fractures via an intraoral approach, Extraoral open reduction and rigid fixation of mandibular subcondylar fractures is controversial among surgeons. An intraoral approach with a percutaneous trocar and miniplates demonstrated satisfactory reduction. This technique can be more easily performed than a preauricular or submandibular incision. and risk of facial nerve damage is diminished. Early function with proper vertical dimension was restored with minimal postoperative morbidity.
Psoriatic arthritis of the temporomandibular joints with ankylosis. Literature review and case reports, Psoriatic arthritis is currently defined as psoriasis associated with chronic. erosive inflammatory arthritis. which is seronegative for rheumatoid factor. A review of the etiology. pathogenesis. diagnosis. and treatment is accompanied by two unusual case reports of psoriatic arthritis affecting the temporomandibular joints with ankylosis.
Periodontium response to a root canal condensing device (Endotec), Two Macaca (fascicularis) monkeys were used to study the effect of two warm endodontic condensation techniques (Endotec and vertical condensation method) on periodontal tissues. The specimens were histologically evaluated at 3 and 32 days after the endodontic treatments were completed. In this study the periodontium was divided into coronal. middle. and apical thirds. Results indicated that there was no heat-related damage to periodontal tissues from either of the two methods employed. However. some Endotec specimens generated small. reactive inflammatory infiltrates that were restricted to the root canal opening or adjacent periodontal membrane. Similarly. some vertical condensation specimens developed periapical inflammatory processes as well. but they were more extensive and comprised the alveolar bone and marrow spaces.
Immediate and delayed direct pulp capping with the use of a new visible light-cured calcium hydroxide preparation, The pulpal response to mechanical exposure and capping either immediately or after 24 hours was investigated in 64 teeth of four cynomolgus monkeys with the use of Dycal. VLC Dycal. or Prisma-Bond. All overlying amalgam restorations were surface-sealed with zinc oxide-eugenol cement. After 2 months the teeth were removed and prepared for histologic examination; dentine bridges were present in almost all teeth filled with Dycal or VLC Dycal. and pulpal inflammation was observed in only one tooth that showed evidence of infection. Dentine bridges were usually incomplete when Prisma-Bond was used. although pulpal inflammation was only observed in 2 of 22 teeth. The success rate of pulp capping delayed for 24 hours was as high as that for immediate capping.
Pulpal response to tricalcium phosphate as a capping agent, The purpose of this study was to evaluate tricalcium phosphate (TCP) as a pulp-capping agent. Two adult male beagle dogs were used for this investigation. Class I cavities were prepared in the posterior teeth and Class V cavities in the anterior teeth. With the use of a rubber dam and high speed with water coolant. minimal pulp exposures were created in both the experimental and control teeth. by means of a 1/2 round bur. Zinc oxide-eugenol was the temporary filling material used to restore all cavities. In each dog. five teeth served as control and were capped with the use of calcium hydroxide. In one dog. 10 teeth from two quadrants were capped with the tested material (TCP). In the other dog. 11 teeth were capped with TCP. Four teeth from the fourth quadrant in each dog were capped with a mixture of calcium hydroxide and TCP in a ratio of 1:1 by weight (50/50 group.) The two dogs were killed after 70 days. The histologic evaluation of the response to the capping agents and at the exposure site was recorded. A total of 39 teeth were evaluated in this study. It was found that TCP as a capping agent precipitated the highest mean inflammatory response and also demonstrated the highest percentage of reparative dentin formation.
Complications in the use of sodium hypochlorite during endodontic treatment. Report of three cases, In endodontic treatment. solutions of sodium hypochlorite are widely used as an irrigating agent. It is an effective solvent of both necrotic and vital tissues. which makes it toxic to the surrounding tissues. Complications are rarely reported. Nevertheless. the acute symptoms caused by the toxic reaction must not be underestimated. Causes. treatment. and prevention of complications of sodium hypochlorite use are discussed. and three case reports are presented.
Variations in adult cortical bone mass as measured by a panoramic mandibular index, This study defines a new radiomorphometric index of mandibular cortical bone mass. the panoramic mandibular index (PMI). Differences in the index in a population of 353 adult subjects. equally divided by sex. age (30 through 79 years). and racial group (black. Hispanic. white). were evaluated. The data were analyzed with respect to side. racial group. sex. age. and combinations of these variables. Blacks were found to have a greater mean PMI than Hispanics or whites. who were statistically similar. Age-related changes comparing younger and older age groups within each sex and racial group indicated a significant decrease in mean PMI with increasing age in black and Hispanic women. The mean PMI in white men increased with advancing age.
Assessment of bone remodeling in the temporomandibular joint by serial uptake measurement of technetium 99m-labeled methylene diphosphonate with a cadmium telluride probe, Regional uptake of technetium 99m-labeled methylene diphosphonate was measured serially over time to follow the healing course of surgically generated lesions. induced unilaterally in the condyles of beagles. A small portable cadmium telluride probe was used for radiation detection. with and without a gold collimator attached. Radioactivity was measured at six periarticular sites on both the operated and the contralateral control sides and expressed as a ratio with respect to a reference site over the sagittal suture. The use of a collimator was crucial to separate the activity associated with bone mineralization in the condylar head from that arising in the adjoining bones. The uptake in the condylar region increased 2 weeks after surgery and remained at a constant level above the presurgery baseline (p less than 0.05) until termination of the study (10 weeks). Postmortem histologic examinations confirmed the high bone turnover level by revealing newly formed bone as well as the presence of osteoclasts. The time course of nuclide uptake in the temporomandibular joint is different from the general pattern of rise and fall of activity displayed in other bones and indicates the persistence of bone remodeling processes during a prolonged period of at least 10 weeks.
Electronic thermography in the assessment of internal derangement of the temporomandibular joint. A pilot study, Current diagnostic imaging methods to evaluate internal derangement of the temporomandibular joint (TMJ) include arthrotomography. arthroscopy. computed tomography. and magnetic resonance imaging. Most of these techniques either require ionizing radiation or are invasive. and all are expensive. Electronic thermography (ET) is an alternative diagnostic imaging modality that is inexpensive. nonionizing. and noninvasive. The purpose of this pilot study was to assess ET in the diagnosis of internal derangements of the TMJ. The study population consisted of 11 patients with internal derangement. and 12 normal patients. ET was conducted with an infrared thermographic unit. at 1.0 degrees and 0.5 degrees C sensitivity. Results from subjective blinded interpretations by two experts for the diagnosis of internal derangement of the TMJ were as follows: sensitivity. 86% (+/- 7.8%); specificity. 78% (+/- 7.1%). Results from objective measurements of thermal symmetry of the TMJ region were as follows: normal subjects. 89.3% (+/- 3.0%); internal derangement patients. 66.1% (+/- 16.2%); t21 = -4.89. p less than 0.01. In conclusion. ET appears to have some promise as a diagnostic aid in the evaluation of internal derangement of the TMJ. Additional. more extensive studies are needed before thermographic diagnosis of internal derangement is accepted clinically.
Public knowledge about AIDS: a survey of dental school patients. Part I, Surveys have demonstrated that the general public has many misconceptions about acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV) infection. Education has been the mainstay of the public health effort to combat the spread of HIV and AIDS. Some studies have shown an increase in the public's understanding of this disease. A survey of dental patients at a dental school clinic revealed that although misconceptions continue to exist. particularly with regard to AIDS and the dentist. this population had higher levels of knowledge about AIDS than did those in earlier studies.
Public knowledge about AIDS: a survey of dental school patients. Part II, Responses to a questionnaire on acquired immunodeficiency syndrome (AIDS) returned by patients of the Louisiana State University School of Dentistry were compared with responses to an AIDS questionnaire administered by the National Center for Health Statistics (NCHS). Although the questionnaire in this study was not patterned after that used by NCHS. some of the questions were either similar or directly opposite in content. Response patterns were compared and contrasted. In addition. those response patterns in Part I which are significantly different on the basis of demographic characteristics were compared with their counterparts in the NCHS survey.
Development of supernumerary premolars in an orthodontic population, Seven cases exhibiting supernumerary premolar development were detected during a 2-year period during the routine care of approximately 1.100 orthodontic patients. This 0.64% prevalence is more than twice as high as has been previously reported and represents an occurrence rate of 1 per 157 patients. This report describes the summary data for the cases detected and briefly reviews the available literature.
Human breast milk contains bovine IgG. Relationship to infant colic, Previous studies have suggested that an unidentified cow's milk protein. other than beta-lactoglobulin and casein. might play a pathogenetic role in infant colic. Therefore. a radioimmunoassay was used to analyze human breast milk and infant formula samples for the presence of bovine IgG. Milk samples from 88 of the 97 mothers tested contained greater than 0.1 micrograms/mL of bovine IgG. In a study group of 59 mothers with infants in the colic-prone 2- to 17-week age group. the 29 mothers of colicky infants had higher levels of bovine IgG in their breast milk (median 0.42 micrograms/mL) than the 30 mothers of noncolicky infants (median 0.32 micrograms/mL) (P less than .02). The highest concentrations of bovine IgG observed in human milk were 8.5 and 8.2 micrograms/mL. Most cow's milk-based infant formulas contained 0.6 to 6.4 micrograms/mL of bovine IgG. a concentration comparable with levels found in many human milk samples. The results suggest that appreciable quantities of bovine IgG are commonly present in human milk. that significantly higher levels are present in milk from mothers of colicky infants. and that bovine IgG may possibly be involved in the pathogenesis of infant colic.
Childhood urolithiasis: experiences and advances, Between June 1979 and June 1989. 54 children with urolithiasis were evaluated and treated at the Johns Hopkins Children's Center. The most common symptoms were flank or abdominal pain (58%) and gross hematuria (28%). In 46 children (86%). stones were secondary to a preexisting condition and in only 8 (14%) no apparent cause of stone formation could be found. Thirty-six patients (66%) had a solitary stone. most commonly found in the kidney. Urinary tract infections were present in 25 (47%) of the patients who had stones. Stones composed either of calcium oxalate or struvite were the most frequently recovered in these patients with infections. Twenty-one patients (39%) spontaneously passed their stones whereas 23 (43%) required either surgery or extracorporeal shock-wave lithotripsy to resolve stones. Ten (20%) showed recurrence of their urolithiasis. with follow-up examination periods ranging from 1 month to 10 years. Recent advances in the management of urolithiasis and their applicability to the pediatric population are discussed.
Actigraphic home-monitoring sleep-disturbed and control infants and young children: a new method for pediatric assessment of sleep-wake patterns, Two studies were conducted to evaluate actigraphic home-monitoring for the assessment of infants' and children's sleep patterns. In the first study. 11 children (aged 12 to 48 months) were monitored in the laboratory by traditional polysomnography and by actigraphy for one night. Actigraphic automatic sleep-wake scorings were compared with those of the polysomnograph; total agreement rate was 85.3%. In the second study. sleep patterns of 63 sleep-disturbed and 34 control healthy children (aged 9 to 27 months) were compared. These children were home-monitored by actigraph for a mean of 4.45 nights (total 482 nights). Actigraphic data were analyzed by an automated scoring procedure. Sleep quality of the sleep-disturbed children. measured by actigraphically derived sleep percent and number of longer-than-5-minute wakings. was significantly lower than that of the control subjects (P less than .0001). Sleep measures showed significant night-to-night stability in both groups. The stability of specific measures and their age trends were different between the groups. Actigraphic sleep measures alone could discriminate between sleep-disturbed and control children with a highly correct assignment rate of 79.4% and 91.2%. respectively.
Night waking during infancy: role of parental presence at bedtime, Night waking occurs commonly in infants and young children. The goal of this study is to determine whether parents who report being present when their infant falls asleep at bedtime are more likely to report increased frequency of night waking by the infant. Mothers were consecutively recruited when they brought their infants to the clinic for their 9-month well-child visit. A total of 122 mothers agreed to participate and completed a questionnaire consisting of closed-ended. forced choice questions about their infant's feeding and sleeping behavior. and demographic and psychosocial characteristics. For 33% of the mothers. a parent was routinely present when the infant went to sleep. The entire sample of infants averaged 4.1 night wakings during the week prior to questionnaire completion. Infants whose parents were present at bedtime were significantly more likely to wake at night than infants whose parents were not present (6.2 vs 3.1. P = .01). Frequent night waking (seven or more wakings in the prior week) occurred in 28% of the sample. More of the infants whose parents were present experienced frequent night waking compared with infants whose parents were not present (40% vs 22%. P less than .04). When potential confounding variables were controlled by multivariate analysis. parents being present when the child went to sleep was independently associated with night waking (P less than .03). The association of parental presence at bedtime and night waking has implications for preventing and managing disruptive night waking in infancy.
Failure to detect surfactant protein-specific antibodies in sera of premature infants treated with survanta, a modified bovine surfactant, Serum from premature infants enrolled in either single-dose or multidose surfactant replacement studies with bovine lung-based exogenous surfactant (Survanta) were analyzed for antibodies reactive with mixtures of bovine surfactant proteins SP-B and SP-C. Sera from 404 premature infants enrolled in single-dose studies and 1024 premature infants enrolled in multidose studies were analyzed. representing a total of 987 samples and 2743 serum samples. respectively. The sera were obtained from treated and control infants at the time of treatment and 1 week. 4 weeks. and 6 months thereafter. Polyclonal antisera generated in rabbits against the small molecular weight proteins were uniformly reactive with the bovine surfactant test antigens; however. antibodies reacting with the surfactant proteins were never detected by immunoblot analysis with the infant sera. Antibodies against common human viral antigens were readily detected in infant serum samples. The horseradish-peroxidase conjugated second antibodies (antihuman immunoglobin G or antihuman immunoglobins A. G. and M) used in the studies were highly reactive with both immunoglobin G and immunoglobin M classes of human antibodies. Therefore there was failure to detect specific immunological responses to the bovine surfactant proteins present in Survanta after single or multiple doses of exogenous surfactant administered in the perinatal period.
Primary vesicoureteral reflux in the black child, Primary vesicoureteral reflux is a polygenic abnormality due to a deficiency of the ureterovesical junction which allows urine in the bladder to ascend into the ureter and kidney. Fifty-one black children with primary vesicoureteral reflux were evaluated and treated at Children's Hospital from 1976 to 1986. The results of the evaluation and treatment were compared with those of 493 white patients with primary vesicoureteral reflux seen during the same time interval. The general approach to management was nonsurgical. There were no radical differences in the mode of presentation. age at presentation. and age at resolution. The distribution of reflux by maximum grade was not affected by race. Overall. 19 (37%) black children experienced spontaneous resolution of reflux. The mean duration of reflux in black children who had spontaneous resolution was 14.6 months. This duration was statistically significantly shorter than that in white patients with spontaneous resolution of vesicoureteral reflux (P less than .005). Surgical correction was believed to be required in 8 (16%) patients and 8 (16%) were lost to follow-up. Renal scarring demonstrated by intravenous pyelogram or renal scan was initially present in 12 (23%) black patients compared with 65 (13%) white patients. This was due to a higher percentage of renal scarring in black girls which was not explained by distribution of grades of reflux. There was no progression of scarring in our black patients. whereas 3 (0.6%) white patients had progression of scarring. Although vesicoureteral reflex is rarely seen in black patients (9% of series). it has similar demographic features.
Parental presence during procedures in an emergency room: results from 50 observations, This report describes the physician-parent-child encounter during an invasive medical procedure in a pediatric emergency department. Fifty children underwent venipuncture or intravenous cannulation performed by 22 physicians and 6 nurses. The median age of the children was 12 months. Parents remained with their children during 31 (62%) of the 50 procedures. Parents were more likely to stay if they had previously stayed when this child (P = .05) or another (P = .02) had undergone a procedure. Parental decision to stay was not related to parental age. gender. race. marital status. or level of education. nor to the residents' age. gender. or level of training. Only 43% of the parents who did stay were given that option by the residents. and of those who did not stay 37% reported that physicians asked them to leave. Nonverbal cues by the residents. such as pulling the curtain closed or turning their back toward parents. were noted in 58% of the encounters in which parents did not stay. The residents and nurses indicated that parents should stay with their child for the following procedures: laceration repair. 66%; venipuncture. 58%; intravenous cannulation. 48%; arterial blood sampling. 32%; suprapubic aspiration. 20%; and lumbar puncture. 14%. In the emergency room studied. it appears that for venipuncture and intravenous cannulation. the majority of parents stay with their children. Parental decision to stay or leave is frequently made without discussion with the physician.
Ten years of extracorporeal membrane oxygenation: neurodevelopmental outcome, Cf the 87 survivors of extracorporeal membrane oxygenation over a 10-year period. 67 participated in a follow-up study which included neurologic examination (n = 67). cognitive testing (n = 67). and audiologic assessment (n = 33). Matched control subjects for those older than 5 years were also evaluated. Outcome was defined as normal for cognitive scores greater than or equal to 85 and normal neurologic examination results. suspect for cognitive scores 70 through 84 or nonfocal neurologic findings such as hypertonia/hypotonia. and abnormal for cognitive scores less than 70 or abnormal neurologic examination results. Of the 10 school-aged children studied. 9 were normal and there were no differences in mean cognitive scores between subjects and controls (IQ subjects = 109 +/- 12 [SD]. IQ controls = 107 +/- 13). For preschoolers aged 2.7 through 4.11 years. the mean cognitive score was 91 +/- 11 and 7 (70%) were normal. For infants 6 through 30 months. the mean cognitive score was 101 +/- 22 and 27 (57%) were normal. A total of 7 children (21% of those studied) had abnormal audiologic assessments. Three children demonstrated mild high-frequency and 4 moderately severe high-frequency sensorineural hearing loss which was bilateral in 3 and of undetermined laterality in 1. Abnormal neurodevelopmental outcome was significantly associated with cerebral infarction and chronic lung disease. Outcome was not related to demographic or perinatal variables. illness severity prior to extracorporeal membrane oxygenation. or underlying diagnosis. Neurodevelopmental outcome among survivors of extracorporeal membrane oxygenation in this series is consistent with previous reports of morbidity among neonates with severe respiratory failure treated conventionally.
Protracted mononucleosis-like illness associated with acquired cytomegalovirus infection in a previously healthy child: transient cellular immune defects and chronic hepatopathy, Ordinarily. severe disease due to acquired cytomegalovirus (CMV) infection does not occur in immunocompetent children. We describe a previously healthy boy who acquired primary CMV infection at approximately 2 years of age and experienced a 2-year-long debilitating multisystem illness from which he ultimately recovered. Clinical features of this illness included fatigue. poor weight gain. pallor. unexplained fever. musculoskeletal complaints. drenching night sweats. lymphadenopathy. and massive hepatosplenomegaly. Laboratory abnormalities included elevated erythrocyte sedimentation rate. lymphocytosis. and elevated immune complex levels. Cellular immune function was impaired during the illness but was demonstrably normal during convalescence. and there was no other evidence for a known immunodeficiency state. Immunoblot analysis showed enhanced antibody response to a 66-kd infected cell protein after symptomatic recovery. Despite consistently normal indices of hepatic function. liver enlargement persisted after other symptoms had resolved. Liver biopsy demonstrated a mononuclear cell portal tract infiltrate with fibrosis. but CMV could not be demonstrated directly in this tissue. Primary CMV infection has not been reported previously to cause the persistent symptoms seen in this child.
A six-amino acid deletion in basic fibroblast growth factor dissociates its mitogenic activity from its plasminogen activator-inducing capacity, A recombinant deletion mutant of the 155-amino acid form of human basic fibroblast growth factor (bFGF). lacking amino acid residues 27-32 (Lys-Asp-Pro-Lys-Arg-Leu). was expressed in Escherichia coli and purified to homogeneity by heparin-Sepharose affinity chromatography. When maintained in the presence of an equimolar concentration of soluble heparin. the bFGF mutant (M1-bFGF) is as potent as bFGF in stimulating cell proliferation in normal and transformed fetal bovine aortic endothelial cells. in adult bovine aortic endothelial cells. and in NIH 3T3 fibroblasts. However. under the same experimental conditions. M1-bFGF is at least 100 times less efficient than bFGF in stimulating plasminogen activator (PA) production in endothelial cells. as assayed by chromogenic PA assay. SDS/PAGE zymography. and Northern blot analysis of urokinase-type PA mRNA. In the presence of heparin. M1-bFGF binds to bFGF plasma membrane receptors present on endothelial cells in a manner undistinguishable from bFGF. It also induces the same tyrosine phosphorylation pattern when added to NIH 3T3 cells. The data suggest that the PA-inducing activity of bFGF may depend upon a functional domain that differs from those involved in the mitogenic activity of the growth factor and that the binding of bFGF to its plasma membrane receptor may not be sufficient to induce urokinase-type PA production in endothelial cells.
Nerve growth factor stimulates protein tyrosine phosphorylation in PC-12 pheochromocytoma cells, The cellular actions of nerve growth factor (NGF) and epidermal growth factor (EGF) may be mediated by changes in protein phosphorylation. The tyrosine phosphorylation of two predominant proteins of molecular mass 40 and 42 kDa is seen in PC-12 cells treated with NGF or EGF. correlating with activation of a previously identified serine/threonine protein kinase that phosphorylates microtubule-associated protein (MAP). Stimulation of phosphoprotein (pp) 40 and 42 phosphorylation and MAP kinase activity by NGF but not EGF is selectively attenuated by staurosporine and K-252A. Moreover. the time courses of pp40/42 phosphorylation and MAP kinase activation produced by NGF or EGF are identical. Chromatography of lysates from growth factor-treated cells on ion-exchange or hydrophobic-interaction HPLC resolves MAP kinase into two peaks. neither of which precisely coelutes with pp40 or pp42. One of these peaks (II) exhibits no detectable phosphotyrosine. The other peak (I) has some overlap with pp40. However. the activity residing in both peaks is almost completely inhibited after treatment with alkaline phosphatase. suggesting that. at least. serine/threonine phosphorylation is required for the activity of these enzymes. These data indicate that while tyrosine phosphorylation appears to be a critical early event in NGF action. the role of this modification in activation of MAP kinases remains unclear.
Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression, Genetic diversity and relationships among 108 isolates of the bacterium Streptococcus pyogenes recently recovered from patients in the United States with toxic-shock-like syndrome or other invasive diseases were estimated by multilocus enzyme electrophoresis. Thirty-three electrophoretic types (ETs). representing distinctive multilocus clonal genotypes. were identified. but nearly half the disease episodes. including more than two-thirds of the cases of toxic-shock-like syndrome. were caused by strains of two related clones (ET 1 and ET 2). These two clones were also represented by recent pathogenic European isolates. A previous report of a relatively high frequency of expression of exotoxin A among isolates recovered from toxic-shock-like syndrome patients in the United States was confirmed; and the demonstration of this association both within clones and among distantly related clones supports the hypothesis that exotoxin A is a causal factor in pathogenesis of this disease. Near identity of the nucleotide sequences of the exotoxin A structural gene of six isolates of five ETs in diverse phylogenetic lineages was interpreted as evidence that the gene has been horizontally distributed among clones. presumably by bacteriophage-mediated transfer.
Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific, Complementary DNA clones encoding two distinct tumor necrosis factor receptors were isolated from a mouse macrophage cDNA library. The cDNA for murine tumor necrosis factor receptor type 1 (mTNF-R1) predicts a mature polypeptide of 425 amino acids that is 64% identical to its human counterpart. whereas the cDNA of murine tumor necrosis factor receptor type 2 (mTNF-R2) predicts a mature protein of 452 amino acids that is 62% identical to human tumor necrosis factor receptor type 2. The two murine tumor necrosis factor receptors have limited sequence homology (approximately 20% identity) in their extracellular regions but no apparent similarity in their cytoplasmic portions. Northern (RNA) analysis indicates a single 2.6-kilobase (kb) transcript for mTNF-R1; a 3.6-kb and a more predominant 4.5-kb transcript are observed for mTNF-R2. A human cell line transfected with either mTNF-R1 or mTNF-R2 expression vectors specifically bound 125I-labeled recombinant murine tumor necrosis factor alpha (TNF-alpha). Although mTNF-R1 had a similar affinity for both recombinant murine TNF-alpha and human TNF-alpha. mTNF-R2 showed strong specificity for recombinant murine TNF-alpha. This result suggests that the various activities of human tumor necrosis factor alpha reported in mice or in murine cell lines are probably mediated by mTNF-R1.
Gender differences in age effect on brain atrophy measured by magnetic resonance imaging, A prospective sample of 69 healthy adults. age range 18-80 years. was studied with magnetic resonance imaging scans (T2 weighted. 5 mm thick) of the entire cranium. Volumes were obtained by a segmentation algorithm that uses proton density and T2 pixel values to correct field inhomogeneities ("shading"). Average (+/- SD) brain volume. excluding cerebellum. was 1090.91 ml (+/- 114.30; range. 822.19-1363.66). and cerebrospinal fluid (CSF) volume was 127.91 ml (+/- 57.62; range. 34.00-297.02). Brain volume was higher (by 5 ml) in the right hemisphere (P less than 0.0001). Men (n = 34) had 91 ml higher brain and 20 ml higher CSF volume than women (n = 35). Age was negatively correlated with brain volume [r(67) = -0.32. P less than 0.01] and positively correlated with CSF volume (r = 0.74. P less than 0.0001). The slope of the regression line with age for CSF was steeper for men than women (P = 0.03). This difference in slopes was significant for sulcal (P less than 0.0001). but not ventricular. CSF. The greatest amount of atrophy in elderly men was in the left hemisphere. whereas in women age effects were symmetric. The findings may point to neuroanatomic substrates of hemispheric specialization and gender differences in age-related changes in brain function. They suggest that women are less vulnerable to age-related changes in mental abilities. whereas men are particularly susceptible to aging effects on left hemispheric functions.
Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease, Von Hippel Lindau disease (VHL) is a hereditary syndrome. associated with tumors and cysts in multiple organ systems. whose expression and age of onset are highly variable. The availability of a genetic test for the early and reliable detection of individuals carrying the defective gene would be beneficial for VHL patients and their relatives. since many of the manifestations of VHL can be successfully treated if detected in their early stages. while the complications of undetected disease can be devastating. We have previously shown that the VHL gene maps to chromosome 3p. To provide genetic markers for the development of a reliable diagnostic test. and to further narrow and eventually clone the VHL defect. we have generated DNA markers for chromosome 3p. With these markers. we have performed a multipoint genetic linkage analysis in 28 VHL pedigrees. comprising 470 individuals. 164 of whom were affected with VHL. Here we report the identification of tightly linked markers. including flanking markers that bracket the VHL gene to a small region on chromosome 3p25-p26. This finding has several major implications. While visceral cysts of the kidney. pancreas. and epididymis are commonly found in VHL and are considered diagnostic criteria for this disorder. they also occur in the general population. The presence of cysts. unaccompanied by other more typical lesions such as retinal and cerebellar hemangioblastoma. may therefore represent a major diagnostic problem. leading to errors in the assessment of disease status. The application of flanking markers for the VHL gene for presymptomatic diagnostic testing confirms that epididymal cysts are indeed not suitable as a diagnostic criterion in this disorder. Pheochromocytomas occur nonuniformly in VHL families and may also be associated with other hereditary tumor syndromes; our genetic studies imply that the phenotype in VHL families with and without pheochromocytomas is caused by defects within the same gene. The absence or presence of this tumor type is therefore due to the pleiotropic expression of a single gene rather than to the existence of several different genes for VHL. The region on chromosome 3p13-p14 known to contain several chromosomal translocation breakpoints in families with "pure familial renal cell carcinoma" is quite proximal to the VHL locus in 3p25-p26 we have identified. Chromosome 3p may therefore contain two loci for renal cell carcinoma: one gene (or genes) in 3p13-p14 and the VHL gene in 3p25-p26. whose aberration is also associated with other typical manifestations of VHL.(ABSTRACT TRUNCATED AT 400 WORDS).
Osteoclastic inhibition: an action of nitric oxide not mediated by cyclic GMP, The osteoclast is unique in its ability to resorb bone. and excessive osteoclastic activity has been implicated in osteoporosis. Paget disease of bone. rheumatoid arthritis. and the growth of metastases in bone. The activity of this cell is controlled by the main circulating inhibitor. calcitonin. in association with locally produced modulators. We show that nitric oxide (NO) may be an important member of the latter group. NO is produced by the vascular endothelium and nervous system and is involved in both neurotransmission and the regulation of blood pressure. However. our results show that the autocoid is also a potent inhibitor of osteoclast function. NO (30 microM) produced a decrease to approximately 50% of the original osteoclast spread area. Similar effects were also produced by 3-morpholinosydnonimine or sodium nitroprusside. reagents that spontaneously release NO. These shape changes were associated with a reduction of bone resorption after a 24-hr incubation of isolated osteoclasts on devitalized bone slices. NO is thought to act by stimulating guanylate cyclase. with a consequent increase in cyclic GMP. but a different mode of action is likely in the osteoclast since dibutyryl or 8-bromo cyclic GMP have no effect. It should be noted that calcitonin can produce similar changes in shape and activity but is associated with an increase in osteoclast intracellular calcium and cessation of membrane movement; neither of these is produced by NO. suggesting that its mode of action is different. The abundance of NO-producing endothelial cells in bone marrow and their proximity to osteoclasts suggests that marrow endothelial cells may play a physiological role in the regulation of osteoclastic activity.
Aspartylglycosaminuria in the Finnish population: identification of two point mutations in the heavy chain of glycoasparaginase, Aspartylglycosaminuria is an inherited lysosomal storage disease caused by deficiency of glycoasparaginase (EC 3.5.1.26) and occurs with higher frequency among Finns than other populations. We have purified human glycoasparaginase and determined about 90% of the amino acid sequence of its light subunit and greater than 70% of that of its heavy subunit by Edman degradation and mass spectrometry. Additional sequence data were obtained from the cloning and subsequent nucleotide analysis of a cDNA corresponding to the normal human glycoasparaginase gene. The enzyme is encoded by a single mRNA as a single polypeptide that is posttranslationally processed to generate the subunits and is glycosylated. After preparing first-strand cDNA from leukocyte and fibroblast total RNA. we used the polymerase chain reaction to amplify the glycoasparaginase cDNA of eight Finnish aspartylglycosaminuria patients. We demonstrate that the Finnish patients' mRNA sequence differed from the normal sequence by two single-base changes six nucleotides apart from one another in the heavy chain of glycoasparaginase. The first change resulted in the replacement of arginine by glutamine (R161Q). whereas the second change resulted in a cysteine to serine substitution (C163S). Both mutations resulted in novel restriction endonuclease sites and were present in all eight Finnish aspartylglycosaminuria patients originating from different pedigrees. but they were absent from Finnish and non-Finnish controls and a non-Finnish case of aspartylglycosaminuria. These results indicate molecular homogeneity in aspartylglycosaminuria alleles in the Finnish population.
Signs and symptoms of parasitic diseases, This article reviewed the parasitic signs and symptoms most likely to be seen in the office setting. Particular attention has been given to the endemic parasites. The physician will be called upon increasingly to recognize the often subtle and seemingly unrelated symptom complex. Nowhere else in the animal kingdom has the need for species survival taken a more complex and imaginative route. and it will be the primary care physician who will have first chance at the diagnosis and treatment. The long history of successful parasitic adaptations and the variety of body sites infected in man provide a challenging context for the office-based physician trying to make a clinical diagnosis.
The pinworm, Enterobius vermicularis, The pinworm. Enterobius vermicularis. is the most common intestinal parasite in the primary care setting. regardless of race. socioeconomic or cultural circumstances. This article discusses symptoms. diagnosis. and treatment.
Parasites, pets, and people, It is important for the family physician to understand that patients' relationships with their pets play an important role in helping maintain mental and physical health yet provide the potential for causing illness in the patient. Toxocara canis (dog roundworm) and Toxocara cati (cat roundworm) are the ascarids most commonly responsible for VLM and ocular larva migrans in humans. These roundworms live in their adult stage in the small intestine of the dog and cat where their eggs are passed in the feces. The eggs containing the infective larva are very sticky. thus an infant crawling around on the floor can easily pick these up on fingers that almost invariably end up in the mouth. Infections are usually mild and asymptomatic but with a persistent eosinophilia. Ocular larva migrans is the form usually occurring in older children and adults. Some public health veterinarians recommend that a puppy or kitten should not be obtained as a companion for a child who is not old enough to read. thus bypassing the crawling and toddler stages. Hookworm eggs. shed in the feces of infected dogs or cats. develop into the infective second stage within a week. Humans are usually infected when bare areas of skin such as bare feet or the torso come in contact with soil contaminated with the larvae. The second-stage larvae are able to penetrate the intact skin of humans and the foot pads of dogs and cats. In the United States. the common dog hookworm. A. caninum. is a widespread parasite. Human intestinal ancylostomiasis caused by this species is rare. with only six cases recorded in the literature. Infection in humans or animals by the common tapeworm of dogs and cats (Dipylidium caninum) requires ingestion of the intermediate host. the dog or cat flea containing the larva (cysticercoids) of the agent. Many cases in humans are asymptomatic. Dipylidiasis affects mainly infants and young children who may swallow a flea that hops up while the infant is crawling on the floor or fondling the family pet. Humans appear to be highly resistant to the infection. given the high frequency of flea infestation on dogs and cats and the relative rarity of human disease. Pinworms of animal hosts are not transmissible to humans. Humans become an accidental host of dirofilaria when bitten by an infected mosquito. although the microfilaria will not mature to the adult form in humans. Radio-opaque coin-type lung lesions can be noted on radiographs.(ABSTRACT TRUNCATED AT 400 WORDS).
The office diagnosis of common intestinal parasitic diseases, The diagnosis of parasitic infections is becoming more frequent in the ambulatory setting. This article explains collection of specimens. testing. and considerations.
Malaria, Human malaria is caused by four species of the genus plasmodium. The sexual stage of the parasite occurs in the mosquito and asexual reproduction occurs in man. Symptoms of fever. chills. headache. and myalgia result from the invasion and rupture of erythrocytes. Merozoites are released from erythrocytes and invade other cells. thus propagating the infection. The most vulnerable hosts are nonimmune travelers. young children living in the tropics. and pregnant women. P. falciparum causes the most severe infections because it infects RBCs of all ages and has the propensity to develop resistance to antimalarials. Rapid diagnosis can be made with a malarial smear. and treatment should be initiated promptly. In some regions (Mexico. Central America except Panama. and North Africa) chloroquine phosphate is effective therapy. In subsaharan Africa. South America. and Southeast Asia. chloroquine resistance has become widespread. and other antimalarials are necessary. The primary care physician should have a high index of suspicion for malaria in the traveler returning from the tropics. Malaria should also be suspected in the febrile transfusion recipient and newborns of mothers with malaria.
Parasitic diseases. International travel. Preparing your patient, Patients who travel to developing nations are those most likely to encounter parasitic diseases. Using a risk assessment approach and the resources introduced in this article. the primary care physician can prepare them for travel and continue their care on return. Immunizations and patient education are the major modes of prevention. coupled with chemoprophylaxis for malaria and traveler's diarrhea. Traveling pregnant women and young children need special precautions. A large body of preventive and therapeutic knowledge. including parasitology. is at the core of emporiatrics. the science of travel medicine.
The roundworm, Ascaris lumbricoides, Ascaris lumbricoides is a significant health problem. One billion people worldwide are infected. Most frequently it is seen in malnourished people residing in developing countries. Areas with modern water and waste treatment have a low incidence. The major serious sequelae associated with the parasite is intestinal obstruction. which occurs at a rate of 2 per 1000 people infected. Intestinal obstruction is fatal in 6 per 100.000 children. An estimated 20.000 people die of this infection annually. Although effective chemotherapy is available. long-term cure and ultimate eradication of this parasite requires improved sanitation and change in some cultural habits. The incidence in the United States has seemed to decrease. presumably because of improved sanitation. This problem is still encountered occasionally. necessitating familiarity with the clinical manifestations and treatment modalities. A professional explanation of this parasite and its life cycle will go far to eliminate the guilt of parents whose child has "passed a worm.".
Giardiasis [published erratum appears in Prim Care 1991 Jun;18(2):following xii, Giardiasis represents a major protozoan infection for the 1990s. This article reviews this organism for the primary care physician. discussing the characteristics. clinical manifestations. diagnosis. and treatment. Prevention and patient education needs are also presented.
Parasitic diseases. Other roundworms. Trichuris, hookworm, and Strongyloides, Trichuriasis may be asymptomatic or. in heavy infection. lead to profuse. bloody diarrhea and rectal prolapse. Diagnosis is made by finding the distinctive barrel shaped eggs in the stool or in the heavily infested patient. by anoscopy and identification of worms attached to reddened and ulcerated rectal mucosa. Mebendazole is the drug of choice in treatment. Capillariasis. a parasitic infection encountered mainly in the Philippine Islands. is of interest in that the eggs may be confused with the eggs of trichuris. Hookworm disease is generally asymptomatic. but in heavy infection. leads to iron deficiency and hypochromic. microcytic anemia. Diagnosis is made by finding the characteristic hookworm eggs on a examination of a direct fecal film. Accidental invasion of humans by dog and cat hookworm leads to cutaneous larva migrans. also known as "creeping eruption." Human hookworm is treated most effectively with mebendazole. while the rash produced by creeping eruption responds to topical thiabendazole. Strongyloides is fairly common in rural areas of the southeastern United States and may be seen in the urban setting among inmates of mental institutions. prisons. and in immigrants who formerly resided in endemic tropical regions. Because of its remarkable capacity for dissemination of larvae throughout the body. this parasite is now recognized as a serious problem for the patient who is immunocompromised. Diagnosis is made by finding larvae in the stool or by the Enterotest. All infected patients should be treated with thiabendazole. I consider the issue on Drugs For Parasitic Infections. published annually or biannually by The Medical Letter on Drugs and Therapeutics. to be the single best source of information on the treatment of parasitic diseases for primary care physicians.
Cocaine addiction: psychology and neurophysiology [published erratum appears in Science 1991 Aug 2;253(5019):494, Cocaine was considered incapable of producing dependence in 1980 but was recently proclaimed the drug of greatest national health concern. Recent clinical and preclinical investigations demonstrate that cocaine produces unique abuse and withdrawal patterns that differ from those of other major abused drugs and suggest that long-term cocaine abuse produces neurophysiological alterations in specific systems in the central nervous system that regulate the capacity to experience pleasure. It will be necessary to develop clinically pertinent research models before these findings can be considered definitive. but these evolving ideas have already led to applications of promising experimental treatments for cocaine abuse.
An immunogenic Onchocerca volvulus antigen: a specific and early marker of infection, Onchocerciasis (river blindness) is a serious health problem and a severe obstacle to social and economic development. especially in Africa. A complementary DNA fragment coding for an Onchocerca volvulus antigen (OV-16) was cloned and expressed in the plasmid vector pCG808fx. Immune responses to this O. volvulus-specific recombinant antigen were detectable in patients with documented onchocerciasis; the antibody response was also detectable at 3 months and at more than 1 year before infection could otherwise be detected in humans and in chimpanzees experimentally infected with O. volvulus third-stage larvae.
Traumatic occipitoatlantal dislocation, Four patients with traumatic occipitoatlantal dislocation are presented. The dislocations were the result of rapid deceleration motor vehicle accidents. The mechanism of injury was by hyperextension-rotation combined with a distraction force. Three patients sustained multiple injuries. Neurologic findings were variable. One patient with complete cord transection and closed head trauma died 4 days after the injury. In the three surviving patients. the occipitoatlantal dislocation was not diagnosed by the initial examiner. Prompt recognition and stabilization are essential to avoid further neurologic injury. Care must be taken not to increase the dislocation. A halo applied before operation facilitates reduction and allows posterior occipitoatlantal fusion to be performed under optimum conditions.
Cervical spine stabilization. A three-dimensional, biomechanical evaluation of rotational stability, strength, and failure mechanisms, The three-dimensional rotational biomechanical properties of several different types of posterior stabilizing procedures are reported. A severe ligamentous and bony injury was simulated with three vertebral body human cervical spine segments. Good stabilization was noted for all of the repairs in flexion loading. Without polymethylmethacrylate supplementation. none of the repairs was stable in extension. All of the repairs provided reasonable stabilization for lateral bending except for the posterior wiring without methacrylate. and all but the posterior wiring and facet fusion provided reasonable stabilization against axial rotation loading. The supplementation of all of these repairs with polymethylmethacrylate added considerably to the stability of all the constraints. These findings may be useful in clinical decision-making for determining the kind of repairs and postoperative brace protection to use.
Mechanism of production of experimental scoliosis in rabbits, The hypothesis for the mechanism of production of scoliosis. advanced on the basis of morphometric and morphologic studies in human thoracic skeleton. finds further support in the results of an experimental study in rabbits described herein. The removal of transverse processes alone resulted in the production of scoliosis and lordosis. When both transverse processes and facet joints were removed. scoliosis developed rapidly and was considerable. When paraspinal muscles were incised on one side only. however. this resulted in the development of lordosis alone. The convexity of the curve was always toward the operated side. and the apex was almost always at the lowest operated segment. Lordosis was limited to within the operated area. The results of the experiment indicate that scoliosis resulted because of the asymmetry in load transmission through the ribs to the vertebral column in rabbits.
Anterior and combined anteroposterior fusion for lumbar disc pain. A preliminary study, This article reports on a study of 51 consecutive patients (83 lumbar discs) with back pain who underwent anterior interbody lumbar fusion or combined anterior and posterior fusion at the same operation during a 2-year period. All patients met the criteria for diagnosis of a painful internal disc disruption and/or failed back syndrome and have had a lengthy trial of conservative treatment consisting of rest. physical therapy. back support. nonsteroidal anti-inflammatory drug therapy. and guarded activity; this treatment was often supplemented by epidural cortisone injections. pain management. and functional rehabilitation. Patients with prolonged back pain who failed with conservative care after a minimum of 12 months of severely disabling symptoms were selected for surgery on the basis of a positive dynamic discogram reproducing their exact pain and demonstrating a morphologically degenerative disc (internal disc disruption). For the purpose of this study. patients were categorized into three groups and followed up for 15-36 months after the operation. There were no deaths or major complications. and the overall success in achieving measurable diminution of preoperative pain was 80%. This article discusses preliminary conclusions on the efficacy and safety on anterior and anteroposterior fusion for lumbar disc pain.
Toward a rational therapeutic strategy for arachnoiditis. A possible role for d-penicillamine, Twenty-six patients (13 men and 13 women). ranging in age from 38 to 75 years. with surgical and/or radiculographic evidence of chronic adhesive spinal arachnoiditis (CASA) were admitted to a randomly allocated. double-blind. 6-month crossover trial of d-penicillamine (500 mg/day) versus matching placebo. Assessments using subjective and objective criteria at 3-month intervals demonstrated no statistically significant effect with either d-penicillamine or placebo or between them. Thirteen of the 17 patients completing the trial expressed no clear preference. One patient preferred placebo. The remaining three patients who expressed strong preference for d-penicillamine (supported by objective data) subsequently maintained improvement on long-term therapy for up to 5 years. It is concluded that there may be a small subgroup of patients with CASA who might benefit from d-penicillamine therapy.
Hole preparation techniques for transpedicle screws. Effect on pull-out strength from human cadaveric vertebrae, In each of eight thoracolumbar human cadaveric vertebrae. a hole was made through one pedicle into the vertebral body with a drill bit and through the contralateral pedicle with a probe. Identical metal screws were implanted into the holes to equal depths. and maximum pull-out force was determined for each screw. Using a paired Student t test. no significant difference (P = 0.87) was found in pull-out strength between the screws implanted into drilled holes and those implanted into probed holes. In fact. the average pull-out strengths for the two groups differed by less than 2%. The pedicular cortex was broken through during hole preparation in 5 of the 16 pedicles: 3 as a result of drilling and 2 secondary to probing. The average pull-out strength of the screws in these five pedicles was 11.0% less than the average pull-out strength of the screws implanted into the contralateral intact pedicles. Although this does not represent a statistically significant difference (P = 0.15). it suggests that damaging the pedicular cortex may weaken pedicle screw fixation.
Symptomatic gas-containing disc herniation. Report of four cases, Intradiscal gas collection. causing the radiographic vacuum phenomenon. is a common finding on radiographic studies of the lumbar spine. Four cases of radiographically documented and surgically confirmed cases of herniated discs containing gas are presented. All four patients presented with radicular symptoms secondary to the gas-containing herniations. Minimal nuclear material was found at surgery; however. all patients experienced relief after the operation.
Limitations of indium leukocyte imaging for the diagnosis of spine infections, The usefulness of indium-111 white blood cell (WBC) scintigraphy in the detection of spine sepsis was studied in 22 patients who had open or percutaneous biopsies for microbiologic diagnosis. The indium images in 18 patients with vertebral infection were falsely negative in 15 (83%) and truly positive in 3 (17%). All four patients with negative cultures and histology had true-negative scans. The indium-111 WBC imaging results yielded a sensitivity of 17%. a specificity of 100%. and an accuracy rate of 31%. Prior antibiotic therapy was correlated with a high incidence of false-negative scans and photon-deficient indium-111 WBC uptake. The usefulness of indium-111 WBC scintigraphy for the diagnosis of vertebral infection may be limited to those patients who have not been treated with antibiotics previously.
Advances in the analysis of corneal topography, Recent advances in topographic analysis have provided powerful tools for detecting subtle. but clinically significant. alterations of corneal contour. This article compares keratometry. keratoscopy. and computer-assisted topographic analysis and provides specific examples of the sensitivity of computer-assisted systems in revealing topographic alterations that were not previously discernable. Quantitative descriptors of corneal topography such as the surface asymmetry index. the surface regularity index. and simulated keratometry value augment the information provided by color-coded topographic maps.
Management of blow-out fractures of the orbital floor [editorial, The management of orbital fractures has long been controversial. In some cases. surgical repair is required. and early repair is more successful than secondary reconstruction. In other cases. slow resolution of diplopia over four to six months obviates surgery. In an editorial and two separate articles. the authors elucidate indications for and results of the early vs. late surgical repair of orbital blow-out fractures.
A case for myopia, This case presentation reviews the refractive options facing a myopic patient who chose to remain myopic after cataract extraction. The factors leading to this choice are explained.
Miotics and retinal detachment: upgrading the community standard, The majority of ophthalmologists who responded to a questionnaire regarding the relationship between miotics and retinal detachment felt that such a relationship does exist. and that myopia and aphakia/pseudophakia predispose to the formation of new retinal breaks or to retinal detachment from pre-existing breaks with miotics. Horseshoe breaks and dialyses are pre-existing lesions that should be treated prophylactically prior to miotic therapy. Patients with no predisposing pathology or whose eyes have lattice degeneration or operculated breaks should be warned of possible retinal detachment prior to starting miotics. Not performing a peripheral retina examination prior to prescribing a miotic is acceptable. but not optimal. medical practice. Examining the peripheral retina or obtaining a retina consultation prior to prescribing a miotic may be beneficial to the patient and could be invaluable in the defense of litigation.
Frequency and significance of occult late potentials on the signal-averaged electrocardiogram in sustained ventricular tachycardia after healing of acute myocardial infarction, The quantitative and morphologic characteristics and significance of late potentials on the signal-averaged electrocardiographic QRS complex remain unknown. To assess this. the signal-averaged electrocardiogram of 48 patients (mean age +/- standard deviation 62 +/- 9 years) with sustained ventricular tachycardia (VT) after healing of acute myocardial infarction and late potentials were analyzed. Late potentials could be classified into 3 morphologic subtypes: type I late potentials (19 patients. 40%) occurred in the terminal 40 ms of the QRS complex; type II late potentials (16 patients. 33%) started before the end of the QRS complex and extended 30 +/- 17 ms into the ST segment; type III late potentials (13 patients. 27%) started after the end of the QRS complex in the ST segment and ended 67 +/- 27 ms after the end of the QRS complex. The amplitude of the late potentials in type III. when compared with types I and II. was significantly lower. whereas the QRS duration on the electrocardiogram in type I. when compared with types II and III. was significantly longer. Computer algorithm based on noise failed to identify most type III late potentials. No difference was noted in age. sex. site of the myocardial infarction. and rate of induced VT among the 3 types.
Left ventricular diastolic function in patients with left ventricular systolic dysfunction due to coronary artery disease and effect of nicardipine, To assess the effect of nicardipine on left ventricular (LV) diastolic function independent of concurrent effects on loading conditions in patients with LV systolic dysfunction due to coronary artery disease. equihypotensive doses of intravenous nitroprusside and nicardipine were administered to 12 patients with congestive heart failure due to previous myocardial infarction (LV ejection fraction less than 0.40). LV micromanometer pressure and simultaneous radionuclide volume were obtained during a baseline period. during nitroprusside infusion. during a second baseline period and during nicardipine infusion. Mean systemic arterial pressure decreased an average of 21 mm Hg with nitroprusside and 19 mm Hg with nicardipine. A greater decrease in LV end-diastolic pressure was observed with nitroprusside (29 +/- 2 to 15 +/- 2 mm Hg. p less than 0.01) than with nicardipine (29 +/- 2 to 25 +/- 3 mm Hg. p less than 0.05). There was a decrease in the time constant of relaxation during nitroprusside but not during nicardipine infusion. There was enough overlap in LV volumes in the baseline and nitroprusside periods to compare diastolic pressure-volume relations over a common range of volumes in 4 patients. and enough overlap in the baseline and nicardipine periods in 11 patients. The relation was shifted downward in 3 of 4 patients taking nitroprusside and in 6 of 11 patients taking nicardipine. The relation between end-diastolic pressure and volume was not shifted with nicardipine.
A new method for estimating preexcitation index without extrastimulus technique and its usefulness in determining the mechanism of supraventricular tachycardia, The preexcitation index has been shown to be useful in determining the mechanism of paroxysmal supraventricular tachycardia (SVT) and the site of the accessory pathway in atrioventricular (AV) reentrant tachycardia. To test whether a preexcitation index could be computed analytically instead of by scanning the whole SVT cycle with extrastimuli. 19 patients with SVT were studied. The new index was computed using the following formula: (AV conduction time during SVT) + (ventriculoatrial conduction time during ventricular pacing at the SVT cycle length) - (SVT cycle length). There was a strong correlation between the preexcitation index determined by the extrastimulus technique and the new index in 15 patients in whom the preexcitation index could be determined (r = 0.99. p less than 0.01). The value on the new index was greater than 90 ms only in patients with dual AV nodal pathways. In the 4 patients in whom the preexcitation index could not be determined by the extrastimulus technique. the new index could differentiate AV reentrant tachycardia (index for 2 patients. 60 and 60 ms. respectively) from AV nodal reentrant tachycardia (index for 2 patients. 100 and 105 ms. respectively). In conclusion. the new index provided help in determining the mechanism of SVT. even when retrograde atrial preexcitation by a ventricular extrastimulus did not occur.
Usefulness of the electrophysiology laboratory for evaluation of proarrhythmic drug response in coronary artery disease, Two potential manifestations of proarrhythmic responses to type IA antiarrhythmic agents in the electrophysiology laboratory were evaluated in 122 patients with chronic coronary artery disease and previous myocardial infarction: (1) conversion of uniform nonsustained ventricular tachycardia (VT) into sustained VT after drug administration. and (2) induction of sustained VT by fewer extrastimuli after drug administration. Forty-two patients were evaluated for nonsustained VT. Eighty patients were evaluated for sustained VT: 30 of these had spontaneous sustained VT only while receiving empiric therapy with quinidine or procainamide. whereas the remaining 50 developed spontaneous VT in the absence of antiarrhythmic drugs. All patients underwent programmed stimulation in the baseline state and after procainamide. Four patients had conversion of induced uniform nonsustained VT into the same morphology. but sustained VT after procainamide administration. These responses only occurred in patients evaluated for nonsustained VT. Over 90% of patients presenting with sustained VT had uniform sustained VT induced at the baseline study and after procainamide. regardless of whether the spontaneous arrhythmia occurred only in the presence or absence of antiarrhythmic drugs. There was no significant difference in the change in mode of induction from baseline to procainamide study. regardless of whether patients had developed spontaneous VT only in the presence or absence of antiarrhythmic drugs. One patient with no inducible VT at the baseline study had inducible uniform sustained VT after procainamide administration. and 1 patient with inducible VT at baseline developed spontaneous sustained uniform VT after procainamide administration. Both patients had developed spontaneous sustained VT only while receiving therapy with type IA agents.
Effects of aerobic exercise training on symptomatic women with mitral valve prolapse, The effects of a 12-week aerobic exercise training protocol on 32 symptomatic women with mitral valve prolapse were studied. Subjects were randomly assigned to control or exercise groups. Exercise subjects completed a 12-week (3 times per week) exercise training program based on guidelines established by the American Heart Association for phase II cardiac rehabilitation programs; control group subjects maintained normal activities. Before and after training. subjects underwent maximal multistage treadmill testing. and measurements were obtained for plasma catecholamine levels at rest and during peak exercise; they completed the State Trait Anxiety Inventory and General Well-Being Schedule. Weekly symptom frequency of chest pain. arm pain. palpitations. shortness of breath. fatigue. headache. mood swings. dizziness and syncope were monitored for the 12-week period. Data were analyzed using multivariate analysis of variance. multivariate analysis of covariance. and analysis of covariance with repeated measures. Compared with control subjects. the exercise group showed a significant (p less than 0.05) decrease in State Trait Anxiety Inventory scores. an increase in General Well-Being scores. an increase in functional capacity and a decline in the frequency of chest pain. fatigue. dizziness and mood swings. No statistically significant differences were noted in catecholamine levels at rest or during peak exercise. These findings support the use of aerobic exercise in the management of symptomatic women with mitral valve prolapse.
Ventricular late potentials and induced ventricular arrhythmias after surgical repair of tetralogy of Fallot, Ventricular tachycardia (VT) and sudden death are rare but recognized complications after surgical repair of tetralogy of Fallot. We prospectively studied 31 patients (19 boys and 12 girls. mean age +/- standard deviation 7 +/- 4 years) with postoperative tetralogy of Fallot. by means of right-sided cardiac catheterization. 24-hour Holter monitoring. body-surface and intracavitary signal-averaging (gain 10(5) to 10(6). filters of 100 and 300 Hz) and programmed ventricular stimulation (1 and 2 extrastimuli. 3 basic cycle lengths. right ventricular apex and outflow tract). All patients were asymptomatic and none had documented or suspected ventricular arrhythmias. Ventricular late potentials were detected in 10 of 31 patients (32%) and spontaneous ventricular arrhythmias in 12 of 31 patients (39%). No sustained VT was induced by programmed ventricular stimulation but nonsustained VT was induced in 3 patients (10%). Patients with inducible VT more often had late potentials (3 of 3 vs 7 of 28. p less than 0.01). and spontaneous ventricular premature complexes (VPCs) during Holter monitoring (3 of 3 vs 9 of 28. p less than 0.05). To predict VT inducibility. late potentials had a sensitivity of 100%. a specificity of 75%. a positive predictive value of 30% and a negative predictive value of 100%. For spontaneous VPCs. the figures were 100. 68. 25 and 100%. respectively. It is concluded that shortly after repair of tetralogy of Fallot. the presence of both spontaneous VPCs and ventricular late potentials are associated with an increased incidence of inducible VT. Conversely. the absence of VPCs and ventricular late potentials may identify patients at low risk of subsequent ventricular arrhythmias.
Thallium-201 stress scintigraphy in Takayasu arteritis, Thirty-eight women with Takayasu arteritis were studied using thallium-201 stress myocardial scintigraphy to assess the prevalence and pathophysiology of the perfusion abnormality. Twenty (53%) had abnormal scintigraphic findings (group A). Abnormal scans were divided into 3 groups: permanent defects in 6. reversible defects in 7 and slow washout in 7. The remaining 18 patients had normal scintigrams (group N). Group A had a tendency to be older and to have a high prevalence of complicated significant aortic regurgitation. Interventricular thickness plus left ventricular posterior wall thickness (26 +/- 7 vs 17 +/- 2 mm. p less than 0.01) and left ventricular mass (267 +/- 121 vs 133 +/- 39 g. p less than 0.01) were all greater in group A on echocardiography. The mean value of the central aortic pressure in systole was 170 +/- 15 mm Hg in the 7 catheterized patients in group A. Coronary ostial stenoses were present in 2 group A patients who showed reversible defects on scintigrams. These data indicate that the abnormal perfusion detected by imaging in patients with Takayasu arteritis was responsible for a decrease in coronary reserve or myocardial damage. or both. due to long-standing systemic hypertension or aortic regurgitation. Coronary artery disease should be considered if a reversible defect is present.
Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee), A double-blind. crossover. 8-wk study was conducted to compare effects of the tocotrienol-enriched fraction of palm oil (200 mg palmvitee capsules/day) with those of 300 mg corn oil/d on serum lipids of hypercholesterolemic human subjects (serum cholesterol 6.21-8.02 mmol/L). Concentrations of serum total cholesterol (-15%). LDL cholesterol (-8%). Apo B (-10%). thromboxane (-25%). platelet factor 4 (-16%). and glucose (-12%) decreased significantly only in the 15 subjects given palmvitee during the initial 4 wk. The crossover confirmed these actions of palmvitee. There was a carry over effect of palmvitee. Serum cholesterol concentrations of seven hypercholesterolemic subjects (greater than 7.84 mmol/L) decreased 31% during a 4-wk period in which they were given 200 mg gamma-tocotrienol/d. This indicates that gamma-tocotrienol may be the most potent cholesterol inhibitor in palmvitee capsules. The results of this pilot study are very encouraging.
Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias, Normolipemic and genetically hypercholesterolemic pigs of defined lipoprotein genotype were fed a standard diet supplemented with 50 micrograms/g tocotrienol-rich fraction (TRF) isolated from palm oil. Hypercholesterolemic pigs fed the TRF supplement showed a 44% decrease in total serum cholesterol. a 60% decrease in low-density-lipoprotein (LDL)-cholesterol. and significant decreases in levels of apolipoprotein B (26%). thromboxane-B2 (41%). and platelet factor 4 (PF4; 29%). The declines in thromboxane B2 and PF4 suggest that TRF has a marked protective effect on the endothelium and platelet aggregation. The effect of the lipid-lowering diet persisted only in the hypercholesterolemic swine after 8 wk feeding of the control diet. These results support observations from previous studies on lowering plasma cholesterol in animals by tocotrienols. which are naturally occurring compounds in grain and palm oils and may have some effect on lowering plasma cholesterol in humans.
Dietary fats and cancer, Evidence relating dietary fat to cancer at sites such as the breast and colon is provided by experiments showing that animals fed high-fat diets develop cancer at these sites more readily than do animals fed low-fat diets and by epidemiological data from different countries showing strong positive correlations between cancer incidence and mortality. and level of dietary fat. Experiments on animals have indicated that polyunsaturated vegetable oils promote cancer more effectively than do saturated fats or polyunsaturated fish oils. whereas in the epidemiological data. total dietary fat correlates with cancer incidence and mortality at least as well as does any particular type of fat. Case-control and cohort studies have not shown strong indications of a relationship between dietary fat and cancer. perhaps because of methodological difficulties inherent in such studies. The weight of evidence continues to indicate that long-term adherence to a low-fat diet can reduce the risk of some common types of cancer.
The total iron-binding capacity in iron poisoning. Is it useful, Traditionally. a serum iron concentration in excess of the total iron-binding capacity (TIBC) is considered as an indication for deferoxamine therapy in acute iron poisoning. We observed a reversible elevation of the TIBC in patients with iron poisoning that coincided with their acute hyperferremia and have hypothesized that this is a laboratory aberration. We tested this hypothesis in vitro and found that the addition of iron to test serum samples produced a related increase in the TIBC. and alteration of the assay by providing additional adsorbent prevented this occurrence. We also evaluated the reproducibility of the TIBC as performed by 500 laboratories on 10 different reference samples. The mean coefficient of variation was 16%. which was unsatisfactory. We concluded that the TIBC should not be used in the decision for the initiation of deferoxamine therapy in acute iron poisoning. Furthermore. high TIBC values that are occasionally seen in patients with iron poisoning should not be considered as providing a protective effect.
Influenza vaccination in the prevention of acute otitis media in children, We studied a new approach to the prevention of acute otitis media through the administration of influenza vaccine to 187 day-care center children aged 1 to 3 years before the influenza A epidemic of 1988-1989. The control group consisted of 187 unvaccinated children of similar age and background. During the 6-week study period. influenza A infection was diagnosed in five (3%) of 187 vaccinees and in 29 (16%) of 187 controls. Acute otitis media developed in three (60%) of five vaccinees with an influenza A infection compared with 18 (67%) of 27 controls (excluded were two children with a double viral infection). The incidence of acute otitis media associated with influenza A was reduced by 83% in the vaccinees. The total number of children with acute otitis media in the vaccine group was 35. compared with 55 in the control group. disclosing a 36% reduction among the vaccinees. We conclude that influenza vaccination decreases the incidence of acute otitis media in children during an influenza A epidemic. suggesting also that other vaccines against respiratory viruses may be an effective way to reduce the incidence of acute otitis media.
Endoscopic nasobiliary catheter drainage in biliary and pancreatic disease, Nasobiliary catheter drainage was first introduced a decade ago. It provides drainage of the biliary system and facilitates interventional procedures of the biliary and pancreatic system. both for therapy and research purposes. The present review addresses the designs of nasobiliary catheters. the technique of insertion. and indications for drainage. with special emphasis on the management of bile duct stones and associated complications. Its potential application in biliary research is discussed further. Certain caveats in the performance of nasobiliary drainage are also included. All of these emphasize the need for this technique to be included in therapeutic endoscopy training.
Gastrointestinal complications after cardiac transplantation: a spectrum of diseases, Cardiac transplantation has become an accepted treatment modality for end-stage cardiac failure. The gastrointestinal (GI) tract represents a potential source of posttransplant morbidity and mortality. To define the scope of this problem. records of all patients undergoing cardiac transplantation at UCLA between January 1984 and July 1989 were reviewed. In all. there were 120 patients (90 males and 30 females) with a mean age of 45.4 yr. Among them. there were 61 patients (51%) who developed a total of 112 posttransplant GI complications. Of the entire 120 patients. 41 (34%) developed minor complications and 20 (17%) sustained major GI morbidity. Eighteen patients (15%) underwent either endoscopy or surgical intervention. These data suggest that most cardiac transplant recipients will experience some form of GI complication. although most are minor and can be managed conservatively. However. when major. life-threatening complications occur. evaluation and intervention should proceed expeditiously. The gastroenterologist and GI surgeon should play complimentary roles in the care of these complicated patients.
A 20-minute breath test for helicobacter pylori, In this study. we evaluated a simplified rapid 14C-urea breath test for the diagnosis of Helicobacter pylori. Fasting patients undergoing initial assessment for H. pylori drank 5 microCi of 14C-urea in 20 ml of water. Breath was collected at intervals for 30 min. Samples were counted in a beta-counter. and the results were expressed as counts per minute (cpm). In the same week. patients underwent endoscopy. and a blinded investigator examined biopsy samples of gastric mucosa by culture and histology for H. pylori. There were 49 H. pylori-negative (HP-) and 104 H. pylori-positive (HP+) patients in the study. HP+ patients expired a mean of 4398 cpm (SD 2468) per mmol CO2 in a sample taken 20 min after ingestion of the isotope. In contrast. HP--patients expired only 340 cpm (SD 196). If the mean +3 SD of HP- patients was used as a cutoff value. the 20-minute sample gave a sensitivity of 97% and a specificity of 100% for detecting H. pylori. The radiation exposure from this test is less than 1% of that received from an upper gastrointestinal series. and the short collection time makes it both convenient and cost effective.
Protein-losing gastroenteropathy detected by technetium-99m-labeled human serum albumin, Gastric and fecal clearance of alpha 1-antitrypsin were measured in three cases of protein-losing gastroenteropathy and in two control cases. Abdominal scintigraphy using 99mTc-labeled human serum albumin was performed in all five subjects. All three cases of protein-losing gastroenteropathy showed 99mTc activity in the gastrointestinal tract. In the patient with hypertrophic gastropathy. the activity was seen initially in the stomach and duodenum. In the patients with intestinal lymphangiectasia. the activities were initially in the small bowel. We conclude that 99mTc scintigraphy was useful. not only in diagnosing protein-losing enteropathy. but. also. in detecting the responsible region of the gastrointestinal tract.
Alternate-day prednisone treatment and treatment maintenance in Crohn's disease, We have reviewed our data from 55 patients with Crohn's disease (CD) treated with alternate-day prednisone (average dose: 25 mg every other morning) between 1966 and 1989 for a mean duration of 6.6 yr. Daily divided corticosteroid doses were given to all patients with active disease that had not been responsive to supportive measures and. in almost all cases. not responsive to sulfasalazine alone. After initial remission was achieved. patients were switched to alternate-day doses. Treatment evaluations utilized global assessment and the CD activity index of Harvey and Bradshaw (CDAI-HB) shown to correlate closely with the National Cooperative Crohn's Disease Study (NCCDS) activity index (CDAI). CDAI-HB scores of 0-1 indicated no or minimal activity. whereas scores of 2-15 indicated progressive activity. With the CDAI-HB and global assessments. in agreement in all cases. 33 patients (60%) showed favorable responses with 95% confidence intervals (CI) of 46.8 to 73.2. Comparing the results with a literature-based 20% spontaneous long-term remission rate. the data are significant at p less than 0.01. Serious complications were gratifyingly low. with no observed instances of osteonecrosis. It is concluded that alternate-day prednisone treatment and treatment maintenance. with or without concomitant sulfasalazine. after conventional induction of remission with daily steroid doses. is a reasonable treatment option for patients with CD not responsive to sulfasalazine alone.
Prospective randomized study on the effect of ranitidine against injection ulcer after endoscopic injection sclerotherapy for esophageal varices, Thirty-five consecutive patients undergoing endoscopic injection sclerotherapy for esophageal varices were randomly allocated to either ranitidine-administered group (18 patients) or ranitidine-nonadministered group (17 patients). in an attempt to evaluate the efficacy of ranitidine for prevention and healing of postinjection ulcer with a prospective randomized trial. Two of seventeen patients in the nonadministered group dropped out of this trial because of development of gastric ulcer. so 18 patients in the first group were evaluated and compared with the 15 remaining patients in the second group. Sclerotherapy was performed with 5% ethanolamine oleate and 0.6% polydocanol; the mean number of injection courses and the mean amount of sclerosant were the same in both groups. Moreover. there was no significant difference between the two groups in either the occurrence rate or the size of injection ulcer 1 wk after the last session. However. the persistence rate of ulcer 1 month after last injection in the ranitidine-administered group was significantly lower than that in the ranitidine-nonadministered group (6.3% vs. 38.5%. p less than 0.05). Our study demonstrated that ranitidine administration will help to hasten healing of postinjection ulcer. although it was not effective for prevention of injection ulcer.
Hepatocellular carcinoma: comparison of clinical features among ethnic groups in an area of low prevalence, We retrospectively surveyed the clinical features of 73 cases of hepatocellular carcinoma at two hospitals over a 12-yr period. The population was heterogeneous. with 39% representing immigrants from regions of high hepatitis B and hepatocellular carcinoma prevalence. The yearly incidence of cases was constant over the 12 yr. Patient data were analyzed by grouping into three broad categories based on origin from known high. medium. or low prevalence hepatocellular carcinoma zones. In this fashion. differences in clinical presentation were observed. Asians (N = 12) were younger. invariably presented with pain; 82% had markers of hepatitis B and did not have features of chronic liver disease. In contrast. Westerners (N = 45) were older by more than a decade. One-quarter were HBV positive and almost two-thirds were alcoholic. The clinical presentation of this group was more varied. over one-third presenting with features of decompensated liver disease or variceal bleeds. Mediterranean patients (N = 16) had features intermediary between the two other groups. A logistic regression model clinically separated patients with hepatitis B-related hepatocellular carcinoma from those with alcohol-related hepatocellular carcinoma. suggesting different ongoing pathogenetic influences.
Boronate affinity chromatography of gamma-glutamyltransferase in patients with hepatocellular carcinoma, We analyzed the serum gamma-glutamyltransferase (gamma-GT) by boronate affinity chromatography to ascertain the presence or absence of any changes in the binding properties of gamma-GT toward boronate gels in patients with hepatocellular carcinoma and liver cirrhosis. and in normal controls. The mean gamma-GT activity ratio of the bound (peak 2) and nonbound (peak 1) fraction in patients with hepatocellular carcinoma was significantly higher than that in patients with liver cirrhosis or in normal controls. Thus. the gamma-GT. which has adjacent cis-hydroxyl groups in its carbohydrate moieties. was found to increase in the serum of patients with hepatocellular carcinoma. The positivity rate was examined in patients with hepatocellular carcinoma and liver cirrhosis. using a cut-off level for the peak 2:peak 1 ratio of 1.05 (mean + 2 SD of liver cirrhosis). Nineteen (42.2%) patients with hepatocellular carcinoma had a ratio of peak 2:peak 1 higher than 1.05. Nine of the 19 patients who had serum alpha-fetoprotein levels below 100 ng/ml had an elevated peak 2:peak 1 ratio. In total. 77.8% of the occurrence of hepatocellular carcinoma could be detected by a combination of these two markers. Three patients who had developed hepatocellular carcinoma during the course of cirrhosis but remained negative for alpha-fetoprotein throughout the course developed higher levels of peak 2:peak 1 ratio when hepatocellular carcinoma occurred. These results indicate that the two markers. the peak 2:peak 1 ratio of serum gamma-GT activity and serum alpha-fetoprotein level. may be considered to serve as complementary markers for the diagnosis of hepatocellular carcinoma.
Successful treatment of pancreatic pseudocyst with a somatostatin analogue and catheter drainage, We report a patient with bile duct stone-induced pancreatitis who subsequently developed a large pseudocyst that became infected after endoscopic retrograde cholangiopancreatography (ERCP) was done for extraction of the stones. Percutaneous external drainage allowed control of the infection. but failed to seal the pseudocyst. We then treated the patient with a long-acting somatostatin analogue which shrunk the cyst within a week. Patients with pancreatic pseudocyst resistant to drainage should be offered a course of somatostatin before surgery is contemplated.
Systemic treatment of AIDS-related Kaposi's sarcoma: results of a randomized trial, PURPOSE: Patients with acquired immunodeficiency syndrome (AIDS)-related epidemic Kaposi's sarcoma generally respond well to cytotoxic chemotherapy. However. due to the associated myelosuppression. these patients are at risk for developing complicating infections that may affect survival. We therefore conducted a multi-center randomized clinical trial comparing single-agent against combination chemotherapy in advanced AIDS-related Kaposi's sarcoma. Low-dose chemotherapy was employed to evaluate its role in combination therapy for this disease and the toxicities associated with the lower intensity. PATIENTS AND METHODS: Sixty-one patients with extensive mucocutaneous Kaposi's sarcoma or visceral involvement were randomized for treatment with low-dose Adriamycin (doxorubicin. 20 mg/m2) alone (31 cases) or in combination with bleomycin and vincristine (ABV) (30 cases). Patients were randomized within strata based on prognostic features associated with shorter survival in prior studies. Both treatment arms were evenly matched at study entry. RESULTS: Complete and partial tumor remissions were significantly higher with ABV (88%) than with Adriamycin alone (48%) (p = 0.004). The median survival was 9 months in both groups. Study entry criteria significantly associated with shorter survival included CD4 lymphocyte counts less than 100/mm3. hemoglobin level less than 10 g/dL. a history of constitutional symptoms. and a prior history of opportunistic infection(s). Toxicities were similar in both arms. and the regimens were well tolerated. Neutropenia (granulocyte count less than 1.000/mm3) occurred in 34% of patients receiving Adriamycin alone and in 52% of patients receiving ABV and was progressive in successive courses of chemotherapy in both treatment arms. The development of AIDS-defined opportunistic infections was relatively infrequent during therapy (14%). CONCLUSIONS: Low-dose ABV is an effective chemotherapy regimen for the treatment of extensive Kaposi's sarcoma. ABV chemotherapy is associated with significantly higher responses than Adriamycin alone and with acceptable toxicity.
Clinical presentation of hemochromatosis: a changing scene, PURPOSE: To investigate the changing modes of clinical presentation and diagnosis in 93 patients with familial hemochromatosis and to compare the results with other reports from 1935 to the present. PATIENTS AND METHODS: The presenting features and the frequency of signs and symptoms were analyzed in 93 homozygotes from 56 families. RESULTS: Hemochromatosis was detected by chance in 40% of the 56 probands. Abdominal pain (16%). joint pains (11%). and weakness (9%) were prominent features that brought the patient to the physician. Although 38% of the male patients had loss of libido and impotence. these were not identified as presenting features. Features of liver disease (84%). arthritis (11%). and diabetes (2%) led the physician to the diagnosis. Impotence and testicular atrophy were notable. by their absence. in alerting physicians to the presence of hemochromatosis. Screening of family members led to the detection of 37 homozygotes. of whom 46% were asymptomatic. Among this group. arthropathy and gonadal failure were the most common symptoms. The classic triad of hepatomegaly. diabetes. and pigmentation was present in only 8% of patients. Clinical features were rare in patients with less than 5 g of exchangeable body iron and invariably present in those with more than 16 g. CONCLUSION: The presenting clinical features of hemochromatosis have changed since the original description of the disease in 1935. Family studies have led to the earlier discovery of more homozygous women and earlier detection with less iron loading and. as a result. fewer signs and symptoms.
Epidemiology of severe hypoglycemia in the diabetes control and complications trial. The DCCT Research Group, PURPOSE: The present study describes the epidemiology of severe hypoglycemia and identifies patient characteristics or behaviors associated with severe hypoglycemia in patients with insulin-dependent diabetes mellitus (IDDM) participating in the Diabetes Control and Complications Trial (DCCT). PATIENTS AND METHODS: The DCCT is a multicenter randomized clinical trial designed to compare the benefits and risks of intensive therapy with those of conventional management of IDDM. The DCCT's feasibility phase demonstrated that intensive therapy. with the aim of achieving glucose levels as close to the non-diabetic range as possible. was accompanied by a threefold increase in severe hypoglycemia compared with conventional therapy. This report is based on the first 817 subjects who entered the DCCT. with a mean follow-up of 21 months. RESULTS: Two hundred sixteen subjects reported 714 episodes of severe hypoglycemia; 549 (77%) occurred in intensively treated subjects. The incidence of severe hypoglycemia in the intensive treatment group ranged from two to six times that observed with conventional treatment. Severe hypoglycemia occurred more often during sleep (55%); 43% of all episodes occurred between midnight and 8 AM. Of episodes that occurred while subjects were awake. 36% were not accompanied by warning symptoms. In intensively treated subjects. predictors of severe hypoglycemia included history of severe hypoglycemia. longer duration of IDDM. higher baseline glycosylated hemoglobin (HbA1c) levels. and a lower recent HbA1c. Multivariate analyses failed to yield predictive models with high sensitivity. CONCLUSIONS: In the DCCT. intensive treatment of IDDM increased the frequency of severe hypoglycemia relative to conventional therapy. Intensive treatment may cause even more frequent severe hypoglycemia when applied to less selected and less motivated populations in the clinical practice setting. These findings underscore the importance of determining the benefit-risk ratio of intensive and standard therapy of IDDM.
Efficacy and compliance with cholestyramine bar versus powder in the treatment of hyperlipidemia, PURPOSE: The purpose of the study was to compare the powder and the bar forms of cholestyramine to determine efficacy and patient compliance. SUBJECTS AND METHODS: A prospective. randomized trial was conducted that included 83 healthy men and women with hyperlipidemia greater than the 90th percentile for low-density lipoprotein (LDL) or total cholesterol. Patients were randomly assigned to receive either cholestyramine powder. two packets (8 g). twice daily. or cholestyramine confectionery bar. in maple or mint flavors. two bars (8 g). twice daily. Fasting serum total cholesterol. LDL cholesterol. high-density lipoprotein (HDL) cholesterol. and triglycerides were measured at baseline. after 6 to 8 weeks of following the American Heart Association Step I diet alone. and after 8 weeks of taking either the cholestyramine bar or powder. RESULTS: Total cholesterol decreased significantly (p less than 0.01) by 16% in the bar group and 17% in the powder group. LDL cholesterol decreased by 28% and 29% in the bar and powder groups. respectively (p less than 0.01). There was no significant change in HDL cholesterol. Triglycerides increased in both groups. by 29% in the bar group and by 25% in the powder group. There was no difference between bar and powder in the effect on blood lipids. The majority of the lipid-lowering effect was seen within 14 days. Mean patient endpoint compliance with the therapy was 91.8 +/- 3.6% in the bar group and 94.8 +/- 2.1% in the powder group. There was no difference between groups. CONCLUSION: The cholestyramine confectionery bar is as effective as cholestyramine powder in the treatment of hyperlipidemia. The majority of the lipid-lowering effect is seen within 14 days of therapy. Although patient compliance is comparable between the two forms. gastrointestinal side effects were slightly greater with the bar form. Therefore. although the bar offers an alternative form of therapy. there appears to be no advantage with regard to patient compliance or palatability.
Prosthetic valve endocarditis due to Cardiobacterium hominis occurring after upper gastrointestinal endoscopy, Bacterial endocarditis secondary to endoscopic procedures has been convincingly documented in only four cases. We describe a case of prosthetic valve endocarditis due to Cardiobacterium hominis that developed after upper gastrointestinal endoscopy. Because of this. we recommend subacute bacterial endocarditis prophylaxis in patients who have a prior history of endocarditis or valve replacement.
Acute psychoses associated with the use of ciprofloxacin and trimethoprim-sulfamethoxazole, Although adverse drug reactions are a well-recognized cause of mental status changes in the elderly. antimicrobials are rarely implicated. Three patients with serious organic brain disease developed paranoid psychosis after therapy with trimethoprim-sulfamethoxazole or ciprofloxacin was begun. One of the patients was accidently rechallenged and again developed a psychotic reaction. The acute psychoses did not improve with moderate doses of major tranquilizers but resolved completely with drug discontinuation.
Synergism of ara-C-imuvert combination in aborting the development of transplanted chloroleukemia in the rat, The development of chloroleukemia in the rat after transplantation of C51 chloroma cells can be aborted by treatment with an exogenous source of differentiating activity (DA) or by stimulation of endogenous DA production by the administration of Imuvert. a biologic response modifier. Success or failure of treatment was determined by the ratio of DA to leukemic cell load. Accordingly. in the present study we examined the hypothesis that treatment with cytosine arabinoside (ARA-C) to reduce the leukemic cell load coupled with Imuvert would be more effective than either given alone. Treatment with ARA-C-Imuvert aborted the development of chloroleukemia in 79% of the animals in contrast to 0%. 9% and 45% in animals treated with buffer. ARA-C. or Imuvert respectively. These results suggest that stimulation of endogenous DA in combination with cytoreductive agents offers a potentially curative treatment for myelogenous leukemia.
Anti-inflammatory effects of pentoxifylline in claudication, We measured neutrophil elastase/alpha 1 proteinase inhibitor complex (E/alpha) levels by ELISA in plasma samples drawn from 19 patients with claudication. before and at 1 and 2 months after initiation of pentoxifylline (PTF). 400 mg. p.o. tid. Plasma E/alpha levels declined in all eight patients whose initial values were more than 300 ng elastase per ml. Whole blood viscosity (wbv) was reduced by two months' treatment in 12 of 14 patients tested. The relative change in wbv was significantly related to the relative change in E/alpha (R2 = 0.8). for patients with elevated initial E/alpha levels. suggesting a common or related mechanism for the two effects. Plasma crosslinked fibrin D-dimer fragments (XDP) measured by ELISA as indicators of coagulation activity were lower compared to pretreatment levels in 9 of 10 samples drawn when symptoms were improved on PTF. whereas they were increased in 6 of 9 samples drawn when symptoms were worse or unchanged. Plasma viscosity. C-reactive protein and alpha 1-acid-glycoprotein did not change significantly with PTF treatment. Together these findings are consistent with the possibility that reduced microvascular neutrophil activation and coagulation play a role in the clinical efficacy of PTF in intermittent claudication.
Plasma HDL cholesterol concentrations are correlated to bile cholesterol saturation index in the African green monkey, In an attempt to determine if plasma lipoprotein concentrations correlate with the bile cholesterol saturation index in the African green monkey. we have studied a group of adult male animals available from a long-term study investigating the effects of dietary fat and cholesterol on cholesterol metabolism and atherosclerosis. The animals were fed diets containing 0.8 mg cholesterol/kcal or 0.03 mg cholesterol/kcal for five years. Within each dietary cholesterol group. animals received 42% of dietary calories as fat. enriched with either saturated or polyunsaturated fat. Using stepwise multiple linear regression. high density lipoprotein (HDL) cholesterol concentration was found to be the best plasma lipid predictor of the bile cholesterol saturation index. When the cholesterol saturation index of a fasting gallbladder bile specimen was compared to the plasma HDL cholesterol level for individual animals. a significant positive correlation was noted for animals fed polyunsaturated fat. (r = 0.68) and for animals fed saturated fat (r = 0.72). For any value of HDL cholesterol. however. the cholesterol saturation index was higher in animals fed polyunsaturated fat compared to saturated fat. Since plasma HDL cholesterol levels were positively correlated with the bile cholesterol saturation index in adult male African green monkeys. we conclude that a metabolic link exists between plasma HDL cholesterol concentrations and bile cholesterol saturation. perhaps due to enhanced delivery of cholesterol to the liver by HDL.
Enhanced expression of oncogene-encoded mRNA in a rat model of colon cancer, We have studied the expression of oncogene-encoded mRNAs in a rat model of colon cancer. In this model. rats are intrarectally administered several low doses of the direct-acting carcinogen. N-methyl-N-nitrosourea (MNU). Tumors. predominantly adenomas. develop 5-7 months following administration of the carcinogen. and many of these progress to carcinomas. Upon assaying the steady-state levels of oncogene-encoded transcripts in normal rat colon. we found that fos and N-myc are highly expressed; H-ras. K-ras. myc. myb. and neu messages are present at lower levels; and N-ras. abl. and raf mRNAs are absent. When we compared transcript levels in rat tumors to those in normal colons from the same animal. we observed a 2-4 fold increase in both myc- and H-ras-encoded mRNAs and a 2-7 fold increase in myb message. but no change in expression of any of the 7 other genes. To test whether this increased expression is related to tumor production or is simply a result of the more rapid cellular turnover observed in tumor tissue. the level of oncogene-encoded transcripts was assayed in colonic mucosae of rats given two treatments known to enhance cell turnover and DNA synthesis in the colon. Neither acute application of MNU nor a diet containing 1% cholic acid caused any change in the level of oncogene-encoded mRNAs in rat colons. thus suggesting that the increased abundance of myc. myb. and H-ras messages in tumors is associated with tumor formation. The enhancement of expression of these genes in adenomas. as well as in carcinomas. further suggests that these alterations occur relatively early during the tumorigenic process.
Continuous 5-fluorouracil infusion and alpha interferon in advanced cancers: a report of initial treatment results, Twenty-four patients with advanced metastatic cancer were treated with continuous intravenous 5-fluorouracil infusion 200-300 mg/m2/day and alpha interferon 3 million units subcutaneously 3 times per week. The average duration of treatment was 87 days (range 22-204 days). 5-fluorouracil could be infused 66% of the planned time on treatment. and patients received an average of 60% of the planned interferon injections. Objective tumor responses were seen in 6 of 17 previously untreated patients (35%). Twenty-two of the 24 patients (92%) experienced toxicity (greater than or equal to ECOG grade II) that required treatment interruption and subsequent dose reduction predominantly for the following reasons: mucositis (67%). hand-foot syndrome (21%). and leukopenia (25%). The incidence of treatment limiting toxicity is higher than previously observed with 5-fluorouracil infusion alone. This suggests true augmentation of 5-fluorouracil effect by interferon. 5-Fluorouracil infusion and alpha interferon is a potentially useful combination that needs further evaluation in future phase II and phase III trials.
Nonsteroidal anti-inflammatory gastropathy: from theory to practice, The success of nonsteroidal anti-inflammatory drugs in managing joint inflammation and pain has come at the cost of impressive side effects. particularly in the gastrointestinal tract. This manuscript reviews the magnitude of the problem. the risk factors. and presentation of nonsteroidal gastropathy. It also presents some points in the prevention and management of the disorder.
Age-related osteoporosis, Osteoporosis is a common disease that results in 1.2 million fractures each year in the United States. The morbidity and mortality as well as the financial impact from this disease is substantial. There has been considerable progress in our understanding of this disorder. but studies commonly include only early postmenopausal individuals. At the same time. it is clear that there are major epidemiologic. physiologic. and clinical differences between early postmenopausal and older individuals. These considerations raise the issue of the appropriateness of generalizing evaluation and treatment recommendations from younger to older patients. This review will focus on the age-related changes in bone physiology as it relates to osteoporosis and consider the available evidence for using commonly used (calcium) or approved (estrogen and calcitonin) agents in the elderly patient.
Epikeratoplasty with nonlyophilized tissue in children with aphakia, We studied 75 epikeratoplasty procedures using nonlyophilized tissue performed by eight ophthalmic surgeons in 70 eyes (47 patients) to correct for aphakia in children less than 8 years of age (mean age. 3.4 +/- 2.1 years). Of the 47 patients in the study. 24 were girls and 23 were boys; 23 patients had bilateral surgery. Seven of the epigrafts required removal; two were not replaced. and five underwent successful repeat epikeratoplasty. Overall. the success rate (that is. the percentage of epigrafts that remained optically and functionally clear throughout the course of this study) for the epikeratoplasty procedure was 89% (62 of 70 eyes) for initial surgery and 96% (67 of 70 eyes) for repeat surgery. The average spherical equivalent was +14.4 +/- 3.7 diopters preoperatively and +0.3 +/- 2.9 diopters one year after the operation. One year after the final surgical procedure. 42 of 56 eyes (75%) were within 3 diopters of emmetropia. In the 29 verbal patients. best-corrected visual acuity was 20/100 or better in 25 (86.2%) one year after the operation.
Neuro-imaging and positron emission tomography of congenital homonymous hemianopsia, Congenital homonymous hemianopsia is an uncommon asymptomatic visual field defect discovered typically in young adult life that is caused by a diverse group of insults to the retrochiasmal afferent visual system occurring prenatally. at birth. or during early childhood. We treated eight patients with congenital homonymous hemianopsia; seven with damage involving the optic radiations and one with an abnormality of the optic tract. We performed positron emission tomography using 18F-fluoro-2-deoxyglucose on two patients with dense homonymous hemianopsias. lesions of the contralateral optic radiations. and largely intact occipital cortex. These studies showed minimal abnormalities in resting visual cortex glucose metabolism of the affected visual cortex.
Infectious keratitis and cyanoacrylate adhesive, We studied three patients with infectious keratitis that occurred after cyanoacrylate gluing despite prophylactic antibiotic therapy. Two patients developed culture-positive bacterial ulcers. one caused by a methicillin-resistant Staphylococcus aureus and the other by Haemophilus influenzae. The third patient developed a fungal keratitis. Two patients required penetrating keratoplasty. Each infection and perforation was concealed by the opaqueness of the glue. The pain of the infectious ulcers may have been obscured by the ocular surface irritation and drying induced by glue. Tissue toxicity. microbial colonization. use of bandage lenses. and long-term broad-spectrum antibiotics may precipitate glue-related corneal infections. Masking of underlying infection and the development of resistant organisms should be considered when using this mode of therapy.
Initial glaucomatous optic disk and retinal nerve fiber layer abnormalities and their progression, We attempted to identify the initial glaucomatous changes of the optic disk and retinal nerve fiber layer and to analyze how these changes subsequently progressed. Of 61 eyes of 61 patients with ocular hypertension. 23 (38%) developed glaucoma during ten years of follow-up (range. five to 15 years). The initial sign of glaucomatous damage was diffuse enlargement of the optic disk cup in ten of 23 eyes or generalized thinning of the nerve fiber layer without localized changes in 12 of 23 eyes. We found localized optic disk damage in ten of 23 patients and localized retinal nerve fiber layer damage in 11 of 23 patients alone or in combination with diffuse damage. In 13 of 23 eyes. the cupping ended up in diffuse enlargement with even more profound thinning of the neural rim in the upper and lower temporal disk margins. There seems to be great variability in the appearance and progression of the initial glaucomatous optic disk and nerve fiber layer abnormalities in patients with increased intraocular pressure.
The effects of Nd:YAG laser iridotomy on the corneal endothelium, We studied 18 eyes of 18 patients undergoing Nd:YAG laser peripheral iridotomy for occludable anterior chamber angles. A Q-switched laser was used for all treatments. Preoperative and postoperative pachymetry and corneal endothelial cell counts were obtained centrally. in the nontreated superonasal quadrant. and in the treated superotemporal quadrant. No significant differences were found between preoperative and postoperative corneal thickness at any site. A small decrease in endothelial cell count (95 cells/mm2) at the treated site was statistically significant (P = .04).
The systemic distribution of Epstein-Barr virus genomes in fatal post-transplantation lymphoproliferative disorders. An in situ hybridization study, The systemic distribution of Epstein-Barr virus (EBV) genomes was studied in paraffin-embedded tissues from 12 fatal cases of Post-transplantation lymphoproliferative disease (PTLD). using an in situ hybridization technique employing an alpha-35S-dCTP-radiolabeled BamHI-W fragment of EBV DNA. The presence of EBV was documented in various PTLD-involved organs. The hybridization signal for the virus localized predominantly in the abnormal lymphoid cells. but signals also were detected in hepatocytes and/or adrenal cortical cells in five cases. The distribution of autoradiographic label within the lymphoid cells was focal and its intensity varied from field to field suggesting a nonuniformity of the viral genomic load in the infected tissues. Recruitment of EBV genome-bearing cells was not observed into inflammatory mononuclear infiltrates found in organs without histopathologic evidence of PTLD.
Cingulin, a specific protein component of tight junctions, is expressed in normal and neoplastic human epithelial tissues, Cingulin is a 140-kd protein localized on the cytoplasmic face of avian tight junctions. The expression of cingulin in human normal and neoplastic colonic tissue has been investigated with an antiserum against chicken cingulin. Human cingulin shares its apparent molecular mass and localization with avian cingulin. In normal colonic epithelium. villous adenomas. and differentiated adenocarcinomas. cingulin staining is observed in the junctional region of the polarized cells lining the surface. the crypts. and the glandular lumina. In poorly differentiated adenocarcinomas. labeling also is observed at the interface between cancer tissue and stroma. or in clumps of malignant cells. forming a pattern that highlights the presence of small. compressed lumina. The cingulin content of four adenocarcinomas. estimated by immunoblotting and densitometry. was higher than that of the normal tissue (150% to 230%). Cingulin was detected in a metastasis from a colon adenocarcinoma but not in nonepithelial tissues and neoplasias. suggesting that cingulin may be a useful marker in the characterization of colonic and probably other epithelial neoplasias.
Human coronary transplantation-associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft endothelial cells, Occlusive disease of coronary arteries of engrafted hearts is the major obstacle to long-term survival of human cardiac allografts. The pathogenesis of this process remains uncertain. The identity and localization of cells found in transplantation-associated arteriosclerosis lesions from human cardiac allografts were evaluated. and their expression of class II major histocompatibility complex (human leukocyte antigen-DR [HLA-DR]). surface molecules required for recognition of foreign cells by CD4+ T lymphocytes. was noted. Expanded intimas of transplanted coronary arteries contain T lymphocytes (both CD4+ and CD8+ in approximately equal number) and HLA-DR+ macrophages. both localized primarily in a ring immediately below the luminal endothelium. a distribution strikingly different from that in typical atherosclerosis. Coronary arterial endothelium from six of six transplanted hearts studied bore high levels of HLA-DR. Normal human arteries or usual atherosclerotic lesions have few if any HLA-DR+ endothelial cells. The significance of these findings was tested by evaluating the ability of HLA-DR+ arterial cells to interact with allogeneic T cells in vitro. Endothelial cells (but not smooth muscle cells) cultured from human arteries stimulated foreign CD4+ T cells to proliferate and augmented their secretion of interleukin-2. These findings suggest that ongoing stimulation of recipient T lymphocytes by HLA-DR+ endothelium of donor coronary arteries contributes to a sustained regional immune response. Consequent local release of cytokines may regulate smooth muscle cell proliferation and matrix accumulation within the coronary arteries of allografted hearts.
The rapid detection of clonal T-cell proliferations in patients with lymphoid disorders, A series of T-cell proliferations in peripheral blood. bone marrow. or tissue samples were analyzed for clonality. The technique used employs the polymerase chain reaction to amplify portions of the rearranged T-cell receptor beta chain genes. using primers recognizing conserved sequences of the variable. diversity. and joining region segments. We examined 17 cases of T-cell lymphoma or leukemia; a clone was identified in 13 cases (76%) overall and in 7 of 8 cases (87.5%) in which both beta-chain alleles were known to be rearranged. as shown by restriction enzyme analysis. No clonal rearrangements were detected in samples from 13 non-T-cell disorders. including B-cell lymphomas. reactive lymphoid proliferations. and nonlymphoid tumors. This method is useful for detecting clones in thymic and post-thymic T-cell malignancies and has the advantages of being extremely rapid (a result is obtained within hours of the biopsy procedure). requiring no radiolabeling. using only a small amount of tissue. and being applicable to formalin-fixed. paraffin-embedded tissue.
Oncogene amplification in breast cancer, To refine the analysis of gene amplification in breast cancer. the authors have developed sensitive methods that can be used to screen nucleic acid prepared from a variety of sources. In their analysis. Southern hybridization and DNA dot-blot analysis were used to screen 49 breast cancer DNAs for Myc. Neu. and Int-2 gene amplification. The analysis detected minimal one extra gene copy) as well as expanded (two or more extra gene copies) gene amplifications. and in addition. distinguished between gene amplification and aneuploidy as the cause of extra gene copies. These quantitative methods were adapted to patient specimens routinely available in the anatomic pathology laboratory. including fresh tumor tissue. tumor nuclei discarded during estrogen receptor analysis. and paraffin blocks. One minimal gene amplification was found in three cases of intraductal cancer. Of 25 cases of nonmetastatic invasive cancer. 28% had at least one extra Myc gene. whereas 24% had Neu. and 21% had Int-2 gene amplification. Of 21 cases of metastatic invasive cancer. 43% had Myc. 43% had Neu. and 40% had Int-2 gene amplification. Among the nonmetastatic cancers. 47% had one. 12% had two. and 4% had three amplified genes. Within the metastatic cancers. 48% had one. 28% had two. and 5% had three amplified genes. Our data suggest relationships between tumor progression and both incidence and size of Myc. Neu. and Int-2 gene amplification.
Rosenthal fibers share epitopes with alpha B-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin. Immunoelectron microscopy with colloidal gold, Ultrastructural immunoreactivities of alpha B-crystallin. glial fibrillary acidic protein (GFAP). ubiquitin. and vimentin in Rosenthal fibers (RFs) isolated from an Alexander's disease brain were investigated using nonosmium and low-temperature embedding technique. The morphology of RFs embedded in Lowicryl K4M resin was well preserved after treatment with 0.5% Triton X-100. alpha B-crystallin immunoreactivity was present in RFs of various sizes and was the strongest in loosely scattered deposits. which were considered to be the initial stage of RFs. Glial fibrillary acidic protein immunoreactivity in RFs was heavy. homogeneous throughout RFs. and equivalent to that in networks of glial filaments. Immunoreactivities of both alpha B-crystallin and GFAP were mainly restricted to the high electron-dense areas within RFs and were proved to exist close to each other by double immunolabeling. Rosenthal fibers were negative for vimentin. Ubiquitin immunoreactivity was relatively homogeneous in RFs with small diameters. but in RFs with large diameters. the immunoreactivity diminished in the center. Based on these observations. combined with the tendency of self-aggregation of alpha B-crystallin. it is conceivable that RFs are huge aggregation products of alpha B-crystallin involving GFAP. and that ubiquitination may be a consequent phenomenon. as it may be in other intracytoplasmic inclusions. such as neurofibrillary tangles and Lewy bodies.
Simian immunodeficiency virus infection of macaque bone marrow macrophages correlates with disease progression in vivo, The pathogenesis of hematopoietic abnormalities associated with infection of susceptible hosts with either simian immunodeficiency virus (SIV) or human immunodeficiency virus (HIV) is not fully understood. To determine if bone marrow cells are infected with SIV and if the pattern of viral infection is correlated with the severity of disease and abnormalities in hematopoiesis. 23 SIV-infected rhesus monkeys were examined by immunohistochemistry and in situ hybridization. By immunohistochemistry. only four monkeys were positive for SIV core protein p27. while in situ hybridization revealed viral RNA in the bone marrow of 15 monkeys. Simian immunodeficiency virus RNA was consistently expressed in the bone marrow from monkeys with severe lymphoid depletion (11 of 11). but less so in monkeys with follicular hyperplasia (0 of 2) or mild lymphoid depletion (4 of 10). In animals with mild lymphoid depletion. bone marrow cells infected with SIV were mainly mononuclear cells that appeared to be of myelomonocytic lineage. In contrast. monkeys with severe lymphoid depletion had SIV RNA localized to larger mononuclear cells with abundant cytoplasm often located in small lucent areas of the stroma. These SIV RNA-positive mononuclear cells were positive for the macrophage determinant CD68 as demonstrated by immunohistochemistry. Furthermore the stage of simian acquired immune deficiency syndrome. as indicated by lymphoid morphology. and SIV localization in the bone marrow were correlated with the incidence of anemia. bone marrow hyperplasia. and abnormal distribution of macrophages in the bone marrow. These results indicate that. in common with other animal lentiviral infections. the macrophage is a major target of SIV infections in the bone marrow.
Cellular events associated with inflammatory angiogenesis in the mouse cornea, The aim of this study was to establish an angiogenesis model in the mouse and to define immunohistochemically the cellular events that precede angiogenesis. After chemical cauterization of the murine cornea. neovascularization was observed within 36 hours. The cellular infiltrate was analyzed by using antibodies on cryostat and paraffin sections and by histochemical staining for mast cells. It was found that neither T lymphocytes nor mast cells nor macrophages in a more mature stage of development were part of the infiltrate that preceded the ingrowth of new blood vessels. Instead. the infiltrating cells appearing from 3 hours on were granulocytes and inflammatory monocytes. as detected by an antibody against the calcium-binding protein MRP14. The authors conclude that the induction of angiogenesis during nonspecific inflammation is associated with the early influx of myelomonocytic cells. but not with the infiltration of mature macrophages. T lymphocytes. or mast cells. This study shows that immunohistochemical analysis of cauterized murine corneas presents a useful tool for further studies on cells and cell products involved in the angiogenic process.
Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis, Interleukin-1 (IL-1) has been implicated as a regulatory protein in the development and clinical sequelae of atherosclerosis. To determine which cells in the atherosclerotic plaque synthesize IL-1 in situ. the authors evaluated histologic sections of iliac arteries from cynomolgus monkeys using probes for IL-1 alpha and beta. A polyclonal antibody to IL-1 alpha and beta was used to determine if proteins were concomitantly produced. The predominant cells expressing IL-1 alpha and beta mRNA were foam cells in the intima. Adherent leukocytes and vascular smooth muscle cells (VSMCs) expressed mRNA for IL-1 alpha. Microvascular endothelium expressed mRNA for both IL-1 alpha and beta. IL-1 proteins were located frequently in cells expressing IL-1 mRNA. These results indicate that endothelium and VSMCs. in conjunction with macrophages. serve as localized sources of IL-1 protein synthesis. These findings suggest that vascular cells may contribute directly to the pathogenesis of atherosclerotic vascular disease by actively secreting potent biologic mediators that modify vascular and immune cell function.
Detection of Opisthorchis viverrini by monoclonal antibody-based ELISA and DNA hybridization, Monoclonal antibody-based enzyme-linked immunosorbent assay and DNA hybridization techniques were developed and evaluated for their potential in the detection of Opisthorchis viverrini infection in humans. A mixture of three IgG1 monoclonal antibodies (MAb) specific for the 89 kDa metabolic product of O. viverrini was captured on a microtiter plate by rabbit anti-mouse IgG and used in a sandwich ELISA for the detection of parasite antigen. The 89 kD component bound to the MAb was detected with biotinylated rabbit IgG antibody to O. viverrini metabolic products. As little as 0.05-0.1 ng of the antigen could be detected by this technique. A specific O. viverrini DNA probe constructed from a repetitive DNA segment containing 340 base pairs was used in a dot blot hybridization for the detection of parasite DNA. The labeled probe constructed as such could detect DNA released from as few as five O. viverrini eggs. Both methods were specific for O. viverrini and their sensitivity was comparable with that of the classical parasitological technic.
Analysis of isotype-specific antifilarial antibody levels in a Haitian pediatric population, Previous studies of antifilarial antibodies in a pediatric population residing in an area with endemic Wuchereria bancrofti filariasis have demonstrated age related shifts in antifilarial immunity. To further characterize humoral responses in Haitian children. serum samples from 129 patients (3 months-15 years of age) were analyzed by ELISA for isotype-specific antifilarial antibody responses. Age-stratified analysis of geometric mean antibody titers showed significant increases in antibody titers of all isotypes with age in the amicrofilaremic population. Antifilarial IgG1. 2. and 3 levels were higher in amicrofilaremic children than in microfilaremic children. significantly so for IgG2 and IgG3. In contrast. IgG4 antibody levels were higher in microfilaremic subjects than in amicrofilaremic subjects. A multivariate. unconditional. logistic regression model was developed from these data to predict infection status. The model correctly classified 91.6% of the amicrofilaremic subjects. but only 55.6% of the microfilaremic subjects.
Evidence for specific suppression of gametocytemia by Plasmodium falciparum in residents of hyperendemic Irian Jaya, An epidemiologic study of hyperendemic malaria in Arso PIR. a village in northeastern Irian Jaya (Indonesian New Guinea). revealed evidence suggesting suppression of gametocytemia independent of immune control of the asexual parasitemia. A total of 240 people. representing ages between 2 and 60 years. were followed by biweekly blood film examination for 16 weeks beginning in November 1987. Two distinct subpopulations were represented--1) life-long residents of Irian Jaya. and 2) transmigrants from Java who arrived in Irian Jaya 20 months before the surveillance effort began. Twenty-five percent of blood films from natives and 31% from Javanese were positive for falciparum malaria; of these. the rate of gametocytemia was 21% for natives. and 42% for the Javanese transmigrants (P less than 0.001). This difference could not be explained by differences in the frequency or grade of parasitemia. illness. or by known patterns of antimalarial consumption. Similarly. in Wor. a village near Arso PIR. the gametocyte rate for P. falciparum diminished from 83% to 25% in transmigrants from Java between their eleventh and twenty-fifth month of residence in Irian Jaya. a period during which the falciparum malaria rate remained stable between 30% and 50%. An immunofluorescent antibody test using whole. acetone-fixed gametocytes as substrate revealed correlation between antibody titer and protection from gametocytemia among the semi-immune natives of Arso PIR. but not among the Javanese. Specific immune suppression of gametocytes. independent of immune control of asexual parasites. can explain all of these observations.
A longitudinal study of seroreactivities to Plasmodium falciparum antigens in infants and children living in a holoendemic area of Liberia, Investigators studied 348 children age 0-10 years. living in a holoendemic area of Liberia. for parasitological. serological and clinical parameters. The age-specific parasite rate increased towards the 7-10 year-old age group in which it was 86.8%. The geometrical mean parasite density decreased from the 3-4 year-old age group. in which fewer episodes of clinical malaria were observed. Antibodies to crude Plasmodium falciparum parasite antigens were detected in all children. The (EENV)6 seropositive rate was a maximum of 67.9% in the 3-11 month-old age group. It declined to a minimum of 31.7% in the 5-6 years age group after which it increased slowly in the 7-10 years age group. Antibodies to the synthetic peptide (NANP)6 showed a steady seropositive rate after the age of 3 months. between 30.0% and 39.3% in all the age groups up to 10 years. No statistically significant correlation was found between seropositivity to (EENV)6 and malarial parasitemia. In contrast. a statistically significant positive correlation was found between seropositivity to (NANP)6 and parasite rates. The antibody response for the individual child was transient to both Pf155/RESA. measured by immunofluorescence. and to (EENV)6 and (NANP)6. measured by ELISA. especially in the younger age groups of this study population. Parasitological and clinical immunity developed before a stable antibody response to these defined malaria antigens was established. These antibodies may still contribute to the immune protection against malaria. but they were not reliable parameters for protective immunity in the population we studied.
Naturally acquired circumsporozoite antibodies and their role in protection in endemic falciparum and vivax malaria, The role of naturally acquired circumsporozoite (CS) antibodies in protection against falciparum and vivax malaria was evaluated in a group of Thai endemic villagers using a prospective cohort and a case-control study design. There was no evidence of protection by either the presence of positive CS antibody levels at the presumed time of sporozoite exposure or in individuals who persistently had measurable levels of the antibodies. The study defined levels of CS antibodies that were not protective in natural infection.
How long should catheter-acquired urinary tract infection in women be treated? A randomized controlled study, OBJECTIVE: To determine the optimal management of catheter-acquired bacteriuria after short-term catheter use in women. PATIENTS: Asymptomatic patients (119) with catheter-acquired bacteriuria were randomly assigned to receive no therapy. a single dose (320-1600 mg) of therapy with trimethoprim-sulfamethoxazole. or 10 days (160-800 mg twice daily) of therapy. Thirty-two patients with lower tract symptoms alone received a single dose or 10 days of therapy. and 10 patients with upper tract symptoms or signs received 10 days of therapy. MAIN RESULTS: The mean and median durations of catheter use were 6 and 4 days. respectively. Bacteriuria resolved within 14 days without therapy in 15 of 42 (36%; 95% CI. 21% to 51%) asymptomatic patients. Seven of the remaining patients developed symptoms. Single-dose therapy resolved infection in 30 of 37 patients (81%; CI. 68% to 94%); 10 days of therapy resolved infection in 26 of 33 (79%; CI. 65% to 93%). For patients with lower tract symptoms alone. resolution rates with single-dose therapy or 10 days of therapy were similar (11 of 14 [79%] and 13 of 16 [81%]. respectively). Ten days of therapy resolved infection in 6 of 9 (67%) patients with upper tract symptoms. Infection was resolved more often in women who were less than or equal to 65 years than in older women (62 of 70 [89%] versus 24 of 39 [62%]; P less than 0.001). Bacteriuria resolved spontaneously more frequently in younger (14 of 19 [74%] compared with 1 of 23 older women [4%]; P less than 0.001). Single-dose therapy resolved infection in 31 of 33 (94%) patients who were less than or equal to 65 years. CONCLUSIONS: Asymptomatic bacteriuria after short-term catheter use frequently becomes symptomatic and should be treated. For asymptomatic patients and patients with lower tract symptoms alone. single-dose therapy was as effective as 10 days of therapy; it was very effective in women who were less than or equal to 65 years. Bacteriuria resolved spontaneously within 14 days after catheter removal more commonly in women who were less than or equal to 65 years and both types of therapy were less effective in older women.
Corticosteroid use and peptic ulcer disease: role of nonsteroidal anti-inflammatory drugs, OBJECTIVE: To estimate the relative risk for peptic ulcer disease that is associated with the use of oral corticosteroids. DESIGN: A nested case-control study. SETTING: Tennessee Medicaid program. PARTICIPANTS: The case patients (n = 1415) were hospitalized between 1984 and 1986 for gastric or duodenal ulcer or for upper gastrointestinal hemorrhage of unknown cause. The controls (n = 7063) were randomly selected from Medicaid enrollees not meeting the study criteria for inclusion as case patients. MEASUREMENTS AND MAIN RESULTS: The estimated relative risk for the development of peptic ulcer disease among current users of oral corticosteroids was 2.0 (95% CI. 1.3 to 3.0). However. the risk was increased only in those who concurrently received nonsteroidal anti-inflammatory drugs (NSAIDs); these persons had an estimated relative risk associated with current corticosteroid use of 4.4 (CI. 2.0 to 9.7). In contrast. the estimated relative risk for those corticosteroid users not receiving NSAIDs was 1.1 (CI. 0.5 to 2.1). Persons concurrently receiving corticosteroids and NSAIDs had a risk for peptic ulcer disease that was 15 times greater than that of nonusers of either drug. CONCLUSION: Discrepant findings among earlier studies regarding steroids and the risk for peptic ulcer disease could in part be due to differences in the use of NSAIDs among study participants. The high risk for peptic ulcer disease associated with combined use of NSAIDs and corticosteroids indicates the need to prescribe this drug combination cautiously.
The Takagi Automatic Tangent Screen ATS-85 analyzer for the detection of glaucomatous patients, The effectiveness of a new visual field analyzer. the Takagi Automatic Tangent Screen ATS-85. in detecting glaucomatous patients was studied. The study population consisted of three groups of subjects: normal healthy volunteers. glaucomatous patients with defective visual fields. and glaucomatous patients with early visual-field defects. Our results indicated that the screening program of the ATS-85 could be a useful instrument particularly for epidemiologic investigations.
The influence of hemodialysis on intraocular pressure: III. Aqueous humor dynamics and tissue hydration, Intraocular pressure. aqueous flow. outflow facility. outflow resistance. and both corneal and lens thickness were measured in patients receiving regular hemodialysis three times a week to test for induced variations of these parameters. No statistically significant differences occurred in any of the measurements taken. This study confirms that patients undergoing hemodialysis are not susceptible to glaucomatous disease.
Tests of EEG localization accuracy using implanted sources in the human brain, The accuracy with which electrical sources in the brain can be localized by using electroencephalograms measured on the scalp is not well known. In this study. tests of localization accuracy were performed by using implanted dipolar sources in the human brain. These dipoles are created by passing a weak (subthreshold) current through intracerebral electrodes implanted in the brains of epileptic patients for seizure monitoring. The locations of these dipoles are accurately known from roentgenographs. First. 16 electroencephalograms produced by these dipoles were recorded. then inverse solutions were calculated for the apparent sources of these electroencephalograms. Finally. the locations of the apparent sources were compared with the known locations of the implanted dipoles to determine localization error. The average localization error for a total of 28 dipoles in 3 subjects was 1.1 cm. These results indicate that good localization accuracy for focal sources in the brain can be provided by scalp electroencephalograms.
Human microglial cells: characterization in cerebral tissue and in primary culture, and study of their susceptibility to HIV-1 infection, Neuropathological studies have shown that human immunodeficiency virus type 1-infected cells within the brain express several markers characteristic of macrophages and could either be microglial cells. or monocytes invading the CNS. or both. To better define the target cells of human immunodeficiency virus type 1 within the brain. we have studied human microglial cells. both in vivo and in vitro. and compared them to monocytes for their antigenic markers and their susceptibility to human immunodeficiency virus type 1 infection. Brain-derived macrophages were isolated from primary cortical and spinal cord cultures obtained from 8 to 12-week-old human embryos. The isolated cells presented esterase activity. phagocyted zymosan particles. expressed several (Fc receptors. and CD68/Ki-M7 and CD11b/CR3 receptors) of the macrophagic antigenic markers. and appeared to be resident microglial cells from human embryonic brain. Conversely. brain-derived macrophages did not express antigens CD4. CD14. or CD68/Ki-M6. which are easily detected on freshly isolated monocytes. Using these antigenic differences between isolated microglial cells and monocytes. we have observed that two populations of macrophages could be individualized. In the normal adult brain. microglial cells were numerous in both the gray and the white matter. The infrequent cells sharing antigens with monocytes were found almost exclusively around vessels. In 8 to 12-week-old human embryos. microglial cells were found in both the parenchyma and the germinative layer. Cells sharing antigens with monocytes were only found at the top of and inside the germinative layer. In brain tissue from patients with human immunodeficiency virus type 1 encephalitis. cells sharing antigens with monocytes are abundant not only around the vessels but also in the parenchyma. In double-labeling experiments. human immunodeficiency virus type 1-infected cells showed monocyte antigens. Finally. microglial cells also differ from monocytes in their in vitro susceptibility to human immunodeficiency virus type 1 infection; after stimulation by r-TNF alpha or GmCSF. monocytes but not microglial cells can replicate human immunodeficiency virus type 1. This in vitro difference in human immunodeficiency virus type 1 susceptibility between monocytes and microglial cells together with the presence of monocytic antigens within the brain tissue of human immunodeficiency virus type 1-infected patients suggest that human immunodeficiency virus type 1-infected cells within the brain are either monocytes that have crossed the blood-brain barrier and spread through the tissue or perivascular microglial cells that. after phagocyting infected blood lymphocytes. subsequently contain viral antigen and migrate to brain tissue.
Capillary prolactin measurement for diagnosis of seizures, Measurement of serum prolactin levels can be useful in the diagnosis of epilepsy. since prolactin levels often rise after seizures. but not after most imitators of epilepsy. Utility of the test is limited by the need to obtain blood 10 to 20 minutes after the episode. The present study documents the validity of prolactin measurements using capillary blood. which was obtained by the finger-stick method after a possible seizure and then applied to filter paper. Venous and capillary prolactin levels were determined 10 to 20 minutes after seizure-like episodes in 20 patients who were studied in an epilepsy monitoring unit. Venous and capillary prolactin values correlated. with a Pearson coefficient of 0.90. Using a criteria of any elevation above the laboratory upper limit of normal. capillary prolactin values correctly identified seizure versus pseudoseizure in 9 (100%) of 9 patients with generalized tonic-clonic seizures. in 5 (71%) of 7 patients with complex partial seizures. and 4 (100%) of 4 patients with pseudoseizures. Prolactin values were unaffected by leaving filter paper samples at room temperature for up to 1 week. This study suggests the utility of diagnostic capillary blood collection kits to assist in the diagnosis of epilepsy in outpatients.
Effects of head trauma from motor vehicle accidents on Parkinson's disease, During 1 year we monitored changes in clinical disability scores in 10 patients with Parkinson's disease (PD) who sustained head trauma from motor vehicle accidents. Disability significantly increased immediately after trauma. but returned to baseline levels in subsequent weeks. These patients' signs deteriorated over the subsequent year. but this decline was equivalent to that of a matched control group with PD who did not have a motor vehicle accident or trauma. Based on these data. we conclude that trauma or stress caused by motor vehicle accidents can transiently exacerbate parkinsonian dysfunction without causing persistent increased disability or an alteration in disease course.
Increased HTLV-I proviral DNA in HTLV-I-associated myelopathy: a quantitative polymerase chain reaction study, Using the polymerase chain reaction. we quantitated the amount of human T-lymphotropic virus type I (HTLV-I) proviral DNA in peripheral blood mononuclear cells from 18 patients with HTLV-I--associated myelopathy/tropical spastic paraparesis; 17 HTLV-I carriers without HTLV-I--associated myelopathy/tropical spastic paraparesis. with or without other autoimmune or inflammatory diseases; and 19 seronegative control subjects. The HTLV-I proviral DNA was 10- to 100-fold higher in the patients and in the HTLV-I carriers without HAM/TSP who had autoimmune or inflammatory diseases than in the carriers without autoimmune or inflammatory diseases. The patients who had had onset of myelopathy at a younger age (15 to 39 years) had an extremely high level of HTLV-I proviral DNA in the early phase. as compared with findings in those with a late onset of myelopathy (at 44 to 61 years). The large increase in HTLV-I proviral DNA in peripheral blood mononuclear cells is presumably closely related to the development of autoimmune or inflammatory processes in HTLV-I carriers. including HTLV-I--associated myelopathy/tropical spastic paraparesis.
Quinolinic acid in cerebrospinal fluid and serum in HIV-1 infection: relationship to clinical and neurological status, Quinolinic acid is an "excitotoxic" metabolite and an agonist of N-methyl-D-aspartate receptors. Of patients infected with human immunodeficiency virus type 1 (HIV-1) who were neurologically normal or exhibited only equivocal and subclinical signs of the acquired immunodeficiency syndrome (AIDS) dementia complex. concentrations of quinolinic acid in cerebrospinal fluid (CSF) were increased twofold in patients in the early stages of disease (Walter Reed stages 1 and 2) and averaged 3.8 times above normal in later-stage patients (Walter Reed stages 4 through 6). However. in patients with either clinically overt AIDS dementia complex. aseptic meningitis. opportunistic infections. or neoplasms. CSF levels were elevated over 20-fold and generally paralleled the severity of cognitive and motor dysfunction. CSF concentrations of quinolinic acid were significantly correlated to the severity of the neuropsychological deficits. After treatment of AIDS dementia complex with zidovudine and treatment of the opportunistic infections with specific antimicrobial therapies. CSF levels of quinolinic acid decreased in parallel with clinical neurological improvement. By analysis of the relationship between levels of quinolinic acid in the CSF and serum and integrity of the blood-brain barrier. as measured by the CSF:serum albumin ratio. it appears that CSF levels of quinolinic acid may be derived predominantly from intracerebral sources and perhaps from the serum. While quinolinic acid may be another "marker" of host- and virus-mediated events in the brain. the established excitotoxic effects of quinolinic acid and the magnitude of the increases in CSF levels of the acid raise the possibility that quinolinic acid plays a direct role in the pathogenesis of brain dysfunction associated with HIV-1 infection.
Regional variation in brain lactate in Leigh syndrome by localized 1H magnetic resonance spectroscopy, Localized water-suppressed 1H magnetic resonance spectroscopy was performed in an 11-month-old infant with Leigh syndrome. Spectra obtained from the basal ganglia. occipital cortex. and brainstem showed elevations in lactate. which were most pronounced in regions where abnormalities were seen with routine T2-weighted magnetic resonance imaging. This approach has allowed us to examine metabolism in brain tissue directly and noninvasively. and may provide a sensitive means for evaluating metabolic disease and the response to therapy in the brain.
Thoracotomy in the octogenarian, Octogenarians are rarely referred for thoracic operations. presumably owing to the perceived morbidity of thoracotomy and the presumed frailty and limited life span of the 80-year-old patient. To determine if these concerns are valid. we reviewed our operative experience in 50 patients 80 years of age or older (mean age. 82.7 years; range. 80 to 91 years; 29 men. 21 women) undergoing thoracotomy between Nov 1. 1980. and May 1. 1990. for cancer (39 patients) and benign disease (11 patients). Procedures included 25 lobectomies (24 cancer. 1 abscess). 4 pneumonectomies (all cancer). 3 esophagectomies (1 perforation. 2 cancer). 3 explorations for cancer. 2 bullectomies. 12 wedge or segmental resections (5 open lung biopsies. 5 cancer. and 1 each for benign nodule and hemoptysis). and 1 thymectomy. Five patients (10%) were operated on emergently for massive hemoptysis (1). Boerhaave's syndrome (1). or rapidly progressive respiratory insufficiency (3) with an operative mortality of 80%. Mortality for elective cases was significantly lower (13%. p less than 0.01). Major complications occurred in 19 patients (38%). Univariate analysis performed to identify predictors of operative mortality demonstrated no significant relationship between operative death and patient age. sex. type of operation. diagnosis of malignancy. or the presence of either cardiac disease or chronic obstructive lung disease. Twenty-three patients are alive 2 months to 5 years after thoracotomy. Actuarial survival for the 45 elective patients was 56% and 44% at 1 and 2 years. respectively.
Prospective, randomized trial of palliative treatment for unresectable cancer of the esophagus, To evaluate the best method of palliation for obstructing nonresectable squamous cell carcinoma of the mid or distal esophagus. 27 patients were prospectively randomized to one of three treatment arms: (1) esophageal intubation with an Atkinson tube (AT. 10 patients). (2) esophageal intubation followed by radiation therapy (AT/RT. 8 patients). and (3) endoscopic laser therapy followed by irradiation (L/RT. 9 patients). Pretreatment characteristics were similar in the three groups. There was no procedure-related mortality. There were eight total complications related to the tube and none related to laser treatment (p = 0.02). Mean survival was 119 days in the AT group. 72 days in the AT/RT group. and 169 days in the L/RT arm (p = not significant). Quality of survival was most dependent on swallowing ability. and the swallowing score increased by 2.3 units in the AT group. 1.8 units in the AT/RT group. and 1.4 units in the L/RT group (p = not significant). Adding RT to laser therapy significantly increased time in treatment (mean. 38.7 days) when compared with the AT group (mean. 12.5 days) (p less than 0.001). However. only 1 patient required repeat laser ablation. It is concluded that AT and L/RT result in good palliation as measured by relief of dysphagia and survival time. However. morbidity of AT is significantly greater than that of L/RT. Laser and radiation therapy with a reduced total dosage of RT or with a change in fractionation schedule to limit treatment time is the preferred method of palliation.
Tricuspid valve repair for tricuspid valve endocarditis: tricuspid valve "recycling", Tricuspid valve endocarditis traditionally has been treated with either valve excision or valve replacement. To avoid implantation of foreign material in an infected field. we have applied the principles of mitral valve repair to 4 patients with tricuspid valve endocarditis. On preoperative echocardiography. all patients had 3 to 4+ tricuspid regurgitation. evidence of progressive right ventricular enlargement. and mobile vegetations. In each case. up to three quarters of the anterior leaflet was excised en bloc with infected chordae and papillary muscle heads. Surgical procedures included standard quadrangular resection. conversion to a bicuspid valve. and pericardial patch replacement of the anterior leaflet with mobilization of basal chordae to replace resected marginal chordae. On postoperative echocardiography. tricuspid regurgitation and right ventricular dimensions were reduced in 2 of 4 patients in spite of loss of leaflet tissue. All excised valve tissue demonstrated bacteria on Gram stain or culture. Nonetheless. all repaired valves were successfully sterilized without recurrent infections. Tricuspid valve repair can allow eradication of infection with potential for improving valve competency in complicated tricuspid valve endocarditis.
Closed heart cryoablation of the His bundle using an anterior septal approach, His bundle cryosurgical ablation using a closed heart anterior septal approach was used in 6 patients. There were 3 men and 3 women. aged 24 to 73 years. Three patients had atrial fibrillation and 2 patients had atrial flutter (2 with combined episodes of atrial tachycardia). One patient had atrial tachycardia. Five patients had no structural heart disease and 1 patient had left ventricular dilatation (ejection fraction. 0.35). All patients undergoing His bundle cryosurgical ablation had permanent heart block without intraoperative complications (mean follow-up. 25 months). Closed heart anteroseptal cryoablation of the His bundle is effective and is an alternative to attempted catheter ablation.
The safety of low-dose prednisone before and immediately after heart-lung transplantation, Preoperative steroid use has been considered a contraindication to heart-lung as well as lung transplantation. Moreover. most centers delay prednisone administration until 2 to 3 weeks postoperatively until airway healing is secure. We have performed 19 heart-lung transplantations and four single-lung transplantations since 1983. Five recipients (4 heart-lung. 1 single lung) had received prednisone. 5 to 40 mg daily. for 2 to 10 years preoperatively. All recipients were administered prednisone. 0.5 mg/kg daily. starting on postoperative day 1. with a taper to 0.2 mg/kg daily by 4 weeks. Minnesota antilymphocyte globulin (for 10 days). cyclosporine. and azathioprine were also employed. Bronchoscopy. lavage. and transbronchial biopsies were performed every 2 weeks for 3 months postoperatively. No patient had a serious airway complication; 2 heart-lung recipients. not on prednisone preoperatively. had a minor tracheal slough detected on bronchoscopy that resolved spontaneously. Actuarial survival after heart-lung transplantation is 84% +/- 8% and 69% +/- 16% at 1 year and 2 years. respectively. We conclude that prednisone commencing at a dose of 0.5 mg/kg daily from the first postoperative day is a safe practice after heart-lung transplantation. The long-term use of low-dose prednisone before heart-lung transplantation does not preclude normal tracheal healing. The safety of prednisone before and immediately after single-lung transplantation awaits confirmation by further experience.
Percutaneous transaortic closure of postinfarctional ventricular septal rupture, We report a case of successful closure of a postinfarctional ventricular septal defect by means of the transaortic approach with a balloon catheter. This method brought about substantial improvement in cardiopulmonary function before an elective operation and made it possible to successfully perform the operation on the patient. an 81-year-old woman. on the 22nd day of admission.
Intrapericardial pheochromocytoma, In a 34-year-old man with hypertension and increased urinary catecholamine excretion for 12 years. an m-[131I]iodobenzylguanidine scan and chest computed tomography located an intrapericardial pheochromocytoma in the left atrium. The tumor was excised through a left thoracotomy with cardiopulmonary bypass and circulatory arrest. At 34-month follow-up. blood pressure and urine catecholamine levels were normal. In the 15 cases of intrapericardial pheochromocytoma treated by resection reported in the literature. all 11 survivors were symptom-free except 1 who had residual left atrial tumor and multiple skeletal metastatic lesions. Computed tomography directed by the m-[131I]iodobenzylguanidine scan can be used for detailed location of the tumor. Appropriate surgical approach and use of cardiopulmonary bypass are critical in the resection of these highly vascular tumors.
Excimer laser angioplasty during aortocoronary bypass grafting, Laser coronary angioplasty using the 308-nm Excimer laser was successfully performed intraoperatively during coronary artery bypass grafting. It achieved a reduction of the left anterior descending artery stenosis from 99% to 25% as seen on angioscopy. without evidence of vascular perforation or intimal disruption. The Excimer laser offers the opportunity for intraoperative endovascular remodeling and recanalization and has a potential role as an adjunct to existing standard coronary artery bypass grafting protocol.
Coronary ostial reconstruction: technical issues, Coronary ostial reconstruction may be the preferred alternative to reestablish antegrade myocardial revascularization in patients with isolated ostial stenosis. The technical steps of reconstruction are described. The ultrasonic aspirator is a helpful implement in the dissection of the left main and the proximal right coronary arteries. Satisfactory results of coronary ostial reconstruction in the current era seem to fulfill its promise.
Patch aortotomy for aortic valve replacement after previous coronary artery bypass grafting, Exposure for aortic valve operations after previous coronary artery bypass grafting may be technically difficult owing to the presence of patent vein grafts on the proximal aorta. A patch or "island" aortotomy technique that allows excellent exposure of the aortic valve is presented here. In select patients this approach may facilitate cardioplegia administration.
New operative method for distal aortopulmonary septal defect, A new technique is described for repairing distal aortopulmonary septal defect with aortic origin of the right pulmonary artery in a 26-day-old neonate. To prevent the narrowing of the proximal right pulmonary artery in the distal aortopulmonary septal defect caused by conventional intraluminal prosthetic patch reconstruction. rerouting of the right pulmonary artery using native aortic wall tissue without artificial material was performed. This method seems to be superior to the conventional method. especially during the neonatal period.
Change in cholesterol awareness and action. Results from national physician and public surveys, The National Heart. Lung. and Blood Institute. Bethesda. Md. sponsored national telephone surveys of practicing physicians and the adult public in 1983. 1986. and 1990 to assess attitudes and practices regarding high serum cholesterol levels. Each time. approximately 1600 physicians and 4000 adults were interviewed. Trends show continuing change in medical practice and public health behavior relating to serum cholesterol. In 1990. physicians reported treating serum cholesterol at considerably lower levels than in 1986 and 1983. The median range of serum cholesterol at which diet therapy was initiated was 5.17 to 5.66 mmol/L (200 to 219 mg/dL) in 1990. down from 6.21 to 6.70 mmol/L (240 to 259 mg/dL) in 1986 and 6.72 to 7.21 mmol/L (260 to 279 mg/dL) in 1983. The median ranges for initiating drug therapy were 6.21 to 6.70 mmol/L (240 to 259 mg/dL) in 1990. 7.76 to 8.25 mmol/L (300 to 319 mg/dL) in 1986. and 8.79 to 9.28 mmol/L (340 to 359 mg/dL) in 1983. The number of adults who reported having had their cholesterol level checked rose from 35% to 46% to 65% in 1983. 1986. and 1990. respectively. Between 1983 and 1990. the number of adults reporting a physician diagnosis of high serum cholesterol increased from 7% to 16%; the number reporting a prescribed cholesterol-lowering diet increased from 3% to 9%. Reports of self-initiated diet efforts reached a high of 19% in 1986 and decreased to 15% in 1990 compared with 1% in earlier years. In 1990. over 90% of physicians reported awareness and use of the recommendations from the Report of the National Cholesterol Education Program Expert Panel on Detection. Evaluation. and Treatment of High Blood Cholesterol in Adults. and the public reported marked increases in awareness of dietary methods to lower serum cholesterol. These changes suggest educational gains; the data also suggest areas for continued cholesterol educational initiatives.
The neglected medical history and therapeutic choices for abdominal pain. A nationwide study of 799 physicians and nurses, A random national sample of 501 physicians and 298 nurse practitioners was presented a case vignette describing a patient with epigastric pain and endoscopy showing diffuse gastritis. Respondents were encouraged to request further information and then were asked for recommendations. History available if requested included substantial use of aspirin. coffee. cigarettes. and alcohol. and severe psychosocial stress. More than one third of the physicians chose to initiate therapy without seeking a relevant history. Nearly half of all physicians indicated that a prescription would be the single most effective therapy; 65% recommended a histamine antagonist. By contrast. only 19% of nurse practitioners opted to treat without taking further history; the nurse sample asked an average of 2.6 questions vs 1.6 for physicians; only 20% of the nurses recommended a prescription medication. These findings raise concerns about the adequacy of basic history taking in this setting and the underuse of nonpharmacologic approaches in favor of excessive reliance on prescription drugs. even when not indicated by clinical circumstances.
Zidovudine (AZT) for treatment of patients infected with human immunodeficiency virus type 1. An evaluation of effectiveness in clinical practice, To learn about the patterns of use and the effectiveness of zidovudine therapy in clinical practice. we conducted an observational cohort study of 86 patients with human immunodeficiency virus type 1 infection. All patients were followed up for at least 6 months after starting zidovudine (AZT) therapy. Of the 86 patients. 78 (91%) initially received full-dosage zidovudine (1200 mg/d). and eight received a reduced dosage (600 mg/d). During follow-up. the number able to maintain full-dosage zidovudine therapy decreased to 54 (63%) at 3 months and 40 (47%) at 6 months. Thirty-five patients required dosage reductions that lasted at least 7 days and were not preceded by an adverse outcome (death or opportunistic infection). Overall. adverse outcomes occurred for nine (26%) of those with dosage reductions compared with 22 (43%) of 51 patients with no previous dosage change. Even after adjusting for baseline cytopenias and the time of the dosage reductions. adverse outcomes did not occur significantly more often in patients who received reductions in their zidovudine dosage. Our results indicate that full-dosage zidovudine therapy cannot be maintained for most patients infected with human immunodeficiency virus. but that clinicians need not be pessimistic about treatment outcomes when dosage reductions are needed.
Effect of transdermal nicotine delivery as an adjunct to low-intervention smoking cessation therapy. A randomized, placebo-controlled, double-blind study, To assess the smoking cessation efficacy of transdermal nicotine patches as an adjunct to low-intervention therapy. we conducted a double-blind. placebo-controlled trial in 158 smokers. Participants were randomly assigned to one of the following three study regimens that required daily application of two 15-cm2 patches: (1) 24-hour nicotine delivery. (2) nicotine delivery during wakeful hours only. and (3) placebo. The impact of the three regimens on smoking cessation rates and tobacco withdrawal symptoms was examined. During the last 2 weeks of the trial. 39% of the 24-hour nicotine regimen delivery group. 35% of those on wakeful hour nicotine regimens. and 13.5% of the placebo treatment group achieved abstinence. Self-reported quit rates for the two nicotine patch-wearing regimens. as compared with that for the placebo group. continued to be significantly higher at 6 months. Moreover. compared with placebo. the transdermal nicotine patches significantly reduced tobacco withdrawal symptoms during the first few weeks of quitting. The differences in quit rates and tobacco withdrawal symptoms between the two active groups were not statistically significant. The patches were well tolerated both topically and systemically. We concluded that transdermal nicotine. when used as an adjunct to low-intervention therapy. significantly reduced tobacco withdrawal symptoms and enhanced smoking cessation rates.
Cyclic antidepressants and the risk of hip fracture, To determine whether cyclic antidepressants increase the risk of hip fracture. we conducted a population-based case-control study in the Canadian province of Saskatchewan. We identified 4501 persons 65 years of age or older with a first hospitalization for hip fracture between 1977 and 1985 and 24.041 comparable controls. Current antidepressant users had a relative risk of hip fracture of 1.6 (95% confidence interval. 1.3 to 1.9). Medical record review for a sample of 164 cases suggested this finding was not due to confounding by body mass. impaired ambulation. functional status. or dementia.
Effect of salt restriction on urine hydroxyproline excretion in postmenopausal women, Fasting calcium and hydroxyproline excretion are related to fasting sodium excretion in postmenopausal women. We postulate that calcium excretion is sodium dependent and that hydroxyproline excretion is calcium dependent. Therefore. we sought to lower urinary hydroxyproline. which is a marker of bone resorption. by lowering urinary sodium. Fasting urine samples were obtained from 59 postmenopausal women before and after 2 to 7 days of dietary salt restriction. The urinary sodium-to-creatinine ratio fell from 16 to 7; calcium to creatinine. 0.30 to 0.26; and hydroxyproline to creatinine. 18.2 to 16.8. In the 28 subjects with starting sodium-to-creatinine ratios greater than 15. the hydroxyproline-to-creatinine ratio fell from 19.6 to 16.3. Salt restriction may be one way of reducing bone resorption in postmenopausal women. particularly in those whose sodium intake is high.
Adult hereditary fructose intolerance, Hereditary fructose intolerance was diagnosed in a 69-year-old man on the basis of his medical history and the response to an intravenous fructose tolerance test. Three men of the same age as our patient were used as control subjects. Since the severity may vary and affected individuals self-impose fructose and sucrose restriction. they are essentially symptom free. The diagnosis can only be suspected by taking a careful dietary history. The prevalence of this condition in adults is unknown. It is rare but is likely to be more common than data in the literature would indicate.
Immersion foot. A problem of the homeless in the 1990s, The syndrome of immersion foot is being seen with increasing frequency among the homeless population. It represents the effects of injury by water absorption in the stratum corneum of the skin of the feet. The taxonomy of this disorder is confusing and the many colorful pseudonyms should probably be dropped in favor of a simple classification based on the temperature of the water and the duration of exposure. When uncomplicated by infection or ischemic injury. immersion foot will quickly resolve with conservative measures only. More complicated cases may require antibiotics and surgical treatment. This syndrome may be exacerbated by disturbances of cognition. peripheral neuropathy. peripheral vascular disease. or the use of tobacco or vasoconstrictor drugs such as cocaine. A major contributing factor seems to be lack of shelter in the homeless population. Attention to foot care problems among the homeless and education concerning preventive measures are incumbent on physicians who care for the indigent.
Angiofollicular lymph node hyperplasia and peripheral neuropathy. Case report and literature review, A man with multicentric angiofollicular lymph node hyperplasia and a polyclonal gammopathy developed a debilitating sensory-motor peripheral neuropathy that resolved with plasma-pheresis and immunosuppressive therapy. Fourteen similar cases have been reported in the literature; however. to our knowledge. this is the first report of successful treatment with plasma-pheresis. Severe peripheral neuropathy usually occurs in the setting of multicentric. plasma cell-type disease with hypergammaglobulinemia and is often responsive to immunosuppressive therapy.
Immunophenotypic analysis of acute lymphoblastic leukemia using routinely processed bone marrow specimens, Monoclonal antibodies have been recently developed that react with antigens expressed on T and B lymphocytes in routinely processed. paraffin-embedded lymphoid tissues. In this study. we assessed bone marrow clot and/or core biopsy sections of 19 cases of acute lymphoblastic leukemia (ALL) using routinely decalcified. B5- or formalin-fixed. paraffin-embedded sections and a panel of monoclonal antibodies. including LN1. LN2. L26. Leu-22. UCHL-1. and LCA. Each case had been previously phenotyped using freshly obtained aspirate material and a standard immunophenotypic protocol. Our results demonstrate the utility of the LN2 antibody in differentiating between precursor B-cell (pre-B) and precursor T-cell ALL. The LN2 antibody stained 11 of 12 cases of pre-B ALL and did not react with any of the seven T-cell ALLs. The other antibodies tested were less helpful. The Leu-22 antibody stained both pre-B and T-cell ALLs. while the results with UCHL-1 revealed peculiar nuclear staining of pre-B and T-cell ALLs; this we attributed to processing artifact. The L26 antibody reacted with only one case of pre-B ALL (also CD20 antigen positive). while the LN1 antibody did not react with any pre-B ALLs. Neither L26 nor LN1 stained any cases of T-cell ALL. The LCA antibody stained in only four (21%) of 19 cases. two pre-B and two T-cell ALLs. The results also suggest that this panel of antibodies may be useful in differentiating ALL from mature B-cell and T-cell lymphomas involving the bone marrow.
Nonbacterial thrombotic endocarditis in Hong Kong Chinese, Fifty-two Hong Kong Chinese cases of nonbacterial thrombotic endocarditis at autopsy were reviewed to ascertain if there was any difference in autopsy incidence. associated diseases. age and sex incidence. distribution of infarcts. and pattern of valve involvement compared with that in previously reported series. The overall autopsy incidence was 0.68%. within the range of previous reports. Forty-one cases (79%) were associated with malignant neoplasms; the remaining 11 cases were associated with miscellaneous disorders. Adenocarcinoma was associated with 27 (52%) of the cases. Unusual findings were the association of five cases with intrahepatic cholangiocarcinoma and four cases with esophageal squamous carcinoma. This is explicable on the basis of a higher incidence of these two tumors in Hong Kong Chinese than in Western populations. ie. the source of most other reported series. Sex and age incidence. the distribution of infarcts. and the pattern of valve involvement were similar to those reported in other series of nonbacterial thrombotic endocarditis.
Mechanism of fibrous capsule formation surrounding hepatocellular carcinoma. Immunohistochemical study, In 14 cases of hepatocellular carcinoma with capsule. we studied the mechanism of capsule formation by the immunoperoxidase technique using antibodies to types I. III. and IV collagen. antilaminin antibody. and anti-prolyl hydroxylase antibody. Marked round cell infiltration was observed in the noncancerous side of the capsule and around compressed hepatocytes near the capsule. Thin capsules were composed primarily of type III collagen produced by an increased number of fibroblasts. transitional Ito cells. and hepatocytes near the capsule. In thickened capsules. the noncancerous side consisted primarily of type III collagen and the cancerous side of types I and III collagen. Type I as well as type III collagen was produced by fibroblasts. transitional Ito cells. and hepatocytes. The capsule thus formed is suggested to be part of the defense mechanisms against the growth of hepatocellular carcinoma.
Undifferentiated carcinoma of the ovary, Thirty-five cases of ovarian carcinomas. which had as the predominant histologic component solid areas of epithelial cells without differentiation into mullerian carcinomas. were reviewed. The patients' ages ranged from 39 to 72 years (mean age. 54 years). Two patients had clinical stage I disease. one had stage II. 26 had stage III. and six had stage IV. Microscopically. the malignant cells formed large groups or sheets with desmoplastic stroma around them. Foci of papillary serous carcinoma. unclassified adenocarcinoma. or transitional cell carcinoma were seen in 26 tumors. foci of necrosis were seen in 30 tumors. and vascular invasion was seen in seven tumors. Six of 13 carcinomas tested expressed CA125 reactivity. and 12 of 13 carcinomas reacted to B72.3 monoclonal antibody. The primary tumors were treated by aggressive surgical reduction in 32 patients and by multiple biopsy procedures in three patients. After the first operation. 30 patients had residual disease. smaller than 2 cm in five patients and larger than 2 cm in 23 patients. After surgery. 33 patients received chemotherapy; three of these 33 also received radiotherapy. One patient was treated with postsurgical radiotherapy only. and one patient refused further treatment. Thirty-four patients (97%) died of disease between 8 and 108 months (mean. 27 months) after initial surgery. 29 patients died in less than 32 months. Four patients (11%) survived more than 5 years: two patients with stage I disease who died at 82 and 102 months. one patient with stage II who died at 72 months. and one patient with stage III who has no evidence of disease after 116 months. Five-year survival of patients with undifferentiated ovarian carcinoma is worse than the reported survival of patients with serous carcinoma or ovarian carcinoma with a pattern resembling transitional cell carcinoma. The distinction between these three carcinomas that have solid areas carries prognostic significance.
Electron microscopic study of an unusual posttransplant glomerular lesion, Glomerular lesions are frequently seen in renal allografts and are usually classified into transplant glomerulopathy and posttransplant glomerulonephritis. The latter is subdivided into donor-related. de novo. and recurrent glomerulonephritis. We report a distinctive posttransplant glomerular lesion that does not fit into any diagnostic category mentioned above. This lesion was characterized by the presence of global. diffuse. subepithelial. electron-lucent deposits. in addition to the usual features of transplant glomerulopathy. This unusual usual lesion. to the best of our knowledge. has been reported only once and. indeed. was recognized in only one of 297 renal allograft biopsy specimens in our file. Although the classification. pathogenesis. and origin of this rare lesion remain to be elucidated. it can be associated with nephrotic syndrome. deterioration of renal function. and eventual graft loss.
Frozen-section analysis of allograft renal biopsy specimens. Reliable histopathologic data for rapid decision making, Rapid tissue diagnosis during acute events associated with renal transplantation is often necessary to permit immediate decisions regarding initiation or modification of therapy. To achieve this. we performed frozen section analyses with cryoprotected alcoholic Bouin's-fixed tissue. which permits evaluation within 2.5 hours. During a 30-month period. 200 allograft biopsies were performed; 68 frozen sections were obtained when deemed necessary by the clinical team. We compared frozen-section diagnoses with those following regular evaluation of the biopsy specimen. Agreement in diagnoses occurred in 61 (88.4%) of 69 specimens. Acute rejection was the dominant diagnosis (n = 39); others were acute tubular necrosis. cyclosporine toxicity. chronic rejection. and infection. Major misdiagnoses included acute vascular processes (three capillary and/or venous thromboses and one vascular inflammation); acute cellular rejection was missed in two cases. reflecting a sampling error. Secondary diagnoses not of immediate therapeutic importance were detected in seven frozen sections and missed in nine. These included chronic glomerulopathies. nephrosclerosis. and mild chronic rejection. Although acute vascular phenomena may be difficult to recognize in frozen sections. we conclude that allograft biopsy frozen-section analysis is a valuable part of the care of transplant recipients.
Squamous metaplasia of the peritoneum, The capacity of the peritoneal serosa to undergo metaplasia to mullerian-type epithelium is well recognized. We report a case of squamous metaplasia of the peritoneum that was studied by light microscopy. Immunohistochemical techniques. and electron microscopy. The pathogenesis of peritoneal squamous metaplasia is obscure. but may be a response to chronic irritation.
Compensatory mechanisms in degenerative neurologic diseases. Insights from parkinsonism, In animal models of parkinsonism. the ability to lose a substantial proportion of dopaminergic neurons without behavioral deficits does not derive from other systems taking over function of the dopaminergic pathway. The surviving nigrostriatal projection increases both the rate of synthesis and the release of dopamine. as compensatory adjustments. This capacity allows at least a fivefold rise in dopamine delivery per neuron. and this enhancement is potentiated further by receptor up-regulation. Decreased reuptake. due to loss of nerve endings. may also lead to augmented occupancy of dopamine receptors. and so constitute yet another compensatory mechanism. In humans. positron emission tomography has revealed subclinical impairment of the dopaminergic nigrostriatal pathway in subjects at risk for parkinsonism caused by 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine and Lytico-Bodig (the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam). However. the separation of patients with clinically overt idiopathic parkinsonism from controls is less marked in vivo (by positron emission tomography) than in postmortem analysis (by neurochemical assay). This disparity may be attributable to the reduction in the number of nigrostriatal nerve endings. leading. in vivo. to a relative increase of extracellular dopamine because active reuptake into the nerve endings is an important mechanism for removing dopamine from the synaptic cleft. In contrast. in a postmortem setting. dopamine that is not sequestered in the storage vesicles of nerve endings is readily available for biochemical degradation during the interval between death and brain analysis. Finally. it is also possible that differences may derive. in part. from dissimilar kinetic systems for handling exogenous and endogenous levodopa.
Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson's disease. One-year follow-up of first clinical trial, Experimental studies in rodents show that beta-nerve growth factor can increase the survival. neurite outgrowth. and functional effect of grafts of adrenal chromaffin cells to the basal ganglia. We. therefore. have begun to investigate whether treatment with nerve growth factor might also increase the functional effect of autografts of adrenal medullary tissue in patients with Parkinson's disease. Previous studies have shown that stereotactic implantation of adrenal tissue pieces produces a transient functional improvement that lasts for a few months. This report describes a trial of grafting of adrenal chromaffin tissue into the putamen. supported by infusion of nerve growth factor. The patient is a 63-year-old woman with a 19-year history of Parkinson's disease. now complicated by on-off phenomena and drug-induced hyperkinesia. despite optimized medical management. The left adrenal gland was removed. and the medulla was dissected into 1- to 2-mm3 pieces in a solution containing nerve growth factor purified from mouse submandibular gland. Pieces were implanted in six tracts 3 to 4 mm from a previously placed cannula in the left putamen. Through the cannula. nerve growth factor was infused for 23 days for a total dose of 3.3 mg. Clinical assessment consisted of global ratings for rigidity and/or hypokinesia and for drug-induced hyperkinesia. Measures of gait and fine-motor control were also made. The motor readiness potential and auditory evoked potentials were recorded.
Idiopathic intracranial hypertension without papilledema, We describe 10 patients with idiopathic intracranial hypertension who did not have papilledema. Idiopathic intracranial hypertension without papilledema. although rarely reported. may well be a clinically important headache syndrome. Historical and demographic features of patients with idiopathic intracranial hypertension without papilledema are similar to those of patients with papilledema. Obese women with chronic daily headache and symptoms of increased intracranial pressure. pulsatile tinnitus. history of head trauma or meningitis. an empty sella on imaging studies. or a headache that is unrelieved by standard therapy should have a diagnostic lumbar puncture. Findings from laboratory and neurologic investigations are normal in most patients with idiopathic intracranial hypertension without papilledema. Initial management should include removal of possible inciting agents. weight loss if applicable. and standard headache therapy. Lumbar puncture and diuretic therapy should precede a trial of corticosteroids. Surgery (lumboperitoneal or ventriculoperitoneal shunt or perhaps optic nerve sheath fenestration) may be indicated for prolonged incapacitating headache that is not responsive to medical management or lumbar puncture.
Tuberous sclerosis complex in Olmsted County, Minnesota, 1950-1989, The incidence of tuberous sclerosis complex in Olmsted County. Minnesota. was 0.28 per 100.000 person-years from 1950 through 1989. the point prevalence on December 31. 1989. was 6.9 per 100.000 persons. and the incidence at birth was 6.0 per 100.000 live births. The incidence was 0.13 per 100.000 person-years from 1950 through 1974 and 0.46 per 100.000 person-years from 1975 through 1989. The higher rate of diagnosis during the later period is believed to be due to the use of computed tomography. Of the 12 patients considered in this study. one patient presented with seizures and severe intellectual disability. six patients presented with seizures. three patients presented with multiple facial angiofibroma. and two patients were asymptomatic.
Standard and controlled-release levodopa/carbidopa in patients with fluctuating Parkinson's disease on a protein redistribution diet. A preliminary report, Ten patients with Parkinson's disease (PD) with motor fluctuations that responded to a protein redistribution diet were studied. All 10 patients were receiving standard Sinemet (levodopa/carbidopa). Five randomly selected patients were changed from standard Sinemet to a controlled-release form of Sinemet. The other five patients continued to receive standard Sinemet. To maintain the same degree of control of PD in the five patients switched to the controlled-release form of Sinemet. the daily levodopa intake increased. While receiving optimal therapy (standard Sinemet or controlled-release Sinemet) and a protein redistribution diet. all 10 patients then underwent hourly videotaping and blood sampling (for plasma levodopa levels) during 2 consecutive days. Videotapes were blindly reviewed for PD disability. dyskinesia. and the time required to walk a measured distance. Comparing the two groups. standard Sinemet with controlled-release Sinemet. respectively. mean levodopa requirements were 505 and 1895 mg. plasma levodopa levels were 6.1 and 17.6 mumol/L. and abnormal involuntary movement scale scores were 14 and 26. Their mean PD disability scores did not differ statistically or clinically. Also no statistically significant differences were noted in either their mean walking times or their mean daily dose frequencies.
Neuroanatomic differences between dyslexic and normal readers on magnetic resonance imaging scans, The areas of six bilateral brain segments in the right and left hemispheres. on a horizontal brain section. and the area of subdivisions of the corpus callosum. on a midsagittal brain section. were measured on magnetic resonance images obtained from 21 dyslexic and 29 control subjects. In the entire group. the frontal half of the horizontal brain section showed asymmetry. with the right side being larger. whereas posteriorly only the occipital polar segment was asymmetrical. with the left side being larger. Dyslexic subjects exhibited asymmetry. with the right side greater than the left side. in contrast to the relatively symmetrical pattern that is normally observed in the midposterior segment that corresponds to the angular gyrus. In the corpus callosum. dyslexic subjects were found to have a larger splenium than nondyslexic subjects. and dyslexic female subjects were found to have a larger splenium than dyslexic male subjects. Because transcallosal pathways connecting the left and right angular gyrus regions traverse through the splenium of the corpus callosum. the above findings in dyslexic subjects suggest an anatomic abnormality in the angular gyrus region.
Magnetic resonance imaging white matter lesions and cognitive impairment in hypertensive individuals, To search for a morphologic basis of cognitive impairment possibly associated with essential hypertension. we studied 35 otherwise asymptomatic hypertensive individuals (mean age. 38.7 years; range. 22 to 49 years) and 20 normotensive control subjects (mean age. 37.9 years; range. 26 to 49 years) using neuropsychologic tests and magnetic resonance imaging. Irrespective of drug treatment. hypertensive individuals performed significantly worse than did control subjects when assessed for verbal memory and total learning and memory capacity. while there were no differences in test results of visual memory. attention. vigilance. and reaction time. The hypertensive individuals also described themselves as less active but ranked similar on five other mood subscales. Punctate high-signal intensities of the white matter were found almost twice as often in the hypertensive group (38%) as in the control group (20%). There was no difference in test performance between hypertensive individuals with and those without white matter lesions. however. Our results confirm the presence of subtle neuropsychologic deficits and indicate a higher frequency of white matter signal abnormalities in essential hypertension. as shown on magnetic resonance imaging. but do not indicate a correlation of these findings with each other.
Right parietal stroke with Gerstmann's syndrome. Appearance on computed tomography, magnetic resonance imaging, and single-photon emission computed tomography, We examined a patient who exhibited Gerstmann's syndrome (left-right disorientation. finger agnosia. dyscalculia. and dysgraphia) in association with a perioperative stroke in the right parietal lobe. This is the first description of the Gerstmann tetrad occurring in the setting of discrete right hemisphere pathologic findings. A well-localized vascular lesion was demonstrated by computed tomography. magnetic resonance imaging. and single-photon emission computed tomographic studies. The patient had clinical evidence of reversed functional cerebral dominance and radiologic evidence of reversed anatomic cerebral asymmetries.
Prospective corneal topographic analysis in surgery for postkeratoplasty astigmatism, Computer-assisted photokeratoscopy was used to evaluate the topographic characteristics of corneas preoperatively and postoperatively in seven patients who underwent surgery for correction of postkeratoplasty astigmatism. The steep hemimeridians were typically separated by an angle other than 180 degrees (mean. 162.5 degrees) and the flat hemimeridians were often not orthogonal to the steep hemimeridians. Asymmetry of power (1.5 or more diopters) between these two major hemimeridians was also observed in three patients. Relaxing incisions were placed in the two steep hemimeridians and compression sutures were placed in the flat hemimeridians. The mean percent of reduction of astigmatism (vector-corrected) was 81.1%. The amount of keratometric astigmatism. and the degree of asymmetry of the hemimeridians were not correlated with the percent of reduction of astigmatism after placement of the relaxing and compression sutures. Computer-assisted topographic analysis may prove useful in planning transverse keratotomies centered on the steep hemimeridians and in placement of compression sutures in flat hemimeridians.
Late-onset elevation in intraocular pressure after neodymium-YAG laser posterior capsulotomy, We retrospectively studied the long-term change in intraocular pressure after neodymium-YAG laser posterior capsulotomy. Uncomplicated extracapsular cataract extraction with posterior chamber intraocular lens implantation was performed in 446 consecutive normal eyes (401 patients). 237 (53%) of which subsequently underwent uncomplicated neodymium-YAG laser posterior capsulotomy. Late-onset elevation in intraocular pressure was seen in three eyes (1.4%) after cataract surgery alone (mean follow-up. 2.7 +/- 1.7 years) and in 14 eyes (5.9%) after cataract and laser surgeries (mean follow-up. 3.0 +/- 1.1 years). This difference was statistically significant (P less than .03). These results suggest that. in addition to immediate changes in intraocular pressure. neodymium-YAG laser posterior capsulotomy may be associated with an increase in intraocular pressure long after the laser surgery. even in normal eyes without obvious postoperative complications.
The ocular effects of gases when injected into the anterior chamber of rabbit eyes, We studied the toxic effects of sulfur hexafluoride and perfluoropropane in comparison with air. balanced salt solution. hyaluronate sodium. and aqueous humor in a rabbit model. Sixty normal pigmented rabbits were studied during a period of 4 weeks. The variables studied were slit-lamp biomicroscopic examination of the anterior segment. intraocular pressure as measured by pneumotonometry. corneal thickness and endothelial cell count as measured by specular microscopy. lens opacity by Scheimpflug photography. and light and transmission electron microscopy. All three gases were more toxic to the cornea and lens than were balanced salt solution. hyaluronate. and aqueous humor. However. 15% perfluoropropane and 50% sulfur hexafluoride were no more toxic to the eye than air was. Therefore. this study suggests that nonexpansile mixtures of perfluoropropane and sulfur hexafluoride may be beneficial and relatively safe in re-forming persistently flat anterior chambers in situations where the use of air is being considered.
Relationship between arthroscopic evidence of cartilage damage and radiographic evidence of joint space narrowing in early osteoarthritis of the knee, We examined the relationship between articular cartilage degeneration. as visualized arthroscopically. and joint space narrowing (JSN) in standing anteroposterior knee radiographs of 161 patients with chronic knee pain. The majority of these patients had radiographic findings of mild osteoarthritis. Twenty-five (33%) of the 76 patients in the series whose radiographs showed tibiofemoral JSN had grossly normal articular cartilage in both tibiofemoral compartments at arthroscopy (false-positive). The specificity of medial JSN for the presence of medial compartment articular cartilage degeneration was 0.61. i.e.. only 61% of patients with normal (grade 0) medial compartment cartilage had a normal medial joint space. Of 22 patients with greater than 50% medial JSN. 9 (41%) had normal articular cartilage in the medial compartment at arthroscopy. Of 6 patients with greater than 50% lateral JSN. 3 (50%) had normal lateral compartment articular cartilage at arthroscopy. Among 36 patients with greater than 25% JSN who had neither medial nor lateral compartment articular cartilage degeneration. JSN was associated with articular cartilage degeneration in the patellofemoral compartment in 8 (22%). with meniscus degeneration in 18 (50%). and with both in 8 (22%). Thus. in these patients with chronic knee pain. radiographic evidence of JSN in the tibiofemoral compartment did not permit confident prediction of the status of the articular cartilage.
T cell proliferation induced by Borrelia burgdorferi in patients with Lyme borreliosis. Autologous serum required for optimum stimulation, The cellular immune response to Borrelia burgdorferi was studied in 24 patients with seropositive and seronegative Lyme borreliosis. 30 patients with arthritides of different origin (non-Lyme arthritides). and 20 normal blood donors. By far. the strongest T cell stimulation was induced by incubation with autologous serum; there was a significantly lower response or no response after incubation with allogeneic or heterologous sera. In patients with Lyme borreliosis. including seronegative patients. there was a strikingly elevated proliferation in response to whole B burgdorferi bacteria (mean 64.750 dpm) compared with that of normal donors (mean 19.700 dpm; P less than 0.0001) and especially that of non-Lyme arthritis patients (mean 11.600 dpm; P less than 0.0001). Levels of proliferation declined significantly in patients with Lyme borreliosis after successful antibiotic treatment. Parallel cultures using B burgdorferi and Treponema phagedenis as antigens showed that cells from patients with Lyme borreliosis responded significantly more to B burgdorferi than to T phagedenis. but this did not occur with cells from individuals with non-Lyme arthritides. There was no correlation between disease stages and proliferation values. These data indicate that lymphocyte proliferation assays may provide an important tool for the diagnosis of Lyme borreliosis. most notably in patients with arthritides and in those who are seronegative. Conversely. the lack of reactivity appears to be a strong indicator of the absence of active Lyme disease. It seems to be crucial. however. to use autologous sera in these assays.
Elimination of soluble 123I-labeled aggregates of IgG in patients with systemic lupus erythematosus. Effect of serum IgG and numbers of erythrocyte complement receptor type 1, Using soluble 123I-labeled aggregates of human IgG (123I-AHIgG) as a probe. we examined the function of the mononuclear phagocyte system in 22 patients with systemic lupus erythematosus (SLE) and 12 healthy controls. In SLE patients. a decreased number of erythrocyte complement receptor type 1 was associated with less binding of 123I-AHIgG to erythrocytes and a faster initial rate of elimination of 123I-AHIgG (mean +/- SEM half-maximal clearance time 5.23 +/- 0.2 minutes. versus 6.58 +/- 0.2 minutes in the controls). with possible spillover of the material outside the mononuclear phagocyte system of the liver and spleen. However. multiple regression analysis showed that serum concentrations of IgG were the most important factor predicting the rate of 123I-AHIgG elimination. IgG concentration may thus reflect immune complex clearance. which in turn. would influence the inflammatory reaction. in SLE.
A potential role for microbial superantigens in the pathogenesis of systemic autoimmune disease, We have attempted herein to demonstrate how microbial superantigens could promote an abnormal form of "cognate" T helper-B cell interaction. analogous to that which may occur during GVH disease. leading to B cell activation and systemic autoimmunity. In vitro studies performed at our laboratory and others have demonstrated that resting human B cells bind microbial superantigens and present them to superantigen-reactive autologous T helper cells. resulting in T cell activation and polyclonal IgM and IgG production by the superantigen-bearing B cells. In vitro studies of microbial superantigen-mediated murine T helper-B cell interactions demonstrate preferential help for B cells that have encountered specific antigen. Both in humans and in mice. the cellular interactions involved and the B cell responses induced are highly analogous to those mediated by allospecific T helper-B cell interaction. Finally. the results of studies carried out on T cell-deficient (nude) mice suggest that microbial superantigens may trigger similar T helper cell-dependent polyclonal IgM and IgG responses in vivo. These mice will be studied over time and tested for the development of autoantibodies characteristic of SLE and of autoimmune organ system damage. the occurrence of which are predicted by our model.
Restriction fragment length polymorphism of the tumor necrosis factor region in patients with ankylosing spondylitis, Although ankylosing spondylitis (AS) is known to be strongly associated with the class I major histocompatibility complex antigen HLA-B27. B27 is probably not the only genetic factor involved in the pathogenesis of AS. Because of the involvement of tumor necrosis factor (TNF) in cartilage damage and the localization of the TNF genes in the proximity of the HLA-B locus. we investigated the association between AS and TNF alleles. The frequencies of the restriction fragment length polymorphisms linked to the TNF genes were determined in 73 AS patients and 81 controls. No differences were observed between AS patients and controls with respect to the frequencies of the TNF restriction fragment length polymorphisms.
The mutations in the fibronectin gene described in Japanese patients with systemic sclerosis are not present in Dutch patients, Recently. a mutant fibronectin gene was identified in skin fibroblasts obtained from sclerotic lesions of 7 Japanese patients with systemic sclerosis (SSc). Two point mutations were found adjacent to the cell-attachment tetrapeptide DNA sequence in exon 7 of the fibronectin gene. In the present study. we investigated whether these point mutations are present in the fibronectin gene of Dutch patients with SSc. We were unable to demonstrate the point mutations in the Dutch SSc patients studied.
Severe fibromyalgia after hypophysectomy for Cushing's disease, We report a case of fibromyalgia occurring after hypophysectomy for Cushing's disease. Clinical examination revealed tender points at 12 of the 18 tender point sites described in the American College of Rheumatology 1990 criteria for the classification of fibromyalgia. The cause of fibromyalgia remains unknown. In our patient. hypophysectomy may have played a role by disturbing endorphin secretion and pain modulation.
Lipid screening: is it enough to measure total cholesterol concentration?, OBJECTIVES--To determine whether measurement of total cholesterol concentration is sufficient to identify most patients at lipoprotein mediated risk of coronary heart disease without measurement of triglyceride and high density lipoprotein (HDL) cholesterol concentrations. DESIGN--Cross sectional screening programme. SETTING--Six general practices in Oxfordshire. PATIENTS--1901 Men and 2068 women aged 25-59. MAIN OUTCOME MEASURE--Cardiovascular risk as assessed by fasting venous plasma concentrations of total cholesterol. triglyceride. and HDL cholesterol. RESULTS--2931 Patients (74% of those screened) had a total cholesterol concentration of less than 6.5 mmol/l. If the triglyceride concentration had not been measured in these patients isolated hypertriglyceridaemia (greater than or equal to 2.3 mmol/l) would have remained undetected in 185. Among these 185 patients. however. 123 were overweight or obese and only 18 (0.6% of those screened) had an increased risk associated with both a raised triglyceride concentration (greater than or equal to 2.3 mmol/l) and a low HDL cholesterol concentration (less than 0.9 mmol/l). Conversely. in the 790 patients with predominant hypercholesterolaemia (cholesterol concentration greater than or equal to 6.5 mmol/l and triglyceride concentration less than 2.3 mmol/l) measurement of HDL cholesterol concentration showed that 348 (9% of those screened) had only a moderately increased risk with a ratio of total to HDL cholesterol of less than 4.5 and 104 had a low risk with a ratio of less than 3.5. CONCLUSIONS--Fasting triglyceride and HDL cholesterol concentrations identify few patients at increased risk of coronary heart disease if the total cholesterol concentration is less than 6.5 mmol/l. HDL cholesterol and triglyceride concentrations should. however. be measured in patients with a total cholesterol concentration exceeding this value. Total cholesterol concentration alone may overestimate risk in a considerable number of these patients. and measurement of HDL cholesterol concentration allows a more precise estimate of risk. Measurement of the triglyceride concentration is required to characterise the lipoprotein abnormality. A patient should not be started on a drug that lowers lipid concentrations without having had a full lipoprotein assessment including measurement of HDL cholesterol concentration.
Long-term follow-up of children with Down syndrome with cardiac lesions [published erratum appears in Clin Pediatr (Phila) 1991 Feb;30(2):128, Two hundred and eighty four patients with Down Syndrome (DS) were seen between 1951-1989. One-hundred and fourteen (40.1%) had a [corrected] cardiac murmur at presentation. A definitive cardiac diagnosis was established in 47 (41%) patients. of which 38 had long term follow-up. Fifteen (33%) patients had atrioventricular canals. There were 21 males and 17 females. with a mean age of 5.3 years. Fifteen (39%) patients were in functional class (FC) I. 16 (42%) in FC II. six (15%) in FC III. and one patient in FC IV at the time of presentation. There were 18 survivors (13 in the surgical group and five in the nonsurgical group) and 20 nonsurvivors (four in the surgical group and 16 in the nonsurgical group). Causes of death in the nonsurgical group included congestive heart failure. pneumonia. and pulmonary vascular disease. and occurred at a mean age of 8.4 years. Post-operative complications accounted for deaths in three of the four surgical patients. The survivors in the surgical group are presently in FC I/II. In the nonsurgical group. there was increased mortality. especially in those who presented in an earlier era. and a deterioration in functional class on follow-up due to the development of pulmonary vascular disease. Our data suggest that a) patients with Down syndrome and heart disease are helped by cardiac surgery with stabilization and improvement of their functional class; b) deterioration in functional class is seen in patients with Down syndrome with cardiac lesions who are managed nonsurgically [corrected] and c) mortality remains high in such patients treated nonsurgically due to development of pulmonary vascular disease and congestive heart failure.
Pharmacokinetics of gentamicin in neonatal patients supported with extracorporeal membrane oxygenation, This analysis of gentamicin pharmacokinetics involved 15 neonates supported by extracorporeal membrane oxygenation (ECMO). Two sets of blood samples were obtained from each neonate while supported by ECMO. The mean volume of distribution. elimination half-life. and clearance calculated from the first set of samples were 0.62 liters/kg. 7.6 hours. and 1.17 ml/kg/minute. respectively. Mean values from the second set of samples were 0.61 liters/kg. 7.9 hours and 0.99 ml/kg/minute. respectively. There were no statistical differences (p greater than 0.05) between the pharmacokinetics calculated from the first and second set of samples. A comparison of our results with those of others involving neonates not supported by ECMO failed to demonstrate any major impact of ECMO on the pharmacokinetics of gentamicin.
A double-masked evaluation of lignocaine-prilocaine cream (EMLA) used to alleviate the pain of retrobulbar injection, A randomised. placebo controlled. double-masked study was undertaken in 115 patients undergoing cataract surgery to assess the efficacy of the anaesthetic cream EMLA (eutetic mixture of local anaesthetic. lignocaine-prilocaine) in alleviating the pain of retrobulbar injection. Sixty three patients received the EMLA cream and 52 the placebo cream. The pain was assessed objectively by the anaesthetist. who observed the reaction of the patient on needle insertion. and subjectively by the patient. Significantly lower pain scores were recorded in patients treated with EMLA cream (anaesthetist's observation: p less than 0.01. patient's assessment: p less than 0.006). No patients experienced serious side effects in either treatment group.
Genetic counselling in retinoblastoma: importance of ocular fundus examination of first degree relatives and linkage analysis, We report an unusual family pedigree segregating the retinoblastoma predisposition gene. Expression of the phenotype in different individuals in this family ranges from asymptomatic gene carriers. regressed tumours. through unifocal to bilateral multifocal lesions. Because of the unusual pattern of inheritance in this family. initial genetic counselling at a local hospital did not take into account the possibility of incomplete penetrance of the gene. and complete ophthalmological examination of unaffected family members was not undertaken. We have used DNA probes from within the retinoblastoma predisposition gene for unequivocal identification of gene carriers. The subsequent demonstration of regressed tumours in founder members of the family confirmed the diagnosis of a dominantly inherited disease. The circumstances of the management of this family emphasises the need for specialist ophthalmic examination of first degree relatives and detailed genetic analysis of all such families with DNA probes.
Use of a blue filter in visual field analysis, One hundred and twenty seven eyes of 127 patients were studied by means of a Kodak 47B Wratten blue gelatin filter in conjunction with the Friedmann Mark 1 visual field analyser. There were 49 patients in the normal group. 50 patients in the ocular hypertension group. and 28 patients in a group with early glaucoma. A simple scoring system did not show a useful difference between these three groups. However. use of a derived threshold value for each target group designated by the letters B to P (giving selective blue field scores) differentiated between normal subjects and those with early glaucomatous field loss. When used with a calculated upper limit of normal to give a specificity of 96%. this test had a sensitivity of 64%. Of the ocular hypertension group 22% gave abnormal results in comparison with normal persons. This simple adaptation to the Friedmann protocol may aid the ophthalmologist in the detection and confirmation of early glaucoma.
Effect of partial cryoablation on retinopathy of prematurity, Cryotherapy has been shown to be an effective treatment for retinopathy of prematurity stage 3. It is said to reduce the unfavourable outcome of the disease by 50%. The accepted method of therapy includes ablation of the whole avascular retina from the ridge to the ora serrata. This is achieved by two to three rows of cryoapplications. When 360 degrees cryo treatment is performed. it requires 52 cryo applications. We present our method of cryotherapy which involves only one row of cryoapplications in the avascular retina anterior to the fibrovascular ridge. An average of 25-30 cryoapplications was required for a 360 degrees treatment. The anatomical results in 23 babies are presented. Complete regression of active retinopathy was found in all.
Glucose tolerance and blood pressure: long term follow up in middle aged men [published erratum appears in BMJ 1991 Apr 20;302(6782):939, OBJECTIVE--to investigate the role of glucose tolerance in the development of hypertension. DESIGN--Retrospective analysis of the results of a health check up in a group of clinically healthy middle aged men in the late 1960s (median year 1968). The subjects were invited to enter into a primary prevention trial for cardiovascular disease in 1974. when they underwent clinical examination for risk factors. The trial was completed in 1979. when the men were re-examined. Follow up was in 1986. SETTING--Institute of Occupational Health. Helsinki. Finland and second department of medicine. University of Helsinki. SUBJECTS--In all. 3490 men born during 1919-34 participated in a health check up in the late 1960s. In 1974. 1815 of these men who were clinically healthy were entered into a primary prevention trial for cardiovascular disease. On clinical examination 1222 of the men were considered at high risk of cardiovascular disease. Of these. 612 received an intervention and were excluded from the study. A total of 593 men were without risk factors. The study comprised all of the men who did not have an intervention (n = 1203). In 1979. 1120 men were re-examined. and in 1986 945 men attended follow up. There were two groups for analysis: one comprising all subjects and the other comprising only men who were normotensive in 1968 and for whom complete information was available. INTERVENTIONS--By 1979. 103 men were taking antihypertensive drugs. and by 1986. 131 were taking antihypertensive drugs and 12 were taking drugs for hyperglycaemia. MAIN OUTCOME MEASURES--Blood glucose concentration one hour after a glucose load. blood pressure. and body weight were measured in 1968. 1974. and 1979. In 1986 blood pressure and body weight were recorded. RESULTS--Men who were hypertensive in 1986 had significantly higher blood pressures (p less than 0.0001) and (after adjustment for body mass index and alcohol intake) significantly higher blood glucose concentrations one hour after a glucose load at all examinations than those who were normotensive in 1986. Regression analysis showed that the higher the blood glucose concentration after a glucose load in 1968 the higher the blood pressure during the following years. Those men between the second and third tertiles of blood glucose concentration in 1968 had a significantly higher risk of developing hypertension (odds ratio 1.71. 95% confidence interval 1.05 to 2.77) compared with those below the first tertile. CONCLUSION--In this study men who developed hypertension tended to have shown an increased intolerance to glucose up to 18 years before the clinical manifestation of their disorder. Blood glucose concentration one hour after a glucose load was an independent predictor of future hypertension.
Diagnosing breast carcinoma in young women, OBJECTIVE--To assess the individual and combined diagnostic accuracy of clinical examination. mammography. and fine needle aspiration biopsy in young women with breast cancer. DESIGN--Analysis based on case notes of patients presenting with breast cancer during 1971-89. SETTING--A combined breast clinic. PATIENTS--Consecutive series of 81 women aged less than 36 with histologically proved breast cancer presenting with a discrete mass over 19 years. MAIN OUTCOME MEASURES--Results of clinical examination. xeromammography or conventional mammography. fine needle aspiration biopsy. and examination of tissue removed by surgery. RESULTS--The clinical diagnosis was correct in 47 women and radiography in 35. Fine needle aspiration biopsy was correct in 47 of the 63 women in whom it was successfully performed. Fine needle aspiration was significantly more accurate than mammography (78% v 45%. p less than 0.01). Ten (16%) patients had negative results on clinical examination. mammography. and fine needle aspiration. CONCLUSION--Mammography alone seems inadequately sensitive to detect breast cancer in young patients. When all investigations give negative results excision biopsy is the only way of obtaining a definitive diagnosis.
Is risk of Kaposi's sarcoma in AIDS patients in Britain increased if sexual partners came from United States or Africa? [published erratum appears in BMJ 1991 Mar 30;302(6779):752, OBJECTIVE--To determine whether the risk of Kaposi's sarcoma in patients with AIDS is increased by sexual contact with groups from abroad with a high incidence of Kaposi's sarcoma. DESIGN--Analysis of risk of Kaposi's sarcoma in patients with AIDS. according to country of origin of their sexual partners. SETTING--United Kingdom. PATIENTS--2830 patients with AIDS reported to the Communicable Disease Surveillance Centre and the Communicable Disease (Scotland) Unit up to March 1990. of whom 566 had Kaposi's sarcoma. MAIN OUTCOME MEASURES--Percentage of patients with AIDS who had Kaposi's sarcoma. RESULTS--537 of 2291 homosexual or bisexual men (23%) with AIDS had Kaposi's sarcoma; 10% (14/135) of the men and women who acquired HIV by heterosexual contact had Kaposi's sarcoma. None of the 316 subjects who acquired HIV through non-sexual routes had Kaposi's sarcoma. Kaposi's sarcoma was more common among homosexual men whose likely source of infection included the United States (171/551. 31%) or Africa (9/34. 26%) than among those infected in the United Kingdom (119/625. 19%) (p less than 0.05). CONCLUSION--The data suggest that Kaposi's sarcoma is caused by a sexually transmissible agent which was introduced into the British homosexual population mainly from the United States [corrected].
Magnetic resonance imaging in the assessment of rheumatoid arthritis--a comparison with plain film radiographs, Conventional radiography lacks sensitivity in early rheumatoid disease. MRI with its advantages of soft tissue discrimination and multiplanar imaging facility might detect earlier disease. This study compares the MR images and conventional radiographs of 11 rheumatoid patients' wrists and carpi. In all cases. erosions were more extensive and numerous on the MR images compared to plain radiographs. MR is useful in detecting early aggressive disease and in monitoring the response to treatments.
Circadian variations in the superoxide production, enzyme release and neutrophil aggregation in patients with rheumatoid arthritis and controls, Patients with rheumatoid arthritis (RA) experience fluctuations of symptoms throughout the day. These could be due to mechanical changes or modification of the inflammatory mechanisms. In the present paper we studied fluctuations of superoxide production (O2). enzyme release (beta-glucuronidase and lysozyme) and neutrophil aggregation in the peripheral blood of eight healthy volunteers and eight patients with RA. Although enzyme release was greater in patients with RA. no significant difference was found throughout the day. neither in control nor in patients. Similar results were obtained when studying neutrophil aggregation. On the contrary. the superoxide production. determined at 8:00. 14:00. and 20:00 h. was 6.3 +/- 0.5. 4.40 +/- 0.4 and 6.26 +/- 0.3. respectively. in patients with RA and 6.65 +/- 0.7. 4.7 +/- 0.7 and 7.27 +/- 0.4 in the controls. The values obtained at 14:00 h were significantly lower (alpha = 0.01). There were no differences in the curve form between patients and controls.
Wegener's granulomatosis occurring in siblings, A brother and sister sibling pair with Wegener's granulomatosis (WG) are described. Previous reports of familial WG are reviewed.
Visual function after optic neuritis: a preliminary study, We assessed visual function after recovery from optic neuritis in 15 consecutive patients using five objective tests: colour vision testing with Ishihara colour plates and with D15 colour desaturated spots. Humphrey automated perimetry. contrast acuity testing with Regan letter charts and testing of visual evoked response (VER). Recovery of visual function was not found to be dependent on presenting Snellen visual acuity or treatment with oral steroids. The most sensitive measures of residual visual deficit were mean defect on automated perimetry. low-contrast acuity and VER.
Autosomal dominant megalocornea with congenital glaucoma: evidence for germ-line mosaicism, After the presentation of a newborn with congenital glaucoma. four additional members in two generations of a family were found to be affected with megalocornea. The absence of the disorder in the parents of three affected siblings can be explained by autosomal recessive inheritance. autosomal dominant inheritance or germ-line mosaicism. Each affected member showed iris stroma hypoplasia. miotic pupils and defects of the iris pigment epithelium. Less frequently encountered features included increased axial length. high myopia and congenital cataract. Most of the abnormalities can be accounted for by a disturbance in the growth and development of neural crest cells of the anterior chamber angle.
Retinal detachment as a complication of retrobulbar anesthesia, The authors report an unusual case of retinal detachment after cataract surgery in a 48-year-old man in which it appeared that the retrobulbar needle passed through the sclera and tracked beneath the retina before perforating the retina superior to the disc. The cause of the detachment was not clearly defined until a depigmented line was observed after reattachment of the retina.
Anterior segment mesenchymal dysgenesis associated with partial duplication of the short arm of chromosome 2, We present a case of partial duplication of the short arm of chromosome 2 (karyotype 46.XX. dup [2p21-2p25]) in a newborn girl. The infant was born at 41 weeks of gestation and died approximately 3 hours after birth. At autopsy the characteristic dysmorphic features (hypertelorism. high. prominent forehead. micrognathia and low-set. malformed ears) and numerous other congenital malformations were observed. Bilateral microcornea with opacities was noted. Histopathological examination of the eyes showed dysgenesis of Bowman's membrane. with glycosaminoglycan deposition and a series of structural anomalies that form part of the anterior segment mesenchymal dysgenesis (ASMD) complex. To our knowledge this is the first case of partial duplication of the short arm of chromosome 2 in which the ocular histopathological features have been studied. Our case provides a further example of the association of ASMD with a chromosomal abnormality.
Contrast sensitivity changes in background diabetic retinopathy, Previous reports of contrast sensitivity in diabetic patients have shown conflicting results. We evaluated contrast sensitivity using Cambridge low-contrast sensitivity charts in 22 diabetic patients (22 eyes without retinopathy and 16 eyes with background retinopathy on fluorescein angiography) and 10 control subjects (20 eyes) matched for age and sex. The mean contrast threshold values at a spatial frequency of 4 cycles/degree were 0.46%. 0.60% and 0.43% in the three groups of eyes respectively. Contrast sensitivity was significantly lower in the diabetic eyes with retinopathy than in the normal eyes (p = 0.011) or the diabetic eyes without retinopathy (p = 0.033). This test may be of value in screening diabetic patients for retinopathy in primary care facilities.
Successful reinduction therapy with amsacrine and cyclocytidine in acute nonlymphoblastic leukemia in children. A report from the Childrens Cancer Study Group, Amsacrine (AMSA) and cyclocytidine were studied as retrieval therapy in 122 pediatric patients with acute nonlymphoblastic leukemia (ANLL). Patients either failed to achieve sustained initial remissions or were in relapse. Induction therapy consisted of intravenous (IV) AMSA (75 mg/m2) from days 1 to 5 and subcutaneous cyclocytidine (600 mg/m2) from days 1 to 7. Maintenance therapy consisted of IV etoposide (VP-16) (100 mg/m2) for 5 days and IV AMSA (100 mg/m2) on day 1. Of 122 patients. 109 were evaluable. There were 13 early deaths. Ninety-six patients received adequate therapy defined as completion of two courses of therapy. Of these 96 patients. 52 achieved complete remission. Fifteen of 33 patients who failed initial induction achieved complete remission. Eighteen of 39 patients who were resistant to anthracyclines had complete responses. There was no direct evidence of AMSA-induced cardiotoxicity. Remission duration was 28 days to 3 or more years (median. 98 days). AMSA and cyclocytidine were effective retrieval therapy for patients who were in relapse or unresponsive to frontline therapy. Duration of remission was short (median. 98 days).
Evolution of neuropathy and myopathy during intensive vincristine/corticosteroid chemotherapy for non-Hodgkin's lymphoma, Neuropathy and myopathy are common sequelae of intensive chemotherapy protocols that contain vincristine and corticosteroids. The authors prospectively monitored the evolution of neuropathy and myopathy during an intensive 12-week chemotherapy program for patients with intermediate and high-grade non-Hodgkin's lymphoma. In this study. vincristine was administered by bolus injection followed by a 3-day continuous intravenous (IV) infusion (total dose of 2.0 mg/m2 every other week); the maximum dose of vincristine was not arbitrarily limited. Cronassial. a mixture of four naturally occurring gangliosides. was administered in a randomized double-blind test to evaluate whether this agent could prevent vincristine-induced neuropathy. High doses of dexamethasone (50 mg/d for 3 days weekly or every other week) were also prescribed. Patients were monitored every 4 weeks with comprehensive physical and neurologic examinations and electrophysiologic studies of peripheral nerve function. Twenty-seven patients were fully evaluable. Weakness was a prominent adverse reaction in this study. and all patients had moderate to severe signs and symptoms of neuropathy and myopathy. Cronassial (100 mg) administered by intramuscular (IM) injection daily provided no protection against the development of neuropathic symptoms. Vincristine typically impaired fine-motor coordination initially. whereas corticosteroids were associated with delayed development of proximal muscle weakness. Results of electrodiagnostic studies did not add to the clinical examination results. The authors conclude that symptomatic weakness due to neuropathy or myopathy appears in a predictable manner during intensive vincristine/corticosteroid-based treatment protocols. Simple clinical tests can be used to rapidly distinguish between toxic effects due either to vincristine or corticosteroids. and routine implementation of these tests can prevent inappropriate dose attenuation of these agents.
Accelerated fractionation for high-grade cerebral astrocytomas. Preliminary treatment results, A Phase I/II accelerated fractionation study for high-grade cerebral astrocytomas began in October 1987. Forty-two patients. 25 men and 17 women. were entered in the study. Median age was 58.5 years of age (range. 32 to 78 years). Performance status was 0. 1. 2. and 3 on Eastern Cooperative Oncology Group (ECOG) scale for 13. 19. 9. and 1 patients. respectively. Thirty-six patients had undergone partial resection. and six had stereotactic biopsy only. All patients had histologically proven astrocytomas (6 Grade 3. and 36 Grade 4). Treatment consisted of radiation therapy doses of 4400 cGy in 22 daily fractions to the whole brain plus a boost of 1600 cGy in 8 fractions given concomitantly with the last 8 whole-brain treatments using a twice daily schedule with an interfraction interval of 8 hours. Median survival time was 57 weeks from the date of starting irradiation. Survival was 50% and 28% at 1 and 2 years. respectively. Alopecia and scalp erythema were seen in all patients; nine patients had localized areas of moist desquamation in the retroauricular region. Decreased hearing and serous otitis media were seen in five patients within 1 to 2 months from the end of treatment. Increasing somnolence was marked in eight patients with progressive deterioration of performance status; computerized axial tomography (CAT) scan studies in all eight patients showed evidence of disease recurrence with associated brain edema and mass effect. Three patients had a second resection for a recurrent tumor with no evidence of brain necrosis at craniotomy. To date. the accelerated fractionation schedule appears to be well tolerated with valuable shortening of overall treatment time. The preliminary results are encouraging. and longer follow-up time is required to evaluate tumor control and toxicity.
A phase II study of piritrexim in combination with methotrexate in recurrent and metastatic head and neck cancer, Thirty patients with recurrent and/or metastatic head and neck cancer were treated with sequentially administered methotrexate (MTX) and piritrexim (PTX). The treatment schedule consisted of intravenous (IV) MTX (50 mg/m2) administered on day 1 and oral PTX (75 mg/m2) administered twice daily on days 8 to 12. Courses were repeated every 21 days with dose escalation in subsequent courses aimed at achieving Grade 1 toxicity. Two patients were not evaluable for response. 5 (17%; 95% confidence interval. 4% to 30%) had a partial response (PR). 10 had stable disease. and 13 had progressive disease. All five responses were seen in patients with regional lymph nodes as measurable disease. The median time to progression for all patients was 1.4 months. and the median survival was 6.7 months. Generally. this regimen was well tolerated with only mild toxicity seen during cycle 1 in the majority of patients. Dose escalation in subsequent cycles was possible in a high percentage of patients. Although the overall response rate and survival figures in this Phase II trial were disappointing. the doses and schedule used in this trial may have been suboptimal as reflected by the low incidence of moderate to severe toxicity. Additional evaluation of this combination of drugs in a more aggressive schedule may be warranted.
Effect of 17 beta-estradiol on the growth of an estrogen receptor-positive human esophageal carcinoma cell line, Receptors for estrogen and for androgen in the nucleus and cytosol (ERn. ERc. ARn. and ARc. respectively) were studied on two newly established human esophageal carcinoma cell lines. ES-25C and ES-8C. ES-25C was ERn+ (the binding content 4.0 fmol/mg protein. Kd 0.09 nM). ERc-. ARn-. and ARc-. No receptors were found in ES-8C. Various doses of 17 beta-estradiol (E2) were added in vitro to investigate its effect on the growth of these cell lines. No effect of E2 was observed on ER--ES-8C cell line. The growth of ES-25C cell was significantly inhibited at the doses of 10(-10) and 10(-12) mol/l E2 compared with the control. The doubling time of 10(-12) mol/l E2-treated cells was 32 hours whereas that of control was 20 hours. This slower growth was reflected in the deduction of cells in S-phase utilizing 5-bromo 2'-deoxyuridine (BrdU) labeling. The current results strongly suggest that the growth inhibition of ER+ esophageal cancer cell by E2 is mediated by signal transduction induced by the estrogen-estrogen receptor system.
DNA image cytometry. A prognostic tool in squamous cell carcinoma of the esophagus, In 45 patients who underwent an esophagus resection due to a squamous cell carcinoma. in addition to the TNM classification and usual morphologic criteria. the paraffin-embedded material underwent deparaffinization. was rehydrated. and was mechanically and enzymatically processed into a single-cell solution. For evaluating the DNA histogram this was analyzed with the help of automatic single-cell cytophotometric study. The method. contrary to that of flow cytometric study. allows for the selective analysis of tumor cells due to the electronically. previously given selection criteria. whereas artifacts. stroma. and infection cells remain excluded from analysis. The multivariate analysis shows that the prognosis is only correlated with DNA content of the tumor cells. Patients with diploid tumors had a median survival time of 32 months as compared with the 22 months of patients with hypotriploid tumors. and 6.5 months with hypertriploid tumors. DNA cytometric analysis should be included when diagnosing patients with esophagus carcinoma.
Mixed glioblastoma multiforme and sarcoma. A clinicopathologic study of 26 radiation therapy oncology group cases, Twenty-six cases are reported of gliosarcoma (GS) retrieved from a series of 1479 glioblastomas (GBM) that were part of five consecutive. randomized Phase II or III malignant glioma protocols initiated by the Radiation Therapy Oncology Group between 1974 and 1983. The clinicopathologic features of these 26 cases. including actuarial survival times. were compared with the remaining 1453 GBM. The minimal qualitative and quantitative histologic criteria required to diagnose GS are presented. In most cases the sarcomatous component was a malignant fibrous histiocytoma; a minority were fibrosarcoma. No significant differences between GS and GBM were found with regard to age. sex. pretreatment Karnofsky performance status. tumor location. size. median survival (8.3 and 9.6 months. respectively). and actuarial survival. None of the treatment regimens. which included various combinations of radiation therapy and chemotherapy. improved the survival of GS over GBM. Selective involvement of the temporal lobe by GS was not found. and the frequency of GS was determined to be only 1.8% of all GBM.
Bronchioloalveolar adenocarcinoma with myoepithelial cells, A unique variant of papillary lung carcinoma in a 58-year-old woman with both Clara cell and myoepithelial components is reported. The tumor was characterized by the presence of glandular spaces lined by two cell layers. The superficial (luminal) layer was made up of columnar cells with ultrastructural and immunohistochemical features of Clara cells. and occasional interspersed type 2 pneumocytes. The cells of the basal layer possessed ultrastructural and immunohistochemical features of myoepithelial cells. Myoepithelial cells have not previously been reported in a bronchioloalveolar adenocarcinoma.
Depressed adenoma of the stomach, revisited. Histologic, histochemical, and immunohistochemical profiles, For 52 patients with depressed adenomas of the stomach. histopathologic studies were done on 56 tumors and for 43 of them. histochemical and immunohistochemical features were examined. In addition. nondepressed adenomas (n = 57) and the depressed type of early gastric adenocarcinomas of the well-differentiated variety (n = 44) were studied as the controls. Depressed adenomas in the majority (73%) involved the entire thickness of the mucous membrane of the stomach with tubules of atypical epithelium. presenting a severe grade in many of the cases (41%). Paneth's cells were found in cases of a depressed adenoma. in significantly higher percentages (61%) than in those with a nondepressed adenoma (P less than 0.01). The frequency of cases with argyrophil cells was also higher in depressed adenoma (63%) than in nondepressed adenoma (36%) or in cases of early gastric carcinoma (32%). Carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 were noticed in tumor cells. immunohistochemically in 28% of the cases with depressed adenoma. the frequency being intermediate between cases of a benign nondepressed adenoma (6% for both CEA and CA 19-9) and cases of early gastric carcinoma (71% for CEA and 66% for CA 19-9). No difference was noticed in lectin reactivity and mucin content between depressed and nondepressed adenomas. whereas tumor cells in the early depressed carcinoma had a higher lectin reactivity and less mucin content than those seen in the adenomas. It would thus appear that depressed adenoma is a benign neoplastic lesion; however. the malignant potential of this lesion is somewhat higher than the nondepressed counterpart. as indicated by the immunoreactivity to tumor markers and follow-up results reported by colleagues previously.
Stage I small cell carcinoma of the vulva treated with vulvectomy, lymphadenectomy, and adjuvant chemotherapy, Neuroendocrine small cell carcinoma is a lethal. but rare. tumor that arises most frequently in the lung. Small cell cancer also rarely may occur in the female genital tract. usually in the cervix. This article concerns the fourth reported case of neuroendocrine small cell carcinoma of the vulva. Previously. small cell carcinoma of the vulva has been treated with regional therapy including surgery and radiation. Survival has been poor. however. due to the propensity of these tumors to metastasize early in the course of the disease. Recently. the median survival of patients with small cell carcinoma of the lung has been improved with the use of chemotherapy. The authors review the literature on the treatment of small cell carcinoma of the vulva and report on a patient who was treated successfully with vulvectomy and inguinal lymphadenectomy followed by adjuvant chemotherapy.
Vascular entrapment of intra-aortic balloon after short-term balloon counterpulsation, Prolonged. continuous intra-aortic balloon (IAB) counterpulsation for several weeks can result in balloon entrapment secondary to thrombus formation in the balloon lumen. In this report. we describe a patient who developed IAB entrapment. early (1 wk) after initiation of counterpulsation. A trace amount of blood was noted in the tubing connecting the balloon catheter to the console for 3 days prior to IAB malfunction and vascular entrapment. We suggest that the balloon catheter be removed immediately when blood is detected in the external connecting tubing even if the IAB is functioning satisfactorily.
Cortical blindness after coronary angiography: a rare but reversible complication, Transient cortical blindness is a recognized complication after vertebral and cerebral angiography but is a rare event after cardiac angiography. The development of cortical blindness appears to be an adverse reaction to the contrast agent which results in an osmotic disruption of the blood-brain barrier which appears to be selective for the occipital cortex. Patient outcome appears to be generally favorable with return of vision within 24-48 hr. This study describes three patients who had transient cortical blindness after cardiac catheterization and reviews what is known about this unusual problem.
Origin of the left main coronary artery from the "non-coronary" sinus of Valsalva, A case is described in which the left main coronary artery arises from the posterior sinus of Valsalva in an otherwise normal heart. This coronary anomaly did not result in any functional obstruction or myocardial ischemia but represents only the third such anomaly described in the English language literature.
PTCA of gastroepiploic bypass, A technique for percutaneous transluminal coronary angioplasty (PTCA) of gastroepiploic bypass is described using standard PTCA devices. Severe spasm of gastroepiploic bypass occurred. Modification of guide catheter position is suggested to avoid inducing gastroepiploic bypass spasm.
New technologies for the treatment of obstructive arterial disease, The well-known limitations of balloon angioplasty include unpredictable abrupt closure. chronic total occlusion. diffuse disease. and restenosis. among other factors. These limitations have prompted the development of new technologic approaches to angioplasty including laser applications for plaque ablation. mechanical device applications for plaque removal/debridement. and stent devices for structural maintenance of vascular lumen patency. Devices which directly apply laser energy for ablation of plaque material include a balloon-centered laser angioplasty system. excimer laser ablation catheter systems. and a fluorescence-guided spectral feedback laser system. Experience with these devices indicates that plaque can be successfully ablated by using laser energy. Vessel perforation and dissection are complications reported with these devices and the effects of laser angioplasty on restenosis remain unclear. Indirect application of laser energy has been tested by using a "hot tip" catheter and a laser balloon angioplasty system. Although the hot tip device has received FDA approval for use in peripheral arteries. it appears to have very limited applications in the coronary arteries. Laser balloon angioplasty appears to be beneficial in the setting of threatened acute closure; the device continues to be evaluated for potential beneficial impact on restenosis. Mechanical atherectomy catheters are designed to remove atherosclerotic plaque from the arterial system and include the AtheroCath. the Transluminal Extraction Catheter (TEC). and the Pullback Atherectomy Catheter (PAC). The Rotablator is an atheroablation device which debrides the obstructing plaque material with distal embolization of the particulate debris. Successful removal/debridement of atherosclerotic plaque has been demonstrated with the AtheroCath. Rotablator. and the TEC device. Pre-clinical studies demonstrate successful removal of plaque material with the PAC device. Despite the theoretic advantage of removing plaque material when performing angioplasty with these devices. there has been little or no reduction in restenosis rates based on a significant experience with the AtheroCath and the Rotablator. Intravascular stent devices including one self-expanding device design and two balloon-expandable device designs have been employed successfully in the elective setting to treat recurrent restenosis lesions. Two of the devices have been successfully tested in the setting of threatened acute closure. Early follow-up studies suggest some improvement in restenosis rates in certain clinical settings following intravascular stenting. Acute and subacute thrombosis remain substantial problems for stent devices and very aggressive anticoagulation regimens are necessary to minimize the adverse events. In summary. a number of a new technologic approaches for treatment of atherosclerotic lesions have been developed and are undergoing significant clinical evaluation.(ABSTRACT TRUNCATED AT 400 WORDS).
Percutaneous balloon versus surgical closed commissurotomy for mitral stenosis. A prospective, randomized trial, BACKGROUND. We performed a prospective. randomized trial comparing percutaneous balloon commissurotomy with surgical closed commissurotomy in 40 patients with severe rheumatic mitral stenosis. METHODS AND RESULTS. Data were analyzed by investigators who were masked to treatment assignment or phase of study. Patients randomized to balloon (n = 20) or surgical (n = 20) commissurotomy had severe mitral stenosis without significant baseline differences (left atrial pressure. 26.1 +/- 4.2 versus 27.6 +/- 6.2 mm Hg; mitral valve gradient. 18.0 +/- 4.2 versus 19.7 +/- 6.3 mm Hg; mitral valve area. 1.0 +/- 0.2 versus 1.0 +/- 0.4 cm2. respectively). At 1-week follow-up after balloon commissurotomy. pulmonary wedge pressure was 14.3 +/- 7.2 mm Hg; mitral valve gradient was 9.6 +/- 5.1 mm Hg; and mitral valve area was 1.6 +/- 0.6 cm2 (all p less than 0.0001). At 1-week follow-up after surgical closed commissurotomy. wedge pressure was 13.7 +/- 5.4 mm Hg; mitral valve gradient was 9.4 +/- 4.2 mm Hg (both p less than 0.0001); and mitral valve area was 1.6 +/- 0.7 cm2 (p less than 0.003). At 8-month follow-up. improvement occurred in both groups: Mitral valve area was 1.6 +/- 0.6 cm2 in the balloon commissurotomy group (p less than 0.002) and was 1.8 +/- 0.6 cm2 in the surgical closed commissurotomy group (p less than 0.0001). There was no difference between the groups at 1-week or 8-month follow-up (all p greater than 0.4). One case of severe mitral regurgitation occurred in each group; complications were otherwise related to transseptal catheterization. There was no death. stroke. or myocardial infarction. Cost analysis revealed that balloon commissurotomy may substantially exceed the cost of surgical commissurotomy in developing countries. whereas it may represent a significant savings in industrialized nations. CONCLUSIONS. We conclude that percutaneous balloon commissurotomy and surgical closed commissurotomy result in comparable hemodynamic improvement that is sustained through 8 months of follow-up.
Identification of acute myocardial infarction patients suitable for early hospital discharge after aggressive interventional therapy. Results from the Thrombolysis and Angioplasty in Acute Myocardial Infarction Registry, BACKGROUND. Very early (day 4) hospital discharge has recently been proposed for selected patients with acute myocardial infarction (MI). The purpose of this study was to determine the most useful factors for identifying acute MI patients treated with aggressive interventional therapy who could be safely discharged on day 4. METHODS AND RESULTS. We studied 708 patients enrolled in the Thrombolysis and Angioplasty in Acute Myocardial Infarction trials I-III. Patients dying in the first 3 days and those with early (days 1-3) emergency coronary artery bypass graft surgery (CABG). late elective CABG (greater than or equal to day 4). or urgent/emergency CABG resulting from a late elective coronary angioplasty were excluded. The remaining 580 patients were randomly divided into a training sample (group 1) that was used to build a logistic regression model for predicting the absence of a late major complication and a test sample (group 2) that was used to validate this model. For this study. patients were considered appropriate for day 4 hospital discharge if they did not experience any of the following for 30 days after MI: death. reinfarction. cardiogenic shock. pulmonary edema. sustained hypotension. sustained ventricular tachycardia. high-grade atrioventricular block. acute ventricular septal defect. and recurrent ischemia necessitating urgent CABG. In group 1. four variables were independent predictors of freedom from late major complications: absence of early sustained ventricular tachycardia or ventricular fibrillation. absence of early sustained hypotension or cardiogenic shock. fewer coronary arteries with significant (greater than or equal to 75%) stenosis. and a higher left ventricular ejection fraction. In group 2. 23% of patients had a logistic model prediction of a 3% or less chance of a late complication. These patients had no deaths or reinfarctions by day 30 and a 3% late major complication rate. CONCLUSIONS. The results of early cardiac catheterization and the absence of selected early (days 1-3) major complications do allow identification of a low risk subgroup of acute MI patients that may be suitable for very early discharge.
Expected gains in life expectancy from various coronary heart disease risk factor modifications, BACKGROUND. Despite much evidence that modifying risk factors for coronary heart disease can decrease morbidity and mortality. little is known about the impact of risk-factor modification on life expectancy. METHODS AND RESULTS. We used the Coronary Heart Disease Policy Model. a state-transition computer simulation of the US population. to forecast potential gains in life expectancy from risk-factor modification for the cohort of Americans turning age 35 in 1990. Among 35-year-old men. we projected that the population-wide increase in life expectancy would be about 1.1 years from strict blood pressure control. 0.8 years from smoking cessation. 0.7 years from reduction of serum cholesterol to 200 mg/dl. and about 0.6 years from weight loss to ideal body weight. For women. reducing cholesterol to 200 mg/dl would have the greatest estimated impact-a gain of 0.8 years-whereas smoking cessation. blood pressure control. or weight loss would yield population-wide gains of 0.7. 0.4. and 0.4 years. respectively. Gains for 35-year-old individuals having a given risk factor are greater. We estimate that. on average. male smokers would gain 2.3 years from quitting smoking; males with hypertension would gain 1.1-5.3 years from reducing their diastolic blood pressure to 88 mm Hg; men with serum cholesterol levels exceeding 200 mg/dl would gain 0.5-4.2 years from lowering their serum cholesterol level to 200 mg/dl; and overweight men would gain an average of 0.7-1.7 years from achieving ideal body weight. Corresponding projected gains for at-risk women are 2.8 years from quitting smoking. 0.9-5.7 years from lowering blood pressure. 0.4-6.3 years from decreasing serum cholesterol. and 0.5-1.1 years from losing weight. Eliminating coronary heart disease mortality is estimated to extend the average life expectancy of a 35-year-old man by 3.1 years and a 35-year-old woman by 3.3 years. CONCLUSIONS. Population-wide gains in life expectancy from single risk-factor modifications are modest. but gains to individuals at risk can be more substantial.
Logistic discriminant analysis improves diagnostic accuracy of exercise testing for coronary artery disease in women, BACKGROUND. Diagnostic accuracy of the exercise electrocardiogram in women has been shown to be limited for the detection of coronary artery disease. New diagnostic methods based on computer analysis of the exercise electrocardiogram and multivariate analysis have improved the diagnostic value of exercise testing in male subjects. The aim of the present study was to assess whether the diagnostic value of exercise testing can be enhanced in women by using multivariate analysis of exercise data. METHODS AND RESULTS. Between 1978 and 1984. 135 infarct-free women underwent exercise testing and coronary angiography. Significant coronary artery disease was present in 41% of the patients. In this first group. maximal exercise variables were submitted to a stepwise logistic analysis. Work load. heart rate. and ST60X were selected to build a diagnostic model. The model was tested in a second group of 115 catheterized women (significant coronary artery disease in 47%) and of 76 volunteers. We compared the present model with conventional analysis of the exercise electrocardiogram. with ST changes adjusted for heart rate. and with a previously described analysis. In both groups. sensitivity was better with the present model (66% and 70%) than by conventional (68% and 59%) and by the previously described analysis (57% and 44%) without a loss of specificity (85% and 93%). Receiver-operator characteristic curves showed also a better diagnostic accuracy with the present model. CONCLUSIONS. In women. logistic analysis of exercise variables improves the diagnostic value of exercise testing. It yields a significantly better sensitivity without a loss of specificity.
Patients with two types of atrioventricular junctional (AV nodal) reentrant tachycardia. Evidence that a common pathway of nodal tissue is not present above the reentrant circuit, BACKGROUND. The site of the reentrant circuit in atrioventricular (AV) junctional reentrant tachycardia has not been defined; in particular. the existence of a common pathway of AV nodal tissue above the reentrant circuit is controversial. METHODS AND RESULTS. Two types of AV junctional reentrant tachycardia were induced in each of three patients at electrophysiological study. In one type of tachycardia (anterior). the onset of atrial activity occurred from 0 to 12 msec before the onset of ventricular activation. and earliest atrial activity was recorded near the His bundle. In the second type of tachycardia (posterior). the ventriculoatrial intervals were longer (76-168 msec). and earliest atrial activity was recorded near the mouth of the coronary sinus. In individual patients. the two types of tachycardia had different cycle lengths. Posterior AV junctional reentrant tachycardia was not a fast-slow form of AV junctional reentry in at least two of the three patients. Surgical cure was attempted in two patients. In one patient. anterior AV junctional reentrant tachycardia was abolished by dissection of the anterior perinodal atrium. but posterior AV junctional reentrant tachycardia could still be induced. At reoperation 4 months later. dissection of the posterior perinodal atrium abolished posterior AV junctional reentrant tachycardia while preserving AV conduction. CONCLUSION. Differences in ventriculoatrial intervals and cycle lengths and the results of selective surgery suggest that the two types of AV junctional reentrant tachycardia used different reentrant circuits. These observations imply that a common pathway of AV nodal tissue is not present above the reentrant circuit and suggest that perinodal atrium is part of these circuits.
Thallium reinjection after stress-redistribution imaging. Does 24-hour delayed imaging after reinjection enhance detection of viable myocardium, BACKGROUND. Thallium reinjection immediately after conventional stress-redistribution imaging improves the detection of viable myocardium. as many myocardial regions with apparently "irreversible" thallium defects on standard 3-4-hour redistribution images manifest enhanced thallium uptake after reinjection. Because the 10-minute period between reinjection and imaging may be too short. the present study was designed to determine whether 24-hour imaging after thallium reinjection provides additional information regarding myocardial viability beyond that obtained by imaging shortly after reinjection. METHODS AND RESULTS. We studied 50 patients with chronic stable coronary artery disease undergoing exercise thallium tomography. radionuclide angiography. and coronary arteriography. Immediately after the 3-4-hour redistribution images were obtained. 1 mCi thallium was injected at rest. and images were reacquired at 10 minutes and 24 hours after reinjection. The stress. redistribution. reinjection. and 24-hour images were then analyzed qualitatively and quantitatively. Of the 127 abnormal myocardial regions on the stress images. 55 had persistent defects on redistribution images by qualitative analysis. of which 25 (45%) demonstrated improved thallium uptake after reinjection. At the 24-hour study. 23 of the 25 regions (92%) with previously improved thallium uptake by reinjection showed no further improvement. Similarly. of the 30 regions determined to have irreversible defects after reinjection. 29 (97%) remained irreversible on 24-hour images. These findings were confirmed by the quantitative analysis. The mean normalized thallium activity in regions with enhanced thallium activity after reinjection increased from 57 +/- 13% on redistribution studies to 70 +/- 14% after reinjection but did not change at 24 hours (71 +/- 14%). In regions with irreversible defects that were unaltered by reinjection. mean regional thallium activity did not differ from the reinjection to the 24-hour studies (57 +/- 17% and 58 +/- 17%. respectively). Twenty-four-hour imaging after reinjection showed improvement in only four of 35 irreversible regions (involving three of the 50 patients). CONCLUSIONS. These data indicate that thallium reinjection at rest after 3-4 hours of redistribution provides most of the clinically relevant information pertaining to myocardial viability in regions with apparently irreversible thallium defects. Hence. thallium reinjection may be used instead of 24-hour imaging in most patients in whom a persistent thallium defect is observed on conventional redistribution images.
Inhibition of dipyridamole-induced ischemia by antianginal therapy in humans. Correlation with exercise electrocardiography, BACKGROUND. Dipyridamole echocardiography test (DET: two-dimensional echocardiographic monitoring with dipyridamole infusion up to 0.84 mg/kg in 10 minutes) is a useful tool for the noninvasive diagnosis of coronary artery disease. Aims of the present study were to assess the effects of antianginal drugs on dipyridamole-induced ischemia and to evaluate whether drug-induced changes in DET response may predict variations in exercise tolerance. METHODS AND RESULTS. Fifty-seven patients with angiographically assessed significant coronary artery disease (greater than 70% lumen reduction in at least one major coronary vessel) performed a DET and an exercise electrocardiography test (EET) in random order both off treatment and on antianginal drugs (beta-blockers. calcium antagonists and nitrates. alone or in various combinations). The criterion for DET positivity was a transient dyssynergy of contraction absent or of a lesser degree in the baseline examination. In DET. two parameters were evaluated: the dipyridamole time (i.e.. the time from onset of dipyridamole infusion to obvious dyssynergy) and the wall motion score index. DET sensitivity was 91% off therapy and fell to 65% under therapy (p less than 0.01). In the 37 patients who had a positive DET both off and on therapy. the dipyridamole time increased from 6 +/- 3 (off therapy) to 8 +/- 3 minutes (on therapy) (p less than 0.01). The wall motion score index at peak dipyridamole went from 1.38 +/- 0.14 to 1.31 +/- 0.14 (p less than 0.01). EET and DET yielded concordant (positive versus negative) results in 41 of 57 (71%) patients off and in 35 of 57 (61%) on therapy (p = NS). In the subgroup of 38 patients with both positive DET and EET without treatment. the therapy-induced variations in exercise time were significantly correlated with the variations in dipyridamole time (r = 0.5; p less than 0.01). not with variations in wall motion score index (r = 0.3; p = NS). CONCLUSIONS. 1) Antianginal therapy can protect from dipyridamole-induced ischemia and 2) the therapy-induced changes in DET response parallel variations in exercise tolerance and might be useful for the objective. exercise-independent assessment of the therapy efficacy.
Screening for total cholesterol. Do the National Cholesterol Education Program's recommendations detect individuals at high risk of coronary heart disease?, BACKGROUND. The National Cholesterol Education Program (NCEP) has provided guidelines for identification of persons at high risk of coronary heart disease (CHD) because of lipid abnormalities. These recommendations are based on total cholesterol as the initial screening tool and have become the stimulus for clinic- and community-based screening programs nationwide. However. the use of the guidelines may be problematic because individuals may have total cholesterol levels in the desirable range but low density lipoprotein (LDL) or high density lipoprotein (HDL) levels considered at high risk. This study evaluates the ability of the NCEP screening recommendations to identify correctly persons at high risk of CHD because of lipid abnormalities. METHODS AND RESULTS. Using the NCEP guidelines. we simulated a population-based screening program with data from visits 1 and 2 of the Lipid Research Clinics Program Prevalence Study. Individuals were considered to be at high risk of CHD if they had LDL levels greater than 160 mg/dl or HDL levels less than 35 mg/dl. Following the NCEP process. 21% of those with high LDL concentrations and 66% of those with low HDL concentrations would not be routinely referred for immediate treatment. Overall. 41% of those at high risk of CHD would not be promptly evaluated. The sensitivity of the guidelines for promptly identifying individuals with lipoprotein abnormalities is 59%. CONCLUSIONS. This relatively low sensitivity of total cholesterol as a screening tool should be the impetus for rethinking the screening guidelines. Specifically. the cost-benefit ratio of routine screening for lipoproteins. particularly HDL cholesterol. needs to be carefully considered.
Association between blood pressure and serum lipids in a population. The Tromso Study, BACKGROUND. High blood pressure has been associated with elevated atherogenic blood lipid fractions. but epidemiological surveys often give inconsistent results across population subgroups. A better understanding of the relation between blood pressure and blood lipids may provide insight into the mechanism(s) whereby hypertension is associated with increased risk of coronary heart disease. METHODS AND RESULTS. We assessed the cross-sectional relations of serum total cholesterol. high density lipoprotein (HDL) cholesterol. non-HDL cholesterol (total minus HDL cholesterol). and triglyceride levels with blood pressure in a population of 8.081 men 20-54 years old and 7.663 women 20-49 years old. Stratified analyses and multivariable methods were used to control for potential confounding anthropometric and lifestyle variables. Total and non-HDL cholesterol levels increased significantly with increasing systolic or diastolic blood pressure in both sexes. Men 20-29 years old had steeper regression slopes for blood pressure by total cholesterol level than did women of similar age. In men. the association between blood pressure and total cholesterol level decreased with age. whereas in women. it increased with age. Body mass index modified the relation. whereas smoking. physical activity. and alcohol consumption had little influence on the association. Triglyceride levels increased with blood pressure. but this relation was weak in lean subjects. HDL cholesterol level correlated positively with blood pressure in population subgroups having a high alcohol consumption. CONCLUSION. These results support the hypothesis that there are biological interrelations between blood pressure and blood lipids that may influence the mechanisms whereby blood pressure is associated with risk of coronary heart disease.
Fibrocellular tissue response after percutaneous transluminal coronary angioplasty. An immunocytochemical analysis of the cellular composition, BACKGROUND. Restenosis after initial. successful percutaneous transluminal coronary angioplasty (PTCA) is due to fibrocellular proliferation. METHODS AND RESULTS. The present study focused on the nature of fibrocellular tissue in humans by use of immunocytochemical techniques. Four hearts (five coronary arteries) were investigated; time lapse between PTCA and death varied between 20 days (two arteries) and 1 year 7 months. Proliferating cells stained positive with smooth muscle cell-specific monoclonal antibodies. Cells from early proliferative lesions (20 days) have a phenotypic expression different from cells in "old" lesions. Proliferating cells stained positive with vimentin but were negative with desmin. irrespective of the lesion's age. CONCLUSIONS. The findings indicate a change in actin isoform expression of smooth muscle cells while adapting to a pathological state.
Interventricular coronary steal induced by stenosis of left anterior descending coronary artery in exercising pigs, BACKGROUND. In pigs and humans. the left anterior descending coronary artery (LAD) supplies the left ventricular anterior wall (LVAW). anterior septum. and paraseptal band of the right ventricular anterior wall (RVAW). The purposes of our study were 1) to study the LAD flow distribution in these walls during preexercise. exercise. and exercise with LAD stenosis and 2) to analyze regional wall motion under these conditions. METHODS AND RESULTS. Nine pigs were instrumented with sonomicrometers for measuring percent wall thickening (%WTh) in LVAW. RVAW. and lateral (control) walls of both ventricles. a hydraulic occluder at the LAD origin. an LV pressure transducer. and catheters for radioactive microsphere injection (left atrium) and blood withdrawal (aorta). One month later. regional %WTh and flows were measured during preexercise. exercise. and continuing exercise with LAD stenosis resulting in more than 50% reduction in systolic LVAW %WTh with regard to exercise. LAD stenosis caused a dramatic decrease in total mean +/- SD LVAW subendocardial flow with regard to exercise (28.7 +/- 8 to 9.1 +/- 3.2 ml.min-1. p less than 0.0001) but not significant changes in either LVAW subepicardial flow or RVAW flow. The transmural distribution of flows within the LAD bed (as percentages of the total LAD flow in each experimental condition) showed that LAD stenosis redistributed flows with regard to exercise such that the LVAW subendocardial flow decreased from 26.4 +/- 4.2% of the total LAD flow to 11.8 +/- 4.3% (p less than 0.0001). whereas LVAW subepicardial flow increased from 32.9 +/- 2.3% of the total LAD flow to 45.5 +/- 7.9% (p less than 0.0001) and RVAW increased from 12 +/- 4.9% of the total LAD flow to 18.7 +/- 7.2% (p less than 0.0005). With exercise plus LAD stenosis. LVAW %WTh decreased from 43.2 +/- 8.4% to 17.2 +/- 9.7% (p less than 0.0001). but RVAW %WTh did not change. CONCLUSIONS. In the LAD bed of exercising pigs. LAD stenosis induces. in addition to transmural steal. an interventricular steal favoring the RVAW at the expense of the LVAW subendocardium. This steal results in preserved RVAW thickening despite severe LVAW hypokinesia.
Estimation of myocardial infarct size with ultrasonic tissue characterization, BACKGROUND. Ultrasonic tissue characterization (UTC) can distinguish normal from infarcted myocardium. Infarcted myocardium shows an increase in integrated backscatter and loss of cardiac cycle-dependent variation in backscatter. The cyclic variation of backscatter is closely related to regional myocardial contractile function; the latter is a marker of myocardial ischemia. The present study was designed to test the hypothesis that intramural cyclic variation of backscatter can map and estimate infarct size. METHODS AND RESULTS. Transmural myocardial infarction was produced in 12 anesthetized. open-chest dogs by total occlusion of the left anterior descending coronary artery for 4 hours. A real-time ultrasonic tissue characterization instrument. which graphically displays integrated backscatter Rayleigh 5. cardiac cycle-dependent variation. and patterns of cyclic variation in backscatter. was used to map infarct size and area at risk of infarction. Staining with 2.3.4-triphenyltetrazolium chloride (TTC) and Patent Blue Dye was used to estimate infarct size and the area at risk. respectively. The ratio of infarct size to area at risk of infarction determined with UTC correlated well with that determined with TCC (r = 0.862. y = 23.7 +/- 0.792x). Correlation coefficients for infarct size and area at risk were also good (r = 0.736. y = 12.3 +/- 737x for infarct size and r = 0.714. y = 5.80 +/- 1.012x for area at risk). However. UTC underestimated both infarct size and area at risk. CONCLUSIONS. Ultrasonic tissue characterization may provide a reliable. noninvasive method to estimate myocardial infarct size.
Nifedipine protects the heart from the acute deleterious effects of cocaine if administered before but not after cocaine, BACKGROUND. We tested the hypothesis that nifedipine. a calcium channel blocker. could ameliorate the toxic effects of cocaine on the myocardium. METHODS AND RESULTS. In an initial protocol. anesthetized dogs were pretreated with nifedipine or saline and then administered cocaine (10 mg/kg. i.v. bolus). Coronary blood flow. heart rate. mean arterial pressure. and the first derivation of left ventricular pressure (dP/dt) were measured at baseline. 2 minutes. and 15 minutes after cocaine administration. Nifedipine pretreatment prevented the early cocaine-induced decrease in coronary blood flow and improved left ventricular dP/dt compared with untreated control animals. After cocaine. ejection fraction fell in the saline group to 37 +/- 3% but increased in the nifedipine group to 59 +/- 4% (p less than 0.05). In a second protocol. vehicle or intravenous nifedipine was administered after an infusion of cocaine (10 mg/kg). In contrast to pretreatment. there was no significant improvement in left ventricular function or coronary blood flow in nifedipine-treated versus control animals. Data from the study also suggested that cocaine acts directly on the myocardium. Within seconds of cocaine bolus administration. coronary blood flow in control animals increased to a peak level 59 +/- 14% higher than before cocaine and left ventricular dP/dt decreased by 23 +/- 5%. providing evidence that cocaine causes direct depression of myocardial function independent of a decrease in myocardial blood flow. CONCLUSIONS. We conclude that nifedipine administered as a pretreatment protects against the depression of myocardial function and decrease in coronary blood flow caused by acute cocaine administration. However. when nifedipine is given after cocaine. no improvement is seen. Cocaine has a direct negative inotropic effect on the heart that is independent of a decrease in coronary blood flow.
Hypertension in African-Americans, A considerable disparity exists between African-Americans and US Caucasians in the incidence. severity. and management of hypertension. As a consequence. overall hypertension-related morbidity and mortality rates are at least threefold to fivefold higher in African-Americans than in Caucasians. Alarmingly high frequencies of stroke. end-stage renal disease. congestive heart failure. and left ventricular hypertrophy occur in African-Americans. To bring this crisis under control will require a renewed commitment to expanded research. improved public health measures. and more effective clinical intervention. Current hypertension control programs must be expanded and adequately funded. In addition. primary prevention of hypertension should be strongly recommended for the US population. especially African-Americans.
Hypertensive heart disease in African-Americans, Hypertensive heart disease is a frequent complication in hypertensive African-Americans because of inadequate high blood pressure control. Moreover. African-Americans may be predisposed to develop LVH earlier in life and more readily than Caucasians. and it may be more malignant. The appearance of both LVH and congestive heart failure are ominous developments in individual patients. and early detection of LVH is mandatory for adequate management and reversal of this complication. if possible. Additional research is needed. and new. sensitive tools for detecting LVH will accelerate such studies. Further investigations are also needed on the reversibility of LVH. preferred antihypertensive agents for accomplishing reversal. and whether expected benefits result.
Coronary artery disease in African-Americans, Contrary to opinions generally accepted in the past. CHD is very common in both African-American men and women. with incidence rates approaching those of US Caucasians. Higher prevalence of hypertension. diabetes. cigarette smoking. and obesity all contribute to the high level of CHD in African-Americans. Additional research is needed about the interrelations and management of various risk factors for CHD in African-Americans outside of the sudden death of African-Americans outside of the hospital is urgent. and special attention should be given to accessibility and use of health services by minority populations.
Heart disease in Asians and Pacific-Islanders, Hispanics, and Native Americans, Heart disease is the leading cause of death for Asian-Americans and Pacific-Islanders. Hispanic-Americans. and Native Americans. Generally. heart disease death rates are lower in these population groups than in Caucasians. with the notable exception of Native Americans under the age of 35. Of particular interest are data for southwestern US Native Americans and Mexican-Americans. which indicate low CHD prevalence rates despite high rates of obesity. diabetes mellitus. increasing hypertension. and low socioeconomic status. Much more research is needed to explain these and other observations. Intervention in those risk factors already identified is necessary. particularly in prevention of obesity and diabetes.
Interleukin 1 beta is expressed predominantly by enterocytes in experimental colitis, The cytokine interleukin 1 beta is an important mediator of inflammatory processes capable of inducing eicosanoid production. T-cell activation. and increased vascular permeability. In this study. in situ hybridization techniques were used to delineate the kinetics and cellular source of induced interleukin 1 beta in acute experimental colitis. The induction of interleukin 1 beta messenger RNA was an early phenomenon and occurred predominantly in undifferentiated cells located in the basal part of the mucosal crypts but not in differentiated enterocytes. The undifferentiated enterocytes retained the messenger RNA during differentiation and migration to more apical parts of the crypts. These results suggest that induction of interleukin 1 beta messenger RNA in enterocytes is causally related to the subsequent inflammatory changes seen in acute experimental colitis.
Effect of indomethacin on gastric mucosal blood flow around acetic acid-induced gastric ulcers in rats, Repeated administration of indomethacin markedly delays spontaneous healing of experimental gastric ulcers induced in rats. To elucidate the underlying mechanism. the effect of indomethacin on the gastric mucosal blood flow around ulcers was examined. Gastric ulcers were induced 5 days after submucosal injection of an acetic acid solution into the stomachs of rats. Blood flow was determined by the hydrogen gas clearance method. The blood flow around ulcers was significantly higher than that in rats without ulcers up to 2 weeks after ulceration but had returned to within the normal range 3 or 4 weeks later. Indomethacin. administered SC at 1 mg/kg once or repeatedly for 1-4 weeks. had little or no effect on the blood flow in normal rats. However. such treatment significantly reduced the blood flow by 20%-30% of the corresponding control levels in rats with ulcers. Prostaglandin E2. administered SC at 3 mg/kg once. markedly prevented the reduction in the blood flow due to indomethacin. The administration of prostaglandin E2. with indomethacin for 4 weeks resulted in a significantly higher blood-flow level than the control and prevented the delay in ulcer healing. Omeprazole. administered SC at 30 mg/kg once or repeatedly with indomethacin for 4 weeks. had an insignificant effect on the blood flow around ulcers but prevented the delay in ulcer healing. In conclusion. the delayed ulcer healing caused by indomethacin might be partly related to the reduced blood flow around the ulcers.
Expression of enzymatically active sucrase-isomaltase is a ubiquitous property of colon adenocarcinomas, Adenocarcinoma of the colon is one of the most prevalent and lethal of all human malignancies. The early diagnosis and management of this disease could be improved if biological markers. whose expression was restricted to malignant colon cells. were identified. Sucrase-isomaltase is a glycoprotein hydrolase expressed throughout the small intestine and fetal colon but not in the normal adult colon. This study shows that the expression of enzymatically active sucrase-isomaltase is a ubiquitous property of primary and metastatic colon adenocarcinoma. Significant sucrase enzyme activity (i.e.. greater than 5 mU/mg protein) was observed in 16 colon carcinomas but not in adjacent normal colon mucosa. Sucrase-isomaltase messenger RNA was identified in all tumors using reverse transcriptase polymerase chain reaction. Using a quantitative polymerase chain reaction analysis. this study shows that the amount of sucrase-isomaltase messenger RNA in tumors examined (3.4 x 10(-8) to 3.19 x 10(-7) micrograms/micrograms total RNA) was greater than in adjacent mucosa (0 to 3.4 x 10(-8) micrograms/micrograms total RNA). This induction of sucrase-isomaltase messenger RNA and enzyme activity was corroborated by immunostaining. Of 30 colon adenocarcinomas examined. 80% were positive for sucrase-isomaltase. In addition. all colon carcinoma metastases examined were positive for sucrase-isomaltase. The staining pattern was distinct and demarcated tumor cells from the surrounding histologically normal tissue. No sucrase-isomaltase staining was seen in normal mucosa from the same patients. With the exception of lung. no sucrase-isomaltase immunostaining was observed in a variety of examined noncolonic adenocarcinomas. Thus. the specificity and ubiquity of sucrase-isomaltase expression in adenocarcinomas of the colon can be exploited to improve the clinical management of this disease. In addition. studies on the structure of the sucrase-isomaltase gene and its regulatory elements should contribute toward understanding the alteration of gene expression by oncogenic transformation of the colonic mucosa.
Neurohormonal factors in functional dyspepsia: insights on pathophysiological mechanisms, Neurohormonal factors were investigated in 10 patients with functional dyspepsia who had normal or slow upper gut transit and 10 age- and sex-matched healthy controls. Gastric and small bowel motility and transit. jejunal responses to luminal distention and IM neostigmine. gut hormones. and vagal and sympathetic functions were studied. Slow upper gut transit was defined by a gastric emptying slope less than 0.3%/min or 10% small bowel transit time greater than 300 minutes. Four patients with slow transit had reduced postprandial antral motility and gut hormone responses. Two of the four patients had vagal and sympathetic dysfunction. In 6 patients with normal transit. balloon distention in the jejunum was perceived at a lower volume (32.7 +/- 5.9 mL) than in controls (46.6 +/- 3.0 mL). Pressure responses to balloon distention were reduced in 5 and exaggerated in 1 patient; abnormal efferent vagal (2 patients) and sympathetic (1 patient) function were also documented. In view of the normal transit. motility. and jejunal pressure responses to neostigmine in all 6 patients. the abnormal response to distention suggests afferent dysfunction. Functional dyspepsia is a heterogenous disorder. Abnormal transit is sometimes associated with disorders of extrinsic neural control. but the latter are also found in patients with normal transit. Increased perception of intraluminal stimuli in those with normal transit suggests a disturbance in afferent function.
Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis, All patients greater than or equal to 16 years old with a diagnosis of ulcerative colitis were identified in five well-defined catchment areas. representing 12.7% of the Swedish population. Exactly 1500 patients were retrieved. giving a point prevalence of 170/10(5) inhabitants. It was possible to obtain liver function test results less than 2 years old in 94% of the patients and to obtain endoscopic retrograde cholangiographic results in 65 of the 72 patients with abnormal serum alkaline phosphatase values. Primary sclerosing cholangitis was diagnosed in 55 of the patients (3.7%). The prevalence of the disease was 5.5% in patients with substantial colitis and 0.5% in patients with distal colitis. There was a marked male predominance in cholangitis patients compared with colitis patients without cholangitis. Ninety-five percent of the patients with cholangitis had substantial colitis. which was more than the 62% of patients without cholangitis who had colitis. Female patients with cholangitis were older than male patients at the time of diagnosis of both cholangitis and colitis. which contrasted to the equal age at diagnosis of colitis in male and female patients without cholangitis.
Diagnosis of Budd-Chiari syndrome by pulsed Doppler ultrasound, Computed tomography and real-time ultrasonography may not be conclusive for the diagnosis of the Budd-Chiari syndrome; in many cases more information may be needed. especially on vascular alterations. Doppler ultrasonography provides qualitative data on flow direction and pattern. thereby contributing significantly to diagnosis. Eight cases in which hepatic vein patency was unclear and presence of intrahepatic vessels resembling hepatic veins raised problems of interpretation in real-time ultrasonography are described. In some cases. patency or occlusion of the upper portion of the inferior vena cava were difficult to identify with real-time ultrasonography. Doppler ultrasonographic investigation showed flow in the hepatic veins to be completely absent in two cases and reversed in another two. In the remaining four cases. a flat waveform was evident. Flow in the inferior vena cava was reversed in four cases and showed a flat waveform in three other cases. Portal vein thrombosis was detected in only one case. whereas the remaining seven patients showed slow hepatopetal flow. These findings demonstrate that absent or reversed flow in the hepatic veins and/or flat flow in the hepatic veins associated with reversed flow in the inferior vena cava may be considered diagnostic for the Budd-Chiari syndrome. For this series the sensitivity of Doppler ultrasonography was 87.5%.
Stimulation of pancreas and gastric carcinoma cell growth by interleukin 3 and granulocyte-macrophage colony-stimulating factor, Hematopoietic growth factors have recently been well characterized by complementary DNA cloning. For human epidermal growth factor. granulocyte-macrophage colony-stimulating factor recombinant proteins have been expressed in Escherichia coli. To reduce the toxic side effects of chemotherapy on the bone marrow. recombinant human granulocyte-macrophage colony-stimulating factor and recombinant human interleukin 3 were applied to patients suffering of gastrointestinal cancers. To determine the influence of recombinant human granulocyte-macrophage colony-stimulating factor and recombinant human interleukin 3 on human pancreas and gastric cancer cell cells in vitro. a sensitive microculture test system was established that allows precise quantification of proliferation. A more than twofold enhancement of proliferation was observed by interleukin 3 and granulocyte-macrophage colony-stimulating factor in two of two cell cultures derived from gastric carcinoma cells. while two of nine cultures from pancreas carcinoma cells have shown enhanced cell growth in the presence of recombinant human interleukin 3 or recombinant human granulocyte-macrophage colony-stimulating factor. In comparison. recombinant human epidermal growth factor increased cell growth in two of two gastric and in five of nine pancreas carcinoma cultures. In general. 1-10 ng/mL of the growth factors yielded the highest growth rate. but even 1-pg amounts produced increased cell growth. Expression of messenger RNA for granulocyte-macrophage colony-stimulating factor. interleukin 3. and the oncogene HER2/neu remained undetectable in all of the tested cell lines. while the various abundance of messenger RNA for the epidermal growth factor receptor was different in each cell line. The reported results imply that the hematopoietic growth factors interleukin 3 and granulocyte-macrophage colony-stimulating factor influence cellular growth of pancreas and gastric carcinoma cells by a paracrine mechanism and may possess a more general regulatory function than originally anticipated.
Endosonographic TNM staging of extrahepatic bile duct cancer: comparison with pathological staging, Endosonography was performed preoperatively in 33 patients with common bile duct carcinoma and in 43 patients with carcinoma of the common hepatic duct and its bifurcation. The results were correlated with the histology of resected specimens according to the new (1987) TNM (tumor. node. metastasis) classification. Endosonography was accurate in the evaluation of the depth of tumor infiltration. Overall accuracy for common bile duct carcinoma and common hepatic duct carcinoma was 82.8% and 85%. respectively. Endosonography was helpful in diagnosing regional lymph node metastases but not accurate in diagnosing nonmetastatic lymph nodes. With common bile duct carcinoma. the incidence of lymph node metastasis increased with progressive depth of tumor infiltration. No such correlation was found in common hepatic duct carcinomas. In the staging of distant metastasis. this technique was limited by the low-penetration depth of ultrasonography. Thus. additional transcutaneous ultrasonography or computed tomography was necessary for complete staging. The routine use of the biopsy channel for endosonographically guided aspiration puncture will further enhance the diagnostic value of endosonography in the future.
Neutrophil cytoplasmic antibodies: a link between primary sclerosing cholangitis and ulcerative colitis, Whether serum autoantibodies to neutrophil cytoplasmic components. previously found in ulcerative colitis. are also associated with primary sclerosing cholangitis was determined. In an enzyme-linked immunosorbent assay for immunoglobulin G neutrophil antibodies. neutrophil binding by primary sclerosing cholangitis sera was significantly greater than that for primary biliary cirrhosis. chronic hepatitis B. and chronic non-A. non-B hepatitis. Similar differences were seen when sera from patients with primary sclerosing cholangitis without evidence for ulcerative colitis were compared with sera from liver disease controls. Perinuclear immunofluorescence staining of neutrophils was exhibited by the majority of ulcerative colitis. primary sclerosing cholangitis. and primary sclerosing cholangitis without ulcerative colitis sera. The combination of elevated immunoglobulin G neutrophil antibodies and a perinuclear pattern was 65% sensitive and 100% specific for primary sclerosing cholangitis compared with the liver disease control sera. It is concluded that neutrophil cytoplasmic antibodies in ulcerative colitis and primary sclerosing cholangitis may be markers of shared underlying immunopathogenic mechanisms. Identification of the target antigen(s) may facilitate understanding of the underlying immune response and development of an improved disease marker assay.
Influence of the thyroid on exocrine pancreatic function, Exocrine pancreatic function was studied in 15 patients with hypothyroidism and 15 healthy subjects by means of the amino acid consumption test. a new tubeless test based on the measurement of plasma amino acid uptake by the pancreas during pancreatic enzyme synthesis stimulation. Nine of the 15 patients were also studied after they had become euthyroid following thyroxine treatment. Pancreatic function was significantly reduced in patients with hypothyroidism compared with healthy subjects. Treatment with thyroxine restored pancreatic function to normal. In two additional hypothyroid patients studied by means of duodenal intubation. pancreatic secretion of both bicarbonate and enzymes was found to be significantly decreased. It was concluded that the thyroid gland plays an essential role in maintaining the functional integrity of the exocrine pancreas in humans.
Redevelopment of hepatitis B surface antigen after renal transplantation, A patient with chronic hepatitis B virus (HBV) and chronic renal failure received a renal transplantation. Hepatitis B surface antigen (HBsAg) disappeared. and antibodies to HBsAg appeared 10 months before transplantation. Liver tests showed no abnormality at transplantation. Six months later. chronic hepatitis reactivated. antibodies to HBsAg disappeared. and HBsAg reappeared. Hepatitis B virus DNA was demonstrated with polymerase chain reaction in the serum collected before transplantation. This observation suggests that low level HBV replication was present before transplantation despite the absence of detectable HBsAg and was reactivated under immunosuppressive therapy after transplantation.
Expandable venous stents for treatment of the Budd-Chiari syndrome, The goals of treatment of the Budd-Chiari syndrome are relief of portal hypertension. relief of inferior vena cava syndrome. if present. and preservation of hepatic function. This study presents a patient with clinical resolution of the Budd-Chiari syndrome after placement of expandable metallic stents in the inferior vena cava and hepatic veins. A 26-year-old man with severe ascites and lower extremity edema but with relatively preserved hepatic function had a small gradient across a suprahepatic caval web. large gradients across an intrahepatic caval stenosis and the left hepatic vein. and an occluded right hepatic vein. Under angiographic control. web and caval stenosis were balloon-dilated. and modified Gianturco expandable metallic stents were placed in the intrahepatic vena cava. The left hepatic vein was dilated twice and a stent was placed. All gradients were completely eliminated. There were no complications and after 1 year. the stents have fully expanded without migration. edema and ascites have resolved. hepatic function has normalized. and the patient has returned to work. This new technique provides a simple. safe. effective. relatively inexpensive. and potentially long-lasting treatment for selected patients with the Budd-Chiari syndrome.
Piezoelectric lithotripsy and soft tissue injury. Safety limits in the experimental and clinical setting, Controversy surrounds the capacity of extracorporeal shock wave lithotripsy to cause soft tissue injury. This study examines the influence of different dosages of shock waves on the gall bladder in both humans and an animal model. Sixty one guinea pigs were divided into groups and subjected to different numbers of shock waves (6.000. 24.000. and 48.000) at different frequencies (2.5. 5.0. 10. 20 shock waves per second) and sacrificed at different intervals. Soft tissue damage after lithotripsy seemed to be related to the number of shock waves administered. In addition. repeated administration of low dose lithotripsy (at weekly intervals for six weeks) did not seem to produce a cumulative injury. Finally. in the animals sacrificed one month after receiving high dose lithotripsy. no soft tissue damage was evident. indicating satisfactory healing. Thirty patients were subjected to either high dose (36.000 shock waves) or low dose (6.000 shock waves) lithotripsy 24 hours before elective cholecystectomy. Both macroscopic and microscopic evidence of soft tissue injury were detected in a significantly higher percentage of patients who received a high dose in a single treatment (p less than 0.05). The group who received repeated low dose lithotripsy showed no evidence of cumulative injury. We conclude that low dose lithotripsy produces minimal soft tissue injury and is safe when repeated up to six times at weekly intervals.
Symptoms and investigative findings in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy and biopsy over a five year period, This study analysed clinical features and laboratory investigations in 145 patients with tuberculous peritonitis diagnosed by peritoneoscopy at this hospital between 1984 and 1988. Tuberculous peritonitis was found in 2% of all patients with tuberculosis and in 59.8% of all those with abdominal tuberculosis admitted to the hospital during the study period. Tuberculous peritonitis was more common in women than men (1.4:1) and was most frequently encountered in the third and fourth decades of life. The commonest presenting symptoms were abdominal swelling (73.1%). fever and night sweats (53.8%). anorexia (46.9%). weight loss (44.1%). and abdominal pain (35.9%). The mean duration of symptoms was 1.5 months. Ascites was the commonest (95.2%) physical sign. Tuberculin skin testing was positive in 57.6% of patients (n = 118). The mean erythrocyte sedimentation rate was 75 mm/1st hour (n = 58). Chest radiography on 98 patients showed pleuropulmonary pathology in 40 patients (40.8%). Sputum examination confirmed active pulmonary tuberculosis in 26 patients. The ascitic fluid was an exudate in 96.4% and a transudate in 3.6% of patients. with 91.3% showing a straw coloured ascites. Cirrhosis. detected by biopsy specimen. was a finding in 6.2% of patients.
Ten years' experience with an elemental diet in the management of Crohn's disease, The immediate and longterm outcome of treating patients with acute Crohn's disease with an elemental diet was studied retrospectively. Successful diet induced remission was achieved in 96 of 113 patients (85%) regardless of age. sex. site or severity of disease. or associated complications of strictures. fistula. or perianal disease. Treatment was unsuccessful in 17 patients (15%). but there were no features at the outset of treatment that distinguished these patients from those who had successful remission. The longterm outcome of treatment was assessed over a five year period by analysis of life tables and survival curves. Twenty two per cent of the patients relapsed within six months of treatment and thereafter the annual relapse rate was 8-10%. Patients with disease complicated by fistula or perianal involvement had early relapse. approaching 100% for the latter. A further retrospective comparison of longterm outcome of diet v steroid induced remissions showed no significant difference in the relapse rates between the two groups at one. three. and five years.
Future needs for ERCP: incidence of conditions leading to bile duct obstruction and requirements for diagnostic and therapeutic biliary procedures, Although the development of endoscopic methods of treatment for biliary obstruction has proceeded rapidly in recent years. endoscopic retrograde cholangiopancreatographic (ERCP) services are patchily distributed. A recent survey by the British Society of Gastroenterology has shown that almost half the district general hospitals questioned did not have a sphincterotomy service available locally. To assess the level of provision required. two investigations have been undertaken. Firstly. an epidemiological study of bile duct obstruction has been carried out in the South Western Region. Secondly. the actual surgical and endoscopic workload in treating obstructive jaundice has been analysed in two health districts. Using present incidence and treatment rates at least 50 ERCPs per 100.000 of the population per year are estimated to be required in the future. Surgical treatment rates can be expected to fall as the number of therapeutic ERCPs increases. The implications of this estimate in equipment and staffing terms are discussed.
Defective jejunal brush border membrane sodium/proton exchange in association with lethal familial protracted diarrhoea, The spectrum of clinical disease associated with specific defects in jejunal brush border membrane sodium/proton exchange is poorly defined and only two patients have been described so far. Jejunal brush border membrane transport studies were performed in a boy who presented with lethal familial protracted diarrhoea in the first few days of life. Using jejunal brush border membrane vesicles prepared from conventional jejunal biopsy specimens. initial sodium uptake under H+ gradient conditions was found to be only 6% of the mean control value. In contrast. sodium stimulated glucose uptake was normal. Our data confirm the importance of a congenital defect in this exchanger as a cause of severe sodium-losing diarrhoea and extend the spectrum of disorders characterised by a specific defect in brush border membrane Na+/H+ exchange to include some forms of lethal familial protracted diarrhoea.
Power of oesophageal peristalsis can be controlled voluntarily, The hypothesis that oesophageal peristalsis can be modified voluntarily was explored. Six healthy male volunteers and eight female patients with angina like chest pain underwent oesophageal manometry. Each was asked to take a series of swallows. and to vary their size. in random order. by taking either a big gulp or a little swallow. None of the subjects experienced difficulty in doing so. In both groups the amplitude of oesophageal contractions were significantly greater after big gulps than little swallows (p less than 0.01) and this was true for wet (82.0 v 68.9 mmHg) and dry swallows (52.3 v 43.3 mmHg). For the patients' wet swallows the mean values were 73.0 and 56.0 mmHg. Thus. the amplitude of oesophageal peristalsis can be controlled voluntarily. This effect may account for some of the within subject variation in the amplitude of oesophageal contractions. During oesophageal manometry subjects should be encouraged to standardise the size of their swallows whenever possible. Patients with symptoms related to abnormal oesophageal peristalsis such as dysphagia. heartburn. and chest pain may benefit from biofeedback training.
Small bowel morphology in British Indian and Afro-Caribbean subjects: evidence of tropical enteropathy, Distal duodenal biopsy specimens taken from 30 white. 35 Indian. and 20 Afro-Caribbean residents of West Birmingham during routine endoscopy for dyspepsia. were assessed by dissecting microscopy and morphometry. Finger-shaped villi were significantly less frequent in the Indian and Afro-Caribbean subjects than in the white subjects when assessed by dissecting microscopy (p less than 0.005). and both immigrant groups had decreased mucosal thickness (p less than 0.01). villous height (p less than 0.001). villous:crypt ratios (p less than 0.01) and enterocyte height (p less than 0.05) compared with the white group. In the Indian subjects. villous height and villous:crypt ratios correlated significantly with the time since the last visit to the Indian subcontinent (p less than 0.005). Serum alkaline phosphatase values were significantly higher in the Indian subjects compared with the whites (p less than 0.02). and serum globulins were increased in both the Afro-Caribbean and Indian subjects (p less than 0.01). There were no correlations between morphometric indices and body habitus or biochemical or haematological indices and the long term effect of the morphological changes is not clear.
Identification of different laminin binding proteins in basolateral cell membranes of human colorectal carcinomas and normal colonic mucosa, The adhesive properties of tumour cells to laminin. the major glycoprotein of basement membranes. play a crucial part in the complex process of tumour invasion and metastasis. We therefore investigated the expression of laminin binding proteins in isolated basolateral cell membranes of human colorectal carcinomas and the adjacent normal colonic mucosa. Cell membrane binding assays and immunoblotting experiments showed appreciable quantitative and qualitative differences in the expression of these proteins in neoplastic and normal tissue. Epithelial basolateral cell membranes of colorectal carcinomas bound five to eight times more radioactive labelled laminin than basolateral cell membranes of the adjacent normal colonic epithelium. The expression of laminin binding proteins with Mr 66.000-69.000 daltons corresponding to the so called 'Mr 67.000 dalton laminin receptor' was three to four times higher in colorectal carcinomas than in normal colonic epithelium. In addition. laminin binding proteins with higher molecular weights. which may be related to the family of integrins. were also increased in colorectal carcinomas. In particular. laminin binding proteins with Mr 180.000 daltons were exclusively expressed on neoplastic epithelial cells of human colorectal carcinomas. Our data suggest that certain classes of laminin binding proteins may be selectively expressed on colonic tumour cells. leading to an increased capacity for migration. invasion. and metastasis.
Regulation of the oncodevelopmental expression of type 1 chain ABH and Lewis(b) blood group antigens in human colon by alpha-2-L-fucosylation, Blood group antigen expression in the distal human colon is related to the development of the organ and is modified by malignant transformation. To elucidate the biochemical basis for these changes. we have (a) analysed the activity of glycosyltransferases coded for by the H. Se. Le. X. and A genes. in tissue biopsy specimens from normal and malignant proximal and distal human colon; (b) characterised the glycosphingolipids expressed in the various regions of normal and malignant colon by immunostaining of high performance thin layer chromatography plates; and (c) located the antigens on tissue sections from the same subjects by immunohistochemistry. In both secretors and non-secretors we found a significantly higher activity of alpha-2-L-fucosyltransferases in carcinomatous rectal tissue than in tissue from normal subjects. whereas the other transferase activities studied showed no significant differences. The acceptor substrate specificity suggested that both the Se and the H gene dependent alpha-2-L-fucosyltransferases are increased in carcinomas. In non-malignant tissue the only enzyme which showed appreciably higher activity in caecum than in rectum was alpha-2-L-fucosyltransferase. Immunochemistry and immunohistochemistry showed alpha-2-L-fucosylated structures in normal caecum from secretors and in tumour tissue from both secretors and non-secretors. We conclude that the alpha-2-L-fucosyltransferases control the expression of ABH. and Lewis(b) structures in normal and malignant colon.
Extracorporeal shock wave lithotripsy of gall stones: an in vitro comparison between an electrohydraulic and a piezoceramic device, A comparative study of the effectiveness of two types of lithotripter in fragmenting gall bladder stones is reported. The machines used were a Piezolith 2300. which generates shock waves by the piezoceramic principle. and a Dornier MPL 9000. which produces the shock waves by underwater spark discharge. With each machine. corresponding stones of 45 pairs of weight and volume matched calculi (median volume 0.5 cm3. median diameter 10.5 mm) obtained at cholecystectomy were treated. All stones were successfully disintegrated (fragments smaller than 2 mm) with up to 5400 (median 628) shocks with the Piezolith and 3450 (median 428) shocks with the MPL 9000 lithotripters. With the Piezolith. operating at the highest power setting. a 1.65 fold median higher number of shocks was required for stone fragmentation than with the MPL 9000 at a medium power setting. Stone volume seemed to be the only determinant which affected ease of fragmentation; composition and density of the stones as assessed by computed tomography did not seem to be governing factors.
Symptomatic and silent gall stones in the community, The prevalence of gall stone disease in a stratified random sample of 1896 British adults (72.2% of those approached) was established using real time ultrasound. The prevalence rose with age. except in women of 40-49 years. so that at 60-69 years. 22.4% of women and 11.5% of men had gall stones or had undergone cholecystectomy. The cholecystectomy rate of people with gall stone disease was higher in women than in men (43.5% v 24%. p less than 0.05). Very few subjects with gall stones had convincing biliary symptoms. In women. 10.4% had symptoms according to a questionnaire definition of biliary pain and 6.3% according to conventional history taking. while no men at all admitted to biliary pain. Nevertheless. cholecystectomy in men had nearly always been preceded by convincing biliary symptoms. The age at cholecystectomy was. on average. nine years less than the age at detection of silent gall stones in both sexes. It is concluded that either gall stones are especially prone to cause symptoms in younger people or that there are two kinds of cholelithiasis - symptomatic and silent. The lack of symptomatic gall stones in cross sectional surveys is probably due to their rapid diagnosis and treatment.
Quantitative nuclear DNA content in fine needle aspirates of pancreatic cancer, The quantitative nuclear DNA content of nuclei from fine needle aspirations from 70 patients with pancreatic cancer was measured using an image analyser system. Retrospective analysis of patients indicated that cases with tumour stemlines in the diploid region had the best chance for radical surgery (p less than 0.006) and the best probability of survival (p less than 0.0004). The prognosis for patients with tetraploid stemlines was intermediate and was poorest for patients with no stemlines in the diploid-tetraploid region. From those parameters assessed postoperatively. only the tumour stage added appreciable information on prognosis to the preoperative quantitative DNA content obtainable. Therefore. in patients with pancreatic cancer the quantitative DNA content should be taken into account in planning treatment and assessing prognosis. Furthermore. the quantitative DNA content may have a major role in stratification for further treatment trials.
Outpatient AIDS care squeezed by high costs, low payments, Thanks to the rapid growth in outpatient AIDS care. many people with AIDS are living longer and improving their quality of life. experts agree. But these successes come with a high price tag. And growing demand. inadequate reimbursement. and tougher competition for federal and foundation funds have put the squeeze on hospitals with large caseloads. These hospitals are hoping to get some financial relief from the Ryan White Care Act. targeted at areas hardest hit by AIDS.
Brain and liver angiotensinogen messenger RNA in genetic hypertensive and normotensive rats, The brain's renin-angiotensin system in integrally involved in the regulation of blood pressure and fluid/mineral metabolism. Enhanced activity of the angiotensin system in the brain has been implicated as a possible source of the hypertension and the elevated salt appetite of the spontaneously hypertensive rat. as compared with the Wistar-Kyoto rat. This study tested whether these inbred strains of hypertensive and normotensive rats differ in central or peripheral expression of the gene coding for angiotensinogen. the prohormone for the angiotensin peptides. Angiotensinogen messenger RNA was measured in the brain by in situ hybridization and in the liver by Northern blot analysis. using a synthetic oligonucleotide. There was a 28% greater expression of the angiotensinogen gene in the region of the anteroventral hypothalamus. preoptic area. and medial septum of the hypertensive strain. There were no differences between strains in liver angiotensinogen gene expression. These results are consistent with the possibility that enhanced elaboration of the angiotensin prohormone in the brain contributes. in part. to the hypertension or the elevated salt appetite of the spontaneously hypertensive rat.
Role of prostanoids in renin-dependent and renin-independent hypertension, We investigated the role of prostanoid-mediated pressor mechanisms in setting the level of blood pressure in renin-dependent and renin-independent models of hypertension in unanesthetized rats. Intravenous administration of a blocker of thromboxane A2/prostaglandin endoperoxide receptors. SQ29548 (2 mg/kg bolus injection plus 2 mg/kg/hr for 3 hours). reduced from 162 +/- 4 to 144 +/- 5 mm Hg (p less than 0.05) the blood pressure of rats with aortic coarctation-induced hypertension at 7-14 days after coarctation when plasma renin activity is greatly increased. In contrast. treatment with SQ29548 was without effect on the blood pressure of either normotensive or hypertensive rats (i.e.. aortic coarctation-induced hypertension at 90-113 days after coarctation. deoxycorticosterone-salt-induced hypertension) having normal or depressed values of plasma renin activity. The blood pressure-lowering effect of SQ29548 in the early phase of aortic coarctation-induced hypertension was positively correlated with the prevailing plasma renin activity and could not be demonstrated in hypertensive rats pretreated with indomethacin. We attribute the hypotensive effect of SQ29548 to interference with pressor mechanisms that depend on activation of thromboxane A2/prostaglandin endoperoxide receptors and suggest that such prostanoid-mediated mechanisms are operational and contribute to an increase in blood pressure in angiotensin-dependent forms of hypertension. Also prostanoid-mediated vasodepressor mechanisms are operational in the early phase of aortic coarctation-induced hypertension since the blood pressure of rats pretreated with SQ29548 was increased by the subsequent administration of indomethacin. Accordingly. the blood pressure of rats with aortic coarctation-induced hypertension is influenced by the interplay of prostanoid-mediated pressor and vasodepressor mechanisms.
Effect of hydralazine on the mesenteric vasculature of hypertensive rats, To test whether structural alterations observed in the mesenteric vasculature of Wistar-Kyoto spontaneously hypertensive rats (SHR) were dependent on the presence of hypertension. male SHR and Wistar-Kyoto normotensive (WKY) rats were treated in utero and postnatally with hydralazine up to 28 weeks of age. Treated SHR. WKY. and untreated WKY rats had comparable blood pressures that were less than those of untreated SHR. Treatment altered the dimensions of the superior mesenteric. intermediate-sized. and small arteries of the mesenteric vasculature. In the case of the superior mesenteric artery and intermediate vessels. hydralazine treatment increased the lumen and medial cross-sectional areas of the arteries in WKY rats and slightly decreased both parameters in SHR. Within the small arteries. treatment significantly increased the lumen size in SHR but not WKY rats and had no significant effect on the media of the vessels. Despite the above alterations. the media-to-lumen cross-sectional area ratios remained significantly elevated in SHR over WKY rats in both the treated and control groups of animals within all classes of arteries. The results indicate that there is an inherent increase in the quantity of media surrounding the arteries of SHR when compared with WKY rats that cannot be abolished by normalizing the blood pressure in utero and postnatally with hydralazine treatment. In SHR. such changes persist not only in arteries that exhibit an increase in the media-to-lumen ratio before hypertension but also in the superior mesenteric artery in which an increase in the ratio occurs after hypertension development.
Effects of alpha 1-blockade on arterial compliance in normotensive and hypertensive rats, The effects of blockade of alpha 1-adrenergic receptors on the mechanical properties of the arterial wall were studied in 10 spontaneously hypertensive rats (SHR) as compared with 10 matched normotensive Wistar-Kyoto (WKY) rats. Ascending aortic pressure and flow were recorded in open-chest anesthetized rats. and the systemic arterial compliance was calculated. Intravenous injection (1 mg/kg) of Urapidil. a selective alpha 1-adrenergic antagonist. induced a significant decrease in arterial pressure (-26%. p less than 0.01 and -37%. p less than 0.001 in WKY rats and SHR. respectively) without significant changes in cardiac output. In control conditions. systemic arterial compliance was lower in SHR (3.29 +/- 1.52 microliters/mm Hg) than in WKY rats (4.35 +/- 1.35 microliters/mm Hg. p less than 0.01). Urapidil injection induced significant increases in systemic arterial compliance values in both strains (p less than 0.001). In another set of experiments (15 WKY rats and 15 SHR). the carotid compliance (microliters/mm Hg) was determined from the arterial volume-pressure relation under control conditions. after local incubation with Urapidil. and after total abolition of the vascular smooth muscle by KCN. In WKY rats. the carotid compliance increased markedly after incubation with Urapidil at doses corresponding to 1 mg/kg (+31%. p less than 0.01). A further increase in the carotid compliance was observed after KCN poisoning (+11%. p less than 0.05). In SHR. incubation with Urapidil at doses corresponding to 2 mg/kg were necessary to induce a significant increase in compliance (+38%). At this dosage. there was no further increase in compliance after KCN poisoning.
Rapid baroreceptor resetting in Dahl salt-sensitive rats, Dahl salt-sensitive rats rapidly become hypertensive when exposed to a high salt diet. but Dahl salt-resistant rats maintain normal blood pressure on a high salt diet. A defect in baroreceptor afferents is thought to play a key role in the low sensitivity of baroreceptor reflexes in Dahl salt-sensitive rats even in the prehypertensive stage during low salt treatment. In the present study. we tested whether differences in rapid resetting ability might contribute to differences in baroreceptor function in Dahl rats. Four groups of rats were tested: salt-sensitive and salt-resistant rats on low salt and high salt diets (0.15% and 8.0% NaCl). We compared the rapidly resetting responses of baroreceptors from each group using an in vitro preparation. Rapid resetting was assessed for each aortic baroreceptor (n = 46) by linear fit of the relation of pressure threshold and conditioning mean arterial pressure. Each group had a wide range of resetting ratios (the slope of the resetting relation). Despite higher initial pressure thresholds in salt-sensitive rats on a high salt diet. resetting ratios among the four groups were similar. Thus. the ability of Dahl salt-sensitive baroreceptors to rapidly reset is preserved. despite high dietary salt and a genetic predisposition to dysfunction. The present findings in Dahl rats reinforce the results of recent studies of rapid resetting during spontaneous and renal hypertension. which suggests that the rapid resetting process is remarkably resistant to factors that compromise baroreceptor function.
Plasma norepinephrine and dihydroxyphenylglycol in essential hypertension, The aim of the present study was to examine whether essential hypertension is associated with altered plasma concentrations of dihydroxyphenylglycol. the principal presynaptic metabolite of norepinephrine. Forearm venous plasma dihydroxyphenylglycol and norepinephrine were determined at rest and during graded orthostasis in 47 normotensive control subjects and 58 outpatients with essential hypertension. There was no group difference in age. At supine rest as well as during sitting and standing. hypertensive subjects had plasma norepinephrine concentrations similar to those in normotensive control subjects. but plasma dihydroxyphenylglycol concentrations were higher than those in normotensive control subjects. Both groups showed a linear relation between plasma dihydroxyphenylglycol (ordinate) and plasma norepinephrine (abscissa). The resulting regression line was steeper (p less than 0.02) and its ordinate intercept higher (p less than 0.01) in hypertensive than in control subjects. Eleven normotensive and 14 hypertensive subjects were also tested 3 hours after desipramine (1.5 mg/kg orally) was administered to inhibit neuronal norepinephrine reuptake. The drug did not alter plasma norepinephrine. but did reduce plasma dihydroxyphenylglycol and did abolish plasma dihydroxyphenylglycol responses to upright posture in both groups of subjects. The mean plasma dihydroxyphenylglycol concentration observed in the presence of desipramine again was higher in the hypertensive than in the control group (p less than 0.01) and closely agreed. in both groups. with the dihydroxyphenylglycol concentration given by the ordinate intercept of the dihydroxyphenylglycol versus norepinephrine regression line in the absence of desipramine.
Prognostic significance of exercise versus resting blood pressure in hypertensive men, The outcome of 143 male hypertensive patients. investigated in the period 1972-1982. was ascertained in 1989 to determine if brachial artery pressure measured during a progressive graded exercise test on the bicycle ergometer is a better predictor of mortality and cardiovascular events than pressure at rest. During the total follow-up time of 1.573 patient years. 27 patients suffered at least one fatal or nonfatal cardiovascular event and 13 patients died. Using the Cox regression model. the age-adjusted relative hazard rates of systolic pressure at supine rest. at 50 W. at peak work load. and at 50% of peak exercise capacity were significant for total mortality (p less than or equal to 0.01) and for cardiovascular events (p less than or equal to 0.03). Pressure during exercise. however. did not significantly (p = 0.11-0.97) predict the outcome of the patients when age and pressure at rest were taken into account. The results were similar for diastolic pressure. In conclusion. intra-arterial pressures at rest and during submaximal and peak exercise significantly predict mortality and the incidence of cardiovascular events in hypertensive men. independent of age. However. there is no additional prognostic precision of the exercise pressures when age and the rest pressure are taken into account.
Metoprolol versus thiazide diuretics in hypertension. Morbidity results from the MAPHY Study, The present study in hypertensive men (40-64 years old) with untreated diastolic blood pressure above 100 mm Hg was aimed at investigating whether metoprolol (n = 1.609) given as initial treatment would lower the risk for coronary events (sudden death and myocardial infarction) more effectively than thiazide diuretics (n = 1.625). A substantial part of this study was the metoprolol arm of the Heart Attack Primary Prevention in Hypertension (HAPPHY) study. The HAPPHY study was a pooling of the effect of different beta-blockers. mainly metoprolol and atenolol. in which no favorable effect in relative risk was observed for atenolol as compared with diuretics. In the present study. 255 patients suffered definite coronary events during follow-up; 25% of these events were fatal. 39% were acute myocardial infarctions. and 36% were silent myocardial infarctions. The risk for coronary events was significantly lower in patients on metoprolol than in patients on diuretics (111 versus 144 cases. p = 0.001. corresponding to 14.3 versus 18.8 cases/1.000 patient years and a relative risk of 0.76 at the end of the trial; 95% confidence interval 0.58-0.98). This difference in risk has potentially important implications for clinical practice because of the large number of hypertensive patients who are at increased risk for coronary events. Because a placebo group. for ethical reasons. could not be included. relative risk can only be expressed in relation to diuretics. There was no difference between the two treatment groups in baseline characteristics. blood pressure during follow-up. or stroke rates. Thus. the difference in risk for coronary events is probably mediated via mechanisms other than blood pressure control. However. present data might suggest that different beta-blockers may have different efficacy in preventing coronary events. The reasons for this possibility are as yet unknown.
Independence of pressure reactivity from pressure levels in Tecumseh, Michigan, The relation between blood pressure level and reactivity to mental arithmetic and isometric exercise was investigated in 169 men and 120 women (average age. 32.3 years) from the village of Tecumseh. Mich. In the entire population. the correlation between baseline blood pressure and blood pressure response to both stressors was not significant. Blood pressure reactivity to both stressors was not increased in participants with borderline hypertension (one clinic reading of more than 140 mm Hg systolic and/or 90 mm Hg diastolic). When subjects were classified according to blood pressure response (below and above the 80th percentile). the hyperreactors to mental and physical stress had normal baseline blood pressure values. The hyperreactors also had clinic-to-home blood pressure differences similar to those of the rest of the population. Participants who had borderline hypertension at age 32 years had significantly elevated blood pressures at ages 5. 8. 12. 21. and 22 years. Those who were hyperreactors at age 32 years had normal blood pressures as children and young adults. Results of the present study lend no support to an association between higher blood pressures and blood pressure hyperreactivity. Study participants in Tecumseh will be recalled for future examinations. The independence of blood pressure levels from blood pressure reactivity offers a unique opportunity to prospectively evaluate their separate effects on cardiovascular morbidity.
Stress and sodium intake in neural control of renal function in hypertension, The interaction between genetic and environmental factors is important in the pathophysiology of hypertension. By examining the effects of two environmental factors--acute psychoemotional stress and dietary sodium intake--in rats with genetic hypertension. an important influence on central neural mechanisms governing the renal sympathetic neural control of renal function has been demonstrated. Additional studies of the central opioid systems have demonstrated an important role of opioid peptides in modulating the renal functional responses to acute psychoemotional stress. The observed renal functional alterations--antidiuresis. antinatriuresis. and renal vasoconstriction--are known to be capable of contributing to the initiation. development. and maintenance of the hypertensive process.
Abnormal cardiovascular reactivity in borderline and mild essential hypertension, Cardiovascular and hemodynamic reactivity was evaluated with M-mode echocardiography. phonocardiography. and carotidography in correlation with circulating catecholamine levels in 25 normotensive subjects. 15 borderline hypertensive patients. and 42 mildly hypertensive patients during isometric exercise at 30% of the maximum force for 3 minutes. At rest. norepinephrine and epinephrine levels were significantly higher. and the cardiac index was similarly increased in both groups of hypertensive patients. but the cardiac mass index was significantly increased only in the mildly hypertensive group. During isometric exercise. the sympathoadrenal reactivity as well as the pressor and chronotropic responses were similar in normotensive subjects and both groups of hypertensive patients. However. the variations in blood pressure were achieved through totally different hemodynamic mechanisms in normotensive subjects and hypertensive patients. In normotensive subjects. the increase in blood pressure could be linked mainly to an increase in cardiac contractility and performance. whereas in either group of hypertensive patients. the increase in blood pressure was mainly associated with an increase in peripheral resistance. These observations are consistent with the hypothesis of a blunted beta-adrenergic reactivity and a predominance of alpha-adrenergic vascular reactivity in borderline and mildly hypertensive patients. This phenomenon. which appears to be unrelated to age or severity of hypertension. could be an important mechanism underlying the development of hypertension in humans.
Biochemical evidence of sympathetic hyperactivity in human hypertension, Radiotracer measures of norepinephrine overflow to plasma are well suited for studying both human sympathetic nervous system responses to mental stress and sympathetic nervous pathophysiology in human hypertension. With an experimental laboratory stressor (cognitive challenge). we noted a preferential activation of the cardiac sympathetic outflow; however. in fainting reactions ("vasovagal syncope"). which occur infrequently during the course of central venous catheter placement under local anesthesia. the converse was seen--an almost total withdrawal of cardiac sympathetic activity. In primary human hypertension (particularly in younger patients). a differentiated activation of the sympathetic outflow to the heart and kidneys is present. based on measurements of norepinephrine spillover to plasma. It is uncertain whether this is attributable to behavioral factors and represents a component of the defense reaction. We previously reported overflow of norepinephrine into the cerebrovascular circulation (with high internal jugular venous sampling) in humans. Because this is resistant to ganglion blockade. brain neurons--not the cerebrovascular sympathetics--are the presumed source. In a preliminary study. we found higher rates of norepinephrine spillover into the cerebrovascular circulation in patients with essential hypertension than in healthy subjects. suggesting that an underlying increase in central nervous system norepinephrine turnover may be the basis for the increased sympathetic outflow.
Methodological problems in evaluation of cardiovascular effects of stress in humans, Cardiovascular effects of stress in humans are often assessed by application of physical or emotional stimuli in a laboratory environment. Although this method provides important information. these procedures have several limitations. First. blood pressure and heart rate responses to laboratory stressors are characterized by a limited within-subject reproducibility. Second. there is poor correlation between blood pressure and heart rate responses to different stressors. which implies that individual reaction to stress may be estimated differently according to the test used. Finally. these responses bear only a limited relation to 24-hour or daytime blood pressure variability. that is. they reflect to only a limited extent the tendency of blood pressure to vary during daily activities. If assessed by techniques that allow blood pressure to be continuously recorded for 24 hours in ambulatory subjects. blood pressure variability represents a possible approach to observation of cardiovascular reactivity away from an artificial laboratory environment. However. whether blood pressure variability should be expressed as a percentage or in absolute values is controversial. Furthermore. although naturally occurring stress may markedly increase blood pressure. 24-hour blood pressure variations also depend on factors that are not related to emotional stimuli. Thus. the study of cardiovascular responses to stress in humans encounters several problems. regardless of the method used.
Effect of stress on diagnosis of hypertension, Blood pressure assessment by a physician elicits an alerting reaction and a pressor response in the patient. The magnitude and time course of this response are described for a large number of hypertensive subjects in whom the assessments were performed during ambulatory intra-arterial blood pressure monitoring. In nearly all of the subjects. the physician's visit was accompanied by blood pressure and heart rate increases that peaked within 4 minutes and then declined. The response was characterized by a relatively high average value; a large between-subject variability; no relation with patient age. baseline hemodynamic values. and responses to laboratory stressors; and no attenuation with multiple repetition of the physician's visit. On the other hand. the increase in blood pressure was considerably less when blood pressure assessment was made by a nurse than when it was made by a physician; in both instances. a 10-minute wait was associated with marked reduction of the initial response. Thus. the stress inherent in usual blood pressure-measuring procedures is responsible for considerable overestimations of patients' blood pressures. There are means by which this can be minimized. although a residual error is likely to remain in most subjects. Whether the stress-devoid blood pressure is a better prognostic index than the stress-related one remains unknown.
Stress management in the treatment of mild primary hypertension, The use of simple relaxation-based stress management procedures in the treatment of mild primary hypertension has been the subject of extensive study. Stress management appears to lead to reliably greater reductions in pressure than a variety of control procedures. The mechanisms underlying these effects are obscure. and research has not identified which patients will benefit most from treatment. Preliminary data suggest that stress management may reduce the risk of coronary heart disease. but much research must be done if this is to be confirmed. It is suggested that such research should take into account the possibility that stress management may have beneficial effects on more than just hypertension-related aspects of the cardiovascular disease process.
Management of hypertension by reduction in sympathetic activity, The sympathetic nervous system may initiate or maintain hypertension. and a range of approaches that reduce sympathetic activity is often of value in management. These may include nonpharmacological methods. such as the various forms of behavioral therapy (e.g.. meditation. relaxation. and biofeedback techniques); weight reduction and avoidance of particular foods and agents that stimulate sympathetic activity (including caffeine and alcohol). and regular physical exercise. Pharmacological therapy includes centrally acting drugs such as alpha-methyldopa. clonidine. and reserpine; ganglionic blockers such as hexamethonium; agents acting on sympathetic nerve terminals such as guanethidine and debrisoquine; and drugs that may act at multiple sites. such as the beta-adrenergic blockers. The role of reducing sympathetic activity in the current management of hypertension and its complications is considered in this overview.
Hemodynamic determinants of vascular changes in hypertension and atherosclerosis, Several new concepts are reviewed concerning structural and functional changes in atherosclerotic and hypertensive blood vessels. First. in regard to modulation of vascular changes. atherosclerosis appears to progress more slowly during hypotension than during normotension. This finding may have implications for the optimal level of blood pressure. Second. structural "remodeling" of the vessel wall occurs in both atherosclerosis and hypertension. Remodeling helps to preserve the arterial lumen despite intimal proliferation in atherosclerosis. In contrast. remodeling (which differs from vascular hypertrophy) reduces the vascular lumen in chronic hypertension. Third. functional changes impair active vasodilator responses in both atherosclerotic and hypertensive vessels. in part by endothelium-dependent mechanisms. Finally. we propose that leukocytes as well as platelets may be important cellular mediators of spasm in atherosclerotic arteries.
Anterior spinal fixation after lumbar corpectomy. A study in dogs [published erratum appears in J Bone Joint Surg [Am] 1991 Jul;73(6):952, An animal model was developed to simulate an unstable lumbar burst fracture that had been treated with corpectomy. A fifth lumbar laminectomy. partial facetectomy. and corpectomy was performed in twenty-one dogs. In seven dogs (the control group). a biodegradable polymer spacer was used to create a definite failure of fusion (Group I). Seven dogs were treated with a traditional anterior arthrodesis with an autogenous ulnar strut and without instrumentation (Group II). The remaining seven dogs were treated with an ulnar strut and anterior Kaneda instrumentation that was of an appropriate size for the dog (Group III). At twenty-four weeks. the results were analyzed in terms of the rate of fusion. biomechanical rigidity. neuropathological findings. and histomorphometric data on the vertebral response. The rate of fusion was significantly higher in Group III. in which the Kaneda device had been used. than it was in either Group I or Group II. in which instrumentation had not been used. Biomechanically. the spines in Group III were stiffer in torsion than those in Group I or II. There was no difference between groups in terms of the number of neuropathological changes in the spinal cord. Histomorphometric analysis showed that no meaningful device-related osteopenia occurred in the vertebrae that were spanned by the fixation device. Trabecular density was increased in the vertebrae in which the instrumentation was anchored.
A new diagnostic test for carpal tunnel syndrome, A new test. called the carpal compression test. consists of application of direct pressure on the carpal tunnel and the underlying median nerve. The results of the Tinel percussion test. the Phalen wrist-flexion test. and the new test were evaluated in thirty-one patients (forty-six hands) in whom the presence of carpal tunnel syndrome had been proved electrodiagnostically. as well as in a control group of fifty subjects. For the diagnosis of carpal tunnel syndrome. the carpal compression test was found to be more sensitive and specific than the Tinel and Phalen tests.
Radial tunnel syndrome. An investigation of compression neuropathy as a possible cause, Conventional electromyographic and nerve-conduction studies usually do not show abnormalities in patients who have a clinical diagnosis of radial tunnel syndrome. Therefore. posterior interosseous nerve-conduction measurements were performed during forced supination in patients who had this syndrome. Only one of sixteen patients had a major increase in latency. Our data do not support the hypothesis that the signs and symptoms in most patients who have a diagnosis of radial tunnel syndrome are caused by compression of the posterior interosseous nerve.
The efficacy of suction drains after routine total joint arthroplasty [published erratum appears in J Bone Joint Surg [Am] 1991 Jun;73(5):791, A prospective study of thirty-eight patients (seventy-six knees) who had had a primary bilateral total knee replacement and twelve patients (twenty-four hips) who had had a primary bilateral total hip replacement was conducted to assess the effect of postoperative suction drainage on wound-healing. A suction drain was placed on each patient's right operative wound. while no drains were used on the left. Otherwise. the same operative technique and method of closure were used in all wounds. Statistical analysis of the results showed no difference between the two sides with regard to the incidences of swelling or persistent drainage. Return of active function of the quadriceps and of range of motion of the knee in patients who had had a total knee replacement was also unaffected by the use of suction drains. We concluded that the routine use of suction drains for wounds is unnecessary after uncomplicated total joint arthroplasty.
Proximal placement of the acetabular component in total hip arthroplasty. A long-term follow-up study, A retrospective review was undertaken of thirty-seven hips (thirty-four patients) that had had a complex cemented total hip arthroplasty. In these hips. circumstances had necessitated that the center of the hip be placed farther proximally. as measured from the interteardrop line. than the anatomical position that is normally used. The mean duration of clinical and roentgenographic follow-up was eleven years (range. seven to seventeen years). and the mean age of the patients was fifty-one years (range. sixteen to seventy-three years). Most of these hips had a major deficiency or defect of the acetabular bone stock. or both. Of the six acetabular components (16 per cent) that became loose and were followed for ten years. only one needed revision. Because this study was aimed specifically at assessment of the acetabular component. if the femoral component alone needed revision. the final clinical rating that was used was the one obtained after the femoral revision. Thirty-one hips (84 per cent) were rated as having a good or excellent result; they had an average Harris hip-rating score of 43 points preoperatively and 93 points postoperatively. Thirty-three of the thirty-seven acetabular components were not substantially displaced laterally as compared with the anatomical location that is normally used. Our findings suggest that. when circumstances dictate. proximal positioning of the acetabular component without lateral displacement can give an acceptable result in cemented total hip-replacement procedures.
Interlocking nailing for the treatment of femoral fractures due to gunshot wounds, Fifty-six patients who had a fracture of the femur due to a low-velocity gunshot injury were treated with interlocking nailing with the Grosse-Kempf nail. Patients who had an isolated fracture were treated by intravenous administration of antibiotics followed by delayed interlocking nailing. Ninety-three per cent of the fractures had Grade-III or IV comminution. At an average duration of follow-up of sixteen months (range. twelve to twenty-nine months). the results of closed interlocking nailing were excellent. All of the fractures united an average of twenty-three weeks (range. fourteen to forty weeks) after the nailing. There were no apparent infections in the entire series. There were two delayed unions and seven malunions. Five patients had a serious associated vascular injury; four of these five had interlocking nailing immediately after vascular repair. The fractures united without any residual vascular insufficiency.
Occult papillary microcarcinoma of the thyroid--a potential pitfall of fine needle aspiration cytology, The use of fine needle aspiration cytology detected papillary carcinoma in two patients with multinodular goitre measuring 0.7 cm and 0.9 cm in diameter. respectively. Like most of the cases from previous large series. the tumours progressed slowly as shown by absence of enlarged glands on surgical exploration and no clinical signs of metastasis after two and five years of follow up. This study shows that aspiration cytology can detect a virtually harmless occult papillary carcinoma that will oblige patients to have surgery. This very occasional "pitfall" of fine needle aspiration should not preclude this well known beneficial method from being used in the management of thyroid disease.
Ki-67 staining in histological subtypes of breast carcinoma and fine needle aspiration smears, Thirty four cases of invasive breast carcinoma were analysed for heterogeneity of Ki-67 reactivity in a tumour. and proliferative activity in various histological subtypes was compared. The growth factions determined in areas of central and peripheral tumour were the same. Mucinous and lobular carcinoma showed lower Ki-67 activity than ductal carcinomas. When ductal carcinomas were subdivided according to their dominant growth pattern. the carcinomas with a solid or comedo growth pattern showed the highest proliferative activity. These results largely confirm data from previous cell kinetic studies on the incorporation of radioactively labelled thymidine. A correlation between the growth fraction determined by Ki-67 in fine needle aspiration smears and cryostat sections of corresponding tumours was shown. implying that the immunostaining of cytological smears gives a reliable impression of the growth fraction of a tumour and may therefore be used in prospective studies.
c-erbB-2 expression in different histological types of invasive breast carcinoma, Sections of 149 breast carcinomas were examined for the over-expression of c-erbB-2 oncoprotein using the avidin-biotin immunoperoxidase technique and two different specific antibodies. These included the polyclonal antibody 21N and the monoclonal antibody 4D5. The tumours were divided into two main groups. The first included 75 cases of invasive ductal and classic invasive lobular carcinomas. The second group consisted of 74 cases with histological types known to have a good prognosis. including mucinous. alveolar variant of invasive lobular. medullary. tubular. cribriform and papillary carcinomas. Fifteen (20%) tumours of the first group were positive with the two antibodies. Fourteen of these were of the ductal type and one was a mixed invasive ductal and lobular carcinoma. Ten of the pure ductal cases had areas of comedo carcinoma. The intraductal elements in a further tumour were positively stained with 21N antibody only. None of the second group of tumours. which included histological types known to have good prognosis. stained with 4D5. although one mucinous carcinoma was positively stained with 21N. These findings suggest that in invasive breast carcinoma immunostaining for c-erbB-2 is mainly seen in a subgroup of ductal tumours. and that almost all other histological types. especially those associated with good prognosis. lack this expression.
DNA flow cytometry of follicular non-Hodgkin's lymphoma, S-phase fraction. an index of cellular proliferation. and DNA ploidy were measured by DNA flow cytometry in a retrospective study of lymph node biopsy specimens from 83 cases (before treatment) of follicular non-Hodgkin's lymphoma. Working Formulation categories B and C. The correlations between these measures and survival. clinical stage. symptoms and histopathological factors were investigated. Aneuploidy was rare (n = 16) and had no effect on length of survival or transformation to high grade lymphoma. The overall mean S-phase fraction was 3.6%; for the whole series increasing S-phase fraction was associated with decreased survival. A high S-phase fraction (more than 5%) in initial biopsy specimens was also associated with an increased risk of subsequent high grade transformation at relapse. There was no difference between the survival or proliferative activity of tumours composed of mainly small cleaved cells compared with those composed of mixed small and large cells. There was no difference in survival or proliferative activity between tumours showing a pure follicular growth pattern and those with a mixed follicular and diffuse growth pattern. Multifactorial analysis showed that an S-phase fraction of more than 5% and B symptoms were the most important factors determining survival in these follicular non-Hodgkin's lymphomas.
Automated microparticle enzyme immunoassays for IgG and IgM antibodies to Toxoplasma gondii, Fully automated microparticle enzyme immunoassays (MEIA) for the IMx immunoassay analyser were developed to detect IgG and IgM antibodies to Toxoplasma gondii. The IgG MEIA results are expressed in International Units (IU) of IgG antibody interpolated from a six point calibration curve covering the range from 0 to 300 IU/ml. Reproducible results were obtained from a calibration curve stored in the instrument for at least one month. The qualitative IgM MEIA expresses results as an index using a single calibrator included in each run. The Toxo IgG MEIA and Toxo IgM MEIA were in 98% and 97% agreement. respectively. with the reference assays used. Twenty four sera can be completely processed in about 35 minutes.
Primary squamous cell carcinoma of the terminal ileum, A case of squamous cell carcinoma of the terminal ileum with no underlying duplication or inflammatory disorder is described. The neoplasm seemed to have originated from the surface epithelium. invading the wall and metastasising to the regional lymph nodes. The 65 year old patient was free of disease three years after having had the tumour removed. Previous reports of squamous carcinoma of the small intestine have been associated with intestinal duplication or metastatic disease from distant sites.
Cells containing factor XIIIa and pulmonary fibrosis induced by bleomycin, To show the clinical importance of cells containing FXIIIa in pulmonary fibrosis induced by bleomycin. the distributions of FXIIIa and collagenous components were investigated immunohistochemically in both normal lung tissues and those affected by bleomycin. In the normal tissues FXIIIa-containing cells were sparse. but they were numerous in the pulmonary fibrotic tissues. especially in the subpleural area and around the blood vessels of alveolar septa. where slight to moderate fibrosis was seen. and in the intra-alveolar fibrinous exudate. In the collagenous scar-like areas. however. these cells were fewer in number and their FXIIIa expression was depleted. These findings suggest that cells containing FXIIIa have an important role in the development of pulmonary fibrosis induced by bleomycin.
Comparative yield of Salmonella typhi from blood and bone marrow cultures in patients with fever of unknown origin, Over three years. a comparative study on 100 selected patients with fever of unknown origin was undertaken to determine the yield of Salmonella typhi from their blood and bone marrow cultures. The results indicate that in patients who had an infection with S typhi the organism was isolated from the bone marrow in all of them and from the blood in only 66%. This suggests that bone marrow cultures may be attempted when blood cultures are negative for bacterial growth after three to four days of incubation.
Long-term treatment of hereditary angioedema with attenuated androgens: a survey of a 13-year experience, Fifty-six patients affected with hereditary angioedema have been followed during long-term prophylaxis with attenuated androgens. The treatment was started in patients who had one or more severe attacks per month. In 24 patients. the therapy lasted for more than 5 years. The minimal effective dose usually did not exceed 2 mg/day of stanozolol or 200 mg/day of danazol. Only in two patients were these doses not sufficient to achieve the complete disappearance of symptoms. Irregular menstruation. but rarely amenorrhea. was the only significant side effect. One patient had to stop the therapy because of laboratory signs of hepatic cell necrosis. In one patient. danazol was administered during the last 8 weeks of pregnancy without side effects for the mother but with transient signs of virilization for the female baby. To find a biochemical marker for the minimal effective dose of androgen derivatives. we measured the plasma levels of C1 C1 INH complexes at different doses of stanozolol in four patients with hereditary angioedema. We found that these complexes. elevated before treatment. promptly reverted to normal values during androgen therapy and remained normal with any reduction of the dose of the drug as long as the patient remained symptom free. Therefore. the measurement of C1 C1 INH complexes appears to reflect the activity of the disease and not the amount of androgen that is administered.
Altered T cell subpopulations and lymphocytes expressing natural killer cell phenotypes in patients with progressive systemic sclerosis, Scleroderma (progressive systemic sclerosis [PSS]) is known to be associated with abnormal T cell immunoregulation. In the present study. we evaluated lymphocyte phenotypes in patients with PSS and normal control subjects by flow cytometry and monoclonal antibodies for total T (CD3). T suppressor (CD8). T helper (CD4). T helper-inducer (CDw29). T suppressor-inducer (CD45R). human leukocyte antigen. DR+B (CD19). DR+T. and natural killer subsets. HNK-1 (CD57) and NKH-1 (CD56) cells. Patients with PSS compared to normal subjects had significantly lower percentages of CD3+ (p less than 0.005) and CD8+ (p less than 0.05) (similar to several patients with rheumatoid arthritis also evaluated). as well as CD45R (p less than 0.05). T+DR+ (p less than 0.05). and NKH-1 (CD56) (p less than 0.0005) cells. Patients with PSS with late-limited or generalized disease had lower percentages of CD8+. CD19. NKH-1+. and CDw29. but higher percentages of CD4+. HNK-1. and CD45R cells compared to patients with early stage disease. but these results were not statistically significant. These unique alterations in patients with PSS may prove to be useful in monitoring the stage of disease activity for therapy and further define immunologic defects.
Airway responsiveness in atopic dermatitis, Twelve of 123 patients with atopic dermatitis (AD) were screened by questionnaire and spirometry for the absence of smoking. hay fever. and respiratory disorders. Seven of these 12 patients had a positive methacholine challenge test. None of eight patients with another skin disorder. psoriasis. screened in a similar fashion. had a positive methacholine challenge. We conclude that hyperresponsive airways are a frequent finding in patients with AD and that similar mechanisms may account for the cutaneous physiologic and pharmacologic abnormalities that have been observed in AD.
Source of the aeroallergen of soybean dust: a low molecular mass glycopeptide from the soybean tela, Airborne soybean allergens in the dust generated during the unloading of soybeans in the harbor caused asthma epidemics in Barcelona. Spain. The major allergen causing the epidemics was a glycopeptide less than 14 kd molecular mass abundant in soybean dust. This allergen occurs in all parts of the soybean plant at all stages of growth. but the telae (hulls) and pods are by far the richest source. Small amounts of a similar cross-reacting allergen are found in some other grain dusts. The botanical function and significance of this soybean plant component is not known nor is the potential for airborne dispersion of this allergen at other grain-handling sites.
Cellular and biochemical characteristics of bronchoalveolar lavage fluid in symptomatic nonallergic asthma, We have undertaken cellular and biochemical examination of bronchoalveolar lavage fluid from nonallergic patients with asthma to determine the nature and degree of inflammatory process in symptomatic asthma. Six patients with asthma (mean methacholine provocative concentration causing a 20% fall in FEV1 was 0.26 mg/ml) and six control subjects underwent fiberoptic bronchoscopy with bronchoalveolar wash. The patients with asthma shed a higher number of epithelial cells into lavage fluid than normal control subjects (p less than 0.05). Their lavage fluid also contained increased numbers of neutrophils (p less than 0.025). eosinophils (p less than 0.025). and basophilic cells (p less than 0.025). and increased proportion of activated T cells (p less than 0.05). The basophilic cells were mast cells. as indicated by positive labeling with the monoclonal antibody MCG35. Biochemical analysis of lavage fluid demonstrated exudation of protein molecules in airways of patients with asthma with increased contents of albumin (p less than 0.05) and fibronectin (p less than 0.05). In the lavage fluid of patients with asthma. there were also increased amounts of interleukin-1-beta (IL-1-beta) (p less than 0.025). interleukin-6 (IL-6) (p less than 0.025). and granulocyte-macrophage. colony-stimulating factor (GM-CSF) (p less than 0.05). as compared with lavage fluid of normal control subjects. Immunocytochemical evaluation of lavage cells demonstrated that IL-1-beta. IL-6. and GM-CSF were mostly produced by nonciliated epithelial cells and/or monocytes. IL-1. IL-6. and GM-CSF can prime granulocytes to respond to other stimuli and can promote T cell activation.
A combined single-blind, double-blind, placebo-controlled study to determine the reproducibility of hypersensitivity reactions to aspartame, Aspartame is an O-methyl ester composed of phenylalanine and aspartic acid. After its final approval as a sweetener in 1981. a number of reports of adverse reactions to aspartame appeared in the literature. To explore the pathogenesis of such reactions. we initiated a study in July 1986 to identify subjects with hypersensitivity reactions to aspartame with blinded challenge procedures. The study was closed after 32 months. During that time. we advertised in local newspapers and worked closely with the local community of allergists and dermatologists in an attempt to recruit subjects with hypersensitivity reactions to aspartame. A total of 61 self-referrals and physician referrals were screened. with 20 referrals evaluated in clinic. After this evaluation. 12 patients underwent single- and double-blind challenge with up to 2000 mg of aspartame. No subject with a clearly reproducible adverse reaction to aspartame was identified. In summary. we found that it is difficult to recruit study subjects with a history of hypersensitivity reactions to aspartame and that subjects who believed themselves allergic to aspartame did not have reproducible reactions.
The prevention of immediate generalized reactions to radiocontrast media in high-risk patients, The use of lower osmolality radiocontrast media (RCM) has been associated with satisfactory radiographic opacification and a reduced incidence of severe reactions. The higher cost without clearly established benefit of these media have limited their use. This investigation assessed the incidence of immediate generalized reactions (IGRs) to repeated RCM IGRs in pretreated high-risk patients who received iopamidol or iohexol during 200 procedures (181 intravascular). All patients had experienced a previous IGR to a conventional RCM. Pretreatment consisted of prednisone. 50 mg. 13. 7. and 1 hour before the procedure and diphenhydramine. 50 mg. 1 hour before the procedure in 140 intravascular infusions. Ephedrine. 25 mg. 1 hour before the infusion was added to prednisone-diphenhydramine in 41 cases. Only one (0.7%) urticarial reaction occurred in 141 procedures with prednisone-diphenhydramine. No repeated IGR occurred with the three-drug regimen. The reaction rate after pretreatment with prednisone-diphenhydramine or prednisone-diphenhydramine-ephedrine and use of conventional contrast media during 800 intravascular procedures was 9.1%. and with pretreatment and lower osmolality contrast media in 181 intravascular infusions. it was 0.5% (chi 2 = 14.35; p less than 0.001). Lower osmolality contrast media should be the contrast media of choice for patients with a prior IGR to conventional contrast media. In addition. patients should receive prednisone-diphenhydramine-ephedrine or prednisone-diphenhydramine prophylaxis.
Does post-operative nasal packing cause nocturnal oxygen desaturation, Previous studies have shown an increased frequency and duration of apnoeic episodes during sleep when the nose is occluded. The aim of this study was to ascertain whether oxygen desaturation occurs with nasal occlusion by post-operative packing. Continuous digital pulse oximetry was carried out before and after submucous resection of the nasal septum in 17 otherwise healthy patients. Post-operative nasal packing produced a statistically significant change in oxygen saturation during sleep. The change was. however. of such small magnitude that it is unlikely to be clinically significant.
Bilateral carcinoma of the external auditory meatus, A 65-year-old woman had suffered for two months from bilateral tinnitus and discharge. pain in the right ear. and loss of hearing. Biopsy showed carcinoma of the squamous type on both sides. Tomography revealed bone destruction on the right. The patient was treated with radiotherapy. Two months after treatment. tomography showed tumour regression on the right side. but progression on the left. The literature on this subject is reviewed.
Wegener's granulomatosis in two siblings: a family study, Two brothers with Wegener's granulomatosis are presented. HLA status and associated genes in the brothers and the immediate family are explored. No specific association could be found with tissue types within the family.
Intracordal Teflon injection: a question of timing, Intracordal Teflon injection is commonly performed for recurrent laryngeal nerve palsy. It is generally agreed that injection should not be performed for a period of six months from the onset of an 'idiopathic' paralysis. A case is presented in which recovery occurred late. after intracordal injection. with unfortunate results. Successful removal of the Teflon is described. The advisability of a longer wait before surgery for 'idiopathic' recurrent laryngeal nerve palsy is considered.
Malignant fibrous histiocytoma of the larynx, Malignant fibrous histiocytomas of the upper respiratory tract are rare. aggressive mesenchymal neoplasms. We report a case of a glottic malignant fibrous histiocytoma of the larynx on a 54 year old man. Only a few have been reported in the English literature. The clinical behaviour and degree of malignancy of these tumours cannot be predicted. Wide. aggressive excision of the tumour with a margin of normal tissue appears to be the treatment of choice. About two years after total laryngectomy the patient is well and free of disease.
Massive thyroid oncocytoma, A patient with a massive thyroid oncocytoma is presented. The symptoms of hoarseness and dysphagia were due to compression and were relieved by surgical excision of the tumour.
Lateral cephalometric analysis of children with otitis media with effusion: a comparison with age and sex matched controls, Previous reports from this department have established significant differences in the morphology of the nasopharynx between patients with otitis media with effusion (OME) and normal controls. This study has used lateral cephalometric analysis to investigate these differences in greater detail. Skeletal and soft tissue measurements were recorded in 50 patients with bilateral OME and were compared with 50 age and sex matched normal controls. Various points were plotted enabling 23 different linear dimensions and three angles in and around the nasopharynx to be compared. The results show significant differences between the two groups in the skeletal and soft tissue dimensions of the nasopharynx. The children with OME have a smaller nasopharynx with a suggestion that this may be due to a difference both in the rate and timing of growth.
Radiology for cochlear implants, One fifth of patients selected for cochlear implants have such bony irregularities in the cochlear duct that full insertion of a multichannel electrode array is impossible. Three cases of cochlear deafness are presented where pre- and post-operative radiology played an important part in the management. Standard CT at 2 mm cuts is compared with ultra high resolution CT at 1 mm cuts. The pitfall of poor definition is that the inexperienced surgeon may find himself unexpectedly drilling out an obliterated cochlear duct. Sections 30 degrees caudal to Reid's infra orbito-meatal base line at 1 mm intervals give maximum information for minimum radiation. Plain films show the placement of individual platinum electrode contacts in relation to the spiral 'frequency map' of the cochlea. This is vital information for the audiologist who has to route specific frequencies to specific sites within the ear for a good hearing result.
Tinnitus severity measured by a subjective scale, audiometry and clinical judgement, Tinnitus is discussed. with particular reference to the problem of assessing severity. The authors argue that tinnitus severity can only usefully be determined by measuring the impact of tinnitus on an individual. and therefore propose a scale to estimate severity in these terms. Data presented on 112 members of a tinnitus self-help group. demonstrated the reliability of a Subjective Tinnitus Severity Scale (S.T.S.S.). with a coefficient alpha of 0.84. This indicates a high degree of internal consistency. i.e.: statistically this scale is measuring aspects of a single dimension. The validity was established in a separate sample of 30 clinic attenders. where mean S.T.S.S. scores were found to correlate highly with two independent clinical ratings of severity (r2 = 0.76. p less than 0.001. and r2 = 0.73. p less than 0.001). Additionally. in these patients S.T.S.S. scores were significantly associated with several audiometric variables. although the correlations were of low magnitude.
Postoperative radiotherapy in the management of spinal cord ependymoma, Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this series was 40 years (range 1 to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the conus medullaris and 24 the cauda equina. Forty ependymomas were grade I and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only. 33 had partial or subtotal resection. and 14 had complete resection. Forty-three patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years. respectively. On univariate analysis. age. histological grade. postoperative neurological function. and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients with tumor grades II to IV compared to grade I (p less than 0.005. 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p less than 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery. 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%. and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.
Growth hormone deficiency following radiation therapy of primary brain tumors in children, The medical records of 123 patients treated for brain tumors at Children's Hospital and Medical Center. Seattle. Washington. between 1985 and 1987 were reviewed. The endocrinological complications of radiation therapy and the effectiveness of growth hormone (GH) replacement therapy were assessed. These were the first 2 years after synthetic GH became available. The disease pathology was confirmed at craniotomy or biopsy in 108 patients. Ninety-five children completed radiation therapy and 65 of these were alive at the time of review; these 65 children represent the study population. The most common tumor types were medulloblastoma. craniopharyngioma. and ependymoma. Endocrine evaluation was initiated with changes in the patients' growth velocity. Patient workup included skeletal x-ray films for determination of bone and analysis of thyroxin. thyroid-stimulating hormone. and somatomedin-C levels. Following 1-dopa and clonidine stimulation. provocative studies of GH levels were performed. Growth hormone failure and short stature were observed in 26 children. most commonly in the 2nd year after tumor treatment. Eight patients with GH failure were also hypothyroid. Hormone replacement therapy was initiated with recombinant GH. 0.05 mg/kg/day. and all children so treated showed an increase in height. with eight patients experiencing catch-up growth. There were no complications of therapy or tumor recurrence. Studies of baseline bone age and somatomedin-C levels on completion of radiation therapy are recommended. Comprehensive endocrine studies should follow changes in the patients' growth velocity. With early GH replacement. catch-up growth is possible and normal adult heights may be achieved.
Unilateral facetectomy approach for lateral lumbar disc herniation, Forty-one patients with herniated lumbar discs in a lateral location underwent unilateral complete facetectomy for removal of their disc herniation. The diagnosis was made by computerized tomography in all patients. The follow-up period varied between 4 and 60 months. with an average of 22.4 months. All patients underwent dynamic lumbar spine x-ray films with flexion and extension exposures at various times during their follow-up period. The results were excellent in 35 patients. good in three. and poor in three. One patient suffered spinal instability postoperatively and required lumbar fusion because of back pain. Unilateral facetectomy gives an excellent view of the affected nerve root and the herniated disc. and the risk of spinal instability is very low.
Immunocytochemical evidence of lymphocytic derivation of neoplastic cells in malignant angioendotheliomatosis, Neoplastic angioendotheliomatosis is a rare disorder usually characterized by primarily cutaneous or neurological symptoms. Approximately 40 cases of malignant angioendotheliomatosis with primary central nervous system (CNS) symptoms have been reported. Some investigators have postulated a hematopoietic origin for this neoplasm. Most of the literature. however. has perpetuated the idea that the often bizarre symptoms seen with this entity result from neoplastic endothelial cell proliferation within the small vessels of affected organs. including the brain and spinal cord. This report describes the immunohistochemical examination and confirmation of the cell of origin of this neoplasm based on five previously unpublished cases of malignant angioendotheliomatosis with primarily CNS symptoms. It includes the first documentation of a T-cell lymphoma presenting as malignant angioendotheliomatosis. All cases include autopsy findings. and in four cases the diagnosis was made postmortem. One case was proven by stereotactic biopsy. but the patient succumbed as a result of severe intracranial bleeding that occurred at the time of biopsy. Tissues were studied with avidin-biotin peroxidase immunohistochemical techniques using a panel of monoclonal antibodies directed against the leukocyte common antigen. LN-1. LN-2. and anti-Factor VIII. and also using Ulex europaeus agglutinin 1. Based on the results obtained. the authors conclude that the proliferative cells seen within the vessel lumina are of lymphocytic origin and agree that the condition should more properly be designated intravascular lymphomatosis. The therapeutic implications of this conclusion point to the possible administration of chemotherapy and radiotherapy in an effort to achieve remissions in an otherwise relentlessly progressive neurological disorder.
Intravascular streaming during carotid artery infusions. Demonstration in humans and reduction using diastole-phased pulsatile administration, Intra-arterial carotid artery chemotherapy for malignant gliomas is limited by focal injuries to the eye and brain which may be caused by poor mixing of the drug with blood at the infusion site. This inadequate mixing can be eliminated in animal models with diastole-phased pulsatile infusion (DPPI) which creates 1-ml/sec spurts during the slow blood flow phase of diastole. Before treatment with intracarotid cisplatin. 10 patients with malignant gliomas were studied to determine whether intravascular streaming occurs after intracarotid infusion in humans. and if so. if it is reduced with DPPI. Regional cerebral blood flow (rCBF) studies were performed by intravenous injection of H2(15)O and positron emission tomography. This was followed by supra- or infraophthalmic internal carotid artery (ICA) injections of H2(15)O with either continuous infusion or DPPI. Local H2(15)O concentration in the brain was determined and the images of radiotracer distribution in the continuous infusion and DPPI studies were compared to the rCBF images. Intravascular streaming of the infusate was identified by a heterogeneous distribution of the infused H2(15)O in brain compared to rCBF. Extensive and variable intravascular streaming occurred in three patients who received infusions into the supraophthalmic segment of the ICA. Some brain areas received up to 11 times the expected radiotracer delivery. while other regions received as little as one-tenth. This streaming pattern was markedly reduced or eliminated by DPPI. In the five patients who received infraophthalmic infusions. a minimally heterogeneous distribution of the infusate was detected. The authors conclude that extensive intravascular streaming accompanies supraophthalmic ICA infusions in patients. The magnitude of streaming can be substantially reduced or eliminated with DPPI. Those who perform intra-arterial infusion should consider using DPPI to assure uniform drug delivery to brain.
Evidence against leukotrienes as mediators of brain edema, Leukotrienes are powerful metabolites of arachidonic acid which are known to increase the permeability of peripheral blood vessels. These substances are found in brain tissue in association with cerebral ischemia. and in brain tumors. Therefore. it has been proposed that leukotrienes have a mediator function in brain edema. This hypothesis was subjected to further experimental analysis in this study. in which the authors investigated whether: 1) superfusion of the exposed brain surface with leukotrienes increases the permeability of extraparenchymal blood vessels in vivo; 2) intraparenchymal infusion of leukotrienes induces brain edema; and 3) pharmacological inhibition of leukotriene formation by BW755C. an inhibitor of leukotriene synthesis. reduces formation of brain edema from a standardized traumatic insult. The pial vessels of the parietal cortex of cats were examined by fluorescence microscopy during cerebral superfusion with the leukotrienes C4 (LTC4). D4 (LTD4). or E4 (LTE4) by using an open cranial window preparation. Intravenous Na(+)-fluorescein served as an in vivo blood-brain barrier (BBB) indicator. Superfusion of the pia with leukotrienes (up to 2 microM) did not open the barrier to fluorescein. but was associated with a significant constriction (up to 25%) of arterial and venous vessels. In experiments with slow infusion of leukotriene B4 (LTB4) or LTC4 into the white matter of feline brain. the tissue water content was subsequently determined in serial brain slices using the specific gravity method. Tissue water profiles obtained after a 15-microM infusion of either LTB4 or LTC4 were virtually identical with those of control animals infused with mock cerebrospinal fluid. Thus. neither LTB4 nor LTC4 led to an augmentation of infusion-induced brain edema. In a final series. a cold lesion of the left parietal cortex was induced in rabbits. Twenty-four hours later. swelling of the exposed hemisphere was quantified by gravimetrical comparison of its weight with that of the contralateral nontraumatized hemisphere. Eight animals received BW755C intravenously prior to and after trauma to inhibit formation of leukotrienes. Seven rabbits were infused with an equivalent volume of saline as a control study. The resulting hemispheric swelling was 7.7% +/- 0.6% (mean +/- standard error of the mean) 24 hours later in animals receiving BW755C and 7.8% +/- 1.2% in the control group. indicating that inhibition of leukotrienes was ineffective in preventing formation of vasogenic brain edema. The findings demonstrate that leukotrienes administered to the brain in concentrations occurring under pathological conditions do not open the BBB nor do they induce brain edema.(ABSTRACT TRUNCATED AT 400 WORDS).
Percutaneous thecoperitoneal shunt for syringomyelia. Report of three cases, Between January and April. 1990. three consecutive cases of syringomyelia were treated by percutaneous placement of thecoperitoneal shunts. Two of these patients had undergone craniovertebral decompression earlier at other centers and the third was treated primarily by a thecoperitoneal shunt. In each case. the syrinx was associated with Chiari I malformation. although the clinical presentation was due to a myelopathy. All three patients obtained unequivocal benefit from this simple procedure. Postoperative magnetic resonance images showed considerable shrinkage of the cysts corresponding with clinical improvement.
Successful treatment of a pineal endodermal sinus tumor. Case report, A patient with a pineal endodermal sinus tumor is presented who was successfully treated by a combination of surgery. adjuvant chemotherapy. and craniospinal irradiation. Two years after diagnosis. he is free of any disease. A review of the literature shows that such an outcome is very unusual. A multidisciplinary treatment is recommended for this rare tumor. using chemotherapy as adjuvant treatment.
The Dolenc technique for cavernous sinus exploration (cadaveric prosection). Technical note, This report describes a surgical approach to the cavernous sinus. Based on the work of Parkinson. Dolenc. and other pioneering investigators. a comprehensive surgical approach for the treatment of lesions of the cavernous sinus is distilled and presented in 12 simple steps. The approach to surgical exploration of this region is divided into an extradural and intradural phase. each with six steps. The bony. neural. and/or vascular structures of each step are discussed. These steps may be used in their entirety for total exploration of the cavernous sinus. but also in part for lesions that involve only limited regions of the cavernous sinus. Either by design or circumstance. every intracranial neurosurgeon will eventually be led to the cavernous sinus region. and a clear understanding of cavernous sinus anatomy should be part of their armamentarium.
A frameless, armless navigational system for computer-assisted neurosurgery. Technical note, A computer-assisted neurosurgical navigational system has been developed which displays intraoperative manipulation on the preoperative computerized tomography (CT) scans or magnetic resonance (MR) images. The system consists of a three-dimensional digitizer. a personal computer. and an image-processing unit. Utilizing recently developed magnetic field modulation technology. the three-dimensional digitizer determines the spatial position and orientation angles of the resin probe. triangle-shaped pointer. or suction tube with a small attached magnetic field sensor. Four fiducial markers on the scalp were used to translate the spatial data of the probe onto the preoperative CT scans or MR images of the patient. With this frameless. armless navigational system. CT or MR-imaging stereotaxy can be applied to conventional open neurosurgery without limiting the operative field or interfering with the surgical procedures.
Clinical application of PET for the evaluation of brain tumors, The combination of FDG and PET has demonstrated clinical utility in the evaluation of patients with brain tumors. At the time of diagnosis. FDG PET provides information concerning the degree of malignancy and patient prognosis. After therapy. FDG PET is able to assess persistence of tumor. determine degree of malignancy. monitor progression. differentiate recurrence from necrosis. and assess prognosis. Other studies using PET provide information that may be clinically useful. Determination of tumor blood flow and permeability of the blood-brain barrier may help in the selection of appropriate therapy. Amino acid imaging using 11C-methionine is being evaluated in patients with brain tumors and provides different information than FDG imaging.
Epilepsy, As surgical treatments for adult and pediatric forms of epilepsy have become more refined. methods for noninvasive localization of epileptogenic foci have become increasingly important. Detection of focal brain metabolic or flow abnormalities is now well recognized as an essential step in the presurgical evaluation of many patients with epilepsy. Positron emission tomography (PET) scanning is most beneficial when used in the context of the total clinical evaluation of patients. including scalp EEG. invasive EEG. neuropsychologic testing. etc. Metabolic PET studies also give insight into pathophysiologic mechanisms of epilepsy. The dynamic nature of the interictal hypometabolism observed with 18[F]FDG in some patients suggests that excitatory or inhibitory neurotransmitters and their receptors may be involved. An exciting current application of PET scanning is the use of tracers for neurotransmitter receptors in the study of epilepsy patients. Mu and non-mu opiate receptors have been extensively studied and are beginning to give new insights into this disorder. Increased labeling of mu receptors in temporal neocortex using 11C-carfentanil has been demonstrated and. in some patients. supplements the clinical localization information from 18[F]FDG studies. Increased mu opiate receptor number or affinity is thought to play a role in anticonvulsant mechanisms. Specificity of increased mu receptors is supported by the absence of significant changes in non-mu opiate receptors. Other brain receptors are also of interest for future studies. particularly those for excitatory neurotransmitters. Combined studies of flow. metabolism. and neuroreceptors may elucidate the factors responsible for initiation and termination of seizures. thus improving patient treatment.
Use of the metabolic tracer carbon-11-acetate for evaluation of regional myocardial perfusion, The high first-pass myocardial extraction fraction of carbon-11-acetate suggests that its initial uptake depends on blood flow. Accordingly. regional uptake of 11C-acetate at 4 min was compared to regional perfusion determined with nitrogen-13-ammonia in 119 segments in 15 patients with stable coronary artery disease by two methods. A close correlation was observed between initial relative myocardial concentrations (segmental activity normalized to maximal activity) of both tracers (11C-acetate = 0.88; 13N-ammonia + 0.079; s.e.e. = 0.064. r = 0.94. p less than 0.001). Furthermore. segmental net extractions (E.F). as calculated from the input function and segmental activities. of the two tracers correlated closely by E.FC-11 = 0.55E.FN-13 + 0.080 (s.e.e. = 0.045. r = 0.87. p less than 0.001). These relationships indicate that initial regional myocardial uptake of 11C-acetate reflects perfusion and that 11C-acetate permits near simultaneous evaluation of regional oxidative metabolism and of regional myocardial perfusion.
Metabolic activity in the areas of new fill-in after thallium-201 reinjection: comparison with positron emission tomography using fluorine-18-deoxyglucose, Reinjection of thallium-201 after recording the 3-hr delayed scan often demonstrates improvement in areas of persistent abnormalities. To determine the metabolic activity of these areas. the changes seen on stress/redistribution/reinjection thallium SPECT were compared with PET using fluorine-18-fluorodeoxyglucose (FDG) in 18 patients with coronary artery disease. Of 48 segments showing no redistribution on the delayed scan. the reinjection scan identified new fill-in in 20 segments (42%). all of which demonstrated FDG uptake. In contrast. only 7 of the 28 segments (25%) showing no fill-in after reinjection were PET viable (p less than 0.01). Eleven patients had coronary bypass graft surgery after the radionuclide study. The majority of the segments showing redistribution (87%) and new fill-in after reinjection (65%) improved in wall motion. whereas only eight segments (25%) without new fill-in improved after surgery. Of those without new fill-in. two segments showing PET ischemia improved in wall motion. whereas the remaining six segments showing PET scar did not improve after surgery. Thus. the segments showing new fill-in after reinjection are PET viable myocardium. However. reinjection thallium imaging still underestimates the extent of tissue viability compared to PET imaging.
Regional wall thickening of left ventricle evaluated by gated positron emission tomography in relation to myocardial perfusion and glucose metabolism, Regional wall thickening was assessed by electrocardiographically gated positron emission tomography (ECG-gated PET) in 26 patients with coronary artery disease. The standardized percent count increase from end-diastole to end-systole (S-percent Cl) was calculated as an index of wall thickening. The S-percent Cl was 77.8% +/- 28.9% in the segments with normal perfusion at rest. 51.9% +/- 29.5% in those with mild hypoperfusion. and 32.8% +/- 30.9% in those with severe hypoperfusion (p less than 0.001. each). Among the segments with resting hypoperfusion. the S-percent Cl was 38.9% +/- 31.5% in those without stress-induced ischemia and 48.7% +/- 30.9% in those with ischemia (p less than 0.05). Furthermore. among resting severe hypoperfusion. the S-percent Cl was 23.0% +/- 23.9% in the segments without fluorine-18-fluorodeoxyglucose (FDG) uptake and 37.8 +/- 32.9% in those with FDG uptake (p less than 0.05). These results suggest that stress-induced ischemia and FDG accumulation correlated with wall thickening. Thus. quantitative analysis of regional wall thickening seems to be useful for combined analysis of regional function. perfusion and metabolism in coronary patients.
Innovative approach in the diagnosis of gliomatosis cerebri using carbon-11-L-methionine positron emission tomography, A case of gliomatosis cerebri was studied with positron emission tomography (PET). Carbon-11-L-methionine (11C-Met) accumulated in the diffusely infiltrative tumorous area more widely and accurately than the lesion detected by conventional x-ray computerized tomography (CT) or magnetic resonance (MR) imaging. Autopsy findings three months after the time of the PET study showed good anatomical correspondence between the extent of densely aggregated tumor cells and the region with high uptake of 11C-Met. PET may offer an innovative approach in the delineation of gliomatosis cerebri. which has not been clearly recognized by CT or MR.
Peptide containing nerves in human synovium: immunohistochemical evidence for decreased innervation in rheumatoid arthritis, The innervation of normal and rheumatoid human synovium was studied by immunofluorescence microscopy. Antibodies against the general neuronal marker protein gene product (PGP) 9.5 and specific neuropeptides were used. We observed sensory nerves containing substance P (SP) and calcitonin gene related peptide (CGRP) as well as autonomic sympathetic fibers immunoreactive for neuropeptide tyrosine (NPY). its C terminal peptide (C-PON) and the catecholamine synthesizing enzyme tyrosine hydroxylase (TH). Three subpopulations of nerve fibers labelled with SP and CGRP were identified: some stained for SP or CGRP only and others contained both peptides. NPY/C-PON and TH labelled predominantly perivascular nerves. Quantification of immunostained nerves revealed a significantly decreased innervation of rheumatoid synovia. The densities of both PGP 9.5 and neuropeptide containing nerves were lower in all rheumatoid samples. Our results are compatible with a local release of neuropeptides into joint fluid and point to a disturbed neuronal control of rheumatoid synovial tissue.
Antibody to interleukin 1 inhibits the cartilage degradative and thymocyte proliferative actions of rheumatoid synovial culture medium, Cartilage breakdown in rheumatoid arthritis results from (a) lytic action by synovial enzymes. and (b) release of synovial catabolin. now believed to be a form of interleukin 1 (IL-1). causing chondrocytes to degrade their matrix. Rheumatoid synovial culture media were tested for their ability to stimulate cartilage degradation (proteoglycan release from bovine nasal cartilage discs) and thymocyte proliferation (3H-thymidine incorporation) in the absence or presence of anti-IL-1. Degradation of living cartilage. stimulated 2-fold by synovial culture media. was inhibited up to 80% by anti-IL-1. Residual breakdown in living cartilage and synovial culture media induced breakdown in dead cultures were of similar magnitude. and both were unaffected by antibody treatment. Proteoglycan products released from synovial culture media treated cartilage were of smaller average molecular weight (Sepharose CL-2B). and such size reduction was inhibited by anti-IL-1 treatment. Synovial culture media that stimulated cartilage degradation also stimulated thymocyte proliferation; the latter was fully suppressible by anti-IL-1. One of 8 synovial culture media contained an inhibitor(s) of thymocyte proliferation. removable by dialysis. We conclude (1) rheumatoid synovial catabolin activity is due to a form of IL-1. (2) A minor nonsuppressible component of synovial culture media stimulated breakdown. identical in living and killed cartilage. is due to passive transfer of enzymic activity. (3) Cultured rheumatoid synovium releases both IL-1 and an inhibitor(s) of IL-1 action.
Identifying subclasses of patients with rheumatoid arthritis through cluster analysis, Nonhierarchical cluster analysis was used to classify 92 patients with rheumatoid arthritis drawn from a community rheumatology practice into 5 groups on the basis of biochemical measures and disease indices. The major differentiating variables were the number of active joints. number of damaged joints. overall disease activity. extraarticular complications. and history of joint surgery. Although the 5 subclasses were equivalent on measures of psychological functioning. they differed systematically on such health outcome measures as mobility. physical activity. and dexterity. Relationships between the taxonomy produced through cluster analysis and conventional classifications are discussed. and directions for further investigation are noted.
Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition, In a population of 564 patients with rheumatoid arthritis (RA). the onset of symptoms has been studied in relation to age. sex and last menstrual period for women. Median age of menopause was 49 years (3rd percentile: 32 years and 97th percentile: 56 years). Median age of first symptoms was 45 years in women and 50 in men. The individual interval between menopause and first symptoms has a Gaussian distribution with mean at time 0. implying that the average woman develops the first symptoms at the time of her menopause. The F:M ratio of all patients was 2.3; with increasing age the F:M ratio decreased from 3.7 before 30 years of age to 1 after the 6th decade of life. with a peak at the age of 40-44 years. A possible effect of age related changes in sex hormone levels on the pathogenesis of RA is suggested.
Clinical course and predictors of length of stay in hospitalized patients with rheumatoid arthritis, Patients admitted for therapy of active rheumatoid arthritis were prospectively followed throughout their hospital stay. Average length of stay was 17.1 days. Serial global assessments. whether determined by rheumatologist. physiotherapist or patient appeared to improve linearly until at least hospital day 21. From admission to discharge. mean global assessment scores improved by about one third. Poor global assessment. high disability index. and the presence of comorbid disease and anemia on admission. as well as admission late in the week. were predictive of prolonged hospital stay.
Adverse experience with methotrexate during 176 weeks of a longterm prospective trial in patients with rheumatoid arthritis, Adverse experience occurred with a high frequency in a longterm (greater than 3 years). prospective. double blind. followed by an open trial of methotrexate (MTX) therapy in 45 patients with rheumatoid arthritis (RA). Adverse experiences occurred in 96% of patients. and the discontinuation rate was 44% over 176 weeks. No hepatic or pulmonary fibrosis occurred. Unusual toxicities included weight loss (2 patients). systemic fungal infections (2 patients). and transient noncirrhotic ascites (1 patient). Baseline white blood cell counts and creatinine may help predict adverse experiences. The full dose-toxicity spectrum of MTX RA is not yet fully defined.
Declines in the range of motion and malalignment in hands of patients with juvenile rheumatoid arthritis studied over 6 years, Quantitative total joint scores including range of motion. malalignment. opposition of the thumb to the digits and combined distal-proximal-metacarpophalangeal joint flexion were determined in the hands and wrists of 56 patients with juvenile rheumatoid arthritis over six years. Most of the patients with duration of disease less than 5 years showed relatively normal hand function. reflected by low total and subtotal scores. However. significant declines of the respective variables reflected by pathological total and subtotal scores were seen in patients with duration of disease longer than 5 years. Decrease of the range of motion. total joint scores and malalignment were significantly correlated with the duration of disease.
Arthritis impact measurement scales: reliability of a French version and validity in adult Still's disease, The Arthritis Impact Measurement Scales (AIMS) questionnaire was administered to 57 patients with adult Still's disease (ASD) and 104 controls. Six of the 9 scales were consistent for both groups (Cronbach's alpha greater than or equal to 0.70). Two scales. Mobility and Dexterity. were consistent for ASD only (alpha greater than or equal to 0.70). The reliability of a French version of the AIMS was similar to the standard AIMS. Of the 13 associations evaluating criterion related validity of the AIMS in ASD. 11 were statistically significant. We conclude that the French and standard AIMS are comparable and that this questionnaire is reliable and valid for assessing outcome in ASD.
Synovial inflammation in patients with early osteoarthritis of the knee, While synovitis is common in advanced osteoarthritis (OA). its prevalence and severity in patients with early or mild OA are uncertain. In our study synovial biopsies from patients with arthroscopic evidence of OA whose radiographs were normal. or showed only mild/moderate changes of OA. were examined to determine the prevalence and severity of lining cell proliferation and mononuclear cell infiltration. Synovitis was present in only 16 of 29 patients (55%) who underwent arthroscopy because of chronic knee pain and were found to have OA; no synovium from 50% of the 22 patients in this group with full thickness cartilage ulceration showed infiltration with mononuclear cells. Similarly. no evidence of synovitis was seen in biopsies from 7 of 14 additional patients with OA who did not have knee pain but who underwent arthroscopy to evaluate joint instability. An association was seen between synovial mononuclear cell infiltration and thickness of the synovial lining cell layer (p less than 0.03). but lining cell hyperplasia was found in samples from only 12% of the patients with OA in our series. The severity of OA cartilage lesions was unrelated to severity of synovitis and no topographic relationship was found between cartilage ulceration and synovitis.
The distribution of S-100 protein in articular cartilage from osteoarthritic joints, The distribution and localization of S-100 protein was compared with safranin-O staining and H and E morphology in relatively unaffected. degenerative. and osteophytic regions of human articular cartilage from 26 joints obtained at the time of total joint replacement for osteoarthritis. S-100 protein immunoreactivity in osteophyte cartilage was more intense than in unaffected regions and comparable to the staining intensity found in metaplastic cartilage tufts in degenerating cartilage. Immunoreactivity for S-100 protein appeared more prominent in the deep layers of osteophyte cartilage adjacent to areas of matrix calcification.
Locomotor diseases in sculpture, In the sculpture The Adoration of the Magi by the 13th century sculptor Arnolfo di Cambio deformities characteristic of arthritis may be seen in the hands of the central magus.
Intraarticular osmic acid in postinfectious arthritis persisting after treated bacterial arthritis, We describe 4 patients successfully treated with intraarticular osmic acid for post-infectious arthritis persisting after apparent eradication of bacteria from the infected joint. In addition the bactericidal effect of osmic acid in vitro is demonstrated. We conclude that treatment with osmic acid carries no risk of iatrogenic infection; on the contrary. an antibacterial effect seems likely.
Resident physician substance use in the United States, A national survey was conducted to determine patterns of drug use among 3000 American resident physicians. Sixty percent (1785) of the residents surveyed responded. This report evaluates the prevalence of drug use among the respondents. when they initiated drug use. and their reasons for current use. Substance use rates are compared with other studies of resident physicians and with a sample of their nonphysician age peers surveyed the same year. Heavy substance use patterns were not observed among resident physicians. They had significantly lower rates of use for most psychoactive substances than their peers in the general population but did report higher rates of past-month use of alcohol and benzodiazepines. A sizable minority began using benzodiazepines and prescription opiates during their residency years-the stage in physicians' training when they first receive prescribing privileges. Current users of benzodiazepines and opiates used these drugs primarily for self-treatment rather than recreation. These two substances are often associated with impairment at later stages in the physician's career.
Substance use among senior medical students. A survey of 23 medical schools, Senior students at 23 regionally distributed medical schools received an anonymous questionnaire designed to examine current and prior use of tobacco. alcohol. and nine other drugs. The overall response rate was 67% (N = 2046). Substance use prevalence rates during the 30 days preceding the survey included alcohol. 87.5%; marijuana. 10.0%; cigarettes. 10.0%; cocaine. 2.8%; tranquilizers. 2.3%; opiates other than heroin. 1.1%; psychedelics other than LSD (lysergic acid diethylamide). 0.6%; amphetamines. 0.3%; barbiturates. 0.2%; LSD. 0.1%; and heroin. 0.0%. Compared with national. age-related comparison groups. senior medical students reported less use of all substances during the past 30 days and the past 12 months. except for alcohol. tranquilizers. and psychedelics other than LSD. Substantial new drug use after entry into medical school was reported only for tranquilizers. Seven students (0.2%) admitted to current dependence on a substance other than tobacco. four of these implicating marijuana. Thirty-three students (1.6%) believed that they currently needed help for substance abuse. Only 25.7% were aware of any policy on substance abuse at their own school.
The epidemiologic necropsy for abdominal aortic aneurysm, The epidemiologic necropsy measures the occurrence of unsuspected disease through the examination of necropsy records. The estimates of unsuspected disease should approximate what occurs in the living population. The necropsy records of the University of Kansas Medical Center (Kansas City) from 1950 to 1984 were examined for the occurrence rate of abdominal aortic aneurysms. Each adult patient was categorized as (1) without abdominal aortic aneurysm. (2) abdominal aortic aneurysm discovered as a necropsy surprise. or (3) abdominal aortic aneurysm diagnosed or suspected during life. Necropsy detection rates of unsuspected abdominal aortic aneurysms were compared with those found in five published screening surveys. The necropsy detection rate in men was 81 (0.019) of 4155 and was 28 (0.009) of 3142 in women. a difference that was statistically significant. When the necropsy series was adjusted to reflect the same demographic composition as the screening surveys. the results from necropsy and screening were statistically similar. In particular. two surveys from the United Kingdom showed screening detection rates among white men of 0.072 compared with a necropsy detection rate of 0.058. These results further support the use of the epidemiologic necropsy as a research tool for estimating the reservoir of disease in the population.
Diagnostic and therapeutic technology assessment. Reassessment of automated percutaneous lumbar diskectomy for herniated disks, Although the safety of the APLD procedure is clearly established both by reports in the published literature and by a consensus of the DATTA panelists. there was no consensus among the DATTA panelists on the effectiveness of the procedure. The average 75% success rate reported in the larger studies contrasts with the 95% success rate reported for laminectomy and diskectomy. For APLD. careful patient selection is essential. Candidates must have failed an adequate trial of conservative therapy (bed rest and limitation of activity) and have disk herniation documented by appropriate imaging studies. These studies are important because they can demonstrate not only the degree of herniation. but also whether it is contained within the annulus and if any free fragments are present. For herniated lumbar disks with nuclear material outside and contiguous with the annulus. a statistically significant consensus of DATTA panelists believed that APLD is an inappropriate procedure. Another study has shown that the procedure can be taught to other surgeons without compromising patient safety. and. as reported. this holds with large numbers of cases. In appropriately selected patients. the clinical trade-off of APLD appears to be between a procedure with a 75% success rate with low risk and rapid recovery vs one with a 95% success rate and a more prolonged recovery. A research question is whether APLD could be extended to patients who have undergone previous surgery whose disks reherniate after a successful laminectomy. Conversely. does an APLD procedure that fails to relieve symptoms complicate subsequent laminectomy? It is recognized that there is a need for prospective. controlled. randomized clinical trials comparing APLD with laminectomy to resolve these and other issues.
Elevation of ambulatory systolic blood pressure in hypertensive smokers. A case-control study, Although smoking raises blood pressure. the office blood pressure measurements of smokers are the same as. or lower than. those of nonsmokers. To resolve this paradox. we compared the office and 24-hour ambulatory blood pressures of 59 untreated hypertensive smokers with 118 nonsmoking hypertensives matched for age. sex. and race. The office blood pressures of the smoking and nonsmoking groups were 141/93 and 142/93 mm Hg. respectively. The awake ambulatory systolic blood pressure was significantly higher in the smokers (145 vs 140 mm Hg). This difference was greater among patients over the age of 50 years (153 vs 142 mmHg). and absent among patients under 50 years (140 vs 139 mm Hg). Blood pressures during sleep did not differ between the two groups (121/76 vs 123/77 mm Hg). We conclude that. among white hypertensives above the age of 50 years. smokers maintain a higher daytime ambulatory systolic blood pressure than nonsmokers even though blood pressure measured in the office is similar.
Anesthesia, cardiopulmonary bypass, and the pregnant patient, For the perioperative management of pregnant patients with severe cardiac or aortic disease who require a cardiac surgical procedure and cardiopulmonary bypass. a close. cohesive. working relationship must exist among several medical and surgical specialties. For appropriate management. the well-being of both the mother and the fetus must be considered. The best interests of the mother and the fetus may not coincide. and optimal therapy for one may be inappropriate for the other. We present 10 cases of severe cardiac or aortic disease in pregnant women who required surgical intervention. Eight patients underwent cardiopulmonary bypass during pregnancy. and two patients had cesarean section performed immediately before cardiopulmonary bypass. We also discuss the pertinent pharmacologic aspects related to the perioperative period and the management of cardiopulmonary bypass for the pregnant patient.
Functional myocardial impairment in children treated with anthracyclines for cancer, A non-invasive exercise method was used to look for myocardial damage in apparently normal children who had received moderate doses of anthracyclines for treatment of cancer. 19 children (mean [SD] age 10.6 [4.3] years) who had received anthracyclines (mean total dose 230 [119] mg/m2) and 10 who had received other cytotoxic drugs (mean age 13.3 [4.9] years) were selected from 263 children attending routine follow-up examinations. They underwent measurement of heart rate. blood pressure. and left ventricular dimensions by echocardiography before and after exercise on a bicycle for a maximum of 10 min. All 29 were in remission. All the subjects showed normal fractional shortening (FS = left ventricular end-diastolic minus end-systolic diameter as a percentage of the end-diastolic diameter) at rest. but the increase in FS on exercise was significantly lower in the children who had received anthracyclines than in those who had not (3 [16]% vs 23 [17]%; p less than 0.05). This difference remained significant after adjustment for age and drug exposure. However. there were no significant differences between the groups in the adjusted mean percentage changes on exercise in heart rate or systolic or diastolic blood pressure. Disease type had no effect on the cardiological indices. Thus. many children who have received anthracyclines may have suffered subclinical myocardial damage. Post-exercise echocardiography seems a useful non-invasive method for detecting such damage. Long-term cardiological follow-up of these patients is needed.
Oncogene expression in cervical intraepithelial neoplasia and invasive cancer of cervix, Expression of the oncogenes Ha-RAS. c-MYC. and ERB-2 was investigated with an automated image analysis system in 12 specimens of normal cervix. 10 of cervical intraepithelial neoplasia (CIN) grade 1. 24 of CIN 3. and 10 of invasive cancer of the cervix. There was amplification of all three oncogenes in CIN 3 and invasive cancer compared with normal cervix and CIN 1. The difference was most pronounced with an antibody to the RAS p21 protein. with no overlap between CIN 3 and the normal range. This method might be useful in screening for cervical neoplasia. and for the determination of which CIN lesions require treatment.
Next-day memory impairment with triazolam use, The prevalence. rate. and degree of memory impairment for next-day activities during a short. intermittent course of bedtime doses of triazolam. temazepam. and placebo were assessed in a double-blind parallel-group study. 5 of the 6 subjects in the triazolam group reported at least one episode of next-day memory impairment/amnesia. with a total of 12 episodes being reported for the 30 subject-drug nights (a rate of 40%). In the temazepam group there were no such episodes of memory impairment. Immediate and delayed recall were also tested and related to whether active drug or placebo had been taken the night before. Impairment of delayed recall was significantly and several times greater than that in the temazepam or placebo groups. Next-day memory impairment/amnesia after a bedtime dose of triazolam tended to increase with continued or intermittent drug use. Cognitive impairments associated with triazolam probably represent a spectrum of organic brain dysfunction. with memory impairment/amnesia and confusion being the commonest. and milder manifestations and hallucinations and delusions the more severe and less common. features.
Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting-enzyme inhibition [published erratum appears in Lancet 1991 May 11;337(8750):1174, Left ventricular dysfunction can be improved with angiotensin-converting-enzyme inhibition started 1 week after myocardial infarction or later. To see whether earlier intervention may confer greater benefit. a double-blind study was carried out in which 100 patients with Q wave myocardial infarction. but without clinical heart failure. were randomly allocated treatment with captopril 50 mg twice daily or placebo starting 24-48 h after onset of symptoms. Left ventricular volumes were measured regularly during 3 months of treatment and after a 48 h withdrawal period by means of two-dimensional echocardiography. The placebo group showed significant increases in left ventricular end-diastolic (LVEDVI) and end-systolic (LVESVI) volume indices. with the ejection fraction unchanged. By contrast. the captopril group showed a slight but not significant rise in LVEDVI and a significant reduction in LVESVI with ejection fraction increased significantly. At 3 months there was a 4.6% difference in the change in ejection fraction from baseline between the groups (p less than 0.0001). Most of the treatment benefit was evident at 1 month and there were no changes in left ventricular volumes after 48 h withdrawal of treatment at 3 months. Heart failure requiring treatment with frusemide developed in 7 patients in each group during the study period; 3 of these (1 captopril-treated. 2 placebo-treated) had to be withdrawn from the trial with severe heart failure requiring open treatment. Thus early treatment with captopril is effective in preventing the ventricular dilatation that can occur after Q wave myocardial infarction.
Thromboxane dominance and prostacyclin deficiency in habitual abortion, To evaluate the significance of vasoactive prostanoids in habitual abortion. we measured urinary excretion of prostacyclin metabolites (6-keto-PGF1 alpha and 2.3-dinor-6-keto-PGF1 alpha) and of thromboxane A2 metabolites (TxB2 and 2.3-dinor-TxB2) during 25 pregnancies in 22 women with recurrent spontaneous abortion (RSA). The control group were 16 pregnant women with no history of abortion. Ultrasound examination at first follow-up appointment showed a living fetus in 23 pregnancies of women with RSA. 9 of these pregnancies ended in abortion; 14 continued to term as did all the pregnancies in the control group. Compared with controls. women with RSA had a lower (p less than 0.05) ratio of prostacyclin to thromboxane between weeks 4 and 7 of gestation and a lower (p less than 0.01) output of 2.3-dinor-6-keto-PGF1 alpha between weeks 8 and 11. Women whose pregnancies ended in abortion had higher (p less than 0.05) output of 2.3-dinor-TxB2 between weeks 4 and 7 of gestation and lower (p less than 0.01) excretion of 2.3-dinor-6-keto-PGF1 alpha between weeks 8 and 11 compared with women whose pregnancies proceeded to term. We conclude that deficiency of vasodilatory prostacyclin may be a factor in habitual abortion.
Raised exercise diastolic blood pressure as indicator of ischaemic left ventricular dysfunction, 91 (16.8%) of 541 consecutive patients investigated for chest pain or after recent uncomplicated myocardial infarction had a rise in diastolic blood pressure (DBP) of more than 15 mm Hg during a symptom-limited treadmill test. 63 also had electrocardiographic evidence of ischaemia. but 28 did not have 1 mm ST segment depression. of whom 24 had angiographic evidence of more than 70% stenosis of two or more major coronary arteries. 55 of these 91 patients underwent coronary artery bypass surgery; repeat angiography in 22 at 12 months showed an improved left ventricular ejection fraction in 18 who had a normal postoperative DBP response. but no change in ejection fraction in the 4 who still had an abnormal rise in DBP on exercise. Exercise-induced ischaemia may cause a reversible fall in cardiac output that sometimes leads to reflex vasoconstriction and a rise in DBP before a fall in systolic blood pressure or ECG evidence of ST segment depression. An abnormal DBP response to exercise may identify some patients at high risk of myocardial infarction who might otherwise have false-negative exercise tests.
Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5, Gene targeting in mouse embryo-derived stem cells has been used to disrupt the homeobox gene hox-1.5. Mice heterozygous at the hox-1.5 locus appear normal. whereas hox-1.5-/hox-1.5- mice die at or shortly after birth. These homozygotes are athymic. aparathyroid. have reduced thyroid and submaxillary tissue and exhibit a wide range of throat abnormalities. In addition. they often feature defects of the heart and arteries as well as craniofacial abnormalities. These deficiencies are remarkably similar to the pathology of the human congenital disorder DiGeorge's syndrome.
Left neglect for near but not far space in man, It has been suggested that. among the many visual areas of the human brain. there might be one set of spatial maps specialized for 'near' (peripersonal) and another for 'far' (extrapersonal) space. A distinction between 'grasping distance' and 'walking distance'. or between a 'reaching field' and a pointing or throwing field has commonly been made. Evidence for such a division has been found in monkeys. Unilateral ablation of the frontal eye field (area 8) produces a more prominent inattention (or 'neglect') for objects in contralesional far space than in near space; by contrast. unilateral ablation of frontal area 6. which receives direct projections from area 7b (the rostral part of the inferior parietal lobules) results in inattention to visual stimuli limited to contralesional near space. Despite predictions that comparable dissociations should be found in man. there has been no convincing evidence. We report here such evidence in a patient with a unilateral right hemisphere stroke. Within peripersonal space. he showed severe left visuo-spatial neglect on conventional tests. including the highly sensitive task of line bisection. When line bisection was performed in extrapersonal space. neglect was abolished or attenuated.
Does prostaglandin confer significant advantage over oxytocin infusion for nulliparas with pre-labor rupture of membranes at term, Ninety-four nulliparous women with a poor cervical score (less than 6) who had premature rupture of membranes at term were randomized by sealed envelope into two groups. One group received immediate stimulation of labor with oxytocin infusion. The second group received two prostaglandin E2 (PGE2) 3-mg pessaries 4 hours apart. followed by oxytocin infusion. if necessary. The interval between initiation of therapy to onset of labor was significantly longer in the PG group. but the length of labor was similar in both groups. The maximum dose of oxytocin needed was significantly higher in the oxytocin group. The cesarean delivery rate in the oxytocin group was 14.9%. compared with 19.1% in the PG group (not significantly different). All seven cesareans in the oxytocin group and seven of nine in the PG group were for failed stimulation of labor. Neonatal Apgar scores at 1 and 5 minutes and admission to the neonatal intensive care unit were similar in the two groups. The incidence of maternal and neonatal infection was small and was not different in the two groups. The use of PGE2 3-mg pessaries 4 hours apart. followed by oxytocin infusion if necessary. did not confer any benefit over the use of intravenous oxytocin in obstetric or neonatal outcome when both agents were started a few hours after admission.
Epidural anesthesia, episiotomy, and obstetric laceration, The relationships among epidural anesthesia. forceps use. parity. episiotomy. and laceration were studied in 9493 uncomplicated vertex deliveries of spontaneous onset and normal course. The use of epidural anesthesia was not associated with an increased incidence or severity of birth-canal trauma. Episiotomy was associated with a decreased rate of perineal laceration. but an overall increase in the rate of perineal trauma. The trauma that did occur with episiotomies was four times more likely to be major than that when no episiotomy was performed.
The role of chorioamnionitis and prostaglandins in preterm labor, Spontaneous preterm labor remains a significant cause of high morbidity and mortality in the newborn. Chorioamnionitis with an associated rise in prostaglandins (PGs) is thought to be one of the factors responsible for the onset of preterm labor. In this study. 52 placentas and membranes from gestations of 35 weeks' or fewer were collected. Tissue samples of membranes and placentas were incubated in pseudoamniotic fluid. and the levels of PGs and leukotriene B4 were assayed. Swallowed amniotic fluid aspirated from the infants' stomachs was analyzed for PGs and examined microscopically for the presence of degenerate neutrophilic polymorphonuclear leukocytes (pus cells) and bacterial organisms. Prostaglandins E and F and leukotriene B4 production were significantly higher in the membranes and placentas with chorioamnionitis than in those without. Although the comparison of PG levels in the gastric fluid of infants with and without chorioamnionitis did not reach statistical significance. there was a trend toward higher levels of PGs with chorioamnionitis. Prostaglandin E levels from membranes and placentas and PGF from placentas were significantly elevated in the gastric fluid of infants with pus cells and organisms. These findings support the hypothesis that chorioamnionitis may initiate preterm labor.
The effect of magnesium sulfate on the biophysical profile of normal term fetuses, Forty term pregnant women with singleton breech gestations admitted for external cephalic version underwent biophysical profile testing before any fluid infusion or medication. After magnesium sulfate had been infused for contraction prophylaxis. the maternal serum magnesium level was measured and a second biophysical profile was performed. The mean (+/- SD) serum magnesium was 5.1 +/- 1.0 mg/dL. The biophysical profile score decreased significantly. reflecting a decrease in fetal breathing activity. In patients with therapeutic maternal serum magnesium levels. loss of any component of the biophysical profile other than respiration cannot be attributed to the elevation in magnesium concentration.
Placenta previa is not an independent risk factor for a small for gestational age infant, Previous studies have presented conflicting evidence on the association between intrauterine growth retardation (IUGR) and placenta previa. with some groups reporting rates of IUGR as high as 16-19%. However. most of these studies failed to include a control population. included patients with other factors known to be associated with IUGR (eg. chronic hypertension. fetal anomalies. pregnancy-induced hypertension. insulin-dependent diabetes mellitus. etc). and/or did not confirm the patient's estimated gestational age. During the study period of January 1. 1980 through June 30. 1990. 54.969 deliveries occurred at the three affiliated hospitals of the Maternal-Fetal Medicine Division of the University of Connecticut Health Center. Review of the delivery records revealed 179 singleton pregnancies with documented placenta previa and without the above exclusion factors. One hundred seventy-one of these 179 study patients were compared with 171 women without placenta previa matched for confirmed gestational age. race. parity. and fetal sex. The incidence of small for gestational age (SGA) infants was 4.1% (seven of 171) in the study group and 5.8% (ten of 171) in the control group. Mean birth weights were 2559 and 2476 g. respectively. Neither difference was statistically significant. These results suggest that the prenatal diagnosis of an SGA fetus in a pregnancy complicated by placenta previa should not simply be attributed to abnormal placental implantation. Furthermore. routine ultrasonic examinations for growth in pregnancies complicated by placenta previa are not indicated.
The postmenopausal adnexal mass: correlation between ultrasonic and pathologic findings, One hundred two postmenopausal women underwent ultrasonographic evaluation of adnexal masses before surgery. Twenty-nine (28%) had malignant tumors and 73 (72%) had benign tumors. Two of 33 patients with a "simple cyst" smaller than 5 cm in diameter by ultrasound had malignant ovarian tumors. Twenty-two of the 52 women (42%) with "complex masses" by ultrasound and five of the 17 (29%) with solid tumors had ovarian cancer. For predicting malignancy in ovarian tumors. abdominal ultrasonography had a positive predictive value of 39% and a negative predictive value of 94%. If a negative sonogram had been relied upon. 6% of malignant ovarian tumors in postmenopausal women might have been missed.
A double-blind, randomized trial of 0.5% podofilox and placebo for the treatment of genital warts in women, Patient-applied formulations of 0.5% podofilox (podophyllotoxin) were evaluated for the treatment of external genital warts in a double-blind. placebo-controlled study. Seventy-two women were enrolled and. using a randomized. computer-generated list. assigned to receive either active drug or placebo in a 2:1 ratio. Patients were instructed to apply the medication to their external warts twice each day for 3 consecutive days. followed by 4 days without treatment. This cycle was repeated at weekly intervals for a maximum of 4 weeks (and a minimum of 2 weeks). Patients were evaluated weekly for the first month and then at weeks 6 and 10. The number of warts present was recorded and the overall improvement was assessed. The treated area was examined. the patients were questioned about any adverse effects. and standard hematologic/biochemical studies were conducted. The final results showed that podofilox cleared 74% of the total wart count. compared with an 18% regression in the placebo group (P less than .001). The investigators' assessments of improvement correctly distinguished active drug from placebo at every observation point. Local untoward effects were minor and transient. There was no evidence of systemic effects. It is concluded that patient-applied podofilox is a safe and effective therapy for genital condylomata in women. When available. this drug will simplify the treatment of genital warts by providing a patient-applied alternative therapy.
Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases, In an ongoing clinical trial. 100 patients with an unruptured ectopic pregnancy of 3.5 cm or less in greatest dimension were treated with an outpatient protocol of methotrexate and citrovorum factor chemotherapy. Methotrexate and citrovorum were given on alternating days until the hCG titer had decreased by 15% on 2 consecutive days. The patients ranged in age from 16-40 years. gravidity from 1-8. and parity from 0-5. Twenty-three patients had a previous ectopic pregnancy. Of the 100 patients. 96 (96%) received methotrexate/citrovorum as primary therapy and four (4%) were treated for persistent hCG titers after a conservative surgical procedure. The tubal pregnancies of patient nos. 1-50 were confirmed by laparoscopy. whereas patient nos. 51-100 were diagnosed according to a nonlaparoscopic algorithm. Four patients of 100 failed medical therapy and required surgery. Of these. one had an ectopic pregnancy with cardiac activity. one ruptured after intercourse. and the remaining two cases had no specific identifiable risk factors. Of the ectopic pregnancies with cardiac activity. 80% were successfully treated. Five patients (5%) had methotrexate-related side effects. all after the fourth dose. but none required treatment for these side effects. Hysterosalpingograms done on 58 patients subsequently demonstrated tubal patency in 84.5% on the involved side. To date. 37 pregnancies have occurred in this group. of which 31 (89.2%) were intrauterine and four (10.8%) were recurrent ectopic pregnancies. We conclude that methotrexate/citrovorum is safe. effective. and helps to preserve reproductive performance when used as primary therapy for unruptured ectopic pregnancy and for treatment of persistent disease following a conservative surgical procedure.
Single-dose methotrexate for treatment of ectopic pregnancy, Methotrexate treatment of unruptured ectopic pregnancy is safe and effective and preserves reproductive potential. Previous protocols have required multiple methotrexate doses with or without citrovorum rescue. The purpose of this study was to determine whether patients with an unruptured ectopic pregnancy 3.5 cm or less in greatest dimension could be treated with single-dose intramuscular methotrexate (50 mg/m2) without citrovorum rescue. Thirty-one patients were eligible for this outpatient treatment protocol. One patient withdrew from follow-up. leaving 30 patients (96.8%) in the study group. Patients had a mean age of 28.5 years (range 18-37) and a mean gravidity of 3.0 (range 1-8); nine of 30 (30%) had previously undergone a salpingectomy for ectopic pregnancy. Pre-treatment hCG titers ranged from 130-16.700 mIU/mL (mean 4558). Pre-treatment transvaginal sonography visualized the ectopic in 28 of 30 patients (93.3%) and revealed cardiac activity in six patients. Patients were monitored with hCG titers three times per week for the first week. and then weekly until the hCG was less than 15 mIU/mL. A complete blood count and liver enzymes were obtained before treatment and on day 7. All patients had a continued rise in hCG titer for at least 3 days after methotrexate injection. although all levels began to decline by day 7. No patient required a second dose of methotrexate and no patient experienced any side effects. Twenty-nine of 30 patients (96.7%) were successfully treated. Six of 30 (20%) experienced an increase in lower abdominal pain between days 5-10. and two were hospitalized overnight for observation.
Ovarian cancer screening, For populations in which preventive measures have been applied for the more common causes of death. the early detection of ovarian cancer becomes the next focus of efforts to reduce premature death among women. Data regarding the effectiveness of ultrasonography in detecting early-stage ovarian cancer are reviewed. Ultrasonography is more sensitive than pelvic examination in detecting ovarian abnormalities but lacks specificity in distinguishing benign from malignant ovarian lesions. Combined with serum CA 125 levels. ultrasonography may provide an effective screening tool. although cost-effectiveness has not been demonstrated and its effectiveness in reducing mortality from ovarian cancer has not been completely evaluated. Guidelines are presented for the use of ultrasonography in evaluating the postmenopausal ovary.
Detection of macrosomia by the individual fetal growth curve assessment method, The value of the Rossavik growth model [P = c(t)k + s(t)] was evaluated in 39 patients with singleton pregnancy who had neonatal weight outcome above the 90th percentile of our birth weight distribution for gestational age. Individual fetal growth curve standards for head and abdominal circumferences. femur diaphysis length. and weight were determined from the data of two scans obtained before 26.1 weeks' gestation and separated by an interval of at least 5 weeks. Projected crown-heel lengths were calculated from projected femur diaphysis length values. Comparisons between actual and predicted birth characteristics were expressed by the Growth Potential Realization Index (GPRI) and Neonatal Growth Assessment Score (NGAS). Excessive growth at birth was seen in almost all cases as indicated by high GPRI for weight and abdominal circumference and abnormal NGAS values. In eight of the 33 patients who delivered after 38 weeks. excessive growth was detected only by comparing birth characteristics to their predicted values at 38 weeks' gestation. Our data suggest that individual growth curve standards may identify several patterns of excessive fetal growth that could represent different pathophysiologic mechanisms. ie. failure to terminate growth after 38 weeks versus a defect in a still unknown growth regulator. The individual fetal growth curve standards method gives additional information and discriminates well between normal and excessive fetal growth.
Percutaneous transvesical chorionic villus sampling: an alternative approach to the retroverted uterus, In 458 consecutive chorionic villus sampling (CVS) procedures. we observed a significant influence of uterine position upon sampling efficacy. Compared with anteverted (N = 243) or axial (N = 149) locations. the retroverted uterus (N = 66) was associated with a lower mean sample weight per aspiration (22. 18. and 15 mg. respectively; P less than .01) and a greater frequency of multiple-pass procedures (23. 31. and 52%. respectively; P less than .0001). To improve sampling efficiency in selected cases of uterine retroversion. we adopted a transvesical approach. When compared with transabdominal or transcervical techniques. transvesical CVS had the highest single-pass success rate (33. 33. and 60%. respectively). Only one in 30 transvesical cases required three placental passes. compared with nine of 36 retroverted uteri sampled by either transabdominal or transcervical techniques (P less than .05). The mean transvesical sample weight was 18.7 mg; at least 10 mg was retrieved in all cases. Post-procedure bleeding occurred in four instances and an additional patient suffered a spontaneous loss at 16 weeks' gestation. Aneuploidy was found in four of 30 biopsy specimens. and the remaining pregnancies either have delivered at term (N = 18) or are continuing (N = 7). Our preliminary experience suggests that selected use of this CVS method may improve sampling efficiency without increasing the incidence of complications.
Surgical treatment of overcorrection following radial keratotomy: evaluation of clinical effectiveness, Secondary hyperopia following radial keratotomy (RK) may result from an initial overcorrection or from a continued effect of the procedure with time. We retrospectively evaluated the effect of surgical intervention for the management of overcorrection following RK in six patients who had undergone reopening of all RK incisions. followed by irrigation and closure of the incisions with 10-0 mersilene sutures. Three patients with prior 4-incision RK. with follow-up of 4 to 26 months. were steepened a mean of 1.63 diopters keratometrically; three patients with prior 8-incision RK. with follow-up of 3 to 12 months. were steepened a mean of 1.46 D keratometrically. Comparison of intraoperative with postoperative keratometry demonstrated a substantial loss of effect with time. which stabilized by 2 months in 4-incision RK patients and by 3 months in 8-incision RK patients. Nevertheless. placement of interrupted sutures across reopened radial incisions consistently induced central corneal steepening in these six patients.
Posterior chamber IOL implantation with suboptimal posterior capsular support, A posterior chamber intraocular lens (PC/IOL) was implanted in 24 patients with suboptimal posterior capsular support due to preoperative or intraoperative rupture of the posterior capsule or zonules in which at least six clock hours of peripheral zonular support remained. The PC/IOLs were implanted. with ciliary sulcus haptic placement. with special attention to sulcus fixation of the haptics over the zone of residual zonular support. All of the IOLs have remained centered after a mean follow-up 10.5 months. We conclude that a PC/IOL can be successfully implanted and its position maintained if at least six clock hours of peripheral zonules remain.
Atonic pupil: an unusual complication of cataract surgery, Eight cases of atonic pupil. an unusual complication following cataract surgery. are presented. Six of the eyes involved had intracapsular cataract extraction and anterior chamber intraocular lens implantation; one case underwent extracapsular cataract extraction with a posterior chamber intraocular lens implantation; the other had an extracapsular procedure with no implant. The etiology is unknown. but we believe the most likely one is that the sodium hyaluronate used in all these patients caused a temporary reduction of the iris blood supply by mechanical factors or by a vasoconstriction induced by some toxicity of the material that produced a lesion on the iris sphincter.
Early postoperative prognostic indicators following trabeculectomy, We compared prognostic indicators manifesting within the first 2 postoperative days. with filtration status 3 months following trabeculectomy in 51 primary open-angle glaucoma patients. Patients with an avascular area in the filtering bleb 2 days after surgery had a significantly lower (P less than .05) intraocular pressure (IOP) (12.6 mm Hg) 3 months postoperatively than patients with vascular blebs (16.3 mm Hg). However. neither the height. breadth. or transparency of the filtering bleb. presence of microcysts. anterior chamber depth. nor IOP during the first 2 postoperative days were related significantly to the filtration status at 3 months.
Argon laser trabeculoplasty medical therapy to prevent the intraocular pressure rise associated with argon laser trabeculoplasty, A prospective. randomized. investigator-masked. parallel study compared the capability of five different intraocular pressure (IOP) lowering agents to prevent acute IOP elevations following argon laser trabeculoplasty. Two hundred sixty eyes (patients) received either apraclonidine 1% (125 eyes). pilocarpine hydrochloride 4% (37 eyes). timolol maleate 0.5% (35 eyes). dipivefrin 0.1% (32 eyes). or acetazolamide 250 mg (31 eyes) both 1 hour before and immediately following 360-degree argon laser trabeculoplasty. Apraclonidine was the only medication that significantly decreased mean IOP from baseline. Only 4 (3%) of the apraclonidine-treated eyes had IOP rises greater than 5 mm Hg. This frequency was significantly lower than that found in eyes treated with acetazolamide (39%). dipivefrin (38%). pilocarpine (33%). or timolol (32%).
Surface-wrinkling maculopathy as a potential complication of trabeculectomy: a case report, We report a case of "crinkled cellophane maculopathy" which developed during the first few days following an uneventful trabeculectomy in a high myopic patient with primary open-angle glaucoma. We suggest pathogenic mechanisms that may have induced such premacular lesions. emphasizing the patient's high myopia combined with a postoperative inflammatory reaction.
The effect of aminoguanidine on the blood-retinal barrier in streptozocin-induced diabetic rats, The effect of aminoguanidine hydrochloride (AG) on the blood-retinal barrier was studied in rats with streptozocin-induced diabetes. Half of the rats were given AG (100 mg/kg/day) while the remainder received no treatment. Vitreous fluorophotometry was performed on all rats before STZ injection and 2 weeks after induction of diabetes mellitus. Two weeks after STZ injection the mean 60-minute vitreous fluorescein concentration following dye injection had increased more in the nontreated group than in the AG-treated group. suggesting that AG may have some beneficial effect on the breakdown of the blood-retinal barrier.
Orbital volume augmentation with adjustable prefabricated methylmethacrylate subperiosteal implants, Prefabricated right and left subperiosteal implants were used in nine anophthalmic sockets to correct superior sulcus deformities. The advantages of these implants include increased stability. easy insertion under direct visualization and the possibility of easy retrieval if necessary. and custom modification for volume and shape intraoperatively. with the addition of methylmethacrylate. There were no extrusions. implant migrations. or infections. Complications included mild undercorrection. upper eyelid blepharoptosis. and transient ectropion.
Blood supply of nerve roots and dorsal root ganglia, The number of patients who suffer from radicular symptoms due to degenerative diseases of the lumbar spine is increasing. This article discusses the differences in anatomic structure between spinal nerve roots and peripheral nerves. Blood supply and cerebrospinal fluid flow are explained. and the effect of mechanical compression. direct and indirect. is shown as a possible cause of symptoms.
Neurogenic and nonneurogenic pain and inflammatory mediators, Pain is not a simple perception. Although millions of people suffer because of it and billions of dollars are spent trying to eradicate it. we are only in our infancy of understanding the very complex interactions necessary to perceive or distort our feelings of pain. We must continue to seek a better understanding of not only our patients' macroscopic impression of pain. but we must look microscopically at each cell involved in the whole of the pain process. A time will come when our molecular understanding will provide us with the means to unlock the secrets of pain. We have come a long way since the time of Descartes in our understanding of the neurophysiology and anatomy of pain. but we have a great deal more work to do if we are going to provide our patients with better remedies in the future.
Industrial back pain complaints. A broader perspective, Industry has looked to medicine for assistance in developing screening and prevention programs to reduce the problem of industrial back injuries. Unfortunately. little is known about the pathology underlying most back symptoms. and few risk factors for industrial back pain complaints have been clearly and consistently identified. These limitations in knowledge have placed obvious constraints on the design of effective intervention programs. Recent information on the importance of perceptions of the nonphysical work environment and other psychosocial factors provide a broader perspective of the industrial back pain problems that may lead to more enlightened and effective approaches.
Magnetic resonance imaging in the evaluation of low back pain, Many observers believe that magnetic resonance has become the procedure of choice for lumbar spine imaging. This article includes discussions of technique. normal anatomy. degenerative disc disease. and the use of paramagnetic contrast agents. Numerous figures are provided to illustrate explanations.
Current status of percutaneous discectomy and chemonucleolysis, This article provides an updated review of chemonucleolysis and percutaneous discectomy. Dr. Herkowitz recommends discontinuing the use of chymopapain. Percutaneous discectomy may play a small role in the invasive management of a lumbar disc herniation.
Nonfunctional mutants of the retinoblastoma protein are characterized by defects in phosphorylation, viral oncoprotein association, and nuclear tethering, We have examined the functional consequences of mutations present in defective alleles of the retinoblastoma susceptibility gene (RB1) isolated from two spontaneously arising tumors. Unlike cDNA clones expressing the wild-type protein p110Rb. those encoding the two mutant proteins failed to induce the appearance of senescent cells in transfected Saos-2 human osteosarcoma cells. The mutant proteins were also defective in binding to the E1A oncoprotein. were unable to become hyperphosphorylated. and failed to become tightly associated with nuclear structures. We conclude that mutations in two distinct regions of the protein concomitantly affect these four aspects of p110Rb function.
Expression of a soluble and functional form of the human beta 2 integrin CD11b/CD18, Polymorphonuclear cells and monocytes (phagocytes) are a critical component of host defense against infections. However. these cells also play a significant role in host tissue damage in many noninfectious diseases. such as ischemia-reperfusion injury syndromes and rejection of transplanted organs. The leukocyte adhesion molecule family CD11/CD18 (beta 2 integrins) is critical to the function of polymorphonuclear cells and monocytes in inflammation and injury. Inherited deficiency of CD11/CD18 impairs phagocyte chemotaxis. adhesion and transmigration across endothelium. and clearance of invading microorganisms through phagocytosis and cell-mediated killing. Furthermore. murine monoclonal antibodies directed against the CD11b/CD18 (CR3) heterodimer have been shown to reduce. by 50%-80%. phagocyte-mediated ischemia-reperfusion injury in several organ systems. such as the myocardium. liver. and gastrointestinal tract and to inhibit development of insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice. Expression of CD11b/CD18 in a soluble and functional form might therefore be potentially useful as an anti-inflammatory agent. We have now expressed a recombinant soluble heterodimeric form of this human beta 2 integrin. normally expressed as two noncovalently associated membrane-bound subunits. The secreted receptor exhibited direct and specific binding to its ligand. iC3b. the major complement C3 opsonin. and inhibited binding of polymorphonuclear cells to recombinant interleukin 1-activated endothelium.
Negative regulation of the major histocompatibility complex class I promoter in embryonal carcinoma cells, Transcription of major histocompatibility complex (MHC) class I genes is negatively regulated in undifferentiated F9 mouse embryonal carcinoma cells via the conserved upstream regulatory region. This region contains constitutive enhancers and an inducible enhancer. the interferon consensus sequence (ICS). that is responsible for interferon-induced transcription. A series of mutations in the ICS. but not in the enhancer elements. resulted in an increase in expression of the MHC class I promoter in F9 cells. However. these ICS mutants did not increase promoter activity in F9 cells differentiated after retinoic acid treatment. Results of mobility-shift DNA-binding assays and methylation interference experiments showed that undifferentiated F9 cells contained a factor(s) that bound to a sequence within the 5' and central part of the ICS. This binding site. termed the MHC negative regulatory element (NRE). coincided with the site of mutations that increased promoter activity in F9 cells and was distinct from the element to which interferon-response factors bind. The factor(s) that binds to the MHC NRE was not detected in differentiated F9 cells treated with retinoic acid or in other cells expressing MHC class I genes. Finally. introduction of concatenated. double-stranded NRE oligomers. but not oligomers of unrelated sequences. into F9 cells abolished negative regulation of the MHC class I promoter activity. providing evidence that the NRE binding factor is responsible for repression of the MHC class I genes in F9 cells.
Sequestrin, a CD36 recognition protein on Plasmodium falciparum malaria-infected erythrocytes identified by anti-idiotype antibodies, The CD36 molecule expressed by human endothelial cells is a receptor for the adhesion of erythrocytes infected with the human malaria parasite Plasmodium falciparum. A CD36-specific monoclonal antibody. OKM8. inhibits the adhesion of malaria-infected erythrocytes (IRBC) to purified CD36 and cells expressing CD36. Monospecific polyclonal anti-idiotype (anti-Id) antibodies. raised against monoclonal antibody OKM8. expressed determinants molecularly mimicking the CD36 binding domain for the adhesion of IRBC. Purified rabbit anti-Id antibodies reacted with the surface of IRBC by immunofluorescence. directly supported the adhesion of wild-type P. falciparum malaria isolates. and inhibited IRBC cytoadherence to melanoma cells. An approximately 270-kDa protein was immunoprecipitated by the anti-Id antibodies from surface-labeled and metabolically labeled IRBC and was competitively inhibited by soluble CD36. These results support the hypothesis that CD36 is a receptor and the approximately 270-kDa protein. sequestrin. is a complementary ligand involved in the adhesion of IRBC to host-cell endothelium. Sequestrin is a candidate malaria vaccine antigen. and anti-Id antibodies that recognize this molecule may be useful for passive immunotherapy of cerebral and severe P. falciparum malaria.
Transplantation of wheat germ agglutinin-positive hematopoietic cells to prevent or induce systemic autoimmune disease, Hematopoietic stem cell defects are thought to be involved in the etiopathogenesis of systemic autoimmune disease. Positively selected. stem cell-enriched populations of wheat germ agglutinin-positive (WGA+) low-density bone marrow and fetal liver cells from normal and autoimmune-prone mice were used to determine whether reciprocal transplantation of stem cells between normal and autoimmune-prone mice inhibits or causes development of autoimmune disease. NZB recipients of DBA/2 stem cell populations analyzed greater than 100 days after bone marrow or fetal liver cell transplantation showed decreased levels of anti-DNA antibodies and decreased glomerular lesions when compared with nontreated NZB mice or NZB recipients of NZB stem cell preparations. Female DBA/2 recipients of WGA+ NZB bone marrow cell or fetal liver cell transplants exhibited elevated serum autoantibody levels and developed glomerular lesions characteristic of NZB mice when analyzed greater than 100 days after transplantation. These pathological disturbances were not observed in DBA/2 recipients of DBA/2 stem cell preparations. The data indicate that WGA+ stem cells from autoimmune-prone NZB mice contain the genetic defects responsible for the development of systemic autoimmune disease.
Production of site-selected neutralizing human monoclonal antibodies against the third variable domain of the human immunodeficiency virus type 1 envelope glycoprotein, Cell lines secreting IgG1 human monoclonal antibodies (mAb) to the envelope glycoprotein. gp120. of human immunodeficiency virus (HIV) have been produced by transformation of peripheral blood cells from HIV-infected individuals and by fusion of transformed cells to a human-mouse heteromyeloma cell line (SHM-D33). Two human mAbs were site-selected by means of a 23-mer synthetic peptide spanning a portion of the third variable domain of gp120 from the MN strain of HIV. The two heterohybridomas produce three times more IgG than do their parent lymphoblastoid cell lines. The specificities of these mAbs have been mapped to sequences near the tip of the disulfide loop of the gp120 third variable domain. Lys-Arg-Ile-His-Ile and His-Ile-Gly-Pro-Gly-Arg. respectively. The mAbs have dissociation constants of 3.7 x 10(-6) M and 8.3 x 10(-7) M. neutralize HIVMN in vitro at nanogram levels. and bear the characteristics of antibodies associated with protective immunity in vivo.
Tissue distribution of the dystrophin-related gene product and expression in the mdx and dy mouse, We have previously reported a dystrophin-related locus (DMDL for Duchenne muscular dystrophy-like) on human chromosome 6 that maps close to the dy mutation on mouse chromosome 10. Here we show that this gene is expressed in a wide range of tissues at varying levels. The transcript is particularly abundant in several human fetal tissues. including heart. placenta. and intestine. Studies with antisera raised against a DMDL fusion protein identify a 400.000 Mr protein in all mouse tissues tested. including those of mdx and dy mice. Unlike the dystrophin gene. the DMDL gene transcript is not differentially spliced at the 3' end in either fetal muscle or brain.
Patterns of gene expression that characterize the colonic mucosa in patients at genetic risk for colonic cancer, We have used a computer-driven scanning and image-processing system to identify a panel of 30 cDNA clones whose pattern of expression in individual biopsy specimens distinguishes the flat. normal-appearing colonic mucosa of patients in two genetic groups at high risk for development of colorectal cancer from that of normal colonic mucosa in low-risk individuals. The two high-risk groups. familial adenomatous polyposis and hereditary nonpolyposis colon cancer. are indistinguishable based on the pattern of expression of the 30 selected clones. This suggests that the extensive pleiotropic effects of the inherited loci. which may play an important role in the mechanism of increased risk and early onset of the disease. are similar in these populations.
Class II-restricted presentation of an endogenously derived immunodominant T-cell determinant of hen egg lysozyme, An in vitro model was used to investigate the potential for different structural forms of endogenous antigen to be processed and presented by major histocompatibility complex class II molecules. For this purpose the class II-restricted presentation of an immunodominant epitope of hen egg lysozyme [HEL-(46-61)] was studied in class II-positive B-lymphoma cells (M12.C3) transfected with genes encoding HEL molecules either (i) secreted in high (hi) or low (lo) amounts as soluble antigen [sHEL(hi/lo)]. (ii) localized within the endoplasmic reticulum (ER)/salvage compartment (ER-HEL). or (iii) anchored on the cell surface as an integral membrane protein (mHEL). The corresponding sHEL. ER-HEL. and mHEL gene products were expressed as predicted except that HEL determinants accumulated in the culture supernatant as well as on the cell membrane of mHEL-transfected cells. Class II-positive cells endogenously expressing all three forms of HEL antigen constitutively presented the immunodominant HEL-(46-61) determinant with differential efficiency (mHEL. sHEL greater than ERHEL) to a class II-restricted T hybridoma. A second T hybridoma recognized endogenous HEL-(46-61) determinants constitutively presented on sHEL(hi) and mHEL transfectants but not on sHEL(lo) or ERHEL transfectants. The formation of HEL-(46-61)/I-Ak complexes in the ERHEL and sHEL(lo) transfectants was therefore limiting. Mixing experiments with different antigen-presenting cells indicated that the HEL-(46-61) determinant was derived from endogenous antigen rather than by reuptake of shed or secreted HEL determinants. We conclude that MHC class II molecules can present some antigenic determinants derived from endogenous proteins that are sequestered in the ER/salvage compartment as well as distally transported in the form of secretory or membrane antigens.
Oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control, Mammalian ribosomal protein (rp) mRNAs are subject to translational control. as illustrated by their selective release from polyribosomes in growth-arrested cells and their underrepresentation in polysomes in normally growing cells. In the present experiments. we have examined whether the translational control of rp mRNAs is attributable to the distinctive features of their 5' untranslated region. in particular to the oligopyrimidine tract adjacent to the cap structure. Murine lymphosarcoma cells were transfected with chimeric genes consisting of selected regions of rp mRNA fused to non-rp mRNA segments. and the translational efficiency of the resulting chimeric mRNAs was assessed in cells that either were growing normally or were growth-arrested by glucocorticoid treatment. We observed that translational control of rpL32 mRNA was abolished when its 5' untranslated region was replaced by that of beta-actin. At the same time. human growth hormone (hGH) mRNA acquired the typical behavior of rp mRNAs when it was preceded by the first 61 nucleotides of rpL30 mRNA or the first 29 nucleotides of rpS16 mRNA. Moreover. the translational control of rpS16-hGH mRNA was abolished by the substitution of purines into the pyrimidine tract or by shortening it from eight to six residues with a concomitant cytidine----uridine change at the 5' terminus. These results indicate that the 5'-terminal pyrimidine tract plays a critical role in the translational control mechanism. Possible factors that might interact with this translational cis regulatory element are discussed.
Molecular cloning of PC3, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization, PC3 is an immediate early gene induced by nerve growth factor in PC12 cells. a cell line derived from a tumor of the adrenal medulla that undergoes neuronal differentiation in the presence of nerve growth factor. This induction is independent of new protein synthesis as it can occur in the presence of cycloheximide. PC3 is also induced with similar kinetics. but at lower levels. by membrane depolarization (both in vivo and in vitro) and epidermal growth factor. It is induced at much lower levels by fibroblast growth factor and interleukin 6. In vivo it is found expressed in tissues. such as brain at embryonic day 13.5. placenta. amnion. and spleen. which are proliferating and/or differentiating. The deduced protein sequence from the cDNA indicates the presence of a signal peptide. suggesting that PC3 is secreted.
Anti-tumor activities of immunotoxins made of monoclonal antibody B3 and various forms of Pseudomonas exotoxin [published erratum appears in Proc Natl Acad Sci U S A 1991 Jun 1;88(11):5066, B3 is a monoclonal antibody that reacts with a carbohydrate epitope present on a variety of proteins located on the surface of many cancer cells and a limited number of normal tissues. We evaluated the cytotoxic activity of immunotoxins composed of monoclonal antibody B3 coupled to native Pseudomonas exotoxin (PE) or two recombinant forms of Pseudomonas exotoxin. PEArg57 or LysPE40. a form of PE with a deletion of the cell binding domain. All three conjugates were cytotoxic to human cell lines expressing the B3 antigen on their surface. The survival of each of the three immunotoxins in the circulation of mice was determined after administering the immunotoxin i.v. The half-life in blood of B3-PE and B3-PEArg57 was 20 hr. whereas the half-life of B3-LysPE40 was 4 hr. The short half-life of B3-LysPE40 may be due to the absence of domain I of PE. To determine the therapeutic effects of the three immunotoxins. they were given intraperitoneally to nude mice bearing subcutaneous A431 tumors. All three immunotoxins caused complete regression of 50-mm3 tumors with no toxic effects to the animals at therapeutic doses. Furthermore. substantial regression was also noted with much larger tumors. Our data indicate that the monoclonal antibody B3. when coupled to PE or recombinant forms of PE. may be useful for the treatment of tumors expressing B3 antigen. The therapeutic window was largest with B3-LysPE40. which can be administered in higher doses because it lacks sequences in domain I of PE that enable PE to bind to nontarget cells.
Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer disease, Immediate post-training intracerebroventricular administration of a synthetic peptide homologous to beta protein of brain amyloid. [Gln11]beta-(1-28). caused amnesia for footshock active avoidance training in mice in a dose-dependent fashion. This effect was specific to memory processing since the peptide did not cause amnesia when injected 24 hr after training nor did it disturb storage or retrieval of older memories. Shorter fragments of the amyloid beta protein consisting of residues 12-28. 18-28. and 12-20 also were amnestic when given intracerebroventricularly. residues 12-20 being least effective. The hippocampus. a brain structure importantly involved in learning and memory. consistently shows severe pathological changes and deposition of amyloid in patients with Alzheimer disease. Immediate post-training bilateral intrahippocampal injection of [Gln11]beta-(1-28) produced amnesia at much lower doses than did [Gln11]beta-(1-28) injected intracerebroventricularly. Thus these experimental results suggest a possible direct role of amyloid beta protein or fragments thereof in an aspect of the spectrum of cognitive deficit in Alzheimer disease.
Human response against NP-4, a mouse antibody to carcinoembryonic antigen: human anti-idiotype antibodies mimic an epitope on the tumor antigen, Anti-idiotype antibodies (Ab2) were purified from a cancer patient treated with NP-4. a murine monoclonal antibody to carcinoembryonic antigen (CEA). These Ab2 were specific for NP-4 and inhibited the binding between NP-4 and CEA. BALB/c mice immunized with these human Ab2 produced anti-Ab2 antibodies that were also reactive with the CEA epitope recognized by NP-4. These results indicate that human Ab2 to NP-4 can antigenically mimic the CEA epitope recognized by NP-4.
High expression of the DNA methyltransferase gene characterizes human neoplastic cells and progression stages of colon cancer, DNA methylation abnormalities occur consistently in human neoplasia including widespread hypomethylation and more recently recognized local increases in DNA methylation that hold potential for gene inactivation events. To study this imbalance further. we have cloned and localized to chromosome 19 a portion of the human DNA methyltransferase gene that codes for the enzyme catalyzing DNA methylation. Expression of this gene is low in normal human cells. significantly increased (30- to 50-fold by PCR analysis) in virally transformed cells. and strikingly elevated in human cancer cells (several hundredfold). In comparison to colon mucosa from patients without neoplasia. median levels of DNA methyltransferase transcripts are 15-fold increased in histologically normal mucosa from patients with cancers or the benign polyps that can precede cancers. 60-fold increased in the premalignant polyps. and greater than 200-fold increased in the cancers. Thus. increases in DNA methyltransferase gene expression precede development of colonic neoplasia and continue during progression of colonic neoplasms. These increases may play a role in the genetic instability of cancer and mark early events in cell transformation.
Induction of transforming growth factor beta 1 resistance by the E1A oncogene requires binding to a specific set of cellular proteins, Transforming growth factors beta (TGF-beta s) are potent inhibitors of epithelial cell growth in culture and might play a similar role in vivo. Several studies have suggested that acquisition of TGF-beta resistance is an important step in epithelial tumor development. Here. we show that resistance to TGF-beta 1 growth inhibition can be induced by transformation of keratinocytes with the E1A. but not the ras. oncogene. Mutational analysis revealed that these effects closely correlate with the ability of E1A proteins to bind to the retinoblastoma gene product (p105) as well as to three other cellular proteins (p60. p107. and p300). Only partial resistance to TGF-beta 1 growth inhibition was elicited by E1A mutants that bind to a subset of proteins. whereas complete resistance was induced by E1A mutants that bind to all four proteins together. Total protection against TGF-beta growth inhibition was also induced by concomitant introduction into cells of an E1A mutant binding to the p60/p105/p107 proteins and one binding to p300. In parallel with these effects. epidermal transglutaminase. a marker of keratinocyte differentiation. was induced by TGF-beta in control but not in E1A-transformed cells. TGF-beta 1 receptor levels were only partially down-modulated by an intact E1A gene and not significantly affected by the various truncated mutants. Thus. the ability of E1A to induce TGF-beta resistance depends on its ability to bind. and presumably inactivate. several cellular proteins that may be involved in transmission of the TGF-beta signal and seem to act downstream from its receptor(s).
Hepatic iron overload: quantitative MR imaging, Iron deposits demonstrate characteristically shortened T2 relaxation times. Several previously published studies reported poor correlation between the in vivo hepatic 1/T2 measurements made by means of midfield magnetic resonance (MR) units and the hepatic iron content of iron-overloaded patients. In this study. the authors assessed the use of in vivo 1/T2 measurements obtained by means of MR imaging at 0.5 T using short echo times (13.4 and 30 msec) and single-echo-sequences as well as computed tomographic (CT) attenuation as a measure of liver iron concentration in 10 severely iron-overloaded patients with beta-thalassemia major. The iron concentrations in surgical wedge biopsy samples of the liver. which varied between 3 and 9 mg/g of wet weight (normal. less than or equal to 0.5 mg/g). correlated well (r = .93. P less than or equal to .0001) with the preoperative in vivo hepatic 1/T2 measurements. The CT attenuation did not correlate with liver iron concentration. Quantitative MR imaging is a readily available noninvasive method for the assessment of hepatic iron concentration in iron-overloaded patients. reducing the need for needle biopsies of the liver.
Dynamic gadolinium-enhanced rapid acquisition spin-echo MR imaging of the liver, Rapid acquisition spin-echo (RASE) magnetic resonance (MR) imaging allows for coverage of the entire liver with highly T1-weighted SE images during a single 23-second breath-holding period. The RASE sequence was implemented in conjunction with rapid intravenous injection of gadopentetate dimeglumine to enable performance of dynamic contrast material-enhanced MR imaging of the liver. Prospective evaluation of 24 patients with 62 liver lesions 1 cm or greater in diameter was performed. Images obtained with RASE were devoid of respiratory-related ghost artifacts or edge blurring. The dynamic contrast-enhanced RASE technique resulted in contrast-to-noise and contrast-to-artifact values and time efficiency measures significantly greater (P less than .05) than those obtained with use of conventional T1- and T2-weighted pulse sequences. indicating a higher likelihood for lesion detectability. Lesion conspicuity was maximal during or immediately following bolus administration of gadopentetate dimeglumine. with lesions often becoming obscured at delayed postcontrast imaging.
Radiologic features of closed loop obstruction: analysis of 25 confirmed cases, The obstruction of a segment of bowel at two points results in a closed loop obstruction. Progression to strangulation is not an invariable component of this entity when surgical intervention is delayed. Enteroclysis is increasingly being used to evaluate obstruction of the small intestine. The authors retrospectively analyzed 25 surgically confirmed cases of closed loop obstruction and noted four enteroclysis features suggestive of the diagnosis: (a) crossing defects obstructing two segments of a loop of bowel secondary to dense adhesive bands (14 patients). (b) focal fixation of two limbs or twisting of the folds at the point of obstruction suggestive of volvulus (three patients). (c) abdominal wall herniation with obstruction (six patients). and (d) focal intraperitoneal segregation of a loop of bowel with tight obstruction suggestive of internal herniation (two patients). Recognition of the different patterns allows prompt preoperative radiologic diagnosis prior to strangulation.
Renal tolerance for ioxaglate in patients with chronic renal failure [published erratum appears in Radiology 1991 Jul;180(1):291], The authors sought to evaluate renal tolerance for ioxaglate sodium meglumine used as a contrast agent in patients with chronic renal failure. Eight male patients (mean age. 55 years +/- 5) with chronic renal insufficiency (glomerular filtration rate less than 60 mL/min) who underwent diagnostic cardiac catheterization were enrolled. Renal clearance of inulin and rho-aminohippuric acid and urinary enzyme excretion were studied 1 day before and 1 day after administration of 167 mL +/- 43 of ioxaglate. None of the patients experienced any adverse reactions. All the patients had markedly depressed renal clearance values before angiography. Mean serum creatinine level. glomerular filtration rate. effective renal plasma flow. and urinary beta 2-microglobulin excretion were unaltered by angiography. After the procedure. only one patient had an increase in serum creatinine level of more than 10% (from 115 to 159 mumol/L [1.3 to 1.8 mg/dL]). with a decrease in glomerular filtration rate from 34 to 27 mL/min. In this patient. serum creatinine level and glomerular filtration rate normalized within 72 hours. Using accurate and sensitive renal function tests. the authors have shown that ioxaglate may be used safely in patients with chronic renal failure.
Benign and malignant adrenal masses: CT distinction with attenuation coefficients, size, and observer analysis, In a retrospective study of adrenal masses evaluated with computed tomography (CT). lesion x-ray attenuation was compared with size and radiologists' interpretations in discriminating benign lesions from malignant ones. Unenhanced CT attenuation coefficient and size were analyzed electronically in 55 patients with 66 adrenal masses. There were 38 nonhyperfunctioning adenomas in 33 patients and 28 malignant masses in 22 patients. Primary extraadrenal malignancies were present in 45 of the 55 patients. Three blinded readers characterized the adrenal masses using a seven-point scale of certainty. Results were subjected to receiver operating characteristic (ROC) analysis. The mean CT attenuation coefficient for benign adrenal masses was -2.2 HU +/- 16.0 and was significantly different from the mean for malignant lesions (28.9 HU +/- 10.6). The area under the ROC curve for CT attenuation coefficients (0.91 +/- 0.04) was significantly larger than that for lesion size (0.84 +/- 0.05) or best observer interpretation (0.84 +/- 0.05). A threshold CT attenuation value of 0 HU had a sensitivity-to-specificity ratio of 47%:100% for characterizing benign adrenal masses. whereas a threshold attenuation of 10 HU had a ratio of 79%:96%.
Acute renal failure: possible role of duplex Doppler US in distinction between acute prerenal failure and acute tubular necrosis, Ultrasonography (US) of the native kidneys is commonly requested for acute renal failure (ARF). although in most cases the examination results are negative. To detect changes in the Doppler waveform associated with ARF and determine whether Doppler US can provide significant diagnostic information not available with standard US. 91 patients with ARF were studied to determine a mean resistive index (RI) for each patient. Forty-six patients had acute tubular necrosis (ATN) with a mean RI +/- 1 standard deviation of .85 +/- .06. which was significantly higher than the mean RI of .67 +/- .09 in 30 patients with prerenal ARF (P less than .01). Fifteen patients had ARF due to non-ATN intrinsic renal disease (mean RI. .74 +/- .13). An elevated RI (greater than or equal to .75) occurred in 91% of patients with ATN versus only 20% of patients with prerenal azotemia. Patients with severe liver disease (hepatorenal syndrome) are a subset of those with prerenal ARF that accounted for most of the elevated RIs in this group. The study demonstrates that intrarenal Doppler US allows detection of changes associated with ARF far more often than standard US. More important. Doppler US may be helpful in distinguishing ATN from prerenal azotemia.
True hermaphroditism: sonographic demonstration of ovotestes, A 15-year-old boy with normal external genitalia presented with severe bilateral gynecomastia. intermittent painful scrotal swelling. and a recent history of scrotal trauma. Ultrasound (US) revealed testicles of normal size with diffusely heterogeneous echotexture due to scattered cysts. Ovotestes were found at surgery and pathologic examination. Bilateral partial gonadectomies were performed. Four months later he had testicular pain and swelling. US revealed bilateral multiseptate cystic masses. After repeat surgery. he is now free of symptoms. The diagnosis of true hermaphroditism and ovotestis should be considered in a phenotypic male adolescent with gynecomastia when testicular parenchyma is heterogeneous at US because of multiple scattered cysts.
Abnormal testicular function: potential of P-31 MR spectroscopy in diagnosis, Phosphorus-31 MR spectroscopy of the human testis was performed on healthy volunteers (n = 17) and oligospermic (n = 7) and azoospermic patients (n = 4). All patients in the latter group had the Sertoli-cell-only syndrome. Determination of the ratios of phosphomonoesters (PMs) to adenosine triphosphate (ATP). phosphodiesters (PDs) to ATP. and inorganic phosphate (Pi) to ATP made it possible to discriminate among these three groups. The testicular PM/ATP ratio was 1.71 +/- 0.03 (mean +/- standard deviation) in the healthy volunteers and dropped to 1.41 +/- 0.06 (P less than .001 in comparison with healthy volunteers) in the oligospermic patients and to 1.22 +/- 0.07 (P less than .001) in the azoospermic patients. The testicular PD/ATP ratio did show a slight increase from 0.52 +/- 0.10 in healthy volunteers to 0.68 +/- 0.09 (not significant) for oligospermic patients and to 0.83 +/- 0.10 (P less than .01) for azoospermic patients. The Pi/ATP ratio did not show significant differences between healthy volunteers (0.12 +/- 0.07) and oligospermic patients (0.23 +/- 0.08) but was elevated in the azoospermic patients (0.79 +/- 0.12) (P less than .001).
Arterial stent placement with use of the Wallstent: midterm results of clinical experience, Self-expandable stents of the Wallstent type were used in 26 iliac and 15 femoropopliteal artery lesions of 31 patients to treat stenoses or occlusions. The indications were confined to complex lesions. including residual stenoses and dissections after percutaneous procedures or previous surgery in the iliac artery lesions. and long-segment (mean. 13.5 cm) occlusions with inadequate response to percutaneous recanalization in the femoropopliteal artery lesions. In the iliac artery group. after stent placement. 96% of the lesions were patent at a mean follow-up of 16 months (range. 6-30 months). In the femoropopliteal artery group. of 11 patients available for follow-up. only six had patent stents at 7-26 months (mean. 20 months). Four of these six patients required one to three secondary interventions. Self-expanding endoprostheses are of great value in complex iliac artery lesions where simple balloon dilation is insufficient. Stent placement for long femoral artery lesions should be performed with utmost reserve. and the extent of stent placement should be as short as possible.
Periodic mammographic follow-up of probably benign lesions: results in 3,184 consecutive cases, The author prospectively evaluated the value of periodic mammographic surveillance among 3.184 consecutive cases of nonpalpable. probably benign breast lesions detected with mammography. Follow-up consisted of four mammographic examinations during a 3- or 3.5-year period. Clinical outcome was ascertained in each case after the study period. whether or not patients complied with the protocol. Probably benign lesions were subsequently found to be malignant in 17 cases (positive predictive value for cancer. 0.5%). Fifteen of the 17 cancers were identified by means of interval mammographic change prior to development of a palpable mass; all 17 were stage 0 or stage 1 tumors. All 17 women who had cancer currently show no evidence of tumor recurrence (median duration of follow-up. 5 years). These results should help establish the validity of managing mammographically detected. probably benign lesions with periodic mammographic surveillance. By decreasing the number of biopsies of benign lesions and thereby substantially reducing costs. this approach may help overcome a major barrier to widespread use of mammographic screening.
Bronchiolitis obliterans after lung transplantation: findings at chest radiography and high-resolution CT. The Toronto Lung Transplant Group, Although bronchiolitis obliterans (BO) is seen commonly after heart-lung transplantation. its occurrence after lung transplantation appears to be relatively infrequent. In the 55 single- and double-lung transplantations performed at Toronto General Hospital. 41 patients have survived longer than 3 months and four (10%) have developed pathologically proved BO. Chest radiographic findings in these four patients included slight to moderate decreased peripheral vascular markings (n = 3). slight to moderate volume loss (n = 2). subsegmental atelectasis (n = 2). and new. thin. linear. irregular areas of increased opacity (n = 2). High-resolution computed tomography (HRCT) demonstrated mild peripheral bronchiectasis (n = 4) and decreased peripheral vascular markings (n = 3). Although the radiographic and HRCT findings did not appear to be specific for posttransplantation BO. they may be of value in suggesting the diagnosis of BO within this patient population.
Midgut volvulus in infants: diagnosis with US. Work in progress, The authors present findings from ultrasound (US) studies that can alert sonologists to the possibility of midgut malrotation complicated by volvulus in neonates and infants. A fluid-filled. distended duodenum seen at US examination in infants is a nonspecific sign of duodenal obstruction. as well as one of the signs of midgut malrotation. In addition. dilated. thick-walled bowel loops. mainly to the right of the spine. and peritoneal fluid were found at abdominal US examinations of three infants with midgut malrotation complicated by volvulus. In one infant with uncomplicated midgut malrotation. only signs of duodenal obstruction were present. The findings at US of duodenal obstruction associated with thickened bowel loops to the right of the spine and peritoneal fluid should lead the sonologist to suspect midgut malrotation complicated by volvulus. a potentially fatal condition. and an upper gastrointestinal series should then be performed to confirm the diagnosis.
Chondromyxoid fibroma: radiographic appearance in 38 cases and in a review of the literature [published erratum appears in Radiology 1991 Aug;180(2):586, Thirty-eight cases of histologically confirmed chondromyxoid fibroma were reviewed and their radiographic features recorded. These findings. coupled with a review of the English-language medical literature. suggest that this rare. benign bone tumor has a characteristic but not specific radiographic appearance and may often mimic more common tumors. Chondromyxoid fibroma may occur anywhere in the skeleton. but almost half of the cases occur around the knee. The possibility of chondromyxoid fibroma should always be considered when a focal bone lesion is evaluated that has geographic bone destruction. a sclerotic rim. lobulated margins. and septation. The diagnosis of chondromyxoid fibroma is most likely when the patient is in the 2nd decade of life.
Apparent avascular necrosis of the hip: appearance and spontaneous resolution of MR findings in renal allograft recipients, The sensitivity of magnetic resonance (MR) imaging in the detection of avascular necrosis (AVN) of the hip and natural history of the MR findings were determined prospectively in renal allograft recipients. a group at risk for development of the disease. One hundred four patients were studied up to 24 months after transplantation. In 25 hips in 14 patients. MR findings were consistent with AVN. Pain developed in seven hips in four patients; in each hip. the MR images showed abnormality before the onset of symptoms. Plain radiographs showed abnormality in all hips that became painful; however. the plain radiographs of 17 of 18 asymptomatic hips in which MR imaging showed evidence of AVN showed no abnormality over a mean follow-up period of 16 months. All MR lesions in the symptomatic hips were larger than those in the asymptomatic cohort. MR lesions in seven hips (in five asymptomatic patients) regressed in size; in six hips. the MR images returned to normal. The findings suggest that some patients with MR evidence of AVN of the hip have spontaneous improvement.
Bone marrow: ultrasmall superparamagnetic iron oxide for MR imaging, An ultrasmall superparamagnetic iron oxide (USPIO) preparation was evaluated as a potential intravenous contrast agent for magnetic resonance (MR) imaging of bone marrow. One hour after administration of USPIO (40. 80. and 160 mumols of iron per kilogram body weight) in rats and rabbits. T1 and T2 relaxation times were. respectively. approximately 30%. 50%. and 65% lower than precontrast relaxation times. Maximum decrease in relaxation times of marrow occurred within 1-24 hours after intravenous administration; thereafter. relaxation times slowly returned to normal within 7 days. In vivo MR imaging of rabbits and rats confirmed that USPIO decreases signal intensity of red and yellow marrow. The decrease was most marked with gradient echo pulse sequences. An animal model of intramedullary tumor demonstrated the potential of USPIO to enable differentiation between tumor and normal red marrow. USPIO-enhanced MR imaging improves detection of smaller tumors and allows differentiation of tumor deposits from islands of hyperplastic or normal red marrow.
Optic neuritis and orbital lesions: lipid-suppressed chemical shift MR imaging, A derivative of the Dixon method. chopper fat suppression. was used in the magnetic resonance imaging evaluation of 40 patients: 37 with suspected optic nerve lesions. predominantly optic neuritis. and three with orbital lesions. In patients with optic neuritis. the technique was sensitive. allowing detection of 29 of 34 visual-evoked-response-confirmed lesions on T2-weighted lipid-suppressed images. There were no false-positive studies. Sensitivity for detection of optic neuritis was 89%; specificity. 100%; and accuracy. 86%. The technique was also useful for depicting inflammatory changes in the orbital apex due to fungal abscess and confirming the fatty nature of an extraconal dermoid tumor. A slight increase in noise and mild accentuation of susceptibility effects at interfaces of air. bone. and brain did not degrade images significantly. The chopper-based technique requires only standard imaging time and has usual spin-echo sensitivity. The results are comparable to short-inversion-time inversion-recovery imaging. without the constraints of sequence limitations or artifacts at fat and water interfaces.
Postoperative lumbar spine: contrast-enhanced chemical shift MR imaging, A modified fat-suppression pulse sequence (consisting of combined frequency-selective fat presaturation followed by a spin-echo acquisition when fat and water magnetization vectors have opposite phase) was used to optimize the conspicuity of intravenous enhancement by gadopentetate dimeglumine on magnetic resonance images in 10 patients previously operated on for lumbar discogenic disease as well as in two patients with herniated disks who had not previously undergone surgery. This technique produced the greatest degree of fat suppression in the phantom study. In six of the patients who had previously undergone surgery. epidural enhancement was more obvious on the fat-suppressed images than on conventional spin-echo images. while in four patients. enhancement was equivalent. The herniated disks in two patients not previously operated on were not enhanced with either technique. Contrast enhancement was universally distinguishable from fat signal and from nonenhancing water-containing tissue on the fat-suppressed images obtained after contrast material administration. This technique may reduce the need for precontrast imaging. Furthermore. postoperative enhancement of nerve roots was more obvious on fat-suppressed images in seven of eight patients. This finding might represent previously undiagnosed degrees of arachnoidal inflammation. which may be a factor in the failed back syndrome.
Equivalent total doses for different fractionation schemes, based on the linear quadratic model, A majority of patients receiving radical radiation therapy are treated with 1.8-2.0-Gy fractions. a dose that has evolved from clinical experience. However. other fractionation schemes can be advantageous. When fractionation is altered. the total dose prescribed should lead to equivalent or higher tumor control with the same or less tissue toxicity. To facilitate the use of different fractionation schemes. the authors compiled tables for equivalent biologic doses for late toxicity in normal tissues and tumoricidal doses for epithelial tumors. for various fraction sizes. The linear quadratic model according to Fowler was used. It is shown how these tables should be modified for proliferation of tumors during the course of radiation therapy. The tables make the use of different fractionation schemes easy. They also allow adjustment of total dose if fractionation needs to be changed during the course of treatment.
Meckel cave lesions: percutaneous fine-needle-aspiration biopsy cytology, The authors describe the novel combination of two traditional methods to facilitate diagnosis of Meckel cave lesions. which may otherwise require craniotomy to obtain adequate tissue samples. Fine-needle-aspiration biopsy cytology was performed on tissue obtained with a percutaneous approach via the foramen ovale with use of fluoroscopic guidance and intravenous analgesia during an outpatient procedure. This new application of fine-needle-aspiration biopsy cytology results in decreased patient morbidity and significant cost reduction.
Contrast venography in patients with very edematous feet: use of transdermal illumination to aid in vein puncture, Contrast venography can be technically difficult or impossible in patients with very edematous feet. The authors report a simple technique that uses transdermal illumination of the edematous subcutaneous tissue to enable visualization of a vein and also guide the needle into the vein. This technique has been used successfully in eight patients in whom conventional attempts at vein puncture had failed.
Immunogenicity of low-dose intradermal recombinant DNA hepatitis B vaccine, Low-dose intradermal vaccination with plasma-derived hepatitis B vaccine has been shown to give high rates of seroconversion at greatly reduced vaccine cost. We report a study comparing two groups given lower doses (1.0 or 1.5 microgram) of recombinant-derived vaccine intradermally with a control group given the standard intramuscular dose. Of the 132 randomized medical students and hospital employees. 95 completed the study. Rates of seroconversion and peak antibody titers were comparable. though antibody rose more slowly and fell somewhat faster in the intradermal groups. Increasing the intradermal dose did not improve response. Most intradermal vaccinees (80%) developed small (average 2 to 3 mm) areas of local induration. which faded slowly. Low-dose intradermal vaccination with recombinant hepatitis B vaccine results in high rates of seroconversion (greater than 90% in each protocol) at a cost that will allow individual practitioners and program with limited budgets to offer vaccination.
Effects of prednisone on human immunodeficiency virus infection, Prednisone is used to treat a number of complications of the human immunodeficiency virus (HIV) infection. but there is little information about the immunologic consequences of such therapy. We gave prednisone to six boys with hemophilia who were infected with HIV in order to study its effects on their clinical status. serum immunoglobulins. lymphocyte populations. and serum HIV antigen concentrations. Most patients had clinical improvement while taking prednisone; platelet counts increased in five. weight increased in four. and adenopathy abated in two patients during the study. Serum IgG concentrations declined in all patients. but there were no significant changes in serum IgA or IgM concentrations. There was no consistent or significant change in the number of percentage of CD3. CD4. CD8. or CD19 lymphocytes. HIV antigen was present in the serum of one patient. and its concentration did not change during the study. None of the patients became HIV antigen seropositive during the study. These results indicate that prednisone administration was associated with clinical improvement without deleterious immunologic effects when given to children with HIV infection.
Pregnancy outcome in patients with repeat visits to the labor observation area near term, Patients whose pregnancies are near term and who repeatedly visit the labor observation area but are found not to be in labor and have no clear diagnosis for their complaints remain a source of concern for the obstetrician. In order to determine whether this is a population with special perinatal risks. such cases were reviewed over a 4-month period at Charity Hospital in New Orleans. Seventy-one patients were identified who had repeatedly visited the labor observation area near term. Compared with those in the general obstetrics population. these patients had a significantly increased risk of cesarean section for "failure to progress." Repeat visitors to the labor observation area should be viewed as having a high risk for later abnormalities of active labor. Careful management of labor abnormalities in such patients could theoretically lower their need for cesarean section.
Differences in black and white infant birth weights: the role of maternal demographic factors and medical complications of pregnancy, In a retrospective study of 18.631 deliveries among women of low income. we examined the association of racial disparities in mean birth weight with population differences in maternal demographic characteristics and antepartum-intrapartum medical complications. The study population consisted of inborn. nonreferred. singleton. low-income patients delivered on the nonprivate service after at least five prenatal care visits. Repeat cesarean sections were not included. The mean birth weight for black infants was 214 g less than that for white infants. Black and white mothers differed significantly in marital status. age. and years of education. Black and white mothers also differed significantly in the incidence of chronic hypertension. preeclampsia-eclampsia. anemia. amnionitis. fever on admission. and sexually transmitted diseases. In this population. controlling for maternal demographic characteristics and medical complications of pregnancy produced a predicted mean birth weight for black infants that was 100 g less than that for white infants (53% of the observed racial difference in mean birth weight).
Panic disorder among patients with chronic fatigue, Among 200 adults with a chief complaint of chronic fatigue evaluated in an internal medicine practice. currently active panic disorder was diagnosed in 26 patients (13%). a frequency tenfold greater than that in the general population. Panic disorder preceded or was coincidental with the onset of chronic fatigue in 21 of these patients. In comparison with the rest of the study cohort. significantly more patients with panic disorder had a history of severe depression. including persistent thoughts of death or suicide. Moreover. more patients with panic disorder showed a lifetime tendency to have physical symptoms that remained unexplained after medical evaluation. Our findings suggest that treatable panic disorder is an important contributor not only to major depression and somatization. but also to the etiology and clinical presentation of chronic fatigue in patients in an outpatient practice.
Arsenic exposures in Mississippi: a review of cases, Arsenic poisonings occur in Mississippi despite public education campaigns to prevent poisonings in the home. We reviewed 44 Mississippi cases of arsenic exposures occurring from January 1986 to May 1990. We compared the epidemiologic differences between unintentional and intentional poisonings. Cases were found and characterized through the two toxicology laboratories and hospital records. Arsenic-based rodenticides were the arsenic source in 23 of the 44 exposures. Other sources were monosodium methylarsenate (4 cases). dodecyl ammonium methane arsonate (5 cases). and other compounds (12 cases). Of the 44 exposures. 27 were unintentional. 7 were suicide attempts. 6 were homicide attempts. and 4 were of unknown intent. Of the 27 unintentionally exposed patients. 19 were black and 14 were male; their median age was 3 years. Of the 13 intentionally poisoned persons. 9 were male and 10 were black. with a median age of 28 years. Six of the seven patients who attempted suicide were white; four of the six victims of attempted homicide were black. We recommend removal of remaining bottles of arsenic-based rodenticides from store shelves. and we urge practicing physicians to warn patients of the dangers of using such rodenticides.
Endoscopic palliative management of rectal cancer, Laser ablation and bipolar coagulation have been used to palliate rectal cancer and avoid surgery. Indications are distal metastatic disease. extensive local invasion. obstruction and bleeding from nonresectable rectal tumor. or refusal of surgery. From Jan 1. 1986. to Jan 1. 1989. I saw 26 patients who met those criteria; 19 already had metastatic disease and three repeatedly refused abdominoperineal resection. A two-laser approach using both CO2 and Nd:YAG lasers was used in patients with low-lying lesions; others were treated by the Nd:YAG laser only. For rectal tumors. bipolar esophageal tumor probes were used via the rigid sigmoidoscope. The number of laser sessions averaged three per patient. and the number of bipolar coagulation sessions averaged five per patient. Bleeding followed bipolar coagulation in one patient. There were no perforations in either treatment group. and no patient has required colostomy. Of the 19 patients who already had metastatic disease. 12 are still alive. the longest survival being 20 months. Of those medically unfit for surgery. three have died of coincidental disease. and one is alive with controlled rectal cancer after 16 months. All three patients who refused surgery are alive; the longest survival is 13 months.
Identification and treatment of retinopathy of prematurity: an update and review, The risk of retinopathy of prematurity (ROP) is higher in infants with a birth weight less than 1501 g (3 lb 5 oz). Identification programs coupled with refined treatment procedures can reduce visual impairment in infants with ROP. Physicians providing in-hospital care to these infants should ensure that ophthalmologic referral has been established before hospital discharge. Physicians examining these infants for their 6-week checkups are also vital safeguards in the ROP screening and referral process.
Maternal cocaine abuse and fetal anomalies: evidence for teratogenic effects of cocaine, We have reported the case of an infant exposed prenatally to cocaine who had congenital anomalies. adding to the growing evidence suggesting cocaine's potential for teratogenicity. The infant. born at 36 weeks' gestation. had bilateral asymmetric upper limb amputation defects. The mother had moderate to severe uterine bleeding during the second trimester of pregnancy after she used intravenous cocaine. We hypothesize that the infant's anomalies are due to cocaine embryopathy. which resulted in amnion rupture or vascular disruption. We believe that cocaine embryopathy should be considered in the differential diagnosis of infants with congenital anomalies such as limb amputation defects.
Combined use of nifedipine and diltiazem for the treatment of severe hypertension, Calcium channel blockers are a heterogeneous group of drugs that have enhanced our ability to concurrently control blood pressure. treat coronary artery disease. and avoid many of the side effects of previously available antihypertensive agents. Patients with severe hypertension may require multiple agents for adequate control of blood pressure because of either poor control with one agent or side effects from high doses of a single agent. Laboratory investigations have shown a synergistic effect on receptor binding. as well as increased drug levels with the concurrent use of diltiazem and a dihydropyridine calcium channel blocker (nifedipine or nicardipine). It is as yet unknown whether these effects on receptor binding and increased drug levels translate into greater clinical efficacy in blood pressure control. We have reported what we believe to be the first case in which this interaction was used successfully to control previously poorly controlled hypertension. while minimizing side effects.
Primary angiosarcoma of the brain, We have described a 32-year-old black woman who had a primary angiosarcoma of the right occipital lobe. All three previously reported cases have been fatal within 1 year. Our patient is doing well more than 3 1/2 years after surgery.
Pott's disease of the cervical spine, Tuberculosis of the cervical spine is relatively rare. and the diagnosis is often delayed. Roentgenograms and computerized tomography of the cervical spine can provide important diagnostic clues. Chemotherapy is the mainstay of treatment. but when neurologic deficits are present the best treatment is debridement and anterior spinal fusion combined with antituberculous chemotherapy. The incidence of tuberculosis is increasing in parallel with the growing numbers of immunocompromised patients. Awareness of the manifestations of cervical Pott's disease may lead to earlier diagnosis and treatment of affected patients.
Posttraumatic stress disorder in burn patients, Posttraumatic stress disorder can occur in burn patients and may delay a patient's recovery. We have described the case of such a patient whose posthospital course was complicated by an untreated. coexisting PTSD.
Pregnancy after Fontan repair of tricuspid atresia, We have described a patient who had a cyanotic congenital heart disease (type Ib tricuspid atresia). with initial palliation accomplished in childhood via a Glenn procedure. In 1985. she had a Fontan repair with the Bjork modification; 3 years later she achieved her first pregnancy at age 27. Maternal Doppler echocardiography in early pregnancy showed good flow through the constructed conduit. with normal left ventricular size and function. Fetal echocardiography at 22 weeks' gestation via two-dimensional. M-mode. pulsed Doppler. and color flow mapping revealed no evidence of fetal cardiac disease. At 25 weeks' gestation recalcitrant preterm labor developed. and the infant was delivered spontaneously. Labor. delivery. and puerperium were uncomplicated. and the newborn (though too premature to survive) was of appropriate weight for gestational age. without evidence of congenital heart disease or other anomalies. We believe this is the first report of pregnancy and spontaneous delivery in a patient who has had Fontan repair of a congenital heart defect.
Exercise response in 404 young men with asthma: no evidence for a late asthmatic reaction, As the existence of a late reaction in exercise induced asthma is controversial. peak expiratory flow (PEF) was measured for up to 13 hours after a running test in 404 consecutive young male army conscripts undergoing assessment of their asthma. In 294 subjects (73%) the immediate post-exercise fall in PEF was 10% or more; the mean (SD) fall in PEF in this group was 27% (15%). Nine patients with exercise induced asthma had a fall in PEF of 20% or more 4-13 hours after the exercise test. In these possible "late responders." however. the change in PEF 4-13 hours after exercise was similar to the change in PEF on control days before and after the exercise day. and the lowest PEF during this period was similar to the lowest measurements on the control days. These nine subjects showed pre-exercise bronchodilatation. Their pre-exercise PEF. from which the percentage fall in PEF was calculated. was 24% (9%) higher than the mean PEF level on control days. This study supports the view that what appears to be a "late asthmatic reaction" after exercise is an artefact. Spontaneous within day fluctuation in pulmonary function. pre-exercise bronchodilatation. and the fact that airflow obstruction persists after the early postexercise response may give a false impression of an exercise induced late asthmatic response in patients with labile airways.
Prescribed fenoterol and death from asthma in New Zealand, 1981-7: a further case-control study, The association between inhaled fenoterol and death from asthma has been investigated further by studying 112 asthma deaths (cases) during 1981-7 in patients aged 5-45 years who had been admitted to a major hospital for asthma during the 12 months before death. Two age matched control groups were chosen. Control group A comprised 427 patients who had been admitted to hospital for asthma during the calendar year that the corresponding death occurred and who had also had a previous admission for asthma in the previous 12 months. Control group B comprised 448 patients admitted to hospital for asthma during the calendar year in which the admission of the corresponding case occurred. The inhaled fenoterol odds ratio was 2.11 (95% confidence interval (CI) 1.37-3.23. p less than 0.01) when group A was used as the control (the approach used in previous studies). and 2.66 (95% CI 1.74-4.06. p less than 0.01) with group B as the control (the approach recommended by critics of previous studies). Markers of chronic asthma severity were associated with asthma death when control group B was used. but not when control group A was used (which indicates that these markers were indirectly matched for when control group A was used). Information was also collected on various markers of acute asthma severity and prescription of psychotropic drugs. but it was found that these were not important confounders. These findings address the major criticisms of previous case-control studies of this issue. and add support to the hypothesis that inhaled fenoterol increases the risk of death in patients with severe asthma.
Cystic fibrosis. 4. Abnormalities of airway epithelial function and the implications of the discovery of the cystic fibrosis gene, Details of ion transporting abnormalities in cystic fibrosis airway epithelium are now known. The central hypothesis. that excessive drying of the airway surfaces is a primary event that leads to all the manifestations of the respiratory insufficiency in cystic fibrosis. is not proved. The hypothesis is. however. consistent with the known transporting abnormalities and is strengthened by the modest clinical improvement produced by a strategy designed to correct the transporting abnormalities. The discovery of the cystic fibrosis gene. together with the presumed structure of the protein product. provides a focal point that must eventually connect the functional abnormalities with the genetic defect. The cellular function of the cystic fibrosis transmembrane regulator must now be the major target in research on cystic fibrosis. Strategies for treatment based on known cellular and molecular abnormalities are beginning to emerge but will be undoubtedly more focused once the responsibility of the cystic fibrosis transmembrane regulator is known.
A video system for investigating breathing disorders during sleep, A system has been developed for investigating breathing during sleep that superimposes physiological signals on a video image of the patient. with the combined image plus sound recorded on video tape for later analysis. Signals normally displayed include oxygen saturation. airflow. chest wall motion. electroencephalogram. and electrooculogram; but others can be recorded if desired. The information is displayed on a timebase appropriate for the recognition and analysis of respiratory events during sleep. In addition. use is made of normally invisible video lines to record the analogue voltage waveforms so that on replay this information can be displayed on a fast timebase for analysing the more rapidly changing waveforms of electrophysiological signals. The system allows detailed polysomnography to be performed in the normal ward setting with the subject monitored overnight by the nursing staff. Subsequent analysis of the synchronised video. audio. and analogue signals allows measurement of the conventional indices obtained by polysomnography and aids their interpretation.
Iron lung: bronchoscopic and pathological consequences of aspiration of ferrous sulphate, Acute bronchial damage was caused by aspiration of a ferrous sulphate tablet. early histological changes (unlike in the few previously reported cases) being observed in the biopsy specimens.
Therapeutic dilemmas in management of cystine calculi, The appropriate management of patients with cystine calculi necessitates a fundamental understanding of the pathophysiology of cystinuria and a working knowledge of the available therapeutic modalities. The following case reports and review of the literature serve to illustrate that successful treatment involves a multidimensional approach to eradication of calculi with long-term follow-up aimed at prevention.
Urinary excretion of oxalate by patients with renal hypercalciuric stone disease. Effect of chronic treatment with hydrochlorothiazide, Hydrochlorothiazide is employed to reduce calcium excretion in patients with urinary stone disease secondary to renal leak hypercalciuria. Because the drug also has been reported to be a competitive inhibitor of oxalate excretion by the renal tubules. we sought to determine whether chronic use indeed affected the amount of oxalate excreted. Patients taking hydrochlorothiazide 50 mg daily did not have a statistically significant reduction in twenty-four-hour urinary oxalate on their customary diets (pretreatment 37 +/- 3 mg/day [mean +/- S.E.M.; N = 22]; at one year 36 +/- 3 mg/day [N = 22]; at two years 37 +/- 3 mg/day [N = 16]). In 12 patients who voluntarily collected twelve-hour urine specimens after dinner on the third day of a low-oxalate diet and again the next day after a 1 g oxalate load. hydrochlorothiazide had no significant effect on oxalate excretion (19 +/- 2.3 mmol oxalate/mol creatinine on hydrochlorothiazide versus 20.6 +/- 2.6 mmol off the drug after low oxalate meal; 50 +/- 7.8 mmol/mol creatinine on hydrochlorothiazide versus 56.2 +/- 7.5 mmol off the drug after an oxalate load). As expected. there was a significant reduction in urinary calcium excretion and thus of calcium oxalate urinary saturation during hydrochlorothiazide administration. Hydrochlorothiazide by itself is not sufficient to reduce oxalate excretion in patients with renal leak hypercalciuria.
Continuous systemic 5-fluorouracil infusion in refractory prostatic cancer, Twenty patients with metastatic prostatic cancer were treated on an ambulatory basis with continuous 5-fluorouracil (5-FU) infusion 250-300 mg/M2 per day through a chronic indwelling central venous catheter. All patients had symptomatic. progressive disease despite previous standard therapies. Partial remission was seen in 2 of 20 patients (10%). stable disease in 9 of 20 (45%). and progressive disease in 9 of 20 (45%); mean duration of benefit in responding and stable disease patients was six months. Improvement in pain and ECOG performance status were seen in most of the patients in the responding and stable disease categories. Forty percent of the patients experienced no significant drug toxicity; treatment interruption was necessary for stomatitis in 6 patients (30%). hand/foot syndrome in 3 patients (15%). and diarrhea in 1 patient (5%). No significant myelosuppression or other significant organ toxicities were encountered. Continuous systemic venous infusion of 5-FU may provide significant palliative effect for some patients with symptomatic. refractory carcinoma of the prostate.
Transvenous occlusion of clinical and subclinical varicoceles, Forty-four subfertile men with a palpable or clinically suspected varicocele underwent physical examination. nuclear scan. and testicular venography. The ability of these tests to detect a varicocele was compared. The sensitivity of physical examination was 0.94 on the left and 0.35 on the right. Specificity was 0.22 on the left and 0.77 on the right. The sensitivity of nuclear scan was 0.97 on the left and 0.73 on the right. Specificity was 0.56 on the left and 0.50 on the right. Patients with varicoceles demonstrated by venography were treated with testicular vein embolization. There were no complications except two asymptomatic subintimal injections. both of which occurred on the right side. A total of 19 patients had pre- and post-embolization semen analyses performed. The total motile sperm count increased from 27.0 million to 35.5 million. The overall pregnancy rate in the embolization-treated group was 43.7 percent.
Fine-needle aspiration cytology of xanthogranulomatous pyelonephritis, Fine-needle aspiration cytology of xanthogranulomatous pyelonephritis in a fifty-seven-year-old Japanese woman is reported. Foamy cells and cells showing a gland-like pattern originating from degenerative renal tubules were found in the aspirated smears. Multinucleated giant cells and cells with pale yellowish cytoplasm were seen in the imprint smears at operation. These findings were diagnostic for xanthogranulomatous pyelonephritis. The cytologic diagnostic differences among xanthogranulomatous pyelonephritis. well-differentiated renal cell carcinoma. and renal oncocytoma are also described.
Adrenal cortical carcinoma: flow cytometric study of 22 cases, an ECOG study, Flow cytometric studies of archival material from 22 adrenal carcinomas demonstrated aneuploidy in 21 of 22 cases. Heterogeneity of nuclear DNA was found in 14 of the 22 cases. Eight of these showed distinct aneuploid and diploid populations. and 6 showed multiple aneuploid cell lines. The heterogeneity was detected because numerous paraffin-embedded samples of each tumor could be examined. No correlation was found between either aneuploidy or heterogeneous DNA content and patient survival. response to therapy. or hormone secretion.
Human papillomavirus segregation patterns in genital and nongenital warts in prepubertal children and adults, This study compared the segregation patterns of human papillomavirus (HPV) in genital and nongenital warts in prepubertal children and adults. HPV 2 was detected in most nongenital warts in children and adults. whereas neither HPV 6 or 11 was detected at nongenital sites in either group with the use of in situ or Southern blot hybridization analyses. Of nine genital tract lesions in children. HPV 2 was detected in two and HPV 6 or 11 in six. More than 90% of cases of regional tract condylomata in adults contained HPV 6 or 11. HPV 2 was not detected in any of 99 genital tract lesions in adults. It is concluded that HPV 6/11 cannot proliferate at nongenital cutaneous sites and HPV 2 can proliferate in the genital tract of children but not adults. Thus. the detection of HPV 6 or 11 in a genital wart in a child implies. assuming cutaneous transmission. infection from a genital site. whereas the detection of HPV 2 presumes nongenital transmission.
Laboratory correlates and prognostic significance of granular acute lymphoblastic leukemia in children. A Pediatric Oncology Group study, As part of a comprehensive prospective clinicopathologic study by the Pediatric Oncology Group (POG). 2.092 children with acute lymphoblastic leukemia (ALL) were evaluated by uniform morphologic. cytochemical. and immunologic methods to assess the frequency and implications of granular lymphoblasts. All cases were Sudan black or myeloperoxidase negative and met French-American-British (FAB) morphologic criteria for ALL. Granular ALL. characterized by the presence of more than 5% marrow blasts with at least three clearly defined azurophilic cytoplasmic granules. was identified in 56 of the 1.252 fully studied cases (4.5%). The frequency of granular features did not differ among early pre-B (4.3%). pre-B (3.6%). and T (5.8%) ALL; no cases were identified among the 12 patients with B ALL. Within the early pre-B/pre-B group. granular ALL was equally distributed between good- and poor-risk clinical groups but was more frequent among FAB L2 than FAB L1 cases (12% vs. 2%; P less than or equal to 0.001). Patients were treated with standard POG protocols for early pre-B/pre-B and T ALL. Complete remission (CR) rates were significantly lower for those with granular lymphoblasts. regardless of risk group. immunophenotype. or FAB type. Analysis of event-free survival (EFS) showed a significantly poorer outcome for granular early pre-B/pre-B cases with FAB L2 morphologic characteristics (P less than 0.001) and for those classified as poor risk (P = 0.015). These findings suggest a relationship between granules and L2 morphologic characteristics in childhood ALL and indicate that the presence of granular lymphoblasts conveys a worse prognosis for certain subgroups of children with ALL.
Kaposi's sarcoma in the bone marrow of a patient with AIDS, The authors report a case of Kaposi's sarcoma (KS) involving the bone marrow of a patient with acquired immune deficiency syndrome (AIDS). The morphologic features. differential diagnosis. immunostaining pattern. and unusually low frequency of marrow involvement by AIDS-related KS are discussed.
Vascular proliferation as an unusual cause of hemorrhagic diathesis in myelofibrosis, One year after splenectomy. a patient with myelofibrosis developed spontaneously large hematomas that were not due to coagulation abnormalities or functionally defective platelets. At autopsy. the liver. muscle. and skin showed extramedullary hematopoiesis associated with capillary proliferation and extravasation of blood. These findings indicate that neovascularization can be an additional cause of bleeding in myeloproliferative disorders and might be induced by neoplastic hematopoietic cells.
Comparison of the Gen-Probe PACE 2 system, direct fluorescent-antibody, and cell culture for detecting Chlamydia trachomatis in cervical specimens, A chemiluminescent-labeled DNA probe (Gen-Probe PACE 2 System) for detection of Chlamydia trachomatis in endocervical specimens was evaluated. For each specimen. tissue cell culture. direct immunofluorescent staining (DFA). and DNA probe assay were performed. Thirty of 318 (9.4%) specimens were positive for C. trachomatis. The sensitivities. specificities. and positive and negative predictive values of the DNA probe compared with cell culture were 93%. 98%. 85%. and 99%. respectively. and for DFA these same values were 81%. 99%. 83%. and 99%. respectively. The Gen-Probe PACE 2 System is a reliable method for the rapid detection of endocervical chlamydial infection.
Comparison of Papanicolaou's stain with the Gomori methenamine silver (GMS) stain for the cytodiagnosis of Pneumocystis carinii in bronchoalveolar lavage (BAL) fluid, The cytodiagnosis of Pneumocystis carinii (PC) in bronchoalveolar lavage (BAL) fluids has traditionally required a special stain such as Gomori's methenamine silver (GMS) stain. Recent reports indicate that identification of foamy alveolar casts (FACs) with Papanicolaou's (Pap) stain may provide a sensitive and less complicated way of making the diagnosis. To confirm these observations. results on a series of 318 BALs were reviewed. PC was identified on 65 (20%) specimens from 54 patients. Pap stains and GMS stains were positive on 56 (86%) of these BALs. Pap stains were positive on seven (11%) specimens that had negative GMS stains. PC was later confirmed on these specimens by other methods. Only two (3%) BALs had positive GMS stains and negative Pap stains. The results of this study confirm other reports that show that PC can be sensitively diagnosed with the Pap stain. The authors suggest that routine special stains for PC are unnecessary on BALs.
Serum hepatitis B virus DNA in hepatitis B virus seropositive and seronegative patients with normal liver function, The presence of hepatitis type B virus (HBV) DNA in serum specimens from 926 apparently healthy people with normal liver functions was determined by polymerase chain reaction; 41.2% of people with positive results for HBV surface antigen (HBsAg) (94 of 228) and 95.2% of people with positive results for HBV e antigen (HBeAg) (60 of 63) were found to have positive results for serum HBV DNA. On the other hand. serum HBV DNA was found in 11.0% (77 of 698) of HBsAg-negative people and in 13% (69 of 530) of those who had positive results for serum antibodies directed against HBsAg. The results seem to suggest that HBV DNA can be found in a significant portion of apparently healthy people with normal liver function who are either seronegative for HBsAg or seropositive for antibodies directed against HBsAg.
The study of serum apoprotein levels as indicators for the severity of angiographically assessed coronary artery disease, Serum apoprotein A-I (Apo A-I) and B (Apo-B) concentrations were determined in 40 subjects undergoing coronary angiography for past myocardial infarction and angina pectoris. and the authors studied the relationship between the apoprotein concentrations and the severity of coronary artery disease (CAD). During this study. serum total cholesterol. triglyceride. and high-density lipoprotein. low-density lipoprotein. and very low density lipoprotein cholesterol concentrations were determined to control analysis. The results showed that the decrease in serum Apo A-I levels was the best indicator distinguishing CAD from non-coronary artery disease; the Apo B/Apo A-I ratio had the most consistent association with the severity of CAD as assessed by angiography; Apo B/Apo A-I values ranging from 0.98 to 1.00 might be considered critical values for early CAD.
Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men, The liver enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). which are responsible for the oxidative metabolism of ethanol. are polymorphic in humans. An allele encoding an inactive form of the mitochondrial ALDH2 is known to reduce the likelihood of alcoholism in Japanese. We hypothesized that the polymorphisms of both ALDH and ADH modify the predisposition to development of alcoholism. Therefore. we determined the genotypes of the ADH2. ADH3. and ALDH2 loci of alcoholic and nonalcoholic Chinese men living in Taiwan. using leukocyte DNA amplified by the PCR and allele-specific oligonucleotides. The alcoholics had significantly lower frequencies of the ADH2*2. ADH3*1. and ALDH2*2 alleles than did the nonalcoholics. suggesting that genetic variation in both ADH and ALDH. by modulating the rate of metabolism of ethanol and acetaldehyde. influences drinking behavior and the risk of developing alcoholism.
The parental origin of the single X chromosome in Turner syndrome: lack of correlation with parental age or clinical phenotype, We have used X- and Y-linked RFLPs to determine the origin of the single X chromosome in 25 live-born individuals with Turner syndrome. We determined that 18 individuals retained a maternal X (Xm) and that seven retained the paternal X (Xp). No occult mosaicism was detected. We found no differences in either maternal or paternal ages for the two groups. The ratio of maternal X to paternal X is just over 2:1. which is consistent with the expected proportion of meiotic or mitotic products. with equal loss at each step. given the nonviability of 45.Y. Six phenotypic or physiologic characteristics were assessed: (1) birth weight. (2) height percentile at time of testing. (3) presence of a webbed neck. (4) cardiovascular abnormalities. (5) renal abnormalities. and (6) thyroid autoimmunity. There were no significant differences in birth weights or heights between the girls who retained the maternal X or the paternal X. In addition. no differences between the groups could be appreciated in the incidence of the physical. anatomic. or physiologic parameters assessed.
Twenty-seven nonoverlapping zinc finger cDNAs from human T cells map to nine different chromosomes with apparent clustering, cDNA clones encoding zinc finger structures were isolated by screening Molt4 and Jurkat cDNA libraries with zinc finger consensus sequences. Candidate clones were partially sequenced to verify the presence of zinc finger-encoding regions; nonoverlapping cDNA clones were chosen on the basis of sequences and genomic hybridization pattern. Zinc finger structure-encoding clones. which were designated by the term "Kox" and a number from 1 to 32 and which were apparently unique (i.e.. distinct from each other and distinct from those isolated by other laboratories). were chosen for mapping in the human genome. DNAs from rodent-human somatic cell hybrids retaining defined complements of human chromosomes were analyzed for the presence of each of the Kox genes. Correlation between the presence of specific human chromosome regions and specific Kox genes established the chromosomal locations. Multiple Kox loci were mapped to 7q (Kox 18 and 25 and a locus detected by both Kox 8 cDNA and Kox 27 cDNA). 8q24 5' to the myc locus (Kox 9 and 32). 10cen----q24 (Kox 2. 15. 19. 21. 30. and 31). 12q13-qter (Kox 1 and 20). 17p13 (Kox 11 and 26). and 19q (Kox 5. 6. 10. 22. 24. and 28). Single Kox loci were mapped to 7p22 (Kox 3). 18q12 (Kox 17). 19p (Kox 13). 22q11 between IG lambda and BCR-1 (locus detected by both Kox 8 cDNA and Kox 27 cDNA). and Xp (Kox 14). Several of the Kox loci map to regions in which other zinc finger structure-encoding loci have already been localized. indicating possible zinc finger gene clusters. In addition. Kox genes at 8q24. 17p13. and 22q11--and perhaps other Kox genes--are located near recurrent chromosomal translocation breakpoints. Others. such as those on 7p and 7q. may be near regions specifically active in T cells.
Linkage analysis in spinal muscular atrophy, by six closely flanking markers on chromosome 5, The proximal spinal muscular atrophies (SMA) represent the second most common autosomal recessive disorder. after cystic fibrosis. The gene responsible for chronic SMA has recently been mapped to chromosome 5q by using genetic linkage studies. Among six markers mapping to this region. five were shown to be linked with the SMA locus in 39 chronic SMA families each containing at least two affected individuals. Multilocus analysis by the method of location score was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for SMA is between loci D5S6 and D5S39. The genetic distances between these two markers are estimated to be 6.4 cM in males and 11.9 cM in females. Since meiosis were informative with D5S39 and D5S6 in 92% and 87% of SMA families. respectively. it is hoped that the present study will contribute to the calculation of genetic risk in SMA families.
Chromosomal origin of small ring marker chromosomes in man: characterization by molecular genetics [published erratum appears in Am J Hum Genet 1991 Aug;49(2):503, Ten cases of small ring chromosomes which did not stain with distamycinA/DAPI and did not possess satellite regions associated with nucleolus-organizing regions are described. In situ hybridization with a battery of biotinylated pericentric repeat probes specific either for individual chromosomes or for groups of chromosomes allowed the identification of the chromosomal origin of these marker chromosomes. There was one example of a marker derived from each of chromosomes 1. 3. 6. 14. 16. 18. 20. 13 or 21. and the X. and there were two examples of markers derived from chromosome 12. One case possessed two markers. one derived from chromosome 6. and one derived from the X. The mechanism of generation of ring marker chromosomes is discussed. Five of seven cases who could be phenotypically assessed were abnormal. Three of these--the first with a ring chromosome derived from chromosome 1; the second with two markers. one derived from chromosome 6 and the other from the X chromosome; and the third with a ring chromosome derived from chromosome 20--each possessed distinctive facies. Additional cases with identified rings may allow the delineation of new chromosomal syndromes.
Exonic point mutations in NADH-cytochrome B5 reductase genes of homozygotes for hereditary methemoglobinemia, types I and III: putative mechanisms of tissue-dependent enzyme deficiency, We analyzed the NADH-cytochrome b5 reductase gene of hereditary methemoglobinemia type I and type III. by using PCR-related techniques. The mutation in type I is a guanine-to-adenine substitution in codon 57 of exon 3 of the NADH-cytochrome b5 reductase gene. and the sense of this codon is changed from arginine to glutamine. In type III the mutation is a thymine-to-cytosine transition in codon 148 of exon 5. causing leucine-to-proline replacement in type III. The former mutation abolishes the MspI recognition site. Homozygosity for the former mutation in a patient with type I was confirmed by restriction analysis of PCR-amplified fragments and by dot blot hybridization of amplified products with allele-specific oligonucleotide probes. The latter mutation generates a recognition site for MspI. Amplification of exon 5 by PCR followed by digestion with MspI revealed homozygosity for this mutation in patients with type-III. Putative mechanisms of tissue-dependent enzyme defects in hereditary methemoglobinemia are discussed.
The spectrum of beta-thalassemia mutations in Taiwan: identification of a novel frameshift mutation, Seventy-four beta-thalassemia genes from 37 unrelated beta-thalassemia-major patients were systematically characterized by using PCR. dot-blot hybridization. and direct sequencing of amplified genomic DNA. We found that six mutations--namely. II-654. 41/42. -28. 17 beta. -29. and 27/28--were prevalent. accounting. respectively. for 45.9%. 28.4%. 10.8%. 10.8%. 1.4%. and 2.7% of studied patients. The 27/28 mutation has at codon 27-28 a cytosine insertion which has never been reported before. These results indicate that four oligo-probes (II-654. 41/42. -28. and 17 beta) allow allele-mutant determination by oligonucleotide analysis in 95.9% of this group of patients. and direct sequencing can be carried out for other samples. These data will facilitate the prenatal diagnosis of this disease by DNA analysis in Taiwan.
c-myc protooncogene polypeptide expression in endometriosis, The c-myc protooncogene and its polypeptide product are important regulators of cell proliferation and differentiation. and ovarian steroids are believed to stimulate growth of various uterine cell types through altered expression of the c-myc gene. To determine whether c-myc expression may also be involved in the growth and development of endometriosis. we assessed c-myc expression in eutopic and ectopic endometrial tissue obtained from women undergoing surgery for endometriosis. Immunocytochemistry using a monoclonal antibody to the c-myc protein demonstrated positive staining of glandular and stromal cell nuclei. and cytoplasmic staining of glandular but not stromal cells in both eutopic and ectopic endometrium. These findings suggest that c-myc expression may be an important regulator of cell proliferation in endometriotic tissue.
Serum interleukin-6 levels correlate with disease status in patients with epithelial ovarian cancer, Interleukin-6 is a pleiotropic cytokine with a wide range of effects. including induction of B-cell and cytotoxic T-cell differentiation. and induction of acute phase reactant production by hepatocytes. Interleukin-6 also can act as an autocrine growth factor in malignancy. Various cell types produce interleukin-6. including T and B cells. monocytes. fibroblasts. and some solid tumor cells. In previous work we detected the production of substantial amounts of interleukin-6 by human ovarian cancer cells. including the ovarian cancer cell lines CAOV-3. OVCAR-3. and SKOV-3. and several primary ovarian tumor cultures. In this study we retrospectively examined 90 separate serum specimens for interleukin-6 in 36 patients with epithelial ovarian cancer. The mean serum interleukin-6 concentration of those ovarian cancer patients with macroscopic disease (n = 57) was 0.26 +/- 0.04 U/ml (mean +/- SEM). Healthy adult donors have interleukin-6 serum levels of 0.12 +/- 0.03 U/ml. Sixteen of 21 ovarian cancer patients with macroscopic disease (76%) had elevated (greater than 0.20 U/ml) levels of serum interleukin-6. with levels approaching 1 U/ml in some patients (p less than 0.01). Of those nine patients with bulky tumor (residual greater than 2 cm). eight (89%) had an elevated interleukin-6 level (mean. 0.31 +/- 0.05). while eight of 12 (66%) with minimal residual disease (less than 2 cm) had elevated levels. Only two of 15 (13%) patients who were in clinical remission and who had microscopic disease had elevated values. Of the 36 patients. 22 were CA 125 negative (less than 35 U/ml). and of these. four had elevated interleukin-6 levels. Of the 14 patients with an elevated CA 125 level. 12 (86%) had elevated interleukin-6 levels. In those 16 patients in whom serial levels of interleukin-6 were measured. rising levels were found over a 3 to 4 month interval in nine (56%); this correlated with tumor progression. Furthermore. the subsequent survival of patients was shown to correlate with the level of interleukin-6. such that patients whose levels were elevated greater than 0.20 U/ml interleukin-6 survived a mean of 12.5 months. compared with 27.2 months for patients with normal levels (p less than 0.001). These data support the concept that interleukin-6 may be a useful tumor marker in some patients with epithelial ovarian cancer. as it correlates with the tumor burden. clinical disease status. and survival.
Screening and detection of congenital malformation, Congenital malformations often occur sporadically and unpredictably. and a method of population screening to identify at-risk pregnancies would be of great value. Routine ultrasonography has some appeal in this regard. Unfortunately. the literature indicates a relatively poor sensitivity. with usually 30% or less of malformations identified or suspected by this means. Substantially better results have been described with ultrasonography targeted on the basis of screening ultrasonography or clinical findings. but these studies involve highly selected subjects examined carefully by experienced ultrasonographers. and their results are not relevant to population screening. A questionnaire survey of experts in the field indicated disagreement with the separation of screening and targeted ultrasonography. widely varying estimates of the accuracy of either. and average changes of $209 and $263. respectively. Theoretical considerations of the various types of malformations. their frequencies. and the likelihood of ultrasonographic detection reveal a minority of defects in which ultrasonography is both accurate and useful clinically. Ultrasonography seems to be of little potential as a means of screening for congenital malformation because of relatively low sensitivity and uncertain cost effectiveness.
Carrier screening for cystic fibrosis: implications for obstetric and gynecologic practice, Cystic fibrosis. which is one of the most common autosomal recessive disorders. has a carrier frequency of approximately 1 in 25 among whites in the United States. In this population approximately 75% of the mutations in patients with cystic fibrosis correspond to a 3 base pair deletion that results in the loss of a phenylalanine residue at amino acid position 508 (designated delta F508) from the coding region of the cystic fibrosis gene. Currently. only about half of the couples at risk can be identified as cystic fibrosis carriers. We support conclusions of the National Institutes of Health Workshop on Population Screening for the Cystic Fibrosis Gene. which state that carrier testing should be offered to all individuals or couples with a family history of cystic fibrosis. Good science and solid educational and counseling strategies must be in place before screening for cystic fibrosis is routinely offered to those with a negative family history. Pilot programs that investigate research questions in the delivery of population screening for cystic fibrosis carriers are urgently needed.
Intrauterine transfusion treatment of nonimmune hydrops fetalis secondary to human parvovirus B19 infection, Congenital human parvovirus B19 infection presented in this case as nonimmune hydrops fetalis that resulted from aplastic anemia at 20 weeks' gestation. Intravascular transfusion therapy led to resolution of the hydrops and a term delivery of an appropriately grown neonate.
The significance of amniotic fluid volume during intrapartum fetal acoustic stimulation, The relationship of intrapartum fluid volume to the fetal response to acoustic stimulation was investigated in 112 patients who were in the latent phase of labor. Amniotic fluid volume appears to play an insignificant role in the genesis of fetal heart rate decelerations that occur after fetal acoustic stimulation. regardless of the amount of amniotic fluid present.
Coffee during pregnancy: a reproductive hazard, Coffee is consumed in large quantities worldwide and any adverse effects would likely have important public health consequences. Because of the widespread exposure to coffee and other caffeine-containing beverages and because teratogenic effects of caffeine have been recorded in several species since 1960. women are concerned that there may be reason to limit their intake of coffee when pregnant. Several human studies on birth defects have been conducted and the overall results do not implicate coffee as a likely human teratogen. However. there is some evidence that consumption of three or more cups of coffee per day may have a modest effect on lowering infant birth weight. Studies of coffee consumption and increased rates of spontaneous abortion and delayed time to conception are inconsistent and conclusions cannot yet be drawn.
Cell adhesion molecules and the regulation of development, Cell adhesion molecules. in conjunction with the other morphoregulatory molecules. substrate adhesion molecules and cell junctional molecules. are dynamically expressed in coordinate patterns throughout development. Their activities are linked to a variety of cellular processes. and their ability to influence mechanochemical processes allows them to influence a variety of other fundamental developmental events. The clinical significance of these molecules remains to be determined. but they are clearly involved in a number of pathologic conditions and could become the focus of a wide range of diagnostic techniques and eventually even therapeutic designs.
Macrophage-conditioned media enhance endometrial stromal cell proliferation in vitro, It has been hypothesized that the activated peritoneal macrophages of endometriosis. rather than being a response to ectopic endometrium. may contribute to its pathogenesis. This study attempts to define the effect of macrophage-derived growth factors on endometrial stromal cell growth in vitro. as well as the interaction between estrogen and these growth factors. Mouse endometrial stromal cells were prepared and cultured in either a serum-containing. insulin-free medium or a serum-free. insulin-containing medium. and the effects of adding 10% macrophage-conditioned medium on [3H]thymidine incorporation were assessed. Results indicate that macrophage-conditioned medium will increase incorporation in the presence of insulin but not in insulin-free media. Serum can substitute for macrophage-conditioned medium. but the two together show no additive or synergistic effect. The effect of estrogen on this system was determined. and results indicate that estrogen will perform the function of insulin. with an optimal concentration of 10(-10) to 10(-12) mol/L. Thus macrophage-conditioned medium appears to function as a competence growth factor. and estrogen (in appropriate concentrations) functions as a progression growth factor.
Cuba's response to the HIV epidemic, BACKGROUND: Cuba's response to the human immunodeficiency virus (HIV) epidemic has been to conduct mass testing of the population to ascertain seroprevalence. to enforce mandatory relative quarantine of persons testing positive. and to implement educational interventions using media and school-based programs. METHODS: Interview with the Vice-Minister of Health and review of available data. RESULTS: Reports to date show a very low seroprevalence rate without evidence of a widespread epidemic. Sexual contact with foreign-born persons is the primary risk factor. Possible advantages of Cuba's policy include rapid reduction in the risk of HIV transmission by infected blood products. an opportunity for focused education and secondary prevention. and limitation of new infections. Possible disadvantages include the restriction of individual freedom in those who are not guilty of any illegal act. quarantine of persons with false positive HIV tests. and ongoing transmission because of the incomplete nature of the quarantine. The policy is expensive and may displace other public health priorities. The content of the media-based educational interventions has emphasized rational medical information in unimaginative formats with a limited focus on prevention. CONCLUSIONS: The issue of personal responsibility for behavioral change versus government imposed regulations is at the core of Cuba's HIV policy. The quarantine policy may paradoxically permit most Cubans to feel that they are personally invulnerable to the HIV epidemic.
Adult survivors of childhood sexual abuse and subsequent risk of HIV infection, BACKGROUND: Epidemiologic description of long-term adverse health effects of childhood sexual abuse is lacking. despite estimates that perhaps 30 percent of adults have experienced sexual assault in childhood. METHODS: In an adult cohort enrolled to investigate causes of transmission of human immunodeficiency virus. we identified current behaviors affecting risk of infection that were associated with a history of early sexual abuse. One hundred and eighty-six individuals provided information on the occurrence of abuse and subsequent sexual and drug using activities. RESULTS: Approximately half of the women and one-fifth of the men reported a history of rape during childhood or adulthood. Twenty-eight percent of the women and 15 percent of the men recalled that they had been sexually assaulted during childhood. People who reported childhood rape compared with people who did not were four times more likely to be working as prostitutes (90 percent confidence interval = 2.0. 8.0). Women were nearly three times more likely to become pregnant before the age of 18 (90% CI = 1.6. 4.1). Men who reported a history of sexual abuse had a twofold increase in prevalence of HIV infection relative to unabused men (90% CI = 1.0. 3.9). CONCLUSIONS: The disturbing prevalence of early sexual abuse and its possible health-related consequences call for prompt and routine investigation of sexual abuse histories. Identification of sexual victimization may be an important component for management of risk factors for human immunodeficiency virus.
Urolithiasis in Tennessee: an occupational window into a regional problem, BACKGROUND: Urinary tract stones (stones) are believed to be unusually common in the southeastern United States but neither the incidence of nor the risk factors for stones are known. METHODS: In three well-defined occupational populations in eastern Tennessee. we assessed the prevalence. incidence. and cumulative incidence of stones and measured biochemical risk factors for lithogenesis. RESULTS: The age-adjusted prevalence of stones was 18.5 percent in Tennessee compared to 7.7 percent among White males in US NHANES (prevalence ratio 2.4. 95% CI 1.7. 3.3). The cumulative incidence (risk) was 27.8 percent by age 65. higher than in any other reported population. Risk factors were age. a family history. and urinary saturation with calcium-oxalate (COAX). Persons with a positive family history and the highest measured CAOX index had a predicted lifetime risk of 88.8 percent. Biochemical factors affecting lithogenesis were hypercalciuria. hyperoxaluria. and low urine volume. CONCLUSION: Future research should characterize the geographic boundaries of a southeastern "stone-belt" and explore genetic and dietary hypotheses that might explain it.
A comparison of injury death rates in China and the United States, 1986, BACKGROUND: The importance of injury as a public health problem is not well recognized in many developing countries. Data have recently become available on injury mortality in China. METHOD: We compared Chinese injury data based on a 100 million population segment for 1986 with data for the United States. RESULTS: The age-adjusted death rate from all injuries for China exceeds the rate for the US (69.0 vs 61.3 per 100.000). The US has higher death rates from motor vehicle crashes. fires. and homicide; China has greater mortality from drowning. poisoning. falls. and suicide. Especially noteworthy in China are the high drowning rates among young children and the elderly and the high suicide rates in rural areas among young adults and the elderly. CONCLUSION: Injury is an important public health problem in China. exceeding in many respects the problem in the United States. It is urgent for China to place high priority on injury research and prevention.
Comparison of two growth charts in Lesotho: health workers' ability to understand and use them for action, BACKGROUND: Two growth monitoring charts widely used for growth monitoring in Africa (the Road-to-Health (RTH) and the Growth Surveillance (GS] were compared in order to assist the Government of Lesotho to decide on an appropriate national growth chart. METHODS: Thirty-four health workers were taught and tested on the RTH during a first week of training and on the GS during a second week (the RTH-GS group). while the order was reversed for another 25 trainees (the GS-RTH group). The health workers were trained and tested on their ability not only to use and interpret the two charts. but also to make the right decisions about specific actions to be taken when growth faltering occurs. RESULTS: There was no difference between scores to the RTH and GS charts after one week of training. After the second week of training. the scores to the RTH chart improved and became better than those to the GS chart. The scores to the GS test did not increase with previous knowledge of the RTH chart. CONCLUSIONS: For this reason and others discussed in the paper. the RTH chart was recommended for nationwide use in Lesotho. The adoption of this recommendation was facilitated by the close involvement in this research of public and private agencies responsible for growth monitoring in Lesotho.
Comparison of AIDS knowledge, attitudes, and behaviors among incarcerated adolescents and a public school sample in San Francisco, Data collected from incarcerated youth (n = 113) and a public school sample (n = 802) demonstrate that both adolescent groups have a high level of AIDS knowledge. Incarcerated youth are less aware of HIV risk-reduction behaviors and report markedly higher rates of HIV risk behaviors. Incarcerated youth are at substantially increased risk of HIV infection relative to their school-based counterparts and should be a primary target of HIV prevention programs.
Hyperendemic urban blastomycosis, Within the United States. blastomycosis is primarily endemic in the Mississippi and Ohio River valleys. but reliable figures as to its prevalence and incidence are scarce. A review of pathology department files and medical records from three hospitals in Rockford. Illinois. revealed 32 documented cases of blastomycosis in an eight and one-half year period beginning in March 1981. Twenty-three of these cases were urban since they occurred within the Rockford census tract boundaries--an incidence more than 3.5 times greater than expected in an endemic area. Addresses of patients in 18 of the 23 cases were concentrated at the northeast and southwest ends of the city. Implications are discussed.
Use of a medical center's computerized health care database for notifiable disease surveillance, The sensitivity of a medical center's inpatient and outpatient database to detect notifiable diseases was examined. Only 53 percent of inpatient and 7 percent of outpatient laboratory-confirmed cases of shigellosis. salmonellosis. giardiasis. and hepatitis were identified by an automated search for matching diagnosis codes. Reasons for lack of sensitivity include nonavailability of laboratory results at the time of diagnosis assignment. use of a standardized encounter form with limited preselected diagnosis codes. and pre-emptying of the infectious disease diagnosis by other diagnoses.
Physical activity on the job and cancer in Missouri, We conducted a series of case-control studies to investigate the risks of 16 cancer types in relation to occupational physical activity. These studies were based on Missouri Cancer Registry data for 17.147 White male cancer patients registered between 1984 and 1989. Colon cancer risk was increased for both the moderate (odds ratio (OR) = 1.1; 95% confidence interval (CI) = 1.0. 1.3) and low (OR = 1.2; 95% CI = 1.0. 1.5) activity levels. Similar elevations were observed for prostate cancer at the moderate (OR = 1.1; 95% CI = 1.0. 1.3) and low (OR = 1.5; 95% CI = 1.2. 1.8) levels of activity. and for cancer of the testis at the low activity level (OR = 2.2; 95% CI = 1.3. 3.7). An opposite trend (p less than 0.01) was noted for lung cancer. which showed decreased risk at the moderate (OR = 0.9; 95% CI = 0.8. 1.0) and low (OR = 0.8; 95% CI = 0.6. 0.9) activity levels. These associations suggest that further study of the relationship between physical activity and site-specific cancer risk is warranted.
Determinants of late stage diagnosis of breast and cervical cancer: the impact of age, race, social class, and hospital type [published erratum appears in Am J Public Health 1991 Aug;81(8):980, Previous studies of the relationship between cancer stage. age. and race have not controlled for social class and health care setting. Logistic regression analyses. using information from the New York State Tumor Registry and area-level social class indicators. demonstrated that. in New York City. older Black. lower class women in public hospitals were 3.75 and 2.54 times more likely to have late stage breast or cervical cancer. respectively. than were younger White. high social class women in non-public hospitals.
New York State HIV seroprevalence project: goals, windows, and policy consideration, In the summer of 1987. the New York State Department of Health embarked on an extensive effort to determine the prevalence of trends of HIV infection in the state. Sero-surveillance for antibody to HIV was undertaken by blind testing of available blood samples. Six populations were selected as windows on the epidemic: newborns. homeless adolescents. prisoners. and clients of family planning. STD. and drug treatment clinics. Testing of all newborns in New York State began in December 1987. and all six study windows were operational by June 1988. As of March 1990 blind testing for HIV antibody had been performed on more than 725.000 blood specimens in these six studies. Collectively these seroprevalence activities are providing invaluable information and impetus to preventive actions and public policy.
Comparison of newborn screening records and birth certificates to estimate bias in newborn HIV serosurveys, Implicit in the New York State Newborn HIV Seroprevalence Study is the assumption that newborns of all New York State residents are tested for human immunodeficiency virus (HIV) antibodies. We examined this assumption by describing that part of the 1988 New York newborn population not tested in the HIV seroprevalence study and assessing any bias contributed by this group. Of the expected total HIV specimens 1.5 percent were never received by the Newborn Screening Program. 0.5 percent were invalid specimens for which no repeat specimen could be obtained. and 1.7 percent were unsuitable or of insufficient quantity to be tested for HIV antibody. Thus 96.3 percent of all 1988 New York newborns were tested for HIV antibody. Black infants from New York City and low-birthweight infants were represented disproportionately among those not tested. Assignment of all untested newborn to HIV-positive status increased the seroprevalence rate 17 percent (0.64 percent to 0.75 percent).
Projection of AIDS incidence in women in New York State, The results of the Newborn HIV Seroprevalence Study in New York State for 1988 were used to estimate the number of human immunodeficiency virus (HIV)-infected women of childbearing age in 1988. The estimate was accomplished for each of 80 age. racial/ethnic. and geographic strata by dividing the number of seropositive newborns by the 1988 estimated fertility rate. Summing across strata yielded a total of 23.430 infected women age 15 to 44 years in 1988. From this estimate a tree model was used to estimate the number of women infected during 1981-88. Back calculation was used to distribute these infections over time. and the selected incubation distribution was used to estimate future AIDS cases for this population: 8.295 cases by 1993.
Hospitalization of HIV-seropositive newborns with AIDS-related disease within the first year of life, The purpose of this study was to estimate the proportion of HIV-seropositive newborns hospitalized for an AIDS-related diagnosis within 12 months of birth and to characterize these hospitalizations. The number of HIV-seropositive infants born December 1987 through June 1988 was derived from the blinded New York State Newborn HIV Seroprevalence Study. The number of infants who were born in these same months and hospitalized with an ARD within 12 months of birth was obtained from a data base containing information on all hospital discharges in New York State. Comparisons were made on the basis of month of birth. Of infants born during the study period. 995 tested positive for HIV antibody. and 151 infants (15 percent) were hospitalized with an ARD within 12 months of birth. The 151 ARD cases had a total of 240 hospitalizations. accounting for 5.772 patient days. Fifty-six percent of the ARD cases were diagnosed within six months of birth.
HIV seroprevalence in a facility for runaway and homeless adolescents, In October 1987. the New York State Department of Health initiated a study to determine the prevalence of antibody to HIV in clients of a facility for runaway and homeless adolescents in New York City. A risk-assessment component was added in May 1988. As of December 1989. a total of 2.667 adolescents had been tested. and 142 (5.3 percent) were found to be HIV-seropositive (males 6.0 percent. females 4.2 percent). The seroprevalence rate increased from 1.3 percent for 15-year-olds to 8.6 percent for 20-year-olds. Hispanics had the highest seroprevalence rate (6.8 percent). followed by non-Hispanic Whites (6.0 percent) and non-Hispanic Blacks (4.6 percent). HIV seropositivity was associated with intravenous drug use. male homosexual/bisexual activity. prostitution. and history of another sexually transmitted disease. The alarmingly high prevalence of HIV infection in this selected population illustrates the immediate need for prevention programs for adolescents.
The AIDS epidemic in New York State, New York State has reported more AIDS cases (26.576) through November 1989 than any other state. accounting for 23 percent of all reported cases in the nation at the time. New York City has reported 22.231 (84 percent) of the statewide cases. The epidemiology of AIDS in New York State has been easily influenced by the large number of cases among IVDUs. Whereas intravenous drug use accounts for 16 percent of adult/adolescent cases in the rest of the nation. it accounts for 39 percent of the cases in New York State. Intravenous drug use is the leading exposure category among racial minorities. with a disproportionately high rate of cases among Blacks and Hispanics. The epidemic among women and children has also been severe. resulting from intravenous drug use by women. heterosexual transmission from drug users to women. and perinatal transmission to their children.
HIV seroprevalence surveys: impetus for preventive activities, Seroprevalence determinations of human immunodeficiency virus are essential for design and implementation of preventive strategies. By demonstrating the severity of HIV infections within communities. New York State surveys have spurred preventive interventions. including information to the public and health care providers and increased counseling and testing of women of reproductive age. In high-prevalence areas the community health workers have been employed in preventive activities. Specific information has been provided to county health departments on zip code areas with high HIV seroprevalence rates. Serosurveys revealed that the magnitude of HIV infection in adolescents is much larger than indicated by case reports. Various seroprevalence studies confirmed higher rates of infection with increasing age and minority status and a strong association with intravenous drug use. Combining data provided by seroprevalence studies in a given community enables planners to assess the extent of infection in that community and in groups important to transmission of the virus.
The alkalinisation of bupivacaine for intercostal nerve blockade [published erratum appears in Anaesthesia 1991 Aug;46(8):707, A double-blind randomised study was performed to investigate the effect of pH adjustment of bupivacaine. with adrenaline 1:200.000. on the duration of block and pain relief after intercostal nerve blockade following thoracotomy. One group (n = 10) received bupivacaine with adrenaline 1:200.000 (pH = 4.1) and the other (n = 10) received alkalinised bupivacaine with adrenaline 1:200.000 (pH = 6.9). There was no significant difference in block duration (mean 23.9 and 26.4 hours respectively) visual analogue pain scores or morphine usage. Patients were more likely to have a block during the first 12 hours if they received alkalinised bupivacaine (p less than 0.01. Chi-squared test). A progressive regression of block. not previously described. was observed. explicable by means of spread of local anaesthesia to adjacent intercostal nerves. Alkalinisation of bupivacaine with adrenaline for intercostal nerve blockade has little clinical benefit.
Introducing an acute pain service, An acute pain service in a new district general hospital is described. We have reported incidence of severe pain. common postoperative anaesthetic problems and patient satisfaction in relation to the analgesic technique. Over half the patients were treated by intermittent intramuscular injection of opioid. but increase in the use of continuous intravenous therapy and in particular patient-controlled analgesia. was welcomed by both medical and nursing staff.
General anaesthesia and undrained pneumothorax. The use of a computer-controlled propofol infusion, A patient who required pleurectomy had a 30% pneumothorax when she was presented for anaesthesia. She had refused to have this drained. and it had not responded to conservative management. She was anaesthetised using a computer-controlled propofol infusion system. without the use of nitrous oxide. and a chest drain was inserted before the institution of positive pressure ventilation. This technique reduces the hazards associated with general anaesthesia in the presence of an undrained pneumothorax. It may be a safe alternative method of induction of anaesthesia in other conditions in which positive pressure ventilation must be avoided. such as bronchopleural fistula.
Posthypoxic myoclonus (the Lance-Adams syndrome) in the intensive care unit, The neurological assessment of patients admitted to the intensive care unit after successful resuscitation from cardiopulmonary arrest may be difficult. We describe the cases of two patients who developed myoclonus within 24 hours of hypoxic respiratory and cardiac arrest. Initially. the clonic movements were thought to be generalised convulsions and were treated as such. until it became evident that the patients were aware and distressed. Posthypoxic myoclonus is a rare complication of successful cardiopulmonary resusitation. Recognition depends on the awareness that the syndrome exists. and is important so that correct therapy can be instituted. There may be important prognostic implications. Both our patients had normal intellectual recovery with moderate residual neurological disability from their movement disorder.
Potential errors in pulse oximetry. II. Effects of changes in saturation and signal quality, The published studies of pulse oximeter performance under conditions of normal. high and low saturation. exercise. poor signal quality and cardiac arrhythmia are reviewed. Most pulse oximeters have an absolute mean error of less than 2% at normal saturation and perfusion; two-thirds have a standard deviation (SD) of less than 2%. and the remainder an SD of less than 3%. Some pulse oximeters tend to read 100% with fractional saturations of 97-98%. Pulse oximeters may be suitable hyperoxic alarms for neonates if the alarm limit chosen is directly validated for each device. Pulse oximeters are poorly calibrated at low saturations and are generally less accurate and less precise than at normal saturations; nearly 30% of 244 values reviewed were in error by more than 5% at saturations of less than 80%. Ear. nose and forehead probes respond more rapidly to rapid desaturation than finger probes. but are generally less accurate and less precise. Ear oximetry may be inaccurate during exercise. Low signal quality can result in failure to present a saturation reading. but data given with low signal quality warning messages are generally no less accurate than those without. Cardiac arrhythmias do not decrease accuracy of pulse oximeters so long as saturation readings are steady.
Premedication: an audit, A prospective study of routine premedication management was carried out at a large teaching hospital. Many patients received their premedication at times inappropriate for it to be effective. Several patients receiving regular medication had this suddenly stopped pre-operatively. Prolonged fasting occurred in both elective and emergency groups of patients. Benzodiazepines and opioids were prescribed most frequently and drying agents were used widely. Antacids. H2-blockers and agents to promote gastric emptying were used very little despite the potential of aspiration in many groups of patients. This audit of activity has revealed several areas of practice that can either be improved immediately or warrant detailed investigation.
Importance of RAA system and the treatment of patients with ACE inhibition after myocardial infarction, There is activation of the renin angiotensin system after both complicated and uncomplicated myocardial infarction. Angiotensin II increases myocardial oxygen consumption whilst reducing coronary flow and is also directly toxic to the myocardium. Angiotensin converting enzyme inhibitors produce beneficial haemodynamic and neuroendocrine changes in patients with acute left ventricular failure. and may have a role in selected patients with cardiogenic shock. There is evidence to suggest that they might prevent the development of late cardiac failure by limiting the extent of post infarction ventricular dilation. Further research is necessary to define their role in the treatment of acute myocardial infarction.
Double-blind placebo-controlled trial of buflomedil in the treatment of Raynaud's phenomenon: six-month follow-up, The efficacy of buflomedil in reducing the mean daily frequency and severity of winter ischemic attacks has been shown in a randomized. double-blind. placebo-controlled trial including 31 patients (16 in the buflomedil group. 15 in the placebo group) suffering from idiopathic Raynaud's phenomenon and followed up for six months. The efficacy was confirmed by nail fold capillaroscopy. which showed a significant alleviation of hemodymanic disturbances and background pallor in comparison with the placebo. Results in terms of clinical and laboratory safety parameters assessed over a six-month period were satisfactory. thus demonstrating the possibility of a long-term treatment.
Incidence of aneurysms in Takayasu's arteritis, The angiographic findings of Takayasu's arteritis in a series of 113 patients were reviewed. Predominant findings were stenotic or occlusive changes. but fusiform or saccular aneurysms were also found in 36 patients (31.9%) in the various sites of aorta and its major branches. Multiple aneurysms were found in 15 patients. The most common site of aneurysms was the ascending aorta (16 patients); in 7 of the patients these were complicated by aortic regurgitation. Aneurysms developed in the aortic arch in 3 patients. in the descending aorta in 11. in the abdominal aorta in 7. and in the major branches of the aortic arch in 9 patients. In 2 patients. follow-up angiograms showed enlargement of the aneurysms. and rupture of the aneurysm occurred in 1 patient. Aneurysms were found even in young patients. A fifteen-year-old female showed a huge aneurysm in the ascending aorta as the initial manifestation of this disease. Thickening of the walls of aneurysms was common and characteristic. This study revealed the moderately high incidence of aneurysms of various sites of arteries in patients with Takayasu's arteritis. The authors conclude that aneurysm. as well as occlusive changes. can be a primary lesion.
Compliance in clinical trials of two nonbronchodilator, antiasthma medications, An electronic monitoring device was used to assess patient compliance during clinical trials of two new aerosolized nonbronchodilator. antiasthma drugs. Compliance was poor. but similar. in both trials. Patients took the study drug as instructed on a mean of 37.3% days (range 10% to 77%) in one trial and 37.4% days (range 0% to 63%) in the other. Both underuse and overuse were observed. Underuse was seen on a mean of 38.9% days (range 9% to 81%) and 46.0% (range 15% to 80%) respectively; overuse on a mean of 23.5% days (range 6% to 54%) and 16.6% days (range 0% to 41%). In some patients ten or more activations of the device were recorded at the same time. In six patients such multiple simultaneous activations were recorded on two or more separate days. These patients were among the most noncompliant in the study. Multiple simultaneous activations frequently followed underuse days or preceded followup visits. suggesting the possibility of duplicity. Overall compliance was such that valid conclusions about efficacy of the drugs could only have been drawn in six of 34 patients.
Asthmatic patients with panic disorders: report of three cases with management and outcome, Panic disorders. a subgroup of the primary anxiety disorders. have an estimated worldwide prevalence of 2.5% to 5%. Although the causes of these disorders have not been completely elucidated. it seems that environmental and genetic factors in addition to central nervous system biochemical abnormalities play important roles. Mild to moderate anxiety levels may prove advantageous in the management of asthmatics but when their anxiety level becomes maladaptive. as in the case of panic attacks. their medical care is placed in jeopardy. Herein are three case reports of asthmatics who also exhibited panic disorders and their clinical outcome. It is concluded that a team approach. involving the primary physician and psychologist or psychiatrist. is beneficial in the long-term management of these patients.
Bambuterol: a new long acting bronchodilating prodrug, Bambuterol. a carbamate prodrug of terbutaline as a 5. 10. or 20-mg tablet. was given once every evening to patients with asthma in a randomized double-blind crossover study. Twenty milligrams improved pulmonary functions over 24 hours; 5 and 10 mg did not. Few side effects were observed.
Improved stability in oral delivery of albuterol provides less variability in bronchodilation in adults with asthma, The objective of this randomized. single-blind. parallel group study was to determine whether a more constant rate of albuterol delivery from tablets provides less variability in bronchodilation. Thirty-eight adult patients were enrolled with FEV1 between 40% to 80% of predicted normal and greater than or equal to 15% reversibility. Eighteen patients received Volmax. 8 mg bid. and 20 patients received Proventil Repetabs. 8 mg (as two 4-mg tablets) bid. The magnitude and duration of bronchodilation were determined after the first dose and at steady state on treatment day 7 by measuring serial values of pulmonary function for 12 hours on each day. Interpatient variability in bronchodilation was calculated for each study day did not differ significantly between treatments. the interpatient variability in bronchodilation with Volmax was. on average. one-half of that experienced with Proventil Repetabs. Adverse events. mainly headache and tremor. were comparable between Volmax and Proventil Repetabs. This study demonstrates that Volmax achieves less variable bronchodilation through a more constant rate of drug delivery from the onset of therapy.
Once daily triamcinolone acetonide nasal spray is effective for the treatment of perennial allergic rhinitis [published erratum appears in Ann Allergy 1991 Jun;66(6):457, A randomized. double-blind. placebo-controlled. parallel group study was conducted in 11 centers to evaluate the safety and efficacy of a once-a-day regimen of 110 micrograms. 220 micrograms; and 440 micrograms of triamcinolone acetonide intranasal aerosol versus placebo in relieving the symptoms of rhinitis in 305 adult and older pediatric patients with perennial allergic rhinitis. Nasal stuffiness. nasal discharge. sneezing. nasal itching and the nasal index (the sum of the mean scores of the first three symptoms) averaged over the first 6 weeks and second 6 weeks of the study were significantly reduced in patients who received the 220 micrograms/day and the 440 micrograms/day dosages. The 110 micrograms/day group had a reduction in these nasal symptoms. but only the sneezing and nasal index were significantly (P less than .05) better than placebo. During the last 6 weeks of the study. patients were allowed to take oral back-up medication for their nasal symptoms; all three groups receiving triamcinolone nasal aerosol took less back-up medication than did the placebo group. There were no significant adverse effects or laboratory abnormalities noted during this study. Intranasal triamcinolone acetonide 220 micrograms and 440 micrograms. used once-a-day for 12 weeks is clinically and statistically superior to placebo for the treatment of perennial allergic rhinitis.
The allergic patient who is noncompliant and abusive: dealing with the adverse experience, The field of Allergy-Immunology is involved with the care of patients with chronic illness. The care of these patients is enhanced when the physician has established good rapport with the patient. The noncompliant. disruptive behavior of some patients can try the patience of even the most understanding physicians and. in turn. impede the delivery of care. Interactions with this type of patient may leave the physician with feelings of guilt. frustration. and helplessness. We review such an encounter with the purpose of describing how to deal with this type of patient and to guide the physician in responding to this adverse behavior. Such patients will usually require limits to be set on behavioral acting out for their own best interest. Further. it is often necessary to make continued care contingent on compliance with the ground rules set. The physician must be aware of his or her adverse feelings toward the patient and be able to interpret the behavior in the context of the psychiatric disorder so that appropriate psychologic help for the patient can be provided.
Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study, OBJECTIVE: To investigate whether isosorbide-5-mononitrate (Is-5-Mn) given with propranolol reduces hepatic portal pressure more than does propranolol alone in patients with cirrhosis. DESIGN: A randomized controlled trial. PATIENTS: Fifty patients with cirrhosis and esophageal varices entered and 42 completed the study. INTERVENTION: Twenty-one patients received oral propranolol at increasing doses until their resting heart rate was reduced by 25%. and 21 patients received oral propranolol (on the same schedule) plus oral Is-5-Mn. 40 mg twice a day. MEASUREMENTS: Hepatic vein pressure gradient. liver function. and splanchnic and systemic hemodynamics before and after 3 months of continuous therapy. MAIN RESULTS: At 3 months. the hepatic venous pressure gradient decreased more (P less than 0.01) in patients given propranolol plus Is-5-Mn (19%. from 18.4 +/- 3.9 to 14.9 +/- 3.8 mm Hg; 95% CI. -2.4 to -4.5 mm Hg) than in those given propranolol alone (10%. from 18.2 +/- 3.5 to 16.3 +/- 3.1 mm Hg; CI. -1.1 to -2.7 mm Hg). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol. but in 50% of patients receiving combined therapy (P less than 0.02). There were statistically significant decreases in hepatic blood flow and the intrinsic clearance of indocyanine green after propranolol therapy. but not after combined therapy. The treatments caused similar reductions in azygos blood flow and cardiac output. CONCLUSIONS: The long-term combined administration of propranolol plus Is-5-Mn reduces portal pressure more than propranolol alone without adverse effects on hepatic perfusion and liver function. Whether this greater hemodynamic effect translates into better clinical efficacy should be determined in randomized controlled trials.
The physiologic basis of diuretic synergism: its role in treating diuretic resistance, Diuretic drugs usually improve edema when used judiciously. Some patients. however. become resistant to their effects. Diuretic resistance may result from dietary indiscretion. poor compliance. impaired bioavailability. imparied diuretic secretion into the lumen of the renal tubule. or because other drugs interfere with diuretic activity. When easily treatable causes of diuretic resistance have been excluded. resistance often reflects the intensity of the stimuli to sodium retention. Recent experimental work has indicated ways in which the kidney adapts to chronic diuretic treatment and has indicated how these adaptations may limit diuretic effectiveness. First. nephron segments downstream from the site of diuretic action increase sodium-chloride (NaCl) reabsorption because the delivered NaCl load increases. Second. diuretic-induced contraction of the extracellular fluid volume stimulates kidney tubules to retain NaCl until the next dose of diuretic is administered. Third. kidney tubules themselves may become hypertrophic because they are chronically stimulated by diuretic-induced increases in NaCl delivery. These adaptations all increase the rate of NaCl reabsorption and blunt the effectiveness of diuretic therapy. When diuretic resistance is present. using a second diuretic drug that acts in a different nephron segment is often effective. Recent experimental results suggest that a second class of drug may act synergistically with the first by blocking the adaptive processes that limit diuretic effectiveness. On the basis of an understanding of the mechanisms of diuretic adaptation and resistance. treatment regimens can be designed to block specific adaptive mechanisms and to improve diuretic therapy.
First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use, The first exposure of gram-negative bacilli to an aminoglycoside antibiotic in vitro induces a biphasic bactericidal response and adaptive drug resistance (G. L. Daikos. G. G. Jackson. V. T. Lolans. and D. M. Livermore. J. Infect. Dis. 162:414-420. 1990; G. G. Jackson. G. L. Daikos. and V. T. Lolans. J. Infect. Dis. 162:408-413. 1990). The therapeutic implications were examined in netilmicin treatment of a Pseudomonas aeruginosa infection of normal and neutropenic mice. For 2 h after the first dose. the bactericidal rates were rapid. 0.75. 1.0. and 1.5 log10 CFU/h with doses of 10. 30. and 60 mg/kg. respectively. Each twofold increase in dosage reduced the number of surviving bacteria fivefold. Between 2 and 6 h. the second-phase bactericidal rate was slow. less than or equal to 0.3 log10 CFU/h. regardless of the dose. In a multiple-dose regimen. the same amount of netilmicin given in one dose was 70 and 90% more effective than two or three doses. respectively. Doses calculated to keep the drug level in plasma above the MIC were less effective than regimens giving first exposure to a high drug concentration. Adaptive resistance occurred when doses were given more than 2 h after the start of treatment. Temporary survival of bacteremic neutropenic mice was 60 to 70% greater with a second dose at 2 h than after a longer interval. In a thigh infection of neutropenic mice treated every 2 h. doses 4. 6. and 8 h after the first one showed no bactericidal effect.
Antibacterial activities in vitro and in vivo and pharmacokinetics of cefquinome (HR 111V), a new broad-spectrum cephalosporin, Cefquinome is a new injectable aminothiazolyl cephalosporin derivative. It is stable against chromosomally and plasmid-encoded beta-lactamases and has a broad antibacterial spectrum. Staphylococcus aureus. streptococci. Pseudomonas aeruginosa. and members of the family Enterobacteriaceae (Escherichia coli. Salmonella spp.. Klebsiella spp.. Enterobacter spp.. Citrobacter spp.. and Serratia marcescens) are inhibited at low concentrations. Cefquinome is also active against many strains of methicillin-resistant staphylococci and enterococci. Its in vitro activity against gram-negative anaerobes is very limited. The high in vitro activity of cefquinome is reflected by its high in vivo efficacy against experimental septicemia due to different gram-positive and gram-negative bacteria. We studied the pharmacokinetic properties of cefquinome in mice. dogs. pigs. and calves. After single parenteral administrations. cefquinome displayed high peak levels. declining with half-lives of about 0.5. 0.9. 1.2. and 1.3 h. respectively. The areas under the concentration-time curve determined for dogs and mice showed linear correlations to the given doses. In dogs the urinary recovery was more than 70% within 24 h of dosing.
Immunoenhancing properties and antiviral activity of 7-deazaguanosine in mice, The nucleotide analog 7-deazaguanosine has not previously been reported to possess biological (antiviral or antitumor) properties in cell culture or in vivo. Up to 10(5) U of interferon per ml was detected in mouse sera 1 to 4 h following oral (200-mg/kg of body weight) and intraperitoneal (50-mg/kg) doses of the compound. 7-Deazaguanosine also caused significant activation of natural killer and phagocytic cells but did not augment T- and B-cell blastogenesis. Intraperitoneal treatments of 50. 100. and 200 mg/kg/day administered 24 and 18 h before virus inoculation were highly protective in mice inoculated with lethal doses of Semliki Forest or San Angelo viruses. Less but still significant survivor increases were evident in treated mice infected with banzi or encephalomyocarditis viruses. In most cases. the degree of antiviral activity was similar to that exhibited by the biological response modifier 7-thia-8-oxoguanosine. 7-Thia-8-oxoguanosine was more potent than 7-deazaguanosine against encephalomyocarditis virus in mice. however. Oral efficacy was achieved with 7-deazaguanosine treatments of greater than or equal to 100 mg/kg against all virus infections. whereas 7-thia-8-oxoguanosine is reported to be devoid of oral activity in rodents. Thus. 7-deazaguanosine represents the first reported orally active nucleoside biological response modifier exhibiting broad-spectrum antiviral activity against particular types of RNA viruses.
Furazolidone and nitrofurantoin in the treatment of experimental Pneumocystis carinii pneumonia, Furazolidone and nitrofurantoin. oral nitrofuran derivatives with broad-spectrum antimicrobial properties already in clinical use. were compared for activity against Pneumocystis carinii in an immunosuppressed rat model of P. carinii pneumonia. Furazolidone exhibited only slight activity as a prophylactic agent but was moderately effective in the therapy of pneumocystosis. The median histologic score and organism count fell from 4+ and 10(8) to 10(9) cysts per lung. respectively. in the controls to 1+ to 2+ and 10(7) to 10(8) cysts per lung. respectively. in the furazolidone-treated groups. However. these results were not as good as those obtained with the standard drug. trimethoprim-sulfamethoxazole (0+. 10(6) to 10(7) cysts per lung). Nitrofurantoin showed little anti-P. carinii activity despite different doses or drug preparations. The high doses of furazolidone used here and their toxic effects on the rats will probably discourage investigation of this drug in the treatment of pneumocystosis in humans. Nevertheless. since many nitrofurans have been synthesized. further exploration of this class of compounds might be helpful in developing new anti-P. carinii agents or in studying structure-activity relationships.
Prospective study of Clostridium difficile intestinal colonization and disease following single-dose antibiotic prophylaxis in surgery, A total of 108 volunteers undergoing an elective surgical procedure were randomly given a single 2-g intravenous prophylactic dose of either a cephalosporin or mezlocillin. Stool samples were cultured for Clostridium difficile the day before the operation and later on postoperative days 4. 7. and 14. C. difficile was detected in 23.0% of patients who received a cephalosporin (cefoxitin. 8.3%; cefazolin. 14.3%; cefotetan. 20.0%; ceftriaxone. 25.0%; cefoperazone. 43.7%). in 3.3% of patients given mezlocillin. and in none of 15 control volunteers given no antimicrobial agent. No patient experienced diarrhea.
Aztreonam pharmacokinetics in burn patients, The pharmacokinetics of aztreonam in eight adult patients with severe burn injuries (total body surface area burn. 49% +/- 21% [mean +/- standard deviation]) were studied. The time of initiation of study following burn injury was 7.0 +/- 1.4 days. Four patients at first dose and at steady state were studied. Aztreonam concentrations were measured by high-performance liquid chromatography. and a two-compartment model was used to fit the data. No significant differences in any pharmacokinetic parameters between first dose and steady state were observed. Volume of distribution of the central compartment after first dose (0.14 liters/kg) and volume of distribution at steady state (0.31 liters/kg) were approximately 30% higher than those reported for other patient populations. Total drug clearance and renal drug clearance when normalized to creatinine clearance (CLCR) were similar to those previously reported for other critically ill patients. CLCR was strongly correlated with renal drug clearance (r = 0.94) and total drug clearance (r = 0.95). The extent and degree of burn (percent second or third degree burn) were poorly correlated with all pharmacokinetic parameters with the exception of the volume of distribution at steady state. which was correlated with both total body surface area burn (r = 0.95) and percent second degree burn (r = 0.83). Aztreonam pharmacokinetics are altered as a result of thermal injury; however. CLCR can be used to assess the clearance of aztreonam in burn patients.
Effects of acute and chronic ethanol administration on thiamine metabolizing enzymes in some brain areas and in other organs of the rat, The effect of ethanol (4.7 g/kg body wt intragastrically as a single dose or once daily for 35 days) on the levels of the thiamine metabolizing enzymes (thiamine pyrophosphokinase. TPKase; thiamine pyrophosphatase. TPPase; and monophosphatase. TMPase) was studied in different organs (liver. kidney. small intestine. heart and skeletal muscle) and nervous regions (cerebral cortex. cerebellum. medulla oblongata. pons. corpus callosum. hypothalamus and sciatic nerve) of the rat. In order to evaluate the non-specific effects of the stress of gastric gavage and of the additional caloric intake. appropriate control groups of animals were treated intragastrically with water or with a saccharose solution isoenergetic with ethanol respectively. All animals were reared on a nutritionally adequate diet supplying amounts of thiamine higher than the recommended daily requirement. Enzymatic activities were determined quantitatively by biochemical methods. Tissue TPKase levels were generally reduced by both acute and chronic ethanol administration. TPPase levels were generally reduced after acute and increased after chronic ethanol treatment. Changes in brain TMPase levels were similar to those observed for TPPase. In visceral organs and skeletal muscle TMPase activity was increased by chronic ethanol treatment as compared to acute ethanol administration. In conclusion. ethanol exerts a marked influence on the tissue levels of the thiamine metabolizing enzymes: the activity of the enzymes dephosphorylating thiamine phosphates is increased whereas the activity of the thiamine pyrophosphate synthesizing enzyme is reduced. These changes may contribute to an important extent to the disturbances in thiamine cellular uptake and metabolism observed in alcoholism.
Acamprosate appears to decrease alcohol intake in weaned alcoholics, Five hundred and sixty-nine alcoholics were included in a double-blind placebo-controlled randomized multicenter study of the effects of Acamprosate (calcium acetylhomotaurinate (CA). 1.3 g/day) on indicators of alcoholic relapse after withdrawal. One hundred and eighty-one patients in the CA group versus 175 in the placebo group completed the three-month study. The major efficacy criterion was plasma gamma-glutamyl transpeptidase (GGT). as an indicator of recent alcohol ingestion. This analysis was completed by criteria concordance analysis on a number of indicators of alcohol intake. Patients in both groups were similar initially. After 3 months of treatment. the patients in the CA group had significantly lower GGT (1.4 +/- 1.56 versus 2.0 +/- 3.19 times normal. P = 0.016). All significant differences (P less than 0.05) or trends (0.10 greater than P greater than 0.05) were in favor of a superior effect of CA over placebo. The major side-effect of CA was diarrhea (present in 13% of CA patients versus 7% of placebo. P = 0.04). CA proved superior to placebo on the evolution of markers of alcohol ingestion at three months. in this large-scale multicenter study. It could be a new modality in the drug therapy of alcoholism. not involving an antabuse effect. an antidepressant action. or conditioning.
In vivo accelerated acetaldehyde metabolism using acetaldehyde dehydrogenase-loaded erythrocytes, Human erythrocytes were loaded with homogeneous acetaldehyde dehydrogenase (AcDH) purified from Alcaligenes Eutrophus (an enzyme species with an apparent Km for acetaldehyde similar to the mitochondrial enzyme). using an encapsulation procedure based on hypotonic haemolysis. isotonic resealing and reannealing. The AcDH-overloaded erythrocytes contained 1.55 +/- 0.25 I.U. of AcDH activity per ml of packed erythrocytes. a value 12-15 times higher than that of corresponding unloaded or native red cells. The AcDH-loaded erythrocytes were found to metabolize 4 +/- 0.8 mumol of acetaldehyde/hr/ml of red blood cells. whereas the glycolytic activity was almost unmodified. Estimates of intracellular adenine nucleotides showed 50% ATP decay in the AcDH-loaded cells when incubated in the presence of acetaldehyde concentrations higher than 50 microM. whereas the [NAD+]/[NADH] ratio was strongly decreased but to the same extent as in control cells. suggesting that this was due to the acetaldehyde itself and not to the presence of encapsulated AcDH. Similar results were obtained using mouse erythrocytes. AcDH-overloaded mouse red blood cells from donor animals were also injected intraperitoneally into compatible recipients (Balb/C) and 80 to 85% of these were found to enter into circulation within 24 hr and to circulate with a half-life of 6-7.3 days (normal half-life 11 days). Following an acute dose of ethanol (2g/kg intraperitoneally). blood levels of acetaldehyde were significantly lower in mice receiving the AcDH-loaded erythrocytes than in controls. Blood levels of ethanol were also lower in the treated mice compared to controls. These results show that AcDH-overloaded erythrocytes can perform in vitro and in vivo as bioreactors improving alcohol and acetaldehyde metabolism. and suggest that administration of these cells to alcoholic patients could be of value in restoring to normal. or improving. alcohol and acetaldehyde metabolism.
The effects of swabbing the skin on apparent blood ethanol concentration, The swabbing of the arm with ethanol before venepuncture significantly raised the apparent blood ethanol concentration. when compared to the unswabbed arm. In contrast. when isopropanol was substituted for ethanol in these studies. no change in the blood ethanol concentration was determined.
Acute effects of ethanol on cultured myocardial cells: an ultrastructural study, Myocardial cells in monolayer culture were examined ultrastructurally at various times (5 min-24 hr) after addition of ethanol (12.5-500 mM). At 5 min. all concentrations of ethanol induced mitochondrial fusion and a remarkable increase in glycogen granules. and the mitochondrial outer membrane seemed more fragile. These initial ultrastructural changes then recovered with time. Glycogen granules were decreased. then returned to normal more rapidly as the ethanol concentration was increased. Mitochondrial fusion and fragile appearance of the outer membrane were hardly seen at 1 hr in the presence of 12.5 or 50 mM ethanol. but were still evident with higher ethanol concentrations (200 and 500 mM). though less frequently than at 5 and 30 min. Furthermore. 'giant mitochondria' (with at least a five-fold increase in sectional area) appeared in the presence of 200 and 500 mM ethanol with increasing time of exposure. These results are discussed in relation to the direct effects of ethanol.
Selective antagonistic effects of exposure to bright light on the hypothermic action of ethanol, Flinders Sensitive and Resistant Lines of rats. which are differentially sensitive to the hypothermic effects of both muscarinic agonists and ethanol. were exposed to full spectrum artificial bright light for eight days. because exposure to bright light has been shown to blunt hypothermic responses to muscarinic agonists. There was a selective blunting of the hypothermic effects of ethanol. but no significant change in the intoxicating effects of ethanol. as measured by evaluation of the righting reflex. The selective effect of exposure to bright light on the hypothermic actions of ethanol suggests that bright light may be modifying the function of only a limited number of brain regions. including the hypothalamus.
Profiles of ethanol-induced microsomal alkoxyresorufin (alkoxyphenoxazone) O-dealkylation: comparison with phenobarbital- and Aroclor 1254-induced systems, The O-dealkylation of various substituted alkoxyphenoxazones by liver microsomes from rats chronically fed ethanol is compared with that from pair-fed controls to determine whether there is any catalytic selectivity which could serve as an indicator for induction of cytochrome P-450j. Microsomes derived from animals pretreated with the better characterized inducers phenobarbital and Aroclor 1254 were also studied as positive controls. The specific activities (units/mg microsomal protein) but not the turnover numbers (units/nmol cytochrome P-450) were significantly increased by ethanol ingestion compared to pair-fed controls for methoxy-. ethoxy-. and pentoxy-resorufin O-dealkylation. Ethanol ingestion produced a significant increase in both specific activity and turnover number for the O-dealkylation of benzyloxy-resorufin. The degrees of induction of alkoxyresorufin-O-dealkylation activity measured for EtOH-induced microsomes range from 1.7 for methoxyresorufin to 4.8 for benzyloxyresorufin and are small in comparison to the values for phenobarbital and Aroclor 1254. This pattern of induction suggests that the minor isoforms induced by phenobarbital may be propagated by chronic ethanol ingestion.
Alcohol use and limitations in physical functioning in a sample of the Los Angeles general population, The authors examined the relationships between drinking and perceived current health and physical functioning for a general household sample of Mexican Americans and non-Hispanic whites. These relationships differed by sex and by the presence or absence of medical and psychiatric comorbidity. but not by ethnicity. Among men with a chronic medical illness. current abstinence was uniquely associated with poor current health and physical functioning. especially when current abstinence was combined with a past history of alcohol disorder. Among men without a chronic medical illness. a history of alcohol disorder (irrespective of current drinking) was uniquely associated with poorer functioning. For women. among the medically or psychiatrically ill. drinking was not strongly associated with physical functioning; while among women without chronic medical or psychiatric illness. a history of drinking was uniquely associated with poor physical functioning. The authors interpret the findings in terms of adverse effects of drinking and chronic medical conditions on functioning and the tendency of physically limited and chronically medically ill persons to stop drinking.
Young people and drinking: results of an English national survey, An account is presented of a survey of self-reported drinking habits and beliefs about alcohol amongst a national sample of teenagers in England. Fieldwork was conducted during 1988 and 1989 and involved 27 systematically selected state secondary (high) schools. Respondents were virtually all aged 14-16. The majority of teenagers reported drinking only moderate amounts of alcohol. Even so. a third of the males and nearly a fifth of the females reported having at some time consumed the equivalent of five and a half pints of beer on a single occasion. Factual knowledge about alcohol was not high and more than half of the study group supported a reduction in the legal minimum age at which alcohol may be purchased in licensed premises.
Teenage heavy drinkers: alcohol-related knowledge, beliefs, experiences, motivation and the social context of drinking, During 1988 and 1989 a survey was conducted of the drinking habits and alcohol-related beliefs of a national sample of teenagers in England. Data were obtained from 6.244 respondents virtually all aged 14-16. Heavy drinkers were significantly more likely to report drinking in a mixed sex group than were other teenagers. They were also more likely than others to have drunk illegally in licensed premises. and were distinctive from other teenagers in relation to their self-reported reasons for drinking and their alcohol-related beliefs.
Alcohol training in south-east England: a survey and evaluation, In 1982. the University of Kent at Canterbury introduced a multi-disciplinary diploma course in alcohol counselling and consultation. The purpose of the report which follows is to assess the existing range and level of alcohol services and training in south-east England against which the course was set up. and to appraise the course itself against its aims and objectives. The first part of the study was based on a questionnaire survey of senior administrators in Health and Social Services in London and the South East. and the examination of the course was based on student progress. The results from the first part of the study are bleak. Respondents believed that the majority of clients with alcohol problems were simply not detected. and a lack of resources to mount satisfactory training schemes was among the principal reasons. Only a minority of the organizations provided secondary-level training of any sort. and the majority placed alcohol problems at the bottom of their priorities for training and. by implication. for services overall. The results from the second part of the study were more encouraging. While there was little to suggest that students' knowledge and attitudes changed during the course. there were a number of small changes in behaviour. The most hopeful findings. however. came from students' and managers' perceptions. where one of the most positive outcomes of the course was a perceived growth in student maturity. confidence. and role security.
Epitopes of the HIV-1-negative factor (nef) reactive with murine monoclonal antibodies and human HIV-1-positive sera, Murine monoclonal antibodies (MAbs) raised against a recombinant nef protein fragment of human immunodeficiency virus type 1 (HIV-1) strain BH10 were characterized by an epitope mapping system using overlapping decapeptides. Four different immunogenic regions were identified. Ten human HIV-1-positive sera were tested in the same epitope mapping system. seven of these were reactive with four immunogenic regions. Two of the nef-specific epitopes recognized by human sera overlapped with the epitopes defined by the murine monoclonal antibodies. The reactivity of the monoclonal antibodies with the recombinant nef protein and with infected and uninfected cells were investigated in a variety of test systems. The results are discussed with respect to homologous regions of nef and cellular proteins.
Effect of early programmes of high and low intensity exercise on physical performance after transmural acute myocardial infarction, Does a programme of light exercise training after acute myocardial infarction produce the same improvement in treadmill performance as aerobic exercise training? Three hundred and eight men from a consecutive series of 479 men with transmural (Q wave) acute myocardial infarction. admitted to a single coronary care unit. were randomly allocated to eight weeks of group aerobic exercise training or group light exercise. Groups were well matched for all characteristics other than site of infarction. which did not significantly affect results. Mean (SD) physical working capacity (metabolic equivalents) determined by treadmill testing at the start of the study (in the third week after infarction) was 6.8 (2.2) v 6.7 (2.5) METs. at the end (in the eleventh week after infarction) 10.8 (2.3) v 9.9 (2.4) METs. and at 12 month review 10.8 (2.4) v 10.7 (1.9) METs for the exercise training group and the light exercise group respectively. The difference of 0.9 METs at the end of the study was the only significant difference between groups. There were no significant intergroup differences at any stage in resting and maximal heart rate. resting and maximal systolic blood pressure. or rate-pressure product. Apart from a small temporarily greater physical working capacity. the physical benefits of aerobic exercise training were equally well achieved by group light exercise.
Balloon atrial septostomy under echocardiographic control: six years' experience and evaluation of the practicability of cannulation via the umbilical vein, Balloon atrial septostomy was undertaken under cross sectional echocardiographic control in 63 consecutive infants: in no case was fluoroscopic imaging required. The procedure was performed in the cardiac catheterisation laboratory. ward side room. or at the bedside in the neonatal intensive care unit. Catheterisation via the umbilical vein was attempted in 37 infants aged less than 48 hours old and was successful in 27. No complication was clearly attributable to the procedure though two infants died. A nine day old child died from disseminated intravascular coagulation the day after septostomy by the iliofemoral route and another. aged nine days. died of necrotising enterocolitis which had developed when he was eight days old. after umbilical catheterisation at eight hours. Balloon atrial septostomy is a safe and easy procedure under cross sectional echocardiographic imaging control. Catheterisation via the umbilical vein was safe. easy to perform. and is appropriate in infants aged less than 48 hours.
Two cases of left superior vena cava draining directly to a left atrium with a normal coronary sinus, The most common variation in the thoracic systemic venous system is a persistent left superior vena cava draining to a coronary sinus. A rare anomaly is a persistent left superior vena cava connecting directly to the left atrium. In this situation it is believed that the coronary sinus must be absent. This report describes two cases of a persistent left superior vena cava draining to a left atrium with a normal coronary sinus.
Aortic-ventricular tunnel in a neonate: diagnosis and management based on cross sectional and colour Doppler ultrasonography, A five day old symptom free neonate was referred for assessment of a to and fro murmur associated with large volume pulses. Cross sectional echocardiography and colour flow mapping confirmed the diagnosis of an aortic-ventricular tunnel with forward flow into the aorta and regurgitant flow into the ventricle through both the tunnel and the dilated aortic valve ring. Surgical correction by patch closure of the aortic end of the tunnel was successfully undertaken two weeks later without any additional investigations. Postoperative echocardiography and colour flow imaging showed no aortic regurgitation and normal left ventricular dimensions and function.
Impending paradoxical embolism: a rare but important diagnosis, A man aged 50 presented with a history of a cerebrovascular accident and arterial embolism at two discrete peripheral sites. Echocardiography showed thrombus trapped in an interatrial site and impending paradoxical embolism was diagnosed. Treatment with heparin was started and the potentially embolic intracardiac material was removed at open heart surgery. The patient was treated with warfarin and made a good recovery. This is only the third case report of impending paradoxical embolism diagnosed in life.
Electrocardiographic findings in a patient with pure septal infarction, The electrocardiogram in a 65 year old man in whom pure septal infarction had been produced by occlusion of the septal branch during percutaneous transluminal coronary angioplasty showed that this had led to the disappearance of septal Q waves and reciprocal ST segment depression in the inferior leads.
Coronary sinus blood flow and coronary haemodynamic function in children: measurement by the continuous thermodilution method with coronary sinus cannulation via the femoral vein, In 19 children with Kawasaki disease without any cardiac sequelae the coronary sinus was cannulated via the femoral vein with a specially designed flow catheter and coronary sinus blood flow was measured by the continuous thermodilution method. There was a statistically significant positive correlation between coronary sinus blood flow and age. body surface area. and left ventricular mass. but coronary sinus blood flow per left ventricular mass (100 g) was negatively correlated with age. body surface area. and left ventricular mass. Coronary vascular resistance was negatively correlated with age. body surface area. and left ventricular mass. Younger children require a much greater coronary blood flow per left ventricular mass and have a higher coronary vascular resistance than older children and adolescents. These results may indicate that coronary blood flow is less efficient in childhood than in adolescence or adulthood.
Postoperative protein metabolism: effect of nursing elderly patients for 24 h after abdominal surgery in a thermoneutral environment, We have studied the effect of intraoperative body heat conservation and 24-h thermoneutrality on postoperative whole body protein turnover using stable isotope methodology in a group of elderly patients undergoing colorectal surgery for rectosigmoid adenocarcinoma. Two groups of eight patients were studied. One group (control. or cold) received routine intraoperative and postoperative care. All patients in the second group (warmed) were maintained at normothermia during anaesthesia and surgery; these patients were nursed after surgery in a warm room (ambient temperature 28-30 degrees C) for a period of 24 h. General anaesthesia. surgical care and nutritional support were similar in both groups. A constant nutritional intake. based on nitrogen 0.1 g kg-1 day-1 and energy 20 kcal kg-1 day-1. was provided orally for 7 days before surgery and i.v. after operation for 4 consecutive days. Whole body protein breakdown and synthesis. as assessed by stable isotope methodology. increased significantly 2 and 4 days after surgery in both groups (P less than 0.01). but the increase in protein breakdown in the warmed group on day 2 was significantly less than that in the cold group (P less than 0.05). The increase in leucine oxidation in the warmed group on the 2nd day after surgery was not significant. and was less than the increase observed in the cold group (P less than 0.05). However. by the 4th day. leucine oxidation was enhanced significantly in both groups (P less than 0.01).
Plasma concentrations of bupivacaine following combined sciatic and femoral 3 in 1 nerve blocks in open knee surgery, We administered combined femoral 3 in 1 and sciatic nerve blocks to provide postoperative pain relief in 22 consecutive patients undergoing elective knee replacement surgery under spinal anaesthesia. The patients were allocated randomly to two groups. In group A (n = 11) the blocks were performed with 0.5% bupivacaine (with adrenaline) 3 mg/kg body weight and in group B (n = 11) 0.5% plain bupivacaine in the same dose was used. Serial plasma concentrations of bupivacaine were measured for up to 2 h and the duration of postoperative analgesia was measured in both groups. No significant differences were found between the two groups. There were no clinical signs or symptoms of bupivacaine toxicity in each group. This study demonstrated that. after combined sciatic and 3 in 1 femoral block. concentrations of bupivacaine associated with toxicity were not reached. even though the dose of bupivacaine administered exceeded the manufacturer's recommended dose by 50%.
Comparison of four subarachnoid solutions in a needle-through-needle technique for elective caesarean section, We have used both spinal and extradural anaesthesia with a 26-gauge. long spinal needle through a 16-gauge Tuohy needle for elective Caesarean section. Four different subarachnoid solutions of bupivacaine were compared: 0.5% heavy bupivacaine alone. or with adrenaline. fentanyl or adrenaline and fentanyl. The incidence of complications and time of regression of the sensory block were analysed. The technique is recommended because it allows rapid onset of anaesthesia and the advantages of an extradural catheter. The subarachnoid solution of choice was 0.5% heavy bupivacaine 12.5 mg with fentanyl 10 micrograms.
Optimal dose of lignocaine for preventing pain on injection of propofol, The purpose of this study was to define the optimum dose of lignocaine required to reduce pain on injection of propofol. We conducted a prospective. randomized. double-blind trial on 310 patients undergoing anaesthesia. Patients were allocated to four groups according to the lignocaine dosage: group A (control). no lignocaine; group B. lignocaine 0.1 mg kg-1; group C. lignocaine 0.2 mg kg-1; group D. lignocaine 0.4 mg kg-1. Our results showed that a dose of lignocaine 0.1 mg kg-1 significantly reduced the incidence of pain and that there was no improvement when the dose was increased.
Molecular evaluation of response to all-trans-retinoic acid therapy in patients with acute promyelocytic leukemia, The advent of retinoic acid (RA) in the treatment of acute promyelocytic leukemia (APL) has led to a high frequency of short-lasting complete remissions (CR). We studied the response to RA by molecularly analyzing the RA receptor alpha (RAR alpha) locus. which has recently been shown to be rearranged in all APLs. Southern blot analysis demonstrated that the RAR alpha rearrangements persisted in the APL samples containing maturing myeloid cells 2 to 3 weeks after the start of RA treatment. but disappeared after 5 to 8 weeks. when the patients achieved CR. Our investigations provide clear evidence that CR occurs at molecular level and that there is reconstitution of an apparently normal. nonclonal hematopoiesis. Further. it shows that RA acts by triggering differentiation rather than by exerting a cytotoxic effect on the leukemic clone.
Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens, A randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.
Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia, 4'-Demethoxydaunorubicin (idarubicin [IDR]) is a new anthracycline that differs from its parent compound by the deletion of a methoxy group at position 4 of the chromophore ring. This minor structural modification results in a more lipophilic compound with a unique metabolite that has a prolonged plasma half-life as well as in vitro and in vivo antileukemia activity. To determine its activity in acute myelogenous leukemia (AML). 130 consecutive adult patients between the ages of 16 and 60 with newly diagnosed disease were randomized in a single institution study to receive either IDR in combination with cytosine arabinoside (Ara-C) or standard therapy with daunorubicin (DNR) and Ara-C. The trial was analyzed using the O'Brien-Fleming multiple testing design that allowed for periodic inspection of the data at specific patient accession points. After accrual of 60 patients per arm. analysis showed that patients who received IDR/Ara-C had a superior response compared with those who received standard therapy: 48 of 60 patients (80%) achieved complete remission on the former arm compared with 35 of 60 patients on the latter (58%. P = .005). Logistic regression analysis of factors associated with complete response indicated that treatment with IDR/Ara-C offered a significant advantage to patients who presented with a high initial white blood cell count compared with treatment with DNR/Ara-C. The degree of marrow aplasia was approximately the same on each arm as was nonhematologic toxicity. Overall survival for patients on the IDR/Ara-C arm was 19.5 months compared with 13.5 months on the DNR/Ara-C arm (P = .025) at a median follow-up of 2.5 years. We conclude that IDR/Ara-C can effectively replace standard therapy with DNR/Ara-C in adult patients less than age 60 with newly diagnosed AML.
Engraftment after infusion of CD34+ marrow cells in patients with breast cancer or neuroblastoma, The CD34 antigen is expressed by 1% to 4% of human and baboon marrow cells. including virtually all hematopoietic progenitors detectable by in vitro assays. Previous work from our laboratory has shown that CD34+ marrow cells can engraft lethally irradiated baboons. Because the CD34 antigen has not been detected on most solid tumors. positive selection of CD34+ cells may be used to provide marrow cells capable of engraftment. but depleted of tumor cells. In seven patients with stage IV breast cancer and two patients with stage IV neuroblastoma. 2.5 to 17.5 x 10(9) marrow cells were separated by immunoadsorption with the anti-CD34 antibody 12-8 and 50 to 260 x 10(6) positively selected cells were recovered that were 64 +/- 16% (range 35% to 92%) CD34+. The patients received 1.0 to 5.2 x 10(6) CD34-enriched cells/kg after marrow ablative therapy. Six patients engrafted. achieving granulocyte counts of greater than 500/mm3 at 34 +/- 10 (range 21 to 47) days and platelets counts of greater than 20.000/mm3 at 46 +/- 14 (range 28 to 66) days posttransplant. Five of these patients showed durable engraftment until the time of death 82 to 386 days posttransplant. One patient failed to sustain engraftment associated with metastatic marrow disease. Three patients died at days 14. 14. and 17 posttransplant. two of whom had evidence of early engraftment. These studies suggest that CD34+ marrow cells are capable of reconstituting hematopoiesis in humans.
In vivo platelet activation in beta-thalassemia major reflected by increased platelet-thromboxane urinary metabolites, Increased frequency of thromboembolic events has been recently observed in patients with beta-thalassemia major (TM). Platelet function anomalies including impaired aggregation. increased circulating aggregates. and our finding of shortened platelet survival indicate that platelets may be involved in the hypercoagulability in thalassemia. Consequently. we used a technique based on thin layer chromatography purification and enzyme immunoassay to measure urinary metabolites of thromboxane A2 (TXA2) and prostacyclin (PGI2) in nine splenectomized patients with beta-TM regularly transfused. five non-splenectomized patients with beta-thalassemia intermedia (TI). and 20 healthy individuals. A significant 4- to 10-fold increase was observed in the urinary excretion of 2.3-dinor-TXB2. 11-dehydro-TXB2 and 2.3-dinor-6-keto-PGF1 alpha in patients with TM and TI as compared with healthy controls. No significant differences were found in the concentrations of these metabolites between TM and TI patients. Six TM patients received a very low dose of aspirin (20 mg/day) for 7 days. A significant decrease was observed in the urinary concentrations of 2.3-dinor-TXB2 and 11-dehydro-TXB2 derived from platelets. However. the levels of urinary 2.3-dinor-6-keto-PGF1 alpha reflecting vascular production and TXB2 and 6-keto-PGF1 alpha originating from the kidney were not significantly changed. These results are consistent with those of increased in vivo production of TXA2 because of endogenous platelet activation.
The majority of peripheral blood monoclonal IgM secreting cells are CD5 negative in three patients with mixed cryoglobulinemia, The mixed cryoglobulinemia is considered to be a nonmalignant human B-cell proliferation that frequently produces a monoclonal IgM with anti-IgG activity (rheumatoid factor). Using murine monoclonal anti-idiotypic antibodies specific for private or minor idiotopes on monoclonal IgM from three patients suffering from nonmalignant mixed cryoglobulinemia. we investigated the presence of the CD5 antigen on the monoclonal IgM producing cells in these patients. It is shown by two-color cytofluorometric analysis that the majority of the peripheral blood monoclonal IgM rheumatoid factor secreting cells is CD5 negative in these three patients. One of the monoclonal rheumatoid factor K variable regions was sequenced at the protein level and belongs to the human VK III group. as a high proportion of monoclonal rheumatoid factors and some B-cell chronic lymphocytic leukemia (CLL) membrane bound Igs. Thus. despite the preferential use of similar VK genes and the absence of somatic mutation affecting these variable regions in both malignant B-cell CLL and nonmalignant mixed cryoglobulinemia. these proliferating B cells differ in the CD5 membrane expression.
Differentiation of a human eosinophilic leukemia cell line (EoL-1) by a human T-cell leukemia cell line (HIL-3)-derived factor, Differentiation of a human eosinophilic leukemia cell line. EoL-1. induced by the culture supernatant of a human ATL cell line. HIL-3 (HIL-3 sup) was compared with differentiation induced by defined cytokines. HIL-3 sup induced EoL-1 cells to express eosinophilic granules and segmented nuclei after 6 to 9 days of incubation. HIL-3 sup also induced the expression of Fc epsilon receptor II (Fc epsilon RII/CD23) and an eosinophil differentiation antigen EO-1 mainly on eosinophilic granule (+) cells. Furthermore. HIL-3 sup induced EoL-1 cells to respond to an eosinophil chemotactic factor. platelet activating factor. HIL-3 cells express messenger RNA (mRNA) of interleukin-5 (IL-5). macrophage colony-stimulating factor (M-CSF). and IL-3 but not granulocyte CSF (G-CSF). Granulocyte-macrophage CSF (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) were detected in the HIL-3 sup. Recombinant IL-2 (rIL-2). rIL-3. rIL-4. rIL-5. rM-CSF. and rGM-CSF did not induce eosinophilic granules. rG-CSF induced a few eosinophilic granule (+) cells. and TNF-alpha. which did not induce eosinophilic granules by itself. enhanced the ability of G-CSF to induce them. However. G-CSF and TNF-alpha did not induce the expression of Fc epsilon RII and EO-1 antigen. Moreover. anti-G-CSF. anti-TNF-alpha. anti-GM-CSF. anti-IL-3. and anti-IL-5 antibodies did not suppress the effect of HIL-3 sup on the differentiation of EoL-1 cells. All the data suggest that HIL-3 sup contains an unidentified factor that induces differentiation of EoL-1 cells. and that EoL-1 cells and HIL-3 sup provide an important model for the examination of differentiation mechanisms and functions of eosinophils.
Detection of Epstein-Barr virus messenger RNA in Reed-Sternberg cells of Hodgkin's disease by in situ hybridization with biotinylated probes on specially processed modified acetone methyl benzoate xylene (ModAMeX) sections, Microscopic intracellular detection of Epstein-Barr virus (EBV) messenger RNA in Reed-Sternberg cells of Hodgkin's disease (HD) was possible by in situ hybridization. in tissue sections prepared by a method termed modified acetone methyl benzoate xylene (ModAMeX). The ModAMeX method was initially developed for simultaneous optimal preservation of leucocyte differentiation antigens and morphology. Two biotinylated DNA probes. corresponding to the same BamHI-W (internal repeat) of the EBV genome were used. EBV mRNA was detected in neoplastic cells in 16 of 54 (30%) lymph node biopsy specimens from usual subtypes of HD (lymphocyte predominance. 0/5; nodular sclerosis. 4/22; mixed cellularity. 12/26; unclassified. 0/1). EBV mRNA was also detected in the lymph node biopsy of 1 additional human immunodeficiency virus (HIV)-related case of HD (mixed cellularity) and in 2 of 4 cases of B-cell lymphomas occurring in patients with acquired immunodeficiency syndrome (AIDS). In other non-Hodgkin's lymphomas. EBV mRNA was detected in only 1 of 41 cases. Cases of HD positive for EBV mRNA were immunostained by CD30 and CD15 antibodies. The hybridization signals were exclusively restricted to Reed-Sternberg cells and variants. When analyzed retrospectively. no statistically significant correlation emerged between hybridization findings. EBV serology. or disease outcome over the 3 years of the availability of ModAMeX technique. The findings support the contention of a direct role of EBV in the pathogenesis of HD. at least in some cases.
Two-step differentiation of AML-193 leukemic line: terminal maturation is induced by positive interaction of retinoic acid with granulocyte colony-stimulating factor (CSF) and vitamin D3 with monocyte CSF, The human AML-193 cell line requires exogenous granulocyte-monocyte colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) for growth in liquid or semisolid medium. However. these CSFs do not stimulate the differentiation of the cell line. We show that addition of all-trans retinoic acid (RA) or 1.25 dihydroxyvitamin D3 (D3) induces AML-193 cells to differentiate into the granulocytic or monocytic lineage. respectively. On the other hand. addition of either G- or M-CSF alone exerts virtually no differentiative effect. Terminal granulocytic or monocytic differentiation was observed when AML-193 cells were treated with RA and G-CSF. or D3 and M-CSF. respectively. as evaluated by cell morphology. analysis of surface antigens. and phagocytic functions. These positive interactions indicate that the differentiating activity of G- and M-CSF on leukemic cells may be unmasked by preliminary treatment with RA and D3. respectively. ie. the physiologic inducers override the leukemic differentiation blockade and CFSs exert their differentiative activity on the unblocked leukemic cells. These preliminary observations on a single cell line may pave the way for the designing of clinical protocols combining physiologic inducer(s) and hematopoietic growth factor(s) in the treatment of acute leukemia.
Autologous bone marrow transplantation in acute myelogenous leukemia: in vitro treatment with myeloid-specific monoclonal antibodies and drugs in combination, We report the results of a preclinical study comparing four different purging protocols using a promyelocytic human cell line HL-60 and myeloid leukemic progenitor cells (colony-forming unit-leukemic [CFU-L]) from acute myelogenous leukemia (AML) patients assayed in semisolid culture. We studied the antileukemic effect of (1) Single-cycle complement-mediated lysis by two different monoclonal antibodies (MoAbs) (M195 [CD33] and F23 [CD13] 40 micrograms/mL). reactive with distinct antigens found on early myeloid cells and monocytes. used alone and in combinations; (2) 4-Hydroperoxycyclophosphamide (4-HC) (80 mumol/L or 100 mumol/L) alone; or (3) combined with VP-16 (5 micrograms/mL) and (4) a cocktail of 1 through 3 as above (combined immunochemotherapy). More than 4 logs of HL-60 tumor cell elimination were observed after 1 hour of incubation with both MoAbs plus 4-HC + VP-16 while the single treatment (immunotherapy or chemotherapy) provided 1.5 and 3.5 logs of colony-forming inhibition. respectively. When the same protocols were tested on cryopreserved leukemic cells from eight patients with AML. we observed a mean value of CFU-L inhibition of 92.3% +/- 2.5% SD. 95.5% +/- 1.4% SD. and 99% +/- 0.8% SD after MoAbs and complement lysis. 4-HC. and 4-HC + VP-16 treatment. respectively. The combined treatment of MoAbs and 4-HC + VP-16 produced more than 3-log reduction of CFU-L colony formation. By comparison. the mean recovery of committed normal bone marrow progenitors after incubation with MoAbs and complement was 12% for CFU-granulocyte-macrophage (CFU-GM). 22.9% for burst-forming unit erythroid (BFU-E). and the recovery following 4-HC + VP-16 treatment was 4.4% for CFU-GM and 5.6% BFU-E. In subsequent experiments. highly purified CD34+ blast cells. enriched by positive selection. and stimulated in liquid culture by cytokines (interleukin-1 [IL-1]. IL-3. and combination of both) or MO-conditioned medium (MoCM). demonstrated that immunochemotherapy spares hematopoietic colony-forming cells earlier than day 14 CFU-GM. in vitro.
Clonal analysis of T-cell deficiencies in autotransplant recipients, We have used limiting dilution culture methods to determine the frequency of mitogen-responsive T cells in peripheral blood of patients after bone marrow autotransplantation. and have compared their responsiveness to that of allotransplant recipients and normal controls. Autotransplant patients were found to have low responder cell frequencies in tests for lymphokine-secreting helper function. and for IL-2 dependent proliferator and cytotoxic function. Multiple regression analysis showed that function was lower in autotransplant patients than in allorecipients. and lower in male patients for all three functional assays. Patients with clinically significant infection tended to have lower proliferative function in both transplant groups and lower cytotoxic function in the allotransplant population. Graft-versus-host disease was associated with lower T-cell function. but was present only in the allotransplant group; therefore. it cannot account for the even lower levels of function observed in the autotransplant population. Because we observe deficits in T-cell regeneration in autotransplant recipients that are even more severe than in allorecipients. we postulate that cellular immunodeficiency after bone marrow transplantation may reflect limitations in thymic-dependent repopulation rather than an effect of genetic disparity between host and donor (eg. clinical or subclinical graft-versus-host).
Merkel cell tumour: clinical behaviour and treatment, We have reviewed 30 reports of Merkel cell tumour and described a further five cases in order to establish a database and from this more clearly define the biology of this tumour. prognostic factors that govern outcome. and optimal management. After excision alone of the primary lesion. local recurrence occurred in 39 per cent of patients and regional failure occurred in 46 per cent. In contrast. in patients treated by excision plus prophylactic treatment (adjuvant node dissection and/or adjuvant radiation). local recurrence occurred in 26 per cent and regional failure in 22 per cent. Locoregional recurrence carried an ominous significance with 67 per cent of patients subsequently dying of the disease. For patients who either presented with regional disease or later developed regional disease. the best outcome (44 per cent survival with mean follow-up of 40 months) was obtained following treatment by therapeutic node dissection with or without radiation. In contrast. treatment of regional disease with radiation alone was associated with only a 20 per cent survival rate. Unfavourable prognostic factors included young age. lesions sited in the head and neck or trunk. male sex. and the presence of locoregional failure and/or systemic disease. We conclude that Merkel cell tumours behave in a similar manner to the aggressive variants of melanoma and that minimal treatment consists of wide surgical resection of the primary lesion (with a margin of 2.5-3 cm) coupled with resection and probably also radiation of regional disease if present. In addition. consideration should be given to prophylactic node dissection in node negative patients. especially in those patients with unfavourable prognostic factors.
Conventional versus laparoscopic cholecystectomy and the randomized controlled trial. Cholecystectomy Study Group, We considered using a randomized trial to assess the value of laparoscopic cholecystectomy in the treatment of symptomatic gallstones. The pros and cons for the timing of such a trial were in favour of not beginning the trial until surgeons learned to use the new procedure safely and effectively. and until key endpoints and outcome indices could be identified and assessed using valid measures. Instead an observational study was implemented to monitor the learning curve of surgeons as they mastered the laparoscopic equipment and procedures. and to assess the responses of the patients to the procedure. In the first 100 patients. the procedure proved to be as safe and feasible to use as conventional surgery. and there were strong benefits in terms of quicker recovery of the patients with less pain. discomfort. and a reduced length of hospital stay. The responses of the surgeons and the patients to the new procedure now place ethical constraints on the planning of a randomized controlled trial. Currently. comprehensive surveillance and monitoring of laparoscopic cholecystectomy is the only realistic method with which to assess the impact of this new technology in our clinic.
Laparoscopic cholecystectomy: the Dundee technique, A total of 61 patients was subjected to laparoscopic cholecystectomy. The procedure was completed in 60 cases and converted to open operation in one (2 per cent). The morbidity rate was low (total 7 per cent. major 2 per cent. blood transfusion rate 5 per cent). The median duration of the laparoscopic cholecystectomy with cholangiography was 135 min (range 65-270 min). The operation took less time to complete in patients with functioning gallbladders than in those with non-functioning fibrotic organs (median 120 versus 175 min). The majority of patients required opiate analgesia despite infiltration of the stab wounds with bupivacaine. The mean (s.d.) hospital stay was 2.9 (1.5) days. The median time to resume work or full activity after discharge was 11 days.
Population-based study of surgery in juvenile onset ulcerative colitis, A geographically based cohort of 37 children with ulcerative colitis has been derived by sampling from Scottish Hospital In-patient Statistics. Surgical histories were examined and analysed by actuarial methods. and the major operations performed were compared with operations for ulcerative colitis in the Lothians' Surgical Audit. Fourteen of the 37 patients had a total of 26 operations (15 major. 11 minor). Sixteen per cent had major surgery within 5 years of onset of symptoms. and the types of operation were similar to those recorded in Lothians' Surgical Audit. Operation rate was significantly lower than that for a parallel cohort of patients with Crohn's disease. With a mean follow-up of 7.4 years. seven (19 per cent) patients have a permanent stoma and there has been one death.
Natural history of indeterminate colitis, The long-term outcome of patients with a pathological diagnosis of indeterminate colitis on a colectomy specimen was investigated. The case records of 46 such patients operated on for inflammatory bowel disease between 1960 and 1983 were reviewed. Using the preoperative clinical information. pathological and radiological reports. it was possible to divide the patients into three groups: group 1. probable Crohn's disease (19 cases); group 2. probable ulcerative colitis (11 cases); and group 3. indeterminate colitis (16 cases). The patients were followed for a minimum of 2.5 years (median 10. range 2.5-28 years). During this period the probable diagnosis changed in five cases only. One patient in group 1 (Crohn's disease) was subsequently considered to have ulcerative colitis (group 2). The other four patients were all in group 3. Three were reclassified as ulcerative colitis and the fourth as Crohn's disease on the finding of a single granuloma in a rectal biopsy. No case in group 3 required subsequent small bowel surgery. These data suggest that patients continuing with a diagnosis of indeterminate colitis in spite of careful preoperative and postoperative assessment are unlikely to show features of Crohn's disease in the long term. This may be important when considering a subsequent restorative proctectomy.
Light reflection rheography: an effective non-invasive technique for screening patients with suspected deep venous thrombosis, Light reflection rheography is a simple non-invasive technique for assessing venous function in the leg. One hundred and twenty-four patients referred for venography with a clinically suspected deep venous thrombosis were investigated by light reflection rheography to determine the accuracy of the technique in diagnosing acute thrombosis. In half of the patients venography confirmed a deep venous thrombosis. Light reflection rheography had a sensitivity of 92 per cent and a specificity of 84 per cent in detecting acute thrombosis. The technique had a negative predictive value of 92 per cent in selecting those patients with no thrombosis. Light reflection rheography can be performed at the bedside or in the radiography department which makes it a suitable technique for screening patients with suspected deep venous thrombosis.
Long-term follow-up of elderly patients with locoregional breast cancer treated with tamoxifen only, One hundred and thirteen women aged 70 years or more with locoregional breast cancer were treated with tamoxifen alone as primary treatment. They were followed for a minimum of 5 years. Complete response occurred in 38 women. partial response in 17. no change in 34 and progressive disease in 24. Where progressive disease occurred. or where patients relapsed after an initial response. the most suitable conventional therapy was given. The actuarial 5-year survival rate was 49.4 per cent for all patients and was much higher (92 per cent) in those showing an initial complete response. Seventy patients (61.9 per cent) were not controlled by tamoxifen alone to death or most recent follow-up. Tamoxifen provides an alternative treatment for operable breast cancer in older women in the short term and may be particularly suitable for those with concurrent disease or who are unwilling to undergo surgery. The low morbidity rate from tamoxifen must be balanced against the need to maintain close follow-up. In the medium to long term. sole primary treatment by tamoxifen delays more definitive therapy.
Mammography in the management of patients with small breast cancers, Findings on mammography resulted in a change of treatment policy in 17 of 200 patients with small breast cancers (T1/T2 less than 4 cm. N0/N1. M0). Twelve patients were considered unsuitable for conservation therapy because of mammographic evidence of either extensive in situ carcinoma or more than one focus of invasive carcinoma. These patients were treated by mastectomy and histology confirmed widespread in situ carcinoma or multifocal/multicentric invasive carcinoma. Seven patients were found to have unsuspected contralateral lesions on mammography. of which five were subsequently shown to be malignant. Routine preoperative mammography is essential in the management of patients with small breast cancers.
Gunshot wound of the abdomen: role of selective conservative management, This prospective study includes 146 patients with gunshot wounds of the abdomen. One hundred and five patients (72 per cent) had an acute abdomen on admission and were operated on immediately. The remaining 41 patients (28 per cent) had minimal or equivocal abdominal signs and were observed with serial clinical examinations. Seven of the observed patients needed subsequent laparotomy. but there was no mortality or serious morbidity. Had a policy of mandatory exploration for abdominal gunshot wound been applied the incidence of unnecessary or negative laparotomies would have been 27 per cent. By using a policy of selective conservatism this figure was only 5 per cent. We suggest that abdominal gunshot wounds should be assessed and managed exactly like knife wounds. Physical examination is reliable in detecting significant intra-abdominal injuries. Many carefully selected patients with abdominal gunshot wounds can safely be managed non-operatively.
Major trauma: a district general hospital experience, A retrospective review of all patients with major trauma admitted to a busy suburban district hospital was conducted over a 1-year period. Outcome for each patient was assessed using the TRISS system which calculates the probability of survival based on anatomical extent of injury and degree of physiological disturbance at the time of admission. Thirty-nine patients were admitted following major trauma. of whom nine died. Seven of the deaths were in patients with a greater than 50 per cent chance of survival according to the TRISS system. In contrast. four patients survived who had a greater than 50 per cent chance of death. Details of these 11 cases are given. The numbers of patients who were referred to neurosurgeons and cardiothoracic surgeons in regional specialist centres were recorded. as was the relative contribution of general and orthopaedic surgeons in our own hospital. We conclude that. in the absence of specialized trauma centres. a reasonable standard of care for patients who have sustained major trauma can be delivered in a district general hospital.
Long-term survival in patients operated on for benign peptic ulcer disease, Survival rate was analysed in a cohort of 6459 patients who had undergone partial gastrectomy for benign ulcer disease and who had survived the first year after operation. The cohort was followed for 27-35 years. There was a slight but significant decrease in relative survival rate to 92 per cent (95 per cent confidence interval 87-97 per cent) 35 years after operation. No decrease in relative survival rate was observed during the first 20 years after operation. There was no difference by gender or surgical procedure. but patients operated on for gastric ulcer. compared with duodenal ulcer. and patients operated on at younger ages had a poorer relative survival rate. The effects of partial gastrectomy on survival. both overall and by diagnosis or age at operation. are probably attributable to confounding factors linked with the peptic ulcer disease rather than to the surgical procedure itself. We conclude that partial gastrectomy seems to have very little impact on survival once the patient has survived the first year after operation.
A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer, This study evaluated combined 5-fluorouracil (5FU) and doxorubicin as postoperative adjuvant chemotherapy for patients who had undergone potentially curative resection of a primary gastric adenocarcinoma. One hundred twenty-five eligible and evaluable patients were stratified according to extent of surgical resection. location of the primary tumor within the stomach. and lymph node status. They were then randomized to either receive three cycles of chemotherapy or be observed. The median time from patient entry was 7 years. Results showed no significant difference in time to recurrence. The 5-year survival rate was 33% for the observation arm and 32% for the adjuvant therapy arm. The data excluded a 16% improvement in the 5-year survival rate for patients receiving chemotherapy with a P value less than 0.05. There were two drug-related fatalities due to sepsis. These results demonstrate no substantive benefit for this chemotherapy regimen as postoperative adjuvant treatment of resected gastric cancer.
Severe, symptomatic, dose-limiting hypophosphatemia induced by hepatic arterial infusion of recombinant tumor necrosis factor in patients with liver metastases, Twenty-two patients with liver metastases received 45 courses of recombinant tumor necrosis factor (rTNF) by hepatic arterial infusion in doses ranging from 12.5 to 175 micrograms/m2/d for 5 days by continuous infusion. The induction of statistically significant. dose-related. severe. albeit transient. hypophosphatemia (less than 1.0 mg/dl) associated with clinically significant. right-sided myocardial dysfunction and severe lassitude was observed. These side effects were promptly reversed after rTNF was stopped and intravenous phosphate supplementation was started. As no significant or consistent increase in urinary phosphate excretion was detected. the rTNF-induced hypophosphatemia probably resulted from an intracellular shift of phosphate. Since tumor regression was clearly associated with the lowest levels of serum phosphate. hypophosphatemia may be important in the antitumor effects of rTNF.
13-cis-retinoic acid induces cellular differentiation and durable remission in refractory cutaneous Ki-1 lymphoma, A 35-year-old man with refractory cutaneous Ki-1 lymphoma was salvaged successfully with oral 13-cis-retinoic acid (1 mg/kg/day). He had a complete remission lasting for 20 months before a single nodule recurred on his skin. Excisional biopsy of the recurrent tumor revealed a distinct morphologic change. suggesting cellular differentiation toward a more benign phenotype. No significant side effects were noted except mild xerostomia. bone pain. and hyperlipidemia. The authors believe that 13-cis-retinoic acid should be considered in the treatment of cutaneous Ki-1 lymphoma.
Progesterone receptor in hepatocellular carcinoma. Correlation with androgen and estrogen receptors, Progesterone receptors (PgR). estrogen receptors (ER). and androgen receptors (AR) were assayed consecutively for hepatocellular carcinoma (HCC) that was surgically removed from 19 men and three women. The methods of receptor assay were the enzyme immunoassay (EIA) for PgR and the dextran-coated charcoal (DCC) technique for ER and AR. The patients ranged in age from 32 to 77 years (average. 60.3 years). No patients had received any specific anti-cancer therapy before tissue collection. All patients but one had underlying liver disease: cirrhosis in 13 and chronic hepatitis in eight. The positive rate of each receptor was 18% for PgR. 48% for ER. and 82% for AR. The titer was highest for AR. intermediate for ER. and lowest for PgR. The titers of PgR in four PgR-positive patients ranged from only 1.1 to 3.0 fmol/mg of protein. There was no relationship between PgR. ER. and AR in terms of positivity and titer. Also. other clinical and histopathologic data did not influence the positivity or concentration of these three sex hormone receptors. It can be concluded that no or little PgR exists in the cytosol of untreated HCC.
Humoral immunodeficiency in T-cell chronic lymphocytic leukemia. An immunologic assessment, The humoral antibody immunodeficiency in two patients with T-cell chronic lymphocytic leukemia (T-CLL) appeared to be the result of immunoregulatory abnormalities in the leukemic T-cell populations. Both patients had CD4+ CD45R+ "virgin" or suppressor-inducer T-CLL. but Patient 1 had hypogammaglobulinemia and Patient 2. immunoglobulin (Ig) M hypergammaglobulinemia. Although. CD25+ interleukin-2 (IL-2) receptors were present on leukemic T-cells of both patient. OKT9+ (CD71) transferrin receptors and OKT10 (CD38) activation antigens were found only on Patient 2's cells. Highly elevated amounts of IL-2 was secreted from phytohemagglutinin-stimulated and concanavalin A-stimulated T-cells in both patients. In Patient 1 with hypogammaglobulinemia. immune defects involve T-cells. first an intense suppressor activity on B-cell-induced IgM and IgG synthesis and. second. deficient production of B-cell growth factor (BCGF) and B-cell differentiation factor (BCDF). In Patient 2. highly elevated BCGF and IgM-specific BCDF was secreted by T-cells. a mechanism leading to IgM hypergammaglobulinemia in this patient. These studies stress the importance of BCGF and BCDF activity of leukemic T-cells in humoral antibody immunodeficiency disorders in T-CLL cases.
The expression of proliferative-associated nuclear antigen p105 in gastric carcinoma, The expression of proliferation-associated nuclear antigen p105 of gastric carcinomas was studied by multiparameter flow cytometric and immunohistochemical technique. Multiparameter flow cytometric analysis revealed that p105 expression was rarely observed in the resting cells of normal gastric epithelium. On the contrary. the immunofluorescence (IF) intensity of cancer cells in G1 phase was approximately two-fold to three-fold greater than that of G0 phase of cancer cells or normal gastric epithelium. The p105 antigen content of cancer cells increased with cell cycle progression. and increased more rapidly in cells in late S-phase than in cells in G0 and early S-phase. Microphotometric study demonstrated that cells in M-phase exhibited a dramatic increase in the amount of the antigen. and the IF intensity of the mitotic cells were approximately five-fold to ten-fold greater than that of cells in G1 and S-phase. These results indicate that the antigen demonstrated by the p105 monoclonal antibody is present in the G1. S. G2. M-phases. but not in the G0 phase. Immunohistochemical technique demonstrated that patients with lymph node metastases are more likely to have high p105-positive rates than did node-negative patients. The mean p105-positive rates of aneuploid tumors was significantly higher than those of diploid tumors. From these results the authors speculate that the measurement of p105-positive rates may be a powerful prognostic indicator of gastric carcinoma.
Antibody-fluorescein conjugates for photoimmunodiagnosis of human colon carcinoma in nude mice, To improve the detectability of tumors by light-induced fluorescence. the use of monoclonal antibodies (MoAb) as carriers of fluorescent molecules was studied. As a model for this approach. the biodistribution of an anticarcinoembryonic antigen (CEA) MoAb coupled to fluorescein was studied in mice bearing a human colon carcinoma xenograft. In vitro. such conjugates with fluorescein-MoAb molar ratios ranging from four to 19. doubly labeled with 125I. showed more than 82% binding to immobilized CEA. In vivo. conjugates with a fluorescein-MoAb molar ratio of ten or less resulted in a tumor uptake of more than 30% of the injected dose of radioactivity per gram tumor at 24 hours. Tumor to liver. kidney. and muscle ratios of 20. 30 and 72. respectively. were obtained 48 hours after injection of the 125I-MoAb-(fluorescein)10 conjugate. The highest fluorescence intensity was always obtained for the tumor with the anti-CEA MoAb conjugate; whereas in control mice injected with fluoresceinated control immunoglobulin G1. no detectable increase in tumor fluorescence was observed. To compare these results with a classically used dye. mice bearing the same xenografts received 60 micrograms of Photofrin II. The intensity of the fluorescence signal of the tumor with this amount of Photofrin II was eight times lower than that obtained after an injection of 442 ng of fluorescein coupled with 20 micrograms of MoAb. which gave an absolute amount of fluorescein localized in the tumor of up to 125 ng/g of tumor. These results illustrate the possibility of improving the specificity of in vivo tumor localization of dyes for laser-induced fluorescence photodetection and phototherapy by coupling them to MoAb directed against tumor markers.
Growth-hormone releasing hormone in a bronchial carcinoid, The case is reported of a 43-year-old patient with a peripherally located bronchial carcinoid tumor containing large amounts of immunoreactive and bioactive growth-hormone releasing hormone (GHRH). Because no GHRH was found in the peripheral circulation. there was no quantitative or qualitative derangement of growth-hormone secretion. The tumor was excised completely by thoracotomy.
Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma, Catecholamines are involved critically in the mechanisms of liver cell proliferation by acting on hepatic alpha-1 and beta-2 adrenoceptors. To identify the role of these receptors in human hepatocellular carcinoma (HCC). the density was examined of alpha-1 and beta-2 adrenoceptors with their affinity and coupling of beta-2 adrenoceptors to adenylate cyclase in HCC tissue and in nonadjacent/nontumor tissue from the same livers. Studies were also done on healthy livers from age-matched and sex-matched patients undergoing abdominal surgery for nonhepatic diseases. Twenty-two HCC had a decrease of about 72% in alpha-1 adrenoceptor density compared with their nonadjacent/nontumor tissue and a decrease of about 40% compared with healthy controls. Nonadjacent/nontumor tissue from HCC patients had a 125% increase in alpha-1 adrenoceptor density compared with healthy livers. Twenty-three of 24 HCC had an increase of about 180% in beta adrenoceptor density compared with their nonadjacent/nontumor tissue and healthy controls. Beta adrenoceptors were coupled to adenylate cyclase. as evidenced by a guanosine triphosphate-mediated right shift in (-)-isoproterenol competition isotherms and by cyclic adenosine monophosphate (cAMP) production after stimulation with (-)-isoproterenol. The HCC tissue yielded a larger increase in cAMP than nonadjacent/nontumor tissue and healthy controls. The authors conclude that a higher density of alpha-1 adrenoceptors in nonadjacent/nontumor tissue from HCC characterizes the "healthy" part of the liver in HCC patients and that an increase in beta-2 and a decrease in alpha-1 adrenoceptor densities characterize the tumor part of the liver in human HCC.
Pyruvate kinase activity and isozyme composition in normal fibrous tissue and fibroblastic proliferations, Pyruvate kinase (PK) was studied in 57 fibroblastic and fibrohistiocytic proliferations and normal fibrous tissue (n = 10). The specific activity was significantly increased in malignant tumors (1.67 +/- 0.25) compared with normal tissue (0.26 +/- 0.04; P less than 0.001) and benign proliferations (0.52 +/- 0.05; P less than 0.005). Although an overlap exists between aggressive fibromatosis and the benign group. high values of PK activity are indicative of Grade 2 and 3 malignancy. Significant shifts in isozyme pattern. favoring the expression of K-type subunits were found in tumors with a metastasizing potential and aggressive fibromatosis. These changes in the isozyme pattern of PK in aggressive fibromatosis may act as another argument to place them in the category of malignant fibroblastic tumors.
Expression of glutathione S-transferase-pi messenger RNA in human esophageal cancers, The expression of human glutathione S-transferase-pi (GST-pi) in resected primary esophageal tumors and in matching normal esophageal mucosa from 25 patients undergoing radical surgery was measured by RNA blot hybridization. The RNA transcript levels of GST-pi in the tumor tissues were higher than those in normal tissues in 20 of 25 cases (80%). The mean GST-pi mRNA value in the tumor tissues (n = 25) was significantly (P less than 0.01) elevated as compared with that in background mucosa (n = 29). and in ten of 25 tumors (40%) the level of GST-pi mRNA exceeded the mean normal tissue value by two standard deviations (normal mean value + 2 X SD). The results obtained from the current experiment thus suggests that GST-pi might be a useful marker for human esophageal cancer. No correlation between GST-pi mRNA level and clinical stage or histologic characteristics was apparent.
Flow cytometric analysis of nuclear DNA content in advanced gastric cancer and its relationship with prognosis, Cell nuclear DNA content was determined by flow cytometric analysis in 270 patients with deeply infiltrating (beyond the submucosa) cancer. so-called advanced gastric cancer. Aneuploidy was observed in 150 cases (55.6%). Multivariate analysis showed that the DNA ploidy pattern was the third significant prognostic factor behind peritoneal dissemination and liver metastasis. The 5-year survival rate of diploid patients (62.9%) was significantly higher than that of aneuploid patients (22.7%) (P less than 0.01). This trend was most clear in patients with Stage III and IV tumors. Among aneuploid cases the high DNA index group indicated a worse prognosis than the low DNA index group. It was thus assumed that the DNA ploidy pattern was a useful prognostic indicator of advanced gastric cancer.
Oncogene expression in the liver tissue of patients with nonneoplastic liver disease, The expression of cellular oncogenes in nonneoplastic human liver tissue was examined to determine if there was a correlation between oncogene expression and physiologic regeneration in liver disease. Human liver tissue specimens from 70 patients with various histologic findings from almost normal to cirrhosis were examined (using northern blot analysis) for the expression of nine cellular oncogenes. With c-K-ras. four RNA bands (5.6-kilobase [kb]. 2.1-kb. 1.5-kb. and 1.2-kb RNA species) were detected in all liver tissue examined. Expression of c-fos was also detected in a few samples examined when 50-micrograms samples of total RNA were applied. Other oncogenes such as H-ras. myc. erbB. raf. fms. fes. and myb were not detected. These results indicate that particular oncogene(s) may not be highly expressed during liver regeneration in human liver disease. or that populations of regenerating hepatocytes may be too small to show significant elevations of oncogene expression. The new finding of a constant expression of c-K-ras in human liver tissue suggests that it is linked to essential hepatocellular function rather than carcinogenesis.
A prospective evaluation of the effect of tumor cell DNA content on recurrence in colorectal cancer, Tumor cell DNA (ploidy) content was measured prospectively in samples from 320 patients resected for colorectal cancer with a minimum follow-up time of 2 years. All patients were followed and those with recurrence were investigated carefully. There was no correlation between tumors with an abnormal cellular DNA content (aneuploid or tetraploid) and patient age. sex. tumor site. pathologic stage. or histologic grade. In 236 patients who underwent potentially curative operations. 75 (32%) had local and/or distant recurrence. The recurrence rate was significantly higher (test statistic. 4.3; P = 0.04) for those patients with aneuploid tumors (52 of 142. 37%) compared with those with diploid tumors (23 of 94. 24%). The subgroups of patients where ploidy exerted an effect were in patients with Stage B tumors or mobile tumors and in patients over 65 years of age. Further analysis showed that there was a twofold increase in local recurrence and a threefold increase in distant recurrence in patients with aneuploid tumors. but no excess of patients who had both local and distant recurrence. Measurement of DNA ploidy can identify a group of patients undergoing curative surgery for colorectal cancer at high risk for recurrence. In combination with clinicopathologic factors. DNA ploidy may be useful in analyzing the results of trials and in planning adjuvant therapy.
Prognostic significance of the proportion of Ki-67-positive cells in adult T-cell leukemia, The authors examined peripheral blood samples from patients with adult T-cell leukemia (ATL) using the monoclonal antibody Ki-67 which detects a nuclear antigen present in actively proliferating cells. In patients with chronic ATL. the percentage of Ki-67-positive cells was significantly lower than in acute ATL patients (median values. 3.3% versus 18.9%. P less than 0.001). Furthermore. there was a significant inverse correlation between the percentage of Ki-67-positive cells and the length of survival (P less than 0.001). Serum lactic dehydrogenase (LDH) levels also showed a significant inverse correlation with survival. but this was less strong than that for Ki-67 (0.01 less than P less than 0.02). Thus. Ki-67 positivity appears to indicate the aggressiveness of ATL. and can possibly be used for the clinical classification of ATL patients as well as for the prediction of prognosis.
Estimate of breast cancer risk reduction with weight loss, Upper body fat localization has been associated with an increased risk of cancer. This study demonstrated that 64.2% of 124 women with at least a 4.5-kg weight loss decreased their upper body fat localization. as measured by a reduction in their suprailiac-thigh skin fold ratio and other skin fold thicknesses associated with upper body fat localization. Based on a risk model previously developed for breast cancer and upper body fat localization. a reduction in estimated breast cancer relative risk of 45% was calculated for the entire group of women who lost 4.5 kg or more in weight. Greater weight loss further reduced upper body fat localization and estimated breast cancer risk based on this model.
Patterns of care related to age of men with prostate cancer, A chart review study was done of 242 Stages A2 to D1 cancer patients to determine whether the age of patients with prostate cancer influenced their physicians' management strategies. Ten hospitals of varying size. medical-school affiliation. and patient socioeconomic status participated in this study. Patterns of prostate cancer care were examined using sets of branching logic standards in the form of criteria maps. A chart-based comorbidity index was used to control for the effect of coexisting diseases on cancer management. Regression models indicated that patient age affected the intensity of both the diagnostic evaluation and therapy. even after controlling for independent factors such as comorbid disease and individual hospital differences. Patients aged 75 years and older had significantly less intensive clinical staging workups and use of surgical and radiation therapies compared with patients aged 65 to 74 years and patients aged 50 to 64 years. In conjunction with similar results noted in studies of elderly patients with other malignancies. these results suggest that age bias is likely to be widespread. Physicians need to consider life expectancy. the ability of the patient to tolerate diagnostic procedures and therapies. and the quality of life in making treatment decisions.
Congenital malignant melanoma of the eye, Twenty-three cases of congenital malignant melanoma have previously been reported. Here the authors report the first case of a congenital malignant melanoma arising in the eye. A newborn girl had a large pigmented ocular tumor. hepatomegaly. and multiple pigmented skin and choroidal lesions. The histopathologic diagnosis was of a malignant melanoma with hepatic metastases. The skin and choroidal lesions were considered to be congenital melanocytic nevi. The most plausible pathogenetic link between these two conditions was that the malignancy had arisen as a second-hit mutation within a choroidal congenital melanocytic nevus. Despite widespread metastases the baby. treated by surgery and chemotherapy. survives in good health. aged 2 years. 10 months.
Tobacco, alcohol, and coffee and cancer of the pancreas. A population-based, case-control study in Quebec, Canada, A population-based. case-control study of pancreatic cancer was carried out in greater Montreal between 1984 and 1988. A total of 179 cases and 239 population-based controls were interviewed. This study was part of the SEARCH program of the International Agency for Research on Cancer of the World Health Organization. A strong positive association was observed between total cigarette smoking and risk of pancreatic cancer (odds ratio [OR] = 3.76; 95% confidence interval [CI]. 1.80 to 7.83). The OR for current smokers in the highest quintile of number of cigarettes was 5.15 compared with 3.99 for exsmokers. Those who consumed alcohol were in general at lower risk than nondrinkers. Coffee drinkers were collectively at lower risk than nondrinkers. particularly when coffee was consumed with meals. not on empty stomach.
Transgenic mice as models of hemopoiesis, A useful approach to establishing the biologic actions. in vivo. of granulocyte-macrophage colony-stimulating factor (GM-CSF) is to assess the consequences of long-term elevation of the factor in transgenic mice. Two lines of transgenic GM-CSF mice were analyzed. The major abnormality exhibited was an elevation in the number of macrophages. eosinophils. and polymorphs in the peritoneal and pleural cavities. Disease states exhibited by the lines were dependent on the insertion site of the GM-CSF gene. These disease states seem best explained on the basis of CSF-mediated macrophage activation and may provide valuable clues as to the cause of comparable human diseases such as malignant histiocytosis. polymyositis. or rheumatoid arthritis.
Interleukin-3. Biologic effects and clinical impact, Human interleukin-3 (IL-3) is expressed in yeast and has a specific activity of 5 x 10(7) U/mg of protein. It exerts functional and proliferative effects on multiple hematopoietic cell lineages including the neutrophil. eosinophil. basophil. monocytic. and thrombopoietic cell lines. IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF) share common binding capacities on hematopoietic cells. Each of these agents has entered clinical trials. The clinical experiences with IL-3 alone and in combination with GM-CSF in a Phase I/II trial are summarized in this report.
The future of cytokine combination therapy, The hematopoietic growth factors including colony-stimulating factors (CSF) and interleukins (IL) have overlapping and pleiotropic effects on proliferation and differentiation of progenitor cells and stem cells. The regulatory signals can influence terminal differentiation and the cell cycle status. self-renewal. and differentiation of early pluripotential stem cells. Synergistic interactions between CSF and IL have been shown. both in vitro and in vivo. to be critical in hematopoietic regulation. The future of clinical trials of cytokines in congenital and acquired myelosuppressed states lies in the selective use of appropriate combinations of these regulatory macromolecules.
Pulmonary concerns and the exercise prescription, When writing an exercise prescription. the contributions of the pulmonary system are commonly forgotten. The lung has a tremendous potential to improve its work output. and its contributions are only realized when pulmonary disease or environmental stresses of altitude limit pulmonary performance. At altitudes of 5000 feet above sea level. hypoxia is significant in limiting aerobic capacity. and the exercise prescription should follow relative percentages of VO2max guided by the training heart rate rather than actual work output. Training at altitude will improve performance at altitude. but training at altitude does not always improve sea level performance. Suggestions of using longer recovery intervals. sojourns back and forth from sea level to altitude. and shorter-duration. high-intensity exercise sessions may help improve sea level performance. but more research is needed. The limitations of reactive airway disease and exercise-induced asthma can be minimized with proper attention to training techniques. environmental modifications. and pharmacologic treatment. In the 1984 Olympics. 41 medals were won by athletes with the diagnosis of reactive airway disease. Finally. the crippling limitations of chronic obstructive bronchopulmonary disease can be improved by a proper exercise rehabilitation program that uses an accurate and thorough assessment procedure prior to beginning an exercise program. Also. careful follow-up and continual monitoring of cardiac rhythm. oximetry. and exercise intensity of the pulmonary impaired patient will result in optimal improvement in the patient's sense of well-being. tolerance to dyspnea. and increased ability to do aerobic work. as well as an enhanced quality of life.
Exercise in women. Effects on reproductive system and pregnancy, Exercise may have a significant effect on the reproductive system in women; however. it is doubtful if exercise alone causes the hypothalamic amenorrhea. which is probably multifactorial in origin. Pregnancy is also affected by exercise. although long-term or deleterious effects have not been documented.
Weight control and exercise, Obesity in the United States can truly be called a national epidemic. The associated health risks and diseases present a tremendous drain to the economy. The most effective program to lose and maintain a desirable body weight incorporates a combination of restriction in caloric intake with an increase in caloric expenditure through exercise. A gradual approach of losing 1 or 2 pounds per week has proved to be the most effective. Men should strive to maintain approximately 15% body fat and women 25% body fat. Weight-reduction programs that demonstrate phenomenal weight loss in a short period will not work over the long term and may represent a significant health risk. The ability to lose fat and maintain a desirable body weight is not easy but can be attained through a firm commitment to a healthy life style.
Keeping fit when injured, Staying physically fit while injured can improve the patient's outlook. both physiologically and psychologically. and help him or her return to regular activities completely. safely. and with decreased risk of re-injury. Although treating and protecting the injured area is of primary concern. it is important to then look beyond the injury. toward keeping the rest of the body as fit as possible. Whether through alternative sports. cross training. or water exercise. the patient can preserve the integrity of the injured joint. keep the noninjured muscles active. and maintain ever-important cardiovascular fitness. The exercise prescription for the injured athlete should emphasize our most vital muscle. the heart.
The role of exercise in the primary and secondary prevention of coronary artery disease, Over the past 30 years. mortality rates from coronary artery disease (CAD) have decreased by more than 30% in the United States. However. CAD remains the major public health problem in this country. There is now substantial evidence linking exercise training to a reduced risk for CAD and for mortality after myocardial infarction. The actual mechanism by which physical activity aids in reducing the risk for developing or dying from CAD has still to be elucidated. Several highly plausible mechanisms have been postulated. including decreased myocardial oxygen demand. increased myocardial oxygen supply. reduced propensity toward ventricular arrhythmias. reduced platelet aggregation. increased plasma fibrinolytic activity. and modification of multiple CAD risk factors. Irrespective of the precise mechanism. it now appears that lower levels of physical activity are needed to reduce the risk for CAD than are needed to optimize cardiorespiratory fitness. In this regard. we recommend that the type. frequency. intensity. and duration of exercise training be modulated to achieve a weekly energy expenditure of between 14 and 20 kilocalories per kilogram of body weight. Although aerobic activities should be emphasized. muscle strengthening and flexibility exercises should also be incorporated into the training program in order to promote musculoskeletal health.
The acute and chronic antihypertensive effects of ketanserin cannot be explained by blockade of vascular serotonin, type 2, receptors or alpha 1-adrenergic receptors, The mechanism underlying the antihypertensive effect of acute and chronic administration of ketanserin was investigated in eight hypertensive patients. Intrabrachial artery infusions of serotonin and the selective alpha 1-adrenergic receptor agonist methoxamine were given before and 1 hour after a single oral dose of 20 mg ketanserin and after 4 weeks of treatment with 20 to 40 mg twice daily. Blood pressure was reduced by ketanserin both after the initial dose (p less than 0.01) and after 4 weeks of treatment (p less than 0.01). During placebo. serotonin. 1 ng/kg/min. increased forearm blood flow by 51% +/- 9% (p less than 0.01). whereas the highest dose induced a decrease in flow (-33% +/- 6%; p less than 0.01). Methoxamine elicited a vasoconstriction (p less than 0.001). These effects of serotonin and methoxamine were not influenced by either the initial dose of ketanserin or after 4 weeks of treatment. It is concluded that serotonin cannot be considered a general endogenous pressor agent in these patients. The antihypertensive effects of ketanserin cannot be attributed to either vascular alpha 1-receptor or serotonin. type 2. receptor blockade.
Disposition of drugs in cystic fibrosis. I. Sulfamethoxazole and trimethoprim, The disposition of sulfamethoxazole and trimethoprim. after constant rate intravenous administration (10 mg/kg/hr sulfamethoxazole and 2 mg/kg/hr trimethoprim for 1 hour). was investigated in adult patients with cystic fibrosis (n = 7) and in age-matched healthy subjects (control subjects. n = 8). The total plasma clearance of sulfamethoxazole was found to be increased in cystic fibrosis (0.0262 +/- 0.0064 L/hr/kg) when compared with that found in control subjects (0.0188 +/- 0.0043 L/hr/kg). This increase in clearance was found to be primarily attributable to an increase in the metabolic clearance of sulfamethoxazole to N4-acetylsulfamethoxazole (0.00903 +/- 0.00247 versus 0.00355 +/- 0.00049 L/hr/kg) with the renal clearance of sulfamethoxazole remaining unchanged. These conclusions were not altered when the pharmacokinetic parameters were computed for the unbound drug or when they were normalized with respect to body surface area. These data indicate that. in cystic fibrosis. the enzymes mediating the metabolism of sulfamethoxazole to N4-acetylsulfamethoxazole. N-acetyltransferase(s). may be induced. activated. or both. or that the uptake of sulfamethoxazole by cells that metabolize sulfamethoxazole to N4-acetylsulfamethoxazole is enhanced. The total plasma clearance of trimethoprim was also found to be increased in cystic fibrosis (0.1808 +/- 0.0440 L/hr/kg) when compared with that found in control subjects (0.1139 +/- 0.0193 L/hr/kg). In contrast to sulfamethoxazole. this increase in clearance was found to be primarily attributable to an increase in the renal clearance of trimethoprim (0.1240 +/- 0.0299 versus 0.0720 +/- 0.0166 L/hr/kg). These data indicate that the tubular secretion of trimethoprim may be enhanced in cystic fibrosis.
The effect of food on pharmacokinetics and pharmacodynamics of fenoldopam in class III heart failure, Eighteen patients with New York Heart Association class III congestive heart failure were given single 100 mg oral doses of fenoldopam with food or fasting in a random-order single-blind crossover trial. Before and after each fenoldopam dose. thermodilution cardiac output. right atrial pressure. pulmonary artery pressure. and pulmonary capillary wedge pressure (PCWP) were measured with a balloon-tipped pulmonary artery catheter. and heart rates and blood pressures were recorded with an automated sphygmomanometer. Compared with fasting. bioavailability of fenoldopam was decreased significantly when administered with food: mean peak plasma fenoldopam level decreased from 26.5 (+/- 4.1 SEM) ng/ml to 10.9 (+/- 1.7 SEM) ng/ml (p = 0.0004) and mean area under the concentration-time curve was decreased from 44.7 (+/- 5.8 SEM) ng.hr/ml to 26.8 (+/- 4.1 SEM) ng.hr/ml (p = 0.0001). Fenoldopam administration to fasting patients resulted in decreases in mean arterial pressure. systemic vascular resistance. and PCWP and significant increases in cardiac index without change in heart rate. The maximum changes in mean cardiac index. systemic vascular resistance. and PCWP were greatest 1 hour after oral administration and did not persist beyond 3 hours after administration. In fasting patients. changes in cardiac index were correlated with plasma fenoldopam levels. whereas changes in PCWP and mean arterial pressure did not correlate significantly with the observed fenoldopam level.
Pharmacokinetics of fosinopril in patients with various degrees of renal function, Single-dose kinetics of fosinopril. a new phosphorus-containing angiotensin-converting enzyme inhibitor and its active diacid. fosinoprilat. were investigated in patients with mild. moderate. or severe renal impairment and in those with normal renal function. After an intravenous dose of 14C-fosinoprilat (7.5 mg). total body clearance of fosinoprilat was significantly greater (p less than 0.05) in patients with normal renal function than in renally impaired patients but was not related to the degree of renal impairment in patients with creatinine clearance values of 11 to 72 ml/min/1.73 m2. Decreases in renal clearance were compensated for by increases in hepatic clearance. so that total clearance was maintained. After oral 14C-fosinopril (10 mg). plasma kinetics and bioavailability of fosinoprilat were similar for the three groups of renally impaired patients. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin-converting enzyme inhibitors.
Rebound insomnia after only brief and intermittent use of rapidly eliminated benzodiazepines, In three parallel groups. brief and intermittent administration and withdrawal of triazolam. 0.5 mg. temazepam. 30 mg. and placebo were assessed in a 12-night sleep laboratory study of 18 subjects with insomnia. With this intermittent schedule both drugs improved sleep. with about one-third reduction in total wake time; this reduction was significant for temazepam but not for triazolam. Even though the periods of drug administration were quite brief. withdrawal of triazolam consistently produced rebound insomnia. with increases in total wake time above baseline of 61% and 51%. respectively. for the first night of each withdrawal period. With temazepam this effect was more variable. with total wake time increased only with the second withdrawal period (39%). Thus these findings indicate that even under conditions of brief. intermittent use and withdrawal. triazolam and. to a lesser degree. temazepam produce rebound insomnia after abrupt withdrawal. thereby predisposing to drug-taking behavior and increasing the potential for drug dependence.
Normal coding sequence of insulin gene in Pima Indians and Nauruans, two groups with highest prevalence of type II diabetes, The nucleotide sequence of the insulin gene was determined in American Pima Indians and Micronesian Nauruans. two populations in whom the prevalence of non-insulin-dependent (type II) diabetes mellitus is the highest in the world. The insulin gene was amplified by the polymerase chain reaction to generate single-stranded DNA suitable for direct sequencing. The nucleotide sequences of the coding and adjacent regions of the insulin gene in six Pima Indians and two Nauruans with type II diabetes were identical to previously published insulin gene sequences of nondiabetic subjects.
Low sex-hormone-binding globulin concentration as independent risk factor for development of NIDDM. 12-yr follow-up of population study of women in Gothenburg, Sweden, Serum sex-hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG) concentrations were evaluated as risk factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). myocardial infarction. stroke. and premature death in a prospective study of 1462 randomly selected women. aged 38-60 yr. over 12 yr of observation. In multivariate analysis. taking only age into consideration as a confounding factor. low initial concentration of SHBG was significantly correlated to the incidence of NIDDM and stroke. and high initial concentration of CBG was correlated to the incidence of NIDDM. There were also significant correlations between SHBG and CBG concentrations on one hand and possible risk factors for the end points studied. such as serum triglycerides. serum cholesterol. fasting blood glucose. body mass. body mass index. waist/hip ratio. smoking habits. and systolic blood pressure. on the other. When these possible confounders. in addition to age. were taken into consideration in multivariate analyses. only the inverse significant correlation between SHBG and NIDDM remained. The increased incidence of diabetes was confined to the lowest quintile of SHBG values. where it was 5-fold higher than in the remaining group. This incidence was further increased to 8- and 11-fold in the lowest 10 and 5% of the values. respectively. We conclude that SHBG is a uniquely strong independent risk factor for the development of NIDDM in women.
Progressive deterioration of endocrine function after intraportal but not kidney subcapsular rat islet transplantation, In inbred streptozocin-induced diabetic rats. the long-term function of different endocrine pancreatic isografts was compared. Isolated islets transplanted into the portal vein showed a progressive deterioration of function over time. In contrast. islets under the kidney capsule sustained a constant long-term function controlling all clinical signs of diabetes. Recipients of kidney subcapsular islets displayed normal growth rate. peripheral serum glucose and insulin levels. and metabolic parameters. However. their functional reserve was markedly reduced as revealed by diminished glucose tolerance and reduced insulin-secreting capacity after an intravenous glucose challenge. Vascularized whole-organ pancreatic grafts with portal venous drainage led to complete normalization of all parameters determined in this study. This study showed that the long-term function of islets transplanted under the kidney capsule is superior compared with islets transplanted into the portal vein.
Insulin secretory response to secretagogues by perifused islets from chronically glucose-infused rats, Perifused islets from rats infused for 7 days with 40% glucose exhibited an altered secretory response to selected stimuli. Both phases of insulin release were blunted when 20 mM L-leucine was tested; the secretory response to a subsequent leucine stimulation was also blunted compared with the control group. The ability of 20 mM alpha-ketoisocaproate to stimulate the release of insulin was also greatly diminished in islets from glucose-infused rats. The secretory response to 50 microM tolbutamide plus 7 mM glucose by perifused islets from glucose-infused rats was 45% lower than in the control group. In addition. the response to a subsequent 10 mM glucose stimulation was lost. On the other hand. islets from glucose-infused rats responded to 20 microM forskolin plus 16.7 mM glucose with on significant change in the amount of insulin released during both phases of stimulation compared with the control group. The response to 100 nM phorbol 12-myristate 13-acetate was 3.1-fold higher in islets from glucose-infused compared with saline-infused rats. The finding that chronic infusions of glucose lead to selective impairment of the secretory response to fuel stimuli and agents such as tolbutamide that act on metabolically regulated K+ channels gives support to the notion that alterations in the generation of metabolic coupling signals might be involved in the phenomenon described here.
Importance of hepatic glucoreceptors in sympathoadrenal response to hypoglycemia, To ascertain whether hepatic glucoreceptors are important to hypoglycemic counterregulation. a localized euglycemic clamp was employed across the liver during general hypoglycemia. Dogs were infused peripherally with insulin (18-21 pmol.kg-1.min-1) for 150 min to induce systemic hypoglycemia. During the liver-clamp (LC) protocol. glucose was infused via the portal vein to maintain euglycemia at the liver. In control experiments. i.e.. matched infusion (MI). glucose was infused peripherally at a rate determined to yield similar arterial glycemia levels in the two protocols. Arterial glucose concentrations were not different between protocols during the final hour of insulin infusion (3.26 +/- 0.21 and 3.25 +/- 0.21 mM during LC and MI. respectively; P = 0.91). Calculated hepatic glucose concentrations during the same period were significantly higher for LC (5.22 +/- 0.23 mM) than for MI (3.25 +/- 0.21 mM). During MI. both epinephrine and norepinephrine rose significantly from basal values of 562 +/- 87 pM and 1.21 +/- 0.19 nM to plateaus of 3691 +/- 1097 pM (P = 0.0001) and 2.38 +/- 0.35 nM (P = 0.0002). respectively. However. during LC. the elevation in epinephrine was suppressed by 42 +/- 8% (P = 0.015) relative to MI. Six of seven animals demonstrated a suppression in the norepinephrine response. averaging 32 +/- 13% (NS. P = 0.068). The glucagon response to hypoglycemia was unaffected by the level of hepatic glycemia. Hepatic hypoglycemia is essential to produce the full sympathoadrenal response to insulin-induced hypoglycemia.
Comparison of 1,5-anhydroglucitol, HbA1c, and fructosamine for detection of diabetes mellitus, To evaluate the use of serum 1.5-anhydroglucitol (AG) levels in screening for diabetes mellitus. we compared the sensitivity and specificity of HbA1c. fructosamine (FA). and AG in 1620 randomly selected subjects in 11 institutions throughout Japan. Most individuals were receiving diet and/or drug therapy for diabetes. Subjects were separated into four groups based on World Health Organization criteria: nondiabetic control subjects. subjects with impaired glucose tolerance (IGT). patients with diabetes. and patients with other disorders without IGT. The overlap of AG values between each group was less than that of HbA1c or FA values. AG levels were significantly correlated with fasting plasma glucose (r = -0.627). HbA1c (r = -0.629). and FA (r = -0.590) levels. If we took 14 micrograms/ml as the normal lower limit. AG level was highly specific (93.1%). and a decreased AG level indicated diabetes mellitus (84.2% sensitivity). According to the selectivity index (sensitivity value times specificity value). AG determinations were superior to both HbA1c and FA measurements for diabetes screening. When combinations of these tests were used. only AG and HbA1c together were slightly better than AG alone. Thus. together with other advantages of AG. e.g.. its wide variance with relatively fair glycemic control and the negligible influence of the sampling conditions. AG level has more potential than HbA1c or FA level as a screening criterion for diabetes.
Effects of media conditions, insulin, and dexamethasone on insulin-receptor mRNA and promoter activity in HepG2 cells, Numerous physiological agents and conditions modulate cellular insulin sensitivity by downregulating or upregulating total cellular insulin receptors. In this study. we examined the effects of replacing complete medium in the absence or presence of insulin on the regulation of insulin-receptor gene expression in cultured human hepatoma cells (HepG2). Failure to replace complete medium resulted in growth arrest of HepG2 cells and a six- to sevenfold increase in insulin-receptor mRNA due to the prolongation of insulin-receptor mRNA half-life. Northern analysis revealed multiple insulin-receptor mRNA species; the largest species (11 kilobases) was disproportionately increased in growth-arrested cells. High concentrations of insulin (500 ng/ml) induced a 33.8% decrease in the abundance of insulin-receptor mRNA (n = 14). At lower concentrations. a trend of inhibition was observed but was not statistically significant. Insulin (500 ng/ml) did not affect insulin-receptor mRNA stability. The effect of conditioned media. insulin. and dexamethasone on insulin-receptor promoter activity was also examined. Various constructs of the 5'-flanking region of the insulin-receptor gene were attached immediately upstream to a chloramphenicol acetyltransferase (CAT) reporter gene and transiently transfected into HepG2 cells via a pBR322-derived plasmid (pCAT). In cells replaced with complete medium. 12 and 118% of the promoter activity was contained within 578 and 877 base pairs. respectively. from the major translational initiation site. Conditioned media from growth-arrested cells in culture for 7 days increased promoter activity approximately twofold in 48 h. However. this increase failed to localize to any specific region on the insulin-receptor promoter.
Evolution of insulin secretory response to glucose by perifused islets from lean (FA/FA) rats chronically infused with glucose, Chronic infusion of nondiabetic rats with glucose for up to 7 days modified the insulin secretory response by subsequently perifused islets. Thus. on the 1st day of infusion with 40% glucose. the islets responded to 16.7 mM glucose with a 3.9-fold increase in insulin release during the first 10 min with no significant change during the second-phase insulin output compared with the control group. On the 2nd day. there was a 2-fold enhancement of insulin release during the initial 10 min of stimulation. the second phase being a similar to control islets. On the 5th day of infusion. the pattern of insulin release was not significantly different from the control group. After 7 day of infusion. there was a 46% decrease in first-phase and a 33% decrease in second-phase insulin response to glucose. The response to 10 mM arginine plus 5 mM glucose was not modified by chronic glucose infusion. Priming experiments indicate that islets from rats infused for 7 days were not able to recover the normal pattern of secretion in vitro. Islets from 7-day glucose-infused rats contained 75% more protein and had a significantly higher insulin content than control islet. suggesting that insulin synthesis is not involved in the loss of the response observed. Glucose metabolism by the islets was modified by glucose infusion with a significant increase in glucose utilization and no changes in glucose oxidation. suggesting that alterations in mitochondrial oxidative events are involved in the phenomenon of desensitization.
Contribution to postprandial hyperglycemia and effect on initial splanchnic glucose clearance of hepatic glucose cycling in glucose-intolerant or NIDDM patients, Excessive amounts of glucose enter the systemic circulation when patients with non-insulin-dependent diabetes mellitus (NIDDM) eat a carbohydrate-containing meal. To determine the contribution of hepatic glucose cycling (defined as the net effect of glucose/glucose-6-phosphate cycling and uptake and release of glucose from hepatic glycogen) to postprandial hyperglycemia. diabetic. glucose-intolerant. and nondiabetic subjects were fed mixed meals. The meal contained both [2-3H]glucose (an isotope that is extensively detritiated during hepatic glucose cycling) and [6-3H]glucose (an isotope that is not detritiated during hepatic glucose cycling). Of the 50 g of carbohydrate contained in the meal. approximately 4-8 g underwent hepatic glucose cycling. Although total cycling of ingested glucose did not differ between diabetic. glucose-intolerant. and nondiabetic subjects (361 +/- 67 vs. 494 +/- 106 vs. 322 +/- 44 mumol.kg-1.5 h-1. respectively). the data suggested that hepatic cycling was increased in the diabetic and glucose-intolerant individuals but not in the nondiabetic subjects during the first 2 h after eating. Hepatic cycling during the first 2 h after eating was correlated with the prevailing glucagon concentration (r = 0.6. P less than 0.01) and increased (P less than 0.05) as hepatic glucose release increased. Hepatic glucose cycling had a marked effect on the measurement of so-called initial splanchnic glucose uptake. Nevertheless. however measured. initial splanchnic glucose uptake was not decreased and. if anything. was increased in diabetic and glucose-intolerant patients. Integrated postprandial hepatic glucose release increased (r less than 0.01) with the severity of fasting hyperglycemia.
Control of expression of insulin resistance and hyperglycemia by different genetic factors in diabetic C57BL/6J mice, The inheritance of the tendency to develop diet-induced non-insulin-dependent (type II) diabetes was analyzed in crosses between diabetes-prone C57BL/6J (BL/6) mice and diabetes-resistant A/J mice. The effects of a diabetogenic diet on blood glucose and insulin levels. insulin sensitivity. and weight were evaluated in F1 and both (BL/6 X A/J) F1 X BL/6 and (BL/6 X A/J) F1 X A/J backcross mice. These results suggest that diet-induced hyperglycemia is largely determined by a recessive gene and diet-induced insulin resistance by a dominant gene. Analyses of both backcrosses indicated that insulin sensitivity and blood glucose levels were unrelated. suggesting that they are controlled by different genetic factors. This conclusion was supported by data from nine recombinant inbred BXA strains in which no correlation was observed between these variables. Furthermore. insulin sensitivity and body weight correlated differently in the two backcross groups. suggesting that insulin resistance is not simply a function of obesity. The number of genes that predominantly influence diabetic traits was estimated by comparing the variance observed in (BL/6 X A/J) F1 X BL/6 backcross mice with that observed in parental mice. The data suggest that relatively few genes predominantly affect the diabetic phenotype in this murine model.
Antibiotic use in the treatment of non-streptococcal pharyngitis, Treatment of non-streptococcal pharyngitis (NSP) varies among physicians. Recent data regarding difficult-to-culture bacterial pathogens have increased interest in antibiotic treatment of NSP. This study examined physician behavior regarding antibiotic treatment of NSP in preparation for a prospective clinical trial. The records of 358 patients with pharyngitis-related diagnoses from a large private family physician practice and an urban hospital's housestaff clinic were reviewed. No significant relationship between the presence of streptococcus and the prescribing of antibiotics was found. Physicians gave antibiotics to 50% of patients with clinical signs and symptoms of pharyngitis. Many of these tested negative for streptococcus. Physicians used antibiotics effective against Mycoplasma and Chlamydia less than one half of the time. Projected costs of drug treatment for patients with NSP was $1.200. Family medicine educators are encouraged to monitor their own and their residents' antibiotic prescribing behaviors when treating common upper respiratory infections.
The relationship of cocaine to headache in polysubstance abusers, In a questionnaire survey of inpatient polysubstance abusers it was found that cocaine relieved migraine-type headaches much more often in chronic headache sufferers than in those with only occasional headaches (p less than .05). However. cocaine could also bring on headaches after several hours. both in chronic headache sufferers and in those not subject to headaches. The facts that cocaine may relieve headache immediately. and also may precipitate headaches several hours after use. suggests that the well-known vasoconstrictive actions of cocaine may be responsible. Migraineurs seem more susceptible to some of these effects of cocaine than are people without chronic headaches.
"Hemicrania continua": a clinical review, Hemicrania continua (HC) is a headache entity completely responsive to indomethacin. Since 1984. 18 cases have been described. 15 females and 3 males. i.e. a F:M ratio of 5.0. The finding of a female preponderance. like that in chronic paroxysmal hemicrania. is a new observation. HC is. in general. a unilateral headache in the sense that it sets in on one side and subsequently sticks to this side. In two cases. both sides might possibly be involved. when the pain was at its maximum. In another (somewhat dubious) case the headache was bilateral. The pain was continuous from the beginning in 8 of 18 cases (early stage ratio continuous: non-continuous = 0.8). Over time. the headache developed a continuous character in 16 of the 18 cases. producing a "continuous: non-continuous ratio" of 8:1. The intensity of pain generally was moderate and was not reported as excruciatingly severe by any patient. The autonomic involvement from a clinical point of view. was clearly less pronounced than that of other unilateral headaches. such as cluster headache and chronic paroxysmal hemicrania.
Psychophysiological parameters of migraine and muscle-contraction headaches, Previous headache studies have been unable to verify the presumed presence of headache. Attempting to correct this design fault. the present study assessed four psychophysiological measures (frontalis EMG. temporal BVP. temporal and finger skin temperature) and salient subjective measures in 13 migraineurs. eight muscle-contraction headache sufferers. and 13 age-matched normals. All subjects submitted to two 30-minute sessions of quiet monitoring. and for the headache subjects. one of the sessions was headache active. A bogus. but convincing preliminary "assessment" revealed insufficient headache activity in the headache active session. forcing subjects to reschedule that session in the future when a strong headache was present. A parallel manipulation was employed with the normal subjects. A MANOVA failed to discriminate within- or between-group differences on the psychophysiological measures. Self-reported pain was uncorrelated with the psychophysiological indices. These results cast further doubt on the validity of the psychophysiological measures employed in this study. the same ones routinely endorsed by headache researchers and therapists. We discuss problems of recruitment. compliance. and attrition in basic headache research.
The role of family structure, functioning, and pain modeling in headache, In an initial attempt to examine relationships between family functioning and chronic headache disorders. the present study examined: a) family structure characteristics. b) family functioning. and c) family pain modeling. Subjects completed an assessment battery consisting of several measures of family functioning. Analyses showed that migraine sufferers (N = 42) as compared to headache-free controls (N = 59) were more likely to describe their families as emphasizing clear organization. structure. rules. and overall control. but less likely to encourage emotional expression. No differences were found between tension headache subjects (N = 43) and headache-free controls. While only an initial exploration of the importance of family characteristics in chronic headache. these results suggest that there are important differences in headache subjects' (particularly migraine) reports of family environment and functioning.
Bioelectrical impedance assay (BIA) of total body composition in alcohol-induced migraine patients. Preliminary report, "Whole body composition" was investigated in 30 people subject to alcohol-induced migraine. The control group was 30 people matched for age. sex. height and weight. who were not subject to migraine and who consumed moderate amounts of alcohol. The following were evaluated: anthropometric data. alcohol intake in grams per day. total body water. fat-free mass. fat mass. and body mass index (kg/m2). Two methods of measurement were used: skin fold thickness evaluation. and bioelectric impedance assay (BIA). BIA is a non-invasive method based on the principle that lean tissues conduct a low frequency alternating current of electricity better than do fatty tissues. Body mass index was increased in the alcohol-induced migraine patients (p less than 0.04). as was fat mass. (p less than 0.03) as evaluated by skin fold measurements. Bioelectric impedance assay demonstrated a slight total body water increase in alcohol-induced migraine patients (p less than 0.07). Possibly. if this total body water increase was reflected at the neuronal level. the bioelectric properties of the migrainous brain may be altered. thus creating a hypothetical link with the phenomenon of spreading depression.
Percutaneous transluminal coronary angioplasty in the elderly: early and long-term results, The immediate and long-term efficacy of coronary angioplasty in the elderly was determined by studying 752 patients greater than or equal to 65 years old and comparing patients greater than or equal to 75 years old with those 65 to 74 years old. The oldest patients were more highly symptomatic. were more likely to be in heart failure. had more multivessel disease and were more likely to undergo multivessel dilation. The immediate success rate of angioplasty was higher in the oldest patients (92.8% versus 82%) (p = 0.0003). The hospital mortality rate was also higher (6.2% versus 1.6%) (p less than 0.001). Long-term overall survival was high. However. long-term event-free survival was lowest in the oldest patients. and recurrent severe angina was particularly common. Thus. in very elderly patients. coronary angioplasty is usually successful. but extra caution is warranted; also. long-term relief from angina is less common than in younger patients.
Symptom-limited exercise testing causes sustained diastolic dysfunction in patients with coronary disease and low effort tolerance, Exercise stress testing is routinely used for the noninvasive assessment of coronary artery disease and is considered a safe procedure. However. the provocation of severe ischemia might potentially cause delayed recovery of myocardial function. To investigate the possibility that maximal exercise testing could induce prolonged impairment of left ventricular function. 15 patients with angiographically proved coronary disease and 9 age-matched control subjects with atypical chest pain and normal coronary arteries were studied. Radionuclide ventriculography was performed at rest. at peak exercise. during recovery and 2 and 7 days after exercise. Ejection fraction. peak filling and peak emptying rates and left ventricular wall motion were analyzed. All control subjects had a normal exercise test at maximal work loads and improved left ventricular function on exercise. Patients developed 1 mm ST depression at 217 +/- 161 s at a work load of 70 +/- 30 W and a rate-pressure product of 18.530 +/- 4.465 mm Hg x beats/min. Although exercise was discontinued when angina or equivalent symptoms occurred. in all patients diagnostic ST depression (greater than or equal to 1 mm) developed much earlier than symptoms. Predictably. at peak exercise patients showed a decrease in ejection fraction and peak emptying and filling rates. Ejection fraction and peak emptying rate normalized within the recovery period. whereas peak filling rate remained depressed throughout recovery (p less than 0.002) and was still reduced 2 days after exercise (p less than 0.02). In conclusion. in patients with severe impairement of coronary flow reserve. maximal exercise may cause sustained impairement of diastolic function.
The threshold for myocardial ischemia varies in patients with coronary artery disease depending on the exercise protocol, It is generally accepted that angina pectoris and. presumably. myocardial ischemia occur at a fixed heart rate-systolic blood pressure product in a given patient. This concept of a fixed threshold has recently been challenged. To evaluate the effects of varying exercise intensity on the ischemic threshold. 33 patients with coronary artery disease and provokable myocardial ischemia. documented by thallium-201 myocardial perfusion imaging. underwent two exercise tests 2 to 7 days apart. A symptom-limited incremental treadmill exercise test was followed by a 20 min submaximal treadmill test at an intensity approximating 70% of the peak heart rate attained during the incremental test. During the incremental exercise test. angina pectoris developed in 16 patients and 17 patients were asymptomatic. At least 0.1 mV of ST segment depression developed in all subjects during the incremental exercise test at a mean exercise duration of 5.3 +/- 2.6 min. a rate-pressure product of 19.130 +/- 5.735 and oxygen uptake of 19.6 +/- 7.0 ml/kg per min. During the submaximal exercise test. 28 (85%) of the 33 patients had significant ST segment depression. Of these patients. 24 (86%) were asymptomatic. including 10 patients who had previously reported anginal symptoms during the incremental test. The average time to onset of 0.1 mV ST segment depression during the submaximal test was 8.1 +/- 4.5 min. These changes occurred at a rate-pressure product of 15.250 +/- 3.705 and an oxygen uptake of 14.3 +/- 5.9 ml/kg per min. and were significantly (p less than 0.001) lower than values observed during the graded exercise.
Orifice variability of the stenotic aortic valve: evaluation before and after balloon aortic valvuloplasty, The effects of balloon aortic valvuloplasty on orifice variability of the stenotic sclerocalcific aortic valve were evaluated by hemodynamic measurements of aortic valve function in 14 patients before balloon aortic valvuloplasty. during nitroprusside infusion before valvuloplasty. 48 h after valvuloplasty and during nitroprusside infusion 48 h after valvuloplasty. Aortic valve function was assessed by aortic valve area calculations with use of the Gorlin and Cannon formulas. Nitroprusside infusion before balloon aortic valvuloplasty caused no change in mean aortic valve gradient but a significant increase in mean aortic transvalvular flow from 186 +/- 46 to 202 +/- 61 ml/s (p less than 0.05). in Gorlin aortic valve area from 0.49 +/- 0.17 to 0.53 +/- 0.21 cm2 (p less than 0.05) and in Cannon aortic valve area from 0.45 +/- 0.18 to 0.49 +/- 0.22 cm2 (p less than 0.05). Nitroprusside infusion 48 h after valvuloplasty induced no change in mean aortic valve gradient but a significant increase in mean aortic transvalvular flow from 214 +/- 61 to 254 +/- 78 ml/s (p less than 0.005). in Gorlin aortic valve area from 0.71 +/- 0.25 to 0.83 +/- 0.32 cm2 (p less than 0.01) and in Cannon aortic valve area from 0.78 +/- 0.33 to 0.88 +/- 0.40 cm2 (p less than 0.05). Forty-eight hours after valvuloplasty. nitroprusside infusion induced a larger increase (40 +/- 40 ml/s) in mean transvalvular flow than before valvuloplasty (16 +/- 27 ml/s; p less than 0.05) and a larger increase (0.12 +/- 0.14 cm2) in Gorlin aortic valve area than before valvuloplasty (0.05 +/- 0.07 cm2; p less than 0.05).
Impact of left ventricular hypertrophy on ventricular arrhythmias in the absence of coronary artery disease, Left ventricular hypertrophy has a grave prognosis. Ventricular arrhythmias may account for a large portion of this poor prognosis. but the contribution of coronary artery disease has not been excluded. The occurrence of ventricular arrhythmias was investigated by 24 h ambulatory electrocardiographic (ECG) monitoring in 49 hypertensive patients who had normal findings on coronary arteriography. The presence of left ventricular hypertrophy was assessed by both ECG and echocardiography. The frequency and complexity of ventricular arrhythmias were significantly related to the presence of left ventricular hypertrophy whether it was defined by wall thickness (interventricular septum or posterior wall greater than or equal to 1.2 cm) or by left ventricular mass indexed to height (left ventricular mass/height greater than or equal to 163 g/m in men and greater than or equal to 121 g/m in women). The relation between left ventricular mass or wall thickness to ventricular arrhythmia was graded and continuous; for every 1 mm increase in the thickness of interventricular septum or posterior wall there was an associated two- to threefold increase. respectively. in the occurrence and complexity of ventricular arrhythmias. In conclusion. left ventricular hypertrophy is associated with an increase in the frequency and complexity of ventricular arrhythmias in the absence of coronary artery disease. and the relation is graded and continuous.
Regular ventricular rhythms in patients with symptomatic paroxysmal atrial fibrillation, Paroxysmal atrial fibrillation is a grossly irregular tachycardia. Forty-nine patients with paroxysmal atrial fibrillation who were taking a variety of antiarrhythmic medications including the class IC agents propafenone and flecainide were followed up for a median of 371 days with use of transtelephonic electrocardiogram (ECG) monitoring to document symptomatic rhythms. Eighteen patients had 96 episodes of regular tachycardia; the cumulative incidence rate was 25% at 6 months. 33% at 1 year and 41% at 18 months. Eighty of the 96 episodes occurred with a heart rate less than or equal to 180 beats/min and could have been explained by atrial flutter with 2:1 block. However. nine patients had a total of 16 episodes with a rate greater than 180 beats/min that were probably not due to atrial flutter with block; the cumulative incidence rate of these fast regular tachycardias was 14% at 6 months. 17% at 1 year and 25% at 18 months. QRS duration during the first episode of regular tachycardia was significantly longer in patients taking a class IC drug (median 105 vs 90 ms. p less than 0.001 Wilcoxon rank sum test). In contrast to drug therapy with amiodarone or the combination of digoxin and verapamil. the QRS duration of regular tachycardias during class IC therapy was directly related to the tachycardia heart rate (Spearman's rank. p less than 0.01). All episodes of fast. regular tachycardias with a QRS duration greater than 120 ms occurred in patients taking a class IC drug. Clinicians treating patients with paroxysmal atrial fibrillation should expect a substantial incidence of regular tachycardia in addition to atrial fibrillation.
Effect of infarct location on myocardial salvage assessed by technetium-99m isonitrile, To investigate the influence of infarct location on myocardial salvage. technetium-99m isonitrile was injected into 43 patients with a first myocardial infarction before early reperfusion therapy. Primary coronary angioplasty was performed in 22 patients and successful intravenous thrombolytic therapy was given to 15 patients. both within 6 h of the onset of chest pain. Patency of the infarct-related artery was confirmed by angiography in all 37 patients. In the remaining six patients (three with and three without early thrombolytic therapy) the infarct-related artery remained occluded. Single photon emission computed tomography was performed within 6 h of the administration of technetium-99m isonitrile and repeated at the time of hospital discharge. Radionuclide ejection fraction at discharge was significantly lower for patients with anterior infarction (0.41 +/- 0.12) than for those with inferior infarction (0.56 +/- 0.09. p less than 0.001). Early perfusion defect size. a measure of myocardium at risk. was greater in patients with anterior than in those with inferior infarction (52 +/- 9% vs. 18 +/- 10% of the left ventricle. p = 0.0001) as was final defect size (30 +/- 20% vs. 9 +/- 8%. p less than 0.01). The change in myocardial perfusion. an estimate of myocardial salvage. was also greater in patients with anterior infarction (24 +/- 16% vs. 10 +/- 7%. p less than 0.01). However. the proportion of jeopardized myocardium salvaged (salvage index) was not significantly different between patients with anterior or inferior infarction (0.49 +/- 0.34 vs. 0.59 +/- 0.35. p = NS).
A new approach to the assessment of tomographic thallium-201 scintigraphy in patients with left bundle branch block, To determine whether a new approach to interpretation could improve the accuracy of thallium-201 single photon emission computed tomography (SPECT) for detection of left anterior descending coronary artery disease in patients with left bundle branch block. 69 patients were evaluated. Forty-four had angiographically proved coronary artery disease; the remaining 25 were considered to have a "low" (mean 13.5 +/- 6.4%. range 3.4% to 24.9%) likelihood of disease before thallium-201 scintigraphy. The conventional scintigraphic criterion for detection of left anterior descending artery disease (septal. anterior or apical defects) was compared with a new criterion that required the apex to be abnormal to indicate left anterior descending disease. The normalcy rates in the low likelihood patient group were significantly improved by using the new approach. from 16% to 80% (p less than 0.0001) by visual analysis and from 24% to 64% (p = 0.003) by quantitative SPECT polar map analysis. The sensitivity for left anterior descending disease was similar for the conventional and the new method by visual (100% vs. 94%) and quantitative (100% vs. 83%) analyses. In contrast. the specificity was significantly improved by using the new approach. from 14% to 79% (p = 0.0006) by visual analysis and 14% to 64% (p = 0.007) by quantitative analysis. In conclusion. septal and anterior thallium-201 SPECT defects are common in patients with left bundle branch block without coronary artery disease. resulting in low specificity for left anterior descending artery disease. The normalcy rates and accuracy for detection of left anterior descending coronary artery disease were significantly better when an apical defect was used as the criterion for disease.
Comparison of the ramp versus standard exercise protocols, To compare the hemodynamic and gas exchange responses of ramp treadmill and cycle ergometer tests with standard exercise protocols used clinically. 10 patients with chronic heart failure. 10 with coronary artery disease who were asymptomatic during exercise. 11 with coronary artery disease who were limited by angina during exercise and 10 age-matched normal subjects performed maximal exercise using six different exercise protocols. Gas exchange data were collected continuously during each of the following protocols. performed on separate days in randomized order: Bruce. Balke and an individualized ramp treadmill; 25 W/stage. 50 W/stage and an individualized ramp cycle ergometer test. Maximal oxygen uptake was 16% greater on the treadmill protocols combined (21.4 +/- 8 ml/kg per min) versus the cycle ergometer protocols combined (18.1 +/- 7 ml/kg per min) (p less than 0.01). although no differences were observed in maximal heart rate (131 +/- 24 versus 126 +/- 24 beats/min for the treadmill and cycle ergometer protocols. respectively). No major differences were observed in maximal heart rate or maximal oxygen uptake among the various treadmill protocols or among the various cycle ergometer protocols. The ratio of oxygen uptake to work rate. expressed as a slope. was highest for the ramp tests (slope +/- SEE ml/kg per min = 0.80 +/- 2.5 and 0.78 +/- 1.7 for ramp treadmill and ramp cycle ergometer. respectively). The slopes were poorest for the tests with the largest increments in work (0.62 +/- 4.0 and 0.59 +/- 2.8 for the Bruce treadmill and 50 W/stage cycle ergometer. respectively).
Atrial fibrillation in patients with an accessory pathway: importance of the conduction properties of the accessory pathway, To investigate how the electrophysiologic properties of the accessory pathway affect the occurrence of atrial fibrillation in the Wolff-Parkinson-White syndrome. programmed stimulation data of 57 patients with overt pre-excitation and 33 patients with a concealed accessory pathway with documented circus movement tachycardia were reviewed. Atrial fibrillation had occurred spontaneously in 31 (54%) of the 57 patients with the Wolff-Parkinson-White syndrome and in 1 (3%) of the 33 with a concealed accessory pathway (p less than 0.001). Sustained atrial fibrillation was induced in 23 of 31 patients with the Wolff-Parkinson-White syndrome and spontaneous atrial fibrillation (Group A). in 7 of 26 patients with the Wolff-Parkinson-White syndrome without spontaneous atrial fibrillation (Group B) and in 5 of 33 patients with a concealed accessory pathway (Group C). The anterograde effective refractory period of the accessory pathway was shorter in Group A than in Group B (252 versus 297 ms. p less than 0.001). There were no differences among groups in PA interval. right to left atrium conduction time. cycle length of tachycardia and atrial and retrograde accessory pathway effective refractory period. Atrial fibrillation is more frequent in patients with the Wolff-Parkinson-White syndrome than in those with a concealed accessory pathway. Patients with overt pre-excitation and atrial fibrillation have a shorter anterograde accessory pathway refractory period. It seems therefore that the anterograde rather than the retrograde conduction properties of the accessory pathway are the critical determinants of atrial fibrillation in the Wolff-Parkinson-White syndrome.
Long-term (2 year) beneficial effects of beta-adrenergic blockade with bucindolol in patients with idiopathic dilated cardiomyopathy, Beta-adrenergic blockade represents a promising therapeutic approach to idiopathic dilated cardiomyopathy. Bucindolol. a new beta-blocker. showed favorable effects in a short-term (3 month) trial in idiopathic dilated cardiomyopathy. To assess long-term response. 20 study patients (7 of 9 patients previously assigned to the placebo group and 13 of 14 patients previously assigned to bucindolol therapy) received long-term bucindolol therapy and were followed up for a mean of 23 +/- 4 months (range 17 to 30). The mean patient age was 49 years (range 29 to 66) and the median duration of disease was 11 months (range 1 to 190). Ten patients were in functional class II and 10 were in class III; 15 patients were men. At the end of the common follow-up time. all 20 patients were alive. 17 continued to receive bucindolol (mean dose 176 mg/day. range 25 to 200). and 2 underwent cardiac transplantation. Left ventricular ejection fraction increased from a baseline value of 25 +/- 8% to 35 +/- 13% (n = 19 pairs. p less than 0.001). Functional class improved in 12. was unchanged in 5 and deteriorated in 3 (p = 0.056). Exercise time was maintained (9.4 +/- 3.1 versus 9.1 +/- 3.5 min. n = 19. p = NS). as was maximal oxygen uptake (19.2 +/- 4.9 versus 18.8 +/- 5.7 ml/kg per min. n = 19. p = NS). Thus. long-term bucindolol therapy leads to substantial increases in ejection fraction and to improved functional class while stable exercise performance is maintained.
Acute effects of parenteral beta-blockade on regional ventricular function of infarct and noninfarct zones after reperfusion therapy in humans, Although the mechanism is unknown. clinical trials have suggested that intravenous beta-adrenergic blockade may prevent early cardiac rupture after myocardial infarction. Previous studies have examined effects of beta-blockers on global left ventricular function after myocardial infarction; however. few data exist regarding their immediate effects on regional function or in patients after successful reperfusion. Therefore. 65 patients in whom thrombolysis with or without coronary angioplasty achieved reperfusion at 4.6 +/- 1.7 h from symptom onset were studied. Low osmolarity contrast ventriculograms were obtained immediately before and after administration of 15 mg of intravenous metoprolol (n = 54) or placebo (n = 11). Intravenous metoprolol immediately decreased heart rate (from 92 to 76 beats/min. p less than 0.0001). increased left ventricular diastolic volume (from 150 to 163 ml. p less than 0.001) and systolic volume (from 72 to 77 ml. p less than 0.0005) but did not change systolic and diastolic pressures. Although there was no difference in ejection fraction after metoprolol. centerline chord analysis revealed reduced noninfarct zone motion (from 0.41 to 0.12 SD/chord. p less than 0.05). improved infarct zone motion (from -3.1 to -2.9 SD/chord. p less than 0.01) and smaller circumferential extent of hypokinesia (from 30 to 27 chords. p less than 0.05). Patients with dyskinesia of the infarct zone had the most striking improvement in infarct zone wall motion. Because these changes occurred immediately after beta-blockade. they could not be attributed to myocardial salvage. No significant changes in heart rate. left ventricular volumes or regional wall motion were apparent in the control group.
Effect of beta-blockade on low heart rate-related ischemia during mental stress, To explore the effect of beta-adrenergic blockade on low heart rate-related (mental stress) ischemia. 19 patients with coronary artery disease were randomized into a double-blind crossover trial of metoprolol. 100 mg twice daily. and underwent serial mental stress/bicycle exercise studies. Mental stress-induced wall motion abnormalities occurred at a lower heart rate than exercise-induced wall motion abnormalities during placebo administration (81 +/- 16 vs. 123 +/- 20 beats/min. p less than 0.05). Metoprolol reduced the mean magnitude of exercise-induced wall motion abnormalities (2.8 +/- 2.0 vs. 1.6 +/- 2.4. p = 0.003); improvement was related to the magnitude of hemodynamic beta-blockade effect. Metoprolol did not significantly reduce the mean magnitude of mental stress-induced wall motion abnormalities (3.0 +/- 2.2 vs. 2.6 +/- 2.2). although individual responses predominantly either improved (50%) or worsened (29%). Unlike exercise. the magnitude of hemodynamic beta-blockade did not predict mental stress response and metoprolol did not block mental stress-induced blood pressure elevations. Patients with abolition of exercise-induced ischemia were more likely to have reduction of mental stress-induced ischemia. Patients whose ischemia worsened with metoprolol during mental stress had more easily inducible ischemia. as assessed by exercise-induced placebo wall motion abnormality. chest pain and prior myocardial infarction. Beta-blockade was associated with a lowering of ischemia-related hemodynamic thresholds compared with placebo. These results suggest that beta-blockade has a variable effect on low heart rate-related ischemia that may be due to a lack of effect on mental stress-induced blood pressure elevation in patients with easily induced ischemia or to effects on coronary vasomotor tone. or both.
Role of combination drug therapy with a class IC antiarrhythmic agent and mexiletine for ventricular tachycardia, The combination of mexiletine and a class IC antiarrhythmic agent (encainide. propafenone or flecainide) was evaluated by electrophysiologic testing in 14 patients with a history of sustained ventricular tachycardia whose tachycardia remained inducible during therapy with the class IC drug alone. During the control drug-free state. all patients had inducible ventricular tachycardia. with a mean cycle length of 260 ms (range 190 to 400). During monotherapy with the IC agent the tachycardia remained inducible in each patient. but there was a significant increase in the cycle length to 340 ms (240 to 500) (p less than 0.001). The effective refractory period of the ventricle was not altered. Treatment with mexiletine (oral in 13 and intravenous in 1) was begun and electrophysiologic testing was repeated. Ventricular tachycardia in one patient was rendered noninducible and one patient had arrhythmia aggravation. The tachycardia in the remaining 12 patients remained inducible but its average cycle length increased further to 392 ms (340 to 460) (p = NS). Nine patients had rate slowing and the average cycle length of the ventricular tachycardia in this group was significantly increased (302 to 388 ms. p less than 0.05). The average effective refractory period was significantly increased during combination therapy (267 ms) compared with no drug therapy (235 ms) and therapy with the class IC drug alone (247 ms) (p less than 0.05). After a mean follow-up interval of 22 months. seven patients continue on the combined treatment and have no ventricular tachycardia.
Scintigraphic assessment of sympathetic innervation after transmural versus nontransmural myocardial infarction, To evaluate the feasibility of detecting denervated myocardium in the infarcted canine heart. the distribution of sympathetic nerve endings using I-123 metaiodobenzylguanidine (MIBG) was compared with the distribution of perfusion using thallium-201. with the aid of color-coded computer functional map in 16 dogs. Twelve dogs underwent myocardial infarction by injection of vinyl latex into the left anterior descending coronary artery (transmural myocardial infarction. n = 6). or ligation of the left anterior descending coronary artery (nontransmural myocardial infarction. n = 6). Four dogs served as sham-operated controls. Image patterns were compared with tissue norepinephrine content and with histofluorescence microscopic findings in biopsy specimens. Hearts with transmural infarction showed zones of absent MIBG and thallium. indicating scar. Adjacent and distal regions showed reduced MIBG but normal thallium uptake. indicating viable but denervated myocardium. Denervation distal to infarction was confirmed by reduced norepinephrine content and absence of nerve fluorescence. Nontransmural myocardial infarction showed zones of wall thinning with decreased thallium uptake and a greater reduction or absence of MIBG localized to the region of the infarct. with minimal extension of denervation beyond the infarct. Norepinephrine content was significantly reduced in the infarct zone. and nerve fluorescence was absent. These findings suggest that 1) MIBG imaging can detect viable and perfused but denervated myocardium after infarction; and 2) as opposed to the distal denervation produced by transmural infarction. nontransmural infarction may lead to regional ischemic damage of sympathetic nerves. but may spare subepicardial nerve trunks that course through the region of infarction to provide a source of innervation to distal areas of myocardium.
Effects of prolonged transesophageal echocardiographic imaging and probe manipulation on the esophagus--an echocardiographic-pathologic study, Transesophageal echocardiography is being increasingly utilized in the operating room and intensive care and ambulatory settings. However. to date no data are available concerning possible trauma of the transesophageal echocardiographic technique to the esophagus due to probe insertion. manipulation or direct ultrasound energy transmission. To test the hypothesis that transesophageal manipulations caused no traumatic or thermal injury to the esophageal mucosa. 12 animals were studied with continuous transesophageal echocardiography for a period of variable duration (mean 4.6 h +/- 51 min). The study group consisted of four monkeys (mean weight 5.7 +/- 0.6 kg and eight mongrel dogs (mean weight 29.8 +/- 1.4 kg). The eight dogs were studied during right heart bypass with full heparinization for 6.6 +/- 0.2 h. whereas the four monkeys were studied for 60 to 90 min in the absence of cardiopulmonary bypass and anticoagulation. Immediately after completion of transesophageal echocardiography in each case. the esophagus was entirely excised. Detailed macroscopic and microscopic examination of the esophagus revealed no significant mucosal or thermal injury. This preliminary animal study suggests that transesophageal echocardiography is safe for the esophageal mucosa in animals as small as 5 kg in weight. despite prolonged use and in the presence of systemic anticoagulation.
Efficacy of multiple balloon aortic valvuloplasty procedures. The Mansfield Scientific Aortic Valvuloplasty Registry Investigators, To determine the efficacy of a second balloon aortic valvuloplasty procedure in comparison with the original procedure. 47 patients (18 men. 29 women; mean age 77 +/- 10 years) who underwent two balloon aortic valvuloplasty procedures over a mean interval of 6.4 months between procedures (range 2 days to 15 months) were retrospectively examined. The mean pressure gradient across the aortic valve was significantly higher before the first than before the second valvuloplasty procedure (62 +/- 21 vs. 53 +/- 21 mm Hg; p less than 0.05) and after the first compared with after the second procedure (32 +/- 13 vs. 28 +/- 14 mm Hg; p less than 0.05). The cardiac output and stroke volume after the first procedure were significantly greater than the values for these variables after the second procedure (4.4 +/- 1.1 vs. 3.8 +/- 1.1 liters/min; p less than 0.05; and 54 +/- 17 vs. 47 +/- 15 ml/beat; p less than 0.05. respectively). There were no significant differences in the change observed in any variable between the first and second procedures. At a mean follow-up interval of 5.3 months (range 6 days to 15 months) after the second procedure 18 (38%) of the 47 patients had died. 12 (25%) required surgical valve replacement and 4 (8%) required a third valvuloplasty procedure. Overall. 31 (66%) of 47 patients met clinical failure end points after the second procedure. Three patients had two failure end points. The 47 patients were divided into two groups on the basis of the interval between valvuloplasty procedures.
Peptide inhibition of myointimal proliferation by angiopeptin, a somatostatin analogue, Vascular smooth muscle cell hyperplasia is a major component of atherogenesis in various animal models. Angiopeptin. a cyclic octapeptide analogue of somatostatin. markedly inhibits myointimal proliferation in response to endothelial cell injury in the rat carotid artery. rabbit aorta and iliac arteries and in coronary arteries of transplanted rabbit hearts. Angiopeptin does not affect serum lipid profiles in nonhuman primates. It is unlikely. therefore. that its antiproliferative effect is mediated by alterations in cholesterol metabolism. Angiopeptin and other peptide analogues of somatostatin are potent inhibitors of growth hormone release and insulin-like growth factor-1 production. However. inhibition of smooth muscle cell proliferation in vivo is not a property common to all somatostatin analogues. This suggests that plasma growth hormone and growth hormone-dependent insulin-like growth factor-1 production are not physiologic stimuli for myointimal proliferation in vivo. Angiopeptin inhibits 3H-thymidine incorporation into rat carotid artery explants. suggesting a local effect on autocrine or paracrine mechanisms regulating cell growth. In view of its potent inhibitory effect on smooth muscle cell replication. angiopeptin may have clinical utility in preventing restenosis after percutaneous transluminal coronary angioplasty and in preventing accelerated coronary atherosclerosis after cardiac transplantation.
Use of the perforated balloon catheter to infuse marker substances into diseased coronary artery walls after experimental postmortem angioplasty, A perforated balloon catheter was used in human coronary arteries after postmortem angioplasty had been performed. The catheter used has a standard angioplasty balloon with a pattern of laser-produced holes. 25 microns in size. which generate streams of fluid under pressure. Studies of the routes by which marker substances enter diseased arterial tissue when infused by the perforated balloon after experimental angioplasty are described. A colored marker dye entered the new crevices and dissection planes created by the angioplasty. but did not extend greater than 2 cm either proximal or distal to the perfused segment. Horseradish peroxidase entered tissue not only from the lumen and adventitia as occurs with its infusion into normal tissue with the perforated balloon. but also extended from new crevices and dissection planes created by the angioplasty. Platelet aggregation. coagulation and cell proliferation. the likely causes of restenosis after angioplasty. originate in the sites of greatest tissue disruption and blood stasis. These postmortem studies suggest that active drugs are delivered to the arterial wall in a manner likely to be effective in preventing these events.
Gene transfer into vascular cells, The goal of gene therapy is to introduce foreign deoxyribonucleic acid (DNA) into somatic cells to correct or prevent disorders caused by the malfunction of genes within a diseased individual. Overexpression of recombinant genes at specific sites within the vasculature can provide insights into vascular biology and potential treatments for various cardiovascular disorders such as restenosis. Methods for the introduction of foreign DNA into endothelial and vascular smooth muscle cells have been developed recently. These include the genetic modification of endothelium in vitro and implantation in vivo on arterial segments. direct infection of the arterial wall in vivo with a replication-defective retroviral vector expressing a recombinant gene and direct transfer of genes into vascular cells in vivo with use of liposomes. Although still in its formative stages. gene transfer into the vasculature holds promise as a potential treatment for vascular diseases. including atherosclerosis and restenosis. This approach may also provide insight into the role of specific gene products in the development of pathologic lesions.
Intravascular ultrasound guidance for catheter-based coronary interventions, Intravascular ultrasound is a new method for visualizing the details of vascular pathology. providing high resolution images of plaque and thrombus. This review summarizes the potential applications of ultrasound imaging in the guidance of balloon angioplasty. atherectomy. laser ablation and stenting. Ultrasound differs from angiography and angioscopy in its ability to penetrate below the surface of the vessel lumen. demonstrating specific aspects about the distribution and composition of plaque. Because the different layers of the arterial wall have different acoustic properties. ultrasound catheters are able to define the layers of normal wall in comparison with plaque. Particularly in combination with therapeutic techniques designed to remove or ablate plaque. ultrasound may prove useful in maximizing the amount of plaque treated and minimizing trauma to normal vessel wall components. Combined imaging/therapeutic devices are in the pilot phase of development and show promise for enhancing the safety and efficacy of the catheter devices.
Evaluation of long-term weight changes after a multidisciplinary weight control program, The American Medical Association Council on Scientific Affairs recently emphasized the importance of nutritionally sound weight reduction diets and changes in life-style to promote long-term weight control. The purpose of this study was to evaluate long-term effectiveness and to identify predictors of success of an intensive multidisciplinary program utilizing the time-calorie displacement diet. a low-fat. high-complex-carbohydrate diet. to promote and maintain reduced body weight. In 213 obese adults consecutively entering the program. including dropouts. weight loss averaged 6.3 kg (0.4 kg/week) and 16% of excess weight over 7 months of treatment. The 78 (37%) completing the recommended 15 visits lost a mean of 10.8 kg and 28% of their excess weight while under treatment. Weight loss was largely predicted by number of visits. which was more important than treatment duration. An increased number of visits was predicted by being married. being female. and reporting a usual diet low in snack foods. Of 147 patients contacted at posttreatment follow-up. 53% maintained their weight loss or continued to lose weight an average of 25 months later and 24% experienced weight rebound but were still below their pretreatment weight; only 23% regained their lost weight. Mean net weight loss from pretreatment to follow-up was 8.0 +/- 1.0 kg (mean +/- standard error of the mean). No factor significantly predicted posttreatment weight rebound. Results suggest that a nutritionally sound diet. prescribed in a multidisciplinary program and emphasizing life-style changes. can result in long-term weight control in a majority of patients treated.
Effect of a very-low-calorie diet on body composition and resting metabolic rate in obese men and women, Very-low-calorie diets (VLCDs) provide a rapid decrease in total body weight. but limited data are available regarding the extent of fat loss and whether body fat distribution is altered. The purpose of this study was to investigate body composition. body fat distribution. and resting metabolic rate in obese men and women and to compare bioelectrical impedance analysis (BIA) with hydrodensitometry before and after 12 weeks of treatment in a VLCD program. Body composition was assessed by hydrodensitometry and BIA. Circumference measures were used to determine waist:hip and waist:thigh ratios. Seventeen subjects lost a mean of 24.2 kg. A mean of 75.5% of the weight loss was adipose tissue as measured by hydrodensitometry. BIA underestimated body fat percentage compared with hydrodensitometry in this obese population. Waist:hip and waist:thigh ratios showed a small but significant decrease. implying a decreased risk for diabetes and cardiovascular disease after weight loss. Resting metabolic rate. as measured by oxygen consumption. dropped 23.8% during the 12 weeks of the VLCD. The findings indicate that a VLCD can provide a rapid weight loss of more than 75% fat and a concomitant decrease in waist:hip and waist:thigh ratios. The findings also indicate that BIA may not be a useful tool in assessing fat loss in obese subjects. Finally. it appears that the decrease in resting metabolic rate that occurs during treatment with VLCD does not correlate with changes in lean body mass.
Reconstitution of an active surface CD2 by DNA transfer in CD2-CD3+ Jurkat cells facilitates CD3-T cell receptor-mediated IL-2 production, To investigate the requirements for CD2 expression in the activation of T lymphocytes via the CD3-TCR complex. we produced and characterized a series of CD2-variants of the IL-2 producing Jurkat leukemia cell line. J32 (surface phenotype. CD2+. CD3+. CD28+). These mutants were derived by radiation and immunoselection. and were cloned under limiting dilution conditions. A total of 3 out of 30 of these mutants selectively lost the expression of both CD2 surface molecules and CD2 mRNA. and retained the expression of the CD3-TCR complex and the CD28 molecule. A mitogenic combination of anti-CD2 antibodies (9.6 + 9-1) failed to stimulate activation of these variants as measured by mobilization of intracellular Ca2+ and by IL-2 production. The CD2- mutants stimulated with anti-CD3 or anti-TCR mAb revealed an 8- to 32-fold decrease in IL-2 production and IL-2 mRNA accumulation as compared with the parental cells. No alteration of CD3-TCR-induced mobilization of intracellular Ca2+ was observed in the CD2- mutants. Reconstitution of CD2 expression by gene transfer in two J32 CD2- mutants restored IL-2 production and IL-2 mRNA accumulation in responses to both anti-CD2 and anti-CD3-TCR mAb. These results are the first direct demonstration of the requirement for CD2 molecules in optimizing IL-2 response in human T cells stimulated via CD3-TCR complex.
Studies on the induction of anterior chamber-associated immune deviation (ACAID). 1. Evidence that an antigen-specific, ACAID-inducing, cell-associated signal exists in the peripheral blood, The anterior chamber of the eye is an immunologically privileged site. Recent evidence indicates that this privilege is an actively acquired immune state in which a unique form of systemic immune deviation exists. anterior chamber-associated immune deviation (ACAID). ACAID is characterized in part by the generation of Ag-specific splenic T lymphocytes that mediate suppression of induction and expression of delayed hypersensitivity and that suppress production of C-fixing antibodies. Delayed hypersensitivity and C fixation are usually associated with extensive nonspecific inflammation and innocent bystander tissue injury. It is. therefore. believed that ACAID represents physiologic adaptations of the immune system that mitigate wanton destruction of the anatomically delicate visual axis. thereby preserving sight. while at the same time providing selective immune protection. As a means of examining the potential contribution of the eye to ACAID induction. we have studied the immune properties of blood harvested from mice that had received BSA into the anterior chamber 48 h earlier. We found that an Ag-specific "signal" is present in the blood of these mice; when blood was transfused into naive syngeneic mice. regulatory cell populations were induced and the recipients were unable to display BSA-specific delayed hypersensitivity. Further analysis of this signal revealed it to be associated with the leukocyte fraction. but not with either the plasma or RBC components of whole blood. Among leukocytes. the suppression-inducing activity correlated positively with cells bearing the mature macrophage marker F4/80 and negatively with cells bearing Thy-1. surface Ig. and class II MHC molecules. These findings are discussed with regard to the potential intraocular sources of the ACAID-inducing signal and the possible mode of action of this factor.
Murine IgE and IgG responses to melittin and its analogs, Melittin. a bee-venom peptide of 26 amino acids. induces IgE and IgG responses in man and animals. The antibody response was shown previously to be specific primarily for the C-terminal 6 residues and its T cell epitope in H-2d restricted mice was shown to be in residue 11-19 of melittin. To study the relationship of peptide structure and immunogenicity in mice. we have prepared a series of melittin analogs varied in length and composition at the C-terminus. Immunogenicity of the analogs for IgG and IgE responses was found to correlate with two factors: a peptide length of more than 24 residues and the presence of a hydrophilic C-terminal region preferably with two to four cationic groups. These factors result in the ability of peptide to bind to cell membranes. Analogs that possess these features are good immunogens whereas those lacking any of these features are weak immunogens.
Epitopes of the p70 and p80 (Ku) lupus autoantigens, High titer autoantibodies to the Ku Ag. a DNA-protein complex containing 70- and approximately 80-kDa protein subunits (p70 and p80. respectively). are found in sera of certain patients with systemic lupus erythematosus and related disorders. Autoepitopes of the Ku Ag were identified and partially characterized by expressing fragments of the p70 and p80 cDNA as fusion proteins in bacteria. Systemic lupus erythematosus sera reacted on immunoblots with at least three epitopes of p70 (amino acids 560-609. 506-535. and 115-467). and three epitopes of p80 (amino acids 682-732. 558-681. and 1-374). These six antigenic regions had distinct amino acid sequences. and were also immunologically distinct. as determined by using immunoaffinity-purified auto-antibodies to particular epitopes. Detailed mapping of the strongly antigenic region near the C terminus of p70 revealed a complex conformational or discontinuous epitope. the antigenicity of which was abolished by deleting either amino acids 560-571 or 601-609. The C terminus of p80 may also contain a discontinuous or conformational epitope(s). Although only some sera reacted with p70 or p80 on immunoblots. all sera that immunoprecipitated the native Ku complex reacted with native Ku by ELISA. and inhibited the binding of mAb directed at epitopes of native Ku. Taken together. these studies indicate that anti-Ku autoantibodies target a diversity of independent epitopes located on p70. p80. and the intact Ku complex. and that a significant portion of the autoantibodies in most patients' sera is directed against conformational/discontinuous epitopes.
Differential synthesis of 5-lipoxygenase in peripheral blood and synovial fluid neutrophils in rheumatoid arthritis, In order to investigate 5-lipoxygenase enzyme regulation in neutrophils during an inflammatory reaction. we studied 5-lipoxygenase mRNA levels. as well as de novo enzyme synthesis. in resting and activated neutrophils isolated from normal individuals and patients with rheumatoid arthritis. The approach used was to analyze these activities in resting peripheral blood neutrophils of normal individuals on the one hand and in peripheral blood and matched synovial fluid neutrophils isolated from patients with rheumatoid arthritis on the other hand. Our first observation was that resting peripheral blood neutrophils of either normal individuals or patients show detectable levels of 5-lipoxygenase mRNA and are able to synthesize the enzyme de novo. Our second observation was that inflammatory activated neutrophils from synovial fluid reveal lower 5-lipoxygenase mRNA levels and enzyme synthesis than do the patient-matched peripheral blood cells. This is in spite of the fact that. for other proteins. synovial fluid neutrophils are equally or more active than their peripheral blood counterparts. We conclude that peripheral blood neutrophils are capable of synthesizing the enzyme. thus ensuring the turnover of the protein. Furthermore. complex regulatory mechanisms appear to take place in response to inflammation as it occurs in synovial fluids of patients with rheumatoid arthritis. leading to decreased mRNA levels and enzyme synthesis. Possible mechanisms of regulation are discussed and are presently under investigation.
Immunologic and structural characterization of the dominant 66- to 73-kDa antigens of Borrelia burgdorferi, The 66- to 73-kDa proteins of Borrelia burgdorferi are dominant immunogens and expressed in all strains of B. burgdorferi. The humoral response to these Ag occurs relatively early during the course of infection. Two-dimensional Western blot analysis of this group of Ag revealed them to consist of a tetrad of proteins with apparent molecular mass of 66. 68. 71. and 73 kDa. Furthermore. in this study we demonstrate the 66-kDa protein to be a potent inducer of lymphoproliferation in the patient immune to B. burgdorferi. Monospecific polyclonal antibodies and mAb demonstrate that each of these proteins was immunologically distinct. However. direct amino acid sequence of the 66- and 68-kDa Ag was almost identical and had a high level of sequence similarity to the GroEL heat-shock protein (Hsp60) of Escherichia coli and the 60-kDa immunodominant protein of Treponema pallidum. The amino terminal sequence of the 71- and 73-kDa proteins of B. burgdorferi was almost identical and these proteins had remarkable sequence similarity to the DnaK heat-shock protein of E. coli (Hsp70). It appears likely. therefore. that proteins related to the heat-shock family are potent immunogens of B. burgdorferi.
Ig gene rearrangements on individual alleles of Abelson murine leukemia cell lines from (C57BL/6 x BALB/c) F1 fetal livers, We have previously shown that selection of Ig H chain V region genes used by colonies obtained from splenic B cells and fetal liver pre-B cells was dependent on strain-specific factors. Moreover. by examining the V gene usage in strains congenic at the Igh locus. we also determined that the strain-specific factor was encoded by sequences lying outside of the Igh locus. We decided to examine whether there are differences in Vh gene rearrangement between alleles in an F1 strain. To do this analysis we chose to examine the relative Ig H chain V region gene usage of pre-B cell lines derived from (C57BL/6 x BALB/c)F1 fetal liver cells by Southern blot analysis. We found a high frequency of Vh-gene rearrangements (77% of the alleles had VDJ rearrangements) and these rearrangements occurred to Vh-genes throughout the Vh locus and were not confined to the D-proximal Vh-genes as has been previously observed with lines from other mouse strains. The Vh-gene usage pattern is similar on both alleles indicating that at least one of the determinants of which Vh-gene is used is trans-acting and acts similarly on each allele. Furthermore. one allele. Ighb (donated by the C57BL/6 parent). rearranged Vh-genes more frequently than the other allele. Igha (donated by the BALB/c parent) suggesting that one of the determinants of Vh-gene rearrangement may be acting in an allele-specific manner.
Immune dysfunction in mice with plasmacytomas. I. Evidence that transforming growth factor-beta contributes to the altered expression of activation receptors on host B lymphocytes, Plasmacytoma-bearing mice (PC-mice) develop a polyclonal B cell immunodeficiency syndrome characterized by marked impairment of: a) primary antibody responses and b) proliferative responses to B cell mitogens. The present investigations used two-color flow cytometry to examine B lymphocytes from the spleens and lymph nodes of PC-mice and found decreased surface membrane expression of surface IgM (sIgM). transferrin receptors (TfR) and IgE FcR (CD23). increased expression of class II MHC. but normal expression of B220. Mel-14. Fc gamma RII. and Fc mu R. These changes were not related to the H chain class or the amount of Ig produced by the plasmacytoma. When cultured with IL-4. B lymphocytes from PC-mice increased their expression of sIgM and class II MHC. but not of CD23. Several findings implicate transforming growth factor-beta 1 (TGF-beta 1) in the mechanism that modulates receptor expression on B lymphocytes in PC-mice: a) ascites fluid from PC-mice contains large quantities of TGF-beta 1; b) supernatants of cultured spleen cells from PC mice contain up to eightfold more TGF-beta than is found with normal spleen cells; c) cloned plasmacytoma cells produce TGF-beta in vitro; and d) the abnormal phenotype of B cells from PC-mice. i.e.. decreased CD23. sIgM. and TfR. and increased class II MHC. is induced on normal B cells cultured in the presence of TGF-beta 1. Because sIgM. TfR. class II MHC. and CD23 are molecules that play fundamental roles in the activation of normal B cells. their modulation by TGF-beta 1: a) identifies molecular mechanisms that could account for some of the known immunosuppressive properties of TGF-beta 1 and b) implicates TGF-beta in the pathogenesis of the polyclonal B cell immunodeficiency that is characteristic of plasma cell tumors.
Culture and properties of cells derived from Kaposi sarcoma, We describe the establishment of four continuous cell cultures isolated from pleural or peritoneal fluid of patients with Kaposi sarcoma (KS) and show evidence that these cells are derived from vascular endothelium. Although provision of an extracellular matrix (fibronectin. laminin. or matrigel) was essential. the cell cultures were not dependent on exogenously added growth factors (platelet-derived growth factor. epidermal growth factor with or without heparin) for continuous culture. Specific staining for endothelial cell (EC) markers (factor VIII. Ulex europaeus type 1 lectin) and the secretion of endothelin. a vascular EC product. were demonstrated. The KS cells secreted large amounts of cytokines (granulocyte-macrophage-CSF. TNF-alpha. IL-1 beta. and especially IL-6). Conditioned media from the KS cells caused normal capillary EC to proliferate. The KS cells synthesized fibroblast growth activity in amounts sufficient to induce the proliferation of normal EC and fibroblasts. These data support the existence of a paracrine pathway of EC proliferation in KS and suggest that KS cells could sustain their own growth via an autocrine mechanism.
Experimental autoimmune encephalomyelitis is exacerbated by IL-1 alpha and suppressed by soluble IL-1 receptor, To assess the role of IL-1 in the development of experimental autoimmune encephalomyelitis (EAE). the effects of in vivo treatment with IL-1 alpha or an IL-1 antagonist on the clinical course of EAE were evaluated. First. Lewis rats were immunized with guinea pig myelin in CFA and treated for 19 consecutive days with i.p. injections of recombinant human IL-1 alpha. Clinical signs of paralysis in the IL-1 alpha-treated groups were of longer duration and of greater severity compared to placebo injected controls. In addition. more weight loss was observed in the IL-1 alpha-treated groups compared to controls. This enhanced weight loss was not due to IL-1 alpha injections alone as CFA-treated rats injected with IL-1 alpha did not lose weight when compared to placebo injected. CFA-treated controls. Second. soluble mouse rIL-1R (sIL-1R). which binds both IL-1 alpha and IL-1 beta. was given as an IL-1 antagonist. Treatment of guinea pig myelin/CFA immunized rats with sIL-1R for 13 consecutive days significantly delayed the onset of EAE. reduced the severity of paralysis and weight loss. and shortened the duration of disease. Treatment with sIL-1R was most effective in reducing EAE if administered for 15 consecutive days immediately after immunization. Shortened 5-day treatment regimens spanning days 1 to 5. days 6 to 10. or days 11 to 15 after immunization were less effective in reducing EAE. These data suggest that IL-1 may initiate or promote inflammation within the central nervous system. In addition. specifically blocking the biological activity of IL-1 in vivo by soluble receptors may prove beneficial for the treatment of autoimmune or inflammatory diseases.
Analysis of the pivotal residues of the immunodominant and highly uveitogenic determinant of interphotoreceptor retinoid-binding protein, Interphotoreceptor retinoid-binding protein (IRBP). a retinal-specific Ag. induces experimental autoimmune uveitis in a variety of animals. We have previously shown that sequence 1169-1191 of bovine IRBP is the immunodominant epitope of this protein in Lewis rats and is highly immunogenic and uveitogenic in these rats. The active site of peptide 1169-1191 was determined by testing its truncated forms. The shortest peptide to be immunologically active was found to be 1182-1190 (WEGVGVVPD). To determine the role of individual residues of this sequence. we have tested the immunologic activities of nine analogs of peptide 1181-1191. in which each of residues 1182-1190 was substituted with alanine (A). The tested activities included the capacity to induce experimental autoimmune uveitis and cellular responses in immunized rats. as well as the capability to stimulate lymphocytes sensitized against IRBP or the parent peptide 1181-1191. Analogs that did not stimulate these lymphocytes were also tested for their capacity to competitively inhibit the proliferative response to 1181-1191. Analogs A(1184). A(1186). and A(1187) resembled 1181-1191 in their activities. whereas the other analogs exhibited remarkably reduced activities. with several patterns being noticed. Analog A(1182) was inactive in all tests. Analog A(1190) was very weakly uveitogenic and non-immunogenic. but it stimulated lymphocytes sensitized against IRBP or 1181-1191 when added at exceedingly high concentrations. Analogs A(1183) and A(1185) resembled A(1190) in being weakly uveitogenic and A(1185) was also found to be poorly immunogenic. In addition. relatively high concentrations of A(1183) and A(1185) were needed to stimulate lymphocytes sensitized against IRBP or 1181-1191. However. a different pattern of activities was exhibited by analogs A(1188) and A(1189). These peptides were uveitogenic and immunogenic. but failed to stimulate lymphocytes sensitized to IRBP or 1181-1191. Furthermore. A(1188) and A(1189). but not A(1182). also inhibited the response to 1181-1191 of a cell line specific toward this parent peptide. The data are interpreted to show that residues 1188 and 1189 are involved in the interaction of the peptide with the TCR. whereas residues 1182 and 1190 and. perhaps. 1183 and 1185. are pivotal for the binding of peptide 1181-1190 to the MHC molecules on APC.
Association of murine lupus and thymic full-length endogenous retroviral expression maps to a bone marrow stem cell, Recent studies of thymic gene expression in murine lupus have demonstrated 8.4-kb (full-length size) modified polytropic (Mpmv) endogenous retroviral RNA. In contrast. normal control mouse strains do not produce detectable amounts of such RNA in their thymuses. Prior studies have attributed a defect in experimental tolerance in murine lupus to a bone marrow stem cell rather than to the thymic epithelium; in contrast. infectious retroviral expression has been associated with the thymic epithelium. rather than with the bone marrow stem cell. The present study was designed to determine whether the abnormal Mpmv expression associated with murine lupus mapped to thymic epithelium or to a marrow precursor. Lethally irradiated control and lupus-prone mice were reconstituted with T cell depleted bone marrow; one month later their thymuses were studied for endogenous retroviral RNA and protein expression. Recipients of bone marrow from nonautoimmune donors expressed neither 8.4-kb Mpmv RNA nor surface MCF gp70 in their thymuses. In contrast. recipients of bone marrow from autoimmune NZB or BXSB donors expressed thymic 8.4-kb Mpmv RNA and mink cell focus-forming gp70. These studies demonstrate that lupus-associated 8.4-kb Mpmv endogenous retroviral expression is determined by bone marrow stem cells.
IL-4 is required for the IgE and IgG1 increase and IgG1 autoantibody formation in mice treated with mercuric chloride, Previous studies have established that in susceptible mouse strains. such as A.SW (H-2s). repeated injections of subtoxic doses of HgCl2 induce increased serum levels of total IgE and IgG1. high serum titers of antinuclear autoantibodies (ANo1A). and immune-complex glomerulonephritis. Moreover. it has been shown that susceptibility is determined by H-2As and that Th cells are required for the induction of these immunopathologic alterations by HgCl2. In the present study we showed that treatment in vivo with anti-IL-4 mAb completely abrogated the HgCl2-induced increase in total IgE and partially inhibited the increase in IgG1. but failed to suppress the increase in IgG2A. Furthermore. we showed that IL-4 influences the pattern of IgG subclass distribution among ANo1A of HgCl2-treated mice. Whereas treatment with anti-IL-4 mAb significantly reduced the titers of IgG1 ANolA. it increased those of IgG2A. IgG2B. and IgG3 ANolA. Thus. these results show that IL-4 contributes to the optimal formation in vivo of murine IgG1 and that it is involved in the autoantibody formation of a systemic autoimmune disease. The available evidence suggests that HgCl2 induces an increased production of IL-4 by Th2 cells. If this is correct. it implies that MHC class II alleles determine whether the preferential response to HgCl2 is made by Th1 or Th2 cells and. hence. the type of immunopathologic alterations ensuing.
Studies on the induction of anterior chamber-associated immune deviation (ACAID). II. Eye-derived cells participate in generating blood-borne signals that induce ACAID, Despite an ever increasing body of information concerning general in vivo immune reactivity to exogenous Ag. relatively little is known concerning regional tissue influences on these responses. One expression of regionally distinct immune regulation is the deviant form of systemic immunity induced after the introduction of Ag. such as BSA. into the anterior chamber of the eye--anterior chamber-associated immune deviation (ACAID). ACAID is characterized by a selective. systemic immune deficiency in which both Ag-specific delayed hypersensitivity (DH) and complement-fixing antibody production are impaired by populations of Ts lymphocytes. although other immune effector modalities are preserved. Recent evidence demonstrates that the blood of mice that receive an anterior chamber injection of BSA 48 h earlier contains leukocytes capable of inducing cell-mediated Ag-specific efferent suppression of DH similar to that seen in mice with ACAID. Additional analysis of these bloodborne suppression-inducing leukocytes revealed them to express the mature macrophage/monocyte marker F4/80. On the basis of these findings. we wished to determine the source of the ACAID-inducing cells present in the peripheral blood of mice after anterior chamber inoculation of BSA. The data reveal that cells harvested from the normal eye are capable of selective induction of DH suppressive activity similar to that seen in ACAID. Interestingly. this property is unique to F4/80 expressing cells of the iris and ciliary body (I/CB). F4/80- I/CB cells do not possess this property. Although the F4/80 expressing cells that are present in extraocular sites do not constitutively possess ACAID-inducing properties. exposure of these cells to the anterior chamber microenvironment endows them with this ability. Finally. I/CB cells exposed to Ag in situ. via direct anterior chamber Ag inoculation. induce suppressed Ag-specific DH reactivity when infused into naive syngeneic recipients--a form of systemic immune deviation similar to that seen in mice with ACAID. The results presented here represent the first in vivo description of APC. altered by factors in a local microenvironment. that can initiate a systemic immune response characterized by Ag-specific immune suppression.
Effects of cytokine combinations on acute phase protein production in two human hepatoma cell lines, We evaluated the effects of binary combinations of four cytokines on production of the positive acute phase proteins alpha-1 antichymotrypsin. haptoglobin and fibrinogen. and the negative acute phase proteins albumin and alpha-fetoprotein (AFP) in two human hepatoma cell lines. The effects of the cytokine combinations on the five proteins varied; each protein exhibited a unique and specific pattern of response to the cytokine combinations. In Hep G2 cells. antichymotrypsin was induced by all four cytokines. IL-6. IL-1. TNF-alpha. and transforming growth factor beta 1 alone. and their effects in binary combinations could be attributed to additive or minimally synergistic interactions. Fibrinogen was induced only by IL-6 and this induction was inhibited by IL-1 alpha. TNF-alpha or transforming growth factor beta 1. Haptoglobin was also induced only by IL-6. but TNF-alpha was the only cytokine that inhibited this induction at all concentrations of IL-6. Each of the four cytokines alone down regulated production of AFP and albumin. However. binary combinations of the four cytokines were simply additive. for the most part. in inhibiting AFP production. whereas the inhibitory effects of combinations of cytokines on albumin production differed significantly from simple additive effects. These observations. taken together with studies of effects of cytokine combinations on other acute phase proteins. indicate that the various acute phase proteins respond differently to different combinations of cytokines and that the potential exists for highly specific regulation of synthesis of individual plasma proteins by cytokine interactions. These findings imply that the acute phase response in vivo represents the integrated sum of multiple. separately regulated changes in gene expression.
Conformational structure of a monoclonal anti-idiotypic antibody to the monoclonal anti-adenocarcinoma-associated carbohydrate antibody YH206, The mAb AI206 (IgG1) is an anti-Id antibody of mAb YH206 (IgM) to adenocarcinoma-associated carbohydrate Ag and inhibits the reaction of mAb YH206 to YH206 Ag at low concentrations. By Western blot analysis. mAb AI206 only reacted with unreduced mAb YH206. whereas it did not react with reduced mAb YH206. Furthermore. mAb AI206 reacted with IgM subunit (180 kDa). F(ab')2 (110 kDa). and F(ab) (50 kDa) of pepsin-treated unreduced mAb YH206. Thus. mAb AI206 recognized the structure of F(ab) of mAb YH206. The mAb YH206 reacted with unreduced mAb AI206. F(ab')2 (110 kDa). and F(ab) (50 kDa) of pepsin-treated unreduced mAb AI206. It is presumed that mAb YH206 and mAb AI206 recognize each other in an unreduced condition but not a reduced condition. The recognition of such a conformational Id on F(ab) is important. Because mAb YH206 recognized the carbohydrate on YH206 Ag as well as the peptide on mAb AI206. the conformation on F(ab) of mAb AI206 may mimic the carbohydrate structure on YH206 Ag. In fact. YH206 antibody activity was induced in syngeneic mouse serum immunized with mAb AI206. These observations suggest that the internal image of YH206 carbohydrate Ag is preserved within the conformational Id on F(ab) of mAb AI206.
Fc epsilon RI-mediated hydrolysis of phosphoinositides in ghosts derived from rat basophilic leukemia cells, Aggregation of the high affinity receptor for IgE (Fc epsilon RI) on mast cells by a polyvalent Ag leads to hydrolysis of phosphoinositides (PI) catalyzed by phospholipase C (PI-PLC). To understand this phenomenon in molecular terms. it is important to obtain active. cell-free preparations. In extensive preliminary studies. we could not demonstrate Fc epsilon RI-mediated activation of PI-PLC in plasma membranes prepared by conventional methods from rat basophilic leukemia cells. We now report a stepwise approach involving preparation of cytoplasts from such cells and then hypotonic lysis of the cytoplasts to obtain active membrane vesicles. These membranes. best described as "ghosts." appear to reseal after losing greater than 90% of their soluble. cytoplasmic components and contain receptors that when aggregated. activate PI-PLC to hydrolyze endogenous phospholipids. Per unit of plasma membrane. the ghosts retain approximately 25% of Fc epsilon RI-mediated stimulation of PI-PLC relative to the cells. This activity requires ATP. magnesium. phosphoenolpyruvate. and. to a limited degree. calcium. Although an adequate amount of phosphatidylinositol biphosphate is present. the predicted spike of (1.4.5)-inositol trisphosphate is not seen. and the predominant inositol phosphate isomer is (1.4)-inositol bisphosphate. This is the first report of Fc epsilon RI-mediated activation of PI-PLC in a cytoplasm-depleted system that demonstrates activation of endogenous enzyme acting on endogenous substrate. In addition. it is the first such report for any receptor of the Ig superfamily.
Human monoclonal antibodies specific for capsular polysaccharides of Klebsiella recognize clusters of multiple serotypes, We report the generation and the characterization of a set of human monoclonal antibodies (HmAb) specific for Gram-negative bacteria of Klebsiella pneumoniae. The eight human hybridomas secrete either IgM kappa. IgA1 kappa. or IgA2 kappa antibodies. One HmAb binds bacteria of only one serotype. Five HmAb recognize non-overlapping clusters of 2. 3. or 10 different serotypes. The remaining two HmAb both recognize three serotypes. Two serotypes are recognized by both HmAb. and in addition both HmAb bind one more nonidentical serotype. These results suggest that in man. epitopes are immunodominant. different from serotype-specific determinants detected by conventional rabbit antisera. Screening of clinical isolates revealed that the HmAb recognize not only representative typing strains but also most isolates of the corresponding serotype. In addition. most of the isolates that were non-typable by polyclonal antisera were recognized by one of the HmAb. Fine specificity analyses revealed that all HmAb are highly specific for the isolated capsular polysaccharides (CPS) of bacteria within the corresponding cluster of serotypes. However. the avidity of a HmAb for the different CPS can differ significantly. Taken together. our results suggest that the unequivocal interactions between HmAb and CPS offer the basis for an alternative. better defined classification system. and that passive immunization with a limited number of HmAb may provide a feasible strategy for the protection against the majority of fatal. nosocomial infections with multidrug-resistant strains of K. pneumoniae.
Characterization of an immunoreactive 93-kDa core protein of Borrelia burgdorferi with a human IgG monoclonal antibody, Lyme borreliosis is an infectious disease caused by the tick-borne spirochete Borrelia burgdorferi. which carries the potential for chronic infection. Ag on the etiologic Borrelia are currently being defined structurally and their ability to elicit immune responses delineated. EBV can be used to immortalize human B. burgdorferi-specific B cells from infected donors and generate antibodies against antigenic epitopes encountered in natural infection. A human mAb secreting EBV-transformed B cell line. D7. has been developed that is specific for a 93-kDa B. burgdorferi protein and has been used to characterize this potentially important Ag. D7 produces an IgG3 antibody that detects the 93-kDa Ag as well as smaller fragments at 46 kDa and lower molecular mass. The antibody detects similar epitopes on all B. burgdorferi isolates tested and on a Borrelia hermsii protein with molecular mass greater than 100 kDa but binds poorly to Treponema species. In contrast. polyclonal sera from Lyme disease patients show little binding to the homologous Ag in B. hermsii. Structurally. the 93-kDa protein is associated with the flagellum and may be firmly anchored in the protoplasmic cylinder. It is not solubilized by nonionic detergent treatment of the whole Borrelia. Antibodies against a comparable m.w. protein are present in sera from patients with both early and late infection. Thus. antibodies against this Ag are a sensitive and specific marker of Borrelia infection. This Ag is likely of structural importance and may represent a target of host defenses.
Precursors of both conventional and Ly-1 B cells can escape feedback inhibition of Ig gene rearrangement, Experiments with transgenic mice carrying rearranged Ig transgenes have shown that membrane bound Ig molecules cause feedback inhibition of endogenous Ig gene rearrangement. However. this inhibition is never complete. It has been postulated that escape from feedback may be a property of the Ly-1 B cell subset. whereas rearrangement of endogenous Ig genes may be completely inhibited in conventional B cells. This possibility was investigated in transgenic mice carrying a lambda transgene under the control of the H chain enhancer. It was found that kappa producing B cells in these lambda transgenic mice were for the most part. although not exclusively. of the conventional B cell phenotype. Examination of peritoneal exudate cells revealed that a large proportion of Ly-1 B cells also express kappa. Adoptive transfer of bone marrow from adult lambda transgenic mice. a source of conventional B cell precursors. resulted in the production of relatively high levels of serum kappa 2 to 3 mo after transfer into recipient SCID mice. A high proportion of donor B cells in the spleen produced endogenous kappa protein with or without co-production of lambda. It is concluded that precursors of both conventional and Ly-1 B cells can escape feedback inhibition of L chain gene rearrangement.
Murine tumor cells transduced with the gene for tumor necrosis factor-alpha. Evidence for paracrine immune effects of tumor necrosis factor against tumors, Studies of the anti-tumor activity of TNF-alpha in vivo have been hampered by the need to administer systemically toxic doses of the cytokine to obtain a curative response. To facilitate studies of the effect of high local concentrations of TNF-alpha on tumor growth and host immunity. a newly induced murine sarcoma was transduced with the gene for human TNF-alpha and the biologic characteristics of these cells were examined. We identified high and low TNF-producing tumor clones which exhibited stable TNF secretion over time. Significant amounts of membrane associated TNF were found in a high-TNF producing clone as well. No difference in the in vitro growth rates between TNF-producing and nonproducing cell lines was observed. In contrast. in vivo studies demonstrate that although unmodified parental tumor cells grew progressively when implanted s.c. in animals. tumor cells transduced with the TNF gene were found to regress in a significant number of animals after an initial phase of growth. This effect correlated with the amount of TNF produced and could be blocked with a specific anti-TNF antibody. Regressions of TNF-producing cells occurred in the absence of any demonstrable toxicity in the animals bearing these tumors. TNF-producing tumor cells could function in a paracrine fashion by inhibiting the growth of unmodified. parental tumor cells implanted at the same site. The ability of tumor cells to regress was abrogated by in vivo depletion of CD4+ or CD8+ T cell subsets and animals that had experienced regression of TNF-producing tumors rejected subsequent challenges of parental tumor. Our studies thus show that tumor cells elaborating high local concentrations of TNF regress in the absence of toxicity in the host and that this process requires the existence of intact host immunity. Studies of the lymphocytes infiltrating the gene modified tumors and attempts to use TNF gene modified tumor infiltrating lymphocytes to deliver high local concentrations of TNF to the tumor site without inducing systemic toxicity are underway.
Identification of male-factor semen samples prior to insemination and in vitro fertilization, Semen analyses carried out as part of the clinical in vitro fertilization or intrauterine insemination protocols provide important information that determine the type of clinical treatment of the male partner and the sperm processing method. It is postulated that the sperm of male-factor patients cannot survive hypoosmotic stress conditions because of defective sperm membrane function. To test this. 0.1 ml of semen from each of 102 patients was placed in 1.0 ml of 150 mosmol/liter eosin citrate fructose solution and incubated for 30 min at 37 degrees C. The percentage viability of the sperm cells was then determined. The results indicated that patients with two or more abnormal semen parameters had a significantly lower percentage viability while in the hypoosmotic solution (40.6 +/- 4.7%). in contrast to non-male-factor patients (69.0 +/- 1.6%). Donor sperm (N = 32) serving as controls (73.3 +/- 2.1%) had a viability in hypoosmotic solution similar to that of non-male-factor patients. The data suggest that sperm of male-factor patients are less able to survive the hypoosmotic stress conditions as shown by the percentage viability in hypoosmotic solution and emphasize the importance of using less stressful sperm processing methods for in vitro fertilization or insemination in these patients.
Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group, Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years. a second group received bacillus Calmette-Guerin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age. sex. and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia. myalgia. fever. and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate. and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.
A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma, We conducted a long-term follow-up (median. 10.5 years) of patients included in a randomized trial of levamisole versus placebo as surgical adjuvant therapy in 203 patients with malignant melanoma. Of the patients randomized. 104 received levamisole. and 99 received placebo. The results show that there is no difference between the treatment and control groups with regard to any of the three end points analyzed. These included disease-free interval. time to appearance of visceral metastasis. and survival. Moreover. there was no significant difference between the treatment and control groups after adjusting for age. sex. or stage of disease.
Low-dose ACOP-B and VABE: weekly chemotherapy for elderly patients with advanced-stage diffuse large-cell lymphoma, Elderly patients with advanced-stage diffuse large-cell lymphomas (DLCLs) are either excluded from or under-represented in most clinical trials of combination chemotherapy regimens because they tolerate treatment poorly and usually have a worse outcome. We report two brief weekly chemotherapy regimens designed specifically for elderly patients. Eligible patients were aged 65 to 85 years. had advanced-stage DLCL (diffuse mixed. diffuse large-cleaved or noncleaved. immunoblastic. or diffuse large-cell not otherwise specified). Advanced stage was defined as Ann Arbor stage III or IV or stage I or II with a mass greater than 10 cm or B symptoms. Low-dose doxorubicin. cyclophosphamide. vincristine. bleomycin. and prednisone (LD-ACOP-B) accrued 40 patients between March 1983 and September 1985; 65% achieved a complete response (CR). there were two toxic deaths. the actuarial failure-free survival (FFS) is 19%. disease-specific survival (DSS) 30%. and overall survival (OS) 28%. with a maximum follow-up of 6 years. The regimen of etoposide. doxorubicin. vincristine. bleomycin. and prednisone (VABE) accrued 32 patients between July 1985 and June 1987; 63% achieved a CR. there were two toxic deaths. and the actuarial FFS is 34%. DSS 45%. and OS 36%. with a maximum follow-up of 4 years. There is no difference in FFS. DSS. or OS between these two regimens. VABE caused more myelosuppression and infectious complications. although the toxic death rates were similar. We prefer LD-ACOP-B because follow-up is longer and toxicity is less.
Multivariate analysis of prognostic factors in stage IV follicular low-grade lymphoma: a risk model, We analyzed the records of 96 previously untreated patients with stage IV follicular low-grade lymphoma (FLGL) uniformly treated with cyclophosphamide. doxorubicin. vincristine. prednisone. and bleomycin (CHOP-Bleo) chemotherapy from 1972 to 1982. The overall complete remission (CR) rate was 77%. At a median follow-up of 138 months. the 10-year cause-specific survival rate was 42% with a median survival of 100 months. Failure-free survival (FFS) was 15% at 10 years with a median FFS of 30 months. Multivariate analysis showed peripheral lymph node size (LN). degree of marrow involvement. and sex. in that order. to be important for FFS. while the number of extranodal sites (#ENS). LN. sex. and degree of marrow involvement were important for cause-specific survival. We devised a tumor burden (TB) model. incorporating #ENS. LN. and degree of marrow involvement. Three groups were identified with statistically significant differences in cause-specific survival and FFS. Those with low TB (one ENS exclusive of extensive marrow and nodal disease less than 5 cm) had a 10-year cause-specific survival of 73% compared with 24% for patients with high TB (greater than or equal to two ENS and nodal disease greater than or equal to 5 cm) (P less than .001) and 40% for those with intermediate TB (either greater than or equal to 2 ENS. or extensive marrow only. or nodal disease greater than 5 cm) (P = .050). Patients with low TB had a 10-year FFS rate of 32%. while the intermediate and high TB groups had 10% and 9% FFS. respectively (P = .003). Because sex was a very strong prognostic variable. we created a risk model for survival and FFS based on TB and sex. Females with low TB had the best prognosis (92% survival and 50% FFS at 10 years) and males with high TB had the worst outlook (median survival and FFS. 43 and 12 months. respectively). Other TB-sex combinations defined two groups with statistically significant differences in survival but comparable FFS. This model should aid in the design and analysis of future trials.
Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial, The Eastern Cooperative Oncology Group (ECOG) conducted a study in which patients with advanced chronic lymphocytic leukemia (CLL) were randomized between a regimen consisting of chlorambucil (30 mg/m2 orally day 1) and prednisone (80 mg orally days 1 to 5) (C + P) administered every 2 weeks and a more intensive regimen of cyclosphosphamide (300 mg/m2 orally days 1 to 5). vincristine (1.4 mg/m2 intravenously [IV] day 1). and prednisone (100 mg/m2 orally days 1 to 5) (CVP) given every 3 weeks. Treatment was continued for up to 18 months to maximal response. Of the 122 eligible patients. 60 received C + P. while 62 received CVP. With a median follow-up of 7 years. there were no significant differences in survival (4.8 v 3.9 years. P = .12). complete remission (CR) rate (25% v 23%; P = .83). or duration of response (2.0 v 1.9 years; P = .78) between C + P and CVP. Toxicity was modest despite the prolonged treatment. The long median survival of 4.1 years for stage III and IV patients is superior to that usually reported. This could stem from continuing treatment to maximal response rather than an increase in intensity of therapy. These results are comparable to those reported with cyclophosphamide. doxorubicin. vincristine. and prednisone (CHOP) therapy by other investigators. The data suggest that intermittent C + P administered to maximal response continues to be the standard treatment approach for advanced CLL.
Recombinant interferon alfa given before and in combination with standard chemotherapy in children with acute lymphoblastic leukemia in first marrow relapse: a Pediatric Oncology Group pilot study, Recombinant interferon alfa (rIFN-alpha) was given to 31 children with acute lymphoblastic leukemia (ALL) in first on-therapy marrow relapse as the sole treatment (30 megaunits/m2/d intravenously x 10 days) before standard four-drug reinduction and during multiagent continuation therapy (30 megaunits/m2 subcutaneously x 3 consecutive days every 3 weeks). After 10 days of rIFN-alpha. there were two partial remissions (PRs); seven additional patients had either greater than or equal to 25% reduction in the percentage of marrow blast cells or hypoplastic marrow. Two patients had progressive disease with an increase in leukocyte counts. All patients experienced influenza-like symptoms. and there were isolated instances of severe abdominal pain and personality change. Dose-limiting toxicity comprised grade III/IV transaminase elevation (two patients) and syncope with personality change (one patient). Twenty-three of 31 children (74%) subsequently achieved marrow remission using standard agents. One patient was taken off study during teniposide (VM-26) and cytarabine (ara-C) consolidation due to toxicity. Continuation therapy including rIFN-alpha pulse was well tolerated in the remaining children; only one patient required rIFN-alpha dosage reduction (for CNS toxicity). rIFN-alpha toxicity did not necessitate reductions in doses of standard chemotherapy agents or significant delays in therapy. Five patients remain in remission at 26+ to 36+ months; 13 patients relapsed in marrow. one in the meninges (7 months). and one in meninges. mediastinum. and lymph nodes (2 months). Two children were removed from study for marrow transplant. In summary. high-dose rIFN-alpha alone had a modest antileukemic effect. In contrast to the clinical experience with combined rIFN-alpha and chemotherapy in adults. rIFN-alpha given in a pulse-like manner throughout continuation therapy did not compromise the intensity of the standard chemotherapy regimen.
Recombinant interferon beta: a phase I-II trial in children with recurrent brain tumors, A multicenter phase I-II trial of intravenous (IV) human recombinant interferon beta (rIFN-beta; Betaseron; Triton Bioscience Inc. Almeda. CA) was conducted in children with recurrent or progressive primary brain and spinal cord tumors. A total of 29 patients were enrolled: high-grade astrocytoma (12). brainstem glioma (nine). and primitive neuroectadermal tumor (three). ependymoma (two). germ cell (two). and spinal cord astrocytoma (one). Betaseron was given by IV infusion over 30 minutes 3 times per week (Monday-Wednesday-Friday [MWF]). Four dose levels were studied. and at least three patients were entered at each dose level. The treatment plan began with a three-step dose escalation for each patient over 6 weeks (initiation phase). The dose-escalation schema for the four dose levels was: 50-100-200. 100-200-400. 200-300-500. and 300-400-600 x 10(6) (M) IU/m2. Patients experiencing an objective response or stable disease after 6 weeks entered the maintenance phase at the final escalated dose. ie. 200. 400. 500. or 600 mlU/m2 (MWF). Common transient effects included chills. fever. and fatigue. Dose-limiting toxicities were hematologic. hepatic. and CNS. The maintenance maximum-tolerable dose (MTD) was 500 mlU/m2. ie. dose level 3. Response was assessed at completion of the initiation phase and at 2-month intervals during the maintenance phase. Objective partial responses were seen in patients with high-grade astrocytoma (two) and brain-stem glioma (two). Thus. four of 21 (19%) assessable patients had partial responses for a median of 4 months. Eight patients had stable disease for a median of 5+ (2 to 14+) months. Antineoplastic activity has been identified in children with high-grade astrocytomas and brainstem gliomas in a dose-intensive regimen.
Radiotherapy improves the outlook for patients older than 1 year with Pediatric Oncology Group stage C neuroblastoma, Children older than 1 year of age who have neuroblastoma with complete or partial removal of the primary tumor and positive intracavitary lymph nodes (Pediatric Oncology Group [POG] stage C) are a small but higher-risk subset of patients. To further evaluate the importance of identifying patients with POG stage C neuroblastoma and to assess the efficacy and toxicity of adding concurrent radiation therapy (RT) to chemotherapy (CT) in these children. a randomized study was conducted. Eligible patients received cyclophosphamide 150 mg/m2 orally days 1 to 7 and Adriamycin (doxorubicin; Adria Laboratories. Columbus. OH) 35 mg/m2 intravenously (IV) on day 8 (CYC/ADR) every 3 weeks for five courses with or without RT to primary tumor and regional lymph nodes (24 to 30 Gy/16 to 20 fractions). Second-look surgery was advised to evaluate response and to remove residual disease. Continuation therapy alternated CYC/ADR every 3 weeks with cisplatin 90 mg/m2 day 1 followed by teniposide 100 mg/m2 day 3 (CDP/VM) for two courses each. Secondary CT with CDP/VM alone was available for patients not achieving complete response (CR) following induction treatment and second-look surgery. Of 29 eligible patients randomized to CT alone. 13 achieved CR. and nine are disease-free (NED) 1 to 52 months (median. 35 months) off therapy. Twenty-two of 33 eligible cases treated with CT/RT attained CR. and 19 are NED 1 to 77 months (median. 23 months) off therapy. Local and metastatic relapses occurred in both arms. Differences in CR. event-free survival. and survival rates were significant. P = .013. .009. and .008. respectively. Surgical compliance was excellent and complications uncommon. Therapy was tolerable in both groups but hematopoietic toxicity was more common in the CT/RT arm. We conclude that POG stage C neuroblastoma in children older than 1 year of age is a higher-risk group that should be identified. that CT/RT provides superior initial and long-term disease control compared with CT alone in this patient subset. and that the occurrence of metastatic failures in both treatment groups suggests a need for more aggressive chemotherapy.
Clinical features and results of therapy for children with paraspinal soft tissue sarcoma: a report of the Intergroup Rhabdomyosarcoma Study, Soft tissue sarcomas of the paraspinal region comprised 3.3% (56 of 1.688) of the patients entered and eligible on Intergroup Rhabdomyosarcoma Studies I (IRS-I) and II (IRS-II) (1972 to 1984). These lesions tended to be greater than 5 cm in diameter at diagnosis. invaded the spinal extradural space. and were of the extraosseous Ewing's sarcoma or undifferentiated sarcoma subtype in 55% (30 of 56) of the cases. Patients with tumors in clinical groups II. III. and IV were treated with radiotherapy (XRT) and vincristine-dactinomycin (VA) or VA plus cyclophosphamide (VAC) +/- doxorubicin. Clinical group I patients treated on IRS-II did not receive XRT. while those on IRS-I were randomized to receive VAC +/- XRT. Forty-four of the paraspinal patients (79%) achieved a complete response (CR) compared with 77% (1.260 of 1.632) for patients with disease in other sites. Twenty-seven patients (55%) subsequently relapsed (five local. three regional. four local and distant. and 14 distant). The proportion of patients surviving 5 years by clinical group (stage) from I to IV were 50%. 50%. 62%. and 27%. respectively. Paraspinal patients had somewhat poorer survival than patients with disease in other sites. both in IRS-I and IRS-II; the percentage of paraspinal patients surviving 5 years was 50% and 52% for IRS-I and IRS-II. respectively. whereas these percentages were 55% and 63% for patients with disease in other sites. Histology did not influence the CR rate. but unexpectedly. patients who had embryonal rhabdomyosarcoma (RMS) had the poorest overall survival rate. We concluded that patients with paraspinal lesions may require extended-field radiation therapy to reduce the high local failure rate and more intensive chemotherapy to achieve better local and systemic tumor control.
Consolidation with intraperitoneal cisplatin in first-line therapy of advanced ovarian cancer, Seventy-five patients with advanced epithelial ovarian cancer were treated with a combined modality regimen of systemic. induction chemotherapy followed by intraperitoneal therapy (IPT). All patients underwent initial surgery for staging and/or cytoreduction followed by cisplatin 20 mg/m2 intravenously (IV) for 5 days and cyclophosphamide 600 mg/m2 on day 4 every 3 to 4 weeks for two to four cycles. Patients were then evaluated for IPT and. if eligible. had an intraperitoneal (IP) catheter placed. IPT consisted of cisplatin 60 mg/m2 in 2 L on day 1 and IV cyclophosphamide 600 mg/m2 on day 2 every 3 weeks for three to six cycles. Patients who demonstrated a clinical complete response (CCR) were then referred for second-look laparotomy (SLL). Of 71 patients who completed the induction phase. 53 (75%) were eligible for IPT. and 49 patients entered the therapy phase. Toxicity of the combined modality approach was acceptable and did not differ from our previous experience using the same drugs systemically. Thirty-two of the 49 patients who completed IPT achieved a CCR. which was confirmed by SLL in 20 patients. Twenty recurrences were documented in the 32 CCR patients. 13 occurred in patients after SLL. Projected median survival of all patients is 38 months. Median survival correlated with amount of residual disease following initial surgery (23 months for bulky v 45 months for minimal residual; P less than .001) and with performance status ([PS]; 24 months for PS 2. 3 v greater than 46 months for PS O; P less than .001). Patients who presented with bulky tumors were less likely to reach the consolidation IPT phase. Incorporation of IP cisplatin into the first-line regimen for treatment of ovarian cancer does not appear to have major impact on the survival of all treated patients when compared with our historical control series. Combined IV and IPT cisplatin and cyclophosphamide is feasible with acceptable toxicity. Its impact on response and survival may be limited to only "good-prognosis" patients.
Prognostic factors in unselected patients with nonseminomatous metastatic testicular cancer: a multicenter experience, Between 1981 and 1986. 200 consecutive patients with metastatic nonseminomatous testicular cancer were entered into the Swedish Norwegian Testicular Cancer (SWENOTECA) project from 14 hospitals. The treatment plan was four chemotherapy cycles (cisplatin. vinblastine. and bleomycin) followed by surgical resection of residual tumor masses. After a median observation time of 75 months. the overall 5-year survival rate was 82%. In a univariate analysis. the following parameters influenced the prognosis significantly: the extent of the disease (Medical Research Council [MRC] grouping); the prechemotherapy levels of serum alpha-fetoprotein (AFP). human chorionic gonadotropin (HCG). and lactate dehydrogenase (LDH); the patients' age; the presence of extrapulmonary hematogeneous metastases; and/or particularly large lymph node metastases. Patients fared better when more than 3 weeks elapsed between orchiectomy and start of chemotherapy as compared with those who were treated within this interval. The place of treatment (a large oncology unit v smaller units) also represented a significant prognostic factor for patients with large-volume (LV) and very-large-volume (VLV) disease combined. Multivariate analysis (Cox regression proportional hazards model) performed in all 193 assessable patients showed the following adverse prognostic factors: high-volume metastatic burden. age older than 35 years. prechemotherapy AFP greater than 500 micrograms/L and/or HCG greater than 1.000 U/L. and an interval between orchiectomy and start of chemotherapy of less than 3 weeks. The place of treatment also significantly influenced the final outcome. If patients with LV and VLV disease were combined. the presence of two of the following risk factors represented an additional prognostic factor: AFP greater than 1.000 micrograms/L. HCG greater than 10.000 U/L. liver metastases. brain metastases. bone metastases. retroperitoneal tumor greater than or equal to 10 cm. and mediastinal tumor greater than or equal to 5 cm.
Sequential high-dose methotrexate and fluorouracil combined with doxorubicin--a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group, In a prospective phase III multicenter trial. 213 patients with advanced measurable or nonmeasurable gastric cancer were randomized to receive methotrexate (MTX). fluorouracil (5-FU). and Adriamycin (doxorubicin; Farmitalia Carlo Erba. Milan. Italy) (FAMTX) or 5-FU. Adriamycin. and mitomycin (FAM). The results show a significantly superior response rate (41% v 9% [P less than .0001]). and survival (median. 42 weeks v 29 weeks [P = .004]) for FAMTX. There was a cumulative thrombocytopenia in FAM and not in FAMTX. The FAMTX protocol should be the reference treatment in future clinical trials that seek to improve the therapeutic outcome in advanced gastric cancer.
Routine imaging studies for the posttreatment surveillance of breast and colorectal carcinoma, Current recommendations on follow-up procedures for patients who have been treated for cancer include imaging studies and other laboratory tests at relatively frequent intervals. At least two questions should be asked to evaluate the benefits of this practice for patients: Do frequent routine surveillance tests detect recurrences "earlier" in asymptomatic patients? and Does earlier treatment of these recurrences reduce morbidity or prolong survival? The practical import of surveillance with imaging and laboratory tests for recurrence in patients with cancer of the breast and colon is discussed. Reported autopsy data. findings at elective reoperation. and clinical data have been examined to ascertain the justification for routine periodic tests in the treated but asymptomatic patient. It is concluded that earlier detection of a local recurrence or of metastatic disease through periodic tests in the asymptomatic patient with breast or colon cancer rarely alters the treatment or the outcome. A notable exception is regular screening mammography following treatment for adenocarcinoma of the breast.
Intraoperative electron beam radiation therapy for primary locally advanced rectal and rectosigmoid carcinoma, To improve local control and survival in patients with primary locally advanced rectal and rectosigmoid carcinoma. intraoperative electron beam radiation therapy (IORT) has been used with a combination of moderate- to high-dose preoperative radiation therapy and surgical resection. Sixty-five patients underwent resection with the intention of using IORT if areas at high risk for local recurrence were apparent at surgery. For 20 patients undergoing complete resection with IORT. the 5-year actuarial local control and disease-free survival (DFS) was 88% and 53%. respectively. The results for 22 patients with pathologically documented residual carcinoma were less satisfactory with a 5-year actuarial local control and DFS of 60% and 32%. respectively. In this latter group. local control and DFS correlated with the extent of residual disease: patients with only microscopic disease had a 5-year actuarial local control and DFS of 69% and 47%. respectively. whereas for patients with macroscopic disease. these figures were 50% and 17%. respectively. For 18 patients undergoing complete resection without IORT or additional postoperative radiation therapy. the 5-year actuarial local control and DFS was 67% and 53%. respectively. Because local failure will occur in at least 30% of patients undergoing partial resection with or without IORT as well as patients undergoing complete resection of advanced tumors without IORT. additional postoperative radiation therapy should be considered.
Intravenous carboplatin for recurrent malignant glioma: a phase II study, Thirty patients with recurrent malignant glioma were treated with intravenous (IV) carboplatin (CBDCA) every 4 weeks at a starting dose of 400 mg/m2 escalating to 450 mg/m2. All patients had documented recurrent tumor after prior radiotherapy but had not received prior chemotherapy. Of 29 assessable patients. four (14%) responded to the treatment for 44. 51+. 72. and 91 weeks; 10 (34%) achieved stable disease (S); while 15 (52%) had progressive disease (P). The total response (responses plus S) rate was 48%. with a median time to progression (MTP) of 26 weeks in these patients; the MTP for all 29 patients was 11 weeks. The toxic effects were mainly hematologic. with thrombocytopenia and granulocytopenia being mild at 400 mg/m2 and 450 mg/m2 doses. NO neurotoxicity or renal toxicity was encountered. These results suggest that CBCDA given at 400 mg/m2 or 450 mg/m2 every 4 weeks is marginally active in patients with recurrent malignant gliomas. Since hematologic toxicity is mild. a higher dose could possibly be given. and may increase the response rate.
Limited sampling models for doxorubicin pharmacokinetics, Although doxorubicin is one of the most commonly used antineoplastics. no studies to date have clearly related the area under the concentration-time curve (AUC) to toxicity or response. The limited sampling model has recently been shown to be a feasible method for estimating the AUC to facilitate pharmacodynamic studies. Data from two previous studies of doxorubicin pharmacokinetics were used. including 26 patients with sarcoma and five patients with breast cancer or unknown primary. The former were divided into a training data set of 15 patients and a test datum set of 11 patients. and the latter patients formed a second test data set. The model was developed by stepwise multiple regression on the training data set: AUC (nanogram hour per milliliter) = 17.39 C2 + 163 C48-111.0 [dose/(50 mg/m2)]. where C2 and C48 are the concentrations at 2 and 48 hours after bolus dose. The model was subsequently validated on both test data sets: first test data set--mean predictive error (MPE). 4.7%; root mean square error (RMSE). 12.4%; second test data set--MPE. 4.5%. RMSE. 9.2%. An additional model was also generated using a simulated time point to estimate the total AUC for a daily x 3-day schedule: AUC (nanogram hour per milliliter) = 44.79 C2 + 175.65 C48 + 47.25 [dose/(25 mg/m2/d)]. where the C48 is obtained just prior to the third dose. We conclude that the AUC of doxorubicin after bolus administration can be adequately estimated from two timed plasma concentrations.
Wilms' tumor: status report, 1990. By the National Wilms' Tumor Study Committee, Rapid advances in the understanding of Wilms' tumor (WT) and its management are being made both in the laboratory and the clinic. Molecular genetic research has implicated loss of a tumor suppressor gene on the short arm of chromosome 11 as one of the pathways responsible for the development of the neoplasm. Preconception maternal (hair dyes) and paternal (occupation) exposures to environmental agents have been the subject of epidemiologic studies of possible risk factors. Histopathologic analyses have identified several different and less common tumor types among those previously aggregated under the WT rubric. WT itself has been subdivided into the so-called favorable histology (FH) and anaplastic forms. the prognosis being worse for the latter. Clinical research has standardized management by surgery. chemotherapy. and radiation therapy (RT) and furthered the identification of risk factors. Patients can now be stratified according to tumor type and stage. and the intensity of treatment modulated accordingly; eg. RT at low doses is used in only 25% of National Wilms' Tumor Study (NWTS) patients without distant metastases. Before the NWTS. it had been given to almost all and at higher doses. Chemotherapy. whether given pre- or postoperatively. is based on dactinomycin and vincristine with Adriamycin [( ADR] doxorubicin; Adria Laboratories. Columbus. OH) added for high-risk patients. The currently used NWTS combined modality therapy for WT patients has dramatically improved survival rates; 95% now are alive 2 years after treatment. Remaining questions are the identification of the late effects of the treatments used and the further refinement of therapy to reduce iatrogenic complications to a minimum.
Antiviral effects of 3'-fluorothymidine and 3'-azidothymidine in cynomolgus monkeys infected with simian immunodeficiency virus, An acute infection with simian immunodeficiency virus (SIVSM) in cynomolgus monkeys was used to evaluate the antiviral effects of 3'-fluorothymidine (FLT) and 3'-azidothymidine [zidovudine (ZDV)]. Neither compound prevented the infection despite dosing prior to virus inoculation. FLT was about ten times more potent than ZDV in delaying the appearance of SIVSM antigen in the monkeys. The serum half-life of FLT was longer than that of ZDV and ZDV was bound to plasma proteins to about 60% while FLT was virtually unbound. It is proposed that the in vivo difference in potency between ZDV and FLT could. at least partly. be explained as the combined effects of a longer plasma half-life and a higher free concentration of FLT and possibly a higher intracellular concentration of the triphosphate of FLT.
Postexposure chemoprophylaxis: approval criteria for clinical trials, Five scenarios are proposed that investigators and clinicians might consider in the evaluation of an investigational drug for postexposure chemoprophylaxis. They are (a) safety as the only standard required for an indication for postexposure chemoprophylaxis; (b) efficacy of the drug for treatment of HIV-infected patients as a sufficient criterion for an indication for postexposure chemoprophylaxis; (c) a classic placebo-controlled trial as the basis for evaluation of postexposure chemoprophylaxis; (d) a clinical trial design that evaluates outcome in relation to varying times from exposure to initiation of treatment; and (e) combination therapy. Federal regulations are sufficiently flexible to allow demonstration of safety and efficacy of an investigational drug for this indication. The necessary element is that both safety and efficacy be demonstrated in an objective and reliable manner.
Synergistic anti-Pneumocystis carinii effects of erythromycin and sulfisoxazole, Pneumocystis carinii pneumonitis was effectively prevented in 90% of immunosuppressed rats by the administration of 100 mg of erythromycin and 300 mg/kg/day of sulfisoxazole. All of the untreated control and erythromycin-treated animals developed the infection and 80% of rats given sulfisoxazole alone had the pneumonitis. A similar pattern of response occurred when the drugs were used therapeutically for rats with established P. carinii pneumonitis. The erythromycin and sulfisoxazole ratio of 1:3 was the most effective of several dose combinations tested. The established safety record from three decades of clinical use of this drug combination plus the broad spectrum of coverage for other causes of diffuse pneumonitis such as Chlamydia. Mycoplasma. and Legionella warrant further study of erythromycin-sulfisoxazole in AIDS patients.
Resolution of vesicoureteral reflux in completely duplicated systems: fact or fiction, A total of 60 patients (71 renal units) with grade 2/5 vesicoureteral reflux into the lower pole moiety of a completely duplicated system was managed by medical surveillance and is compared to an identically managed age. race and sex matched control population with a similar degree of reflux into a single collecting system. During a median 2-year observation period reflux ceased spontaneously in 10% of the patients with duplication compared to 35% of the control population (p less than 0.01). Comparisons between the 2 study groups failed to reveal a difference in the incidence of break-through urinary tract infections. advancing degrees of reflux and/or the development or progression of renal scarring (p greater than 0.5). Despite the fact that the resolution rate in duplex systems is significantly lower than that of a single system. it is apparent that cessation of grade 2/5 reflux into a duplicated ureter will occur and that a trial of medical management is an appropriate initial method of therapy.
Cloacal anomalies and other urorectal septal defects in female patients: a spectrum of anatomical abnormalities, The anatomy and management of 16 female patients with urorectal septal defects have been reviewed. The diagnosis was often confused by the anomalous appearance of the external genitalia. and the internal arrangements of the urinary tract. genital tract and lower intestinal tract were frequently bizarre and unpredictable. Because of the potential of these patients for secondary infection and sepsis. a prompt and thorough anatomical evaluation in such cases is essential. Initial treatment should be directed toward decompression of the involved organ systems and definitive reconstruction should be deferred until the child is older. at which time the emphasis should be upon a simultaneous multisystem repair performed. whenever possible. in 1 stage.
A report of familial carotid body tumors and multiple extra-adrenal pheochromocytomas, A case of familial carotid body tumors and multiple extra-adrenal pheochromocytomas is reported. The carotid body tumors. resected previously. were bilateral and associated with 4 intra-abdominal extra-adrenal pheochromocytomas. Magnetic resonance imaging was far superior to computerized tomography and 131iodine-metaiodobenzylguanidine in visualizing the intra-abdominal lesions. and may soon become the imaging technique of choice in the evaluation of patients with suspected pheochromocytoma.
Urinary hematin calculi, We report 2 cases of nephrolithiasis owing to hematin stones. One patient had no apparent explanation for this finding. while the other was receiving warfarin anticoagulation for a prosthetic aortic valve. The chemical nature. etiology and clinical features of hematin calculi are discussed.
Primary malignant melanoma of the scrotum: case report and literature review, Malignant melanoma of the scrotum is the rarest of primary genitourinary melanomas. with only 3 cases reported previously. We present an additional case of this often aggressive malignancy. The pertinent literature is reviewed and the current management strategies are discussed.
Urophonographic studies of benign prostatic hypertrophy, The sonic detection and recording systems of urethral sounds generated during micturition were developed. This procedure was tentatively postulated as "urophonography" and its recording diagram as a "urophonogram". Classification of urophonograms was done on the basis of analyzing normal healthy male volunteers and patients with benign prostatic hyperplasia. Four types of urophonograms were demonstrated according to the shape and characteristics. Types 1. 2. 3 and 4 were characterized by a diamond shape. irregular occurrences of sound spikes. the mixture of Types 1 and 2 and no remarkable sound spikes respectively. Types 1. 2. and 3 were found in BPH. while Type 4 was demonstrated in normal healthy male volunteers. After prostatectomy a high percentage of Type 4 was demonstrated. The frequency (Hz) of these sounds was around 650. Diamond shape sound showed higher value of power gain (dB) than irregular type sound. The wave length was around 0.50 (m). Comparison of urophonographic studies with conventional uroflowmetric investigation was undertaken. Urophonography was useful for investigations of dysfunctional voiding and lower urinary tract obstruction.
Renal reconstruction after injury, During an 11-year period 1.363 patients presented to our institution with renal trauma. Renal exploration was performed in 127 patients (133 renal units). Most patients had multiple organ injuries. as indicated by a mean blood loss of 4.160 ml. and a mean injury severity score of 25.8. Absolute indications for exploration were bleeding and pulsatile perirenal hematoma and relative indications included urinary extravasation. nonviable renal tissue and incomplete staging. Renal surgery was required in 2.4% of the blunt injuries. 45% of the stab wounds and 76% of the gunshot wounds. Salvage was successful in 88.7% of the kidneys explored and total nephrectomy was required in 11.3%. The success rate was based on early vascular control and reconstructive techniques of "renorrhaphy." partial nephrectomy. vascular repair and coverage with omental pedicle flaps. Complications occurred in 9.9% of the cases but none resulted in renal loss. When indicated. renal exploration after trauma is safe and in a high percentage of cases reconstruction will be successful.
Endoscopic laser lithotripsy: safe, effective therapy for ureteral calculi, At our lithotripsy department more than 400 patients with renal or ureteral calculi have been treated with a pulse-dye laser for stone disease. We review our experience during an 11-month period when a total of 223 patients was treated. Of these patients 204 whose ureteral calculi were treated by laser lithotripsy are available for followup. The data in this series demonstrate that a miniaturized ureteroscopic system is of paramount importance in laser lithotripsy. allowing access into the ureter without dilation in the majority of patients (165 of 204). Lack of dilation is associated with a decrease in pain and postoperative hospitalization. Satisfactory stone fragmentation was accomplished in 198 of 204 procedures in this series with use of the laser alone. A low complication rate was observed. Endoscopic laser lithotripsy is a safe. reliable and cost-effective method of therapy for ureteral calculi in a community hospital setting.
Urinary tract stones: a complication of the Kock pouch continent urinary diversion, Urinary tract stone disease has been found to be a later complication associated with the construction of the Kock pouch continent urinary diversion. Of 383 patients who underwent Kock pouch diversion between August 1982 and December 1986 stones developed in the pouch in 64 (16.7%). usually on exposed staples or eroded Marlex used to construct the nipple valves. Stones have recurred in 13 of the 64 patients (22%). Most stones were removed endoscopically with techniques similar to those used for percutaneous stone removal. Risk factors for stone formation include Marlex collar erosion and acute pyelonephritis. Changes in surgical techniques with elimination of the Marlex collar and a reduction in the number of staples have reduced the incidence of this later complication to 10%.
A new technique for continent urinary reservoir reconstruction, A new technique for urinary reservoir reconstruction has been applied to 14 patients following radical cystectomy. The sigmoid colon was used in 10 cases and the ileum in 4. The pouch is constructed of adjacent detubularized intestinal segments. The continence mechanism is achieved by the formation of a double-jacket intestinal tube anastomosed to the skin. All patients except 1 were continent during stressful situations and resting with easy catheterization of the pouch. Urodynamic study in 3 cases showed a low pressure sigmoid reservoir with an average of 15 cm. water. and the tube had good tone with an average of 35 cm. water and a 5.5 cm. functional length. The technique is simple. can be applied to either the sigmoid colon or ileum and results in urinary continence with easy catheterization.
Electroejaculation following retroperitoneal lymphadenectomy, Transrectal electroejaculation was performed in 24 men who were anejaculatory from retroperitoneal lymphadenectomy. Of the men 23 had undergone retroperitoneal lymphadenectomy because of testis cancer. Seminal emission was achieved in all patients. In 21 patients greater than 10 x 10(6) progressively motile sperm with normal morphology were obtained. The average sperm count and motilities obtained were 289 x 10(6) and 18%. respectively. for the antegrade fractions. and 2.051 x 10(6) and 13%. respectively. for the retrograde fractions. Of the 3 azoospermic failures 2 had chemotherapy-induced testicular damage and 1 had carcinoma in situ of the remaining testis. A total of 19 couples underwent artificial insemination with electroejaculated sperm. There were 7 pregnancies achieved in 74 insemination cycles (36.8% of the couples conceived for a 9% cycle fecundity). Routine semen parameters could not predict which couples would be successful in achieving pregnancy. There were 2 first trimester spontaneous abortions. Five healthy children have been born. Electroejaculation is an excellent treatment for anejaculation that persists following retroperitoneal lymph node dissection.
Transperitoneal endosurgical lymphadenectomy in patients with localized prostate cancer, The main appeal of radiotherapy for carcinoma of the prostate lies in the low morbidity and good subsequent quality of life. The handicap of this approach is the absence of adequate staging through pelvic lymphadenectomy. A new operation with minimal morbidity for the patient is presented and described in detail: endosurgical (laparoscopic) pelvic lymphadenectomy. This operation can be performed on an outpatient basis and is extremely well tolerated by the patient. The results of the first 12 consecutive cases indicate that. with experience. the procedure can be performed within a reasonable time limit (90 to 205 minutes) and that the number of lymph nodes removed (right and left obturator fossae mean 7.6 and 7.1. respectively) is adequate. Endosurgical lymphadenectomy adds only minimal morbidity to the radiotherapeutic treatment of prostatic cancer but permits more accurate staging and. therefore. counseling of the patients.
Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles, The influence of preservation or excision of the neurovascular bundles on return of sexual function is analyzed. Between 1982 and 1988. 600 men 34 to 72 years old underwent radical retropubic prostatectomy for prostate cancer. Of the 503 patients who were potent preoperatively and followed for a minimum of 18 months 342 (68%) are potent postoperatively. Three factors were identified that correlated with the return of sexual function: 1) age. 2) clinical and pathological stage. and 3) surgical technique (preservation or excision of the neurovascular bundle). In men less than 50 years old potency was similar in patients who had both neurovascular bundles preserved (90%) and patients who had 1 neurovascular bundle widely excised (91%). With advancing age of more than 50 years sexual function was better in patients in whom both neurovascular bundles were preserved than in patients in whom 1 neurovascular bundle was excised (p less than 0.05). When the relative risk of postoperative impotence was adjusted for age the risk of postoperative impotence was 2-fold greater if there was capsular penetration or seminal vesicle invasion. or if 1 neurovascular bundle was excised (p less than 0.05). These data indicate that the return of sexual function postoperatively in men more than 50 years old is quantitatively related to preservation of autonomic innervation. In these men when it is necessary to excise the neurovascular bundle on 1 side. consideration in the future should be given to approaches that may restore autonomic function through nerve regeneration. for example partial excision of the bundle or cavernous nerve grafts.
Cause-specific mortality among physicians with differing life-styles, We compare the mortality experience of medical school graduates from Loma Linda University (LLU [n = 4342]) and the University of Southern California (USC [n = 2832]) with each other and with that of contemporaneous. white. American men. When compared with US white men from the general population. both USC and LLU graduates had below expected deaths for all causes (USC. standardized mortality ratio [SMR] = 76; LLU. SMR = 56). although deaths due to cerebrovascular disease. airplane accidents. and suicides were elevated for USC (SMRs = 132. 360. and 218. respectively). The LLU graduates had a risk similar to that of the USC graduates for fatal cancer. with a mortality ratio (MR) of 0.92 (95% confidence interval. 0.67 to 1.26); but half the risk of fatal atherosclerotic disease. with MRs of 0.58 (0.46 to 0.73) and 0.66 (0.43 to 0.99) for coronary and cerebrovascular disease. respectively; and three times the risk of fatal airplane accidents. The overall mortality rate of LLU physicians was only 75% as high as that of the USC physicians and only 56% as high as that of the US male population at large. We attribute this reduced mortality mainly to the low cardiovascular mortality rates. which may be accounted for by the life-style of the substantial proportion of Seventh-day Adventists among LLU graduates.
Teaching intubation skills using newly deceased infants, This prospective study was designed to (1) test the hypothesis that the majority of families of newly dead infants in a tertiary neonatal intensive care unit would consent to their infants' being intubated for teaching purposes. (2) determine factors related to family consent. and (3) determine the effects of participation on resident physicians and respiratory therapists. Family consent for intubation was requested following 44 (80%) of the 55 deaths that occurred during the 10-month study period. Of these requests. 32 (73%) were granted. Proportionately more white than black families consented and consent was positively related to autopsy permission. Fifty-three (75%) of 71 trainees completed a mailed questionnaire after their first intubation experience. Although each respondent found the experience helpful. many reported mixed feelings categorized as doubt about participating. apprehension and discomfort. respect for the body. appreciation for the opportunity. a sense of achievement. and feelings of comfort knowing that consent had been obtained. These findings confirm our initial hypothesis and suggest that (1) newly dead infants can be a valuable resource for teaching intubation skills. and (2) others considering a similar approach need to be aware of and sensitive to trainees' feelings.
Reduced intravascular catheter infection by antibiotic bonding. A prospective, randomized, controlled trial, We report a prospective. randomized. controlled clinical trial to evaluate the efficacy of antibiotic-bonded catheters in reducing the incidence of intravascular catheter-related infections. Ninety-three central venous catheters and 85 arterial catheters were studied in the surgical intensive care unit. Study catheters were pretreated with the cationic surfactant tridodecylmethylammonium chloride. The anionic antibiotic. cefazolin. was bonded before insertion of the catheters by immersing them in a 50-mg/mL solution. Fourteen percent of the 81 catheters in the control group were infected. compared with 2% of the 97 antibiotic-bonded catheters. Staphylococcus epidermidis was the most common organism obtained. There was no significant difference in the number of colonized or clinically inflamed catheter insertion sites. None of the 100 antibiotic immersion solutions yielded anything on microbiologic culture. We conclude that antibiotic bonding is an efficient. safe. and cost-effective method of reducing intravascular catheter infection in patients who are in intensive care units.
Doppler sonographic imaging of the vascular system. Report of the Ultrasonography Task Force. Council on Scientific Affairs, American Medical Association, Ultrasonic vascular imaging has been used for more than 20 years to define vascular anatomy. pathologic changes in vessel size. and perivascular abnormalities. In the last decade. development of duplex Doppler technology has permitted the evaluation of both anatomic vascular features and physiologic blood flow parameters in a variety of locations. Doppler "color flow" imaging promises to expand these applications. In many instances. duplex Doppler technology has replaced more invasive angiographic procedures for evaluation of suspected vascular abnormalities. Improved ultrasound duplex technology. combined with the relatively inexpensive. rapid. noninvasive aspects of ultrasonography has made it a valuable screening examination for suspected flow abnormalities.
Adolescent smoking and drinking: are they "epidemics", During adolescence. cumulative prevalences of ever using alcohol and ever smoking a cigarette increase systematically and dramatically. We applied a statistical theory of the transmission of epidemic infectious disease to model life-time prevalences of smoking and drinking. Alcohol use prevalences fit closely to a logistic curve used to model an epidemic process that assumed adolescents have random contacts with one another each year. An "adequate contact" will convert a nondrinker to drinking status if he/she is contacted; drinkers average .48 adequate contacts per year. Smoking prevalences were fit assuming both that the entire population was "at risk" and that some individuals were "immune": the mean contact parameter was .28 for smoking if no immune class was assumed and .77 if an immune class was assumed. Extensions of these epidemic process models could include individual differences in contact rates and transitions among several smoking or drinking statuses (e.g.. non-user. experimenter. regular user and recovered user).
Alcoholics Anonymous-Narcotics Anonymous model inpatient treatment of chemically dependent adolescents: a 2-year outcome study, Many hospital and residential chemical dependency treatment facilities utilize Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) principles and practices in therapeutic programming. Although well-known and broadly endorsed and supported. such AA/NA approaches have received little research attention especially in regard to chemically dependent adolescents. The present study examined chemical usage and social-civil-productive functioning in 157 male and female chemically dependent adolescents at 6. 12 and 24 months after leaving an AA/NA-based treatment program. Results revealed that both treatment completers and noncompleters (those who left treatment prematurely against professional/medical advice) demonstrated less chemical use after their respective hospitalizations than before. Although significantly higher percentages of both male and female treatment completers were found abstinent/essentially abstinent at 6 months post discharge in contrast to noncompleters. abstinence rates. particularly for male subjects. declined sharply by 1 and 2 years after treatment. Results indicated that the AA/NA model is a promising approach in treating chemically dependent adolescents. but that much attention to relapse prevention methods is necessary.
Parental alcoholism: an examination of male and female alcoholics in treatment, This study investigated the implications of parental alcoholism in 639 male and female alcoholics who were in treatment. In comparison with persons who did not report a parental history of alcoholism (PA-). the 264 offspring of alcoholics (PA+) were characterized by higher levels of alcohol dependency and alcohol-related consequences. increased reports of use of other drugs and higher levels of MMPI-measured psychopathology. Comparisons of PA+ patients with PA- patients with the same age of onset of problematic alcohol use suggested that PA+ persons are characterized more by an early onset of alcoholism than by a more severe form of the disorder. Results with female PA+ alcoholics were similar to those obtained with their male counterparts. although PA+ women exhibited very high levels of MMPI-measured psychopathology in comparison to both PA+ men and PA- women.
Adult children of alcoholics: profiles of wellness amidst distress, This research investigated the psychological adjustment of adult children of alcoholics. Few studies have explored the long-term effects of this childhood experience. The total sample (N = 239) included 114 adult children of alcoholics and 125 sociodemographically comparable adults from nonalcoholic family environments. The sample was further divided into young- and middle-adult age groups and men and women. All respondents completed a self-report instrument that included standardized measures of psychological well-being. emotional distress. personality characteristics and psychological development. Results indicated that adult children of alcoholics did not differ from the comparison group on the majority of measures that assessed multiple aspects of psychological well-being and personality development. However. adult children of alcoholics scored significantly higher on the measures of anxiety and depression than did adults from nonalcoholic families. Few gender differences were obtained in the overall pattern of results. The findings are discussed in light of the generally negative clinical descriptions of adult children of alcoholics and the need to implement future research that will explain the apparent variability in the psychological functioning of adult children of alcoholics.
Agreement between subject and collateral verbal reports of alcohol consumption in older adults, The accurate measurement of alcohol consumption in natural environments is a focal empirical issue in studies of the determinants of drinking. Four studies investigated agreement between subject and collateral questionnaire reports of drinking by adults over age 60 years (N = 83). and three of these studies also assessed agreement between daily subject and collateral prospective reports of subject drinking over 4 (Study 2) or 12 (Studies 3 and 4) week intervals. Subject and collateral questionnaire reports were significantly correlated. Excellent agreement was found for the group of subjects for self-monitoring reports of the number of drinking days and quantity of alcohol consumption per day. including reports of the temporal patterning of consumption. but variability in agreement existed across subject-collateral pairs. The discussion focuses on the conditions conductive to accurate measurement and on the importance of investigating predictor variables of individual differences in the accuracy of verbal reports of alcohol consumption.
Alcohol and fatal injuries in Oklahoma, To assess the usefulness of medical examiner data in describing the relationship between alcohol use and fatal injuries. 1978-84 data from the Office of the Chief Medical Examiner (ME). State of Oklahoma. was examined. In each year in the study period. approximately 1.500 deaths resulted from unintentional injuries (UI) and 800 deaths resulted from intentional injuries (i.e.. suicides and homicides). For persons who died on the same day they were injured. testing for blood alcohol ranged from 90% of homicide victims. to 73% of suicide victims and to 66% of UI victims. Alcohol was associated with 52% of homicides. 49% of UI and 40% of suicides. Alcohol was detected most often in samples from Hispanic men and from Native Americans of both sexes. This study suggests that state public health agencies and researchers should consider the use of ME data for epidemiologic information on the relationship between alcohol and injury-related mortality and for surveillance of these problems.
A change from public to private sale of wine: results from natural experiments in Iowa and West Virginia, Several proposals to change the existing structure of state alcoholic beverage control authorities have been advanced over the past 10 years in the United States. Most call for eliminating or substantially reducing the state's role in retail sales of alcohol. particularly distilled spirits and wines. In recent years the states of Iowa and West Virginia eliminated state monopolies for retail sales of wine. and now allow such sales by privately-owned licensed establishments. Using time-series methods. we assessed the effects of these policy changes on the alcoholic beverage market in each state. Privatization was associated with statistically significant increases in wine sales in Iowa and West Virginia. after controlling for an initial stocking effect and broader nationwide trends in alcohol sales in the 1980s. In addition. there was a net increase in absolute alcohol consumed in both states across all beverages (beer. wine and distilled spirits) associated with privatization.
Relation between HIV-1 syncytium inhibition antibodies and clinical outcome in children, Syncytium formation. a feature of HIV-1-induced cytopathology. allows the virus to propagate through cell-to-cell spread. An assay has been developed to measure antibodies (syncytium inhibition. SI) that inhibit this process. Two cell lines were used: the indicator cells. which are not HIV-1 infected. bear CD4 receptors on their surface; the fusogenic HIV-1 infected cells. which do not release virus but are responsible for initiating syncytium formation. are free of CD4 receptors. Co-cultivation of about 10(5) of each of these cells induces the emergence of 70-100 multinucleated giant cells within 48 h. Sera from 34 children born to HIV-1-infected mothers were tested by western blot (WB) and SI assay. SI antibodies were detected in the blood of 15 (65%) of 23 WB-positive children and in none of 11 WB-negative children. There were striking differences in prevalence and titre of SI antibodies in children with lymphocytic interstitial pneumonitis (LIP) compared with those with opportunistic infections (OI). All 8 children with LIP had SI antibodies ranging in titre from 40 to greater than 320. By contrast. only 2 of 7 with OI had SI antibodies. in both of whom the SI titre was 20 (p less than 0.05). No sera from children who had seroreverted contained SI antibodies. The findings point to the need to identify the specific HIV-I peptides or epitopes responsible for syncytium formation since SI antibodies correlate with clinical outcome in children.
Maternal filarial infection as risk factor for infection in children, Familial clustering of filarial infection was investigated through random house-to-house surveys of 643 individuals in Leogane. Haiti. an area with endemic Bancroftian filariasis. Children of infected mothers were 2.4 to 2.9 times more likely to be infected than were those of amicrofilaraemic mothers. Filarial-specific cellular responsiveness in amicrofilaraemic children born to infected mothers was lower than that in amicrofilaraemic children born to amicrofilaraemic mothers. No effect of paternal infection status was seen. The findings show that maternal infection is a risk factor for filarial infection in children and is associated with altered parasite-specific immune reactivity.
Prevalence and incidence of Becker muscular dystrophy, We measured the prevalence and incidence of Becker muscular dystrophy in the Northern Health Region of England. UK. Patients were identified from the records of the Regional Neurological Centre and Muscular Dystrophy Group laboratories. Newcastle upon Tyne. and by writing to local doctors. We used cDNA probes and/or dystrophin immunolabelling of muscle-biopsy samples to prove the diagnosis of all cases. Results were compared with the known prevalence and incidence of Duchenne muscular dystrophy. 73 patients alive and resident in the Northern Health Region were identified. giving a prevalence rate of 2.38/100.000. This compares with a prevalence of Duchenne muscular dystrophy of 2.48/100.000. The cumulative birth incidence of Becker muscular dystrophy (at least 1 in 18 450 male live births) was about one third that of Duchenne muscular dystrophy (1 in 5618 male live births). suggesting that the disorder is more common than previously thought.
Reduction of transmission of shigellosis by control of houseflies (Musca domestica), The effect of control of houseflies on the incidence of diarrhoea and shigellosis was evaluated in a prospective crossover intervention study at two military field bases several kilometers apart. In early summer. 1988. intensive fly control measures (mainly bait and trap strategy) were introduced on one base. while the other served as a control. After 11 weeks. as new cohorts arrived. the intervention was abruptly discontinued in the first base and instituted in the second for the next 11 weeks. The study was repeated the next summer. Overall. fly counts were 64% lower on the bases exposed to fly control measures (p = 0.024). Concomitantly. clinic visits dropped by 42% (p = 0.146) for diarrhoeal diseases and by 85% for shigellosis (p = 0.015). as did rates of seroconversion. by 76% (p = 0.024) for antibodies to Shigella and by 57% (p = 0.006) for antibodies to enterotoxigenic Escherichia coli. The findings indicate that houseflies. acting as mechanical vectors. transmit Shigella (and possibly enterotoxigenic E coli) diarrhoeal infections.
Exercise and the incidence of upper respiratory tract infections, We examined illness patterns in a cohort of 530 male and female runners who completed a monthly log for 12 months. The average number of upper respiratory tract infections (URTIs) per person per year for the cohort was 1.2. An upper respiratory tract infection was indicated by the report of any of the following symptoms; runny nose. sore throat. or cough. Using a multiple logistic regression model. the following factors were found to be associated with having one or more URTIs in the follow-up period: living alone (odds ratio = 2.27. 95% CI = 1.01. 5.09). running mileage (486-865 miles. odds ratio = 2.00. 95% CI = 1.01. 2.78; 866-1388 miles. odds ratio = 3.50. 95% CI = 1.52. 4.44; greater than 1388 miles. odds ratio = 2.96. 95% CI = 1.30. 3.68). body mass index greater than the 75th percentile (odds ratio = 0.58. 95% CI = 0.35. 0.94). and male gender (odds ratio = 0.14. 95% CI = 0.03. 0.68). A significant interaction was found to exist between gender and alcohol use. with the association between alcohol use and upper respiratory tract infections being positive in males and negative in females. These results suggest that running dosage (mileage) is a significant risk factor for upper respiratory tract infections in this group of exercisers.
Effect of ultrasound therapy on the repair of Achilles tendon injuries in rats, The purpose was to determine the effects of selected regimens of ultrasound therapy on the rates of repair of injured Achilles tendons of rats. Specific dependent variables examined were tendon breaking strength and rate of collagen formation. A puncture technique was used to induce injuries to both Achilles tendons of rats. Continuous ultrasound was administered to the left tendon for 4 min per treatment session at an intensity of 1.5 W.cm-2. Rats were sacrificed 2. 5. 9. 15. and 21 d following injury for measurement of tendon breaking strength and 3 and 5 d postinjury for analysis of collagen synthesis. Breaking strength was defined as the minimum force required to completely rupture the tendon. Collagen synthesis was indicated by the conversion of labeled proline to hydroxyproline. The breaking strengths of the treated tendons were significantly greater than strengths of the untreated tendons 5. 9. 15. and 21 d postinjury. Collagen synthesis was increased in the treated tendons compared with the untreated tendons 5 d postinjury. The results indicate that ultrasound treatment increases the rate of repair of injured Achilles tendons of rats. The results are also consistent with an association between increased collagen synthesis and greater breaking strength during tendon repair.
Athletic footwear: unsafe due to perceptual illusions, Modern athletic footwear provides remarkable plantar comfort when walking. running. or jumping. However. when injurious plantar loads elicit negligible perceived plantar discomfort. a perceptual illusion is created whereby perceived impact is lower than actual impact. which results in inadequate impact-moderating behavior and consequent injury. The objective of this study was to examine how plantar tactile (mechanical) events affect perceived plantar discomfort. Also. we evaluated the feasibility of a footwear safety standard we propose. which requires elimination of the above illusion. Twenty subjects gave numerical estimates of plantar discomfort produced by simulated locomotion (concurrent vertical (0.1-0.7 kg.cm-2) and horizontal (0.1-0.9 kg.cm-2) plantar loads). with the foot supported by either a smooth rigid surface or a rigid surface with 2 mm high rigid irregularities. Vertical or horizontal load alone evoked no discomfort (P greater than 0.05). whereas together. discomfort emanated from loads as low as 0.4 kg.cm-2. Irregularities heightened discomfort by a factor of 1.89. This suggests that the proposed safety standard is feasible. since compliance could be achieved simply by adding surface irregularities to insoles and by other changes that heighten localized plantar loads. However. until this standard is adhered to. it might be more appropriate to classify athletic footwear as "safety hazards" rather than "protective devices".
Renal hemodynamics and the renin-angiotensin-aldosterone system in normotensive subjects with hypertensive and normotensive parents, BACKGROUND AND METHODS. The kidney is important in blood-pressure regulation. but its role in the development of essential hypertension is still subject to debate. We compared renal hemodynamics. measured in terms of the clearance of para-aminohippuric acid and inulin. and the characteristics of the renin-angiotensin-aldosterone system in three groups of normotensive subjects at different degrees of risk for hypertension: 41 subjects with two normotensive parents. 52 with one normotensive and one hypertensive parent. and 61 with two hypertensive parents. The subjects ranged in age from 7 to 32 years. RESULTS. The mean renal blood flow was lower in the subjects with two hypertensive parents than in those with two normotensive parents (mean difference [+/- SE]. 198 +/- 61 ml per minute per 1.73 m2 of body-surface area; P = 0.002). Moreover. both the filtration fraction and renal vascular resistance were higher in the subjects with two hypertensive parents (filtration fraction: mean difference. 3.0 +/- 1.1 percentage points; P = 0.006; renal vascular resistance: mean difference. 2.7 +/- 0.8 mm Hg per deciliter per minute per 1.73 m2; P = 0.006). The subjects with two hypertensive parents had lower plasma concentrations of renin (mean difference. 3.3 +/- 1.6 mU per liter; P = 0.03) and aldosterone (mean difference. 111 +/- 36 pmol per liter; P = 0.003) than those with two normotensive parents. The differences could not be explained by the small differences in blood pressure between the groups. The values in the subjects with one hypertensive and one normotensive parent fell between those for the other two groups. CONCLUSIONS. Renal vasoconstriction is increased and renin and aldosterone secretion is decreased in young persons at risk for hypertension. These findings support the hypothesis that alterations in renal hemodynamics occur at an early stage in the development of familial hypertension.
Preoperative transcatheter closure of congenital muscular ventricular septal defects, BACKGROUND. Surgical repair of muscular ventricular septal defects. particularly those associated with complex heart lesions carries a higher risk of reoperation and death than the repair of membranous defects. Closing a muscular defect through an incision in the systemic ventricle may cause late ventricular dysfunction. In a collaborative approach to this problem. we undertook preoperative transcatheter closure of muscular ventricular septal defects remote from the atrioventricular and semilunar valves. followed by the surgical repair of associated conditions. METHODS. In 12 patients selected jointly by a cardiologist and a cardiac surgeon. we attempted preoperative transcatheter umbrella closure of 21 defects. Half the patients had associated complex heart lesions; the others had had pulmonary-artery banding to reduce the amount of left-to-right shunting. Half had severe ventricular septal deficiency. RESULTS. All 21 defects were successfully closed without major complications. Subsequent cardiac surgery for associated conditions in 11 of the 12 patients resulted in a mean pulmonary-to-systemic flow ratio of 1.1. indicating minimal residual left-to-right shunting; 1 patient awaited surgical repair. No deaths. reoperations. or late complications have occurred after a follow-up of 7 to 20 months. CONCLUSIONS. A collaborative approach using transcatheter closure followed by the surgical repair of associated cardiac lesions may decrease rates of operative mortality. reoperation. and left ventricular dysfunction in patients with muscular ventricular septal defects.
Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine, Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors. three different dopamine receptors (D1. D2. D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics. clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine. however. has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors. but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.
Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant, Most of the transcriptional effects of cyclic AMP are mediated by the cAMP response element binding protein (CREB). After activation of cAMP-dependent protein kinase A. the catalytic subunits of this enzyme apparently mediate the phosphorylation and activation of CREB. As cAMP serves as a mitogenic signal for anterior pituitary somatotrophic cells. we investigated whether CREB similarly regulates proliferation of these cells. We prepared transgenic mice expressing a transcriptionally inactive mutant of CREB (CREBM1). which cannot be phosphorylated. in cells of the anterior pituitary. If CREB activity is required for proliferation. the overexpressed mutant protein would effectively compete with wild-type CREB activity and thereby block the response to cAMP. As predicted. the CREBM1 transgenic mice exhibited a dwarf phenotype with atrophied pituitary glands markedly deficient in somatotroph but not other cell types. We conclude that transcriptional activation of CREB is necessary for the normal development of a highly restricted cell type. and that environmental cues. possibly provided by the hypothalamic growth hormone-releasing factor. are necessary for population of the pituitary by somatotrophic cells.
Processing of the precursor of NF-kappa B by the HIV-1 protease during acute infection, Transcription of the human immunodeficiency virus type-1 (HIV-1) genome is regulated in part by cellular factors and is stimulated by activation of latently infected T cells. T-cell activation also correlates with the induction of the factor NF-kappa B which binds to two adjacent sites in the HIV-1 long terminal repeat. This factor consists of two DNA-binding subunits of relative molecular mass 50.000 (50K) associated with two 65K subunits. It is located in the nucleus in mature B cells. but is present in other cell types as an inactive cytoplasmic complex. External stimuli. including those that activate T cells. result in nuclear translocation of active NF-kappa B. The cloning of the complementary DNA for the 50K subunit helped to identify an exclusively cytoplasmic 105K precursor (p105) (V.B.. P.K. and A.I.. manuscript submitted). The expression of active NF-kappa B might therefore also be regulated by the extent of processing of p105. Because HIV-1 requires active NF-kappa B for efficient transcription. we tested the effect of HIV-1 infection on the processing of the human 105K precursor. We show here that the HIV-1 protease can process p105 and increases levels of active nuclear NF-kappa B complex.
Treatment for obesity: a nutrient balance/nutrient partition approach, This paper examines the treatment of obesity. using a feedback model of nutrient regulation. A feedback model contains afferent signals and a central controller that transduces afferent information into efferent signals that modulate the controlled system. Using this model and the receptor hypothesis for drug action. a variety of current and potential therapeutic approaches are discussed. Among the more promising approaches would be cholecystokinin agonists. small molecules that mimic ketoacids. agonists to corticotropin-releasing hormone. beta-3 agonists. antagonists to opioid peptides. antagonists to neuropeptide Y. glucocorticoid receptor antagonists. and growth hormone agonists. Since a number of mechanisms can influence body fat and nutrient partitioning. it is likely that optimal therapy will involve use of more than one pharmacologic agent.
Technical procedures and software for magnification-corrected morphometry of optic disk photography, In order to obtain a new diagnostic tool for the early diagnosis of glaucoma. we developed a method based on computerized analysis of the optic disk. cup and neuroretinal rim areas. A fundus camera. a personal computer and a graphic tablet are employed. Suitable software was developed for calculating the areas (disk. cup and rim) providing an index. the rim/disk ratio. The method revealed high repeatability and reproducibility. The simplicity and speed of the procedure make this test suitable for routine clinical use in the early diagnosis of glaucoma.
Mononuclear cell phenotypes and immunoglobulin gene rearrangements in lacrimal gland biopsies from patients with Sjogren's syndrome, Immunocytochemical studies of lacrimal gland biopsies obtained from eight patients with Sjogren's syndrome revealed the major component of the mononuclear cell infiltrates to be comprised of B cells and Leu-3+ T-helper cells. which were present well in excess of control glands. Three of seven cases that were tested harbored cells that stained with monoclonal antibodies against different components of Epstein-Barr virus (EBV); one of the biopsies also contained cells that bore cytomegalovirus antigens. Immunoglobulin-gene rearrangements. but not T-cell receptor rearrangements. were demonstrated in one of two Sjogren's lacrimal gland biopsies tested. The authors conclude that the destruction of the tubuloacinar architecture of lacrimal gland tissue in Sjogren's syndrome appears secondary to lymphoproliferation of B cells and T-helper cells. probably derived from primary lymphoid follicles. Productive infection of lacrimal gland tissue with EBV may play a role in the pathogenesis of the syndrome in selective cases.
Role of posterior vitreous detachment in idiopathic macular holes, The role of posterior vitreous detachment in the formation of idiopathic macular hole was evaluated in 310 eyes. The eyes were classified according to the stage of the initial macular pathology: group 1. macular cyst; group 2. early macular hole; and group 3. fully developed macular hole. The initial prevalence of posterior vitreous detachment was 0% (none of 15 eyes) in group 1. 6% (three of 50 eyes) in group 2. and 27% (67 of 245 eyes) in group 3. During the study. all 15 eyes in group 1 and all 43 eyes in group 2 for which data were obtained progressed to fully developed macular holes without the occurrence of posterior vitreous detachment. The findings strongly suggested that most idiopathic macular holes develop in the absence of posterior vitreous detachment and that the pathogenesis of the holes may be independent of the occurrence of posterior vitreous detachment.
Photoreceptor rosettes with blue cone opsin immunoreactivity in retinitis pigmentosa, Immunocytochemistry has rarely been performed on donor retinas from patients with retinitis pigmentosa (RP). due to routine storage of tissues in fixatives that reduce or destroy antigenicity. The authors have developed a method to circumvent this problem and report light and electron microscopic histopathology and immunocytochemistry of an unusual retina from a 76-year-old man with multiplex RP. The retina shows loss of photoreceptors throughout (particularly rods). shortened foveal cone outer segments. and displaced photoreceptors in rosettes and tubules. an atypical pattern for RP. Antigenicity was recovered in this retina by treatment with sodium borohydride. and 17 antigens normally found in retina are present with expected distribution. although many cells have abnormal morphology. Most cone outer segments are immunoreactive with anti-blue but not anti-red/green cone opsin. whereas blue cone sensitivity is preferentially lost in many cases of RP. Psychophysical testing of the patient's sister. who has the same retinal disease. showed reduced rod and red/green cone sensitivities. This was consistent with the diminished numbers and size of rods and red/green cones found by immunocytochemistry in her brother's retina. The sister did not show blue cone hypersensitivity characteristic of a recently described retinal degeneration known as the "enhanced S cone syndrome.".
Immunopathology of vitreous and retinochoroidal biopsy in posterior uveitis, The authors used immunopathologic techniques to study vitreous and/or retinochoroidal biopsies from 23 patients with posterior uveitis unresponsive to conventional therapy or who had developed significant complications despite therapy. Results indicated that during active uveitis from many causes. T-helper cells predominated in the vitreous and retinochoroidal biopsies. Monocytes were not prominent constituents except in several cases of granulomatous etiology (e.g.. syphilis and acute retinal necrosis). Class II major histocompatibility complex (MHC) antigens were increased on the retinal vascular endothelium. implicating an important role for these cells in the local cellular immune response. These results may be of great importance in our understanding of uveitis. as well as being helpful in categorizing posterior uveitis. permitting appropriate therapy to be given.
The level of tryptase in human tears. An indicator of activation of conjunctival mast cells, Tryptase. a neutral endoprotease. is secreted by activated mast cells in human tissues. Tryptase levels in various body fluids have been used as an indicator of mast cell activation. The authors determined tryptase levels in unstimulated tears collected from the following groups of patients: (1) normal control. (2) nonallergic ocular inflammation. (3) asymptomatic seasonal allergic conjunctivitis. (4) symptomatic seasonal allergic conjunctivitis. (5) vernal conjunctivitis. and (6) contact lens-associated giant papillary conjunctivitis. They also assessed the release of tryptase into the tear fluid after provoking the conjunctiva with (7) allergens. (8) compound 48/80. and (9) rubbing. Tryptase levels were elevated in tears of patients with active ocular allergy and also increased after provoking the conjunctiva with allergens in atopic subjects and with compound 48/80 and rubbing in nonatopic subjects. Tryptase levels in tear fluid may prove useful as a clinical indicator of mast cell involvement in ocular allergic disorders. In provocation experiments. tryptase levels may be used to evaluate and compare different mast cell stabilizing agents.
Role of staphylococcal toxin production in blepharitis, Lid isolates of Staphylococcus aureus and coagulase-negative staphylococci (CNS) from controls (12 S. aureus and 110 CNS) and from patients with blepharitis (17 S. aureus and 171 CNS) were tested for production of alpha. beta. delta. epsilon. and previously undescribed hemolytic toxins. because toxin production has been implicated as a cause of blepharoconjunctivitis. The electrolyte content of agar media required for toxin production was first investigated. Alpha-lysin was found to be produced by all isolates of S. aureus colonizing lids of normal controls and patients with blepharitis. but by none of 281 CNS isolates. A new toxin was identified. having low molecular weight (5 kd). produced by one CNS strain isolated from a blepharitic lid. It was produced on basic nutrient agar that lacked sodium but contained glucose. which inhibited production of alpha-lysin. It hemolyzed rabbit and sheep erythrocytes and. surprisingly. was neutralized by polyclonal antiserum to alpha-lysin. This may explain occasional reports of alpha-lysin production by CNS. The overall results do not support a hypothesis of hemolytic toxin production by staphylococci as a general cause of blepharitis.
Effect of pregnancy and pain on cerebrospinal fluid immunoreactive enkephalins and norepinephrine in healthy humans, Endogenous spinal opioid or noradrenergic system activation may increase pain threshold during pregnancy and following a painful stress. Variation in spinal antinociceptive activity is also postulated to explain in part the large variability in postoperative opioid analgesic requirements. In this study. spinal noradrenergic and opioid activity. as reflected by the CSF concentrations of norepinephrine and immunoreactive enkephalins (total enkephalin-containing peptides). was determined in 58 women prior to surgery. The CSF concentration of these substances did not differ between pregnant and non-pregnant women. CSF norepinephrine tended to be greater in pregnant women who had experienced painful labor than in those who had not (1240 +/- 300 vs. 570 +/- 160 pmol/l; P = 0.056) and these women self-administered less morphine following cesarean section than those without labor pain (64 +/- 4 vs. 86 +/- 7 mg/24 h; P less than 0.01). However. CSF concentration of norepinephrine or immunoreactive enkephalins did not correlate with postoperative morphine use. These results suggest that spinal immunoreactive enkephalin and noradrenergic activity are not increased during pregnancy. However. pain may activate spinal noradrenergic pathways affecting pain sensation.
Hypalgesic efficacy of acupuncture on experimental pain in man. Comparison of laser acupuncture and needle acupuncture, The analgesic effect of acupuncture on cutaneous heat stimuli of 43 degrees C has been evaluated in a controlled experimental study with healthy. informed volunteers. Laser acupuncture was administered to 39 probationers using a helium-neon laser under double-blind conditions. The point Hegu (L.I.4) and Jianqian (Extra.) on both sides were each irradiated for 1 min. Forty probationers were needled with stainless steel needles in the point Hegu (L.I.4) on both sides under single-blind conditions. Pain threshold was measured in terms of the time (in msec) that the probationers needed to perceive the cutaneous heat stimulus of 43 degrees C. The painful stimulus was generated by a computer-controlled standardized procedure. The Wilcoxon test was used for the statistical evaluation. Laser acupuncture did not change the pain threshold. Needle acupuncture did. however. increase the pain threshold compared with the initial value (alpha = 0.1%). The difference compared with the control group. where a placebo point was needled. was also significant (alpha = 5%). This controlled experimental study proves the analgesic effect of needle acupuncture on painful heat stimuli. Laser acupuncture had no effect on pain threshold in this study.
Dimensions of pain-related cognitive coping: cross-validation of the factor structure of the Coping Strategy Questionnaire, Previous research has demonstrated a relationship between cognitive pain coping activity and adjustment in pain patients. The empirically derived dimensions of coping activity. as measured by scales from the Coping Strategy Questionnaire (CSQ). however. have varied across investigations. The purpose of this investigation was to determine both the content and number of dimensions of the CSQ and to explore the potential moderating influence that sociodemographic and patient history variables may have on the latent structure of the CSQ. A total of 620 patients from 5 different chronic pain patient samples were used to assess the generalizability of the dimensions across samples. Confirmatory factor analytic procedures identified a 3-factor solution in most of the samples that was robust across various demographic characteristics. Two factors appeared particularly robust: one reflected conscious use of cognitive coping strategies (with high loadings on ignoring pain and coping self-statements) and another reflected self-efficacy beliefs concerning pain (with high loadings on ability to control and decrease pain). A third factor. which was somewhat less stable. appeared to reflect avoidance of pain by attention to non-pain-related mental activity (with high loadings on diverting attention and praying and hoping). Scales reflecting catastrophizing cognitions and behavioral coping strategies did not consistently load on the above dimensions. Issues concerning the conceptualization and measurement of pain-related cognitive coping dimensions are discussed.
Pain and vascular reflexes in man elicited by prolonged noxious mechano-stimulation, Interdigital webs of the hands of human volunteers were pinched for periods of 2 min duration to induce tonic pain perceptions. During stimulation. the subjects gave estimates of their pain level at 10-sec intervals on a visual analogue scale. and the stimulus induced changes of the skin blood flow in the stimulated hand was assessed by photo-plethysmography. Sustained pinching induced a tonic reflex vasoconstriction in the stimulated hand with rather slow adaptation rate and no signs of habituation between trials. Step increases of the pinching force in the course of a stimulus were reflected by a decrease in plethysmogram amplitude as well as by increased pain ratings. although the subjects were usually unaware of these steps. Lowering the stimulus strength induced opposite. albeit much smaller effects in both pain ratings and vascular reactions. It is concluded that the vasomotor responses described in this paper are mediated by nociceptor input and reflect the processing of this input mainly at a spinal level.
Laser treatment applied to acupuncture points in lateral humeral epicondylalgia. A double-blind study, Forty-nine patients suffering from lateral humeral epicondylalgia were enrolled in a double-blind study to observe the effects of Ga-As laser applied to acupuncture points. The Mid 1500 IRRADIA laser machine was used. wavelength: 904 nm. mean power output: 12 mW. peak value: 8.3 W; frequency: 70 Hz (pulse train). Localization of points: LI 10. 11. 12. Lu 5 and SJ 5. Each point was treated for 30 sec resulting in a dose of treatment of 0.36 J/point. The patients were treated 2-3 times weekly with 10 treatments in all. Follow-ups were done after 3 months and 1 year. No significant differences were observed between the laser and the placebo group in relation to the subjective or objective outcome after 10 treatments or at the follow-ups.
Maxillary advancement for mandibular prognathism: indications and rationale, The surgical correction of mandibular prognathism has traditionally involved posterior repositioning of the mandibular body. This treatment approach corrects the skeletal disproportion at the expense of reducing facial skeletal volume and can unpredictably result in inadequately supported soft tissues with loss of skeletal definition. In an effort to avoid these sequelae of mandibular reduction. 18 patients diagnosed as having mandibular prognathism were treated with maxillary advancement surgery at the Le Fort I level. Mean patient SNB angle was 85.2 degrees. as compared with a normal 79 +/- 3 degrees. Maxillae were documented to be in normal position relative to both cranial base and Frankfort horizontal. The mean maxillary advancement was 6.9 mm. with a range of 4.5 to 8.8 mm. All patients required genioplasty to reduce vertical chin height and/or to laterally shift the chin. At the time of follow-up (mean 16.2 months). all patients retained cephalometric data suggestive of enlarged mandibles and excessive anterior facial divergence. However. maxillomandibular harmony and facial convexity had been restored without sacrificing skeletal volume. Treatment results demonstrated these faces to be skeletally well proportioned despite lower face protrusion that was beyond "normal." Postoperative appearances were characterized by a well-supported soft-tissue envelope and a highlighted skeletal foundation. creating angular. well-defined lower faces. These findings support the credibility of maxillary advancement as the procedure of choice in selected individuals with mandibular prognathism. Indications and an aesthetic rationale for this surgical approach are presented.
Orthognathic surgery in cleft patients treated by early bone grafting, For the past 25 years at Children's Memorial Hospital in Chicago a protocol has been followed for complete clefts that involves placement of an infant maxillary orthopedic appliance prior to lip closure. surgical closure of the lip. autogenous split-rib grafts to the alveolus to stabilize maxillary segments. and palatal closure. generally within the first year of life. The oldest 36 patients whose skeletal growth was for all practical purposes finished have been followed to determine the need for and type of orthognathic surgery. Of the total sample. 8 patients (22.2 percent) required some type of sagittal orthognathic surgery (1 patient in this group also required vertical maxillary alignment) and 2 patients required maxillary augmentation only in the form of an onlay graft. This report may serve as a baseline for others who wish to report on the incidence and type of orthognathic surgery in their cleft palate centers.
Conservation therapy for breast cancer following augmentation mammaplasty, Breast conservation therapy (wide local excision. axillary lymph node dissection. and whole-breast irradiation) is an increasingly popular alternative to mastectomy for breast cancer patients. A sizable (and growing) number of breast cancers occur in women with prior augmentation mammaplasty. Augmented breast cancer patients are currently being treated with conservation therapy. but no study has investigated complications and cosmetic results of radiation therapy specifically in this group of women. Between 1981 and 1988. we used conservation therapy in 17 augmented breast cancer patients. Fifteen patients were available for follow-up. In 10 (67 percent). significant capsular contracture occurred in the irradiated breast an average of 12 weeks following completion of treatment. Four patients have undergone revisionary surgery to correct symptoms arising from contracture. This poor outcome contradicts the results reported in previously published studies. We conclude that irradiation of the breast for cancer in augmented women results in a high incidence of scar-tissue contracture and poor cosmetic results.
The early management of flap necrosis in breast reconstruction, Flap necrosis is a potential complication of any type of breast reconstruction. Of 302 breast reconstructions performed by the author at the University of Texas M.D. Anderson Cancer Center. some degree of flap necrosis occurred in 59 (19.5 percent). Small areas of flap necrosis can be managed with simple observation. but secondary healing may not be complete for months. Early and aggressive excision of the ischemic tissue with immediate primary closure often can achieve rapid primary healing. In addition. early revision and reshaping of the breast may. in selected patients. permit achievement of a significantly better final result. This is true not only for TRAM and latissimus dorsi flaps. but also for the mastectomy flap necrosis sometimes encountered in immediate reconstruction with simple implants or tissue expanders.
Quadrilateral space syndrome: diagnosis and operative decompression technique, We present a series of five patients with quadrilateral space syndrome. All patients had the diagnosis made on the basis of (1) tenderness over the quadrilateral space. (2) paresthesia over the lateral shoulder and upper posterior arm. and (3) deltoid weakness associated with decreased shoulder abduction. A history of trauma was present in each patient. The operative technique described utilizes a cosmetically acceptable incision and is without the need to divide the deltoid from its origin on the scapular spine. The technique minimizes postoperative bleeding and facilities rehabilitation. Arteriography of the posterior circumflex humeral artery was not found necessary to make the diagnosis of axillary nerve entrapment in the quadrilateral space.
Untreated cleft lip in an aged patient, An unusual case of unrepaired bilateral incomplete cleft lip in a 66-year-old female patient is presented. Since the cleft had been untreated for such a long time. the local anatomy was severely altered. For this reason. the situation was faced as an ordinary gap and was successfully repaired by advancement of the lateral segments of the lip and excision of the Burow triangles from the perialar region. Since there was no skeletal involvement. cephalometric findings were absent. so the interest of the case focuses on the age of the patient and the method of repair.
The desmoid tumor: "benign" neoplasm, not a benign disease, The desmoid tumor is a rare neoplasm which. because of its histopathologic appearance. has been traditionally considered to be benign. Despite its benign microscopic features. it has an aggressive local behavior and. if not excised adequately. has a tendency to recur locally and invade neighboring structures with significant potential for morbidity. deformity. or even death. Two cases of recurrent extraabdominal desmoid tumors are presented not only because they are highly representative of this disease. but also because they emphasize the need for aggressive surgical treatment. Also. they are unusual and challenging cases from a reconstructive standpoint. Based on this experience and on the most recent literature. we believe that this tumor. regardless of its microscopic features. should be addressed and treated as a malignancy.
Salvage of proximal humeral amputations with a remnant forearm flap, Spare-part surgery of upper extremity avulsions may facilitate primary soft-tissue healing and prosthetic rehabilitation. This procedure also may be applicable to the management of analogous proximal lower extremity avulsions where a short femoral stump and a shortage of soft tissue exist.
Role of antibody-dependent cellular cytotoxicity in defense against herpes simplex virus infections, Antibody-dependent cellular cytotoxicity (ADCC) to cells infected with herpes simplex virus (HSV) is a mechanism of destruction of these cells by a combination of antiviral antibody and immunoglobulin Fc receptor-positive leukocytes. It has been well defined in vitro as a rapid lytic response utilizing minute amounts of IgG antibody. In vitro studies have shown ADCC restriction of the spread of virus. In vivo studies using adoptive transfer of human or murine ADCC effector cells plus antibody and ADCC-active. nonneutralizing F(ab1)2 antibody fragments or monoclonal antibodies have demonstrated the important role of this response in animal models of HSV infection. In humans. ADCC effector function and/or antibody levels have been associated with the outcome of infection. especially in immunocompromised patients and neonates. Reconstitution of this mechanism with appropriate antibodies or cytokines in high-risk hosts. with the resultant amelioration of severe HSV infection. will validate ADCC as a critical component of antiviral defense.
Epidemiology, antimicrobial susceptibility, pathogenicity, and significance of Bacteroides fragilis group organisms isolated at Los Angeles County-University of Southern California Medical Center, The epidemiology of species of the Bacteroides fragilis groups isolated at Los Angeles County-University of Southern California Medical Center was examined. In addition. frequency of resistance to six beta-lactam antibiotics (cefmetazole. cefotetan. ceftizoxime. imipenem. penicillin. and cefoxitin) and to clindamycin. chloramphenicol. and metronidazole was determined for each species. While B. fragilis was most commonly isolated. the other species of the B. fragilis group accounted for half of the isolates. Seven percent of 1.128 patients with infections due to species of the B. fragilis group were bacteremic. A review of bacteremic cases indicated that non-fragilis species were highly pathogenic. Resistance to clindamycin ranged from 8% to 22% among species and was most common among isolates of Bacteroides distasonis and Bacteroides thetaiotaomicron. Significant differences in antimicrobial activity were noted among the agents tested. Only imipenem. chloramphenicol. and metronidazole were predictably effective against non-fragilis species of the B. fragilis group. Prompt identification of species and susceptibility testing of clinical isolates of this group are needed if a newer beta-lactam agent or clindamycin is to be used for initial therapy.
The polymerase chain reaction: amplifying our options, The polymerase chain reaction (PCR) has had a major impact on our ability to detect infectious agents. However. the impact of PCR has not been uniform throughout the discipline of infectious disease but instead has been applied in various contexts. depending on the current level of diagnostic sophistication for a given disease. The application of PCR in four contexts is presented along with a discussion of the potential of this technique to elucidate the natural history of infectious disease and to serve as a tool for the molecular elucidation of acute and chronic illness.
A three-year study of positive blood cultures, with emphasis on prognosis, A study of 37.156 blood cultures over a 3-year period yielded 1.972 positive blood culture episodes. of which 63% were of clinical significance. 26% represented contamination. 7% represented transient bacteremia. and 3% were of indeterminate significance. Mortality curves were calculated for clinically significant bacteremia according to etiologic organism and source. Several curves with different shapes were demonstrated. Quantitative differences were noted between cases of bacteremia arising from different sources and caused by different organisms. No mortality was associated with bacteremia of bone and joint origin. Mortality from bacteremic pneumococcal pneumonia. bacteremia with Escherichia coli of urinary tract origin. endocarditis. and beta-hemolytic streptococcal bacteremia showed an early plateau effect. with a drop before day 20. Cases of bacteremia from intravascular sources other than endocarditis were associated with no initial mortality. but mortality rose progressively after day 5. Bacteremia related to most organisms and sources was associated with mortality that continued until at least day 20.
Protracted outbreak of severe delta hepatitis: experience in an isolated Amerindian population of the Upper Orinoco basin, In an investigation of a 21-year-old epidemic of severe hepatitis. 80 serum samples were studied from two isolated Yanomami Amerindian populations of the Upper Orinoco basin in Venezuela. Of the assayed samples. 30.6% were positive for hepatitis B surface antigen (HBsAg). 53.7% were considered to reflect immunity to infection with hepatitis B virus (HBV). and only 16.2% were believed to reflect susceptibility to HBV infection; 82.5% of the samples tested positive for any marker of HBV infection. Thirty-one (39.7%) of 78 samples were also positive for antibody to delta antigen. including 91.6% of those positive for HBsAg and 20.9% of those immune to HBV. Our findings provide evidence of a high prevalence of HBV infection in this population. Furthermore. the high prevalence of antibody to delta antigen strongly suggests that coinfections with HBV or superinfections with hepatitis delta virus (HDV) in HBV carriers may be an important factor in the occurrence of an unusually high number of cases of fulminant hepatitis and of chronic liver disease. Serum samples obtained at the beginning of the outbreak 13 years earlier from 36 selected cases in the same population revealed a high rate of HBV infection (96.5%). All six HBsAg carriers from whom enough serum remained to be assayed were positive for antibody to delta antigen. Our findings indicate that the outbreak coincided with the introduction of HDV into a population with an already-high prevalence of HBV infection.
Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae isolates causing systemic infections in Spain, 1979-1989, Serotypes and antibiotic susceptibilities were determined for 2.197 Streptococcus pneumoniae strains isolated from patients with systemic infections over an 11-year period. The predominant serogroups and serotypes. in order of decreasing frequency. were 3. 6. 23. 19. 9. 1. 5. 8. 7. 14. 4. and 15; these types accounted for more than 75% of the strains studied. Altogether. 93% of the pneumococci belonged to groups or types included in the 23-valent pneumococcal vaccine. Overall. 65.5% of pneumococci were resistant to one or more drugs. The incidence of penicillin-resistant pneumococci rose from 6% in 1979 to 44% in 1989. and the degree of penicillin resistance also increased throughout the study. Overall. the resistance rates were 28% for penicillin. 56% for tetracycline. 43% for chloramphenicol. and 5% for erythromycin. Seventy-one pneumococcal isolates resistant to all four antibiotics tested were found. The prevalence of pneumococcal resistance in Spain is. as far as we know. among the highest published to date.
The infusion center: a model for outpatient parenteral antibiotic therapy, Outpatient parenteral treatment of infectious diseases has developed from primitive beginnings to its present state as the standard of care in many areas. The large infusion center described here is headed by physicians who specialize in infectious diseases and occupies a free-standing building where the pharmacy. laboratory. physicians' offices. examination rooms. and finance departments are centralized for efficiency. flexibility. and convenience. Each patient is seen by a physician. pharmacist. and nurse; these health care professionals share data about the patient and offer 24-hour coverage of questions and emergencies. Treating a wide variety of diseases. physicians utilize their experience and the center's intercommunication system to choose drugs most suitable for outpatient use and to carry on research. Costs in the center run between 50% and 60% lower than those in the hospital. Reimbursement. although difficult in the past. has improved considerably. but some third-party payers. including Medicare. have not reimbursed for outpatient intravenous antibiotic therapy.
Selection and training of patients for outpatient intravenous antibiotic therapy, Outpatient intravenous antibiotic therapy (OPIVAT) requires selection of patients who are medically and psychologically stable. are capable of being trained to administer iv medications. will not abuse the iv system. and have insurance coverage. Patients with conditions such as osteomyelitis. septic arthritis. pelvic inflammatory disease. endocarditis. and skin and soft tissue infections are appropriate candidates. As clinical experience grows. patients with increasingly complex conditions are being successfully treated at home. Before OPIVAT can be utilized. mode of iv access. length of therapy. antibiotic selection. laboratory tests. and physician of record must be determined. Patients must be instructed how to handle emergencies. With appropriate training. such patients learn to properly manage drugs and equipment and to recognize complications. Patients who cannot be treated at home may be candidates for OPIVAT under direct medical supervision. Technical advances in pumps and catheters--as well as future changes in Medicare reimbursement--may greatly increase the number of patients who are capable of receiving OPIVAT.
A program of outpatient parenteral antibiotic therapy for serious pediatric bacterial infections, A program set up in the Soroka University Medical Center. Beer Sheva. Israel. offers outpatient parenteral antibiotic therapy (OPAT) for children with serious bacterial infections. The following criteria must be met before a child is placed in this program: OPAT must be a suitable form of treatment for the infection. an appropriate drug must be available. the parents must be cooperative and well-informed. and 24-hour-a-day telephone communication and transportation between the home and hospital must be available. With use of ceftriaxone administered im. the OPAT program has shown positive results: a cure rate of 98.5% and an estimated savings of 1.334 hospital days for 140 patients over a 17-month period.
Management of children with occult bacteremia who are treated in the emergency department, Occult bacteremia. which precedes many serious infections in children. is most often due Streptococcus pneumoniae. Haemophilus influenzae. Neisseria meningitidis. or Salmonella species. Diagnosis on the basis of clinical judgment is unreliable. although the presence of certain risk factors may suggest the diagnosis. These risk factors include an age of 3 months to 3 years. a temperature of greater than or equal to 39.0 degrees C. and a white blood cell count of greater than or equal to 15.000/mm3. Although results are delayed. a culture of blood is the only definitive test. Studies suggest that treatment with various antibiotics may be helpful. but that some drugs. particularly orally administered amoxicillin. should not be relied on to eliminate occult bacteremia or prevent its most serious sequela. meningitis.
Characteristics of the ideal antibiotic for prevention of wound sepsis among military forces in the field, Prompt administration of antibiotics is of the utmost importance in the treatment of wounds inflicted during a war or disaster. A single injection of a broad-spectrum drug with a long half-life should be given prophylactically to personnel on the battlefield to provide bactericidal coverage from the earliest possible moment after injury occurs. The antibiotic must remain effective at least throughout the period of transport to hospital and surgery. Use of antimicrobial agents will never replace careful surgical debridement. and these drugs should be used again later only if a bacterial infection develops. Other considerations include the choice of a drug that penetrates tissue thoroughly. is simple to store and administer. is easily available. and is cost effective.
Chemoprophylaxis for bacterial infections: principles of and application to meningococcal infections, Chemoprophylaxis with antibiotics is both feasible and desirable for prevention of a potentially serious disease when specific groups at risk can be defined and when a safe. effective. and affordable prophylactic agent is available. Although the Advisory Committee on Immunization Practices recommends rifampin for prophylaxis of meningococcal disease. there are failures of treatment and adverse reactions associated with the administration of this drug. and it cannot be used during pregnancy. In 1987. during an outbreak of group A meningococcal disease in Saudi Arabia. the efficacy of a single intramuscular dose of ceftriaxone was compared with the standard regimen of rifampin for eradication of pharyngeal carriage of Neisseria meningitidis among persons at risk. Follow-up cultures indicated successful eradication for 97% of those who received ceftriaxone and 75% of those who received rifampin. Thus. although ceftriaxone exceeds rifampin in fulfilling the criteria for an effective prophylactic agent. recommendations regarding its use still must be made with caution because of limited clinical experience.
Use of outpatient parenteral antibiotic therapy in a health maintenance organization, Outpatient parenteral antibiotic therapy in a health maintenance organization (HMO). as carried out at the Lovelace Medical Center in Albuquerque. New Mexico. has been effective for ambulatory patients (who received their injections at one of the HMO facilities) and for nonambulatory patients (who were visited in their homes by members of the HMO's home health care team). Over a 17-month period. implementation of these procedures resulted in savings of as much as 73% per day over the costs for similar treatment of similar infections in hospitalized patients. The savings derived from treating nonambulatory patients were slightly less than those from treating ambulatory patients because of the costs for home health care personnel.
A virus-encoded "superantigen" in a retrovirus-induced immunodeficiency syndrome of mice, The development of an immunodeficiency syndrome of mice caused by a replication-defective murine leukemia virus (MuLV) is paradoxically associated with a rapid activation and proliferation of CD4+ T cells that are dependent on the presence of B cells. The responses of normal spleen cells to B cell lines that express the defective virus indicated that these lines express a cell surface determinant that shares "superantigenic" properties with some microbial antigens and Mls-like self antigens. This antigen elicited a potent proliferative response that was dependent on the presence of CD4+ T cells and was associated with selective expansion of cells bearing V beta 5. This response was markedly inhibited by a monoclonal antibody specific for the MuLV gag-encoded p30 antigen.
Engraftment and development of human T and B cells in mice after bone marrow transplantation, A model for human lymphocyte ontogeny has been developed in a normal mouse. Human bone marrow. depleted of mature T and B lymphocytes. and bone marrow from mice with severe combined immunodeficiency were transplanted into lethally irradiated BALB/c mice. Human B and T cells were first detected 2 to 4 months after transplantation and persisted for at least 6 months. Most human thymocytes (30 to 50 percent of total thymocytes) were CD3+CD4+CD8+. Human immunoglobulin was detected in some chimeras. and a human antibody response to dinitrophenol could be generated after primary and secondary immunization.
Dynamic tracking of cardiac vulnerability by complex demodulation of the T wave, A link is found between T wave alternans and vulnerability to ventricular fibrillation. and a new approach is provided for quantification of susceptibility to malignant arrhythmias. Complex demodulation reveals that alternation of the electrocardiogram is concentrated during the first half of the T wave. coinciding with the vulnerable period of the cardiac cycle. During myocardial ischemia and reperfusion. there are marked increases in the degree of T wave alternans that parallel the established time course of changes in vulnerability. The influence of the sympathetic nervous system in arrhythmogenesis is also accurately detected. Ultimately. complex demodulation of the electrocardiogram could provide a technique for identification and management of individuals at risk for sudden cardiac death.
Evaluation of female urinary incontinence, The use of urodynamic testing must be selective and based on the particular patient's complaints. In today's cost-conscious health care environment. a diagnosis based on one or two tests is preferable to exposing each patient to the full battery of available tests. For most patients. a cystometrogram and voiding cystourethrogram can confirm a variety of clinical suspicions. A cystometrogram best indicates how the bladder is behaving during filling. The voiding cystourethrogram allows the physician to observe the bladder and urethra during voiding and offers an excellent view of the anatomic relations of the urologic organs in the pelvis. The other important benefit of urodynamics is the objective data made available in hardcopy as a baseline study to be utilized for comparison in the future. The normal sequence of testing is a noninvasive uroflow study to determine the baseline flow rate. The postvoiding residual volume of urine is then determined. A cystometrogram and electromyography can then be done. the latter if there is a suggestion of neurologic disease or if otherwise indicated to determine bladder behavior on filling. Variations that are helpful when a patient fails to have a bladder contraction include having the patient in an upright or seated position during the test. A bethanechol supersensitivity test may be indicated as well. The urethral pressure profile may be done as the catheter is withdrawn and the bladder is already filled. The filled invasive flow rate can then be compared with the free flow rate. Sometimes. one of these rates is abnormal. and there is a question about whether the abnormality is real. The residual urine volume can be determined by subtracting the volume the patient voids from the filling volume. In the end. the key to urodynamic evaluation is the interpretation of the test. which should be made only by the individual actually performing the test. It truly is necessary for the physician to be there in person. Selective use of urodynamics can target an appropriate treatment for most patients. The female patient who complains of incontinence in whom the history suggests detrusor instability may benefit from a trial of cholinolytic therapy if no anatomic defect is present. In this type of patient. a surgical procedure may not be of benefit. whereas the cholinolytic therapy probably will work. This is a good reason for always choosing the appropriate urodynamic tests for evaluating and planning treatment for patients with urinary incontinence.
Male urethral sphincteric anatomy and radical prostatectomy, Continence after radical prostatectomy is a multifactorial problem with no clear common denominator. At the heart of success is proper patient selection and operative skill in the precise dissection of the sphincteric anatomy. In general. surgeons who know the anatomy protect the patient by virtue of less blood loss. better margins of resection. and greater functional preservation.
Postprostatectomy incontinence. Pathophysiology, evaluation, and management, Given the prevalence of bladder dysfunction (i.e.. poor compliance or detrusor instability) as a cause of postprostatectomy incontinence. urodynamic studies are essential in the evaluation of such patients. Appropriate management strategies based on the findings of a pertinent history and physical examination. appropriate radiologic studies. and urodynamics optimize the opportunity for successful treatment. Because bladder dysfunction frequently accompanies sphincter insufficiency. bladder dysfunction must be diagnosed and treated effectively before implantation of an artificial urinary sphincter.
Evaluation of the causes and severity of geriatric incontinence. A critical appraisal, The evaluation of urinary incontinence in the elderly differs from that in younger patients because of altered or nonspecific disease presentation. the different spectrum of pathophysiology. greater variation between individuals and. in some cases or settings. variable treatment goals. Evaluation must be multifactorial and extend beyond the genitourinary system. because many age-related conditions and the drugs used to treat them can cause or exacerbate urinary incontinence. Voiding records are a reliable measure of severity. although studies of their validity are still lacking. History-taking requires more time in this age group. Stress incontinence symptoms remain very sensitive. whereas obstructive symptoms fall in predictive value. Clinical algorithms based on a combination of symptoms and simple bedside examination and maneuvers may prove most useful in specific settings such as nursing homes. The targeting and interpretation of the physical examination must also change because of age-related conditions (e.g.. BPH. atrophic vaginitis) and prevalent comorbid diseases. especially neurologic ones. The Q-tip. elevation. and pessary tests for stress incontinence offer little diagnostic or therapeutic information in the elderly. Routine laboratory tests should be performed to exclude reversible causes of urinary incontinence. while interpretation of the urinalysis must consider the prevalence of asymptomatic bacteriuria. No radiographic studies are routinely needed; bead-chain cystourethrography and IVU in particular probably offer little additional information. Voiding cystourethrography. although little studied. offers dynamic data that may be helpful. especially in evaluating outlet obstruction. Bedside cystometry is simple but may be insensitive to the most prevalent type of detrusor instability in the institutionalized elderly. Finally. multichannel urodynamic study is safe and feasible even in frail elderly patients and should be considered when empiric therapy is risky or has failed. complicated comorbidity exists. or surgery is anticipated.
Pediatric urinary incontinence, A clear understanding of the current concepts. pathophysiology. and typical symptoms of voiding dysfunction and pure nocturnal enuresis usually allows the clinician to distinguish these troublesome but benign problems from true underlying pathological conditions of the urinary tract. If a careful history confirms that wetting is the only symptom. and the pattern of wetting is consistent with uninhibited bladder contractions. or if the wetting occurs only during sleep. initial empiric treatment rather than invasive investigation is our preference. On the other hand. if the wetting is associated with infection or persistent dysuria. or if the history or pattern of wetting is suggestive of anatomic or neurogenic causes. a complete investigation of the urinary tract is necessary prior to initiating therapy.
Surgical procedures for uncomplicated ("routine") female stress incontinence, Routine incontinence in the woman is defined as stress urinary incontinence associated with a hypermobile urethra and bladder neck that has not been subjected to an operative procedure. Although urgency and occasional urgency incontinence may accompany the symptoms of stress incontinence. they are not a significant component of the patient's complaints. Regardless of technique. the goal common to all procedures designed to cure stress urinary incontinence is to immobilize and support the hypermobile urethra. The support provided by the operation creates a foundation on which the urethra can be compressed shut during abdominal straining. The operation of choice is determined by its ability to provide this strong foundation over a long period of time. Although numerous reports have been published outlining the results of bladder neck suspension. most authors have not utilized objective long-term follow-up when assessing cure rates. We prefer either the Burch colpourethropexy or the modified Pereyra needle bladder neck suspension because the vaginal wall is firmly supportive without interfering with the delicate mechanisms of the urethra.
Treatment of female incontinence secondary to urethral damage or loss, Damage to the urethra may be functional or anatomic. In the former. to some extent. the urethra functions merely as a tube. Anatomic damage ranges from small urethrovaginal fistulas to total loss of the urethra. vesical neck. and trigone. For functional damage. the goal is compression of the proximal urethra. and the author favors a pubovaginal fascial sling. which is described. In the author's view. the best results in anatomic loss are obtained by performing an appropriate anti-incontinence procedure at the time of urethral reconstruction.
Evaluation and management of incontinence after implantation of the artificial urinary sphincter, Despite the fact that the AS-800 artificial urinary sphincter represents a significant advance in the treatment of urinary incontinence. for many reasons. incontinence persists or recurs in a small percentage of cases. This is often a challenging problem to manage; however. a logical and sequential approach (as outlined in the algorithm in Figure 2) will aid in successful diagnosis and treatment.
Incontinence after augmentation cystoplasty and internal diversion, The collective published experience with continent urinary diversions. together with our own. indicates that there are certain basic principles with regard to continence. which is dependent on: (1) the pressure generated by the reservoir; (2) the outflow resistance of the outlet; and (3) detubularization. which is crucial to diminish the uninhibited involuntary bowel contractions. Detubularized ileal pouches provide the lowest pressures (less than 20 cm H2O). Although the majority of patients (approximately 85%) who have a low-pressure ileal neobladder are completely continent. a few experience persistent nocturnal incontinence as a result of low resting urethral pressure. Numerous continence methods have been described. each with its own unique set of problems. The most physiologic continence mechanism is the external urethral sphincter in men. It is clear that total continence with this mechanism is not assured. Other factors such as reservoir contractions. overflow incontinence. decreased sphincter tone. and loss of the normal vesicourethral reflex play an important role in nocturnal incontinence. However. understanding these contributing elements will allow us to refine the construction of a continent physiologic bladder substitute.
Electrical stimulation. A physiologic approach to the treatment of urinary incontinence, Appropriate management of patients with urinary incontinence requires access to a variety of methods. Electrical stimulation. although so far proportionally small in the armamentarium of methods. is founded on physiologic principles and has the advantage of being curative without significant side effects.
Condensing osteitis of the clavicle: a rare but frequently misdiagnosed condition, Condensing osteitis of the clavicle is a benign. often painful disorder. marked by bony sclerosis at the sternal end of the clavicle. It can be mistaken for other abnormalities such as Friedrich disease. bone island. osteoid osteoma. sternoclavicular osteoarthritis. and even a metastasis and osteosarcoma. Clinical. radiologic. scintigraphic. and histologic features of this condition are discussed and a brief overview of the treatment is provided. Three histologically proved cases are added to the 13 previously reported in the literature. Recognition of condensing osteitis of the clavicle may avoid the occasional unnecessarily aggressive diagnostic approach taken to search for a malignant tumor.
MR appearance of the distended iliopsoas bursa, The purpose of this essay is to illustrate the MR appearance of the distended iliopsoas bursa. The bursa must be recognized on MR scans to avoid confusing it with malignant neoplasms and other lesions.
1990 ARRS Executive Council Award. Intravascular sonography in the detection of arteriosclerosis and evaluation of vascular interventional procedures, The purpose of this study was to evaluate the use of intravascular sonography for the detection of arteriosclerosis and to determine the effects of vascular interventional procedures on the arterial wall. A catheter-based 20-MHz transducer was used. Forty patients were studied. Twelve had clinical evidence of peripheral vascular disease. 13 were healthy renal donors. and 15 underwent vascular interventional procedures. The aorta and the ipsilateral iliac artery were examined in real time under fluoroscopic guidance and the results were compared with angiography. Sonography in eight of the 13 renal donors showed arterial wall abnormalities in the absence of angiographic evidence of disease. Sonography of the 15 patients after angioplasty or atherectomy demonstrated plaque fractures. intramural dissections. or atherectomy grooves. Our experience suggests that intravascular sonography is of value in reducing the use of angiography to monitor progress or complications of vascular interventional procedures.
Conventional screen/film vs reduced exposure photostimulable phosphor plate imaging in lower extremity venography: an ROC analysis, Half-exposure phosphor plates used in venography substantially reduce the total X-ray exposure to a patient while increasing the chance that all images will be of excellent diagnostic quality. Simultaneous half-exposure phosphor plate and full-exposure conventional screen/film venograms were obtained of 35 patients and compared by using receiver operating characteristic (ROC) analysis. The area under the ROC curve ranged from 0.67 to 0.78 for conventional films and 0.68 to 0.91 for phosphor plates. Group performances on conventional films vs phosphor plates were not statistically different. No statistically significant difference in individual performance with the two techniques was seen in seven of the eight interpreters at the 95% confidence level. The eighth interpreter performed significantly better with phosphor plates than with conventional films. Interpreters with and without specific experience in phosphor plate venography were grouped separately. and performance of the two groups was compared in each technique. No difference in performance was found between the groups when interpreting conventional venograms. but. when interpreting phosphor plate venograms. the group with specific experience performed significantly better than they had with conventional venograms. and significantly better than the other group did at interpreting either conventional or phosphor plate venograms. We conclude that phosphor plate venograms made at a 50% reduction in X-ray exposure are equal to. and may surpass. conventional screen/film venograms for diagnosing acute venous thrombosis of the calf and thigh. We recommend expanding the indications for phosphor plate radiography to include contrast venography of the lower extremities.
Ligamentous compression of the celiac axis: CT findings in five patients, Compression of the celiac trunk by the median arcuate ligament of the diaphragm is an uncommon angiographic and surgical finding that rarely may be symptomatic. We retrospectively reviewed contrast-enhanced abdominal CT scans in five patients with severe ligamentous compression of the celiac axis. confirmed by surgery and/or angiography. and compared the findings with those of enhanced scans of 100 consecutive patients without known ligamentous compression. In all five patients with ligamentous celiac artery compression. CT showed effacement or narrowing of the celiac trunk by an anterior soft-tissue band. Dilated peripancreatic collateral vessels were seen in four cases. and poststenotic dilatation of the distal celiac trunk was seen in two cases. The normal appearance of the vasculature was seen in the majority (76%) of the 100 control subjects. but in eight patients the celiac origin was obscured on CT scans. and in 16 patients the celiac trunk appeared narrow or effaced. Our experience suggests that severe ligamentous celiac artery compression can be identified on CT. However. the isolated CT finding of effacement or obscuration of the celiac axis occurs sufficiently often in normal patients that it is not adequate evidence to establish the diagnosis of celiac artery compression.
Anaphylaxis associated with latex allergy during barium enema examinations, During the interval from January 1989 to March 1990. signs and symptoms of anaphylaxis developed in six patients during barium enema examinations in our institution. In all six cases the symptoms of anaphylaxis began during the procedure. usually within 10 min of starting the examination. The principal manifestation of anaphylaxis was severe hypotension. usually accompanied by edema and urticaria. The symptoms were considered potentially life threatening in all patients. and one patient died despite prompt recognition of the anaphylactic nature of the reaction and resuscitative efforts. Serum samples were obtained within a few hours of the reaction in two patients and at autopsy in the fatal case: all three samples showed elevated concentrations of mast cell tryptase. demonstrating the systemic release of anaphylactic mediators. In vitro tests demonstrated the presence of immunoglobulin E antibodies specific for latex allergens in five of the six cases. Further in vitro inhibition tests confirmed the specificity of the antibodies for latex allergens and demonstrated that similar allergens were found in both raw latex. latex gloves. and catheter balloons. Only one patient was willing to undergo a skin test. and her skin test was positive for extracts of latex products. After considering multiple possibilities. we conclude that the reactions associated with barium enemas observed in these six patients are most probably the result of latex allergy.
Colorectal cancer: cross-sectional imaging for staging of primary tumor and detection of local recurrence, This review describes the use of cross-sectional imaging in the staging of colorectal carcinoma and detection of local recurrence. The contributions of CT. MR imaging. and sonography are discussed and illustrated. Colorectal carcinoma is the second most common tumor in the United States and the most common cancer in the gastrointestinal tract. The prognosis for patients with this neoplasm is closely related to the extent of tumor at the time of diagnosis. Accurate noninvasive preoperative assessment of tumor stage by one or a combination of radiologic techniques would enable appropriate treatment to be planned in each case. Also. determination of possible tumor recurrence would permit effective monitoring of success of therapy and surgical intervention for recurrent disease before widespread metastasis occurs.
Factors affecting the development of pneumothorax associated with thoracentesis, This study is a retrospective survey of the variables that may influence the development of pneumothorax after thoracentesis. In a 30-month period. a computer search of hospital records identified 342 thoracenteses. of which 154 were done with conventional techniques by the clinical services. and 188 were done with sonographic guidance. Other factors surveyed included the patients' age. sex. underlying pulmonary disease. and overall clinical condition; the size of the effusion; the type of tap (diagnostic or therapeutic); the amount and type (exudate or transudate) of fluid acquired; and the size of the needles used. The technique used was the most significant single risk factor affecting the development of pneumothorax (18% for clinical vs 3% for sonography-guided thoracenteses). The incidence of pneumothorax decreased when a smaller amount of pleural fluid was aspirated (mean. 246 ml aspirated from patients who did not vs 472 ml from those who did develop pneumothorax) and when thin needles were used (4% pneumothorax with 20-gauge or smaller and 18% with larger than 20-gauge needles). The other factors surveyed did not influence the development of pneumothorax. Our results show that sonography-guided thoracentesis is complicated by pneumothorax significantly less often than is thoracentesis done with conventional techniques. Use of the smallest possible needle and aspiration of the smallest possible amount of fluid will also result in fewer cases of pneumothorax.
Inverted colonic diverticulum: air contrast barium enema findings in six cases, A polypoid elevation of the colonic wall was identified on air contrast barium enema in six patients. The abnormality in each case was found to be an inverted colonic diverticulum. Inverted diverticula appeared as broad-based. smooth. sessile polyps measuring 1.5-2.0 cm. In five of the six patients a characteristic central umbilication and/or evidence of barium within the polyp could be identified. The diagnosis was confirmed in three patients by demonstrating an everted diverticulum replacing the suspected lesion. In the remaining three patients. two of whom had normal findings on colonoscopy. the diagnosis was strongly suggested by the presence of barium extending into the substance of the mass. Additional radiologic maneuvers or a second study may permit accurate diagnosis if the possibility of inverted diverticulum is considered. However. even when the diverticulum cannot be demonstrated. a central umbilication or barium within a smooth intraluminal projection should suggest inverted diverticulum and prevent unnecessary endoscopy or inadvertent diverticulectomy.
CT of AIDS-related lymphoma, A spectrum of CT findings in patients with AIDS-related lymphoma (ARL) is illustrated herein. When a solid mass anywhere in the body is encountered in a patient with AIDS. lymphoma must be considered in the differential diagnosis. Although the CT findings alone generally are not enough for a specific diagnosis of lymphoma. this frequently will be suggested as the most likely diagnosis. facilitating further workup. CT-guided biopsy is useful in providing tissue diagnosis in many cases.
Subcapsular hepatic necrosis in liver transplantation: CT appearance, Eleven cases of subcapsular hepatic necrosis were found in 47 hepatic transplantation patients who underwent CT examination between the second and 14th postoperative day. CT examinations of all 11 cases showed nonenhancing hypodense subcapsular areas with irregular contours in the liver. Major vessels were free of obstruction. Anatomic correlation. possible in one case. confirmed the diagnosis. Size disproportion between the graft and the recipient abdominal cavity reduced hepatic blood flow and caused abnormal pressure points. One or both of these factors could result in ischemia in subcapsular areas and explain the subcapsular necrosis. Although it has good prognosis without treatment. subcapsular hepatic necrosis is important to recognize to avoid confusion with liver necrosis after vascular thrombosis.
Angiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by different mechanisms of action, Angiotensin converting enzyme (ACE) inhibitors enhance contractile function of myocardium "stunned" by a brief episode of coronary artery occlusion. yet their mechanism(s) of action remain unresolved. In addition to possible hemodynamic effects. ACE inhibitors may stimulate the synthesis of cardioprotective prostaglandins. Furthermore. the beneficial effects of ACE inhibitors that contain a sulfhydryl group may be due in part to the ability of thiol compounds to act as nonspecific antioxidants or direct scavengers of cytotoxic oxygen-derived free radicals. To investigate this question we compared the effects of (1) the sulfhydryl-containing ACE inhibitor zofenopril. (2) the sulfhydryl-containing stereoisomer of captopril (SQ 14.534) with essentially no ACE inhibitor properties. (3) the nonsulfhydryl-containing ACE inhibitor enalaprilat. and (4) solvent alone. given at the time of reperfusion. on recovery of contractile function after 15 minutes of coronary occlusion in the anesthetized open-chest dog. Segment shortening in control animals remained depressed or "stunned" after reperfusion. recovering to only -5 +/- 12% of baseline preocclusion values at 3 hours after reperfusion. In contrast. all three treatment agents attenuated postischemic dysfunction: segment shortening was restored to 33 +/- 12%. 54 +/- 6%. and 83 +/- 5% of baseline values at 3 hours after reflow in dogs treated with SQ 14.534 (p less than 0.05). zofenopril (p less than 0.01). and enalaprilat (p less than 0.01). respectively (all vs control value). These improvements in segment shortening did not appear to be the result of altered oxygen supply or demand after reperfusion. inasmuch as no significant differences in systemic hemodynamic parameters or myocardial blood flow were observed among the groups. In the second phase of the study. we found that the improved contractile function associated with enalaprilat treatment could largely be reversed by infusion of the potent cyclooxygenase inhibitor indomethacin: segment shortening was reduced from 69 +/- 12% at 2 hours after treatment/reperfusion to 38 +/- 12% at 2 hours after indomethacin infusion (p less than 0.01 vs 2 hours after reperfusion). Infusion of indomethacin had no effect. however. on the improved contractile function associated with zofenopril treatment. We therefore conclude that sulfhydryl- versus nonsulfhydryl-containing agents enhance contractile function of stunned myocardium by different mechanisms of action: enalaprilat attenuates postischemic dysfunction at least in part by a prostaglandin-mediated mechanism. whereas the salutary effects of zofenopril and SQ 14.534 may be due in part to the antioxidant properties of the sulfhydryl moiety.
Regional myocardial function after repetitive brief episodes of ischemia: effect of altering the duration of the reperfusion period, How recovery of regional contractile function in myocardium is influenced by alterations in the duration of reperfusion after repetitive brief coronary artery occlusions was investigated in chronically instrumented. conscious dogs. All animals underwent five 5 minute left anterior descending coronary artery occlusions with a final 5-hour reperfusion period. Dogs were randomly assigned to one of three groups determined by the duration of reperfusion (5. 10. or 15 minutes) between successive 5-minute occlusion periods. A shortening of the duration of the reperfusion period between occlusions led to reduced recovery and progressive deterioration in systolic shortening after multiple occlusion-reperfusion sequences. With 15-minute reperfusion periods. the percentage of segment shortening (%SS) during the first through fourth reperfusion periods ranged from 17.1 +/- 2.6% to 18.2 +/- 1.8% and did not differ from the preocclusion control value (18.8 +/- 1.7%) by the end of the final reperfusion period. In contrast. in those dogs with 5-minute reperfusion periods. %SS was significantly reduced from the preocclusion control value (20.2 +/- 2.2%) at the completion of the final 5-hour reperfusion period (11.4 +/- 1.5%). Results of the present study indicate that after only a few brief periods of coronary artery occlusion. rapid and cumulative deterioration in regional contractile function can occur when the duration of intermittent reperfusion is sufficiently brief.
Dipyridamole-induced decrement of functional recovery of postischemic reperfused myocardium in conscious dogs with well-developed coronary collateral circulation, The effects of dipyridamole (20 and 40 micrograms/kg/min intravenously) on the time course of functional recovery of myocardium after five 5-minute coronary artery occlusions and four 5-minute reperfusions and a subsequent 5-hour reperfusion period were studied in chronically instrumented. conscious dogs with well-developed coronary collateral circulation. In comparison with vehicle-treated control dogs. those given dipyridamole (20 and 40 micrograms/kg/min. respectively) 15 minutes before and during coronary occlusion had a greater depression of regional segment shortening (38 +/- 7% and 19 +/- 4%. respectively. vs control levels of 69 +/- 10% of preocclusion values) during acute coronary artery occlusion. After a 5-hour reperfusion period. segment shortening returned to preocclusion values in the control group but remained decreased in the dipyridamole groups (87 +/- 4% and 75%. respectively). These results suggest that dipyridamole in a dose-dependent manner exacerbates recovery of contractility of postischemic reperfused myocardium in dogs with well-developed coronary collateral circulation.
Attenuation of myocardial ischemia during coronary occlusion by ultrashort-acting beta adrenergic blockade, To assess the effect of the ultrashort-acting beta blocker esmolol on ischemia induced by acute coronary occlusion. we studied 16 patients undergoing coronary angioplasty. Doppler echocardiography and ECG monitoring were performed continuously before. during. and after balloon occlusion in the drug-free state and during esmolol infusion. Fourteen of the 16 patients had ST segment elevation during balloon inflation. However. maximal ST segment elevation (2.1 +/- 1.5 mm vs 1.7 +/- 1.3 mm. p less than 0.001) and duration of ST segment elevation (68 +/- 20 seconds vs 54 +/- 19 seconds. p less than 0.05) were both significantly reduced during esmolol infusion. Furthermore. the decrease in ejection fraction seen during drug-free balloon occlusions was significantly blunted during esmolol infusion. In the baseline state ejection fraction decreased from 55% to 38% (p less than 0.05) during coronary occlusion compared with a decrease from 52% to 49% (p = NS) during esmolol infusion. In addition. esmolol appeared to delay the onset of segmental wall motion abnormalities after coronary occlusion. occurring at a mean of 40 seconds after balloon inflation versus a mean of 31 seconds in the absence of beta blockade (p less than 0.05). Thus the use of ultrashort-acting beta blockade appears to diminish the extent and delay the onset of myocardial ischemia during acute coronary occlusion.
Two-dimensional Doppler echocardiographic correlation of dipyridamole-thallium stress testing with isometric handgrip, To determine how frequently new wall-motion abnormalities that are indicative of ischemia accompany thallium redistribution. 47 consecutive patients underwent two-dimensional echocardiography during routine dipyridamole-thallium stress testing. A secondary aim of the study was to determine whether the addition of isometric handgrip exercises to the standard dipyridamole imaging protocol increased the frequency of wall-motion abnormalities or thallium redistribution. Echocardiograms and thallium scans were independently interpreted. and wall-motion abnormalities that appeared with dipyridamole. handgrip exercise. or both were compared with results of thallium imaging. Five of 24 patients with thallium redistribution had new wall-motion abnormalities. and the extent (number of segments) of thallium redistribution in these five patients was significantly greater than in those who did not have well-motion abnormalities (p less than 0.03). The addition of isometric handgrip exercises to the imaging protocol did not distinguish between patients with and without new wall-motion abnormalities or thallium redistribution. Thus new wall-motion abnormalities infrequently accompany thallium redistribution in routine dipyridamole stress testing in spite of the addition of handgrip exercises. but when new wall-motion abnormalities are present. they are associated with a greater area of thallium redistribution.
Prognostic significance of the Karnofsky Performance Status score in patients with acute myocardial infarction: comparison with the left ventricular ejection fraction and the exercise treadmill test performance. The MILIS Study Group, The prognostic significance of functional status has not been previously studied in the setting of acute myocardial infarction. We assessed the Karnofsky Performance Status (KPS) score. a simple functional status scale that is commonly used to categorize physical ability. in 849 patients with acute myocardial infarction who were enrolled in the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study. We then compared the KPS score with other predictors of prognosis in these patients. In patients who presented with acute myocardial infarction. a lower KPS score (less than 8 on a scale of 1 to 10) 3 weeks before the index infarction was associated with a higher incidence of congestive heart failure. in-hospital cardiac arrest. and mortality during hospitalization. as compared with patients with KPS scores greater than or equal to 8 (each p less than 0.001). Cumulative 1-year and 4-year mortality rates were significantly higher in patients with KPS scores less than 8. as compared with patients with KPS scores greater than or equal to 8 (42.5% vs. 12.6% at 1 year and 61.6% vs 25.1% at 4 years. respectively; both p less than 0.001). The left ventricular ejection fraction on admission was significantly lower in patients with KPS scores less than 8. as compared with those with KPS scores greater than or equal to 8 (p less than 0.019). The cumulative mortality rate was equally well predicted by low KPS score and by left ventricular ejection fraction (both p less than 0.0001).
Digitalis and beta-blocking agents: effects on depression following myocardial infarction, Depression is frequently seen in patients following myocardial infarction (MI). many of whom are receiving digitalis glycosides. beta-blockers. or other agents that may exert central nervous system (CNS) effects. In a prospective study of the clinical significance of post-MI depression. 335 patients were assessed using a standardized diagnostic interview for depression at 8 to 10 days. and 190 were reinterviewed at 3 to 4 months. Patients prescribed digitalis. beta-blockers. or other cardioactive medications at hospital discharge were identified. Logistic regression analyses were performed to determine the contribution of these agents to depression at 3 to 4 months. controlling for medical and sociodemographic factors as well as for baseline depression. Treatment with digitalis predicted depression at 3 to 4 months (p less than 0.05); no other medications. including beta-blockers. predicted depression (p greater than 0.10). Digitalis may have CNS effects that contribute to depression post-MI and this finding should be considered in the differential diagnosis of depression in cardiac patients.
Exercise-induced myocardial dysfunction in patients with coronary artery disease with and without angina, Left ventricular dysfunction during exercise is considered a relatively sensitive marker of ischemia in patients with coronary artery disease. The purpose of this study was to determine whether exercise-induced myocardial dysfunction was more severe in patients with angina than in patients with ischemia without angina. Seventy-seven patients with angiographically documented coronary artery disease and an abnormal left ventricular response to exercise were studied by means of gated blood pool imaging. The arteriographic and functional parameters of 24 patients with angina during exercise testing imaging. The arteriographic and functional parameters of 24 patients with angina during exercise testing were compared with those of 53 patients who were pain free at the time of the test. Both groups were similar with regard to rate of multivessel disease (50% vs 51%. p = NS) and prior myocardial infarction (46% vs 51%. p = NS). as well as age. sex. and history of angina. Mean global ejection fraction remained unchanged (but abnormal) in both groups of patients during exercise. Furthermore. evidence of new regional asynergy during exercise assessed by a five-point scoring system was found to be equally abnormal in the two groups. Results of this study suggest that the severity of exercise-induced global and regional left ventricular dysfunction is independent of the presence of absence of angina during exercise testing.
Factors associated with atrial fibrillation in Q wave anterior myocardial infarction, To elucidate the role of inflammatory and hemodynamic factors in the genesis of atrial fibrillation in acute myocardial infarction. 228 patients with a first Q wave anterior myocardial infarction were studied. Forty-nine patients had pericarditis (detection of pericardial rub by careful auscultation). and 36 patients had echocardiographically demonstrated hydropericardium (presence of pericardial effusion without pericardial rub). During the first 3 days after admission. transient episodes of atrial fibrillation were observed in 10 patients (20%) with pericarditis (group 1). 15 patients (42%) with hydropericardium (group 2). and 20 patients (14%) without pericarditis and hydropericardium (group 3). Although there was no significant difference in the incidence of atrial fibrillation between groups 1 and 3. patients in group 2 had a significantly higher incidence of atrial fibrillation than those in groups 1 and 3. Pulmonary capillary wedge pressure and the number of advanced asynergic segments were found to be the important factors discriminating the three groups by multivariate analysis. Therefore atrial fibrillation after acute Q wave anterior infarction was not related to the inflammatory infiltration involving the atria but to the increase in atrial pressure resulting from hemodynamic change caused by more extensive myocardial damage.
Suppressive effect of SUN1165 on supraventricular tachycardia, The electrophysiologic properties of SUN1165 and its suppressive effect on supraventricular tachycardia were assessed in 14 patients. nine with atrioventricular reentrant tachycardia (AVRT) and five with atrioventricular nodal reentrant tachycardia (AVNRT). This new agent prolonged the PR interval and QRS duration but did not alter the QT interval or the corrected QT interval. It did not alter the sinus cycle length or sinus node recovery time. The drug prolonged the AH interval. HV interval. and intraatrial conduction time but did not change the effective refractory periods of the right atrium or right ventricle. SUN1165 prevented the induction of tachycardia in six of nine patients with AVRT by a complete retrograde block of the accessory pathway and prevented AVNRT in four of five patients by a complete retrograde block of the fast atrioventricular nodal pathway as well. We conclude that SUN1165 is very effective in preventing AVRT or AVNRT. Larger studies with more patients are warranted.
Determination of pulse wave velocities with computerized algorithms, Careful determination of pulse wave velocity is important in the study of arterial viscoelastic properties. wave reflections. and ventricular-arterial interactions. In spite of its increasingly widespread use. there is as yet no standardized method for its determination. Most studies have manually identified the transit time of the pressure wave front as it travels over a known distance in the arterial system. but the issues of accuracy and reproducibility have not been addressed. This study was designed to investigate the efficacy of four computerized algorithms in the determination of pulse wave velocities in invasive as well as in noninvasive pressure determinations. The four methods were the identification of: (1) the point of minimum diastolic pressure. (2) the point at which the first derivative of pressure is maximum. (3) the point at which the second derivative of pressure is maximum. and (4) the point yielded by the intersection of a line tangent to the initial systolic upstroke of the pressure tracing and a horizontal line through the minimum point. High-fidelity aortic pressure recordings were obtained in 26 patients with a multi-sensor micromanometer catheter. Noninvasive brachial and radial pressure waveforms were recorded in 11 volunteers with external piezoelectric transducers. The results show that the first derivative method consistently provided results that were different from the other methods for both the invasive and noninvasive methods because of changes in the structure of the upstroke as the arterial pulse propagates distally. Although the minimum method worked well for the invasive determinations. it was erratic with the noninvasive determinations. probably because of the higher amount of noise and reflection in the latter. Among the four algorithms. the second derivative and the intersecting tangents methods worked well with both invasive and noninvasive determinations with mean variation coefficients of less than 7% and correlation coefficients between the methods of greater than 0.90 for all data. In conclusion. computerized algorithms allow accurate determination of pulse wave velocity in invasively and noninvasively measured arterial pressure waveforms.
Oral enoximone therapy in chronic heart failure: a placebo-controlled randomized trial. The Western Enoximone Study Group, In a parallel study design. 164 patients with New York Heart Association Functional class II or III heart failure were randomized to receive either enoximone given as 50 mg three times a day. or 100 mg three times a day. or a matching placebo. All patients were receiving digitalis and/or diuretics and had left ventricular ejection fractions less than or equal to 45. Exercise tests were performed after 1. 4. 8. and 12 weeks of treatment. Enoximone produced significantly greater increases in exercise time than placebo treatment at weeks 4 and 8 (p = 0.012. p = 0.029. respectively) but not after 12 weeks. Left ventricular ejection fraction increased significantly after the first dose of enoximone but not after 12 weeks of long-term therapy. Heart failure symptoms and the physicians' evaluations of cardiac status were significantly improved in both enoximone therapy groups during the first 4 weeks of evaluation when compared with evaluations of cardiac status in the placebo group. Diuretic doses were increased more frequently for patients who were receiving a placebo. Adverse events were reported with similar frequency in the placebo and 50 mg enoximone treatment groups; 100 mg enoximone resulted in a significantly greater incidence of adverse events. Mean heart rate and ventricular ectopic activity were not significantly different among the three treatment limbs. Enoximone appears to improve exercise tolerance. ventricular function. and symptoms of heart failure for 4 to 8 weeks. Heart rate. ventricular ectopic activity. and mortality rate were not increased.
Natural history of dilated cardiomyopathy in children, To assess the natural history and potential risk factors in childhood dilated cardiomyopathy. we investigated 25 patients (ages 9.6 +/- 4.4 years) who presented after they were 2 years old. All patients had symptoms of congestive heart failure and reduced contractility with a dilated left ventricle at presentation. Two factors at presentation were significantly different between patients who died less than 1 year after the presentation (n = 14) and those who survived for more than 1 year (n = 9); cardiothoracic ratio (65.1% +/- 6.8% vs 57.1% +/- 6.1%. p less than 0.01) and left ventricular ejection fraction (31.3% +/- 7.0% vs 40.0% +/- 6.2%. p less than 0.05). Irrespective of intensive medical therapy. dilated cardiomyopathy in children had a poor prognosis; the actuarial survival rate was 41% at 1 year and 20% at 3 years. Other forms of therapy should be considered in the early stages of dilated cardiomyopathy in this high-risk group.
Sinus parasystole, Sinus parasystole is the expression of a protected nondominant sinus pacemaker. which is totally independent of the dominant rhythm. Two forms of sinus parasystole are described: (1) an active form. where both the dominant and the parasystolic pacemakers are located within the sinus node and (2) a passive form. where the basic rhythm is ectopic and the sinus pacemaker is protected as a result of complete retrograde SA block. Three cases of sinus parasystole are analyzed. In the active form of the arrhythmia the parasystolic sinus P waves are identical to those of the basic sinus rhythm. The diagnosis is suggested by variably coupled premature sinus P waves occurring with mathematically related intervals. This relationship between the parasystolic intervals can not be precise whenever complicating factors such as modulation occur. The recognition of active sinus parasystole is difficult. since the parasystolic P waves do not differ from basic P waves. so that the pattern resembles that of sinus arrhythmia or sinus extrasystoles. The passive form of sinus parasystole is more easily recognized due to the clear-cut difference between the dominant ectopic atrial waves and the "parasystolic" sinus P waves. which manifest with variable coupling intervals and reflect mathematically related intervals in between.
Clinical correlates of the molecular and cellular actions of magnesium on the cardiovascular system, Magnesium is a ubiquitous element that participates in metabolic processes essential for life. Magnesium acts as a metallic cofactor in more than 300 enzymatic reactions; notably it is essential for all reactions requiring ATP. Magnesium also functions as a transmembrane and intracellular modulator of other ions. Altered magnesium homeostasis. particularly a deficiency. can cause alterations in metabolic functions that result in clinically recognizable events. Recognition of magnesium deficiency is problematic. since there is no test that will reliably and consistently detect this condition. A high index of suspicion for magnesium deficiency is necessary and treatment should be given when indicated. This article reviews the molecular and cellular actions of magnesium and correlates these basic scientific findings with clinically recognized cardiovascular events in humans. In addition. management guidelines are delineated.
Coronary artery stenting after angioplasty with self-expanding parallel wire metallic stents, Parallel wire stents were implanted over exchange guide wires at percutaneous transluminal coronary angioplasty sites in 27 canine coronary arteries that were predilated with slightly oversized balloons. Stents were stainless steel. self-expandable. 3.5 to 4.5 mm in diameter. 9 to 12 mm in length. and were made of 10 wires that were longitudinally laser-welded in a zig-zag design. The compressible stent was delivered by the withdrawal of a Teflon outer catheter (4.2 to 4.9F) and the push of a polyethylene inner catheter. Aspirin. 80 mg per day. was given from the day before the study began. and heparin (150 U/kg) was administered during implantation. Quantitative angiography and pathologic examinations were performed at day 0 and at weeks 2. 4. 12. 26 and 52. The coronary angiographic diameter at the stent site immediately after stenting marginally increased from diameter before stenting: 3.22 +/- 0.40 mm versus 3.14 +/- 0.37 mm (p = 0.03). and during a mean of 14 weeks of follow-up. remained unaltered from immediate post-stenting: 3.29 +/- 0.43 mm versus 3.22 +/- 0.40 mm (p = NS) with no stent displacement. Comparisons of patency and thrombosis between heparin-coated and uncoated stents. between left anterior descending and circumflex arteries. and among the three different diameters of stents showed uniformly good results. At microscopy. the wires were oriented perfectly and embedded in the arterial wall. and by 2 weeks they were covered by mucopolysaccharide ground substance. smooth muscle cells. and an almost complete monolayer of neoendothelial cells.
Early experience with the smart laser in the treatment of atherosclerotic occlusions, A dual-laser system (helium-cadmium and pulsed dye) capable of continuous computer analysis of spectroscopic characteristics of tissue fluorescence. which can distinguish atherosclerotic plaque from components of normal arterial wall. was used to deliver laser energy to ablate plaque. During a 1-year period this system was used to facilitate balloon angioplasty of short (3 to 17 cm) total occlusions of the superficial femoral or popliteal arteries only when standard angioplasty techniques were ineffective. During the year of the study. in one institution 415 patients were subjected to arteriography of the lower extremities for leg ischemia (397 for limb salvage indications). Standard angioplasty techniques were used in 94 of these patients; 218 patients were unsuitable for standard angioplasty. did not fulfill criteria for "smart" laser treatment. and underwent standard bypass operations. Only 11 patients (plus six others in the second institution) requiring treatment fulfilled the criteria for use of the "smart" laser. In 10 patients the occluding lesion was traversed by the laser wire (diameter 0.021 inch). and luminal patency was effectively restored by balloon angioplasty to greater than or equal to 70% of the most normal-appearing segment of that artery. Satisfactory luminal patency has persisted for 2 to 12 months (mean 6 months) in nine patients; the lesion in the tenth patient restenosed at 3 months. The laser procedure was unsuccessful in all three patients with occlusions greater than 10 cm and in four others. Although there were three microperforations with the laser wire. there were no clinically significant complications.
Reproducibility of Doppler echocardiographic quantification of aortic and mitral valve stenoses: comparison between two echocardiography centers, Doppler echocardiography has been widely used as a noninvasive method to quantify valvular heart diseases. This study assessed the variability between 2 echocardiography centers concerning 2-dimensional and Doppler echocardiographic results in the quantification of mitral and aortic valve stenoses. Forty-two patients were studied by 2 different echocardiography centers in a blinded. independent fashion. In patients with aortic and mitral valve stenosis. mean and maximal flow velocities were measured. The aortic valve orifice area was calculated according to the continuity equation. Mitral valve orifice area was determined by direct planimetry and by pressure half-time. In patients with an aortic valve stenosis. a close relation between the 2 centers was found for the maximal and mean flow velocities (coefficient of correlation. r = 0.72 to 0.92; coefficient of variation. 3.7 to 7.7%). A close correlation and a small observer variability was found for the flow velocity ratio determined by flow velocities measured in the left ventricular outflow tract and over the stenotic valve (r = 0.88; coefficient of variation. 0.01 +/- 0.009). In contrast. there was a poor correlation between the diameter of the left ventricular outflow tract and the aortic orifice area (r = 0.36 and 0.59. respectively). In patients with a mitral valve stenosis. mean and maximal velocities were closely correlated (r = 0.85 and 0.77. respectively). Velocities were not found to be significantly different between the 2 centers. Variability between the 2 centers for the mitral valve orifice area was 9.8% (2-dimensional echocardiography) and 5.7% (pressure half-time).
Prediction of death and myocardial infarction by radionuclide angiocardiography in patients with suspected coronary artery disease, The prognostic value of radionuclide angiocardiography was examined in patients with suspected coronary artery disease. Nine hundred and eight patients who underwent rest and exercise radionuclide angiocardiography without subsequent cardiac catheterization were followed for a median of 4.6 years. Fifty-two cardiovascular deaths and 28 nonfatal myocardial infarctions occurred during the follow-up period. Thirty-nine radionuclide angiocardiographic and clinical variables were analyzed in association with the end points of cardiovascular death. total cardiac events and death from all causes using the Cox proportional hazards model and Kaplan-Meier survival estimates. Univariable analysis identified the exercise ejection fraction as the best predictor of cardiovascular death (chi-square = 82). total cardiac events (chi-square = 84) and death from all causes (chi-square = 66). A small subset of patients (n = 45) with an exercise ejection fraction less than 0.35 were at high risk for future cardiac events. whereas most patients (n = 776) had an exercise ejection fraction greater than or equal to 0.50 and a low probability of a subsequent event. Three variables--the exercise ejection fraction. the exercise change in heart rate. and gender--contained independent prognostic information determined by multivariable analysis. The exercise ejection fraction was the strongest independent predictor (p less than 0.0001) for every end point. The measurement of ventricular function during exercise provides important independent prognostic information in patients with suspected coronary artery disease. Radionuclide angiocardiography successfully identifies patients requiring invasive assessment. and the low probability of cardiac events in patients with good exercise ventricular function obviates the need for interventional therapy.
Circadian variation of transient myocardial ischemia in the early out-of-hospital period after first acute myocardial infarction, Circadian rhythms have been demonstrated in acute myocardial infarction (AMI) and in other clinical cardiac dysfunctions. The purpose of this study was to elucidate whether a circadian pattern of transient myocardial ischemia exists after first AMI. Prospectively. 24-hour ambulatory ST-segment monitoring was initiated at discharge on day 11 +/- 5 in 123 consecutive survivors of first AMI. A total of 93 ischemic episodes (91 asymptomatic) occurred in 21 of the 123 patients (17%) (mean duration of 30 minutes. range 4 to 292). A significant circadian rhythm of transient myocardial ischemia was found with a peak activity occurring in the evening hours (p less than 0.01). Thus. 43% of ischemic episodes and 42% of ischemic time occurred between 6 P.M. and 12 midnight. The characteristics of morning and evening episodes were similar. except for the heart rate at maximal ST-segment depression. which was significantly higher during morning episodes (p less than 0.02). Patients with transient myocardial ischemia had a diurnal distribution similar to the circadian variation displayed during ischemic activity. Thus. 16 of the 21 patients had ischemic episodes from 6 P.M. to 12 midnight versus 10 patients from 6 A.M. to 12 noon (p less than 0.01). The 24-hour mean minimal heart rate was significantly higher in patients with than without ischemic episodes (p less than 0.02). In conclusion. this study has established a significant circadian peak of transient myocardial ischemia in the evening hours in survivors of first AMI. Whether the pattern displayed is due to endogenous biologic functions or cyclic variations. or both. in the external environment needs to be clarified.
Usefulness of weightlifting training in improving strength and maximal power output in coronary artery disease, The effects of 10 weeks (20 sessions) of combined weightlifting and aerobic training (n = 10) were compared with the effects of aerobic training alone (n = 8) on indexes of strength and aerobic exercise capacity in 18 men with coronary artery disease (CAD). Initial test performance was similar between groups. After aerobic training. the maximal load that could be lifted once only (1-repetition maximum) in single-arm curl. single-leg press and single-knee extension exercises increased by 13% (11.8 to 13.3 kg; p less than 0.01). 4% (97.0 to 101.0 kg; difference not significant) and 5% (28.2 to 29.7 kg; difference not significant). respectively; corresponding gains with combined weightlifting and aerobic training were 43% (12.2 to 17.4 kg; p less than 0.01). 21% (99.0 to 120.0 kg; p less than 0.01) and 24% (29.0 to 36.0 kg; p less than 0.01). After aerobic training. the initial 1-repetition maximum could be lifted an average of 4 times. compared with 14 times after combined training. Maximal progressive incremental cycle ergometer power output increased by 2% in the aerobic control group (1.088 to 1.113 kpm/min; difference not significant) and by 15% (1.030 to 1.180 kpm/min; p less than 0.05) in the experimental group. Cycling time at 80% of initial maximal power before attaining a Borg (0 to 10) rating of perceived exertion of 7 (very severe) increased by 11% (604 to 672 seconds; difference not significant) and by 109% (541 to 1.128 seconds; p less than 0.05) in the control and weight-trained patients. respectively.
Transient myocardial ischemia during daily life in rest and exertional angina pectoris and comparison of effectiveness of metoprolol versus nifedipine, The clinical characteristics of 65 patients with mixed angina were classified by means of (1) a questionnaire investigating the proportion of symptoms occurring at rest and on effort. (2) an exercise stress test. (3) 24-hour ambulatory Holter monitoring. and (4) coronary arteriography. According to the questionnaire. the proportion of effort-induced anginal episodes ranged from 1 to 99%. The ischemic threshold during exercise testing ranged from 110 x 10(2) to 350 x 10(2) mm Hg x beats/min. At least 1 episode of ST-segment depression was observed in 29 of the 65 patients during Holter monitoring. Ischemic episodes during Holter monitoring were more frequent (p less than 0.05) in patients reporting greater than or equal to 50% of anginal attacks on effort. with moderate to severe limitation of exercise capacity and with multivessel coronary artery disease. The effect on ambulatory ischemia of a 6-week treatment with a beta blocker (metoprolol CR. 200 mg once daily) or a dihydropyridine calcium antagonist (nifedipine retard 20 mg twice daily) were then compared according to a double-blind. parallel group design. Metoprolol significantly reduced the number and duration of the ischemic episodes during daily life (p less than 0.05) irrespective of the patients' clinical characteristics. Nifedipine was ineffective. particularly in patients with angina predominantly on effort and with a moderate to severe reduction in exercise tolerance. It is concluded that in patients with mixed angina. ischemic episodes during daily life are more likely to occur in patients with a clinical presentation suggesting poor coronary reserve.
Progression and regression of minor coronary arterial narrowings by quantitative angiography after fenofibrate therapy, To study the effects of fenofibrate. a lipid-lowering medication. on patients with coronary artery disease. 191 minor coronary narrowings in 42 patients with coronary artery disease were analyzed by quantitative coronary angiography using computer-assisted contour detection. Computed parameters were percent diameter reduction and percent plaque area. A prospectively formed intervention group of 21 patients treated with special diet and fenofibrate (200 to 400 mg/day) was checked every 6 weeks with regard to risk factors. After a mean interval of 21 months. coronary angiography was repeated. using the same x-ray system and nearly identical projections. The intervention group was angiographically compared at follow-up with an untreated comparison group. also comprising 21 patients. Both groups had high initial serum cholesterol (mean 311 mg/dl) and low-density lipoprotein (LDL) cholesterol levels (mean 235 mg/dl). Only among the treated patients did lipid levels change significantly: cholesterol. -19%; LDL cholesterol. -20%; high-density lipoprotein cholesterol. +19%; and triglycerides. -30%. At angiographic follow-up. the changes in percent diameter reduction and percent plaque area correlated positively with the mean serum and LDL cholesterol levels of the intervention group. Significant differences were found in the change in percent plaque area between both groups. The intervention subgroup with angiographic regressions (11 patients) had significantly lower serum and LDL cholesterol levels than the intervention subgroup with angiographic progressions (10 patients). These results indicate the beneficial effect of fenofibrate on minor coronary narrowings. Because of its high reproducibility in measuring minor narrowings. quantitative coronary angiography proved to be a suitable method for angiographic follow-up.
Transtelephonic electrocardiographic monitoring of cardiac rehabilitation exercise sessions in coronary artery disease, Transtelephonic monitoring of a single-lead electrocardiogram and on-demand 2-way voice communication were accomplished at 1.865 exercise sessions for 67 cardiac patients. Exercise sessions occurred either at the patients' homes or at remote hospital sites and began an average of 25 or 14 weeks. respectively. after hospital dismissal. Monitoring centers provided experienced nurses to direct all exercise sessions. The transtelephonic monitoring equipment was reliable with only one instance of system failure observed. A broad spectrum of patients with coronary artery disease. including some classified at higher risk. participated in the program. Patients exercised with a variety of equipment (cycle ergometer. treadmill. arm ergometer. cross-country ski simulator. combination arm-leg cycle ergometer. rowing machine). for 30 to 50 minutes. 1 to 3 times each week. No medical emergencies occurred. although 18 specific problems were discovered that led to further evaluation or change in the medical program of specific patients. Transtelephonic monitoring of cardiac rehabilitation exercise sessions at home and at remote hospitals appears safe and is attractive because not all patients have access to supervised exercise programs; this exercise assessment helps to maximally use highly trained cardiac rehabilitation personnel.
Spectral turbulence analysis of the signal-averaged electrocardiogram and its predictive accuracy for inducible sustained monomorphic ventricular tachycardia, This study was designed to assess the accuracy of a new noninvasive frequency analysis method for predicting patients with inducible sustained monomorphic ventricular tachycardia (VT) at electrophysiologic study and hence the risk of spontaneous ventricular tachyarrhythmias. Signal-averaged electrocardiograms from 3 orthogonal bipolar surface leads were evaluated using a microcomputer-based frequency analysis system that performs analysis of conventional time-domain late potentials as well as incorporating a new technique for spectral analysis of relatively short. overlapping signal segments spanning the whole QRS complex. The spectral analysis technique measured abnormalities anywhere in the entire QRS complex and did so without dependence on any arbitrarily defined frequency. duration or amplitude cutoffs. The hallmark of arrhythmogenic abnormality was hypothesized to be frequent and abrupt changes in the frequency signature of the QRS wave front velocity as it propagates throughout the ventricle around areas of abnormal conduction. resulting in a high degree of spectral turbulence. One-hundred forty-two subjects were studied. including 71 totally normal control subjects ("true negatives"). 33 with both late potentials by time-domain analysis and inducible sustained monomorphic VT ("true positives"). 28 with late potentials but no evidence of spontaneous or inducible sustained monomorphic VT ("false positives") and 10 with inducible sustained monomorphic VT but absence of time-domain late potentials ("false negatives"). The frequency analysis technique correctly classified 100% of the true negatives. 97% of the true positives. 86% of the late potentials false positives and 60% of the late potentials false negatives. The total predictive accuracy of frequency analysis for all groups was 94%. compared with 73% for time-domain late potential analysis. The results suggest that a high degree of spectral turbulence of the overall QRS signal during sinus rhythm may provide a more accurate marker for the anatomic-electrophysiologic substrate of reentrant tachyarrhythmias than detection of late potentials in the terminal QRS region by either time- or frequency-domain analysis. Spectral turbulence analysis is applicable to patients irrespective of the QRS duration and the presence or absence of bundle branch block.
A generalized description of Wenckebach behavior with analysis of determinants of ventricular cycle-length variation during ambulatory electrocardiography, Although variation in ventricular cycle length during Wenckebach-type second-degree atrioventricular block traditionally has been explained by the direction of incremental change in PR lengthening preceding the blocked complex. changing PP intervals can also affect Wenckebach periodicity. A generalized algebraic solution was derived to define changing ventricular cycle length as a function of both changing PP and changing incremental PR interval behavior in Wenckebach block. Based on this solution. the determinants of cycle-length variation were examined for 65 episodes of Wenckebach block detected by ambulatory electrocardiography in 51 patients. As previously demonstrated. only 20% (13 of 65) of Wenckebach episodes were characterized by the "classic" shortening of RR intervals; in contrast. ventricular cycle length increased in 57% (37 of 65) and remained constant in 23% (15 of 65) of cases. Algebraic analysis of these episodes revealed that the direction of ventricular cycle-length change preceding the blocked complex was primarily determined by the direction of change of incremental PR intervals in only 35% (23 of 65) of Wenckebach episodes; RR change was governed by the direction of change of preceding PP intervals in 34% (22 of 65) and by equal change of PP and incremental PR intervals in 31% (20 of 65) of these episodes. Both inverse and concordant relationships between changing RP and PR intervals were primarily determined by the direction of PP variation during in vivo Wenckebach block. These data confirm that classic Wenckebach block is less common than "atypical" Wenckebach periodicity and demonstrate that RR variation in Wenckebach block is governed by the changing PP interval as often as by the changing incremental PR interval.
Dyslipidemic effects of cigarette smoking on beta-blocker-induced serum lipid changes in systemic hypertension, To assess the effects of beta blockers on lipids and apolipoproteins in cigarette smokers and nonsmokers. 330 patients with systemic hypertension received 1 month of placebo and 6 months of beta-blocker monotherapy. Serum total cholesterol. triglycerides. high-density lipoprotein (HDL) cholesterol. low-density lipoprotein (LDL) cholesterol. and apolipoproteins A1 and B were measured. Total cholesterol increased with propranolol (smokers vs nonsmokers. 8 vs 2%); increased for smokers and decreased for nonsmokers with atenolol (8 vs -3%). metoprolol (6 vs -1%) and pindolol (7 vs -6%); and decreased for both groups with celiprolol (-3 vs -10%). HDL cholesterol decreased with propranolol (smokers vs nonsmokers. -8 vs -18%). atenolol (-7 vs -2%) and metoprolol (-12 vs -1%); increased for smokers and decreased for nonsmokers with pindolol (11 vs -2%); and increased for both groups with celiprolol (5 vs 6%). Similar trends were observed with LDL cholesterol and the total/HDL cholesterol ratio. It is concluded that early noncardioselective beta blockers such as propranolol have significant dyslipidemic effects in both smokers and nonsmokers. Cardioselective drugs such as atenolol and metoprolol. or drugs with partial agonist activity such as pindolol. have variable effects. Celiprolol. a new. highly cardioselective beta 1 blocker with partial beta 2 agonist activity and vasodilatory properties. has favorable effects on lipids and minimizes the dyslipidemic effects associated with smoking.
Sympathetic responses of patients with congestive heart failure to cold pressor stimulus, Studies in patients with congestive heart failure (CHF) demonstrate blunting of sympathoexcitatory responses to baroreflex perturbation. Whereas experimental and limited clinical evidence suggests impairment of baroreflex mechanisms as the etiology of these attenuated responses. an alternative mechanism would be an inability of patients with CHF to increase sympathetic neural outflow above markedly elevated baseline levels. Hemodynamic and sympathetic neural responses (peroneal microneurography) were therefore compared of normal subjects (n = 10) and patients with CHF (n = 10) during the non-baroreflex sympathoexcitatory stimulus of the cold pressor test. The cold pressor stimulus produced increases in arterial pressure and heart rate in both groups. During hand immersion in ice water. normal subjects demonstrated significant increases in muscle sympathetic nerve activity expressed as burst frequency (20 +/- 2 to 28 +/- 3 bursts/min. p less than 0.01). total integrated nerve activity (224 +/- 41 to 342 +/- 62 U/min. p less than 0.05). and total activity corrected for accompanying changes in heart rate (375 +/- 81 to 538 +/- 118 U/100 heart beats. p less than 0.05). Similarly. despite elevated control levels of sympathetic activity. patients with CHF also demonstrated significant sympathoexcitatory responses to the cold pressor stimulus. with increases in muscle sympathetic nerve burst frequency (60 +/- 7 to 67 +/- 7 bursts/min. p less than 0.01) total integrated nerve activity (818 +/- 159 to 1.015 +/- 191 U. p less than 0.001). and total activity corrected for accompanying changes in heart rate (1.008 +/- 178 to 1.173 +/- 201 U/100 heart beats. p less than 0.01).
Molecular analyses of an acidic transthyretin Asn 90 variant, A mutation in transthyretin (TTR Asn 90) has been identified in the Portuguese and German populations. This variant has a lower pI and was found by screening analyses in 2/4.000 German subjects and in 4/1.200 Portuguese by using either double one-dimensional (D1-D) electrophoresis with isoelectric focusing (IEF) or hybrid isoelectric focusing in immobilized pH gradient (HIEF) as the final separation step. The Portuguese population sample was from the area where TTR Met 30-associated familial amyloidotic polyneuropathy (FAP) prevails. and it was divided into (a) a group of 500 individuals belonging to FAP kindreds and (b) a group of 700 collected at random. HIEF showed two particular situations: (1) one case. from an FAP kindred. was simultaneously carrier of the Met 30 substitution and the acidic variant. and (2) one individual. from the randomly selected Portuguese sample. had only the acidic monomer. Comparative peptide mapping. by HPLC. of the acidic variant carriers and of normal TTR showed the presence of an abnormal tryptic peptide. not present in the normal TTR digests. with an asparagine-for-histidine substitution at position 90 explained by a single base change of adenine for cytosine in the histidine codon. This was confirmed at the DNA level by RFLP analyses of PCR-amplified material after digestion with SphI and BsmI. In all carriers of the Asn 90 substitution. no indicators were found for an association with traits characteristic for FAP.
Cytogenetic analysis of sperm from a man heterozygous for a pericentric inversion, inv (3) (p25q21), Human sperm chromosomes were studied in a man heterozygous for a pericentric inversion of chromosome 3(p25q21). The pronuclear chromosomes were analyzed after in vitro penetration of golden hamster eggs. A total of 144 sperm were examined: 69.2% were chromosomally balanced and 30.8% were recombinant. Of the balanced complements. the proportion with a normal chromosome 3 (37.6%) was approximately equal to the proportion with an inverted 3 (31.6%). Of the recombinant complements. the proportion of sperm with a duplication q/deletion p (17.3%) was approximately equal to the reciprocal event of duplication p/deletion q (13.5%). The recombinant chromosome 3 with a duplication q and deletion p has been observed in several abnormal children. but the duplication p/deletion q has never been reported. My results demonstrate that both recombinant chromosomes are produced as expected from an unequal number of crossovers within an inversion loop. In all likelihood the duplication p/deletion q chromosome is an early embryonic lethal because of the amount of genetic material deleted. The proportions of X-bearing (48.9%) and Y-bearing sperm (51.1%) were not significantly different from the expected 1:1 ratio. There was no evidence for an interchromosomal effect. Of the three inversions studied by human sperm chromosome analysis. recombinant chromosomes have been observed only in this case.
Use of the robust sib-pair method to screen for single-locus, multiple-locus, and pleiotropic effects: application to traits related to hypertension, Robust sib-pair linkage analysis can be used as a screening tool in the search for the potential involvement of single-loci. multiple-loci. and pleiotropic effects of single loci underlying phenotypic variation. Four large families were each ascertained through one adult white male with essential hypertension. The robust sib-pair method was used to screen these families for evidence of linkage between 39 quantitative traits related to hypertension and 25 genetic marker loci. All traits were analyzed on the untransformed. square-root and log-transformed scales. Among other findings. there is a suggestion of linkage between the 6-phosphogluconate dehydrogenase locus on chromosome 1p36 and mean fifth-phase diastolic blood pressure. There may also be linkage between the following markers and traits: the adenylate kinase-1 marker and/or the Lewis blood group marker and the traits height. weight. and biacromial breadth; the glyoxylase I marker and the traits upper-arm circumference and suprailiac skinfold thickness; the ABO blood group and adenylate kinase-1 markers on chromosome 9q34 and the third component of complement marker on chromosome 19p13 and dopamine-beta-hydroxylase; and the P1 blood group and the traits weight and 1-h postload serum glucose level.
Testing for association between disease and linked marker loci: a log-linear-model analysis, One approach frequently used for identifying genetic factors involved in the process of a complex disease is the comparison of patients and controls for a number of genetic markers near a candidate gene. The analysis of such association studies raises some specific problems because of the fact that genotypic and not gametic data are generally available. We present a log-linear-model analysis providing a valid method for analyzing such studies. When studying the association of disease with one marker locus. the log-linear model allows one to test for the difference between allelic frequencies among affected and unaffected individuals. Hardy-Weinberg (H-W) equilibrium in both groups. and interaction between the association of alleles at the marker locus and disease. This interaction provides information about the dominance of the disease susceptibility locus. with dominance defined using the epidemiological notion of odds ratio. The degree of dominance measured at the marker locus depends on the strength of linkage disequilibrium between the marker locus and the disease locus. When studying the association of disease with several linked markers. the model becomes rapidly complex and uninterpretable unless it is assumed that affected and unaffected populations are in H-W equilibrium at each locus. This hypothesis must be tested before going ahead in the analysis. If it is not rejected. the log-linear model offers a stepwise method of identification of the parameters causing the difference between populations. This model can be extended to any number of loci. alleles. or populations.
Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism, The debrisoquine/sparteine polymorphism is associated with a clinically important genetic deficiency of oxidative drug metabolism. From 5% to 10% of Caucasians designated as poor metabolizers (PMs) of the debrisoquine/sparteine polymorphism have a severely impaired capacity to metabolize more than 25 therapeutically used drugs. The impaired drug metabolism in PMs is due to the absence of cytochrome P450IID6 protein. The gene controlling the P450IID6 protein. CYP2D6. is located on the long arm of chromosome 22. A pseudogene CYP2D8P and a related gene CYP2D7 are located upstream from CYP2D6. This gene locus is highly polymorphic. After digestion of genomic DNA with XbaI endonuclease. restriction fragments of 11.5 kb and 44 kb represent mutant alleles of the cytochrome CYP2D6 gene locus associated with the PM phenotype. In order to elucidate the molecular mechanism of the mutant allele reflected by the XbaI 11.5-kb fragment. a genomic library was constructed from leukocyte DNA of one individual homozygous for this fragment and screened with the human IID6 cDNA. The CYP2D genes were isolated and characterized by restriction mapping and partial sequencing. We demonstrate that the mutant 11.5-kb allele results from a deletion involving the entire functional CYP2D6 gene. This result provides an explanation for the total absence of P450IID6 protein in the liver of these PMs.
Identification of a mutation in the arylsulfatase A gene of a patient with adult-type metachromatic leukodystrophy, To analyze the genetic abnormality in a Japanese patient with adult-type metachromatic leukodystrophy (MLD). we first elucidated the genomic organization of the human arylsulfatase A (ASA) gene and then compared the nucleotide sequences of exons and splice junctions of the mutant ASA gene to those of a normal control. We have identified a new mutation. a G-to-A transition in exon 2. which results in amino acid substitution of Asp for 99Gly. In a transient expression study. COS cells transfected with the mutant cDNA carrying 99Gly----Asp did not show an increase of ASA activity. which confirms that the mutation is a cause of adult-type MLD.
Proline at position 36: a new transthyretin mutation associated with familial amyloidotic polyneuropathy, Familial amyloidotic polyneuropathy (FAP) is associated with the deposition of an abnormal transthyretin (TTR) molecule. We have studied DNA from a family of Greek descent with FAP. The proband's TTR gene was asymmetrically amplified by using PCR and then was sequenced directly. to reveal a cytosine-for-guanine substitution in codon 36. This substitution removes a recognition site for endonuclease Fnu4HI. Allele-specific PCR was employed for diagnosis of the mutation. The predicted amino acid change of alanine to proline at position 36 was confirmed by protein sequencing of the proband's plasma TTR.
2,8-Dihydroxyadenine lithiasis in a Japanese patient heterozygous at the adenine phosphoribosyltransferase locus, All reported cases of 2.8-dihydroxyadenine (DHA) lithiasis have been due to functional homozygous deficiency of adenine phosphoribosyltransferase (APRT). Here we describe the first case of DHA lithiasis in a patient who has functional APRT activity in cultured lymphoblasts. The patient is heterozygous for Japanese-type (type II) APRT deficiency as demonstrated by starch-gel electrophoresis and DNA sequence analysis. We also demonstrate the use of starch-gel electrophoresis for differentiation between the type II mutant enzyme and the wild-type enzyme.
Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT, The inactivation of two alleles at a locus on the short arm of chromosome 11 (band 11p13) has been suggested to be critical steps in the development of Wilms tumor (WT). a childhood kidney tumor. Two similar candidate WT cDNA clones (WT33 and LK15) have recently been identified on the basis of both their expression in fetal kidney and their location within the smallest region of overlap of somatic 11p13 deletions in some tumors. These homozygous deletions. however. are large and potentially affect more than one gene. Using a cDNA probe to the candidate gene. we have analyzed DNA from both normal and tumor tissue from WT patients. in an effort to detect rearrangements at this locus. We report here a patient with bilateral WT who is heterozygous for a small (less than 11 kb) germinal deletion within this candidate gene. DNA from both tumors is homozygous for this intragenic deletion allele. which. by RNA-PRC sequence analysis. is predicted to encode a protein truncated by 180 amino acids. These data support the identification of this locus as an 11p13 WT gene (WT1) and provide direct molecular data supporting the two-hit mutational model for WT.
Antiretroviral therapy and immunomodulators in patients with AIDS, A number of studies have illustrated the effectiveness of hematopoietic growth factors in managing treatment-related cytopenias in patients with human immunodeficiency virus (HIV) infection. One of these factors. granulocyte-macrophage colony-stimulating factor. has been shown to restore absolute neutrophil counts in patients with acquired immunodeficiency syndrome (AIDS) and Kaposi's sarcoma receiving a combination of zidovudine (AZT) and interferon alfa. A combination of granulocyte colony-stimulating factor and erythropoietin has also been demonstrated to alleviate both neutropenia and anemia in patients with advanced AIDS or AIDS-related complex receiving zidovudine. Hematopoietic growth factors. in combination with each other and with antiretroviral agents. thus have an important supportive role to play in the treatment of patients with HIV disease.
Antiretroviral therapy in combination with interferon for AIDS-related Kaposi's sarcoma, In vitro studies have shown that 3'-azido-3'-deoxythymidine (zidovudine. AZT) and interferon synergistically inhibit the replication of the human immunodeficiency virus type 1 (HIV) in peripheral blood mononuclear cells at concentrations achievable in patients. Interferon alfa can cause lesions to regress in patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi's sarcoma (KS). Although zidovudine has no significant effect on the regression of these lesions. it does have antiviral activity in these patients as manifested by a decline in serum HIV antigen. However. when used separately. the two drugs can have serious side effects in some patients. In addition. the development of zidovudine-resistant strains has been noted in patients with advanced HIV disease receiving zidovudine for nine months or longer. Three in vivo trials have been initiated to assess possible advantages of combination therapy with zidovudine and interferon alfa in patients with AIDS-related KS. The incidence of serious adverse reactions. therapeutic efficacy. and the rate of emergence of zidovudine-resistant strains of HIV were evaluated. Preliminary results indicate that combination therapy with interferon alfa and zidovudine can safely be administered to patients with AIDS-related KS in doses that elicit antitumor and antiviral responses and discourage the potential emergence of zidovudine-resistant HIV strains.
Relative resistance of primary HIV-1 isolates to neutralization by soluble CD4, Replication of the human immunodeficiency virus type 1 (HIV-1) underlies the pathogenesis and progression of the acquired immunodeficiency syndrome (AIDS). A soluble form of the virus receptor. CD4. has been developed as a potential therapeutic agent with good activity against laboratory strains of HIV-1 in vitro. However. quantitative virologic studies performed to date on the blood of patients receiving recombinant soluble CD4 (sCD4) demonstrated no efficacy in vivo despite good drug levels in serum. These results led us to examine the neutralizing activity of sCD4 against multiple primary HIV-1 isolates from infected patients. The findings demonstrate that primary isolates were significantly more resistant to sCD4 than were laboratory strains. which suggests a need to reevaluate CD4-based therapies and to conduct better designed preclinical studies that include experiments performed on patient viral isolates.
Epidemiology, pathophysiology, and management of isolated systolic hypertension in the elderly, Isolated systolic hypertension (ISH) is a common disorder in the elderly. carrying with it a high risk of cardiovascular morbidity and mortality. Environmental and age-related factors believed to contribute to ISH include obesity. declining physical activity. stress. and such dietary changes as increased salt intake and decreased intake of calcium and potassium. Increased rigidity of the aorta resulting in reduced compliance is an important hemodynamic feature. but factors that increase peripheral resistance also appear to play a role. Antihypertensive drugs have been shown to effectively and safely lower the systolic blood pressure elevations characteristic of ISH. To date. use of low drug doses and careful titration of dosage have avoided significant orthostatic hypotension and undue lowering of the diastolic pressure. Studies of relatively small groups of patients suggest that antihypertensive drugs can lower the risk of cardiovascular morbidity/mortality associated with ISH but the definitive answer awaits results of the ongoing large-scale Systolic Hypertension in the Elderly Program trial. In the interim. management should begin with conservative measures such as weight loss. salt restriction and. possibly. calcium supplementation. If this fails. drug therapy should be considered in patients with systolic blood pressures above 180 mm Hg and in those with systolic readings between 160 and 180 mm Hg who have concomitant cardiovascular risk factors. To date. no controlled trials of sufficient size have demonstrated that one drug class is more effective than another in treating ISH. Drug therapy should be tailored to the individual patient. starting with a low dose of a single drug and. if necessary. slowly increasing dosage until a systolic blood pressure under 160 mm Hg is attained.
The aging hypertensive kidney: pathophysiology and therapeutic options, The aging kidney undergoes hemodynamic changes characterized by reductions in glomerular filtration rate and effective renal plasma flow. These functional changes are associated with loss of renal mass related to changes in the intrarenal vasculature. The reduced glomerular filtration surface area and subsequent microcirculatory adaptations enhance the risk for development of renal diseases associated with systemic diseases. Hypertensive nephrosclerosis accounts for 26% of all end-stage renal disease in the United States; the median age of those affected is 67 years. Hemodynamic and structural changes observed in the essential hypertensive kidney suggest an accentuation of the physiologic aging process. Initially observed hemodynamic changes. which may be reversible with specific drug therapy. suggest that excessive production of angiotensin II plays a role. Progressive renal impairment may occur despite control of systemic hypertension. Renal protection appears to require therapeutic normalization of both systemic and glomerular capillary pressures. The latter may depend on a drug's ability to attenuate the intrarenal effects of angiotensin II on the renal microcirculation. Drug classes with renal protective potential include angiotensin-converting enzyme inhibitors and calcium antagonists. However. long-term clinical trials are required to assess the potential advantages of specific drug therapies in preventing the development and/or progression of hypertensive arteriolar nephrosclerosis.
Practical considerations in treating the elderly hypertensive patient, More than half of all older Americans die of cardiovascular diseases. Hypertension is a major risk factor for cardiovascular diseases. and its prevalence increases with age. Older patients are both at higher risk for end-organ complications and less likely than younger ones to survive such complications as myocardial infarction and stroke. Clinical studies have shown that reduction of elevated blood pressure is beneficial in many older persons. Optimal selection of antihypertensive therapy requires consideration of the special characteristics of the elderly. who differ from their younger counterparts in physiology. response to therapy and frequency of concomitant illnesses and medications. Calcium antagonists are particularly effective in these patients; other agents are useful in selected situations. Drugs that are likely to cause central nervous system side effects or orthostatic hypotension generally should be avoided in this patient population. Therapy should begin with a low dose and be titrated upward slowly. thus avoiding excessive reduction of blood pressure and the development of orthostatic hypotension. Treatment should be altered as necessary to minimize side effects that may impair quality of life or lead to poor compliance.
Epidemiology and evaluation: steps toward hypertension treatment in the 1990s, The percentage of persons in the United States over age 65--especially over 85--is increasing more rapidly than other age groups. Two thirds of people over age 65 have blood pressure higher than 140 mm Hg systolic or 90 mm Hg diastolic. Isolated systolic hypertension (systolic blood pressure greater than 160 mm Hg with diastolic blood pressure less than 90 mm Hg) is also highly prevalent. In a number of clinical trials. treatment of diastolic hypertension in the elderly has been shown to be beneficial. although the value of treatment of isolated systolic hypertension is not yet established. The benefit of antihypertensive therapy on the incidence of stroke and heart failure has been clearly established. but prevention of the atherosclerotic complications of high blood pressure (sudden death or myocardial infarction. for example) has not been convincingly demonstrated. Since clinical trials designed to investigate this atherosclerotic complication of hypertension have relied on stepped-care regimens (diuretics and beta blockers). the question arises whether the use of different drugs might have a better effect on prevention of myocardial infarction. The basis for this supposition includes the known adverse effects of diuretics and beta blockers on electrolytes. lipid metabolism. glucose metabolism. insulin resistance. and quality of life. Hypertension treatment in the 1990s will focus on the mechanisms by which blood pressure is lowered by various antihypertensive agents. as well as individualization of drug therapy based on coexisting diseases and conditions. Emphasis will be placed on use of monotherapy whenever possible; diuretics in low doses will probably be used more frequently for second-line therapy. In recognition of their lack of adverse lipid effects and their tolerability. first-line therapy with alpha blockers. angiotensin-converting enzyme inhibitors. and calcium antagonists will become increasingly common. The goal of antihypertensive therapy will be to extend the life expectancy of hypertensive patients to that of subjects without high blood pressure; hopefully. these new treatment approaches will bring us closer to that goal.
Vascular injury: mechanisms and manifestations, Abnormalities in regulatory mechanisms for calcium handling play a key role in cell death and tissue necrosis. In the cardiovascular system this applies to the vasculature and the myocardium alike. In the aged population. where hypertension is a known risk factor. manifestations of vascular injury include atherogenesis and stroke. The newly developed dihydropyridine-based calcium antagonist amlodipine was used in investigations to determine whether calcium antagonists with sustained activity. in addition to lowering blood pressure. slow the development of atherogenesis in rabbits receiving high cholesterol diets. or reduce mortality in stroke-prone hypertensive rats. To establish whether this drug protects the vasculature against excessive atheroma formation in the presence of high cholesterol intake. rabbits were given 2% cholesterol in addition to their normal food intake and either 0. 1. or 5 mg/kg/day amlodipine orally for either 8 or 12 weeks. One day after the conclusion of the treatment protocol. the thoracic aorta was excised. assayed for calcium or cholesterol concentrations. and stained to identify sudanophilic-positive lesions. Amlodipine caused a time- and dose-dependent reduction in lesion formation. calcium overload. and cholesterol level. In the second series of experiments. amlodipine (5 mg/kg/day) was added to the diets of stroke-prone hypertensive rats. Treatment was initiated at age 5 weeks and continued for 30 weeks. During the treatment period. systolic blood pressure was reduced in the amlodipine-treated rats (166 +/- 9 mm Hg) versus those treated with placebo (248 +/- 12 mm Hg) (p less than 0.001). A significant reduction in mortality was observed in the amlodipine-treated rats (p less than 0.001). with 93% surviving versus only 26% in the placebo group at the end of the 30-week treatment period. Concomitantly. cardiac hypertrophy was attenuated in the treated group compared with the placebo group (heart-to-body weight ratios of 4.5 +/- 0.01 vs 5.8 +/- 0.6. respectively [p less than 0.01]). These results extend the evidence that calcium antagonists provide vascular protection in animal models. This finding may become increasingly important in the management of an aging hypertensive population.
The assessment and treatment of performance anxiety in musicians, OBJECTIVE: Performance anxiety in musicians may be severe enough to require intervention but has been the subject of relatively little clinical research. The authors' objectives were to describe the results of a comprehensive clinical and laboratory assessment and to perform a double-blind. placebo-controlled study comparing buspirone. cognitive-behavior therapy. and the combination of these treatments for performance anxiety. METHOD: Ninety-four subjects were recruited by mass media announcements and were seen in a university-based outpatient psychiatric clinic. Assessments were 1) questionnaires for all 94 subjects. 2) diagnostic interview of 50 subjects. and 3) laboratory performance of 34 subjects. Treatment conditions were 1) 6 weeks of buspirone. 2) 6 weeks of placebo. 3) a five-session. group cognitive-behavior therapy program with buspirone. or 4) the cognitive-behavior therapy program with placebo. Treatment outcome measures included subjective anxiety ratings and heart rate measures during a laboratory performance. a questionnaire measure of performance confidence. and a blind rating of musical performance quality. RESULTS: All subjects fulfilled criteria for DSM-III-R social phobia. Of the 15 full-time professional musicians. ten had tried propranolol and three had stopped performing. Most of the subjects had substantial anxiety and heart rate increases during laboratory speech and musical performances. Cognitive-behavior therapy resulted in statistically significant reductions in subjective anxiety. improved quality of musical performance. and improved performance confidence. Buspirone was not an effective treatment. CONCLUSIONS: Cognitive-behavior therapy is a viable treatment approach for performance anxiety in musicians.
Cortical magnetic resonance imaging changes in elderly inpatients with major depression, OBJECTIVE: The purpose of the study was to determine if magnetic resonance imaging (MRI) scans of elderly depressed patients differ from MRI scans of age-matched control subjects and age-matched patients with Alzheimer's disease. METHOD: The authors studied 21 patients 60 years or older with major depression. 16 patients with Alzheimer's disease. and 14 age-matched control subjects. RESULTS: Compared to control subjects. depressed patients had greater cerebral sulcal and temporal sulcal atrophy; larger sylvian fissures. lateral ventricles. third ventricles. and temporal horns; and greater severity of subcortical white matter lesions. Depressed patients also had more basal ganglia lesions but similar levels of periventricular hyperintensity. There were no differences between depressed patients with and without delusions on any MRI measure. Depressed patients who received ECT had more temporal horn atrophy and greater subcortical abnormality summary scores than normal subjects. Cortical sulcal atrophy correlated with age at onset of depression. CONCLUSIONS: The findings suggest that elderly hospitalized depressed patients have greater cortical as well as subcortical atrophy and more basal ganglia lesions than age-matched normal control subjects. The correlation of these abnormalities with outcome remains unknown.
Changes in brain glucose metabolism in cocaine dependence and withdrawal, OBJECTIVE: The authors investigated changes in brain function associated with cocaine dependence and withdrawal to provide clues regarding the processes that lead to the uncontrollable self-administration of cocaine. METHOD: They measured regional brain metabolism with [18F]-fluorodeoxyglucose (FDG) and positron emission tomography in 15 outpatients with the diagnosis of cocaine abuse and 17 normal comparison subjects. Ten of the patients were studied less than 1 week after they had last had cocaine. and five were studied 2-4 weeks after withdrawal. RESULTS: Patients studied within 1 week of cocaine withdrawal but not those studied within 2-4 weeks of cocaine withdrawal had higher levels of global brain metabolism as well as higher levels of regional brain metabolism in the basal ganglia and orbitofrontal cortex than did normal subjects. probably as a consequence of less brain dopamine activity. There was also a significant relationship between the number of days since cocaine withdrawal and regional brain glucose metabolism in the orbitofrontal cortex and in the basal ganglia. and the correlations between cocaine craving and metabolic activity were significant in the prefrontal cortex and the orbitofrontal cortex. CONCLUSIONS: Although the time-dependent fall in metabolic activity suggests that the higher metabolic activity observed less than a week after cocaine withdrawal may represent a nonspecific expression of drug withdrawal. the selectivity of changes in glucose metabolism for the basal ganglia and for the orbitofrontal cortex suggests that the regional metabolic changes seen in cocaine abusers during detoxification are related to changes in brain dopamine activity.
Comparison of acetorphan with clonidine for opiate withdrawal symptoms, OBJECTIVE AND METHOD: The authors compared the effects of acetorphan. an enkephalinase inhibitor. with those of clonidine for the treatment of the opioid withdrawal syndrome. Nineteen patients addicted to heroin or synthetic opiates who were undergoing drug withdrawal and displayed a withdrawal syndrome according to DSM-III criteria were studied for 5 days in a hospital setting. In a double-blind trial. 10 subjects were given acetorphan intravenously and nine were given clonidine; objective signs and subjective symptoms of withdrawal were recorded. RESULTS: On several objective signs. the effect of acetorphan was more marked than that of clonidine. whereas the two drugs exhibited similar efficacy with respect to the subjective components of withdrawal. No side effect was noted in the subjects who received acetorphan. CONCLUSIONS: Enkephalinase inhibition may constitute a novel and safe therapeutic approach to the opioid withdrawal syndrome.
Hypnotically induced auditory hallucinations and the mouth-opening maneuver: a failure to duplicate findings, OBJECTIVE: The authors sought to replicate the part of a study by Bick and Kinsbourne in which hypnotically induced auditory hallucinations in normal volunteer subjects were abolished by requiring the subjects to open their mouths. METHODS: Sixty-four normal volunteer subjects were hypnotized. and an attempt was made to induce auditory hallucinations. The subjects in whom hallucinations were successfully induced were then asked to perform the mouth-opening maneuver and the control maneuvers of putting their fingers in their ears or squeezing their eyes shut in an effort to end the hallucinations. RESULTS: Sixteen subjects reported having hallucinations. None of them reported that a hallucination was abolished by opening the mouth or closing the eye; four reported ending hallucinations by putting their fingers in their ears. CONCLUSIONS: Opening the mouth does not affect auditory hallucinations induced by hypnosis in normal persons. The most likely reason for the discrepancy between the results of this experiment and those of the Bick and Kinsbourne study is that the design of the latter study was faulty because it permitted demand characteristics to influence the results.
Imipramine treatment of methadone maintenance patients with affective disorder and illicit drug use, Of 17 consecutive patients receiving methadone maintenance treatment who had primary or chronic depression. nine (53%) improved in both mood and drug abuse after imipramine treatment. This finding suggests a potential for helping such dual-diagnosis patients reduce drug abuse and associated risk for HIV. Further controlled trials are warranted.
Cellular intermediate filament networks and their derangement in alcoholic hepatitis, Intermediate filaments are major components of most eukaryotic cells that form from the polymerization of protein subunits that are expressed in tissue and development specific fashions. The interactions of intermediate filaments with a myriad of other cellular proteins and structures give rise to a complex overall cellular architecture that is likely responsible for cellular well-being. The mature 10-nm filaments are relatively stable cellular structures. but the intermediate filaments undergo major morphological and biochemical changes. especially during mitosis. differentiation. and in response to certain drugs. Evidence exists that hepatocyte intermediate filaments (keratin filaments) are deranged in alcoholic hepatitis. an inflammatory liver disease of alcoholics and heavy spree drinkers. The classical and characteristic pathological hepatocyte inclusion bodies of alcoholic hepatitis. Mallory bodies. are composed in part of normal keratins that likely derive from the pre-existing hepatocyte intermediate filament network. It is unclear if intermediate filament network derangement in alcoholic hepatitis is directly caused by the actions of ethanol or its metabolites on intermediate filaments or their associated structures. or whether alcohol causes a cellular insult or injury elsewhere and a subsequent response (e.g.. immune) causes intermediate filament network derangement. The precise mechanisms responsible for intermediate filament derangement remain to be elucidated; however. experimental data exist that support and refute several hypotheses. Hopefully. further studies will help determine a better overall understanding of the abnormalities of intermediate filaments and their relationship to the pathophysiology of alcoholic hepatitis and other diseases.
Ethanol induced morphologic alterations during growth and maturation of cardiac myocytes, Alteration of growth and development of cells exposed to ethanol during embryogenesis contributes to dysmorphism. The mechanism(s) of these alterations remains an enigma. This paper describes studies of an in vitro cardiac myocyte model in which the major effort was to investigate growth and development parameters in an obligate interacting multicellular system. The well defined events of in vitro myogenesis allow for documentation or dysgenesis and altered growth in the presence of the taratogen. ethanol. The cells exposed to ethanol did not mature morphologically or functionally compared with controls. Increasing concentrations of ethanol appear to have a graded damaging effect. The greater the concentration of ethanol the more profound the dyssynchronous growth. The morphologic correlates were multinucleation. and alteration in the ultrastructural organization of cell-cell contacts and myofilaments. Correlation of these findings with those observed in dysgenic muscle of human infants and rat pups exposed to ethanol in utero. may provide at least a partial understanding of the teratogenic manifestation of ethanol in embryogenesis and organogenesis.
Molecular changes associated with ethanol-induced growth suppression in the chick embryo, In humans and in animal models the most frequently observed alcohol-related birth defect (ARBD) is intrauterine growth retardation (IUGR). The central nervous system (CNS) is sensitive to the growth inhibitory effects of in utero ethanol exposure and neonatal CNS alterations with associated behavioral deficits are a likely result of maternal ethanol consumption. Presently. little information exists as to the biochemical mechanism by which ethanol inhibits fetal CNS growth. Further. it is unknown if there are genetic differences in maternal or fetal responses to ethanol. Ongoing research using a chick model indicates that pharmacologically appropriate doses of ethanol (less than 30 mM) inhibit brain growth and reduce CNS 3'.5'-cyclic adenosine monophosphate (cyclic AMP) with an associated 50% decrease in the binding of cyclic AMP by the regulatory subunit (RII) of protein kinase A. Furthermore. there is a specific loss of phosphorylation of RII by kinase catalytic subunit as a result of ethanol exposure. Because tissue cyclic AMP content and the degree of RII phosphorylation are important parameters for the regulation of protein kinase A catalytic activity. it is hypothesized that these alterations may be biochemical transformations that underlie ethanol-induced growth suppression.
Alcohol induction of ferritin expression in a human hepatoblastoma cell line (HEP G2), Hyperferritinemia. an unclear mechanism. is frequently observed in chronic alcoholics. The aim of this work was to study the effect of alcohol on ferritin expression in a human hepatoblastoma cell line. HepG2. This cell line proved to be sensitive to alcohol. since alcohol increased gamma-GT activity both in cells and media. The most striking result was the increase of ferritin in cells and media by alcohol. Moreover. this effect was specific. since it contrasted with a decrease in total protein synthesis and secretion. a decrease in transferrin excretion and a lack of effect on orosomucoid. In our model. alcohol was able to induce. in a specific manner. ferritin expression.
The Michigan Alcoholism Screening Test: false positives in a college student sample, The Michigan Alcoholism Screening Test (MAST). designed and validated by Selzer (1971). is widely used to screen for persons with alcohol problems. The most recent version of the MAST includes the question "Have you ever attended a meeting of Alcoholics Anonymous (AA)?" This question may contribute to false positive identifications. as it does not specify whether attendance is for the subject's own problem drinking. In the current research. 114 college students completed the MAST along with an additional question: "Have you ever attended a meeting of Alcoholics Anonymous because of your own problem drinking?" The results indicated that seven of 114 subjects (6.1%) attained inflated MAST scores because they had attended an Alcoholics Anonymous meeting. but not for their own problem drinking. It is suggested that the wording to the Alcoholics Anonymous question on the MAST be changed to reduce the number of false positive identifications produced by this instrument.
Overall functioning and criteria of progress in rehabilitation of alcohol abusers: longitudinal analyses of changes, The aim was to compare alcohol consumption and vocational adjustment as criteria of rehabilitation progress of alcoholics. with regard to links to concomitant changes in functioning in other life areas. Thirty-four advanced alcohol abusers in rehabilitation were examined twice with an interval of 2 years between each examination. Change scores in alcohol consumption and work capacity were correlated with change scores in social network. activities. life-satisfaction. psychological well-being. psychiatric symptoms. and biomedical functioning. Improved drinking habits were connected with some changes in overall functioning. however not solely in a favorable direction. Negative mood changes were especially noteworthy. Improvements in vocational adjustment. on the other hand. appeared to be somewhat more unequivocally and encompassingly associated with amelioration in the wider range of functioning. The results indicate that drinking measures alone are not sufficient indicators of progress in rehabilitation and underscores the need of more global criteria of general adjustment.
Alcohol use by alcoholics with and without a history of parental alcoholism, The association between parental history of alcoholism and the nature of alcoholism was assessed using a more reliable measure of family history (Family Tree Questionnaire) and a more comprehensive inventory of alcoholism (Alcohol Use Inventory) than used in earlier studies. Parental alcoholism was associated with more severe alcoholism on most parameters of alcohol use (age of onset. quantity. frequency. preoccupation. and sustained use) and alcohol-related problems (social. vocational. physical. cognitive. and loss of control). The association between parental history of alcoholism and more severe alcoholism in the probands was independent of age of onset of alcoholism. current age. socioeconomic background. and marital status. Parental history positive (PH+) alcoholics were more reliant on alcohol to manage their moods but did not differ significantly from parental history negative (PH-) alcoholics in the use of alcohol to improve sociability or mental functioning or to cope with marital problems. Surprisingly. the degree of concern. guilt. and worry over the negative consequences of drinking was not significantly different for PH+ alcoholics although the negative consequences were clearly much more severe for this group. While the data are inconclusive about the reasons for more severe alcoholism in PH+ alcoholics. greater reliance on ethanol to manage moods and a relative insensitivity to negative consequences could theoretically account for the vulnerability to more severe alcoholism found in PH+ alcoholics.
Effect of abstinence from alcohol on the depression of glutathione peroxidase activity and selenium and vitamin E levels in chronic alcoholic patients, Glutathione peroxidase activity and selenium and vitamin E levels were measured in the plasma and erythrocytes of 25 chronic alcoholic patients without liver cirrhosis before and after 14 days of abstinence from alcohol. and compared with the levels in 25 sex- and age-matched healthy controls. Before abstinence. all three levels were shown significantly depressed in the alcoholic patients compared with the controls. in both plasma (80. 71. and 89% of control values) and erythrocytes (68. 70. and 83% of control values). After a 14-day abstinence period with no dietary supplementation. a trend towards normalization was noted in erythrocyte (vitamin E and glutathione peroxidase 74 and 91% of control values respectively). in whole blood selenium (82%) and plasma in vitamin E (74%). However. plasma selenium and glutathione peroxidase values were lower than pre-abstinence values (76% and 86% of control values respectively). Our results point to a deficiency in the antioxidant defense system of chronic alcoholics before the occurrence of severe liver disease. This lack of protection against lipoperoxides is all the more important in circumstances like chronic alcohol consumption. in which lipid peroxidation is known to increase. However. the present study also demonstrated that during 14 days of a normal diet free of ethanol. a rapid trend occurred towards the normalization of the factors.
Cutaneous vasomotor sensitivity to ethanol and acetaldehyde: subtypes of alcohol-flushing response among Chinese, A cutaneous test has been applied in examination of the flushing response to ethanol and acetaldehyde in 402 Chinese of Han ethnicity. Using this noninvasive method. five response subtypes have been observed: (A) fast flushing to both ethanol and acetaldehyde; (B) fast flushing only to ethanol but not to acetaldehyde; (C) slow flushing to ethanol only; (D) no response either to ethanol or to acetaldehyde; (E) vasoconstriction to ethanol. or to both ethanol and acetaldehyde. A total of 94% in subtype (A) are reported to be flushers. while only 25% was reported in subtype (D). Other physiological responses. such as tachycardia. dizziness. headache. drowsiness. and nausea are less frequent after alcohol ingestion. The recent history of consumption of alcohol of the subjects in different subtypes was also obtained. Although alcohol-induced flushing is thought to be a deterrent factor to heavy consumption of alcohol. the frequency of drinking of alcoholic beverages was not found to be different between flushers and nonflushers.
Isoflurane partially preserves energy balance in isolated hepatocytes during in vitro anoxia, We investigated whether a volatile anesthetic (1.5% isoflurane or 1.0% halothane) or an added anaerobic energy source (10 mM glucose or fructose) could act directly on liver cells to protect energy status during 20-30 min of anoxia. We used hepatocytes freshly isolated from fed rats or rats that had fasted. suspended them in Krebs' buffer. and incubated them in sealed flasks under O2/CO2 or N2/CO2 (95%:5%). The adenosine triphosphate (ATP) to adenosine diphosphate (ADP) ratio (ATP/ADP) measured cellular energy balance--the balance between overall ATP supply and demand. Lactate levels measured the extent to which ATP was supplied by the nonmitochondrial pathway. (anaerobic) glycolysis. Maximum values of energy balance were seen in cells from fed rats incubated in the presence of glucose and O2. When glucose was replaced by fructose. ATP/ADP decreased and lactate increased. During anoxia (O2 replaced by N2). increases in lactate were also seen with glucose; and ATP/ADP decreased to similarly low values with both substrates. In cells from fasted rats. ATP/ADP decreased significantly below the value for cells from fed rats only in the presence of glucose and O2. Compared with cells from fed rats. cells from fasted rats showed decreased lactate in the face of decreased ATP/ADP. suggesting that glycolysis was impaired. Isoflurane partially prevented anoxia-induced decreases in ATP/ADP. This protective effect on energy balance occurred equally with glucose and fructose. but was not seen in cells from fasted rats or with halothane. Thus. 1 MAC isoflurane and some factor(s) related to the fed state combined to protect partially the energy balance in anoxic liver cells through action(s) at the cellular level.
Intratracheal surfactant administration restores gas exchange in experimental adult respiratory distress syndrome associated with viral pneumonia, The effect of intratracheal surfactant administration was studied in rats with adult respiratory distress syndrome associated with infection with nebulized Sendai virus. Thirty-six hours after infection. animals (n = 7) showed severely impaired gas exchange and acidosis during artificial ventilation (PaO2 = 152.2 +/- 18.7. PaCO2 = 65.3 +/- 19.2. pH = 7.26 +/- 0.11) with a pressure-controlled mode. standard frequency of 35/min. peak airway pressure of 15 cm H2O (15/0). inspiratory/expiratory ratio of 1:2. and F1O2 = 1. Gas exchange improved (P = 0.02) with increased ventilator pressures with PEEP (25/4). Forty-eight hours after infection. blood gas tensions could no longer be significantly improved by these same ventilator settings (PaO2 = 123.8 +/- 31.0. PaCO2 = 95.1 +/- 43.6. pH = 7.12 +/- 0.16. n = 9). At this time. surfactant replacement dramatically increased arterial oxygenation within 5 min (PaO2 = 389.4 +/- 79.9) and resulted in a fourfold increase in PaO2 within 2 h. It is concluded that intratracheal surfactant administration is a promising approach in the treatment of respiratory failure during adult respiratory distress syndrome associated with viral pneumonia.
Effect of halothane on arrhythmogenic responses induced by sympathomimetic agents in single rat heart cells, The combination of catecholamines and halothane has long been recognized as arrhythmogenic. The purpose of this study was to evaluate whether the mechanism of this interaction originates at the single cell level. The incidence of spontaneous contractile waves occurring between stimulated beats (interbeat waves). early aftercontractions. and late aftercontractions was measured in rat myocytes exposed to sympathomimetics with and without halothane. Each of these endpoints in single cells has the potential to produce arrhythmias in multicellular preparations. Interbeat waves and late aftercontractions were observed with isoproterenol (1 X 10(-7) M) and norepinephrine (1-3 X 10(-7) M). The incidence of these phenomena was significantly reduced in the presence of 0.30 mM halothane. Early aftercontractions occurred in the presence of isoproterenol (1 X 10(-7) M). norepinephrine (1-3 X 10(-7) M). and phenylephrine (5-10 X 10(-6) M). There was a statistically significant decrease in the incidence of early aftercontractions in the presence of 0.30 mM halothane. These results indicate that the mechanism behind the clinically observed increased arrhythmogenicity of catecholamines with halothane does not arise at the level of single ventricular cells because halothane inhibited sympathomimetic-induced arrhythmogenic activity in this model. The probable mechanisms rather include altered impulse propagation. which might lead to phenomena such as reentry.
Effects of nitrous oxide on coronary pressure and regional contractile function in experimental myocardial ischemia, To determine whether nitrous oxide (N2O) worsens myocardial ischemia by diminishing coronary pressure. we performed two sets of experiments using an acutely instrumented swine model of regional coronary ischemia. In constant pressure experiments (n = 11). coronary pressure and heart rate were kept constant as N2O (77%-79%) was substituted for N2 in the inspired gas. Nitrous oxide decreased systolic shortening. measured by sonomicrometry. from 68.0% to 63.6% (P less than 0.05) of preischemic control values in the ischemic zone and from 116.2% to 103.2% (P less than 0.05) of control values in the adjacent normal myocardium. There was no disproportionate effect of N2O on ischemic myocardium. and the N2O-induced depression of contractile function was fully reversible. In a series of constant external stenosis experiments (n = 13). the effects of N2O on heart rate. mean arterial pressure. and the coronary stenosis itself were not controlled. In these experiments. substitution of N2O for N2 induced deterioration in both the ischemic zone (systolic shortening decreased from 68.7% to 58.4% of preischemic control values. P less than 0.05) and in the adjacent normal myocardium (systolic shortening decreased from 113% to 102.9% of preischemic control. P less than 0.05). Nitrous-oxide-induced ischemic zone contractile dysfunction was often not reversible. The pressure gradient across the coronary stenosis did not increase and peripheral coronary pressure did not decrease because of N2O. Diffusion hypoxia was also excluded. This study confirms that N2O has a significant but mild depressant effect on the performance of both normal and ischemic myocardium.
Droperidol prevents serotonin-induced bronchospasm in the guinea pig, The effects of droperidol on bronchoconstriction induced by serotonin (5-HT) were studied in mechanically ventilated. paralyzed guinea pigs that had been anesthetized with pentobarbital. Droperidol did not modify the resting bronchial tone but prevented the bronchoconstrictor effects of 5-HT in a dose-related manner. Pretreatment with propranolol. hexamethonium. or prazosin did not alter the protective effects of droperidol on 5-HT-induced bronchoconstriction. The bronchoconstrictor responses to histamine or acetylcholine were not affected by droperidol. These results suggest that the protective effects of droperidol on 5-HT-induced bronchoconstriction are mediated through 5-HT receptor blockade on bronchial smooth muscle.
Prolongation of the pharmacologic effect of intrathecal meperidine by the use of a lipid solution of it, The possibility of prolonging the effect of intrathecally injected meperidine by the use of a lipid solution was examined in this study. An aqueous solution of 5% meperidine HCl. 250 micrograms/kg. and an equimolar solution of meperidine dissolved in iophendylate (Pantopaque) were injected subarachnoidally in two groups of rabbits (n = 9 in each) with chronically implanted catheters in the subarachnoid space at the level of L7-8. The effect of each injection was assessed by evaluation of the pain threshold in the animal's hind limbs and of the degree of motor blockade produced. The duration of analgesia and of motor blockade were significantly longer when the lipid solution was used. Six of nine animals that received the aqueous solution of 5% meperidine HCl exhibited temporary signs of agitation (i.e.. biting of hind limbs). None of the animals given the lipid solution of the drug did. The findings are attributed to the slow release of meperidine from the lipid phase that serves as a drug depot in the cerebrospinal fluid. The approach presented is suggested as a basis for the development of lipid solutions that might prolong the duration of spinal analgesia produced by a single intrathecal injection.
An alternative strategy for infection control of anesthesia breathing circuits: a laboratory assessment of the Pall HME Filter, Contaminated breathing systems have been responsible for nosocomial upper respiratory tract and pulmonary infections in patients undergoing general anesthesia. The current infection control guidelines for anesthesia breathing circuits require single-patient use or high-level disinfection of breathing tubes. y-connector. and reservoir bag. An alternative infection control strategy has been suggested that incorporates placement of a microbial filter downstream from the y-connector between the circuit and the patient. This laboratory study assessed the capacity of the Pall HME Filter as a bidirectional barrier to transmission of bacteria between the y-connector of an anesthesia circle breathing system and a test lung. The investigators modified a sterile circle system to allow aerosolization of a suspension of 10(9) Micrococcus luteus over 5 h into the inspiratory limb proximal to the y-connector or downstream from the filter into the test lung. Cultures indicated that the Pall HME Filter placed between the y-connector and the test lung completely prevented transmission of bacteria in both directions. The results of this study suggest that the Pall HME Filter could be used as an effective microbial barrier between the anesthesia circle breathing system and the patient as part of an alternative strategy for infection control.
Pentamorphone for management of postoperative pain, The efficacy. duration. and safety of the synthetic opioid pentamorphone in the treatment of acute postoperative pain were evaluated in a randomized. double-blind study of 72 patients given 0.08. 0.16. or 0.24 micrograms/kg of pentamorphone or a placebo intravenously in the recovery room after major abdominal or orthopedic surgery. Only patients given 0.24 micrograms/kg of pentamorphone experienced decreased pain intensity and increased sedation. both transient in duration. Although the two higher doses of pentamorphone delayed the patient's request for supplemental morphine. the total amount of morphine required within the first hour was not different between treatments. No acute cardiorespiratory changes were observed. Pentamorphone (0.08-0.24 micrograms/kg) was ineffective for treating acute postoperative pain after major surgery.
Alterations in erythrocyte rheology in patients with severe peripheral vascular disease: 1. Cell volume dependence of erythrocyte rigidity, The erythrocyte rigidity of patients suffering from severe peripheral vascular disease (PVD) was measured by a filtration method using 3 microns pore size filters. Filtration pressures for both PVD patients and normal subjects showed a cell volume dependency. and patient filtration pressures were normalized to cell volume to evaluate intrinsic. ie. nonvolume dependent. abnormalities in erythrocyte deformability. A significant (p less than 0.001) increase in cell rigidity was found in 44 of 54 PVD patients in comparison with volume-matched normal controls. No significant difference was found between patient mean corpusculer hemoglobin (MCH) and normal MCH at any given mean corpuscular volume (MCV). indicating that observed increases in erythrocyte rigidity are not attributable to changes in patient MCH. Therefore. the mechanism of increase in erythrocyte rigidity for PVD patients still needs further investigation into such parameters as levels of adenosine triphosphate.2.3-DPG. and membrane fluidity (calcium- and/or protein-binding membrane. cholesterol and phospholipid content of membrane. etc). as well as other aspects of erythrocyte physiology.
The use of ionic and nonionic contrast agents and the effects of hydration in the post cardiac transplant patient with moderate renal insufficiency, To determine the effects of ionic (diatrizoate) and nonionic (iopamidol) contrast and of hydration. 90 asymptomatic cyclosporine-treated cardiac transplant patients with moderate renal insufficiency (serum creatinine greater than or equal to 1.5 mg/dL) undergoing cardiac catheterization were evaluated. All patients were hydrated with intravenous fluid (5% dextrose and 0.5 normal saline) over a twelve-hour period prior to catheterization and with oral fluids thereafter. Thirty patients received iopamidol (Group I) and 60 were given diatrizoate (Group II). Renal function was determined the day before and after catheterization in all patients of Group I and in 30 patients of Group II (Group IIa). In the remaining 30 patients of Group II renal function was also determined before contrast administration (Group IIb). The dose of dye was similar in all groups (I: 139 +/- 55 mL. IIa: 140 +/- 58 mL. IIb: 128 +/- 38 mL). There was a significant decrease in BUN (I: 41 +/- 10 to 33 +/- 8 mg/dL [p less than 0.005]. IIa: 42 +/- 9 to 33 +/- 8 mg/dL mg/dL [p less than 0.001]. IIb: (44 +/- 12 to 34 +/- 10 mg/dL [p less than 0.005]) and a small decrease in serum cratinine after catheterization (I: 2.0 +/- 0.3 to 1.9 +/- 0.3 mg/dL. IId: 2.0 +/- 0.3 to 1.9 +/- 0.3 mg/dL. IIb: 2.1 +/- 0.4 to 1.8 +/- 0.4 mg/dL [p less than 0.005].
Investigations on the biochemical characteristics of chronically underperfused muscle, During operation. biopsies from the gastrocnemius muscle and. in some cases. from the sartorius muscle were taken from 32 patients with peripheral arterial occlusive disease and from 5 subjects with normal peripheral circulation. In patients with inadequate circulation only during exercise. when compared with the control group. increased activities of enzymes involved in oxidative metabolism (malate dehydrogenase. nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase. cytochrome C oxidase. creatine kinase). in amino acid metabolism (asparate aminotransferase. alanine aminotransferase). and in anaerobic glycoysis (lactate dehydrogenase) were found. In patients with circulatory disturbances that manifested themselves already at rest. enzyme activities were. with the exception of LDH. lower than those of patients with exclusively exercise-related insufficiency. By means of intraindividual comparisons with the corresponding enzyme activities in the sartorius muscle. the author was able to show that the changes found were not simply the result of differences in training conditions. The diminished concentrations of energy-rich phosphate are an expression of the anaerobic metabolic state in patients with inadequate circulation at rest. It is concluded that chronic ischemia of muscle leads to changes in the energy metabolism of the cell. In the presence of more nearly adequate circulation at rest. the portion of oxidative potential of the total energy metabolism increases. In contrast. if there is an inadequate circulation at rest. the mainly anaerobic glycolysis becomes quantitatively predominant.
The role of platelet-activating factor in asthma, There is a large body of in vitro. animal. and now human data that provide strong support for PAF as being an important mediator of asthma and airway hyperreactivity. Unfortunately. there is little direct. unequivocal evidence that this is so. Direct evidence will come from studies that test the effectiveness of potent. nontoxic. PAF receptor antagonists in patients with asthma. Another issue that needs to be addressed is the mechanism by which PAF produces bronchoconstriction and. in particular. airway hyperreactivity. Studies exploring the effect of PAF on inflammatory cell populations and functions in the lung. on other mediators (i.e.. leukotrienes). and on the nonadrenergic. noncholinergic nervous system in human subjects are needed. Finally. identification of the basis for the variable response to PAF in normal subjects and in patients with asthma should provide further insight into PAF's mechanism of action and the pathogenesis of asthma and airway hyperreactivity.
The role of leukotrienes in allergic rhinitis: a review, Leukotrienes are potent proinflammatory mediators. Our understanding of their role in allergic rhinitis has increased. but further. extensive investigation is required. The sulfidopeptide LTs are generated during the immediate response to antigen provocation and are probably increased during the late inflammatory phase and during seasonal exposure. The source of LTC4 in the early allergic reaction includes the mast cell. but other cell types may also contribute. LTD4 causes nasal congestion and increased blood flow. but not sneezing or significant rhinorrhea. Studies in which LT generation was pharmacologically reduced support a role for these mediators in allergic rhinitis. There is now a need to evaluate the more potent. recently developed. LT antagonists in rhinitis. These agents should help establish the relative importance of LTs to the many other inflammatory mediators that are implicated in the pathogenesis of allergic rhinitis. Such knowledge will broaden and improve our choice of therapeutic modalities for this disease.
Recurrent laryngeal nerve section for spastic dysphonia: 5- to 14-year preliminary results in the first 300 patients, This presentation compares the preoperative voice recordings and the latest follow-up voice recordings. made 5 to 14 years postoperatively. of the first 300 patients with various degrees of spastic dysphonia whom we treated with recurrent laryngeal nerve (RLN) sections from 1975 to 1982. Voice therapy was usually given afterward and in some patients. when necessary. "fine tuning" surgery was performed later. The 243 patients who could be located were asked to answer a questionnaire regarding their voice production and communication abilities. and to make a voice recording. The preoperative and long-term postoperative voice recordings were analyzed by means of perceptual voice evaluation and acoustic analysis of the voice spectra. Fifteen percent developed recurrence of mild to moderate spasticity 6 to 24 months after the RLN section. This was curable with laser vocal cord thinning via direct laryngoscopy. Eighty-two percent of patients had little or no voice spasticity 5 to 14 years after their RLN section. The experimental alternative of injecting botulin directly into the vocal cord to temporarily paralyze it is discussed.
Vocal fold medialization by surgical augmentation versus arytenoid adduction in the in vivo canine model, There are a variety of methods for treating unilateral vocal cord paralysis. but to date there have been few studies that compare these phonosurgical techniques by using objective measures of voice improvement. Vocal efficiency is an objective voice measure that is defined as the ratio of the acoustic power produced by the larynx to the subglottic air power. Vocal efficiency has been found to decrease with glottic disorders such as vocal cord paralysis and carcinoma. This study compared the effects of vocal fold medialization by surgical augmentation to those of arytenoid adduction on the vocal efficiency. videostroboscopy. and acoustics (jitter. shimmer. and signal-to-noise ratio) of a simulated unilateral vocal cord paralysis in an in vivo canine model. Arytenoid adduction was superior to surgical augmentation in vocal efficiency. traveling wave motion. and acoustics.
Cellular changes in Reissner's membrane in endolymphatic hydrops, A quantitative morphologic study of the cellular changes in human Reissner's membrane (RM) was performed under light microscopy on 30 normal temporal bones from 15 subjects. and on 20 temporal bones from 10 subjects with endolymphatic hydrops. The cellular density of the epithelial and mesothelial layers of normal RMs decreased with increasing age. In endolymphatic hydrops. cellular proliferation and decreased cellular density of a distended RM were observed. and these changes occurred more remarkably in epithelial cells. Decreased cellular density in RM was correlated to the degree of endolymphatic hydrops. These findings indicate an involvement of the epithelial cellular changes in the pathogenesis of endolymphatic hydrops. Our results suggest that cellular changes in RM may cause dysfunction of radial flow leading to ionic disturbance of endolymph. which provides a possible mechanism of hearing loss in endolymphatic hydrops.
Esophageal foreign bodies in children. 15-year review of 484 cases, The findings of a retrospective analysis of the charts of 426 children admitted on 484 occasions with diagnoses of esophageal foreign bodies that were managed at the Hospital for Sick Children for 15 years to the end of 1989 are reported. In the majority of cases. ingestion of the foreign body was either witnessed or suspected. Removal was completed with the use of general anesthesia with endotracheal intubation in 90% of cases. The postcricoid area was the commonest site for impaction. Coins were the commonest foreign body. Approximately 5% of children had more than one foreign body. Fifty-nine children had esophageal anomalies. Thoracotomy or laparotomy for the retrieval of foreign bodies was necessary in less than 1% of patients. Complications occurred in 13% of patients; there were no deaths.
Neonatal and pediatric microsubglottiscope set, A microsubglottiscope for infants and children has been developed for microlaryngeal surgery in the glottic and subglottic regions of the larynx. The universal handle allows selection of several sizes of blades to be used according to the patient's anatomic limitations. The tips of these blades have been designed specifically to give exposure to the subglottis and upper trachea under microscopic magnification. A needle adapter for jet ventilation has been included. The authors have used this instrument in young infants and children for diagnosis and for laser resection of subglottic stenosis. hemangioma. and suprastomal granuloma. and have found the exposure to be superior to that obtained with conventional microlaryngoscopes.
Tinnitus: the hidden epidemic. A patient's perspective, The author describes his personal experience with tinnitus as well as various medical practitioners. He also discusses possible avenues for tinnitus research and suggests educational efforts that otolaryngology organizations might initiate.
Leiomyosarcoma of the trachea. Case report, Leiomyosarcoma of the trachea is a rare primary tumor of the upper airway. Twelve cases have been reported in the English-language literature. Our experience with a patient with leiomyosarcoma of the cervical trachea is presented. The classic symptoms. diagnosis. and surgical management of this case are contrasted with those of the previously reported cases. The surgical technique used for our patient. primary tumor resection with skin grafting and placement of a Montgomery Laryngeal Stent. is a unique and effective treatment.
Oral monomorphic adenomas, Monomorphic adenomas of the oral cavity have a predilection for the anterior mouth. particularly the upper lip. Two of the monomorphic adenomas. the inverted ductal papilloma and the canalicular adenoma. are biologically benign. but unfamiliarity with their histopathologic appearance can lead to a misdiagnosis of malignancy. The clinical and pathologic features of each are presented.
Pharmacokinetics of ceftazidime in serum and suction blister fluid during continuous and intermittent infusions in healthy volunteers, The pharmacokinetics of ceftazidime were investigated during intermittent (II) and continuous (CI) infusion in eight healthy male volunteers in a crossover fashion. The total daily dose was 75 mg/kg of body weight per 24 h in both regimens. given in three doses of 25 mg/kg/8 h (II) or 60 mg/kg/24 h with 15 mg/kg as a loading dose (CI). After the third dose (II) and during CI. serum and blister fluid samples were taken. Seven new blisters were raised for each timed sample by a suction blister technique. Blisters took 90 min to form. Samples were then taken from four blisters (A samples) and 1 h later were taken from the remaining three (B samples). The concentration of ceftazidime was determined using a high-performance liquid chromatography method. After II. the concentrations in serum immediately after infusion (t = 30 min) and 8 h after the start of the infusion were 137.9 (standard deviation [SD]. 27.5) and 4.0 (SD. 0.7) micrograms/ml. respectively. The half-life at alpha phase (t1/2 alpha) was 9.6 min (SD. 4.6). t1/2 beta was 94.8 min (SD. 5.4). area under the concentration-time curve (AUC) was 285.4 micrograms.h/ml (SD. 22.7). total body clearance was 0.115 liter/h.kg (SD. 0.022). and volume of distribution at steady state was 0.178 liter/kg (SD. 0.023). The blister fluid (A) samples showed a decline in concentration parallel to that of the concentrations in serum during the elimination phase with a ratio of 1:1. The t1/2 of the A samples was 96.4 min (SD. 3.2).
Comparative in vitro and in vivo activities of six new monofluoroquinolone and difluoroquinolone 3-carboxylic acids with a 7-azetidin ring substituent, E-4502. E-4501. E-4500. E-4480. E-4474. and E-4441 are new monofluorinated or difluorinated quinolone agents that are chemically characterized by the presence of an azetidin ring. with different C'-3 substituents. at position 7 of the molecular structure. The MICs of the difluorinated compounds E-4501. E-4474. and E-4441 for 90% of isolates were 0.06 to 1. 0.06 to 1. and 0.12 to 1 microgram/ml. respectively. against gram-positive organisms (staphylococci. streptococci. and Enterococcus faecalis); 0.0015 to 0.12. 0.015 to 0.12. and 0.03 to 0.12 microgram/ml. respectively. against members of the family Enterobacteriaceae except Providencia spp.; and 1. 1. and 2 micrograms/ml. respectively. against Pseudomonas aeruginosa. E-4501. E-4474. and E-4441 inhibited all anaerobic bacteria at concentrations of 1. 2. and 4 micrograms/ml. respectively. Difluorinated compounds were significantly more active than the corresponding monofluorinated analogs E-4502. E-4500. and E-4480 against aerobic and facultatively anaerobic organisms. as well as against anaerobes. Considering monofluorinated and difluorinated compounds. activity in moderate ascending order was observed in quinolones containing an amine and a methyl group (E-4441 and E-4480). an amine group (E-4474 and E-4500). and a methylamine group (E-4501 and E-4502) in the C'-3 position of the azetidin ring. E-4501. E-4474. and E-4441 were more active than norfloxacin and DR-3355 [S-(-)-ofloxacin]. had activities comparable to or slightly lower than that of ciprofloxacin against gram-negative bacteria. and were more active than all the reference quinolones against gram-positive organisms and anaerobes.
Activities of pefloxacin and ciprofloxacin against experimental malaria in mice, We investigated the in vivo antimalarial activities of pefloxacin and ciprofloxacin in Swiss albino mice infected intravenously with 5 x 10(6) Plasmodium yoelii N67 parasites 1 h before treatment. Groups of 20 mice received a subcutaneous injection of 40. 80. or 160 mg of ciprofloxacin or pefloxacin per kg of body weight every 8 h for 3 days. Parasitologic activity was assessed on day 4. and survival was assessed on day 21. Control mice had a fulminant course with a parasitemia of 61.3% +/- 12.1% on day 4. and 90% of the mice were dead on day 21. The lower dosages of pefloxacin and ciprofloxacin (40 and 80 mg/kg) were not efficient. With 160 mg/kg. ciprofloxacin achieved an 85.8% reduction in parasitemia and 17 of 20 mice survived. Pefloxacin achieved a 92.8% reduction in parasitemia. and all mice survived. All treated. noninfected control mice survived. With ciprofloxacin. the antimalarial activity was similar with injections of 240 mg/kg every 12 h but was strongly diminished with injections of 160 mg/kg every 12 h. With pefloxacin. similar activities were observed with injections of 160 mg/kg every 8 h or injections of 160 or 240 mg/kg every 12 h. With both drugs. this activity was highly reduced when the treatment was delayed by 24 h. This underlines the need to provide treatment within the first hours after infection to achieve an optimal effect in this rapidly lethal experimental model of malaria. Pefloxacin and. to a lesser extent. ciprofloxacin are potent antimalarial drugs which might prove useful in the treatment of less rapidly aggressive human malaria.
Pharmacokinetics of lomefloxacin in renally compromised patients, The single-dose pharmacokinetics of orally administered lomefloxacin (400 mg) were studied in normal subjects and in patients with various degrees of renal function. The subjects were classified by creatinine clearance (CLCR) normalized for body surface area: group 1. CLCR of greater than 80 ml/min/1.73 m2; group 2. CLCR of 80 to greater than 40 ml/min/1.73 m2; group 3. CLCR of 40 to greater than 10 ml/min/1.73 m2; and group 4. CLCR of less than or equal to 10 ml/min/1.73 m2. Each group consisted of eight subjects. The pharmacokinetics of lomefloxacin were significantly influenced by renal function. There were significant differences in the elimination rate constant. half-life. area under the concentration-time curve from 0 h to infinity. apparent total drug clearance. renal clearance. and apparent nonrenal drug clearance between the four renal function groups. Mean half-lives for groups 1. 2. 3. and 4 were 8.09. 9.11. 20.90. and 44.25 h. respectively. There were no significant differences between the renal groups for maximum concentration of the drug in serum and apparent volume of distribution. Age had no apparent effect on lomefloxacin disposition. There was a significant relationship between CLCR and lomefloxacin total body clearance (r = 0.92. P = 0.001) and renal clearance (r = 0.94. P = 0.001). Despite a predominate renal route of elimination. nonrenal lomefloxacin clearance significantly decreased with decreasing renal function (r = 0.72. P = 0.001). Mean lomefloxacin excretion rates over 48 h were 60.7. 56.0. 29.1. and 1.0% of the administered dose for groups 1. 2. 3. and 4. respectively.
Effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against herpes simplex virus type 1 infection in immunosuppressed mice, 1-beta-D-Arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) reduced the mortality rates of (i) 7-week-old. cyclophosphamide-treated. immunosuppressed mice (CYP mice) intraperitoneally infected with a moderately virulent strain of herpes simplex virus type 1 and (ii) 4-week-old CYP mice infected with a less virulent strain at doses of 20 and 50 mg/kg of body weight twice daily and 5 mg/kg. respectively. The degree of efficacy of BV-araU was equivalent to that of acyclovir in 4-week-old CYP mice infected with the less virulent strain. BV-araU (20 mg/kg) suppressed viral growth in various organs of CYP mice.
Penicillinase production and in vitro susceptibilities of Staphylococcus lugdunensis, Of 59 clinical isolates of Staphylococcus lugdunensis. 76% were beta-lactamase negative. with penicillin G MICs of less than or equal to 0.13 microgram/ml. and 24% were beta-lactamase positive. with penicillin MICs of greater than or equal to 0.5 microgram/ml. Bimodal distributions were observed also with ampicillin. ampicillin-sulbactam. and amoxicillin-clavulanate. All strains were susceptible to oxacillin. cephalothin. gentamicin. rifampin. and vancomycin; 98% were erythromycin susceptible.
Serum endothelin-1 concentrations and cold provocation in primary Raynaud's phenomenon, To determine whether the vasoconstriction in Raynaud's phenomenon is associated with raised concentrations of the endothelium-derived vasoconstrictor endothelin (ET-1). responses to cold pressor testing were examined in 7 subjects with primary Raynaud's phenomenon and in 7 control subjects. Baseline serum ET-1 levels (pg/ml). as measured by radioimmunoassay. were three times higher in Raynaud's subjects (5.3 [SEM 1.7] pg/ml) than in controls (1.7 [0.3]). With progressive local cooling digital arterial pulsatility. as measured by plethysmography. fell earlier and to a greater extent in Raynaud's subjects than in controls. with a half-maximum decrement in pulsatility occurring at 27 [2.6] degrees C and 18 [0.5] degrees C. respectively. Temperature reduction sufficient to cause loss of pulsatility in the Raynaud's subjects produced increases in ET-1 concentrations in both groups that were greater in Raynaud's (10.3 [4.4] pg/ml) than in control subjects (2.7 [0.9] pg/ml). Serum ET-1 in the contralateral arm rose in parallel to but to a lesser extent than that in the cold-challenged arm. Increases in ET-1 concentrations were temporally related to loss of pulsatility but followed the onset of symptoms. Thus the increased basal and stimulated serum endothelin concentrations in Raynaud's disease are associated with the enhanced. prolonged vasospasm of this disorder.
Ethanol-induced inhibition of testosterone biosynthesis in rat Leydig cells: role of mitochondrial substrate shuttles and citrate, The mechanisms by which ethanol inhibits testicular testosterone synthesis in rats were studied in vitro using isolated rat Leydig cells. The ethanol-induced inhibition was reversed by 4-methylpyrazole. an alcohol dehydrogenase inhibitor. suggesting that ethanol metabolism was responsible for this inhibition. L-glutamate and pyruvate. when added to the Krebs-Ringer incubation medium. reversed the inhibition by ethanol. The membrane glutamate receptor agonists kainic acid and quisqualic acid had no effects. indicating metabolic mechanisms for the L-glutamate action. This was verified also by observations that the metabolic transaminase inhibitors aminooxyacetate and cycloserine inhibited testosterone synthesis. In the amino acid supplemented Krebs-Ringer. pyruvate could not fully prevent inhibition by ethanol alone. but addition of L-glutamate to this medium abolished ethanol-induced inhibition. Experiments performed using a new inhibitor of testosterone biosynthesis in intact Leydig cells. triethylcitrate. indicated that active citrate metabolism. and/or efflux from mitochondria. was essential for the steroidogenic pathway from pregnenolone to testosterone in the smooth endoplasmic reticulum. The early steps of hCG stimulation before pregnenolone formation were most sensitive to its effect. Our results indicate that the inhibition of steroidogenesis by ethanol results from decreased availability of the metabolites involved in the substrate shuttles maintaining the NAD(P)H redox states between the mitochondrial and the smooth endoplasmic reticulum compartments. and that the inhibition can be overcome by a proper selection of exogenous sources for these metabolites.
Functional and structural adaptation of the parotid gland to medium-term chronic ethanol exposure in the rat, Male rats were maintained on a regimen of twice daily intragastric administration of ethanol or a calorifically equivalent sucrose solution for thirty days. A second control group received no intragastric solution and all groups received chow and water ad libitum. Parotid saliva elicited by pilocarpine was collected by unilateral duct cannulation. The parotid flow rate over the initial post-stimulatory five minute period was raised by 44% in ethanol-dosed rats and the salivary sodium concentration was also raised. in line with higher flow rate. There were no histopathological changes related to ethanol or sucrose dosing. but stereological analysis showed a 64% increase in the proportional volume of intralobular vascular tissue in ethanol-dosed rats. These quantified histological findings suggest that parotid intralobular haemodynamics may be altered after chronic ethanol-dosing and this may contribute to the hypersecretory response exhibited by the ethanol-dosed rats.
Abnormal low density lipoproteins composition in some chronic alcoholics: a possible mechanism, Decreased plasma low density lipoproteins (LDL) cholesterol and apolipoprotein B (apo B) levels are observed in heavy alcohol drinkers. LDL composition was determined in 16 alcohol addicts immediately after a period of alcohol abuse. Cholesterol to apo B ratio in the LDL fraction was significantly higher in the alcoholic group when compared with controls. In half of them the ratio exceeded 1.75. LDL subfractionation showed that in all subjects with atypically high LDL cholesterol to apolipoprotein B ratio. most of the LDL was in the form of a light subfraction. Acetylation in vitro showed that the heavy LDL subfraction was modified to a greater extent than the light subfraction. This suggests that the low apo B levels often observed after heavy drinking may arise from enhanced removal of the heavy LDL subfraction from the bloodstream.
Intellectual impairment in male alcoholics, The factors associated with intellectual impairment in male alcoholics have been studied in a group of subjects without the confounding complications of chronic alcoholism. It has been shown that intellectual impairment is dependent on the degree of subject anxiety and is independent of any co-existing biochemical disturbance. An hypothesis is offered to explain this observation.
Psychoactive substance use disorder in youth suicide, Fifty-eight consecutive suicides committed between 1984 and 1987 by adolescents and young adults (age 15-29 years) from an urban community were the subject of retrospective investigations through interviews with survivors and analyses of registers and medical records. Psychoactive substance use disorder in accordance with DSM-III-R was present in 47% of the youth suicides investigated. predominantly as alcohol dependence. Substance use disorder often coexisted with a borderline personality disorder or schizophrenia. Secondary depression was a frequent final factor. Dependence had developed in all females and most males. The median duration of substance use was 9 years. Substance use preceded suicidal behaviour by two years. Exposure to parental substance misuse during childhood. early parental divorce and parasuicide in the family were more frequent among subjects with substance use disorder than among other subjects. The social situation was often characterized by unemployment and legal problems. Previous inpatient care was more common than among other subjects.
Treatment of subungual hematomas with nail trephination: a prospective study, Subungual hematoma is a commonly encountered problem in the emergency department. We designed a prospective. observational study to determine if treatment of simple subungual hematomas (SUH) by nail trephination alone is without cosmetic or infectious complications. Over a 2-year study period. 48 patients met inclusion criteria. Radiographs of all digits were taken to detect distal phalangeal fracture and SUH size was measured. Nail trephination was performed using electrocautery. and all patients reported relief of pain after the procedure. Follow-up was achieved in 45 of 48 patients with a total of 47 SUH. Average follow-up period was 10.3 +/- 4.3 months. By patient history. average time for the nail to grow back was 4.0 +/- 2.6 months. No complications of infection. osteomyelitis. or major nail deformities occurred in any patients treated by nail trephination. regardless of SUH size or presence of fracture. In simple SUH. regardless of size. nail removal with suture repair of the nail bed. as suggested in previous studies. is unnecessary.
An evaluation of physiological parameters of stress in the emergency department, Seven physiological parameters previously used in stress research were studied to determine which would be able to quantitate levels of stress and study interventions in the emergency department setting. Eighteen emergency medicine personnel were prospectively studied. Sequential measurements of heart rate. respiratory rate. systolic blood pressure. diastolic blood pressure. skin temperature. serum norepinephrine. and serum epinephrine were recorded during multiple shifts in the emergency department. These parameters were assessed in repeated measures analysis of variance models with the subject's stress score of the shift and a calculated stress score of the shift. Respiratory rate demonstrated a significant association with the score of the shift over time within subjects (P = .0228). Skin temperature showed a significant trend over time (P = .0001) and in relation to how stressful the subject perceived the shift to be (P = .0006). A significant association was detected between epinephrine change over the shift and the subject's perception of the stress of the shift (P = .0217). and the stress score of the shift (P = .0009). Sequential serum epinephrine appears to be an objective measure of both perceived stressfulness of a shift and objective stress scoring of the shift. Respiratory rate changes and skin temperature changes over a shift may also be useful to measure stress in individuals in this setting.
Clinical comparison of ocular irrigation fluids following chemical injury, This study tested the hypothesis that four ocular irrigating solutions were equally irritating during copious irrigation. We conducted a prospective. double-blind study of patients with chemical exposure to the eye. Each underwent cross-over irrigation with all of the following in random order: normal saline (NS). lactated Ringer's (LR). normal saline adjusted to pH 7.4 with sodium bicarbonate (NS + Bicarb). and Balanced Saline Solution Plus (BSS Plus. Alcon Laboratories. Fort Worth. TX). Compared with traditional NS and LR. NS + Bicarb tended to be more comfortable. BSS Plus was statistically superior (P less than .05) to NS and preferred over LR and NS + Bicarb. Three patients demanded discontinuance of NS or NS + Bicarb infusions. All solutions had comparable normalization of conjunctival pH and degree of injection. Alternate solutions including BSS Plus should be considered for use in those patients whose poor tolerance to normal saline threatens to delay or interrupt eye irrigation following a chemical injury.
Emergency department management of thyrotoxic crisis with esmolol, A previously healthy 26-year-old woman presented to the emergency department complaining of a severe. throbbing. and bifrontal headache. Initial vital signs were pulse rate. 130 beats/min; blood pressure. 128/50 mm Hg; temperature. 100.1 degrees F. Shortly thereafter the patient's pulse and temperature increased to 170 beats/min and 103 degrees F. respectively. Physical examination showed a tremulous. anxious woman in moderate distress who had a diffusely and symmetrically enlarged thyroid gland. A diagnosis of thyrotoxic crisis was made. and appropriate therapy instituted. including the use of an esmolol infusion for control of hypersympathetic activity. A review of the clinical presentation. diagnosis. and management of thyrotoxic crisis is presented.
Dextromethorphan poisoning reversed by naloxone, Dextromethorphan. a common ingredient in cough syrups. has rarely been described to cause toxicity. The authors describe an unusual case of a known asthmatic presenting with somnolence. who appeared to be in end-stage respiratory failure. Her partial response to routine naloxone. 1 mg. was surprising. However. additional naloxone was required to completely normalize the patient's mental status. The authors suggest naloxone be administered in doses of 0.4 mg or more intravenously in suspected dextromethorphan overdose.
Massive bilateral diaphragmatic rupture after an apparently minor automobile accident, A case of massive bilateral diaphragmatic rupture following a low impact motor vehicle accident is described. The patient experienced herniation of intraabdominal contents into the thoracic cavity. but suffered no additional injuries. Few cases of bilateral diaphragmatic rupture have been reported and no cases of acute bilateral rupture have been described as an isolated injury. Diaphragmatic rupture in general may be a difficult injury to recognize. Based on our review of recent cases of diaphragmatic rupture (1979-1990). most patients presenting acutely have additional trauma (89.9%) but only vague symptoms related to their diaphragmatic insult. A chest roentgenogram may be a useful diagnostic tool. although many patients with diaphragmatic rupture have only nonspecific findings. A nasogastric tube placed prior to chest roentgenogram may enable the physician to recognize the injury more readily. A high index of suspicion is required to recognize diaphragmatic rupture and should be maintained for all victims of motor vehicle accidents with abnormal but nondiagnostic chest roentgenograms.
Disposition of spontaneous pneumomediastinum, In the evaluation of spontaneous pneumomediastinum. it is important to exclude pathological causes of pneumomediastinum. including Boerhaave's syndrome. which carries a high mortality rate. The literature varies greatly as to the care of patients with presumed spontaneous pneumomediastinum. The authors present an illustrative case of spontaneous pneumomediastinum treated with intravenous antibiotics and intensive care unit (ICU) admission despite a normal esophagram. Spontaneous pneumomediastinum is a benign entity that may not require observation in an ICU. and patients may do as well with close outpatient follow-up. For those patients in which the etiology of the pneumomediastinum is unclear. a contrast esophagram is recommended to assess for esophageal disruption. The signs. symptoms. pathophysiology. and disposition of spontaneous pneumomediastinum are discussed.
Emergency management of the nondeflating Foley catheter balloon, Inability to remove a self-retaining (Foley) catheter may result from failed attempts to deflate its balloon. In this article. the authors review the causes of inability to deflate Foley catheters as well as the various techniques for their removal.
Severe cyanide poisoning from the ingestion of an acetonitrile-containing cosmetic, A 39-year-old woman ingested 59 mL of Super Nail Nail Off (American International Industries. Hollywood. CA) (containing 99% acetonitrile) in a suicide attempt. Following a latent period of approximately 12 hours. the patient developed cyanide poisoning with severe metabolic acidosis. seizures. and shallow respirations. She responded to the administration of sodium nitrite and sodium thiosulfate. although the administration of nitrite produced bradycardia and hypotension. She developed several relapses over the course of her hospitalization and each time responded to sodium thiosulfate administration. The patient developed hypernatremia from the sodium load given to her; hemodialysis and charcoal hemoperfusion were initiated to correct the hypernatremia and to attempt to remove cyanide. thiocyanate. and acetonitrile. On the fifth hospital day. the patient was fully recovered and was discharged.
Cyanide toxicity from acetonitrile-containing false nail remover, A patient presented without symptoms 30 minutes after ingesting acetonitrile. also known as methylacyanide. He had prompt gastric lavage and activated charcoal administration. Hours later. the onset of clinical toxicity was heralded by mental status abnormalities and vomiting prior to a generalized seizure. Following administration of sodium thiosulfate. the patient made an uneventful recovery. A blood cyanide level drawn shortly after presentation. but reported after the patient had been discharged. documented significant exposure. During hospitalization. cyanide toxicity was inferred from the history of ingestion of acetonitrile. plus a significant absence of venous blood hemoglobin desaturation. Because even small amounts can be harmful and toxicity is delayed. all acetonitrile ingestions should be presumed dangerous. Patients should be observed and repeatedly evaluated for at least 24 hours. In the absence of cyanide level determinations. lethargy. vomiting. seizures. and the lack of normal venous blood hemoglobin desaturation are clues to cyanide toxicity.
Report of a WHO informal consultation on preclinical and clinical aspects of the use of immunomodulators in HIV infection. Geneva, 3-5 April 1989. World Health Organization Global Programme on AIDS, A wide spectrum of immunomodulatory strategies offer promise for treating people with HIV infection; however. numerous gaps still exist in our understanding of the normal regulation of the immune system during the progression of HIV infection. Preclinical development of immunomodulators must include a strong rationale for the use of the immunomodulating substance substantiated by appropriate laboratory studies. in vitro as well as in vivo. Preclinical studies must demonstrate the safety of the proposed therapeutic agent. including an assessment of the potential for adverse effects on immune function and virus replication. Combined therapeutic modalities should also be appropriately evaluated at the preclinical level. Clinical evaluations should be instituted only after a strong rationale is substantiated and safety concerns are fully considered. Initial studies should be conducted with patients at an intermediate stage of HIV disease progression. Immunomodulators may exhibit unusual dose-response patterns. and this should be considered when designing the trials. The consultation recommended that WHO continue to provide a forum for the timely exchange and validation of information related to the development and clinical evaluation of immunomodulators for the treatment of individuals infected with HIV.
Lymphocyte population changes in cats naturally infected with feline immunodeficiency virus, Feline immunodeficiency virus (FIV) is associated with feline acquired immunodeficiency syndrome (FAIDS) and has been suggested as a model for HIV-induced human AIDS. The most obvious immunological defect in HIV infection is a reduction in CD4+ cell numbers and an inversion of the CD4:CD8 ratio. To determine whether the same is true in FIV infection. we analyzed by flow cytometry using a panel of monoclonal antibodies to feline lymphocyte populations the CD4:CD8 ratios in cats naturally infected with the virus. We report that 13 of 19 FIV-infected cats had ratios below the 5th percentile of normal cats (0.57. established from analysis of 39 normal cats) and 18 of 19 had ratios below 1. Repeated analyses over a period of several months revealed the inverted ratios to be consistent. Analysis of lymphocyte numbers in FIV-infected cats shows that the inverted ratios are due to a decrease in CD4+ T cells. while CD8+ T and B cells remain relatively normal in number. Analysis of a group of cats with a variety of other chronic diseases. including feline leukemia virus (FeLV) infections. revealed a near-normal distribution of CD4:CD8 ratios. These findings are similar to those in HIV infections and indicate that. like HIV. FIV causes a selective reduction in CD4+ cells and should be an excellent model for studying retrovirus-induced AIDS.
Induction of feline immunodeficiency syndrome by feline leukemia virus: pituitary and adrenocortical dysfunctions, Seven young cats were injected with feline leukemia virus (FeLV); six of them became viremic. All of the viremic cats developed AIDS-related symptoms. i.e. lymphopenia. neutropenia. thymic atrophy. and wasting syndrome. along with an altered pituitary and adrenocortical function. These symptoms closely resemble human AIDS induced by HIV. It was discovered that. after 2 weeks of infection. the average amount of plasma adrenocorticotropic hormone (ACTH) detected in the infected cats was reduced by 29% in comparison with that before the infection. In contrast to the second week. the fifth week of infection showed a 94% increase of plasma ACTH which then dropped back down to 38% after the sixth and seventh weeks. This opposing biphasic pattern of change was also observed in the plasma cortisol content of the infected cats. The amount of change in plasma cortisol did not correlate with the detected increase in plasma ACTH. indicating a weak adrenal response to pituitary action.
Isolation of HIV-1 from seropositive people living in Cotonou, Benin, Benin is located in West Africa and is situated between HIV-2 and HIV-1-endemic zones. The first cases of HIV-1 infection in Benin were reported in 1987. Since then. AIDS cases have been diagnosed there and the number of known HIV-seropositive people has rapidly increased. Blood samples were collected from 14 seropositive and 11 seronegative patients living in the main city. Cotonou. and their peripheral blood mononuclear cells were cultured. In seven of the seropositive cases. a retrovirus was detected by measurement of Mg2(+)-dependent reverse transcriptase activity and electron microscopy. HIV-1 antigen assay and genomic analysis indicated that the isolated viruses belong to the first serotype. In each positive case. an HIV-1 DNA probe hybridized to the RNA extracted from the virus and six isolates were found positive by the polymerase chain reaction using HIV-1-specific primers.
AIDS and HIV infection in Uganda--are more women infected than men, In countries in sub-Saharan Africa. HIV is transmitted primarily heterosexually. HIV infection and AIDS in women not only affects women's health but also has implications for the other members of society. Maternal infection is the source of most childhood HIV infection in Africa and maternal health is a strong predictor of child survival. In Uganda. a review of passive AIDS surveillance has shown almost equal numbers of clinical cases reported in men and women. However. in three population-based HIV serosurveys. women were consistently found to have a higher infection rate (approximately 1.4 times) than men. In addition. both AIDS case surveillance and seroprevalence studies demonstrate an earlier age of presentation and mean age of infection in women. The higher rate of HIV infection in women suggests either differential rates of transmission between women and men. higher rates of female sexual exposure to infected men. or longer survival among HIV-infected women compared with men. Although further studies are required to illuminate both the biology and the epidemiology of heterosexual HIV transmission in Africa. these findings of earlier and higher infection rates in women have important implications for women's health and child survival in Uganda and indicate the need for specially targeted interventions to reduce transmission in this group.
Establishment of a phylogenetic survey system for AIDS-related lentiviruses and demonstration of a new HIV-2 subgroup, We designed a universal primer (UNIPOL) for DNA amplification of AIDS-related viruses. The phylogenetic tree constructed from the presumed sequences amplified with UNIPOL was representative of the tree calculated from whole pol gene sequences so far reported. UNIPOL was able to amplify the sequences of all four major groups of primate lentiviruses and also that of a distinct virus from a Ghanaian patient with an AIDS-related complex. designated GH-2. This strain scarcely hybridizes with known HIV/simian immunodeficiency virus (SIV) DNA probes. Sequence analysis of the only amplified fragment revealed rapidly that GH-2 was quite similar to the recently reported HIV-2ALT(D205) and that these two viruses form a new subgroup distint from known HIV-2 and SIVmac/SIVsm in the large HIV-2 group. This system will be useful for further phylogenetic study of various primate lentiviruses.
Seroprevalence and clinical manifestations of HIV-1 infection in Kananga, Zaire, The objective of this study was to ascertain the seroprevalence and clinical manifestations of HIV-1 infection in Kananga. Zaire. in 1988. In the city of Kananga (population 300.000). eight out of 258 (3.1%) consecutive. asymptomatic. prenatal patients were seropositive. Of 452 consecutive blood donors at our institution. eight (1.8%) were seropositive. Sixty per cent of 299 consecutive. seropositive. clinically ill adults presented with chronic diarrhea. fever or weight loss (Centers for Disease Control group IVA). The male-to-female ratio of symptomatic. seropositive patients was 1:1.5. Women who indicated on a socioeconomic questionnaire that they engaged in 'commerce' (meaning possibly that they were petty traders. wholesale brokers. or prostitutes) were more often HIV-seropositive than women who did not engage in 'commerce' (P less than 0.001).
Sequential autonomic function tests in HIV infection, Cardiovascular autonomic function tests were carried out on 22 men at varying stages of HIV infection. Thirteen were asymptomatic. seven had persistent generalized lymphadenopathy. and two had Kaposi's sarcoma. Pupil cycle times were also measured. Except for one subject with definite autonomic abnormalities. all the rest had almost normal test results. There were no correlations between individual tests of immune function and the autonomic test results. The tests were repeated 9-18 months later in 12 men. four of whom were taking zidovudine at that time. Although there was evidence of progression of HIV-associated immune dysfunction. there was no significant deterioration in autonomic function. In the single patient with abnormal autonomic function. these changes appeared to reverse on treatment with zidovudine.
Human monoclonal anti-basement membrane zone antibodies derived from virally transformed lymphocytes of a patient with bullous pemphigoid recognize epitopes associated with hemidesmosomes, The purpose of this study was to determine the ultrastructural localization of the epitopes recognized by two human monoclonal antibodies designated 5E and 10D. that were derived from virally transformed lymphocytes from a patient with bullous pemphigoid (BP). Previous immunoblotting showed that 5E but not 10D reacted with a 230-kDa protein in extracts of normal human skin. In the present study. indirect immunofluorescence showed that both 5E and 10D bound to the epidermal side of 1 M NaCl-separated normal human skin. Immunoperoxidase electron microscopy showed that 5E and 10D formed discontinuous focal deposits along the basal region of the epidermal basal cells in normal human skin in a similar localization to that seen with whole BP sera. Post-embedding immunogold electron microscopy demonstrated binding of both monoclonal antibodies to the intracellular components of hemidesmosomes. As far as we are aware. 5E and 10D are the first monoclonal antibodies to be described that recognize epitopes of BP antigen associated with hemidesmosomes and should serve as useful probes for future studies.
Tissue kallikrein and kininogen in human sweat glands and psoriatic skin, The cellular localization of immunoreactive tissue kallikrein and kininogen was studied in normal and psoriatic human skin. Immunoreactivity to both enzyme and substrate was observed in secretory granules of the dark cells in the secretory fundus (acinus) of the sweat glands. Double immunostaining revealed a segmental distribution of the two antigens. Each acinar section contained either tissue kallikrein or kininogen. However. there appeared to be a junctional zone in which both were present. but in separate dark cells. Immunoreactivity for both antigens was also observed in close apposition to the luminal microvilli of the duct cells. No specific immunostaining was seen in sebaceous glands. hair follicles. keratinocytes and other cells of the secretory unit such as myoepithelial or clear cells. In psoriatic skin there were in addition many neutrophils immunoreactive for tissue kallikrein in the epidermis and psoriatic scales. Mitogenic action of kinins may account to some extent for the characteristic accelerated turnover of epidermal cells in psoriasis and locally applied kinin antagonists may prove of value in the treatment of this disease.
An immunohistological study of desmosomes in Darier's disease and Hailey-Hailey disease, The immunocytochemical distribution of desmosomal components was determined in involved skin from eight patients with Darier's disease. five patients with Hailey-Hailey disease and two patients with transient acantholytic dermatosis as well as skin from four normal controls. Sections were stained using monoclonal antibodies to the desmosomal proteins dp1 and dp2 (desmoplakins) and the desmosomal glycoproteins dg1 (desmoglein). and dg2 and dg3 (desmocollins). There was normal expression of desmosomal proteins and glycoproteins at the periphery of the keratinocytes in the perilesional skin in Darier's disease. in Hailey-Hailey disease and in transient acantholytic dermatosis. In the lesional skin there was reduced expression of desmosomal proteins and glycoproteins in the basaloid 'buds' at the base of the lesions. but there was bright diffuse staining of the acantholytic cells. Focal intracellular staining was detected within many of the acantholytic keratinocytes in Hailey-Hailey disease and within some of these cells in Darier's disease. Suction blisters were used to induce fresh acantholysis in lesional skin in Darier's disease and clinically uninvolved skin in Hailey-Hailey disease. The results indicated that acantholysis precedes the development of intracellular staining. Although there are immunopathological abnormalities in the distribution of desmosomal proteins and glycoproteins in both Darier's disease and Hailey-Hailey disease. the changes are probably secondary to internalization of desmosomal components with breakdown and redistribution of antigens rather than a primary deficiency in the synthesis of these proteins. Focal internalization was more widespread in Hailey-Hailey disease than in Darier's disease and the differences in the distribution of desmosomal components in these diseases confirm that they are distinct entities.
Sunscreen protection against UVB, UVA and blue light: an in vivo and in vitro comparison, The photoprotection against UVB. UVA and blue light provided by a widely prescribed sunscreen (RoC 15+ A+B) was compared with two new products containing microfine titanium dioxide (Sun E45 lotion SPF 15 and Sun E45 cream SPF 20). Comparisons were made in vivo using photosensitive patients with either chronic actinic dermatitis or erythropoietic protoporphyria. and in vitro using a newly developed spectrophotometric assay. Good agreement was obtained between the in-vivo and in-vitro methods at each waveband. All products showed high protection against UVB radiation. but the products containing microfine titanium dioxide showed significantly higher protection against both UVA and blue light than RoC 15+ A+B. Products containing microfine titanium dioxide are likely to offer superior photoprotection in those patients who are abnormally sensitive to long wavelength ultraviolet radiation than products which are currently available on prescription.
Destruction of tumour parenchyma in basal cell carcinoma by tumour-associated neutral proteases: a histochemical study, Proteolytic activity was demonstrated histochemically in frozen sections of basal cell carcinomas (BCCs). After incubation of tissue sections in 0.1 M phosphate buffer with 0.25 M NaCl the tumour epithelium was almost completely destroyed. The basal and squamous cell layers of the epidermis disintegrated to varying degrees. particularly where they were directly in contact with tumour epithelium. Serine and metalloprotease inhibitors diminished this tissue destruction. Iodoacetate enhanced tumour destruction. urea and potassium thiocyanate even more so. The high proteolytic activity of BCC demonstrated in this study may be an important factor in the proliferative. invasive and destructive behaviour of this tumour.
Carcinoma erysipeloides, We report an 83-year-old woman with carcinoma erysipeloides due to an occult carcinoma. Immunohistochemical study of skin biopsies showed reactivity to S-100 protein and human milk fat globule antigen indicating that the tumour originated in the breast.
Point mutations in the L-type pyruvate kinase gene of two children with hemolytic anemia caused by pyruvate kinase deficiency, The molecular alterations responsible for the characteristic enzyme abnormalities in pyruvate kinase (PK) deficiency were investigated in two unrelated children homozygous for PK deficiency. Both variant enzymes were characterized according to the recommendations of the International Committee for Standardization in Haematology. Genomic DNA was specifically amplified by the polymerase chain reaction. Normal and mutant alleles of the L-type PK gene were analyzed by nucleotide sequencing. Heterozygosity of the parents was confirmed by allele-specific oligonucleotide hybridization. In PK Linz a C to T base exchange at position 394 of the L-type PK gene was found. As a result. the 132nd amino acid of the mutant enzyme. arginine (CGC). is replaced by cysteine (TGC). The affected amino acid residue is located within the deduced active site of the protein and the enzyme variant shows strongly altered allosteric properties. PK Beirut shows a C for T substitution at position 1058. changing the 353 amino acid from threonine (ACG) to methionine (ATG). In contrast to PK Linz. this amino acid lies outside the deduced substrate binding site and kinetic parameters of PK Beirut are close to normal. Both enzyme variants show a markedly reduced specific activity and thermolability.
Increased serum levels of granulocyte colony-stimulating factor in patients with severe congenital neutropenia, Severe congenital neutropenia (SCN). also known as Kostmann Syndrome. is characterized by a maturation arrest of myelopoiesis at the level of promyelocytes with absence of neutrophils in bone marrow (BM) and blood. Hypotheses of the pathophysiology of SCN include (1) defective production of granulocyte colony-stimulating factor (G-CSF). and/or (2) defective response to G-CSF. To exclude defective G-CSF production we tested sera from patients with SCN for the presence of G-CSF using Western blot analysis and NFS-60 proliferation assay. Using these assays we were able to detect increased G-CSF serum levels in SCN patients (150 to 910 pg/mL) as compared with normal controls (between undetectable and 100 pg/mL). These results suggest that patients with SCN have no defect in G-CSF production but a defective response of neutrophil precursors to endogenous G-CSF.
A new congenital abnormal fibrinogen Ise characterized by the replacement of B beta glycine-15 by cysteine, A new case of heterozygous dysfibrinogenemia characterized by the replacement of NH2-terminal amino acid of fibrin beta-chain was found in a 50-year-old man. Despite a prolonged thrombin time. the propositus' fibrinogen had a normal reptilase time with the normal release of fibrinopeptide A. Release of fibrinopeptide B by thrombin was strongly affected. but a very high concentration of thrombin almost completely released fibrinopeptide B with a normal elution pattern on reversed-phase high performance liquid chromatography (HPLC). Lysylendopeptidase-cleavage of purified B beta-chains analyzed on HPLC showed the decrease of one peptide compared with the normal and the appearance of an abnormal peptide peak. These peptides were treated with thrombin and further separated on HPLC. Amino acid sequence analysis of the abnormal peptide demonstrated that B beta glycine-15. NH2-terminus of the fibrin beta-chain. was replaced by cysteine. These findings will be of particular importance because they strongly support the hypothesis that the NH2-terminal portion of the fibrin beta-chain is involved in the polymerization reaction by thrombin. The propositus' daughter and two sisters had the same abnormal fibrinogen. This unique inherited abnormal fibrinogen was designated as fibrinogen Ise. During these studies. we found that a very high concentration of thrombin cleaves not only the A alpha Arg19-Val20 bond but also the COOH-terminal region of alpha-chains. which results in the generation of further degraded alpha-chains with apparent molecular weights of 44.000 or less.
Clinical significance of soluble CD30 antigen in the sera of patients with untreated Hodgkin's disease, The soluble form of the CD30 antigen (sCD30). an 88-kd glycoprotein that is released by Hodgkin's-derived cell lines in vitro. can be detected in patients with Hodgkin's lymphoma. adult (HTLV-1+) T-cell leukemia. rare cases of non-Hodgkin's lymphoma. and acute infectious mononucleosis (anti-EBV-IgM+). In a prospective study of 90 consecutive untreated patients with newly diagnosed Hodgkin's disease who were treated according to the protocols of the German Hodgkin Study group. 22% had detectable levels of sCD30 in their serum. sCD30 was only detected in patients with B symptoms (20 of 44 or 45%). and maximum sCD30 levels (88 U/mL) were found in stage IVB. Of 87 patients evaluable for response. sCD30+ patients had significantly lower rates of complete remission (9 of 20 or 45% v 60 of 67 or 90%; P less than .001) and higher rates of progressive disease (9 of 20 or 45% v 6 of 67 or 9%; P less than .001) than CD30+ patients. Similarly. freedom from treatment failure curves were significantly worse for CD30+ patients (P = .0003). sCD30 disappeared after successful treatment. but increased in patients with progressive disease. It was never detected in patients in complete remission or in healthy controls. We conclude that sCD30 is a valuable marker for disease activity and has prognostic significance in Hodgkin's disease.
Possible mechanism of selective killing of myeloid leukemic blast cells by lymphokine-activated killer cells, Major histocompatibility complex-unrestricted lymphokine-activated killer (LAK) cells have been proposed as therapy for a variety of hematologic malignancies. Because these cells recognize and kill their targets independently of their antigen specific CD3 receptor. it is unclear how they might discriminate between normal and malignant cells. We now propose one such mechanism for the selective killing of myeloid leukemia blasts. While both CD2+ and CD2- activated killer cells may inhibit the clonogenic growth of myeloid leukemia cells. only the CD2+ subset effectively inhibits the growth of normal myeloid (granulocyte-macrophage and granulocyte) progenitors. This difference appears to reflect differential requirements for cell adhesion molecule recognition between normal and malignant progenitor cells. Inhibition of the growth of normal granulocyte-macrophage colonies by CD2+ LAK cells is blocked by antibodies to the CD2-lymphocyte function-associated antigen 3 (LFA-3) (CD58) cell adhesion system. In contrast. these antibodies have no effect on CD2+ LAK-mediated inhibition of malignant cell clonogenic growth. Instead. antibodies to the LFA-1 (CD11a/CD18)-intercellular adhesion molecule 1 (ICAM-1) (CD54) adhesion system reduce inhibition. These differences correspond to differential expression of the CD54 cell adhesion molecule by normal and malignant myeloid progenitor cells because less than 15% of normal CD34 positive cells are CD54+ while greater than 85% of CD34+ acute myeloid leukemia blasts express the CD54 antigen. LFA-3. the ligand for CD2. is strongly expressed by erythrocytes. and these cells competitively inhibit killing of normal but not malignant clonogenic cells in an analogous way to the effects of monoclonal antibody to the CD2-LFA-3 adhesion system. The operation of this effect in vivo may be a basis for selective cytotoxicity by CD2+ LAK against clonogenic myeloid blast cells. and could be exploited further with infusion of appropriate monoclonal antibodies.
Effect of tumor necrosis factor-alpha on the proliferation of leukemic cells from children with B-cell precursor-acute lymphoblastic leukemia (BCP-ALL): studies of primary leukemic cells and BCP-ALL cell lines, The effect of recombinant tumor necrosis factor-alpha (rTNF-alpha) on the primary leukemic blasts and leukemic cell lines derived from children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) was studied. The proliferation of leukemic cells from the bone marrow of 11 of 13 patients (seven at diagnosis. four in relapse) and from the 697 (BCP-ALL) cell line was significantly inhibited by rTNF-alpha at the lowest dose tested (0.1 ng/mL). as measured by 3H-TdR uptake. The degree of inhibition was variable. ranging from 17% to 78%. Furthermore. a dose-dependent inhibitory effect was observed. with approximately 70% mean inhibition of DNA synthesis detected when cells from 12 of 13 patients were incubated with 100 ng/mL of rTNF-alpha for 3 days. In contrast. rTNF-alpha did not inhibit another BCP-ALL cell line (EU-1/ALL) established recently in our laboratory. Studies indicated that the TNF-alpha gene was expressed by the primary leukemic blasts of one TNF-resistant case in his third relapse and by EU-1 cells. Also. TNF-alpha protein was detected by Western blot analysis and enzyme-linked immunoabsorbent assay in the supernatant of EU-1 cells; this is the first report of TNF production by a BCP-ALL cell lines. The production of TNF-alpha mRNA and protein was not detected in the 697 cell line and in the primary leukemic blasts from six patients (four at diagnosis. two in relapse) whose leukemic cells were inhibited by TNF. The partially purified TNF-alpha obtained from the EU-1 cell line also suppressed the proliferation of TNF-sensitive primary leukemic cells. and this inhibitory activity was abolished by an anti-TNF-alpha specific antibody. Our results demonstrate that TNF-alpha is an inhibitor of in vitro proliferation of BCP-ALL cells from most patients. The TNF-resistant leukemic cells from a few patients and the EU-1 cell line express TNF mRNA. suggesting that the induction of TNF gene expression is associated with the development of TNF resistance.
Blood-borne fragments of fibronectin after thermal injury, Fibronectin is an adhesive protein that can promote phagocytosis and endothelial cell adhesion. Plasma fibronectin declines following burn in animals and patients. potentially due to its complexing with circulating collagenous debris as well as its rapid binding to sites of tissue injury. Such depletion of fibronectin initiates an opsonic deficiency of the plasma. In view of the sensitivity of fibronectin to proteolytic enzymes. an additional factor that could contribute to the decrease of plasma opsonic activity after burn is the proteolytic fragmentation of fibronectin in the blood. In the current study. we determined if fibronectin fragments appear in the blood of anesthetized rats after a sublethal full-thickness skin burn of 15% to 16% of body surface. Plasma fibronectin concentration was quantified by enzyme-linked immunosorbent assay and the presence of fibronectin fragments in plasma was determined by immunoblot analysis. All blood was collected in an antiprotease mixture to yield final plasma concentrations of 0.15% EDTA. 3mmol/L phenylmethylsulfonyl fluoride. and 3 mmol/L iodoacetate to prevent degradation of fibronectin after sampling. Plasma fibronectin decreased 60% to 70% within 30 minutes post-burn. and this low level lasted for at least 4 hours. Within 30 minutes post-burn. two prominent fragments of fibronectin with a molecular weight of 110 +/- 2.2 kd and 122 +/- 3.3 Kd. respectively. were also detected in the plasma. Peak concentration of these fragments was detected at 60 minutes post-burn. but their level declined by 4 hours. By 4 hours. both bands appeared to resolve into doublets. To rule out the possibility that the fragments of fibronectin detected in the plasma were actually generated by coagulation enzymes activated at the site of peripheral blood sampling. rapid direct inferior vena cava sampling was performed. which also yield the presence of the fragments. Thus. fibronectin fragments exist in the plasma following thermal injury. Because fragments of fibronectin can compete with the intact fibronectin molecule with respect to its ability to stimulate macrophage phagocytosis. such fragments may contribute to altered systemic phagocytic host defense following thermal injury. Furthermore. because fibronectin peptides can compete with matrix fibronectin and impair adhesion of cultured endothelial cells. such circulating fragments may also influence the integrity of the vascular barrier.
Thalassemia intermedia: moderate reduction of beta globin gene transcriptional activity by a novel mutation of the proximal CACCC promoter element, A patient with homozygous beta thalassemia of German/Italian descent was found to be doubly heterozygous for the common IVS1-110 G----A mutation of the beta globin gene and for a novel C----T mutation of the proximal CACCC-box of the beta globin gene promoter at position -87 relative to the transcription start site (cap). Transcription analysis in an HeLa cell transfection assay indicated a 45% to 51% residual activity of the gene with the -87 C----T mutation relative to normal. further underlining the physiologic role of the affected promoter element. The finding of an only moderately reduced transcriptional activity of the beta globin gene with the -87 C----T mutation corresponds well with the clinical phenotype of the reported patient. which is characterized by a late onset of symptoms. moderate anemia. and normal physical development. The ethnically German mother of the propositus has minimal anemia with only slightly changed red blood cell indices. which can also be explained by the relatively high residual activity of the gene with the -87 C----T mutation.
NADPH, not glutathione, status modulates oxidant sensitivity in normal and glucose-6-phosphate dehydrogenase-deficient erythrocytes, Glucose-6-phosphate dehydrogenase (G6PD) deficiency is characterized by the loss of NADPH and enhanced erythrocyte oxidant sensitivity. Historically. it has been theorized that the elevated oxidant sensitivity of G6PD-deficient erythrocytes arises as the direct consequence of decreased intracellular glutathione (GSH) concentrations. To directly investigate the basis of G6PD deficiency oxidant sensitivity. the effects of altered GSH and NADPH concentrations were examined in normal and G6PD-deficient erythrocytes. The results of this study demonstrated that GSH depletion. by 1-chloro-2.4-dinitrobenzene (CDNB). had no effect on hemoglobin oxidation in response to hydrogen peroxide (H2O2) generating systems (phenazine methosulfate and menadione bisulfite) in either normal or G6PD-deficient cells. Furthermore. a fourfold to sixfold increase in intracellular GSH concentration also did not protect against H2O2-generating systems in the normal or G6PD-deficient erythrocytes. Conversely. introduction of an NADPH-generating system (purified G6PD) into G6PD-deficient cells resulted in a significant decrease in oxidant sensitivity and an ability to cycle GSH. Further experiments demonstrated that the reduced oxidant sensitivity of the G6PD-reconstituted erythrocytes was not due to the maintenance of GSH levels because CDNB-mediated depletion of GSH did not alter this protective effect. Analysis of these results demonstrated a direct correlation between NADPH. but not GSH. concentration and hemoglobin oxidant sensitivity.
Studies of allogeneic bone marrow and spleen cell transplantation in a murine model using ultraviolet-B light, Ultraviolet irradiation inhibits alloreactive and mitogen-induced responses and might reduce both graft-versus-host and host-versus-graft reactions after bone marrow transplantation (BMT). We have studied proliferative responses to mitogens and reactivity in mixed lymphocyte culture after irradiation with ultraviolet (UV)-B light using splenocytes from Balb/c (H-2d) and CBA (H-2k) mice. Response to mitogens and in MLC was strongly inhibited by 20 J/m2 and abolished at 50 J/m2. Clonogenic cell recovery (CFU-GM; CFU-S) after UV-B irradiation was also reduced. When bone marrow and spleen cells were transplanted from parent (Balb/c) animals into F1 hybrid (Balb/c X CBA) recipients. all animals died with features indicative of graft-versus-host disease (GVHD) in 34 days. If the grafts were first irradiated with 100 J/m2 of UV-B at a mean wavelength of 310 nm. then 76% survived to day 80 when they were killed and shown to have normal marrow cellularity. The remainder died in marrow aplasia or of GVHD. H-2 typing in a group of surviving recipients showed either donor hematopoiesis only (8 of 15). mixed allogeneic chimerism (5 of 15). or recipient type hematopoiesis (2 of 15). Higher doses (200 to 300 J/m2) were detrimental to survival with 88% of recipients dying in marrow aplasia. Syngeneic BMT in Balb/c mice showed slower hematopoietic reconstitution when the grafts were first irradiated with 100 J/m2. After BMT from Balb/c to CBA mice all recipients of unirradiated grafts died within 54 days. By contrast. after graft irradiation with 100 J/m2 survival of recipient animals to day 80 was 59%. If these grafts were treated with 50 J/m2 survival was only 26% with an increase in deaths due to GVHD. Hematopoiesis at day 80 in a group of survivors studied by Ig heavy chain allotyping indicated donor type hematopoiesis in 6 of 10 (50 J/m2) and 2 of 9 (100 J/m2). These data indicate that UV-B irradiation inhibits lymphocyte reactivity and can prevent GVHD. However. there is clear in vitro and in vivo evidence of stem cell damage. such that autologous marrow recovery was demonstrated in a proportion of recipients. In parent----F1 UV-irradiated transplants. sustained hematopoietic recovery was effected in the majority by donor stem cells.
A combined approach for purging multidrug-resistant leukemic cell lines in bone marrow using a monoclonal antibody and chemotherapy, Selective removal of malignant cells (purging) from bone marrow (BM) is a concern in autologous BM transplantation (ABMT). Use of vincristine. etoposide. or doxorubicin for purging could be rendered ineffective by the presence of multidrug-resistant (MDR) tumor cells. To circumvent this particular problem. we investigated whether 17F9. a monoclonal IgG2b antibody directed against the cell surface product of the MDR gene. P-glycoprotein. is effective in selective removal of MDR cells from BM when used with rabbit complement (C'). Using two different cell lines we have demonstrated that 17F9 + C' selectively lyses MDR-positive cells. Three rounds of antibody + C' resulted in 96.4% +/- 3.6% kill of K562/DOX and 100% +/- 0% of CEM/VLB cells. Mixtures of malignant cells and normal BM resulted in 99.85% removal of K562/DOX and 99.91% removal of CEM/VLB clonogenic cells. This treatment did not affect normal committed precursors compared with C' alone. The addition of the cytotoxic agent etoposide (VP-16) following antibody purging results in a 4.6 log reduction of malignant cells. Furthermore. this antibody was effective when used against patients' leukemic blasts. These results suggest the use of 17F9 + C' is effective and selective for removal of MDR cells from BM before ABMT and the addition of VP-16 enhances the purging efficacy.
Variability in physicians' decisions on caring for chronically ill elderly patients: an international study, OBJECTIVES: To determine what treatment decisions physicians will make when faced with an incompetent elderly patient with life-threatening gastrointestinal bleeding and to identify the factors that affect their decisions. DESIGN: Survey. SETTING: Family practice. medical and geriatrics rounds in academic medical centres and community hospitals in seven countries. PARTICIPANTS: Physicians who regularly cared for incompetent elderly patients. OUTCOME MEASURE: A self-administered questionnaire containing three case vignettes. Each provided the same details on an incompetent elderly patient; however. one gave no information about the wishes of the patient and his family (no directive). the second provided a do-not-resuscitate (DNR) request. and the third included a detailed therapeutic and resuscitative effort chart (DTREC) requesting maximum therapeutic care without admission to the intensive care unit (ICU). The four treatment options were supportive care only. limited therapeutic care. maximum therapeutic care without admission to the ICU and maximum care with admission to the ICU. MAIN RESULTS: Treatment decisions varied and were systematically related to age. level of training and country (p less than 0.001). The older physicians and those in family medicine were less likely than the others to choose aggressive treatment options. Brazilian and US physicians were the most aggressive; Australian physicians were the most conservative. The DNR request resulted in a significant decrease in the number of physicians choosing aggressive options (p less than 0.001). The DTREC resulted in a move toward more aggressive treatment. as outlined in the directive (p less than 0.001). Overall. however. about 40% of the physicians chose a level of care different from what had been requested. Furthermore. over 10% would have tried cardiopulmonary resuscitation despite the DNR request. CONCLUSION: Treatment of incompetent elderly patients with life-threatening illness varies widely within and between countries. Uniform standards should be developed on the basis of societal values and be communicated to physicians.
Dispersion of refractoriness in canine ventricular myocardium. Effects of sympathetic stimulation, In 18 dogs on total cardiopulmonary bypass. the average interval between local activations during artificially induced ventricular fibrillation (VF interval) was measured from extracellular electrograms. simultaneously recorded from up to 32 ventricular sites. VF intervals were used as an index of local refractoriness. based on the assumption that during ventricular fibrillation. cells are reexcited as soon as they have recovered their excitability. In support of this. microelectrode recordings in two hearts during ventricular fibrillation did not show a diastolic interval between successive action potentials. Refractory periods determined at a basic cycle length of 300 msec with the extrastimulus method correlated well with VF intervals measured at the same sites. Thus. this technique allows assessment of spatial dispersion of refractoriness during brief interventions such as sympathetic stimulation. The responses to left. right. and combined stellate ganglion stimulation varied substantially among individual hearts. This was observed both in dogs with an intact (n = 12) and decentralized (n = 6) autonomic nervous system. Individual ventricular sites could show effects of both left and right stellate ganglion stimulation (42% of tested sites) or show effects of left-sided stimulation only (31%) or right-sided stimulation only (14%). In 13% of sites. no effects of stellate stimulation were observed. Apart from these regional effects. the responses could be qualitatively different; that is. within the same heart. the VF interval prolonged at one site but shortened at another in response to the same intervention. although shortening was the general effect and prolongation the exception. Whenever sites responded to stellate ganglion stimulation with a shortening of VF interval. this shortening was approximately 10% for left. right. or combined stimulation. whether the autonomic nervous system was intact or decentralized. In six of 12 hearts in the intact group. there was a distinct regional effect of left stellate ganglion stimulation; in the other six hearts. the effects were distributed homogeneously over the ventricles. In three hearts. the effect of left stellate ganglion stimulation was strongest in the posterior wall. and in the other three hearts. in the anterior wall. The effects of right stellate ganglion stimulation were restricted to the anterior or lateral part of the left ventricle. Dispersion of VF intervals increased after left and combined stellate ganglion stimulation in the intact group and after right stellate ganglion stimulation in the decentralized group. but not significantly in every heart. This points to a marked individual variation with regard to the effects of sympathetic stimulation on electrophysiological properties of the heart.
Endothelial dysfunction in response to psychosocial stress in monkeys, The current study was designed to evaluate the effects of a disrupted social environment on the endothelial integrity of various vascular segments in male cynomolgus monkeys (Macaca fascicularis). Each of 20 single-caged adult monkeys was fed a diet comparable to a person's ingestion of 240 mg cholesterol/day for a 10-week baseline period and then was introduced as a stranger into a four-member social group for 3 days. Half of the monkeys received a beta-adrenergic blocking agent (metoprolol) via subcutaneous implant 2 days before and during group housing. The social manipulation produced persistent sympathetic arousal as evidenced by significantly elevated heart rates among untreated monkeys (p less than 0.01) but not among their metoprolol-treated counterparts. whose heart rate declined (p less than 0.05). After the social manipulation. all monkeys were necropsied and evaluated for endothelial incorporation of immunoglobulin G (as an indicator of cell death). endothelial cell replication. the presence of adherent leukocytes. and arterial low density lipoprotein permeability and concentration. At branching sites in the thoracic aorta. immunoglobulin G incorporation and endothelial cell replication were significantly greater in untreated monkeys than in metoprolol-treated monkeys (p less than 0.01 for both analyses); no differences existed at nonbranch sites. Endothelial cell replication in the coronary arteries (where immunoglobulin G incorporation was not examined) was also greater among untreated than among metoprolol-treated monkeys. No significant differences were observed between treatment groups in arterial low density lipoprotein permeability or leukocyte adherence; estimates of arterial low density lipoprotein concentrations were higher among untreated than among metoprolol-treated monkeys. but only in the abdominal portion of the aorta. These results indicate that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial dysfunction. effects that may be prevented by treatment with a beta-adrenergic blocking agent.
A unified model of atrioventricular nodal conduction predicts dynamic changes in Wenckebach periodicity, The atrioventricular (AV) node responds in a complex fashion to changes in activation rate. A variety of approaches have been used to explain these dynamic AV nodal responses. but none has been able to account fully for AV nodal behavior. Three specific rate-dependent properties of the AV node have been described: 1) time-dependent recovery after excitation. 2) an effect of short cycles to advance recovery ("facilitation"). and 3) a gradual slowing of conduction in response to sustained. high-frequency activation ("fatigue"). We hypothesized that a model incorporating quantitative descriptors of all three processes might be able to account for a wide variety of AV nodal behaviors. Quantitative descriptors of AV nodal recovery. facilitation. and fatigue were developed based on AV nodal conduction changes during selective pacing protocols in seven autonomically blocked dogs. These descriptors were incorporated into a set of mathematical equations that define AV nodal conduction of any beat based on activation history. The equations were then applied to predict pacing-induced Wenckebach periodicity in each dog. Experimental data were obtained after nine to 19 step decreases in atrial cycle length into the Wenckebach zone in each animal. Observed behaviors included complex patterns of block. a progressive increase in the level of block over 5 minutes of rapid pacing. and periods of alternating patterns of block. The model accurately predicted the onset of AV block at each cycle length. the relation between conduction ratio and cycle length as a function of time. and the changing patterns of Wenckebach periodicity during sustained atrial pacing. All three terms of the model equation (describing recovery. facilitation. and fatigue) were essential to account fully for the observed behaviors. Elimination of AV nodal fatigue from the model resulted in failure to account for time-dependent changes in Wenckebach patterns. whereas exclusion of facilitation led to consistent overestimation of the degree of AV block at each cycle length. We conclude that a mathematical model incorporating terms to describe recovery. facilitation. and fatigue accurately predicts a wide range of Wenckebach-type behavior and that complex conduction patterns of the AV node can be fully accounted for by simple functional AV nodal properties.
Carotid sinus baroreceptor reflex in dogs with experimental heart failure, We have previously demonstrated a decrease in baroreceptor discharge sensitivity in dogs with experimental heart failure. In the present study. we determined the sensitivity of the carotid sinus baroreceptor reflex in dogs with pacing-induced heart failure. The carotid sinus baroreceptor reflex sensitivity was determined by pressurizing one carotid sinus with all other baroreceptor and cardiopulmonary receptor inputs removed. The data were analyzed by plotting carotid sinus pressure-mean arterial pressure curves and carotid sinus pressure-renal sympathetic nerve activity curves in the two groups of dogs. The peak arterial pressure during carotid hypotension was significantly depressed in dogs with heart failure compared with normal dogs (107.1 +/- 5.7 versus 139.8 +/- 7.0 mm Hg. p less than 0.001). Mean arterial pressure range. renal sympathetic nerve activity range. and peak slope were significantly decreased in the heart-failure group. To determine if this depression was completely due to depression of baroreceptor discharge per se. or to alterations in central or end-organ responsiveness. similar experiments were performed by stimulating the carotid sinus nerve and evaluating frequency. voltage. and duration of stimulation on the resultant mean arterial pressure and renal sympathetic nerve activity. As was the case with carotid sinus pressurization. electrical stimulation caused a significantly smaller change in mean arterial pressure in heart-failure dogs compared with the normal dogs. However. there was no significant difference between normal and heart-failure dogs for the renal sympathetic nerve activity-electrical stimulation curves. These data strongly suggest that the depressed carotid sinus baroreceptor reflex in heart failure is not solely the result of depressed baroreceptor responsiveness but may be related to poor end-organ responses and normal central control of renal sympathetic outflow.
Distinction between metabolic and myogenic mechanisms of coronary hyperemic response to brief diastolic occlusion, We monitored an index of coronary vascular resistance (mean aortic pressure/mean coronary flow) in 19 heart-blocked conscious dogs paced at 60 beats/min and instrumented with an aortic pressure catheter. left circumflex artery electromagnetic flow probe. and a coronary occluder. Cessation of pacing for a single beat resulted in a long diastole control (LDC) intervention beat of 2-second duration characterized by a progressive rise in diastolic coronary vascular resistance index. A 400-msec coronary artery occlusion early in a long diastole (LD4) dramatically inhibited the rate of rise in resistance index during the first 600 msec (phase 1) after occlusion. Partial recovery of the resistance index rise rate was evident during the remaining 400 msec (phase 2) of the long diastole. In nine dogs. LDC and LD4 intervention beats were instituted during two conditions of myocardial metabolic activity in which the myogenic stimuli associated with coronary occlusion would be similar: 1) paired pacing and 2) normal pacing plus intravenous adenosine and phenylephrine infusions (AP) to maintain mean aortic pressure and coronary flow at paired pacing levels. During paired pacing. the LD4-LDC differences in phase 1 and 2 resistance index rise rates (-69 +/- 18 and -48 +/- 31 mmHg/ml/sec2. respectively) were greater than during normal pacing plus AP (-32 +/- 14 and -1 +/- 32 mm Hg/ml/sec2. phase 1 and 2. respectively) (p less than 0.05). These differences are consistent with operation of a metabolic mechanism in response to occlusion.
Beneficial effects of alpha 1-adrenoceptor activity on myocardial stunning in dogs, This study was undertaken to elucidate whether alpha-1 adrenoceptor activity is beneficial to contractile dysfunction during reperfusion after a brief period of ischemia (stunned myocardium) in 54 open-chest dogs. Contractile dysfunction assessed by fractional shortening (FS) was observed 3 hours after the onset of reperfusion following 15 minutes of complete occlusion of the left anterior descending coronary artery. Pretreatment with prazosin (4 micrograms/kg/min i.c.) further deteriorated contractile dysfunction compared with the untreated condition (12.7 +/- 0.6% versus 6.9 +/- 0.4% with prazosin treatment. p less than 0.001). Conversely. alpha 1-adrenoceptor agonists. methoxamine (1.0 microgram/kg/min i.c.) and norepinephrine (0.24 microgram/kg/min i.c.) with rauwolscine and propranolol. significantly attenuated contractile dysfunction (FS in the methoxamine-treated group. 17.3 +/- 0.3%. p less than 0.001 versus the untreated group; FS in the norepinephrine-treated group. 18.0 +/- 0.9%. p less than 0.05 versus 13.6 +/- 1.1% in the propranolol group). Both adenosine release and hyperemic coronary flow response during the early reperfusion period were significantly attenuated in the prazosin-treated group. and both were enhanced in the alpha 1-adrenoceptor stimulation groups. These results suggest that beneficial effects of alpha 1-adrenoceptor activity may be due to the enhanced release of adenosine. To test the cause-effect relation between the extent of adenosine release and contractile dysfunction during reperfusion. 8-phenyltheophylline was infused to block adenosine receptors in the methoxamine-treated group. The treatment with 8-phenyltheophylline completely abolished (FS. 7.4 +/- 0.3%) the beneficial effect of the enhanced adenosine release by alpha 1-adrenoceptor stimulation. Furthermore. in the prazosin-treated group. adenosine (9 micrograms/kg/min) was additionally infused into the left anterior descending coronary artery 5 minutes before and 2 hours after the onset of reperfusion. Both hyperemic coronary flow and contractile dysfunction (FS. 17.3 +/- 0.3%) recovered to the levels of the alpha 1-adrenoceptor stimulation groups. However. treatment with papaverine could not prevent deleterious effects of prazosin despite the fact that comparable hyperemic flow was obtained. Instead. lactate production up to 10 minutes after the onset of reperfusion was significantly larger (p less than 0.01) despite augmented contractile function in the prazosin-treated and the 8-phenyltheophylline with methoxamine-treated groups compared with the untreated group. The electron microscopic examination revealed no irreversible myocardial injury with and without pharmacological interventions. Thus. we conclude that alpha 1-adrenoceptor activity can reduce the magnitude of myocardial stunning and that its cellular mechanism is due to enhanced adenosine release by alpha 1-adrenoceptor activity.(ABSTRACT TRUNCATED AT 400 WORDS).
Intracellular calcium and ventricular fibrillation. Studies in the aequorin-loaded isovolumic ferret heart, To elucidate the role of changes in [Ca2+]i in the induction of ventricular fibrillation (VF). Ca2+i signals. epicardial electrical potentials. and isovolumic left ventricular pressure were simultaneously recorded in isolated intact ferret hearts loaded with aequorin. a bioluminescent protein. When the preparations were perfused with 3 microM acetylstrophanthidin and 8 mM Ca2+. or with a low Na+ solution (18 mM Na+. 100 mM Li+). spontaneous transitions to the VF state were consistently observed within a short period of time. The initiation of spontaneous VF was preceded by development of a Ca2+i overload state. coincidental with the ascending phase of diastolic Ca2+i oscillations. and was followed by further elevation in Ca2+i levels. which were associated with augmented Ca2+i oscillations of a saw-toothed pattern. Pretreatment with 10 microM ryanodine. which blocked Ca2+i oscillations in the preparation. did not eliminate inducibility of VF by means of AC electrical stimulations; however. VF no longer occurred spontaneously. and the threshold for VF induction increased markedly. In the absence of a state of Ca2+i overload. spontaneous defibrillation occurred within a minute after the initiation of VF. We conclude that 1) VF can be induced in the absence of Ca2+i oscillations; however. 2) Ca2+i oscillations play a crucial role as a trigger for VF and therefore are an important determinant of the vulnerability to VF; and 3) the augmented Ca2+i oscillations after the transition to VF state may support the maintenance of this type of arrhythmia.
Intracellular calcium transients in myocardium from spontaneously hypertensive rats during the transition to heart failure, To investigate the mechanism of impaired myocardial function after long-term pressure overload. we studied cardiac muscle mechanical contraction and intracellular calcium transients using the bioluminescent indicator aequorin. Left ventricular papillary muscle preparations were examined from three groups of rats: 1) aging spontaneously hypertensive rats (SHR) with clinical and pathological evidence suggesting heart failure (SHR-F group). 2) age-matched SHRs with no evidence of heart failure (SHR-NF group). and 3) age-matched normotensive Wistar-Kyoto rats (WKY group). Isometric force development was depressed in both SHR groups relative to the WKY group. Resting [Ca2+]i was lower in the SHR-F group. and the time to peak [Ca2+]i was prolonged in this group. The relative increases in peak [Ca2+]i with the inotropic interventions of increased [Ca2+]o and the addition of isoproterenol were similar among groups. Although inotropy increased in all groups with increased [Ca2+]o. after isoproterenol. inotropy increased only in the WKY group. Thus. in SHR myocardium. [Ca2+]i increased after isoproterenol. but inotropy failed to increase. Myosin isozymes were shifted toward the V3 isoform in both SHR groups; the V3 isoform was virtually 100% in papillary muscles from the SHR-F group. These changes may reflect events directly contributing to the development of heart failure or represent adaptive changes to chronic pressure overload and heart failure.
Role of the sarcolemma in triggered propagated contractions in rat cardiac trabeculae, We have recently described that after contractions propagate through multicellular cardiac muscle preparations. These propagating contractions are triggered in damaged regions of rat right ventricular trabeculae during relaxation of electrically stimulated twitches. Propagation of triggered contractions has been attributed to calcium ions that diffuse along the preparation. causing calcium-induced calcium release from the sarcoplasmic reticulum in adjacent cells. In the present study we have investigated a possible role of the sarcolemma and delayed afterdepolarizations (DADs) in the initiation and propagation of triggered propagated contractions (TPCs) in multicellular preparations. We studied whether 1) TPCs are accompanied by delayed sarcolemmal depolarizations. 2) such depolarizations mediate local contraction. and 3) an intact sarcolemma is required for propagation of contractions. TPCs that remained stable for prolonged periods of time could be induced by trains of 15 stimuli (2 Hz. 15-second intervals) at lowered temperature (19-21 degrees C) of the superfusing Krebs-Henseleit medium and a [Ca(2+)]o of 1.0-1.5 mM. Although TPCs could be induced at 38 degrees C and a [Ca2+]o of 3.0-4.0 mM. they disappeared within 10 minutes. Force was measured with a silicon strain gauge; length and shortening of sarcomeres were measured at two sites of the muscle using laser diffraction techniques. Membrane potential was measured with flexible microelectrodes. Saponin was used to selectively render the sarcolemma permeable to small ions and molecules. Propagation velocity of TPCs in intact trabeculae varied from 1.7 to 13.4 mm/sec at 19-21 degrees C. TPCs were accompanied by DADs that could reach threshold and induce triggered arrhythmias. Changes in latency. duration. and force of TPCs. induced by changing [Ca(2+)]o or the number of conditioning stimuli. were closely matched by changes in latency. duration. and amplitude of DADs; DADs consistently preceded TPCs. on average by 60 msec. Local heating of the muscle. by applying a current through an insulated platinum wire (diameter 100 microns) that touched the muscle. interrupted propagation of TPCs reversibly. DADs were. in the absence of a local contraction. still recorded distal to the heated site. In muscles that were treated with saponin and exposed to solutions approximating the intracellular milieu. spontaneously occurring local contractions that propagated in both directions (at velocities of 70-200 microns/sec) were elicited at a bathing calcium concentration of approximately 0.6 microM. Below this threshold. propagated contractions could be triggered by pressure ejection of a calcium-containing solution from a microelectrode positioned close to the trabecula.(ABSTRACT TRUNCATED AT 400 WORDS).
Relative roles of cardiac and arterial baroreceptors in vasopressin regulation during hemorrhage in conscious dogs, To determine the relative roles of cardiac and sinoaortic baroreceptors in mediation of arginine vasopressin (AVP) release. hemorrhage was performed in five groups of conscious splenectomized dogs: 1) all nerves intact; 2) either chronic surgical or acute pharmacological (intrapericardial lidocaine) cardiac denervation (CD); 3) chronic sinoarotic denervation (SAD); 4) combined chronic sinoartic denervation plus either chronic or acute cardiac denervation (SAD + CD); and 5) all nerves intact. but with ganglionic blockade. Hemorrhage (0.5 ml/min/kg) reduced mean arterial pressure similarly in the intact and CD groups. Decreases in mean arterial pressure were augmented in SAD. SAD + CD. and ganglion-blocked groups compared with responses in intact and CD groups. There were no differences in responses of plasma AVP to hemorrhage in the intact and CD groups. but the AVP response was significantly blunted in the SAD + CD group as compared with SAD alone. When compared during the early stage of hemorrhage. at the same reduction in mean arterial pressure. the rise in AVP was greater in the ganglion-blocked group than in the SAD + CD group. but was less than in the intact group. With a protocol to reduce mean arterial pressure by 20 mm Hg over the same period (42 +/- 0.6 minutes) in four of the groups. the blood volume required to reduce mean arterial pressure by 20 mm Hg was similar in the intact (20 +/- 1 ml/kg) and CD (21 +/- 1 ml/kg) groups. but was less in the SAD (12 +/- 1 ml/kg) and SAD + CD (12 +/- 1 ml/kg) groups. Again. similar increases were observed in AVP between the intact (50 +/- 9 pg/ml) and CD (51 +/- 9 pg/ml) groups. whereas increases in AVP were diminished in the SAD (11 +/- 3 pg/ml) and SAD + CD (7 +/- 2 pg/ml) groups. In the presence of an AVP antagonist. decreases in mean arterial pressure and increases in total peripheral resistance with hemorrhage were affected similarly in both the intact and CD groups. whereas hemodynamic impairment by AVP blockade was less marked in the SAD and SAD + CD groups. These results indicate that cardiac receptors are not the major regulators of AVP release during progressive hemorrhage in conscious dogs. However. when the complicating influences of sinoaortic reflexes were eliminated. a modest role for cardiac receptors was uncovered.
Oxalate, silicon and vanadium in acquired cystic kidney disease, We have investigated the importance of several clinical and laboratory parameters on the development of acquired cystic kidney disease (ACKD) as detected by ultrasonography in 19 patients who had received dialysis therapy for at least three years. We were particularly interested on the possible effect of the serum levels of oxalate and silicon. which can produce tubular obstruction. and that of vanadium. which can affect cell proliferation. The severity of ACKD increased with the duration of dialysis and was greater in men than in women. Positive correlations were observed between the grades of ACKD and the levels of hemoglobin. hematocrit. and parathyroid hormone. while there was a negative correlation between ACKD and serum ferritin levels. The serum levels of oxalate. silicon. and vanadium. pre- and postdialysis. were markedly and significantly higher than those in normal controls. but there was no significant correlation between these levels and the duration of dialysis therapy or severity of ACKD. The pre- and postdialysis levels of vanadium were not significantly different. while the levels of oxalate and silicon were significantly lower in the postdialysis samples. No significant correlations were detected between ACKD and age of the patients. blood pressure. protein catabolic rate. efficiency of dialysis index. or the serum levels of iron. sodium. potassium. calcium. phosphorus. aluminum. and beta 2-microglobulin.
Effects of an acute protein load on urinary albumin excretion in kidney donors, In six kidney donors with normal baseline urinary albumin excretion (UAE) we studied the behavior of the UAE after 150 g of a meat protein meal and after a carbohydrate meal of equal caloric (1.370 kcal). water (1 liter) and sodium content (51 mEq). The mean creatinine clearance (Ccr) increased significantly after a protein load at the first (p less than 0.01) and second hour (p less than 0.05). while it did not change after the carbohydrate meal. The mean UAE increased significantly after the protein meal at the first (p less than 0.05) and second hour (p less than 0.05). while after the carbohydrate meal the mean values were increased at the first (p less than 0.05). second (p less than 0.05) and third hour (p less than 0.05). Furthermore. the mean values of UAE after the protein meal were significantly higher (p less than 0.05) than those found at the same time after the carbohydrate meal. Diuresis and natriuresis increased significantly after both meals. These findings show that the increased UAE after the protein meal may be due to a further increase in Ccr in the hyperfiltering remaining kidney. while the smaller increase in the UAE observed after the carbohydrate meal may be due to water load and increased urine flow. which impairs albumin tubular reabsorption. The prognostic importance of microalbuminuria after either meal is therefore uncertain.
Pharmacokinetics of active vitamins D3, 1 alpha-hydroxyvitamin D3 and 1 alpha, 25-dihydroxyvitamin D3 in patients on chronic hemodialysis, Two active forms of vitamin D3. 1 alpha. 25-dihydroxyvitamin D3 (1 alpha. 25 [OH] 2D3) and 1 alpha-hydroxyvitamin D3 (1 alpha. [OH] D3) are widely used for treating osteodystrophy in patients with chronic renal failure. Since the pharmacokinetics of these agents during long-term oral administration are unclear. we measured the circulating concentrations of 1 alpha. 25 (OH) 2D before and after their long-term oral administration in patients receiving maintenance hemodialysis. After 12 weeks of treatment with a daily dose of 1 alpha. (OH) D3 (0.5 micrograms). the administration of a single dose (2 micrograms) of 1 alpha. (OH) D3 showed that the area under the curve over 24 h (AUC) was increased significantly compared with day 1 of therapy. In contrast. after the treatment with a daily dose of 1 alpha. 25 (OH) 2D3 (0.25 micrograms). a single dose of 1 alpha. 25 (OH) 2D3 (1 microgram) did not exhibit this effect on the AUC. A single dose of each agent produced no significant change in either the peak increment above basal values or the elimination half-time (T 1/2) of circulating plasma 1 alpha. 25 (OH) 2D. The overall basal concentration of 1 alpha. 25 (OH) 2D achieved by 1 alpha. (OH) D3 after 12 weeks of administration was cumulative. but this effect was not observed in patients on 1 alpha. 25 (OH) 2D3. These data indicate that the pharmacokinetics of the two forms of active vitamin D3 did not differ as to peak increment and T1/2 except for the AUC. even after long-term dosage.
Preoperative and postoperative evaluations by means of three-dimensional computed tomography in cases of Chiari osteotomy, Three-dimensional computed tomography was employed to investigate the changes of pelvic and hip morphology in nine adult cases of congenital hip dysplasia. Six cases were treated with Chiari pelvic osteotomy and were reexamined postoperatively using the same technique. This new method clearly showed a number of important anatomic features that were not easy to detect with conventional roentgenography. Information provided by three-dimensional computed tomography imaging is useful in selecting the appropriate type of surgical treatment and in evaluating the results of Chiari pelvic osteotomy.
The incidence of fracture of the proximal femur in two million Canadians from 1972 to 1984. Projections for Canada in the year 2006, Reported increases in the number of fractures of the proximal femur in Europe are greater than can be explained by demographic changes alone. This trend was assessed in Canada by examining hospital discharge records from the provinces of Saskatchewan and Manitoba from 1972 to 1984. The annual number of first fractures of the proximal femur in persons older than 50 years of age increased 59.7% in women and 42.2% in men during this time period. In most of the five-year age groups the percentage of increase in the number of fractures exceeded the percentage of increase in population of that age group. Annual age-specific incidences (by five-year age groups) increased exponentially with age. doubling every six years. and reached a maximum value of 4% in women older than 90 years of age. Annual age-adjusted incidences increased significantly over the study period in men and women. For the whole of Canada in 1987. it is estimated that there were 13.193 first fractures of the proximal femur in women and 4610 in men. and that in the year 2006 these will rise to 22.922 and 7846. respectively. The actual increase will be considerably greater if the age-specific incidences continue to increase as they have from 1972 to 1984. The gradual decline in physical activity. which contributes to bone loss. may be one etiological factor of this trend during the last half century.
Intraoperative measurement of rotational stability of femoral components of total hip arthroplasty, High out-of-plane forces acting on the hip joint can produce important rotational micromotion of the femoral component. This micromotion at the prosthesis interface may be detrimental to the stability of the implant. In cementless femoral implants this could prevent bone ingrowth. and in the cemented component this could cause generation of particulate debris. lysis. and loosening. The introduction of the torque wrench micrometer for assessment of intraoperative femoral component stability can quantify the initial stability of primary cementless femoral components and critically evaluate the stability (at either the initial or revision arthroplasty) of both cemented and cementless femoral components. It allows the surgeon to produce a known torque in the direction and magnitude of the out-of-plane forces that load the hip in vivo.
Some new trends of biomechanical studies in traumatology and orthopedics, This article presents four recent areas of research in biomechanics with clinical application. The first area describes quantification of the functional condition of the lower extremity using biomechanical parameters based on theoretical assumptions for a new mathematical model of walking. The second area describes the mechanism of spinal compression fractures from dorsal impact trauma. Preliminary data are derived from anatomic specimen studies. The third area is a description and justification of a new endoprosthetic design. including experimental observations on canine species. for total knee arthroplasties with a unique biomechanical design using a synthetic ribbon for creation of a "rolling joint." The fourth area of investigation deals with the normal and pathologic distribution of pressure on the plantar surface of the foot using an electronic measuring system. along with statistical indices; this system may be able to diagnose various foot deformities by automated methods.
Changes in patellofemoral compressive force after anterior or anteromedial displacement of tibial tuberosity for chondromalacia patellae, Patellofemoral compressive force was measured before and after anterior displacement of the tibial tuberosity for patellofemoral disorders on 30 knees in 28 patients. All patients selected for this experiment were those who obtained relief of pain in the activities of daily living. Twenty-five women and three men. with an average age of 54 years (range. 21-79 years). were followed an average of 38 months (range. 24-84 months). The maximum strength of knee extension was measured by a myodynamometer with the knee at 45 degrees flexion. Patellofemoral compressive force was calculated using a vector of quadriceps muscle power. At the final follow-up evaluation. the quadriceps lever arm increased in all knees with an average rate of increase of 20% +/- 2%. The maximum strength of knee extension increased in all but three knees with an average rate of increase of 147% +/- 27%. Patellofemoral compressive force increased in 22 knees. was unchanged in five. and decreased in three. with an average rate of increase of 67% +/- 15% compared with the preoperative level.
Rehabilitation after high tibial osteotomy and unicompartmental arthroplasty. A comparative study, Ten patients with medial gonarthrosis treated by unicompartmental arthroplasty were matched with ten patients who had high tibial osteotomy; their courses of rehabilitation were evaluated. All patients regained motion without problems. with no difference between the groups. Muscle torque was measured by a Cybex II dynamometer. The results six months postoperatively were better in the patients treated by unicompartmental arthroplasty than they were 12 months postoperatively in the patients treated by high tibial osteotomy. In the prosthesis group there was an increase in the maximal gait velocity and the duration of single support. In the osteotomy group there was no significant change. This difference in the results of rehabilitation constitutes an argument for arthroplasty in aged patients.
Prognosis for patients with medial gonarthrosis. A 16-year follow-up study of 189 knees, All 189 knees (157 patients) that had had primary medial compartment arthrosis in 1972 were followed until 1988. After 14 years. tibial osteotomy had been performed in 85 knees and arthroplasty in 33 knees. No major surgery had been performed in 71 knees; of these 71 knees. 31 patients (40 knees) had died. Of the remaining 23 patients (31 knees). the majority had an unsatisfactory knee and managed only on a low activity level. In 20 of 24 knees. progress of the arthrosis was recorded roentgenographically. Because natural course of medial gonarthrosis has a poor prognosis. the majority of patients suffering from this condition will eventually have major knee surgery.
Clinical course and roentgenographic changes of osteonecrosis in the femoral condyle under conservative treatment, The history of osteonecrosis in the femoral condyle of the knee was observed in 15 knees in 14 patients. averaging 62.8 years in age (range. 23-79 years). There were nine women and five men. The average follow-up period was 4.9 years (range. one to 12 years). Spontaneous osteonecrosis was found in 11 patients and steroid-induced osteonecrosis in three. The medial femoral condyles were involved in 13 knees and the lateral femoral condyles in two. The maximum width of the lesion was measured on anteroposterior roentgenograms and an osteonecrotic lesion less than 10 mm wide was rated as small. Cases of small osteonecrotic lesions displayed no remarkable changes with respect to stages and limb alignment. The average size of the steroid-induced osteonecrotic lesions was significantly larger than that of the spontaneous type. The size of the osteonecrotic lesions at the follow-up examination was compared to that observed at the initial diagnosis in 12 knees. Eight of these lesions displayed increases in dimension of more than 18% over the initial size at diagnosis.
Instability of the hindfoot after lesion of the lateral ankle ligaments: investigations of the anterior drawer and adduction maneuvers in autopsy specimens, The mobility patterns in the tibiotalocalcaneal joint complex with a solitary lesion of the anterior talofibular ligament (ATL) and a combined lesion of the ATL and calcaneofibular ligament (CFL) were studied in 22 human lower-extremity autopsy specimens mounted in a kinesiologic testing device. A solitary lesion of the ATL increased the anteroposterior (AP) laxity in the ankle joint in the entire range of flexion. with a maximum median of 3.1 mm in neutral flexion. Further cutting of the CFL increased AP laxity most obviously in dorsiflexion. A solitary lesion of the ATL resulted in a minor instability in adduction. whereas further lesion to the CFL increased adduction in the entire range of flexion. with a maximum median of 14.2 degrees in dorsiflexion. The anterior drawer maneuver can reveal a combined lesion of the ATL and CFL if performed with the tibiotalocalcaneal joint complex in dorsiflexion. Significant clinical instability in adduction will only take place when a combined lesion of the ATL and CFL is present.
Dislocation of the peroneal tendons in neonates and infants, Twenty-three cases of dislocation of the peroneal tendons were found during routine orthopedic examinations of neonates and infants. All but one case was without foot deformity. One case was treated with a cast. and the others received no treatment. Follow-up observations revealed that the dislocations resolved spontaneously in almost all cases. This condition seems to be not as rare as had been previously considered. Dislocations of the peroneal tendons in neonates and infants without foot deformity should be untreated and allowed to resolve spontaneously.
Treatment of forearm fractures by Hoffman external fixation. A study of 93 patients, Ninety-three patients with acute fractures of the diaphysis of one or both bones of the forearm were treated by a Hoffmann external fixator. using a half-frame configuration. Whenever possible. closed methods of reduction were used. The versatility of the Hoffmann external fixator allows multiple attempts and possible secondary resumption of the reduction. The half-frame configuration is stable enough. allowing the restoration and maintenance of the precise anatomy of the forearm bones and early active postoperative motion. The median length of retention of the external fixator was 13 weeks. Because of the elastic type of fixation. a solid periosteal callus was usually obtained. Non-union occurred in 8.5% of the patients. One refracture at the former fracture site was observed.
Ipsilateral radial head dislocation and radial shaft fracture. A case report, Dislocation of the radial head in an adult is an uncommon injury. The mechanism of injury is considered to be due to hyperpronation of the forearm. Fracture-dislocations of the forearm are well described and involve both the radius and the ulna. A dislocation of the head of the radius with an ipsilateral fracture of the shaft of the radius seems not to have been reported; the mechanism of injury can only be postulated.
Plating of the fibula. Its potential value as an adjunct to external fixation of the tibia, There is added stability when plate fixation of the fibula supplements the external fixator used in treating tibial fractures associated with a segmental defect. An anatomic specimen model of a Grade III open fracture of the tibia with an associated fibular fracture was used in this study. Fibular internal fixation using an AO standard plate was performed on one of each of five matched pairs of legs. These were then subjected to identical loads in compression and torsion. The numeric values obtained during loading in all modes were converted to ratios between each of the tested pair to directly compare the effect of stabilization of the fibula. The final results showed that in each case. the preparation with fibular plating had improved resistance to deformation in axial loading. On average. the plated specimens were 2.2 times stiffer. In torsion. plating the fibula did not appear to affect the resistance of the construct to the applied load. Supplemental plate fixation of the fibula in fractures of the tibia with segmental defects may improve subsequent morbidity. The increased rigidity of the system may be sufficient to allow partial to full weight bearing immediately after surgery. This may have significant value in the management of the polytraumatized patient.
Repair of three-month-old experimental meniscal lesions in rabbits, Repair of three-month-old longitudinal meniscal lesions in the central avascular portion of the knee joint was investigated in 18 rabbits. Three months after a longitudinal incision was made in the avascular portion of the meniscus. no healing was observed. At that time a full-thickness radial cut from the lesion to the joint capsule. without using synovial flaps or implants. was performed in ten of the 18 rabbits. Three months later. nine of the ten menisci had healed mainly with cartilaginous tissue. although the repaired areas were different from the normal fibrocartilage both histologically and at gross inspection. Synovitis with hyperplasia of the lining cells. which was present in all cases at the time of repair. may play an important role in the healing process.
Autologous marrow injection as a substitute for operative grafting of tibial nonunions, Autologous marrow injection was used to stimulate healing in 20 ununited tibial fractures over a five-year period. The technique was employed in conjunction with cast immobilization in ten cases and intramedullary nail fixation in ten cases. Marrow stimulated a callus formation sufficient to unite eight of the ten nonunions immobilized with casts and all ten of the fractures immobilized by intramedullary nails. Bone-marrow injection was as effective as past open autologous grafting but with considerably fewer disadvantages. The technique provides a promptly renewable and reliable source of osteogenic stem cells with numerous advantages compared with standard open-grafting techniques.
Forecasting of the course and outcome of shock in severe mechanical traumas, The ability to forecast the course and outcome of severe mechanical trauma would aid clinicians in making decisions concerning the treatment of patients. Multifactorial regression models. developed from data obtained from 933 patients with polytrauma and shock. have a high predictive value. A two-part data sheet was developed to give a rating system that predicts the duration of shock in patients that survive and the life span in patients that eventually die. Factors considered in developing the rating system include systemic hemodynamics. hematocrit number. blood density. arteriovenous difference in oxygen saturation. and rectocutaneous temperature gradient. among others.
HLA-D antigens and Paget's disease of bone, HLA-A. -B. -C. -DR. and -DQ antigens were determined in 25 Ashkenazi Jews with Paget's disease of bone. HLA-DR2 was more frequent in the Pagetic patients compared with 57 healthy controls of the same ethnic origin. This finding concurs with a previous report and raises the possibility that HLA-DR2 may be associated with Paget's disease of bone. probably by predisposing the bone cells to viral infection.
Bone growth and remodeling after distraction epiphysiolysis of the proximal tibia of the rabbit. Effect of electromagnetic stimulation, The effect of pulsed electromagnetic stimulation on bone formation was tested in a lower-limb-lengthening model in the rabbit. Limb lengthening was performed by distraction epiphysiolysis. A specially designed external distraction device allowed 10 mm of lengthening of the tibia. Coils to generate a pulsed electromagnetic field were clipped onto the distractor. Stimulation started after a distraction period of three weeks and was continuous for 18 weeks. A control group received the same treatment without stimulation. Bone formation in the elongated zone was evaluated by computed tomography. scintigraphy. and histology. Bone healing involved accretion of callus followed by a process of remodeling. resulting in the formation of a solid cortex. The formation of a diaphysislike structure at the original site of the metaphysis progressed from the distal end of the elongated zone upward. Electromagnetic stimulation had no effect on the rate or extent of bone formation and remodeling.
Microsurgery in hand and forearm reconstructive surgery, Recent developments in microsurgery have provided new approaches to the management of severe injuries of the upper extremities. Free vascularized autotransplants used in the treatment of severe hand and forearm injuries have provided significant advantages over conventional methods. in terms of both treatment and functional outcomes. These advances have reduced the treatment time and provided more effective treatment for patients.
The role of lysosomes in the pathogenesis of unicameral bone cysts, Unicameral bone cyst fluid possesses N-acetyl-beta-D-glucosaminidase. beta-glucuronidase. PZ-peptidase. cathepsin D. acid phosphatase. N-acetyl-beta-D galactosaminidase. and beta-galactosidase activities. The activities of lysosomal enzymes in the cyst fluid are. as a rule. higher than in the serum. whereas the total protein content is lower. The content of collagen degradation products in the cyst fluid is higher compared to the serum. In bone cavity wall tissues. the collagen content is decreased. Adenosine 3':5'-cyclic phosphate and cyclic guanosine 3.5'-monophosphate accumulate in the cyst cavity. However. in some cases. there is no correlation among the activities of lysosomal enzymes in the cyst fluid. blood serum. and cyst wall tissues. The ratios of lysosomal enzyme activities in the cyst fluid differ from those in the cyst wall tissues. cultured skin fibroblasts. and blood polymorphonuclear leucocytes. The lack of coincidence of enzymatic spectra of the cyst fluid. wall tissues. and serum is suggestive of the diversity of ways of lysosomal enzyme enter the cyst cavity. i.e.. blood. cyst fluid cells. and cyst cavity walls. The cysts with different locations (i.e.. active and latent cysts) have similar lysosomal lytic potentials. The presence in the cyst cavity of extracellular lysosomal enzymes and collagen degradation products testifies to the permanent corrosion of the cyst cavity walls from the inside as well as to the increase in the osmotic pressure of the cyst fluid. Lysosome destruction should be regarded as an important pathogenetic factor that requires surgical or pharmacologic correction or both in the course of bone cyst management.
Surgical correction of recurrent volar dislocation of the distal radioulnar joint. A case report, Recurrent volar dislocation of the distal ulna is an unusual injury. The role of various anatomic structures in providing stability of the distal radioulnar joint is controversial. Surgical reconstruction of the distal radioulnar joint was performed in a 25-year-old woman. A sling procedure was performed along with reconstruction of the fibrous osseous canal of the extensor carpi ulnaris (ECU). The ECU appears to play a role in stabilizing the distal radioulnar joint. When dislocation of the ECU tendon is noted intraoperatively. reconstruction of the fibrous osseous canal should be done.
Per Primam thumb replantation for all patients with traumatic amputations, Forty-two complete thumb replantations performed between 1980 and 1984 were reviewed. The mean follow-up time was 14 months. Replantation was attempted for all thumb amputations regardless of mechanism or severity of injury. Sixteen (38%) failed intraoperatively or postoperatively. Thumbs with narrow zones of injury showed a significantly higher survival rate than those with wide zones of injury. Eighty percent of those with poor arterial flow intraoperatively ultimately failed. despite pharmacologic treatment and multiple vein-graft anastomoses. Two thumbs with no vein repairs ultimately survived. Reexploration for loss of perfusion succeeded in 60% of cases. Total metacarpophalangeal and proximal interphalangeal active motion postoperatively averaged 68 degrees. Median static two-point discrimination returned to 11 mm. Avulsed thumbs survived in 46% of cases. Replantation should be attempted in all cases of thumb amputation. as success cannot be predicted by mechanism or severity of injury. Thumbs with poor intraoperative flow (20%) or no venous return (50%) can survive and should not be primarily amputated. Vein grafting is not mandatory if shortening allows anastomoses to be tension free. Prompt reexploration of acute vascular occlusions is worthwhile.
Results of innominate osteotomy in the treatment of Legg-Calve-Perthes disease, Twenty-seven patients with Legg-Calve-Perthes disease were treated by innominate osteotomy. Satisfactory results were achieved in 96% of the patients. with a mean follow-up period of 9.3 years. Eleven patients included in assessment seven years previously were reassessed. Ten of these 11 patients showed improvement with continued growth in the shape of the affected femoral heads. A preoperative center-edge angle of less than 20 degrees is of prognostic importance. The presence or absence of a subchondral fracture before and at the time of surgery has not been found to influence the long-term results significantly.
Persistence of supply dependency of oxygen uptake at high levels of delivery in adult respiratory distress syndrome, OBJECTIVE: To identify any plateau in oxygen consumption (VO2) when oxygen delivery (DO2) is increased in patients with the adult respiratory distress syndrome (ARDS). DESIGN: Clinical prospective study; multiple regression analysis was done to assess the relationship between VO2 and DO2 for pooled data and for each individual patient. SETTING: University hospital ICU. PATIENTS: Twenty consecutive patients aged 18 to 78 yrs (mean 43.5) in whom ARDS was present during their ICU stay. INTERVENTIONS: Multiple measurements were obtained in individual patients (mean number of measurements 40. range 20 to 83) and mathematical models were fitted to both pooled and individual patient data. DO2 ranged from 212 to 1550 mL/min.m2 with a maximum of 758 to 1550 mL/min.m2 (mean 1136). Because of the large variations between patients. it was not justifiable to describe a relationship for the pooled data and each case was analyzed individually. MEASUREMENTS AND MAIN RESULTS: We found the optimal regression model to be linear in 13 patients. cubic in four. and either cubic or linear in one. Two patients demonstrated no significant relationship. The relationship for the group was determined from each patient's data and was best described by linear regression. CONCLUSIONS: In no patient was there evidence of a plateau. despite high levels of DO2 being achieved in all patients.
Efficacy of dopamine and norepinephrine for treatment of hemodynamic compromise in amitriptyline intoxication, BACKGROUND AND METHODS: Dopamine and norepinephrine were evaluated for treatment of hemodynamic compromise in amitriptyline intoxication. Fifteen anesthetized dogs underwent hemodynamic monitoring and amitriptyline intoxication. and received three infusion rates of dopamine (5. 15. and 30 micrograms/kg.min) and three infusion rates of norepinephrine (0.25. 0.5. and 1.0 micrograms/kg.min). sequentially. with hemodynamic measurements at each dose. Data were analyzed using repeated-measures analysis of variance; p less than .05 was considered significant. RESULTS: Amitriptyline intoxication lowered cardiac output. peak left ventricular dP/dt. and mean arterial pressure (MAP). All doses of norepinephrine and the two higher doses of dopamine increased cardiac output. MAP. and peak left ventricular dP/dt during the intoxicated state. Both agents restored all variables to preintoxication values. Values obtained at the highest doses of the two drugs were not different for any variable. CONCLUSION: Dopamine and norepinephrine each appeared effective in reversing amitriptyline-induced hemodynamic alterations.
Echo/Doppler and hemodynamic correlates of vasodilator responsiveness in primary pulmonary hypertension, To determine correlates of acute vasodilator responsiveness in primary pulmonary hypertension. we retrospectively studied 25 patients. comparing 41 resting echo/Doppler and nine resting catheterization variables with the maximal reduction in pulmonary vascular resistance achieved during vasodilator trials. Twelve vasodilators were tested (mean. 5.6 drugs per patient; range. three to eight). Eight patients were vasodilator responsive. as defined by a reduction in pulmonary vascular resistance greater than or equal to 30 percent in response to at least one agent. Univariate and multivariate analyses revealed only Doppler pulmonic peak flow velocity to be an independent correlate of responsiveness (p less than 0.05). Responders differed from nonresponders in having a higher Doppler pulmonic peak flow velocity (PV) (SD 81 +/- 24 vs 64 +/- 15 cm/s; p = 0.05). lower mean right atrial pressure (RAP) (6 +/- 4 vs 13 +/- 7 mm Hg; p = 0.04). and longer median survival (37 vs 5 months; p = 0.03). Seven of eight responders had RAP less than or equal to 10 mm Hg. and all responders had PV greater than 60 cm/s. Seven of ten patients with both RAP less than or equal to 10 and PV greater than 60 and one of the 15 remaining patients were vasodilator responsive (p less than 0.001). Thus. echo/Doppler and invasive hemodynamic parameters correlate with acute vasodilator responsiveness in primary pulmonary hypertension. Patients with low PV and high RAP values were almost never vasodilator responsive. Doppler pulmonic peak velocity and mean RAP may be useful in identifying patients most likely to respond to acute vasodilator trials and those in whom testing is unlikely to yield positive results.
Peripheral vascular tone in sepsis, Septic shock is characterized as a distributive form of circulatory failure. We examined the relationship of changes in forearm arterial. venous. and microvascular tone to the severity of sepsis. The study population consisted of ten control patients. 15 patients with sepsis. and eight patients with sepsis and shock. Patients treated with inotropic. vasopressor. or vasodilator drugs were excluded from the study. Forearm venous capacity (MVC). forearm venous tone (F-VT). arterial blood flow (FBF). forearm arterial resistance (FAR). and hyperemic response (FBF-RH) were measured using air plethysmography. MVC was decreased and VT increased in septic and septic shock patients. FBF was decreased with modest increases in FAR in septic and septic shock patients. FBF-RH was significantly reduced in both septic and septic shock patients. Decreases in FVT and attenuation of the reactive response to hyperemia occurred early in sepsis in patients without clinical evidence of hypoperfusion. In our patients. progressive vasodilatation in skeletal muscle was not associated with severe sepsis. These changes appear to be proportional to the severity of sepsis and are most pronounced in patients with circulatory failure.
Nebulized atropine sulfate in the treatment of acute asthma, Conflicting reports have appeared concerning the role of anticholinergic agents in the treatment of acute asthma. This study was designed to determine whether atropine sulfate. the only anticholinergic agent currently available in the United States for nebulization. increases bronchodilation when added to an inhaled beta-adrenergic agonist during the initial treatment of an acute asthma attack. Adults asthmatics (n = 40) with acute asthma attacks were randomized to receive metaproterenol (5 percent solution. 0.3 ml) either alone or with atropine sulfate (2.5 mg). by nebulization. Spirometry. vital signs. and the presence of side effects 0. 30. 60. and 120 minutes after treatment were determined. There were no significant differences between the metaproterenol alone and metaproterenol plus atropine sulfate groups in regard to age. duration of asthma. baseline spirometry. or side effects. No differences were noted between the two groups regarding changes in FEV1 and FVC from baseline (expressed in milliliters or as a percentage of baseline) during the observation period. We conclude that nebulized atropine sulfate yields no additional benefit when added to metaproterenol during the initial treatment of an acute asthma attack.
A controlled trial of long-term bronchodilator therapy in cystic fibrosis, To evaluate the effect of long-term bronchodilator therapy in CF patients with demonstrated bronchial hyperresponsiveness. we first performed methacholine challenges to determine responsiveness. then entered 27 patients (16 methacholine responders and 11 nonresponders) into a two-month double-blind crossover trial of albuterol. 90 micrograms by inhalation four times a day vs placebo. Among the responders. daily PEFR measures improved significantly more during treatment with albuterol (12 +/- 32 L/min) than with placebo (-0.4 +/- 19 L/min; p less than 0.05). In addition. a clinically important level of improvement in PEFR (15 percent increase) was reached significantly more frequently in the responders. Methacholine nonresponders had no change in PEFR on either albuterol or placebo. Daily symptom scores as well as spirometry measurements at biweekly visits did not show significant changes. We conclude that long-term therapy with inhaled albuterol improves lung function in CF patients. but only in those with bronchial hyperresponsiveness as demonstrated by methacholine challenge.
Time course of recovery from frostbitten phrenics after coronary artery bypass graft surgery, Bilateral diaphragmatic paralysis developed in a patient after coronary artery bypass graft surgery during which cold cardioplegia was used. The patient's progress and eventual recovery over an 18-month period is described. with particular reference to chest wall motion and respiratory pressure measurements.
Conjugated estrogens reduce endothelial prostacyclin production and fail to reduce postbypass blood loss, Intravenous conjugated estrogens correct bleeding times and reduce bleeding in uremia. gastrointestinal telangiectasias. and liver disease. One study found a similar benefit in patients undergoing open heart surgery. The mechanism by which conjugated estrogens improve bleeding times is unknown. We report on the effect of estrogens on endothelial prostacyclin production and bleeding in coronary bypass surgery. In a randomized. double-blind trial. 16 male patients undergoing elective coronary artery bypass surgery received four daily infusions of conjugated estrogens (0.6 mg/kg/day) or placebo. preoperatively. Groups were similar with respect to age. preoperative hemostatic profiles. and pump time. Conjugated estrogens significantly reduced greater saphenous vein endothelial prostacyclin production in the estrogen group compared to control subjects. Postoperative blood loss was not reduced. with a trend toward increased blood loss in the treatment group. We have shown that conjugated estrogens reduce endothelial prostacyclin production and fail to reduce blood loss in coronary bypass surgery.
Temporal trends in chronic obstructive lung disease case fatality in hospitalized US veterans: 1970-1987, Vital statistics data have suggested that age-adjusted mortality from chronic obstructive lung diseases (CLD) is increasing. The present investigation has used the US Veterans Administration (VA) hospital computer database to determine whether trends in CLD case fatality follow trends in CLD population mortality. Data for male patients discharged from 172 VA hospitals from 1970 through 1987 were utilized. Patients were included if they had a CLD as a first-listed hospital discharge diagnosis. did not have any of a number of smoking-related cardiovascular or malignant diseases. and were born in the years 1900 through 1939. While crude case fatality for all CLD increased from 5.2 percent in 1970 to 7.4 percent in 1987. age-adjusted case fatality decreased from a peak of 8.5 percent in 1971 to 5.8 percent (95 percent confidence interval. 5.4 to 6.61 percent) in 1987. This trend was seen for all CLD diagnoses. including asthma. Age-specific case fatality decreased for each successive 5-year birth cohort. and age at death remained relatively constant over the last 14 years of the study. The declining case fatality could not be explained by changes in the ICD coding rubrics. The extent to which case fatality has been declining due to improved treatment and/or cohort-related changes in tobacco smoke exposure could not be determined definitively from the data.
Empyema thoracis. Factors influencing morbidity and mortality, The effects of delay in surgical treatment and the choice of operation on morbidity associated with empyema thoracis were evaluated in 122 consecutive patients. Patients (71 from a private practice and 51 from an inner-city trauma/indigent care facility) eligible for study were divided into treatment groups of chest tube only (CT = 39) and open drainage (OD = 19). or decortication (DC = 65). Delay in treatment was defined as greater than 3 days from recognition of empyema to CT and greater than 14 days to OD or DC when chest tubes were inadequate or were not used initially. Delay in OD significantly increased total illness (p = 0.023). days until removal of chest tubes (p = 0.037). and hospital stay (p = .048). but did not affect postoperative stay. Delay in DC increased total illness (p = 0.0001). but did not affect other variables. Delay in CT increased mortality from 3.4 percent to 16 percent. Delay did not increase mortality in OD and DC. DC was superior to OD in patients requiring major operation in total illness days (DC = 36.1 vs OD = 106.1) (p = 0.0005). days until removal of tubes (DC = 7.5 vs OD = 78.3) (p = 0.0001). and postoperative stay (DC = 11.6 vs OD = 17.3) (p = 0.018). Overall mortality was lowest in the DC group (6.1 percent). Delay in treatment increases morbidity and DC is more effective than OD in reducing morbidity and mortality when surgical intervention is necessary.
A 19-year follow-up of tuberculin reactors. Assessment of skin test reactivity and in vitro lymphocyte responses, Tuberculin skin test reactivity decreases with time such that repeat PPD skin testing may result in reactions of less than 10 mm. This reactivity may be boosted in some individuals with a second tuberculin skin test. The immunologic basis of these observations remains unclear. We studied the relationship between skin-test reactivity and in vitro blastogenic response to PPD in a cohort of 22 individuals (aged 28 to 81 years) known to be tuberculin reactors (induration greater than or equal to 10 mm) in 1970. In 1989. 18 subjects remained reactive to PPD on the first skin test and responded to PPD in vitro (mean incorporation of 3H-thymidine by peripheral blood mononuclear cells. 22.650 cpm). Three subjects reverted (induration in response to PPD less than 10 mm) and lost in vitro reactivity to PPD (mean incorporation of 3H-thymidine. 2.205 cpm). One subject boosted (increase of induration of at least 6 mm to greater than or equal to 15 mm) on the second skin test and showed a concomitant in vitro boost in the blastogenic response to PPD (from 1.008 cpm to 47.837 cpm). In this cohort. interpretation of the two-step tuberculin skin test correlated closely with in vitro proliferative responses. Over a 19-year period. the majority of individuals maintained skin test reactivity and strong in vitro responses to PPD despite a lack of ongoing exogenous exposure to Mycobacterium tuberculosis. The immunologic basis for reversion appears to depend in part on a loss of lymphocyte blastogenic capacity. In the one individual who exhibited the booster phenomenon. repeat antigen stimulation resulted in a dramatic increase in the in vitro blastogenic responses.
Bronchoalveolar lavage cell data in amiodarone-associated pneumonitis. Evaluation in 22 patients, To assess the value of bronchoalveolar lavage (BAL) for diagnosis. understanding. and treatment of amiodarone-associated pneumonitis. we examined the results of BAL total and differential cell counts and phenotyping of lymphocytes in 22 patients with this lung disorder and in 33 normal subjects. Overall. the total cell count was found to be almost the same as that seen in control subjects; the macrophage population was significantly reduced. and the lymphocyte. neutrophil. and eosinophil populations were increased in absolute number and percentage. When results were analyzed individually. BAL data appeared to be distributed according to two patterns. In the first pattern. there was no abnormal lymphocytosis. In the second pattern a lymphocyte alveolitis was found in percentage and in absolute number. This lymphocyte alveolitis was present either alone or associated with neutrophil alveolitis or with eosinophil alveolitis. In the first pattern. despite the normal level of the lymphocyte population. the percentage of CD4 T-lymphocytes and the CD4:CD8 T-lymphocyte ratio were significantly lowered. In the second pattern the CD8 T-lymphocyte count was increased in absolute number and percentage. with a low CD4:CD8 ratio. In six patients relavaged two to four months after amiodarone withdrawal. there was a significant fall in alveolar lymphocytosis. but the progressive increase in the neutrophil population over time seemed to be associated with the seriousness and progression of the disease. Finally. these findings closely resembled those obtained in patients with hypersensitivity pneumonitis due to inhalation of organic dust and suggest that an underlying immunologic cell-mediated mechanism may play a role in this iatrogenic pulmonary disease.
Suppression of ventilatory muscle activity in healthy subjects and COPD patients with negative pressure ventilation, We evaluated the ability of NPV to suppress EMGd and EMGint in seven patients with severe COPD and five normal subjects. Subjects were studied either without (A) or with mouthpiece and nose clip (B). Electromyographic suppression was assessed comparing EMG activity during NPV with the control activity without a mouthpiece and prior to the initiation of the NPV run. In normal subjects. in A. NPV resulted in a partial suppression of EMGd; in B. prior to NPV. EMGd rose compared with A prior to NPV. In patients. in A. NPV resulted in a suppression of both EMGd and EMGint. In B. prior to NPV. both EMGd and EMGint rose compared with A prior to NPV. Thus. it seems that NPV is able to produce a consistent reduction in inspiratory muscle EMG activity. This variable NPV ability would have to be assessed for better selection criteria for patient candidates in a rehabilitation program.
The COPD Self-Efficacy Scale, Many individuals with COPD develop a lack of confidence regarding their ability to avoid breathing difficulty while participating in certain activities. however minimal the physical demands of the activity may be. This lack of confidence may be expressed as low self-efficacy. As a result of low self-efficacy. COPD patients may refrain from many routine activities of daily living. Identifying situations in which individuals with COPD experience low self-efficacy would allow the development of specific treatment interventions designed to increase the patient's self-efficacy in those situations and consequently increase activity. We developed a 34-item COPD Self-Efficacy Scale (CSES) to assess self-efficacy in individuals afflicted with COPD. The CSES has good test-retest reliability (r = .77). excellent internal consistency (Cronbach's alpha = .95). and a five-factor structure (negative affect. intense emotional arousal. physical exertion. weather/environmental. and behavioral risk factors.
Facilitation of mechanical ventilation in status asthmaticus with continuous intravenous thiopental, Mechanical ventilation in status asthmaticus is associated with a significant mortality and morbidity. To facilitate intermittent positive pressure ventilation (IPPV). we have used continuous IV thiopental (thiopentone) together with traditional ventilatory techniques. With this policy. we were able to achieve rapid correction of arterial blood gas tensions in a group of 20 severe asthmatics requiring IPPV. By 1 hour. peak airway pressure (PAP) had fallen from 58.6 +/- 15.7 to 30.2 +/- 10.9 cm H2O (p less than 0.001). During the same period. PaCO2 fell from 51.3 +/- 15.3 to 40.17 +/- 8.2 mm Hg (p less than 0.05) and pH rose from 7.25 +/- 0.1 to 7.33 +/- 0.1 (p less than 0.001). Morbidity was low and in particular. no episode of barotrauma was noted. All patients survived the acute attack and were successfully liberated from the ventilator. We conclude that these results are largely attributable to our use of early and continuous IV anesthesia induced by thiopental.
Tidal volume reduction in ARDS. Effect on cardiac output and arterial oxygenation, During continuous positive pressure ventilation (CPPV). mean airway pressure and lung volume will be influenced both by the tidal volume (VT) employed and the amount of positive end-expiratory pressure (PEEP). The effect of varying levels of CPPV on PaO2 and cardiac output (Q) has been previously assessed by adjusting the level of PEEP at constant VT. This study examined the influence of a 200-ml reduction in VT. at a constant PEEP of 15 cm H2O. on the PaO2 and Q of 21 patients with adult respiratory distress syndrome (ARDS). The relationship between change in Q and change in total respiratory system compliance (Cst) after VT reduction was also examined. VT reduction from 14.1 +/- 0.8 ml/kg to 11.2 +/- 0.9 ml/kg yielded an increase in Q (+ 15 +/- 12 percent. p less than 0.01) without a significant change in PaO2 (-6.3 +/- 15.0 mm Hg. p = 0.08). Cst increased with VT reduction (+ 3.1 +/- 1.8 ml/cm H2O). There was only a modest correlation (r = +0.42. p = 0.06) between delta Q percent and delta Cst following VT reduction. VT reduction at high level PEEP may yield a significant improvement in Q and net O2 delivery. but the degree of hemodynamic improvement is variable and is not reliably predicted noninvasively by measurement of Cst.
Angiographic evolution of coronary atherosclerosis in patients receiving propranolol. A two-year follow-up, STUDY OBJECTIVE: To test whether propranolol may influence the progression of coronary atherosclerosis. DESIGN: Repeat coronary angiography after two year treatment and evaluation of changes in coronary narrowings. SETTING: Subjects with effort angina of recent onset requiring coronary angiography and medical treatment. PATIENTS: 80 untreated patients. with a greater than or equal to 50 percent focal narrowing on a major coronary branch associated or not with a less than 50 percent stenosis of other major branches. They were randomized to isosorbide dinitrate (40 mg bid) (group 1. control group) or to propranolol (80 mg qid) (group 2. treatment group). RESULTS: At restudy. there were more diseased vessels and These narrowings per patient in both groups. Multivessel involvement and greater than or equal to 50 percent obstructions were also augmented. These changes were not statistically significant. Patients with progression of the stenotic tracts (both greater than or equal to 50 percent and less than 50 percent were 19 (48 percent) in group 1 and 28 (70 percent) in group 2 (p less than 0.05). Narrowings with progression were 25 in group 1 and 48 in group 2. Thirteen narrowings in group 1 and 15 in group 2 were newly detected at restudy. Eighteen patients (45 percent) in group 1 and nine (23 percent) in group 2 had a steady disease. Smoking. high blood pressure. family history of coronary disease. blood glucose values and lipid levels were considered; the only significant group differences were 31 percent rise of total triglyceride and 23 percent decrease of HDL cholesterol in patients who were treated with propranolol. CONCLUSIONS: Propranolol showed an adverse influence on coronary atherosclerosis. regarding the evolution of both greater than or equal to 50 percent and less than 50 percent narrowings and not the formation of new stenoses. Changes in serum lipid values might have a role.
Surgical drainage of lung abscess complicating acute community-acquired pneumonia, Two cases of severe community-acquired pneumonia requiring IPPV and complicated by the development of lung abscess were successfully treated with early surgical drainage. This procedure may be a life-saving measure in certain instances.
Pneumonia preceding respiratory failure. A rare, easily misleading clinical manifestation in adult Arnold-Chiari malformation, A 47-year-old woman was admitted for bilateral lower lobe pneumonia with respiratory distress. Two episodes of respiratory failure developed despite improvement of pneumonia after antibiotic chemotherapy. Loss of consciousness and quadriplegia accompanied the last episode of respiratory failure. Arnold-Chiari malformation type 1 was diagnosed and a suboccipital craniectomy was performed. The neuromuscular and respiratory disorders greatly improved after operation. We believe that ACM 1 should be considered when an adult develops unexpected respiratory failure after improvement of the primary pulmonary condition. This disease is potentially treatable by surgical management. and if it is misdiagnosed. will be fatal.
Hemoptysis complicating AICD patch placement controlled by temporary selective bronchial balloon occlusion, This is the first reported case of an automatic implantable cardioverter-defibrillator patch placement complicated by hemoptysis. It is also notable because the patient's massive hemoptysis was managed by a balloon occlusion catheter inserted into the segmental bronchus through the endotracheal tube with fluoroscopic guidance.
A world record marathon runner with silent ischemia without coronary atherosclerosis, A 62-year-old world record marathon runner was found to have silent ischemia manifested by a very abnormal stress test. whereas at autopsy nine months later. there was virtually no coronary atherosclerosis nor other disease of the coronary microvasculature. However. there was focal fibrosis of the papillary muscles consistent with remote ischemia secondary to possible CV. It is postulated that endurance-related high catecholamine levels might have been responsible.
Prostate cancer, Prostate cancer is the most common malignancy in men and the second leading cause of cancer deaths. Although the mortality rate for prostate cancer has remained unchanged for 50 years. new advances have changed classic concepts in the diagnosis and management of patients with this disease. Our understanding of the anatomy and natural history of patients with prostate cancer has been enhanced. The ability to diagnose early stage prostate tumors has been improved by the introduction of prostate-specific antigen and transrectal ultrasound. Clinical staging of patients with prostate cancer has been refined. which has decreased adverse effects of inappropriate treatment. Modifications in the technique of radical prostatectomy have minimized the morbidity associated with this procedure. making it a more attractive therapeutic option. DNA ploidy analysis holds promise as a predictor of response to hormonal therapy. New agents are available to reduce adverse effects of hormonal therapy. In addition. traditional ideas about the timing of hormonal therapy and the use of total androgen blockade are being challenged. These changes may presage an improved quality of life and improve survival for patients with prostate cancer.
Management of solitary pulmonary nodules, The solitary pulmonary nodule (SPN). a single intrapulmonary spherical lesion that is fairly well circumscribed. is a common clinical problem. About half of SPNs seen in clinical practice are malignant. usually bronchogenic carcinomas. Some nodules are primary tumors of other kinds or metastatic. Virtually all benign SPNs are tuberculous or fungal granulomas. The standard management of the SPN of unknown cause is prompt surgical removal unless benignity is established by prior chest roentgenograms showing that the nodule has been stable (i.e.. showing no growth) for 2 years or by the presence of a "benign" pattern of calcification. Less universally accepted criteria for benignity include (1) transthoracic needle aspiration biopsy (TNAB) showing a specific benign process. and (2) patient's age under 30 to 35 years. Bronchoscopy has a low diagnostic yield. particularly for benign nodules. SPNs usually grow at constant rates. expressed as the "doubling time" (DT). A nodule with a DT between 20 and 400 days is usually malignant. Benign nodules usually have a DT greater than 400 days. The prospective determination of DT by serial chest roentgenograms (the "wait and watch" strategy) is widely criticized but has clinical utility in special circumstances. particularly if the likelihood of malignancy is low and/or the anticipated surgical mortality is high. The presence and pattern of calcification are best shown by high-resolution thin-section computed tomography (CT). Diffuse. laminated. central or "popcorn" patterns of calcification indicate benignity. An eccentric calcium deposit or a stippled pattern does not rule out malignancy. CT densitometry will often show "occult" calcification in nodules that show no direct visual evidence of calcium deposition. The characteristics of the edge of the nodule correlate with the likelihood of malignancy. Nodules with irregular or spiculated margins are almost always malignant. The probability that the nodule is malignant (pCA) is related to the age of the patient. the diameter of the nodule. the amount of tobacco smoke inhalation. the overall prevalence of malignancy in SPNs. the nature of the edge of the lesion. and the presence or absence of occult calcification. It is possible by Bayesian techniques to combine these factors to calculate a more precise and comprehensive prediction of pCA in any given nodule. The 5-year survival after nodule resection depends on the size of the nodule at the time of surgery; it may be as high as 80% with nodules that are 1 cm in diameter. Lymph node involvement is uncommon with small tumors. and many authorities question the need for CT staging in such cases.(ABSTRACT TRUNCATED AT 400 WORDS).
Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women, We have previously described hypertrophy of neurons containing estrogen receptor mRNA in the infundibular nucleus of postmenopausal women. In the present investigation we identified peptide mRNAs in the hypertrophied neurons and determined whether postmenopausal neuronal hypertrophy was accompanied by changes in gene expression. In the first study in situ hybridization was performed on sections from hypothalami of postmenopausal women (n = 3) using synthetic 35S-labeled cDNA probes complementary to mRNAs encoding estrogen receptor. substance-P (SP). neurokinin-B (NKB). POMC. cholecystokinin. dynorphin. CRF. enkephalin. galanin. neuropeptide-Y. GH-releasing hormone. and tyrosine hydroxylase. Neuronal cross-sectional areas and cell densities were measured with the aid of a computer microscope system. Neurons labeled with the NKB and SP probes were comparable in size. morphology. and distribution to the hypertrophied neurons containing estrogen receptor mRNA. In contrast. neurons labeled with other cDNA probes were sparsely distributed (CRF and dynorphin). smaller in size (neuropeptide-Y. galanin. GH-releasing hormone. enkephalin. cholecystokinin. and POMC). or located anterior to the hypertrophied population (tyrosine hydroxylase). In the second study sections from hypothalami of premenopausal (n = 3) and postmenopausal (n = 3) women were incubated with cDNA probes complementary to SP or NKB mRNAs. The mean cross-sectional areas of postmenopausal infundibular neurons containing NKB and SP mRNAs increased to 194% and 176% of premenopausal values. respectively. The autoradiographic grain densities of infundibular neurons labeled with either probe were also significantly increased in the postmenopausal group. Finally. the numbers of labeled neurons/tissue increased 6-fold (SP) and 15-fold (NKB) in the postmenopausal infundibular nucleus. These data demonstrate that human menopause is associated with marked increases in hypothalamic NKB and SP gene expression. We propose that neurons containing estrogen receptor. SP. and NKB mRNAs participate in the hypothalamic circuitry regulating estrogen negative feedback in the human.
Hypocalcemic effect of physiological concentrations of corticosterone in adrenalectomized-parathyroidectomized rats, We have confirmed the serum calcium-raising effect of adrenalectomy in young male rats 5-6 h after parathyroidectomy that was first observed by others many years ago. (The phenomenon has also been reported in cats. dogs. and mice.) In addition. we have shown that adrenalectomy raises the serum ionized calcium as well as total calcium and that the effect occurs in young female as well as in young male rats. Furthermore. we have found that the serum calcium-raising effect of adrenalectomy occurs if the adrenalectomy is performed several days before parathyroidectomy or 6 h after parathyroidectomy. as well as at the same time as the parathyroidectomy. When the rats were adrenalectomized 7-9 days before parathyroidectomy and given small daily life-maintaining doses of corticosterone or cortisone acetate. this glucocorticoid treatment did not reverse the adrenalectomy effect. This led us to think at first that the effect of adrenalectomy must be due to the loss of an unknown adrenal factor rather than to loss of glucocorticoid. Additional experiments. however. in which corticosterone or hydrocortisone was administered by continuous release pellets. demonstrated conclusively that a small continuous supply of corticosterone (within the physiological range as determined by immunoassay of plasma) was sufficient to reverse the adrenalectomy effect. The results with hydrocortisone were similar at even lower doses than of corticosterone. Somewhat higher doses of corticosterone or hydrocortisone reduced the serum calcium even below the parathyroidectomy level. In a preliminary investigation of the specificity of the glucocorticoid effect we found that aldosterone. dehydroepiandrosterone. or estradiol had no effect on serum calcium under similar conditions. We conclude that the fall in serum calcium after parathyroidectomy in rats is due in part to the hypocalcemic effect of endogenous corticosterone. Thus. the loss of corticosterone after adrenalectomy explains the serum calcium-raising effect of adrenalectomy in parathyroidectomized rats. These results also suggest that glucocorticoids at physiological levels have a significant effect on calcium metabolism in general.
Tissue-specific expression and thyroid hormone regulation of the endogenous placental growth hormone variant and chorionic somatomammotropin genes in a human choriocarcinoma cell line, Human (h) placenta-derived choriocarcinoma cell lines (BeWo. JAR. and JEG-3) were examined for expression of pituitary GH (hGH-N) as well as placental GH variant (hGH-V) and chorionic somatomammotropin (hCS. encoded by the hCS-A or hCS-B gene). RNA was isolated and assessed using hGH-N complementary DNA since hGH and hCS genes share more than 90% sequences similarity. The relative expression is BeWo greater than JAR greater than JEG-3. In BeWo cells expression of placental hCS-A. hCS-B. and hGH-V genes. but not pituitary hGH-N. is observed using polyadenylated RNA and oligonucleotide probes specific for the different family members. The absence of hGH-N expression in BeWo cells is not due to deletion or gross rearrangement of the gene. No difference was seen between the hGH/hCS genes in genomic DNA from these cells and the DNA from placenta and pituitary when analyzed by restriction digestion and blotting. Treatment of BeWo cells with 10 nM T3 results in a 6-fold increase in messenger RNA from placental members of the hGH gene family. Levels of hCS-A. hCS-B. and hGH-V transcripts are all elevated. Cellular and secreted proteins from BeWo cells were analyzed by Western blotting. and a band of about 22 kilodaltons was detected using a polyclonal antibody which cross-reacts with hGH-V and hCS. The level of 22 kilodalton band in samples of cellular as well as released protein was increased by T3 treatment. BeWo cells provide a model system for studying hGH-V and hCS regulation as well as tissue-specific expression.
Characterization of a liver low Michaelis-Menten constant 3',5'-cyclic adenosine monophosphate phosphodiesterase activity sensitive to thyroid status, These studies were undertaken to assess the subcellular distribution and some biochemical properties of the hepatic cAMP phosphodiesterase(s) whose activity is modulated by the thyroid status in the rat. Thyroidectomy led to a 2-fold increase in low Michaelis-Menten constant (Km) cAMP phosphodiesterase activity in Golgi-endosomal fractions. but little affected this activity in crude particulate fractions. On analytical sucrose density gradients. an increase in cAMP phosphodiesterase activity in particulate elements which equilibrated at densities 1.17-1.22 was also observed. Acute insulin treatment did not further increase cAMP phosphodiesterase activity in Golgi-endosomal fractions of thyroidectomized rats. Up to 75% of the cAMP phosphodiesterase activity associated with Golgi-endosomal fraction of euthyroid and hypothyroid rats was inhibited by cGMP (IC50. 10 microM and 1 microM. respectively). Activity was also potently inhibited by griseolic acid. cilostamide. and cilostazole (IC50. less than 1 microM) but was much less sensitive to R0-20-1724 (IC50. 1 mM). Treatment of Golgi-endosomal fractions by a hypotonic extract of rat liver lysosomes led to the solubilization of 50% of low Km cAMP phosphodiesterase activity. On sucrose density gradients. the solubilized activity migrated as a slightly asymmetrical peak with a sedimentation coefficient of 6 S in euthyroid rats and 6.9 S in hypothyroid rats. On nondenaturing polyacrylamide gel electrophoresis. the activity migrated as two majors peaks with Rf values of 0.23 and 0.50; only the activity associated with the fast-moving peak was increased by thyroidectomy. On diethylaminoethyl-Sephacel chromatography. four peaks of cAMP phosphodiesterase activity. two of which were cGMP-inhibitable. were resolved. Thyroidectomy increased the activity associated with one of the cGMP-inhibitable peaks (eluted at 0.7-0.9 M sodium acetate) and led to the appearance of a new peak of activity (eluted at 0.4 M). which was not sensitive to cGMP. These results show that the low Km phosphodiesterase activity associated with liver Golgi-endosomal fractions. previously shown to be increased in hyperinsulinemic rats. is also increased in hypothyroid animals. They also suggest that. based on pharmacological and physical criteria. the enzyme species affected by the thyroid status belongs to the cGMP-and cilostamide-inhibited subclass of low Km cAMP phosphodiesterases.
Assessment of glucose transporter gene expression using the polymerase chain reaction, We used a novel adaptation of the polymerase chain reaction to examine relative levels of mRNA encoding two members of the facilitative glucose transporter gene family. the GLUT1 or erythrocyte/HepG2/brain isoform and the GLUT4 or insulin-regulatable isoform. The method was fast (vs. hybridization methods). required no specific probe. and used total RNA samples of less than 1 microgram. Taking advantage of regions of structural similarity and differences between the two isoforms. we designed a single set of oligonucleotide primers capable of amplifying both GLUT1 and GLUT4 cDNAs such that their respective products could be resolved on the basis of a 12 base pair size differential. Hence. reverse transcription and complementary DNA amplification could be carried out for both transcripts using identical primers in the same reaction tube. Using this methodology. we examined the relative amounts of GLUT4 and GLUT1 mRNAs in several rat tissues. As expected based on prior reports using Northern analysis. rat brain contained only GLUT1 mRNA and skeletal muscle contained a large predominance of GLUT4 mRNA. Both isoform mRNAs were found in adipose tissue whereas adipose cells. heart and diaphragm contained predominantly GLUT4 mRNA. Induction of diabetes with streptozocin decreased the GLUT4 to GLUT1 ratio in adipose tissue 4-fold and 24 h of insulin treatment of the diabetic rats increased this ratio 9- to 10-fold. Insulin treatment of normal rats increased this ratio by 70%. Hindlimb skeletal muscle GLUT4 mRNA was quantified in diabetic and insulin-treated diabetic rats as a function of brain GLUT1 mRNA added as an internal standard. Using this methodology. no significant difference in muscle GLUT4 mRNA was noted as a result of 24 h of insulin therapy. In summary. quantitative PCR may be used to compare mRNA levels encoding specific members of a gene family either within given cells or tissues or as affected by physiological perturbations. Subject to certain limitations discussed within. this methodology may be useful in future measurements of glucose transporter mRNA. especially when only small tissue or cell samples are available.
Effects of N-methyl-D,L-aspartic acid on luteinizing hormone secretion in normal mice and in hypogonadal mice with fetal preoptic area implants, Many aspects of reproductive function are corrected in hypogonadal mice with preoptic area grafts (HPG/POA). Gonadotropin release and gonadal development are dependent on the presence of GnRH cells within the grafts and GnRH innervation of the median eminence. This study examined the effect of a known modulator of GnRH secretion. N-methyl-D.L-aspartic acid (NMA). in adult normal and HPG/POA male and female mice. All HPG/POA males had significant testicular development after graft surgery. and most HPG/POA females were in constant vaginal estrus and showed ovarian and uterine development; a few also demonstrated ovulatory cyclicity after pregnancies initiated by reflex ovulation. Groups of normal and HPG/POA males that were intact (INT) or castrated (CX) 7 days before testing were challenged with saline. NMA (20 mg/kg). and GnRH (100 ng/0.1 ml). Sequential blood samples from awake animals were obtained via intracardiac catheters for evaluation of plasma LH. There were significant increases in plasma LH after NMA challenge in normal INT [n = 15; 0 min. 0.26 +/- 0.02 (mean +/- SE); 10 min. 1.20 +/- 0.10 ng/ml; P less than 0.05] and normal CX (n = 13; 0 min. 0.36 +/- 0.06. 10 min. 3.25 +/- 0.27). Plasma LH secretion in response to NMA was significantly correlated (r = 0.786; P less than 0.001) with plasma LH release after the GnRH challenge in normal males. In contrast. only 3 of 17 HPG/POA (1 INT and 2 CX) showed increased circulating LH after NMA challenge. despite heightened pituitary sensitivity to GnRH. Normal and HPG/POA female mice were ovariectomized (OX) or OX and estrogen primed (OXE2) 7 days before testing. Intact cycling normal and cycling HPG/POA mice were tested in estrus (EST). There was a greater response to NMA in normal OX (n = 8; 0 min. 0.39 +/- 0.02; 10 min. 1.44 +/- 0.28) than in OXE2 (n = 13; 0 min. 0.29 +/- 0.01; 10 min. 0.52 +/- 0.07) despite similar gonadotroph sensitivity to GnRH. There was also a significant increase in plasma LH in response to NMA in HPG/POA-OX (n = 7; 0 min. 0.50 +/- 0.10; 10 min. 1.62 +/- 0.22) and HPG/POA-OXE2 (n = 12; 0 min. 0.39 +/- 0.04; 10 min. 1.31 +/- 0.26). Plasma LH levels after NMA treatment were significantly correlated with responses to GnRH in female HPG/POA (r = 0.58; P less than 0.03). but not in normal females. Neither normal-EST nor HPG/POA-EST had increased LH release after NMA challenge. perhaps due to the low gonadotroph sensitivity in this state.(ABSTRACT TRUNCATED AT 400 WORDS).
Porcine adrenal adrenocorticotropic hormone receptors: characterization, changes during neonatal development, and response to a stressor, ACTH receptors were characterized in the porcine adrenal cortex using a biologically active [125I] Tyr23.Phe2.Nle4ACTH(1-38) analog. and a 149.000 X g(av) total particulate tissue preparation. Binding of this labeled ACTH analog to adrenocortical ACTH receptors was demonstrated to be time and temperature dependent. tissue and hormone specific. saturable. reversible. have a binding optimum at pH 7.5. and be dependent on the presence of Ca++. Scatchard analyses of saturation data using the computer program LIGAND indicated a single class of high affinity binding sites [association constant (Ka) = 2.00 +/- 0.25 10(9) M-1)]. Hill plots of saturation data had slopes (b = 0.83 +/- 0.09) that did not differ from 1. and hence also indicated a single class of binding sites. The rate constant of association (k1 = 3.72 +/- 1.19 X 10(8) min-1M-1) was compatible with the known rapidly occurring action of ACTH in pigs in vivo. Kinetic experiments also indicated the ACTH receptors to be of high affinity (4.18 +/- 0.54 X 10(10) M-1; n = 4). Receptor-associated degradation occurring to analog during incubations involved cleavage of the peptide into fragments rather than deiodination and could be partially prevented by use of 0.01% bacitracin. Subsequently. a study was conducted to determine changes in the ability of piglets to respond. in terms of plasma cortisol. to the physiological and psychological stressor of overnight maternal deprivation (MD) at various neonatal ages (days 3-31 of age); to measure age-related and stressor-associated changes in adrenal ACTH receptors; and to associate any changes in adrenal response with changes in ACTH receptors. Plasma cortisol obtained by venipuncture did not vary with age in either control or MD piglets but was elevated by MD (16.98 +/- 2.5 vs. 68.3 +/- 8.2 ng/ml). There was no effect of MD and associated hormonal perturbations on adrenal ACTH receptors. However. there were significant age-related differences in these receptors. with a 1.6-fold increase in concentrations (55.6 +/- 12.0 fmol/mg protein). and a 63% decrease (P less than 0.05) in affinity (4.19 +/- 0.86 x 10(8) M-1) evident at 17 days of age compared with 10 and 24 days of age. The significance of these age-related changes in ACTH receptors for adrenal function remains to be determined; however. it is evident that in neonatal pigs. there is no stress nonresponsive period.
Differential effects of prolonged hyperglycemia on in vivo and in vitro insulin secretion in rats, The purpose of this study was to investigate the effects of a 48-h glucose (30% wt/vol) infusion in unrestrained catheterized healthy rats (HG) on subsequent in vivo and in vitro insulin response to glucose. High hyperglycemia (400-450 mg/dl) and resulting hyperinsulinemia (1.2 +/- 0.1 mU/ml vs. 0.15 +/- 0.03 mU/ml in controls) were maintained throughout the infusion period. Glucose-induced insulin secretion was examined in vivo 3 h after the end of infusion by performing either a glucose tolerance test or a hyperglycemic clamp (225 mg/dl for 60 min). In addition. in vivo insulin secretion was studied on day 1. 3. 5. and 7 after the end of glucose infusion by performing glucose tolerance tests. Insulin secretion was also investigated in vitro. using the isolated perfused pancreas technique. 3 h and 1 day post glucose infusion. During glucose tolerance tests and hyperglycemic clamps performed at 3 h. insulin secretion was much greater in HG rats than in controls. and remained increased until day 5. By contrast. when studied in vitro 3 h after the end of the infusion. glucose-induced insulin release from isolated perfused pancreases was impaired in HG rats as compared with controls. and the insulin response to arginine was dramatically increased. However. insulin secretion in vitro returned partially to normal after day 1. These data indicate that prolonged hyperglycemia has quite different effects on the subsequent insulin secretion in vivo or in vitro. It impairs. but reversibly. glucose-induced insulin secretion in vitro. whereas it increases it durably in vivo. This suggests that humoral and/or nervous interferences can counterbalance the possible perturbing effects of prolonged hyperglycemia on the normal B cell responsiveness to glucose.
Effects of short and long duration hypothyroidism and hyperthyroidism on the plasma adrenocorticotropin and corticosterone responses to ovine corticotropin-releasing hormone in rats, We report here a study of the plasma ACTH and corticosterone responses to synthetic ovine CRH (oCRH) in hypothyroid and hyperthyroid rats studied 7. 15. and 60 days after either thyroidectomy or the administration of pharmacological doses of T4. The purpose of this study was to further clarify the time-dependent effects of alterations in thyroid status on the functional integrity of the hypothalamic-pituitary-adrenal axis and to aid in the interpretation of the oCRH stimulation test in hypo- and hyperthyroid states. Our data demonstrate that hypothyroid rats have a significant reduction in the cerebrospinal fluid (CSF) levels of corticosterone and a significant decrease in adrenal weight in association with significant increases in the plasma ACTH response to oCRH. On the other hand. the corticosterone response to the ACTH released during the oCRH stimulation test was significantly reduced in hypothyroidism. With increasing duration of thyroidectomy-induced hypothyroidism. there was a progressive fall in CSF corticosterone levels. a progressive increase in the plasma ACTH response to oCRH. and a gradual normalization of the corticosterone responses to the ACTH released during oCRH stimulation. Our findings in hyperthyroid rats were generally the converse of those seen in hypothyroidism. Hence. there was a significant increase in the CSF levels of corticosterone and a significant increase in adrenal weight in association with an initial slight decrease in the ACTH response to oCRH. On the other hand. the corticosterone response to the ACTH released during oCRH stimulation was significantly increased. There was a gradual increase in the magnitude of the rise in CSF corticosterone levels with time. as well as a gradual normalization of adrenocortical responses during oCRH stimulation. The ACTH plasma clearance rates were similar in hypo-. hyper-. and euthyroid rats. Our data do not permit definitive identification of the precise locus in the hypothalamic-pituitary-adrenal axis that is principally affected by experimentally induced alterations in thyroid status. However. these data are most compatible with a subtle hypothyroid-induced centrally mediated adrenal insufficiency and a subtle hyperthyroid-induced centrally mediated hypercortisolism. These data also suggest that alterations in hypothalamic-pituitary-adrenal function in states of disturbed thyroid function become somewhat more pronounced as the duration of thyroid dysfunction increases. The fact that pituitary-adrenal responses to oCRH are consistently altered in states of thyroid dysfunction may be relevant to the clinical interpretation of oCRH stimulation tests.(ABSTRACT TRUNCATED AT 400 WORDS).
Tumor necrosis factor-alpha inhibits 1,25-dihydroxyvitamin D3-stimulated bone Gla protein synthesis in rat osteosarcoma cells (ROS 17/2.8) by a pretranslational mechanism, Tumor necrosis factor-alpha (TNF alpha). a 17.000 mol wt protein. mediates a variety of immunological and inflammatory events. TNF alpha is a potent inhibitor of bone collagen synthesis and stimulator of osteoclastic bone resorption. the net effect of which is to cause bone loss. We have previously reported that TNF alpha inhibits the synthesis of collagen by osteoblastic cells in culture out of proportion to effects on total protein synthesis. suggesting that inhibition of bone formation by TNF alpha may be due to selective inhibition of matrix protein synthesis. To further test this hypothesis and to evaluate the mechanism of TNF alpha action. we studied the effect of TNF alpha on synthesis of the osteoblast-specific bone Gla protein (BGP) by ROS 17/2.8 cells. which have the osteoblast phenotype. Cells were cultured with 10 nM 1.25-dihydroxyvitamin D3 to stimulate BGP secretion. followed by the addition of TNF alpha (1-100 ng/ml) in 1.25-dihydroxyvitamin D3-containing medium. TNF alpha (10 ng/ml) inhibited BGP secretion to 42 +/- 5%. 19 +/- 10%. and 15 +/- 3% of control values after 24. 48. and 72 h of treatment. After 48 h. inhibition of BGP secretion was observed with 2 ng/ml TNF alpha and was maximum with 100 ng/ml. To determine the effect of TNF alpha on total protein synthesis. cells were pulse labeled with [14C]leucine during the last 4 h of TNF alpha treatment. and incorporation of radioactivity into trichloroacetic acid-precipitable protein in cell layer and medium was determined. The TNF alpha inhibition of BGP secretion was independent of changes in [14C]leucine incorporation. suggesting that TNF alpha did not have a general inhibitory effect on total protein synthesis. Cell number was not affected by TNF alpha. Northern analysis of steady state BGP mRNA revealed a dose-dependent decrease in the BGP/cyclophilin mRNA hybridization signal intensity after 24 h of treatment. The maximum inhibitory effect was 41 +/- 5% of the control value with 100 ng/ml TNF alpha. The effect of TNF alpha on steady state BGP mRNA levels was not prevented by treatment of cells with cycloheximide. suggesting that TNF-induced new protein synthesis was not required for TNF alpha action. These results suggest that the mechanism of TNF alpha inhibition of BGP synthesis includes a pretranslational site and support the hypothesis that TNF alpha inhibits bone formation by a selective inhibition of matrix protein production.
Central insulin administration reduces neuropeptide Y mRNA expression in the arcuate nucleus of food-deprived lean (Fa/Fa) but not obese (fa/fa) Zucker rats, By acting in the brain. insulin suppresses food intake. whereas neuropeptide Y (NPY) has the opposite effect. Since fasting increases NPY gene expression in the hypothalamic arcuate nucleus (ARC) and also lowers circulating insulin levels. we hypothesized that the anorexiant effect of insulin could result from insulin inhibition of NPY gene transcription in the ARC. Therefore. we determined whether the administration of insulin (200 mU per 12 hrs) into the 3rd cerebral ventricle of lean (Fa/Fa) female Zucker rats (n = 5) during 48 hrs of food deprivation reduces the expression of preproNPY mRNA in the ARC compared to vehicle-treated controls (n = 5). Coronal sections of rat brain were hybridized with an oligonucleotide probe complementary to preproNPY mRNA and apposed to x-ray film. Hybridization was quantified in both the ARC and the hippocampal dentate gyrus by computerized image analysis of the resulting autoradiographs. Central insulin significantly reduced the area of hybridization in the ARC (0.235 +/- 0.017 mm2; mean +/- SE) compared to vehicle-treated controls (0.331 +/- 0.037 mm2; p less than 0.05). but was without effect in the hippocampus. Thus. insulin reduced the expression of mRNA for NPY specifically in the ARC. Since the genetically obese (fa/fa) Zucker rat is insensitive to the anorexiant effect of insulin and over-expresses NPY in the ARC. we next tested the hypothesis that insulin does not suppress NPY mRNA expression in the ARC of these rats. Consistent with this hypothesis. central insulin administration to obese Zucker rats during 48 hrs of food deprivation (n = 6) did not lower hybridization area in the ARC compared to vehicle alone (n = 4) (0.286 +/- 0.036 vs. 0.248 +/- 0.019 mm2; p greater than 0.05). We conclude that insulin suppresses the expression of mRNA for NPY in the ARC of fasted lean but not obese Zucker rats. Regulation of hypothalamic NPY gene expression by insulin may account for its anorexiant effect. and a defect in this action may contribute to certain forms of obesity.
Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Effect of age, race, and socioeconomic status, A causative role is now accepted for Helicobacter (formerly Campylobacter) pylori in type B gastritis. and evidence is accumulating that H. pylori infection plays a major contributory role in peptic ulcer disease. Preliminary studies have reported that the prevalence of H. pylori infection increases with age. but detailed information on the prevalence of the bacteria in any defined population and on the factors that may influence the pattern of distribution remains scanty. In the present study. a sensitive enzyme-linked immunosorbent assay and a [13C] urea breath test were used to investigate the prevalence of H. pylori infection among 485 healthy asymptomatic volunteers between the ages of 15 and 80 residing in the Houston metropolitan area. H. pylori infection was present in 52%. The prevalence of H. pylori infection increased rapidly with age at 1%/yr for the overall population. The frequency of H. pylori infection was higher in blacks (70%) than whites (34%) (P less than 0.001); this difference remained after adjustments were made for age. gender. educational level. income. and use of tobacco or alcohol. H. pylori infection was independent of gender but was closely correlated with socioeconomic class. There were significant inverse correlations between age-adjusted frequency of H. pylori infection and income and between educational level and H. pylori infection. There was no association between H. pylori infection and consumption of alcohol or nonsteroidal antiinflammatory drug use or smoking. Having pets was associated with a lower frequency of H. pylori infection. but this was highly associated with higher socioeconomic status. The mode(s) of transmission of H. pylori is unknown. but the social patterns of H. pylori infection are consistent with fecal-oral transmission as one important pathway. Socioeconomic factors seem to determine the age of acquisition.
Differential activation of ornithine decarboxylase and tyrosine kinase in the rectal mucosa of patients with hyperplastic and adenomatous polyps, Hyperplastic polyps are considered to be benign colonic lesions with almost no potential for malignant transformation. Recent reports have shown an increased association of hyperplastic polyps with adenomatous polyps and have advocated a full colonoscopy in patients who harbor hyperplastic polyps. Hyperproliferative mucosa is known to be associated with adenomatous polyps. but its relationship to hyperplastic polyps is unknown. In the present pilot study. it is determined whether a change in mucosal proliferative patterns is observed in patients who harbor only hyperplastic polyps or a history of hyperplastic polyps relative to those who harbor both hyperplastic polyps and adenomatous polyps by measuring ornithine decarboxylase and tyrosine kinase activity in macroscopically normal rectal mucosa. Fifteen patients had either adenomatous polyps proximally or harbored adenomatous polyps and hyperplastic polyps. Seven patients had hyperplastic polyps and 15 patients had a prior history of hyperplastic polyps with no polyps found during the current examination. The ornithine decarboxylase activity of the rectal mucosa with proximal adenomatous polyps or both polyp types was significantly higher than that of hyperplastic polyps. the history of hyperplastic polyps. or controls. and values for hyperplastic polyps and the history of hyperplastic polyps were similar to controls. On the other hand. tyrosine kinase activity in the rectal mucosa of patients with both or either polyp type was elevated without any significant difference between hyperplastic and adenomatous polyps. Thus. it is concluded that although increased ornithine decarboxylase activity in rectal mucosa suggests the presence of adenomatous polyps or a combination of adenomatous with hyperplastic polyps. increased tyrosine kinase activity suggests the presence of any type of polyp.
Ultrastructural morphometry of gastric endocrine cells before and after omeprazole. A study in the oxyntic mucosa of duodenal ulcer patients, Long-term toxicological experiments with inhibitors of acid secretion were found to induce hyperplasia and eventually carcinoid tumors of the enterochromaffin-like cells of the oxyntic mucosa. To evaluate the effects of 6 months' treatment with omeprazole in humans. the oxyntic endocrine cells were morphometrically investigated at the ultrastructural level in five patients with active duodenal ulcer. No omeprazole-induced changes were found in the volume density of the total endocrine cell population and specific cell types (including the enterochromaffin-like cell) as well as in the other cytological parameters investigated (number of cell profiles per unit area. mean cross-sectional area of cell profiles. nuclear-cytoplasmic ratio. and density of cytoplasmic secretory granules). Both pretreatment and post-treatment values in our patients with duodenal ulcer significantly differed from those of a previous investigation of healthy volunteers with regard to the volume density of enterochromaffin-like cells and non-granulated cells. which increased. and of D cells. which markedly decreased. The latter result may provide a cellular basis for impairment in the paracrine release of fundic somatostatin in peptic ulcer disease. Finally. morphometric data on endocrine cell volume density provided by electron microscopy were found to correlate with those obtained in the same patients using light microscopy techniques (Grimelius silver impregnation and chromogranin A immunostaining). It is concluded that 6 months' treatment with pharmacological doses of omeprazole is devoid of appreciable trophic effect on endocrine cells of human oxyntic mucosa.
Anti-neutrophil cytoplasmic antibodies in ulcerative colitis. Comparison with other colitides/diarrheal illnesses, Previous studies from this laboratory showed that serum anti-neutrophil cytoplasmic antibodies. distinct from those associated with active Wegener's granulomatosis. are present in the majority of patients with ulcerative colitis. In this study. the specificity of anti-neutrophil cytoplasmic antibodies for ulcerative colitis as compared with other colitides and diarrheal illness was determined. In a blinded study. test samples of serum were screened for anti-neutrophil immunoglobulin G in a fixed neutrophil enzyme-linked immunosorbent assay. Levels of neutrophil binding by immunoglobulin G and titers of anti-neutrophil immunoglobulin G in sera from patients with ulcerative colitis and patients with ulcerative colitis post colectomy were each significantly greater than the levels and titers for normal controls and patients with a variety of other colitides and diarrheal illnesses. Levels of neutrophil binding for colonic Crohn's disease. bacterial/amoebic colitis. the irritable bowel syndrome with diarrhea. and other miscellaneous diarrheal illnesses were not significantly different than the levels for normal controls. Although the levels of binding for collagenous colitis were significantly less than the levels for ulcerative colitis. they were significantly greater than the levels for normal controls. Patterns of neutrophil binding by serum samples that were positive in the enzyme-linked immunosorbent assay were determined by indirect immunofluorescence. Perinuclear staining was the predominant pattern shown by sera from patients with ulcerative colitis. The combination of a positive value in the enzyme-linked immunosorbent assay and a perinuclear immunofluorescence pattern was 60% sensitive and 94% specific for ulcerative colitis. It is concluded that anti-neutrophil cytoplasmic antibodies in ulcerative colitis are not simply an epiphenomenon related to inflammation of the colon. Identification of the antigen(s) to which these autoantibodies are directed may facilitate understanding of the underlying immune response and may allow development of an assay that is more sensitive and specific for ulcerative colitis.
Influence of nutritional substrates on the formation of volatiles by the fecal flora, The influence of metabolic substrates on the formation of volatile compounds by the colonic flora was measured in a fecal incubation system. The presence of carbohydrates (0. 25. and 50 mg/20 mL fecal suspension) led to a dose-related increase in the formation of alcohols and H2 and to a dose-related decrease in the formation of toxic mercaptans. This effect seemed to be independent of pH. The presence of albumin or fat (50 mg/20 mL fecal suspension) as substrates for the colonic flora gave rise to the formation of significantly higher amounts of methanethiol. Small amounts of pentane were found in the headspace after incubation with oil. These data show that the formation of volatile metabolites by the colonic flora is greatly influenced by the available substrates.
Frequency of inflammatory bowel disease in offspring of couples both presenting with inflammatory bowel disease, A private practice was surveyed for prevalence of inflammatory bowel disease (IBD) in husband-wife partners and in their children. Among approximately 2500 patients with IBD in our files. 19 couples were identified. They were subdivided into group A (n = 5) in which both partners had symptoms of IBD before marriage; group B (n = 7) in which only one spouse had IBD before marriage and the other partner experienced symptoms afterwards; and group C (n = 7) in which neither spouse had symptoms before marriage but IBD subsequently developed in both. In group B. the disease developed in the second spouse 2-16 years after marriage (mean. 6.4 years). In group C. IBD developed in the first spouse 0.3-41 years after marriage and in the second spouse 1-14 years after the first spouse (mean. 6.8 years). Thirty-five children have been born to 16 of the couples. Two children died before age 20. Of the surviving 33 children. IBD has already developed in 12 (36%). Among the other 21 unaffected children. 1 had uveitis at age 9 and 10 are still under the age of 21. perhaps too young to have yet developed IBD. The frequency of IBD in children was slightly higher if both parents had already developed IBD at the time of conception (67%) compared with when only 1 parent (50%) or neither parent (50%) had developed IBD when conception occurred. Although these data do not distinguish genetic from environmental factors. they show a higher risk of IBD in children when both parents have this illness.
Ceftriaxone-associated gallbladder sludge. Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate, Ceftriaxone. a third-generation cephalosporin. is partially excreted into bile. With its clinical use. the formation of gallbladder sludge detected by ultrasonography has been reported. Four surgical specimens were examined and no gallstones were found. Instead. fine precipitates of 20-250 microns were present. Microscopically. there was a small number of cholesterol monohydrate crystals and bilirubin granules among an abundant amount of granular-crystalline material that was not morphologically cholesterol monohydrate crystals. The chemical composition of the precipitates (n = 4) was determined. There was a small amount of cholesterol (1.7% +/- 0.8%) and bilirubin (13.9% +/- 0.74%). The major component of the precipitate was a residue. On further analysis using thin-layer chromatography. high-performance liquid chromatography. and electron microprobe analysis. the residue was identified as a calcium salt of ceftriaxone. The residue also had identical crystal morphology and chromatographic elution profile as authentic calcium-ceftriaxone standards. It is concluded that ceftriaxone. after excretion and being concentrated in the gallbladder bile. can form a precipitate. The major constituent has been identified as a ceftriaxone-calcium salt.
Glucagon-induced alteration of serum bile acid level in patients with liver cirrhosis, Percent changes in serum total bile acid level after IV administration of 1 mg glucagon were measured in 61 cirrhotics. Thirty-three of 38 cases with Child's grade A disease showed a reduction of total bile acid level at 15 minutes; this level was maintained in the majority of them until 120 minutes. A similar mode of serial changes in total bile acid level was also shown in the cases with Child's grade B disease. On the other hand. only 2 of 10 cases with Child's grade C showed a reduction of total bile acid level at 15 minutes. Reduction of total bile acid level at 15 minutes after glucagon administration was mimicked by infusion of dibutyryl cyclic adenosine monophosphate. However. in 3 of 6 cases with elevated total bile acid level at 15 minutes after glucagon administration. dibutyryl cyclic adenosine monophosphate induced a reduction of total bile acid level. Also. it was confirmed that glucagon enhances the uptake of taurocholate into freshly isolated rat hepatocytes by activating Na(+)-dependent. carrier-mediated membrane transport system and observed that its effect is associated with elevation of Vmax (0.6114 nmol.min-1 x 10(6) cells-1 without glucagon; 0.975 nmol.min-1 x 10(6) cells-1 in glucagon added) but not with affecting Km (13.58 mumol/L without glucagon; 13.71 mumol/L with glucagon) or protein synthesis which is inhibited by cycloheximide. These observations suggest that glucagon enhances Na(+)-coupled membrane transport of bile acids in the liver and causes the reduction of serum total bile acid level and that a lack of this response may be indicative of membrane dysfunction in the liver.
Hypoechoic lesions in fatty liver. Quantitative study by histomorphometry, Ten patients with fatty liver changes were subjected to liver biopsies. In seven. ultrasonography showed focal hypoechogenicity within a "bright" liver. generally interpreted as focal sparing. Three patients had hyperechoic areas surrounded by "normal" parenchyma usually felt to represent local fat accumulation without diffuse involvement. Morphometric analysis was used to determine the total area occupied by fat (area density) and the number of lipid droplets (numerical density) per microscopic field in lesional and perilesional specimens. Compared with respective perilesional values. hypoechoic lesional numerical densities were significantly lower in 6 of 7 patients; the three hyperechoic samples had significantly higher values. In most cases. lesional and perilesional area densities were not significantly different. These hypoechoic focal lesions are believed to be merely areas in which a similar quantity of fat is contained in fewer droplets. and focal hyperechogenicity is believed to result from a larger number of fat-filled vacuoles with respect to that of the surrounding parenchyma. Variation in the number of solid-liquid interfaces causes the ultrasonic contrast between these lesions and the similarity fatty liver parenchyma surrounding them.
Human gallbladder morphology after gallstone dissolution with methyl tert-butyl ether, The effects of methyl tert-butyl ether exposure on the human gallbladder in five patients who were treated for gallstones by contact dissolution is described. Two patients underwent cholecystectomy within 1 week of methyl tert-butyl ether treatment. one patient 2 weeks after. another 10 weeks after. and one 12 weeks after. Indications for cholecystectomy were bilirubinate stones (resistant to methyl tert-butyl ether). catheter dislodgement. bile leakage. and gallstone recurrence (2 patients). Gallstones were dissolved completely in three patients. there was approximately 50% stone reduction in one patient. and no dissolution occurred in the fifth patient. Each gallbladder was examined grossly and histologically. Electron microscopic evaluation was performed in one cases. Typical inflammatory findings of chronic cholecystitis were observed in each gallbladder and were most conspicuous in the submucosa; the mucosal and serosal surfaces were intact. Mild acute inflammatory changes were noted in the submucosa in the two patients with the shortest interval between methyl tert-butyl ether administration and cholecystectomy. There were no ulcerations in the mucosa and no unusual wall thickening or fibrosis in any patient. These observations support the safety of methyl tert-butyl ether perfusion in the human gallbladder; the mild acute changes may be a transient and reversible phenomenon.
Role of high total protein in gallbladder bile in the formation of cholesterol gallstones, While it is generally accepted that cholesterol supersaturation of bile is of key importance in the rapid formation of cholesterol crystals. the role of total biliary protein and pH in the pathogenesis of cholesterol gallstones is less well understood. The relation of cholesterol saturation. total protein. and pH was studied in 73 gallbladder bile samples with and 35 gallbladder bile samples without cholesterol crystals. In samples containing crystals. a trend to higher values of cholesterol and to a higher cholesterol saturation index was observed. However. significantly (P = 0.02) higher concentrations of total protein were found in samples with crystals [0.80 +/- 0.40 g/dL (8.0 +/- 4.0 g/L)] than in samples without crystals [0.63 +/- 0.26 g/dL (6.3 +/- 2.6 g/L)]. Moreover. of 22 bile samples with total protein concentrations greater than 10.0 g/L. cholesterol crystals were detected in all but 2. Total lipids. bile acids. phospholipids. and pH values were not significantly different in the two groups of bile samples. It was concluded that high biliary protein concentrations are frequently associated with cholesterol crystals and may. therefore. be a possible risk factor in the pathogenesis of cholesterol gallstones.
Pulsed dye laser lithotripsy of bile duct stones, Efficacy and safety of pulsed dye laser lithotripsy was tested in 25 consecutive patients in whom bile duct stones could not be extracted after endoscopic sphincterotomy. The patients had one to six (mean. 1.8) bile duct stones (diameter. 10-35 mm; mean. 18 mm) located in the common bile duct (18 cases). the intrahepatic bile ducts (6 cases). or in a long cystic duct stump (1 case). Different approaches were tested depending on the presence of a T tube and on the localization of the bile duct stones. When a T tube was present (7 cases). the lithotripsy was performed under direct vision using a choledochoscope inserted through the T-tube tract. In 18 patients without a T tube in place. the lithotripsy was performed under fluoroscopy using a retrograde approach in case of common bile duct stones (14 cases) or under choledochoscopy using a percutaneous transhepatic approach in case of intrahepatic bile duct stones (4 cases). Fragmentation of all the bile duct stones and a complete bile duct clearance were obtained in all 11 cases with procedures performed under direct vision as compared with only 5 of 14 cases with procedures under fluoroscopic control. Moreover. 6 of the 9 failures using the latter approach were offered another session using a choledochoscope inserted through a percutaneous transhepatic tract and were also successfully treated. No complication related to the laser beam was noted. It is concluded that pulsed dye laser lithotripsy of bile duct stones (that are unable to be removed by standard endoscopic techniques) is safe and efficacious provided that it is performed under direct vision. Technical refinements are needed before this procedure can be reliably performed under fluoroscopy.
Intestinal and renal calcium-binding protein in rats with experimental short bowel syndrome, Intestinal calcium-binding protein (calbindin-D9K) and renal calcium-binding protein (calbindin-D28K) levels were measured by enzyme-linked immunoadsorbent assays in rats with short bowel syndrome induced by resection of about 85% of the small intestine. Rats with short bowel syndrome had significantly lower mucosal concentrations of calbindin-D9K (P less than 0.001) and a parallel reduction of both intestinal calcium absorption (P less than 0.001) and p-1.25-dihydroxyvitamin D (P less than 0.01) in spite of a general hypertrophy of the duodenal mucosa. Interestingly. the renal concentration of calbindin-D28K was significantly elevated (P less than 0.05) in rats with short bowel syndrome. a change apparently related to factors independent of vitamin D.
Kinetics of pulmonary leukocyte sequestration in man during hemodialysis with different membrane-types, Although it has been suggested that pulmonary sequestration of leukocytes could account for membrane-dependent white blood cell depletion in HD. direct evidence in patients is still lacking. Therefore a study was initiated to test whether and how leukocytes distribute in the lung circulation during HD with different membranes. Thirteen patients suffering from chronic renal failure underwent lung scintigraphy during HD with cuprophane (n = 3). hemophane (n = 8) and polysulfone (n = 2) lowflux capillary dialyzers. Isolated autologous leukocytes were labelled with 99m-Technetium and reinfused before starting HD. Distribution of leukocyte related activity was registered by lung scintigraphy. In comparison to normal lung scintigraphy performed without HD. an impressive redistribution peak was demonstrated 10-20 min after the start of HD with cuprophane and also to a lesser extent with hemophane. When HD was performed with polysulfone the decrease in activity was delayed but no real redistribution was obtained. In accordance with other phenomena. such as peripheral leukopenia and changes in granulocyte oxidative metabolism. pulmonary sequestration of leukocytes takes place in man in the initial phase of HD and appears to be strongly dependent on the type of membrane.
Effect of anticoagulant on biocompatibility in membrane plasmapheresis, The effect of heparin or citrate anticoagulation on blood cellular. complement pathway and coagulation pathway was investigated in a membrane plasma exchange procedure. Two membrane plasma separators constructed of cellulose di-acetate (CA) and polyvinyl chloride (PVC) were evaluated with heparin or citrate alone for anticoagulation in a 26 year old male with myasthenia gravis. Maximum white blood cell counts decrease was 21% at 30 min for the CA with heparin while no decrease was observed for the other schemes. Platelet counts changes were comparable between heparin and citrate. while the PVC groups showed less changes than the CA groups. The CA groups. regardless of the type of anticoagulant used. indicated that complement activation occurred via the classical pathway within the module in addition to the activation via alternative pathway for the CA with heparin. In the PVC groups. complement activation was noted to occur only when heparin was used for anticoagulation. PT and PTT showed slight increases with citrate. while they were remarkably prolonged with heparin. Citrate showed less changes in cellular and humoral factors compared to heparin. CA with heparin was the most activating combination of membrane material and anticoagulant. while the PVC with citrate was the least activating combination.
Congenital malformation of the lymphatics of the small intestine, Of 300 congenital malformations of the lymphatics of the small intestine investigated. 120 were operated upon. Intestinal lymphography shows no injection of the cisterna chyli and histology proves that the mesenteric lymph nodes are abnormal. The induced hyperlipidemia test permits a biochemical diagnosis. Modifications of the flow of the chyle secondary to the hypoplasia of the cisterna chyli were studied: (1) in the abdominal cavity. (2) in the extraperitoneal region and the lower limb. (3) in the thorax. especially the chyle drainage channels from the diaphragm towards the cervical region. Our investigations have established that the following diseases are produced by malformation of the lymphatics of the small intestine: protein losing enteropathy. chyloperitoneum. chyluria. lymphedema with chyle reflux. chylothorax. chylopericardium. chyle reflux in the pulmonary lymphatics. hypoproteinemia and food allergies. A better understanding of the pathophysiology of the malformations of the intestinal lymphatics permits a more rational treatment of the diseases produced by this anomaly.
Transinguinal dissection of the femoral artery for aorto-bifemoral bypass, The authors report a surgical technique for high approach to the common femoral artery. just below the inguinal ligament. which can be useful in cases of difficult dissection of the femoral region or those with diffuse fibrosis or multiple scars. It is also useful when there is a concomitant inguinal hernia to repair.
The long-term clinical outcome of patients with tricuspid atresia. II. Influence of surgical procedures, One-hundred and eleven patients with tricuspid atresia were seen during 1972-1982 and thirteen of these were not operated upon. The remaining 98 patients have undergone at least one operation. Those with low pulmonary blood flow had 1-4 shunt procedures; in 15 patients with high pulmonary blood flow the pulmonary artery was banded. The mortality rate after the first shunt was 10% (8/82). 9% after the second shunt (3/32) and 12% after the third and fourth shunts. Three out of 15 (20%) patients died after pulmonary artery banding. Twenty three patients underwent a Fontan operation and five died (22%); eighteen survivors are clinically well (after 1-7 years). One patient required a pacemaker implantation and revision of his Fontan procedure. The survivors of the palliative operations and the unoperated patients were more restricted. the older ones having developed pulmonary vascular obstructive disease. chronic heart failure or arrhythmias.
Myocardial protection with Hamburg oxygenated crystalloid cardioplegic solution for multiple coronary bypass and multivalvular replacement, We evaluated myocardial protection with Hamburg oxygenated crystalloid cardioplegic solution in a double study. Part I was a prospective metabolic study. measuring myocardial adenosine triphosphate (ATP) and creatine phosphate (CP) contents before and after ischemia in 30 coronary bypass (CABG) patients. During ischemia. CP levels decreased significantly. whereas ATP did not. After 10 minute of reperfusion. mean ATP contents were 90% of preischemic values and CP levels increased to 85% of preischemic values. Spontaneous myocardial defibrillation was seen in 93.3% of patients. Part II included evaluation of early postischemic myocardial function in 228 patients. 48 with multiple valve replacement (MUVR) and 180 with CABG. Spontaneous myocardial defibrillation was seen in 90.3%. Cardiac index. measured before and 1 and 12 hours after surgery. increased significantly in the postischemic period (from 1.95 +/- 0.9 to 2.5 +/- 0.7 l/min m2 in MUVR. p 0.04; from 2.2 +/- 0.6 to 2.7 +/- 0.7 l/min/m2 in CABG. p 0.01). Myocardial infarction frequency was 3% among CABG patients. and unrelated to the number of distal anastomosis or to aortic cross-clamp time. Early postoperative mortality was 6.2% for MUVR and 0.5% for CABG. Thus. oxygenated cardioplegia with Hamburg solution preserves high-energy phosphate compounds and prevents ischemic injury. with excellent short-term clinical results.
Diastolic mechanical properties of the left ventricle after global ischemia, The purpose of this study was to evaluate left ventricular (LV) diastolic mechanical properties after induced global ischemia using reliable new methods. The diastolic function of nonoxygenated crystalloid solution (CC sO2) was compared with those of oxygenated crystalloid (CC cO2) and oxygenated fluorocarbon cardioplegic (FC cO2) solutions. Postischemic ventricular performance was studied in 3 equal (no. 7) groups of dogs subjected to 120 minutes of global ischemia induced at an average myocardial temperature of 18.5 +/- 1.4 degrees C. LV diastolic function (chamber and myocardial stiffness) and relaxation (the exponential fall in LV pressure) were evaluated by sonomicrometry and Millar micrometers before ischemia and at 45 and 60 minutes after ischemia. LV chamber and myocardial stiffness in the CC sO2 group was significantly (p less than 0.05) elevated after ischemia. while the CC cO2 and FC cO2 groups did not show increases in LV chamber and myocardial stiffness after ischemia. LV relaxation before and after ischemia was not changed in any group. The myocardial water content of the CC sO2 group was significantly higher than that of the CC cO2 and FC cO2 groups (p less than 0.05). We conclude that (1) the postischemic increase in LV chamber stiffness in the CC sO2 group was dependent not only on the increase in intrinsic myocardial stiffness but also due to an increase in myocardial edema. and (2) there was no correlation between the LV relaxation rate and the leftward shift of diastolic compliance curves in the CC sO2 group.
Cavitary lesions close to heart valve rings. A necropsy study of 13 cases, Necropsy reports of 13 patients with 15 cavitary lesions situated close aortic or mitral valve rings were studied in patients who ranged in age from 1 month to 57 (mean 24.9) years; 10 patients were male. Infective endocarditis occurred in 7 patients. rheumatic heart disease in 4. congenital heart diseases in 4. previous valve replacement in 4. and syphilis in 1 patient. Diameters of the cavitary lesions ranged between 1.2 and 10.5 cm; the aortic valve ring was involved in 11 patients; cavitary thrombosis occurred in 2 cases; the orifice communicating the cardiac chamber with the cavitary lesions was situated above the aortic leaflet in 5 lesions. below the aortic leaflet in 4 lesions. and above and below the aortic leaflets in 3 lesions. The mitral valve ring was involved in 3 lesions. Thus. different etiologies may be involved in the pathogenesis of these lesions; positions of the lesion may vary in relation to the valve ring. and the lesions may be a morphological expression of the fragility of the fibrous skeleton of the heart.
Rupture of the posterior wall of the left ventricle after mitral valve replacement, During a 20 year period from 1970 to 1989. 1100 patients underwent mitral valve replacement. Rupture of the posterior wall of the left ventricle occurred in seven patients (0.6%); four in the operating room and three in the postoperative room. It was possible to institute CP bypass in six patients and in all of them bleeding was controlled successfully. with repair by an external approach. Only one patient survived. We believe that institution of CP bypass and reinfusion of cardioplegic solution is a major determinant of the outcome.
Bovine internal thoracic artery graft. Successful use at urgent coronary bypass surgery, Bovine internal thoracic artery grafts (Bioflow) were successfully utilized in two patients for emergency coronary artery bypass grafting (CABG). One patient was an 80-year-old man with severe varicose veins and a calcified ascending aorta. Heart failure occurred after triple CABG with bilateral internal thoracic and gastroepiploic arteries. The addition of a Bioflow graft to the circumflex artery restored good cardiac function. The second case was a 54-year-old man whose patent old saphenous vein graft was accidentally injured at reoperation. Emergency use of the Bioflow to bypass the right coronary artery in combination with the right gastroepiploic artery graft to the anterior descending artery resulted in an excellent outcome. The two Bioflow grafts were patent at the 20th and 10th postoperative days. respectively. These cases strongly suggest the efficacy of Bioflow during emergency situations in CABG.
Congenital mitral regurgitation associated with total anomalous pulmonary venous drainage. Report of a rare combination, A case of congenital mitral regurgitation associated with total anomalous pulmonary venous drainage. successfully treated surgically. is reported. To our knowledge. this combination has not been reported in the literature.
Comparing dentists' attitudes and knowledge concerning AIDS: differences and similarities by locale, A stratified random sample of 1.351 general practitioners in the continental United States was surveyed to determine dentists' attitudes relevant to treating AIDS/HIV+ patients and knowledge regarding the transmission of HIV infection. Survey results were analyzed nationally and by practice locale: high HIV+ prevalence urban areas. other urban areas. rural areas. While there are differences in fear-related HIV attitudes among GPs in the three locales. they are not present in attitude toward willingness to treat and knowledge of AIDS transmission. For dentistry. such findings in large part refute the National Commission on AIDS charges regarding the treatment of AIDS in rural America.
Dietary habits of elderly persons with diabetes, The dietary habits and nutrient intakes of a group of 151 persons with diabetes were compared with those of a group without diabetes in a random postal survey of 3.000 individuals aged 65 years and older residing in Adelaide. South Australia. A semiquantitative food frequency questionnaire was used. The response rate was 77%. Only 64% of individuals with diabetes reported following a diabetic diet at the time of the survey. and only 6% were consuming a high-carbohydrate. low-fat diet (greater than or equal to 50% energy intake from carbohydrate and less than or equal to 30% from fat). The dietary habits of elderly persons with diabetes suggested an awareness of the need to limit simple sugars; however. adherence to the latest recommendations concerning dietary fat and fiber was poor. Individuals with diabetes had lower intakes of refined carbohydrate but were just as likely as those without diabetes to eat high-fat foods. and they ate eggs and cheese more frequently. Those with diabetes were no more likely than those without diabetes to consume the recommended complex-carbohydrate and fiber-rich foods. The extent of adherence to current dietary recommendations for the management of diabetes was found to be independent of sex. age. occupational status. educational attainment. marital status. living arrangements (alone vs with a spouse). and source of income.
Herpes simplex virus hepatitis after solid organ transplantation in adults, Twelve patients developed herpes simplex (HSV) hepatitis a median of 18 days after solid organ transplantation. This is earlier than cytomegalovirus hepatitis. which usually occurs 30-40 days after transplantation. Eight recipients (67%) died. and in seven. the diagnosis was made at autopsy or less than 48 h before death. Clinical manifestations associated with mortality were hypotension. disseminated intravascular coagulation (DIC). metabolic acidosis. gastrointestinal bleeding. and bacteremia. Laboratory abnormalities at diagnosis associated with mortality were high creatinine. low platelet counts. prolonged partial thromboplastin time. and a high percentage of band forms on the blood smear. Disseminated HSV disease was noted in four of six patients who had an autopsy and included involvement of lungs in three and the gastrointestinal tract in three. Five recipients developed DIC and all died. Pathologically. HSV hepatitis has two forms. focal and diffuse. All three patients with diffuse liver pathology died. However. three of seven with focal liver pathology survived with antiviral therapy. which suggests that early diagnosis and treatment may be lifesaving. None of these patients had received prophylactic acyclovir. It is possible that acyclovir prophylaxis may be able to prevent this disease.
The A/Mallard/6750/78 avian-human, but not the A/Ann Arbor/6/60 cold-adapted, influenza A/Kawasaki/86 (H1N1) reassortant virus vaccine retains partial virulence for infants and children, Characteristics of avian-human (ah) and cold-adapted (ca) influenza A/Kawasaki/9/86 (H1N1) reassortant vaccine viruses were compared in 37 seronegative adults and 122 seronegative infants and children. The 50% human infectious dose (HID50) in infants and children was 10(2.9) and 10(2.6) TCID50 for the ah and ca vaccine. respectively. The ah influenza A/Kawasaki/9/86 reassortant was reactogenic: 24% of infants and children infected with greater than or equal to 100 HID50 had fever greater than or equal to 39.4 degrees C. Since H3N2 ah vaccines were previously shown to be adequately attenuated. it is reasonable to suggest that the genes that code for hemagglutinin and neuraminidase of the H1N1 virus apparently influence the reactogenicity of reassortant viruses derived from the avian influenza A/Mallard/New York/6750/78 donor virus. Because this avian virus does not reproducibly confer a satisfactory level of attenuation to each subtype of influenza A virus. it is not a suitable donor virus for attenuation of wild-type influenza viruses. In contrast. the ca A/Ann Arbor/6/60 donor virus reliably confers attenuation characteristics to a variety of H1N1 and H3N2 influenza A viruses.
Evaluation of serology and nasopharyngeal cultures for diagnosis of pertussis in a vaccine efficacy trial, Nasopharyngeal cultures and titer rises in paired sera were evaluated in a placebo-controlled pertussis vaccine efficacy trial. IgG ELISA for filamentous hemagglutinin (FHA) identified 30 (88%) of 34 placebo recipients and 33 (89%) of 37 vaccine recipients with culture-verified Bordetella pertussis infections. whereas IgG ELISA for pertussis toxin (PT) showed higher diagnostic sensitivity in the placebo group than in the vaccine groups. The CHO cell assay did not improve sensitivity. Children with Bordetella parapertussis infections had rises of titers of antibody to FHA of the same magnitude as children with B. pertussis infections. Sensitive serologic criteria. based on the intraassay variations. identified 105 additional culture-negative cases with significant titer rises in paired sera. IgG ELISA for FHA and PT and IgA ELISA for FHA were reliable assays. and bacterial isolation rates were lower in vaccine recipients than in placebo recipients with serologically defined pertussis.
Pulsed-field gel electrophoresis of Campylobacter jejuni and Campylobacter coli genomic DNA and its epidemiologic application, Genomic DNA from 12 different Campylobacter jejuni and 10 Campylobacter coli isolates was digested with SmaI and analyzed by pulsed-field gel electrophoresis (PFGE) and 16S rRNA hybridization studies. Although the two Campylobacter species displayed species-specific restriction and hybridization patterns. significant intraspecies differences were observed. Combined PFGE and hybridization pattern analysis failed to provide any more epidemiologic information than was obtained from PFGE restriction profiles alone. Therefore. results from these studies indicate that PFGE analysis of SmaI-restricted genomic DNA provides a reliable means of differentiating C. jejuni from C. coli and may represent a more practical approach to epidemiologic studies than combining conventional DNA restriction digestion pattern with RNA hybridization procedures.
Improved amphotericin B activity by a monoclonal anti-Cryptococcus neoformans antibody: study during murine cryptococcosis and mechanisms of action, Current therapy of cryptococcosis is unsatisfactory. particularly in patients with AIDS. Experimental cryptococcosis models in DBA/2 mice were used to determine whether the murine monoclonal anticryptococcal antibody (designated E1) might potentiate the chemotherapeutic effect of amphotericin B (AmB). According to the inoculum size. these mice died spontaneously from acute pneumonia (high inoculum) or from brain swelling (lower inoculum). AmB and E1 together significantly improved the survival of mice in both models compared with AmB alone. The mechanisms by which E1 might potentiate AmB activity were investigated in vitro. When cryptococci were preincubated with AmB or another polyene antibiotic. nystatin. there was an augmented binding of E1. AmB enhanced phagocytosis by unstimulated peritoneal macrophages in the presence of E1 or normal rabbit immunoglobulins. Normal and immune IgG deserve further study to determine under what circumstances the chemotherapeutic effect of AmB can be enhanced.
Immunity to onchocerciasis: recognition of larval antigens by humans putatively immune to Onchocerca volvulus infection, Immunoblot analyses were done using sera from 12 individuals without evidence of onchocerciasis and 16 with active infection from an area of Guatemala holoendemic for onchocerciasis. For adult antigens from Onchocerca volvulus. no differences in antigen recognition could be identified between the two groups. In contrast. when infective larval (L3) antigen preparations derived from the related animal parasite Onchocerca lienalis were used. IgG from the "immune" individuals preferentially recognized a 45- to 50-kDa triplet and a 22-kDa L3 antigen. When L3 antigens of Brugia malayi were used. sera from putatively immune individuals identified a high-molecular-weight triplet/quadruplet plus several additional antigens of lower molecular weights that were recognized by sera from few (or none) of the infected patients. These findings define some differences in antibody specificity in onchocerciasis patients and therefore might define potential target antigens of humoral host defense. The exact nature of such defenses is unknown.
Evidence of nonsusceptibility to diethylcarbamazine in Wuchereria bancrofti, This study assessed Wuchereria bancrofti-infected patients who received diethylcarbamazine (DEC) to determined if drug levels were comparable between individuals who continued to harbor circulating microfilariae and those whose blood became clear of parasites. between those with high and low microfilaria counts. and between infected and noninfected persons. Haitian volunteers undergoing treatment for W. bancrofti and two nonendemic controls were enrolled. DEC levels in serum and urine samples were determined using a gas chromatographic method. No correlation was found between pre- and posttreatment microfilarial levels and drug levels. Drug levels were comparable in persons with or without residual microfilaria and in infected and uninfected persons. These results indicate that incomplete drug regimens. differences in serum drug levels. and inadequate drug dosage are not the primary causes of treatment failure and suggest there is a degree of parasite tolerance for DEC.
Simian immunodeficiency virus infection of macaques: end-stage disease is characterized by widespread distribution of proviral DNA in tissues, Four simian immunodeficiency virus (SIV)-infected macaques in the terminal stages of AIDS were studied. Easily detectable unintegrated proviral DNA was present in nearly every tissue (lymphoid and nonlymphoid) examined. SIV-specific immunohistochemistry revealed that macrophages or macrophage-like cells were the predominant reservoirs for SIV. High burdens of infectious SIV were also characteristic of end-stage disease. At the molecular level. sequence analyses of molecular clones derived directly from tissue demonstrated that SIV. like other RNA viruses. exists as a mixture of closely related genomes. Viruses derived by cocultivation seemed to be selected for their ability to grow in tissue culture and did not represent the wide spectrum of genotypes in tissues. These data indicate that SIV-induced immunodeficiency is a complex. multisystem disease and that SIV replication. in addition to impairing the immune system. may have direct deleterious effects on multiple organ systems.
The declining transmission of hepatitis A in Thailand, Hepatitis A antibody was almost universal among Thai children 10-15 years ago. To assess whether transmission of hepatitis A among Thai children had declined. contemporary antibody prevalence and seroconversion rates were determined. Antibody prevalence in 1987-1988 among children in Bangkok declined since 1977 for all ages studied. most markedly among young children. Among 453 low-income urban schoolchildren. there were no seroconversions over a 10- to 12-month period (95% confidence interval [CI] for incidence. 0-0.8%). Antibody prevalence among rural children also declined between 1985 and 1989. though rates were higher than those in Bangkok. Antibody prevalence differed by community. The annual rural infection rate was 1.1% (CI. 0.8%-1.6%). The pattern of rural hepatitis A transmission was focal. Increased numbers of susceptible children in Thailand. where hepatitis A virus still circulates. sets the stage for rising rates of symptomatic disease in adults.
Detection of polyadenylated RNA in hepatitis B virus-infected peripheral blood mononuclear cells by polymerase chain reaction, Polymerase chain reaction (PCR) with a reverse transcriptase step characterized a specific transcription activity in hepatitis B virus (HBV)-infected peripheral blood mononuclear cells (PBMC) in two patients (1 and 2) with chronic hepatitis positive for antibody to hepatitis B core antigen (HBc). Patient 1 was also coinfected with human hepatitis delta virus. A patient who cleared HBV replication after antiviral treatment with vidarabine served as negative control. HBV-specific RNA poly A sequences were detected by PCR in PBMC of patients 1 and 2 even without detectable HBV DNA (patient 2) as shown by dot blot and PCR assays. RNA sequences were found in both the nucleus and cytoplasm. The demonstration of HBV mRNA sequences within PBMC suggests the transcription of viral DNA. in agreement with the findings of HBV surface antigen in PBMC. The results in patient 1 demonstrated HBV mRNA sequences in leukocytes even without PCR-detectable HBV DNA sequences. likely due to ongoing hepatitis delta virus replication.
Quantitative analysis of inflammatory cell influx, procollagen type I synthesis, and collagen cross-linking in incisional wounds: influence of PDGF-BB and TGF-beta 1 therapy, Platelet-derived growth factor (PDGF-BB homodimer) and transforming growth factor-beta 1 (TGF-beta 1) are potent wound-healing hormones that accelerate incisional repair. To identify more precisely and quantitatively the stage(s) of wound healing influenced by growth-factor therapy. we investigated the three sequential tissue repair processes--inflammatory cell influx. intracellular procollagen type I (PC-I) synthesis. and collagen cross-linking--in recombinant growth factor--treated wounds. Using newly developed automated. quantitative image-analysis techniques. we observed that PDGF-BB markedly augmented the directed migration of macrophages into wounds during the first week after wounding and triggered and earlier and more sustained influx of PC-I--containing fibroblasts into the wound when compared with results in TGF-beta 1-treated or control wounds (p = 0.015 at day 2; p = 0.007 at day 21). In contrast. automated image analysis revealed TGF-beta 1-treated wound fibroblasts had a nearly twofold increase in intracellular levels of PC-I protein when compared with PDGF-BB-treated or control wound fibroblasts (p = 0.004 at day 4). However. the influence of TGF-beta 1 was transient. and the longer duration of PDGF-BB activity suggested a later influence. perhaps on the collagen remodeling phase. which is ultimately required for increased wound strength. To address this possibility. collagen cross-linking in growth factor-treated wounds was inhibited by beta-aminoproprionitrile (BAPN) treatment. and wound breaking strength was analyzed. Both PDGF-BB and TGF-beta 1 continued to enhance repair in BAPN-treated rats. indicating that they do not function primarily at the level of collagen cross-linking. Thus. PDGF-BB appears to enhance the inflammatory phase of wound healing to indirectly trigger PC-I synthesis. whereas TGF-beta 1 quantitatively enhances PC-I synthesis directly. accounting for their differing duration of activities within healing wounds.
Effect of dietary NaCl on norepinephrine turnover in the Dahl rat, To evaluate neural mechanisms in salt-sensitive hypertension. norepinephrine turnover rates were measured in peripheral tissues and selected brain areas of Dahl salt-sensitive and salt-resistant rats receiving either 1% or 7% NaCl diets for 5 weeks. Norepinephrine turnover was determined by measuring tissue norepinephrine in untreated animals or in separate groups killed 2. 4. 6. and 10 hours after alpha-methyl-tyrosine. Plasma volume (radiolabeled albumin) was also measured. Arterial pressure of Dahl S rats receiving 7% NaCl (167 +/- 4 mm Hg) was higher (p less than 0.001) than that of Dahl S rats receiving 1% NaCl (141 +/- 3mm Hg). which was higher (p less than 0.001) than that of Dahl R rats receiving both NaCl intakes. Norepinephrine turnover was increased (p less than 0.01) by 7% NaCl in both heart and brown adipose tissue in Dahl S rats. whereas norepinephrine turnover in Dahl R rats was decreased (p less than 0.01) by the 7% NaCl intake in the heart and kidney. On the high NaCl intake. norepinephrine turnover in heart and adipose tissue was lower (p less than 0.05) in Dahl R rats than in Dahl S rats. In brain stem tissue. with the 1% NaCl diet. norepinephrine turnover was higher (p less than 0.001) in Dahl S rats than in Dahl R rats. and norepinephrine turnover was inhibited (p less than 0.001) by the high NaCl intake in Dahl S rats but not in Dahl R rats. In posterior hypothalamus. norepinephrine turnover was inhibited (p less than 0.01) by the high NaCl intake in Dahl R rats but not in Dahl S rats.
Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis, In hereditary hemochromatosis (HH). increased intestinal iron absorption leads to the development of iron overload. To examine the abnormal regulation of iron absorption in this disorder. we analyzed mucosal iron kinetics in six patients with HH and in five normal subjects by using a compartmental model of intestinal iron absorption and systemic ferrokinetics. Subjects were given simultaneous oral and intravenous tracer doses of iron 59-labeled citrate and iron 55-labeled transferrin. respectively. Plasma and whole-body radioactive iron levels were then monitored serially during the next 2 weeks. and mucosal iron transport rate constants were estimated by non-linear least-squares fit of the model to these data. Iron absorption was inversely related to serum ferritin concentration in both normal subjects and patients with HH but was higher in relation to serum ferritin level among the latter (p less than 0.0002). Analysis of mucosal iron kinetics demonstrated a similar inverse relationship between the rate constant for mucosal iron uptake and serum ferritin among all subjects combined. but the mean uptake rate constant in patients with HH did not differ from that of normal subjects (p = 0.71). The mean rate constant for incorporation of iron into the mucosal storage pool in patients with HH also was comparable to that of normal subjects (p = 0.94). In contrast. the rate constant for transfer of mucosal iron to the plasma was higher in patients with HH than in normal subjects for any given serum ferritin level (p less than 0.0001). and the transfer rate constant accounted for 87% of the variability in iron absorption among all subjects. We conclude that the increased iron absorption in HH is mediated primarily by an increase in the rate constant for transfer of mucosal iron to the plasma.
Acoustic rhinometry used as a method to monitor the effect of intramuscular injection of steroid in the treatment of nasal polyps, Acoustic rhinometry is a new method which describes the geometry of the nasal cavity and the epipharynx. The method. based on the reflection of an acoustic signal entered into the nasal cavity. can be used to evaluate the cross-sectional area of the nasal cavity as a function of distance from the nostril. The method has. together with nasal expiratory peak flow (NPF) and nasal index based upon a self assessment score. been used to evaluate. in an objective and dynamic way. the effect of systemic treatment of nasal polyps with steroids in a series of eight patients with recurrent nasal polyposis. The study shows a significant relationship between these three parameters before and after systemic treatment of nasal polyps with steroids. It is concluded that in this study acoustic rhinometry had an accurate and objective method for measuring the geometry of the nasal cavity before and after treatment for processes which block the nasal cavity.
CT of the paranasal sinuses and functional endoscopic surgery: a critical analysis of 100 symptomatic patients, CT scans of 100 patients from the Rhinology Clinic at the Royal National Throat. Nose and Ear Hospital were reviewed in order to test the precepts forming the basis of functional endoscopic sinus surgery. especially as they relate to the radiological investigation. These were: (a) the site of origin of sinus infection. (b) The relevance of certain anatomical variants in the middle meatus to sinus infection and (c) The use of CT as the radiological method of diagnosis in all cases. Obstruction in the middle meatus and ostiomeatal complex was associated with an increased incidence of opacity in the sinuses but the primary site of disease was not established: the concept that sinus disease takes origin in the middle meatus was not proven. Anatomical variants in the middle meatus were not associated with an increase in sinus opacity and there was no evidence that these anomalies have any effect on sinus disease by causing middle meatal stenosis. The radiological assessment of patients with inflammatory naso-sinus disease should start with plain X-ray. CT is unnecessary as a routine examination. It should be reserved for the pre-operative assessment of patients for endoscopic surgery. its main function being to show important anatomical landmarks.
Combined study to assess the role of calcium alginate swabs and ligation of the inferior tonsillar pole in the control of intra-operative blood loss during tonsillectomy, Bleeding is the major source of morbidity and mortality of tonsillectomy and most operative time is spent securing haemostasis. Calcium alginate reduces experimental wound blood loss. This study assessed the efficacy of alginate swabs during tonsillectomy and inferior tonsillar pole ligation in the control of blood loss during tonsillectomy. Ninety-nine tonsillectomy patients were randomized to gauze or alginate swab use. A haemoglobinometer measured blood losses collected by suction during dissection and by swab until haemostasis was secured. Operative time. complications and healing were also assessed. Mean total blood losses and operative times were similar for the two groups. Swab blood loss was significantly lower for surgeons who ligated the lower tonsillar pole. compared with surgeons who used a snare. This finding was independent of swab type. Independent assessment showed no difference in the healing rate. Alginate swabs offer no advantage over gauze in terms of blood loss. operative time or complications of tonsillectomy. The results show that routine lower pole ligation significantly reduces post-dissection blood loss. We suggest that this technique should be more widely adopted.
Scleroma of the upper respiratory passages: a CT study, Scleroma is a chronic specific granulomatous disease endemic in Egypt. The nasal cavities were all affected in the 37 patients examined. The paranasal sinuses and nasopharynx were involved in 17 patients. while the larynx and upper trachea were affected in five patients. four of whom were females. Twenty-three patients were in the granulomatous stage; the rest of the patients were in the atrophic and fibrotic stages. The main nasal and nasopharyngeal CT findings were soft tissue masses of variable sizes. The lesions were characteristically homogenous. non-enhancing and had distinct edge definition; adjacent fascial planes were not invaded. The subglottic area was involved in laryngeal and tracheal scleroma. The lesions were mainly in the form of concentric irregular narrowing of the airway. In the trachea. crypt-like irregularities were diagnostic of scleroma. Intra-orbital. intra-cranial and infratemporal parapharyngeal scleromatous masses were detected in one patient.
Sensorineural hearing loss and the Marinesco-Sjogren syndrome, Sensorineural hearing loss has not been previously reported in patients with the Marinesco-Sjogren Syndrome. Two siblings are described where hearing was initially normal but subsequently deteriorated.
Maxillary sinus barotrauma with fifth cranial nerve involvement, A case of neurapraxia of the infraorbital nerve occurring as a result of maxillary sinus barotrauma in a diver is presented. Existing reports of a similar nature are reviewed and the pathogenesis of cranial nerve involvement in barotrauma is discussed. Guidelines for treatment are suggested.
Post cricoid lymphangioma, A 69-year-old female patient presented with symptoms characteristic of globus pharyngeus and barium swallow examination was normal. Her symptoms persisted and pharyngoscopy was undertaken; a post-cricoid polyp was found and removed. Histological examination revealed this to be a lymphangioma. Histological appearances. pathogenesis and treatment are discussed. The case illustrates that persisting symptoms presenting as globus pharyngeus should be further investigated to exclude rare lesions.
Metastatic meningioma in the neck, Although meningiomas represent 15 per cent of tumours of the central nervous system. they rarely metastasize. A case is presented in which metastasis to a cervical lymph node occurred. together with local recurrence. nine years after initial diagnosis and treatment. This case serves to illustrate that malignant meningioma is a rare cause of a neck mass.
Does hyperkinetic circulation constitute a pre-hypertensive stage? A 5-year follow-up of haemodynamics in young men with mild blood pressure elevation, In a previous haemodynamic examination. 44 young men (18-22 years) with blood pressure elevation above the 98th percentile. mean arterial blood pressure (MAP) greater than or equal to 95 +/- 6 mm Hg. showed an increased cardiac index (dye-dilution) and an enhanced resistance at maximal vasodilation of the hand (venous occlusion plethysmography during hyperaemia). This latter finding suggested arteriolar wall hypertrophy. However. the subgroup with the highest cardiac index (greater than or equal to 3.86 1 min-1 x m2) (n = 18) displayed normal vascular resistance at maximal dilation in comparison with the normotensive control group (n = 29). Consequently. functional signs of arteriolar hypertrophy were restricted to individuals with normal or low cardiac index. At the re-investigation 5 years later. a significant reduction in blood pressure was observed in the normotensive control group (MAP: from 88 +/- 7 to 85 +/- 7 mm Hg. P less than 0.05). There was no change in individuals with initially elevated blood pressure. Furthermore. cardiac index fell significantly with time in this latter group. Thus. the blood pressure elevation in the hypertensive group. previously mainly dependent on high blood flow was. 5 years later. more related to an increased total peripheral resistance. (delta total peripheral resistance = 8%). However. no definite evidence indicating development of hypertrophy of the resistance vessels of the hand was observed during the follow-up period. Since the hyperkinetic subgroup did not display a concomitant fall in blood pressure with cardiac output. our results do not support the theory that the hyperkinetic form of borderline hypertension is a temporary phenomenon. explained by the inclusion of anxious individuals afraid of the experimental situation. Hyperkinetic hypertension may be the initial phase of sustained hypertension in a subgroup of the future hypertensive population.
Habitual leisure-time physical activity is associated with differences in various risk factors for coronary artery disease, Various risk factors for coronary artery disease (CAD) were compared in 100 healthy. male factory workers. divided into two groups of 50 each on the basis of their leisure-time activity. The two groups. designated as sedentary and physically active. were similar in terms of age and body mass index. but the physically active group had a significantly slower pulse rate. In addition. the plasma glucose and insulin responses to an oral glucose load were significantly lower in physically active individuals. Furthermore. fasting plasma triglyceride concentration was significantly lower and the high-density lipoprotein-cholesterol concentration was higher in the physically active individuals. Thus. substantial benefits in terms of CAD risk were associated with increased leisure-time physical activity.
Rectal potential differences in irritable bowel syndrome and in inflammatory bowel diseases in man, We have studied rectal potential difference (pd) in 200 subjects: 30 healthy volunteers or control patients. 46 patients with irritable bowel syndrome (IBS) and painless diarrhoea (group I). 60 IBS patients without diarrhoea (group II) and 64 patients with inflammatory bowel disease (IBD) with (group III. n = 41) or without (group IV. n = 23) rectal involvement. Pd measurement used a rectal perfused probe and a subcutaneous needle both connected. via agar-KCl bridges. to calomel electrodes and a millivoltmeter. Statistical analysis used Student's t-test for paired and unpaired data and Mann-Whitney U-test as appropriate. Mean rectal pd values were. respectively -43.5 +/- 8.7 mV in control group. -32.9 +/- 10.2 mV in IBS-group I patients (P less than 0.001). -41.3 +/- 12 mV in IBS-group II patients (NS). -21.4 +/- 14.1 mV in IBD patients with rectal involvement (P less than 0.001). and -45.1 +/- 14.3 mV in IBD-group IV patients (NS). A histological examination was performed in 36 IBS patients; mean rectal pd was significantly decreased in patients showing abnormal patterns (n = 27. pd = -31.8 +/- 9 mV) compared to patients with normal mucosa (n = 9. pd = -41.1 +/- 6.5 mV; P less than 0.01). These results show that: (1) potential difference is significantly decreased in patients with ulcerative and rectal involvement; (2) in patients with Crohn's disease. normal rectal pd values do not assess the appearance of colonic mucosa above; (3) patients with IBS and diarrhoea also present a significant diminution in mean rectal pd. Although the mechanisms involved remain unclear. rectal pd measurement appears to be an objective test for intestinal mucosae weakness in functional or inflammatory diseases of the large intestine and rectum.
A double-blind placebo-controlled study of the efficacy and tolerability of ebastine against hayfever in general practice patients, Ebastine is an H1 antihistamine. Using a double-blind. parallel group randomized study design. the efficacy and the tolerability of oral ebastine (10 mg daily escalating to 40 mg daily according to clinical need) was compared over 4 weeks during 1986 with matching placebo in 40 general practice patients suffering from hayfever. Ebastine (19 patients) was more effective (P less than 0.05) than placebo (21 patients) against symptoms of running nose. itching nose. sneezing and blocked nose. Ebastine was superior to placebo in respect of the total symptom score as well as when judged by the investigators' and the patients' opinion of overall efficacy. Ebastine caused few adverse events. none of which resulted in a patient being withdrawn from treatment. Significantly more patients were withdrawn because of inefficacy from the placebo (n = 12) than from the ebastine (n = 3) treatment group (P less than 0.02). It is concluded that ebastine (10-40 mg daily) is an effective and well tolerated treatment for hayfever.
Chronic infectious mononucleosis; a case report, A 39-year-old woman had an adenitis colli followed by anaemia. splenomegaly. atypical lymphoid cells in blood with increased B-lymphocytes. reduced T-suppressor/cytotoxic cells. increased polyclonal IgM. high titres of EB VCA IgG. EB EA IgD&R +/- and EBNA IgG-. The disease progressed slowly for 2 years. splenectomy was followed by clinical improvement; spleen morphology was compatible with a benign disease of viral origin.
Mortality rates from multiple sclerosis: geographical and temporal variations revisited, A review of the United Kingdom (UK) multiple sclerosis (MS) literature suggests that over the last three decades prevalence and estimated incidence rates have increased. while mortality rates have been declining. UK mortality data over a 30 year period have been studied to examine temporal and geographical variations. to estimate changes in survival. and to examine the relationship between mortality and morbidity trends. The study has shown an overall decline in mortality throughout the UK of approximately 25% over the 30 year period ending in 1983. and a reduction in the mortality differential between Scotland. and England and Wales. but no positive correlation has been found between mortality and morbidity. The overall decline in death rate in females was 23% and in males 30% over the 30 years of the survey. The total number of deaths declined by 39% between the five year periods 1954-58 and 1979-83 in Scotland compared with a 10% decline for England and Wales. Estimated median age of death increased from 52 to 59 years and the improvement in survival over the period of study was similar for both countries and is unlikely to have contributed to the reduction in mortality differential. Within England and Wales regional mortality rates did not show a clear north-south gradient. The decline in the mortality differential between Scotland and England (if not artefactual) may provide an important aetiological clue in the search for the cause of multiple sclerosis. and the rate of decline suggests an environmental rather than a genetic aetiology.
Neurofibrillary tangles in dementia pugilistica are ubiquitinated, Ubiquitin. a protein thought to be involved in the ATP-dependent non-lysosomal degradation of abnormal proteins. has already been identified as a component of neurofibrillary tangles in Alzheimer's disease. We have examined ubiquitin immunoreactivity in a unique collection of brains from 16 ex-boxers including 11 with dementia pugilistica. Neurofibrillary tangles of dementia pugilistica were labelled with an affinity purified antiserum to ubiquitin. and BF10. a monoclonal antibody to a neurofilament epitope.
Cerebrospinal fluid tumour markers in patients treated for meningeal malignancy, The results of cerebrospinal fluid (CSF) biochemical markers were compared with conventional CSF cytology in patients treated for leptomeningeal metastases from extra cranial malignancies. For lumbar CSF. before treatment. no statistically significant difference of the probabilities of being positive was found between CSF cytology and a classification by linear discriminant analysis. based on patient's age. of beta-glucuronidase and beta 2-microglobulin. During treatment. classification by linear discriminant analysis was found more often positive than cytology. Possible mechanisms for this difference are discussed. For ventricular CSF a correlation was found between CSF cytology and beta-glucuronidase for solid tumours. and between CSF cytology and beta 2-microglobulin for haematological malignancies. Reference values for ventricular protein. CEA beta-glucuronidase and beta 2-microglobulin were obtained for cytological negative samples.
Motor inhibition from the brainstem is normal in torsion dystonia during REM sleep, The maintenance of axial atonia during REM sleep was monitored in 14 patients with primary torsion dystonia. 10 patients with secondary torsion dystonia. and 10 normal subjects using submental EMG and video EEG telemetry. The excitability of the corticospinal tract during REM sleep was also assessed using scalp magnetic stimulation in seven patients and three controls. During REM sleep dystonic patients had well maintained atonia evidenced by infrequent bursts of submental activity. no episodes of complex semi-purposeful behaviour and reduced motor responses to magnetic stimulation. These findings suggest that the inhibitory centres in the region of the locus coeruleus and their descending pathways to the spinal alpha motor neurons are intact in torsion dystonia.
Cognitive behaviour therapy in chronic fatigue syndrome, Fifty patients fulfilling operational criteria for the chronic fatigue syndrome (CFS). and who had been ill for a mean of five years. were offered cognitive behaviour therapy in an open trial. Those fulfilling operational criteria for depressive illness were also offered tricyclic antidepressants. The rationale was that a distinction be drawn between factors that precipitate the illness and those that perpetuate it. Among the latter are cognitive factors such as the belief that physical symptoms always imply tissue damage. and behavioural factors such as persistent avoidance of activities associated with an increase in symptoms. Therapy led to substantial improvements in overall disability. fatigue. somatic and psychiatric symptoms. The principal problems encountered were a high refusal rate and difficulties in treating affective disorders. Outcome depended more on the strength of the initial attribution of symptoms to exclusively physical causes. and was not influenced by length of illness. These results suggest that current views on both treatment and prognosis in CFS are unnecessarily pessimistic. It is also suggested that advice currently offered to chronic patients. to avoid physical and mental activity. is counterproductive.
Autonomic function in Friedreich's ataxia, Autonomic function studies were performed on 15 patients with Friedreich's ataxia. and the results compared with those of 76 healthy subjects. There was an increase in resting supine heart rate. attributed to cardiac abnormalities. Other tests of sympathetic and parasympathetic function were normal. The normal autonomic function studies are consistent with the pathological findings of degeneration predominantly of large diameter myelinated fibres with sparing of small myelinated and unmyelinated fibres.
Use of the polymerase chain reaction to detect herpes simplex virus DNA in paraffin sections of human brain at necropsy, The feasibility of detecting herpesvirus DNA in paraffin sections of routinely fixed and processed human necropsy brains by use of the polymerase chain reaction (PCR) was assessed. A 110 bp segment of the thymidine kinase gene of herpes simplex virus type 1 (HSV1) could readily be amplified in sections from the brains of six patients with acute HSV1 encephalitis but not from those of six patients with other neurological diseases. including varicella-zoster encephalitis and herpes simplex virus type 2 encephalitis. Primers suitable for amplifying c-myc were included in the PCRs for assessment of DNA preservation. This was found to be adequate to allow amplification of c-myc DNA in sections from all of the brains studied. The PCR provides a simple and specific means of detecting HSV1 DNA in routinely processed necropsy material.
Neuropsychological deficit in haemophiliacs with human immunodeficiency virus, Neuropsychological impairment is widely accepted as being common in acquired immunodeficiency syndrome (AIDS) but infrequent in asymptomatic human immunodeficiency virus (HIV)-infected individuals. The neuropsychological function of a homogenous sample of HIV-infected haemophiliacs was investigated. Neuropsychological impairment. the nature of which is compatible with that described in the existing literature. was found in one of four AIDS cases. Eleven AIDS related complex (ARC) and 12 asymptomatic HIV-infected individuals were free of neuropsychological deficit.
Changes in rat plasma apolipoproteins and lipoproteins during moderate protein deficiency: potential use in the assessment of nutritional status, To test apolipoprotein sensitivity as protein deficiency markers. concomitant evolution of plasma apolipoproteins (apo) and usual nutritional markers (transthyretin. albumin. transferrin) were followed during a 28-d protein restriction in young male Wistar rats. In addition. plasma lipids and chemical composition of lipoproteins were assayed by d 28. The control and the deficient groups were fed 18% and 6% casein diets. respectively. By d 28 the protein-deficient group exhibited hypotriglyceridemia resulting from the decrease in VLDL triacylglycerols; free cholesterol and phospholipids were increased. reflecting the increment in LDL-HLDL1. In plasma total lipoproteins. apo BH. AI and E were not different than controls in the deficient group. Apolipoprotein AIV decreased after d 14 and was significantly less than in controls at d 28. Apolipoprotein BI was considerably reduced by d 14 (43% less) and d 28 (52% less) compared with the control group. Apolipoproteins C + AII were significantly lower in the protein-deficient group by d 14 (43%). By d 28. VLDL apo C were decreased 60% by protein restriction. Transthyretin level was 20% lower in the protein-deficient group by d 7 but returned to control values by d 14. A moderately lower value was observed for albumin by d 7 and d 14 and for transferrin by d 28. These results indicate that. in this model. apo BI and C are more sensitive to protein depletion than usual nutritional markers.
Dietary lead and calcium: effects on blood pressure and renal neoplasia in Wistar rats, We examined the potential of increased Ca in the diet to modify the effects of Pb on tissue metal concentrations. blood pressure and the incidence of renal tumours. We randomly assigned 48. 5-wk-old male Wistar rats to one of six treatment groups. They were fed a low (0.2%) or high (4.0%) Ca diet for 31 wk and given 0. 1.0 or 100 micrograms Pb/mL in drinking water. In the low Ca groups. increasing concentrations of Pb produced graded increases in mean blood pressure. Rats receiving 4.0% Ca had higher mean blood pressures than the animals fed the 0.2% Ca diet. The 4.0% Ca diet also caused renal and urinary bladder stones to develop in some rats. The high Ca diet did not prevent dose-dependent increases in tissue Pb accumulation. but it caused significant decreases in kidney Cu. femur Mg and Fe in kidney. liver and testis. Femur Mg and Fe and liver Fe concentrations were lowest in rats receiving 4.0% Ca and 100 micrograms Pb/mL. Precancerous and cancerous renal lesions occurred to the greatest extent in the rats receiving 100 micrograms Pb/mL and the high Ca diet. These results suggest that high dietary Ca does not protect against Pb-induced increases in blood pressure or Pb accumulation in tissues and may often produce nephrocalcinosis. In addition. high dietary Ca in the presence of Pb may increase the incidence of renal tumors.
The impact of varying degrees of iron nutriture on several functional consequences of iron deficiency in rats, The impact of varying severities of iron-deficiency anemia on fasting blood glucose. plasma triiodothyronine. heart norepinephrine concentrations and resting oxygen consumption were evaluated. Male weanling Sprague-Dawley rats were assigned to one of six dietary groups (4. 6. 11. 16. 23 or 40 mg Fe/kg diet) for 6 wk. Hemoglobin. liver iron and transferrin saturation were significantly lower in the 4 and 6 mg Fe/kg diet groups relative to the other groups and were indicative of anemia. low tissue iron stores and impaired erythropoiesis. Fasting blood glucose and heart norepinephrine concentrations were significantly higher and lower. respectively. in the 4 and 6 mg Fe/kg diet groups than the three highest dietary Fe groups. Although fasting blood glucose was significantly inversely correlated (r = -0.89. P = 0.0001) with hemoglobin concentration; a significant quadratic relationship (R 2 = 0.70. P = 0.0001) existed between hemoglobin and heart norepinephrine concentration. Differences in plasma triiodothyronine concentrations and resting oxygen consumption were not significant among the groups. Thus. base on hemoglobin concentration as an index of the severity of iron deficiency. these findings demonstrate that certain physiological manifestations of iron deficiency occur at even moderate-to-mild degrees of anemia.
Alterations in splenic lymphoid cell subsets and activation antigens in copper-deficient rats, Rats were nursed by dams fed a diet containing adequate (6 micrograms/g) or deficient (0.6 micrograms/g) Cu during the lactation period and weaned to the same diet. Splenic mononuclear cells were isolated and the phenotypic profile determined by flow cytometry after immunolabelling with monoclonal antibodies to cell surface markers. Total splenic mononuclear cell yield and the relative percentage and absolute number of T-cells and the CD4+ (helper) and CD8+ (cytotoxic) T-subsets were decreased in Cu-deficient male rats. The relative percentage. but not the absolute numbers. of splenic B-cells and macrophages was increased by Cu deficiency. The percentage of splenic mononuclear cells from male rats that expressed interleukin-2 receptors and transferrin receptors in vivo was increased by Cu deficiency. In contrast. dietary Cu deficiency did not affect the yield and phenotypic profile of splenic mononuclear cells in female rats. Reactivity of splenic mononuclear cells to T-cell mitogens was decreased in Cu-depleted male and female rats. However. mitogen-induced increases in levels of interleukin-2 receptor and transferrin receptor were similar in cultures of splenic mononuclear cells obtained from control rats and rats subjected to restricted dietary intake of Cu only during the postlactation period. Thus. decreased mitogenic blastogenesis on exposure of cells from Cu-deficient rats does not reflect a nonspecific impairment of cellular activation.
Prenatal protein malnutrition and maternal behavior in Sprague-Dawley rats, Female Sprague-Dawley rats were provided with an adequate (25% casein) or low (6% casein) protein diet. fortified with methionine. starting 5 wk prior to gestation and continuing until the birth of their pups. At birth. the offspring were fostered to well-nourished lactating dams as follows: in Experiment 1. litters contained eight prenatally malnourished pups; in Experiment 2. litters consisted of four pups with prenatal malnutrition and four well-nourished pups; control litters for both experiments contained eight well-nourished pups. In Experiment 1. the time spent in passive nursing and pup grooming was significantly higher for dams rearing previously malnourished pups than for those rearing control litters. In Experiment 2. mixed litters were groomed less frequently than control litters. but there was no significant difference between groups for any other measure. In both experiments. the prenatally malnourished pups showed similar body weight deficits relative to well-nourished pups. These findings underscore the usefulness of mixed litters in studying the later effects of prenatal malnutrition because later deficits in brain function are less likely to be attributable to changes in the early rearing environment.
The value of single versus multiple sections for detection of lymph node metastasis, This study was undertaken to determine the value of serial sectioning of lymph nodes as an aid in optimally examining cervical specimens for metastasis. The presence or absence of lymph node metastasis in 802 lymph nodes obtained from 51 consecutive neck dissection specimens were initially determined by the routine method. examination of one section from each node. This examination revealed 40 lymph nodes with metastatic involvement. Further study of the 716 lymph nodes that were initially interpreted as free of tumor by serial sectioning added only two positive nodes. Thus. serial sectioning did not contribute significantly to the detection of lymph node metastasis.
Retrospective analysis of 135 secondary alveolar cleft grafts using iliac or calvarial bone, This retrospective study summarizes experience with 135 secondary alveolar cleft bone graft procedures over 8 years. The overall success rate was 83.7%. The group of patients (n = 108) that had particulate cancellous bone and marrow obtained from the iliac crest as donor bone had an 89.8% success rate. The group (n = 27) that had calvarial bone as the donor material had a success rate of only 63%. It is felt that inferior results with calvarial bone are probably related to the procurement technique. In both the iliac crest and calvarial groups. there was a trend toward declining success rates with advancing age of the patient. Morbidity associated with these procedures. consistent with other reported series. was low.
The transconjunctival approach for treating orbital trauma, Twelve patients with a variety of maxillofacial injuries were treated with a transconjunctival incision and lateral canthotomy for orbital floor. and inferior and lateral rim reconstruction. Mean follow-up was 12 months. during which time no immediate or delayed complications developed. The exposure and access was satisfactory in all cases for reduction and rigid fixation of both inferior and lateral rim through a single incision.
Biomechanical properties of resorbable poly-L-lactide plates and screws: a comparison with traditional systems, Poly-L-lactide (PLA) plates and screws were tested in vitro in porcine ribs for uniaxial pullout and four-point bending strength. Results were compared to conventional systems (stainless steel and titanium). The biomechanical testing suggests that PLA screws have properties suitable for fixation of sagittal split osteotomies. Poly-L-lactide plates have indications in areas of low stress and noncompressive load.
Reflex bradycardia during TMJ arthroscopy: case report, A case of bradycardia occurring during TMJ arthroscopy is presented. A similar case of the TVR has not previously been reported. This reflex must be recognized by oral and maxillofacial surgeons who perform arthroscopy.
Iron status with different infant feeding regimens: relevance to screening and prevention of iron deficiency, The objective of this study was to evaluate the benefit of screening for anemia in infants in relation to their previous diet. The iron status of 854 nine-month-old infants on three different feeding regimens and on a regimen including iron dextran injection was determined by analysis of hemoglobin. serum ferritin. and erythrocyte protoporphyrin levels and of serum transferrin saturation. Infants were categorized as having iron deficiency if two or three of the three biochemical test results were abnormal and as having iron deficiency anemia if. in addition. the hemoglobin level was less than 110 gm/L. The prevalence of iron deficiency was highest in infants fed cow milk formula without added iron (37.5%). intermediate in the group fed human milk (26.5%). much lower in those fed cow milk formula with added iron (8.0%). and virtually absent in those injected with iron dextran (1.3%). The corresponding values for iron deficiency anemia were 20.2%. 14.7%. 0.6%. and 0%. respectively. The use of iron supplements is therefore justified in infants fed cow milk formula without added iron. even when there is no biochemical evidence of iron deficiency. The low prevalence of iron deficiency in the group fed iron-fortified formula appears to make it unnecessary to screen routinely for anemia in such infants. These results also support the recommendation that infants who are exclusively fed human milk for 9 months need an additional source of iron after about 6 months of age.
Renal functional reserve in long-term survivors of unilateral Wilms tumor, We hypothesized that long-term survivors of unilateral Wilms tumor would have a decreased renal functional reserve secondary to the consequences of hyperfiltration in the nephrons of the remaining kidney. Therefore we evaluated the renal functional reserve in 12 long-term survivors of Wilms tumor after unilateral nephrectomy (mean +/- SE: 15 +/- 1.1 years; range 9 to 23 years). We measured the creatinine clearance before and after an acute. oral protein load to determine the renal functional reserve. Study subjects and control subjects were matched for age. gender. and body surface area. The basal creatinine clearances were similar (Wilms group 132 +/- 13 vs control group 142 +/- 11 ml/min/1.73 m2; p = not significant (NS]. There was no significant difference in the renal functional reserve between long-term survivors of Wilms tumor and matched control subjects (Wilms group 17 +/- 11 vs control group 25 +/- 11 ml/min/1.73 m2; p = NS). The change in creatinine clearance was not secondary to volume expansion because the fractional excretion of sodium was unchanged with protein loading (Wilms group before loading 0.92 +/- 0.12 vs after loading 0.99 +/- 0.13 (p = NS); control group before loading 0.91 +/- 0.12 vs after loading 1.0 +/- 0.14 (p = NS)). We conclude that up to 15 years after nephrectomy for unilateral Wilms tumor in childhood. there is no evidence of hyperfiltration injury.
Cardiopulmonary resuscitation of apparently stillborn infants: survival and long-term outcome, To determine the outcome of apparently stillborn infants who received cardiopulmonary resuscitation. we studied the short- and long-term outcome of 93 infants who had an Apgar score of 0 at 1 minute of age and were resuscitated at birth. Sixty-two (66.6%) responded and left the delivery room alive; 26 (42%) of the 62 infants died in the neonatal period and 36 infants were discharged home; of the 36 infants. three subsequently died during infancy. Of the 33 survivors. ten were lost to follow-up after discharge. Developmental assessment of 23 of 33 long-term survivors revealed normal outcome in 14 (61.7%). abnormal results in 6 (26%). and suspect status in 3 (13%). Fifty-eight infants had an Apgar score of 0 at greater than or equal to 10 minutes of age and all except one died; the surviving infant has an abnormal developmental outcome. We conclude that 39% of apparently stillborn infants who were resuscitated survived beyond the neonatal period and that 61% of the 23 survivors who were available for developmental follow-up had normal development at the time of last examination. Survival was unlikely if there was no response after 10 minutes of resuscitation.
Nursery Neurobiologic Risk Score: important factor in predicting outcome in very low birth weight infants, We developed a nursery Neurobiologic Risk Score (NBRS) based on potential mechanisms of brain cell injury in preterm infants and correlated it with developmental outcome at the corrected ages of 6. 15. and 24 months. The NBRS was determined at 2 weeks of age and at the time of discharge from intensive care in 58 preterm infants with birth weights less than or equal to 1500 gm. The NBRS correlated significantly with the Bayley Scales of Infant Development. Mental Development Index (MDI) (r = -0.61 to -0.40) and Psychomotor Development Index (PDI) (r = -0.59 to -0.46). and with abnormal neurologic examination findings (r = 0.59 to 0.73) at the three testing periods. Although 12 of the 13 items composing the NBRS individually correlated with one or more outcome variables. seven items (infection. blood pH. seizures. intraventricular hemorrhage. assisted ventilation. periventricular leukomalacia. and hypoglycemia) accounted for almost all of the explained variance. Logistic regression of individual items demonstrated intraventricular hemorrhage to be the most important item for predicting the MDI at 24 months; pH was the most influential item for predicting the PDI at every testing period. A shorter. revised NBRS that included only the seven significant items demonstrated as strong a correlation with developmental outcome as the original NBRS. A revised 2-week score of greater than or equal to 5 or a discharge score of greater than or equal to 6 demonstrated 100% specificity and had a 100% positive predictive value for an abnormal outcome at 24 months of age in this group of infants. We conclude that the NBRS identifies during the intensive care nursery stay those infants at highest risk for an abnormal outcome related to nursery events. In addition. analysis of NBRS items provides insight into the relative importance of individual factors for influencing mental. motor. and neurologic outcome.
Anthropometric measurements in a newborn population in west Africa: a reliable and simple tool for the identification of infants at risk for early postnatal morbidity, The predictive value of anthropometric measurements in the identification of infants at risk for early postnatal morbidity was assessed in a cohort of 490 neonates born in Yaounde. Cameroon. Mid-arm circumference (MAC). head circumference. weight. and length were measured within 6 hours of birth. and the gestational age. individual MAC/head circumference ratio. and individual ponderal index were calculated. A detailed questionnaire on gestational medical history was also obtained from the mothers. All infants were then closely monitored during the first 72 hours after delivery for the appearance of symptoms requiring medical intervention and treated accordingly. Low birth weight (LBW) was observed in 37.75%. prematurity in 25.5%. and small size for gestational age in 14.1% of the neonates. Gestational medical problems were reported by 44.3% of the mothers; malaria was the most frequent. Early postnatal morbidity was observed in 26% of the infants; infection (53%). respiratory distress (26%). hypoglycemia (26%). and convulsions (11.7%) accounted for most of the problems. The MAC correlated best of all variables with birth weight (r = 0.91); a value of less than or equal to 9.5 cm had a 93% sensitivity and a 90.5% specificity in the prediction of LBW. An MAC cutoff value of less than or equal to 9.5 cm was also the best of all variables in the prediction of early postnatal morbidity. and 85.2% sensitivity and 74.3% specificity were achieved. We conclude that in developing countries. where scales are not always available and the overburdened maternity wards cannot allow for medical surveillance of every infant. the MAC can be used in the estimation of birth weight. Moreover. an appropriately calculated cutoff value of MAC may serve as a reliable indicator of LBW and of infants at risk for early postnatal morbidity.
Suppression of gastric acid secretion by intravenous administration of famotidine in children, This study was designed to establish appropriate dosing requirements for intravenous use of famotidine. a new H2-receptor antagonist. in pediatric patients. Eighteen children. 2 to 69 months of age (mean +/- SD: 31 +/- 23 months). were treated with intravenously administered famotidine to prevent bleeding of the upper gastrointestinal tract. Continuous intragastric pH monitoring was carried out to ascertain the effectiveness of various intravenous doses. An initial dose of 0.4 mg/kg was given and repeated only after the intragastric pH had dropped to less than 4.0 for 2 hours. Increased doses were given (0.8. 1.2. and 1.6 mg/kg) if the previous dose did not raise the intragastric pH to greater than 4.0 for greater than or equal to 6 hours. Sixteen patients achieved an intragastric pH greater than or equal to 4.0 for greater than or equal to 6 hours. 13 with a dose of 0.4 mg/kg. and three with a dose of 0.8 mg/kg. The mean duration of continuous pH greater than 4.0 per dose was 9.0 +/- 7.5 hours. Ten patients received two or more intravenous doses of famotidine; the mean duration of pH greater than 4.0 after the second dose was less than that after the first (14.9 +/- 8.0 hours vs 6.9 +/- 3.2 hours. p less than 0.01). We conclude that intravenous famotidine therapy raises gastric pH to greater than 4.0 for approximately 9 hours in most children. Prolonged intravenous use of famotidine rapidly leads to a decreased duration of efficacy. necessitating intragastric pH monitoring to assess the effectiveness of treatment.
Effects of selected beta-adrenergic blocking agents on sleep stages in spontaneously hypertensive rats, The effects on sleep of six beta-adrenergic blockers (propranolol. dilevalol. pindolol. metoprolol. celiprolol and atenolol) which differ in their pharmacological characteristics were studied in spontaneously hypertensive rats. Electroencephalographic activity was recorded for 6 hr after p.o. administration of drugs or vehicle. and the stages of wakefulness. rapid eye movements (REM) sleep and non-REM sleep (non-REM) were classified thereafter. In separate experiments antihypertensive activity of each drug was assessed by the tail-cuff technique. The most common effect of the beta-blockers examined was a decrease of the duration of REM. The effect was marked for propranolol (10-100 mg/kg). celiprolol (10-100 mg/kg) and pindolol (1-10 mg/kg). whereas it occurred at low doses. but not at high doses for metoprolol (10 mg/kg) and atenolol (3 and 10 mg/kg). Dilevalol induced a moderate REM decrease at 30 mg/kg only. For the beta-1 antagonists. the dose reducing REM substantially (ED30) was slightly above (1.4- to 3.7-fold) that effective on blood pressure (ED10). whereas the separation was high for pindolol (17.4-fold) and dilevalol (22.4-fold). Conversely. propranolol displayed a weak antihypertensive activity in this model and was more potent on REM than in reducing blood pressure. Propranolol. celiprolol and atenolol also increased duration of wakefulness. Considering the pharmacological characteristics of the beta-blockers examined. it is suggested that selective beta-1 antagonism and interaction with other neurotransmitters. such as serotonin. are relevant to the potential effects of this class of antihypertensive drugs on sleep function.
Verapamil-induced blockade of voltage-activated K+ current in small-cell lung cancer cells, Verapamil. Ca++ channel antagonist. has proven clinically useful in the reversal of multiple drug resistance. which is a major detriment to chemotherapy. Recently. verapamil alone has been shown to diminish proliferation in a variety of neoplastic cell lines. Using the patch-clamp technique. the action of verapamil on voltage-gated K+ channels in two cell lines of human small-cell carcinoma of the lung. NCI-H146 and NCI-H82. was investigated. With inward Na+ current suppressed. virtually all control cells exhibited a slowly inactivating outward current that was insensitive to alterations in the external Ca++ concentration. Externally applied verapamil enhanced the rate and extent of outward K+ current (IK) inactivation. Verapamil at a concentration of 20 microM diminished peak IK. evoked by a test pulse to +60 mV from a holding potential of -80 mV. from 1.38 +/- 0.11 nA (mean +/- S.E.M.. n = 29 cells) to 0.56 +/- 0.13 nA (n = 11) and caused IK to decay to less than 20% of the peak current within 60 msec. After blocking IK and Na+ current. Ca++ current (ICa) was measured in the presence of 10 mM Ca++. The addition of 100 microM verapamil to the external bath resulted in a 53% reduction of H146 ICa. Peak ICa fell from 81 +/- 9 pA (n = 22) to 38 +/- 8 pA (n = 12). Examination of the whole-cell K+ current on single cells before and immediately after the addition of 100 microM verapamil clearly revealed that the drug had no effect on the initial activation phase of IK. suggesting that K+ channels first open before interacting with the drug.
Effects of DM-9384, a cyclic derivative of GABA, on amnesia and decreases in GABAA and muscarinic receptors induced by cycloheximide, The effects of N-(2.6-dimethyl-phenyl)-2-(2-oxo-1-pyrrolidinyl)-acetamide [DM-9384]. a cyclic derivative of GABA. were investigated in the cycloheximide (CXM)-induced amnesia animal model using the passive avoidance task. Pre- and post-training and pre-retention test administration of DM-9384 attenuated the CXM-induced amnesia as indicated by prolongation of step-down latency. Aniracetam. another cyclic derivative of GABA. also showed antiamnesic effects. Scopolamine. a muscarinic ACh receptor antagonist. and the GABA antagonists. picrotoxin and bicuculline. all antagonized the antiamnesic effects of DM-9384. CXM decreased the number of GABAA and muscarinic ACh receptor binding sites. DM-9384 not only inhibited this effect but actually increased the latter. These results suggest that DM-9384 attenuates CXM-induced amnesia by interacting with GA-BAergic and AChergic neuronal systems and enhancing protein synthesis in the brain.
Role of endothelium on the effects of neuropeptide Y in mesenteric resistance arteries of spontaneously hypertensive and Wistar-Kyoto normotensive rats, The role of the endothelium in the effects of neuropeptide Y (NPY) and norepinephrine was investigated in mesenteric resistance arteries of the spontaneously hypertensive rat (SHR) and of the normotensive Wistar-Kyoto rat (WKY). Endothelium-dependent relaxation to acetylcholine (1 microM) was reduced in arteries of SHR compared with WKY. In the presence of the endothelium. the vessels of the two strains responded similarly to norepinephrine and NPY (100 nM) produced only a slight contraction. After removal of the endothelium. the response to norepinephrine was greater in WKY than in SHR. Furthermore. endothelium denudation enhanced markedly contraction elicited by NPY in WKY (up to 40% of the maximal effect of norepinephrine). but not in SHR. NPY potentiated the contractile response to low concentrations of norepinephrine (less than 300 nM) in both strains regardless whether the endothelium was intact or not. These results indicate that the contractile responses to NPY and to norepinephrine are inhibited by the endothelium in vessels of WKY. but not in those of the SHR. Furthermore. the potentiating effect of NPY occurs via an endothelium-independent mechanism in mesenteric arteries of both SHR and WKY. It is proposed that the differential responses between the two strains are related to abnormal function of the endothelium and to decreased responsiveness of smooth muscle cells in mesenteric resistance arteries of SHR compared to WKY.
Endothelin binding in brain of normotensive and spontaneously hypertensive rats, The endothelins (ETs) are a recently discovered family of peptides which appear to be involved in hemodynamic regulation; they have potent vasoconstrictor properties and dose-related effects on blood pressure when administered peripherally. Little is known about the role of ET in the brain. The purpose of this study was to characterize the binding properties of various ETs in the brain of normotensive (Wistar-Kyoto) and hypertensive (spontaneously hypertensive) rats. [125I]ET 1 was prepared using the enzymobead lactoperoxidase method and purified by high-pressure liquid chromatography. Membrane fractions were prepared from homogenates of various brain regions. A differential distribution of ET binding was found among the 14 brain regions studied. The cerebellum. brainstem and area postrema/nucleus tractus solitarius had the highest binding. whereas the cortex. pituitary and septum had the least binding. Competition experiments performed with hypothalamus. brainstem and cerebellum demonstrated different Ki values for the ET studied. ET 2 had the highest affinity with a Ki of 4 x 10(-1) M. whereas the ET analog. Ala3.11-ET 1. had the lowest affinity with a Ki of 3 x 10(-10) M. Saturation experiments indicated a single class of high-affinity receptors in cerebellar (Kd = 2.5 x 10(-11) M. maximal binding Bmax = 1.25 x 10(-12) mol/mg) and hypothalamic membranes (Kd = 1.9 x 10(-11) M. Bmax = 0.93 x 10(-12) mol/mg). No differences in Kd or Bmax were detected between Wistar-Kyoto and spontaneously hypertensive rats hypothalamic and cerebellar tissues. The results of this study suggest a role for ET in the brain. but revealed no differences between normotensive and hypertensive strains.
Hemicholinium-3 derivatives A-4 and A-5 alter choline metabolism in NB41A3 neuroblastoma cells, A-4. A-5 and HC-3 are experimental bis tertiary and quaternary amines which have been shown to be potent inhibitors of the sodium-dependent. high affinity choline uptake system. When incubated with neuroblastoma cells. experimental compounds A-4. A-5 and HC-3 inhibit choline metabolism. Over a 24-hr incubation. A-4. A-5 and HC-3 produced a significant decrease in total choline accumulation. choline incorporation into phospholipid and free choline content. However. despite decreases in choline incorporation into phospholipid. no change occurred in content of phosphatidylcholine. Treatment of cells with A-4. A-5 and HC-3 resulted in an increase in the incorporation of S-adenosyl-methionine into phosphatidylcholine. However. the incorporation of ethanolamine or serine into phosphatidylcholine was not increased. Phosphatidylcholine turnover was decreased in cells treated with A-4 and A-5. A-4. A-5 and HC-3 produce significant decreases in choline metabolism; however. the cells are able to maintain membrane integrity by decreasing turnover of phosphatidylcholine and increasing phosphatidylcholine synthesis through the methylation pathway. These studies suggest that the biological effects of A-4 and A-5 are independent of membrane perturbations.
Tonic pain perception in the mouse: differential modulation by three receptor-selective opioid agonists, The proposition that tonic nociception models are more analogous to clinical pain than traditional acute models prompted our previous development of a modified mouse paw formalin test. To discern possible modulatory roles and site(s) of action of endogenous opioid systems. the receptor-preferring agonists sufentanil (mu). U-50.488H (kappa) and [D-Pen2.5]enkephalin (DPDPE. delta) were evaluated for antinociceptive activity in the formalin paradigm by systemic (except DPDPE). spinal and supraspinal routes. All observations were done under blind conditions. Doses causing overt behaviors that indicated a breach of receptor specificity (during the observation period) were rejected. Higher doses of centrally administered DPDPE (greater than 0.3 micrograms/mouse. intrathecal; greater than 3 micrograms/mouse. intracerebroventricular) induced a behavioral syndrome traditionally associated with mu agonism. and thus were not considered for this study. A50 values from behaviorally acceptable dose ranges for mean percent analgesia (reduction of paw licking compared to controls) were: trans-(+/- )-3.4-dichloro-N-methyl-N-[U-50.488H 2-pyrrolidinyl)cyclohexyl]-benzeneacetamide methanesulfonate.U-50.488H--3200 nmol/kg. subcutaneous. 1100 nmol/kg. intrathecal and 314 nmol/kg. intracerebroventricular; sufentanil--11.1 nmol/kg. subcutaneous. 8.6 nmol/kg. intrathecal; and DPDPE--inactive. On the basis of our dose-response data. we suggest that. in mice. kappa and mu. but not delta. opioid receptors modulate tonic pain perception at both spinal and supraspinal loci. The results also support inclusion of the modified formalin test in preclinical evaluations of potential kappa agonists.
Electrophysiological and binding studies on intact NCB-20 cells suggest presence of a low affinity sigma receptor, Whole cell voltage clamp studies were performed on NCB-20 cells to examine physiological responses to drugs possessing affinities for sigma receptors. Those drugs [haloperidol. alpha-(4-fluoro-phenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutano l (BMY-14802). pentazocine. N-allylnormetazocine (SKF-10047). 3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (3-PPP). phencyclidine. 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). (+)-5-methyl-10.11-dihydro-5H-dibenzo-[a.d]cyclohepten-5.10-imine maleate (MK-801)] caused an apparent inward current. which was due to blockade of a tonic. outward potassium current. The rank order of drug potencies in producing this effect generally resembled the rank orders of sigma-receptor affinities for the drugs. except that a reverse stereoselectivity was observed for several drugs. [3H](+)-SKF-10047 labeled two sites in intact NCB-20 cells (Kd = 49 nM. Bmax = 1.0 pmol/mg protein and Kd = 9.6 microM. Bmax = 69 pmol/mg protein). The high affinity site was similar pharmacologically to the sigma receptor assayed in membrane fragments from NCB-20 cells. However. the low affinity site showed a slightly different profile. highlighted by a reverse stereoselectivity. The rank order of drug potencies was as follows at the low affinity site: haloperidol greater than BMY-14802 greater than (-)-pentazocine greater than (+)-pentazocine greater than (-)-SKF-10047 greater than (-)-3-PPP greater than (+)-SKF-10047 greater than (+)-3-PPP greater than phencyclidine greater than TCP greater than MK-801.
(+-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine, an M1 selective cholinergic agonist, attenuates cognitive dysfunctions in an animal model of Alzheimer's disease, AF102B [(+-)-cis-2-methyl-spiro(1.3-oxathiolane-5.3')quinuclidine]. a structurally rigid analog of acetylcholine. was investigated in a number of neurochemical. pharmacological and behavioral tests related to cholinergic functions. AF102B induced atropine-sensitive contractions of isolated guinea pig ilea and trachea preparations with EC50 values of 3.5 and 3 microM being 87- and 1.3-fold less potent than acetylcholine. respectively. Binding studies using the radioligands pirenzepine. cis-dioxolane and quinuclidinyl benzilate in rat cerebral cortex and quinuclidinyl benzilate in cerebellar homogenates indicated that AF102B was a potent and highly selective M1-type muscarinic probe. being more selective for M1 receptors than oxotremorine. carbachol and AF102A (the trans-isomer of AF102B). AF102B had a 3-fold higher apparent affinity for M1 receptors than the prototype M1 agonist. McN-A-343. cis- and trans-AF30 (other rigid analogs of acetylcholine). Treatment of rat cortical homogenates with Cu++ ions did not modify the affinity observed for the muscarinic antagonists atropine. scopolamine and pirenzepine. whereas increasing the proportion of high affinity sites for the agonists oxotremorine-M. carbachol and McN-A-343. The apparent affinity of AF102B also increased by Cu++ treatment suggesting that this compound interacts with rat cerebral cortex muscarinic receptors as an agonist. AF102B did not affect high affinity choline transport. choline acetyltransferase and acetylcholinesterase activities in rat brain preparations. In rats treated with AF64A (the cholinotoxin ethylcholine aziridinium ion; 3 nmol/2 microliters/side i.c.v.). AF102B (1 mg/kg p.o. or i.p.). AF102A (1 mg/kg i.p.). cis-AF30 (1 mg/kg. i.p.) and physostigmine (0.06 mg/kg i.p.). each reversed cognitive impairments in a step-through passive avoidance task. Both AF102B and AF102A (1 mg/kg i.p.). but not physostigmine (0.1 mg/kg i.p.). were effective also in reversing reference memory impairments in a Morris water maze test. Repetitive administrations of AF102B (0.2 mg/kg/day i.p.) improved AF64A-induced working memory deficits in the Morris water maze test. but did not affect open field behavior. The data show that the selective M1 agonist AF102B can restore AF64A-induced cognitive impairments. without producing adverse central and peripheral side effects at the effective doses and this can indicate its potential use for the treatment of Alzheimer's disease.
Increased negative inotropic effect of calcium-channel blockers in hypertrophied and failing rabbit heart, The effects on ventricular function of calcium channel blockers and isoproterenol were studied in isovolumically beating perfused control rabbit hearts and in hearts subjected to a double pressure plus volume overload studied at the early phase of heart failure. In control hearts. isoproterenol produced an increase of systolic ventricular function and relaxation that was maximal at 10(-7) M. In failing hearts. inotropic state increase in response to isoproterenol was significantly smaller (P less than .01) with no observed lusitropic effect. In control hearts. verapamil and diltiazem produced dose-dependent decreases of ventricular function which were larger with verapamil than with diltiazem (median drug concentration50 of developed pressure was. respectively. 1163 +/- 131 nM and 4524 +/- 451 nM. P less than .001). In failing hearts. contractility decrease was larger than in control hearts (median drug concentration50 of developed pressure was 604 +/- 69 nM and 2691 +/- 580 nM with verapamil and diltiazem. respectively). In contrast. Ro 40-5967. a new calcium-channel blocker. did not produce reductions of inotropic state with concentrations up to 10(-5) M. All three calcium-channel blockers produced a 2-fold increase of coronary flow at 10(-6) M. We conclude that the deleterious effect of verapamil and diltiazem in heart failure is due. at least in part. to a direct depressant effect of these drugs on contractility. which is larger than in control hearts. Additionally. the in vivo sympathetic compensation is probably reduced. as indicated by the decreased ventricular responsiveness to isoproterenol.
Altered renal fibronectin excretion in early adriamycin nephrosis of rats, The anticancer drug adriamycin (ADR) induces severe nonselective glomerular proteinuria in rats. The proliferation of the glomerular mesangium in chronic ADR nephrosis suggests a disturbed metabolism of extracellular matrix proteins. In the present study the structural protein fibronectin was analyzed by immunological methods in urine and plasma in two rat strains after a single injection of 5 mg of ADR/kg b.wt. After ADR administration the excretion of 220 kd-plasma fibronectin. identified by its electrophoretic mobility and Western blotting. increased. This was confirmed by quantitative measurement (ELISA) of total urinary fibronectin (ADR-treated Munich Wistar Fromter rats: 85.4 +/- 49.5 ng/hr. N = 31; controls: 1.7 +/- 0.7 ng/hr. N = 26; day 7 after ADR injection). Control urines contained distinct fragments of fibronectin with a molecular weight range of 40 to 60 kd. It is suggested that these fragments did not originate from plasma inasmuch as only little correspondence between the fibronectin patterns of urine and plasma was found. and also because in ADR-treated rats the excretion of the fibronectin fragments decreased from day 4 of ADR administration. The data suggest that the urinary fibronectin fragments are released from cellular fibronectin during the normal catabolism of the glomerular extracellular matrices. and that ADR interferes in the metabolism of matrix components. Only as a consequence of an enhanced glomerular permeability is plasma fibronectin excreted in ADR-treated rats.
Methanol-induced visual toxicity in the rat, Human methanol poisoning is characterized by formic acidemia. metabolic acidosis and blindness or serious visual impairment. Nonprimate species are ordinarily resistant to the accumulation of formate and the associated metabolic and visual toxicity. A nonprimate model of methanol-induced visual toxicity was developed using rats treated with subanesthetic concentrations of nitrous oxide to inhibit the oxidation of methanol's toxic metabolite. formic acid. Methanol-intoxicated rats developed formic acidemia. metabolic acidosis and visual toxicity within 36 hr of methanol administration analogous to the human methanol poisoning syndrome. Visual dysfunction was measured as reductions in the flash-evoked cortical potential and electroretinogram. which occurred coincident with blood formate accumulation. Alterations in the electroretinogram occurred at formate concentrations lower than those associated with other visual changes and provide functional evidence of direct retinal toxicity in methanol poisoning.
Comparison of the ability of adult and pediatric trauma scores to predict pediatric outcome following major trauma, The Pediatric Trauma Score (PTS) has been identified as the only accurate and adequate means of predicting outcome in pediatric trauma. In answer to the increasing number of trauma patients arriving at local hospitals. the ability of the adult Trauma Score (TS) to predict pediatric trauma outcome was tested. Of the total 2.604 pediatric trauma cases in the North Carolina State Trauma Registry. 441 had both a PTS and TS available for analysis. The primary measures of outcome were emergency department and hospital dispositions. Logistic regression demonstrated that TS (R2 = 0.50) was a stronger predictor of pediatric outcome and PTS (R2 = 0.35) for emergency department disposition and TS (R2 = 0.63) with PTS (R2 = 0.51) for hospital disposition. The correlation between TS and PTS was high (R = 0.8). Stepwise discriminant analysis demonstrated that TS was the stronger predictor of outcome and the PTS added only 9% (partial R2 = 0.09) more accuracy to TS for emergency department disposition and only 6% (partial R2 = 0.06) for hospital disposition. The results of this research demonstrate that TS is a useful method of predicting outcome in pediatric trauma. The use of both scores for each patient does not increase the predictive value of the scores.
Limitations of the TRISS method for interhospital comparisons: a multihospital study, The value of the TRISS method for interhospital comparisons of trauma care was studied using data for 5.616 consecutive patients from three trauma centers and five community hospitals. Z-scores were used to compare mortality rates. Three limitations of the method were documented: 1) the lack of homogeneity within the patient subcategory of penetrating injuries. specifically between patients with gunshot versus stab wounds; 2) the inability of the TRISS method to predict the survival rate of patients suffering low falls; and 3) the inability of the TRISS method to account for multiple severe injuries to a single body part. Remedies to the first two of these limitations can be addressed within the present TRISS method. A remedy for the third requires a new method.
Helicopter transport of trauma victims: does a physician make a difference, We studied the impact of physician presence on helicopter transportation of trauma victims during two periods; when physicians were part of the flight team and when they were not. Our data failed to demonstrate that physician participation in flights had an impact on patient outcome. The groups were comparable in average distance traveled. initial Trauma Scores. number of organ systems injured. and the final Injury Severity Scores. Each group showed an improved survival over that predicted by comparison with the Multiple Trauma Outcome Study cohort. No difference was found in the number of procedures performed at the scene. en route. or on arrival at the hospital. Untreated injuries were slightly higher in the physician-present group. It appears that experienced nurses and paramedics. operating with well-established protocols. can provide aggressive care that yields equal outcome results compared with those of a flight team that includes a physician.
The role of microvascular free flaps in salvaging below-knee amputation stumps: a review of 22 cases, Twenty-two cases of traumatic below-knee amputation stumps with inadequate soft-tissue coverage salvaged with microvascular free flaps were reviewed retrospectively. All patients would have required an above-knee amputation for prosthesis fitting had microvascular free flaps not bee utilized. A total of 24 flaps were used in 22 patients; parascapular 11 (46%). foot filet six (25%). latissimus dorsi four (17%). lateral thigh. tensor fascia lata. and groin one (4%). Free flaps were performed immediately after injury in five (21%) cases. within the first week in two (8%). between 1 and 3 months in 12 (50%). and after 3 months in five (21%). Fifty per cent of the patients had significant other injuries. The patients had a total of 107 operations (mean. 4.9) related to their injury: 33 (mean. 1.5) of those operations were after the free flap. 27 (25%) of which were either performed because of a complication of the free flap or for revision of the free flap. Complications included partial necrosis in five (21%). neuroma in three (13%). hematoma in two (8%). donor site complication in two (8%). thrombosis requiring reoperation in one (4%). and flap failure in one (4%). Patient followup ranged from 12 to 116 months. All patients maintained a functional below-knee prosthetic level. The mean time to ambulation was 5.75 months. and was not significantly affected by flap complications. Most patients employed before their injury were employed after their injury. Despite a protracted course in these severe injured trauma patients. a functional below-knee amputation level was preserved in all cases utilizing microvascular free flaps.
The reliability of physical examination in the evaluation of penetrating extremity trauma for vascular injury: results at one year, All cases of penetrating extremity trauma (PET) seen at an urban trauma center were prospectively studied to determine the accuracy and safety of physical examination as the sole mode of evaluation for vascular injury. All patients with PET producing obvious or "hard" signs of vascular injury underwent immediate surgery. All asymptomatic proximity wounds were observed in hospital for 24 hours before discharge to outpatient followup. Patients with non-proximity wounds were discharged immediately. Patients with shotgun wounds and thoracic outlet injuries also underwent arteriography. Of 2.674 trauma patients evaluated during the 1-year study period. 310 (11.6%) had 366 penetrating extremity wounds. most (71%) occurring in the lower extremities. Gunshots caused most (82%) of the wounds. followed by stabs or lacerations (14.5%). and shotguns (3%). Clinically occult wounds in proximity to major limb vessels were the most common (78%) category of clinical presentation. followed by asymptomatic non-proximity wounds (16%). and wounds producing hard signs (6%). There were two missed vascular injuries. both in the asymptomatic proximity group (0.7% false negatives). Every patient taken immediately to surgery for hard signs had major arterial injury requiring repair. for a 100% positive predictive value for physical examination. No mortality or morbidity were related to protocol management. These results to date support prior reports of a negligible incidence of significant vascular injury following clinically occult proximity PET. and further suggest that the overall predictive value of physical examination of PET for vascular injury approaches 100%.
Vascular proximity: is it a valid indication for arteriography in asymptomatic patients, The role of arteriography in asymptomatic patients with penetrating extremity wounds in proximity to major vessels is controversial. This prospective study was designed to evaluate a precise definition of proximity. determine the incidence of positive arteriograms. and correlate angiographic interpretation with operative findings. Proximity was defined as any wound located within 1 cm of a major vessel. Excluded were patients with a pulse deficit. bruit. thrill. history of arterial hemorrhage. expanding hematoma. nerve deficit. fracture. or significant soft-tissue injury. One hundred sixty arteriograms were performed in 146 patients. One hundred forty-three (89.4%) were true-negatives. Seventeen (10.6%) were suggestive of injury. These included seven (4.4%) true-positive arteriograms. six (3.8%) false-positive studies. and four (2.5%) positive arteriograms in patients who were not operated upon. The angiographic report correlated with operative findings in five (38.5%) of 13 patients. These data confirm the low incidence (4.4%) of vascular injury in asymptomatic patients. The use of extremity angiography when proximity is the sole indication in an asymptomatic patient with a normal vascular examination must be questioned.
Non-invasive vascular tests reliably exclude occult arterial trauma in injured extremities, We evaluated the ability of noninvasive vascular tests to exclude clinically significant occult arterial damage in injured extremities. In a preliminary study. a Doppler arterial pressure index (API) (the systolic AP in the injured extremity divided by the AP in an uninvolved arm) of less than 0.90 was found to have sensitivity and specificity of 95% and 97%. respectively. for major arterial injury. The negative predictive value for an API greater than 0.90 was 99%. Because these values suggested that noninvasive vascular tests might effectively be substituted for "exclusion" arteriography in patients at risk for silent extremity arterial injuries. we then conducted a trail in which arteriography was performed in extremity trauma victims only when the API was less than 0.90. Among 100 traumatized limbs (84 penetrating. 16 blunt) in 96 consecutive patients. 16 of 17 limbs (94%) with an API less than 0.90 had positive arteriographic findings. and seven underwent arterial reconstruction. Among 83 limbs with an API greater than 0.90. followup (including duplex scanning in 64 limbs) revealed five minor arterial lesions (four pseudoaneurysms. one arteriovenous fistula) but no major injuries. Arteriograms for extremity trauma fell from 14% to 5.2% of all angiographic studies performed (p less than 0.001. Chi-square). These studies suggest that noninvasive vascular tests can reliably exclude major occult arterial damage in injured extremities. Screening for such injuries with Doppler arterial pressure measurements. reserving arteriography for limbs in which the API is less than 0.90. is safe. accurate. and cost effective.
Interaction of sodium and volume in fluid resuscitation after hemorrhage, Some measures of the efficacy of fluid resuscitation after hemorrhage are blood volume restitution (BVR) and attenuation of the neuroendocrine response. We compared the effectiveness of resuscitation with 0.9% NaCl and 3.0% NaCl in chronically prepared awake dogs after 30% hemorrhage. Each dog was bled on four occasions and resuscitated by four protocols: 1) full resuscitation (infusion to return and maintain mean arterial pressure (MAP) at control +/- 10 mm Hg) with 3.0% NaCl (HS); 2) full resuscitation with 0.9% NaCl (NS); 3) under-resuscitation with a volume of 0.9% NaCl equal to the subject's previous 3.0% NaCl requirement (SV); and 4) no fluid therapy (NR). Approximately three times more volume was needed to restore MAP with NS vs. HS. and thus the amount of Na administered was not different in these groups. Net volume balance was positive in the NS and SV groups but negative in the HS group due to marked saline diuresis. Net Na balance was positive in all three fluid-treated groups. but significantly higher in the HS group (p less than 0.01). MAP remained below baseline in the SV and NR groups (p less than 0.05). BVR exceeded 100% in NS and HS early in resuscitation. but BVR was not sustained in the HS group. Total plasma protein increased in all three fluid treated groups. Responses of all hormones were completely attenuated in the NS group. ACTH. cortisol. and AVP responses were promptly attenuated in the HS group. but remained greater than control. In the SV group. all hormone levels except renin returned to control values. but more slowly than the other groups. ACTH and cortisol correlated best with BVR; AVP. PRA. and aldosterone correlated with MAP restoration. In summary. resuscitation with either HS or NS can achieve similar MAP restoration. Hypertonic saline produces a more rapid increase in BVR and MAP. but the BVR improvement is transient. Resuscitation with HS incurs an intracellular water debt which is aggravated by a saline diuresis. Hormonal attenuation is linked either to BVR (ACTH. cortisol) or to MAP restoration (renin. AVP). Thus the optimal resuscitation regimen may consist of initial infusion of hypertonic saline followed by sufficient hypotonic solution to restore interstitial fluid volume and normal cellular hydration.
The role of angiography in penetrating neck trauma, Seventy-two consecutive patients who underwent neck arteriography were reviewed to assess recent suggestions that angiography is not indicated in asymptomatic patients with penetrating neck trauma. Proximity to major neck vessels without signs or symptoms of vascular trauma was the reason for angiography in ten of 26 patients with proven arterial injuries. Physical examination had a specificity of 80% and a sensitivity of 61% in this series. There was no correlation between mechanism or location of penetration and the likelihood of clinically significant injury. We conclude that recent recommendations suggesting that arteriography is unnecessary in asymptomatic patients with penetrating neck trauma are premature. Further investigations of larger patient samples are necessary to determine if "proximity" should be abandoned as an indication for arteriography. We advocate that. until additional data are accumulated. urgent arteriography and esophagography or operative exploration are indicated in stable asymptomatic patients with neck wounds which violate the platysma.
A novel approach to military combat trauma education, A heterogeneous group of 77 physicians on compulsory or reserve military service were exposed to a 5-day course in trauma management. specifically designed for military medical personnel. Cognitive knowledge of trauma care delivery of the medical officers was assessed by means of multiple-choice written tests. which were held before and upon completion of the course. The significantly improved (p less than 0.0001) scores of the post-course test demonstrate the value of a condensed trauma educational program. Analysis of the background variants (i.e.. medical education. military. and residency training. and time since graduation) revealed that the relatively short but intensive course sufficed to surmount the difficulties inherent in instructing a student body composed of individuals with dissimilar professional experience. We advocate the institution of a compact course in trauma treatment. with the specific aim of enhancing the medical officer's knowledge in this critical field of medical care.
Three cases of femoral head fracture in a single car accident, Three cases of femoral head fractures in a single car accident are described. The outcome of these relatively uncommon fractures after 14 months of followup is fair for the Pipkin Type I and II lesions and good for the Pipkin Type IV one. A review of consulted literature has been added.
Trigger finger: report of an unusual case, Locking of a finger is a common condition usually caused by tightness of the fibrous sheaths around the flexor tendons. A case of a locking finger with an unusual traumatic cause and perioperative findings is presented. Different causes of trigger fingers. especially traumatic. reported in the literature are briefly discussed. and the importance of differing between traumatic and nontraumatic causes for locking phenomena is emphasized.
Evaluation of the patient presenting with headache, In order to treat the patient presenting with headache successfully. one must carefully question. examine. and study the complete patient as well as his or her complaint of headache. Through direct and indirect questioning. a complete history may be obtained by exploring present illness. past medical history. family history. personal and social history. and systems review. A detailed medical and neurologic examination is also necessary to evaluate the complaint of headache. A comprehensive screening laboratory profile should be employed. but neurodiagnostic studies should only be used judiciously. A combined medical and neurologic approach will permit appropriate identification and effective treatment of the specific headache disorder rather than the isolated complaint of headache.
Migraine headaches, Once the definitive diagnosis of migraine has been formulated. the physician has many options available for abortive and prophylactic therapy. Nonpharmacologic modalities. including behavioral modification methods such as biofeedback training. may also be considered. Migraine does not necessarily have to disrupt the lives of those afflicted. The patient with mixed headache presents a more difficult diagnostic and therapeutic problem. These patients can also be helped when the disorder is identified. and inpatient therapy for these patients may be required.
Migraine equivalents and complicated migraine, Migraine equivalents and complicated migraine are entities in which definition is difficult. presentations are pleomorphic. diagnosis is treacherous. pathophysiology is obscure. and treatment is uncertain. A useful principle is to regard them as diagnoses of exclusion that require aggressive and comprehensive investigation. Rational treatment consists of migraine prophylaxis using agents with minimal vasospastic potential and. in some cases. acetylsalicylic acid for platelet disaggregation. The prognosis for both complicated migraine and migraine equivalents is good; when patients with these diagnoses come to harm. it is often because the diagnosis is incorrect.
Diagnosis and treatment of cluster headache, This article classifies cluster headaches as distinct from other types of headaches and gives guidelines for diagnosis and treatment. Explanations of the pathophysiology and pathogenesis of cluster headaches are included also.
Diagnosis and treatment of muscle contraction (tension-type) headaches, Acute tension-type headache is a very common condition that rarely is a problem in treatment. Chronic tension-type headache. however. is often a difficult therapeutic problem. The pathogenesis is not well understood. but both peripheral muscle contraction and central pain-modulating systems are probably involved. Therapy usually works best when multiple techniques are used. including pharmacologic. psychological. and physiologic modalities.
Posttraumatic headache and the postconcussion syndrome, Although headache is the most common sequelae of head injury. the posttraumatic headache is associated frequently with dizziness. irritability. lack of concentration. and intolerance to alcohol ingestion as a part of a symptom complex known as the postconcussion syndrome. This article clarifies the definitions of acute traumatic headache. posttraumatic headache. and the postconcussion syndrome and improves diagnostic ability. making the assessment and treatment of patients with these three conditions more accurate and effective.
Drug abuse and headache, Substance abuse has been reported frequently in chronic headache patients. The problem exists in most Western countries. Abuse of various compounds frequently leads to a state of dependency. Prescription as well as over-the-counter agents are often abused. Aspirin. acetaminophen. and caffeine are the most frequently abused compounds. Butalbital. ergot alkaloids. NSAIDS. and narcotic and oral or intranasal sympathomimetics are often abused. Patients with chronic daily headache complain of symptoms that may suggest a mixed-type headache. Features of migraine and muscle contraction headache often coexist in these individuals. It has been suggested that the most frequent cause for the transformation of a periodic headache into a daily headache is substance abuse. Substance abuse and drug dependency have multiple causes. and the etiology will reside with the compounds that are used to excess. The problem may arise as a result of poor instructions from the physician. improper diagnosis with gradual escalation in amounts of drug consumed. or a reinforcement mechanism and a brain stimulation-reward effect. The brain reward system has been studied with narcotics and psychomotor stimulants. It may be activated to a lesser degree with ergotamine. barbiturates. and other abused substances. The long-term effects of substance abuse are contingent on the compounds that are used. They may result in organ damage. medical complications. vascular injury. and a refractory state with chronic headache that eludes successful management of the headache disorder. Patients exhibit a less-than-satisfactory quality of life and are often depressed. Treatment includes outpatient care in cooperative. less dependent patients. Often patients will require inpatient management in order to discontinue use of the abused agents. Pharmacologic agents. behavior modification. psychotherapy. dietary intervention. and acupuncture may be necessary to treat the patient. Each patient must be treated by an interested physician. and the patient will require one or more of the preceding measures for a successful outcome. Often abused compounds must be discontinued in order to obtain a satisfactory response in an individual with chronic headache.
Pathogenesis of migraine, Endothelial cells are not just a semipermeable membrane that forms a barrier between the blood and the vascular smooth muscles. This cell system is a highly active metabolic endocrine organ. It not only produces a number of important substances in vascular and neural homeostasis but also inactivates vasoactive substances such as serotonin and bradykinin. In addition. it produces endothelin-1 and angiotensin II; more importantly in the context of migraine. endothelial cells produce the vasodilators prostacyclin and EDRF-NO. both of which are local (paracrine) hormones. The physiologic function of endothelial cells is affected by aspirin. which prevents prostacyclin formation but has little effect on normal blood pressure. From this information. one can infer that endothelial cell production of prostacyclin does not play an important part in normal cardiovascular control. On the other hand. the administration of Ng-monomethyl-L-arginine causes immediate increases in blood pressure. Because the administration of this substance inhibits the release of EDRF-NO. it appears that this paracrine endothelial hormone actively dilates the normal circulation. It is of cardinal importance that damage or flow perturbations of cell membranes of the endothelial lining of blood vessels cause an increased production of prostaglandins. However. smooth muscle cells underlying the endothelial lining also synthesize prostacyclin. This mechanism is thought to be held in reserve to reinforce local production of prostacyclin and vasodilatation when cell damage to the endothelial lining occurs and EDRF-No is not produced. Many theories for the causation of migraine have been proposed. and some have been reviewed. Those holding sway tend to ignore inconsistencies and cite supporting evidence in favor of their pet explanation only. I therefore have no hesitation to show that the best explanation at present. based on the most recent cellular evidence. explains all features of migraine and the response of migraineurs to therapy. The endothelial cell is the most likely site of the primary abnormality (Fig. 1). Although under physiologic circumstances perivascular innervation and endothelial systems closely interact in the control of vascular tone during pathologic conditions such as ischemia. the dominant role in protecting the circulation is endothelium-mediated. The biology of headache is so diverse and our ignorance sufficiently pervasive that the investigation of endothelial cell function may solve the mystery of migraine. To match the postulated crucial role of the endothelial cell in the pathogenesis of migraine. another cell would have to be ubiquitously present throughout the vasculature and not just confined to the central nervous system.(ABSTRACT TRUNCATED AT 400 WORDS).
Detection of chimeric BCR-ABL genes in acute lymphoblastic leukaemia by the polymerase chain reaction, Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL) is most common in adults and is associated with poor prognosis. Since karyotypic identification of the Philadelphia translocation has been hampered by technical difficulties. we used the polymerase chain reaction (PCR) to look for the BCR-ABL rearrangement in stored samples from a selected group of 314 German ALL patients. BCR-ABL transcripts were found in 77 of 179 adults and were restricted to those with B-precursor leukaemias. 55% of adult common ALL patients had BCR-ABL and its presence correlated with poor overall survival and remission duration. Of 135 children with common ALL. 5 (6%) primary cases and 8 (17%) with recurrent neoplasias were PCR-positive. We recommend prospective evaluation of BCR-ABL analysis with PCR in patients with a B-precursor leukaemia.
Liposomal amphotericin B in drug-resistant visceral leishmaniasis, The treatment of visceral leishmaniasis (VL) may be complicated by drug toxicity or intolerance. and by drug resistance. Amphotericin B (AmB) is effective. but its use is limited by toxicity: renal impairment. anaemia. fever. malaise. and hypokalaemia are common. Liposomes have been proposed as an effective way to target drugs at macrophages. which are the cells infected in visceral leishmaniasis. In animals AmB incorporated into liposomes is highly effective against experimental leishmaniasis. with low toxicity. This report is of the successful treatment of a patient with multiply drug-resistant visceral leishmaniasis with a commercially prepared formulation of liposomal amphotericin B (L-AmB) ('AmBisome'. Vestar. San Dimas. California. USA). We also report. for comparison. a patient treated with conventional AmB. and preliminary studies in mice comparing the two agents.
Lung function improvement in asthma with a cysteinyl-leukotriene receptor antagonist, In a double-blind study ten asthmatic patients with impaired lung function received the cysteinyl-leukotriene receptor antagonist ICI 204.219 (40 mg by mouth) and placebo in random order on 2 days at least 1 week apart. The increase in forced expiratory volume in 1 s (FEV1) above baseline was significantly greater after ICI 204.219 than after placebo. This effect persisted after nebulised salbutamol. These findings suggest that cysteinyl-leukotrienes are one of the causes of persistent bronchoconstriction in chronic asthma.
Introduction: obesity: diet composition, energy expenditure, and treatment of the obese patient, The association of obesity with increased risks for developing hypertension. diabetes. cardiovascular disease. and cancer has made it a complex health problem. Exacerbating the problem is the realization that there are multiple factors. both physiological and psychological. that interact to induce obesity. as well as a myriad of components that may be useful in the curtailment of obesity. The aim of this symposium is to provide a wider understanding of the elements behind the development and reduction of obesity.
Diet composition, energy intake, and nutritional status in relation to obesity in men and women, There are dietary factors besides the total energy value of food that can affect adiposity by disrupting the balance between energy intake and expenditure. The purpose of this paper was to examine how perturbation of these dietary factors that control energy balance affects adiposity. There is a substantial amount of evidence suggesting that obesity is not associated with overeating. but with a high dietary fat-to-carbohydrate intake ratio. Physiological adaptations to energy-reduced dieting facilitate both weight regain and make it more difficult to lose weight during subsequent dieting attempts. Since obesity may be better characterized by diet composition than by energy intake. successful weight-loss programs should include diet compositional changes in their regimes.
Heredity and the path to overweight and obesity, Overweight and obesity are not homogeneous phenotypes as individuals differ in terms of the regional distribution of the excess weight or fat. Overweight and obesity are also complex multifactorial phenotypes influenced by both genetic and nongenetic determinants. Heritability of fat mass or percent body fat derived from underwater weighing measurement reaches about 25% of the age and gender adjusted phenotypic variance. Based on twin and parent-child data. it has been reported that the heritability of resting metabolic rate. thermic response to food. and energy cost of submaximal exercise. adjusted for the proper concomitants. is as high as 40%. The level of habitual physical activity also exhibits a significant heritability level on the order of about 25%. Experimental overfeeding with identical twins demonstrates that there are inherited differences in body weight and body composition response. The most important factor identified thus far to account for the individual differences in response to long-term overfeeding is a nutrient partitioning characteristic. namely the proportion of fat vs lean tissue gained. The high gainers are those storing energy primarily in the form of fat. while the low gainers are storing relatively more in the form of lean tissue.
An unusual stress fracture in a multiple sport athlete, Most overuse injuries are a direct result of repetitive stresses which may create a condition of maltraining. Young athletes are no exception to this rule. Swimming and baseball both create stresses to the humerus which may result in injuries to the shoulder and upper extremity. Stress fractures (fatigue fractures) are usually limited to the lower extremity (i.e.. tibia or metatarsal). Upper extremity stress fractures. especially of the humerus. are very uncommon. Precipitating factors include repetitive stresses. low grade external forces. rapid application of muscular force to the bone. or an underlying disease or pathologic weakness of the bone. The majority of these fractures are primarily due to abnormal and repetitive stresses to bones. This case study examines the mechanism of injury. clinical presentation. and treatment of a clinically apparent stress fracture which ultimately converted to an overt humerus fracture in a 14-yr-old cross-trained athlete.
Chronic compartment syndrome caused by aberrant fascia in an aerobic walker, The following is a case presentation of a 36-yr-old female athlete who presented with the symptoms and signs of chronic anterior compartment syndrome. Pre-exercise and post-exercise tissue pressure measurements revealed increased compartment pressures in both of her anterior leg compartments. Aberrant fascial bands overlying and compressing the anterior compartments were discovered at the time of surgery. Fasciotomies led to complete recovery and return to previous levels of athletic activity. This is the first report of aberrant fascia as a cause of chronic anterior compartment syndrome.
Experimental pain thresholds and plasma beta-endorphin levels during exercise, Experimental pain thresholds (electrical intracutaneous finger and dental pulp stimulation) and plasma hormone levels (beta-endorphin. cortisol. and catecholamines) were measured in ten healthy sportive men before. during. and after progressively more strenuous physical exercise. In a double-blind study conducted on two different days. 20 mg of the opioid-antagonist naloxone or placebo was administered prior to exercise. A significant pain threshold elevation was found during exercise for finger (ANOVA. P less than 0.004) and dental pulp stimulation (P less than 0.01). Pain threshold elevation was most pronounced during maximal exertion. at which time the subjects reported the greatest subjective fatigue. Thresholds remained elevated 10-15 min after the end of exercise. and. 60 min after exercise. thresholds returned to baseline values. The subjective magnitude estimation of suprathreshold stimuli was significantly reduced (P less than 0.0001) 5-10 min after exercise. Plasma beta-endorphin. cortisol. and catecholamines increased significantly (P less than 0.0005. all values) during exercise. Plasma beta-endorphin levels did not correlate significantly with pain thresholds (r = -0.37. NS). Naloxone failed to affect pain thresholds. although beta-endorphin and cortisol increased significantly more (P less than 0.02) during exercise after naloxone. It is concluded that short-term. exhaustive physical exercise can evoke a transient elevation in pain thresholds. This exercise-induced elevation in pain threshold does not. however. appear to be directly related to plasma endorphin levels.
Prevalence of the sickle cell trait in an athletic West African population, The prevalence of the sickle cell trait in a school for elite young athletes in Cameroon. West Africa. was examined in order to evaluate whether the choice of an athletic career was influenced by its presence. The presence of hemoglobin AS was found in 27 of the 145 students attending the school (18.6%). Since the frequency of the sickle cell trait in the general Cameroonian population is 17.3%. we conclude that its presence is not a determinant factor involved in the choice of a professional sportive activity.
Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity [published errata appear in N Engl J Med 1991 Jul 4;325(1):71 and 1991 Aug 15;325(7):524], BACKGROUND. Amyotrophic lateral sclerosis is a progressive neurologic disorder that commonly results in paralysis and death. Despite more than a century of research. no cause of. cure for. or means of preventing this disorder has been found. In a minority of cases. it is familial and inherited as an autosomal dominant trait with age-dependent penetrance. In contrast to the sporadic form of amyotrophic lateral sclerosis. the familial form provides the opportunity to use molecular genetic techniques to localize an inherited defect. Furthermore. such studies have the potential to discover the basic molecular defect causing motor-neuron degeneration. METHODS AND RESULTS. We evaluated 23 families with familial amyotrophic lateral sclerosis for linkage of the gene causing this disease to four DNA markers on the long arm of chromosome 21. Multipoint linkage analyses demonstrated linkage between the gene and these markers. The maximum lod score--5.03--was obtained 10 centimorgans distal (telomeric) to the DNA marker D21S58. There was a significant probability (P less than 0.0001) of genetic-locus heterogeneity in the families. CONCLUSIONS. The localization of a gene causing familial amyotrophic lateral sclerosis provides a means of isolating this gene and studying its function. Insight gained from understanding the function of this gene may be applicable to the design of rational therapy for both the familial and sporadic forms of the disease.
Bile porphyrin analysis in the evaluation of variegate porphyria, BACKGROUND: Variegate porphyria is a genetic disorder of porphyrin metabolism in which patients may have both neurologic dysfunction and photocutaneous lesions. Biochemical confirmation of the diagnosis can be difficult. particularly in patients without neurologic dysfunction at the time of testing. The demonstration of increased fecal excretion of porphyrin is frequently used for this purpose. but levels may be normal. Since elevated fecal porphyrin levels in variegate porphyria are presumably a consequence of increased biliary excretion. we evaluated whether analysis of porphyrins in bile distinguishes better between patients with variegate porphyria and controls. METHODS: Bile samples were collected by duodenal aspiration from 10 patients with proved variegate porphyria who had no neurologic symptoms when they were studied and 17 control subjects. Bile and fecal porphyrin levels were measured fluorometrically. RESULTS: The mean total porphyrin concentration in bile in the patients with variegate porphyria was significantly higher than that in the controls (67.8 vs. 0.71 mumol per liter; P less than 0.00002). There was more than a ninefold difference between the highest level in any control subject and the lowest level in any patient with variegate porphyria. The mean fecal porphyrin level in the patients with variegate porphyria also differed significantly from that in the controls (0.79 vs. 0.14 mumol per gram of dry weight; P less than 0.007). but four patients had levels within the control range. CONCLUSIONS: The concentration of porphyrin in bile is higher in patients with variegate porphyria than in controls. and the difference is greater than that for fecal porphyrin. Bile porphyrin measurements may be helpful in the evaluation of asymptomatic patients suspected of having variegate porphyria.
Zidovudine and the natural history of the acquired immunodeficiency syndrome, BACKGROUND AND METHODS: We sought to describe the trends in survival from 1983 to 1989 among persons with the acquired immunodeficiency syndrome (AIDS) and to examine the relative effects on the natural history of AIDS of zidovudine use and demographic and clinical characteristics. This longitudinal. observational. population-based study used data from the Maryland Human Immunodeficiency Virus Information System. a data base that links information from the Maryland AIDS Registry with data on public and private health care claims. vital statistics. and hospital. long-term care. and ambulatory care records. RESULTS: The median survival after diagnosis among persons with AIDS (n = 1028) was 140 days longer for those given their diagnoses between 1987 and 1989 than for those given their diagnoses between 1983 and 1985 (450 vs 310 days). Among the 714 persons in whom AIDS was diagnosed after April 1987 (when zidovudine became available). two-year survival was greater among men than women (P less than 0.03). among persons less than 45 years old than among older persons (P less than 0.001). among non-Hispanic whites than among minorities (P less than 0.001). and among persons whose category of human immunodeficiency virus transmission was homosexual contact than among those with heterosexual. transfusion-related. or less common modes of transmission (P less than 0.02). In all the analyses the groups with the longer survival were more likely to have received zidovudine. The median survival among those who received zidovudine was 770 days. as compared with 190 days among those who never received the drug (P less than 0.001). By proportional-hazards analysis. zidovudine therapy was the factor most strongly associated with improved survival. CONCLUSIONS: For Maryland residents with AIDS there has been an improvement in survival since 1987. Zidovudine therapy and perhaps other aspects of care associated with it have contributed substantially to the improved survival.
Intra-ocular pressure variations during extracorporeal circulation and some influencing factors, Intra-ocular pressure (IOP) variations during extracorporeal circulation (ECC) and some influencing factors were studied prospectively in 38 patients undergoing cardiovascular surgery. IOPs were measured pre-operatively. during ECC (after 5 min. 10 min. 25 min and every 15 min thereafter). and on the 1st. 2nd and 3rd postoperative days. IOP. haematocrit. arterial perfusion pressure. partial O2 pressure. partial CO2 pressure. pH and blood bicarbonate levels were measured simultaneously. After the beginning of ECC. arterial perfusion pressure and haematocrit values decreased suddenly. while IOP raised immediately. Sudden increase of blood volume in the beginning of ECC can be the probable cause of IOP elevation. Afterwards. IOP levels decreased to pre-ECC levels. We think that the drop is due to the effect of mannitol in the priming solution and hyposecretion of aqueous humour due to insufficient nutrition-oxygenation of corpus ciliaris after haemodynamic stabilization.
Double-blind study in the treatment of normal tension glaucoma with naftidrofuryl, Naftidrofuryl is an antiserotonin S2-specific agent. with the three following effects: (1) peripheral vasodilatation. (2) antiaggregation and (3) increase in cellular metabolic. These effects could be interesting in the management of the optic nerve ischemia of glaucomatous patients and especially of those with normal tension glaucoma. The administration of 2 x 200 mg/day of naftidrofuryl during 6 weeks to 12 patients with normal tension glaucoma has shown an improvement of the visual acuity and the visual field compared with a 6-week period of placebo administration. with a double-blind study method. It suggested that naftidrofuryl might be administered as a useful complement to conventional hypotensive therapy. since it acts positively on the glaucomatous optic nerve damage.
Very low birth weight outcomes of the National Institute of Child Health and Human Development Neonatal Network, This report describes the neonatal outcomes of 1765 very low birth weight (less than 1500 g) infants delivered from November 1987 through October 1988 at the seven participating centers of the National Institute of Child Health and Human Development Neonatal Intensive Care Network. Survival was 34% at less than 751 g birth weight (range between centers 20% to 55%). 66% at 751 through 1000 g (range 42% to 75%). 87% at 1001 through 1250 g (range 84% to 91%). and 93% at 1251 through 1500 g (range 89% to 98%). By obstetric measures of gestation. survival was 23% at 23 weeks (range 0% to 33%). 34% at 24 weeks (range 10% to 57%). and 54% at 25 weeks (range 30% to 72%). Neonatal morbidity included respiratory distress (67%). symptomatic patent ductus arteriosus (25%). necrotizing enterocolitis (6%). septicemia (17%). meningitis (2%). urinary tract infection (4%). and intraventricular hemorrhage (45%. 18% grade III and IV). Morbidity increased with decreasing birth weight. Oxygen was administered for greater than or equal to 28 days to 79% of less than 751-g birth weight infants (range between centers 67% to 100%). 45% of 751- through 1000-g infants (range 20% to 68%). and 13% of 1001- through 1500-g infants (range 5% to 23%). Ventilator support for greater than or equal to 28 days was given to 68% of infants at less than 751 g. 29% at 751 through 1000 g. and 4% at greater than 1000 g. Hospital stay was 59 days for survivors vs 15 days for infants who died. Sixty-nine percent of survivors had subnormal (less than 10th percentile) weight at discharge. The data demonstrate important intercenter variation of current neonatal outcomes. as well as differences in philosophy of care and definition and prevalence of morbidity.
Varicella vaccine (VARIVAX) in healthy children and adolescents: results from clinical trials, 1987 to 1989, A total of 3303 healthy children and adolescents. aged 12 months to 17 years. were vaccinated with one of five production lots of a live attenuated varicella vaccine (VARIVAX) containing 1000 to 1625 plaque-forming units per dose. The vaccine was generally well tolerated. Ninety-six percent (2381/2475) of vaccinees responded to vaccination by producing antibody as measured by a glycoprotein-based enzyme-linked immunosorbent assay; 99% (569/576) of those tested maintained antibody at 1 year following vaccination. The incidence of varicella following household exposure in vaccinees was approximately 12%; household contact historically results in 87% infection. Nearly all of the vaccinees who had varicella after vaccination had a clinically modified disease.
Role of a soy-based lactose-free formula in the outpatient management of diarrhea, The introduction of a soy-based. lactose-free formula during the acute phase of diarrheal illness in infants has been shown to reduce stool output and duration of diarrhea in hospitalized patients. In the United States. most infants with acute diarrhea are treated as outpatients. In the present study. infants with diarrhea who were treated as outpatients were randomly assigned to receive either a soy-based. lactose-free formula alternating with oral rehydration solution from the beginning of therapy ("early feeding") or oral rehydration solution alone for the first 24 hours of therapy. followed by a soy-based. lactose-free formula alternating with oral rehydration solution (control group). Twenty-nine infants were randomly assigned to the early-feeding group and 27 to the control group. Twenty-one (72%) of 29 in the early-feeding group resolved their diarrhea at the end of 48 hours of therapy compared with 12 (44%) of 27 in the group fed oral rehydration solution only (P = .02). It is concluded that the introduction of a soy-based. lactose-free formula from the beginning of therapy for acute diarrhea in children treated as outpatients is safe and may shorten duration of diarrhea while maintaining adequate caloric intake.
Carrying as colic "therapy": a randomized controlled trial, In healthy infants. crying behavior is reduced significantly by "supplemental" carrying; that is. increased carrying throughout the day in addition to that which occurs during feeding and in response to crying. To determine whether the recommendation to increase carrying would be effective as a therapy for colic. 66 mothers of infants 4 weeks of age or less who came to their pediatricians with complaints of crying problems ("colic") were randomized to receive standard pediatric advice (standard group) or standard advice plus the recommendation to increase supplemental carrying by 50% (supplemental group). Overall. the supplemental group carried their infants 6.1 hours/d throughout the intervention period. an increase of 2.2 hours/d (56%) more than that provided by the standard group. Despite this significant increase in carrying. there was no difference between groups in the duration or frequency of crying. fussing. or cry/fuss at any time throughout the intervention period. When the greatest treatment effect was expected at 6 weeks. the supplemental group infants cried only 3 minutes less per day (95% confidence interval: 37 minutes less to 32 minutes more per day). We conclude that. compared with standard pediatric advice to be "responsive." supplemental carrying does not reduce crying and fussing behavior further in infants who have colic. In marked contrast to healthy infants. this apparent resistance to increased carrying may indicate an important difference in state regulation and control in infants with colic.
Release of benzalkonium chloride from a heparin-bonded umbilical catheter with resultant factitious hypernatremia and hyperkalemia, Elevated serum sodium and potassium levels were recently observed when sampled through a heparin-bonded umbilical catheter and measured with certain ion-selective electrodes. The cationic surfactant. benzalkonium chloride (BZC). is known to falsely elevate those cations in serum. Inasmuch as most heparin-bonded umbilical catheters use BZC during the bonding process. an in vitro study was performed to estimate the quantity of BZC released and the duration of sodium and potassium elevations during pooled sera infusion. Three heparin-bonded umbilical catheters and 3 silastic umbilical catheters were first flushed with 0.3 mL of normal saline and then perfused with pooled sera (sodium. 142 mEq/L; potassium. 4.6 mEq/L) at 2.5 microL/h. Effluent samples were collected from 0 to 8 hours and analyzed by ion-selective electrodes. Elevated serum sodium concentrations from 160 to greater than or equal to 250 mEq/L and potassium concentrations from 6.0 to greater than or equal to 9.6 mEq/L were observed. The BZC concentration in the catheter effluent was measured by mass spectrometry. with peak values of 10 micrograms/mL detected by this method. When varying concentrations of BZC (1 to 100 micrograms/mL) were added directly to pooled serum. a dose-dependent increase in serum sodium was observed. These data demonstrate that BZC released from heparin-bonded umbilical catheters elevates serum electrolyte values measured with some ion-selective electrodes. The observed increase in sodium and potassium concentrations may lead to clinical errors in management. Benzalkonium chloride is associated with myriad of linical symptomatology. Whether this amount of BZC is toxic in the small premature neonate is presently unknown.
Pediatric acquired immunodeficiency syndrome hospitalizations in New Jersey, This study examines all acquired immunodeficiency syndrome (AIDS) hospitalizations during 1987 for children younger than 13 years of age in New Jersey. with the AIDS diagnosis confirmed through a match with the state AIDS Registry. Days of hospitalization and cost for 318 admissions and annual utilization measures for the 74 children in the sample were analyzed by sex. age. race/ethnicity. hospital. discharge status. payer. and a severity-of-illness proxy. These measures were also compared with those for 3152 admissions of 1623 New Jersey adolescents and adults with AIDS hospitalized during 1987. Children with AIDS averaged 14.09 days and $8636 per admission. 4.35 admissions per year. and 60.96 days of hospitalization per year at an average cost of $37.110. The severity-of-illness proxy was the best predictor of hospital utilization and mortality. Hospitals varied widely in their proportions of very short and very long stays that signal possibly inappropriate utilization. Medicaid patients had relatively high utilization measures. and Hispanic children. relatively low measures. Per-admission utilization of children was similar to that of adults. but annual hospital utilization was significantly higher for children. Reimbursable outpatient and home care services appear to reduce inappropriate utilization.
Outbreak of Kawasaki syndrome in Denver, Colorado: association with rug and carpet cleaning, Between October 1984 and January 1985. the largest outbreak of Kawasaki syndrome reported to date in the continental United States (62 cases) occurred in the Front Range of the Rocky Mountains. extending from Colorado Springs. Colorado. to Cheyenne. Wyoming. Fifty-two (84%) of these Kawasaki syndrome patients lived in the Denver metropolitan area. A case-control study revealed that 16 (62%) of 26 Kawasaki syndrome patients compared with 10 (20%) of 49 matched control subjects had a history of exposure to shampooed (19%) or spot-cleaned (81%) rugs or carpets within 30 days of the Kawasaki syndrome onset date (odds ratio = 5. P less than .01). The time of exposure to shampooed or spot-cleaned rugs or carpets for 9 of 10 Kawasaki syndrome patients who had a single exposure and for all 6 Kawasaki syndrome patients who had multiple exposures were clustered within an interval 13 to 30 days before the onset of illness. Although the reason for this unusually large outbreak remains obscure. it is the third in which a statistically significant association between Kawasaki syndrome and rug or carpet cleaning has been found.
Diphenoxylate-atropine (Lomotil) overdose in children: an update (report of eight cases and review of the literature), Eight pediatric accidental overdoses of diphenoxylate-atropine (Lomotil) are reported. and 28 literature cases are reviewed. This overdose is primarily an opioid intoxication. occasionally associated with atropine toxicity. Only 6 of 36 children showed signs of atropine overdose (central nervous system excitement. hypertension. fever. flushed dry skin). Contrary to popular belief. atropine effects occur before. during. or after opioid effects. Opioid overdose (central nervous system and respiratory depression with miosis) predominated or occurred without any signs of atropine toxicity in 33 cases (92%). Diphenoxylate-induced hypoxia was the major problem and was associated with slow or fast respirations. hypotonia or rigidity. cardiac arrest. and in 3 cases cerebral edema and death. Respiratory depression recurred 13 to 24 hours after the ingestion in 7 cases and was probably due to accumulation of difenoxine. an active metabolite of diphenoxylate. Recommended treatment is intravenous naloxone for depressed or inadequate respirations. followed by continuous intravenous naloxone infusion. prompt gastric lavage. repeated administration of activated charcoal. and close monitoring for 24 hours.
Cognitive development of children following early repair of transposition of the great arteries using deep hypothermic circulatory arrest, Twenty-eight children who underwent corrective cardiac surgery in early infancy had developmental evaluations to explore whether cardiopulmonary bypass perfusion variables are associated with later cognitive function. All had transposition of the great arteries repaired by the arterial switch operation using deep hypothermic circulatory arrest. The mean duration of deep hypothermic circulatory arrest was 64 +/- 10 minutes (mean +/- SD). Median age at repair was 4 days (range 1 to 125 days). Tests of development were administered at age 7 to 53 months: Bayley Scales for children younger than 30 months of age (n = 18) and McCarthy Scales for older children (n = 10). Overall cognitive development score was 101.2 +/- 11.1. Duration of deep hypothermic circulatory arrest was not associated with performance. However. for core cooling periods of less than 20 minutes' duration. shorter cooling periods were associated with lower scores (r = .85. n = 11. P less than .001). These data suggest that patients undergoing relatively long periods of deep hypothermic circulatory arrest may require some minimum time of cardiopulmonary bypass cooling to avoid central nervous system injury.
Valvular heart disease. A correctable cause of congestive heart failure, Surgical repair of mitral. aortic. and tricuspid valves and balloon valvuloplasty for mitral stenosis are being done more and more often. These complex procedures require accurate and high-quality imaging techniques to guide the physician in decision making before surgery and in assessment of success during surgery. Dr Currie describes the use of echocardiography in diagnosis and management of patients with various forms of valvular heart disease.
Motion sickness. Helping patients tolerate the ups and downs, The sensory conflict theory provides a useful framework for understanding motion sickness. Few modifications of this model have been proposed since its publication. The weak link in the study of motion sickness has been the failure to delineate the anatomic structures that correspond to the model's components. Effective pharmacotherapy is available for treatment of motion sickness. The choice should be based on the need to provide prophylaxis for or treatment of symptoms and on the side effect profile of the drug.
Determining the cause of anemia. General approach, with emphasis on microcytic hypochromic anemias, In the vast majority of cases. the cause of microcytic hypochromic anemia is clearly suggested by the patient history. physical examination results. red cell indexes. and peripheral blood smear. Thus. further diagnostic testing. if necessary. can be very selective. When the underlying cause of anemia is obscure. the serum ferritin concentration should be measured first. If it is normal or increased. serum iron and free erythrocyte protoporphyrin levels can be determined. The serum iron level is low in anemias caused by iron deficiency and chronic disease but normal or elevated in those resulting from the thalassemias. hemoglobin E disorders. and lead toxicity. The free erythrocyte protoporphyrin level is elevated with iron deficiency. the anemia of chronic disease. and lead toxicity but normal with thalassemias and hemoglobin E disorders. Results of these two test indicate which of the more specific tests is most likely to yield the correct diagnosis.
Nonprescription drugs and hypertension. Which ones affect blood pressure, Hypertensive patients should be aware of the possible effects of nonprescription medications on blood pressure control. For absolute safety. no adrenergic agents should be used. Nasal phenylephrine hydrochloride is probably the safest of these agents. and pseudoephedrine hydrochloride may also be safe. Phenylpropanolamine hydrochloride and ephedrine sulfate are probably best avoided. The effects of other adrenergic agents (eg. epinephrine) on blood pressure have not been clinically evaluated. Ibuprofen may elevate blood pressure if taken in maximum over-the-counter doses for more than a few days. The ethanol and sodium chloride content of nonprescription drugs taken in recommended doses does not appear to pose a great hazard.
Methodologic considerations in assessment of cognitive function in chronic fatigue syndrome, Rigorous and standardized assessment of cognitive function is an important component of any multidisciplinary study of chronic fatigue syndrome. The present paper describes some methodologic issues that need to be addressed to maximize the yield from any neuropsychiatric evaluation of the syndrome.
Assessment of depression in patients with chronic fatigue syndrome, Assessment of the relationship of depression to chronic fatigue syndrome (CFS) is a complicated but important topic. This relationship may range from the misdiagnostic (i.e.. depression misidentified as CFS) to the etiologic (i.e.. CFS causes an organic affective syndrome). Assessment should focus on the symptoms and syndromes of depressive disorder. utilization of a single rating scale to assess presumed depression is discouraged. and alternate approaches to classification that allow for symptomatic overlap of a major depressive disorder and CFS are suggested. Careful attention needs to be given to the use of external validating criteria in empiric studies. such as natural history. clinical course (including treatment response). and family history.
Serologic and virologic epidemiology of Epstein-Barr virus: relevance to chronic fatigue syndrome, Patients considered to have chronic fatigue syndrome (CFS) have been reported to exhibit an increased antibody response to Epstein-Barr virus (EBV) early antigen complex and capsid antigen. findings that suggest some relationship between EBV and CFS. However. the serologic findings have not been totally consistent among different study groups. and the antibody patterns in asymptomatic individuals may be similar. Moreover. patients with symptomatology indicative of CFS do not appear to have an abnormal burden of EBV in body fluids and manifest only a variable. mild degree of EBV-specific cell-mediated responses. The evidence is growing that the serologic findings of an enhanced EBV state in individuals with CFS-like manifestations. as well as the subsequent reports of increased antibody titers to other viruses. reflect a generalized underlying immunologic dysfunction in these patients. Future studies with criteria-defined CFS study groups in which determinations are made of antibody responses to newly identified EBV-associated nuclear antigen components and distinct EBV proteins in addition to specific virologic and immunologic analyses of EBV may be worthwhile as a means of clarifying the association between EBV and CFS.
History of chronic fatigue syndrome, Chronic fatigue syndrome is not a new medical condition. For centuries its confusing array of features has been attributed to numerous environmental. metabolic. infectious. immunologic. and psychiatric disturbances. This is a review and critique of many of these alternative diagnoses. sufficient to provide a historical background for current thinking about the disorder.
Serologic and immunologic responses in chronic fatigue syndrome with emphasis on the Epstein-Barr virus, Although patients with chronic fatigue syndrome (CFS) can be diagnosed by clinical criteria. the lack of specific laboratory criteria delays or prevents the diagnosis and contributes to the quasi-disease status of the syndrome. A resurgence of interest in the syndrome has followed reports suggesting that CFS may be associated with chronic active infection due to the Epstein-Barr virus. Analysis of reports to date shows that the mean titers of antibodies to viral capsid antigen and to early antigen are greater for patients with CFS than for healthy individuals; this is particularly evident in cases for which serial samples were tested. However. these differences do not prove the cause of CFS. Cell-mediated immune responses in patients with CFS vary from study to study. and the number and function of natural killer cells in those patients are the most variable factors. Rates of isolation of virus from saliva do not differ. but in one comparison study with a large number of subjects. more lymphocytes that contained virus were isolated from patients than from controls. Other viruses. such as the Coxsackie B virus. have been implicated as causes of CFS in studies from Great Britain. The use of a working definition of CFS and standardized tests to address abnormalities revealed by laboratory tests among homogeneous populations should allow determination of useful tests for the diagnosis of CFS and studies of its mechanisms.
Chronic fatigue syndrome in northern Nevada, The clinical and laboratory findings from studies of patients with chronic fatigue syndrome (CFS) from northern Nevada are summarized. Physicians caring for these patients have estimated that greater than 400 patients with CFS from northern Nevada and nearby communities in California were identified between 1984 and 1988. As a result of these studies. a cluster of clinical and laboratory features associated with the illness in moderately to severely affected patients has been identified: profound fatigue of prolonged duration; cervical lymphadenopathy; recurrent sore throat and/or symptoms of influenza; loss of cognitive function manifested by loss of memory and loss of ability to concentrate; myalgia; impairment of fine motor skills; abnormal findings on magnetic resonance imaging brain scan; depressed level of antibody to Epstein-Barr virus (EBV) nuclear antigen; elevated level of antibody to EBV early antigen restricted component; elevated ratio of CD4 helper to CD8 suppressor cells; and strong evidence of association of this syndrome with infection with human herpesvirus 6. More-serious and longer-lasting neurologic impairments. including seizures. psychosis. and dementia. have also been observed in some of these patients.
Defining the chronic fatigue syndrome, The recently published working definition of the chronic fatigue syndrome (CFS) is a necessary first step toward a consistent effort to research this controversial illness. Before this definition was developed. cases often were defined vaguely. according to the perceptions and biases of the individual researchers. so that the results of some studies were unclear. However. few specific diagnostic parameters for CFS exist. and the new definition may not delineate a single clinicopathologic entity. Future efforts at researching this illness should be aimed at identifying parameters that differentiate CFS from psychiatric conditions such as major depression and from other defined chronic diseases. Because CFS may be the result of multiple disease processes. the separate study of well-defined subgroups of patients with CFS is appropriate. Such subgroups of patients are probably more likely to have common pathogenetic features than are patients with CFS as a whole group.
Chronic fatigue syndrome: thoughts on pathogenesis, Studies have shown that a proportion of patients with severe chronic infection due to Epstein-Barr virus (EBV) lack antibody to a component of EBV nuclear antigen. However. it is not clear whether this circumstance is one of cause or effect in regard to the pathogenesis of chronic fatigue syndrome (CFS); it is clearly not pathognomonic since it also occurs in persons infected with the human immunodeficiency virus and--rarely--in those with other EBV-related conditions. Stress and depression may be other pathogenetic mechanisms that could reactivate EBV and lead to CFS; examples of this phenomenon are given. The syndrome might also follow certain other viral infections as part of a process that has been called postinfectious neurasthenia. Currently. the cause(s) and cure of CFS. a common and distressing syndrome. are enigmatic and require multidisciplinary study.
Issues and problems in the conduct of epidemiologic research on chronic fatigue syndrome, The epidemiologic research approach is perhaps most appropriate for initial studies of chronic fatigue syndrome since the syndrome is vaguely defined. scientific knowledge about it is limited. and an infectious etiology is suspected. Several priority needs appropriate for epidemiologic research are identified. including a refinement of diagnostic criteria; a greater understanding of the natural history of the syndrome; basic incidence. prevalence. and mortality statistics; information on whether asymptomatic cases exist; etiologic studies of possible heterogeneity of cases; investigations of clusters of cases; and determinations of whether patients with the syndrome have an increased risk of malignancy. Because of the lack of cogent etiologic hypotheses regarding the syndrome. case-control studies are identified as a high priority for research. The many difficulties encountered in conducting such research are discussed and approaches to dealing with these problems are suggested.
Chronic fatigue syndrome and depression: cause, effect, or covariate, Depressed mood and the psychiatric diagnosis of major depressive episode (MDE) are common findings in patients with chronic fatigue syndrome (CFS). The relationship between depression and CFS is unclear and may be explained by one of four models: (1) CFS is an atypical manifestation of MDE; (2) depression is the result of CFS as either an organic mood syndrome or an adjustment reaction; (3) CFS and MDE are covariates; and (4) the diagnosis of MDE is artifactual. The evidence for these models is discussed. The potentially confounding effect of depression on tests of immune function and neuropsychological testing is described. The implications of these different models for the design of studies of CFS are examined.
Symptoms and signs of chronic fatigue syndrome, This review summarizes the symptoms and signs seen in patients with chronic fatigue syndrome (CFS). It is based on the authors' experience with two cohorts of approximately 510 patients with chronic debilitating fatigue and on the reported experience of other investigators with similar patients. The most characteristic symptoms of CFS are the sudden onset of an infectious-type illness. the subsequent chronic and debilitating fatigue. and postexertional malaise; many patients also have recurrent fevers. pharyngitis. adenopathy. myalgias. sleep disorders. and cognitive impairment.
Sources of confounding in immunologic data, Standardization of immunologic tests requires control of inter-assay. intra-assay. and biologic variation. It is important to determine the distribution of each immunologic marker level to be studied in an appropriate control population of adequate size. Valid interpretation of results requires consideration of the complex interactions of components of the immune system as well as of interactions of the immune system and other physiologic regulatory systems.
Validation of biologic markers for use in research on chronic fatigue syndrome, Unresolved aspects of chronic fatigue syndrome can be addressed by research involving biologic markers. These may be any molecular. biochemical. physiological. or other biologic parameter obtainable from biologic specimens. The use of biologic markers in research requires their validation as dependent or independent variables. Additionally. other characteristics of markers such as reliability of assays. background level. confounding factors. interpretations. and legal and ethical implications should be considered before the use of markers in research. A checklist is provided for evaluating a biologic marker before its inclusion in research.
Analysis of clinical, epidemiologic, and laboratory data on chronic fatigue syndrome, Much of the research conducted on chronic fatigue syndrome (CFS) is exploratory. The researchers' overall goal is to use clinical. epidemiologic. and laboratory data to provide clues about the etiology of this syndrome. In preparation for this symposium. a review of numerous publications on CFS has indicated that the literature generally does not reflect the application of optimal statistical methods for exploration of data. Whenever the researchers' aim is to generate hypotheses. modern methods designed specifically for exploratory data analysis are likely to provide greater insights into any patterns of data than are the traditional approaches to hypothesis testing. In addition. the use of formal methods of data synthesis for ongoing and future research on CFS is a means of strengthening collaborative efforts and of improving the ability of researchers to interpret the evidence available that relates to specific etiologic factors. The inclusion on the research team of experienced biostatisticians. who would oversee the statistical methods and the development of innovative analyses. is recommended.
Deep UV photochemistry of chemisorbed monolayers: patterned coplanar molecular assemblies, Deep ultraviolet (UV) irradiation is shown to modify organosilane self-assembled monolayer (SAM) films by a photocleavage mechanism. which renders the surface amenable to further SAM modification. Patterned UV exposure creates alternating regions of intact SAM film and hydrophilic. reactive sites. The exposed regions can undergo a second chemisorption reaction to produce an assembly of SAMs in the same molecular plane with similar substrate attachment chemistry. The UV-patterned films are used as a template for selective buildup of fluorophores. metals. and biological cells.
The trk proto-oncogene product: a signal transducing receptor for nerve growth factor, The trk proto-oncogene encodes a 140-kilodalton. membrane-spanning protein tyrosine kinase (p140prototrk) that is expressed only in neural tissues. Nerve growth factor (NGF) stimulates phosphorylation of p140prototrk in neural cell lines and in embryonic dorsal root ganglia. Affinity cross-linking and equilibrium binding experiments with 125I-labeled NGF indicate that p140prototrk binds NGF specifically in cultured cells with a dissociation constant of 10(-9) molar. The identification of p140prototrk as an NGF receptor indicates that this protein participates in the primary signal transduction mechanism of NGF.
Chimeric NGF-EGF receptors define domains responsible for neuronal differentiation, To determine the domains of the low-affinity nerve growth factor (NGF) receptor required for appropriate signal transduction. a series of hybrid receptors were constructed that consisted of the extracellular ligand-binding domain of the human epidermal growth factor (EGF) receptor (EGFR) fused to the transmembrane and cytoplasmic domains of the human low-affinity NGF receptor (NGFR). Transfection of these chimeric receptors into rat pheochromocytoma PC12 cells resulted in appropriate cell surface expression. Biological activity mediated by the EGF-NGF chimeric receptor was assayed by the induction of neurite outgrowth in response to EGF in stably transfected cells. Furthermore. the chimeric receptor mediated nuclear signaling. as evidenced by the specific induction of transin messenger RNA. an NGF-responsive gene. Neurite outgrowth was not observed with chimeric receptors that contained the transmembrane domain from the EGFR. suggesting that the membrane-spanning region and cytoplasmic domain of the low-affinity NGFR are necessary for signal transduction.
Uncoupling of the spectrin-based skeleton from the lipid bilayer in sickled red cells, The distribution of spectrin and band 3 in deoxygenated reversibly sickled cells was visualized by immunofluorescence and immunoelectron microscopy. Antibodies against band 3. the major lipid-associated transmembrane protein. labeled the entire cell body. including the entire length of the long protruding spicule. whereas antibodies against spectrin labeled only the cell body and the base region of the spicules. The results suggest that the formation of long spicules during sickling is associated with a continuous polymerization of hemoglobin S polymers. presumably through gaps in the spectrin-actin meshwork. and a subsequent uncoupling of the lipid bilayer from the submembrane skeleton.
Spatial control of gut-specific gene expression during Caenorhabditis elegans development, The nematode Caenorhabditis elegans was transformed with constructs containing upstream deletions of the gut-specific ges-1 carboxylesterase gene. With particular deletions. ges-1 was expressed. not as normally in the gut. but rather in muscle cells of the pharynx (which belong to a sister lineage of the gut) or in body wall muscle and hypodermal cells (which belong to a cousin lineage of the gut). These observations suggest that gut-specific gene expression in C. elegans involves not only gut-specific activators but also multiple repressors that are present in particular nongut lineages.
Fifteen-year results of ambulatory compression therapy for chronic venous ulcers, A nonoperative approach to venous stasis ulceration of the lower extremity. consisting of initial bedrest. ulcer cleansing. dressing changes. and ambulatory elastic compression stocking therapy. has been maintained for over 15 years. All patients had class III. severe chronic venous insufficiency. One hundred five of 113 patients (93%) experienced complete ulcer healing in a mean of 5.3 months. One hundred two patients were compliant with elastic compression stockings. and 11 patients were noncompliant. Complete ulcer healing occurred in 99 of 102 patients (97%) who were compliant versus six of 11 patients (55%) who were noncompliant (p less than 0.0001). The influence of noncompliance. previous venous ulceration. previous venous surgery. previous known deep venous thrombosis. peripheral arterial insufficiency (ankle brachial systolic blood pressure index less than or equal to 0.60). pretreatment ulcer duration. ulcer size. age. sex. diabetes. smoking. and photoplethysmography venous refill time on ulcer healing was determined by logistic regression analysis. Only noncompliance with elastic compression stockings (p less than 0.0001) and a pretreatment ulcer duration of more than 9 months (p = 0.02) significantly decreased initial ulcer healing. Posthealing follow-up was available in 73 patients for a mean of 30 months. Fifty-eight patients (79%) continued to be compliant with stockings; 15 patients were noncompliant. Total ulcer recurrence in patients who were compliant was 16%. Five-year lifetable recurrence was 29%. All patients who were noncompliant had recurrent ulceration by 36 months. Previous ulceration. previous venous surgery. and peripheral arterial insufficiency had no effect on ulcer recurrence (p greater than 0.05).
Serosal invasion as the single prognostic indicator in stage IIIA (T3N1M0) gastric cancer, Prognostic factors of gastric cancer with positive serosal invasion and regional lymph node metastasis were evaluated by multivariate analysis. Sixty-seven patients with the T3N1M0 subgroup of stage IIIA disease were evaluated. in which 34.9 +/- 13.4 nodes were dissected in extended lymph node dissection. and 6.5 +/- 6.2 were metastatic. Routine postoperative systemic chemotherapy with mitomycin C and N1-(2'-tetrahydrofuryl)-5-fluorouracil was administered. With this approach. the 5-year survival rate of stage IIIA disease was 47.6%. By Cox proportional hazards model. diameter of serosal invasion was the only significant determinant of prognosis in the T3N1M0 subgroup. The predicted 5-year survival rate for 24 patients with serosal invasion less than 3.0 cm in diameter was 59.5%. compared with 11.5% for 38 patients with invasion of 3.0 cm or larger in diameter. The number of metastatic nodes and the type of operation (total gastrectomy or less than total gastrectomy) did not affect the prognosis. When gastric cancer has both positive serosal invasion and metastatic regional lymph nodes. the diameter of serosal invasion is the more important factor for predicting prognosis.
Development of a computer-aided surgery system: three-dimensional graphic reconstruction for treatment of liver cancer, Simulation of the needle puncture and volume estimation for the tumors in the liver were carried out with the three-dimensional image reconstruction system. which consists of a medical image acquisition system. a data processing system. and a graphic display. A set of sliced-image data from a computerized tomography and/or a magnetic resonance imaging was used to reconstruct the liver. the vessels. and the tumors of the patients with liver cancer. A good agreement of anatomic locations of both the intrahepatic vessels and the tumors between the reconstructed liver model and the echography done intraoperatively was observed. Surgical simulations with these graphic models clearly indicated safety areas for needle puncture in the laser coagulation therapy. In addition liver volumes were calculated within 3% of error in comparison to the measured values. These results indicate that the computer-aided surgery system is a highly promising method that avoids cumbersome stereoscopic recognition of the anatomical location of the diseased area and the vessels. before and after surgery.
Complete external iliac artery disruption after percutaneous aortic valvuloplasty in two young children: successful repair with hypogastric artery transposition, The majority of vascular injuries in young children are iatrogenic. This is a report of two complete external iliac artery disruptions occurring during percutaneous transfemoral balloon aortic valvuloplasty in a 2-year-old and a 5-year-old child. The damaged external iliac artery was bypassed by extensively mobilizing the hypogastric surgery and rotating it upward to anastomose it to the proximal common femoral artery. Normal limb pulses. function. and growth were noted in follow-up.
Assessment of aortoiliac obstructive disease by Doppler spectrum analysis of blood flow velocities in the common femoral artery at rest and during reactive hyperemia, Aortoiliac obstructive disease was assessed by Doppler spectrum analysis of blood flow velocities in the common femoral artery measured both at rest and during reactive hyperemia. The intraarterial femoral artery pressure measured at rest and during reactive hyperemia served as the "gold standard" for the definition of a hemodynamically significant aortoiliac stenosis. Our results. obtained from 93 patients (136 limbs). showed that differences between Doppler spectra obtained from limbs with a hemodynamically significant aortoiliac stenosis and those from limbs without were more pronounced during reactive hyperemia than at rest. The best assessment of aortoiliac obstructive disease could be obtained with a combination of parameters derived from Doppler spectra measured at rest and during reactive hyperemia. With these parameters. obtained by multivariate analysis. 85% of the limbs were diagnosed correctly compared with the gold standard. If angiographic data were added to the gold standard. even 91% of the limbs were diagnosed correctly. We conclude that analysis of Doppler spectra-obtained noninvasively from the common femoral artery at rest and during reactive hyperemia provides an accurate hemodynamic assessment of the aortoiliac segment.
Topical flurbiprofen decreases burn wound-induced hypermetabolism and systemic lipid peroxidation, We studied the effect of the topical application of the nonsteroidal anti-inflammatory agent. flurbiprofen. on postburn hypermetabolism and systemic lipid peroxidation. Twelve sheep with a 15% total body surface third-degree burn were monitored over a 4-day postburn period. In six sheep. a single application of a 5% flurbiprofen cream was placed on the burn wound on day 3. Data were compared to both burned and nonburned controls (n = 6). All animals were killed on day 4. Oxygen consumption was increased at day 3 by 28% +/- 10% over the preburn value in all animals. Flurbiprofen significantly attenuated the increase in oxygen consumption. returning the value essentially to baseline by 12 hours after application. Lung and liver peroxidation. as measured by malondialdehyde. was significantly increased in the burned. nontreated sheep at day 4 from a control value of 45 +/- 9 and 110 +/- 12 to 60 +/- 6 and 310 +/- 71 nmol/gm tissue. respectively. In flurbiprofen-treated animals. values were 42 +/- 8 and 160 +/- 18 nmol/gm at day 4. significantly attenuated from burn alone. Protein-rich burn lymph flow remained fourfold increased in both groups. indicating a persistent increase in burn tissue vascular permeability. not modified by flurbiprofen. Burn wound biopsies revealed bacterial contents of less than 10(4) organisms/gram tissue in all animals. We conclude that topical flurbiprofen significantly decreases burn wound-induced systemic hypermetabolism and oxidant-induced lipid peroxidation seen at 3 days after burn injury. but does not attenuate the remaining local burn-wound vascular permeability.
Pathologic and hemodynamic sequelae of unilobar biliary obstruction and associated liver atrophy, A patient is presented with unilobar biliary obstruction associated with marked liver atrophy and compensatory hypertrophy. Characteristically she was not jaundiced and had no portal hypertension. Quantitative measurements of the degree of hepatocyte hyperplasia showed that over 50% of cells in the hypertrophied lobe were hyperplastic. Surprisingly. a similar percentage of cells in the atrophied lobe were also hyperplastic. No difference was found in the size of hepatocytes between the two lobes or among the hepatocyte subpopulations in the atrophied lobe. The findings in this case suggest (1) lobar atrophy induces a hyperplastic response in more than one half of the cells of the contralateral lobe; (2) the development of atrophy consequent on biliary obstruction is likely the result of destruction of whole cells rather than cytoplasmic loss; (3) the development of a hyperplastic response within the atrophied lobe is a new finding and is consistent with the hormonal theory of hepatic regeneration; and (4) striking compensatory hypertrophy of the liver is associated with normal portal venous pressure.
Evaluation of the transfusion effectiveness of various platelet concentrates by means of an in vitro perfusion technique, An in vitro perfusion technique was used for the assessment of the effectiveness of platelet concentrates (PCs) administered to patients with bone marrow failure. Denuded rabbit arterial segments mounted in annular chambers were exposed to nonanticoagulated blood drawn directly from the antecubital vein. This perfusion system allows the direct visualization of platelet-subendothelium interactions. The deposition of platelets on exposed subendothelium and the presence of fibrin were evaluated morphometrically. Perfusions were performed before and 10 and 120 minutes after the transfusion of PCs that had been obtained by apheresis and administered immediately after collection (A) or separated by centrifugation of blood units and transfused 24 hours after storage at 22 degrees C (B) or 4 degrees C (C). Bleeding times were also determined systematically. The deposition of platelets on the subendothelium increased significantly (p less than 0.01) 10 minutes after transfusions of A and B PCs. but the presence of fibrin did not differ from pretransfusion values. Two hours after the administration of A or B PCs. the improvement of platelet deposition persisted. By then. the presence of fibrin increased markedly (p less than 0.01). The deposition of platelets was not modified after the transfusion of C PCs. but the presence of fibrin was augmented significantly at both posttransfusion times. Comparisons between bleeding times and morphometric results pointed to a possible role of fibrin formation in contributing to primary hemostasis.
Transfusion-transmitted babesiosis: a case report from a new endemic area, The seventh documented case of babesiosis transmitted by transfusion is reported. Both the donor and the recipient are residents of Connecticut. where the presence of endemic babesiosis has only recently been established. As the range of Babesia microti. and its vector the Ixodes dammini tick. continues to expand. clinicians and blood bank directors should be aware that cases of transfusion-transmitted babesiosis may occur in newly endemic areas.
Postoperative analgesic requirements following flumazenil administration, The effect of flumazenil (RO 15-1788) on postoperative analgesic requirements was evaluated in 30 postoperative patients. This prospective investigation was a double-blind. placebo-controlled trial in patients undergoing general anesthesia supplemented by midazolam and fentanyl or sufentanil. Patients received either flumazenil (n = 20) or placebo (n = 10) by random assignment. Analgesic requirements were measured in morphine equivalents (MEs) and were recorded for a three-hour period following the administration of flumazenil. All patients received the assigned treatment within five minutes of arrival to the postanesthesia room. Total ME requirements were 4.1 +/- 3.8 mg for the flumazenil group and 4.5 +/- 4.6 mg (p = 0.71) for the placebo group. Patient analgesic requirements were also assessed when patients were adequately alert. For the flumazenil group this time period was 6.2 +/- 12.7 minutes versus 52.9 +/- 28.4 minutes for placebo (p less than 0.01). MEs (flumazenil 4.1 +/- 3.8 mg vs. placebo 3.7 +/- 3.2 mg) were not significantly different (p = 0.57) when similar levels of consciousness were compared. The onset of pain was more rapid with flumazenil patients as evidenced by the first analgesic dose at 15.7 +/- 25.1 minutes for the flumazenil group versus 34.7 +/- 43.7 for the placebo group; however. these data were not statistically different (p = 0.144). These results suggest that flumazenil does not increase postoperative analgesic requirements during the immediate postanesthesia period; however. patients receiving flumazenil may experience an earlier onset of postoperative pain.
Severe hyponatremia: an association with lisinopril, A 63-year-old white woman with a history of hypertension and chronic obstructive pulmonary disease presented to the emergency room with worsening shortness of breath. anorexia. coughing. increased thirst. and leg edema of two weeks' duration. Medications included lisinopril 10 mg/d. which had been started six weeks earlier. sustained-release theophylline 300 mg q12h. and an albuterol inhaler. The lisinopril was discontinued on admission. Serum sodium concentration was 109 mmol/L; the osmolality of the blood and of the urine were 253 mOsmol and 438 mOsmol. respectively. with a specific gravity of 1.025 and a urine sodium of 17 mmol/L. The hyponatremia initially was considered to be the syndrome of inappropriate antidiuretic hormone secretion in response to the patient's suspected pneumonia. Due to worsening blood pressure. lisinopril was restarted and the serum sodium concentration dropped from 134 to 126 mmol/L. Evaluation of the patient's hyponatremia included assessment of thyroid. adrenal. hepatic. and cardiac function that were within normal limits. The patient was discharged on the following medications: sustained-release theophylline 300 mg tid. prednisone 10 mg/d. albuterol inhaler 2 puffs q6h. and sustained-release verapamil 240 mg/d for blood pressure control. Her serum sodium concentration has remained between 135 and 140 mmol/L during hospitalizations for exacerbations of chronic obstructive pulmonary disease and for pneumonias 10 and 12 months after discharge.
Nafarelin acetate: a gonadotropin-releasing hormone agonist for the treatment of endometriosis [published erratum appears in DICP 1991 Mar;25(3):321, Nafarelin acetate is a gonadotropin-releasing hormone (GnRH) agonist proven as effective as danazol in treating endometriosis. Its proposed mechanism of action is the desensitization of pituitary GnRH receptors leading to a decrease in gonadotropin release. and ovarian hormone serum concentrations similar to those achieved in postmenopausal women. Nafarelin decreases or ablates the physical symptoms associated with endometriosis. and pregnancy rates following therapy with this drug are comparable to rates observed after danazol therapy. Nafarelin is administered by nasal inhalation and has been generally well tolerated. It is associated with a high incidence of adverse effects but they are rarely severe enough to cause withdrawal from treatment. and those occurring most frequently--hot flashes. vaginal dryness. and decreased libido--are a consequence of the hypoestrogenemia induced by the drug. Increased bone turnover occurs in women on nafarelin but biochemical parameters return to pretreatment concentrations by six months after termination of treatment. This agent's place in the therapy of endometriosis will be determined as clinical experience accumulates.
A review of carbamazepine's hematologic reactions and monitoring recommendations, Early case reports of fatal hematologic effects attributed to carbamazepine (CBZ) resulted in extensive monitoring recommendations by the manufacturer. The rarity of blood dyscrasias led many authors to question the manufacturer's guidelines. Thus the manufacturer removed specific monitoring guidelines. allowing physicians to monitor CBZ using their clinical judgment. This article reviews case reports and studies of CBZ's hematologic effects. Due to their rapid onset. daily laboratory checks would be necessary to monitor for aplastic anemia. agranulocytosis. and thrombocytopenia. These adverse effects are best monitored by informing patients and physicians to carefully watch for signs and symptoms. Leukopenia develops more slowly. occurring in approximately 12 percent of children and 7 percent of adults. Its onset is typically within the first three months of treatment. with patients at risk having a low or low-normal pretreatment white blood cell (WBC) count. Leukopenia often reverses. even if CBZ is continued. Based upon our review of the literature. we recommend monitoring of those high-risk patients during the first three months of treatment with the frequency being determined by results of each laboratory value. WBC counts less than 3000/mm3 or neutrophil counts below 1000/mm3 warrant a decrease in dose with frequent monitoring or CBZ discontinuation. if necessary.
Current and future drugs for acid-peptic disease: a plethora of opinions on possible mechanisms of action, Sixty-seven invited participants involved in the development. evaluation. and use of therapies for acid-peptic disorders participated in a meeting to discuss the scientific basis for healing actions of ulcer drugs and the prospects for future developments ("Realities of Mucosal Protection in the Upper Gastrointestinal Tract." Lausanne. Switzerland. November 8-10. 1987). Eighty-one key statements were prepared and subsequently analyzed on the basis of a voting system. Of the 45 statements that dealt with existing therapies. only 3 statements showed positive consensus (agreement of two-thirds or more of voters) about mechanisms of ulcer healing. Participants agreed that both (1) hydrogen/potassium adenosine triphosphatase inhibitors and (2) histamine H2 antagonists healed ulcers solely by acid inhibition. and (3) that sucralfate works by topical action. Substantial uncertainty about the mechanisms by which bismuth compounds and antacids heal ulcers was noted as well as their wide range of effects. The mechanism of ulcer healing by prostaglandins and the clinical relevance of antiulcer effects of drugs demonstrated in acute studies with animals were also controversial. There was greater agreement among participants about unexplored drug effects that might produce ulcer healing. Of the 36 such mechanisms surveyed. the most support went to therapies aimed at enhancement of mucosal blood flow. epithelial restitution. and mucosal alkaline secretion or inhibition of luminal pepsin activity. The diversity of opinions among participants suggests a high level of empiricism in the development of ulcer healing drugs apart from those that inhibit acid secretion. This empiricism probably arises from inadequate understanding of processes of mucosal injury and repair.
Management of common finger injuries, Family physicians can manage most finger injuries. including uncomplicated fractures. proximal interphalangeal joint dislocations. closed tendon injuries and ligament sprains. Finger injuries that can cause long-term morbidity may present as minor sprains. Diagnosis requires a thorough history. systematic examination and radiographic evaluation.
Mechanical devices for the treatment of erectile dysfunction, Almost all men with erectile dysfunction can be successfully treated. External erection devices are safe and effective for the management of partial impotence. If external devices fail to produce adequate penile engorgement or if they cannot be used. invasive treatments are available. Penile implants remain the gold standard for the management of erectile impotence. especially complete impotence. A satisfaction rate of 80 to 90 percent can be expected with all of the currently available implants. Attention to surgical detail and proper patient selection usually produce an excellent functional and anatomic result.
Ambulatory blood pressure monitoring in hypertension, Compared with blood pressure measurements in the office setting. ambulatory blood pressure monitoring offers a more accurate and reliable method of diagnosing and managing hypertension. Indications for ambulatory blood pressure monitoring include borderline hypertension. a discrepancy between home and office blood pressure measurements. persistent blood pressure elevation in the office with no end-organ damage. episodic elevations of blood pressure or suggestive symptoms. hypertension resistant to treatment. episodic angina not related to exercise. end-organ damage but normal office blood pressure readings. and evaluation of the efficacy of antihypertensive agents. Several cases are presented for review.
Disposable contact lenses, Disposable soft contact lenses are an alternative to conventional extended-wear lenses and provide an acceptable margin of safety and convenience for the wearer. The lenses are worn for one to two weeks and then discarded. Buildup of tear film deposits is minimized. and the need for cleaning and disinfecting solutions is eliminated. The long-term safety of disposable contact lenses is unknown.
Dementing illness: the patient, caregiver and community, Care of the elderly patient with dementing illness involves not only the patient but also the family and other caregivers. and the community. An evaluation and treatment plan must go beyond the patient's immediate medical problems to examine the caregiver's needs and the community services available.
Pediatric Advanced Life Support: Part II. Fluid therapy, medications and dysrhythmias, The first part of this two-part article discussed the equipment needed for pediatric resuscitations and the techniques used for cardiopulmonary assessment. airway securance. circulatory maintenance and intravascular access. In this second part. additional life support measures are reviewed. including fluid therapy. resuscitation medications and the management of cardiac rhythm disturbances.
Clomipramine for obsessive-compulsive disorder, Obsessive-compulsive disorder affects about 2 percent of the U.S. population and can be quite disabling. Clomipramine is the only drug approved for the treatment of obsessive-compulsive disorder. Its efficacy is unique among tricyclic antidepressants and may be related to its relatively high potency in affecting serotonergic neurotransmission. The drug has many anticholinergic effects. but it is relatively well tolerated by the patients for whom it is effective. A 0.4 percent incidence of seizures. a potentially serious side effect. has been observed. Other antidepressants that are relatively selective for serotonergic (as opposed to noradrenergic) transmission may be as effective as clomipramine in the treatment of this disorder; controlled studies are under way. Clomipramine at low doses is also effective in the treatment of panic disorder and has been used successfully in the treatment of premature ejaculation.
Blood pressure during sleep: antihypertensive medication, To investigate whether excessive reduction of blood pressure (BP) by antihypertensive medications correlates with myocardial infarction. especially during sleep in elderly patients. we used telemetry and cuvette dye-dilution methods to assess the direct BP and the hemodynamics of 68 inpatients with essential hypertension during wakefulness and sleep. There were 25 patients greater than or equal to 60 years old (OH-group) and 43 were less than or equal to 59 years old (YH-group). Of the OH-group. 36% showed high BP during the day. with marked decreases (minimum BP less than 110/70 mm Hg) during sleep. Average cardiac index (CI) of the OH-group was low during wakefulness and extremely low during slow-wave sleep. Changes of mean BP in the OH-group correlated with changes in total peripheral vascular resistance index (TPRI) during sleep. but this correlation was not observed in the YH-group. The antihypertensive effects on nocturnal BP of the various medications was: central adrenergic inhibitors less than or equal to beta blockers with intrinsic sympathomimetic activity less than or equal to alpha (alpha beta) blockers less than or equal to angiotensin-converting enzyme inhibitors less than or equal to calcium antagonists. Because BP and CI were found to be very low and TPRI seems to play an important role in BP regulation in sleeping elderly patients. excessive antihypertensive medication may be harmful to this subgroup. However. because the effects on nocturnal BP differ among various antihypertensive treatments. further research is required on the relation between antihypertensive medication and the hemodynamics of sleeping elderly hypertensive patients.
Autonomic nervous system dysregulation in human hypertension, An increased sympathetic drive combined with decreased parasympathetic inhibition is found in patients with borderline hypertension. who characteristically have rapid heart rates. high cardiac output and relatively normal vascular resistance (hyperkinetic state). In established hypertension. cardiac output is normal. vascular resistance is elevated and signs of increased sympathetic drive are absent. Apparently hemodynamics and sympathetic drive change during hypertension. The mechanism of the hemodynamic transition in the course of hypertension is well understood. Cardiac output returns from elevated to normal values as beta-adrenergic receptors down-regulate and stroke volume decreases (due to decreased cardiac compliance). The high blood pressure induces vascular hypertrophy. which in turn leads to increased vascular resistance. The mechanism of the change of sympathetic tone from elevated in borderline hypertension to apparently normal in established hypertension can best be explained within the conceptual framework of the "blood-pressure-seeking" properties of the brain. In hypertension. the central nervous system seeks to maintain systemic blood pressure at the higher level. As hypertension advances and vascular hypertrophy develops. arterioles become hyperresponsive to vasoconstriction. At this point. less sympathetic drive is needed to maintain pressure-elevating vasoconstriction. and the central sympathetic drive is down-regulated. The etiology of increased sympathetic drive in hypertension remains unresolved. Subjects with increased sympathetic drive are also usually overweight and have elevated levels of insulin. cholesterol and triglycerides. as well as decreased high-density lipoproteins. Future research must focus on the link between coronary risk factors and sympathetic overactivity in hypertension.
Bopindolol: Czechoslovak experience with a new beta blocker in the treatment of hypertension, Bopindolol is a nonselective beta blocker with mild intrinsic sympathomimetic activity. One of the drug's main benefits is its prolonged effect. lasting for 24 hours. which makes it possible to administer bopindolol in a single daily dose. a fact that may improve patient adherence to therapy. A double-blind study was performed in two centers. comparing bopindolol with metoprolol in 86 hypertensive patients. Baseline diastolic blood pressure (BP) was 100 to 120 mm Hg. The effects of bopindolol or metoprolol on BP and heart rate were similar: return to normal values was achieved in 70% of patients with either drug. A 6-month study at another center found that bopindolol did not affect the levels of total cholesterol. low-density and high-density lipoprotein cholesterol or triglycerides. Another 12-month study documented a decrease in total cholesterol. apolipoprotein (apo) A1 and apo B. The apo A/B ratio rose. thus improving the atherosclerotic index. No deterioration of glucose tolerance or immunoreactive insulin response to glucose was seen after 6 months of bopindolol administration. Bopindolol satisfactorily modifies not only resting but also exercise BP during isometric and isotonic load. thus reducing BP fluctuation during physical activities of the hypertensive patient. The drug exerts no effect on renal and liver function. electrolyte balance and hematologic parameters. Bopindolol is a very useful drug of first choice in mild and moderate hypertension. Bopindolol's main advantages include its prolonged action. good tolerance and a beneficial effect on risk factors of atherosclerosis (lipid and carbohydrate metabolism).
Review of state-of-the-art beta-blocker therapy, Beta-adrenoceptor blocking drugs have been used in the treatment of hypertension for more than 2 decades. During this time they have reached the position of first-line therapy for hypertension and are recommended as such by the Joint National Committee (U.S.A.) in 1988 and by the World Health Organization/International Society of Hypertension in 1983 and 1989. This is because of the favorable relationship between the antihypertensive efficacy of these drugs and the rate and severity of their adverse effects. Of particular interest is the possibility that beta blockers may protect against coronary artery disease (CAD). With regard to secondary prevention against CAD. statistically highly significant and clinically relevant reductions of mortality and the risk of reinfarction have been shown in prospective. double-blind. placebo-controlled trials. A primary preventive effect against CAD. on the other hand. has only been shown in open trials without placebo control. However. in spite of the lack of clear proof. this effect still appears to be a logical possibility. Some new findings with beta blockers appear to be of particular interest: beta blockade may reduce myocardial necrosis in patients with marked elevations of plasma catecholamines due to traumatic head injury; a similar protective effect in other situations of severe stress. e.g.. acute myocardial infarction. would be of great clinical value. Experimental studies also suggest that beta blockers may have antiatherosclerotic effect in animals fed an atherogenic diet and subjected to stress. Again. clinical confirmation of such results would be of great significance.
Interrupting the adaptive changes in congestive heart failure, Circulating plasma concentrations of norepinephrine. renin. angiotensin and vasopressin are increased in congestive heart failure. By increasing ventricular afterload. heart failure is further worsened. which in turn--in a vicious cycle--stimulates neurohumoral vasoconstrictor mechanisms. Furthermore. because of the compensatory but excessive stimulation of the sympathomimetic system. a down-regulation and desensitization particularly of the myocardial beta 1 receptors and depletion of myocardial catecholamine occurs in chronic heart failure. These defects may be restored toward normal by interventions that attenuate the activity of the sympathetic nervous system. A direct approach to modify the excessive vasoconstriction is to administer systemic vasodilator drugs. but despite favorable short-term effects. tolerance developed to most of these drugs during long-term treatment. One reason for the loss of effectiveness is the reflex activation of the sympathetic system. which increases vasoconstrictor hormone concentrations. Activation of the renin-angiotensin system can be modified effectively by angiotensin-converting enzyme inhibitors that have shown favorable responses in patients with chronic heart failure. Beta-blocking agents interfere with endogenous sympathetic activation and have produced beneficial effects in patients with congestive cardiomyopathy. Long-term treatment is associated with up-regulation of the number of beta receptors and an improved responsiveness to catecholamines. Owing to the negative inotropic effects of beta-blocking agents. some of the patients with severe heart failure deteriorated hemodynamically and clinically. Theoretically. it should be advantageous to have a substance that combines protection against excessive beta stimulation with a mild inotropic support to prevent cardiac decompensation. This may be achieved by a selective beta 1-partial agonist like xamoterol.
Adaptive changes in the periphery and their therapeutic consequences, Systemic vasoconstriction in chronic heart failure is due to several compensatory mechanisms with different time courses. Peripheral vasoconstriction mediated by increased sympathetic tone and activation of the plasma renin-angiotensin system may act primarily for short-term control. The effects of the vascular renin-angiotensin system. impaired flow-dependent. endothelium-mediated dilation (resulting from chronically reduced flow) and structural alterations of the vessel wall slowly emerge with time. In addition. fluid retention may contribute to increased vascular stiffness in chronic heart failure. Improved cardiac output with acute administration of vasodilators and inotropes is not immediately translated into increased blood flow to skeletal muscle. because (1) the reversal of the peripheral alterations described develops slowly over time (in fact. vasodilators and inotropes given acutely may cause redistribution of blood flow in skeletal muscle without improving oxygen availability); and (2) intrinsic abnormalities of skeletal muscle exist in chronic heart failure (e.g.. due to chronic deconditioning. resulting in reduced oxidative capacity of skeletal muscle. as suggested by ultrastructural analysis and nuclear magnetic resonance spectroscopy). Drugs that interfere with the underlying compensatory mechanisms (e.g.. renin-angiotensin system) without development of tolerance during long-term therapy exert beneficial effects after long-term treatment (e.g.. the beneficial effects of angiotensin-converting enzyme inhibitors are. in part. due to peripheral mechanisms--the inability of the peripheral vessels to dilate--and to improvement of peripheral oxygen extraction).
Neuroendocrine activation in congestive heart failure, Several changes in neuroendocrine activity follow failure of cardiac function to satisfy peripheral requirements and contribute to the clinical syndromes of heart failure. Afferent pathways are poorly understood and triggers are both central and peripheral. involving attenuation of atrial and arterial baroreceptor activity. Efferent sympathetic activity is generally increased with resulting vasoconstriction. but responses are organ-specific and differ among heart. kidney. lung and skeletal muscle. Changes in cardiac sympathetic activity are inadequately understood. Enhanced cardiac norepinephrine spillover contrasts with reduced tissue concentration and impaired activity of synthetic enzymes and neuronal catecholamine uptake. Beta-receptor down-regulation further complicates overall adrenergic responsiveness and the balance between enhancement of contractile function and reduction in arrhythmia threshold. Activation of the renin-angiotensin system is potentiated by the sympathetic nervous system and may contribute to vasoconstrictor hyporesponsiveness. Angiotensin II may in turn facilitate the central and peripheral effects of sympathetic activation and the release of vasopressin from the pituitary. Our understanding of the role of vasodilator peptides in heart failure remains rudimentary. It is likely that vasoconstrictor neuroendocrine response adversely influences optimal cardiac function in heart failure and may promote arrhythmogenesis. The neuroendocrine response in individual organs. however. requires intensive study.
Assessment of exercise tolerance in chronic congestive heart failure, In patients with chronic heart failure. exercise capacity is poorly related to cardiac hemodynamics. and peripheral circulation is an important determinant of exercise tolerance. The ability of the muscle vasculature to dilate is markedly impaired. in part. because of exaggerated neurohumoral activity increasing vascular wall stiffness. For this reason. increasing cardiac output is not sufficient to increase exercise capacity if not accompanied by improving vascular reactivity. The poor reliability and reproducibility of exercise tolerance assessed by maximal exercise duration or maximal attained work load (particularly on a treadmill) has led to widespread measurement of respiratory gas during exercise. Peak oxygen consumption (peak VO2). even if it is symptom-limited. has been shown to be a very reproducible criterion of exercise tolerance; moreover. because VO2 is the product of cardiac output and arteriovenous oxygen difference. it also has a qualitative hemodynamic significance. Ventilatory threshold can be determined before maximal exercise; however. problems of determination limit the practical value of this criterion. Unfortunately. peak VO2 lacks sensitivity to detect minor improvement or impairment of symptoms during daily life. although these are significant to the patient. Submaximal exercises have been proposed for this purpose and are currently being evaluated.
Assessment of quality of life, Assessment of quality of life has emerged in recent years as an important part of the overall evaluation of drug therapy and health care in general. Measurement techniques for this difficult assessment range from simple unqualified questions on patient well-being to complex statistical analyses of a wide range of lifestyle and activity variables. The factors that influence quality of life during chronic drug therapy differ in the treatment of symptomatic (e.g.. heart failure) vs asymptomatic (e.g.. hypertension) disease. and include drug side effects. relief of symptoms. improved prognosis. return to work. physical activity and the need for further hospital treatments. The manifestation of quality of life varies for different people leading to lack of agreement on the precise definition. The absence of standardization of methods of measurement also contributes to this and leads to lack of comparability of studies and unreasonable claims by some drug manufacturers. Further complicating issues in multicenter trials across countries include language problems and interethnic differences in "sickness" behavior. The recently introduced quality-adjusted life year (QALY) index. designed to take account of both the quality and duration of life in assessing the outcome of treatments. may avoid some of these problems. By classifying illness states (the Rosser index) on the basis of disability and distress. and comparing outcomes in terms of improved prognosis. QALYs have already been used for cost/benefit analyses of a number of new and expensive therapies. Like other methods. QALYs have problems related to variability in individual appreciation of life values. To date. a perfect method of quality of life assessment remains elusive.
Postprandial thermogenesis in lean and obese subjects after meals supplemented with medium-chain and long-chain triglycerides, The thermic effect of medium-chain triglycerides (MCTs) was studied in six lean and six obese young males by evaluating postprandial thermogenesis (PPT) after the ingestion of mixed meals containing either 38 g long-chain triglycerides (LCTs) or 30 g MCTs plus 8 g LCTs. Postabsorptive resting metabolic rate (RMR) was higher (P less than 0.05) in the obese individuals than in the lean ones. PPT. evaluated as 6-h incremental areas above RMR. was greater (P less than 0.05) in both groups after meals containing MCTs. The thermic effect of MCTs was 119.7 +/- 33.9 and 144.7 +/- 48.8 kJ/6 h in the lean and the obese subjects. respectively. The postprandial response of glucose. insulin. and free fatty acids did not depend on the type of oil contained in the meal. Our study shows that PPT is enhanced in both lean and obese subjects when LCTs in a mixed meal are replaced with MCTs.
Barley and wheat foods: influence on plasma cholesterol concentrations in hypercholesterolemic men, Twenty-one mildly hypercholesterolemic men aged 30-59 y were provided with comparable barley and wheat foods for each of 4 wk in a crossover-designed experiment. The purpose of the study was to examine the influence of two sources of dietary fiber (nonstarch polysaccharides. NSP) on blood lipids and glucose concentrations. Barley contains beta-glucan as a source of soluble dietary fiber (DF) whereas wheat contains the largely insoluble cellulose and hemicellulose fiber. Total dietary fiber increased from a previous intake of 21-38 g/d during the period of study for the two groups. Consumption of barley relative to wheat foods was associated with a significant fall in both plasma total cholesterol (6%. P less than 0.05) and in low-density-lipoprotein cholesterol (7%. P less than 0.02) whereas triglyceride and glucose concentrations did not change significantly. It is concluded that barley dietary fiber is more effective than wheat dietary fiber at lowering blood cholesterol in hypercholesterolemic men.
Lipid, lipoprotein, and hemostatic effects of fish vs fish-oil n-3 fatty acids in mildly hyperlipidemic males, The effects of fish and fish oil on lipids. hemostasis. and blood pressure were compared in 25 mildly hyperlipidemic men who received 4.5 g eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) daily for 5 wk. Six additional subjects served as controls. Fish and fish oil lowered plasma triglycerides 20% and 28% and very-low-density-lipoprotein (VLDL) triglycerides 42% and 52%. respectively (all P less than 0.05 compared with control). High-density-lipoprotein (HDL) cholesterol increased by 10% and 9%. with 34% and 32% increases in the proportion of HDL2 particles for fish and fish oil. respectively. Changes in total cholesterol. LDL cholesterol. apolipoprotein B. and blood pressure with fish and fish oil were not significantly different from changes for the control diet. The fish lowered fibrinogen (15.7%) and thromboxane (10.5%) and increased bleeding time (10.8%) (P less than 0.05 compared with control). Eating fatty fish and fish oil produced comparable lipid and lipoprotein changes. but only the fish improved hemostatic factors.
Essential fatty acid deficiency associated with the use of a medium-chain-triglyceride infant formula in pediatric hepatobiliary disease, Serum phospholipid fatty acid patterns were determined by gas chromatography in four infants with hepatobiliary disease receiving a formula with a high content of medium-chain-triglyceride (MCT) oil. All four infants demonstrated signs of essential fatty acid deficiency. characterized by decreased arachidonic acid and increased palmitoleic and oleic acids. All had substantial concentrations of the pathologic triene 5.8.11-eicosatrienoic acid. Three of four had decreased linoleic acid concentrations and abnormal ratios of triene to tetraene (5.8.11-eicosatrienoic acid: arachidonic acid). greater than 0.38. One patient may have experienced growth failure due to abnormal essential fatty acid status. Infants with the potential for fat malabsorption should only receive MCT-oil feedings with well above the generally recommended requirements for linoleic acid (3% of total caloric intake).
Lactose digestion from yogurt: influence of a meal and additional lactose, Lactose in yogurt is better digested than lactose in other dairy foods by lactase-deficient individuals. in part because of intraintestinal activity of yogurt microbial beta-galactosidase (beta-gal). The survival and activity of yogurt beta-gal depend on gastrointestinal transit. pH. and viability of the yogurt culture. To evaluate the ability of yogurt beta-gal to digest lactose when yogurt is consumed with food or with additional lactose. 22 healthy lactose-maldigesting individuals were fed 10 test meals. Results of breath-hydrogen expiration. incidence of symptoms. and enzyme and lactose content of gastric aspirates indicate that the consumption of a meal with yogurt does not inhibit. and may slightly improve. lactose digestion from yogurt. However. yogurt beta-gal appears unable to assist in the digestion of additional lactose beyond that normally present in yogurt.
Consumption of prunes as a source of dietary fiber in men with mild hypercholesterolemia, Forty-one free-living adult men with mild hypercholesterolemia (5.2-7.5 mmol/L) voluntarily participated in an 8-wk crossover study designed to determine the effect of prunes as a source of fiber on plasma cholesterol and on fecal output and bile acid concentration. During the prune period. subjects supplemented their usual diets with 12 prunes (100 g; 6 g dietary fiber) daily. Plasma low-density-lipoprotein cholesterol was significantly lower after the prune period (3.9 mmol/L) than after the grape-juice-control period (4.1 mmol/L). Fecal bile acid concentration of lithocholic acid was significantly lower after the prune period (0.95 mg bile acid/g dry wt stool) than after the grape-juice-control period (1.20 mg bile acid/g dry wt stool). Both fecal wet and dry weights were approximately 20% higher after the prune period than after the grape-juice-control period. Total bile acids (mg/72 h) did not significantly differ between experimental periods.
Electroencephalographic changes and periodontal status during short-term vitamin B-6 depletion of young, nonpregnant women, As part of a larger investigation to determine the effect of animal vs. plant proteins on the vitamin B-6 requirement of young women. clinical changes during vitamin B-6 depletion were documented. Eight healthy young women were confined to a metabolic unit and fed a defined formula diet nearly devoid of vitamin B-6 (less than 0.05 mg/d). Serial electroencephalographic (EEG) tracings. peripheral nervous system tests. periodontal evaluations. and biochemical measures of vitamin B-6 status were conducted. Within 12 d on the depletion diet. two of the eight women exhibited abnormal EEG tracings. These changes were readily reversed by repletion of vitamin B-6 at the 0.5-mg/d level. Biochemical measures reflected lowered vitamin B-6 status but were not predictive of the onset of EEG changes. No detectable alterations in oral or periodontal status were found. nor did plaque flora change markedly. This study is the first report of EEG changes occurring in women undergoing vitamin B-6 depletion and the first report to document EEG changes in adults within 12 d on a vitamin B-6-depletion regimen.
Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults, The effect of vitamin B-6 deficiency on immune response was studied in eight healthy elderly adults. The protocol consisted of a 5-d baseline (BL) period; a vitamin B-6-depletion period of less than or equal to 20 d; three stages of vitamin B-6-repletion. each lasting 21 d; and a 4-d final phase. The amounts of vitamin B-6 ingested during the different phases of the study were 3.00. 15.00. 22.50. and 33.75 micrograms.kg body wt-1.d-1. respectively. During the final phase the subjects ingested 50 mg vitamin B-6/d. Fasting blood was collected at the end of each period. Vitamin B-6 depletion significantly decreased percentage and total number of lymphocytes. mitogenic responses of peripheral blood lymphocytes to T- and B-cell mitogens. and interleukin 2 production. These indices returned to BL values after the third vitamin B-6-repletion period. when the total vitamin B-6 intakes were 1.90 +/- 0.18 mg/d for women and 2.88 +/- 0.17 mg/d for men. Vitamin B-6 deficiency impairs in vitro indices of cell-mediated immunity in healthy elderly adults. This impairment is reversible by vitamin B-6 repletion.
A 1-y walking program and increased dietary calcium in postmenopausal women: effects on bone, The effects of a supervised 1-y walking program and increased dietary calcium (milk supplement. 831 mg/d. vs placebo drink. 41 mg/d) on bones were examined in 36 postmenopausal women (60.2 +/- 6.5 y). Trabecular bone-mineral density (BMD) of the lumbar spine (L1-L3). measured by computed tomography. increased by 0.5% in exercising women (n = 18) and decreased by 7.0% in sedentary women (n = 18; P = 0.02). Femoral-neck BMD measured by dual-photon absorptiometry (DPA) increased by 2.0% in women consuming high dietary calcium (n = 18) and decreased by 1.1% in those on moderate calcium intake (n = 18; P = 0.001). Neither exercise nor dietary calcium had an effect on lumbar spine (L2-L4) measured by DPA. distal radius measured by single-photon absorptiometry. or total body calcium measured by in vivo neutron activation. The varying proportions and rates of turnover of trabecular and cortical bone from one site to another suggest that exercise and high dietary calcium may preferentially alter bone density at different skeletal sites.
Greater influence of central distribution of adipose tissue on incidence of non-insulin-dependent diabetes in women than men, Many studies have shown an increased prevalence of non-insulin-dependent diabetes (NIDDM) in individuals with an unfavorable body fat distribution. but there are still relatively few prospective studies on this topic. We present data on the 8-y incidence of NIDDM in Mexican-American men and women according to their degree of central adiposity. measured by the ratio of subscapular to triceps skinfold thicknesses. Subjects were initially enrolled in the San Antonio Heart Study. a population-based study of diabetes in Mexican Americans and non-Hispanic whites. Sixteen of 254 initially nondiabetic men and 27 of 366 initially nondiabetic women developed diabetes. Central adiposity was more strongly associated with diabetes incidence in women than in men. After adjustment for overall adiposity (measured by body mass index). women in the highest and in the middle tertile of centrality had a significantly higher risk of diabetes than did women in the lowest tertile [odds ratio (OR) = 10.70. P = 0.008. highest vs lowest tertile. and OR = 8.55. P = 0.032. middle vs lowest tertile; for men OR = 3.70 and OR = 1.38. respectively].
Dietary restriction on serum thyroid hormone levels, To determine the long term effects of a protein sparing fast on serum thyroid hormone levels. the authors studied 38 obese patients ingesting a diet of 320 kcal for up to 13 weeks. The high baseline serum triiodothyronine (T3) levels decreased significantly by the first week. further decreased by the third week. and this lower level persisted for the duration of the fast until realimentation. Serum free T3 index followed the same general pattern as did serum T3 levels. Serum reverse T3 increased significantly by the first week. but by week three. the reverse T3 level had begun to fall. although still significantly increased above baseline. By week seven. reverse T3 had decreased to almost baseline and remained not significantly changed from the baseline to 13 weeks. Serum thyroxine (T4) increased significantly by the first week in all patients. but by the third week had returned to baseline levels which persisted to 13 weeks. The free T4 index and free T4 concentrations showed the same increment at week one and then returned to baseline levels. There were no significant changes in serum thyroxine-binding globulin (TBG) or thyroid-stimulating hormone (TSH) concentrations. The changes in serum T3 and reverse T3 levels are attributable to alterations in peripheral 5'-monodeiodination of T4 and reverse T3 induced by the protein sparing fast.
Human gammaglobulin use in the treatment of severe thrombocytopenia associated with sarcoidosis, Thrombocytopenia associated with sarcoidosis is an uncommon. yet potentially lethal. complication. The traditional treatment for the thrombocytopenia has been steroid therapy followed by splenectomy if steroid therapy fails. The use of human immunoglobulin as a potential therapy in a patient afflicted with thrombocytopenia and sarcoidosis is reviewed.
Human gene therapy, Recent advances in molecular genetics have made possible the use of retroviral "vectors" to transfer cloned human genes into somatic cells. With this new technology. the genetic defect underlying many recessive inherited disorders can probably be corrected by inserting a normal gene into the patient's hematopoietic stem cells. This article reviews the design and safety of the viral vectors and the results of in vivo studies in mice and large animals that have led to the first human trials. Other target cells for gene transfer. such as endothelial cells. fibroblasts. keratinocytes. and hepatocytes. are also discussed. The use of recombinant retroviruses for gene transfer in vivo is still a new area of research. but the feasibility of "gene therapy" for genetic disorders is rapidly gaining medical and scientific acceptance.
Blood-cell velocity in the nailfold capillaries of patients with normal-tension and high-tension glaucoma, We compared the capillary blood-cell velocity in the fingertips of 30 patients with high-tension glaucoma. 30 patients with normal-tension glaucoma. and 30 control subjects by nailfold capillaroscopy. There were no measurable differences in the morphologic findings. The blood-flow velocity. however. was reduced significantly in the patients with normal-tension glaucoma compared with the control subjects (P less than .05). This difference was especially pronounced after cold provocation (P less than .0005). After cooling. 25 of 30 patients with normal-tension glaucoma had a blood standstill of 12 seconds or more. whereas only three of 30 control subjects and four of 30 patients with high-tension glaucoma had a measurable blood standstill.
Recognition and removal of the posterior cortical vitreous during vitreoretinal surgery for impending macular hole, Vitreoretinal surgery for impending macular hole includes recognition and removal of the posterior cortical vitreous. Previously described surgical techniques for removal of cortical vitreous used either rigid instruments (a tapered extrusion needle or a barbed microvitreoretinal blade) or a short fenestrated soft-tipped suction needle. We used a technique with the cannulated extrusion needle that detects the presence of the posterior cortical vitreous and facilitates safe removal of this layer from the retina. Although this technique is most useful when performing vitrectomy for impending macular hole. it may also be used during vitrectomy for other conditions with uncertain detachment of the posterior cortical vitreous.
Isoflurane anesthesia and myocardial ischemia: comparative risk versus sufentanil anesthesia in patients undergoing coronary artery bypass graft surgery. The SPI (Study of Perioperative Ischemia) Research Group, Whether isoflurane has the potential to produce coronary artery steal and associated myocardial ischemia is still controversial. Previous studies addressing this issue in humans did not purposefully control hemodynamics or use continuous measures of myocardial ischemia. The authors used transesophageal echocardiography (TEE) and continuous Holter electrocardiography (ECG) to study the relative risk of myocardial ischemia during isoflurane or sufentanil anesthesia under strict control of hemodynamics in 186 high-risk patients undergoing elective coronary artery bypass graft (CABG) surgery. Overall. hemodynamics were well controlled (increased heart rate = 9.8%; increased systolic blood pressure = 7.1%; decreased systolic blood pressure = 10.8% of total prebypass time compared with preoperative baseline values). with no difference between the two anesthetics. In the 162 patients with interpretable TEE recordings. moderate to severe TEE ischemic episodes (grade change greater than or equal to 2) developed in 33 (21%) during the prebypass period. with no difference between isoflurane (12 of 56 = 21%) and sufentanil (21 of 106 = 20%) (P = 0.97). The duration and severity of TEE episodes were not significantly different between the two groups. No correlation was observed between TEE ischemic episodes and isoflurane concentrations (range 0.47-1.75%). In the 181 patients with interpretable ECG recordings. ECG evidence of ischemia developed in 34 (19%) during the prebypass period. with no difference between isoflurane (12 of 59 = 20%) and sufentanil (22 of 122 = 18%) (P = 0.87). The duration and severity of electrocardiographic ischemic episodes were also similar in patients receiving either isoflurane or sufentanil. Four of the 62 patients (6%) who received isoflurane had an adverse cardiac outcome versus 15 of 124 patients (12%) who received sufentanil (P = 0.34). The authors' findings demonstrate that. when hemodynamics are controlled. the incidence of myocardial ischemia (TEE or ECG) during isoflurane and sufentanil anesthesia is similar.
Is the pressure rate quotient a predictor or indicator of myocardial ischemia as measured by ST-segment changes in patients undergoing coronary artery bypass surgery, Perioperative myocardial ischemia is associated with an increased risk of perioperative myocardial infarction (PMI). Several attempts have been made to define intraoperative hemodynamic predictors of myocardial ischemia. In a canine preparation with coronary stenosis. a pressure rate quotient (PRQ = mean arterial pressure/heart rate) less than one (PRQ less than 1) indicated subendocardial myocardial ischemia. The authors tested this hypothesis in patients undergoing elective coronary artery bypass graft operation (CABG). using electrocardiogram (ECG) ST-segment changes (leads II/V5) to diagnose myocardial ischemia. Sixty (n = 60) patients having CABG surgery were prospectively studied before initiation of cardiopulmonary bypass. Calibrated ECG leads II and V5 (diagnostic mode) were monitored continuously and recorded with the use of a Hewlett-Packard computer ST-segment analyzer. In addition. arterial and pulmonary artery pressures were monitored. Ischemia was defined as new-onset ST deviation (greater than or equal to 1 mm from the baseline ECG). ECG and hemodynamic data were stored at 2-min intervals for subsequent computer analysis. Serial creatinine phosphokinase (CPK) X MB (%) determinations and 12-lead ECGs were collected for the initial 3 postoperative days. Of the 3.463 intervals (2 min) available for study. 3.322 (96%) were satisfactorily recorded for 60 patients. Ischemia occurred during 65 intervals in 9 patients (9 of 60). of which only 34% (22 of 65) were associated with a PRQ less than 1 (P less than 0.01). In contrast. there were 466 intervals during which PRQ was less than 1. but without ECG evidence of ischemia.
The EEG as a monitor of midazolam amnesia: changes in power and topography as a function of amnesic state, In order to identify EEG parameters that might be specific for identifying amnesia during midazolam infusion. we examined changes in the EEG power spectrum associated with a period of amnesia. determined by inability to recall a sequence of numbers and objects presented verbally. after intravenous midazolam 0.07 mg/kg in ten normal volunteers. Measurements were taken at baseline. during infusion immediately before and after the onset of amnesia. immediately at end of infusion. and 0.5 and 1.5 h after infusion. All subjects had onset of amnesia during infusion. were completely amnesic by the end of infusion. partially amnesic 0.5 h after infusion. and had complete recall by 1.5 h after infusion. The EEG beta power increased and alpha power decreased during amnesic periods. The beta 1/alpha power ratio was the parameter most specific for amnesia. From a baseline value of 0.20 +/- 0.05 (standard error of the mean [SEM]). it increased to 0.96 +/- 0.26 at the end of infusion and decreased to 0.61 +/- 0.15 0.5 h after infusion. By 1.5 h after infusion. all EEG parameters had returned to baseline values. Beta power changes associated with midazolam amnesia were most pronounced in the Fz and Cz lead positions. and alpha power changes were most pronounced in the Oz position. We conclude that 1) EEG power values. particularly the beta 1/alpha ratio. can identify periods of amnesia after midazolam infusion; 2) specific EEG changes and the presence of amnesia vary with the probable serum concentration of midazolam; and 3) the characteristic EEG pattern during partial or complete amnesia varies as one moves across the cerebral cortex.
Naloxone-sensitive, pregnancy-induced changes in behavioral responses to colorectal distention: pregnancy-induced analgesia to visceral stimulation, This study examined the feasibility of using colorectal distention as a noxious visceral stimulus in rat pregnancy-induced analgesia studies as well as the influence of naloxone on the pregnancy-induced changes in the behavioral response to a noxious visceral stimulus. In the first part of the study. we compared the effects of pregnancy on several forms of noxious stimulation (colorectal distention. hypertonic saline induced writhing. tail flick. and hot plate). After determination of prepregnant baseline values. one group of rats (n = 35) was mated and retested on days 7 and 21 of gestation and 1. 3. 5. 7. and 14 days after parturition. After baseline determinations on day 21 and postpartum day 1. the animals received a subcutaneous injection of naloxone 1.0 mg/kg and were retested. A nonpregnant control group of animals (n = 7) was tested in the same manner. On day 21 of gestation and postpartum days 1 and 3. significant changes (higher threshold or longer latency to response) were observed after all but the writhing test. High-dose naloxone (1.0 mg/kg) significantly reduced the increases observed on day 21 and post-partum day 1. Nonpregnant rats demonstrated no significant change on any test day. The second part of the study evaluated a possible influence of low-dose naloxone on pregnancy-induced analgesia to visceral stimulation (colorectal distention) in another group of pregnant rats (n = 44). The significant increase in threshold on day 21 of gestation was not changed by intravenous (i.v.) naloxone 1.0. 2.3. or 3.0 micrograms/kg. whereas 5.0 and 20.0 micrograms/kg naloxone significantly decreased the observed pregnancy-induced analgesia.
Mental disorders among alcoholics. Relationship to age of onset and cerebrospinal fluid neuropeptides, Eighty-one percent of 339 alcoholics participating in a research program were found to have associated mental disorders. Alcoholics with onset of heavy drinking before 20 years of age had significantly more antisocial personality traits. drug abuse. bipolar disorder. panic disorder. suicide attempts. and paternal alcoholism than alcoholics with onset after age 20 years. Alcoholics with onset before and after 20 years of age also differed significantly from each other for cerebrospinal fluid concentrations of diazepam-binding inhibitor and somatostatin. These results support the notion that age of onset may delineate subgroups of alcoholics with significant clinical and neurochemical differences.
Depression among alcoholics. Relationship to clinical and cerebrospinal fluid variables, Although depression is common among alcoholics. its determinants are poorly understood. Among 339 alcoholics. 111 (33%) had a history of major depression. Depressed. compared with never-depressed alcoholics. had a higher daily alcohol intake. more lifetime diagnoses of other anxiety and affective disorders and drug abuse. more had attempted suicide. and more reported alcoholism in both parents. Depressed alcoholics also had significantly lower cerebrospinal fluid levels of the dopamine metabolite homovanillic acid and of gamma-aminobutyric acid. Among subgroups of depressed alcoholics. secondary compared with primary depressives were more often divorced. of lower social status. with an earlier onset of alcoholism. and higher Michigan Alcohol Screening Test scores. Secondary depressives also had significantly lower cerebrospinal fluid concentrations of homovanillic acid than never depressed alcoholics. These results suggest that certain psychosocial variables. alcohol consumption. and neurochemical variables may be specifically associated with depression in alcoholics.
Personality and cerebrospinal fluid monoamine metabolites in alcoholics and controls, Alcoholics as a group have been consistently reported to show differences from controls on various personality inventories. Moreover. neurobiologic substrates have been postulated to underlie personality dimensions. Therefore. we compared alcoholics with controls on measures of personality and investigated relationships between measures of personality and cerebrospinal fluid monoamine metabolite concentrations. The alcoholics were significantly different from controls on many personality measurements. There were significant. negative correlations between interview-derived lifetime aggression scores and cerebrospinal fluid concentrations of both the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid. However. there were no significant correlations between any cerebrospinal fluid monoamine metabolite concentrations and scores on personality inventories.
Characterization of DSM-III-R criteria for uncomplicated alcohol withdrawal provides an empirical basis for DSM-IV, The DSM-III-R criteria for uncomplicated alcohol withdrawal require the presence of coarse tremor of the hands. tongue. or eyelids plus one of a number of other clinical features. We examined the validity and other characteristics of these items in 137 patients in pure alcohol withdrawal using the reliable and valid Clinical Institute Withdrawal Assessment for Alcohol. The DSM-III-R items of hand tremor amplitude. nausea or vomiting. headache. transient hallucinations. autonomic hyperactivity (increased pulse or sweating). and anxiety correlated significantly with total score and significantly indicated clinical severity. Addition of an "agitation" item improved the correlation. The diagnostic accuracy is greater than 95% if any two or more items are present. The number of positive items. of which tremor can be one. to grade clinical severity shows that a score of 2 indicates "very mild"; 3. "mild"; 4. "moderate"; and 5. "severe.". We propose that an Alcohol Withdrawal Diagnostic Inventory and a DSM-III-R-compatible brief Clinical Institute Withdrawal Assessment for Alcohol are useful for clinical research. where graded symptom characterization is needed. Our data may be helpful in the development of criteria for DSM-IV.
Carbamazepine treatment in patients discontinuing long-term benzodiazepine therapy. Effects on withdrawal severity and outcome, Forty patients with a history of difficulty discontinuing long-term. daily benzodiazepine therapy were randomly assigned. under double-blind conditions. to treatment with carbamazepine (200 to 800 mg/d) or placebo. A gradual taper (25% per week reduction) off benzodiazepine therapy was then attempted. Five weeks after taper. significantly more patients who had received carbamazepine than placebo remained benzodiazepine free. this despite the fact that no statistically significant differences in withdrawal severity could be demonstrated. Patients receiving carbamazepine reported a larger reduction in withdrawal severity than patients receiving placebo. but only at a trend level. and only on the daily patient-rated withdrawal checklist. Eleven patients (28%) required antidepressant therapy for depression or panic when assessed at 12-weeks follow-up. The results of this pilot investigation suggest that carbamazepine might have promise as an adjunctive drug therapy for the benzodiazepine withdrawal syndrome. particularly in patients receiving benzodiazepines in daily dosages of 20 mg/d or greater of diazepam equivalents.
Human T-cell leukemia/lymphoma viruses. Life cycle, pathogenicity, epidemiology, and diagnosis, Human T-cell leukemia/lymphoma virus type I (HTLV-I) was discovered in 1980. and it subsequently was found to be the cause of adult T-cell leukemia/lymphoma. A progressive neurologic disease known as tropical spastic paraparesis. or HTLV-I-associated myelopathy. has also been linked to infection with HTLV-I. A related virus. HTLV type II (HTLV-II). has been isolated from patients with hairy-cell leukemia. but it has not been proved to be the cause of any disease. In late 1988. US blood banks began screening all blood donations for antibodies to HTLV-I/II. This program has resulted in the identification of many unexpectedly seropositive blood donors and provided much information about the prevalence of HTLV-I/II in the United States. In this article. I review the replication of these agents. as well as their pathogenesis. diagnosis. and mechanisms of spread.
Culture vs direct antigen assays for detection of microbial pathogens from lower respiratory tract specimens suspected of containing the respiratory syncytial virus, Following the introduction of effective antiviral chemotherapy. rapid antigen assays have been utilized increasingly. instead of cell cultures. for detection of the respiratory syncytial virus from lower respiratory tract specimens. Because antigen assays. unlike cell culture. cannot amplify low levels of the virus to a detectable level. assay sensitivity is especially dependent on high-quality specimens. In addition. the assays are unable to detect other viruses or bacteria with which the patient may be infected. This review summarizes results from clinical studies of the performance of cell cultures and the more commonly used antigen assays. describes factors that may lead to false-positive or false-negative test results. and makes recommendations for the selection of procedures for the reliable detection of microbial pathogens from patients suspected of being infected with respiratory syncytial virus.
Spurious serologic test results in patients receiving infusions of intravenous immune gammaglobulin, Intravenous immune gammaglobulin (IVIgG) has a definite role in the modern armamentarium of therapies for immunocompromised patients. Intravenous IgG is manufactured from the plasma of a large number of donors and contains antibodies against numerous infectious agents. Patients who receive infusions of IVIgG may test false-positive for a variety of viral. bacterial. and other infectious diseases when serologic determinations are performed on their blood samples. It is important that laboratories performing serologic testing be aware that patients have been infused with IVIgG. so that spurious laboratory results can be identified. Serologic testing on implicated lots of IVIgG and on the patient's pretreatment sample may aid in correctly identifying a spurious serologic result due to therapy with IVIgG.
Bone marrow and peripheral blood findings in patients with extreme thrombocytosis. A report of 63 cases, Sixty-three bone marrow (BM) and peripheral blood specimens from patients with platelet counts of 1000 x 10(9)/L or greater were examined in an attempt to determine if any BM or peripheral blood findings could be used reliably to distinguish primary thrombocythemia from other myeloproliferative disorders and extreme examples of reactive thrombocytosis. Our results indicated that the BM findings in primary thrombocythemia were quite similar to those in polycythemia vera and chronic granulocytic leukemia with associated extreme thrombocytosis. However. statistically significant differences between the BM findings in myeloproliferative disorders and extreme reactive thrombocytosis were found in the numbers of megakaryocytes. presence or absence of megakaryocyte clusters. stainable iron. cellularity. and reticulin content. We concluded that BM examination is a useful procedure as an aid in determining the cause of extreme thrombocytosis.
S100 protein-positive sustentacular cells in malignant and locally aggressive adrenal pheochromocytomas, The absence or presence of S100-positive sustentacular cells has been previously shown to be correlated with benign and malignant pheochromocytomas and paragangliomas. We evaluated a total of 17 malignant and recurrent or locally aggressive adrenal pheochromocytomas for their quantity of sustentacular cells. An absence of sustentacular cells was demonstrated in the majority of malignant cases. while the locally aggressive or recurrent group usually contained an abundance of these cells. However. in one malignant case a constant moderate number of sustentacular cells in the primary site and in two sequential metastases was found. We conclude that the absence of sustentacular cells in pheochromocytomas may indicate a lesion with a greater potential for metastasis and that sustentacular cells. when they are present in a malignant pheochromocytoma. are an integral part of the tumor.
Glycoprotein Ib bioassays. Activity levels in Bernard-Soulier syndrome and in stored blood bank platelets, Glycoprotein Ib (GP-Ib) is a major platelet receptor protein concerned with von Willebrand-factor binding. platelet agglutination. and platelet adhesion. and it is required for normal hemostasis. By the use of botrocetin (venom coagglutinin). both quantitative and semiquantitative assays for GP-Ib activity were developed. The latter assay uses limiting dilutions of botrocetin as a measure of GP-Ib activity. Platelets. stored up to 23 days under blood bank conditions. were assayed by the limiting dilution test. Values of GP-Ib were progressively diminished after 9 to 10 days of storage. reaching levels of less than 10% at 23 days. Platelets from a subject with Bernard-Soulier syndrome showed less than 10% GP-Ib activity. These assays appear to be a specific measure of functional GP-Ib activity. and. when combined with GP-Ib antigen measurement by other methods. they provide a means for further characterizing GP-Ib abnormalities.
Cytomegalovirus endomyocarditis in a transplanted heart. A case report with in situ hybridization, A 64-year-old man underwent cardiac transplantation for long-standing severe dilated cardiomyopathy. Postoperative complications included primary cytomegalovirus (CMV) infection with several episodes of moderate acute rejection and severe pneumonia. Six months after transplantation. an endomyocardial biopsy specimen revealed focal necrotizing myocarditis with intranuclear inclusions consistent with CMV. The patient subsequently developed fulminant pneumonia and died 7 months after transplantation. Postmortem examination revealed that the cause of death was acute necrotizing bronchopneumonia due to Staphylococcus aureus. with underlying CMV pneumonitis. The transplanted heart had left ventricular hypertrophy with multiple organizing myocardial infarcts. moderate coronary atherosclerosis. and organizing thrombi of the left atrium. Characteristic inclusions of CMV were identified. predominantly within endothelial cells. in the left coronary artery. left ventricular endocardium. and myocardium. With in situ hybridization. the presence of CMV was verified in the inclusions. as well as in many fibroblasts without inclusions. In situ hybridization is warranted in myocardial biopsy specimens when suspicious inclusions or infiltrates are present. to confirm CMV infection. so that appropriate therapy can be initiated.
Differential diagnosis of adult hemoglobin A, F, and S conditions. A case of G gamma-beta(+)-hereditary persistence of fetal hemoglobin, Hemoglobin (Hb) S/beta(+)-thalassemia is a hemoglobinopathy of variable but potentially severe clinical course. The condition is usually confirmed by the presence of a microcytic anemia and elevated levels of Hbs S. F. and A2 by electrophoresis. However. other less common disorders of Hb structure and synthesis may exhibit laboratory findings that mimic Hb S/beta(+)-thalassemia but have a more favorable prognosis. We present a case occurring in a man with clinical and laboratory features that were suggestive of Hb S/beta(+)-thalassemia but with normocythemia. Although nonmicrocytic variants of beta(+)-thalassemia. including concomitant nutritional deficiencies. were considered. high-pressure liquid chromatography revealed nearly all of the patient's fetal Hb to contain only G gamma chains. This pattern is most consistent with the rate but clinically benign condition of Hb S/G gamma-beta(+)-hereditary persistence of fetal Hb. a nondeletional type of hereditary persistence of fetal Hb. We discuss a diagnostic approach to adult Hb A. F. and S conditions. including thalassemias and thalassemia-like syndromes.
A new oral lavage solution vs cathartics and enema method for preoperative colonic cleansing, Sulfate free-electrolyte lavage solution is a new osmotically balanced electrolyte gut lavage solution for colon surgery that has been formulated for improved taste and reduced water and electrolyte changes. Sixty patients were prospectively randomized to receive a 1-day preparation with sulfate free-electrolyte lavage solution or a 3-day preparation using a clear liquid diet. cathartics. and enemas. The patient groups were similar in age. race. male-female ratio. and the types of colonic resections performed. Colonic cleansing was better with sulfate free-electrolyte lavage solution (100% vs 63% "good" to "excellent" cleansing). Patient tolerance evaluated by a questionnaire showed more overall discomfort with sulfate free-electrolyte lavage solution but no difference between the preparations in individual symptoms of fullness. cramping. nausea. or vomiting. One patient developed a low level of serum potassium after a cathartic and enema preparation. while there were no complications with sulfate free-electrolyte lavage solution. Patient taste questionnaires showed a slight preference for sulfate free-electrolyte lavage solution (53%) over a polyethylene glycol electrolyte lavage solution (47%). This study confirms that sulfate free-electrolyte lavage solution is a safe and effective method of preoperative colonic cleansing.
Biliary surgery after cardiac transplantation, Many patients have undergone successful cardiac transplantation. These patients are at risk of developing the same surgical diseases as the general population. The side effects of immunotherapy may mandate intervention at a different point in the natural history of these processes. From February 1984 through December 1989. 24 patients underwent an operative biliary tract procedure following cardiac transplantation. Seventeen patients underwent elective cholecystectomy with intraoperative cholangiography. The mean hospital stay was 5.4 days. and there was no morbidity or mortality. Seven patients underwent urgent procedures; four of them developed severe complications and three died as a result of their biliary tract disease. Two patients in the urgent group had previously exhibited symptoms of biliary tract disease. and five were previously asymptomatic. There was no significant difference in time from transplantation to biliary procedure between the elective group (mean. 17 months; range. 3 weeks to 47 months) and the urgent group (mean. 18 months; range. 3 weeks to 44 months). Patients who undergo cardiac transplantation should be screened for cholelithiasis. The presence of symptoms should not be required before recommending operative intervention.
Level of axillary involvement by lymph node metastases from breast cancer is not an independent predictor of survival, We examined the relationship of axillary level of lymph node metastases from clinical stage I and II breast cancer to overall survival and disease-free survival rates in 135 patients who underwent complete axillary lymph node dissection to determine if anatomic level of axillary involvement (I vs II vs III) is an independent prognostic factor. All patients underwent either modified radical mastectomy or lumpectomy with axillary dissection and whole breast radiotherapy for breast cancer. Median follow-up was 6.9 years. We found no difference in overall survival or disease-free survival between patients whose highest or only level of axillary involvement was level I compared with patients whose highest or only level was II. Although patients whose highest level of nodal involvement was III had significantly worse overall survival and disease-free survival rates than patients whose highest nodal involvement was I or II. when patients were stratified by the total number of positive nodes (one to three vs four or more). there was no difference in overall survival or disease-free survival rates between levels I. II. and III. These findings indicate that the level of axillary involvement for stage II breast cancer is not of independent prognostic significance.
The effect of a trauma system on the outcome of patients with pancreatic trauma, Patients suffering pancreatic trauma before and after the creation of a regional trauma center were analyzed. Between 1975 and 1982. before the trauma system was established. 80 patients (10 per year) with pancreatic injury were treated. From 1984 to 1987 (after trauma system implementation). 58 patients (19 per year) with pancreatic injury were treated. There were no significant differences in demographics. mechanisms of injury. types of pancreatic wound. or associated injuries. Sixteen (20%) patients with pancreatic injury during the study period died before the trauma center was established. Of these. 13 (81%) died of hemorrhage. In contrast. five (9%) patients with pancreatic injury who were treated after the trauma center was operational died. Only one death was due to hemorrhage. By relative risk. a patient was 2.67 times more likely to die and 17 times more likely to die of hemorrhage before the presence of the trauma center than after (P less than .03). In this study of a patient population suffering severe intra-abdominal injuries. Organ Injury Outcome Analysis demonstrates that development of a trauma system significantly improves outcome.
Tumor necrosis factor and interleukin 1 appearance in experimental gram-negative septic shock. The effects of plasma exchange with albumin and plasma infusion, To study the effect of plasma removal vs plasma administration on the appearance of tumor necrosis factor (TNF) and interleukin 1 in septic shock. 24 anesthetized piglets were inoculated with live Escherichia coli. Plasma exchange with albumin was performed in one group. Fresh-frozen plasma was administered to a second group. A third group served as nontreated controls. Following plasma exchange. a reduction in both TNF and interleukin 1 levels occurred. whereas plasma infusion was followed by a decrease in TNF levels only. No significant differences were observed between the two treated groups with respect to survival or cardiovascular performance. with both being significantly enhanced compared with the controls. High levels of TNF and interleukin 1 correlated with depressed cardiovascular performance in the early phase of the shock. Our results confirm the important role of TNF and interleukin 1 as early mediators of septic shock. However. the benefit of reducing cytokine activity in later stages of septicemia seems to be dubious.
Avoiding reoperation for indeterminate thyroid nodules identified as malignant after surgery, Thyroid nodules that are indeterminate as carcinoma by needle biopsy before surgery and by study of frozen sections at the time of surgery are occasionally identified to be malignant in later studies. If only a lobectomy has been performed. the advisability of reoperation to remove the remaining thyroid tissue to facilitate radioactive iodine therapy may cause concern. To obviate this difficulty as well as to reduce the occurrence of nodules later in a preserved contralateral thyroid lobe and to provide additional thyroid tissue for study. contralateral subtotal or near total lobectomy has been performed for indeterminate thyroid nodules. The small remnant of remaining thyroid tissue can later be ablated by radioactive iodine if desired. Of 37 patients with indeterminate thyroid nodules. none required reoperation. although the diagnosis of carcinoma was established after surgery for eight patients. three of whom were treated with radioactive iodine.
Cystic duct cholangiography during laparoscopic cholecystectomy, At present. there is no consensus regarding the routine use of intraoperative cholangiography during cholecystectomy. We describe a reliable technique for performing cystic duct cholangiography during laparoscopic cholecystectomy. Using this technique. we were able to cannulate the cystic duct in 97% of patients. completely visualize the biliary tree and duodenum in 93% of patients. and identify unsuspected choledocholithiasis in 3% of patients. Treatment options for the management of choledocholithiasis demonstrated by cholangiograms during laparoscopic cholecystectomy include conversion to an open cholecystectomy and common duct exploration. or endoscopic sphincterotomy and common duct stone extraction following laparoscopic cholecystectomy.
Indications for and the technique of local resection of tumors of the papilla of Vater, Local resection of tumors of the papilla of Vater was performed in six cases (three benign adenomas and three adenocarcinomas). Pathology was suggested in all cases by endoscopic biopsy and confirmed by operative excision. A method of excision of the tumor and reconstruction of the pancreaticobiliary apparatus was used that eliminated all gross and microscopic disease. Only one of the patients with benign disease (familial polyposis) suffered from local recurrence. All three patients with malignant tumors developed local recurrences within 2 years of resection. Local resection seems to be a viable alternative to Whipple's resection in patients with benign tumors. In malignant cases. local resection should be considered only a palliative procedure and confined to elderly patients with severe concomitant disease and patients in whom a more radical procedure would incur an undue surgical risk.
Access to health care. One neurologist's perspective, Millions of residents of the United States have difficulty obtaining health care. Barriers impeding access to care include poverty. physical unavailability of health care services. absence of health insurance. and physicians unwilling to care for uninsured patients. Many patients do not successfully use health services because of educational. cultural. and language barriers. A major access barrier is lack of health insurance. Over 30 million people in the United States have none. the so-called medically indigent. Among them are over 3 million people with neurologic disorders. They have additional barriers to overcome because often they cannot work. cannot drive. have difficulty using public transportation. and have major cognitive and communication impairments. Medical and governmental bodies are debating solutions to the health care access crisis. Physicians should actively participate in this national debate. Neurologists should address the special needs of patients with neurological disorders.
Regional cerebral blood flow in developmental stutterers, Stuttering is a poorly understood communication disorder with a 1% global prevalence. Recently. there has been a resurgence of interest in a neurogenic origin for the disorder. although no research has established clear neurological differences between "developmental" (stuttering onset in childhood) stutterers and nonstutterers. We have used xenon 133 single-photon emission computed tomography to study regional cerebral blood flow (rCBF) in 20 stutterers. Analysis revealed global. absolute flow reductions. Relative flow asymmetries (left less than right) were identified in three hemispheric regions: anterior cingulate and superior and middle temporal gyri. Milder changes were found in the left inferior frontal gyrus. Stutterers had rCBF values below median for either anterior cingulate or middle temporal gyri. With one exception. severe stutterers had rCBF values below median for the anterior cingulate gyrus. All stutterers with rCBF values above median in the cingulate gyrus had rCBF values below median in the middle temporal gyrus. and severity of their disorder was either mild or moderate. Our findings suggest that stuttering is a neurogenic disorder involving recognized cortical regions of speech-motor control.
Familial inclusion body myositis among Kurdish-Iranian Jews, We report two cases of adult-onset. slowly progressive limb-girdle muscle weakness with a remarkable sparing of quadriceps muscles that developed in patients from different families of Iranian-Kurdish-Jewish origin. Each patient had a similarly affected sibling. The findings by means of muscle biopsies showed abnormalities typical of inclusion body myositis. including abundant lined vacuoles and characteristic cytoplasmic inclusions of 15- to 18-nm filaments. Remarkably. many vacuolated muscle fibers showed immunoreactivity to neural cell adhesion molecule. a fetal muscle antigen. The common origin of these patients from an isolated ethnic group with frequent consanguinity and the familial incidence is indicative of a genetic causation or predisposition. probably with an autosomal recessive inheritance. This familial myopathy is one of several clinical syndromes that share the typical pathological findings of inclusion body myositis. The pathogenic relationship between these different familial forms and the more common sporadic form of inclusion body myositis is not known.
Altered cutaneous sensation in trigeminal neuralgia, Noninvasive quantitative somatosensory tests were used to measure sensory perception thresholds on the faces of 26 patients with idiopathic trigeminal neuralgia. The affected divisions were determined by the presence of trigger zones. Elevations of thresholds of sensations subserved by both large- and small-diameter fibers were found both in the affected and in the unaffected adjacent divisions when compared with the healthy side. The findings are interpreted as further evidence of combined peripheral and central pathologic conditions in idiopathic trigeminal neuralgia.
Clinical issues relating to the diagnosis of mild dementia in a British community survey, Many epidemiologists base their diagnoses of dementia on scores on brief cognitive tests. but the border between normal aging and mild dementia is so poorly understood that simple demarcations cannot adequately encapsulate the wealth of clinical material that needs to be taken into account in assigning diagnostic labels. Data from a British study of the prevalence and natural history of dementia. in which diagnoses of dementia were made by clinicians using a new. standardized interview schedule. are presented to demonstrate the effects of physical disability. psychiatric illness. and other factors on memory impairment and performance in everyday life. Our purpose is not to insist that clinicians are always correct but rather to highlight the complexities involved and the need for investigators to be more open about the way in which they distinguish between physical. psychiatric. and cognitive infirmities.
Allochiria vs allesthesia. Is there a misperception, Allochiria is the mislocation of sensory stimuli to the corresponding opposite half of the body or space. Obersteiner (1882) introduced the term allochiria (Greek allos = other + chiria = hand). and more than 20 authors employed it in this context over the next 25 years. Stewart (1894) described a related phenomenon in which stimuli are displaced to a different point on the same extremity. He noted that the displacements were different than allochiria and coined the term allachaesthesia (ie. allesthesia) (Greek allache = elsewhere + aisthesis = perception). Despite this historical background. Jones (1907) redefined both terms in an attempt to increase diagnostic specificity and attributed allochiria to hysteria. Jones' reinterpretation does not appear to be justified historically. etymologically. or scientifically and has resulted in contradictory definitions of allochiria and allesthesia in present-day medical dictionaries and neurologic textbooks. We advocate a return to usage consistent with the original descriptions and word derivations.
Acute stimulation of renin secretion changes the multiple form profile of active plasma renin, Active renin is composed of multiple forms with variable isoelectric points. In this study. the relative proportions of five major active renin forms in human peripheral venous plasma were compared before and 2 h after stimulation of renin secretion with both converting enzyme inhibition (quinapril) and upright posture in five patients with essential hypertension. The five major active renin forms were separated by shallow gradient isoelectric focusing and quantitated by radioimmunoassay of generated angiotensin I. Plasma renin activity increased from 1.2 to 5.1 ng AI/mL/h (P less than .05). This was accompanied by a significant increase in the proportions of the two most basic renin forms and a significant decrease in the proportion of the most acidic form in venous plasma. Although the mechanism cannot be determined from this study. the altered renin form profile observed could have resulted from preferential renal secretion and/or altered hepatic extraction of the more basic forms. An altered renin form profile in response to acute stimulation has important physiologic implications. Since the relatively basic renin forms are preferentially degraded they possess shorter half-lives. Additionally. the multiple forms of active renin may be functionally heterogenous. Thus. acute stimulation of renin secretion may result in circulating renin with a shorter duration of action and different functional effects than renin released under steady state conditions.
Intracellular free magnesium and high energy phosphates in the perfused normotensive and spontaneously hypertensive rat heart. A 31P NMR study, We have employed 31P nuclear magnetic resonance (NMR) spectroscopy to examine the relationship between cytosolic free Mg2+ ([Mg2+]in). intracellular pH. high energy phosphates. and genetic hypertension using the Wistar-Kyoto rat (WKY) as a control and the spontaneously hypertensive rat (SHR) as a model for essential hypertension. The mean systolic blood pressures (measured using the tail cuff method) of control and hypertensive rats (aged 7 to 12 weeks) were 113 +/- 4 mm Hg (mean +/- 2 SE. n = 14) and 162 +/- 5 mm Hg (mean +/- 2 SE. n = 17). respectively. Intracellular free Mg2+ levels were significantly depleted in the isolated Langendorff perfused hypertensive rat hearts (452 +/- 39 mumol/L. mean +/- 2 SE. n = 17) compared to control hearts (756 +/- 52 mumol/L. n = 14); however. intracellular pH did not differ in the SHR hearts (7.02 +/- 0.03. mean +/- 2 SE. n = 7) compared with controls (7.03 +/- 0.03. n = 7). Although we could not demonstrate a statistically significant difference in the levels of P-creatine or ATP. intracellular Pi was two-fold higher (5.71 +/- 2.28 mmol/L v 2.92 +/- 0.66 mmol/L. n = 4) and the phosphorylation potential. [MgATP]/[MgADP][Pi]. was correspondingly lower (3.0 X 10(4) +/- 1.6 x 10(4) v 8.3 X 10(4) +/- 1.4 X 10(4) (mol/L)-1. n = 4) in SHR compared to WKY hearts. These data demonstrate free magnesium depletion in heart muscle and indicate an alteration in cardiac bioenergetics in essential hypertension.
Suppressive effect of sulfate on the development of hypertension in DOCA-salt hypertensive rats, The purpose of this study was to examine the effect of the sulfate ion on blood pressure in DOCA-salt hypertension. which involves increased sympathetic nervous activity. Male Wistar rats were divided into four groups. and received one of the following drinking solutions: distilled water [control]. 171 mmol/L sodium chloride [NaCl group]. 171 mmol/L sodium chloride plus 12 mmol/L magnesium sulfate [S(+) group]. or 171 mmol/L sodium chloride plus 12 mmol/L magnesium chloride [S(-) group]. In the S(+) group. the elevation of systolic blood pressure (SBP; mm Hg) was significantly attenuated (168 +/- 17 v 213 +/- 26. P less than .005) and intraerythrocyte calcium concentration (R-Ca; mumol/L cells) was significantly lower (11.5 +/- 3.0 v 17.4 +/- 6.5. P less than .05) than in the S(-) group. The cardiac norepinephrine content (H-NE; ng/100 g tissue) of the S(+) group was significantly lower than that of the S(-) group. SBP was correlated negatively with H-NE (r = -0.70. P less than .001) and positively with R-Ca (r = 0.45. P less than .005). R-Ca was negatively correlated with H-NE (r = -0.36. P less than .05). These results suggest that the replacement of chloride with sulfate ion suppresses the development of hypertension in DOCA-salt rats at least in part by its inhibitory effect on sympathetic nervous activity through the decreased intracellular calcium concentration.
Angiotensin-induced growth related metabolism is activated in cultured smooth muscle cells from spontaneously hypertensive rats and Wistar-Kyoto rats, Smooth muscle cells from spontaneously hypertensive rats (SHR) proliferate in culture faster than those isolated from sex- and age-matched Wistar-Kyoto (WKY) animals. There was no difference in the kinetics of S6 kinase activation in the two cultures. but later metabolic events associated with proliferation were stimulated earlier in SHR cells than in WKY. eg. activation of ornithine decarboxylase. Both cell types elaborated an extensive extra-cellular matrix in culture composed of a different blend of connective tissue macromolecules. Matrix material from SHR cells was more stimulatory to growth of WKY cultures than their own matrices. Angiotensin stimulated the growth and synthesis of extra-cellular matrix material in SHR more than in WKY derived vascular smooth muscle cell cultures.
Evaluation of the Ca2+ distribution in aortic tissue of spontaneously hypertensive and normotensive rats [letter, In the present study. particle-induced X-ray emission (PIXE) was used to get information on the spatial distribution of Ca2+ in aortas of spontaneously hypertensive rats (SHR) and normotensive controls aged 1 week. 4 weeks. and 12 weeks. To differentiate changes in Ca2+ metabolism in hypertensive arteries from secondary phenomena due to the arteriosclerosis. the animals were examined in the earliest stage of hypertension. It was found that the Ca2+ content was not elevated in the aortic smooth muscle of SHR aged 1 week (n = 11). as compared to normotensive controls (n = 10) (186.8 +/- 89.9 micrograms Ca2+/g tissue v 254.0 +/- 173.3 micrograms Ca2+/g). The Ca2+ content was raised (P less than .05) in the aortic smooth muscle of SHR aged 4 weeks (n = 13). as compared to 12 WKY rats (4 weeks) (726.0 +/- 130.4 micrograms Ca2+/g tissue v 440.3 +/- 214.4 micrograms Ca2+/g) and in 17 SHR (3 months). as compared to 13 WKY rats. respectively (3390.1 +/- 729.9 micrograms Ca2+/g tissue v 1632.1 +/- 569.5 micrograms Ca2+/g). The results confirm the age-related increase in the arterial Ca2+ content in normotensive rats and demonstrate additionally that this age-related rise in arterial Ca2+ content is accelerated in SHR.
Hypertension and vascular disease, The use of antihypertensive drug treatment has altered the natural history of hypertension. Whereas congestive heart failure. cerebral hemorrhage. and renal failure were the major complications of untreated severe hypertension. myocardial infarction and thrombotic stroke have emerged as the major problems in treated hypertensives. None of the major therapeutic trials in hypertension have provided evidence that reducing blood pressure reduces the risk of atherosclerotic complications of hypertension. Hypertension certainly aggravates the severity of atheromatous lesions in experimental animals and. thus. may do so in humans. However. atherosclerosis is more closely related to disturbances in lipoprotein metabolism than to other factors. The common finding that serum cholesterol is raised in hypertensive patients may be due to atherosclerosis being the primary lesion. with the hypertension as a secondary complication rather than the primary lesion.
Shortcomings of current antihypertensive therapy, Effective antihypertensive agents have been available for the last four decades. Their use in the treatment of hypertension has resulted in a marked decline in hypertension-induced morbidity and mortality. There are. however. some notable shortcomings with the currently available antihypertensive therapies. including disappointing effects against coronary artery disease and the fact that. even with treatment. hypertensive patients still have considerably higher cardiovascular morbidity and mortality than matched normotensives. This may be due to insufficient lowering of the elevated arterial pressure in hypertensive patients. In theory. overtreatment may also constitute a risk. considering the J-curve phenomenon. Other factors which may play a role are the different pathophysiological mechanisms in stroke and myocardial infarction. the potentially negative metabolic effects induced by some antihypertensive drugs. the importance of cardiovascular hypertrophy (in particular. left ventricular hypertrophy). and the inability of some antihypertensive agents to reverse such changes. To rectify some of these shortcomings. a more effective antihypertensive therapy is required. Ideally. an antihypertensive agent should provide effective lowering of blood pressure. in most patients to normotensive levels. while being devoid of potentially negative metabolic effects. It should also induce reversal of the changes of cardiovascular hypertrophy and. if possible. limit tissue damage if and when a vascular complication occurs.
Clinical pharmacology of calcium antagonists, There have been major advances in the understanding of the basic pharmacology of drugs acting upon voltage-dependent and receptor-activated calcium channels using patch-clamp techniques. The structure of the L channel is known and the (different) binding sites for various calcium antagonists have been identified using the methods of molecular biology. Although calcium slow-channel antagonists are very widely used in the treatment of hypertension. advances in the clinical pharmacology of angina and. to a lesser extent. cardiac arrhythmias. have not kept up with the basic research in molecular biology. All of the calcium antagonists in current use dilate arteries. and their therapeutic action largely depends on this property. There is evidence of differences in response between arteries and veins. and some degree of selectivity between vascular territories. but the goal of much more specific or localized vasodilation has not been achieved. The most prominent difference between the three main classes of antihypertensive drugs is the mild reflex increase of heart rate seen with the dihydropyridines and the bradycardia seen with verapamil. Most of the side effects of calcium antagonists are also based on vasodilatation. such as flushing and headache. The mild edema often seen with the dihydropyridines probably depends on the changes in capillary pressure brought about by arterial dilatation. Despite their undoubted efficacy as vasodilators. there are no studies thus far which allow any conclusions as to the long-term effect of calcium antagonists on the morbidity and mortality due to hypertension.
Do otolaryngologist-head and neck surgeons and/or chemotherapy have a role in the treatment of head and neck cancer, We provide an update on the current status of chemotherapy in the treatment of head and neck cancer. The role of the otolaryngology--head and neck surgeon in this important clinical research is underscored. Those involved with treating patients with head and neck cancer must understand the mechanisms of clinical cancer research. Physicians in academic and community settings can be intimately involved in this treatment.
The lower trapezius island musculocutaneous flap revisited. Report of 45 cases and a unifying concept of the vascular supply, The lower trapezius island musculocutaneous flap is valuable in head and neck reconstruction. It offers thin. pliable tissue and a long arc of rotation to reach virtually any defect in the head and neck. Recent reports have shown unacceptably high rates of failure and have questioned the reliability of the vascularity. We report our experience with 45 reconstructions using the lower trapezius island musculocutaneous flap. The literature is reviewed and the vascular anatomy is described in detail. The concept of angiosomes is applied to the trapezius muscle to help explain the reasons for flap failure and to provide guidelines for flap design and harvest.
Factors influencing palatoplasty and pharyngeal flap surgery, An experience of 154 patients undergoing palatoplasty or pharyngeal flap surgery at the University of California. Davis. Medical Center (Sacramento) was retrospectively analyzed. There were 114 palatoplasties. 37 pharyngeal flaps. and three combined palatoplasty and pharyngeal flap procedures performed. Factors that could affect postoperative airway compromise. as well as those thought to influence the number of days hospitalized postoperatively. were evaluated using a three-way analysis of covariance. Some degree of airway compromise occurred in 24 patients. The duration of mouth-gag usage strongly correlated with the incidence and severity of airway compromise. Neither steroids nor antibiotics decreased the incidence of respiratory compromise. However. steroids were associated with a decrease in number of days hospitalized (2.7 days vs 4.2 days). The use of intraoperative antibiotics was also associated with a shorter hospitalization (3.5 vs 4.0 days) and with fewer cases of postoperative fever. The high correlation between significant respiratory compromise and duration of mouth-gag usage. as well as clinical observations. suggest that airway compromise in these patients is due to edema of the tongue and related structures secondary to ischemia.
A case-control study of the effects of birth by caesarean section on intrapartum and neonatal mortality among twins weighing 1500-2499 g, The aim of this nationally-based. matched case-control study was to assess the impact of birth by caesarean section on intrapartum. and neonatal mortality among twins weighing 1500-2499 g. born in Sweden between 1973 and 1983. By using data held at the National Medical Birth Registry. Stockholm. 91 such pregnancies (study cases) where one or both twins died were identified. For each case. two controls (in all 182 pregnancies) were allotted at random from the rest of the twin pregnancies. with similar birthweight (+/- 100 g) and year of delivery (+/- 1 year). The number of twins that died was reduced from 73 during the first four years to 22 between 1977 and 1980. and to 6 during the last 3 years of the study period. Almost a quarter (23.1%) had a lethal malformation. The caesarean section rate increased during the study period. but did not differ between cases and controls (chi 2 = 1.0; P greater than 0.05). The analysis could not confirm a significant difference between cases and controls regarding the number of infants born vaginally in non-vertex presentation (chi 2 = 0.1; P greater than 0.05). The results of this study appear to indicate that birth by caesarean section was not a major factor related to the improved fetal outcome.
Perceived risk not actual risk predicts uptake of amniocentesis, A consecutive cohort of 71 women eligible for amniocentesis because they were over 38 years of age completed questionnaires during the first trimester of pregnancy. Sixty-one women underwent amniocentesis. an uptake rate of 86%. Uptake was associated with a less negative attitude towards termination of an affected baby and a higher perceived risk of the fetus being abnormal. It was not associated with actual age-related risks. There was no significant relation between actual risk and perceived risk. The results of this study suggests that it is important for doctors to understand the basis of women's decisions to have amniocentesis. and the difference between actual and perceived risk if they are to communicate effectively with women about the test and their options.
The use of cervicography in a primary screening service, The cervicography and concurrent endocervical brush smear results obtained in 1162 women screened at the Marie Stopes Clinic were analysed. Colposcopy and biopsy results were obtained for positive cases. A comparison was made with a group of 1007 women attending the same clinic for routine cytology only. Nearly 10% of women who were screened by cervicography had a technically defective cervicogram. the main single reason being that the view was obscured by blood. Routine cytology was positive in 1%. while cervicography was positive in 13%. where positivity was defined as a result leading to a recommendation for colposcopy. The false positive rate for cervicography was 26%. Even after adjustment. this difference was highly significant (P less than 0.0001).
The antineutrophil antibody in uveitis, Ninety eight patients with uveitis of various types were tested for the presence of the antineutrophil antibody or ANCA by an indirect immunofluorescence method. This antibody is found in patients with diseases associated with small vessel vasculitis. including Wegener's granulomatosis and microscopic polyarteritis. Eleven true positive cases were found. A positive test was not associated with the anatomical site of the uveitis but was related to the time course of the disease. In particular single/repeated rather than nonrecurrent uveitis was associated with a positive test. Three groups of patients seem more likely to have positive tests: those with bilateral chronic posterior uveitis; a group with an anterior uveitis which is single/repeated who were younger than 46 at disease onset and had isolated eye disease; and an older group. aged 60 years or more at onset. with single/repeated uveitis and systemic features.
Changes in keratometry following trabeculectomy, The results of keratometry following trabeculectomy are presented. In contrast to the effects of wound gape after cataract extraction. trabeculectomy produces a reduction in the vertical corneal radius. An initial corresponding increase in horizontal radius is found immediately postoperatively. but this is not apparent by two and seven weeks after surgery. A possible explanation for these findings is proposed.
Bupivacaine versus bupivacaine plus fentanyl for epidural analgesia: effect on maternal satisfaction, OBJECTIVE--To compare a combination of epidural fentanyl and bupivacaine with bupivacaine alone for epidural analgesia in labour and to evaluate factors in addition to analgesia that may influence maternal satisfaction. DESIGN--A prospective randomised pilot study. SETTING--Birmingham Maternity Hospital. SUBJECTS--85 primiparous women who requested epidural analgesia in labour and their babies. INTERVENTIONS--Group 1 mothers were treated with bupivacaine conventionally. group 2 mothers with bupivacaine and fentanyl in a more complex way designed to provide satisfactory analgesia but with less troublesome side effects. MAIN OUTCOME MEASURES--Overall maternal satisfaction. maternal perception of epidural analgesia and its side effects. and aspects of mothers' psychological states during labour. quantified using 100 mm visual linear analogue scales; the frequency of normal and operative deliveries; and measurements of neonatal wellbeing. RESULTS--Satisfaction was higher in group 2 mothers (median group difference +3 mm. 95% confidence interval +1 to +5. p = 0.012): this was associated with more normal deliveries (difference between proportions 0.23. 95% confidence interval +0.03 to +0.42); greater self control (median group difference -7 mm. -17 to -2. p = 0.003); and reduced unpleasantness of motor blockade (-10 mm. -19 to -5. p less than 0.001). sensory blockade (-5 mm. -11 to -2. p = 0.002) and shivering (-5 mm. -18 to 0. p = 0.046) at the expense of mild itching (0 mm. 0 to 0. p less than 0.001). Group 1 mothers found restricted movements more unpleasant (-1 mm. -11 to 0. p = 0.006) and were more sleepy (-4 mm. -20 to 0. p = 0.032). The addition of fentanyl to bupivacaine reduced the requirement for local anaesthetic (-33 mg. -55 to -15. p less than 0.001) without compromising analgesia. No adverse effects in neonates were attributed to the use of fentanyl. CONCLUSIONS--The already high maternal satisfaction from conventional epidural analgesia can be improved; epidural fentanyl may be combined with bupivacaine to reduce operative deliveries and confer other advantages that may increase maternal satisfaction. Further investigations should be performed to determine the exact mechanisms of these findings and. in particular. to develop a safe method of delivering such analgesia to women.
Parental occupations of children with leukaemia in west Cumbria, north Humberside, and Gateshead, OBJECTIVE--To determine whether parental occupations and chemical and other specific exposures are risk factors for childhood leukaemia. DESIGN--Case-control study. Information on parents was obtained by home interview. SETTING--Three areas in north England: Copeland and South Lakeland (west Cumbria); Kingston upon Hull. Beverley. East Yorkshire. and Holderness (north Humberside). and Gateshead. SUBJECTS--109 children aged 0-14 born and diagnosed as having leukaemia or non-Hodgkin's lymphoma in study areas during 1974-88. Two controls matched for sex and date and district of birth were obtained for each child. MAIN OUTCOME MEASURES--Occupations of parents and specific exposure of parents before the children's conception. during gestation. and after birth. Other adults living with the children were included in the postnatal analysis. RESULTS--Few risk factors were identified for mothers. although preconceptional association with the food industry was significantly increased in case mothers (odds ratio 2.56; 95% confidence interval 1.32 to 5.00). Significant associations were found between childhood leukaemia and reported preconceptional exposure of fathers to wood dust (2.73. 1.44 to 5.16). radiation (3.23. 1.36 to 7.72). and benzene (5.81. 1.67 to 26.44); ionising radiation alone gave an odds ratio of 2.35 (0.92 to 6.22). Raised odds ratios were found for paternal exposure during gestation. but no independent postnatal effect was evident. CONCLUSION--These results should be interpreted cautiously because of the small numbers. overlap with another study. and multiple exposure of some parents. It is important to distinguish periods of parental exposures; identified risk factors were almost exclusively restricted to the time before the child's birth.
Case-control study of leukaemia and non-Hodgkin's lymphoma in children in Caithness near the Dounreay nuclear installation [published erratum appears in BMJ 1991 Apr 6;302(6780):818], OBJECTIVE--To examine whether the observed excess of childhood leukaemia and non-Hodgkin's lymphoma in the area around the Dounreay nuclear installation is associated with established risk factors. or with factors related to the plant. or with parental occupation in the nuclear industry. DESIGN--Case-control study. SETTING--Caithness local government district. SUBJECTS--14 cases of leukaemia and non-Hodgkin's lymphoma occurring in children aged under 15 years diagnosed in the area between 1970 and 1986 and 55 controls matched for sex. date of birth. and area of residence within Caithness at time of birth. MAIN OUTCOME MEASURES--Antenatal abdominal x ray examination; drugs taken and viral infections during pregnancy; father's occupation; father's employment at Dounreay and radiation dose; distance of usual residence from the path of microwave beams. preconceptional exposure to non-ionising radiation in the father; and other lifestyle factors. RESULTS--No raised relative risks were found for prenatal exposure to x rays. social class of parents. employment at Dounreay before conception or diagnosis. father's dose of ionising radiation before conception. or child's residence within 50 m of the path of microwave transmission beams. Results also proved negative for all lifestyle factors except an apparent association with use of beaches within 25 km of Dounreay. However. this result was based on small numbers. arose in the context of multiple hypothesis testing. and is certainly vulnerable to possible systematic bias. CONCLUSION--The raised incidence of childhood leukaemia and non-Hodgkin's lymphoma around Dounreay cannot be explained by paternal occupation at Dounreay or by paternal exposure to external ionising radiation before conception. The observation of an apparent association between the use of beaches around Dounreay and the development of childhood leukaemia and non-Hodgkin's lymphoma might be an artefact of multiple testing and influenced by recall bias.
Interactions of serum copper, selenium, and low density lipoprotein cholesterol in atherogenesis, OBJECTIVE--To investigate the interactions between serum copper. selenium. and low density lipoprotein cholesterol concentrations with regard to the progression of carotid atherosclerosis. DESIGN--Longitudinal study of a cohort of middle aged men followed up for 24 months. SETTING--Epidemiological survey of the population of seven communities in eastern Finland. SUBJECTS--126 men aged 42. 48. 54. or 60 at examination randomly selected from a population based sample of 2682 men. MAIN OUTCOME MEASURES--Increase in maximal carotid intima media thickness. RESULTS--The mean increase in the maximal common carotid intima media thickness after two years was greater in men with high serum copper concentrations (0.16 mm compared with 0.08 mm in men with concentrations less than 17.6 mumol/l; p = 0.010). those with low serum selenium concentrations (0.15 mm compared with 0.09 mm in men with concentrations greater than or equal to 1.40 mumol/l; p = 0.035). and those with raised serum low density lipoprotein cholesterol concentrations (0.15 mm compared with 0.08 mm in men with concentrations less than 4.0 mmol/l; p = 0.032) after adjustment for age and cigarette pack years in a three way analysis of covariance. A raised serum low density lipoprotein concentration was associated with accelerated progression of atherosclerosis only in men with higher than median serum copper concentrations (net difference 0.22 mm; p less than 0.001 for two way interaction). and this synergism was even more pronounced in men with serum selenium concentrations below the median value (net difference 0.41 mm; p = 0.042 for three way interaction). CONCLUSION--These data provide evidence of a synergistic effect of copper (a pro-oxidant). a low serum concentration of selenium (a cofactor of an enzyme that scavenges free radicals). and low density lipoprotein cholesterol concentration in atherogenesis.
Use of computerised general practice data for population surveillance: comparative study of influenza data, OBJECTIVE--To assess the potential for using routine computerised general practice data for surveillance of illness. DESIGN--Comparison of the incidence of influenza during the 1989 epidemic derived from a computerised database with that derived from the Royal College of General Practitioners's weekly returns service--a well established predominantly manual surveillance system. SETTING--433 general practices throughout the United Kingdom that used a commercial computer system linked to a central databank. MAIN OUTCOME MEASURE--Incidence of influenza. RESULTS--The slope of the influenza epidemic curve was essentially the same whether derived from the routine computerised data or royal college's weekly returns service data. and the computerised data were geographically consistent. Throughout the study period. however. the computer derived incidence was between one third and one quarter of that derived from the royal college's system (which is served by practitioners trained in surveillance methods). The peak weekly rates were 164 cases per 100.000 for the computerised system and 583 cases per 100.000 for the royal college's surveillance system. CONCLUSIONS--The apparent underreporting in the routine computerised data probably reflects lack of motivation and experience in disease surveillance and haphazard computer entry (particularly of consultations that took place outside of the surgery and consultations that did not result in a prescription). along with overestimation of the population under surveillance. Nevertheless. routine computerised surveillance allows rapid data collection from a large number of practices over a wide geographical area and would greatly augment existing methods.
The interchangeability of radioisotope and X-ray based measurements of bone mineral density, Lumbar spine and femoral neck bone mineral density (BMD) were measured with a Novo radioisotope based dual photon densitometer and with a Lunar X-ray densitometer in 94 subjects attending a Metabolic Bone Disease Clinic. There was a strong correlation between results obtained from each machine for the same skeletal site. The correlation coefficients for the spine and femoral neck were 0.97 and 0.88. respectively. The differences between results from each machine were normally distributed with a mean bias of 37.5% for the spine and 27.8% for the femur. which arise principally from differences in machine calibration. In each case the BMD was greater when measured by X-ray absorptiometry. The range for the bias was approximately 25-50% for the spine and 10-45% for the femoral neck. The results from these two machines are not interchangeable. When subjects who are participating in long term studies using a radioisotope densitometer are transferred to an X-ray densitometer. an individual conversion factor must be measured at each site for each subject.
Ultrasound of the pelvis and renal tract combined with a plain film of abdomen in young women with urinary tract infection: can it replace intravenous urography? A prospective study, Urinary tract infection (UTI) is common in women and intravenous urography (IVU) is a frequently requested radiological investigation for recurrent UTI. The aim of this study was to assess whether pelvic and renal ultrasound combined with a plain film of the abdomen (KUB) could replace IVU as the initial radiological investigation in young women with recurrent UTI. Ninety-four young women with recurrent UTI who were referred for IVU were studied. Ultrasound of the pelvis and renal tract was performed. and information obtained from ultrasound and KUB was compared with that obtained from the IVU examination. Patient management was altered as a result of radiological investigation in eight cases. A case of staghorn calculus and a case of pelviureteric junction obstruction were diagnosed by both IVU and ultrasound with KUB. An intrarenal abscess was diagnosed by ultrasound in a patient with a normal IVU. In addition ultrasound demonstrated significant findings in the pelvis. including ovarian and uterine abnormalities and an ectopic and an intrauterine pregnancy. In all cases the patient had symptoms referable to the urinary tract and a history of documented UTI. The KUB did not yield any unsuspected finding not diagnosed by ultrasound. but did serve to delineate more clearly the extent of calculus disease in two patients. We suggest that ultrasound of the pelvis and renal tract combined with a KUB should be the radiological investigation of choice in young women with UTI.
Unsuspected sphincter damage following childbirth revealed by anal endosonography, Anal endosonography was performed in 62 consecutive patients with incontinence of flatus or faeces following obstetric trauma. and in 18 parous controls. Of the incontinent group. 90% had defects in the external sphincter. 65% in the internal sphincter and 44% disruption of the perineal body. compared with none of the controls. This triad of lesions is pathognomonic of obstetric trauma. Anal endosonography revealed a higher prevalence of sphincter damage than expected from anorectal physiology tests. and therefore has a role in screening patients following complicated or difficult deliveries.
Application of the linear-quadratic model with incomplete repair to radionuclide directed therapy, The linear-quadratic (LQ) model for fractionated external beam therapy has been modified by previous authors to include the effects due to an exponentially decaying dose rate. However. the LQ model has now been extended to include a general time varying dose rate profile. and the equations can be readily evaluated if an exponential radiation damage repair process is assumed. These equations are applicable to radionuclide directed therapy. including brachytherapy. Kinetic uptake data obtained during radionuclide directed therapy may therefore be used to determine the radiobiological dosimetry of the target and non-target tissues. Also. preliminary tracer studies may be used to pre-plan the radionuclide directed therapy. provided that tracer and therapeutic amounts of the radionuclide carrier are identically processed by the tissues. It is also shown that continuous radionuclide therapy will induce less damage in late-responding tissues than 2 Gy/fraction external beam therapy if the ratio of the maximum dose rate and the sublethal damage repair half-life in the tissue is less than 1.0 Gy. Similar inequalities may be derived for beta-particle radionuclide directed therapy. For example. it can be shown that radionuclide directed therapy will induce less damage to slowly repopulating tissue than 2 Gy/fraction external beam therapy for the same total dose if the maximum percentage initial uptake in tissue is less than 0.046%/g or 0.23%/g for an injected activity of 50 mCi of 90Y or 131I. respectively.
The influence of diet on urinary risk factors for stones in healthy subjects and idiopathic renal calcium stone formers, The daily intake of 103 recurrent idiopathic calcium stone formers and 146 controls was assessed by means of a computer-assisted 24-h dietary record. Timed 24-h urine samples were collected over the same period to assess the relationship between dietary intake of nutrients and urinary risk factors for calcium stones. After standardisation for sex. age and social status a total of 128 subjects underwent final statistical analysis; 64 renal stone formers and 64 controls. Significant increases in the consumption of animal and vegetable protein and purine were identified as the nutritional factors that distinguished renal stone formers from controls. As expected. the daily urinary excretion of calcium and oxalate was higher and the daily urinary excretion of citrate was lower in stone formers than in controls. No difference with respect to daily urinary uric acid excretion was recorded. Daily urinary excretion of calcium was correlated to dietary protein intake while daily urinary oxalate was correlated to dietary vitamin C intake. It was concluded that renal stone formers could be predisposed to stones because of their dietary patterns. A link between the protein content of the diet and urinary calcium was confirmed. but dietary animal protein had a minimal effect on oxalate excretion.
Acute changes in kidney function following extracorporeal shock wave lithotripsy for renal stones, Seventeen patients were subjected to analysis of various renal functional parameters before and after extracorporeal shock wave lithotripsy (ESWL) for renal stones. Thirteen patients were observed at 2 weeks and 3 months. Glomerular filtration rate (GFR) was not influenced by ESWL as based on unchanged serum levels of creatinine. beta 2-microglobulin and creatinine clearance. A significant increase in urinary excretion of beta 2-microglobulin. N-acetyl-beta-glucosaminidase and alkaline phosphatase. with return to pre-treatment values within 4 to 5 days. reflected transient disturbances in proximal tubular function. Urinary albumin excretion was increased 0-24 h after ESWL. No significant alterations were observed in plasma renin activity or serum aldosterone due to ESWL. Serum lactic dehydrogenase remained significantly increased for 2 weeks. In addition. significant changes in several blood and urine parameters were caused by immersion in water and intravenous infusions during treatment and were not specifically due to ESWL.
Intrarenal pressure following pyeloplasty or percutaneous surgery, In a study of 37 patients it was shown that recording the intrapelvic pressure is a safe and reliable means of judging the best time to remove a nephrostomy tube. No post-operative complications were encountered and the procedure has the added advantage of avoiding the use of X-rays.
Ambulatory urodynamics, Long-term ambulatory urodynamic monitoring has been employed in 20 patients in an attempt to detect detrusor abnormality not appreciated by conventional cystometry. In 9 female patients with the "urge syndrome" it detected 2 previously unrecognised cases of detrusor instability; in 4 enuretic patients. only 1 of whom was known to be unstable previously. unstable contractions were confirmed. and 2 of 7 cystoplasty patients had high amplitude contractions detected only on ambulatory assessment. The technique provides a more sensitive index of lower urinary tract function than conventional cystometry in such patients.
Relationship between bladder morphology and long-term outcome of treatment in patients with high pressure chronic retention of urine, A group of 32 men undergoing bladder outflow surgery for high pressure chronic retention (HPCR) of urine were studied prospectively. At the time of treatment marked morphological changes in the bladder wall were demonstrated histologically. but after a mean follow-up of 42.9 months residual urine had decreased significantly and renal function had improved or stabilised in 28 patients (84%). Four patients deteriorated but in 3 of these another potential cause for loss of renal function was present. The majority of patients have a good long-term prognosis following treatment for HPCR.
Urodynamic study of ileocystoplasty in the treatment of idiopathic detrusor instability, Enterocystoplasty is being used with increasing frequency in the treatment of patients with idiopathic detrusor instability. We have performed a prospective clinical and urodynamic study of this procedure in 11 patients using both conventional (CMG) and ambulatory monitoring techniques (AM). Nine of 11 patients were satisfied with the symptomatic outcome. but 7 relied on clean intermittent self-catheterisation (CISC) to achieve a good result. Urodynamic studies demonstrated a significant increase in residual urine volume from 48 +/- 72 ml before to 347 +/- 298 ml after operation. but there was only a small and statistically insignificant increase in cystometric capacity. Detrusor instability. present before operation in all patients. could still be demonstrated in over half of them after operation. However. a significant decrease in the severity of instability was found after operation as assessed by an increased volume at first unstable contraction. The bladder volume before operation at which the first unstable contraction occurred was smaller in those who still had persistent instability after enterocystoplasty compared with those in whom instability could not be identified after operation. These results suggest that all patients about to undergo ileocystoplasty should be trained in the use of CISC. In selected patients with idiopathic detrusor instability refractory to other treatment. this procedure can yield satisfactory results.
Adverse urinary symptoms after total abdominal hysterectomy--fact or fiction, Urinary symptoms before and after total abdominal hysterectomy in a study group of 80 pre-menopausal women were compared with those in a control group of 78 pre-menopausal women who had dilatation and curettage alone. No urinary symptom was found more commonly after hysterectomy than after curettage. whilst stress incontinence was less common in the study group. Transient symptoms occurred more frequently after hysterectomy.
Functional and urodynamic characteristics of bladder substitution with detubularised right colonic segment, A total of 19 patients underwent bladder replacement with a detubularised right colonic segment; 14 males underwent complete substitution after cystoprostatectomy and 5 females had augmentation after subtotal cystectomy. The mean follow-up time was 20 months. Urodynamic evaluation showed a low pressure reservoir with a mean capacity of 580 ml and normal closure pressure. Sensitivity of the bladder to cold was normal in the augmentation group but was lacking in all patients in the total substitution group. In all except 1 patient the neobladder emptied effectively upon straining without significant residual urine. Seventeen patients were completely continent by day and 10 by night; 1 patient developed hyperchloraemic acidosis requiring treatment. Bladder substitution is superior to the standard ileal or colonic conduits with regard to quality of life. and the use of a right colonic segment is functionally comparable with neobladders composed of the ileum or a combination of the right colon and ileum. The latter are more difficult to fabricate and so may have more complications.
Toxicity study of first and second generation hydrogel-coated latex urinary catheters, The hydrogel-coated urinary catheter is a novel formulation in which the coating hydrogel polymer is claimed to reduce the level of cytotoxicity frequently associated with the use of latex catheters. This study was undertaken to measure cytotoxicity using in vivo techniques. Twelve first generation and 5 second generation hydrogel-coated latex catheters were evaluated in vivo using canine urethras. The results showed all catheters to cause minimal inflammatory changes of the urethral mucosa (toxicity score 0-1.2/6).
Surgical management of primary hyperhidrosis, Primary hyperhidrosis. although lacking a precise definition and of unknown aetiology. disrupts professional and social life and may lead to emotional problems. A variety of treatment methods are used to control or reduce the profuse sweating which involves mainly the palms. soles and axillae. The simplest method. the application of topical agents. is usually attempted first for axillary and plantar sweating. Iontophoresis may provide relief especially in patients with plantar or palmar involvement. In severe cases operative intervention is necessary. Excision of sweat glands is successful in patients with axillary hyperhidrosis but the role of suction-assisted removal of axillary sweat glands remains to be determined. Sympathectomy remains the standard by which other treatments must be judged. For upper thoracic sympathectomy a variety of surgical approaches are used with satisfactory relief of hyperhidrosis. Complications related to the surgical approach. such as Horner's syndrome. brachial plexus injuries. pneumothorax and painful scars may occur. while following sympathectomy compensatory hyperhidrosis is usual and hyperhidrosis may recur. Plantar hyperhidrosis which may be exacerbated or ameliorated by upper thoracic sympathectomy and which fails to respond to non-operative intervention is relieved by lumbar sympathectomy.
Anal endosonography in the investigation of faecal incontinence, Forty-four consecutive patients with incontinence of solid stool of traumatic or idiopathic aetiology were examined by anal endosonography and standard anorectal physiology tests. Anal endosonography showed an external anal sphincter defect in four out of 11 (36 per cent) patients with idiopathic (neurogenic) incontinence. In the remaining seven patients both parts of the sphincter were intact and a linear relationship was found between the resting anal canal pressure and the endosonographic thickness of the internal anal sphincter. Twenty-eight out of 33 (85 per cent) patients with incontinence of traumatic origin had external sphincter defects. confirmed by concentric needle electromyogram mapping in the 19 patients in whom this was performed. Eleven of these 28 (39 per cent) patients also had disruption of the internal sphincter. Anal endosonography has revealed significant abnormalities in patients with faecal incontinence and has a complementary role to anorectal physiology in the routine investigation of these patients.
Biliary bile acid profiles in familial adenomatous polyposis, Patients with familial adenomatous polyposis have an excess risk for adenomas and cancers of the upper and lower gastrointestinal tract. In the upper intestine these lesions occur mainly around the ampulla of Vater and they parallel mucosal exposure to bile. In view of this finding and of evidence that bile acids play a role in colorectal carcinogenesis. biliary bile acid profiles were determined in 29 patients with familial adenomatous polyposis (12 before colectomy. 17 after colectomy) and in 28 patients without familial adenomatous polyposis (all with colons in situ). Patients with familial adenomatous polyposis had a higher total biliary bile acid concentration than the others. The bile of patients with polyposis had a greater proportion of chenodeoxycholic acid and a lower proportion of deoxycholic acid than did the bile of patients without polyposis. The ratio of chenodeoxycholic acid and its metabolite lithocholic acid to cholic acid and its metabolite deoxycholic acid. which is related to subsequent bile acid profiles in the colon. was higher in patients with polyposis. Because bile acids influence cellular proliferation. these findings may be of importance with respect to intestinal adenoma and cancer growth.
Changes in hepatic haemodynamics and hepatic perfusion index during the growth and development of hypovascular HSN sarcoma in rats, Experimental liver tumours were induced in the Hooded Lister rat by the intraportal inoculation of 10(6) HSN sarcoma cells. The hepatic perfusion index was raised 10 days after the inoculation of cells (at the micrometastatic stage) and when overt tumour was present 20 days after inoculation. Overt tumours were hypovascular compared with normal liver. Portal venous flow and portal venous inflow fell significantly when the hepatic perfusion index was increased. but hepatic arterial flow did not alter. Portal vascular resistance and splanchnic vascular resistance were both increased in tumour-bearing animals but portal pressure. arteriosystemic shunting and portosystemic shunting did not increase significantly at any stage during the growth of hepatic tumour. These findings confirm that the hepatic perfusion index can be elevated in the presence of both micrometastic and overt hepatic tumour and that the changes are not due to either arteriosystemic shunting or mechanical portal venous obstruction.
Oestrogen receptor D5 antibody is an independent negative prognostic factor in gastric cancer, Recent studies have demonstrated oestrogen receptors in tissues other than those considered to be sex hormone responsive. for instance in gastric cancer. In vitro experiments have shown oestradiol to be trophic to gastric cancer cell lines. The effect of D5 (an oestrogen receptor-related protein) status on survival was therefore studied in a group of 188 consecutive patients undergoing surgery for gastric cancer. Ninety-two patients (49 per cent) were positive for the D5 antibody. There were no differences between the D5-positive and D5-negative groups for age or adverse prognostic features such as high grade tumours or advanced stage. The D5-negative patients had a significant survival advantage over the D5-positive patients. The 95 per cent confidence interval for survival in the patients with D5-negative tumours was 63-101 weeks compared with 39-66 weeks for the patients with D5-positive tumours (Mantel-Cox statistic = 4.15. P = 0.042). Prognostic factor analysis with a Cox proportional hazards model showed tumour stage (P = 0.001) and D5 status (P = 0.003) to be significant independent factors in gastric cancer. Lauren type. grade and gender were not significant independent factors in this small series.
Suturing or stapling in gastrointestinal surgery: a prospective randomized study. West of Scotland and Highland Anastomosis Study Group, A prospective randomized study of 1004 patients is reported. comparing surgical stapling and manual suturing techniques in the construction of gastrointestinal anastomoses. The incidence of clinical leaks was similar between the two groups (sutured 3.2 per cent. stapled 4.7 per cent; P = 0.22). while for radiological leaks the incidence was significantly higher in the sutured group (12.2 per cent versus 4.1 per cent. P less than 0.05). Stapling instruments afforded significantly quicker anastomoses. mean(s.e.m.) 28.1(0.7) versus 14.3(0.5) min (P less than 0.001). and quicker operations. 115.5(2.4) versus 103.8(2.2) min (P less than 0.001). The two groups were found to be comparable in other respects such as operative mortality. requirements for blood transfusion. incidence of infective complications. recovery of gastrointestinal function and postoperative hospital stay.
Improving results in the treatment of gastric cancer: an 11-year audit, Of 280 patients presenting to one hospital with gastric cancer between 1975 and 1985. 97 (35 per cent) did not undergo surgery and 29 per cent (54 out of 183) of those who did had no resection performed. The 30-day operative mortality rate in the study period was 15 per cent (28 out of 183) but in the subsequent 4-year period this fell to 7 per cent (5 out of 69). The survival rate correlated significantly with depth of invasion but not with tumour site or degree of differentiation. The incidence of early gastric cancer in this series was 5 per cent but the 5-year survival rate in this group was 52 per cent suggesting that the true incidence might be even lower. The overall 5-year survival rate in our area 20 years ago was only 5.2 per cent but in this series it was 11 per cent overall and 24 per cent after resection. and with actuarial correction 15 per cent overall and 28 per cent after resection. The continuing improvement in operative mortality rates and in 5-year survival rates gives grounds for optimism. but the disease must be diagnosed earlier if this improvement in outlook is to continue.
Non-ominous micrometastases of gastric cancer, So-called R2 or wider meticulous node dissection was performed in 1368 patients with resected gastric cancer invading beyond the submucosa but without distant metastases. Survival rates were similar in subsets of patients with or without microscopic node metastases and macroscopically normal lymph nodes. The extent of node metastases has previously been shown to be one of the two most important prognostic factors in gastric cancer without distant metastases. and its lack of impact in these patient groups was not explained by the imbalance of other prognostic factors. The findings indicate that micrometastases of gastric cancer are curable by a wide node dissection made in the absence of palpable abnormality. They also offer the possibility that an extensive node dissection may yield good stage-specific survival rates. in part because of upstaging of patients. The findings should influence the recording of node metastases for evaluation of stage-specific treatment results and for research purposes.
POSSUM: a scoring system for surgical audit, POSSUM. a Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity. is described. This system has been devised from both a retrospective and prospective analysis and the present paper attempts to validate it prospectively. Logistic regression analysis yielded statistically significant equations for both mortality and morbidity (P less than 0.001). When displayed graphically zones of increasing morbidity and mortality rates could be defined which could be of value in surgical audit. The scoring system produced assessments for morbidity and mortality rates which did not significantly differ from observed rates.
Effect of antiplatelet drug therapy on the retinal vascular pattern in experimental diabetes mellitus, We performed a study to evaluate the effect of acetylsalicylic acid (ASA) plus dipyridamole on the retinal vascular pattern over 3 months in rats with experimental diabetes mellitus. Rats treated with ASA alone showed a continuous vascular bed and less tortuous vessels than untreated diabetic rats. Rats treated with ASA plus dipyridamole showed a continuous vascular bed. scarce tortuous vessels and vascular diameters similar to those in nondiabetic control rats. The findings were related to aortic prostacyclin production: treatment with ASA alone produced a reduction in prostacyclin production. whereas treatment with ASA plus dipyridamole resulted in normal prostacyclin production. ASA alone or with dipyridamole inhibited collagen-induced aggregation in whole blood by 57% compared with the untreated diabetic rats.
The concept of corticosteroid cataractogenic factor revisited, Formation of posterior subcapsular cataracts is a known complication of systemic corticosteroid therapy. However. the relation between steroid dosage. cumulative dose and type of steroid on one hand and the subsequent formation of cataract on the other is unclear. We carried out a study to determine the incidence of posterior subcapsular cataracts in 64 children who had undergone renal transplantation and to attempt to determine what factors were associated with cataract formation. Cataracts were detected in 17 (26%) of the patients. The steroid dosage. cumulative dose and duration of therapy were not associated with cataract formation. There was a significant difference in the distribution of HLA-CW3 antigen between the patients with cataracts and those without cataracts. The reason for the link between corticosteroid therapy and formation of posterior subcapsular cataracts remains unclear.
Hexagonal keratotomy for intraocular lens miscalculation, As the result of miscalculation of the intraocular lens before cataract surgery. hyperopia and anisometropia developed in a 67-year-old woman. Hexagonal keratotomy performed 7 years later under topical anesthesia with a 5-mm marker resulted in a myopic shift of 4.37 dioptres and an uncorrected visual acuity of 20/25.
A dose-response study of nalbuphine for post-thoracotomy epidural analgesia, The analgesic efficacy and side-effects of epidural nalbuphine (0.075-0.3 mg.kg-1) were compared with epidural morphine 0.1 mg.kg-1 in a randomised double-blind study in post-thoracotomy patients. The drugs were administered via a lumbar epidural catheter one hour before the end of surgery. Efficacy was assessed using visual analogue pain scores and supplementary iv fentanyl requirements; respiratory function was studied with an inductive plethysmograph and arterial blood gas analysis; and plasma nalbuphine levels were measured. Pain scores and fentanyl supplementation were lowest in the morphine group (P less than 0.01). No dose-response effect was apparent in the nalbuphine dose-range studied. Respiratory depression was more common in patients receiving morphine (higher mean PaCO2P less than 0.01. more frequent apnoeas greater than 15 sec P less than 0.05. and incidence of PaCO2 greater than 50 mmHg requiring naloxone P less than 0.01). There were no differences in haemodynamic variables. sedation. or other side-effects among the groups. The pharmacokinetic profile of epidural nalbuphine was similar to that seen with rapid iv injection. The results indicate that. relative to morphine. lumbar epidural nalbuphine is an ineffective analgesic after thoracotomy. Despite the lower incidence of respiratory depression its administration by this route cannot be recommended.
Venous emboli occurring caesarean section: the effect of patient position, The effect of position. horizontal versus 5 degrees reverse Trendelenburg's. on the incidence of venous emboli during Caesarean section was evaluated in 207 patients. Venous emboli were diagnosed using precordial ultrasonic Doppler monitoring. In the horizontal position. 44% (60 of 134) parturients had venous emboli compared with 1% (1 of 73) parturients in the 5 degrees reverse Trendelenburg's position (P less than 0.0001). Epidural anaesthesia was performed in 171 patients. and 36 patients had general anaesthesia. In the epidural group. pulse oximetric haemoglobin oxygen desaturation and complaints of chest pain and/or dyspnoea were associated with the venous emboli. Venous emboli. probably air. occur frequently during Caesarean section with the patient in the horizontal position. This occurrence was minimized by placing the patient in the 5 degrees reverse Trendelenburg's position.
Intraoperative defect in haemostasis in a child receiving valproic acid, This report describes the development of an intraoperative defect in haemostasis which occurred during surgery for lengthening of the heel cords and release of hip contractures in a patient receiving valproic acid. A review of the literature failed to find any other cases of a valproic acid-induced bleeding disorder occurring under anaesthesia and surgery. While recognized in the non-surgical literature. this case reports the first in which the development of a valproic acid-induced haemostatic defect occurred under anaesthesia. The subsequent course is discussed and some pathophysiological mechanisms are presented. It is suggested that for patients receiving valproic acid preoperative education should include PT/PTT. platelet and fibrinogen counts and bleeding time so that abnormal coagulation states can be recognized.
Acute airway management in the critically ill child requiring transport, Airway compromise was found to be a common problem in children requiring critical care transport to our hospital. This retrospective review of 39 infants and children was undertaken to assess the frequency and degree of airway compromise in these children. to document the management required and to determine who performed it. Ninety-seven per cent of children had airway difficulties associated with their disease. and one-third of these required further airway management on the arrival of the transport team. Airway specialists had not been involved in the care of these children before the arrival of the transport team. This indicates that greater attention should be paid to airway management as soon as children are identified as being sufficiently ill to require transport to a tertiary care facility.
Intracoronary thrombus formation causes focal vasoconstriction of epicardial arteries in patients with coronary artery disease, BACKGROUND. Experimental studies have demonstrated that intracoronary platelet aggregation and thrombus formation may induce marked vasoconstriction of epicardial arteries with endothelial injury. METHODS AND RESULTS. To examine the effects of intracoronary thrombus formation on coronary vasomotor tone of human epicardial arteries in vivo. we studied 15 patients who developed intracoronary thrombi adherent to the guide wire during balloon dilatation. Epicardial artery luminal area was evaluated by quantitative coronary angiography proximal and distal to the site of intracoronary thrombus formation and in a reference vessel before and after thrombus formation as well as after intracoronary injection of 0.2-0.3 mg nitroglycerin. All artery segments distal to the site of thrombus formation showed vasoconstriction with a luminal area reduction of -27.4 +/- 17.1% (p less than 0.001). whereas proximal vessel segments and reference vessels not manipulated during percutaneous transluminal coronary angioplasty did not demonstrate any significant luminal area changes during thrombus formation. Angiographic measurements after advancing the guide wire with the adherent thrombus (performed in six of the 15 patients) revealed in all patients that vasoconstriction did develop at a new site distal to the thrombus persistence of the initial vasoconstriction now residing proximal to the thrombus. Thus. there was a sequential association between thrombus formation and subsequent distal vasoconstriction. Intracoronary injection of nitroglycerin abolished the thrombus-induced vasoconstriction. No significant luminal area changes were observed in 20 patients without angiographic evidence of intracoronary thrombus formation. CONCLUSIONS. Intracoronary thrombus formation during percutaneous transluminal coronary angioplasty causes focal vasoconstriction of epicardial arteries in patients with coronary artery disease. Although caution must be advised in the extrapolation of this phenomenon. which was observed in a manipulated artery during coronary angioplasty. the vasoconstrictor response to intracoronary thrombus formation in vivo may play an important role in the dynamic mechanisms of acute coronary heart disease syndromes.
Immediate postoperative aspirin improves vein graft patency early and late after coronary artery bypass graft surgery. A placebo-controlled, randomized study, BACKGROUND. The efficacy of aspirin for prevention of thrombotic graft occlusion after coronary artery bypass grafting (CABG) depends both on the dosage and time window of administration. Early and late graft patency were therefore assessed in a prospective. double-blind. randomized. placebo-controlled trial of aspirin. 324 mg daily. given within 1 hour of CABG. METHODS AND RESULTS. Angiographic graft patency was determined at 1 week (231 patients) and 1 year (219 patients) after CABG. The early vein graft occlusion rate was 1.6% on aspirin and 6.2% on placebo (p = 0.004). and late graft occlusion rate was 5.8% on continued aspirin and 11.6% on placebo (p = 0.01). New graft occlusion between 1 week and 1 year was less common in patients on aspirin than on placebo (4.3% versus 7.4%. p = 0.013). The protective effect of aspirin against occlusion persisted in most subgroups of graft type. graft flow. diameter of recipient artery. location of grafted artery. and endarterectomy. Mean chest tube blood loss for the first 24 hours was 571 ml for the aspirin group and 563 ml for the placebo group. Red cell transfusion requirements were 902 ml in the aspirin group and 934 ml in the placebo group (p = NS). The reoperation rate was 4.8% in the aspirin group and 1% in the placebo group (p = 0.1). CONCLUSIONS. Immediate postoperative administration of aspirin (324 mg) improves early graft patency and. with continued usage. protects against further occlusion up to 1 year after CABG. Postoperative blood loss was similar in the two groups; however. aspirin was associated with a nonsignificant higher rate of reoperation.
Short-term effect of dynamic exercise on arterial blood pressure, BACKGROUND. To quantify the duration of postexercise hypotension at different exercise intensities. we studied six unmedicated. mildly hypertensive men matched with six normotensive controls. METHODS AND RESULTS. Each subject wore a 24-hour ambulatory blood pressure monitor at the same time of day for 13 consecutive hours on 3 different days. On each of the 3 days. subjects either cycled for 30 minutes at 40% or 70% maximum VO2 or performed activities of daily living. There was no intensity effect on the postexercise reduction in blood pressure. so blood pressure data were combined for the different exercise intensities. Postexercise diastolic blood pressure and mean arterial pressure were lower by 8 +/- 1 (p less than 0.001) and 7 +/- 1 mm Hg (p less than 0.05). respectively. than the preexercise values for 12.7 hours in the hypertensive group. These variables were not different before and after exercise in the normotensive group. Systolic blood pressure was reduced by 5 +/- 1 mm Hg (p less than 0.05) for 8.7 hours after exercise in the hypertensive group. In contrast. systolic blood pressure was 5 +/- 1 mm Hg (p less than 0.001) higher for 12.7 hours after exercise in the normotensive group. When the blood pressure response on the exercise days was compared with that on the nonexercise day. systolic blood pressure (135 +/- 1 versus 145 +/- 1 mm Hg) and mean arterial pressure (100 +/- 1 versus 106 +/- 1 mm Hg) were lower (p less than 0.05) on the exercise days in the hypertensive but not in the normotensive group. We found a postexercise reduction in mean arterial pressure for 12.7 hours independent of the exercise intensity in the hypertensive group. Furthermore. mean arterial pressure was lower on exercise than on nonexercise days in the hypertensive but not in the normotensive group. CONCLUSION. These findings indicate that dynamic exercise may be an important adjunct in the treatment of mild hypertension.
Functional role of the epicardium in postinfarction ventricular tachycardia. Observations derived from computerized epicardial activation mapping, entrainment, and epicardial laser photoablation, BACKGROUND. Conventionally. monomorphic sustained ventricular tachycardia in patients with remote myocardial infarction is believed to originate from the subendocardium. In a previous study. we demonstrated that electrical activation patterns during ventricular tachycardia occasionally suggest a subepicardial rather than subendocardial reentry. METHODS AND RESULTS. This study prospectively evaluated the functional role of the epicardium in postinfarction ventricular tachycardia with complex intraoperative techniques including computerized electrical activation mapping. entrainment. observation of changes in activation pattern during successful epicardial laser photoblation. and histological study. Five of 10 consecutive patients undergoing intraoperative computerized activation mapping had 10 ventricular tachycardia morphologies displaying epicardial diastolic activation These 10 "epicardial" ventricular tachycardias revealed the following global activation patterns: monoregional spread (two). figure-eight activation (five). and circular macroreentry (three). Entrainment of ventricular tachycardia using epicardial stimulation was successfully performed from an area of slow diastolic conduction in four tachycardia morphologies. During entrainment. global activation remained undisturbed with recordings showing a long stimulus to QRS interval. unchanged QRS morphology. and pacing capture of all components of the reentry circuit. Neodymium:yttrium aluminum garnet laser photocoagulation was delivered during ventricular tachycardia to epicardial sites of presumed reentry. Epicardial photoablation terminated five of five figure-eight tachycardias. two of three circular macroreentry tachycardias but not the monoregional tachycardias. Electrophysiological recordings during epicardial laser photocoagulation demonstrated progressive prolongation of ventricular tachycardia cycle length and apparent interruption of the presumed reentrant circuit. Histological evaluation of the reentrant region (three patients) showed a rim of surviving myocardium under the epicardial surface. CONCLUSIONS. This study suggests that 1) chronic postinfarction ventricular tachycardia may result from subepicardial macroreentry. 2) slow conduction within the reentry circuit can be localized by computerized mapping and epicardial entrainment. and 3) ventricular tachycardia interruption by laser photocoagulation results from conduction delay and block within critical elements of the reentrant pathway. Viable subepicardial muscle fibers may constitute the underlying pathology.
Localization of gene for familial hypertrophic cardiomyopathy to chromosome 14q1 in a diverse US population, BACKGROUND. Familial hypertrophic cardiomyopathy. an inherited primary cardiac abnormality characterized by ventricular hypertrophy. is the leading cause of sudden death in the young. Recent application of restriction fragment length polymorphism markers has provided provocative results. with localization to chromosome 18 (Japanese studies). 16 (Italian studies). 14 (US and French-Canadian studies). and two (National Institutes of Health studies) indicating genetic heterogeneity. Interpretation remains speculative until at least one of these loci is confirmed in unrelated pedigrees by independent investigators. METHODS AND RESULTS. We studied eight unrelated families of varied ethnic origins across the United States. DNA from each individual was digested with restriction enzymes TaqI or BamHI and analyzed by Southern blots followed by hybridization with probes T cell receptor alpha (TCRA). myosin heavy chain beta. D14S25. and D14S26. Multipoint linkage analysis showed a maximum lod score of 4.3. placing the locus 10 cM from D14S26 between D14S26 and TCRA. with an odds ratio of 20.000:1 and 90% confidence limits of 12 cM proximal to D14S25 to 4 cM distal to TCRA. The probability of linkage to 14q1 was more than 99%. CONCLUSIONS. These results indicate that the loci for familial hypertrophic cardiomyopathy in our families is primarily 14q1 but does not exclude other loci in a small proportion of the families. Thus. 14q1 appears to be the locus for familial hypertrophic cardiomyopathy in a significant proportion of the US population.
Echocardiographic detection of coronary artery disease during dobutamine infusion, BACKGROUND. Two-dimensional echocardiography performed during dobutamine infusion has been proposed as a potentially useful method for detecting coronary artery disease. However. the safety and diagnostic value of dobutamine stress echocardiography has not been established. METHODS AND RESULTS. In this study. echocardiograms were recorded during step-wise infusion of dobutamine to a maximum dose of 30 micrograms/kg/min in 103 patients who also underwent quantitative coronary angiography. The echocardiograms were digitally stored and displayed in a format that allowed simultaneous analysis of rest and stress images. Development of a new abnormality in regional function was used as an early end point for the dobutamine infusion. No patient had a symptomatic arrhythmia or complications from stress-induced ischemia. Significant coronary artery disease (greater than or equal to 50% diameter stenosis) was present in 35 of 55 patients who had normal echocardiograms at rest. The sensitivity and specificity of dobutamine-induced wall motion abnormalities for coronary artery disease was 89% (31 of 35) and 85% (17 of 20). respectively. The sensitivity was 81% (17 of 21) in those with one-vessel disease and 100% (14 of 14) in those with multivessel or left main disease. Forty-one of 48 patients with abnormal echocardiograms at baseline had localized rest wall motion abnormalities. Fifteen had coronary artery disease confined to regions that had abnormal rest wall motion. and 26 had disease remote from these regions. Thirteen of 15 patients (87%) without remote disease did not develop remote stress-induced abnormalities. and 21 of 26 (81%) who had remote disease developed corresponding abnormalities. CONCLUSIONS. Echocardiography combined with dobutamine infusion is a safe and accurate method for detecting coronary artery disease and for predicting the extent of disease in those who have localized rest wall motion abnormalities.
Noninvasive identification of myocardium at risk in patients with acute myocardial infarction and nondiagnostic electrocardiograms with technetium-99m-Sestamibi, BACKGROUND. Patients who have chest pain without electrocardiographic ST elevation are not candidates for thrombolytic therapy in most clinical trials. This study examined the value of technetium-99m-Sestamibi tomographic imaging to assess myocardial perfusion in patients during chest pain without ST elevation. METHODS AND RESULTS. Tc-99m-Sestamibi was injected in 14 patients who had chest pain without ST elevation. who subsequently developed enzymatic evidence of myocardial infarction within 24 hours. Tomographic imaging was performed 1-6 hours after injection. Thirteen of 14 patients showed significant perfusion defects indicative of acute myocardial infarction consistent with absent perfusion (20 +/- 15% of the left ventricle; range. 2-53%); one patient had normal images. Because of the absence of definitive electrocardiographic changes. only five patients received reperfusion therapy within 6 hours of the onset of chest pain. Regional wall motion abnormalities were present in nine of nine patients undergoing contrast ventriculography and correlated with the location of the Tc-99m-Sestamibi perfusion defect. At the time of subsequent coronary angiography. total arterial occlusion was present in 11 of the 14 patients. The infarct-related artery could be identified in 13 of the 14 patients. In six of these 13 patients. the left circumflex was the infarct-related artery. CONCLUSIONS. Patients who have chest pain without electrocardiographic ST elevation may have arterial occlusion and significant myocardium at risk. Tc-99m-Sestamibi imaging may be of benefit in identifying these patients early so that they can be considered for acute reperfusion therapy.
On the mechanisms of ventricular tachycardia acceleration during programmed electrical stimulation, BACKGROUND. The pathophysiological mechanisms leading to acceleration of ventricular tachycardia (VT) are still unclear. METHODS AND RESULTS. High-resolution epicardial mapping was used to study the mechanisms of VT acceleration by programmed electrical stimulation (PES) in a model of sustained reentrant VT in Langendorff-perfused rabbit hearts (n = 40). Three different mechanisms responsible for acceleration of VT were identified: 1) induction of double-wave reentry (n = 6). defined as the occurrence of two successive activation waves circulating in the same direction in the same circuit; 2) change to a functionally determined circuit (n = 4). defined as reentry of the impulse around a functional line of block without involvement of a fixed obstacle; and 3) change of the reentrant circuit to reentry within a different. faster anatomic pathway (n = 3). Analysis of 81 episodes of sustained monomorphic VT induced by PES in 74 patients with clinically documented sustained VT in the setting of chronic coronary artery disease showed that in 22 episodes VT was suddenly accelerated by PES (mean cycle length. from 345 +/- 73 to 277 +/- 71 msec. p less than 0.01). CONCLUSIONS. With the observations made in the experimental model. the following tentative classification of the mechanisms of VT acceleration of the 22 episodes was made: 1) induction of double-wave reentry in two. 2) change to a functionally determined circuit in four. and 3) change to reentry within a faster anatomic circuit in 16. Simple criteria suggest that these mechanisms may apply in the clinical situation.
Correlation of circulating von Willebrand factor levels with cardiovascular hemodynamics, BACKGROUND. Valvular heart disease is associated with a decreased platelet circulating time and a thrombotic tendency. The possibility that these events are related to changes in von Willebrand factor (vWF). a multimeric glycoprotein released from endothelial cells and platelets that mediates platelet adhesion to the vascular subendothelium. has not been examined. METHODS AND RESULTS. We measured the vWF antigen (vWF:Ag) concentration in 43 patients undergoing cardiac catheterization for the evaluation of mitral (n = 17) or aortic (n = 10) stenosis or nonvalvular heart disease (n = 16). Mean vWF:Ag concentration was significantly higher in patients with mitral stenosis than in those without (212 +/- 84 versus 150 +/- 79 units/dl. p less than 0.02); this elevation was associated with a significant elevation of pulmonary vascular resistance (PVR) in the patients with mitral stenosis (186 +/- 49 versus 133 +/- 81 dynes-sec-cm-5. p less than 0.02). The vWF:Ag levels in the entire group of patients (regardless of the presence or type of valvular disease) varied directly with PVR (r = 0.72. p less than 0.0001) and with pulmonary artery pressure (r = 0.60. p less than 0.0001) and inversely with cardiac output (r = 0.64. p less than 0.0001). Changes in PVR. pulmonary artery pressure. or cardiac output could not be correlated with circulating levels of fibrinogen or beta-thromboglobulin. which may be released from activated platelets. nor with the endothelial cell product tissue plasminogen activator. CONCLUSIONS. The association of high vWF:Ag levels with increased PVR and decreased cardiac output in patients both with and without mitral stenosis suggests a hemodynamically induced increase in the endothelial release of vWF. which might contribute to a thrombotic tendency in these patients.
Diagnostic implications of spectral and temporal analysis of the entire cardiac cycle in patients with ventricular tachycardia, BACKGROUND. Available methods for analysis of signal-averaged electrocardiograms (ECGs) have a low-positive predictive accuracy for identifying patients at risk for ventricular arrhythmias. Identification of the spectral and temporal features in ECGs that distinguish patients prone to ventricular tachycardia (VT) is a prerequisite to implementing refinements in methods that increase the diagnostic power of the signal-averaged ECG. METHODS AND RESULTS. Fast Fourier transforms and time-domain reconstructions based on inverse fast Fourier transforms were computed over the entire cardiac cycle of signal-averaged ECGs of sinus beats from 40 patients with myocardial infarction and sustained VT. 41 with infarction without VT. and 20 normal controls. Ventricular depolarization and repolarization were analyzed by procedures that obviate limited resolution due to short data segments and window functions. Spectral magnitudes of ECGs from patients in each group were compared. and the phase data were used for time-domain reconstructions to determine the temporal distributions of distinguishing frequency bands during the cardiac cycle. Magnitudes of 1-7-Hz frequencies were increased (from p less than 0.05 to p less than 0.00001). and magnitudes of 13-56-Hz and 70-128-Hz frequencies were decreased (from p less than 0.05 to p less than 0.00001) in the spectra of ECGs from patients with VT compared with patients without VT. Time-domain reconstructions demonstrated that 1-7-Hz frequencies were detectable throughout the QRS complex. ST segment. and T wave in ECGs from each group. The 13-56-Hz and 70-128-Hz frequency bands not only contributed to the terminal QRS and ST segment but were also detectable throughout the QRS complex of ECGs from patients with VT. CONCLUSIONS. Results define new spectral and temporal features in signal-averaged ECGs from patients with VT that are excluded from analysis by available techniques that limit the bandwidth or restrict interrogation to portions of the cardiac cycle. These findings provide an objective basis for developing new indexes for signal-averaged ECG analysis.
A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex, BACKGROUND. In the differential diagnosis of a tachycardia with a wide QRS complex (greater than or equal to 0.12 second) diagnostic mistakes are frequent. Therefore. we investigated the reasons for failure of presently available criteria. and we identified new. simpler criteria and incorporated them in a stepwise approach that provides better sensitivity and specificity for making a correct diagnosis. METHODS AND RESULTS. A prospective analysis revealed that current criteria had a poor specificity for the differential diagnosis. The value of four new criteria incorporated in a stepwise approach was prospectively analyzed in a total of 554 tachycardias with a widened QRS complex (384 ventricular and 170 supraventricular). The sensitivity of the four consecutive steps was 0.987. and the specificity was 0.965. CONCLUSIONS. Current criteria for the differential diagnosis between supraventricular tachycardia with aberrant conduction and ventricular tachycardia are frequently absent or suggest the wrong diagnosis. The absence of an RS complex in all precordial leads is easily recognizable and highly specific for the diagnosis of ventricular tachycardia. When an RS complex is present in one or more precordial leads. an RS interval of more than 100 msec is highly specific for ventricular tachycardia. This new stepwise approach may prevent diagnostic mistakes.
Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy, BACKGROUND. Exercise-induced abnormalities during thallium-201 scintigraphy that normalize at rest frequently occur in patients with hypertrophic cardiomyopathy. However. it is not known whether these abnormalities are indicative of myocardial ischemia. METHODS AND RESULTS. Fifty patients with hypertrophic cardiomyopathy underwent exercise 201Tl scintigraphy and. during the same week. measurement of myocardial lactate metabolism and hemodynamics during pacing stress. Thirty-seven patients (74%) had one or more 201Tl abnormalities that completely normalized after 3 hours of rest; 26 had regional myocardial 201Tl defects. and 26 had apparent left ventricular cavity dilatation with exercise. with 15 having coexistence of these abnormal findings. Of the 37 patients with reversible 201Tl abnormalities. 27 (73%) had metabolic evidence of myocardial ischemia during rapid atrial pacing (myocardial lactate extraction of 0 mmol/l or less) compared with four of 13 patients (31%) with normal 201Tl scans (p less than 0.01). Eleven patients had apparent cavity dilatation as their only 201Tl abnormality; their mean postpacing left ventricular end-diastolic pressure was significantly higher than that of the 13 patients with normal 201Tl studies (33 +/- 5 versus 21 +/- 10 mm Hg. p less than 0.001). There was no correlation between the angiographic presence of systolic septal or epicardial coronary arterial compression and the presence or distribution of 201Tl abnormalities. Patients with ischemic ST segment responses to exercise had an 80% prevalence rate of reversible 201Tl abnormalities and a 70% prevalence rate of pacing-induced ischemia. However. 69% of patients with nonischemic ST segment responses had reversible 201Tl abnormalities. and 55% had pacing-induced ischemia. CONCLUSIONS. Reversible 201Tl abnormalities during exercise stress are markers of myocardial ischemia in hypertrophic cardiomyopathy and most likely identify relatively underperfused myocardium. In contrast. ST segment changes with exercise and systolic compression of coronary arteries on angiography are unreliable markers of inducible myocardial ischemia in hypertrophic cardiomyopathy. Apparent cavity dilatation during 201Tl scintigraphy may indicate ischemia-related changes in left ventricular filling. with elevation in diastolic pressures and endocardial compression.
Adenosine increases sympathetic nerve traffic in humans, BACKGROUND. Adenosine is an effective hypotensive agent in experimental animals and in anesthetized patients. producing little if any evidence of reflex sympathetic activation. In contrast. adenosine increases systolic blood pressure and heart rate in conscious subjects. To determine whether this response is related to sympathetic activation. we studied the cardiovascular and respiratory effects of adenosine in normal subjects while measuring muscle sympathetic nerve traffic through direct recordings from a peroneal nerve. METHODS AND RESULTS. Adenosine (80 micrograms/kg/min i.v.) increased heart rate (+32 +/- 3 beats/min). systolic blood pressure (+10 +/- 2 mm Hg). and minute ventilation (+7 +/- 1 l/min). This was accompanied by a dose-dependent increase in muscle sympathetic nerve activity (from 198 +/- 52 to 451 +/- 92 units/min). Adenosine also produced a small. but consistent. decrease in diastolic blood pressure (-6 +/- 3 mm Hg). Adenosine produced a greater increase in sympathetic nerve traffic (145 +/- 32% above baseline) than did nitroprusside (65 +/- 16%) at doses that resulted in equivalent decreased in diastolic blood pressure. Arterial baroreceptor unloading. therefore. could not totally explain the increase in sympathetic traffic produced by adenosine. CONCLUSIONS. Given the constellation of findings of increased ventilation and sympathetic activity. we. therefore. propose that adenosine increases sympathetic tone by activating afferent nerves. including arterial chemoreceptors. Contrary to the known inhibitory actions of adenosine on central and peripheral efferent systems. this and other reports suggest that adenosine-induced activation of afferent nerves. leading to sympathetic activation. may be a more widespread phenomenon than previously recognized.
Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy, BACKGROUND. Left ventricular (LV) midwall geometry has been described conventionally as the sum of the chamber radius and half of the wall thickness; this convention is based on the assumption of uniform transmural thickening during systole. However. theoretical considerations and experimental data indicate that the inner half (inner shell) of the LV wall thickens more than the outer half (outer shell). Thus. an end-diastolic circumferential midwall fiber exhibits a relative migration toward the epicardium during systole. As a result. the conventional method provides an overestimate of the extent of the midwall fiber shortening. METHODS AND RESULTS. We developed an ellipsoidal model with a concentric two-shell geometry (nonuniform thickening) to assess midwall fiber length transients throughout the cardiac cycle. This modified midwall method was used in the analysis of LV cineangiograms from 15 patients with systemic arterial hypertension and 14 normal subjects. Study groups were classified according to LV mass index (LVMI): 14 normal subjects (group I). eight hypertensive patients with a normal LVMI (group II). and seven hypertensive patients with an increased LVMI (group III). There were no significant differences in LV end-diastolic pressure or volume among the three groups; the ejection fraction was slightly greater in group II (70 +/- 5%) than in groups I (65 +/- 8%) and III (66 +/- 4%). but this trend did not achieve statistical significance. Values for endocardial and conventional midwall fractional shortening (FS) were also similar in the three groups. By contrast. FS by the concentric two-shell geometry (modified midwall method) in group III (16 +/- 2%) was significantly less than that seen in groups I and II (21 +/- 4% and 21 +/- 5%. respectively; both p less than 0.05). This difference achieves greater importance when it is recognized that mean systolic circumferential stress was lower in group III (151 +/- 22 g/cm2) than in groups I and II (244 +/- 37 g/cm2 and 213 +/- 38 g/cm2. respectively; both p less than 0.01). The midwall stress-shortening coordinates in six of the seven group III patients were outside the 95% confidence limits for the normal (group I) subjects. Thus. despite a normal ejection fraction. systolic function is subnormal in hypertensive patients with LV hypertrophy. CONCLUSIONS. Chamber dynamics provide an overestimate of myocardial function. especially when LV wall thickness is increased. This is due to a relatively greater contribution of inner shell thickening in pressure-overload hypertrophy.
Evidence for superoxide radical-dependent coronary vasospasm after angioplasty in intact dogs, BACKGROUND. Active oxygen species can influence vascular tone and platelet activation through a variety of mechanisms. This study assessed the role of the superoxide anion. the hydroxyl radical. and hydrogen peroxide in vasoconstriction and mural thrombosis after coronary artery angioplasty in intact dogs. METHODS AND RESULTS. Injury was induced by inflation of a balloon catheter 50 +/- 6% above baseline arterial diameter; dogs were followed for 2 hours before death. Epicardial coronary diameters at arteriography and extent of thrombus deposition at serial histological sections were analyzed in controls (n = 20) and in dogs pretreated with superoxide dismutase (SOD. a superoxide radical scavenger. n = 10); other dogs were pretreated with the hydrogen peroxide scavenger catalase (n = 8). the iron chelator deferoxamine (n = 6). or the hydroxyl radical scavenger 1.3-dimethyl-2-thiourea (n = 9). Angioplasty-induced injury was similar among groups. After angioplasty. control dogs exhibited localized and persistent vessel constriction. which was maximal at the initial 5 minutes (28.9 +/- 6.3% diameter decrease versus baseline). Corresponding arterial diameters of SOD-treated dogs were 24-69% larger (95% confidence interval. p less than 0.001) than controls at 5 minutes and. on average. 32% larger than controls thereafter (p less than 0.01). Vasoconstriction was not prevented by the other treatments. The SOD dose used accounted for inhibition of zymosan-stimulated blood cytochrome c reduction versus baseline (7 +/- 3 versus 30 +/- 6 nmol/min/10(6) cells. respectively. p = 0.003); such inhibition occurred in no other group. Prevalence of mural thrombosis was similar among all groups. but large thrombi (greater than 15% of lumen area) were absent in SOD-treated dogs. contrary to control group (p = 0.028); other groups were similar to control. In the absence of injury. SOD alone induced no change in coronary diameter. coronary blood flow. or platelet aggregation. CONCLUSIONS. These data provide evidence implicating the superoxide radical in the genesis of vasoconstriction after coronary angioplasty in vivo. Such effects seem to be independent of its conversion to hydroxyl radicals and availability of hydrogen peroxide or catalytic iron complexes.
Cardioreparative effects of lisinopril in rats with genetic hypertension and left ventricular hypertrophy, BACKGROUND. In genetic and acquired hypertension. a structural remodeling of the nonmyocyte compartment of the myocardium. including the accumulation of fibrillar collagen within the interstitium and adventitia of intramyocardial coronary arteries and a medial thickening of these vessels. represents a determinant of pathological hypertrophy that leads to ventricular dysfunction. METHODS AND RESULTS. To evaluate the benefit of angiotensin converting enzyme inhibition in reversing this interstitial and vascular remodeling in the rat with genetic spontaneous hypertension (SHR) and established left ventricular hypertrophy (LVH). we treated 14-week-old male SHR with oral lisinopril (average dose. 15 mg/kg/day) for 12 weeks. Myocardial stiffness and coronary vascular reserve to adenosine (800 micrograms/min) were examined in the isolated heart; myocardial collagen and intramural coronary artery architecture were analyzed morphometrically. In lisinopril-treated SHR compared with 14-week-old baseline or 26-week-old untreated SHR and age- and sex-matched Wistar-Kyoto (WKY) controls. we found 1) a regression in LVH and normalization of blood pressure. 2) a complete regression of interstitial fibrosis. represented by a decrease of interstitial collagen volume fraction from 7.0 +/- 1.3% to 3.2 +/- 0.3% (p less than 0.025; WKY. 2.8 +/- 0.5%). 3) normalization of myocardial stiffness constant from 19.5 +/- 0.9 to 13.7 +/- 1.3 (p less than 0.025; WKY. 13.8 +/- 2.2). 4) a reversal of intramural coronary artery remodeling. including a decrease in the ratio of perivascular fibrosis to vessel lumen size from 1.4 +/- 0.2 to 0.4 +/- 0.1 (p less than 0.025; WKY. 0.6 +/- 0.1) and medial thickening from 12.3 +/- 0.6 to 7.4 +/- 0.5 microns (p less than 0.005; WKY. 7.4 +/- 0.4 microns). and 4) a restoration of coronary vasodilator response to adenosine from 12.3 +/- 0.9 to 26.0 +/- 1.4 ml/min/g (p less than 0.005; WKY. 21.8 +/- 2.2 ml/min/g). Thus. in SHR with LVH and adverse structural remodeling of the cardiac interstitium. lisinopril reversed fibrous tissue accumulation and medial thickening of intramyocardial coronary arteries and restored myocardial stiffness and coronary vascular reserve to normal. CONCLUSIONS. These cardioreparative properties of angiotensin converting enzyme inhibition may be valuable in reversing left ventricular dysfunction in hypertensive heart disease.
Hemodynamic and electrophysiological actions of cocaine. Effects of sodium bicarbonate as an antidote in dogs, BACKGROUND. Cocaine abuse has been implicated as a cause of death due to sudden cardiac arrest. METHODS AND RESULTS. We examined the hemodynamic and electrophysiological effects of cocaine administered as a series of 5-mg/kg i.v. boluses coupled with a continuous infusion in anesthetized dogs. Sodium bicarbonate (50 meq i.v.) was administered as a potential antidote in 11 of 15 dogs. and intravenous 5% dextrose was given in the remaining four. In a dose-dependent fashion. cocaine significantly decreased blood pressure. coronary blood flow. and cardiac output; increased PR. QRS. QT. and QTc intervals and sinus cycle length; and increased ventricular effective refractory period and dispersion of ventricular refractoriness. No afterdepolarizations were noted in the monophasic action potential recording. Nonsustained monomorphic ventricular tachycardia occurred spontaneously in two dogs. and sustained ventricular tachycardia could be induced by programmed stimulation at the end of the dosing protocol in five of 11 animals. Sodium bicarbonate promptly decreased cocaine-induced QRS prolongation to nearly that measured at baseline but had no effect on the other electrocardiographic or hemodynamic variables. In one dog. sodium bicarbonate administration was associated with reversion of ventricular tachycardia to sinus rhythm. CONCLUSIONS. We conclude that high-dose cocaine possesses negative inotropic and potent type I electrophysiological effects. Sodium bicarbonate selectively reversed cocaine-induced QRS prolongation and may be a useful treatment of ventricular arrhythmias associated with slowed ventricular conduction in the setting of cocaine overdose.
Dipyridamole echocardiography. A new diagnostic window on coronary artery disease, Dipyridamole echocardiography testing is a highly feasible. inexpensive. and safe diagnostic tool. with excellent specificity and good sensitivity--especially in patients with multivessel disease and/or resting dyssynergy--for the diagnosis of coronary artery disease. The test does not offer an "all or none" binary result but rather a complex stratification of the ischemic response along the coordinates of time and space. accurately identifying the degree of physiological impairment of coronary reserve. the severity and extent of coronary disease. the geographic location of the area at risk. and the prognostic outlook. It offers highly competitive diagnostic information versus more sophisticated. time-consuming. and costly radionuclide techniques; in comparison with other stress echocardiography techniques. it is more feasible than exercise and less invasive and better tolerated than pacing. The electrocardiogram usefully integrates the information provided by the mechanical marker of ischemia during dipyridamole testing. The finding of echocardiographically silent ST segment depression represents a clue to the identification of angiographically normal coronary arteries. On the basis of this evidence. dipyridamole testing with two-dimensional echocardiography and 12-lead electrocardiography can be considered a reasonable choice for the exercise-independent diagnosis of coronary artery disease.
Dobutamine versus dipyridamole echocardiography in coronary artery disease, Dobutamine and dipyridamole echocardiography are gaining popularity as exercise-independent stress tests for the diagnosis of coronary artery disease. To compare the feasibility. sensitivity. and specificity of dobutamine echocardiography to dipyridamole echocardiography. we conducted both tests. on different days and in random order. on 35 patients with chest pain and suspected coronary artery disease. Dobutamine was administered in scalar doses up to 40 micrograms/kg per minute and dipyridamole up to 0.84 mg/kg for 10 minutes. Dobutamine echocardiography testing was positive in eight of 16 (50%) patients with single-vessel disease and in 11 of 12 (92%) patients with multivessel disease. resulting in an overall sensitivity of 68% for the presence of coronary artery disease. Dipyridamole echocardiography testing showed the same sensitivity as dobutamine in patients with multivessel disease but a lower sensitivity (31%) in single-vessel disease. resulting in an overall sensitivity of 57%. The specificity of both tests was 100%. An ST segment shift of more than 1 mm compared with baseline was documented in 74% of the positive dobutamine echocardiography tests and in 81% of the positive dipyridamole echocardiography tests. No major complications occurred during both tests. Ventricular arrhythmias occurred in 11 patients with dobutamine and in none with dipyridamole (31% versus 0%. p less than 0.001). Thus. in our selected population dobutamine echocardiography testing demonstrated a similar overall sensitivity and specificity for the diagnosis of coronary artery disease compared with dipyridamole. with a slightly better sensitivity for single-vessel disease but a greater arrhythmogenic potential.
Stress testing in the period after infarction, Dipyridamole echocardiography is gaining popularity as an exercise-independent diagnostic method in patients with suspected or demonstrable coronary artery disease. To assess its safety. feasibility. and diagnostic accuracy in patients recovering from uncomplicated acute myocardial infarction. 131 patients had the test before hospital discharge. The results were compared with those of maximum treadmill testing. We found that dipyridamole-induced transient asynergy remote from the infarct zone was more sensitive (74% versus 53%. p less than 0.05) and specific (97% versus 68%. p less than 0.01) than treadmill testing for detecting multivessel coronary artery disease. In a subgroup of 42 patients treated with thrombolytic therapy. dipyridamole echocardiography was able to detect in 27 the presence of jeopardized but viable myocardium in the infarct zone. An excellent correlation was found between dipyridamole echocardiography responses and infarct vessel patency. Finally. the prognostic impact of dipyridamole echocardiography on patients recovering from acute myocardial infarction was assessed in a consecutive series of 151 patients. Eighteen months of event-free survival was significantly different in patients with positive versus negative dipyridamole echocardiography results (76.1% versus 50.8%. p less than 0.01). The test was also superior to treadmill testing in predicting cardiac events. Thus. dipyridamole echocardiography performed early after acute myocardial infarction is safe. feasible. and accurate for predicting the extent of coronary artery disease and 18-month clinical outcome.
Physiological assessment of sensitivity of noninvasive testing for coronary artery disease, The sensitivity of three noninvasive tests for coronary artery disease was assessed by means of quantitative indexes of disease severity in three different groups of patients. The overall population consisted of 110 subjects with limited coronary artery disease and no myocardial infarction. Planar dipyridamole-201Tl scintigraphy was evaluated in 31 patients. computer-assisted exercise treadmill in 28. and high-dose dipyridamole echocardiography testing in 51. Sensitivity was assessed by rigorous gold standards to define disease severity. such as measurement of minimum cross-sectional area and percent area of stenosis. by quantitative computerized coronary angiography (Brown/Dodge method). On the basis of the results of previous studies. the presence of physiologically significant coronary artery disease was indicated by a stenotic minimum cross-sectional area (MCSA) of less than 2.0 mm2 or a greater than 75% area of stenosis. With MCSA as the gold standard. dipyridamole-201Tl scintigraphy. computerized exercise treadmill. and dipyridamole echocardiography testing showed sensitivities of 52%. 54%. and 61%. respectively. in the three different patient cohorts enrolled. With percent area of stenosis as the gold standard. the sensitivity figures obtained for dipyridamole-201Tl. computerized exercise treadmill. and dipyridamole echocardiography testing were 64%. 54%. and 69%. respectively. For each of the three tests. sensitivity increased with increasing lesion severity. Sensitivity was also better in patients with left anterior descending coronary (LAD) disease when compared with patients with left circumflex or right coronary artery disease. Results of these studies. which were obtained with more strict patient selection criteria and by more rigorous gold standards than previous studies. demonstrate that in patients with limited coronary artery disease none of the tests evaluated is definitely superior in sensitivity.
Anaerobic threshold in patients with exercise-induced myocardial ischemia, The aim of the present study was to investigate the ventilatory anaerobic threshold in patients with exercise-induced myocardial ischemia. Ventilatory volumes and gas exchanges were measured during treadmill stress testing in 36 patients (11 with previous myocardial infarction) with electrocardiographic criteria of myocardial ischemia during the test and in 23 healthy. untrained control subjects of equivalent age. The anaerobic threshold was detected in 32 of 36 patients (89%) and in 22 of 23 control subjects (96%). The anaerobic threshold was significantly lower in patients than in control subjects (13.5 +/- 1.9 versus 19.7 +/- 1.7 ml/kg per minute VO2. p less than 0.001). In the 21 patients without previous myocardial infarction. the anaerobic threshold was also significantly lower than in the control subjects (13.9 +/- 1.6 versus 19.7 +/- 1.7 ml/kg per minute VO2. p less than 0.001). Among the 21 patients without previous myocardial infarction. the 12 with a low ischemic threshold. which occurred during the first three steps of the modified Bruce protocol. had an anaerobic threshold significantly lower than the other nine patients (13.1 +/- 1.5 versus 14.9 +/- 1.0 ml/kg per minute VO2. p less than 0.01). However. even in the patients with a moderate to high ischemic threshold. the anaerobic threshold was significantly lower than in the control subjects (p less than 0.001). These data show that the anaerobic threshold can be measured in the great majority of patients with exercise-induced myocardial ischemia. The low anaerobic threshold level indicates a relevant functional impairment in these patients.
Right coronary artery disease. Pathophysiology, clinical relevance, and methods for recognition, Among the clinical manifestations of ischemic heart disease. right coronary artery (RCA) disease offers a wide variety of right and left ventricular ischemic involvement. including prevalent right ventricular dysfunction and severe cardiac failure. Whether the right ventricular impairment is dependent primarily on ischemia of the right ventricle or requires a concomitant left ventricular dysfunction remains debatable. To assess the pathophysiology and clinical relevance of RCA-related ischemia. a systematic study of patients with single RCA disease (either vasospastic angina at rest or typical stable angina) was undertaken by radionuclide ventriculography. A high incidence of ischemia-induced right ventricular dysfunction was observed (93% and 95% in angina at rest and on effort. respectively). either alone or associated with left ventricular impairment. These results were compared with those obtained in a control population with isolated left anterior descending artery disease and either primary or secondary angina pectoris. We infer that the impairment of the right ventricle was related primarily to right ventricular ischemia and that left ventricular dysfunction alone did not cause an important depression of right ventricular systolic function. In conclusion. the clinical manifestations of RCA disease can be protean; the right ventricle can be the target of ischemia. and recognition of its impairment poses diagnostic problems. Radionuclide ventriculography and two-dimensional echocardiography. together with stressors of coronary flow reserve. are reliable techniques for assessing RCA-related ischemia.
Dipyridamole echocardiography stress testing in hypertensive patients. Targets and tools, Arterial hypertension can provoke a reduction in coronary flow reserve through several mechanisms that are not mutually exclusive. namely. coronary artery disease. left ventricular hypertrophy. and microvascular disease. These different targets of arterial hypertension should be explored with different diagnostic markers. The transient dyssynergy detected by two-dimensional echocardiography and evoked during dipyridamole infusion is a marker of coronary disease that is equally reliable in normotensive and hypertensive individuals. On the contrary. dipyridamole-induced ST segment depression is frequently elicited in hypertensive patients when angiographically assessed coronary disease is absent. This ischemiclike electrocardiographic response can be found in echocardiographically assessed left ventricular hypertrophy. However. even when left ventricular mass is normal. dipyridamole-induced ST segment depression is associated with an impaired coronary flow response to pacing. which is consistent with microvascular disease. Whether echocardiographically silent electrocardiographic changes are simply diagnostic noises transmitting a misleading false positive response or a potentially important clinical marker of early myocardial damage remains a pivotal though still unanswered question.
Exercise testing in patients with microvascular angina, The widespread use of exercise testing for the detection of myocardial ischemia in patients suspected of having coronary artery disease led to the detection of ischemic changes in many subjects who subsequently were found to have angiographically normal epicardial vessels--the false positive response. Such a result is usually interpreted as indicating that the subject's chest pain is of noncardiac origin. For the past several years. we have studied the mechanism of pain resembling angina that occurs in patients with normal epicardial coronary arteries demonstrated by angiography; we believe these studies have shed some light on this problem. Patients with angiographically normal coronary arteries who present because of a history of angina-like pain and/or ischemic changes detected during exercise electrocardiogram testing were evaluated by measuring great cardiac vein flow (under baseline conditions and after cardiac pacing. with and without intravenous administration of ergonovine) and by radionuclide angiography before and during exercise. We found that a substantial number of these subjects showed inadequate coronary vasodilator reserve and had exercise-induced left ventricular dysfunction suggestive of myocardial ischemia. We concluded from our results that there is a distinct clinical syndrome of myocardial ischemia caused by abnormal resistance responses of the prearteriolar coronary microvasculature. We now refer to this syndrome as microvascular angina. In a series of 115 patients with documented microvascular angina. we also found that only 10% had ischemic ST changes with exercise testing (2% of the men and 17% of the women developed ischemic ST segment changes).
Comparison of exercise testing with studies of coronary flow reserve in patients with microvascular angina, Abnormal small coronary artery function may cause limited coronary flow responses to stress. resulting in anginal symptoms and ischemia in some patients with chest pain despite angiographically normal coronary arteries. To assess the exercise hemodynamic correlates of coronary flow abnormalities measured in the cardiac catheterization laboratory. 105 patients with microvascular angina (defined as an increase in coronary vascular resistance during pacing stress after ergonovine administration in the absence of significant epicardial constriction and associated with provocation of the patient's typical chest pain) and 27 patients without any coronary flow abnormality (normal) were analyzed. Of the 105 patients with microvascular angina. 75 had normal electrocardiographic responses to treadmill exercise testing. 22 had ischemic responses. and eight had bundle branch block during exercise. All 27 normal patients had normal electrocardiographic responses to exercise. Patients with ischemic electrocardiographic responses (0 +/- 7%. p less than 0.01). and those with bundle branch block (-2 +/- 6%. p less than 0.01) had abnormal left ventricular ejection fraction responses to exercise compared with the normal group. who demonstrated an 8 +/- 6% increase in left ventricular ejection fraction by radionuclide angiography during exercise. and microvascular angina patients with a normal electrocardiographic response to exercise. who demonstrated a 5 +/- 7% increase in ejection fraction. Although the microvascular response to ergonovine was no different among the three microvascular angina exercise groups. the administration of dipyridamole caused less coronary vasodilation in those patients with apparently ischemic or bundle branch block responses to exercise compared with those with normal electrocardiograms during exercise.
Prognostic impact of stress testing in coronary artery disease, Observational data prospectively collected permit the examination of a complex set of decisions. including the decision not to perform any stress testing. Patients with or without previous myocardial infarction admitted for coronary evaluation and not submitted to any stress testing because of clinical reasons are at a higher risk for subsequent death. For prognostication. no test has been better validated than exercise electrocardiography: it can identify patients at low and high risk for future cardiac events among those without symptoms. with typical chest pain. and with previous myocardial infarction. In patients with triple-vessel disease. the results of exercise also allow those at low and high risk to be recognized. Both exercise radionuclide angiography and 201Tl scintigraphy (the latter in larger patient populations) have also demonstrated significant prognostic value on patients with or without previous myocardial infarction. Neither one has shown superiority to the other in prognostication. So far. they have been considered the only viable alternatives to exercise electrocardiography stress testing for diagnosis and prognostication. However. their costs limit their extensive application. Preliminary data suggest that intravenous dipyridamole echocardiography can be used for both diagnosis and prognostication of coronary artery disease; moreover. the prognostic information derived from dipyridamole echocardiography testing seems independent of and additive to that provided by exercise electrocardiography. Further prospective studies on larger patient populations are needed to better define the prognostic value of dipyridamole echocardiography testing.
Algorithm to predict triple-vessel/left main coronary artery disease in patients without myocardial infarction. An international cross validation, Logistic regression was applied to the clinical. risk factor. and exercise data of consecutive angiographic referrals without prior myocardial infarction to determine an algorithm predicting the probability of triple-vessel/left main coronary artery disease. These data were obtained from a total of 1.074 such subjects from patient populations at four centers (Cleveland Clinic Foundation. Cleveland. Ohio; Hungarian Institute of Cardiology. Budapest. Hungary; the university hospitals. Zurich and Basel. Switzerland; and the Veterans Administration Medical Center. Long Beach. Calif.) and used to derive four separate probability algorithms. Each algorithm is based on patient data from study samples at three of the four centers and consists of 272 logistic functions. which are related to linear combinations of 13 variables (age. sex. type of chest pain. systolic blood pressure. resting electrocardiogram. serum cholesterol. fasting blood sugar. achieved exercise work load. achieved heart rate. exercise-induced angina and hypotension. heart rate-adjusted resting ST depression. and exercise ST slope). The four algorithms were cross validated by testing them on the populations not involved in their derivation. The resulting probabilities in the four test groups were then compared with the angiographic findings of triple-vessel/left main coronary artery disease. The discriminatory power of all the algorithms was fair to good (area under receiver operating characteristic curve. 0.68. 0.75. 0.82. 0.85) in the test groups. The algorithm did not significantly underestimate or overestimate disease probability except in one center (Long Beach).
Alterations of platelet membrane microviscosity in essential hypertension, 1. The metabolism of blood platelets. taken as an accessible model of excitable cells. has been reported to be altered in hypertension. Most of the identified alterations concern the functions of various plasma membrane constituents. 2. A possible modification of membrane microviscosity was investigated by 1.6-diphenyl-1.3.5-hexatriene and 1-[4-(trimethylamino)phenyl]-6-phenyl-1.3.5-hexatriene fluorescence depolarization. In order to determine whether or not the membrane structures probed by these indicators were related to platelet physiological functions. the cytosolic free Ca2+ concentration was determined in parallel. 3. At physiological temperature. the fluorescence anisotropy of 1-[4-(trimethylamino)phenyl]-6-phenyl-1.3.5-hexatriene was decreased in untreated hypertensive patients (0.276 +/- 0.002 versus 0.288 +/- 0.002. n = 23 and 22. P less than 0.001). indicating a lowered microviscosity at the lipid-water interface of cell membrane. It correlated inversely with blood pressure (P less than 0.001) and cytosolic free Ca2+ concentration (P less than 0.030). On the contrary. 1.6-diphenyl-1.3.5-hexatriene fluorescence anisotropy was observed to vary with sex but not with blood pressure. 4. These results suggest that structural membrane modifications may participate in the various functional abnormalities observed in platelets from hypertensive patients.
Cardiac and whole-body [3H]noradrenaline kinetics during adrenaline infusion in man, 1. To investigate the possible role of adrenaline as a modulator of noradrenaline release from the sympathetic nervous system. the responses of cardiac and whole-body noradrenaline kinetics to intravenous infusions of adrenaline (30 ng min-1 kg-1) and matching saline placebo were determined at rest and during supine bicycle exercise in 16 patients undergoing cardiac catheterization. in whom beta-adrenoceptor antagonists had been discontinued for 72 h. 2. At rest and compared with placebo. infusion of adrenaline was associated with a small increase in arterial plasma noradrenaline from 211 +/- 29 pg/ml to 245 +/- 29 pg/ml (P less than 0.05). Increases in whole-body noradrenaline spillover to arterial plasma were larger (from 282 +/- 40 ng min-1 m-2 to 358 +/- 41 ng min-1 m-2. P less than 0.01) and there was a trend towards an increase in whole-body noradrenaline clearance. Cardiac noradrenaline clearance was modestly increased during adrenaline infusion. but cardiac noradrenaline spillover was not altered despite increases in heart rate and coronary sinus plasma flow. Adrenaline infusion was associated with symptomatic myocardial ischaemia in four of 14 patients with coronary heart disease. 3. Supine bicycle exercise was associated with significant increases in peripheral noradrenaline concentrations and in cardiac and whole-body noradrenaline spillover. The increases on exercise were not significantly different for these variables during saline and adrenaline infusions. 4. Infusion of adrenaline to produce 'physiological' increases in plasma adrenaline concentration was associated with an increase in total noradrenaline release. as assessed by whole-body noradrenaline spillover to plasma.
Influence of neuropathy on the microvascular response to local heating in the human diabetic foot, 1. The diabetic neuropathic foot exhibits excess arteriovenous anastomotic shunt flow due to a reduced sympathetic vasoconstrictor tone. Local axon reflexes (mediating postural vasoconstriction. for example) are preserved even in severe diabetic neuropathy. This excess shunt flow and its local neurogenic control may be important in the development of complications of the neuropathic limb. 2. The response of arteriovenous anastomoses to local heating was assessed in 13 diabetic patients with neuropathy (12 insulin-dependent). 10 diabetic control patients (seven insulin-dependent) and 10 normal control subjects. The aim was to study the local reflex control of arteriovenous flow when central sympathetic tone had been largely removed. 3. The change in skin blood flow on local heating to 44 degrees C was measured by using a laser Doppler flowmeter in standard environmental conditions with the foot at heart level. Two sites were assessed: (i) the plantar surface of the great toe (a site in which skin blood flow is dominated by arteriovenous shunt flow) and (ii) the dorsum of the foot (a site without anastomotic flow). 4. It was found that when heat was applied to the plantar surface of the great toe in the diabetic patients with neuropathy a paradoxical decrease in flow through arteriovenous anastomoses occurred. flow declining to 65% (P less than 0.05) of its resting value. This could be compared with an increase in flow over the same time period of 262% and 228% (P less than 0.01) in diabetic control patients and normal subjects. respectively.
Aging and renal function, Reflection on the circumstances of the elderly permits one to understand the risk factors for renal disease that are present in that population; to consider what impact impairment of the primary functional capacities of the kidney will have; to structure a diagnostic work-up; and finally. to close the loop by modifying care in order to protect the elderly from renal insufficiency.
Extracorporeal shock wave lithotripsy: indications and technique, In spite of some long-term uncertainties. this new method for treating stones has one tenth the morbidity and risk of any comparable method of stone removal. at least in the short term. Extracorporeal shock wave lithotripsy can be used to treat 70% to 80% of stones that would otherwise require surgery to be removed. Using ESWL in conjunction with endoscopic procedures means that less than 1% of patients with stones will need an open surgical procedure. The need for metabolic evaluation and prevention of stone disease should continue to be emphasized. however. despite the lowered morbidity of treatment.
Endoscopic treatment by snare electrocoagulation prior to Nd:YAG laser photocoagulation in 85 voluminous colorectal villous adenomas, The association of endoscopic resection with Nd:YAG laser photocoagulation was used to treat benign colorectal villous adenomas. Eight-five patients were included: 49 with surgical contraindications. 35 for whom surgical resection appeared to be too hazardous. and 1 who refused surgery. Forty-five tumors had an axial extension between 1 and 3 cm. and 40 tumors had an axial extension of at least 4 cm. Diathermic snare resection was performed to remove large tumoral fragments prior to laser photocoagulation of the residual flat lesions. Treatments were repeated every 15 days until total tumor destruction was achieved. A carcinoma was detected in biopsy specimens obtained during endoscopic treatment of five patients. Two patients were lost to follow-up. Treatment results could be analyzed in 78 patients. Successful treatment was achieved in 67 patients. Tumor destruction was complete in 77 percent of patients who had lesions of at least 4 cm diameter and in 93 percent of patients with smaller lesions. The axial extension of the tumor was the main factor affecting the results of treatment. No major complications occurred. During the average 103-week follow-up period. 21 percent of the patients with total tumor destruction had a recurrence. The risk of recurrence was correlated with the number of initial treatment sessions and previous surgery treatment. It would appear that the treatment with endoscopic resection prior to Nd:YAG laser photocoagulation is a safe and effective method in the destruction of colorectal villous adenomas.
Mucosal cell proliferation of the rectal stump in ulcerative colitis patients after ileorectal anastomosis, The proliferative activity and polyamine levels of the rectal epithelium in unoperated ulcerative colitis patients and in ulcerative colitis patients after total colectomy and ileorectal anastomosis were determined and compared with control subjects. Cell proliferation was evaluated in rectal biopsies by in vitro 3H thymidine incorporation by measuring the labeling index and the position of labeled cells along the crypt; polyamines were determined with a chromatographic method. In ulcerative colitis patients the labeling index was significantly increased. and labeled cells were shifted toward the upper part of the crypt when compared with controls. Ileorectal anastomosis patients showed a normalization of the labeling index and a distribution of labeled cells similar to controls. Polyamine levels were also increased in ulcerative colitis patients; in ileorectal anastomosis patients. the level of polyamines was decreased in respect to unoperated patients and return to normal values except for spermine. Because the increased proliferation and higher polyamine levels are related to increased colon cancer risk. our results confirm that ulcerative colitis is a risk factor for the development of carcinoma. Ileorectal anastomosis may reduce this risk through a normalization of mucosal cell proliferative activity and of some polyamine levels.
Sugar in the reduction of incarcerated prolapsed bowel. Report of two cases, Incarcerated. prolapsed rectum. colostomies. and ileostomies. when viable. may be reduced using ordinary table sugar. The placing of sugar granules on the incarcerated bowel results in a decrease in tissue edema and spontaneous bowel reduction. The technique. case reports. and a review of the literature are herein reported.
Simultaneous esophageal pH monitoring and scintigraphy during the postprandial period in patients with severe reflux esophagitis, To compare reflux events detected by intraesophageal pH monitoring with that of scintigraphy. we simultaneously performed both techniques along with esophageal manometry in nine patients with severe reflux esophagitis. Two hundred eighteen reflux events were detected in the recumbent posture after a meal during a 40-min interval. Both techniques simultaneously detected only 23% of all reflux events. Scintigraphy alone detected 61% of all reflux events as opposed to 16% for pH monitoring. Of those reflux events diagnosed only by scintigraphy. more occurred while the intraesophageal pH was less than 4 (ie. during an acid-clearing interval) than while the intraesophageal pH was greater than 4 (ie. when intragastric contents were neutralized by the meal). Most reflux events occurred during periods of stable. but low LES pressure. While reflux events diagnosed by scintigraphy significantly decreased during the second of two 20-min postprandial intervals. those by pH monitoring tended to increase. That simultaneous scintigraphy and pH monitoring agreed on less than 1/3 of all reflux events not only underscores the fact that both techniques measured different physical components of the esophageal refluxate (ie. volume vs acid concentration. respectively). but also were influenced by different physiologic events such as the ingestion of a meal. gastric emptying. and esophageal acid clearance.
Ethanol-induced gastric injury. Role of submucosal venoconstriction and leukotrienes, Under in vivo microscopic observation. intragastric ethanol instillation has been seen to cause a prompt. marked constriction of submucosal venules. followed by congestion in mucosal capillaries and severe gross mucosal lesion formation. This study was designed to test the hypothesis that the venoconstriction is mediated by leukotrienes and that inhibition of the venoconstriction would protect against ethanol injury. Intragastric application of the leukotriene receptor antagonist MK-571 inhibited both venoconstriction and gross lesion formation. However. although local submucosal application of MK-571 inhibited venoconstriction. it did not protect the overlying gastric mucosa against ethanol injury. We conclude that leukotrienes play a significant pathogenetic role in ethanol-induced gastric mucosal injury. but while the venoconstriction. mediated by leukotrienes. is one of the factors that promote lesion formation. it is not an essential one.
Towards a less costly but accurate test of gastric emptying and small bowel transit, Our aim is to develop a less costly but accurate test of stomach emptying and small bowel transit by utilizing selected scintigraphic observations 1-6 hr after ingestion of a radiolabeled solid meal. These selected data were compared with more detailed analyses that require multiple scans and labor-intensive technical support. A logistic discriminant analysis was used to estimate the sensitivity and specificity of selected summaries of scintigraphic transit measurements. We studied 14 patients with motility disorders (eight neuropathic and six myopathic. confirmed by standard gastrointestinal manometry) and 37 healthy subjects. The patient group had abnormal gastric emptying (GE) and small bowel transit time (SBTT). The proportion of radiolabel retained in the stomach from 2 to 4 hr (GE 2 hr. GE 3 hr. GE 4 hr). as well as the proportion filling the colon at 4 and 6 hr (CF 4 hr. CF 6 hr) were individually able to differentiate health from disease (P less than 0.05 for each). From the logistic discriminant model. an estimated sensitivity of 93% resulted in similar specificities for detailed and selected transit parameters for gastric emptying (range: 62-70%). Similarly. combining selected observations. such as GE 4 hr with CF 6 hr. had a specificity of 76%. which was similar to the specificity of combinations of more detailed analyses. Based on the present studies and future confirmation in a larger number of patients. including those with less severe motility disorders. the 2-. 4-. and 6-hr scans with quantitation of proportions of counts in stomach and colon should provide a useful. relatively inexpensive strategy to identify and monitor motility disorders in clinical and epidemiologic studies.
Monocyte zinc and in vitro prostaglandin E2 and interleukin-1 beta production by cultured peripheral blood monocytes in patients with Crohn's disease, This study investigated the relationship between zinc status and prostaglandin E2 and interleukin-1 beta production by cultured monocytes in patients with Crohn's disease. Monocyte zinc was significantly decreased in both 12 inpatients and 22 outpatients compared with controls (P less than 0.001) but lymphocyte and polymorphonuclear cell zinc were normal. When cultured monocytes from 10 outpatients with Crohn's disease were stimulated with lipopolysaccharide. prostaglandin E2 production increased markedly. coupled with a fall in monocyte zinc. In matched controls. prostaglandin E2 production was significantly less and monocyte zinc remained stable. No difference in interleukin-1 release was noted between patients and controls. The addition of prednisolone to cell cultures suppressed prostaglandin E2. interleukin-1 synthesis. and monocyte zinc did not change. Zinc chloride augmented prostaglandin E2 production in patients. but not controls. and interleukin-1 remained stable. These results demonstrate a link between low monocyte zinc concentration and excessive prostaglandin production in patients with Crohn's disease.
Protooncogenes and growth factors associated with normal and abnormal liver growth, Hepatocyte replication during liver regeneration depends on extrinsic (circulating) and intrinsic (intrahepatic) factors. Two important growth factors produced in the regenerating liver are discussed. TGF alpha. an autocrine. stimulatory growth factor. and TGF beta. a paracrine inhibitory factor. The balance between the activities of these factors is likely to play an important role in regulating hepatocyte proliferation. The expression of some protooncogenes occurs sequentially during the first few hours after partial hepatectomy and is a marker for the entry of hepatocytes into the cell cycle (proliferative competence). As hepatocytes become competent to proliferate. they respond to TGF alpha and other growth factors and enter a proliferative phase. It is possible that TGF beta 1 serves as a stop signal for liver regeneration but the mechanisms by which TGF beta inhibits hepatocyte DNA synthesis are still unknown.
Reproductive outcome after unilateral tubocornual anastomosis and contralateral salpingostomy by microsurgery, A unilateral tubocornual anastomosis and a contralateral salpingostomy for unilateral proximal and contralateral distal occlusive disease yield similar fertility as does pure tubocornual anastomosis for proximal occlusive disease. Ascending inflammation is postulated as the mechanism for tubal occlusion. with distal sparing from disease if the initial insult results in initial occlusion of the proximal portion of the oviduct.
Anaphylactic reaction because of intrauterine 32% dextran-70 instillation, Anaphylactic reaction associated with hysteroscopy using 32% dextran-70 as a distending medium is a rare phenomenon. We report anaphylactic reaction associated with hysteroscopy using dextran that was delivered manually in three otherwise healthy women occurring within a 6-month period. The rapidity and pressure of dextran administered might facilitate intravascular absorption and predispose patients to this phenomenon.
Serum androsterone conjugates differentiate between acne and hirsutism in hyperandrogenic women, OBJECTIVE: To determine if among hyperandrogenic women acne may be differentiated from hirsutism by markers of peripheral androgen metabolism. DESIGN: Prospective outpatient study of 36 hyperandrogenic women and controls divided into groups based on the presence or absence of significant hirsutism and the presence or absence of moderate to severe acne. Serum levels of adrenal and ovarian derived androgens were elevated but similar in all patient groups. INTERVENTIONS: Measurement of serum androgens including metabolites of 5 alpha-reductase activity: 3 alpha-androstanediol glucuronide and sulfate and androsterone (A) glucuronide and sulfate. RESULTS: 3 alpha-androstanediol glucuronide and sulfate were elevated in all groups (P less than 0.05) and could differentiate between hirsute and nonhirsute patients but were similar in patients with and without acne. Serum A glucuronide and sulfate were only significantly elevated in patients with acne (P less than 0.01) and were higher than levels in controls and hirsute patients without acne. Ratios of precursor androgens to A glucuronide and sulfate were significantly higher in patients with acne compared with patients without acne (P less than 0.05). CONCLUSIONS: Altered peripheral metabolism in acne may favor the formation of A conjugates. which may help differentiate acne from hirsutism among hyperandrogenic women.
Increased circulating levels of bromocriptine after vaginal compared with oral administration, OBJECTIVE: To compare the circulating levels of bromocriptine after oral and vaginal administration of the drug. DESIGN: Experimental PARTICIPANTS: Seven ovulatory female volunteers and one hyperprolactinemic patient. INTERVENTIONS: Ovulatory volunteers were randomized to receive either oral or vaginal bromocriptine (2.5 mg). In a second session. the subjects were crossed-over to bromocriptine by the alternate route. An additional hyperprolactinemic patient received vaginal bromocriptine only. MAIN OUTCOME MEASURE: Serum bromocriptine and prolactin (PRL) levels were measured hourly for 12 hours in the normal volunteers and for 10 hours in the hyperprolactinemic patient. RESULTS: Circulating bromocriptine levels were significantly higher after vaginal bromocriptine after the 7th hour (P less than 0.05). The reduction in serum PRL was significantly greater after oral administration between 2 and 6 hours. CONCLUSIONS: Vaginally administered bromocriptine may result in a reduction in the overall dose required. thereby improving compliance without compromising therapeutic efficacy.
Oral contraceptives increase insulin-like growth factor binding protein-1 concentration in women with polycystic ovarian disease, Insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro. OBJECTIVE: To investigate the effect of oral contraceptive (OC) pills. given for 3 months. on serum gonadotropin. androgen. IGF-I. and IGFBP-1 concentrations. and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects. PATIENTS: Seven women with PCOD and five healthy control subjects. INTERVENTIONS: An oral glucose tolerance test (OGTT) was performed before and after treatment with OC. RESULTS: After treatment with OC. serum luteinizing hormone. androstenedione. and free testosterone levels decreased. and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration. which was unchanged during OGTT. decreased from basal level of 326 +/- 70 micrograms/L to 199 +/- 28 micrograms/L after treatment with OC in the women with PCOD. whereas no change was found in the control subjects (from 235 +/- 11 micrograms/L to 226 +/- 11 micrograms/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24 +/- 7 micrograms/L to 73 +/- 14 micrograms/L in the women with PCOD. This increase was constant during the OGTT. In the control subjects. treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44 +/- 11 micrograms/L to 61 +/- 9 micrograms/L). CONCLUSION: The combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.
Lipoprotein-cholesterol levels in infertile women with luteal phase deficiency, OBJECTIVE: To determine if reductions in plasma progesterone (P) secretion seen in luteal phase deficiency (LPD) might be because of reduced availability of circulating low-density lipoprotein (LDL) or high-density lipoprotein (HDL). known substrates for corpus luteum P synthesis. DESIGN: We measured plasma lipoproteins in the luteal phase of the menstrual cycle in 39 infertile women. These women were divided into two groups on the basis of endometrial biopsies; the LPD group had biopsies that were greater than or equal to 3 days out-of-phase. SETTING: All participants were recruited from the Reproductive Endocrinology and Infertility Clinic at the University of Washington. an institutional tertiary care center. PATIENTS. PARTICIPANTS: Eighteen women had in-phase and 21 had out-of-phase LPD biopsies. MAIN OUTCOME MEASURE: Lipoprotein levels were obtained in a fasted state on the day of the luteal phase on which the biopsy was performed. RESULTS: No difference in covariates that affect lipoprotein levels such as obesity. age. and alcohol use were observed between the two groups. No significant differences between groups were found for triglycerides. total cholesterol. very low density lipoprotein. LDL. HDL. HDL2. and HDL3 concentrations. However. LPD was associated with a reduction in the extent to which: age and obesity are associated with higher triglycerides; obesity is associated with a lower HDL2; and alcohol is associated with a higher HDL3-cholesterol. CONCLUSIONS: Lipoproteins on average are not different in LPD. suggesting reasons other than a deficient plasma lipoprotein cholesterol source as the explanation for decreased P secretion. A lesser interaction between LDL or HDL and obesity. age. and alcohol in LPD could signify an influence of the altered hormonal milieu of LPD on the way lipoproteins interact with covariates and could lead to differences in lipoproteins between normal and LPD subjects at the extremes of the lipoprotein distribution.
Therapeutic donor insemination: a prospective randomized study of scheduling methods, OBJECTIVE: To compare basal body temperature (BBT) graphs and urinary luteinizing hormone (LH) monitoring in scheduling therapeutic donor insemination. DESIGN: Participants were prospectively randomized to the BBT or LH groups. SETTING: Participants were private patients of the Reproductive Endocrine Division at Washington University School of Medicine. PATIENTS: Inclusion criteria were designed to assure an isolated male factor. Seventy-four of 113 patients completed the study; 18 had ongoing treatment at the end of the study. INTERVENTIONS: Basal body temperature graphs were physician interpreted and appointments prospectively chosen. Luteinizing hormone patients monitored daily urine samples and scheduled an appointment the day after the detected surge. MAIN OUTCOME MEASURES: Fecundity rates. cumulative pregnancy rates. and cost per pregnancy were all prospectively evaluated. RESULTS: Life table analysis yielded a 6-month cumulative probability of pregnancy of 36.3% in the LH group and 65.1% in the BBT group (P less than 0.025). The total cost per pregnancy was lower in the BBT group (+6.212 versus +3.997; P less than 0.001). CONCLUSIONS: This randomized prospective study demonstrates significant therapeutic and economic advantages when therapeutic donor insemination is prospectively scheduled by BBT graphs.
Computer-assisted assessment of human sperm morphology: comparison with visual assessment, OBJECTIVE: Sperm morphology classification was analyzed by the computer-assisted semen analysis equipped with the Morphologizer II (Cryo Resources Ltd.. New York. NY) was compared with the traditional manual method. DESIGN. SETTING. PATIENTS: Fifty stained semen smears from men attending the infertility clinic of a tertiary referral institution were studied. MAIN OUTCOME MEASURES: Sperm head morphology was classified by the two methods into the following forms: normal. small oval. big oval. taper. and amorphous. RESULTS: Overall. the classifications of mean percent normal. small. and amorphous head forms were similar in the two methods. However. the differences between paired values obtained by the two methods were highly variable (range from -20% to +20%). The large differences between the methods were related to the large coefficients of variations present when classifying abnormal sperm morphology even by the same experienced technician. Only the percent normal spermatozoa could be classified by both methods with acceptable precision. In contrast. the variations in the morphometric analyses between the different semen smears were very small. CONCLUSIONS: There was no advantage of the morphologizer over the manual method in sperm morphology classification. The clinical value of morphometric parameters of spermatozoa has to be defined.
Computer-assisted assessment of human sperm morphology: usefulness in predicting fertilizing capacity of human spermatozoa, OBJECTIVE: The usefulness of sperm morphology to predict the outcome of human sperm fertilizing capacity was examined. DESIGN. SETTING. PATIENTS: Semen samples from 50 male patients attending the infertility clinic of a tertiary referral institution were studied. MAIN OUTCOME MEASURES: Sperm morphology was classified both by visual assessment and computer-assisted image analysis. In addition. morphometric analysis of the spermatozoa was measured by the morphologizer. Multivariate discriminant analysis was used to evaluate the usefulness of these morphology parameters for predicting the outcome of the zona-free hamster oocyte sperm penetration assay. RESULTS: The manually derived percent of spermatozoa with normal and small head were selected to be of discriminating value in predicting the outcome of the zona-free hamster oocyte penetration test. The accuracy of correctly classifying the outcome of zona-free hamster oocyte penetration test by these two parameters in combination was 84%. whereas assessment of sperm morphology with morphometric analysis by the morphologizer selected a total of eight variables. which together predicted sperm fertilizing capacity with 74% accuracy. Addition of the morphologizer-derived parameters to those derived manually did not significantly improve the predictive value. CONCLUSION: We conclude that the results of the zona-free hamster egg penetration test could be predicted using manual assessment of sperm morphology and computer-assisted morphometric analysis did not add further information.
Metabolic effects of fish-oil supplementation in patients with impaired glucose tolerance, To determine the impact of fish-oil supplementation on glucose and lipid metabolism in patients with impaired glucose tolerance (IGT). 30 ml fish oil containing 3.8 g eicosapentaenoic acid (EPA; 20:5 omega 3) and 2.5 g docosahexaenoic acid (DHA; 22:5 omega 3) were given to eight obese subjects with IGT (mean +/- SD age 50.3 +/- 8.0 yr) in addition to their regular diet for 2 wk. Studies were performed in randomized order versus an isocaloric control period with a washout phase of 3 wk. Hyperinsulinemic clamp examinations (1 and 10 mU.kg-1.min-1) were performed. Glucose disposal rate (M value) rose from basal 14.3 +/- 5.1 to 17.9 +/- 4.4 mumol.kg-1.min-1 after fish oil (P less than 0.001) during the 1-mU clamp. whereas no change was seen during the 10-mU clamp (without fish oil. 42.2 +/- 8.9 mumol.kg-1.min-1; with fish oil. 45.1 +/- 9.8 mumol.kg-1.min-1;NS). Basal hepatic glucose output remained unaffected by fish oil. whereas fractional glucose clearance after intravenous glucose loading (2.4 mmol/kg body wt. t = 30 min) tended to increase (K value: without fish oil. 2.15 +/- 1.02%/min; with fish oil. 2.74 +/- 1.26%/min; NS). Neither the fasting concentrations of glucose and insulin nor induced glycemia and insulin response during intravenous glucose loading calculated as incremental area under the curve changed after fish-oil supplementation.
T-lymphocyte changes linked to autoantibodies. Association of insulin autoantibodies with CD4+CD45R+ lymphocyte subpopulation in prediabetic subjects, The onset of insulin-dependent (type I) diabetes is predictable before hyperglycemia by the presence of islet cell autoantibodies (ICAs) and competitive insulin autoantibodies (CIAAs). CIAA+ICA+ first-degree relatives of individuals with type I diabetes have increased numbers of CD4 cells bearing the CD45R antigen and reciprocal depressions of the CD4 cells bearing the CD29 determinant. In addition. depressed CD4/CD8 ratios are present. In this study. we investigated the correlation between autoantibody levels and T-lymphocyte changes in the prediabetic state. The data demonstrate a clear linear relationship between rising CIAA levels. a marker of disease rate. and rising elevations in the CD4+CD45R+/CD4+CD29+ ratio in 37 CIAA+ICA+ and CIAA+ICA- relatives (r = 0.93). In marked contrast. the degree of CD4/CD8 depression found in individuals with prediabetes or long-term diabetes failed to correlate with either CIAA (r = 0.32) or ICA (r = 0.29) levels. The investigation of T-lymphocyte changes in siblings of individuals with type I diabetes with different stable autoantibody patterns (CIAAs and/or ICAs). and thus varying risks for diabetes. revealed differences in the prediabetic groups. Fifteen CIAA+ICA- relatives with high CIAA levels (greater than 80 nU/ml) had high CD4+CD45R+/CD4+CD29+ ratios (P = 0.03) and depressed CD4/CD8 ratios (P = 0.008). In contrast. CIAA+ICA- relatives with low CIAA levels (39-80 nU/ml). and thus low risk of diabetes. had no alteration in their CD4/CD8 ratio (P = 0.75) or CD4+CD45R+/CD4+CD29+ ratio (P = 0.33). Nineteen CIAA-ICA+ siblings with a predicted intermediate risk for diabetes showed heterogeneity in the presence of T-lymphocyte abnormalities.
Endocrine-metabolic function in remission-phase IDDM during administration of cyclosporine, We have studied the endocrine-metabolic status of patients in non-insulin-receiving (NIR) remission of insulin-dependent diabetes mellitus (IDDM) within 6-60 mo of diagnosis during administration of cyclosporine. in comparison with nondiabetic subjects. IDDM patients in NIR remission were recognized when target glycemic control (plasma glucose and mean capillary blood glucose levels less than 7.8 mM before meals) was maintained without administration of insulin for at least 2 wk. In so-called isoglycemic tests. 50 g glucose was administered orally. and the glycemic curve was simulated in a subsequent study by programmed intravenous infusion of glucose. Under these conditions. the subjects with diabetes exhibited obvious glucose intolerance: acute beta-cell responses to intravenous glucose were virtually absent but significant. although subnormal responses were present after oral glucose. The responses of plasma immunoreactive gastric inhibitory polypeptide to oral glucose were normal. After bolus intravenous injections of glucose. the patients with diabetes again exhibited glucose intolerance; acute responses of immunoreactive insulin (IRI) and C-peptide were present. although grossly obtunded. On intravenous infusion of arginine (30 g in 30 min). the patients with diabetes showed substantial but subnormal increases in plasma IRI and C-peptide. Intravenous infusion of arginine elicited increments of plasma immunoreactive glucagon (IRGI) in both groups. and this response was slightly exaggerated in the patients with diabetes. On ingestion of a standard mixed meal (Sustacal) delivering 600 cal. there was a modest but significantly greater increase in plasma glucose levels in the diabetic subjects.
Regulation of rat insulin-receptor kinase by glucose in vivo, The effects of acute and chronic hyperglycemia on the kinase activity of insulin receptors in vivo were studied in the rat. Skeletal muscle-derived insulin receptors were isolated. with preservation of the in vivo phosphorylation state. from nondiabetic rats subjected to hyperinsulinemic clamps at either euglycemia (mean 5.2 mM) or hyperglycemia (14.4 mM) or from streptozocin-induced diabetic rats at euglycemia (5.1 mM) or hyperglycemia (14.2 mM). Kinase activity toward histone of insulin receptors from nondiabetic animals rendered hyperglycemic for 80-90 min was 50% higher than that of receptors from rats clamped at euglycemia (mean +/- SE 4.5 +/- 0.4 vs. 3.0 +/- 0.3 fmol of phosphate into histone. respectively. P less than 0.02). although kinase activity of receptors isolated from animals rendered diabetic for 10-14 days before hyperglycemic or euglycemic clamps showed no such effect. These results suggest that acute hyperglycemia may increase insulin-receptor kinase activity in vivo. possibly augmenting glucose disposal thereby. whereas the chronic hyperglycemia of diabetes mellitus results in metabolic derangements that nullify this effect.
Raynaud's phenomenon. An update, The pathogenesis of primary Raynaud's phenomenon remains an enigma. Most evidence favors a local abnormality in the digital arteries as opposed to an increased activity of the sympathetic nervous system. The local fault may involve the alpha 2-adrenergic receptors. which are most important in reflex sympathetic vasoconstriction. Cooling blood vessels increase the sensitivity of alpha 2-adrenergic receptors. increased levels of alpha 2-adrenergic receptors are present in primary Raynaud's disease. and patients show an increased sensitivity to alpha 2-adrenergic receptor agonists on finger blood flow. Serotonin has also been implicated. but the evidence is not compelling. In secondary Raynaud's phenomenon. vasospastic attacks can often be explained by a low arterial distending pressure. a thickened vessel wall. or absence of beta-adrenergic receptor activity. Diagnosis of primary Raynaud's disease relies on a typical history and normal physical examination. laboratory studies. and nailfold capillaroscopy. Finger systolic blood pressures during local cooling with ischemia may be helpful to document vasospastic attacks but does not distinguish primary from secondary Raynaud's phenomenon. The treatment of Raynaud's phenomenon is usually conservative. Pavlovian conditioning or biofeedback may be beneficial. When drug therapy is necessary. the calcium channel entry blocker nifedipine or sympatholytic agents have been shown to decrease the frequency and duration of vasospastic attacks in about two thirds of patients. although subjective improvement does not usually correlate with objective testing. Direct-acting vasodilators have not been shown to be of definite benefit. New therapies include prostaglandins. captopril. and the serotonergic antagonist ketanserin. Surgical sympathectomy has not been beneficial.
Agonist-sensitive calcium stores in arteries from steroid hypertensive rats, The present study characterizes cellular calcium stores that are sensitive to norepinephrine and caffeine in arteries from deoxycorticosterone acetate hypertensive rats. Mesenteric arteries from normotensive and hypertensive rats were excised and cut into helical strips for isometric force recording. In calcium-free solution. phasic contractile responses to norepinephrine (5.9 x 10(-9) to 5.9 x 10(-6) M). but not caffeine (0.3-30 mM). were greater in hypertensive arteries. D-600. a calcium channel blocker. or removal of the endothelium did not alter phasic contractions to norepinephrine or caffeine. In contrast. contractions to both norepinephrine and caffeine were inhibited by ryanodine. a drug that depletes calcium from intracellular stores. An inhibitor of phospholipase C (2-nitro-4-carboxyphenyl N.N-diphenylcarbamate) attenuated contractions to norepinephrine but not those to caffeine. The augmented response to norepinephrine in hypertensive rats did not occur early after implantation of the mineralocorticoid. suggesting that this vascular change may not play a role in the development of high blood pressure in this experimental model. The augmented response to norepinephrine was reduced in mineralocorticoid-treated rats maintained on a low sodium diet. and these rats had blood pressures in the normotensive range. Because contractile responses to caffeine were not enhanced in arteries from hypertensive rats. we conclude that the cellular store for calcium is not enlarged compared with that in normotensive arteries. In contrast. the mobilization of calcium from cellular stores by norepinephrine is augmented in mineralocorticoid hypertension. This augmented response may be linked to altered phospholipase C activity and thus to an augmented action of inositol trisphosphate that releases calcium from intracellular sites.
Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism, Angiotensin II. when given in low doses. raises blood pressure slowly. When tested in vitro on vascular smooth muscle cells. it has mitogenic and trophic effects; it is not known if it has these effects in vivo. Our purpose was to determine whether vascular hypertrophy develops during slow pressor infusion of angiotensin II and. if so. whether it is pressure induced. Three experiments were done in rats infused subcutaneously with angiotensin II (200 ng/kg/min) by minipump for 10-12 days. Experiment 1: Angiotensin II gradually raised systolic blood pressure (measured in the tail) from 143 +/- 2 to 208 +/- 8 mm Hg (mean +/- SEM). significantly suppressing plasma renin and increasing threefold (NS) plasma angiotensin II. There was no loss of peptide in the pump infusate when tested at the end of the experiment. Experiment 2: In the perfused mesenteric circulation. vasoconstrictor responses to norepinephrine. vasopressin. and KCl were enhanced in rats given a slow pressor infusion of angiotensin II. but sensitivity of responses was not altered. This combination of changes suggests that vascular hypertrophy develops during slow pressor infusion of angiotensin II. Experiment 3: Vessel myography was done after angiotensin II infusion with and without a pressor response. Angiotensin II raised systolic blood pressure. increased heart weight. and produced myographic changes of vascular hypertrophy in the mesenteric circulation. increasing media width. media cross-sectional area. and media/lumen ratio. Hydralazine given with angiotensin II prevented the rise of pressure and the cardiac effect but not the vascular changes. Two-way analysis of variance showed that angiotensin II significantly increased media width. media cross-sectional area. and media/lumen ratio. all independent of hydralazine. Thus. although hydralazine inhibits the pressor and cardiac effects of angiotensin II. suggesting a pressor mechanism for the cardiac change. it does not inhibit structural vascular change. which suggests that at least part of the effect has a non-pressor mechanism.
Once-daily fosinopril in the treatment of hypertension, This multicenter. dose-ranging study evaluated the antihypertensive effectiveness of once-daily administration of fosinopril sodium in 220 patients with supine diastolic blood pressure of 95-115 mm Hg. After a 4-week placebo period. patients were randomly assigned to double-blind therapy with either placebo or 10. 40. or 80 mg fosinopril once daily for 4 weeks. If treatment goals were not met. chlorthalidone 25 mg/day was added for weeks 5 to 8. Thereafter. patients could enter the long-term. open-label phase and receive 10-80 mg/day fosinopril plus chlorthalidone. if needed. After 4 weeks of monotherapy. the average decreases in supine diastolic blood pressure were 9% (10 mg). 11.5% (40 mg). and 12.5% (80 mg) compared with 6% in the placebo group. After 8 weeks. the average decreases. with or without diuretic therapy. were 12.5-18.2%. compared with 10.8% with placebo. Blood pressure continued to be well controlled. and the patients showed no evidence of tachyphylaxis or tolerance through 12-15 months of treatment. Fosinopril was well tolerated. During the short-term phase. no patient withdrew because of adverse events possibly related to fosinopril; during the long-term phase. nine of 148 patients (6.1%) withdrew for that reason. In patients with mild-to-moderate hypertension. once-daily fosinopril (40 and 80 mg) provided significant antihypertensive effects with or without diuretic therapy. The 10 mg dose was effective in some patients and may be considered a starting dose.
Red blood cell lithium-sodium countertransport in the tecumseh blood pressure study, Human essential hypertension has more than one cause. but to dissect out subtypes. markers are required. The maximal activity of red blood cell lithium-sodium countertransport has been shown to be increased in hypertensive patients in case-control and population-based studies; in the latter. its distribution is a mixture of two overlapping but distinguishable subpopulations. In the present study. we classified 705 participants in the Tecumseh Blood Pressure Study as having either normal (mean. 0.234 mmol/l cells/hr; n = 614) or high (mean. 0.463 mmol/l cells/hr; n = 91) red blood cell lithium-sodium countertransport to determine if the red blood cell marker is associated with distinctive physiological characteristics. We found that subjects with elevated lithium-sodium countertransport have higher average blood pressure and a greater prevalence of hypertension than those with normal countertransport and that elevated blood pressure had been present since youth. Hemodynamically. the high countertransport group is characterized by elevated vascular resistance. whereas sympathetic nervous system activity appears to be slightly depressed. Subjects with increased lithium-sodium countertransport. compared with those with normal countertransport. have significantly lower average left ventricular mass index and only very infrequently demonstrate left ventricular hypertrophy. Our results support the usefulness of measurements of the maximal activity of red blood cell lithium-sodium countertransport as a way of distinguishing subgroups in the population. Our data are consistent with the idea that subjects with an elevated maximal activity for red blood cell lithium-sodium countertransport are a subset of the population with a genetic lesion that predisposes them to the development of essential hypertension.
Body weight is more important than family history of hypertension for left ventricular function, Left ventricular function was studied in young men with a positive family history of hypertension for two generations (n = 15). The findings were compared with three control groups: one age-. sex-. and weight-matched group with a negative family history of hypertension (n = 14); one normotensive control group unselected as regards family history of hypertension (n = 27); and one group also unselected regarding family history of hypertension but selected with blood pressure criteria to have mild blood pressure elevation (n = 59). The group with a positive family history of hypertension. in comparison with the normotensive control group. was heavier. had higher blood pressure. increased left ventricular wall thickness. increased left ventricular mass. and signs of changes in diastolic and systolic left ventricular function. There were no differences in these variables between the group with a positive family history and the other two control groups. Data clearly indicated that subjects with a positive family history of hypertension. as well as subjects with mild blood pressure elevation. were heavier than the normotensive control group. It is not possible to judge. with available data. if the changes in left ventricular morphology and function in the two groups with a different family history of hypertension and in the group with mild blood pressure elevation occurred as a physiological response to the increase in afterload or if the neurohormonal and metabolic disturbances leading to the condition of slight overweight also affected left ventricular function.
Relation of obesity and diet to sympathetic nervous system activity, The hypothesis that dietary intake and obesity stimulate the sympathetic nervous system was investigated in a cross-sectional study of 572 men aged 43-85 years from the Normative Aging Study. Habitus was represented by body mass index. as a measure of overall adiposity. and by the ratio of abdomen-to-hip circumference (abdomen/hip ratio). as a measure of centripetal fat distribution. Sympathetic activity was assessed by measurement of 24-hour urinary norepinephrine excretion. Increased body mass index and total caloric intake were independently associated with increased 24-hour urinary norepinephrine excretion (p = 0.0001 and p = 0.0055. respectively). In addition. mean urinary norepinephrine excretion was higher in subjects classified as either hyperglycemic (serum fasting glucose greater than or equal to 113 mg/dl) and hyperinsulinemic (serum fasting insulin greater than or equal to 19 microIU/ml) (p = 0.0023) or in subjects classified as either hyperglycemic or hyperinsulinemic (p = 0.0063) than the mean urinary norepinephrine excretion in normal subjects. These relations were demonstrated to be independent of age. smoking status. and physical activity. Our results are consistent with the hypothesis that insulin mediates sympathetic stimulation in response to dietary intake and increases sympathetic nervous system activity in the obese.
Similar prevalence of renovascular hypertension in selected blacks and whites, Renovascular hypertension is a potentially curable form of high blood pressure that is thought to be extremely rare among blacks. We demonstrate. however. that in a clinically selected population. the prevalence of renovascular hypertension is similar in blacks and whites. We prospectively evaluated 167 hypertensive subjects who had one or more clinical features known to be associated with renovascular hypertension. All subjects had captopril-stimulated peripheral renin measurements and conventional renal arteriography. All significant renal artery stenoses (greater than 50% luminal narrowing) were treated with percutaneous transluminal angioplasty or surgery. Renovascular hypertension was diagnosed if there was a blood pressure response to interventional therapy. according to the criteria established by the Cooperative Study of Renovascular Hypertension. Of the total group evaluated. 24% (39 of 167) had renal artery stenosis and 14% (23 of 167) had renovascular hypertension. Renal artery stenosis or occlusion was found in 27% (26 of 97) of whites and 19% (13 of 67) of blacks (p = 0.27). Renovascular hypertension was diagnosed in 18% (17 of 97) of whites and 9% (6 of 67) of blacks evaluated (p = 0.25). Renovascular hypertension was associated with severe or refractory hypertension and with smoking. but there were no racial differences in these associations. Blacks with renovascular hypertension tended to have low captopril-stimulated peripheral renin activity. We conclude that blacks with clinical features suggestive of renovascular hypertension should be evaluated with angiography. Captopril-stimulated plasma renin may not be useful in detecting blacks with renovascular hypertension. but this and other potential screening tests require further evaluation.
Pathophysiology of renovascular hypertension, Renovascular hypertension has its experimental counterpart in the two-kidney. one clip model (Goldblatt hypertension). From the study of this model. a general pathophysiological scheme has evolved suggesting that temporal stages in the development and maintenance of hypertension are regulated by complicated hormonal and neural interrelations. The central roles played by the renin-angiotensin system and the renal nerves is discussed as they relate to other hormones. In addition. the possible contribution of converting enzyme inhibitors to understanding the pathophysiology of this condition is discussed.
Initial blood pressure fall on stand up and exercise explained by changes in total peripheral resistance, To elucidate the underlying mechanisms of the initial fall in blood pressure on standing upright from the supine position. we measured the beat-to-beat changes in intra-arterial pressure in eight healthy male subjects in response to standing. Changes in stroke volume. cardiac output. and total peripheral resistance were computed from the pressure waveform using a pulse contour method. To determine possible mechanisms for the changes observed on standing. similar measures were made on passive tilting and a brief (3-s) bout of cycle exercise. Standing elicited a transient 25% (23-mmHg) fall in mean blood pressure as a result of a 36% fall in total peripheral resistance. Head-up tilt elicited a gradual change in haemodynamic parameters. which reached plateau levels in 20-30 s. Cycling elicited a transient 17% (18-mmHg) fall in blood pressure and a 41% fall in total peripheral resistance. In addition. we measured right atrial and esophageal pressures in two subjects on standing and cycling and found a 10- to 15-mmHg rise in right atrial pressure without a corresponding change in esophageal pressure. This points to the cardiopulmonary reflex as the primary effector of peripheral vasodilation. but we cannot exclude the possibility that 1) local metabolic vasodilation and 2) central command-mediated cholinergic vasodilation contributed to the fall in vascular resistance.
Chest wall motion during epidural anesthesia in dogs, To determine the relative contribution of rib cage and abdominal muscles to expiratory muscle activity during quiet breathing. we used lumbar epidural anesthesia in six pentobarbital sodium-anesthetized dogs lying supine to paralyze the abdominal muscles while leaving rib cage muscle motor function substantially intact. A high-speed X-ray scanner (Dynamic Spatial Reconstructor) provided three-dimensional images of the thorax. The contribution of expiratory muscle activity to tidal breathing was assessed by a comparison of chest wall configuration during relaxed apnea with that at end expiration. We found that expiratory muscle activity was responsible for approximately half of the changes in thoracic volume during inspiration. Paralysis of the abdominal muscles had little effect on the pattern of breathing. including the contribution of expiratory muscle activity to tidal breathing. in most dogs. We conclude that. although there is consistent phasic expiratory electrical activity in both the rib cage and the abdominal muscles of pentobarbital-anesthetized dogs lying supine. the muscles of the rib cage are mechanically the most important expiratory muscles during quiet breathing.
Changes in upper airway resistance during progressive normocapnic hypoxia in normal men, The effects of normocapnic progressive hypoxia on nasal and pharyngeal resistances were evaluated in nine normal men. To calculate resistances. upper airway pressures were measured with two low-bias flow catheters; one was placed at the tip of the epiglottis and the other in the posterior nasopharynx. and we measured flow with a Fleish no. 3 pneumotachograph connected to a tightly fitting mask. Both resistances were obtained during a baseline period and during progressive normocapnic hypoxia achieved by a rebreathing method. We collected the breath-by-breath values of upper airway resistances. minute ventilation. O2 and CO2 fractions. arterial O2 saturation (SaO2). and changes in functional residual capacity (inductance vest). The central respiratory drive was evaluated by the mouth occlusion pressure 0.1 s after the onset of inspiration (P0.1). and breath-by-breath P0.1 values were estimated by intrapolation from the linear relationship between P0.1 and SaO2. In each subject both resistances decreased during the hypoxic test. The slope of the decrease in resistance with decreasing SaO2 (%baseline/%SaO2) was steeper for pharyngeal resistance than for nasal resistance [2.67 +/- 0.29 and 1.61 +/- 0.25 (SE). respectively; P less than 0.05]. The slope of the decrease in resistance with increasing P0.1 (%baseline/cmH2O) was -0.24 +/- 0.05 for nasal resistance and -0.39 +/- 0.07 for pharyngeal resistance (P less than 0.05). Functional residual capacity progressively increased during the test. but the decrease in resistance was greater than expected from an isolated increase in lung volume. We conclude that nasal and pharyngeal resistances decrease during progressive normocapnic hypoxia.
Maturation of respiratory reflex responses in the piglet, Stimulation of chemo-. irritant. and pulmonary C-fiber receptors reflexly constricts airway smooth muscle and alters ventilation in mature animals. These reflex responses of airway smooth muscle have. however. not been clearly characterized during early development. In this study we compared the maturation of reflex pathways regulating airway smooth muscle tone and ventilation in anesthetized. paralyzed. and artificially ventilated 2- to 3- and 10-wk-old piglets. Tracheal smooth muscle tension was measured from an open tracheal segment by use of a force transducer. and phrenic nerve activity was measured from a proximal cut end of the phrenic nerve. Inhalation of 7% CO2 caused a transient increase in tracheal tension in both age groups. whereas hypoxia caused no airway smooth muscle response in either group. The phrenic responses to 7% CO2 and 12% O2 were comparable in both age groups. Lung deflation and capsaicin (20 micrograms/kg iv) administration did not alter tracheal tension in the younger piglets but caused tracheal tension to increase by 87 +/- 28 and 31 +/- 10%. respectively. in the older animals (both P less than 0.05). In contrast. phrenic response to both stimuli was comparable between ages: deflation increased phrenic activity while capsaicin induced neural apnea. Laryngeal stimulation did not increase tracheal tension but induced neural apnea in both age groups. These data demonstrate that between 2 and 10 wk of life. piglets exhibit developmental changes in the reflex responses of airway smooth muscle situated in the larger airways in response to irritant and C-fiber but not chemoreceptor stimulation.
Separation of late bronchial responses from airway hyperresponsiveness in allergic sheep, Allergic sheep with antigen-induced early and late responses were used to determine whether airway hyperresponsiveness (AHR) to carbachol is present during the late response and whether blocking the late response with the leukotriene D4 (LTD4) antagonist MK-571 also blocks this AHR. To do this. we first showed that MK-571 blocked the antigen-induced late response. and then. in a separate study. we determined the effect of MK-571 treatment on airway responsiveness 6 h after antigen challenge (at the start of the late response). MK-571 (5 mg. by metered dose inhaler) given 30 min before and 4 h after Ascaris suum challenge had no effect on the acute response to antigen but blocked (P less than 0.05) the late response compared with placebo (n = 7). In the second study (n = 6). the antigen-induced acute increases in mean specific lung resistance (sRL) were also similar in the placebo (249%) and drug trials (247%). By 6 h postchallenge. however. mean sRL in the placebo trial began to increase (54%. P less than 0.05). whereas in the drug trial mean sRL was baseline. Nevertheless. AHR was apparent in both trials as indicated by a mean twofold leftward shift in the dose-response curves to inhaled carbachol (P less than 0.05 vs. prechallenge). Bronchoalveolar lavage at 6 h showed that MK-571 did not prevent the inflammatory cell influx into the lung. These observations suggest that although LTD4 may be a mediator of the late response in sheep. it is not a primary mediator affecting cholinergic AHR during this period.
Strength and skeletal muscle adaptations in heavy-resistance-trained women after detraining and retraining, Six women who had participated in a previous 20-wk strength training study for the lower limb detrained for 30-32 wk and subsequently retrained for 6 wk. Seven untrained women also participated in the 6-wk "retraining" phase. In addition. four women from each group volunteered to continue training an additional 7 wk. The initial 20-wk training program caused an increase in maximal dynamic strength. hypertrophy of all three major fiber types. and a decrease in the percentage of type IIb fibers. Detraining had relatively little effect on fiber cross-sectional area but resulted in an increased percentage of type IIb fibers with a concomitant decrease in IIa fibers. Maximal dynamic strength decreased but not to pretraining levels. Retraining for 6 wk resulted in significant increases in the cross-sectional areas of both fast fiber types (IIa and IIab + IIb) compared with detraining values and a decrease in the percentage of type IIb fibers. The 7-wk extension accentuated these trends such that cross-sectional areas continued to increase (nonsignificant) and no IIb fibers could be found. Similar results were found for the nonpreviously trained women. These data suggest that rapid muscular adaptations occur as a result of strength training in previously trained as well as non-previously trained women. Some adaptations (fiber area and maximal dynamic strength) may be retained for long periods during detraining and may contribute to a rapid return to "competitive" form.
Chemical and postural influence on scalene and diaphragmatic activation in humans, The electromyographic activity of the diaphragm (EMGdi) and scalene muscle (EMGsc) was studied in the supine and upright positions. respectively. during hyperoxic progressive hypercapnic rebreathing (HCVR) in five healthy males. End-expiratory esophageal pressure (EEPes) was quantified on a breath-to-breath basis as a reflection of altered end-expiratory lung volume. There was no significant difference in the slopes of EMGdi. expressed as a percentage of maximum at total lung capacity vs. minute volume of ventilation (VI). between the supine and upright positions [0.79 +/- 0.05 (SE) vs. 0.92 +/- 0.17. respectively]. In contrast. the slope of the regression line relating EMGsc to VI was steeper in the upright than in the supine position (0.69 +/- 0.05 vs. 0.35 +/- 0.04. respectively; P less than 0.005). Positive EEPes at comparable VI at the ends of HCVRs were of greater magnitude upright than supine (3.27 +/- 0.68 vs. 4.35 +/- 0.60 cmH2O. respectively. P less than 0.001). We conclude that altering posture has a greater effect on scalene and expiratory muscle activity than on diaphragmatic activity during hypercapnic stimulation.
Classical conditioning of ventilatory responses in humans, A classical conditioning experiment. in which an auditory stimulus was paired with a hypoxic stimulus. was carried out on 34 normal subjects assigned to two groups (experimental and control). Each subject took part in one session divided into two phases. acquisition and test. In the acquisition phase. eight hypoxic and eight auditory stimuli were paired in the experimental group and unpaired in the control group. In the test phase. which was identical for the two groups. the hypoxic stimuli were suppressed and three purely auditory stimuli were presented. Significant differences between the two groups in ventilatory response to these auditory stimuli provided evidence for conditioning. In the control group. no significant changes were elicited by the auditory stimuli. whereas a conditioned increase in total cycle duration was observed in the experimental group. The conditioned response closely resembled the first component of the hypoxic response. Analysis of the pattern of the conditioned response. along with postexperimental interviews. strongly suggests that this response was not mediated by volitional factors.
Modeling: optimal marathon performance on the basis of physiological factors, This paper examines current concepts concerning "limiting" factors in human endurance performance by modeling marathon running times on the basis of various combinations of previously reported values of maximal O2 uptake (VO2max). lactate threshold. and running economy in elite distance runners. The current concept is that VO2max sets the upper limit for aerobic metabolism while the blood lactate threshold is related to the fraction of VO2max that can be sustained in competitive events greater than approximately 3.000 m. Running economy then appears to interact with VO2max and blood lactate threshold to determine the actual running speed at lactate threshold. which is generally a speed similar to (or slightly slower than) that sustained by individual runners in the marathon. A variety of combinations of these variables from elite runners results in estimated running times that are significantly faster than the current world record (2:06:50). The fastest time for the marathon predicted by this model is 1:57:58 in a hypothetical subject with a VO2max of 84 ml.kg-1.min-1. a lactate threshold of 85% of VO2max. and exceptional running economy. This analysis suggests that substantial improvements in marathon performance are "physiologically" possible or that current concepts regarding limiting factors in endurance running need additional refinement and empirical testing.
Simultaneous potentiation and fatigue in quadriceps after a 60-second maximal voluntary isometric contraction, Potential mechanisms of fatigue (metabolic factors) and potentiation (phosphate incorporation by myosin phosphorylatable light chains) were investigated during recovery from a 60-s maximal voluntary isometric contraction (MVC) in the quadriceps muscle of 12 subjects. On separate days before and for 2 h after the 60-s MVC. either a 1-s MVC or electrically stimulated contractions were used as indexes to test muscle performance. Torque at the end of the 60-s MVC was 57% of the initial level. whereas torques from a 1-s MVC and 50-Hz stimulation were most depressed in the immediate recovery period. At this time. muscle biopsy analyses revealed significant decreases in ATP and phosphocreatine and a 19-fold increase in muscle lactate. Conversely. isometric twitch torque and torque from a 10-Hz stimulus were the least depressed of six contractile indexes and demonstrated potentiation of 25 and 34%. respectively. by 4 min of recovery (P less than 0.05). At this time. muscle lactate concentration was still 16 times greater than at rest. An increased phosphate content of the myosin phosphorylatable light chains (P less than 0.05) was also evident both immediately and 4 min after the 60-s MVC. We conclude that the 60-s MVC produced marked force decreases likely due to metabolic displacement. while the limited decline in the twitch and 10-Hz torques and their significant potentiation suggested that myosin phosphorylation may provide a mechanism to enhance contractile force under conditions of submaximal activation during fatigue.
Attenuated carotid body hypoxic sensitivity after prolonged hypoxic exposure, Prolonged exposure to hypoxia is accompanied by decreased hypoxic ventilatory response (HVR). but the relative importance of peripheral and central mechanisms of this hypoxic desensitization remain unclear. To determine whether the hypoxic sensitivity of peripheral chemoreceptors decreases during chronic hypoxia. we measured ventilatory and carotid sinus nerve (CSN) responses to isocapnic hypoxia in five cats exposed to simulated altitude of 5.500 m (barometric pressure 375 Torr) for 3-4 wk. Exposure to 3-4 wk of hypobaric hypoxia produced a decrease in HVR. measured as the shape parameter A in cats both awake (from 53.9 +/- 10.1 to 14.8 +/- 1.8; P less than 0.05) and anesthetized (from 50.2 +/- 8.2 to 8.5 +/- 1.8; P less than 0.05). Sustained hypoxic exposure decreased end-tidal CO2 tension (PETCO2. 33.3 +/- 1.2 to 28.1 +/- 1.3 Torr) during room-air breathing in awake cats. To determine whether hypocapnia contributed to the observed depression in HVR. we also measured eucapnic HVR (PETCO2 33.3 +/- 0.9 Torr) and found that HVR after hypoxic exposure remained lower than preexposed value (A = 17.4 +/- 4.2 vs. 53.9 +/- 10.1 in awake cats; P less than 0.05). A control group (n = 5) was selected for hypoxic ventilatory response matched to the baseline measurements of the experimental group. The decreased HVR after hypoxic exposure was associated with a parallel decrease in the carotid body response to hypoxia (A = 20.6 +/- 4.8) compared with that of control cats (A = 46.9 +/- 6.3; P less than 0.05).
Carbohydrate metabolism during intense exercise when hyperglycemic, The effects of hyperglycemia on muscle glycogen use and carbohydrate metabolism were evaluated in eight well-trained cyclists (average maximal O2 consumption 4.5 +/- 0.1 l/min) during 2 h of exercise at 73 +/- 2% of maximal O2 consumption. During the control trial (CT). plasma glucose concentration averaged 4.2 +/- 0.2 mM and plasma insulin remained between 6 and 9 microU/ml. During the hyperglycemic trial (HT). 20 g of glucose were infused intravenously after 8 min of exercise. after which a variable-rate infusion of 18% glucose was used to maintain plasma glucose at 10.8 +/- 0.4 mM throughout exercise. Plasma insulin remained low during the 1st h of HT. yet it increased significantly (to 16-24 microU/ml; P less than 0.05) during the 2nd h. The amount of muscle glycogen utilized in the vastus lateralis during exercise was similar during HT and CT (75 +/- 8 and 76 +/- 7 mmol/kg. respectively). As exercise duration increased. carbohydrate oxidation declined during CT but increased during HT. Consequently. after 2 h of exercise. carbohydrate oxidation was 40% higher during HT than during CT (P less than 0.01). The rate of glucose infusion required to maintain hyperglycemia (10 mM) remained very stable at 1.6 +/- 0.1 g/min during the 1st h. However. during the 2nd h of exercise. the rate of glucose infusion increased (P less than 0.01) to 2.6 +/- 0.1 g/min (37 mg.kg body wt-1.min-1) during the final 20 min of exercise. We conclude that hyperglycemia (i.e.. 10 mM) in humans does not alter muscle glycogen use during 2 h of intense cycling.
Aerosolized surfactant treatment of preterm lambs, To evaluate the potential for aerosolized surfactant treatments of surfactant deficiency. twin lamb fetuses were delivered at 130-132 days gestational age and received nebulized natural surfactant (Neb NS). nebulized Survanta (Neb Surv). tracheally instilled natural surfactant (Inst NS). or nebulized saline (Neb Saline). Neb NS and Neb Surv groups had significant increases in ventilatory efficiency index and dynamic compliance values (P less than 0.05). Both groups also had pressure-volume curves that were comparable to the Inst NS group. The Neb Saline control group had deterioration of the ventilation efficiency index and dynamic compliance values over time as well as pressure-volume curves that demonstrated smaller lung volumes compared with all three surfactant-treated groups (P less than 0.01). Delivery of aerosolized surfactant to the lung was only approximately 2 mg lipid/kg for the nebulized groups. a dose one-twentieth of that previously noted to be effective in instillation protocols. Distribution histograms of the aerosolized surfactant-treated groups differed from the instilled animals as there was more deposition in the right upper lobes and tracheae in the nebulized groups compared with the instilled group (P less than 0.05). Pulmonary blood flow was not altered by aerosolized surfactant treatment. Administration of aerosolized surfactant to preterm lambs improved lung function at a very low surfactant dose.
Metabolic and respiratory effects of flow-resistive loading in preterm infants, Oxygen consumption (VO2) was measured during hypoventilation induced by moderate-sized flow-resistive loading in 12 preterm infants. and the results were compared with those obtained under basal conditions immediately before and after the loaded run. each of which lasted for 7-10 min. Loading was performed with a continuous flow-resistive load (inspiratory and expiratory). which was approximately threefold greater in magnitude than the intrinsic resistance of preterm infants. VO2. minute ventilation (VE). transcutaneous oxygen tension (PtCO2). and transcutaneous carbon dioxide tension (PtcCO2) were continuously monitored. Results revealed that VE decreased significantly with loading. from 336 +/- 103 to 231 +/- 58 (SD) ml.min-1.kg-1 (P less than 0.001). while returning to basal levels of 342 +/- 59 ml.min-1.kg-1 after discontinuation of the load. VO2 decreased from 7.2 +/- 1.2 to 5.9 +/- 0.9 ml.min-1.kg-1 with loading (P less than 0.001) and returned to 7.2 +/- 1.2 ml.min-1.kg-1 at the second basal measurement. PtcCO2 remained unchanged with loading. and PtcCO2 only increased from 39 +/- 8 to 41 +/- 9 Torr (P less than 0.05) with loading. while returning to 40 +/- 9 Torr at the second basal measurement. Results indicate a decrease in the metabolic rate and ventilation with loading. with relatively little increase in PtcCO2. These data can explain prior observations that minimal disturbances in oxygen and carbon dioxide tensions occur with hypoventilation during flow-resistive loading in neonates. although the precise mechanism for this reduction remains to be determined.
Myocardial biochemical and hemodynamic adaptations to chronic tachycardia, The purpose was to determine the biochemical and hemodynamic adaptations of the myocardium to chronic tachycardia. Cardiac pacemakers were implanted in Yorkshire pigs and set at a rate of 180 beats/min for a period of 35-42 days. Animals were then anesthetized with pentobarbital sodium. Myocardial blood flow and hemodynamics were determined at three different heart rates (i.e.. 120. 180. and 220 beats/min). Tissue samples were then taken for microsphere and biochemical analyses. Chronically paced hearts maintained better cardiac function and had consistently higher left ventricular blood flow with a higher endocardial-to-epicardial ratio. The activities of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase were 23 and 45% greater in the paced hearts. respectively. The sarcoplasmic reticulum adenosinetriphosphatase activity was 55% greater in the paced hearts. whereas the myosin adenosinetriphosphatase was the same as in the control hearts. Polyacrylamide gels of the ventricular myosin isoforms showed only the V3 type to be present in both the control and paced hearts. These findings show that the heart of a large mammal adapts to chronic tachycardia (i.e.. 180 beats/min) by elevating the aerobic and calcium-sequestering capacities without altering its myosin type.
Synthesis of albumin and acute-phase proteins in perfused liver after burn injury in rats, The acute-phase response that follows injury and sepsis is characterized by increased hepatic synthesis of specific secreted proteins while production of albumin is decreased. The effect of burn injury on specific synthesis rates of secreted hepatic proteins has not been reported. In this study. Sprague-Dawley rats received either a 30% flame burn (n = 12) or a sham burn (n = 12) and were allowed to recover for 11 days. Burned animals showed slower weight gains and a 25% to 30% higher resting energy expenditures compared with controls. On postburn day 11. synthesis of secreted hepatic proteins was measured by incorporation of leucine during a 2-hour isolated liver perfusion. Synthesis of total secreted proteins. the seromucoid fraction. and complement component C3 was significantly increased in burned animals. whereas synthesis of albumin was unaltered. In spite of unchanged albumin synthesis. plasma albumin concentrations were 50% lower in burned animals than in control animals throughout the postburn period. These findings suggest that decreased albumin synthesis is not the only mechanism responsible for persistent hypoalbuminemia that follows burn injury.
Comparison of silver sulfadiazine 1% with chlorhexidine digluconate 0.2% to silver sulfadiazine 1% alone in the prophylactic topical antibacterial treatment of burns, Wound bacterial colonization in 118 patients treated with chlorhexidine digluconate 0.2% in silver sulfadiazine 1% applied daily to the burn wounds was compared to that of 135 comparable patients similarly treated with silver sulfadiazine 1%. With chlorhexidine digluconate 0.2% in silver sulfadiazine 1%. colonization by Staphylococcus aureus was less frequent (38%) than with silver sulfadiazine (54%. p = 0.016). No statistical difference was found for colonization by Enterococcus faecalis. Pseudomonas aeruginosa. or Enterobacter cloacae. Washing of the wounds of 65 patients with chlorhexidine gluconate 4% during daily dressing changes was associated with reduced wound colonization by S. aureus (35% versus 51%. p = 0.03) and P. aeruginosa (8% versus 16%. p = 0.08) when compared to the 188 washed with nonantibacterial soap. Chlorhexidine. whether added to the topical agent silver sulfadiazine (chlorhexidine digluconate 0.2%) or in the bath soap (chlorhexidine gluconate 4%). decreased colonization by S. aureus.
Local random fasciocutaneous flaps for repair of the burned elbow, Wound management of the burned elbow is not always possible with a skin graft alone. Rather than resort to distant pedicle flaps or the complexity of microsurgical tissue transfers. local fasciocutaneous flaps may provide a better source for vascularized tissue. "Random" fasciocutaneous flaps do not require isolation of any discrete vessel. but must be designed to parallel the longitudinal axis of perifascial circulation in the upper extremity. Therefore no vessel in the major extremity need ever be violated. and muscle function is always preserved. Excision-to-fascia techniques for burn escharectomy should probably be minimized in the elbow region. because if the fascia remains intact. the overlying skin-grafted subcutaneous fat will survive flap transposition as a fasciocutaneous flap. Local flaps allow for earlier rehabilitation. and the donor defect is restricted to the already deformed ipsilateral extremity.
How soon is safe? Ambulation of the patient with burns after lower-extremity skin grafting, Patients with burns of the lower extremity that require skin grafting were randomized into three groups to determine when postgraft ambulation could be safely resumed. Dangling protocol was initiated on postoperative day 6. 8. or 10. and ambulation was started on the next day. Grafts were evaluated at six stages on a five-point scale. In the 22 patients who completed the study. there was no significant difference in scores of the three groups. There was a significant difference in length of hospital stay when patients who dangled on postoperative day 6 were compared with patients who dangled on postoperative day 10.
Enhancement of humoral immunity by heterologous lipid peroxidation products resulting from burn injury, Lipid peroxidation products (conjugated dienes) extracted from the plasma of scald-burned rats were injected intraperitoneally in mice before immunization of the mice with sheep erythrocytes. Five-day plaque-forming cell assays showed that mice receiving conjugated dienes isolated from the plasma of burned rats had enhanced specific immunoglobulin M antibody production compared to mice receiving dienes from normal rat plasma or sheep erythrocytes alone. These observations suggest that lipid peroxidation products in the plasma of burned animals may modulate the humoral immune response.
A nineteen-year review of nurse-authored abstracts presented to the American Burn Association. Implications for the future, The previous investigations of nurse authors have impact on and provide guidance for the future paths of research endeavors. A review of the past 19 years of American Burn Association abstract presentations was performed to identify nurse-authored presentations and describe their nature and content. Nurse authors were identified on 18% of all abstracts presented and were primary authors of 7.7% of all abstracts presented. Those who collaborated most frequently with nurse authors were other nurses (41%) and physicians (37%). Descriptive studies were most frequently presented. followed first by reports and then by experimental designs. Fewer than one half of the reported studies possessed statistical support for their findings. Nurse authors are most frequently investigating issues of direct patient care. such as wound management. medications. complications. and psychosocial issues.
Tap-water scald burns. Awareness is not the problem, Review of admissions to a regional burn center showed that tap-water burns were an injury of pediatric. elderly. and neurologically impaired patients. A study was designed to measure general knowledge of tap-water injury and awareness of tap-water temperatures in homes. All those surveyed realized the potential for tap-water scald burns in their homes. and few believed that they could tolerate hot-only tap water at home for as long as 30 seconds. Respondents who had previous experience with tap-water burns had not lowered the settings of their water-heater thermostats. Economical but effective programs must be developed to encourage burn-reduction behaviors in high-risk groups.
Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism, The effects of the antiandrogen drugs cyproterone acetate (CPA) and spironolactone on hair growth and androgen levels were compared in a randomized study of 48 hirsute women. Twenty six subjects completed 6 months of therapy with 100 mg/day CPA and 19 subjects completed 6 months of 100 mg/day spironolactone. All except 10 subjects received concomitant estrogen therapy. Measured objectively. total hair diameter fell by 17.1% with spironolactone (P less than 0.001). and by 16.8% with CPA (P less than 0.001). The diameter of the hair medulla fell by 17.8% with spironolactone (P less than 0.01). and by 31.7% with CPA (P less than 0.001). There was no difference between the drugs in their effect on hair diameter. Plasma testosterone levels also fell significantly with both drugs. As a subjective assessment of treatment efficacy. the frequency with which subjects performed cosmetic measures was recorded. This fell by 38% with spironolactone and by 44.7% with CPA (P less than 0.001 both drugs). and again there was no difference between the drugs. Side effects caused cessation of treatment in one subject taking CPA and two subjects taking spironolactone. and milder side effects were noted in two further subjects from each treatment group. We conclude that spironolactone and CPA. in the dosages used in this study. are effective and well tolerated agents for the treatment of hirsutism. and that neither drug demonstrates a particular advantage over the other.
The effect of human chorionic gonadotropin and pregnancy on the circulating level of relaxin, The effect of hCG and pregnancy on the circulating levels of relaxin was investigated in 48 women undergoing in vitro fertilization and embryo transfer (ET) for the treatment of infertility. Subjects were allocated randomly to receive hCG (Profasi; 2000 IU. im) or placebo on the day of ET (day 0) and on day 3 after ET (day 3). Samples of peripheral blood were taken on days -4. 6. and 10. An additional sample was taken on day 22 from women who became pregnant. The subjects were allocated retrospectively to 1 of 4 groups: no pregnancy. no hCG (NP); pregnancy. no hCG (P); no pregnancy. hCG (NPH); and pregnancy. hCG (PH). Two patients with blighted ova and one with a tubal pregnancy were excluded from the analysis. The concentrations of relaxin were similar and rose significantly in all groups at each time point (P less than 0.05). On day 6 there was no significant difference in the increment between the groups. but by day 10. circulating levels in the P compared to the NP and those in the PH compared to the NPH group were significantly greater (P less than 0.05). By day 22 the difference between the PH and the P groups was significant (P less than 0.05). Relaxin levels correlated with progesterone levels on day 10 in the NP and P groups (r = 0.633; P less than 0.05 and r = 0.697; P less than 0.05. respectively) and with estradiol levels in the P group only on days 6 and 22 (r = 0.659; P less than 0.05 and r = 0.783; P less than 0.05. respectively). These data demonstrate that in women undergoing in vitro fertilization. relaxin levels increase during the luteal phase. and in those women who establish a pregnancy. the values are significantly greater by day 10. The administration of hCG in the early luteal phase. before implantation. to women who subsequently become pregnant significantly increased the level of circulating relaxin on day 22. The positive correlation between relaxin levels and ovarian steroid levels in the groups not receiving exogenous hCG suggests that a common factor may control the release of both.
Peripheral glucose metabolism in acromegaly, The present study was designed to determine the effect of chronic GH excess on forearm muscle glucose uptake and oxidation during the postabsorptive state and after an oral glucose challenge. Nine normal subjects and 10 nondiabetic acromegalic patients (5 of them with normal glucose tolerance) were studied after an overnight fast (12-14 h) and for 3 h after the ingestion of 75 g glucose. Peripheral glucose metabolism was analyzed by the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. Decreased forearm glucose uptake was observed in the acromegalic patients compared to that in the normal subjects (380 +/- 84 vs. 709 +/- 56 mumol/100 mL forearm.3 h) with diminished nonoxidative glucose metabolism (262 +/- 81 vs. 572 +/- 53 mumol/100 mL forearm.3 h). The acromegalics with normal glucose tolerance also showed decreased forearm glucose uptake and nonoxidative glucose metabolism compared to normal subjects (271 +/- 124 vs. 709 +/- 56 and 133 +/- 110 vs. 572 +/- 53 mumol/100 mL forearm.3 h. respectively). Muscle glucose oxidation did not differ significantly in normal subjects. the entire group of acromegalic patients. and the acromegalics with normal glucose tolerance (137 +/- 18 vs. 118 +/- 22 vs. 138 +/- 34 mumol/100 mL forearm.3 h. respectively). Serum FFA levels and lipid oxidation rates were similar in the normal subjects and the acromegalic patients. and declined in a similar fashion after glucose ingestion. Insulin levels were significantly higher in acromegalic patients than in normal subjects before and after glucose loading. In conclusion. this study showed that the insulin resistance occurring in the presence of chronic GH excess is accompanied by impaired muscle glucose uptake and nonoxidative glucose metabolism. which are early derangements because they are also observed in acromegalic patients with normal glucose tolerance.
Evidence that high dose cortisol-induced Na+ retention in man is not mediated by the mineralocorticoid receptor, We have previously shown that high dose cortisol (F; 240 mg/day)-induced Na+ retention and systolic blood pressure (BP) increases are not inhibited by the glucocorticoid (type II) receptor antagonist RU486. Adequacy of type II receptor blockade with RU486 was clearly demonstrated. indicating that the Na+ retention was not mediated through the glucocorticoid receptor. Spironolactone (Sp: 400 mg/day). in a preliminary assessment. also did not inhibit F-induced Na+ retention. The purpose of this study was to determine whether the Na+ retention produced by F administration is mediated by the type I receptor by comparing the effects of F to a potent type I agonist [9 alpha-fludrohydrocortisone (9 alpha FF)] with and without Sp administration. The effects of the two agonists and Sp on urinary K excretion and BP were also compared. Normal male volunteers. on a constant daily diet for 10 days. received either F (240 mg/day) or 9 alpha FF (3.0 mg/day) with or without Sp (400 mg/day) for the last 5 days. The mean cumulative reductions in Na+ excretion during the 5 days compared to baseline values before hormone administration were 255 +/- 38 and 494 +/- 81 mmol/5 days for F (n = 9) and 9 alpha FF (n = 5). respectively (P = 0.01). Sp (n = 5) completely inhibited 9 alpha FF-induced Na+ retention (494 +/- 81 vs. -37 +/- 130 mmol/5 days; P less than 0.01). but had no effect (n = 5) on F-induced Na+ retention (255 +/- 38 vs. 193 +/- 50 mmol/5 days; P = NS). After the expected first day kaliuresis. the effects of both steroids on net cumulative urinary K+ excretion were minimal. Systolic BP was increased by F. but not 9 alpha FF. and Sp did not inhibit this increase. A 2-fold greater Sp-inhibitable Na(+)-retaining effect of the mineralocorticoid demonstrates that the failure of Sp to block F-induced Na+ retention is not due to inadequate type I receptor blockade. Based on these findings and earlier studies. we conclude that high dose (stress level) F-induced Na+ retention and systolic BP increase are not mediated by either the mineralo- or glucocorticoid receptor in normal man.
A study of the serum concentration of tumor necrosis factor-alpha in thyroidal and nonthyroidal illnesses, We have studied serum concentrations of immunoassayable tumor necrosis factor-alpha (TNF alpha) and iodothyronines (T4. T3. and rT3) in normal subjects (n = 16) and patients with nonthyroidal illnesses (NTI; n = 13). hyperthyroidism (n = 10). and hypothyroidism (n = 9). The mean (+/- SEM; femtomoles per mL) serum concentration of TNF alpha was 45 +/- 4.3 in normal subjects. 84 +/- 38 in NTI. 54 +/- 6.0 in hyperthyroidism. and 50 +/- 10 in hypothyroidism; the various values did not differ significantly from one another. Serum TNF alpha was well within the normal range in all NTI patients. except one patient with a brain glioma and infection in whom it was elevated (540 fmol/mL). There was no significant correlation between serum TNF alpha and serum T4. T3. or rT3 levels in NTI patients. Similarly. there was no correlation between serum TNF alpha and serum thyroid hormone (T3 or T4) levels when data in normal subjects were combined with those in NTI patients. The dialyzable fraction of T3 and the free T3 concentration did not correlate with serum TNF alpha levels. However. there was a tendency toward a positive correlation between dialyzable fraction of T4 and the serum concentration of TNF alpha in NTI (r = 0.54; n = 11; 0.05 greater than P less than 0.1). The relationship between these two parameters became more clear when data in normal subjects and NTI patients were combined for statistical analysis (r = 0.59; n = 22; P less than 0.005). The free T4 concentration correlated positively with serum TNF alpha levels whether the data in NTI patients were analyzed alone (r = 0.93; P less than 0.001) or in combination with data from normal subjects (r = 0.85; P less than 0.001). Our data suggest that circulating TNF alpha may contribute to elevated free T4 in NTI. However. it is not a universal or common factor in the pathogenesis of other alterations in serum thyroid hormone levels in NTI (euthyroid sickness syndrome).
Single and multiple dose pharmacokinetics of methionyl growth hormone in children with idiopathic growth hormone deficiency, The pharmacokinetics (PK) of methionyl GH (metGH) were characterized in 20 newly diagnosed GH-deficient children (19 males; 12.9 +/- 3.3 yr old; initial height. 138.8 +/- 16.2 cm; weight. 32.1 +/- 13.1 kg) after the first dose (FD) of metGH and again after 4-5 weeks of multiple dosing (MD). All subjects received a total metGH dose of 0.3 mg/kg.week by sc administration. but were randomized to receive the drug daily (D; n = 12; dose. 0.043 mg/kg) or three times per week (TIW; n = 8; dose. 0.1 mg/kg). After drug administration. repeated blood samples (n = 14) were obtained over a 10-h period. Concentrations of metGH from each sample were determined using a monoclonal antibody radiometric assay (range of linearity. 0.5-40.0 ng/ml; coefficient of variation. less than 4%). Plasma concentration vs. time data were curve fit using a nonlinear weighted least squares algorithm which permitted calculation of the following PK parameters (mean +/- SEM; FD vs. MD group): elimination rate constant (0.23 +/- 0.04 vs. 0.25 +/- 0.04 h-1). absorption rate constant (0.43 +/- 0.05 vs. 0.48 +/- 0.04 h-1). elimination half-life (t1/2; 3.01 vs. 2.77 h). total plasma clearance (CL/F; 0.32 +/- 0.02 vs. 0.54 +/- 0.09 L/h.kg). and apparent volume of distribution (VDss/F; 2.2 +/- 0.14 vs. 3.15 +/- 0.28 L/kg). Both the CL/F and VDss/F of metGH were significantly greater when data from the entire study population were compared on the basis of FD vs. MD administration. With the exception of a larger VDss/F in subjects who received daily (3.6 +/- 0.4 L/kg) vs. TIW metGH (2.4 +/- 0.2 L/kg). no significant differences were found for the PK parameters between the D and TIW dosing groups. In all subjects. absorption of metGH was slow. with an average time to reach maximum concentration (Tmax) of 4.4 h and an absorption t1/2 that ranged from 1.4-1.8 h. Proportionality was also found between the dose and the area under the plasma concentration vs. time curve. suggesting dose-independent PK of metGH. Our data demonstrate that the PK of metGH after sc administration to children are markedly different from those previously reported in adults and. also. do not vary as a consequence of dosing schedule (i.e. D vs. TIW). The apparent increase in CL/F and VDss/F for met GH with multiple dosing may reflect concentration-dependent changes in plasma binding of the drug or. alternatively. represent the effect of increased body mass on the pharmacokinetics of GH.
Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin--studies in families not selected for autoimmune thyroid disease, Recently the tendency to produce autoantibodies to thyroid peroxidase (TPO Ab) and thyroglobulin (Tg Ab) was shown to be inherited as an autosomal dominant characteristic in women but not in men. Because of potential bias in this study which was carried out in families with autoimmune thyroid disease (AITD). the inheritance of thyroid autoantibodies has been evaluated in 49 families unselected for autoimmune thyroid disease. Among these families (24 with facioscapulohumeral disease. 10 with Friedreich's ataxia. and 15 with schizophrenia) the prevalences of TPO Ab and Tg Ab were 27.8% and 26.7%. respectively. in women and 9.2% and 11.7%. respectively. in men. In 40 families where one or more individual had TPO Ab and/or Tg Ab. segregation analysis showed that the tendency to make antibodies was consistent with a Mendelian dominant trait in women but not in men. In young women. however. the prevalence of both TPO Ab and Tg Ab increased with age. rising from 14% and 10%. respectively. at age 15-24 to 35% and 40% at age 35-44. As this is inconsistent with a simple dominant hypothesis. a further segregation analysis by age was carried out in the families unselected for thyroid disease together with 16 pedigrees with AITD previously studied and two additional large AITD families. The results of the combined analysis provided strong support for the hypothesis of dominant inheritance but also showed significant reduction in gene expression among women aged 15-24 yr.
Prolactin secretion and corpus luteum function in women with luteal phase deficiency, Luteal phase deficiency (LPD) as a clinical infertility problem is considered to have a heterogeneous etiology. Hyperprolactinemia has long been considered a causative factor of LPD. In this context we investigated PRL secretion in 18 women with LPD. All of the subjects were infertile with 2 out of phase (greater than 2 days) endometrial biopsies; 10 of the women also had daily blood samples. this latter subgroup had significantly decreased integrated luteal phase progesterone (P) levels compared to normal women with in-phase biopsies. PRL secretion was investigated as follows: 1) daily blood levels; 2) pulsatile secretion patterns in 3 cycle phase [early follicular (12 h); late follicular (12 h); midluteal (24 h)]. 3) LH-PRL coupling. and 4) nocturnal patterns. Results were compared to findings in 36 normal women. The mean daily levels of PRL over the menstrual cycle were not different between the two groups (LPD. 12.1 +/- 1.5; normal. 13.8 +/- 0.8 microgram/L; P = 0.3). There was no correlation between luteal phase integrated P and PRL levels for either group. There was a small difference in the PRL pulse amplitude in the early follicular phase between the LPD and normal women (2.6 +/- 0.3 vs. 5.5 +/- 1.3 micrograms/L; P less than 0.05). There were no significant differences between groups in PRL pulse frequency or mean level during the 12 or 24 h in any cycle phase. There was an equivalent amount of LH-PRL pulse coupling in both groups in all three cycle phases. Diurnal and nocturnal PRL secretion was studied by breaking the 24 h data (midluteal) into day (0700-2300 h) and night (2300-0700) segments. Mean PRL levels were higher at night in both groups (LPD. 15.9 vs. 12.6; normal. 15.4 vs. 9.3 micrograms/L; P less than 0.05). as expected. There were no differences in nocturnal PRL secretory patterns between the two groups. In summary. we have serious reservations whether abnormalities in PRL secretion are a common or integral part of the pathophysiology of LPD. From previous work we know these subtle abnormalities in PRL secretion in LPD are associated with definite abnormalities in gonadotropin secretion. We believe these gonadotropin abnormalities are probably more significant in terms of decreased P secretion.
Bicarbonate secretion in vivo by rat distal tubules during alkalosis induced by dietary chloride restriction and alkali loading, To examine in vivo the separate effects on distal tubule JtCO2. of dietary chloride restriction. bicarbonate loading. and changes in luminal chloride concentration. we microperfused distal tubules at a physiologic flow rate (8 nl/min) with solutions containing either 45 or 0 mM chloride (after gluconate substitution). Rats were fed a diet containing zero. minimal. or normal amounts of chloride. while drinking either water or a solution of 0.15 M sodium bicarbonate. Neither extracellular fluid volume contraction nor negative chloride balance ensued. Analysis of covariance with repeated measures demonstrated that dietary chloride. drinking sodium bicarbonate. and perfusion with either 45 mM or zero chloride. each have separate and significant modulating effects on distal tubule bicarbonate secretion. During mild alkalemia. there is modest bicarbonate secretion which is significantly different from zero (-9.9 +/- 3.2 pmol.min-1.mm-1. P less than 0.01). and which is suppressed after perfusion with zero chloride. In contrast. during more pronounced metabolic alkalosis after supplemental bicarbonate drinking. the bicarbonate secretory flux is brisk (-26 +/- 3 pmol.min-1.mm-1) and significantly different from zero and persists (-11 +/- 3 pmol.min-1.mm-1) even during perfusion with zero luminal chloride. Accordingly. in this two-day model of alkalosis induced by dietary chloride restriction. there is regulatory secretion of bicarbonate by distal tubules in vivo which is modulated by luminal chloride concentration.
Generation and analysis of clonal IgM- and IgG-producing human B cell lines expressing an anti-DNA-associated idiotype, This study describes a methodology for generating stable. cloned. EBV-transformed IgG- and IgM-producing human B cell lines. Using these lines we have characterized immunoglobulin V gene utilization in an anti-DNA-associated idiotypic system. The 31 anti-DNA-associated idiotype is encoded preferentially by the VK1 gene family. and. in all probability. reflects a germ line gene-encoded framework determinant. Analysis of these lines indicates that the DNA-binding antibodies produced by B cell lines from SLE patients may differ from DNA binding myeloma proteins and from natural autoantibodies.
Mechanisms of disruption of the articular cartilage surface in inflammation. Neutrophil elastase increases availability of collagen type II epitopes for binding with antibody on the surface of articular cartilage, We recently observed that specific antibodies to type II collagen do not bind in appreciable amounts to the intact surface of articular cartilage. whereas antibodies to the minor collagen types V. VI. and IX do. These results suggest that the outermost cartilage surface layer prevented interaction of the antibodies with the major collagen type in articular cartilage. The present studies were designed to investigate the pathogenic mechanisms involved in the disruption of the cartilage surface layer in inflammatory arthritis. Articular cartilage obtained from rabbits undergoing acute antigen-induced arthritis of 72 h duration showed a significant increase in binding of anti-type II antibody to cartilage surfaces compared with normal control cartilage (P less than 0.01). Augmentation of anti-type II binding was also observed upon in vitro incubation of bovine articular slices or intact rabbit patellar cartilage for 1 h with human polymorphonuclear neutrophils (PMN). PMN lysates. or purified human PMN elastase. This increase was not inhibited by sodium azide. nor was it enhanced by incubation of cartilage with the strong oxidant hypochlorous acid. Chondrocyte-mediated matrix proteoglycan degradation in cartilage explants cultured in the presence of cytokines failed to increase antibody binding appreciably. The augmentation in antibody binding seen with PMN lysates was inhibited by the nonspecific serine-esterase inhibitor PMSF. but not by the divalent metal chelator EDTA. The elastase-specific inhibitor AAPVCMK also inhibited most of the PMN-induced increase in antibody binding. whereas the cathepsin G-specific inhibitor GLPCMK was much less effective. Incubation of intact cartilage with purified human PMN elastase indicated that this serine esterase could account for the increase in anti-type II collagen antibody binding to intact cartilage surfaces. These studies suggest that in an inflammatory response. PMN-derived elastase degrades the outer layer of articular cartilage. exposing epitopes on type II collagen. They also help clarify the pathogenic mechanisms involved in early articular cartilage damage in inflammatory joint diseases.
Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma, We have attempted to identify mRNA for IL-5 in endobronchial mucosal biopsies from asthmatics and controls. using the technique of in situ hybridization. Bronchial biopsies were obtained from 10 asthmatics and 9 nonatopic normal controls. A radio-labeled cRNA probe was prepared from an IL-5 cDNA and hybridized to permeabilized sections. These were washed extensively before processing for autoradiography. An IL-5-producing T cell clone derived from a patient with the hyper-IgE syndrome was used as a positive control. As a negative control. sections were also treated with a "sense" IL-5 probe. Specific hybridization signals for IL-5 mRNA were demonstrated within the bronchial mucosa in 6 out of the 10 asthmatic subjects. Cells exhibiting hybridization signals were located beneath the epithelial basement membrane. In contrast. there was no hybridization in the control group. No hybridization was observed with the sense probe. The six IL-5 mRNA-positive asthmatics tended to have more severe disease than the negative asthmatics. as assessed by symptoms and lung function. and showed a significant increase in the degree of infiltration of the bronchial mucosa by secreting (EG2+) eosinophils and activated (CD25+) T lymphocytes. Within the subjects who showed positive IL-5 mRNA. there was a correlation between IL-5 mRNA expression and the number of CD25+ and EG2+ cells and total eosinophil count. This study provides evidence for the cellular localization of IL-5 mRNA in the bronchial mucosa of asthmatics and supports the concept that this cytokine regulates eosinophil function in bronchial asthma.
Plasma lipid transfer protein as a determinant of the atherogenicity of monkey plasma lipoproteins, This study was undertaken to determine potential tissue sources of plasma cholesteryl ester transfer protein (CETP). and to assess the influence of CETP on lipoprotein concentrations and atherosclerosis. In a group of 28 cynomolgus monkeys fed high fat. high cholesterol diets. plasma CETP concentration was strongly correlated with the abundance of CETP mRNA in liver and in adipose tissue. and with the output of CETP in liver perfusates. Plasma CETP concentration showed a strong inverse correlation with HDL cholesterol concentrations (r = -0.62. P less than 0.001) and a positive correlation with LDL cholesterol concentration (r = 0.54. P less than 0.005) and molecular weight (r = 0.57. P less than 0.001). The extent of coronary artery atherosclerosis was positively correlated with LDL cholesterol concentration and molecular weight. and with plasma CETP concentration. Thus. in monkeys fed an atherogenic diet. individual variation in CETP mRNA abundance in liver and adipose tissue probably plays a major role in the determination of plasma CETP levels. In plasma. CETP influences the distribution of cholesteryl esters between LDL and HDL. and CETP concentration appears to be a key determinant of the relative atherogenicity of the plasma lipoproteins.
Remodeling of ventricular conduction pathways in healed canine infarct border zones, Remodeling of myocyte interconnections may be an important determinant of ventricular tachycardia in regions bordering healed infarcts. We used quantitative electron microscopy to characterize the distribution of gap junctions in 10 canine left ventricles 3-10 wk after coronary occlusion. In three normal canine left ventricles analyzed ultrastructurally. myocardial gap junctions were distributed anisotropically; gap junction profile length was significantly greater in the transverse than in longitudinal planes of section. In infarct border zone tissues. the normal anisotropic distribution was completely abolished and fewer gap junctions per unit intercalated disk length were observed. Analysis of individual gap junction profile length distributions revealed selective disruption of the largest gap junctions that collectively comprised only 9.6% of total junction profiles. but encompassed nearly 40% of aggregate gap junction length in the transverse plane of section. Three-dimensional reconstructions of myocyte interconnections by high resolution quantitative light microscopy of serial sections demonstrated a reduction in the number of cells connected by intercalated disks to a single myocyte from 11.2 +/- 1.0 in normal myocardium to 6.5 +/- 1.3 in border zone tissues (P less than 0.001). Connections of cells in primarily side-to-side apposition were reduced by 75%. whereas primarily end-to-end connections were reduced by only 22% (P less than 0.05). These alterations would disproportionately enhance axial resistivity in the transverse direction. potentially contributing to development of reentrant arrhythmias.
Rheumatoid factors isolated from patients with autoimmune disorders are derived from germline genes distinct from those encoding the Wa, Po, and Bla cross-reactive idiotypes, To better understand the structural basis for rheumatoid factor activity. the nucleotide sequence of the light chain variable regions of nine human monospecific IgM rheumatoid factors were analyzed. Rheumatoid factors were isolated from three patients with rheumatoid arthritis. a patient with systemic lupus erythematosus. and a normal individual. The VL gene segments used by these rheumatoid factors are not as restricted as previous work on mixed cryoglobulin rheumatoid factors had suggested. Each of the different VK families is represented and there are two examples where a V lambda gene segment is used. Molecules with structures similar to those of the Wa and Po CRI. characteristic of mixed cryoglobulin rheumatoid factors. are not common among these rheumatoid factors isolated from patients with rheumatoid arthritis. While there are clear examples of rheumatoid factors that are direct copies of germline genes. most of the sequence data suggest that the processes of antigenic selection and somatic mutation contribute significantly to the generation of monospecific rheumatoid factors in patients with autoimmune disease.
Identification of the viral genes responsible for growth of strains of reovirus in cultured mouse heart cells, Viral growth in specific tissue is usually required in order to lead to pathology. Two reovirus isolates (type 1 Lang and type 3 Dearing) differ in their capacity to grow in cultured mouse heart cells. The mammalian reoviruses contain a genome of 10 double-stranded RNA gene segments. By the use of 37 reassortant viruses (consisting of viruses with different combinations of genes derived from the two parents). difference in capacity of different strains to grow in heart cells was mapped to three different genes. all of which encode viral core proteins: the M1 gene (P less than 0.000044); the L1 gene (P = 0.00094); and the L3 gene (P = 0.019). Using the same set of reassortant viruses. the L1 (P = 0.00015) and L3 (P = 0.0065) genes were involved in differences of the ability of viral strains to grow in mouse L cells (fibroblasts). but the M1 gene (P = 0.12) was not. These findings suggest that the M1 gene plays an important and specific role in determining the relative capacity of certain viral strains to grow in the heart. Thus. we have identified viral genes responsible for differing growth capacity in heart muscle cells in culture. These findings provide a novel system for studies of viral myocarditis at a molecular genetic level.
Unlike thyrotropin, thyroid-stimulating antibodies do not activate phospholipase C in human thyroid slices, The effects of thyroid-stimulating antibodies (TSAb) and of thyrotropin (TSH) were compared. on the generation of cyclic AMP and inositol phosphates (InsP). in human thyroid slices incubated in vitro. and on the Rapoport cyclic AMP bioassay. The TSAb positive sera were obtained from 19 patients with Graves' disease. In 14 experiments with the slices system. TSH significantly increased cyclic AMP accumulation (TSH. 0.03-10 mU/ml) as well as the cyclic AMP-independent inositol trisphosphate (InsP3) generation (TSH. 1-10 mU/ml). In the same 14 experiments. TSAb (0.10-28 mg/ml) enhanced cyclic AMP intracellular levels as expected while they did not induce any InsP accumulation. Even when TSAb increased cyclic AMP levels to the same or higher values as those obtained with TSH concentrations allowing InsP3 generation. TSAb were still unable to activate the phosphatidylinositol-Ca2+ cascade. The patterns of the response curves of TSAb and TSH on cyclic AMP accumulation were different. suggesting that different mechanisms may be involved. In addition. unlike TSH. TSAb were not able to stimulate H2O2 generation. which in human tissue mainly depends on the activation of the phosphatidylinositol-Ca2+ cascade. Immunoglobulins from six additional Graves' patients lacking measurable cyclic AMP-stimulating activity in both slices and cells systems did not activate phospholipase C either. In conclusion. our results show that TSAb do not share all the metabolic actions of TSH on human thyroid tissue. The data provide support for the concept that the pathogenesis of Graves' disease can be fully accounted for by the ability of TSAb to stimulate adenylate cyclase. This work also confirms that TSH activates the cyclic AMP and the phosphatidylinositol cascade by independent pathways in the human thyroid.
A mutation in CYP11B1 (Arg-448----His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin, Steroid 11 beta-hydroxylase (P450c11) deficiency (failure to convert 11-deoxycortisol to cortisol) causes less than 10% of cases of congenital adrenal hyperplasia in most populations. but it is relatively frequent in Jews of Moroccan origin. P450c11 is encoded by the CYP11B1 gene which is located on chromosome 8q22 along with a homologous gene of unknown function. CYP11B2. To identify mutations in CYP11B1 associated with 11 beta-hydroxylase deficiency in Moroccan Jews. oligonucleotides were used that selectively amplified portions of CYP11B1 in polymerase chain reactions without amplifying CYP11B2. Sequence analysis of amplified fragments from one patient revealed a single base substitution in exon 8. codon 448 from CGC (arginine) to CAC (histidine). This residue is within the "heme binding" peptide that contains a cysteine that is a ligand to the heme group. The equivalent of Arg-448 is found in every known eukaryotic P450. and therefore it seems likely that a mutation of this residue would adversely affect enzymatic activity. 11 of 12 affected alleles from six Moroccan Jewish families carried the mutation in codon 448. This mutation is not normally present in CYP11B2 and thus appears to have arisen in CYP11B1 as a true point mutation rather than a gene conversion.
Barrier function regulates epidermal DNA synthesis, We examined the possibility that the cutaneous permeability barrier regulates epidermal DNA synthesis in two acute and two chronic models of barrier perturbation. In animals treated topically with acetone. DNA synthesis is increased 102%. in tape-stripped animals 127%. in essential fatty acid deficient animals 50%. and in animals chronically treated with topical lovastatin 64%. This linkage between disturbances in barrier function and increased DNA synthesis is further supported by specific and correlative observations: (a) in these disparate models. artificial replacement of the barrier with a water-impermeable membrane inhibits the expected increase in DNA synthesis; (b) the extent of the burst in DNA synthesis is proportional to the degree of barrier abrogation; (c) the inhibition of DNA synthesis by membranes is directly related to the degree of permeability of these occlusive membranes. i.e.. the more impermeable the greater the degree of inhibition; (d) topical treatment with lipids that restore barrier function corrects the increase in DNA synthesis; and (e) barrier abrogation with acetone produces an increase in epidermal DNA synthesis without altering bulk protein synthetic rates in contrast to events known to follow injury or cell replacement. Autoradiographic studies show that the increase in DNA synthesis after acetone treatment is limited to the epidermal basal layer. This constellation of findings strongly suggests that cutaneous barrier function is one factor that regulates epidermal DNA synthesis.
Apoptosis as a mechanism of cell death in cultured T lymphoblasts acutely infected with HIV-1, The mechanisms by which HIV-1 infection kills T lymphocytes are not clearly established. Apoptosis is an internally programmed cell death pathway that may regulate both T cell development and senescence. and that is characterized by cleavage of DNA at internucleosomal regions. The present experiments show that acute HIV-1 infection of MT2 lymphoblasts and activated normal peripheral blood mononuclear cells induces apoptosis. The addition of anti-gp120 neutralizing antibody. after HIV-1 infection of MT2 cells. permitted sustained high levels of viral replication. but blocked apoptosis and cell death. Apoptosis may account for the direct cytopathologic effects of HIV-1 in T cells.
Apolipoprotein C-III(Lys58----Glu). Identification of an apolipoprotein C-III variant in a family with hyperalphalipoproteinemia, Apolipoprotein C-III is a major protein constituent of triglyceride rich lipoproteins and HDL. It occurs in plasma in three isoforms differing by their sialic acid content. Apo C-III putatively inhibits lipolysis and the apo E mediated hepatic uptake of remnants from triglyceride rich particles. We identified a heterozygous carrier of an apolipoprotein C-III variant by the presence of additional bands after isoelectric focusing (IEF) of VLDL. Structural analysis of the variant protein by HPLC. time-of-flight secondary ion mass spectrometry. and automated gas phase sequencing revealed a lysine to glutamic acid replacement in position 58. The underlying A to G exchange was verified by direct sequencing subsequent to amplification by polymerase chain reaction of exon 4 of the apo C-III gene. Family studies revealed vertical transmission of this defect. The two variant carriers exhibited plasma concentrations of HDL cholesterol and apo A-I above the 95th percentiles of sex matched controls whereas the unaffected father and sister showed normal values. The plasma concentrations of apo C-III in the two variant carriers were decreased by 30-40% compared with those of the two unaffected family members and to random controls. Using two-dimensional immunoelectrophoresis as well as IEF and subsequent scanning densitometry. we found that the low serum concentration of apo C-III was a consequence of diminished concentrations of the variant apo C-III isoproteins in both VLDL (15% of normal) and HDL (25% of normal). Apo C-III(Lys58----Glu) heterozygotes possessed unusual HDL as demonstrated by nondenaturing gradient gel electrophoresis. They consisted mainly of HDL2b and contained a proportion of atypically large particles. enriched in apo E. with a Stokes diameter of 13-18 nm and resembling HDLc. In conclusion. heterozygosity for a structural apo C-III variant--apo C-III(Lys58----Glu)--was identified in two hyperalphalipoproteinemic subjects characterized by the presence of low plasma apo C-III concentrations and atypically large HDL.
A truncated species of apolipoprotein B (B67) in a kindred with familial hypobetalipoproteinemia, We describe a kindred in which the proband and 6 of his 12 children have hypobetalipoproteinemia. The plasma lipoproteins of the affected subjects contained a unique species of apolipoprotein (apo) B. apo B67. in addition to the normal species. apo B100 and apo B48. The size of apo B67 and immunochemical studies with a panel of apo B-specific antibodies indicated that apo B67 was a truncated species of apo B that contained approximately the amino-terminal 3.000-3.100 amino acids of apo B100. Sequencing of genomic apo B clones revealed that affected family members were heterozygous for a mutant apo B allele containing a single nucleotide deletion in exon 26 (cDNA nucleotide 9327). This frameshift mutation is predicted to result in the synthesis of a truncated apo B containing 3.040 amino acids. Apo B67 is present in low levels in the plasma but is easily detectable within the very low density lipoprotein and low density lipoprotein fractions. Examination of the proband's immediate family revealed seven normolipidemic subjects and seven subjects with hypobetalipoproteinemia. In the affected subjects. the mean total and low density lipoprotein cholesterol levels were 120 and 42 mg/dl. respectively. A significantly higher mean high density lipoprotein cholesterol level was found in the affected subjects (75 vs. 55 mg/dl). We hypothesize that the elevated high density lipoprotein cholesterol levels in subjects heterozygous for the apo B67 mutation may be metabolically linked to the low levels of apo B-containing lipoproteins in their plasma.
Correction of enhanced Na(+)-H+ exchange of rat small intestinal brush-border membranes in streptozotocin-induced diabetes by insulin or 1,25-dihydroxycholecalciferol, Diabetes was induced in rats by administration of a single i.p. injection of streptozotocin (50 mg/kg body wt). After 7 d. diabetic rats were further treated with insulin or 1.25-dihydroxycholecalciferol [1.25(OH)2D3] for an additional 5-7 d. Control. diabetic. diabetic + insulin. and diabetic + 1.25(OH)2D3 rats were then killed. their proximal small intestines were removed. and villus-tip epithelial cells were isolated and used to prepare brush-border membrane vesicles. Preparations from each of these groups were then analyzed and compared with respect to their amiloride-sensitive. electroneutral Na(+)-H+ exchange activity. using 22Na uptake as well as acridine orange techniques. The results of these experiments demonstrated that (a) H+ gradient-dependent 22Na uptake as well as Na+ gradient-dependent transmembrane H+ fluxes were significantly increased in diabetic vesicles compared to their control counterparts. (b) kinetic studies demonstrated that this enhanced 22Na uptake in diabetes was a result of increased maximal velocity (Vmax) of this exchanger with no change in apparent affinity (Km) for Na+. (c) serum levels of 1.25(OH)2D3 were significantly lower in diabetic animals compared with their control counterparts; and (d) insulin or 1.25(OH)2D3 treatment restored the Vmax alterations to control values. without any significant changes in Km. concomitant with significantly increasing the serum levels of 1.25(OH)2D3 in diabetic animals. These results indicate that Na(+)-H+ activity is significantly increased in proximal small intestinal luminal membranes of streptozotocin-induced diabetic rats. Moreover. alterations in the serum levels of 1.25(OH)2D3 may. at least in part. explain this enhanced antiporter activity and its correction by insulin.
Association of circulating receptor Fc gamma RIII-positive monocytes in AIDS patients with elevated levels of transforming growth factor-beta, Monocytes in the circulation of normal individuals express two receptors for the constant region of immunoglobulin. Fc gamma RI and Fc gamma RII. In contrast. we have observed that AIDS monocytes express significant levels of a third Fc gamma R. Fc gamma RIII (CD16). which is normally associated with activation or maturation of the monocyte population. By dual-fluorescence analysis using a monoclonal antibody specific for Fc gamma RIII (MAb 3G8). 38.5 +/- 3.2% of the LeuM3 (CD14)-positive monocytes in AIDS patients were CD16 positive as compared to 10.4 +/- 1.0% for healthy individuals (n = 29; P less than 0.005). Furthermore. AIDS monocytes expressed Fc gamma RIII-specific mRNA which is expressed minimally or not at all in control monocytes. As a recently identified inducer of Fc gamma RIII expression on blood monocytes. transforming growth factor-beta (TGF-beta) was found to be elevated in the serum and/or plasma of AIDS patients. Moreover. incubation of normal monocytes with AIDS serum or plasma induced CD16 expression which correlated with serum TGF-beta levels (r = 0.74. P less than 0.001) and was inhibited with a neutralizing antibody to TGF-beta. Thus. the increased CD16 expression on peripheral blood monocytes in AIDS patients may be the consequence of elevated circulating levels of the polypeptide hormone TGF-beta.
Regulation of tumor necrosis factor gene expression by ionizing radiation in human myeloid leukemia cells and peripheral blood monocytes, Previous studies have demonstrated that ionizing radiation induces the expression of certain cytokines. such as TNF alpha/cachectin. However. there is presently no available information regarding the molecular mechanisms responsible for the regulation of cytokine gene expression by ionizing radiation. In this report. we describe the regulation of the TNF gene by ionizing radiation in human myeloid leukemia cells. The increase in TNF transcripts by x rays was both time- and dose-dependent as determined by Northern blot analysis. Similar findings were obtained in human peripheral blood monocytes. Transcriptional run-on analyses have demonstrated that ionizing radiation stimulates the rate of TNF gene transcription. Furthermore. induction of TNF mRNA was increased in the absence of protein synthesis. In contrast. ionizing radiation had little effect on the half-life of TNF transcripts. These findings indicate that the increase in TNF mRNA observed after irradiation is regulated by transcriptional mechanisms and suggest that production of this cytokine by myeloid cells may play a role in the pathophysiologic effects of ionizing radiation.
Expression of endothelial-leukocyte adhesion molecule-1 in elicited late phase allergic reactions, To better understand the events involved in the local migration of inflammatory cells into sites of allergic reactions. we studied expression of the cytokine inducible endothelial cell (EC) neutrophil adhesion molecule. endothelial-leukocyte adhesion molecule (ELAM-1). in sequential skin biopsies from patients with respiratory allergy during the late phase reaction (LPR) between 20 min and until 24 h after intradermal allergen (ragweed or dust mites) injection. In 7 of 7 atopic patients but in only 1 of 4 apparently normal controls. allergen induced appearance of ELAM-1 on EC. ELAM-1 expression occurred concurrently with the development of inflammatory cell infiltrates by 3-4 h after intradermal injection. Saline injected sites in all subjects were negative. Skin organ cultures demonstrated that allergen could produce the same EC changes in vitro whether allergen was injected in vivo 20 min before culture or added during skin culture. These EC changes in organ culture were inhibited by the presence of combined anti-sera to both TNF-alpha and IL-1. but not by antisera to either cytokine alone. We conclude that EC activation occurs in elicited LPR and suggest that cytokine-induced EC activation may play a role in the migration of inflammatory cells into allergic skin reactions. Furthermore. resident cells in the skin rather than infiltrating leukocytes appear to be the source of the cytokines that mediate endothelial activation.
Subcellular characteristics of phospholipase A2 activity in the rat kidney. Enhanced cytosolic, mitochondrial, and microsomal phospholipase A2 enzymatic activity after renal ischemia and reperfusion, Phospholipase A2 (PLA2) activities in cytosolic. mitochondrial. and microsomal fractions of rat kidneys were characterized under control conditions. after ischemia. and subsequent to ischemia and reperfusion. Two forms of PLA2 activity were present in the cytosolic fraction: a high molecular weight form. active against phosphatidylcholine (PC). and phosphatidylethanolamine (PE). which upon purification has a molecular mass of 110 kD; and smaller form (Mr approximately 14 kD). active against PE. In mitochondrial and microsomal fractions a single form (Mr approximately 14 kD). active against both PC and PE. was dominant. Activities in each fraction were optimal at pH 8.5-9.5. Cytosolic PLA2 activity was enhanced when Ca2+ concentration [( Ca2+]) was increased over the range of 10(-7) to 10(-6) M. Mitochondrial PLA2 activity required higher [Ca2+] for activation (greater than 10(-6) M). After 45 min of ischemia cytosolic PLA2 activity was decreased. whereas mitochondrial and microsomal activities were increased. When ischemia was followed by 1 h of reperfusion. cytosolic. mitochondrial. and microsomal activities were enhanced. Ischemia alone did not change the gel filtration chromatography patterns of PLA2 activity. but ischemia and reperfusion resulted in the appearance of a new peak of activity in cytosolic and mitochondrial fractions (Mr approximately 2-3 kD). Thus. the rat kidney has multiple forms of PLA2 activity. likely representing distinct enzymes. with Ca2+ dependencies suggesting regulation by Ca2+ in vivo. Ischemia and reperfusion result in stable increases of PLA2 activity in each subcellular fraction. perhaps related to covalent modifications of PLA2's. which likely account for membrane phospholipid degradation. and increased tissue levels of unsaturated free fatty acids.
Targeted enzyme therapy of experimental glomerulonephritis in rats, We sought to determine whether systemic administration of proteases ameliorates membranous nephritis induced in rats by immunization and challenge with cationic bovine gamma globulin. and whether targeting of protease to glomerular capillaries increases efficacy. Proteases substituted with biotin were targeted via the cationic protein avidin A. which by virtue of its charge has affinity for the glomerular basement membrane. Despite identical pretreatment proteinuria. rats given untargeted protease (biotin-conjugated without avidin. or unconjugated plus avidin) had significantly less proteinuria than saline-treated controls and nephrotic rats given avidin plus biotin-conjugated (targeted) protease had even less proteinuria and reduced glomerular rat IgG and C3. Among more severely nephrotic rats. targeted protease was again more effective than untargeted protease at reducing proteinuria. and also decreased the size of electron-dense glomerular deposits. hypercholesterolemia. and creatininemia. Inactivated targeted proteases had no effect on proteinuria. hypercholesterolemia. or azotemia. Finally. active targeted protease did not affect proteinuria in the nonimmune mediated nephrosis induced by puromycin aminonucleoside. We conclude that systemic protease can specifically diminish glomerular immune deposits. proteinuria. hyperlipidemia. and creatininemia associated with experimental immune complex glomerulonephritis but not toxic nephrosis. and that targeted protease is more effective than untargeted protease.
Is there a link between fluoridated water and osteosarcoma, To test the hypothesis that fluoride is a risk factor for osteosarcoma. a case control study compared the complete residential fluoride histories of osteosarcoma patients with matched hospital-based controls. Fluoridation was not found to be a risk factor for osteosarcoma in the study population. The trend in the data from this small sample study suggests the hypothesis that a protective effect may exist against the formation of osteosarcoma for individuals consuming fluoridated water.
Copy task performance and urinary incontinence in Alzheimer's disease, The relationship between behavioral symptoms and cognitive impairment in Alzheimer's Disease (AD) is only poorly understood. The aim of the present study was to examine cognitive correlates of urinary incontinence in AD. Although incontinence is generally accepted as an accompaniment of AD. it was our clinical impression that it correlated poorly with global measures of cognitive impairment. A retrospective pilot study of 17 incontinent demented patients and 17 continent patients. matched for age. sex. and total score on the Folstein Mini-Mental Status Exam (MMSE). revealed a striking association between an inability to do a copy task and urinary incontinence. A prospective study confirmed this finding in a sample of 45 patients meeting DSMIII-R diagnostic criteria for dementia. probable Alzheimer's disease. The 17 incontinent patients did not differ from the 28 continent patients in age. sex distribution. or total score on the MMSE. However. the incontinent subjects scored significantly lower on a cube copying task. Qualitative analysis revealed that the drawings by incontinent patients showed features comparable with those observed in the drawings by patients with right-sided parietal lesions. in particular. poor representation of perspective and spatial orientation. Further investigation of the relationship between copying performance and incontinence may have implications for understanding the cortical mechanisms of urinary continence. The present results also underscore the limitations of the MMSE as a measure of dementia severity and suggest there are areas of cognitive ability which are inadequately assessed by MMSE but which may be of major important in understanding the loss of functional skills in the dementing patient.
Are there clinical and epidemiological differences between familial and non-familial Alzheimer's disease, To determine whether there are clinical and epidemiological differences between familial and non-familial Alzheimer's disease. we studied 151 patients with the clinical diagnosis of Dementia of the Alzheimer Type (DAT). Eighty-four index patients (56%) had at least one relative with reported DAT-type memory loss; the remaining 67 did not. For comparison. patients with a positive family history were grouped into a suspected familial DAT (FDAT). and those with a negative family history were grouped into a suspected non-familial DAT (NFDAT). There were no significant differences between FDAT and NFDAT patients with respect to age of symptom onset. survival time. rate of cognitive decline. motor function. behavioral signs or symptoms. head trauma. thyroid dysfunction. maternal age. or birth order. There were no significant differences between pedigrees of FDAT and NFDAT patients in respect to the prevalence of Down's syndrome or age of mortality. To examine a more "familial" set of FDAT patients. an FDAT subgroup (F2DAT) consisting of 33 index patients with two or more affected relatives with DAT-type memory loss was compared to the 67 NFDAT patients in a similar analysis. No significant differences were found. However. NFDAT index patients had a higher reported prevalence of head trauma than those patients in the F2DAT subgroup (NFDAT 22%. F2DAT 7%. OR = 4.2. CI = 0.9-20.0. P = 0.08). Thus severe head trauma may be a more important etiological factor in the non-familial form of DAT. To better examine this tendency. future studies should be conducted utilizing a larger number of pedigrees and familial criteria which account for the number of persons at risk and the age at onset of disease.
Rationale for a primary prevention study using low-dose aspirin to prevent coronary and cerebrovascular disease in the elderly, The benefits of prophylactic aspirin therapy to prevent cardiovascular and cerebrovascular disease in asymptomatic individuals remains unclear. The rationale for developing a multicentered. double-blind. placebo-controlled clinical trial to determine whether low-dose aspirin (100 mg daily) prevents cardiovascular and cerebrovascular morbidity and mortality in persons aged 70 years and over with no evidence of pre-existing cardiovascular or cerebrovascular disease is described. Sample size calculations have indicated that 15.000 subjects would be required over a 4-year follow-up period in order to demonstrate a 20% reduction in overall cardiovascular mortality at the 0.01 level with a power of 0.8. Such a large-scale community-based clinical trial has never been conducted in Australia in this age group. Therefore the PACE (prevention by low-dose aspirin of cardiovascular disease in the elderly) pilot study has been developed to test recruitment strategies and methods and ascertaining disease end-points.
Unexplained weight loss in the ambulatory elderly, Significant unexplained and unintentional weight loss was found in 45 elderly patients who were identified by computer search of the diagnostic files of seven family practice centers. We performed a case series chart review study which revealed that 24% of the 45 cases had no definitive etiology for the weight loss after two years of extensive clinical investigation. Depression was found to be the most common diagnosis made (18%) followed by cancer (16%). Only four patients died during the study period and all had cancer. The most prevalent diagnosis in this group of ambulatory elderly patients did not prove to be cancer. as often though. but rather "unexplained weight loss." CT scans were not found to be helpful as screening tests in the evaluation of weight loss. Using the data from this study. the diagnostic evaluations of elderly patients with unexplained weight loss may be more efficiently directed.
A controlled study of disruptive vocalizations among geriatric residents in nursing homes, This paper reports the results of a controlled study comparing geriatric residents in nursing homes who displayed disruptive vocalizations with residents in a comparison group. Two 350-bed nursing homes were surveyed. and it was found that 11% of the residents engaged in disruptive vocalizations. at least once per week. of sufficient severity to require consideration in the resident's care plan. Results show that disruptive vocalizers were more functionally impaired and were more likely to receive a diagnosis of dementia. They were also more likely to display a higher activity level and to experience sleep disturbance and to be prescribed neuroleptic medications. Descriptive data are presented on typology of disruptive vocalizations. likely situations for their occurrence. and the utilization and perceived efficacy of common interventions. Suggestions are made regarding behavioral treatments for this vexing problem.
Immunohistologic and ultrastructural comparison of the dermal papilla and hair follicle bulb from "active" and "normal" areas of alopecia areata, The "active" edges of patches of alopecia areata and normal areas from the same scalp (i.e.. bearing normal terminal hair) from seven patients with alopecia areata were investigated immunohistologically. Similar areas from a further eight patients were examined using light and electronmicroscopy. "Active" and "normal" areas of alopecia areata scalps were immunohistologically similar and varied from normal controls in the number. distribution. and ratio for T4 and T8-positive cells. Similarly the ultrastructural changes seen in the "active" areas when compared to normal controls were also present in the "normal" areas of alopecia areata scalps. The most significant differences found between normal "control" follicles and both "active" and "normal" areas of alopecia areata scalps were the polymorphic nature of the dermal papilla cells and the loss of cellular organization within the dermal papillae taken from alopecia areata scalps. In addition. the junction between the dermal papilla and the bulb of the hair follicle. the dermo-epithelial junction of the hair follicle bulb. demonstrated critical changes in follicles taken from both "active" and "normal" areas of alopecia areata scalps. These results support the suggestion of a subclinical state of alopecia areata and indicate that further work on the etiology of alopecia areata should be directed towards the "normal" areas of alopecia areata scalps. in particular the cells of the dermal papilla and the dermo-epithelial junction of the hair follicle bulb.
Inflammatory properties of neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8) in human skin: a light- and electronmicroscopic study, Neutrophil-activating protein-1/interleukin 8 (NAP-1/IL-8). purified to homogeneity from lipopolysaccharide-stimulated human peripheral blood monocytes. was injected intracutaneously into human skin. Sequential biopsy specimens were taken in order to investigate the sequence of ultrastructural changes induced by the cytokine. Whereas intracutaneous injection of 100 ng of NAP-1/IL-8 per site caused no macroscopic changes. by histology infiltration with polymorphonuclear leukocytes (PMN) and monocytes was present within 1 h and increased at 3 and 5 h. No lymphocyte infiltration was noted. The first ultrastructural changes (30 min) consisted of the presence of cytoplasmic 7-nm microfilament bundles. as well as numerous protrusions of the luminal plasma membrane of endothelial cells (EC). As a striking feature. multiple 100- to 160-nm electron lucent vesicles could be observed in the EC cytoplasm. These structures differed from plasmalemmal vesicles and suggest secretory activity. When PMN and monocytes appeared in the vascular lumen (1 h and later). the number of 100-160-nm electron-lucent vesicles had decreased significantly. In contrast to C5a-injected skin sites. mast cell degranulation was absent.
Neuropeptides enhance irritant and allergic contact dermatitis, It is supposed that neuropeptides participate in the regulation of delayed-type hypersensitivity (DTH) reactions. However. their function in this kind of immune response is not known presently. Therefore. in vivo studies were initiated to test the effect on allergic (ACD) and irritant contact dermatitis (ICD) of the neuropeptides substance P (SP). calcitonin gene-related peptide (CGRP). and somatostatin (SOM). which are released from afferent neurons in the skin. Each neuropeptide was applied topically at the site of contact with the allergen (oxazolone) or irritant (croton oil) during the challenge and sensitization phase of contact dermatitis. The intensity of the inflammation was measured as an increase of ear-swelling response. which represents the degree of plasma extravasation in the early phase of inflammation. Neuropeptides alone led only to a distinct vasodilation. All three neuropeptides were equally able to increase allergic and irritant inflammation. Even minor irritant stimuli were enhanced. Beyond that. CGRP was able to boost sensitization. whereas SOM and SP did not show any effects on the sensitization process. The results presented demonstrate that neuropeptides increase plasma extravasation independent of the pathogenesis of inflammation and may act as priming substances for other mediators of increased vascular permeability. In addition. CGRP enhances the sensitization process.
Production of interleukin-1 and interleukin-6 by human keratinocytes and squamous cell carcinoma cell lines, Cultured human keratinocytes and squamous cell carcinoma (SCC) cell lines were analyzed for the presence of ribonucleic acid (RNA) transcripts for the cytokines interleukin-1 and interleukin-6 and for these proteins. This study demonstrates that both cytokines are synthesized and secreted by both normal keratinocytes and SCC lines. The rate of secretion of these cytokines can be augmented in response to a variety of stimuli including tumor necrosis factor-alpha. granulocyte-macrophage colony stimulating factor. transforming growth factor-beta and the combination of lipopolysaccharide and phorbol myristate acetate. Interleukin-1 and interleukin-6 have been reported to influence the proliferation of cultured human fibroblasts. However. these cytokines had no significant effect on the proliferation of human keratinocytes or the SCC lines tested. Although it seems unlikely that interleukin-1 or interleukin-6 could directly influence keratinocyte proliferation in vivo. the capacity of these cells to synthesize and release these cytokines supports earlier observations that keratinocytes may play an important role in augmenting an immune or inflammatory response.
Cancer screening by primary care physicians. Can we explain the differences?, BACKGROUND. Physicians perform cancer screening tests less often than recommended. METHODS. Forty primary care physicians were surveyed to assess their knowledge. attitudes. and experiences regarding cancer and cancer screening. and patients' medical records were reviewed to measure physicians' screening rates. RESULTS. Over 80% of physicians believed doctors should urge screening. On average. 23% of their patient visits were scheduled primarily for preventive care interventions. Screening performance scores expressed the percentage of compliance with the American Cancer Society's recommendations and demonstrated the low levels of compliance for six out of seven tests; however. there was substantial variance in performance among physicians. The best predictors of screening performance were (1) the percentage of visits scheduled primarily for prevention (mammography. and pelvic and breast examinations [P less than .05]); and (2) the number of medical journals read regularly (stool occult blood test [P less than .01]. sigmoidoscopy [P less than .01]. and Papanicolaou smear [P less than .02]). Also. female physicians performed more Papanicolaou smears (P less than .05) and scheduled more visits for preventive care (P less than .001). CONCLUSIONS. A small group of predictors explain large portions of the variance in cancer screening performance.
Physician recommendations for screening mammography: results of a survey using clinical vignettes, BACKGROUND. Although experts estimate that 30% of breast cancer deaths could be prevented if women were screened according to published guidelines. fewer than 50% of physicians follow screening mammography guidelines. and fewer than 30% of women are screened with mammography. METHODS. Physician recommendations for screening mammography were examined in a questionnaire mailed to 300 randomly selected physicians of the Ohio Academy of Family Physicians. Physicians responded with their likelihood of recommending screening mammography to 24 clinical vignettes that high-lighted patient. mammographic. and encounter characteristics. RESULTS. Seventy-one percent responded. Ninety-one percent reported almost always recommending screening mammography to a 55-year-old woman at her yearly examination. They were significantly less likely to recommend mammography to women who were young (40 years old). were old (70 years old). were poor. had small breasts. had painful mammograms. did not want the doctor to look for cancer. lived in a nursing home. or were retarded. Physicians recommended mammography less often when the mammography unit was far away or produced poor quality films or ambiguous interpretations. When physicians ran behind schedule. perceived a more urgent medical problem during the encounter. or saw a woman for an acute visit. they recommended mammography significantly less often. CONCLUSIONS. Patient. mammographic. and encounter characteristics significantly limit physician recommendations for screening mammography as assessed by clinical vignettes. These characteristics must be addressed if breast cancer mortality is to be reduced with early screening.
Relationship of stress, distress, and the immunologic response to a recombinant hepatitis B vaccine, BACKGROUND. Many studies have investigated the relationship between psychosocial factors and the susceptibility to infectious diseases. Fewer studies have investigated the relationship between stress and the immunologic response to vaccines. A follow-up study was designed to investigate the relationships between stress. distress. and the antibody response to a recombinant hepatitis B vaccine. METHODS. Eighty-one seronegative medical students received a standard immunization protocol of a recombinant hepatitis B vaccine. Six months after the first dose. corresponding to the induction phase of immunization. each subject completed both the Survey of Life Experiences and the Symptom Distress Check List to assess levels of stress and distress during that period. Three months after the third dose. corresponding to the booster phase of immunization. each subject completed the same questionnaires and was also tested for a quantitative hepatitis B surface antibody titer. Correlations were statistically analyzed using Pearson's correlation coefficient and stepwise multifactorial regression analysis. RESULTS. Higher levels of negatively perceived stress. irascibility. depression. and anxiety during the induction phase of immunization were significantly associated with higher peak antibody titers. Together these psychosocial factors accounted for 5.8% of the variance. and were as strong a determinant of peak antibody titer as was age. CONCLUSIONS. In addition to the known vaccine-related and biological factors. psychosocial factors appear to affect the immune response to a recombinant hepatitis B vaccine. The positive direction of the correlation raises the question of whether the effect of psychosocial factors on antibody formation is different from their effect on antibody function.
Posttraumatic stress disorder following recent-onset psychosis. An unrecognized postpsychotic syndrome, Clinical experience with psychotic patients early in the course of their illness suggested that symptoms of posttraumatic stress disorder (PTSD) may not be uncommon after recovery from an acute psychotic episode. Thirty-six patients recovering from an acute psychotic episode within 2 to 3 years of onset of their illness were assessed as inpatients and followed up on two occasions during the year after discharge. The prevalence of PTSD was found to be 46% at 4 months and 35% at 11 months. measured by a questionnaire linked to DSM-III criteria. The relationships between negative symptomatology and PTSD symptoms and between depressive symptomatology and PTSD symptoms were also examined; a significant correlation was found only for the latter. The psychopathological. preventive. and therapeutic implications of these findings are discussed. and future research strategies are proposed.
Short- and long-term psychological status following stroke. Short form MMPI results, Indices of self-reported depression and psychological adjustment after stroke were evaluated using a short form of the MMPI. Patients with poststroke periods of 2 to 6 and 7 to 24 months were selected. and indices of general intellectual functioning and lesion size/location were obtained. Despite similar levels of intellectual functioning and lesion parameters. the longer duration group showed significantly higher depression scores and significant (T greater than 70) elevations on several other clinical scales of the MMPI. In contrast. the mean overall profile of the short-duration group was roughly within normal limits. These findings have implications for the clinical assessment and treatment of stroke patients and long-term psychological adjustment after stroke.
Multidimensionality and state dependency of alexithymia in recently sober alcoholics, In this study. we a) examined the appropriateness of using a single global score to represent alexithymia and b) constructed a model to examine the relationship between alexithymia and depression in recently sober alcoholics applying for inpatient care. To measure alexithymia. we used the Toronto Alexithymia Scale (TAS); to measure depression. we used the revised Beck Depression Inventory (BDI). Factor analyses identified three alexithymia factors (Feelings. Daydreaming. and External Thinking) and two depression factors (Somatic-Performance and Cognitive-Affective). The three TAS factors were not positively related to each other; the two BDI factors were. We used LISREL software to examine the relationships between the TAS factors and the BDI factors. The only two significant unidirectional coefficients were between the TAS-Feelings factor and the two BDI factors. Our results suggest that in recently sober alcoholics. alexithymia. as measured by the TAS. consists of three independent. unrelated dimensions. Moreover. only the dimension associated with an inability to identify feelings and to distinguish them from bodily sensations is related to depressive symptoms. To determine whether this alexithymia feelings dimension actually is dependent on situational depression and/or anxiety will require confirmation in additional samples. such as primary alexithymics and patients with major depressive disorders.
A new mouse mutant with progressive motor neuronopathy, A new autosomal-recessive mouse mutant with progressive motor neuronopathy (pmn) is described. Homozygotes develop paralysis of the hindlimbs during the third week of life. Soon thereafter the forelimbs also become weak. and all mice die six to seven weeks after birth. Heterozygotes are normal. Skeletal muscles show neurogenic atrophy without histological signs of reinnervation. Axonal degeneration apparently starts at the endplates and is prominent in the sciatic nerve and its branches and the phrenic nerve. Axonal sprouts are abundant. There is no evidence of demyelination. and unaffected nerve fibers are normally myelinated. Sensory axons are spared. Almost all distal motor axons have disappeared in four to five weeks after birth. Ventral nerve roots show a reduced diameter of the largest fibers but no fiber deficits. The ventral horn cells show slight chromatolysis. The corticospinal tract is normal. but in terminally ill animals the fasciculus gracilis. the rubrospinal tract and possibly also reticulospinal fibers degenerate. The brain is histologically normal. The disease manifests itself in a dying-back fashion in the distal portion of the motor neurons and may represent an animal model of hereditary motor neuron diseases in man.
Borna disease virus replicates in astrocytes, Schwann cells and ependymal cells in persistently infected rats: location of viral genomic and messenger RNAs by in situ hybridization, Borna disease (BD) is an immune-mediated neurological disease caused by infection of the nervous system with a negative strand RNA virus. Borna disease virus (BDV). The host range for BDV is broad and extends from birds to primates. A BDV-like agent may cause disease in humans. Until recently. BDV-infected neural cells could only be identified immunocytochemically using serum from BDV-infected animals. The advent of BDV cDNA clones allowed definition of the relationship between viral nucleic acids and viral proteins in vivo. In situ hybridization with strand-specific RNA probes from a BDV cDNA clone. pAF4. identified BDV genomic RNA and BDV mRNAs in neurons. astrocytes. Schwann cells and ependymal cells in an anatomic distribution consistent with that of BDV proteins. Genomic RNA was contained primarily within the nucleus. whereas mRNAs were found in both the nuclear and cytoplasmic compartments. Viral RNAs were demonstrated in neurons expressing BDV proteins and in glial cells by combined techniques of immunocytochemistry and in situ hybridization.
Reactive astrogliosis is widespread in the subcortical white matter of amyotrophic lateral sclerosis brain, Widespread astrogliosis exists in the subcortical white matter in amyotrophic lateral sclerosis (ALS). As revealed by glial fibrillary acidic protein (GFAP) immunostaining. the gliosis has the morphological properties of an active process. It is present in the midfrontal. inferior parietal. temporal. cingulate. and occipital cortices. as well as in the motor cortex. Compared to matched regions from other neurological diseases. the gliosis in ALS does not appear to be the nonspecific result of a progressive. degenerative disease. In cell number and apparent cell size. the gliosis is comparable to that present in neurological diseases known to have white matter gliosis. Cytologically. the gliosis most closely resembles that present in cases of cerebral infarction. The basis for this similarity is unknown.
Nuclear exercise testing and the management of coronary artery disease, Three hundred seventy-eight patients referred for nuclear exercise testing were classified using demographics and symptoms into low. intermediate. and high coronary disease likelihood categories. These likelihood groups constituted 15%. 41%. and 15% of referrals. respectively. Patients with prior infarction or disease at angiography (proven disease) made up the remaining 29% of patients. Only 2% of low likelihood patients had typical angina. but physicians diagnosed coronary disease in 64%. prescribed antianginal therapy in 50%. and were considering catheterization in 28% of these patients. all as frequently as for patients with intermediate or high likelihoods for disease. Patients with proven disease were treated differently in that 79% were receiving antianginal therapy and 56% were considered for catheterization (p less than 0.001). Nuclear exercise test results reduced the perceived need for catheterization in all groups. on average by 49%. Nuclear exercise tests are a standard by which patients are managed. sometimes substituting for the traditional role of the history in physician decision making.
Reproducibility of quantitative planar thallium-201 scintigraphy: quantitative criteria for reversibility of myocardial perfusion defects, Fifty-two paired stress/delayed planar 201TI studies (27 exercise studies. 25 dipyridamole studies) were processed twice by seven technologists to assess inter- and intraobserver variability. The reproducibility was inversely related to the size of 201TI perfusion abnormalities. Intraobserver variability was not different between exercise and dipyridamole studies for lesions of similar size. Based upon intraobserver variability. objective quantitative criteria for reversibility of perfusion abnormalities were defined. These objective criteria were tested prospectively in a separate group of 35 201TI studies and compared with the subjective interpretation of quantitative circumferential profiles. Overall. exact agreement existed in 78% of images (kappa statistic k = 0.66). We conclude that quantification of planar 201TI scans is highly reproducible. with acceptable inter- and intraobserver variability. Objective criteria for lesion reversibility correlated well with analysis by experienced observers.
Left ventricular regional wall motion assessment by radionuclide ventriculography: a comparison of cine display with Fourier imaging, Radionuclide ventriculography and contrast ventriculography were performed in two comparable projections on 50 patients with suspected coronary artery disease. The efficacy of conventional cine display and Fourier image analysis of the radionuclide ventriculogram was compared using contrast ventriculography as the gold standard. Of seven different combinations of Fourier images. the combination of left anterior oblique amplitude and phase and left posterior oblique amplitude and phase provided the highest sensitivity (87%). specificity (83%). accuracy (86%). and kappa coefficient (0.64). To increase statistical power. segment data were collapsed to global data in which a heart was considered normal if all segments were normal and abnormal if one or more segments were abnormal. Fourier images had higher sensitivity (Fourier 87%. cine 47%); lower specificity (Fourier 83%. cine 92%). higher accuracy (Fourier 86%. cine 58%). and higher kappa coefficient (Fourier 0.64. cine 0.25). and these differences were statistically significant (p less than 0.01).
Evaluation of indium-111-labeled antifibrin monoclonal antibody for the diagnosis of venous thrombotic disease, The potential advantage of using 111In-antifibrin (111In-AF) monoclonal antibody for the diagnosis of deep venous thrombosis (DVT) was studied in 44 patients with suspected DVT (27 underwent heparin therapy before 111In-AF injection). All patients had contrast venography (considered as the gold standard) and 111In-AF scintigraphy within 24 hr. Two to 3 mCi of 111In-AF were injected intravenously. and planar scintigraphy of the limbs was recorded within 10 min (17 times). 3 hr (44 times). and 18 hr (39 times). Indium-111-AF images were then interpreted without knowledge of the results of the other examinations. The DVT diagnostic accuracy of 111In-AF was greater when interpretation was based on images recorded at different time periods after injection. Indium-111-AF sensitivity for diagnosis of DVT was 85% (29/34) and was not apparently decreased by heparin therapy. None of the 10 patients with negative contrast venography had a positive 111In-AF scan. The results demonstrate the importance of recording serial images and the excellent accuracy of 111In-AF for diagnosing DVT.
Changes in quantitative SPECT thallium-201 results associated with the use of energy-weighted acquisition, The effect of utilizing energy-weighted acquisition on quantitative analysis of SPECT thallium-201 images was evaluated by simultaneously acquiring energy-weighted and windowed projection images in ten patients. The paired image sets were processed identically and evaluated by probability analysis of defect magnitude as indicated by a commercially available software analysis package. It was predicted that defect magnitude would increase as a result of improved image contrast. This was confirmed experimentally. One should be cautious in relying on strict quantitative criteria in cardiac studies with thallium-201. especially when major changes in the imaging system or technique are introduced.
Radiation dosimetry for the adult female and fetus from iodine-131 administration in hyperthyroidism, Through a study of the iodine kinetics of 127 patients. we have developed radiation dose estimates to major organs and the fetus for patients with varying degrees of hyperthyroidism. We observed a negative correlation between maximum thyroid uptake and biologic half-time of iodine in the thyroid and used this correlation to predict the biologic half-time at fixed values of maximum thyroid uptake. Dose estimates to the bladder. gonads. marrow. thyroid. uterus. and whole body were estimated for maximum thyroid uptakes from 20% to 100%. Bladder dose varied from 0.6 to 1.0 mGy/MBq and dose to the uterus varied from 0.036 to 0.063 mGy/MBq under different model assumptions. Dose estimates to the fetus and fetal thyroid were approximated at all stages of pregnancy. Average fetal dose was a maximum between 0 and 2 mo of pregnancy. with the maximum ranging from 0.048 mGy/MBq to 0.083 mGy/MBq. depending on model assumptions. Some radiation risks for irradiation of the fetus and the fetal thyroid are discussed.
Reversal of intrapulmonary shunting in cirrhosis after liver transplantation demonstrated by perfusion lung scan, A young girl with biliary atresia leading to cirrhosis developed respiratory complications with hypoxemia. Intrapulmonary shunting was diagnosed with a 99mTc-MAA perfusion lung scan. which showed marked systemic activity. The shunting resolved after liver transplantation. The perfusion lung scan offers an efficient method to screen patients with cirrhosis in whom intrapulmonary shunts are suspected and to follow their progress.
Orbit-related variation in spatial resolution as a source of artifactual defects in thallium-201 SPECT, The cause of 180-degree diametrical artifactual defects in clinical thallium-201 SPECT imaging was investigated using phantom simulation. This artifact was observed on SPECT images acquired with a "body contour" or "peanut" orbit. It was hypothesized that this artifact was caused by differences in spatial resolution that occur when the heart-to-detector distance changes employing noncircular orbits. To test this hypothesis. a series of planar static images of a normal cylindrical phantom was obtained at varying distances from the camera detector head. From these images. tomographic acquisition files were created that simulated tomographic data acquired with circular orbits and elliptical orbits. The reconstructed phantom short-axis slices showed no artifacts for circular orbits. However. for various elliptical orbits. significant regional nonuniformity. similar to the artifacts noted in patients. was observed. The degree of nonuniformity correlated with the long-short axis ratio of elliptical orbits (r = 0.98). In addition. circular orbits with the phantom in an eccentric position resulted in similar nonuniformities. It is concluded that a noncircular tomographic orbit can create characteristic artifacts on thallium-201 SPECT images. For rotational thallium 201 SPECT. a circular orbit with the heart in the center of rotation should be employed.
Nursing and public policy. What is the high ground, To be effective in public policy formation. nurses must establish standards of care and advocate changes in financing and healthcare organization for persons who are not well served. The author delineates four areas (out-of-hospital prenatal and postnatal care; care of chronically mentally ill adults and severely emotionally disturbed youths; care for the elderly. especially in nursing homes; and care of the disabled and the chronically and terminally ill) where nurses should be the authority for much of the care provided. The author concludes that evolving dissatisfaction with the healthcare system means that nurses have the opportunity to make major contributions to the organization of all parts of the system. as it is ultimately put together. if they do the research and advocacy that is needed.
Predictors of left atrial thrombus in mitral valve disease, OBJECTIVE: To determine the risk factors for left atrial thrombus (LAT) and the prevalence of thrombi in cases of mitral valve disease whose severity was judged to necessitate surgical intervention. DESIGN: Hospital record review of all operative cases from 1982 to 1985. SETTING: A community serving a referral population encompassing 1.5 million people. Only two hospitals in the geographic area performed cardiac surgery. and both hospitals' records were reviewed. PATIENTS: All 372 patients who underwent either mitral valve replacement or open mitral commissurotomy. MAIN RESULTS: Twenty-six patients (7%) were noted to have LAT at surgery. Five preselected factors were significantly (p less than 0.05) associated with LAT in univariate analysis: female gender. prior history of embolism. prior anticoagulant therapy. mitral stenosis (MS). and atrial fibrillation (AF). In logistic regression analysis. only MS and AF remained as significant independent predictors of LAT. Mitral stenosis patients in sinus rhythm had a relatively low [2.4 +/- 3.3% (observed +/- 95% confidence interval)] likelihood of having an LAT. Likewise. mitral regurgitation patients in sinus rhythm (n = 139) had an extremely low (0.7 +/- 1.4%) prevalence of LAT. In contrast. MS patients in AF (n = 122) had a prevalence of LAT of 18.0 +/- 6.8%. CONCLUSIONS: These findings indicate that. overall. LAT in mitral valve disease may be less common than previous studies have suggested. In addition. mitral valve disease patients who remain in sinus rhythm appear to have a low risk of harboring an LAT. Conversely. MS patients. especially those in AF. appear to be at high risk of harboring an LAT. These results may be helpful in formulating strategies for the use of prophylactic anticoagulation in categories of patients with clinically severe mitral valve disease. or perhaps in estimating the likelihood of a cardiac source of embolism in mitral valve disease patients with suspected cerebral or peripheral emboli.
Primary care clinician compliance with cholesterol treatment guidelines, OBJECTIVE: To determine the rate and predictors of clinician compliance with treatment guidelines for high cholesterol in a primary care practice and establish quality assurance thresholds for monitoring patient management. DESIGN: Retrospective chart audit one year after high (greater than 240 mg/dL) cholesterol level. PATIENTS: 257 (243 after exclusions) consecutive patients with serum cholesterol levels greater than 240 mg/dL. SETTING: Primary care practice of group-model university-based HMO. INTERVENTIONS: None. MEASUREMENTS and MAIN RESULTS: In the one-year interval following the index elevated cholesterol level. 67% of 243 patients had received documented dietary counseling. 53% had had a follow-up cholesterol test. and 8% were started on drug treatment. Only two patients (1.8%) without a history of hypercholesterolemia prior to the index level were started on drug treatment. compared with 18 patients (15%) with such a history. The odds (and 95% confidence intervals) of patient dietary counseling increased twofold (1.35 to 2.95) for each 25-mg/dL increment in serum cholesterol. and by 1.45 times (1.12 to 1.87) for each additional coronary risk factor. Patients who had high cholesterol levels obtained as isolated determinations had 2.46 times (1.32 to 4.64) higher odds of being followed by counseling than did those whose levels had been obtained as part of a chemistry panel. CONCLUSIONS: Compliance with National Cholesterol Education Panel guidelines for dietary counseling. but not drug therapy. was higher in this setting than in other published compliance studies. Quality assurance monitoring of compliance with dietary counseling and obtaining lipid measurements using a threshold approach are suggested. A similar approach to drug therapy of hypercholesterolemia appears premature.
Care for caregivers: a support group for staff caring for AIDS patients in a hospital-based primary care practice, OBJECTIVE: To assess the types of stress experienced by health care personnel caring for AIDS patients and to develop ways to reduce that stress. DESIGN: A multidisciplinary support group for AIDS caregivers met weekly for three months. providing a context for the meaningful expression of personal and professional concerns about AIDS-related care. SETTING: A hospital-based primary care group practice at Beth Israel Hospital. Boston. PARTICIPANTS: Health care personnel caring for patients with AIDS. CONCLUSIONS: Those who care for people with AIDS need support systems to help them gain some mastery over the complex clinical and emotional problems raised by the illness. During the course of this support group. the members moved from feeling overwhelmed to a new sense of confidence. collegiality. and understanding of their own and others' emotional reactions. and a renewed approach to the care of these patients.
Ranitidine improves certain cellular immune responses in asymptomatic HIV-infected individuals, Human immunodeficiency virus (HIV) infection is characterized by a progressive impairment in immunocompetence leading to severe opportunistic infections and malignancies. In a double-blind. placebo-controlled study. the potential impact of immunomodulation by oral ranitidine. 600 mg daily. for 28 days was studied in 18 HIV-positive patients (CDC group II). All were without clinical signs of infections and were not treated with other known immunomodulating agents. Several immunological parameters related to HIV infection were studied and confirmed to be impaired early in HIV infection. Spontaneous and in vitro interleukin-2- and interferon-alpha-stimulated natural killer cell activity improved in the ranitidine-treated patients in contrast to a decrease in nontreated patients (#p less than 0.03. #p less than 0.01. #p less than 0.02 between groups. respectively). Furthermore. T-cell blastogenesis to phytohemagglutinin stimulation and soluble interleukin-2 receptors in serum increased in ranitidine-treated patients compared with nontreated patients (#p less than 0.01). However. ranitidine treatment did not change CD4+ cell counts. Although the significant improvement in immunocompetence shown in this study is small. the present result indicates the need for further trials with immunomodulation by ranitidine in HIV-infected individuals.
Brain growth and cognitive improvement in children with human immunodeficiency virus-induced encephalopathy after 6 months of continuous infusion zidovudine therapy, The ventricular area at the level of the foramen of Monro was measured from axial x-ray computed tomography (CT) scans obtained prior to and 6 months after the initiation of continuous infusion of zidovudine (ZDV) in eight children with human immunodeficiency virus-induced encephalopathy. Evidence of moderate to severe central atrophy was present on initial CT scans (p less than 0.05). Ventricular area and ventricular brain area ratio (VBR) decreased after ZDV therapy in seven of eight children (mean decrease of 21.5 and 20%. respectively. p less than 0.05). The degree of decrease in VBR correlated with reductions in cerebrospinal fluid (CSF) protein concentration (r = 0.93. p less than 0.01). but not lymphocyte T4 or T8 counts. Intelligence quotients (IQs) improved in all seven children tested (mean improvement of 17.7%. p less than 0.01) and correlated significantly with reductions in CSF protein concentration (r = -0.85. p = 0.003). The magnitude of IQ changes was not significantly correlated with the magnitude of changes in ventricular area. We conclude that the cognitive improvement of HIV encephalopathy seen after 6 months of continuous infusion of ZDV is accompanied by reduction in brain atrophy and decreased CSF protein. suggesting an ameliorating effect of ZDV on the pathogenesis of AIDS encephalopathy in children.
Lack of evidence for HIV-2 infection among at-risk individuals in Brazil, Recent reports have indicated the possibility that HIV-2 has been introduced into groups at risk for AIDS in Brazil. We studied sera collected in 1987 and 1988 from 1.821 at-risk individuals from diverse regions in Brazil. Of the 1.821 sera. 367 (20%) were confirmed as being positive for HIV-1 antibodies by enzyme-linked immunosorbent assay (ELISA). immunofluorescence (IF). and Western blot. An additional 33 (2%) sera displayed some reactivity to HIV-2-infected cells by IF. All 33 sera were subsequently tested in HIV-1 and HIV-2 Western blots as well as an ELISA using HIV-1- or HIV-2-specific peptides. All sera were confirmed as positive for HIV-1 and negative for HIV-2 antibodies in both assays. We conclude that caution should be used in the interpretation of serologic cross-reactivity between HIV-1 and HIV-2 and that there is no evidence that HIV-2 has entered groups at risk for HIV infection in Brazil.
Prevalence of HIV antibody among a group of paraphilic sex offenders, Serum specimens from 77 paraphilic sex offenders in treatment at a major community-based sexual disorders clinic were examined for human immunodeficiency virus (HIV) infection. In addition to their paraphilic ("sexually deviant") activities. most patients had also had nonparaphilic sexual contacts with consenting adult partners. These patients had engaged in a variety of sexual behaviors that involved real or potential exchange of body fluids. In spite of that fact. data analysis revealed that none of the 77 paraphilic patients was seropositive for HIV infection as assessed by recombinant enzyme-linked immunosorbent assay (ELISA).
Amyloidosis in a case of ankylosing spondylitis with a review of the literature, A 53-year-old man with a 20-year history of ankylosing spondylitis presented with proteinuria and acute renal insufficiency. Amyloidosis was diagnosed on renal biopsy. The association of secondary amyloidosis has been described with collagen vascular diseases. however. a review of the literature reveals few cases associated with the spondyloarthropathies. We were able to find only 2 cases in the American literature. Thus. although a rare complication. amyloidosis should be considered in the differential diagnosis of proteinuria and renal insufficiency in spondyloarthropathy.
Sacral insufficiency fractures: an often unsuspected cause of low back pain, We describe a patient with sacral insufficiency fractures presenting as acute onset low back pain without antecedent trauma. Sacral insufficiency fractures are an often unsuspected cause of low back pain. The clinical presentation and plain radiograph findings can mimic metastatic disease. leading to unnecessary investigations and treatment. However. the location. linearity. and appearance of these fractures on computed tomography is very characteristic and obviates the need for further evaluation.
Prediction of short-term prognosis by biopsychosocial variables in patients with juvenile rheumatic diseases, We describe physical symptoms and signs. laboratory data and psychosocial assessments for 84 children (age 1-17) hospitalized for the first time with suspected or definite rheumatic disease. At 16 months (range 7-28) followup change of disease severity was assessed based on hospital records. The patients were categorized as unchanged/worse (n = 36) or improved (n = 48). A linear discriminant model applying a combined set of 6 medical and 2 psychosocial variables characterized correctly 68 of 84 patients (81%). The variables were age at onset. disease severity. months of disease duration. presence of rheumatic disease in the family. erythrocyte sedimentation rate (ESR). thrombocytes. total behavior problem score on the Child Behavior Checklist and maternal distress. By discriminant function analysis of biopsychosocial variables more homogeneous groups may be obtained. Study of such groups may improve prediction of the prognosis.
The L1 protein as a new indicator of inflammatory activity in patients with juvenile rheumatoid arthritis, L1 is a major granulocyte and monocyte protein with Mr 36.5 kDa. It is released during leukocyte activation and detected in plasma by use of an enzyme immunoassay. In our study. L1. erythrocyte sedimentation rate (ESR). C-reactive protein (CRP). orosomucoid and haptoglobin were analyzed in 127 patients with juvenile rheumatoid arthritis (79 pauci. 33 poly and 15 systemic). L1. ESR and the acute phase proteins were all found to have positive correlations with the clinical joint assessments. with L1 having the strongest correlations. High correlation coefficients were found between L1 and orosomucoid (r = 0.83). ESR (r = 0.72). haptoglobin (r = 0.71) and CRP (r = 0.65). with p less than 0.001 for all the correlations.
Restriction fragment length polymorphism analysis of HLA-DR, DQ, DP and C4 alleles in Caucasians with systemic lupus erythematosus, HLA-DR. DQ. DP and C4 null alleles were determined by restriction fragment length polymorphism (RFLP) analysis in 60 Caucasian patients with systemic lupus erythematosus (SLE) and 66 controls. DR3 (DRw17) and DQw2.1 were increased in frequency in the patients with SLE associated with the presence of C4A null genes. HLA-DP alleles determined by RFLP analysis of genomic DNA as well as of PCR amplified DNA were not associated with SLE or any clinical or autoantibody subset thereof. No DR. DQ. or C4 null gene association was found with renal or neuropsychiatric involvement or nDNA antibodies (or levels thereof). These data suggest that the primary predisposition to SLE lies with HLA-DR or C4 null alleles. and not with HLA-DP.
Longterm cyclosporine therapy in rheumatoid arthritis, Sixteen patients who had shown a good clinical response to cyclosporine therapy during a randomized 6-month double blind study comparing cyclosporine with D-penicillamine in active rheumatoid arthritis. had an opportunity to participate in an open study with cyclosporine. The initial daily dose of cyclosporine was 5 mg/kg. Before the planned maximal duration of 18 months. there were 6 premature discontinuations. 2 because of inefficacy. 2 because of side effects. and 2 for other reasons. During the study there was an improvement in all clinical variables. Even under the strict conditions of our trial there was an irreversible loss of about 15% of renal function. Suggestions are given to minimize the chance of nephrotoxicity.
Education level and rheumatoid arthritis: evidence from five data centers, Data on 2.006 patients with rheumatoid arthritis (RA) for 1984 and 1986 were analyzed from 5 American Rheumatism Association Medical Information Systems patient centers to assess covariates of future disability. The dependent variable was the Health Assessment Questionnaire disability index. measured in 1986. Independent variables. measured in 1984. include years of schooling. age. age squared. sex. labor force status. occupation. marital status. race. income. sedimentation rate. log latex. number of tender joints. and duration of illness. A negative association between schooling and the disability index is strongly apparent for men and weaker in women. Results for men persist even after adjustment for occupation and income. but not after additional adjustment for biological variables. The effects of schooling upon progression of RA are complex and interpretation requires simultaneous assessment of a variety of other variables. Causal effects of level of schooling are seen with a social science perspective which considers the biologic data to represent dependent variables yet cannot be inferred from a clinical model which considers the biology of the disease as an independent variable.
Palindromic rheumatism: a response to chloroquine, We reviewed 71 patients with palindromic rheumatism. The average length of followup was 3.6 years. Fifty-one patients received antimalarial therapy. Forty-one of the 51 patients experienced marked improvement with 77.5% reduction in frequency and 63% reduction in duration of attacks. Sixteen out of the 71 patients developed persistent arthritis in the form of rheumatoid arthritis (12 patients). systemic lupus erythematosus (2 patients). Crohn's disease (1 patient) and asymmetric seronegative arthropathy (1 patient). Chloroquine therapy. therefore. seems effective in relieving palindromic rheumatism.
A behaviorally effective model for training of general health professionals by a rheumatology team, This project evaluated a model for inservice arthritis education based in part on principles of applied behavior analysis. Thirty-seven public health nurses (PHN) from 10 rural midwestern counties received instruction about screening and management of patients with arthritis; a random half of counties also received public and physician information interventions designed to increase arthritis referrals to community physicians under specific circumstances. In clinic interviews with patients of PHN showed modest. but significant. increases in 14 of 16 target behaviors attributable to inservice education. Because measured arthritis impact was low in this older adult population. physician referral rates were not affected by either intervention. This model illustrates generalizable behavior modification guidelines that are useful adjuncts to traditional procedures for development of professional arthritis education.
Controlled trial of hypnotherapy in the treatment of refractory fibromyalgia, In a controlled study. 40 patients with refractory fibromyalgia were randomly allocated to treatment with either hypnotherapy or physical therapy for 12 weeks with followup at 24 weeks. Compared with the patients in the physical therapy group. the patients in the hypnotherapy group showed a significantly better outcome with respect to their pain experience. fatigue on awakening. sleep pattern and global assessment at 12 and 24 weeks. but this was not reflected in an improvement of the total myalgic score measured by a dolorimeter. At baseline most patients in both groups had strong feelings of somatic and psychic discomfort as measured by the Hopkins Symptom Checklist. These feelings showed a significant decrease in patients treated by hypnotherapy compared with physical therapy. but they remained abnormally strong in many cases. We conclude hypnotherapy may be useful in relieving symptoms in patients with refractory fibromyalgia.
Stimulatory response towards the 65 kDa heat shock protein and other mycobacterial antigens in patients with rheumatoid arthritis, Molecular mimicry between mycobacterial antigens and components of human articular cartilage has been suggested to initiate the onset of rheumatoid arthritis (RA). Therefore. the proliferative response of peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MNC) towards a variety of mycobacterial antigen preparations was tested in patients with RA and various non-RA inflammatory joint diseases. The antigen panel included a recombinant 65 kDa heat shock protein of mycobacterial origin which has recently been shown to stimulate arthritogenic rat T cell clones. In our study. no significant response towards the 65 kDa protein was observed with PBMNC of patients with or without RA. When compared to normal donors. the reactivity towards heat killed BCG M. tuberculosis and purified protein derivative was reduced in the blood of patients with RA while enhanced in the non-RA group. however these differences did not reach statistical significance. The data obtained with PBMNC were in striking contrast to the proliferative response of SFMNC. In the majority of cases both with RA and non-RA joint diseases the latter compartment was far better stimulated by mycobacterial antigens including the 65 kDa protein compared to corresponding PBMNC. However. in some cases an enhanced stimulation of SFMNC was also obtained with tetanus toxoid. Our data suggest that the enhanced reactivity of SFMNC may be a common feature of several inflammatory joint diseases and is not restricted to RA. These findings may indicate a preferential homing of antigen reactive (memory) T cells to the inflamed joints while the circulating pool of lymphocytes is depleted of this population.
Regional distribution of mast cells and peptide containing nerves in normal and adjuvant arthritic rat synovium, Simultaneous visualization of nerves and mast cells in the rat synovium was possible with double staining. Thus. a direct comparison could be made of nerves and mast cells in the ankle joints of healthy rats and in those with severe adjuvant induced polyarthritis. Nerves were studied with avidin-biotin-peroxidase complex (ABC) immunostaining. using heterologous antisera to protein gene product 9.5 (PGP 9.5). a recently discovered neural protein. and the neuropeptides substance P and calcitonin gene related peptide (CGRP). Mast cells were visualized by metachromatic staining of granule heparin. With double staining of sections. a parallel distribution of mast cells and nerves in all parts of the normal synovium was noted. In rats with adjuvant induced arthritis. a near total parallel disappearance of mast cells and nerves in the synovium occurred. In the arthritic rat such mast cell/nerve "units" were only present in the region where synovium attaches to bone. The observed regional depletion of both nerves and mast cells in arthritis may be of importance in the pathophysiology of arthritis.
Longterm treatment with nonsteroidal antiinflammatory drugs in rheumatoid arthritis: a prospective drug survival study, The longterm use of nonsteroidal antiinflammatory drugs (NSAID) was studied in a consecutive sample of 148 patients with recently diagnosed rheumatoid arthritis. A survival analysis was done in which treatment terminations due to side effects and to insufficient therapeutic effect were used as index causes. Cumulative drug 'survival' of indomethacin with treatment terminations due to untoward reactions as endpoints was significantly less compared to naproxen and diclofenac (p less than 0.001). No significant difference with termination due to lack of efficacy as index cause was observed (p greater than 0.90). No influence of sex or age on the drug survival with the different endpoints mentioned above could be established.
Response to sulfasalazine in rheumatoid arthritis: life table analysis of a 5-year followup, Eighty-six patients with rheumatoid arthritis treated with sulfasalazine were followed for 5 years. or until treatment was discontinued. At the end of 5 years. there was a 22% probability of successfully continuing treatment. Most adverse effects developed in the first 3 months of treatment. In 38 patients treatment was discontinued because of inefficacy. In 18 of these. a brief period of improvement was followed by clinical relapse. Twenty were regarded as having no useful response to sulfasalazine. The treatment continuation rate of 22% at 5 years is in marked contrast to the pessimistic longterm evaluations of second line drugs that have recently been reported.
Is the beneficial effect of sulfasalazine due to inhibition of synovial neovascularization, Angiogenesis is fundamental to support the continued synovial proliferation observed in rheumatoid arthritis. We investigated the effects of sulfasalazine and its metabolites on endothelial cell proliferation. a prerequisite to angiogenesis. At concentrations achieved in vivo sulfapyridine inhibited basal and endothelial cell growth factor stimulated endothelial cell proliferation. Sulfasalazine and 5 amino salicylic acid had no effect.
T cell subpopulations in the labial minor salivary gland histopathologic lesion of Sjogren's syndrome, The majority of T cells constituting the focal lymphocytic infiltrates in the labial minor salivary glands of patients with Sjogren's syndrome bear the helper phenotype (CD4); activation is expressed by class II (HLA-DR) MHC products. In our immunohistologic study of snap frozen minor salivary gland biopsies from 16 patients with primary Sjogren's syndrome. it was shown that the majority (77%) of the infiltrating T cells exhibit the memory helper/inducer phenotype (UCHL-1) and express LFA-1 molecules. In addition most of the T cells express the alpha beta receptor while only 2.8% express the gamma delta receptor. Our findings suggest that these T cell infiltrates in patients with primary Sjogren's syndrome may explain the intense B lymphocyte hyperreactivity observed in the exocrine glands of patients with Sjogren's syndrome.
The relationship between soluble interleukin 2 receptor levels and antidouble stranded DNA antibody levels in patients with systemic lupus erythematosus, Levels of soluble interleukin 2 receptors (IL-2R) have been found to be elevated in the serum of patients with systemic lupus erythematosus (SLE) and are considered an indication of immune system activation in this disease. To assess the relationship between soluble IL-2R levels and other serological markers. we compared levels of soluble IL-2R and anti-double stranded DNA (anti-dsDNA) antibodies in SLE sera. In a cross sectional study of 34 patients with SLE. soluble IL-2R levels were elevated compared with healthy individuals (1126 U/ml vs 235 U/ml. p less than 0.0001). and a significant correlation between levels of soluble IL-2R and anti-dsDNA antibodies was present (r = 0.543. p = 0.0009). In a longitudinal study of 10 additional patients. the time courses of soluble IL-2R levels and anti-dsDNA antibody measurements were similar in 3 patients. In 7 patients. substantial differences in the levels of soluble IL-2R and anti-dsDNA antibodies over time were observed. including marked changes in anti-dsDNA antibody levels that were accompanied by only minor changes in soluble IL-2R levels. and soluble IL-2R measurements that were persistently elevated despite generally low anti-dsDNA antibody levels. Our results indicate that soluble IL-2R levels may not always parallel other serological markers of SLE. suggesting measurement of different facets of immune system activation by various assays.
Fibronectin release by systemic sclerosis and normal dermal fibroblasts in response to TGF-beta, To determine whether enhanced matrix synthesis by systemic sclerosis (SSc) fibroblasts in vitro is due to increased responsiveness to transforming growth factor-beta (TGF-beta). fibronectin release by SSc and normal fibroblasts (7 pairs) was measured at various concentrations of TGF-beta. In the absence of TGF-beta. SSc fibroblasts released 30 +/- 22% more fibronectin than normal fibroblasts. While both SSc and normal fibroblasts increased fibronectin release at all concentrations of TGF-beta tested. the percentage increases were not statistically greater for the SSc fibroblasts even though 4 of the SSc fibroblasts strains were selectively sensitive to low concentrations of TGF-beta. TGF-beta increased cell numbers of both SSc and normal strains equally. Our data confirm abnormal regulation of fibronectin gene expression in SSc fibroblasts and suggest increased sensitivity to TGF-beta by some SSc fibroblast strains.
Expression of osteonectin, decorin, and transforming growth factor-beta 1 genes in fibroblasts cultured from patients with systemic sclerosis and morphea, A characteristic feature of fibroblasts cultured from affected skin areas of patients with systemic sclerosis (SSc) and localized scleroderma (morphea) is excessive activation of collagen biosynthesis. To elucidate the nature of fibroblast activation in scleroderma we have studied the expression of 3 noncollagenous connective tissue components. osteonectin. small dermatan sulfate proteoglycan (proteoglycan II. decorin). and transforming growth factor-beta 1 (TGF-beta 1). by measuring their mRNA levels in fibroblast cultures from 6 patients with SSc and 3 with morphea. A clear correlation was observed between the increase in type I collagen and osteonectin mRNA in these cell lines. The apparent overproduction of osteonectin by scleroderma fibroblasts is in accordance with the suggested activation of osteonectin expression during tissue remodeling. The levels of decorin mRNA showed marked variation in the cell lines. but were in no correlation with collagen or osteonectin mRNA. The levels of TGF-beta 1 mRNA were found to be slightly elevated in fibroblasts grown from affected scleroderma skin. This may suggest that this potent activator of collagen production has a role during the initial activation of dermal fibroblasts both in SSc and morphea.
Cellular localization of the target structures recognized by the anti-Jo-1 antibody: immunofluorescence studies on cultured human myoblasts, Antibodies to Jo-1 (alpha Jo-1) are most characteristically detected in patients with the idiopathic inflammatory muscle disease polymyositis (PM). The Jo-1 antigen has previously been identified as histidyl-tRNA synthetase (HRS). In order to clarify the cellular localization of the antigenic targets recognized by the alpha Jo-1 antibody. immunofluorescence (IF) studies were performed with cultured human myoblasts. Incubation with alpha Jo-1 positive sera demonstrated granular cytoplasmic as well as nuclear staining. but only the cytoplasmic fluorescence was specifically inhibited by preabsorbing the sera with recombinant histidyl-tRNA synthetase (rHRS). A polyclonal rabbit anti-rHRS sera demonstrated granular cytoplasmic IF which was also specifically inhibited by preincubation with rHRS protein. Alpha Jo-1 negative healthy control or patient sera demonstrated nonspecific low intensity staining. 35S methionine biosynthetically labelled myoblast cell extracts immunoprecipitated with alpha Jo-1 positive sera and analyzed by SDS-PAGE revealed a specific band of the same molecular weight as the rHRS antigen. Our studies demonstrate that alpha Jo-1 specifically binds to antigen in the cytoplasm of cultured myoblasts. Alpha Jo-1 has been shown to inhibit HRS activity in vitro. Given the importance of aminoacyl tRNA synthetases such as HRS to intracellular protein assembly. intracytoplasmic binding and enzyme inhibition in vivo may potentially contribute to the pathogenesis of autoimmune muscle damage in PM.
Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout, In order to establish the degree of renal malfunction necessary for colchicine toxicity in patients receiving it daily for the prevention of recurrent acute gout. we obtained serum creatinine levels and measured or estimated creatinine clearances in a consecutive series of 17 patients with demonstrated colchicine myotoxicity. An estimate of creatinine clearance. based on ideal body weight and age. was nearly always 50 ml/min or less. and was the most practical predictor of the risk of toxicity. By comparison. patients with gout from the same clinical data base. but without myotoxicity. had normal renal function. The data yield clear guidelines for safe use of colchicine chronically.
Immunologic effects of plasmapheresis synchronized with pulse cyclophosphamide in systemic lupus erythematosus, Extensive immunologic evaluation was made of a patient with severe systemic lupus erythematosus (SLE) undergoing 6 cycles of plasmapheresis combined with pulsed cyclophosphamide therapy. Clinical remission ensued accompanied by normalization of levels of circulating autoantibodies. immune complexes. complement proteins. interleukin 2 (IL-2) and IL-2 receptor. High spontaneous peripheral blood lymphocyte proliferation fluctuated widely with plasmapheresis. but was consistently reduced after cyclophosphamide. Circulating B cells fell by 85% and remained low at one year. despite recovery of the serum IgG level. Circulating T cells declined by 48%. chiefly in the immunologically naive CD4+CD45R+ T cell subset. This was associated with the emergence of a CD8+DR+CDw29+ T cell subset signifying immunologically mature. activated cytotoxic/suppressive T cells. which might have served to control the autoreactive B and T cell populations. Pulsed cyclophosphamide synchronized with plasmapheresis profoundly affected the immune system of our patient. The association of these immunological changes with clinical recovery warrants further investigation of this new therapeutic approach in SLE.
Clinically unsuspected inclusion body myositis, We describe a patient with inclusion body myositis presenting as chronic. therapy resistant polymyositis. Our report highlights the slow evolution of inclusion body myositis in some patients. and emphasizes the diagnostic importance of examining one or more muscle biopsy specimens by both frozen section and electron microscopy.
Projections of the incidence of non-Hodgkin's lymphoma related to acquired immunodeficiency syndrome, Advances in antiretroviral therapy and treatment or prophylaxis against opportunistic infection have resulted in prolongation of the survival of patients with acquired immunodeficiency syndrome (AIDS). Previous research has demonstrated an association between AIDS and risk of non-Hodgkin's lymphoma (NHL). In addition to the approximately 3% of individuals found to have NHL at the time of AIDS onset. others continue to develop NHL following AIDS diagnosis. Data from the Surveillance. Epidemiology. and End Results (SEER) Program of the National Cancer Institute demonstrated a sharply increasing incidence of NHL among men in the age range 20-49 years since 1983 in the United States. Based on new data on the risk of NHL following AIDS diagnosis. on estimates of improved survival following AIDS diagnosis. and on projections of future AIDS incidence. we considered four sets of assumptions and estimated the number of AIDS-related NHL cases in 1992 to be between 2900 and 9800. Three of these projections were higher than the estimate of 4700 cases obtained by linear extrapolation of SEER incidence trends. These projections of AIDS-related NHL incidence suggest that between 8% and 27% of all NHL cases that occur in the United States in 1992 will arise as a consequence of infection with the human immunodeficiency virus (HIV). imposing a substantial health care burden. More research into the pathogenesis of lymphoma and new approaches to antiretroviral and antilymphoma therapy will be necessary to prevent and treat this formidable complication of infection with HIV.
Tumor growth dependent on Kaposi's sarcoma-derived fibroblast growth factor inhibited by pentosan polysulfate, A neoangiogenic response is critical for the unrestricted growth of solid tumors beyond a few millimeters in diameter. Release of adequate growth-stimulating activity from tumor cells is obviously required for the stimulation of blood vessel growth. and blockade of such stimulatory activity should repress tumor growth at the microscopic level. To test this hypothesis and to study appropriate inhibitors. we used a human adrenal cancer cell line (SW-13/K-fgf) engineered to secrete Kaposi's sarcoma-derived fibroblast growth factor (K-FGF). which we previously showed to induce growth of highly vascularized subcutaneous tumors in animals by autocrine and paracrine stimuli. In the present study. we tested different polysulfates for their selective inhibition of proliferation induced by K-FGF versus proliferation independent of K-FGF. Suramin and dextran sulfate showed slight selective inhibition of K-FGF-induced proliferation. ie. inhibition three- and five-fold greater. respectively. than the inhibition of proliferation independent of K-FGF. In contrast. heparin was inactive. The heparin analogue pentosan polysulfate (PPS). however. showed selective inhibition that was more than 2000-fold greater. The inhibitory effects of PPS on growth of SW-13/K-fgf cells. as well as endothelial cells. were fully reversible by an excess of added FGF. Daily intraperitoneal injections of PPS were tolerated well by athymic nude mice and prevented growth of subcutaneous SW-13/K-fgf tumor xenografts. PPS will be a useful tool to elucidate the effects of FGFs in vitro and in vivo and appears to be a prototype for the development of tumoricidal therapy based on targeting of growth factors.
Serotonin antagonists: a new class of antiemetic agents, Despite a number of significant advances over the past decade. prevention and treatment of chemotherapy-induced emesis remain formidable problems. particularly with cisplatin-containing regimens. Nearly one third of patients receiving high-dose cisplatin still experience substantial emesis despite the best available conventional antiemetics. and the toxic effects of these agents remain quite troublesome. In recent years. a new class of agents. the serotonin antagonists. has been identified. These agents hold promise for clinical utility in a wide range of areas. Selective antagonists of the serotonin (5-hydroxytryptamine) type 3 (5-HT3) receptor have proven in early clinical trials to be potent antiemetic agents in patients receiving cytotoxic chemotherapy. with efficacy comparable to or superior to that of conventional antiemetics. Toxic effects to date with the 5-HT3 receptor antagonists have been modest. The current state of knowledge with respect to these agents as antiemetics for patients receiving cytotoxic chemotherapy is summarized.
Phase I and pharmacokinetic trial of intraperitoneal etoposide in combination with the multidrug-resistance-modulating agent dipyridamole, Dipyridamole synergistically enhances the sensitivity of human ovarian carcinoma cells to etoposide in vitro. We conducted a phase I trial to investigate the feasibility of using dipyridamole to selectively increase the sensitivity to etoposide of tumors confined to the peritoneal cavity. Etoposide and dipyridamole were administered as a continuous 72-hour intraperitoneal infusion to 16 patients. The maximum tolerated dose of etoposide was 175 mg/m2 per day when administered with dipyridamole at a fixed dose of 24 mg/m2 per day. Dose-limiting toxic effects were leukopenia and thrombocytopenia. No other major toxic effects were observed. The free peritoneal etoposide and dipyridamole concentrations varied with the etoposide dose rate. reaching 218.9 and 25.3 microM. respectively. at an etoposide dose rate of 175 mg/m2 per day. The free etoposide and dipyridamole concentrations attained were well within the range needed for synergistic interaction.
Distribution of porfiromycin in EMT6 solid tumors and normal tissues of BALB/c mice, The distribution of porfiromycin was studied in BALB/c mice bearing EMT6 mammary tumors. The levels of 3H in blood and most tissues peaked approximately 15 minutes after intraperitoneal injection of [3H]porfiromycin. The levels of radioactivity present in most of the tissues and in the tumors were similar at 4 hours and 24 hours after administration. Most of the normal tissues showed uniform. low grain densities when analyzed by autoradiography; the liver and the small intestine had the highest labeling densities. Only kidney. bladder. and tumor showed differential distributions of grains from [3H]porfiromycin. In the kidney. higher grain counts were found in cortex than in medullary regions; grains were uniformly distributed within each region. In the bladder. the highest labeling densities were found in regions near the lumen. Tumor regions that had some necrotic features or regions of necrosis that included some viable cells showed higher labeling intensities than healthy-looking tumor regions. probably because the abnormal microenvironments in these regions led to increased rates of activation of porfiromycin to electrophilic species. These findings show that porfiromycin can reach and be activated in tumor regions containing cells resistant to many chemotherapeutic agents and to x rays. The results also support the concept that agents such as porfiromycin can target cells in specific microenvironmental subpopulations of solid tumors.
Bone mineral density in premenopausal women receiving long-term physiological doses of levothyroxine, Total body and regional bone mineral density (BMD) levels were determined in 26 premenopausal women with Hashimoto's thyroiditis receiving long-term physiological doses of levothyroxine sodium replacement therapy. The BMD levels of each patient were compared with the mean of the BMD levels of age-matched normal controls. The mean levothyroxine sodium dose was 111 +/- 6 micrograms/d. and the mean duration of treatment was 7.5 +/- 5.3 years (range. 1 to 24 years). Dietary calcium intake was similar in both groups. as were serum thyroxine. triiodothyronine. free thyroxine index. and thyrotropin levels. Women receiving the levothyroxine treatment had normal total body BMD levels but had significantly lower BMD levels at the femoral neck (-5.7%). femoral trochanter (-7.0%). Ward's triangle (-10.6%). both arms (right. -7.8%; left. -8.9%). and pelvis (-4.9%). In contrast. lumbar spine BMD levels were similar in the two groups. There was no correlation between the total body or different regional BMD levels and the duration or dosage of levothyroxine treatment or thyroid function test results. However. the z score of the femoral neck of these patients showed a significant negative correlation with their serum free thyroxine index levels. We conclude that patients receiving physiological doses of levothyroxine may have decreased bone density. Thyroid functions in patients receiving long-term levothyroxine treatment should be closely monitored and bone densitometry should be performed in patients at risk for osteoporosis.
Prognostic significance of the number of metastatic lymph nodes in patients with gastric cancer, To confirm the prognostic significance of the number of the metastatic lymph nodes (MLN) in cases of gastric cancer. the results of surgical treatment of 668 patients with primary gastric cancer were analyzed retrospectively. Five-year survival rates were calculated with reference to the number of MLN. namely. none (89.2%). one to three (77.4%). four to six (55.8%). and seven or more (36.2%). Furthermore. even when the cancer had invaded the serosa. 5-year survival was significantly more frequent in patients with one to three MLN (71.7%) than in those with four to six (35.5%) or more than six (31.5%) (P less than 0.01). and the 5-year survival was close to that of patients with no MLN (70.5%). Not only qualitative but also quantitative evaluation of lymph node metastasis is essential for estimating the prognosis of patients with gastric cancer.
Perioperative chemotherapy in oral cancer, This is an interim report of a study of perioperative adjuvant chemotherapy following radical surgery for oral cancer. based on the hypothesis of Goldie and Coleman. 135 patients of alveolobuccal carcinoma. clinically stage III and IV. were entered on the protocol. After a curative resection. they were randomized. The test arm received methotrexate 50 mg/m2 on the 3rd. 10th. and 17th postoperative days. The control arm was only observed. This analysis at 12 months showed a disease free survival of 71% in the test arm vs. 45% in the control arm. which is statistically highly significant (P less than 0.01). Analysis of recurrence pattern showed that recurrence at the primary site was dramatically reduced during the first 6 postoperative months (P less than 0.01). Our study provided further clinical evidence in support of the concepts of Goldie and Coleman that the timing of chemotherapeutic drugs is very critical for a successful end result.
Cytoreduction and sequential resection: a hope for unresectable primary liver cancer, For decades. unresectable primary liver cancer (PLC) determined by operation was incurable. However. a retrospective study of 24 years' materials with unresectable PLC indicated that 5-year survival of unresectable PLC has increased from 0% in 1966-1977 (n = 137) to 16.9% in 1978-1989 (n = 345). This encouraging improvement was mainly a result of cytoreduction therapy followed by sequential resection. Multimodality combination treatment with hepatic artery ligation. plus hepatic artery infusion with chemotherapy. plus radioimmunotherapy (or radiotherapy) yielded the highest sequential resection rate (30.6%) and 5-year survival (28.0%) as compared with double combination and single modality treatment. The 5-year survival of 33 patients receiving sequential resection after cytoreduction therapy was 63.2%. It is suggested that cytoreduction and sequential resection might offer a hope for surgically verified unresectable PLC.
Diagnosis and treatment of primary and recurrent retroperitoneal liposarcoma, We retrospectively reviewed 16 patients in whom primary retroperitoneal liposarcoma was diagnosed and treated. These patients were classified according to the first definitive surgical procedure employed: complete excision with or without radiotherapy; partial excision followed by radiotherapy; only biopsy of tumor followed by radiotherapy. Distribution of tumors according to histologic type was: well differentiated myxoid type. 10; poorly differentiated myxoid type. 4; and mixed type. 2. The main factor in determining resectability was extent and fixation of tumor to vital structures. Recurrent retroperitoneal disease developed in four patients all of whom underwent secondary intervention. We concluded from our experience that complete surgical excision is the most effective primary therapeutic approach for patients with primary and recurrent retroperitoneal liposarcoma.
Carcinoid tumour of the gastrointestinal tract: prognostic factors and disease outcome, This study represents retrospective analysis of 87 patients with a carcinoid tumour of the gastrointestinal tract seen and followed in the British Columbia Cancer Agency (BCCA) from 1960 to 1986. In 49 cases. the primary site was the small bowel. The rest of the cases were distributed as follows: 11 appendix. 10 rectum. 5 stomach. and 7 undetermined. We extrapolated the Dukes' and modified Astler-Coller surgicopathological classifications used for colorectal cancer for use in our cases of carcinoid tumour of the gastrointestinal tract. A strong correlation was found. using this staging. with disease-specific survival. Other prognostic factors included histologic differentiation. the presence of macroscopic residual disease after initial surgery. and level of 5-hydroxyindoleacetic acid (5-HIAA) in urine. Among 51 patients with surgically grossly removed disease. there was a tendency for the development of distant and distant/locoregional recurrence more often than locoregional recurrence alone. The liver was the commonest site of distant recurrence. Analysis of the effect of radiotherapy or chemotherapy on carcinoid tumour of the gastrointestinal tract proved unsuccessful because only a small portion of the patients had this treatment. and it was used mainly for palliation.
Effects of a three-drug antineoplastic protocol of wound healing in rats: a biomechanical and histologic study on gastrointestinal anastomoses and laparotomy wounds, Using biomechanical and histologic approaches. the effect of perioperative administration of a drug protocol containing 5-fluoruracil. Adriamycin. and mitomycin C (FAM) on the healing of gastrointestinal anastomoses and laparotomy wounds in rats was examined. Application of FAM immediately before operation resulted in significant impairment of wound healing in the early postoperative period. Once the proliferation of fibroblasts and collagen synthesis had led to an increase of mechanical strength. no negative effect on wound healing could be detected applying the same chemotherapeutic agents. These findings indicate the early inflammatory phase of the wound healing process to be most vulnerable to the chemotherapeutic effects. This has significant implications if the theoretical advantages of starting adjuvant chemotherapeutic treatment in the immediate postoperative period are implemented.
Influence of surgical resection before and after chemotherapy on survival in small cell lung cancer, We attempted to define the role of surgery in the treatment of small cell lung cancer (SCLC). Of 81 patients with clinically localized SCLC. 36 underwent surgical resection: 19 underwent initial resection with postoperative chemotherapy. while the remaining 17 were treated initially with chemotherapy. then resection. The remaining 45 patients were treated with a combination of chemotherapy and radiotherapy. The 5-year survival for the 36 surgical patients was 38%; median survival time (MST) was 33 months. Nineteen patients treated with postoperative chemotherapy showed a 42% 5-year survival. while 17 patients treated with preoperative chemotherapy showed a 33% 5-year survival. This difference was not significant. However. stage III survival tended to be better in patients with preoperative chemotherapy (MST. 29 months) than in those who had had postoperative chemotherapy only (MST. 17 months). Although survival of the 45 nonsurgical patients was poor. stage I and II patients. or those with complete remission showed a 25% 5-year survival with an MST of 33 months. and a 21% 5-year survival with an MST of 25 months. respectively. We thus concluded that initial resection combined with postoperative chemotherapy is beneficial for patients with stage I. and probably stage II disease. For resectable stage III. particularly in patients with N2 disease. adjuvant resection after chemotherapy may be a favorable choice in the management of SCLC. For advanced stage III. complete remission by chemotherapy should be attempted in combination with radiotherapy.
Latissimus dorsi musculocutaneous flap for elbow extension, The latissimus dorsi mycocutaneous flap has developed a reputation for its versatility in both skin and soft tissue coverage and for restoration of elbow function in both flexion and extension. In a case presented. a large extra-abdominal desmoid was removed along with the entire deltoid and three-quarters of the triceps. The latissimus dorsi was elevated with a large overlying skin island and rotated on its neurovascular pedicle into the defect in the posterior shoulder and upper arm to replace the resected triceps and deltoid muscle. and to provide coverage in this region.
Double-inlet ventricle presenting in infancy. I. Survival without definitive repair, Survival before definitive operations was studied in 191 infants with double-inlet ventricle presenting before 1 year of age (1973 to 1988. median follow-up 8.5 years). The morphologic spectrum was broad. with a great prevalence of associated lesions. The actuarial survival rate before definitive repair was 57% at 1 year. 43% at 5 years. and 42% at 10 years. worse than prior reports because of the younger age at entry into our series. Analysis of univariate risk factors established that right atrial isomerism (18% of the group. relative risk 2.9). common atrioventricular orifice (42%. 2.0). pulmonary atresia (20%. 3.4). obstruction of the systemic outflow tract (18%. 2.5). and extracardiac anomalous pulmonary venous connection (13%. 3.1) were strongly associated with poorer survival. Pulmonary stenosis (40%. 0.35). balanced pulmonary blood flow (9%. 0.40). and presentation at an older age (3%. 0.42 to 0.18) were beneficial (p less than 0.05 to 0.0001). Multivariate analysis allowed the creation of patient-specific curves for prediction of survival for different anatomic and physiologic variants of double-inlet ventricle. A simple additive index was then derived from the multivariate Cox coefficients to enable stratification of risk for these morphologic subgroups of patients and so assist in the making of clinical decisions in infancy.
Photodynamic therapy of oncogene-transformed cells, Photodynamic therapy with dihematoporphyrin ether sensitizes malignant cells to damage by 630 nm light. The in vitro. in vivo photodynamic therapy sensitivity of a cell line transformed by the Kirsten ras oncogene (45342) was studied to establish a new photodynamic therapy model. With the colony formation assay. neither light alone nor dihematoporphyrin ether alone affected 45342 survival. Energy-dependent photodynamic therapy effects were seen in vitro in dihematoporphyrin ether-incubated and light-exposed cells (90% cytotoxicity = 950 joules/m2; 99% cytotoxicity = 1575 joules/m2; p2 less than 0.05). Subcutaneous allografts of 45342 were established in nu/nu mice. and ideal route (intravenous or intraperitoneal) of dihematoporphyrin ether delivery. dihematoporphyrin ether tissue kinetics. and in vivo photodynamic therapy effects were examined. Intravenous administration not only gave higher levels of the sensitizer in various tissues. but also was associated with less variation than the intraperitoneal route. Selective dihematoporphyrin ether retention was documented in the tumors at 24 hours after injection compared with other tissues. and photodynamic therapy with 0.3 W/cm2 to a total dose of 150 joules/cm2 led to progressive coagulative tumor necrosis and tumor regression. These studies confirm that transformed. malignant cells are sensitive to photodynamic therapy. and this model may prove in future studies to increase efficacy to photodynamic therapy (i.e.. with dihematoporphyrin ether delivery by monoclonal antibodies).
Soft tissue sarcomas of the chest wall. Results of surgical resection, Primary soft tissue sarcomas of the chest wall are uncommon. and data concerning treatment and results are sparse. Most studies have categorized these tumors as truncal sarcomas and inferred a poor prognosis. To assess the results of surgical treatment. we reviewed our 40-year experience. Methods: Records of 189 patients admitted to our institution from 1948 to 1988 were reviewed. Pathologic material was available for review in the 149 cases (79%) that comprise this report. Survival was calculated by the Kaplan-Meier method. with comparisons by log-rank analysis and significance defined as p less than 0.05. Results: Ages ranged from 3 weeks to 86 years (median. 38 years); the ratio of male to female patients was 2:1. The initial complaint was mass or pain in 97% of the cases. Ninety sarcomas (60%) were high grade and 59 (40%) were low grade. Histologic types were as follows: desmoid tumor (n = 32. 21%); liposarcoma (n = 23. 15%); rhabdomyosarcoma (n = 18. 12%); fibrosarcoma (n = 17. 11%); embryonal rhabdomyosarcoma (n = 14. 9%); malignant peripheral nerve tumor (n = 13. 9%); malignant fibrous histiocytoma (n = 11. 7%); spindle cell sarcoma (n = 4. 3%); tenosynovial sarcoma (n = 3. 3%); hemangiopericytoma (n = 3. 3%); alveolar soft part sarcoma (n = 3. 3%); and other types (n = 12. 9%). Resection was the primary treatment in 140 cases (94%). Local recurrence developed in 27%. Metastases occurred in 52 (35%) of the cases (metachronous in 42. synchronous in 10) and were more common in patients with high-grade disease (46/90. 51%) than in those with low-grade disease (6/59. 10%). Overall 5-year survival was 66%. Five-year survival rate for those with high-grade sarcomas (49%) was significantly lower than that for low-grade sarcomas (90%. p less than 0.0001). Tumor size and age of patient were not prognostic. Conclusions: Survival of patients with primary soft tissue sarcomas of the chest wall after resection is similar to that of patients with sarcomas of the extremities. Resection alone provides acceptable survival (90% at 5 years) for those with low-grade sarcomas. but adjuvant treatment should be considered for those with high-grade sarcomas.
Reduction of infarct size by systemic amino acid supplementation during reperfusion, The amino acids aspartate and glutamate. in combination. were evaluated as a means of reducing infarct size and improving cardiac function during reperfusion in an intact pig having an acute anteroseptal infarct. Three groups of 6 pigs each were randomly studied in a blinded manner: control (no amino acids). aspartate/glutamate 3 mmol/L. and aspartate/glutamate 13 mmol/L. The left anterior descending coronary artery was occluded distal to its first diagonal branch for 60 minutes followed by reperfusion for 6 hours. Aspartate and glutamate were administered systemically immediately before reperfusion. The following parameters were measured: infarct size and percent area at risk. global metabolic function. global and regional myocardial function. and tissue parameters of metabolic function. The results clearly showed a significant decrease in infarct size from 60% of the area at risk in control pigs to 37% in both 3 mmol/L and 13 mmol/L amino acid groups. Cardiac output. coronary blood flow. and global oxygen consumption were not significantly affected by the use of amino acids relative to the control group. Global left ventricular mechanical function was also not adversely affected by the infarct and was not altered by amino acid administration. Regional function. however. was significantly decreased by occlusion of the left anterior descending coronary artery in all groups to near 20% and only significantly recovered to 64% in the 13 mmol/L amino acid group. Adenosine triphosphate and acetyl coenzyme A measurements documented significant increases in the 13 mmol/L amino acid group relative to the control group. The conclusions of this study strongly support aspartate/glutamate supplementation for stunned. reperfused myocardium. It is apparent that the effect of amino acid supplementation on glycolysis is directly translated into improved regional function and reduced infarct size.
Experimental evaluation of myocardial protective effect of prostacyclin analog (OP-41483) as an adjunct to cardioplegic solution, A stable prostacyclin analog (OP-41483) was evaluated for myocardial protective effect against global ischemia with the use of cardioplegia. Isolated canine hearts (n = 25) were exposed to 60 minutes of warm (37 degrees C) global ischemia after the arrest by crystalloid cardioplegia. Prostaglandin analog was given in three different ways: preadministration (700 ng/kg body weight per minute) before ischemia for 30 minutes (group I. n = 5). given as a component of cardioplegic solution (600 ng/ml. group II. n. = 6). and post-administration (25 ng/kg body weight per minute) during reperfusion for 30 minutes (group III. n = 7). During reperfusion. coronary sinus blood flow. 6-keto-prostaglandin F1 alpha in coronary sinus blood. and myocardial oxygen consumption were measured during reperfusion. As a result. groups II and III showed significantly better global left ventricular function (developed pressure. maximum dP/dt. and diastolic compliance) than the control group (without prostaglandin analog. n = 7) and group I. Myocardial oxygen consumption at reperfusion (1 minute) was significantly larger in group II than in the control group. 6-keto-prostaglandin F1 alpha flux was significantly larger in group II than in the other three groups during reperfusion. The results indicated that prostaglandin analog has a beneficial effect on myocardial protection under global ischemia with cardioplegia. particularly when used as a component of cardioplegic solution and also during reperfusion. The mechanism may relate to the cytoprotective effect (including protection of endothelium with enhanced endogenous prostacyclin production at reperfusion and also to the modulation of reperfusion per se.
Coronary artery bypass grafting in the octogenarian, We have performed coronary bypass grafting in 25 patients 80 years of age or more. The patients' preoperative conditions were characterized by recent myocardial infarction (16/25. or 64%). obesity (15/25. or 60%). hypertension (14/25. or 56%). and left ventricular dysfunction (21/25. or 84%). There were no deaths in the hospital or within 30 days of operation (0/25. or 0%). Postoperative complications occurred in five cases (20%). Complications were leg incision infection (2/25. or 8%). urinary tract infection (1/25. or 4%). stroke (1/25. or 4%). and transient neurologic deficit (1/25. or 4%). There were no instances of reoperation for bleeding. perioperative myocardial infarction. renal failure. pulmonary failure. intraaortic balloon pump use. or sternotomy infection in these patients. Eleven patients (44%) were hospitalized for fewer than 10 days after operation. and all but two (23/25. or 92%) were discharged within 20 days after operation. All patients were followed up. and survival and New York Heart Association functional class were determined. Cumulative survival rate was 94% at 1 year and 88% at 5 years. The cumulative percent survival rate with class I or II function was 92% at 1 year and 80% at 5 years. No patient had recurrent angina.
Valve-related complications with the Hancock I porcine bioprosthesis. A twelve- to fourteen-year follow-up study, Valve-related morbidity and mortality after heart valve replacement with the Hancock I porcine bioprosthesis has been retrospectively analyzed. From June 1974 through December 1976. 253 Hancock I bioprostheses (150 mitral and 103 aortic) were inserted in 220 selected patients who survived the operation and had follow-up until June 1989 (mean follow-up 13.5 years. with an accumulative follow-up of 2956.4 patient-years). One hundred seventeen patients had mitral valve replacement. 70 had aortic valve replacement. and 33 had combined mitral and aortic valve replacement. There were 27 thromboembolic events. The probability of being free from thromboembolism at 14 years was 81.0% +/- 7.4% for the mitral valve replacement group. 85.4% +/- 6.7% for the aortic group. and 67.1% +/- 18.4% for the mitral-aortic group. Fifteen episodes of prosthetic valve endocarditis occurred. There were 10 instances of nonstructural dysfunction (paravalvular leaks) in seven mitral valves (4.6%) and in three aortic valves (2.9%). One hundred twenty-two bioprostheses in 106 patients resulted in structural deterioration. The probability of freedom from structural deterioration at 14 years was 37.2% +/- 3.9% for the mitral group. 43.9% +/- 7.1% for the aortic group. and 30.1% +/- 8.9% for the mitral-aortic group. The logistic regression analysis between age at the time of operation and bioprosthetic life (structural deterioration-free period) demonstrates a linear regression curve (r = 0.53). There were 56 late deaths (27 patients died at reoperation). The actuarial survival rate (including hospital mortality) at 14 years was 57.2% +/- 5.4% for the entire series. with no statistically significant difference between groups. The probability of remaining free from valve-related morbidity and mortality at 14 years was 16.7% +/- 4.8% for the mitral group. 20.8% +/- 6.2% for the aortic group. and 14.0% +/- 7.0% for the mitral-aortic group. The long-term results of this series show that the clinical performance of the Hancock I porcine valve appears satisfactory during the first 6 years. The behavior of this bioprosthesis at 14 years' follow-up changes drastically. because only a minor group of patients is free from valve-related complications. justifying the restriction of its use for selected patients.
A five-year appraisal and hemodynamic evaluation of the Bjork-Shiley Monostrut valve, Two hundred forty-four Bjork-Shiley Monostrut valves were implanted in 225 consecutive patients from October 1983 to December 1988. Aortic valve replacement was performed in 90 patients. mitral valve replacement in 118. and double valve replacement in 16 patients. One patient had tricuspid valve replacement. There were 100 female patients and 125 male patients with a mean age of 54 years (range 2 to 71 years). Present data were completely available for all patients. The cumulative follow-up was 541 patient-years with a mean of 2 years. 5 months. The closing date for follow-up was July 1989. and the closing interval was 2 months. The early mortality rate was 3.1%. and the late mortality rate. 3.1%. The 5-year survival rate was 88% +/- 2.0%: 87% +/- 3.0% for aortic valve replacement. 91% +/- 3.3% for mitral valve replacement. and 75% +/- 9.6% for double valve replacement. The actuarial rates of freedom from thromboembolism at 5 years were 93% +/- 3.2% for aortic. 96% +/- 1.4% for mitral. and 94% +/- 6.1% for double valve replacement. There were no instances of structural valve deterioration. Actuarial rate of freedom from valve-related morbidity and mortality was 86% +/- 2.0% at 5 years: 86% +/- 9.5% for aortic. 87% +/- 3.3% for mitral. and 75% +/- 7.3% for double valve replacement. Effective valve areas (average) of 12 mitral and 12 aortic valve prostheses were calculated at rest and during bicycle exercise: 2.4 cm2 at rest and 2.8 cm2 during exercise in 27 mm aortic valves. 2.4 cm2 at rest and 3.0 cm2 during exercise in 25 mm aortic valves. 2.0 cm2 at rest and 2.4 cm2 during exercise in 27 mm mitral valves. and 2.6 cm2 at rest and 2.5 cm2 during exercise in 29 mm mitral valve. On the basis of our follow-up period of 5 years. we have judged the Bjork-Shiley Monostrut valve reliable. with a low incidence of valve-related morbidity and with acceptably satisfactory hemodynamic characteristics at rest and during exercise.
Adjuvant brachytherapy for treatment of chest wall sarcomas, Thirty patients treated with surgical resection and brachytherapy for chest wall sarcoma at Memorial Sloan-Kettering Cancer Center from 1980 through 1987 were reviewed. Patients selected to receive adjuvant irradiation were those for whom there was doubt as to the completeness of surgical resection. Overall 5-year survival and locoregional control after brachytherapy were 65% and 54%. respectively. Locoregional control was similar for tumors treated at initial diagnosis (12 patients). at the time of recurrence (13 patients). or for tumors that were metastatic to the chest wall (five patients). Six patients with tumors larger than 10 cm in maximum dimension had a locoregional recurrence rate of 69% versus a recurrence rate of 39% for 18 patients with smaller tumors (p = 0.27). Fifty-four percent of high-grade tumors recurred locoregionally versus 28% of low-grade tumors (p = 0.37). Bone invasion or the presence of positive resection margins was not clearly associated with a higher locoregional failure rate. Only one patient (1/28; 7%) was known to have had recurrence within the irradiated area. Eight patients (8/28; 37%) had recurrence adjacent to the implanted area. and the precise failure site could not be determined for the remaining two patients. Because of the relatively high risk of regional versus in-field recurrence. patients with chest wall sarcoma who receive adjuvant treatment should be treated primarily with external-beam irradiation to allow more generous coverage of the tumor bed. Brachytherapy could be used as a tumor bed "boost" treatment. In patients undergoing resection of recurrent tumor in a previously irradiated site. adjuvant brachytherapy. without external-beam irradiation. should be considered to reduce the risk of extensive soft tissue necrosis.
Surgical management of lung metastases. Usefulness of resection with the neodymium:yttrium-aluminum-garnet laser with median sternotomy, Between May 1969 and September 1989. 677 metastatic lesions were resected during 107 operations in 100 patients with pulmonary metastases from various primary sites at the Center for Adult Diseases. Osaka. Japan. Of those patients. 65 underwent conventional lateral thoracotomy. and 35 patients had median sternotomy. No significant difference existed in actuarial survival after the first operation to remove the metastases between the two patients groups. Furthermore. local excision of 418 lesions was performed in 25 patients with the neodymium:yttrium-aluminum-garnet (Nd:YAG) laser. Of those. 18 patients had undergone a one-stage operation for bilateral lesions through a median sternotomy approach. Although our study was not randomized. survival of the 25 patients treated with the Nd:YAG laser tends to be longer than survival of the 75 patients for whom the Nd:YAG laser was not used. We concluded that aggressive excision and evaporation of multiple lung metastases with the Nd:YAG laser under median sternotomy is a safe and promising variation in technique and that this approach will expand the scope of surgical indications for metastatic lung tumors. For a clearer demonstration of the influence of differences in surgical techniques on long-term survival it is necessary to conduct randomized prospective studies of the surgical techniques.
Double-inlet ventricle presenting in infancy. III. Outcome and potential for definitive repair, The fate of 191 infants with double-inlet ventricle was studied to determine the influence of morphologic characteristics at presentation and subsequent management on the potential for. and timing of. definitive repair by the Fontan operation or ventricular septation. At presentation. 136 patients (71%) were potential candidates for a Fontan procedure. Actuarial survival was better than for those deemed unsuitable for either definitive option (n = 55; 68% versus 28% at 1 year; p less than 0.001). but still. only 78 patients (57%) were known to be alive and suitable candidates at 2 years of age. This was largely due to death after presentation with low cardiac output (n = 19) and at palliative operation (20 of 98 surgically treated patients). The adverse events of late sudden death (n = 14) and the development of new features precluding a Fontan operation (n = 18) mostly occurred before 4 years of age (n = 22). Patients requiring no operation and those who underwent a systemic-pulmonary arterial shunt fared better than those who underwent isolated banding of the pulmonary trunk (9/13 and 25/42 alive and suitable versus 14/33; p less than 0.05). and than those who required aortic arch repair together with banding (1/12; p less than 0.01). because of the development of subaortic stenosis in the latter group. In contrast. only 43 patients (23% of all 191 patients) had morphologic features that were additionally compatible with future ventricular septation. Actuarial survival free of adverse events for these 43 patients was similar to that of the 136 patients considered suitable for a Fontan operation. Thus management in infancy must be aimed at maintaining potential for a future Fontan operation. which itself should not be delayed. for most patients. beyond 3 years of age. because of the prevalence of adverse events with increasing age.
Scheduling of revaccination against hepatitis B virus, Studies have shown that to maintain protection against infection after a primary course of hepatitis B immunisation. revaccination can be scheduled on the basis of an anti-hepatitis B virus surface antigen (anti-HBs) titre obtained 1 month after the booster dose. However. schemes which require post-booster testing may present practical difficulties. We applied a random-effects regression model to data from 118 Senegalese infants given three injections of hepatitis B vaccine about 6 weeks apart and a booster injection at 13 months. and show that revaccination can be scheduled on the basis of an anti-HBs titre recorded at the time of the booster dose. We also show that titre-at-booster is no less accurate in predicting future titre than 1-month post-booster titre. In several other studies the post-booster decline in anti-HBs conforms to the same mathematical description. indicating the generality of our findings.
Chromosome translocation and c-MYC activation by Epstein-Barr virus and Euphorbia tirucalli in B lymphocytes, Dual exposure to Epstein-Barr virus and purified 4-deoxyphorbol ester derived from the plant Euphorbia tirucalli induced a high frequency of chromosomal rearrangements in human B lymphocytes in vitro. Rearrangements most commonly affected chromosome 8. the chromosome most often showing structural changes in Burkitt's lymphoma (BL) cells. E tirucalli is indigenous in parts of Africa where BL is endemic and may be an important risk factor for the disease.
Dietary effects on breast-cancer risk in Singapore, It is suspected that diet influences the risk of getting breast cancer. A study of diet and breast cancer was done among 200 Singapore Chinese women with histologically confirmed disease and 420 matched controls. A quantitative food-frequency questionnaire was used to assess intakes of selected nutrients and foods 1 year before interview. Daily intakes were computed and risk analysed after adjustment for concomitant risk factors. In premenopausal women. high intakes of animal proteins and red meat were associated with increased risk. Decreased risk was associated with high intakes of polyunsaturated fatty acids (PUFA). beta-carotene. soya proteins. total soya products. a high PUFA to saturated fatty acid ratio. and a high proportion of soya to total protein. In multiple analysis. the variables which were significant after adjustment for each other were red meat (p less than 0.001) as a predisposing factor. and PUFA (p = 0.02). beta-carotene (p = 0.003). and soya protein (p = 0.02) as protective factors. The analysis of dietary variables in postmenopausal women gave uniformly non-significant results. Our finding that soya products may protect against breast cancer in younger women is of interest since these foods are rich in phyto-oestrogens.
Cholera--New Jersey and Florida, Through April 30. 1991. epidemic cholera has been reported from five countries in South America: Brazil. Chile. Colombia. Ecuador. and Peru. In addition. in the United States a total of 10 confirmed cases of epidemic-associated cholera have been reported in Georgia. New Jersey. and Florida. This report summarizes information regarding the cases reported in New Jersey and Florida.
Primary and secondary syphilis--United States, 1981-1990, Since 1985. the number of primary and secondary (P&S) syphilis cases reported in the United States has been increasing. In 1990. 50.223 cases were reported. a 9% increase from 1989. The incidence of 20 cases per 100.000 persons. a 75% increase from 1985. is the highest since 1949. This report summarizes the incidence of P&S syphilis during 1990 and provides comparison data from 1981-1990.
Epidemic early syphilis--Escambia County, Florida, 1987 and July 1989-June 1990, In Escambia County. Florida. the average number of early syphilis cases reported per quarter increased from 15 in 1987 to 75 in 1990 (Figure 1). To identify potential reasons for this epidemic. the Florida Department of Health and Rehabilitative Services and CDC used patient interview records to compare characteristics of patients with syphilis diagnosed before and during the epidemic. This report summarizes the characteristics of 82 patients diagnosed and treated from January through December 1987 (the preepidemic period) and 256 patients diagnosed and treated from July 1989 through June 1990 (the epidemic period).
Perceptual filling in of artificially induced scotomas in human vision, Patients with scotomas or blind-spots in their visual field resulting from damage to the visual pathways often report that the pattern from the rest of the visual field 'fills in' to occupy the scotoma. Here we describe a novel technique for generating an artificial perceptual scotoma which enabled us to study the spatial and temporal characteristics of this filling-in process. A homogeneous grey square subtending 1.5 degrees was displayed against a background of twinkling two-dimensional noise of equal mean luminance. On steady eccentric fixation for 10 s the square vanished and was filled in by the twinkling noise from the surround. Using this display we found that 'filling in' is an active visual process that probably involves creating an actual neural representation of the surround rather than merely ignoring the absence of information from the scotoma; filling in can occur separately for colour and texture. suggesting separate mechanisms; the filling-in process does not completely suppress information from the scotoma. even after an image has faded completely from consciousness it can nevertheless contribute to motion perception; and the process can be strongly influenced by illusory contours.
Peptide selection by MHC class I molecules, Synthetic peptides have been used to sensitize target cells and thereby screen for epitopes recognized by T cells. Most epitopes of cytotoxic T lymphocytes can be mimicked by synthetic peptides of 12-15 amino acids. Although in specific cases. truncations of peptides improves sensitization of target cells. no optimum length for binding to major histocompatibility complex (MHC) class I molecules has been defined. We have now analysed synthetic peptide captured by empty MHC class I molecules of the mutant cell line RMA-S. We found that class I molecules preferentially bound short peptides (nine amino acids) and selectively bound these peptides even when they were a minor component in a mixture of longer peptides. These results may help to explain the difference in size restriction of T-cell epitopes between experiments with synthetic peptides and those with naturally processed peptides.
Enhancement of T-cell activation by the CD43 molecule whose expression is defective in Wiskott-Aldrich syndrome, CD43 (sialophorin. leukosialin. leukocyte large sialoglycoprotein). a heavily sialylated molecule found on most leukocytes and platelets. was initially identified as a major glycoprotein of mouse. rat and human T cells. CD43 expression is defective on the T cells of males with the Wiskott-Aldrich syndrome. an X chromosome-linked recessive immunodeficiency disorder. Affected males are susceptible to opportunistic infections and do not respond to polysaccharide antigens. reflecting defects in cytotoxic and helper T-cell functions. Anti-CD43 monoclonal antibodies have a modest costimulatory effect on T cells. natural killer cells. B cells and monocytes. and one such antibody has been shown to activate T cells directly. To investigate a possible physiological role for CD43. a complementary DNA encoding the human protein was introduced into an antigen-responsive murine T-cell hybridoma. We observed that CD43 enhances the antigen-specific activation of T cells and that the intracellular domain of CD43. which is hyperphosphorylated during T-cell activation. is required for this function. We also found that antigen-presenting cells can bind specifically to immobilized purified CD43 and that the binding can be inhibited by liposomes containing CD43 as well as by anti-CD43 monoclonal antibodies.
Incidence and characteristics of retinopathy of prematurity in a low-income inner-city population, The authors have prospectively studied the incidence and nature of retinopathy of prematurity (ROP) in 159 consecutive preterm infants at an institution serving a predominantly black and Hispanic. low-income. inner-city population. Overall. ROP developed in 73 (46%) of the 159 patients. However. ROP developed in 54 (72%) of 75 patients with birth weight under 1200 grams. Significant high-risk factors observed were low birth weight (P less than 0.001). short gestation period (P less than 0.001). and extended supplemental oxygen administration period (P less than 0.001). Other significant factors were the presence of intraventricular hemorrhage (P less than 0.01) and respiratory distress syndrome (P less than 0.01). An additional factor observed to be significant for the development of severe ROP (stages III-V) was sepsis (P less than 0.01). Race and maternal history of substance abuse were not found to be significant factors. The unusually high incidence (72%) of ROP in low birth weight infants found in this study may be due to limited prenatal care and other maternal factors such as inadequate nutrition.
Protein S deficiency and bilateral branch retinal artery occlusion, A macular branch retinal artery occlusion developed in the right eye of a 25-year-old woman when she was 38 weeks pregnant. She subsequently presented 5 days postpartum with a branch retinal artery occlusion in her left eye. Although her initial work-up did not reveal a source for her occlusions. subsequent studies have documented a deficiency of protein S.
Displacement of the optic nerve head by acute changes in intraocular pressure in monkey eyes, The authors used the Humphrey Retinal Analyzer to study the effect of acute changes in intraocular pressure (IOP) on the topography of the optic nerve head in normotensive and hypertensive eyes of cynomolgus monkeys. Chronically elevated IOP was produced monocularly in monkeys by argon laser angle treatment. In 8 hypertensive eyes. the mean IOP of 51 mmHg was lowered acutely to 15 mmHg with a needle placed in the anterior chamber. In 12 normotensive eyes. the mean IOP of 16 mmHg was similarly increased to 45 mmHg. Simultaneous stereophotographs were taken both before and within 15 minutes after the IOP change. The surface of normotensive optic nerve heads moved posteriorly a mean of 17.8 microns after IOP elevation (P less than 0.02). The surface of hypertensive optic nerve heads moved anteriorly 47.4 microns after IOP lowering (P = 0.1); this change was significantly less in nerve heads with larger and deeper cups (P less than 0.02). Significant changes were not detected in disc diameter or vein diameter with acute changes in IOP. Measurable shifts in the position of the optic nerve head surface when IOP is altered may provide a future prognostic test for glaucomatous optic neuropathy.
Glaucoma-like discs with subsequent increased ocular pressures, Four patients with glaucoma-like discs. normal visual fields. and normal ocular pressures (less than 21 mmHg). first detected by direct ophthalmoscopy. were followed without treatment. Increased ocular pressures (greater than or equal to 21 mmHg) subsequently developed in these patients at an average of 8.1 years after the recognition of their glaucoma-like discs. Before the increased ocular pressure developed. two patients showed retinal nerve fiber layer loss and one showed optic disc hemorrhages. There are two possible hypotheses to explain this sequence of events. The first is that the optic discs and nerve fiber layer defects were produced by abnormal diurnal levels of ocular pressures or levels of ocular pressure. although less than 21 mmHg. which may be abnormal for the optic disc. The second hypothesis is that there are two independent events. one producing abnormalities in the optic disc and nerve fiber layer and a second producing the increased ocular pressure.
Measurement of optic disc and neuroretinal rim areas in normal and glaucomatous eyes. A new clinical method, A technique based on indirect ophthalmoscopy has been devised to enable measurement of structures in the posterior pole of the eye. It has been used to measure clinically the maximal and minimal diameters of both the optic disc and cup of 130 normal eyes from 66 patients and 33 optic discs from 20 patients with glaucomatous visual field loss. The disc area and neuroretinal rim area were derived mathematically for each eye. In the normal group the neuroretinal rim area was strongly correlated with the disc area (r = 0.89. P less than 0.0001). Only 9.1% of the glaucomatous group fell within the 95% prediction interval for the normal group. indicating a high degree of sensitivity and specificity for predicting the presence of visual field loss. Discs associated with mild field loss could be discriminated from those associated with moderate or severe field loss on the basis of disc and rim area measurements.
Association between intraocular pressure peaks and progression of visual field loss, Little is known about the relation between diurnal variations of intraocular pressure (IOP) and prognosis for glaucomatous visual field damage. The association between apparent progressive loss of visual field and the occurrence of IOP peaks was studied. Pressure peaks were detected by a self-tonometer in the natural environment of patients with glaucoma. The study groups consisted of patients with and without a strong indication of progressive visual field losses. all with IOPs of 22 mm Hg or less obtained in the ophthalmologist's office. Patients apparently undergoing progressive visual field loss were found to have significantly more frequent IOP peaks than patients with stable visual fields. A statistical evaluation indicated that. in a population with a 30% prevalence of progressive loss of visual field. 75% of the patients with peaks have progressive loss and 75% of those without peaks do not have visual field progression. Intraocular pressure peaks were thus shown to have an association with the apparent progression of vision loss independent of the mean IOP. Home tonometry appeared to be a promising tool for identifying patients at increased risk of developing visual field loss who may require intensified follow-up and an alteration in clinical management. However. the present study must be complemented by a prospective study.
Reliability of visual field results over repeated testing, Fifty-one normal subjects. 337 with ocular hypertension. and 55 patients with glaucoma underwent C-30-2 testing on the Humphrey Field Analyzer on at least three occasions over a 6-year period. The time between tests was approximately 1 year. Using the manufacturer's standard for a reliable field (false-positive and false-negative rates. less than 33%; fixation losses. less than 20%). no trends in the proportion of reliable fields or the component indices were observed over time. Four percent of normal subjects. 9% of those with ocular hypertension. and 8% of patients with glaucoma were unable to meet the reliability standard every time they were tested. This repeated lack of reliability was due almost exclusively to fixation losses. However. patients with glaucoma were more likely to have repeatedly high false-negative responses than those with ocular hypertension or normal subjects. providing further evidence that false-negative responses are more indicative of glaucoma than of patient reliability.
Evaluation of optic nerve sheath fenestration in pseudotumor cerebri using automated perimetry, Evaluation of the efficacy of optic nerve sheath fenestration in pseudotumor cerebri has been hindered by a lack of quantitative indicators of visual function before and after treatment. Nine patients (14 eyes) were treated who had pseudotumor with optic nerve sheath fenestration. in whom automated perimetry was used as a major parameter in the decision to undertake surgery and in evaluating the results. Visual field results demonstrated significant improvement in this group of patients. Seven of 8 eyes with total loss less than 1500 dB had improvement or no further deterioration. Using results of the last preoperative examination as baseline. it was found that six of the eight had improvement over 150 dB. In one patient. a slight deterioration occurred postoperatively. Those eyes with total loss above 1500 dB demonstrated stabilization of fields postoperatively. Statistical analysis of total loss preoperatively and postoperatively for this group of patients demonstrated significant improvement for five of the six comparisons investigated. Average preoperative total loss and average postoperative total loss were not significantly different. Comparisons of results of the last preoperative examination to those of the first postoperative and most recent follow-up examinations. and evaluation of average total loss postoperatively showed significant improvement had occurred. Results of the first postoperative examination and those of the most recent follow-up examination showed significant improvement from the average preoperative total loss.
Diurnal variation of intraocular pressure of normal-tension glaucoma. Influence of sleep and arousal, The measurement of the diurnal variation of intraocular pressure (IOP) is indispensable for the diagnosis of normal-tension glaucoma (NTG). To determine the diurnal variation of IOP. its measurement has to be made repeatedly for 24 hours. which interferes with patients's sleep at night and may influence the physiologic IOP variation. The authors studied the IOP variation in 82 NTG suspects. whose IOP was first measured every 2 hours for 24 hours. The following night they were suddenly aroused without any notice and IOP was measured. The diurnal IOP variation of NTG patients was found to be similar to that of the normal population and there was no significant difference in the IOP values at the same time points on the two successive nights. Sleep may have little. if any. influence on diurnal IOP variation in NTG patients.
A comparison of treated and untreated glaucoma suspects, One hundred forty-three patients with intraocular pressures (IOPs) above 22 mmHg and without visual field defects or any obvious evidence of optic nerve damage were randomly assigned to either a timolol treatment group or no treatment in a 6-year prospective clinical trial. Endpoints were defined as reproducible visual field defects on automatic perimetry. disc hemorrhages. or stereophotographically documented optic nerve head changes. Endpoints developed in 42 patients: 28 visual field defects. 8 changes in disc appearance. and 6 disc hemorrhages. Of the 42 patients. 20 were treated and 22 were not. Survival analysis showed no statistically significant differences in failure time to any endpoints between the two groups. In the untreated group. the time to failure of disc change was related to the mean IOP during the study and also to the changes in the IOP from baseline. A significant correlation was found between initial cup-to-disc ratio and survival time to visual field defects in the untreated group.
MK-507 versus sezolamide. Comparative efficacy of two topically active carbonic anhydrase inhibitors, Topical carbonic anhydrase inhibitors MK-507 and sezolamide hydrochloride (previously known as MK-417) were compared in a double-masked. randomized. placebo-controlled study in 82 patients with bilateral primary open-angle glaucoma or ocular hypertension. MK-507 was given every 8 or 12 hours. sezolamide every 8 hours. or placebo every 8 or 12 hours for 4 days. Both drugs lowered intraocular pressure (IOP) substantially. MK-507 was somewhat more active than sezolamide. with a peak mean IOP reduction of 26.2% for MK-507 versus 22.5% for sezolamide. although the difference between the treatments was not statistically significant. These drugs may have potential in the treatment of glaucoma.
Mitomycin as adjunct chemotherapy with trabeculectomy, Preliminary experience is reported in using mitomycin to improve the prognosis in trabeculectomy operations considered otherwise likely not to succeed. The medication is applied intraoperatively during an otherwise standard trabeculectomy procedure. Surgery was considered successful if the pressure was lowered to a predetermined target level. the only vision reduction was believed to be on the basis of cataract development. and there was no progression of cupping or visual field loss. With a follow-up of 6 to 42 months. the overall success rate is 84%.
Graft survival in four common groups of patients undergoing penetrating keratoplasty, Graft survival rates and causes of graft failure were evaluated for 1046 consecutive keratoplasties in four groups: keratoconus. Fuchs' dystrophy. pseudophakic bullous keratopathy with retained intraocular lenses (IOLs). and pseudophakic/aphakic bullous keratopathy with secondary lens implants. Patient follow-up averaged 23 months (range. 1-84 months). There was a significant difference in graft survival among the four groups. P less than 0.0001. The keratoconus and Fuchs' groups had the highest survival rates and pseudophakic bullous keratopathy with retained IOLs the lowest rate. Problems with the external surface of the graft caused the largest number of graft failures. Grafts for pseudophakic bullous keratopathy with retained posterior chamber lenses had a significantly higher failure rate from rejection and endothelial decompensation. 5.1%. compared with less than 1.0% in keratoconus. Fuchs' dystrophy. or bullous keratopathy with secondary implants (P less than 0.0005).
T cells and trachoma. Their role in cicatricial disease, Frozen sections of tarsoconjunctival biopsies with trachomatous scarring from 14 black adults undergoing corrective surgery for trichiasis. and "normal" tissue from three postmortem controls. were immunohistochemically stained for the major T- and B-cell subsets. and for macrophages and monocytes. T cells outnumbered B cells by 2 to 17 times. and macrophages and monocytes by approximately 20 times in all specimens. Biopsies were categorized as "inflamed" if a cumulative inflammatory score of cellular staining in the substantia propria with CD4. CD8. and OKM1 monoclonal antibodies was greater than that of control tissues. CD4+ lymphocytes predominated over CD8+ lymphocytes in 5 of 7 inflamed biopsies. whereas CD8+ lymphocytes predominated over CD4+ lymphocytes in 5 of 7 noninflamed biopsies. Lymphoid aggregates were present in five inflamed biopsies. but lacked germinal centers. centrally located B cells. or parafollicular T cells typical of the acute stage of trachoma. CD4+ and CD8+ lymphocytes also were observed in the epithelium and lumen of Meibomian glands. These observations indicate that the inflammatory infiltrate of the tarsoconjunctiva in the cicatricial stage of trachoma is comprised predominantly of T cells. and suggests that T cells may be involved in the genesis of tarsal thickening and conjunctival scarring seen in the later stages of trachoma.
Eccrine acrospiroma (clear cell hidradenoma) of the eyelid. Immunohistochemical and ultrastructural features, A 46-year-old man underwent excision of a left lower eyelid mass that had enlarged over a 2-month period. Pathologic examination showed the mass to be an eccrine acrospiroma. a benign adnexal tumor that rarely arises in the eyelid. Light microscopic and ultrastructural examination showed two types of cells to comprise the tumor: eosinophilic cells with intracytoplasmic tonofilaments. and clear cells with intracytoplasmic glycogen granules. Immunohistochemical stains were positive for cytokeratins AE 1.3. epithelial membrane antigen. carcinoembryonic antigen. and muscle specific actin in tumor cells.
Retinoblastoma in older children, A review of 400 consecutive patients with retinoblastoma who presented to the Ocular Oncology Service at Wills Eye Hospital showed that 34 (8.5%) patients were older than 5 years of age at the time of initial diagnosis. The tumor was active in 26 (76%) cases and inactive (retinoma) in 8 (24%). An evaluation of the 26 patients with active retinoblastoma showed several unique features. At the time of diagnosis. their median age was 6 years and the oldest was 18 years. In 20 (77%) cases. the patient volunteered symptoms that prompted the eye examination; the presenting symptoms included leukocoria (9 cases). decreased vision (9 cases). strabismus (4 cases). pain (1 case). floaters (1 case). and no symptoms (2 cases). All of the 26 patients (100%) had unilateral sporadic retinoblastoma. Misdiagnosis before referral was common in these older children with active retinoblastoma. Five patients (19%) had prior vitrectomy for presumed vitreous hemorrhage or endophthalmitis while the retinoblastoma was unsuspected clinically. one patient (4%) had cryotherapy for presumed Coats disease. and one (4%) was observed for 7 months for presumed vitreous hemorrhage. The clinician should seriously consider the possibility of retinoblastoma in children who present with signs of unexplained vitreous hemorrhage or endophthalmitis. even if they are older than 5 years of age.
Variation in axial length and anatomical landmarks in strabismic patients [published erratum appears in Ophthalmology 1991 Jul;98(7):1005, The authors calculated axial length measurements in 185 consecutive patients undergoing strabismus surgery and found a mean measurement of 21.98 +/- 1.59 mm (range. 18.75-25.37 mm). Although significant correlation between axial length. refractive error. and age was found. wide variation was present. which indicates that age and refractive error could not accurately predict axial length. Based on a formula derived from a geometric model to determine the equator-limbus distance. given the axial length. the authors found that the equator had a mean distance from the limbus of 11.56 +/- 1.75 mm (range. 9.10-13.76 mm). Based on the variability found at surgery for the insertion-limbus distance. the number of millimeters of recession of the medial rectus from the insertion that would have been necessary to place it at the equator ranged between 3.5 and 8.5 mm in this series. and for the lateral rectus. 3.5 mm to 7.0 mm. The number of millimeters necessary to recess the lateral rectus to its point of tangency with the globe ranged between 9.5 and 14.4 mm.
Efficient immortalization of luminal epithelial cells from human mammary gland by introduction of simian virus 40 large tumor antigen with a recombinant retrovirus, When defined in terms of markers for normal cell lineages. most invasive breast cancer cells correspond to the phenotype of the common luminal epithelial cell found in the terminal ductal lobular units. Luminal epithelial cells cultured from milk. which have limited proliferative potential. have now been immortalized by introducing the gene encoding simian virus 40 large tumor (T) antigen. Infection with a recombinant retrovirus proved to be 50-100 times more efficient than calcium phosphate transfection. and of the 17 cell lines isolated. only 5 passed through a crisis period as characterized by cessation of growth. When characterized by immunohistochemical staining with monoclonal antibodies. 14 lines showed features of luminal epithelial cells and of these. 7 resembled the common luminal epithelial cell type in the profile of keratins expressed. These cells express keratins 7. 8. 18. and 19 homogeneously and do not express keratin 14 or vimentin; a polymorphic epithelial mucin produced in vivo by luminal cells is expressed heterogeneously and the pattern of fibronectin staining is punctate. Although the cell lines have a reduced requirement for added growth factors. they do not grow in agar or produce tumors in the nude mouse. When the v-Ha-ras oncogene was introduced into two of the cell lines by using a recombinant retrovirus. most of the selected clones senesced. but one entered crisis and emerged after 3 months as a tumorigenic cell line.
A site-specific deletion in mitochondrial DNA of Podospora is under the control of nuclear genes, In the filamentous fungus Podospora anserina. the association of two nuclear genes inevitably leads to a "premature death" phenotype consisting of an early end of vegetative growth a few days after ascospore germination. Mycelia showing this phenotype contain a mitochondrial chromosome that always bears the same deletion. One of the break points is exactly at the 5' splice site of a particular mitochondrial intron. suggesting that the deletion event could result from molecular mechanisms also involved in intron mobility. One of the nuclear genes involved in triggering this site-specific event belongs to the mating-type minus haplotype; the other is a mutant allele of a gene encoding a cytosolic ribosomal protein.
Surface appearance and instability of empty H-2 class I molecules under physiological conditions, Recent evidence suggests that endogenously produced antigenic peptides are required for assembly of major histocompatibility complex class I chains with beta 2-microglobulin and transport to the cell surface. The RMA-S mutant cells are thought to be defective in intracellular peptide loading to class I molecules and. therefore. devoid of class I surface expression. Here we report that at physiological temperature (37 degrees C) "empty" class I molecules appear at the cell surface of RMA-S cells where they can be trapped with H-2 antibodies. In the absence of the stabilizing ligand. the class I molecules rapidly alter their conformation but remain at the cell surface as demonstrated with a rabbit antiserum. Such denatured H-2 molecules can also be found on normal wild-type RMA cells. However. their amount is strongly reduced after culture of RMA cells with a class I binding peptide. These findings indicate that empty class I molecules appear at the surface not only on mutant but also on normal cells. suggesting that in normal cells the supply with peptides is limited.
Vitamin D deficiency causes a selective reduction in deposition of transforming growth factor beta in rat bone: possible mechanism for impaired osteoinduction, We demonstrated previously that implants of bone matrix prepared from vitamin D-deficient (-D) rats were less osteoinductive and contained less extractable mitogenic activity compared with control implants prepared from vitamin D-replete (+D) rats and proposed that bone from -D rats is deficient in one or more specific growth factors. To test this hypothesis. bones from rats that were fed either +D or -D diets and kept in the dark for 8 wk were extracted and assayed for insulin-like growth factors I and II (IGF-I and IGF-II) and transforming growth factor beta (TGF-beta). the three most abundant growth factors in rat bone. and osteocalcin. Serum calcium. 25-hydroxyvitamin D3 and 1.25-dihydroxyvitamin D3 [1.25(OH)2D3] were determined at sacrifice. In -D rats. there were significant reductions in serum calcium. 25-hydroxyvitamin D3. and 1.25(OH)2D3 and skeletal TGF-beta but no differences in extractable skeletal protein. IGF-I. IGF-II. or osteocalcin compared with +D rats. To determine whether 1.25(OH)2D3 increased TGF-beta production by bone cells. we treated mouse calvaria for 6 days and mouse osteoblasts for 2 days with 10 nM 1.25(OH)2D3. Production of TGF-beta was increased almost 100% by 1.25(OH)2D3. We conclude that vitamin D deficiency reduces deposition of TGF-beta in rat bone and that diminished skeletal TGF-beta could contribute to the previously observed decrease in osteoinduction in implants from -D rat bone. The findings support the possibility that vitamin D and bone-derived TGF-beta are required for normal repair of the skeleton.
Proenkephalin A in bone-derived cells, Enkephalins. a group of small peptides with opiate-like activity. have been defined originally as neuropeptides. Recent reports showed. using in situ hybridization. that the enkephalin-encoding gene. proenkephalin A (pEnkA). is expressed in nondifferentiated cells of diverse mesodermal lineages. The transient expression of pEnkA in these tissues during organogenesis suggests that this gene is involved in processes such as differentiation and/or cell proliferation. In situ hybridization revealed that bone and cartilage are among the tissues that express pEnkA most actively during organogenesis. Here we show that pEnkA mRNA is abundant in normal calvaria-derived cells and in osteosarcoma-derived cell lines ROS 17/2.8 and ROS 25/1. In addition. pEnkA-derived peptides are synthesized and secreted by these cells. as revealed by specific RIA. pEnkA expression in ROS cells is decreased by osteogenin. an osteoinductive factor. and by the calcium-regulating hormone. 1.25-dihydroxyvitamin D3. whereas the osteoblastic phenotype marker. alkaline phosphatase. is increased by these factors. These results together with the inhibitory effects of pEnkA-derived peptides on alkaline phosphatase activity in ROS 17/2.8 cells suggest that pEnkA is involved in bone development and provide a model system for further analysis of pEnkA expression during this process.
Assembly and deacetylation of N-acetylglucosaminyl-plasmanylinositol in normal and affected paroxysmal nocturnal hemoglobinuria cells, Decay-accelerating factor (DAF) is anchored in cell membranes by a glycosyl-plasmanylinositol (GPI) moiety that is transferred to it en bloc in the rough endoplasmic reticulum. To analyze the biochemical reactions involved in preassembly of this structure. a human hematopoietic cell-free system was employed. Incubation of cell extracts with UDP-[3H]GlcNAc and butanol partitioning of reaction mixtures yielded two products similar in TLC mobility to intermediates described in Trypanosoma brucei. Both species were sensitive to Bacillus thuringiensis phosphatidylinositol-specific phospholipase C. indicative of association of [3H]GlcNAc label with a plasmanylinositol-containing acceptor. In contrast to trypanosome intermediates. which contain phosphatidylinositol (1.2-diacylglycerophosphoinositol). however. alkali treatment and phospholipase A2 digestion generated butanol-phase products characteristic of glycosylated plasmanylinositol (1-alkyl-2-acylglycerophosphoinositol). Kinetic and pulse-chase experiments indicated that the slower-migrating species was a product of the faster and that it. but not the faster. was sensitive to both GPI-specific phospholipase D and nitrous acid deamination. consistent with conversion of GlcNAc- to GlcN-plasmanylinositol. Accordingly. acetic anhydride acetylation retransformed the slower species back to the faster. Further incubation with cell extracts converted the slower species into more polar products. Lysates of normal and of affected blood leukocytes from two paroxysmal nocturnal hemoglobinuria (PNH) patients supported assembly of the two intermediates within 1 min. Thus. the initial enzymes mediating human GPI-anchor assembly are GlcNAc-plasmanylinositol transferase and GlcNAc-plasmanylinositol deacetylase. their substrates contain plasmanylinositols. and the products of their activities are normal in affected PNH cells.
Anti-Mullerian hormone Bruxelles: a nonsense mutation associated with the persistent Mullerian duct syndrome, The persistent Mullerian duct syndrome (PMDS) is characterized by the persistence of Mullerian derivatives. uterus and tubes. in otherwise normally virilized males. In a previous study. we showed that this syndrome is heterogeneous. with lack of production of anti-Mullerian hormone (AMH) by testicular tissue accounting for only some. AMH-negative. cases of this disorder. We have characterized the point mutation responsible for an AMH-negative PMDS in three siblings: a guanine to thymine transversion at position 2096 in the fifth exon changes a GAA triplet. coding for glutamic acid. to a TAA stop codon. The mutation could also be recognized. using the polymerase chain reaction. on RNA produced in trace amounts by a lymphoblastic cell line. The translation product. although undetectable in testicular tissue. could be visualized in culture medium of cells transfected with the mutant gene.
Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer, Loss of heterozygosity (LOH) on the short arm of chromosome 17 (17p) was found in 27 of 52 (52%) previously untreated primary breast cancers. There was a significant correlation between this 17p allelic loss and two parameters associated with aggressive tumor behavior: high cellular proliferative fraction and DNA aneuploidy. These correlations with high cellular proliferative fraction and DNA aneuploidy were not found in tumors with LOH at nine other chromosome locations. The p53 gene. a putative tumor suppressor gene located at 17p13. was examined for aberrations to determine whether it is the target for the 17p LOH in breast cancer. Unlike other types of human cancer. there were no homozygous deletions or rearrangements of the p53 gene. and only 2 of 13 (15%) were mutated in the conserved region where mutational "hot spots" have been previously located. Therefore. we hypothesize that. in breast cancer. either loss or inactivation of gene(s) on chromosome 17p other than the p53 gene or a different mechanism of p53 gene inactivation may be responsible for the observed high labeling index and DNA aneuploidy associated with LOH at 17p.
Role for the Epstein-Barr virus nuclear antigen 2 in viral promoter switching during initial stages of infection, During latent Epstein-Barr virus (EBV) infection of human B lymphocytes. six viral nuclear antigen (EBNAs) are expressed from long primary transcripts by means of alternative splicing and alternative polyadenylylation sites. These transcripts initiate from one of two promoters. Cp or Wp. that function in a mutually exclusive fashion. Wp is exclusively utilized during the initial stages of infection of primary B lymphocytes. followed by a switch to Cp usage. These studies have been extended to show that (i) a mutant EBV strain lacking the gene encoding EBNA 2 fails to switch from Wp to Cp usage in primary B lymphocytes. although the virus contains a functional Cp; (ii) a region from -429 to -245 base pairs upstream of Cp is essential for Cp activity in B lymphocytes. but only in the context of upstream and downstream sequences; (iii) this region contains an EBNA 2-dependent enhancer; and (iv) DNase I protection employing nuclear extracts from B and T lymphocytes revealed a B-cell-specific footprint in the region of the EBNA 2-dependent enhancer. These results support a model for viral promoter switching during the initial stages of infection in which Wp activity leads to the expression of EBNA 2. followed by activation of Cp through the EBNA 2-dependent enhancer.
Screening for renovascular hypertension, The most common curable cause of high blood pressure is renovascular hypertension. Although hypertension is common in the United States. only a minority. approximately 1%. of patients have a renovascular cause. Using clinical criteria. a subgroup of these patients can be selected in which the prevalence of renovascular hypertension will be approximately 15%. In these selected patients. it is appropriate to proceed to a radiographic screening modality to look for a significant renal artery stenosis. The choice of modality should reflect the strengths and expertise of each specific institution. Hypertensive urography is no longer recommended for screening. Excellent results have been reported with intravenous DSRA in institutions where a strong interest in this procedure exists. Furthermore. intravenous DSRA is easily coupled with the collection of renal vein samples for renin assay. Intravenous DSRA. however. has not maintained widespread use. Although the radionuclide renogram is no longer adequate as a radiographic screening tool. stimulation with an ACE inhibitor. such as captopril or enalaprilat. may produce excellent results. In many institutions. this is the most appropriate examination. Furthermore. it is relatively noninvasive. Merely detecting a significant renal artery stenosis does not. however. mean the patient has renovascular hypertension. Both hypertension and a renal artery stenosis may be present and not be causally related. Because renovascular hypertension is. at least initially. renin mediated. the demonstration of increased renin production by the ipsilateral kidney should confirm renovascular hypertension. Prospective application of these results to patients undergoing revascularization techniques. however. has been disappointing. This may be related to problems in patient preparation. sample collection. renin assay. or even the physiology of chronic hypertension. which is incompletely renin mediated. Thus. offering revascularization only to those patients with lateralizing renal vein renins is not appropriate. If radiographic screening is limited to those patient at greatest likelihood for a renovascular etiology. intra-arterial DSRA or conventional arteriography may be used. These techniques most reliably detect renal artery stenosis. Their main disadvantage lies in their relatively invasive nature. as an arterial puncture is required. The poor predictive value of selective RVRRs implies that revascularization may be attempted without awaiting those results. If percutaneous transluminal renal angioplasty can be performed with a satisfactorily low complication rate. both the diagnostic and the interventional procedure may be undertaken at the same setting. It is expected that further refinements in these diagnostic procedures. particularly with the use of stimulating drugs such as ACE inhibitors. will lead to further improvement in the diagnostic results.(ABSTRACT TRUNCATED AT 400 WORDS).
Contemporary concepts in imaging urinary tract obstruction, Imaging techniques for renal obstruction remain in a continual state of flux. An improved data base has been developed for renal ultrasonography. permitting a more precise evaluation of hydronephrosis. Rigidity with regard to an algorithm for renal obstruction is not recommended because it would be fixed at a point in time and dependent upon the equipment and expertise of a given institution. In all likelihood ultrasonography will continue to be used as the primary screening tool. A role for the intravenous urogram remains. especially in the acute presentation of renal obstruction. It is interesting to note that the initial description of the percutaneous nephrostomy tube was as a diagnostic technique in patients who had long-standing ureteropelvic junction obstruction. Prediction of recoverability of the kidneys was not possible without relieving the obstruction and assessing the ability of the postobstructive kidney to function. Recoverability of renal function cannot be assessed on a short-term basis but takes time. Up to 8 weeks is necessary before the kidney has established its new baseline level of function. The percutaneous nephrostomy has become an integral tool for the interventional radiologist and is used in treatment. Indeed. its treatment role is important. and even today we must be careful not to assess the kidneys' functional status after placement of the nephrostomy tube without allowing the renal unit sufficient time for recovery. The future undoubtedly will bring further tremendous changes in our assessment of renal obstruction. It is important that radiologists position themselves at the forefront of these developments.
Radiology of continent urinary diversion, The continent urinary diversions described in this article represent only a small number of the techniques that have been reported in the urologic literature. An attempt has been made to discuss diversions that are currently in common use or have been recently described and hold potential for becoming more widely accepted. The radiologist with a basic understanding of continent urinary diversions plays an important role in evaluating patients who have had these procedures. Complications can be detected and evaluated and occasionally treated with interventional techniques. As continent urinary diversions become more frequently performed. it is important that radiologists become aware of their construction techniques. radiographic appearance. function. and potential complications.
Neurogenic bladder simplified, Neurogenic bladder dysfunction. if not properly diagnosed and treated. can lead to rapid deterioration of renal function by compromise of the upper urinary tracts. Two major categories of neurogenic bladder (detrusor hyperreflexia areflexia) have been discussed including the pathophysiology of the voiding dysfunction and the typical radiographic findings. Radiologists studying patients with suprasacral cord lesions should be aware of the causes. symptoms. and treatment of autonomic dysreflexia. Although video urodynamics is the state-of-the-art modality for evaluating complex or refractory neurogenic bladder. the practicing radiologist with an understanding of this condition can detect many radiographic changes in the lower urinary tract that suggest neurogenic dysfunction of various types.
The role of imaging in prostate cancer, For patients with prostate cancer. diagnostic imaging can play three roles: screening. staging. and monitoring. Bayesian analysis dictates that if the prior probability of cancer is relatively low or if the consequences of a false-positive result are unacceptable. the test must be optimally specific. If the prior probability of cancer is high or if the consequences of missing it are unacceptable. the test must be optimally sensitive. For screening. the consequences of a miss are slight. and the consequences of labeling an insignificant cancer significant are serious. Thus. a very specific test is required. No current imaging modality fulfills this criterion. For staging. the prior probability of significant disease is relatively high. and the consequences of a miss serious. so a very sensitive test is required. Transrectal sonography. plus biopsy under sonographic control. fulfills this criterion for local disease. as does a bone scan for bone metastases. For monitoring. the prior probability is high. and the consequences of a miss serious. so a very sensitive test is needed. The bone scan is sensitive for bone metastases. Although CT is not sensitive for detecting lymph node metastases. it has practical clinical advantages over other imaging modalities for monitoring purposes in that it can detect disease in multiple structures at once. It is the only test that can monitor prostate size. the size of the lymph nodes. and whether hydronephrosis or liver metastases are present all in the scope of one examination.
Prostatic urethroplasty with balloon catheter as a nonsurgical alternative for benign prostatic hyperplasia, Prostatic urethroplasty with a balloon catheter is an easy procedure to perform. but certain guidelines must be followed to avoid complications. This procedure will reduce the overall treatment cost of benign prostatic hyperplasia significantly. Preliminary results range from 70% to 85% symptomatic improvement or resolution of the prostatism symptoms. Its recurrence rate is still not known. but a small one is expected. Nevertheless. because of the noninvasiveness. low cost. and simplicity of the procedure. it potentially could be repeated. if necessary. This procedure is one that when it is done in combination with another specialist. in this case a urologist. the patient will benefit by the use of the expertise of both the urologist's knowledge of the disease of the urinary system and the interventional radiologist's skills with catheters and guide wires.
Contemporary imaging approach to pediatric urologic problems, This article has tried to do two things: review the more commonly used imaging modalities and apply them to the topics of obstruction and reflux. Increasingly. sonography is the initial diagnostic tool. obviously the only one usable in utero. The VCUG is the next most important method. especially in working out the often confusing sonographic images of the upper urinary tracts. Nuclear medicine remains drastically underused; it is the best way to detect parenchymal inflammatory disease and offers a method of examination and follow-up that requires low dosages and allows quantification of data. It will be interesting 10 years from now to review this subject and see what remains of the old and current methods and what will emerge.
Varicoceles. Radiologic diagnosis and treatment, The association of clinically apparent varicoceles with male subfertility and infertility has been noted in the urology literature since the late nineteenth century. and surgical ligation of varicoceles has been considered appropriate therapy in an attempt to improve semen quality and increase fertility for the past 40 years. It has been established by several authors cited herein that varicocele size does not predict prognosis after ligation reliably. Because subclinical varicoceles may affect testicular function and histologic characteristics adversely and because age at time of therapy may affect probability of successful enhancement of fertility. the interest of radiologists and urologists has been directed toward diagnosis and treatment of both clinically obvious and clinically occult varicoceles. particularly in young adult men or adolescent boys. Testicular growth after varicocele ligation in adolescent boys also suggests a benefit from early intervention. Sonographic evidence of a varicocele must be correlated with analysis of semen for sperm density. motility. and morphology. as not all patients with varicoceles are infertile. Although surgical therapy is standard for varicocele occlusion. fairly extensive evidence exists to show that percutaneous transvenous occlusion of varicoceles is feasible. safe. and effective. particularly in the setting of varicocele recurrence after conventional surgical treatment.
Vasculogenic impotence. Duplex and color Doppler imaging, Varicoceles. although only occasionally symptomatic. are reported to occur in 20% to 50% of infertile or subfertile men. Ligation or occlusion of the spermatic vein in these patients has improved semen quality in many instances. Recently. it has been recognized that varicoceles can be bilateral or subclinical and thus detected only by imaging. Sonographic diagnosis of varicoceles and percutaneous occlusive therapy are reviewed in this article.
Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey ras-1 gene, Genetic factors contribute to heart disease. In this study. linkage analyses have been performed in a family that is predisposed to sudden death from cardiac arrhythmias. the long QT syndrome (LQT). A DNA marker at the Harvey ras-1 locus (H-ras-1) was linked to LQT with a logarithm of the likelihood ratio for linkage (lod score) of 16.44 at theta = 0. which confirms the genetic basis of this trait and localizes this gene to the short arm of chromosome 11. As no recombination was observed between LQT and H-ras-1. and there is a physiological rationale for its involvement in this disease. ras becomes a candidate for the disease locus.
Protection against malaria by vaccination with sporozoite surface protein 2 plus CS protein, The circumsporozoite (CS) protein has been the target for development of malaria sporozoite vaccines for a decade. However. immunization with subunit vaccines based on the CS protein has never given the complete protection found after immunization with irradiated sporozoites. BALB/c mice immunized with irradiated Plasmodium yoelii sporozoites produced antibodies and cytotoxic T cells against a 140-kilodalton protein. sporozoite surface protein 2 (SSP2). Mice immunized with P815 cells that had been transfected with either SSP2 or CS genes were partially protected. and those immunized with a mixture of SSP2 and CS transfectants were completely protected against malaria. These studies emphasize the importance of vaccine delivery systems in achieving protection and define a multi-antigen sporozoite vaccine.
Biohybrid artificial pancreas: long-term implantation studies in diabetic, pancreatectomized dogs, Diabetic complications such as neuropathy. retinopathy. and renal and cardiovascular disease continue to pose major health risks for diabetic patients. Consequently. much effort has focused on approaches that could replace conventional insulin therapy and provide more precise regulation of blood glucose levels. The biohybrid perfused artificial pancreas was designed to incorporate islet tissue and a selectively permeable membrane that isolates this tissue from the immune system of the recipient. Biohybrid pancreas devices containing canine islet allografts were implanted in ten pancreatectomized dogs requiring 18 to 32 units of injected insulin daily. These implants resulted in good control of fasting glucose levels in six of these animals without further exogenous insulin for periods of up to 5 months.
Role of newer antimicrobial agents in the treatment of mixed aerobic and anaerobic infections, Mixed infections with aerobic and anaerobic bacteria are being recognized with increasing frequency in clinical practice. Several concepts regarding such infections are clinically significant for the physician. These include the presence and significance of species in the Bacteroides fragilis group at clinical sites of infection. the facilitation of B. fragilis virulence by beta-lactamase producing aerobic bacteria and the role of enterococci in such infections. In response to the need for new forms of therapy for mixed aerobic and anaerobic infections. several new classes of antimicrobial agents have been introduced. Some of these allow for the potential option of monotherapy in certain clinical settings. In addition to clinical and microbiologic efficacy. safety and cost-effectiveness are factors that must be addressed with regard to these agents.
Design and evaluation of clinical trials of antimicrobial agents in surgery, Comparative trials of antibiotic therapy must be properly designed to produce meaningful results. Trials in the treatment of intra-abdominal infections are especially difficult to perform. Problems include finding adequate samples of comparable patients. establishing objective criteria by which to assess outcomes and controlling for the effects of nonexperimental factors. These difficulties are among the reasons many comparative trials of antibiotic therapy for intra-abdominal infection fail to find a difference in efficacy between the experimental regimens. Those trials that do demonstrate a therapeutic difference usually compare an adequate regimen against one that is clearly deficient; for example. one that lacks coverage of anaerobic organisms. For hospital acquired or surgical infections. the treatment regimen with the most extensive published support is the combination of an aminoglycoside and clindamycin. Single agent therapy for intra-abdominal infections may also be appropriate. Further clinical studies are needed. but two of the most promising agents are ticarcillin and clavulanic acid and imipenem and cilastatin.
Early treatment of ischemic stroke with a calcium antagonist, We performed a feasibility and safety study (phase II) of nicardipine. a calcium antagonist. in 57 patients. The objectives of the study were to begin therapy as early as possible (less than or equal to 12 hours) after the onset of ischemic stroke and to administer as high a dose as possible. All patients received an intravenous infusion of nicardipine for 72 hours. starting with a dose of 3 mg/hr and increasing to a maximum dose of 7 mg/hr. Upward titration of the dose was limited by a 10% decrease in blood pressure or a 20 beats/min increase in pulse. Intravenous therapy was followed by 30 days of oral therapy. The mean +/- SD interval from onset of stroke to commencement of therapy was 9.1 +/- 5.4 hours. Adverse reactions consisted primarily of hypotension requiring discontinuation of therapy in four patients. Score on a graded neurologic examination increased from 41/100 at baseline to 64/100 at 3 months for the 41 patients completing follow-up. There was no correlation between the dose of nicardipine administered and outcome. but the 11 patients starting therapy less than or equal to 6 hours after onset did better than those starting therapy 6-12 hours after onset. Further study of very early therapy with nicardipine is justified.
Medullary arteries in aging and dementia, We examined sclerotic changes of the medullary arteries in 110 nonneuropsychiatric patients ranging in age from the second to the ninth decades. in 20 patients with subcortical arteriosclerotic encephalopathy (Binswanger's disease). and in 20 patients with dementia of the Alzheimer type. The principal sclerotic change was fibrohyaline thickening of the wall. which began to appear during the late fourth decade. increased in incidence gradually with age. and was most severe in patients with subcortical arteriosclerotic encephalopathy. Morphometry showed that the sclerotic changes of the medullary arteries were most prominent in the frontal lobe. followed by the parietal. occipital. and temporal lobes. in both the nonneuropsychiatric and demented groups. The sclerotic rate in the frontal lobe of patients with dementia of the Alzheimer type was slightly higher than that in the nonneuropsychiatric patients (p less than 0.05) but far less than that in the patients with subcortical arteriosclerotic encephalopathy (p less than 0.001). The sclerotic rate correlated well with the degree of ischemic white matter changes as well as with blood pressure.
Leukoaraiosis and ventricular enlargement in patients with ischemic stroke, We studied the relationship between ventricular size and nonspecific periventricular lucency on computed tomograms (leukoaraiosis) in 192 patients with ischemic stroke. Leukoaraiosis did not occur in 21 patients less than 50 years of age; ventricular size could not be measured in an additional 29. Leukoaraiosis was graded from 0 to 4 on a semiquantitative scale; bicaudate. frontal horn. and posterior horn indices were used as measures of ventricular size. Patients with leukoaraiosis were older (difference between means 7 years. t = 5.3. df = 140. p less than 0.0001) and had larger bicaudate indices (difference between means 0.023. t = 3.54. df = 140. p = 0.0007) than patients without leukoaraiosis. Multiple regression analysis demonstrated that the effects of age and leukoaraiosis were independent. No effect of lesion type (cortical or lacunar infarct. or both) on bicaudate index could be demonstrated. Larger values for the bicaudate index were associated with a predominantly anterior location of leukoaraiosis. The frontal horn and occipital horn indices increased with age. but we could not find an effect of leukoaraiosis on these indices.
Angiographic vasospasm and release of platelet thromboxane after subarachnoid hemorrhage, We studied adenosine diphosphate-induced platelet aggregation and the associated release of thromboxane B2 in 49 patients with subarachnoid hemorrhage in relation to angiographic vasospasm. Postoperative cerebral angiography was performed less than or equal to 3 (median 1) days after surgery for an aneurysm 5-14 days after subarachnoid hemorrhage. Correspondingly. one sample from each patient was taken within 24 hours either before or after angiography. The occurrence of severe as well as diffuse. moderate. or severe angiographic vasospasm was associated with the presence of delayed cerebral ischemia (p less than 0.05). Patients with diffuse angiographic vasospasm had significantly higher (p less than 0.05) values for thromboxane B2 release than the others. even after adjustment by the clinical grades on admission and before surgery. the timing of surgery. the time from subarachnoid hemorrhage to angiography and blood sampling. and nimodipine therapy. Severe and diffuse angiographic vasospasm were also associated with poor outcome at 1 year (p less than 0.05). Our results suggest that augmented release of platelet thromboxane may be involved in the pathogenesis of vasospasm in large cerebral arteries.
Nuclear magnetic resonance spectroscopy study of human brain after cardiac resuscitation, We used 31P nuclear magnetic resonance spectroscopy to study the cerebral metabolic function of eight patients with severe postischemic anoxic encephalopathy secondary to cardiac arrest. Spectroscopy was performed at 18 +/- 13 and 64 +/- 20 hours after resuscitation. Glasgow Coma Scale scores at the time of initial and repeat spectroscopy were 3.6 +/- 1.2 and 3.5 +/- 1.2. respectively. In those patients whose spectra were of adequate quality to monitor pH. all demonstrated tissue alkalosis in at least one brain region. The mean brain pH at initial spectroscopy was 7.14 +/- 0.09 and was significantly alkalotic when compared with age- and sex-matched normal controls (pH = 6.98 +/- 0.04. p less than 0.0001). Five of the eight patients showed at least one region of persistent alkalosis at repeat spectroscopy. whereas one patient demonstrated severe acidosis with a pH of 6.42. Spectra demonstrated marked metabolic heterogeneity. ranging from normal in appearance to complete obliteration of all high-energy phosphates with only inorganic phosphate remaining.
Superoxide dismutase decreases mortality, blood pressure, and cerebral blood flow responses induced by acute hypertension in rats, Oxygen radicals are known to be produced by the cerebral vasculature during acute. pressor-induced hypertension and are also known to inactivate endothelium-derived relaxing factor. The objective of our present study was to determine if the oxygen radical scavenger superoxide dismutase (24.000 units/kg plus 1.600 units/kg/min) alters the pressor. cerebral blood flow. and mortality responses to systemic norepinephrine in rats. Increasing doses (0.01-30 micrograms/kg i.v.) of norepinephrine were given by bolus injection to eight rats. and changes in the cortical microcirculatory blood flow were measured by laser-Doppler flowmetry. Superoxide dismutase shifted the norepinephrine-blood pressure and -cerebral blood flow dose-response curves moderately. but significantly. to the right such that it took more norepinephrine to reach a given blood pressure. However. superoxide dismutase had no effect on the autoregulation of cerebral blood flow. Additionally. whereas five (63%) of the eight control rats died after the 10 micrograms/kg norepinephrine dose. all eight rats treated with superoxide dismutase survived this dose. The mechanism by which superoxide dismutase reduced mortality is uncertain. The blood pressure and cerebral blood flow results suggest that superoxide dismutase prevents oxygen radicals from destroying endothelium-derived relaxing factors. which reduce the pressor effects of norepinephrine.
Time course of intracellular edema and epileptiform activity following prenatal cerebral ischemia in sheep, The role of edema in the pathogenesis of hypoxic-ischemic injury in the immature brain is controversial. We studied 15 chronically instrumented fetal sheep following transient cerebral ischemia. to estimate changes in extracellular space using an impedance technique. to quantify the electroencephalogram with real-time spectral analysis. and to assess histologic outcome 3 days after the insult. These measurements were made in the parasagittal cortex. There was a rapid loss of extracellular space from 5 +/- 2 minutes after the onset of ischemia. Following 10 minutes of ischemia (n = 7) the intracellular edema peaked but then quickly resolved (6 +/- 4 minutes). and mild selective neuronal loss was seen. In contrast. the swelling was biphasic after 30-40 minutes of ischemia (n = 8). The early edema resolved slowly (28 +/- 12 minutes) but incompletely. and secondary swelling began at 7 +/- 2 hours and peaked at 28 +/- 6 hours. The early swelling was the more severe. Postinsult epileptiform activity began at 8 +/- 2 hours and peaked at 10 +/- 3 hours; later there was laminar necrosis of the underlying cortex. The secondary decrease of extracellular space indicates that a progressive loss of membrane function started with the onset of postischemic epileptiform activity. The increased metabolic load of the epileptiform activity may have worsened this delayed deterioration.
Non-germ cell tumors of testis, Testicular tumors of non-germ cell origin represent from 5 percent to 10 percent of all testicular neoplasms. Included in this group are sex cord/gonadal stromal tumors. most originating from Leydig or Sertoli cells. mixed tumors. and tumors of mesenchymal or hematopoietic origin. In addition. various miscellaneous lesions. tumor-like conditions. and secondary testicular tumors may be classified as non-germ cell tumors. This review covers the presentation. diagnosis. and treatment of these rare lesions.
Biofeedback therapy technique for treatment of urinary incontinence, Biofeedback treatment of urinary incontinence is a management method that has low risk and therapeutic efficacy for selected patients. Biofeedback therapy techniques vary widely and have not been well described or standardized. A technique for biofeedback therapy is described that allows accurate signal monitoring and assures appropriate biofeedback to the patient. External anal sphincter electromyographic performance is presented to the patient as a color line graph with pitch variable audio feedback. The method has complete flexibility in providing biofeedback training according to patient performance level and is one that can be easily interpreted by patients who have voiding dysfunctions.
Intracavernous pharmacotherapy in psychogenic impotence, Twenty-five men with psychogenic impotence but without serious psychopathology were considered for intracavernosal therapy with papaverine hydrochloride and phentolamine mesylate. A total of 20 proved suitable and began self-injection in conjunction with sex therapy; 8 patients had return of spontaneous erections without pharmacotherapy. although one of them needs to keep the medication in his refrigerator. The other 12 patients are continuing self-injection therapy. Psychotherapy with self-injection may be helpful in the management of psychogenic erectile impotence.
Ureteroscopic retrieval of proximally located ureteral stents, Indwelling self-retaining ureteral stents are important for the maintenance of urinary drainage in the ureter threatened by obstruction by neoplasm. edema. or calculus. Proximal migration of the stent into the ureter prevents simple cystoscopic retrieval and necessitates removal by other techniques. In this series both rigid and flexible ureteroscopes were used to remove stents from locations ranging from the renal pelvis to the distal ureter in 16 patients. Three-pronged wire graspers was the retrieval instrument most frequently used. Stents were removed in all patients without complication. Ureteroscopy provides the most convenient and least invasive technique for removing stents proximally located in the upper urinary system.
Renal malignant fibrous histiocytoma, The clinical. radiographic. and pathologic findings of 2 cases of malignant fibrous histiocytoma (MFH) of the renal capsule are reported and the 17 previous cases in the literature reviewed. Preoperative differentiation from renal adenocarcinoma was precluded by the overlap in clinical. laboratory. and radiologic findings. although MFH usually presented with a normal urine analysis and less parenchymal involvement on imaging studies. Pathologic differential diagnosis and therapeutic approaches are presented.
Experience with indeterminate mammograms, Most radiologists recommend follow-up mammography in 3 to 6 months for asymptomatic patients with mammographic lesions that do not appear suspicious enough to warrant immediate biopsy. In this retrospective cohort study. the medical records of 776 patients were audited 24 to 35 months after mammography to estimate the frequency of indeterminate lesions. the probability of malignancy. and the rate of patients' compliance with recommendations. Almost 2% of patients retested after an indeterminate mammogram were found to have breast cancer (95% confidence limits 0.2% and 5.9%). Only 26% of the patients retested during the audit period had the test within the suggested upper limit of 6 months. We conclude that timely follow-up after an indeterminate mammogram is advisable and that for the population we studied. compliance with this recommendation is low.
Acquired immunodeficiency syndrome and human immunodeficiency virus infection in Nevada, We summarize information from three sets of epidemiologic data: the Nevada AIDS [acquired immunodeficiency syndrome] Surveillance System. which contains information about every case identified within the state boundaries through September 1989; the human immunodeficiency virus (HIV) seroprevalence reporting systems. which currently include data on all HIV-positive reports submitted statewide to public health authorities; and surveys on the knowledge. attitudes. and behaviors of Nevadans concerning HIV-related disease. The Nevada State AIDS Task Force outlined major policy recommendations. nearly half of which concerned testing; only 2 dealt with preventing HIV transmission. Greater efforts should go into education. particularly directed toward groups at greatest risk of exposure to HIV. and to improve community-based care of infected persons.
Overview of osteoporosis, Osteoporosis is a common age-related disorder manifested clinically by skeletal fractures. especially fractures of the vertebrae. hip. and distal forearm. The major cause of these fractures is low bone mass. although an increase in trauma due to falls in the elderly also contributes. There are multiple causes for the low bone mass which. in any given individual. may contribute differently to the development of the osteopenia. The most important groups of causes are failure to achieve adequate peak bone mass. slow bone loss due to processes relating to aging. the menopause in women. and a variety of sporadic behavioral. nutritional. and environmental factors that affect bone mass in some but not in other individuals. The most important approach is prevention. Drugs and behavioral factors known to cause bone loss should be eliminated and perimenopausal women should be evaluated for possible preventive administration of estrogen. For patients with fractures due to established osteoporosis. the only drugs approved by the Food and Drug Administration are the antiresorptive agents calcium. estrogen. and calcitonin. Formation-stimulating regimens. however. are being developed and may be available for clinical use in the foreseeable future. These regimens may be capable of increasing bone mass to above the fracture threshold. thereby resulting in a clinical cure of the osteoporosis.
Role of adjuvant therapy in colorectal cancer, After nearly three decades of consistently disappointing adjuvant therapy trials in resectable colorectal cancer. recently emerging results offer some basis for cautious optimism. Adjuvant fluorouracil-containing regimens appear to confer a modest treatment benefit in completely resected colonic adenocarcinomas. The two most promising chemotherapy approaches at present appear to be the fluorouracil-levamisole and fluorouracil-leucovorin regimens. The optimal schedule and dose of these agents remains to be determined. Portal vein chemotherapy infusion studies have yielded promising but inconclusive results to date. As data from completed or ongoing large group studies become available. the role of this modality will be better clarified. In rectal cancer. adjuvant radiotherapy alone has a modest but consistent ability to reduce local recurrence without demonstrating any survival advantage. The optimal dose and sequencing of radiotherapy remains poorly defined. Two completed cooperative group studies strongly suggest that the optimal use of radiotherapy is in combination with chemotherapy. The independent role of chemotherapy in rectal cancer remains unclear. There is suggestive evidence that adjuvant chemotherapy is more effective with rectal cancer than with primaries arising proximal to the peritoneal reflection. Despite the large number of unresolved questions that remain. the following interim treatment recommendations can be made: 1. Patients with Dukes' B and C rectal and colonic adenocarcinomas should be entered into an appropriate adjuvant clinical trial when feasible. 2. Outside the setting of a protocol. there is a sound rationale to treat Dukes' B and C rectal cancer with combination chemotherapy and postoperative radiotherapy. The chemotherapy could consist of fluorouracil either alone or combined with leucovorin. 3. In more proximal colonic tumors (above the pelvic peritoneal reflection). recently described improvements in survival for patients with Dukes' B disease suggests that adjuvant therapy should be withheld in this group when not participating in a clinical study. Patients with Dukes' C tumors should receive fluorouracil-levamisole.
Electrophysiologic testing, Any attempt to group clinical states according to those in which EPS is indicated and those in which EPS is contraindicated is difficult because of a considerable overlap. With this one reservation in mind. indications for EPS can be classified in three general groups. These include a group in which the procedure is helpful and frequently indicated. a group in which the procedure is occasionally of benefit but more often there is a difference of opinion among investigators as to its utility. and a third group in which EPS is rarely helpful. often contraindicated. and on occasion harmful. The clinical states and the utility of the EPS in each are summarized in Table 1.
Prevalence of lipoprotein (a) [Lp(a)] excess in coronary artery disease, Lipoprotein (a) [Lp(a)] is composed of 1 low-density lipoprotein (LDL) particle. to which 1 molecule of apolipoprotein (a) is covalently linked. Elevated levels of Lp(a) have been associated with coronary artery disease (CAD) and Lp(a) has been shown to be highly heritable. Our purpose was to determine the prevalence of familial Lp(a) excess in patients with CAD. We determined plasma levels of Lp(a) in 180 patients (150 men and 30 women) with angiographically documented CAD before age 60 years. and in 459 control subjects (276 men and 183 women) clinically free of cardiovascular disease. In addition. Lp(a) levels were determined in families of 102 of the CAD probands (87 men and 15 women). No gender differences in Lp(a) levels were observed between men and women (patients or control subjects). Patients with CAD had higher Lp(a) levels than did control subjects (19 +/- 21 vs 13 +/- 15 mg/dl. p less than 0.001). The prevalence of Lp(a) excess (defined as greater than 90th percentile of controls) was 17% in patients with CAD (p less than 0.05). Lp(a) levels were not correlated with cholesterol. LDL cholesterol. high-density lipoprotein (HDL) cholesterol or apolipoproteins A-I or B. There was a weak correlation between Lp(a) and triglycerides (r = 0.166. p less than 0.05) in patients and control subjects. Stepwise discriminant analysis revealed that Lp(a) was a risk factor for the presence of CAD in men. independent of smoking. hypertension. diabetes. LDL and HDL cholesterol. or apolipoprotein A-I and B levels. Family studies revealed that Lp(a) levels are strongly genetically determined.
Results of multivessel percutaneous transluminal coronary angioplasty in persons aged 65 years and older, Between 1981 and 1990. 1.373 patients. aged greater than or equal to 65 years (mean 71.2 +/- 4.9). underwent 1.640 multivessel percutaneous transluminal coronary angioplasty (PTCA) procedures. Of these. 224 patients (13.6%) had a left ventricular ejection fraction less than or equal to 40%. 412 (25.1%) had prior coronary artery bypass grafting (CABG) and 48 (2.9%) had left main artery dilatation. Of the 1.640 PTCA procedures. 697 were in patients with 2-vessel disease and 943 were in patients with 3-vessel disease. A mean 3.5 lesions were dilated per patient. with an overall angiographic success rate of 96%. Complete revascularization was achieved in 857 (52%). A total of 52 patients (3.2%) had a major in-hospital complication: 27 patients (1.6%) died. 24 (1.4%) had a Q-wave myocardial infarction. and 14 (0.8%) underwent emergent CABG. Stepwise logistic regression analysis identified ejection fraction less than or equal to 40% (p less than or equal to 0.001). 3-vessel disease (p less than or equal to 0.01). female gender (p less than or equal to 0.02). and PTCA between 1981 and 1985 (p less than or equal to 0.05) as independent predictors of mortality. Of the 1.373 patients. 1.023 have been followed for greater than or equal to 1 year (mean follow-up 32.5 +/- 21.3 months). There were 156 (15.2%) late deaths. 81 (7.9%) recurrent myocardial infarctions. and 162 (15.8%) coronary artery bypass operations. Actuarial survival. computed from the time of hospital discharge. was 92% at 1 year. 86% at 3 years and 78% at 5 years. Repeat PTCA was required in 371 patients (36.3%).
Outcome after major dissection during coronary angioplasty using the perfusion balloon catheter, Coronary artery dissection is an infrequent but serious complication of coronary angioplasty that can lead to periprocedural vessel occlusion. emergency bypass surgery. myocardial infarction or death. Recently. a perfusion balloon catheter was developed that permits passive perfusion of blood through the central lumen of the catheter. It enables prolonged balloon inflations to be performed and has been used to provide distal blood flow after coronary occlusion. To evaluate the effectiveness of the perfusion balloon catheter in patients with major coronary dissections. 36 consecutive patients treated with the perfusion balloon catheter were compared with 46 consecutive patients treated before its availability. The 2 groups were similar in terms of clinical. angiographic and initial procedural characteristics. Use of the perfusion balloon catheter permitted a significantly longer inflation than standard balloon inflation (average 18 +/- 5 min). Angiographic success was significantly greater with the perfusion balloon catheter (84 vs 62% for conventional therapy). whereas complications were markedly reduced (48 vs 78%). With the perfusion balloon catheter there were fewer deaths (2 vs 6%). myocardial infarctions (14 vs 40%) and emergency bypass operations (11 vs 25%). The findings of this retrospective comparison demonstrate that the perfusion balloon catheter is effective for the management of major dissections after coronary angioplasty. The use of the perfusion balloon catheter should be considered when a major coronary dissection occurs and when emergency bypass surgery is contemplated.
Correlation of quantitative angiographic parameters with changes in left ventricular diastolic function after angioplasty of the left anterior descending coronary artery, This study evaluates the changes in left ventricular (LV) diastolic filling after percutaneous transluminal coronary angioplasty and the relation of such changes to quantitative angiographic measurements of the severity of coronary narrowings. Pulsed Doppler echocardiographic measurements were performed in 40 patients with single left anterior descending artery narrowing before. and 10 and 30 days after angioplasty. Minimal luminal diameter and percent diameter stenosis of coronary lesions were measured by computer-assisted quantitation. The ratio of early to late diastolic flow velocities (E/A ratio). time velocity integral of early diastolic filling period (Ei) and the ratio of early and late diastolic filling periods (Ei/Ai ratio) increased gradually after angioplasty. Minimal luminal diameter correlated significantly with the percent changes in E/A ratio (r = 0.59 at 10 days. r = 0.57 at 30 days). Ei (r = 0.53 at 10 days. r = 0.55 at 30 days) and Ei/Ai ratio (r = 0.41 at 10 days. r = 0.49 at 30 days). Percent diameter stenosis showed overall weaker correlations than minimal diameter with the percent changes in E/A ratio (r = 0.39 at 10 days. r = 0.32 at 30 days) and Ei (r = 0.38 at 10 days. r = 0.31 at 30 days). Thus. LV diastolic filling improves serially after coronary angioplasty in patients with 1-vessel disease. The magnitude of improvement in diastolic filling correlates better with minimal luminal diameter than percent diameter stenosis. Therefore. minimal luminal diameter is a better predictor of changes in Doppler transmitral flow parameters after angioplasty than percent diameter stenosis.
Left and right ventricular systolic function and exercise capacity with coronary artery disease, This prospective study of symptom-limited supine ergometry was conducted to determine the contributions of right ventricular (RV) and left ventricular (LV) systolic function to the exercise capacity of a cohort of patients with coronary artery disease (CAD). Patients with unstable angina. angiographically proven CAD (n = 53) and stable symptoms after medical therapy or angioplasty were included. Documented myocardial infarction (greater than or equal to 2 weeks before exercise) was present in 43 of 53 patients. Angina was the limiting symptom in 11 of 53; the other 42 stopped exercise with dyspnea or fatigue. or both. Oxygen consumption was measured on-line during exercise with a metabolic cart. RV ejection fraction and LV ejection fraction were measured by validated methods from gated blood pool radionuclide ventriculography. There were weak but statistically significant correlations between exercise oxygen consumption and exercise RV ejection fraction (r = 0.30. p less than 0.05) and between exercise oxygen consumption and exercise LV ejection fraction (r = 0.38. p less than 0.01). Multivariate regression analysis. including exercise RV ejection fraction. exercise LV ejection fraction and exercise heart rate versus exercise oxygen consumption revealed a better relation (r = 0.48. p less than 0.005) than any variable in univariate regression. The values of RV and LV ejection fraction at rest did not correlate significantly (r = 0.2. difference not significant). but the exercise values did correlate weakly (r = 0.41. p less than 0.01). The reserve of LV ejection fraction. defined as exercise minus rest value. correlated weakly with exercise oxygen consumption (r = 0.32. p less than 0.05).
Effects on quality of life with comprehensive rehabilitation after acute myocardial infarction, This investigation was designed to determine the impact of a brief period of cardiac rehabilitation. initiated within 6 weeks of acute myocardial infarction (AMI). on both disease-specific and generic health-related quality of life. exercise tolerance and return to work after AMI. With a stratified. parallel group design. 201 low-risk patients with evidence of depression or anxiety. or both. after AMI. were randomized to either an 8-week program of exercise conditioning and behavioral counseling or to conventional care. Although the differences were small. significantly greater improvement was seen in rehabilitation group patients at 8 weeks in the emotions dimension of a new disease-specific. health-related Quality of Life Questionnaire. in their state of anxiety and in exercise tolerance. All measures of health-related quality of life in both groups improved significantly over the 12-month follow-up period. However. the 95% confidence intervals around differences between groups at the 12-month follow-up effectively excluded sustained. clinically important benefits of rehabilitation in disease-specific (limitations. -2.70. 1.40; emotions. -4.86. 1.10. where negative values favor conventional care and positive values favor rehabilitation) and generic health-related quality of life (time trade-off. -0.062. 0.052; quality of well-being. -0.042. 0.035) or in exercise tolerance (-38.5. 52.1 kpm/min); also. return to work was similar in the 2 groups (relative risk. 0.93; confidence interval. 0.71. 1.64).
Mechanism of augmented left atrial pump function in myocardial infarction and essential hypertension evaluated by left atrial pressure-dimension relation, To analyze left atrial (LA) pump function in normal subjects. in patients with essential hypertension and in patients with a healed myocardial infarction. LA dimension (aortic-root echogram) and pressure (catheter-tip manometer) were simultaneously recorded in 25 patients (8 normal subjects. 7 with hypertension and 10 with myocardial infarction). The pressure-dimension relation of the left atrium was composed of 2 loops: the A loop (expressing the pump function of the left atrium) and the V loop. LA dimension at the beginning of active LA shortening was significantly greater in hypertensive subjects (33 +/- 3 mm) and in those with myocardial infarction (32 +/- 4 mm) than in normal subjects (28 +/- 3 mm) (p less than 0.01. p less than 0.05. respectively). The area of the A loop significantly increased in subjects with hypertension (48 +/- 3 mm Hg.mm. p less than 0.01) and in subjects with myocardial infarction (29 +/- 10 mm Hg.mm. p less than 0.05). compared with normal subjects (20 +/- 8 mm Hg.mm). The mean fractional shortening velocity of the left atrium significantly increased in subjects with hypertension. compared with normal subjects and those with myocardial infarction (p less than 0.05 for both). LA peak wall tension during the LA active contraction period significantly increased with hypertension and with myocardial infarction. compared with normal subjects (p less than 0.01. p less than 0.05. respectively). The area of the A loop was directly proportional to the LA dimension at the beginning of active LA shortening (r = 0.53). p less than 0.01).
Carcinoma arising within fibroadenomas of the breast. A clinicopathologic study of 105 patients, The authors report the clinicopathologic features of 105 carcinomas arising within fibroadenomas (FAs) of the breast. The mean age of the patients was 44 years. The presentation and gross characteristics of these tumors rarely differed from those of uncomplicated FAs. Carcinoma in situ (CIS) was the predominant type of malignancy (95%) found to arise in FAs. and lobular and ductal types occurred with equal frequency. Nine of ten FAs harboring an invasive carcinoma also contained CIS supporting the origin of the infiltrative component in the FAs. CIS within FAs was associated with in situ malignancy in surrounding breast tissue in 21% of cases. Age. fibroadenoma size. and type and extent of CIS were similar in patients with disease limited to the FA and in those with associated malignant disease in the remainder of the breast. Axillary nodal metastases were not detected. Sixty-three patients were observed for a mean period of 8.4 years. Only one of 26 patients with CIS within an FA who was treated conservatively developed an ipsilateral carcinoma. None of the 26 developed contralateral carcinoma; however. 3 of 23 with similar lesions. who were treated by mastectomy. did so. The contralateral carcinomas were invasive in two patients. one of whom died with distant metastases. Seven patients with FAs harboring lobular CIS underwent bilateral mastectomy. Their postoperative course was uneventful. None of seven patients with invasive carcinoma arising in an FA. two of whom were treated conservatively. succumbed to disease. However. one developed contralateral carcinoma. The authors recommend breast-conserving therapy for CIS arising in an FA.
Pediatric fine-needle aspiration biopsy, A total of 135 fine-needle aspiration (FNA) biopsies from varying sites were performed in 123 children (mean. 10.5 years; range. one day to 18 years) over a five-year period. One hundred thirty (96.3%) biopsy specimens were satisfactory for evaluation. Seventy-nine cases were nonneoplastic (60.8%); among these cases. a specific diagnosis of infectious disease was made in 17 (13.1%). A diagnosis of neoplastic disease was made in 50 (38.5%) cases. of which 14 (10.8%) were benign. 28 (21.5%) were malignant. and 8 (6.2%) were neoplasms of uncertain biologic potential. The sensitivity of pediatric FNA biopsies was 90.6%. specificity 100%. positive predictive value 100%. negative predictive value 94.7%. and efficiency of the test 96.5%. There were no false-positive diagnoses and there were four false-negative diagnoses. three of which involved aspirates of the central nervous system (CNS). Ancillary studies. including immunocytochemistry (20 cases). electron microscopic examination (18 cases). microbiologic culture (8 cases). cytogenetic studies (7 cases). and flow cytometry (3 cases). were performed on the aspirated material. enabling a more specific diagnosis or supplying additional information in many cases. Definitive diagnosis by FNA biopsy enabled radiation therapy and/or chemotherapy to be administered for unresectable malignant neoplasms. provided material for culture of infectious lesions. identified benign lesions not needing surgery. and aided the surgeon in planning the extent of surgery in resectable malignant neoplasms. These results support the greater use of FNA biopsy in the pediatric population.
Liposarcoma of the thyroid gland. Fine-needle aspiration cytology, immunohistology, and ultrastructure, A 56-year-old woman presented with a rapidly growing tumoral mass of the thyroid. In fine-needle aspirates. neoplastic cells were interpreted as undifferentiated (anaplastic) carcinoma. In contrast. histologic examination of tissue samples revealed a tumor with features suggestive of myxoid liposarcoma. The non-epithelial nature was confirmed by immunohistochemical and electron microscopic evaluation. Immunostains for vimentin and S-100 protein were positive. whereas no reactivity was obtained for epithelial markers. Ultrastructurally. the tumor consisted of poorly differentiated mesenchymal cells and lipoblastic elements in various stages of differentiation. Review of the literature reveals only one previous report of thyroid liposarcoma. the diagnosis of which was based on conventional light microscopic studies.
Immunoglobulin expression in B-cell lymphoma. Immunohistochemical study of 345 cases, Immunoglobulin expression was studied in a series of 345 cases of B-cell lymphoma by immunohistochemical studies and correlated with the histopathologic classification with the use of the Working Formulation. Immunoglobulin expression was present in 254 cases (74%) of B-cell lymphomas (IgM kappa. 122; IgM lambda. 82; light chain only. 40; mu heavy chain only. 10). Immunoglobulin expression occurred with the greatest frequency in lymphomas of small lymphocytic. small cleaved cell. and small noncleaved cell histologic types (93%. 100%. 100%. respectively) and occurred with the least frequency in lymphomas of large cell (cleaved and noncleaved) and immunoblastic histologic types (59% each). Other lymphomas demonstrated intermediate frequencies of immunoglobulin expression. An excess of cases expressing lambda light chain was noted overall (kappa-lambda ratio of 1.3; expected. 2.0) and was particularly evident for intermediate lymphocytic and follicular mixed histologic types (kappa-lambda ratios of 0.8 and 0.9. respectively). Immunoglobulin expression in B-cell lymphomas varies as a function of cellular differentiation as reflected in the histologic type and grade of the Working Formulation. An excess of cases expressing lambda light chain in specific histologic categories suggests the possibility that lymphocytes bearing the lambda light chain rearrangement may be more susceptible to certain types of lymphomatous transformation.
Rapid diagnosis of Legionella infection by a nonisotopic in situ hybridization method, The authors report a nonradioactive adaptation of DNA hybridization technology for the direct detection of Legionella organisms in situ in routinely processed histologic specimens. The probe used consisted of synthetic oligodeoxynucleotides. complementary to the ribosomal RNA of all clinically relevant Legionella species. labeled with biotinylated dUTP at their 3' ends. By in situ DNA hybridization and detection with an avidin-alkaline phosphatase complex. Legionella was visualized by light microscopy within the alveoli of lung specimens in 9 of 13 direct fluorescent antibody- or culture-positive cases of Legionnaires' disease. No cross-hybridization was observed in lung specimens infected with Pseudomonas aeruginosa. Klebsiella pneumoniae. Streptococcus pneumoniae. or other pathogens. The authors' results illustrate a novel adaptation of in situ DNA hybridization techniques. usually used for viruses. to the detection of a bacterial organism. The method enables direct visualization of bacterial nucleic acid in infected tissues and may facilitate early diagnosis and treatment of legionellosis.
Limited efficacy of leukopoor platelets for prevention of febrile transfusion reactions, Leukopoor red cell components have a reduced incidence of febrile transfusion reactions. An analogous efficacy for leukopoor platelets has not been convincingly established. The authors analyzed the transfusion records of 36 patients (26 women. 10 men) who received leukopoor platelets following febrile reactions to unmodified platelets. These patients received 409 unmodified transfusions (mean/patient 11) with 84 febrile reactions (rate 20.5%). Reaction rates to unmodified. non-HLA-matched single donor platelets (14.0%) and HLA-matched platelets (6.5%) were significantly lower than to pooled concentrates (27.2%) (P less than .01 and P less than .001. respectively). Of 623 leukopoor transfusions (mean/patient 17). 84 resulted in reactions (13.5%). Although leukodepletion significantly lowered the overall reaction rate as compared with unmodified products (P less than .02). a majority of patients (28 of 36) continued to have reactions. When individual reaction rates to unmodified and leukopoor transfusions were compared. only two patients showed a significant decrease in their reaction rate with leukopoor platelets. It appears that most susceptible patients continue to react to leukopoor platelets. particularly when pooled concentrates are used. and many patients show no reduction in reaction rate.
Creatine kinase isoenzyme band mimicking CK MB on agarose gel electrophoresis, The authors report the case of an 80-year-old man with prostatic disease whose serum contained an aberrant band in the MB position on agarose gel electrophoresis of creatine kinase (CK) isoenzymes. The authors demonstrated that the band probably was CK BB; the patient had no evidence of myocardial infarction. Contrary to most previous reports of such cases. the aberrant enzyme did not appear to be linked with IgG. IgA. or IgM; it also did not behave as if attached to a chelatable cation. Care must be taken to avoid mistaking such bands for CK MB.
The impact of nonidentical ABO cadaveric renal transplantation on waiting times and graft survival, Blood type O recipients of cadaveric renal transplants have longer pretransplant waiting periods than blood type A. B. and AB recipients. To evaluate reasons for and consequences of this discrepancy. we studied both the frequency of various donor and recipient blood type combinations and their outcomes. Among 37.659 cadaveric renal transplants performed during 1983 through 1989. there were 2.625 transplants (7%) received by patients of compatible but nonidentical blood types. Of 18.575 type O donor organs. 16.784 were received by type O patients for a recipient to donor ratio of 0.9. The corresponding ratios were greater than 1.0 for all other blood types (1.02 for blood type A. 1.14 for type B. and 2.18 for type AB). This causes blood type O patients to have a lower access to transplantation and to have significantly longer waiting times than patients of all other blood types. This inequality of access diminished significantly (P less than 0.001) over the years. but did not resolve by 1989. Analysis of relative risk for first graft loss by multiple regression (Cox) showed that transplantation across compatible blood types had a 9.1% higher risk (P less than 0.1) than that of transplantation among identical blood types. Cadaveric renal transplantation within identical blood types optimizes access to transplantation and avoids further aggravating past disadvantages for blood type O recipients.
Calcium acetate control of serum phosphorus in hemodialysis patients, Calcium acetate has many characteristics of an ideal phosphorus binder. It is a readily soluble salt that avidly binds phosphorus in vitro at pH 5 and above. One-dose/one-meal balance studies show it to be more potent than calcium carbonate or calcium citrate. We studied chronic (3-month) phosphorus binding with calcium acetate in 91 hyperphosphatemic dialysis patients at four different centers. All phosphorus binders were stopped for 2 weeks. Calcium acetate at an initial dose of 8.11 mmol (325 mg Ca2+) per meal was then used as the only phosphorus binder. Dose was adjusted to attempt control of predialysis phosphorus level less than 1.78 mmol/L (5.5 mg/100 mL). Final calcium acetate dose was 14.6 mmol (586 mg) Ca2+ per meal. Sixteen patients developed mild transient hypercalcemia (mean. 2.84 mmol/L [11.4 mg/dL]. Initial phosphorus values in mmol/L (mg/dL) were 2.39 (7.4); at 1 month. 1.91 (5.9); and at 3 months. 1.68 (5.2). Initial calcium values in mmol/L (mg/dL) were 2.22 (8.9); at 1 month. 2.37 (9.5); and at 3 months. 2.42 (9.7). Initial aluminum values in mumol/L (micrograms/L) were 2.99 (80.7); and at 3 months were 2.54 (68.4). Initial C-terminal parathyroid hormone (C-PTH) values in ng/mL were 14.6; at 1 month. 11.9; and at 3 months. 13.2. Sixty-nine patients then entered a double-blind study. Phosphorus binders were stopped for 1 week. Calcium acetate (at a dose established in a prior study) or placebo was then administered for 2 weeks. Next. patients were crossed to the opposite regimen for 2 weeks. Initial phosphorus was 2.36 mmol/L (7.3 mg/100 mL) and calcium 2.22 mmol/L (8.9 mg/100 mL).
Intratracheal injection of endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation, The nature of the endogenous mediators that down-regulate and curtail the exodus of neutrophils into local acute inflammatory sites is unknown. In the present report. interleukin-6 (IL-6) and transforming growth factor beta (TGF beta). members of a family of macrophage-derived proteins known as cytokines. are shown to inhibit significantly the acute neutrophilic exodus caused by an intratracheal injection of endotoxin (LPS). a proinflammatory component of the cell walls of gram-negative bacteria. Transforming growth factor beta (10 micrograms) and IL-6 (10 micrograms) coinjected intratracheally with LPS (10 micrograms) each inhibited the number of neutrophils in 6-hour bronchoalveolar lavage (BAL) specimens by approximately 50%. The intratracheal coinjection of IL-6. TGF beta. and LPS inhibited the LPS-induced neutrophilic inflammatory exodus by nearly 75%. Interleukin-6 also is shown to be endogenously upregulated within the lung after intratracheal challenge with endotoxin. providing evidence that IL-6 may represent an endogenous negative feedback mechanism to inhibit endotoxin-initiated cytokine-mediated acute inflammation. Interleukin-6 and TGF beta both strongly inhibited the quantity of TNF-alpha recovered in the BAL fluid of LPS-challenged rats. suggesting that downregulation of LPS-induced TNF-alpha production within the lung represents one mechanism whereby IL-6 and TGF beta exert an antiinflammatory action. Interleukin-6 and TGF beta represent novel pharmacologic and. probably. endogenous inhibitors of acute inflammation.
Cell-cycle-related staining patterns of anti-proliferating cell nuclear antigen monoclonal antibodies. Comparison with BrdUrd labeling and Ki-67 staining, Monoclonal antibodies (MAbs) to nuclear antigens are increasingly used as tools to obtain valuable information concerning the proliferative characteristics of various types of cancer. Prerequisite for the application of these MAbs in surgical pathology is establishment of the level of expression and/or cellular distribution of the antigens in relation to distinct cell-cycle compartments. In this study the topologic distribution of proliferating cell nuclear antigen (PCNA). an auxiliary protein of DNA polymerase delta. as recognized by human autoantiserum (AK) and two recently developed MAbs (19A2 and 19F4). was evaluated. Using cultured human cancer cells as a model system. and providing optimal fixation/permeation procedures are applied. these antibodies display a high affinity for PCNA bound to nuclear replicon clusters. resulting in distinct granular staining patterns. A more diffuse nucleoplasmic PCNA staining was mainly restricted to non-S-phase cells; in methanol-fixed cells. staining intensity of this form relative to the replicon-bound form appeared higher after staining with 19A2 than with 19F4 or AK. Comparing PCNA expression (detected with 19A2) with the expression of the Ki-67 antigen. PCNA-negative cells are also Ki-67 negative. In MCF-7 human breast cancer cells treated with 10(-6) mol/l (molar) tamoxifen. the fraction of nuclei showing replication patterns decreased from 42% to 8% within 8 days. but PCNA and Ki-67 antigens remained detectable in most cells during this interval. indicating a relatively slow decrease of antigen expression in cells that have entered a quiescent state. Treatment of MCF-7 cells with 10(-6) mol/l methotrexate resulted in a rapid accumulation of cells with an early S-phase DNA content; PCNA replication patterns showing a frequency distribution reflecting this DNA content were observed up to 48 hours after treatment. This indicates that the presence of replication patterns as visualized with anti-PCNAs is not a measure of replicative activity per se. It is concluded that. providing nuclear non-S-phase PCNA staining is faint relative to staining of replicon clusters. anti-PCNA antibodies may be excellent markers to detect in situ cells with S-phase DNA contents.
Quantitative assessment of the age of fibrotic lesions using polarized light microscopy and digital image analysis, Reliable histologic methods for gauging the maturity of fibrotic lesions are limited. making interventions in the healing process difficult to assess. As collagen ages there is enhanced birefringence due to increased molecular and fibrillar organization. The purpose of this study was to develop a microscopal technique to quantify this process and to determine its ability to distinguish scars of varying ages. Fibrosis in the rat gracilis muscle was studied 5 to 63 days after superficial injury. Sections were stained with picrosirius red and illuminated with monochromatic. polarized light. The microscope fields were digitized using a computer-video system yielding an image in which noncollagenous material was dark (gray level 0) and collagen was depicted by grey levels 1 to 255. In the fibrosis model used. the collagen area fraction plateaued at 80% by day 21. The median collagen grey level increased progressively as the scar aged. It is concluded that this histologic. nondestructive technique can reliably quantify age-related optical properties of fibrotic collagen and that this could be used to determine the maturity of fibrotic lesions.
The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis, The synthesis of collagen and EIIIA-containing cellular fibronectin in certain forms of pulmonary fibrosis occurs in discrete locations: in the Masson bodies in bronchiolitis obliterans with organizing pneumonia and in focal clusters of fibroblasts (fibroblastic foci) within airspaces in usual interstitial pneumonia. These sites were examined by electron microscopy and immunohistochemistry using antibodies against cytoskeletal markers and extracellular matrix components in biopsies from three patients with bronchiolitis obliterans with organizing pneumonia and four patients with usual interstitial pneumonia. Fibroblasts of both Masson bodies and fibroblastic foci expressed vimentin and alpha smooth muscle actin but not desmin. distinguishing them from true smooth muscle. In both structures fibroblasts with well-formed actin filament bundles were aligned parallel to one another. enmeshed in a matrix of fibronectin-containing fibrils (microtendons) that linked cells and collagen bundles. Similar features characterize the phase of contraction during the healing of skin wounds. This suggests that active contractions of fibroblasts plays a role in the remodeling of the lung in pulmonary fibrosis.
Somatostatin receptors in differentiated ovarian tumors, The presence of somatostatin receptors was investigated in 57 primary human ovarian tumors using in vitro receptor autoradiography with three different somatostatin radioligands. 125I-[Tyr11]-somatostatin-14. 125I-[Leu8. D-Trp22. Tyr25]-somatostatin-28. or 125I-[Tyr3]-SMS 201-995. Three cases. all belonging to epithelial tumors. were receptor positive; specifically 1 of 42 adenocarcinomas. 1 of 3 borderline malignancies. and 1 of 2 cystadenomas. Four other epithelial tumors (3 fibroadenomas. 1 Brenner tumor). 4 sex cord-stromal tumors (2 fibrothecomas. 2 granulosa cell tumors). and 2 germ cell tumors (1 dysgerminoma. 1 teratoma) were receptor negative. In the positive cases. the somatostatin receptors were localized on epithelial cells exclusively. were of high affinity (KD = 4.6 nmol/l [nanomolar]). and specific for somatostatin analogs. These receptors bound somatostatin-14 and somatostatin-28 radioligands with a higher affinity than the octapeptide [Tyr3]-SMS 201-995. Healthy ovarian tissue had no somatostatin receptors. A subpopulation of relatively well-differentiated ovarian tumors. therefore. was identified pathobiochemically on the basis of its somatostatin receptor content. This small group of somatostatin receptor-positive tumors may be a target for in vivo diagnostic imaging with somatostatin ligands.
Decrease in the AgNOR number in Dunning R3327 prostate cancers after treatment with an agonist and antagonist of luteinizing hormone-releasing hormone, The argyrophilic staining of the nucleolar organizer region (AgNOR) in cells of Dunning R3327 rat prostate tumors was studied and the effect of hormonal treatments on their appearance was analyzed. The nuclei of the control tumor cells contained 4.1 +/- 0.17 AgNOR granules. Treatment of rats for 8 weeks with luteinizing hormone-releasing hormone (LH-RH) agonist (D-Trp-6-LH-RH) and antagonist SB-75 induced a marked inhibition of tumor growth and decreased significantly (P less than 0.01) the number of Ag-NORs in the tumors to 2.89 +/- 0.10 AgNOR granules/cell in the group given the agonist and to 2.82 +/- 0.10 after therapy with the highest dose of the antagonist. A reduced AgNOR number (3.14 +/- 0.16) also was found after 3 days of treatment with SB-75 (P less than 0.05). but the AgNORs returned to near control values 1 week after the short-term therapy. showing the reversibility of these changes. These results suggest that the AgNOR method. which was widely tested on human tumors in the past few years. can be a valuable technique in experimental tumor pathology and useful in the evaluation of the effects of various treatments.
Comparison of blood aldehyde dehydrogenase activities in moist snuff users, cigarette smokers and nontobacco users, The aldehyde dehydrogenase (ALDH; EC 1.2.1.3) activity was determined in samples of whole blood and in isolated erythrocytes and leukocytes from users of Swedish moist snuff. cigarette smokers and non-tobacco-using controls. The mean whole blood ALDH activity of the smokers was reduced by 21% (p less than 0.001) when compared to the controls. while that of the snuff users was reduced by only 8% (not significant). Similar but somewhat less pronounced differences were obtained both in the assays with erythrocytes and leukocytes. In the cigarette smokers. the whole blood activity correlated significantly (r = -0.79. p less than 0.001) with the plasma concentration of cotinine. the major metabolite of nicotine. whereas no correlation was observed for the users of moist snuff. Similar plasma nicotine and cotinine levels were found in smokers and snuff users. which indicates that the reduced blood ALDH activity in smokers is not caused by nicotine or any of its metabolites. but more likely. by components formed during combustion of tobacco. Since a reduced blood ALDH activity has previously been suggested as an indicator of excessive alcohol consumption. the present results show that. in future studies on blood ALDH. the smoking habits should also be taken into account.
Symptoms of anxiety in inpatient alcoholics with and without DSM-III-R anxiety diagnoses, Self- and observer-rating scales were administered to alcohol-dependent inpatients during acute withdrawal and regularly for 3 weeks. Following a structured diagnostic interview (SCID) at the end of the 3rd week of hospitalization. subjects were divided into two groups: a dual-diagnosed group (alcohol dependence and anxiety disorder) and an alcohol-only group (no other current Axis I diagnosis). The results demonstrated that the dual-diagnosed subjects experienced higher anxiety levels during and after acute alcohol withdrawal. All rating scales (i.e.. Sheehan Patient Rated Anxiety Scale. Spielberger State Anxiety Inventory. Zung Rating Scale for Anxiety. and Hamilton Rating Scale for Anxiety) were analyzed to obtain the best combination of sensitivity and specificity. Taken together. the results indicate that it may be possible to identify alcoholics who require additional psychiatric evaluation early in treatment. This would allow a treatment plan which could be used to address both psychiatric and substance abuse problems.
Development of tolerance to inhibitory effect of ethanol on endothelium-dependent vascular relaxation in ethanol-fed rats, Rats were maintained on liquid diets containing ethanol (35% of total calories) or an equicaloric volume of sucrose instead of ethanol for 10 wk. Vascular strips of isolated rat aortas were mounted in organ chambers to record isometric tension. Ethanol in vitro inhibited the endothelium-dependent relaxation responses to acetylcholine and ATP in both pair-fed control and ethanol-fed rats. The inhibitory effect of ethanol was greater in the pair-fed rats. In addition. the magnitudes of these relaxation responses in the absence of ethanol in vitro in pair-fed rats were similar to those in the presence of ethanol in ethanol-fed rats. In the absence of ethanol in vitro. the relaxations in response to acetylcholine and ATP in the ethanol-fed rats were greater than in the pair-fed rats. These results suggest that chronic ethanol consumption can induce tolerance to ethanol-induced inhibition of endothelium-dependent relaxation responses to acetylcholine and ATP. and that the relaxations can become adapted to the presence of plasma levels of ethanol. which may inhibit the relaxation in vivo. The augmented relaxation in the ethanol-fed rats may result from the mechanism causing tolerance to the inhibitory effect of ethanol.
Effect of acute ethanol on esophageal motility in cat, In man. acute ethanol administration decreases lower esophageal sphincter pressure (LESP). prolongs the duration. and lowers the amplitude of esophageal contractions. These changes may contribute to gastroesophageal reflux and esophagitis. To evaluate the underlying mechanisms of these changes an animal model is needed. Hence. we studied the effect of various doses of ethanol on esophageal motility in cats. an animal with an esophagus similar to man's. Similar to man. intravenous administration of ethanol significantly decreased LESP and amplitude of lower (smooth muscle portion) esophageal contractions. It also prolonged the duration of lower esophageal contractions. even through it had no effect on contraction velocity. The effect of ethanol on upper (striated muscle portion) esophagus was different. Ethanol had no effect on the amplitude of contractions. whereas it prolonged their duration and decreased their velocity. The effect of acute ethanol on LESP in four withdrawing alcoholic cats was similar to controls. However. the acute effect of ethanol on the esophageal contractions was less marked in alcoholics. Bilateral cervical vagotomy and intravenous injection of the neurotoxin tetrodotoxin before the administration of ethanol did not prevent the effect of ethanol on LESP. This data suggests that cat esophagus is a good model for studying the underlying mechanisms of the effects of acute ethanol because its response is similar to the esophagus of man. and the acute effect of ethanol on LESP is not neurally mediated but is the result of its direct effect on muscle.
Serum beta-hexosaminidase and alpha-mannosidase activities as markers of alcohol abuse, In 25-alcohol-dependent patients in whom detoxication treatment has been introduced serum total beta-hexosaminidase. thermostable beta-hexosaminidase. alpha-mannosidase and gamma glutamylotransferase (GGT) and serum high density lipoprotein (HDL) cholesterol were determined during alcohol withdrawal. The assays were also performed in a group of dependent individuals after a 1 month or longer period of abstinence. Marked increase in beta-hexosaminidase activity was observed in intoxicated patients. The activity decreased rapidly after the cessation of drinking. resembling the decrease in HDL cholesterol level in its dynamics. The alpha-mannosidase activity rise was less pronounced and its normalization was slow. similar to the GGT activity normalization rate. The rise of beta-hexosaminidase activity was mostly due to the thermostable component of the enzyme. Total beta-hexosaminidase or thermostable beta-hexosaminidase activity determinations appear to be simple and reliable markers of alcohol abuse.
Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes, In order to clarify the relationships between acetaldehyde (Ac-CHO) metabolism and low Km (mitochondrial) aldehyde dehydrogenase (ALDH2) genotypes. hepatic ALDH2 activity was determined and serial changes of blood Ac-CHO levels after ethanol administration were analyzed in the individuals homozygous for the normal ALDH2 genes. heterozygous for the normal and mutant ALDH2 genes. and homozygous for the mutant ALDH2 genes. Genomic DNA was extracted from white blood cells and genotyping of ALDH2 was performed using the polymerase chain reaction technique and slot blot hybridization with synthesized oligonucleotide probes specific to the normal and mutant ALDH2 genes. ALDH2 activity was not detectable in the liver in two cases of the mutant homozygote. In four out of eight cases of the heterozygote. hepatic ALDH2 activity was measurable. although the activity was lower compared with that in the normal homozygote. Blood ethanol levels after alcohol administration were not different among the three different ALDH2 genotypes. Blood Ac-CHO levels after drinking of alcohol were significantly higher in the heterozygotes and the mutant homozygotes than in the normal homozygotes. The levels after a moderate amount of ethanol (0.8 g/kg of body weight) in a case of the mutant homozygote were not different from those of the heterozygotes. However. the levels after a small amount of ethanol (0.1 g/kg of body weight) were significantly higher in the mutant homozygotes than in the heterozygotes. These results indicate that hepatic ALDH2 activity is lacking completely. and metabolism of Ac-CHO in the liver is severely impaired in the homozygotes of the mutant ALDH2 genes.
The influence of the renin gene on alcohol consumption in Dahl rats, A rat renin allele (the S-allele) has been identified in Dahl rats which cosegregates with increases in blood pressure. Rats with a double dose of the allele--the salt-sensitive hypertensive rats--have low renin activity compared with the salt-resistant hypertensive rat that does not have this S-allele. Alcohol consumption in rats has also been shown to vary with renin activity. and the possible involvement of renin activity in the genetics of alcohol consumption was suggested by previous work showing that the alcohol-preferring P line of selected rats had low renin levels. In the present study we examined alcohol consumption in a group of inbred Dahl rats. which have a double dose of the S renin allele. and in a group of selected Dahl rats. which have only a single dose of this S-allele. After an initial acclimation period. these two groups were first given daily 1-hr access to ascending concentrations of alcohol (3%. 6%. 8% w/v) over a 34-day period followed by continuous access to alcohol for a further 10 days. Water and food were always available. Regardless of whether alcohol was rationed or continuously available. the rats with the double dose of the S-allele drank significantly more alcohol than the rats that had only a single dose of this allele. These findings suggest that genetically mediated alterations in the renin gene may exert a significant influence on alcohol consumption and may be a component in the etiology of alcoholism.
Suppression of natural killer cell activity by ethanol consumption and food restriction, Effects of 4-week food restriction and ethanol consumption on natural killer (NK) cell activity and carcass composition were evaluated. Female. C57BL/6 mice given water (H2O) or ethanol (20% w/v. ETOH) ad libitum were placed in one of three dietary groups: unrestricted (UNR). moderately restricted (MR. 2.2 g/day). or severely restricted (SR. 1.8 g/day). Food restriction alone (MR. SR) significantly reduced body. spleen. and thymus weights; carcass lipid content (SR only); spleen cell number; and baseline and interleukin-2 (rIL-2) stimulated NK cell activities. Ethanol consumption was unaffected by food restriction and in restricted mice it did not suppress food intake. Thus. average calories derived from ethanol increased from 30% (UNR) to 40% (SR) with the degree of food restriction in these groups. Mice given ethanol and restricted food intake had at least as heavy or heavier body. spleen. and thymus weights than water-drinking (H2O) counterparts. Spleen cell number was reduced in ethanol-consuming (ETOH). food restricted groups compared with UNR H2O control. Baseline NK cell activity was suppressed 50% to 90% in all ETOH and food-restricted groups. rIL-2 stimulated NK cell activity was suppressed 18% to 76% in food restricted mice independent of ethanol intake. These results indicate that supplementary ethanol calories did not enhance NK cell activity in UNR ETOH mice. nor did they protect splenic NK cell activity from the suppressant effects of food restriction. Ethanol consumption significantly increased carcass lipid content in all groups compared with their H2O counterparts. This increase was largely responsible for the preservation of body weight in ETOH mice especially during food restriction.
The structure of drinking-related consequences in alcoholic women, This study examines the structure of drinking-related consequences in women in treatment facilities by describing indices that were constructed by submitting 69 measures to factor analysis. Two hundred fifty-four (254) alcoholic women responded to self-report interview items that measured the consequences that the respondent perceived to follow or result from her drinking. The items were submitted to a series of exploratory principal component analyses. Nine factors. social withdrawal. sexuality. early effects. maternal role. accidents. symptoms. work. illness. and relationship conflict. emerged in the rotated solution. with the majority of coefficient alphas in the 0.6 to 0.8 range. Internal reliabilities for the indices remained sufficiently high across age subgroups in the sample.
Videotape versus computer interactive education in alcoholic and nonalcoholic controls, Few studies have evaluated the ability of the alcoholic patient to learn treatment-related information and all have involved conventional educational modalities such as videotape or lecture. Since computer interactive (CI) programs allow for individualization. feedback. and active learning. we were interested in determining whether CI would prove to be a more effective educational/treatment modality for male alcoholic patients than the conventional videotape (V) modality. The current study compared the relative effectiveness of the CI and V educational interventions for VA alcoholic patients and a cognitively and sociodemographically matched sample of nonalcoholic VA patients. The 91 male alcoholic subjects (46 V. 45 CI) were lower socioeconomic outpatients in a VA Alcoholism Treatment program. Control subjects were 35 nonalcoholic men (18 V. 17 CI) attending an outpatient medical clinic at the same facility. All subjects were individually exposed in a single session to a 1 hr intervention on the Medical Effects of Alcohol. Baseline knowledge was measured prior to the intervention using a 21-item multiple choice test. while learning and retention were assessed with the same instrument 24 hr after the intervention. All four subgroups (two types of subjects x two types of intervention) identified approximately three more items correctly at the post-test than at baseline. Thus. neither alcoholics for nonalcoholics acquired more information when exposed to the CI intervention. Further. no differences were found overall in the learning of the alcoholic and nonalcoholic subjects. The implications of these findings and their limitations are discussed.
The effects of prenatal alcohol use on the growth of children at three years of age, In this prospective study of substance use during pregnancy. women were interviewed in their 4th and 7th prenatal months. and women and children were assessed at 24 hr. 8. 18. and 36 months postpartum. Data are presented on the outcome of 519 children at age 3. At 3 years. children who were exposed prenatally to alcohol were smaller in weight. length. and head circumference. They also had an increased number of minor physical anomalies. These effects were found even after controlling for nutritional and environmental factors. The persistence of growth effects at age 3 suggests that children exposed to alcohol prenatally may have a diminished capacity for growth.
Interrelationship between activation of dopaminergic pathways and cerebrospinal fluid concentration of dopamine tetrahydroisoquinoline metabolite salsolinol in humans: preliminary findings, The main objective of this study was to determine whether the activation of dopaminergic pathways. through adrenal-caudate transplantation. stimulated the production of dopamine and salsolinol in cerebrospinal fluid (CSF) of patients with Parkinson's disease. Dopamine sulfate and salsolinol sulfate in CSF specimens were measured by radioenzymatic technique. The results of this study demonstrated that the replacement of degenerative nigrostriatal neurons with new dopamine-producing cells by adrenal brain transplants in patients with Parkinson's disease resulted in significant increase (p less than 0.05) in CSF levels of free dopamine. dopamine sulfate. free salsolinol. and salsolinol sulfate as compared with preoperative levels. Moreover. the oral administration of L-dopa to these transplanted patients caused substantial (p less than 0.001) elevation in CSF levels of free dopamine (before L-dopa. 146 +/- 57 pg/ml; after L-dopa. 575 +/- 207 pg/ml). dopamine sulfate (before L-dopa. 1966 +/- 945 pg/ml; after L-dopa. 41679 +/- 29326 pg/ml). free salsolinol (before L-dopa. 43 +/- 29 pg/ml; after L-dopa. 186 +/- 90 pg/ml). and salsolinol sulfate (before L-dopa. 405 +/- 477 pg/ml; after L-dopa. 2908 +/- 2572 pg/ml). respectively.
Acute in vivo effects of low ethanol concentration on the capacity of urea synthesis in rats, We studied the effect of acute exposure. by constant intravenous infusion. to a low blood ethanol concentration (range 8-14 mmol/l) on the in vivo capacity of urea-N synthesis (CUNS). alanine elimination. and the nitrogen retention in fed and fasted rats. Alanine was infused to obtain a constant blood concentration of alpha-amino nitrogen between 7.3 and 11.7 mmol/l. at which concentrations urea synthesis is at maximum. CUNS was calculated after nephrectomy as accumulation of urea in body water. elimination of alanine as alanine infusion rate corrected for accumulation. and nitrogen retention as the difference. In the fed state ethanol decreased CUNS from 7.84 +/- 0.32 mumol N/(min 100 g body weight (BW] (mean +/- SEM) (n = 7) to 6.30 +/- 0.58 (n = 6) (p less than 0.001) and in the fasted state from 8.25 +/- 0.27 mumol N/(min 100 g BW) (n = 10) to 6.90 +/- 0.25 (n = 10) (p less than 0.001). In the fed state ethanol increased the elimination of alanine from 6.49 +/- 0.28 mumol/(min 100 g BW) (n = 7) to 6.95 +/- 0.25 (n = 6) (p less than 0.01). and in the fasted state decreased it from 6.25 +/- 0.12 mumol/(min 100 g BW) (n = 10) to 5.67 +/- 0.20 (n = 10) (p less than .001).
Alcohol and secobarbital effects as a function of familial alcoholism: extended intoxication and increased withdrawal effects, Response differences following administration of alcohol between adult males with a positive (FHP) versus negative (FHN) family history of alcoholism have been demonstrated in previous research and are thought to be related to risk for developing alcoholism. If this is so. the pharmacological breadth of addiction risk conferred by a positive family alcoholism history might be studied by determining whether FHP subjects show different responses than FHN to drug classes other than alcohol. We have previously reported on the acute effects of ethanol as compared with secobarbital in FHP and FHN subjects and found that FHP subjects showed greater sensitivity across a variety of subjective measures than FHN subjects for both drug classes. The data reported here are based on an extended data collection period of 3 to 18 hr postingestion. following completion of the acute laboratory portion of the study. Specifically. in the present study. dose-effect timecourse functions for a variety of physiological (heart rate. blood pressure. and breath alcohol level). subjective (analog mood. drug effect. and withdrawal. Subjective High Assessment Scale (SHAS]. and psychomotor measures (Digit Symbol Substitution Test and numeric recall) were examined in FHP and FHN college-aged males for secobarbital (0. 100. 200 mg daily) and ethanol (1 g/kg daily). FHP and FHN subjects were matched on light-to-moderate drinking patterns. anthropometric dimensions. age. years of schooling. and drug use. FHP subjects reported more extended intoxication and greater withdrawal effects following both ethanol and the high dose of secobarbital than did FHN subjects.
Comparison of lumbar plexus block versus conventional opioid analgesia after total knee replacement, A randomised controlled study was undertaken to assess the analgesic efficacy of continuous lumbar plexus block for the first 48 hours after total knee replacement surgery. Boluses of 0.5% bupivacaine with adrenaline 1 in 200.000 (0.3 ml/kg) were administered through a cannula inserted into the neurovascular sheath of the femoral nerve. Thirteen patients who received this block required significantly less morphine than a control group of 16 patients. Pain scores were similar and there were no complications related to this technique.
Vasovagal asystole during spinal anaesthesia, A patient in whom vasovagal asystole was induced by the performance of a spinal anaesthetic in the upright position is described. This illustrates the importance of routine monitoring of the electrocardiograph during regional anaesthesia. The risk of vasovagal syncope may be increased by the use of the sitting position and by the omission of anxiolytic premedication.
Real-time ultrasound for the detection of deep venous thrombosis, PURPOSE: Accurate diagnosis of deep venous thrombosis (DVT) is a clinical problem in emergency practice. A prospective trial was conducted comparing real-time ultrasound with contrast venography in the diagnosis of proximal DVT. METHODS: Seventy patients whose clinical presentations mandated diagnostic evaluation for DVT had real-time ultrasound of the involved leg followed by contrast venography. Initial readings of ultrasound and venography were compared with each other and with final readings to assess reliability of interpretation. RESULTS: Final ultrasound readings agreed with final venogram readings in all patients. Negative initial ultrasound readings agreed with final venogram readings in 56 of 56 patients (negative predictive value. 100%; 95% confidence interval. 94 to 100). Eighteen patients had positive initial ultrasound readings compared with 14 who had positive final venogram readings (positive predictive value. 78%; 95% confidence interval. 55 to 91). CONCLUSION: Negative real-time ultrasonography reliably excludes proximal DVT. Positive ultrasound reliably diagnoses proximal DVT only in experienced hands.
Magnetic resonance imaging for calf deep venous thrombophlebitis, STUDY OBJECTIVE: To compare magnetic resonance imaging (MRI) of the calf with venography for patients with suspected calf deep venous thrombophlebitis (DVT). DESIGN: Ten consecutive adult patients with suspected calf DVT received venography and. within 48 hours. MRI scans. The tests were reviewed blindly by two radiologists. and results of the tests were compared. SETTING: The emergency department of a large teaching hospital with an annual census of 60.000 patients. MAIN RESULTS: All patients with negative venograms had no suggestion of DVT on MRI scan. Two of these patients had other significant demonstrable abnormalities. Four of the five patients with positive venograms had positive calf MRI scans. One patient with a venogram that was difficult to interpret had no DVT on MRI. A thigh DVT was seen on his venogram and was suggested by MRI findings. CONCLUSION: MRI may replace ascending venography as the standard for diagnosis of calf DVT.
Probability of appendicitis before and after observation, STUDY OBJECTIVE: To examine patients with abdominal pain for changes in probability of appendicitis during observation. STUDY DESIGN: Retrospective cohort study. SETTING: University-affiliated community hospital. METHODS: 252 patients with abdominal pain who were examined underwent short-term (10.4 hours) observation (95% confidence interval [CI]. 8.7. 12.1) before the decision to operate during a one-year period. Alvarado's scoring system and a probability-of-diagnosis nomogram were used to assign scores and estimate probability of appendicitis. MEASUREMENTS AND RESULTS: In the study group. mean score of patients with appendicitis increased after observation from 6.8 (95% CI. 6.2. 7.4) to 7.8 (95% CI. 7.3. 8.3). corresponding to a change in probability of appendicitis from 50% to 65%. Mean score of patients without appendicitis decreased from 3.8 (95% CI. 3.5. 4.1) to 1.6 (95% CI. 1.58. 1.62). corresponding to a change in probability from 35% to 22%. The difference between mean scores for patients with and without appendicitis increased from 2.6 (95% CI. 2.0. 3.2) to 6.2 (95% CI. 6.15. 6.25) during observation. The study group initially had intermediate probability of appendicitis (score. 4.35; 95% CI. 4.04. 4.66) compared with high probability for patients who went directly to surgery after their initial evaluation (63 patients; score. 7.59; 95% CI. 7.05. 8.73) and low probability for patients with abdominal pain who were sent home after their initial evaluation without observation or surgery (2.097 patients; score. 1.87; 95% CI. 1.48. 2.26). CONCLUSION: In this group of patients with intermediate initial probability of appendicitis. observation improved the ability to distinguish patients with from those without appendicitis.
A randomized comparison of atropine and metaproterenol inhalational therapies for refractory status asthmaticus [published erratum appears in Ann Emerg Med 1991 Sep;20(9):1031, STUDY OBJECTIVE: To compare the forced expiratory volume in one second (FEV1) response to inhaled anticholinergic with the response to beta-adrenergic solutions in adults with refractory status asthmaticus. DESIGN: After the decision was made to hospitalize. 40 patients were prospectively randomized in a double-blind trial to receive either atropine sulfate or metaproterenol by nebulizer. SETTING: A county teaching hospital emergency department. TYPE OF PARTICIPANTS: Adults requiring hospitalization for refractory status asthmaticus. INTERVENTIONS: Standard therapies for acute bronchospasm. followed by either 1.5 mg atropine or 15 mg metaproterenol by nebulizer. MEASUREMENTS AND MAIN RESULTS: The two groups were similar on entry into the study. including mean FEV1 measurements (0.70 L atropine/0.60 L metaproterenol. P greater than .05). Compared with baseline. The FEV1 improvement for the metaproterenol group was statistically significant (+ 0.18 L. P = .05; + 31%. P less than .05). whereas the improvement with atropine did not reach significance (+0.09 L or +10%. P greater than .05). Comparing the two groups. statistically significant differences favoring metaproterenol were found in the percent improvement in the FEV1 (+10% atropine/+31% metaproterenol. P less than .05) and in the percentage of patients experiencing at least a 15% decrease in their FEV1 below baseline (35% atropine/10% metaproterenol. P less than .05). No patient suffered adverse side effects. CONCLUSION: For the majority of adults with refractory status asthmaticus. an additional beta-adrenergic inhalation treatment results in greater FEV1 improvement than that resulting from the addition of an atropine inhalation.
Multiple doses of activated charcoal: time for reappraisal, Multiple-dose charcoal therapy has become a popular treatment for many overdoses. It is generally perceived as a simple. inexpensive. effective. and safe procedure that decreases morbidity and mortality by enhancing drug excretion. However. increased drug clearance has been shown definitively for only a few drugs. and improved outcome has not been demonstrated conclusively for any overdose. Recently. there have been several reports of complications due to this intervention. The role of this pharmacologic curiosity in the management of the acutely poisoned patient requires reassessment.
The rise in the total iron-binding capacity after iron overdose, STUDY OBJECTIVES: To determine if and to what extent the total iron-binding capacity (TIBC) would increase following an iron overload. and to identify specific iron-binding proteins that might be responsible for the increased TIBC. DESIGN: A prospective laboratory investigation. SETTING: A certified regional poison control center. PARTICIPANTS: Six healthy adult male volunteers. MEASUREMENTS AND MAIN RESULTS: All volunteers ingested 20 mg/kg of elemental iron. Blood samples were drawn at hourly intervals for eight hours and analyzed for serum iron. TIBC. transferrin. ferritin. lactoferrin. glucose. bicarbonate. and WBC. Within two hours of ingestion. subjects developed symptoms of toxicity. including nausea. lightheadedness. vomiting. severe crampy abdominal pain. and voluminous diarrhea. The TIBC was statistically significantly increased at all points measured from one to six hours. Despite rising above 300 micrograms/dL in five of six subjects. the serum iron never exceeded the TIBC in any subject. Transferrin and ferritin did not increase to account for the increased TIBC. The lactoferrin levels did increase. but they did not correlate with significant increases in the TIBC. CONCLUSIONS: Twenty mg/kg of elemental iron caused clinical toxicity in this study. and after iron overload the colorimetric TIBC increased by unknown mechanisms.
Whole-bowel irrigation as a treatment for acute lithium overdose, STUDY OBJECTIVE: To determine if gastrointestinal decontamination using whole-bowel irrigation (WBI) was an effective treatment for acute ingestion of sustained-release lithium. METHODS: In a two-phase. crossover protocol. ten normal volunteers ingested in each phase 0.80 mEq/kg sustained-release lithium carbonate. In the second phase. WBI was begun one hour after lithium ingestion. and 10 L of polyethylene glycol solution were administered over five hours. Serum samples were collected every half hour for six hours. every hour for an additional six hours. and then every 24 hours for as long as 72 hours after ingestion. These samples were analyzed for lithium concentration. The area under the lithium serum concentration-versus-time curve was calculated for each phase. RESULTS: The average area under the lithium serum concentration-versus-time curve in the WBI phase was 67% +/- 11% less than that in the control phase (P less than .0005 using a two-tailed Student's t test). The mean serum lithium concentration was significantly decreased (P = .03) within one hour of beginning WBI. CONCLUSION: WBI is an effective treatment for acute ingestion of sustained-release lithium. We recommend it as the decontaminant procedure of choice in this situation.
The golden hours of the myocardial infarction: nonthrombolytic interventions, Emergency care of patients with acute myocardial infarction requires active decision making to use agents that may improve morbidity and mortality. Thrombolysis remains the primary tool to accomplish this goal. Other pharmacologic agents. including lidocaine. nitrates. calcium channel blockers. beta-blockers. and aspirin. have been used acutely in myocardial infarction in the hopes of preventing death and salvaging myocardium. The decision to select one or all of these agents requires a knowledge of the clinical evidence of their efficacy and risk-to-benefit ratios. The clinical studies of the use of these agents acutely in the management of myocardial infarction are reviewed.
Clinical characteristics of angiotensin-converting enzyme inhibitor-induced angioedema, We present the cases of two patients with angiotensin-converting enzyme (ACE) inhibitor-induced angioedema that required intubation for life-threatening airway compromise. This side effect has been previously reported with all ACE inhibitors. but its incidence and potential for a fatal outcome may not be fully appreciated. A review of the literature reveals 227 reports of this reaction with an overall incidence of approximately 0.1% to 0.2%. The etiology is nonimmunogenic and thought to be related to accentuated bradykinin activity. There is no clinical profile that identifies patients at increased risk for this side effect. There are unique clinical characteristics to this idiosyncratic reaction: angioedema may suddenly occur even though the drug has been well tolerated for months or years; symptoms may regress spontaneously while the patient continues the medication. erroneously prompting an alternative diagnosis; the pathology has a special predilection for the tongue. a circumstance that renders orotracheal and nasotracheal intubation difficult; symptoms may progress rapidly despite aggressive medical therapy. necessitating emergency airway procedures; and a rebound phenomenon following successful medical therapy has been described. We recommend intensive medical treatment before angioedema is severe enough to thwart standard methods to ensure a protected airway. Once even minor angioedema is attributed to an ACE inhibitor. an alternative class of antihypertensive medication should be chosen. Individuals with a history of idiopathic angioedema probably should not be given ACE inhibitors.
Hiccups (singultus): review and approach to management, Hiccups are a common. and fortunately usually transient. benign malady. Occasionally. however. hiccups fail to resolve spontaneously. resulting in patient fatigue and incapacitation and the need for the affected individual to seek medical care for resolution of the problem. The approach to the management of these patients consists of the identification and treatment of serious underlying causes of the episode as well as therapeutic interventions to achieve hiccup resolution.
Electronic weaponry--a question of safety [published erratum appears in Ann Emerg Med 1991 Sep;20(9):1031, Electronic weapons represent a new class of weapon available to law enforcement and the lay public. Although these weapons have been available for several years. there is inadequate research to document their safety or efficacy. Two of the most common. the TASER and the stun gun. are reviewed. The electronic weapon was initially and still is approved by the US Consumer Product Safety Commission; its approval was based on theoretical calculations of the physical effects of damped sinusoidal pulses. not on the basis of animal or human studies. These devices are widely available and heavily promoted. despite limited research into their safety or efficiency and despite recent animal studies documenting their potential for lethality.
Bronchial challenge with adenosine causes the release of serum neutrophil chemotactic factor in asthma, In order to investigate the mechanism of adenosine-induced bronchoconstriction in asthma. serum neutrophil chemotactic activity (NCA) was measured in normal individuals and patients with asthma before and 5 min after bronchoprovocation testing with adenosine. Challenge testing was terminated when the FEV1 fell by 20% or a concentration of 10 mg/ml was reached. Participants were separated into three groups: six asthmatics hyperresponsive to adenosine (Group 1). seven asthmatics hyperresponsive to histamine but not adenosine (Group 2). and six normal subjects (Group 3). The mean percentage increase in NCA was 84% for Group 1 (p less than 0.001). 29% for Group 2 (p less than 0.05). and only 13% for Group 3. No significant increase in NCA was observed after histamine challenge in seven individuals with asthma derived from Groups 1 and 2. Four patients from Group 1 were rechallenged after treatment with therapeutic doses of oral theophylline. Theophylline therapy was associated with a significant attenuation of the increase in NCA at the concentration of adenosine which caused a 20% decrease in FEV1 before treatment (18% versus 84%. p less than 0.01). The concentration of adenosine which caused a 20% drop in FEV1 was increased at least twofold for each of the four patients. Analysis of NCA by gel filtration chromatography demonstrated an increase in a high molecular weight neutrophil chemotactic factor in the serum of two Group 1 patients after adenosine challenge. Release of a high molecular weight neutrophil chemotactic factor is consistent with a mast cell source for inflammatory mediators in adenosine-induced bronchoconstriction. The therapeutic effects of theophylline. a potent adenosine antagonist. in asthma may therefore occur in part through the inhibition of this process.
Glucocorticoid receptor characteristics in monocytes of patients with corticosteroid-resistant bronchial asthma, The mechanism of corticosteroid resistance in bronchial asthma has been studied by determining the rank order of potency for different corticosteroids in inhibiting the generation of a 3 kD molecule from peripheral blood monocytes isolated from corticosteroid-sensitive (CS) and corticosteroid-resistant (CR) asthmatic subjects. which augments leukotriene B4 (LTB4) generation by human neutrophils (PMN) stimulated by calcium ionophore. In addition. binding studies with (3H) dexamethasone have been performed to determine the dissociation constant (Kd) and receptor numbers (Ro) in the monocytes of these two groups of subjects. The concentration of corticosteroid producing 50% inhibition (IC50) was 600 nM. 70 nM. and 0.5 nM for hydrocortisone. methylprednisolone. and dexamethasone. respectively. in monocytes from CS individuals. There was only weak inhibition of the generation of enhancing activity by the corticosteroids in the CR asthmatic individuals. The dexamethasone Kd was 2.45 +/- 0.58 nM (mean +/- SEM. n = 6) in the CS group and 1.6 +/- 0.35 nM (mean +/- SEM. n = 6) in the CR group of patients (p = 0.14). The Ro in the CS group was 3.605 +/- 984 binding sites per nucleus (mean +/- SEM. n = 6) and 4.757 +/- 692 binding sites per nucleus (mean +/- SEM. n = 6) in the CR group (p = 0.23). These findings indicate that corticosteroid resistance in bronchial asthma cannot be explained by abnormalities in corticosteroid receptor characteristics.
Effect of canister temperature on performance of metered-dose inhalers, We studied the effects of ambient temperatures between 0 degrees C and 42 degrees C in an anatomically realistic model of the upper airway ventilated with warm. moist air. Metered-dose inhalers of metaproterenol maintained at the experimental temperatures were activated in the mouth of the model at the onset of inspiration. We measured the amount of drug released and that which was able to penetrate the model at each temperature. At low canister temperatures considerably more drug was released than at higher temperatures. However. at higher temperatures much more drug was able to traverse the upper airway. raising lower airway deposition from 17.7% at 4 degrees C to 32.2% at 37 degrees C. Aerosol size became progressively smaller as temperature was raised: mass median diameter (MMD) was 3.65 microns at 0 degrees C and 2.50 microns at 37 degrees C. These findings are most likely due to greater canister vapor pressures at higher temperatures. We conclude that patients should probably be instructed to prewarm metered-dose inhaler canisters prior to use when canister temperatures are low.
A controlled trial of colchicine to reduce the elastase load in the lungs of ex-cigarette smokers with chronic obstructive pulmonary disease, A great deal of experimental evidence suggests that emphysema in smokers is caused by the action of neutrophil elastase on lung elastin. In order to test this hypothesis. it is necessary to find a drug that reduces the load of neutrophil elastase in the lungs of patients with emphysema. In a previous study we treated smokers with emphysema with colchicine. a drug that prevents neutrophil elastase secretion. to determine if it would reduce the elastase burden in the lungs. Colchicine was unable to reduce the elastase load while the stimulus of smoking continued. In this study we treated ex-smokers with emphysema to determine if colchicine could reduce the elastase burden in the lungs. The objective of the study was to determine if colchicine can reduce the elastase load and putative indicators of elastase load in the lungs of patients with chronic obstructive pulmonary disease. The study was a prospective. double-blind. randomized. and placebo-controlled clinical trial. The subjects were outpatients seeking treatment at the University of Texas Health Center at Tyler. We studied 16 ex-cigarette smokers between 45 and 75 yr of age with lung disease defined by FEV1 less than 70% of predicted but greater than 1.2 L whose airflow obstruction was less than 20% reversible with bronchodilators. Colchicine or placebo was taken by mouth in disguised capsules. 0.6 mg three times per day. Volunteers were placed on a baseline bronchodilator regimen of theodur by mouth and albuterol by inhalation. Blood. urine. and bronchoalveolar lavage fluids were obtained after 1 wk of stabilization.
Effect of dexamethasone on pulmonary inflammation and pulmonary function of ventilator-dependent infants with bronchopulmonary dysplasia, Seventeen ventilator-dependent premature infants with bronchopulmonary dysplasia (BPD) were enrolled in a double-blind. placebo-controlled study to determine the effects of 3 days of intravenously administered dexamethasone (0.5 mg/kg/day) on pulmonary function. pulmonary inflammation. and the requirement for respiratory support (FIO2. ventilator peak pressure [PP]. and respiratory rate [RR]). Assessment of pulmonary function included measurement of FVC. flow at 25% vital capacity (V25). and static compliance of the respiratory system (Crs). whereas pulmonary inflammation was assessed by the neutrophil count. ratio of elastase/2 x alpha-1-antitrypsin. and the concentrations of albumin and fibronectin in the tracheobronchial lavage (TBL) fluid. After 3 days of placebo treatment there were no significant changes in any of the measured parameters. In contrast. the dexamethasone-treated group demonstrated a significant decrease in respiratory support (FIO2: 50 versus 36%; PP: 21 versus 16 cm H2O; RR: 22 versus 14 breaths/min) and improved pulmonary function (Crs: 0.63 versus 0.85 ml/cm H2O/kg; V25: 23 versus 68 ml/s/kg). In addition. pulmonary inflammation was suppressed in the dexamethasone-treated group (neutrophils: 23 versus 11 x 10(4)/mg albumin: elastase/2 x alpha-1-antitrypsin: 0.24 versus 0.10; albumin: 7.1 versus 3.5 mg/dl; fibronectin: 33 versus 17 micrograms/mg albumin). We conclude that short-term treatment with dexamethasone improves pulmonary function and suppresses pulmonary inflammation as well as decreasing the respiratory support required by ventilator-dependent premature infants with BPD.
Complement is activated in the upper respiratory tract during influenza virus infection, The purpose of this pilot study was to determine whether complement is activated in the upper respiratory tract during experimental influenza virus infection in human volunteers. Seven subjects were challenged with influenza A/Bethesda/1/85 (H3N2). and four subjects received placebo. C3a and C5a concentrations were measured by radioimmunoassay in nasal lavage fluids before challenge and for 8 days after challenge. A significant increase (p less than 0.05) in C3a and C5a concentrations was demonstrated in lavage fluids from subjects who developed influenza illness as compared with uninfected control subjects and infected subjects who remained asymptomatic. Maximal levels of C3a and C5a were detected during the recovery phase of illness. These results suggest that complement is activated in the airway in response to influenza illness.
Differential activation of mixed venous and arterial neutrophils in patients with sepsis syndrome and acute lung injury, Neutrophil (PMN) functions. such as production of toxic oxygen (O2) metabolites. adherence. and chemotactic properties. are modified during local tissue inflammation and sepsis. We hypothesized that PMN would be primed during their transit through injured tissue beds. which in turn can lead to modulation or retention of the primed PMN by downstream tissues like the lungs. We tested this hypothesis by measuring the transpulmonary gradient of hydrogen peroxide (H2O2) production by zymosan-activated PMN. We examined the mixed venous to arterial difference in H2O2(delta H2O2) produced by zymosan-activated PMN in septic patients without lung infiltrates. patients with lung injury. and a control group of patients undergoing elective surgery or coronary catheterization. Septic patients had higher mixed venous H2O2/10(6) PMN. whereas lung injury patients had higher arterial H2O2/10(6) PMN. The control group had the same H2O2/10(6) PMN in mixed venous and arterial blood. The delta H2O2 in septic. lung injury. and control groups were 0.35 +/- 0.22. -0.31 +/- 0.48. and -0.01 +/- 0.04 nmol H2O2/10(6) PMN. respectively. The mixed venous to arterial H2O2 gradient distinguished septic patients from the control and lung injury patients (p less than 0.05). Our results are consistent with the hypothesis that in septic patients PMN are primed in the periphery and downregulated or sequestered in the lung. and in lung injury patients PMN are primed in the lung and sequestered in the periphery. Alternatively. neutrophil-endothelial interactions may downregulate toxic O2 metabolite production by PMN during their transit through microvascular beds.
Amiodarone-induced pulmonary inflammation. Correlation with drug dose and lung levels of drug, metabolite, and phospholipid, To investigate the hypotheses that amiodarone-induced pulmonary inflammation may be related to direct drug toxicity. groups of 10 or more Wistar rats were fed amiodarone by gavage at concentrations of 175. 300. 400. and 500 mg/kg/day. or vehicle alone. After 6 wk of drug feeding. the rats were examined for histologic and cellular evidence of pulmonary inflammation. In addition. the amounts of amiodarone. the major metabolite of amiodarone N-desethylamiodarone (N-des). and phospholipid in the lungs were determined. We found that rats fed 175 mg/kg of amiodarone were essentially no different from control animals. The 175 mg/kg group had normal lung histologies. no change in lavage cell counts or differential counts. and very little amiodarone. N-des. or phospholipid in the lungs. In contrast. the three high-dose groups had abnormal lung histologies along with increases in lavage cell counts and change in differential counts. There were also significant increases in the amounts of amiodarone. N-des. and phospholipid in the lung. We conclude that the development of amiodarone-induced pulmonary inflammation is dose dependent. and that there is a direct correlation between the amount of amiodarone. N-des. and phospholipid in the lung with the development of inflammation. It therefore appears that the drug is directly toxic to lung tissue.
Histopathologic pulmonary changes from mechanical ventilation at high peak airway pressures, We investigated the histopathologic pulmonary changes induced by mechanical pulmonary ventilation (MV) with a high peak airway pressure and a large tidal volume in healthy baby pigs. Eleven animals were mechanically ventilated at a peak inspiratory pressure (PIP) of 40 cm H2O. a respiratory rate (RR) of 20 min-1. a positive end-expiratory pressure (PEEP) of 3 to 5 cm H2O. and an FIO2 of 0.4. High airway pressure MV was terminated in 22 +/- 11 h because of severe hypoxemia in the animals. Five of the baby pigs were killed for gross and light microscope studies. The pulmonary changes consisted of alveolar hemorrhage. alveolar neutrophil infiltration. alveolar macrophage and type II pneumocyte proliferation. interstitial congestion and thickening. interstitial lymphocyte infiltration. emphysematous change. and hyaline membrane formation. Those lesions were similar to that seen in the early stage of the adult respiratory distress syndrome (ARDS). The remaining six animals were treated for 3 to 6 days with conventional respiratory care with appropriate ventilator settings. Prominent organized alveolar exudate in addition to lesions was also found in the five animals. These findings were indistinguishable from the clinical late stage of ARDS. Six control animals were mechanically ventilated at a PIP of less than 18 cm H2O. a RR of 20 min-1. a PEEP of 3 to 5 cm H2O. and an FIO2 of 0.4 for 48 h. They showed no notable changes in lung functions and histopathologic findings. Aggressive MV with a high PIP is often applied to patients with respiratory distress to attain adequate pulmonary gas exchange.
The increased responsiveness to inhaled methacholine in asthma: combination of causative factors, In asthma the dose-response curve to inhaled methacholine (MCh) is shifted leftwards and shows an increased slope and maximum. Two factors might contribute to the different form and position of this curve: (1) mediator-induced airway muscle hypersensitivity and (2) thickening of the airway wall. We attempted to estimate the effect of a combination of these two factors on the increase in airway resistance of a single isolated human airway to increasing concentrations of MCh. The result suggests that mediator-induced hypersensitivity to cholinergic stimuli may explain a small part of the leftward shift of the asthmatic dose-response curve to MCh. especially at lower levels of bronchoconstriction. and that increased thickness of the airway wall may be more important for the increased slope and maximum of the asthmatic dose-response curve.
Nasal continuous positive airway pressure facilitates respiratory muscle function during sleep in severe chronic obstructive pulmonary disease, Patients with chronic respiratory insufficiency due to severe chronic obstructive pulmonary disease (COPD) and presumed respiratory muscle fatigue may benefit from therapeutic maneuvers aimed at reducing the magnitude of inspiratory muscle effort. Recent work has demonstrated that continuous positive airway pressure (CPAP) can significantly reduce inspiratory effort and work of breathing in COPD patients with acute respiratory failure. Accordingly it was reasoned that prolonged CPAP administration may similarly reduce the work of breathing in stable COPD patients with chronic respiratory insufficiency. thereby allowing recovery from respiratory muscle fatigue. The purpose of this study was to determine the feasibility of employing nasal CPAP during sleep as a means of implementing this approach to reducing inspiratory muscle effort in such patients. Standard polysomnographic parameters were recorded during nocturnal administration of nasal CPAP in eight stable patients with severe COPD (FEV1 = 26.7 +/- 3.9% of predicted). Esophageal pressure. diaphragmatic (EMGdi) and parasternal intercostal (EMGic) electromyographic activity. arterial oxyhemoglobin saturation (SaO2). and transcutaneous PCO2 (PtcCO2) were also measured. Breathing pattern was determined by respiratory inductive plethysmography. In each patient an optimum level of nasal CPAP could be determined that produced consistent reductions in indices of inspiratory muscle effort without changing tidal volume or breathing frequency. Highly significant reductions in the tidal excursions of esophageal pressure and the pressure-time integral for the inspiratory muscles occurred at the optimum CPAP level in all patients. EMGdi and EMGic were similarly reduced. SaO2 and PtcCO2 were unaffected by CPAP. These results indicate that nasal CPAP can effectively reduce inspiratory muscle effort during sleep in patients with severe COPD.
The effect of positive reinforcement on hourly compliance in nasal continuous positive airway pressure users with obstructive sleep apnea, Previous reports have described compliance with nasal continuous positive airway pressure (nCPAP) for the treatment of obstructive sleep apnea (OSA) only in terms of the number of patients able to use it beyond their initial trial night or those continuing after some home use. Because of a possible difference between the level of compliance (mean number of hours of use per 24 h) needed for symptomatic relief of OSA versus cardiovascular improvement. the level of hourly compliance in chronic nCPAP users may be important. The first part of this study prospectively examines compliance in a stable population of OSA patients already using nCPAP for 6 months to 2 yr. The second part is a prospective randomized. crossover study examining the effect of weekly (three times) then monthly (twice) positive reinforcement on hourly compliance of new nCPAP users for 3 months versus no reinforcement for 3 months. Positive reinforcement consisted of telephone discussions with the patients about the severity or complications of OSA. benefits of nCPAP. and suggestions about minimizing side effects. Using self-assessment scales. each patient reported the perceived level of improvement from the untreated to the treated condition and the prevalence and severity of side effects from the nCPAP therapy. The level of compliance in stable. chronic nCPAP users with OSA was 6.1 +/- 2.2 h/24 h (n = 9). For the new nCPAP users during the nonreinforced period. the mean compliance was 6.0 +/- 2.8 h/24 h; that during the reinforcement period was 6.0 +/- 2.7 h/24 h (NS). There was no significant correlation between perceived improvement in OSA symptoms or between the perceived side effects of nCPAP versus hourly compliance.
Uvulopalatopharyngoplasty in obstructive apnea. Value of preoperative localization of site of upper airway narrowing during sleep, We hypothesized that those obstructive sleep apnea (OSA) patients with upper airway collapse during sleep within the transpalatal airway would have a more favorable response to uvulopalatopharyngoplasty (UPP) than those patients with obstruction within the hypopharyngeal airway. We tested this hypothesis in seven OSA patients with transpalatal and seven with hypopharyngeal obstruction undergoing UPP. Preoperatively the apnea/hypopnea index (AHI) was different between palatal and hypopharyngeal obstructors. 37.8 +/- 6.0 (+/- SEM) and 63.9 +/- 6.3. respectively (p less than 0.05). but the apnea-associated arterial oxygen desaturation and the lowest sleep saturation level were not different between the two groups. Postoperatively the AHI was 17.6 +/- 7.2 in the palatal obstructors and 40.3 +/- 15.6 in the hypopharyngeal obstructors (both p less than 0.05 from preoperative AHI). The palatal obstructors had a significant decrease in the percentage of sleep time spent apneic and the hypopharyngeal obstructors had a significant decrease in the hypopnea. but not apnea. time following surgery. The palatal obstructors had a significantly higher postoperative arterial oxygen saturation than the hypopharyngeal obstructors. Two hypopharyngeal obstructors worsened postoperatively. In addition we found that regardless of the site of the obstruction preoperatively. all obstructions occurred at the level of the palate postoperatively. We conclude that patients with preoperative transpalatal obstruction had diminution in obstructive apneas and those with hypopharyngeal obstruction had diminution in hypopneas but not apneas. Oxygenation was better postoperatively in the palatal obstructors. and none worsened postoperatively. These results suggest that identification of the site of upper airway obstruction in OSA may be beneficial.
Validity of diurnal sleep recording in the diagnosis of sleep apnea syndrome, Two polysomnographic studies were performed in 35 subjects who had a clinical suspicion of sleep apnea syndrome: one study was done at night (N) (from 10:00 p.m. to 8:00 a.m.) and the other during the day (D) starting after lunch (from noon to 5:00 p.m.). N and D sleep studies were performed in random order at a minimal interval of 36 h. No treatment (drug. CPAP) was initiated between the two studies. Both studies included the recording of sleep stages (EEG. EOG. EMG). nasal and mouth flows. thoracoabdominal movements. electrocardiogram. and SaO2 (ear oximetry). D sleep was present in all but one subject. As expected. the total sleep time (TST) was significantly shorter during the D than during the N study (2.6 +/- 0.2 and 6.2 +/- 0.2 h. respectively. mean +/- SEM. p less than 0.001. Wilcoxon's signed-rank test). Stages III-IV and REM were significantly less represented during the D (13.1 +/- 2.4 and 7.7 +/- 1.3%. respectively) than during the N study (18.5 +/- 1.7 and 15.3 +/- 0.8%. p less than or equal to 0.005). From the results of the N study. the diagnosis of sleep apnea syndrome (apnea index greater than 5 and/or apnea + hypopnea index greater than 10) was made in 25 patients. and it was confirmed by the same criteria in 22 by the D sleep recording. There was a significant correlation between the N and D values for these indices (r greater than or equal to 0.9. p less than 0.0001).
Altitude and allergy to house-dust mites. A paradigm of the influence of environmental exposure on allergic sensitization, To further investigate the possibility of a cause and effect relationship between exposure to house-dust mite (HDM) allergens and respiratory disease associated with dust mite sensitivity. we compared schoolchildren living in the Alps. where exposure to HDM is low. with those living at sea level. where it is high. The study included 933 schoolchildren from the fourth and fifth grades. The protocol included the standardized 1978 American Thoracic Society (ATS) questionnaire for children. skin testing using common aero-allergens and controls. and antigenic measurements of dust samples from mattresses (Group I antigen). The prevalence of asthma with positive skin test to HDM and the overall prevalence of positive skin test to HDM were significantly lower in mountain schoolchildren. The mean geometric HDM antigenic level in mattresses was much lower in the Alps (0.36 micrograms/g dust) than at sea level (15.8 micrograms/g dust). In contrast. the prevalence of hay fever and positive skin test to grass pollens as well as the overall prevalence of positive skin tests to grass pollens were significantly higher in the Alps. These data illustrate a striking relationship between exposure to environmental allergens and atopic sensitization.
Prolonged protection against methacholine-induced bronchoconstriction by the inhaled beta 2-agonist formoterol, Formoterol fumarate is a new. high-affinity. beta 2-adrenergic receptor agonist that causes bronchodilation for at least 12 h. The purpose of this study was to compare the magnitude and duration of the effect of inhalation of formoterol (12 and 24 micrograms). albuterol (200 micrograms). and placebo in terms of protection against methacholine-induced bronchoconstriction. The 16 stable adult asthmatic subjects were studied on four separate study days. On each study day the subjects inhaled 2 puffs of the study medication. and methacholine tests were performed at 30 min and 4. 8. and 12 h later. Results were expressed as the provocative concentration of methacholine required to cause a 20% fall in FEV1 (PC20). At 30 min. 12 and 24 micrograms formoterol caused a mean 14- to 20-fold decrease in responsiveness. and albuterol a 12-fold decrease. However. albuterol had no significant protective effect at 4 h or thereafter. whereas there was still an 8-fold decrease in responsiveness for 24 micrograms formoterol and a 6-fold decrease for 12 micrograms formoterol at 12 h. This study has shown that both doses of formoterol were still actively protective against induced bronchoconstriction 12 h after inhalation. with minimal side effects. This suggests that formoterol may prove to be a very useful bronchodilator for the treatment of patients with asthma who have significant airway hyperresponsiveness or nocturnal symptoms and who require inhaled beta 2-agonists at least twice daily.
Pre-existing fractures and bone mass predict vertebral fracture incidence in women, OBJECTIVE: To determine the independent contributions of bone mass and existing fractures as predictors of the risk for new vertebral fractures. SUBJECTS: Postmenopausal Japanese-American women. MEASUREMENTS: Baseline measurements of the distal radius. the proximal radius. and the calcaneus were obtained in 1981 using single-photon absorptiometry. Measurements of the lumbar spine were obtained in 1984 using dual-photon absorptiometry. Prevalent vertebral fractures were identified using dimensions measured on lateral radiographs; vertebral height values more than 3 SD below vertebra-specific means were considered to indicate fracture. Statistical models were used to evaluate the utility of bone mass and existing (prevalent) fractures to predict the risk for new fractures during an average follow-up of 4.7 years. MAIN RESULTS: Differences of 2 SD in bone mass were associated with fourfold to sixfold increases in the risk for new vertebral fractures. A single fracture at the baseline examination increased the risk for new vertebral fractures fivefold. Presence of two or more fractures at baseline increased the risk 12-fold. A combination of low bone mass (below the 33d percentile) and the presence of two or more prevalent fractures increased the risk 75-fold. relative to women with the highest bone mass (above the 67th percentile) and no prevalent fractures. Stature. body mass index. arm span. and spinal conditions such as scoliosis. osteoarthritis. and sacroiliitis did not predict fracture incidence (P greater than 0.05). Weight was marginally predictive (P = 0.04) of fracture incidence but became nonpredictive after adjusting for bone mass (P greater than or equal to 0.05). CONCLUSIONS: Both bone mass and prevalent vertebral fractures are powerful predictors of the risk for new vertebral fractures. Combining information about bone mass and prevalent fracture appears to be better for predicting new fractures than either variable alone. Physicians can use these risk factors to identify patients at greatest risk for new fractures.
In vitro ciliogenesis in respiratory epithelium of cystic fibrosis patients, Nasal epithelial cells. dissociated from nasal polyps of three cystic fibrosis patients. were cultured on collagen gels until all cilia were lost. and then the cells were released in suspension as cell sheaths to form aggregates and vesicles. Cilia reappeared after 1 week. The number of ciliated cells increased progressively and within 1 month large areas of the aggregates were ciliated. These newly formed cilia were ultrastructurally normal. The ciliary activity as well coordinated and resulted in continuous movements of the aggregates in the culture medium. In the supranuclear cytoplasm the different ciliogenetic precursors were found: fibrogranular aggregates with occasionally small tubules. deuterosomes with procentrioles. kinetosomes. basal bodies. and short cilia. Initial stages of ciliary shaft formation. such as elevation of the apical membrane above the basal bodies without axonemal ultrastructure. could be well documented. The results indicate that in cystic fibrosis. ciliogenesis and the resulting ciliary activity in vitro are indistinguishable from those seen in cells from control tissue.
Pharmacokinetics and antibacterial efficacy of cefpirome (HR 810) in experimental Escherichia coli and Haemophilus influenzae type b meningitis, Cefpirome (HR 810) is a new cephalosporin related to cefotaxime that has potent bactericidal activity against a broad spectrum of gram-negative and gram-positive organisms. The pharmacokinetics and bacteriological efficacy of cefpirome administered as a single intravenous dose were assessed in rabbits with experimental Haemophilus influenzae type b and Escherichia coli K1 meningitis. The mean penetrations into the cerebrospinal fluid (CSF) in relation to the amount of drug in serum of animals infected with H. influenzae and E. coli were 25 and 54%. respectively. The median CSF bactericidal titers were 1:128 against both organisms at 1 h of uninfected animals. the mean penetration was 4.5%. There was a significant reduction in the concentrations of bacteria in CSFs of both groups of animals treated with cefpirome compared with that in untreated groups. Mortality was also significantly lower in treated animals than it was in untreated animals. Intravenous administration of dexamethasone before the cefpirome dose did not compromise penetration. bactericidal titers. or antibacterial activity of cefpirome in CSF.
Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine, The efficacy of dapsone alone or combined with pyrimethamine against Toxoplasma gondii was investigated experimentally. For in vitro studies. a sensitive immunoassay was used for assessment of Toxoplasma growth in tissue cultures; dapsone was found to have a significant inhibitory effect at a concentration of 0.5 micrograms/ml in the cultures. and the 50% inhibitory concentration was estimated to be 0.55 micrograms/ml. When pyrimethamine and dapsone were combined. an important synergistic effect which was associated with morphological alterations of the parasites was observed. In vivo studies were performed in a murine model of acute toxoplasmosis in which a tissue culture method was used to estimate the parasite burden in the blood. lungs. and brains of infected mice. Dapsone alone. which was administered at 100 mg/kg/day for 10 days from day 1 after infection. was unable to prevent parasite dissemination and only delayed the time to death of treated mice compared with the time of death of untreated controls. When dapsone and pyrimethamine (18.5 mg/kg/day) were administered in combination from day 4 after infection. parasites were cleared from blood and organs within 6 days. but relapses were observed 15 days after the cessation of therapy. When treatment was started at day 1 after infection. 100% of mice survived and relapses were not observed. suggesting a good efficacy of this combination for preventive therapy.
Association with prior fluoroquinolone therapy of widespread ciprofloxacin resistance among gram-negative isolates in a Veterans Affairs medical center, We performed a case-control study of risk factors for the acquisition of ciprofloxacin-resistant gram-negative isolates in a Veterans Affairs medical center. Sixty-five patients with resistant isolates and 50 control patients were identified. Prior fluoroquinolone use was significantly more frequent among patients with resistant isolates than it was among controls (58 versus 20%; P = 0.0001). The association with prior quinolone use was stronger in the long-term-care division (81 versus 32%; P = 0.0005) than it was in the acute-care division (29 versus 0%; P = 0.015). On multivariate analysis. prior receipt of a fluoroquinolone was the single most significant risk factor for isolation of a ciprofloxacin-resistant gram-negative organism (P = 0.0001).
8-Aminoquinolines from Walter Reed Army Institute for Research for treatment and prophylaxis of Pneumocystis pneumonia in rat models, Three 8-aminoquinolines from the Walter Reed Army Institute for Research (WRAIR). WR6026. WR238605. and WR242511. strongly inhibited Pneumocystis carinii growth in vitro at 1 microgram/ml. This activity was similar to that of primaquine. In rat therapy models. the WRAIR compounds affected Pneumocystis pneumonia at doses as low as 0.25 mg/kg (WR242511) or 0.5 mg/kg (WR6026 and WR238605). At these doses. primaquine alone was ineffective as therapy. In a rat prophylaxis model. all three WRAIR 8-aminoquinolines were extremely effective at daily doses of 0.57 mg/kg. showing activity greater than that of primaquine at this dosage and comparable to that of trimethoprim-sulfamethoxazole at 50/250 mg/kg.
Efficacy of halofuginone lactate against Cryptosporidium parvum in calves, The efficacy of halofuginone lactate against natural Cryptosporidium parvum infection in 150 neonatal market calves of a mixed Belgian breed was tested. The drug was administered orally in the milk replacer over a period of 3 to 14 days at doses ranging from 30 to 500 micrograms/kg of body weight. Over a period of 4 weeks. the animals were examined twice a week for shedding of C. parvum oocysts and were scored semiquantitatively for diarrhea. Weight gain was assessed after 2 and 4 weeks. Subclinical infections by rota-. corona-. and bovine picobirnaviruses were equally distributed in the different groups. In total. 93% of the unmedicated calves eliminated C. parvum within 10 days after arrival at the rearing unit and 62% of them showed diarrhea. Immediately after treatment with halofuginone was started. no more signs of Cryptosporidium-associated diarrhea were established. From the level of 60 micrograms/kg on. oocysts were no longer detected in 98% of animals 5 to 6 days after the start of treatment. Animals remained negative for at least 7 days after withdrawal of the drug. From 7 to 10 days after withdrawal. some animals excreted oocysts again. The number of shedders was closely linked with increasing doses of the drug. which indicates that lower doses do not interrupt infection completely and allow development of immunity. In this respect. a dose of 60 to 125 micrograms/kg over a period of 7 days seems most appropriate in practice. Toxic side effects were noticed only at 500 micrograms/kg.
Differing activities of quinolones against ciprofloxacin-susceptible and ciprofloxacin-resistant, methicillin-resistant Staphylococcus aureus, The in vitro activities of nine quinolones (seven fluoroquinolones. nalidixic acid. and acrosoxacin) against methicillin-resistant Staphylococcus aureus (MRSA) were compared with those of the glycopeptides teicoplanin and vancomycin. MICs against 160 strains of ciprofloxacin-susceptible (MIC. less than 2.0 micrograms/ml) MRSA and 40 strains of ciprofloxacin-resistant (MIC. greater than or equal to 2.0 micrograms/ml) MRSA were determined. The following MICs for 50% of the strains tested (in micrograms per milliliter) were obtained for ciprofloxacin-susceptible and -resistant strains. respectively: tosufloxacin. 0.06 and 2.0; ofloxacin. 0.25 and 16; ciprofloxacin. 0.5 and 16; pefloxacin. 0.5 and 32; acrosoxacin. 1.0 and greater than 256; enoxacin. 1.0 and 64; fleroxacin. 1.0 and 32; norfloxacin. 2.0 and 64; nalidixic acid. 64 and 512; teicoplanin. 1.0 and 1.0; vancomycin. 2.0 and 2.0. In mutation rate studies using a range of antibiotic concentrations to reflect those achievable in vivo. resistant mutants grew only on plates containing nalidixic acid (rate of mutation to resistance. 10(-7) to 10(-8) and on plates containing low concentrations of ciprofloxacin. enoxacin. and norfloxacin (rate of mutation to resistance. 10(-8) to 10(-9). In time-kill studies. 99.9% killing was found within 8 h for all of the quinolones tested (norfloxacin and nalidixic acid were not tested). Teicoplanin and vancomycin were less rapidly bactericidal. For the clinical isolates of ciprofloxacin-resistant MRSA. different levels and patterns of quinolone resistance were found. Generally. cross-resistance among the fluoroquinolones was complete; however. incomplete cross-resistance did occur with the nonfluorinated quinolone acrosoxacin.
Uptake of sparfloxacin and norfloxacin by clinical isolates of Staphylococcus aureus, The amount of sparfloxacin uptake was higher than that of norfloxacin uptake in Staphylococcus aureus. Moreover. energy-dependent reduction in quinolone uptake. probably due to active efflux of the quinolone. was observed. The reduction in quinolone uptake appeared to be associated with quinolone resistance in S. aureus.
Prolonged malaria prophylaxis with chloroquine and proguanil (chloroguanide) in a nonimmune resident population of an endemic area with a high prevalence of chloroquine resistance, One hundred thirty nonimmune subjects living in Yaounde. Cameroon. completed an 18-month prospective study on the efficacy and safety of weekly chloroquine and daily proguanil (chloroguanide) (Ch-P) in malaria prevention. A total of 9 of 78 Ch-P-treated subjects and 26 of 52 subjects who received no prophylaxis contracted Plasmodium falciparum infection during this period (P less than 0.00005). These two groups were comparable for demographic parameters and degree of exposure. Clinical manifestations were of similar severities in the two groups. but parasite counts were significantly higher in the subjects who received no prophylaxis (P less than 0.00005). Side effects of prophylaxis were frequent (31%). minor. and related to chloroquine. and they usually resolved within 4 to 6 weeks. Prolonged administration of Ch-P is safe and effectively prevents P. falciparum malaria in an endemic area with a high prevalence of chloroquine resistance.
In vitro activities of acridone alkaloids against Pneumocystis carinii, Acridone alkaloids isolated from plants of the family Rutaceae have antiplasmodial activity in rodent models of malaria. Because a variety of antimalarial agents have also been shown to have activity against Pneumocystis carinii. we tested six of these alkaloids in an established culture model for P. carinii. Atalaphillinine and glycobismine A inhibited growth of cultured P. carinii at concentrations of 2.7 and 1.7 microM. respectively. This potency of effect is similar to that of chloroquine (3 microM) but somewhat less than that of primaquine (0.4 microM). which was previously evaluated in the same system.
Magnitude and duration of UV-B-induced tolerance, Using repeated minimal erythema dose (MED) testing. we investigated the magnitude and duration of tolerance to short-wave UV radiation in the B range (UV-B) in 37 patients with psoriasis who received at least 12 UV-B phototherapy treatments. Without substantial erythema developing. half of the patients received UV-B doses in excess of 13 times their pretreatment MED dose and a fourth received UV-B doses in excess of 28 times their pretreatment MED dose. On average. tolerance faded to about half that present at the last UV-B treatment in 3 weeks. Six weeks after therapy was stopped. most posttreatment MEDs were less than twice the pretreatment MED. The magnitude of tolerance achieved and the rate of decay did not vary with skin type. Our findings indicate that repeated exposures to suberythemal or mildly erythematous doses of UV-B can induce exceptional degrees of tolerance to UV-B radiation. The duration of this increase in tolerance is. however. short.
Tretinoin accelerates healing after trichloroacetic acid chemical peel, We conducted a double-blind. placebo-controlled. prospective. randomized study to assess the effects of tretinoin pretreatment on healing after trichloroacetic acid (TCA) chemical peel. Sixteen male patients (mean age. 67 years) with actinically damaged skin were treated daily with 0.1% tretinoin and placebo creams to the left and right halves of the face and the left and right forearms and hands. respectively. for 14 days prior to the 35% TCA peel. We subjectively noted that during the peel. "frosting" was more pronounced and uniform and occurred earlier in tretinoin-pretreated skin in 94% of the patients. Healed skin was measured planimetrically. and the healed area was determined with point stereology. Regardless of pretreatment. the face healed twice as fast as the forearm or hand. In all regions. the mean area healed was significantly greater in skin that had been pretreated with tretinoin. The differences between tretinoin and placebo. respectively. in healed skin were maximal after 5 days for the face (68% vs 52%). after 11 days for the forearms (72% vs 24%). and after 9 days for the hands (61% vs 29%). After 7 days. 75% of the tretinoin-pretreated hemifaces were completely healed. as opposed to 31% of the placebo-pretreated hemifaces. By visual inspection. we could not appreciate a cosmetic difference between tretinoin- and placebo-pretreated skin 2 weeks and 3 months after the TCA peel. We conclude that 0.1% tretinoin pretreatment for 2 weeks prior to the TCA peel will significantly speed healing. which may result in greater patient satisfaction. Patients presently being treated with tretinoin who later undergo a TCA peel might be expected to have similar results.
Pachyonychia congenita tarda. A late-onset form of pachyonychia congenita, Pachyonychia congenita is an autosomal dominant disorder that usually develops in early infancy. We have observed five patients with the onset of the typical subungual hyperkeratoses of pachyonychia during the teenage years. Leukokeratosis and keratoderma of the palms and soles were associated. The family history of three of the patients suggests that pachyonychia congenita tarda is also inherited in an autosomal dominant manner.
Preschool vision screening, Although a good case for preschool screening for vision defects can be made there is very little evidence that existing programmes are effective in practice. A comparative trial of three different methods of preschool vision screening is described. Some 7000 children initially aged 5 months (younger cohorts) and 30 months (older cohorts) in three matched areas entered the trial during 1987. During 18 months of follow up new visual and ocular defects among these children were ascertained through ophthalmology outpatients and from optician records. Screening at 35 months by an orthoptist based in the community is superior to conventional health visitor surveillance at 30 months and to an agreed programme of primary care screening for squint at 30-36 months as judged by screening sensitivity (100% v 50% v 50%) and the incidence of treated target conditions (17 v 3 v 5 per 1000 person years). A notable feature in the area served by the orthoptist is that 13 children received treatment for straight eyed visual acuity loss from among 1000 children whereas there were no such cases among 2500 in the comparison areas. In the younger cohorts (that is. screening at age 5-9 months) all three programmes showed equally poor results. only one of the eight treated target conditions arising from all 3500 younger children being screen detected.
Macromolecular absorption and cows' milk allergy, The absorption of macromolecules was analysed by measuring serum concentrations of human alpha-lactalbumin after feeding human milk. using a competitive radioimmunoassay. The control group consisted of 78 children fed by cows' milk formula; concentrations of alpha-lactalbumin in their serum were low. The median concentrations in the different age groups varied between 7-13 micrograms alpha-lactalbumin/1 serum/1 human milk/kg body weight. Twenty-eight children with cows' milk allergy were studied before introduction of a diet free of cows' milk. Nineteen had gastrointestinal and nine skin symptoms. High serum alpha-lactalbumin concentrations were found. Only two children had alpha-lactalbumin concentrations below 100 micrograms alpha-lactalbumin/1 serum/1 human milk/kg body weight. Altogether 76 children on a diet free of cows' milk were studied directly after a cows' milk challenge; 26 developed symptoms. They had significantly higher serum alpha-lactalbumin values than the 50 children with no symptoms upon challenge. Eighteen of the 26 children with symptoms had serum alpha-lactalbumin concentrations of more than 100 micrograms/1 serum/1 human milk/kg body weight in contrast with two of the 50 with no symptoms. Total serum IgE antibodies were analysed in 43 children. No correlation was found between concentrations of serum IgE and serum alpha-lactalbumin in the children with cows' milk allergy.
Ureteric sludge syndrome, Four cases of a form of obstructive uropathy previously unreported in children are described. All presented with oligoanuria and either flank pain or fluid retention and had evidence of crystalline sludge in their lower ureters. Three cases had an underlying crystalluria.
Pain and measles, mumps, and rubella vaccination, Seventy-seven children (mean age 44.2 months) were entered in a randomised double blind study to find out if two commonly used measles. mumps. and rubella (MMR) vaccines (Pluserix and MMR II) caused pain on injection. Pain was judged by the amount of crying. Infants given MMR II were 2.31 times more likely to cry than those given Pluserix.
Indwelling cannula for insulin administration in diabetes mellitus, Experience with an indwelling subcutaneous Teflon cannula for insulin delivery to 10 children with diabetes mellitus is described. There were no significant complications during a one year trial period. The device may particularly benefit children during the early phase after diagnosis and for those with true needle phobia.
Non-invasive assessment of pulmonary arterial pressure in healthy neonates, Doppler echocardiograms were carried out on 51 healthy babies three times during the first 72 hours of life to estimate pulmonary arterial systolic pressure by measuring regurgitant tricuspid jet velocity and applying the Bernoulli equation. Tricuspid regurgitation was detected at some stage in all preterm babies and most of those born at full term. Pulmonary arterial pressure could be measured from peak regurgitant velocity in babies with pansystolic regurgitation. The incidence of pansystolic regurgitation among 34 term babies at 0-12. 13-36. and 32-72 hours of age was 22. 27. and 19%. and in 17 preterm babies (within the same age groups) was 53. 50. and 31%. respectively. Estimates of pulmonary artery pressure in the term babies were in accord with known catheter values. Pressure fell rapidly during the first day in all 51 babies. The ratio of pulmonary:systemic arterial pressure was comparable between the two groups throughout. Ductal flow patterns mirrored the fall in this ratio with age--bidirectional flow was associated with a ratio of between 0.88:1 and 1.22:1 and high velocity left to right flow with a ratio of between 0.49:1 and 0.66:1. Both these techniques are noninvasive ways of assessing neonatal pulmonary arterial pressure.
Fatal persistent pulmonary hypertension presenting late in the neonatal period, Two cases of fatal idiopathic persistent pulmonary hypertension presented late in the neonatal period. Lungs were examined histologically by light and electron microscopy. and immunocytochemical studies were used to identify nerves. There was extension of medial smooth muscle distally along the arterial pathway so that most precapillary arteries had completely muscular walls. which in some cases completely obliterated the vessel lumen. Enlarged endothelial cells also contributed to the reduction in the size of the lumen. Nerve fibres accompanying muscular arteries were found in the alveolar region. more distal than is normal. The predominant neuropeptide was the vasoconstrictor tyrosine. Possible aetiological factors in persistent pulmonary hypertension of the newborn are increased muscularity of the peripheral pulmonary arteries antenatally. an increase in the number of vasoconstrictor nerves. or an imbalance in the production of leukotrienes and prostacyclins in the perinatal period.
Survival and place of treatment after premature delivery, In a one year prospective study in the Trent region we examined the short term outcome (survival to discharge) of all infants who required admission to a baby care unit. Infants of less than or equal to 28 weeks' gestation who received all their perinatal care in one of five large centres (each providing more than 600 ventilator days/year) showed significantly better survival rates than infants electively treated throughout their entire course at one of the 12 smaller units (34 survivors from 65 infants (52%) compared with eight survivors from 37 infants (22%). These differences occurred despite the elective transfer of many of the sickest infants from the smaller units to the larger. Differences in survival between more mature infants were not significant. These results support the policy that there should be a more centralised neonatal service for those infants at or below 28 weeks' gestation.
Birthweight ratio revisited, In order to test the hypothesis suggested in a recent report that the birthweight ratio might be a useful predictor of several important clinical outcome measures in babies of less than 31 weeks' gestation. we examined the association between the birthweight ratio and aspects of both short and long term outcome in 436 Leeds babies of less than 31 weeks' gestation. Unlike the report. and contrary to what we had expected. we were unable to find any significant association between birthweight ratio and length of time on the ventilator. mortality. neurological outcome. or intellectual outcome.
Comparison of triggering systems for neonatal patient triggered ventilation, The efficacy of two triggering systems was compared during neonatal patient triggered ventilation: the Graseby MR10 respiration monitor and airway pressure changes. Ten preterm infants were studied. median gestational age 33 weeks (range 28-35). Patient triggered ventilation was administered via the SLE ventilator at a series of inflation times (0.24. 0.3. and 0.4 seconds). Comparison was made between the trigger systems of the trigger delay. inflation volume delivered. and proportion of spontaneous respiratory efforts detected. The airway pressure trigger gave a superior performance: at the two lower inflation times the trigger delay was shorter and inflation volume delivered greater. At the longest inflation time a greater proportion of respiratory efforts were detected. We conclude the airway pressure trigger should be used in preference to the respiration monitor as the triggering system of choice for neonatal patient triggered ventilation.
Heart transplantation in children, Orthotopic cardiac transplantation has been performed in 15 consecutive neonates and children since 1987. Diagnoses include hypoplastic left heart syndrome (5 patients). critical aortic stenosis with small left ventricle (1 patient). complex cyanotic heart disease (6 patients). and cardiomyopathy (3 patients). Twelve patients survived operation and have been followed from 1 to 45 months. Patients less than 6 years of age are managed with cyclosporine +/- azathioprine; in older patients steroid weaning is attempted. Monitoring for rejection is performed with serial echocardiography in patients under 6 years of age; older patients undergo serial biopsies. Actuarial freedom from rejection was 26% 3 months after operation; 47% were free of infection 6 months after operation. There have been no late deaths. Actuarial survival at 3 years is 79%. Nine patients have undergone postoperative catheterization. Resting hemodynamics were normal in every patient. All long-term survivors are asymptomatic and fully active. It is concluded that cardiac transplantation in neonates and children is an effective treatment option for end-stage cardiomyopathy or otherwise incurable congenital heart disease. Long-term survivors have excellent potential for full rehabilitation.
Brush border transport of glutamine and other substrates during sepsis and endotoxemia, The effects of severe infection on luminal transport of amino acids and glucose by the small intestine were investigated. Studies were done in endotoxin-treated rats and in septic patients who underwent resection of otherwise normal small bowel. In rats the kinetics of the brush border glutamine transporter and the glutaminase enzyme were examined. In patients the effects of severe infection on the transport of glutamine. alanine. leucine. and glucose were studied. Transport was measured using small intestinal brush border membrane vesicles that were prepared by Mg++ aggregation/differential centrifugation. Uptake of radiolabeled substrate was measured using a rapid mixing/filtration technique. Vesicles demonstrated 15-fold enrichments of enzyme markers. classic overshoots. transport into an osmotically active space. and similar 2-hour equilibrium values. The sodium-dependent pathway accounted for nearly 90% of total carrier-mediated transport. Kinetic studies on rat jejunal glutaminase indicated a decrease in activity as early as 2 hours after endotoxin secondary to a decrease in enzyme affinity for glutamine (Km = 2.23 +/- 0.20 mmol/L [millimolar] in controls versus 4.55 +/- 0.67 in endotoxin. p less than 0.03). rather than a change in Vmax. By 12 hours the decrease in glutaminase activity was due to a decrease in Vmax (222 +/- 36 nmol/mg protein/min in controls versus 96 +/- 16 in endotoxin. p less than 0.03) rather than a significant change in Km. Transport data indicated a decrease in sodium-dependent jejunal glutamine uptake 12 hours after endotoxin secondary to a 35% reduction in maximal transport velocity (Vmax = 325 +/- 12 pmol/mg protein/10 sec in controls versus 214 +/- 8 in endotoxin. p less than 0.0001) with no change in Km (carrier affinity). Sodium-dependent glutamine transport was also decreased in septic patients. both in the jejunum (Vmax for control jejunum = 786 +/- 96 pmol/mg protein/10 sec versus 417 +/- 43 for septic jejunum. p less than 0.01) and in the ileum (Vmax of control ileum = 1126 +/- 66 pmol/mg protein/10 sec versus 415 +/- 24 in septic ileum. p less than 0.001) The rate of jejunal transport of alanine. leucine. and glucose was also decreased in septic patients by 30% to 50% (p less than 0.01). These data suggest that there is a generalized down-regulation of sodium-dependent carrier-mediated substrate transport across the brush border during severe infection. which probably occurs secondary to a decrease in transporter synthesis or an increase in the rate of carrier degradation.(ABSTRACT TRUNCATED AT 400 WORDS).
Ruptured aneurysm of the descending thoracic and thoracoabdominal aorta. Analysis according to size and treatment, Acute rupture was confirmed at operation in 117 patients treated for descending thoracic or thoracoabdominal aortic aneurysm. Descending thoracic (n = 80) aortic rupture occurred into lung or esophagus in 8. the pleural cavity in 49. and the mediastinum in 23. Upper abdominal aortic (n = 37) rupture occurred into peritoneal cavity in 3 and into retroperitoneal tissues in 34. Aneurysmal size (range. 5 to 17 cm; median. 8 cm) could be determined retrospectively in 86 patients; 59 (74%) descending thoracic and 27 (73%) abdominal aorta. Size (external diameter) in the former was 8 (14%). 5 to 6 cm; 21 (36%). 6 to 8 cm; 23 (39%). 8 to 10 cm; and 7 (12%) greater than 10 cm. Size at the abdominal site was similar. Thus size was not greater than 10 cm in 52 (88%) (range. 5 to 10 cm). which contradicts opinions that thoracic aneurysms rupture only when size exceeds 10 cm. Twenty-nine patients (25%) were hypotensive (systolic blood pressure less than 100 mmHg). of whom 16 (55%) had cardiac arrest before operation. Associated conditions included advanced age (greater than or equal to 75 years) in 26 (22%). coronary artery disease in 41 (35%). chronic obstructive pulmonary disease in 46 (39%). renal insufficiency in 25 (21%). and cardiovascular disease in 22 (18%). The overall early survival rate (30-day) was 89 of 117 patients (76%); 69% in patients with hypotension. 56% of patients with cardiac arrest. 88% in good-risk patients. Five-year (Kaplan-Meier) survival was 28%. Because elective operation is associated with 92% survival. this should be considered before rupture when aneurysm is 5 cm or larger in good-risk patients. in patients with symptomatic aneurysms. and in most patients with larger aneurysms.
Poisonous snakebite in central Texas. Possible indicators for antivenin treatment, Sixty-seven patients hospitalized for poisonous snakebite between 1975 and 1990 were managed by elevation. tetanus prophylaxis. intravenous fluids and antibiotics. and often by a limited excision of the bite site in the Emergency Department. with sequential laboratory studies as needed. Antivenin was used for systemic envenomation. and 23 of the 67 patients (34%) received 133 vials. Thirteen of the twenty-three patients (56%) had adverse reactions to the antivenin. Two significant observations arose. First age was an indicator. Eleven of eighteen patients 12 years or younger (61%) received antivenin. whereas 12 of 49 patients older than 12 years (24%) received antivenin (p = 0.0085. Fisher's exact test). Second species of snake was an indicator. Sixty-two snakes were identified (93%). Of 39 rattlesnake (Crotalus and Sistrurus) bites. 20 patients received antivenin (53%). but of 23 copperhead and water moccasin (Agkistrodon) bites. only three patients (12.5%) received antivenin (p = 0.0025). Antivenin may be indicated for use in systemic rattlesnake envenomation. especially in younger patients.
Limb salvage versus traumatic amputation. A decision based on a seven-part predictive index, In severe traumatic injuries to the lower extremity. it is often a difficult decision to attempt heroic efforts aimed at limb salvage or to amputate primarily. To answer this question. the authors performed a 5-year review of 70 limbs in 67 patients. Patients were identified as presenting with major lower extremity trauma and an associated arterial injury. Nineteen (27%) of the 70 limbs were amputated. Limb salvage was not related to the presence or absence of shock and order of repair (orthopedic or vascular). No statistical difference was noted between the time of injury to operative repair in either the amputated or limb salvage group. Limb salvage was related to warm ischemia time and the quantitative degree of arterial. nerve. bone. muscle. skin. and venous injury. A limb salvage index (LSI) was formulated based on the degree of injury to these systems. All 51 patients with an LSI score of less than 6 had successful limb salvage (p less than 0.001). All 19 patients with an LSI score of 6 or greater had amputations (p less than 0.001). Although statistics cannot replace clinical judgment. this index can be a valuable objective tool in the evaluation of the patient with a severely traumatized extremity.
Management of penetrating colon injuries. A prospective randomized trial, Fifty-six patients with penetrating colon injuries were entered into a randomized prospective study. Management of the colon injury was not dependent on the number of associated injuries. amount of fecal contamination. shock. or blood requirements. Twenty-eight patients were treated with primary repair or resection and anastomosis and 28 patients were treated by diversion (24 colostomy. 3 ileostomy. 1 jejunostomy). The average Penetrating Abdominal Trauma Index score was 23.9 for the diversion group and 26 for the primary repair group. There were five (17.9%) septic-related complications in the diversion group. This included four intra-abdominal abscesses and one subcutaneous wound infection. There were six (21.4%) septic-related complications in the primary repair group. This included one wound infection. two positive blood cultures. and three intra-abdominal abscesses. There were no episodes of suture line failure in the primary repair/anastomosis group. The authors conclude that. independent of associated risk factors. primary repair or resection and anastomosis should be considered for treatment of all patients in the civilian population with penetrating colon wounds.
Effects of calcium chloride administration on the postischemic isolated rat heart, Hypercalcemic reperfusion of the postischemic heart has been associated with ventricular dysfunction and with ultrastructural changes in the mitochondria. The isolated working rat heart model was used to correlate ventricular function. mitochondrial damage. and high-energy phosphate content with degree and timing of hypercalcemia during reperfusion. When administered early during reperfusion. calcium chloride caused a dose-dependent deterioration in ventricular function. whereas calcium augmented function when it was administered after a 15-minute period of normocalcemic reperfusion. Hearts treated with calcium early during reperfusion demonstrated more mitochondrial damage and decreased stores of adenosine triphosphate than those in which calcium administration was delayed. The data indicate that a period of normocalcemic reperfusion should precede calcium administration in the postischemic heart. Mitochondrial damage resulting in decreased synthesis of adenosine triphosphate is likely the cause of ventricular dysfunction associated with calcium administration in the postischemic heart.
Temporary external DDD pacing after cardiac operations, Temporary atrial and ventricular pacing in the DVI. VVI. and AOO modes using atrioventricular sequential DVI devices is routinely used in cardiac operations. This study evaluated a new temporary external DDD pacemaker (Medtronic 5345 External Pulse Generator) capable of ten pacing modes. Thirty-nine devices have been applied to 38 adult patients (27 male. 11 female) after a variety of open heart procedures. Group 1 had atrial pacing wires placed 1.5 to 2.0 cm apart superiorly on the right atrium. group 2 had atrial wires placed 1.0 to 1.5 cm apart on the right atrial free wall. and group 3 had atrial wires placed on the right atrial free wall 0.8 cm apart. using a Silastic ring for fixation. Ventricular wires were placed on the free wall (group 1) or the diaphragmatic surface (groups 2 and 3) of the right ventricle. Postoperative atrial and ventricular sensing and pacing thresholds were obtained on return to the intensive care unit; analysis of variance demonstrated a significantly greater atrial sensing threshold in group 3. Four patients in group 1 permanently lost atrial sensing. 1 patient in group 2 intermittently lost atrial sensing at 24 hours with return at 36 hours postoperatively. and 1 patient in group 1 lost ventricular sensing capability. All other patients had adequate atrial and ventricular sensing capability documented until elective pacemaker removal (mean. 166 hours; range. 17 to 667.5 hours). Nineteen patients required some form of temporary pacing postoperatively; 11 patients demonstrated hemodynamic benefit from a pacing mode that is not available on the currently used DVI devices. and 7 of these required true DDD pacing capability. Six patients benefited from atrial pacing with adequate atrial sensing and simultaneous ventricular backup. Burst pacing with the device was used successfully to treat postoperative atrial flutter in 2 patients. We conclude that temporary external DDD pacing is feasible and effective in postoperative cardiac surgical patients. Atrial sensing is possible in most patients but electrode positioning is important for adequate thresholds. In some patients. hemodynamic as well as electrophysiologic improvement can be demonstrated with universal DDD pacing capability as compared with standard DVI pacing.
Erythropoietin deficiency after coronary artery bypass procedures, Erythropoietin is the primary regulator of erythropoiesis. Erythropoietin has been shown to increase exponentially in response to linear decreases in hematocrit in normal. unstressed animals. However. the effect of operation. with its attendant stress. on erythropoietin levels is unknown. The purpose of this study is to evaluate the effect of surgical stress on erythropoietin. Twenty otherwise healthy patients scheduled for elective surgical procedures were studied. The cholecystectomy group included 10 patients who underwent cholecystectomy for documented stone disease. Ten patients who underwent coronary artery bypass procedures constituted the coronary artery bypass grafting group. Patients were studied preoperatively as well as on the first and second postoperative days. The hematocrit and erythropoietin levels were similar in both groups preoperatively. The hematocrit in the coronary artery bypass grafting group was lower than that of the cholecystectomy group on postoperative day 1 (0.31 versus 0.36; p less than 0.003) and postoperative day 2 (0.30 versus 0.36; p less than 0.001). During the first two postoperative days the erythropoietin levels were similar between groups. The data show that postoperative erythropoietin levels are similar after coronary artery bypass grafting. despite more severe anemia. when compared with cholecystectomy. This suggests that after coronary artery bypass grafting there is a relative deficiency of erythropoietin. Administration of recombinant human erythropoietin to patients undergoing surgical procedures could correct the erythropoietin deficiency and accelerate postoperative erythropoiesis.
Autologous blood transfusion with recombinant human erythropoietin in heart operations, The effects of recombinant human erythropoietin (rHuEPO) on improving the anemia associated with autologous blood collection before open heart operations and on improving the postoperative anemia were studied. The study was carried out on 18 patients undergoing coronary artery bypass operations; 400 mL of autologous whole blood was taken from each patient 2 weeks before operation and was subsequently used in the operation. and rHuEPO (100 U.kg-1.day-1) was given intravenously for 2 weeks before operation and for 1 week after operation. The group in which iron preparations were also administered intravenously was designated as group I (10 patients). and the group in which rHuEPO was given alone was designated as group II (8 patients). In group III. as a control group. 11 past patients were used in whom 400 mL of autologous whole blood was collected 2 weeks before operation but neither rHuEPO nor iron preparations were given. After autologous blood collections. the hemoglobin levels improved in group I. group II. and group III. in that order. and with significant differences among them. It was shown that rHuEPO was effective in ameliorating the anemia associated with preoperative autologous blood collection. and the effect was further enhanced with intravenous supplementing iron preparations. After operation. the anemia markedly improved while rHuEPO was administered. but the hemoglobin levels decreased rapidly when the administration was terminated. Further studies are needed regarding the use of rHuEPO after operation.
Hospital mortality and long-term survival after pulmonary resection in the elderly, We have studied the hospital mortality and long-term survival in two groups of patients: those between 50 and 69 years of age (group 1. n = 136) and those older than 70 years of age (group 2. n = 43). The two groups were similar in terms of the distribution of histological type and postsurgical staging. The patients were treated by either lobectomy or pneumonectomy; the lobectomy rate was similar in both groups: 61% and 51% (not significant). Hospital mortality for group 1 was 4.4% and for group 2. 6.9%. Mortality was higher in both groups after pneumonectomy compared with lobectomy. but this was not significant (group 1. 6.2% versus 1.9%; group 2. 9.1% versus 4.7%). Hospital mortality after pulmonary resection was greater in the elderly. but this was not significant (lobectomy: 1.9% [group 1] versus 4.7% [group 2]; pneumonectomy: 6.2% [group 1] versus 9.1% [group 2]. The overall long-term survival at 2 and 4 years was 62.3% and 50.0% for group 1 and 72.5% and 66.6% for group 2. We suggest that the operative risk in the elderly is not prohibitive and the long-term results are acceptable. Patients should not be denied operation on the basis of age alone.
Traumatic mitral valve rupture in a child, The case of a 6-year-old boy who ruptured his mitral valve after blunt chest trauma and who subsequently had successful mitral valve replacement with a size 25 St. Judge Medical prosthesis is reported. The diagnosis. investigation. and treatment of traumatic valvar rupture are discussed.
Agglutination of blood cardioplegia by cold-reacting autoantibodies, Cold-reacting autoantibodies occasionally occur in patients requiring cardiac operations. This report describes the clinical course of 1 patient with cold-reacting autoantibodies and intracoronary agglutination of the blood cardioplegia solution. Observations made in vivo and in vitro are considered in discussing recommendations for the management of extracorporeal circulation and cardioplegic arrest in patients with clinically silent cold-reacting autoantibodies.
Blast injury to the thoracic esophagus, Blast injury causing pneumatic disruption of the esophagus is a rare and potentially lethal injury. The mortality and morbidity rate are high unless the injury is promptly recognized and treated. Our experience with a midesophageal perforation resulting from a blast injury emphasizes the importance of awareness of this condition and of the chest radiograph in making an early diagnosis.
Dissectors for pulmonary thromboendarterectomy, Even with circulatory arrest during pulmonary thromboendarterectomy. continued back-bleeding obscures the operative field. This necessitates frequent interruptions of dissection to allow aspiration with a second instrument. Therefore. pulmonary thromboendarterectomy dissectors are described that allow simultaneous suction of blood from the operative field. Before the use of these dissectors. circulatory arrest time was 59 +/- 23 minutes in 124 consecutive patients. In the last 10 consecutive patients using these dissectors. the mean circulatory arrest time has been 52 +/- 22 minutes (p = not significant). It is anticipated that with a larger database. the ability to aspirate blood simultaneously during the dissecting process will result in a significant shortening of circulatory arrest time.
What does Cruzan mean to the practicing physician?, The United States Supreme Court's recent decision in the Cruzan case declared that the states have broad powers to formulate their own rules in "right to die" cases. The Court held that competent adults have a constitutionally protected "liberty interest" that allows them to accept or refuse medical treatments. Since liberty interests are subject to rational state regulation. the narrow holding in Cruzan affirmed Missouri's authority to require a "clear and convincing" evidence standard to determine a patient's wishes before life-sustaining treatment could be withdrawn from a formerly competent adult now in a persistent vegetative state. For practicing physicians. some of the implications of Cruzan are as follows: (1) For competent adult patients. physicians should respect patient wishes regarding life-sustaining treatment. (2) Physicians also should discuss with competent patients their wishes for life-sustaining treatment at a future time. when a patient may no longer be able to participate in such decisions. (3) Physicians should record these wishes in a legally acceptable instrument that addresses two aspects of care that may arise in the future if the patient becomes incompetent. What would the patient want done? Who would the patient wish to designate as a surrogate or proxy? (4) For patients who are now incompetent. but for whom decisions must be made about life-sustaining treatment. physicians should focus on the previously expressed wishes of the patient rather than on the patient's current quality of life or on the wishes of the patient's family.
Clinical characteristics of patients in the persistent vegetative state, Little is known concerning the specific clinical characteristics of patients in persistent vegetative states (PVS). Fifty-one patients from four nursing homes. approximately 3% of the total patients. were identified as being in a PVS. The mean age of the patients was 64.8 +/- 3.2 years (range. 19 to 96 years) and the mean duration of the PVS was 3.3 +/- 5.0 years (range. 1 to 16.8 years). with 13 patients' PVS being longer than 5 years. Cerebrovascular accidents and dementia were the most common causes of the PVS. accounting for 32 of the cases (63%). In the younger patients cerebral trauma secondary to motor vehicle accidents was the most common cause. All 51 patients were fed via tube feeding and 35 patients had urinary catheters (75%). All patients were receiving daily medications. with greater than 50% taking daily vitamins. Over 30% were taking digitalis and/or diuretics and over 32% were taking H2 blockers. Transfer of patients to an acute care hospital was not uncommon. with 31 patients (61%) requiring 63 acute care hospitalizations during their stay in the nursing home. As expected. infections were the most common reason for acute care hospitalization. although 15 of the patients were hospitalized for surgical procedures. Another common problem encountered by the patients was pressure sores. with 78% of patients requiring specific therapy for at least one pressure sore. Surprisingly. only 27 (53%) of 51 patients had a specific resuscitation status designation in the medical chart. and neither presence of a chart designation nor specific resuscitation order was related to the patient's age or the cause or duration of PVS. From these data it would appear that clinical characteristics of patients in PVS are variable. Some patients are young. others are old. The cause varies from cerebrovascular accidents to cerebral trauma. Survival may be prolonged; complications are not uncommon. with some patients requiring acute care hospitalization.
Cessation of driving and unsafe motor vehicle operation by dementia patients, We surveyed 522 consecutive patients from a dementia clinic to assess duration of driving after disease onset and instances of unsafe motor vehicle operation in the preceding 6 months. Among the 333 patients licensed to drive at the onset of dementia. the median duration of driving after onset was 28.6 months. Patients with a clinical diagnosis of Alzheimer's disease drove significantly longer than those with other dementia syndromes. Of the 93 patients still driving at the time of the survey. approximately one third were reported to have had at least one form of unsafe motor vehicle operation in the past 6 months. including 21 patients with motor vehicle accidents. Motor vehicle accidents were associated with use of prescription medications with sedative properties and with lower subjective ratings of the patient's driving ability by the informant.
Risk factors and early extracoronary atherosclerotic plaques detected by three-site ultrasound imaging in hypercholesterolemic men. Prevention Cardio-vasculaire en Medecine du Travail METRA Group, Ultrasonic detection of atherosclerotic plaque of carotid abdominal aortic and femoral arteries and evaluation of risk factors were performed in 208 hypercholesterolemic men without cardiovascular disease. Twenty-six percent of them had no plaque. Plaque at the carotid. aortic. and femoral sites was found in 37%. 48%. and 53% of subjects. respectively. Plaque was associated (1) in carotid arteries with increased total and low-density lipoprotein cholesterol; (2) in the aorta with increased age. pressure. glycemia. and smoking; and (3) in femoral arteries with increased age. systolic pressure. low-density lipoprotein cholesterol. and smoking. Multiple regression analysis showed correlations between carotid plaque and low-density lipoprotein cholesterol; aortic plaque and age. smoking. glycemia. and pressure; femoral plaque and age. smoking. and pressure. This suggests that multiple risk factors influence lesions. and risk profile differs according to atherosis site.
Screening for alcoholism by life-style risk assessment in a community hospital, In a community hospital. physicians identified with unusually high frequency (90%) the alcoholics they admitted to a medical-surgical service when life-style risk assessment was performed routinely. Identification rates were retrospectively evaluated based on chart documentation; 100 consecutive admissions receiving assessment interviews were compared with 100 consecutive admissions for a period 6 months later. During the screening period. plans addressing alcohol-related problems routinely appeared in the discharge summaries (71%). referral recommendations were frequently made for residential alcoholism treatment (52%). and intentions were stated to follow-up alcohol abuse problems in the office (43%). Decreases in these rates were observed when life-style risk assessment was not performed. Identification was made in 57% of patients; plans were stated concerning alcohol-related problems in 29%; residential referral was recommended in 5%; and office follow-up was arranged for 24%. The risk assessment program was economical and well received by the patients. the physician staff. and the hospital administration. No specialized program for physician education was utilized.
Anonymous human immunodeficiency virus surveillance and clinically directed testing in a Newark, NJ, hospital, From September 1988 to August 1989. in a university hospital in Newark. NJ. 3529 serum and plasma specimens from patients with admitting conditions presumably not associated with human immunodeficiency virus (HIV) infection (Centers for Disease Control. Atlanta. Ga. Sentinel Hospital Surveillance System criteria) were tested anonymously for the presence of type 1 HIV (HIV-1) antibody. Of these specimens. 269 (7.6%) were confirmed HIV-1 seropositive. Overall. 10.3% of male patients and 4.8% of female patients were seropositive. Persons 25 to 44 years old had the highest HIV-1 seroprevalence- 20.9% for male and 7.5% for female patients. Based on this anonymous testing. the number of HIV-infected hospitalized patients discharged in 1988 was estimated. Data on hospital-confirmed HIV-infected patients tested on the basis of clinical suspicion suggest that only 40% of HIV-infected patients were actually tested for HIV-1 infection as part of their medical care in this hospital. These data demonstrate a high prevalence of HIV infection in this patient population and suggest that hospitals serving populations with a high HIV seroprevalence offer routine screening for HIV infection as part of good medical care.
Dementia. Age-dependent incidence, prevalence, and mortality in the old old, Age has been reported as a strong risk factor for dementia. Supporting data have been derived mainly from prevalence studies. which had varied criteria and sample compositions that precluded direct comparisons. especially among those aged 85 years and older. Data regarding rates of dementia are presented based on 85 incident cases in the Bronx (NY) Aging Study. a prospective study of 488 initially nondemented. old old persons (mean age on entry. 79 years). Overall. the incidence rate over 8 years of follow-up for all-cause dementia was 3.4 per 100 per year (43% Alzheimer's disease. 30% mixed Alzheimer's and vascular. and 27% other). Incidence rose significantly. irrespective of gender. as subjects were followed up through three age intervals--ages 75 to 79 years (1.3/100 per year). 80 to 84 years (3.5). and 85 years and older (6.0). The comparable age-associated prevalence rates of dementia were 3.7%. 12.2%. and 23.9%. respectively. with an overall period prevalence of 22.8%. Additionally. there was a threefold greater mortality associated with dementia. In conclusion. despite the shortened life expectancy of demented persons. dementia is a highly prevalent condition among those aged 85 years and older. Public policy attention is warranted. since this group is the fastest growing population subgroup.
Vancomycin-induced thrombocytopenia, Vancomycin-induced thrombocytopenia has only been reported once previously in the medical literature. We describe a patient in whom sudden severe reversible thrombocytopenia developed on two separate occasions after exposure to vancomycin hydrochloride. A 54-year-old man was admitted to the hospital for bilateral swelling and erythema of his extremities. At the time of admission he received 2 days of vancomycin therapy without incident. On day 14 he was reexposed to vancomycin and thrombocytopenia developed. with a nadir value of 17 x 10(9)/L. On day 30. a single dose of vancomycin was administered. and thrombocytopenia once again developed. with a nadir value of 11 x 10(9)/L. Hematologic cytopenias are infrequent adverse effects of vancomycin therapy. It is postulated that these effects may be due to an immunologically mediated mechanism. With the increasing use of vancomycin due to the emergence of methicillin-resistant Staphylococcus aureus. this case should alert clinicians to this rare but potentially lethal manifestation of vancomycin.
Clinicopathologic correlation of diode laser burns in monkeys, One hundred twenty-five retinochoroidal photocoagulation burns. produced by a transpupillary diode laser (810 nm) in six eyes of three cynomolgus monkeys. were evaluated by clinicopathologic correlation for up to 9 weeks after laser treatment. Diode burns of clinical grade 2 strength were comparable to those described for argon laser. However. diode burns of clinical grade 3 strength produced choroidal changes more intense than those described for argon laser. Where present underneath photocoagulation sites. ciliary nerves in choroid or sclera consistently showed scarring. Prospective randomized controlled clinical trials to document possible clinical equivalence or superiority of diode treatment have not yet been performed. Potential clinical advantages of the diode laser include its weight. size. durability. price. absence of visible flash. and its ability to produce burns that profoundly affect the choroid.
Vitreous surgery for idiopathic macular holes. Results of a pilot study, Idiopathic macular holes are generally considered an untreatable condition. We used modern vitrectomy techniques to evaluate two questions: (1) Is it possible to reattach the retina around the macular hole? (2) If it is reattached. will the patient's central vision improve? In 30 (58%) of 52 patients. we were able to reattach successfully the detached macula with our surgical procedure. In 22 (73%) of the 30 patients in whom the macula was successfully reattached. there was an improvement in visual acuity of two lines or better. In the 22 patients in whom reattachment of the macular hole was not obtained. there was no significant improvement in visual acuity. Thus. the overall success rate for improved vision postoperatively was 42% (22/52). Complications related to surgery were observed in eight patients (15%) early in our experience with this procedure and included increase in the size of the macular hole. mottling of the retinal pigmented epithelium. and a vascular occlusion. Our clinical observations indicate that the treatment of macular holes by vitrectomy may offer some promise for this otherwise untreatable condition. In patients in whom reattachment was successful. the technique used appeared to allow for clinically significant improvements in visual acuity. However. additional work on increasing surgical success and minimizing surgical complications. as well as a further understanding of the mechanism of retinal reattachment. is required before widespread use of this procedure for treating macular holes.
Optic nerve sheath decompression for nonarteritic ischemic optic neuropathy improves multiple visual function measurements, Optic nerve sheath decompression was performed in seven patients with nonarteritic anterior ischemic optic neuropathy. Visual function was evaluated by measurement of visual acuity with standardized Early Treatment Diabetic Retinopathy Study charts. color vision testing. quantitation of relative afferent pupillary defects with neutral-density filters. and Goldmann and Humphrey perimetry. Visual acuity improved markedly in all patients (at least doubling of the visual angle); the peripheral visual field expanded by at least 20 degrees (as measured by Goldmann perimetry) in six patients. Three patients also experienced marked improvement in color vision. relative afferent pupillary defect. and foveal sensitivity. Our experience supports the possible beneficial effect of optic nerve sheath decompression in patients with nonarteritic anterior ischemic optic neuropathy.
Stimulation of tear secretion and treatment of dry-eye disease with 3-isobutyl-1-methylxanthine, We examined the effect of topically applied 3-isobutyl-1-methylxanthine (IBMX). a known secretagogue. on tear secretion and dry-eye disease in a clinical study. We found that IBMX produced a dose-dependent decrease in tear film osmolarity that was significant at 3.0 mmol/L (P less than .0005) in patients with dry-eye disease. This effect was not blocked by prior administration of proparacaine hydrochloride (P less than .05). Throughout a 4-week. open-label. vehicle-controlled study. IBMX decreased tear film osmolarity significantly. whereas vehicle alone did not. After 4 weeks. mean (+/- SEM) osmolarity in IBMX-treated eyes decreased from 325 +/- 3.2 mOsm/L to 312 +/- 1.8 mOsm/L but remained unchanged in vehicle-treated eyes (323 +/- 4.4 mOsm/L vs 320 +/- 4.2 mOsm/L). In our study. IBMX was significantly more effective than vehicle alone in decreasing rose bengal staining (P less than .02). Hence. topical IBMX stimulated tear secretion and decreased ocular surface disease in patients with dry-eye disease.
Photorefractive keratectomy to create toric ablations for correction of astigmatism, Excimer laser photorefractive keratectomy. developed to perform radially symmetric ablations to correct myopic or hyperopic refractive errors. was used to create toric ablations designed to correct cylindrical errors. An expanding slit was created. with no refractive change intended parallel to the slit opening. and central flattening was induced in the meridian in which the slit was expanded. In polymethyl methacrylate blocks. the induced cylinder (as measured with a lensometer) agreed closely (r2 = .99) with intended change. and in plastic corneas. induction of the cylinder could be demonstrated with computer-assisted topographic analysis. Adult pigmented rabbits underwent induction of toric ablations in two-diopter increments; measured keratometric change correlated with desired change (r2 = .87 at 3 weeks; r2 = .89 at 12 weeks). Toric ablations with the excimer laser appear to represent a promising strategy for the correction of cylindrical errors that do not rely on creation of deep corneal incisions. excisions. or compression sutures.
En bloc removal of inflammatory fibrocellular membranes from the iris surface in endophthalmitis, Dense inflammatory fibrocellular membranes may develop over the iris in an eye with endophalmitis. completely obliterating any view of the posterior segment and hindering vitrectomy. To remove this debris. the edge of the membrane is first lifted from the surface of the iris with a small microvitreoretinal blade inserted through a limbal wound. The membrane is then engaged with an iris hook that is rotated until the debris is tightly wound on the shaft of the instrument. The iris hook is then removed from the anterior segment. delivering the inflammatory debris en bloc. This technique limits possible surgical trauma to the anterior segment and provides an excellent specimen for culture.
The American College of Rheumatology criteria for the classification and reporting of osteoarthritis of the hip, Clinical criteria for the classification of patients with hip pain associated with osteoarthritis (OA) were developed through a multicenter study. Data from 201 patients who had experienced hip pain for most days of the prior month were analyzed. The comparison group of patients had other causes of hip pain. such as rheumatoid arthritis or spondylarthropathy. Variables from the medical history. physical examination. laboratory tests. and radiographs were used to develop different sets of criteria to serve different investigative purposes. Multivariate methods included the traditional "number of criteria present" format and "classification tree" techniques. Clinical criteria: A classification tree was developed. without radiographs. for clinical and laboratory criteria or for clinical criteria alone. A patient was classified as having hip OA if pain was present in combination with either 1) hip internal rotation greater than or equal to 15 degrees. pain present on internal rotation of the hip. morning stiffness of the hip for less than or equal to 60 minutes. and age greater than 50 years. or 2) hip internal rotation less than 15 degrees and an erythrocyte sedimentation rate (ESR) less than or equal to 45 mm/hour; if no ESR was obtained. hip flexion less than or equal to 115 degrees was substituted (sensitivity 86%; specificity 75%). Clinical plus radiographic criteria: The traditional format combined pain with at least 2 of the following 3 criteria: osteophytes (femoral or acetabular). joint space narrowing (superior. axial. and/or medial). and ESR less than 20 mm/hour (sensitivity 89%; specificity 91%). The radiographic presence of osteophytes best separated OA patients and controls by the classification tree method (sensitivity 89%; specificity 91%). The "number of criteria present" format yielded criteria and levels of sensitivity and specificity similar to those of the classification tree for the combined clinical and radiographic criteria set. For the clinical criteria set. the classification tree provided much greater specificity. The value of the radiographic presence of an osteophyte in separating patients with OA of the hip from those with hip pain of other causes is emphasized.
Morphologic and morphometric changes in synovial membrane associated with mechanically induced osteoarthrosis, We sought to determine whether synovial leukocytic inflammation is a primary event in mechanically induced osteoarthrosis. Repetitive impulse loading (50 ms duration at 60 Hz for 40 minutes each day) was applied to the right hindlimbs of 24 New Zealand white rabbits for 3. 6. or 9 weeks. The synovial membrane from the medial suprapatellar area was examined qualitatively using transmission electron microscopy and quantitatively using light microscopic morphometry. The results indicate that synovial inflammation is not a primary event in this mechanically induced osteoarthrosis. but synovial hyperplasia occurs prior to histologically evident cartilage destruction at 6-9 weeks.
Treatment of rheumatoid arthritis with monoclonal CD4 antibody M-T151. Clinical results and immunopharmacologic effects in an open study, including repeated administration, Recent experimental and clinical data point to the T helper lymphocyte subset as playing a central role in the pathogenesis of rheumatoid arthritis (RA). Thus. a therapeutic strategy aimed specifically at the CD4 T cell subset is warranted. We treated patients with active RA for 7 days with a daily dose of 20 mg of CD4 monoclonal antibody M-T151. administered intravenously over 30 minutes. There were no negative side effects. According to changes in the combined parameters of Ritchie articular index. pain assessment. grip strength. and morning stiffness. 6 patients had a good response. Clinical improvement was greatest approximately 2 weeks after termination of the therapy and lasted from 4 weeks to 6 months. Of the serologic parameters of inflammation. only the C-reactive protein level improved in the patients with a favorable response. Close immunologic monitoring revealed a transient. selective depletion of CD4+ T cells after each infusion. During the entire treatment period. residual circulating CD4+ cells were found to be coated with CD4 antibody. whereas free antibody was detected in the serum only for approximately 8 hours after each infusion. Immediately after infusion. soluble CD4 antigen appeared in the serum. In addition to the cell-bound CD4 antibody. complement components could be detected on the surface of the remaining CD4+ cells. The proliferative response of peripheral blood mononuclear cells to purified protein derivative was significantly diminished 4 weeks after cessation of antibody treatment. Six patients showed a weak antibody response to mouse immunoglobulin. In 4 of the responders who received a second course of therapy (2 of them as outpatients). a therapeutic effect was noted that was similar to that after the first course. Only 1 patient. who had low titers of serum IgE anti-mouse Ig antibodies. showed a mild anaphylactic reaction at the end of the second course of therapy. Treatment of RA with the monoclonal CD4 antibody M-T151 seems to be a promising alternative. although the optimal dose and the regimen of administration are still to be defined.
Diversity of rheumatoid synovial tissue T cells by T cell receptor analysis. Oligoclonal expansion in interleukin-2-responsive cells, The synovitis of rheumatoid arthritis (RA) is characterized by infiltrates of CD4+ T lymphocytes. To determine the clonal diversity of these cells. we cloned T cells with interleukin-2 (IL-2). alone or with phytohemagglutinin (PHA). directly from actively inflamed synovial tissue obtained at synovectomy. A total of 205 clones from 4 specimens was analyzed for T cell receptor (TCR) gene rearrangements using Hind III and Eco RI digests with beta chain and gamma chain complementary DNA probes. A comparison of the TCR rearrangements enabled us to determine if the T cell clones arose from the same or different precursor cells. Most of the T cell clones (92%) had distinct TCR gene rearrangement patterns. indicating a unique clonal origin. However. a few clones (1 quadruplicate and 6 pairs) with identical TCR rearrangements were identified. and these clonal multiples were most commonly found in clones selected with IL-2 alone. Mass cultures were propagated with IL-2. alone or with PHA. and at each passage. cells were removed for TCR analysis. The later passages of the lines selected with IL-2 had oligoclonal TCR rearrangements. whereas no oligoclonal rearrangements were found in the PHA + IL-2-selected cell lines. The TCR rearrangements in the later passages of the IL-2 mass cultures were often identical to the TCR rearrangements that were found in the IL-2-derived clonal multiples. These findings indicate that while the majority of CD4+ T cells within the actively inflamed rheumatoid joint have diverse clonal origins. small numbers of clonal multiples and oligoclonal populations are present. and these cells may be enriched in an IL-2-responsive T cell subset.
Defective CD2 pathway T cell activation in systemic lupus erythematosus [published erratum appears in Arthritis Rheum 1991 Jul;34(7):926, CD2 (T11; sheep erythrocyte receptor) is the surface component of an alternative. antigen-independent pathway of human T cell activation. The response to certain anti-CD2 antibodies is relatively independent of accessory cell signals and therefore provides a direct measurement of T cell function. The CD2 pathway may be important in the differentiation of thymocytes. on which the expression of CD2 precedes the appearance of the CD3-T cell receptor complex. In view of the impaired T cell regulation of immune responses in patients with systemic lupus erythematosus (SLE). we examined the activation of peripheral blood lymphocytes by anti-CD2 antibodies in 57 SLE patients and 32 normal control subjects. The CD2 pathway response was lower in the SLE patients (P less than 0.0001); 18 of the 57 SLE patients had a lower response than any of the control subjects. The SLE low-responder patients did not differ from the normal-responder patients in terms of disease activity or use of antiinflammatory and immunosuppressive medications. Low responses to anti-CD2 were corrected to normal by the coaddition of a submitogenic amount of phorbol myristate acetate (1 ng/ml). In some low-responder patients. the responses were normalized by the removal of non-T cells. The data indicate that some SLE patients have impaired responses to CD2 pathway activation and that this may reflect intrinsic T cell defects and/or regulatory influences of non-T cells.
Detection and quantification of human anti-Sm antibodies using synthetic peptide and recombinant SmB antigens, Anti-Sm-positive sera from patients with systemic lupus erythematosus (SLE) recognize a major epitope located within the carboxyl-terminal 27 amino acids of a recombinant SmB fusion protein. To determine whether a synthetic peptide corresponding to this region could be used as an antigen to detect anti-Sm antibodies. sera were typed as anti-Sm positive or anti-Sm negative by counterimmunoelectrophoresis (CIE). Twenty-three SLE sera that were anti-Sm positive by CIE. 22 that were anti-Sm negative by CIE. and 42 sera from patients with other autoimmune diseases were tested for anti-Sm antibodies by enzyme-linked immunosorbent assay (ELISA). using either the synthetic peptide (C27) or a recombinant SmB (rSmB) fusion protein as the antigen. More than 90% of the sera that were anti-Sm positive by CIE were also positive by both the C27 and rSmB ELISAs. and an additional 2 SLE sera originally typed as anti-Sm negative were found to be positive (1 by the C27 ELISA. 1 by the rSmB ELISA). due to the greater sensitivity of the ELISAs. In the rSmB ELISA. anti-Sm antibodies were not detected in any of the sera from patients with other autoimmune diseases. whereas 3 patients with anti-U1 RNP antibodies (1 each with polymyositis. scleroderma. and mixed connective tissue disease) had a positive result in the C27 ELISA. These results indicate that both the C27 synthetic peptide and rSmB are excellent antigens for use in ELISAs to quantify anti-Sm antibodies.
Increased interleukin-2 production in response to human type I collagen stimulation in patients with systemic sclerosis, Peripheral blood mononuclear cells (PBMC) from patients with systemic sclerosis (SSc) produced increased amounts of interleukin-2 (IL-2). in a dose-dependent manner. in response to stimulation with human type I collagen. whereas PBMC from normal subjects did not. At a dose of 50 micrograms human type I collagen/10(6) PBMC. PBMC from SSc patients (n = 17) produced 8 times as much IL-2 as did PBMC from 16 normal subjects (P less than 0.005) and 3 times as much as did PBMC from a group of 13 rheumatoid arthritis patients (P less than 0.05). In contrast. IL-2 production by PBMC after nonspecific stimulation with the mitogen. phytohemagglutinin. did not differ among the SSc. rheumatoid arthritis. and normal control groups. Cell depletion experiments indicated that the IL-2-producing cells in SSc patients are CD4+. Thus. SSc patients have CD4 cells that are specifically sensitized to human type I collagen and can produce increased levels of IL-2. Measurement of IL-2 production stimulated by human type I collagen may be useful in evaluating disease activity. and further investigation of this process may contribute to the delineation of the pathogenesis of SSc.
In vivo effects of interleukin-1 on articular cartilage. Prolongation of proteoglycan metabolic disturbances in old mice, We investigated the effects of intraarticular injections of interleukin-1 alpha (IL-1 alpha) into the knee joints of young (3-month-old) and old (18-month-old) C57Bl/10 mice. In this in vivo study. 35S-sulfate incorporation and release were used to compare the effects of IL-1 on patellar cartilage proteoglycan metabolism. IL-1-induced stimulation of proteoglycan degradation was confined to the first 24 hours after injection in both young and old animals. and was only slightly lower in old cartilage than in young. In old patellar cartilage. IL-1-induced suppression of proteoglycan synthesis appeared to be more prolonged. Also. the amount of time needed to restore the cartilage matrix. characterized by proteoglycan synthesis above normal levels. was longer in old animals. Histologic analysis confirmed the retarded recovery in the cartilage of old mice. Autoradiography showed that the chondrocytes of the medial side of the femorotibial area were most vulnerable to IL-1-induced suppression of proteoglycan synthesis. especially the medial tibial plateau. As with the patellar cartilage. IL-1-induced suppression of proteoglycan synthesis in this area of articular cartilage was more prolonged in old animals. Our data indicated that the impact of IL-1 on articular cartilage is higher in old mice and that. consistent with certain loci found to be at risk in experimental osteoarthritis. there are sites at which IL-1 is more likely to act.
Collagen-induced arthritis in an outbred group of rhesus monkeys comprising responder and nonresponder animals. Relationship between the course of arthritis and collagen-specific immunity, It is speculated that the autoimmune response to type II collagen (CII) is a driving force in the pathogenesis of human rheumatoid arthritis (RA). In this report. we describe the relationship between the induction of collagen arthritis and the CII-specific humoral. as well as cellular. immune response in rhesus monkeys. Ten of 14 monkeys immunized with bovine type II collagen (B-CII) developed polyarthritis. Susceptible animals showed a T cell response to B-CII; resistant animals did not. After the primary immunization. the humoral response to B-CII. as well as to rhesus monkey type II collagen. was dominated by antibodies of the IgM isotype in the susceptible animals and by antibodies of the IgG isotype in the resistant animals. Because of the close phylogenic relationship between the rhesus monkey and humans. these data contribute valuable information about the role of CII-specific immunity in the pathogenesis of human RA.
Systemic sclerosis associated with cutaneous exposure to solvent: case report and review of the literature, Sclerodermatous skin changes and systemic sclerosis have been reported to occur as a result of contact with several different organic solvents. We describe a 41-year-old man who developed systemic sclerosis after working for 15 years in a foundry. where he had extensive cutaneous contact with multiple organic solvents (trichloroethane. xylene. trimethylbenzene. and naphthalene). Cutaneous exposure to organic solvents may be a factor in the etiology of some cases of systemic sclerosis.
Trade-off between gestational age and miscarriage risk of prenatal testing: does it vary according to genetic risk?, It has been generally assumed that as genetic risk rises. so the higher procedure-related miscarriage rates of diagnostic tests done earlier in gestation become more acceptable. To test the hypothesis a decision tree was used. in which the only differences between two tests A and B were that A was carried out earlier in pregnancy and was more likely to cause miscarriage. Over a wide range of rankings for the three outcomes (procedure-related miscarriage of a normal baby. early termination of pregnancy after test A. late termination of pregnancy after test B). the expected utility (relative desirability) of an earlier. but more risky. test was greater at a high (1 in 4) than at a low (1 in 100) genetic risk.
Influence of age on atelectasis formation and gas exchange impairment during general anaesthesia, We have studied the effects of anaesthesia on atelectasis formation and gas exchange in 45 patients of both sexes. smokers and nonsmokers. aged 23-69 yr. None of the patients showed clinical signs of pulmonary disease. and preoperative spirometry was normal. In the awake patient. partial pressure of arterial oxygen (PaO2) decreased with increasing age (P less than 0.001) and the alveolar-arterial oxygen partial pressure difference (PAO2-PaO2) increased with age (P less than 0.001). Shunt. assessed by the multiple inert gas elimination technique. was small (mean 0.5%) and uninfluenced by age. However. there was an increasing dispersion (log SD Q) of ventilation/perfusion ratios (VA/Q) and increasing perfusion of regions of low VA/Q (VA/Q less than 0.1) with increasing age (P less than 0.001 and P less than 0.05. respectively). No patient displayed any atelectasis as assessed by computed x-ray tomography of the chest. During inhalation anaesthesia (halothane or enflurane) with mechanical ventilation. 39 of 45 patients developed atelectasis and shunt. There was a strong correlation between the atelectatic area and the magnitude of shunt (r = 0.81. P less than 0.001). Atelectasis and shunt did not increase significantly with age. whereas log SD Q and perfusion of regions with low VA/Q ratios did (r = 0.55. P less than 0.001 and r = 0.35. P less than 0.05. respectively). Awake. the major determinant of PaO2 was perfusion of regions of low VA/Q ratios. which increased with age. During anaesthesia shunt influenced PaO2 most. low VA/Q being a secondary factor which. however. was increasingly important with increasing age. thus explaining the well-known age-dependent deterioration of arterial oxygenation during anaesthesia.
Cranio-caudal movement of the sternum on induction of anaesthesia, The cranio-caudal movement of the sternum was studied by the technique of video magnification during induction of anaesthesia with thiopentone 2-4 mg kg-1 i.v. in 20 patients. Anaesthesia produced no consistent change in end-expiratory position of the sternum; there was a range of movement from 3.1 mm cephalad to 5.4 mm caudad. There was a significant relationship between movement and degree of obesity of the patient (P less than 0.01). with the sternum tending to caudal movement in the obese patient.
Hypoxaemia during anaesthesia--an observer study, We have investigated 296 inpatients in a single-blind observer study to determine the incidence. degree and duration of hypoxaemia during anaesthesia. The clinical recognition of hypoxaemia. period of time until recognition and risk factors were studied. Oxygen saturation (Spo2) was monitored continuously with a pulse oximeter (Ohmeda. model 3700). One or more episodes of mild hypoxaemia (Spo2 86-90%) were recorded in 53% of patients. Severe hypoxaemia with Spo2 values less than 81% were recorded in 20% of patients. The mild hypoxaemic episodes lasted up to 34.6 min (mean 2.3 min) and 70% were not detected by the anaesthetist. In the remaining 30% of episodes. the anaesthetist diagnosed the complication with a mean time delay of 70 s. After intervention a mean time delay of 57 s was recorded until Spo2 exceeded 90%. Utilizing a stepwise multiple logistic regression analysis. we found that risk factors associated with a greater incidence of hypoxaemia were patient age (P less than 0.005) and anaesthetic technique (P less than 0.00001). We conclude that hypoxaemic episodes in our operating rooms are common during anaesthesia and suggest preoxygenation in all patients in addition to administration of supplementary oxygen during arousal from anaesthesia and during transfer to the recovery room.
Reversal of benzodiazepine sedation with the antagonist flumazenil, The effectiveness of the benzodiazepine antagonist. flumazenil. was evaluated in a randomized double-blind clinical study in which diazepam 0.2 mg kg-1 or midazolam 0.1 mg kg-1 was used for i.v. sedation. We studied 120 day-case patients undergoing gastroscopy and treated with either flumazenil 0.1-2 mg or placebo after the procedure. Psychometric assessment of four aspects of recovery over a 3-h period showed that flumazenil attenuated the sedative effects of the benzodiazepines. but did not antagonize the sedation completely. For patients sedated with diazepam. there was a significant effect of flumazenil on speed of motor co-ordination after 90 min (P less than 0.01). and for those given midazolam a similar effect was found at 20 min (P less than 0.01). However. after 3 h all four groups of patients had not returned to baseline performance in accuracy of motor co-ordination (P less than 0.01) and cortical arousal (P less than 0.05). and the two groups sedated with diazepam still displayed memory deficits (P less than 0.05). Flumazenil did not attenuate the subjective experience of sedation as measured by visual analogue scales. These results indicate that sedation is multidimensional. differentially affecting the hierarchy of cognitive functions. In day-cases. antagonism of benzodiazepine sedation with flumazenil would not hasten the safe discharge of patients.
Influence of the lumbar interspace chosen for injection on the spread of hyperbaric 0.5% bupivacaine, Forty patients undergoing elective Caesarean section were allocated randomly to receive hyperbaric 0.5% bupivacaine 2.5 ml at either the L2-3 (n = 20) or L4-5 (n = 20) interspace. Spinal injection was performed with a 29-gauge needle in 38 patients and a 25-gauge needle in two. The onset time to analgesia at T10 and T6 was significantly faster and the level of analgesia at 5 and 10 min after injection significantly higher after injection at L2-3. Maximum height and range of analgesia. the level of analgesia at 15 and 20 min after injection and the number of episodes of hypotension were not significantly different between the two groups. One case of post-dural puncture headache was recorded after use of a 29-gauge needle. Overall. the choice of lumbar interspace influenced the rate of onset of analgesia. but not the final dermatomal level (mean and range) of analgesia achieved.
Effect of ketanserin on intraoperative blood loss during total hip arthroplasty in elderly patients under general anaesthesia, We have studied the effect of ketanserin. a selective serotonin S2-receptor antagonist. on surgical bleeding in a double-blind. placebo-controlled study in elderly patients undergoing total hip arthroplasty. One group of patients (n = 9) received ketanserin 10 mg i.v. followed by an infusion of 0.075 mg kg-1 h-1. The second group (n = 8) received placebo. Both groups were comparable with regard to age. height and body weight. Mean intraoperative blood loss was 454 ml with ketanserin and 894 ml with placebo (P = 0.004; Wilcoxon two-sample test). Mean duration of the operation was less with ketanserin (112 min) than with placebo (134 min) (P = 0.004). but rate of blood loss was also less with ketanserin (4.1 vs 6.7 ml min-1; P = 0.03). In the ketanserin group. mean arterial pressures tended to be less than in the placebo group. Reductions in central venous pressure were similar in both groups. There were no complications in relation to the use of ketanserin.
Delayed excitatory reaction following interaction of cocaine and monoamine oxidase inhibitor (phenelzine), A case report is presented in which a patient receiving the monoamine oxidase inhibitor. phenelzine. developed a delayed excitatory reaction following administration of topical cocaine spray during anaesthesia for vocal cord surgery. The pharmacological basis of the drug interaction is discussed.
Substance P antagonist inhibits immediate and delayed type cutaneous hypersensitivity reactions, The role of substance P (SP) in allergic reactions of the skin was investigated. Spantide. a competitive inhibitor of SP. was injected intracutaneously into the volar aspect of the forearm prior to the following challenges: benzalkonium chloride (irritant delayed reaction). tuberculin (immunological delayed reaction). UVB irradiation. benzoic acid (non-immunological contact urticaria). different food allergens and latex (in patients with immunological contact urticaria). Only the immunological reactions of contact urticaria and the reaction to tuberculin were suppressed by the SP antagonist. indicating that SP is involved in their pathogenesis.
Hailey-Hailey disease: a widespread abnormality of cell adhesion, Suction has been used to investigate cell adhesion in clinically normal skin in Hailey-Hailey disease. We have demonstrated that there is a widespread subclinical abnormality in keratinocyte adhesion in this disease. There may be a synthesis of functionally deficient adhesion junctions. increased breakdown of adhesion junctions or abnormalities in other adhesion proteins in the epidermis in Hailey-Hailey disease. The findings contrast with those in Darier's disease in which abnormal cell adhesion was only demonstrable in clinically involved skin.
Absorption of hydrocortisone from the skin reservoir in atopic dermatitis, Percutaneous absorption of hydrocortisone was measured in four children and three adults with atopic dermatitis after the application of 1% hydrocortisone cream and again 12 h after the application of a moisturizer containing 80% water and 5% propylene glycol to the same areas. A significant increase in the level of the plasma cortisol was observed after both applications and these levels were still elevated at 24 h. Topically applied hydrocortisone. stored in eczematous skin. could be released from this reservoir by a moisturizer containing propylene glycol.
PUVA treatment of psoriasis in the United Kingdom, Information concerning the operation of 134 PUVA units in 96 dermatology centres in the U.K. was collected by a postal questionnaire. The most common protocol was to give PUVA three times weekly in the treatment of psoriasis. and to choose the initial dose of UVA according to skin type. However. the initial UVA dose encompassed a range of five or more within each skin type.
Relative efficacy of 335 and 365 nm radiation in photochemotherapy of psoriasis, The action spectrum for the induction of phototoxic erythema by treatment with 8-methoxypsoralen (8-MOP) and UVA peaks at around 335 nm. Because earlier investigations reported peak phototoxic activity at 365 nm. we compared the antipsoriatic efficacy of 335 and 365 nm in an oral psoralen photochemotherapy (PUVA) regimen using a monochromator. PUVA with 335 nm was twice as effective as with 365 nm. with respect to both erythemogenicity and the cumulative dose required for clearing psoriasis. However. 335 and 365 nm were equally effective if delivered in equal erythema doses. It appears that in human skin the antipsoriatic activity of 8-MOP parallels its erythemogenicity.
Polymorphic light eruption with contact and photocontact allergy, We report a patient with long-standing polymorphic light eruption (PLE) who developed a photocontact allergy to mexenone and several contact allergies. The occurrence of multiple contact and photocontact allergies in PLE and the possible relationship of such allergies to the pathogenesis of PLE are discussed.
Can health education increase uptake of cervical smear testing among Asian women, OBJECTIVES--To determine the effects of three different methods of providing health education on the uptake of cervical smear testing among Asian women. and to evaluate the acceptability of different health education materials. DESIGN--Prospective cohort study over one year of effects of written materials by post. personal visit to give written materials. and personal visit to show a video on the uptake of smear testing. Techniques included a personally administered questionnaire. SETTING--Leicester. a city with a large Asian population. SUBJECTS--737 randomly selected Asian women aged 18 to 52 who were not recorded on the central cytology laboratory's computer as ever having had a cervical smear test. 159 declined to participate or were not contactable. INTERVENTIONS--Women were randomised into four groups: visited and shown a video (263). visited and shown a leaflet and fact sheet (219). posted a leaflet and fact sheet (131). not contacted at all (124). MAIN OUTCOME MEASURES--Cervical smear test recorded on computer within four months after intervention. RESULTS--57 (37%. 26% of group) of the women visited and given leaflets and 80 (47%. 30% of group) shown the video attended for cervical smears. Only six (5%) of those who were not contacted and 14 (11%) of those sent leaflets had a smear test during the study. CONCLUSION--Health education interventions increased the uptake of cervical cytology among Asian women in Leicester who had never been tested. Personal visits were most effective irrespective of the health education materials used. but there was some evidence that home viewed videos may be particularly effective in one of the most hard to reach groups: Urdu speaking. Pakistani Moslems. Written translated materials sent by post were ineffective.
Routine examination in the neonatal period, OBJECTIVE--To assess the value of the second neonatal examination as a medical surveillance procedure. DESIGN--Prospective survey of routine neonatal examinations and the abnormalities identified during 8 March-30 June 1988. SETTING--Maternity unit with an annual birth rate of 5700. SUBJECTS--For first neonatal examination: 1795 babies born in the unit during the 115 day observation period. For second routine examination: 1747 babies (97.3%) discharged from postnatal ward. MAIN OUTCOME MEASURES--Missed abnormalities (present but not previously noted); minor abnormalities (superficial infection or trivial or transient abnormalities not requiring intervention); and important abnormalities (unlikely to have been present at first examination but requiring intervention). RESULTS--An abnormality was detected in 158 (8.8%) infants on first neonatal examination. 1428 (79.6%) babies had a routine second examination. which disclosed 63 previously undetected abnormalities. Of these. seven (11%) would have been present on first examination. 49 (78%) were considered minor. and seven (11%) important--the most consequential being dislocatable hips (four infants). Thus an important finding was detected by only 0.5% of second examinations. CONCLUSIONS--A second thorough examination in the early neonatal period cannot be justified as a screening procedure. A repeat examination of the hips alone in the first week of life is necessary.
Computed tomography of cranial metastatic malignant melanoma: features, early detection and unusual cases, The cranial computed tomographic (CT) scans reported as showing metastatic disease in patients with malignant melanoma (MM) seen at the Westminster Hospital over a 5 year period were reviewed. Ninety-eight patients with intracranial metastatic MM were identified. Twelve had an initial scan which was reported as normal and particular attention was given to these to see if. in retrospect. any early features of metastatic disease were discernible. Fifty-eight cases showed the "typical" features of intracranial MM; the remainder were unusual in appearance. behavior. or site. Radiological regression was shown in only seven cases on follow-up scans; all but one of these patients had one or two large metastases. No significant lesion was thought to have been missed on a scan after the administration of intravenous contrast medium. but the lesions of three patients were difficult to discern on plain scans. Thus when MM metastasis is suspected. the use of the contrast-only scan is advocated.
Ultrasonic evaluation of gallbladder function prior to non-surgical treatment of gallstones, A comparative analysis of ultrasonic and oral cholecystographic assessment of gallbladder function in symptomatic patients with cholelithiasis is presented. Ultrasonic evaluation demonstrated non-contractile gallbladders in all but one patient with non-opacification during oral cholecystography. whereas all those opacifying on oral cholecystography contracted on ultrasonography. Both techniques showed similar abilities to quantify the size and number of biliary calculi within the limits necessary to determine suitability for treatment. Although computed tomography remains necessary to quantify gallstone density prior to non-surgical treatment. ultrasonography is a safe. acceptable. cheap and preferable alternative to oral cholecystography in assessing gallbladder function.
Imaging of neonatal pulmonary sequestration including Doppler ultrasound, Seven cases of neonatal pulmonary sequestration are reviewed which illustrate the varied clinical presentations and radiological findings. In four patients. real time ultrasound scanning was used to image the chest and the features are described. In three cases. the systemic supplying artery was demonstrated by duplex Doppler scanning and further invasive investigations were avoided; after a chest radiograph. this should be the examination of choice in the investigation of a neonate with a possible pulmonary sequestration.
Patient dose and risk in mammography, Patient dose in mammography is estimated by two different methods which are compared and which give good agreement. A mean tissue dose of about 1 mGy per film is found for a breast of 4.5 cm compressed thickness. Variables which affect dose are then considered quantitatively. including compressed breast thickness. tube potential. grids. magnification and beam collimation. The variables having the greatest effect are breast thickness and magnification. For example. an 8 cm breast receives about four times the mean tissue dose of a 3.5 cm breast. Similarly. using a magnification factor of about 2. dose is increased about four times in the primary beam. but the adverse consequences may be largely removed with conventional collimation to part of the breast only. Finally. the dose estimates are combined with existing data on breast cancer induction to predict the risk of carcinogenesis in a breast screening programme. For example. in a screening centre performing 15.000 examinations per year. only one induced cancer is predicted in about 7 years of screening under average UK conditions of age and breast thickness.
Cesarean sections in Alberta from April 1979 to March 1988, OBJECTIVES: To determine (a) trends in the cesarean section rate in Alberta from April 1979 to March 1988. (b) the contribution of different primary indications to the overall increase in the cesarean section rate and (c) trends in the cesarean section rate by residence of the mother. DESIGN: Retrospective study. PARTICIPANTS: Women who gave birth in acute care hospitals in Alberta during the study period. Indications for cesarean section were defined by a hierarchic classification system. Geographic regions were identified according to the mother's residence. MAIN RESULTS: The crude cesarean section rate increased from 13.2 to 17.3 per 100 deliveries between 1979-80 and 1987-88. Previous cesarean section accounted for 54% of the increase. breech presentation for 17%. fetal distress for 17% and dystocia for 10%. The contribution of previous cesarean section was due to the substantial increase in the number of women presenting with a previous cesarean section. The cesarean section rate among women who had previously had the procedure decreased from 96.7% in 1979-80 to 84.6% in 1987-88. The crude cesarean section rates by region varied from 10.3 to 22.3 per 100 deliveries. CONCLUSIONS: Further efforts to reduce the rate of cesarean section among women who have previously undergone the procedure are needed to control the rate of cesarean section in Alberta. Decreasing the rate of primary cesarean section is also an important goal.
Adequacy of preparation for barium enema among elderly outpatients, OBJECTIVE: To determine whether outpatients 75 years of age or older have a higher rate of inadequate bowel preparation for barium enema and of complications associated with the preparation and the test than patients aged 55 to 74 years. DESIGN: Cross-sectional survey. SETTING: Radiology department in a teaching hospital. PATIENTS: Patients 55 years or older referred for a barium enema from March to August 1988. OUTCOME MEASURES: All films were reviewed independently by a study radiologist blind to the staff radiologist's report. Patients were interviewed by telephone within several days after the test to assess the occurrence of problems during the preparation or the test. MAIN RESULTS: Of the 213 patients assessed 72 were excluded: 43 refused to participate or could not be contacted. 16 had previously undergone colonic surgery. and 13 were excluded for other reasons. The remaining 141 patients were separated into three age groups: those 55 to 64 years (46 patients). those 65 to 74 (47) and those 75 or older (48). In 104 cases (74%) the bowel had been prepared adequately; there was no significant difference between the three groups with regard to the adequacy of preparation. The incidence of problems reported by the patients did not differ significantly between the groups. CONCLUSIONS: Outpatients aged 75 years or more are no more likely than those aged 55 to 74 to have problems with bowel preparation or the barium enema itself. Age should not be a criterion for exclusion from barium enema. To try to lower the rate of poor bowel preparation clinicians and radiologists should consider counselling patients more carefully about the importance of proper preparation. Also. the current method of preparation could be examined to determine whether simple changes would significantly improve colon cleanliness.
Intraoperative radiation therapy for recurrent head and neck cancer, Forty-seven patients with recurrent head and neck cancer in a previously irradiated field were treated with surgical resection and intraoperative radiation therapy (IORT). Recurrent disease occurred at a median of 18 months from primary treatment. and was at the primary tumor site in 31 and metastatic to regional lymph nodes in 16. Recurrences were squamous cell carcinomas in 42 and adenoid cystic in five. Surgical resection left microscopic residual disease in 41 and gross residual in six. All patients received IORT with a median of 20 Gy. Two-year actuarial survival is 54.9%. and 15 patients are alive and disease free with a median survival of 29 months. Two-year actuarial local control is 61.5%. A trend toward increased survival (P less than 0.09) and local recurrence control (P = 0.05) was noticed when treating microscopic residual disease as opposed to gross residual disease. Perioperative mortality was seen in 8.5% and there was no increase in morbidity secondary to IORT. The authors believe that surgical resection and IORT is an effective treatment modality for head and neck cancers recurrent in previously irradiated fields and is adaptable to tertiary care hospitals.
In vitro radiation resistance among cell lines established from patients with squamous cell carcinoma of the head and neck, Twenty-five squamous cell carcinoma (SCC) cell lines from 20 patients with head and neck cancer were assessed for radiosensitivity in vitro using a 96-well plate assay. Four non-SCC lines were also tested. Radiation sensitivity of individual cell lines was compared using the area under the survival curve (AUC) as a measure of the mean inactivation dose. Tumor lines were tested with either a cobalt-60 (60Co) gamma-irradiator having a dose rate of 100 cGy/minute or with a 4-meV photon beam having a dose rate of 200 cGy/minute. The mean AUC of the 25 SCC cell lines was 188 +/- 7 (SEM) cGy (range. 100 to 250 cGy) whereas the four non-SCC lines had a mean AUC of 225 +/- 9 cGy. The SCC cell lines with mean inactivation dose values greater than 188 cGy were classified as relatively radioresistant whereas those with values less than 188 cGy were considered relatively radiosensitive. In seven cases SCC cell lines were derived from patients who had already received radiation therapy. In four of these cases the tumor cell lines were radioresistant (AUC. 210 to 250) but in the other three cases the tumor lines were radiosensitive (AUC. 160 to 180). Thus. failure of a tumor to respond to radiation did not always select for radioresistant cells. The mean of the AUC for cell lines from previously irradiated patients (197 +/- 11 cGy) did not differ significantly from that of the cell lines from patients who received no prior radiation therapy (182 +/- 9 cGy). However. among radiation-resistant lines those from the four previously irradiated patients were significantly more resistant (mean AUC = 235 +/- 9) than seven other radioresistant lines from nonirradiated patients (mean AUC. 208 +/- 4) (P = 0.0194). In four cases more than one cell line was derived from different tumor specimens in the same patient. In each of these cases the lines from the same patients were similar to one another in their degree of radioresistance. Based on these observations the authors conclude that the degree of in vitro radiation resistance is an inherent property of some squamous cell tumors.
Retinoblastoma. The long-term appearance of radiated intraocular tumors, A retrospective analysis of 50 patients with retinoblastoma was undertaken to determine the appearance of intraocular retinoblastoma that had received external beam radiation a minimum of 10 years previously. Of the 91 tumors found in 59 eyes. 76 (84%) continued to be ophthalmoscopically visible after 10 years. The most common ophthalmoscopic appearance was a Type III regression pattern. The type of radiation regression pattern correlated with the pretreatment volume of the tumor. The largest tumors (mean. 10.0 disc diameter [dd]) became Type I regression patterns. whereas the smallest tumors (mean. 1.0 dd) completely disappeared. This represents the first long-term follow-up of the intraocular status of radiated retinoblastoma.
Is craniospinal irradiation required to cure children with malignant (anaplastic) intracranial ependymomas, Between 1970 and 1989. 17 children with histologically malignant intracranial ependymomas received treatment at the University of Pennsylvania (Philadelphia. PA). Eleven were treated with prophylactic cranial or craniospinal irradiation plus a local boost (CS-XRT). five with local (L-XRT) irradiation only. and one was treated without (NRT) irradiation. With a median survival of 2 years and a median follow-up time for long-term survivors of 6.0 years. five of 11 patients who received CS-XRT are alive compared with none treated with L-XRT and none treated with NRT. Two-year actuarial survival rates are 40% (L-XRT) and 52% (CS-XRT). When examined for other factors. age and local radiation dose remain the most significant prognostic indicators of survival. The 2-year actuarial survival for children younger than 4 years at diagnosis is 20% compared with 83% for their older counterparts. Likewise. the 2-year survival for patients treated with local radiation doses over 4500 cGy was 55% compared with 0% for patients treated with lesser doses. To date there are a total of 28 recurrences. All have occurred with local components except for six (unknown) who died before the exact site(s) could be determined. There is no significant difference in the failure rates outside the original tumor bed in the three groups. These data suggest that local relapse remains the most significant component of failure. Because intrinsic and extrinsic factors such as age and radiation dose seem to be interrelated and at least as important as the use of craniospinal irradiation. the need for prophylactic treatment for children with anaplastic ependymoma could neither be substantiated nor refuted. The use of local radiation alone. however. should be restricted to carefully designed clinical trials in which meticulous pretreatment evaluation is performed. and vigilant posttreatment evaluation of the spine and brain is mandatory.
Importance of histologic condition and treatment of pediatric cerebellar astrocytoma, Histologic classification and treatment of pediatric cerebellar astrocytomas is an area of controversy. At the Medical College of Wisconsin. 34 patients less than 15 years of age (median. 7.3 years of age) with cerebellar astrocytomas were seen from 1965 to 1988. Effect of histologic condition and treatment on overall survival (OS) and progression-free survival (PFS) was analyzed. Progression was defined as radiographic evidence of an enlarging mass and/or signs and symptoms indicative of advancing disease. Histologic material was reviewed and classified by the system of Winston and Gilles. Twenty-eight patients had glioma A tumors. and six patients had glioma B tumors. For patients with glioma A (n = 28). 5-year actuarial OS rate was 100%. For patients with glioma B (n = 6). 5-year actuarial OS rate was 41%. PFS rate was 66% and 0% for patients with glioma A and glioma B. respectively. The poorer PFS for patients with B histologic tumors was statistically significant (P less than 0.001). The median time to progression was 36 months and 23 months for patients with glioma A and B. respectively. Patients were retrospectively divided into total resection and observation. total resection and irradiation. subtotal resection and observation. and subtotal resection and irradiation groups. which were composed of 12. 2. 3. and 17 patients. respectively. Five-year actuarial OS rates were 100%. 50%. 50%. and 100%. respectively. PFS rates were 60%. 50%. 33% and 58%. respectively. These data support the Gilles classification as a prognostic tool because patients with B tumors had a higher incidence of disease progression and accounted for all deaths. Postoperative irradiation after subtotal resection seems to be beneficial. but additional investigation. ideally with a prospective randomized trial. will be necessary to firmly establish this.
Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group, Between 1977 and 1985. the Gynecologic Oncology Group (GOG) conducted three clinical trials in locally advanced carcinoma of the cervix. clinical Stages I to IVA as classified by the International Federation of Gynecology and Obstetrics (FIGO). All 626 patients had primary carcinoma of the cervix and underwent operative assessment of the para-aortic (PA) lymph nodes. Patients received standardized external radiation therapy to the pelvis or to the pelvis and PA lymph nodes followed by one or two brachytherapy applications. To date. no statistically significant differences in progression-free interval (PFI) or survival time have been identified between the randomization treatment arms on any of these studies. Basic similarities among these studies led us to pool these data to identify patient characteristics and tumor characteristics associated with an increased risk of treatment failure. Multi-variate analysis showed patient age. performance status (PS). PA lymph node status. tumor size. and pelvic node status to be significantly associated with PFI. When modeling for survival. all these factors and clinical stage and bilateral extension were significant.
Mammographically detected breast cancer. Results with conservative surgery and radiation therapy, At Yale-New Haven Hospital (New Haven. CT) treatment of early stage breast cancer with conservative surgery and radiation therapy (CS & RT) has been utilized with increasing frequency since the 1960s. The authors have reviewed their experience with specific reference to the outcome of those patients whose breast cancer was detected on routine screening mammography. To achieve adequate follow-up. only patients treated before December 1984 are included in this analysis. Of 438 patients treated with CS & RT before December 1984. a total of 41 patients (9%) had nonpalpable lesions detected on routine screening mammography and were treated with CS & RT to the intact breast. Only two patients received adjuvant hormonal therapy and no patients received adjuvant systemic therapy. There has been only one breast failure and one death due to cancer in this group of patients resulting in actuarial survival and breast recurrence-free rates of 100% at 5 years and 92% at 10 years. These results stress the importance of routine screening mammography and raise questions regarding the role of adjuvant systemic therapy in this selected group of patients.
Reirradiation for extremity soft tissue sarcomas. Local control and complications, The treatment for patients who have locally recurrent soft tissue sarcoma of the extremity after surgery and radiation therapy is primarily amputation. A second course of radiation and local excision is usually not considered because of two major concerns: radiation complications and inability to achieve local disease control. This study examines the clinical course of 32 patients who received a second course of radiation for soft tissue sarcoma. Four groups of patients were defined by the sequence of radiation (preoperative and postoperative) and surgery. Despite high cumulative doses of radiation. complications requiring amputation were rare. Local tumor control was achieved with a second course of preoperative radiation and wide local excision in 15 of 18 (84%). However. local excision and a second course of postoperative radiation resulted in eight of 14 (57%) local failure and cannot be recommended as a comparable therapy to amputation.
Radiation therapy as local treatment in Ewing's sarcoma. Results of the Cooperative Ewing's Sarcoma Studies CESS 81 and CESS 86, The Cooperative Ewing's Sarcoma Studies. CESS 81 and CESS 86. are multiinstitutional trials with more than 80 participating institutions from Germany. the Netherlands. Austria. and Switzerland. Treatment consists of four courses of multiagent chemotherapy and local therapy. Local therapy was not randomized and was either radical surgery or resection plus postoperative irradiation or definitive radiation therapy. Here results according to local therapy have been analyzed for 93 protocol patients with localized Ewing's sarcoma (ES) who have been recruited in CESS 81 from January 1981 to February 1985 and 122 protocol patients recruited in CESS 86 from January 1986 to November 1989. The 3-year relapse-free survival (RFS) was 55% in CESS 81 and 62% in CESS 86. In CESS 81. the RFS was better for surgically treated than for irradiated patients. In this study there was an extremely high incidence of local failures (50%) after definitive irradiation. In CESS 86. however. the results after radiation therapy have been improved markedly (3-year RFS 67% after radiation therapy. 65% after surgery. and 62% after resection plus irradiation). Possible explanations for the improvement of radiotherapeutic results are as follows: selections for patients for radiation therapy. start of local therapy. and quality of radiation therapy. In CESS 86. irradiated patients were randomized to receive either conventionally fractionated irradiation with less intense chemotherapy or hyperfractionated irradiation with simultaneous chemotherapy. There was no difference in treatment results at the time of analysis. The authors conclude that selection of patients for local treatment modalities and quality of treatment performance has an impact on local and overall treatment results in ES.
Increased cisplatin tissue levels with prolonged arterial infusion in the rat, Prolonged arterial infusions of cisplatin (DDP) have been effective in the treatment of regionally confined malignancies. It is unclear whether the route or schedule of DDP administration was responsible for the observed therapeutic benefit. To resolve this issue. tumor and normal tissue platinum (Pt) levels were determined in rats bearing hind-limb rat mammary tumors after intravenous (IV) and intra-arterial (IA) DDP infusions of constant dose and varying lengths. Infusions of DDP at 6 mg/kg were conducted IA over 30 minutes. and 3. 6. 24. and 48 hours and IV over 30 minutes and 48 hours. After infusion. Pt concentrations in solubilized tissue homogenates were measured by flameless atomic absorption spectroscopy. Maximum tumor Pt levels were seen after 48-hour IA infusion (29.3 micrograms Pt/mg tissue). IA infusions of 24 hours or less resulted in significantly lower Pt levels. Maximum tumor Pt concentration after IV administration was only 0.98 micrograms/mg tissue (48-hour infusion). Muscle Pt levels adjacent to the tumor were highest in the IA infused extremities. but at the 48-hour interval. were 53-fold less than tumor levels. Tumor and adjacent muscle Pt levels were not significantly different from each other after IV administration. This study provides pharmacologic evidence that lengthening the duration of IA DDP infusion increases tumor levels of Pt over that of IV or rapid IA administrations. The benefit of prolonged IA DDP infusions is dependent upon both route and schedule of drug administration.
Mammographic densities and risk of breast cancer, To determine the relation of mammographic densities to subsequent breast cancer risk. a case-control study was undertaken using prediagnostic mammograms of screening program participants. Mammograms of cases (n = 266) and controls (n = 301) were blindly assessed for mammographic densities. which were measured by planimetry. The odds of breast cancer increased steadily with increasing breast density (test for trend. P less than 0.0001). Breast cancer odds was 1.7 for densities between 5% and 24.9%. 2.5 for 25% through 44.9%. 3.8 for 45% through 64%. and 4.3 for densities of 65% and greater (referent = less than 5% densities). Odds ratios also increased with increasing densities among women with the P2 and DY mammographic patterns. These findings suggest that the percentage of mammographic densities in the breast can predict breast cancer risk more accurately than a qualitative assessment of mammographic patterns.
Intraoperative radiation therapy for Wilms' tumor in situ or ex vivo, Patients with bilateral Wilms' tumor who have local recurrence after undergoing maximum-dose multitechnique therapy are problematic. The role of surgery in the management of these patients is changing from ablation to preservation of renal tissue. Bilateral nephrectomy is reserved as a last resort. Intraoperative radiation therapy (IORT) is advantageous to conservative management. as illustrated by the current cases of two children with recurrent Wilms' tumors in their remaining kidneys. Both children underwent limited surgery and precisely directed IORT. In one patient the nephron-sparing surgery and IORT were performed in situ. In the other the kidney was removed. treated with ex vivo bench surgery and radiation surgery. and then reimplanted. The adjuvant use of IORT. either in situ or ex vivo. in nephron-sparing surgery permits complete obliteration of gross and microscopic disease while maximizing residual renal function.
Intracarotid chemotherapy with etoposide and cisplatin for malignant brain tumors, Chemotherapy for tumors of the central nervous system has a limited efficacy presumably because of restricted blood-brain barrier permeability. The advantage of regional intra-arterial administration of anticancer drugs is an increased uptake during the first passage of the drugs through tumor capillaries. Twenty patients with high-grade astrocytomas (HGA) and 28 patients with metastatic brain tumors (MBT) received intracarotid/intravertebral infusion of etoposide and cisplatin. Eight patients with HGA who underwent incomplete resection responded to chemotherapy alone. Four additional patients had complete resection of the tumor. Median survival time of the group (responders and nonresponders) has been 14 months. Twelve patients with MBT responded to chemotherapy alone (six had complete response [CR]. and six had partial response [PR]) with a median survival time of 7 months. Intra-arterial chemotherapy (IAC) appears to be effective with acceptable toxicities. Accrual of additional patients is required before a final conclusion can be reached.
Solitary minute hepatocellular carcinoma. A study of 14 patients, Fourteen patients with clinical Stage I hepatocellular carcinoma (T1N0M0) were studied. All patients were asymptomatic. and their conditions were detected by alpha-fetoprotein (AFP) serosurvey and/or ultrasonography (US) either in the natural population in the early years of the study or in the high-risk population in the later years of the study. Cirrhosis was present in all patients. Radical resection was performed in all patients. There were no operative deaths or hospital deaths in this series. The 5-year survival rate after resection was 100%. There were seven long-term survivors in this series (14.2 years (alive). 11.3 years (alive). 8.8 years (alive). 8.8 years. 7.9 years. 7.6 years (alive). and 7.2 years after resection). The authors discuss aspects concerning early diagnosis. treatment. and prognosis of hepatocellular carcinoma (HCC).
Preoperative high-dose leucovorin/5-fluorouracil and radiation therapy for unresectable rectal cancer, Twenty patients with primary or recurrent unresectable rectal cancer limited to the pelvis were entered on a Phase I trial of preoperative pelvic radiation therapy (RT) (5040 cGy) and two cycles of combined high-dose leucovorin (LV) and 5-fluorouracil (5-FU). followed by surgery and ten cycles of postoperative LV/5-FU (sequential). Maximum tolerated doses (MTD) were determined for preoperative combined LV/5-FU and RT and for postoperative sequential LV/5-FU. 5-FU was escalated 50 mg/m2 while the LV remained constant at 200 mg/m2. The initial doses of 5-FU were combined LV/5-FU and RT (200 mg/m2) and sequential LV/5-FU (325 mg/m2). The median follow-up time was 14 months. The resectability rate was 89%. and the pathologic complete response rate was 21%. The MTD for combined LV/5-FU and RT was 300 mg/m2; therefore. the recommended dose of 5-FU is 250 mg/m2. The recommended dose of 5-FU for sequential LV/5-FU is 375 mg/m2. The dose-limiting toxicities in this trial were diarrhea. tenesmus. increased bowel movements. dysuria. and myelosuppression. For the six patients who received 5-FU at the recommended dose level. the median low counts were leukocyte count. 3.7/microliters (range. 2.4 to 4.9/microliters); hemoglobin. 9.0 g/dl (range. 8.2 to 11.9 g/dl); and platelet count (X1000). 146/microliters (range. 89 to 182/microliters). The incidence rate of any Grade 3 toxicity was 17% (diarrhea and frequent bowel movements). The recommended doses of 5-FU used in this protocol were well tolerated. Because there was a long delay before optimal doses of 5-FU could be delivered. the authors do not recommend that high-dose LV be used in conjunction with combined 5-FU and RT with the treatment regimen as currently designed. However. because the resectability and complete response rates were higher than those previously reported for preoperative RT alone. the authors are encouraged by the combined technique approach. New trials are currently being undertaken to determine if the use of a low-dose LV regimen is more tolerable.
Concomitant whole-abdominal radiation and intraperitoneal chemotherapy in advanced ovarian carcinoma. A pilot study, Because the use of cisplatin-based chemotherapy for ovarian carcinoma has not significantly improved 5-year survival rates compared with either whole-abdominal radiation (WAR) or single-agent chemotherapy. a pilot study was begun to assess the feasibility of concomitant radiation and chemotherapy. Eleven previously untreated patients with Stages III and IV ovarian carcinoma were treated concomitantly with 2000 cGy of WAR and intraperitoneal (IP) cisplatin followed by additional IP cisplatin after debulking surgery. Toxicity was moderate to severe. Sixty-four percent of patients had Grades 3 to 4 hematologic toxicity. and 36% required hospitalization for sepsis during WAR/IP cisplatin. Hematologic toxicity was less pronounced during IP cisplatin alone. All patients experienced moderate gastrointestinal toxicity. The average percentage of total body weight lost was 13.5%. Fifty-five percent of all patients demonstrated a complete clinical response to therapy. and patients with minimal postoperative residual disease fared better. One patient with persistent disease had acute nonlymphocytic leukemia (ANLL) 24 months after initial diagnosis. No patients with residual disease greater than 20 mm survived. while 50% of patients with less than 20 mm are clinically free of disease. Toxicity appears to be additive with the combination of WAR and IP cisplatin. Therapeutic efficacy was comparable with standard chemotherapy regimens. but no therapeutic or survival advantages were demonstrated with the use of this treatment protocol.
Adjuvant external beam therapy for pathologic stage I and occult stage II endometrial carcinoma, Eighty-six patients with pathologic Stage I or occult Stage II carcinoma of the endometrium and myometrial invasion and/or Grade 2 or Grade 3 histologic condition received whole-pelvis external radiation therapy (RT) after extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy. Twenty-one patients received 4250 cGy in 25 daily fractions for 5 weeks (Group 1). 28 received 4500 cGy in 25 daily fractions for 5 weeks (Group 2). and 37 received 5100 cGy in 30 daily fractions for 6 weeks (Group 3). Seventeen patients had intravaginal brachytherapy after whole-pelvis RT. Local recurrence developed in two patients (2.3%) (one in Group 1 and one in Group 2). Statistical analysis showed that the depth of myometrial invasion significantly influenced survival (P = 0.016). Tumor grade. pathologic stage. whole-pelvis radiation dose. and the use of brachytherapy did not influence survival. Complications occurred in 9.5% of patients in Group 1. 24.7% in Group 2. and 40.5% in Group 3. Three patients who received brachytherapy had rectal injuries. The authors conclude that 4250 cGy in 25 fractions for 5 weeks of whole-pelvis RT appears to induce fewer complications than higher doses. and may be sufficient to prevent local recurrence in most patients who require adjuvant RT. A clinical trial is needed to determine the optimum dose-time-fractionation regimen.
Immunohistochemical evidence of immune responses to tumor-associated antigens in lymph nodes of colon carcinoma patients, The authors investigated by immunohistochemical study the drainage of three tumor-associated antigens in unaffected regional lymph nodes of colon cancer patients. The study was conducted using monoclonal antibodies (MoAb) directed against different epitopes of the tumor-associated glycoprotein. TAG-72 (CC-49. CC-83. B72.3). of the carcinoembryonic antigen (CEA) (COL-4. COL-12). and of the colon-associated antigen. CAA (anti-CAA). The authors detected immunohistochemical reactions of MoAb CC-49 and anti-CAA with antigen-presenting cells (APC). such as peritumoral and sinus macrophages and lymphatic endothelial cells and with specific areas of germinal centers in lymph nodes draining 11 of 24 colorectal carcinomas studied. The corresponding primary tumors expressed the TAG-72 and CAA antigens. No immunostaining was detectable in lymph nodes using the anti-CEA MoAb. even when the primary tumors strongly expressed the specific epitopes. In germinal centers of regional lymph nodes. the immunostaining was often distributed at the periphery with a characteristic crescentic or circular pattern. which strongly suggested the exposure of the specific epitopes defined by MoAb CC-49 and anti-CAA on follicular dendritic cells. This would indicate that these epitopes are selectively recognized and presented to germinal center B-cells. This phenomenon may have clinical and diagnostic implications.
Expression of c-erbB-2 oncoprotein in gastric carcinoma. Immunoreactivity for c-erbB-2 protein is an independent indicator of poor short-term prognosis in patients with gastric carcinoma, Correlations of c-erbB-2 protein expression with clinical outcomes of gastric carcinomas were studied in 189 gastric carcinomas. There were 23 (12.2%) carcinomas with evidence of c-erbB-2 protein in which the reaction was localized to the cell membrane. There was no significant association between c-erbB-2 staining and the macroscopic or histologic type of the carcinomas. c-erbB-2-stained tumors were more likely to be associated with serosal invasion. nodal involvement. and peritoneal metastasis. than c-erbB-2-unstained ones. In addition. c-erbB-2 was stained in none of early gastric carcinomas. The 5-year survival rates of the c-erbB-2 protein-positive and the protein-negative group were 11% and 50%. respectively. When the c-erbB-2 tissue status and seven clinicopathologic variables as conventional prognostic factors were entered simultaneously into the Cox regression model. serosal invasion. hepatic metastasis. peritoneal metastasis. nodal status. and c-erbB-2 tissue status emerged as independent prognostic variables. The results suggested that c-erbB-2 protein expression might be enhanced in advanced stages during the progression of gastric carcinoma. In this particular group of patients. immunoreactivity for c-erbB-2 protein is an indicator of poor short-term prognosis.
Phosphate metabolites and steroid hormone receptors of benign and malignant breast tumors. A Nuclear Magnetic Resonance study, Phosphorous 31 (31P) nuclear magnetic resonance (NMR) spectra were recorded from perchloric acid extracts of benign and malignant breast tumors. The spectra were correlated with the histopathologic diagnosis and the steroid receptor status of the tumor. Higher relative content of the lipid-derived metabolite glycerolphosphoethanolamine (GPE). the high-energy nucleoside phosphates (nucleoside-diphosphate [NDP]. nucleoside-triphosphate [NTP]). and sugar esters of uridine diphosphate (UDPS) appeared in the carcinomas. Malignant tumors also showed a lower ratio of phosphoethanolamine to phosphocholine (PE/PC) than benign conditions. Lower content of the lipid-derived metabolite glycerolphosphocholine (GPC) and high content of the high-energy compound phosphocreatine (PCr) were associated with malignant tumors having high content of estrogen receptors (ER). High PCr content was also associated in the carcinomas with high progesterone receptors (PgR) content. In the benign tumors NDP and NTP were higher in tumors with high PgR content. The authors suggest that 31P magnetic resonance spectroscopy (MRS) of the breast can provide additional variables to diagnose malignancy. and when combined with magnetic resonance imaging (MRI). invasive procedures may be avoided. It also seems that levels of PCr and GPC obtained from the spectra can serve as markers to hormonal receptor status of breast carcinomas. and may be used in addition to the ER and PgR content to improve prediction of the response to hormonal therapy. Additional development requires in situ MRI and MRS combined studies.
The prevalence and epidemiology of luteal-phase deficiency in normal and infertile women, The difficulty in determining the prevalence and epidemiology of LPI lies in the ambiguity of diagnosis. To define the abnormal. a complete delineation of normal is first required; this has been disregarded for most diagnostic criteria of this disorder. Once normal is defined. a link between the abnormal state and subfertility is required to demonstrate clinical relevance; this has yet to be shown with any form of LPI criteria. Despite this. some pieces of the puzzle are apparent. In the form of a short luteal phase LPI is present in roughly 5% of ovulatory cycles. The rate also tends to increase at the extremes of reproductive age. The rate of hormonal- or biopsy-diagnosed LPI appears to be in approximately the same range. although the criteria for diagnosis are much more poorly defined. and the rate of "abnormal" is often built into the definition. Finally. ongoing development of more precise and accurate tools for diagnosis promises to produce more and better data in the future to furnish the clinician with greater insight into the rate and overall importance of LPI as a cause of infertility.
Achlorhydria-induced hypergastrinaemia: the role of bacteria, 1. Studies of Helicobacter pylori show that microbes can alter gastrin release. Lack of gastric acid (achlorhydria) causes hypergastrinaemia and allows bacteria to grow within the stomach. We speculated that the bacteria contribute to the rise in gastrin seen after acid inhibition. and tested the idea by comparing plasma gastrin levels during inhibition of acid secretion between germ-free and conventional rats. 2. Matched germ-free and conventional rats (n = 8 per group) received either vehicle (saline) or one of two doses of the histamine-H2-receptor antagonist loxtidine for 1 week. Gastrin was measured in cardiac blood by a specific r.i.a. 3. Plasma gastrin concentrations in germ-free and conventional rats were 59 +/- 11 pmol/l (mean +/- SEM) and 36 +/- 8 pmol/l. respectively. after vehicle. and 153 +/- 30 pmol/l and 181 +/- 27 pmol/l. respectively. after loxtidine at a dose of 10 mg day -1 kg -1. which partially inhibits acid secretion. Administration of loxtidine at a dose of 70 mg day -1 kg-1. which completely inhibits acid secretion. did not produce a significant extra rise in plasma gastrin concentration in germ-free rats (178 +/- 11 pmol/l). but further elevated plasma gastrin concentrations to 278 +/- 26 pmol/l in conventional rats (P less than 0.005 compared with germ-free rats). 4. Loxtidine produced a dose-dependent rise in the number of eosinophils in the gastric mucosa of conventional rats. 5. We conclude that partial inhibition of gastric acid secretion increases gastrin release independently of bacteria. but that bacteria are involved in the further rise in gastrin which occurs on more profound inhibition of gastric acid secretion.
A study of thyroglobulin and peroxidase activity in the thyroid tissue of patients with non-endemic non-toxic nodular goitre, 1. A study was made of the activity of the enzyme thyroid peroxidase and of the concentration. carbohydrate composition and the degree of iodination of thyroglobulin in the thyroid glands of 60 patients with non-endemic non-toxic goitre in the nodular phase and in those of 25 control subjects. 2. Thyroid peroxidase activity was determined by the guaiacol assay and was significantly higher in patients with non-endemic non-toxic goitre than in control subjects (3.60 +/- 2.51 and 2.07 +/- 1.08 mumol of guaiacol oxidized min-1 g-1 of tissue. respectively; ranges 0.16-10.57 and 0.52-4.85 mumol of guaiacol oxidized min-1 g-1 of tissue. respectively; P less than 0.05). 3. Thyroglobulin was purified by precipitation with ammonium sulphate and Sephadex G-200 gel filtration. Two protein peaks were obtained which were identified as thyroglobulin and measured by radioimmunoassay. The concentration of thyroglobulin in the first peak was 98.94 (SD 84.87. range 0.60-455.54) mg/g of tissue for the patients with non-endemic. non-toxic goitre and 51.41 (SD 28.34. range 14.99-106.39) mg/g of tissue for the control subjects (P less than 0.01). The second peak showed 1.26 (SD 1.27. range 0.09-6.50) mg of thyroglobulin/mg of tissue for the group with non-endemic non-toxic goitre and 0.51 (SD 0.25. range 0.15-0.98 mg of thyroglobulin/mg of tissue) for the control subjects (P less than 0.01). 4. The carbohydrate composition of thyroglobulin was determined by acid hydrolysis and colorimetry. evaluating the levels of hexoses. hexosamines and sialic acid.
Long-term reproducibility of Borg scale estimates of breathlessness during exercise, 1. The intensity of breathlessness in normal subjects during exercise was measured on seven occasions over a 40-week study period to assess the long-term repeatability of Borg scale estimates of breathlessness. 2. In all subjects there was a significant correlation (P = 0.0001) between breathlessness and minute ventilation. Minute ventilation measured at each work rate did not differ between the seven exercise tests (P greater than 0.05). 3. There was no significant difference between the mean Borg scores (measured with respect to a given level of ventilation) in 5 of the 7 test weeks (P greater than 0.05). The slope of the relationship Borg score/minute ventilation did not differ between the seven exercise tests (P greater than 0.05). 4. Breathlessness estimation was highly reproducible both after 1 week and after 40 weeks of the study (both P greater than 0.05). 5. The duration without testing between consecutive tests did not affect reproducibility: the mean Borg score was as equally reproducible after an interval of 22 weeks without testing as after an interval of 1 week (P greater than 0.05). 6. The Borg scale provides a reliable technique for studying the sensation of breathlessness over extended time periods.
Triacylglycerol in the human erythrocyte: quantification and fatty acyl turnover in normal subjects and chronic alcoholics, 1. Triacylglycerol in erythrocytes from normal human subjects was estimated to average 2.7 +/- 0.7 nmol/10(10) cells. equivalent to 0.07% of total lipids or 0.3% of neutral lipids. 2. The specific activity of triacylglycerol labelling attained by incubating intact erythrocytes with [3H]oleic acid was 10 nmol/mumol. a value 20-fold higher than that of the highest labelled phospholipid. sphingomyelin; as isolated by ultracentrifugation over a density gradient. the youngest erythrocytes exhibited a labelling rate 10-fold higher than that of older cells. 3. The triacylglycerol content was not modified in erythrocytes from chronic alcoholics. whereas the mean rate of triacylglycerol labelling was 31% (P less than 0.05) higher than that of control subjects. and did not normalize 4 weeks after alcohol withdrawal. 4. These results indicate that triacylglycerol. although a quantitatively minor component. is one of the most active metabolites in the lipid matrix of the human erythrocyte membrane and appears to be implicated in the membrane response to antagonistic agents.
Total body calcium in patients with inflammatory bowel disease: a longitudinal study, 1. Serial measurements of total body calcium have been made by prompt gamma-neutron activation analysis in 13 patients with inflammatory bowel disease over a mean period of 23 months. Changes in spinal trabecular bone mineral density and radial shaft bone mineral content were also assessed by using quantitative computed tomography and single photon absorptiometry. respectively. 2. The mean annual decreases (95% confidence intervals) were: total body calcium. 7.8% (-12.0 to -3.7%; P less than 0.001); spinal trabecular bone mineral density. 2.5% (-5.0 to +0.1%; 0.05 less than P less than 0.1). radial bone mineral content. 2.1% (-3.4 to -0.8%; P less than 0.01). 3. No significant correlations were found between rates of change of the three variables. However. there were significant positive correlations between the baseline values for total body calcium and radial bone mineral content (r = 0.638. P less than 0.05). spinal bone mineral density and radial bone mineral content (r = 0.854. P less than 0.01). and total body calcium and spinal bone mineral density (r = 0.876. P less than 0.001). 4. These results demonstrate rapid decreases in total body calcium in patients with inflammatory bowel disease which. in conjunction with the significant decrease in radial shaft bone mineral content. indicate increased rates of cortical bone loss. Whilst values for bone mass at different skeletal sites showed positive correlations within individuals. no relationship was found between the rates of change in bone mass at these sites. 5. The rapid bone loss observed in some subjects emphasizes the importance of early detection of osteoporosis by bone densitometry and the need for effective prophylactic measures to be established in this group of patients.
Adrenoceptors on blood cells from patients with primary Raynaud's phenomenon, 1. alpha 2-Adrenoceptors on platelet membranes and beta 2-adrenoceptors on lymphocytes were studied in 24 patients with primary Raynaud's phenomenon and in 24 age- and sex-matched control subjects. In two subgroups. a standardized mental arithmetic test and a finger-cooling test were performed. 2. Baseline blood pressure. heart rate and forearm blood flow did not differ between the two groups. 3. Baseline skin microcirculation (laser Doppler flux) was decreased in primary Raynaud's phenomenon (19 +/- 15 arbitrary units) compared with control subjects (33 +/- 14 arbitrary units) (P less than 0.01). 4. Baseline plasma noradrenaline concentration (2.00 +/- 1.44 versus 1.16 +/- 0.36 nmol/l) and alpha 2-adrenoceptor density (301 +/- 119 versus 210 +/- 82 fmol/mg) were increased in patients with primary Raynaud's phenomenon in comparison with the control subjects. The alpha 2-adrenoceptor density/beta 2-adrenoceptor density ratio in patients with primary Raynaud's phenomenon was. with a value of 0.37 +/- 0.04. higher than in the control subjects. where a value of 0.25 +/- 0.02 was measured (P less than 0.001). Plasma adrenaline concentration. beta 2-adrenoceptor density and the antagonist affinity to both receptor subtypes did not differ between both groups under baseline conditions. 5. Whereas during the finger-cooling test no differences were seen in the responses of the parameters measured. the mental arithmetic test induced an increase in laser Doppler flux in patients with primary Raynaud's phenomenon and a decrease in the control group.
Autonomic mechanisms underlying intraocular pressure changes during insulin-induced hypoglycaemia in normal human subjects: effects of pharmacological blockade, 1. A fall in intraocular pressure is induced by acute hypoglycaemia in humans. The role of the autonomic nervous system in mediating this response was investigated in 24 normal volunteers in whom hypoglycaemia was induced with intravenous soluble insulin. under four experimental conditions: (1) control (n = 6). (2) non-selective alpha-adrenoceptor blockade (phentolamine) (n = 6). (3) non-selective beta-adrenoceptor blockade (propranolol) (n = 6) and (4) cholinergic blockade (atropine) (n = 6). Intraocular pressure was measured by using an applanation tonometer. In 12 subjects intraocular pressure was measured during each type of pharmacological blockade of similar duration without induction of hypoglycaemia. to assess the effects of individual antagonists. 2. In the control study intraocular pressure fell during hypoglycaemia from 15 +/- 1.0 to 10 +/- 1.3 mmHg (P less than 0.01) 10 min after the autonomic reaction. beta-Adrenoceptor blockade caused a reduction in intraocular pressure from 15 +/- 1.1 to 9 +/- 1.0 mmHg (P less than 0.001) before the administration of insulin. and when hypoglycaemia was induced intraocular pressure decreased further to 7 +/- 1.0 mmHg (P less than 0.05. compared with immediately before insulin). A decrease in intraocular pressure of similar magnitude was observed with propranolol alone (16 +/- 1.0 to 10 +/- 1.0 mmHg. P less than 0.05). 3. Cholinergic blockade had no immediate effect on intraocular pressure. and the reduction in intraocular pressure during hypoglycaemia was of similar magnitude to that observed during the control study.
Measurement of whole-body protein turnover in insulin-dependent (type 1) diabetic patients during insulin withdrawal and infusion: comparison of [13C]leucine and [2H5]phenylalanine methodologies, 1. The aims of this study were twofold: (i) to investigate the ability of a recently described [2H5]phenylalanine method for quantifying whole-body protein turnover during acute physiological perturbation; (ii) to determine specifically whether the previously observed increase in protein synthesis on insulin withdrawal in insulin-dependent (type 1) diabetic patients seen when employing the [13C]leucine technique could be corroborated by using [2H5]phenylalanine. 2. Whole-body protein turnover was measured by both the [2H5]phenylalanine and [13C]leucine primed continuous infusion methods applied simultaneously to six type I post-absorptive diabetic patients during insulin withdrawal and infusion. 3. Values were determined by the [13C]leucine method by measuring either [13C]leucine (primary pool) or alpha-[13C] ketoisocaproic acid (reciprocal pool) enrichment in plasma. 4. Values of whole-body protein breakdown during insulin withdrawal derived from the [2H5]phenylalanine and primary and reciprocal pool [13C]leucine models respectively were 3.54 +/- 0.43. 3.85 +/- 0.41 and 4.62 +/- 0.44 g day-1 kg-1 (means +/- SD). Insulin infusion resulted in a significant reduction (P less than 0.02) to 3.07 +/- 0.34. 3.05 +/- 0.26 and 3.82 +/- 0.4 g day-1 kg-1. respectively. Synthesis values fell significantly but by a smaller amount than breakdown. resulting in increased (P less than 0.05) net protein deposition. regardless of the model used. 5. These data demonstrate that the [2H5]phenylalanine and [13C]leucine methods generate similar results both in absolute and relative terms in response to short-term insulin infusion. 6. The confirmation of increased whole-body protein synthesis during insulin withdrawal by two independent methods supports the validity of this observation.
Extent of pulmonary emphysema in man and its relation to the loss of elastic recoil, 1. We assessed lung density. determined by computerized tomography. as a measure of emphysema and related this to lung function and measurement of the elastic recoil of the lung in normal subjects and patients with chronic obstructive lung disease. 2. We found a significant correlation between measurements of elastic recoil pressure at 90% of total lung capacity and both the forced expiratory volume in 1 s (r = 0.80. P less than 0.001) and the transfer factor for carbon monoxide (r = 0.70. P less than 0.001). Measurements of elastic recoil of the lung also correlated with lung density as measured by computerized tomography scanning (P less than 0.001). 3. Multiple regression analysis demonstrated a correlation between the density of the lowest fifth percentile of the computerized tomography lung-density histogram. and both the natural logarithm of the shape parameter of the pressure-volume curve (P less than 0.01). and the transfer factor for carbon monoxide (P less than 0.01). However. the mean computerized tomography lung density correlated. in addition. with the elastic recoil pressure of the lungs at 90% of total lung capacity (P less than 0.001). 4. Since the elastic recoil pressure correlates with computerized tomography lung density. and hence with emphysema. and since elastic recoil pressure also correlates with the forced expiratory volume in 1 s. these results suggest that loss of elastic recoil is one determinant of airflow limitation in patients with chronic obstructive lung disease.
Basal fuel homoeostasis in symptomatic human immunodeficiency virus infection, 1. In eight clinically stable symptomatic human-immunodeficiency-virus-infected patients and in seven healthy control subjects. glucose and fat metabolism were studied. using indirect calorimetry and primed continuous infusions of [3-3H]glucose and [14C]palmitate. 2. Studies were performed in the post-absorptive state (16 h of overnight fasting) and again after 22 h of overnight fasting. 3. In the post-absorptive state. net fat oxidation and triacylglycerol ('triglyceride') concentrations were significantly higher in the patients. but concentrations and turnover of free fatty acids were not significantly different between patients and control subjects. After 22 h of overnight fasting. free fatty acid turnover in the patients rose to significantly higher levels when compared with the control subjects. 4. Post-absorptive glucose oxidation. glucose turnover and glucose clearance did not differ between patients and control subjects. Although fasting induced a significantly greater decline in glucose turnover in the patients. plasma glucose concentrations decreased comparably in patients and control subjects. 5. No differences were found in plasma concentrations of insulin or of the counter-regulatory hormones between patients and control subjects. 6. It is concluded that the metabolic adaptation to short-term starvation in clinically stable human-immuno-deficiency-virus-infected patients differs from that in healthy control subjects. Short-term starvation results in a significantly greater fall in glucose turnover. whereas fat metabolism is clearly stimulated. These alterations cannot be explained by differences in the concentrations of insulin or of the counter-regulatory hormones.
Effects of contractile activity on muscle damage in the dystrophin-deficient mdx mouse, 1. Isolated extensor digitorum longus muscles from control C57BL/10 and mutant dystrophin-deficient C57BL/10 mdx mice have been studied in vitro to determine whether dystrophin deficiency influences the susceptibility of muscle to contractile activity-induced damage. 2. mdx muscles were found to release reduced amounts of intracellular creatine kinase compared with control tissue in response to excessive contractile activity with or without simultaneous stretching of the muscle to 130% of its resting length. 3. In contrast. prostaglandin E2 release from mdx muscle was elevated compared with control tissue in response to either form of contractile activity or to treatment with the calcium ionophore A23187. 4. These results do not support the hypothesis that dystrophin-deficient muscle is more susceptible to damage induced by contractile activity. but suggest that dystrophin deficiency influences the activity of muscle membrane phospholipase enzymes.
Doxepin therapy for postprandial symptomatic hypoglycaemic patients: neurochemical, hormonal and metabolic disturbances, 1. Three oral glucose tolerance tests were performed in each of 32 symptomatic postprandial hypoglycaemic patients (before placebo. before doxepin therapy and after doxepin therapy). Plasma neurotransmitters were determined in parallel with assays of plasma insulin and glucose levels. 2. Three different types of patients were distinguished. Type I showed a low noradrenaline/adrenaline ratio. high dopamine levels and low platelet 5-hydroxytryptamine (serotonin) levels during basal periods. After a glucose load. late peaks of dopamine and free 5-hydroxytryptamine. which coincided with the symptoms but not with the nadir of plasma glucose. were observed. Type II showed a low basal plasma noradrenaline/adrenaline ratio. After a glucose load. progressive increases in adrenaline and decreases in glucose were seen. Adrenergic symptoms coincided with the nadir of glucose. Although type III patients showed hyperinsulinaemia after a glucose load similar to the other types of patient. they did not show hyperglycaemia. but rather exhibited a sustained and progressive reduction in plasma glucose. These patients were characterized by a high basal plasma noradrenaline/adrenaline ratio. high basal plasma levels of 4-hydroxy-3-methoxyphenylethyleneglycol and high basal levels of platelet 5-hydroxytryptamine. all of which increased after a glucose load. Systolic and diastolic blood pressure decreases paralleled reductions in heart rate and glucose. The nadir of plasma glucose occurred simultaneously with the appearance of symptoms (weakness. heartburn. oppressive chest pain. tension headache. abdominal cramps. dizziness. etc.). Therapy with doxepin led to disappearance of the symptoms within 3-4 weeks. Normalization of all other disordered variables (cardiovascular. metabolic and neurochemical. and the clonidine test) paralleled the disappearance of the symptoms. 3. Symptoms varied in the three types of patients and we conclude that they are related to hypoglycaemia-induced disorders of plasma neurotransmitters. rather than to hypoglycaemia per se. We postulate that an uncoping stress situation (type I and II patients) and depression (type III patients) underlie the physiopathological mechanisms.
Differential stimulation by oxygen-free-radical-altered immunoglobulin G of the production of superoxide and hydrogen peroxide by human polymorphonuclear leucocytes, 1. The effect of free-radical-altered IgG (monomer and polymer u.v.-irradiated IgG). compared with that of native and heat-aggregated IgG. on the production rate of superoxide anion and hydrogen peroxide by granulocytes (polymorphonuclear leucocytes) from normal blood and granulocytes obtained from the blood and synovial fluid of patients with rheumatoid arthritis was studied. 2. Similar rates of superoxide production by granulocytes from normal blood at rest and in the presence of any form of IgG were found. In contrast. the rate of hydrogen peroxide production could be stimulated in a dose-dependent fashion by monomer or polymer u.v.-irradiated IgG. 3. The stimulatory effect of free-radical-altered IgG on the rate of hydrogen peroxide production did not occur in the presence of 2-deoxyglucose. which deprives the NADPH:O2 oxidoreductase of its substrate NADPH by inhibition of glycolysis and the pentose phosphate pathway. This points to a stimulatory effect on the direct divalent reduction of oxygen without intermediate superoxide production by this enzyme complex. 4. Granulocytes obtained from the blood and synovial fluid of patients with rheumatoid arthritis reacted differently to polymer u.v.-irradiated IgG. In the presence of this stimulus the rate of release of both superoxide and hydrogen peroxide was increased. Furthermore. these granulocytes synthesized superoxide and hydrogen peroxide at a higher rate than did granulocytes from normal blood in the presence of serum-treated zymosan but not in the presence of phorbol myristate acetate. 5. Taken together. these results indicate that the rate of superoxide and hydrogen peroxide production by the granulocyte NADPH:O2 oxidoreductase depends on the pathological condition of the donor and the type of stimulus used.
Use of continuous noninvasive measurement of oxygen consumption in patients with adult respiratory distress syndrome following shock of various etiologies, OBJECTIVE: To describe the patterns of cardiac index. oxygen delivery (DO2). oxygen consumption (VO2). and oxygen deficit (or excess) and to compare invasive and noninvasive monitoring systems for evaluation of these oxygen transport patterns. DESIGN: Descriptive study of oxygen transport interrelationships throughout critical illness in a consecutive series of surviving and nonsurviving patients with adult respiratory distress syndrome (ARDS). SETTING: University-affiliated city hospital. PATIENTS: A consecutive series of 55 critically ill patients with ARDS after shock of various etiologies. MEASUREMENTS AND RESULTS: Noninvasive VO2 was measured by a continuous. on-line. real-time device developed in our department. Inspired and expired oxygen concentrations were measured using a polarographic oxygen analyzer. Minute ventilation measurements were time integrated over 7-min intervals. Cardiac index. DO2. and VO2 were simultaneously measured invasively by pulmonary artery thermodilution catheters. together with arterial and mixed venous blood gases. There was good agreement (r2 = .60) in VO2 measured by the invasive and noninvasive methods. The estimated oxygen deficit or excess was calculated as the difference between the actual measured VO2 standardized for body temperature pressure saturated and the normative standard VO2 of each patient corrected for temperature and sedation (VO2 need). A total of 317 monitoring days in 55 patients were analyzed; 25 survivors were monitored for a mean of 4.6 +/- 2.9 days and 30 nonsurvivors were monitored for 6.9 +/- 6.6 days. Survivors had significantly higher cardiac index. DO2. and VO2 values. Generally. oxygen excesses were found in the survivors and oxygen deficit was observed in the nonsurvivors. Survivors did not reach a plateau in their DO2-VO2 patterns. In the septic nonsurviving patients and both nonseptic groups by contrast. a plateau was observed in the DO2-VO2 pattern. Surviving septic patients had a critical DO2 of 16 mL/min.kg (700 mL/min.m2) and a critical VO2 of 3.5 mL/min.kg (145 mL/min.m2). CONCLUSIONS: Monitoring of VO2 and DO2 variables is useful for evaluation of tissue oxygenation and titration of therapy in critically ill patients. Noninvasive monitoring of VO2 values are in good agreement with VO2 values calculated from invasive measurements of cardiac index. The increased DO2 and VO2 values are not attributable to mathematical coupling of erroneous cardiac index values.
Oxygen consumption in sepsis and septic shock, This review article examines the pathophysiology of septic shock. with special attention to the concept of supply-dependent consumption and the implications this concept has for therapy. Patients with septic shock require higher levels of oxygen delivery (DO2) to maintain aerobic metabolism. When DO2 is inadequate. peripheral tissues switch to anaerobic metabolism and oxygen consumption decreases. The lactic acidosis that occurs is a reasonable clinical marker of supply dependency and inadequate tissue perfusion. Maximizing DO2 is an important part of the hemodynamic resuscitation of patients with septic shock. To achieve this goal. intravascular volume must be restored and the myocardial depression associated with sepsis must be treated to optimize cardiac output. The normalization of arterial lactate concentration is a reasonable goal of resuscitative efforts.
Efficacy of daily routine chest radiographs in intubated, mechanically ventilated patients, OBJECTIVE: To determine the efficacy of daily routine chest radiographs in intubated. mechanically ventilated patients. DESIGN: With approval of our Institutional Review Board. data were collected prospectively to compare bedside clinical assessment of the patient with the routine chest radiograph in determining the occurrence of new findings. Before review of the daily chest film. patients underwent careful evaluation of clinical and physiologic variables by critical care physicians. who then documented the new findings and the diagnostic and therapeutic interventions required. These results were compared with the interpretations of the daily chest film by radiologists blinded to the clinical assessment. Correlations were made of the new major (requiring immediate intervention) and new minor (abnormal but not requiring immediate intervention) findings noted by clinical assessment and chest radiography. SETTING: This study was conducted in a ten-bed medical/surgical ICU admitting 650 to 750 patients/yr. a majority of whom require intubation and mechanical ventilation. PATIENTS: Seventy-seven episodes of intubation and mechanical ventilation in 74 patients were evaluated. Only patients with translaryngeal intubation and a requirement for mechanical ventilation beyond 24 hrs were considered for inclusion in this study. Major admitting diagnoses included malignancy. aspiration pneumonia. sepsis. liver failure. chronic obstructive pulmonary disease. and adult respiratory distress syndrome. INTERVENTIONS: Specific interventions were not made by study design; instead. clinical practice with and without the routine chest radiograph was compared. MEASUREMENTS AND MAIN RESULTS: The measure of comparison between the chest radiograph and clinical assessment was the correlation between the two for a number of major and minor findings defined in advance. A total of 538 chest radiographs were examined; of these. 354 (65.8%) did not disclose either new major or new minor findings as defined. One hundred sixty-three radiographs disclosed only new minor findings. 40.5% of which were anticipated by bedside assessment. However. in 13 (17.6%. 95% confidence interval 9% to 26%) of our 74 patients. new major findings were discovered only by chest radiography. CONCLUSIONS: These data demonstrate that. while a large percentage of radiographs will not disclose new findings. routine daily studies have a substantial impact on the management of intubated. mechanically ventilated patients in the ICU. These findings support the use of daily chest radiographs in critically ill patients.
Efficacy and safety of potassium infusion therapy in hypokalemic critically ill patients, OBJECTIVE: To evaluate the efficacy and safety of potassium replacement infusions in critically ill patients. DESIGN: Prospective cohort study. SETTING: Multidisciplinary critical care unit. PATIENTS: Forty-eight critically ill adult patients. age 25 to 86 yrs. Patients entered the study when hypokalemia (potassium less than 3.5 mmol/L) was noted on routine laboratory blood analysis. Most common primary diagnoses on ICU admission included postoperative cardiac surgery (n = 9). sepsis and multiple organ system failure (n = 9). complicated myocardial infarction (n = 7). and respiratory failure (n = 5). INTERVENTION: Potassium chloride infusions (20. 30. or 40 mmol in 100 mL normal saline over 1 hr) were administered to patients for serum potassium levels of less than 3.5 but greater than 3.2 mmol/L (n = 26). 3.0 to 3.2 mmol/L (n = 11). and less than 3.0 mmol/L (n = 11). respectively. Serum and urine potassium levels were monitored during and for 1 hr after the infusion. MEASUREMENTS AND RESULTS: All patients tolerated the infusions without evidence of hemodynamic compromise. ECG change. or new dysrhythmia requiring treatment. The mean maximum potassium increase was 0.5 +/- 0.3 mmol/L. 0.9 +/- 0.4 mmol/L. and 1.1 +/- 0.4 mmol/L in the 20-. 30-. and 40-mmol groups. respectively. The increase in serum potassium was maximal at the completion of the infusion and was significant (p less than .05) compared with baseline in all groups. Peak potassium levels were the same in patients with normal renal function (n = 33) compared with those with renal insufficiency (n = 15). Urinary excretion of potassium increased in all groups during the infusion and was significant (p less than .05) in the 30- and 40-mmol groups. but was no greater in those patients who had received diuretics (n = 8) compared with those patients who had not (n = 40). CONCLUSIONS: In the select group of hypokalemic patients studied. potassium infusions of 20 to 40 mmol delivered over 1 hr were safe to administer and effectively increased serum potassium levels in a dose-dependent and predictable fashion. Furthermore. these results were independent of the patient's underlying renal function or associated diuretic administration.
Pentoxifylline in resuscitation of experimental hemorrhagic shock, BACKGROUND: Pentoxifylline improves survival in animal models of hemorrhagic shock. The purpose of this study was to determine the physiologic effects of pentoxifylline in hemorrhagic shock that may be responsible for improved survival. METHODS: Randomized. prospective. blinded trials in Sprague-Dawley rats subjected to hemorrhage and resuscitation. with or without pentoxifylline. RESULTS: Pentoxifylline had no effect on BP or cardiac output. However. tissue oxygenation and oxygen consumption were increased with pentoxifylline resuscitation. Pentoxifylline resuscitation also significantly decreased polymorphonuclear leukocyte adhesiveness. CONCLUSIONS: Pentoxifylline improves tissue oxygenation and oxygen consumption posthemorrhage and this effect is not due to increased cardiac output. Therefore. it must be due to improved microcirculatory blood flow. This effect may be due to decreased polymorphonuclear leukocyte adhesiveness induced by pentoxifylline resuscitation.
Oxygen free radicals: effect on red cell deformability in sepsis, OBJECTIVE: To examine the effect of alpha-tocopherol. a free radical scavenger. on RBC deformability. mixed venous hemoglobin saturation (SvO2). arterial-venous oxygen content difference (C[a-v]O2). pHv. and survival during sepsis. DESIGN: Randomized controlled study. INTERVENTIONS: Sprague-Dawley rats were randomized to three groups: sham. cecal ligation and puncture. or alpha-tocopherol/cecal ligation and puncture (pretreatment with alpha-tocopherol before cecal ligation and puncture). MEASUREMENTS AND MAIN RESULTS: The cecal ligation and puncture group had a significantly (p less than .05) higher SvO2 and lower C (a-v)O2. pHv. and survival rate when compared with alpha-tocopherol/cecal ligation and puncture and sham groups. No difference in pHa existed between groups. CONCLUSIONS: The alpha-tocopherol treatment improves survival in sepsis. RBC deformability during sepsis is prevented by alpha-tocopherol. suggesting that free radicals may cause the decrease in RBC deformability. This study provides indirect evidence that decreased RBC deformability may play a role in the physiologic peripheral shunting and decreased microcirculatory flow that occurs during sepsis.
Congestive gastropathy and Helicobacter pylori: an endoscopic and morphometric study, Congestive gastropathy is a frequent cause of upper gastrointestinal haemorrhage in patients with portal hypertension. The pathogenesis is thought to involve venous congestion with gastric mucosal capillary dilatation. We studied the relation between gastric mucosal capillary dilatation. measured morphometrically. and endoscopic appearances in 74 patients with portal hypertension and 20 control subjects. We also investigated the frequency of gastric colonisation with Helicobacter pylori. Mucosal capillaries in patients were significantly dilated compared with control subjects (p less than 0.001) but the degree of dilatation was not related to the severity of the endoscopic appearances. H pylori was identified in 19 of 74 (26%) patients but was not related to the severity of the endoscopic appearances. These results suggest that other factors in addition to mucosal venous and capillary congestion are important in the pathogenesis of endoscopic congestive gastropathy and that gastric colonisation with H pylori is unlikely to be one of these factors.
Nicotine induced gastric injury. A quantitative macroscopic and microscopic analysis of the protective effects of sucralfate and feeding, Nicotine. while an important component of cigarettes. does not cause gross gastric mucosal damage. although its microscopic effect remains unknown. We have evaluated the histology and the microvascular permeability of (a) the effect of nicotine alone or in combination with ethanol on the gastric mucosa of rats and (b) the effect of feeding and sucralfate on the mucosa of rats treated with nicotine and ethanol. Mucosal injury was assessed histologically by the depth of injury and microvascular permeability by the leakage of fluorescein isothiocyanate-labelled albumin. Our results show that nicotine induced microscopic mucosal damage and accentuated the damage induced by alcohol. The damaging effects on mucosa of nicotine and ethanol. alone or in combination. were reduced by pretreatment with sucralfate. Similarly. feeding reduced the degree of mucosal injury. Nicotine and ethanol increased leakage of albumin into the interstitium and the leakage was reduced after sucralfate pretreatment. This study substantiates the adverse effect of smoking on mucosal damage. Vascular factors are probably involved in the pathogenesis.
Small intestinal function and dietary status in dermatitis herpetiformis, Small intestinal morphology and function were assessed in 82 patients with dermatitis herpetiformis. 51 of whom were taking a normal diet and 31 a gluten free diet. Methods used were histopathological evaluation of jejunal mucosal biopsy specimens. quantitation of intraepithelial lymphocytes. cellobiose/mannitol permeability test. tissue disaccharidase values. serum antigliadin antibodies. and formal assessment of dietary gluten content by a dietician. There was no correlation between dietary gluten intake and the degree of enteropathy in the 51 patients taking a normal diet. whereas biopsy specimens were normal in 24 of the 31 patients on a gluten free diet. all previously having been abnormal. Eighteen patients on gluten containing diets had normal jejunal histology and in seven of these all tests of small intestinal morphology and function were entirely normal. Intestinal permeability was abnormal and serum antigliadin antibodies were present in most patients with enteropathy. Studies of acid secretion in seven patients showed that hypochlorhydria or achlorhydria did not lead to abnormal permeability in the absence of enteropathy. This study shows that a combination of objective tests of small intestinal architecture and function will detect abnormalities in most dermatitis herpetiformis patients. including some with histologically normal jejunal biopsy specimens. Nevertheless there is a small group in whom all conventional intestinal investigations are entirely normal.
Superoxide production by Crohn's disease neutrophils, Neutrophil superoxide anion production was measured in healthy subjects and in patients with quiescent and active Crohn's disease using superoxide dismutase inhibitable cytochrome C reduction. Three stimuli were used: phorbol 12-myristate 13-acetate (PMA1). phorbol 20-oxo-20-deoxy 12-myristate 13-acetate (PMA2). and Candida albicans in serum. Normal neutrophils produced significantly more superoxide anion than Crohn's disease neutrophils with both PMA1 (mean (SD) 9.6 (2.2) v 8.6 (1.8) nmol/10(6) cells/5 minutes. p = 0.04) and PMA2 (1.8 (0.8) v 0.8 (0.77) nmol/10(6) cells/5 minutes. p = 0.00004). With C albicans in serum. normal and Crohn's disease neutrophils produced similar amounts of superoxide anion (4.4 (1.5) v 4.3 (1.7) nmol/10(6) cells/30 minutes. not significant). Results were independent of disease activity. Superoxide anion production by PMA-stimulated Crohn's disease neutrophils is significantly lower than by normal neutrophils.
Increased cell membrane arachidonic acid in experimental colorectal tumours, Tumour cell membrane fatty acid composition was investigated using an animal model of colorectal carcinogenesis. Eighty six male Wistar rats were fed experimental diets containing either 5% saturated fat or 20% saturated fat. Colorectal tumours were induced by intraperitoneal injection of azoxymethane. and control rats received saline. Animals were killed at intervals up to 26 weeks after the last injection of carcinogen for histology and lipid analysis. Cell membrane fatty acids in colonic mucosa and colorectal tumours were determined by gas liquid chromatography. Animals fed the 20% fat diet developed more carcinomas (28 cancers in 14 rats) than those fed the 5% fat diet (14 cancers in 15 rats; chi 2 = 8.03. p = 0.0046) but they did not develop significantly more adenomas (28 and 24 respectively). Cell membrane fatty acid analysis showed a considerable increase in the content of arachidonic acid (20:4. n-6) in the tumours (mean (SEM) 11.7 (1.5)%) compared with colonic mucosa (4.2 (0.4)%; p less than 0.05). Dietary fatty acid composition was also found to influence the profile of fatty acids in the colonic mucosa. This study suggests that a high saturated fat diet promotes the malignant transformation of colorectal adenomas. The colorectal tumours were characterised by an increased cell membrane arachidonic acid. the precursor of putative cancer promoting prostaglandins.
Histological and immunohistochemical study of the gall bladder lesion in primary sclerosing cholangitis, The histological features and type of mononuclear cell infiltrate in gall bladders from six patients with primary sclerosing cholangitis were studied using routine staining techniques and immunohistochemistry. Control studies were performed using the gall bladders from six patients (age and sex matched) with chronic cholecystitis and four with primary biliary cirrhosis. A range of histological abnormalities was present in gall bladders from patients with primary sclerosing cholangitis including a mild to moderate degree of epithelial hyperplasia. pseudogland formation. and mononuclear cell infiltrate of the epithelium; moderate to severe chronic inflammatory cell infiltrate and fibrosis affecting the superficial and deep layers of the gall bladder wall; and minimal smooth muscle hypertrophy. These abnormalities were non-specific and were also present in gall bladders from patients with chronic cholecystitis and primary biliary cirrhosis. Vasculitis and granulomas were not present in the patients with primary sclerosing cholangitis. Immunohistochemistry showed that the superficial and deep mononuclear cell infiltrate in primary sclerosing cholangitis gall bladders was composed predominantly of lymphocytes. in contrast to chronic cholecystitis where macrophages were found in similar or greater numbers. Moreover. T lymphocytes (activated and resting) were present throughout the lymphocytic infiltrate and were apposed to the base and interdigitated between the biliary epithelial cells in significantly greater numbers than in chronic cholecystitis gall bladders. B lymphocytes were present only in lymphoid follicles. Comparative studies using liver biopsy specimens from three of the primary sclerosing cholangitis patients showed a similar T lymphocyte portal tract infiltrate.
Treatment of refractory peptic ulcer with omeprazole or continued H2 receptor antagonists: a controlled clinical trial, We tested the hypothesis that the gastric H+/K+ adenosine triphosphatase inhibitor. omeprazole. because of its different mode of action and pronounced inhibitory effect on gastric acid secretion. may be more effective in peptic ulcer that is refractory to histamine H2 receptor antagonist treatment than continuing the same therapy. Altogether 107 patients (duodenal ulcer. n = 88; prepyloric ulcer. n = 14; gastric ulcer. n = 3; mixed sites. n = 2) with refractory peptic ulcer - that is ulcer unhealed after at least two months' treatment with cimetidine 0.8 g or 1 g daily or with ranitidine 0.3 g daily - were randomly allocated to receive either omeprazole 40 mg daily (n = 54) or to continue treatment with the same H2 receptor antagonist and at the same dose (n = 53) for up to eight weeks. The patients in the two treatment groups were well matched demographically. Healing by 'intent to treat' analysis was as follows: at four weeks. omeprazole 46 of 54 (85%). H2 receptor antagonist 18 of 53 (34%) (p less than 0.0001); and at eight weeks. 52 of 54 (96%) and 30 of 53 (57%) respectively (p less than 0.0001). One patient was lost to follow up but of the 22 patients whose ulcers were shown to be unhealed at endoscopy after receiving continued H2 receptor antagonist treatment. 21 healed in four to eight weeks when changed to omeprazole.
Metachronous occurrence of collagenous colitis and ulcerative colitis, Collagenous colitis and ulcerative colitis are distinct disorders. A 67 year old woman with clinical and histological evidence of collagenous colitis had an abrupt symptomatic exacerbation while taking anti-inflammatory treatment with sulphasalazine and prednisone. Repeat colorectal endoscopy showed active mucosal inflammation and colonic biopsy specimens were consistent with active ulcerative colitis. After bowel rest. total parenteral nutrition. intensification of the anti-inflammatory regimen. and withdrawal of non-steroidal anti-inflammatory drugs (which she had taken continuously for osteoarthritis) diarrhoea abated. Colorectal biopsy specimens obtained when the patient's symptoms had improved showed inactive ulcerative colitis with no evidence of collagenous colitis. This may be the first case to be reported of the metachronous association of collagenous and ulcerative colitis.
A therapeutic dilemma: suppressive doses of thyroxine significantly reduce bone mineral measurements in both premenopausal and postmenopausal women with thyroid carcinoma, We measured lumbar spine. femoral neck. and forearm bone mineral (BMD) in 24 women (14 premenopausal and 10 postmenopausal) who had been treated with total thyroidectomy and 131 Iodine ablation therapy for nonanaplastic thyroid carcinoma and 24 case controls. At the time of the study. all patients were free of cancer (negative 131 Iodine whole body scan and serum thyroglobulin levels less than 0.3 micrograms/L) and all were receiving doses of T4 sufficiently high to prevent a rise in a serum thyroid-stimulating hormone concentration after an iv bolus of TRH. Femoral neck BMD were significantly reduced in both the premenopausal women (89 +/- 3.8% of case controls. 95% CI. 81 to 98) and postmenopausal women (77 +/- 3.9% of case controls; 95% CI. 68 to 86) receiving T4. Lumbar spine BMD and forearm BMD were unaffected in the premenopausal women. but significantly reduced in the postmenopausal women receiving T4 (lumbar spine BMD = 84 +/- 6.2% of case controls; 95% CI. 70 to 98 and forearm BMD = 89 +/- 5.6% of case controls; 95% CI. 76 to 101). Serum bone Gla-protein. a marker of bone turnover. was significantly increased in both the premenopausal and the postmenopausal women receiving T4 compared to case controls (P less than 0.001 for the difference between patient groups and controls). Whereas the cumulative dose of T4 was highly correlated with the femoral neck BMD in the premenopausal patients (r = 0.528; P less than 0.05); the presence of hypogonadism was the main determinant of the lumbar spine and forearm BMD. This data confirms that premenopausal and postmenopausal women receiving suppressive doses of T4 for thyroid carcinoma have diminished bone mineral measurements and are at risk for osteoporosis.
Measurement of bone collagen degradation in hyperthyroidism and during thyroxine replacement therapy using pyridinium cross-links as specific urinary markers, Urinary excretion of the bone collagen derived pyridinium cross-links pyridinoline (PYD) and deoxypyridinoline (DPD) was measured in 19 patients (4 M:15 F) with untreated thyrotoxicosis. and 20 pre-. and 20 postmenopausal women taking T4 100-200 micrograms daily for autoimmune hypothyroidism. Both PYD and DPD excretion (nanomoles per mmol creatinine) was elevated in the thyrotoxic patients compared to 287 controls; median 131 vs. 26 and 37.5 vs. 7.2. respectively. P less than 0.0001. In premenopausal women mean urinary pyridinium cross-link excretion and serum osteocalcin levels were similar in both T4-treated and matched control groups. despite suppression of serum TSH concentrations to below 0.1 mU/L in 14 of the 20 taking T4. In postmenopausal women mean (+/- 1 SE) urinary PYD excretion (nanomoles per mmol creatinine) was raised in those taking T4. relative to euthyroid controls; 40.0 +/- 2.7 vs. 32.1 +/- 2.3. P less than 0.05. DPD excretion and serum osteocalcin levels were also higher. but not significantly. When only the T4-treated women with a subnormal serum TSH were considered the difference in PYD excretion was more marked. and mean DPD excretion was also significantly elevated; 13.7 +/- 1.3 vs. 10.1 +/- 0.8. P less than 0.05. Conclusion: bone collagen breakdown is increased in thyrotoxicosis. and in postmenopausal women taking sufficient T4 to suppress serum TSH. Similarly treated premenopausal women appear to be at lower risk.
Lack of enhanced responsiveness of plasma 18-hydroxycorticosterone and aldosterone to adrenocorticotropin as well as to angiotensin-II during moderate sodium depletion in type II diabetic subjects with normoreninemia, Responses of plasma aldosterone (PA) and its precursor steroids to alpha ACTH-(1-24) (85.2 nmol. iv) injection and graded angiotensin-II (AII) infusions (3.90 and 7.80 pmol/kg.min for 30 min at each dose) on both 170 and 100 mmol sodium intakes were assessed in 25 type II diabetic subjects with normoreninemia and 11 age-matched normal subjects. The diabetic subjects and the normal subjects did not differ in mean blood pressure. serum electrolytes. and creatinine clearance. except for an increase in fasting plasma glucose (P less than 0.001) in the diabetic subjects. A 100-mmol sodium intake for 4 days produced an increase in basal plasma renin activity (P less than 0.01). plasma 18-hydroxycorticosterone (18-OHB; P less than 0.05). and PA (P less than 0.05). and a decrease in urinary sodium excretion (P less than 0.001) in the two groups. These parameters were similar in the two groups. ACTH injection produced significant increases in plasma cortisol. plasma corticosterone. plasma 18-OHB. and PA (P less than 0.005 or P less than 0.001). and graded AII infusions produced significant increases in plasma 18-OHB and PA (P less than 0.05 or P less than 0.01) during both 170- and 100-mmol sodium intakes in the two groups. In the diabetic subjects. however. the responses of plasma 18-OHB and PA to both ACTH injection and graded AII infusions on a 100-mmol. but not on a 170-mmol. sodium intake were subnormal (P less than 0.05 or P less than 0.01) and were similar to those on a 170-mmol sodium intake. These results indicate a lack of enhanced responsiveness of plasma 18-OHB and PA to both ACTH and AII during moderate sodium restriction in nonazotemic type II diabetic subjects with normoreninemia. It appears that these subjects have selective unresponsiveness of adrenal zona glomerulosa to sodium depletion per se. but not to ACTH or AII.
Luteinizing hormone (LH) secretory burst duration is independent from LH, prolactin, or gonadal steroid plasma levels in amenorrheic women, The possible presence of LH pulsatile secretion has been studied in patients with hypothalamic amenorrhea [LH plasma levels. less than 3 (n = 35) or greater than 3 IU/L (n = 18)]. amenorrhea associated with hyperandrogenemia (n = 31). or hyperprolactinemia (n = 10). Patients were sampled every 10 min for 4 h. and LH plasma concentrations were determined by the use of an immunofluorimetric assay. The program Detect was used for both pulse detection and data deconvolution. i.e. for instantaneous secretory rate computation. on LH time series. The presence of episodic LH secretion was observed in all patients. and LH pulse frequency ranged between 3.5 +/- 0.3 and 3.8 +/- 0.2 peaks/4 h among the four groups. LH pulse amplitude was significantly reduced in patients affected by hypothalamic amenorrhea with LH plasma levels lower than 3 IU/L (0.7 +/- 0.1 IU/L; P less than 0.01) and significantly increased in patients with hyperandrogenic amenorrhea (6.8 +/- 0.3 IU/L; P less than 0.01) compared to levels in the other groups under study. Instantaneous secretory rate computation permitted the optimal resolution of the secretory events and demonstrated that the duration of gonadotrope secretory bursts ranged from 22.8 +/- 1.4 to 26.8 +/- 2.3 min in amenorrheic patients and did not depend on LH. PRL. or sex steroid plasma levels. In conclusion. the present study shows the presence of significant LH pulsatile release in amenorrheic patients. suggesting that in amenorrheic. as in normally cycling. women the secretory bursts from the gonadotropes have the same duration. despite the plasma LH. PRL. or steroid hormone levels.
The interaction of proinsulin with the insulin-like growth factor-I receptor in human liver, muscle, and adipose tissue, Because of the sequence homology and tertiary structure similarities between proinsulin (PI) and insulin-like growth factor-I (IGF-I). it is possible that PI interacts with the IGF-I receptor with higher affinity than insulin. To test this hypothesis in man. we have partially purified IGF-I receptors from liver. muscle. and adipose tissue and studied their interaction with PI. insulin. IGF-I. and IGF-II. With some tissue to tissue variation. [125I]insulin binding was 4- to 8-fold greater than IGF-I binding. Unlabeled IGF-I at about 1 x 10(-9 M. IGF-II at about 1 x 10(-8) M. and insulin at about 1 x 10(-6) M displace 50% the binding of [125I]IGF-I to its receptor. whereas PI at 1 x 10(-6) M displaces less than 20% of the binding of [125I]IGF-I to its receptor. We conclude that in human liver. muscle. and adipose tissue. PI does not interact with the IGF-I receptor at a higher affinity than insulin. and the affinity of IGF-I receptors is several-fold lower than that of insulin receptors. It is. therefore. unlikely that if PI were to be administered to man any of its biological effects would be by interacting with the IGF-I receptor.
Alterations in the hypothalamic-pituitary-adrenal axis in actively drinking alcoholics, The impact of chronic alcohol abuse on the hypothalamic-pituitary-adrenal (HPA) axis was investigated in actively drinking. nondepressed alcoholics with no evidence of liver disease. Fourteen male alcoholics and 13 matched nonalcoholics were studied. Although alcoholics and controls had similar decrements in cortisol levels after metyrapone blockade. plasma ACTH and 11-deoxycortisol levels in alcoholics were 60% (P less than 0.05) and 40% (P less than 0.05). respectively. of control values. To further clarify defects in the HPA axis of the alcoholic group. each subject underwent a CRH stimulation test. Compared to control subjects. alcoholics had a significantly blunted plasma ACTH response to CRH stimulation (P less than 0.05). Timing of the peak plasma ACTH response was altered in alcoholics. Whereas all control subjects had a peak plasma ACTH response 30 min after CRH administration. 50% of alcoholics demonstrated a peak plasma ACTH response 60 min after CRH administration. and 50% demonstrated a peak plasma ACTH response 30 min after CRH. To determine if adrenal function was also impaired. alcoholics and controls underwent a standard (250 micrograms) and a submaximal (0.250 micrograms) Cortrosyn stimulation test. Controls demonstrated a significant cortisol response to both standard and low dose Cortrosyn. Although alcoholics had a cortisol response similar to that of controls after the standard dose of Cortrosyn. they did not have a statistically significant rise in cortisol after the submaximal dose of Cortrosyn. Twenty-four-hour urinary free cortisol levels were 2-fold higher in alcoholics compared to controls. In summary. although a subset of alcoholics demonstrated enhanced basal production of cortisol. most alcoholics had a blunted response to acute intervening stress. including CRH. low dose ACTH-(1-24). and metyrapone blockade. These data suggest that alcoholics have ethanol-induced HPA axis injury. resulting in an inappropriately reduced response to nonethanol-induced stress.
Ovarian control of pituitary hormone secretion in early human pregnancy, To determine the influence of ovarian relaxin on the secretion of pituitary GH and PRL in vivo. we evaluated circulating serum hormone levels in 17 pregnant patients with functional corpora lutea (group I) and compared them to levels in 10 patients with premature ovarian failure (POF; group II) who became pregnant with egg donation and did not have corpora lutea. Group II patients had exogenous hormonal support. Serum relaxin (RLX). GH. PRL. estradiol (E2). and progesterone levels were measured weekly by RIA from weeks 4-8 of pregnancy. Analysis of variance and covariance were used to determine hormonal relationships. Serum RLX was present in the natural pregnancy group. with a mean of 1.94 micrograms/L over the study period. Serum RLX was undetectable in the POF patients (less than 0.16 micrograms/L). No significant difference in PRL or progesterone levels between the two groups was noted. E2 levels showed an upward trend in both groups with time and were significantly higher in patients of the POF group than in group I women (P = 0.001). GH levels were significantly higher in the natural cycle patients (P = 0.02) despite lower E2 levels. These data provide additional support for the concept that RLX production in early pregnancy originates from the corpus luteum. They suggest that a luteal product. probably RLX. stimulates GH secretion in early pregnancy. This is a previously undescribed role for RLX in pituitary physiology during human pregnancy.
Somatostatin reduces 3H-thymidine incorporation and c-myc, but not thyroglobulin ribonucleic acid levels in human thyroid follicular cells in vitro, The action of somatostatin (SRIH) on 3H-thymidine (thy) incorporation and on c-myc and thyroglobulin RNA levels in a suspension of follicles from normal and goitrous human thyroid was examined. SRIH. at 10(-7) M concentration. inhibited basal thy incorporation (maximally by 4 h lasting for up 24 h). which effect was greater in goiter than in normal thyroid and was also detected in growing adherent epithelial cells. Moreover. in a follicle suspension SRIH prevented TSH-stimulated thy incorporation. both in normal and in goitrous thyroid. Basal expression of c-myc RNA was not affected by SRIH in either tissue. whereas the TSH-stimulated c-myc RNA level was significantly reduced in goiter. No effect of SRIH was observed on basal or TSH-stimulated thyroglobulin RNA levels. SRIH did not alter basal cAMP concentrations in normal or goitrous follicles. but it significantly reduced TSH-stimulated cAMP accumulation both in normal thyroid and in goiter. Overall. our data indicate a direct inhibitory action of SRIH on growth. but not on differentiation. of human thyroid. probably by a mechanism not entirely cAMP dependent.
Suppression of counterregulatory hormone response to hypoglycemia by insulin per se, Although assessment of counterregulatory hormone responses to hypoglycemia relies upon insulin to lower the glucose level. it is not known if the exogenous insulin does used itself influences the magnitude of the hormone response. To assess this. 12 normal subjects randomly received 2 hypoglycemic clamp studies in which the only variable was the insulin dose (0.6 or 5.0 mU/kg-min). Despite 10-fold differences in circulating insulin (265 +/- 29 vs 2576 +/- 222 pmol/L respectively). the hypoglycemic stimulus did not vary. Glucose levels fell over one hour. and then were maintained for two hours at the same hypoglycemic plateau (approximately 3.1 mmol/L for each study) by a variable glucose infusion. Although basal counterregulatory hormone levels in low and high dose studies were indistinguishable. during hypoglycemia the response of epinephrine. growth hormone. and glucagon was significantly suppressed when the degree of hyperinsulinemia was increased. We conclude that raising the magnitude of hyperinsulinemia suppresses the magnitude of the counterregulatory hormone response to hypoglycemia in normal subjects. This modulating effect of insulin per se is yet another variable in the interpretation of hypoglycemic counterregulation.
Positive regulation of human thyrotropin receptor mRNA by thyrotropin, We have assessed the influence of natural and recombinant thyrotropin (TSH) on mRNA specific for the human TSH receptor (TSHR) in normal and abnormal adult human thyroid monolayer cells. Using physiological concentrations of TSH (less than 100 mU/L). a marked increase in the level of TSHR mRNA was observed within 12 hours and reached a greater than 1000% increase after 24 hours exposure. At high TSH concentrations (greater than 1000 mU/L). this increase in TSHR-specific mRNA was markedly reduced. However. at no time were basal TSHR mRNA levels suppressed even with 100 U/L of TSH for 48 hours. These observations demonstrate ligand-induced up-regulation of the human TSHR mRNA by physiologically relevant concentrations of TSH.
Effect of cetirizine on histamine- and leukotriene D4-induced bronchoconstriction in patients with atopic asthma, Cetirizine. a derivative of hydroxyzine. is a new compound with potent antihistaminic property without antiserotonin and anticholinergic activities. The effect of both a single dose (15 mg) and 7 days of treatment (15 mg twice daily) with cetirizine. a potent H1 antagonist on bronchoconstriction induced by histamine and leukotriene D4 (LTD4) has been examined in 10 patients with mild atopic asthma in a placebo-controlled. double-blind. crossover study. Cetirizine. after a single dose and 7 days of treatment with placebo. the geometric mean values of the provocative concentration of histamine causing a 20% fall in FEV1 (millimolars) were 1.60 (95% confidence interval. 0.82 to 3.11) and 1.67 (0.77 to 3.65). compared with 118.07 (77.22 to 180.54) (p less than 0.0001) and 53.16 (20.50 to 137.84) after cetirizine administration (p less than 0.0002). The mean inhibition after a single dose was twofold higher than after 1 week of treatment (p less than 0.05). After a single dose and 7 days of treatment with placebo. the geometric mean values of the provocative concentration of LTD4 causing a 20% fall in FEV1 (micromolars) were 2.26 (1.74 to 2.94) and 2.37 (1.77 to 3.17). compared with 3.90 (2.60 to 5.86) (p less than 0.05) and 3.21 (2.28 to 4.52) after cetirizine administration. This result suggests that cetirizine is a potent H1 antagonist in the human airways. Diminished activity after 1 week of treatment suggests subsensitivity of H1 receptors developing in human airways. The small protective effect after a single dose against LTD4-induced bronchoconstriction indicates a nonspecific rather than a specific receptor antagonism.
Regulation of human basophil activation. I. Dissociation of cationic dye binding from histamine release in activated human basophils, Human basophil activation was demonstrated by histamine release (HR) and by the decrease of the toluidine blue-positive basophils (TB+). In four experimental systems. TB+ number decreased in the absence of HR (1) in basophils from atopic subjects stimulated by allergen concentrations below the threshold for HR. (2) in basophils sensitized by anti-2.4-dinitrophenyl IgE stimulated by noncovalently linked 2.4-dinitrobenzene sulfonic acid-human serum albumin (also. the threshold for decrease of TB+ required lower concentrations of sensitizing anti-2.4-dinitrophenyl IgE than for HR). (3) in low Ca++ medium. and (4) in the presence of the Na+/H+ exchanger. monensin. These results suggest that (1) there is a lower threshold for TB+ decrease than for HR in allergen concentration. number of membrane IgE molecules. and number of IgE cross-linkings; moreover. external Ca++ requirement is lower for decrease of TB+ than for HR and (2) TB+ decrease reflects either granule exocytosis or. in the absence of HR. biochemical changes (most probably cation exchanges) altering the interaction of the basic dye with the granules. Thus. monitoring decrease in TB+ allows detection of basophil activation in the absence of HR.
Immunotherapy with cat- and dog-dander extracts. V. Effects of 3 years of treatment, The effect of a 3-year course of cat or dog immunotherapy (IT) was evaluated in 32 patients with a history of asthma on exposure to cat or dog. Twenty-one subjects (14 children and seven adults) received cat IT and 11 subjects (six children and five adults) received dog IT. Bronchial challenges with allergen and histamine were performed once a year. Specific IgE. IgG1. and IgG4 were measured. and skin prick tests were done in connection with the challenges. Allergen sensitivity decreased significantly in both treated groups (p less than 0.001 and p less than 0.05 in the cat-allergen and dog-allergen treated groups. respectively). Bronchial hyperreactivity measured by the provocative concentration of histamine causing a 20% decrease in peak expiratory flow in the cat-allergen treated patients (p less than 0.001) but not in the dog-allergen treated patients. Skin sensitivity decreased in both groups (p less than 0.01 and p less than 0.05). whereas specific IgE increased initially but dropped to the pretreatment level during the second year. Specific IgG1 and IgG4 increased during the first and second year in the cat-allergen treated group (p less than 0.01 and p less than 0.001). whereas only IgG4 increased in the dog-allergen treated group (p less than 0.01). Five cat-allergen treated children and one of the adults who completed 3 years of therapy had mild systemic reactions. We conclude that cat IT ameliorated bronchial allergen sensitivity and bronchial hyperreactivity and resulted in an adequate antibody response. Dog IT was less efficacious but led to attenuation of bronchial allergen sensitivity.
Cutaneous responses to anticholinergics: evidence for muscarinic receptor subtype participation, We conducted a series of experiments to determine if anticholinergics induce immediate cutaneous wheal-and-flare responses in normal volunteers. We performed intradermal skin testing in seven healthy volunteers (three atopic and four nonatopic) with 20 nmol of atropine. All subjects had an immediate wheal-and-flare response to atropine. To determine if this cutaneous response was due to anticholinergics in general. skin testing was also performed to scopolamine and ipratropium. These agents also produced immediate wheal-and-flare responses in all subjects. but they less potent than atropine. Pretreatment with antihistamines equivalently inhibited wheal-and-flare responses to both histamine and atropine. indicating a possible mast cell role. The potential role of M1. M2. and M3 muscarinic receptor subtypes was evaluated by use of the selective antagonists. pirenzepine (M1). 11[[2-1[(diethylamino)methyl]-1-piperidinyl]-acetyl]-5. 11-dihydro-6H-pyrido[2.3-b][1.4]benzodiazepine-6-one (AFDX-116) (M2). and 4-diphenylacetoxy-N-methylpiperidine (4-DAMP) (M3). Cutaneous wheal responses induced by pirenzepine and 4-DAMP were relatively equivalent and larger than responses induced by AFDX-116 at doses less than 200 nmol. At 200 nmol. all three muscarinic receptor subtype antagonists induced equivalent wheal formation. We then compared the cutaneous wheal responses to these specific muscarinic receptor antagonists based on their relative affinity for their respective muscarinic receptor subtype. This comparison suggested that M1 or M2. but not M3. muscarinic receptor subtypes may be important in anticholinergic-induced cutaneous wheal-and-flare responses. We propose that there may be an M1 or M2 muscarinic autoreceptor that inhibits the release of acetylcholine and other neurotransmitters.
Release of eosinophil granule proteins during IgE-mediated allergic skin reactions, To determine whether the eosinophil (EOS). a prominent component of human allergic skin reactions. releases its potentially pathogenic components in vivo. we appended collection chambers to the bases of unroofed skin blisters and challenged the sites for varying time periods with either pollen antigen (Ag) or buffer (B)-control solutions. In seven sensitive subjects. continuous challenge with pollen Ag consistently induced release of more major basic protein (MBP) and eosinophil-derived neutrophil (EDN) than did B solution. Low levels of both MBP and EDN were observed during the first hour with increased accumulation during the second to fifth hour. Comparison of Ag- versus B-challenged site responses in individual subjects demonstrated significantly higher levels of both MBP and EDN at Ag than at B sites during the second to fifth hour. Levels of both MBP and EDN in the second to fifth hour correlated significantly with histamine release in the same sites in the first hour (r = 0.66 and 0.83. respectively). Imprints of the skin bases of the chambers after 5 hours demonstrated variable numbers of EOS at the Ag-challenged sites and only occasional EOS at the B-challenged sites; most cells on the skin bases were neutrophils. However. immunofluorescence localization of MBP in biopsy specimens of the blister bases revealed striking extra cellular MBP deposition. These findings indicate that EOS components accumulate in vivo in IgE-mediated human skin reactions. even when prominent EOS accumulation is not visualized. possibly because the EOS are degranulated in the allergic-reaction site. Release of EOS components in these reactions may be linked to earlier mast cell activation.
The effect of nedocromil sodium on the early and late reaction and allergen-induced bronchial hyperresponsiveness, Bronchial hyperresponsiveness (BHR) to methacholine was studied in 14 patients with asthma and five healthy control subjects. with and without pretreatment with nedocromil sodium. 3 and 24 hours after allergen challenge. Eleven patients demonstrated a dual asthmatic response. A significant decrease in the provocative concentration causing a 20% fall in FEV1 was found from a geometric mean starting value of 1.18 mg/ml on the control day to 0.24 mg/ml (p less than 0.001) and to 0.17 mg/ml (p less than 0.001) 3 and 24 hours after allergen challenge. A significant correlation was observed between the increased BHR at 3 hours and the magnitude of the late response (r = -0.57; p less than 0.05). Nedocromil sodium (6 mg) significantly inhibited the increase in BHR. 1 mg/ml (p less than 0.001) at 3 hours and 0.50 mg/ml (p less than 0.001) at 24 hours. Nedocromil sodium shifted the severity of the early allergic reaction (EAR) from mean -34.8% to -6.9% and inhibited the later allergic reaction (LAR) from -30.5% to +0.4% (p less than 0.005). From the study can be concluded that nedocromil sodium inhibits the EAR and LAR and the allergen-induced increase in BHR. The inhibitory effect of nedocromil sodium on the LAR may be related to its ability to inhibit the increased BHR before the development of the LAR.
Multiple Amb a I allergens demonstrate specific reactivity with IgE and T cells from ragweed-allergic patients, The relationship between the structure and abundance of an inhaled protein and its potential for causing an allergic response is unknown. This study analyzes Amb a I. a family of related proteins formerly known as Ag E. that comprise the major allergens of short ragweed (Ambrosia artemisiifolia). T cells isolated from ragweed allergic patients were shown to proliferate in response to purified Amb a I.1 protein from pollen in in vitro secondary cultures. demonstrating the presence of T cell stimulatory epitopes in Amb a I.1. Three recombinant forms of Amb a I (Amb a I.1. Amb a I.2. and Amb a I.3) obtained as cDNA derived from pollen mRNA were expressed in bacteria. All three recombinant forms were shown to be specifically recognized by pooled ragweed-allergic human IgE on immunoblots. confirming these gene products are important allergens. An examination of immunoblots probed with sera derived from allergic patients revealed a variation in IgE binding specificity. A minority of patients' IgE exclusively reacted with recombinant Amb a I.1. whereas most patients' IgE reacted with Amb a I.1 as well as Amb a I.2 and Amb a I.3 proteins. A detailed examination of the reactivity of T cells derived from 12 allergic patients to these recombinant Amb a I forms revealed that these allergens are all capable of stimulating T cell proliferation in in vitro assays. It is concluded that the allergic response to ragweed pollen in most allergic patients is composed of a reaction to multiple related Amb a I proteins at both the B and T cell levels.
Anti-P autoantibody production requires P1/P2 as immunogens but is not driven by exogenous self-antigen in MRL mice, Considerable evidence supports the idea that autoantibody production in human and murine SLE is Ag driven. To determine whether Ag (the ribosomal P proteins) could initiate autoantibody production in lupus mice. 34 MRL/lpr mice were immunized with mouse riboosomal proteins in Freund's adjuvant. Neither intact ribosomes. denatured total mouse ribosomal proteins. nor the purified mouse ribosomal proteins. P1 and P2. induced the production of anti-P autoantibodies in the MRL/lpr mice. In contrast to these negative findings. MRL/lpr mice immunized with Artemia salina ribosomes produced anti-P antibodies as well as anti-P autoantibodies. Although the induced anti-P autoantibodies bound exclusively to the carboxyl terminus. these anti-P antibodies differed from spontaneously occurring anti-P autoantibodies in their predominant binding to mouse P0 on immunoblots and their preferential reactivity against A. salina synthetic peptides by ELISA. Induction of anti-P antibodies required the presence of P1 and P2 on the ribosome because ribosomal cores devoid of P1 and P2 dimers did not induce anti-P. Despite the presence of approximately 80 ribosomal proteins. autoantibodies to other mouse ribosomal proteins were rarely observed. Immunization of MRL/+ mice and a normal H-2-matched strain of mice. C3H. also resulted in anti-P antibodies reactive with the A. salina P proteins and mouse P0. Whereas anti-P levels gradually declined in C3H mice. anti-P levels either remained elevated (MRL/lpr) or showed a secondary rise (MRL/+) at the onset of autoimmunity. These observations indicate that: i) high levels of autologous Ag are not sufficient to drive antiribosomal autoantibody production in MRL mice. ii) multivalency of the P proteins may explain their potent immunogenicity and ability to break tolerance. and iii) immunized MRL mice show an abnormal persistence of high level anti-P production presumably reflecting T cell activation of presensitized B cells.
Epidermal Langerhans cells are not principal reservoirs of virus in HIV disease, Several reports implicate Langerhans cells of skin as susceptible targets. reservoirs. and vectors for transmission of HIV: 1) numbers of Langerhans cells in skin of HIV-infected patients were decreased about 50% of that in control skin; 2) as many as 30% of Langerhans cells in the skin of HIV-infected patients were morphologically abnormal; 3) viral particles typical for HIV were identified in or around 2 to 5% of these cells; and 4) infectious HIV was isolated from skin biopsies of infected patients. These results were consistent with similar observations of HIV-infected macrophages in such tissues as brain. lung. and lymph node. Despite these findings. other investigators find no evidence for virus infection in the epidermis of HIV-infected patients by any of several immunohistochemical or ultrastructural criteria. To address this controversy. we obtained skin from 28 HIV-seropositive subjects at various clinical stages by full thickness biopsy or suction blister. Samples were analyzed by transmission electron microscopy for presence of HIV virions. by immunofluorescent staining for viral proteins. by in situ hybridization for HIV-specific mRNA. by polymerase chain reaction amplification of virus-specific DNA. and by direct virus isolation by coculture of epidermis onto monocyte target cells. By any of these techniques. demonstration of HIV in the epidermis of infected patients was equivocal and even then. infrequent. In contrast. viral DNA was detected from the dermis of the same skin samples (26 of 28 samples). Moreover. the number and morphology of Langerhans cells in skin of infected patients were within normal limits. regardless of stage of disease. These studies in toto suggest that a role for Langerhans cells as a principal viral reservoir or vector of transmission is highly unlikely.
In vitro infection with HIV enables human CD4+ T cell clones to induce noncognate contact-dependent polyclonal B cell activation, Eleven (nine CD4+ and two CD8+) protein purified derivative-specific and eight tetanus toxoid-specific T cell clones (TCC). established from the peripheral blood of healthy persons. were cocultured in vitro with irradiated mononuclear cells from patients infected by HIV in the presence of PHA and polybrene. Two weeks post-HIV exposure. all 17 CD4+. but neither of the two CD8+. TCC exhibited integration of HIV in their genoma. as detected by polymerase chain reaction analysis. and released HIV into their supernatants. as detected by measuring both reverse transcriptase activity and p24 Ag. When co-cultured with either autologous or allogeneic B cells. all CD4+ HIV-infected TCC induced the synthesis of extraordinarily high amounts of IgM. IgG. and IgA. In contrast. their noninfected counterparts could provide helper function for Ig synthesis by autologous B cells only in the presence of the specific Ag (or anti-CD3 antibody). and induced allogeneic B cells to synthesize Ig only upon stimulation with anti-CD3 antibody. The supernatants of HIV-infected TCC failed to stimulate Ig synthesis in B cells. More importantly. when HIV-infected clonal T blasts and B cells were cultured in different chambers separated by a millipore membrane. permeable to molecules but not to cells. Ig synthesis did not occur. The Ig synthesis induced by HIV-infected TCC was also markedly inhibited by the addition in culture of either anti-CD4 or anti-LFA-1 antibody. In contrast. HIV-infected TCC maintained their ability to provide helper function for Ig synthesis in the absence of any stimulus. even after fixation with p-formaldehyde. These data demonstrate that in vitro infection with HIV enables human T cells to stimulate Ig synthesis by B cells by an Ag-nonspecific. MHC-unrestricted. contact-dependent mechanism. This may explain. at least in part. the hypergammaglobulinemia and other phenomena related to polyclonal B cell activation frequently seen in HIV-infected persons.
Inflammatory edema induced by interactions between IL-1 and the neuropeptide calcitonin gene-related peptide, The neuropeptide calcitonin gene-related peptide (CGRP) is a potent vasodilator with a long duration of action. CGRP is widely distributed and is present in perivascular nerves of tissues that include skin and the synovium. In this study we have investigated the possibility that CGRP can modulate the inflammatory actions of the cytokine IL-1 by using an inflammatory model in rabbit skin. The intradermal injection of IL-1 (1.4 x 10(-14) mol/site) alone stimulated little edema formation. However. when IL-1 was injected with CGRP (10(-11) mol/site). a highly significant edema was observed. and neutrophil accumulation induced by IL-1 was potentiated. These results suggest that the action of IL-1 as a potent mediator of increased microvascular permeability is only observed when skin blood flow is increased in this model. This was confirmed by experiments in which PGE2 (3 x 10(-9) mol/site) at a dose with a similar duration of vasodilator action as CGRP (10(-11) mol/site) also potentiated edema induced by IL-1. Further experiments investigated the mechanism by which IL-1 increased microvascular permeability. Edema induced by IL-1 was dependent on de novo protein synthesis and the presence of circulating neutrophils. However. selective platelet-activating factor and histamine H1 antagonists had no inhibitory effect on this response. Thus it appears that when a microvascular bed is dilated by the long-lasting vasodilator CGRP. edema induced by IL-1 is clearly observed. These results highlight a potentially important synergistic interaction between cytokines and neuropeptides in inflammation.
In vitro selection of a cell line for resistance to lysis by tumor necrosis factor-alpha selects for reduced tumorigenicity, Experimentally. TNF-alpha can mediate the hemorrhagic necrosis of certain tumors. Furthermore. evidence indicates that natural cytotoxic (NC) activity. a cell-mediated cytolytic activity that utilizes TNF-alpha in the lysis of target cells. is involved in preventing the outgrowth of certain NC/TNF-alpha-sensitive tumor cells. These observations raise the issue of whether soluble TNF-alpha normally serves as a tumor surveillance mechanism preventing the outgrowth of some tumors. To address this issue. we have used TNF-alpha to select TNF-alpha-resistant variants from the NC/TNF-alpha-sensitive mouse fibroblast cell line 10ME. Previously. we have demonstrated that 10ME is tumorigenic in immune-deficient mice but fails to form tumors in normal mice. Moreover. selection of NC-resistant variants from 10ME selects for both TNF-alpha resistance and tumorigenicity in normal mice. As cells that have been selected for NC resistance form tumors in normal mice. whereas the NC-sensitive parental cell line does not. it seems that escape from NC activity is sufficient to significantly increase the tumorigenic potential of the cell line. We show that the selection with TNF-alpha. although associated with NC resistance. does not increase the tumorigenic potential of 10ME cells but reduces it. Thus. NC activity appears to function as a mechanism to prevent tumor formation. and escape from NC activity allows for tumor formation; TNF-alpha does not have similar activity. Moreover. this suggests that NC activity is not equivalent to soluble TNF-alpha activity. but utilizes TNF-alpha more efficiently than soluble TNF-alpha. or NC activity involves both TNF-alpha and other effector mechanisms.
IL-8 in septic shock, endotoxemia, and after IL-1 administration, Much effort has been directed toward elucidating the host response to sepsis and inflammation. resulting in the definition of a cascade of endogenous mediators that direct metabolic and immunological responses. Here we report that IL-8. a novel cytokine produced by a variety of cells in vitro in response to stimulation with bacterial LPS and the proinflammatory cytokines. appears in the circulation of primates in vivo during septic shock. sublethal endotoxemia. and after the administration of IL-1 alpha. The magnitude of the IL-8 response correlates with the severity of the insult. and levels of IL-8 peak relatively late. after those of TNF-alpha and IL-1 beta. and simultaneously with those of IL-6. IL-8 has been primarily defined as a selective activator and chemoattractant of neutrophils. and we demonstrate that after LPS or IL-1 alpha infusion. circulating neutrophil numbers rapidly recover from an initial neutropenia while IL-8 concentrations are maximal. supporting the hypothesis that IL-8 influences circulating leukocyte populations in vivo. We conclude that IL-8 is another participant in the cytokine cascade elicited by sepsis and inflammation and. as such. may play a significant role in host defense and disease.
A role for IgE in intestinal immunity. Expression of rapid expulsion of Trichinella spiralis in rats transfused with IgE and thoracic duct lymphocytes, In these experiments we characterize the protective antibodies in immune serum that interact synergistically with immune thoracic duct lymphocytes (TDL) to induce rapid expulsion (RE) of Trichinella spiralis in adult rats. Antibodies with both reaginic and nonreaginic activity mediated RE upon passive transfer to adult rats that had been adoptively transfused with immune TDL 7 days earlier. In serum collected 28 days after a primary infection. the most important antibody was homocytotropic IgE. Native IgE produced by active infection was isolated from 28-day immune serum by salt precipitation and/or by sequential affinity chromatography. The murine mAb A2 and B5 (anti-rat IgE) were conjugated separately to Sepharose 4B affinity columns for affinity separations. IgE was shown to be pure by gel electrophoresis and Western blots and its m.w. was estimated at approximately 190.000. As little as 183 micrograms of purified IgE could induce RE after passive transfer to adult rats. The IgE was shown to be functional by PCA activity. Ag-binding on Western blots. and skin sensitization; the latter could be blocked by pretreatment with 1R162. a rat myeloma IgE. Monoclonal IgG of any isotype transferred in amounts up to 35 mg/rat could not transfer RE to rats previously transfused with TDL cells. Immune serum collected 3 mo after the primary infection contained insufficient IgE to transfer RE. but complex non-IgE fractions were protective. The data thus demonstrate that IgE is a functional Ig in the rat capable of mediating the rejection of challenge nematode infections of the gut in the absence of other specific Ig. Secondly. other Ig may also play a role. in particular. several weeks after the primary infection when specific IgE levels in serum have declined.
Antiviral activity and dose optimum of recombinant macrophage colony-stimulating factor on herpes simplex genitalis in guinea pigs, The antiviral activity of recombinant human macrophage CSF (M-CSF) against genital herpes simplex virus type-2 (HSV-2) infection in guinea pigs was investigated. M-CSF stimulates proliferation of human and guinea pig peripheral blood monocytes. specifically the plastic adherent esterase-positive mononuclear cells. When anti-HSV-2 activity of M-CSF was evaluated in guinea pigs by 6 daily injection (s.c.) of M-CSF at various doses (5 x 10(5) to 7 x 10(7) U/kg). we found 2 x 10(6) U/kg to be the optimum dose for protective efficacy against primary HSV-2 infection. Either at a lethal. 5 x 10(5) pfu. or sublethal 5 x 10(4) pfu of virus challenge. animals treated with the optimum regimen of M-CSF exhibited lower herpetic lesion scores (p less than 0.005). and lower mortality (p less than 0.025) than animals in placebo group. M-CSF treatment increased the HSV-infected cell killing activities of plastic-adherent mononuclear cells. indicating that in vivo administration of M-CSF may activate the antiviral effects of guinea pig macrophages that may play a role in protection against severity and mortality of herpetic disease.
Cytokine-induced enhancement of ICAM-1 expression results in increased vulnerability of tumor cells to monocyte-mediated lysis, Pretreatment of the human melanoma cell line. A375. and the human colon carcinoma cell line. HT-29. with certain cytokines was found to increase the vulnerability of these cells to monocyte-mediated killing. This activity was found to correlate with increased expression of intercellular adhesion molecule-1 (ICAM-1) on the tumor cells and was blocked by anti-ICAM-1 antibodies. Both IFN-gamma and TNF induced large increases in the ICAM-1 expression on both cell lines and increased the susceptibility of the tumor cells to monocyte-mediated killing. IFN-alpha and IL-1 beta. however. induced only small increases in ICAM-1 expression and enhanced the lysis of the A375 cells but not the HT-29 cells by monocytes. These differences may be the result of a higher basal expression of ICAM-1 found on the A375 cells when compared with the HT-29 cells. These data indicate that regulation of ICAM-1 expression on tumor cells can alter the vulnerability of these cells to lysis by monocytes.
Radiological study of primary spontaneous CSF rhinorrhoea, A radiological study of skull base anatomy was performed in patients presenting with primary spontaneous CSF rhinorrhoea. Radiology correctly identified the fistula site in 90 per cent of cases. Contrast CT imaging was found to be the most suitable technique for identifying the presence and site of CSF fistulae. However. pre-contrast bony dehiscences were identified in all patients leaking from the cribriform plate region. More significantly. all of these patients showed deviation of their crista galli. a radiological sign hitherto unreported. These findings support the theory that congenital bony dehiscence is the aetiological basis for this condition. The importance of radiology in the management of this condition is emphasized.
Information leaflets in the rhinitis clinic, Failure to get relief from topical steroid nasal spray is often blamed on poor administration knowledge. In a population of patients referred to the rhinitis clinic who have failed to get relief from topical steroid nasal spray when prescribed by the general practitioner. lack of patient education only accounts for 28 per cent of patient treatment failures and other factors e.g. poor compliance. erroneous diagnosis or severity of rhinitis will be responsible for the rest. Information leaflets are considered to be a good idea by nearly all patients but this study demonstrates that they would only be of therapeutic benefit to a minority of patients.
Human papilloma virus and carcinoma of the laryngopharynx, The presence of human papillomavirus (HPV) genomes 6. 11. 16 and 33 in 16 patients with laryngopharyngeal carcinomas was examined by means of a polymerase chain reaction. HPV genomes were detected in 75 per cent of cases. In hypopharyngeal carcinoma. HPV 6 and 11 were present in adjacent tissue but absent from the tumour. HPV 16 and 33 were present in 40 per cent of laryngeal tumours and adjacent tissue. These results suggest that HPV 16 and 33 may be closely associated with the development of some laryngopharyngeal carcinomas.
Experience of pulse oximetry in children with croup, We report our experience with 199 patients requiring admission with a diagnosis of croup over an 18 month period. The value of using pulse oximetry to monitor these children was critically examined. Twenty-nine patients with clinically significant stridor were monitored for an average of 12 hours. There was poor correlation of clinical status and respiratory rate with hypoxia as shown by the technique. with frequent dips in oxygen saturation being caused by technical problems such as movement artefact. Pulse oximetry is a useful adjunct to the clinical assessment of croup. but cannot be relied upon solely for monitoring these labile patients.
Acanthoma fissuratum, Acanthoma fissuratum secondary to the use of spectacles is a rare clinical finding associated with an ill-fitting frame. An interesting case is presented to highlight such a problem. Surgical excision of such lesions is recommended with advice to the patient regarding the suitable fitting of spectacles.
Degree of coronary artery disease predicted by exercise testing, The ability of exercise testing to predict the extent of coronary artery disease was examined in 268 male patients undergoing both coronary angiography and bicycle testing with electrocardiography before coronary artery bypass surgery. When maximal ST-depressions limited by symptoms increased from 0 to 4 mm or more. the percentage of patients with 'serious' coronary disease. defined as either triple vessel disease or left main stem stenosis. increased from 50% to 80% (P = 0.0001). The patients in the lowest third of physical work capacity showed only a slightly increased risk of serious disease. This tendency was abolished in patients who were using beta-blockers. whereas the relationship between ST-depression and disease was not affected by this medication. The probability of finding left main stem stenosis in a patient increased from 5 to 30% with increasing ST-depression: beta-blockers did not affect this relationship. but there was no additional predictive effect of implicating the level of physical work capacity. It is concluded that traditional electrocardiography during exercise is of value when selecting patients for angiography. but that the physical work level obtained during the test does not predict the degree of coronary pathology.
Glycaemic thresholds for hypoglycaemic symptoms, impairment of cognitive function, and release of counterregulatory hormones in subjects with functional hypoglycaemia, Nine patients with food-relieved hypoglycaemic symptoms. in whom insulinoma and other organic diseases presenting with hypoglycaemia had been ruled out. and nine matched controls. participated in the study. Subjects were studied during a 5-h controlled (Biostator) insulin-induced (1-2 mU kg-1 min-1) hypoglycaemic clamp. After 1 h of euglycaemia. we aimed to lower the glucose level in arterialized venous blood in a stepwise manner at 30-min intervals to 3.5. 3.0. and 2.0 mmol l-1. and to withhold these levels for a further 30 min. At euglycaemia and at the end of the latter steps. the visual reaction time and cognitive function (digit span. letter cancellation and trail making) were tested. together with recording symptoms and signs of hypoglycaemia. Counter-regulatory hormones were measured at 20-min intervals. In the patients. clinical signs and symptoms of hypoglycaemia developed at median blood glucose levels of 2.6-2.8 and 2.8-3.1 mmol l-1. respectively. By contrast. the blood glucose levels were 0.4-0.8 mmol l-1 lower in control subjects (P less than 0.05). Similarly. the median threshold for deterioration of visual reaction time was 2.8 mmol l-1 in patients and 2.1 mmol l-1 in controls (P less than 0.01). A similar trend was observed for the results of the neuropsychological tests. Visual reaction time deteriorated in all subjects. whereas the cognitive function of some of the subjects in each group remained unchanged during hypoglycaemia. The glycaemic thresholds for release of cortisol. glucagon and growth hormone were significantly higher in patients (P less than 0.05). whereas the thresholds for catecholamine release showed no significant difference from controls. Despite the comparable glucose infusion rates required to sustain each of the hypoglycaemic levels in the two groups. the control subjects achieved lower glucose levels. suggesting that there is resistance to insulin or glucose in functional hypoglycaemia. In conclusion. the present study suggests that the existence of a higher threshold for symptoms and signs. as well as for deterioration of brain function. may explain every-day hypoglycaemic symptoms. despite normal glucose levels. in subjects with functional hypoglycaemia. However. the hypothesis should be tested further using a blinded approach. including euglycaemic control studies.
Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients, One thousand and ten patient years of oral anticoagulant therapy with vitamin-K-antagonists were reviewed with regard to major bleeding complications. The incidence of bleeding that necessitated hospital admission was 2.7% per year (95% confidence limits. 1.7-3.7%). The major source of bleeding was the alimentary tract. whereas no cases of intracranial bleeding were found. Various factors with potential effects on the bleeding risk were evaluated by multivariate statistical analysis. and the following independent risk factors were identified: age greater than 75 years and hypertension increased the bleeding risk by 10.5% and 4.5%. respectively. Each recorded prothrombin value significantly below the therapeutic range increased the bleeding risk by 3.9%. and each year of treatment increased the risk by 2.0%. These figures may be used to estimate the risk of major bleeding in an individual patient. Current treatment with thiazide diuretics was found to increase the bleeding risk by 5.2%. However. this observation requires further documentation and analysis. Although no lethal episodes of bleeding occurred. the developing field of indications for oral anticoagulant therapy should be considered on the basis of a continuous substantial risk of major bleeding.
Acupuncture in angina pectoris: does acupuncture have a specific effect, To overcome the methodological problems of blinding the patients and the acupuncturist in acupuncture trials. 33 patients with stable angina pectoris. who were randomized to either genuine or sham acupuncture. received electroacupuncture by another acupuncturist. and the change in skin temperature was recorded. It was found that the change in skin temperature correlated significantly with the degree of improvement following both genuine and sham acupuncture. Fourteen patients with no decrease in skin temperature exhibited a significantly better response to acupuncture than 19 patients who showed a decrease in skin temperature (G II). In the former group. there was a 15% median improvement in exercise tolerance (G II 0%). a 67% improvement in anginal attack rate (G II 38%). and an 84% improvement in nitroglycerine consumption (G II 50%). A significant correlation was found between the duration of disease and the effect of acupuncture. It is concluded that both genuine and sham acupuncture have a specific effect on some angina pectoris patients in addition to the effect of pharmacological therapy.
Third-degree atrioventricular block in an athlete, There is a wide spectrum of changes in the resting electrocardiograms of athletes. We here present a case of third-degree atrioventricular block in an asymptomatic young athlete.
In situ replacement of vascular prostheses infected by bacterial biofilms, Late prosthetic graft infections are commonly the result of coagulase-negative staphylococci that survive within a biofilm on prosthetic surfaces and provoke perigraft inflammation. The indolent nature and microbiologic characteristics of bacterial biofilm infections coupled with the morbidity of graft excision and extraanatomic bypass grafting prompted us to use in situ graft replacement in 15 patients admitted to the hospital with 17 infected graft segments at a mean (+/- SEM) time interval of 70 +/- 16 months after graft implantation (n = 6) or revision (n = 9). Since 1986. 17 grafts (14 aortofemoral. 2 axillofemoral. and 1 femoropopliteal) infected by bacterial biofilms have been treated. Signs on admission included femoral pseudoaneurysm (n = 7). perigraft abscess (n = 6). or graft-cutaneous sinus tract (n = 4). No patient exhibited septicemia. At operation graft incorporation was absent and Gram's stain of perigraft exudate showed polymorphonuclear leukocytes but no bacteria. Culture of explanted graft material isolated coagulase-negative staphylococci (n = 12). Staphylococcus aureus (n = 1). and no growth (n = 2). All patients were successfully treated by a regimen that included parenteral antibiotics. removal of involved graft material. excision of inflamed perigraft tissue. and in situ replacement with an expanded polytetrafluoroethylene prosthesis. No deaths. graft thromboses. or deep wound infections occurred after operation. Recurrent graft infection did not develop during a follow-up interval that ranged from 5 to 50 months (mean. 21 months). Diagnosis of vascular prosthesis infection caused by bacterial biofilms can be based on signs at admission and operative findings. Complications of this perigraft infection can be eradicated by antibiotic administration. local debridement. and in situ graft replacement.
Inadequacy of saphenous vein grafts for cross-femoral venous bypass, A mathematic model of unilateral iliac vein obstruction was used to establish the theoretic basis for selecting saphenous vein or a larger diameter prosthetic cross-femoral venous bypass graft for relief of obstructive venous hypertension. Common femoral vein resting and postexercise peak flows. and common femoral vein and saphenous vein diameters were measured in 18 healthy individuals and used to estimate the pressure gradient (dP) across 20 cm long cross-femoral venous bypass grafts of saphenous vein or 4. 6. 8. 10. and 12 mm prosthetic conduits. in the presence of a transpelvic venous collateral network of varied cross section. The upper limits of normal for the gradients in our model (dPstd) were set at 4 mm Hg for resting flows and 6 mm Hg after exercise. Mean saphenous vein diameter was 4.3 +/- 0.22 mm. which was 36.5% +/- 1.73% of common femoral vein diameter. When the saphenous veins of two thirds of the individuals in our study were used as theoretic cross-femoral venous bypass conduits. greater than 80% of postobstruction peak cross-femoral venous bypass graft flow had to be carried by collaterals to maintain a gradient less than or equal to dPstd. We demonstrated that 4.5 to 6.0 mm diameter saphenous cross-femoral venous bypass grafts would be hemodynamically efficacious in relieving venous hypertension. but only when implanted in parallel with an existing venous collateral network that limited the preoperative dP to 4.5 to 7.5 mm Hg at resting flows and 7.0 to 11.5 mm Hg after exercise; only 44% of saphenous veins were adequate for cross-femoral venous bypass grafts by these criteria.
Infrapopliteal bypass for severe ischemia: comparison of autogenous vein, composite, and prosthetic grafts, Results of 253 consecutive bypass grafts to infrapopliteal arteries were reviewed. Most (92%) were placed for rest pain (103) or tissue loss (130). Autogenous veins were used in 175 (69%) cases. composite vein-prosthetic grafts were used in 45 (18%). and prosthetic grafts alone were used in 33 (13%). Follow-up ranged from 0 to 101 months (mean. 19 months); 37 grafts (15%) were lost to follow-up. The operative mortality rate was 4%. and 5-year patient survival rate was 44%. Limb salvage was 82% at 5 years. The 5-year patency of vein grafts (63%) exceeded that of both composite (28%) and prosthetic (7%) grafts (p = 0.005 and p = 0.00007. respectively); but the patency of composite and prosthetic grafts did not differ significantly (p = 0.29). The patency of reversed vein (59%) and in situ vein grafts (74%) was not significantly different at 5 years (p = 0.34). Patency was also not affected by the site of the proximal or distal anastomoses or diabetes. The major determinant of long-term patency in infrapopliteal reconstructions continues to be graft material. Composite grafts offered no clear advantage over prosthetic grafts. and both should be used only when there is no other alternative to amputation.
The mechanisms and prevention of intravascular fluid loss after occlusion of the supraceliac aorta in dogs, Mechanisms of intravascular fluid depletion after temporary occlusion of the supraceliac aorta were investigated in a canine model. During ischemia and reperfusion. hemodynamic parameters. superior mesenteric artery flow. intestinal mucosal perfusion. and mucosal permeability were monitored. After 12 hours of reperfusion. the volumes of intravenous electrolyte fluid required to maintain hemodynamic stability and fluid lost into the gastrointestinal tract and peritoneal cavity were measured. The distribution of total body water was analyzed by use of radionuclide dilution techniques. Group A animals underwent laparotomy only. group B had the supraceliac aorta occluded for 45 minutes. group C had superoxide dismutase administered after 45 minutes of aortic occlusion. and group D animals were exposed to mild hypothermia during a similar ischemia and reperfusion period. No significant difference was found in mean superior mesenteric artery flow or mucosal perfusion during ischemia among groups B. C. and D. During reperfusion superior mesenteric artery flow returned to values similar to control in all groups. Aortic occlusion increased mucosal permeability most significantly in group B (p less than 0.01). Mean intravenous fluid requirements (ml/mg) were the following: group A. 80 +/- 5; group B. 201 +/- 9 (p less than 0.01); group C. 116 +/- 7 (p less than 0.05); group D. 245 +/- 24 (p less than 0.05). Mean gastrointestinal fluid loss was highest in the hypothermic group and smallest if superoxide dismutase was given. Mean intracellular fluid volume was increased in groups B and D compared with group A (p less than 0.01).
Lipid peroxidation: a possible factor in late graft failure of coronary artery bypass grafts, Atherosclerosis is the paramount cause of late vein graft failure after coronary artery bypass grafting. Lipid peroxidation. which may play a significant role in the initiation and progression of atherosclerosis. was examined in segments of vein grafts (n = 6) harvested at reoperation for coronary disease. These were analyzed for cholesterol. phospholipid. triglyceride. and lipid peroxides. Nonatherosclerotic vascular tissues. including coronary arteries (n = 6). saphenous veins (n = 9). and donor aortic specimens (n = 11) were analyzed for comparison. Risk factors for atherosclerosis including elevated serum cholesterol and triglycerides. smoking. and hypertension were more frequent in patients with coronary artery disease compared to organ donors. Lipid peroxides were elevated in explanted vein grafts when compared to either saphenous vein. coronary artery or donor aorta. Lipid peroxides were not significantly different in saphenous vein when compared to coronary artery. but levels in both of these tissues were greater than in donor aorta. Although increased levels of lipid peroxides in explanted veins may simply reflect morphologic changes in these grafts. the known effects of lipid peroxides on a number of biochemical events suggest that they may contribute directly to graft failure after coronary artery bypass grafting.
Autogenous vein graft repair of injured extremity arteries: early and late results with 134 consecutive patients, Autogenous vein tissue is recognized as the preferred material for extremity revascularizations that require the use of a conduit. However. the results after vascular repair of injured extremity arteries with autogenous vein interposition or bypass grafts have not been well defined. This study was done to determine both the early and late patency and limb salvage rates as well as the graft infection rate of autogenous vein repairs of injured extremity arteries. The records of 134 consecutive patients with acute extremity arterial injuries requiring repair with a reversed autogenous vein graft over a recent 5-year period were reviewed. Follow-up graft patency was defined by the presence of a palpable pulse and an extremity Doppler-derived pressure index of greater than or equal to 0.9 distal to the arterial repair. Cumulative patency was assessed by the life-table method. Acute graft thrombosis occurred in two patients. one of whom underwent successful graft thrombectomy. Four patients (3%) required extremity amputation: one patient with a thrombosed vein graft and three patients with patent vein grafts but nonsalvageable limbs as a result of myonecrosis (2) or osteomyelitis (1). No perioperative graft infections occurred. One hundred twenty-eight patients (97%) had an intact extremity and a patent vein graft at the time of hospital discharge. One hundred three patients (80%) were examined at 30 days. and all grafts were patent. Seventy-three patients (57%) were available for follow-up at intervals exceeding 6 months. and 40 patients (31%) were followed-up for periods exceeding 24 months.
Use of duplex scanning in the diagnosis of arteria profunda femoris stenosis, To evaluate the accuracy of duplex scanning in diagnosing arteria profunda femoris stenoses in patients with concomitant superficial femoral artery occlusions. 123 femoral artery bifurcations were examined in 103 patients. Peak systolic and time-averaged maximal flow velocity parameters were measured in the arteria profunda femoris and compared with independently performed angiography. For detecting stenoses greater than 30% diameter reduction (50% by area) of the arteria profunda femoris. duplex scanning had a sensitivity of 91% and 96%. a specificity of 85% and 98%. a positive predictive value of 86% and 98%. and a negative predictive value of 91% and 96%. for a peak systolic velocity of 180 cm/sec and more. and for a time-averaged maximal velocity of 50 cm/sec and more in the arteria profunda femoris. respectively. The day-to-day variability for peak systolic and time-averaged maximal velocity parameters was low with correlation coefficients between velocity measurements on both days of 0.96 and 0.98 (n = 20). respectively. In 10 patients with arteria profunda femoris stenoses and superficial femoral artery occlusions. undergoing percutaneous transluminal angioplasty of arteria profunda femoris stenosis. the duplex scan revealed a reduction in stenotic peak systolic velocity from 330 +/- 84 to 163 +/- 50 cm/sec and a decrease in stenotic time-averaged maximal velocity from 156 +/- 47 to 54 +/- 17 cm/sec after the interventional procedure. These results show that peak systolic and time-averaged maximal velocities are accurate parameters to detect significant arteria profunda femoris stenosis in patients with superficial femoral artery occlusions.
Endothelial cell seeding, Endothelial cell seeding is the transplantation of vascular endothelial cells to denuded vascular surfaces. Seeding theoretically reduces the probability of graft or vessel thrombosis and of neointimal fibrous hyperplasia. Thus far. clinical seeding trials disclosed modest improvements in patency and the development of hyperplastic anastomotic lesions in failed grafts. Seeding inefficiency theoretically contributes to anastomotic hyperplasia. The inefficiency is linked to two steps in the seeding process. namely harvesting and cell retention. Of these. cell retention on the seeded surface is the more critical. Priorities for future research should be set first on the retention of seeded endothelium in vitro and second on improved and standardized methods of cell harvesting.
Microvessel derived endothelial cell isolation, adherence, and monolayer formation for vascular grafts, MVECs can be isolated from animal and human fat in quantities and in a pure enough form to produce a cell-lined vascular graft. In animal studies grafts treated with these cells are associated with prolongation of graft patency. In human implants definitive expression factor VIII related antigen cells has been performed on an MVEC treated graft at 9 months. Further studies will be necessary to provide further insight into the healing and long-term behavior of these grafts. both with respect to the thrombogenicity of the surface as well as the influence on anastomotic hyperplasia.
Delayed sleep phase syndrome response to melatonin, The actions of melatonin on the sleep-wake cycle were investigated by means of a randomised. double-blind. placebo-controlled trial in 8 subjects with a delayed sleep phase syndrome attending a sleep disorders clinic. In randomised order the subjects received placebo or melatonin 5 mg daily for 4 weeks with a 1 week washout period between the treatments. Drug or placebo was given at 2200 h. 5 h before the mean time of sleep onset determined by pretrial sleep logs. In all 8 subjects sleep onset time (mean advance 82 [range 19-124] min; p less than 0.01) and wake time (117 [10-187] min; p less than 0.01) were significantly earlier during melatonin treatment than during placebo. Mean total sleep time was slightly less on melatonin (8 h 12 min) than on placebo (8 h 46 min). Alertness acrophase calculated from the subjects' ratings of alertness made every 2 h while awake was unaltered. Melatonin may act as a phase-setter for sleep-wake cycles in subjects with a delayed sleep phase syndrome.
Therapeutic effects of genetically engineered toxin (DAB486IL-2) in patient with chronic lymphocytic leukaemia, In DAB486IL-2 the receptor-binding domain of native diphtheria toxin is replaced by human IL-2 sequences. This recombinant fusion protein is selectively cytotoxic for cells bearing high-affinity IL-2 receptors--eg. leukaemic cells. A patient with chronic lymphocytic leukaemia who did not respond to gamma interferon and conventional antileukaemic drugs has responded to DAB486IL-2.
Survival of classic cholera in Bangladesh, During the present cholera pandemic the El Tor biotype of Vibrio cholerae has completely displaced the classic biotype. except in Bangladesh. We studied the distribution of these two biotypes in twenty-four rural districts during epidemics in 1988-89; there was clustering of the classic biotype in the southern region and of the El Tor biotype in all other regions. These findings suggest that the southern coastal region is now (and may always have been) the habitat of classic cholera. The selective distribution of V cholerae O1 biotypes in Bangladesh may have been affected by ecological changes occurring in the country.
Hyaline globules reacting positively with zidovudine antibody in brain and spinal cord of AIDS patients, Histology of the central nervous system in nine AIDS showed extracellular hyaline globules in the white matter of the brain and the spinal cord. In immunohistochemical studies with a battery of antibodies. the only positive reaction of these globules was with an antibody to zidovudine. High-performance liquid chromatography showed the presence of a zidovudine isomer in eluates of brain tissue from these patients.
Prospective cohort study of prone sleeping position and sudden infant death syndrome, Studies of the link between prone sleeping position and sudden infant death syndrome have been criticised on grounds of recall bias and for not taking into account possible confounding effects. To avoid recall bias and to allow measurement of important biological factors a prospective cohort study of the cause of sudden infant death syndrome (SIDS) is being conducted. The infants included are those at high risk of the syndrome as assessed by a perinatal score. Of the 3110 members of the cohort born between January. 1988. and end of March. 1990. 23 infants later died of SIDS. Sleep position information was available for 15 of these. Matched analysis to control for the confounding effects of infant birthweight and maternal age indicated that prone sleeping position was associated with an increased risk of SIDS (OR 4.47 95% Cl [1.30-15.43]). The findings are strengthened by the results of a concurrent retrospective case-control study of 42 SIDS cases in which the prone position was also associated with an increased risk of SIDS (unadjusted OR 3.45 [1.59-7.49]).
Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer, Timing of operation in relation to menstrual phase might affect outlook in premenopausal women with operable breast cancer. We examined the records of 249 such women treated between 1975 and 1985. and compared overall and recurrence-free survival in those whose operation was 3-12 days after their last menstrual period (LMP) (group 1. n = 75) with those in whom it was 0-2 or 13-32 days after LMP (group 2. n = 174). Overall and recurrence-free survival were greatly reduced in group 1 women (p less than 0.001 for both). Actuarial survival at 10 years was 54% in group 1 versus 84% in group 2. This effect was independent of other factors. was of much the same importance as nodal status in multivariate analysis. was largely confined to histologically node-positive cases. seemed to be greater in women with small tumours (less than or equal to 2 cm). and was seen in patients with oestrogen-receptor positive and negative tumours. Thus phase of menstrual cycle at operation is of great importance for long-term outlook in premenopausal women with breast cancer.
Who will operate on Africa's 3 million curably blind people, About half the 6 million blind people in sub-Saharan Africa have surgically curable cataract. The available manpower and resources can only provide services for less than 10% of the new blind cataract patients each year. and little is being done for the estimated 3 million "cataract backlog". A serious limiting factor to the development of prevention of blindness programmes is lack of trained manpower. Despite an increase in the number of ophthalmologists trained in cataract surgery (which varies greatly from country to country). this number is not keeping pace with increased demand for eye-care services. especially in large rural populations. Initiatives that will help to overcome this dilemma are specific post-graduate courses in community ophthalmology in Africa. plans to develop a one-year diploma in ophthalmology course for English-speaking West African countries. and a proposal to upgrade a similar course in Zimbabwe. Additionally there is a need for the training of more ophthalmic assistants. cataract surgeons. and nurses in the diagnosis and management of common ophthalmic disorders. Experienced expatriate ophthalmologists also have an important role in the teaching of doctors and ophthalmic assistants how to select patients and carry out successful inexpensive cataract surgery with appropriate technology and limited facilities.
AAEM case report #22: polymyositis, Polymyositis usually presents with progressive proximal muscle weakness. increased serum levels of muscle enzymes. inflammatory changes on muscle biopsy. and characteristic electromyographic (EMG) abnormalities. Motor unit action potential (MUAP) changes of configuration. duration. and amplitude are the most frequently observed EMG abnormality. Fibrillation potentials are commonly seen and tend to reflect active disease. diminishing after successful medical management or disease regression. Other muscle diseases can present with similar electromyographic abnormalities. thereby necessitating muscle biopsy for definitive diagnosis.
Electrophysiological findings in localized hypertrophic mononeuropathy, Localized hypertrophic mononeuropathy (LHM) is a rare foccal neuropathy associated with perineurial cell proliferation due to an undefined stimulus. We report a case of LHM involving the proximal ulnar nerve in a 13-year-old boy. Serial clinical and electrophysiological observations were done. including intraoperative recordings directly from the nerve on two occasions. The evolution of abnormalities. as documented by electrophysiological and immunohistochemical studies. is compatible with a process of progressive thinning of myelin sheaths. culminating in axonal degeneration in later stages. Intraoperative recording of nerve action potentials was used to guide surgical management of the lesion. Ultimately. there was a good clinical and electrophysiological response to resection of the lesion and sural nerve fascicular grafting.
Light and electron microscopic studies on localization of myoglobin in skeletal muscle cells in neuromuscular diseases, The localizations of myoglobin in skeletal muscle cells of patients with Duchenne muscular dystrophy (DMD). myotonic dystrophy (MyD). and amyotrophic lateral sclerosis (ALS) were studied by immunohistochemistry and immunoelectron microscopy. In normal skeletal muscle cells. myoglobin was localized mainly in the I-band region. In degenerating muscle cells of patients with DMD and MyD. myoglobin was also demonstrated in the distended lumen of the internal membrane system and in the intermyofibrillar space. through which it seemed to pass into the extracellular space. No myoglobin was detected in opaque fibers or in some of small-sized fibers in DMD muscle. In patients with ALS the staining intensities of myoglobin varied in different muscle cells. but myoglobin was restricted to the I-band region in many muscle cells. These findings suggest that changes in the localization of myoglobin in skeletal muscle cell sensitively reflect the pathologic status of muscle cells.
Muscle regeneration following segmental necrosis in tenotomized muscle fibers, The aim of this study was to determine how the new myotendinous junctions were re-established at the proximal and distal ends of the soleus muscle after tenotomy. Both proximal and distal tendons of the soleus muscle in mature female rats were severed. The animals were killed and the soleus muscles were removed and prepared for light and electron microscopic examination 1. 3. 5. 7. 14. 21. 28. and 42 days after the operation. It was found that segmental fiber destruction followed by removal by macrophages occurred at the ends of the soleus muscle fibers. This resulted in the liberation and myogenic activation of satellite cells. By 3 days after tenotomy the fusion of myoblasts to form myotubes could be seen. The myotubes developed within the original basal lamina and reattached to the surviving non-necrotic segments and grew in both length and width so that by 6 weeks postoperation. normal myotendinous junctions had been reformed. This study is the first to show that re-establishment of the myotendinous junction following tenotomy is accomplished by regeneration of the necrotic ends of the tenotomized fibers.
Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease, BACKGROUND. Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds. including the pulmonary circulation. However. the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS. We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter. 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS. Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g. P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference. increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation. 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation. 85.3 +/- 2.6 percent). By contrast. rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001. as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60. P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68. P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55. P less than 0.01). but not to the forced expiratory volume in one second (r = 0.19. P not significant). CONCLUSIONS. Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.
A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group, BACKGROUND. In primary biliary cirrhosis the hepatic lesions may result. at least in part. from the intracellular accumulation of potentially toxic endogenous bile acids. Preliminary work suggests that the administration of ursodiol (also called ursodeoxycholic acid). a hydrophilic bile acid without hepatotoxicity. leads to improvement in the condition of patients with primary biliary cirrhosis. METHODS. We conducted a two-year. multicenter. double-blind trial to compare the efficacy of ursodiol with that of placebo. Patients with biopsy-proved primary biliary cirrhosis were randomly assigned to receive either ursodiol (13 to 15 mg per kilogram of body weight per day) (n = 73) or placebo (n = 73). Treatment failure was defined as a doubling of bilirubin levels to more than 70 mumol per liter or the occurrence of a severe complication (ascites or variceal bleeding) or an adverse reaction. RESULTS. Treatment failed in 6 patients in the ursodiol group. as compared with 13 in the placebo group (P less than 0.01 by Cox regression model). A single patient in each group withdrew because of minor adverse effects. After two years of treatment. the proportion of patients with clinically overt disease decreased only in the ursodiol group (P less than 0.02). The patients treated with ursodiol had significant improvements in serum levels of bilirubin. alkaline phosphatase. alanine aminotransferase. aspartate aminotransferase. gamma-glutamyltransferase. cholesterol. and IgM (all P less than 0.001); the antimitochondrial-antibody titer (P less than 0.01); and the Mayo risk score (P less than 0.001). Follow-up analysis of 95 liver-biopsy specimens showed a significant improvement in the mean histologic score (P less than 0.002) and in all the characteristic histologic features except fibrosis only in the group given ursodiol. CONCLUSIONS. Ursodiol is a safe and effective treatment for primary biliary cirrhosis.
Severity and specificity of cognitive impairment in Alzheimer's, Huntington's, and Parkinson's diseases and progressive supranuclear palsy, To investigate differences in severity and specificity of cognitive impairment among various neurodegenerative diseases. we tested groups of patients presenting with senile dementia of the Alzheimer type (SDAT; 44). progressive supranuclear palsy (PSP; 45). Huntington's disease (HD; 35) and Parkinson's disease (PD; 164). with an extensive neuropsychological battery. We found dementia. as defined by a global intellectual performance 2 standard deviations lower than mean control values. in 93% of SDAT. 66% of HD. 58% of PSP. and 18% of PD patients. Specific features of cognitive impairment distinguished the four groups of patients once they were matched for level of intellectual deterioration: remote memory and linguistic disorders in SDAT. frontal lobe-like abnormalities in PSP. concentration and acquisition disorders in HD. There was no specific alteration in demented PD patients. This study demonstrates the frequency of dementia in predominantly subcortical degenerative diseases and indicates that "subcortical dementia." rather than being a homogeneous entity. should be divided into specific subtypes of cognitive impairment related to different underlying specific lesions of each disease.
Effects of phosphatidylserine in age-associated memory impairment, We treated 149 patients meeting criteria for age-associated memory impairment (AAMI) for 12 weeks with a formulation of phosphatidylserine (100 mg BC-PS tid) or placebo. Patients treated with the drug improved relative to those treated with placebo on performance tests related to learning and memory tasks of daily life. Analysis of clinical subgroups suggested that persons within the sample who performed at a relatively low level prior to treatment were most likely to respond to BC-PS. Within this subgroup. there was improvement on both computerized and standard neuropsychological performance tests. and also on clinical global ratings of improvement. The results suggest that the compound may be a promising candidate for treating memory loss in later life.
Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT, We previously compared the diagnostic capabilities of MRI of the head with CT. evoked potentials. and CSF oligoclonal banding (OB) analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). To examine the ability of MRI and other paraclinical tests to predict the diagnosis of clinically definite MS (CDMS). we did a systematic clinical follow-up of 200 patients who were previously reported. In that study. 85 of 200 could be diagnosed as having laboratory-supported definite MS (LSDMS). In follow-up. we excluded one patient diagnosed as LSDMS who in retrospect was considered to have had CDMS at entry and 15 patients who were eventually diagnosed as having other diseases. After a mean follow-up of 2.1 years. 55 of the remaining 184 patients (30%) had developed CDMS. Thirty-eight of 84 patients with an original diagnosis of LSDMS (45%) and 17 of the remaining 100 patients with suspected MS (17%) had become CDMS. Forty-six of the 55 patients who developed CDMS in follow-up (84%) had an initial MRI that was strongly suggestive of MS. Fifty-two of those 55 CDMS patients (95%) had at least one MS-like abnormality on MRI when originally studied. In contrast. 38 of 55 (69%) had CSF OB. 38 of 55 (69%) had an abnormal VEP. 35 of 55 (64%) had an abnormal SEP. and 21 of 55 (38%) had an abnormal CT when first studied. MRI was the most sensitive single paraclinical test for predicting CDMS. CDMS developed during follow-up in 46 of the 94 patients (49%) whose initial MRI was strongly suggestive of MS.
Dystrophin expression and somatic reversion in prednisone-treated and untreated Duchenne dystrophy. CIDD Study Group, The mechanism by which prednisone improves muscle strength and function in Duchenne muscular dystrophy (DMD) is unknown. We addressed the possibility that clinical improvement was related to prednisone-induced alterations in skeletal muscle dystrophin. We performed muscle biopsies on patients at the conclusion of a randomized. double-blind. 6-month trial of prednisone and analyzed dystrophin content using Western blots and antibody staining of tissue sections. These studies demonstrated no significant differences in dystrophin content between treatment (prednisone 1.5 mg/kg/d. n = 12; prednisone 0.75 mg/kg/d. n = 9) and placebo (n = 12) groups. Of interest. however. was the presence of varying numbers of dystrophin-positive fibers (revertants) occurring individually or in clusters in antibody-stained tissue sections of more than one-half of the Duchenne patients. Mutation analysis revealed that revertants occurred in DMD patients with identifiable deletions half of the Duchenne patients. Mutation analysis revealed that revertants occurred in DMD patients with identifiable deletions or duplications. and in nondeletion patients. Prednisone treatment did not influence the prevalence of revertants. Revertants are most likely due to a second-site mutation occurring in a somatic cell allowing for restoration of the translational reading frame of the dystrophin transcript.
Persistent neurotoxicity of systemically administered interferon-alpha, Fourteen cancer patients had evidence of persistent neurotoxicity of interferon-alpha therapy long after their treatment was discontinued. Although most of the cognitive symptoms were mild to moderate in severity. they were incapacitating to these individuals in their usual work. The neuropsychological test abnormalities were not attributable to subsequent therapy. disease status. or other medical problems. The pattern of deficits was consistent with frontal-subcortical dysfunction. Of the four patients who had follow-up assessment. two had improved and two had deteriorated. These findings suggest that in some cases interferon neurotoxicity is not reversible.
Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction, Previous frequency estimates of cognitive dysfunction in multiple sclerosis have ranged from 54 to 65 percent. These studies may overestimate the frequency in the general MS population. since the patients in these studies were recruited from clinic populations. In the present study. we administered a comprehensive neuropsychological test battery to 100 community-based MS patients and 100 demographically matched healthy controls. Of 31 cognitive test indices examined. 48 MS patients and five controls were impaired on four or more test indices. yielding an overall frequency rate of 43% for the MS group. The pattern of cognitive decline was not uniform: MS patients were more frequently impaired on measures of recent memory. sustained attention. verbal fluency. conceptual reasoning. and visuospatial perception. and less frequently impaired on measures of language and immediate and remote memory. We developed a brief (20-minute) screening battery empirically by selecting the four most sensitive test indices from the comprehensive battery. The brief battery yielded a sensitivity value of 71% and a specificity value of 94% in discriminating cognitively intact from impaired MS patients. as defined by the comprehensive battery. Cognitive impairment was not significantly associated with illness duration. depression. disease course. or medication usage. but was significantly (albeit weakly) correlated with physical disability.
Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning, We designed a study to assess the specific contribution of cognitive dysfunction to multiple sclerosis patients' problems in daily living. Based on the results of a comprehensive neuropsychological test battery. we classified 100 MS patients as either cognitively intact (N = 52) or cognitively impaired (N = 48). In addition to a neurologic examination. MS patients completed questionnaires on mood and social functioning. underwent a comprehensive in-home occupational therapy evaluation. and were rated by a close relative or friend regarding specific personality characteristics. While there were no significant differences between the two groups on measures of physical disability and illness duration. patients in the cognitively impaired group were less likely to be working. engaged in fewer social and avocational activities. reported more sexual dysfunction. experienced greater difficulty in performing routine household tasks. and exhibited more psychopathology than cognitively intact patients. These findings suggest that cognitive dysfunction is a major factor in determining the quality of life of patients with MS.
Induction of speech arrest and counting errors with rapid-rate transcranial magnetic stimulation, Six adult epileptic patients underwent rapid-rate transcranial magnetic stimulation (rTMS) at stimulation rates of up to 25 Hz with an 11-cm water-cooled round coil held flat on the scalp. centered over 15 different positions on each side of the scalp. The trains of stimuli were for 10 seconds while the patients counted aloud. rTMS centered over D5 or D7 induced reproducible speech arrest in all patients and counting errors in three when applied at lower intensities. There were no such speech disturbances by rTMS centered over the different positions on the right side. Intracarotid amobarbital test (IAT) demonstrated left hemispheric language dominance in all patients. Lateralization of speech arrest induced by rTMS correlated with the IAT results and may be helpful for noninvasive determination of hemispheric language dominance.
Postprandial hypotension: microneurographic analysis and treatment with vasopressin, To clarify the mechanism of postprandial hypotension (PPH). we made microneurographic analyses of patients with PPH and 10 healthy controls by recording multi-unit vasoconstrictive impulses of muscle sympathetic nerve activity (MSNA) directly from the tibial nerve fascicles during a glucose tolerance test. Oral intake of 75 grams glucose in 225 ml of water produced significant and prolonged hypotension in all patients and an increase in MSNA in all healthy subjects. Insulin and glucose responses were not significantly correlated with arterial blood pressure reduction. PPH was prevented by an infusion of vasopressin (0.3 U/min) given before glucose intake. These results suggest that PPH is caused by the lack of sympathetic compensation for the systemic hypotensive stress of splanchnic blood pooling that occurs after food ingestion. and that prior treatment with vasopressin reduces the portal venous flow by constricting the splanchnic vessels in patients with PPH.
Linkage analysis of juvenile parkinsonism to tyrosine hydroxylase gene locus on chromosome 11, We performed linkage analyses of juvenile parkinsonism with autosomal recessive inheritance (AR-JP) to chromosome 11p15.5 locus including tyrosine hydroxylase (TH). Harvey-ras-1 (HRAS). and insulin (INS) genes by analyzing genomic DNA from 28 members of seven Japanese AR-JP families containing 10 affected individuals. We used the methods of pairwise linkage analysis (LIPED) and multipoint linkage analysis (LINKAGE) for genetic linkage to the chromosome 11p15.5 markers and detected recombination events between AR-JP locus and TH gene. Multipoint linkage analysis excluded the linkage in the interval between TH and HRAS. as well as 11 cMo distal to TH and 8.5 cMo distal to HRAS. a total of approximately 23 cMo on chromosome 11p.
Encephalo-myelo-radiculo-ganglionitis presenting as pandysautonomia, A 68-year-old man developed pandysautonomia with severe orthostatic dysfunction. fixed heart rate. low serum levels of norepinephrine and epinephrine. absent sympathetic skin responses. and pupillary abnormalities. CSF protein was 92 mg/dl. In spite of a good recovery following corticosteroid administration. a relapse occurred. with accompanying sensory symptoms confined to both arms. Fatal sudden cardiac arrest occurred after 4 months. Autopsy revealed numerous lymphocytic infiltrates. predominantly in autonomic and sensory ganglia and. to a lesser extent. in the nerve roots. spinal cord. and brainstem without evidence for an underlying tumor. This case provides histopathologic evidence for an inflammatory etiology of panautonomic neuropathy in some patients.
Biopterin-dependent hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase, We describe the clinical. neurologic. and biochemical findings in 10 patients with 6-pyruvoyl tetrahydropterin synthase (6-PTS) deficiency from seven families. all of whom originate from one large tribe in Saudi Arabia. This deficiency presents with severe. early onset of failure to thrive. neurologic deterioration. and morbidity and mortality secondary to repeated episodes of bronchopneumonia or cardiorespiratory abnormalities. The urinary pterin excretion pattern indicates deficient activity of 6-PTS. which has been confirmed by direct enzyme assay in red blood cells of three patients. We treated our patients with combined use of tetrahydrobiopterin 20 mg/kg/d. L-dihydroxyphenylalanine 15 mg/kg/d. carbidopa 3.75 mg/kg/d. and L-5-hydroxytryptophan 5 mg/kg/d. Neurologic findings improved significantly in all after 5 to 24 months. Although head circumference and weight returned to the lower limit of normal in four. height normalized only in one of seven patients. Despite an unrestricted diet during combined therapy. blood phenylalanine and urinary excretion of neopterin and biopterin returned to normal.
Outcome of psychogenic seizures in children and adolescents compared with adults, We compared outcome of psychogenic seizures documented by video-EEG in 18 nonepileptic children and adolescents (ages 8 to 18; median. 14.5 years old) and 20 adults (ages 25 to 56; median. 34.0 years old). Outcome was significantly better for the younger patients at 1 year. 2 years. and 3 years after diagnosis. At these follow-up times. the percentages of children and adolescents free of psychogenic attacks were 73%. 75%. and 81%; at the same follow-up times. the percentages of adults free of psychogenic attacks were only 25%. 25%. and 40%. Factors leading to better outcome for younger patients may have been different psychological mechanisms at different ages of onset and greater effectiveness with earlier intervention.
Second occurrence of spinal epidural metastases, We reviewed records of 79 men with spinal epidural metastases diagnosed from July 1984 to July 1989. imaged by myelography or MRI. and treated with radiation therapy. Thirteen men (16%) had second epidural metastases. The mean time between lesions that developed within two vertebral bodies of a prior lesion was 2.8 months. compared with 15.2 months for lesions that were three or more vertebral bodies from a prior lesion. Some secondary spinal metastases occurring soon after the initial metastasis may represent regrowth of tumor at the border of the radiation port. suggesting that larger radiation ports be constructed for patients with lengthy expected survival times.
Treatment of Parkinson's disease with proglumide, a CCK antagonist, Proglumide. a cholecystokinin antagonist. did not improve Parkinson's disease in a preliminary drug treatment trial.
Screening for gynecologic cancer, Screening principles. methods. and terminology are discussed for cervical. endometrial. and ovarian cancers. Incidence and mortality. risk factors. adjuncts to screening. and historic perspectives are also covered.
Detection of breast cancer, Routine screening has been shown to reduce the mortality from breast cancer in asymptomatic women. All women should be instructed in breast self-examination. and should begin a program of screening mammography and breast physical examination on an annual basis beginning at the age of 40. Most early breast cancers can be adequately treated without ablative surgery.
Hormone replacement therapy and coronary heart disease, Proper use of postmenopausal hormone replacement has been the subject of debate for decades. Prevailing medical opinion has swung between enthusiastic endorsement and extreme caution. The wave of optimism over estrogen's beneficial effects on menopausal symptoms and skeletal health was temporarily set back by the evidence that linked estrogen to endometrial cancer. Once studies showed that progestogen cotherapy could protect against this adverse effect. physicians were again encouraged to prescribe hormone replacement. Since 1980. increasing epidemiologic and experimental evidence has suggested a hitherto unappreciated and immense CHD health benefit from use of postmenopausal estrogen therapy. Although addition of progestogen may offset the cardiovascular benefits of estrogen slightly. its use is reasonable and practical. No woman need be subjected to unopposed estrogen's carcinogenic effects on her endometrium. Based on available evidence. hormone replacement therapy. appropriately administered. is both safe and beneficial. Unfortunately. there is no single way to prescribe it. The treating physician must make a series of best judgments. Practically speaking. this entails. in each case. finding the form of therapy that is acceptable to the patient and that provides the greatest health benefits with the least likelihood of adverse affects. Our prescribing habits have evolved in the last 15 to 20 years. We have better discrimination of the woman most likely to benefit; improved therapy through use of newer formulations. dosages. routes. and schedules; and more appropriate implementation of monitoring procedures. Although questions remain. we should not let our imperfect knowledge dissuade us from more widespread prescribing of hormone replacement therapy.
Avoiding sexually transmitted diseases, As the spectrum of sexually transmitted diseases (STDs) has broadened to include many infections that are not readily cured. prevention of STDs has become more important than ever. Primary prevention methods include abstinence. careful selection of sexual partners. condoms. vaginal spermicides. and a vaccine for hepatitis B. Condoms will protect against STDs only if they are used consistently and correctly; vaginal spermicides may also reduce risk of certain STDs. Health care providers should routinely counsel women on methods to reduce risk of STDs.
Issues in adolescent gynecologic care, Adolescence is a period of transition from childhood to adulthood. During this period. the potential for high-risk behaviors that may negatively impact on gynecologic health care are great. To enhance the potential for optimal care of this group of individuals. the physician must understand that (1) adolescents must be active participants in the decision making concerning their gynecologic health. (2) adolescents need to be able to communicate their concerns about gynecologic health in a confidential forum. and (3) there are areas of early gynecologic development and maturation for which anticipatory guidance is required.
Dysuria and urinary tract infections, It has been estimated that up to 25% of American women may experience acute dysuria yearly. Many physicians commonly equate dysuria with urinary tract infection and will treat empirically without adequate evaluation. This therapeutic trial of antibiotics represents undertreatment for many patients and inappropriate treatment for others. It is important that physicians understand that dysuria is only a symptom that can be produced by many different clinical entities.
Premenstrual syndrome, Because researchers are still seeking the cause of PMS. we cannot recommend a single treatment approach that will work satisfactorily with all women who have the syndrome. Investigators have made progress. however. toward defining and diagnosing the condition. We also can help women whose lives are disrupted each month by prescribing specific approaches to symptom management.
Substance abuse in women, Substance abuse in women is a substantial problem. This article covers the issues surrounding abuse of alcohol. illicit and prescription drugs. and cigarettes in women. Specifically. for each group of substances. the epidemiology and complications are presented. as well as the physician's role in detection and treatment.
Use of mammography in screening for breast cancer, Recognizing the enormous impact that quality breast screening mammography can have on reducing breast cancer deaths. we need to determine when women's and physician's perceived restrictions for mammography examination impede the progress of its use for early cancer detection. A uniform system should emphasize valid communication and education between women and their physicians. Women seek to have a voice in their medical treatment. Yet that responsibility has an emotional price. Physicians and patients must decide together on the most appropriate strategies to enhance communication and adopt specific guidelines they will adhere to. to detect and cure early breast cancer. Women must be educated about breast screening mammography. and physicians must increase their efforts to proclaim its importance. Women need be assured the trend is toward using the most modern mammographic techniques. Quality medical care is medicine's purpose and in women's best interest. At present. no other diagnostic method is equivalent to mammography and capable of providing an equivalent impact on improving the detection and cure rate of breast cancer. Despite medical activities designed to reduce uncertainty in medicine. scientific evidence has not provided systematic answers as to the "best" way to approach issues of quality. cost. accessibility. or communication for breast screening mammography. No particular expert opinion or preference prevails for breast screening protocols. What is needed is adoption of a multidisciplinary approach. educating and motivating women and physicians to participate in breast screening activities. With trends directed toward high-volume breast screening operations. low-cost. quality mammography must be available and be impeccably performed. Some activities are natural subjects for financial quantification. It is objectionable to assume. however. that we can accurately place and agree on dollar amounts alone to represent the costs and benefits of screening mammography. The gaps between practices and attitudes about the benefits. risks. and costs of screening mammography suggest that people are not satisfied with the way physicians. women. influential groups. or regulatory agencies are balancing all of the elements. Better communication must exist between physicians and their peer groups involved in performing responsible mammography. Better communication must be achieved between physicians and women to take advantage of the usefulness of quality breast screening mammography. High-quality screening programs must be linked to third-party reimbursement and to legislation. if we are to make a difference. Screening mammography deserves our medical. economic. social. and political attention and action.
Management of severe frontobasilar skull fractures, Immediate reconstruction of severely comminuted frontobasilar skull fractures involving the frontal sinus can be accomplished safely if the sinus is cranialized and the floor of the anterior cranial fossa is totally reconstructed. Operative time can be reduced if the pieces of the frontal bone are reassembled and stabilized with rigid fixation devices out of the surgical field and thus made ready for reinsertion as a single unit after any necessary neurosurgical procedures are completed. Immediate reconstruction provides postoperative protection for the brain and eliminates the need to return the patient to the operating room for cranioplasty at a later date.
Penetrating wounds of the neck, The management of penetrating wounds of the neck provides several decision-making steps that remain controversial. The two basic concepts of management include the idea that all wounds deep to the platysma should be explored and (the more conservative concept) that selective neck exploration should be based on a battery of tests to identify traumatic injuries. The areas of agreement within these two schools of thought include exploration of wounds with obvious injury. exploration of wounds in which patients cannot be stabilized satisfactorily for further testing. and the idea that all patients with wounds deep to the platysma should be admitted to the hospital. The remaining issues. including the need for angiography. barium swallow. or endoscopy. still are contested. Mandatory exploration of neck wounds became popular during World War II. The weapons used. the lack of accurate testing. and delays in treatment caused by transport problems played significant roles in the development of this policy. Proponents of mandatory exploration of neck wounds contend that delays in treatment result in increased mortality rates. Also delays caused by lengthy diagnostic testing have resulted in rapid exsanguination of patients who might otherwise have been surgically salvageable. These factors. along with the potential for undetected injuries and the associated complications (including false aneurysms and mediastinitis) favor mandatory exploration. Advocates of routine neck explorations also note the low morbidity rates associated with a neck exploration. Reported rates of negative exploration are high. however. approaching 45%. and mortality rates vary from 2% to 9%. Selective neck exploration has gained popularity in some centers because of the lower negative exploration rates associated with this treatment. while comparable mortality rates are achieved. May found a negative exploration rate of 12% in his series of selective neck explorations and a mortality rate of approximately 3%. Furthermore. Noyes found that the hospital stay for patients with selective observation management not requiring a neck exploration was 2.8 days. compared with 4.2 days for patients with mandatory but negative neck explorations. A summary of diagnostic techniques and their indications in selecting patients with penetrating neck wounds for surgery is presented in Table 5. It has become apparent that both selective and mandatory explorations of neck wounds play important roles in treatment.(ABSTRACT TRUNCATED AT 400 WORDS).
Condylar neck fractures of the mandible, Despite the effectiveness and many advantages of closed reduction of condylar neck fractures. open reduction techniques offer the advantage of anatomic repositioning of the fracture. which may reduce resultant deformities. malocclusion. and temporomandibular joint derangements in patients with complex subcondylar fractures. This objective is best achieved with rigid plate and screw fixation to obtain the stability required for immediate function. This article presents guidelines for the experienced surgeons who wish to address this controversial problem.
Management of nasal fractures, Fracture of the nasal skeleton is a relatively common injury. Satisfactory treatment requires appropriate skills. diagnosis. and management. Some injuries require immediate attention; others are better treated in delayed fashion. Closed reduction provides satisfactory treatment in the majority of nasal fractures; however. open reduction often is a more appropriate choice. Injuries to the nasal septum should be recognized and given proper treatment.
Nasolacrimal injuries. Evaluation and management, The tear drainage system is disrupted in 17% to 21% of nasoethmoidal fractures and. to a lesser degree. other midfacial fractures. When epiphora or dacryocystitis occurs. evaluation should include the Jones dye tests. probing of the ductal system. or dacryography. Dacryocystorhinostomy is the treatment of obstruction distal to the common canaliculus.
Management of orbital blow-out fractures, The sequelae of the blow-out fracture can be predicted from a knowledge of the pathophysiology of the fracture as well as an accurate history and clinical and radiologic examination of the patient. The main indications for exploration and repair are acute changes in globe position and mechanical restriction of gaze. Surgery should be performed at 7 to 10 days posttrauma. For the surgeon who possesses the skills and expertise. reparative procedures should help the patient and infrequently cause complications.
The IPR inventory: development and psychometric characteristics, The purpose of this study was to develop. validate. and norm a measure of dimensions of interpersonal relationships that are salient to nursing: social support. reciprocity. and conflict. The selection of these concepts was guided by social exchange and equity theories. In the first phase of the study. 44 respondents were interviewed to provide narrative data from which to develop items so that items would be grounded in lived experience. Content validity of items was judged by a panel of 11 experts. The revised 39-item instrument was tested in successive steps with a total of 340 students. patients. and community residents for reliability and validity. including internal consistency reliability. test-retest reliability. factor analysis. and three forms of validity assessment (theory testing. contrasted groups. and multitrait-multimethod comparison). The three subscales of social support. reciprocity. and conflict demonstrated repeated internal consistency and test-retest reliability. Strong evidence of construct validity was demonstrated for the social support and the conflict subscales; validity of the reciprocity subscale was equivocal.
Effect of injected long-acting epinephrine in addition to aerosolized albuterol in the treatment of acute asthma in children, The additional effect. if any. of subcutaneous. long-acting epinephrine (Sus-Phrine) to aerosolized albuterol for acute pediatric asthma was studied. Over an eight-month period. patients were enrolled in a prospective. randomized. controlled trial. All patients were recruited and studied in a pediatric emergency department. Forty-three children between the ages of three and 12 years. with a mean age of 8.9 years. presenting with acute asthma were enrolled. Group 1 received Sus-Phrine. 0.005 ml per kg before albuterol aerosols. as appropriate. Group 2 only received albuterol aerosols. There was no significant difference in the extent of improvement between the two groups at either 20 minutes or two hours for clinical score. peak flow. or respiratory rate. Subcutaneous. long-acting epinephrine provides no additional benefit to a beta-2 agonist by nebulization for children with acute asthma.
Traumatic atlanto-occipital dislocation in children: review and report of five cases, Traumatic atlanto-occipital dislocation has usually been considered incompatible with life. However. reports on survivors stress the need for early clinical diagnosis of this condition. particularly in the context of multiple trauma. in order to avoid life-threatening diagnostic manipulations and to provide adequate treatment. Five instances of atlanto-occipital dislocation in children observed during the last two years prompted this report. since four of them survived only temporarily. The radiologic and computed tomographic (CT) findings have been reevaluated. Use of metrizamide CT is advised in clinically suspected cases with inconclusive radiologic workup.
Trabecular structure: preliminary application of MR interferometry, A new approach to probe the structure of trabecular bone in the vertebral bodies in humans was evaluated. and preliminary data are presented. The proposed method is based on the hypothesis that the presence of two physical phases--bone and bone marrow--causes a magnetic field distribution across the imaging voxel. The resulting spread in resonance frequency produces line broadening. which is measured as the decay rate of the region of interest signal intensity that has the properties of an interferogram. The interferogram is the result of two principal chemically shifted components of bone marrow--fat and water--getting in and out of phase with one another while being attenuated by T2* processes from the magnetic field distribution within the measuring volume. The time constant for the decay (T2*) can then be obtained by means of curve-fitting techniques. T2* in healthy persons is found to increase slightly with age. However. patients with osteoporosis (low bone mineral density and/or spine compression fractures) have significantly prolonged T2* values. which are interpreted as arising from an increase in the intertrabecular space.
Truncation artifact: a potential pitfall in MR imaging of the menisci of the knee, Because truncation artifacts on magnetic resonance (MR) images may be confused with meniscal tears. measures to suppress them were investigated in a human cadaver knee and prospective and retrospective studies of patients. The artifacts were most prominent when the acquisition matrix was 128 x 256 and the 128-pixel (phase-encoded) axis was in a superoinferior (SI) orientation. An anteroposterior (AP) orientation of the 128-pixel axis or use of a 256 x 256 acquisition matrix reduced the prominence of or nearly eliminated the artifacts. A review of reports of MR imaging and arthroscopic examinations of 83 knees yielded eight menisci that were falsely interpreted at MR imaging as having tears. Retrospective review of the images suggested that the errors were due to truncation artifacts in two cases. Truncation artifacts will cause relatively little difficulty if diagnostic observers are aware of their characteristics and simple steps are taken to minimize their prominence. including acquiring images in 192 x 256 or 256 x 256 matrices or AP rather than SI orientation of the phase-encoded (128-pixel) axis of 128 x 256 matrices.
Unimpinged and impinged anterior cruciate ligament grafts: MR signal intensity measurements, Regionalized magnetic resonance (MR) signal intensities were quantitatively measured in impinged and unimpinged anterior cruciate ligament (ACL) grafts. Images were obtained with a 1.5-T imager. and signal intensity was measured in the proximal. middle. and distal thirds of the graft. In 15 unimpinged ACL grafts. the signal intensity remained low and did not vary during the 1st year of graft implantation (45 images). In contrast. 17 impinged ACL grafts showed an increase in signal intensity in the distal two-thirds of the graft that persisted 1-3 years after implantation (P less than .001). Unimpinged grafts were placed in tibial tunnels posterior and parallel to the slope of the intercondylar roof. Reconstructions with anterior tibial tunnels resulted in graft impingement that caused increases in graft signal intensity. This increase demonstrates a clear association between surgical technique and the subsequent MR appearance of the graft.
Infected knee prosthesis: diagnosis with In-111 leukocyte, Tc-99m sulfur colloid, and Tc-99m MDP imaging, Forty-one possible cases of infected total knee prostheses studied with indium-111-labeled leukocyte scintigraphy were retrospectively reviewed. Twenty-four of the prostheses were studied with technetium-99m methylene diphosphonate bone scintigraphy and 19 with Tc-99m sulfur colloid marrow scintigraphy. Nine prostheses were infected. and 32 were uninfected. The accuracy of combined labeled leukocyte and sulfur colloid marrow imaging (95%) was higher than that of labeled leukocyte scintigraphy alone (78%). bone scintigraphy alone (74%). or combined labeled leukocyte and bone scintigraphy (75%). The authors conclude that combined labeled leukocyte and sulfur colloid imaging is an accurate method for diagnosis of infected knee prostheses. In this series. this technique was superior to labeled leukocyte and bone imaging. alone or in combination.
Biceps tendon dislocation: evaluation with MR imaging, The magnetic resonance (MR) images from six patients with biceps tendon dislocation--two in whom it was surgically proved and four in whom it was suspected--were retrospectively evaluated. The dislocated tendon can be identified medial to the bicipital groove. best seen on the axial and oblique coronal and sagittal images. Associated abnormalities of the biceps tendon include thickening (n = 3). high signal intensity (n = 3). and surrounding fluid (n = 4). The factors thought to contribute to dislocation can also be well seen on MR images. These include abnormal shape of the bicipital groove (n = 2). disruption of the coracohumeral ligament (n = 6). disruption (n = 4) and thinning (n = 1) of the subscapularis tendon. and supraspinatus tendon tear (n = 4). Since MR imaging is becoming the modality of choice for the evaluation of shoulder derangements. familiarity with the appearance of biceps tendon dislocation on MR images is important.
Plantar fasciitis: MR imaging, The clinical presentation of plantar fasciitis may be mimicked by a number of other painful heel conditions. Thus. magnetic resonance (MR) imaging was used to develop objective morphologic criteria to establish a diagnosis of plantar fasciitis in eight patients. Sagittal T1-weighted and coronal intermediate and T2-weighted images of symptomatic and asymptomatic feet were obtained; additional sequences were used for symptomatic feet. Maximum thickness of the plantar fascia was significantly increased (P less than .0001) in patients with plantar fasciitis (sagittal. 7.40 mm +/- 1.17. and coronal. 7.56 mm +/- 1.01) compared with age- and sex-matched volunteers (sagittal. 3.22 mm +/- 0.44. and coronal. 3.44 mm +/- 0.53) and young male controls (sagittal. 3.00 mm +/- 0.8. and coronal. 3.00 mm +/- 0.0). Furthermore. nine of 10 feet with plantar fasciitis had areas of moderately increased signal intensity in the substance of the fascia. MR imaging may provide an objective assessment of the morphologic changes associated with plantar fasciitis. as well as assist in excluding other causes of heel pain.
Effect of bone distribution on vertebral strength: assessment with patient-specific nonlinear finite element analysis, Three-dimensional quantitative computed tomographic (QCT) studies of the lumbar spine were extended with finite element analysis (FEA) to include bone distribution in assessment of vertebral body strength. Fifty-nine FEA models were created from data from 43 patients. 28 with no evidence of osteoporosis and 15 with previous vertebral fractures. Simulated loads were applied to the vertebral models to estimate vertebral strength. Yield strength in the models from patients with osteoporosis was 0.22-1.05 MPa (average. 0.57 MPa +/- 0.26 [mean +/- standard deviation]). compared with 0.80-2.79 MPa (1.46 +/- 0.52. P less than .001) in patients with normal bone. Yield strength of vertebrae in patients with osteoporosis uniformly fell below approximately 1.0 MPa. with minimal overlap between patients with osteoporosis and those with normal bone compared with the overlap in bone mineral content and trabecular mineral density. Reproducibility of the FEA technique was 12.1% in a subgroup of patients with normal bone. A constant relationship between cortical and trabecular contributions was observed in patients with osteoporosis but not in control patients.
Dynamic gadolinium-enhanced MR imaging of the spleen: normal enhancement patterns and evaluation of splenic lesions, The authors studied the ability to improve detection of splenic lesions during suspended respiration with dynamic gadolinium-enhanced T1-weighted spin-echo magnetic resonance (MR) imaging. In the first phase of the study. normal splenic contrast material enhancement patterns were assessed in 10 control patients without splenic lesions. A heterogeneous signal intensity pattern was observed in 11 patients with splenic lesions during bolus injection of gadopentetate dimeglumine. with conversion to homogeneous enhancement 1 minute later. Mean splenic enhancement was 321% during bolus injection. with a rapid return toward baseline signal intensity thereafter. In the second phase. evaluation of 18 splenic lesions detected with contrast-enhanced computed tomography in 11 patients revealed that dynamic gadolinium-enhanced MR pulse sequences significantly improved lesion conspicuity and detectability compared with conventional T1-and T2-weighted pulse sequences. Contrast-to-artifact ratio measurements were 0.5. 3.7. and 9.3 for conventional T1-weighted. T2-weighted. and dynamic gadolinium-enhanced MR images. respectively.
Intraarterial portography with gadopentetate dimeglumine: improved liver-to-lesion contrast in MR imaging, Magnetic resonance imaging during arterial portography (MRAP) was performed by the authors in a selected group of 12 patients with hepatic lesions. A low dose of gadopentetate dimeglumine (4 mL of a 0.5-mol/L solution. corresponding to a dose of 0.05-0.07 mmol/kg) was injected into the superior mesenteric artery during acquisition of breath-holding gradient-echo or rapid acquisition spin-echo images. Images were always acquired during the first passage of gadopentetate dimeglumine through the liver parenchyma. An increase in liver-to-lesion contrast was obtained with MRAP imaging (contrast-to-noise ratio = 8 +/- 1.8 vs 19 +/- 2.7). Signal intensity enhancement of the liver was high (signal-to-noise ratio = 9.48 +/- 2.42). while the lesion presented no significant enhancement (signal-to-noise ratio = 0.55 +/- 0.22). Lobar portal vein thrombosis was detected in one patient owing to lack of enhancement of the left lobe of the liver. No side effects related to administration of iodinated and paramagnetic contrast agents were observed. This new technique provides specific enhancement of liver parenchyma with improved liver-to-lesion contrast.
Shock wave lithotripsy of gallstones: results and 12-month follow-up in 174 patients, At the authors' institution. as part of the on-going Dornier National Biliary Lithotripsy Study. 174 patients with gallstones were randomly assigned to receive either ursodeoxycholic acid (UDCA) or placebo for 6 months after undergoing extracorporeal shock wave lithotripsy (ESWL). Six weeks after ESWL. 40 (23%) patients were re-treated for gallstone fragments larger than 5 mm in diameter. No significant difference in the UDCA- and placebo-treated patients was noted. The overall 6- and 12-month stone-free rates for all patients with initially noncalcified stones were as follows: UDCA patients. 31% and 36%. respectively. and placebo patients. 21% and 23%. respectively (P less than .05). In patients with a single. noncalcified gallstone that was at most 20 mm in diameter. the 12-month stone-free rates were as follows: UDCA patients. 60%. and placebo patients. 33% (P less than .01). Patients with noncalcified stones that were 11-20 mm in diameter who were treated with UDCA had a higher rate of stone clearance than placebo patients. At 6 months. the authors' previous study demonstrated no significant difference in the two groups of patients. However. the stone-free rate at 12 months was noted to be significantly higher for patients with a single. noncalcified stone that was at most 20 mm in diameter begun on UDCA than for all other groups of patients.
Liver metastases: results of percutaneous ethanol injection in 14 patients, Percutaneous ethanol injection (PEI) was performed under ultrasound (US) guidance in the outpatient department in 14 patients with 21 metastases 1.0-3.8 cm in diameter. The primary cancer was colorectal adenocarcinoma (seven patients). adenocarcinoma of the stomach (four patients). abdominal leiomyosarcoma (one patient). gastrinoma of unknown origin (one patient). and bronchial carcinoid (one patient). The indicators of therapeutic efficacy were US. computed tomography. fine-needle biopsy. and serologic markers. No complications occurred after a total of 175 treatment sessions. Complete response was obtained in 11 lesions. nine of which were less than 2 cm in diameter. and in all endocrine metastases (four lesions in two patients) with a maximum. recurrence-free follow-up of 38 months. Carcinoembryonic antigen values decreased in all patients but one for a 2-6-month period. The natural course of metastatic disease strictly limits the applicability of PEI. a local treatment. Single. metachronous. nonoperable metastasis of adenocarcinoma and endocrine metastases seem to be the only indications for PEI.
Hepatocellular carcinoma: treatment with a combination therapy of transcatheter arterial embolization and percutaneous ethanol injection, In an attempt to obtain complete tumor necrosis in large hepatocellular carcinoma (HCC) lesions. the authors studied the clinical and histologic findings of a new combination therapy. percutaneous ethanol injection (PEI) with transcatheter arterial embolization (TAE) (pretreatment with TAE and subsequent PEI) in 15 patients with a single. large (3.0-9.0 cm in diameter). encapsulated lesion of HCC. Two weeks after TAE. PEI was performed under ultrasound guidance. A total of four to 11 injections were administered at a rate of one injection twice a week. During the follow-up period (range. 7-23 months). all lesions were reduced in size and no evidence of HCC was present at contrast material-enhanced computed tomography or angiography in nine of 11 patients who did not subsequently undergo surgery. Six patients had a follow-up of 1 year or more. for a 1-year survival rate of 100%. Four patients subsequently underwent surgical resection; complete necrosis of the tumor was observed in all four. The authors conclude that a combination of PEI and TAE is an appropriate treatment for patients with large. encapsulated HCC lesions who are poor surgical risks.
Persistent bile leak after liver transplantation: biloma drainage and endoscopic retrograde cholangiopancreatographic sphincterotomy, Persistent bile leaks after liver transplantation were successfully treated in three patients with percutaneous or surgical drainage of bilomas and endoscopic retrograde ampullary sphincterotomy. In all three patients. biliary anastomoses were achieved by means of choledochocholedochostomies. with a T-tube stent in the anastomosis. The bile leaks led to subhepatic bilomas that had persistently high catheter outputs (greater than 200 mL per 24 hours) for longer than 1 month. Biloma drainage decreased shortly after sphincterotomy.
Mesenteric vascular anatomy at CT: normal and abnormal appearances, The appearance of the mesenteric vessels on computed tomographic scans was evaluated in 187 patients to determine the variations in the anatomic relationships between the mesenteric vessels in normal patients. in patients with malrotation. and in patients with abdominal masses. In 166 patients (88.8%). a portion of the cranial segment of the superior mesenteric vein (SMV) was anterior and to the right of the superior mesenteric artery (SMA). although other normal configurations also occurred. A portion of the cranial segment of the SMV was directly anterior to the SMA in 15 patients (8.0%) and directly to the right of the SMA in 16 patients (8.6%). Of eight patients with complete inversion of the SMA and SMV. one had normal midgut rotation. two had malrotation. and six had neoplasms that displaced the vessels (one of these six also had malrotation). Of eight patients with inversion of only a part of the mesenteric vessels. none had malrotation. Although mesenteric inversion should stimulate a careful evaluation for malrotation. it is not pathognomonic of this condition.
Pulmonary blastoma: a rare childhood malignancy, Pulmonary blastoma is a rare primary malignancy of the lung. with few cases reported in children. The tumor consists of mesenchymal and epithelial components resembling the fetal lung. Seven children (aged 18 months to 5 years) with pulmonary blastoma were studied. The pulmonary radiographic patterns seen were a large. space-occupying solid mass with opacification of the hemithorax and preexisting cystic disease with a small solid tumor component. Computed tomographic images showed a low-attenuation mass with whorls of high-attenuation solid tissue. Four of the seven patients died within 2 years despite surgery and therapy; of the three surviving patients. one has recurrent disease.
Primary and metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose analogue 2-[F-18]-fluoro-2-deoxy-D-glucose, The authors assessed whether breast cancers can be detected by means of positron emission tomography (PET) with the positron-emitter-labeled glucose analogue 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG). In 12 patients with primary and/or metastatic breast cancer. PET images of F-18 distribution in vivo were obtained approximately 1 hour after intravenous injection of 10 mCi of FDG. Scan findings were correlated with other imaging data and physical examination and biopsy results. Ten of 10 primary breast cancers were imaged by means of FDG PET with a tumor:background FDG uptake ratio of 8.1 (median). Ten of 10 bone metastases were imaged with a tumor:normal bone uptake ratio of 6.05 (median). Five of five known soft-tissue metastases and four previously unsuspected nodal lesions were found with PET. No false-positive foci of FDG uptake were demonstrated. In two cases with negative mammograms due to dense breast parenchyma. FDG PET clearly delineated the primary tumors. These preliminary data demonstrate the feasibility and substantial potential of PET scanning with FDG to detect and localize both primary and metastatic breast cancers.
Treatment of thoracic multiloculated empyemas with intracavitary urokinase: a prospective study, The authors prospectively treated 10 consecutive patients with multiloculated empyemas with intracavitary instillation of urokinase via a percutaneous drainage catheter. Urokinase (100.000 IU) in 100 mL of 5% dextrose in water was instilled into the pleural cavity via a percutaneous drainage catheter. After overnight clamping. the catheter was opened and the empyema drained with use of negative suction (20 cm H2O). Intermittent irrigation of the catheter with normal saline was performed to prevent clogging of the catheter. Complete drainage of multiloculated empyemas was accomplished in nine patients by means of intracavitary instillation of urokinase via a single 8-F catheter. One patient showed complete drainage of multiloculated empyema. but recurrent empyema appeared in the site of a previous tube thoracostomy. A total of 100.000-700.000 IU (mean. 400.000 IU) of urokinase were needed for complete drainage in all patients. Plasminogen and fibrin degradation product levels in empyema fluid were determined before instillation of urokinase to demonstrate any fibrinolytic action. No complications occurred.
Nonneoplastic enhancing lesions mimicking intracanalicular acoustic neuroma on gadolinium-enhanced MR images, The authors describe five patients with nonneoplastic lesions of the facial and/or vestibulocochlear nerves that demonstrated focal enhancement within the internal auditory canal on magnetic resonance (MR) images. MR and surgical findings for four patients with unilateral sensorineural hearing loss and one with Ramsay Hunt syndrome were reviewed. Three patients with hearing loss underwent surgical exploration and decompression of the internal auditory canal. The MR findings in all four patients with hearing loss were similar: Focal enhancement of the internal auditory canal was depicted on postcontrast T1-weighted images. Nonneoplastic lesions of the seventh and eighth cranial nerves may show focal enhancement on MR images. which mimics the appearance of a small intracanalicular neuroma. This potential for misdiagnosis may have important therapeutic implications.
Meningioangiomatosis: clinical, radiologic, and histopathologic correlation, Meningioangiomatosis (MA) is a rare. benign. hamartomatous lesion of the leptomeninges; MA has been considered to be a forme fruste of neurofibromatosis. A review of pathology records for patients with MA who were seen between 1970 and 1989 at the authors' institutions revealed four patients (three male and one female; aged 2.5-21.0 years; mean. 10.8 years) with a history of seizures but without the stigmata or family history of neurofibromatosis. Three patients had undergone either computed tomographic (CT) or magnetic resonance (MR) imaging studies. All patients had undergone craniotomies to obtain tissue for pathologic analysis; a peripheral. leptomeningeal lesion was found in all four patients. At CT in two patients. the lesions were most consistent with calcification. At T2-weighted MR imaging in one patient. the lesion demonstrated a hyperintense periphery with associated edema of the white matter. Histopathologic examination demonstrated characteristic features of MA--cortical meningovascular fibroblastic proliferation and leptomeningeal calcification. The accurate diagnosis of MA is important since MA is a benign. surgically correctable cause of seizures.
Prostate cancer: correlation of MR images with tissue optical density at pathologic examination, To explain the variability in detection of prostate cancer with magnetic resonance (MR) imaging. the authors correlated preoperative MR findings in 28 patients with tissue optical density (TOD) measurements on whole-mount pathologic slides prepared from radical prostatectomy specimens. TOD was used as an indicator of the degree of tissue compactness or openness. TOD measurements from proved cancers and from pathologic regions corresponding to MR lesions (areas of low signal intensity seen at T2-weighted MR imaging) were compared with TOD measurements from adjacent. nonmalignant tissue. TOD measurements corresponding to MR lesions were higher than noncancerous tissue measurements in all cases (P less than .005). Although most of these lesions represented cancers (21 of 30). nine of 30 represented benign tissue that was composed mainly of densely packed fibromuscular stroma (30% false-positive results). Thus. signal intensity appeared to be related to TOD rather than to a specific histologic tissue type. and the finding of a peripheral zone lesion with low signal intensity did not necessarily indicate the presence of a cancer.
Percutaneous nephrostomy tube placement: an outpatient procedure, The authors report their experience with 56 percutaneous nephrostomies (PCNs) performed on an outpatient basis on 55 patients. Complications included pain that required use of parenteral medication in four patients. bleeding in three that resolved spontaneously. and shaking chills or fever in 12. This last complication. considered to be a sign of sepsis and treated with antibiotics. occurred more frequently than the 1.4%-4.5% infectious complication rate reported in the literature. Antibiotic use during and after PCN significantly decreased the likelihood of sepsis. In the high-risk group. antibiotic administration during and after PCN decreased the risk of developing signs of sepsis from 50% to 9%. On the basis of the authors' results and the findings in the literature about antibiotic prophylaxis. guidelines are recommended to improve the safety of PCN as an outpatient procedure. In the majority of instances PCN should still be considered to be more safely performed as an inpatient procedure at this time.
Spatial and temporal registration of cardiac SPECT and MR images: methods and evaluation, Image registration may assist in the integration of information from multiple sources by allowing direct point-for-point comparisons of studies. To determine the usefulness of such a technique. a method for the spatial and temporal registration of four-dimensional single photon emission computed tomographic (SPECT) and magnetic resonance (MR) cardiac images was developed. Automatically detected left ventricular endocardial surfaces were used to determine the best transform between the two sets of surface points. and that transform was applied to the original SPECT image. A fused image created from the MR and the transformed SPECT images combined the information in both. The authors tested the method with seven patient studies. Registration reduced the distance between the MR and SPECT left ventricular endocardial surfaces by 30%. to an average of 2.7 mm. The authors found that. by using the fused images. perfusion abnormalities could be easily localized and correlated to high-resolution endocardial wall motion and systolic wall thickening.
Coaxial needle technique for lumbar puncture in the morbidly obese patient, The authors describe a method of enhancing the ease of lumbar puncture in the morbidly obese patient. In their experience. the coaxial needle technique shortens fluoroscopic and total procedure times when obtaining cerebrospinal fluid for laboratory analysis or when performing myelography.
Pulmonary nodule: evaluation with spiral volumetric CT, Spiral volumetric computed tomography (CT) was used prospectively in 20 patients with a suspected solitary pulmonary nodule less than 1 cm in diameter on plain chest radiographs. Four additional nodules were detected with spiral CT than were detected with conventional CT. This technique required a 12-second breath hold; patient cooperation was excellent.
Method and theory of monophasic action potential recording, MAP recordings have been at the cradle of cardiac electrophysiology but only recently. through safer and simpler technology. have gained wider access to clinical electrophysiology. In contrast to conventional electrode catheter recordings. MAP recording devices provide precise information not only of the local activation time but of the entire local repolarization time course as well. Although the MAP does not reflect the absolute amplitude or upstroke velocity of transmembrane action potentials. it delivers highly accurate information on the action potential duration and configuration. including early afterdepolarizations as well as relative changes in transmembrane diastolic and systolic potential changes. Based on available data. the MAP probably reflects the transmembrane voltage of cells within a few millimeters of the exploring electrode. MAPs can be recorded by catheter technique from the endocardial surface and by special probes from the epicardium in the operating room. The contact electrode technique is preferable over suction electrodes because it is safer and simpler to use in patients and because it produces more stable. longer-lasting signals. A modified contact MAP catheter incorporates pacing electrodes and permits simultaneous assessment of action potential duration and refractoriness. This not only facilitates the use of MAP catheters in routine electrophysiological studies but also is important for assessing the voltage-independent effects of antiarrhythmic drugs on refractoriness. MAP recordings offer the opportunity to study. in the in situ heart. a variety of pertinent electrophysiological phenomena including. for example. effects of cycle length changes and antiarrhythmic drugs on action potential duration or the role of afterdepolarizations in the genesis of triggered arrhythmias. Due to vigorous heart beating. movement artifacts may occur and need to be distinguished from true abnormalities in the action potential time course. With these limitations in mind. MAP recordings are a valuable addition to clinical electrophysiological studies.
Experimental therapy of human glioma by means of a genetically engineered virus mutant, Malignant gliomas are the most common malignant brain tumors and are almost always fatal. A thymidine kinase-negative mutant of herpes simplex virus-1 (dlsptk) that is attenuated for neurovirulence was tested as a possible treatment for gliomas. In cell culture. dlsptk killed two long-term human glioma lines and three short-term human glioma cell populations. In nude mice with implanted subcutaneous and subrenal U87 human gliomas. intraneoplastic inoculation of dlsptk caused growth inhibition. In nude mice with intracranial U87 gliomas. intraneoplastic inoculation of dlsptk prolonged survival. Genetically engineered viruses such as dlsptk merit further evaluation as novel antineoplastic agents.
Clinical long-term results of anterior discectomy without interbody fusion for cervical disc disease, There were 55 patients (soft disc. 21 and spondylosis. 34) who underwent anterior cervical discectomy without fusion (ACD) using an operating microscope. Discectomy of a single level was performed on 48 cases and two levels on 7. There were 37 patients with radiculopathy. and 18 patients with myelopathy or myeloradiculopathy who were followed clinically for 2-13 years postoperatively. Overall 81% of patients were improved in soft disc herniation. and no significant differences were noted between the group of radiculopathy and myelopathy. In spondylosis all but one patient reported initial relief of their preoperative symptoms; however. overall improvement was noted in only 16 patients (47%). The causes of symptomatic deterioration after ACD for spondylosis were later symptomatic recurrence in 5 patients. severe neck pain in 4. and development of new symptoms due to adjacent spur formation in 2. The authors eventually added interbody fusion in 4 cases. Cervical spine roentgenograms almost always showed a loss of height of the interspace and an anterior angulation immediately after ACD. but the alignment of the spine tended to improve with time. so that. at last follow-up. 82% had a good alignment. A spontaneous osseous fusion occurred in 74% of cases. An adjacent spur formation was observed in 3 patients with spondylosis. The most troublesome complication was neck and/or scapular pain. This pain usually subsided spontaneously. but this continued for more than 4 years postoperatively in 4 patients with spondylosis. Using an operating microscope ACD is a safe and effective procedure for patients with soft disc herniation. but the authors still prefer anterior cervical discectomy with interbody fusion for the patients with advanced spondylosis.
Orientation and moment arms of some trunk muscles, The orientations and moment arms of nine trunk muscles: latissimus dorsi. iliocostalis. longissimus dorsi. obliquii. rectus and transversalis abdominis. quadratus lumborum. and iliopsoas were obtained on embalmed specimens. Each muscle was considered as one or several. linear or curvilinear. lines of action. Origins. insertions. and points along the length of main bundles were digitized for each muscle using a three-dimensional digitizer. The results obtained from seven male specimens are presented and will permit more refined biomechanical models.
Anterior spine fusion using Zielke instrumentation for adult thoracolumbar and lumbar scoliosis, Analysis of adult patients undergoing anterior spine fusions with Zielke instrumentation between January 1983 and November 1986 was performed. Objectives were to review results of surgical treatment and identify factors affecting results. Charts. 3 foot standing anteroposterior and lateral and supine maximal side bending radiographs were reviewed. Subjective data were obtained by telephone. There were 26 patients. average age 41 years. Average radiographic follow-up was 48 months. Indications were pain and curve progression. Average correction was 63% of the instrumented curve. Average change of lordosis was 8 degrees and kyphosis was 6 degrees. Apical vertebral rotation corrected an average of 37%. Complications were: eight hardware failures. one deep infection. and two psychiatric events. The high-risk groups: curves greater than 60 degrees. patients older than 50 years of age. and rigid curves.
Study of correlation between intradiscal pressure and magnetic resonance imaging data in evaluation of disc degeneration. Therapeutic issue with percutaneous nucleotomy, Intradiscal pressure and volume measurements using discomanometry were correlated to features of degeneration noted with magnetic resonance (MR) imaging in 36 discs in patients scheduled for percutaneous nucleotomy. Discomanometric data (intradiscal pressure and degree of pressure loss at 0 and 60 seconds after intradiscal infusion. area under the pressure curve. and discal volume) were not correlated with the MR data (degree of disc height loss and degree of signal intensity loss on T2-weighted images). Results of nucleotomy were strongly correlated with discomanometric data but not with the studied MR factors. Discomanometry by evaluating the physical status of discs. may predict results of percutaneous nucleotomy and consequently play a major role in patients selection.
Congenital laminar defect of the upper lumbar spine associated with pars defect. A report of eleven cases, Lumbar spondylolysis generally is considered to be a fatigue fracture of the pars interarticularis. and no unequivocal case of congenital spondylolysis has been reported. The authors describe 11 cases of unilateral spondylolysis (possibly congenital laminar defect associated with pars defect) of the upper lumbar spine. They have roentgenographic characteristics distinct from conventional spondylolysis of the lumbar spine. including hypoplasia of the spinal accessory process. rotation of the spinous process contralaterally to the spondylolysis. and prominent ipsilateral lamina. The anomaly found in these 11 patients probably is congenital. and its clinical significance is not known.
Diptheroids and associated infections as a cause of failed instrument stabilization procedures in the lumbar spine, Between February 1985 and October 1987. the authors identified seven patients with occult lumbar spine infections associated with the presence of spinal fixation hardware. Six of these infections were with organisms of low virulence; four of the seven patients had polymicrobial infections. All of the polymicrobial infections contained a Diptheroid as one of the isolates. Two of the seven patients studied had normal sedimentation rates. All had white blood cell counts less than 12.000 cells. Imaging studies were not helpful with the exception of one case with a positive gallium scan. The diagnoses were supported by clinical presentation. pathologic tissue changes. positive cultures. and response to therapy. Successful therapy was obtained by removal of hardware and treatment with antibiotics.
Automated percutaneous discectomy, Automated percutaneous discectomy is a new. safe procedure for treating herniated lumbar discs still contained by the annulus or posterior longitudinal ligament. In 1985. one of the authors reported a percutaneous nucleus aspiration technique using a 2-mm aspiration probe. This small probe produced minimal tissue damage. allowing the procedure to be done on an outpatient. In this series. 518 patients were treated using this technique for an overall success rate of 85%. Compensation patients. elderly patients. and patients with previous surgery were treated successfully using percutaneous discectomy on an outpatient basis. No intraoperative or postoperative complications occurred.
Anterior plating in thoracolumbar spine injuries. Indication, technique, and results, The selection of surgical approach for patients suffering from acute thoracolumbar spinal trauma is presently imbued with great controversy. The surgical method chosen depends on the type of fracture. anatomic and biomechanical factors. and the habits and experience of the surgeon involved. Due to new techniques for the posterior approach and the use of internal fixators. the indications for the anterior approach must be reassessed. The primary indication for anterior decompression and grafting is narrowing of the spinal canal with neurologic deficits that cannot be resolved by any other approach. Additional indications are seen in patients with vertebral body fractures with complete comminution and dislocation. noncorrectable burst fractures. and late misalignments. After removal of vertebral body and intervertebral disc fragments. autogenous bone should preferably be used for interposition. Different plates can be used for instrumentation. While anterior plates most often offer complete stability for the thoracic spine and a dorsal plating in this region can turn out to be quite difficult. in the lumbar spine. especially with destruction of additional posterior structures. one must think of subsequent surgical intervention for increased stability and compressive posterior fusion with short-armed internal fixators. So far. we have gained experience from treating 39 patients with anterior decompression and stabilization. One of 19 patients with Frankel Grades A and B and 50% of the remaining 20 patients had improved one Frankel grade. Only a few of the patients with incomplete neurologic symptoms had back pain. All except for one returned to work. According to radiologic examinations. the average loss of correction amounted to 7%.
The Syracuse I-plate, The Syracuse I-Plate is a versatile neutralization plate for anterior spinal fixation following decompression for burst fractures and pathologic vertebral body destruction by tumor. In this article. the history. current use. and indications are discussed. The anterior approach and application of the I-plate to the lower thoracic and lumbar spine is presented. as well as a brief summary of a current clinical series of 34 patients. Fusion rates were high and hardware failure most frequent in patients with associated osteoporosis or extensive posterior disruption. such that the device was contraindicated in cases of extensive three-column injuries or significantly osteoporotic bone.
Application of posterior plating and modifications in thoracolumbar spine injuries. Indication, techniques, and results, Out of 281 patients with recent injuries to the thoracic and lumbar parts of the spine. 243 underwent posterior plating. Of these. 172 patients had an average follow-up of 3.2 years. The consecutive analysis of morphologic results led to modifications of the original Roy-Camille technique. In analogy to the system developed by Zielke for anterior derotation spondylodesis. plates were used in combination with VDS screws. threaded rods. and nuts. thus creating an implant with initial angle variability but final angle stability. The development of transpedicular reduction and cancellous bone grafting for the treatment of vertebral body fractures. later supplemented by transpedicular discectomy and intercorporal cancellous bone grafting. effected a significant improvement in the results of posterior plating. Although the use of traditional plating was followed by correction losses of 14 degrees. the loss could be reduced to less than 6 degrees by the new system. which nearly corresponds to the physiologic anatomy of the spine.
Posterior fixation of thoracic and lumbar spine fractures using DC plates and pedicle screws, A prospective investigation of internal fixation of acute thoracic and lumbar spine fractures using pedicle screws and dynamic compression plates was performed. This article details the results of 23 patients who were followed for an average of 20 months. The indications for the procedure were an unstable fracture--dislocation below the eighth thoracic vertebra or low lumbar fractures that would be difficult to treat with conventional spinal implants. The patients were divided into three groups based on the fracture pattern and the level of the fracture. Group I consisted of fracture--dislocation injuries at the thoracic level and thoracolumbar junction. Group II patients sustained lumbar fracture--dislocations. and Group III contained lumbar burst fractures. Sagittal and coronal angles as well as anterior and posterior vertebral body height were measured at the injury level preoperatively. postoperatively. and at 3-month intervals. Statistical analysis of these angles demonstrated that Group I and III patients had significant correction of their relative kyphotic deformity after surgery; however. there were no differences in kyphotic angle at the 3-month interval. Despite this eventual return to preoperative angles. all patients except one developed solid fusion. There was no increase in neurologic deficit. One patient developed an asymptomatic pseudarthrosis demonstrated by breakage of both plates through unfilled screw holes at the motion segment. Other complications included one wound infection. one case of arachnoiditis after an intradural bone fragment was excised. and one dural tear created by a Kirschner wire. which did not result in a neurologic deficit or a cerebrospinal fluid leak.
Operative treatment of spinal fractures with the AO internal fixator, A multicentered prospective trial to investigate the usefulness of the AO spinal internal fixator for the treatment of thoracolumbar fractures and fracture-dislocations was undertaken. This pedicle screw-rod system was effective in stabilizing a variety of unstable fracture patterns. It was effective in decompressing the canal of retropulsed bony fragments associated with burst fractures. By the use of this implant. sagittal plane deformity was easily corrected.
Biomechanics of spinal fixation and fusion, Recent experiments have shown that in the sheep spine a displacement of 5.2 mm and a strain of 36% was present at the lumbosacral joint. where fusion almost never occurred when multiple. small (5 mm x 14 mm) cancellous and corticocancellous bone grafts were placed in an interlocking fashion across the decorticated lamina of the lumbar spine and sacrum. A displacement of 1.2 mm and a strain of 10% was found at the L5-L6 joint. where fusion always occurred when the same type of bone grafts were applied in the same manner (described above) over the decorticated lamina of L5 and L6. Firm fixation of the lumbosacral spine and bone graft has brought about an arthrodesis in this model. presumably because the displacement and strain had been limited to acceptable levels. Data are presented to support the concept that. because the spine is composed of bony elements separated by a disc with viscoelastic properties. the biomechanics of spinal fixation and fusion are different than the biomechanics of long bone fixation and fracture healing. These differences should be considered in the design and use of spinal fixation devices.
Effects of rigidity of an internal fixation device. A comprehensive biomechanical investigation, Internal fixation with instrumentation often accompanies surgical fusion to augment spinal stability. provide temporary fixation while the surgical fusion mass unites. and enhance postoperative mobilization of a patient. Some surgeons. however. feel that the existing plate-screw designs are too rigid and are the primary cause of "iatrogenic" adverse effects clinically observed. A three-part study. involving in vitro experimental protocol. analytical finite-element-based models. and an in vivo canine investigation. was undertaken to study the role of decreasing rigidity of a device on the biomechanical response of the stabilized segments. Two alternatives--the use of one variable screw placement (Steffee plate [unilateral. 1VSP model]) as opposed to two VSP plates (bilateral. 2VSP model) and two VSP plates with polymer washers placed in between the integral nut and plate (2MVSP model)--were considered for achieving a reduction in the rigidity of the conventional VSP system. The load-displacement data obtained from the in vitro experiments and the stress distributions within the stabilized and intact models predicted by the finite-element models revealed that the unilateral VSP system is less rigid and is likely to reduce stress shielding of the vertebral bodies compared with the 2VSP model. The undesirable effects associated with the use of the 1VSP plate system are the presence of coupled motions due to the inherent asymmetry and the likely inability to provide enough rigidity for decompression procedures requiring a complete excision of the disc. The use of two MVSP plates overcomes these deficiencies.
Reconstruction of failed lumbar surgery with narrow AO DCP plates for spinal arthrodesis, Forty-five patients underwent surgical reconstruction with transpedicular fixation of the lumbar spine with narrow AO DCP plates. Preoperatively. all patients underwent spinal imaging with either magnetic resonance imaging. computed tomography. or myelogram as well as provocative discography to determine the location and the number of symptomatic segments. The minimum follow-up in this series was 2 years. The determination of solid posterior fusion in the presence of plate instrumentation was difficult. The patients in the series were classified as having 1) solid fusion; 2) radiographic flaws within the posterolateral fusion without implant failure; or 3) frank pseudarthrosis with implant failure. Thirty-six (80%) of the patients had a solid fusion. 9 of whom required an additional anterior interbody fusion to obtain symptom control. Twenty percent of the patients in the series had radiographic evidence of reabsorption without implant failure. Four patients in the series (8.8%) had screw breakage. three of which required anterior interbody fusions. The highest rate of reabsorption and pseudarthrosis implant failure was in the 12 patients who had three-level instrumentation; 33% of these patients required anterior interbody fusion to obtain a solid arthrodesis. The average preoperative pain scale was 8.9. and the average postoperative pain scale was a 3.3. Twenty-two patients in the series were cigarette smokers and had a slightly lower fusion rate than non-smokers. They did. however. have a higher use of narcotics after surgery. Forty percent of the patients in this series continued to have radiculopathy after their reconstruction. This study demonstrates the utility of transpedicular fixation in salvage lumbar surgery in obtaining a solid arthrodesis with a beneficial clinical result. Anterior interbody fusions are highly successful in the management of pseudarthrosis and implant failure after transpedicular instrumentation.
Direct anterior fixation of dens fractures with a cannulated screw system, Anterior screw fixation of dens fractures appears to be an optimal method of treatment for these injuries. Anatomic dens fracture reduction with stable internal screw fixation satisfies the established principles of the AO/ASIF. Iatrogenic trauma is minimized by the use of an anterior surgical approach. and no supplemental bone grafting is required. This procedure is quite prone to complications when performed improperly or in contraindicated situations. The use of meticulous surgical technique along with a newly designed cannulated screw system has evolved this procedure into an established form of treatment at our department. Since 1982. 23 patients were treated with direct screw fixation of dens fractures. The overall rate of fracture union was 92.3%. and fracture resolution averaged 5.5 months. The major complication rate of 17% (4/23) resulted from inappropriate use of this technique. The 11 most recent cases. all of which involved stabilization with cannulated screws. resulted in only a single complication (9%) and an average fracture healing time of 3.5 months. A recommended operative technique for anterior screw fixation of dens fractures will be presented along with a discussion of potential sources of difficulty or failures.
Odontoid fractures treated by anterior odontoid screw fixation, While odontoid fractures are common injuries. disagreement exists regarding treatment. Some authors claim a high rate of pseudoarthrosis and have therefore recommended early posterior fixation and fusion. This. however. results in decreased cervical rotation. Therefore. it has been recommended that a more direct approach to the fracture be taken. Results on anterior screw fixation in 14 patients are reported. The technique was found to be especially useful in multiple trauma patients. patients who refuse halo treatment. and in some nonunions.
Treatment of cervical spine injuries with anterior plating. Indications, techniques, and results, This study analyzed 86 patients who sustained a cervical spine injury and who had 93 anterior surgical interventions of the cervical spine. The average age of the patients was 39 years. the mean follow-up 40 months. Twenty-two patients had predominantly vertebral body fractures (burst or tear-drop fractures) and were treated by bisegmental anterior bone grafting and plating. Sixty-four patients had predominantly posterior lesions. either discoligamentous or osteoligamentous. and were treated by unisegmental bone grafting and plating. Forty-three patients were neurologically intact. There were no relevant complications except in one patient. who needed reoperation because of a secondary redislocation due to a technically insufficient osteosynthesis. The technique of anterior bone grafting and plating is shown to be straight-forward. atraumatic. and reliable for predominantly anterior lesions as well as for posterior injuries when performed properly. This clinical experiences does not support experimental data and earlier clinical work. which advocate posterior surgery over anterior surgery and assert that anterior surgery should not be done in predominantly posterior lesions.
Biomechanics of fixation systems to the cervical spine, The biomechanical evaluation of a cervical spine implant must include flexural and torsional testing if it is used for stabilizing a traumatic unstable motion segment. A cadaveric model is presented that allows flexural and torsional testing of a cervical spine motion segment. measuring the tilting angle. the translation. and the torsional angle. After measuring the intact segments. in the first series. a so-called posterior instability was created and stabilized posteriorly with the hook-plate and sublaminar wiring; anteriorly with the H-plate; and with combinations of these implants. In a second series. their stabilizing effect after complete discoligamentous instability was tested. With isolated posterior instability. it was found that the flexural stability is preserved. whereas torsional stability is markedly reduced. In cases of isolated posterior instability. only hook plating alone or its combination with anterior H-plating seemed to bring about a higher torsional stability than the intact specimen. In cases of complete discoligamentous instability. only anterior H-plate and posterior hook plate procedures combined or the hook plate alone was able to guarantee both torsional and flexural stability higher than the intact spine. Exclusive posterior wiring without postoperative external immobilization in complete discoligamentous instability may result in permanent subluxation of the functional unit. Exclusive anterior H-plate fixation in complete discoligamentous instability requires additional external immobilization in the postoperative phase to prevent flexion and torsion.
Series of ninety-two traumatic cervical spine injuries stabilized with anterior ASIF plate fusion technique, This report details the results of 92 patients who underwent a single anterior procedure involving appropriate anterior decompression. tricortical inlay bone grafting. and application of anteriorly applied cervical vertebral plates and screws for the treatment of their acute lower cervical spine trauma. This allowed for needed anterior spinal decompression. correction of deformity. and excellent initial stability. A lightweight SOMI orthosis was used in the immediate postoperative period and continuing for 3 months on average. Follow-up detected a less than 2% incidence of significant complications related specifically to the use of anterior hardware and an excellent fusion rate (98.9%) occurring on average at 3.2 months postoperatively. Anterior decompression. bone grafting. and metallic osteosynthesis are thought to provide a valuable means of treating acute lower cervical spine trauma.
Posterior stabilization of the cervical spine with hook plates, Hook-plate fixation is designed for posterior cervical stabilization from C2 to C7. Indications remain the same as for standard posterior fixations. The prime indications are discoligamentous injuries. The plates are hooked under the lower laminas and attached to the articular masses of the upper vertebra by oblique screws. An H-graft is placed between the spinous processes. The vertebrae are compressed together by the plates at three points. the facet joints. and graft. The resulting pre-stressed system is stable in all directions. A protocol for safe reduction of cervical dislocations is observed. Of 70 patients treated from 1979 to 1986. 51 were examined 12-54 months after surgery. All fusions consolidated. Two neurologic complications not attributable to the fixation occurred. Other major complications were not seen.
Posterior internal fixation with screw plates in traumatic lesions of the cervical spine, Posterior internal fixation associated with bone fusion is indicated in those traumatic cervical spines in which an additional posterior direct action is required to achieve reduction and/or decompression. The internal fixation device is represented by screw plates allowing strong anchorage. short fixation. and light postoperative immobilization. Twenty-three cases of posterior internal fixation in traumatic cervical spines are presented. In selected cases. the results can be estimated as very good with respect to instability. spinal balance involvement. canal stenosis. and reversible neurologic involvement.
Posterior cervical arthrodesis with AO reconstruction plates and bone graft, The efficacy of posterior arthrodesis of the cervical spine with AO reconstruction plates and autogenous bone graft was evaluated in a prospective study. The technique of surgical exposure and the application of the reconstruction plates fixed with screws to the lateral masses is described in detail. Of 30 patients with unstable cervical spines. all had solid fusions based on flexion and extension radiographs at follow-up averaging 17.8 months. No patient's neurologic function deteriorated. All incomplete spinal cord injuries improved at least one Frankel level. There were no neurologic or vascular complications. At follow-up. three patients had fusions extending one level longer than those instrumented. Three other patients had an increase in kyphosis compared with the operative reduction. which was not clinically significant. Although a single screw loosened in three other patients. none had an increased deformity. and all progressed to successful arthrodesis. This technique is particularly advantageous when spinous processes. laminas. and facets are injured or deficient. or when facet-type fusions are indicated.
Anterior plate fixation in spine tumor surgery. Indications, technique, and results, Anterior decompression by vertebrectomy is now well established as the procedure of choice to optimize neurologic recovery in patients with a deficit due to tumor involvement of the vertebral body. Fifteen patients with tumor involvement of the cervical or thoracic spine and neurologic deficit were treated by single-stage anterior decompression and AO plate stabilization. No patient suffered neurologic deterioration after surgery. All patients with thoracic lesions who were unable to walk on presentation and who managed to survive their primary disease improved to a level that allowed independent ambulation with a frame. There were no problems. such as loss of fixation or deformity. It is concluded that standard AO plates provide adequate stabilization of the cervical and thoracic spine after vertebrectomy for tumor involvement.
The many faces of multivisceral transplantation, The transplantation of multiple abdominal viscera. including liver-duodenum-pancreas. liver-stomach-duodenum-pancreas and liver-intestine. is being performed with increasing frequency and success. These procedures and other variations are derived from a seldom used multivisceral operation in which all of the foregoing organs are transplanted en bloc. It is described herein how the full multivisceral transplantation and its less extensive derivatives are based on the same principles of procurement. preservation and postoperative management. With all of these multiple organ permutations and with intestinal transplantation alone. management is complicated by inclusion in the grafts of a large lymphoreticular component that is capable of causing graft versus host disease (GVHD). Because of a systematic error in therapeutic philosophy. past efforts have been directed at altering or damaging the lymphoreticular cells by pretreatment of the donor or of the organs with drugs. irradiation or other means. From recent observations. the alternative approach is suggested of keeping these lymphoid depots intact. which then become the site of two way cell traffic after transplantation. With the use of powerful immunosuppression. such as that provided with FK 506. the donor lymphoreticular cells can circulate in the recipient without causing clinical GVHD. and the lymphoreticular cells in the graft become those of the recipient (local chimerism) without causing rejection. Even with avoidance of rejection and GVHD. metabolic interrelations between the grafted organs. and also between the graft organs and retained recipient viscera can affect the fate of the individual transplanted organs or retained recipient organs. The best delineated of these metabolic influences are mediated by the endogenous splanchnic hepatotrophic factors. of which insulin has been the most completely studied. An understanding of these various immunologic and nonimmunologic factors combined with more potent immunosuppression that is now available is sure to stimulate efforts at transplantation of abdominal organs and particularly of the hollow viscera that have resisted such clinical efforts.
Relationship between proteolytic enzymes and atherosclerosis in aortic aneurysms, Aortic elastase and aortic collagenase were assayed in 38 patients who underwent an operation for thoracic or infrarenal aneurysm or infrarenal aortic occlusive disease and in 15 control patients (heart or kidney donors). Elastase was elevated in normal aortas of the infrarenal region (1.10 milliunits per gram. p less than 0.05). and in atherosclerotic descendens aneurysms (1.24 milliunits per gram. p less than 0.05). compared with the ascending aorta. when normal; aneurysmatic specimens revealed similar low elastolytic activities (0.10 milliunits per gram). The highest elastase content was found in infrarenal aneurysms (4.65 milliunits per gram). Collagenase assays yielded no significant differences. although higher activities were extracted from aortas of the infrarenal region. Coexistent atherosclerosis and wall destruction were evaluated by macroscopic and histologic investigation. All infrarenal specimens demonstrated severe atherosclerotic wall degeneration with depletion of elastic fibers. As the atherosclerotic specimens did not differ from normal aortas by protease assay. the higher elastase of infrarenal samples compared with the thoracic aorta suggests a more rapid fiber metabolism in the infrarenal region. The significantly elevated elastolytic activity of infrarenal aneurysms points to the decisive role of elastase in infrarenal aneurysm formation.
Inoperable recurrence after breast-conserving surgical treatment and radiotherapy, Factors associated with inoperable local recurrence were investigated by a clinical and pathologic review of 596 patients with Stages I and II carcinoma of the breast treated by breast-conserving operations and megavoltage radiotherapy. After a median follow-up period of 71 months. 13 of 70 local recurrences observed were anatomically unsuitable for salvage surgical treatment. affecting 2.2 per cent of patients initially treated. In most. inoperable recurrences clinically resembled primary inflammatory carcinoma of the breast. All inoperable failures occurred in patients with invasive ductal carcinoma and were associated with the presence of unfavorable prognostic features (positive nodes. histologic grade 3. negative estrogen receptor. vascular invasion and lymphocytic stromal reaction). Despite doxorubicin-based chemotherapy. prognosis after inoperable recurrence was quite poor. although survival time in excess of two years was seen in receptor positive. lower grade recurrent tumors in which treatment included hormone therapy.
Management of the nonvertex second twin, We reviewed twin deliveries during a five year period at North Carolina Memorial Hospital and Wake County Medical Center in which Twin B presented as nonvertex. We compared three delivery routes: primary abdominal delivery. breech extraction of the second twin and external version of the second twin. There was no difference in neonatal outcome between the delivery routes. Mothers in the external version group were more likely than those in the breech extraction group to undergo abdominal delivery of the second twin. These women also required more emergency anesthesia. had a higher blood loss and stayed in the hospital longer after delivery.
Evaluation of conservative therapy for exomphalos, Two management patterns were identified in 36 patients with exomphalos--primary surgical closure and initial topical therapy with delayed surgical closure. Primary surgical closure of minor exomphalos was well tolerated in 15 patients. but was associated with a high local and systemic morbidity rate in 14 patients with major defects. In contrast. initial topical therapy with silver sulphadiazine and delayed closure in seven matched patients with a major defect were well tolerated and did not prolong duration of hospitalization. Enteral feeding was more readily established and subsequent fascial closure facilitated in the conservatively treated group. It was suggested that this method should be more often considered in the management of all instances of major exomphalos.
Effects of subarachnoid hemorrhage and a thromboxane A2 synthetase inhibitor on intracranial prostaglandins, The effects of subarachnoid hemorrhage (SAH) on intracranial prostaglandins (PGs) were studied in canines. Subarachnoid hemorrhage was produced by the "two hemorrhage" method. Basilar artery caliber and regional cerebral blood flow (rCBF) in the occipital cortex were reduced by 42% and 43% during delayed vasospasm. respectively. Once delayed vasospasm had developed. intravenous infusion of OKY-046. a selective inhibitor of thromboxane (TX) A2 synthetase. induced no significant change in angiographic vasospasm but caused a significant increase in rCBF. In delayed vasospasm. cortical levels of PGF2 alpha were significantly decreased. whereas plasma levels of PGF2 alpha and TXB2 in the transverse sinus were significantly increased. The intravenous infusion of OKY-046 in delayed vasospasm induced a significant increase in cortical PGF2 alpha and PGE in the occipital cortex. and caused a significant increase in plasma 6-keto-PGF1 alpha and a significant decrease in plasma TXB2 in the transverse sinus. In delayed vasospasm. decreased cortical levels of PGF2 alpha may reflect a decrease in rCBF and increased plasma PGF2 alpha and TXB2 levels may reflect enhancement of intravascular coagulation. These PGs have very strong and various biological activities. The results suggest that SAH induces complicated changes of intracranial PGs and OKY-046 can improve these pathological changes.
Symptomatic intrasellar arachnoid cyst: case report, A case of a large symptomatic intrasellar arachnoid cyst with suprasellar extension is reported. A 53-year-old man was admitted because of decreased visual acuity. Magnetic resonance imaging showed a large intrasellar cyst extending into the suprasellar cistern. with compression of optic nerves. The intensity of the cyst was identical to that of the surrounding subarachnoid space on both T1-. T2-. and proton density-weighted images. Transsphenoidal surgery was performed. but subsequent refilling of the cyst required additional transcranial surgery. Analysis of the cerebrospinal fluid-like cystic fluid revealed high levels of protein and pituitary hormones. Histological study revealed that the cyst wall was composed of connective tissue and arachnoid cells. which were ultrastructurally characterized by a number of desmosomes. Diagnostic. surgical. and pathological features of intrasellar arachnoid cysts are discussed.
Paraganglioma of the cauda equina: case report with magnetic resonance imaging description, The case of a 35-year-old white man with a cauda equina syndrome is presented. Magnetic resonance imaging confirmed the diagnosis. and radiation treatment successfully treated the condition.
Magnetic resonance imaging of human spinal cord infarction, Magnetic resonance images obtained in two cases of spinal cord infarction are described: one with hemorrhagic thoracic cord infarct. the other with ischemic cervical cord infarct with sequential magnetic resonance imagings. An enlarged cord with strand-shape or longitudinal hypointensity on both T1- and T2-weighted images was noticed in the hemorrhagic infarct; hypointensity on the T2-weighted image was thought to be due to hemosiderin. which shortens T2 relaxation. In the ischemic infarct. a small. round area of hypointensity on T1-weighted images. and of hyperintensity on T2-weighted images. noted 9 hours postictus ("early infarct") changed on the 22nd day to a cephalocaudal strandlike hypointensity on T1-weighted image. which was enhanced by Gd-DTPA. The hypointensity suggested "pencil-like softening" in "medium" age infarct. On postictal day 49. it showed an extensive homogeneous hypointensity involving several segments of the cord on T1-weighted images and hyperintensity on T2-weighted images with negative Gd-DTPA enhancement suggesting "late transverse infarct." We considered that these changes are of value in diagnosing spinal cord infarcts on magnetic resonance imagings.
Bone turnover during high dose inhaled corticosteroid treatment, This study was performed to determine the effects of high doses of two inhaled corticosteroids. beclomethasone dipropionate and budesonide. on biochemical indices of bone turnover (urinary hydroxyproline:creatine and calcium:creatinine ratios. plasma alkaline phosphatase. and parathyroid hormone). Twelve healthy male doctors. aged 25-36 (mean 30) years. were studied. After a week's run in period eight subjects inhaled beclomethasone dipropionate 2000 micrograms/day and eight inhaled budesonide 1800 micrograms/day for 28 days; this was followed by a week without any treatment. During treatment with beclomethasone dipropionate there was a significant increase in the hydroxyproline:creatinine ratio (a 46% increase at 28 days). and a fall in serum alkaline phosphatase activity (a 7.4% fall at 28 days). There were no significant changes during budesonide treatment. Thus high dose inhaled beclomethasone dipropionate increased biochemical markers of bone resorption and reduced serum alkaline phosphatase. a marker of bone mineralisation. A prospective study in asthmatic patients is indicated to assess the long term effects of high dose inhaled corticosteroids on bone mass.
Does the substitution of cisplatin in a standard four drug regimen improve survival in small cell carcinoma of the lung? A comparison of two chemotherapy regimens, Ninety five patients with small cell carcinoma of the lung were randomly assigned to one of two chemotherapy regimens (VACE or CVACE). each consisting of six cycles at three week intervals. The VACE regimen consisted of six cycles of vincristine 1.2 mg/m2. doxorubicin 40 mg/m2. and cyclophosphamide 700 mg/m2 on day 1 plus etoposide 110 mg/m2 daily for three days. The CVACE regimen was identical to the VACE regimen for cycles 3 and 4; cycles 1. 2. 4. and 6 consisted of etoposide 110 mg/m2 for three days plus cisplatin 100 mg/m2 with mannitol diuresis on the second day. Forty eight patients received VACE and 47 CVACE. Side effects resulted in withdrawal of four patients receiving VACE and six receiving CVACE. Three deaths were attributed to VACE and one to CVACE. Median survival did not differ between the two treatments overall. though there was a small increase in median survival in partial responders receiving CVACE. It is concluded that replacing four of the six cycles of VACE (vincristine. doxorubicin. cyclophosphamide. and etoposide) with etoposide and cisplatin conferred no overall advantage.
Effect of a 5-lipoxygenase inhibitor on leukotriene generation and airway responses after allergen challenge in asthmatic patients, The effect of a single oral dose (800 mg) of zileuton (A-64077). a specific 5-lipoxygenase inhibitor. on the early and late airway responses to inhaled allergen was studied in a randomised. double blind. placebo controlled. and crossover trial in nine subjects with atopic asthma. Leukotriene generation was also assessed in vivo by measuring urinary leukotriene (LT) E4 excretion. and ex vivo by measuring calcium ionophore stimulated whole blood LTB4 production. Zileuton almost completely inhibited ex vivo LTB4 production but reduced urinary excretion of LTE4 by only about half. There was a trend for the early asthmatic response to be less on the day of zileuton treatment. but this did not reach statistical significance (p = 0.08). The zileuton induced reduction in maximum fall in FEV1 in the early asthmatic response was. however. significantly related to the reduction in urinary LTE4 excretion (r = 0.8). but not to the reduction in LTB4 generation ex vivo. There was no significant change in the allergen induced late asthmatic response. or in the increase in airway responsiveness to methacholine following antigen. The results provide some support for the hypothesis that the cysteinyl leukotrienes have a role in the allergen induced early asthmatic response. More complete in vivo inhibition of 5-lipoxygenase may be needed to produce a significant reduction in airway response to allergen challenge.
Effect of GR32191, a potent thromboxane receptor antagonist, on exercise induced bronchoconstriction in asthma, Previous work suggests a role for mast cell derived mediators in exercise induced asthma. The contribution of newly generated contractile prostaglandins to exercise induced asthma was assessed by using a potent and orally active thromboxane (TP1) receptor antagonist. GR32191. The effect of 120 mg GR32191 on exercise induced asthma was observed in 12 asthmatic subjects. For the exercise challenge the subjects performed six minutes of treadmill exercise. breathing dry air at a work load that had previously been shown to induce a fall in FEV1 of 25% or more from the pre-exercise baseline. No effect of GR32191 on pre-exercise baseline airway calibre was evident. There was no significant difference in the mean maximum percentage fall in FEV1 from baseline after exercise between drug and placebo (placebo 30.2%. GR32191 day 31.6%). It is concluded that the thromboxane antagonist GR32191 has no effect on exercise induced asthma. This suggests that prostaglandins. including PGD2. that act via the thromboxane receptor do not have an important role in exercise induced asthma.
Relation between nocturnal symptoms and changes in lung function on lying down in asthmatic children, Nocturnal symptoms are common in young asthmatic children. Such symptoms may be caused by increased impairment of lung function when they adopt the supine posture. Thirty one children aged 2.8-8.3 years were studied. of whom 20 had asthma (10 with frequent nocturnal symptoms) and 11 had no respiratory problems (control subjects). Peak expiratory flow (PEF) was measured with a Wright's peak flow meter and functional residual capacity (FRC) by a helium gas dilution technique after 30 minutes of lying supine; the values were compared with FRC measured sitting and PEF standing. Peak flow fell significantly on adoption of the supine posture in the asthmatic children. but there was no difference in this fall between the asthmatic children with and without nocturnal symptoms. FRC also fell on adoption of the supine posture. but the decrease in FRC was significant only in the control children and the asthmatic children without nocturnal symptoms. The failure to find a greater fall in PEF or a greater change in FRC on adoption of the supine posture among asthmatic children with nocturnal symptoms suggests that mechanisms other than increased impairment of lung function are responsible for nocturnal asthma.
Platelet activation in nocturnal asthma, Platelet activation may be a factor in the bronchial hyperresponsiveness that characterises asthma. As hyperresponsiveness is increased at night. changes in platelet activation over 24 hours were related to the diurnal changes in peak expiratory flow and plasma catecholamine concentrations in five subjects with asthma and five normal subjects. The effect of muscarinic receptor blockade with intravenous atropine at 0400 hours on these measurements was also studied. Platelet activation. assessed as the ration of beta thromboglobulin to platelet factor 4. was highest when the peak expiratory flow rate was at its lowest in the asthmatic subjects. There was no correlation between platelet activation and plasma catecholamine concentrations. Intravenous atropine did not alter the ratio of beta thromboglobulin to platelet factor 4. suggesting that parasympathetic activity is not the cause of the increased platelet activation at night.
Paraquat induced pulmonary fibrosis in three survivors, Pulmonary lesions following paraquat poisoning are believed to be almost invariably fatal. The three patients reports here survived despite persistent radiological change. One of the patients died after taking a larger dose of paraquat one year later. and at necropsy histological changes attributable to the two episodes of paraquat poisoning were apparent.
Prognostic parameters in spontaneous intracerebral hematomas with special reference to anticoagulant treatment, We examined a series of 200 consecutive patients with spontaneous intracerebral hematoma clinically and by computed tomography. excluding patients with trauma. aneurysm. or tumor. Hematoma volume varied from 1 to 230 (average 35) ml. and overall mortality was 30% (60 patients). Of the 200 patients. 14% (28) were receiving anticoagulants; among these 28 patients hematoma volume averaged 72 ml and mortality 57% (16 patients). The 140 survivors were followed for 2-24 months. Our findings indicate that anticoagulation therapy after previous cerebral infarction or embolism of cardiogenic origin did not predispose to intracerebral hemorrhage. Prognosis was poor when the initial level of consciousness was low and the hematoma volume exceeded 50 ml in combination with dilatation of the contralateral ventricle. An intracerebral hematoma of greater than 80 ml volume was always fatal. regardless of therapy. With volumes of 40-80 ml. early surgical evacuation of the lobar hematoma may improve outcome.
Clinical survey of ischemic cerebrovascular disease in children in a district of Japan, Ischemic cerebrovascular disease in children is relatively rare. To clarify the clinical features of ischemic stroke occurring in infants and children. we evaluated 54 cases of cerebral infarction. excluding cases of moyamoya disease. in patients less than 16 years old at 24 clinics in the Tohoku (northeast) district of Japan. We observed two incidence peaks. one in little children and the other in junior high school students. Infection and minor head trauma were more frequently seen prior to ischemic strokes than was heart disease. The middle cerebral artery region. including the basal ganglia. was most commonly affected (49 patients. 91%) on computed tomograms. Angiography was performed in 48 patients (89%) and showed various types of occlusive lesions. mostly affecting the middle cerebral artery. Hemiparesis was the most common form of disability following ischemic strokes (48 patients. 89%). Surgical treatment was carried out in seven patients (13%). The clinical course of these cases showed that the recovery of children after a stroke tends to be better than that of adults. but that permanent disabilities. such as hemiparesis or mental retardation. occur commonly. Further investigation of juvenile cerebrovascular disease is important to prevent ischemic strokes in children.
Changing rates of stroke in the province of Quebec, Canada: 1981-1988, Using more than 37.000 hospital discharges attributed to hemorrhagic or occlusive stroke in the province of Quebec. Canada. we analyzed trends in stroke incidence during the period 1981-1988. There were large and statistically significant (p less than 0.05) increases in the rates of hemorrhagic stroke over this period. Dramatic increases occurred among men in the rates of both intracerebral (International Classification of Diseases--Ninth Revision [ICD9] code 431) and intracranial (ICD9 code 432) hemorrhagic strokes (40-204% depending on age). In contrast. the rates of occlusion of the precerebral arteries (ICD9 code 433) declined in younger men and women but increased substantially (107%) in older men. Rates of occlusion of the cerebral arteries (ICD9 code 434) declined in men over the age of 50 years and in women aged 50-79 years. Despite the decline in the rate of occlusion of the cerebral arteries. the rate of hemorrhagic stroke appears to have increased. Changes in the hospitalization rates for hemorrhagic stroke were not accompanied by consistent decreases in the case-fatality rate. This finding tends to support the hypothesis of an actual increase in the hospitalization rate fo hemorrhagic stroke rather than an artifactually elevated rate due to enhanced diagnosis by computed tomography.
Effect of recirculation on exacerbation of ischemic vascular lesions in rat brain, Using electron microscopy. we investigated the small arteries and veins in ischemic lesions induced by occlusion of the ostium of the middle cerebral artery in 42 rats. We observed endothelial denudation in the small arteries of rats receiving occlusion for greater than 6 hours. When the occluding cylinder was removed to allow for reperfusion. however. 2 hours of occlusion was sufficient for endothelial denudation to occur. Medial smooth muscle cells seemed to be more vulnerable to ischemia than endothelial cells because ultrastructural changes in the former cells preceded endothelial denudation. Moreover. endothelial denudation definitely exacerbated vascular changes so that medial necrosis appeared to be complete beneath the denuded areas. allowing erythrocytes. platelets. and exogenous tracers to penetrate into the cytoplasm of smooth muscle cells. These arterial lesions seemed to be repaired 10 days after removal of the occluding cylinder following 2 hours of occlusion. On the other hand. small veins in the ischemic lesion did not show endothelial denudation or medial necrosis. Our study suggests that arterial changes in ischemic lesions play a role in exacerbating the brain edema caused by recirculation after ischemia.
Amphetamine promotes recovery from sensory-motor integration deficit after thrombotic infarction of the primary somatosensory rat cortex, The present studies were undertaken to examine 1) whether d-amphetamine sulfate administered to rats well after thrombotic infarction of the vibrissal cortical barrel-field within the primary somatosensory cortex affected the rate and completeness of behavioral recovery and 2) whether a dose-response relation exists between d-amphetamine sulfate dose and recovery of function. In a learning task requiring sensory-motor integration. 41 rats were trained to perform a motor response in a T-maze consequent to the detection of a vibrissal deflection cue. Once training was complete. unilateral (n = 29) or sham (n = 12) infarction was produced by a noninvasive photochemical technique. After infarction. T-maze performance was assessed repeatedly in rats receiving 2 (n = 10) or 4 (n = 10) mg/kg d-amphetamine sulfate or saline (n = 9) 24 hours prior to testing on days 4. 6. 9. and 11. The sham-operated control rats received d-amphetamine sulfate (n = 7) or no injections (n = 5). All three infarcted groups displayed a reliable and sustained behavioral deficit in performance that was not present in the sham-operated control animals. Although the performance of each infarcted group improved over the testing sessions after the first injection. the amphetamine-treated groups improved at a faster rate than the saline-injected group. The results further demonstrated a dose-response effect. with the 4 mg/kg amphetamine group recovering to within preinfarction levels 6-8 days earlier than the 2 mg/kg amphetamine and saline-injected groups. Moreover. both amphetamine-treated groups recovered more completely than the saline-injected group. Quantification of the chronic infarct area revealed no differences among the amphetamine-treated and saline-injected groups. These data provide further evidence of the facilitatory effect of d-amphetamine sulfate on recovery from brain injury and extend this effect to the enhancement of recovery subsequent to thrombotic infarction of the primary somatosensory cortex.
Allopurinol pretreatment improves evoked response recovery following global cerebral ischemia in dogs, The reperfusion of previously ischemic tissue may lead to the formation of highly reactive free radicals that promote tissue injury. Xanthine oxidase has been implicated as one source of these free radicals. We examined the role of xanthine oxidase in brain injury using a cerebrospinal fluid compression model of global cerebral ischemia with 15 minutes of ischemia and 4 hours of reperfusion. Seven dogs were pretreated with the xanthine oxidase inhibitor allopurinol (50 mg/kg for 5 days). Neurophysiological recovery was monitored with cortical somatosensory evoked potentials. As an attempt to correlate brain recovery with the mechanism of protection. free brain malondialdehyde was measured at the end of reperfusion by high-performance liquid chromatography. Brain water content was measured by wet-dry weights. Compared with seven untreated control dogs. allopurinol pretreatment significantly improved recovery of somatosensory evoked potentials after 4 hours of reperfusion. However. the amount of free malondialdehyde in the allopurinol-treated dogs was 32% greater than that in the controls. Brain water content was similar in the two groups. These results suggest that xanthine oxidase contributes to brain injury after ischemia and reperfusion. However. tissue damage caused by xanthine oxidase may be mediated through mechanisms other than free radical production.
Acetazolamide or dexamethasone use versus placebo to prevent acute mountain sickness on Mount Rainier, Eighteen climbers actively ascended Mount Rainier (elevation 4.392 m) twice during a randomized. double-blind. concurrent. placebo-controlled. crossover trial comparing the use of acetazolamide. 250 mg. dexamethasone. 4 mg. and placebo every 8 hours as prophylaxis for acute mountain sickness. Each subject was randomly assigned to receive placebo during one ascent and one of the active medications during the other ascent. Assessment of acute mountain sickness was performed using the Environmental Symptoms Questionnaire and a clinical interview. At the summit or high point attained above base camp. the use of dexamethasone significantly reduced the incidence of acute mountain sickness and the severity of symptoms. Cerebral and respiratory symptom severity scores for subjects receiving dexamethasone (0.26 +/- 0.16 and 0.20 +/- 0.19. respectively) were significantly lower than similar scores for both acetazolamide (0.80 +/- 0.80 and 1.20 +/- 1.05; P = 0.25) and placebo (1.11 +/- 1.02 and 1.45 +/- 1.27; P = .025). Neither the use of dexamethasone nor that of acetazolamide measurably affected other physical or mental aspects. Compared with placebo. dexamethasone appears to be effective for prophylaxis of symptoms associated with acute mountain sickness accompanying rapid ascent. The precise role of dexamethasone for the prophylaxis of acute mountain sickness is not known. but it can be considered for persons without contraindications who are intolerant of acetazolamide. for whom acetazolamide is ineffective. or who must make forced. rapid ascent to high altitude for a short period of time with a guaranteed retreat route.
Safety belts and public health. The role of medical practitioners, Medical practitioners have helped the public become aware of the importance of health-promoting life-style changes such as getting more exercise and abstaining from smoking. They can likewise help their patients protect themselves from the threat of automobile crash injury. Safety belt use remains too low. and increased use offers unusual potential for averting death and disability. Various characteristics associated with a failure to use safety belts can be used to help identify patients at high risk of traffic injury. These include male sex. persons who are ethnic minorities. young people. poor people. those with low educational levels. and persons with negative attitudes to seat belt use. Various methods and resources are available to help practitioners provide appropriate safety belt advice to patients. although the specific resources available vary from place to place. At a minimum. patients need to be told that a proper use of occupant protection can at least double the chances of avoiding death or severe injury in an automobile crash.
A public health approach to cholesterol. Confronting the 'TV-auto-supermarket society', Coronary heart disease has been proved to be associated with a "high-risk" diet and with elevated blood cholesterol levels. The National Cholesterol Education Program has embarked on a campaign based on intensive medical treatment of 60 million Americans with high blood cholesterol levels. but the degree of benefit of dietary change or pharmaceutical intervention or both to reduce blood cholesterol values remains a subject of disagreement within the scientific community. Evidence from comparative international studies suggests that to lower coronary heart disease mortality substantially. dietary alterations and general societal changes must be greater than those possible under the National Cholesterol Education Program's approach of physician-centered patient counseling. The nation's priority to prevent coronary heart disease should be a public policy approach. the goal of which is to reduce for the entire population all coronary disease risk factors. In the dietary area. three proposals to reduce the availability of atherogenic foods are the use of warning labels on atherogenic foods. the prohibition of advertising for such high-risk foods. and the imposition of an excise tax on the same foods. We must confront the "TV-auto-supermarket society" that underlies our nation's high rate of coronary heart disease.
Simvastatin: a review of its pharmacology and clinical use, Simvastatin. a chemical derivative of lovastatin. is an antihyperlipidemic medication that inhibits hydroxymethylglutaryl coenzyme A reductase. Animal and clinical data suggest simvastatin is twice as potent as lovastatin. It lowers serum cholesterol by inhibiting hepatic synthesis of cholesterol and. more importantly. by increasing the number of low-density lipoprotein (LDL) receptors present on hepatic cellular membranes. Simvastatin. when used at doses of 40 mg/d in patients with heterozygous familial hypercholesterolemia. significantly reduces total cholesterol (greater than 30 percent) and LDL cholesterol (35-45 percent) and tends to reduce triglycerides and raise high-density lipoprotein (HDL) cholesterol. The agent is also effective in patients with polygenic hypercholesterolemia. familial dysbetalipoproteinemia. and nephrotic syndrome. Addition of cholestyramine to simvastatin enhances the LDL cholesterol-lowering effect to approximately 55 percent. Common clinical adverse effects reported with simvastatin use include headaches and gastrointestinal complaints. Transient elevations in serum transaminases and creatine phosphokinase have also been seen. Based on data currently available. the drug's clinical activity and adverse-effect profile are similar to those of lovastatin. Therefore. there is no need for formularies to contain both medications. To choose between the two. one needs to consider the incidence of adverse effects and the daily cost of each product when used at equally effective doses. That information is now now available and. until it is. a clear recommendation cannot be made. Simvastatin. presently marketed in several countries. is investigational in the U.S. but is expected to be available soon.
The Cytobrush effect on Pap smear adequacy, One hundred twenty-four Papanicolaou smears were studied to compare the yield of endocervical cells obtained with the Cytobrush/Ayre spatula method to that of the cotton-tipped applicator/Ayre spatula method. Forty-nine of the 62 Pap smears (79%) obtained with the combination Cytobrush/Ayre spatula method contained endocervical cells. compared to 22 of the 62 smears (35%) obtained with the cotton swab/Ayre spatula method (chi 2 = 24.02. P less than 0.0001). The Cytobrush/Ayre spatula method obtained endocervical cells in 14 of 17 (82.4%) of the patients with stenotic ora. compared to 0 of 12 (0%) patients for the cotton swab/Ayre spatula method (P less than 0.001). The Cytobrush/Ayre spatula method obtained endocervical cells in 8 of 11 (72.7%) postmenopausal patients. compared to 4 of 14 (28.6%) patients for the cotton swab/Ayre spatula method (P = 0.05). Using the cervical Cytobrush for Pap smears increases the recovery rate of endocervical cells. which may improve the detection of cervical dysplasia in the patient population as a whole. in postmenopausal women. and in women with stenotic cervical ora.
Social stressors, social supports, and self-esteem as predictors of morbidity in adults with chronic lung disease, Psychosocial correlates of morbidity and functional status were examined in 44 white adults with chronic lung disease. Demographic characteristics. functional status. stressful life changes. social supports. and self-esteem were assessed at baseline by a self-administered questionnaire. Hospital days. bed-disability days. restricted-activity days. and physician visits were then measured prospectively by mailed questionnaire over the next 6 months. There were no cross-sectional associations of psychosocial variables with demographic characteristics. Better functional status (measured by the Sickness Impact Profile) was associated with a lower 12-month life-change score (measured by the Social Readjustment Rating Scale). with stronger social supports (measured by a 13-item index). and with higher self-esteem (measured by the Rosenberg Scale). On bivariate analysis. higher life-change score predicted higher levels of all four morbidity variables; low social supports predicted increased bed days. restricted-activity days. and physician visits; and low self-esteem predicted high restricted-activity. After controlling for demographic characteristics and baseline function by multivariate analysis. low social supports continued to predict higher rates of physician visits. but the other associations of psychosocial variables with morbidity were no longer statistically significant. The results suggest that patients with weak social supports have increased use of physician services.
Temporal arteritis with normal erythrocyte sedimentation rate, The erythrocyte sedimentation rate (ESR) is used to differentiate temporal arteritis from other forms of headache in the elderly. Though temporal arteritis can occur with a normal ESR. this is not generally appreciated in primary care. The case reported here is a 74-year-old woman with biopsy-proven temporal arteritis; her ESR was 22 mm/hr. Of note. her hematocrit was more than 40 percent. a condition previously reported to be associated with temporal arteritis and a normal ESR. This discussion focuses on the diagnosis of temporal arteritis and its associated symptoms.
Intestinal parasites in Cambodians: comparison of diagnostic methods used in screening refugees with implications for treatment of populations with high rates of infestation, We performed a retrospective review of screening parasitology examinations on a Cambodian refugee population served by an urban neighborhood health center. Five-hundred twenty of 1084 patients were examined for ova and parasites either by purged stool. which was examined immediately. or preserved stool. examined at a teaching hospital and proprietary laboratories. Overall. 335 (64 percent) of the tested patients had at least one parasite. The prevalence of infection varied by test technique (purged stool examined immediately. 86 percent; preserved stool examined at a hospital. 65 percent; preserved stool sent to a proprietary laboratory. 31 percent. P less than 0.01). In this population where Entamoeba histolytica infection was 44 percent as measured by the purged warm stool technique. the cold preserved stool test had a measured relative sensitivity of 33 percent. Assuming a selectivity of 99 percent. it would take eight negative tests to reach a greater than 95 percent negative predictive value. The high rate of intestinal carriage of pathogenic parasites in this population and the insensitivity of commonly available diagnostic tests make routine presumptive treatment of intestinal parasites an option when the purged stool examination is unavailable.
Experience with rapid latex agglutination testing for group A streptococcal pharyngitis in a pediatric group office laboratory, We evaluated 2401 patients with suspected streptococcal pharyngitis with the Culturette 10-minute Group A Strep ID test during a 6-month period in order to determine its suitability for rapid diagnosis in a busy private office practice. Duplicate throat swabs were obtained for each child. and latex agglutination was performed within 15 minutes. In children with negative latex agglutination results. the second swab was cultured. All latex agglutination results were available within 20 minutes of collection. while the patients waited in the office. Seven hundred thirty-eight specimens were positive by latex agglutination. Seventy-eight of the 1663 latex negative specimens contained group A streptococci on culture (sensitivity 90 percent). Approximately 60 percent of these latex-negative. culture-positive specimens demonstrated 3(+)-4+ growth in culture. unlike previous studies ascribing false-negative latex results to low colony count specimens. Fifty percent of bacitracin-susceptible streptococci tested were not group A. indicating a relatively high occurrence of nongroup A beta-hemolytic streptococcal carriage in this patient population. The use of latex agglutination for detection of group A streptococcal pharyngitis was well-suited to our office practice. even during an extremely busy winter season. Although this assay appears to have a relatively high sensitivity. it is still prudent to culture latex-negative swabs to exclude group A streptococcal infection. The significance of nongroup A beta-hemolytic streptococci in our patient population was unclear. Further refinements are necessary.
Buspirone effect on tobacco withdrawal symptoms: a pilot study, Tobacco withdrawal symptoms hamper smoking cessation. This was a pilot study of buspirone. a new azapirone anxiolytic. for tobacco withdrawal. Thirteen smokers entered an open clinical trial. Smokers were titrated to 30 mg/day of oral buspirone for 2 weeks prior to cessation. Tobacco withdrawal and Spielberger state-anxiety scales were used at baseline. on the quit date. and then at 24 hours. 48 hours. 1 week. and 2 weeks after abrupt cessation. At the final visit. smokers compared their withdrawal experience with previous cessation attempts. Two patients (15 percent) could not tolerate the medication and did not attempt smoking cessation. Of the remaining 11 smokers. 3 (27 percent) rated withdrawal relief "very definite." 6 (55 percent) "moderate." and 2 (18 percent) "slight." More than two-thirds of the smokers believed that their difficulty concentrating. craving. restlessness. and anxiety were improved compared with earlier tobacco withdrawal attempts. Five patients (46 percent) reported decreased smoking urges during the 2-week medication titration period. Tobacco withdrawal symptoms and state-anxiety scores changed significantly during the study (P less than 0.05). These results are encouraging. but they should be interpreted with caution because of the small sample size and lack of placebo control. Buspirone effect on tobacco withdrawal symptoms should be studied in a randomized. controlled clinical trial.
Recent advances in MR imaging/spectroscopy of cerebral ischemia, Recent advances in high-resolution MR imaging and multinuclear spectroscopy have stimulated studies of the functional relationships between tissue hypoperfusion. cellular energy depletion. and brain edema associated with cerebral ischemia. The very slow (microns/sec) random translational motion of water protons in various brain tissues and intracranial fluid compartments can now be assessed with MR diffusion imaging. More slowly diffusing protons in ischemic tissues can be differentiated from normal parenchyma. CSF. and flowing blood. enabling the detection and localization of ischemic regions within minutes of the onset of stroke. Perfusion imaging "snapshots." obtained in as little as 25 msec with echoplanar MR methods. permit the evaluation of tissue washin/washout kinetics of contrast agents in the microvasculature. and thus the quantification of brain perfusion on a regional basis. Also. delineation of major intra- and extracranial arterial and venous structures with MR angiography. acquired with two- or three-dimensional Fourier transformation techniques. has enabled accurate noninvasive assessments of vascular occlusive disease. Finally. improvements in MR spectroscopic techniques have facilitated investigations of metabolic regulation and bioenergetics in experimental animal models of cerebral ischemia. as well as in stroke patients. Combined MR imaging and spectroscopy will likely play an important role in differentiating reversibly from irreversibly ischemic brain tissues and in the investigation of various neuroprotective pharmaceuticals.
Mammographic and CT findings after breast reconstruction with a rectus abdominis musculocutaneous flap, This essay illustrates the radiologic appearance of the reconstructed breast and the abdominal wall after breast reconstruction with a transverse rectus abdominis musculocutaneous (TRAM) flap. The findings are based on a retrospective study of 42 mammograms. 17 abdominal CT scans. and two CT scans each of the chest and pelvis of patients who underwent this procedure.
Altered swallowing function in elderly patients without dysphagia: radiologic findings in 56 cases, Swallowing disorder is an increasing problem in our aging population. A majority of these patients have a functional abnormality of the oral. pharyngeal. and/or esophageal stage of swallowing. However. what constitutes normalcy is not well understood. and baseline swallowing in elderly persons without dysphagia has not been adequately described. We therefore evaluated 56 persons with a mean age of 83 years who had no symptoms of dysphagia or eating difficulty. Videofluoroscopy and radiographs with the subject erect and recumbent were obtained. Normal deglutition. as defined in young persons. was present in only 16%. Oral abnormalities (difficulty ingesting. controlling. and delivering bolus relative to swallowing initiation) were seen in 63%. Pharyngeal dysfunction (bolus retention and lingual propulsion or pharyngeal constrictor paresis) was seen in 25%. Pharyngoesophageal segment abnormalities were observed in 39% (mostly cricopharyngeal muscle dysfunction). Esophageal abnormalities (mostly motor in nature) were observed in 36%. What has been described as swallowing dysfunction in young persons may not be abnormal in very elderly persons. It is difficult to distinguish the effect of normal aging from the effects of specific diseases or gradual degenerative changes.
Clinical stage I carcinoma of the cervix: value of MR imaging in determining degree of invasiveness, The depth of tumor invasion measured at histologic examination is the most important prognostic factor in early-stage carcinoma of the uterine cervix. The ability of MR to estimate the depth of tumor invasion was studied in 47 patients who subsequently underwent radical hysterectomy. In two patients. MR failed to detect tumors with infiltration depths of 2 and 4 mm. The maximum sagittal tumor length along the axis of the cervix (D) and the maximum tumor area on sagittal (S) and axial (A) images were measured with MR. The depth of tumor infiltration determined histologically (I) correlated with the degree of infiltration noted on MR images. The univariate correlation coefficients for log I vs log D. log S. and log A were .87. .84. and .77. respectively. By stepwise inclusion of the variables in a multivariate analysis. the contributions to the coefficient of determination from including log S and log A after log D were less than 1%. The regression analysis showed that the best estimate for the depth of invasion was close to half of the sagittal tumor length measured on MR. I = D/2. Our experience shows that MR is valuable in determining the degree of invasiveness in clinical stage I tumors.
The deformed petrous bone: a new plain film sign of premature lambdoid synostosis, Towne-view skull radiographs of 38 infants with unilateral lambdoid synostosis were reviewed. The diagnosis of lambdoid synostosis was based on other plain film findings. CT findings. or clinical examination. All patients had deformity of the ipsilateral petrous bone. presumably because of pressure caused by redirected brain growth. Specific changes included flattening of the petrous ridge and depression of the roof of the mastoid portion of the petrous bone and adjacent structures such as the semicircular canals. Flattening of the petrous ridge and depression of the roof of the mastoid portion of the petrous bone are useful signs of lambdoid synostosis when sutural closure has produced sutural indistinctness rather than sclerosis.
Treatment of primary sclerosing cholangitis with oral methotrexate, Ten patients with well-documented primary sclerosing cholangitis who had no signs of portal hypertension or liver failure were treated with oral pulse methotrexate for at least 1 yr. The methotrexate dose averaged 15 mg/wk (0.2 mg/kg/wk). All six patients who were symptomatic became asymptomatic within 1-5 months of starting methotrexate. Biochemical tests of liver function improved in all patients. The alkaline phosphatase value decreased from a mean (+/-SD) of 373 +/- 210 IU to 140 +/- 77 IU (p = 0.0008). the mean alanine aminotransferase (ALT) from 115 +/- 74 to 76 +/- 79 U/L (p = 0.005). and the mean aspartate aminotransferase (AST) value from 88 +/- 37 to 57 +/- 40 U/L (p = 0.007). The improvement in mean bilirubin (1.19 +/- 1.41 to 0.67 +/- 0.25 mg/dl) was not statistically significant. Serum albumin remained normal (3.97 +/- 0.46 to 4.22 +/- 0.36 g/dl). Nine patients had a repeat liver biopsy after 1 yr of methotrexate therapy. Six of the nine showed histologic improvement with a reduction in inflammation. The other three liver biopsies were unchanged. Repeat cholangiograms were done in six patients. Two showed improvement. In one of the two. who had early disease. the cholangiogram became normal. and the liver biopsy was markedly improved. The other four cholangiograms showed no progression of disease. No toxicity was detected in these 10 patients. These results suggest that low-dose oral methotrexate therapy is effective in primary sclerosing cholangitis if treatment is begun before signs of portal hypertension or liver failure occur.
A prospective, controlled analysis of endoscopic cytotechniques for diagnosis of malignant biliary strictures, We prospectively collected brushings and bile for cytology in 30 consecutive patients with bile duct strictures (17 malignant. 13 benign) who were assessed by endoscopic retrograde cholangiography. When appropriate. the cellular debris on stents that were removed from individuals who were managed with these devices was evaluated for malignant cells as well. Our aim was to assess the value of these endoscopic cytotechniques for making a diagnosis of obstructing cancer of the biliary tract. A cumulative total of 78 specimens were obtained. Overall. sensitivity was highest for stent (36%) and brush (33%) cytology. compared with results obtained from bile (6%). If the results for all methods are combined. 47% of patients with cancer (eight of 17) could be diagnosed by one or more cytological technique. There were no false-positive results (specificity. 100%). Our results show that brush and stent cytology are nearly equivalent for detecting cancer. but because a diagnosis is delayed until the endoprosthesis is removed (mean 3.4 months). the brush technique is preferred. Results for bile cytology are marginal. Specificity for these cytotechniques is high; therefore. a positive result by any method is sufficient evidence for cancer. and other invasive diagnostic procedures are unnecessary.
The effect of transcutaneous nerve stimulation on sphincter of Oddi pressure in patients with biliary dyskinesia, Vasoactive intestinal polypeptide (VIP) has been postulated as a neuropeptide with inhibitory neurotransmitter activity in nonadrenergic noncholinergic pathways. Transcutaneous electric nerve stimulation (TENS) relaxes the lower esophageal sphincter in patients with achalasia. Such response is accompanied by a 30% increase in VIP concentrations in the systemic circulation. Since the sphincter of Oddi (SO) receives a very dense VIP nerve supply. we evaluate the effect of TENS on SO motor activity and on VIP plasma concentrations in patients with biliary dyskinesia and in healthy volunteers. TENS was performed with a pocket stimulator for 45 min. SO pressure and VIP levels were obtained before and after 45 min of TENS. In patients with SO dyskinesia. TENS produced a significant decrease in SO pressure from 80.1 +/- 11.9 mm Hg to 58.3 +/- 9.7 mm Hg p less than 0.01); this was accompanied by a significant increase in VIP plasma levels from 21.1 +/- 0.5 pg/ml to 32.6 +/- 1.5 pg/ml (p less than 0.01). In healthy volunteers. TENS did not produce significant changes in SO pressure. However. a significant increase in VIP plasma values was observed (p less than 0.01). No significant changes in amplitude. duration and frequency of SO phasic contractions were observed in either of the two groups evaluated. We conclude that. in patients with SO dyskinesia. TENS decreases SO basal pressure. possibly by a direct action of the released VIP in the systemic circulation. In healthy volunteers. TENS increases VIP plasma values without significant effect on SO basal pressure. These findings suggest that the response to TENS may be mediated by VIP. It is also possible that the alterations seen in patients with biliary dyskinesia may be due to impairment of the VIP nerve supply at the level of the SO.
Frequency of abnormal sphincter of Oddi manometry compared with the clinical suspicion of sphincter of Oddi dysfunction, Patients with pancreaticobiliary pain or idiopathic pancreatitis have been classified as having definitive (type I). presumptive (type II). or possible (type III) sphincter of Oddi dysfunction (SOD) based on clinical. laboratory. and ERCP data. This study was undertaken to determine the frequency of abnormal sphincter of Oddi manometry (SOM) when patients are classified by this system. Two hundred and thirteen patients with pancreaticobiliary pain were evaluated clinically; SOM. ERCP. and ductal contrast drainage time tests were performed. For biliary types I. II. and III. the frequency of abnormal SOM was 85.7%. 55.1%. and 28.1%. respectively. Similarly. for pancreatic types I. II. and III. an elevated basal sphincter pressure occurred in 92.3%. 58.2%. and 35.1%. respectively. When patients with an abnormal basal sphincter pressure were characterized by the magnitude of the elevation. the manometric profiles were similar for types I. II. and III. These data suggest that elevated sphincter pressure occurs more frequently in type III patients than previously reported. and supports consideration of SOM when evaluating and treating type II and type III patients.
The value of pancreatic pseudocyst amylase concentration in the detection of pseudocyst communication with the pancreatic duct, The aims of the study were to compare the results of endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous cystopancreatography (PCP) in the detection of the communication between the pancreatic pseudocyst and the pancreatic duct. and to assess the reliability of the increased amylase concentration in the pseudocyst content as an indicator of the existence of communication between the pancreatic pseudocyst and the pancreatic duct system. Forty-three patients were included in the study. Pseudocystic fluid content was obtained by percutaneous aspiration. Twenty-four patients had pseudocyst amylase concentrations above 64 Wolgemuth units (WU). and 19 patients had less than 64 WU. The communication between pseudocyst and the pancreatic duct was determined in 22 patients by ERCP and in 13 patients by PCP. all in the group with increased pseudocyst amylase concentration. Due to high sensitivity and specificity of pseudocyst amylase concentration for the existence of pseudocyst communication with the pancreatic duct. we conclude that guided percutaneous aspiration of the pancreatic pseudocyst with the determination of amylase concentration in the fluid can replace ERCP as a method of choice for the detection of pseudocyst communication with the pancreatic duct.
Endoscopic findings in carcinoid tumor of the duodenum, The endoscopic findings in six patients with carcinoid tumor of the duodenum were analyzed. Radiographic and endoscopic examinations revealed a smooth and round elevation (measuring 5-20 mm in diameter) in the duodenal bulb. In three patients. the lesion was accompanied by an irregularly shaped erythematous depression. a characteristic endoscopic finding of this tumor. Because the endoscopic forceps biopsy technique led to an accurate diagnosis. we wish to stress the clinical value of the endoscopic modalities.
Incomplete lower esophageal sphincter relaxation in subjects with peristalsis: prevalence and clinical outcome, Incomplete lower esophageal sphincter relaxation is recognized in achalasia and has been reported in subjects with esophageal spasm. We reviewed 500 consecutive manometric studies from a 3-yr period to determine the prevalence of this manometric finding. its association with other motility abnormalities. and the clinical outcome of subjects without associated aperistalsis (i.e.. without achalasia). We identified 60 subjects with incomplete lower sphincter relaxation. 17 of whom had at least some normal peristalsis (3.4% of the total). Mean lower sphincter residual pressure for these 17 subjects (4.5 +/- 2.8 mm Hg) was intermediate between those with achalasia (11.7 +/- 6.8 mm Hg) and those with normal relaxation (0.1 +/- 0.2 mm Hg). Both peristaltic and contraction abnormalities in the esophageal body were prevalent in the 17 subjects compared with those who had normal relaxation. Outcome with conservative medical therapy after a mean follow-up of 3.3 yr was not significantly related to presence of peristaltic or contraction abnormalities at presentation. and 71% of subjects with or without these concomitant findings had improvement or complete resolution of symptoms. Only one subject worsened and was treated with pneumatic dilation. We conclude that incomplete relaxation of the lower esophageal sphincter without aperistalsis is uncommon. symptom regression occurs with conservative therapy. and pneumatic dilation appears rarely required over a modest follow-up period.
Endoscopic removal of gastric lipoma: diagnostic value of endoscopic ultrasonography, A 47-yr-old male with gastric lipoma is presented. X-ray and endoscopic examinations revealed a submucosal tumor on the posterior wall of the gastric antrum. Endoscopic ultrasonography demonstrated the hyperechoic mass in the submucosa without continuity to the muscularis propria. by which the lesion was diagnosed as lipoma. The lesion was successfully removed by endoscopic polypectomy without complications. The cross-sections of the removed specimens were quite consistent with the ultrasonographic findings. Endoscopic ultrasonography is valuable in assessing the exact extent of the tumor and in determining whether or not endoscopic polypectomy is called for.
Estimating the likelihood of severe coronary artery disease, PURPOSE: To determine which clinical characteristics obtained by a physician during an initial clinical examination are important for estimating the likelihood of severe coronary artery disease. and to determine whether estimates based on these characteristics remain valid when applied prospectively and in different patient groups. PATIENTS AND METHODS: We examined clinical characteristics predictive of severe disease in 6.435 consecutive symptomatic patients referred for suspected coronary artery disease between 1969 and 1983. RESULTS: Eleven of 23 characteristics were important for estimating the likelihood of severe coronary artery disease. A model using these characteristics accurately estimated the likelihood of severe disease in an independent sample of 2.342 patients referred since 1983. The model also accurately estimated the prevalence of severe disease in large series of patients reported in the literature. CONCLUSIONS: These findings suggest that the clinician's initial evaluation can identify patients at high or low risk of anatomically severe coronary artery disease. Cost-conscious quality care is encouraged by identifying patients at higher risk for severe coronary artery disease who are most likely to benefit from further evaluation.
Effects of acetylsalicylic acid on renal function in patients with chronic heart failure, PURPOSE: We conducted a double-blind. placebo-controlled trial to determine whether the administration of acetylsalicylic acid has adverse effects on renal function in patients with moderate chronic congestive heart failure with and without stimulation of the renin system. PATIENTS AND METHODS: Forty patients were randomly assigned to one of the following four groups: Group 1. low sodium diet and placebo; Group 2. low sodium diet and acetylsalicylic acid; Group 3. normal sodium diet and placebo; or Group 4. normal sodium diet and acetylsalicylic acid. Patients were studied over 8 days. After Day 5. patients in Groups 2 and 4 received acetylsalicylic acid (500 mg three times a day). The low sodium diet consisted of 13.6 mmol of sodium per day and the normal sodium diet consisted of 136 mmol of sodium per day. RESULTS: The low sodium diet resulted in a highly significant increase in the plasma renin (2p = 0.0001). aldosterone (2p = 0.0006). and urinary prostaglandin E2 (2p = 0.01) concentrations and the renal potassium excretion (2p = 0.0009). whereas renal sodium excretion was significantly reduced (2p = 0.0001). Severe sodium depletion led to a reduction of the glomerular filtration rate (2p = 0.007). which was independent from cyclooxygenase inhibition. In patients on the low sodium diet. acetylsalicylic acid reduced the elevated urinary prostaglandin E2 levels to normal values without changing the renal sodium excretion rate. In patients with a normal sodium intake. acetylsalicylic acid significantly reduced the renal sodium excretion rate by 29% (2p = 0.04). CONCLUSION: We conclude that severe sodium depletion has adverse effects on kidney function in patients with heart failure due to a reduction in the glomerular filtration rate. Administration of acetylsalicylic acid in doses that reduce the synthesis of renal prostaglandin E2 significantly reduces renal sodium excretion.
Improvement in severe onchocercal skin disease after a single dose of ivermectin, PURPOSE: Skin disease is the most common clinically important manifestation of onchocerciasis. Ivermectin. a newly available drug. is well tolerated and effective in Onchocerca volvulus infection. However. little information is available regarding its effect on onchocercal skin disease. The purpose of this study was to examine. in patients with well-characterized onchodermatitis. the effect of a single dose of ivermectin. SUBJECTS AND METHODS: Twenty-one persons with severe onchodermatitis were followed over a 6-month period. In order to evaluate the effect of ivermectin on their skin lesions. photographic transparencies were made before treatment and at 3 and 6 months after treatment. These were then evaluated in a blinded fashion. RESULTS: Following a single dose of 150 micrograms/kg. there was a significant improvement in dermatitis in the first 3 months after treatment. All 14 persons with the worst skin disease showed improvement. The drug had no demonstrable effect on depigmented lesions over the period of observation. Treatment was well tolerated. CONCLUSION: Single-dose ivermectin shows promise as the first acceptable treatment for severe onchocercal dermatitis.
Psychotropic drug prescribing for hospitalized patients with acquired immunodeficiency syndrome, PURPOSE: The purpose of this study was to investigate the prescribing practices for the use of psychoactive medication in treating hospitalized patients with the acquired immunodeficiency syndrome (AIDS). PATIENTS AND METHODS: The medical charts were studied for all patients admitted to a 20-bed AIDS inpatient ward from July through December 1986. One hundred and fifty-one patient-admissions comprised the sample. The average age of the patients was 37 years. and the average length of the hospital stay was 13 days. Retrospective chart review collected demographic data. length of stay. medical diagnosis. psychiatric history. and mental status on admission. Data on psychoactive drugs included the reasons for use. maximum daily dose and duration. and side effects ascribed to the drugs. RESULTS: Psychoactive drugs were used in 89% of the cases. Anxiolytics accounted for 49% of the psychoactive prescriptions. and hypnotics made up 43% of these prescriptions. The five most frequently used psychoactive drugs were benzodiazepines. The most frequent reasons for psychotropic prescriptions were insomnia (39%). psychologic distress (20%). and nausea (16%). The most frequently used anxiolytic and anti-psychotic medications were used in moderate dosage. while the most frequently used antidepressant was prescribed in low dosage. CONCLUSIONS: Hospitalized AIDS patients are highly likely to be prescribed a psychotropic medication. especially an anxiolytic or hypnotic. Anxiolytics are used for several purposes. including reduction of nausea associated with the use of antibiotics. Antidepressants and antipsychotics are rarely used. Practitioners must be sensitive to the presence of psychiatric conditions presenting as insomnia or disturbed mood so that the most specific and appropriate treatments can be used.
Asthmatic responses to airborne acid aerosols, BACKGROUND: Controlled exposure studies suggest that asthmatics may be more sensitive to the respiratory effects of acidic aerosols than individuals without asthma. This study investigates whether acidic aerosols and other air pollutants are associated with respiratory symptoms in free-living asthmatics. METHODS: Daily concentrations of hydrogen ion (H+). nitric acid. fine particulates. sulfates and nitrates were obtained during an intensive air monitoring effort in Denver. Colorado. in the winter of 1987-88. A panel of 207 asthmatics recorded respiratory symptoms. frequency of medication use. and related information in daily diaries. We used a multiple regression time-series model to analyze which air pollutants. if any. were associated with health outcomes reported by study participants. RESULTS: Airborne H+ was found to be significantly associated with several indicators of asthma status. including moderate or severe cough and shortness of breath. Cough was also associated with fine particulates. and shortness of breath with sulfates. Incorporating the participants' time spent outside and exercise intensity into the daily measure of exposure strengthened the association between these pollutants and asthmatic symptoms. Nitric acid and nitrates were not significantly associated with any respiratory symptom analyzed. CONCLUSIONS: In this population of asthmatics. several outdoor air pollutants. particularly airborne acidity. were associated with daily respiratory symptoms.
A randomized trial to evaluate the risk of gastrointestinal disease due to consumption of drinking water meeting current microbiological standards, BACKGROUND: This project directly and empirically measured the level of gastrointestinal (GI) illness related to the consumption of tapwater prepared from sewage-contaminated surface waters and meeting current water quality criteria. METHODS: A randomized intervention trial was carried out; 299 eligible households were supplied with domestic water filters (reverse-osmosis) that eliminate microbial and chemical contaminants from their water. and 307 households were left with their usual tapwater without a filter. The GI symptomatology was evaluated by means of a family health diary maintained prospectively by all study families over a 15-month period. RESULTS: The estimated annual incidence of GI illness was 0.76 among tapwater drinkers compared with 0.50 among filtered water drinkers (p less than 0.01). These findings were consistently observed in all population subgroups. CONCLUSION: It is estimated that 35% of the reported GI illnesses among the tapwater drinkers were water-related and preventable. Our results raise questions about the adequacy of current standards of drinking water quality to prevent water-borne endemic gastrointestinal illness.
Risk assessment and control of waterborne giardiasis, BACKGROUND: Waterborne giardiasis has been increasing in the United States with 95 outbreaks reported over the last 25 years. The Safe Drinking Water Act has mandated control of this pathogen. METHODS: A risk assessment model was developed to estimate risk of infection after exposure to treated waters containing varying levels of Giardia cysts. The model was defined by a dose-response curve developed from human feeding studies for Giardia and assumed 2L of water consumption per day. Data on concentrations and distribution of the organism in source waters were used to assess exposure after varying reductions achieved through treatment. RESULTS: In surveys reporting prevalence and levels of Giardia cyst contamination. average levels of cysts in surface waters ranged from 0.33 to 104/100L; from pristine watersheds (protected from all human activity) 0.6 to 5/100L. Yearly risks were 4.8 x 10(-3) for systems using polluted waters and 1.3 x 10(-4) for pristine waters with a 10(-3) treatment reduction. CONCLUSION: Public Health officials will need to work with the water industry to ensure a risk of less than 1/10.000 for source waters with 0.7 to 70 cysts per 100 liters through treatment achieving reduction of 10(-3) to 10(-5). respectively. of Giardia cysts.
Lyme disease: a proposed ecological index to assess areas of risk in the northeastern United States, BACKGROUND: Recent public awareness has resulted in a demand for information about ways to reduce the risk of acquiring Lyme disease. METHODS: Twenty-two school properties and recreational areas within a Lyme disease endemic area of central Monmouth County. New Jersey were evaluated for risk of transmission using an ecological index on the suitability. amount. and access to Ixodes dammini habitat by target human populations and the abundance of infected adult ticks. RESULTS: The characterization of tick habitat accurately predicted the elimination of 11 sites from concern. Of the remaining 11 sites. six were classified high risk and five as moderate risk. On-site tick surveys identified infected I. dammini adults at only four sites (three risk; one moderate risk). CONCLUSIONS: These results indicate that the use of selected ecological parameters provides a cost-effective method to rapidly identify areas at risk for Lyme disease transmission.
Cancer rates after the Three Mile Island nuclear accident and proximity of residence to the plant, BACKGROUND: In the light of a possible link between stress and cancer promotion or progression. and of previously reported distress in residents near the Three Mile Island (TMI) nuclear power plant. we attempted to evaluate the impact of the March 1979 accident on community cancer rates. METHODS: Proximity of residence to the plant. which related to distress in previous studies. was taken as a possible indicator of accident stress; the postaccident pattern in cancer rates was examined in 69 "study tracts" within a 10-mile radius of TMI. in relation to residential proximity. RESULTS: A modest association was found between postaccident cancer rates and proximity (OR = 1.4; 95% CI = 1.3. 1.6). After adjusting for a gradient in cancer risk prior to the accident. the odds ratio contrasting those closest to the plant with those living farther out was 1.2 (95% CI = 1.0. 1.4). A postaccident increase in cancer rates near the Three Mile Island plant was notable in 1982. persisted for another year. and then declined. Radiation emissions. as modeled mathematically. did not account for the observed increase. CONCLUSION: Interpretation in terms of accident stress is limited by the lack of an individual measure of stress and by uncertainty about whether stress has a biological effect on cancer in humans. An alternative mechanism for the cancer increase near the plant is through changes in care-seeking and diagnostic practice arising from postaccident concern.
An analysis of occupational blood lead trends in Manitoba, 1979 through 1987, BACKGROUND: While regulations for workplace lead exposure become more strict. their effectiveness in decreasing blood lead concentrations and the method by which this is attained have not been evaluated. METHODS: An analysis was conducted of 10.190 blood lead samples from employees of 10 high-risk workplaces collected in Manitoba. 1979-87. as part of regulated occupational surveillance. RESULTS: A significant decrease in blood lead concentrations was observed overall as well as for each individual company. A 1979 government regulation to reduce blood lead to below 3.38 mumol/L (70 micrograms/dl) was followed by a drop in blood lead concentrations; a 1983 order to reduce blood leads to below 2.90 mumol/L (60 micrograms/dl) was not followed by such a drop. Longitudinal analysis by individual workers suggested that companies were complying by use of administrative control. i.e.. removing workers to lower lead areas until blood lead levels had fallen. then returning them to high lead areas. CONCLUSION: Focusing upon blood lead as the sole criterion for compliance is not effective; regulations must specifically require environmental monitoring and controls. Biological surveillance serves as "back-up" to environmental surveillance and this database illustrates the usefulness of a comprehensive centralized surveillance system.
Socioeconomic status and survival from soft-tissue sarcomas: a population-based study in northern Italy, BACKGROUND AND PURPOSE: Differential prognosis among cancer patients according to socioeconomic status (SES) has been reported. We analyzed survival from soft tissue sarcomas (STS) according to different SES indicators. METHODS: We followed up all the adult patients with a new diagnosis of STS occurring between 1.1.1981 and 31.12.1983 in an area of Northern Italy (N = 86). RESULTS: The overall three-year survival rate was 57 percent. After adjustment for confounders. both low education and blue collar jobs were negatively associated with survival. CONCLUSIONS: The results suggest that patients of low SES have a poorer prognosis for STS.
Pesticide poisoning surveillance through regional poison control centers, The purpose of this study is to describe pesticide exposure in the population of callers to Minnesota Regional Poison Centers. Case files from 1988 reporting pesticide exposure to humans were identified in cooperation with the Minnesota Center for Health Statistics. Data analysis was conducted by computer using SAS statistical package. Of the 1.428 case files indicating pesticide as the primary substance of exposure to Minnesota residents. a mean age of 5 years (range. one month to 85 years) was identified; 50 percent of all cases were below age 3 years. Males accounted for 1.3 times as many cases as females. Insecticide was identified in the largest percentage of case files (74 percent) followed by herbicide (12 percent). rodenticide (11 percent) and fungicide-nonmedicinal (3 percent). Ingestion was the most common route of exposure; 85 percent of all calls originated from a residence. While insecticides are still the most common types of pesticide call. herbicide has surpassed insecticide in production and sales in the US. In this study. herbicide type exposure calls present a much different picture than other pesticide types. The usefulness of poison control centers for examination of pesticide poisoning is explored. Since reporting occurs coincidental with the exposure and its associated symptoms. each pesticide poisoning report could potentially serve as a true sentinel health event.
Lead exposure in outdoor firearm instructors, This study was conducted to determine lead exposure of firearm instructors at an outdoor firing range. while cadets were firing nonjacketed and jacketed lead ammunitions. The breathing zone air for lead exceeded the Occupational Safety and Health Administration standard of 50 micrograms/m3 for two instructors during firing exercises using nonjacketed bullets. The use of totally copper-jacketed bullets reduced the breathing zone lead levels by 92 percent for instructor #1 and by 96 percent for instructor #2; subsequent blood lead levels showed a significant decline in both instructors.
Endemic giardiasis and municipal water supply, To test the hypothesis that endemic giardiasis may be transmitted by unfiltered municipal water supplies. the incidence of laboratory-confirmed giardiasis was studied in a natural experiment due to the arrangement of the public water supply of Dunedin. New Zealand. The incidence rate ratio was 3.3 (90% CI = 1.1. 10.1) for the population receiving unfiltered (microstrained) water relative to that using sand filtered water. In a parallel case-control study of incident cases. the odds ratio for giardiasis and unfiltered (microstrained) water supply was 1.8 (90% CI = 0.5. 6.9).
Measuring physical activity with a single question, Using 1.004 subjects enrolled in a worksite health promotion program. this report evaluated the validity of a single question about participation in regular exercise. Measured at baseline. this one question had a significant age-adjusted association with body mass index (p less than 0.0001 in women and p = 0.001 in men). HDL cholesterol (p less than 0.0001 in women). and oxygen capacity (p = 0.0007 in women and p = 0.002 in men). Thus. one self-reported question can provide useful information about who is and who is not participating in regular exercise. The potential validity of a single exercise question is particularly relevant in complex epidemiologic studies where lengthy questionnaires highlight the importance of brief instruments.
Serologic response to treatment of infectious syphilis, OBJECTIVE: To evaluate the serologic response to treatment of patients with infectious syphilis. DESIGN: Historical cohort study of all cases of infectious syphilis in Alberta from 1981 to 1987. PATIENTS: A total of 1090 patients were entered; 857 with primary syphilis. 183 with secondary syphilis. and 50 with early latent disease. Two hundred and eight patients were excluded who either were pregnant. had negative serologic results before treatment. had clinical relapse. were treatment failures. or were lost to follow-up. INTERVENTIONS: All 882 evaluable patients were treated with a recommended antibiotic regimen for infectious syphilis and returned for re-assessment including repeat serologic testing. MEASUREMENTS AND MAIN RESULTS: Seventy-two percent (95% CI. 66% to 77%) and 56% (CI. 43% to 70%) of patients with initial episodes of primary or secondary syphilis had seroreverted according to rapid plasma reagin (RPR) test results by 36 months. A 2- and 3-tube decline was seen by 6 and 12 months in primary and secondary syphilis. Early latent syphilis resulted in only a 2-tube decrease at 12 months. Serologic response was not affected by sex. age. race. or sexual orientation. Patients with their first infection were more likely to experience RPR seroreversal than those with repeat infections. The RPR reversal rates also depended on the pretreatment titer and stage of disease. At 36 months. 24% (CI. 20% to 28%) of patients had nonreactive fluorescent treponemal antibody absorption tests (FTA-Abs). and 13% (CI. 11% to 15%) had nonreactive microhemoglutination tests for Treponema pallidum (MHA-TP). CONCLUSIONS: Adequate therapeutic response for syphilis must be based on illness episode and the pretreatment RPR titer. Treponemal tests can demonstrate seroreversion after 36 months. and a negative treponemal test does not rule out a past history of syphilis.
Bypass surgery for chronic stable angina: predictors of survival benefit and strategy for patient selection, The variable mortality risk associated with chronic stable angina calls for careful selection of patients for coronary artery bypass grafting (CABG) if the aim of management is to prolong life. The randomized and observational studies done in the last 20 years have identified the variables relevant to patient selection and thus have provided a rational basis for such clinical decisions. These studies showed that the sicker the patient. as gauged by relevant measures of coronary disease and cardiovascular morbidity. the more likely it is that CABG will prolong life. A CABG-related improvement in survival is therefore more likely to occur the worse the left ventricular function; the greater the number of diseased vessels; the more proximal the location of coronary lesions (more muscle is threatened by such lesions); the greater the severity of the lesions as determined by angiography; the more severe the angina; the more easily provocable the ischemia or the more extreme the measures of ischemia; and. within limits. the older the patient. Greater survival gain after CABG also occurs in patients with peripheral vascular disease. in patients with baseline electrocardiographic ST-segment and T-wave changes. and probably in women. Thus. patients are likely to live longer after CABG if they have left main disease; three-vessel disease with left ventricular dysfunction (ejection fraction less than 50%). class III or IV angina. provocable ischemia. or disease in the proximal left anterior descending coronary artery; two-vessel disease with proximal left anterior descending artery involvement; and two-vessel disease with class III or IV angina as well as either severe left ventricular dysfunction alone or moderate left ventricular dysfunction together with at least one proximal lesion. When the decision of whether to do CABG is less clear-cut. the presence of peripheral vascular disease. female sex. baseline electrocardiographic ST-segment and T-wave changes. or older age (over 60 but under 80 years) should weigh in favor of doing CABG. In general. patients with single-vessel disease do not seem to derive survival benefit from CABG.
Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double-blind study, OBJECTIVE: To compare the effects of azathioprine and methotrexate on progression of radiologic damage in patients with rheumatoid arthritis. DESIGN: Double-blind. randomized 48-week trial. PATIENTS: Sixty-four patients with active rheumatoid arthritis who either have not responded to or who have reacted with side effects to at least parenteral gold and D-penicillamine. INTERVENTIONS: Either azathioprine. 100 mg daily. or methotrexate. 7.5 mg weekly. was administered orally. Depending on the clinical effect after 8 weeks. the dosage was increased to either azathioprine. 150 mg. or methotrexate. 15 mg. The dosages for nonsteroidal anti-inflammatory drugs and prednisone were held stable. MEASUREMENTS: Clinical and laboratory assessments were done by the same physician every 4 weeks for the first 24 weeks and every 8 weeks thereafter. Radiographs of hands. wrists. and feet obtained at baseline and after 24 and 48 weeks were scored by one rheumatologist blinded to medication and clinical findings. MAIN RESULTS: Initial radiologic scores were comparable in both groups and correlated with disease duration (r = 0.38). An intention-to-treat analysis after 24 and 48 weeks showed significantly fewer new erosions in the methotrexate group compared with the azathioprine group (difference. 2.0 [95% CI. 0.2 to 3.9] and 3.5 [CI. 1.3 to 5.8]. respectively). The change in total joint score was also significantly less pronounced in the methotrexate group compared with the azathioprine group after 24 weeks (difference. 2.8 [CI. 0.2 to 5.2]) and after 48 weeks (difference. 3.9 [CI. 0.3 to 7.4]). Radiologic stabilization after 48 weeks was present in 10% of the azathioprine group compared with 29% of the methotrexate group. CONCLUSIONS: Patients with rheumatoid arthritis treated with low-dose methotrexate showed significantly less radiologic progression than patients treated with azathioprine. This result suggests that methotrexate therapy is clinically superior in these patients.
Leber's idiopathic stellate neuroretinitis, Leber's idiopathic stellate neuroretinitis. originally known as Leber's stellate maculopathy. is an uncommon syndrome characterized by unilateral optic disc swelling followed by the development of a macular star due to leakage of capillaries within the optic disc. It is seen in patients 50 years of age or younger and usually resolves spontaneously without visual sequelae. This entity should be recognized and distinguished from more serious diseases causing septic neuroretinitis or papillitis. We present a case which was initially thought to be septic retinitis.
Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis, From 1982 through 1987. 128 families. who were instructed in the use of rectally administered diazepam (R-DZP) for the treatment of severe epileptic seizures. were surveyed. Sixty-seven families returned questionnaires and met inclusion/exclusion criteria; the results were used to analyze the medical. psychosocial. and economic impact of this program during the first year following instruction. Twenty-six families did not use R-DZP. primarily because of patient improvement. Among families using R-DZP. a total of 428 doses were administered to 41 children. R-DZP was effective in controlling seizures in 85% of patients. Adverse reactions usually were mild. consisting of drowsiness and/or behavioral changes. Compared to the year prior to instruction. emergency room visits decreased in both R-DZP-treated and -nontreated children; however. cost-savings were greater for the R-DZP group ($1.039.00 vs $420.00 per patient per year). Improvements in quality of life associated with the availability of R-DZP were observed by 58% of users and 27% of nonusers which included improved management of their children's seizures. increased flexibility in family activities. and greater peace of mind. R-DZP appears to be a practical method in the effective treatment of severe seizures at home.
Differential effects of gallium nitrate on proliferation of brain tumor cells in vitro, Gallium nitrate possesses antineoplastic activity against certain solid tumors; however. no studies exist regarding the effect of this metal on brain tumor cell proliferation. Several human brain tumor and rhabdomyosarcoma cell lines were incubated with increasing concentrations of gallium nitrate and cell proliferation was assessed by 3-(4.5-dimethylthiazol-2-yl)-2. 5-diphenyltetrazolium bromide assay. The growth of medulloblastoma 324. rhabdomyosarcoma TE671. and RD cells was markedly inhibited by gallium nitrate. while glioblastoma cell growth was only moderately inhibited (U373 cells) or actually stimulated (U87 cells). Gallium inhibited the cellular uptake of 59Fe; however. this block in 59Fe uptake was variable and closely paralleled the inhibitory effects of gallium on cell growth. Intracellularly. gallium may interfere with DNA synthesis by inhibiting ribonucleotide reductase. Such effects may be of relevance in the treatment of brain tumors with this metal.
Cerebral abnormalities in congenital myotonic dystrophy, The brain structure of 14 infants born with congenital myotonic dystrophy at 2 hospitals was evaluated by cranial ultrasonography. and the findings were correlated with clinical and neuropathologic data. Ventricular dilation was diagnosed in 11 infants (78%). Seven infants died during the neonatal period; all had ventricular dilation which remained essentially static. In the ultrasound scans of the 5 infants with ventricular dilation. Of the 7 survivors. 4 had ventricular dilation born at 1 hospital. 4 had widening of the interhemispheric fissure. Macrocephaly. a previously unrecognized finding in congenital myotonic dystrophy. was present in 10 infants (71%). 8 of whom presented with ventricular dilation. None had clinical evidence of increased intracranial pressure. There was no ventricular obstruction in the 4 brains examined pathologically. Histologic examination revealed minor expression of neuronal migrational disturbances in each patient. Macrocephaly together with the ultrasonographic and neuropathologic findings in our patients suggest that these abnormalities may originate in an external hydrocephalus.
Improvement of auditory brainstem responses after treatment with zidovudine in a child with AIDS, A 6 1/2-month-old boy with acquired immunodeficiency syndrome was treated with zidovudine for 12 months. He experienced a marked improvement in clinical and neurologic status. Auditory brainstem responses were recorded before. at 6 months. and after 12 months of therapy; interpeak latency I-V. which was initially delayed. demonstrated progressive shortening that was greater than could be attributed to maturation alone. Auditory brainstem response improvement after zidovudine therapy has not been reported previously.
Myelin splitting in the spongy lesion in Leigh encephalopathy, A spongy lesion consists of numerous vacuoles. mainly in the central gray matter. and is a characteristic finding in subacute necrotizing encephalopathy (Leigh encephalopathy); the cause of this lesion is unknown. An ultrastructural study on the vacuolated lesions in the left putamen of a patient with subacute necrotizing encephalopathy due to a deficiency of mitochondrial enzyme complexes I and IV revealed that the vacuoles were formed through the splitting of myelin. Because myelin splitting is commonly caused by toxic or metabolic diseases in humans and experimental animals. we believe that the vacuolation was due to the splitting of myelin which was caused by abnormal mitochondrial metabolism. even though this lesion is most commonly found in the white matter. We do not know whether the spongy lesion is formed only through myelin splitting in patients with subacute necrotizing encephalopathy; however. myelin splitting must play an important role in the formation of the spongy lesion.
Giant axonal neuropathy and leukodystrophy, An 11-year-old Persian boy. born to consanguineous parents. manifested a progressive gait abnormality beginning at 5 years of age. A severe cerebellar disorder developed with associated dysfunction of the peripheral nervous system. but no sign of mental impairment. The sensory and motor nerve conduction velocities were greatly reduced. especially in the lower extremities. Cerebrospinal fluid protein was normal. Computed tomography and magnetic resonance imaging revealed leukoencephalopathy. especially in the cerebellum. but also in periventricular areas. The diagnosis of giant axonal neuropathy was established by biopsy of the sural nerve. The few previous histologic examinations have documented hyperplasia of the microfibrils which accumulate in the axons as well as in neurilemma. endothelial. and perineural cells. This is the first report of involvement of supraspinal portions of the central nervous system documented by postmortem examination after in vivo imaging methods corroborated the morphologic concomitants of the clinical symptoms.
Diastolic disease in left ventricular hypertrophy: comparison of M mode and Doppler echocardiography for the assessment of rapid ventricular filling, OBJECTIVE--To investigate possible discrepancies between M mode and Doppler echocardiography in assessing early diastolic filling. DESIGN--Forty seven patients with left ventricular hypertrophy due to aortic stenosis and 26 healthy controls with a similar age range were studied by M mode. Doppler. apexcardiography. and phonocardiography. The patients also underwent cardiac catheterisation. M mode echograms were digitised by a computer. Early diastolic filling in both groups as assessed by the two techniques was compared. SETTING--A tertiary cardiac referral centre with facilities for non-invasive and invasive investigations. SUBJECTS--Patients referred for assessment of aortic stenosis who had left ventricular hypertrophy. MAIN OUTCOME MEASURES--Filling velocities on Doppler and rates of wall thinning and dimension increase on M mode. RESULTS--Digitised M mode indices of diastolic filling (peak wall thinning rate 6.4 (3.0) v 10.0 (3.0) cm/s and peak rate of dimension increase 9.3 (3.3) v 16 (4.5) cm/s) in the patients and controls were consistently different. In contrast. the Doppler A/E ratio and peak E wave velocity were not; they varied widely among patients with left ventricular hypertrophy. In part. this variability was because the Doppler A/E ratio. but not the digitised M mode indices. was very sensitive to the abnormalities of isovolumic relaxation frequently present in left ventricular hypertrophy. The Doppler A/E ratio varied similarly with age in both normal and hypertrophied hearts; in the patients with ventricular hypertrophy the peak rate of dimension increase depended on age only. whereas the thinning rate was independent of age in both the patients and controls. Neither the A/E ratio nor the M mode indices could be related to the left ventricular end diastolic pressure or the peak aortic pressure difference. CONCLUSIONS--When Doppler and M mode techniques are used to assess rapid filling in patients with left ventricular hypertrophy the M mode indices are more consistently abnormal. The two methods measure different aspects of left ventricular diastolic function and should be regarded as complementary rather than interchangeable.
Sensitivity and speed of colour Doppler flow mapping compared with continuous wave Doppler for the detection of ventricular septal defects, Twenty nine patients (aged from three months to 37 years) with confirmed or suspected ventricular septal defects were studied separately by three examiners who used colour flow mapping and imaging. or continuous wave Doppler and imaging. or a combined reference examination. Colour flow mapping identified 19 of the 25 patients with a ventricular septal defect. continuous wave Doppler echocardiography identified 18. and the combined reference examination identified 24. Two of four patients without ventricular septal defect had a false positive result with colour flow mapping and none had a false positive result with continuous wave Doppler examination. During the reference examination continuous wave Doppler identified 24 patients with ventricular septal defects and colour flow mapping identified 23. In two patients a second ventricular septal defect was found by colour flow mapping. and confirmed by continuous wave Doppler. There was no significant difference in time to diagnosis between the two techniques. Colour flow mapping aids identification of multiple ventricular septal defects but is not faster and has lower specificity than continuous wave Doppler. A combination of the two techniques gave the highest sensitivity and specificity.
Factors influencing the persistence of shunting within 24 hours of catheter occlusion of the ductus arteriosus, Catheter occlusion of the persistent ductus arteriosus recently became clinically available with a Rashkind (USCI Bellerica. Massachusetts. USA) umbrella occluder system. A few patients. however. had residual left to right shunting after the procedure. The impact of soaking the foam of the device in a thrombin solution to enhance clotting and of using a device with a diameter of 12 or 17 mm was assessed in 117 consecutive patients undergoing catheter closure. The frequency of residual shunting detected by colour flow Doppler 24 hours after the procedure was the same whether or not thrombin was used.
Pulmonary blood flow after total cavopulmonary shunt, The pattern of pulmonary blood flow was studied in three patients after a total cavopulmonary shunt procedure. Doppler studies showed a phasic pattern of flow which varied with the respiratory cycle. Pulmonary blood flow was increased with normal inspiration. and was much augmented by the Mueller manoeuvre. This suggests that flow was occurring when a negative intrathoracic pressure was generated. During a brief Valsalva manoeuvre blood flowed away from the lungs. With a sustained Valsalva manoeuvre there was no spontaneous forward flow; instead there was low velocity pulsatile pulmonary blood flow that coincided with ventricular systole. Left ventricular cavity dimensions decreased. reflecting a considerably reduced pulmonary blood flow. Pulmonary blood flow after the total cavopulmonary shunt operation is critically dependent on changes in intrathoracic pressure. This has important implications in terms of the immediate postoperative management of these patients.
Analysis of left ventricular wall movement before and after reimplantation of anomalous left coronary artery in infancy, Five infants who underwent direct reimplantation or redirection of an anomalous left coronary artery from the pulmonary artery to the aorta were studied. There were no deaths from the procedure. Anastomoses were patent at a mean follow up of 33 months. Left ventricular angiograms before and after operation were digitised frame by frame. Analysis of wall motion showed considerable generalised hypokinesia with no change in cavity shape before operation. After reimplantation there was a significant improvement of global ventricular function as assessed by ejection fraction and end diastolic shape index. There was also a tendency for the shape index change to increase; this was compatible with better global systolic function. Three of the four patients who were restudied showed normal isometric and contour wall motion plots. One child. the oldest at the time of operation. still showed asynchronous onset of contraction and isovolumic relaxation. The procedure offers a low risk of mortality and a high rate of patency of the anastomosis. Improvement of ventricular function can be remarkable and its extent cannot be assessed simply by ejection fraction measurements.
Balloon dilatation of pacemaker induced stenosis of the superior vena cava, A 53 year old woman with symptomatic pacemaker associated superior vena cava syndrome was treated successfully with balloon angioplasty. She was well six months after the procedure.
Diagnosis of mitral valve aneurysm by transoesophageal echocardiography, In a patient with mitral valve aneurysm precordial echocardiography suggested a mistaken diagnosis of infective endocarditis. Transoesophageal echocardiographic examination established the correct diagnosis. which was subsequently confirmed at operation. Transoesophageal echocardiography gives better resolution of lesions associated with the mitral valve than precordial examination and may improve the diagnostic accuracy.
Low energy catheter ablation of right ventricular outflow tract tachycardia, A 38 year old woman with a structurally normal heart presented with near syncope and had right ventricular outflow tract tachycardia. She was intolerant of antiarrhythmic medication and underwent low energy catheter ablation. Six non-arcing shocks of 25 J were delivered to the right ventricular outflow tract. No further ventricular tachycardia occurred during a follow up of seven months without antiarrhythmic treatment.
The effect of alpha-interferon on bone marrow megakaryocytes and platelet production rate in essential thrombocythemia, In 10 patients with previously untreated essential thrombocythemia (ET). by using 111In-labeled platelets and megakaryocyte morphometry. the relation between platelet production rate and bone marrow megakaryocytes was evaluated before and during alpha-2b-interferon (IFN) therapy. A highly significant decrease in platelet count occurred during IFN therapy; the platelet counts. at baseline and after 2 and 6 months of IFN therapy. were 1.102 +/- 345 x 10(9)/L. 524 +/- 169 x 10(9)/L (P less than .0001). and 476 +/- 139 x 10(9)/L (P less than .0001). respectively. The decrement in platelet count was mainly a result of diminished platelet production rate. which at baseline and after 2 and 6 months of IFN therapy was 89 +/- 30 x 10(10) platelets/d. 53 +/- 18 x 10(10) platelets/d (P = .0033). and 45 +/- 20 x 10(10) platelets/d (P less than .0001). respectively. Also. a slight shortening of platelet mean life-span (MLS) was observed in response to IFN treatment; platelet MLS was 7.96 +/- 0.69 days at baseline and 6.68 +/- 1.30 days (P = .012) after 6 months of IFN therapy. IFN induced a significant decrease in bone marrow megakaryocyte volume; both megakaryocyte nuclear and cytoplasmatic volumes were affected. The mean megakaryocyte volume was 372 +/- 126 x 10(2) pL/microL at baseline and 278 +/- 147 x 10(2) pL/microL (P = .049) after 6 months of IFN therapy. However. the number of megakaryocytes did not show any significant change in response to IFN. It is concluded that alpha-IFN reduces platelet production rate and the peripheral platelet count in ET mainly through an anti-proliferative action on the megakaryocytes and to a considerably lesser degree by a shortening of platelet MLS.
Bone modulation in sustained hematopoietic stimulation in mice, To understand the etiology of bone modulation and hypercalcemia observed in granulocytosis of a tumor-bearing animal model and to gain insight into the implication of sustained hematopoietic stimulation on the bone tissue. in vivo responses of normal mouse hematopoietic and bone tissues to long-term injections of recombinant human and murine granulocyte colony-stimulating factor (G-CSF). murine granulocyte-macrophage CSF (GM-CSF). and human erythropoietin were quantitatively analyzed. Osteoclast activation was estimated by the osteoclast-endosteal ratio. determined by morphometric analyses of femoral sections. Medullary and bone areas were measured on transverse ground bone sections of the tibia. Recombinant murine G-CSF provoked marked granulocytosis associated with significant increases in the number of marrow granulocytes and their progenitors. and caused expansion of granulopoietic marrow into fatty marrow. The bone of G-CSF-treated mice showed a significant increase in endosteal osteoclast numbers with medullary area enlargement and a reduction in the bone thickness; indicative of endosteal bone resorption. Although GM-CSF had little effect on granulopoiesis. it caused peritoneal macrophages to increase and induced similar bone changes as those observed in G-CSF treatment. Enhanced erythropoiesis stimulated by erythropoietin was also associated with evidence of endosteal bone resorption. Bone changes induced by these growth factors were not associated with hypercalcemia. These animal studies document association of bone modulation in sustained stimulation of hematopoiesis. and implicate important physiologic effects of hematopoietic growth factors on skeletal tissue in vivo.
Characterization of macrophage colony-stimulating factor in body fluids by immunoblot analysis, We characterized the molecular species of human macrophage colony-stimulating factor (hM-CSF) found in serum and urine. using immunoblot analysis after partial purification on an antibody-bound affinity column. Although antibodies were prepared using the recombinant product of the large form of hM-CSF with a molecular weight (MW) of 85 Kd as the antigen. this immunoblot system was also capable of detecting the small form of hM-CSF with a MW of 40 to 60 Kd. A single band with a MW of 43 Kd. which reacted with anti-recombinant hM-CSF IgG but not with control IgG. was found when serum and urine from normal adults underwent electrophoresis on reduced sodium dodecyl sulfate-polyacrylamide gel and subsequent immunoblotting. This band represented a subunit of the large form of hM-CSF. because the large form of hM-CSF is a homodimer of a subunit with a MW of 43 Kd and the small form of hM-CSF is a homodimer of a subunit with a MW of 20 to 30 Kd. Analysis of serum and urine from leukemic patients and pregnant women. who had higher serum levels of hM-CSF than normal adults. showed only a single band with a MW of 43 Kd as a hM-CSF-specific molecule. These results suggest that the large form of hM-CSF is the major species in human body fluids.
Incidence of aplastic anemia in Bangkok. The Aplastic Anemia Study Group, The annual incidence of aplastic anemia in metropolitan Bangkok. Thailand. and its five suburban provinces was prospectively determined. All patients first diagnosed during the period from January through December 1989 who met specific clinical and pathologic criteria were included. Thirty-two cases were identified. yielding an overall incidence of 3.7 per million. The incidence rates for the age groups 0 through 24. 25 through 59. and over 60 years were 4.3. 3.2. and 2.1 per million. respectively; the highest rate. 7.2 per million. was found for individuals aged 15 to 24 years. The male-to-female ratio was 1.9. The incidence of aplastic anemia in Bangkok is higher than that reported in recent European studies. The peak rate in young persons is almost fourfold higher than in comparable recent western studies and suggests an environmental etiology peculiar to Thailand.
Pharmacokinetics of activated protein C in guinea pigs, Protein C is a vitamin K-dependent zymogen of the serine protease. activated protein C (APC). an important regulatory enzyme in hemostasis. In view of the potential of human APC as an anticoagulant and profibrinolytic agent. the pharmacokinetics and tissue distribution of APC were studied in guinea pigs. The plasma elimination of a trace dose of 125I-APC was biphasic following an initial rapid elimination of approximately 15% of the injected dose within 1 to 2 minutes. This rapid removal of 125I-APC from the circulation was found to be a result of an association with the liver regardless of the route of injection. Essentially identical results were obtained with active site-blocked forms of APC generated with either diisopropylfluorophosphate or D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. which indicates that the active site was not essential for the liver association. Accumulation of all three forms of APC in the liver peaked at 30 minutes and then declined as increasing amounts of degraded radiolabeled material appeared in the gastrointestinal tract and urine. Removal of the gamma-carboxyglutamic acid (gla) domain of diisopropylphosphoryl-APC resulted in a 50% reduction in the association with liver and an accumulation in the kidneys. Protein C and protein S were cleared from the circulation at rates approximately one-half and one-fourth. respectively. that of APC. Both in vitro and in vivo. APC was found to form complexes with protease inhibitors present in guinea pig plasma. Complex formation resulted in a more rapid disappearance of the enzymatic activity of APC than elimination of the protein moiety. These findings indicate two distinct mechanisms for the elimination of APC. One mechanism involves reaction with plasma protease inhibitors and subsequent elimination by specific hepatic receptors. The other mechanism involves the direct catabolism of APC by the liver via a pathway that is nonsaturable over a substantial dose range and independent of the active site. This pattern of elimination is distinctly different from that observed with the homologous coagulation enzymes thrombin. factor IXa. and factor Xa.
Characterization of the binding domains on platelet glycoproteins Ib-IX and IIb/IIIa complexes for the quinine/quinidine-dependent antibodies, Sera of 12 patients with quinine/quinidine-induced thrombocytopenia showed drug-dependent antibody binding to glycoprotein (GP) Ib-IX complex. The reaction with GPIb-IX complex of 11 of these 12 sera was strongly inhibited by the complex-specific monoclonal antibodies (MoAbs) AK1 and SZ1. The exception was a quinine-induced serum designated BU. The reaction of the six quinidine-induced sera was also partially blocked by an anti-GPIX MoAb. FMC25. Only 3 of the 12 patient sera showed drug-dependent antibody binding to GPIIb/IIIa. which was strongly inhibited by the anti-GPIIIa MoAb 22C4. and the anti-GPIIb alpha MoAb SZ22. With detergent-solubilized Serratia metalloprotease-treated platelets. quinine/quinidine-induced sera. except BU. immunoprecipitated a membrane-bound proteolytic fragment of GPIb-IX complex. In contrast. BU immunoprecipitated glycocalicin and a 40-Kd peptide tail fragment of GPIb alpha from the cell supernatant. Using purified GPIb-IX complex or its components as the target antigen. all the quinine-induced sera. except BU. immunoprecipitated GPIb-IX complex but failed to immunoprecipitate GPIb. GPIX. or the complex reformed from GPIb and GPIX. The quinidine-induced sera strongly immunoprecipitated purified GPIb-IX complex. weakly immunoprecipitated purified GPIX and the recombined complex. but did not immunoprecipitate purified GPIb. The combined data suggest that one quinine-dependent antibody (BU) recognizes an epitope in the peptide tail region of GPIb alpha and the other five quinine-dependent antibodies react with a complex-specific epitope on the membrane-associated region of GPIb-IX complex. whereas each of the six quinidine-induced sera contain two drug-dependent antibodies. one reactive with the GPIb-IX complex-specific epitope and the other reactive with GPIX. The binding domain(s) on GPIIb/IIIa for the quinine/quinidine-dependent antibodies appear to be sterically close to the epitopes for 22C4 and SZ22.
Granulocyte colony-stimulating factor in cerebrospinal fluid from patients with meningitis, Granulocyte colony-stimulating factor (G-CSF) in the cerebrospinal fluid from patients with meningitis was measured by our modified enzyme-linked immunosorbent assay for G-CSF. The minimal detection level was 20 pg/mL G-CSF. In patients with bacterial meningitis. the G-CSF levels in the cerebrospinal fluid were extremely elevated. showing a mean value of approximately 1.500 pg/mL. On the other hand. G-CSF levels in the cerebrospinal fluid from 67% patients with aseptic meningitis were moderately increased. showing a mean value of about 80 pg/mL. whereas G-CSF levels in 33% samples remained undetectable. The G-CSF levels and neutrophil counts in the cerebrospinal fluid were proven to be related by Spearman's rank correlation coefficient analysis (r = .724). These elevations of G-CSF levels at inflammation sites associated with bacterial meningitis may indicate that G-CSF plays an important role in the combat of bacterial infections.
Correlation of response of aplastic anemia patients to antilymphocyte globulin with in vitro lymphocyte stimulatory effect: predictive value of in vitro test for clinical response, Therapy with antilymphocyte globulin (ALG) has been shown to be effective in restoring hematopoiesis to some patients with aplastic anemia. It would be useful to have a method for predicting those likely to be responders versus nonresponders. The mode of immunostimulatory action of ALG is of interest in addition to its immunosuppressive action. We examined in vitro the distribution of the proliferative responses of ALG-stimulated peripheral blood mononuclear cells (PBMCs) obtained from 18 patients with aplastic anemia. eight of whom responded to ALG and 10 who did not. We found a significant difference in the proliferative response of PBMCs obtained from the eight responders versus the 10 nonresponders (P less than .01). Two-color flow cytometry analysis of the patients' PBMCs stimulated by ALG in vitro showed that the CD4-positive subsets were activated to a greater extent by ALG than the CD8-positive subsets. Moreover. a positive correlation with the clinical response of patients to ALG with granulocyte-macrophage colony-stimulating factor produced by their PBMCs stimulated by ALG suggests that the immunostimulatory property of ALG has an important role in the treatment of aplastic anemia. Our results suggest that the clinical response to ALG therapy is correlated with its lymphocyte proliferative effect in vitro. and indicates that the assessment of the proliferative response of PBMCs in vitro would be useful in predicting the clinical response to ALG therapy.
Human herpesvirus-6 in human lymphomas: identification of specific sequences in Hodgkin's lymphomas by polymerase chain reaction, In search of a possible involvement of the human herpesvirus type 6 (HHV-6) in human Hodgkin's and non-Hodgkin's lymphomas. we studied the levels of anti-HHV-6 antibodies in the sera of 94 cases by an immunofluorescence assay. as well as the presence of HHV-6 sequences in the affected tissues of 66 cases by polymerase chain reaction. using one set of primer oligonucleotides. Our results showed higher anti-HHV-6 antibody titers in human lymphomas than in normal blood donors. but the difference is statistically significant only when normal donors are compared with Hodgkin's lymphoma cases. HHV-6 sequences were detected in 3 of 25 Hodgkin's lymphomas and 0 of the 41 cases of non-Hodgkin's lymphomas studied. The three cases positive for HHV-6 sequences belong to the nodular sclerosis-lymphocyte depletion histologic subtype and share remarkable similarities in their clinical features. Furthermore. Southern blot analysis of total genomic DNA obtained from the neoplastic tissues of two of the three patients showed the same restriction fragment length polymorphism. Our results suggest that: (1) the high level of anti-HHV-6 antibodies in Hodgkin's disease is due to an activation of the immune system not related to the presence of HHV-6 sequences in affected lymph nodes; (2) the presence of HHV-6 sequences in human lymphoid tissues is not a frequent event. rather it is in fact a very rare event in non-Hodgkin's lymphomas. while in Hodgkin's cases it is more frequent than previously reported on the basis of Southern blot analysis; and (3) the presence of HHV-6 sequences in Hodgkin's lymphomas may have a relation with the clinical presentation of the disease.
Functional properties of the beta-globin locus control region in K562 erythroleukemia cells, In this report. we compare the function of the human beta-globin locus control region (LCR) in three K562 erythroleukemia cell assays. including (1) a transient transfection assay for "classical" enhancer activity. (2) a colony assay that detects "productive integration events." and (3) an assay that detects the ability of LCR fragments to confer hemin inducibility on linked. stably integrated gamma-globin promoters. Various LCR fragments were inserted into an expression vector consisting of an A gamma-globin promoter driving the neomycin phosphotransferase gene (gamma-neo). Using these vectors. we determined that a 2.5-kb DNA fragment containing LCR sites I through IV (previously named mu locus activation region [mu LAR]) had activity in all three assays; of the individual LCR sites. only site II was highly active in all three assays. One region within site II. consisting of tandem AP-1/NF-E2 consensus elements. had approximately 10% as much colony assay activity as the entire mu LAR. However. this region did not have detectable activity in a transient enhancer assay in uninduced K562 cells. nor was it capable of conferring hemin inducibility on linked gamma-globin promoters in stably transfected cells. Finally. we tested the ability of the mu LAR to activate promoters (beta-globin and cathepsin G) that are not normally expressed in K562 cells. beta-neo was minimally activated by the mu LAR in transient transfection experiments. The mu LAR increased the number of stably transfected colonies produced by beta-neo. but the absolute number of beta-neo colonies. with or without the mu LAR. was approximately 10% to 20% that of gamma-neo. In contrast. a minimal cathepsin G promoter was activated by the mu LAR in K562 cells. Our results suggest that LCR functions are dependent in part on the environments and the promoters with which the LCR is tested.
Antilymphocytic antibodies and marrow transplantation. XIV. Antibody-induced suppression of graft-versus-host disease in C3-decomplemented mice differentiates two T-cell-depletion pathways, Remarkable differences in the suppression of graft-versus-host disease (GVHD) have been found for anti-Thy-1 antibodies to relate to (1) antigen density and antibody coating on the target cells. (2) antibody isotype. and (3) uptake of complement subcomponent C1q. Regarding (2) and (3) we now demonstrate that depletion of the third complement component C3 by cobra venom factor (CVF) differentiates two T-cell elimination pathways in mice: four rat IgG2c anti-Thy-1 monoclonal antibodies (MoAbs) with low uptake of mouse C1q lost most of their T-cell-depleting and consequently GVHD-preventing effect in C3-depleted H2 IA incompatible semiallogeneic (C57BL/6xCBA)F1 mice. In contrast. eight rat IgG2b. mouse IgG2a. and 2b anti-Thy-1 MoAbs with high affinity for C1q still remained strongly T-cell-depleting and prevented GVHD even in fully mismatched CBA mice depleted of C3. In conjunction with our observation that anti-Thy-1 MoAbs also suppress GVHD in C5-deficient AKR mice. we conclude that complete complement activation until T-cell lysis is not required for our antibodies to be effective in vivo. Activation. but only until deposition of C3b on target-cells for opsonisation via C3b receptors. is necessary with the less immunosuppressive anti-Thy-1 IgG2c isotype with low affinity for C1q. Mouse C1q uptake and C3/C4 deposition on target cells were measured with labeled antibodies and localized in T-cell areas. Interestingly. not even activation until C3b is necessary with the most immunosuppressive C1q-high-affine isotypes. As far as the latter is concerned. we discuss whether elimination of antibody-coated cells via Fc receptors is enhanced by binding to C1q-receptors and/or by intercalating C1q expressed on macrophages.
The performance of two tympanic thermometers in a pediatric emergency department, In a prospective. unblinded. controlled study. 303 children underwent comparison of rectal (RT) and right-sided tympanic membrane (TMT) temperatures. Digital electronic thermometers were used for RT. while two different infrared detection devices assessed TMT. The performance of TMT devices were compared using correlation with RT. fever detection. and ease of use. Correlation between RT and the two devices was good. r = 0.70 and r = 0.69. with little influence of patient age on performance. Using receiver operating characteristics curves to assess fever screening. Thermoscan performed somewhat better than First Temp. Staff rated the Thermoscan as significantly easier to use.
Tympanic membrane temperatures compared to rectal and oral temperatures, One hundred thirty-seven children at the Cleveland Clinic Foundation were enrolled in a study comparing the accuracy and acceptability of tympanic membrane temperatures taken with Thermoscan to rectal or oral temperatures taken by IVAC electronic thermometers. The mean age of the rectal/ear group was 1.2 +/- 0.86 years (range 0.08-5.0 years) with 22 females and 21 males. The mean age of the oral and ear group was 9.0 +/- 4.24 years (range 3-18 years) with 44 females and 50 males. Significantly large (p less than 0.01) correlation coefficients were present between temperatures in the left ear and right ear (0.92). rectal and mean ear (0.77) and oral and mean ear (0.68). The temperature difference between mean ear and rectal measurements was -1.1 degree +/- 0.51 degree C and the temperature difference between the mean ear and oral measurements was -0.20 degrees +/- 0.59 degrees C. A relative lack of correlation between ear and oral temperatures was noted with flat tympanograms. otoscopically diagnosed middle ear effusion. and with red-white or red tympanic membranes. However. small subgroup sizes (6-16) may have contributed to this lack of correlation. Parents and physicians were impressed by the 2.5 second speed of the new technique. However. younger children were nearly as likely to resist and cry with ear as with rectal temperatures. Parents were comfortable with the ease. cleanliness and safety of ear temperatures. While these data indicate a strong correspondence of ear temperatures with oral and rectal temperatures. parents were not as confident of ear temperatures' accuracy.
Behavioral aspects of temperature-taking, Ear thermometry addresses two basic psychological aspects of fevers. The first one is obvious: the battle of the rectal temperature can be eliminated by ear thermometry. The second one addresses the overtreatment of tactile fevers. Tactile temperature taken by feeling the forehead occurs in 50% to 90% of homes. Half of warm foreheads occur in afebrile children who are warm because they're releasing heat generated by a recent activity or bath. If an actual temperature were measured. these children wouldn't be mislabeled as having fever and unnecessarily treated.
Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity, Methylprednisolone pharmacokinetics and its directly suppressive effects on plasma cortisol. blood histamine (basophils). and circulating helper T cells were evaluated in six obese (at least 35% above ideal body weight) men and six nonobese male volunteers. Methylprednisolone doses of 0.6 mg/kg total body weight were administered as the 21-succinate sodium salt. Absolute clearance (in liters per hour) of methylprednisolone was 40% less in the obese subjects. Total volume of distribution (Vss) of methylprednisolone was unchanged (about 120 L). but when normalized for total body weight. Vss per kilogram was less in obesity. The patterns of cortisol. blood histamine. and helper T cell responses after methylprednisolone administration were similar in both groups. but more profound effects were observed in the obese subjects. Pharmacodynamic models were applied for these immediate effects of methylprednisolone based on the premise that receptor interactions of steroids are followed by rapid suppression of the circadian rhythm of cortisol and recirculation of basophils and helper T cells. which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. Similar IC50 values for the three effects were obtained in both groups. indicating no intrinsic pharmacodynamic differences in sensitivity to these methylprednisolone effects in obesity. However. methylprednisolone should be administered on the basis of ideal body weight. and the dosing interval should be potentially lengthened because of decreased methylprednisolone clearance in obesity.
Population pharmacokinetics of intravenous indomethacin in neonates with symptomatic patent ductus arteriosus, The population pharmacokinetics of intravenous indomethacin were investigated with 665 indomethacin serum concentrations from 83 neonates (mean +/- SD: gestational age. 28.8 +/- 2.5 weeks; postnatal age. 5.7 +/- 4.7 days; birth weight. 1.13 +/- 0.40 kg) receiving indomethacin for symptomatic patent ductus arteriosus. A one-compartment open model was used for pharmacokinetic analysis. Hypotheses were tested to determine which developmental and demographic data influenced clearance (CL) and volume of distribution (V(area)). In the final regression equation CL and V(area) were modeled as a function of body weight and postnatal age (PNA) from 0 to 20 days. Final estimates were as follows: CL (ml/hr) = 2.63.weight (kg) + 0.244.PNA (days) and V(area) (L) = 0.28.weight (kg) + 0.0041.PNA (days). The coefficients of variation for interindividual variability in CL and V(area) were 77% and 28%. respectively. Intraindividual variability was 19%. These mean population parameter estimates should prove useful in designing dosage regimens to achieve desired indomethacin concentrations for neonates from 0 to 20 days of age with symptomatic patent ductus arteriosus.
Conservative treatment of rheumatic disorders in the elderly, Rheumatic syndromes are the most common cause of limited activity and disability in elderly patients. Those over age 65 are particularly susceptible to adverse reactions to antirheumatic therapy. especially to nonsteroidal antiinflammatory drugs (NSAIDs). A therapeutic approach that emphasizes safety by fully utilizing nondrug therapy. employing conservative prescribing techniques. and monitoring high-risk patients for adverse reactions is the focus of this article.
Minimizing the systemic effects of glaucoma medications, Glaucoma accounts for over 3 million office treatment visits annually. While effective. all antiglaucoma drugs. both topical and systemic. have potential and sometimes fatal side effects. Knowledge of the systemic sequelae can prompt early recognition and appropriate adjustment of treatment. Simple preventive measures can be offered to patients which will reduce their chance of systemic absorption of ocularly applied drugs.
Relationship between esophageal varices and azygos vein evaluated by cineportography, The relationship between esophageal varices and the azygos vein. which is generally considered to drain the major part of the variceal blood flow. was evaluated by percutaneous transhepatic cineportography in 35 patients with portal hypertension. We classified the patients into three groups. Those patients in whom most of the variceal blood drained into the azygos vein were designated the azygos-type group (n = 18). Those in whom most of the blood flowed into the brachiocephalic venous system were defined as the cervical-type group (n = 5). and those in whom the varices were drained by both the azygos vein and the brachiocephalic venous system were called the combined-type group (n = 12). Highly developed esophageal varices were recognized endoscopically in all patients in the combined-type and cervical-type groups. whereas some of the patients in the azygos-type group had less well-developed varices. In the azygos-type group. a tendency for the varices to be more severe as their drainage into the azygos vein became more cephalad was noted. Evaluation of the drainage of esophageal varices was considered useful not only for obtaining full comprehension of the significance of the azygos vein but also for assessing the suitability for sclerotherapy. Percutaneous transhepatic cineportography was useful for this purpose because it enables visualization of even the most minute amounts of blood flow.
Sex hormones in postmenopausal women with primary biliary cirrhosis, To evaluate serum sex hormone profiles in nonalcoholic postmenopausal women with liver disease. 25 women with primary biliary cirrhosis (11 in cirrhotic stage) and 46 healthy controls were studied. The patients had significantly (p less than 0.05) elevated serum concentrations of estrone and androstenedione and significantly (p less than 0.05) lower concentrations of estrone sulfate. dehydroepiandrosterone sulfate and 5 alpha-dihydrotestosterone compared with the 46 controls. Serum concentrations of sex hormone binding globulin. testosterone. non-sex hormone binding globulin-bound testosterone and non-protein-bound testosterone did not differ significantly (p greater than 0.05) between primary biliary cirrhosis patients and controls. Patients in the cirrhotic stage had significantly (p less than 0.05) higher concentrations of sex hormone binding globulin than did controls. Patients in the cirrhotic stage had significantly (p less than 0.05) higher sex hormone binding globulin and estrone sulfate levels compared with noncirrhotic patients with primary biliary cirrhosis. Otherwise. no significant differences were observed between cirrhotic and noncirrhotic patients. The observed changes in steroid concentrations may be a consequence of hepatic dysfunction.
Double-blind investigation of the effects of propranolol and placebo on the pressure of esophageal varices in patients with portal hypertension, This study was aimed at investigating the effects of propranolol on esophageal variceal pressure in patients with portal hypertension. Variceal pressure was measured at endoscopy using a miniature pressure-sensitive gauge in 20 patients with portal hypertension. Measurements were obtained under baseline conditions and 20 min after double-blind administration of propranolol (0.15 mg/kg; n = 10) or an identical amount of placebo (normal saline. 0.3 ml/kg; n = 10). Under baseline conditions. variceal pressure was similar in propranolol and placebo groups (14.1 +/- 5 mm Hg vs. 14.9 +/- 6.6 mm Hg. respectively; not significant). Placebo had no significant effect on variceal pressure (baseline = 14.9 +/- 6.6 mm Hg; placebo = 15.5 +/- 6.6 mm Hg; not significant). and values after placebo administration were closely correlated with baseline values (r = 0.98; y = 1.1 + 0.97 x; p less than 0.0001). In contrast. propranolol caused a significant decrease in the pressure of esophageal varices (from 14.1 +/- 5 mm Hg to 11.3 +/- 4.4 mm Hg; p less than 0.0002). No significant changes in the size of esophageal varices were observed after propranolol or placebo administration. This study shows (a) the endoscopic pressure-gauge technique has a low variability and may be used to assess acute drug-induced changes in variceal pressure; and (b) propranolol causes significant decreases in variceal pressure in patients with portal hypertension and esophageal varices.
Morphological changes of hepatic microcirculation in experimental rat cirrhosis: a scanning electron microscopic study, Morphological changes of hepatic microcirculation. especially peribiliary plexus. in experimental rat cirrhosis that resulted from the repeated intraperitoneal injections of N-diethylnitrosamine. 100 mg/kg body weight/one shot/week. were examined by scanning electron microscope. Control rats were treated with saline. Whole blood vessels of the rats were perfused by saline and stuffed with methylmethacrylated resin. Multiple nodular changes were seen in the livers after the five injections (5 wk) of N-diethylnitrosamine. and diffuse nodular transformations mimicking human cirrhosis after six injections (6 wk) were also seen. Overall changes in experimental rats were numerous vascular channels mainly composed of venous branches around the parenchymal nodules. increased arterioportal anastomoses and flattening of veins. especially hepatic vein branches. Peribiliary plexuses of the experimental rats were much richer in the vessels than those of the controls. and many dilated veins. ramified from portal vein branches. were present in the former. Direct connections between peribiliary plexuses and sinusoids or between peribiliary plexuses and portal veins increased in the experimental rats. Studies concerning microcirculatory changes of peribiliary plexuses in experimental rat cirrhosis are rare. It was concluded that the abnormal peribiliary plexuses in this experimental series might participate in a collateral circulation under a state of portal hypertension.
MSG and hydrolyzed vegetable protein induced headache: review and case studies, Monosodium glutamate (MSG). an established headache trigger. has become far more prevalent in canned. packaged and prepared foods over the past decade. The presence of MSG in food may be difficult to detect since the terms "natural flavor." "flavoring." or "hydrolyzed vegetable protein (HVP)." all may appear on food labels to refer to MSG. according to current FDA food labeling codes. HVP typically contains 10-30% MSG. Case studies are presented in which the elimination of all food sources of MSG resulted in decreased headache frequency. Information and food lists helpful in identifying dietary MSG and HVP are presented. When patients are put on an MSG-free trial diet. attention needs to be given to identification of the wide variety of foods containing MSG and HVP.
The relationship between MMPI cluster membership and diagnostic category in headache patients, Only one study has examined MMPI cluster profiles in the headache population. The present study expanded on this previous investigation by using a large sample size (N = 485) and a greater number of diagnostic categories. The five MMPI clusters replicated previous findings in the chronic pain literature. These MMPI cluster groups were compared to 5 diagnostic categories (migraine. cluster. post-trauma. tension. mixed). No relationship was found between cluster type and headache diagnosis. While the diagnostic groups were found to differ on measures of pain severity. sex and age. cluster groups did not. It is proposed that MMPI scale types reflect a patient's response to pain and are more likely to be the result of coping resources than headache-related personality style. Future research with additional. non-pain populations and prospective studies is suggested.
The association of frequent headaches with personality and life events, The associations between personality traits. life events and frequent headaches were studied in a sample of 5766 adult subjects between 20 and 65 years of age from the general population. Subjects with at least weekly headaches had more life events and higher inadequacy. social inadequacy. rigidity and injuredness than subjects with less frequent headaches. These relationships were not observed in subjects of 50 years of age and older. with the exception of the association with inadequacy. From the traits measured. inadequacy had the highest odds ratios for frequent headaches and showed a modest interaction with the presence of a life event. These findings are in agreement with Sarason's interactional model.
The differential effects of biofeedback in the treatment of menstrual and nonmenstrual migraine, The aim of the present study was to investigate the effects of biofeedback training in the treatment of menstrual and nonmenstrual migraine. Accordingly. 39 female patients suffering from both migraine associated. and migraine not associated. with menstrual periods were drawn from a pool of research volunteers enrolled in a biofeedback treatment program for migraine headaches. All patients were required to complete 5 weeks of daily self-monitoring of headache and menstruation activity immediately before and after treatment. and again at 6-month follow-up. Within-subjects comparisons of the effects of biofeedback on menstrual and nonmenstrual migraine. and between-subjects comparisons of the effects of biofeedback on patients suffering predominantly from either menstrual or nonmenstrual migraine showed that biofeedback is just as effective in reducing menstrual migraine as it is in reducing nonmenstrual migraine. Questions as to whether or not these conclusions can apply to patients who experience migraine headaches only during. or shortly before or after. menstruation. are raised.
On pain mechanisms in cluster headache, Various possible pathophysiological mechanisms to explain the pain in cluster headache are reviewed. Several locations for the initiation of pain along the primary afferent pathways in cranial nerves are discussed. together with the local mechanisms that might be responsible. These include neurogenic inflammation of large cranial vessels. irritation of vascular pain fibres by compression of dilated vessels in bony canals. and irritative foci in or around cranial sensory ganglia. In particular. recent neuroanatomical and pharmacological findings on nociceptive innervation of the intracranial segment of the internal carotid artery are commented upon. The possibilities for referred pain to explain the location of pain is illustrated. Evidence for involvement of central pain modulatory systems in the pain production is discussed. Finally a synthesis is made of the probable peripheral and central pain mechanisms in the disease.
Dysmegakaryopoiesis in myelodysplastic syndromes (MDS): an immunomorphometric study of bone marrow trephine biopsy specimens, An immunohistochemical and morphometric analysis was performed on trephine biopsy specimens of the bone marrow in 40 patients (23 men and 17 women. mean age 62 years) with different subtypes of myelodysplastic syndromes (MDS) to determine dysmegakaryopoiesis. but particularly precursor cells--that is. pro- and megakaryoblasts. In 31 of the 40 patients the numbers of megakaryocytes were increased which was associated with a predominance of smaller cell forms (micromegakaryocytes). Compared with periodic acid Schiff. immunostaining with a formalin resistant monoclonal antibody against glycoprotein IIIa (Y2/51(CD61) showed a clinically important proportion of immature elements. These could be designated pro- and megakaryoblasts by taking morphometric measurements on smears and bone marrow sections. There was a relevant increase in the number of promegakaryoblasts in 32 patients. consistent with uncontrolled expansion of the precursor pool. Seventeen repeated bone marrow biopsy specimens taken after chemotherapy largely showed a decrease in the numbers of megakaryocytes including the precursor cell population. Moreover. morphometric evaluation disclosed that micromegakaryocytes in MDS differ significantly from those in chronic myeloid leukaemia (CML) due to distinctive nuclear features and a disturbed nuclear:cytoplasmic ratio. These changes generate a more pleomorphic or atypical appearance of this cell population in MDS. compared with micromegakaryocytes in CML. It is concluded that the disproportionate increase in megakaryocyte precursors and the grossly abnormal aspects of micromegakaryocytes in MDS are characteristics of the severe defect involving haematopoiesis in this disorder.
Immunohistochemical demonstration of neurone specific enolase in bone marrow infiltrated by neuroblastoma, One hundred and two bone marrow samples were analysed by histological and immunohistochemical methods for neurone specific enolase (NSE). The biopsies were performed to determine the extent of bone marrow disease in 84 neuroblastomas. nine embryonal rhabdomyosarcomas. five Ewing's sarcomas. two cases of Hodgkin's disease and two lymphoblastic lymphomas. Twenty seven (32%) of neuroblastoma bone marrows showed metastases by conventional histological techniques and 33 (39%) after immunohistochemical staining with NSE. Five embryonal rhabdomyosarcomas. five Ewing's sarcomas. and two lymphoblastic lymphomas showed bone marrow metastases. Only one of these cases was reactive for NSE. NSE represents a very sensitive immunomarker for the follow up of neuroblastoma and improves detection of bone marrow invasion by neuroblastoma.
Congenital mesoblastic nephroma: possible prognostic and management value of assessing DNA content, The case records and pathology of all children with kidney tumours treated in the West Midlands Health Authority Region (WMHAR) from 1957 to 1986 were reviewed. The histology was reviewed by a panel of three paediatric pathologists. Thirteen (6%) out of 211 cases were considered to have congenital mesoblastic nephroma (CMN). Nine were of the conventional type. three of the atypical cellular type. and one mixed. DNA ploidy was investigated and showed two of the tumours to be aneuploid and nine diploid (tissue was not available in the two other cases). The two aneuploid tumours were of atypical cellular and mixed histology. respectively; the diploid tumours were of the conventional type in eight cases and atypical cellular in one. The atypical cellular type has been reported to behave more aggressively. but the benefit of additional treatment after surgery to prevent recurrence remains unclear. Measurement of DNA content by flow cytometry. together with histological subclassification. may be useful in selecting patients who will benefit from further treatment after surgery.
Evaluation of a commercial ELISA for serodiagnosis of Helicobacter pylori infection, A commercial ELISA for the detection of Helicobacter pylori IgG antibodies was evaluated using serum from 242 patients attending an endoscopy clinic. The efficacy of the ELISA was assessed in relation to the histological detection of H pylori on antral mucosal biopsy specimens. In patients under 61 years of age (n = 138) the ELISA was 97.5% sensitive and 85.5% specific for H pylori infection. with a positive predictive value of 91% and a negative predictive value of 96%. Over the whole group the sensitivity of the ELISA was 93.8% and the specificity 79.3%. The positive predictive value and negative predictive values were. respectively. 90% and 87%. These results suggest that the Bio-Rad GAP IgG H pylori ELISA is suitable for serodiagnosis of H pylori infections for most clinical purposes and thus makes H pylori serology available to routine diagnostic laboratories.
A silver enhanced, gold labelled, immunosorbent assay for detecting antibodies to rubella virus, A silver enhanced. gold labelled. immunosorbent assay (SEGLISA) for the detection of IgG antibodies to the rubella virus in human serum was developed. Pre-coated microtitre wells are used as the immobilised base of rubella antigens on to which any rubella antibodies from patient samples will bind. This antigen/antibody complex is then visualised firstly by gold labelled anti-immunoglobulin G. which binds to any human IgG that may be present. and then by silver amplification. resulting in a black permanent deposit on the microtitre well surface. Patient samples (n = 121) were screened using a commercially available enzyme linked immunosorbent assay (ELISA) and an equivalent SEGLISA. Results were comparable but the SEGLISA does not have the disadvantages associated with enzyme labels. The silver deposit may also be read visually or the dried plate may be stored for future reference.
Chronic myelomonocytic leukaemia associated with T cell receptor delta gene rearrangement, Morphological. immunophenotypic. and genetic analyses were carried out on peripheral blood. bone marrow. and pharyngeal biopsy material from a patient with chronic myelomonocytic leukaemia (CMML). Morphological analysis of bone marrow was diagnostic of CMML; immunophenotypic analysis of peripheral blood and bone marrow were negative for B and T cell antigens. and immunochemistry performed on the pharyngeal extramedullary infiltrate showed the presence of large monocytoid cells which stained positively for muramidase. Genotypic analysis. however. showed clonal rearrangement of the T cell receptor (TCR) delta chain gene. a marker of T cell or. less commonly. B cell lymphoid neoplasms. Other TCR genes. beta and gamma. were germline in all tissues examined. TCR delta is rearranged in precursor B cell and most T lymphoid neoplasms. A small proportion of cases (10%) of acute myeloid leukaemia (AML) also show rearrangement of the TCR delta gene. To date TCR delta rearrangement has not been described in CMML. The aberrant TCR delta rearrangement shown in this patient with CMML provides further evidence of the clonal nature of this disorder.
Stability of buffered lidocaine and epinephrine used for local anesthesia, Buffered lidocaine has been recently recommended for local anesthesia. as there is less pain on injection of the buffered solution. Reduced pain on injection of lidocaine and epinephrine buffered to a neutral pH was confirmed in 20 subjects (P less than .01). Concentrations of buffered lidocaine and epinephrine were performed in order to evaluate their stability. Buffered lidocaine dropped to 66.1% of initial concentrations after 4 weeks when stored at 25 degrees C. Buffered epinephrine fell to 1.34% of its initial concentration under similar conditions. Buffered lidocaine and epinephrine maintained 94.54% and 82.04%. respectively. of their initial concentrations after 4 weeks when refrigerated at 0-4 degrees C. Both lidocaine and epinephrine maintained greater than 90% concentration 2 weeks after buffering when stored at 0-4 degrees C. This permits batch buffering of lidocaine with epinephrine and storage for periods up to 2 weeks when properly refrigerated.
The prevention and management of postdermabrasion complications, The complications of keloids. pigment changes. loss of skin texture. and enlarged facial pores remain a problem with dermabrasion patients. Their occurrence can be reduced by proper patient selection. proper dermabrasion technique. proper wound management. and prompt treatment. Keloids are rapidly resolved with the use of flurandrenolide tape covered with positive-pressure chin-strap dressings. Streaks of hyperpigmentation are lightened with a combination of sunscreen. opaque makeup. tretinoin. and hydroquinone lotions. The loss of skin texture can be prevented by not abrading too deeply and avoiding subsequent bacterial contamination during wound healing. However. enlarged skin pores in the central portion of the face and hypopigmentation can be permanent complications.
Two studies of pacing in the nursing home, Two studies concerning pacing by nursing home residents are presented. The first was a cross-sectional survey of 402 residents. which found that 39% of the subjects were pacers. In comparison to residents who did not pace. the pacers had fewer medical diagnoses. better appetites. and had resided in the facility for fewer years. Additionally. pacing was positively related to cognitive impairment and to past life-threatening experiences. Results of the second study. an observational study of six cognitively impaired residents who paced frequently. showed that these residents paced more when the environmental conditions were conducive to pacing (e.g.. adequate lighting. enough room within which to pace). We believe that pacing is a reflection of good health within the nursing home population and suggest that caregivers may want to encourage rather than inhibit this behavior in some nursing home residents.
Disability, residential mobility, and changes in living arrangements, The extent of mobility and changes in living arrangements associated with disability were studied using data from the 1984-86 Longitudinal Study of Aging. It was hypothesized that persons with significant limitations in their ability to perform normal daily activities (ADLs and IADLs) in 1984 would be more likely to move. more likely to be living with others in 1986. and more likely to have entered an institution between 1984 and 1986 than those without limitations. When only those variables that were measured in 1984 were used as predictors. this turned out to be true for institutionalization and for living with others in 1986. However. among those remaining in households. residential mobility showed little relationship to disability when other variables were controlled. When the change in disability between 1984 and 1986 was added to the prediction equation. there were strong relationships between changes in disability and both residential mobility and adjustment in living arrangement. suggesting that people respond quickly to significant changes in disability. However. because we cannot be sure that the changes in disability preceded the mobility or changes in living arrangements. we cannot claim to have established a causal link between these events.
Spinal cord stimulation in 60 cases of intractable pain, Sixty patients with spinal cord stimulators implanted for intractable pain lasting up to 50 years were followed for up to nine years. Forty seven per cent derived significant benefit. 23% modest benefit. 20% experienced no effect and 6.7% were made worse. Two were made worse after initial benefit. Complications. indications and factors relevant to the mode of action are discussed.
Epilepsy and employment. A community based survey in an area of high unemployment, A community based survey was undertaken to assess the work record of patients with epilepsy in an area of high unemployment. One hundred and thirty seven epileptic patients were identified from a population of 23.837 persons of employable age registered with three urban group practices in North East England. The unemployment rate for economically active patients with epilepsy was 46% compared with 19% for an age and sex matched control population (p less than 0.01). Fifty nine per cent of patients with active epilepsy were unemployed. In those with an associated neurological or psychiatric handicap and those who were unskilled manual workers the unemployment rates were 79% and 77%. respectively. Patients with epilepsy were less likely to leave school with qualifications or undergo subsequent training or apprenticeships. They were more likely to be unskilled manual workers. single and living in rented accommodation. In an area of high unemployment patients with epilepsy have disproportionately greater difficulty finding work. High unemployment rates among patients with epilepsy are only one aspect of a spectrum of social and economic disadvantage.
Abnormal most-rapid isometric contractions in patients with Parkinson's disease, Fast isometric elbow flexor muscle contractions of specified amplitude in six normal subjects were compared with those of 11 patients with Parkinson's disease. Despite treatment. all patients exhibited deficits in this motor task. Three patients were able to produce rapid force pulses with normal contraction times. but the variability of their force responses was increased in comparison with the highly stereotyped responses produced by normal subjects. The other eight patients had prolonged contraction times and segmentation of the force profiles. The integrated area of the first agonist EMG burst and the rate of development of force (dF/dt) were less at any target level than what was needed to produce a fast response. The area of the EMG burst. however. did increase with target amplitude. and the relative increase of dF/dt. with target amplitude. was normal. It is concluded that the motor program subserving fast muscle contraction is preserved in Parkinson's disease. but its execution is characterised by improper scaling of motor output.
Occidental type cerebromuscular dystrophy: a report of eleven cases, Occidental type cerebromuscular dystrophy (OCMD) forms a substantial distinct group within congenital muscular dystrophy (CMD). These patients invariably present with amyotrophy. multiple joint contractures. facial muscle involvement. normal or nearly normal intelligence. leukodystrophic appearance on CT scan. and dystrophic changes in muscle.
CSF monoamine metabolites, cholinesterases and lactate in the adult hydrocephalus syndrome (normal pressure hydrocephalus) related to CSF hydrodynamic parameters, Monoamine metabolites. cholinesterases and lactic acid in lumbar cerebrospinal fluid (CSF) were investigated on patients with the adult hydrocephalus syndrome (idiopathic normal pressure syndrome; AHS. n = 15). Alzheimer's disease (AD. n = 14). multi-infarct dementia (MID. n = 13) and controls (n = 21). Patients had clinical and CSF hydrodynamic investigations. Monoamine concentrations were determined by reversed-phase liquid chromatography. cholinesterases and lactate were determined photometrically. In the AHS patients. CSF monoamine concentrations were not significantly different compared with controls. AD or MID patients. AHS and AD patients showed a similar reduction of CSF acetylcholinesterase activity compared with controls. Positive correlations were found in concentrations of CSF homovanillic acid. CSF 5-hydroxyindoleacetic acid and CSF lactic acid versus CSF outflow conductance (that is. resistance against CSF outflow) in the AHS patients. A similar pattern was observed in a subgroup of MID patients characterised by dilated ventricles and disturbed CSF hydrodynamics. These data suggest that a low CSF outflow conductance may facilitate the clearance of acidic substances from the arachnoid space at the probenecid sensitive active transport site. Alternative explanations would be that a pathologically low CSF outflow conductance is accompanied by an inverse caudorostral flow of CSF or a compromised trans-ependymal diffusion.
Carcinomatous meningitis: antibody-guided therapy with I-131 HMFG1, Seven patients with carcinomatous meningitis were administered intrathecal I-131 labelled monoclonal antibody HMFG1. Clinical responses were seen in two patients. with a long term survivor at 32 months. Aseptic meningitis occurred in 4/7 patients. but more serious toxicity was observed in the form of seizures (2/7 patients) and myelosuppression (3/7 patients). Partial obliteration of the subarachnoid space was identified as a potential problem in patients with advanced disease.
Intermittent long-term adrenocorticosteroid treatment of myasthenia gravis, It is widely accepted that a long-term. alternate-day administration of adrenal corticosteroids after thymectomy is one of the most effective treatments of myasthenia gravis. However. some patients with myasthenia gravis show a tendency to develop steroid dependency. and require extremely prolonged administration of fairly high doses of steroids. Various types of adverse reactions to steroids are likely to occur in such cases. To avoid this. intermittent. single-dose administration of steroids was performed on a trial basis in the present study. Prednisolone. in doses of 50-100 mg. was given once every 3-7 days in three steroid-dependent myasthenic patients. in one case for up to 6 years. The effects of the intermittent treatment were as good as. and adverse effects less frequently found than in single-dose. alternate-day administration.
Plasma profiles of adrenocorticotropic hormone, cortisol, growth hormone and prolactin in patients with untreated Parkinson's disease, Plasma profiles of prolactin. growth hormone. adrenocorticotropic hormone (ACTH) and cortisol were evaluated in a group of untreated patients with idiopathic Parkinson's disease and a group of healthy age-matched controls. Plasma integrated concentrations of all hormones except prolactin were significantly lower in the patients as compared with the controls; however. prolactin nocturnal peak concentration was significantly elevated in the patients; nocturnal growth hormone levels were significantly reduced in the Parkinson group; ACTH and cortisol plasma concentrations were also consistently lower during most of the day in the patients with Parkinson's disease. These data confirm the presence of a hypothalamic disturbance in patients with idiopathic Parkinson's disease. which can affect pituitary function.
Type 2a fibre rhabdomyolysis in myoadenylate deaminase deficiency, A 31-year-old woman developed an acute. potentially fatal rhabdomyolysis of undetermined origin. Muscle biopsy revealed selective lysis involving exclusively type 2a fibers. Myoadenylate-deaminase (MAD) deficiency was proven by a negative histochemical reaction as well as by an enzymatic biochemical determination. The significantly greater energetic dependence of type 2a fibres on MAD explains their selective damage. The patient's mother also suffers from a similar muscle disease of still unclarified origin.
Transient loss of consciousness: the value of the history for distinguishing seizure from syncope, We studied 94 consecutive patients (age 15 or over) to investigate which aspects of the history and clinical findings help to distinguish seizures from syncope and related conditions. Clonic movements or automatism observed by an eyewitness classified an event as a seizure. The seizure group consisted of 41 patients and the syncope group of 53 patients. The likelihood ratio was used to calculate the predictive power of single findings and logistic regression to analyse combinations of findings. The best discriminatory finding was orientation immediately after the event according to the eyewitness and the age of the patient in the absence of an eyewitness report (P less than 0.001). We found a seizure five times more likely than syncope if the patient was disoriented after the event and three times more likely if the patient was less than 45 years of age. Nausea or sweating before the event were useful to exclude a seizure. Incontinence and trauma were not discriminative findings.
Polyneuropathy induced by m-tolyl methyl carbamate intoxication, A 55-year-old woman who attempted suicide by ingesting 200 ml of m-tolyl methyl carbamate (MTMC) is reported. She was comatose for 3 days and. upon recovery. had notable paraesthesia in her lower limbs and difficulty in walking. Neurological examination revealed sensorimotor polyneuropathy. Sural nerve biopsy revealed marked axonal degeneration with a moderate decrease of myelinated fibres.
Brainstem compression by basilar artery anomalies as visualized by MRI, The use of MRI in the diagnosis of vascular anomalies of the basilar artery is demonstrated in two cases. The first patient had a partially thrombosed giant aneurysm of the basilar artery; the second had an atypical course of the basilar artery. MRI is indicated whenever other imaging procedures do not provide a definite diagnosis or the use of contrast medium for conventional X-ray examination or computed tomography is contraindicated.
Screening of gene deletions by polymerase chain reaction in Japanese patients with Duchenne muscular dystrophy, Gene deletions were screened in 49 Japanese Duchenne muscular dystrophy patients from 43 families. using the polymerase chain reaction. Enzymatic amplification was carried out on six regions prone to deletion. Fifteen of 43 families (33%) had gene deletions in at least one of the six regions. This frequency was almost the same as that previously reported in Caucasians. The mid-part of the dystrophin gene was the location most frequently deleted. The frequency of deletion of the region encompassing exon 45 was higher in Japanese families (18.4%) than in Caucasians.
Long-term nervous system damage from radiation of the spinal cord: an electrophysiological study, A group of 13 patients suffering from Hodgkin's disease who had undergone chemotherapy and radiotherapy (above and below the diaphragm) approximately 10 years earlier was studied. The total chemotherapeutic dose was similar for all patients; the radiotherapy dose. however. was standard for 7 patients. while the other 6 received much higher dosages over limited regions of the spinal cord. Although most of these patients appeared normal both clinically and on magnetic resonance imaging. a neurophysiological study was performed to determine whether there was any involvement of the central or peripheral nervous system. Motor conduction velocity and sensory conduction velocity were measured in the lower limbs as well as spinal- and scalp-recorded somatosensory evoked potentials (SEPs) in response to stimulation of the posterior tibial and sural nerves at the ankle. In addition. motor evoked potentials were recorded from the upper and lower limbs during cortical stimulation. All neurophysiological data were normal in patients who had received a standard radiation dose. while most of those who had been exposed to higher doses showed altered cortical SEPs and a slowing of central conduction time (D10-P1). Thus even though they were asymptomatic. these patients appeared to have sustained CNS damage. mainly at the level of the spinal cord.
Mild and moderate endometriosis. Comparison of treatment modalities for infertile couples, A series of 1.268 consecutive patients with stage I and II endometriosis (American Fertility Society classification) were treated for the disease. In 675. no other factors contributed to their infertility. Among these patients. with no problems other than mild endometriosis. 57% (16/28) became pregnant when treated expectantly. 54% (51/95) after being treated medically. 47% (9/19) after laparoscopic cautery treatment. 81% (147/181) after laparoscopic laser treatment and 84% (97/116) after conservative surgery (laparotomy). Statistical analysis of the pregnancy rates revealed no difference between expectant. medical and laparoscopic cautery treatment. No difference was noted between laparotomy and laser laparoscopy; however. there was a statistically significant difference between these treatments and expectant. medical and cautery treatment. Similar results were seen with stage II endometriosis in couples with no contributing factors other than endometriosis: 39% of patients (23/59) became pregnant after medical treatment. 70% (80/115) after laser laparoscopy and 74% (46/62) after undergoing major conservative treatment (laparotomy). A statistically significant difference between medical treatment and laparotomy as well as laser laparoscopy was noted. However. no such difference existed between laparotomy and laser laparoscopy. Therefore. it appears that in experienced hands the use of laser laparoscopy in stage I and II endometriosis is as successful as major surgery and statistically significantly better than expectant. medical and laparoscopic cautery treatment.
Obstetric outcome in women after multiple spontaneous abortions, Obstetric outcome in 88 women with a past history of three or more consecutive pregnancy losses was studied. The results were compared to those in our total obstetric population for the same period (control group). The incidence of small-for-gestational-age infants. prematurity. low-birth-weight infants and toxemia in the study group was not significantly different from that in the control group. Gestational diabetes and chronic hypertension. however. occurred more frequently in the study group than in the control group (P less than .001). These data could be helpful in counseling women with repeated pregnancy loss.
Recurrent spontaneous pregnancy loss. Investigation and reproductive follow-up, Between July 1. 1985. and Dec 31. 1988. 187 women referred to the University of British Columbia Medical Genetics Clinical Unit for two or more consecutive. unexplained. spontaneous pregnancy losses were evaluated for seven categories of possible etiology. Follow-up of the total subsequent reproductive experience was obtained in 171 cases. For those who became pregnant. achievement of a live birth was tabulated according to the number of previous pregnancy losses. age at the investigation and abnormalities found in the investigation. Overall. 81.8% of those who became pregnant after the evaluation and with a known outcome or outcomes at follow-up had a live birth-78% of primary aborters (no previous liveborn infant) and 86.3% of secondary aborters (previous liveborn infant).
Ectopic pregnancy in women with previous tubal sterilizations at a Canadian community hospital, A Canadian community hospital review of women with ectopic pregnancies revealed that 7.6% had had a previous tubal sterilization. This rate was higher than reported previously.
Microcirculatory flow changes after initial resuscitation of hemorrhagic shock with 7.5% hypertonic saline/6% dextran 70, In rabbits. laser Doppler flow probes were placed in the jejunum and on the renal cortex. Pulsed Doppler probes were implanted on the abdominal aorta and superior mesenteric and femoral arteries for measuring blood flow velocity. Cardiac output was measured by thermal dilution. Either 30% or 40% of the calculated blood volume was withdrawn through a carotid catheter. After 30 or 60 minutes. an initial bolus of either lactated Ringer's (LR. 16 ml/kg) or 7.5% hypertonic saline/6% dextran 70 (HSD; 4 ml/kg) IV was followed by unlimited IV LR (administered as rapidly as possible) to restore systemic arterial blood pressure to the prehemorrhage levels. With HSD. arterial pressure corrected more rapidly (p less than 0.05). and the initial hemodilution was greater (p less than 0.05). but there were no differences by two hours. With HSD. cardiac output (90%-100% vs. 130%-160% of control; p less than 0.05). plasma Na+ (139-140 mM vs. 146-148 mM; p less than 0.05) and plasma osmolarity (292-295 mOsm vs. 308-310 mOsm; p less than 0.05) were all significantly higher than the values with LR. but there was no effect on blood flow velocities through the infrarenal aorta. femoral artery. or superior mesenteric artery. Renal cortical perfusion (56% vs. 97% of control; p less than 0.05) and jejunal mucosal perfusion (83% vs. 162% of control; p less than 0.05) were significantly higher with HSD. HSD had no detectable effect on bacterial translocation at 24 hours. Thus: 1) HSD restores blood flow more rapidly to the gut mucosal and kidney microcirculations than initial resuscitation with LR; 2) the mechanism could be associated with a transient hemodilution and persistent increases in plasma Na and osmolarity. which reduce hemorrhage-induced cell swelling and blood viscosity changes; and 3) laser Doppler analysis could aid in the diagnosis of reperfusion injury after shock.
Adequate crystalloid resuscitation restores but fails to maintain the active hepatocellular function following hemorrhagic shock, Studies have shown that active hepatocellular function is depressed early after trauma-hemorrhage and persists despite resuscitation with two or three times (x) the volume of maximum bleedout (MB) with lactated Ringer's solution (LR). However. it is not known if a larger volume of fluid resuscitation corrects this dysfunction. To study this. rats were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the MB volume was returned in the form of LR. and then resuscitated with 4x or 5x the volume of MB with LR. Three doses of indocyanine green (ICG) were given intravenously and [ICG] measured in vivo using an in-vivo hemoreflectometer. The initial velocity of the clearance of ICG was calculated. Maximal velocity of the clearance (Vmax: the number of functional ICG receptors) and kinetic constant (Km: the efficiency of the active transport) were determined from the Lineweaver-Burk plot. Vmax decreased during hemorrhage. was restored to control levels at 0-4 hours after resuscitation. but decreased at 4-8 hours after resuscitation despite restoration of cardiac output following resuscitation with 5x LR. This could be the result of increased TNF release. The Km also decreased during hemorrhage. but increased at 0-1.5 hours and remained at control levels even 4-8 hours after resuscitation. Thus the failure of Vmax to remain at control levels following adequate fluid resuscitation may form the basis of cellular dysfunction and multiple organ failure after severe hemorrhagic shock.
Eicosanoids regulate tumor necrosis factor synthesis after hemorrhage in vitro and in vivo, The aim of this investigation was to determine whether PGE2 regulates TNF release in vitro and in vivo following hemorrhage. To study this. C3H/HeN mice were bled to a mean blood pressure (BP) of 35 mm Hg. maintained for 60 minutes. and then resuscitated. For in vitro studies. peritoneal (pM phi) and splenic (sM phi) macrophages obtained at 2 hours and 24 hours after hemorrhage were stimulated with LPS for 24 or 48 hours with or without ibuprofen (IBU). For in vivo studies. M phi were harvested 24 hours following hemorrhage with and without IBU treatment and stimulated with LPS for 48 hours. The decreased TNF release by pM phi but not sM phi from hemorrhaged mice was restored by IBU in vitro. IBU treatment in vivo significantly enhanced TNF release by pM phi compared with untreated hemorrhaged animals. while TNF release by sM phi was only slightly increased. These data indicate a major role of PGE2 in the regulation of TNF release by pM phi following hemorrhage.
The effect of nociceptive stimulation on the changes in hemodynamics and oxygen transport induced by hemorrhage in anesthetized pigs, The effects of somatic nociceptive afferent stimulation on aspects of cardiac function and oxygen transport were examined in a model of hemorrhage in anesthetized pigs. The brachial nerves were stimulated (BNS) alternately to obtain a rise in heart rate of 18% and in mean arterial pressure of 17%. This stimulation was started 75 minutes before the start of hemorrhage and maintained throughout and after the withdrawal of blood. The animals were bled at a rate of 0.75 ml/min.kg until a total of 30 ml/kg had been removed. At the end of hemorrhage the reductions in cardiac index (CI). stroke volume (SV). and left ventricular stroke work (LVSW) were greater in the BNS group compared with controls. The nociceptive stimulation also elicited greater reductions in oxygen delivery (DO2I) and oxygen consumption (VO2) and a greater rise in the arterial plasma lactate concentration. Thus it seems that nociceptive stimulation exacerbates the changes in systemic oxygen transport and cardiac function induced by hemorrhage.
Bacterial translocation and its relationship to visceral blood flow, gut mucosal ornithine decarboxylase activity, and DNA in pigs, The relationship of bacterial translocation to gut blood flow and mucosal integrity was studied in pigs. Three groups of miniature pigs were studied: sham injured (controls) (n = 7). 50% mechanical reduction in blood flow to the superior mesenteric artery (SMA) and celiac artery (CA) (n = 6). and a 40% third-degree cutaneous flame burn (n = 9). Forty-eight hours after injury. animals were killed and organ samples obtained for analysis. Bacteria of the same biotype as that found in the intestinal lumen were present in the mesenteric lymph nodes (MLN) of 9 of 9 burned pigs and 5 of 6 pigs undergoing partial vascular occlusion. The DNA content and ornithine decarboxylase (ODC) activity were increased in the colon mucosa of animals from both the reduced-flow and burn-injured groups compared with control animals. Decreased blood flow to the gut may contribute to the development of bacterial translocation. In addition. intestinal regenerative capacity remains intact 48 hours after injury.
Down-regulation of homing receptors: a mechanism for impaired recruitment of human phagocytes in sepsis, Receptors known as DREG adhesion molecules on human neutrophils and monocytes provide for homing of these phagocytic leukocytes to sites of inflammation. They mediate the initial adhesive interaction of the leukocytes to vascular endothelial cells and are then shed from the cell surface in response to chemotactic factors and inflammatory mediators. Systemic accumulation of these agents following major injury or sepsis may therefore promote shedding of DREG receptors from circulating leukocytes and impair their recruitment to sites of inflammation. To test this hypothesis. we have analyzed the expression of DREG receptors on neutrophils and monocytes from 25 patients admitted to the Surgical Intensive Care Unit. Receptor expression was measured by flow cytometry of cells stained with murine monoclonal DREG-56 anti-DREG antibody. For 14 nonseptic patients. mean monocyte positivity for DREG was reduced from 64% to 40%. For 11 septic patients. mean neutrophil and monocyte positivity for DREG was reduced from 94% to 82% and 64% to 34%. respectively. These results suggest that monocytes are more affected than neutrophils in vivo by conditions expected to stimulate shedding of DREG and that sepsis promotes shedding of these adherence receptors. Accumulation of DREG-negative monocytes in association with sepsis may be sufficient to impair their recruitment to inflammatory sites and limit their contribution to host defense against infection and tissue repair.
Whipple procedure for trauma: is duct ligation a safe alternative to pancreaticojejunostomy, The use of pancreatic duct ligation (DL) during a Whipple procedure for trauma has been reported but not analyzed. We reviewed 13 cases of DL and compared the results with that reported for the Whipple procedure for trauma with pancreaticojejunostomy (PJ). The mortality rate of DL was 53.8%. Pancreatitis occurred in three cases (23.1%) and caused one death. Pancreatic fistulae occurred in 50% of patients surviving two or more days after DL. No long-term survivor developed overt diabetes mellitus. Malabsorption occurred in 50% of the long-term survivors of DL. When the DL and PJ groups were compared no statistically significant difference could be found in either mortality or pancreatic morbidity. The 46.2% survival rate for DL warrants its consideration as a technique available to trauma surgeons when faced with an unstable patient unable to tolerate further operative therapy.
Continuous automated monitoring of somatosensory evoked potentials in posttraumatic coma, Using a microcomputer system. 36 patients were continuously monitored with somatosensory evoked potentials (SSEPs) following closed head injury. The mean duration of monitoring was five days. The patients' GCS scores at the start of monitoring ranged from 3-10. Mortality was 44%. Of 14 patients who had initial absence of SSEP activity after the N20 wave or lost this activity during the period of monitoring. 12 died and two remained vegetative. Eighteen of 22 patients who had preservation or enhancement of this activity had a functional survival (3-month outcomes. p less than 0.001). The best outcomes were observed in the patients with the greatest number of peaks and highest amplitudes in the SSEPs. often in spite of increased intracranial pressure (ICP). The management of three patients was altered as a result of SSEP monitoring. We conclude that continuous monitoring of SSEPs is a useful adjunct in the management of comatose head-injured patients.
Validity of applying adult TRISS analysis to injured children, Injury severity measures are becoming increasingly important for quality assurance and injury research. TRISS analysis. which uses the Revised Trauma Score (RTS) and Injury Severity Score (ISS) to predict survival. is an effective tool for comparing outcomes between trauma centers. It has been argued that blunt trauma outcome differs between children and adults. yet the Major Trauma Outcome Study (MTOS) adult data base (ages 15-54 years) regression weights have been used by others to calculate TRISS scores for injured children. This study appears to be the first to perform TRISS analysis on groups of children and adults treated by the same surgeons using the same treatment protocols to assess the validity of applying "adult" TRISS analysis to children. The charts of 346 consecutive children (ages 0-14) and 346 random adults (ages 15-54) admitted to a regional trauma center for isolated blunt trauma over a 30-month period were reviewed for demographics. mechanism of injury. RTS. ISS. and survival. Statistical evaluation included TRISS survival analysis and calculation of the Z statistic. The median ISS was 10 for both children and adults. The Z statistics for children and adults were similar (1.85 and 1.81). Analysis demonstrated the groups to be statistically identical with a nonsignificant trend toward improved survival compared with the MTOS baseline group. These data support the use of existing TRISS analysis for evaluation of pediatric trauma care.
Brachial plexus anesthesia for outpatient surgical procedures on an upper extremity, We retrospectively reviewed 543 brachial plexus blocks performed on 526 outpatients. Most (98%) of the blocks were performed by means of the axillary approach. Various techniques were used. including paresthesia. transarterial fixation. nerve stimulation. or a combination of techniques; a high success rate was achieved with each of them. Only 7% of the blocks were incomplete and thus necessitated either general anesthesia or block supplementation with thiopental sodium and nitrous oxide. No persistent neurologic deficit was ascribed to the anesthetic technique. This review indicates that brachial plexus block. especially with use of the axillary approach. is a safe and effective option for outpatient surgical procedures on an upper extremity.
6-mercaptopurine therapy in selected cases of corticosteroid-dependent Crohn's disease, Nineteen patients (12 children and 7 adults) with severe Crohn's disease. all of whom were dependent on corticosteroids. were treated with 6-mercaptopurine. All patients received a daily dose of 6-mercaptopurine of 50 mg; in two pediatric patients with a poor response after 2 months. the dosage was increased to 75 mg/day. A complete or partial response to 6-mercaptopurine therapy was noted in 47% of patients. and therapy failed in 53%. The age of the patients. prior resection. or initial symptoms did not influence the response. The clinical response was better in male than in female patients and in patients with involvement of both the small intestine and the colon than in those with only enteritis. 6-Mercaptopurine is a possible alternative to long-term corticosteroid therapy or surgical treatment in selected patients with severe Crohn's disease.
Management of patients with myelodysplastic syndromes, The myelodysplastic syndromes are composed of a group of clonal hematologic neoplasms. the course of which is complicated by ineffective hematopoiesis or leukemic transformation (or both). Therapeutic results may have been misleading in the past. Most patients have been managed with supportive measures. such as transfusions of erythrocytes. administration of antibiotics. and transfusions of platelets during active bleeding episodes. These supportive measures have prolonged and improved the quality of life of patients with myelodysplastic syndromes. Vitamin supplementation (folate. vitamin B12. and pyridoxine) has seldom been rewarding. Differentiation agents such as cis-retinoic acid and 1.25-dihydroxyvitamin D3 have been of benefit in only a limited number of patients. Androgens have not been useful. although danazol. which is an attenuated androgen. has been effective in a subset of patients with the presence of cell-bound platelet antibodies. Low-dose cytarabine. which has been studied extensively because of its differentiating activity in vitro. is associated with a generally low rate of complete remission and substantial toxicity. Antileukemic therapy is generally useful in young patients with rapidly progressive disease. Several hematopoietic growth factors are currently being evaluated in clinical trials; their use in combination or in conjunction with chemotherapy may be opening new horizons for these patients. With improvements in the prevention and treatment of graft-versus-host disease. allogeneic transplantation is a viable option for patients younger than 55 years of age who have severe cytopenias.
Tissue characterization of an unusual right atrial mass by magnetic resonance imaging, In a 70-year-old man who had angina. exercise-induced ventricular tachycardia. and presyncopal symptoms. transthoracic and transesophageal echocardiography disclosed a large atrial mass that resembled a myxoma. Subsequent evaluation by magnetic resonance imaging identified the mass as an intracardiac lipoma attached to the posterior wall of the right atrium. a diagnosis that was confirmed by surgical intervention. Thus. the diagnostic utility of magnetic resonance imaging as an adjunct to echocardiographic evaluation of intracardiac masses was demonstrated.
Prospective, randomised, multicentre trial of effect of protein restriction on progression of chronic renal insufficiency. Northern Italian Cooperative Study Group, A multicentre. prospective trial was organised to clarify the role of protein restriction in the progression of chronic renal insufficiency (CRI). 456 adult patients were assigned either a low-protein diet (0.6 g/kg body weight daily; n = 226) or a "normal" controlled-protein diet (1.0 g/kg daily; n = 230) and were stratified into three groups (A-C) with increasing baseline plasma creatinine concentrations. Each patient was followed up for 2 years or until an endpoint (a doubling of the baseline plasma creatinine or a need for dialysis) was reached. The difference between the diet groups in cumulative renal survival defined by these endpoints (27 low-protein. 42 controlled-protein) was of borderline significance (p less than 0.06). The difference in renal survival between the low-protein and controlled-protein diet groups was of borderline significance in group A (0 vs 4 endpoints). significant in group B (10 vs 21 endpoints; p less than 0.025). and not significant in group C. There were no differences among the diet groups or subgroups in mean plasma creatinine concentrations. creatinine clearance. the slope of the plasma creatinine reciprocal. or mean blood pressures. Compliance was good in the controlled-protein group but poor for the low-protein diet: the difference in protein intake between the groups was substantially less than that required by the protocol. However. there was no correlation between the progression of renal failure and protein catabolic rate. These findings offer little. if any. support to the hypothesis that protein restriction retards CRI progression: careful medical care and a "normal" controlled protein intake also allow very slow progression of CRI.
Antibodies to gp41 and nef in otherwise HIV-negative homosexual man with Kaposi's sarcoma, A homosexual man with histologically confirmed Kaposi's sarcoma remained seronegative for HIV-1. HIV-2. and HTLV-1 on conventional tests over a 4-year period. HIV cultures were also negative on thirteen separate occasions. However. serum antibodies to synthetic peptide analogues of the gp41 and nef regions of HIV-1 were consistently detected on an enzyme immunoassay. Tests with the polymerase chain reaction with primers directed to the gag and env regions were negative. The antigens to which the antibodies were produced might have come from a defective HIV mutant. another retrovirus. or a hitherto unknown "agent of Kaposi's sarcoma" with similar antigenic epitopes.
Field evaluation of alternative HIV testing strategy with a rapid immunobinding assay and an agglutination assay, A rapid immunobinding assay ('HIVCHEK'. Ortho) and an agglutination assay ('Serodia-HIV'. Fujirebio) were evaluated as an alternative to enzyme-linked immunosorbent assay (ELISA) and western blot under field conditions in Africa for detection of antibody to human immunodeficiency virus (HIV). 7106 specimens were tested at 25 laboratories in Kenya. Ghana. Senegal. and Zaire. HIVCHEK was used as a screening test. and serodia-HIV as a supplemental test to evaluate these assays in an alternative testing strategy to the standard ELISA/western blot testing procedure. In each country. HIVCHEK was more sensitive and specific than ELISA when compared with western blot. The sensitivity of HIVCHEK ranged from 87.0 to 96.3% and the specificity from 99.0 to 100%. The sensitivity and specificity of serodia-HIV ranged from 85 to 98% and from 88 to 98%. respectively. The sensitivity and specificity were affected by the presence of HIV-2 in Ghana and Senegal. Overall. with an HIV-1 prevalence of 14.8% in Kenya and 22.5% in Zaire. the sensitivities of the alternative strategy were 96.4% and 91.4%. the specificities 99.6% and 100%. the positive predictive values 97.6% and 100%. and the negative predictive values 99.3% and 97.9% for Kenya and Zaire. respectively. With this testing format there was an estimated average cost saving of up to 82% over the conventional strategy with ELISA/western blot. This procedure constitutes a reasonable alternative to the standard ELISA/western blot combination.
Lipoinjection for unilateral vocal cord paralysis, Injection of Teflon paste is a commonly accepted procedure to improve the caliber of voice in unilateral vocal cord paralysis. There are several drawbacks to Teflon injection. among them respiratory obstruction (from overinjected Teflon) and unsatisfactory voice quality (Teflon causes stiffness of the vocal folds). This paper is a preliminary report on lipoinjection instead of Teflon injection into a paralyzed vocal fold. Fat appears to impart a soft bulkiness to the injected cord. while allowing it to retain its vibratory qualities. It is autologous material and can be retrieved if excessively overinjected. The fate of autologous fat injected into a paralyzed vocal cord remains unknown. Most of the literature on lipoinjection concerns repairs of depressed scars or breast augmentation. Our longest follow-up has been 12 months. Three patients have had this procedure. and the results appear to be very encouraging.
Basement-membrane thickening of the vocal cords in sudden infant death syndrome, Sudden infant death syndrome remains the leading cause of death in infants between the ages of 1 month and 1 year. Diagnosis at autopsy is usually reached by process of elimination. as no obvious cause of death is recognized. The larynges of 23 sudden infant death syndrome victims. as well as 6 infants and 3 fetuses who died of other known causes. were examined in this study. While thickening of the basement membrane of the vocal cords was apparent in all sudden infant death syndrome victims. no such finding was present in the larynges of infants and fetuses dying of other causes. Thus. it is suggested that basement-membrane thickening may serve as a diagnostic tool for identification of sudden infant death syndrome at autopsy.
Recurrent and/or metastatic head and neck squamous cell carcinoma: a clinical, univariate and multivariate analysis of response and survival with cisplatin-based chemotherapy, One hundred two patients with recurrent and/or metastatic head and neck squamous cell cancer were entered into four consecutive phase II trials. all cisplatinum (C-DDP. 100 mg/m2/cycle)-based. The two combinations tried were C-DDP. bleomycin. and fluorouracil (CFB) on 54 patients. and cisplatinum and vindesin in 36 patients (CV). The CFB combination was given with C-DDP by continuous infusion over 96 hours (23 patients) or on day 1 (31 patients). The CV regimen was also given in two different schedules. with VDS at 3 mg/m2/g weekly (12 patients) or by a 96-hour continuous infusion (0.6 to 1.0 mg/m2/d) in 24 patients. The following variables: sex. age. performance status. previous therapy. local recurrence. length of disease-free interval (DFI). distant metastases. weight loss. primary site. histological differentiation. type of chemotherapy. previous chemotherapy. evaluable/measurable disease. erythrosedimentation rate. and their relation with response to chemotherapy (WHO) and survival were submitted to both univariate and multivariate analysis (Cox). Overall response rate (RR:CR + PR) was 25 (28%) of 90. In the CFB protocols. RR was 12 (22%) of 54 vs. 13 (38%) of 36 (P = 0.15. NS) in the CV combination group. For the four different combinations the RR was CFB C-DDPci 7 (30%) of 23. CFB C-DDP 1 hour 5 (16%) of 31. CV VDS weekly 2 (17%) of 12. CV VDSci 11 (45%) of 24. The patient populations were very different. with the latest combination consisting of metastatic patients exclusively. Univariate analysis of multiple variables showed age less than 60 years. PS:0 or 1. no previous therapy. absence of local relapse. metastatic disease. long DFI. and that measurable disease was significant for the probability of response. Median survival was 7 months for the 90 evaluated patients. 5 months for nonresponders. and 9 months for responders (P = 0.01). In the univariate analysis. significant factors for survival were PS:0 or 1. a weight loss below 10%. long DFI. response to chemotherapy. erythrosedimentation rate (ESR) of less than 30 mm/1st hr. presence of bone metastasis. and the number of metastases. Multivariate analysis shows PS. the absence of local relapse. and disease-free interval as significant prognostic factors for response. Multivariate analysis factors of significance for survival were PS. weight loss. and response to chemotherapy. The analysis of the clinical pattern showed an evolution in RR from 3 (8%) of 36 on previously irradiated local recurrent disease to 8 (73%) of 11 in previously untreated patients with metastatic disease at presentation.(ABSTRACT TRUNCATED AT 400 WORDS).
Facial nerve regeneration through autologous nerve grafts: a clinical and experimental study, Human facial nerve regeneration was compared in two systems: autologous neural cable grafts (N = 56) and direct end-to-end anastomosis (N = 34). The data were analyzed based on the following criteria: facial symmetry and muscle tone at rest. degree of total facial reinnervation. voluntary motion. synkinesis. and electrophysiologic testing. Facial tone and symmetry at rest. and electrophysiologic tests were similar. while voluntary motion and facial reinnervation were decreased and synkinesis increased in the autologous cable graft repairs. Electrophysiologic tests failed to distinguish between the two repair methods in successful regenerates. Neural cable grafts were associated with more mass movement and less fine precise emotive facial movement. Excellent cable graft repair results diminish with time because of continual progressive synkinesis. which may take up to 4 years to develop. Eight-millimeter neural cable graft repairs of the buccal division of the facial nerve in rabbits (N = 8) demonstrate. at 5 weeks. equal myelinated and more unmyelinated axons than in the normal nerve controls. Neural cable graft repairs demonstrate two features not found in the normal nerve: 1. myelin debris and 2. two subpopulations of axons--extrafascicular and intrafascicular. Myelin debris predisposes towards extrafascicular axon regeneration. Extrafascicular axons are the major neurite regenerates (63%). Intrafascicular axons are the major reinnervators of the distal transected nerve stump. Electrophysiologic studies demonstrate decreased conduction velocities which are related to the number and size of myelinated axonal regenerates. The implications for neurite reinnervation of the autologous cable graft and their role in synkinesis are discussed.
The phenotype of the X-linked dystonia-parkinsonism syndrome. An assessment of 42 cases in the Philippines, The clinical phenotype of X-linked recessive torsion dystonia was documented in 42 affected individuals from 21 families. In 7 families. there were 9 sibships (core families) with 2 or more affected individuals available for evaluation. The ages of the patients ranged from 29 to 79 years with a mean of 46.2 +/- 10.1 years; the mean age of onset of dystonia was 35.0 +/- 8.0 years with a range of 12 to 48 years; and the mean duration of illness was 11.1 +/- 7.9 years. First manifestations were noted in the lower extremities in 36%. the axial musculature in 29%. the upper extremities in 23%. and in the head in 12% of the cases. The majority of patients displayed gait abnormalities (90%). leg dystonia (79%). oromandibular dystonia (64%). neck dystonia (57%). blepharospasm (57%). and truncal dystonia (52%). The disease generalized in 90% of the cases within 1 to 11 years of onset (median duration. 5 years). Overall. the condition was disabling. but the Fahn-Marsden disability score did not correlate with age of onset. duration of illness. site of onset. rate of generalization. or presence of parkinsonism. Thirty-six percent of the cases displayed at least 1 of the following "parkinsonian symptoms": bradykinesia. tremor. rigidity. loss of postural reflexes and a shuffling gait. Parkinsonism was diagnosed as definite in 14%. probable in 2%. and possible in 19% of the cases. Given this high association of dystonia and parkinsonism. we propose to call the disorder X-linked dystonia-parkinsonism syndrome (XDP).
Human infection with Salmonella dublin, Twenty-seven cases of human infection with Salmonella dublin were identified over a 12-year period at the University of California at San Diego-affiliated hospitals. Important epidemiologic risk factors were the ingestion of unpasteurized dairy products or treatment with nutritional therapy that included raw calf-liver extracts. Nearly all patients had underlying chronic diseases. Like Salmonella choleraesuis. S. dublin infections were associated with a high incidence of bacteremia (91%). metastatic sites of infection (30%). and mortality (26%) relative to other non-typhoidal Salmonellae. This pattern of disease expression may be related to a plasmid-encoded virulence factor common to both of these organisms.
Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current, BACKGROUND. Surgical or catheter ablation of accessory pathways by means of high-energy shocks serves as definitive therapy for patients with Wolff-Parkinson-White syndrome but has substantial associated morbidity and mortality. Radiofrequency current. an alternative energy source for ablation. produces smaller lesions without adverse effects remote from the site where current is delivered. We conducted this study to develop catheter techniques for delivering radiofrequency current to reduce morbidity and mortality associated with accessory-pathway ablation. METHODS. Radiofrequency current (mean power. 30.9 +/- 5.3 W) was applied through a catheter electrode positioned against the mitral or tricuspid annulus or a branch of the coronary sinus; when possible. delivery was guided by catheter recordings of accessory-pathway activation. Ablation was attempted in 166 patients with 177 accessory pathways (106 pathways in the left free wall. 13 in the anteroseptal region. 43 in the posteroseptal region. and 15 in the right free wall). RESULTS. Accessory-pathway conduction was eliminated in 164 of 166 patients (99 percent) by a median of three applications of radiofrequency current. During a mean follow-up (+/- SD) of 8.0 +/- 5.4 months. preexcitation or atrioventricular reentrant tachycardia returned in 15 patients (9 percent). All underwent a second. successful ablation. Electrophysiologic study 3.1 +/- 1.9 months after ablation in 75 patients verified the absence of accessory-pathway conduction in all. Complications of radiofrequency-current application occurred in three patients (1.8 percent): atrioventricular block (one patient). pericarditis (one). and cardiac tamponade (one) after radiofrequency current was applied in a small branch of the coronary sinus. CONCLUSIONS. Radiofrequency current is highly effective in ablating accessory pathways. with low morbidity and no mortality.
Immunomodulation of experimental allergic encephalomyelitis by antibodies to the antigen-Ia complex, Autoimmune diseases occur when T lymphocytes become activated on recognizing self antigen linked to the autologous class II molecule of the major histocompatibility complex (MHC). The resulting complex of antigen MHC T-cell receptor could be a target for treatment of autoimmune diseases. Studies in which each component is blocked separately might be limited by interference in non-relevant immune responses that either use the same set of T-cell-receptor V gene segments or are linked to the same MHC. We report here an attack by a specific antibody on the unique antigenic site formed by the binding of two components of the trimolecular complex. the autoantigen bound to the self MHC. We tested its effect in experimental allergic encephalomyelitis. an acute neurological autoimmune disease which is widely regarded as a model for autoimmune disorders and which is mediated by CD4+ T cells recognizing myelin basic protein (BP). or its peptides. in association with self Ia. We made monoclonal antibodies which bound only the complex of BP and I-As. These antibodies blocked the proliferative response in vitro to the encephalitogenic determinant of BP and reduced the response to intact BP. without affecting the response to a nonrelevant antigen-purified protein derivative of tuberculin presented on syngeneic macrophages. They also inhibited experimental allergic encephalomyelitis in H-2s mice. Hence. antibodies directed specifically to the autoantigen-Ia complex. may offer a highly selective and effective treatment in autoimmune diseases.
A randomized study of closure of the peritoneum at cesarean delivery, This study was conducted to test the hypothesis that nonclosure of the visceral and parietal peritoneum during low transverse cervical cesarean delivery is not associated with increased intraoperative or immediate postoperative complications. One hundred thirteen patients scheduled for low transverse cervical cesarean were randomized to either closure of both the visceral and parietal peritoneum with absorbable suture (N = 59) or no peritoneal closure (N = 54). Patients were cared for in the usual postoperative manner without reference to treatment group. There were no demographic differences between the groups and no differences in method(s) of anesthesia. operative indication(s). or use of peripartum epidural narcotics. The incidence of fever. endometritis. or wound infection was similar between groups. There were no differences in the number of patients requiring parenteral narcotic analgesia or in the number of doses per patient. The number of oral analgesic doses was significantly greater with closure than without (P = .014). The frequency with which postoperative ileus was diagnosed in each group was similar. and there was no difference regarding the day on which patients were advanced to liquid or select diets. Bowel stimulants were administered more frequently to the closure than to non-closure patients (P = .03). The average operating time was shorter for the open group than for the closure group (P less than .005). We conclude that non-closure of the visceral and parietal peritoneum at low transverse cervical cesarean delivery appears to have no adverse effect on immediate postoperative recovery. may decrease postoperative narcotic requirements. allows less complicated return of bowel function. and provides a simplified and shorter surgical procedure.
Monoamniotic twins: a retrospective controlled study, Monoamniotic twins are uncommon but are at high risk (reportedly 50%) for perinatal death. commonly from cord accidents. Until recently the diagnosis of monoamniotic twinning was seldom made before delivery. but modern ultrasound technology permits diagnosis during prenatal care. creating a management dilemma. This is a report of the experience with monoamniotic twins of 20 or more weeks' gestation at the University of Iowa Hospitals from 1961-1989. Twenty monoamniotic twin pregnancies were compared with 40 monochorionic. diamniotic controls regarding antepartum and intrapartum complications. Overall. monoamniotic twins were delivered earlier. were more likely to die in utero. and had lower birth weights than diamniotic twins. When only live-born twins were considered. however. there were no differences in gestational age at delivery. birth weight. or 5-minute Apgar scores. No fetal death occurred after 32 weeks. suggesting that prophylactic preterm delivery may not be indicated in all cases. Labor and vaginal delivery were not associated with an increased risk of fetal death.
Cellular immunity in preeclampsia: alterations in T-lymphocyte subpopulations during early pregnancy, T-lymphocyte subpopulations were evaluated longitudinally in 62 primigravidas. Beginning early in the second trimester. women who later developed preeclampsia showed a significantly lower proportion of T-helper cells compared with those who remained normotensive (27.0 +/- 7.1 versus 34.7 +/- 7.9%; P less than or equal to .001). The decrease in the T-helper cell count occurred several weeks before the development of preeclampsia and reverted to normal 6-10 weeks postpartum.
Prolonged third stage of labor: morbidity and risk factors, Although retained placenta is a major cause of postpartum hemorrhage. there is no general agreement regarding when manual placental extraction is indicated to prevent hemorrhage. We sought to determine the following: 1) what duration of the third stage of labor is abnormal. 2) what duration is associated with complications. and 3) what antecedent conditions are associated with prolonged third stage. We studied 12.979 consecutive. singleton vaginal deliveries over an 11-year period. Third-stage duration had a log-normal distribution. with a geometric mean of 6.8 minutes. a median of 6 minutes. and an interquartile range of 4-10 minutes. A third stage of 30 minutes or longer occurred in 3.3% of the deliveries. The incidence of postpartum hemorrhage. transfusion. and D&C remained constant in third stages less than 30 minutes. then rose progressively. reaching a plateau at 75 minutes. The increase in these complications after 30 minutes was observed with both spontaneously delivered and manually extracted placentas. In a logistic regression analysis. factors significantly associated with prolonged third stage included: preterm delivery (odds ratio 3.81). delivery in a labor bed (odds ratio 2.17). preeclampsia (odds ratio 1.76). augmented labor (odds ratio 1.47). and nulliparity (odds ratio 1.45). Because there was no increase in hemorrhage until the third stage exceeded 30 minutes. we suggest that in the absence of bleeding. manual placental extraction is not indicated until 30 minutes have elapsed.
Plasma oxytocin but not prostaglandin F2 alpha metabolite levels at cerclage may predict preterm delivery, Plasma oxytocin and prostaglandin F2 alpha metabolite (PGFM) concentrations were measured in 45 patients admitted for cerclage during the second trimester. Samples were collected before. 3 hours after. and 3 days after the Shirodkar procedure. Uterine activity was recorded by external tocography twice daily for 30 minutes. Twenty-eight women with uncomplicated pregnancy and commensurate gestational age served as controls. Cervical length. measured by ultrasonography. was significantly shorter before cerclage (36 +/- 2 mm) than after cerclage (43 +/- 2 mm) or compared with controls (48 +/- 1 mm). Bishop scores ranged from 3-6 (median 4) in the cerclage group and 0-1 (median 0) in controls. Fifteen cerclage patients and one control delivered preterm 5-22 weeks after the procedure. Initial plasma PGFM levels were significantly higher in cerclage patients than in controls. The cerclage procedure caused an immediate rise in plasma PGFM and a subsequent fall below initial levels to control values. Neither the initial levels of PGFM nor the increments 3 hours after cerclage correlated with the outcome of pregnancy. By contrast. plasma oxytocin levels before cerclage were significantly higher in patients who subsequently delivered preterm than in those who delivered at term. Cerclage resulted in a significant fall in plasma oxytocin at 3 hours in patients with preterm delivery. but after 3 days the oxytocin levels had returned to the precerclage values. Patients who had increased uterine contractions had significantly higher plasma oxytocin levels but lower PGFM levels than those without contractions.
The histologic reliability of laser cone biopsy of the cervix, Laser conization of the cervix has been advocated as the technique of choice for the treatment of cervical intraepithelial neoplasia (CIN) in preference to ablative techniques. because it provides a specimen for histologic diagnosis while retaining the advantages of an outpatient procedure with minimal short- and long-term morbidity. To determine whether specimens so obtained are adequate for reliable histologic diagnosis. we reviewed 77 laser conizations performed for lesions confirmed to contain CIN in a colposcopically directed biopsy and satisfying the criteria for local ablation and scored the cones for the presence of epithelial denudation and laser coagulation artifact that interfered with the diagnosis of CIN or the assessment of the margins of excision. Thirty specimens (39%) were negative for CIN. Twenty-eight (36%) showed extensive epithelial denudation. ten (13%) contained coagulation artifact that made recognition of CIN extremely difficult or impossible. and in 11 (14%). assessment of margins was extremely difficult or impossible because of laser coagulation artifact. We conclude that these difficulties with the histologic interpretation of laser cone specimens make it an unsuitable excisional technique when reliable histologic diagnosis of cervical lesions is required.
A comparison of adenocarcinoma and squamous cell carcinoma of the cervix, A comparison and survival analysis of 203 patients (21%) with adenocarcinoma and 756 (79%) with squamous cell cancer of the cervix for the time period 1970-1985 is reported. The mean number of new cases of adenocarcinoma (N = 12) remained the same. while squamous cell cases decreased from 57 to 32. The clinical features were compared; oral contraceptive usage. node status. diabetes. and symptoms of bleeding were not related to cell type. Nulliparity was more frequent in patients with adenocarcinoma. whereas obesity and smoking were more frequent in patients with squamous cell cancer. Survival in stage I was significantly influenced by the cell type. Patients with stage I squamous cell disease had a 90% 5-year survival. compared with 60% for adenocarcinoma (P less than .0001). Other features that influenced survival included node status (P = .001). poor differentiation of tumor histology (P = .001). diabetes (P = .001). and Papanicolaou smear interval (P = .001). Patients undergoing radical hysterectomy were analyzed separately. and adenocarcinoma cell type significantly influenced survival (P = .0008). Patients with stage II squamous cell disease had a 62% survival. compared with 47% for adenocarcinoma (P = .01); patients with stage III squamous cell disease had a 36% survival. compared with 8% for adenocarcinoma (P = .002). The percentage of adenocarcinoma has increased because of the decreased number of patients with squamous cell disease. Stage-for-stage survival is significantly decreased for patients with adenocarcinoma as opposed to squamous cell disease.
Autoantibodies associated with endometriosis: can their detection predict presence of the disease, To evaluate the usefulness of autoantibody detection as a nonoperative method of diagnosing endometriosis. we tested 221 sera from 215 patients from the infertility. gynecology. and gynecologic oncology services by an indirect immunofluorescence assay using monolayer cultures of an endometrial carcinoma cell line. The assay showed positive cytoplasmic staining. demonstrating a sensitivity of 83% in the patients with laparoscopically confirmed endometriosis. The specificity of the assay was 65% for the infertility patients and 76% for the infertility and gynecology patients combined. Several gynecologic cancer patients showed either nuclear or nuclear and cytoplasmic staining. but few showed exclusive cytoplasmic staining. These initial results suggest that detection of antibodies might be useful for the diagnosis of endometriosis.
Serum levels of CA 125 are elevated in patients with active systemic lupus erythematosus, Levels of CA 125 were measured in the serum of 37 female patients with systemic lupus erythematosus. The patients were classified into two groups according to the absence or presence of signs of disease activity: inactive (N = 9) and active disease (N = 28). CA 125 levels were higher in the group of patients with active disease. In the remission group the median was 9 U/mL (range 4-132). whereas in the group of patients with active disease. the median was 18 U/mL (range 2-272). Among patients with active disease. values higher than the generally accepted upper limit of 35 U/mL were found in ten of 28 cases.
Abdominal-retroperitoneal sacral colpopexy for the correction of vaginal prolapse, Complete genital or vaginal prolapse affects a large number of middle-aged to elderly females. Satisfactory correction of prolapse with maintenance of vaginal patency has been a challenge to the pelvic surgeon for many years. We present a retrospective review of 147 patients undergoing abdominal sacral colpopexy using dacron graft or expanded polytetrafluoroethylene. The anatomical basis of repair. operative technique. and results are described. Ninety-three percent of the patients experienced long-term success over 5 years. including those with previous failed repairs. Both short- and long-term complication rates were acceptable. Only four patients experienced graft erosion. and only one of those had recurrent prolapse. Abdominal sacral colpopexy offers those affected with genital prolapse an opportunity for long-term relief. with maintenance of a patent vagina.
Pipelle endometrial sampling in patients with known endometrial carcinoma, The purpose of this prospective clinical trial was to determine the reliability of the Pipelle endometrial biopsy instrument in recovering adequate tissue for confirmation of the diagnosis of endometrial cancer in patients with known endometrial carcinoma. and to compare endometrial histology of the sampling specimen with that of the subsequent hysterectomy specimen. Forty patients were enrolled in this study. All biopsies were performed in the office without anesthesia. The patients had a median age of 62 years (range 40-83). Discomfort was reported by the patient as mild. moderate. or severe; only two patients (5.0%) reported severe pain. There were no complications experienced with endometrial sampling. Thirty-nine of 40 specimens (97.5%) confirmed endometrial carcinoma; therefore. this study yielded a 97.5% sensitivity for the Pipelle endometrial sampling device. Comparing Pipelle and hysterectomy histology for individual patients. the histologic grade was the same in 29 (74.4%). while the Pipelle demonstrated a more advanced degree of differentiation in five (12.8%) and a lesser degree in five (12.8%). There was no residual tumor identified in one hysterectomy specimen (2.5%). Among the 12 patients who had a D&C for diagnostic purposes before referral. the Pipelle biopsy correlated with the D&C histology in ten of 12 (83.3%) and revealed a more advanced grade of tumor in one (8.3%) and a more differentiated grade in one (8.3%). In one patient. the D&C histology was adenocarcinoma grade 1. with the Pipelle demonstrating atypical hyperplasia and the hysterectomy specimen interpreted as endometrial adenocarcinoma in situ. This study demonstrates the Pipelle to be an accurate device for endometrial sampling in patients with endometrial carcinoma.
Combined relaxing incisions and epikeratophakia for the correction of aphakia and high postkeratoplasty degree astigmatism, A combined surgical procedure consisting of corneal relaxing incisions and epikeratophakia was used to correct high-degree postkeratoplasty astigmatism and aphakia in two patients. Both patients achieved their final refractive result as soon as 1 month after suture removal (2 and 3 months after surgery. respectively). Keratometric readings showed a reduction of approximately 20.00 diopters in one case and 10.00 D in the other. while the spherical equivalent changed from +10.00 D to +0.50 D in one eye and from +7.50 D to +1.75 D in the other. Spectacle correction was prescribed for both patients. At the last follow-up visit. about 2 years after surgery. these values were unchanged. The main advantage of the combined technique over two separate procedures was that postoperative visual rehabilitation was faster. Equally important was the stability of the refractive result over a long period of time after surgery. as well as the absence of negative effects on the preexisting corneal graft. In spite of the technical complexity of a combined surgical procedure. this approach probably represents the best choice in rare cases such as the ones reported here.
Nocardia asteroides infection following scleral buckling, We report a case of delayed external ocular Nocardia asteroides infection following scleral buckling for rhegmatogenous detachment. Surgical removal of the exoplant material allowed isolation and identification of the organism. Topical and systemic antibiotic therapy following exoplant removal yielded a favorable result.
Crescentic resection for the treatment of pellucid corneal marginal degeneration, The left eye of a patient with bilateral pellucid marginal corneal degeneration was treated by crescentic resection of the affected part. The treatment. while it has not been monitored over the long term. appears to have many advantages over penetrating keratoplasty.
Comparison between the effect of two different widths of circular lamellar keratectomy on refraction and corneal curvature in rabbits' eyes, Twenty rabbits' eyes were subjected to circular lamellar keratectomy. Two trephines were used to mark rings at a depth of 0.3 mm. and the lamellar cornea in between was removed. A 1-mm-wide ring was removed from the right eyes. and a 0.5-mm-wide ring from the left ones. We found that removing a 1-mm ring more effectively corrected hypermetropia (3.09 +/- 1.72 diopters) than removing a 0.5-mm ring (1.81 +/- 0.95 D).
Pigmented pupillary pseudomembranes as a complication of argon laser iridotomy, Two cases are reported in which pupillary pigment occlusion occurred after argon laser iridotomy. reducing visual acuity and preventing fundus visualization. Laser-induced inflammation and subsequent long-term miotic therapy are probably responsible for this complication. Periodic pupillary dilatation is recommended in eyes that require miotics to control their intraocular pressure after laser iridotomy.
The partial dissection trabeculectomy, We retrospectively reviewed the results of the first 20 procedures of a modification of the penetrating trabeculectomy ab externo procedure in which an attempt is made to limit subconjunctival fibrosis at the filtering site. With a follow-up ranging from 2 to 29 months. the average intraocular pressure was reduced from 33 to 12 mm Hg.
Coping and adaptation in children with diabetes, The purpose of this study was to investigate the influence of age. coping behavior. and self-care on psychological. social. and physiologic adaptation in preadolescents and adolescents with diabetes. Children (N = 103) with insulin-dependent diabetes mellitus (IDDM) between 8 and 18 years of age and their parents participated in the study. Findings indicated that preadolescent children were significantly less depressed. less anxious. coped in more positive ways. had fewer adjustment problems. and were in better metabolic control than their adolescent counterparts. Age and secondary sexual development were related to psychosocial adaptation and metabolic control of the diabetes. Further. those who coped by avoiding their problems and who were more depressed were the most likely to have problems in both adjustment and metabolic control with 56% of the variance in metabolic control explained by the variables studied. These findings indicate that preadolescents and adolescents cope differently with a chronic illness. and that interventions should be designed to identify and help those with inappropriate coping styles.
Acoustic discrimination of three types of infant cries, The ability of acoustic characteristics. both separately and in linear combination with others. to differentiate among procedural pain-induced. hungry. and fussy crying was explored using audiorecordings of cries from healthy 2 to 4-month-old infants. Fussy cries were less tense than hungry or pain-induced cries and pain-induced cries had significantly stronger second formant amplitudes than fussy or hungry cries. Formants and tenseness were important contributors to a linear combination of acoustic measures. derived from discriminant function analysis. which correctly classified 74% of the procedural pain-induced crying specimens. The inability of this linear combination of acoustic measures to identify correctly approximately one-third of the cry specimens suggests that the discrete acoustic differences among the three situationally defined types of crying is not large.
Uncertainty in gynecological cancer: a test of the mediating functions of mastery and coping, The purpose of this study was to test a portion of the uncertainty in illness model to determine whether mastery would be strengthened or weakened under conditions of uncertainty. and to test the ability of mastery and coping to function as mediators in the model. Mastery was proposed to mediate the relationship between uncertainty and the appraisal of danger and opportunity. Coping was proposed to mediate the relationships between danger or opportunity and emotional distress. Data were collected on a sample of 131 women receiving treatment for gynecological cancer. Findings support mastery as weakened under conditions of uncertainty and functioning as a situationally specific personality factor. Mastery was a significant mediator of the relationship between uncertainty and the appraisal of danger and opportunity; although the mediation effect for the relationship between uncertainty and danger was stronger. While two coping strategies were found to function as significant mediators between danger or opportunity and emotional distress. the mediation effect was very small.
The prevalence of substance abuse among registered nurses, The purpose of this research was to estimate the prevalence of substance abuse and depression among a population-based sample of registered nurses. In addition. to estimate the degree to which substance abuse and depression were associated with nurses. a comparison was made between nurses and other employed individuals. Respondents were obtained from a probability sample of households that were part of the National Institute of Mental Health Epidemiologic Catchment Area Program (ECA). Of the adults interviewed as part of the ECA. 143 were under age 65 and currently working as registered nurses. These nurses were matched by neighborhood of residence (census tract) and gender to a comparison group of non-nurses from the ECA who were also employed at the time of interview. Estimates of the odds of substance use and depression among the nurses (n = 143) and non-nurses (n = 1410) were calculated. Nurses were no more likely to have engaged in illicit drug use or to have experienced depression than non-nurses. Nurses were also less likely to have experienced problems with alcohol abuse than non-nurses.
Nonsteroidal anti-inflammatory drugs and peptic ulcer disease. An overview, Evidence is accumulating that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is linked to ulceration of the stomach and duodenum and can cause significant. life-threatening ulcer complications. The mechanism of action seems to be both topical damage to the mucosal barrier and the systemic effect of a reduction in levels of mucosal prostaglandins. Patients especially at risk are the elderly. those with concomitant debilitating disease. those with a history of ulcers. and those taking corticosteroids. Histamine2 blockers are reported to significantly reduce the incidence of NSAID-induced duodenal ulcer. and misoprostol (Cytotec) has been shown to significantly reduce the incidence of NSAID-induced gastric ulcer. Prophylaxis with these agents should be considered for high-risk patients who need NSAID therapy to maintain a reasonable life-style.
Gastroesophageal reflux disease. When antacids aren't enough, Gastroesophageal reflux disease is a very common condition that is usually manifested by heartburn or regurgitation. Reflux esophagitis. caused by mucosal exposure to the backflow of caustic gastric contents. is primarily a result of lower esophageal sphincter dysfunction. Diagnostic workup varies but commonly includes esophagoscopy. 24-hour esophageal pH monitoring. and radiography of the upper gastrointestinal tract. Treatment. which progresses from simple life-style changes and antacids to histamine2 receptor antagonists to omeprazole (Prilosec) or surgery. is tailored to individual needs and is generally successful.
When migraine is more than a headache. Stroke in a young patient, Stroke rarely occurs in a young patient with migraine. Nevertheless. vascular headache can lead to catastrophic neurologic consequences. and severe headache associated with persistent neurologic deficits poses a complex diagnostic problem.
Recent developments in the diagnosis and management of patients with transient ischaemic attacks and minor ischaemic strokes, Appropriate management of the patient with transient focal neurological symptoms must start with accurate clinical diagnosis. Wider use of clear diagnostic criteria and symptom checklists. and better knowledge of the clinical features of the 'funny turns' which are not related to transient focal cerebral ischaemia could reduce the present variability in clinical diagnosis of transient ischaemic attacks. More accurate clinical diagnosis contributes to better selection of the most appropriate investigation strategy for each patient. A basic minimum standard of investigation is outlined and perhaps provides a suitable template for audit. Patients with transient ischaemic attacks which are definitely in the carotid distribution may be eligible for entry in trials of carotid endarterectomy. Prudent use of duplex ultrasound studies of the carotid arteries in patients with appropriate symptoms is an effective way to reduce the costs of investigations and their complications (i.e. the number of strokes associated with cerebral angiography). Digital venous subtraction angiography has. by comparison. many disadvantages as a screening tool. Advances in management include: recent statistical overviews which have emphasized the need to consider blood pressure and plasma cholesterol reduction in a large proportion of patients. and the value of long term anti-platelet therapy in reducing the risks of stroke. myocardial infarction and vascular death in both males and females. The value of anticoagulants in patients with atrial fibrillation and transient ischaemic attacks or minor stroke is being tested in current trials.
Low-dose cyclopenthiazide in the treatment of hypertension: a one-year community-based study, After an 8-week placebo period. 73 patients whose diastolic blood pressures were between 90 and 110 mmHg were randomly assigned to receive 125 micrograms (low dose) or 500 micrograms of cyclopenthiazide (standard dose) for a period of one year. Blood pressure was measured in the patient's home by the same observer at two-weekly intervals during an 8-week placebo run-in period. every 4 weeks for a further 12 weeks and at 24. 36 and 52 weeks thereafter. Serum potassium. urate. glucose. glycosylated haemoglobin. total and HDL cholesterol. and apolipoproteins were measured at the end of the placebo period and at 4. 8. 24 and 52 weeks of active treatment. Twelve of the 73 patients had an inadequate antihypertensive response--five on the higher dose and seven on the lower dose. One patient receiving 500 micrograms was withdrawn because of adverse effects. In the remaining 60 patients. systolic and diastolic blood pressures were significantly reduced when compared with pretreatment values in both treatment groups throughout the one year period. The decreases in blood pressure were not significantly different from each other (p greater than 0.65). Three patients on 500 micrograms required potassium supplements. Maximum decreases in the serum potassium of 0.52 mmol/l (500 micrograms dose) and 0.14 mmol/l (125 micrograms dose) were observed at 24 weeks of treatment in the remaining 57 patients. The differences between the two doses at this time were statistically significant (p less than 0.05). as were the increases in serum urate observed at 4. 8 and 24 weeks (p less than 0.05).
Effect of recombinant alpha 2 interferon with or without prednisone in Chinese HBsAg carrier children, Ninety Chinese hepatitis B surface antigen (HBsAg) carrier children. aged 2-17 years. positive for hepatitis B e antigen (HBeAg) and hepatitis B virus DNA on at least three occasions in 6 months. were randomized into 3 groups. Thirty children received syrup vitamin B complex as control. 29 received 6 weeks of placebo syrup followed by 16 weeks of recombinant alpha 2b-interferon [intron A (rIFN2b)]. 5 x 10(6) u/m2 subcutaneously thrice weekly; and 31 received 6 weeks of syrup prednisone (0.6 mg/kg tailed to 0.2 mg/kg) followed by 16 weeks of recombinant alpha 2b-interferon as above. The placebo/prednisone syrup was given on a double-blind basis. At 24 months of follow-up. persistent loss of hepatitis B virus DNA occurred in none of the children in the control group. in one child receiving recombinant alpha 2b-interferon alone. who also seroconverted to anti-HBe and anti-HBs and in five children receiving interferon with steroid priming (p = 0.0571 compared with controls). with four seroconverting to anti-HBe and one also seroconverting to anti-HBs. A rise of transaminases to above twice the upper limit of normal levels during the first 7 months of follow-up occurred in one subject in the control group. four in the group receiving alpha 2b-interferon alone and nine in the group receiving recombinant alpha 2b-interferon with steroid priming (p = 0.0144 compared with controls). Side effects of the steroid were negligible; those of recombinant alpha 2b-interferon were transient and acceptable. We conclude that 6 weeks of prednisone followed by 16 weeks of recombinant alpha 2b-interferon is of use in inducing persistent loss of hepatitis B virus DNA (16.1 per cent) and e-seroconversion (12.9 per cent) in a proportion of Chinese HBsAg carrier children: the prednisone probably enhances the immunomodulatory effect of recombinant alpha 2b-interferon.
Hypomagnesaemia in elderly hospital admissions: a study of clinical significance, Serum magnesium estimations carried out on 1576 consecutive elderly patients at the time of hospital admission revealed that 10.7 per cent had a serum magnesium level below 0.7 mmol/l. with 4.4 per cent of the total having a serum level less than 0.65 mmol/l. Hypokalaemia was frequently associated with hypomagnesaemia. for which diuretic therapy was the most commonly found predisposing factor. Outcome of illness. measured at six months in terms of mortality. duration of hospital stay and percentage of patients discharged from hospital. was no worse in patients admitted with hypomagnesaemia than in normomagnesaemic controls.
Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome, The fragile X syndrome. a common cause of inherited mental retardation. is characterized by an unusual mode of inheritance. Phenotypic expression has been linked to abnormal cytosine methylation of a single CpG island. at or very near the fragile site. Probes adjacent to this island detected very localized DNA rearrangements that constituted the fragile X mutations. and whose target was a 550-base pair GC-rich fragment. Normal transmitting males had a 150- to 400-base pair insertion that was inherited by their daughters either unchanged. or with small differences in size. Fragile X-positive individuals in the next generation had much larger fragments that differed among siblings and showed a generally heterogeneous pattern indicating somatic mutation. The mutated allele appeared unmethylated in normal transmitting males. methylated only on the inactive X chromosome in their daughters. and totally methylated in most fragile X males. However. some males had a mosaic pattern. Expression of the fragile X syndrome thus appears to result from a two-step mutation as well as a highly localized methylation. Carriers of the fragile X mutation can easily be detected regardless of sex or phenotypic expression. and rare apparent false negatives may result from genetic heterogeneity or misdiagnosis.
Fragile X genotype characterized by an unstable region of DNA, DNA sequences have been located at the fragile X site by in situ hybridization and by the mapping of breakpoints in two somatic cell hybrids that were constructed to break at the fragile site. These hybrids were found to have breakpoints in a common 5-kilobase Eco RI restriction fragment. When this fragment was used as a probe on the chromosomal DNA of normal and fragile X genotype individuals. alterations in the mobility of the sequences detected by the probe were found only in fragile X genotype DNA. These sequences were of an increased size in all fragile X individuals and varied within families. indicating that the region was unstable. This probe provides a means with which to analyze fragile X pedigrees and is a diagnostic reagent for the fragile X genotype.
Weight-loss practices of overweight adults, Data from the Behavioral Risk Factor Surveillance System. 1985-1988. were used to assess differences in weight-loss practices of overweight adults by sex and race. Data were available for 112.108 respondents from 21 states. aged greater than or equal to 18 y. Overweight was defined as body mass index greater than or equal to 27.3 for women and greater than or equal to 27.8 for men. Weight-loss practices were defined as increasing physical activity only. eating fewer calories only. increasing physical activity and eating fewer calories only. increasing physical activity and eating fewer calories. and not trying to lose weight. The weight-loss practice most frequently reported by overweight women was increasing physical activity and eating fewer calories (blacks. 32%; whites. 33%). Overweight men most frequently reported not trying to lose weight (blacks. 55%; whites. 49%). Although the prevalence of overweight for black women was twice that for white women. weight-loss practices were similar for both groups. Prevalence of overweight was similar for black and white men but weight-loss practices differed slightly.
Prevalence of overweight and obesity in US Hispanic populations, Previous studies showed that Hispanics have higher levels of overweight and obesity than do US whites. The Hispanic Health and Nutritional Examination Survey (1982-1984) provides the basis for examining the physical characteristics of this population on a wider scale than previously possible. Data for body mass index (BMI; weight/height2) and triceps and subscapular skinfold thicknesses were examined for the 7052 Mexican Americans. 1307 Cubans. and 2690 Puerto Ricans for whom each of these measurements were available. Prevalence of obesity and overweight was defined as BMI in excess of the 95th and 85th percentiles. respectively. of US reference standards. In male adults prevalence values were. respectively. 10.6% and 33.5% for Mexican Americans. 9.6% and 31.3% for Puerto Ricans. and 9.0% and 34.0% for Cubans. In female adults prevalence values were. respectively. 15.1% and 42.3% for Mexican Americans. 7.8% and 40.7% for Puerto Ricans. and 15.0% and 38.2% for Cubans. Skinfold-thickness data for these populations indicate a centralized distribution of adipose tissue. especially in males. and increased subscapular skinfold thicknesses in older women.
Obesity in Mexican American subgroups: findings from the San Antonio Heart Study, This study describes the prevalence of overweight in 2013 Mexican Americans and 928 non-Hispanic whites. aged 25-65 y. who participated in phase 2 of the San Antonio Heart Study. 1984-1988. and examines differences in overall obesity and body fat distribution among diverse Mexican American subgroups defined by neighborhood. socioeconomic status (SES). and assimilation to mainstream US society. Prevalence of overweight was greater in Mexican Americans than in non-Hispanic whites. and the ethnic difference was greater in women than in men. In Mexican Americans the effects of SES and assimilation on overall obesity and body fat distribution differed by sex group. In men SES and cultural assimilation were associated with less favorable body fat distribution. In women SES and assimilation were associated with lower overall obesity and more favorable body fat distribution. Interventions to reduce obesity in Mexican Americans should take these subgroup differences into account.
Obesity in the Pima Indians: its magnitude and relationship with diabetes, Members of the Pima Indian population are obese. on average. as estimated by the body mass index (BMI). Young adults have had the highest BMIs and there have been modest increases in age- and sex-specific mean BMIs for the past 25 y. These observations suggest that the older adults have had less exposure to factors leading to obesity than have the younger adults. Compared with children studied early in this century. present-day Pima children are much heavier for height. suggesting that the degree of obesity has increased since that time. Obesity in the Pimas is familial and has complex relationships with non-insulin-dependent diabetes mellitus. a common disease in this population. Obesity predicts the development of diabetes; once people have diabetes. however. they tend to lose weight. Thus. obesity should not be studied in this population without also considering diabetes. which tends to limit the degree of obesity.
Body fat and obesity in Japanese Americans, In 1965 a prospective study of greater than 12.000 Japanese men 45-69 y old and living in Japan. Hawaii. and California was initiated. Among the factors measured were height. weight. skinfold thicknesses. and 24-h dietary recall. The mean body mass index (BMI) was substantially lower for Japanese men in Japan than for Japanese men in California or Hawaii for each 5-y age group. Mean BMIs in Hawaii and California were similar. Values for subscapular skinfold thickness were also lower in Japan than in Hawaii or California in all age groups. Although total caloric intake was not greatly different between Japan and Hawaii. the percent caloric intake as fat was two times greater in Hawaii. Thus. these largely first- and second-generation immigrants exhibit increases in body weight that could be expected to significantly affect cardiovascular risk factor levels and endpoints.
Current understanding of the etiology of obesity: genetic and nongenetic factors, Four types of human obesities are defined by topography of fat deposition. The focus of the paper is on the genetic determinants and the nongenetic correlates of the first type. which is commonly defined as excess weight-for-height or excess body fat without a particular concentration of fat in a given area of the body. The heritability of fat mass or percent body fat derived from underwater-weighing assessment of body density reaches approximately 25% of the age- and gender-adjusted phenotypic variance. The within-identical-twin-pair resemblance in the response to a standardized overfeeding protocol emphasizes the importance of the genotype in determining individual differences in body weight and body composition. In this regard. the proneness to store energy primarily as fat or as lean tissue is a major determinant of the response to a caloric surplus.
Is race associated with weight change in US adults after adjustment for income, education, and marital factors, We examined the 10-y change in body mass index (BMI. in kg/m2) of black and white adults who entered the First National Health and Nutrition Examination Survey Epidemiologic Followup Study at ages 25-44 y. In women the mean change in BMI was greater for blacks than for whites despite multiple adjustments. However. the risk of major weight gain (MWG; BMI change greater than or equal to + 5) was nearly identical in black and white women. Womens' MWG was independently associated with low income [odds ratio (OR) = 1.7] and with becoming married (OR = 1.8). The risk of major weight loss (MWL; BMI change less than or equal to -2.5) was lower in black women than in white women (OR = 0.6). In men mean BMI change. MWG (BMI change greater than or equal to + 4) and MWL (BMI change greater than or equal to -2) were not associated with race. but there were effects associated with low income. low education. and marital changes. Black race does not increase the risk of weight gain; in women it may be associated with a reduced likelihood of weight loss.
Predictors of obesity in Mexican Americans, Excess body weight is a risk factor for morbidity and mortality in several studies. The etiology of obesity is. however. poorly understood. We examined the ability of selected behavioral variables to predict weight gain (greater than 6.8 kg) in the San Antonio Heart Study. a population-based study of diabetes and cardiovascular disease in Mexican Americans and non-Hispanic whites. However. we were unable to confirm an effect of dietary variables or level of physical exercise in predicting future obesity in Mexican Americans. To some degree this may be because of the imprecision of the 24-h-dietary-recall technique and the dietary behavior and exercise questionnaires.
Studies of the etiology of obesity in Pima Indians, Studies have been conducted on various metabolic characteristics of lean and obese Pima Indians. including studies of fat-cell morphology. glucose transport. and lipolysis; lipoprotein lipase activities; sodium-potassium ATPase in red cells. adipocytes. and fibroblasts; lipids and lipoprotein metabolism; fatty acid metabolism; and sterol balance. Insulin concentrations. insulin binding. insulin action on glucose disposal. fatty acid metabolism. and islet function were compared in lean and obese individuals. and the relationship between insulin resistance and muscle morphology was explored. To explore potential abnormalities in energy balance. calorie intake and gastric emptying were compared in lean and obese Pimas and measurements of energy expenditure were performed. The data suggest that there are multiple metabolic differences that accompany obesity in Native Americans. A lower metabolic rate was a determinant of future weight gain. and abnormalities in use of free fatty acids and cell insulin action were suggested. which emphasize the need for further studies in these areas.
Obesity in Samoans and a perspective on its etiology in Polynesians, For Samoans. modernization produces obesity and adiposity and concomitant increases in cardiovascular disease risk factors and outcomes. Massive adiposity and high prevalence of obesity characterizes modernizing adult Samoans. Mean body mass index (in kg/m2) at ages 25-54 y is 30-32 for males and 32-36 for females. Prevalence of overweight in female adults is 46% in traditional Western Samoans and 80% in migrants in Hawaii. Five-year longitudinal data show striking weight and fat gain. especially in younger adults and females. An evolutionary perspective on Polynesian adiposity is based on scenarios of the fates of sailors on the voyages of discovery and of settlers in the pioneer island villages. Efficient metabolisms producing rapid adipose-tissue growth could have increased survival among the first Polynesians. Rapid dietary and physical activity changes caused by modernization interacting with such population genetic predispositions may lead to the documented massive adiposity.
Population perspectives on the prevention and treatment of obesity in minority populations, Possible causes of population differences in obesity prevalence are discussed: biologic susceptibility. treatment availability or effectiveness. and shared behavior patterns leading to caloric imbalance. It is argued that obesity in minority groups in the United States is best understood as a variation on a larger cultural theme. the creation of an environment in which highly palatable foods are accessible to all at low cost and physical activity is not required. Inequities in access to health education. treatment services. and environmental opportunities are probably responsible for the exacerbation of obesity and its attendant health conditions in some minority groups. Programs for the prevention of obesity in minority populations need to address these inequities and also to consider ways to counteract the historical trends in the United States toward nutritional excess in the population as a whole.
Obesity prevention, Given the increased risk of overweight and the fact that many weight-related behaviors acquired during childhood and adolescence are likely to be maintained into adulthood. minority teen-agers are a key group to target for obesity-prevention efforts. This paper reflects on three theoretical elements of behavior change in relation to obesity-related knowledge. attitudes. and food behaviors of minority groups in the United States. and it summarizes the status of individual-. family-. school-. and environment-based efforts to prevent or treat obesity in minority adolescents.
Cuidando El Corazon--a weight-reduction intervention for Mexican Americans, Cuidando El Corazon (CEC; Taking Care of Your Heart) was designed to assess the effectiveness of a culturally adapted weight-reduction and exercise program for achieving long-term weight loss in Mexican Americans. CEC used a family-oriented approach to achieve lifestyle change in behavior. Participants were assigned to 1) a booklet-only comparison group that received a manual including behavior change. nutrition. and exercise information and traditional recipes modified in fat content; 2) an individual group that received the same manual and attended year-long classes; or 3) a family group that received a manual and attended classes that emphasized techniques for making changes in the family's eating and exercising habits. The family and individual groups had significantly greater weight losses than the information-only group. Weight loss was greatest in the family-involvement group and least in the information-only comparison group.
Community-based exercise and weight control: diabetes risk reduction and glycemic control in Zuni Indians, Cardiovascular disease is a significant health problem for the Zuni Indians of southwest New Mexico. in part because of high rates of non-insulin-dependent diabetes mellitus (NIDDM). The Zuni Diabetes Project was initiated in July 1983 to reduce rates of obesity and provide primary and secondary prevention of NIDDM. Two studies of the project's activities have been carried out to date. After 2 y of follow-up. diabetic participants in an exercise program compared with diabetic nonparticipants experienced weight loss. a drop in fasting blood glucose values. and reductions in the use of hypoglycemic medications. In a weight-loss competition. 45% (122/271) of the enrollees finished and lost greater than or equal to 2.3 kg. The results of these two studies demonstrate that 1) participation in a community-based exercise program can produce significant weight loss and improvement in glycemic control in Zuni Indians with NIDDM and 2) weight-loss competitions appear to be an important public health model for health-behavior change in communities similar to that of Zuni. NM.
Injuries to the portal triad, We reviewed the management and clinical course of 21 patients with extrahepatic injuries to the portal triad seen over the past 11 years at a Level I trauma center. These represented only 0.21% of patients with multiple trauma admitted during this time. Portal triad injury was never specifically diagnosed preoperatively. Extrahepatic bile duct injury occurred in 4 patients. portal vein injury in 14. and hepatic artery injury in 7; 3 patients had combined injuries. Eleven patients (52%) died. all due to uncontrolled hemorrhage from either an injured portal vein or associated intra-abdominal injuries. Management of the bile duct injuries included drainage alone. bile duct ligation. and Roux-Y hepaticojejunostomy. Survivors of portal vein injury were managed with lateral venorrhaphy. Ligation of the hepatic artery appeared to be optimal for injuries incurred by this vessel. Complications necessitating reoperation or percutaneous drainage procedures were encountered in 8 of 10 surviving patients (80%). Injuries to the portal triad are uncommon. difficult to diagnose. and technically challenging. Mortality is most directly related to uncontrolled intraabdominal hemorrhage. and salvage requires rapid control of bleeding as the first treatment priority.
Anterior sternal retraction for reoperative median sternotomy, The incidence of reoperative median sternotomy for repeat cardiac surgery is increasing. Reoperative median sternotomy is associated with a higher morbidity and mortality than first-time cardiac surgery. A portion of this morbidity and mortality may be due to direct injury to the heart and great vessels in the process of reopening the sternum. We report a new technique utilizing anterior sternal retraction that allows division of adhesions between the undersurface of the sternum and the heart and great vessels under direct vision. This technique enables the surgeon to minimize the risk of serious injury to these underlying structures during reoperative cardiac surgery.
Clinical parameters predictive of malignancy of thyroid follicular neoplasms, Needle aspiration biopsy is commonly employed in the evaluation of thyroid nodules. Unfortunately. the cytologic finding of a "follicular neoplasm" does not distinguish between a thyroid adenoma and a follicular cancer. The purpose of this study was to identify clinical parameters that characterize patients with an increased risk of having a thyroid follicular cancer who preoperatively have a "follicular neoplasm" identified by needle aspiration biopsy. A total of 395 patients initially treated at Vancouver General Hospital and the British Columbia Cancer Agency between the years of 1965 and 1985 were identified and their data were entered into a computer database. Patients with thyroid adenomas were compared to patients with follicular cancer using the chi-square test and Student's t-test. Statistically significant parameters that distinguished patients at risk of having a thyroid cancer (p less than 0.05) included age greater than 50 years. nodule size greater than 3 cm. and a history of neck irradiation. Sex. family history of goiter or neoplasm. alcohol and tobacco use. and use of exogenous estrogen were not significant parameters. Patients can be identified preoperatively to be at an increased risk of having a follicular cancer and accordingly appropriate surgical resection can be planned.
Expression of Her-2/neu oncogene protein product and epidermal growth factor receptors in surgical specimens of human breast cancers, Her-2/neu protein product was immunocytochemically analyzed in 139 breast cancers. Epidermal growth factor receptors were similarly analyzed in 74 breast cancers from the same patient pool. These results were also separated on the basis of estrogen receptor proteins and of combined aneuploidy with elevated S-phase from flow cytometry. Invasive breast cancer yielded a positive label for Her-2/neu protein (26%) and for epidermal growth factor receptor (25%). with no significant difference. Correlations with estrogen receptor labeling yielded differences significant inversely for both Her-2/neu protein (p less than 0.02) and epidermal growth factor receptor (p less than 0.01). Positive Her-2/neu protein labels correlated with a positive combination of aneuploidy and elevated S-phase (37%) and a negative combination of aneuploidy and elevated S-phase (21%). with a statistically nonsignificant difference. Positive epidermal growth factor receptor cases with aneuploidy and an elevated S-phase (75%) and without aneuploidy and elevated S-phase (42%) did differ with significance at p less than 0.05. There were eight cases positive for both Her-2/neu protein and epidermal growth factor receptor. four of six cases with negative estrogen receptor. four of six cases with negative estrogen receptor. six of six cases aneuploid. and five of six cases with an elevated S-phase. All eight cases had threatening disease--either stage III or stage IV. with one case of extensive ductal carcinoma in situ (comedo). Correlation of negative Her-2/neu protein with negative epidermal growth factor receptor was significant (p less than 0.05) in 74 cases. However. positive Her-2/neu protein did not correlate with positive epidermal growth factor receptor; there was a trend toward inverse correlation. We conclude that epidermal growth factor receptor labeling results show similarities to Her-2/neu protein results. but epidermal growth factor receptor tended to correlate with unfavorable ploidy and S-phase. Epidermal growth factor receptor labeling might be useful in breast cancers with macrocysts reported to show high epidermal growth factor activity.
Surgical versus percutaneous drainage of intra-abdominal abscesses, The records of 83 patients with intra-abdominal abscesses treated between 1986 and 1990 were reviewed to determine if there were significant differences in the outcome of patients treated by surgical drainage (n = 41) or percutaneous drainage (n = 42). The two groups were matched for age. abscess location. and etiology. Parametric statistical evaluations included the Student's t test as well as analysis of variance; nonparametric statistics used were chi-square and Wilcoxon rank sums. No significant difference was found in mortality (surgical 14% versus percutaneous 12%) or morbidity (surgical 26% versus percutaneous 29%). The duration of hospital stay was similar. Although there was no significant difference between the two groups in severity of illness as measured by APACHE II scores. these scores were significant in determining prognosis. APACHE II scores were significantly higher in non-survivors of both groups (23 versus 13) and also higher in those developing complications. A subgroup of patients with diverticular abscess was identified in whom percutaneous drainage enabled later resection with primary anastomosis without complication. This study indicates that percutaneous drainage of an intra-abdominal abscess is as efficacious as surgical drainage and that APACHE II scores are prognostic of both potential mortality and morbidity.
Initial two-year results of the Oregon Liver Transplantation Program, During the first 24 months of the Oregon Liver Transplantation Program. which began in October 1988. 94 patients were formally evaluated and 47 adults underwent 54 liver transplantations. Thirty-four percent of patients were veterans. The recipient operation lasted a mean of 7.4 hours (range: 4 to 16 hours). Veno-venous bypass was used routinely at first but selectively later (7 of the last 26 cases). resulting in reduced operating time. Hepatic artery reconstruction was end-to-end anastomosis in 52 cases and iliac conduit in 2. No arterial thrombosis occurred. Biliary reconstruction was choledochocholedochostomy in 83% and choledochojejunostomy in 17%. Biliary complications occurred in 28%. Operative mortality was 2%. and 1-year actual survival was 80%. Patients with hepatitis B fared worse. with four of six dying at a mean of 7.6 months. Overall. the median hospital stay was 30 days. Patients surviving more than 3 months had a mean Karnofsky score of 82%. No significant difference in outcome was noted in patients receiving prophylactic OKT3 monoclonal antibody (used in 45%) versus conventional immunosuppressive therapy. Overall. allograft rejection occurred in 55% of patients. Retransplantation was required in seven patients. three for primary graft nonfunction. two for uncontrolled rejection during induction therapy with OKT3. and two for graft failure secondary to recurrent hepatitis B.
Carotid endarterectomy in a community hospital: a change in physicians' practice patterns, A total of 243 consecutive carotid endarterectomies (CEA) performed at Providence Medical Center in Portland. Oregon. were retrospectively reviewed over a 22-month period. Of these. 137 patients (56%) underwent CEA for asymptomatic disease. 52 (37%) of whom had stenotic lesions of 79% or less. There were 6 deaths (3%) and 12 strokes (5%). Four strokes were in asymptomatic patients. These data prompted development of criteria for CEA: (1) hemisphere-specific transient ischemic attacks. reversible ischemic neurologic deficits. or amaurosis fugax with an appropriate carotid lesion; (2) completed stroke with major recovery and significant carotid stenosis; (3) asymptomatic lesion with greater than 80% stenosis (D+) either by carotid arteriogram or non-invasive lab evaluation; and (4) other indications only with a supporting second opinion from a disinterested vascular surgeon. neurosurgeon or neurologist. A prospective review followed institution of the guidelines. In 21 months. 148 operations were performed. a 36% reduction over the initial study period. Of these. 46 (31%) were for asymptomatic lesions. Two patients (4%) did not fulfill the guideline criteria. There were six strokes (4%) and no deaths. The reduction of CEAs appears to be related to a significant decrease in "inappropriate" operations being performed. Surgeons' familiarity with the data rather than external pressures seems to be the major factor in changing practice patterns. The decrease in stroke/death rate is not statistically significant.
Role of arteriography in the preoperative evaluation of carotid artery disease, This retrospective study was undertaken to determine the role of arteriography in the treatment of patients being considered for carotid endarterectomy. The results of preoperative classification of disease severity by duplex ultrasound and arteriography were compared. and the impact of arteriography on patient management was ascertained. We reviewed the records of 83 patients who had carotid surgery planned on the basis of their clinical history and duplex scan results and who then underwent arteriography. Duplex scan results agreed with the classification of stenosis by arteriography in 87% of evaluated sides and were within one category in 98%. In 87% of the cases reviewed. the clinical presentation and duplex scan findings were sufficient for appropriate patient management. In the instances that arteriography was useful (13%). the need for arteriography was evident when the duplex scan (1) was technically inadequate or equivocal; (2) showed an unusual distribution of disease. atypical anatomy. or a recurrent lesion; or (3) demonstrated an internal carotid artery with diameter-reducing stenosis of less than 50% in a patient with hemispheric neurologic symptoms despite antiplatelet therapy.
Importance of 6-mercaptopurine dose in lymphoblastic leukaemia, To explore the possibility that higher total dosage of 'maintenance' treatment may have contributed to the recent improvement in outlook of children in the United Kingdom with lymphoblastic leukaemia. details of the amount of 6-mercaptopurine prescribed during the first two years of treatment were studied in an unselected cohort of children diagnosed between 1973 and 1987. Eighty five patients were studied. 30 diagnosed before and 55 after 1980. The group diagnosed after 1980 showed an 18% improvement in relapse free survival at five years. Their median total dose of 6-mercaptopurine had increased by 22%. whereas according to the protocol it should have risen by an average of only 9%. After 1980 boys were prescribed significantly more 6-mercaptopurine than girls. and had fewer dose reductions because of myelosuppression. These findings support the clinical impression that after 1980 an important therapeutic difference resulting from the new United Kingdom acute lymphoblastic leukaemia protocols was an increase in the amount of 6-mercaptopurine that children actually received as a result of changes in prescribing guidelines rather than dose. They also provide further evidence that boys tolerate 6-mercaptopurine better than girls. which may be related to the still unexplained difference in prognosis between the sexes.
Day case ligation of patent ductus arteriosus in preterm infants: a 10 year review, Since 1978. 136 preterm babies received ligation of a patent ductus arteriosus as day cases. A total of 122 babies whose notes were available for review. with a median gestational age of 27 weeks (range 23-35) and median birth weight of 960 g (range 470-2750). were transported distances of up to 80 miles. The median ages at ligation with and without previous medical management with indomethacin were 23 and 15 days. respectively. One hundred and ten (90%) babies were dependent on ventilatory support. but extubation was achieved at a median time of 10 days after ligation. regardless of postnatal age at the time of ligation. There were no deaths associated with the operation. and no complications resulting from transportation. The hospital mortality was 15 (12.3%). and the most important (and significant) adverse factor was a preoperative fractional inspiratory oxygen content greater than 0.3. The results of this study show that day case ligation of the patent ductus arteriosus is safe. and if it is carried out early will reduce the time before extubation and discharge from the intensive care unit.
Breast feeding and protection against neonatal sepsis in a high risk population, Protection against neonatal sepsis by breast feeding was investigated in a developing community. A case-control study was carried out with 42 cases from a hospital and 270 controls. matched for age and socioeconomic conditions from the community. Exclusive breast feeding was extremely rare. most babies being partially breast fed and a few being given formula feed or animal milk. A highly significant odds ratio of 18 was obtained. showing that even partial breast feeding protects against neonatal sepsis in such a population.
Energy content of stools in normal healthy controls and patients with cystic fibrosis, Stool energy losses and the sources of energy within the stool were determined in 20 healthy controls and 20 patients with cystic fibrosis while on their habitual pancreatic enzyme replacement treatment. Stool energy losses were equivalent to 3.5% of gross energy intake in healthy children (range 1.3-5.8%). Despite a comparable gross energy intake. stool energy losses were three times greater in patients with cystic fibrosis than controls averaging 10.6% of gross energy intake (range 4.9-19.7%). Stool lipid could account for only 29% and 41% of the energy within the stool in controls and patients with cystic fibrosis respectively and was poorly related to stool energy. Approximately 30% of the energy within the stool could be attributable to colonic bacteria in both the healthy children and patients with cystic fibrosis. These results suggest that stool energy losses in healthy children are relatively modest but that even when patients with cystic fibrosis are symptomatically well controlled on pancreatic enzyme replacement. raised stool energy losses may continue to contribute towards an energy deficit sufficient to limit growth in cystic fibrosis. As the energy content per gram wet weight remains relatively constant (8 kJ/g). stool energy losses may be estimated from simple measurements of stool wet weight.
Changes in psychosocial adjustment after renal transplantation, The psychological aspects of transplantation were studied in 29 children and adolescents with functioning renal transplants. Most parents rated their child's physical health as considerably improved after transplantation. They also noted improvements in the child's behaviour and in the quality of family life. When compared with a sample of children being treated by hospital haemodialysis. children who had received transplants had more favourable parental views of behavioural and emotional adjustment. better parental psychiatric adjustment. and indications of superior child rated mood. self concept. and social functioning. Children who had received transplants did. however. show an increase in minor behavioural symptoms compared with healthy controls. and most parents required continuing psychological and social support as well as attention to physical aspects of the child's condition. Kidney transplantation is associated with improved psychosocial behaviour in children. but there is a continuing need for support for parents in dealing with minor psychological problems after the transplant.
Nesidioblastosis: evidence for autosomal recessive inheritance, The risk of recurrence of nesidioblastosis is unclear. Thirty patients from 28 families were studied; the marriages were consanguineous in five families. The ratio of subsequent affected to unaffected siblings was similar to that of an autosomal recessive condition and the sex ratio was close to 1.
Familial growth hormone releasing factor deficiency in pseudopseudohypoparathyroidism, A mother with pseudopseudohypoparathyroidism and her short son showed poor spontaneous growth hormone secretion. and provocation tests suggested a deficiency of growth hormone releasing factor. This is the first report of growth hormone releasing factor deficiency in pseudopseudohypoparathyroidism. The boy has responded well to growth hormone treatment over a period of three years.
Antibody-dependent cellular cytotoxicity against HIV-1 in sera of immunized chimpanzees, After immunization of chimpanzees against HIV antigens. antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) were evaluated and compared with anti-HIV-antibody levels detected by enzyme-linked immunosorbent assay (ELISA) and neutralizing antibody titers. Adult chimpanzees were immunized with different HIV-1 (LAV-BRU) antigen preparations: recombinant vaccinia virus (rVV) expressing gp160. p25 or p27nef; formalin- and beta-propiolactone-inactivated whole virus (inHIV); soluble recombinant gp160 either associated or not associated with other HIV proteins; a 25-mer peptide from the V3 region of gp120 coupled with KLH (V3-KLH). Immunization with the various rVV mixtures induced no or borderline ADCC increase above preimmune serum levels. Stronger and more sustained reactivity was elicited by inHIV. Purified HIV antigens elicited ADCC activity when the chimpanzees were naive; ADCC increased or remained at the same level when the animals had been preimmunized with rVV and/or inHIV. This type of reactivity apparently did not depend on whether gp160 alone or mixed with other proteins was used for immunization. The injection of V3-KLH resulted in only little. if any. recall ADCC response. ELISA antibody titers significantly correlated with ADCC and neutralizing antibody titers. but serum ADCC was independent of neutralizing antibody titers. an indication that the two latter serum activities are mediated by independent antibodies. Therefore. ADCC is elicited in the same manner as other antibody activities by the immunization of chimpanzees with inHIV or with purified recombinant HIV antigen preparations. The results obtained from the three chimpanzees of this series. which were subsequently challenged with infectious virus through the intravenous route. suggest that serum ADCC may be considered for vaccination purposes.
Negative correlation between blood cell counts and serum neopterin concentration in patients with HIV-1 infection, Hematopoietic disturbances are common in patients with HIV-1 infection. Recent studies on immune activation markers such as neopterin demonstrate that HIV-1 infection is associated with chronic immune activation. We investigated a possible association between serum neopterin concentrations and blood cell counts (CD4+ T cells. white blood cells. platelets. red blood cells) and hemoglobin and hematocrit in 94 HIV-1-seropositive individuals [52 Walter Reed (WR) stage 1. 31 WR2. one WR5. and 10 WR6]. There were significant negative correlations between neopterin concentrations and CD4+ T cells. hemoglobin. hematocrit and platelets. These correlations were also significant if either only WR1 and WR2 patients or the entire set of data were considered for calculations. Thus. hematological abnormalities are associated with chronic immune activation in patients with HIV-1 infection. Large amounts of neopterin are released by human macrophages on stimulation with interferon-gamma (IFN gamma). and tumor necrosis factor alpha (TNF alpha) further enhances the effect of IFN gamma. Therefore. our data suggest that activated immune cells and specific cytokines such as IFN gamma and TNF alpha are involved inhibiting hematopoiesis.
Delayed recovery of muscle pH after short duration, high intensity exercise in malignant hyperthermia susceptible subjects, Six subjects susceptible to malignant hyperthermia (MHS) and seven control subjects exercised for 4 min at 120% of their calculated maximal oxygen uptake on a bicycle ergometer. Mean (SEM) muscle pH. measured with a needle-tipped electrode in the vastus lateralis muscle. decreased from a resting value of 7.16 (0.04) to 6.78 (0.04) after exercise in the control group. and from 7.15 (0.05) to 6.56 (0.05) in the MHS group (P less than 0.01 compared with control group). A further decrease in muscle pH to 6.68 (0.06) by 5 min after exercise occurred in the control group. followed by incomplete recovery to 7.06 (0.04) 30 min after exercise. In the MHS group. however. muscle pH decreased to 6.45 (0.05) 5 min after exercise before recovering slowly to only 6.64 (0.07) after 30 min (P less than 0.01 compared with control group). There was no difference in muscle temperature. venous pH or venous lactate concentrations between the two groups. The results show that there is abnormal recovery of muscle pH after short-duration. high-intensity exercise in MHS subjects.
Effect of inspired oxygen concentration on the incidence of desaturation in patients undergoing total hip replacement, The effect of inspired oxygen concentration on the incidence of desaturation was studied in two groups of patients (n = 32 and 31) during total hip replacement. During insertion of acrylic bone cement. those patients receiving an inspired fractional oxygen concentration (FIO2) of 0.5 had less desaturation (3%) than those receiving an FIO2 of 0.33 (34%).
Heart rate response to an i.v. test dose of adrenaline and lignocaine with and without atropine pretreatment, In order to evaluate the sensitivity of an adrenaline test dose for detecting intravascular injection and the effect of atropine pretreatment. 90 ASA physical status I and II patients were allocated randomly to two groups. to receive i.v. saline 1 ml (n = 46) or i.v. atropine 0.5 mg (n = 44). Five minutes later. all patients received an i.v. test dose of 2% lignocaine 3 ml with adrenaline 15 micrograms at a rate of 1 ml s-1. The groups were similar with respect to basal heart rate (HR). HR remained unchanged after saline injection. but increased slightly 5 min after atropine injection (mean 78 (SD 15) beat min-1 vs 87 (20) beat min-1 (P less than 0.05). After the test dose of lignocaine with adrenaline. HR increased significantly in both groups at 30 s. 1 and 2 min. and remained increased at 3 min in the atropine group. The maximum increase in HR was greater in the atropine group than in the saline group (31 (4) beat min-1 vs 26 (11) beat min-1 (P less than 0.05). However. when individual maximum HR changes are considered. five patients in the saline group and four in the atropine group had an increase less than or equal to 10 beat min-1. and three patients in the saline group had no change or a decrease in HR. Defining a positive result to a test dose as an increase in HR of greater than 10 beat min-1. the sensitivity of the adrenaline test dose was 83 (5.5)% in the saline group and 91 (3.5)% in the atropine group (ns).
Comparison of orthodox with fibreoptic orotracheal intubation under total i.v. anaesthesia, Fibreoptic orotracheal intubation was compared with orthodox laryngoscopy and tracheal intubation using a total i.v. technique with propofol in 60 ASA I and II patients. There was no significant difference between the two techniques in haemodynamic profile (before. during and following the intubation procedure) and incidence of postoperative sore throat. Minimal oxygen saturation was 96% during the study; maximal end-tidal PCO2 after intubation was 5.4 kPa. Intubation time was faster (P less than 0.01) in the orthodox group (30.7 (SEM 2.3) s) than in the fibreoptic group (52.7 (4.8) s).
Ryanodine contracture: a potentially specific in vitro diagnostic test for malignant hyperthermia, In vitro contracture tests used currently for malignant hyperthermia (MH) do not possess absolute specificity. This is potentially a great problem in the study of the genetic approach which offers the best prospect for the development of a non-invasive diagnostic test for the condition. The calcium release channel of the sarcoplasmic reticulum has been proposed as the site of the MH defect. Ryanodine. which binds avidly to this channel. was shown to differentiate between muscle of MH susceptible and normal patients in terms of in vitro contracture response. This ryanodine contracture response is proposed as a potentially specific in vitro diagnostic test for MH.
Sensitivity, specificity and predictive value of the sensation of warmth as a method of detecting inadvertent subarachnoid injection of local anaesthetic when performing extradural blocks, In order to test if the rate of onset of sensation of warmth in the legs after the injection of 0.5% bupivacaine might discriminate between subarachnoid and extradural injection. 150 urological patients were allocated randomly to receive either spinal anaesthesia with isobaric (IS) or hyperbaric (HS) 0.5% bupivacaine. or extradural anaesthesia with isobaric 0.5% bupivacaine. The volume of the local anaesthetic for spinal anaesthesia and for the extradural test dose was 3-4 ml. The patients were asked to report at once if they had a sensation of warmth in the legs during or after injection of local anaesthetic. The mean time to the sensation of warmth was significantly shorter in the spinal groups (80 (SEM 10) s in IS and 76 (8.0) s in HS) than in the extradural group (558 (38) s). However. six patients in the IS and two in the HS group had no sensation of warmth.
Neurological complications following the use of continuous extradural analgesia with bupivacaine, We describe a patient in whom continuous extradural analgesia with bupivacaine resulted in toxic plasma concentrations causing severe cerebral irritation. We discuss recent studies using continuous extradural bupivacaine. reports of toxicity and comment on the importance of monitoring drug concentrations.
Anaesthesia and congenital agranulocytosis: influence of anaesthetic agent on neutrophil numbers in a patient with Kostmann's syndrome, We describe a 14-month-old male patient with congenital agranulocytosis who received general anaesthesia on three separate occasions during a 6-week period for minor surgery. Granulocyte colony stimulating factor was commenced after the second anaesthetic. Each anaesthetic was followed by profound reductions in neutrophil numbers. irrespective of the agent used. Even the third anaesthetic. which avoided all the common agents thought to have a marrow suppressant effect and given during granulocyte colony stimulating factor therapy. was associated with a marked decrease in neutrophil numbers.
Carboxyhaemoglobinaemia and pulse oximetry, We compared measurements obtained with a pulse oximeter (SpO2) against values obtained from a CO-oximeter in a patient with carbon monoxide poisoning. SpO2 was equal to the sum of the oxyhaemoglobin (HbO) and carboxyhaemoglobin (HbCO) values over the range of HbCO from 30 to 1%. This confirms the experimental findings that pulse oximeters measure HbCO as HbO. The patient was treated with oxygen (FlO2 = 50%) and recovered without any sequelae. Under these circumstances. the half-life of HbCO was approximately 2 h.
Phospholipase activity in the endometrium of women with normal menstrual blood loss and women with proven ovulatory menorrhagia, The activity of phospholipase A2 types 1 and 2 and phospholipase C was measured in the endometrium of women with ovulatory menorrhagia and in those with normal menstrual blood loss. In both groups of subjects phospholipase A2 type 1 activity was significantly higher in the secretory phase than in the proliferative phase (P less than 0.001). The median activity (pmol/mg protein/min) for the proliferative phase was 27.6 in normal subjects and 40.4 in women with ovulatory menorrhagia and for the secretory phase the median activity was 144.5 in normal women and 138.1 in women with ovulatory menorrhagia. There was no difference between the two groups of women at either stage of the cycle. Phospholipase A2 type 2 activity was also higher in the secretory phase than in the proliferative phase (P less than 0.05 for normal subjects and P less than 0.001 for women with menorrhagia). The median activity (pmol/mg protein/min) for the proliferative phase was 94.4 (normal subjects) and 56.6 (women with menorrhagia) and for the secretory phase 148.3 (normal subjects) and 142.5 (women with menorrhagia). The activity of phospholipase A2 type 2 was significantly lower in the proliferative phase of women with ovulatory menorrhagia compared with normal subjects (P less than 0.05). Phospholipase C activity (nmol/mg protein/min) was significantly higher in women with ovulatory menorrhagia (median 8.2) compared with women with normal blood loss (median 5.5) (P less than 0.01).
Controlling Rh haemolytic disease of the newborn in India, The question whether India should institute a national programme of Rh screening and postpartum Rh immune globulin prophylaxis needs to be addressed. especially because of the recent emphasis on primary maternal and child health care. Given the absence of relevant community based data. decision analysis techniques were used to address these issues. The results reveal that the estimated cost per case of Rh HDN prevented through postpartum immune globulin prophylaxis is lower than the cost per case of Rh HDN treated through a curative strategy. However. the financial and infrastructural requirements of the preventive programme mean that such prevention may not be feasible at present. With the achievement of the Indian Government's stated objectives of population control. however. disease incidence should fall by 30% from 5.90/1000 births in 1981 to 4.13/1000 births by the year 2000. even in the absence of a prophylaxis programme.
Fetal umbilical artery velocity waveforms and subsequent neonatal outcome, Flow velocity waveforms (FVWs) from the fetal umbilical artery were recorded from 2178 pregnant women over a 6-year period. All of them had an obstetric factor indicating increased risk of fetal compromise. A total of 6749 studies was recorded. The systolic diastolic (AB) ratio was measured and classified as normal (less than 95th centile). elevated (95-99th centile). high (greater than 99th centile) or extreme (absent diastolic flow). The results of these studies have been related to subsequent fetal and neonatal outcome. An abnormal umbilical artery FVW was associated with shorter gestation and infants with lower birthweight. shorter length and lower ponderal index. There was a highly significant association between an abnormal FVW and the birth of an infant small for gestational age. The significance of the association increased with the increased abnormality of the umbilical artery FVW and this was independent of gestational age. Preterm infants associated with high or extreme AB ratios spent twice as long in the neonatal nursery than those with normal AB ratios. Analysis of 794 pregnancies studies serially indicated that an abnormal FVW in which the AB ratio was increasing. in contrast to a decreasing AB ratio. predicted a poor outcome for both size at birth and duration of neonatal intensive care. We conclude that in high risk pregnancy Doppler umbilical artery FVW studies predict the most compromised fetuses in terms of growth retardation and requirements for neonatal intensive care.
Evaluation of a diagnostic algorithm for heart disease in neonates, OBJECTIVE--To develop. test. and validate an algorithm for diagnosing disease in neonates during an over the telephone referral to a specialist cardiac centre. DESIGN--A draft algorithm requiring only data available to a referring paediatrician was generated. This was modified in the light of a retrospective review of case records. A questionnaire to elicit all the data required by the algorithm was then generated. There followed a prospective three phase evaluation during consecutive over the telephone referrals. This consisted of (a) a conventional phase with unstructured referral consultations. (b) a phase with referrals structured around the questionnaire but independent of the algorithm. and (c) a validation phase with the algorithm (and its previous errors) available during the referral consultation. SETTING--59 paediatric centres in south east England and a central specialist paediatric cardiology unit. PATIENTS--Consecutive neonates (aged less than 31 days) referred with suspected heart disease. The retrospective review was of records of 174 neonates from 1979. In the prospective evaluation (1987-90) the conventional phase comprised 71 neonates (over 5.5 months). the structured phase 203 neonates (over 14 months). and the validation phase 195 neonates (over 12 months). MAIN OUTCOME MEASURES--Diagnostic accuracy (assigning patients to the correct diagnostic category (out of 27)). of the referring paediatrician. the specialist after the referral consultation. and the algorithm as compared with the definitive diagnosis by echocardiography at the specialist centre. and score for the appropriateness of management in transit. RESULTS--Simply structuring the consultation by questionnaire (that is. proceeding from the conventional phase to the structured phase) improved the diagnostic accuracy of both paediatricians (from 34% (24/71 cases) to 48% (97/203) correct) and specialists (from 54% (38/71 cases) to 64% (130/203) correct). The algorithm (structured phase) would have been even more accurate (78% (158/203 cases); p less than 0.01). Management scores in the structured phase were also better than in the conventional phase (80%(162/203 cases)v 58% (41/71) appropriate; p less than 0.01). Management scores would have improved to 91% appropriate (185/203; p less than 0.001) had the algorithmic diagnoses dictated management. The superiority of the algorithm was maintained but not bettered in the validation phase. CONCLUSIONS--Applying the algorithm should reduce the morbidity and mortality of neonates with critical heart disease by aiding clinicians in therapeutic decisions for in transit care.
Acquired renal cystic disease: implications for the urologist, Acquired cystic kidney disease has become increasingly recognised as a significant risk in patients with end-stage renal disease. especially in those maintained on chronic haemodialysis and peritoneal dialysis. A review of the literature indicates that nearly 50% of patients on dialysis for more than 3 years develop renal cystic changes. The major complications of this condition are neoplasia and spontaneous renal haemorrhage. The risk of developing renal carcinoma has been estimated to be more than 30 times higher in dialysis patients with cystic changes than in the general population. Our experience with 5 patients is reported. including 3 with renal tumours and 1 with metastatic disease. Careful surveillance of dialysis patients using yearly ultrasonography and computed tomography is recommended. The evolving indications for radical nephrectomy in this disease are discussed.
Lower urinary tract reconstruction in patients with bladder exstrophy after failed primary treatment in early childhood, The results of neonatal surgery for bladder exstrophy are not very satisfactory. A significant percentage of patients present in later childhood or adolescence for correction of their residual deformities. We have reconstructed 26 patients. correcting their entire urogenital and cosmetic deformity in a one-stage procedure. The results show that one-stage total reconstruction is possible and is preferable to serial correction of the various individual abnormalities. The principles of surgical reoperation in adolescence are the same as those now established for the primary correction in neonatal life.
Interpretation of biopsies of "normal" urothelium in patients with superficial bladder cancer. MRC Superficial Bladder Cancer Sub Group, In the course of a Medical Research Council trial of intravesical chemotherapy. biopsies were taken from apparently normal bladder urothelium near to newly diagnosed superficial bladder cancers in 417 patients. Differences were noted in the rates at which histological features were described in different centres. To gain more information about the reproducibility of the pathological findings. a group of 6 pathologists (5 from the UK and 1 from the USA). all having a special interest in urological pathology. were asked to examine a representative sample of 92 slides. They were then asked to re-examine 30 of them after an interval of at least 6 months. At first examination and at re-examination the slides were assessed using a standard proforma. However. the definitions of the categories were left unspecified for the pathologists to use their own criteria. The 5 UK pathologists then met to establish a consensus view of each slide. The results indicated that: (1) The reporting of non-dysplastic changes varied so much between pathologists as to render it of little value to clinical practice. (2) There were wide variations between different pathologists in the reported incidence of dysplastic change. (3) On a second review the pathologists reproduced their own assessment on only 62% of occasions. (4) Even after discussion between pathologists there was no consensus on the diagnosis of mild as opposed to moderate dysplasia. Consensus was reached on all biopsies which showed either severe dysplasia or carcinoma in situ. (5) In adopting a policy of taking urothelial biopsies. urologists should be aware of the imprecision and lack of reproducibility in the interpretation of such biopsies. (6) Biopsies of cystoscopically normal urothelium may not be a useful guide in defining therapy.
Repair and replacement of deep vein valves in the treatment of venous insufficiency, Venous insufficiency is a widespread condition. the prevalence of venous ulceration being 0.5-1.0 per cent in Western populations. A principal abnormality causing venous insufficiency is deep venous reflux. usually resulting from post-thrombotic valve destruction. Patients undergoing treatment for venous insufficiency should have all venous abnormalities investigated. defined and corrected where possible. Although treatment for superficial and communicating vein incompetence is available. correction of deep vein reflux has been neglected until recently. Deep vein valve physiology. the selection of patients for deep vein valve surgery and methods of valve repair and replacement are reviewed.
Carotid endarterectomy in Great Britain and Ireland: trends and current practice, Of 309 questionnaires on carotid endarterectomy sent to all surgeons in Great Britain and Ireland who might use this technique. 298 (96 per cent) were returned. In all. 110 (37 per cent) of 298 surgeons performed at least one carotid endarterectomy in 1989; 67 performed less than 10 and 43 greater than 10. In total. these 110 surgeons performed 1417 operations in 1989. a situation that has changed little over 5 years since the previous survey. Transient ischaemic attack and minor stroke remain the main indications for carotid endarterectomy; the operation was hardly ever performed for asymptomatic stenosis. By 1989 almost all surgeons initially assessed prospective patients using a technique less invasive than conventional angiography; duplex scanning was used 'always' or 'sometimes' by 70 per cent of surgeons. While 72 per cent of surgeons in 1984 'always' required conventional angiograms before operation. by 1989 only 21 per cent did so. most now relying on less invasive techniques. During operation there was an increasing use of shunts. carotid sinus nerve blockade and patch closure of the arteriotomy. The overall number of carotid endarterectomies performed annually in Great Britain and Ireland has remained steady over the past 5 years and is relatively low for a population of 60 millions. An increase in the number of surgeons performing the operation is almost entirely accounted for by an increase in those performing less than 10 carotid endarterectomies per year.
Predictors of death from aortic aneurysm among middle-aged men: the Whitehall study, Among 18.403 male civil servants examined at age 40-64 years there were 99 deaths attributed to aortic aneurysm during 18 years of follow-up. Each case was matched by age to ten controls who survived longer than the case. The risk of all types of fatal aneurysm was substantially increased for current smokers of manufactured cigarettes (rate ratio compared with lifelong non-smokers = 6.5; 95 per cent confidence interval 2.3-18.7). pipe or cigars (6.7; 1.7-26.5) and hand-rolled cigarettes (25.0; 7.5-83.3). Diastolic blood pressure was strongly associated with dissecting aneurysm (rate ratio per 10 mmHg increase = 2.4; 95 per cent confidence interval 1.7-3.2) and abdominal aneurysm (1.5; 1.2-1.9) but not other aneurysms (1.0; 0.7-1.5). The independent effects of height. adiposity. plasma cholesterol. glucose intolerance. reported angina and intermittent claudication were not significant. Hypertension and smoking. particularly of hand-rolled cigarettes. are confirmed as major and potentially remediable risk factors for fatal aortic aneurysm.
Near-infrared spectroscopy in peripheral vascular disease, Near-infrared spectroscopy has been performed on the calf muscles of 38 subjects. 21 normal controls without vascular disease and 17 patients with peripheral vascular disease. Oxygen consumption was measured in the calf by calculating the rate of conversion of oxyhaemoglobin to deoxyhaemoglobin during a period of tourniquet-induced ischaemia. Postischaemic reoxygenation was also measured. Median oxygen consumption in patients with peripheral vascular disease was 0.10 ml 100 g tissue-1 min-1. while in the control group it was 0.20 ml 100 g tissue-1 min-1 (P less than 0.03. Mann-Whitney U test). The median time taken to reach maximum oxyhaemoglobin levels after ischaemia was 40 s in patients with peripheral vascular disease and 20 s in controls (P less than 0.02). The results indicate that oxygen consumption is reduced in peripheral vascular disease. Near infrared spectroscopy is a non-invasive method for assessing metabolic improvement resulting from surgical or pharmacological treatment.
Prospective randomized trial comparing anal function after hand sewn ileoanal anastomosis with mucosectomy versus stapled ileoanal anastomosis without mucosectomy in restorative proctocolectomy, A prospective randomized trial was performed to compare complications and function after hand sewn ileoanal anastomosis with mucosectomy (group A) with stapled ileoanal anastomosis without mucosectomy (group B) during restorative proctocolectomy. Thirty-two age- and sex-matched consecutive patients under the care of one surgeon were randomized. The median duration of anal dilatation while making the anastomosis was 19 min (range 14-33 min) and 1 min (range 0-39 min) in groups A and B respectively (P less than 0.005). The median level of the anastomosis was at the dentate line (range 0-0.5 cm) in group A and 2 cm above the dentate line (range 0.2-4.0 cm) in group B (P less than 0.005). Seven patients in group A and 11 in group B had at least one postoperative complication (n.s.). One patient in group A and four in group B developed an anastomotic stricture requiring dilatation (n.s.). One patient in group B had the reservoir removed. Function was assessed at a median of 11 months (range 7-15 months) after ileostomy closure in 14 patients in group A. and at a median of 12 months (range 5-17 months) in 14 patients in group B. Median frequency of defaecation per 24 h was 4 in both groups (group A. range 2-7; group B. range 2-10). Night evacuation (greater than once per week) occurred in seven patients in each group. All patients in both groups could delay the desire to defaecate by more than 30 min. Eleven patients in group A and 12 in group B had normal continence. Evidence to date favours a full mucosectomy. Function is not vitiated by this technique and surgical removal of the disease is more complete.
1,25-Dihydroxyvitamin D3 receptors and human colon adenocarcinoma, Epidemiological evidence suggests that dietary calcium and 1.25-dihydroxyvitamin D3 (1.25-(OH)2D3) might have a protective effect against colorectal cancers. Since the presence of receptors is required for steroid action. specific 1.25-(OH)2D3 receptors (RD3) were investigated in biopsies taken at different levels of the colon. The study involved 90 biopsies from patients operated on for colorectal adenocarcinoma. They were paired biopsies from adenocarcinoma tissue and adjacent normal mucosa. In addition. 26 normal intestinal mucosa biopsies from patients without cancer were examined. RD3 receptors were assayed in tissue extract by the dextran-coated charcoal technique and also characterized by sucrose density gradient sedimentation. Scatchard analysis showed a single class of specific high affinity-low capacity sites binding for 1.25-(OH)2D3. The incidence of RD3 was 86 per cent in normal mucosa (n = 77) and lower in carcinoma (n = 34). for which the incidence decreased significantly (P less than 0.001) from right colon (58 per cent) to left colon (37 per cent) and rectum (19 per cent). These data suggest that the normal colon is a potential target organ for 1.25-(OH)2D3 which might modulate calcium transport in the colon. Loss of receptivity to 1.25-(OH)2D3 is associated with malignant transformation.
Prevention of anastomosis leakage: an artificial connective tissue, Anastomosis leakage still causes considerable morbidity and mortality after digestive tract surgery. We report here our experience of the use of reconstituted connective tissue created from elastin. fibronectin and collagen in preventing anastomosis leakage and closing intestinal fistulas. In animal studies (56 rats). this connective tissue was used as a patch applied with fibrin sealant to the edges of a 1 cm diameter colonic defect. In a clinical evaluation. eight patients had an intestinal fistula closed by a simple sewn suture reinforced by a sealed patch and seven patients had a high risk anastomosis reinforced by a sealed patch. in most cases as an alternative to staged surgery. In animal studies. complete reconstitution of the three colonic layers was obtained without retraction and without inflammatory reaction within 40 days. while the patch was slowly resorbed. In clinical trials all 15 defects and anastomoses healed without complication. Three patients died from other causes and. at autopsy. the patch was found to have remained in place covering the suture line. If these results are confirmed by a prospective clinical trial. such biomaterial offers the possibility of reducing the occurrence of anastomosis leakage. especially in high risk circumstances.
Comparison between anal endosonography and digital examination in the evaluation of anal fistulae, A prospective trial was performed comparing the accuracy of digital examination and anal endosonography in defining the anatomy of anal fistulae. Before operation 38 consecutive patients were assessed by the consultant in charge of the case. by a research fellow and by anal endosonography involving two radiologists. These findings were compared with the operative findings. Consultants correctly identified 26 of 33 internal openings. 29 of 34 primary tracks and 15 of 21 secondary tracks. The research fellow correctly identified 26 internal openings. 24 primary tracks and 10 secondary tracks. There was no significant difference between the accuracy of consultants and the research fellow. Anal endosonography identified 10 internal openings based on initial criteria. This rose to 24 when revised ultrasonographic criteria were applied. There was no statistical difference between consultant assessment and anal ultrasonography in correctly identifying intersphincteric and transphincteric tracks. Ultrasonography is unable to assess primary superficial. suprasphincteric and extrasphincteric tracks or secondary supralevator and infralevator tracks. Consultant assessment of secondary supralevator and infralevator tracks was correct in 78 per cent of cases.
Confirmation of endosonographic detection of external anal sphincter defects by simultaneous electromyographic mapping, Anal endosonography was performed in 13 consecutive patients with post-traumatic faecal incontinence. Thirteen acoustic defects in the external anal sphincter (two hyperechoic. four of mixed echogenicity and seven hypoechoic) were analysed electromyographically by locating under ultrasound guidance the tip of a concentric needle within the defect. The electromyographic activity in this zone was compared with ultrasonically normal muscle. Eleven of 13 sonographic defects showed no electrical activity on electromyography. there was one technical electromyography failure. and one defect was too deep to be reached by the electromyography needle. The electromyographic response was normal in each case within ultrasonically normal muscle. Anal endosonography is recommended as the initial investigation to locate defects. which may be confirmed electromyographically thereby limiting the number of painful needle insertions required for complete mapping of the external anal sphincter.
Role of a regional register for familial adenomatous polyposis: experience in the northern region, Within 36 months of its formation the Northern Region Polyposis Registry had increased the number of identified gene carriers of familial adenomatous polyposis from 56 to 65 in a population of 3.1 million and had achieved a 15-fold increase in the number of at-risk relatives being regularly screened. Review of the surgical records at the outset of the registry revealed that the mean age at diagnosis of those patients detected by screening was 24.7 years. whereas it was 36.6 years for those detected by symptoms. Ten of the 31 in the latter group had colorectal carcinomas whilst only one of those detected by screening had a cancer and a significantly higher proportion had sphincter-saving surgery. A regional registry can provide an effective screening and counselling service to surgeons treating patients with familial adenomatous polyposis. At-risk relatives are best assessed by combining results of the different screening procedures now available but the prime requirement of a successful registry is dedicated domiciliary counselling.
Topical application of honey in treatment of burns, A total of 104 cases of superficial burn injury were studied to assess the efficiency of honey as a dressing in comparison with silver sulfadiazine gauze dressing. In the 52 patients treated with honey. 91 per cent of wounds were rendered sterile within 7 days. In the 52 patients treated with silver sulfadiazine. 7 per cent showed control of infection within 7 days. Healthy granulation tissue was observed earlier in patients treated with honey (mean 7.4 versus 13.4 days). Of the wounds treated with honey 87 per cent healed within 15 days as against 10 per cent in the control group. Relief of pain. a lower incidence of hypertrophic scar and postburn contracture. low cost and easy availability make honey an ideal dressing in the treatment of burns.
Community cancer programs as strategic alliances: challenges and guidelines for action, This paper assesses the utility of strategic alliances as a way of expanding and improving the quality of cancer care provided in communities with limited access to major treatment centres. Alliances provide an organizational model for future community-based cancer programs by accommodating a growing need for interdependence among organizations and providers while permitting substantial independence and autonomy. Five managerial challenges to ensuring effective and efficient delivery of cancer services are identified: to secure mutually reinforcing exchanges between and within all levels of cancer care. to develop protocols and programs relevant to the unique characteristics of patients and providers. to provide treatment and cancer control services. to involve interdisciplinary teams of providers at all levels of care and to achieve quality assurance. improvement and evaluation. In addition. the paper includes a set of guidelines to facilitate the implementation of community cancer programs as strategic alliances: reaffirm the role of community oncologists. primary care physicians and nurses as partners in the program; define the structure and culture necessary for commitment rather than simply compliance; redefine the role of management; establish data-monitoring systems; modify reward systems; and set realistic time frames and expectations.
Extracranial-intracranial bypass to reduce the risk of ischemic stroke, Extracranial-intracranial (EC-IC) bypass surgery is an operative procedure in which the superficial temporal artery is anastomosed to the middle cerebral artery. The operation. first described in 1969. was employed to circumvent otherwise surgically inaccessible atherosclerotic lesions high in the internal carotid system or in the middle cerebral artery. This assessment compares the findings from 13 surgical series of EC-IC bypass (1464 patients) with those reported in the only prospective. randomized. cooperative trial of this procedure (1377 patients). Analysis of the outcomes in the 1464 patients included in the surgical series produced insufficient evidence to support a conclusion that post-EC-IC bypass stroke rates were lower than the rates of either the medically or surgically treated groups in the controlled clinical trial. In the absence of reliable. objective evidence of the existence of a group of patients in whom surgical intervention is superior to medical treatment in reducing the frequency of stroke. the results of the single controlled clinical trial. which demonstrated no benefit of bypass. must be accepted as the best evidence currently available.
Transseptal catheterization in adults: enhanced efficacy and safety by low-volume operators using a "non-standard" technique, Transseptal catheterization is often not performed because of concerns about morbidity and mortality. The authors present several refinements of this technique that have allowed a series of cases to be done with minimal morbidity or mortality. This was possible despite limited previous experience in this technique and a relatively low-volume of cases.
Multicenter evaluation of a new fixed-wire coronary angioplasty catheter system: clinical and angiographic characteristics and results, Coronary angioplasty is increasingly used as an attempt to revascularize patients with severe coronary artery disease. To determine the efficacy of such treatment. a new fixed wire angioplasty catheter was evaluated by a multicenter group in a non-randomized fashion in 50 patients. average 58 +/- 11 years (+/- 1 SD). 58% men. Forty-four percent had a prior revascularization procedure (28% angioplasty. 16% coronary bypass surgery). 38% had a prior Q-wave myocardial infarction. 43% had grade 4 angina. and 60% multiple vessel disease. Angioplasty was attempted in 63 lesions which were located in a mid to distal location in 69%. with a proximal tortuosity score of 1.8 (2 = 45-60 degrees entrance angle). and lesion angulation of 1.4 (1 = 45 degrees lesion bend). In 88%. the device was the primary catheter used and in 6%. it was chosen when another system failed. The balloon was able to successfully cross 94% of all lesions attempted. Six lesions were crossed and dilated but significant residual stenoses remained. There were no significant device malfunctions. or angiographic or clinical complications. This feasibility evaluation of this new fixed wire system yielded excellent angiographic results. Although not a comparative study. this analysis suggests that this new generation of angioplasty catheter may improve the safety and efficacy of complex coronary angioplasty.
Heart catheterization in a neonate by interacting magnetic fields: a new and simple method of catheter guidance, Catheter guidance in a critically ill neonate can be difficult and hazardous. A new technique of directing a catheter based on the interaction of magnetic fields is described. A strong external permanent magnet is moved across the body surface to control the magnetic tip of a catheter in the body. We report on the first clinical case of such a heart catheterization in a neonate with complex congenital heart disease. This method can also be used for other invasive investigations in the neonatal period.
Mastoid misery: quantifying the distress in a radical cavity, Seventy-eight mastoid cavities were studied in 39 patients who required revision surgery for troublesome symptoms. A retrospective questionnaire was used to assign a symptom score to each patient in his pre and post-operative condition. The 5 leading symptoms of pain. wax. discharge. smell and giddiness were reviewed. A score of 15 points represented the worst case and zero the best. The average improvement after surgery was 4.7 points. Hearing was not considered in this study.
The sphenoiditis spectrum, This retrospective. comparative study involves 13 patients with sphenoiditis from 2 specialist centres: the Royal National Throat. Nose and Ear Hospital. Gray's Inn Road (7 patients) and the National Hospital for Nervous Diseases. Queen's Square (6 patients). It was found that the ENT patients had a very much longer history. had more nasal symptoms. and suffered none of the neurological complications attributable to the disease. All the neurological patients presented with a complication after a comparatively short history and had few nasal symptoms. One ENT patient was found to have a mucopyocoele. whereas 5 were found in the neurological patients. all of whom had bony deficiencies demonstrated by radiology and at surgery. Once diagnosed and treated the ENT patients all made full recoveries while 3 of the neurological patients remain with sequelae of the disease. Our study suggests that dehiscences of the surrounding bone increase the risk of potentially serious intracranial problems from sphenoiditis. whereas the chronicity of symptoms is of secondary importance.
Cough intensity in the laryngectomee, The exact role or even the necessity for a functioning larynx in the production of an efficient cough is unknown. This study compares the cough intensity of 10 laryngectomees with a control group of 10 individuals with a larynx. There is no significant difference in the peak flow but the time taken to reach the peak flow is prolonged in the laryngectomees. The supramaximal expiratory flow is thus absent. The larynx is not essential for coughing although the different pattern may be less efficient. This simple test may have diagnostic value in assessing the larynx.
Red blood cell deformability in sudden sensorineural deafness: another aetiology, Red blood cell deformability (RCD) was measured by a filtration technique in 12 patients with sudden sensorineural deafness. Five patients had reduced deformability. including 3 out of 4 patients with a recent upper respiratory tract infection. This may be an important factor in sudden deafness. more likely as a complicating factor of other disorders rather than as a truly primary aetiology. Factors and diseases which alter RCD are discussed and a possible link between the viral and vascular causes of idiopathic sudden deafness is suggested. While several lines of therapy seem promising there is still no clinically proved method for improving RCD. With the development of an acceptable therapeutic regimen. we feel that the possibility of reduced RCD should be considered and that a deformability test be included in the work-up of patients with a sudden sensorineural hearing loss.
Second radical neck dissection, We report a series of 96 patients (62 men and 34 women) undergoing a second radical neck dissection for enlarged contralateral cervical nodes after primary treatment of a squamous cell carcinoma of the head and neck. including an ipsilateral radical neck dissection. The proportion of patients requiring a second later neck dissection varied from 0% for tumours of the nasopharynx. nasal cavity and paranasal sinuses. to 5% for tumours of the hypopharynx. The incidence of second neck dissection was not determined by the original T stage of the primary tumour. but patients with enlarged nodes at presentation were 5 times more likely to need a second neck dissection than those with no palpable nodes at presentation. Also. patients with a poorly differentiated tumour were twice as likely to need a second neck dissection as those with a well differentiated tumour. The overall 5-year survival after second neck dissection was 35% and the perioperative mortality 1.92%. Significant factors predicting survival after a second neck dissection were the time to recurrence. the clinical neck node status at recurrence. the number of histologically invaded nodes in the neck and the presence of extra-nodal disease.
Polytomographic radiology in the diagnosis and management of maxillary antral disease as determined by antroscopy, Plain radiology of the maxillary sinus correlates poorly with pathological conditions affecting it as shown by subsequent endoscopic assessment. Tomographic radiology provides a much higher diagnostic yield and in particular is of great value in assessing the 'opaque antrum'. The false positive rate is similar in the two techniques but tomography yielded no false negative diagnoses in this study compared with an incidence of 31% with plain radiology. Sinoscopy remains the definitive method of assessing antral disease but tomographic radiology is a highly accurate screening technique. It provides this accuracy at low cost. low orbital irradiation and more convenience than the newer techniques of CT and MRI scanning which are still not widely available for routine ENT use.
Benign lesions of the vocal folds: uniformity in assessment of clinical diagnosis, The names given to a number of benign lesions of the vocal folds are not well standardized and lead to difficulties in comparing treatment. In the present study photographs of benign lesions of the larynx were presented to groups of clinicians together with a questionnaire. and the answers analysed. The results show great variation between clinicians in interpretation and naming of these lesions. Definitions are suggested for different benign conditions in order to standardize the nomenclature.
Use of serum markers in the diagnosis and management of laryngeal cancer, Many neoplastic diseases are reported to be accompanied by the presence or associated with an increase in biological substances identified as tumour markers. The most common markers implicated in head and neck cancers are CEA. TPA. LASA. SCC. CA 19-9. and ferritin. These markers (except SCC) were evaluated in 50 patients with a laryngeal carcinoma. in 20 patients with benign lesions. and in 20 healthy subjects. The results show for each marker assayed the following sensitivity values (true positives): CEA. 10%; CA 19-9. 30%; TPA. 30%; LASA. 90%; ferritin. 60%. Specificity (true negatives) was as follows: CEA. 85%; CA 19-9. 99.4%; TPA. 98%; LASA. 99.8%; ferritin. 97%. LASA and ferritin seem to be the most suitable markers for patient monitoring because of their higher sensitivity in all phases of cancer disease.
The successful treatment of atypical hemolytic uremic syndrome with plasmapheresis, A seven and a half-year-old boy presented with idiopathic atypical hemolytic uremic syndrome (HUS). He initially appeared to respond to plasma infusions. When he became refractory to plasma infusion. plasmapheresis was initiated. The treatment with plasmapheresis dramatically reversed the deterioration in glomerular filtration rate and platelet count. The use of plasma infusion and plasmapheresis in HUS is discussed. The authors advise the use of plasmapheresis in idiopathic atypical HUS.
Correction of hypophosphatemia in patients on hemodialysis using a calcium-free dialysate with added phosphate, Three patients on long term hemodialysis were found to be hypophosphatemic. They were treated using a calcium-free dialysate to which phosphate was added to give a final concentration of 1 or 2 mmol/l. All corrected their low phosphates. Hypocalcemia developed in two patients when the calcium infusion rate was 15 ml/hour of 10% CaCl2. It is recommended that this should be increased to 20 ml/hour. Under these circumstances. correction of hypophosphatemia is possible with the transfer of approximately 30-35 mmol phosphate over a four-hour dialysis.
Rheumatoid factors in patients with minimal change nephrotic syndrome, Several immunological aberrations. especially T-cell abnormalities. have been shown to be involved in the development of the minimal change nephrotic syndrome (MCNS) although the responsible factors have not been identified. We studied rheumatoid factors (RF). thought to be a consequence of polyclonal B-cell hyperactivation. in sera from patients with MCNS using a sensitive fluorescence immunoassay (FIA). Significant increases of IgG and IgM RFs and marginal increase of IgA RF were observed during the nephrotic stages. Some patients still showed high titers of IgM RF in the early remission phases. The levels of RFs were normalized during complete remission. It was suggested that polyclonal B cell activation might be involved in the development of this disorder along with T cell abnormalities.
Intravenous immunoglobulin therapy of membranous nephropathy: efficacy and safety, Preliminary results of the efficacy of high-dose intravenous human IgG in patients with biopsy-confirmed idiopathic membranous nephropathy (IMGN) were reported. Five patients with normal renal function (creatinine clearance 125.2 +/- 16 ml/min/1.73 m2 BSA) (Group A) and 4 patients with moderate renal insufficiency (creatinine clearance 65.5 +/- 8.3 ml/min/1.73 m2 BSA) (Group B) received pulse doses of IgG (0.4 g/kg BW) for 3 consecutive days; these 3-day boli were repeated 3 times at 21-day intervals; since then for a 10-month period one bolus once every 3 weeks has been administered. Five responder patients at the end of the trial received a new renal biopsy. In 4 Group A patients complete remission of proteinuria (daily proteinuria less than 0.2 g) was observed. whereas 1 patient showed partial remission (proteinuria 2 g/day). In Group B patients. 1 showed complete remission and 2 partial remission; in 1 patient no variation of proteinuria was noted. In responder patients clinical and biological findings of the nephrotic syndrome disappeared and a statistically significant increase of creatinine clearance was observed. In control biopsies at the end of the trial the immunofluorescence staining failed to find immunodeposits and recovery of glomerular lesions at light microscopy. In conclusion. IgG therapy seems to be of benefit to patients with IMGN but a randomized clinical trial to confirm this preliminary report is needed.
Hypothalamic regulatory peptides in obese and lean Zucker rats, 1. Hypothalamic concentrations of nine peptides with experimental effects on energy balance were compared in obese (fa/fa) and lean (Fa/?) male Zucker rats. To determine whether any peptide differences between obese and lean rats might be due to the overweight condition per se. separate groups of obese rats were food-restricted to reduce their body weight to lean values. 2. Concentrations of neuromedin B. a bombesin-like peptide. in the central hypothalamus were significantly higher in obese than in lean rats. This difference was not affected in food-restricted obese rats. 3. Hypothalamic levels of neuropeptide Y. an extremely potent central appetite stimulant. were similar in lean and freely fed obese rats but central hypothalamic levels of neuropeptide Y rose significantly in food-restricted obese rats. 4. These findings suggest that disturbances in hypothalamic neuromedin B concentrations may be involved in the obesity syndrome of the fa/fa Zucker rat. Increased central hypothalamic levels of neuropeptide Y in food-restricted rats suggest that this peptide may help to defend body weight by stimulating eating after weight loss.
Clarification of the identity of the major M2 autoantigen in primary biliary cirrhosis, 1. In primary biliary cirrhosis. the major M2 autoantigen. reacting with antimitochondrial antibodies in sera from greater than 90% of patients. has been identified as the E2 component of the pyruvate dehydrogenase complex. However. two recent reports suggest that alternative polypeptides may be major autoantigens. 2. The evidence that a 75 kDa subunit of complex I of the respiratory chain is a major autoantigen (Frostell. Mendel-Hartvig. Nelson. Totterman. Bjorkland & Ragan. Scand. J. Immunol. 1988; 28. 157-65) is refuted. The findings of Frostell et al. can be explained by contamination of complex I with the pyruvate dehydrogenase complex. evidence for which is presented here. 3. Inspection of the partial amino acid sequence of an unidentified mitochondrial autoantigen (Muno. Kominami. Ishii. Usui. Saituku. Sakakibara & Namihisa. Hepatology 1990; 11. 16-23) shows that it is the E1 beta-subunit of the pyruvate dehydrogenase complex. previously identified as a major autoantigen. and not a 'new' alternative major autoantigen. 4. These findings substantiate previous work showing that the mitochondrial M2 autoantigens identified so far in primary biliary cirrhosis are all polypeptide components of the pyruvate dehydrogenase complex or the other related 2-oxo acid dehydrogenase complexes.
Effect of destruction of the vascular endothelium upon pressure/flow relations and endothelium-dependent vasodilatation in resistance beds of spontaneously hypertensive rats, 1. Pressure/flow relationships were determined in the in situ blood-perfused superior mesenteric and hindquarters vascular beds of spontaneously hypertensive rats and Wistar-Kyoto normotensive rats before and after destruction of the endothelium with detergent. The effects of indomethacin on the regression of pressure on flow were also investigated in the spontaneously hypertensive rats. as were the endothelium-dependent relaxations in response to carbachol in the mesenteric bed. 2. In the spontaneously hypertensive rats the regression line of pressure on flow in the two vascular beds was both steeper and more elevated than in the Wistar-Kyoto rats. showing that there was greater resistance to flow in the hypertensive animals. Destruction of the endothelium significantly increased the slope of the regression in both Wistar-Kyoto and spontaneously hypertensive rats: the increases in the Wistar-Kyoto rats were 2.4 +/- 0.3 fold (mesenteric) and 2.0 +/- 0.5 fold (hindquarters) which were comparable with the respective increases of 1.6 +/- 0.3 fold and 1.8 +/- 0.3 fold in the spontaneously hypertensive rats. 3. Indomethacin (5 mg/kg. intravenously) had no effect on the pressure/flow relations in either of the vascular beds of the spontaneously hypertensive rats. 4. The dose-response curves for the endothelium-dependent vasodilatation in response to carbachol were not significantly different in spontaneously hypertensive and Wistar-Kyoto rats. 5. The results suggest that tonic release of endothelium-derived relaxing factor has similar effects in modulating resistance vessel tone in vivo in both hypertensive and normotensive rats.
Plasma profiles and removal rates of inorganic sulphate, and their influence on serum ionized calcium, in patients on maintenance haemodialysis, 1. Regular dialysis treatment is reported to remove inorganic sulphate. but not to restore its level to normal. To evaluate the adequacy of modern dialysis techniques in maintaining the sulphate balance. intra- and interdialysis plasma profiles and removal rates of sulphate were studied in 20 stable patients on maintenance haemodialysis. The influence of sulphate levels on the distribution of calcium-complex species was also investigated. 2. Sulphate was determined by ion-exchange chromatography of both serum ultrafiltrates. taken at the start of. during. at the end of. and at 24 h and 48 h after a dialysis session. and whole diffusate collections. Dialyser clearances of sulphate were assessed by two independent procedures and compared with those of urea and creatinine. on two different methods of dialysis. i.e. traditional haemodialysis with Cuprophan hollow fibre filters. and haemodiafiltration with high-flux Polysulphone or polyacrylonitrile dialysers. Concentrations of the main serum ions were determined before and after dialysis and used to solve a multiple mass balance equation system by which concentrations of the calcium-complex species were calculated. 3. Before dialysis. sulphate levels were eight times those determined in 17 control subjects and remained higher than normal at the end of dialysis. These changes were independent of the dialysis procedure. There was a close correlation between serum levels of sulphate and creatinine. Dialyser clearances of sulphate were comparable with those of creatinine. but lower than those of urea. Clearances of all solutes were higher on haemodiafiltration.
Ranitidine suppresses aluminium absorption in man, 1. Intragastric pH monitoring was performed before and after the single-blind administration of ranitidine or placebo (saline) in eight healthy subjects and four patients with end-stage renal disease who were on regular haemodialysis. 2. The subjects were studied on two occasions and were given aluminum hydroxide (1185 mg) orally 90 min after the administration of ranitidine or saline. 3. Plasma aluminum concentrations and. in normal men. urinary excretion of aluminum were monitored before and after the oral aluminum load. 4. Intragastric pH increased significantly with ranitidine but not with placebo (P less than 0.001). Urinary aluminum excretion increased significantly after the administration of aluminum hydroxide during the placebo phase (P less than 0.001) but not during the ranitidine phase. Plasma aluminium concentrations were higher in the patients with renal failure than in the normal subjects (P less than 0.05). but were unchanged in both groups after the oral aluminium load. 5. This study shows that gastric pH is an important factor in the modulation of aluminum absorption in man. and indicates that reducing gastric acid secretion with ranitidine may reduce the toxicity of orally administered aluminium compounds.
Evidence for altered Na+/H+ antiport activity in cultured skeletal muscle cells and vascular smooth muscle cells from the spontaneously hypertensive rat, 1. Intracellular pH and Na+/H+ antiport activity were determined by a fluorimetric method in cultured skeletal muscle cells (myoblasts) and aortic vascular smooth muscle cells from spontaneously hypertensive and normotensive Wistar-Kyoto rats. 2. The intracellular pH was significantly more alkaline at three different extracellular pH values in both myoblasts and vascular smooth muscle cells from the spontaneously hypertensive rats than in those from the normotensive control rats. 3. A kinetic analysis of the Na+/H+ antiport activity in these cells showed that the raised activity in the spontaneously hypertensive rats was due to an increased maximal transport capacity in vascular smooth muscle cells and to an increase in the affinity of the antiport for internal H+ in the myoblasts. 4. When the extracellular pH was reduced in the skeletal muscle cells of both types of rat. the intracellular pH fell. However. in vascular smooth muscle cells. a reduction in the extracellular pH was not associated with a fall in the intracellular pH. This resistance of the intracellular pH to changes in the extracellular pH differentiates vascular smooth muscle cells from other cells that have been studied in this way.
Deglycosylation of alpha 1-proteinase inhibitor is impaired in the faeces of patients with active inflammatory bowel disease (Crohn's disease), 1. alpha 1-Proteinase inhibitor (alpha 1-antitrypsin) was excreted in the faeces of patients with inflammatory bowel disease in different molecular forms: Mr-51.000 and Mr-45.000 forms were widely found in the stools of patients with active disease. whereas a Mr-38.000 species was frequently recovered from healthy subjects and patients with quiescent disease (Mizon. Becuwe. Balduyck et al. Clin. Chem. 1988; 34. 2268-70). 2. N-Terminal sequencing of the Mr-38.000 form of alpha 1-proteinase inhibitor. after SDS/PAGE and electrotransfer on polyvinyl difluoride membranes. showed that it differed from plasma alpha 1-proteinase inhibitor by the loss of 17 N-terminal amino acids. 3. Carbohydrate analysis of the isolated Mr-38.000 form revealed a total lack of neutral sugars. 4. In contrast. the Mr-51.000 form of alpha 1-proteinase inhibitor is glycosylated and thus could be differentiated by virtue of its reactivity with concanavalin A. The analysis of 25 faecal extracts from patients with Crohn's disease allowed us to confirm that the presence of the glycosylated form of alpha 1-proteinase inhibitor was closely related to the degree of inflammation. 5. From these data. it may be hypothesized that the hydrolytic activity of some glycosidases is greatly reduced in active Crohn's disease.
Collagenous colitis: pathophysiologic considerations, Collagenous colitis. a cause of watery diarrhea characterized by a distinctive band of collagen under the surface epithelium of the colon. has been recognized with increasing frequency in recent years. The pathophysiology of collagenous colitis remains obscure. The thickening of the subepithelial collagen layer may be a response to chronic inflammation or a local abnormality of collagen synthesis. The precise mechanism of the diarrhea in collagenous colitis is also unclear. and it has not been possible to link the diarrhea directly to the excess collagen deposition. The relationship between collagenous colitis and lymphocytic colitis. another type of microscopic colitis. remains to be defined; elucidating the relationship between the two disorders may provide clues to the pathophysiology of both.
Effect of cisapride on chronic idiopathic constipation in children, The efficacy of cisapride. a new prokinetic drug. as a treatment for chronic functional constipation of childhood was studied in 20 constipated children. Each subject had a stool frequency less than 4/week and/or total gastrointestinal transit time greater than 33 hr and was randomly assigned to double-blind treatment with either cisapride (N = 10) or placebo (N = 10) for 12 weeks. Stool habits. total gastrointestinal transit time. and anorectal motility were evaluated in all children before and at the end of the treatment period. Cisapride significantly increased stool frequency from 1.2 +/- 0.6 to 5.1 +/- 1.9 stools/week (mean +/- SD; P less than 0.05). whereas the lesser effect of placebo was not significant (1.2 +/- 0.8 to 2.8 +/- 0.8 stools/week; P = 0.4). Both treatments significantly (P less than 0.05) decreased laxative or suppository use. Total gastrointestinal transit time was decreased by cisapride (90.8 +/- 9.2 hr to 57.2 +/- 20.2 hr; P less than 0.05) but was not affected by placebo. Anorectal manometry showed that cisapride. but not placebo. significantly decreased the rectoanal inhibitory reflex threshold and the conscious rectal sensitivity threshold. It is concluded that cisapride improves gastrointestinal motility and bowel habits in children with chronic idiopathic constipation and may be useful in the management of some children with this disorder.
Inhibitor of interleukin-1 alpha and interleukin-1 beta-induced T-cell activation in serum of patients with active Crohn's disease, Interleukin-1 is a family of polypeptides with a wide spectrum of immunoinflammatory activities pertinent to Crohn's disease. including T-cell activation. Using specific enzyme-linked immunosorbent assays. only sera from two of 19 patients (11%) with active Crohn's disease contained interleukin-1 alpha and interleukin-1 beta activity. Using the thymocyte proliferation assay. sera from the same patients contained significantly increased inhibitory activity against interleukin-1 alpha (P = 0.025) and interleukin-1 beta-induced cell activation (P = 0.00005) as compared with controls. Changes in both interleukin-1 alpha (P = 0.020) and interleukin-1 beta (P = 0.012) inhibitor concentrations correlated significantly with changes in clinical disease activity. None of the patient sera contained IgG or IgM autoantibodies to IL-1 alpha. nor did they exert significant inhibitory activity against interleukin 1 beta in the fibroblast prostaglandin E2-induction assay. Taken together. these data provide evidence for the presence of one or several regulators of interleukin-1-induced T-cell activation in sera from patients with active Crohn's disease.
Mucosal and systemic IgA anti-gliadin antibody in celiac disease. Contrasting patterns of response in serum, saliva, and intestinal secretions, Serum IgA anti-gliadin antibody estimation is a recognized screening method for celiac disease. However. celiac disease is primarily a small intestinal mucosal disorder. and so we have examined the possibility that secreted. mucosal IgA anti-gliadin antibody might provide a more relevant measure of gluten sensitivity than that obtained from serum tests. Serum IgA anti-gliadin antibody and serum. salivary. and small intestinal aspirate IgA anti-gliadin antibody were measured by enzyme-linked immunosorbent assay. Serum IgA and IgG anti-gliadin antibody were markedly increased in untreated celiacs (N = 31) as compared to normals (N = 20) or disease controls (N = 39) (P less than 0.0001). Levels were lower in treated (N = 30) than untreated celiacs (P less than 0.001). In intestinal aspirates both untreated and treated patients had similar levels of IgA anti-gliadin antibody (P = 0.48). but both were significantly higher than in controls (P less than 0.01). Salivary IgA anti-gliadin antibody. by contrast. was not increased in celiac patients as compared to controls. Serum IgA anti-gliadin antibody was the most sensitive (84%) and specific (95%) test for detecting untreated celiac disease. It was also the most useful in patient follow-up where it provides an early objective indicator of adherence to a gluten-free diet. Mucosal IgA responses to gliadin in celiac disease appear to be compartmentalized. with different portions of the gastrointestinal tract functioning as separate immunological organs. Our results also demonstrate that serum and secretory IgA production are under independent control.
IgA antiendomysial antibody test. A step forward in celiac disease screening, Serum IgA antiendomysial antibodies (EmA) were found in 61 (87%) of 70 adults and children with untreated celiac disease. whereas IgA antigliadin antibodies (AGA) and IgA R1-antireticulin antibodies (R1-ARA) were positive in 71% and 47%. respectively. of the same patients. Two of the nine untreated celiacs negative for IgA EmA showed positivity for IgA AGA. While IgA AGA and R1-ARA disappeared in all the celiacs tested one year after gluten-free diet. IgA EmA persisted at low titer in seven (18%) of these 38 subjects. although the jejunal biopsy showed a complete regrowth of jejunal villi. All the disease control patients as well as the blood donors tested were always negative for the three IgA antibodies. Our results state that the search for both IgA EmA and AGA gives the best results in the screening of celiac disease. since the positivity for at least one of these two antibodies allows identification with a 100% specificity of the 90% of untreated celiac patients.
U.S. experience with omeprazole in duodenal ulcer. Multicenter double-blind comparative study with ranitidine. The Omeprazole DU Comparative Study Group, To assess the comparative efficacy of omeprazole 20 mg. a proton pump inhibitor. versus ranitidine 150 mg twice a day. an H2-receptor antagonist. in healing duodenal ulcers we performed a randomized. double-blind. multicenter trial in 309 patients with endoscopically diagnosed ulcers. Patients were treated for up to four weeks and were seen at week 2 and at week 4. if unhealed at week 2. for determination of ulcer status by endoscopy. review of daily self-assessment symptom diaries. and clinical laboratory including fasting serum gastrin. Gastrin levels were repeated two weeks after cessation of study medication. Evaluation of baseline demographic and laboratory parameters demonstrated no significant differences between the two groups at entry. At week 2. 42% of the omeprazole and 34% of the ranitidine-treated patients were healed (P = NS). At week 4. there was a 19% advantage in ulcer healing for the omeprazole-treated patients in comparison to those treated with ranitidine (82% vs 63%. respectively. P less than 0.05). Healing of ulcers greater than or equal to 1.0 cm occurred in 83% of those treated with omeprazole versus 37% treated with ranitidine (P less than 0.01). There were no significant differences in rate of pain relief or incidence of clinical laboratory abnormalities. Mean fasting serum gastrin value during treatment increased over the baseline in both groups. (P less than 0.05). The percent change was significantly greater with omeprazole but few patients had elevations above the upper limit of normal for the assay. Both drugs were well tolerated. Omeprazole 20 mg demonstrated superiority in healing duodenal ulcers at four weeks in comparison to ranitidine 150 mg twice daily and was more effective in healing ulcers greater than or equal to 1.0 cm.
Insulin and glucagon therapy of acute hepatic failure, When insulin and glucagon are administered to rats with severe liver injury. survival is enhanced with an attenuation of the liver injury compared to that of untreated controls. In rats with acute liver injury both hormones produce a rapid normalization of hepatic protein content following initiation of DNA synthesis. When rats receive both hormones after partial hepatectomy. the first burst of DNA synthesis reaches a maximum earlier than that seen in controls. Both hormones enhance the increment of hepatic putrescine essential for DNA synthesis through activation of ornithine decaroxylase and/or spermidine-N1-acetyltransferase. The enhancement of putrescine content by each hormone is additive. Putrescine supplementation promotes hepatic DNA synthesis after hepatectomy. Based on these data. we conclude that a combination of insulin and glucagon is effective in the therapy of acute hepatic failure in rats. The restoration of liver function as well as the stimulation of liver cell proliferation via putrescine production may contribute to this effect.
Inhibitors of hepatic DNA synthesis in fulminant hepatic failure, In certain etiological groups of patients with fulminant hepatic failure. poor survival may be due to lack of liver regeneration. In vitro experiments have shown that fulminant hepatic failure serum is cytotoxic to rabbit hepatocytes and inhibits DNA synthesis on short-term incubation with isolated regenerating rat hepatocytes. When fulminant hepatic failure serum is injected into partially hepatectomized rats at the time of maximal DNA synthesis. [3H]thymidine incorporation into hepatic DNA is reduced significantly. The effect is greater with sera obtained from patients with fulminant hepatic failure due to non-A. non-B hepatitis or an adverse drug reaction and is associated with a less than 10.000-dalton fraction. No stimulation of DNA synthesis is observed with injection of the greater than 10.000-dalton serum fraction into normal rats. In preliminary experiments. no increase in epidermal growth factor production has been found in liver failure. Overall. the substances present in fulminant hepatic failure serum appear to be inhibitory rather than stimulatory for liver cell regeneration.
Cytologic brushings of ductal lesions during ERCP, Cytologic brushings of ductal lesions noted at ERCP are a reliable method of diagnosing malignancy. However. prior studies have involved only small numbers of patients. This study presents the results of attempted brushings in 69 patients. A satisfactory specimen was obtained in 62 patients (90%). The overall sensitivity was 44% with 100% specificity. Common bile duct brushings had a higher sensitivity rate than did pancreatic brushings. Similarly. biliary tract cancer was more likely to be diagnosed than was pancreatic cancer by brushing. Markedly atypical cells were identified in 36% of patients with a false negative cytology result. These findings were not seen in patients with benign disease. Two patients developed mild pancreatitis and one developed cholangitis. It is unclear what role the act of brushing had on causing these complications.
Endoscopic pulsed dye laser lithotripsy of gallbladder calculi in vivo, We have evaluated the efficacy and safety of pulsed dye laser lithotripsy of gallbladder calculi using a percutaneous endoscopic technique in a porcine model. Fragmentation was readily achieved in vivo. Using a combination of laser lithotripsy and saline lavage. complete removal of all stone debris was feasible through a 24 F tract (N = 3). However. the degree of fragmentation required rendered removal through a smaller tract inefficient. a mean 53% of stone mass being retrievable through a 16 F tract (N = 11). Repeated laser activation at 1 mm from the gallbladder mucosa produced minimal injury. regardless of pulse energy. When the laser fiber was pressed against the mucosa. perforation of the gallbladder was possible at therapeutic pulse energy. but this did not lead to clinical sequelae. We conclude that the pulsed dye laser is a safe and effective means of fragmenting gallbladder calculi in vivo.
Endoscopic retrograde hemorrhoidal sclerotherapy using 23.4% saline: a preliminary report, Historically. injection sclerotherapy has had a prominent role in the treatment of symptomatic hemorrhoids. Concern over sclerosant-related morbidity and dissatisfaction with anoscopic injection techniques has limited the application of this modality in the United States. This study reports an initial evaluation of 23.4% saline. used as a nonallergenic sclerosant. in the flexible endoscopic treatment of symptomatic internal hemorrhoids. Initial results in 19 patients with symptomatic grade I. II. or III hemorrhoids suggest that the technique is very effective in relieving bleeding. and frequently alleviates prolapse as well. The technique has proven to be well tolerated and associated with high patient satisfaction and low complication rates. with no serious complications noted. This modality is eminently suited for single session examination and therapy of the patient undergoing endoscopic evaluation for lower gastrointestinal bleeding whose findings are limited to hemorrhoidal disease.
Parameters for and safety of contact Nd:YAG laser irradiation of early gastric cancer: an in vitro study, Early gastric cancers have been treated by endoscopic contact Nd:YAG laser irradiation. The extent of thermal damage produced by this laser system has been inadequately investigated. In an in vitro study we have shown that contact laser probes produce consistent and reproducible thermal lesions in the human stomach wall. Contact laser energies of 40 to 60 joules are optimal for the ablation of early gastric cancer. Energies greater than 90 joules are associated with a high incidence of gastric perforation. Contact laser probes may have advantages over non-contact laser techniques for the endoscopic treatment of early gastric cancer in patients who are unfit for major surgery.
In vivo solute elimination of paired filtration dialysis, Paired filtration dialysis (PFD) is a new dialysis strategy whereby a hemofilter and a hemodialyzer are coupled in series. It has been assumed that this approach allows a better solute elimination than conventional hemodialysis (HD). allowing a shortening of dialysis time. To evaluate this hypothesis. solute elimination with PFD either with 0.4 m2 polysulphone (PS) and 1.36 m2 cuprophan (CU) 3x3 h/wk. or with 0.4 m2 PS and 1.06 m2 CU 3x4 h/wk. was compared to HD with 1.36 m2 CU. 3x4 hours weekly in the same patients. During PFD. 10L were ultrafiltered and substituted by saline. Overall extraction of UV absorbing solutes (MW less than 10.000 Dalton). and extraction of individual solutes identified by high performance liquid chromatography (HPLC) were compared as well as urea kinetics. For PFD 3x3 h overall extraction of UV-absorbing compounds and of hippuric acid was significantly higher than for HD 3x4 h (p less than 0.05). Overall extraction of UV-absorbing compounds and of all but one individual compound under study was markedly higher for PFD 3x4 h vs conventional HD 3x4 h (p less than 0.01). in spite of a higher diffusive area with the latter technique. No differences in urea kinetics were observed for the 3 strategies. It is concluded that solute extraction during PFD is higher than during HD. if the treatment time is the same. Even if treatment is shortened to 3x3 h weekly. solute extraction with PFD is at least as efficient as with HD.
Comparison of polyamide and polypropylene membranes for plasma separation, Plasma separation experiments were made with polyamide experimental prototype hollow-fiber plasma filters with surface areas between 0.025 m2 and 0.1090 m2 using bovine blood collected in acid citrate dextrose (ACD). The maximum filtration velocity rose with the wall shear rate gamma w as gamma w 0.72 +/- 0.02 and decreased with the length of fiber L as L-0.41 with a correlation coefficient of 0.97 +/- 0.02. The results were similar to those with polypropylene fibers. We also investigated the occurrence of hemolysis as a function of shear rate and transmembrane pressure. The free hemoglobin concentration of filtered plasma was checked using a U.V. spectrophotometer. It was concluded that polyamide membrane filters can be safely used for plasma separation from blood.
A comparison of hypertensive and nonhypertensive coronary care patients' cardiovascular responses to visitors, Patients with and without hypertension in a coronary care unit (n = 24) were compared with respect to cardiovascular responses to both a family visit and an interview by an investigator. Variables for each of the four cardiovascular indicators (systolic blood pressure. diastolic blood pressure. heart rate. and premature ventricular contractions) included the value before. the highest value during. the lowest value during. and the value after each social interaction condition. The highest group means for systolic blood pressure and heart rate were significantly higher for patients with hypertension than for patients without hypertension under both the interview and visit conditions. Differences in cardiovascular responses were not significantly greater for family visits than for interviews for patients with hypertension compared with those without hypertension. Thus. although hypertensive patients had greater cardiovascular reactivity to both social interaction conditions than nonhypertensive patients in the coronary care unit. family visits were no more physiologically stressful than a comparative interaction condition.
Failure of early electrocardiogram to predict successful thrombolysis. Effect of stunned myocardium, We investigated the value of the modified Selvester QRS score in predicting reperfusion in 74 patients with an acute myocardial infarction who were treated with intravenous streptokinase. Coronary angiography and time to peak creatine kinase level were used to determine the success of thrombolytic therapy. At 6 weeks a significant difference was seen between the QRS score of the patients in whom thrombolysis was successful compared with those in whom there was no reperfusion. There was. however. no difference between the QRS score of these groups of patients at 1 week. The ejection fraction at 1 week was 60% and 51%. respectively. The failure of the early electrocardiogram to predict reperfusion and improved left ventricular function may be a consequence of the stunned myocardium.
Factors affecting decisions made by family members of patients with severe head injury, An exploratory descriptive study was conducted to determine factors affecting decisions made by families of patients with severe head injury during the first two stages of recovery. Nineteen family members of 11 patients participated in this study. Five interviews of each family member were conducted over a 1-month period after the injury. Sixty decisions were identified by family members. Six factors: personal functioning. relationships. information. uncertain outcomes. environment. and emotions. were found to affect these decisions. The six factors identified by family members have specific implications for nursing.
Tracheal resection and reconstruction: indications, surgical procedure, and postoperative care, Nursing management of the patient undergoing tracheal resection and reconstruction is not well described in the literature. Over the last 25 years. nurses in the respiratory surgical intensive care unit at Massachusetts General Hospital in Boston have cared for more than 600 patients who have undergone this procedure. Using a diagnostic format. we have developed a plan of care for this patient population. In this article. the etiology of tracheal obstruction. its diagnosis and surgical correction. and nursing care of the patient after tracheal resection and reconstruction are presented.
Effect of aluminized covers on body temperature in patients having abdominal surgery, An unintended fall in body temperature is commonly associated with surgery. One promising strategy to help conserve body heat is use of covers made of aluminum-coated plastic. We compared the effect of three combinations of the covers (head cover. body covers. both) and a control condition on tympanic temperature in 60 adults having major abdominal surgery under general anesthesia. The covers were applied from the time of transport to the operating room until exit from the postanesthesia care unit (PACU). Tympanic temperature was measured with an infrared thermometer. Between transport and PACU entry. the four groups had mean temperature decreases ranging from 1.6 degrees to 2.3 degrees F (0.9 degree to 1.3 degrees C). After controlling for background variables affecting body temperature. adjusted PACU entry temperature was higher in the two groups with aluminized body covers. Regression analysis showed that use of the body covers accounted for 7% of the temperature variance at PACU entry and predicted a 0.9 degree F (0.5 degree C) higher temperature at that time. These findings indicate that aluminized body covers help to reduce heat loss in patients having major abdominal surgery.
Potential for injury: trauma after cardiopulmonary resuscitation, Cardiopulmonary resuscitation (CPR) is a technique that saves lives and is a measure that critical care practitioners use without hesitation. Potential complications from CPR. however. include injury. The reported incidence of such injuries ranges from 21% to more than 65%. Unfortunately. even properly executed CPR can lead to injury. The incidence of most common injuries. such as injury to the skin. bony thorax. and upper airway. may be limited by performance of proper basic and advanced life support. Limiting these injuries is important. Discovering them in successfully resuscitated victims. however. is critical to long-term recovery and rehabilitation. As future techniques for CPR evolve. further research needs to focus on those techniques that limit the potential for injury.
Refractoriness for ultrasonically nebulized distilled water and histamine after histamine challenge, Refractoriness for bronchial provocation frequently occurs after different challenge tests used to assess bronchial hyperresponsiveness in asthmatic patients. We investigated whether histamine inhalation could cause refractoriness for bronchoconstriction induced by ultrasonically nebulized distilled water (UNDW) and whether histamine causes tachyphylaxis for a subsequent histamine challenge in nine stable asthmatic patients. Preinhalation of histamine induced a significant diminished bronchoconstrictor response to UNDW cumulative dose of inhaled UNDW causing a 20% fall in forced expired volume in 1 s. The mean increased from 3.5 +/- 0.8 to 11.8 +/- 2.6 (SE) ml after histamine challenge (P less than 0.01). However. repeated inhalation of histamine did not change the bronchoconstrictor response to histamine within 1 h after rechallenge (P greater than 0.5). The magnitude of refractoriness for UNDW inhalation after preinhalation of histamine was correlated to the bronchoconstrictor response to histamine (r = 0.73. P less than 0.05). We conclude that inhaled histamine can induce refractoriness for UNDW. which seems to be related to the degree of bronchial hyperresponsiveness.
Force-velocity and 30-s Wingate tests in boys at high and low altitudes, The effects of high altitude (HA. 3.700 m) on performance during a force-velocity test (maximal anaerobic power. MAnP) and a 30-s Wingate test (mean power. P) were studied in boys 7-15 yr of age. Forty-seven children acclimatized to HA were compared with 101 living at low altitude (LA. 330 m). They had the same good nutritional status and the same level of physical activities [average 5.4 +/- 1.1 (SD) and 5.2 +/- 1.9 h/wk at HA and LA. respectively]. They performed the two tests using the same calibrated cycle ergometer. For the Wingate test. O2 uptake (VO2) during the 30 s and the peak of blood lactate concentration ([L]p) during the recovery were also measured. No difference in MAnP was observed between HA and LA. P. [L]p. and VO2 were lower at HA. This suggests that the altitude of 3.700 m did not affect the performance of the force-velocity test but reduced that of the Wingate test. This decrease in P was linked to a lower participation of glycolysis and aerobic metabolism. The latter is related to a reduced aerobic performance at HA. In addition. the slopes of the relationships between age and MAnP. P. and [L]p were the same at HA and LA. indicating that chronic hypoxia did not alter the development of the anaerobic metabolism during puberty.
Effect of ventilation with soluble and diffusible gases on the size of air emboli, Pulmonary hypertension resulting from venous air embolism is known to increase after ventilation with highly soluble and diffusible gases. Exacerbation of the hypertension could be due to further blockage of the circulation if the bubbles enlarge as a result of ingress of gas by diffusion. This mechanism has been frequently cited but lacks direct proof. To determine directly whether intravascular air bubbles actually enlarge when highly soluble and diffusible gases are inspired. we used microscopy to measure the size of gas emboli in vivo. When air bubbles were injected into the right atrium. the bubbles that appeared in pulmonary arterioles were larger during ventilation with helium or nitrous oxide than with air. Air bubbles injected into the pulmonary artery enlarged when the inspired gas was changed to helium or nitrous oxide. The direction. magnitude. and timing of changes in bubble size were consistent with a net diffusion of gas into the bubbles. These data support the idea that venous air emboli enlarge during ventilation with soluble and diffusible gases and thereby cause further vascular obstruction.
Dextran sulfate inhibits PMN-dependent hydrostatic pulmonary edema induced by tumor necrosis factor, We tested the hypothesis that neutrophil sequestration is required for the development of tumor necrosis factor- (TNF) induced neutrophil- (PMN) dependent pulmonary edema. TNF (3.2 X 10(5) U/kg ip) was injected into guinea pigs 18 h before lung isolation. After isolation. the lung was perfused with a phosphate-buffered Ringer solution. Dextran sulfate (mol wt 500.000) prevented the changes in pulmonary capillary pressure (Ppc; 8.5 +/- 0.8 vs. 12.8 +/- 0.8 cmH2O). lung weight gain (dW; +0.240 +/- 0.135 vs. +1.951 +/- 0.311 g). and pulmonary edema formation or wet-to-dry wt ratio [(W - D)/D; 6.6 +/- 0.2 vs. 8.3 +/- 0.5] at 60 min induced by PMN infusion into a TNF-pretreated lung. The unsulfated form of dextran had no protective effect [Ppc. dW. and (W - D)/D at 60 min: 11.9 +/- 0.9 cmH2O. +1.650 +/- 0.255 g. and 7.3 +/- 0.2. respectively]. whereas the use of another anionic compound. heparin. inhibited the TNF + PMN response [Ppc. dW. and (W - D)/D at 60 min: 5.6 +/- 0.4 cmH2O. +0.168 +/- 0.0.052 g. and 6.4 +/- 0.2. respectively]. Isolated lungs showed increased PMN myeloperoxidase (MPO) activity compared with control in TNF-treated lungs at baseline and 60 min after PMN infusion. Dextran sulfate. dextran. and heparin inhibited the increase in MPO activity. The data indicate that inhibition of PMN sequestration alone is not sufficient for the inhibition of PMN-mediated TNF-induced hydrostatic pulmonary edema and that a charge-dependent mechanism mediates the protective effect of dextran sulfate.
Oxygen transport during steady-state submaximal exercise in chronic hypoxia, Arterial O2 delivery during short-term submaximal exercise falls on arrival at high altitude but thereafter remains constant. As arterial O2 content increases with acclimatization. blood flow falls. We evaluated several factors that could influence O2 delivery during more prolonged submaximal exercise after acclimatization at 4.300 m. Seven men (23 +/- 2 yr) performed 45 min of steady-state submaximal exercise at sea level (barometric pressure 751 Torr). on acute ascent to 4.300 m (barometric pressure 463 Torr). and after 21 days of residence at altitude. The O2 uptake (VO2) was constant during exercise. 51 +/- 1% of maximal VO2 at sea level. and 65 +/- 2% VO2 at 4.300 m. After acclimatization. exercise cardiac output decreased 25 +/- 3% compared with arrival and leg blood flow decreased 18 +/- 3% (P less than 0.05). with no change in the percentage of cardiac output to the leg. Hemoglobin concentration and arterial O2 saturation increased. but total body and leg O2 delivery remained unchanged. After acclimatization. a reduction in plasma volume was offset by an increase in erythrocyte volume. and total blood volume did not change. Mean systemic arterial pressure. systemic vascular resistance. and leg vascular resistance were all greater after acclimatization (P less than 0.05). Mean plasma norepinephrine levels also increased during exercise in a parallel fashion with increased vascular resistance. Thus we conclude that both total body and leg O2 delivery decrease after arrival at 4.300 m and remain unchanged with acclimatization as a result of a parallel fall in both cardiac output and leg blood flow and an increase in arterial O2 content.
Ventilation in newborn rats after gestation at simulated high altitude, Pregnant rats were kept at a simulated altitude of 4.500 m (PO2 91 Torr) for the whole of gestation and returned to sea level 1 day after giving birth. During pregnancy. body weight gain and food intake were approximately 30% less than in controls at sea level. Measurements were made on the 1-day-old (HYPO) pups after a few hours at sea level. In normoxia. ventilation (VE) measured by flow plethysmography was more (+17%) and O2 consumption (VO2) measured by a manometric method was less (-19%) than in control (CONT) pups; in HYPO pups VE/VO2 was 44% greater than in CONT pups. In acute hyperoxia. VE/VO2 of HYPO and CONT pups decreased by a similar amount (15-20%). indicating some limitation in O2 availability for both groups of pups in normoxia. However. VE/VO2 of HYPO pups. even in hyperoxia. remained above (+34%) that of CONT pups. HYPO pups weighed slightly less than CONT pups. their lungs were hypoplastic. and their hearts were a larger fraction of body weight. An additional group of female rats was acclimatized (8 days) to high altitude before insemination. During pregnancy. body weight gain and food intake of these females were similar to those of pregnant rats at sea level. Measurements on the 1-day-old pups of this group were similar to those of HYPO pups. We conclude that newborn rats born after hypoxic gestation present metabolic adaptation (low VO2) and acclimatization (high VE/VO2). possibly because of hypoxemia. Maternal acclimatization before insemination substantially alters maternal growth in hypoxia but does not affect neonatal outcome.
Allopurinol-induced effects in premature baboons with respiratory distress syndrome, To test the hypothesis that administration of allopurinol could modify the response to prolonged hyperoxia in premature baboons (140 days gestation) with respiratory distress syndrome. we evaluated physiological. pathological. and lung biochemical parameters in groups of premature baboons treated with mechanical ventilation and exposed to various amounts of oxygen for 6 days. Three groups of experimental animals were studied. including animals that received oxygen as needed to maintain arterial oxygen between 60 and 80 Torr [inspiratory O2 concentration- (FIO2) PRN]. animals that received 100% oxygen continuously but also received allopurinol intravenously at a dose of 10 mg.kg-1.day-1 (FIO2-1.0 + allopurinol). and animals that received 100% oxygen continuously and the vehicle for allopurinol administration (FIO2-1.0). Pathological examinations of the experimental animals showed evidence of lung injury in both 100% oxygen-exposed groups. but the allopurinol-treated animals had findings more compatible with the FIO2-PRN group. with relatively few macrophages or polymorphonuclear lymphocytes being present in lung tissue. Lungs of animals treated with allopurinol were also more distensible and had a trend toward decreased lung water compared with the FIO2-1.0 group. Allopurinol-treated animals were able to induce lung glutathione concentrations and glutathione-related and antioxidant enzyme activities compared with the normoxic control (FIO2-PRN) group. Ventilator pressure requirements were also decreased in the allopurinol-treated animals compared with the FIO2-1.0 controls after 42 h. These data suggest that treatment of hyperoxia-exposed premature baboons with allopurinol for the first 6 days of life results in significant changes in lung responses and antioxidant defenses compared with vehicle-treated baboons exposed to 100% oxygen for the same time period.
Ventilatory responses to hypoxia and hypercapnia in awake rats pretreated with capsaicin, Ventilatory responses to hypoxia and hypercapnia were measured by indirect plethysmography in unanesthetized unrestrained adult rats injected neonatally with capsaicin (50 mg/kg) or vehicle. Such capsaicin treatment ablates a subpopulation of primary afferent fibers containing substance P and various other neuropeptides. Ventilation was measured while the rats breathed air. 12% O2 in N2. 8% O2 in N2. 5% CO2 in O2. or 8% CO2 in O2. Neonatal treatment with capsaicin caused marked alterations in both the magnitude and composition of the hypoxic but not hypercapnic ventilatory response. The increase in minute ventilation evoked by hypoxia in the vehicle-treated rats resulted entirely from an increase in respiratory frequency. In the capsaicin-treated rats the hypoxic ventilatory response was significantly reduced owing to an attenuation of the frequency response. Although both groups responded to hypoxia with a shortening in inspiratory and expiratory times. rats treated with capsaicin displayed less shortening of both respiratory phases. By contrast. hypercapnia induced a brisk ventilatory response in the capsaicin-treated group that was similar in magnitude and pattern to that observed in the vehicle-treated group. Analysis of the components of the hypercapnic ventilatory responses revealed no significant differences between the two groups. We. therefore. conclude that neuropeptide-containing C-fibers are essential for the tachypnic component of the ventilatory response to hypoxia but not hypercapnia.
Differential activation within costal diaphragm during rapid-eye-movement sleep in cats, Simultaneous recordings of the diaphragmatic electromyogram (EMG) were made from two separate regions of the costal diaphragm in six normal cats. The diaphragmatic activities were always synchronous and the amplitudes and rates of rise were similar during slow-wave sleep. In contrast. during natural rapid-eye-movement (REM) sleep. different activity was often present in the two leads. These differences were in the time of onset and offset. as well as in the amplitude and spike patterns. and occurred in approximately 5-20% of the diaphragmatic bursts averaged over the entire REM sleep period. With respect to eye movement density. the rate of differential activation was higher during periods of high density (26%) than in the absence of eye movements (1%) in the four animals for which these data were available. Differential activation of portions of the costal diaphragm is apparently a normal event of REM sleep. This could result from descending state-specific phasic neuronal activity that bypasses the medullary respiratory generator. Differential activation of portions of the diaphragm could contribute to disordered ventilation during REM sleep.
Development of the pulmonary vasculature in newborn lambs: structure-function relationships, Our objectives were 1) to describe the quantitative light microscopy and ultrastructure of newborn lamb lungs and 2) to correlate hemodynamic changes during normoxia and hypoxia with the morphology. By light microscopy. we measured the percent muscle thickness (%MT) and peripheral muscularization of pulmonary arteries and veins from 25 lambs aged less than 24 h. 2-4 days. 2 wk. and 1 mo. At the same ages. lungs were isolated and perfused in situ and. after cyclooxygenase blockade with indomethacin. total. arterial (delta Pa). middle (delta Pm). and venous pressure gradients at inspired O2 fractions of 0.28 (mild hyperoxia) and 0.04 (hypoxia) were determined with inflow-outflow occlusion. During mild hyperoxia. delta Pa and delta Pm fell significantly between 2-4 days and 2 wk. whereas during hypoxia. only delta Pm fell. The %MT of all arteries (less than 50 to greater than 1.000 microns diam) decreased. and peripheral muscularization of less than 100-microns-diam arteries fell between less than 4 days and greater than 2 wk. Our data suggest that 1) the %MT of arteries determines normoxic pulmonary vascular resistance. because only arterial and middle segment resistance fell. 2) peripheral muscularization is a major determinant of hypoxic pulmonary vasoconstriction. because we observed a fall with age in peripheral muscularization of less than 100-micron-diam arteries and in delta Pm with hypoxia. and 3) the arterial limit of the middle segment defined by inflow-outflow occlusion lies in 100- to 1.000-microns-diam arteries.
Differing activities of medullary respiratory neurons in eupnea and gasping, Our purpose was to compare further eupneic ventilatory activity with that of gasping. Decerebrate. paralyzed. and ventilated cats were used; the vagi were sectioned within the thorax caudal to the laryngeal branches. Activities of the phrenic nerve and medullary respiratory neurons were recorded. Antidromic invasion was used to define bulbospinal. laryngeal. or not antidromically activated units. The ventilatory pattern was reversibly altered to gasping by exposure to 1% carbon monoxide in air. In eupnea. activities of inspiratory neurons commenced at various times during inspiration. and for most the discharge frequency gradually increased. In gasping. the peak discharge frequency of inspiratory neurons was unaltered. However. all commenced activities at the start of the phrenic burst and reached peak discharge almost immediately. The discharge frequencies of all groups of expiratory neurons fell in gasping. with many neurons ceasing activity entirely. These data are consistent with the hypothesis that brain stem mechanisms controlling eupnea and gasping differ fundamentally.
Effect of slowly increasing elastic load on breathing in conscious humans, Because the detection of added loads is a function of the step change in load relative to background level of load (Weber's law). we reasoned that detection may be delayed if the load is increased in very small steps over a protracted period. This would permit the study of subliminal load responses over a greater range than would otherwise be possible. In 13 healthy males. an external elastic load (delta E) was added in very small steps (load increased every few seconds) such that delta E increased from zero to 6.0 cmH2O/l in 18 min. Each subject underwent a control study in which an identical protocol was followed but no load was added. Five subjects sensed the load after a variable period of load application. Their results were discarded. In the remaining eight subjects. there was no perception of increased load throughout the 18 min. By comparison with the control studies in the same subjects. there was a progressive reduction in tidal volume and breath duration with loading. To assess the response to an increase in load associated with perception. in five of the eight "nonsensers" the load was suddenly doubled (delta E = 6 cmH2O/l) at the end of the 18 min of progressive nonsensed loading. This evoked perception in all subjects and was associated with highly variable responses in tidal volume and breath duration. We conclude that tachypnea associated with elastic loading in conscious humans is a reflex response that is facilitated by consciousness but does not require perception.
Spectral vs. compartmental averaging of VA/Q distributions: confidence limits, We have investigated the method of statistical averaging as a nonparametric approach to obtain a representative ventilation-perfusion (VA/Q) distribution that exemplifies the family of compatible solutions for multiple inert gas elimination data. The variability of the compatible solutions was examined by determining the standard deviation of the statistical average. For six inert gases. it can be predicted that a distribution with up to seven contiguous nonzero VA/Q compartments can be uniquely recovered. whereas the compatible family becomes more diverse. the broader the distribution. For a given compatible family consisting of multimodal distributions with various phase relationships. the average distribution was found to display an uncharacteristically unimodal shape as a result of modal smoothing. To avoid this possible artifact. an alternative approach was adopted in which statistical averaging was performed in the frequency domain. For both deterministic and empirical data. the energy spectra of all feasible VA/Q distributions displayed a well-defined low-frequency band that was invariant within the compatible family and with a bandwidth that approximated the predicted sampling cutoff frequency. The nonuniqueness of the result was ascribable to a variable high-frequency band that was due to an aliasing effect. For a wide range of clinical data. the representative distributions resulting from compartmental and spectral averaging were indistinguishable from each other and had little variability both in the VA/Q and frequency domains. For these cases. therefore. the resolving power of the recovery algorithm was not critical. Finally. an efficient method of finding the average distribution was proposed.
Changes of lung surfactant and pressure-volume curve in bleomycin-induced pulmonary fibrosis, We investigated whether alveolar surface force increased and participated in the lung pressure-volume relationship in bleomycin-induced pulmonary fibrosis in hamsters and. if so. whether lung surfactant was hampered in the lungs. On the air-filled pressure-volume curve. decreases of lung volume from control level were significantly higher at 3-8 cmH2O pressure on day 10 than on day 30. Because the change of lung tissue elasticity evaluated from the saline-filled pressure-volume curve was equal for the 2 days. the higher decrease of air volume on day 10 was due primarily to contribution of alveolar surface force. Pressure differences between deflation limbs of air-filled and saline-filled pressure-volume curves. which represented net alveolar surface force. were significantly higher at any lung volume between 50 and 90% total lung capacity on day 10. but almost no significance was observed on day 30. Phospholipid concentration in bronchoalveolar lavage fluid significantly decreased on day 10 but had improved by day 30. Analysis of phospholipid species in purified lung surfactant showed decreased fractions of disaturated phosphatidylcholine and phosphatidylglycerol on day 10. Surface-active properties of the surfactant. measured by a modified Wilhelmy balance. were remarkably hampered on day 10. but most of them had improved by day 30. We consider that the quantitative and functional abnormalities of lung surfactant have a part in the aggravation of lung mechanics in the acute phase of pulmonary fibrosis.
Pulmonary vascular distensibility of arterial, middle, and venous regions in newborn lambs, The pulmonary circulation in the adult is characterized by being relatively distensible. but whether the newborn lung shares this feature is less certain. We perfused isolated lungs treated with indomethacin from lambs of four ages (less than 1. 2-4. 12-14. and 30-32 days) to determine the effects of increasing left atrial pressure on the pulmonary vascular pressures measured by vascular inflow and outflow occlusion. An index of pulmonary vascular distensibility was assessed by comparing the slope of the pulmonary vascular pressure at the upstream end of a region as a function of the pressure at the downstream end of the region. A vascular distensibility index (VDI) of 1 indicates a rigid nondistensible system. whereas a VDI less than 1 indicates some degree of distensibility. During normoxia. lungs from all age groups were relatively indistensible as determined by VDI for the total vasculature (VDItotal) as well as for the different regions based on occlusion pressures (VDIarterial. VDImiddle. and VDIvenous). There were significant effects of age on the VDItotal. with decreases in the normoxic values occurring over the first 12-14 days of age. indicating an increase in pulmonary vascular distensibility. Only the VDIvenous was similarly affected by increasing neonatal age. Hypoxia significantly reduced the VDItotal in these same age groups. In addition. hypoxia. which increased the pressure gradients of the arterial and middle regions. significantly increased the VDIarterial in the youngest and oldest age groups but significantly decreased the VDImiddle at all ages by approximately 50%. In summary. we observed age-related changes in the vascular distensibility of the pulmonary circulation. with the VDItotal decreasing with increasing postnatal age.
Abdominal muscle activity during CO2 rebreathing in sleeping neonates, Comparison of the abdominal muscle response to CO2 rebreathing in rapid-eye-movement (REM) and non-REM (NREM) sleep was performed in healthy premature infants near full term. Eight subjects were studied at a postconceptional age of 40 +/- 1.6 (SD) wk (range 38-43 wk) during spontaneous sleep. Sleep stages were defined on the basis of electrophysiological and behavioral criteria. and diaphragmatic and abdominal muscle electromyographic activity was recorded by cutaneous electrodes. The responses to CO2 were measured by a modified Read rebreathing technique. The minute ventilation and diaphragmatic and abdominal muscle electromyographic activities were calculated and plotted against end-tidal CO2 partial pressure. Both the ventilatory and diaphragmatic muscle responses to CO2 decreased from NREM to REM sleep (P less than 0.05). Abdominal muscles were forcefully recruited in response to CO2 rebreathing during NREM sleep. In REM sleep. abdominal muscle response to CO2 was virtually absent or decreased compared with NREM sleep (P less than 0.05). We conclude that 1) the abdominal muscles are recruited during NREM sleep in response to CO2 rebreathing in healthy premature infants near full term and 2) the abdominal muscle recruitment is inhibited during REM sleep compared with NREM sleep. and this REM sleep-related inhibition probably contributes to the decrease in the ventilatory response to CO2 rebreathing in REM sleep.
Comparison of muscle sympathetic responses to hemorrhage and lower body negative pressure in humans, We compared changes in muscle sympathetic nerve activity (SNA) during graded lower body negative pressure (LBNP) and 450 ml of hemorrhage in nine healthy volunteers. During LBNP. central venous pressure (CVP) decreased from 6.1 +/- 0.4 to 4.5 +/- 0.5 (LBNP -5 mmHg). 3.4 +/- 0.6 (LBNP -10 mmHg). and 2.3 +/- 0.6 mmHg (LBNP -15 mmHg). and there were progressive increases in SNA at each level of LBNP. The slope relating percent change in SNA to change in CVP during LBNP (mean +/- SE) was 27 +/- 11%/mmHg. Hemorrhage of 450 ml at a mean rate of 71 +/- 5 ml/min decreased CVP from 6.1 +/- 0.5 to 3.7 +/- 0.5 mmHg and increased SNA by 47 +/- 11%. The increase in SNA during hemorrhage was not significantly different from the increase in SNA predicted by the slope relating percent change in SNA to change in CVP during LBNP. These data show that nonhypotensive hemorrhage causes sympathoexcitation and that sympathetic responses to LBNP and nonhypotensive hemorrhage are similar in humans.
Coordination of swallowing and respiration in unconscious subjects, We investigated the coordination of swallowing and breathing in 11 unconscious patients with an endotracheal tube in place during the recovery period from general anesthesia. Swallows occurred during both the inspiratory and expiratory phases with no preponderant occurrence during either phase. When a swallow occurred during inspiration. the inspiration was interrupted immediately and was followed by expiration. but the durations of both inspiration and expiration were progressively increased as the time from the onset of inspiration to the onset of swallowing was progressively delayed. A swallow coinciding with the expiratory phase progressively prolonged the duration of the expiration that had been interrupted as the timing of swallowing was progressively delayed. Repeated swallows invariably and in a predictable manner caused changes in the breathing pattern. Thus when the frequency of regularly repeated swallows was relatively high. the breathing pattern was characterized by regular. shallow. and rapid breaths. When the frequency of regularly repeated swallows was relatively low. the breathing pattern was characterized by regular. deep. and slow breaths. When the frequency of repeated swallows was irregular. the breathing patterns were characterized by inconsistent changes in tidal volume and respiratory frequency. Our results indicate that. in unconscious subjects. some mechanisms integrating respiration and swallowing are operative and responsible for changes in breathing patterns during swallowing.
Axillary granular parakeratosis, The term axillary granular parakeratosis is proposed for a unique axillary eruption with distinct histopathologic features. Four middle-aged to elderly patients (three women. one man) had unilateral or bilateral. usually pruritic. hyperpigmented to bright red patches in the axillae. Biopsy specimens revealed severe compact parakeratosis with the stratum corneum measuring 80 to 250 microns in maximal thickness. maintenance of the stratum granulosum. remarkable retention of keratohyaline granules throughout the stratum corneum. and vascular proliferation and ectasia. A contact reaction to an antiperspirant/deodorant is suspected as the cause. We speculate that the offending agent alters the maturation sequence of the stratum granulosum and stratum corneum. possibly by interfering with the degradation of filaggrin precursor to filaggrin units.
Systematic underreporting of cutaneous malignant melanoma in Massachusetts. Possible implications for national incidence figures, An independent tabulation of incidence of cutaneous malignant melanoma in Massachusetts indicates that 12% and perhaps as many as 19% of new cases of cutaneous malignant melanoma in Massachusetts are not recorded in the Massachusetts Cancer Registry. significantly more than the expected 5% (p = 0.0001). The increasing number of nonhospital medical settings in which melanomas can be diagnosed and/or treated appears to account for this discrepancy. We suspect that these findings in Massachusetts also apply to cancer reporting systems in other regions of the United States. We suggest that the true incidence of cutaneous malignant melanoma in Massachusetts. and perhaps in the United States. may be significantly higher than reported.
Immunohistologic evaluation of the effect of cyclosporine treatment on the lichen planus immune infiltrate, We have investigated immunohistologically the cutaneous immune infiltrate in the lesions of five patients with severe. extensive lichen planus of recent onset before and after 15 days of oral. low-dose cyclosporine therapy (3 mg/kg/day). Before therapy. we observed an abnormal bandlike cellular infiltrate localized in the papillary dermis. composed mostly of CD3+ cells. with a prevalence of CD4+ cells. Infiltrating lymphocytes showed markers of activation (HLA-DR antigens and interleukin 2 receptor). and there were many Langerhans (CD1+) cells in the dermal infiltrate. After 15 days of cyclosporine therapy. we observed a dramatic decrease in the total number of T cells and a corresponding decrease in interleukin 2 receptor-positive activated CD25+ cells and in antigen-presenting cells (CD1+ and CD14b+). These changes were concurrent with clinical improvement. Our results are compatible with the hypothesis that the inhibition of CD4 T cells by cyclosporine might explain the drug's therapeutic action and that the interaction between antigen-presenting cells and CD4 T cells is important in the pathogenesis of lichen planus.
Multiple basal cell carcinomas and HLA frequencies in southern Australia, An association between HLA-DR1 and the development of multiple basal cell carcinomas was detected in southern Australia. A reduction in HLA-DR4 was found in patients with basal cell carcinoma compared with a local control group. The relative risk for HLA-DR1 was 2.1. which was lower than that for persons in farther countries from the equator.
Atypical polypoid dermatofibroma: report of two cases, Two cases of a hitherto undescribed special variant of dermatofibroma are reported. A man and a woman. aged 57 and 52 years. respectively. had slowly growing cutaneous tumors on the lower extremities. The tumors were exophytic and polypoid. 10 and 6 cm in maximal diameters. respectively; they were covered by rough nonulcerated skin and were joined by a short pedicle to an indurated base. Histologic examination showed some features of an otherwise conventional dermatofibroma. whereas the polypoid component was hypercellular and showed striking atypia and scattered mitotic figures. After 32 and 28 months' follow-up. the lesions did not recur after surgical excision. We suggest the term atypical polypoid dermatofibroma to summarize the special clinicopathologic features of these tumors.
HLA typing in polymorphous light eruption, Human leukocyte antigen typing of 41 white patients with polymorphous light eruption (limited concept) showed no significant differences when compared with the typing of 51 white control subjects. We previously found that actinic prurigo. an idiopathic photodermatosis particularly associated with Amerindians. has a positive association with antigens A24 and Cw4 and a negative association with A3. We suggest. on the basis of both laboratory and clinical findings. that polymorphous light eruption (limited concept) and actinic prurigo are two different and distinct diseases.
Incidence of nonmelanoma skin cancer in New Hampshire and Vermont, A survey of skin cancer occurrence between June 1979 and May 1980 among residents of New Hampshire and Vermont identified 277 cases of squamous cell carcinoma and 1761 cases of basal cell carcinoma. The age-adjusted incidence rates for squamous cell carcinoma (32 per 100.000 in men. 8 per 100.000 in women) and for basal cell carcinoma (159 per 100.000 in men. 87 per 100.000 in women) were similar to those reported in other populations in the northern United States. Skin cancer incidence was particularly high among men more than 70 years of age and a large proportion (greater than 30%) of patients 55 years or older had a history of at least one previous skin cancer.
Acitretin plus UVB therapy for psoriasis. Comparisons with placebo plus UVB and acitretin alone, UVB radiation is beneficial for the treatment of psoriasis vulgaris. Patients with recalcitrant disease. however. are slow to respond to UVB phototherapy with and without the use of coal tars or emollients. Etretinate and. more recently. acitretin have proved useful. but clinical improvement is slow when they are used as monotherapy in plaque psoriasis. Each drug also produces side effects. some of which are dose related. This study was designed to compare results of treatment with UVB combined with either acitretin (50 mg/day) or placebo to determine if psoriasis would respond faster and to less cumulative exposure to UVB and acitretin. The psoriatic disease cleared to a greater degree in patients treated with acitretin-UVB with fewer treatments and smaller amounts of UVB radiation than in patients treated with either placebo-UVB or acitretin alone.
UVABA therapy for psoriasis. Efficacy with shortened treatment times with the combined use of coal tar, anthralin, and metal halide ultraviolet machines, Rapid clearing of psoriasis in a psoriasis treatment center setting has been obtained with a combination of short-contact coal tar. phototherapy from high-pressure metal halide lamps (consisting of UVA and UVB). and short-contact high-potency anthralin therapy. These intensive 1 1/2- to 2-hour treatment sessions done three or four times weekly were as efficacious as reported responses to PUVA therapy or conventional psoriasis day care therapy. The treatment schedule allows minimal time away from work. decreased hours per week in contact with crude coal tar. shortened UV treatment times. decreased cost. and a low risk of side effects. It is suggested that the use of UVA and UVB combined with anthralin (UVABA) is effective for many patients with moderate to severe psoriasis.
A 12-month treatment of severe psoriasis with acitretin: results of a Canadian open multicenter study, Both etretinate and its principal metabolite. acitretin. are efficacious in the treatment of psoriasis. Because patients with severe psoriasis often require chronic therapy. this study was undertaken to determine the efficacy. tolerability. and safety of acitretin in patients on continuous treatment for 12 months. The initial daily dose of 50 mg was taken for 4 weeks. Thereafter the dose was increased or decreased by 10 mg at monthly intervals (10 to 70 mg) to produce the optimal response with minimal toxicity. Seventy percent of the patients who completed 12 months of treatment showed marked improvement. All patients experienced adverse reactions; dry lips. hair loss. skin peeling. pruritus. and nail disorders were the most frequent. Fourteen patients were withdrawn from the study because of one or more intolerable adverse reactions.
Comparison of mometasone furoate 0.1% cream and hydrocortisone 1.0% cream in the treatment of childhood atopic dermatitis, We conducted a 6-week randomized. blinded study that compared mometasone furoate 0.1% cream. applied once daily. and hydrocortisone 1.0% cream. applied twice daily. in 48 children with moderate to severe atopic dermatitis. Mometasone furoate. a moderate-potency steroid. produced significantly greater improvement than the low-potency hydrocortisone used twice daily. The difference in therapeutic response was particularly evident in patients with involvement of more than 25% of their body surface area. Morning plasma cortisol levels were assayed before treatment. after 1 week of therapy. and at the end of the clinical trial. Plasma cortisol levels were transiently suppressed in one child who was treated with hydrocortisone and in none of the children treated with mometasone.
Combined curettage and excision: a treatment method for primary basal cell carcinoma, A retrospective study of 403 primary basal cell carcinomas treated with aggressive curettage followed immediately by excision revealed microscopic tumor present in the curettage margin in 64 (15.9%) of the patients and in the excisional margin in 12 (2.5%) after curettage and excision. In 92% (11 of 12) of patients with persistent tumor after the combined curettage and excision technique the tumors were of the aggressive growth (fibrosing. sclerosing. scirrhous. and morpheaform) variety of basal cell carcinoma. Both lateral and deep margins were involved with tumor. The short-term cure rate was 97.6% for the combined technique. Excluding aggressive growth BCCs. the use of curettage allows the surgeon to define tumor borders better before excision. This proves especially beneficial in tumors with clinically indistinct borders.
Leiomyosarcoma of the buttock, A 56-year-old man had a deeply invasive leiomyosarcoma of the right buttock. Leiomyosarcomas of the skin and subcutaneous tissues are rare. and most occur on the extremities. Wide local excision is the therapy of choice.
Unusual presentation of cutaneous metastatic malignant melanoma, This report describes an unusual presentation of cutaneous metastases suspected to have occurred through lymphatic spread in a patient with malignant melanoma. Punctate papular skin lesions correlated histologically with small tumor foci in the papillary dermis.
Accuracy of computer-interpreted electrocardiography in selecting patients for thrombolytic therapy. MITI Project Investigators, A prehospital computer-interpreted electrocardiogram (ECG) was obtained in 1.189 patients with chest pain of suspected cardiac origin during an ongoing trial of prehospital thrombolytic therapy in acute myocardial infarction. Electrocardiograms were performed by paramedics 1.5 +/- 1.2 h after the onset of symptoms. Of 391 patients with evidence of acute myocardial infarction. 202 (52%) were identified as having ST segment elevation (acute injury) by the computer-interpreted ECG compared with 259 (66%) by an electrocardiographer (p less than 0.001). Of 798 patients with chest pain but no infarction. 785 (98%) were appropriately excluded by computer compared with 757 (95%) by an electrocardiographer (p less than 0.001). The positive predictive value of the computer- and physician-interpreted ECG was. respectively. 94% and 86% and the negative predictive value was 81% and 85%. Prehospital screening of possible candidates for thrombolytic therapy with the aid of a computerized ECG is feasible. highly specific and with further enhancement can speed the care of all patients with acute myocardial infarction.
Effect of mitral regurgitation on pulmonary venous velocities derived from transesophageal echocardiography color-guided pulsed Doppler imaging, The effect of mitral regurgitation on pulmonary venous flow velocity was studied in 66 patients undergoing transesophageal echocardiography. Nine patients were studied intraoperatively before and after surgery. so that 75 pulmonary venous flow tracings were analyzed. Fifty-four patients had no significant (0 to 1+) mitral regurgitation and 21 had significant (2 to 3+) mitral regurgitation. Comparison of both groups revealed significant differences in the pulmonary venous flow pattern. In patients with no significant mitral regurgitation. the peak systolic velocity was higher (55 +/- 16 vs. -4 +/- 16 cm/s; p less than 0.0001) and the peak diastolic velocity was lower (43 +/- 13 vs. 59 +/- 17 cm/s; p less than 0.01) when compared with values in patients with significant mitral regurgitation. Consequently. the peak systolic/diastolic velocity ratio was significantly higher in the patients without significant mitral regurgitation (1.4 +/- 0.5 vs. 0.4 +/- 1.3; p less than 0.0001). The same trend was noted with respect to the systolic and diastolic velocity integrals. As the degree of mitral regurgitation increased. the peak diastolic velocity and diastolic velocity integral increased. whereas the peak systolic velocity and systolic velocity integral decreased. In patients with severe mitral regurgitation. the systolic flow became reversed (retrograde). The sensitivity of reversed systolic flow for severe mitral regurgitation was 90% (9 of 10). the specificity was 100% (65 of 65). the positive predictive value was 100% (9 of 9). the negative predictive value was 98% (65 of 66) and the predictive accuracy was 99% (74 of 75).
Effects of exercise on transmitral gradient and pulmonary artery pressure in patients with mitral stenosis or a prosthetic mitral valve: a Doppler echocardiographic study, Doppler echocardiography was used to determine changes in transmitral gradient and pulmonary artery pressure after exercise in 12 patients with mitral stenosis and 11 patients with a prosthetic mitral valve. The mean transmitral gradient in the mitral stenosis group was 9 +/- 7 mm Hg at rest and increased to 17 +/- 8 mm Hg after exercise. In patients with a prosthetic mitral valve. exercise resulted in an increase in mean transmitral gradient from 5 +/- 2 to 8 +/- 3 mm Hg. Calculated pulmonary artery systolic pressure increased with exercise from 41 +/- 19 to 70 +/- 32 mm Hg in the mitral stenosis group and from 28 +/- 8 to 39 +/- 15 mm Hg in patients with a prosthetic valve. Exercise Doppler echocardiographic evaluation of changes in transmitral gradient and pulmonary artery systolic pressure was found to be technically simple and an important addition to the noninvasive evaluation of patients with mitral valve disease.
Echocardiographic prediction of left ventricular volume after myocardial infarction, Left ventricular volume is a strong determinant of survival after acute myocardial infarction. The aim of this study was to determine which clinical and echocardiographic criteria assessed early after myocardial infarction would predict later left ventricular dilation. Forty-eight patients with uncomplicated transmural myocardial infarction had echocardiography 5 to 10 days after myocardial infarction and assessment of clinical variables including peak creatine kinase and sum of electrocardiographic ST segment elevation. Left ventricular dimensions were measured from the echocardiogram in the parasternal view and also in the apical four and two chamber views at the level of the mitral leaflets. papillary muscles and apex. A cardiac wall motion score was obtained by segmental analysis of the apical views. Echocardiographic left ventricular volume was measured after 1 year from the apical views with use of a Simpson's rule method. Initial clinical and echocardiographic variables were correlated with the left ventricular volume at 1 year. There was a significant relation between the initial four and two chamber end-diastolic dimensions and the left ventricular volume at 1 year. particularly for dimensions measured at the apical level (four chamber R2 = 0.66. p = 0.0001. two chamber R2 = 0.61. p = 0.0001). Other clinical variables. parasternal left ventricular dimensions and cardiac wall motion score were not significantly related to left ventricular volume. A powerful three variable model obtained by multiple regression and including the initial two chamber apical dimension. cardiac wall motion score and body surface area accounted for 82% of the variation in left ventricular volume at 1 year.
Effects of posture, Valsalva maneuver and respiration on atrial flutter rate: an effect mediated through cardiac volume, The effects of passive upright tilting from 0 degrees to +60 degrees (n = 27). Valsalva maneuver (n = 16) and respiration (n = 10) on the rate of atrial flutter were studied in 27 patients. After tilting to +60 degrees. the atrial flutter cycle length shortened in all patients from 247.5 +/- 7 to 236.7 +/- 6.9 ms (range of shortening 1 to 21 ms. p less than 0.001). The Valsalva maneuver (strain of 40 mm Hg) shortened the flutter cycle length during the strain (phase 2) from 242.2 +/- 4.6 to 230.5 +/- 5 ms (range of shortening 2 to 19 ms. p less than 0.001). In 10 patients whose respiration was monitored. the flutter cycle length consistently prolonged during inspiration and shortened during expiration. Combined beta-adrenergic and muscarinic receptor blockade in six patients did not significantly alter the flutter cycle length at rest or the effects of the various maneuvers on the changes in flutter cycle length. This study revealed that the atrial flutter cycle length can be shortened by passive upright tilting. the strain phase of the Valsalva maneuver and expiration. Changes in flutter cycle length were independent of autonomic tone. implying that by decreasing cardiac volume. these maneuvers affect characteristics of the atrial flutter circuit. thereby producing dynamic changes in the rate of atrial flutter.
Intermediate septal accessory pathways: electrocardiographic characteristics, electrophysiologic observations and their surgical implications, Intermediate septal accessory pathways are located in close proximity to the atrioventricular (AV) node and His bundle. have unique features that distinguish them from typical anterior and posterior accessory pathways and have been associated with a high risk for unsuccessful pathway division and the production of complete AV block after surgery. Between July 1986 and May 1990. 4 of 70 patients (3 men and 1 woman; mean age 33 +/- 13 years) undergoing surgery for accessory pathway division were found to have an intermediate septal accessory pathway. The presenting arrhythmia was atrial fibrillation with rapid anterograde conduction over the accessory pathway in two patients and recurrent orthodromic reciprocating tachycardia in two patients. In all patients. the delta wave on the electrocardiogram (ECG) was inverted in lead V1. but two patterns of delta wave configuration were observed. In three patients (type 1 intermediate septal accessory pathway). the delta wave was upright in lead II. inverted in lead III and isoelectric in lead a VF; the transition from a negative to an upright delta wave occurred in lead V2. The fourth patient exhibited a different delta wave pattern (type 2 intermediate septal accessory pathway). The delta wave was upright in each of leads II. III and aVF; the transition from a negative to an upright delta wave occurred at lead V3. Intraoperative electrophysiologic study localized the atrial insertion of type 1 pathways to the midpoint of Koch's triangle close to the AV node.
Paired comparisons of efficacy of intravenous and oral procainamide in patients with inducible sustained ventricular tachyarrhythmias, Thirty-eight patients who had inducible sustained ventricular tachycardia during baseline programmed electrical stimulation underwent electrophysiologic testing after both intravenous and oral administration of procainamide. Each had presented clinically with documented sustained ventricular tachycardia or out of hospital cardiac arrest not associated with acute myocardial infarction. In 23 patients (61%) (Group I) the arrhythmia became noninducible during an intravenous infusion of procainamide. Oral procainamide was subsequently administered and retesting was carried out after dose titration to match plasma concentration at the end of the intravenous study. Among the 23 patients in Group I the mean (+/- SD) plasma procainamide level was 7.2 +/- 2.8 micrograms/ml after intravenous dosing and 7.9 +/- 2.5 micrograms/ml after oral dosing (p = 0.09). In 15 (65%) of the 23 patients. sustained ventricular arrhythmia was inducible on oral therapy with comparable plasma procainamide levels (intravenous = 6.3 +/- 2.1 micrograms/ml. oral = 7.5 +/- 2.1 micrograms/ml). The other eight patients (35%) had concordant responses to repeat testing with comparable intravenous (mean 9.0 +/- 3.3 micrograms/ml) and oral (8.8 +/- 3.1 micrograms/ml) plasma procainamide levels. In the additional 15 patients (Group II) sustained ventricular tachyarrhythmia remained inducible on intravenous procainamide therapy and the patients were retested on oral therapy with similar plasma concentration (p = 0.05). In seven patients (47%) sustained ventricular tachyarrhythmia was noninducible on treatment with oral procainamide (mean plasma level 7.6 +/- 2.7 micrograms/ml) after failure of intravenous procainamide (mean plasma level 10.3 +/- 2.3 micrograms/ml).
Straddling mitral valve with hypoplastic right ventricle, crisscross atrioventricular relations, double outlet right ventricle and dextrocardia: morphologic, diagnostic and surgical considerations, The clinical. surgical and morphologic findings in five cases of a rare form of straddling mitral valve are presented. Three patients were diagnosed by two-dimensional echocardiography. cardiac catheterization and angiocardiography and two had diagnostic confirmation at autopsy. All five cases shared a distinctive and consistent combination of anomalies: 1) dextrocardia; 2) visceroatrial situs solitus. concordant ventricular D-loop and double outlet right ventricle with the aorta positioned to the left of and anterior to the pulmonary artery; 3) hypoplasia of right ventricular inflow (sinus) with tricuspid valve stenosis or hypoplasia; 4) large right ventricular infundibulum (outflow); 5) malalignment conoventricular septal defect; 6) straddling mitral valve with chordal attachments to the left ventricle and right ventricular infundibulum; 7) severe subpulmonary stenosis with well developed pulmonary arteries; and 8) superoinferior ventricles with crisscross atrioventricular (AV) relations. The degree of malalignment between the atrial and ventricular septa was studied quantitatively by measuring the AV septal angle projected on the frontal plane. The AV septal angle in the two postmortem cases was 150 degrees. reflecting marked malalignment of the ventricles relative to the atria. This AV malalignment appears to play an important role in the morphogenesis of straddling mitral valve. As judged by a companion study of seven postmortem cases. the more common form of straddling mitral valve with a hypertrophied and enlarged right ventricular sinus had less severe ventricular malposition than did the five rare study cases with hypoplastic right ventricular sinus. A competent mitral valve. low pulmonary vascular resistance and low left ventricular end-diastolic pressure were found at cardiac catheterization in the three living patients who underwent a modified Fontan procedure and are doing well 2.2 to 5.8 years postoperatively.
Percutaneous radiofrequency catheter ablation for supraventricular arrhythmias in children, Nineteen procedures were performed in 17 children. aged 10 months to 17 years. using catheter radiofrequency applications for the management of malignant or drug-resistant supraventricular tachyarrhythmias. Diagnoses were junctional ectopic tachycardia in 1 patient. atrioventricular (AV) node reentrant tachycardia in 4 and accessory pathway-mediated tachycardia in 12. Accessory pathway locations were left lateral (n = 4). posteroseptal (n = 3). left posterior (n = 2). right posterolateral (n = 1). right posterior paraseptal (n = 1). right intermediate septal (n = 1) and right anterior (n = 1). Ablation of accessory pathways was performed using 20 to 40 W of energy. The catheter was passed retrograde to the left ventricle in patients with a left-sided pathway and anterograde to the right atrium in those with a right-sided or posteroseptal pathway. In the 12 patients with an accessory pathway. radiofrequency applications were successful in 11 pathways and failed in 2. There were no recurrences of accessory pathway-mediated tachycardia. Atrioventricular node reentrant tachycardia was treated by AV node modification using 15 W of energy applied until first degree AV block occurred. After radiofrequency catheter ablation. there was a prolonged AH interval. tachycardia was not inducible and tachycardia recurred in one patient. For the patient with junctional ectopic tachycardia. 15 to 18 W of energy was delivered at the site of the maximal His bundle electrogram until sinus rhythm and normal AV conduction appeared. After a recurrence. a second procedure abolished tachycardia and AV conduction. In summary. radiofrequency catheter ablation was initially successful in 17 of 19 procedures and ultimately curative in 14 (82%) of 17 patients with no serious complications. Radiofrequency catheter ablation appears to be a safe and effective method for the management of supraventricular tachyarrhythmias in children.
Acute effects of delayed reperfusion on myocardial infarct shape and left ventricular volume: a potential mechanism of additional benefits from thrombolytic therapy, The purpose of this study was to characterize the effects of late reperfusion on myocardial infarct shape and to quantitate associated changes in left ventricular volume. Reperfusion was delayed until there was no salvage of ischemic myocardium. Dogs underwent 6.5 h of left anterior descending coronary artery occlusion (n = 5) or 5.5 h of occlusion and 1 h of reperfusion (n = 5). Infarct shape was measured with pairs of ultrasonic crystals implanted circumferentially in the mid myocardium. Infarct stiffness was determined from end-diastolic pressure-segment length curves produced by aortic clamping. Left ventricular volume was measured with three pairs of endocardial ultrasonic crystals and the effect of infarct shape change on left ventricular volume was determined. Infarct size. expressed as a percent of the area at risk. was similar in reperfused (97 +/- 1%) and nonreperfused (98 +/- 1%) hearts. After coronary artery occlusion. infarct segments became akinetic and functional dilation. measured as end-diastolic ultrasonic crystal separation. increased to a similar extent in reperfused (24 +/- 7%) and nonreperfused (19 +/- 3%) hearts. In 13 additional dogs that underwent reperfusion and instrumentation with endocardial ultrasonic crystals for volume measurement. left ventricular volume increased 42 +/- 6% over the preocclusion level (p less than 0.001). Within minutes of reperfusion. the infarct stiffened. infarct dilation decreased to 1 +/- 4% over the baseline preocclusion level (p less than 0.05 vs. prereperfusion) and left ventricular volume decreased to 16 +/- 11% over the baseline level (p less than 0.01 vs. postocclusion). Thus. coronary artery reperfusion reverses initial infarct dilation. Changes in infarct dilation occur immediately after reperfusion and are accompanied by infarct stiffening and a decrease in left ventricular volume. Reperfusion can affect infarct shape and stiffness at a point in time when myocardial salvage is no longer possible.
End-systolic regional wall stress-length and stress-shortening relations in an experimental model of normal, ischemic and reperfused myocardium, Assessment of left ventricular function is influenced by a number of hemodynamic factors. The purpose of this study was to evaluate the end-systolic regional wall stress-dimension relation in a series of 25 mongrel dogs. In Group A (n = 18) the regional wall stress-velocity of circumferential fiber shortening relation was measured before and after three interventions: volume infusion. metoprolol infusion and dobutamine infusion. The electrocardiogram. left ventricular pressure and its first derivative (dP/dt). arterial pressure and echocardiograms were recorded at baseline and after phenylephrine administration (to increase afterload). For each dog values for regional wall stress were plotted against the velocity of circumferential fiber shortening. For all dogs the relations were inversely linear (r = -0.65 to -0.98). Volume infusion increased end-diastolic volume (p less than 0.05) without shifting the slope or intercept of the relation. indicating its independence from preload. Dobutamine caused a shift in the intercept to the right but no change in slope and metoprolol shifted the relation to the left without altering the slope. The effect of ischemia and reperfusion on the end-systolic regional wall stress-length relation was examined in Group B (n = 7). at baseline. after 5 min of mid-left anterior descending coronary artery occlusion and after 10 min of reperfusion. Afterload was increased by hydraulic aortic occlusion. Regional wall stress was lowest at baseline. highest during ischemia and intermediate after reperfusion (100.2 +/- 32.1. 193.5 +/- 81.5. 141.9 +/- 67.6 kdyn/cm2. respectively. p less than 0.001). The end-systolic regional wall stress-length relation was linear during baseline. ischemia and reperfusion (r = 0.96. 0.95. 0.98. respectively. p less than 0.05). Ischemia caused an increase in the slope and a shift in the intercept to the right compared with baseline. Reperfusion represented an incomplete return toward baseline. This study demonstrates that the regional wall stress-velocity of circumferential fiber shortening relation is linear. independent of preload. incorporates afterload and is sensitive to changes in contractility. In addition. the regional wall stress-length relation can be measured in a nonhomogeneously contracting left ventricle and is predictably altered by ischemia and reperfusion. This relation may prove useful to determine whether alterations in regional systolic function result from changes in local load or contractility in the left ventricle with a regional wall motion abnormality.
Effect of graded reductions of coronary pressure and flow on myocardial metabolism and performance: a model of "hibernating" myocardium, The term "hibernating" myocardium has been applied to chronic left ventricular dysfunction without angina or ischemic electrocardiographic changes in patients with coronary artery disease that is reversed by therapy that increases myocardial blood flow. To investigate the relation between coronary blood flow and ventricular function experimentally. graded reductions in coronary artery pressure were produced in isolated perfused rat hearts as contractile performance (peak systolic pressure and its first derivative [dP/dt]) and metabolic variables were measured using phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy. As coronary pressure and flow were reduced. significant reductions in myocardial oxygen consumption and contractile performance were observed. which returned to control levels when coronary artery pressure and flow were restored to baseline values. Two phases of metabolic abnormality were observed. With modest reductions in coronary perfusion. proportionate reductions in myocardial oxygen consumption and contractile behavior were accompanied by a slight reduction in creatine phosphate but no significant lactate production. With greater reductions in coronary artery pressure and flow. creatine phosphate decreased more. adenosine triphosphate levels and myocardial pH decreased significantly and myocardial lactate production increased. The balanced reductions in myocardial contractility and oxygen consumption without metabolic abnormalities traditionally associated with "ischemia" observed in the first phase provides evidence in normal hearts for resetting of the myocardial contractile behavior and oxygen consumption in the presence of reduced coronary flow (that is. hibernating myocardium). The data suggest that reductions in adenosine diphosphate and the index of the reduced form of nicotinamide adenine dinucleotide (NADH) (lactate formation) do not explain the coupling between coronary artery pressure and flow and myocardial oxygen consumption as contractile performance decreases.
Should elective endoscopic sphincterotomy replace cholecystectomy for the treatment of high-risk patients with gallstone pancreatitis? [editorial, Since the introduction of endoscopic sphincterotomy approximately 15 years ago. the indications for this procedure have expanded. Currently endoscopic sphincterotomy is the procedure of choice for management of retained common bile duct stones following cholecystectomy. It is also being used more frequently for choledocholithiasis with an intact gallbladder in high-risk patients and in some patients with acute gallstone pancreatitis. In patients recovering from an episode of gallstone pancreatitis. standard practice has been subsequent cholecystectomy with possible exploration of the common bile duct. To avoid surgery in high-risk patients. we propose that an elective endoscopic sphincterotomy may be a reasonable therapeutic option regardless of whether common bile duct stones are present at the time of ERCP. A prospective trial is needed to examine this issue since to date there is no literature on endoscopic sphincterotomy in the absence of choledocholithiasis for gallstone pancreatitis in patients with intact gallbladders.
Rapid growth of untreated esophageal squamous-cell carcinoma in 10 patients, We documented the natural history of esophageal carcinoma and its rapid growth by measuring the change in tumor diameter radiographically in 10 patients during an observation period because the diagnosis had been missed. Nine men and one woman (age range. 48-74 years; mean. 60 years) were included in the study. Eight patients had undergone esophagography for gastrointestinal complaints and had lesions missed on the initial interpretation that were apparent on retrospective review after the patient had returned with more severe complaints and undergone repeat studies; two patients had refused treatment. The tumor was squamous-cell carcinoma in all. The treatment-free retrospective observation period ranged from 4 to 19 months (mean. 12.2 months) and was shorter for elevated (mean. 9.2 months) than for depressed lesions (mean. 16.8 months). The longitudinal diameter increased from 10-100 mm initially (mean. 30.5 mm) to 32-150 mm (mean. 74.9 mm). No correlation existed between the increase in size and histologic features. This documentation of the rapid increase in the size of esophageal carcinoma involving at least the submucosa confirms clinical impressions of the aggressive nature of this lesion and offers an explanation of why this disease is seldom detected at an early stage and long-term survival is so poor after the early stage of disease.
Primary small-cell carcinoma of the esophagus. Report of 11 cases and review of the literature, Primary small-cell carcinoma of the esophagus is an uncommon esophageal malignancy. This report details the clinical and pathologic aspects of 11 cases seen at our institution over 20 years. as well as 123 other cases reported in the literature. Small-cell carcinomas of the esophagus show considerable histologic heterogeneity. Neurosecretory granules can be found in the majority of cases and some show evidence of multidifferentiation. Like primary small-cell cancers of the lung. those in the esophagus are highly aggressive. are usually associated with spread at the time of diagnosis. and have a dismal prognosis regardless of treatment. The possible origin of this interesting variety of esophageal neoplasm is also discussed.
The effect of endoscopic laser therapy on survival in patients with squamous-cell carcinoma of the esophagus. Further experience, Although endoscopic laser therapy is effective for symptom palliation in esophageal cancer. few studies have investigated its effect on survival. We previously reported a 300% improvement in survival in 10 patients with squamous-cell carcinoma of the esophagus after endoscopic Nd:YAG laser energy. We now report a study to determine if the survival advantage persisted after treating an additional 26 patients. Thirty-six patients with squamous-cell carcinoma of the esophagus treated with endoscopic laser therapy were compared to 20 controls identified by our hospital Tumor Registry. There was no difference between the groups with respect to age. sex. race. location of tumor. or clinical stage. More control patients (25%) had previously undergone surgery than laser patients (0%) (p less than 0.05). Survival analysis demonstrated a significant improvement in overall survival (p less than 0.05). with an improvement in median survival from 5.7 to 9.7 months (p less than 0.05). One-year survival was 38% in laser patients. compared to 20% in control patients. Our experience continues to demonstrate that endoscopic laser therapy is effective in prolonging life as well as palliating the symptoms of patients with squamous-cell esophageal carcinoma.
The role of sustained achlorhydria in bleeding peptic ulcer, Twenty-five patients with bleeding peptic ulcers were randomized to receive either ranitidine 50 mg 8 hourly i.v. (control group) or a continuous nasogastric antacid infusion at the rate of 0.5 ml/min along with an i.v. injection of cimetidine 100 mg/h (treatment group). Twelve patients were included in the control group and 13 in the treatment group. The mean gastric pH on therapy was significantly higher in the treatment group (7.88 +/- 0.37) than in the control group (5.00 +/- 0.55) (p less than 0.001). and the gastric pH was noted to be greater than 7 on 95% of the occasions in the treatment group and on 8.6% of the occasions in the control group. An overall control of bleeding was achieved in 92.3% of the patients in the treatment group and 50% of the patients in the control group (p less than .05). Thus. the failure of therapy was significantly more common in the control group than in the treatment group (p less than 0.05). and more patients of the control group had to undergo emergency surgery than that in the treatment group. None of the patients in the treatment group. but 16.6% of the patients in the control group. died during the study period in the hospital stay. We conclude that in patients with bleeding peptic ulcer an intensive medical therapy comprising hourly injections of cimetidine (or presumably of other H2 blockers) and continuous nasogastric antacid infusion can achieve sustained achlorhydria. better control of bleeding. and reduce the need for emergency surgery.
Constrictive pericarditis masquerading as Budd-Chiari syndrome, Budd-Chiari syndrome (BCS) and constrictive pericarditis (CP) share many common clinical features. Over the last year we encountered three patients in whom CP clinically mimicked BCS. Two of the three did not even have raised jugular venous pressure. One patient with severe jaundice and hepatic coma ultimately died. Liver biopsy features were not discriminating. The final diagnosis of CP was established by echocardiography. chest computed tomography (CT). or cardiac catheterization. We conclude that in all patients with apparent BCS and atypical features. a noninvasive test like echocardiography or chest CT should be done to rule out treatable illness like CP before embarking on such invasive procedures as liver biopsy for diagnosis.
Paraesophageal hernia causing colonic obstruction, In a paraesophageal hernia. the esophagogastric junction remains below the hiatus while portions of the fundus or other parts of the stomach herniate in front and to the left of the esophagogastric junction through the hiatus into the thorax. We describe an unusual presentation of a paraesophageal hernia. in which herniation of the splenic flexure of the colon led to colonic obstruction.
Virchow-Troisier's lymph node in hepatocellular carcinoma, Virchow-Troisier's lymph node is rarely found in patients with hepatocellular carcinoma. When present. it may or may not accompany spread of the tumor to mediastinal lymph nodes. In a 20-year-old South African black man with hepatocellular carcinoma. a Virchow-Troisier's node was evident clinically and confirmed at necropsy. Mediastinal lymph nodes were not involved by tumor. and the malignant cells probably gained access to the thoracic duct by way of lymphatic spread to the hepatic lymph nodes in the porta hepatitis and the celiac nodes. both of which were seen at necropsy to be extensively invaded by tumor.
Intrahepatic cholangiocarcinoma with sarcomatous transformation: an autopsy case, We report an adult case of intrahepatic cholangiocarcinoma with remarkable sarcomatous changes. At autopsy a yellowish-white tumor (8 x 6 cm) was found in the left hepatic lobe. and there were several daughter nodules in both hepatic lobes. Histologically. most of the main tumor. and all of the daughter nodules examined. showed sarcomatous changes (spindle- or fusiform-shaped and pleomorphic cells). Histologic examination of a whole slice of the main tumor disclosed a focus of adenosquamous carcinoma (cholangiocarcinoma) within the tumor. Frequent transitions between adenosquamous carcinoma areas and sarcomatous areas suggested that sarcomatous transformation occurred in cholangiocarcinoma and then grew to spread rapidly. Immunohistochemically. squamous carcinoma and. to a lesser degree. adenocarcinoma elements were strongly positive for keratin and epithelial membrane antigen. both being also weakly positive in sarcomatous cells. supporting that possibility. Vimentin was positive only in sarcomatous elements. Cholangiocarcinoma should be included in the list of hepatic tumors showing sarcomatous change.
The plain abdominal film accurately estimates extent of active ulcerative colitis, The aim of our study was to establish whether plain abdominal film can accurately assess the extent of active ulcerative colitis. Ninety-seven ulcerative colitis patients were studied. in whom the extent of the macroscopic lesion was established either by colonoscopy (n = 75) or by resection (n = 22). Of these. 42 had proctosigmoiditis. 12 left-sided colitis. 12 subtotal colitis. and 31 total colitis. Nine well-tested features were used for the radiological classification of lesion extent. The radiologists were not given any clinical information. Seventy-eight patients (80.4%) were correctly classified by plain abdominal film (r = 0.86); the best concordance was achieved for proctosigmoiditis and total colitis (80.9 and 90.3%. respectively). In total colitis the most reliable radiological features were "irregularity of the mucosal edge" and "increased thickness of the colon wall. " which were present in 74.2 and 67.7%. respectively. of the correctly classified patients. The fourfold combination of these two features with "loss of haustral clefts" and "empty right colon" was present only in patients with total colitis. and at least one of these features was present in all but one of them. Conversely. all nine abnormalities were absent in 73.8% of patients with proctosigmoiditis. In conclusion. plain abdominal film is a reliable tool for judging the extent of lesion in active ulcerative colitis. It seems particularly accurate in total colitis. where. in the acute phases. it is most important to avoid invasive examinations.
Human T cells in the SCID-hu mouse are phenotypically normal and functionally competent, SCID-hu mice are heterochimeric animals that are constructed by transplanting human fetal thymus (Thy). liver (Liv). and/or lymph nodes into congenitally immunodeficient C.B-17 scid/scid (SCID) mice. Sensitive and specific two-color flow cytometric assays were used to evaluate human lymphocytes from peripheral blood of SCID-hu mice. Kinetic studies presented in this report show long term T lymphopoiesis in SCID-hu mice. Approximately one-half of SCID-hu mice constructed with Thy and Liv tissue develop detectable levels of circulating human T cells by 4 mo after transplantation. The average level of circulating human cells in SCID-hu mice is generally less than 2% of the total lymphoid cells in the peripheral blood of these mice. Some SCID-hu mice with as high as 13% human lymphocytes. however. have been detected. Nearly all human cells in the peripheral blood of SCID-hu mice are CD3+ cells that express TCR-alpha beta. The percentages of gamma delta+. CD4+. CD8+. CD25+. CD69+. and Leu-8+ cells among CD45+ cells in SCID-hu blood are similar to the levels found in adult peripheral blood. On average. 74% of SCID-hu T cells express CD45RA and 18% express CD29. Functional studies demonstrate that cells from SCID-hu Thy/Liv grafts or human T cells from SCID-hu peripheral blood are functionally competent to respond to mitogens or allogeneic human cells in vitro. They are similar to fetal thymocytes or adult T cells. respectively. in these responses. These studies demonstrate that the SCID-hu mouse is a useful model for the analysis of human immune differentiation and function in vivo.
Recognition of peptides that are immunopathogenic but cryptic. Mechanisms that allow lymphocytes sensitized against cryptic peptides to initiate pathogenic autoimmune processes, Interphotoreceptor retinoid binding protein (IRBP) is a glycoprotein that localizes in the retina and induces inflammatory changes in this tissue in immunized animals. Certain IRBP-derived peptide determinants are also immunopathogenic. and we have previously shown that these determinants could be either immunodominant or cryptic. Lymphocytes sensitized against the cryptic peptides do not recognize whole IRBP in vitro. and yet these lymphocytes must recognize the protein in vivo to initiate the autoimmune pathogenic process. We have examined here two hypothetical explanations for this dissociation: 1) It is possible that when IRBP is processed in vitro. immunodominant peptide determinants compete with the cryptic ones and inhibit their interaction with the MHC molecules on the APC. This explanation was ruled out here by the finding that the immunodominant peptide 1179-1191 ("W10") did not inhibit the response to a cryptic one. 1158-1180 ("R4"). when added at equivalent and even moderately higher concentrations. 2) The second hypothesis proposes that the cryptic antigenic sites are not generated from IRBP by the APC in vitro. whereas enzymes in the retina digest the protein to yield fragments that generate these antigenic sites upon processing by the APC. In line with this hypothesis. we have found that cleavage of IRBP by certain endoproteinases (Asp-N. Glu-C. or V-8) produced molecules that were recognized in culture by lymphocytes sensitized to the immunopathogenic but cryptic peptide R4. This study. therefore. describes a putative Ag processing mechanism that results in IRBP recognition and. consequently. the initiation of an autoimmune process by lymphocytes sensitized against a cryptic peptide. Furthermore. experiments with R4 and other cryptic peptides have shown that cleavage fragments of up to 38 residues in length can be presented by APC. to stimulate lymphocytes sensitized against these peptides. No responses were stimulated. however. by fragments of 75 or more residues. The data thus provide new insights into the processing and presentation of cryptic peptide determinants by APC.
Defective thymic T cell activation by concanavalin A and anti-CD3 in autoimmune nonobese diabetic mice. Evidence for thymic T cell anergy that correlates with the onset of insulitis, In nonobese diabetic (NOD) mice. T cells play a major role in mediating autoimmunity against pancreatic islet beta-cells. We and others previously reported that age-related alterations in the thymic and peripheral T cell repertoire and function occur in prediabetic NOD mice. To study the mechanism responsible for these T cell alterations. we examined whether a defect exists in the thymus of NOD mice at the level of TCR-mediated signaling after activation by Con A and anti-CD3. We found that thymocytes from NOD mice respond weakly to Con A- and anti-CD3-induced proliferation. compared with thymocytes from control BALB/c. BALB.B. (BALB.B x BALB.K)F1. C57BL/6. and nonobese non-diabetic mice. This defect correlates with the onset of insulitis. because it can be detected at 7 to 8 weeks of age. whereas younger mice displayed a normal T cell responsiveness. Thymic T cells from (NOD x BALB/c)F1 mice. which are insulitis- and diabetes-free. exhibit an intermediate stage of unresponsiveness. This T cell defect is not due to a difference in the level of CD3 and IL-2R expression by NOD and BALB/c thymocytes. and both NOD CD4+ CD8- and CD4- CD8+ mature thymic T cells respond poorly to Con A. BALB/c but not NOD thymic T cells respond to Con A in the presence of either BALB/c or NOD thymic APC. suggesting that the thymic T cell defect in NOD mice is intrinsic to NOD thymic T cells and is not due to an inability of NOD APC to provide a costimulatory signal. The defect can be partially reversed by the addition of rIL-2 to NOD thymocytes. To determine whether a defect in signal transduction mediates this NOD thymic T cell unresponsiveness. we tested whether these cells elevate their intracellular free Ca2+ ion concentration in response to Con A. An equivalent Con A-induced increase in Ca2+ ion concentration in both NOD and BALB/c thymocytes was observed. suggesting a normal coupling between the CD3 complex and phospholipase C in NOD thymocytes. In contrast to their low proliferative response to Con A or anti-CD3. NOD thymocytes respond normally (i.e.. as do BALB/c thymocytes) to the combinations of PMA plus the Ca2+ ionophore ionomycin and PMA plus Con A but weakly to Con A plus ionomycin. Our data suggest that the age-related NOD thymocyte unresponsiveness to Con A and anti-CD3 results from a defect in the signaling pathway of T cell activation that occurs upstream of protein kinase C activation.
Release of the cytokines colony-stimulating factor-1, granulocyte-macrophage colony-stimulating factor, and IL-6 by cloned murine vascular smooth muscle cells, Vascular smooth muscle cells were cultured from the mesenteric arteries of MRL lpr/lpr. MRL +/+. CBA/J. or C3H/HeJ mice and evaluated for their ability to synthesize a range of cytokines. Vascular smooth muscle cells of MRL +/+. MRL lpr/lpr. and CBA/J origin released biologically significant amounts of CSF-1 and IL-6 and relatively low but detectable amounts of granulocyte macrophage-CSF (GM-CSF) but not IL-2. IL-3. or IL-4. Vascular smooth muscle cells of C3H/HeJ origin produced lower amounts of CSF-1 and IL-6. and GM-CSF was barely detectable. Production of these cytokines did not require the exogenous growth factors present in FCS and occurred. although at lower levels. in serum-free medium supplemented with insulin. transferrin. and albumin. Cloned lines of MRL +/+ vascular smooth muscle cells. with electron microscopic and immunochemical properties of vascular smooth muscle cells. produced CSF-1. IL-6. and GM-CSF. establishing that vascular smooth muscle cells were a direct source of CSF-1. IL-6. and GM-CSF. These observations highlight the need for experiments to directly address the question of whether vascular smooth muscle cells constitutively produce these cytokines under physiologic conditions in vivo and suggest that vascular smooth muscle cells may participate actively in inflammation by releasing cytokines that are active on lympho-hemopoietic and other cells.
Retinoic acid-induced growth inhibition of a human myeloma cell line via down-regulation of IL-6 receptors, In this report we demonstrate that retinoic acid (RA) down-regulated the number of IL-6R on human leukocyte cell lines. including the myeloma cell line AF10. and two B cell hybridomas that correspond to cells at earlier stages of B cell development. Using AF10 cells. whose growth was determined to be mediated by the autocrine action of IL-6. we found that RA reduction of IL-6R was concentration-dependent over a range of 10(-11) to 10(-5) M and corresponded to the ability of the retinoid to inhibit cell proliferation. The down-regulation of IL-6R number by RA was accompanied by reduced IL-6R mRNA expression. RA did not affect endogeneous IL-6 synthesis or secretion from AF10 cells. However. addition of exogenous rIL-6 could overcome RA-induced growth inhibition. Menthol. a structurally unrelated compound to RA. also suppressed IL-6R expression and. correspondingly. inhibited cell growth. Taken together. our results suggest that the antiproliferative action of RA on AF10 cells is caused by reduction of IL-6R expression and subsequent inhibition of IL-6-mediated autocrine growth. These findings suggest the possibility that down-regulation of IL-6R is a means by which RA can modulate immune function.
Human extracellular recombinant phospholipase A2 induces an inflammatory response in rabbit joints, Phospholipase A2 (PLA2) enzymes hydrolyze membrane phospholipids liberating fatty acid and lysophospholipid. This event is thought to be the rate-limiting step in the generation of the lipid proinflammatory mediators. the eicosanoids and possibly platelet-activating factor. For this reason. extracellular forms of PLA2 have been postulated to be a component of the inflammatory cascade in certain biologic settings. In the synovial fluid of patients with inflammatory arthritides. substantial amounts of PLA2 activity have been found. and subsequently. one enzyme was purified. cloned. and expressed. Here we show that the pure recombinant enzyme free of any proinflammatory contaminants elicits a dramatic inflammatory. arthritogenic response when injected into the joint space of healthy rabbits. Within 24 h. extensive leukocyte infiltration and hyperplasia of the synovial lining cells were observed. and prostaglandin production in the joint space increased. In comparison. pancreatic PLA2(2) had little activity in this system. whereas a very inflammatory cobra venom enzyme was intermediate in its effects. In view of the presence of the enzyme in inflamed joints. the fact that its synthesis and secretion can be induced by proinflammatory cytokines and its proinflammatory biologic activity. we suggest that synovial PLA2 plays an exacerbating role in acute episodes in chronic inflammatory conditions such as rheumatoid arthritis.
Defective neutrophil function in the autoimmune mouse strain MRL/lpr. Potential role of transforming growth factor-beta, Patients with systemic autoimmune diseases such as SLE and rheumatoid arthritis have increased rates of morbidity and mortality caused by infection. Although this increased risk of infection has been primarily attributed to therapeutic immuno-suppression. some reports exist of defective polymorphonuclear leukocytes (PMN) function in these patients. The purpose of the present work is to investigate the recruitment of PMN phagocytic function in a murine model of autoimmunity. the MRL/lpr mouse. PMN from MRL/lpr. but not from congenic MRL/n mice. exhibit a marked defect in the amplification of FcR-mediated phagocytosis stimulated by various inflammatory mediators. This defect is acquired and correlates with the onset of the autoimmune disease observed in this strain. In addition. MRL/lpr but not MRL/n PMN exhibit a defect in extravasation into the thioglycollate-inflamed peritoneum. Incubation of MRL/n PMN in MRL/lpr serum induces a defect in the amplification of PMN phagocytic function identical to that observed with MRL/lpr PMN. The activity in the serum that induces this defect is neutralized by an antibody to TGF-beta but not by control antibodies. Incubation of murine and human PMN with purified TGF-beta induces an identical defect in stimulated FcR-mediated ingestion. In addition. TGF-beta-treated MRL/n PMN fail to extravasate into the thioglycollate-inflamed peritoneum after injection into normal MRL/n recipient mice. In addition. direct injection of TGF-beta into MRL/n mice also reduces the percentage and number of PMN in the thioglycollate-stimulated peritoneal exudates of these mice. The defect in PMN extravasation and phagocytic function was not caused by failure of the defective PMN to modulate the expression of the adhesion molecules. Mac-1 and Mel-14. These data indicate that defects in PMN function can be observed in a murine model of autoimmunity and that spontaneous production of TGF-beta possibly may play a crucial role in the pathogenesis of the defective PMN function in this animal model.
Initiation of delayed-type hypersensitivity by low doses of monoclonal IgE antibody. Mediation by serotonin and inhibition by histamine, Elicitation of delayed-type hypersensitivity (DTH) responses by DTH effector T cells requires a prior phase of DTH initiation. This consists of an immediate hypersensitivity-like response mediated by Ag-specific DTH-initiating factors that are analogous to IgE antibodies in that they sensitize tissue mast cells for release of the vasoactive amine serotonin (5-HT). Experiments were conducted to determine whether IgE mAb injected i.v.. or 5-HT injected locally. could initiate DTH. It was found that small doses of IgE (1 microgram/mouse). or of 5-HT (50 to 500 ng locally). which mediated small immediate responses. were optimal for DTH initiation. Even lower doses of IgE (10 ng/mouse). or of 5-HT (5 ng locally). which did not mediate macroscopically measurable immediate responses. were capable of DTH initiation. Higher doses of IgE (10 to 100 micrograms/mouse). which mediated large immediate responses. were not able to initiate DTH. A similar dose response for DTH initiation was found with IgG1 mAb. which is another mast cell-sensitizing isotype of Ig. The inability of high doses of IgE or IgG1 to mediate DTH initiation was probably caused by local release of large inhibitory amounts of histamine. because systemic treatment with the histamine-2 receptor antagonist cimetidine allowed high doses of IgE to initiate DTH. Thus. IgE and IgG1 antibodies could initiate DTH via release of small amounts of 5-HT. but simultaneous release of large amounts of histamine were inhibitory. probably via an effect on histamine-2 receptors of recruited T cells. We concluded the following: 1) IgE or IgG1 antibodies can initiate DTH; 2) DTH initiation need not be associated with macroscopically detectable early responses; 3) mast cell release of 5-HT acts positively whereas release of histamine acts negatively in murine DTH; 4) Ag-specific factors are not the only mechanism of DTH initiation.
Persistent infection with lymphocytic choriomeningitis virus enhances expression of MHC class I glycoprotein on cultured mouse brain endothelial cells, Brain endothelial cells (EC) represent a major component of the blood/brain barrier. which activated CTL cross to enter the central nervous system. Several viruses also penetrate the central nervous system through the blood stream via the brain EC. The studies reported here focus on understanding the principles and consequences of interactions among viruses. lymphocytes. and EC in the brain. As shown persistent but not acute infection by lymphocytic choriomeningitis virus enhances the expression of MHC class I glycoproteins on the brain EC of mice. This increase in MHC expression during viral infection does not seem to result from the release of cytokines. However. replicative virus is required. because UV inactivated virus fails to enhance MHC expression. Viral determinants appear on EC surfaces after infection and serve as targets for CTL directed lysis. In contrast. neurons (OBL 21 neuronal cell line). which express negligible amounts of MHC class I glycoproteins. show no gain in MHC markers during persistent viral infection and are not targets for virus-specific CTL killing.
Guatemalan human onchocerciasis. I. Systematic analysis of patient populations, nodular antigens, and specific isotypic reactions, The population from five Guatemalan plantations in areas endemic for onchocerciasis was surveyed. and 1032 individuals were recruited to participate in our study. From physical examination. past clinical history (5 to 8 yr). laboratory evidence and sample availability. a group of 778 long term residents with confirmed disease status were selected for detailed examination. We were able to identify 268 long term residents of endemic areas who had never been infected. 44 of these are from hyper- and mesoendemic areas. The 44 uninfected individuals from the hyper- and mesoendemic areas. because of their considerable exposure to this disease. were classified as "putatively immune." Intact nodules containing adult worms of Onchocerca volvulus were homogenized in the presence of protease inhibitors and fractionated into particulate and aqueous isotonic soluble antigens. Systematic analysis of these Ag fractions showed considerable amounts of Ig. presumably associated with Ag in the form of immune complexes. Individual specific antibody reactions from all 778 patients to nodule Ag were examined. Reactions to O. volvulus antigens by antibodies from patients with confirmed parasitic infections were almost exclusively restricted to IgG1 and IgG4 isotypes. Antigenic activity appeared to be primarily associated with low molecular mass (14 to 29 kDa) components. Some competitive blocking of antibody activities of other isotypes by IgG1 was observed. most notable was that of IgG3 and IgA. IgG4 and IgM activities were not significantly blocked.
Guatemalan human onchocerciasis. II. Evidence for IgG3 involvement in acquired immunity to Onchocerca volvulus and identification of possible immune-associated antigens, Ag-specific isotypic differences in immune response to Onchocerca volvulus Ag were assessed for 778 long term residents of endemic Guatemalan areas by quantitative ELISA with 5-min incubation steps and immunoblot. The study population was separated into five groups based on clinical status: N+F+. N+F-. N-F+. N-F-H+. and N-F-H-. where N = O. volvulus adults (nodule). F = microfiladermia. and H = history of O. volvulus infection. A subset of 44 individuals with high exposure to onchocerciasis from the N-F-H- group were critically evaluated and designated as "putatively immune." IgG1 reactivity to O. volvulus Ag was elevated in the majority of infected persons. but not in putatively immune individuals. Specific IgG3 levels. however. were equally elevated in all groups. The majority of N+F- persons also had elevated IgG1 levels. but they were lower than those found in F+ persons. IgG3 reactivities to a group of antigens at 20 kDa (GP20) were seen in many uninfected persons and some N+F- persons. In contrast. most F+ persons. react to this Ag with IgG1 and not IgG3. A mangabey inoculated with the infectious larval stage of O. volvulus (L3). but showed no signs of infection. began to recognize GP20 at 2 wk postinoculation. Early recognition of GP20 was possibly elicited by the larval stage. Purified nodule Ag from N+F+ individuals contained GP20. however. identical nodule Ag prepared from N+F- individuals did not. These data suggest that GP20 Ag may be common to both uterine microfilaria and the infectious larval stages. The fact that GP20 is predominantly recognized by IgG3 in putatively immune persons and some N+F- persons suggests that this increased IgG3 activity may be important in acquired immunity to onchocerciasis.
A randomized clinical trial of alprazolam versus progressive muscle relaxation in cancer patients with anxiety and depressive symptoms, A randomized nonblinded study was performed in three cancer centers to test over a 10-day period the efficacy of (1) a triazolobenzodiazepine. alprazolam. 0.5 mg three times a day and (2) use of a behavioral technique in which patients were trained in progressive muscle relaxation at an initial session with a behavioral psychologist and then asked to listen at home to an audiotape of the session three times a day. Of 147 cancer patients who met entry levels of distress and completed the study. uncontrolled for site or disease stage. 70 were randomized to drug. 77 to relaxation. Four measures of anxiety and depression were used: Covi. Raskin. Affects Balance. and Symptoms Checklist-90 (SCL-90). Results showed that both treatment arms resulted in significant (P less than .001) decrease in observer and patient-reported anxious and depressed mood symptoms. Although both treatment arms were effective. patients receiving the drug showed a slightly more rapid decrease in anxiety and greater reduction of depressive symptoms. These findings confirm efficacy of both alprazolam and relaxation to reduce cancer-related anxiety and depression. As safe. inexpensive. and effective interventions. physicians should consider their use in cancer patients experiencing anxiety and depressive symptoms.
Therapeutic effects and pharmacokinetics of recombinant human granulocyte-macrophage colony-stimulating factor in childhood cancer patients receiving myelosuppressive chemotherapy, Twenty-five children with refractory solid tumors were given recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) in escalated doses of 60 to 1.500 micrograms/m2 as 2-hour intravenous infusions. beginning 24 hours after myelosuppressive treatment with cisplatin and etoposide. Tolerance to rhGM-CSF was exceptional even at dose levels that exceeded the maximum-tolerated dosage (MTD) reported for adults. The agent produced dose-related increases in platelet and neutrophil counts. resulting in significantly shorter durations of severe neutropenia and thrombocytopenia (P less than .01 for each analysis). At the higher dosages (greater than or equal to 750 micrograms/m2). treatment with rhGM-CSF reduced the median number of days of antibiotic therapy for fever and neutropenia by approximately one half. We conclude that rhGM-CSF is well tolerated by leukopenic children in doses as high as 1.500 micrograms/m2. An MTD was not reached in this study. The ability of the growth factor to reduce severe neutropenia and thrombocytopenia suggests it will have an important role in the management of childhood solid tumors.
Absence of synergistic effects of CNS treatments on neuropsychologic test performance among children, Three hypotheses are proposed to account for neurobehavioral impairments following treatment with cranial radiation therapy (CRT) and intrathecal (IT) chemotherapy: CNS treatments exert a synergistic effect (A x B). an additive effect (A + B). or a single-agent effect (A or B). Eighty-five long-term survivors of non-CNS cancers aged 6 to 16 years were classified into groups on the basis of CNS treatments: CRT-IT (n = 25). CRT-No IT (n = 11). No CRT-IT (n = 24). and No CRT-No IT (n = 25). Study I findings did not provide support for synergistic mechanisms; nonorthogonal analysis of variance showed interaction effects (CRT x IT) restricted to tactile-perceptual speed. However. main effects were significant for a single agent (CRT) across a wide range of measures. General intelligence. academic achievement. verbal knowledge and reasoning. and perceptual-motor abilities were found to be significantly lower among CRT-treated groups. Study II findings provided additional support for the role of CRT; Pearson correlations within the CRT-No IT group indicated significant negative associations between CRT dose estimates for cortical regions and perceptual-motor abilities.
Improved survival at 2 and 5 years in the LMCE1 unselected group of 72 children with stage IV neuroblastoma older than 1 year of age at diagnosis: is cure possible in a small subgroup, The objectives of this study were to determine (1) the role of selection before bone marrow transplantation (BMT). (2) the role of vincristine. melphalan. and total body irradiation (TBI) as consolidation of induction therapy for stage IV over 12 months at diagnosis. and (3) the role of immunomagnetic purging in metastatic neuroblastoma. Among 72 consecutive unselected patients. 10 were not grafted (four died at induction: two in complete remission [CR]. two in partial remission [PR]); three had bone marrow progression before harvest; one had uncontrolled progression; and two had parental refusal). Sixty-two patients were grafted (23 in CR/very good PR [VGPR] and 39 in PR). Among the 62. 33 were consolidated with at least 90% excision of their initial tumor excised (53.2%). 15 with catecholamine secretions (24.2%). 22 with minor bone marrow involvement (35.5%). and 31 with positive bone scan (50%). Median observation time is 59 months. Progression-free survival (PFS) for the 10 excluded patients was 20% at 2 years and 0% at 4 years. PFS for the grafted population (n = 62) is 40% at 2 years. 20% at 4 years. and 13% at 7 years. No difference was observed between patients grafted in CR/VGPR or in PR. However. a group of 19 children was grafted resulting in complete normalization of metastasis (regardless of primary-site tumor status). In this group. PFS at 59 months was 38% with no relapses up to 7 years post-BMT. A group of 31 patients with no bone involvement at BMT was also identified. PFS at 5 years is 30% compared with 12% for bone-positive patients at BMT. Moreover. the 11 children presenting at diagnosis with no bone involvement (Evans stage IVS or stage C Memphis) and consolidated with BMT had PFS at 5 years of 50% with no late relapses. A subgroup of stage IV neuroblastoma patients older than 1 year of age at diagnosis may be curable with this therapeutic approach. and the use of multivariate analyses to search for prognostic factors is warranted in currently existing international registries.
The prognostic significance of autologous bone marrow transplant in advanced neuroblastoma, This report provides strong evidence for conducting a controlled randomized clinical trial of autologous bone marrow transplantation versus conventional chemotherapy in childhood neuroblastoma. which is disseminated beyond the intracavity nodes. and which is diagnosed in children older than 12 months of age. On the basis of two Pediatric Oncology Group (POG) studies. one a surgery plus conventional chemotherapy study (POG 8441) and the other an elective autologous transplant pilot protocol (POG 8340). there was no significant prognostic benefit of switching in remission from the surgery plus chemotherapy protocol to the transplant protocol (P = .91) or of switching in remission from the surgery plus chemotherapy protocol to any transplant (P = .75). The analysis is based on 116 patients achieving a complete or partial remission. 32 of whom received transplants on the pilot protocol. and 17 of whom received transplants outside the pilot protocol. While potential selection bias precludes cause-effect conclusions. these data strongly suggest that a large randomized trial of autologous bone marrow transplantation should be conducted before accepting this form of therapy as standard.
Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma, We examined the efficacy of five commonly used drugs. teniposide (VM26). cisplatin (CDDP). cyclophosphamide (CPM). doxorubicin (DOXO). and vincristine (VCR) in a retrospective analysis of 44 clinical trials of induction chemotherapy for stage IV neuroblastoma patients newly diagnosed at older than 1 year of age. Dose intensity (DI) of each drug was calculated as milligrams per square meter per week. Linear regression analyses showed that the Dls of VM26 and CDDP had the greatest influence on clinical outcomes (ie. proportion of major response. median survival. and median progression-free survival [PFS]). while those of CPM and DOXO were less significant. VCR had no influence on the three clinical end points. Although many protocols extended treatment to more than 1 year. none of these end points correlated positively with the duration of therapy. Twenty-one weeks appeared adequate for achieving superior response. median survival. and median PFS. These results suggest that maximal dose intensification of selective drugs over a short duration may improve the outcome of patients with poor-risk neuroblastoma.
The impact of breast-conserving treatment and mastectomy on the quality of life of early-stage breast cancer patients: a review, In recent years. doubt has been shed on the necessity of mastectomy for women with early-stage breast cancer. Apart from purely medical studies comparing (radical) mastectomy to less intruding surgical treatment. a number of studies (N = 18) have been published investigating the impact of breast-conserving treatment versus mastectomy on quality of life. We review these studies with respect to medical issues (treatment modality. stage of disease). methodologic issues (design. measurement moment. sample size). and results (psychologic discomfort. changes in life patterns. fears and concerns). It is concluded that there is no solid proof of a better psychologic adjustment after breast-conserving treatment and that there are no substantial differences between the different treatment modalities in changes of life patterns and fears and concerns. However. the results with respect to body image and sexual functioning favor the use of breast-conserving treatment.
Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions, Multiple systemic therapies have been used to treat patients with endometrial cancer. Although progestins have been the standard initial treatment for metastatic disease for the past 30 years. they are effective in only 20% of patients. and several large randomized trials have failed to demonstrate any benefit in the adjuvant setting. Alternative agents such as tamoxifen have shown modest activity. Few studies have investigated combinations of hormonally active drugs. Doxorubicin and cisplatin are the most active cytotoxic agents; a current randomized study is comparing the combination of these drugs with single-agent doxorubicin. Maximizing the effectiveness of established drugs. possibly with hematopoietic growth factors. and identifying alternative hormonal and cytotoxic agents with a sound scientific rationale will hopefully increase the effective treatment options for these patients.
Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial, The study population included 136 patients with stage IA. IB. IIA. IIB. or IIIA1 Hodgkin's disease. The median follow-up is 7.5 years. Among the 30 patients with peripheral IA disease. all patients achieved a complete response (CR) with radiation therapy. and no patient has relapsed. Patients of other stages were randomized to receive radiation therapy or mechlorethamine. vincristine. procarbazine. and prednisone (MOPP). Among the 51 patients randomized to receive radiation therapy. 49 (96%) achieved complete remission. 17 (35%) have relapsed. and 10 (20%) have died. Fifty-two of the 54 (96%) assessable patients randomized to receive MOPP obtained CRs. seven (13%) have relapsed. and four (7%) have died. The projected 10-year disease-free survival of patients randomized to receive radiation therapy is 60%; for those randomized to receive MOPP. it is 86% (P2 = .009 in favor of MOPP). The projected 10-year overall survival for patients randomized to radiation therapy is 76%. and for MOPP-treated patients it is 92% (P2 = .051 in favor of MOPP). When the randomized patients with massive mediastinal disease or stage IIIA1 disease were excluded from the analysis. the disease-free (67% for radiation v 82% for MOPP) and overall survival (85% for radiation v 90% for MOPP) were not significantly different between the two arms. Subset analysis showed significant superiority of MOPP in the treatment of the following patient groups: stage IIIA1 or massive mediastinal disease. no B symptoms. initial erythrocyte sedimentation rate greater than 20 mm. four or more sites of disease. and younger than age 40 years. Preliminary analysis of this ongoing study shows that MOPP chemotherapy is at least as effective as radiation therapy in the treatment of the specific groups of early-stage Hodgkin's disease patients randomized. The final assessment of these two diverse treatment options will depend largely on the long-term survival and the incidence of early- and late-treatment complications for which patients are continuing to be observed.
Phase I-II studies of yttrium-labeled antiferritin treatment for end-stage Hodgkin's disease, including Radiation Therapy Oncology Group 87-01 [published erratum appears in J Clin Oncol 1991 Aug;9(8):1516, Radiolabeled antiferritin immunoglobulin (Ig) preparations were tested in patients with advanced. end-stage Hodgkin's disease. Four patients received indium-111 (111In)-labeled monoclonal antiferritin (QCI). Targeting was not observed in tumor-bearing areas. Instead. scans showed rapid accumulation of QCI in normal liver. Forty-five patients were injected with 111In-labeled polyclonal antiferritin (rabbit. pig. or baboon). Forty (89%) patients showed tumor uptake. with dosimetric estimates ranging from 300 to 3.000 cGy in 1 week for the subsequently administered yttrium-90 (90Y)-labeled antiferritin. Yttrium-labeled antibody caused hematologic toxicity. Treatment-induced toxicity was not observed in any other organ system. Intravenous autologous bone marrow cells. 18 days after the yttrium infusion. accelerated hematopoietic recovery in eight patients receiving 30 mCi or 40 mCi. Hematopoietic recovery after a 20 mCi 90Y-labeled antiferritin infusion was not influenced by an autologous bone marrow transplant. Two patients receiving 20 mCi and one patient receiving 50 mCi remained aplastic after transplantation for unknown reasons. In 29 assessable patients. a 62% response rate was observed; nine of the 18 responses were complete. Responses ranging from 2 to 26 months were more commonly noted in patients with small tumors and long disease histories. Dosimetric calculations did not predict for responses. Recurrences frequently occurred in new areas instead of areas exhibiting bulky disease at the start of the treatment. Complete responses after 90Y antiferritin were significantly (P less than .02) more frequent than in a previous study with iodine-131 (131I) antiferritin. Further improvements are needed to make this new treatment modality curative.
The prognosis of Hodgkin's disease in older adults, This investigation was undertaken to assess the apparent poor survival of older patients with Hodgkin's disease. The clinical course of Hodgkin's disease in 136 patients. 60 to 79 years of age. was compared with that of 223 patients. 40 to 59 years of age. The patients registered from November 1977 through December 1983 had not been previously treated. and were treated at eight cancer centers. When the prognosis of all patients was examined by age. a definite change in the pattern of survival first appeared in the 60- to 69-year-old cohort. The entire older group (60 to 79 years) experienced twice the risk of dying from Hodgkin's disease and four times the risk of dying from other causes than did the younger group. In both groups. stage of disease was the strongest factor in predicting adjusted survival. Delay in treatment and advanced stage at presentation were not characteristic of Hodgkin's disease in older patients as has been postulated. Older patients responded to therapy with a similar complete remission rate (84% v 88% in the younger group. P = .24). From this study. we conclude that (1) Hodgkin's disease in the older adult does not have a different natural history. its major risk factors are similar to those known in other age groups. and thus should be amenable to existing therapeutic approaches; and (2) the prognosis of older patients with Hodgkin's disease has been obscured in previous studies by the inclusion of deaths due to other causes in survival estimates.
The prognostic significance of pretreatment serum lactate dehydrogenase in patients with small-cell lung cancer, Pretreatment serum lactate dehydrogenase (LDH) levels were assayed in 288 patients presenting with small-cell lung cancer (SCLC) between 1976 and 1985. Patients were routinely staged by physical examination. chest x-ray. bone. brain. and liver scans. and bone marrow evaluation. Clinical response and survival were assessed following treatment with combination chemotherapy as part of four clinical trials. Patients with extensive disease (ED) presented with a higher incidence (108 of 147. 73%) of abnormally elevated LDH (greater than 193 IU/L) than those (65 of 141. 46%) with limited disease (LD) (P = 2 x 10(-6)). Forty percent of patients had an initial normal LDH level and a higher response rate (89 of 108. 82%; complete response [CR]. 47%) than those with elevated values of LDH (119 of 156. 76%; CR. 29%). The CR rate varied inversely with the level of LDH in patients with LD (P = .026) but not in those with ED (P = .300). The median survival time and 1-year and 2-year survival rates for patients with elevated LDH were 39 weeks and 33% and 6%. respectively. whereas for those with a normal LDH level these were 53 weeks and 54% and 16%. respectively. Patients with LD and elevated levels of LDH manifested a higher relative death rate (1.63:1) when compared with patients with LD and LDH in the normal range (P = .0083). The survival of patients with ED did not differ between those with normal and elevated levels of LDH (P = .273). A significant survival advantage persisted for patients with LDH in the normal range following adjustments for extent of disease. performance status (PS). and treatment protocol (P = .044. log-rank analysis). In conclusion. serum LDH appears to be a significant independent pretreatment prognostic factor in patients with SCLC that correlates with stage of disease. response to treatment. and survival.
Myeloablative therapy and unpurged autologous bone marrow transplantation for poor-prognosis neuroblastoma: report of 34 cases, From October 1984 to November 1987. 34 patients aged from 1 year 1 month to 7 years 7 months with resistant or relapsed neuroblastoma (NB) (group 1. 10 patients). unselected disseminated NB (group 2. 14 patients). or selected disseminated NB (group 3. 10 patients) received myeloablative therapy (MAT) followed by unpurged autologous bone marrow transplantation (ABMT) at the end of an intensive protocol. which included high-dose chemotherapy and surgery to the primary tumor. Median time from diagnosis to MAT and ABMT was 6 months (5 months from last relapse to MAT and ABMT in the relapsed patients). The MAT regimen included vincristine. fractionated total body irradiation (TBI). and melphalan. Seventeen patients were grafted in complete remission (CR). five in very good partial remission (VGPR). 10 in partial remission (PR). and two in progressive disease (PD). The acute toxic death rate was 2.9%. The overall progression-free survival was 29%. The median progression-free survival was 20 months for the 17 patients grafted in CR. 6 months for the five patients grafted in VGPR. and 12 months for the 10 patients grafted in PR.
A randomized trial of chemotherapy followed by pelvic radiation therapy in stage IIIB carcinoma of the cervix, Because of the poor results in stage III B carcinoma of the cervix with standard treatment using radiotherapy alone. we designed a randomized trial to determine whether administration of chemotherapy before pelvic irradiation would improve survival. Between May 1984 and August 1986. 107 patients with previously untreated squamous cell carcinoma were randomly assigned. after stratification by age (less than 50 v greater than 50 years). extent of parametrial involvement (unilateral v bilateral). and lymphangiographic findings (negative v positive) to pelvic radiotherapy (RT; arm A) or three cycles of chemotherapy (CT; bleomycin. vincristine. mitomycin. and cisplatin [BOMP]). followed by the same radiotherapy regimen (CT + RT; arm B). The groups were balanced by age. performance status. extent of parametrial involvement. bulkiness of cervical disease. nodal involvement. and presence of hydronephrosis. Minimal follow-up is 34 months. A complete local response was observed in 32.5% of the patients in arm A and in 47% of the patients in arm B (P = .19). Overall 5-year survival rates were 39% for the RT arm and 23% for the CT + RT approach (P = .02). Toxicity was severe in arm B and included fatal pulmonary toxicity in four patients. Locoregional and distant failures were similar in both groups. We conclude that. despite a satisfactory response rate. neoadjuvant BOMP chemotherapy adversely affects survival in stage III B cervical cancer and is associated with unacceptable toxicity.
Phase II trial of weekly or biweekly intraperitoneal mitoxantrone in epithelial ovarian cancer, Previous experimental and clinical evaluation has suggested that ovarian cancer is sensitive to the cytotoxic effects of mitoxantrone at concentrations achievable within the peritoneal cavity after intraperitoneal (IP) administration. Unfortunately. the use of the drug delivered IP at high doses (20 mg/m2 in 2 L normal saline [NS]) on a monthly schedule is compromised by severe local effects secondary to the irritant properties of the drug. To reduce toxicity and take advantage of minimal systemic drug exposure following IP administration. we treated 28 patients with a lower drug concentration of mitoxantrone (10 mg/m2 in 2 L NS). but on a weekly or every other week schedule (total. 12 courses). Compared with the monthly program. this regimen caused less pain. allowed for a higher cumulative dose of mitoxantrone to be delivered. and resulted in less serious treatment-related morbidity. Four of 13 assessable patients (31%) whose largest tumor was less than or equal to 1 cm in diameter demonstrated a surgically defined response. All responding patients had failed previously or exhibited a minimal response to cisplatin. Despite the improved toxicity profile of this regimen. the overall response rate was similar to the monthly program. probably secondary to inadequate IP drug distribution in many patients. Future investigative efforts using IP mitoxantrone as therapy for ovarian cancer might focus on developing methods to improve drug delivery to all sites of tumor within the peritoneal cavity (eg. intraoperative therapy. increased treatment volumes. and antiinflammatory agents to reduce adhesion formation).
Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma, We retrospectively analyzed the likelihood of regional nodal failure (RNF) for 1.624 patients with stage I or II invasive breast carcinoma treated with conservative surgery and radiotherapy (RT) at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1985. The median follow-up time was 77 months. RNF was the first site of failure for 38 of the 1.624 patients (2.3%). The incidence of axillary failure for patients undergoing axillary dissection (AXD) who were irradiated to the breast only was 2.1% (nine of 420) for patients with negative nodes and 2.1% (one of 47) for patients with one to three positive nodes. The incidence of supraclavicular failure in these two groups was 1.9% (eight of 420) and 0% (zero of 47). respectively. The incidences of axillary and supraclavicular failure in patients without clinically suspicious axillary involvement who did not have AXD but were treated with RT were 0.8% (three of 355) and 0.3% (one of 364). respectively. Despite various combinations of salvage surgery. RT. and systemic therapy. only 47% of patients (18 of 38) achieved complete regional control after nodal relapse. We conclude that RNF is uncommon in patients treated to the breast alone following an adequate AXD when the axillary nodes are negative or when one to three nodes are positive. RNF is also uncommon in patients with a clinically uninvolved axilla treated with nodal RT without AXD. Symptoms of RNF can be controlled in most but not all patients. Further study is needed to determine if the benefits of RT in preventing a small number of symptomatic RNF outweigh the potential toxicity for any subgroup of patients.
Prognostic factors for local recurrence in the conservatively treated breast cancer patient: a cautious interpretation of the data, Between 1962 and 1984. a total of 433 patients were treated at Yale-New Haven Hospital with conservative surgery and radiation therapy (CS + RT) to the intact breast. As of January 1990. with a minimum assessable follow-up of 5 years and a median follow-up of 8.21 years. there have been a total of 50 breast recurrences resulting in a 5-year actuarial breast recurrence rate of 8%. Of all clinical factors tested. young age was the most significant prognostic factor for local recurrence (P less than .03). In addition. patients with pathologically involved lymph nodes were noted to have a lower local recurrence rate than patients with pathologically negative axillae (P less than .05). These findings were especially notable given the fact that the node-positive group had a higher percentage of T2 tumors and a higher percentage of patients in the young age group. These paradoxical findings. however. may be explained by the fact that 88% of the node-positive patients underwent adjuvant systemic therapy in the form of either systemic chemotherapy or hormonal therapy. while only 8% of node-negative patients underwent any adjuvant systemic therapy. When analyzed as a function of adjuvant therapy. those patients receiving adjuvant therapy had a lower local recurrence rate than those patients not receiving adjuvant therapy (P less than .08). We conclude that adjuvant systemic therapy impacts on the ipsilateral breast recurrence rate in patients treated with CS + RT. The implications of this study in light of the widespread use of adjuvant systemic therapy are discussed.
Anterolateral transthoracic transvertebral resection of an intramedullary spinal arteriovenous malformation. Case report, The case is reported of a 16-year-old girl with an anterior thoracic spinal cord arteriovenous malformation (AVM) who presented with subarachnoid hemorrhage and sudden change in lower-extremity strength. Spinal angiography revealed a Type II (glomus) intramedullary AVM at the T7-8 level fed by multiple branches of the anterior spinal artery. The AVM was successfully resected using an anterolateral transthoracic approach. The details of this approach and its use for surgery of anterior thoracic spine lesions are described.
A new surgical approach to subcortical lesions: balloon inflation and cortical gluing. Technical note, A cortical incision performed with inflation of a balloon to create a channel has been used in an approach to deep lesions with minimal damage to cerebral tissue. The balloon is slipped over a blunt needle and. once in place. is inflated through the needle. Postoperative sealing of the incision with fibrin glue avoids the subdural collection of cerebrospinal fluid such as is sometimes observed when the ventricle is opened during surgery.
Suprascapular nerve entrapment. A series of 27 cases, Suprascapular nerve entrapment is an acquired neuropathy secondary to compression of the nerve in the bony suprascapular notch. A series of 27 cases. the largest reported to date. is presented and examined as to the best and most appropriate method of diagnosis and treatment. The entity is described in detail as to its origin. anatomy. and pathophysiology.
Isoflurane-induced attenuation of motor evoked potentials caused by electrical motor cortex stimulation during surgery, Dysfunction of spinal motor conduction during surgical procedures may not be reflected by changes in somatosensory evoked potential waveforms. A method of monitoring that allows direct and continuous assessment of motor function within the central nervous system during surgery would be useful. This paper describes one such method utilizing noninvasive electric cortical stimulation to evoke muscle activity (the motor evoked potential. or MEP) during surgery. The effect of isoflurane (superimposed on a baseline of N2O/narcotic anesthesia) on MEP's in response to cortical stimulation is specifically examined. Eight patients undergoing elective neurosurgical operations were included in the study. All patients received a background of general anesthesia and partial nondepolarizing neuromuscular blockade. The motor cortex was stimulated electrically via self-adhesive scalp electrodes. Electromyographic responses from multiple muscles were measured with subdermal electroencephalograph-type needle electrodes. Motor responses to stimulation were continually recorded on magnetic tape for off-line analysis. Once closing of the surgical incision was begun. a series of four to five stimuli of constant magnitude were applied to obtain "baseline" MEP responses. Patients were then ventilated with isoflurane for up to 8 minutes. during which time stimuli were continued every 15 to 20 seconds. Comparison was made of MEP responses for trials before. 1 minute after. and 5 minutes after the addition of isoflurane. All patients demonstrated reproducible motor responses to cortical stimulation during surgery. Addition of isoflurane [isoflurane)exp. less than or equal to 0.5%) to pre-existing anesthesia caused marked attenuation of MEP amplitudes in all patients within 5 minutes of its application. without affecting neuromuscular transmission as judged by direct peripheral nerve stimulation. It is concluded that: 1) monitoring motor system integrity and function with electric transcranial cortical stimulation during surgery is feasible when utilizing an N2O/narcotic anesthetic protocol; and 2) the quality of data obtained will likely suffer with the addition of isoflurane.
Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. A Pediatric Oncology Group study, In a randomized postoperative trial. adjuvant post-irradiation chemotherapy. consisting of nitrogen mustard. vincristine. procarbazine. and prednisone (MOPP). was tested versus radiation therapy alone for newly diagnosed medulloblastoma in patients between 1 and 21 years of age. Patients treated with irradiation plus MOPP had a statistically significant increase in overall survival rate at 5 years posttreatment compared to patients treated with radiation therapy alone (74% vs. 56%; p = 0.06. adjusted for race and gender). Although the overall study failed to show a statistically significant advantage for irradiation plus MOPP in event-free survival (p = 0.18). statistical significance was attained in children 5 years of age or older (p = 0.05). More severe hematological toxicities occurred in the group with irradiation plus MOPP; however. this hematotoxicity appeared to be tolerable and acceptable. These results suggest that patients may benefit from combined irradiation and chemotherapy following surgery for medulloblastoma.
Developmental anterobasal temporal encephalocele and temporal lobe epilepsy, The authors describe the association between an antero-basal temporal lobe encephalocele and medically intractable temporal lobe epilepsy in three patients treated successfully by surgery. Two men and one woman. aged 26 to 37 years (mean 31 years). had onset of complex automatism and generalized seizures in their second and fourth decades (mean age 22.7 years). They had been epileptic for 6 to 14 years (mean 8.3 years) before surgery. Preoperative electroencephalograms localized ictal epileptic activity to the left mesial temporal lobe in all cases. and neuropsychological testing revealed dominant temporal lobe dysfunction. Magnetic resonance (MR) imaging demonstrated an anteromedial basal temporal encephalocele extending into the pterygopalatine fossa through a bone defect at the base of the greater sphenoid wing in the region of the foramen rotundum and pterygoid process. a discrete center of embryonal chondrification. At surgery. the encephaloceles were found in front of the uncus. and an area of gliosis extended from the encephalocele to the amygdalohippocampal region. All patients have been seizure-free following anterior temporal resection and amygdalohippocampectomy including the encephalocele. These three cases delineate a condition of disordered embryogenesis wherein a developmental anterobasal temporal encephalocele acts as the substrate for temporal lobe epilepsy. This lesion may be diagnosed preoperatively with MR imaging and should be considered in the differential diagnosis of late-onset temporal lobe epilepsy.
Prevention of cerebral vasospasm by actinomycin D, The role of endothelin. a newly found vasoconstrictor peptide. is examined in the pathogenesis of cerebral vasospasm after experimental subarachnoid hemorrhage (SAH) in the dog. Endothelin immunoreactivity was overexpressed in the endothelium of the vasospastic basilar artery. Because endothelin synthesis is regulated at the messenger ribonucleic acid transcription level. the effect of actinomycin D. a ribonucleic acid synthesis inhibitor. was studied as a means of preventing vasospasm. It was found that treatment with intravenous actinomycin D for 5 days beginning on the day of SAH completely inhibited the development of vasospasm. This novel experimental therapy may lead not only to the elucidation of the pathogenesis of cerebral vasospasm but also to the availability of a prophylactic adjuvant therapy for patients with SAH.
Ischemic neuronal damage after acute subdural hematoma in the rat: effects of pretreatment with a glutamate antagonist, The ability of a competitive N-methyl-D-aspartate (NMDA) receptor antagonist (D-CPP-ene) to reduce irreversible brain damage has been examined in a rodent model of acute subdural hematoma. Acute subdural hematoma was produced by the slow injection of 400 microliters homologous blood into the subdural space overlying the parietal cortex in halothane-anesthetized rats. Brain damage was assessed histologically in sections at multiple coronal planes in animals sacrificed 4 hours after induction of the subdural hematoma. Pretreatment with D-CPP-ene (15 mg/kg) significantly reduced the volume of ischemic brain damage produced by the subdural hematoma from 62 +/- 8 cu mm (mean +/- standard error of the mean) in vehicle-treated control rats to 29 +/- 7 cu mm in drug-treated animals. These data demonstrate the anti-ischemic efficacy of NMDA antagonists in an animal model of intracranial hemorrhage in which intracranial pressure is elevated. and suggest that excitotoxic mechanisms (which are susceptible to antagonism by D-CPP-ene) may play a role in the ischemic brain damage which is observed in patients who die after acute subdural hematoma.
Radioimmunoassay of insulin-like growth factors in cyst fluid of central nervous system tumors, Tumor cells are characterized by abnormalities in growth and metabolism. including the autocrine secretion of certain growth factors. The authors have previously shown the presence of insulin-like growth factor receptors in tumors of the central nervous system (CNS) and in this study examine whether CNS tumors are capable of autocrine secretion of insulin-like growth factors in situ. To investigate the production of insulin-like growth factors I and II by CNS tumors. the authors have developed specific radioimmunoassays for these growth factors. In situ production of insulin-like growth factors was studied by immunoassay of CNS tumor cyst fluid aspirated at the time of surgery from 12 cystic tumors: seven primary brain tumors. four metastatic tumors. and one spinal schwannoma. For immunoassay. cyst fluid was treated overnight with acetic acid. then insulin-like growth factors were separated from binding proteins by a refined solid-phase technique. then dried and reconstituted in immunoassay buffer. Normal human serum and cerebrospinal fluid served as controls. Insulin-like growth factor I was detected in all 12 tumors studied. In contrast. insulin-like growth factor II was detected only in three low-grade astrocytomas. the spinal schwannoma (which had the highest insulin-like growth factor II level of all tumors studied). and three metastatic lung cancers. These results suggest that CNS tumors may be capable of autocrine production of insulin-like growth factors in situ. Furthermore. there appears to be a difference in the type of insulin-like growth factors produced by different types of CNS tumors. Preferential production of insulin-like growth factors may be an important marker of tumor differentiation and useful as a diagnostic tool.
A small dose of soluble alginate-fiber affects postprandial glycemia and gastric emptying in humans with diabetes, Seven men with well-controlled. noninsulin-dependent (type 2) diabetes ingested on two different mornings. in random order. meals with or without a 5.0-g sodium alginate supplement (algae-isolate. 75% soluble fiber). The meals contained similar amounts of digestible carbohydrates. fat and protein. The gastric emptying rate of the meal containing sodium alginate. measured by detection of 51Cr mixed into the meals. was significantly slower than that of the fiber-free meal. Sodium alginate also induced significantly lower postprandial rises in blood glucose. serum insulin and plasma C-peptide. The diminished glucose response after the addition of sodium alginate could be correlated to the delayed gastric emptying rate induced by the fiber (rs = 0.92. P less than 0.01).
Serum gastrin increases with increasing dietary calcium but not with increasing dietary fat or fiber in Fischer-344 rats, We studied the effects of dietary calcium. fat and fiber on serum gastrin in Fischer-344 rats in a full factorial experiment as part of a larger study of diet and colon cancer risk factors. Nine- to 10-wk-old male rats were fed standard or experimental diets for 4 wk. Wheat bran was the sole source of fiber. Wheat bran levels were 0. 2.5. 10 and 20%; fat levels were 1. 5 and 10%; calcium levels were 0.18. 0.52 and 1.04% of diet weight. On d 29 serum was collected and stored at -80 degrees C until analyzed. There was a significant (P less than 0.0001) dose-dependent increase in serum gastrin from 102 to 173 ng/L. with increasing calcium. No other significant changes in serum gastrin were noted with the dietary changes. A long-term change in the level of serum gastrin. caused by dietary modification. will influence the trophic effect that gastrin has on colonic mucosa as well as on colon carcinomas. We speculate that calcium supplementation. although slowing colonic proliferation. might have an undesirable effect on the growth of early undetected colonic tumors.
Brain energy consumption in ethanol-treated, Long-Evans rats, The cerebral metabolic rate of glucose utilization (CMRGlc) was measured in rats fed liquid diets containing ethanol for 8 wk. after removal of ethanol from the diet and after acute ethanol intoxication. Control rats were pair fed the liquid diets containing isoenergetic amounts of dextrin-maltose. Quantitative autogradiography using [6-14C]glucose measured CMRGlc at the level of individual structures. Digital image techniques created stereograms of brain energy consumption from the autoradiographs. These techniques provided information about CMRGlc throughout the brain. Rats given the ethanol liquid diet drank constantly throughout the day and night. Neuropathological examination of brain revealed no abnormalities from ethanol consumption. Acute ethanol administration to control rats produced a decrease in CMRGlc throughout the brain that was most prominent in structures concerning auditory. visual. memory and motor functions. Chronic ethanol consumption did not reduce CMRGlc to the same degree as acute ethanol intoxication; in fact. it affected only a few structures. The removal of ethanol from chronic ethanol-treated rats for a period of 18 h caused CMRGlc to rise above control values throughout the brain. However. there were no seizures or other evidence of brain dysfunction.
Reduction of cardiac hypertrophy in renal hypertensive rabbits with pindolol, Arterial pressure. cardiac mass and coronary flow reserves were measured in untreated and chronically pindolol-treated rabbits. prepared as either one-kidney one clip (1K1C) hypertensive or uninephrectomized (sham) controls. Pindolol (200 micrograms/kg/day) was administered for either 23 or 30 days. beginning 1 week after. or the day of initial surgery. respectively. Coronary flow was measured. at day 30. using radioactive microspheres. during base-line and adenosine infusion (0.4 mg/kg/min) in anesthetized open-chest preparations. Heart weight of untreated 1K1C animals (9.13 +/- 0.73 g) was significantly greater than the controls (7.19 +/- 0.77 g). Myocardial mass of 1K1C (9.93 +/- 0.86 g) and sham controls (7.40 +/- 0.31 g) were unaffected by chronic pindolol for 23 days. Cardiac hypertrophy was prevented in 1K1C animals treated with pindolol for 30 days (7.53 +/- 1.28 g). Untreated 1K1C animals were hypertensive compared to sham controls (116 +/- 12 and 78 +/- 7 mm Hg) and neither pindolol regime affected blood pressure. Bradycardia was evident in all pindolol-treated animals. Base-line coronary flow was higher in the untreated 1K1C animals compared to untreated controls (228 +/- 43 vs. 182 +/- 31 ml/min/100 g). After chronic pindolol treatments. 1K1C base-line blood flows were reduced (158 +/- 48 and 175 +/- 59 ml/min/100 g. for 23- and 30-day protocols). Adenosine vasodilated flows were not different between the untreated 1K1C and sham animals and were not affected by pindolol treatment. Therefore. hypertension and cardiac hypertrophy were dissociable in this model when pindolol was administered from the onset of hypertension. This suggests immediate involvement of beta adrenergic activation in the development of hypertrophy.
Staurosporine facilitates recovery from the basal forebrain-lesion-induced impairment of learning and deficit of cholinergic neuron in rats, Alzheimer's disease is characterized by the loss of cholinergic neurons in the nucleus basalis of Meynert and by a primary loss of memory function. Since staurosporine has been reported to induce differentiation in human neuroblastoma cells in vitro. we studied the effects of staurosporine on the amnesia induced by basal forebrain-lesion in rats. Staurosporine (0.05 and 0.1 mg/kg intraperitoneal) attenuated the impaired performance of water maze and passive avoidance tasks. even though the drug administration began 2 weeks after the lesion. Moreover. staurosporine (0.1 mg/kg) partially reversed the decrease of choline acetyltransferase activity in the fronto-parietal cortex induced by basal forebrain-lesion. These results suggest that staurosporine attenuates impairment of learning through reversal of damage to cholinergic neurons induced by basal forebrain-lesion. This evidence indicates that neurotrophic factor-like substances may be used in novel therapeutic approaches to Alzheimer's disease.
An insulin-independent mechanism of intrathecal morphine-induced hypoglycemia in mice: mediation through a central alpha-2 adrenergic pathway, Studies on the mechanism of the hypoglycemia caused by the i.t. administration of morphine (40 micrograms) to nonfasted. unanesthetized mice included assessment of effects of i.t. morphine on circulating levels of immunoreactive insulin and glucagon. on body temperature. as well as testing the effects of i.p. pretreatment with antagonists of cholinergic. beta adrenergic. alpha-1 adrenergic. alpha-2 adrenergic. serotonergic and opioid receptors. Serum levels of insulin were not significantly affected at 30 and 60 min after i.t. morphine. but plasma glucagon levels were significantly increased at both time points. Rectal temperature decreased significantly in mice given either saline or morphine i.t.. but there was no significant difference between the two groups over time. Atropine (2 mg/kg). propranolol (10 mg/kg). prazosin (2 mg/kg) and methysergide (2 mg/kg) did not affect morphine-induced hypoglycemia. Naloxone (20 mg/kg) antagonized i.t. morphine. Mecamylamine (2 mg/kg) produced a moderate hypoglycemia in control mice. which appeared to be additive to that caused by i.t. morphine. Yohimbine (1-4 mg/kg i.p.) also produced a moderate hypoglycemia in control mice. but caused a dose-related antagonism of i.t. morphine. The centrally active alpha-2 antagonist. L-657.743 (2S-trans)-1.3.4.5'.6.6'.7.12b-octahydro-1'.3'-dimethylspiro -(2H-benzofuro- (2.3-a)quinolizine-2.4'(1'H)pyrimidin)-2-(3'H)-one hydrochloride) (4-20 mg/kg i.p.). but not the peripherally selective alpha-2 antagonist. L-659.066 (2R-trans)-N-(2-(1.3.4.6.7.12b-he xahydro-2'- oxospiro(2H-benzofuro(2.3-a) quinolizine-2.4-imidazolidin)-3'-yl)ethyl)methanesulfonamide hydrochloride) (4-20 mg/kg i.p.). caused a dose-related antagonism of i.t. morphine. The i.t. coadministration of yohimbine (2 or 10 micrograms) or L-659.066 (10 micrograms) with morphine exhibited no antagonism.
Bradykinin-stimulated inositol phosphate production in NG108-15 cells is mediated by a small population of binding sites which rapidly desensitize, [3H]Bradykinin (BDK) binds to two distinct binding sites (P less than .01. N = 12) in NG108-15 cell membranes; (site 1: Kd1 = 3.09 x 10(-10) M. Bmax1 = 242 +/- 24 fmol/mg protein) and (site 2: Kd2 = 1.94 x 10(-8) M. Bmax2 = 491 +/- 75 fmol/mg protein). Although site 1 comprises only 33 +/- 4% (N = 12) of the total binding site population. comparison of the binding affinity and functional potency for BDK agonist analogs exhibiting differential selectivity for the two sites reveals that this high affinity site is the receptor mediating inositol monophosphate (IP) production in this cell line. BDK-stimulated IP production undergoes a very rapid (5 min) desensitization that is characterized by both a loss in agonist potency (EC50 = 3.57 x 10(-9) M vs. 1.94 x 10(-10) M in controls; P less than .001. N = 12) and a decrease in amplitude of response (fold stimulation = 1.45 +/- 0.06 vs. 1.80 +/- 0.09 in controls; P less than .01. N = 12). Only the decrease in response amplitude is attenuated by down-regulation of protein kinase C by prior long term treatment of the cells with 12-O-tetradecanoylphorbol 13-acetate (TPA). indicating an involvement of protein kinase C activation in the desensitization process. Desensitization is accompanied by down-regulation of site 1 only (Bmax1 = 71 +/- 8 fmol/mg (N = 10; P less than .001 vs. controls)); Bmax2 and the Kd for BDK at both sites remain unchanged. further supporting the contention that site 1 is the functionally relevant receptor. In contrast to the functional data. long term TPA treatment does not attenuate the receptor down-regulation. indicating that the rapid desensitization involves both receptor-related and postreceptor mechanisms. The implications of this property of the BDK receptor for analog design and receptor classification are discussed.
Roles of adenosine and theophylline on the recovery of adenine nucleotides in postischemic cultured renal tubular cells, The effect of adenosine (ADO) on the recovery of cellular adenine nucleotides (AN) was evaluated in the cultured cells deprived of oxygen and substrates (ischemia) and in nonischemic cells (control). The primary cultured cells were obtained from microdissected rabbit proximal straight tubules. Ten-day-old cultured cells were made ischemic for 6 hr. and allowed to recover for 24 hr. At the end of ischemia. cells were incubated with ADO. theophylline (T). dipyridamole (D). coformycin (C) or combined agents for 3 hr. Total AN (TAN) were determined after 3 and 24 hr of recovery. The results. after 3 hr of incubation. suggest that in both control and ischemic cells. ADO is taken up by cultured cells and is preferentially converted to nucleotides. This effect is blocked by D. which inhibits ADO uptake. uninfluenced by C. which inhibits ADO deaminase and potentiated by T. which inhibits 5'-nucleotidase. After 24 hr of recovery. the beneficial effects of ADO alone or combined D. C. or T. on TAN were not seen in control cells. In contrast. in the ischemic cells. after 24 hr of recovery. ADO + T normalized ATP. ADP and TAN to the preischemic levels. T alone significantly increased ATP after 24 hr of recovery. To demonstrate further that the beneficial effect of T is due to inhibition of 5'-nucleotidase. cells were treated with adenosine alpha. beta-methylene diphosphate in the same manner as T. Combined ADO + adenosine alpha. beta-methylene diphosphate normalized ATP. ADP and TAN after 24 hr of recovery. This finding suggests that inhibition of 5'-nucleotidase improves postischemic AN.
MCI-154, a novel cardiotonic agent, reverses the acidic pH-induced decrease in responses of cardiac myofilaments to Ca++: comparison with sulmazole and pimobendan, In the present study. we have examined the effects of decreasing pH from 7.0 to 6.6 on the tension developed by direct activation of the myofilaments in chemically skinned fibers from guinea pig papillary muscles. We then compared the effects of the novel inotropic agents MCI-154. pimobendan and sulmazole. which have direct action on cardiac myofilaments. on the acidic pH-induced changes in responses of the contractile system to Ca++. The reduction of pH from 7.0 to 6.8 shifted the pCa (-log[Ca++] M)-tension relation curve to the right with no change in maximum tension. However. the reduction of pH from 7.0 to 6.6 shifted the pCa tension relation curve to the right and also depressed maximum force development. These effects were reversible by returning to neutral pH (pH 7.0). but were not overcome by increasing the free [Ca++] (decreasing pCa from 4.4 to 4.0). The amplitude of pMg-ATP (-log[MgATP]M)-tension curve in the absence of free Ca++ (Ca++ less than 1 nM. bell-shaped curve) was shifted downward by reducing pH from 7.0 to 6.6. MCI-154 (1-100 microM) reversed the acidic pH-induced decrease of tension development which was activated by pCa 5.8 in a concentration-dependent manner. Moreover. the acidosis induced reductions of maximum tension (pCa. 4.4) and pMgATP 6.0-activated tension (Ca++ less than 1 nM) were also reversed by MCI-154 (1-100 microM) in a concentration-dependent manner.
The role of serotonin-1A receptor activation and alpha-1 adrenoceptor blockade in the hypotensive effect of 5-methyl-urapidil, Our study had three purposes: 1) to determine whether 5-methyl-urapidil. topically applied to the ventrolateral medulla. produces hypotension by activating serotonin-1A (5-HT1A) receptors. 2) to determine whether 5-methyl-urapidil given i.v. produces hypotension in part by activating 5-HT1A receptors in the ventrolateral medulla. and 3) to determine the specific site within the ventrolateral medulla where 5-methyl-urapidil elicits a hypotensive response. In terms of the first purpose. 5-methyl-urapidil applied bilaterally to the intermediate area of the ventral surface of the medulla (1.2 micrograms/side) of chloralose-anesthetized cats produced a decrease in mean arterial pressure of -39 +/- 4 mm Hg (N = 8). Prior blockade of 5-HT1A receptors at this site with bilateral application of spiperone (30 micrograms/side) prevented the hypotensive effect of 5-methyl-urapidil (mean blood pressure now increased by 5 +/- 4 mm Hg). Pretreatment with the alpha-1 adrenoceptor antagonist. prazosin. did not prevent the hypotensive effect of 5-methyl-urapidil. In terms of the second purpose. spiperone applied bilaterally to the ventral surface of the medulla counteracted a significant portion of the hypotensive effect of 5-methyl-urapidil given by the i.v. route. The dose of 5-methyl-urapidil given intravenously was below the dose that produces alpha-1 adrenoceptor blockade. In terms of the third purpose. microinjection of 5-methyl-urapidil into central nervous system sites associated with the intermediate area was found to have its greatest hypotensive effect at the subretrofacial nucleus. Mean arterial pressure decreased by 74 +/- 14 mm Hg (N = 3) after bilateral microinjection of 25 ng of the drug.
High energy pulsed dye laser lithotripsy: management of ureteral calcium oxalate monohydrate calculi, High energy pulsed dye laser lithotripsy (Candela MDL-2000). with energy output upgraded to a maximum of 140 mJ. at the laser fiber tip using the 320 mu core fiber. was compared to the initially commercialized device. with the energy output fixed at 60 mJ. using the 200 mu core fiber (Candela MDL-1). A total of 31 treatments in 28 patients was performed with the Candela MDL-1 device. Complete disintegration or at least fragmentation to spontaneously passable fragments occurred in 18 of 31 cases (58%). Only in 11 of the 24 calcium oxalate monohydrate calculi (46%) was fragmentation achieved. Another 73 laser lithotripsies in 72 patients were performed with the Candela MDL-2000 device. Complete disintegration or at least fragmentation to spontaneously passable fragments was achieved in 67 of 73 treatments (92%). Calcium oxalate monohydrate calculi were successfully treated in 41 of 45 procedures (91%). There was no response to the laser treatment in the only cystine calculus.
Use of the Benchekroun hydraulic valve as a catheterizable continence mechanism, Problems with continence and access for catheterization with previous continent stoma techniques have led us to search for an alternate method. We report our initial experience with the Benchekroun hydraulic valve in 9 patients. Five patients underwent creation of an ileocolic bladder: for myelodysplasia in 1. after cystectomy for bladder cancer in 2 and for exstrophy in 2. Two patients underwent conversion from an uncatheterizable Indiana pouch because of exstrophy (1) and interstitial cystitis (1). Two patients underwent small bowel augmentation of a small. poorly compliant bladder with an abdominal Benchekroun stoma: 1 had exstrophy and 1 had myelodysplasia. Patient age ranged from 7 to 63 years. Two patients had de novo creation of an ileocolic bladder. whereas 7 had bladder or previous bowel conduits incorporated in the continent reservoirs. At up to 20 months of followup all patients had diurnal and nocturnal continence. and none had experienced serious long-term complications. Problems were encountered in 5 patients. One patient had a valve fistula that was surgically revised. One patient experienced transient difficulty with catheterization when the reservoir was overdistended and a false passage developed. Three patients had stomal stenosis and require periodic dilation. We believe the Benchekroun hydraulic valve to be a useful adjunct in the construction of a continent urinary reservoir. It is easy to construct. provides reliable continence and is easy to catheterize. Furthermore. it may be applied to standard ileocolic bladders either de novo or as a salvage procedure for failed efferent limbs.
Effect of apomorphine on penile tumescence in men with psychogenic impotence, In a double-blind study using physiological recording of penile tumescence. brachial subcutaneous apomorphine hydrochloride injections elicited penile erections in men with psychogenic impotence. This observation is compatible with the hypothesis of central dopaminergic involvement in human penile erection. Since apomorphine is believed to induce erections by its effect on brain monoamine pathways. apomorphine response may have diagnostic use in evaluating the etiology of erectile failure.
Outpatient 3-piece inflatable penile prosthesis, The 3-piece inflatable penile prosthesis was implanted in 74 consecutive organically impotent outpatients during the last 4 years. The classical infrapubic surgical approach required minor alterations to adapt to the outpatient setting. This cost-reducing technique is safe medically and cogent financially.
Electromagnetic extracorporeal shock wave lithotripsy in children, Extracorporeal shock wave lithotripsy (ESWL) was performed for the treatment of urinary tract calculi in 28 children. All treatments were done with the standard Siemens Lithostar device in situ: no special adaptations for adequate positioning of children are required to target the stone precisely. A total of 42 calculi in 30 renal units was treated. requiring 50 ESWL sessions. The mean energy used was 16.4 kv. and the number of shock waves averaged 3.188. Mean fluoroscopy time per session was 1.5 minutes. In 26 of 50 sessions (52%) general anesthesia was needed for the child to remain perfectly still. A complete stone-free rate was achieved in 38 of 42 calculi (90.5%): after 1 session in 30 (71.4%). after 2 sessions in 6 (13.7%) and after 3 sessions in 2 (4.8%). Five staghorn calculi were treated with ESWL monotherapy. A complete stone-free result was obtained after 3 treatments in 2 patients. while 2 had residual fragments in the lower pole (5 mm. after 6 sessions and 11 months of followup in 1. and 7 mm. after 3 sessions and 3 months of followup in 1). A cystine staghorn stone necessitated open nephrolithotomy after 3 sessions without any fragmentation. One impacted sacroiliac ureteral stone required endoscopic laser lithotripsy. Except for these 2 failures no adjuvant procedures were needed. There were no intraoperative or postoperative complications and minor skin bruising at the coupling site after 3 treatments did not require any therapy. We conclude that electromagnetic ESWL with the standard Lithostar unit is a safe and effective method to treat calculi throughout the urinary tract in children.
The blood supply to preputial island flaps, The prepuce is formed by a combination of folding and epithelial proliferation. and separates from the glans after it has developed a blood supply. The arterial input. through 4 branches from the external pudendal arteries. is terminal and after birth supplies the outer and inner preputial surfaces in succession. Similarly. the venous return arises from small veins running transversely in the prepuce that connect to larger subcutaneous veins along the dorsal aspect of the shaft. Because the 2 preputial surfaces have a single blood supply they must be treated as 1 unit. Unfolding the prepuce leaves the former inner segment with only a terminal blood supply. The pedicle containing the superficial blood supply must remain attached to the skin flap or it will be devascularized. However. since this circulation goes exclusively to the flap. the more proximal portion of the prepuce that was raised to form the pedicle becomes ischemic when used as ventral cover. A double-faced flap avoids this complication.
Modified cruciate incision for transabdominal radical nephrectomy, Experience with multiple organ harvesting procedures as well as orthotopic liver transplantation has provided for excellent extensive upper abdominal surgical exposure. We report use of a modified cruciate incision for transabdominal radical nephrectomy.
Repair of a traumatically amputated penis with return of erectile function, Repair of the amputated penis may be successful using macroscopic and microscopic surgical realignments. However. to date. no one has reported return of erectile function documented by nocturnal penile tumescence. We report a case of traumatically amputated penis with microscopic repair and return of erectile function documented by nocturnal penile tumescence. In addition. the current literature regarding microscopic versus nonmicroscopic repair is reviewed.
Fibrin glue vasal anastomosis compared to conventional sutured vasovasostomy in the rat, Vasectomy reversal has become a frequently performed surgical procedure with best results obtained with the use of the operating microscope and microsurgical technique. The present study was undertaken to evaluate the use of fibrin glue ("Tisseel". Immuno U.S.. Inc.) for vasovasostomy and to compare this technique to conventional sutured vasovasostomy. Utilizing 60 male Sprague Dawley rats. a conventional two layered sutured anastomosis of vasovasostomy (30 rats) was compared to a fibrin glue technique of vasal anastomosis (30 rats). The fibrin glue technique was performed with two transmural sutures. was unstented. and utilized the biological glue to seal the anastomosis. The contralateral vas of each animal underwent vasectomy and reapproximation of unligated ends so that the rate of spontaneous recanalization could be accessed. Rats were sacrificed at 24 hours. one week. four weeks. and three months postvasovasostomy. The vasal specimens were evaluated for gross patency. presence and size of sperm granuloma. mean flow rates at varying infusion pressures. tensile strength measurements and histologic studies. Combining the one and three month groups. a similar patency rate was obtained by either technique; 83% (n = 18) for the sutured group. and 90% (n = 21) for the fibrin glue group. The rate of spontaneous recanalization of the contralateral vasa in the one and three month animals was 8% (n = 38). The mean flow rates obtained at high and low infusion pressures were not statistically different for the two techniques. The tensile strength of the glue anastomosis averaged 78% of the tensile strength achieved by the conventional sutured technique. The incidence of sperm granuloma after vasovasostomy was 28% for the fibrin glue group and 61% for the sutured group. Additionally. 67% of granulomas were small (less than 3 mm.) in the glue group. compared to only 36% in the sutured group. Histology revealed similar morphological changes in the area of anastomosis with either technique. Operative time for sutured vasovasostomy averaged 24 minutes. compared to an average of 11 minutes for the glue assisted vasovasostomy. The use of fibrin glue allowed the performance of a sperm tight patent anastomosis that had the advantages of reduced incidence of sperm granuloma formation. reduced operative time. and less microsurgical skill required to perform the anastomosis.
The human penis: an unusual penetration of NPY-immunoreactive nerves within the medial muscle coat of the deep dorsal vein, The deep dorsal penile vein was obtained from seven patients undergoing surgery for erectile dysfunction. The veins were studied histologically and immunohistochemically for serotonin. dopamine beta-hydroxylase. vasoactive intestinal polypeptide. neuropeptide Y. substance P. calcitonin gene-related peptide. somatostatin. and [Leu]- and [Met]enkephalin. Histologically. the deep dorsal vein was found to be a large muscular vein with a thin endothelial lining. The tunica media was composed of an inner longitudinally and an outer circularly arranged smooth muscle layer. Numerous vasa vasorum (up to 30 in a single transverse section) were found in the tunica adventitia. The greatest density of nerves supplying the deep dorsal vein and vasa vasorum were neuropeptide Y-immunoreactive nerves followed (in a decreasing order) by vasoactive intestinal polypeptide- and dopamine beta-hydroxylase-immunoreactive nerves. Substance P-. calcitonin gene-related peptide- and somatostatin-immunoreactive nerves. but not serotonin-. [Leu]- and [Met]enkephalin-immunoreactive nerves. were occasionally found around the deep dorsal vein. All these nerve fibers were confined to the adventitial-medial border except neuropeptide Y-immunoreactive nerves which in addition penetrated the tunica media to the subendothelial layer of the deep dorsal vein. In contrast. neuropeptide Y-immunoreactive nerves supplying the vasa vasorum were always confined to the adventitial-medial border. The possible function of the medial innervation of the deep dorsal vein by neuropeptide Y-immunoreactive nerves is discussed.
Internalization of bacille Calmette-Guerin by bladder tumor cells, Mechanisms by which intravesical bacille Calmette-Guerin (BCG) treatment mediates antitumor activity are currently poorly understood. We have determined that both human bladder tumor (T-24) and mouse bladder tumor (MBT-2) cells are capable of internalizing the BCG and have characterized this process in vitro. The internalization of BCG by T-24 and MBT-2 cells was verified by histochemistry and electron microscopy. Time dependent internalization of BCG was observed with a maximum occurring at three hrs. Internalization was significantly inhibited by both incubation at 4C and cytochalasin B; conditions known to inhibit phagocytosis. Ultrastructural studies suggested that BCG were transported to membrane bound intracellular compartments and were degraded. The compartments containing the degraded mycobacteria labeled with the fluid phase marker HRP which is known to be transported to lysosomes in a variety of cell types. To determine if the internalization process occurred in vivo. we examined bladder washings of patients treated with intravesical BCG. The majority of the cells in the bladder washings were inflammatory cells which contained ingested BCG. In addition. internalized and degraded BCG were identified in urothelial cells. These data demonstrate that BCG are internalized by transitional epithelial cells both in vitro and in vivo. The internalization process is inhibitable by temperature and microfilament disruption. The potential therapeutic implications of this process and its relationship to antitumor activity of BCG therapy are currently being investigated.
HIV infection among members of the US Army Reserve Components with medical and health occupations, Over 58.000 members of the US Army Reserve Components tested for human immunodeficiency virus (HIV) antibody had military or civilian medical occupations. The availability of HIV status and occupational information permits the assessment of prevalence and incidence of infection in this population. Levels of infection were not higher among women or among currently married men with medical occupations compared with those with nonmedical occupations. Prevalence and incidence were elevated among never-married men with either military or civilian medical occupations compared with never-married men with nonmedical occupations. Based on reported civilian occupation. male registered nurses and men with other medical occupations. excluding physicians and dentists. had a significantly higher prevalence of infection than men with nonmedical occupations. The patterns of infection suggest that the higher levels of infection found among never-married men with medical occupations may not be entirely due to occupational exposure. These findings may have applications in the design and interpretation of results of health care worker HIV surveillance programs.
Gynecologic sonography. Report of the ultrasonography task force. Council on Scientific Affairs, American Medical Association, Sonography. because it is nonionizing. is the preferred imaging modality for the female pelvis. Traditionally. transabdominal. transcystic studies were performed However. development of transvaginal and transrectal transducers has led to enhanced imaging capabilities of the pelvis. These new technologies will likely improve our ability to understand gynecologic pathology. The clinical use of pelvic ultrasonography depends on a thorough understanding of normal anatomy and cyclical changes and on the relative limitations of the imaging modality in specifically characterizing pathologic processes. This article reviews the accepted role of pelvic sonography in gynecologic disease and provides a preview of some of the potential applications of recent advances in sonographic technology.
Biased estimates of expected acute myocardial infarction mortality using MedisGroups admission severity groups, This study examines whether the MedisGroups admission severity groups give unbiased estimates of 30-day mortality in 3037 Medicare-aged patients who were hospitalized in 1985 through 1986 with acute myocardial infarction. The average observed death rate for all acute myocardial infarction patients in the study who were in a given admission severity group was used to estimate the expected death probability for each case in a given group. (This is the same method used by the Pennsylvania Health Care Cost Containment Council for risk adjusting hospital mortality by diagnosis related groups in that state.) When compared with observed deaths. estimates of expected mortality were significantly biased for many patient attributes (eg. age. location of acute myocardial infarction. history of congestive heart failure. serum potassium level. serum urea nitrogen level. pulse rate. and blood pressure). These results are consistent with a conclusion that the MedisGroups scoring algorithm omits some important risk variables. inappropriately includes some other variables reflecting postadmission status. and gives the wrong weights to some appropriate risk variables. To the extent that these findings are also applicable to current MedisGroups scoring algorithms and to other conditions and procedures. MedisGroups admission severity groups cannot fairly adjust for interhospital case mix differences in outcome studies.
Epidemiology of women with AIDS in the United States, 1981 through 1990. A comparison with heterosexual men with AIDS, In the United States. women account for an increasing number and percentage of adults with the acquired immunodeficiency syndrome (AIDS). Overall. 51% of women with AIDS were infected through intravenous drug use and 29% through heterosexual contact; the proportion of intravenous drug users decreased. while the proportion attributed to heterosexual contact increased. between 1986 and 1990. Most women with AIDS were black or Hispanic (72%); residents of large metropolitan areas (73%). especially cities along the Atlantic coast; and of reproductive age (15 to 44 years) (85%). However. the proportion of women with AIDS reported by smaller cities and rural areas has increased from 22% in 1986 to 28% in 1990. The male-to-female ratio of heterosexuals with AIDS has remained about 2.4:1 since 1987. A comparison of women with AIDS to heterosexual men with AIDS showed that these two groups were similar by age. race. and geographic distribution. Also. survival times from AIDS diagnosis to death for women and heterosexual men with AIDS were not significantly different.
Current role of digitalis therapy in patients with congestive heart failure, Digitalis has been used in the treatment of chronic congestive heart failure for 215 years. In this article. numerous clinical studies and trials that have evaluated the efficacy of digitalis in the treatment of patients with congestive heart failure are reviewed. The data indicate that digitalis is a valuable therapeutic agent for relieving symptoms and improving exercise performance and left ventricular function in patients with congestive heart failure. Comparison of the various advantages and disadvantages of digitalis with alternative therapies in patients with congestive heart failure shows an important continuing role for digitalis therapy.
Optical properties of normal, diseased, and laser photocoagulated myocardium at the Nd: YAG wavelength, Laser photocoagulation of the myocardium effectively destroys arrhythmogenic foci. The purpose of this study was 1) to compare the optical properties of canine myocardium before and after photocoagulation. 2) to compare the canine model with clinical cases by measuring the optical properties of human myocardium. and 3) to assess the optical properties of human myocardial scar and epicardial fat tissue. Measured optical properties were the absorption coefficient. mu a; scattering coefficient. mu s; and scattering anisotropy factor. g. Optical measurements were performed at 1064 nm wavelength on thin plane parallel tissue slices using the integrating sphere method with glass hemispheres on either side of the sample. The study showed 1) an increase of the scattering coefficient by 40% and a two- to threefold increase in reduced scattering coefficient as a result of photocoagulation; 2) that the mu a (0.035 +/- 0.024 mm-1) and mu s (17.9 +/- 3.8 mm-1) of human myocardium were not significantly different from mu a (0.043 +/- 0.021 mm-1) and mu s (17.3 +/- 2.2 mm-1) of canine myocardium. whereas the human g (0.964 +/- 0.005) was slightly different from the canine g (0.974 +/- 0.008); and 3) that the mu a (0.021 +/- 0.016 mm-1) of epicardial fat and mu s (13.8 +/- 1.1 mm-1) of myocardial scar were significantly lower than those of normal myocardium. A dynamic model of laser-tissue interaction incorporating these changes and inhomogeneities is necessary to better describe light distribution during laser photocoagulation.
Dye laser photocoagulation through experimentally induced retinal hemorrhage, The histological effects of photocoagulation obtained by using each of 4 wavelengths of the dye laser (577. 590. 610. and 630 nm) on experimentally induced retinal hemorrhage in cat eyes were examined. Energy from 577. 590. and 610 nm laser was directly absorbed by red blood cells in the retinal hemorrhage and destroyed the inner layers of the retina. Red blood cells were not directly coagulated with the use of 630 nm laser. and the retinal pigment epithelial cells (RPE cells) and choroidal melanocytes were coagulated. These results suggest that the use of yellow or orange dye lasers for photocoagulative therapy in a retinal hemorrhage is dangerous. because of the risk for destruction of the inner layers of the retina. A 630 nm dye laser is useful for photocoagulation of a retinal hemorrhage. while the laser energy is unable to reach the RPE cells and the choroid with the use of other wavelengths.
Photodynamic therapy for rat pituitary tumor in vitro and in vivo using pheophorbide-a and white light, This is the first report on the use of photodynamic therapy (PDT) for rat pituitary tumor in vivo. Rat pituitary tumor (GH3) cells were cultured. GH3 tumor was subcutaneously implanted in nude mice. and pheophorbide-a (Ph-a) and white light were prepared. Photocytotoxicity proportional to Ph-a concentration. intensity of irradiation. and incubation time was observed in vitro. Despite the delay in the disappearance of Ph-a from the tumor. Ph-a in the pituitary gland rapidly decreased after intravenous administration in vivo. Through PDT. the tumor grossly disappeared. the plasma levels of rat growth hormone secreted from the tumor also remarkably decreased. and the development of giantism was inhibited. These results indicate that PDT is effective against rat pituitary tumor.
Interspersion of fragmented fiber's splinters into tissue during pulsed alexandrite laser lithotripsy, Laser induced shockwave lithotripsy (LISL) on artificially inserted human renal calculi was realized in explanted pig ureters. A pulse stretched Alexandrite solid state laser was used at 750nm. Pulses of 350ns and 1 microseconds duration were transmitted through a 250 microns all silica fiber onto a stone surface. keeping the fiber tip in contact with a stone close to the ureter wall. The high power density of the 350 ns pulses lead to an optical breakdown inside the distal fiber tip causing fiber fragmentation of about 28 mm/100 pulses. Deep penetration of the fiber fragments into the ureter wall was proven histologically. Fiber fragmentation was avoided by increasing the pulse duration up to 1 microseconds. Riks for patient treatment caused by short pulse lithotripsy are discussed.
The HIV/AIDS epidemic: the first 10 years, On June 5. 1981. the first cases of an illness subsequently defined as acquired immunodeficiency syndrome (AIDS) were reported by health-care providers in California and CDC. As of May 31. 1991. state and local health departments had reported to CDC 179.136 AIDS cases among persons of all ages in the United States. By the end of 1991. AIDS will be the second leading cause of death among men 25-44 years of age and is likely to be one of the five leading causes of death among women aged 15-44 years in the United States.
Measles--United States, 1990, As of May 10. 1991. local and state health departments reported a provisional total of 27.672 measles cases in the United States for 1990--a 52.1% increase over the 18.193 cases reported for 1989--and 89 suspected measles-associated deaths. Cases were reported from 49 states and the District of Columbia. The overall incidence rate in 1990 was 11.1 cases per 100.000 population. This report summarizes epidemiologic features of measles cases reported for 1990 and compares findings with cases reported for 1989.
A phase I evaluation of the safety and immunogenicity of vaccination with recombinant gp160 in patients with early human immunodeficiency virus infection. Military Medical Consortium for Applied Retroviral Research, BACKGROUND. Despite multiple antiviral humoral and cellular immune responses. infection with the human immunodeficiency virus (HIV) results in a progressively debilitating disease. We hypothesized that a more effective immune response could be generated by post-infection vaccination with HIV-specific antigens. METHODS. We performed a phase I trial of the safety and immunogenicity of a vaccine prepared from molecularly cloned envelope protein. gp160. in 30 volunteer subjects with HIV infection in Walter Reed stage 1 or 2. The vaccine was administered either on days 0. 30. and 120 or on days 0. 30. 60. 120. 150. and 180. HIV-specific humoral and cellular immune responses were measured; local and systemic reactions to vaccination. including general measures of immune function. were monitored. RESULTS. In 19 of the 30 subjects both humoral and cellular immunity to HIV envelope proteins increased in response to vaccination with gp160. Seroconversion to selected envelope epitopes was observed. as were new T-cell proliferative responses to gp160. Response was associated with the CD4 cell count determined before vaccination (13 of 16 subjects [81 percent] with greater than 600 cells per milliliter responded. as compared with 6 of 14 [43 percent] with less than or equal to 600 cells per milliliter; P = 0.07) and with the number of injections administered (87 percent of subjects randomly assigned to receive six injections responded. as compared with 40 percent of those assigned to three injections; P = 0.02). Local reactions at the site of injection were mild. There were no adverse systemic reactions. including diminution of general in vitro or in vivo cellular immune function. After 10 months of follow-up. the mean CD4 count had not decreased in the 19 subjects who responded. but it had decreased by 7.3 percent in the 11 who did not respond. CONCLUSIONS. This gp160 vaccine is safe and immunogenic in volunteer patients with early HIV infection. Although it is too early to know whether this approach will be clinically useful. further scientific and therapeutic evaluation of HIV-specific vaccine therapy is warranted. Similar vaccines may prove to be effective for other chronic infections.
A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis, BACKGROUND. A nosocomial outbreak of fulminant hepatitis B occurred in five patients in Haifa. Israel. Previous investigations identified the suspected source as a carrier of hepatitis B surface antigen who was positive for antibodies to hepatitis B e antigen and had chronic liver disease. We examined the strain of hepatitis B virus (HBV) that caused this epidemic. in order to identify specific mutations in the precore or core region. METHODS. The presence of HBV was identified by polymerase-chain-reaction amplification of viral DNA in serum from the source patient. the five patients with fulminant hepatitis B. and five controls with acute. self-limited hepatitis B. The amplified viral HBV DNA samples were then cloned and sequenced. RESULTS. Sequence analysis of viral DNA established that the same HBV mutant with two mutations in the precore region was present in the source patient and the five patients with fulminant hepatic failure. This HBV mutant had significant sequence divergence from other known HBV subtypes in the X. precore. and core regions. Cloned HBV DNA derived from a hospitalized patient who had subclinical hepatitis B at the same time as the outbreak and from four other control subjects with acute. self-limited hepatitis B all contained the wild-type sequence in the precore region. CONCLUSIONS. In the outbreak we studied. a mutant hepatitis B viral strain was transmitted from a common source to five patients who subsequently died of fulminant hepatitis B infection. Naturally occurring viral mutations hepatitis B infection. Naturally occurring viral mutations in the HBV genome may predispose the infected host to more severe liver injury.
X-chromosome inactivation may explain the difference in viability of XO humans and mice, Only about 1% of human XO conceptuses survive to birth and these usually have the characteristics of Turner's syndrome. with a complex and variable phenotype including short stature. gonadal dysgenesis and anatomical defects. Both the embryonic lethality and Turner's syndrome are thought to be due to monosomy for a gene or genes common to the X and Y chromosomes. These genes would be expected to be expressed in females from both active and inactive X chromosomes to ensure correct dosage of gene product. Two genes with these properties are ZFX and RPS4X. both of which have been proposed to play a role in Turner's syndrome. In contrast to humans. mice that are XO are viable with no prenatal lethality (P. Burgoyne. personal communication) and are anatomically normal and fertile. We have devised a system to analyse whether specific genes on the mouse X chromosome are inactivated. and demonstrate that both Zfx and Rps4X undergo normal X-inactivation in mice. Thus the relative viability of XO mice compared to XO humans may be explained by differences between the two species in the way that dosage compensation of specific genes is achieved.
Syndrome of the cervical plexus caused by high cervical nerve root compression, Lesions affecting the roots of the cervical plexus can cause a syndrome not previously described. The C3-C4 disc space is the most likely to be involved. but pressure on the C5 root can also produce facial. auricular. or retroauricular pain. Motor innervation to the diaphragm can be affected. and even the uppermost disc space at C2-C3 might be implicated. Findings on examination findings are sparse. although sensory impairment in areas of cervical plexus innervation has been observed. In a series of 1000 cervical decompression cases (both anterior and posterior) for disc disease or similar processes. only 10 instances of this syndrome have been found. Paresthesia or episodic shock-like pain affecting the ear. para-auricular. lower occipital. and mandibular areas prompted by head turning or extension are the most common complaints.
The correlation between immunological reaction in the arterial wall and the time course of the development of cerebral vasospasm in a primate model, To investigate the role of immunological reactions in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH). the authors studied the correlation between immune/inflammatory reactions in the arterial wall and the time course of vasospasm in primates. Twenty monkeys were divided into four groups of 5 animals each: 1) a control group of sham-operated animals. 2) animals subjected to angiography 3 days after the induction of SAH (3-day SAH). 3) animals subjected to angiography 7 days after SAH (1-week SAH). and 4) animals subjected to angiography 7 and 14 days after SAH (2-week SAH). To induce SAH. the main cerebral arteries on the right were dissected free of the arachnoid. and an autologous blood clot was placed around the arteries. To evaluate vasospasm. all animals underwent a baseline angiogram before SAH; angiography was repeated at different intervals in each group. as outlined above. Histopathological changes and the deposition of the immunoglobulin IgG in the arterial wall were evaluated immunohistochemically in each group. The cerebral arteries on the side of the clot showed evidence of mild vasospasm (-24.6% reduction) on the angiogram performed on Day 3. severe vasospasm (-51.7%) on Day 7. and mild vasospasm (-12.8%) on Day 14. The infiltration of inflammatory cells was most marked in the spastic arterial wall in the 1-week SAH group. In the 2-week SAH group. severe myonecrosis and intimal disruption were observed. even in the vessels that showed only mild vasospasm. and the inflammatory reactions had almost abated.
Intracerebral hemorrhage after lumbar myelography with iohexol: report of a case and review of the literature, Intracranial hemorrhage is an uncommon complication of dural puncture. In most instances. hematomas are subdural; they may be unilateral or bilateral. Rarely are intraparenchymal cerebral hemorrhages related to dural puncture. This report describes a delayed occurrence of bilateral intraparenchymal hemorrhages in a 38-year-old woman 7 days after lumbar myelography with iohexol. A review of the literature is presented.
Traumatic atlantooccipital dislocation with survival, Survival after traumatic atlantooccipital dislocation is rare. Only long-term survivors have been reported in the literature; however. improved prehospital care is likely responsible for the increase in the number of these patients seen at neurotrauma centers over the last decade. Associated severe and persistent neurological deficits are common in the few survivors. We report the case of a 10-year-old boy with traumatic atlantooccipital dislocation and a severe neurological injury. Low-field magnetic resonance imaging provided the additional diagnosis of an associated cervicomedullary epidural hematoma. The patient underwent emergency operative evacuation of the hematoma and an occipital-cervical fusion with internal fixation. He had a remarkable recovery in neurological function and achieved stable bony fusion 3 months postoperatively. With early recognition of this entity. improved neuroradiological imaging techniques. and aggressive treatment. patients may survive with significant neurological recovery.
Stabilization of the cervical spine in spondyloepiphyseal dysplasia congenita, Spondyloepiphyseal dysplasia congenita is an inheritable bone dysplasia causing abnormalities that manifest at birth and primarily involve the spine and proximal epiphyses. The clinical findings include short-trunk dwarfism. myopia. frequent retinal detachment. shortening of the spine and proximal extremities. mild thoracic kyphoscoliosis. a barrel-shaped thorax. a short neck. and mild ocular hypertelorism. The characteristic radiographic features are a generalized delay in ossification. flattening and dysplasia of the vertebral bodies. pelvic dysplasia. and retarded ossification of the femoral head and neck. Other radiographic features of interest to the neurosurgeon may be platybasia. kyphoscoliosis. lumbar hyperlordosis. and odontoid hypoplasia. A case of spondyloepiphyseal dysplasia congenita is presented in which an unstable and markedly dysplastic cervical spine was stabilized with Halifax interlaminar clamps and sublaminar wires. The clinical findings and radiographic features are presented and the etiology and neurosurgical management of spondyloepiphyseal dysplasia congenita are discussed.
Neurenteric cyst located dorsal to the cervical spine: case report, A patient with a neurenteric cyst located dorsal to the cervical spine and associated with occult cervical spinal dysraphism is described. The embryological theories that might explain the occurrence of such a lesion are discussed.
Aneurysmal bone cyst of the odontoid process: case report, Aneurysmal bone cysts (ABCs) are relatively uncommon. benign lesions. Fully 50% occur in long bones and 20% in the vertebral column. mostly in patients under 20 years of age. We report a case of an ABC in the odontoid process of a 74-year-old who sought treatment for pain and myelopathy. This is the first case reported of an ABC of the odontoid process.
Pineal teratoma and its relationship to intracerebral development: case report, A teratoma of the pineal region in a 20-year-old Australian Aborigine is presented in which an unusual location of the straight sinus and tentorium cerebelli suggests that the tumor arose before 4 months of gestation. In addition. this case provides some insight into the development of the falx cerebri. which might arise from the midline fusion of the left and right tentoria cerebelli caused by the dorsal development of the telencephalon.
Hematoma in the posterior fossa secondary to a tangential gunshot wound of the occiput: case report and discussion, The case of 16-year-old boy who incurred a subdural hematoma in the posterior fossa an intracerebellar hematoma after a tangential civilian gunshot wound is reported. The skull was not fractured. and yet surgically significant clots required removal. The patient recovered. The discussion centers on the mechanism of injury and seriousness of tangential gunshot wounds and traumatic hematomas in the posterior fossa.
Benign recurrence of a pilocytic cerebellar astrocytoma 36 years after radical removal: case report, A benign recurrence of a cerebellar juvenile astrocytoma was found in a 52-year-old woman 36 years after the initial radical removal. which was performed when she was 16 years of age. To our knowledge. this is the third detailed case report of the late benign recurrence of cerebellar astrocytoma after total removal. The problem of recurrence of cerebellar astrocytoma is reviewed.
Impact of the human immunodeficiency virus epidemic on mortality in children, United States, To assess the effect of the human immunodeficiency virus (HIV) epidemic on mortality in US children younger than 15 years of age and to identify associated causes of death. the authors examined final national mortality statistics for 1988. the most recent year for which such data are available. In 1988. there were 249 deaths attributed to HIV/acquired immunodeficiency syndrome (AIDS) in children younger than 15 years of age. Associated causes of death listed most frequently on 270 death certificates with any mention of HIV/AIDS included conditions within the AIDS surveillance case definition (30%). pneumonia (excluding Pneumocystis carinii pneumonia) (17%). septicemia (10%). and noninfectious respiratory diseases (8%). The impact of HIV/AIDS as a cause of death was most striking in the 1-through 4-year-old age group and in black and Hispanic children. particularly in the Northeast. By 1988 in New York State. HIV/AIDS was the first and second leading cause of death in Hispanic and black children 1 through 4 years of age. accounting for 15% and 16%. respectively. of all deaths in these age-race groups. With an estimated 1500 to 2000 HIV-infected children born in 1989. the impact of HIV on mortality in children will become more severe.
Hypochloremic metabolic alkalosis from ingestion of a chloride-deficient infant formula: outcome 9 and 10 years later, In 1978 and 1979 two infant formulas. Neo-Mull-Soy and Cho-Free. were found to be deficient in chloride. The Centers for Disease Control received reports that hypochloremic metabolic alkalosis (HMA) had developed in 141 children as a result of exposure to these formulas. Thirty-five of these children were examined at 9 and 10 years of age and compared with a group of 32 children who were exposed to the chloride-deficient formulas but were not reported to experience HMA and a group of 61 children who received chloride-sufficient soy formulas in infancy. The control children were matched to the HMA children on sex. race. age. and maternal education. Growth characteristics. performance on the Wechsler Intelligence Scale for Children-Revised (WISC-R). the Boston Naming Test. the Rey-Osterrieth Test. the Clinical Evaluation of Language Fundamentals-Revised (CELF-R). and subtests from several other speech and language tests were compared across the groups. After adjustment for family income and the level of the father's education. significantly lower scores were observed in the HMA children on the WISC-R Arithmetic subtest (mean = 10.5) compared with the soy control children (mean = 12.0. P less than .05) and on the WISC-R Coding subtest (mean = 9.0) compared with the soy control children (mean = 10.8. P less than .01). All the WISC-R subtest scores were. however. within the normal range. Although no significant differences occurred on the CELF-R between groups. the risk of an HMA child falling below the range expected for a standard population was increased on the CELF-R Composite Total. Receptive. and Expressive Language scores: risk ratios = 2.14. 2.14. and 3.03 respectively. Significant differences were observed between the children exposed. both HMA and non-HMA children. and the soy control children for behavioral problems as determined by the Achenbach Childhood Behavioral Checklist. It is concluded that as a group. children with documented HMA appear to have recovered from their growth failure and have normal cognitive development. They may. however. be at risk for deficits in language skills that require expressive language abilities.
Early vaginal bleeding, late prenatal care, and misdating in adolescent pregnancies, Vaginal bleeding early in pregnancy may be mistaken for menstrual bleeding and delay entry into prenatal care by delaying the diagnosis of pregnancy. This study tests the hypotheses that (1) more adolescents report early first-trimester vaginal bleeding than do adults and (2) a history of vaginal bleeding is associated with later entry into prenatal care. particularly among adolescents. Reports of early vaginal bleeding were prospectively obtained from black. predominantly primiparous. unmarried poor women (136 adolescents and 53 adults). As hypothesized. more adolescents reported early first-trimester vaginal bleeding than did adults (16.9% vs 5.7%; P less than .01). Adolescents who reported early vaginal bleeding also entered prenatal care later (16.2 weeks) than did adolescents who reported no bleeding (12.7 weeks) (P less than .03); this was not true for adults. If dating of the gestation is based solely on last menstrual period history. inflation of the incidence of preterm births to adolescents and the mean birth weights of those preterm neonates may occur. The findings suggest that new strategies focusing on the recognition of menstrual irregularities as a symptom of pregnancy may be needed to promote early prenatal care among adolescents. Additionally. adolescent pregnancies should be dated by both ultrasound and Dubowitz examinations.
Review of intubation in severe laryngotracheobronchitis, Of 208 children who required relief of severe airway obstruction due to laryngotracheobronchitis by an artificial airway (nasotracheal intubation or tracheostomy) during a 10-year-period. 181 (87%) were intubated and later extubated. Twenty-seven children (13%) had tracheostomies performed. The tracheostomies were for severe subglottic narrowing precluding the passage of an adequate size endotracheal tube in 10 children. and for severe endotracheal tube trauma in 17 children. Five children developed acquired subglottic stenosis (2.4% of 208) and 1 of these has a retained tracheostomy. One child died of cardiac disease. The remaining 202 children had no long-term complications of laryngotracheobronchitis. intubation. or tracheostomy. It is concluded that nasotracheal intubation is a satisfactory artificial airway for laryngotracheobronchitis. Endoscopic evaluation in a selected group of these children will identify those with significant intubation trauma or severe subglottic narrowing in whom continued intubation may cause permanent subglottic damage. The low incidence of acquired subglottic stenosis in this series supports the practice of selective endoscopy and tracheostomy.
Knowledge and attitudes of day care center parents and care providers regarding children infected with human immunodeficiency virus, It was hypothesized that parents and child care providers are not prepared to accept children infected with human immunodeficiency virus (HIV). who are increasing in number. into the day care center setting. To determine their knowledge and attitudes toward HIV transmission. 219 parents in 4 day care centers and 176 care providers in 12 day care centers were given confidential questionnaires. More than 98% of respondents knew that sex and needle sharing can transmit HIV; 84% of parents and 77% of care providers knew that contact with blood can transmit HIV. There was. however. uncertainty about transmission via many common contacts in day care centers: human bites. urine. stool. tears. and vomit; kissing; sharing of food and eating utensils; and diaper changing areas. Only 43% of parents said they would allow their child to stay in the same room with a child who was infected with HIV. In a multiple logistic regression model. the unwillingness of parents to have their child stay in the same room with a child who was infected with HIV was significantly (P less than .0001) associated with black ethnicity. beliefs that such a child is likely to infect others (40%) and is dangerous to others (58%). and fear of their child being exposed to HIV (86%). Care providers' unwillingness to care for a child infected with HIV in the classroom (48%) was significantly (P less than .0001) associated with beliefs that such a child is likely to infect others (44%) and that common day care center contacts can transmit HIV (62%).
Children with chronic illness: family and parent demographic characteristics and psychosocial adjustment, This paper presents the results of an epidemiologic study that compares and contrasts psychosocial characteristics of parents and family units of children with chronic illness or physical disability (chronic health problems) with those of healthy children. Data were derived from the Ontario Child Health Study of 1869 randomly selected families. with 3294 children aged 4 to 16 years. In the absence of significant differences between parents and families of children with chronic illness alone and those with physical disability. these groups were combined for analysis. for which odds ratios (OR) or t tests were used. Significant positive findings included increased rates of parental treatment for "nerves" (mothers' OR = 2.1. fathers' OR = 1.9) and increased maternal negative affect scores (Bradburn Affect Balance Scale) (P less than .001) among parents of children with chronic health problems. Important negative findings (95% confidence interval of the OR included 1) included no increase in single-parent families (OR = 1.2). social isolation (OR = 1.0). or alcohol problems (OR = 1.2) among parents of children with chronic health problems. Categorically defined family dysfunction did not differ between the two groups (OR = 1.1). These data contrast with several clinic-based studies and suggest that. in a widely generalizable population survey. families of children with chronic health problems including physical disability do not suffer a marked excess of dysfunction. although some indicators of individual parent psychosocial problems were modestly elevated.
Neonatal adenovirus infection: four patients and review of the literature, Four newborns with adenovirus infection are described. and the profile of neonatal adenovirus disease is outlined based on the cases of these newborns and nine previously described. Characteristic historical features included prolonged rupture of membranes. maternal illness. vaginal delivery. and onset of illness within the first 10 days of life. Clinical findings included lethargy. fever or hypothermia. anorexia. apnea. hepatomegaly. bleeding. and progressive pneumonia. Thrombocytopenia. coagulopathy. and hepatitis were typical laboratory manifestations. Illness was severe and generally unremitting; only two survivors have been reported. Pathologic changes were prominent in lung. liver. and brain. Virus isolates. predominantly serotypes 3. 7. 21. and 30 were obtained from multiple sites and organs. Epidemiologic evidence suggests that viral acquisition from the mother. perhaps via the birth canal. is a major mode of transmission. Neonatal adenovirus infection. which is frequently disseminated and generally fatal. should be considered in the differential diagnosis of neonatal sepsis and pneumonia.
Virus burden in human immunodeficiency virus type 1-infected children: relationship to disease status and effect of antiviral therapy, The human immunodeficiency virus type 1 (HIV-1) was isolated from the plasma and peripheral blood mononuclear cells (PBMCs) from each of 21 infected children. The mean titers in plasma were 7 and 165 tissue culture-infective doses per milliliter in 9 children with asymptomatic (P-1) and 12 with symptomatic (P-2) infection. respectively (P = .0013). Significantly higher viral titers were found in PBMCs obtained from P-2 compared with P-1 children: 1920 vs 25 tissue culture-infective doses per 10(6) PBMC (P = .0018). In symptomatic patients at least 1 in 520 circulating mononuclear cells harbored HIV-1. No correlation was found between the viral burden and CD4+ lymphocyte counts. A decrease in the HIV-1 titers was noted both in PBMCs and plasma of symptomatic patients treated with zidovudine for 2 to 7 months. It is concluded that symptomatic children harbor a higher amount of the virus in plasma and PBMCs than asymptomatic children. Zidovudine treatment for 2 months or more decreased the amount of HIV-1 in PBMCs and plasma.
Peer problems in Tourette's disorder, To explore the social adjustment and peer relationships of children with Tourette's disorder. 29 patients with mild to moderate Tourette's disorder were studied. Children underwent neuropsychological testing. The patients completed self-esteem scales and their parents and teachers completed behavior rating scales. Peer relationships were examined with the Pupil Evaluation Inventory. which is a sociometric questionnaire completed by the child's classmates and provides measures of aggression. withdrawal. and likability. As a group. Tourette's disorder patients were significantly more withdrawn. more aggressive. and less popular than their classmates. Thirty-five percent of the children with Tourette's disorder received the lowest rating in the class on one or more of the Pupil Evaluation Inventory factors. These social problems were not predicted by the frequency or duration of tics. A clinical diagnosis of attention-deficit hyperactivity disorder and teachers' ratings on the summary scale of the Child Behavior Checklist and the Pupil Evaluation Inventory did predict poor adjustment. It is concluded that social adjustment is a major difficulty for many children with Tourette's disorder. irrespective of tic severity.
A link between double-strand break-related repair and V(D)J recombination: the scid mutation, We show here that mammalian site-specific recombination and DNA-repair pathways share a common factor. The effects of DNA-damaging agents on cell lines derived from mice homozygous for the scid (severe combined immune deficiency) mutation were studied. Surprisingly. all scid cell lines exhibited a profound hypersensitivity to DNA-damaging agents that caused double-strand breaks (x-irradiation and bleomycin) but not to other chemicals that caused single-strand breaks or cross-links. Neutral filter elution assays demonstrated that the x-irradiation hypersensitivity could be correlated with a deficiency in repairing double-strand breaks. These data suggest that the scid gene product is involved in two pathways: DNA repair of random double-strand breaks and the site-specific and lymphoid-restricted variable-(diversity)-joining [V(D)J] DNA rearrangement process. We propose that the scid gene product performs a similar function in both pathways and may be a ubiquitous protein.
Functional domains of the poliovirus receptor, A number of mutant cDNAs of the human poliovirus receptor were constructed to identify essential regions of the molecule as the receptor. All mutant cDNAs carrying the sequence coding for the entire N-terminal immunoglobulin-like domain (domain I) confer permissiveness for poliovirus to mouse L cells. but a mutant cDNA lacking the sequence for domain I does not. The transformants permissive for poliovirus were able to bind the virus and were also recognized by monoclonal antibody D171. which competes with poliovirus for the cellular receptor. These results strongly suggest that the poliovirus binding site resides in domain I of the receptor. Mutant cDNAs for the sequence encoding the intracellular peptide were also constructed and expressed in mouse L cells. Susceptibility of these cells to poliovirus revealed that the entire putative cytoplasmic domain is not essential for virus infection. Thus. the cytoplasmic domain of the molecule appears not to play a role in the penetration of poliovirus.
Hormonal modulation of a gene injected into rat heart in vivo, We demonstrate gene transfer into rat heart in vivo by the direct injection of plasmid DNA. Injection of gene constructs driven by retroviral and cellular promoters resulted in detectable levels of reporter gene activities. The cellular promoter and 5' flanking sequence (positions -613 to +32) were derived from the rat alpha-myosin heavy chain gene whose expression in vivo is restricted to cardiac muscle and is positively regulated by thyroid hormone. After DNA injection. activity of the firefly luciferase gene coupled to the myosin heavy chain promoter and regulatory sequence was detected in heart but not in skeletal muscle and was significantly increased in response to thyroid hormone treatment. Consequently. expression of injected genes can be targeted to specific cell types in vivo and can be modulated by the hormonal status of the animal. This approach provides a means of mapping the elements of genes that regulate their responses to complex stimuli that cannot be modeled in vitro.
Purinergic regulation of bradykinin-induced plasma extravasation and adjuvant-induced arthritis in the rat, We assessed the contribution of ATP and adenosine (i) to a major sign of acute inflammation. plasma extravasation (PE). in the rat knee joint and (ii) to the severity of joint injury in adjuvant-induced experimental arthritis. a chronic inflammatory disease. PE induced by local infusion of bradykinin. which we have previously shown to depend on the sympathetic postganglionic neuron terminal. was markedly enhanced by coinfusion of either ATP or the adenosine A2-receptor agonist 2-[4-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenos ine. Bradykinin-induced PE was inhibited by coinfusion of the ATP receptor antagonist adenosine 5'-[alpha.beta-methylene]triphosphate. the A2-receptor antagonist 3-(5H-thiozolo[2.3b]quinazolin-3-yl)phenol monohydrochloride. or the adenosine A1-receptor agonist N6-cyclopentyladenosine. The joint injury associated with experimental arthritis. which is reduced in severity in sympathectomized rats. was also markedly attenuated by daily administration of either ATP (40% reduction) or adenosine (55% reduction). These results demonstrate that the purines ATP and adenosine (acting at the A2 receptor). cotransmitters in the sympathetic postganglionic neuron terminal. enhance bradykinin-induced sympathetic postganglionic neuron terminal-dependent PE but inhibit the joint injury of arthritis. These opposing purinergic effects on PE and joint injury suggest that enhanced PE protects against joint injury.
Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis, Using an oligonucleotide hybridization assay. we studied the clinical implication of wild-type hepatitis B virus (HBV) and a HBV mutant that is unable to secrete hepatitis B e antigen (HBeAg) because of a translational defect due to a stop codon in the pre-C region in 106 hepatitis B surface antigen-positive patients with chronic hepatitis B. Wild-type HBV was detected in 31 of 42 (73.8%) HBeAg-positive patients. whereas a mixed viral population was present in 10 (23.8%). Significant differences in the severity and outcome of liver disease were not observed in the two groups of patients. However. the emergence of HBeAg-minus HBV in wild-type HBV carriers was associated with an exacerbation of liver disease and was followed by the presence of antibodies against HBeAg (anti-HBe) in serum in 50% of the cases. In 61 of 64 (95.3%) anti-HBe-positive patients. HBeAg-minus HBV was the predominant virus: HBeAg-minus HBV was detected in 42 patients (65.6%). whereas both wild-type and HBeAg-minus HBV were present in 19 (29.7%). HBeAg-minus HBV was associated with a course of hepatitis characterized by flare-ups of liver cell necrosis interspersed with periods of asymptomatic HBV carriage (P less than 0.01). These data support the hypothesis that genetic heterogeneity of HBV significantly influences the course and outcome of chronic hepatitis B. Wild-type HBV secreting HBeAg induces immunologic tolerance and causes chronic infection. HBeAg-minus HBV might be unable to induce chronic infection without the helper function of wild-type HBV. but it appears to be more pathogenic. Once chronic infection is established. HBeAg-minus HBV variants may prevail and displace wild-type virus.
Low temperature and peptides favor the formation of class I heterodimers on RMA-S cells at the cell surface, RMA-S murine cells have a mutation that interferes with the assembly of class I major histocompatibility complex (MHC) heterodimers and are deficient in the expression of class I molecules on the cell surface. The mutant phenotype has been reported to be normalized upon incubation of RMA-S cells at 25 degrees C. We find that much of the increased expression of class I heterodimers is dependent on culturing RMA-S cells in bovine serum or with purified bovine beta 2-microglobulin. Furthermore. epitopes that are associated with class I MHC molecules that have bound xenogeneic beta 2-microglobulin are preferentially formed on RMA-S cells cultured at 25 degrees C. These heterologous class I molecules are thermolabile. Increased expression of class I molecules has also been observed on RMA-S cells incubated at 37 degrees C in the presence of class I-restricted peptides. We find that the increased expression of Db molecules induced by influenza virus nucleoprotein residues 365-380 is similarly dependent on culturing RMA-S cells in bovine serum or with purified bovine beta 2-microglobulin.
Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1, Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that mediates endothelial leukocyte interactions by inducing expression of adhesion molecules. In this report. we demonstrate that human dermal mast cells contain sizeable stores of immunoreactive and biologically active TNF-alpha within granules. which can be released rapidly into the extracellular space upon degranulation. Among normal human dermal cells. mast cells are the predominant cell type that expresses both TNF-alpha protein and TNF-alpha mRNA. Moreover. induction of endothelial leukocyte adhesion molecule 1 expression is a direct consequence of release of mast cell-derived TNF-alpha. These findings establish a role for human mast cells as "gatekeepers" of the dermal microvasculature and indicate that mast cell products other than vasoactive amines influence endothelium in a proinflammatory fashion.
Characterization of genetic variation and 3'-azido-3'-deoxythymidine- resistance mutations of human immunodeficiency virus by the RNase A mismatch cleavage method, The RNase A mismatch cleavage method has been applied to the characterization of natural genetic variation of human immunodeficiency virus (HIV) from different geographical areas. The approach provides a rapid and simple assay for the analysis of differences in closely related viral isolates and allows the establishment of phylogenetic relationships between epidemiologically distinct viruses. Our results show a broad clustering of circulating viruses according to their geographical distribution. We also have analyzed the temporal appearance of mutations associated with the acquisition of resistance to 3'-azido-3'-deoxythymidine (AZT). The results show that mutations in codon 215 of the viral reverse transcriptase can be detected readily by this method in HIV isolates and also directly in peripheral blood from HIV-infected individuals after in vitro amplification of viral sequences with the polymerase chain reaction. The specific recurrence of identical double-nucleotide substitutions in epidemiologically and geographically distant viruses suggests that the restricted amino acid substitutions at this position selected by drug exposure are a critical. rate-limiting step in the acquisition of drug resistance.
Correction of a human beta S-globin gene by gene targeting, As a step toward using gene targeting for gene therapy. we have corrected a human beta S-globin gene to the normal beta A allele by homologous recombination in the mouse-human hybrid cell line BSM. BSM is derived from a mouse erythroleukemia cell line and carries a single human chromosome 11 with the beta S-globin allele. A beta A-globin targeting construct containing a unique oligomer and a neomycin-resistance gene was electroporated into the BSM cells. which were then placed under G418 selection. Then 126 resulting pools containing a total of approximately 29.000 G418-resistant clones were screened by PCR for the presence of a targeted recombinant: 3 positive pools were identified. A targeted clone was isolated by replating one of the positive pools into smaller pools and rescreening by PCR. followed by dilution cloning. Southern blot analysis demonstrated that the isolated clone had been targeted as planned. The correction of the beta S allele to beta A was confirmed both by allele-specific PCR and by allele-specific antibodies. Expression studies comparing the uninduced and induced RNA levels in unmodified BSM cells and in the targeted clone showed no significant alteration in the ability of the targeted clone to undergo induction. despite the potentially disrupting presence of a transcriptionally active neomycin gene 5' to the human beta A-globin gene. Thus gene targeting can correct a beta S allele to beta A. and the use of a selectable helper gene need not significantly interfere with the induction of the corrected gene.
Inhibition of Moloney murine leukemia virus-induced leukemia in transgenic mice expressing antisense RNA complementary to the retroviral packaging sequences, Recombinant plasmids pLP psi as and pCP psi as were constructed by positioning the Moloney murine leukemia virus (M-MuLV) proviral packaging (psi) sequences in reverse orientation under the transcriptional regulation of lymphotropic promoter/regulatory elements from the M-MuLV long terminal repeat or the cytomegalovirus immediate-early region. Linear fragments containing the antisense psi and the appropriate transcriptional regulatory sequences from these plasmids were introduced into the mouse germ line by zygote microinjection. The chromosomal integration. germ-line transmission. and lymphocyte-directed expression of the antisense psi RNA were confirmed. Control (nontransgenic) and transgenic mice containing either the pLP psi as or the pCP psi as sequences were infected with M-MuLV on the day of birth and assayed for signs of leukemia between 12 and 14 weeks of age with standard assay procedures. While 31% (11 of 36) of the control. nontransgenic. mice developed leukemia. none of the antisense psi transgenic mice developed any symptoms of leukemia. The pCP psi as sequences were also introduced into mouse NIH 3T3 cells and stably transformed cell lines were isolated. When infected with M-MuLV these cells were shown to produce virus devoid of packaged viral RNA.
Murine adenovirus infection of SCID mice induces hepatic lesions that resemble human Reye syndrome, Murine adenovirus type 1 (MAV-1) infection of CB-17 SCID mice (which are homozygous for the severe combined immunodeficiency mutation) induces hepatic histopathologic and ultrastructural features that are strikingly similar to human Reye syndrome. Gross pathologic examination of MAV-1-infected mice revealed only pale yellow liver tissue. Histopathologic studies of tissue from MAV-1-infected mice revealed diffuse hepatic injury manifested by microvesicular fatty degenerative changes of hepatocytes and electron microscopic evidence of focal mitochondrial swelling with disruption of cristae and depletion of glycogen. Serum aminotransferase activities increased markedly in the infected animals; however. plasma ammonia levels were not elevated at the times assayed. Although all mice infected with MAV-1 died. neutralizing anti-MAV-1 monoclonal antibodies provided a dose-dependent delay in the appearance of clinical disease and hepatic histopathologic findings. Other findings included rare viral inclusions with only minimal inflammation in spleen. adrenal. and liver of infected mice. Our findings indicate that MAV-1 infection of SCID mice may provide important insights into the pathogenesis of the hepatic lesions of Reye syndrome.
Mitogenic effects of coagulation factor XII and factor XIIa on HepG2 cells, The structure of coagulation factor XII (Hageman factor). inferred from its DNA sequence. includes two epidermal growth factor (EGF)-homologous domains in its amino-terminal region. This suggests that factor XII may exhibit EGF-like activities. Reciprocal antigenic cross-reactivity between factor XII and EGF was shown by exposing purified human factor XII or mouse EGF to anti-mouse EGF or anti-human factor XII. Western blot analysis showed that anti-mouse EGF recognized intact factor XII at 80 kDa. Together. these results suggest that the EGF-homologous domains are accessible for anti-EGF binding in native factor XII. To determine whether factor XII has mitogenic activity. HepG2 or L cells (10(4) cells per well) were grown in serum-free medium in the presence or absence of factor XII or kaolin-activated factor XII (factor XIIa). Both factors XII and XIIa (6.0 micrograms/ml) enhanced cell proliferation by approximately 2-fold (P less than 0.001 and P less than 0.005. respectively). In contrast. L cells. which are not EGF target cells. were not affected by either factor XII or factor XIIa. Various doses of factor XII enhanced cell proliferation. [3H]thymidine incorporation. and [3H]leucine incorporation in HepG2 cells cultured under the same conditions. These data indicate that factor XII. like EGF. is a mitogen for HepG2 cells and suggest a possible autocrine role in the liver.
Decreased adherence of interleukin 6-treated breast carcinoma cells can lead to separation from neighbors after mitosis, Interleukin 6 (IL-6) has been shown to inhibit the proliferation. but increase the motility. of wild-type ZR-75-1 human ductal breast carcinoma cells. a line of cells that resemble closely the malignant cells cultured from the ascitic effusion. IL-6-treated cells lose their epithelial character. become stellate or fusiform in shape. and migrate away from neighbors. In the wild-type ZR-75-1 cells. IL-6 causes cell-cell separation in preformed colonies as well as postmitotically. We have now investigated the action of IL-6 in clone B ZR-75-1 cells. which are morphologically distinct from wild-type ZR-75-1 cells. In the more polygonal rather than cuboidal clone B cells. IL-6 did not cause early inhibition of DNA synthesis and it caused little cell-cell separation in preformed colonies. However. IL-6 treatment markedly prolonged the interval between mitosis and readherence of daughter cells to their neighbors and the substratum. Supernatants from IL-6-treated cultures contained detached viable cells in increased numbers. Intermitotic intervals were prolonged in IL-6-treated cultures. IL-6-treated dividing breast carcinoma cells are characterized by an increased probability of separation from neighbors and the substratum.
Marfan syndrome is closely linked to a marker on chromosome 15q1.5----q2.1, Marfan syndrome is a systemic disorder of the connective tissue inherited as an autosomal dominant trait. The disorder imparts significant morbidity and mortality. The etiology of the disorder remains elusive. A recent study localized the gene for Marfan syndrome on chromosome 15. We present data showing that marker D15S48 is genetically linked to Marfan syndrome. Pairwise linkage analysis gave a maximum lod (logarithm of odds) score of Z = 11.78 at theta = 0.02. Furthermore our data suggest that the Marfan syndrome locus is possibly flanked on either side by D15S48 and D15S49.
Interrater reliability of videotaped observational gait-analysis assessments, The purpose of this study was to determine the interrater reliability of videotaped observational gait-analysis (VOGA) assessments. Fifty-four licensed physical therapists with varying amounts of clinical experience served as raters. Three patients with rheumatoid arthritis who demonstrated an abnormal gait pattern served as subjects for the videotape. The raters analyzed each patient's most severely involved knee during the four subphases of stance for the kinematic variables of knee flexion and genu valgum. Raters were asked to determine whether these variables were inadequate. normal. or excessive. The temporospatial variables analyzed throughout the entire gait cycle were cadence. step length. stride length. stance time. and step width. Generalized kappa coefficients ranged from .11 to .52. Intraclass correlation coefficients (2.1) and (3.1) were slightly higher. Our results indicate that physical therapists' VOGA assessments are only slightly to moderately reliable and that improved interrater reliability of the assessments of physical therapists utilizing this technique is needed. Our data suggest that there is a need for greater standardization of gait-analysis training.
A rotational method of bilateral cleft lip nose repair, Repairs of the bilateral cleft lip nasal deformity have focused on lengthening the lower columella by adding lip. nasal structure. or a piece of ear. In these methods. the raised true columella worsens the dorsal dislocation of the lateral crura of the alar cartilages and the lateral and dorsal displacement of the alar domes. We believe that lengthening the upper columella from above is more anatomic and reasonable than lengthening the lower columella. A method for reconstructing the upper columella by medial and ventral rotation of the dislocated alar domes is described. Figi's "flying bird" incision was extended to the columellar base along the nostril margin. Through this incision. the lower one-third of the nose. including the alae and nostril floors. was undermined widely. The inner layers. the nostrils. were freed from the surrounding tissues. except in the region of the columella and the septum. and rotated medially in the opposite direction of Cronin's technique. The resulting nasal shape. involving the columellar length and the concavity between the nasal tip and lateral ala. improved in 11 patients.
Modified skin incisions for mastectomy: the need for plastic surgical input in preoperative planning, Skin-sparing mastectomy by definition describes the procedure of mastectomy. either simple or modified radical. with a minimum amount of skin excision. The surgical skin excision must: (1) include the nipple-areola complex. (2) include the biopsy site. and (3) allow for access to the axilla for possible dissection. In 27 mastectomies. the senior author has had direct input in the preoperative skin planning. All patients underwent immediate breast reconstruction. In large-breasted women. the mastectomy was performed to a Wise-type pattern. In small-breasted women. the mastectomy involved minimal skin excision followed by reconstruction. Non-continuous incisions were frequently used in small-breasted women. thereby minimizing breast scarring. When appropriately applied. skin-sparing mastectomy can greatly improve the final aesthetic result of the breast.
Interrelationship of capsule thickness and breast hardness confirmed by a new measurement method, All implants initiate a foreign-body response that leads to their encapsulation by scar tissue. In order to better understand this encapsulation process and the differences between soft (comfortable) and firm (contracted) breasts. we studied 22 patients who had come in for reaugmentation during a 2-year period. The capsules removed were prepared and measured using a new method. The capsules were (1) removed and stored in physiologic solution until the time of measurement (30 minutes to 2 hours) and (2) measured using a Mitutoyo dial-thickness gauge (MDTG) that employs a uniform pressure of 85 gm. The measurements revealed that soft breasts (Baker 1) have the thinnest scar-tissue capsules. which ranged in thickness from 0.002 to 0.010 inches. Firm breasts yielded the thickest capsules. Baker 3 measured between 0.010 and 0.078 inches thick. and Baker 4 measured between 0.018 and 0.162 inches thick. We also compared the precision of measurement between the MDTG and a standard (screw-type) micrometer by taking a series of readings on a soft. pliable substance (textured silicone rubber).
Free-tissue transfer in elderly patients, A retrospective survey was undertaken to evaluate the success of free-tissue transfer (free flap) in the elderly. During a 70-month period. 199 free flaps were performed in 151 patients at the Western Pennsylvania Hospital. 60 of these involving 47 patients over the age of 60. Primary coverage rates differed significantly between the elderly and younger age groups (68.5 versus 85.3 percent. respectively); however. eventual coverage rates (92.6 versus 96.3 percent). minor complication rates (34.0 versus 34.6 percent). mortality rates (2.1 versus 1.0 percent). flap revision rates (32 percent of patients versus 30 percent). and length of postoperative hospitalization (18.7 versus 18.8 days) were not significantly different in the two groups. Among the elderly. significant increases in flap loss rates were noted with the use of end-to-side arterial anastomosis. placement of the anastomosis within a zone of injury. and the use of the gracilis muscle donor site. Our data suggest that the primary cause of free-flap failure is construction of the anastomosis within a zone of injury. Free-tissue transfer is a valuable option in the repair of tissue defects in the elderly and should not be denied as a treatment because of patient age.
Human antibody response following multiple injections of bovine collagen, The enzyme-linked immunosorbent assay (ELISA) was selected to further characterize the human antibody response to Zyderm (ZCI). Our studies have involved both patients and volunteers. Five patients with delayed cutaneous hypersensitivity reactions to Zyderm were positive for anti-Zyderm antibody. Six of nine patients treated with Zyderm who never displayed cutaneous reactions did develop significant levels of anti-Zyderm serum antibody. Some of these patients progressively increased their antibody levels. None of the volunteers who received multiple skin-test doses (0.1 cc) of Zyderm developed significant levels of anti-Zyderm antibody. Polyvalent anti-Zyderm antibody titers among patients with positive ELISA absorbance ranged from 1:16 to greater than 1:128. All were positive for antibodies of the IgG subtype; half were positive for the IgA subtype. None was positive for IgM or IgE subtype. We did not observe cross-reactivity between patient anti-bovine collagen sera and commercially prepared antibodies to human anti-collagen types I. II. and III. Given the frequency of current Zyderm use. it seems evident that for most patients. biologic exposure to collagen does not pose a health hazard. Nevertheless. because of the scarcity of data pertaining to the long-term significance of humoral anti-Zyderm antibodies. physicians and patients should be aware that unanswered questions remain whenever clinical use of injectable collagen is recommended.
Avulsion injuries of the thumb, Avulsion amputations of the thumb are generally thought to have a worse prognosis after replantation than other amputations. We report the results of 17 thumbs that had an avulsion amputation and were replanted. Fourteen of the 17 survived (82 percent). Our experience indicated that the survival rate was improved by restoring continuity of at least two veins and two arteries. using a Y-shaped vein graft and the princeps pollicis artery for the source of arterial circulation. Nerve grafts were used to bridge defects in avulsed digital nerves. When possible. avulsed tendons were reattached to their muscle. Key pinch strength was 60 percent of normal. and grip strength was always less than that of the normal hand. The age of the patients and the cold ischemia time had no significant effect on either survival or function of the replanted thumb. When excellent venous backflow occurred immediately after the vessel repair and continued for at least 20 minutes. the thumb always survived without complications.
Successful replantation of an amputated nasal tip by microvascular anastomosis, Successful microsurgical replantation of a completely avulsed nasal tip is presented. The result is excellent. The technical challenge involved no sizable veins for drainage. This problem was solved by an artery-to-vein shunting. For facial avulsions. there is nothing superior to the original tissue. and replantation should always be attempted first.
LAV revisited: origins of the early HIV-1 isolates from Institut Pasteur, Two of the first human immunodeficiency virus type-1 (HIV-1) strains isolated were authenticated by reanalyzing original cultured samples stored at the Collection Nationale de Culture des Microorganismes as well as uncultured primary material. Cloned polymerase chain reaction products were used to analyze coding sequences of the V3 loop in the gp120 glycoprotein. The original isolate HIV-1 Bru. formerly called LAV. was derived from patient BRU. HIV-1 Lai was derived from patient LAI and contaminated a HIV-1 Bru culture between 20 July and 3 August 1983. The culture became. in effect. HIV-1 Lai. identifiable by a unique motif in the V3 loop. Because of this contamination two. rather than one. HIV-1 isolates were sent to the Laboratory of Tumor Cell Biology at the National Cancer Institute on 23 September 1983. Original HIV-1 Bru was indeed present in the sample marked JBB/LAV. However the M2T-/B sample harbored HIV-1 Lai. a strain capable of growing on established cell lines. The striking similarity between HIV-1 Lai (formerly LAV-Bru) and HTLV-3B sequences remains.
Stasis ulcers: the role of compliance in healing, The goal in treating a stasis ulcer is rapid and permanent reepithelialization of the ulcer bed. The patient can reach this goal by strict compliance with a program taught and continually reinforced by the physician. The program teaches about the effects of the force of gravity on the flow of blood and lymph in the lower extremities in various positions. The program consists of three rules for the patient to follow: (1) Never sit with legs below heart level. (2) Never stand still. Walk in place or even while sitting (if sitting is necessary). (3) Always wear compressive stockings or pneumatic leggings when walking. I present four case histories demonstrating the different rates of healing of stasis ulcers during noncompliance and during compliance with the physiologic methods of controlling edema and venous stasis in the legs.
Inoperable endobronchial obstructing lung carcinoma treated with combined endobronchial and external beam irradiation, Thirty patients with symptomatic inoperable endobronchial obstructing lung cancer received combined external beam radiotherapy and temporary endobronchial iridium Ir 192 implants. External beam irradiation doses ranged from 5700 to 6600 cGy. Patients were given two to four temporary iridium Ir 192 implants for endobronchial radiotherapy. Individual implant doses ranged from 500 to 1500 cGy. Total implant doses ranged from 1125 to 3000 cGy. Total treatment doses ranged from 7080 cGy to 10.000 cGy. Seventy-seven percent of patients had a complete local endobronchial response to treatment. and 13% had a partial response. Ninety percent of patients experienced an improvement in their performance status using an Eastern Cooperative Oncology Group (ECOG) scale. Survival from the end of treatment was 39% at 1 year and 21% at 2 years. with the median survival at 10 months. The data from this study indicate that this form of treatment of inoperable endobronchial obstructing lung cancer is feasible and leads to a high percentage of local tumor response. improvement in patient performance status. and possibly improved survival.
Adenocarcinoma of the pancreas: current management of resectable and locally advanced disease, Surgical resection alone for patients with adenocarcinoma of the pancreas has rarely resulted in cure. and long-term survival is uncommon. The magnitude of the operation has historically prevented many patients from receiving multimodality therapy with systemic chemotherapy or radiation (external beam and intraoperative). Improved rates of operative morbidity and mortality. technical advances in intraoperative radiotherapy. and encouraging results from studies combining radiation and chemotherapy have renewed interest in innovative treatments for this disease. We review the rationale for the current management of patients with resectable and locally advanced adenocarcinoma of the pancreas and the current trial at The University of Texas M.D. Anderson Cancer Center.
Colorectal cancer: current trends in initial clinical manifestations, Colorectal carcinoma (CRC) is a common cause of cancer morbidity and mortality in the United States. There continues to be controversy regarding the effectiveness and feasibility of various screening programs for CRC. To determine how cases of CRC are currently detected. we reviewed a series of 246 consecutive patients with well-documented pathologic staging and clinical presentation. Patients with low stage CRC (0 or A) had smaller tumors. were less likely to be anemic at presentation. and were more likely to have tumors located in the left side of the colon than patients with tumors at stage B or higher. Thirty-two of the 246 tumors were detected in asymptomatic patients through screening. These tumors were more likely to be of a lower stage than those in patients with active gastrointestinal symptoms. In our experience active screening programs detect a relatively small number of CRCs. A majority (66%) of CRCs are still detected from symptoms referable to the gastrointestinal tract.
Biopsy of the prostate guided by transrectal ultrasonography: early experience in a teaching community hospital, Transrectal ultrasonography (TRUS) was used to guide 277 biopsies of the prostate in 182 patients. The Bard Biopty system was used. Of these 182 patients. 107 (59%) had benign changes. and 75 (41%) had malignant lesions. Of those with cancer. 40% (30/75) had negative results of digital rectal examination (DRE). The cancer detection rate by TRUS was 40.7%. and by DRE alone it was 24.2%. Use of TRUS before transurethral resection of the prostate (TURP) in 47 patients with negative findings on DRE yielded 22 cancerous lesions (47%). We advocate this method in patients with abnormalities detected on DRE or with elevated levels of prostate-specific antigen or prostatic acid phosphatase. and as preoperative screening in patients having TURP because of the potential impact of a preoperative diagnosis of cancer upon the choice of treatment.
Management of the asymptomatic patient with a stab wound to the chest, We prospectively studied 126 asymptomatic patients who had a total of 144 stab wounds (average size. 2 cm) to the chest to determine their need for hospitalization. Their average age was 32 years; 102 of them were men. Four left against medical advice. The remaining 122 patients were judged to be asymptomatic when inspiratory and expiratory chest roentgenograms. recorded serially over a 24-hour period. revealed no intrathoracic trauma. Subcutaneous air was found in five of the patients. and an aorto-right ventricular fistula was found in one patient during his follow-up visit to the clinic a week later. The fistula was repaired uneventfully. No late-developing complications were detected in a review of the charts a year later. We believe a patient with a stab wound to the chest but with no evidence of intrathoracic injury may be appropriately managed with limited observation. including serial inspiratory and expiratory roentgenograms of the chest.
Clinical utility of transesophageal echocardiography, Routine transthoracic echocardiography fails to generate images of diagnostic quality in a significant number of patients who are obese. uncooperative. or unable to be properly positioned (eg. patients receiving ventilatory assistance). and in those with severe chronic obstructive pulmonary disease. chest wall deformities. or recent thoracic surgical procedures. In addition. posterior structures in the heart such as the left atrium. left atrial appendage. atrial septum. and mitral valve are seen with poorer resolution than structures closer to the anterior chest wall. Placement of a sonographic transducer in the esophagus immediately behind the heart circumvents these limitations. Newly developed probes are well tolerated by sedated conscious patients as well as by patients receiving ventilatory assistance in the intensive care unit and those under general anesthesia. Consequently. transesophageal echocardiography is now available for further enhancement of cardiac diagnosis in outpatients. for evaluating the hemodynamic status of critically ill patients in the intensive care unit. for intraoperative assessment of cardiac repairs. and for intraoperative cardiac monitoring in noncardiac surgical procedures. A series of case examples from our practice during a recent 1-year period illustrates the clinical utility of this technique in these settings.
Iodine 131 metaiodobenzylguanidine scintigraphy of medullary carcinoma of the thyroid [published erratum appears in South Med J 1991 Jul;84(7):816, 937, We have presented a case of sporadic medullary carcinoma of the thyroid with documentation of localization of tracer 131I-MIBG within the primary neoplasm. A review of the nuclear medicine literature of localization techniques for MCT demonstrates that 131I-MIBG. while an excellent choice for diagnosis of pheochromocytoma and neuroblastoma. produces low yield and unpredictable concentration in other neural crest apudomas. including MCT. A low incidence of true-positive results with 131I-MIBG uptake and a high incidence of false-negative results make this radiopharmaceutical a suboptimal choice for diagnostic studies. but a potentially promising one as a therapeutic agent.
Prominent subarachnoid spaces in a patient with complex congenital heart disease, The presence of prominent subarachnoid spaces and ventriculomegaly on cranial computerized tomographic scans has been described in multiple generalized systemic illnesses in the pediatric population. We have described an infant with severe congenital heart disease who had. on a cranial CT scan for evaluation of developmental defects. demonstrated this appearance.
Plain film of intracardiac foreign bodies: the blurring effect, We report two cases of gunshot wounds of the chest. in each of which a bullet was retained in the pericardial sac. Because the bullets appear to be out of focus. one may think they are in the cardiac chambers. but the images of bullets retained in the pericardial sac may also be blurred due to the spinning effect of the heartbeat on the bullet.
Reconstruction of the sternum and anterior chest wall using autologous tissues, We have described the successful reconstruction of a completely resected anterior chest wall using autologous tissues. This case demonstrates feasibility despite known potential contamination and serious postoperative physiologic dysfunction.
Gastric villous adenoma: radiologic features, The high incidence of malignant transformation of gastric villous adenoma requires prompt diagnosis of this rare tumor. We have reported the case of such a tumor in a 29-year-old man. The radiologic appearance of a gastric soft tissue mass with a reticular pattern is highly diagnostic.
Acute intermittent porphyria with atypical neuropathy, The patient we have described had lower extremity numbness. paresthesias. constipation. urinary retention. and sexual dysfunction. Laboratory evaluation confirmed a diagnosis of acute intermittent porphyria (AIP). Vitamin B6 and glucose therapy initiated resolution of symptoms. The sensory neuropathy described here is unusual. and we believe sexual dysfunction is a previously unreported manifestation of AIP.
Multi-infarct dementia, subcortical dementia, and hydrocephalus, The diagnostic evaluation of dementia is directed toward the identification of treatable causes. It can be facilitated by classification of the dementia into one of four categories: attentional. amnestic. cognitive. and intentional. Intentional dementia reflects dysfunction of frontal lobe systems. components of which include the frontal cortex. basal ganglia. thalamus. limbic structures. and subcortical white matter. Disorders that affect one or more of these components and produce intentional dementia include Binswanger's disease. Parkinson's disease. Huntington's disease. HIV infection. closed head injury. normal pressure hydrocephalus. neoplasms. syphilis. vitamin B12 deficiency. multiple sclerosis. and a number of uncommon degenerative and acquired syndromes. Depression may resemble intentional dementia. Guidelines for diagnosis and management are discussed.
Comparison of needle aspiration cytologic diagnosis with excisional biopsy tissue diagnosis of palpable tumors of the breast in a community hospital, Fine needle aspiration cytologic examination has not extensively been used in our hospital in the work-up evaluation of solid tumors of the breast and its reliability as a basis on which to perform definitive treatment of carcinoma of the breast was in question. One hundred and five aspiration cytologic specimens were obtained from palpable solid tumors of the breast just prior to excisional biopsy. Specimens were numbered and submitted to three different staff pathologists for diagnosis in a single blind manner. Results were then compared with tissue diagnosis of the same tumors. Of 105 specimens taken at biopsy of the breast. 28 malignant lesions were diagnosed on the final tissue report. Of those. ten were diagnosed as malignant (Class V). two were highly suspicious (Class IV) and six were insufficient specimens (Class O). Of those diagnosed as class IV and V by the results of cytologic examination. all were malignant on permanent section for a specificity of 100 per cent and a sensitivity of 36 per cent. The cytologic diagnoses of Classes I. II and III did not correlate with any histologic report. benign or malignant. Malignant growths were misdiagnosed by cytologic examination in 36 per cent and missed because of inadequate specimens in 28 per cent. We believe that a Class V cytologic finding is sufficient basis on which to perform definitive treatment of carcinoma of the breast provided rigid criteria are used. There is a learning curve associated with this diagnostic modality.
The accuracy of malignant diagnoses established by fine needle aspiration cytologic procedures of mammary masses, Fine needle aspiration cytologic studies are being used with increasing frequency to diagnose carcinoma of the breast. To determine whether or not a diagnosis of carcinoma established by cytologic examination is sufficiently accurate to proceed to treatment without tissue confirmation. we have examined our results in a series of 109 patients who had 111 aspiration cytologic procedures followed by open biopsy between January 1985 and June 1987. From this group. 39 specimens were read as malignant and 19 were read as suspicious. Thirty-eight of 39 specimens with positive readings were from lesions that proved to be malignant on subsequent open biopsy. Seventeen of 19 suspicious specimens were also from malignant lesions. Three of 17 specimens that were inadequate and nine of 36 negative specimens were from lesions that were later shown to be malignant. Our single false-positive result occurred on cells that had been air dried during preparation in the early months of experience with this technique at our institution. Re-evaluated later in our series. the same specimen was called suspicious rather than malignant. We conclude that a positive reading on fine needle aspiration is highly accurate. The positive predictive value should be 100 per cent. once experience is gained in preparing and interpreting the material. Open biopsy is necessary for inadequate. negative or suspicious specimens to exclude a malignant lesion if the clinical or mammographic findings are consistent with carcinoma.
Surgical and chemotherapeutic treatment of hepatic metastases from carcinoma of the breast, To date. no five year survival rates have been reported for patients with hepatic metastases (HM) from breast origin treated by chemotherapy or hormone therapy. This study was done to evaluate whether or not surgical excision of such metastatic disease associated with chemotherapy has any effect on such a poor prognosis. Between May 1985 and September 1988. 22 patients with a diagnosis of isolated (solitary or multiple) HM have been surgically treated. The therapeutic approach also included systemic preoperative and postoperative chemotherapy. Laparotomy findings for those 22 patients are presented. There were benign hepatic lesions in four patients (four different histologic types) and hepatectomy was done in two patients. Diffuse metastatic disease contraindicated any attempt at hepatic resection in six patients. Hepatectomy was possible in 12 patients. There was no postoperative mortality and minimal morbidity. One-half of the patients with metastases had one or more positive lymph nodes at the hepatic pedicule. Median survival time for 12 patients treated by hepatectomy was 37 +/- 9 months after hepatectomy and 42 +/- 3 months after the discovery of HM. Eleven patients had other metastases after an average period of 11.8 months after hepatectomy. and the liver was the first site of recurrence in eight. One patient underwent a hepatectomy twice. Two patients were free of disease 29 to 46 months postoperatively in spite of poor prognostic features on the excised specimen. Although the median survival time was two times better than with usual treatment. we believe this procedure is of doubtful benefit. In this situation. hepatectomy acts as cytoreductive surgical treatment. with the main limiting factor being the relatively low effectiveness of chemotherapy. This type of therapy can be applied only to a restricted number of patients. and if we decide to proceed with this study. we will have to modify the protocol of chemotherapy radically.
Selective contraindications based on multivariate analysis for operative cholangiography in biliary lithiasis, This study was done to select patients with a low risk of common bile duct (CBD) stones in whom operative cholangiography could be avoided. Operative cholangiography was performed upon 511 patients. Two different groups of patients were identified--patients with CBD stones visualized by CBD exploration (n = 90) and patients with no CBD stones at the time of operative cholangiography (n = 421). Multivariate analysis (stepwise logistic regression) showed that five variables were correlated with the presence of CBD stones--size of CBD equal to or greater than 12 millimeters. gallstones equal to or less than 10 millimeters. advanced age. chronic or acute cholecystitis and past history of biliary colic. Using a scoring system. a group of patients with a low risk (less than 2 percent) of CBD stones could be easily determined. In this group of patients. operative cholangiography may be avoided.
Observations and current operative management of congenital lumbar hernias during infancy, Congenital hernias in the lumbar region are very uncommon. Approximately 10 per cent of all lumbar hernias are congenital and the vast majority are unilateral. We report our experience with seven congenital lumbar hernias in six infants treated during a five year period. All patients presented in the first year of life with abnormal protrusions in the lumbar region. In addition to the lumbar hernia. major associated malformations. including caudal regression anomalies. diaphragmatic hernia. ureteropelvic junction obstruction. cloacal exstrophy and lipomeningocele. were observed in 66 per cent of the infants and were consistent with lumbocostovertebral syndrome. In five patients. unilateral defects were repaired primarily. One patient with bilateral lumbar hernia underwent staged repair. The larger right-sided defect was repaired using a polytetrafluoroethylene prosthesis. At a second operation two months later. the small left-sided hernia was closed primarily. All patients have done well without recurrence with a follow-up period ranging from four to 48 months. Early repair of congenital lumbar hernias in infants after correction of other life-threatening conditions is advocated. Unlike the acquired variety. congenital lumbar hernia may include a more extensive deficiency of the entire lateral abdominal wall extending to the rectus sheath and inguinal ligament and satisfactory closure of the defect without prosthetic material may be difficult or impossible.
Blood contact and exposure in the operating room, We prospectively studied 684 operations from all surgical specialties to describe the frequency and character of blood contact and exposure during the procedures. Blood contact was defined as percutaneous. mucous membrane. nonintact skin or intact skin contact of patient blood with any member of the operative team. Blood exposure was defined as contact in any of the preceding categories excluding intact skin. Over-all. 28 per cent of the patients had one or more blood contact events that involved 293 operating room personnel. Risk of blood contact was significantly greater for cardiothoracic (p less than 0.001). trauma (p less than 0.003) and obstetric cesarean section (p less than 0.021) procedures when compared with all other procedures. Three services (Ophthalmology. Transplant and Oral Surgery) had no contact events. The remaining nine had rates ranging from 17 to 33 per cent. Eight per cent of the procedures (n = 54) resulted in blood exposure to 63 individuals. Percutaneous exposure occurred in 3 per cent of all procedures. Blood contact events increased with increasing operative time. Blood contact most commonly occurred among circulating nurses (n = 79). anesthesia personnel (n = 65). surgeons (n = 59) and first assistants (n = 49). Despite increased concerns over the risk of occupationally acquired viral diseases. blood contact and exposure continue to be frequent events. Surgeons must assume that all patients are potentially infected and should adopt universally applied standards of behavior to minimize contact with blood.
Pericardio-peritoneal window for malignant pericardial effusion, Pericardio-peritoneostomy for malignant and non-hemorrhagic pericardial effusion is effective. This method relieves the patients of their symptoms and enables them to be discharged within 24 hours.
Valve deformity and balloon mechanics in percutaneous transvenous mitral commissurotomy, Percutaneous transvenous mitral commissurotomy (PTMC) using balloon catheters has emerged as an alternative therapeutic modality for patients with mitral stenosis. When used initially in the United States. a single balloon. designed for peripheral arterial angioplasty. was passed across the intraatrial septum for mitral dilatation. The results were less than ideal. with resultant valve areas between 1.0 and 1.5 cm2. Double balloon dilatation was introduced and yielded valve areas between 1.5 and over 2.0 cm2. However. the double balloon technique is substantially more cumbersome. requires passage of two catheters through the atrial septum with an incidence of atrial septal defect. and results in significant hemodynamic sequelae during the procedure. This report describes a novel single balloon for PTMC. In contrast to the more conventionally used peripheral arterial balloons. this device was specifically designed for mitral stenosis. Results in 25 patients (mean age 60 +/- 5 years; range 29 to 87 years) showed an increase in value area from 0.9 +/- 0.2 cm2 to 1.6 +/- 0.5 cm2 (p less than 0.001). In contrast to the results reported with conventional balloon dilatation. there was no difference in the resultant valve area or in the incidence of complications among patients with more severely deformed valves compared with patients with more "ideal" valves for commissurotomy. An in vitro comparison of the pressure-volume characteristics of the conventional versus the Inoue balloon showed the latter to be more compliant. reaching nominal inflated diameter at 2.0 +/- 0.4 atm versus 3.3 +/- 0.5 atm for conventional balloons (p less than 0.005).
Acute effect of percutaneous transluminal mitral commissurotomy on QT interval: possible role of afterload in contraction-excitation feedback, Percutaneous balloon valvuloplasty for pulmonary or aortic stenosis results in QT prolongation. a finding supporting the presence of contraction-excitation feedback in man. Though afterload reduction alters the QT interval. the effect of changes in preload on ventricular repolarization is yet unknown. To test whether diastolic stretch modified ventricular repolarization. the change in the QT interval was determined in 15 patients who underwent percutaneous transluminal mitral commissurotomy (PTMC) for mitral stenosis. After successful PTMC. the QT interval was prolonged in five. shortened in two. and was unchanged in eight patients. but the mean QT interval in 15 patients did not change (406 +/- 31 msec versus 412 +/- 40 msec. p = NS). However. linear regression analysis revealed a strong correlation between changes in the QT interval and those in systemic vascular resistance (r = -0.83. p less than 0.01). These data indicated that changes in the QT interval after PTMC were small compared with those seen with valvuloplasty for pulmonary or aortic stenosis. and were dependent on afterload but not on preload.
Propranolol therapy alters estimation of potential cardiovascular risk derived from submaximal postinfarction exercise testing, We studied the effect of propranolol administration on risk assessment based on submaximal exercise testing performed early after myocardial infarction. A total of 70 patients with recent infarction underwent modified Bruce treadmill testing with simultaneous measurement of expired gases in the absence of antianginal agents including beta-antagonists. Among these. 31 patients who had at least one of the following abnormalities--ST depression greater than or equal to 1 mm (22 patients). chest pain (four patients). or treadmill time less than 360 seconds (12 patients)--were studied in a randomized double-blind fashion and received either placebo or 240 mg of propranolol/day. A total of 28 patients completed the randomized phase and were able to undergo repeat exercise testing an average of 3.4 +/- 1.8 days later. Randomized groups were equivalent at baseline except for a higher peak oxygen consumption and carbon dioxide production (p less than 0.05) in the propranolol compared with the placebo group; these differences were taken into account in statistical analyses of the study data. Resting heart rate (59 +/- 1.2 versus 82 +/- 4.2 beats/min) and peak heart rate x systolic blood pressure (14.208 +/- 496 versus 20.075 +/- 1.062) were both significantly less (p less than 0.01) after propranolol than after placebo. Eight of nine patients treated with placebo maintained ST depression greater than or equal to 1 mm from the initial to the randomized exercise test. compared with only 4 of 13 receiving propranolol (p less than 0.01). In those with continued ST depression. time to positivity was significantly longer in those receiving propranolol compared with those taking placebo (538 +/- 73 versus 318 +/- 44 seconds. p less than 0.05). In contrast. the peak ratio between carbon dioxide production and oxygen consumption was higher in those receiving propranolol compared with those receiving placebo (0.93 +/- 0.04 versus 0.81 +/- 0.03. p less than 0.05). We conclude that propranolol therapy reduces evidence of ischemia and changes traditional estimates of potential cardiac risk derived from submaximal postinfarction exercise testing.
Duration of ST segment depression after exercise-induced myocardial ischemia is influenced by body position during recovery but not by type of exercise, To assess whether the duration of ischemic ST segment depression after exercise can be modified by changes in body position during recovery or with different types of exercise. 18 patients with chronic stable angina. positive exercise test results. and documented coronary artery disease were prospectively studied. Every patient underwent testing with three different exercise protocols: (1) Bruce (Bruce-standing recovery). (2) abrupt onset of exercise (abrupt). and (3) modified Bruce protocol preceded by a 10-minute warm-up period (warm-up). After exercise test patients recovered in a sitting position. In addition. all patients performed a fourth exercise (Bruce protocol). but this time they recovered in the supine position (Bruce-supine recovery). Time and heart rate-blood pressure product at 1 mm ST segment depression were similar for Bruce-standing recovery. abrupt. and Bruce-supine recovery protocols (5.1 +/- 2. 4.4 +/- 2. and 5.2 +/- 2 minutes and 20.8 +/- 4. 21.3 +/- 4. and 20.4 +/- 4 beats/min x mm Hg x 10(-3). respectively. Heart rate and heart rate-blood pressure product at peak exercise did not differ in Bruce-standing recovery. abrupt. and Bruce-supine recovery. Maximal ST segment depression was -2.0. -1.9. and -2.0 mm with Bruce-standing recovery. abrupt. and Bruce-supine recovery exercise. respectively. and -1.5 mm with warm-up exercise (p less than 0.05). Duration of ST segment depression into recovery was significantly prolonged after Bruce-supine recovery exercise (9.4 + 5 minutes) compared with Bruce-standing recovery. abrupt. and warm-up protocols (6.8 + 3. 5.9 + 4. and 5.0 + 3 minutes. respectively; p less than 0.05).
A prospective evaluation of the immediate reproducibility of the signal-averaged ECG, The purpose of this investigation was to prospectively evaluate the immediate reproducibility of the signal-averaged electrocardiogram (SAECG). A total of 114 patients undergoing evaluation for ventricular arrhythmias were enrolled in this protocol. Two consecutive SAECG's (40 Hz bidirectional high-pass filtering with a computer-automated system) were performed 10 minutes apart. Abnormal SAECG parameters were defined as (1) vector QRS duration more than 120 msec. (2) terminal root mean square (RMS) voltage less than 20 microV. and (3) low-amplitude signal (LAS) duration more than 40 msec. An SAECG was defined as abnormal if at least one vector parameter was abnormal. There was close correlation between vector parameters during the two SAECG observations: QRS duration had the highest reproducibility (r2 = 0.97. p less than 0.001) followed by terminal RMS voltage (r2 = 0.92. p less than 0.001). and LAS duration (r2 = 0.90. p less than 0.001). The mean (+/- SD) percentage of change between the two recordings was 2% +/- 2% of the QRS duration. 13% +/- 22% for terminal RMS voltage. and 7% +/- 11% for LAS duration. The reproducibility of an initially normal SAECG was 92% and of an initially abnormal SAECG. 96%. Seventeen patients (15%) had a change in one of the three vector parameters between the two recordings. There were no clinically significant differences between the 17 patients in whom the SAECG was nonreproducible and the 97 patients in whom the SAECG was reproducible. However. reproducibility was significantly higher in patients with an initially normal versus an initially abnormal SAECG (92% vs 76%. p = 0.03).
Relationship between redistribution on exercise thallium-201 scintigraphy and repetitive ventricular premature beats in patients with recent myocardial infarction, The relationship between myocardial ischemia detected by exercise thallium-201 scintigraphy and repetitive ventricular premature beats (VPBs) during ambulatory monitoring was evaluated in 57 patients with recent myocardial infarction. Multivariate analysis was performed to obtain the relatively important factor related to repetitive VPBs with the use of the following variables: age. redistribution. left ventricular ejection fraction. serum potassium and magnesium concentration. QRS score. left ventricular aneurysm. and the number of diseased vessels. Thirty-five patients had redistribution. but only three of them had repetitive VPBs during exercise testing. The average heart rate before 79% of 398 episodes of repetitive VPBs during ambulatory monitoring was in the range of 56 to 70/min. These data indicate that most of repetitive VPBs during ambulatory monitoring were not provoked by exercise-induced acute myocardial ischemia. However. redistribution was found to be an important factor associated with repetitive VPBs. The electrical abnormality relating to a substrate characterized by chronic reversible ischemia may explain the association between redistribution and repetitive VPBs.
Long-term follow-up after sustained monomorphic ventricular tachycardia: Causes, pump failure, and empiric antiarrhythmic therapy that modify survival, We analyzed the actuarial cardiac mortality rate of 295 consecutive patients with sustained monomorphic ventricular tachycardia who were referred to us between 1978 and 1988. Patients were divided into four groups: group I of 156 patients with coronary disease. group II of 55 patients with nonischemic left ventricular disease. group III of 65 patients with right ventricular disease. and group IV of 19 patients without detectable heart disease. Patients were treated empirically according to a prospective schema: (1) class I antiarrhythmic drugs. (2) in case of recurrence of ventricular tachycardia: amiodarone or beta-blockers. (3) in case of recurrence of ventricular tachycardia: drug combinations or surgery. The mean follow-up duration was 61 +/- 40 months after the first occurrence of ventricular tachycardia. and the clinical outcome was known in 67.5% of patients at 5 years. The actuarial mortality rates were considerably higher in groups I and II compared with those in groups III and IV (p less than 0.01). The mortality rate was slightly higher in group I than in group II (p less than 0.05). In groups I and II. actuarial mortality rate were much higher when left ventricular ejection fraction was less than 0.30 (p less than 0.01). Comparisons between treatments showed no difference in actuarial mortality rates in patients with ventricular tachycardia and left ventricular ejection fraction greater than 0.30.
Comparison of the results of electrophysiologic testing after short-term and long-term treatment with amiodarone in patients with ventricular tachycardia, The results of electrophysiologic testing after short-term and long-term treatment with amiodarone were compared in 71 patients with ventricular tachycardia. Electrophysiologic testing was performed in the baseline state after 11 +/- 3 days of treatment with 1.2 to 2.4 gm/day of amiodarone. and after 13 +/- 4 weeks of therapy with a daily amiodarone dose of 400 mg. After short-term therapy. 62% of the patients had an adequate response to amiodarone. In 27 patients who were hemodynamically unstable. ventricular tachycardia was induced and became noninducible or hemodynamically stable after combination therapy with a class I agent. Among 18 patients who did not have inducible ventricular tachycardia after short-term therapy. eight (44%) had inducible. hemodynamically unstable ventricular tachycardia after long-term treatment with amiodarone. On the other hand. six of the 27 patients who had hemodynamically unstable ventricular tachycardia after short-term therapy had an adequate response after long-term treatment with amiodarone. Therefore an adequate electrophysiologic response after short-term therapy does not guarantee a similar response after long-term treatment. and an inadequate response after short-term therapy does not always predict a similar response after long-term therapy.
Ventriculoatrial intervals during narrow complex reentrant tachycardia in children, Ventriculoatrial (VA) intervals during narrow complex tachycardia were measured in a pediatric population. The VA intervals were similar to those in adults but were slightly shorter. In the pediatric subjects values less than 60 msec excluded the participation of an accessory pathway in the tachycardia circuit. Three out of 11 patients with atrioventricular nodal reentrant tachycardia (AVNRT) had VA values greater than or equal to 70 msec. while 5 of 28 patients with orthodromic reciprocating tachycardia (ORT) had values less than or equal to 70 msec. Using a cut-off value of 70 msec as the sole criteria to distinguish between ORT and AVNRT could lead to errors in classification of the underlying mechanism of the tachycardia.
The role of enhanced vagal activity on ischemic ventricular tachycardia: pharmacologic basis of inefficiency, The effects of pharmacologic modulation of vagal activity on ischemic ventricular tachycardia were evaluated in 21 conscious dogs after permanent left anterior descending coronary artery (LAD) occlusion. Studies were done on spontaneous ventricular tachycardia (cycle length 383 +/- 100 msec. n = 21). 24 to 72 hours after LAD occlusion. and on inducible sustained monomorphic ventricular tachycardia (cycle length 251 +/- 30 msec. n = 6). 4 to 7 days after LAD occlusion. Edrophonium (1 mg/kg intravenously). a cholinesterase inhibitor. and methacholine (0.1 to 1 mg intravenously). a muscarinic agonist. had no significant effect on the rate or QRS morphology of either type of tachycardia. despite severe slowing of the sinoatrial rate. Similarly. atropine (up to 60 micrograms/kg intravenously) had no effect on the rate and QRS morphology of either type of tachycardia. In an attempt to enhance myocardial drug delivery to the ischemic and infarcted left ventricle. edrophonium (1 mg/kg) and methacholine (0.1 to 0.2 mg) were injected retrogradely through the great cardiac vein. This did not impart any significant therapeutic advantage over the systemic intravenous route. Sympathetic beta blockade did not affect the therapeutic outcome (n = 5) with either edrophonium or methacholine. It is concluded that direct or indirect enhancement of cardiac vagal activity has no effect on ischemic ventricular tachycardia in this model of subacute myocardial infarction. The lack of efficacy appears to be independent of myocardial drug delivery to ischemic ventricular site(s) and background sympathetic activity. Such a lack of efficacy may be caused by ischemia-mediated degeneration of vagal nerve terminals. by altered responsiveness of muscarinic receptors at infarcted arrhythmogenic myocardial sites. or both.
Study of P wave morphology in lead V1 during supraventricular tachycardia for localizing the reentrant circuit, Paroxysmal supraventricular tachycardia (SVT) is a benign form of tachycardia that generally does not require costly evaluation. The purpose of this study was to describe a new sign permitting delineation of the mechanism of SVT by analysis of the P wave in lead V1 and the left atrial electrogram. which may be registered by the esophageal electrode. Among 146 patients with SVT. 72 had a ventriculoatrial interval greater than 70 msec. The P wave in lead V1 during SVT was discernible in 69 of them. The precession of the left atrial electrogram on the P wave in lead V1 was always associated with reentry through a left lateral (n = 37) or posteroseptal (n = 4) accessory atrioventricular (AV) connection. When the P wave in lead V1 preceded or occurred simultaneously with the left atrial electrogram. reentry was through either the AV node or a right-sided accessory AV connection. On the other hand. although the P wave in lead V1 was more frequently negative in reentry through a right-sided connection and positive in reentry through a left-sided connection. the polarity was not specific enough to identify the reentry. The precession of the left atrial electrogram recorded by the esophageal electrode on the P wave in lead V1 during SVT was a specific criterion of reentry through a left accessory AV connection. and this technique could be useful for preliminary localization of the accessory connection before electrophysiologic study.
Noninvasive determination of left ventricular output and wall stress in volume overload and in myocardial disease by cine magnetic resonance imaging, The current study used cine magnetic resonance imaging to determine the effect of increasing severity of valvular regurgitation on systolic wall stress and to demonstrate that wall stress was disproportionately increased in relation to the severity of regurgitation in patients with myocardial disease. A total of 39 patients with predominantly mitral (n = 22) or aortic (n = 17) regurgitation with (n = 13) and without (n = 26) myocardial disease and 10 normal volunteers were examined with cine magnetic resonance imaging (MRI) at 1.5 T. Left ventricular (LV) cardiac output (CO) and peak systolic (PS) wall stress (WS) and end-systolic (ES) WS were calculated from blood pressure recordings. carotid pulse tracings. and wall thickness (h) and diameter (D) measurements obtained from cine MRI. Patients were classified into three degrees of severity according to their LV regurgitant volume (RV). Myocardial disease was defined by an ejection fraction (EF) of less than 40%. Mean LV EF was 61 +/- 3% in normal volunteers. 64 +/- 3% in patients with regurgitation. and 25 +/- 2% in patients with myocardial disease. LV CO was directly related to RV in patients without myocardial disease. whereas it was disproportionately low in relation to RV in patients with myocardial disease. PS WS was significantly higher in severe mitral and/or aortic regurgitation compared with moderate. mild. and no mitral and/or aortic regurgitation. Compared with the degree of regurgitation. PS WS was disproportionately higher in patients with myocardial disease. Thus LV CO and WS rise progressively with increasing severity of regurgitation. Disproportionately high systolic WS relative to RV indicates the presence of myocardial disease.
Left ventricular mechanics in preeclampsia, Increased systemic vascular resistance and contracted blood volume are characteristic findings in preeclampsia. These alterations in cardiovascular hemodynamics can adversely affect ejection phase indices of left ventricular performance making it difficult to separate abnormalities resulting from changes in load from those caused by depressed myocardial contractility. To address this issue the contractility-sensitive. load-independent relationship between left ventricular end-systolic wall stress and rate-corrected velocity of fiber shortening was assessed in 10 nulliparous patients with preeclampsia. Comparisons were made with data obtained from 10 age-matched normotensive women with uncomplicated pregnancies (control subjects). Studies were performed by means of two-dimensionally targeted M-mode echocardiography and calibrated carotid pulse tracings during early labor. 1 day after delivery. and 4 weeks after delivery. During early labor and 1 day after delivery. patients with preeclampsia had elevated blood pressure and increased total systemic resistance. These parameters returned to normal by 4 weeks after delivery. Before delivery and 24 hours after delivery. the patients with preeclampsia had lower overall left ventricular performance (as measured by cardiac output and rate-corrected velocity of fiber shortening) and higher left ventricular afterload (as measured by left ventricular end-systolic wall stress) when compared with control subjects. These differences were no longer present 4 weeks after delivery. Despite the time-related intergroup differences in hemodynamics. left ventricular contractility was similar between normotensive and preeclamptic subjects at all stages of the study. Thus when load is eliminated as a confounding variable. the decrements in overall left ventricular performance measured in patients with preeclampsia reflect a mechanically appropriate response to increased afterload rather than an abnormality in the ventricular contractile state.
Left atrial ball thrombus: review of clinical and echocardiographic manifestations with suggestions for management, Left atrial ball thrombus is an infrequent clinical syndrome. which can have a catastrophic outcome but can be readily treated when recognized. It is usually a complication of long-standing rheumatic mitral stenosis. Symptomatic presentation is variable: fragmentation of the thrombus followed by peripheral embolization will produce ischemia or infarction of myocardium. brain. viscera. or extremities; random. intermittent. partial. or total occlusion of the mitral valve orifice may cause syncope. pulmonary congestion. and occasionally sudden death in other patients. Embolic and obstructive phenomena may also occur together. Cardiac physical findings usually suggest mitral stenosis; variability in the intensity of the diastolic rumble is common. Two-dimensional echocardiography is the gold standard for identifying ball thrombus. Cardiac catheterization provides assessment of coronary artery status when needed. The outcome of untreated ball thrombus is unlikely to be favorable. The results of anticoagulation and thrombolysis are unpredictable and potentially as harmful as no treatment at all. Current evidence although scant suggests that prompt surgical removal of the free thrombus. often in conjunction with mitral valve repair or replacement. is the appropriate therapeutic course in most patients.
Transcatheter closure of patent ductus arteriosus with buttoned device: first successful clinical application in a child, Several devices are available for transcatheter closure of PDA. Most of the available devices either require complicated intracardiac maneuvering or need a large-sized sheath for implantation of the device. A recently described "buttoned" device developed by Sideris et al. that can be delivered across the ductus via a 7F sheath had undergone successful trials in animal models. Because of the ease of device implantation and the requirement for a smaller-sized sheath for delivery than that used with other devices. we have used this custom-made double-disc device in a 5-year-old child and have shown successful closure of the ductus by angiography and by color Doppler studies. Further clinical trials with this device seem warranted.
Acute positive inotropic intervention: the phosphodiesterase inhibitors, Phosphodiesterase inhibitors that are selective for cAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure. which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved. only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular cAMP and ionic calcium. In addition. a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither beta-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides. complementary and synergistic to the actions of catecholamines. and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction. open heart surgery. or infectious or toxic myocarditis). heart failure resulting from right ventricular systolic dysfunction. and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance.
Modulation of venous tone in heart failure, Venodilatation may be an important property in drugs used to treat heart failure. Deductions about venous tone from standard hemodynamic studies may be misleading since filling pressures may be reduced by improved left ventricular function. To study the venodilator properties of drugs. we have modified a radionuclide blood pool method and shown that venous volume is increased by 10% after glyceryl trinitrate but is unchanged after the arteriolar dilator hydralazine. In patients with congestive cardiac failure. the calcium channel blocker. felodipine. causes a marked reduction in systemic vascular resistance and left ventricular filling pressures. but venous volume remains unchanged. In a similar group of patients comparable arterial and central effects are seen after the administration of captopril. but venous volume increases by 16%. and this increased venous volume is sustained after 3 months of long-term treatment. Milrinone has been used to treat both acute and chronic heart failure. As expected of a phosphodiesterase inhibitor. it exhibits inotropic properties in animals and humans and also causes arterial vasodilatation. We have studied its effects on venous tone in 10 patients with severe heart failure (New York Heart Association classes III to IV). Milrinone was given intravenously at a loading dose of 50 micrograms/kg followed by an infusion of 0.5 micrograms/kg/min. After treatment. cardiac index. which was measured by thermodilution. increased from 1.8 +/- 0.48 to 2.3 +/- 0.65 L/min/m2 (p less than 0.001); pulmonary artery wedge pressure fell from 23 +/- 6 to 11 +/- 5 mm Hg (p less than 0.001); and systemic vascular resistance index decreased from 4296 to 3168 dynes.sec.cm-5/m2 (p less than 0.001).
Effects of a twenty-four-hour milrinone infusion in patients with severe heart failure and cardiogenic shock as a function of the hemodynamic initial condition, The systemic and pulmonary arterial hemodynamics of 40 patients with severe congestive heart failure were determined during a 24-hour infusion of milrinone (0.5 micrograms/kg/min) after a loading dose of 50 micrograms/kg. A subgroup (n = 18) with severe cardiac pump dysfunction and three patients in cardiogenic shock were analyzed separately; their hemodynamic response was compared with that of the total group (n = 40). After 15 minutes of intravenous therapy with milrinone. the total group (n = 40) showed an increase of 65% in cardiac index; in the subgroup (n = 18) cardiac index increased by 94% after 15 minutes and by 106% after 30 minutes. Likewise. pulmonary capillary wedge pressure decreased after 30 minutes in both the total group (n = 40) and the subgroup (n = 18). The heart rate showed an overall tendency to decrease. The systolic blood pressure tended upward and remained statistically unchanged in the total group. whereas in the subgroup in which pressure was initially low. there was an increase in the systolic pressure after 1 hour and a further increase after 24 hours. Mean arterial pressure also rose in this subgroup. The early improvement in all measured hemodynamic parameters was sustained throughout the 24-hour infusion period. Development of tolerance was not observed. nor were any clinically symptomatic side effects or symptomatic arrhythmias. Thus intravenous milrinone is a safe medication for the rapid and prolonged improvement in hemodynamics. specifically in patients with severely restricted cardiac pumping function.
Phosphodiesterase III inhibition or adrenoreceptor stimulation: milrinone as an alternative to dobutamine in the treatment of severe heart failure, High levels of endogenous plasma catecholamines in patients with severe congestive heart failure induce a down-regulation of the myocardial beta-adrenoreceptors and thus cause adrenoreceptor agonists. such as dobutamine. to be less effective in the treatment of these patients. Phosphodiesterase III inhibitors work independent of adrenoreceptor activity and plasma catecholamine levels; thus these agents are likely to be more effective in the treatment of severe heart failure. The present study compares both the initial and late hemodynamic effects of dobutamine and milrinone during sequentially administered 24-hour infusions. Twenty patients with severe heart failure (New York Heart Association class III. n = 4; New York Heart Association class IV. n = 16) were investigated. Dobutamine could be administered at the prescribed maximum dose of 15 micrograms/kg/min for 24 hours in only 15 of 20 patients. In three patients the dose was reduced or dobutamine infusion completely stopped because of a drug-related increase in heart rate greater than 140 beats/min. Another 2 of 20 patients showed no hemodynamic improvement over 3 hours at the maximum dose of 15 micrograms/kg/min. Dobutamine administration was also discontinued in these patients on account of the existing unfavorable hemodynamic condition. and therapy with intravenous milrinone was started. All 20 patients responded to milrinone without side effects. although comparison of the hemodynamic effects during a 24-hour infusion was possible in only 15 patients. The 15 patients studied over both observation periods experienced an increase in heart rate from 88.8 to 105.6 beats/min (+ 1 hour; p less than or equal to 0.001) when receiving dobutamine but had no increase with milrinone. Stroke volume increased during dobutamine infusion from 19.3 to 28.9 ml/m2 (+49.6%) after 1 hour and then fell continuously to 25.2 ml/m2 after 12 hours; during milrinone therapy. stroke volume increased from 18.8 to 31.2 ml/m2 (+66%; p less than or equal to 0.001) and remained at this level until the end of the infusion (30.2 ml/m2). Pulmonary capillary wedge pressure (PCWP) decreased (p less than or equal to 0.001) immediately during milrinone therapy from 26.5 to 16.2 mm Hg after 30 minutes and stabilized at 20.1 mm Hg after 24 hours. During dobutamine infusion PCWP showed a delayed decrease from 27.8 to 19.0 mm Hg after 6 hours and subsequently rose to 22.7 mm Hg after 24 hours.(ABSTRACT TRUNCATED AT 400 WORDS).
Myocardial perfusion scintigraphy during maximal coronary artery vasodilation with adenosine, Pharmacologic coronary vasodilation as an adjunct to thallium-201 myocardial perfusion scintigraphy provides an important alternative form of stress that has been increasingly used in patients unable to perform an exercise stress test. Although dipyridamole has traditionally been used for this purpose. there are several compelling reasons why adenosine may be a preferable agent. First. dipyridamole acts by blocking the reuptake and transport of adenosine. which is the effective substance responsible for coronary vasodilation. Second. exogenous adenosine has a very short half-life (less than 2 seconds). which explains its very short duration of action as well as the brief. self-limiting duration of its side effects. Third. the adenosine infusion is controllable and may be increased or decreased as desired. Fourth. the coronary vasodilation induced by the doses of adenosine we recommend (140 micrograms/kg/min) may be more profound than that induced by the standard dipyridamole dose. Our experience to date. with nearly 1.000 patients studied. shows the adenosine thallium-201 test to be practical and well tolerated. with high sensitivity (87%) and specificity (94%) for detecting coronary artery disease.
Exercise thallium-201 perfusion scintigraphy in the assessment of coronary artery disease, Exercise thallium-201 perfusion scintigraphy has been used extensively over the last decade for the detection and localization of coronary artery disease. Single-photon emission computed tomography (SPECT) is a refinement of presently available techniques. offering improved identification over planar imaging of individual vessel stenosis and quantification of the extent of abnormally perfused myocardium. In this review. the planar and SPECT techniques are discussed in light of the most recently published large patient series. and with regard to the many factors that affect the sensitivity and specificity of perfusion imaging in identifying coronary artery disease. The clinical implications of exercise perfusion scintigraphy and its future applications in cardiology practice are discussed.
Myocardial perfusion imaging with technetium-99m-labeled agents, Thallium-201 (201Tl) is suboptimal as a single-photon emitting agent for myocardial perfusion imaging. in view of its low-energy photons and long half-life. To circumvent these limitations. two new myocardial perfusion imaging agents labeled with technetium-99m (99mTc) have been developed. They are Tc-sestamibi and Tc-teboroxime. Clinical trials of myocardial perfusion with both tracers have shown results similar to those obtained with 201Tl for detection of coronary artery disease. Results to date indicate that Tc-sestamibi accurately detects and locates myocardial infarction and can accurately assess both left and right ventricular ejection fractions by the first-pass technique. In addition. research has shown that rest-stress studies can be performed on the same day and that Tc-sestamibi can be used to assess the results of thrombolytic therapy. Tc-teboroxime has excellent myocardial tracer uptake characteristics but is cleared very rapidly from the myocardium. These features make Tc-teboroxime well suited to rapid serial studies. These new technetium myocardial perfusion agents have just become available for routine clinical use and are likely to replace 201Tl in many of its clinical applications.
Assessment of myocardial perfusion by positron emission tomography, Positron emission tomography (PET) represents an advanced imaging technology for the noninvasive evaluation of regional myocardial blood flow. Several blood flow tracers are available. including cyclotron-produced radiopharmaceuticals such as [15O]H2O and [13N]NH3 and generator-produced rubidium-82 ([82Rb]-) and copper-62 ([62Cu]-) pyruvaldehyde-bis-(N-4-methylthiosemicarbazone) (PTSM). 82Rb and [13N]NH3 are the most commonly employed tracers for the qualitative evaluation of regional myocardial perfusion. Their use allows the accurate detection of coronary artery disease in combination with pharmacologic stress. Initial comparative studies with thallium-201 (201Tl) single-photon emission computed tomography (SPECT) have shown that PET has a higher diagnostic accuracy. Beyond improved diagnostic performance. the quantitative flow measurements provided by PET represent an important advance in nuclear cardiology. The radiopharmaceuticals [15O]H2O and [13N]NH3 have been applied for the noninvasive determination of regional coronary reserve. Quantification of blood flow based on tracer kinetic modeling yields blood flow values in close agreement with determinations provided by invasive procedures. The noninvasive quantification of blood flow provides a useful research and clinical tool for the objective assessment of therapeutic interventions as well as pathophysiologic alterations of regional myocardial blood flow in various cardiac diseases.
Assessment of the human coronary circulation using a Doppler catheter, Arteriographic estimates of stenosis severity can fail to reflect the impact of an individual stenosis on delivery of blood to the myocardium. Whether a coronary stenosis is truly flow-limiting can be determined by measuring hyperemic blood flow or coronary flow reserve; however. until recently. the tools needed to measure coronary flow reserve in humans--namely. a method of quantitating coronary blood flow in individual arteries and another method for producing maximal microvascular vasodilation--were not available. Over the last 8 years. our laboratory group has developed a catheter for measuring coronary blood flow velocity in humans. using the Doppler principle. and studied the effects of microvascular vasodilators. These studies have enabled us to measure coronary flow reserve in humans and to characterize some of the effects of focal and diffuse atherosclerosis on the coronary circulation. In addition. we have used flow reserve measurements in the diagnosis of microvascular dysfunction in patients with chest pain and normal coronary arteries and as a means of assessing noninvasive methods for detecting focal coronary artery disease.
Assessment of coronary artery disease using single-photon emission computed tomography with thallium-201 during adenosine-induced coronary hyperemia, Thallium-201 myocardial imaging during dipyridamole-induced coronary hyperemia has been an accepted method for diagnosing coronary artery disease (CAD) and risk stratification. Adenosine is a powerful short-acting coronary vasodilator. Initial results of thallium imaging during adenosine infusion have been encouraging. In 132 patients with CAD and in 16 patients with normal coronary angiograms. adenosine was given intravenously at a dose of 0.14 mg/kg/min for 6 minutes and thallium-201 was injected at 3 minutes. The thallium images using single-photon emission computed tomography were abnormal in 47 of the 54 patients (87%) with 1-vessel. in 34 of 37 patients (92%) with 2-vessel and in 40 of 41 patients (98%) with 3-vessel CAD. The sensitivity was 92% in the 132 patients with CAD (95% confidence intervals. 86 to 96%). In patients with normal coronary angiograms. 14 of 16 patients had normal thallium images (specificity. 88%; 95% confidence intervals. 59 to 100%). The results were very similar when subgroups of patients were analyzed: those without prior myocardial infarction. elderly patients and women. The nature of the perfusion defects (fixed or reversible) was assessed in relation to whether the 4-hour delayed images were obtained with or without the reinjection technique. In patients who underwent conventional delayed imaging. there were more fixed perfusion defects than in patients with reinjection delayed imaging (16 vs 0%. p less than 0.0001). The adverse effects were mild. transient and well tolerated. Thus. adenosine thallium tomographic imaging provides a high degree of accuracy in the diagnosis of CAD. The use of the reinjection technique enhances the ability to detect reversible defects.
Comparative effects of oral molsidomine and nifedipine on methylergometrine-induced coronary artery spasm, Twelve consecutive patients (10 men and 2 women. mean +/- standard deviation age 49 +/- 9 years) with chest pain. angiographically normal coronary arteries and coronary artery spasm documented by methylergometrine testing received a single oral dose of molsidomine (4 mg) or nifedipine (10 mg) in a randomized. double-blind. crossover fashion at a 24-hour interval. Coronary artery spasm was documented during coronary angiography in 6 patients (left anterior descending artery. 3; right coronary artery. 2; left circumflex. 1). In the remaining 6 patients. coronary artery spasm was documented by a positive methylergometrine test performed at the bedside. which provoked ST-segment elevation in the inferior (n = 3). anterior (n = 1) or lateral (n = 2) leads. Ninety minutes after administration of the study medication. methylergometrine testing was performed at the bedside. using incremental doses of up to 0.4 mg of methylergometrine. After molsidomine. 10 patients (83%) had a negative and 2 had a positive test; after nifedipine. 9 patients (75%) had a negative and 3 a positive test. Only 1 patient had a methylergometrine test that remained positive after either molsidomine or nifedipine. Therefore. molsidomine appears as effective as nifedipine in suppressing methylergometrine-induced coronary artery spasm in patients with variant angina. In addition. patients not responding to 1 of the study medications may respond to the other.
Effects of postural changes versus exercise on the electrophysiologic parameters of the accessory pathway, The electrophysiologic profile of the accessory pathway was studied in 17 patients (mean age +/- standard deviation 32 +/- 14 years) with Wolff-Parkinson-White (WPW) syndrome who were either lying down in a supine position. standing. or undergoing isometric or dynamic treadmill exercise. There were significant decreases in the PP interval after isometric exercise. standing and dynamic exercise (supine 764 +/- 224. standing 638 +/- 146. isometric 605 +/- 170. treadmill 455 +/- 86 ms; p less than 0.05). Both anterograde and retrograde accessory pathway refractory periods were measured after a constant drive of 400 ms during lying down supine. standing and isometric and treadmill exercise (Bruce protocol stage II). There was no significant decrease in the anterograde accessory pathway refractory period during isometric exercise (lying down 265 +/- 22 to isometric exercise 256 +/- 13 ms. p less than 0.05). but there were significant decreases (p less than 0.05) during standing (246 +/- 24 ms) and treadmill exercise (235 +/- 17 ms). The retrograde accessory pathway refractory period also showed a significant decrease (supine 272 +/- 16. isometric 267 +/- 23. standing 249 +/- 15. treadmill 237 +/- 17 ms; p less than 0.05). The relative change in refractory periods was greater when patients changed from lying down to standing than when they changed from standing to treadmill exercise. despite obvious higher adrenergic neuronal activities during exercise. These findings suggest that testing the accessory pathway during free standing can give a reliable indication of the sensitivity of the accessory pathway to sympathetic stimulation.
Influence of left ventricular diastolic filling on symptoms and survival in patients with decreased left ventricular systolic function, The relation between left ventricular (LV) filling variables measured by gated blood pool radionuclide ventriculography and clinical symptoms and survival was examined in 93 patients who had decreased LV systolic function. The diastolic data were not significantly associated with clinical symptoms. Time to peak filling rate. peak filling rate and ejection fraction were associated independently with survival free of cardiac death (chi-square = 7.74. 5.91 and 3.92. respectively. by stepwise Cox regression analysis). A short time to peak filling rate or increased peak filling rate was associated with decreased survival. whereas the opposite indicated a good prognosis. One-year Kaplan-Meier survival was 73 and 98% when time to peak filling rate was below or above the median value of 167 ms. respectively. 82 and 90% when peak filling rate was above or below the median value of 1.67 end-diastolic volumes per second. respectively. and 76 and 95% when LV ejection fraction was below or above the median value of 0.35. respectively. Thus. filling variables (time to peak filling rate and peak filling rate) measured by radionuclide ventriculography may be valuable in predicting survival in patients with decreased LV systolic function.
Ventricular function during supine bicycle exercise in univentricular connection with absent right atrioventricular connection, Fourteen patients with univentricular connection. absent right connection (tricuspid valve atresia) and normally related great arteries underwent rest and supine bicycle exercise equilibrium radionuclide blood pool studies. Ejection fraction. heart rate. systemic blood pressure and oxygen saturation (ear oximetry) were measured. There were 6 male and 8 female patients. Mean age +/- standard error of the mean was 14.5 +/- 1.1 years (range 6.3 to 21.1). Eight patients (group 1) had systemic to pulmonary shunts placed as palliation 8.2 +/- 2.2 years before study and 6 patients (group II) had caval to pulmonary shunts placed 11.8 +/- 1.6 years previously. Ejection fraction at rest was 54 +/- 2% and an abnormal response to exercise (failure of ejection fraction to increase greater than or equal to 5% from rest to peak exercise) was found in 9 of 14 patients. When analyzed separately. ejection fraction at rest in group I was higher than in group II; however. this difference disappeared at peak exercise. There was a significant negative correlation between ejection fraction at peak exercise and the interval since palliative surgery. although it was not apparent at rest. These data suggest that ventricular function is compromised during exercise and that abnormal performance is influenced by long-standing volume overload. Importantly. this abnormal state is concealed at rest and the choice of palliative shunting procedure appears to have little effect on normalizing pump performance.
Energy cost of physical activity on a metabolic ward in relationship to obesity, The energy cost of physical activity on a metabolic ward was derived from the difference between the energy requirement to maintain body weight on a metabolic ward and sedentary 24-h energy expenditure measured in a respiratory chamber in 56 nondiabetic male subjects. The cost of physical activity was negatively correlated with body weight (r = -0.67. P less than 0.0001) and with percent body fat (r = -0.48. P less than 0.0005). In a subgroup of 15 subjects selected for strict weight stability (rate of daily weight change less than +/- 35 g/d). similar negative correlations were observed between energy cost of activity and body weight (r = -0.61. P less than 0.01) and percent body fat (r = -0.51. P = 0.05). The ratio of active to sedentary energy expenditure. an index of physical activity. was also negatively correlated with body weight and percent body fat (r = -0.74. P less than 0.002 and r = -0.61. P less than 0.02. respectively). These results suggest that heavier subjects on a metabolic ward are less active and expend less energy in physical activity than do lighter subjects.
Changes in abdominal and gluteal adipose-tissue fatty acid compositions in obese subjects after weight gain and weight loss, The fatty acid compositions of abdominal and gluteal subcutaneous adipose tissues of eight obese subjects were measured after an initial 5-10-wk period of weight maintenance on a liquid-formula diet (40% of calories as corn oil. 45% as carbohydrate. and 15% as protein). after a 10% increase in weight (11-20 kg) on a solid-food diet of each subject's choice (n = 5) or after a 20% decrease in weight (26-37 kg) on 800 kcal/d of the same corn-oil-formula diet (n = 5). After weight gain or weight loss. all subjects maintained their new weights for 2-10 wk on the same corn-oil-formula diet. As hypothesized. there were minimal changes in the concentrations of 41 fatty acids identified in both abdominal and gluteal tissues after all dietary phases. and small site-specific differences in the levels of saturated and monounsaturated fatty acids were not altered. The largest change was a 15% decrease (P less than 0.05) in 18:3n-3 in both abdominal and gluteal tissues during weight loss. despite higher levels in the diet than in the baseline adipose tissue. This decrease occurred without coexisting decreases in 22:5n-3 and 22:6n-3. two elongase-desaturase products of 18:3n-3 that were not detectable in the diet.
Relationship of menopause to skeletal and muscle mass, Cross-sectional and longitudinal changes in body composition with age were examined in white women to determine the relationship of body cell mass to menopause and of body fat to bone mass. There was statistical evidence for a curvilinear component to loss of total body potassium with negligible rates of loss before menopause. Longitudinal measurements also indicated a relationship between the proximity to menopause and the rate of loss of potassium. Total body potassium was significantly related to total body calcium and bone density of the spine. radius. and femoral neck. Total body fat was not related to any of these measurements. We found no evidence that adiposity plays a major role in protecting against bone loss.
The transient hypercholesterolemia of major weight loss, Serum lipoproteins. body composition. and adipose cholesterol contents of six obese women were studied during and after major weight loss by very-low-calorie diets (VLCDs). Subjects started at 168 +/- 11% of ideal body weight. lost 30.3 +/- 3.7 kg in 5-7 mo. followed by 2+ mo in weight maintenance. Serum cholesterol fell from a prediet (baseline) value of 5.49 +/- 0.32 to 3.62 +/- 0.31 mmol/L (P less than 0.01) after 1-2 mo of VLCDs (nadir). after which it rose to 5.95 +/- 0.36 mmol/L (peak. P less than 0.01 compared with nadir and baseline) as weight loss continued. With weight maintenance. serum cholesterol fell to 4.92 +/- 0.34 mmol/L (P less than 0.05 compared with peak). Adipose cholesterol content did not change in peripheral (arm and leg) biopsy sites but rose significantly in abdominal adipose tissue with weight loss. We conclude that major weight loss was associated with a late rise in serum cholesterol. possibly from mobilization of adipose cholesterol stores. which resolved when weight loss ceased.
Psyllium fiber reduces rise in postprandial glucose and insulin concentrations in patients with non-insulin-dependent diabetes, The ability of psyllium fiber to reduce postprandial serum glucose and insulin concentrations was studied in 18 non-insulin-dependent diabetic patients in a crossover design. Psyllium fiber or placebo was administered twice during each 15-h crossover phase. immediately before breakfast and dinner. No psyllium fiber or placebo was given at lunch. which allowed measurement of residual or second-meal effects. For meals eaten immediately after psyllium ingestion. maximum postprandial glucose elevation was reduced by 14% at breakfast and 20% at dinner relative to placebo. Postprandial serum insulin concentrations measured after breakfast were reduced by 12% relative to placebo. Second-meal effects after lunch showed a 31% reduction in postprandial glucose elevation relative to placebo. No significant differences in effects were noted between patients whose diabetes was controlled by diet alone and those whose diabetes was controlled by oral hypoglycemic drugs. Results indicate that psyllium as a meal supplement reduces proximate and second-meal postprandial glucose and insulin concentrations in non-insulin-dependent diabetics.
Response of vitamin B-6 content of muscle to changes in vitamin B-6 intake in men, Previous reports indicated that in growing rats the vitamin B-6 pool in muscle was relatively stable during deficiency but increased in response to increased vitamin B-6 intake. To determine whether human muscle would show a similar response 10 college-aged males received a low vitamin B-6 diet (1.76 mumol/d) for 6 wk followed by 6 wk on a self-selected diet supplemented with 0.98 mmol pyridoxine HCl/d. During depletion. excretion of pyridoxic acid rapidly adjusted to approximate the intake. Plasma pyridoxal phosphate concentrations at the end of the baseline. depletion. and supplementation periods were 81 +/- 51. 9 +/- 3. and 455 +/- 129 nmol/L. respectively. whereas muscle concentrations were 21 +/- 9. 20 +/- 4. and 25 +/- 7 nmol/g. respectively and total vitamin B-6 in muscle was 28 +/- 10. 27 +/- 4. and 35 +/- 10 nmol/g. respectively. These data provide further confirmation that the vitamin B-6 pools in skeletal muscle are resistant to depletion. They also demonstrate that in humans with constant body weight. vitamin B-6 supplementation is not associated with marked increases in vitamin B-6 in muscle.
Determinants of increase in plasma concentration of beta-carotene after chronic oral supplementation. The Skin Cancer Prevention Study Group, We studied the relationship between eight variables. including age. sex. baseline plasma beta-carotene (BC) concentration. and smoking status and the increase in plasma BC in 582 subjects receiving oral supplementation with 50 mg BC/d. Median plasma BC concentrations after 1 y of supplementation increased from 335 nmol/L at entry to 3163 nmol/L. Changes in plasma BC concentrations ranged widely from -313 to 16.090 nmol/L (median 2721 nmol/L). Multivariate analysis revealed that the subject's plasma BC concentration before supplementation was the most important indicator of the amount of increase after supplementation. Nonsmokers. women. and leaner subjects all had larger increases in plasma concentrations although the statistical model could account for relatively little of the variability in subjects' plasma response to BC supplementation (R2 = 0.14). We conclude that between-subject variability in response to daily supplementation with oral BC is very large and that the best predictor of this response is the initial plasma BC concentration.
Ascorbic acid requirements for smokers: analysis of a population survey, The recommended dietary allowance (RDA) of ascorbic acid for smokers was recently increased from 60 to 100 mg. To determine whether this new RDA for smokers is sufficient to reduce the risk of low serum ascorbic acid (AA) concentrations (LoC) to the same concentration as nonsmokers. we analyzed the dietary intakes and serum concentrations of AA in 11.582 adult respondents in the National Health and Nutrition Examination Survey (1976-1980). Serum AA concentrations and the risk of LoC (serum ascorbic acid levels less than 23 mumol/L) for smokers consuming different amounts of AA were compared with those for nonsmokers whose AA intake exceeded the RDA (60 mg). Serum AA concentrations were reduced. and risk of LoC increased. in smokers maintaining AA intakes greater than 60. 100. and 150 mg. Only smokers consuming greater than 200 mg AA/d had serum ascorbate concentrations and risk of LoC equivalent to nonsmokers meeting the RDA.
Pediatric cardiac rehabilitation, Sixteen patients participated in a Pediatric/Young Adult Cardiac Rehabilitation Program that included exercise training. education about cardiovascular diseases. dietary counseling. and counseling on stress management. Seven patients completed the program. and complete data were available on six. The subjects demonstrated significant changes in their hemodynamics and exercise tolerance after completing the program. Resting blood pressure decreased by 7%. from 119 +/- 12 to 111 +/- 10 mm Hg; peak oxygen consumption increased by 20%. from 31.9 +/- 4.3 mL/kg of body weight per minute to 38.4 +/- 6.0 mL/kg of body weight per minute; and exercise treadmill time increased by 21%. from 8.5 +/- 1.4 to 10.3 +/- 1.0 minutes. No complications occurred during exercise training or testing. Supervised exercise training at moderate intensity is safe and produces significant and beneficial changes in hemodynamics and exercise time in children with cardiac disease.
Meconium for drug testing, Samples of meconium from 28 neonates born to women suspected of drug abuse were tested for drugs of abuse (ie. cocaine. morphine. codeine. and marijuana). In each case. testing of urine from the mother. the newborn. or both had been ordered by the attending physician because of suspected maternal drug abuse. Seventeen (61%) of 28 meconium samples tested positive; 28 (60%) of 47 urine samples were positive. Meconium test results were concordant with the results of maternal or newborn urine testing in 24 (86%) of the 28 cases. In three cases. meconium was positive for cocaine when newborn urine was negative; in one case. meconium was negative when maternal urine was positive for cocaine. Compared with the combination of maternal and newborn urine testing. meconium testing had an 82% positive predictive value (14/17) and a 91% negative predictive value (10/11). Collection of meconium is simpler and more reliable than collection of urine. and testing of meconium was easily incorporated into routine procedures at a busy commercial laboratory. Meconium is a useful sample for drug detection in newborns.
Tracking of elevated blood pressure values in adolescent athletes at 1-year follow-up, Resting blood pressures were measured in 467 adolescents during preparticipation physical examinations for high school sports. Fifty-seven of the athletes (12.2%) had significantly elevated blood pressures. Forty-three (79.6%) of 54 subjects demonstrated significantly and persistently elevated blood pressures at 1-year follow-up. A family history of hypertension was positively associated with elevated blood pressures in 46 (80.7%) of 57 subjects compared with controls (23/410 [5.6%]). Consistent with previous studies. subjects with elevated blood pressures had a greater body weight (94.5 +/- 25.7 kg) compared with normotensive subjects (75.2 +/- 14.0 kg). Subjects with elevated blood pressures engaged in heavy resistance weight training (three times a week or more) more often (41/57 [71.9%]) than normotensive subjects (65/410 [15.8%]). These data support the idea that blood pressures measured during routine preparticipation physical examinations for high school sports are a useful tool in screening for elevated blood pressure in adolescents.
Fragile X syndrome: diagnosis using highly polymorphic microsatellite markers, We describe two highly polymorphic microsatellite AC repeat sequences. VK23AC and VK14AC. which are closely linked to the fragile X at Xq27.3. Both VK23AC (DXS297) and VK14AC (DXS292) are proximal to the fragile site. Two-point linkage analysis in 31 fragile X families gave (a) a recombination frequency of 1% (range 0.00%-4%) with a maximum lod score of 32.04 for DXS297 and (b) a recombination frequency of 7% (range of 3%-15%) with a maximum lod score of 12.87 for DXS292. Both of these polymorphisms are applicable to diagnosis by linkage in families with fragile X syndrome. A multipoint linkage map of genetic markers at Xq27.3 was constructed from genotyping these polymorphisms in the CEPH pedigrees. The DXS292 marker is in the DXS98-DXS297 interval and in 3 cM proximal to DXS297.
Genetic and environmental explanations for the distribution of sodium-lithium countertransport in pedigrees from Rochester, MN, An elevated level of erythrocyte sodium-lithium (Na-Li) countertransport has been suggested as a predictor of predisposition to essential hypertension. In order to evaluate whether a single genetic or environmental factor with large effects explains the mixture of distributions in Na-Li countertransport in the general population. complex segregation analyses were conducted by using 1.273 individuals more than age 20 years from 276 pedigrees selected without respect to disease risk factors or health status. Either a single genetic locus or a single environmental factor with large gender-specific effects explained the mixture of distributions for Na-Li countertransport in this sample equally well. In the subsample of pedigrees supporting a single-locus etiology. the single genetic locus explained 29.0% of the variability in adjusted Na-Li countertransport in males and 16.6% of that in females. In a subsample of pedigrees supporting an environmental factor etiology. the environmental factor explained 35.2% of the adjusted Na-Li countertransport in males and 20.5% of that in females. These results suggest that there are at least two different explanations for the mixture of distributions in Na-Li countertransport in the general population. Attempts to relate genetic variation in Na-Li countertransport to risk of essential hypertension must consider that the factor with large phenotypic effects on this trait is gender specific and may not be a single major locus in all pedigrees.
Screening for non-delta F508 mutations in five exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in Italy, Analysis of exons 10. 11. 14a. 15. and 20 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing-gradient-gel electrophoresis (DGGE) allowed the identification of mutations causing cystic fibrosis (CF) in 25 of 109 non-delta F508 chromosomes. as well as identification of a number of polymorphisms and sequence variations. Direct sequencing of the PCR fragments which showed an altered electrophoretic behavior not attributable to known mutations has led to the characterization of four new mutations. two in exon 11. and one each in exons 15 and 20. Screening for the different mutations thus far identified in our patients by the DGGE analysis and other independent methods should allow detection of about 70% of the molecular defects causing CF in Italy. Mutations located in exons 11 and 20 account for at least 30% of the non-delta F508 mutations present in Italian CF patients.
Localization of the translocation breakpoint in a female with Menkes syndrome to Xq13.2-q13.3 proximal to PGK-1, Menkes syndrome is a rare X-linked recessive disorder characterized by an inability to metabolize copper. A female patient with both this disease and an X; autosome translocation with karyotype 46.X.t(X;2)(q13;q32.2) has previously been described. The translocation breakpoint in Xq13 coincides with a previous assignment of the Menkes gene at Xq13 by linkage data in humans and by analogy to the mottled mutations which are models for Menkes disease in the mouse. Therefore. this translocation probably interrupts the gene for Menkes syndrome in band Xq13. We describe here experiments to precisely map the translocation breakpoint within this chromosomal band. We have established a lymphoblastoid cell line from this patient and have used it to isolate the der(2) translocation chromosome (2pter----2q32::Xq13----Xqter) in human/hamster somatic cell hybrids. Southern blot analyses using a number of probes specific for chromosomes X and 2 have been studied to define precisely the location of the translocation breakpoint. Our results show that the breakpoint in this patient--and. therefore. likely the Menkes gene--maps to a small subregion of band Xq13.2-q13.3 proximal to the PGK1 locus and distal to all other Xq13 loci tested.
G gamma and A gamma globin genes are identical from -471 of the promoter midway through gamma IVSII in a Benin beta s haplotype associated with elevated fetal hemoglobin, In seven kindreds in which sickle cell (SS) patients had elevated (greater than 12%) fetal hemoglobin (Hb F). Milner and colleagues reported that a determinant for elevated Hb F and elevated F cells was linked to the beta s gene. Independently. the Senegal (SEN) beta s haplotype has been found in association with elevated Hb F in SS and beta-thalassemia patients. We have used the kindreds of Milner and colleagues to characterize further the association of haplotype and gamma gene DNA sequence variation with Hb F expression. For the largest kindred. Wi. all four SS had high (greater than 14%) Hb F and both SEN and Benin (BEN) haplotypes. Two AS cases carrying SEN had low Hb F and low F cells. while three AS and one CS carrying BEN had elevated Hb F and elevated F cells; only one AS carrying BEN had low Hb F and low F cells. In order to look for genetic alterations that could account for the elevated Hb F of kindred Wi. we sequenced both the G gamma and A gamma genes of the Wi BEN haplotype. The data showed largely identical G gamma and A gamma genes which may have been generated by two gene conversions: the A gamma promoter was like that of G gamma 3' to -471. while the G gamma IVSII was like that of A gamma in its 5' half. In addition. three new mutations were found in gamma IVSII.
A novel mutation in the invariant AG of the acceptor splice site of intron 4 of the beta-hexosaminidase alpha-subunit gene in two unrelated American black GM2-gangliosidosis (Tay-Sachs disease) patients, Samples of genomic DNA from three unrelated American black infants having both biochemical and clinical features of classical infantile Tay-Sachs disease were sequenced following PCR amplification. A G----T transversion was observed in the AG acceptor splice site preceding exon 5 of the beta-hexosaminidase alpha-subunit gene in the first black family. This transversion changed the acceptor splice site from the consensus sequence. AG. to AT. thereby interfering with splicing at this intron 4/exon 5 junction. The proband was homozygous for this mutation; his mother and a brother are heterozygous. The same mutation was found in a second. apparently unrelated. black GM2-gangliosidosis patient. The second patient was a compound heterozygote. as only one allele carried this mutation. The mother and a brother in this second family are carriers for this mutation. while the father and a noncarrier sister are normal for this region of the gene. The third proband did not have this mutation; nor did the mother of a fourth black proband. Eight other independently ascertained non-black. non-Jewish. GM2-gangliosidosis families did not have this mutation. The observation of the same novel mutation in two unrelated black GM2-gangliosidosis patients indicates that the American black population has segregating within it at least one GM2-gangliosidosis mutation which may be specific to this population and not a result of migration.
Fertility retention in the patient with genital prolapse, There are several treatments from which to choose for the patient with symptomatic uterine prolapse who wishes to retain fertility. Transabdominal construction of a sacrocervical "ligament" with transplanted fascia lata femoris is a useful solution to this problem. The technique is described.
The contributions of the nurse and the machine in home uterine activity monitoring systems, The relative contributions of home tokodynamometry and daily nursing telephone contact to the success of preterm birth prevention programs remains a subject of debate. Because investigators have obtained conflicting data. a reinterpretation of published results was undertaken by proposing a dynamic interface between the nurse and the machine. Experience gained from the technology and the development of nursing expertise with assessment of patient symptoms are presented as interdependent factors. both of which are critical to a therapeutic nurse-patient relationship. It is proposed that this combined interactive expertise increases sensitivity to the early recognition of preterm labor. The nurse's role in providing social support to high-risk pregnant women is then identified as a potential additional independent contributing factor to reported observed reductions in preterm births. Discussion focuses on future research. public policy issues. and the need for expanding nurse-patient interactions into the home.
Bleeding patterns during continuous combined estrogen-progestogen therapy, Bleeding and climacteric symptoms were recorded in two groups of postmenopausal women receiving either continuous combined estradiol and norethisterone acetate or estradiol and cyproterone acetate. Out of a sample of 99 postmenopausal women aged 45 to 54 years. 86 completed a 2-year. double-blind. placebo-controlled study. Comparison of the bleeding patterns in the two groups revealed a statistically significant difference: More women in the estradiol-cyproterone acetate group experienced bleeding and for a longer duration. Thirteen women in the estradiol-norethisterone acetate group were amenorrheic. compared with two in the other group. The Kupperman index score in both groups declined to about 30% to 40% of initial values (p less than 0.001). The hot flushes in both treatment groups decreased to a highly significant degree (p less than 0.001). to a value below 20% of baseline values. We conclude that a continuous combination of estrogen and progestogen can produce amenorrhea and symptomatic relief. However. the progestogen components seem to differ in their ability to control bleeding.
Effect of low-dose aspirin on vascular refractoriness in angiotensin-sensitive primigravid women, The hypothesis that an enhanced vasopressor response to angiotensin II in pregnancy may be corrected by suppressing production of platelet thromboxane A2 with low-dose aspirin was tested in a randomized. placebo-controlled. double-blind trial. We studied 36 normotensive primigravid women with an elevated blood pressure response to intravenously infused angiotensin II at 28 weeks' gestation; 18 women received 60 mg of aspirin daily and the same number received matched placebo until 34 weeks' gestation. when angiotensin-sensitivity was again determined. In women taking aspirin. values of thrombin-induced platelet malondialdehyde production were approximately 10% of those determined in the placebo group. indicating marked suppression of thromboxane A2 synthesis. In the aspirin group vascular refractoriness to angiotensin II was restored in 14 of 17 treated women. by comparison with 5 of 15 women in the placebo group who had remained normotensive. These results support the hypothesis that prostacyclin/thromboxane imbalance is an important pathophysiologic factor in the development of the enhanced angiotensin-sensitivity associated with pregnancy-induced hypertensive disorders.
Recurrent failure of in vitro fertilization: role of the hemizona assay in the sequential diagnosis of specific sperm-oocyte defects, The results of predictive fertilization bioassays (hemizona assay. hamster ova-human sperm penetration assay). in vitro fertilization treatment. fertile donor cross-match tests with either sperm or oocytes. and oocyte micromanipulation for assisted fertilization were used to establish a pathophysiologic diagnosis in cases of recurrent failed fertilization in vitro. Disorders of sperm function manifested at the level of zona binding. zona penetration. oolemma fusion. and pronuclear decondensation as well as oocyte anomalies were considered to represent the specific gamete defects that led to abnormal sperm-oocyte interactions (i.e.. failed fertilization). Our findings show that the sequential application of bioassays can elucidate specific sperm or oocyte defects that characterize functional abnormalities among sperm populations.
Umbilical vein administration of oxytocin for the management of retained placenta: is it effective, In a multicenter randomized controlled trial involving 220 women with retained placenta no beneficial effects could be established of intraumbilical vein administration of 10 IU of oxytocin in 20 ml of saline solution. A reduction was not gained in the rate of manual removal of the placenta and there was no decrease in the amount of blood loss. Oxytocin only induced a minor shortening of the median time interval from administration to the spontaneous expulsion of the placenta as compared with a placebo injection. Maternal serum alpha-fetoprotein levels before and after intraumbilical vein injection did not show evidence of fetomaternal transfusion.
CA 125 levels in abruptio placentae, The diagnosis of abruptio placentae is frequently difficult despite ultrasonography; additional diagnostic parameters would be useful. Maternal serum CA 125. which is believed to derive from the decidua. is elevated in the first trimester and immediately after delivery when placental separation occurs. possibly because of decidual disruption. Serum CA 125 was measured in 27 patients beyond 20 weeks' gestation who were first seen with vaginal bleeding and in 17 control patients of similar gestational age and labor status. Mean (+/- SD) CA 125 levels were higher (p less than 0.01) among patients with abruptio placentae (105.9 +/- 115 U/ml) than among those with alternate sources of bleeding (13.7 +/- 10 U/ml) or control patients (18.2 +/- 11.7 U/ml). Mean (+/- SD) serum CA 125 levels in seven control patients within 6 hours post partum (194 +/- 80.5 U/ml) were higher than those among patients first seen with abruptio placentae (p less than 0.01). Sensitivity and specificity of CA 125 for abruptio placentae were 70% and 94%. respectively. Our data support a decidual source for CA 125 and may indicate utility of CA 125 as a marker for abruptio placentae.
Management of severe preeclampsia detected in early labor by prostaglandin A1 or dihydralazine infusions, The presence of severe pregnancy-induced hypertension at the onset of labor requires therapy with a potent hypotensive agent. Prostaglandin A1 is a powerful vasodepressor that augments renal blood flow and glomerular filtration and possesses antiplatelet aggregator and oxytocic properties. A continuous intravenous infusion of prostaglandin A1 (40 to 50 micrograms/min) or dihydralazine (35 to 50 micrograms/min) was administered to 20 women with severe preeclampsia (10 in each group). The induced hypotensive response was similar with both drugs but the maximum reduction in blood pressure was achieved sooner with dihydralazine (4 hours) compared with prostaglandin A1 (7.5 hours). The more gradual hypotensive response is probably less dangerous on placental perfusion than a sudden change. Moreover. the oxytocic property of prostaglandin A1 shortened the time to delivery. which constitutes another potential advantage.
Cervical human papillomavirus deoxyribonucleic acid and cytologic evaluations in gynecologic outpatients, We studied the prevalence and cytologic manifestations of human papillomavirus deoxyribonucleic acid among 2668 gynecologic outpatients. The study population consisted of 1573 women who came into the emergency room. 623 women from an abortion clinic who were seen because of induced first-trimester abortion. and 472 women who had been referred to a colposcopy clinic because of an abnormal Papanicolaou smear finding. A dot blot technique was used for the detection of human papillomavirus types 6/11. 16/18. and 31/33/35. The prevalence of human papillomavirus deoxyribonucleic acid was 4.4% in the emergency room population. 8.8% in the abortion clinic population. and 31.4% in the colposcopy clinic population. Human papillomavirus type 16/18 was most prevalent (3.5%). followed by human papillomavirus type 31/33/35 (3.1%). and human papillomavirus type 6/11 was least prevalent (2.1%). Of all unselected human papillomavirus deoxyribonucleic acid-positive women who were enrolled from the emergency room or from the abortion clinic. 73% had normal cytologic evaluations. Twenty-five percent had benign atypia. and 2% had dyskaryotic changes. No human papillomavirus deoxyribonucleic acid type-specific differences were detected in the distribution of cytologic atypias.
The effect of sterile water blocks on low back labor pain, To evaluate the analgesic effect of intradermal sterile water blocks. 272 women in labor complaining of severe low back pain were randomly assigned to treatment with either sterile water or saline solution blocks. Pain intensity was assessed on a visual analog scale. before the blocks were given and again 1 and 2 hours later. The groups were equal with regard to age. parity. fetal size. progression of labor. and initial pain scoring. Pain scoring 1 and 2 hours after the blocks were given showed a significantly higher degree of analgesia in the sterile water group. No adverse effects were noted. and patient acceptability was high.
Intraamniotic detection of Chlamydia trachomatis deoxyribonucleic acid sequences by polymerase chain reaction, The presence of Chlamydia trachomatis in cervicovaginal cells and amniotic fluid of pregnant women was examined by culture and by polymerase chain reaction deoxyribonucleic acid amplification methods. Chlamydial deoxyribonucleic acid sequences were found in nine of 31 (29.0%) cervicovaginal cell specimens. five of which also were positive by culture method. Amniotic fluid specimens from two of the nine (22.2%) cervicovaginal chlamydial deoxyribonucleic acid-positive women and none from the remaining 22 cervicovaginal chlamydial deoxyribonucleic acid-negative women were found to contain chlamydial deoxyribonucleic acid. The results underscore the significance and frequency of intraamniotic chlamydial infection in women with urogenital chlamydial infections.
Conditions not attributable to a mental disorder: an epidemiological study of family problems, OBJECTIVE: The objective of this research was to identify and measure the differences among three groups of psychiatric outpatients: those with family problems but without mental disorders. those with both family problems and mental disorders. and those with a mental disorder but without family problems. DSM-III V code conditions (conditions not attributable to a mental disorder) other than family problems do occur. but family problems were chosen because of their importance. METHOD: All patients admitted to an outpatient psychiatric clinic during a 2-year period were studied (N = 382). Of these. 92 had V code conditions unrelated to family problems and were excluded. Data are presented on the remaining 290 patients. Sociodemographic variables. DSM-III diagnoses. source of referral. previous and subsequent use of outpatient services. and type of family problem were examined. Patients were from a low-income population and came from three ethnic groups (white. black. and Hispanic). RESULTS: Among whites. more men than women had family problems without mental disorders; among blacks. more women than men had family problems with and without mental disorders. Marital problems occurred most frequently in the group with family problems without mental disorders. and married subjects were more likely to have a V code condition. Professional referrals were more common than other referral sources in all three groups. However. family problems without mental disorders were more likely to occur among those who were referred by their families and had never had psychiatric treatment; patients with family problems and mental disorders were more likely to be self-referred and to have been previously treated; those with a mental disorder but without family problems were usually referred by professionals and almost always had been previously treated. There appeared to be underreporting of family problems among those with family problems and mental disorders and among black men with family problems with and without mental disorders. CONCLUSIONS: More research is needed on the patterns of use of outpatient psychiatric services by individuals with family problems and other V code conditions.
Elevation of plasma concentrations of haloperidol after the addition of fluoxetine, Fluoxetine (20 mg/day) was added for 7-10 days to stable doses of haloperidol given to eight psychotic patients. Mean plasma concentrations of haloperidol were elevated by 20% (p less than 0.05). but extrapyramidal side effects did not increase appreciably. indicating a relatively minor interaction between these agents.
Isolation of Jamestown Canyon virus from boreal Aedes mosquitoes from the Sierra Nevada of California, More than 28.000 mosquitoes in four genera were collected from high elevation (greater than or equal to 1.000 m) areas of California during 1988-89 and tested for virus by plaque assay in Vero cells. Viruses were serogrouped by enzyme immunoassay and serotyped by cross-neutralization. Six strains of Jamestown Canyon virus in the California serogroup were isolated from three species of boreal Aedes in the Aedes communis group of the subgenus Ochlerotatus. All isolates were from mosquitoes collected in Alpine County at approximately 2.300 m elevation in the Sierra Nevada. These included one virus from a pool of male Aedes cataphylla collected in immature stages. which is evidence for vertical transmission; four viruses from adult female Ae. communis (sens. lat.); and one virus from adult female Aedes hexodontus. These are the first isolations of viruses from boreal Aedes mosquitoes in California and the first reported isolations of Jamestown Canyon virus from Ae. cataphylla or Ae. hexodontus.
Potential for mosquito transmission of attenuated strains of Rift Valley fever virus, Studies were conducted to determine if two attenuated strains of Rift Valley fever (RVF) virus could be transmitted by Culex pipiens mosquitoes. Both strains (RVF MP 12 and T1) replicated in and were transmitted by female Cx. pipiens after intrathoracic inoculation. Mosquitoes also became infected with and transmitted the RVF MP12 strain after ingesting virus from a blood-soaked cotton pledget. However. because of the low viremias produced in infected animals. it is unlikely that mosquitoes would become infected by feeding on an animal inoculated with either of these viruses. Although both strains were transmitted by mosquitoes after intrathoracic inoculation. there was no evidence of reversion to a virulent virus.
A killing disease epidemic among displaced Sudanese population identified as visceral leishmaniasis, A fatal disease epidemic affected the Bentiu area in southern Sudan and led to a mass migration of the Nuer tribe searching for treatment. The initially available information revealed a high mortality rate due to a possible occurrence of tuberculosis. malaria. enteric fever or visceral leishmaniasis (VL). Serological screening of 53 of the most severely affected patients in an enzyme-linked immunosorbent assay (ELISA) or an improved direct agglutination test (DAT) revealed positivity for VL. In 39 of those patients. diagnosis was confirmed by identification of Leishmania donovani amastigotes in lymph node or bone-marrow aspirates. In a total of 2714 patients observed. 1195 (44.0%) had clinical symptoms suggesting VL: DAT positive titers (1:3200-greater than or equal to 1:12800) were obtained in 654 (24.1%). of whom 325 were confirmed parasitologically. Forty-two VL cases died before or during treatment. giving a mortality rate of 6.4%. Among the intercurrent infections diagnosed in the VL population (654). respiratory involvements (31.7%) and malaria (10.7%) were most prevalent. With the exception of four (0.6%). all other VL patients (509) responded readily to sodium stibogluconate. The factors initiating the outbreak are discussed. Malnutrition and nomadic movements to potential VL endemic areas appeared to be the most important. HIV infection as a possible predisposition seemed remote considering the clinical and epidemiological similarity to VL occurring in East Africa. adequate humoral response in DAT. and immediate positive response to specific anti-Leishmania chemotherapy.
Phlebotomus guggisbergi (Diptera: Psychodidae), a vector of Leishmania tropica in Kenya, Sand flies were collected in light traps and on oiled papers at four active case sites of human cutaneous leishmaniasis due to Leishmania tropica at Muruku Sublocation. Laikipia District. Kenya. Nearly 5.200 females of five species. including Phlebotomus guggisbergi. were dissected and examined for flagellates. Of 3.867 P. guggisbergi females collected at a multiple case site. 168 (4.3%) harbored mature infections (to include metacyclic promastigotes) of flagellates morphologically identical to Leishmania. while all other flies were negative. Of the infected flies. 164 were collected in a cave near the patients' home. three from crevices on an escarpment immediately behind the house. and one from the bedroom of one of the patients. One hundred sixty-four of the isolates were successfully grown in Schneider's Drosophila medium and harvested for typing by cellulose-acetate electrophoresis. Isoenzyme profiles of the first 22 of these were compared with those of WHO reference strains and well characterized local strains using 12 enzyme loci. The isolates yielded isoenzyme migration patterns that were indistinguishable from those of two L. tropica reference strains and of six L. tropica patient isolates from the same locality. This is the first reported isolation of L. tropica from a sand fly in Kenya. the first reported isolation of Leishmania parasites from P. guggisbergi. and the first confirmed isolation of this Leishmania from a sand fly other than P. sergenti. The finding of such a large number of P. guggisbergi naturally harboring mature infections of L. tropica at an active case site of cutaneous leishmaniasis due to this agent strongly implicates this fly as a vector.
Coexistence of GP195 alleles of Plasmodium falciparum in a small endemic area, Dimorphic variations in the genotype of the precursor to Plasmodium falciparum major merozoite surface antigens or gp195. among wild isolates in a small malaria parasite population were examined using Southern blot hybridization techniques. Hybridization. with DNA fragment probes and oligonucleotide probes derived from variable blocks of known gp195 alleles against 18 wild isolates from Mae Sod district in Thailand. revealed the existence of seven gp195 alleles. two of which were newly identified in this study. In four out of 17 patients. two different alleles coexisted in the circulation. It was furthermore noted that the seven alleles did not occur at the same frequency. but rather several alleles predominated in the population of P. falciparum in this small malaria field.
Oesophagostomiasis, a common infection of man in northern Togo and Ghana, Infection with Oesophagostomum sp. is normally considered a rare zoonosis and up to this time its diagnosis has been based on the demonstration of larvae and young adult worms in the typical nodules formed in the intestinal wall. Only in Dapaong. in North Togo. and Bawku. North Ghana. have larger series of clinical cases been described. In the rural areas around these towns. a survey was made in which stool samples were collected and cultured. Third-stage larvae of Oesophagostomum sp. could be found after 5-7 days of incubation at room temperature. and the prevalence of infection with this parasite was often high but varied from one village to another. It was over 30% in seven villages out of the 15 villages surveyed. Anthelmintic treatment resulted in the evacuation of adult males and females of O. bifurcum. It is concluded that O. bifurcum is a locally common parasite of humans. not requiring an animal reservoir for completion of its lifecycle.
The hypotensive activity of Crotalus atrox (western diamondback rattlesnake) venom: identification of its origin, Viperidae snakes belonging to the genus Crotalus. subfamily Crotalinae. include the species durissus terrificus. durissus durissus. adamanteus. atrox. cerastes. horridus. molossus. scutulatus. viridis and others. All of them. except for the first 2. are found in North America. Crotalus atrox. or diamondback rattlesnakes. live in the southwest United States and in Mexico. This paper describes the fractionation of C. atrox venom in order to isolate and identify its hypotensive agents.
Technical considerations for prophylactic mastectomy in patients at high risk for breast cancer, A study of 5 patients and 10 mastectomy specimens was performed to identify the extent of surgery necessary to completely remove all breast tissue in patients having prophylactic mastectomies. A standard total mastectomy performed for breast cancer was shown to frequently leave breast tissue within the superficial pectoralis major muscle and the lower skin flap. Frozen section analysis of margins was found to be essential to clear the axillary extension of the breast and lower skin flap in particular. The value of more extensive surgery to remove all glandular elements of the breast in the high-risk patient remains to be demonstrated.
Combined use of topical and systemic antibiotics, An animal wound model was used to compare the effectiveness of topical and systemic antibiotics and to examine the validity of using a combined regimen of both routes of antibiotic delivery. Gross infection rates and wound bacterial concentrations were determined after contamination with Staphylococcus aureus or Escherichia coli. Both moderate (10(8) colony-forming units [CFU]) and heavy (10(12) CFU) contamination were studied for each organism. Following moderate contamination. topical and systemic antibiotics were equally effective in reducing both wound bacterial content and infection rate. but there was no benefit from the combined use of both modes of antibiotic delivery. An additive effect of the combined regimen was noted only when the level of wound contamination was heavy.
Conventional versus thrombolytic therapy in spontaneous (effort) axillary-subclavian vein thrombosis, Effort axillary-subclavian vein thrombosis in young patients has produced long-term disability because of the failure of the thrombosed vein to recanalize. Ten consecutive patients treated in our institution were analyzed. All patients were diagnosed by venography. Four patients received thrombolytic therapy. Three of these had complete resolution and one had partial resolution of the symptoms and thrombus. that was confirmed by venography and duplex imaging. The remaining six patients were treated with conventional anticoagulant therapy. Three of these patients had no resolution. one had complete resolution of both symptoms and thrombus. and two had only partial resolution of symptoms but no resolution of thrombus. Thrombolytic therapy appears to be superior to anticoagulation in the dissolution of symptoms in effort vein thrombosis and should be considered in its management if the diagnosis is made early.
Effect of dietary ethanol on gallbladder absorption and cholesterol gallstone formation in the prairie dog, Dietary ethanol has been reported to protect against cholesterol gallstone formation. Because enhanced gallbladder absorption of water is important in cholesterol cholelithiasis. we examined the hypothesis that ethanol acts by inhibiting the absorptive function of the gallbladder. Eighteen adult male prairie dogs were fed a lithogenic liquid diet containing 0.4% cholesterol. Half of the animals received 30% of total calories as ethanol. whereas their pair-fed controls received equicaloric amounts of maltose-dextrin. After 3 months. the gallbladders were inspected for gallstones and crystals. and gallbladder and hepatic bile were analyzed. Cholesterol stones and crystals were present in all nine controls. None of the alcohol-fed animals had stones. but four had cholesterol crystals. Gallbladder cholesterol. phospholipids. and total calcium were significantly decreased in alcohol-fed animals. In both gallbladder and hepatic bile. the cholesterol saturation index was significantly lower in alcohol-fed animals. as was the ratio of trihydroxy to dihydroxy bile salts. The ethanol-supplemented diet produced a significant decrease in the absorption of water by the gallbladder as indicated by changes in the gallbladder bile to hepatic bile ratios of the total bile salt concentration (7.29 +/- 1.25 versus 3.84 +/- 0.56; p less than 0.05) and the total calcium (3.37 +/- 0.24 versus 2.43 +/- 0.29; p less than 0.05). These findings indicate that the protective effect of ethanol may be related to its ability both to inhibit gallbladder absorption of water and to alter the composition of biliary lipids.
Fibrin glue sealing of pancreatic injuries, resections, and anastomoses, Fibrin glue made with highly concentrated human fibrinogen and clotting factors was evaluated as a means of preventing pancreatic fistulas in 15 patients operated on for traumatic and nontraumatic conditions. Fibrin glue was applied directly to penetrating pancreatic injuries. pancreatic suture and staple lines in patients treated by partial resection. and pancreaticointestinal anastomoses. Postoperatively. no patient developed pancreatic fistulas. pancreatic abscesses. or pseudocysts. Fibrin glue sealing of pancreatic injuries. resections. and anastomoses may aid in preventing fistulas after pancreatic surgery. Additional potential uses include the sealing of pancreatic biopsy sites and occlusion of the pancreatic duct in pancreatic transplantation.
Plasma concentrations of bupivacaine after supraclavicular brachial plexus blockade in patients with chronic renal failure, The plasma concentrations of bupivacaine and the latency and duration of anaesthesia after supraclavicular block with 30 ml of 0.5% bupivacaine were measured in 10 patients with chronic renal failure and in 10 patients with normal renal function. No significant difference was found between the two groups in respect of pharmacokinetic parameters. or in block latency or duration.
The Brain laryngeal mask. A comparative study with the nasal mask in paediatric dental outpatient anaesthesia, Fifty ASA grade 1 children. who presented for dental outpatient extraction were studied. They were randomly allocated to two groups after induction: group 1 had conventional nasal mask anaesthesia and group 2 anaesthesia with a laryngeal mask. Group 2 had fewer hypoxic episodes and significantly better arterial oxygen saturations (p less than 0.01). There was no difference between the groups as regards surgical access. difficulty of extraction or bleeding. The laryngeal mask appears to provide an alternative to conventional nasal mask anaesthesia. with better overall oxygenation and would seem particularly suitable for prolonged or difficult extractions.
Airway protection by the laryngeal mask. A barrier to dye placed in the pharynx, Methylene blue was placed in the pharynx of 64 patients undergoing anaesthesia with the laryngeal mask. No leak of dye into the larynx was detected on fibreoptic inspection of the inside of the mask in any subject. The use of the laryngeal mask as a means of protecting the airway during procedures such as minor nasal operations is therefore supported.
Pulse oximetry compared with Doppler ultrasound for assessment of collateral blood flow to the hand, Ischaemic injury to the hand after arterial cannulation is a rare but well documented complication and routine testing of the adequacy of collateral circulation is widely advocated. The widespread availability of the pulse oximeter in the operating theatre. its applicability in circumstances where the patient is unable to cooperate. and its dependence on pulsatile blood flow suggest that this device could potentially be usefully applied to the assessment of collateral blood flow. The reliability of the pulse oximeter to detect the presence or absence of collateral circulation was prospectively compared to Doppler ultrasound in 109 hands from 64 adult patients. Nine hands demonstrated inadequate ulnar collateral flow. one hand demonstrated inadequate radial collateral flow and a persistent median artery was found in one hand. In all patients the results of pulse oximeter testing (probe placed on the thumb correlated precisely with the results obtained with the Doppler device (probe located over the lateral aspect of the superficial palmar arch). These results demonstrate pulse oximetry to be a reliable method of assessing collateral blood flow to the hand before arterial cannulation.
Single operator cardiopulmonary resuscitation in ambulances. Which ventilation device, Cardiopulmonary resuscitation en route to hospital is performed by a single-handed operator in many British ambulances. In this study. three emergency ventilation devices. and mouth-to-mouth breathing. were compared for effectiveness in unintubated patients. Seventeen paramedics used each method on a Laerdal manikin in a randomised order. under identical conditions. Three experienced cardiopulmonary resuscitation instructors repeated the tests in a moving ambulance. There were significant differences in minute volume (p less than 0.01) and number of effective chest compressions (p less than 0.05); mouth-to-mouth breathing produced the best overall results and the simplest device was a close second. The value of automatic ventilators for single-operator cardiopulmonary resuscitation in unintubated patients is questioned.
Cyclopropane and the Datex Capnomac. Effect of cyclopropane on the single wavelength infrared measurement of volatile anaesthetic agents, We report the effect of cyclopropane used for induction of anaesthesia in children on the subsequent measurement of maintenance volatile anaesthetic agents with the single wavelength infrared absorption technique. After using cyclopropane to induce anaesthesia we have observed that falsely high readings of the expired maintenance agent occur for up to 60 minutes when using the Datex Capnomac. This is because of the effect of low concentrations of cyclopropane expired from the patient.
A coaxial technique for facilitating one-lung ventilation, A tube for bronchial intubation is described. A long (48 cm). small bore (5.0 mm internal diameter). cuffed. bronchial plastic tube is inserted coaxially within a large bore tracheal tube (10.0 mm) used for ventilation. The inner tube is designed primarily as a blocker to be inserted with a fibreoptic or optical bronchoscope. but can be effected blindly with a stylet. Several methods of inserting the inner tube and ensuring correct placement were used in 10 males undergoing thoracic surgery. If the bronchial cuff is inflated the tube can be used either as a blocker or as a conduit for suction and conventional and differential ventilatory techniques. Early clinical experience suggests that the technique is an alternative method of facilitating one-lung ventilation.
Wound infiltration of local anaesthetic after lower segment caesarean section, The analgesic efficacy of subcutaneous wound infiltration with 20 ml of 0.5% bupivacaine after elective lower segment section Caesarean section was studied in 28 patients in a double-blind randomised controlled manner using a patient-controlled analgesia system. The mean 24-hour morphine consumption of the placebo group and the bupivacaine group was similar (76 mg and 68 mg respectively). Analysis of the cumulative hourly morphine consumption failed to show any statistically significant differences between the groups. However. on a weight-adjusted basis statistically significant differences in morphine consumption were demonstrated. although these may not be clinically important. Subjective experiences of pain. nausea and drowsiness assessed by linear analogue scoring were similar in both groups.
Evaluation of the effect of perineuronal morphine on the quality of postoperative analgesia after axillary plexus block: a randomized double-blind study, A randomized. double-blind study was performed on 50 patients scheduled for elective hand and forearm surgery under axillary plexus block to evaluate the effect of perineuronal morphine on the quality of postoperative analgesia. Patients were divided into two groups. In group A (n = 25) 5 mg of preservative-free morphine in 1.0 mL of 0.9% saline was added to the local anesthetic solution (20 mL of 1% plain lignocaine. 20 mL of 0.5% plain bupivacaine). They also received an intramuscular placebo injection of 1.0 mL of 0.9% saline in the upper thigh. In group B (n = 25). 1.0 mL of 0.9% saline was added to the local anesthetic solution and patients received an intramuscular injection of 5 mg of preservative-free morphine in 1.0 mL of 0.9% saline in the thigh. The addition of morphine to the local anesthetic solution for the axillary block did not shorten the onset time of the block. improve the quality of postoperative pain relief. or provide longer lasting analgesia than that obtained with intramuscular morphine.
Renal artery imaging: a prospective comparison of intra-arterial digital subtraction angiography with conventional angiography, This study describes a systematic comparison of intra-arterial digital subtraction angiography (DSA) of the main renal arteries with conventional angiography (CA). the currently accepted "gold standard" for the diagnosis of renal artery stenosis. Twenty-five patients scheduled for abdominal aortography for various indications underwent first DSA then CA. The DSA and CA images were evaluated for number of renal arteries. presence and grade of renal artery stenosis. presence of post-stenotic dilation or fibromuscular changes. and diagnostic and pictorial adequacy of the images. DSA was found to be diagnostically adequate in 92% of cases. compared with 96% for CA. In evaluating significant main renal artery stenosis. which the authors assumed to be any stenosis greater than 50%. there were 10 such stenoses seen by CA. DSA also detected 10 cases. but there was 1 false positive and 1 false negative. yielding a sensitivity of 90% and a specificity of 98%. There was also close correlation of DSA and CA for the few cases of post-stenotic dilatation and fibromuscular dysplasia encountered. The authors conclude that DSA is an acceptable substitute for CA in the evaluation of patients for main renal artery stenosis.
The use of magnetic resonance imaging in the study of edema, A method of studying edema using magnetic resonance imaging (MRI) is presented. Three patients with lower extremity edema due to congestive heart failure were imaged with a 0.6 tesla system before and after diuresis. Edge detection algorithms were utilized to precisely outline regions of interest for quantification. Water and nonwater elements were separated within the region of interest to quantify water content. The results show that: (1) Edema can be quantified by use of MRI. (2) Subcutaneous edema is distributed along defined planes (ie. nonuniformly). (3) Increased water content is present not only in the subcutaneous tissue but also in deeper lying muscle.
The acute and chronic effects of G-lasing on femoral vein grafts in dogs, Each year. 5% of all coronary artery bypass operations are repeat procedures. and 15%-30% of coronary artery vein grafts occlude within the first eighteen months postoperatively. To evaluate the macroscopic and histologic effects of G-lasing on vein grafts and their patency. femoral veins were used to bypass bilaterally induced stenoses of femoral arteries in 10 dogs. The left vein grafts were G-lased with a 1.5 mm. hot-tipped argon laser at 5 watts for ninety seconds. while the right grafts were used as the controls. Acutely. each vein graft demonstrated no evidence of charring or perforation. The percentage of endothelium present in the G-lased vein grafts was consistently less than 5%. whereas the control vein grafts had an average of 70%. After ten weeks. the animals were sacrificed. and the vein grafts were evaluated for histologic changes and patency. There were no significant microscopic differences between the G-lased and control vein grafts. A statistically significant difference in graft patency was not achieved between G-Lased and control vein grafts at 10 weeks. but only a small number of grafts were studied. Further studies will be needed to evaluate the effects of G-lasing on the long-term patency of vein grafts.
Circadian blood pressure pattern in patients with treated hypertension and left ventricular hypertrophy, Left ventricular hypertrophy in hypertensives is an important determinant of prognosis. In the present study 45 patients with treated essential hypertension were divided into two groups: 23 patients had normal left ventricular dimension and 22 patients had echocardiographic signs of left ventricular hypertrophy (LVH). All patients were adequately treated during daytime. but ambulatory blood pressure monitoring showed a distinct abnormal pattern in the LVH group characterized by a lack of blood pressure reduction during the night; 16 of 22 patients with LVH had no blood pressure decline during the night. whereas 17 of 23 patients without hypertrophy showed this reduction (P less than 0.01). In conclusion. patients with hypertension and LVH often reveal a lack of blood pressure decline during the night. which may be the reason for the development of left ventricular hypertrophy (and thus should be managed by a different circadian blood pressure therapy) or which may be the consequence of progressive structural changes in the resistance vessels. along with the development of left ventricular hypertrophy. It is suggested that patients with hypertension and left ventricular hypertrophy should have ambulatory twenty-four hour blood pressure monitoring.
ACE inhibitors in the elderly, As the population with hypertension becomes older. it is important to determine the properties of angiotensin-converting enzyme (ACE) inhibitors in the elderly. The pharmacokinetics and efficacy of captopril. enalapril. and a new once-daily ACE inhibitor. quinapril for the treatment of hypertension in young and elderly patients are reviewed. and the safety profiles of these agents in young and elderly patients are discussed. Although the safely profile of all three drugs is very favorable. quinapril tended to be better tolerated by patients of all ages in comparative clinical trials.
Postphlebitic syndrome and general surgery: an epidemiologic investigation, Of a random sample comprising 4581 subjects from The Copenhagen County. 3608 (79%) attended an interview and a general health examination. The subjects were defined as suffering from subjective postphlebitic syndrome if they claimed of lower extremity pain or cramps at rest and from objective postphlebitic syndrome if varicose veins. edema. lower extremity ulcers. or skin changes were present. By means of logistic regression analysis. subjective postphlebitic syndrome was found independently associated with previous thromboembolism. obesity. increasing age. female sex. hormonal therapy. varicose veins. and previous major abdominal surgery. Objective postphlebitic syndrome was associated with previous thromboembolism. obesity. former birthgiving. and high social status. The findings support the view that subclinical deep venous thrombosis in connection with previous surgery may give rise to symptoms in the lower extremities.
Efficacy of ketanserin in the therapy of Raynaud's phenomenon: thermometric data, After a two-week washout (WO) period with placebo 1 capsule/bid. 12 patients suffering from stable Raynaud's phenomenon were treated with ketanserin (K) 40 mg/bid for fifteen days. Blood pressure. heart rate. and laboratory parameters were evaluated at the end of each period. Patients used diary cards to record the number. duration. and intensity of attacks. Computerized thermometry of the fingers was evaluated at basal temperature after acclimatization. 23 degrees C for thirty minutes; after cold test. 10 degrees C for five minutes; and after thermal recovery. 23 degrees C for eighteen minutes. Results were analyzed statistically by use of Student's t-test for paired data (p less than 0.05). No marked changes were observed in the symptoms of the attacks. but K proved effective in significantly reducing the number and duration of daily attacks and in promoting their spontaneous regression. Thermometry revealed a parallel increase in temperatures. particularly basal and recovery values. The data suggest increased flow and decreased vasospasm following 5-HT2 receptor blockade.
Transcutaneous electrical nerve stimulation (TENS) in Raynaud's phenomenon, Transcutaneous nerve stimulation (TENS) has been described as resulting in vasodilatation. The effect of 2 Hz TENS of the right hand during forty-five minutes on skin temperature and plethysmography of the third digit of both hands and feet and on transcutaneous oxygen tension (TcpO2) of the right hand was compared with that of a control study using indifferent stimulation of the iliopsoas region in 8 patients with primary Raynaud's phenomenon. After TENS a slight increase in skin temperature of both hands was found. while plethysmographic amplitude was increased in the contralateral hand only. No changes in TcpO2 occurred. The authors conclude that the observed small effects of TENS are of no clinical value in primary Raynaud's phenomenon.
Usefulness of leg-crossing for maintaining blood pressure in a sitting position in patients with orthostatic hypotension--case reports, The authors report a case with idiopathic orthostatic hypotension in which the patient prevents his blood pressure from falling to a symptomatic level by leg-crossing in a sitting position. Including 4 other patients with orthostatic hypotension and 5 normal subjects. their study found that the changes in blood pressure with leg-crossing inversely correlated with those induced by assuming seated posture from a supine position. Leg-crossing may. therefore. be one of the useful nonpharmacologic measures for maintaining blood pressure in a sitting position in patients with orthostatic hypotension.
Current status of mold immunotherapy, There is evidence to suggest that molds can cause IgE-mediated upper respiratory tract disorders and immunotherapy is efficacious in a select group. The environmental sampling studies show a remarkably small numbers of molds accounting for a majority of the mold load in various diverse locations. These are Cladosporium. Basidiospores. Aspergillus. and Alternaria-Penicillin families. Basidiospores have been underreported in the older studies because of difficulties in their identification. Whether the absolute mold level is the most important factor leading to IgE formation and induction of upper respiratory tract symptoms is uncertain. Certainly. the majority of the studies are based on the assumption that the absolute level of mold in the environment is the most important factor leading to the development of symptoms. but this is not based on strong evidence. A major problem in the majority of the studies is a lack of standardization of extracts which may lead to false negatives on skin testing and thus produce variable data in population evaluations comparing the prevalence of mold to its ability to induce IgE production and symptoms. The best current trials to document the efficacy of mold immunotherapy have been with the standardized Cladosporium extract. Unfortunately. these results cannot be extrapolated to the commercially available mold extracts available in the United States either for immunotherapy or for skin testing. These extracts are highly variable in their potency. prone to high false negative rates. and at best serve as poor skin testing reagents and possibly even worse immunotherapy reagents. Adequately standardized mold reagents are urgently needed to determine whether the Cladosporium data can be extrapolated to them in any meaningful way.
Measurement of leukotriene C4 and D4 in arterial blood of asthmatic patients during remission, We measured the amounts of leukotriene C4 and D4 in the arterial blood of asthmatic patients during remission and compared these with the amounts of leukotrienes in the arterial blood of asthmatic patients during acute asthma. which had been reported in our previous study. Leukotriene C4 and D4 was detected in five patients during remission at 50.68 +/- 8.28 and 36.68 +/- 17.31 pg/mL (mean +/- SD). respectively. In five control subjects. the amounts of leukotriene C4 and D4 were 78.22 +/- 34.65 and 55.06 +/- 13.54 pg/mL (mean +/- SD). respectively. As cited in our previous report. the amounts of leukotriene C4 and D4 in arterial blood of asthmatic patients during acute asthma were 523.33 +/- 737.06 and 495 +/- 304.48 pg/mL. Hence. there were no significant differences in the leukotriene C4 and D4 values between asthmatic patients during remission and control subjects. whereas there was a significant difference in the leukotriene D4 values between asthmatic patients during acute asthma and. asthmatic patients during remission or control subjects (P less than .01). In addition. the leukotriene C4 values in asthmatic patients during acute asthma were larger than in asthmatic patients during remission or control subjects without a significant difference. The amounts of leukotriene C4 and D4 in arterial blood of asthmatic patients may reflect the degree of severity of acute asthma.
Pharmacist advice to asthmatics regarding antihistamine use, Due to the frequency of asthmatics having concurrent allergic symptoms. patients may seek relief from antihistamines. which are currently labeled with warnings against their use in asthmatics. A survey was conducted in the Chicago area to evaluate the advice rendered by pharmacists regarding the use of antihistamines in asthmatics and their opinions about the current product labeling. Thirty percent of the surveys were returned. Nearly half (48%) of the surveyed pharmacists advise their asthmatic customers to avoid antihistamines and 75% of this group recommend avoidance because they believe antihistamines worsen asthmatic symptoms. despite the lack of sufficient clinical data to support this concern. Only 17% of pharmacists advise that antihistamines pose no problems for asthmatics. The latter group is the most aware that there is controversy surrounding the current labeling. Overall. half the pharmacists surveyed believe the current labeling is not appropriate for patients with asthma. Until the labeling is revised. physicians should be aware that pharmacists may advise their asthmatics against using antihistamines even though antihistamines should be only contraindicated in cases of proven adverse reactions.
Association between corticosteroids and psychologic change in hospitalized asthmatic children, Thirty-two children (mean age 14 years) with chronic. severe asthma were evaluated through the course of short-term prednisone "burst" treatment. At high steroid day (mean dose = 61.4 mg). the children reported more symptoms of anxiety and depression and demonstrated diminished verbal memory relative to low steroid day (mean dose = 6.97 mg). Order effects (evaluation at high steroid day first versus low steroid day first) were not significant for these steroid-sensitive variables. No dose-related changes emerged on measures of hyperactivity. attention. impulsivity. or fine motor control. Five subject variables were examined as potential risk factors. No association emerged between psychologic change scores and age. socioeconomic status. IQ. or asthma severity. Significant findings indicated that. as children increasingly demonstrated emotional difficulty or were from dysfunctional families. they were more likely to experience negative psychologic changes associated with high-dose steroids.
Antiinflammatory-antioxidant treatment with a methane sulfonanilide in allergen-induced asthma, Two groups of six asthmatic patients with biphasic bronchospastic response to inhaled Dermatophagoides pteronyssinus allergen extract were studied in a double-blind fashion. Early and late asthmatic reactions to allergen inhalation challenge were determined before and at the end of a 2-week treatment period with nimesulide (100 mg bid orally). a sulfonanilide with antioxidant properties. or placebo. Bronchial responsiveness to methacholine was evaluated 24 hours before and after allergen inhalation challenges. The dose of allergen causing EAR (15% decrease in FEV1) and the severity of LAR (maximum FEV1 fall) were similar before and at the end of the treatment period in both groups. In patients treated with nimesulide. bronchial responsiveness to methacholine was significantly increased after allergen inhalation challenge both before and at the end of the treatment period. These results do not support the hypothesis that the production of oxygen-free radicals plays a significant role in the development of bronchial hyperresponsiveness and late phase reaction to allergen in asthma.
A population-based study of Stevens-Johnson syndrome. Incidence and antecedent drug exposures, To determine the incidence of Stevens-Johnson syndrome. a descriptive epidemiology study was performed using computerized Medicaid billing data from 1980 to 1984 from the states of Michigan. Minnesota. and Florida. The ratio of persons hospitalized with a discharge diagnosis of erythema multiforme (ICD-9-CM code 695.1) to persons with any claim for medical service was first used as an estimate of the incidence rate of the disease. Then. since the ICD-9-CM code for erythema multiforme includes other illnesses in addition to Stevens-Johnson syndrome and because these illnesses are frequently misdiagnosed. the information provided by a review of medical records for a subset of cases of erythema multiforme was used to determine the proportion of patients with true Stevens-Johnson syndrome. The incidence rates of Stevens-Johnson syndrome were 7.1 (6.1 to 8.2). 2.6 (1.6 to 4.0). and 6.8 (4.3 to 10.3) per million per year in each state. respectively. Penicillins. especially aminopenicillins. were frequently used in the 19 patients judged to be true cases of Stevens-Johnson syndrome. In conclusion. Stevens-Johnson syndrome is a uncommon condition. The excess risk of Stevens-Johnson syndrome due to any drug must. therefore. be very low.
Immunoblot assay as an aid to the diagnoses of unclassified cases of pemphigus, With use of an immunoblot assay for both the normal human epidermal extracts and the bovine desmosome preparation. we investigated sera from 18 patients with pemphigus. who exhibited atypical clinical or histologic features and whose diagnoses were difficult to identify. Four sera yielded a 130-kd protein band in the epidermal extracts. which is characteristic of pemphigus vulgaris. A 150-kd protein was identified by nine sera in the epidermal extracts and/or the desmosome preparation. which is known as a pemphigus foliaceus antigen. Five sera demonstrated neither antigen. These results suggest that the immunoblot technique is useful to distinguish pemphigus vulgaris from pemphigus foliaceus and can be a good tool for the diagnosis of pemphigus. especially unclassified cases.
Disseminated hypopigmented keratoses, We present two cases of asymptomatic. widespread keratotic eruptions in young female patients. Clinically. the lesions are well-demarcated. small. hypopigmented. flat-topped papules occurring on the trunk and extremities in a uniform distribution. Skin biopsy specimens from one patient revealed hyperorthokeratosis. papillomatosis. and a normal amount of melanin. We suggest that this is a newly recognized dermatologic entity that may be descriptively termed disseminated hypopigmented keratoses. Disseminated hypopigmented keratoses may be distinguished by clinical and histologic criteria from similar keratotic eruptions. Since the lesions of disseminated hypopigmented keratoses are both inconspicuous and asymptomatic. it is likely that the disorder is more prevalent than our two cases would suggest.
T-cell subsets in drug-induced toxic epidermal necrolysis. Possible pathogenic mechanism induced by CD8-positive T cells, A patient with bromisovalum-induced toxic epidermal necrolysis showed pronounced delayed hypersensitivity to bromisovalum by patch testing. Biopsy specimens from the cutaneous lesion and the site of the positive patch test reaction were analyzed and compared immunohistologically. The findings were similar: most of the mononuclear cells disposed along the dermoepidermal junction and migrating into the epidermis were CD8-positive lymphocytes. whereas the dermal inflammatory infiltrates were composed predominantly of CD4-positive lymphocytes. This case showed the potential usefulness of patch testing in evaluating cases of toxic epidermal necrolysis. We believe that delayed hypersensitivity plays a crucial role in the development of drug-induced toxic epidermal necrolysis. Furthermore. potential effector cells with phenotypic characteristics of CD8-positive lymphocytes (suppressor/cytotoxic T cells) seem to represent important mediators of the epidermal damage of the cutaneous lesion in our case.
Localized vs generalized pyogenic granuloma. A clinicopathologic study, We herein report the unusual case of a previously healthy young man who had spontaneous development of multiple lobular capillary hemangiomata disseminated over the integument. Based on the observation that the single lesions exhibited (immuno)pathologic and ultrastructural features similar. if not identical. to those of late-stage pyogenic granulomas. we propose to nosologically include our patient's eruption within the disease spectrum of pyogenic granuloma. As opposed to the occurrence of localized forms of pyogenic granuloma. the disseminated eruption seen in our patient and in other patients whose cases are reported in the literature cannot be ascribed to physical trauma. As some of these latter patients suffered from an underlying malignant neoplasm. it is tempting to speculate that both exogenous (eg. trauma) and endogenous (eg. tumor cells) factors can lead to the release of mediators promoting the development of these vascular neoplasms.
The laboratory diagnosis of Lyme disease, Growing awareness of Lyme disease. caused by the tickborne spirochete Borrelia burgdorferi has led to a marked increase in laboratory procedures to help in its diagnosis. Despite the frequent ordering of serologic tests specific for Lyme disease. there remains confusion in the accurate interpretation of these tests. Because of the important cutaneous manifestations of B burgdorferi infection. dermatologists should understand the role of the laboratory in Borrelia-related conditions. This article reviews laboratory techniques available for the diagnosis of Lyme disease. The role of histologic findings and culture. the sensitivity. specificity. and reproducibility of commonly used serologic tests. the effects of disease duration and treatment on serologic results. and the future of laboratory diagnosis are described.
Race and weight change in US women: the roles of socioeconomic and marital status [published erratum appears in Am J Public Health 1991 Jun;81(6):688, BACKGROUND. The prevalence of overweight among Black women in the US is higher than among White women. but the causes are unknown. METHODS. We examined the weight change for 514 Black and 2.770 White women who entered the first Health and Nutrtion Examination Survey (1971-75) at ages 25-44 years and were weighed again a decade later. We used multivariate analyses to estimate the weight-change effectgs associated with race. family income. education. and marital change. RESULTS. After multiple adjustments. Black race. education below college level. and becoming married during the follow-up interval were each independently associated with an increased mean weight change. Using multivariate logistic analyses. Black race was not independently associated with an increased risk of major weight gain (change greater than or equal to +13 kg). but it was associated with a reduced likelihood of major weight loss (change less than or equal to -7 kg) (odds ratio - 0.64 [95% CI -0.41. 0.97])]. Very low family income was independently associated with the likelihood of both major weight gain (OR - 1.71 [95% CI - 1.15. 2.55]) and major weight loss (OR - 1.86 [95% CI - 1.18. 2.95]). CONCLUSIONS. Amont US women. Black race is independently associated with a reduced likelihood of major weight loss. but not with major weight gain. Women at greatest risk of weight gain are those with education below college level. those entering marriage. and those with very low family income.
Recent advances in the management of orbital trauma: reconstruction and complications [news, Orbital reconstruction has advanced significantly in the past decade. Proper reconstruction can be undertaken if the surgeon clearly understands the functional orbital anatomy and pathophysiology. the importance of "aggressive" radiographic evaluation. and is comfortable with deep orbital dissection with implant placement such that precise anatomic reconstruction of orbital defects is accomplished.
Standardizing neck dissection terminology. Official report of the Academy's Committee for Head and Neck Surgery and Oncology, The emergence of the multitude of modified techniques for neck dissection procedure has resulted in a nomenclature system that is nonuniform. To eliminate potential misinterpretation. overlap. and lack of standardization. the Academy's Committee for Head and Neck Surgery and Oncology. with input from the Education Committee of the American Society of Head and Neck Surgery. has developed a classification system for these procedures. This has now been adopted by the American Academy of Otolaryngology-Head and Neck Surgery. The classification is based on the following concepts: (1) radical neck dissection is the fundamental procedure with which all other neck dissections are compared. (2) modified radical neck dissection denotes preservation of one or more nonlymphatic structure(s). (3) selective neck dissection denotes preservation of one or more group(s) of lymph nodes. and (4) extended radical neck dissection denotes removal of one or more additional lymphatic and/or nonlymphatic structure(s). Adherence to the principles of this classification system to describe neck dissection techniques should provide an improved method of communication. Furthermore. the system provides a rational framework on which subsequent terminology can be added.
Magnetic resonance imaging vs palpation of cervical lymph node metastasis, In a series of 100 patients with head and neck carcinoma. the preoperative histopathologic findings of palpation and magnetic resonance imaging were compared with regard to both laterality and lymph node level (I through V). The overall error for palpation in detecting affected sides was 32%. Gadolinium-enhanced magnetic resonance images reliably upgraded 60% of the clinically negative necks. the overall error of magnetic resonance imaging being 16%. However. for both modalities. the sensitivity per level was too low to allow for selective neck dissections in case of only one positive level. These findings show that apart from primary tumor grading. magnetic resonance imaging can improve the preoperative grading of cervical lymph nodes. In selected cases. this may change the treatment plan to a "wait-and-see" policy or a more conservative type of neck dissection.
The JH/LVOH method in the quantification of aortic regurgitation: how the cardiac sonographer may avoid an important potential pitfall, Color flow Doppler allows for methods in which to quantitate the severity of valvular regurgitation. In particular. the regurgitant jet height/left ventricular outflow tract height (JH/LVOH) method of quantitating the severity of aortic regurgitation has been validated and is routinely used in the adult echocardiography laboratory. A potential pitfall exists in the measurement of the LVOH. This article points out this potential source of error and. in addition. proposes steps that may be taken by the cardiac sonographer to avoid this potential measurement pitfall.
The value of Doppler echocardiography in the management of patients with valvular heart disease: analysis of one year of clinical practice, Management recommendations based on Doppler echocardiographic examination and cardiac catheterization were compared in a prospective study in 100 consecutive patients who were admitted for evaluation and treatment of suspected valvular heart disease during 1988. Management recommendations were provided independently after both Doppler echocardiography and cardiac catheterization by different and blinded investigators. Criteria for severe (clinically significant) and moderate to mild (insignificant) valvular lesions and management recommendations were agreed on in advance. There was disagreement on the severity of aortic stenosis based on the aortic valve area and maximum instantaneous pressure gradient in 1 of 54 patients. which resulted in differing management recommendations. Mitral stenosis was severe (valve area less than or equal to 1 cm2) at Doppler echocardiography but not at cardiac catheterization in 5 of 14 patients. Because pulmonary artery pressure increase during exercise at cardiac catheterization also suggested severe obstruction. management recommendations were similar. There was a potentially significant disagreement on the severity of aortic regurgitation in 9 of 76 patients and of mitral regurgitation in 14 of 90 patients; however. this did not produce differing management recommendations because with most patients coexistent valvular lesions or an impaired ventricular function mainly determined the ultimate management decision. Although of good quality. Doppler echocardiographic examination was nonconclusive for clinical decision-making in 15% of the study population because of uncertainty about the severity of mitral regurgitation or aortic regurgitation or because of problems in assessing the degree of left ventricular dysfunction in patients with severe regurgitation.
Doppler estimation of changes in pulmonary artery pressure during hypoxic breathing, To assess the use of Doppler echocardiographic screening for abnormal pulmonary vasoreactivity. we measured pulmonary artery pressure in 10 adult patients and 11 normal subjects while recording Doppler right ventricular outflow acceleration time. pre-ejection period. and ejection time. In the normal subjects we also measured the changes in each parameter after 10 minutes of hypoxic breathing (FIO2 = 0.12). Mean pulmonary artery pressure increased by 39% during hypoxia (13 +/- 4.3 to 18 +/- 5.4 mm Hg). In the patients and normal subjects at rest. mean pulmonary artery-pressure correlated well with acceleration time (r = -0.84; standard error of the estimate. 6.6 mm Hg; p = 0.0001). Over the narrow range of mean pulmonary artery pressure in normal subjects at rest. mean pulmonary artery pressure did not correlate well with acceleration time. acceleration time/pre-ejection period. or acceleration time/right ventricular ejection time. However. changes in mean pulmonary artery pressure induced by hypoxic breathing did correlate with changes in acceleration time/right ventricular ejection time (r = 0.73; standard error of the estimate. 2.3 mm Hg; p = 0.01). Doppler ultrasound may offer a noninvasive means for detecting abnormal pulmonary vasoreactivity in asymptomatic individuals at risk for developing pulmonary hypertension.
Tricuspid annular motion, Triscupid annular motion is related to right ventricular systolic function in the same way mitral annulus motion is related to left ventricular function. Tricuspid annular excursion reflects the longitudinal motion of the right ventricle. and the systolic descent of the anulus correlates with systolic venous inflow to the right atrium. However. it has not been shown clearly how to reproducibly quantify this motion. Therefore we describe a method to measure triscuspid annular motion using two-dimensional oriented M-mode echocardiography from the apical view. We studied a group of 10 normal subjects (mean age. 28.7 years; range. 25 to 38 years) and a group of 29 patients (mean age. 57.2 years; range. 20 to 84 years) with disease of the left side of the heart but no evidence of involvement of the right side of the heart. In each subject. tricuspid and mitral annular motion were measured respectively at their lateral. septal or medial. anterior. and posterior margin points. The total tricuspid annular motion for normal subjects was. as follows: lateral. 24.9 +/- 3.5 mm; medial. 20.1 +/- 2.5 mm; anterior. 21.6 +/- 3.8 mm; and posterior. 22.3 +/- 2.3 mm. Interobserver and intraobserver variability was low. with a coefficient of variance for the different annular points ranging from 6.19% to 11.56% between observers and from 4.10% to 7.26% within observer. We conclude that it is possible to measure tricuspid annular motion with this method in a reproducible way and to use it as a diagnostic tool in evaluating function of the right side of the heart.
Right ventricular infarction: recognition and assessment of its hemodynamic significance by two-dimensional echocardiography, To evaluate the ability of two-dimensional echocardiographic indexes to determine the hemodynamic significance of the right ventricular infarction. 24 patients with electrocardiographic evidence of right ventricular infarction were studied. Hemodynamic significance was defined as a jugular venous pressure greater than 17 cm H2O or a right atrial pressure greater than 13 mm Hg. Patients with hemodynamically significant right ventricular infarctions (group I. n = 9) had a 56% incidence of hypotension (blood pressure less than 90 mm Hg) with a mean systolic blood pressure of 93 +/- 23 mm Hg. whereas patients with nonhemodynamically significant right ventricular infarctions (group II. n = 15) had no hypotension and a mean systolic blood pressure of 121 +/- 18 mm Hg (p less than 0.01). The ratio of right atrial to pulmonary capillary wedge pressure was 1.1 +/- 0.6 in group I and 0.6 +/- 0.2 in group II (p less than 0.05). Echocardiography demonstrated right ventricular free wall motion abnormalities in seven patients in group I and in 10 patients in group II. The descent of the right ventricular base was 0.7 +/- 0.2 cm in group I. 1.3 +/- 0.4 cm in group II. and 2.0 +/- 0.2 cm in a group of 20 normal control patients (p less than 0.001 for all comparisons). The respiratory caval index (percentage of collapse of the inferior vena cava with inspiration) was 22% +/- 11% in group I. 45% +/- 15% in group II. and 64% +/- 17% in the control subjects (p less than 0.05 for all comparisons).
The value of transesophageal echocardiography in children with congenital heart disease, With the use of dedicated pediatric single-plane probes. transesophageal echocardiography was performed prospectively in 102 children to determine the potential value of this new technique in the diagnosis (40 patients) and the follow-up of congenital heart disease (29 patients) and as a monitoring technique during the perioperative period or interventional cardiac catheterization (33 patients). The findings were correlated with precordial studies (102 patients). cardiac catheterization (82 patients). epicardial ultrasound findings (18 patients). or surgical inspection (34 patients). The age at investigation ranged from 2.5 months to 14.9 years (mean age. 5.2 years); weight ranged from 3.7 to 52 kg (mean weight. 19.1 kg). Additional information was obtained in 49 patients (48.4%) and was relevant for patient management in 21 patients (20.6%). Major areas of improved diagnostic insight included the following: (1) systemic and pulmonary venous return. (2) atrial morphology. (3) atrioventricular junction abnormalities. (4) left ventricular outflow tract disease. (5) atrial baffle function. and (6) the Fontan circulation. Inherent limitations were as follows: (1) the semiinvasive character of the procedure. (2) the need for heavy sedation or general anesthesia. and (3) the limited imaging planes provided. Transesophageal echocardiography in children can provide important additional diagnostic information on a wide spectrum of congenital heart lesions. The technique would appear to be a highly valuable adjunct to the diagnostic armentarium of the pediatric cardiologist.
Two-dimensional, spectral Doppler, and color flow imaging in adults with acquired and congenital cor triatriatum, Four adult patients ranging in age from 37 to 72 years with cor triatriatum diagnosed by two-dimensional. spectral Doppler. and color flow imaging are presented. including a previously undescribed "acquired" form after orthotopic heart transplantation and the oldest documented patient with cor triatriatum. The echocardiographic features of cor triatriatum with use of surface and transesophageal imaging are reviewed. with particular emphasis on the color flow findings. Color flow imaging has simplified the diagnosis and assessment of cor triatriatum. including the demonstration of other often-associated congenital cardiac anomalies.
Transesophageal echocardiography: detection of an acquired left ventricular-right atrial shunt, Communication between the left ventricle and right atrium has a reported prevalence of less than 1%. Acquired left ventricular--right atrial shunt is caused by chest trauma or valvular surgery. A case of acquired left ventricular--right atrial shunt after aortic valve surgery is reported. The detection was possible by use of echo-Doppler. color flow imaging. and transesophageal echocardiography. Combined use of these modalities and multiple transducer positions when transthoracic echocardiography is used are recommended to make the diagnosis.
Doppler echocardiography for rejection surveillance in the cardiac allograft recipient, Echocardiography is noninvasive. allows real-time visualization of the heart. and can be performed serially without harmful biologic effects. It is also relatively inexpensive compared with other diagnostic modalities used for cardiac transplant rejection surveillance. such as cardiac biopsy. computed tomography. and magnetic resonance imaging. It is free of the potential complications associated with cardiac biopsy. such as accidental disruption of cardiac valves or chordae tendineae. ventricular septal perforation. introduction of bacteria. and the difficulty of obtaining adequate sampling for effective diagnosis as a result of formation of scar tissue. Unlike biopsy. echocardiography does not cause the patient anxiety and discomfort or use many physician and instrument or laboratory resources. Because the results of echocardiography are available within minutes compared with the hours usually needed for biopsy results. it allows prompt decisions regarding patient clinical care and treatment. In our work to date. echocardiography has not replaced the cardiac biopsy in surveillance of rejection in the cardiac transplant patient. but rather has become a useful adjunct to it. When echocardiographic findings indicate changes characteristic of rejection. biopsies are performed earlier. leading to earlier diagnosis and treatment. Furthermore. when echocardiographic findings are stable and negative for rejection. the number of routine cardiac biopsies performed can be reduced. This article discusses the use of echocardiography in surveillance of the cardiac transplant patient and the ability of echocardiography to augment the biopsy and clinical regimens in assessing cardiac allograft rejection.
Excimer laser treatment of corneal surface pathology: a laboratory and clinical study, The argon fluoride excimer laser emits radiation in the far ultraviolet part of the electromagnetic spectrum (193 nm). Each photon has high individual energy. Exposure of materials or tissues with peak absorption around 193 nm results in removal of surface layers (photoablation) with extremely high precision and minimal damage to non-irradiated areas. This precision is confirmed in a series of experiments on cadaver eyes and the treatment of 25 eyes with anterior corneal disease (follow-up 6 to 30 months). Multiple zone excimer laser superficial keratectomy is considered the treatment of choice for rough. painful corneal surfaces. All patients in this group were pain-free postoperatively. Where good visual potential exists. ablation of a single axial zone is recommended and results in improved visual acuity and reduction of glare. A hyperopic shift was noted in this group.
Visual assessment of infants: vernier targets for the Catford drum, Targets comprising a horizontal black line 5' thick offset by 1' were printed on strips to stick to the drums of the Catford Visual Acuity Apparatus. The 'vernier' targets so produced corresponded to the different sizes of Snellen letters from 6/6 to 2/60 when presented at 50 cm. Twenty-five children between the ages of 3 and 12 years with known amblyopia (mostly strabismic) were tested in a double blind trial to compare the visibility of the vernier targets with subjective Snellen acuity. All vernier results. both for better and amblyopic eye. were within one line of Snellen acuity. One hundred and twenty normal preverbal infants with normal eyes under the age of 2 1/2 years were tested with the vernier strips. Normal infants under the age of 6 months recorded a vision of 6/60-2/60; normal infants aged 6 to 12 months recorded 6/24-6/36. and infants between the ages of 1 and 2 1/2 years recorded 6/12-6/18.
Does the pilocarpine phenylephrine provocative test help in the management of acute and subacute angle closure glaucoma, The pilocarpine phenylephrine provocative test (PPPT) has been described as a highly sensitive method to identify eyes suffering from or at risk of angle closure glaucoma (ACG). This paper reports on average 10 years follow-up of the outcome of cases of primary acute ACG and subacute ACG in which the management was determined by the result of the PPPT--a positive result indicating the need for a peripheral iridectomy. a negative result conservative treatment. In spite of a negative PPPT the fellow eyes of cases of acute ACG treated conservatively had a high rate (40%) of development of ACG. Similarly. in eyes with a history of subacute ACG with a negative PPPT. ACG developed at some stage during the follow-up in 60%. Peripheral iridectomy alone resulted in normal intraocular pressure in 63% of eyes that had suffered an attack of acute ACG. In hypertensive eyes that presented with subacute ACG. however. only one eye became normotensive following peripheral iridectomy alone. In the subacute ACG group a positive PPPT was closely related to the presence of glaucomatous optic disc damage. These results indicate that the PPPT lacks sensitivity in detecting eyes at risk of angle closure glaucoma. and a positive result is likely in eyes with damaged outflow that will not respond to peripheral iridectomy.
Medical canthal resection: an effective long-term cure for medial ectropion, The results of 37 medial canthal resection procedures performed for the correction of severe paralytic or involutional medial ectropion are presented with an average follow-up of 5.4 years. Epiphora was improved in 33 out of the 37 cases and all but one patient had an anatomically improved lid-globe apposition. medial canthal angle. and posterofixation of the medial canthus. These results confirmed the long-term value of the operation.
Potential availability of cadaver organs for transplantation, OBJECTIVE--To determine the potential number of cadaver kidney donors by applying defined donor criteria to people dying in hospital. DESIGN--Prospective study of all deaths occurring in 21 hospitals from 1 September 1988 to 31 August 1989. Questionnaires were administered to medical and nursing staff and families of potential donors aged 1-69. SETTING--Acute care hospitals in Gwent. South Glamorgan. Mid Glamorgan. West Glamorgan. Pembrokeshire. and East Dyfed health authorities. serving a population of 2.2 million. MAIN OUTCOME MEASURES--Cause of death. age. ventilation at time of death. diagnosis of brain death. and consideration of consent. RESULTS--Adequate data were available for 9840 of 10.095 hospital deaths (97.5% coverage). 188 patients aged 0-69 were identified as potential organ donors (widest definition). and of these 108 died without being ventilated at the time of death. Tests of brain stem death were formally completed in 57 cases. and organ donation was considered by the families of 47 of these potential donors. 26 patients became organ donors. Patients aged 50-69 with stroke were less likely to be ventilated than those aged less than or equal to 49 (21/96 v 24/34). Families of potential donors aged 20-39 were least likely to give permission. CONCLUSIONS--The supply of donor organs (specifically kidneys) could be increased by altering the management of patients aged 50-69 dying of severe cerebrovascular disease in general medical wards. in particular by increasing the proportion ventilated. The ethics of elective ventilation for the purposes of organ donation require discussion.
Pitfalls of bone scintigraphy in suspected hip fractures, In a review of 2617 patients who were admitted with a suspected fractured neck of femur over a period of five years. 213 had normal or equivocal plain radiographs. and were subsequently investigated by bone scintigraphy. Normal scans were obtained in 127 (60%) cases. Of the remaining 86 cases. 82 (38%) were reported to show fractures of the proximal femur. three showed pubic ramus fractures. and one acetabular fracture was demonstrated. Review and follow-up has revealed eight false positive and two false negative scans. The various factors accounting for these errors are considered. and the clinical implications discussed. Careful analysis of accompanying plain radiographs is stressed when interpreting scintigrams.
Measurement of tissue perfusion by dynamic computed tomography, A method for quantifying tissue perfusion by dynamic computed tomography (CT) is described. By applying a nuclear medicine data processing technique to time-density data from a single-location dynamic CT sequence. tissue perfusion can be determined from the maximum gradient of the tissue time-density curve divided by the peak enhancement of the aorta. Using this method. splenic perfusion was measured at 1.2 ml min-1 ml-1. normal renal cortical perfusion at 2.5 ml min-1 ml-1 and normal renal medullary perfusion at 1.1 ml min-1 ml-1. Changes in cortical and medullary perfusion in renal failure and hypertension were demonstrated. The ability of dynamic CT to provide quantitative functional information is not well recognized and is potentially of value when studying structures. such as the renal cortex and medulla. that cannot be anatomically resolved by standard functional imaging techniques.
Is the coned lateral lumbosacral junction radiograph necessary for radiological diagnosis, The lumbar spine radiographs of 400 orthopaedic outpatients were reviewed to determine if the absence of the coned lateral lumbosacral junction radiograph would lead to a loss in diagnostic accuracy. In 84 (21%) patients the antero-posterior and lateral lumbar spine radiographs failed to visualize adequately the lumbosacral junction. In these patients the coned lateral lumbosacral junction radiograph resulted in 17 (4.5%) diagnoses which would otherwise have been missed. The diagnoses were spondylosis (11). spondylolisthesis (3). spondylolysis (1). Paget's disease (1) and infection (1). Absence of the coned lateral lumbosacral radiograph will result in inadequate demonstration of the lumbosacral junction and a loss in diagnostic accuracy.
Implications of the uptake of 131I-radiolabelled meta-iodobenzylguanidine (mIBG) for the targeted radiotherapy of neuroblastoma, Selective uptake of radiolabelled meta-iodobenzylguanidine (mIBG) in neuroblastoma provides a possible approach to biologically targeted radiotherapy of this disease. A mathematical model was used to predict absorbed doses to tumours of varying size from therapeutic 131I-mIBG. based on measurements of 125I-mIBG uptake in surgically excised tumours from six patients. Two size categories of tumour target were considered: bulk tumour and microscopic disease. The predicted absorbed doses were compared with doses calculated to achieve a 50% probability of tumour cure. The analysis shows that the probability of tumour cure depends strongly on mIBG uptake. effective half-life of mIBG in tumour and tumour diameter. Small microtumours may be relatively resistant to mIBG treatment owing to the limited absorption of 131I beta-energy. The product of patient mass and percentage uptake per unit mass of tumour may be a useful indicator of therapeutic outcome when targeted radiotherapy is used for the treatment of paediatric tumours.
Perioperative respiratory compliance in children undergoing repair of atrial septal defects, Children with atrial septal defects (ASD) have less respiratory compliance (Crs) than normal cohorts. There could be implications for anaesthetic management if these children also have decreased compliance during anaesthesia. To examine the changes in Crs before. during and following surgical correction of the atrial defect. Crs was measured in 29 infants and children. 15 undergoing correction of secundum type atrial septal defects. and a group of 14 children of similar weight undergoing non-thoracic surgery. During sedation. Crs was measured using the single breath technique (SBT) and during anaesthesia. both before and after the surgical procedure. an inflation technique was applied to determine Crs. To investigate the aetiology of the difference in Crs. the pulmonary to systemic flow ratio (Qp:Qs) was determined using echocardiography during sedation in the ASD patients. During sedation. Crs in the ASD group was 52.7 +/- 19.5% less than in the control group. The slope of the line of regression of Crs vs height for the ASD group was significantly less (P less than 0.05) than that of the control group during sedation. However. during anaesthesia. Crs in the ASD group was not significantly different from the control group either before or after surgery. The per cent decrease in Crs during sedation in the children with ASD. in comparison with the control group. did not correlate with the Qp:Qs ratio of the ASD group (r2 = 0.012.NS). We conclude that. in spite of lower Crs during sedation. infants and children with ASD do not have lower Crs during anaesthesia and cardiopulmonary bypass than normal controls undergoing non-thoracic surgery.
Continuous infusion epidural analgesia for obstetrics: bupivacaine versus bupivacaine-fentanyl mixture, Continuous infusion epidural analgesia (CIEA) using a mixture of bupivacaine and fentanyl was evaluated in this randomized. double-blind study involving 75 nulliparous women by comparing the mixture (Group I. Bupivacaine 0.125% and fentanyl 4 micrograms.ml-1 -24 patients) with two concentrations of bupivacaine alone (Group II. bupivacaine 0.25% - 24 patients; and Group III. bupivacaine 0.125% - 27 patients). Epidural anaesthesia was established in Group I with 6 ml 0.125% bupivacaine with fentanyl 50 micrograms and in both Groups II and III with 6 ml 0.25% bupivacaine. In the women whose pain score (Visual Analogue Scale) decreased by at least 50% within 15 min. CIEA was given until delivery. The initial infusion rate in all three groups was set at 7 ml.hr-1. but was decreased in the event of motor block or excessive sensory level. For inadequate analgesia. bupivacaine 0.25% in 3 ml supplements was given every 30 min. as required. During the first stage of labour. 88% of women in Group I reported excellent or good analgesia compared with 92% of women in Group II (NS) and with 59% in Group III (P less than 0.05). The proportion of women reporting excellent/good analgesia during the second stage was approximately 65% in all three groups. The total cumulative dose of bupivacaine in Group I was 54 +/- 36 mg. compared with 107 +/- 47 mg for Group II (P = 0.001). and 71 +/- 41 mg for Group III (NS). Group I patients required less supplementation with bupivacaine than either Group II or III patients during the first stage but only with Group III patients during the second stage.
Haemodynamic interactions of muscle relaxants and sufentanil in coronary artery surgery, The haemodynamic interactions between sufentanil (S) and muscle relaxants (MR) were studied in 40 ASA physical status III or IV patients (four groups of ten) scheduled for coronary artery bypass grafting (ABG). Group I received pancuronium (P) 0.08 mg.kg-1. Group II received vecuronium (V) 0.1 mg.kg-1. Group III received atracurium (A) 0.5 mg.kg-1 and Group IV metocurine 0.1 mg.kg-1 plus pancuronium 0.02 mg.kg-1 (M-P). Sufentanil. 20 micrograms.kg-1 was administered before sternotomy. 10 micrograms.kg-1 being injected before tracheal intubation and 10 micrograms.kg-1 afterwards. Heart rate (HR). ECG leadII and V5. systolic. diastolic and mean arterial and pulmonary blood pressures. central venous pressure (CVP) and pulmonary capillary wedge pressure (W) were measured and recorded at the time of seven strategic events between the pre-induction of anaesthesia period and sternotomy. Cardiac output (CO) and systemic vascular resistances (SVR) were also measured before induction of anaesthesia and after the administration of S 10 micrograms.kg-1 plus the MR. The HR decreased from baseline values in the post-tracheal intubation period in all groups except in P group. The mean arterial pressure also decreased significantly in all groups except in the P group. The CO did not change from baseline values but SVR decreased in all groups. There was no evidence of new myocardial ischaemia according to the ECG monitoring and there was no significant difference in the HR changes between patients who had or who had not received beta-blockers in any group. We conclude that within the present study conditions and design. HR and blood pressure changed least with pancuronium.
Tussive effect of a fentanyl bolus, The aim of this study was to investigate the incidence of pre-induction coughing. after an iv bolus of fentanyl. The study sample was 250 ASA physical status I-II patients. scheduled for various elective surgical procedures. The first 100 were randomly allocated to receive 1.5 micrograms.kg-1 fentanyl via a peripheral venous cannula (Group 1). or an equivalent volume of saline (Group 2). Twenty-eight per cent of patients who received fentanyl. but none given saline. coughed within one minute (P less than 0.0001). The second 150 patients were then randomly assigned to three equal pretreatment groups. Group 3 received 0.01 mg.kg-1 atropine iv one minute before fentanyl. Groups 4 and 5 received 0.2 mg.kg-1 morphine im. and 7.5 mg midazolam po. respectively. one hour before fentanyl. Thirty per cent of patients in Group 3. 6% in Group 4. and 40% in Group 5. had a cough response to fentanyl. Fentanyl. when given through a peripheral cannula. provoked cough in a considerable proportion of patients. This was not altered by premedication with atropine or midazolam. but was reduced after morphine (P less than 0.01). Coughing upon induction of anaesthesia is undesirable in some patients. and stimulation of cough by fentanyl in unpremedicated patients may be of clinical importance.
Central venous air embolism without a catheter, Venous air embolism is a well-recognized complication of central venous catheterization. Although previous reports have documented venous air embolism occurring in a number of ways. including during initial catheterization. when catheters crack or are disconnected. and after catheter removal. no reports mention the possibility of air embolism occurring when a guide wire without a catheter was in place. A patient is presented who displayed signs and symptoms of venous air embolism (tachypnoea. chest pain. and arterial hypoxaemia) during central venous catheter manipulation while a guide wire alone was in place. Pulse oximetry was used to detect hypoxaemia and suggest an aetiology for the patient's clinical symptoms. It is postulated that a previously described gasp reflex or some sort of sustained negative pressure manoeuvre caused venous air embolism around the guide wire and accounted for the patient's signs and symptoms. During central venous catheter placement. a high index of suspicion for venous air embolism should be maintained. pulse oximetry should be used. the skin entrance site should be kept covered by an occlusive dressing. and the patient should be positioned head-down.
Relationships between block-of-twitch and train-of-four fade in the mouse phrenic nerve-diaphragm preparation, The relationships between the block-of-twitch and train-of-four fade in the presence of nondepolarizing neuromuscular blocking drugs (d-tubocurarine. vecuronium and pancuronium) were examined in vitro by measuring the contractile tension from mouse phrenic nerve-diaphragm preparations. The slope of the block/fade relationship differed between onset of and recovery from neuromuscular block following single doses of d-tubocurarine. vecuronium or pancuronium. Decreasing the dose of d-tubocurarine or using a divided dose technique to accelerate onset (i.e.. priming) increased the amount of fade for a given amount of block. In addition. the block/fade relationships for cumulative dosing and sequential dilution were the same when measurements were made at steady-state for several doses. It is concluded that the block/fade relationship in the mouse phrenic nerve-diaphragm preparation is variable. and is related to the time course of the neuromuscular block. In addition. the block/fade relationships for d-tubocurarine. vecuronium and pancuronium did not differ when determined at steady-state.
Intraocular pressure in anaesthetized dogs given flumazenil with and without prior administration of midazolam, This study examined the effect of flumazenil. a benzodiazepine antagonist. on aqueous humour pressure in dogs receiving either midazolam or no benzodiazepine. Twenty-four halothane-anaesthetized dogs were assigned to one of four groups. Group I (n = 6) received saline iv at 0. 45 and 90 min. Group 2 (n = 6) received saline at 0 min. flumazenil 0.0025 mg.kg-1 iv at 45 min and flumazenil 0.16 mg.kg-1 at 90 min. Group 3 (n = 6) received midazolam 1.6 mg.kg-1 at 0 min followed by continuous iv infusion (1.25 mg.kg-1.hr-1). Flumazenil was given at 45 and 90 min as in Group 2. In Group 4 (n = 6) aqueous humour pressure was elevated to about 35 mmHg then midazolam and flumazenil were given as in Group 3. Aqueous humour pressure was determined using a 30-gauge needle placed into the anterior chamber. Saline or flumazenil produced no change in aqueous humour pressure in Groups 1 and 2. In Groups 3 and 4. midazolam decreased aqueous humour pressure from 18 +/- 2 mmHg (mean +/- SD) to 14 +/- 3 mmHg (P less than 0.001) and from 34 +/- 5 mmHg to 31 +/- 3 mmHg (P less than 0.01) respectively. Flumazenil given during continuous infusion of midazolam produced increases of aqueous humour pressure of 2 +/- 1 (P less than 0.01) to 5 +/- 2 mmHg (P less than 0.01) that lasted less than or equal to 12 min. It is concluded that at both normal and elevated aqueous humour pressures flumazenil produces statistically significant but clinically unimportant increases of aqueous humour pressure in anaesthetized dogs receiving midazolam. but not in dogs given no benzodiazepine.
Paradoxically decreased aortic wall stiffness in response to vitamin D3-induced calcinosis. A biphasic analysis of segmental elastic properties in conscious dogs, We studied the aortic elastic behavior in response to vitamin D3-induced accelerated calcinosis in conscious dogs chronically instrumented with a pressure microtransducer and a pair of ultrasonic diameter dimension gauges in the upper descending thoracic aorta. The two functional phases of the elastic segmental properties of the aorta in vivo were discriminated by computation on a beat-by-beat basis from the phasic pressure-diameter (P-D) hysteresis loops in basal conditions and during the transient state of a wide range of pressures obtained mechanically (aortic occlusion) or pharmacologically (angiotensin bolus). The overall P-D curve formed by all P-D hysteresis loops was comprised of two linear relations according to a model that assumes that only elastin is stretched at lower pressures. whereas both elastin and collagen are stretched at higher pressures. The slope of the first linear portion of the P-D curve was considered as the elastin P-D elastic modulus. and the slope of the curve obtained by subtraction between the P-D curve and the extrapolation of the elastin straight line was assumed to be the collagen P-D elastic modulus. After vitamin D3-induced calcinosis. the elastin elastic modulus was unaffected. whereas the collagen elastic modulus decreased significantly during occlusion maneuvers (58.6%. p less than 0.01) and during bolus injections of angiotensin (37.2%. p less than 0.05). The collagen elastic modulus correlated with the serum calcium concentration (r = -0.65. p less than 0.001) and with the aortic pulse pressure (r = 0.51. p less than 0.01). and this relation persisted at constant heart rate. Histopathologic analysis evidenced calcium-depositing elastic lamina. focal disappearance of collagen. and rupture of elastic fibers. The present study shows that accelerated. severe. experimental calcinosis-inducing calcium deposition inside the large artery walls is accompanied by a clear-cut paradoxical reduction in arterial rigidity that is mainly due to functional and structural modification of collagen elasticity.
Effect of digitalis glycosides on norepinephrine release in the heart. Dual mechanism of action, The effect of ouabain on exocytotic and nonexocytotic norepinephrine release was investigated in perfused rat and guinea pig hearts. The overflow of endogenous norepinephrine and its neuronal metabolite 3.4-dihydroxyphenylethyleneglycol (DOPEG) was determined by high-pressure liquid chromatography. DOPEG served as the indicator of free axoplasmic norepinephrine concentrations. The overflow of the norepinephrine cotransmitter neuropeptide Y (NPY) was determined by radioimmunoassay and NPY was used as marker for exocytotic release. Electrical stimulation of the left stellate ganglion resulted in exocytotic norepinephrine release in rat and guinea pig hearts. Ouabain caused an increase in stimulation-induced norepinephrine overflow from rat and guinea pig hearts by 40%. However. overflow of NPY was decreased by 40%. indicating a reduced exocytosis rate. Ouabain increased both norepinephrine and NPY overflow. suggesting enhancement of exocytosis. when neuronal catecholamine uptake (uptake1) was blocked by desipramine or when presynaptic alpha 2-adrenoceptors were inhibited by yohimbine. The results demonstrate an interaction of ouabain with both calcium-dependent exocytosis and uptake1 of norepinephrine. Under calcium-free conditions. ouabain or potassium-free perfusate resulted in norepinephrine release from hearts when the axoplasmic norepinephrine concentration was elevated by the reserpinelike agent Ro 4-1284. This release was independent from neural activity. not accompanied by NPY overflow. and suppressed by the uptake1 blocker desipramine. These findings are in keeping with carrier-mediated nonexocytotic norepinephrine release that is caused by reversal of the transport direction of the uptake1 carrier. During myocardial ischemia nonexocytotic norepinephrine release was accelerated and enhanced by inhibition of Na+.K(+)-ATPase before ischemia. This study demonstrates the potential of digitalis glycosides to interact both with transmitter exocytosis and with the neuronal catecholamine transport system by Na+.K(+)-ATPase inhibition. Interaction with the catecholamine transport system involves both inhibition of norepinephrine inward transport and induction of norepinephrine outward transport. resulting in nonexocytotic norepinephrine release.
Effect of increasing degrees of ischemic injury on myocardial oxidative metabolism early after reperfusion in isolated rat hearts, The present investigation studied the effect of increasing severities of ischemic injury on recovery of oxidative metabolism after reperfusion in isolated rat hearts perfused retrogradely with erythrocyte-containing medium. Hearts subjected to 60 minutes of low-flow ischemia (5% of control perfusion) exhibited delayed but sustained recovery of left ventricular pressure development during reperfusion and preservation of ultrastructure delineated with electron microscopy. Immediately after reperfusion. myocardial oxygen consumption returned to control values. well before left ventricular pressure development recovered. Early after reperfusion release of 14CO2 from [1-14C]palmitate was reduced (-53%. p less than 0.01). Conversely. release of 14CO2 from [U-14C]glucose was increased (+131%. p less than 0.05). After 60 minutes of reperfusion 14CO2 release had completely returned to normal for both labeled substrates. Pulse-labeling experiments indicated that during transient depression of [1-14C]palmitate oxidation more tracer was incorporated into myocardial lipid esters. primarily triglycerides. In contrast to hearts subjected to low-flow ischemia. hearts subjected to 60 minutes of no-flow ischemia exhibited poor recovery of contractile function during the reperfusion period. Electron microscopic examination of reperfused hearts showed advanced myocyte damage consistent with irreversible injury. Interestingly. myocardial oxygen consumption in this group also recovered to control values. The substrate pattern during the early reperfusion period was similar to that of hearts subjected to low-flow ischemia. After 120 minutes of no-flow ischemia. recovery of oxidative metabolism was virtually absent. The results indicate a pronounced dissociation between recovery of oxidative metabolism and of contractile function in reperfused myocardium. The oxidative metabolic rate was disproportionately high compared with contractile function. not only in reversibly "stunned" hearts. but also in severely damaged hearts exhibiting signs of irreversible injury.
Role of cardiac ATP-regulated potassium channels in differential responses of endocardial and epicardial cells to ischemia, Epicardial cells are more susceptible to the electrophysiological effects of ischemia than are endocardial cells. To explore the ionic basis for the differential electrophysiological responses to ischemia at the two sites. we used patch-clamp techniques to study the effects of ATP depletion on action potential duration and the ability of ATP-regulated K+ channels in single cells isolated from feline left ventricular endocardial and epicardial surfaces. During ATP depletion by treatment with 1 mM cyanide (CN-). shortening of action potential durations was significantly greater in epicardial cells than in endocardial cells. Thirty minutes after initiating exposure to 1 mM CN-. action potential duration at 90% repolarization was reduced to 0.70 +/- 0.12 of the control value for endocardial cells versus 0.39 +/- 0.18 for epicardial cells (p less than 0.01). and action potential duration at 20% repolarization was reduced to 0.72 +/- 0.13 for endocardial cells versus 0.12 +/- 0.09 for epicardial cells (p less than 0.01). In both endocardial and epicardial cells. the shortening of action potential by CN- treatment was partially reversed by 0.3 microM glibenclamide; the magnitude of reversal. however. was much greater in epicardial cells. After exposure to 1 mM CN-. the activity of ATP-regulated K+ channels in cell-attached membrane patches was significantly greater in epicardial cells than in endocardial cells. To study the dose-response relation between ATP concentration and open-state probability of the channels. intracellular surfaces of inside-out membrane patches containing ATP-regulated K+ channels were exposed to various concentrations of ATP (10-1.000 microM). The concentration of ATP that produced half-maximal inhibition of the channel was 23.6 +/- 21.9 microM in endocardial cells and 97.6 +/- 48.1 microM in epicardial cells (p less than 0.01). These data indicate that ATP-regulated K+ channels are activated by a smaller reduction in intracellular ATP in epicardial cells than in endocardial cells. The differential ATP sensitivity of ATP-regulated K+ channels in endocardial and epicardial cells may be responsible for the differential shortening in action potentials during ischemia at the two sites.
Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart, The vertebrate heart contains two myosin heavy chain isoforms. alpha and beta. which are differentially expressed. To establish a murine model for gene-targeting experiments. we defined the precise temporal expression of the myosin isoforms during cardiogenesis and obtained quantitative measurements of cardiac performance. The relative levels of the alpha- and beta-cardiac transcripts were determined by isolating the RNA from the hearts of CD-1 mice during development and hybridizing the preparations to probes that detect specifically the alpha- or beta-cardiac myosin heavy chain mRNAs. The data indicate that. although both isoforms are present from the onset of cardiogenesis. the beta-isoform predominates during embryogenesis and fetal development. This relation is reversed after the first day of life with a significant drop in the absolute transcript levels during the switch; and alpha/beta ratio of 16:1 is maintained in the neonate. and the relatively high levels of the alpha-transcript remain throughout the adult stages. To be able to make functional comparisons between normal and transgenic mice. we obtained indexes of myocardial function in isolated retrogradely perfused and in work-performing heart preparations in normal and hypodynamic mouse hearts. We found that the physiology of the mouse heart is similar to the rat heart in that we observed a positive staircase in the force-frequency relation of the mouse Langendorff preparation. We also saw contractile responses of more than twice control induced by paired stimulation and persistent postextrasystolic potentiation. As is the case for the rat. in the work-performing mouse heart. afterload (Starling resistance. pressure) changes produced a steeper Starling function curve than did changes in preload (volume. venous return).
Simulation of high-resolution QRS complex using a ventricular model with a fractal conduction system. Effects of ischemia on high-frequency QRS potentials, Recent studies have analyzed the high-fidelity surface electrocardiographic signal. and efforts have been made to increase the diagnostic sensitivity of the electrocardiogram by observing its high-frequency components. It was found that the high-frequency (150-250-Hz) electrocardiogram appears to detect evidence of transient ischemia with greater sensitivity than visual inspection of the surface electrocardiogram. A finite-element three-dimensional model of the ventricles with a self-similar (fractal) conduction system has been introduced as a bridge to the understanding of electrocardiographic phenomena related to high-frequency potentials. The model was activated. and the dipole potential generated by adjacent activated and resting cells was calculated to obtain a high-resolution QRS complex. Normal and ischemic activation processes was stimulated by regional reduction in conduction velocity. It was found that although the resulted low-frequency QRS complex was not significantly altered from normal conditions. the high-frequency components exhibited morphological changes similar to the ones observed during animal experiments and human studies. Based on the results obtained from the model. it can be concluded that these morphological changes can be attributed to a slowing of conduction velocity in the region of ischemia and that the model is adequate for meeting the challenges imposed by the requirements of high-frequency methods applied in clinical cardiology.
Prolongation of repolarization time by electric field stimulation with monophasic and biphasic shocks in open-chest dogs, Recent studies suggest that 1) electrically induced fibrillation and defibrillation involve prolongation of refractoriness by the shock in addition to stimulation and 2) biphasic waveforms are more efficient for defibrillation than are comparable monophasic waveforms. The purpose of this study was to compare prolongation of action potential duration at 50% repolarization by monophasic and biphasic shocks during paced rhythm. A floating glass microelectrode was used to record intracellularly from the anterior right ventricular epicardium in seven open-chest dogs. After 10 S1 beats paced at an interval of 350 msec. 5-msec and 2.5-msec monophasic shocks and biphasic shocks. with each phase of 2.5 msec. were given via mesh electrodes on either side of the microelectrode. The shock strength was adjusted so that the shock field. measured from eight extracellular electrodes encircling the microelectrode. was about 5 V/cm. Monophasic and biphasic S2 shocks were given starting with an S1-S2 interval of 120 msec. which was increased in 5-msec steps until an action potential was produced by the S2 shock. Both monophasic and biphasic 5 V/cm shock fields caused significant prolongation of action potential duration. The prolongation of action potential duration increased as the S1-S2 interval increased. This prolongation occurred at shorter S1-S2 intervals for 5-msec monophasic shocks than for biphasic shocks.
Glucocorticoid receptor mRNA expression in pulmonary alveolar macrophages in sarcoidosis, The presence of the glucocorticoid receptor was demonstrated by immunocytochemistry in pulmonary alveolar macrophages obtained by bronchoalveolar lavage. Also. GR mRNA content was determined by solution hybridization in PAM from 12 healthy volunteers and in 6 patients with sarcoidosis. No significant differences with regard to GR mRNA expression was detected between the two groups examined. For comparison. lung tissue from three patients undergoing thoracic surgery was examined and found to contain GR mRNA levels in the same range. As an indication of GR function. we also determined the mRNA levels of a glucocorticoid-regulated gene. metallothionein IIA. during basal conditions and after in vitro incubation of PAM with dexamethasone. Neither the control sample nor the dexamethasone-stimulated MTII mRNA values in PAMs differed significantly between the two groups. Solution hybridization is a rapid. sensitive and convenient assay which enables accurate and specific quantitation of GR mRNA in PAM. The GR mRNA content and basal as well as dexamethasone-induced MTII mRNA levels in PAM from patients with sarcoidosis is not significantly different from those in healthy volunteers.
Expiratory computed tomography for assessment of suspected pulmonary emphysema, Results of computed tomography of the lung performed at two levels in upper lung zones at full inspiration and full expiration were compared with results of tests of ventilatory function. lung mechanics. and single breath carbon monoxide diffusing capacity in 64 subjects. many of whom had some form of airflow obstruction. From the CT scans. the mean percentage of pixels in the range -900 to -1.024 Hounsfield units. or pixel index. was determined for each subject. The highest correlations of pixel index with physiologic variables consistent with a diagnosis of emphysema were observed for CT taken at full expiration. In some subjects. the inspiratory CT would give a "false positive" for emphysema when the hyperaeration observed at inspiration was not observed at expiration. We believe that the CT scan taken at full expiration can effectively reveal the abnormal permanent enlargement of airspaces which defines emphysema and provides a noninvasive method of assessing lung morphology in the living human subject.
The effect of maximal doses of formoterol and salbutamol from a metered dose inhaler on pulse rates, ECG, and serum potassium concentrations, In a randomized. double-blind. crossover cumulative study. the individual maximal bronchodilator dosages for formoterol (F) and salbutamol (S) were assessed for their respective influence on ECG. pulse rate. and serum potassium levels in 13 patients with stable and reversible asthma. The following dosages were administered with an interval of 1 h: 12-24-48-(48)-(48) micrograms for F and 100-200-400-400-(400)-(400) micrograms for S. The study day was discontinued if pulse rate was above 140 beats min-1. a flattening of T wave on the ECG was recorded. or a maximal bronchodilation in FEV1 was observed (above 110 percent of the predicted value or an increase in FEV1 in the last two measurements below 5 percent). The maximal individual dose of F administered was 84 micrograms in six patients. 132 micrograms in three patients. 180 micrograms in three patients. and 228 micrograms in one patient. For S. the maximal individual dose was 400 micrograms in three patients. 2.200 micrograms in eight patients. 3.000 micrograms in one patient. and 3.800 micrograms in one patient. The mean maximal increase in FEV1 was 36.0 percent after F and 35.1 percent after S. Pulse rate increased from 73 to S3 beats.min-1 after F and from 75 to 84 beats.min-1 after S (both statistically significant). No pulse rate above 140 beats.min-1 was observed. In the high-therapeutic range (up to 36 micrograms of F and 6.090 micrograms of S). no changes in potassium level were observed. In still higher dosages. mean potassium level decreased from 4.16 to 3.78 mmol.L-1 after F and from 4.02 to 3.88 mmol.L-1 after S (not clinically relevant). The lowest individual potassium level recorded was 3.1 mmol.L-1. No clinically important changes in ECG were observed. In conclusion. very high doses of F and S administered from a metered dose inhaler proved to be safe for patients.
Caffeine consumption decreases the response to bronchoprovocation challenge with dry gas hyperventilation, OBJECTIVE: To determine whether caffeine consumption affects bronchoprovocation challenge (BPC). DESIGN: A prospective. double-blind. placebo-controlled. randomized. crossover trial. PATIENTS: Eleven nonsmoking men. aged 18 to 42 years. with normal baseline spirometry and evidence of exercise-induced bronchospasm. INTERVENTION: On three separate test days. each individual received. in random order. either placebo. 5 mg/kg caffeine. or 10 mg/kg caffeine. and then underwent BPC with eucapnic voluntary hyperventilation (EVH). RESULTS: Caffeine (10 mg/kg) significantly reduced bronchoconstriction compared to placebo (p = 0.02). The reduction in bronchoconstriction correlated with the serum level of caffeine (p = 0.014). CONCLUSIONS: Caffeine decreases bronchoconstriction due to EVH. Caffeine should be eliminated from diet prior to BPC.
Relation between mixed venous oxygen saturation and cardiac index. Nonlinearity and normalization for oxygen uptake and hemoglobin, The ability of mixed venous oxygen saturation (SvO2) monitoring to reflect changes in cardiac index (CI) with therapy in critically ill patients is unclear. To this end. SvO2 and CI were measured before and during an infusion of enoximone and/or dobutamine in 30 patients with advanced heart failure. A nonlinear relationship was observed between SvO2 and CI with the nonlinear correlation coefficient being 0.52. On normalizing for individual differences in hemoglobin and oxygen consumption. this correlation coefficient became 0.90. Further analysis of individual data was performed using linear regression. and the slopes and correlation coefficients were found to span a wide range slope: -10.0 to 30.9 min-m2/L. r: -0.27 to 0.99). However. the mean slope and correlation coefficient for patients with baseline CI and SvO2 less than 21/min/m2 and less than 55 percent were 18.3 min-m2/L and 0.87. respectively. while those for the remainder of patients were only 3.1 min-m2/L and 0.42. respectively. Thus. the nonlinear correlation coefficient of the SvO2-CI relationship in a group of patients is dependent on the homogeneity of their oxygen consumption and hemoglobin concentration. Furthermore. the ability of SvO2 to serve as a therapeutic indicator in any given patient is dependent on baseline SvO2 and CI.
Soluble interleukin 2 receptor in lung cancer. An indirect marker of tumor activity, Circulating levels of the soluble interleukin 2 receptor (sIL-2R) could provide an in vivo measure of the immunologic response to human tumors. We performed a total of 326 sIL-2R serum assays in 126 patients with lung cancer (67 at diagnosis. 59 during and after treatment). 112 patients with pulmonary benign diseases. and 63 voluntary healthy subjects. Patients with lung cancer had a median value of sIL-2R of 791 U/ml. which was superior to that of both controls (398 U/ml. p less than 0.001) and patients with noninflammatory benign diseases (583 U/ml. p less than 0.02). However. infectious pulmonary disorders. such as tuberculosis and pneumonia. were associated with the highest values of the substance (median. 1150 U/ml; p less than 0.001). At the diagnosis of lung cancer. sIL-2R correlated neither with the stage of disease nor with the cell type. On the contrary. posttreatment levels of the receptor were significantly related to disease status (RO = .41. p less than 0.002). particularly in the subgroup of nonsurgical patients (RO = .48. p less than 0.001). Patients with abnormal sIL-2R levels had a nearly significant reduction in survival as compared with patients with normal values (p less than 0.1). Measurements of sIL-2R could be useful in monitoring patients under treatment for bronchogenic carcinoma. as well as in prognostication. In this setting. sIL-2R might open a new class of biologic markers. providing information that is complementary to those of the more classic tumor-derived markers.
Independent oxygen uptake and oxygen delivery in septic and postoperative patients, Previous studies reporting pathologic oxygen supply dependency calculated VO2 as CO x C(a-v)O2. We investigated whether pathologic oxygen supply dependency exists in septic and postoperative patients if VO2 and DO2 are assessed independently. In septic patients. VO2 was 164 +/- 31 and DO2 was 633 +/- 209 ml/min/m2. The slope (b) of the VO2-DO2 regression line VO2 = b x DO2 + a ranged from -0.10 to 0.08 (mean. 0.02 +/- 0.01. p less than 0.05) and was statistically significant in two patients (b = 0.05 and b = 0.08. p less than 0.05). In postoperative patients VO2 was 136 +/- 19 and DO2 was 481 +/- 160 ml/min/m2; b ranged from -0.07 to 0.09 (mean. 0.04 +/- 0.01. p less than 0.001) and was statistically significant in one patient (b = 0.09. p less than 0.01). The lack of a close relationship between independently measured VO2 and DO2 may indicate that septic and postoperative patients in stable hemodynamic condition have no pathologic oxygen supply dependency. Analysis of the VO2-DO2 relationship may not be useful to guide therapy or predict outcome.
Evaluation of the hemodynamic and respiratory effects of inverse ratio ventilation with a right ventricular ejection fraction catheter, Pc-IRV has been shown to have respiratory advantages. compared with CPPV. However. the hemodynamic effects of this ventilation mode have not yet been fully elucidated. We used a REF catheter to monitor the hemodynamic changes in the RV. Fifteen ARDS patients were included in the study. The respiratory data showed a 35 percent decrease of PIP and a 32 percent decrease of VTi and VTe with Pc-IRV 4:1 compared with CPPV. Hemodynamic parameters showed a significant incrase in CI (17 percent) in Pc-IRV 4:1. without change in REF. Observing in retrospect the pressure-volume relationship of the RV. we could differentiate a preload (group 1) and an afterload dependent group of patients (group 2). CI was significantly different in the two groups as it rose only in the preload-dependent patients. RVEDVI showed a significant change in group 1. whereas this was absent in the second group. REF was maintained in switching ventilation from CPPV to Pc-IRV with increasing I:E ratio. Pc-IRV appears to be a good alternative ventilatory mode in comparison with CPPV in a selected group of patients with preload dependency (responders); in these patients with respiratory insufficiency. close hemodynamic monitoring is required to optimize ventilation. especially in relation to the hemodynamic effects.
Fatal airway obstruction caused by a mucous ball from a transtracheal oxygen catheter, A 50-year-old man with pulmonary fibrosis and COPD presented with worsening cough. dyspnea. chest pain. and hypoxemia of no readily apparent etiology. approximately four weeks after insertion of a transtracheal oxygen therapy catheter. Despite vigorous bronchial hygiene therapy. the patient died. Autopsy revealed obstruction of the trachea by a large mucous ball. We point out the nonspecificity of physical and radiologic findings associated with this condition and suggest that serial flow-volume loop analysis or earlier use of fiberoptic bronchoscopy might have been of assistance in premortem diagnosis of the mucous plug.
Native right atrial tamponade with the Jarvik total artificial heart, Following a massive myocardial infarction culminating in cardiogenic shock. a 61-year-old man underwent implantation of the Jarvik 70-ml total artificial heart. On the fifth postoperative day. hemodynamic instability coupled with subtle radiographic changes and impaired mechanical right ventricular diastolic inflow were instrumental in establishing the diagnosis of localized native right atrial tamponade. To our knowledge. this report is the first detailed discussion of this phenomenon.
Termination of central sleep apnea episodes by upper airway stimulation using intermittent positive pressure ventilation, A 52-year-old man presented with pure central sleep apnea syndrome that failed to respond to nasal continuous positive airway pressure (NCPAP) therapy. Intermittent positive pressure stimulation via a nasal mask was instituted using a portable positive pressure ventilator. We found marked reduction in the respiratory disturbance index. number of desaturations. and the number of arousals with this mode of therapy.
Transient prolonged postischemic ventricular dilatation documented by 99mTc MIBI scan, We describe two cases of prolonged postischemic ventricular dilatation during myocardial scintigraphy with 99mTc MIBI. the new perfusion tracer that has only negligible redistribution. Ventricular dilatation. caused by true chamber dilatation and/or subendocardial ischemia. was still present over two hours after the induced ischemic episode. suggesting a prolonged duration of such a commonly believed fleeting scintigraphic finding.
Empyema due to ventriculopleural shunt, Empyema developing seven weeks after craniotomy in a 62-year-old black woman with an ipsilateral ventriculopleural (V-PL) shunt is described. Infection of the pleural space presumably resulted from transfer of organisms from a proximal V-PL shunt infection to the thorax. Empyema resulting from V-PL shunt infection has not previously been reported. Pleural effusions in patients with V-PL shunts must be considered as a potential site of infection with possible development of empyema.
Local dermal hypersensitivity from dobutamine hydrochloride (Dobutrex solution) injection, Two patients had local dermal hypersensitivity at the site of dobutamine hydrochloride (Dobutrex solution) injection. Such local dermal lesions characterized by erythema. pruritus. and phlebitis with or without bullae formation have not been reported previously (to our knowledge). Hypersensitivity reaction to sulfites as a possible mechanism of the dermal lesions was substantiated further by skin tests and peripheral eosinophila. Oral antihistamine therapy can minimize such a minor but bothersome problem.
Does metoclopramide reduce the length of ileus after colorectal surgery? A prospective randomized trial, Between August 1988 and September 1989. 100 consecutive patients who underwent elective abdominal colorectal surgical procedures were prospectively randomized to receive or not to receive metoclopramide. Metoclopramide was intravenously administered every 8 hours from the completion of surgery until a solid food diet was able to be tolerated. Seven patients were not included in the final tabulations because of one death. one small bowel obstruction requiring laparotomy. one anastomotic leak requiring laparotomy. and four protocol violations. Ninety-three patients. 37 men and 56 women (mean age. 59.5; range. 14-89 years) underwent 40 segmental colectomies. 13 total abdominal colectomies. 8 abdominoperineal resections. 8 ileoanal pouch procedures. 7 small bowel resections. and 17 other colorectal procedures. The 40 patients who received postoperative metoclopramide were in Group 1. and the 53 who did not were in Group 2. The mean length of time between laparotomy and commencement of oral fluid and oral solid intake in Groups 1 and 2 were 3.5 and 4.8 days. and 3.5 and 5.0 days. respectively. These differences were not statistically significant (P greater than 0.05). Prolonged ileus was seen in seven patients in Group 1 and in eight patients in Group 2. These differences were also not statistically significant (P greater than 0.05). Prolonged ileus was defined as the need for nasogastric tube reinsertion or discontinuation of oral intake. We conclude that metoclopramide does not significantly alter the course of postoperative ileus.
Anorectal physiology testing. A survey of availability and use, Survey forms were sent to all members of the Coloproctology Section of the Royal Society of Medicine and the American Society of Colon and Rectal Surgeons to obtain their opinions of the availability. actual use. and perceived helpfulness of different methods for the evaluation of the physiology of the colon and rectum. Responses revealed a similarity in age and practice patterns in both groups. Of the 19 methods surveyed. greater than 90 percent of respondents in both groups rely on three traditional methods of patient evaluation: patient history. digital examination. and sigmoidoscopy. Four other methods have gained acceptance by the majority of respondents in both groups: colon transit studies. defecography. perfused-catheter manometry. and rectal compliance. The three methods ranked lowest in availability. actual use. and helpfulness by both groups were single-fiber electromyography. use of a perineometer. and evoked potential studies. Our study provides a baseline for future surveys on the investigative efforts of physicians studying the physiology of the colon. rectum. and anus.
Human papillomavirus type-related DNA and c-myc oncogene alterations in colon cancer cell lines, Although squamous-cell epithelium is the most frequent target site of human papillomavirus (HPV) infection. a similar infection is demonstrated in columnar epithelial cells in this paper. The papillomavirus expression in three cell lines was detected in colorectal adenocarcinoma of Chinese patients. The HPV-16 and HPV-18 DNA sequences were found in colorectal cancer cell lines. which might suggest the correlation of HPV to the etiology of colorectal cancers. In addition. c-myc oncogene was identified by amplification in all three colorectal cancer cell lines. but only normal germ-line fragments were found in control tissue. The correlation between HPV and c-myc. and the implications of these findings in colorectal cancers are also discussed.
Bilateral gluteus maximus transposition for anal incontinence, Seven patients (five men and two women) ranging in age from 26 to 65 years (means = 44) underwent bilateral gluteus maximus transposition for complete anal incontinence. The indications for operation were sphincter destruction secondary to multiple fistulotomies (n = 4). bilateral pudendal nerve damage (n = 2). and high imperforate anus (n = 1). The procedure is performed without the use of a diverting colostomy. The inferior portion of the origin of each gluteus maximus is detached from the sacrum and coccyx. bifurcated. and tunneled subcutaneously to encircle the anus. The ends are then sutured together to form two opposing slings of voluntary muscle. Postoperatively. six patients regained continence to solid stool. two to liquid stool as well. and only one patient in this group was able to control flatus. Although resting pressures remained unchanged. voluntary squeeze pressures were restored by this operation. In addition. rectal sensation was markedly improved. which helps make this a worthwhile procedure for properly selected patients.
Single vs. double stapling technique in colorectal surgery. A prospective randomized trial, Seventy patients after rectosigmoid resection were randomized to a rectal anastomosis either in the single or double stapling technique. There was no statistically significant difference between the two groups. A trend in favor of the double stapling technique was noted: 2.8 percent clinical leaks vs. 8.6 percent in the single stapling technique.
Tumor markers in cancer of the colon and rectum, The primary role that tumor markers for cancer of the colon and rectum have at this time is for postoperative surveillance of those patients resected for cure who are at risk for recurrence of the disease. Carcinoembryonic antigen (CEA) serum levels are followed by most surgeons prospectively after the potentially curative resection. This tumor marker has not been advocated as a screening test for these cancers; however. a preoperative CEA serum level is determined in those patients before the initial surgery for colon or rectal cancer. The serum level of CEA is mainly determined by tumor differentiation and stage of disease. If the CEA serum level begins to increase during the postoperative surveillance period. the recurrence of colon or rectal cancer must be suspected. Further investigations are then performed to identify the location and resectability of the recurrent disease. Monoclonal antibodies labeled with radioisotope are presently being used clinically to identify recurrence of colon and rectal cancer. Used in conjunction with elevated serum CEA levels (or other determinants of recurrent disease) these tumor markers can specifically identify site(s) of cancer recurrence. Theoretically. by attaching cancer-fighting agents (i.e.. chemotherapeutic agents) to the monoclonal antibody. the site of tumor recurrence can be potentially treated. too. Hence. these "tumor-seeking missiles" may one day be used to treat cancer recurrence.
The basis and basics of mechanical ventilation, The development of mechanical ventilators and the procedures for their application began with the simple foot pump developed by Fell O'Dwyer in 1888. Ventilators have progressed through three generations. beginning with intermittent positive pressure breathing units such as the Bird and Bennett device in the 1960s. These were followed by second-generation units--represented by the Bennett MA-2 ventilator--in the 1970s. and the third-generation microprocessor-controlled units of today. During this evolutionary process clinicians recognized Types I and II respiratory failure as being indicators for mechanical ventilatory support. More recently investigators have expanded. clarified. and clinically applied the physiology of the work of breathing (described by Julius Comroe and other pioneers) to muscle fatigue. requiring ventilatory support. A ventilator classification system can help the clinician understand how ventilators function and under what conditions they may fail to operate as desired. Pressure-support ventilation is an example of how industry has responded to a clinical need--that is. to unload the work of breathing. All positive pressure ventilators generate tidal volumes by using power sources such as medical gas cylinders. air compressors. electrically driven turbines. or piston driven motors. Positive end-expiratory pressures. synchronized intermittent mandatory ventilation. pressure support ventilation. pressure release ventilation. and mandatory minute ventilation. are examples of the special functions available on modern ventilators. Modern third-generation ventilators use microprocessors to control operational functions and monitors. Because these units have incorporated the experience learned from earlier ventilators. it is imperative that clinicians understand basic ventilator operation and application in order to most effectively prescribe and assess their use.
Islet allografts in the cryptorchid testes of spontaneously diabetic BB/Wor dp rats: response to glucose, glipizide, and arginine, The aim of this study was to examine insulin and glucagon secretory patterns in successfully transplanted spontaneously diabetic BB/Wor dp rats. Diabetic. BB/Wor dp rats received abdominal. intratesticular islet grafts of MHC-compatible BB/Wor dr donor rats without immunosuppression. After a period of 74 +/- 15 days of normoglycemia. they were given the following challenges: 1) glucose. by mouth. 2) a single oral dose of glipizide. with glucose. and 3) arginine. by iv infusion. The pertinent results included the mean fasting plasma glucose levels of control. Sprague-Dawley (C). of transplanted BB/Wor dp (T). and nontransplanted. insulin treated. diabetic BB/Wor dp (D). and they were. respectively. 97 +/- 4 mg/dl. 110 +/- 3 mg/dl. and 350 +/- 40 mg/dl. Fasting plasma insulin levels in C and T rats were 21.9 +/- 3 microU/ml. and 20.4 +/- 2 microU/ml. respectively. Fasting plasma glucagon levels in C. T. and D. were 37.8 +/- 5.7 pg/ml. 43.4 +/- 4.6 pg/ml. and 47.4 +/- 4.9 pg/ml. respectively. During oral glucose tolerance test. the pattern of insulin secretion in the C and T rats was identical with a peak attained at 15 min. Glucose caused a 70% suppression of plasma glucagon levels in C rats (P less than 0.01); T rats suppressed 14%. but this was not statistically significant; D rats failed to suppress. Glipizide plus glucose caused an improved glucose tolerance in T rats without significantly affecting insulin levels. In the same rats. glipizide resulted in a significant suppression of glucagon compared with levels in the presence of glucose alone. Arginine caused a minimal release of insulin in T rats and a major glucagon secretory response in D rats. Pancreatic glucagon content was significantly (P less than 0.03) lower in C and T. compared with D rats. Furthermore. the transplanted testes of T contained substantial amounts of glucagon. In summary. these data suggest that grafted testes in spontaneously diabetic BB/Wor dp rats contain both beta and alpha-cells and that these cells have the capacity to respond to specific secretagogues independently.
Multihormonal regulation of insulin-like growth factor-binding protein-1 in rat H4IIE hepatoma cells: the dominant role of insulin, Circulating levels of insulin-like growth factor-binding protein-1 (IGFBP-1) and the abundance of hepatic IGFBP-1 mRNA are increased in streptozotocin-diabetic rats and are regulated in accordance with insulin and metabolic status. We recently purified rat IGFBP-1 from medium conditioned by well differentiated rat H4IIE hepatoma cells. Since this cell line provides a useful model for examining the effects of hormones on hepatocellular function. we used H4IIE cells to examine the relative role that insulin and other factors may play in the regulation of IGFBP-1 production. H4IIE cells were stabilized in serum-free medium. then treated with specific hormones. The availability of IGFBPs in conditioned medium was estimated by [125I]IGF-I binding assay. and specific BPs were assessed by Western ligand and immunoblot analyses. The abundance of IGFBP-1 mRNA was determined by Northern and slot blot analysis. Initial studies revealed that [125I]IGF-I-binding activity in conditioned medium was reduced after 24-h incubation with 100 nM insulin (52 +/- 4% of control; P less than 0.001). In contrast. binding activity was increased after only 4 h of incubation with 75 microM 8-(4-chlorophenylthio)cAMP (8-CPT-cAMP) or 1 microM dexamethasone (P less than 0.001 vs. control for each). but these effects were prevented by insulin. Ligand and immunoblotting demonstrated that insulin decreased the production of 32K and 34K forms of IGFBP-1. while both 8-CPT-cAMP and dexamethasone increased the production of IGFBP-1; again. insulin prevented the effects of 8-CPT-cAMP and dexamethasone. Of note. 1 microM rat GH. testosterone. progesterone. or 17 beta-estradiol had no effect on either IGF-binding activity or IGFBP-1 production. Northern and slot blot analyses revealed that 100 nM insulin profoundly lowered the abundance of IGFBP-1 mRNA in H4IIE cells (4 +/- 0.6% of control at 4 h; P less than 0.001). while IGFBP-1 mRNA was increased 2-fold during incubation with 75 microM 8-CPT-cAMP (P less than 0.001) and 9-fold with 1 microM dexamethasone (P less than 0.001). Once again. the effect of insulin was dominant; insulin both prevented and reversed the effects of maximally effective concentrations of 8-CPT-cAMP and dexamethasone. To determine whether this effect of insulin reflected altered generation or stability of IGFBP-1 mRNA. H4IIE cells were incubated with 2.5 micrograms/ml actinomycin-D with or without insulin. and mRNA was quantitated by Northern blot.(ABSTRACT TRUNCATED AT 400 WORDS).
High-affinity androgen binding and androgenic regulation of alpha 1(I)-procollagen and transforming growth factor-beta steady state messenger ribonucleic acid levels in human osteoblast-like osteosarcoma cells, Clinical observations have demonstrated a positive effect of estrogens and androgens on the maintenance of structural bone integrity. This study examines the direct effects of androgenic hormones on the osteoblast-like human osteosarcoma cell line. HOS TE85. Employing radiolabeled dihydrotestosterone (DHT). 2800 saturable. high-affinity (dissociation constant = 0.66 nM) androgen binding sites were detected per HOS TE85 cell. Androgen binding was specific in that DHT and testosterone (T) displayed significantly greater competition than the progestins. progesterone and medroxyprogesterone. The expression of androgen receptors in HOS TE85 cells was further substantiated by Northern analysis. A human androgen receptor complementary DNA probe revealed a 9.5 kilobase transcript which corresponds to the predominant human androgen receptor transcript detected in human male reproductive tissues. Androgens were also found to elicit biological responses in HOS TE85 cells. Physiological concentrations of DHT and T decreased HOS TE85 cell proliferation as assessed by cell count. This finding suggests that DHT may also play a role in osteoblast differentiation. In support of this hypothesis. treatment with T (24 h. 10 nM) enhanced the abundance of both alpha 1(I)-procollagen messenger RNA (mRNA) (5-fold) and transforming growth factor-beta mRNA (2.2 fold). The nonaromatizable androgen DHT (24 h. 10 nM) elicited an increase in the steady state concentration of alpha 1(I)-procollagen mRNA similar to the increase observed with T treatment. Thus. in addition to the recent discovery of estradiol receptors and estrogenic regulation of HOS TE85 cells. it is now evident that these osteoblast-like osteosarcoma cells also express high affinity androgen binding sites and can respond biologically to androgens.
Hypersecretion of islet amyloid polypeptide from pancreatic islets of ventromedial hypothalamic-lesioned rats and obese Zucker rats, To investigate the possible role of islet amyloid polypeptide (IAPP) in the development of type 2 diabetes mellitus. we examined the IAPP content and secretion in pancreatic islets isolated from ventromedial hypothalamic (VMH)-lesioned rats and genetically obese Zucker rats. using a specific RIA for IAPP. Obesity and hyperinsulinemia were observed in rats 21 days after VMH lesioning. IAPP content was increased in the islets of VMH-lesioned rats compared with findings in the sham-operated controls (100.9 +/- 6.6 vs. 72.8 +/- 3.85 fmol/islet; P less than 0.01). Isolated islets of VMH-lesioned rats secreted larger amounts of IAPP in the presence of 2.8 mM and 16.7 mM glucose (2.99 +/- 0.98 and 11.2 +/- 1.29 fmol.islet(-1).3 h-1) than was noted in sham-operated rats (ND and 6.65 +/- 0.78 fmol.islet(-1).3 h-1). In the obese Zucker rats. aged 14 weeks. IAPP concentrations in the islets were elevated compared with lean rats (133.3 +/- 10.6 vs. 84.4 +/- 8.5 fmol/islet; P less than 0.01). The isolated islets secreted larger amounts of IAPP in response to 2.8 mM and 16.7 mM glucose (2.83 +/- 0.88 and 15.81 +/- 1.35 fmol.islet(-1).3 h-1) than did those from lean control rats (0.36 +/- 0.19 and 12.49 +/- 1.20 fmol.islet(-1).3 h-1). These results strongly suggest that overproduction and hypersecretion of IAPP occur in animals with obesity and hyperinsulinemia.
Biochemical and morphological analysis of the interaction of epidermal growth factor and parathyroid hormone with UMR 106 osteosarcoma cells, The interaction of epidermal growth factor (EGF) and PTH with UMR 106 osteosarcoma cells was examined biochemically and morphologically. EGF inhibited PTH-stimulated adenylate cyclase activity in association with a reduction in PTH receptors and a decrease in the activity of the stimulatory guanyl nucleotide-binding protein (Gs). Universal inhibition of agonist-stimulated adenylate cyclase activity did not occur. inasmuch as EGF did not reduce prostaglandin E2-enhanced enzyme activity. The influence of EGF on PTH action correlated with its effect in the UMR 106 cell population of promoting entry into the cell cycle. Morphological analysis with radioautography indicated that both EGF and PTH receptors could be colocalized to certain UMR 106 cells. but that each were more abundantly distributed over discrete UMR 106 cell types. Based on the distribution of [3H]thymidine incorporation. EGF receptors were predominantly found over rapidly proliferating cells. whereas PTH receptors were most densely distributed over more quiescent cells. The results indicate that EGF and PTH receptors are localized over specific types within the heterogeneous population of UMR 106 cells and suggest that EGF may reduce PTH action in these cultures by enhancing the proliferation of progenitor cells lacking PTH receptors and reducing differentiation in this cell population. which leads to PTH receptor-enriched target cells. EGF and PTH receptors may. therefore. be useful as probes to examine both functional interactions and differentiation pathways among cells in osteoblast models in vitro and perhaps in vivo.
Multihormonal control of cell proliferation: opposite effects of two stimulators (17 beta-estradiol and L-triiodothyronine) and one inhibitor (dexamethasone) on F4Z2 pituitary tumor cells, From the MtTF4 tumor of rat pituitary origin we established the F4Z2 cell line whose growth is stimulated by 17 beta-estradiol (E2). Taking E2 actions as references we investigated actions of other effectors on the proliferation. protein. and insulin growth factor-I (IGF-I) secretions of F4F2 cells. Dexamethasone (Dex) and L-T3 were chosen because they have also intracellular receptors and they act in pituitary cells. Cells were cultured in 96-well plates in RPMI 1640 medium supplemented either with charcoal-treated fetal calf serum (CT-FCS) or with BSA and transferrin. Hormones were added at the time of seeding and cells were counted 2-10 days later without renewing the culture medium. The accumulation of immunoreactive IGF-I in conditioned medium was used as an index of IGF-I secretion. For studies on protein secretion. cells were incubated for 24 h with [35S]methionine and labeled proteins were separated by polyacrylamide gel electrophoresis. We found that: 1) L-T3. like E2. stimulated in a dose-dependent and specific manner the proliferation of F4Z2 cells cultured in the presence of 5% CT-FCS; EC50 was: 1 X 10(-11) M and 0.2 X 10(-11) M for L-T3 and E2. respectively. In contrast. L-T3 but not E2 remained active in serum-free medium; 2) Dex was a strong inhibitor of cell proliferation in serum-free medium and in medium supplemented with 5% CT-FCS (EC50: 5 X 10(-9) M). The antiglucocorticoid RU 38 486 prevented this inhibitory effect; 3) when a stimulator (E2 or L-T3) was simultaneously incubated with the inhibitor (Dex) the number of cells depended on the ratio of hormone concentrations. When there was no large excess of one effector this number was intermediary between those counted in the presence of each hormone separately and L-T3 was more potent than E2 in preventing Dex inhibition; 4) Dex. E2. and L-T3 modified the electrophoretic patterns of secreted proteins but there was no evidence for a correlation between these modifications and the inhibition or the stimulation of cell proliferation. and 5) the accumulation of immunoreactive IGF-I was insensitive to E2. increased by L-T3. and markedly decreased by Dex. L-T3 but not E2 prevented the effect of Dex.(ABSTRACT TRUNCATED AT 400 WORDS).
Hypophysectomized rats depend on residual prolactin for survival, Hypophysectomized (Hypox) female Fischer 344 rats had 10-20% lactogenic activity in their serum when compared to controls by the Nb2 lymphoma proliferation assay. If such animals were treated daily with a rabbit antirat PRL serum. their serum lactogenic activity diminished further; severe anemia and immunological anergy developed; and death occurred within 8 weeks. In contrast. untreated Hypox animals increased gradually their serum lactogenic activity. starting on the 7th week after pituitary removal. which rose up to 50% of control levels by week 9. Hypox animals showed normochromic normocytic anemia. a grossly reduced immunocompetence. decreased body. thymus. spleen. adrenal. and ovary weights. and decreased DNA and RNA synthesis in the thymus. spleen. and bone marrow. However. the condition of Hypox animals did not deteriorate further over the 9-week experimental period. All the hematological deficiencies and decrease in organ weights observed in Hypox rats were normalized after grafting with syngeneic pituitaries (SPG). These effects of SPG could be inhibited by additional treatment with antirat PRL serum. Treatment of Hypox animals with ovine PRL had a restoring effect similar to SPG. which was not inhibited by additional antirat PRL serum treatment. Rat and ovine PRL and GH and human placental lactogen all stimulated the incorporation of 3H-thymidine by rat bone marrow cells in vitro. These results indicate that PRL has a multiple trophic effect and is capable of maintaining vital bodily functions for long periods of time.
Luteinizing hormone-releasing hormone alters the hypothalamic effects of morphine in the rat, Female rats exhibit a generalized refractoriness to opiate stimulation during periods of steroid-induced LH secretion. In the present study we evaluated that role of LHRH in this steroid-induced effect on opiate-responsiveness. Central administration to ovariectomized rats of native LHRH or the LHRH agonist [Des-Gly10]LHRH ethylamide causes a dose-dependent refractoriness to the hypothermic effects of morphine. The potency relationship of these two LHRH agonists in antagonizing morphine's effect was consistent with their potency in inducing LH release. Treatment of ovariectomized rats with estradiol benzoate and progesterone in a regimen which induces a preovulatory-like LH surge. antagonized morphine-induced hypothermia. and the LHRH antagonist [D-Phe2. Pro3. D-Phe6] LHRH. reversed the effects of the gonadal steroids. These results indicate that the LHRH secretory dynamics associated with the preovulatory surge of LH may serve to modulate opiate responsiveness and thereby could serve to couple behavioral. sensory. and autonomic events with this neuroendocrine response to gonadal steroids.
Differential effects of insulin-like growth factor (IGF)-I and IGF-II on the expression of IGF binding proteins (IGFBPs) in a rat neuroblastoma cell line: isolation and characterization of two forms of IGFBP-4, The isolation and hormonal regulation of two low molecular weight insulin-like growth factor binding proteins (IGFBPs) present in the conditioned medium (CM) of the rat neuroblastoma cell line B104 cells has been performed. IGFBPs were purified by ZnSO4 precipitation. insulin-like growth factor-I 1IGF-I) affinity chromatography. and reverse phase HPLC. Final isolation and N-terminal analysis was accomplished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. electroblotting to polyvinylidene difluoride membranes. and sequencing of the bound proteins. Two IGFBPs. with apparent Mr of 28K and 24K were coisolated and sequenced. Both proteins had identical N-terminal sequences and appear to be two forms of IGFBP-4. Treatment of the IGFBPs with endoglycosidase-F caused a shift in the apparent Mr of the 28K IGFBP to 24K. However. there was no change in the apparent Mr of the 24K IGFBP. The data from this study suggest that the IGFBP-4 exists as both a glycosylated and nonglycosylated protein. Treatment of B104 cells with IGF-I increased the expression of both the 24K and 28K IGFBPs and also resulted in the appearance of IGFBP-3 and an unknown IGFBP at 29K. When added to subconfluent cells. IGF-I was also mitogenic in B104 cells. Similar to IGF-I. IGF-II treatment increased cell number and resulted in the appearance of IGFBP-3 and the 29K IGFBP. However. IGF-II treatment resulted in a significant decrease (approximately 50%) in the 24K IGFBP and also decreased the 28K IGFBP. This decrease in the expression of the 24K and 28K IGFBPs was dose-dependent and was blocked by addition of IGF-I to the cells. When an IGF-II receptor antibody was added to the cells it mimicked the effects of IGF-II on B104 cells. suggesting that the inhibitory effects of IGF-II are mediated through the type II IGF receptor. Although both IGF-I and IGF-II affected the amount of the 24K IGFBP in the CM. neither peptide affected the expression of the messenger RNA for the 24K IGFBP. In conclusion. we have isolated two IGFBPs from the CM of B104 cells. Both the 24K and 28K IGFBPs appear to be isoforms of the same protein. and sequence data suggest these proteins are two forms of IGFBP-4. IGF-I increases the expression of both of these IGFBPs. whereas IGF-II decreases their expression.(ABSTRACT TRUNCATED AT 400 WORDS).
Homologous desensitization of the insulinotropic glucagon-like peptide-I (7-37) receptor on insulinoma (HIT-T15) cells, Glucagon-like peptide-I(7-37) [GLP-I(7-37)] is an intestinal peptide with potent insulinotropic activities on pancreatic beta-cells in vivo and in vitro. In earlier studies elevated concentrations GLP-I(7-37) inhibited insulin release and cAMP generation in beta-cells. We now show that the GLP-I(7-37) receptor in the glucose-responsive B-cell line HIT-T15 undergoes rapid and reversible homologous desensitization in response to supraphysiological concentrations of GLP-I(7-37). GLP-I(7-37) stimulated insulin release and cAMP generation in a glucose-dependent biphasic manner with a maximum stimulation at 10 nmol/liter. The first-phase insulin secretory response was reduced by 41% at doses of GLP-I(7-37) of 100 nmol/liter and higher. Preperifusion of B-cells with 100 nmol/liter GLP-I(7-37) for 5 or 10 min reduced a subsequent insulin secretory response to 10 nmol/liter GLP-I(7-37) after hormone washout and recovery periods of 10 min (52% and 55% reduction) or 30 min (33% reduction or full recovery). Preperifusion of HIT-T15 cells with 100 nmol/liter glucagon (10 min) or 100 nmol/liter gastric inhibitory peptide (GIP) (10 min) had no effect on the insulin secretory response to 10 nmol/liter GLP-(7-37). Prior exposure of cells to 100 nmol/liter GLP-(7-37) (10 min) did not alter the GIP-induced (10 nmol/liter) insulin release. but 100 nmol/liter GIP (10 min) reduced the insulin secretion during stimulation with 10 nmol/liter GIP by 56%. These data indicate that: 1) the GLP-I(7-37) receptor is subject to rapid and reversible homologous desensitization and. 2) the GLP-I(7-37) receptor on beta-cells is distinct from that of GIP. The recent finding of elevated GLP-I(7-36)amide levels in subjects with noninsulin-dependent diabetes suggest the possibility that a homologous desensitization of the GLP-I(7-37) receptor might contribute to the impaired insulin secretion in this disorder.
Interrelated effects of insulin and glucose on diacylglycerol-protein kinase-C signalling in rat adipocytes and solei muscle in vitro and in vivo in diabetic rats, The effects of insulin and glucose. alone and combined. on diacylglycerol (DAG). protein kinase-C (PKC). and glucose transport were compared in rat adipocytes and solei incubated in medium containing 0-20 mM glucose. In both tissues insulin rapidly stimulated [3H]DAG production from [3H]glycerol; extracellular glucose masked this effect in adipocytes. but not in solei. [3H]Glucose was avidly converted to DAG in adipocytes. and this conversion was enhanced by insulin. In contrast. [3H]glucose was poorly converted to DAG in solei. Glucose alone (5-20 mM) stimulated PKC translocation in adipocytes. but not in solei. Insulin stimulated PKC translocation in both tissues at all glucose concentrations. However. glucose modulated this effect of insulin in adipocytes by 1) decreasing cytosolic PKC and the absolute amount of PKC translocated. and 2) promoting apparent turnover of membrane PKC. In contrast. in solei. glucose did not affect PKC levels or translocation responses to insulin. In keeping with DAG-PKC signalling. the relative glucose transport effects of insulin were influenced by extracellular glucose in adipocytes. but not in solei. These results suggest that 1) glucose-induced PKC translocation requires metabolism of glucose to DAG; 2) glucose activates DAG-PKC signalling in adipocytes. but not in solei; 3) insulin activates DAG-PKC signalling in both tissues at all glucose levels; and 4) glucose may modulate the effects of insulin on DAG-PKC signalling in adipocytes. but not in solei. Consistent with in vitro results. in solei taken directly from diabetic rats. membrane PKC was decreased. and cytosolic PKC was increased. presumably reflecting diminished PKC translocation due to hypoinsulinemia. In contrast. in adipose tissue. cytosolic PKC was decreased. presumably reflecting hyperglycemia-induced PKC translocation. Accordingly. DAG levels were increased in adipose tissue. but not in solei. in diabetic rats. and insulin increased DAG in both tissues.
Dissociation of second messenger activation by parathyroid hormone fragments in osteosarcoma cells, PTH activates multiple second messengers in its target cells. but the level at which the hormonal signal splits into different pathways is still unknown. To achieve insights on this issue. we have studied the structure-function relationship of PTH by analyzing the effects of bovine PTH-(1-34) [bPTH-(1-34)] and PTH fragments truncated at the N-terminus on the intracellular calcium concentration [( Ca2+]i) and cAMP production in the rat osteogenic sarcoma cell line UMR 106-01. [Ca2+]i was measured in single cells using fura-2. When exposed to 10(-7) M bPTH-(1-34). 20% of the cells responded with a transient increase in [Ca2+]i of variable amplitude. Equimolar doses of bPTH-(2-34). propionyl bPTH-(2-34) [(pbPTH-(2-34)]. and bPTH-(3-34) also transiently increased [Ca2+]i. whereas both [tyrosine34]bPTH-(7-34) amide [bPTH-(7-34)] and bPTH-(30-34) were ineffective. The amplitude of the [Ca2+] i transients was dose-dependent. with threshold concentrations of 10(-10) M for bPTH-(1-34) and bPTH-(2-34). and 10(-9) M for bPTH-(3-34). The response rate to the active peptides ranged between 10-30%. without a clear dose-relatedness. A second addition of 10(-7) M bPTH-(1-34) to cells prestimulated with equimolar doses of bPTH-(2-34). pbPTH-(2-34). or bPTH-(3-34) produced another transient. whereas after exposure to 10(-7) M bPTH-(1-34). the cells were completely desensitized to a second homologous stimulation. suggesting that the binding affinity of the truncated peptides for the PTH receptor is lower than that of the intact bPTH-(1-34) fragment. In addition. both bPTH-(1-34) and bPTH-(2-34) dose-dependently stimulated cAMP production. but the former was more potent (ED50 = 10(-9) vs. 10(-7) M. respectively). On the contrary. pbPTH-(2-34). bPTH-(3-34). and bPTH-(7-34) had no effect on cAMP. Pretreating the cells with pertussis toxin to enhance cAMP responses via inhibition of Gi potentiated the effect of bPTH-(1-34) and bPTH-(2-34) and disclosed weak but detectable agonist action of pbPTH-(2-34). These results indicate that specific domains of the PTH molecule are linked to activation of different second messenger pathways; while the first two amino acids are indispensable for activating the cAMP system. generation of the [Ca2+]i signal appears to involve a longer domain. including the amino acid residue in position 3.
Evidence for a specific role of vasopressin in sustaining pituitary-adrenocortical stress response in the rat, In the adult male Wistar rat a 2-fold 2-min restraint stress exposure. repeated 15 min apart. activated the adrenocortical secretion more than a single one would have. However. in rats with a pharmacological block of the endogenous CRF release. exogenous CRH (0.3 micrograms/kg iv). administered 15 min after a first similar dose. was unable to stimulate pituitary-adrenocortical activity above the level attained with the first peptide injection. On the contrary. in the same conditions exogenous arginine vasopressin (AVP) (0.3 micrograms/kg iv) administered 15 min after CRH. was able to further stimulate pituitary-adrenocortical activity. Using the same experimental procedure. oxytocin (0.3 micrograms/kg iv) was found to be totally inactive. The physiological import of these findings was investigated in the Brattleboro rat. genetically lacking in endogenous AVP. in which. unlike the control Long-Evans strain. the 2-fold stress exposure did not cause an increase in plasma corticosterone concentration greater than that of a single exposure. These results suggest that endogenous AVP is essential in sustaining adrenocortical activation in circumstances in which pituitary refractoriness towards CRH stimulation intervenes.
Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients, To establish whether secretion of proglucagon-derived peptides (PGDPs) by the intestinal L cell is nutrient- and/or location-dependent. 0.9% saline. 200 mM glucose. or emulsified fats were administered into the ileal or duodenal lumen of normal rats. Fat administration. but not saline or glucose treatment. significantly increased circulating levels of the intestinal PGDPs in a time-dependent fashion. indicating a selectivity of the L cell in its response to nutrients. Interestingly. the response to duodenal fats was quantitatively and qualitatively identical to the response to ileal fats. despite 50-fold lower concentrations of PGDPs in the duodenum. These results suggest the existence of a duodenal factor that stimulates ileal PGDP secretion in response to fat ingestion. Ileal and plasma levels of gut PGDPs have been reported to be elevated in poorly controlled streptozotocin-diabetic rats. Whether the sensitivity of the L cell to luminal nutrients is altered in diabetes was. therefore. also examined. The L cell responses to luminal nutrients in diabetic rats were not significantly different from those of the normal rat. indicating a normal responsiveness of the L cell. However. independent of changes in glycemia. luminal glucose perfusion significantly decreased circulating glucagon levels in normal rats. but not in diabetics. Furthermore. luminal fat administration increased plasma glucagon levels in normal rats only. These results indicate that moderately controlled diabetes is associated with alterations in the pancreatic A cell. but not the intestinal L cell response to ingested nutrients. The results of the present study indicate that the response of the intestinal L cell to ingested food is nutrient-specific and that this specificity is not altered in diabetes. A duodenal-ileal axis is proposed to contribute to increments in circulating intestinal PGDPs in response to nutrient ingestion.
Molecular cloning of the chicken growth hormone receptor complementary deoxyribonucleic acid: mutation of the gene in sex-linked dwarf chickens, A novel complementary DNA (cDNA) encoding the chicken GH receptor was isolated from a chicken liver cDNA library. using polymerase chain reaction with primers derived from highly conserved sequences of the mammalian GH receptor. The nucleotide sequence predicts a mature protein of 592 amino acids and a 16 amino acid signal peptide that are partially homologous to the sequence reported for the rabbit (53%). rat (58%). and human (50%) GH receptors. Despite this low level of homology. a number of structural features of the GH receptor are conserved. including 7 cysteine residues in the extracellular domain and 5 in the intracellular region. Three transcripts of approximately 4.7. 4.0. and 1.0 kilobases are present on Northern blots of total RNA prepared from the livers of 35-week-old male chickens. Expression of the GH receptor was also detected in a wide range of tissues. The chicken GH receptor cDNA was then used as a probe in Southern and Northern blot analyses of DNA and RNA prepared from livers of sex-linked dwarf chickens. which have undetectable levels of hepatic GH-binding activity. in addition to other endocrine abnormalities. A restriction fragment length polymorphism was found in DNA. and an aberrantly-sized transcript was found in hepatic RNA of the dwarf chicken. These results indicate that a mutation in the GH receptor gene is responsible for the phenotype of the sex-linked dwarf chicken. This type of dwarfism resembles Laron-type dwarfism in humans. where a defect in the GH receptor gene has recently been identified. These receptor-deficient chickens should serve as a unique model system for studying the role of the GH receptor in growth and development.
A selective oxytocin antagonist attenuates progesterone facilitation of female sexual behavior, Although previous studies have demonstrated that exogenous administration of oxytocin (OT) enhances sexual receptivity in female rats. there is no compelling evidence that endogenous OT has a physiological role in the regulation of female sexual behavior. In the current studies we centrally administered d(CH2)5[Tyr(Me)2Thr4.Tyr-NH2(9)]ornithine vasotocin (or OTA). a selective OT receptor antagonist. to block endogenous OT in ovariectomized females primed with different levels of gonadal steroids. After OTA administration (100-1000 ng). females primed with estradiol benzoate (EB; 1 microgram) and progesterone (P; 250 micrograms) showed reductions in both receptive and proceptive behaviors. These effects of OTA were also evident. though less striking. in females primed with higher doses of EB (10 micrograms) and P (250 micrograms). but significant OTA effects were absent in females primed with EB (10 micrograms) alone. Thus. OTA appeared to attenuate P's facilitation of sexual behavior. Surprisingly. these behavioral effects of OTA administration were not apparent immediately. but emerged only when OTA was given with P 4-6 h before behavioral testing. To determine if these delayed. but lasting. behavioral effects were associated with OTA occupancy of the OT receptor. we measured OT receptor binding ex vivo using receptor autoradiography. Six hours after intracerebroventricular administration of OTA (1000 ng). OT receptor binding was reduced at least 75% in the ventromedial nucleus of the hypothalamus relative to control levels of binding. Thus. those OT receptors previously implicated in the regulation of sexual receptivity appear to be significantly blocked throughout the period of OTA's behavioral effects. Together. these studies lend support to the hypothesis that endogenous OT has a physiological role in the regulation of female sexual behavior.
Transcervical selective salpingography: a diagnostic and therapeutic approach to cases of proximal tubal injection failure, OBJECTIVE: Evaluation of selective salpingography for diagnosis and treatment of tubal injection failure during hysterosalpingography (HSG). DESIGN: Prospective study. SETTING: Obstetrics and Gynecology Department. University of Genoa (Italy)--tertiary care. PATIENTS: One hundred eighty infertile women with unilateral or bilateral proximal tubal injection failure during HSG were submitted to the procedure. INTERVENTION: Under fluoroscopy. a 4.5-F nylon catheter (3-F tip) was inserted into the ostium with or without the aid of a J-shaped. coaxial. angiographic guide wire. and 2 to 3 mL of contrast medium were injected. The procedure lasts 20 to 30 sec/tube. MAIN OUTCOME MEASURES: Of 155 tubal ostia. 145 (94.2%) were catheterized. RESULTS: Of the 146 catheterized tubes. 110 (75%) were rendered patent. Of the others. 21 (14.3%) presented hydrosalpinx or distal obstructions. and isthmic obstruction was present in 5 (3.4%). Patency of at least one tube was achieved in 82 (81.2%) of the 101 catheterized women; 8 conceived spontaneously and 11 after gamete intrafallopian transfer to the recanalized tube. CONCLUSIONS: During HSG. selective salpinography can be performed when proximal injection failure is observed to determine its cause or to restore patency.
Increased peripheral T lymphocyte activation in patients with karyotypically normal spontaneous premature ovarian failure, OBJECTIVE: To determine if soluble interleukin 2 (IL-2) receptor measured in serum by an enzyme-linked immunosorbent assay (ELISA) might be useful in managing patients with karyotypically normal spontaneous premature ovarian failure. DESIGN: Prospective. controlled observation. SETTING: Tertiary care research institution. INTERVENTIONS: None. PATIENTS. PARTICIPANTS: Twenty-four patients with karyotypically normal spontaneous premature ovarian failure comprised the study group. Forty-two healthy men and women comprised the normal reference group. MAIN OUTCOME MEASURES: We measured peripheral T lymphocyte human leukocyte antigen locus-DR (HLA-DR) expression and IL-2 receptor expression using monoclonal antibodies and flow cytometry. We measured soluble IL-2 receptor levels in serum using an ELISA. RESULTS: Consistent with previous findings. our patients had significantly higher HLA-DR expression on peripheral T lymphocytes (5.3 +/- 0.46) as compared with controls (3.5 +/- 0.34) (mean +/- SEM. P less than 0.01). Seven patients also had elevated IL-2 receptor expression on peripheral T lymphocytes (P less than 0.05). However. soluble IL-2 receptor levels in the serum did not differ significantly from normals. CONCLUSIONS: Patients with karyotypically normal spontaneous premature ovarian failure have a modest increase in peripheral T lymphocyte activation measured by flow cytometry. This degree of activation does not result in increased soluble IL-2 receptor release measured by ELISA.
Antisperm antibody binding to human acrosin: a study of patients with unexplained infertility, OBJECTIVE: Antisperm antibody binding to acrosin was investigated by Western Blotting. The clinical significance of this binding specificity was assessed in a 2-year clinical follow-up. DESIGN: Consecutive serum samples positive for antisperm antibodies by both enzyme-linked immunosorbent assay and immunobead testing were evaluated for acrosin-binding specificity. SETTING: The patients were followed in an outpatient setting by private infertility specialists. PATIENTS: Sixty-five consecutive infertile referral patients with positive antisperm antibody were evaluated. Clinical follow-up was obtained on 8 of 9 females with evidence of antibody binding to acrosin and 19 of 26 females with no specific binding to acrosin. INTERVENTIONS: Prednisone therapy was given during six courses of intrauterine insemination with husband's sperm. All treatment decisions were made by private physicians independent of the acrosin-binding result. MAIN OUTCOME MEASURES: Pregnancy status was obtained as part of a 2-year follow-up. RESULTS: Acrosin-binding specificity was demonstrated in 10 (15%) of the 65 patients. Two of the 8 women (25%) with antibody binding to acrosin and 6 of the 19 women (32%) with antisperm antibodies but no specific binding to acrosin delivered normal children. CONCLUSIONS: Although antibody-binding specificity to acrosin could be demonstrated. a 2-year clinical follow-up showed no difference in pregnancy rates when compared with women with antisperm antibodies showing no binding specificity to acrosin.
Pregnancy after oocyte donation to a woman with ovarian failure and classical galactosemia, In summary. oocyte and pre-embryo donation may be used to establish pregnancy in women with galactosemia and ovarian failure. Reported is the first pregnancy after pre-embryo donation to a woman with classical galactose-1-phosphate uridyl transferase deficiency. Despite disturbances in galactose metabolism. the endometrial lining responded normally to exogenous hormone replacement and was receptive to pre-embryo implantation. Pregnancy support was provided by exogenously administered oral E2 and IM P for the initial 100 days. at which time placental hormone production solely maintained the gestation.
New visits for abdominal pain in the primary care setting, Abdominal pain is a common problem in primary care. Previous studies of this problem are limited by either the age group examined or the clinical setting. Findings of the 1980 and 1981 National Ambulatory Medical Care Surveys were combined to assess new visits for abdominal pain. A visit to a physician was considered to be for new abdominal pain when: 1) the principal reason for the visit was either stomach or abdominal pain. cramps. or spasms; 2) the visit was not the result of a referral; and 3) the physician had not previously seen the patient for the condition associated with the pain. Abdominal pain was the most frequent reason for a new pain visit. Women sought medical care for new abdominal pain more frequently than men. Most patients saw general practitioners or family physicians for evaluation of their pain. only 5% of patients were subsequently referred. and 6% were hospitalized. Clinical lab tests were ordered in 45% of new abdominal pain visits. while in approximately 20% X-ray procedures were ordered. Seventy percent of the patients were given a prescription. with antacids and antispasmodics being prescribed most frequently.
A qualitative approach to primary care research: the long interview, Qualitative research methods offer useful complements to the traditional epidemiologic approaches most commonly used by primary care researchers. Narrative texts generated through open-ended interviews are one form of qualitative data that may provide useful insights into primary care issues that are otherwise overlooked by more structured designs. This paper presents a step-by-step process for conducting a long interview. a qualitative approach with distinct potential for primary care research. Advantages and limitations of the long interview and its relationship to other qualitative methods are also discussed.
Development of a wearable glucose sensor; studies in healthy volunteers and in diabetic patients, A glucose sensor with a subcutaneous dialysis system was tested in six healthy volunteers during an oral glucose tolerance test and in ten diabetic patients with hyperglycemia during rapid decline of blood glucose levels. There was a good correlation between sensor and blood glucose values. During oral glucose tolerance tests in the volunteers. there was a mean delay of 4.4 minutes in the rise of the value registered subcutaneously and of 8.2 minutes in the fall of the curves. In the diabetic patients the maximum delay was 22 minutes. Nine days after insertion of the dialysis system it was still functioning well.
A randomized study of on-line plasma perfusion over protein A-sepharose and 5-fluorouracil chemotherapy in patients with metastatic colorectal carcinoma, To evaluate the safety of on-line plasma perfusion over protein-A sepharose and the therapeutic advantage of combining plasma perfusion (PP) over protein-A sepharose with 5-fluorouracil (5-FU) chemotherapy in patients with metastatic colorectal carcinoma (MCRC). thirty patients were randomized after surgery of primary CRC to receive a combination of 5-FU and PP over protein-A sepharose (group A). or a combination of 5-FU and PP over sepharose (group B). or 5-FU alone (group C). Bi-weekly on-line PP over 200 ml protein-A sepharose gel (group A) or 200 ml sepharose gel (group B) were performed with a Cobe 2997 blood cell separator for a maximum of 19 treatments per patient. 5-FU was given at 1000 mg/m2/d on days 1-5 of a 4-weekly cycle until progression. PP was well tolerated and no severe or life-threatening toxicity was observed. Mild clinical side-effects consisted of fever and chills (36% in group A. 23% in group B). The most common biological effects of PP over protein-A sepharose were significant drops in IgG (66% of pre-PP values). CH50 and C3 (73% of pre-PP values) and a significant generation of C3a and C5a anaphylatoxins. Tumor response rates were 40% for group A. 0% for group B and 20% for group C. The median survival times tended to be longer in group A (17 months) than in group B (10 months) and in group C (9 months). This is the first randomized trial showing some therapeutic advantage in combining PP over protein-A sepharose with conventional chemotherapy in MCRC.
Measurement of blood flow through AV-fistulae by means of Doppler sonography in regularly haemodialysed patients, In regularly dialyzed patients a variety of pathological events can negatively influence haemodynamics and blood flow through arterio-venous fistula. leading to inadequate blood flow through the dialyzer or disturbances in hemodynamics of the whole body. It therefore appears important to quantify flow velocity and volume flow through the arteriovenous fistula in such cases. We used a Vasoview computer controlled system for noninvasive vascular diagnostics based on B-scan "real-time" ultrasound for imaging the structure of tissue. combined with pulsed Doppler ultrasound for determination of hemodynamics. Thirty patients (16 males and 14 females. aged 45 +/- 10 years; range 23 to 61 years). with different periods spent on hemodialysis (5.5 +/- 3.1 years. range 1 to 11 years) were included in this study. The average systolic. diastolic and mean blood volume flows were 2131.8 +/- 565.8. 972.0 +/- 309.6 and 728.4 +/- 287.4 ml/min. respectively. The mean blood volume flow was calculated by integration of the area under curve of blood flow in one heart cycle on the Doppler signal. It is calculated by the apparatus and displayed on the screen during measurement. The average blood vessel diameter was 9.1 +/- 1.3 mm (mu +/- omega). The results revealed a marked inter-individual variation in volume flow through arteriovenous fistulae of dialyzed uremics (range 240.0 to 1200.0 ml/min). Doppler ultrasound thus appears to be a valuable method for determination of blood flow through arteriovenous fistula of dialyzed uremics as well as for detection of hemodynamics disturbances of interest. such as turbulent blood flow.
A new method to evaluate the CAPD-catheter-exit and other percutaneous devices, A method that has proved to be the most sensitive approach for the early diagnosis of infection of the oral mucosa around dental implants has been used to monitor the exit-sites of percutaneous devices. For three months the state of the skin-catheter interface of 13 CAPD-patients was examined every four weeks. This examination included the measurement of pocket depth with the aid of a periodontal probe. the measurement of SFFR (sulcus-fluid-flow-rate) using standardized filter paper strips and a bacteriological swab of the exit-site. The results obtained demonstrated that SFFR can be measured around percutaneous implants. The measurement of SFFR appeared to be more useful in the monitoring of exit-sites of percutaneous devices than the measurement of pocket depth or the use of bacteriological swabs. Further studies for prolonged periods are necessary to determine whether measurement of SFFR can reliably predict onset of exit-site infection before clinical signs become evident.
Serum alpha-1 acid glycoprotein in chronic renal failure and hemodialysis, The total concentration and concanavalin A (ConA)-dependent microheterogeneity of alpha-1 acid glycoprotein (AAG) were studied in thirty hemodialyzed uremic patients and eighteen non-dialyzed uremic patients. by comparison with healthy volunteers. Serum concentrations of AAG were significantly higher in the non-dialyzed uremic (1.27 +/- 0.47 g/l) and hemodialyzed patients (1.29 +/- 0.33 g/l) than in the volunteers (0.79 +/- 0.09 g/l). The proportions of strongly ConA-reactive AAG fractions were also higher in non-dialyzed uremic (16.7%) and hemodialyzed patients (18.5%) than in volunteers (14.1%). These data may be related to an increase in bi-antennary glycans. as observed in patients on peritoneal dialysis. together with a probable change in sialylation. AAG serum levels and microheterogeneity were similar in non-dialyzed and hemodialyzed patients and did not appear in the dialyzed patients to depend on the type of dialysis membrane used. i.e. cuprophan (CU). cellulose acetate (CA). hemophan (HE). polyacrylonitrile (PAN). and polysulfon (PS). in spite of differences in biocompatibility. In patients dialyzed with CA membranes. there was a distinct decrease in the ConA non-reactive fraction (38.0%) and an increase in ConA slightly-reactive (42.2%) and strongly-reactive (19.7%) fractions. Differences in AAG serum levels and ConA reactivity between patients dialyzed with CA and PAN membranes seem to justify further investigations of other acute-phase reactants and immunological parameters.
Correlates of postural hypotension in a community sample of elderly blacks and whites, Postural hypotension is thought to be prevalent among the elderly. but few community-based studies of this condition have been conducted. In addition. little is known about postural hypotension in blacks despite well documented racial differences in hypertension and stroke. Data on 659 elderly (greater than or equal to 60 years of age) participants in a survey of two rural. biracial townships were analyzed to describe the frequency and correlates of postural hypotension. Twelve percent of the 659 adults experienced a drop of 10 mmHg or greater in systolic blood pressure on going from sitting to standing (supine measures were not available). This degree of postural hypotension was twice as common for whites as for blacks (14.5% vs 7.5%. P = 0.01). Postural hypotension was associated with elevated sitting blood pressure and showed positive but statistically non-significant relationships with anti-hypertensive medications and leanness. The association between race and postural hypotension persisted after adjusting for these and other risk factors (OR = 2.2. 95% CI:1.2.4.0).
Increased serum conjugated dienes in elderly diabetic patients, To determine if lipid peroxidation by-products are increased in the serum of elderly diabetic patients. serum concentrations of conjugated dienes were measured in 45 Type 2 diabetic men over the age of 60 years. and the results were compared to those of 24 age-matched healthy men. Patients with diabetic complications such as retinopathy. nephropathy. neuropathy. peripheral vascular disease. coronary or cerebrovascular disease. (n = 22) had significantly increased serum levels of conjugated dienes (0.4951 +/- 0.065 O.D./mL) compared to healthy controls (0.2368 +/- 0.028 O.D./mL) (P less than 0.01). The level of conjugated dienes in diabetic patients without complications (0.3854 +/- 0.0316 O.D./mL) was intermediate between the level found in control subjects and the level in patients with diabetic complications. The serum levels of conjugated dienes correlated best with serum triglyceride concentration (r = 0.51) and to a lesser extent with serum glucose concentration (r = 0.36). It is concluded that elderly patients with diabetes. especially those with complications. have increased serum levels of lipid peroxidation by-products. This can not be totally attributed to alterations in serum cholesterol. phospholipid. or triglyceride levels.
Mania in the elderly: a 5-7 year follow-up, A 5-7 year follow-up study of elderly individuals hospitalized on an acute psychiatric inpatient service for bipolar disorder. manic phase. demonstrates that the prognosis of mania has improved in the past 30 years. A majority of those hospitalized for mania are alive and living independently 5 years after hospitalization. However. eight of 25 (32%) patients have experienced a decline in Mini-Mental State Exam score to below 24. suggesting a clinically significant cognitive disorder. Mortality rates were higher in the manic group than expected from population norms. Compared to a group of similarly aged individuals hospitalized for unipolar depression. patients with bipolar disorder had an earlier age of onset and a lesser likelihood of being rehospitalized.
The Dubbo study of the health of elderly: correlates of coronary heart disease at study entry, A prospective study of the health of elderly Australians recently commenced in Dubbo. NSW. the study population comprising 1.237 males and 1.568 females 60 years and older. The prevalence rates of coronary heart disease (CHD) and its associated risk factors have been examined in the baseline data. The age-standardized rate of CHD was 23.8/100 in males and 18.1/100 in females. The prevalence rate increased with age until 79 years in males. thereafter declining. The rate increased steadily with age in females. In a multiple logistic model. the following possible predictors of CHD were included: age. cigarette smoking. use of alcohol. exercise. religiosity. years of education. hypertension. diabetes. family history of CHD. body mass index. lipid and lipoprotein variables. The presence of CHD in males was significantly predicted by age. hypertension (odds ratio. OR = 1.40). family history (OR = 2.05). and high density lipoprotein (HDL) cholesterol (OR = 0.78). The significant predictors in females were age. years of education (OR = 0.82). hypertension (OR = 1.45). family history (OR = 1.77). serum triglycerides (OR = 1.30). and HDL cholesterol (OR = 0.73). Hypertension was found to be a stronger predictor of CHD in the younger age group (60-69 years). while diabetes was a predictor of CHD in older males (70-79 years). Our findings require confirmation in the prospective study now in progress.
The epidemiology of skin tears in the institutionalized elderly, While skin tears are a common occurrence in the institutionalized elderly population. nothing has been written about this problem. We retrospectively studied all incident reports during a 1-year period at a large. urban. long-term-care facility to identify residents with skin tears. The overall incidence of skin tears was 0.92 per patient per year. The incidence rate for females. but not for males. increased significantly with age (P = 0.012). The mean length of the skin tear was 1.9 cm +/- 1.4 (mean +/- SD). Eighty percent occurred in the upper extremities. with the most frequent location being the forearm. Almost half of the skin tears reported had an unknown cause. Wheelchairs and accidentally bumping into an object each accounted for a quarter of the skin tears where the cause was known. Transfers and falls contributed to a lesser extent. Impaired mental status was no more likely to be present in residents experiencing a skin tear than in all nursing home residents. Twenty-four of the 147 residents with skin tears had four or more tears. accounting for 40% of all skin tears reported. Ninety-seven percent of the episodes resulted in no attending physicians' orders other than the standing orders. Future studies should be designed to determine if there are adverse consequences of skin tears and to suggest programs to reduce their occurrence.
Survival of patients with dementia, The evidence on survival in dementia is summarized. There are no reliable data on survival after onset of dementia or after first contact with medical services. People with dementia in outpatient clinics and nursing homes have 2-year survival rates of 75% (range 60%-95%) and 50% (range 30%-65%). respectively. Differences in survival between patients with senile dementia of the Alzheimer's type (SDAT) and multi infarct dementia (MID) are small. Women in nursing homes have a better prognosis than men (2-year survival rates. 60% vs 40%). Dementia patients have a considerable excess mortality when compared to the vital statistics. There is no evidence for improvement of survival rates during recent decades. Recommendations for future studies are made.
The incidence of attempted CPR in nursing homes, We studied the frequency with which cardiopulmonary resuscitation (CPR) is attempted on residents of American nursing homes. Each author (all members of the Clinical Practice Committee of the American Geriatrics Society) completed a questionnaire in 1989 about policy and practice regarding CPR during 1988 in each of three to seven nursing homes. by questioning the medical or nursing director or the administrator. Because of the vagaries of nursing home record-keeping. data from some homes were allowed when they were "accurate to within 10%." Data from 58 nursing homes. totalling 10.836 bed-years were available. In 33 of these homes. accounting for 5.425 bed-years. CPR was never attempted. CPR was more likely to be foregone in nursing homes with religious affiliation than in nursing homes without (13 of 17 vs 18 of 38; chi 2 = 4.0; P less than 0.05). Religious affiliation was unknown for three nursing homes. Academic affiliation (10 of 16 vs 20 of 37 in non-affiliated nursing homes) and non-profit status (14 of 19 vs 16 of 23 in for-profit nursing homes) did not significantly affect the likelihood that CPR would never be used. In 31 of 54 nursing homes with explicit do not resuscitate (DNR) policies. CPR was never performed. compared to 2 of 4 homes without such policies. For nursing homes with complete data. there were 1.196 deaths in 32 facilities where CPR was never attempted compared to 1.294 deaths for 24 nursing homes with CPR. For 22 nursing homes without CPR. there were 2.172 emergency room transfers compared to 1.363 emergency room transfers in 18 nursing homes where CPR was attempted.
The proinflammatory cytokines interleukin-1 and tumor necrosis factor and treatment of the septic shock syndrome, Treating the septic shock syndrome with antibodies that block only endotoxin has its limitations. Other targets for treating septic shock include neutralizing antibodies to the complement fragment C5a. platelet-activating factor antagonists. and blockade of endothelial cell leukocyte adhesion molecules. Specific blockade of the proinflammatory cytokines interleukin-1 (IL-1) or tumor necrosis factor (TNF) reduces the morbidity and mortality associated with septic shock. Moreover. blocking IL-1 and TNF likely has uses in treating diseases other than septic shock. Use of neutralizing antibodies to TNF or to IL-1 receptors have reduced the consequences of infection and inflammation. including lethal outcomes in animal models. The IL-1 receptor antagonist. a natural-occurring cytokine. blocks shock and death due to Escherichia coli and ameliorates a variety of inflammatory diseases. Soluble TNF and IL-1 surface receptors. which bind their respective cytokines. also ameliorate disease processes. Current clinical trials are evaluating the safety and efficacy of these anticytokine therapies either alone or together.
New aspects of antimicrobial resistance and the resulting therapeutic dilemmas, Emergence of resistance to antimicrobial agents among previously susceptible organisms continues to be an important obstacle to the successful treatment of bacterial infections. In hospitals. plasmid-mediated resistance to third-generation cephalosporins and monobactams has recently appeared in gram-negative bacilli. due primarily to mutations in TEM- and SHV-type enzymes. Among nosocomial enterococci. vancomycin resistance. beta-lactamase production. and high-level resistance to all aminoglycosides have recently been added to this organism's already formidable armamentarium of resistance properties. Also. resistance to fluoroquinolones and rifampin has been emerging in methicillin-resistant Staphylococcus aureus. In the community. organisms in which resistance plays a particularly important role are shigellae. Haemophilus influenzae. gonococci. and pneumococci. particularly in developing countries. beta-lactamase-producing meningococci have been reported for the first time. The selective pressure generated by the use of antimicrobial agents. together with the ability of bacteria to acquire and spread resistance and the capacity of humans to transmit bacteria. suggest that antimicrobial resistance will continue to be a problem for the foreseeable future.
Zidovudine-associated embryonic toxicity in mice, A novel toxicity associated with zidovudine (AZT). the standard antiviral therapy for infection with human immunodeficiency virus. is described. When AZT was administered to mice to evaluate its safety during gestation. the animals failed to complete pregnancy successfully. Mice receiving AZT during gestation yielded fewer fetuses (P = .003) and greater numbers of resorptions (P = .003) per pregnant mouse compared with untreated animals. Drug effects on adult mice were assessed to determine if toxicity could account for the pregnancy failures. However. adult animals receiving AZT demonstrated no adverse effects with regard to growth. food consumption. activity. or ovarian histology. A direct toxic effect of AZT on the mouse embryo was tested by cultivating single-cell fertilized oocytes in vitro in the presence of increasing concentrations of drug. Exposure to AZT was highly correlated with failure to develop to the blastocyst stage (P less than .001). These data indicate that AZT has a direct toxic effect on the developing mouse embryo. Further analysis of the nature of this toxicity may be important in designing less toxic antiretroviral agents and in planning future uses of AZT.
Transmission of retroviral infection by transfusion of seronegative blood in nonhuman primates, Techniques such as polyclonal B cell activation with pokeweed mitogen (PWM) and polymerase chain reaction (PCR) analysis have documented the existence of simian immunodeficiency virus (SIV)-and human immunodeficiency virus type 1-seronegative but infected humans and nonhuman primates. To establish whether blood from such seronegative but PWM- and PCR-positive monkeys can transmit infection. naive macaques were transfused with whole blood (n = 2) or cultured cells and supernatant fluid (n = 2) from two seronegative but PWM- and PCR-positive sooty mangabeys. After transfusion. three of the four recipients seroconverted. and peripheral blood mononuclear cells from all four recipients secreted SIV-reactive antibodies upon polyclonal activation in vitro and were SIV-positive by PCR that used highly specific gag primer pairs and probe. In addition. CD8+ cells from all four recipients markedly inhibited replication of SIV in autologous cells in vitro. These data suggest caution in the sole use of serologic tests for the detection of retroviral infection and document the ability of such blood samples to transmit infection.
Field trial of oral cholera vaccines in Bangladesh: serum vibriocidal and antitoxic antibodies as markers of the risk of cholera, The relationship of serum vibriocidal (VC) and IgG anti-cholera toxin (CT) antibodies to the risk of cholera was evaluated during the first year of follow-up of recipients of three oral doses of B subunit (BS)-whole-cell vaccine. whole-cell vaccine. or Escherichia coli K12 strain placebo in Bangladesh. Acute sera from 121 cholera patients were compared with sera from 2592 contemporaneous community controls. Each doubling of VC titer was associated. on average. with a 22%-47% reduction of cholera risk in the three groups. In contrast. in the two groups that did not receive BS. anti-CT titers were directly associated with cholera and thus served as markers of higher cholera risk. Each vaccine conferred approximately 65% protective efficacy against cholera. but antibody titers did not correlate with vaccine efficacy. indicating that serum VC and anti-CT antibodies are poor markers of the longitudinal pattern of vaccine efficacy.
Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal Surveillance Working Group, The increasing number of Streptococcus pneumoniae isolates identified as relatively or fully resistant to penicillin or fully resistant to other antimicrobials in the United States supports the need to monitor for this resistance. Thus. 5459 S. pneumoniae isolates submitted to the Centers for Disease Control in 1979-1987 by 35 hospitals in a hospital-based pneumococcal surveillance system were evaluated. The MIC to penicillin or ampicillin was greater than or equal to 0.1 micrograms/ml for 274 (5%) isolates; 1 had an MIC of 4.0 micrograms/ml to penicillin. Seventeen (0.3%) were resistant to erythromycin (MIC. greater than or equal to 8 micrograms/ml). 157 (2.9%) were resistant to tetracycline (MIC. greater than or equal to 16 micrograms/ml). and 34 (0.6%) were resistant to sulfamethoxazole/trimethoprim (MIC. greater than or equal to 76 and 4 micrograms/ml). Isolates relatively resistant to penicillin represented 1.8% of isolates in 1979. 8% in 1982. and 3.6% in 1987. Sixty-five multiply resistant isolates were identified. Pneumococci from the southwestern United States (region 4) were more likely to be relatively resistant to penicillin. Using logistic regression analysis. serotypes 14 and 19A. isolates from region 4. and isolates from middle ear fluid were associated with penicillin resistance (P less than or equal to .008. chi 2. These data confirm that antimicrobial resistance among pneumococcal isolates remained at low levels in the United States through 1987.
Rapid development of ciprofloxacin resistance in methicillin-susceptible and -resistant Staphylococcus aureus, The fluoroquinolones. particularly ciprofloxacin. have been suggested to treat methicillin-resistant Staphylococcus aureus (MRSA) infections and colonization and methicillin-susceptible S. aureus (MSSA) infections. The development of ciprofloxacin resistance in MRSA and MSSA was prospectively evaluated. After 3 months of ciprofloxacin use. high-level resistance (MIC90. 64 micrograms/ml) developed in MRSA and increased at an alarming rate. from none to 79% over a 1-year period. High-level ciprofloxacin resistance also developed in MSSA. increasing to 13.6% over the same period. Antibiograms. phage typing. and plasmid profile analysis suggest that more than one clone of MRSA developed resistance and that ciprofloxacin resistance is not associated with the acquisition of a new plasmid. Most patients had nosocomial acquisition and about one-half had a history of previous ciprofloxacin use. Ciprofloxacin resistance can develop rapidly in S. aureus; thus. ciprofloxacin appears to have limited usefulness in treating staphylococcal infections and colonization. especially those due to MRSA.
Activity of azithromycin against cryptosporidia in immunosuppressed rats, Dexamethasone-immunosuppressed rats infected with Cryptosporidium parvum were used to assess the macrolides azithromycin and spiramycin for anticryptosporidial activity. Azithromycin consistently prevented ileal infection. while spiramycin was ineffective. The anticryptosporidial activity of azithromycin was dose-related. 200 mg/kg/day being the minimum dose that prevented infection. Therapeutically. azithromycin eliminated an established overt infection of the small intestine in immunosuppressed rats. but the infection recurred after azithromycin treatment was stopped. These findings suggest that azithromycin is a potentially useful anticryptosporidial agent and that long-term continuous administration may be necessary to treat cryptosporidiosis in the immunocompromised host.
Relationship between intracellular survival in macrophages and virulence of Haemophilus influenzae type b, The phagocytosis of Haemophilus influenzae type b (Hib) by rat macrophages and the intracellular fate of ingested organisms was investigated using an acridine orange-crystal violet assay. There was a correlation between the ability of organisms to survive in macrophages in vitro and their ability to cause invasive disease. Encapsulated Hib survived and replicated within macrophages. whereas capsule-deficient mutants. although more susceptible to phagocytosis. were killed after ingestion. Differences in lipopolysaccharide also affected the ability of encapsulated Hib to survive in macrophages. The presence of viable intracellular organisms in macrophages in vivo may enhance the persistence of bacteremia and may also be important in mediating the entry of Hib into the central nervous system.
The activity of amoxicillin plus clavulanic acid against Mycobacterium leprae in mice, The activity of amoxicillin plus clavulanic acid against logarithmically multiplying Mycobacterium leprae was evaluated by treating mice by gavage five times weekly with various amounts of the compound from day 60 to day 150 after footpad infection. At 25. 50. and 100 mg/kg. it was inactive; at 200-600 mg/kg. multiplication of M. leprae was entirely prevented for 6-11 months after drug discontinuation. consistent with observations of bactericidal activity for M. leprae. In a confirmatory study in mice. five-times-weekly intraperitoneal ticarcillin plus clavulanic acid. 1000 mg/kg. was not bactericidal for M. leprae. while amoxicillin plus clavulanic acid. 400 mg/kg five times weekly. was weakly bactericidal (80% +/- 14%). In addition. activity of amoxicillin plus clavulanic acid. 400 mg/kg. was evaluated in combination with previously established active drugs dapsone. 0.0001% (in diet). rifampin. 20 mg/kg monthly (by gavage). and kanamycin. 25 mg/kg five times weekly (intraperitoneally). All three combinations were active. and the combination with kanamycin was more active than either drug alone.
Skinfold and body circumferences as measures of body fat patterning in a French female active population: relationships with the metabolic risk profile, Body mass index (BMI). various anthropometric indices of abdominal fat distribution and some metabolic variables (blood lipids. fasting glucose. blood pressure) were measured in 408 French-born women from an occupational population who volunteered for the study. The aim of the study was to determine the best index for describing the relationships between the body fat pattern and the metabolic risk profile. The four age-adjusted circumference ratios (waist/hip. waist/thigh. xiphoid/hip. xiphoid/thigh) showed similar associations with the metabolic variables whereas the three age-adjusted skinfold ratios (epigastric/thigh. mesogastric/thigh. hypogastric/thigh) tended to be more weakly associated with the metabolic variables. particularly with apolipoprotein (Apo) B and fasting glucose. Multiple regression analyses showed that age-adjusted BMI was significantly related to high density lipoprotein (HDL) cholesterol. low density lipoprotein (LDL) cholesterol. Apo A and Apo B. and blood pressure. independently of abdominal fat distribution. After controlling for the effects of BMI. the waist/thigh ratio remained significantly associated to triglyceride. Apo B. fasting glucose. and systolic blood pressure. whereas the waist/hip ratio and the mesogastric/thigh skinfold ratio were significantly related only to triglyceride and systolic blood pressure independently of BMI. With the exception of triglyceride and fasting glucose. the degree of association between the metabolic variables and the abdominal fat distribution tended to be weaker than that observed with the BMI. These results emphasize the importance of the global corpulence in the levels of metabolic variables. However. all indices of abdominal fat distribution were. to varying degrees. independently associated with an unfavorable metabolic profile. Among them. the waist/thigh circumference ratio seems to be a useful indicator of the body fat pattern in women.
A randomized clinical trial of negative pressure ventilation in severe chronic obstructive pulmonary disease: design and methods, This report documents the design and methods of a randomized clinical trial designed to test the effectiveness of home negative pressure ventilation in patients with severe chronic obstructive pulmonary disease. Active negative pressure ventilation was compared with a sham version of the treatment after a pre-trial assessment had indicated the feasibility of the latter. Over 1200 patients in the metropolitan Montreal area were screened. Of these. 348 patients were recruited to enter a 4-week stabilization period. and 184 were subsequently randomized to receive either active or sham negative pressure ventilation. A 5-day in-hospital period was used to train patients in ventilator use and obtain baseline measures of exercise capacity. lung function. respiratory symptoms. and quality of life. Home ventilation treatment took place during a following 12-week period. Respirator use was recorded both from patient logs and from concealed meters installed in the units. Patients received four home visits by physiotherapists during the 12-week period and returned for follow-up to the hospital 4 and 12 weeks post-discharge for reassessment.
Use of factor analysis to consolidate multiple outcome measures in chronic obstructive pulmonary disease, Multiple outcome measures are often used in clinical research and practice. However. the use of multiple measures inflates the probability of a type I error. In this paper. we used factor analysis techniques to reduce multiple outcome measures to a lesser number of orthogonal dimensions. The data were obtained from 119 patients with chronic obstructive pulmonary disease. Each patient had measurements made of 28 variables. including multiple parameters of pulmonary function. exercise tolerance and gas exchange. Factor analysis using a maximum likelihood iterative solution was performed. The factors were then rotated to a varimax solution. The analysis yielded four meaningful factors: exercise tolerance. disease severity. lung volumes and flow rates. Exercise tolerance and disease severity were the most important factors accounting. respectively. for 44 and 13% of the common variance. For further analyses. these composite factors could be used or a representative clinical measure from each factor might be chosen. We conclude that many physiologic measures provide highly correlated information about chronic obstructive pulmonary disease patients. Factor analysis may help reduce these measures into a smaller number of reliable composites.
Observer variability of Osler's maneuver in detection of pseudohypertension, Pseudohypertension in the elderly occurs when blood pressure is overestimated because of inelastic. sclerotic arteries. Osler's maneuver (OM). the palpability of a pulseless artery. is recommended as a non-invasive test to detect pseudohypertension. despite limited data concerning its reproducibility. We assessed the maximum achievable inter-and intra-observer agreement of OM among 6 examiners: cardiologists. geriatricians and general internists. Each examiner performed OM twice on 65 elderly hypertensive men attending the general medicine and geriatric clinics. The inter-observer agreement for brachial and radial examinations was 79 and 70%. while intra-observer agreement was 82 and 75%. respectively. After adjusting for chance agreement the kappa values for inter-observer agreement for brachial and radial arteries were 0.38 (95% confidence interval (CI): 0.21-0.55) and 0.37 (0.28-0.46). respectively. Similarly. the kappa values for intra-observer agreement were 0.45 (95% CI: 0.35-0.55) and 0.49 (0.39-0.59). Kappa values never exceeded 0.6 in any time period. suggesting no training effect. OM cannot be recommended as a screening test for pseudohypertension given this low inter- and intra-observer agreement.
Use of relative weight and Body Mass Index for the determination of adiposity, Relative weight and Body Mass Index (BMI) are commonly used as measures of body fatness in epidemiologic and clinical studies. In order to determine their accuracy. they were compared to body fat measured by underwater weighting and total body water determination in 29 males and 75 females who varied widely in body composition. Relative weights calculated from the Metropolitan Life Insurance Tables correlated so highly with BMI that these measures can be considered to be identical (R2 = 0.992 to 0.999). Linear regression analysis showed a significant correlation between BMI and percentage body fat in men (R2 = 0.68. %fat = 0.99 X BMI -1.32. p less than 0.001) and women (R2 = 0.74. %fat = 0.94 X BMI + 10.77. p less than 0.001). We conclude that relative weight and BMI are nearly identical. and that they are reasonable estimates of body fatness.
The treatment of temporomandibular joint internal derangements using a modified open condylotomy: a preliminary report, A modified open condylotomy was used to treat 44 patients who presented with painful temporomandibular joints. and in whom the clinical and arthrographic findings were indicative of disc displacement. A total of 64 joints (20 bilateral) were operated on. Postoperatively. the patients showed an overall improvement in their functional symptoms. Ninety-one percent of patients had improvement in clicking and popping. and 96% reported decrease in locking. Complaints related to pain and headache were improved 85% and 95%. respectively. The modified technique. as well as the anatomic basis for its use. are discussed.
Attitude variables of dentofacial deformity patients: demographic characteristics and associations, For patients to obtain satisfaction from surgical orthodontic treatment. a concordance needs to exist between the patients' concerns and expectations and the clinician's outcome measures of success. In this study. 231 patients 16 years or older were analyzed to define attributes of treatment that relate to patient satisfaction with outcome. The most prevalent patient concerns were related to facial and dental esthetics. and the effect of the dentofacial deformity on the quality of life was associated with a significantly higher motivation for surgical treatment.
Fetal cleft lip repair in rabbits: postnatal facial growth after repair, We have previously described a model for in utero cleft lip repair in rabbits. Cleft lip and alveolus (CL) were created in fetal rabbits at 24 days gestation (term. 31 days). In this study. postnatal maxillary growth was evaluated in three groups of animals: 1) unoperated controls. 2) unrepaired CL. and 2) repaired CL. The animals were killed at 4. 12. and 26 weeks after birth. Direct cephalometry was performed on dry skulls to evaluate premaxillary width. anterior maxillary length and width. and posterior maxillary width. The results of this study indicate that rabbits that undergo an in utero CL procedure. with or without repair. exhibit no significant decrease in maxillary length and width when compared with controls.
Diagnostic accuracy of temporomandibular joint lower-compartment arthroscopy using an ultrathin arthroscope: a postmortem study, Arthroscopy was performed on the lower temporomandibular (TMJ) joint compartment of 30 fresh cadavers using a newly developed ultrathin arthroscope. Comparison of arthroscopic and dissection findings showed a diagnostic accuracy of 57%. There were both false-positive and false-negative arthroscopic diagnosis. The majority of the false diagnosis occurred in the lateral part of the joint. Iatrogenic damage to the disc occurred in one joint. The study suggests that arthroscopy of the lower joint space of the TMJ can be done with a diagnostic accuracy similar to what has been described for the upper joint space. There appears to be no major risks of iatrogenic damage to the joint structures using an ultrathin arthroscope.
Distribution of valvular incompetence in patients with venous stasis ulceration, Valvular incompetence associated with venous ulceration can occur in the superficial. deep. or perforating systems. Duplex imaging was used to evaluate 95 extremities (78 patients) with current venous ulceration to determine the location of incompetence in each extremity. In addition. in 91 of the 95 extremities the area of the venous ulcer was evaluated for the presence of perforating veins or any other superficial veins or both conditions. Sixty-three (66.3%) of the 95 extremities had multisystem incompetence (superficial and perforating plus superficial and deep plus perforating and deep plus superficial and perforating and deep). whereas single system incompetence (superficial plus perforating plus deep) was seen in only 26 (27.3%). Isolated deep incompetence was identified in only two extremities (2.1%). Furthermore. 45% (41/91) of the ulcers had no duplex evidence of any venous abnormality in the ulcer bed. These data show that the site of valvular incompetence occurred in multiple locations. that isolated valvular incompetence of the deep venous system was uncommon. and that perforating veins were not always in the ulcer bed itself. Because standard venous surgery has traditionally been directed toward only one system. this may provide one explanation for ulcer recurrence. Therefore complete venous evaluation with duplex imaging allowing for surgical intervention directed specifically to the sites of involvement in each system is recommended.
Persistent platelet activation by passivated grafts, Vascular grafts in canines exhibit similar healing patterns to humans in that the graft surface forms a pseudointima over time but endothelializes only near the anastomotic sites. Thus the pseudointima at the midportion of the graft may represent a nidus for persistent platelet activation. The purpose of this investigation was to examine the effect of the maturing graft surface on platelet activation. Long Dacron subcutaneous carotid to aorta grafts (50 cm x 8 mm) were placed in nine dogs. Blood samples were obtained by direct graft puncture. at the proximal and distal ends of the graft. at 1. 24. 48. 72 hours. 1. 2. 3. 4 weeks. and monthly thereafter for 8 months. Seven sham dogs had subcutaneous grafts implanted without arterial anastomoses. and blood samples were drawn from the femoral artery. Platelet counts were determined with a platelet counter. Platelet aggregation and release of adenosine triphosphate was determined with a whole blood aggregometer by use of arachidonic acid. collagen. and adenosine diphosphate as agonists. No difference was found in platelet aggregation to collagen or adenosine diphosphate stimulation across the graft. but platelets released significantly less adenosine triphosphate to collagen and adenosine diphosphate stimulation distally versus proximally. In the graft dogs a decrease in systemic platelet counts of 50% occurred from the preoperative level which persisted over 8 months (p less than 0.01). Also less response occurred to collagen and ADP stimulated platelet aggregation in the graft animals than the sham animals during the first month of study. These data suggest that significant platelet-graft interactions occur even after the graft has formed a mature pseudointima.
The safety of intraaortic balloon pump catheter insertion through suprainguinal prosthetic vascular bypass grafts, To determine the safety of intraaortic balloon pump catheter insertion for critical coronary ischemia through suprainguinal prosthetic bypass grafts. we examined our experience of 19 intraaortic balloon pumps placed through grafts in 17 patients by means of surgical exposure (8) or the percutaneous (11) approach. Fourteen intraaortic balloon pumps were placed through matured grafts at a time remote (2 to 13 years; mean. 7 years) from their vascular bypass surgery. Five were inserted through nonmatured grafts during the same hospitalization as their vascular reconstructive surgery (1 to 12 days; mean. 4 days). One patient. a day after an aortoiliac bypass. died during an urgent. surgical intraaortic balloon pump insertion for cardiogenic shock. All other patients had prompt reversal of their cardiac ischemia. Decreased limb perfusion developed during use of the intraaortic balloon pump in three patients. all of whom had their intraaortic balloon pump placed percutaneously through mature grafts. Two of these required surgical thrombectomy. Ten intraaortic balloon pump insertions in eight patients survived the hospitalization and were followed for a mean of 24 months (range. 2 weeks to 64 months). No localized groin or graft infections were identified. No bleeding complications or pseudoaneurysms occurred. Thus in patients with unstable. severe. cardiac disease. intraaortic balloon pumps can be safely placed through indwelling suprainguinal bypass grafts.
Cerebrovascular hemodynamic changes associated with carotid endarterectomy, To evaluate the effect of carotid surgery on the cerebral circulation. transcranial Doppler sonography and ocular pneumoplethysmography were performed on 36 patients who underwent unilateral carotid endarterectomy. Ocular pneumoplethysmography and transcranial Doppler sonography tests were performed within a week before and after operation. and transcranial Doppler sonography was repeated greater than or equal to 30 days after operation. Middle and anterior cerebral arteries were insonated bilaterally. and flow velocities ipsilateral (iMCAFV or iACAFV) and contralateral (cMCAFV or cACAFV) to the side of surgery were recorded. The iMCAFV and iACAFV increased significantly in the immediate postoperative period. and the iMCAFV remained elevated on the second follow-up study. Patients with greater than or equal to 75% ipsilateral carotid stenosis (N = 23) had increased iMCAFV. iACAFV. and decreased cACAFV after operation. whereas those with less than 75% stenosis (N = 13) had no significant transcranial Doppler sonography changes. Those with greater than or equal to 75% contralateral carotid stenosis (N = 17) had significant increases in iMCAFV. cMCAFV. and iACAFV after operation. whereas those with less than 75% contralateral carotid stenosis had no significant transcranial Doppler sonography changes. A subset of patients (N = 13) did not increase iMCAFV after surgery. The ocular pneumoplethysmography changes were significantly different in both groups when preoperative and postoperative values were compared. We conclude that carotid endarterectomy can cause lasting cerebral hemodynamic changes. but that its effects are not uniform among all patients.
Hemodynamic and metabolic responses to graded microvascular occlusion, The hemodynamic and metabolic consequences of microvascular occlusion. often present in the runoff bed of distal arterial reconstructions. have been difficult to quantitate clinically. To investigate these pathophysiologic relationships. a porcine hindlimb model was developed in which arteriolar patency. which we term outflow capacity. may be quantitatively defined and reduced by serial distal microembolization with 70 microns flow-directed glass bubbles. In 10 anesthetized adult pigs. hindlimb perfusion was limited to femoral artery flow (FAF) by collateral ligation. Serial measurements of outflow resistance (OR). femoral artery flow. and resting muscle pH (mpH). a metabolic index of tissue perfusion. were made as relative outflow capacity (ROC) underwent graded reduction from 1.0 (baseline) to 0 (complete occlusion). Femoral artery flow decreased linearly (FAF = 87 ROC - 3). and outflow resistance increased in hyperbolic fashion (OR = 1.66/ROC) in response to graded peripheral microembolization. whereas resting muscle pH followed a more complex relationship (In mpH = 0.055 ROC + 1.95). An integrated analysis of these results suggests that a 50% to 60% reduction in arteriolar patency represents a critical point beyond which outflow resistance rises rapidly and hindlimb flow decreases to levels that are inadequate to support the metabolic demands of resting tissues.
The effect of ibuprofen on cardiac performance during abdominal aortic cross-clamping, Decreased cardiac output and increased plasma thromboxane have been observed during aortic cross-clamping under general anesthesia. Amelioration of these changes has been reported by preoperative administration of cyclooxygenase inhibitors. but heterogeneity in patients' intravascular volume status has confounded analysis of the drugs' effects in previous studies. We studied hemodynamic conditions in 24 volume-loaded (pulmonary capillary wedge pressure greater than 10 mm Hg) patients undergoing abdominal aortic aneurysm repair under general plus epidural anesthesia. after preoperative double-blind administration of either ibuprofen 800 mg (n = 12) or placebo (n = 12). The hemodynamic response to aortic cross-clamping was similar in both groups. Pulse and mean arterial pressure remained unchanged; cardiac index decreased after aortic cross-clamping from 2.4 +/- 0.1 (mean +/- standard error of the mean [SEM]) to 2.1 +/- 0.1 1/min/m2 in the ibuprofen group and from 2.5 +/- 0.1 to 2.3 +/- 0.2 1/min/m2 in the placebo group (p less than 0.01 versus preclamp values in both groups. multivariate analysis of variance [MANOVA]). but improved after declamping. Both left and right ventricular stroke work indexes followed a similar pattern. Plasma 6-keto prostaglandin Fl alpha (6-k-PGF1 alpha) increased transiently from a baseline level of 304 +/- 44 to 2083 +/- 698 pg/ml plasma in mixed venous blood 30 minutes after incision in the placebo group (p less than 0.05). but no other significant change in plasma 6-keto prostaglandin Fl alpha or in thromboxane B2 occurred in either group at any other time.
Efficacy and duration of antistaphylococcal activity comparing three antibiotics bonded to Dacron vascular grafts with a collagen release system, Type 1 collagen. minimally cross-linked. was used to bind one of three antibiotics (amikacin. chloramphenicol. or rifampin) to double-velour Dacron grafts to develop a prosthesis resistant to infection. Six millimeter disks of graft were placed in separate flasks (specific for each antibiotic) containing albumin in saline and continuously agitated. At daily intervals the solution was changed. and paired graft samples were removed and placed on a blood agar plate confluently streaked with bacteria. The initial zone of inhibition (centimeters squared). the time to 50% reduction of initial inhibition zone. and the overall duration of antibacterial activity were recorded on an exponential model. Grafts bonded with amikacin and chloramphenicol had an overall duration of activity of only 2 and 1 day. respectively. against Staphylococcus aureus. The collagen bonded rifampin grafts had an initial zone of 14.76 cm.2 took 3.92 days to reach 50% of initial inhibition. and had an overall duration of activity of 22.4 days. This was significantly better than grafts preclotted with 1.0 ml of rifampin (60 mg/ml) and 9 ml of blood (10.92 cm.2 1.06 days. and 5.6 days). When tested against a slime-producing Staphylococcus epidermidis (American Type Culture Collection No. 35983). the graft bonded with rifampin had inhibitory activity of up to 27.77 days with a 50% of activity eluted at 4.78 days. significantly better than the preclotted rifampin graft without collagen bonding. These data suggest that rifampin bonded by collagen can protect a vascular graft against infection from S. aureus and S. epidermidis for up to 3 weeks after implantation.
Iron chelation therapy and lung transplantation. Effects of deferoxamine on lung preservation in canine single lung transplantation, Reperfusion injury is a limiting factor in lung transplantation. Deferoxamine is an iron chelator that inhibits the formation of oxygen-derived free radicals. We investigated the effects of deferoxamine on posttransplantation lung function in a canine model of single lung transplantation. Twelve dogs underwent left lung transplantation after 20- to 24-hour hypothermic storage in a modified Euro-Collins solution. In six experiments donor and recipient received a 10 mg/kg dose of deferoxamine before harvest and transplantation. and 10 mg/kg was added to the preservation solution. Arterial oxygen tension. alveolar-arterial oxygen difference. pulmonary vascular resistance. and dynamic lung compliance were measured. Data were recorded for 6 hours after ligation of the native pulmonary artery. At the end of the study the mean arterial oxygen tension was 175.1 mm Hg for the deferoxamine treated group versus 71.1 mm Hg for the control group (p less than 0.001). and the alveolar-arterial oxygen difference was less in the deferoxamine-treated group: 502.3 versus 606.0 mm Hg (p less than 0.001). The mean pulmonary vascular resistance was lower throughout the study. and after 6 hours it was 455.1 dynes/sec/cm(-5) in the deferoxamine-treated group versus 663.7 dynes/sec/cm(-5) in the control group (p less than 0.035). Compliance was similar in both groups. We conclude that deferoxamine improves lung preservation and early posttransplantation function in canine single lung transplantation.
Warm ischemia induces alteration in lung immune cell functions, Warm ischemia is an important factor in early allograft dysfunction. To elucidate cellular events involved in such lung injury. we examined the effects of warm ischemia on the cytotoxic function of lymphocytes retrieved by bronchoalveolar lavage as compared with peripheral blood lymphocytes. Warm ischemia of the lung was induced in eight dogs by crossclamping left hilar structures for 1 hour. Bronchoalveolar cells from ischemia left and unaffected right lungs. as well as blood lymphocytes. were isolated before operation and 2 hours. 72 hours. and 7 days after operation. Lung and blood lymphocytes were assayed for natural killer and lectin-dependent cell-mediated cytotoxicity. Warm ischemia resulted in a significant impairment of natural killer activity within 2 hours of reperfusion (49% of preoperative control cytolysis. p less than 0.01). There was a significant increase in natural killer activity in bronchoalveolar lavage mononuclear cells 72 hours after reperfusion injury (178.4% of preoperative value. p less than 0.01). Interestingly. these functional alterations were not paralleled with changes seen in the peripheral blood lymphocytes or the opposite nonaffected lungs. where the natural killer activity appeared significantly depressed at 72 hours. Similarly. lectin-dependent cell-mediated cytotoxicity was noted to be increased in the bronchoalveolar lavage from the ischemic lung (179.5%. p less than 0.01) but decreased in the bronchoalveolar lavage from the nonaffected lung and peripheral blood lymphocytes at 72 hours after injury. We conclude that warm ischemia is associated with a functional alteration of the local lung immune cells. Such alteration is not observed in cells from the opposite lung or peripheral blood. The observed increase in nonspecific cytotoxicity of bronchoalveolar lymphocytes can be causative in the early damage seen in poorly preserved lung allografts.
The prevalence and management of bronchial anastomotic complications in lung transplantation, The prevalence and management of bronchial anastomosis complications have been assessed in a series of 53 patients undergoing lung transplantation. Of the 50 patients subsequently at risk of airway complications. these problems occurred in seven (14%). Only one patient died as a direct result of the airway complication (2%). Four patients required airway stenting. and their management is discussed. Although airway healing is normal in the majority of patients undergoing lung transplantation (86%). when deficits occur they can usually be successfully managed with conservative treatment. Bronchial stenting may be required on either a temporary or a permanent basis.
Impact of resident training on postoperative morbidity in patients undergoing single valve replacement. Department of Veterans Affairs Cooperative Study on Valvular Heart Disease, As one of the requirements of the Department of Veterans Affairs cooperative study on valvular heart disease. operative and postoperative data were prospectively collected in 964 patients undergoing single valve replacement. The procedure was performed either by a resident under the direct supervision of an attending surgeon (49.5%) or by an attending surgeon (50.5%). There was no difference in operative mortality between the two groups of surgeons when adjusted for patient-related and disease-related risk factors. The proportion of patients who had at least one postoperative complication was slightly but not significantly higher in the attending group (35.8% versus 30.4% for aortic valve replacement. 38% versus 28% for mitral valve replacement. and 36% versus 30% for all single valve replacement procedures). As the significance of each complication varies. we weighted each complication to the associated operative mortality to formulate the morbidity score. An expected complication rate for each group was derived from a multivariate logistic model. and the ratio of observed to expected morbidity was calculated to adjust observed morbidity according to the risk of patients. There was no difference in the observed/expected morbidity ratio between the two groups of surgeons. We conclude that currently used teaching techniques and philosophy to educate cardiac surgical residents. which allow them to take progressive responsibility for cardiac surgical procedures. are well justified. and patient care does not suffer when resident training is enhanced.
Ebstein's anomaly appearing in the neonate. A new surgical approach, Ebstein's anomaly appearing during the neonatal period carries a high mortality rate. These infants exhibit cyanosis. acidosis. and congestive heart failure. The pathophysiologic characteristics consist of severe tricuspid regurgitation and functional pulmonary atresia. As a result of the inability of the right ventricle to generate forward flow through the pulmonary arteries. these infants remain dependent on ductal patency. Since May 1988. five newborn infants with severe Ebstein's anomaly have been admitted for treatment at our institution. At initial examination. they weighed 3.6 +/- 1.8 kg and had a mean oxygen tension of 29.6 +/- 2.3 mm Hg and a mean pH of 7.20 +/- 0.05. Chest roentgenography demonstrated a mean cardiothoracic ratio of 0.81 +/- 0.02. As determined by echocardiography. the right atria were massively enlarged. severe tricuspid regurgitation was present in all patients. and the pulmonary valves were not opening. All infants were dependent on prostaglandin E1 and attempts to wean them from this drug were unsuccessful. Palliative treatment consisted of tricuspid closure with autologous pericardium and an aortopulmonary shunt of 4 mm polytetrafluoroethylene tubing. There were no operative or late deaths. At discharge. mean oxygen tension was 42.2 +/- 0.85 mm Hg and mean systemic oxygen saturation was 83.2% +/- 1.94%. Infants have grown satisfactorily during the follow-up period. Three infants have since returned for further surgical intervention. One infant. at 11 months of age. underwent a Glenn anastomosis for progressive oxygen desaturation. Two infants have returned. at ages 23 and 22 months. for Fontan procedures. which represent their definitive operative management. We believe this new procedure offers excellent palliative treatment for Ebstein's anomaly in critically ill neonates. Feasibility of later definitive correction is demonstrated by the good results obtained with the Fontan procedure in two infants.
Effect of intraoperative aprotinin administration on postoperative bleeding in patients undergoing cardiopulmonary bypass operation, To study the hemostyptic effect of aprotinin (Trasylol) in patients undergoing extracorporeal circulation for coronary artery bypass operations. we randomized 12 of 24 patients to receive aprotinin in high dosage (about 800 mg) during extracorporeal circulation. From the resulting two groups each. one patient was excluded from the study because of postoperative myocardial infarction (control group) and surgical hemorrhage (aprotinin group) leading to a second operation. Although heparin was used for anticoagulation in all 22 patients. all had a marked increase in plasma levels of thrombin-antithrombin III complexes during extracorporeal circulation. indicating an intravasal activation of coagulation. By monitoring the plasma levels of fibrin degradation products in patients without aprotinin therapy. we recorded a concomitant hyperfibrinolysis significantly less pronounced in patients receiving aprotinin (p less than 0.005). The mean total postoperative blood loss was lower in patients receiving aprotinin (620 ml) than in control patients (1000 ml; p less than 0.03). The results confirm previous reports of a hemostyptic effect of aprotinin in cardiac operations. This effect is probably due to a prevention of hyperfibrinolysis.
Plasma prostanoids in neonates with pulmonary hypertension treated with conventional therapy and with extracorporeal membrane oxygenation, Thromboxane may be a mediator of pulmonary hypertension in the neonate. Acute thromboxane-mediated pulmonary hypertension has been described in sheep receiving extracorporeal membrane oxygenation. which raises concerns about a potential thromboxane-mediated exacerbation of pulmonary hypertension in human neonates with severe pulmonary hypertension who are treated with extracorporeal membrane oxygenation. We measured plasma levels of thromboxane. prostaglandin F2 alpha. and 6-keto-prostaglandin F1 alpha in infants with pulmonary hypertension. some of whom were treated medically and some of whom were treated with extracorporeal membrane oxygenation. Plasma levels of all three prostanoids were elevated in infants with pulmonary hypertension and decreased with time. whether the neonates were treated with extracorporeal membrane oxygenation or with medical management alone. In infants treated with extracorporeal membrane oxygenation. we collected samples simultaneously from preoxygenator sites. postoxygenator sites. and umbilical artery catheter. We could demonstrate no significant difference in plasma prostanoid levels across the oxygenator. In two patients. plasma thromboxane and prostaglandin F2 alpha levels measured shortly after a platelet transfusion were distinctly higher in the umbilical artery catheter than in venous samples.
Effects of endurance training on baroreflex sensitivity and blood pressure in borderline hypertension, Physical training offers a potential nonpharmacological strategy for control of mild and borderline hypertension. but its effect on blood pressure is controversial. We investigated the effects of endurance training on waking and sleeping blood pressure and on baroreflex sensitivity in 16 borderline hypertensive patients. First. 8 patients were assessed before and after a 6-month endurance training programme. Then. when it was clear that blood pressures were lower after training. a further 8 patients were studied not only at the end of the training programme but also after 4 months' abstention from exercise (detraining). Measurements were taken of baroreflex sensitivity (response to iv phenylephrine). blood pressure. R-R interval. and blood pressure and R-R variability. Ambulatory blood pressures were measured in 13 patients (7 trained. 6 detrained) and sleep blood pressures in 6 patients (3 trained. 3 detrained). Increased fitness was associated with a decline in resting arterial blood pressure of 9.7 (SE 2.0) mm Hg systolic and 6.8 (1.2) mm Hg diastolic. and with a decline in ambulatory blood pressure of 4.8 (1.4) mm Hg and 7.5 (2.1) mm Hg. respectively; both p less than 0.05. Baroreflex sensitivity was 14.0 (1.8) ms/mm Hg in the unfit and 17.5 (2.0) ms/mm Hg in the fit; p less than 0.05. Sleep blood pressures were not lower in the fit despite longer sleep R-R intervals. These findings indicate that. in some subjects with borderline or mild hypertension. a physical training programme is sufficient to bring the blood pressure within normal limits.
Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility, Female fertility declines with advancing age. To establish whether this age-related reproductive failure results from diminished oocyte quality or uterine/endometrial inadequacy we investigated ovum donation in 35 infertile women. aged 40 years or older (mean 42.7 [SE 0.3]) who had failed at attempts at conception with their own (self) oocytes. Oocytes were donated by 29 young individuals (mean age 33.4 [0.7]) undergoing in-vitro fertilisation (IVF). 8 (5.3%) pregnancies were achieved in 150 cycles of ovulation induction with self-oocytes and 2 (3.3%) in 60 such cycles by in-vitro fertilisation (IVF). but none attained viability. By contrast in 50 cycles with donated oocytes 28 (56%) pregnancies and 15 (30%) deliveries were realised (p less than 0.005). The rate of implantation per embryo transferred was higher (14.7%) with donated oocytes than that with self-oocytes (3.3%) (p less than 0.01). To further elucidate the contribution of age to reproductive outcome. pregnancy results were compared between the young donors and older recipients. Both donors and recipients shared oocytes from the same induced cohort. Rates for clinical pregnancy and delivery did not differ between donors (33% and 23%) and recipients (40% and 30%). Our data suggest that the age-related decline in female fertility is attributable to oocyte quality and is correctable by ovum donation. The uterus can adequately sustain pregnancies even when reproductive potential is artificially prolonged into the late 40s.
Health inequalities among British civil servants: the Whitehall II study, The Whitehall study of British civil servants begun in 1967. showed a steep inverse association between social class. as assessed by grade of employment. and mortality from a wide range of diseases. Between 1985 and 1988 we investigated the degree and causes of the social gradient in morbidity in a new cohort of 10.314 civil servants (6900 men. 3414 women) aged 35-55 (the Whitehall II study). Participants were asked to answer a self-administered questionnaire and attend a screening examination. In the 20 years separating the two studies there has been no diminution in social class difference in morbidity: we found an inverse association between employment grade and prevalence of angina. electrocardiogram evidence of ischaemia. and symptoms of chronic bronchitis. Self-perceived health status and symptoms were worse in subjects in lower status jobs. There were clear employment-grade differences in health-risk behaviours including smoking. diet. and exercise. in economic circumstances. in possible effects of early-life environment as reflected by height. in social circumstances at work (eg. monotonous work characterised by low control and low satisfaction). and in social supports. Healthy behaviours should be encouraged across the whole of society; more attention should be paid to the social environments. job design. and the consequences of income inequality.
A new look at postoperative instructions following cataract extraction, We sought to determine whether. given the decreasing rate of complications associated with cataract surgery and IOL implantation. postoperative restrictions placed on patients undergoing these procedures could be significantly and safely relaxed. We reviewed the charts of 216 patients who had undergone capsulorhexis or "can-opener" capsulotomy. phacoemulsification. and insertion of an oval IOL over a 3-year period. noting any operative or postoperative complications. All of these patients had been examined the day after surgery and. if no complications were noted. had been instructed only to refrain from activities that produced pain. No shield was required. and no instructions were given to restrict showering. hair washing. or any other normal physical activity. We found no complications related to any postoperative activity. These results suggest that current postoperative instructions typically restricting such patients' activities should be reevaluated.
Errors in IOL power calculations for axial high myopia, We studied 115 eyes with axial lengths of 27 mm or more after implantation of a posterior chamber intraocular lens in order to determine discrepancies between the predicted refractions and the actual postoperative refractions. We then reviewed the three major variables used to predict refractions in these eyes--corneal curvature. anterior chamber depth. and axial length measurements--in an attempt to determine whether any of these variables were correlated with the discrepancies. We found that the main reason for postoperative refractive error was inaccurate measurements of preoperative axial length.
Psychological distress and diagnostic subgroups of temporomandibular disorder patients, This study examined the nature and extent of psychological differences among diagnostic subgroups of temporomandibular disorder (TMD) patients. Three subgroups were identified and labeled as: (1) primary myalgia. (2) primary temporomandibular joint (TMJ) problems. or (3) combination myalgia and TMJ problems. Patients' (n = 112) levels of pain and distress were measured using a VAS pain scale. the McGill Pain Questionnaire. the Beck Depression Inventory. the State-Trait Anxiety Scale and the MMPI. Patients with primary myalgia had the highest scores on the pain and distress measures while patients in the combination group scored between the myalgia and TMJ problem subgroups. When differences in pain levels were controlled. the differences among groups on measures of anxiety and depression were attenuated while the differences on measures of somatic overconcern remained significant. Discriminant function analysis using psychological variables to predict diagnostic grouping produced correct identification of 74% of the structural patients and 46% of the myalgia patients. Implications for different etiological factors among the 3 groups are discussed.
Situational and psychophysiological factors in psychologically induced pain, To investigate pain that occurs in the absence of painful stimulation. normal subjects were connected to a sham stimulator and were told that a headache could occur as a result of the electrical current they would receive. Half of the subjects who received this suggestion reported pain. The frequency and intensity of pain reports in a group which was given prior pain experience as a reference point in reporting pain and in a group which was exposed to a manipulation designed to reduce intentional deception were not significantly different from the pain reports of a group not exposed to these manipulations. The frequency of pain reports in subjects not connected to the sham stimulator but still asked to report pain was 25% which was significantly less than the frequency for subjects who were told there would be stimulation to the head. Pain ratings increased as the settings of the sham stimulator were increased. Subjects who reported pain had significantly fewer electrodermal responses to tones signaling them to prepare for a reaction time task. The results suggest that pain can be produced in the absence of peripheral stimulation. The pain does not appear to be due to intentional deception or the lack of a standard for comparison. but is strongly influenced by environmental cues. Psychophysiologically. pain responders were less attentive to signal stimuli.
Pain and impairment beliefs in chronic low back pain: validation of the Pain and Impairment Relationship Scale (PAIRS), Few validated instruments are available to assess beliefs and attitudes that patients have regarding pain. or ability to function despite discomfort. The Pain and Impairment Relationship Scale (PAIRS) was developed to tap these important beliefs and attitudes in chronic pain patients. Preliminary data indicate that the PAIRS is internally consistent and significantly related to impairment in a highly selected pain clinic sample of patients. including some chronic low back pain patients. The present study was designed to extend the validation of the PAIRS to a more general sample of chronic benign low back pain patients. Furthermore. additional tests supported the discriminant. convergent and divergent validity. as well as the reliability and relative independence from favorable self-report response bias of the PAIRS. by respectively demonstrating that: (1) the impairment beliefs assessed with the PAIRS were more prominent in chronic low back pain (CLBP) patients than in matched non-pain. healthy controls; (2) scores on the PAIRS were significantly related to measures of physical impairment. but not to physicians ratings of disease severity; (3) the impairment beliefs assessed with the PAIRS are readily distinguishable from cognitive distortions and emotional distress; (4) PAIRS scores for chronic low back pain patients are relatively consistent over time; and (5) PAIRS scores are not significantly associated with measures of favorable self-report response bias. We conclude that the PAIRS has demonstrated at least preliminary utility for applications by researchers and clinicians interested in chronic pain.
A comparison of two-point discrimination threshold of tactual, non-painful stimuli between chronic low back pain patients and controls, Differences in pain sensitivity between chronic pain patients and healthy controls have been reported. Seltzer and Seltzer extended this line of research in studying the sensitivity to non-painful stimuli. They reported that the 2-point discrimination threshold of chronic pain patients was higher than that of control subjects. However. the study of Seltzer and Seltzer suffered from several methodological shortcomings. Therefore. in the present study we tried to replicate the findings in a group of chronic low back pain patients using a design that was believed to be methodologically stronger. Replication failed: no evidence was found for the hypothesis that chronic pain patients are less sensitive to non-painful stimuli. Further studies on various defined types of acute and chronic pain patients are required.
The effects of experimenter gender on pain report in male and female subjects, An experiment was conducted that investigated the effect of experimenter gender on the report of pain of male and female subjects. In order to evoke gender-related motives. experimenters were selected for their attractiveness. Subjects were asked to rate cold pressor pain in front of either a male or female experimenter. The results indicated that males reported significantly less pain in front of a female experimenter than a male experimenter. The difference in female subjects was not significant although they tended to report higher pain to the male experimenter.
Iontophoresis versus subcutaneous injection: a comparison of two methods of local anesthesia delivery in children, The relative efficacy of local lidocaine anesthesia administered by subcutaneous injection and by iontophoresis was studied in 13 pediatric renal dialysis patients (ages 11-19 years: mean age 15.8 years). Each patient served as his own control at 3 assessment periods. Each type of anesthetic delivery method was administered to either of 2 fistula sites. Patients used visual analogue scales to rate pain. anxiety. and satisfaction for each method. Behavioral observations were made by an observer and a nurse. Paired sample t tests were used to compare the 2 drug delivery methods for patient. observer. and nurse ratings across assessment periods. There were no significant differences between methods for ratings of anxiety before or during the procedure. The injection of lidocaine was rated as more painful by the observer and nurse (with a trend for patients) than the use of iontophoresis. But. the patients and nurse rated the injection method as more effective. Iontophoresis was never rated as superior to the injection method. even after turning over control of drug delivery by iontophoresis to the patient (sessions 2 and 3). Patients were more satisfied with iontophoresis at session 2 when they took over control. but lost enthusiasm by session 3. Three subjects withdrew from the study due to cutaneous burns and prolonged anesthesia delivery time with iontophoresis. Iontophoresis appears to be effective in reducing the pain of dialysis needle insertion but requires further investigation before it can be considered a viable alternative to subcutaneous injection.
The 'tonic' pain-related behaviour seen in mononeuropathic rats is modulated by morphine and naloxone, This study investigated the sensitivity to pharmacological manipulations of a rating method. adapted from the formalin test. to measure the tonic component of the pain-related behaviour induced by creating a peripheral mononeuropathy with 4 loose ligatures around the common sciatic nerve. Although the adequacy of opioid substances in alleviating neuropathic pain is highly controversial. the effects of morphine (1 mg/kg i.v.) and naloxone (1 mg/and 3 micrograms/kg i.v.) were tested 1-2 weeks after the nerve ligatures were established. when pain-related behaviours were well developed. Morphine (1 mg/kg i.v.) induced a potent and prolonged decrease in the pain-rating score at week 2 after surgery. Either at week 1 or week 2. naloxone elicited a bidirectional dose-dependent action: a further increase in the pain-rating score with the high dose (1 mg/kg i.v.). and a paradoxical decrease in the score with the low dose of 3 micrograms/kg i.v. These effects are comparable to those already described in several rat models of inflammatory pain and. in the same model of neuropathy. using a phasic nociceptive test. the measure of the vocalization to paw pressure. A few differences in the effects of naloxone on tonic and phasic pain are noted and discussed.
Bruxism. How to stop tooth grinding and clenching, Bruxism is an oral habit that is usually due to psychological stress or occlusal discrepancy. It occurs more often in children than adults. Damage to the teeth caused by bruxism is irreversible. However. the underlying cause should be treated in order to avoid further dental and periodontal problems.
Anaerobic infections. The basics for primary care physicians, Anaerobic bacteria constitute a major portion of the normal human microflora. and some of them can cause disease in contiguous body parts. especially if there is a mucosal break. Most anaerobic infections are polymicrobial. Because anaerobes are difficult to culture. diagnosis is often made on the basis of clinical clues. Thus. knowledge of the common sites. predisposing conditions. and other representative features of anaerobic infections is critical. For anaerobic infections above the diaphragm. where Bacteroides fragilis is not a common isolate. high-dose penicillin G therapy is usually sufficient. Addition of clindamycin (Cleocin) or metronidazole (Flagyl. Metryl. Protostat) may be necessary for serious infections. Cefoxitin sodium (Mefoxin) or clindamycin is adequate for most anaerobic infections occurring outside the central nervous system. Metronidazole. chloramphenicol. imipenem. or beta-lactam antibiotics combined with beta-lactamase inhibitors may be preferable for serious infections. Appropriate coverage for aerobic bacteria must be included in the treatment regimen. Drainage of abscesses. decompression of infected spaces. debridement of necrotic tissue. and removal of foreign bodies are critical in management of many anaerobic infections.
Allergic and reactive dermatoses. How to identify and treat them [published erratum appears in Postgrad Med 1991 Aug;90(2):54, The epidermis. as the body's first line of defense against many pathogens. reacts in a variety of ways to the assault of foreign antigens. Allergic contact dermatitis. drug eruption. urticaria. and erythema multiforme are examples. The clinician must usually rely on clinical evidence for diagnosis. The first therapeutic strategy is to identify and avoid the antigen or drug causing the reaction. Beyond this. therapy consists of relief of symptoms in mild to moderate cases. In severe cases. systemic treatment can be helpful. but the therapeutic options and their efficacy are limited.
Alpha 1 blockers. Safe, effective treatment for hypertension, Alpha 1-adrenergic blocking agents. used alone or in combination with other medications. are efficacious in the management of hypertension. They are safe and well tolerated. and they offer unique advantages. Their mechanism of action in lowering blood pressure targets elevated peripheral vascular resistance. which is the principal hemodynamic abnormality of essential hypertension. The alpha 1 blockers maintain cardiac output and blood flow to vital organs. and they do not affect renin release. These agents have beneficial lipid and metabolic effects and can improve left ventricular hypertrophy. theoretically having a positive impact on cardiovascular morbidity and mortality. The only drug interaction identified with the alpha 1 blockers is an increased hypotensive effect when they are combined with other antihypertensive agents. A further advantage of the alpha 1 blockers is that. because of the widespread location of alpha 1 receptors. the agents offer potential benefit for a number of disease states. including benign prostatic hyperplasia. They also provide an especially useful antihypertensive choice for middle-aged and elderly patients.
Diagnosis and management of the acute retinal necrosis (ARN) syndrome, The acute retinal necrosis (ARN) syndrome represents a specific pattern of clinical presentation for certain herpes virus infections in the posterior segment of the eye. The classically described triad of the ARN syndrome consists of (1) an arteritis and phlebitis of the retinal and choroidal vasculature. (2) a confluent. necrotizing retinitis that preferentially affects the peripheral retina. and (3) a moderate to severe vitritis. Anterior segment inflammation. optic neuritis. and late retinal detachment are also common features of this disorder. Definitive evidence now implicates at least two members of the herpes virus family; varicella zoster virus and herpes simplex virus as causative agents. This paper summarizes the clinical presentation. as well as the currently recommended treatment regimen for the ARN syndrome. highlighting recent advances that have resulted in a significant improvement in the visual prognosis for affected patients.
Herpes simplex keratitis: role of viral infection versus immune response, The cumulative clinical and experimental data regarding the role of viral infection versus the immune response in the pathogenesis of herpes simplex stromal keratitis and central disciform endotheliitis are discussed. Ultrastructural and viral isolation studies have been performed in only a limited number of cases of human stromal keratitis and disciform endotheliitis. Virus has been isolated from the minority of corneas cultured. whereas viral particles have been demonstrated in selected cases of stromal keratitis. most of which had been treated with steroids at some point in time. The possibility of corneal latency in cases of quiescent herpetic stromal keratitis will require further systematic study. Review of the experimental and clinical findings suggests a dialectical role of the immune response in limiting viral infection. while contributing to corneal opacification and scar formation.
Clinicopathological study of migratory lung infiltrates, Clinical features and the histological appearances of transbronchial lung biopsy specimens were investigated in 11 patients with migratory infiltrates on the chest radiograph. Serum circulating immune complexes were increased at the time that infiltrates were present in all patients and the levels returned to normal as patients recovered clinically and radiologically. The Mantoux test response was negative in most patients. Fifty serial sections were obtained from each paraffin embedded biopsy specimen block and every 10th section was stained (step sectioning) with haematoxylin and eosin. Six patients (group 1) did not have eosinophilic infiltration; four of these had granulation tissue plugs within respiratory bronchioles when the tissue was examined by step sectioning. All had organising pneumonia and interstitial inflammation in the setting of a clinical picture consistent with bronchiolitis obliterans organising pneumonia. In two cases IgG had been deposited in intraalveolar macrophages. Biopsy specimens in five patients (group 2) showed eosinophilic infiltration; four patients had chronic eosinophilic pneumonia and one the Churg-Strauss syndrome. Step sectioning of transbronchial biopsy specimens in patients with migratory pulmonary infiltrates is useful and may support the diagnosis of bronchiolitis obliterans organising pneumonia.
Effect of cetirizine on exercise induced asthma, The effect of oral and inhaled cetirizine. a potent and specific H1 receptor antagonist. was studied in patients with exercise induced asthma. Twelve patients (five male; mean age 35.2 years) were given oral placebo or cetirizine 10 mg twice daily for one week. double blind and in randomised order. and exercised on a treadmill for six to eight minutes at a submaximal work load two hours after the final dose. There was no significant change in baseline FEV1 after treatment and cetirizine failed to inhibit exercise induced bronchoconstriction (maximum falls in FEV1 28% and 27% of baseline). In a further eight patients (four male; mean age 40.8 years) the effect of 1 ml cetirizine (5 and 10 mg/ml) given through a Wright nebuliser was compared with that of placebo in a double blind trial. The fall in FEV1 after exercise was reduced after both concentrations of cetirizine by 15.2% of baseline after 5 mg/ml and by 10.2% after 10 mg/ml. compared with 23.7% after placebo. In two patients cetirizine had no effect. In a further study cetirizine (10 mg/ml) given by inhalation displaced the geometric mean PC20 histamine 13.1 fold to the right by comparison with placebo. The reason for the difference between the effects of oral and of inhaled cetirizine on exercise asthma is not clear but may be related to differences in local concentration in the airway.
Bronchodilator treatment for partially reversible chronic obstructive airways disease, The effect of six weeks' treatment with inhaled terbutaline (1 mg four times a day). optimised doses of theophylline (twice a day). the combination of theophylline and terbutaline. and placebo was studied in a randomised. double blind. crossover trial. Thirty patients with partially reversible chronic airflow obstruction and a mean forced expiratory volume in one second (FEV1) of 1.2 litres that improved by 25% were included in the study. Patients who developed non-infective exacerbations of airflow obstruction that required additional bronchodilator treatment were classed as "treatment failures." Such treatment failure occurred in 23 patients with placebo. in 22 patients with theophylline. in 12 patients with terbutaline. and in two patients taking the two drugs. Mean daily peak flow readings were highest with the combination of the two drugs. followed by terbutaline and then theophylline. and lowest with placebo. Thus a combination of terbutaline and theophylline was superior to either drug alone; inhaled terbutaline was superior to theophylline alone. Theophylline alone does not appear to have much place in the management of patients with partially reversible obstructive airways disease.
Suction drainage: a new approach to the treatment of empyema, Thirteen patients with empyema thoracis were treated with a new suction drainage technique. The method entails passing a catheter into the empyema cavity under ultrasound guidance and using strong suction to drain loculated pus. Eight patients had no recurrence after a single treatment and one patient had no recurrence after two treatments. The procedure was a useful palliative measure in two patients with malignant disease who subsequently died. In one patient failure of the lung to expand after the procedure showed the need for thoracotomy. In one other patient the empyema recurred and decortication was required.
Early catheter removal vs. conventional practice in patients undergoing transurethral resection of prostate, A retrospective analysis of 127 of 146 consecutive patients undergoing transurethral resection of the prostate from February 1985 to January 1988 (3-year period) was performed. The catheter was removed on postoperative day 1 in 66 patients (group I) and on postoperative day 2 in 61 patients (group II). There were no significant differences between the two groups in terms of population age. weight of resected glands. operative time. and management. Both groups I and II had 8 complications following catheter removal. Postoperative hospital stay was reduced by an average of 1.37 days in group I. Total hospital cost was reduced by approximately $466.00. We conclude that catheter removal on postoperative day 1 is safe with no added morbidity while having the advantage of reduced hospital costs.
Patient satisfaction with Mentor inflatable penile prosthesis, Patient satisfaction with the Mentor inflatable penile prosthesis was assessed by sending a thirty-six-item questionnaire to 251 patients who had undergone implantation of the device by the senior author (D.C.M.). A total of 152 (61%) of the patients responded. Recovery time. satisfaction. reasons for dissatisfaction. perceptions of erection quality. and psychosexual parameters were evaluated. Eight-eight percent of the patients were engaging in regular sexual activity. Depending on the definition of satisfaction. 81-89 percent of the respondents reported that they were satisfied with the prosthesis. Sixty-eight percent of the survey group were satisfied with the length. width. and firmness of their prosthetic-induced erection. The majority of patients reported improvement in psychosexual functioning after implantation. Reasons for dissatisfaction included inadequate penile length. insufficient firmness. and difficulty with inflation and deflation of the penile cylinders.
Urethral pressure changes in women with detrusor instability. Bladder or urethral pathologic process, One hundred and fourteen female patients had clinical and urodynamic diagnosis of detrusor instability. They all received oxybutynin chloride (Ditropan) 5 mg t.i.d. for four weeks and evaluation repeated. Sixty-six of the 114 patients (58%) responded favorably to anticholinergic treatment while 48 patients (42%) did not. Based on urethrocystometry. two groups of patients were identified: Group I consisted of 73 women with bladder contraction that preceded any change in urethral pressure. Group II consisted of 41 patients with urethral pressure drop that preceded the detrusor contraction by a few seconds. Sixty-one of the 73 women (84%) in Group I responded favorably to four weeks of anticholinergic therapy while 88 percent (36 of 41) of women in Group II did not (P less than 0.01). Our results suggest that women with bladder contraction that is preceded by urethral relaxation represent a different pathologic entity than women with "classic detrusor instability".
Xanthogranulomatous pyelonephritis in an infant, An unusual case of xanthogranulomatous pyelonephritis (XGP) in an infant is presented. Findings on magnetic resonance imaging. computerized tomography. ultrasound. and intravenous urography in our patient are contrasted with others reported in the literature. Absent were such commonly seen findings as nonfunctioning kidney. hydronephrosis. urinary calculi. and calcifications.
Morphologic changes in detrusor muscles of patients with chronic obstruction of lower urinary tract. Electronmicroscopic and immunohistochemical findings, The anterior bladder wall and actin- and myosin-like immunoreactivities within the detrusor muscles in patients with chronic obstruction of the lower urinary tract were examined by means of a MOP Videoplan image-processing system. electronmicroscopy. and light microscopic immunohistochemistry. The image-processing system demonstrated an excess of connective tissue elements between smooth muscle bundles in the anterior wall of the bladder similar to the results of previous studies dealing with the trabeculated posterior wall. Under electronmicroscopy. myofilaments were shown to be multidirectionally arranged in the smooth muscle cells in contrast to the regular arrangement in controls. Dense areas in the cytoplasm of the detrusor muscle also appeared to be abnormally distorted and/or elongated in the electronmicrographs. In support of these findings. actin- and myosin-like immunoreactivities in the muscle layer of the bladder were significantly less intense than in the controls. These results suggest that chronic obstruction of the lower urinary tract causes histopathologic alterations in both the intervening connective tissue and the detrusor muscle. This study raises the possibility that the aforementioned morphologic abnormalities are involved in the occurrence of uninhibited detrusor contraction and abnormal detrusor reflex in patients with lower urinary tract obstruction.
Experimental evaluation of furosemide renography in unobstructed and partially obstructed upper urinary tracts in pigs, To evaluate the reliability and the constancy of the furosemide renography an experimental evaluation of the test has been performed. A standardized unilateral partial proximal ureteral obstruction was applied to 11 pigs. Preoperatively and again weekly in the three weeks following obstruction a furosemide renogram (FR) was done. The furosemide renography was a very constant parameter in the unobstructed kidney (85%) and in the partly obstructed kidney (85%). A type I FR pattern (O'Reilly classification) was an exact indicator of an unobstructed pelvis. After partial ureteral obstruction. an immediate change in the FR pattern was seen either into type II or type IIIa renography. In this experimental study furosemide renography was found to be a reliable tool in the differentiation between the unobstructed normal renal pelves and the partly obstructed dilated renal pelves.
Factor XIII subunits in relation to some other hemostatic parameters in ulcerative colitis, The hemostatic parameters. particularly with respect to F.XIII subunits. were examined in 48 untreated UC patients (22 at active and 26 at quiescent stage). UC active patients showed a significant decrease of F.XIII subunit "a." compared with healthy subjects. as well as in UC patients in remission. In contrast. the level of F.XIII subunit "b" in each group was similar. Compared with normal subjects. UC active patients revealed a significant decrease in AT III concentration. prolonged ELT. and elevated fibrinogen level. In addition. the elevated titer of SDPS test for SFMC appeared in approximately 40% of those patients. However. no strict relationship was found between the presence of positive SDPS and diminution of AT III. as well as of F.XIIII subunit "a" in active UC state. In patients in remission. AT III level and ELT were similar to those as in the control group. but fibrinogen concentration was elevated. Such constellation of hemostatic parameters may indicate a tendency to blood hypercoagulability in UC active patients. whereas. in general. these changes are not associated with the stage of remission. The present data may also suggest that F.XIII behavior pattern should be taken into account in the clinical management of UC.
Amebic liver abscess: a 15-year experience, Amebic liver abscess is increasingly common in the United States. particularly in the West and Southwest. due to increased immigration from Southeast Asia. Mexico. and Central America. The presentation. course. and treatment of 50 patients treated for amebic liver abscess at a county-community hospital in San Jose. California. between 1974 and 1988 is reviewed. The typical patient is an immigrant. usually a Hispanic male. 20-40 yr old. who presents with fever. right upper quadrant pain. leukocytosis. abnormal serum transaminases and alkaline phosphatase. and a defect on hepatic imaging study. Available serologic testing (i.e.. indirect hemagglutinin antibody) is sensitive and confirms the diagnosis. Most patients respond rapidly and completely to oral metronidazole. The data. compared with other studies. indicate no major change in presentation or management. except for decreasing need to aspirate the abscess for diagnosis.
Endoscopic therapy for gastric cancer in patients more than 80 years old, We prospectively studied 17 gastric cancer patients who were more than 80 yr old. in whom endoscopic therapy was performed. The patients were divided into two groups: the first group included 13 patients in whom curative treatment was attempted. and in 11 (85%) a curative response was achieved. Two patients in this group showed a positive gastric biopsy after 1 and 2 yr. respectively. of therapy: one patient is under current treatment with laser therapy. and the other patient underwent surgery with resection of the stomach. The second group included four patients in whom treatment was aimed at prolonging survival or palliation. and in all four patients. a successful response was obtained. Therefore. our results demonstrate that endoscopic therapy is effective for the treatment of gastric cancer patients over 80 yr old.
Gastroduodenal mucus gel thickness in patients with Helicobacter pylori: a method for assessment of biopsy specimens, The gastroduodenal mucus layer is considered the primary mucosal protective barrier. especially important in the maintenance of a mucosal pH gradient. Thus. the measurement of the mucus layer thickness in various disease states could advance our understanding of gastroduodenal pathophysiology. We present a novel method for measuring the mucus layer in endoscopic biopsy material and compare layer thickness in Helicobacter pylori (HP)-negative and HP-positive specimens. Endoscopic biopsies were obtained from 17 patients with gastroduodenal mucosa harboring HP and from 15 patients without current HP colonization. The thickness of the mucus layer was measured in fresh specimens by the phase-contrast dark-field microscopy technique. In patients with confirmed HP infection. the thickness of the mucus layer (mean +/- SD) was 0.093 +/- 0.033 mm in duodenal. 0.085 +/- 0.027 mm in antral. and 0.105 +/- 0.033 mm in corporal mucosa. In patients without concomitant HP colonization. the thickness of the mucus gel was 0.162 +/- 0.045 mm. 0.175 +/- 0.067 mm. and 0.161 +/- 0.064 mm in duodenum. antrum. and corpus. respectively. The differences between the means were statistically significant (p less than 0.001 for the duodenal. p less than 0.001 for antral. and p less than 0.01 for corporal mucosa). This study suggests that colonization of the gastroduodenal mucosa by HP impairs the mucus layer covering the surface epithelium. This mucus layer impairment may lead to mucosal injury with subsequent development of inflammation and. possibly. peptic ulcer disease.
Gastric emptying in patients with severe reflux esophagitis, The pathogenesis of gastroesophageal reflux (GER) is not fully understood. There have been reports that delayed gastric emptying is a contributing factor in some patients. To determine whether delayed gastric emptying plays a role in the genesis of GER. we correlated gastric-emptying measures obtained by scintigraphic techniques with the degree of acid reflux assessed by esophageal pH monitoring. Ten patients. all of whom had evidence of esophageal mucosal disease and severe acid reflux. were studied. Four of the 10 patients with reflux had prolongation in the lag phase of gastric solid emptying. and one of the four showed prolonged gastric-emptying t1/2. There was no significant difference. however. in the mean gastric-emptying t1/2 between a control group and the patient group. Furthermore. there was no correlation between gastric-emptying measures and degree of acid reflux. We conclude that in this group of 10 patients with severe GER. delayed gastric emptying does not play an important role in the development of gastroesophageal reflux.
The relationship of sodium balance and concomitant diuretic therapy to blood pressure response with calcium channel entry blockers, Marked heterogeneity exists in the response of blood pressure to specific antihypertensive agents. In general. a single therapeutic agent can be expected to provide an adequate blood pressure response in 40% to 60% of hypertensive patients. The addition of a second agent usually extends the response rate to over 85%. The addition of a diuretic to nondiuretic regimens often produces an additive blood pressure-lowering effect. However. calcium channel entry blockers (CCBs) may be an exception. as diuretics do not appear to improve these agents' efficacy. CCBs have a dual mechanism for blood pressure reduction. In addition to their vasodilatory actions. they also promote diuresis and natriuresis. These features account for the striking efficacy of these agents when used as monotherapy in hypertensive patients. Studies have shown that dietary sodium restriction does not appear to improve the efficacy of CCBs. nor is a high-salt diet predictive of a better therapeutic outcome. Recent studies also indicate that the addition of a diuretic to a CCB does not produce a significant or consistent additive antihypertensive effect. Because CCBs do not produce the typical responses of the renin-angiotensin-aldosterone (RAA) system to sodium/volume depletion. their diuretic and natriuretic effects do not result in the same adverse metabolic consequences as experienced with traditional diuretic therapy.
Improvement of cadaver renal transplantation outcomes with verapamil: a review, Although cyclosporin A (CsA) has allowed substantial advances in organ transplantation due to its immunosuppressive properties. its use is complicated by its direct nephrotoxic effects. Initial studies with mice confirmed that CsA caused a dose-related inhibition of the subcapsular microcirculation; subsequent clinical investigations have confirmed this inhibitory effect. Efforts to circumvent CsA-induced nephrotoxicity have focused on calcium antagonists. For example. when the calcium antagonist verapamil was administered before the initiation of CsA. renal blood flow was maintained. Verapamil therapy was also associated with significantly fewer rejection episodes (3 of 22; 14%) within 4 weeks of transplantation than CsA therapy alone (10 of 18; 56%). In a current study. verapamil 10 mg was injected into the renal artery during surgery. followed by 120 mg tid orally for 14 days. This regimen reduced delayed function incidents (the need for dialysis) during the first post-transplant week. Excluding nonfunctioning kidneys and technical failures. there were no graft losses secondary to rejection in patients treated with verapamil. The beneficial effects of verapamil therapy on transplant outcome may be related to its ability to protect cells from ischemia. the selective vasodilation of the efferent arteriole. elevated CsA blood levels. and inherent immunosuppressive properties.
Oral contraceptive use and coronary risk factors in women, The relationship between oral contraceptive use and other coronary artery disease risk factors was examined in 215 nonsmoking women grouped as never. current. or previous users. Current oral contraceptive users had higher triglyceride levels (p less than or equal to 0.001) than other groups. higher systolic blood pressure. and lower plasma HDL-cholesterol levels (p less than or equal to 0.05) than previous users. The effect of oral contraceptive use on plasma triglyceride values persists on multivariate regression analysis independently of age. body mass index. dietary sodium and cholesterol intake. cigarette smoking. and level of physical activity. Oral contraceptive use also has an independent relationship to the plasma total cholesterol/HDL- cholesterol ratio. These findings indicate that oral contraceptive use is adversely associated with plasma lipid and lipoprotein values.
Urinary albumin excretion in patients with familial Mediterranean fever: a pilot study, Amyloidosis of the kidney is the most threatening complication in familial Mediterranean fever (FMF). and colchicine has been shown to reduce its occurrence. In the preclinical stage of kidney amyloidosis. no proteinuria is observed by the standard Albustix method. However. whether these patients have normal or increased urinary albumin excretion is not known. The purpose of this study was to evaluate albumin excretion in FMF patients treated with colchicine and to compare these values to those of a normal control group. Twenty-two subjects with FMF were compared with 16 normal subjects matched with regard to age and body surface area. The two groups did not differ with regard to female/male ratio and arterial pressure. Urine samples were collected overnight while patients were recumbent and in the daytime while they were ambulant. After measuring albumin concentration (Ua) by radio-immunoassay and creatinine concentration through the standard method. the urinary albumin excretion rate (UaV) and urinary albumin creatinine ratio (Ua/c) were calculated. In the FMF group. three patients had microalbuminuria--defined as an albumin excretion rate higher than 20 micrograms/min. Two of them had this condition only in the early morning collection. These three patients were characterized by a longer duration of symptoms (18 vs. 9 years). No patient in the control group had microalbuminuria. The mean UaV in the FMF group did not differ significantly from that of the control group.
Medical problems of homeless and nonhomeless persons attending an inner-city clinic: a comparative study, The identification of homelessness as a national problem has focused attention on defining the needs of this sizable population. Existing studies on the medical problems of the homeless are largely descriptive and are limited by lack of comparison to nonhomeless persons. To help fill this gap in knowledge. we conducted a retrospective study of the medical problems of homeless and nonhomeless persons cared for in an outpatient clinic serving the medically indigent. Homeless persons (n = 150) were more likely to be identified as alcoholic and to be seen for cuts and gynecologic problems than nonhomeless persons (n = 154) (p less than .01). There were no significant differences in the occurrence of other illnesses considered to be prevalent in the homeless. This study is among the first that validates descriptive data on the health problems of homeless persons by using concurrent nonhomeless controls. It may help in designing programs to meet the medical needs of the homeless.
Case report: serendipitous Gaucher's disease presenting as elevated erythrocyte sedimentation rate due to monoclonal gammopathy, Immunoglobulin abnormalities have not been previously noted in totally asymptomatic patients with Gaucher's disease. We report a 40-year-old woman in whom Gaucher's disease was diagnosed during investigation for incidentally discovered elevated erythrocyte sedimentation rate. Further studies revealed IgG(lambda) monoclonal gammopathy. Physical examination and a bone survey disclosed none of the features of Gaucher's disease or multiple myeloma. We conclude that in contrast with previous observations. paraproteinemia may occur with Gaucher's disease even in the absence of splenomegaly or any one of the other features of the disease.
Moricizine: a new agent for the treatment of ventricular arrhythmias, Over the last several years. a number of new antiarrhythmic agents have come into use. One of these promising new drugs. moricizine hydrochloride (Ethmozine). is now available for use in this country. Although similar in some aspects to both quinidine and lidocaine. Moricizine hydrochloride is in many ways unique. The purpose of this review is to summarize the pharmacologic and physiologic effects of moricizine and to outline its clinical use.
Antihypertensive therapy and atherosclerosis, Hypertension and atherosclerosis make independent contributions to the pathogenesis of cardiovascular disease. Diuretics and beta adrenergic blockers. effective antihypertensive medications. exhibit some untoward effects on lipid metabolism. while most other antihypertensive medications tend not to exhibit such effects. In animal models. beta adrenergic blockers. angiotensin converting enzyme (ACE) inhibitors. and calcium antagonists have anti-atherogenic effects. A vascular biological approach to therapy for the patient with both hypertension and atherosclerosis is recommended. This includes effective reduction of blood pressure--preferably with agents that do not adversely affect lipid metabolism--and treatment of lipid metabolism disorders.
The role of azalide antibiotics in the treatment of Chlamydia, Chlamydia trachomatis causes an estimated 4 million infections each year in the United States. Sequelae in women include infertility and ectopic pregnancy. Doxycycline. the current standard therapy. must be taken twice daily for at least 7 days. Patient compliance is often poor. leading to recurrent disease. Azithromycin. a new antibiotic of the azalide class. achieves high and sustained intracellular levels and demonstrates excellent in vitro activity against C. trachomatis. Reported herein are the results of three comparative clinical trials. which demonstrate that single-dose oral therapy with azithromycin is as effective as a standard 7-day twice-daily course of doxycycline in the treatment of uncomplicated genital infections caused by C. trachomatis.
Unilateral frosted branch angiitis, We examined two patients with monocular frosted branch angiitis. The patients were young and healthy; they rapidly developed severe visual loss with thick. white sheathing of the retinal veins and responded promptly to systemic corticosteroids. The fluorescein angiograms showed late leakage from the retinal veins. without evidence of stasis or occlusion. Frosted branch angiitis can be either a unilateral or a bilateral condition. We believe the potential for visual loss and the prompt response to systemic corticosteroids make early. accurate diagnosis and institution of therapy desirable.
The effect of topical antiglaucoma drugs on the results of high-pass resolution perimetry, We conducted a randomly assigned. double-masked. crossover study of the effects of betaxolol. epinephrine. pilocarpine. and timolol on the high-pass resolution perimetry results in normal subjects. The influence of topical administration of these intraocular pressure-reducing drugs was negligible. which confirmed the reliability of high-pass resolution perimetry results. The method seems appropriate for the diagnosis of glaucoma and the follow-up of patients with glaucoma.
Pseudophakic pupillary-block glaucoma in children, We studied 16 children. ranging in age between 3 and 8 years. who had posterior chamber intraocular lens implantation and developed inflammatory pupillary-block glaucoma. Prophylactic peripheral iridectomy had not been performed in any of the eyes. The patients were treated medically. and YAG laser iridotomy was performed successfully one week after initial control of intraocular pressure. Of 16 eyes in which intraocular pressure remained uncontrolled. trabeculectomy was necessary in three eyes and irreversible glaucomatous visual loss occurred in two eyes. Our data demonstrate the need for stringent and more frequent postoperative follow-up of children after intraocular lens implantation. especially during the first four postoperative weeks. Careful long-term follow-up for treatment after cataract is mandatory to prevent development of amblyopia.
Optic nerve sheath decompression for the treatment of progressive nonarteritic ischemic optic neuropathy, We performed optic nerve sheath decompression on four patients (five eyes) with visual loss secondary to nonarteritic anterior ischemic optic neuropathy. Four of the five eyes had marked improvement in visual function after the operation. Optic nerve sheath decompression is an effective treatment for patients with nonarteritic ischemic optic neuropathy and progressive visual loss.
The effect of preoperative flurbiprofen on miosis produced by acetylcholine during cataract surgery, Sustained pupillary dilation during cataract surgery may be achieved with preoperative noncorticosteroidal anti-inflammatory agents such as flurbiprofen. However. these agents may interfere with miosis after injection of acetylcholine. Thirty patients for extracapsular cataract extraction were randomly assigned in a double-masked fashion to receive either a placebo or preoperative 0.03% flurbiprofen every 30 minutes for four doses. All patients also received three doses of 2.5% phenylephrine and 2% cyclopentolate. Pupillary diameter was measured the day before surgery. immediately before the surgical incision. immediately before and five minutes after acetylcholine injection. and the morning after surgery. The flurbiprofen group had a larger mean pupillary diameter before injection of acetylcholine (P less than .001). five minutes after acetylcholine (P less than .001). and on the first postoperative day (P less than .005).
The effect of allograft rejection after penetrating keratoplasty on central endothelial cell density, We identified all patients who had undergone penetrating keratoplasty for keratoconus and were being observed longitudinally (N = 174). During the follow-up period. 57 of 174 patients (33%) showed evidence of an allograft rejection episode. which occurred at an average of eight months after the operation. We analyzed specular photographs of the corneal endothelium. taken before and after the first allograft rejection episode. A significant decrease in endothelial cell density was observed (11.8%. P less than .0001). As a control. we analyzed all available specular photographs from patients with keratoconus who showed no evidence of allograft rejection after penetrating keratoplasty. The observed endothelial cell density decrease (11.8%) in patients with keratoconus undergoing allograft rejection exceeded that found in the control subjects (6.8%) during a comparable time period (P = .06). Severe allograft rejection episodes resulted in a decrease in endothelial cell density that exceeded expected loss significantly (14.8% compared with 6.9%. P = .01). whereas mild allograft rejection episodes were not associated with a loss in endothelial cell density exceeding that expected (1.8% compared with 6.5%. P = .34).
Analysis of athletic performance with prophylactic ankle devices, We evaluated the effect of different ankle support devices on athletic performance. Thirty varsity college athletes were tested with both ankles supported by taping. Swede-O brace. Kallassy brace or left unsupported. The athletes performed four events: broad jump. vertical leap. 10 yard shuttle run. and 40 yard sprint. The events and appliances were randomized to prevent bias by fatigue. Compared to the results when no support was used. ankle taping resulted in a significant decreased performance in the vertical jump (4%). shuttle run (1.6%). and sprint (3.5%) (P less than 0.05). Use of the Swede-O brace decreased performance in the vertical jump (4.6%). broad jump (3.6%). and time of the sprint (3.2%). Results using the Kallassy brace showed a decrease in the vertical jump (3.4%) when compared to no support. The test results of the shuttle run with taping were slower than the Kallassy brace (P less than 0.05). Wearing the Swede-O brace caused the athletes' broad jump distance to decrease more than the Kallassy brace (P less than 0.05). Subjective questionnaires supported the Kallassy brace as the most comfortable support and the one that decreased performance the least. Taping of the ankles is universally accepted for ankle prophylaxis. This study has shown a decrease in performance when ankles are taped compared to ankles with no protection. Since the decreases in performance caused by ankle braces are minor. this should not be used as a criterion for selection of prophylactic support compared to taping.
Analysis of subjective knee complaints using visual analog scales, A questionnaire using a system of visual analog scales was developed for analyzing subjective knee complaints. This system was tested on 117 consecutive patients who had undergone knee surgery and 65 patients at their initial office evaluation of a knee disorder. The validity of and patient affinity for this type of questionnaire was compared with that of three other established subjective evaluation methods. The visual analog scale system was shown to be valid and comparable to other methods while offering several advantages. It brought greater sensitivity and greater statistical power to data collection and analysis by allowing a broader range of responses than did traditional categorical responses. It removed bias that was introduced by examiner questioning. and it allowed graphic temporal comparisons. Most importantly. patient affinity was higher for this type of subjective evaluation than for other methods.
Chondromalacia and chronic anterior instabilities of the knee, In this study. we surveyed a consecutive series of 500 patients who had undergone an open procedure for chronic anteromedial and/or anterolateral instabilities. Those patients who had an open arthrotomy were separated for analysis. All of the patients were examined before and during surgery. A knee sheet. based on the kind used at the Hughston Orthopaedic Clinic in Columbus. Georgia. was used to record all clinical findings. Chondromalacia of the articular surface of the femur was detected at surgery in 161 patients (32%). A statistical analysis showed that the variables directly influencing degenerative changes of the cartilage are: a previous surgery that did not sufficiently restore joint kinematics (chi square = 20.238. P less than 0.001) and a time lapse of more than 30 months between first trauma and surgery (chi square = 21.736; P = 0.001). A higher score on dynamic (jerk or pivot shift) and static (internal and external anterior drawer) tests. indicating instability. or a meniscal tear alone do not statistically correlate with chondromalacia. but together they influence degenerative changes of the cartilage.
Injuries in high-risk persons and high-risk sports. A longitudinal study of 1818 school children, In this Dutch population-based study we attempted to determine the incidence and severity of sports injuries occurring during different kind of sports in a longitudinal way. The study included 1818 school children aged 8 to 17 years. Over a period of 7 months. 399 sports injuries were reported in 324 youngsters. The most common types of injuries were contusions (43%) and sprains (21%). Medical attention was needed in 25% of all cases. Young basketball. handball and korfball players had a nearly 100% chance of suffering one sports injury per year. Volleyball especially had a high incidence rate in practice (6.7 in 1000 hours). Although physical education classes had a low incidence rate. there were significantly more fractures on the upper limb. Etiologically. sports-related factors were much more important than personal-bound factors. The injured youths spent more time in practice than the noninjured ones. both in organized and nonorganized sports (P less than 0.001). High-risk sports were characterized by contact. a high jump rate. and indoor activities. These three factors explained 78% of the total variance. The contact versus noncontact factor accounted for 48% of the medically treated injuries. An additional goal of this study was to explore the seasonal influence as an extrinsic environmental factor. We found that the duration of injury was increased in the spring (P less than 0.05). Specific preventive measures were formulated in order to reduce the number of new and recurring injuries and a proposal was made to implement injury prevention in school curriculums.
Comparative reflex response times of vastus medialis obliquus and vastus lateralis in normal subjects and subjects with extensor mechanism dysfunction. An electromyographic study, Reflex response times of the vastus medialis obliquus and vastus lateralis were evaluated in 41 normal subjects and 16 patients with extensor mechanism dysfunction. The reflex response times for both muscles to a patellar tendon tap were evaluated by electromyography. The latencies of the muscles were statistically analyzed in both groups. In normal subjects. one-tailed paired-sample t-tests determined that the vastus medialis obliquus fired significantly faster than the vastus lateralis (P less than 0.001). In the patients. the vastus lateralis fired significantly faster than the vastus medialis obliquus (P less than 0.001). A chi square goodness of fit test demonstrated a dependency between the order of muscle firing and the type of subject (P less than 0.001). Two-tailed independent-sample t-tests revealed that the patients demonstrated a significantly faster vastus lateralis response time than the normal subjects (P less than 0.001). whereas the vastus medialis obliquus times were not significantly different. This increase in vastus lateralis reflex response time may indicate a motor control problem in the patient with extensor mechanism dysfunction. Results indicate that there is a reversal of the normal muscular firing order between the two muscles in these patients. Patients with extensor mechanism dysfunction may be demonstrating a neurophysiologic motor control imbalance that may account for or contribute to their anterior knee pain.
An analysis of the pivot shift phenomenon. The knee motions and subluxations induced by different examiners, The description of the pivot shift test and its modifications is for the most part based on clinical observations. We wished to precisely determine the knee motions and medial-lateral tibiofemoral compartment subluxations that examiners induce in the knee joint to produce the pivot shift phenomenon. Eleven skilled knee surgeons performed the pivot shift test on an instrumented cadaveric lower limb. The anterior cruciate and superficial medial collateral ligaments (long fibers) of one limb were sectioned to produce an abnormal state. An instrumented spatial linkage allowed all six degrees of freedom motions to be measured. Before and after ligament sectioning we determined the limits of knee motion under defined loading conditions. The tibial and femoral bony landmarks were digitized to determine the positions of the medial and lateral tibial plateaus in reference to the femoral condyles during the pivot shift tests. Each examiner performed his pivot shift test. The analysis of the data showed that examiners typically induced a coupled anterior translation and internal tibial rotation to produce an anterior tibial subluxation. and a coupled posterior translation and external tibial rotation to induce the reduction event. The magnitude of anterior subluxation of each plateau depended upon the examiner's technique. The maximal anterior subluxation of the lateral tibial plateau varied from 14 to 19.8 mm (mean. 17.2 +/- 2.0 mm). whereas anterior subluxation of the medial tibial plateau ranged from 6 to 16.9 mm (mean. 11.2 +/- 3.3 mm).
Anterior knee motion analysis. Measurement and simultaneous radiography, Sixteen patients with a clinically diagnosed chronic ACL deficient knee on one side and a contralateral ACL intact knee were evaluated by arthrometry and simultaneous radiography after epidural anesthesia was induced. The posterior cruciate ligament was intact in all knees. This paper reports only the anterior position of the tibia at the 89 N anterior force level of the KT-1000 arthrometer (as read from the dial) and the anterior tibial position recorded simultaneously by radiography at the 89 N dial tone. A 3 mm difference in anterior tibial position between the two knees of the same patient was considered diagnostic for ACL deficiency. Arthrometrically. 13 of the 16 patients were diagnosed accurately; radiographically. 13 of the 16 met the criterion. Moderately high significant positive correlation of paired values was obtained in ACL deficient knees by the two methods (correlation. 0.58 and two-tail probability. 0.02). In ACL intact knees there was no correlation of paired values (correlation. 0.01 and two-tail probability. 0.98). We found no numerical equivalency between the measurements obtained by the KT-1000 and simultaneous radiography. Neither did we find an apparent pattern to the differences. or formula we could use to interpolate findings of anterior tibial position from one measurement system to the other. We conclude that an examiner can substantiate a clinical diagnosis of chronic ACL deficiency with both methods. Arthrometry alone may be used to repeatedly follow conservatively treated ACL deficient knees without exposing the patient to radiation. Radiographs obtained under known anterior force levels provide a retrievable record to document the exact tibial position in relation to the femur.
The assessment of work-related activities and limitations in knee disorders, The success of knee treatment programs and surgery must be assessed. in part. by both the ability to return patients to work and the documentation of any work-related limitations. Existing occupational rating scales do not rate. in a valid manner. the effect of altered knee function on work activities. We performed a prospective randomized clinical trial in which two different occupational rating systems were tested on 50 patients. One system used job titles and an arbitrary numeric scale for rating occupations; the other used specific criteria for rating job functions according to the intensity. frequency. and duration of certain tasks. The results showed that an effective and valid rating format should consist of five specific objectives: 1) evaluation of different knee functions that typically occur in the work environment; 2) evaluation of work activities separately from sports activities; 3) detection of patients who may have remained at an occupation but who have significantly modified work activities because of knee symptoms; 4) identification of patients who continue to work despite experiencing moderate to severe symptoms; and 5) identification of patients whose work activities decrease because of nonknee-related factors. Furthermore. the results showed that an effective rating system should identify common data reduction errors that can bias the results in analyzing knee-related occupational limitations. The rating system developed circumvents the bias introduced by these anomalies. This system. if adopted by other researchers. would allow for the comparison of treatment results among studies.
Nonunion of a first rib fracture in a gymnast, Isolated fracture of the first rib is uncommon. but has been reported to occur in sports such as basketball. baseball. and dancing. It has not been reported to occur in gymnasts. Usually. these fractures heal with an adequate period of rest. Rarely do first rib fractures become nonunions. They have been felt to be asymptomatic and are usually found incidentally on routine chest roentgenograms. Symptomatic nonunion of a first rib fracture has not been reported previously. Our patient did not respond to nonoperative treatment and required surgical intervention to alleviate her symptoms. We agree that most fractures of this type heal without complications. However. if a persistently symptomatic nonunion ensues. we suggest transaxillary resection of 90% or more of the first rib.
The spectrum of liver and spleen injuries in children: failure of the pediatric trauma score and clinical signs to predict isolated injuries, STUDY OBJECTIVES: To determine whether potentially life-threatening intra-abdominal injuries occur in the absence of multisystem trauma in children. and to determine the usefulness of physical examination and a pediatric triage score in the assessment of liver and spleen injuries in children. DESIGN: Retrospective study. SETTING: Admissions to a children's hospital from October 1982 through September 1989 who were found to have liver or spleen injuries. Seventy-seven patients were identified; 55 were male. 22 were female. Mean age was 9 years and 3 months (+/- 56 months) with a range of 22 months to 20 years. 4 months. Clinical signs were recorded and a Pediatric Trauma Score (PTS) and Injury Severity Score (ISS) were calculated for each patient. MEASUREMENTS AND MAIN RESULTS: Fifty-four patients (70%) had a spleen injury. 18 (23%) had a liver injury. and five (7%) had both liver and spleen injuries. Patients were managed without surgery in 63 of 77 cases (82%); two died. Fifty-one of 77 patients (66%) received an ISS of 18 or less; 26 patients (34%) received a score of more than 18. Forty-four of the 51 patients (86%) with an ISS of 18 or less had a normal pulse (120 or less); 48 of the 51 (94%) had a normal systolic blood pressure (90 mm Hg or more). A strong negative correlation (r = -0.80; P = .001) was found between the two scores for children with multiple severe injuries (ISS of more than 18); there was poor correlation (r = -0.04; P greater than .05) between the two scores for isolated liver or spleen injury (ISS of 18 or less). CONCLUSIONS: We conclude that liver or spleen damage may be present in children without other injuries and must be considered with a high index of suspicion. and that neither the initial clinical findings nor the PTS reliably predicts liver or spleen injuries in children with focal abdominal injuries.
Pediatric ingestions: charcoal alone versus ipecac and charcoal, STUDY OBJECTIVES: To determine the effect of syrup of ipecac (SOI) on time to receive and retention of activated charcoal (AC) and on total ED time. DESIGN: During a two-year period. patients were enrolled in a prospective. randomized. unblinded. controlled trial. SETTING: All patients were recruited and studied in a pediatric emergency department. PARTICIPANTS: Seventy children less than 6 years old (mean age. 2.4 +/- 0.2 years) who presented with mild-to-moderate acute oral ingestions. INTERVENTIONS: Group 1 received SOI before AC. Group 2 received only AC. MEASUREMENTS AND MAIN RESULTS: Group 1 patients took significantly longer to receive AC than group 2 from the time of ED arrival (2.6 +/- 0.1 vs 0.9 +/- 0.1 hours. P less than .0001). Group 1 children were significantly more likely to vomit AC than were group 2 children (18 of 32 vs six of 38. P less than .001). Patients receiving SOI who were subsequently discharged spent significantly more time in the ED than those receiving only AC (4.1 +/- 0.2 vs 3.4 +/- 0.2 hours. P less than .05). CONCLUSIONS: Ipecac delays the administration of AC. hinders its retention. and prolongs ED time in pediatric ingestion patients. These data support the recommendation that AC alone should be the gastrointestinal decontamination method of choice for the mild-to-moderate pediatric ingestion patient presenting to an ED.
Pediatric poisoning from over-the-counter imidazoline-containing products, We present two instructive cases of imidazoline poisoning in young children. Imidazoline decongestants. readily available in numerous non-prescription preparations. can rapidly produce toxicity from oral ingestion and topical application. Signs and symptoms depend on whether peripheral or central alpha 2-adrenergic receptor stimulation predominates. Timely diagnosis depends on a high index of suspicion and careful questioning about the availability of these over-the-counter products. Standard toxicologic management will prevent significant morbidity. No specific antidote exists.
Laparoscopic cholecystectomy, This article describes the first 50 laparoscopic cholecystectomies emphasizing the two-handed technique that is currently used at Marietta Surgical Center. Marietta. Georgia. This procedure has become primarily an outpatient procedure with resumption of normal activities in 7 days (including athletics). Two patients in this series had complications. One patients was converted to an open procedure because of a common duct injury. The other patient developed a biloma 2 weeks following surgery and recovered uneventfully following paracentesis on an outpatient basis.
Bacteriology of the appendix and the ileum in health and in appendicitis, The bacteriology of the ileum and the appendix in appendicitis patients with or without perforation and compared with patients who had "incidental appendectomy" was studied. Of 42 appendicitis patients. 24 (57%) of them had anaerobic bacteria in the appendix compared with two of eight (25%) with normal appendix. Anaerobes were found in the ileal aspirates of 20 of 42 (47.6%) appendicitis patients and two of eight (25%) in normal persons. This suggests that anaerobic bacteria increasingly colonize the appendix and the ileum in cases of appendicitis.
Laparoscopic trancystic choledocholithotomy as an adjunct to laparoscopic cholecystectomy, Laparoscopic cholecystectomy is rapidly becoming the standard operation for symptomatic cholelithiasis. Initially. common duct stones presented a barrier to this treatment modality and are said to be unsuspected in 5-9 per cent of patients. A technique is described that removes common bile duct stones through the cystic duct with a flexible nephroureteroscope. thereby extending the range of laparoscopic cholecystectomy.
Gastrointestinal endoscopy and general surgical practice. Surgical endoscopy versus surgeon endoscopists, Endoscopic studies and treatment are a necessary and vital component of General Surgery practice. Since most of the concepts related to therapeutic endoscopy were conceived and developed in the context of surgical science. it is both appropriate and necessary that surgeons continue their involvement with this modality. Furthermore. within the evolution of surgical science. endoscopic tools will continue to be utilized.
Anastomotic recurrence of carcinoma of the colon and rectum. The value of endoscopy and serum CEA levels, The early diagnosis of anastomotic recurrence after surgery for carcinoma of the colon and rectum is difficult. Whether repeat colonoscopy and serial serum CEA measurements were useful in diagnosing early anastomotic recurrence was examined. A total of 112 patients with carcinoma of the colon and rectum who had undergone resection and anastomosis were followed with frequent colonoscopy and serum CEA measurements. Seventeen patients developed anastomotic recurrence. Fourteen patients had elevated serum CEA levels. and 15 patients had endoscopic evidence suggesting recurrence at the anastomotic site. CT scans of the abdomen and pelvis demonstrated metastatic disease in seven patients. localized anastomotic disease in six patients. and no evidence of disease in four patients. Laparotomy was then carried out in 10 patients. In eight of 10 patients. it was possible to resect localized disease. In a 3-year follow-up study. eight patients were alive. four without any evidence of recurrent disease. Repeat colonoscopy and serum CEA measurements are recommended as postoperative surveillance for carcinoma of the colon and rectum. In select cases laparotomy and resection may prolong survival.
Granular cell tumor of the eyelid, We present a case of granular cell tumor of the eyelid. Although commonly reported elsewhere in the body. this entity rarely occurs in the ocular adnexa.
Pathogenesis of retinal dystrophy in the Royal College of Surgeons rat, The Royal College of Surgeons (RCS) rat is an animal with genetically transmitted progressive retinal dystrophy. We compared histopathologically the RCS rat retina with normal age-matched control retinas (Long-Evans rats) using light and scanning electron microscopy. Retinal degeneration begins with alteration of the rod outer segments. There is a progressive involvement of the entire retina. with all layers affected by 45 days. The three-dimensional view obtained with scanning electron microscopy provides another perspective on the pathogenetic changes of the RCS retina.
Pulmonary edema presenting as positive vitreous pressure, The ocular causes of increased vitreous pressure during intraocular surgery are well known. It can also be precipitated by systemic causes. We describe a patient whose first manifestation of pulmonary edema was forward bowing of the iris and posterior capsule and to increased vitreous pressure. The possible perioperative causes that may contribute to the production of pulmonary edema are examined. Recommendations for dealing with these are presented.
Once-daily aminoglycoside therapy, The once-daily administration of aminoglycosides is an attractive concept. In animal experiments and clinical trials. there is either a reduction in or no influence on the risk of toxicity. Less frequent dosing reduces the contact time between host tissue binding sites and drug. Thanks to the PAE and perhaps other as-yet-unrecognized factors. the fall in the level in serum below the MIC does not appear to impair antibacterial efficacy; in fact. the higher peak level in serum may enhance drug efficacy early in a dosage interval. In neutropenic patients. the in vivo PAE may be lost or small-colony variants with a shorter PAE may be selected unless a concomitant beta-lactam is administered. Because it will be some time before data from clinical trials in the United States are available. because the results from the international trials are encouraging. and because there is potential benefit to patients. it seems reasonable for infectious diseases consultants to cautiously initiate the educational process necessary to implement once-daily aminoglycoside therapy in their institutions.
Efficacy of a loading dose of oral chloroquine in a 36-hour treatment schedule for uncomplicated plasmodium falciparum malaria, The efficacy of a loading dose of 20 mg of chloroquine per kg of body weight per os given at intervals during the first day was evaluated in 27 patients in Madagascar with Plasmodium falciparum malaria. The conventional regimen of 25 mg/kg over 3 days (schedule 1) was thus compared with a regimen of 30 mg/kg over 2 days (schedule 2; one dose of 10 mg/kg followed by two doses of 5 mg/kg at 6-h intervals on the first day and two doses of 5 mg/kg at 12-h intervals on the second day) in terms of their clinical and parasitological efficacies. tolerance. and drug concentration-time curves. At 24 h schedule 2 gave higher chloroquine levels in blood. which induced a more rapid decrease in parasitemia. The time required for a 50% decrease in the initial parasitemia was shorter in patients on schedule 2 (14.3 +/- 1.6 h) than it was in patients on schedule 1 (35.5 +/- 5.4 h; P less than 0.01). Moreover. negative blood smears were obtained more rapidly with schedule 2 (50.8 +/- 3.7 h) than with schedule 1 (72 +/- 8.7 h). As predicted by the drug concentration-time curve. no high. potentially toxic peak drug concentration appeared and no adverse effects were observed with the loading dose regimen (schedule 2). These findings support the idea that a loading dose of 20 mg/kg given at intervals during the first 12 h is well tolerated and can be used to obtain a more rapid decrease in parasitemia and to shorten the treatment time of uncomplicated chloroquine-susceptible falciparum malaria in the field.
Comparison of the effects of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo, A study was performed to investigate the pharmacodynamics of aztreonam and tigemonam against Escherichia coli and Klebsiella pneumoniae in vitro and in vivo. The in vitro concentration-effect relationships were determined in short-term growth experiments. The in vivo dose-effect relationships were determined in an experimental thigh muscle infection in irradiated mice. In this model. E. coli was injected into one thigh muscle and K. pneumoniae was injected into the other. Throughout these experiments aztreonam was administered subcutaneously and tigemonam was administered orally. For analysis of the antibacterial pharmacodynamics. the following parameters were determined: the maximum effect as a parameter for efficacy. the 50% effective concentration (or dose) as a parameter for potency. and the slope of the concentration-effect relationship. To assess the relationship between the concentration of the antibiotic and the antibacterial effect in vivo. the pharmacokinetics of the two drugs in the plasma of mice were determined as well. The maximum in vitro and in vivo effects of aztreonam and tigemonam against both bacteria did not differ substantially. However. both drugs killed E. coli more effectively than K. pneumoniae. indicating that the maximum in vitro effect of these drugs against E. coli was higher than that against K. pneumoniae. The maximum in vivo effect of both drugs against E. coli was similar to that against K. pneumoniae. Furthermore. in vitro aztreonam was about twice as potent as tigemonam. but in vivo the reverse was the case. These findings were explained by pharmacokinetic differences between subcutaneously administered aztreonam and orally administered tigemonam. because concentrations of tigemonam in plasma remained at microbiologically active concentrations longer than those of aztreonam did.
In vitro and in vivo antibacterial activities of E-4497, a new 3-amine-3-methyl-azetidinyl tricyclic fluoroquinolone, The in vitro and in vivo antibacterial activities of a new tricyclic fluoroquinolone. E-4497 [S(-)-9-fluoro-3-methyl-10-(3-amine-3-methyl-azetidin-1-yl)-7-oxo- 2.3-dihydro- 7H-pyrido-(1.2.3-de)-1.4-benzoxazine-6-carboxylic acid]. were evaluated in comparison with those of DR-3355 [S-(-)-ofloxacin]. norfloxacin. and ciprofloxacin. E-4497 was more potent than norfloxacin and as potent as or more potent than DR-3355 and ciprofloxacin against Staphylococcus spp.. Streptococcus spp.. and Enterococcus faecalis. With the exception of Providencia spp.. E-4497 inhibited 90% of the Enterobacteriaceae at less than or equal to 0.25 micrograms/ml. Against enteric bacteria. E-4497 was similar in potency to norfloxacin but less potent than DR-3355 and ciprofloxacin. For Pseudomonas aeruginosa. the MICs of E-4497. DR-3355. norfloxacin. and ciprofloxacin for 90% of strains were 2. 2. 4. and 0.5 micrograms/ml. respectively. Against Clostridium perfringens and Bacteroides fragilis. E-4497 (MICs for 90% of strains. 2 and 8 micrograms/ml. respectively) was two- to fourfold more active than norfloxacin and ciprofloxacin. E-4497 activity decreased moderately in the presence of 10 mM Mg2+. Urine at pH 5.5 caused a significant decrease in activity compared with urine at pH 7.2. However. the presence of serum either had no effect or increased the activity of E-4497. In general. E-4497 was bactericidal at the MIC. In systemic infections with Staphylococcus aureus. Streptococcus pyogenes. Escherichia coli. and Pseudomonas aeruginosa in mice. the protective effect of E-4497 was generally greater than that of norfloxacin and comparable to those of DR-3355 and ciprofloxacin.
Pseudomonas pseudomallei, a common pathogen in Thailand that is resistant to the bactericidal effects of many antibiotics, The purpose of this investigation was to identify newer antimicrobial agents that may be useful in the therapy of melioidosis. The in vitro susceptibilities of 199 clinical isolates of Pseudomonas pseudomallei to 22 antibiotics were determined by standard disk diffusion. and those to 13 antibiotics were determined by agar dilution. Over 90% of the isolates were susceptible to imipenem. piperacillin-tazobactam. piperacillin. ceftazidime. ticarcillin-clavulanate. ampicillin-sulbactam. and carumonam by both methods. Standard disk diffusion yielded unacceptably high false-susceptibility results with aztreonam. ciprofloxacin. and temafloxacin. Piperacillin. ceftazidime. imipenem. and ciprofloxacin were not bactericidal for three selected P. pseudomallei strains as determined by time-kill curve methods. Furthermore. addition of ciprofloxacin to piperacillin. ceftazidime. or imipenem did not enhance bactericidal activity. One hundred ninety-four strains showed weak beta-lactamase production that did not increase upon incubation with cefoxitin. These findings suggest that several newer antimicrobial agents may prove useful in the treatment of melioidosis. However. results of susceptibility studies involving P. pseudomallei and newer agents must be interpreted with caution.
SDZ MRL 953, a novel immunostimulatory monosaccharidic lipid A analog with an improved therapeutic window in experimental sepsis, SDZ MRL 953. a new synthetic monosaccharidic lipid A. was investigated in vitro and in vivo for immunopharmacological activities. In experimental models of microbial infections. the compound was highly protective when it was administered prophylactically either once or three times to myelosuppressed or immunocompetent mice. The 50% effective doses of SDZ MRL 953 varied with the infectious agents and the route of its administration. In all cases. the 50% effective doses were about 10(3) times higher than those obtained with endotoxin from Salmonella abortus equi. SDZ MRL 953 was. however. less toxic than lipopolysaccharide by a factor of 10(4) to greater than 7 x 10(5) times in galactosamine-sensitized mice. The compound was also an effective inducer of tolerance to endotoxin. Hence. repeated dosing with the compound induced a transient resistance (greater than or equal to 1 week) to lethal challenges with endotoxin. In vitro. the compound was devoid of intrinsic antimicrobial activity. but it moderately induced the release of cytokines from monocytes and primed human neutrophils for the enhanced production of reactive oxygen metabolites in response to a soluble stimulus. The results presented here suggest that SDZ MRL 953 may be useful in a clinical setting for enhancing resistance to infections. particularly in patients undergoing myelosuppressive chemotherapy or irradiation. and for the prophylaxis of endotoxin shock.
Effect of SDZ MRL 953 on the survival of mice with advanced sepsis that cannot be cured by antibiotics alone, Stimulation of nonspecific immunity as an additional modality for therapy of sepsis that cannot be cured by antibiotics alone was investigated. SDZ MRL 953. a novel monosaccharidic lipid A analog as a prototype immunostimulant. and cefotaxime or gentamicin were administered to normal or myelosuppressed mice in a state of advanced sepsis caused by Escherichia coli or Staphylococcus aureus. In this novel model. antibiotic therapy was initiated when the infected mice appeared moribund. At this stage. neither pretreatment with the immunostimulant nor therapy with high doses of cefotaxime or gentamicin was effective in protecting the animals from fatal sepsis. However. pretreatment with a single dose of SDZ MRL 953 1 day prior to microbial inoculation dramatically improved the curative effects of the antibiotics. Hence. long-term survival was significantly enhanced with increasing doses of the immunostimulant in the combined therapy. Peritoneal macrophages from SDZ MRL 953-pretreated animals were primed for enhanced production of microbicidal reactive oxygen metabolites in vitro. In conclusion. the results of the present study indicate that SDZ MRL 953 is a potential candidate for use in a clinical setting as an adjunct to antimicrobial therapy for infections that cannot be treated successfully with appropriate antibiotics alone.
Acquired resistance of Nocardia brasiliensis to clavulanic acid related to a change in beta-lactamase following therapy with amoxicillin-clavulanic acid, Previous studies have demonstrated that Nocardia brasiliensis is susceptible to amoxicillin-clavulanic acid and that its beta-lactamases are inhibited in vitro by clavulanic acid. A cardiac transplant patient with disseminated infection caused by N. brasiliensis was treated with this drug combination with good response. but relapsed while still on therapy. The relapse isolate was found to be identical to the initial isolate by using genomic DNA restriction fragment patterns obtained by pulsed field gel electrophoresis. but it was resistant to amoxicillin-clavulanic acid. On isoelectric focusing. the beta-lactamase from the relapse isolate exhibited a shift in the isoelectric point (pI) of its major band from 5.10 to 5.04 compared with the enzyme from the pretreatment isolate. As determined by using values of the amount of beta-lactamase inhibitor necessary to give 50 +/- 5% inhibition of beta-lactamase-mediated hydrolysis of 50 microM nitrocefin. the beta-lactamase of the relapse isolate was also 200-fold more resistant than the enzyme from the pretreatment isolate to clavulanic acid and was more resistant to sulbactam. tazobactam. cloxacillin. and imipenem. The beta-lactamase of the relapse isolate exhibited a 10-fold decrease in hydrolytic activity for cephaloridine and other hydrolyzable cephalosporins compared with that for nitrocefin. Acquired resistance to amoxicillin-clavulanic acid in this isolate of N. brasiliensis appears to have resulted from a mutational change affecting the inhibitor and active site(s) in the beta-lactamase.
Inhibition of rabies virus infection in cultured rat cortical neurons by an N-methyl-D-aspartate noncompetitive antagonist, MK-801, A noncompetitive N-methyl-D-aspartate (NMDA) antagonist. MK-801 (0.5 to 2.0 mM). inhibits rabies virus infection in rat primary cortical neurons. whereas the competitive NMDA antagonist AP5 has no effect. The results suggest that MK-801-mediated inhibition of rabies virus replication. although selective. is not operating through the high-affinity binding site mechanism.
Effectiveness of clarithromycin and minocycline alone and in combination against experimental Mycobacterium leprae infection in mice, As determined by the proportional bactericide method. clarithromycin had strong bactericidal activity against Mycobacterium leprae. Clarithromycin was administered to mice by gavage as 20 daily doses at dosages of 12.5 to 50 mg/kg of body weight. At a dosage of 25 mg/kg. minocycline was more active than clarithromycin at a dosage of 50 mg/kg. Additive effects were displayed with the combination of clarithromycin (50 mg/kg) and minocycline (25 mg/kg). both of which were administered daily by gavage. and of clarithromycin and minocycline. both of which were administered daily by gavage at dosages of 25 mg/kg each. with rifampin at a single oral dose of 10 mg/kg.
Is low birth weight a risk factor for asthma during adolescence, The effect of low birth weight on the incidence of asthma by 17 years of age was investigated by studying medical draft examination records of 20.312 male subjects born in Jerusalem between January 1967 and December 1971. Additional information on birth weight and other demographic factors was abstracted from the Jerusalem Perinatal Study computerised database. A stepwise multiple logistic regression was used to estimate the odds ratios for developing asthma by 17 years of age in 500 g birthweight categories from less than 2000 g to 4500 g. The odds ratios were adjusted for the confounding effects of ethnic origin. social class (determined by area of residence). paternal education. maternal age. and birth order. The group with low birth weights (less than 2500 g. n = 1004) had a significantly increased risk of developing asthma by 17 years of age. with an adjusted odds ratio of 1.44 (95% confidence interval (CI) 0.79 to 2.66) for birthweight group less than 2000 g and 1.49 (95% CI 1.05 to 2.12) for birthweight group 2000-2499 g compared with the reference group of 3000-3499 g. We conclude that infants with birth weights of less than 2500 g may have a higher risk of asthma during childhood and adolescence than infants who were heavier at birth.
Long-term follow up of renal function in IgA nephropathy, Fifty one children with IgA nephropathy verified at biopsy have been followed up clinically and functionally for 0.4-16.8 years from the onset of symptoms. Renal function was evaluated by determining the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) from the clearances of inulin and para-aminohippuric acid. Fifteen (29%) of the children had raised serum creatinine concentrations at the onset. Mean GFR was significantly lower than that of controls at the first investigation. During the follow up GFR and ERPF decreased and were significantly lower than in the controls after eight years of disease. The significant fall in renal function was found in children with proteinuria and especially in boys. in whom GFR and ERPF decreased from a mean (SEM) of 117 (5) and 616 (31) at 2.8 years to 97 (6) and 509 (36) ml/min/1.73 m2 at 7.5 years. Patients with raised serum creatinine concentrations at the onset had significantly lower GFRs. and patients with macroscopic haematuria at this time did not show decreased renal function at follow up. In conclusion. children with IgA nephropathy do not seem to have a benign clinical course. Boys with proteinuria show a significant decrease in renal function during follow up.
Renal histological changes in relation to renal function and urinary protein excretion in IgA nephropathy, Renal function and urinary protein excretion (UPE) were investigated at the time of kidney biopsy in 24 children with IgA nephropathy. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by clearances of inulin and para-aminohippuric acid. For UPE albumin. IgG. beta 2 microglobulin. and creatinine were analysed. Glomerular global/segmental sclerosis and crescents in the biopsy specimens were assessed. and glomerular and tubulointerstitial changes classified on a five degree scale. The patients with tubulointerstitial or mesangial biopsy changes or glomerular sclerosis had significantly lower GFR than those without corresponding lesions. Patients with segmental sclerosis also had higher excretion rates of IgG. which increased with increasing segmental sclerosis. Six patients had GFRs below 2SD of the controls. Within the group of patients with reduced GFR overt albuminuria. a raised excretion rate of IgG. interstitial fibrosis. and advanced mesangial lesions were more frequent. A rising excretion rate of IgG seems to indicate both reduced GFR and increasing segmental glomerulosclerosis and may be a marker of progressive disease.
Changes in body composition and energy expenditure after six weeks' growth hormone treatment, Changes in body composition and energy expenditure were assessed in 15 children after six weeks of human growth hormone (hGH) treatment. Body composition measurements were made by stable isotope labelled water (H2(18)O) dilution. bioelectrical impedance. and skinfold thickness techniques. Energy expenditure was assessed both by indirect ventilated hood calorimetry (resting energy expenditure) and the stable isotope doubly labelled water (2H2(18)O) technique (free living daily total energy expenditure). Mean increases in weight of 0.96 kg and fat free mass of 1.37 kg and a mean decrease in fat mass of 0.41 kg were observed. Significant increases both in resting energy expenditure and free living daily energy expenditure were detected. Absolute changes in fat mass and resting energy expenditure were correlated. The data suggest (i) that the increase in the fat free mass is the most significant early clinical measure of hGH response and (ii) that hGH increases the metabolic activity of the fat free mass. Monitoring such changes may be predictive of the efficacy of hGH in promoting growth.
Infantile meningitis in England and Wales: a two year study, A two year prospective study identified 1922 cases of meningitis in children under 1 year of age. A further 201 cases were identified from other sources. The annual incidence of meningitis during the first year of life was 1.6/1000; during the first 28 days of life it was 0.32/1000. and among postneonatal infants it was 1.22/1000. The male:female ratio was 1.4:1. The overall case fatality rate was 19.8% for neonates and 5.4% for postneonatal infants. Two thirds of deaths identified in the study. 50% of all deaths. were not attributed to meningitis by the Office of Population Censuses and Surveys. Group B beta haemolytic streptococci (28%). Escherichia coli (18%). and Listeria monocytogenes (5%) were most frequently isolated from neonates and Neisseria meningitidis (31%). Haemophilus influenzae (30%). and Streptococcus pneumoniae (10%) from postneonatal infants. At 2-6 months of age N meningitidis meningitis was most common. and at 7-12 months H influenzae predominated. Meningitis caused by group B beta haemolytic streptococci occurred up to 6 months of age and had a consistent mortality of 25%. Neonatal meningitis due to Gram negative enteric rods had a mortality of 32%. Low birth weight was a significant predisposing factor for both neonates and postneonatal infants. In both groups mortality was significantly higher among children admitted in coma. There was no seasonal variation in incidence in either group. Neonates were treated with either group. Neonates were treated with either chloramphenicol (50%) or gentamicin (48%) usually in combination with a penicillin; 40% received a third generation cephalosporin. Of the 1472 postneonatal infants treated 84% received chloramphenicol with a penicillin and 10% received a third generation cephalosporin.
Increasing incidence of coeliac disease in Sweden, Changes in the incidence of coelic disease was studied among children born in Goteborg. Sweden. between 1970 and 1988. A total of 188 patients with coeliac disease were found. Of these. 83% were less than 2 years old at the time of their first duodenal biopsy and 74% of them have so far been verified according to the criteria of the European Society for Gastroenterology and Nutrition (ESPGAN). The cumulative incidence at 2 years of age/1000 liveborn infants increased significantly from 0.31 in the first birth cohort to 2.93 in the last. This increase could only partly be explained by improvements in detection. Weight for age at diagnosis was generally considerably below the reference value. but was slightly less affected towards the end of the period. The increase in incidence of coeliac disease is the first reported since the middle 1970s and makes the disease one of the most common chronic diseases among Swedish children.
How mothers keep their babies warm, Details of room temperature. clothing. and bedding used by night and by day and in winter and in summer were recorded for 649 babies aged 8 to 26 weeks. Room temperature at night was significantly related to outside temperature and duration of heating. Total insulation was significantly related to outside temperature and to minimum room temperature. but there was wide variation in insulation at the same room temperature. High levels of insulation for a given room temperature were found particularly at night and in winter. and were associated with the use of thick or doubled duvets and with swaddling. At least half the babies threw off some or all of their bedding at night. and at least a quarter sweated. Younger mothers and mothers in the lower social groups put more bedclothes over their babies. and the latter also kept their rooms warmer. Many mothers kept their babies warmer during infections.
Pulmonary function and ambient particulate matter: epidemiological evidence from NHANES I, The relationship between pulmonary function and quarterly average levels of total suspended particulates (TSP) was examined for adults who resided in 49 of the locations where the First National Health and Nutrition Examination Survey (NHANES I) was conducted. Statistically significant relationships were observed between TSP levels and forced vital capacity (FVC) and forced expiratory volume at one second (FEV1.0). These relationships remained strong across several specifications and sample changes. e.g.. exclusion of cities with two highest and two lowest TSP levels. restriction of sample to whites only. Anthropometric measurements and socioeconomic characteristics of the subjects were included in the analysis. and we restricted the sample to "never" smokers. The results indicate a 1 standard deviation increase (about 34 micrograms/m3) in TSP from the sample mean of 87 micrograms/m3 was associated with an average decrease in FVC of 2.25%. The results of this analysis also suggest that there is a threshold level (i.e.. approximately 60 micrograms/m3 [quarterly average]) of TSP below which a relationship with pulmonary function ceases to exist.
Respiratory response of humans exposed to low levels of ozone for 6.6 hours, Recent evidence suggests that prolonged exposures of exercising men to 0.08 ppm ozone (O3) result in significant decrements in lung function. induction of respiratory symptoms. and increases in nonspecific airway reactivity. The purpose of this study was to confirm or refute these findings by exposing 38 healthy young men to 0.08 ppm O3 for 6.6 h. During exposure. subjects performed exercise for a total of 5 h. which required a minute ventilation of 40 l/min. Significant O3-induced decrements were observed for forced vital capacity (FVC. -0.25 l). forced expiratory volume in 1 s (FEV1.0. -0.35 l). and mean expiratory flow rate between 25% and 75% of FVC (FEF25-75. -0.57 l/s). and significant increases were observed in airway reactivity (35%). specific airway resistance (0.77 cm H2O/s). and respiratory symptoms. These results essentially confirm previous findings. A large range in individual responses was noted (e.g.. percentage change in FEV1.0; 4% increase to 38% decrease). Responses also appeared to be nonlinear in time under these experimental conditions.
Exposure to asbestiform minerals and radiographic chest abnormalities in a talc mining region of upstate New York, A radiologist in New York reported a high prevalence of pulmonary fibrosis in St. Lawrence and Jefferson counties. The New York State Department of Health responded by conducting a case history study of radiographic abnormalities found in the lung parenchyma and pleura of residents in Lawrence and Jefferson counties. where tremolitic talc has been mined for many years. During a 1-y period. all radiographs from 6 hospitals in the region were reviewed. A B-reader confirmed that 355 of 9.442 patients who were at least 40 y of age (3.8%) had a relevant abnormality; 60% of them reported occupational exposure to asbestiform minerals. and another 15% had a chest condition or injury that could have accounted for the abnormal radiograph. The results should be interpreted cautiously. but there was no evidence of widespread radiographic abnormalities resulting from ambient dust exposure. The data. however. support earlier studies that indicate that talc miners and millers experience excess parenchymal fibrosis and pleural changes. The data also suggest that individuals in the paper industry and construction trades may be at risk.
Dimethylformamide-induced liver damage among synthetic leather workers, Prevalence of liver injury associated with dimethylformamide (DMF) exposure was determined. Medical examinations. liver function tests. and creatine phosphokinase (CPK) determinations were performed on 183 of 204 (76%) employees of a synthetic leather factory. Air concentrations of solvents were measured with personal samplers and gas chromatography. The concentration of DMF in air to which each worker was exposed was categorized. High exposure concentrations of DMF (i.e.. 25-60 ppm) were significantly associated with elevated alanine aminotransferase (ALT) levels (ALT greater than or equal to 35 IU/l). a result that did not change even after stratification by hepatitis B carrier status. Modeling by logistic regression demonstrated that exposure to high concentrations of DMF was associated with an elevated ALT (p = .01). whereas hepatitis B surface antigen (HBsAg) was slightly but independently associated with an elevated ALT (p = .07). In those workers who had normal ALT values. there occurred still significantly higher mean ALT and aspartate aminotransferase (AST) activities. especially among those who were not HBsAg carriers. A significant association existed between elevated CPK levels and exposure to DMF. However. an analysis of the CPK isoenzyme among 143 workers did not reveal any specific damage to muscles. This outbreak of liver injury among synthetic leather workers is ascribed to DMF. It is recommended that the occupational standard for DMF and its toxicity among HBsAg carriers be evaluated further.
Umbilical cord blood lead levels in California, During the fall of 1984. we conducted a survey of umbilical cord blood lead levels of 723 live births that occurred at 5 hospitals located in 5 cities in California. Historical ambient air lead levels were used as a qualitative surrogate of air and dust exposure. The area-specific cord blood means (all means approximately 5 micrograms/dl). medians. deciles. and distributions did not vary among locations. The California distributions included means that were lower than the 6.6 micrograms/dl reported in Needleman et al.'s Boston study in 1979. Indeed. the entire California distribution was shifted to the left of the Boston study distribution. even though 3% of the California cord lead levels exceeded 10 micrograms/dl--the level above which Needleman et al. have documented psychoneurological effects in children during the first few years of life. Fourteen percent of premature babies had cord blood lead levels above 10 micrograms/dl. The association between prematurity (i.e.. less than 260 d gestation) and elevated (greater than 5 micrograms/dl) cord blood lead was observed in all hospitals and yielded a relative risk of 2.9 (95% CI: .9. 9.2) and a population attributable risk of 47%. Further research is needed to confirm this association and to explore the roles of endogenous and exogenous sources of lead exposure to the mothers who give birth to premature infants.
A circulating factor(s) mediates cell depolarization in hemorrhagic shock, Cell depolarization in hemorrhagic shock has been attributed to hypoperfusion. but the mechanism remains unclear. Suspensions of single cell lines loaded with the potential-sensitive fluorescent dye bis-(1.3-dibutylbarbiturioc acid) trimethine oxonal (DIBAC) and exposed for 30 minutes to rat plasma drawn either before or after hemorrhagic shock (bled 20 mL/kg: mean arterial blood pressure less than 40 mmHg) were studied. Plasma drawn after. but not before. hemorrhage led to partial depolarization regardless of cell type (rat H9C2 skeletal muscle. A-10 smooth muscle. C-9 liver. adrenal. kidney. red blood cell [RBC]. white blood cell [WBC]) or species (cat. dog. pig RBC; cat WBC; mouse C2C12 skeletal muscle; and human intestinal smooth muscle [HISM]). Dialysis did not remove the factor(s). suggesting a molecular weight of more than 10.000 daltons. The factor appeared within 5 minutes of shock. The depolarization amplitude increased as a function of plasma concentration and demonstrated saturation kinetics indicating specific receptor binding. Cells were equivalently oxygenated. excluding hypoperfusion as a necessary condition for depolarization. Tumor necrosis factor or platelet activating factor alone or in combination were not effective in this system. Stable measurements can be obtained with this noninvasive system that avoids cell injury consequent to cell impalement with electrodes. This system provides a sensitive in vitro bioassay that should permit identification of the plasma factors mediating cell depolarization. as well as definition of the responsible intracellular mechanisms.
Distribution and survival of Escherichia coli translocating from the intestine after thermal injury, The present investigation was performed to study the kinetics of tissue distribution and deposition of Escherichia coli and endotoxin translocating from the intestine after thermal injury. Escherichia coli was grown in the presence of 14C glucose and both labeled bacteria and endotoxin prepared from the labeled bacteria were used as translocation probes. Escherichia coli (10(8) to 10(10) bacteria) and E. coli endotoxin (100 micrograms per animal) were gavaged into the stomach immediately before a 30%  burn injury was inflicted in mice. Animals were killed 1. 4 and 24 hours after burn injury. Translocation occurred extensively within 1 hour after burn injury. Expressed as amount of radioactivity per gram of tissue. translocation was greatest in the mesenteric lymph node (MLN) followed by spleen. lung. and liver. Translocation of endotoxin was similar to translocation of intact bacteria. with the exception that less radioactivity could be found in the peritoneal cavity and more in the liver. Both intact E. coli and endotoxin translocated directly through the intact bowel wall. Killing of bacteria was greatest in the MLN and spleen. approximating 95% to more than 99% of translocating bacteria. Killing efficiency was lowest in the lungs. It is concluded that estimation of translocation by viable bacterial counts in tissues grossly underestimates the extent of translocation of bacteria and ignores the extent of translocation of endotoxin. Translocation of endotoxin may have biologic significance that is independent of and in addition to translocation of intact bacteria.
Propranolol diminishes extremity blood flow in burned patients, Beta adrenergic blockade diminishes the catecholamine-mediated elevations in heart rate and myocardial contractility that characterize postburn hypermetabolism. To examine how these alterations in cardiac performance affect peripheral perfusion. indirect calorimetry and leg blood flow were measured before and then after a 2-hour intravenous propranolol infusion. Five severely burned patients (55% + 7% total burn surface area). given propranolol at 8 micrograms/kg/minute. had a significant reduction in cardiac index and heart rate with an increased leg vascular resistance resulting in a decrease in extremity perfusion. Four healthy volunteers were given propranolol at 5 micrograms/kg/minute. resulting in a comparable decrease in heart rate. yet there was no change in leg vascular resistance or extremity perfusion. In both patient groups. propranolol decreased the plasma lactate concentration. This suggests that in hypermetabolic patients. beta adrenergic blockade reduces peripheral perfusion and that peripheral perfusion is not a principal determinate of plasma lactate levels. Rather adrenergic blockade appears to decrease lactate concentration as a consequence of the inhibition of lipolysis.
Long-term results of pectoralis major muscle transposition for infected sternotomy wounds, During an 11.5-year period. 100 consecutive patients (79 male. 21 female) underwent repair of an infected sternotomy wound. Sixty-five patients had failed attempts at wound closure by other physicians. Median age was 61.5 years (range. 5 to 85 years). Reconstruction included muscle in 79 patients. omentum in 4. and both in 15. A total of 175 muscles were transposed. including 169 pectoralis major. 3 rectus abdominis. 2 external oblique. and 1 latissimus dorsi. Median number of operations was four (range. 1 to 11). Mechanical ventilation was required in 30 patients. Two perioperative deaths occurred. one related to sepsis. Median follow-up was 4.2 years (range. 1.3 to 13.5 years). Twenty-six patients had recurrent infection. Median time from our closure to recurrence was 5.5 months (range. 0.3 to 27.6 months). Cause of recurrence was inadequate removal of cartilage in 16 patients. bone in 6. and retained foreign body in 4. Eighteen patients had the wound reopened with further resection; 10 had another muscle or omentum transposition. There were 30 late deaths. only one related to recurrent infection. At the time of death or last follow-up. 92 patients had a healed chest wall. Transposition of the pectoralis major muscle remains an excellent method of management for infected sternotomy wounds. Failure is directly related to persistent infection of cartilage. bone. or retained foreign bodies.
Identification, characterization, and quantitation of soluble HLA antigens in the circulation and peritoneal dialysate of renal patients, Human lymphocyte antigen (HLA) class I and class II antigens and beta 2 microglobulin (B2M) were identified in peritoneal dialysate (PD) and serum from patients with end-stage renal disease (ESRD) using monoclonal antibodies in an enzyme-linked immunoassay. The HLA class I and class II antigens each exhibited approximate molecular weights of 50.000 to 60.000 daltons by chromatography on Sepharose CL 6B. Class I antigens in serum and PD fluid were associated with B2M. Free B2M (Mr 11.500) also was detected in both sera and PD fluids. Unlike class I antigens. class II antigens were not found to have attached B2M. Class I and class II antigens eluted from 2-diethylaminoethanol ion exchange gradient columns at 0.07 mol/L (molar) phosphate buffer pH 7.2 and migrated with alpha 2-beta 1 mobility in agarose electrophoresis. Class I antigens were purified from ESRD patients' PD fluid by solid-phase immunoaffinity chromatography. Enzyme-linked immunoassay demonstrated that this purified protein was composed of a class I heavy chain and B2M. Class I allospecificity was confirmed by neutralization on known HLA typing antisera in a microcytotoxicity assay. Soluble HLA class I antigen preparations specifically inhibited blast transformation of responder lymphocytes in mixed lymphocyte culture reactions. Inhibition was dose dependent and ranged from 0% to 95%. The presence of soluble HLA antigens in body fluids may play an important part in the immunologic tolerance to self. This study demonstrates a ready source of large quantities of soluble HLA for detailed analysis.
The MAGPI hypospadias repair in 1111 patients, The meatal advancement and glanduloplasty (MAGPI) procedure was first described in 1981 for the repair of distal hypospadias. In the past decade. our experience has grown to more than 1000 procedures. An excellent surgical result requires careful case selection. avoiding cases with thin or rigid ventral parameatal skin or a meatus too proximal or too wide. The glans wrap to support the advanced ventral urethral wall requires a solid tissue approximation in two layers to prevent a retrusive meatus. Meatal stenosis can be avoided by assuring an adequate dorsal Heineke-Mikulicz tissue rearrangement and making an incision from within the urethral meatus well distally into the urethral groove. The MAGPI procedure routinely is performed on an outpatient basis without any urinary diversion. Our experience in 1111 cases during 12 years has required a second procedure in 1.2% of cases. The overall success rate with the MAGPI procedure suggests that it should continue to be used in the repair of distal hypospadias.
Choledocholithiasis. Endoscopic sphincterotomy or common bile duct exploration, A prospective randomized trial was conducted of preoperative endoscopic sphincterotomy and surgery (ES&S) or surgery alone (SA) in 52 patients with cholecystolithiasis and choledocholithiasis that were candidates for elective surgery. After ES&S 65% of patients were stone free. Eighty-eight per cent of patients with SA were stone free after surgery (p less than 0.05). Three patients in each group had residual stones at the completion of the operation. Five of these six had more than 20 common bile duct (CBD) stones. There was one episode of major hemorrhage in a patient in each group and no deaths. Costs were essentially equal for the individual patient with a successful ES as compared to SA. Societal costs of a program of preoperative endoscopic retrograde cholangiopancreatography and ES would be higher because of the cost of screening for patients with CBD stones. These results do not support preoperative ES as a technique for clearance of the CBD of stones on the basis of efficacy. morbidity rate. or cost.
The economic burden of gallstone lithotripsy. Will cost determine its fate, Gallstone lithotripsy (LITHO) was performed on 52 patients who underwent 107 procedures. Two hundred sixty-seven gallstone patients were screened and 215 (81%) were excluded. Excessive stone burden and nonvisualization by oral cholecystogram (OCG) were the most common reasons for exclusion. The hospital course of 100 excluded patients who later underwent elective cholecystectomy was evaluated for length of hospital stay (2.3 days) and total cost of treatment ($3685.00). Successful fragmentation to less than 5 mm was achieved in 43 LITHO patients (83%). Five LITHO patients (10%) required conversion to operative management. Complications of LITHO included acute cholecystitis (1 of 52 patients) and biliary colic (17 of 52 patients. or 33%). Multiple procedures in one patient were common. Costs for LITHO were calculated in two ways: first the individual cost for each of the 52 candidates; second the cost for successful LITHO was calculated by excluding five patients who required operation as well as five patients (10%) who are predicted failures of LITHO. Including the preoperative evaluation. treatment. recovery room. and follow-up. the individual LITHO cost for 52 patients was $8275.00. If the same total expenditure is calculated after excluding patients who required operation and those predicted to fail. the cost per 'successful' LITHO procedure was $10.245. The cost of 1 year of bile acid therapy is $1949.00 or $2413.00 per 'successful' procedure. Follow-up costs were $1232.00 per patient or $1525.00 per 'successful' procedure. The added LITHO cost incurred by screening eventual noncandidates was $904.00 per successful procedure. The sum of these individual costs was $15.087.00 per success. as compared to $3685.00 for cholecystectomy. No allowance was made for cost of stone recurrence. Lithotripsy costs appear to be sufficiently high to render the procedure unlikely to emerge as the treatment of choice.
Laparoscopic cholecystectomy. Treatment of choice for symptomatic cholelithiasis, Our initial experience with laparoscopic cholecystectomy (LC) for symptomatic cholelithiasis has involved 152 patients. Patient age ranged from 17 to 83 years; most were female (78%). Their average weight was 170 pounds (range. 75 to 365 lbs.). Twenty-two per cent had a single gallstone. while 9% had two to three stones and 64% had more than three stones. Exclusion criteria initially included upper abdominal scarring. severe acute cholecystitis. choledocholithiasis. and inability to tolerate general anesthesia. The first two of these are now only relative contraindications with increased experience. Thirteen of the one hundred fifty-two procedures (8.5%) required conversion to an open operation. Average time of operation was 138 minutes. Intraoperative cholangiography was attempted in 78% of cases and was completed successfully in 66% of those attempted. There have been no deaths. The complication rate has been low: 4% major. 0% life-threatening. and 7.2% minor complications. Postoperative analgesic requirements are remarkably low: 36% of patients required no narcotics after leaving the recovery room. Eighty-seven per cent of patients successfully undergoing LC were discharged by the first postoperative day. Most patients resumed normal activities within 1 week after discharge. Laparoscopic cholecystectomy offers the majority of patients with symptomatic cholelithiasis an improved treatment option. resulting in significantly less postoperative pain. hospitalization. and recuperation time.
Liposarcoma of the esophagus, Liposarcoma is one of the most common soft tissue sarcomas found in adults. yet it rarely develops in the alimentary tract. This report describes the pathological features and management of a liposarcoma of the esophagus.
Mitral valve replacement six years after cardiac transplantation, A 33-year-old man found to have increasing mitral regurgitation and decreasing exercise tolerance 6 years after cardiac transplantation received a mitral bioprosthesis. For 8 months he has been without complications from the valve replacement and is clinically and hemodynamically considerably improved.
Aortic atresia with normal left ventricle, A case of single-stage repair of aortic atresia with normal-sized left ventricle and ventricular septal defect in a neonate is reported. The surgical procedure included rerouting of the left ventricular bloodstream to the pulmonary artery through the ventricular septal defect and connection of the pulmonary trunk to the aortic arch. The right ventricular outflow tract was then reconstructed with an extracardiac valved conduit. Three years after the initial operation. replacement of the valved conduit was performed uneventfully. The clinical status of the child is very satisfactory.
The Fontan procedure: a historical review, Complete bypass of the right ventricle was first performed successfully and subsequently reported by Fontan and Baudet for patients with tricuspid atresia. By eliminating congenital and surgical shunts. ventricular volume overload and pulmonary hypertension were avoided. A logical extension of its predecessor. the partial right heart bypass procedure introduced by Glenn. the Fontan operation has great application for patients with various forms of univentricular heart. It is one of the historic advances in the surgical treatment of congenital heart disease.
Primary cardiac sarcomas, In marked contrast to benign cardiac tumors. primary cardiac sarcomas occur infrequently. Moreover. there is no uniform approach to treating such patients. and the benefits of postoperative chemotherapy are unclear. Between 1964 and 1989. 21 patients with primary cardiac sarcomas underwent surgical resection alone (n = 7). chemotherapy alone (n = 1). or combined operation and postoperative chemotherapy based on adriamycin (n = 13). Twenty-four operations were performed on 20 patients with relief of symptoms in all. Eleven patients had complete resection. Operative mortality was 8.3% (2/24). Histology and originating chamber(s) included angiosarcoma (n = 7; 6/7 in right atrium. 1 in left atrium). malignant fibrous histocytoma (7; all in left atrium). fibrosarcoma (2; 2/2 in left atrium). rhabdomyosarcoma (2; 1 in left atrium. 1 in right ventricle). leiomyosarcoma (2; 1 in left atrium. 1 in left ventricle); and one undifferentiated sarcoma (right atrium). Overall actuarial survival was 14% at 24 months after resection. Patients with complete resection had a median survival of 24 months compared with only 10 months in all other patients (p = 0.035). Postoperative chemotherapy did not enhance survival in patients with incomplete resection. At this time. aggressive and complete surgical resection seems to offer the best hope for palliation and survival in an otherwise fatal disease.
Aprotinin reduces intraoperative and postoperative blood loss in membrane oxygenator cardiopulmonary bypass, To determine whether aprotinin can provide a significant improvement of hemostasis in cardiopulmonary bypass using a membrane oxygenator. we tested this drug in a prospective. randomized. double-blind. placebo-controlled clinical trial. The subjects were 80 male patients undergoing cardiopulmonary bypass for coronary artery bypass grafting. Forty patients received aprotinin and 40 patients served as placebo controls. Aprotinin (4 x 10(6) KIU) was given as a continuous infusion. starting before operation and continuing until after cardiopulmonary bypass; additionally. 2 x 10(6) KIU aprotinin was added to the pump prime. Intraoperative and postoperative bleeding. respectively two thirds and one third of the total perioperative blood loss. were both significantly reduced in the aprotinin-treated group (p less than 0.01). The total average perioperative blood loss. corrected to a hemoglobin concentration of 7 mmol/L. was 550 mL in the aprotinin-treated patients versus 900 mL in the control patients. This reduction in blood loss. furthermore. significantly decreased the amount of postoperative blood transfusions (p less than 0.05) and increased the percentage of patients who did not receive postoperative donor blood from 42% to 68%. Aprotinin increased the activated clotting time significantly during cardiopulmonary bypass. which led to a reduction in heparin usage. The improved hemostasis during operation. despite the prolonged activated clotting time. might even abolish the need for heparin conversion with protamine at the end of cardiopulmonary bypass. thus allowing retransfusion through cardiotomy suction to be continued. which saves the blood that is currently lost with vacuum suction.
Brain protection during circulatory arrest, Previous nuclear magnetic resonance studies in this laboratory have shown a beneficial biochemical effect of antegrade cerebroplegia (CP-A) during hypothermic circulatory arrest. This study compared CP-A with other methods of cerebral protection during hypothermic circulatory arrest to assess the clinical utility of this technique. Twenty-three sheep were divided into four groups: systemic hypothermia alone (SYST) and systemic hypothermia combined with external cranial cooling (EXTNL). retrograde cerebroplegia (CP-R). or CP-A. Cardiopulmonary bypass was started. and the sheep were cooled to 15 degrees C and subjected to 2 hours of circulatory arrest. Cardiopulmonary bypass was restarted. and the animals were rewarmed and weaned from cardiopulmonary bypass. Serial neurological examinations were performed and hourly scores assigned until the animals were extubated. Postanesthetic neurological scores improved in all groups throughout the 6-hour recovery period except the CP-R group. The improvement over time for these scores was similar for the EXTNL and CP-A groups and significantly better than for the SYST or CP-R groups (p = 0.004). The CP-A group had 5 of 7 animals with deficit-free survival despite the similarity in recovery of baseline brainstem function. We conclude that both antegrade infusion of cerebroplegia and external cranial cooling confer distinct cerebroprotective effects after a protracted period of hypothermic circulatory arrest when compared with the other methods studied.
Randomized trial of one-dose versus six-dose cefazolin prophylaxis in elective general thoracic surgery, The objective of this study was to compare the efficacy of one to six doses of cefazolin as prophylaxis in general thoracic surgery using a randomized. double-blind design. Two-hundred eight consecutive patients admitted to a regional thoracic surgery unit for elective thoracotomy and lung resection were eligible for the trial. There were no wound infections in the one-dose group and two in the six-dose group (95% confidence intervals [CI]: -0.008. +0.048 [The positive number refers to the largest possible difference in favor of the one-dose group and the negative number. the largest possible difference in favor of the six-dose group]). Each group had eight postoperative chest infections (CI: -0.075. +0.077) and three empyemas (CI: -0.004. +0.050). Thirty-day mortality was 5% in the one-dose group and 4% in the six-dose group (CI: -0.053. +0.069). Postoperative duration of hospital stay. requirement for antibiotics. and the need for reoperation were comparable. These results suggest that six doses of cefazolin do not confer clinically important benefit beyond that obtained from a single dose for prophylaxis of wound infection in elective general thoracic surgery.
Neodymium:yttrium-aluminum garnet laser-assisted pulmonary resections, The neodymium:yttrium-aluminum garnet laser is a new approach to limited pulmonary resection. It avoids distortion of surrounding pulmonary tissue and potential pleural space problems. which can occur with mechanical stapler resections. We have recently used this laser to manage 39 pulmonary lesions in 20 patients. There were no major postoperative complications. and air leak after resection was minimal. Neodymium:yttrium-aluminum garnet laser excision is a useful method that may have an advantage over mechanical stapling techniques for the limited resection of many pulmonary lesions.
Morbidity and mortality after coronary artery bypass in octogenarians, One hundred fifty seven consecutive octogenarians (mean age +/- standard deviation. 82.4 +/- 1.9 years) underwent coronary artery bypass grafting with hypothermia (mean temperature. 21.8 degrees +/- 1.8 degrees C). hyperkalemic cardioplegia. and cardiopulmonary bypass in a 9-year period. Sixty-six percent were male. Preoperatively. 115 patients (73%) were in New York Heart Association functional class IV. with the remainder being in either class III (23%) or class II (4%). Twenty percent of the patients had major complications including postoperative hemorrhage (15). sepsis (9). cerebrovascular accident (6). third-degree heart block (5). renal failure requiring dialysis (1). and pulmonary embolism (1). The 30-day or in-hospital mortality rate was 7.0%. Mean total hospital stay was 26.1 +/- 17.9 days. One-year and 5-year actuarial survival rates were 85% and 62%. respectively. Higher mortality was seen to be associated with New York Heart Association class IV. left ventricular ejection fraction less than 0.40. and lesser values for cardiac output and cardiac index. At the 6-month postoperative follow-up. 73% of the survivors reported that their general health had improved as compared with before operation. This experience demonstrates that for select octogenarians with unmanageable angina pectoris. coronary artery bypass grafting is an effective therapeutic option.
New technique for pacemaker implantation in the upper chest of children and women, A new lateral approach for implanting pacemaker generators in the chest of women and children is described. Using this technique. 83 women and 21 children were operated on with no early or late complications and with good cosmetic results up to 9 years after operation. This technique prevents formation of visible wide scars above the breast in women and prevents thinning or disruption of the chest incision in children. Ages of the women ranged from 19 to 56 years; children. 5 to 18 years. In 23 patients. this technique was used after wound complications had occurred 7 days to 3 years after use of the standard implantation technique.
Sinus of Valsalva aneurysm eroding into the interventricular septum, We report a case of erosion of an aneurysm of the right sinus of Valsalva into the interventricular septum. The mode of presentation. the preoperative evaluation. and the echocardiographic and nuclear magnetic resonance imaging features are presented. and the cardiac catheterization findings and surgical management of this very rare cardiac pathology are discussed.
Measuring cell proliferation, Histopathology is based on the interpretation of features of the microscopic image. In recent years. there has evolved interest in assessing quantifiable data from these images. with the intent of providing more precise diagnostic and prognostic information. Proliferation characteristics of tumors are among the most important of these data. Methods for measuring cell proliferation are reviewed.
DNA ploidy of spindle cell soft-tissue tumors and its relationship to histology and clinical outcome, With the use of fresh cell suspensions. the DNA ploidy of 11 benign and 27 malignant spindle cell soft-tissue lesions was determined by flow cytometry (37 cases) and/or image cytometry (35 cases). Of the 27 malignant lesions. 10 were low- or intermediate-grade sarcomas. and 17 were high-grade sarcomas. In the malignant lesions. the DNA ploidy was correlated with the histologic grade and the clinical outcome. Of the 11 benign lesions. six had a diploid DNA ploidy pattern. and five were nondiploid by either flow cytometry or image cytometry. All benign cases had a favorable outocome regardless of ploidy. Eight of the 10 low- or intermediate-grade malignant lesions were diploid. whereas two were nondiploid. Of the 17 high-grade sarcomas. 15 were nondiploid by either method of measurement and nine by both. Of the 10 diploid malignant tumors. only one had an unfavorable outcome (malignant mesothelioma with biopsy only). whereas of the 17 malignant lesions that were nondiploid. five had no evidence of recurrent disease. three cases recurred. eight patients died of disease. and one patient died of an unrelated cause. We concluded that (1) ploidy does not differentiate benign from malignant spindle cell soft-tissue tumors. (2) the nondiploid DNA pattern is more common in high-grade than in low- or intermediate-grade sarcomas. and (3) there is a statistically significant relationship between nondiploidy and a worse clinical outcome in sarcomas.
DNA flow cytometric evaluation of serous and mucinous cystic neoplasms of the pancreas, There have been few reports of flow cytometric studies of pancreatic neoplasms. whether endocrine or exocrine. In this report. the DNA content of three mucinous and seven serous cystic tumors of the pancreas was evaluated by flow cytometry on formaldehyde solution-fixed. paraffin-embedded tissue. Two serous cystadenomas were aneuploid. with the remaining five serous and all three mucinous being diploid. All cases had a low S phase (ranging from 0.1% to 3.1%). indicating neoplasms with a low turnover. From these results. it appeared that DNA flow cytometry as an independent factor did not discriminate between the benign pancreatic serous cystadenomas and the more aggressive mucinous cystic neoplasms.
Heterogeneity of epithelial marker expression in routinely processed, poorly differentiated carcinomas, The application of immunohistochemical markers against epithelial antigens has proved useful for studying tumor differentiation and in aiding tumor diagnosis. However. the reactivity of various epithelial markers with poorly differentiated carcinomas (the situation in which they are most often used) has not been well established. As a result. it is unclear how negative results should be interpreted and how often more than one antibody may be needed to document the epithelial nature of poorly differentiated neoplasms. We studied 98 poorly differentiated epithelial tumors with AE1. CAM 5.2. and EMA to assess the use of these markers in their diagnosis. Both CAM 5.2 and EMA provided support for epithelial differentiation in 71% (70/98) of the cases. while AE1 stained 50% (49/98) of the tumors; CAM 5.2 was the single most useful marker in the subset of poorly differentiated neuroendocrine carcinomas. staining 20 (77%) of 26 tumors. Use of these markers in pairs increased the recognition of epithelial differentiation (at least one marker showing positive staining) as follows: AE1/CAM 5.2. 80% (78/98); AE1/EMA. 87% (85/98); and CAM 5.2/EMA. 99% (97/98). Thirty carcinomas stained with all three markers. 34 with two markers. and in 34 cases only one antibody supported epithelial differentiation. Twelve (21%) of 58 tumors showed evidence of S100 reactivity. None of the 71 cases to which PD7 was applied showed staining This study indicates that poorly differentiated carcinomas are heterogeneous in their expression of antigens recognized by AE1. CAM 5.2. and EMA. Moreover. these results quantitate the probability of reactivity with poorly differentiated carcinomas for each marker and support the use of one or more antibodies in a "backup" panel when a negative result is obtained with a single antibody and the diagnosis of carcinoma is still suspected.
Differential diagnosis of cystic neoplasms of the pancreas by fine-needle aspiration, Fine-needle aspiration biopsy of pancreatic lesions is becoming widespread. Pathologists need to be familiar with the cytologic features of pancreatic tumors. of which cystic neoplasms are a distinct subset. Of our 31 pancreatic aspirates diagnostic of neoplasia. six were diagnosed as cystic by radiographic imaging. These cases were compared. Similar symptoms were experienced by all of these patients. although those with malignant tumors lost the most weight. Loss of border definition. ascites. and liver metastases were the only radiologic clues to malignancy. Each entity had distinguishing cytologic features. These cases illustrate the importance of knowing the clinical. radiologic. and cytologic features of pancreatic cystic neoplasms to arrive at a preoperative diagnosis and determine proper treatment.
Microglandular adenosis of the breast. An immunohistochemical comparison with tubular carcinoma, Microglandular adenosis (MA) of the breast is a benign. disorganized proliferation of glands lined by a single layer of cells. As such. differential diagnosis between MA and tubular carcinoma may be challenging in selected cases. A panel of antibodies was applied to 10 cases of MA and 10 of tubular carcinoma to investigate the potential benefit of immunohistochemistry in the separation of these lesions and the possible role of myoepithelial cells in MA. The luminal cells in nine cases of MA were surrounded by a cuff of muscle-specific actin-reactive cells. which also coexpressed cytokeratin and vimentin. The immunophenotype of these cells is characteristic of myoepithelial differentiation. which was heretofore thought to be lacking in MA. This finding demonstrates that myoepithelial cells are indeed present in MA subjacent to luminal epithelial cells; moreover. it distinghuishes MA from tubular carcinoma. all examples of which were actin negative in this analysis. In addition. circumferential type IV collagen deposition was observed around constituent glands of MA in nine cases but was lacking in all tubular carcinomas. Other markers included in this evaluation (S100 protein. gross cystic disease fluid protein 15. carcinoembryonic antigen. estrogen receptor protein) were of no differential diagnostic value.
Primary gastric mantle zone lymphoma. A report of two cases, We report two cases of primary gastric mantle zone lymphoma. Histologic examination revealed numerous lymphoid vague nodules in the mucosa and submucosa of the resected stomach. The neoplastic cells in these nodules were slightly larger than small lymphocytes and had more or less cleaved nuclei. Immunostaining on paraffin-embedded sections showed that the neoplastic cells in the nodules of these cases were LN-1- and LN-2+ and had monotypic immunoglobulin (IgM-lambda and IgM-kappa. respectively). Immunostaining on frozen tissue specimens showed that the neoplastic cells or nodules were positive for surface IgM. surface IgD. alkaline phosphatase. and DRC-1. One third to two thirds of the cells were Leu-1+ (CD5+). These results indicated that these cases were primary gastric mantle zone lymphoma. More attention should be paid to primary gastric mantle zone lymphoma because this disease might be erroneously diagnosed as either pseudolymphoma or reactive lymphoid hyperplasia of the stomach.
Hepatitis B virus DNA in cervicovaginal cells, Hepatitis B virus DNA sequences were detected in seven (12.1%) of 58 cervicovaginal cell specimens that were obtained from pregnant women by polymerase DNA amplification assay. The presence of hepatitis B virus DNA in these cells raises the possibility that infected cervicovaginal cells may be a source through which hepatitis B virus can be transmitted from infected mothers to their newborns and between heterosexual partners.
Patterns of occupational hand injury in pathology. The interaction of blades, needles, and the dissector's digits, Details of injuries and exposures to body fluids while handling tissue that were sustained by 36 pathologists (nine residents and 27 staff pathologists) were ascertained by retrospective questionnaire. In the preceding year 56% (20/36) had sustained a cut or needlestick injury. A total of 72 individual injuries occurred and corresponded to one injury for every 2629 surgical specimens handled and for every 37 autopsies performed. Residents reported a five-fold excess in injuries compared with staff pathologists. The lesions described predominantly (67%) involved the oppositional area consisting of the distal thumb. index. and middle fingers of the nondominant hand; during dissection. when opposed to hold or retract tissue. these digits form a surface that is directly exposed to the cutting edge. and injury to this area may be termed dissector's digital injury. Injuries to other areas of the nondominant hand were much less numerous and the dominant hand was rarely injured. Splashes to the face and eyes and glove punctures were frequent. These injury and exposure rates are probably broadly representative of practice in areas of low acquired immunodeficiency syndrome prevalence and may be improved on with increasing concern about human immunodeficiency virus infection. It is likely. however. that development of comfortable protective devices. based on knowledge of the pattern and circumstances of injury. will be necessary to eliminate these occupational hazards.
Mesenteric vein thrombosis associated with a familial deficiency of free protein S, Signs and symptoms of an acute intra-abdominal emergency developed in a 26-year-old man; this emergency prompted surgical exploration. It was discovered that he had a devitalized small bowel as a result of mesenteric vein thrombosis. An extensive evaluation for hypercoagulable states disclosed that he had a normal total protein S concentration. but by assay and on crossed immunoelectrophoresis studies. he had a decreased concentration of free protein S. A family study demonstrated protein S deficiency in his father and in a sister. On a subsequent determination. the propositus had a decreased concentration of total protein S. This case illustrates the association of protein S deficiency with mesenteric thrombosis and serves to caution that a single determination of total protein S is not an adequate evaluation when the index of suspicion for a hypercoagulable state is high.
Adamantinoid basal cell carcinoma. An ultrastructural study, We describe an adamantinoid basal cell carcinoma that has developed in the mucocutaneous border of the upper lip. An ultrastructural study disclosed three types of cells that were morphologically distinct in the tumor nest. Cells of the first type were basically the same as those of ordinary basal cell carcinoma. Cells of the second type showed varying degrees of cytoplasmic content loss in a worm-eaten pattern and seemed to consist of degenerating cells. Cells of the third type possessed a well-developed rough endoplasmic reticulum filled with medium electron-dense fine substance. which was also seen in the extracellular space. In relationship with the histochemical findings. and based on the histogenesis of adamantinoid basal cell carcinoma. we propose that subpopulations of tumor cells undergo spontaneous degeneration and that the spaces of such disappearing cells are refilled with products containing glycosaminoglycans secreted by another subpopulation of the tumor cells.
Patterns of venous insufficiency in patients with varicose veins, The nature and distribution of venous disease surrounding the development of varicose veins and its treatment is controversial. Using duplex ultrasonography. we evaluated 54 lower extremities in 32 patients with varicose veins who were symptomatic and had obvious varicose veins by clinical examination. Twenty-eight percent had greater saphenous trunk incompetence. 2% had lesser saphenous trunk incompetence. and 96% had branch disease. Deep valvular incompetence was seen in 41%. saphenofemoral junction incompetence in 46%. and incompetence of one or more perforators in 46% of the extremities. Thirty-three percent demonstrated no evidence of associated saphenofemoral junction. deep vein. or perforating vein incompetence. while 20% had concurrent saphenofemoral junction. deep vein. and perforating vein incompetence. These data support the heterogeneity of venous disease seen in patients with varicose veins and suggest that surgical therapy be directed to a patient's specific pattern of incompetence rather than routine saphenofemoral junction ligation or stripping of the greater saphenous trunk.
An extensive experience with postoperative pain relief using postoperative fentanyl infusion, From October 1. 1987 through December 31. 1989. 517 patients who were undergoing both thoracic and abdominal surgical procedures were treated for postoperative pain with epidural fentanyl citrate infusion under the direction of an anesthesia pain service. Infusion rates of 4 micrograms/mL of solution were essentially the same for all subjects. Sixty-five percent of patients experienced superior pain control without the use of adjunctive analgesia. Twenty-eight percent of subjects achieved satisfactory pain control but required additional low-dose analgesics. Only 7% of patients remained uncomfortable despite additional intravenous narcotic administration. There were no deaths or respiratory arrests. Six percent of patients experienced nausea. and 0.8% of the cohort required catheterization for urinary retention. This technique of postoperative pain control was safe and provided excellent results. Catheter position was a major determinant of the efficacy of the method.
A pilot study of sphincter-sparing management of adenocarcinoma of the rectum, After analysis of 26 prospectively accrued patients with distal rectal adenocarcinomas who underwent sphincter preservation treatment. we have concluded that tumors that invade only the submucosa can safely be treated with surgery alone and that tumors that invade the muscularis or further can be safely treated with surgery combined with chemoradiotherapy. None of the patients had either local or distant recurrence. with a median follow-up of 21 months. All patients have been fully continent. The results. although preliminary. imply that resection of distal rectal adenocarcinoma with sphincter preservation. and adjuvant therapy when appropriate. have achieved local and distant control equal to the conventional Miles' abdominoperineal resection. but without the need for a permanent colostomy.
Prognosis after initial recurrence of cutaneous melanoma, We reviewed 231 patients who developed recurrent disease 1 to 218 months after surgical therapy for clinical stage I cutaneous melanoma. Metastatic lesions amenable to surgery. including visceral recurrences. were resected. Adjuvant systemic chemotherapy/immunotherapy or regional hyperthermic perfusion was added in patients with unresected disease. Local irradiation was employed for nonresectable brain or other isolated symptomatic metastases. The overall 5-year survival rate after initial recurrence was 36%. In patients with soft tissue or nodal recurrence. the 5-year survival rates were 49% and 38%. respectively; six (11%) of 53 patients whose initial recurrence was in a visceral organ achieved prolonged remission. Primary lesion anatomic site. thickness. pathologic type. and interval from initial therapy to recurrence were unrelated to survival. Significant prognostic factors included the site of initial metastasis. stage of primary disease. and the successful complete eradication of gross disease by surgical excision or intensive chemotherapy.
Mammographic localization and biopsy of nonpalpable breast lesions. A 5-year study, A malignancy rate of 24% was achieved as a result of needle localizations and biopsies of 548 nonpalpable mammographically detected breast lesions in 507 consecutive patients during a 5-year period. Malignancy was present in 74 (23.8%) of 311 irregular soft-tissue densities. in 40 (19.6%) of 204 cases with clustered microcalcifications. and in 33 cases (54.5%) when both features were present. Same-day admission and discharge were achieved in 491 patients and local anesthesia supplemented with intravenous sedation was used in 73 (74%) of the 98 patients (in 1989) by the end of the study period. Nonpalpable cancers were categorized pathologically as stage 0 in 25 patients (20.8%). stage I in 67 patients (55.8%). stage IIA in 24 patients (20.0%). and stage IIB in four patients (3.3%). The malignancy rate rose sharply from the fourth to the fifth decade.
Biliary patency imaging after endoscopic retrograde sphincterotomy with gallbladder in situ. Clinical impact of nonvisualization, We prospectively performed nuclear biliary patency imaging (HIDA scanning) in 62 patients who had undergone endoscopic retrograde sphincterotomy for management of pancreaticobiliary disease with their gallbladders in situ. Elective cholecystectomy was not recommended because of advanced age. comorbidity. or absence of gallstones. All patients had patent cystic ducts at endoscopic retrograde cholangiopancreatography balloon cholangiography. Eighteen (29.1%) of 62 patients had nonvisualizing HIDA scans. and in 44 (70.9%) of 62 visualization was normal or delayed. Six cholecystectomies were required for colic (n = 1). acute cholecystitis (n = 4). and acute cholecystocholedochal fistula with cholangitis (n = 1). Among the patients with cholelithiasis and nonvisualization (n = 13). five (38.5%) required surgery. whereas only one (4.8%) of 21 patients with cholelithiasis and visualization required surgery. Nonvisualizing HIDA scans are frequent (30%) after endoscopic retrograde sphincterotomy and have no clinical relevance in patients without cholelithiasis but predict the need for cholecystectomy within 16 months in 38.5% of patients with cholelithiasis.
Barrier efficiency of surgical gowns. Are we really protected from our patients' pathogens, Surgical gowns are traditionally worn to protect patients from contamination by the surgical team. Blood routinely covers gowns during surgery and often contaminates surgeons' undergarments and skin. Because of risks to the surgical team by blood-borne pathogens. disposable and reusable gowns were examined. To quantify "strike through." 1440 samples of gown fabric were tested against human blood in an apparatus designed to simulate abdominal pressure during surgery. Representative pressures (0.25 to 2.0 psi) and times (1 second to 5 minutes) were studied. Above 0.5 psi. spun-bond/melt-blown/spun-bond disposable products were more resistant than spun-lace cloth. New cloth gowns were better than those washed 40 times. Spun-bond/melt-blown/spun-bond fabric exposed to blood twice was more protective than spun-lace cloth challenged once. Gowns currently available exhibit varying resistance to strike through; only those with an impervious plastic reinforcement offer complete protection.
Liver viability after ischemia-reperfusion, Lack of a reproducible model to quantitatively assess hepatocellular injury following ischemia has made it difficult to assess new strategies for minimizing hepatic injury. We studied the progression of hepatocellular injury after ischemia and ischemia with reperfusion in rats. Irreversible injury was quantitated using a triphenyltetrazolium chloride assay that was shown to correlate with ultrastructural changes. Adenosine triphosphate decreased to 36% of basal values after 30 minutes. but returned to normal with reperfusion with no decrease in viability. In contrast. viability fell by 30% after 60 minutes of ischemia. and by 64% when 60 minutes of ischemia was followed by reperfusion. We conclude that reperfusion of ischemic liver increases the degree of irreversible damage. The model employed here seems to be useful for studying ischemic and reperfusion injury in the liver.
Lateral thoracotomy for the automatic implantable defibrillator, In 51 patients who required automatic implantable cardioverter defibrillator implantation without additional cardiac procedures. the lead system was implanted using a lateral thoracotomy approach. with complete muscle sparing in the last 24 patients. Exposure was excellent and allowed repositioning of leads for optimal defibrillation thresholds in 18 patients. Five of 19 patients who had previously undergone intrapericardial procedures required intrapericardial dissection for lead placement to provide satisfactory defibrillation thresholds. There were no intraoperative deaths or infarctions. The 30-day mortality rate of 3.9% was comparable with those in other series. and the use of muscle-sparing techniques and supplemental epidural anesthesia prevented pulmonary complications or the need for prolonged ventilatory support. We favor a muscle-sparing lateral thoracotomy incision for automatic implantable cardioverter defibrillator insertion. particularly in patients with a history of previous intrapericardial procedures.
Incidence and prevalence of amyotrophic lateral sclerosis in Harris County, Texas, 1985-1988, The incidence of amyotrophic lateral sclerosis was determined in Harris County. Texas. for the period 1985 through 1988. Amyotrophic lateral sclerosis cases were ascertained from four sources: area neurologists. hospitals. death certificates. and the Muscular Dystrophy Association. The age-adjusted incidences of 1.27 per 100.000 person-years in males and 1.03 per 100.000 person-years in females were lower than recent rates in the northern US. Canadian. and northern European studies but higher than rates in southern European studies. Comparisons with other recent incidence studies show less uniformity in occurrence of amyotrophic lateral sclerosis. in both the overall rates and in the age- and sex-specific patterns. than was suggested by mortality studies. The incidence of amyotrophic lateral sclerosis among blacks and whites was similar. Hispanic males had incidences similar to white males. although a deficit of female Hispanic cases was found in Harris County. The prevalence of amyotrophic lateral sclerosis peaked in the 65- to 74-year age group at 33 per 100.000 population among males and 19 per 100.000 population for females.
Estimated prevalence of dementia among elderly black and white community residents, A stratified random sample of 83 black and 81 white community residents aged 65 years and older in a five-county area in the Piedmont region of North Carolina was evaluated for dementia. using the Diagnostic and Statistical Manual of Mental Disorders. Third Edition. and the National Institute of Neurological Disorders and Stroke--Alzheimer's Disease and Related Disorders Association criteria. Of 164 subjects. 26 were found to be demented. resulting in an estimated prevalence rate of dementia in the five-county area of 16% (95% confidence interval. 7.92 to 24.08) for blacks and 3.05% (95% confidence interval. 0 to 6.91) for whites. The estimated prevalence of dementia for white women (2.9%) was similar to that for white men (3.3%). but the rate for black women was distinctly higher than for black men (19.9% and 8.9%. respectively). Blacks were more likely than whites to have a history of stroke. hypertension. and other chronic disorders that might have contributed to the development of dementia. Apart from differences in rates of institutionalization. no other relevant factors were identified that might explain the difference in the prevalence of dementia in these black and white community residents.
A 'stress' test for memory dysfunction. Electrophysiologic manifestations of early Alzheimer's disease, Long-latency event-related potentials (P300) were assessed in patients with early probable Alzheimer's disease (AD). age-matched controls. and young adults during a task that imposed various degrees of demand on memory. Although patients with AD did not differ from age-matched controls when one item had to be remembered. their P300 potential was dramatically reduced in amplitude or absent with increasing memory load. Aged controls did not differ from young adults on this measure. P300 latency. however. did not differentiate patients with AD. Thus. electrophysiological abnormalities detected in the context of mnemonic demand may provide a sensitive marker of the early stages of probable AD.
Retrospective postmortem dementia assessment. Validation of a new clinical interview to assist neuropathologic study, Neuropathologic studies of dementia and normal aging suffer from a lack of individuals examined for the presence and severity of dementia before death. To increase clinical information in such cases. a retrospective collateral interview was developed. Thirty-nine individuals were studied; 27 had autopsies. In all cases. the autopsy confirmed the Retrospective Collateral Dementia Interview (RCDI) diagnosis of the presence or absence of dementia; the RCDI had a sensitivity of 88% and a specificity of 80% for specifically detecting probable Alzheimer's disease. Agreement between the RCDI and premortem diagnosis was 96%; between RCDI and medical records. 100%. Agreement between RCDI staging of dementia severity and the last assessment of the living subject was 70%; between the RCDI and a brief staging at death. 86%. This validation confirms the value of postmortem interviews with close informants to assess dementia presence and severity.
Regional cerebral blood flow after human cardiac arrest. A hexamethylpropyleneamine oxime single photon emission computed tomographic study, We studied 30 patients 24 hours after out-of-hospital cardiac arrest and 13 age-matched normal controls with the use of technetium Tc 99m-hexamethylpropyleneamine oxime single photon emission computed tomography. All patients were followed up for 12 months or until death. Frontal hypoperfusion (anteroposterior perfusion ratio. less than 0.90) was observed in 23 patients (77%). In eight patients who remained comatose and died. the total size of perfusion defects was larger (38% +/- 20%) than in the 21 patients who recovered consciousness (24% +/- 14%). but the anteroposterior ratio was similar in both of these patient groups (0.83 +/- 0.09) and significantly lower than in the controls (0.96 +/- 0.03). During follow-up. both the anteroposterior perfusion ratio and the relative defect size improved. but frontal hypoperfusion was still observed in seven of 13 patients. After cardiac arrest. regional cerebral blood flow is characterized by frontal hypoperfusion that tends to improve over time but that persists in most patients.
Regional cerebral blood flow correlates of language processes in reading disability, This series of studies tests the hypothesis of abnormal left hemisphere activation in reading-disabled subjects during language task performance. First. a left superotemporal focus of activation. as measured by regional cerebral blood flow. was found to be positively correlated with task accuracy in a group of 69 normal adults. Next. that left superotemporal activation was replicated in a second group of 83 adults whose childhood reading ability was known from standardized tests given in childhood. Finally. in that latter group. childhood reading ability was also found to be inversely correlated with focal activation in a more posterior. temporoparietal area of cortex. Adult reading outcome was statistically unrelated to this finding. The results are interpreted as suggesting a trait anomaly of left hemisphere cerebral activation in adults who were dyslexic as children and as providing an existence proof of individual differences in focal cortical activation sites during constant task demands.
Validation of a clinical antisaccadic eye movement test in the assessment of dementia, The ability to generate antisaccades (eye movements deliberately made in the direction opposite to that of a visual stimulus) may be used to assess central nervous system function in a variety of neurologic and psychiatric disorders. However. the usefulness of this paradigm in clinical practice is limited by the need for an oculographic laboratory. We describe a clinical version of such an antisaccadic task and present normative data from 332 subjects. We also examined clinical antisaccades and cognitive performance in 30 patients with Alzheimer's disease. five patients with Huntington's disease. and 12 patients with pseudodementia. In Alzheimer's disease. error rates in the clinical antisaccadic test correlated well with those from a laboratory-based antisaccadic task measured on the same day by infrared oculography. confirming that the clinical antisaccadic test is a valid analog of the more sophisticated laboratory paradigms. Clinical antisaccadic error rates correlated strongly with the severity of dementia in Alzheimer's disease. and correlations with cognitive performance suggested that the clinical antisaccadic test may have some specificity for frontal lobe dysfunction. Patients with pseudodementia had normal clinical antisaccadic error rates. and the test may therefore be of use in differentiating dementia from pseudodementia. This clinical antisaccadic test provides a simple. reliable. and inexpensive quantitative clinical tool that is of value in the assessment of disturbances of higher cortical function.
Literary neurologic syndromes. Alice in Wonderland, Many neurologic syndromes are named for literary characters. For example. the "Alice in Wonderland" syndrome of altered body perceptions. usually caused by migrainous ischemia. is so called because of the resemblance of its symptoms to the fluctuations in size and shape that plague the main character in Lewis Carroll's 1865 novel Alice in Wonderland. The medical symptoms of distorted body images match the literary description so precisely that illustrations from the original book depict them very accurately. Because Lewis Carroll suffered from classic migraine headaches. scholars have speculated that he may have experienced this syndrome himself.
Central nervous system germinomas. A review, The germinoma represents a less malignant form of germ cell tumor. Depending on the individual's age. this neoplasm constitutes approximately 0.1% to 3.4% of all intracranial tumors. The embryologic origin remains a mystery; however. current theories implicate an aberration in primordial germ cell migration. Clinical presentation depends on tumor location and may involve endocrine. hypothalamic. visual. and cognitive dysfunction. In evaluating midline intracerebral masses. it is imperative that one be aware of the various radiologic appearances. endocrinologic changes. and chemical markers that help to distinguish germinomas from other neoplasms that appear in the pineal. suprasellar. and periventricular regions. Only through the careful evaluation of all available studies can the physician institute appropriate therapies such as biopsy. radiation. and chemotherapy. This article focuses on the epidemiology. embryology. clinical presentation. means of diagnosis. treatment. and outcome of this rare neoplasm.
Observer variation in assessing neurophysical signs among patients with head injuries, As an early phase in the development of a valid and reliable measure of the neurophysical sequelae after head injury. we carried out assessments of interrater agreement on representative items. The purpose of this study was to determine the degree of agreement among expert raters who independently measured neurophysical signs on patients undergoing physical rehabilitation after brain injury. Agreement was described using the index of crude agreement. expected agreement and Kappa. Therapists showed a high degree of agreement on those items forming part of a routine neurological assessment: prehension. coordination. voluntary movements and tendon reflexes. Crude agreement ranged from 77.8-100%. There was considerable discordance in assessing muscle tonus. equilibrium and protective reactions. spinal reflexes. tremor and dysmetria (crude agreement ranged from 49.7-97.9%). Although. the number of subjects was small. the information generated from this study will be useful in refining our instrument for the assessment of neurophysical signs.
Evaluating the safety and potential use of a weight-bearing exercise, Tai-Chi Chuan, for rheumatoid arthritis patients, The safety of a traditional Chinese exercise. Tai-Chi Chuan. on rheumatoid arthritis (RA) patients was evaluated. RA patients. who received 1 h of Tai-Chi Chuan instruction once (n = 20) and twice (n = 15) a week for 10 consecutive wk in two separate studies. showed no deterioration in their clinical disease activities compared with the corresponding controls (n = 11 and 9. respectively). Testing parameters included joint tenderness. joint swelling. time to walk 50 feet. handgrip strength and a written functional assessment. No significant exacerbation of joint symptoms using this weight-bearing form of exercise was observed. Tai-Chi Chuan exercise appears to be safe for RA patients and may serve as an alternative for their exercise therapy and part of their rehabilitation program. Weight-bearing exercises have the potential advantages of stimulating bone growth and strengthening connective tissue. but this effect needs to be documented in long-term studies.
Oxygen free radicals and congestive heart failure, Plasma lipid peroxides (malondialdehyde) and thiols were measured in 45 patients with congestive heart failure and 45 controls. Malondialdehyde concentrations were significantly higher in the patients with congestive heart failure (median 9.0 nmol/ml interquartile range (IQR) 7.9-10.2) than in the controls (median 7.7 nmol/ml (IQR 6.9-9.2)). Plasma thiols were significantly lower in congestive heart failure (median 420 mumol/l (IQR 379-480)) than in the controls (median 463 mumol/l (IQR 445-525)). There was a significant but weak negative correlation between malondialdehyde and left ventricular ejection fraction (r = -0.35) and a positive correlation between plasma thiols and left ventricular ejection fraction (r = 0.39). This study provides clinical support for experimental data indicating that free radicals may be important in heart failure. It also suggests that the degree of free radical production may be linked to the severity of the disease.
Characteristics of left ventricular filling in coronary artery disease and myocardial ischaemia after dipyridamole provocation, Doppler echocardiographic measurement of transmitral filling velocities seems to be a sensitive marker for resting left ventricular diastolic abnormalities in patients with coronary artery disease. The behaviour of these filling velocities during induced myocardial ischaemia. however. has not been fully studied. Left ventricular filling was assessed by pulsed Doppler ultrasound in 21 patients with angina pectoris and coronary artery disease and in five controls (patients with chest pain but without myocardial ischaemia). High dose dipyridamole infusion (0.9 mg/kg over 10 minutes) was used to provoke myocardial ischaemia. which was assessed by symptoms and electrocardiographic ST segment change. Doppler indices of diastolic filling were measured and the results expressed as percentage change from baseline values. Dipyridamole increased the heart rate and reduced systolic blood pressure equally in both groups. In the controls dipyridamole increased the peak filling velocities of both the early and atrial filling waves. In the 12 patients with coronary artery disease who did not develop evidence of myocardial ischaemia. the effect on left ventricular filling velocity resembled that in the controls though the time to peak change was delayed. Six of the nine patients with dipyridamole induced myocardial ischaemia had a significantly reduced maximum changes in early (+30% v +18%) and atrial (-0.2% v +33%) filling velocities compared with the controls. The remaining three patients had a decrease in early filling velocity (-20%) with an associated increase in atrial peak filling velocity (+21%). Dipyridamole increased diastolic filling velocities in the controls. In patients with coronary artery disease there was a variable change in diastolic filling indices which may be attributed either to the degree of myocardial ischaemia or to the different haemodynamic changes occurring during myocardial ischaemia.
Operative survival and 40 year follow up of surgical repair of aortic coarctation, OBJECTIVE--To study early and late mortality after surgical correction of coarctation of the aorta. DESIGN--Data on 223 patients operated on at the Westminster Hospital. London. between 1946 and 1981. were collected and updated by questionnaire. PARTICIPANTS--All 223 patients recorded as undergoing operation for aortic coarctation up to the end of 1981. Fifteen of 197 survivors were lost to follow up; most of them were patients from overseas. OUTCOME AND RESULTS--The early mortality (within one month of operation) was 12% overall. 2.6% for elective surgery. and 0% for the 77 patients undergoing surgery since 1968. Survivors were followed up for a total of 3288 patient years; in 27 follow up lasted more than 30 years. In a few it reached 40 years. Twenty two patients died during this period. 18 from causes that could be attributed to coarctation or its repair. Mortality was highest more than 20 years after the operation. CONCLUSION--Repair increased life expectancy in patients with aortic coarctation. Late problems caused by persistent hypertension or recoarctation became apparent in long term survivors. The increased risk of late mortality associated with the duration of preoperative hypertension was not statistically significant. There were no deaths from cerebrovascular accidents. (In an earlier necropsy series cerebrovascular accidents accounted for 11.8% of deaths.) The incidence of deaths from aneurysms resembled that in the earlier necropsy series.
Fixed subaortic stenosis: anatomical spectrum and nature of progression, Retrospective echocardiographic review identified 58 consecutive infants and children with fixed subaortic stenosis. Mean (SD) age at diagnosis was 4.8 (3.6) years (range two days to 14.7 years). and diagnosis occurred in infancy in eight. Associated cardiac abnormalities were present in 41 (71%) whereas fixed subaortic stenosis was an isolated lesion in 17 (29%). Four types of fixed subaortic stenosis were identified: short segment (47 (81%)). long segment (7 (12%)). posterior displacement of the infundibular septum with additional discrete narrowing of the left ventricular outflow tract (3 (5%)). and redundant tissue arising from the membranous septum (1 (2%)). Echocardiographic studies had been performed before the diagnosis of fixed subaortic stenosis in nine patients. all with associated abnormalities. These were performed in infancy in each and showed a "normal" left ventricular outflow tract in six and posterior deviation of the infundibular septum in three. In 16 patients serial echocardiographic studies had been performed after the diagnosis of fixed subaortic stenosis but before surgery of the left ventricular outflow tract. Rapid evolution of short segment to long segment narrowing was seen in one patient. and tethering of the aortic valve or mitral valve developed in a further four patients. Aortic valve or mitral valve involvement was not seen before the age of three years but was common thereafter (10/40 patients. 25%). Fixed subaortic stenosis may be an "acquired" lesion with the potential for changes in form as well as progression in severity of left ventricular outflow tract obstruction.
Endemic pemphigus foliaceus in western Parana, Brazil (1976-1988). Cooperative Group for Fogo Selvagem Research, Endemic pemphigus foliaceus or fogo selvagem (FS) is a blistering autoimmune disease indigenous to certain states of Brazil. In the state of Parana the disease has been reported in the north-central regions where a total of 632 cases were documented in the period of 1940-80. The present study describes a new focus of FS in the western region of the state of Parana. This focus includes a total of 213 new cases of FS and only 11 cases of pemphigus vulgaris seen in this region from February 1976 to July 1988. Over 90% of these patients were peasants working in agriculture or involved in other outdoor activities.
Fibroblast-keratinocyte interactions in psoriasis: failure of psoriatic fibroblasts to stimulate keratinocyte proliferation in vitro, We have tested in two ways the hypothesis that dermal fibroblasts direct the hyperproliferation of the overlying epidermis in psoriasis. First. culture medium from psoriatic and from normal skin fibroblasts was added to monolayer cultures of foreskin keratinocytes. Second. psoriatic and normal fibroblasts embedded in hydrated collagen lattices were co-cultured with monolayers of foreskin keratinocytes. There was no evidence in either study that psoriatic fibroblast products could stimulate the proliferation of the keratinocytes. or that normal fibroblast products inhibited their proliferation. A positive control for the fibroblasts was provided by leucocyte supernatants. which stimulated keratinocyte proliferation by up to 65%. Our data do not support a primary role for dermal fibroblasts in psoriasis.
Epidermal interleukin 1 in normal skin of patients with HIV infection, Interleukin 1 (IL-1) in the epidermis plays an important role together with Langerhans cells in the activation of the T cells. To determine whether IL-1 could be located in the normal epidermis of 54 patients with HIV infection and related to the stage of the disease. an indirect immunofluorescence technique was used. Intense epidermal fluorescence to IL-1 was noted in the asymptomatic stage II of the disease. whereas there was minimal reactivity in the other stages.
Assessment of a contact-plate sampling technique and subsequent quantitative bacterial studies in atopic dermatitis, The aerobic bacterial flora of 20 patients with atopic dermatitis and 19 control subjects was extensively sampled using the Williamson and Kligman scrub technique and a contact-plate method (cysteine lactose electrolyte deficient media). Comparison of the two quantitative techniques showed that the contact plate is a reliable and convenient alternative to the scrub technique for the quantification of Staphylococcus aureus. micrococci and coagulase negative staphylococci. Quantification of bacterial flora using both techniques showed high rates of colonization by S. aureus on both involved and clinically normal skin of patients with atopic dermatitis. A linear increase in S. aureus counts with increasing severity of dermatitis was found. In contrast. diphtheroids showed a trend of decreasing isolation rates and counts as the severity of the dermatitis increased. Isolation rates and absolute counts for micrococci/coagulase negative cocci were unaffected by the severity of the dermatitis.
Effect of incisional biopsy on subsequent histology of melanocytic naevi, We examined the effect of incisional biopsy on the subsequent histology of 15 benign melanocytic naevi. In all cases the histology of the residual lesion within the second specimen was unchanged apart from the presence of a surgical scar. and in general the definitive excision specimen showed a reduction in melanocytes at the dermo-epidermal junction overlying the scar. In no case were there any features suggestive of melanoma.
Morphological evidence for calcium-dependent association of calgranulin with the epidermal cytoskeleton in inflammatory dermatoses, The association of calgranulins. intracellular calcium-binding proteins. with the keratinocyte cytoskeleton has been studied. These molecules are expressed in various inflammatory dermatoses and in organ-culture explants. Triton X-100 extraction in the presence of calcium or EDTA suggested that calgranulins are detergent insoluble in the presence of calcium. The molecules were localized in a plaque-like structure at the cell periphery in lesional skin and in organ-culture explants. Following induction of calgranulins in vitro there was a redistribution of the intermediate filament cytoskeleton into a perinuclear halo. although desmosomes remained intact. These various features suggest that these members of the S-100 protein family have a role in cytoskeletal changes seen in various skin diseases.
Clinical correlations and prognosis based on hyaluronic acid serum levels in patients with progressive systemic sclerosis, The serum levels of hyaluronic acid (sHA) were measured using an affinoimmunoenzymatic assay in patients with distal (n = 16) and proximal (n = 15) progressive systemic sclerosis (PSS) and in 31 controls. The severity of PSS was evaluated using a standardized organ-involvement score. The mean sHA was significantly higher in the patients with PSS than in controls (mean +/- SD:80 +/- 43.4 micrograms/l vs. 42.3 +/- 19.1 micrograms/l. P less than 0.001). sHA was significantly higher in patients with proximal PSS than in patients with distal PSS (106.4 +/- 44.6 micrograms/l vs. 55.4 +/- 23.8 micrograms/l. P less than 0.001). A positive correlation was found between sHA and the disease score (r = 0.67. P less than 0.001). sHA was also correlated with lung diffusion capacity for carbon monoxide (r = 0.70. P less than 0.001). but only in the those patients who had abnormal lung function. and therefore presumably had lung PSS involvement. We suggest that sHA could be an indicator of the degree of systemic involvement in PSS. Its prognostic value and possible use in the follow up of patients with PSS remain to be clarified.
The action spectrum between 320 and 400 nm for clearance of psoriasis by psoralen photochemotherapy, We have compared the effectiveness of oral 8-methoxypsoralen photochemotherapy (PUVA) using ultraviolet fluorescent lamps with peak emission at either 325. 352 or 370 nm in the treatment of 24 patients with psoriasis. The forearms of each patient were treated three times weekly with two of the three lamps. The erythemal sensitivity of each patient was tested before the first treatment to ensure that equally erythemal doses of radiation were given from each of the lamps. A side-to-side comparison was used to assess response to treatment at weekly intervals for the 6 weeks of the trial. The lamp with peak emission at 325 nm was shown to be significantly superior to either of the other lamps in terms of response assessed at weekly intervals. and time to clearance of psoriasis. An action spectrum. constructed from the median doses required for clearance of psoriasis using each of the lamps. showed that the effectiveness of the radiation decreased exponentially with increasing wavelength throughout the UVA waveband. such that radiation at 320 nm was an order of magnitude more effective than at 360 nm. This suggests that lamps with peak emission around 325 nm will be more effective than those conventionally used in PUVA units with a peak emission at 352 nm. Lamps with peak emission around 325 nm are also highly effective in the treatment of psoriasis with phototherapy alone. Thus a single treatment unit containing these lamps could be used either for PUVA or ultraviolet phototherapy of psoriasis. avoiding duplication or irradiation equipment.
Congenital malignant melanoma, A case is reported of congenital malignant melanoma that occurred in the absence of maternal melanoma or a congenital giant naevus. The patient had the melanoma on the left thigh excised 54 days after birth. but later died at the age of 18 months with multiple metastases.
High-dose cyclophosphamide, carmustine, and etoposide followed by autologous peripheral stem cell transplantation for patients with relapsed Hodgkin's disease, Between February 1986 and March 1990. 56 patients with relapsed Hodgkin's disease treated with high-dose cyclophosphamide. carmustine. and etoposide (CBV) received an autologous peripheral stem cell transplantation (PSCT) rather than an autologous bone marrow transplantation (ABMT) because each patient had a marrow abnormality. either hypocellularity or tumor involvement. At least 6.5 x 10(9) mononuclear cells/kg patient weight were collected from the peripheral blood of each patient. cyropreserved. and returned intravenously following CBV administration. Three patients had an early death 2. 22. and 25 days after PSCT. The actuarial event-free survival for these 56 patients at 3 years was 37% and was at least as good as that reported for relapsed Hodgkin's disease patients treated with CBV and ABMT. The 30 patients who had no marrow metastases at the time of PSC harvesting had an actuarial event-free survival of 47%. while those 26 patients with marrow metastases had a significantly different actuarial event-free survival of 27% (P = .02). CBV and PSCT for patients with relapsed Hodgkin's diseases who have marrow hypocellularity in traditional harvest sites or histopathologic evidence of BM metastases can result in long-term event-free survival.
In vitro effects of hematopoietic growth factors on the proliferation, endoreplication, and maturation of human megakaryocytes, A liquid culture technique was used to study regulation of human megakaryocytopoiesis in vitro. Low-density cells from adult bone marrow were cultured in the presence of normal plasma. plasma from patients with aplastic marrows (AP). recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and interleukin-3 (IL-3). Megakaryocytes (MK) were studied at day 10 of culture by a two-color staining technique using a pool of monoclonal antibodies for their identification and propidium iodide to label DNA. Their ploidy distribution was analyzed by flow cytometry. In some experiments cytoplasmic maturation was also studied by ultrastructural techniques. Normal plasma provides a low number of MK with a ploidy distribution including 8 N and 16 N MK. AP promoted in a dose-dependent manner proliferation of MK and some batches favored endoreplication. This effect was clearly demonstrated when ploidy distribution was compared between normal plasma and AP on parallel marrow cultures. However. ploidy distribution was shifted toward low values compared with uncultured MK. rhGM-CSF had no significant effect on these two parameters. In contrast. rhIL-3 from 0.1 U/mL to 100 U/mL had a proliferative effect but was unable to induce endoreplication. Furthermore. when associated with AP it totally abrogated the effect of AP on endoreplication because in most experiments more than 90% of MK were 2 N and 4 N. This effect was also observed when rhIL-3 was added after 7 days of culture (when it has little proliferative effects). Studies of the maturation of MK grown with rhIL-3 indicate that the majority were small mature cells synthesizing alpha-granules and demarcation membranes. The effect of AP on MK proliferation and endoreplication was not related to IL-6 because its IL-6 content was identical to that of normal plasma and its neutralization did not modify these parameters. In conclusion. this study indicates that liquid culture technique in association with flow cytometry could be a powerful tool in identifying the humoral regulators of human megakaryocytopoiesis.
Detection and characterization of human T-cell lymphotropic virus type I (HTLV-I) associated T-cell neoplasms in an HTLV-I nonendemic region by polymerase chain reaction, Human T-cell lymphotropic virus type I (HTLV-I) associated adult T-cell leukemia/lymphoma (ATLL) occurs endemically in southwestern Japan. the Caribbean. and West Africa. but occurs sporadically in most of the rest of the world. However. because ATLL and non-HTLV-I associated T-cell neoplasms share overlapping clinicopathologic features. the prevalence of ATLL in nonendemic regions is unknown. In this study. 75 T-cell neoplasms randomly procured from the metropolitan New York City area were examined by polymerase chain reaction (PCR) for the presence of integrated HTLV-I proviral sequences. HTLV-I genomic sequences were detected by PCR in 6 of the 75 cases (8%); this result was confirmed by Southern blot hybridization. The clinicopathologic features of the HTLV-I positive and HTLV-I negative T-cell neoplasms were then compared. Although the clinicopathologic features of patients from these two groups overlapped. some findings were more commonly associated with HTLV-I positive neoplasms. Five of the six patients with HTLV-I positive neoplasms were from HTLV-I endemic areas. five were black. five were women. and five were less than 45 years of age. while the majority of the patients with HTLV-I negative T-cell malignancies were elderly white men. The incidence of hypercalcemia and lytic bone lesions was significantly more common among patients with HTLV-I positive T-cell neoplasms (P less than .001 and P = .004. respectively). The immunophenotypes of the HTLV-I positive and negative tumors were similar; however. all HTLV-I positive neoplasms were CD7 negative (P less than .001). In summary. our findings: (1) demonstrate the special clinicopathologic and immunophenotypic features of HTLV-I positive T-cell neoplasms. (2) suggest that most of the rare cases of HTLV-I-associated T-cell neoplasms occurring in HTLV-I nonendemic areas are actually endemic cases; and (3) that PCR is a sensitive. clinically useful technique for identifying HTLV-I associated T-cell neoplasms.
Interleukin-7 differentiates a subgroup of acute lymphoblastic leukemias, The bone marrow stromal cell-derived growth factor interleukin-7 (IL-7) is known to stimulate growth of normal human B-cell precursors. In the present report. we have examined the effect of IL-7 on neoplastic B-cell precursors. Leukemic cells from 20 patients with common acute lymphoblastic leukemia (ALL) were highly purified by removing contaminating T cells and monocytes by rosetting with immunomagnetic beads. IL-7 markedly reduced the DNA synthesis in leukemic cells from three patients. This inhibition of DNA synthesis was accompanied by maturation of the cells. as demonstrated by the induced expression of the differentiation antigens CD19. CD20. CDw75. and surface mu-chain. and a decreased expression of terminal deoxynucleotidyl transferase. By examining G1 parameters. such as MYC. 4F2. and transferrin-receptor levels analyzed by flow cytometry as well as RNA and the cell cycle regulated antigen Ki67. it appeared that the cells were inhibited late in G1. Leukemic cells from the majority of the cases (12 of the 20 patients) responded to IL-7 with enhanced DNA synthesis without detectable maturation. as has been reported for their normal counterparts. Low molecular weight B-cell growth factor greatly potentiated the IL-7-induced growth stimulation of these cells. Thus. we have shown that IL-7 is capable of inhibiting proliferation of leukemic cells isolated from a subgroup of ALLs. and that this growth inhibition is accompanied by maturation of the cells.
Point mutations in the beta-subunit of cytochrome b558 leading to X-linked chronic granulomatous disease, The NADPH:O2 oxidoreductase of phagocytic leukocytes is an important enzyme for the bactericidal activity of these cells. Cytochrome b558 is a membrane component of this enzyme. In X-linked chronic granulomatous disease (Xb- CGD) the phagocytes are defective in the beta-subunit (gp91-phox) of this cytochrome. We have studied the genetic defect in a group of six X-linked CGD patients characterized by complete or partial loss of cytochrome b558 with the use of the polymerase chain reaction. All patients had a different single point mutation in the gp91-phox gene. indicating that the genetic defect in Xb- CGD is very heterogeneous. In one patient the mutation leads to a premature termination codon. In the other five cases these mutations predict incorporation of a different amino acid. The mutations were with one exception found in the N-terminal half of the protein. suggesting that this part of cytochrome b558 is important for the binding of the heme or for formation of a stable complex with p22-phox. Two histidyl residues were found that might be ligands of the heme iron.
Localization of cells producing erythropoietin in murine liver by in situ hybridization, In situ hybridization using antisense RNA probes was used to localize cells that produce erythropoietin (EPO) in the livers of anemic transgenic mice expressing the human EPO gene and in livers of anemic nontransgenic mice. In transgenic mice bled from a hematocrit of 55% to one of 10%. hepatocytes surrounding central veins synthesized large amounts of human EPO mRNA. EPO-producing cells were very rare in the area of portal triads. In transgenic mice bled to a hematocrit of 20%. a similar number and distribution of cells contained human EPO mRNA as was found with a 10% hematocrit. but the cells were less heavily labeled. indicating increased EPO production per cell at 10% hematocrit as compared with 20% hematocrit. No human EPO mRNA was detected in the kidneys of anemic transgenic mice. although endogenous murine EPO mRNA was strongly expressed in cortical interstitial cells. In sections of livers from nontransgenic mice bled from a hematocrit of 45% to one of 10%. only isolated cells produced EPO. When the types of cells could clearly be identified. approximately 80% of these cells were hepatocytes. while 20% had a nonepithelial morphology and were located in or adjacent to the sinusoidal spaces. When the sense strand was used as the RNA probe for in situ hybridization. no labeled cells were seen in normal or anemic livers. These results demonstrate that hepatocytes are responsible for production of EPO in both transgenic and nontransgenic mice and that a second cell type that is similar in morphology to EPO-producing interstitial cells in the kidney also produces EPO in the livers of nontransgenic mice.
Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma, Sixty-nine patients with a history of low-grade B-cell non-Hodgkin's lymphoma (NHL) in sensitive relapse or incomplete first remission underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MoAb)-treated autologous bone marrow transplantation (ABMT). At ABMT. 51 patients had low-grade histology and 18 patients had a history of low-grade NHL that had undergone histologic transformation to a higher-grade NHL. Before ABMT. only 20 of the 51 low-grade patients and 10 of the 18 patients with transformed histologies were in complete remission. Moreover. at the time of marrow harvest. 24 of the low-grade and eight of the transformed histology patients had histologic evidence of lymphoma cells infiltrating the marrow. Following high-dose therapy. only one acute. in-hospital death was observed. There was no significant difference in the disease-free survival (DFS) between patients with low-grade and patients with transformed histologies. Among patients with low-grade NHL. the patients in complete remission before ABMT experienced significantly longer DFS than those in partial remission (P less than .05). This preliminary study suggests that some patients with relapsed low-grade NHL may experience prolonged DFS following high-dose ablative therapy.
Terodiline with bladder retraining for treating detrusor instability in elderly people, OBJECTIVE--To compare terodiline with bladder retraining against placebo with bladder retraining in the treatment of detrusor instability in frail elderly patients. DESIGN--Randomised. double blind. parallel group study. Treatment lasted for six weeks. Frequency of micturition and episodes of incontinence recorded on diary chart by patients. SETTING--Incontinence clinic and a geriatric day hospital at two teaching hospitals. PATIENTS--37 frail but ambulant patients. mean (range) age 80.4 (70-89) years with urinary frequency and urge incontinence. due to detrusor instability. Two patients withdrew before the first assessment (one in each group) and one could not complete the diary chart (placebo group). INTERVENTIONS--19 patients received bladder retraining and terodiline 25 mg daily and 18 bladder retraining and placebo. MAIN OUTCOME MEASURES--Change in urinary frequency and number of episodes of incontinence after six weeks' treatment. Patient's subjective evaluation of symptoms. RESULTS--Little difference was found in the results of treatment with terodiline and placebo. The change in episodes of incontinence per 24 hours was no different in the two groups (95% confidence interval -0.6 to 1.2; p = 0.75) and the difference between treatments in the change in frequency of micturition per 24 hours (-0.2) was not significant (-1.1 to 1.2; p = 0.76). Ten patients taking terodiline thought they had improved compared with seven receiving placebo; this difference was not significant. CONCLUSION--Although the number of patients in each group was small and may have been insufficient to detect a drug effect. the possible benefit of terodiline is likely to be small.
Efficiency of referral for suspected glaucoma, OBJECTIVE--To examine the efficiency of referral for suspected glaucoma to general practitioners and consultants by optometrists. DESIGN--A prospective survey covering 5% of all sight tests performed by optometrists in England and Wales over six months. with analysis of referred patients. SETTING--241 optometrists' practices in areas representative of England and Wales in socioeconomic terms. SUBJECTS--Of 275.600 people attending for a sight test. 1505 were referred with suspected glaucoma (0.9% of those aged over 4%). Outcomes were recorded for 1228 patients. 1103 (90%) of whom attended for examination by a consultant ophthalmologist (8% on a private basis). The analysis was confined to the 704 cases in which the information on diagnosis was received directly from a consultant or general practitioner. MAIN OUTCOME MEASURES--Diagnoses reported by consultant ophthalmologists. Waiting times before an appointment for examination by a consultant ophthalmologist. RESULTS--Glaucoma was confirmed in 283 of the 704 referred patients. and another 222 patients were considered to require further monitoring. In all. 112 (41%) of 275 confirmed cases of glaucoma were in patients with intraocular pressures greater than or equal to 30 mm Hg. At all levels of intraocular pressure the accuracy of referral was greater when the optometrist also recorded the presence of suspicious optic discs or loss of visual field. or both; but only 331 (47%) out of the 704 referred patients had been tested with a field screener. The median waiting time for an NHS clinic appointment was nine weeks. Almost a 10th of confirmed cases of glaucoma were in people in a high risk category for glaucoma who had to wait at least 14 weeks for an appointment. CONCLUSIONS--Closer cooperation. especially at the local level. among consultants. general practitioners. and optometrists is needed to improve testing and referral for suspected glaucoma. Optometrists should be encouraged to perform all the three main tests--ophthalmoscopy. tonometry. and perimetry--in patients before referral and to report precisely on reasons for referral to help prioritisation. The optometrist's referral letter to the general practitioner should always be passed on to the consultant. Similarly. the diagnosis should always be reported back to the optometrist.
Incontinence in the elderly: objective demonstration and quantitative assessment, Subjective and objective methods of demonstrating incontinence and assessing its severity have been compared in a group of elderly patients with a high incidence of severe urge incontinence. It was found that 24-h in-patient monitoring of urine leakage was the most sensitive method of demonstrating incontinence. with videourodynamic testing almost as good. In comparison. a 1-h pad test was poor. Visual inspection during physical examination seldom demonstrated leakage. For quantitative assessment of severity. 24-h monitoring gave the most reproducible results; it was also able to reveal significant changes in severity in response to pharmaceutical treatment. A 1-h pad test was less reproducible and suggested changes that were only poorly consistent with 24-h monitoring. The subjective responses of the patients were not useful in assessing changes in the severity of incontinence. Twenty-four hour monitoring thus stands out as a superior method of demonstrating and assessing incontinence.
Diagnosis and treatment of neurogenic bladder due to partial sacral agenesis, Fifteen patients with partial sacral agenesis were treated over a mean period of 68 months. Partial unilateral agenesis was present in 7 and bilateral sacral agenesis was present in 8. Three important diagnostic features are emphasised: symptoms referable to neurogenic bladder without an obvious neurogenic lesion (all 15 patients); skin or hair abnormalities in the lumbosacral region (9/15) and paraesthesia or other neurological disorders of the lower extremities (8/15). The definitive diagnosis can be made by careful inspection of a plain film of the lumbosacrum. Detrusor contractility was absent in 13 patients but preserved in 2; 11 patients were managed by clean intermittent catheterisation. 2 voided using detrusor contractility and 2 voided by means of the Valsalva/Crede manoeuvre. In 5 patients surgery in the intradural space preserved sexual function and prevented further deterioration in function of the lower extremities but could not restore bladder function that had already deteriorated. Complete continence was achieved in 11 patients and socially acceptable continence in 4. Early diagnosis and conservative treatment with clean intermittent catheterisation are extremely important in management. Should functional deterioration of the bladder and/or sensomotor function of the lower limbs occur. neurosurgery should be performed promptly.
Abnormalities of colonic mucin secretion and metabolic changes after internal urinary diversion for bladder exstrophy. A prospective study, Ten patients with different types of internal urinary diversion for bladder exstrophy were studied prospectively in order to assess metabolic abnormalities and morphological. histochemical and lectin binding changes in the colorectal mucosa. The histochemical and/or lectin binding changes which were found in the majority of patients were identical to those observed in premalignant and malignant conditions of the colon. In some cases they were detectable 3 years after the initial examination but were completely absent from the colorectal mucosa of normal subjects. Metabolic disturbances (metabolic acidosis. increased anion gap. hyperchloraemia) were observed in a substantial number of asymptomatic patients. These findings stress the need for regular endoscopic. histological and metabolic follow-up in these patients and for life-long treatment with bicarbonate or citrate.
Indoramin in the treatment of prostatic bladder outflow obstruction, A series of 40 patients took part in a double-blind. placebo-controlled trial of indoramin in prostatic bladder outflow obstruction. Patients were assessed clinically and urodynamically before and after 4 weeks' treatment. Significant improvement was seen in nocturia. volume voided. flow rates and residual urine. The drug was well tolerated. although 7 patients on treatment and 7 on placebo noted side effects. These results suggest that indoramin may be a useful agent in the symptomatic management of bladder outflow obstruction.
Non-invasive assessment of arteriogenic impotence: a comparative study, This study was undertaken to determine the relative accuracy of computerised Doppler waveform analysis and colour coded duplex ultrasonography in the diagnosis of arteriogenic impotence. Twenty men with ostensibly normal penile haemodynamics were compared with 50 men whose impotence was considered due to compromised penile haemodynamics. In each patient the penile arterial inflow was assessed by both methods of investigation. which were performed at an interval of 2 weeks. The results demonstrated both techniques to be sensitive in detecting penile artery insufficiency but colour coded duplex ultrasonography was significantly more accurate.
Catheter-less suprapubic cystolithotomy in children, Bladder stones in children are common in developing countries and the procedure of choice for their removal is suprapubic cystolithotomy. It is standard practice to drain the bladder for a few days post-operatively to prevent urinary leakage. We have observed that. if the bladder is closed meticulously in 2 layers. bladder drainage by means of a catheter is not required. We have analysed 86 children treated by suprapubic cystolithotomy without a catheter. Size of the stones and intra-operative findings were noted and it was found that 85% of the patients had an excellent result; 10% had a satisfactory result and 4.7% were unsatisfactory. The advantages of the procedure and selection of the patients are discussed.
Selective gene expression in failing human heart. Quantification of steady-state levels of messenger RNA in endomyocardial biopsies using the polymerase chain reaction, BACKGROUND. Evaluation of gene expression in failing human heart has been limited by the availability of cardiac tissue. METHODS AND RESULTS. We used the polymerase chain reaction (PCR) to assess gene expression in small quantities of failing and nonfailing human heart. PCR is a powerful new molecular biological tool that allows a small quantity of DNA to be amplified as much as 1 million-fold. Total RNA was extracted from 3-5 mg samples of human heart and reverse-transcribed to complementary DNA (cDNA). With selected oligonucleotide primers. we used PCR to amplify cDNAs encoding atrial natriuretic peptide. beta-myosin heavy chain. phospholamban. and cytoskeletal beta-actin. To quantify the relative levels of messenger RNA (mRNA) in human heart. a known amount of a control RNA was present in the reverse transcription and PCR reactions. The amount of mRNA in the sample could therefore be assessed in relation to the amount of control product. The control RNA was transcribed from a synthetic DNA template containing primers complementary to those used to amplify the cDNAs of interest. Atrial natriuretic factor mRNA could not be detected in nonfailing human heart but was abundant in ventricular myocardium from failing human heart. In contrast. steady-state levels of phospholamban mRNA decreased. whereas levels of beta-myosin heavy-chain mRNA were unchanged with heart failure. CONCLUSIONS. Alterations in gene expression in the failing human heart appear to be selective. In addition. the present study suggests that PCR provides a rapid and economical way to quantify the expression of multiple genes of interest in endomyocardial biopsy specimens and may therefore be used to advance our understanding of heart muscle disease.
Limb vascular responsiveness to beta-adrenergic receptor stimulation in patients with congestive heart failure, BACKGROUND. In patients with congestive heart failure. the chronotropic and inotropic responses to beta-adrenergic agonists are reduced. It is not known whether desensitization of peripheral beta-adrenoceptors accounts for impaired limb vasodilation in these patients. Accordingly. we studied 14 normal subjects and 13 age-matched patients with congestive heart failure. METHODS AND RESULTS. To distinguish vasodilation mediated by beta-adrenoceptors and adenylate cyclase from that mediated by stimulation of guanylate cyclase. each subject received intrabrachial artery infusions of isoproterenol (1-100 ng/min) and sodium nitroprusside (0.3-10 micrograms/min). respectively. Forearm blood flow was determined by venous occlusion plethysmography. Maximal vasodilative potential. determined during reactive hyperemia. was reduced in the patients with congestive heart failure. The maximal forearm blood flow response to isoproterenol was comparable in patients with heart failure and in normal subjects (8.0 +/- 1.1 versus 9.2 +/- 1.2 ml/100 ml of tissue/min. respectively. p = NS). Furthermore. the dose-response relation to isoproterenol was similar in both groups. Likewise. the forearm vasodilative response to sodium nitroprusside was preserved in the heart failure group. Plasma concentration of norepinephrine was higher in the patients with heart failure (436 +/- 34 versus 201 +/- 74 pg/ml. p less than 0.01). When both groups were considered. there was no correlation between norepinephrine levels and the maximal forearm blood flow response to isoproterenol (r = 0.10. p = NS). CONCLUSIONS. We conclude that beta-adrenoceptor desensitization does not occur in the limb vessels of patients with congestive heart failure.
Effects of long-term enalapril therapy on cardiopulmonary exercise performance after myocardial infarction, BACKGROUND. The Enalapril Postinfarction Exercise (EPIE) trial was designed to study the effect of enalapril treatment on peak and submaximal cardiopulmonary exercise performance over the course of 1 year in men after myocardial infarction with mild exercise intolerance. METHODS AND RESULTS. One hundred sixty men with a peak VO2 less than 25 ml/kg/min and without effort angina were randomized to receive enalapril 20 mg qd or placebo on a double-blind basis. The mean age was 60.3 +/- 7.6 years. All patients received concurrent beta-blocker therapy for secondary prophylaxis. Treatment began at 21 days (group 1. n = 100) or more than 6 months after infarction (group 2. n = 60). Patients underwent exercise with real-time gas-exchange analysis nine times over the course of 48 weeks. In group 1. improvement in exercise performance occurred during the course of the trial in both groups of patients receiving placebo or enalapril. The mean peak VO2 for the placebo-treated patients in group 1 increased from 18.3 +/- 3.4 ml/kg/min by 4.9% at 48 weeks (p less than 0.05). The corresponding values for enalapril-treated patients were 18.9 +/- 3.8 ml/kg/min with a 3.7% increase (p = 0.07). Total exercise time increased in the placebo-treated patients from 645 +/- 96 seconds by 7.3% (p less than 0.01). Corresponding values for enalapril-treated patients were 674 +/- 103 seconds with a 5.4% increase (p less than 0.01). In group 2. the mean peak VO2 at baseline for the placebo-treated patients of 20.3 +/- 3.8 ml/kg/min increased by 4.4% at 48 weeks (p = NS). The corresponding values for enalapril-treated patients were 19.2 +/- 3.6 ml/kg/min with a 2.6% increase (p = NS). Total exercise time increased in the placebo-treated patients from 677 +/- 114 seconds by 0.7% (p = NS). Corresponding values for enalapril-treated patients were 659 +/- 99 seconds with a 1.1% increase (p = NS). There were no significant differences between the placebo and enalapril subgroups at any time with regard to peak VO2. exercise duration. or the VO2 at the anaerobic threshold. CONCLUSIONS. This trial demonstrates that long-term converting enzyme inhibition with enalapril had no significant effect on the peak or submaximal cardiopulmonary exercise performance over the course of 1 year in men after myocardial infarction with only mildly reduced exercise capacity.
Determinants of 2-year outcome after coronary angioplasty in patients with multivessel disease on the basis of comprehensive preprocedural evaluation. Implications for patient selection. The Multivessel Angioplasty Prognosis Study Group, BACKGROUND. To assess the likelihood of intermediate-term event-free survival (freedom from death. coronary artery bypass surgery. and myocardial infarction) in patients with multivessel coronary disease undergoing coronary angioplasty. 350 consecutive patients from four clinical sites were carefully evaluated and followed for 22 +/- 10 months. METHODS AND RESULTS. Eight clinical variables were evaluated at the clinical sites. and 23 angiographic variables describing the number. morphology. and topography of coronary stenoses were evaluated at a core angiographic laboratory. Most patients had Canadian Cardiovascular Society class III or IV angina (72%). two-vessel coronary disease (68%). and well-preserved left ventricular function (mean ejection fraction. 58 +/- 12%; range. 18-85%). Follow-up was complete in 99% of patients. At 2 years. event-free survival was 72%. overall survival was 96%. freedom from bypass surgery was 82%. and freedom from nonfatal myocardial infarction without surgery was 96%. Sequential Cox proportional hazards regression analyses allowing stepwise entry of variables prospectively coded as simple. as of intermediate complexity. or as complex found event-free survival to be independently predicted by low Canadian Cardiovascular Society angina class. no diabetes. no proximal left anterior descending stenoses. and the sum of stenosis simplified risk-territory scores of 15 or less. In the absence of class IV angina and these risk factors. 2-year event-free survival was 87% and overall survival was 100%. In the presence of two or more of these risk factors. event-free survival was less than 50%. CONCLUSIONS. Recognition of risk factors for poor long-term outcome in this setting may improve clinical decision making and provide a framework on which to base meaningful subgroup analyses in randomized trials assessing the efficacy of coronary angioplasty.
Long-term results after balloon pulmonary valvuloplasty, BACKGROUND. The objective of this study was to determine the long-term outcome of patients after percutaneous balloon pulmonary valvuloplasty (BPV) treatment of congenital pulmonary valve stenosis. METHODS AND RESULTS. This study represents a case series with duration (mean +/- SD) of follow-up of 4.6 +/- 1.9 years. Forty-six patients with a median age of 4.6 years (range. 3 months to 56 years) had BPV at one academic institution between June 1981 and December 1986. Mean peak systolic pressure gradients from the right ventricle to the pulmonary artery were as follows: before BPV. 70 +/- 36 mm Hg; immediately after BPV. 23 +/- 14 mm Hg; at intermediate follow-up by cardiac catheterization or Doppler echocardiography at less than 2 years after BPV. 23 +/- 16 mm Hg (n = 33); and at long-term follow-up by Doppler at more than 2 years after BPV. 20 +/- 13 mm Hg (n = 42). BPV acutely reduced the gradient to less than 36 mm Hg for 41 of 46 (89%) patients. Available gradients at long-term follow-up were less than 36 mm Hg for 36 of 42 (86%) patients without additional procedures. A patient age of less than 2 years at the initial BPV was a significant risk factor for gradients over 36 mm Hg at follow-up. CONCLUSIONS. BPV provides long-term relief of pulmonary valvular obstruction in the majority of patients. Close follow-up of patients who require BPV at less than 2 years of age is warranted.
Doppler and echocardiographic characteristics of patients having an Austin Flint murmur, BACKGROUND. The purpose of this study was to investigate the genesis of the Austin Flint murmur using Doppler and echocardiographic imaging. METHODS AND RESULTS. A total of 51 patients having significant aortic insufficiency and an anatomically normal mitral valve were evaluated. They were divided into two groups; 30 patients had an audible Austin Flint murmur (AFM+) and 21 did not (AFM-). All patients had a complete M-mode. two-dimensional. and Doppler echocardiographic examination to characterize left ventricular size and function. motion of the mitral valve. transmitral flow velocities. direction of the aortic insufficiency jet. and severity of aortic insufficiency. There was no significant difference in severity of aortic insufficiency between groups. There was. however. a significant difference in direction of the insufficiency jet. In the AFM+ group compared with the AFM- group. for the parasternal long-axis view 24 (80%) versus eight (38%) had their insufficiency jet directed at the mitral valve. for the apical five-chamber view the values were 25 (83%) versus five (24%). and for the apical long-axis view the values were 27 (90%) versus five (24%); for all comparisons p less than 0.01. There was also a greater frequency of localized anterior mitral leaflet distortion by two-dimensional echocardiography (AFM+:23 [77%] versus AFM-:five [24%]; p less than 0.001) and a greater frequency of Doppler striations overlying the aortic insufficiency jet (AFM+:25 [83%] versus AFM-:seven [33%]; p less than 0.001). Regarding transmitral flow velocities. there was no significant difference in filling patterns or absolute velocities during early or late diastole between groups. There was no gradient by Doppler analysis or by hemodynamics (n = 26) across the mitral valve in either group. There also was no difference in the frequency of preclosure of the mitral valve (AFM+:two versus AFM-:three). Systolic function was similar in both groups. but the left ventricular end-diastolic dimension was significantly greater in the AFM+ group (6.8 +/- 0.8 cm) than in the AFM- group (6.2 +/- 0.7 cm. p = 0.008). CONCLUSIONS. The results of this study suggest that the primary factor responsible for the Austin Flint murmur is the presence of an aortic insufficiency jet directed at the anterior mitral leaflet. This. combined with the biphasic pattern of transmitral flow. distorts the shape of the anterior mitral leaflet as it opens and closes during diastole. making it shudder. The leaflet's shuddering sets up vibrations and shock waves that distort the aortic insufficiency jet. causing the observed Doppler striations and probably the sound of the murmur. There is no evidence from this study to support prior theories that have proposed functional mitral stenosis or diastolic mitral regurgitation as the source of the murmur.
Assessment of aortic regurgitation by the acceleration flow signal void proximal to the leaking orifice in cinemagnetic resonance imaging, BACKGROUND. The proximal acceleration flow region is a laminar flow field that is located immediately upstream from the leaking orifice. The purpose of this study was to evaluate whether cinemagnetic resonance imaging can provide information regarding the proximal acceleration flow region in patients with aortic regurgitation and to analyze the relation between the area of the proximal acceleration flow delineated by cinemagnetic resonance imaging and the severity of aortic regurgitation delineated by angiography. METHODS AND RESULTS. Thirty-eight consecutive patients who underwent aortography were examined by cinemagnetic resonance imaging. The region of proximal flow acceleration was identified as a semicircular-shaped signal void in the aorta during diastole. Cinemagnetic resonance imaging detected the proximal acceleration flow region in 26 of the 30 patients who were proved to have this lesion (sensitivity. 87%). In eight patients without aortic regurgitation according to aortography. no proximal acceleration flow region was detected (specificity. 100%). The area of the acceleration flow signal void from the long-axis view was well correlated with angiographic degree of aortic regurgitation. CONCLUSIONS. Cinemagnetic resonance imaging is useful in detecting the proximal acceleration flow region and permits noninvasive assessment of the severity of aortic regurgitation.
Thrombolytic therapy with streptokinase stimulates collagen breakdown, BACKGROUND. Plasmin is capable of degrading extracellular matrix components such as collagen in vitro. To evaluate the significance of this for in vivo conditions. we set out to study the effect of streptokinase. which acts by converting plasminogen to plasmin. on the serum concentrations of the amino-terminal propeptide of type III procollagen (PIIINP) and the carboxy-terminal propeptide of type I procollagen (PICP). METHODS AND RESULTS. Twenty-three patients with suspected acute myocardial infarction were included in the study; 17 of them received thrombolytic therapy. and six were treated conservatively. PIIINP and PICP were assayed with radioimmunoassays. Kinetics of creatine kinase-MB release were determined to differentiate reperfusers from nonreperfusers. Composite curves of creatine kinase-MB release were constructed for different patient subgroups. During streptokinase infusion the serum concentrations of PIIINP increased rapidly. with a maximum mean increase of 50% (from 2.2 +/- 0.2 to 3.3 +/- 0.3 micrograms/l) in 45 minutes. A similar increase was also observed in two patients who received thrombolytic therapy but did not subsequently develop any myocardial infarction determined on the basis of enzyme release. The relative increase in PIIINP during streptokinase treatment was higher in those acute myocardial infarction patients with probable reperfusion than those with nonprobable reperfusion. Corresponding changes in PIIINP were not seen in the control group. Two days later there was a second increase in serum PIIINP for both patient groups. This change coincided with a similar increase in PICP. CONCLUSIONS. We conclude that streptokinase. probably by activation of plasminogen to plasmin. stimulates the breakdown of type III collagen during thrombolytic therapy. This phenomenon may decrease the risk of rethrombosis of the affected artery if the exposed collagen is responsible for thrombosis formation. but it could also be involved in the development of hemorrhagic complications during thrombolytic therapy. The second increase in PIIINP levels probably indicates type III collagen synthesis of the infarcted area. This investigation represents a pilot study. and more studies on the effects of various thrombolytic agents on interstitial collagen metabolism are obviously needed.
Ultrasonic angioplasty in totally occluded peripheral arteries. Initial clinical, histological, and angiographic results, BACKGROUND. Ultrasonic angioplasty was recently shown to ablate thrombi and atherosclerotic plaques in vitro and to recanalize occluded arteries in experimental animal models. The goal of the present study was to examine the clinical feasibility of ultrasonic angioplasty. METHODS AND RESULTS. Intraoperative ultrasonic angioplasty was performed in vivo on totally occluded peripheral arteries (n = 7). The ultrasonic angioplasty device consists of a 1.6-mm diameter flexible wire attached to a piezoelectric crystal generating ultrasound at 20 kHz. The controls. totally occluded human atherosclerotic femoral arterial segments (n = 6). were crossed mechanically with the ultrasound wire ex vivo but without application of ultrasonic energy. Ultrasonic angioplasty achieved successful recanalization without perforation in all vessels. Angiograms of the treated arteries showed an average lumen patency of 82.5%. Histological examination of the recanalized arteries revealed that the recanalization had taken place through intima diffusely involved with complicated plaque. The treated arteries. compared with the controls. had greater area of recanalized lumen (5.9 +/- 1.8 versus 1.7 +/- 0.4 mm2. p less than 0.05) and more flow (49.3 +/- 16.0 versus 11.8 +/- 4.9 ml/min. p less than 0.03). The damage in treated and control arteries was similar. Size-distribution analysis of the plaque debris from the treated arteries showed that 41 +/- 5% of the debris was 0.2-8 microns. 48 +/- 8% was 8-30 microns. and the remainder was 30-100 microns. In the mechanically crossed arteries. there was a shift in the distribution to larger size debris with 47 +/- 1% greater than 100 microns (p less than 0.001). CONCLUSIONS. Ultrasonic angioplasty may be a useful clinical method for recanalization of total occlusions in patients with peripheral vascular disease. Ultrasonic energy appears to cause controlled injury to the atherosclerotic intima by selectively disrupting the ultrasound-sensitive occlusion.
Beta-blocker treatment of dilated cardiomyopathy. Beneficial effect of carteolol in mice, BACKGROUND. The effects of carteolol. a nonselective beta-adrenergic receptor blocker with intrinsic sympathomimetic activity. were compared with those of metoprolol in a murine model of viral myocarditis and dilated cardiomyopathy caused by encephalomyocarditis virus. METHODS AND RESULTS. In the acute experiment. BALB/c and DBA/2 mice were inoculated with encephalomyocarditis virus. BALB/c mice were then given carteolol at 1 (n = 10). 10 (n = 10). 30 (n = 11). or 100 mg/kg (n = 9) daily. and DBA/2 mice were given carteolol at 1 (n = 9) or 10 mg/kg (n = 9) daily starting the day of inoculation. Controls were given distilled water (n = 23 for BALB/c mice and n = 8 for DBA/2 mice). BALB/c mice were killed on day 7. and DBA/2 mice were killed on day 14. In the subacute experiment. DBA/2 mice were inoculated with the virus and then given carteolol at 1 (n = 12) or 10 mg/kg (n = 16). or distilled water (n = 27) daily. starting on day 14. Mice were killed on day 28. Virus replication. murine survival. heart weight to body weight ratio. and histopathological findings were similar in each group in the acute and subacute experiments. In the chronic experiment. DBA/2 mice were inoculated with the virus and were then given carteolol at 1 (n = 13) or 10 mg/kg (n = 9). metoprolol at 30 mg/kg (n = 9). or distilled water (n = 31) daily. starting on day 14. Mice were killed on day 104. Heart weight to body weight ratio and histopathological scores were significantly lower in mice given carteolol than in the infected control group. Furthermore. left ventricular cavity dimension. left ventricular wall thickness. and myocardial fiber diameter of the left ventricle were significantly reduced in mice given carteolol compared with the control group. Metoprolol did not cause any significant changes compared with the control group. CONCLUSIONS. This study suggests that carteolol prevents the development of myocardial lesions similar to those in dilated cardiomyopathy after myocarditis in the chronic stage.
Effect of exercise intensity and duration on regional function during and after exercise-induced ischemia, BACKGROUND. Transient reversible myocardial dysfunction has been documented after episodes of exercise-induced ischemia. This study was undertaken to determine whether the duration or intensity of exercise affects the severity of postischemic dysfunction in this setting. METHODS AND RESULTS. Ten dogs were instrumented with ultrasonic microcrystals for measurement of wall thickening. with circumflex coronary artery flow probes. and with hydraulic occluders. Dogs performed low-intensity exercise. which was sufficient to increase coronary perfusion 50% above control. and high-intensity exercise. which was sufficient to double coronary blood flow. To investigate the effects of exercise intensity on postischemic dysfunction. we had dogs perform high-intensity exercise for 5 minutes in the presence of a stenosis. On the alternate day. dogs performed low-intensity exercise for 10 minutes in the presence of a stenosis. These two protocols provide equivalent coronary flow debts. Mean transmural blood flow during high-intensity exercise without stenosis (2.61 +/- 0.54 ml/min/g) was significantly higher than that during low-intensity exercise (1.74 +/- 0.61 ml/min/g. p less than 0.002). During high-intensity exercise with coronary artery stenosis. subendocardial blood flow was significantly lower than that during low-intensity exercise with stenosis (0.64 +/- 0.40 versus 1.08 +/- 0.28 ml/min/g. p less than 0.02). This difference in subendocardial perfusion was associated with greater degrees of regional dysfunction during exercise (circumflex wall thickening was 44 +/- 23% of control for high-intensity exercise versus 60 +/- 18% of control for low-intensity exercise. p less than 0.01). In addition. from 10 to 30 minutes after exercise. wall thickening in myocardium perfused by the circumflex coronary artery remained significantly lower after high-intensity exercise than that after low-intensity exercise. To assess the effects of exercise duration on the severity of postischemic dysfunction. we had dogs perform low-intensity exercise in the presence of a coronary stenosis for 10 minutes and low-intensity exercise for only 5 minutes on alternate days. Systolic wall thickening was significantly lower after low-intensity exercise for 10 minutes than after low-intensity exercise for 5 minutes. CONCLUSIONS. High-intensity exercise results in greater degrees of subendocardial hypoperfusion and greater degrees of regional dysfunction both during and after exercise-induced ischemia than does low-intensity exercise. Second. exercise duration also exerts an effect on the severity of postischemic dysfunction. although the magnitude of this effect is less important than the effect of exercise intensity.
Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction, BACKGROUND. We examined the effects of inhalation of 5-80 ppm nitric oxide (NO) gas on the normal and acutely constricted pulmonary circulation in awake lambs. METHODS AND RESULTS. Spontaneous breathing of nitric oxide (an endothelium-derived relaxing factor) at 40 ppm or more reversed acute pulmonary vasoconstriction within 3 minutes either because of infusion of the stable thromboxane endoperoxide analogue U46619 or because of pulmonary hypertension due to breathing a hypoxic gas mixture. Systemic vasodilation did not occur. Pulmonary vasodilation by NO inhalation was produced during infusion of U46619 for periods of 1 hour without observing evidence of short-term tolerance. Pulmonary hypertension resumed within 3-6 minutes of ceasing NO inhalation. In the normal lamb. the pulmonary vascular resistance. systemic vascular resistance. cardiac output. left atrial and central venous pressures were unaltered by NO inhalation. CONCLUSION. Breathing 80 ppm NO for 3 hours did not increase either methemoglobin or extravascular lung water levels or modify lung histology compared with those in control lambs.
Noninvasive estimation of the instantaneous first derivative of left ventricular pressure using continuous-wave Doppler echocardiography, BACKGROUND. The complete continuous-wave Doppler mitral regurgitant velocity curve should allow reconstruction of the ventriculoatrial (VA) pressure gradient from mitral valve closure to opening. including left ventricular (LV) isovolumic contraction. ejection. and isovolumic relaxation. Assuming that the left atrial pressure fluctuation is relatively minor in comparison with the corresponding LV pressure changes during systole. the first derivative of the Doppler-derived VA pressure gradient curve (Doppler dP/dt) might be used to estimate the LV dP/dt curve. previously measurable only at catheterization (catheter dP/dt). METHODS AND RESULTS. This hypothesis was examined in an in vivo mitral regurgitant model during 30 hemodynamic stages in eight dogs. Contractility and relaxation were altered by inotropic stimulation and hypothermia. The Doppler mitral regurgitant velocity spectrum was recorded along with simultaneously acquired micromanometer LV and left atrial pressures. The regurgitant velocity profiles were digitized and converted to VA pressure gradient curves using the simplified Bernoulli equation. The instantaneous dP/dt of the VA pressure gradient curve was then derived. The instantaneous Doppler-derived VA pressure gradients. instantaneous Doppler dP/dt. dP/dtmax. and -dP/dtmax were compared with corresponding catheter measurements. This method of estimating dP/dtmax from the instantaneous dP/dt curve was also compared with a previously proposed Doppler method of estimating dP/dtmax using the Doppler-derived mean rate of LV pressure rise over the time period between velocities of 1 and 3 m/sec on the ascending slope of the Doppler velocity spectrum. Both instantaneous Doppler-derived VA pressure gradients (r = 0.95. p less than 0.0001) and Doppler dP/dt (r = 0.92. p less than 0.0001) correlated well with corresponding measurements by catheter during systolic contraction and isovolumic relaxation (pooled data). The Doppler dP/dtmax (1.266 +/- 701 mm Hg/sec) also correlated well (r = 0.94) with the catheter dP/dtmax (1.200 +/- 573 mm Hg/sec). There was no difference between the two methods for measurement of dP/dtmax (p = NS). Although Doppler -dP/dtmax was slightly lower than the catheter measurement (961 +/- 511 versus 1.057 +/- 540 mm Hg/sec. p less than 0.01). the correlation between measurements by Doppler and catheter was excellent (r = 0.93. p less than 0.0001). The alternative method of mean isovolumic pressure rise (896 +/- 465 mm Hg/sec) underestimated the catheter dP/dtmax (1.200 +/- 573 mm Hg/sec) significantly (on average. 25%; p less than 0.001). CONCLUSIONS. The present study demonstrated an accurate and reliable noninvasive Doppler method for estimating instantaneous LV dP/dt. dP/dtmax. and -dP/dtmax.
Animal models of opiate, cocaine, and cannabis use, A traditional concern with drugs administered during pregnancy has been teratogenicity or the production of gross structural malformations. Beginning in the 1970s. it became increasingly evident that the issue of drug safety and risk assessment went far beyond structural defects. During the 1980s. the newly emerged research specialty of "developmental toxicology" came to encompass a wide range of adverse toxic outcomes that include not only birth defects but also neurobehavioral and other functional effects as well. Substances of use and abuse--the opiates. cocaine. and cannabis--have come to exemplify a diverse group of compounds that produce a broad spectrum of developmental outcomes. Unlike alcohol. neither the use of heroin nor methadone during pregnancy is associated with an increased risk of birth defects but both produce a neonatal abstinence syndrome that can persist for as long as 6 months; follow-up to preschool years suggests possible risk of attention deficit and problems of fine motor coordination. Methodologic weaknesses of opiate animal models. especially with respect of appropriate dosing schedules. have hampered meaningful extrapolation of these studies to human risk assessment. Given the renewed interest in methadone maintenance as an important therapeutic intervention to reduce exposure to the human immunodeficiency virus. better designed animal studies are needed urgently to assess developmental risk. but these must incorporate techniques that better model human pharmacokinetics. Animal models of early cocaine exposure. driven by human reports of serious risk to the fetus and newborn. have found reproductive hazard. risk of neurobehavioral effects as well as altered CNS function. Whereas animal studies need to explore routes of administration other than sc and ig. particularly the volatilized form of cocaine. to date it appears that the processes of somatic growth and morphogenesis in rodents are not as sensitive to cocaine as is the functional development of the CNS. Finally. animal studies of cannabis have taught us some major methodologic and interpretive lessons for the continuing development and refinement of animal models of drugs of abuse. Of particular importance is that poorly controlled experiments that do not adequately consider the confounding influences of maternal toxicity. both prenatally and postnatally. are likely to yield a high rate of false-positive results. This is well illustrated by those studies of cannabis that antedated the current concern for pair-feeding and surrogate fostering. Nearly all of the studies that failed to include nutritional and fostering controls found neurobehavioral effects that included changes in activity as well as impairments in learning and memory.(ABSTRACT TRUNCATED AT 400 WORDS).
Cocaine and pregnancy: clinical and methodologic issues, Although many of the clinical studies of cocaine use in pregnancy completed thus far have suffered from the methodologic issues discussed here. they have been of great value in defining key risk factors and general clinical outcome. With the information now available. it appears safe to conclude that placental dysfunction due to cocaine's vasoconstrictive activity increases risk for intrauterine growth retardation and prematurity; fetal disruption due to acute cocaine-induced vascular compromise places the fetus at risk for structural anomalies; and neurotoxicity due to cocaine's action at the postsynaptic junction places the infant at risk for neurobehavioral abnormalities. There are now needed more sophisticated analytic techniques that can consider the additive and interactive effects of demographic and lifestyle characteristics that place the cocaine-using pregnant woman and her child at risk.
Developmental pathogenesis of defects associated with prenatal cocaine exposure: fetal vascular disruption, Prenatal exposure to cocaine is associated with a spectrum of defects that are secondary to interruption of blood flow to developing or previously developed structures. The defects include prenatal onset growth deficiency. prematurity. abruptio placentae. intercranial hemorrhage. nonduodenal intestinal atresia. limb reduction defects. urinary tract anomalies. and neurodevelopmental problems limited at present to the neonatal period.
Drug addiction, pregnancy, and childbirth: legal issues for the medical and social services communities, There are many new legal issues emerging as a consequence of the large number of women who abuse drugs during pregnancy. As a result. the medical community has to take greater steps to advise women of the consequences of actions taken during pregnancy. Physicians and hospitals also must develop protocols for obtaining informed consent of a parent or legal guardian before drug tests are run on newborns and for reporting cases of infants born drug dependent. This article focuses on the conflicting interests and rights involved and offers some concrete ideas as to how these interests might be balanced.
Drug use in pregnancy: obstetric perspectives, The incidence of perinatal chemical use is undoubtedly much higher than the rate of use detected at any single point during pregnancy. As the prevalence is likely to be 10% or greater in any community. obstetricians need to employ measures to detect chemical use. similar to measures taken to detect birth defects. gestational diabetes. syphilis. gonorrhea. and preeclampsia. The use of screening protocols must be accompanied by an awareness of the need for intervention and treatment resources. Identification of perinatal chemical use should be for purposes of medical and social intervention. not criminal prosecution. Obstetric management should focus on the prevention of preterm delivery and intrauterine growth retardation. It should be recognized that pregnancy provides a unique opportunity for the encouragement of positive health behaviors. Programs that include such components may be able to achieve more lasting effects.
Narcotic use in pregnancy, Narcotic use in pregnancy remains a critical problem in 1990. Maternal and neonatal morbidity and mortality are increased significantly in pregnancies complicated by opioid addiction. Methadone maintenance is an important component of the management of many pregnant opioid addicts. The unavailability in most communities of specialized services dealing with perinatal addiction contributes to the dismal outcome frequently observed. The helpless fetus does not get the opportunity to just say no to drugs. As a society. we must just say no to continuing to ignore this problem.
Computerized analysis of concomitant contact allergens, A statistical study was conducted on 3697 patch-tested patients in order to find any cross-reacting or concomitant allergens. 44 correlations were found. 3 were well-known cross-reacting substances (e.g.. benzocaine and p-phenylenediamine). 7 were unlikely. probably random. findings and the remaining 27 were considered to be either new cross-reacting allergens (e.g.. promethazine and azo dyes) or concomitant allergens found in the same kind of products (e.g.. nickel and cobalt in alloys. ethylenediamine and neomycin in Kenacombin cream. colophony and carba-mix in adhesive bandage).
Epidemiological survey of standard series patch test results and observations on day 2 and day 4 readings, Computer data on 4721 consecutive patients patch tested with an extended standard series were analysed for the frequency of allergic reactions to each substance. Particular attention was given to the negative first reading at day 2 (D2) which later became positive at day 4 (D4). A total of 4210 allergic reactions were recorded. 993 of which were negative on D2 (24%). The most frequent positive reactions were to nickel sulphate (18%). fragrance-mix (8%). colophony (6%). neomycin (6%). cobalt chloride (6%). thiuram-mix (4%) and potassium dichromate (3%). The frequency of negative D2. positive D4 readings was sizeable for all but one substance. primin. with a range of 14% for fragrance-mix to 64% for neomycin. All of 21 positive reactions to primin were recorded on D2. In our opinion. it is unjustified to perform D2-only patch test readings.
Screening for corticosteroid contact sensitivity. Comparison of tixocortol pivalate, hydrocortisone-17-butyrate and hydrocortisone, 3 corticosteroids have so far been tried as markers for corticosteroid contact sensitivity: hydrocortisone. tixocortol pivalate and hydrocortisone-17-butyrate. The present study compared these steroids for screening in addition to a standard patch test series. Of 727 patients. 28 (3.9%) reacted to tixocortol pivalate and 10 (1.4%) to hydrocortisone-17-butyrate; hydrocortisone gave an allergic reaction in 2 of 521 (0.4%) patients. Serial dilutions suggested that tixocortol pivalate. not marketed in Finland. caused allergic reactions which could possibly be cross-reactions to hydrocortisone. In contrast to previously published data. frequent cross-reactions occurred with hydrocortisone-17-butyrate and tixocortol pivalate. All allergic reactions to other corticosteroids found by testing with tixocortol pivalate concurred with reactions to hydrocortisone-17-butyrate. The study suggests that the most effective choice for routine testing for corticosteroid contact sensitivity would be both tixocortol pivalate and hydrocortisone-17-butyrate.
Cutting oil dermatitis on guinea pig skin. (II). Emollient creams and cutting oil dermatitis, The effect of repeated exposure of cutting oil on 8 guinea pigs' skin was evaluated by visual scoring for erythema and skin water vapour loss (SVL) measurement over a 6-week period. The visual scores (measuring severity of erythema) and SVL values were significantly higher on skin treated with cutting oils (positive control) compared to untreated skin (negative control) throughout the study period. The scores and SVL values returned to near-baseline values when cutting oil application was stopped. In addition. the effect of 2 "after-work" emollient creams on 8 guinea pigs' skin repeatedly treated with a cutting oil was assessed by similar methods. The visual scores and SVL values of guinea pig skin that was repeatedly treated with the cutting oil and moisturized with "after-work" emollient creams. were significantly higher than negative and positive control guinea pig skin. It appeared that the 2 "after-work" emollient creams do not alleviate the irritant effect of the cutting oil on guinea pig skin. They appeared to aggravate the irritant effect of the cutting oil.
Contact sensitivity to miconazole with ortho-chloro cross-sensitivity to other imidazoles, A case of allergic contact dermatitis from miconazole is reported. Patch testing with a series of azole antimycotics was positive only to miconazole. isoconazole. tioconazole and oxiconazole. Those reacting are all beta-substituted 1-phenethyl imidazoles with an ortho-chlorine substitution on the aromatic ring. For this hitherto unreported pattern of cross-sensitivity. the designation of "ortho-chloro cross-sensitivity" is proposed.
Effects of insulin deprivation and replacement on in vivo subcutaneous adipose tissue substrate metabolism in humans, The effects of insulin deprivation and replacement on adipose tissue metabolism were investigated in vivo with microdialysis in nine insulin-dependent diabetic patients with no residual insulin secretion. Dialysis probes. implanted in abdominal subcutaneous fat. were continuously perfused. and tissue dialysate concentrations of glycerol (lipolysis index). glucose. lactate. and pyruvate were determined. Comparisons were made with respective metabolite levels in venous plasma. After termination of intravenous insulin infusion. free insulin in plasma fell from 130 to 70 pM. At the same time. glucose levels in plasma and adipose tissue rose in parallel. However. the relative increase in glucose levels was greater in adipose tissue than in blood. On the other hand. the increase in glycerol concentration in adipose tissue (35%) was markedly less than that in venous plasma (250%). Lactate and pyruvate levels in adipose tissue and blood remained unchanged. After the resumption of intravenous insulin. free insulin in plasma rose to approximately 600 pM. At the same time. the glucose levels in blood and adipose tissue decreased rapidly. and the glycerol concentration in these tissues decreased to 50% of the baseline levels. The lactate and pyruvate levels in subcutaneous tissue increased briefly after insulin replacement. whereas the lactate but not pyruvate levels in blood showed a similar increase. The alpha- or beta-blocking agents phentolamine and propranolol in the ingoing tissue perfusate did not influence tissue glycerol at any time during the experiment. We concluded that insulin-induced changes in circulating metabolites only partly reflect variations in adipose tissue substrate kinetics. During insulin deprivation. glucose is accumulated in the adipose tissue extracellular compartment. probably because of reduced utilization by the adipocytes.
Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons, In vivo beta-cell function tests are used increasingly in humans during the preclinical phase of insulin-dependent diabetes mellitus (IDDM). but the severity of the beta-cell loss responsible for the abnormalities seen in these tests is unknown. We have measured several physiological beta-cell function tests--fasting plasma glucose. glucose disappearance constant. fasting insulin. acute insulin responses to arginine (AIRarginine) and glucose (AIRglucose). and glucose potentiation of AIRarginine (delta AIRarginine/delta G) and two direct objective measurements (pancreatic insulin content [PIC] and quantitative beta-cell mass)--in adolescent male baboons (Papio anubis/cyanocephalus). We have correlated in vivo measurements obtained within 3 days after the animals were killed with in vitro estimates of PIC and beta-cell mass in 15 animals. (2 nondiabetic requiring insulin treatment and 13 after varying doses of streptozocin to induce degrees of beta-cell damage ranging from normoglycemia to severe hyperglycemia). There was a strong linear correlation between beta-cell mass and PIC (r = 0.79. P less than 0.001). Physiological measures of beta-cell function were significantly correlated with both PIC and beta-cell mass. The correlations between physiological measures and beta-cell mass were linear and intercepted the beta-cell mass axis at 0.15-0.2 g. suggesting that in vivo measures of beta-cell function approach 0 when there is still approximately 40-50% of the beta-cell mass detectable histologically. With PIC. the linear correlations intercepted the axes close to 0. These findings provide considerable validity to the measurements of beta-cell function used in preclinical IDDM in humans.
Multifactorial origin of hypoglycemic symptom unawareness in IDDM. Association with defective glucose counterregulation and better glycemic control, To assess potential relationships between unawareness of hypoglycemic symptoms and both defective glucose counterregulation and therapy-associated altered glycemic thresholds. symptoms and hormonal responses to hypoglycemia were quantitated during standardized insulin infusion tests in 41 patients with insulin-dependent diabetes mellitus (IDDM). The glycemic thresholds for both neurogenic and neuroglycopenic symptoms (and those for both epinephrine and pancreatic polypeptide release) were at lower plasma glucose concentrations in both patients with defective (n = 9. 22%) and those with adequate glucose counterregulation and. among the latter. in patients with lower compared with higher glycosylated hemoglobin levels. The data are consistent with the concept that both defective glucose counterregulation and improved glycemic control contribute to excessive hypoglycemia in IDDM by reducing awareness of symptoms of developing hypoglycemia and by impairing physiological defenses against hypoglycemia. Thus. hypoglycemic symptom unawareness is multifactorial in origin and may be partly reversible.
Oxidation of spectrin and deformability defects in diabetic erythrocytes, We reasoned that de novo oxidative damage. as a result of increased protein glycosylation. could participate in the mechanisms whereby diabetic erythrocytes acquire membrane abnormalities. To examine this hypothesis. the extent of erythrocyte membrane protein glycosylation and the oxidative status of spectrin. the major component of the erythrocyte membrane skeleton. were examined. Labeling erythrocyte membranes with [3H]borohydride. which labels glucose residues bound to proteins. revealed that several proteins were heavily glycosylated compared with nondiabetic erythrocyte membranes. In particular. the proteins beta-spectrin. ankyrin. and protein 4.2 were the most glycosylated. Although sodium dodecyl sulfate-polyacrylamide gel electrophoresis of diabetic erythrocyte membranes did not reveal any quantitative or qualitative abnormalities in spectrin or other membrane proteins. examination of spectrin oxidative status by amino acid analysis and with cis-dichlorodiammineplatinum(II) (cDDP). a chemical probe specific for protein methionine and cysteine residues. demonstrated that the diabetic spectrin was oxidatively damaged: spectrin from diabetic subjects contained 35% less methionine (P less than 0.002). 15% less histidine (P less than 0.006). and a twofold increase in cysteic acid (P less than 0.001) compared with normal spectrin. Diabetic spectrin bound 32% less cDDP than normal spectrin (P less than 0.001); the lowest cDDP binding was observed with spectrin from insulin-dependent diabetic subjects. The extent of cDDP binding to diabetic spectrin correlated moderately and inversely with glycosylated hemoglobin (GHb) levels (n = 12. r = -0.727). Erythrocyte deformability. measured by ektacytometry. was decreased between 5 and 23% of control measurements (average of approximately 10%) in 21 of 32 diabetic subjects surveyed.
Specific association of HLA-DR4 with increased prevalence and level of insulin autoantibodies in first-degree relatives of patients with type I diabetes, First-degree relatives of patients with insulin-dependent (type I) diabetes (n = 264 from 106 families) were evaluated with HLA typing and determination of competitive insulin autoantibodies (CIAAs) and islet cell autoantibodies (ICAs). The levels of CIAAs in 30 relatives exceeded our upper limit of normal (greater than or equal to 39 nU/ml). and 30 had high-titer ICAs (greater than or equal to 40 Juvenile Diabetes Foundation units [JDF U]). Eleven of the HLA-typed relatives developed diabetes during follow-up. Twenty-three percent (28 of 123) of the relatives with at least one HLA-DR4 allele were CIAA+ (CIAA greater than or equal to 39 nU/ml) versus 4% (6 of 141) among DR4- relatives (P less than 0.0001). Twenty-one of 22 of the highest CIAA values were all in the DR4+ group (DR4+ vs. DR4-. P = 0.003. Wilcoxon's rank-sum test). HLA-DR3 did not correlate with the level of CIAAs. and neither DR3 nor DR4 correlated with titer of ICAs measured in JDF U. We conclude that. in first-degree relatives of patients with type I diabetes. there is a striking association with HLA-DR4 in both the prevalence of relatives exceeding the normal CIAA range and in the level of CIAAs. These data suggest that a gene on HLA-DR4 haplotypes contributes to the level of anti-insulin autoimmunity. and we hypothesize that DR4-associated diabetes susceptibility. distinct from DR3-associated susceptibility. may be secondary to this influence.
Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms, We used the recently described technique of single-stranded conformation-polymorphism (SSCP) analysis to examine the insulin-receptor locus. First. the ability of the method to detect known mutations and polymorphisms in the insulin-receptor coding sequence was assessed. Regions of the insulin-receptor sequence containing 16 different nucleotide changes. 9 in patient genomic DNA and 7 as cloned cDNA in plasmids. were analyzed. All 9 patient genomic DNA mutants and 5 of 7 plasmid mutants exhibited variant SSCP patterns. To investigate the potential of the technique for screening many patients. the 5 exons that encode the tyrosine kinase domain of the insulin receptor were examined in 30 unrelated white subjects with non-insulin-dependent diabetes mellitus (NIDDM). Exons 17-21 were amplified from genomic DNA with polymerase chain reaction and subjected to SSCP analysis. Exons 19. 20. and 21 revealed no bands of aberrant migration. suggesting a high degree of conservation of these sequences. One diabetic subject had an SSCP variant in exon 18. Direct sequencing of this subject's genomic DNA revealed a heterozygous missense mutation (Lys1068----Glu1068). Five different SSCP patterns were detected in exon 17. Based on direct sequencing. these patterns were explained by combinations of three different nucleotide substitutions. two of which were common silent polymorphisms. One subject had a heterozygous missense mutation Val985---- Met985. Allele-specific oligonucleotide hybridization confirmed the presence of these mutations in the appropriate diabetic subjects and also detected the Val985 mutation in heterozygous form in 1 of 13 nondiabetic white subjects. SSCP analysis is a sensitive rapid method for screening for mutations in the insulin-receptor gene.
Dehydration in the elderly: insidious and manageable, Dehydration in the elderly results from inadequate water replacement. and associated mortality may be high when dehydration is severe. The elderly are at an elevated risk for dehydration. due to decreased thirst perception. decreased water intake. abnormal vasopressin responses to osmotic stimuli. and a predisposition to mild nephrogenic diabetes insipidus. In addition. elderly patients with chronic physical and/or mental disabilities are often unable to drink or obtain water themselves. For these high-risk patients. the physician's role is to initiate measures to prevent dehydration. including fluid orders and intake documentation.
An update on home intravenous antibiotic therapy, Home intravenous antibiotic therapy (HIVAT) has proven to be a safe. effective. and cost-saving method to treat appropriately selected patients with bone. soft tissue. respiratory. genitourinary. and cardiac infections. Further. the acceptance of HIVAT by both physicians and patients has been enhanced by the availability of new venous access devices and home IV therapy companies. In determining when to use HIVAT. it is important to carefully consider the individual patient. the disease or medical condition. and antibiotic selection. HIVAT requires a team approach. with the physician. pharmacist. IV therapy nurse. and others playing critical roles in successful treatment plans.
Using occupational history to pinpoint the diagnosis, Occupational exposures lead to a significant number of deaths and new cases of illness among the elderly each year. However. physicians are often unskilled in occupational history-taking and are unfamiliar with the associations between toxic exposures and disease. This article offers physicians a systematic approach to taking an occupational history. then describes the more common types of occupational disease in the elderly and an approach for their recognition.
Managing the growing number of spinal cord-injured elderly, Management of spinal cord-injured patients has generally focused upon young or middle-aged adults victimized by trauma. These days. however. more and more such patients are over 60 and have as much need for informed primary care.
Diagnostic efficiency of an ultrarapid endoscopy room test for Helicobacter pylori, There are several reliable methods for detecting Helicobacter pylori but all have as a major disadvantage the time required to yield a definitive result. We have modified the standard urease test so that a positive result is available in one minute. We describe the use of this test in biopsy specimens from the gastric antrum from 220 consecutive patients referred for upper gastrointestinal endoscopy. The performance of the 'one minute test' was compared with a standard urease test. Gram stain. and microbiological culture. Using culture as the 'gold standard' 80 (36%) of the patients were H pylori positive. The one minute test produced no false positives and showed a sensitivity of 89% and specificity of 100%. while the predictive values of a positive and negative test were 100% and 94% respectively. The diagnostic efficiency of the test was 96% compared to 85% for both the Gram stain and direct urease test. All positive results using the one minute test were available within one minute. The test is easy to prepare and costs approximately pounds 0.04. This new modification of the urease test should be superior to the currently available urease tests because a reliable result will be available in almost 90% of infected individuals even before endoscopy is completed.
Effect of cisapride on delayed gastric emptying in gastro-oesophageal reflux disease, Some patients with gastro-oesophageal reflux disease have delayed gastric emptying. This study investigates the effect of cisapride on gastric emptying in 34 patients with proved reflux and delayed gastric emptying of solids. They were enrolled in a double blind controlled crossover study. Placebo or cisapride (10 mg) tablets were given three times a day for three days followed by further assessment of gastric emptying. The protocol was repeated with the crossover tablet. Gastric emptying was assessed by a dual radionuclide technique. The percentage of a solid meal remaining in the stomach at 100 minutes (% R100 minutes) and the time taken for 50% of the liquid to empty (T50 minutes) were calculated and analysed by the Wilcoxon matched pairs signed ranks test and expressed as medians (ranges). For gastric emptying of solids the initial % R100 minutes (70 (60-100)%) was not significantly different from placebo (71 (35-100)%). After cisapride treatment a significant acceleration (p less than 0.001) in gastric emptying occurred (% R100 minutes. 50.5 (28-93)%). Similarly with gastric emptying of liquids. the initial T50 minute value was 26.5 (12-82) minutes. after placebo the value was 28 (11-81) minutes. but this was significantly accelerated with cisapride (p less than 0.03) to 22.5 (6-61) minutes. The acceleration in gastric emptying occurred in the proximal portion of the stomach for gastric emptying of both solids and liquids suggesting that this is the principal site of action of cisapride. We conclude that cisapride significantly accelerates gastric emptying of both solids and liquids in patients with gastro-oesophageal reflux disease and delayed gastric emptying.
Hyperglycaemia stimulates pyloric motility in normal subjects, The motor correlates of the delay in gastric emptying produced by hyperglycaemia were investigated in 11 healthy volunteers. Fasting gastroduodenal motility was measured during euglycaemia (blood glucose concentration 3-5 mmol/l) and during hyperglycaemia induced by intravenous dextrose (blood glucose concentration 12-16 mmol/l). Antral. pyloric. and proximal duodenal pressures were recorded by a sleeve/sidehole manometric assembly positioned across the pylorus. with the aid of measurements of transmucosal potential difference. During hyperglycaemia there was stimulation of isolated pyloric pressure waves when compared with the euglycaemia period (p less than 0.05). This was associated with inhibition of antral pressure waves (p less than 0.05). In nine of the 11 subjects an episode of duodenal 'phase III like' activity occurred within 15 minutes of the onset of hyperglycaemia. It is proposed that the stimulation of localised pyloric contractions and inhibition of antral contractions contribute to the delayed gastric emptying induced by hyperglycaemia. Abnormal gastric motility in patients with diabetes mellitus may be the result of hyperglycaemia itself. rather than irreversible autonomic neuropathy.
Preoperative evaluation of gastric cancer by endoscopic ultrasound, The preoperative use of endoscopic ultrasound was evaluated in 74 patients with confirmed gastric cancer. It was used in diagnosing the depth of invasion in the gastric wall. the infiltration to the adjacent organs. and the involvement of the perigastric lymph nodes. Results were compared with histological findings in resected specimens. Accuracy in staging gastric cancer using the T grade of the 1987 TNM system was 81.1% (60 of 74 patients). Endoscopic ultrasound provided excellent results compared with computed tomography and conventional ultrasound. particularly in evaluating perigastric lymph node metastasis and direct infiltration to the adjacent organs. The success rate in detecting lymph node metastasis was 50% (11 of 22 patients); the accuracy in diagnosing direct infiltration to the adjacent organs was 60% (three of five patients). This technique is useful in diagnosing malignant invasion and lymph node metastasis of gastric carcinomas but requires further refinement for use in diagnosing the disease itself. Its preoperative use is recommended for establishing surgical and other treatment plans. as well as in predicting the prognosis of gastric cancer.
Structural heterogeneity of faecal alpha 1 antitrypsin shown by immunoblot analysis in patients with Crohn's disease, Faecal alpha 1 antitrypsin was determined in 34 patients with Crohn's disease and in 19 healthy subjects by immune nephelometry. A structural analysis of faecal alpha 1 antitrypsin was carried out using immunoblot analysis under non-reducing conditions. Native serum alpha 1 antitrypsin migrated with an apparent molecular weight of 45 kDa. Proteolytic alpha 1 antitrypsin fragments (5-42 kDa) were specifically immunostained in 13/19 and 22/34 stool samples from control subjects and from patients with Crohn's disease respectively. There was a weak correlation (r = 0.47; p less than 0.02) between the molecular weight of fragmented alpha 1 antitrypsin and the faecal concentration in both groups. indicating that alpha 1 antitrypsin inhibits its own proteolysis by intestinal proteases in a dose dependent way. The incidence of polymeric forms (greater than 45 kDa) was similar in patients (10/34) and control subjects (5/19). In only one case in each group was the native serum form of alpha 1 antitrypsin found in faeces. We conclude that faecal alpha 1 antitrypsin differs structurally from the native serum form. Immunochemical measurements. therefore. reflect rather than represent faecal concentrations of alpha 1 antitrypsin. The controversial results in published reports may be partly explained by these findings. The molecular heterogeneity of faecal alpha 1 antitrypsin is not specifically associated with Crohn's disease.
The presence in experimental animals of a colon specific Mr 40,000 protein(s) with relevance to ulcerative colitis, In patients with ulcerative colitis a colon tissue bound IgG and serum antibodies against an Mr 40.000 colonic protein(s) has been identified. Using an anti-Mr 40.000 protein monoclonal antibody. 7E12H12. by an immunocytochemical method. the protein was localised in human tissue exclusively to colonic epithelial cells. In this study the presence of the Mr 40.000 protein was assessed in experimental animals by the direct and inhibition enzyme linked immunosorbent assays (ELISAs) using the anti-Mr 40.000 protein monoclonal antibody. 7E12H12 (IgM isotype). In addition. a total of 129 specimens including colon. small intestine. gall bladder. biliary tract. and kidney from nine strains of rats and mice. and from human tissue were studied by the immunocytochemical method using 7E12H12. All colon specimens from both humans and animals reacted with 7E12H12 in the immunocytochemical and ELISA assays. None of the non-colonic organs reacted with 7E12H12. While in human colon 7E12H12 recognised the absorptive epithelial cells. in all the animals it recognised mainly the colonic goblet cells. Extracts of animal colon but not of small intestine inhibited the binding of 7E12H12 to the human colon extract. This study shows the presence of an organ specific Mr 40.000 colonic epithelial protein(s) in humans and experimental animals. A differing cellular localisation of the Mr 40.000 protein(s) in human v animal tissue was also shown. Further characterisation of the Mr 40.000 protein(s) may provide important clues regarding the autoimmune mechanisms in ulcerative colitis.
Prognosis in familial non-polyposis colorectal cancer, Familial cases of non-polyposis colorectal cancer have attracted much interest but little is known of their natural history. Using a population based study we have determined whether a positive family history of bowel cancer is an independent prognostic factor. All patients under 55 years with histologically confirmed colorectal cancer in Northern Ireland during the period 1976-8 were studied. The family history was validated in 95% of all nonpolyposis cases (n = 205). Medical history or cause of death were verified for 98% of 1811 first degree relatives. The strength of the family history was assessed using a score that compares the mortality from bowel cancer in the family against the average population mortality. taking account of family size and age structure. The family history score was not predictive of survival neither in univariate analysis or in a Cox's proportional hazards multivariate analysis controlling for age. sex. stage. site. and duration of symptoms. In conclusion. a positive family history does not independently influence prognosis in patients with bowel cancer.
Local eradication of rat colon cancer with photodynamic therapy: correlation of distribution of photosensitiser with biological effects in normal and tumour tissue, Photodynamic therapy is a photochemical technique for the local destruction of tumours. entailing the interaction of light with an administered photosensitiser to produce a cytotoxic effect. We investigated the tissue distribution of the photosensitiser aluminium sulphonated phthalocyanine (AlSPc) in dimethylhydrazine induced colonic tumours and adjacent normal colon in rats. Forty eight hours after intravenous injection. most tumours contained twice as much AlSPc as normal colon. Tumour size and position in the colon did not affect AlSPc concentration. Microscopic fluorescence localisation of AlSPc showed significant photosensitiser accumulation in tumour stroma. whereas tumour and normal mucosa contained similar amounts. Thus. some normal tissue damage. where malignant cells invade normal areas. would inevitably accompany eradication of tumours. Tumour destruction and healing of colon after tumour eradication were examined histologically. There was sharp demarcation between necrotic areas (tumour or normal) and adjacent tissue and. whether the treated area was tumour or normal. healing occurred by regeneration of normal tissue. Some incompletely eradicated large tumours showed evidence of delayed bleeding. The possibility of selective uptake or preferential retention of the photosensitiser in tumours formed the initial basis for investigation of photodynamic therapy. but it is now clear that this is seldom the most important factor for tumour eradication. Of far greater importance is the nature of the biological effect of photodynamic therapy as necrosis of small tumours involving the full thickness of the bowel wall can be achieved with safe healing by regeneration of normal colon. The maximum depth of necrosis produced was only a few millimetres. so this technique is unlikely to be of value as the primary treatment for large colonic tumours but may prove of value for eradicating small lesions or as adjunctive therapy for eradication of small nests of tumour remaining or recurring in the tumour bed after conventional surgery.
Focal nodular hyperplasia of the liver: results of treatment and options in management, Twenty two patients (19 females) with focal nodular hyperplasia were seen between 1973 and 1989. Five were children. and all the adults were aged under 42 years (median 33 years). Fourteen patients (64%) were symptomatic on presentation. Twelve of the 14 adult women had taken the oral contraceptive pill. Twelve patients. nine of whom were symptomatic. underwent hepatic resection shortly after presentation. There were no deaths or major complications. and all remain well on follow up. Four patients underwent either hepatic artery embolisation or ligation. After an interval of six to 10 years they were asymptomatic and only one has histological evidence of residual focal nodular hyperplasia. Of five patients initially treated conservatively. two were asymptomatic and have remained so for three and 13 years. One of the three symptomatic patients became symptom free after stopping the contraceptive pill. The management of focal nodular hyperplasia requires a flexible approach. Lesions which are asymptomatic can be observed with regular ultrasound and treated if they enlarge or become symptomatic. Symptomatic patients who present while taking the contraceptive pill can also have a trial of conservative treatment. Other symptomatic patients. including those who previously took the pill. are best treated by surgical resection. and. where this is not possible. by embolisation.
Effect of a new synthetic ascorbic acid derivative as a free radical scavenger on the development of acute pancreatitis in mice, The therapeutic effects of CV 3611. a new synthetic free radical scavenger prepared from an ascorbic acid derivative. on choline deficient. ethionine enriched (CDE) diet induced acute pancreatitis in mice were evaluated and compared with those of superoxide dismutase. Time/course studies after subcutaneous injection of CV 3611 in normal mice showed a peak plasma concentration of mean (SEM) 0.54 (0.09) micrograms/ml at one hour. with a gradual decrease over the next 10 hours. while a peak concentration in pancreatic tissue of mean (SEM) 425 (33) ng/g tissue was achieved at three hours and the drug was undetectable at 12 hours. Survival rates and activities of pancreatic enzymes (amylase. lipase. elastase I) were compared in control mice and animals that received CV 3611 before or at the time of feeding the CDE diet. The survival rate was observed in a no treatment group and mice given pretreatment or treatment with CV 3611 or superoxide dismutase. The survival rate was significantly better in the treatment group given CV 3611 (p less than 0.02). but superoxide dismutase had no significant effect on survival. The increases in the three serum enzyme activities were significantly less at 48 hours in the groups given pretreatment or treatment with CV 3611 than in the no treatment group. These results indicate that CV 3611. which has been proved to pass through the cell membrane and to have a long half life in plasma and tissue. had an important therapeutic effect on the development of acute pancreatitis. They also suggest that oxygen derived free radicals may play an important role in the development of acute pancreatitis.
Molecular differences between human and experimental pancreaticobiliary diversion-induced rat pancreatic neoplasia, A series of molecular changes are now known to be seen in human pancreatic neoplasia. including the very frequent mutational activation of Kirsten ras oncogene at codon 12. overexpression of the epidermal growth factor receptor. and abnormalities of c-erbB-2 expression. In order to determine whether similar changes can be seen in animal models of pancreatic cancer a molecular analysis of tumours induced in rats by pancreaticobiliary diversion was performed. The polymerase chain reaction was used to amplify portions of the rat Kirsten ras gene and sequence specific oligonucleotide hybridisation was used to define whether sequences were wild type or mutant. No evidence of mutation was found in the Kirsten ras gene at codons 12 or 61. where activating mutations are known to occur. In addition immunohistochemical methods were used to investigate expression of c-erB-2 and the epidermal growth factor receptor but no evidence of abnormal expression was found. We conclude that there are major molecular differences between human and experimental rat pancreatic cancer.
alpha Fetoprotein producing early gastric cancer with liver metastasis: report of three cases, Three cases of alpha fetoprotein producing early gastric cancer are presented. Liver metastases occurred in all patients shortly after curative gastrectomy and all died within two years. The incidence of liver metastasis was significantly higher than that in alpha fetoprotein negative early gastric carcinoma (p less than 0.001). The incidences of lymph node metastasis and invasion in lymph vessels and veins were also substantially higher in this group of patients. Two radical hepatic resections. including extended right lobectomy. were performed on one patient but the tumour recurred immediately.
Undetectable caeruloplasmin values in a patient with autoimmune chronic active hepatitis, Caeruloplasmin is an alpha 2 protein produced in the liver that is responsible for transporting copper in the blood. Caeruloplasmin values are usually high in patients with chronic liver diseases. including chronic active hepatitis: low values. however. are characteristic of Wilson's disease. The case of a 17 year old woman with very low caeruloplasmin values and chronic active hepatitis of the lupoid type is described. Steroid treatment resulted in an increase in the caeruloplasmin concentration and clinical improvement.
Antisense-mediated reduction in thrombospondin reverses the malignant phenotype of a human squamous carcinoma, Thrombospondin (TSP) is a trimeric glycoprotein which is synthesized and incorporated into the extracellular matrix by a wide variety of cells. TSP is involved in a number of cellular processes which govern tumor cell behavior including mitogenesis. attachment. migration. and differentiation. To directly assess the role of TSP in tumor cell growth and spread. a human squamous carcinoma cell line. with high TSP production and an invasive phenotype. was transfected with a TSP cDNA antisense expression vector. Five unique transfected clones were obtained with reduced TSP production. Expression of the transfected antisense sequence in these clones was verified by a ribonuclease protection assay. These clones demonstrated reduced growth rates in vitro when compared with a vector transfected control. After subcutaneous inoculation into athymic mice. the antisense clones formed either no tumors or tumors that were slow growing and highly differentiated. This contrasted with the vector-transfected clone which produced poorly differentiated. rapidly growing. invasive tumors. Our results argue in favor of a direct role for TSP in determining the malignant phenotype of certain human tumors.
Dr(a-) polymorphism of decay accelerating factor. Biochemical, functional, and molecular characterization and production of allele-specific transfectants, The Dra antigen belongs to the Cromer-related blood group system. a series of antigens on decay accelerating factor (DAF). a glycosyl-phosphatidylinositol-anchored membrane protein that protects host cells from complement-mediated damage. We studied the rare inherited Dr(a-) phenotype to ascertain the associated biochemical and functional changes in DAF and to characterize the basis for this polymorphism. Radioimmunoassay assay and flow cytometric analysis of Dr(a-) erythrocytes demonstrated 40% of normal surface expression of DAF but normal levels of several other glycosyl-phosphatidylinositol-anchored proteins. distinguishing this phenotype from that of paroxysmal nocturnal hemoglobinuria. Western blots confirmed this reduced DAF expression and indicated a slightly faster mobility of the molecule on SDS-PAGE. Despite the reduced DAF expression. Dr(a-) erythrocytes functioned normally in the complement lysis sensitivity assay. Utilization of the polymerase chain reaction to amplify mononuclear cell genomic DNA from three unrelated Dr(a-) individuals demonstrated that a point mutation underlies the Dr(a-) phenotype: a C to T change in nucleotide 649 resulting in a serine165 to leucine change. This defines the Drb allele of DAF. which can be distinguished from Dra by a Taq I restriction fragment length polymorphism. We created transfected Chinese hamster ovary cell lines expressing either the Dra or the Drb allelic form of DAF. These allele-specific transfectants were tested by inhibition of hemagglutination or flow cytometry and confirmed the specificity of anti-Dra alloantisera. The allele-specific transfectants could form the basis of a new serological approach to immunohematology.
Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans, Animal studies have demonstrated that activation of the baroreflex by increases in arterial pressure inhibits cardiovascular and ventilatory responses to activation of peripheral chemoreceptors (PC) with hypoxia. In this study. we examined the influences of baroreflex activation on the sympathetic response to stimulation of PC and central chemoreceptors in humans. PC were stimulated by hypoxia (10% O2/90% N2) (n = 6) and central chemoreceptors by hypercapnia (7% CO2/93% O2) (n = 6). Responses to a cold pressor stimulus were also obtained as an internal reflex control to determine the selectivity of the interactive influence of baroreflex activation. Baroreflex activation was achieved by raising mean blood pressure by greater than 10 mmHg with intravenous infusion of phenylephrine (PE). Sympathetic nerve activity (SNA) to muscle was recorded from a peroneal nerve (microneurography). During hypoxia alone. SNA increased from 255 +/- 92 to 354 +/- 107 U/min (P less than 0.05). During PE alone. mean blood pressure increased and SNA decreased to 87 +/- 45 U/min (P less than 0.05). With hypoxia during baroreflex activation with PE. SNA did not increase (50 +/- 23 U/min). During hypercapnia alone. SNA increased from 116 +/- 39 to 234 +/- 72 U/min (P less than 0.01). Hypercapnia during baroreflex activation with PE increased SNA from 32 +/- 25 U/min during PE alone to 61 +/- 26 U/min during hypercapnia and PE (P less than 0.05). Like hypercapnia (but unlike hypoxia) the cold pressor test also increased SNA during PE. We conclude that baroreflex activation selectively abolishes the SNA response to hypoxia but not to hypercapnia or the cold pressor test. The inhibitory interaction of the baroreflex and the peripheral chemoreflex may be explained by convergence of baroreceptor and peripheral chemoreceptor afferents on neurons in the medulla.
Platelets of the Wistar Furth rat have reduced levels of alpha-granule proteins. An animal model resembling gray platelet syndrome, Rats of the Wistar Furth (WF) strain have hereditary macrothrombocytopenia (large mean platelet volume [MPV] with increased platelet size heterogeneity and reduced platelet count). Ultrastructural studies suggest that this anomaly results from erratic subdivision of megakaryocyte cytoplasm into platelets. In this study. we have examined protein profiles of platelets of WF rats for biochemical abnormalities associated with this anomaly. Marked decreases in protein bands with an Mr of 185. 57. 53. 16. 13. and 8 kd were observed in one-dimensional reduced SDS-PAGE gels in WF platelets compared with platelets of Wistar. Long Evans. and Sprague-Dawley rats. These proteins were released into the supernatant when washed platelets were treated with thrombin suggesting that they were alpha-granule proteins. These abnormalities were not present in offspring of crosses between Wistar Furth and Wistar rats; however. they were present in platelets of offspring with large MPV derived from backcrosses of (WF X Wistar) F1 males to WF females. but not in backcross offspring with normal platelet size. Immunoblotting confirmed decreased levels of thrombospondin. fibrinogen. and platelet factor 4 in WF platelets. Electron microscopic examination revealed that platelet alpha granules were usually smaller in Wistar Furth than in Wistar rats. In addition. immunogold electron microscopy demonstrated that the surface connected canalicular system of the large Wistar Furth platelets. contained dense material composed of alpha-granule proteins. not present in Wistar platelets. From these results. we conclude that the Wistar Furth rat platelet phenotype of large mean platelet volume and decreased levels of alpha-granule proteins represents an animal model resembling gray platelet syndrome. The autosomal recessive pattern of inheritance of the large MPV phenotype and platelet alpha-granule protein deficiencies suggests that a component common to both formation of platelet alpha granules. and subdivision of megakaryocyte cytoplasm into platelets. is quantitatively or qualitatively abnormal in Wistar Furth rat megakaryocytes and platelets.
Leukotrienes as mediators in ischemia-reperfusion injury in a microcirculation model in the hamster, Leukotriene (LT)B4 promotes leukocyte chemotaxis and adhesion to the endothelium of postcapillary venules. The cysteinyl leukotrienes. LTC4. LTD4. and LTE4. elicit macromolecular leakage from this vessel segment. Both leukocyte adhesion to the endothelium and macromolecular leakage from postcapillary venules hallmark the microcirculatory failure after ischemia-reperfusion. suggesting a role of leukotrienes as mediators of ischemia-reperfusion injury. Using the dorsal skinfold chamber model for intravital fluorescence microscopy of the microcirculation in striated muscle in awake hamsters and sequential RP-HPLC and RIA for leukotrienes. we demonstrate in this study that (a) the leukotrienes (LT)B4 and LTD4 elicit leukocyte/endothelium interaction and macromolecular leakage from postcapillary venules. respectively. that (b) leukotrienes accumulate in the tissue after ischemia and reperfusion. and that (c) selective inhibition of leukotriene biosynthesis (by MK-886) prevents both postischemic leukotriene accumulation and the microcirculatory changes after ischemia-reperfusion. while blocking of LTD4/E4 receptors (by MK-571) inhibits postischemic macromolecular leakage. These results demonstrate a key role of leukotrienes in ischemia-reperfusion injury in striated muscle in vivo.
The spectrum of molecular alterations in the evolution of chronic myelocytic leukemia, DNA from 135 patients with chronic myelogenous leukemia (CML) at various clinical stages and Philadelphia (Ph1) chromosome positive acute lymphoblastic leukemia was investigated for alterations in a variety of proto-oncogenes which have been implicated in the evolution of CML from its chronic phase to blast crisis. The most common genetic change found in the evolution of typical Ph1 chromosome positive CML to blast crisis was an alteration of the p53 gene involving either a rearrangement. a deletion. or a point mutation in the coding sequence of the gene. Alterations of the p53 gene were found in the myeloid and the rare megakaryocytic variant of blast crisis but were absent in the lymphoid leukemic transformants. Gross structural alterations were seen in 11 of 54 (20%) of myeloid or unknown phenotypes of blast crisis and in only 1 of 44 chronic phase cases. Eight examples of mutations in the open reading frame of the p53 gene at codons 49. 53. 60. 140. 202. 204. 238. and 239 were observed in blast crisis patients. Mutations in the N-RAS gene were rare in typical blast crisis (2 of 27 cases) but were found in megakaryocytic and Ph1 negative myeloid blast crisis. We concluded that heterogeneous alterations in the p53 gene and occasionally in the N-RAS genes accompany the evolution of chronic phase CML to blast crisis.
Depressed contractile function due to canine mitral regurgitation improves after correction of the volume overload [published erratum appears in J Clin Invest 1991 Aug;88(2):723, It is known that long-standing volume overload on the left ventricle due to mitral regurgitation eventually leads to contractile dysfunction. However. it is unknown whether or not correction of the volume overload can lead to recovery of contractility. In this study we tested the hypothesis that depressed contractile function due to volume overload in mitral regurgitation could return toward normal after mitral valve replacement. Using a canine model of mitral regurgitation which is known to produce contractile dysfunction. we examined contractile function longitudinally in seven dogs at baseline. after 3 mo of mitral regurgitation. 1 mo after mitral valve replacement. and 3 mo after mitral valve replacement. After 3 mo of mitral regurgitation (regurgitant fraction 0.62 +/- 0.04). end-diastolic volume had nearly doubled from 68 +/- 6.8 to 123 +/- 12.1 ml (P less than 0.05). All five indices of contractile function which we examined were depressed. For instance. maximum fiber elastance (EmaxF) obtained by assessment of time-varying elastance decreased from 5.95 +/- 0.71 to 2.25 +/- 0.18 (P less than 0.05). The end-systolic stiffness constant (k) was also depressed from 4.2 +/- 0.4 to 2.1 +/- 0.3. 3 mo after mitral valve replacement all indexes of contractile function had returned to or toward normal (e.g.. EmaxF 3.65 +/- 0.21 and k 4.2 +/- 0.3). We conclude that previously depressed contractile function due to volume overload can improve after correction of the overload.
Characterization of in vivo expression of the human papillomavirus type 16 E4 protein in cervical biopsy tissues, The role of human papillomavirus (HPV) proteins in the pathogenesis of cervical intra-epithelial neoplasia (CIN) and invasive cervical cancer is poorly understood. To characterize E4 protein expression in 49 paraffin-embedded cervical biopsies representing different histopathologic grades of disease. antibodies were elicited to a synthetic peptide corresponding to amino acids 20-34 of a protein predicted to be encoded by the HPV 16 E4 open reading frame. The E4 protein was detected throughout the spectrum of CIN. from CIN1 to CIN3. Expression was localized to the cell nucleus. primarily in the superficial layers of the squamous cervical epithelium. Ultrastructural studies showed that the E4 protein was organized into compact. intranuclear arrays 25-35 nm in diameter. E4 protein expression was also demonstrated in some histologically normal tissues containing HPV 16 DNA. but not in any of five cervical cancers containing HPV 16 DNA. These results suggest that E4 protein expression may precede development of light microscopic tissue abnormalities. that it may continue through the spectrum of CIN. and that expression of this protein may be reduced or terminated in invasive cancer. The function of this protein remains unknown. but its nuclear localization may be consistent with a role in viral maturation.
Sp alpha V/41: a common spectrin polymorphism at the alpha IV-alpha V domain junction. Relevance to the expression level of hereditary elliptocytosis due to alpha-spectrin variants located in trans, Spectrin alpha-chain mutants associated with hereditary elliptocytosis are highly variable in their level of expression. It has been assumed that the degree of elliptocytosis can be increased when the spectrin alpha chain. encoded by the alpha gene in trans to the variant. is expressed at a low level. We now provide strong evidence for the existence of low-level expression of spectrin alpha chains. This condition is referred to as the alpha V/41 polymorphism. It has been observed in 15 different families or individuals of French. North African. and African ancestry in which seven distinct elliptocytogenic alpha-spectrin variants were co-inherited. Whenever the alpha V/41 polymorphism was present. the severity of the biochemical. morphological. and. sometimes. the clinical phenotype of elliptocytosis was increased. The alpha V/41 polymorphism was also frequently encountered among 36 unrelated control subjects in the heterozygous or homozygous states. and was entirely asymptomatic in both cases. The main biochemical feature was an increased susceptibility to proteolysis of the alpha IV-alpha V domain junction. Alteration of the facing beta IV domain of spectrin was demonstrated by in vitro spectrin dimer reconstitution experiments. It appears that the alpha V/41 polymorphism is often required for alpha-spectrin elliptocytogenic variants to become manifest in the heterozygous state. Thus. alpha-spectrin-related elliptocytosis may be viewed as a bifactorial condition.
Decreased in vivo glucose uptake but normal expression of GLUT1 and GLUT4 in skeletal muscle of diabetic rats, This study was designed to determine whether altered glucose transporter expression is essential for the in vivo insulin-resistant glucose uptake characteristic of streptozocin-induced diabetes. Immunofluorescence in rat skeletal muscle colocalizes GLUT4 with dystrophin. both intrinsic to muscle fibers. In contrast. GLUT1 is extrinsic to muscle fibers. probably in perineurial sheath. Immunoblotting shows that levels of GLUT1 and GLUT4 protein per DNA in hindlimb muscle are unaltered from control levels at 7 d of diabetes but decrease to approximately 20% of control at 14 d of diabetes. This decrease is prevented by insulin treatment. In adipose cells of 7 d diabetic rats. GLUT4 levels are depressed. Thus. GLUT4 undergoes tissue-specific regulation in response to diabetes. GLUT4 and GLUT1 mRNA levels in muscle are decreased 62-70% at both 7 and 14 d of diabetes and are restored by insulin treatment. At 7 d of diabetes. when GLUT4 protein levels in muscle are unaltered. in vivo insulin-stimulated glucose uptake measured by euglycemic clamp is 54% of control. This reflects impairment in both glycogen synthesis and glycolysis and the substrate common to these two pathways. glucose-6-phosphate. is decreased approximately 30% in muscle of diabetic rats. These findings suggest a defect early in the pathway of glucose utilization. probably at the step of glucose transport. Because GLUT1 and GLUT4 levels are unaltered at 7 d of diabetes. reduced glucose uptake in muscle probably reflects impaired glucose transporter translocation or intrinsic activity. Later. at 14 d of diabetes. GLUT1 and GLUT4 protein levels are reduced. suggesting that sequential defects may contribute to the insulin-resistant glucose transport characteristic of diabetes.
Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans, Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography. peroneal nerve). forearm blood flow (plethysmography). heart rate. and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control. to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses. respectively. and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA. which averaged 21.5 +/- 1.5 bursts/min in control. increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min. respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine. there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.
A new hydrophilic copolymer membrane for dermabrasion, Omiderm. a hydrophilic copolymer membrane. is a new dressing for the postoperative care of the dermabrasion patient. The unique physical properties of this dressing will be examined. Based on the clinical experiences presented. suggestions will be outlined that facilitate the best results from its use following dermabrasion.
The treatment of atypical lipoma with liposuction, Large lipomas may best be treated with liposuction. Once a lipoma enlarges to 4 cm or more. liposuction has several advantages over conventional surgery. A well-demarcated lipoma 15 cm in diameter and deep to muscle was treated by liposuction. Biopsy showed an atypical lipoma. Because the entire tumor was removed by liposuction. we feel that the prognosis is excellent. The cosmesis and morbidity results were far superior to those anticipated with conventional excisional surgery. Small superficial lipomas may be treated by suction lipectomy and the surrounding area can be contoured symmetrically at the same time. whereas large ones can be liposuctioned completely without extensive surgical extirpation and morbidity. Because such big lesions may represent atypical lipomas or liposarcomas. care must be taken to remove the entire tumor.
Heterogeneity in oxygen diffusion around venous ulcers, The pathogenesis of venous ulceration is thought to involve the formation of fibrin cuffs around dermal capillaries. Consistent with a barrier effect of fibrin. it has been shown that the dermal diffusion of oxygen. as measured by transcutaneous oxygen pressure (TcPO2). is decreased in limbs affected by venous ulcer. However. it is unknown whether oxygen diffusion around the perimeter of venous ulcers is uniformly affected. In this study. we investigated TcPO2 values at four different quadrants around the ulcers of 14 patients. the contralateral leg of five patients with unilateral ulcers. and the leg of six normal individuals. These values were also compared to TcPO2 measurements at the chest. Our results indicate that. whereas TcPO2 values in limbs affected by venous ulcers are much lower than normal. there is a great deal of variability in oxygen diffusion around individual ulcers. These findings may represent a heterogeneity in the disease process affecting the leg.
The depth of thermal necrosis using the CO2 laser: a comparison of the superpulsed mode and conventional mode, In order to compare the depth of thermal necrosis on human skin using the superpulse CO2 laser to the conventional CO2 laser. single impacts of various laser settings were fired at both ends of fusiform excisions done for other clinical purposes. These laser impacts were then examined histologically and the superpulse mode was found to limit the depth of thermal necrosis by approximately a factor of two.
Evaluation of different systems for clinical quantification of varicose veins, One hundred twenty-five lower limbs with varicose veins were studied clinically. essentially by palpation. Two specialists in venous pathology scored the severity of the varicose veins from 0 to 20. Comparison between the different clinical parameters and the scores of the specialists showed that two systems of clinical quantification gave good results and were easy to use. One system is the maximum diameter of the largest varicose vein; the other system is the sum of maximum diameters over 7 sections (3 for thigh. 3 for leg. 1 for foot). This latter system gives a more precise evaluation of the clinical severity of the varicose veins.
Sclerotherapy for multiple glomangiomata, Multiple glomangiomata have always been treated by surgical resection. However. sclerotherapy can be used obliterate the majority of these tumors.
Stratospheric ozone depletion and its relationship to skin cancer, Several articles have appeared in the literature regarding the impact of stratospheric ozone depletion on the prevalence of skin cancer due to increasing ultraviolet radiation. While it has been shown that UVB radiation is related to carcinogenesis of both melanoma and non-melanoma skin cancer. it has not definitively been shown that stratospheric ozone depletion is translating into increased penetrating ultraviolet radiation. Estimates of increasing skin cancer in the future are dependent on calculations of UVB increases drawn from data on ozone depletion. The present article describes the history of stratospheric ozone depletion. how it may affect UVB penetration and skin cancer rates. and what is currently being done to prevent man's further detrimental effects on our atmosphere.
Extensive Bowen's disease of the penile shaft treated with fresh tissue Mohs micrographic surgery in two separate operations, Bowen's disease or squamous cell carcinoma in situ is uncommon on the penile shaft. While surgical excision is the treatment of choice. the Mohs micrographic surgical approach ensures microscopically controlled tumor-free margins with preservation of normal tissue. While small- or medium-sized penile excisions heal very well by second intention. large areas of involvement are often grafted to prevent debilitating contractures. We report a case of near circumferential penile Bowen's disease treated by two separate operations that healed by second intention with very good cosmetic and functional results.
Using a low current radiosurgical unit to obliterate facial telangiectasias, A method is presented using the Ellman Surgitron to obliterate facial telangiectasias in an effective manner. One of several types of needles. low current setting. and continuous depression of the footswitch provide efficiency with virtual pain-free operation.
Local anesthetic allergy. Its recognition and avoidance, Local anesthetics are perhaps the most important drugs used in dermatologic surgery. They allow a variety of procedures to be performed safely and comfortably. Although generally well-tolerated. patients frequently report adverse reactions to these agents and may be labeled as "caine sensitive". In this review we will discuss the approach to the patient with possible local anesthetic sensitivity and in particular will focus on the role of skin testing and challenge in evaluating these patients.
An educational device for Mohs micrographic surgery. A three-dimensional model of basal cell carcinoma, Mohs micrographic surgery for skin cancer (fresh-tissue technique) involves the processing of tissue in a complex fashion. The advantages of this method relate to the asymmetric three-dimensional growth of basal cell carcinoma (BCC). A device is described here based on published knowledge about the growth of BCC. The model demonstrates the precise way in which Mohs surgery varies from other surgical approaches to yield higher cure rates in specific circumstances. This device may be helpful in educating residents and medical students about Mohs surgery and in preparing patients for this procedure.
Hairline design and placement, A simple. straight forward. almost mechanical method of drawing the hairline is presented. It is amazing to see how this method. when followed closely. consistently produces a natural. aesthetically pleasing result on all sizes and shapes of heads. It is recognized by the authors that there are a lot of individual variations among hair transplant surgeons and most will be very attractive and quite natural. However. we believe that the following description will provide a good starting point in designing hairlines. and if the basic points are followed. unnatural hairlines will be avoided.
Angiosarcoma of the face and scalp. A case report with complete spontaneous regression, A wide. hemorrhagic lesion occurred on the face and scalp of a 75-year-old woman who had no history of previous trauma to the region. Histology showed features consistent with a diagnosis of angiosarcoma. Clinical and radiologic investigations failed to show any sign of internal involvement. The lesion completely regressed without any therapy within a few months from onset. and the patient is alive and free of disease 36 months after the first observation. Repeated clinicoradiologic investigations failed again to prove visceral diffusion of the tumor. Spontaneous regression of an angiosarcoma is an exceptional event. and only one similar case has been reported in the literature.
A subset of asialo GM1+ cells play a protective role in the occurrence of graft-versus-host disease in mice, In three different murine models of bone marrow (BM) transplantation the capacity of asialo GM1+ cells to suppress graft-vs-host disease (GVHD) was investigated. In a first model. total lymphoid irradiation (TLI)-treated BALB/C mice were given 1 mg of anti-asialo GM1 antibody. This led to the disappearance of functional suppressor cells after TLI. Injections of anti-asialo GM1 into TLI-treated BALB/C mice before infusion of 30 x 10(6) fully allogeneic (C3H) BM cells. led to a significantly decreased survival rate as compared to TLI-treated mice injected with control serum before BM transplantation (survival 29 and 83%. respectively. at 120 days after transplantation. p = 0.0032 log rank). The mortality of the former group was due to GVHD as 1 degree all dying animals showed clinical and histologic signs of GVHD. 2 degrees all animals were chimeric and 3 degrees mice receiving no or syngeneic BALB/C BM had excellent survival rates excluding BM aplasia or increased susceptibility for infections as reason for the mortality of the allogeneic BM recipients. In a second model. asialo GM1+ cells were removed in vitro from the C3H BM inoculum before injection into lethally irradiated (9 Gy) BALB/C recipients. In mice kept in specific pathogen-free conditions. this procedure resulted into a significant mortality (12/12) as compared to mice receiving BM pretreated with control serum (1/12. p = 0.0001 log rank). When kept in conventional housing. GVHD occurred in both groups but much earlier in the group receiving anti-asialo GM1-treated BM (median survival time 6 vs 46 days for the control mice. p = 0.001 log rank). No animal receiving anti-asialo GM1 and treated with syngeneic BM died. thus excluding toxicity. increased susceptibility to infections. or decreased graft take as a cause of mortality. In a last model. asialo GM1 cells were removed from syngeneic BM in a BM transplantation model in which T cell-depleted syngeneic (BALB/C) and non-T cell-depleted allogeneic (C3H) BM was administered to lethally irradiated (9 Gy) BALB/C mice. Also in this model GVHD-related mortality only occurred in the group of mice receiving syngeneic BM from which asialo GM+ cells were depleted before infusion (3/12). Our experiments thus clearly show that asialo GM1+ cells from both recipient (the TLI model) as well as donor origin (the TBI experiments) can suppress the occurrence of GVHD.
Colchicine is a potent adjuvant for eliciting T cell responses, The cytotoxic drug colchicine when administered to mice in conjunction with Ag was shown to have a strong adjuvant effect in generating a specific plaque-forming cell response to the protein Ag OVA. human gamma-globulin and BSA. Dissection of this phenomenon revealed that several T cell activities. including Th function. Ag-induced T cell proliferation and T cell-mediated delayed-type hypersensitivity. were also specifically induced by treating mice with colchicine + Ag. The adjuvant effect of colchicine was observed when the drug and Ag were injected in soluble form. i.e.. no vehicle (e.g.. oil. liposome) was necessary. The potency of colchicine as an adjuvant was equal to or more than that of conventional adjuvants such as CFA or alum.
The influence of avidity on signaling murine B lymphocytes with monoclonal anti-IgM antibodies. Effects of B cell proliferation versus growth inhibition (tolerance) of an immature B cell lymphoma, We have investigated the effect of the avidity of a monoclonal anti-mouse IgM antibody (mAb) on its ability to activate normal B cells vs its capacity to inhibit the growth of an immature B lymphoma. BKS-2. A panel of seven mAb with specificities for four different domains of mu-heavy chain were selected and their relative avidities measured. Of the seven mAb studied. four antibodies (b7-6. Ak11. AK15. and DS1) were found to have relatively higher avidities than three others (AK17. 331.12. and Bet-2). Among them. the mAb b7-6 was highly efficient in inducing proliferation of normal B cells. whereas all others (including the remaining three high avidity mAb) were inefficient in inducing B cell proliferation. This failure cannot be simply related to the differences in their fine specificity because all the mAb became highly stimulatory after coupling to Sepharose beads. With one exception (DS1). avidity was a better predictor of the growth-stimulatory capacity when the antibodies were immobilized. Taken together. these findings suggested that although high affinity was important. there were other factors that might influence the mitogenic potential of a soluble anti-mu mAb. On the other hand. all anti-mu mAb irrespective of their avidity. fine specificity. and isotype were capable of effectively inhibiting the growth of BKS-2 cells. Furthermore. there was a direct correlation between the avidity and the dose of the mAb required to cause half-maximal inhibition of BKS-2 growth. The F(ab) fragments of high avidity mAb b7-6 failed to inhibit the growth of BKS-2 cells. which indicates that a minimal level of cross-linking of the membrane Ig receptor is necessary for causing growth inhibition in BKS-2 cells. Although there was no significant difference in the tolerogenic potential of soluble vs immobilized anti-mu mAb in directly inactivating BKS-2 cells. their growth-inhibitory capacity was remarkably different in the presence of rIL-5. Thus. rIL-5 was effective in partially overcoming the tolerogenic effect of soluble but not immobilized anti-mu mAb. Unlike IL-5. LPS rescued BKS-2 cells from the inhibitory effect of both soluble and immobilized anti-mu antibodies. Altogether. these results suggested that the ligand binding requisites for tolerance induction were less stringent than those for B cell activation. Furthermore. a high affinity interaction between membrane Ig receptor and its ligand appeared to generate a dominant negative signal that was not reversed by lymphokines.
Limited T cell receptor diversity of transplacentally acquired maternal T cells in severe combined immunodeficiency, Circulating maternal T lymphocytes were noted in the peripheral blood of six patients with severe combined immunodeficiency. Phenotypical analyses revealed the presence of both CD4 and CD8 subsets in some but not all cases. The maternal T cells could be stimulated by anti-TCR/CD3 mAb +/- rIL-2. but were virtually silent in the MLR and against the recall Ag purified protein derivative of tuberculin and tetanus toxoid. even in immunized patients engrafted with T cells from a responding mother. Using a panel of mAb against TCR V region gene encoded epitopes including V beta 5. V beta 6. V beta 8. V beta 12. and V alpha 2. we show that maternal T cells displayed a profoundly reduced TCR diversity. characterized by a lack of one or even several TCR V subsets in all six cases and a dramatic (5- to 25-fold) expansion of other TCR V subsets in three cases. In one patient analyzed. limited TCR diversity was also seen in T cells cultured from bone marrow and skin; restimulation experiments of these cells against cells expressing host MHC Ag were unsuccessful. as were attempts to exclusively allocate anti-host proliferative responses of maternal control T cells to the TCR V subsets that had undergone expansion in vivo. We conclude that a severely reduced TCR diversity is a common feature of maternal T cells engrafted in severe combined immunodeficiency patients. These novel findings provide a structural basis to understand the failure of these cells to protect the host from infections and may also help to understand their relative inefficiency to induce lethal. multi-organ. graft vs host disease. Moreover. as an experiment of nature. the reported phenomenon clearly illustrates the functional consequences in vivo of an insufficient TCR diversity.
Protection against experimental encephalomyelitis. Idiotypic autoregulation induced by a nonencephalitogenic T cell clone expressing a cross-reactive T cell receptor V gene, The recovery process in experimental autoimmune encephalomyelitis (EAE) in Lewis rats is characterized by an increasing diversity of T cell clones directed at secondary epitopes of myelin basic protein. Of particular interest. residues 55 to 69 of guinea pig basic protein could induce protection against EAE. A nonencephalitogenic T cell clone. C455-69. that was specific for this epitope transferred protection against both active and passive EAE. Clone C4 was found to express V beta 8.6 in its Ag receptor. and residues 39 to 59 of the TCR V beta 8.6 sequence were found to be highly crossreactive with the corresponding residues 39 to 59 of TCR V beta 8.2. which is known to induce protective anti-idiotypic T cells and antibodies. Like the TCR V beta 8.2 peptide. the V beta 8.6 sequence induced autoregulation and provided effective treatment of established EAE. Thus. the EAE-protective effect of the guinea pig basic protein 55-69 sequence was most likely mediated by T cell clones such as C4 that could efficiently induce anti-TCR immunity directed at a cross-reactive regulatory idiotope.
Clonal analysis of the peripheral T cell compartment of the SCID-hu mouse, Severe combined immunodeficiency (SCID) mice can be transplanted successfully with human fetal liver and thymus (SCID-hu mice). Precursor cells derived from the fetal liver differentiate in the thymus and migrate into the blood as mature T cells. In the present paper. the peripheral T cell compartment of such mice was studied. Peripheral WBC were activated by PHA and cultured in the presence of irradiated human feeder cells. The resultant cell population consisted exclusively of human CD1- CD2+ CD3+ CD7+ T lymphocytes; up to 4% of the T cells expressed the TCR gamma delta. whereas 95 to 100% were TCR alpha beta +. The CD4bright (42 to 66%) and CD8bright (30 to 54%) populations coexpressed variable but low levels of CD8 and CD4. respectively. The T cell cultures from the SCID-hu mice did not display reactivity towards the autologous human EBV-transformed B cell lines (B-LCL). On the other hand. these human T cells proliferated and were cytotoxic against allogeneic human B-LCL. T cell clones were established from cultured SCID-hu T cells. All T cell clones were TCR alpha beta + CD3+ CD2+; 61% of the clones were CD4+ CD8-. 27% were CD8+ CD4-. 11% were CD8+ CD4lo. and 2% were CD4+ CD8lo. None of these clones recognized the autologous B-LCL established from the fetal human donor. Fourteen of 100 T cell clones had specific alloreactivity. as tested on a panel of five B-LCL. Of these 14. two CD8+ CD4lo and two CD8+ CD4- clones were cytotoxic and did not proliferate in response to specific stimulator cells. Furthermore. two CD4+ CD8lo and eight CD4+ CD8- clones proliferated specifically in response to alloantigens. In conclusion. the peripheral human T cells of SCID-hu animals are functional and their TCR repertoire is polyclonal. alloreactive. and devoid of self-reactive cells. Therefore. the SCID-hu mouse can be a suitable model for the study of alloreactivity and allotolerance in vivo. as well as for the study of negative selection in the human thymus.
In vivo administration of recombinant granulocyte-macrophage colony-stimulating factor results in a reversible inhibition of primary B lymphopoiesis, To determine if in vivo administration of granulocyte-macrophage CSF (GM-CSF) affects production of B lymphocytes in the bone marrow. mice were treated with the cytokine and the kinetics of B cell production was analyzed. After 1 wk of GM-CSF treatment. the number of B cell progenitors that express the B220 Ag had fallen fivefold and surface IgM expressing B cells were barely detectable. Although cellularity in the spleen had increased two-fold. due in part to an increase in the number of granulocyte-macrophage progenitor cells. splenic B cell levels were not affected by the GM-CSF treatment. Although numbers of marrow B cells and their immediate progenitors declined due to cytokine treatment. cells capable of rapidly restoring B lymphopoiesis were present in that tissue. After cessation of GM-CSF treatment. B lymphopoiesis resumed in the marrow of the mice and rebounded to supernormal levels at 1 wk after the last GM-CSF injection. This effect may be due to actions of GM-CSF on the B lymphopoietic support capability of the marrow environment. because the overproduction of B cells was not observed when marrow from the GM-CSF donors was used to reconstitute sublethally irradiated severe combined immunodeficient mice.
Immunoprecipitation of membrane proteins from rat basophilic leukemia cells by the antiganglioside monoclonal antibody AA4, In previous studies. mAb AA4 inhibited IgE binding. induced rapid morphologic changes. and blocked histamine release in rat basophilic leukemia (RBL-2H3) cells. It bound to two novel derivatives of ganglioside GD1b (Ag I and Ag II) that appear to be present only in rat mast cells. The present study demonstrates the importance of gangliosides Ag I and Ag II for binding of mAb AA4 to intact cells. We also investigated the presence of gangliosides Ag I and Ag II and proteins immunoprecipitated with mAb AA4 in the parental and four variant cell lines. In comparison with the parental RBL-2H3. two variant cell lines had very low (0.5% and 2.0%) and two others had intermediate levels (9% and 18%) of 125I-AA4 binding. mAb AA4 inhibited 125I-IgE binding to the parental RBL-2H3 cells and to only one variant with intermediate amounts of gangliosides Ag I and Ag II. Therefore. there are variations in the proximity of these gangliosides to the high affinity IgE receptor (Fc epsilon RI) among different cell lines. mAb AA4 immunoprecipitated proteins of 50 to 60. 120. and 135 kDa from 125I-surface labeled cells. These were different from the subunits of Fc epsilon RI. The amount of gangliosides Ag I and Ag II in cell extracts correlated with the number of mAb AA4 binding sites on the cell surface and with the quantity of proteins precipitated from the different cell lines. Thus. these membrane proteins appear to be associated with gangliosides Ag I and Ag II. The binding of mAb AA4 to the surface gangliosides could induce intracellular changes through transmembrane signaling by these proteins.
In vitro efficacy of anti-HIV immunotoxins targeted by various antibodies to the envelope protein, Six different anti-HIV envelope antibodies and one irrelevant control antibody were coupled to ricin A chain and tested for their efficacy in inhibiting HIV tissue culture infections. The anti-HIV antibodies consisted of five monoclonals. three of murine and two of human origin. and one polyclonal preparation prepared by affinity purifying pooled serum antibodies from HIV-infected humans on rgp160. The binding specificity of the antibodies was defined by ELISA by using recombinant envelope proteins and synthetic peptides. and by flow cytometry on HIV-infected cells. The in vitro efficacy of the antibodies was tested by the abilities of the immunotoxins to inhibit protein synthesis in persistently infected cell lines and by their abilities to inhibit HIV production during both acute and persistent infection as measured with an HIV-specific focal immunoassay. The immunotoxins were tested against a panel of distinctly different HIV isolates. The results indicate the following: 1) A mAb to the immunodominant neutralizing loop was highly effective against homologous strains of HIV. but had no activity against heterologous HIV. 2) The efficacy of anti-gp41 mAb varied depending upon the epitope recognized and possibly the affinity of binding to gp41. 3) The polyclonal human anti-gp160 antibodies produced the immunotoxin with the broadest specificity for different HIV strains and the greatest specific activity. This is related to the polyclonal nature of the preparation rather than an increase in relative avidity of the antibody. 4) Activity of an immunotoxin is not a direct function of the binding of the antibody to the surface of infected cells. 5) The ability of an immunotoxin to halt the spread of infection through a tissue culture cell population is dependent upon the ability of the antibody to neutralize the virus as well as the activity of the toxin. Our data suggest that efficacious immunotoxins for the treatment of AIDS may be made with polyclonal anti-envelope antibodies derived from the serum of patients who have been infected with HIV or with appropriately chosen anti-gp41 antibodies.
T cells from tumor-immune mice nonspecifically expanded in vitro with anti-CD3 plus IL-2 retain specific function in vitro and can eradicate disseminated leukemia in vivo, The therapeutic efficacy of adoptive immunotherapy of cancer has been shown to positively correlate with the dose of tumor-immune T cells transferred. Therefore. the success of this therapy is critically dependent on the ability to procure large numbers of functionally active T cells. Previous studies in animal models have shown that the limited therapeutic efficacy of a small number of immune T cells can be greatly enhanced by expansion of T cells in vitro to greater numbers before transfer in vivo. Optimal regimens for T cell expansion in vitro have generally employed the use of intermittent stimulation of the TCR with specific Ag followed by exogenous IL-2. The use of IL-2 alone does not provide for requisite episodic up-regulation of IL-2R. Stimulation of the invariant CD3 portion of the TCR/CD3 complex with antibody to CD3 (anti-CD3) represents an alternative method of up-regulating IL-2R and has been used to nonspecifically induce the growth of Ag-specific T cell lines and clones long-term in vitro with maintenance of function and specificity. The current study examined whether resting T cell populations containing small numbers of memory tumor-specific T cells could be rendered more effective in tumor therapy by nonspecific expansion in vitro with anti-CD3 plus IL-2. Spleens from C57BL/6 mice previously immunized to FBL-3. a syngeneic virus-induced leukemia. were nonspecifically stimulated with anti-CD3 plus IL-2. The resultant T cells were expanded in number. were nonlytic to FBL-3 but retained the ability to become lytic upon specific stimulation by FBL-3. and were effective in specific tumor therapy. The Ag-specific anti-tumor immune function declined on a per cell basis after each cycle of anti-CD3-induced T cell expansion. However. the approach resulted in a substantial increase in total T cell number and an overall net increase in the function of the effector T cell population. Thus. stimulation of tumor-immune T cell populations with anti-CD3 plus IL-2 represents a nonspecific method for expanding the number of specific effector T cells for cancer therapy.
Myxoma of the external auditory meatus, A case of myxoma of the external auditory meatus is described. The patient presented with a recurring tumour which had not been correctly diagnosed although the growth had been removed ten times over a period of two years. The tumour was skin covered. contained gelatinous material and was attached to the tympanic membrane and anterior canal wall. Following recognition of the tumour as myxoma. removal was performed with sufficiently wide margins and there has been no recurrence during follow-up for one year.
Familial multicentric paragangliomas in a child, A 12-year-old girl presented with bilateral carotid-body paragangliomas and a unilateral jugular paraganglioma. The tumours were surgically removed. This is a rare combination of tumours in any patient and previously unreported in a child of this age. Her father died of a cerebellar astrocytoma and her mother underwent surgical removal of a large mediastinal paraganglioma. The association of astrocytoma with familial paragangliomas has never been documented. The literature on the epidemiology and inheritance pattern of familial paragangliomas is reviewed. The need for thorough pre-operative evaluation of the patient and close follow-up of family members is stressed.
Venous haemangioma of the neck and mediastinum, A case of cervico-mediastinal venous haemangioma with diffuse upper respiratory airway involvement is reported. The lesion was considered to be an ordinary supraglottic haemangioma at first. We recommend that adult cases of laryngeal haemangioma should be carefully examined for extra-laryngeal lesions.
Thyroid disease in middle-aged and elderly Swedish women: thyroid-related hormones, thyroid dysfunction and goitre in relation to age and smoking, The prevalence of thyroid disease and the concentration of thyroid hormones and thyrotropin were studied in a random population sample of 1154 women. aged 50-72 years. with special reference to the effect of age and smoking. The prevalence of spontaneous hypothyroidism was 3.3% (previously unknown overt and mild disease 1.3%) and the prevalence of hyperthyroidism was 2.5% (previously unknown disease 0.2%). Clinically suspected hyper- or hypothyroidism (very weak to strong) was recorded in 288 women. but was only verified in three cases. The prevalence of visible and palpable thyroid enlargement was 2.1% and 13-14%. respectively. Total thyroxine concentrations increased and free tri-iodothyronine levels decreased significantly with age (P less than 0.001). The serum thyrotropin concentrations were lower in smoking women than in non-smokers in the 50- and 58-year age groups (P less than 0.05). There was no increase in the prevalence of thyroid disease or goitre in the women who were smokers at the time of the study.
Characteristics of patients resistant to antihypertensive drug therapy, In order to determine the features that characterize refractory hypertension (RH). patients aged less than 65 years in a hypertension clinic were screened. Thirty-six patients on triple drug therapy with a supine diastolic blood pressure (DBP) of greater than or equal to 5 mmHg above an identified target pressure (90-100 mmHg). or a systolic blood pressure (SBP) greater than or equal to 170 mmHg for the last 6 months (greater than or equal to 3 measurements) underwent a thorough clinical investigation. The frequency of renal artery stenosis (RAS) in the RH patients was 30%. The non-RAS patients had a low occupational status. 76% being either manual workers or unskilled non-manual workers (reference group: 42%; P less than 0.01). They were more obese (body mass index (BMI) 28.8 vs. 25.8; P less than 0.01). and had a longer duration of hypertensive disease. RH patients had a higher prevalence of non-insulin-dependent diabetes mellitus (18 vs. 6%; P less than 0.05). and showed a higher prevalence of nervous complaints and mental distress (44% vs. 12%; P less than 0.001) and musculo-skeletal pain (39% vs. 7%: P less than 0.001). It is suggested that refractory hypertension should be investigated and treated bearing psychosocial factors in mind. concurrently with a screening for secondary hypertension.
Low density lipoprotein density and composition in hypercholesterolaemic men treated with HMG CoA reductase inhibitors and gemfibrozil, The effects of HMG CoA reductase inhibitor (lovastatin or simvastatin) and gemfibrozil treatment on low density lipoprotein (LDL) density distribution and composition were studied in male patients with heterozygous familial hypercholesterolaemia (FH) (n = 17) or non-familial hypercholesterolaemia (non-FH) (n = 14). In FH patients the HMG CoA reductase inhibitors reduced 'light' LDL particles (density 1.022-1.033 g ml-1) significantly more than 'heavy' LDL (density 1.033-1.059 g ml-1). while a more uniform reduction of 'light' and 'heavy' LDL occurred in non-FH patients. HMG CoA reductase inhibitor treatment increased the apolipoprotein B (apoB) content and decreased the cholesterol/apoB ratio of LDL in FH patients. Gemfibrozil significantly reduced 'heavy' LDL but not the 'light' LDL fraction in both FH and non-FH patients. and the mean cholesteryl ester content of LDL increased. while the Tg content decreased. in both FH and non-FH patients. The results indicate that HMG CoA reductase inhibitor and gemfibrozil treatment have distinctly different effects on the physico-chemical properties of LDL. reflecting their different modes of action on lipoprotein metabolism.
Plasma chromogranin A + B, neuropeptide Y and catecholamines in pheochromocytoma patients, Plasma levels of chromogranin A + B. neuropeptide Y and catecholamines were analysed before. during and after surgery in seven patients with pheochromocytoma. The aim of the study was to determine the diagnostic sensitivity of these plasma amines and peptides. and to investigate their peroperative fluctuations. Chromogranin A + B in plasma was increased preoperatively in all patients. showed no significant increase during surgery. and normalized postoperatively. Neuropeptide Y. which alone can induce hypertension. was present in high levels in plasma from three patients preoperatively. increased further in four patients during surgery. and was postoperatively low in all patients. Fractionated plasma catecholamines were increased in five patients before surgery. increased in all patients during tumour dissection. and normalized postoperatively. It may be concluded that plasma chromogranin A + B exhibited as high a sensitivity for pheochromocytoma as fractionated urinary catecholamines in the patients studied.
Cholestatic liver reaction during heparin therapy, Three patients are reported who developed liver enzyme abnormalities of a cholestatic pattern. without jaundice. after 10-28 d of heparin treatment. The values normalized within 4 months in all patients. Thus heparin should be added to the list of drugs that may cause a cholestatic liver reaction.
A case of systemic mastocytosis; therapeutic efficacy of ketotifen, A 68-year-old man presented with a 6-month history of fatigue. rhinorrhoea. pruritic skin lesions. left pleural effusion. ascites. oedema and weight loss of 10 kg. Investigations revealed hepatosplenomegaly. retroperitoneal lymphadenopathy. anaemia. leucocytosis with eosinophilia. hypoprothrombinaemia. hypocholesterolaemia and elevation of both gamma glutamyltransferase and alkaline phosphatase. Biopsies of a skin lesion. bone marrow and liver revealed mast cell infiltration. allowing the diagnosis of systemic mastocytosis (SM). Hydroxyzine plus ranitidine were given without success. Hydroxyzine treatment was stopped. and ketotifen was initiated; substantial symptomatic improvement was observed within 8 d. This case report indicates the effectiveness of ketotifen in the symptomatic treatment of SM.
Presenting a diagnosis of cancer: patients' views, BACKGROUND. Although in general. patients in the United States are now told if they have been diagnosed as having cancer. little information is available either about the way in which this is done or about patients' satisfaction with how they are told. METHODS. Thirty-two patients were interviewed who had been given a diagnosis of cancer; one half were being treated at a comprehensive cancer center and one half at a community hospital. The study instrument. presented in a semistructured interview conducted by psychosocial clinicians. included specific questions about the setting and the manner in which the patients were told. their reactions to the diagnosis. and their suggestions of how physicians should inform others who have to be informed of a similar diagnosis. RESULTS. All patients were told of their diagnosis by a physician; 84% of the time the diagnosis was given in person. Patients said that being told with hope. information. and caring. and with respect for their privacy and wishes to have a supportive person present were particularly helpful. Almost 40% of patients reported at the time of the interview that their hopes were directed toward remission and optimal quality of life rather than toward a cure. Four of the six patients whose conditions had initially been misdiagnosed described subsequent mistrust of information received from physicians. CONCLUSIONS. These findings confirm the importance of a physician providing hope for and fostering trust in patients to whom they are presenting the diagnosis of cancer. The results indicate that physicians' help in providing treatment information contributes more to hope than does cheerfulness or optimism. and that patients who have been given a misdiagnosis require special consideration in order to reestablish trust.
Factors affecting compliance with screening sigmoidoscopy, BACKGROUND. A retrospective. qualitative study in a university setting was undertaken to better understand factors influencing patient compliance with screening sigmoidoscopy. METHODS. Individuals who completed screening sigmoidoscopy were interviewed to learn about the physician-patient relationship. general knowledge of cancer. family experience with cancer. exposure to the media. and specific reasons why sigmoidoscopy was completed. RESULTS. Respondents reported that their physician's recommendation had a strong positive influence on their decision to have sigmoidoscopic screening. as did their family and personal experiences with cancer. In all cases. the patients stated that they would not have had a sigmoidoscopy without the recommendation of their physician. Respondents were little influenced by exposure to the media or by famous personalities. CONCLUSIONS. The importance of the physician's recommendation for the patient to have sigmoidoscopy and demonstration of concern with early cancer detection may represent the primary motivating factors in completion of screening sigmoidoscopy.
Enterobacter bacteremia in the community hospital, BACKGROUND. The purpose of this study was to examine the epidemiological and clinical characteristics of Enterobacter bacteremia in the community hospital. where nosocomial infections are not commonly studied. METHODS. The blood culture records of five community hospitals in the Dayton. Ohio. area were reviewed to find cases of Enterobacter bacteremia. The respective hospital charts were then reviewed. RESULTS. Seventy-five episodes of Enterobacter bacteremia were reviewed. Eighty percent (60) of the organisms were nosocomially acquired. and 20% (15) were community acquired. The median age of the patients was 64 years. In 39% (29) of the episodes. fever was not the primary manifestation. The mortality rate was 29% (22). In 30% of the cases. the portal of entry for the bacteremia was unknown. The most common known portals of entry were genitourinary. gastrointestinal or biliary. and peritoneal. The most common underlying disorders were malignancy. postoperative states. and diabetes mellitus. In 9% of the cases. no underlying disorder was detected. The organisms showed high sensitivity to chloramphenicol. aminoglycosides. piperacillin sodium. and cefotaxime sodium. High degrees of resistance were shown to ampicillin. first-generation cephalosporins. and cefoxitin. Eighty-four percent (46) of the patients treated appropriately survived. and 55% (11) of the patients treated inappropriately died. CONCLUSIONS. Enterobacter bacteremia is most commonly nosocomially acquired and appears to be a problem in the community hospital. Appropriate therapy improves rates of patient survival.
Barriers to cholesterol testing in a rural community, BACKGROUND. The purpose of this study was to investigate the factors that determine whether residents in a rural community have their cholesterol tested. METHODS. A population-based survey was conducted in 1987 as part of a community-oriented primary care project that sought to define and address the causes of and burden caused by increased cardiovascular disease in an economically depressed agricultural region of New York. All of the residents living in two towns in the region who were over 16 years of age and who lived in their homes year-round were surveyed. Demographic information was obtained from the participants. as well as information about previous cholesterol testing and their cardiovascular-risk knowledge and behaviors. The serum cholesterol of each participant was measured. RESULTS. Of the 557 households contacted. 508 (91%) households participated. A total of 1063 persons over 16 years of age were surveyed. and 973 (92%) were screened for cholesterol. Overall. 24% reported prior cholesterol testing. Logistic regression analysis identified several independent factors that were associated with a reduced likelihood of ever having had a cholesterol test. These factors included: (1) age under 45 years. (2) having less than 12 years of education. (3) having an income of less than $10.000. (4) not having health insurance. (5) not having visited a physician within the previous year. and (6) practicing three or more high-risk cardiovascular behaviors. The participants' cardiovascular knowledge made no independent contribution to having had their cholesterol levels tested. CONCLUSIONS. Many of the factors that prevent cholesterol testing are socially determined. The results of this study suggest that financial and social barriers are two of the major obstacles to residents of rural communities having their cholesterol levels tested.
Risk factors for gastrointestinal ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) [published erratum appears in J Fam Pract 1991 Jul;33(1):16, Thirteen million individuals in the United States take nonsteroidal anti-inflammatory drugs (NSAIDs) chronically for the relief of pain and inflammation caused by arthritis and related conditions. NSAIDs are valuable and in many cases essential to the management of arthritis pain. Long-term use of NSAIDs. however. can cause gastrointestinal (GI) ulcers and potentially life-threatening ulcer complications. Factors such as older age (greater than or equal to 60 years). a history of peptic ulcer disease. concomitant corticosterid use. cigarette smoking. alcohol use. and high dose or multiple NSAID therapy can increase the risk of GI damage and complications in the chronic NSAID user. Physician awareness of these risk factors is crucial so that the benefits and hazards of NSAID therapy in high-risk patients can be properly weighed. When the decision is made to prescribe NSAIDs. despite the presence of risk factors for NSAID-induced ulcers. patients should be closely monitored. and. in some cases. effective prophylaxis should be initiated. This is especially important since NSAID-induced gastrointestinal ulcers can be asymptomatic. causing serious ulcer complications without warning.
Prediction of the course of pre-type I diabetes, To increase knowledge on the predictability of the onset of insulin-dependent diabetes mellitus (IDDM; type I). we followed 38 subjects less than 18 years of age who had positive results on two or more islet-cell antibody tests and one identical twin who had positive results on one islet-cell antibody test. All 39 patients had longitudinal intravenous glucose tolerance tests to determine the first-phase insulin response (FPIR). Insulin dependence has developed in 10 untreated subjects less than 18 years of age. Of the 10 subjects. insulin dependence developed in eight a mean of 4.6 months after their FPIR fell to less than 30 microU/ml and a mean of 14 months after it fell to less than 46 microU/ml. Nine of the untreated subjects had an FPIR less than 67 microU/ml on at least two occasions and became insulin dependent a mean of 19 months after the value first fell below this level (95% confidence limit = 66.4% to 100%). All but one of the 10 subjects in whom IDDM developed initially had islet-cell antibody levels of greater than 80 JDF units. Insulin autoantibody values at onset were available for 9 of the 10 subjects and were positive (greater than 39 nU/ml) in six. We conclude that the combination of positive results on two islet-cell antibody tests and two diminished FPIRs (less than 67 microU/ml) in subjects less than 18 years of age reliably predicts the onset of IDDM. These data should permit intervention studies to be planned.
Intellectual development in children with congenital hypothyroidism in relation to recommended thyroxine treatment, The relationship between the treatment serum thyroxine level and intellectual development at 2 and 6 years was investigated in 46 Norwegian children with congenital hypothyroidism identified by neonatal screening. The level of serum thyroxine during the first 2 years was positively correlated with the Mental Development Index at 2 years of age (Bayley Scales of Infant Development) and the Verbal IQ at 6 years of age (Wechsler Preschool and Primary Scale of Intelligence). Children with a mean serum thyroxine level greater than 180 nmol/L (14 micrograms/dl) during the first year had a significantly higher Mental Development Index at 2 years and Verbal IQ at 6 years than children with serum thyroxine values less than 129 nmol/L (10 micrograms/dl). Boys had a lower Mental Development Index at 2 years of age than girls (86.9 vs 105.1; p less than 0.001) and a higher frequency of elevated serum levels of thyroid-stimulating hormone during the first year (p = 0.001). No signs of toxic effects of a high hormone level at the time of IQ assessment were detected. However. high serum levels of thyroxine at ages 2 to 4 years in girls were related to lower Performance IQ at age 6 years. The results demonstrate that the serum level of thyroxine is of importance in relation to intellectual development. Thyroxine levels above the upper reference range during the first 2 years were related to best intellectual development at 2 and 6 years.
Assessment of total energy expenditure in free-living patients with cystic fibrosis, The increase in resting energy expenditure (REE) reported in patients with cystic fibrosis (CF) does not necessarily imply an increase in total energy expenditure (TEE). In this study REE was assessed with open-circuit indirect calorimetry. and free-living 24-hour TEE with the heart rate method. Thirteen patients with CF. aged 8 to 24 years. with adequate nutritional status and moderately decreased pulmonary function. were studied. They were compared with 13 healthy control subjects matched for gender. age. height. and nutritional status. Resting energy expenditure was higher in patients with CF (1512 +/- 88 kcal/day) than in control subjects (1339 +/- 76 kcal/day; p less than 0.01). whereas free-living 24-hour TEE (2345 +/- 127 kcal/day and 2358 +/- 256 kcal/day. respectively) and net mechanical work efficiency of walking on a treadmill (20.4 +/- 0.7% and 19.8 +/- 0.6%. respectively) were similar. Respiratory quotient was higher in patients with CF than in control subjects at rest (0.834 +/- 0.009 vs 0.797 +/- 0.008; p less than 0.05). and tended to remain so during physical exercise. indicating a higher contribution of carbohydrate oxidation to energy expenditure. We conclude that in free living conditions. patients with CF can compensate for their increase in REE by a reduction in spontaneous physical activities or other yet undefined mechanisms.
Evidence of hypothalamic-pituitary thyroid abnormalities in children with end-stage renal disease, Patients with end-stage renal disease may have abnormalities of growth and of gonadal and thyroid hormones. so we attempted to determine the mechanisms that may be involved in the altered thyroid function. We evaluated serum thyroid hormone levels. their changes immediately after hemodialysis. the serum thyrotropin (thyroid-stimulating hormone (TSH) response to thyrotropin releasing hormone. and the circadian pattern of serum TSH in nine children with end-stage renal disease who were between 7 1/2 years and 17 years 1 month of age. Seven patients had been receiving hemodialysis for a median of 3.3 years; the other two were receiving continuous ambulatory peritoneal dialysis. Four patients had low serum total thyroxine (T4) values. and all nine had low free T4 values. Mean concentrations of total T4. free T4. and total triiodothyronine (T3). which were significantly less than normal before hemodialysis. returned to normal levels immediately after dialysis. Postdialysis thyroid hormone increases did not correlate with the decrease in weight or the increase in hematocrit observed immediately after dialysis. All but one patient had basal TSH levels within the normal range. Three patients had a deficient TSH response to thyrotropin releasing hormone. and the TSH response was prolonged in all of them. The mean (+/- SD) nocturnal TSH surge was 50 +/- 68%. Five of the eight patients studied had a nocturnal TSH surge below the normal range (95% confidence limits 47% to 300%). Serum free T4 values correlated with the TSH nocturnal surge (r. 0.73; p less than 0.05). Our findings support the hypothesis that some patients with end-stage renal disease have central hypothyroidism.
Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria, Combined 3-methylglutaconic and 3-methylglutaric aciduria. one of the more common urinary organic acid abnormalities. has been observed in at least three clinical syndromes. We studied an additional seven patients with 3-methylglutaconic aciduria. four of whom were best categorized as having the type II syndrome. two as having an "unspecified" syndrome. and one who may have had a primary urea cycle defect. In cultured cells and autopsy tissues derived from patients with the type II and unspecified syndromes. we were unsuccessful in identifying a defect in the leucine degradative pathway distal to 3-methylcrotonyl-coenzyme A carboxylase and in the cholesterol biosynthetic pathway between 3-hydroxy-3-methylglutaryl-coenzyme A reductase and diphosphomevalonate decarboxylase. Further assessment of the cholesterol biosynthetic pathway in several patients with one of the two types of disease also provided no defined abnormality. The primary metabolic defects in the type II and unspecified syndromes remain undefined.
Neonatal opiate abstinence syndrome in term and preterm infants, Data on 178 term and 34 preterm infants born to methadone-maintained mothers were analyzed to assess the effects of neonatal opiate abstinence in infants of varying gestational ages. More mothers in the term group (79%) than in the preterm group (53%) had abused other drugs during pregnancy (p less than 0.001). Mean (+/- SD) gestational age was 39.5 weeks +/- 1.4 for term infants and 34.3 weeks +/- 2.6 for preterm infants. On the basis of a semiobjective symptom scoring scale. term infants had more severe abstinence symptoms and more prominent central nervous system manifestations than preterm infants. The severity of abstinence symptoms correlated with maternal methadone dosage in both term and preterm infants. Maternal multiple drug abuse (e.g.. heroin. cocaine) did not influence severity of abstinence symptoms in either group. More term infants (145/178) than preterm infants (20/34) required treatment for these symptoms (p less than 0.005). In 13 of 178 term infants. compared with 1 of 34 preterm infants. abstinence-related seizures developed. Peak severity occurred 1 to 2 days earlier in term than in preterm infants. A less severe abstinence syndrome in preterm infants may be due to (1) developmental immaturity of either dendritic ramifications. specific opiate receptors. or neurotransmitter function. or (2) reduced total drug exposure during the intrauterine period.
Effects of hydralazine on cardiac performance in infants receiving extracorporeal membrane oxygenation, To determine the effects of afterload reduction on cardiac performance during partial cardiopulmonary bypass. we administered hydralazine to infants who were either normotensive (n = 11) or hypertensive (n = 12) 1 hour after extracorporeal membrane oxygenation (ECMO) was begun. Load-dependent and load-independent measures of cardiac performance and indexes of cerebral blood flow were measured. Infants in both groups had similar weight. heart rate. blood pressure. and inotropic support before ECMO. Shortening fraction was normal in both groups before ECMO (47 +/- 11% vs 49 +/- 10%; p greater than or equal to 0.05). decreased during ECMO (31 +/- 18% vs 39 +/- 12%; p greater than or equal to 0.05). and did not change after administration of hydralazine (31 +/- 12% vs 37 +/- 8%; p greater than or equal to 0.05). Cardiac output was normal in both groups before ECMO (176 +/- 71 vs 157 +/- 72 ml/kg per minute; p greater than or equal to 0.05). decreased during ECMO (120 +/- 80 vs 105 +/- 64 ml/kg per minute; p greater than or equal to 0.05). and did not change after hydralazine administration. Velocity of circumferential fiber shortening. an index of contractility (circumference per second). was normal in both groups before ECMO (1.96 +/- 0.57 vs 1.90 +/- 0.43 circ/sec; p greater than or equal to 0.05). decreased during ECMO (1.18 +/- 0.83 vs 1.56 +/- 0.58 circ/sec; p greater than or equal to 0.05). and did not change after hydralazine administration. The relationship between velocity of circumferential fiber shortening and wall stress was similar in both groups before ECMO. during ECMO. and after hydralazine administration. The cerebral blood flow resistance index was similar in both groups before ECMO (0.70 +/- 0.16 vs 0.70 +/- 0.20; p greater than or equal to 0.05). decreased during ECMO (0.45 +/- 0.13 vs 0.43 +/- 0.09; p greater than or equal to 0.05). and did not change after administration of hydralazine. We conclude that hydralazine does not improve cardiac performance during ECMO.
Recombinant human erythropoietin in the anemia of prematurity: results of a placebo-controlled pilot study, Experimental and clinical data implicate inadequate erythropoietin production as an important reason that infants acquire this anemia and suggest that recombinant human erythropoietin (r-HuEPO) might be used to treat or prevent it. We therefore randomly assigned 20 small premature infants (birth weight less than or equal to 1250 gm) who were highly likely to require erythrocyte transfusions for anemia of prematurity to receive 6 weeks of treatment with either intravenously administered r-HuEPO (at a dose of 100 units/kg twice each week) or a placebo. Hematologic measurements. transfusion requirements. and growth were followed during therapy and for 6 months thereafter. Treated (EPO) and control babies did not differ with respect to weight. hematocrit. overall mean absolute reticulocyte count. calculated erythrocyte mass. or rate of growth. However. reticulocyte counts increased earlier in patients given r-HuEPO. Six of ten babies in the EPO group. and 8 of 10 assigned to the control group. received at least one erythrocyte transfusion during treatment. For all infants the amount of blood sampled for laboratory tests was strongly predictive of the volume of packed erythrocytes transfused (r = 0.890; p = 0.0001). Of nine infants who had less than 20 ml packed erythrocytes removed for laboratory tests. none of four given r-HuEPO received a transfusion. whereas three of five infants assigned to the placebo group received one. No toxic effects were attributable to r-HuEPO. and no significant changes in leukocyte or platelet counts occurred during treatment. Reticulocyte counts were correlated with simultaneous platelet counts and were inversely related to absolute neutrophil counts in both study groups. We conclude that r-HuEPO administration is safe and feasible at the dose studied. Additional controlled trials utilizing higher doses of r-HuEPO and larger numbers of patients are justified.
Ibuprofen in children with cystic fibrosis: pharmacokinetics and adverse effects, Antiinflammatory therapy with ibuprofen has been proposed to retard the progression of lund disease in cystic fibrosis (CF). The pharmacokinetics and toxicity of ibuprofen were investigated in a randomized. double-blind. placebo-controlled. 3-month dose-escalation study in 19 children with CF. 6 to 12 years of age. The subjects received orally and twice daily 300 mg of drug during the first month. 400 mg in the second month. and 600 mg in the third month. Ibuprofen pharmacokinetics and evaluation for adverse effects were performed at the beginning and end of each month. The dose of ibuprofen was increased if peak plasma concentration (Cmax) was less than 50 micrograms/ml. To preserve the blind nature of the study. the dose in matched subjects taking placebo was also increased. The subjects randomly assigned to receive ibuprofen (n = 13) completed 26 months of treatment; placebo subjects (n = 5) completed 12 months. With dose escalation. Cmax and the area under the concentration-time curve from zero to infinity significantly increased (p less than 0.01). The pharmacokinetics of ibuprofen in 13 children with CF who received 13.4 +/- 4.1 mg/kg (mean +/- SD) were compared with those in four healthy children who received a similar dose. Peak plasma concentration (48 +/- 17 micrograms/ml) was decreased by 27% (p = 0.06). the area under the concentration-time curve (6.1 +/- 1.7 mg.min/ml) was decreased by 46% (p less than 0.001). apparent total clearance (2.3 +/- 0.6 ml/min.kg-1) was increased by 77% (p less than 0.01). and apparent volume of distribution during terminal phase (291 +/- 91 ml/kg) was increased by 84% (p = 0.01) in the children with CF. Time to Cmax (66 +/- 20 minutes) and elimination half-life (92 +/- 27 minutes) were not significantly different. No subjects were withdrawn from the study because of side effects. No adverse effects could be attributed to ibuprofen. Thus ibuprofen administration has no significant toxic effects. but Cmax will need to be monitored for effective dosing in patients with CF.
Metabolic tolerance to arginine: implications for the safe use of arginine salt-aztreonam combination in the neonatal period, Two similar cohorts of low birth weight infants whose size was appropriate for gestational age randomly received either aztreonam-arginine plus ampicillin (n = 15) or gentamicin plus ampicillin (n = 15) for empiric treatment of neonatal sepsis. The regimens were infused together with glucose at greater than 5 mg/kg per minute. and immediate (4 hours) and cumulative (3 days) effects were assessed. Serum arginine and insulin values rose immediately after administration of aztreonam (containing 0.15 mmol of arginine per kilogram). but there were no changes in the gentamicin-treated cohort; no differences occurred in either cohort in serum concentrations of glucose. ammonia. potassium. creatinine. and bilirubin. After 3 days of antibiotic therapy (n = 13). the baseline serum arginine concentration was almost twice as high in the aztreonam group and showed a similar further rise and fall during the 4 hours after infusion; arginine urinary fractional excretion (normalized to creatinine clearance) decreased in the gentamicin group. The indirect bilirubin concentration rose more (p less than 0.001) in the aztreonam-treated infants (5.1 to 11.5 mg/dl (87 to 196 mumol/L] than in the gentamicin-treated infants (5.5 to 8.1 mg/dl (94 to 138 mumol/L)). Thus a modest differential bilirubin response and modestly elevated baseline serum arginine level occurred after the 3-day low-arginine doses of this study; serum ammonia and glucose concentrations were not affected. Aztreonam-arginine in neonates was well tolerated metabolically. and we believe that it can be used safely in conjunction with attention to glucose and bilirubin metabolism.
Enhanced tumor growth of both primary and established human and murine tumor cells in athymic mice after coinjection with Matrigel, Previously we found that the reconstituted basement membrane matrix Matrigel. when premixed with human small-cell lung carcinoma cells and injected subcutaneously into athymic mice. permitted tumor growth. whereas cells injected in the absence of Matrigel did not form tumors. In the present study. we examined additional cell types and determined some of the underlying mechanisms involved in the promotion of tumor formation by Matrigel. The tumor cell lines that we studied included transformed mouse Englebreth-Holm-Swarm tumor cells (T-EHS). human submandibular carcinoma A253 cells. mouse melanoma B16F10 cells. human epidermoid carcinoma KB cells. and human primary renal cell carcinoma cells. When coinjected subcutaneously with Matrigel. these cell lines formed rapidly proliferating tumors. Primary biopsy specimens of human colon carcinoma. when dispersed and coinjected with Matrigel. also formed tumors. Only A253. KB. and B16F10 cells formed small tumors in the absence of Martrigel. but a fivefold to tenfold increase in tumor size was observed in the presence of Matrigel. These data demonstrate a useful method for improving the growth of human tumors in athymic mice.
Tumor cell invasion inhibited by TIMP-2, The 72-kd type IV collagenase is a member of the collagenase enzyme family that has been closely linked with the invasive phenotype of cancer cells. Previous studies have shown that both normal cells and highly invasive tumor cells produce the 72-kd type IV procollagenase enzyme in a complexed form consisting of the proenzyme and a novel tissue inhibitor of metalloproteinases. TIMP-2. The balance between activated enzyme and available inhibitor is thought to be a critical determinant of the matrix proteolysis associated with a variety of pathologic processes. including tumor cell invasion. In the present study. we demonstrate that alteration of the metalloproteinase-metalloproteinase-inhibitor balance in favor of excess inhibitor blocks human fibrosarcoma HT-1080 tumor cell invasion of a reconstituted basement membrane. The HT-1080 cell line produces both the 72-kd and the 92-kd type IV collagenases. Alteration of the type IV collagenase-inhibitor balance was achieved by addition of free TIMP-2 or antibodies to 72-kd type IV collagenase. Native. purified TIMP-2 was inhibitory in the range of 1-25 micrograms/mL. Addition of specific antiserum against the 72-kd type IV collagenase. which did not cross-react with the 92-kd type IV collagenase. inhibited HT-1080 cell invasion to the same extent. These results suggest that metalloproteinases. in particular the 72-kd type IV collagenase. are critical for tumor cell invasion of the reconstituted basement membrane. Our findings demonstrate that addition of the endogenous inhibitor TIMP-2 is able to block invasion. Thus. we recommend initiation of in vivo studies of the therapeutic potential of TIMP-2 to block tumor cell invasion and intravasation into the circulation.
Tolerance of the carotid-sheath contents to brachytherapy: an experimental study, Tumor invasion of the carotid artery is a potential indication for brachytherapy. which delivers a high dose of irradiation to residual tumor while limiting the dose to adjacent healthy tissues. The tolerance of carotid-sheath contents to varying doses of brachytherapy. however. has not been clearly established. In order to evaluate brachytherapy effects on carotid-sheath contents. after-loading catheters were implanted bilaterally in 3 groups of 6 rabbits each (18 rabbits). Iridium 192 brachytherapy doses of either 5000 cGy (rad). 9000 cGy. or 13.000 cGy were delivered unilaterally. with the contralateral neck serving as a nonirradiated control in each animal. There were no carotid ruptures and wound healing was normal. Two animals from each group were killed at 6. 20. and 48 weeks. Even at the highest dose (13.000 cGy). nerve conduction studies performed on the vagus nerve prior to sacrifice revealed no increased latency. histologic changes were minimal. and carotid arteries were patent. These observations suggest that the carotid-sheath contents in healthy rabbits could tolerate high doses (up to 13.000 cGy) of low-dose-rate interstitial brachytherapy without complications.
Antibody response against the Epstein-Barr virus-coded nuclear antigen2 (EBNA2) in nasopharyngeal carcinoma, Specific antibody responses against the Epstein-Barr virus-coded nuclear antigen2 (EBNA2) were evaluated. Thirty-five sera from pretreatment patients of nasopharyngeal carcinoma (NPC) and 12 from healthy adults were tested. Although the anti-EBNA2 response did not show any correlation with T stage. overall stage. or histopathology. it showed a correlation with the N stage of the disease. In a serological follow-up study. 17 (85%) of 20 patients showed a correlation on the change of antibody levels to EBNA2 and clinical progression. This suggests that EBNA2 serology might represent a useful marker relative to tumor status.
Nasopharyngeal carcinoma treated at the Finsen Institute, Copenhagen 1965-1985: survival and some prognostic factors, Clinical data from 218 patients consecutively treated for nasopharyngeal carcinoma at the Finsen Institute in Copenhagen during the period 1965 through 1985 have been analyzed for factors of prognostic importance. Of the 218 patients. 47 were Greenland Inuit eskimos and 169 were white Danish. The 5-year crude survival for the entire group of patients was 30%. The two groups of patients differed with respect to the importance of different prognostic factors. Keratinizing tumors were only present in the Danish population. These patients had a highly significant worse outcome than the rest of the Danish (P less than 0.00001). Age. stage. and T classification were important prognostic factors in the Danish population. but not in the Inuit population.
Inhalation of foreign bodies in Chinese children: a review of 400 cases, A retrospective review of 400 Chinese children who had inhaled foreign bodies was undertaken. There has been a yearly increase in the total number of cases of airway foreign bodies removed in our hospital. Fifty-eight percent of the children presenting were from the countryside; 42% were townspeople. Approximately 90% of the patients were under 3 years of age. with the peak incidence of foreign body inhalation occurring between 1 and 2 years of age (57.8%). The male-female ratio was about 1.2:1. About 95% of the removed foreign bodies were organic in origin. The majority of the foreign bodies were found most often in the right bronchial tree (46%). A positive history of foreign body inhalation was obtained in 98% of the cases. Twenty-eight percent of the children presented at the hospital within 24 hours. 71% within 1 week. and 29% more than 1 week after inhaling the foreign body. The most common presenting symptoms of laryngotracheal foreign bodies were cough. wheezing. dyspnea. and hoarseness; those of bronchial foreign bodies were cough. wheezing. decreased air entry. and rhonchi. More than two-thirds of the children with larygotracheal foreign bodies had normal x-ray findings. The most common fluoroscopic findings in those children with bronchial foreign bodies were mediastinal shift (36.8%). obstructive emphysema (35.7%). and normal findings (35%). A total of 348 (87%) bronchial foreign bodies were removed by rigid bronchoscopy (81%). rod-lens bronchoscopy (5%). and spontaneous expulsion (1%); 52 (13%) laryngeal and tracheal foreign bodies were removed by direct laryngoscopy (12%) and tracheotomy (1%). A single endoscopic procedure successfully removed 92.5% of 400 foreign bodies detected in the airways. One child died during bronchoscopy. for a mortality rate of 0.25%.
Endoscopic CO2 laser excisional biopsy of early supraglottic cancer, Endoscopic CO2 laser excisional biopsy of selected early supraglottic cancer patients has been described. None of these patients experienced the perioperative morbidities of bleeding. airway obstruction. or aspiration beyond 3 or 4 days. All patients were treated with full-course standard irradiation therapy after their laser procedures. Our very preliminary data suggest that stage I and stage II patients are effectively treated with endoscopic CO2 laser excisional biopsy. whereas stage III patients should undergo open surgeries where medically possible.
Update: transmission of HIV infection during invasive dental procedures--Florida, Previous reports from an epidemiologic investigation in Florida strongly suggested that three patients (patients A. B. and C) became infected with human immunodeficiency virus (HIV) while receiving dental care from a dentist with acquired immunodeficiency syndrome (AIDS) (1.2). This report describes findings that suggest HIV was transmitted to two additional patients (patients E and G). These two patients had no other confirmed exposures to HIV. had invasive procedures performed by the dentist. and are infected with HIV strains that are closely related genetically to the strains from the three previously reported patients and from the dentist (Table 1). In addition. this report describes the epidemiologic and laboratory investigation of another HIV-infected patient of the dentist (patient F).
Program to increase the accessibility of screening mammography--Rhode Island, 1987-1988, The Rhode Island Department of Health's (RIDH) Breast Cancer Screening Program (RIBCSP) was initiated in 1987; it includes a broad promotional effort targeting women and physicians. a strong quality-assurance program. reductions in the cost of the breast cancer screening examination. and a telephone appointment and tracking system for screening examinations and follow-up care. This report describes and summarizes an evaluation of the RIBCSP.
Invited review: myoblast transfer: a possible therapy for inherited myopathies, A potential therapeutic strategy for genetic diseases is to alter the genetic constitution of the affected tissues by means of grafts of normal precursor or stem cells. Over several years. evidence has accumulated to suggest that primary diseases of skeletal muscle. such as Duchenne muscular dystrophy. may be susceptible to this approach. This review makes a critical examination of such background evidence. and also of more recent data directly addressing the concept of therapy by means of grafts of normal myogenic cells. It is concluded that the data establish the principle that such grafts effect an alteration of the genetic constitution and phenotype of skeletal muscle and. therefore. might be used to alleviate recessively inherited myopathies. Several obstacles to the therapeutic application of this method to human disease are also identified; these seem to be problems of a technical nature rather than of basic principle. and none appears insuperable.
AAEM case report #21: hemifacial spasm: preoperative diagnosis and intraoperative management, A 75-year-old man developed progressive involuntary hemifacial spasm. Electrophysiologic evidence of abnormal cross-transmission between neurons of the facial nerve was demonstrated. Electrodiagnostic studies were used to confirm the diagnosis preoperatively and determine the adequacy of vascular decompression of the facial nerve intraoperatively.
Expression of heat shock protein epitopes in tubular aggregates, Tubular aggregates may be found in a variety of conditions and have been associated with a wide range of chemical and ischemic insults. We report clinical and histological features in a case of myopathy with tubular aggregates. The structure of these tubular aggregates was examined using antibodies to cytoskeletal proteins and heat shock proteins. Epitopes of the 72 kD heat shock protein were expressed in the areas of abnormality in this case and in a case of hypokalemic periodic paralysis with tubular aggregates. Heat shock proteins have a role in the modulation of the tertiary structure of proteins and may be involved in the pathogenesis of tubular aggregates and other microtubular abnormalities in muscle.
Human acid maltase-deficient myogenic cell transformation with origin-defective SV40: characterization of a cloned line, A clonal human skeletal muscle cell line showing acid maltase deficiency (AMD) was established through the transfection of origin-defective SV40 DNA. The low acid alpha-glucosidase activity and glycogenosomes in this clone corresponded to AMD. This clone. in spite of loading glycogenososmes. was competent not only as to proliferation without contact inhibition but also as to myogenic differentiation to some extent. Dexamethasone promoted the formation by the transformant of multinucleated myotubes. which expressed acetylcholine receptors. The existence of glycogenosomes did not seem to affect the proliferation or differentiation of myoblasts. The aberrant acid alpha-glucosidase expressed in the transformed myogenic clone was shown to be biochemically identical to that in AMD fibroblasts. This transformant should be of great value for investigating the pathogenesis of AMD because of the possibility of supplying semi-permanently a uniform myogenic cell line expressing AMD.
Intraoperative recordings of spinal somatosensory evoked potentials to tibial nerve and sural nerve stimulation, Somatosensory evoked potentials (SSEPs) to stimulation of the tibial nerve at the knee (TN-K) and ankle (TN-A). and the sural nerve at the ankle (SN-A). were recorded from 3 or 4 spinal levels during surgery for scoliosis in 11 neurologically normal subjects. With stimulation of all 3 nerves. the propagation velocity along the spine was nonlinear: it was faster over cauda equina and midthoracic cord than over caudal spinal cord. Over the mid-thoracic cord. TN-K SSEP propagation was faster than that of TN-A and SN-A SSEPs. whereas over the caudal spinal cord these values were similar on stimulation of all 3 nerves. These data suggest that fast conducting second order afferent fiber systems contribute to spinal cord SSEPs evoked by stimulating both mixed and cutaneous peripheral nerves.
Why are slow and fast muscles differentially affected during prenatal undernutrition, The biceps brachii and soleus muscles (fast and slow twitch muscles. respectively) were taken from guinea-pig fetuses. undernourished via maternal dietary intake to 60% of ad lib. and examined for differences from their controls. At birth. muscle fiber number was found to be reduced by 26% in the biceps brachii but was unaltered in the soleus muscle. An examination of the muscles at ages through gestation revealed that any reduction in fiber number was associated with a reduction in the secondary/primary fiber ratio. There was a stage in soleus myogenesis at which fiber number was significantly lower than the control. The deficit was corrected by the continuation of secondary fiber hyperplasia beyond the time of usual cessation. A similar delay was found in the biceps brachii but it did not enable recovery to a full complement of fibers. The difference between the 2 muscles was thought to be related to the relative proportions of primary fibers in the muscles. primary fiber development being apparently unaffected by undernutrition in utero.
Dystrophic changes in mdx muscle regenerating from denervation and devascularization, The regenerative capacity of young mdx muscle after a denervating and devascularizing injury (DD) was examined in extensor digitorum longus (EDL) and compared with that of age-matched control mouse EDL. DD of the right EDL was produced at the age approximating the onset of dystrophy in the mdx model. and mice recovered for 2 weeks. Contralateral unoperated EDLs from mdx and control mice served as internal controls for histopathology. myofiber cross-sectional area (CSA). and ultrastructure of fiber regeneration in DD-EDL. Mdx DD-EDL were composed of small. uniformly mature myofibers with mostly peripheral nuclei. This contrasted with control DD-EDL in which fibers were centrally nucleated. In addition. the unoperated mdx EDL exhibited the central nucleation of spontaneous recovery from dystrophy. The CSA distribution of mdx DD-EDL myofibers was significantly shifted toward smaller CSA compared with unoperated mdx EDL. although mean CSA did not differ between the two mdx muscle groups. The CSA distribution of control DD-EDL was significantly different and shifted toward smaller CSA from both unoperated control EDL and from mdx DD-EDL distributions. Ultrastructural features of dystrophy were present in both mdx DD-EDL and in the unoperated mdx EDL. although they appeared more prevalent in the latter. These results suggest that short-term plasticity of mdx muscle recovery from imposed injury may be greater than that of normal muscle in establishing a regenerating fiber population.
Recovery of motor function after spinal-cord injury--a randomized, placebo-controlled trial with GM-1 ganglioside, BACKGROUND. Spinal-cord injury is devastating; until recently. there was no medical treatment to improve recovery of the initial neurologic deficit. Studies in animals have shown that monosialotetrahexosylganglioside (GM-1) ganglioside enhances the functional recovery of damaged neurons. METHODS. A prospective. randomized. placebo-controlled. double-blind trial of GM-1 ganglioside was conducted in patients with spinal-cord injuries. Of 37 patients entered into the study. 34 (23 with cervical injuries and 11 with thoracic injuries) completed the test-drug protocol (100 mg of GM-1 sodium salt or placebo intravenously per day for 18 to 32 doses. with the first dose taken within 72 hours of the injury) and a one-year follow-up period. Neurologic recovery was assessed with the Frankel scale (comprising five categories) and the American Spinal Injury Association (ASIA) motor score (a scale of scores from 0 to 100. derived from strength tests of 20 specific muscles. each scored from 0 to 5). RESULTS. There was a significant difference between groups in the distribution of improvement of Frankel grades from base line to the one-year follow-up (improvement of 0. 1. 2. and 3 grades in 13. 4. 1. and 0 patients. respectively. in the placebo group and 8. 1. 6. and 1 patients. respectively. in the GM-1 group; P = 0.034 by the Cochran-Mantel-Haenszel chi-square test). The GM-1-treated patients also had a significantly greater mean improvement in ASIA motor score from base line to the one-year follow-up than the placebo-treated patients (36.9 vs. 21.6 points; P = 0.047 by analysis of covariance with the base-line ASIA motor score as the covariate). An analysis of individual muscle recoveries revealed that the increased recovery in the GM-1 group was attributable to initially paralyzed muscles that regained useful motor strength rather than to strengthening of paretic muscles. CONCLUSIONS. This small study provides evidence that GM-1 enhances the recovery of neurologic function after one year. A larger study must be conducted. however. before GM-1 is considered efficacious and safe in treating spinal-cord injury.
Sudden death in infants sleeping on polystyrene-filled cushions, BACKGROUND. Infants are at risk for both the sudden infant death syndrome (SIDS) and accidental suffocation. On postmortem examination. however. it is difficult to distinguish one from the other without information from the scene of death. Healthy infants are assumed to be able to turn their heads and. if not otherwise restrained. to obtain fresh air. We assessed this assumption in an investigation of infant deaths that occurred during sleep on cushions filled with polystyrene beads. METHODS. We obtained data on 25 deaths from the U.S. Consumer Product Safety Commission. We also used mechanical and animal models to study physiologic aspects of ventilation relevant to these results. by simulating the effects on an infant of breathing into a cushion. We measured the effects of softness. malleability (molding of the cushion about an infant's head). airflow resistance. and rebreathing of expired gases. RESULTS. All 25 study infants were prone when found dead. and at least 88 percent were face down with nose and mouth obstructed by the cushion. SIDS was the diagnosis in 19 of the 23 infants who underwent autopsy. Our findings show. however. that the cushion would have limited movement of the infant's head to obtain fresh air. and the amount of rebreathing we estimated to have occurred in the infants was lethal in a rabbit model. CONCLUSIONS. Accidental suffocation by rebreathing was the most likely cause of death in most of the 25 infants studied. Consequently. there is a need to reassess the cause of death in the 28 to 52 percent of the victims of SIDS who are found with their faces straight down. Safety regulations setting standards for softness. malleability. and the potential for rebreathing are needed for infant bedding.
Impairment of mitochondrial transcription termination by a point mutation associated with the MELAS subgroup of mitochondrial encephalomyopathies, Defects in mitochondrial DNA (mtDNA) are associated with several different human diseases. including the mitochondrial encephalomyopathies. The mutations include deletions but also duplications and point mutations. Individuals with MELAS (mitochondrial myopathy. encephalopathy. lactic acidosis and stroke-like episodes) carry a common A-to-G substitution in a highly conserved portion of the gene for transfer RNA(Leu(UUR)). Although the MELAS mutation may be comparable to the defect in the tRNA(Lys) gene associated with MERRF (myoclonus epilepsy associated with ragged-red fibres). it is also embedded in the middle of a tridecamer sequence necessary for the formation of the 3' ends of 16S ribosomal RNA in vitro. We found that the MELAS mutation results in severe impairment of 16S rRNA transcription termination. which correlates with a reduced affinity of the partially purified termination protein for the MELAS template. This suggests that the molecular defect in MELAS is the inability to produce the correct type and quantity of rRNA relative to other mitochondrial gene products.
Demethylation of CpG islands in embryonic cells, DNA in differentiated somatic cells has a fixed pattern of methylation. which is faithfully copied after replication. By contrast. the methylation patterns of many tissue-specific and some housekeeping genes are altered during normal development. This modification of DNA methylation in the embryo has also been observed in transgenic mice and in transfection experiments. Here we report the fate in mice of an in vitro-methylated adenine phosphoribosyltransferase transgene. The entire 5' CpG island region became demethylated. whereas the 3' end of the gene remained modified and was even methylated de novo at additional sites. Transfection experiments in vitro show that the demethylation is rapid. is specific for embryonic cell-types and affects a variety of different CpG island sequences. This suggests that gene sequences can be recognized in the early embryo and imprinted with the correct methylation pattern through a combination of demethylation and de novo methylation.
Preclinical detection in studies of the etiology, natural history, and treatment of Parkinson's disease, The development of reliable preclinical detection procedures for idiopathic Parkinson's disease may be the fundamental advance required for the establishment of the cause. the natural history. and ultimately. the prevention of this neurodegenerative disorder. The usefulness of these preclinical markers in efforts to better understand the etiology and development of this disorder will relate to whether they are direct measures of dopamine production or indirect measures such as metabolic changes or comorbidity. whether they can be used in the first or later decades of life. whether they are invasive. and whether they are expensive and sophisticated or simple and cheap. An overview of the criteria for evaluation of the utility of specific markers. as well as an assessment of the importance of early markers in future research. is presented.
Xenobiotic enzyme profiles and Parkinson's disease, Xenobiotic enzymic systems have been studied in Parkinson's disease. Platelet monoamine oxidase-B activity is increased by the use of phenylethylamine but decreased by the use of dopamine as substrate. Enzymes involved with sulfur oxidation and methylation are underactive.
Catechol metabolites in the cerebrospinal fluid as possible markers in the early diagnosis of Parkinson's disease, This paper is a preliminary report of work aiming to elucidate the possible use of 5-S-cysteinyl metabolites of catechols in the cerebrospinal fluid as markers in the early diagnosis of Parkinson's disease (PD). The rationale for this approach is the hypothesis that this disorder is caused by a failure of antioxidative mechanisms to prevent the excessive autoxidation of dopamine and other catechols that yields highly reactive and cytotoxic semiquinones and quinones. 5-S-cysteinyl adducts of these quinones have been detected in human brains. analyzed postmortem. and appear to be formed at an increased rate in elderly individuals. who show an increased loss of dopaminergic neurons.
The potential use of a dopamine neuron antibody and a striatal-derived neurotrophic factor as diagnostic markers in Parkinson's disease, The cerebral spinal fluid (CSF) of patients with Parkinson's disease (PD) contains an antibody that immunocytochemically reacts with dopamine (DA) neurons in the substantia nigra (SN). This antibody was found in 78% of the CSF samples taken from patients with clinical PD. In contrast. only 3% of the CSF samples taken from control patients or patients with neurologic symptoms other than PD possessed this antibody. The production of this antibody might contribute to disease progression but does not appear to be the etiologic factor responsible for PD. In other experiments. concentrates of the CSF of patients with PD enhanced growth of mesencephalic cultures relative to control CSF. Both the antibody and the growth-promoting activity found in CSF are associated with degeneration of the SN and might therefore be useful as potential diagnostic markers for PD.
Preclinical Parkinson's disease: detection of motor and nonmotor manifestations, The advent of possible protective therapies for Parkinson's disease has created a need for methods of diagnosing the disease before the clinical features become fully evident. As a number of motor and nonmotor manifestations of the disease emerge months to years before a diagnosis can be made. a battery of clinical tests might be sufficient to identify individuals at an earlier stage than is currently possible using the standard history and physical examination. A list of questions regarding possible risk factors. specific symptoms. and observations of family members could be combined in a self-administered questionnaire that might identify individuals with a high probability of early. but otherwise undiagnosable. Parkinson's disease. Identification of subtle motor features is another possible screening method. For example. handwriting and speech are commonly affected prior to diagnosis; thus. automated analysis of these motor actions might also provide detection of incipient disease.
Odor identification deficit of the parkinsonism-dementia complex of Guam: equivalence to that of Alzheimer's and idiopathic Parkinson's disease, Olfactory dysfunction is among the first signs of Alzheimer's disease (AD). idiopathic Parkinson's disease (PD). and the parkinsonism-dementia complex (PDC) of Guam. We have recently demonstrated that the odor identification and detection deficits of patients with PD are equivalent to those of patients with mild AD when subtle differences in cognitive function are statistically controlled for by analysis of covariance. In contrast. patients with progressive supranuclear palsy (PSP) and patients with 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP)-induced parkinsonism evidence olfactory function much more similar to that of normal controls. In the present study. we administered the University of Pennsylvania Smell Identification Test and the Picture Identification Test to 24 patients with early signs of the PDC of Guam and statistically compared their test scores to those of 24 early-stage AD and 24 early-stage PD patients of similar age and gender from the United States mainland. Although the PDC group evidenced slightly more difficulty in identifying pictures than did the other 2 groups. the odor identification deficit associated with this disorder was of the same magnitude as that observed in AD and PD. suggesting that olfactory testing cannot be used to distinguish among these 3 diseases and that the olfactory dysfunction of these disorders may reflect a common neurologic substrate.
Abnormal liver enzyme-mediated metabolism in Parkinson's disease: a second look, If toxicant exposure contributes to the cause of Parkinson's disease. poor function of detoxifying enzymes could increase vulnerability for Parkinson's disease. Although no hepatic enzyme system has been shown universally to be dysfunctional in Parkinson's disease patients. several have been suggested to be dysfunctional in subgroups. such as those with young age at disease onset. Specific enzymes implicated include several P450 enzymes. most notably P450 IID6. and cysteine dioxygenase. If hepatic enzyme abnormalities contribute to the development of Parkinson's disease. molecular genetic techniques may allow the development of screening tests to identify at-risk subjects in order to intervene with protective therapies.
Dexamethasone adjunctive treatment for tuberculous meningitis, During a 5-year period. 280 of 2010 patients admitted to the meningitis ward of a referral hospital in Cairo. Egypt. were clinically diagnosed as having tuberculous meningitis and were treated with either antituberculous chemotherapy and dexamethasone or antituberculous chemotherapy alone. Fatality rates and neurologic sequelae were compared for the 2 treatment groups in the 160 patients who had cerebrospinal fluid cultures positive for Mycobacterium tuberculosis. The overall mortality rate of 51% reflects the delay in receiving appropriate therapy (79% with symptoms for more than 2 weeks) and the severity of illness on admission (56% in coma. 39% drowsy). The fatality rate was significantly lower in the group receiving dexamethasone (43% vs. 59%. P less than 0.05). particularly in the drowsy patients (15% vs. 40% P less than 0.04). and in patients surviving long enough to receive at least 10 days of treatment (14% vs. 33%. P less than 0.02). Development of neurologic complications after initiation of therapy (4 vs. 10) and permanent sequelae (6 vs. 13) were significantly lower in the dexamethasone-treated group (P less than 0.02).
Outbreak of neonatal listeriosis associated with mineral oil, In June. 1989. an outbreak of nosocomial listeriosis occurred in Costa Rica. Listeria monocytogenes was isolated from 9 ill infants 4 to 8 days old who were born after the delivery of an infant with early onset listeriosis. One nosocomial infection was fatal. 2 required mechanical ventilation and 1 resulted in hemiparesis. A higher proportion of cases than other infants born during the outbreak were delivered by cesarean section (55% vs. 24%. P = 0.04). Compared with the mothers of 36 random controls. case mothers were more often primiparous (odds ratio. 6.2. P = 0.03) or received general anesthesia before delivery (odds ratio. 4.4. P = 0.09). All infants were bathed with mineral oil from a multidose container. Culture of the oil by cold enrichment grew L. monocytogenes 4b with the same electrophoretic enzyme type as the outbreak strain. We hypothesize that aspiration of contaminated oil may have resulted in systemic listeriosis. General anesthesia may have increased the risk of aspiration. Lung tissue from the infant who died showed lipid-laden macrophages consistent with oil aspiration and had evidence of L. monocytogenes DNA detected by polymerase chain reaction. This is the first nosocomial outbreak of listeriosis in which a common source suggested epidemiologically was microbiologically confirmed. The high attack rate (greater than 200 times the United States rate of perinatal listeriosis) emphasizes the susceptibility of healthy neonates to L. monocytogenes. The results of our study led to the discontinuation of the use of mineral oil for bathing neonates in Costa Rica.
Aseptic meningitis as a complication of mumps vaccination, In 1989 a nationwide surveillance of neurologic complications after the administration of mumps vaccine was conducted in Japan. based on the notification of cases and the testing of mumps viruses isolated from cerebrospinal fluid for their relatedness to the vaccine by nucleotide sequence analysis. Among 630.157 recipients of measles-mumps-rubella trivalent (MMR) vaccine containing the Urabe Am9 mumps vaccine. there were at least 311 meningitis cases suspected to be vaccine-related. In 96 of these 311 cases. mumps virus related to the vaccine was isolated from cerebrospinal fluid. The unusually high incidence may have been partly a result of the adverse media publicity of the problem at the time of surveillance. We analyzed clinical features of 165 and 27 laboratory-confirmed mumps vaccine-related meningitis cases that occurred among the recipients of MMR and monovalent mumps vaccines. respectively. during a 1-year period after the introduction of MMR vaccine. The incidence of vaccine-related meningitis was similar among the recipients of MMR and monovalent Urabe Am9 mumps vaccines. Meningitis was generally mild and there were no sequelae from the illness. The complication was more frequent among male than among female children.
Eradication of poliomyelitis: progress in the Americas, In the span of 5 years since the eradication initiative was launched and only 3 years since external funds were made available. PAHO has been able to develop and implement a comprehensive program strategy for polio eradication that includes the following components: achievement and maintenance of high immunization levels (which include the supplemental strategies of national immunization days and mop-up operations); effective surveillance to detect all new cases; and a rapid response to the occurrence of new cases. Despite yearly increases in the number of cases of acute flaccid paralysis reported to the surveillance system. a decline in reported confirmed cases of polio has occurred since 1986 to record low levels in 1989. Cases in 1989 were reported from only 0.7% of the counties in the Americas. The occurrence of 24 wild-type virus isolates in 1989 were limited to only three geographic areas: northwestern Mexico; the northern Andean Region; and northeastern Brazil. At this writing the clock is ticking with only 3 months left to achieve the goal of interrupting transmission by the end of 1990. If the current level of effort is sustained and special efforts are directed at the remaining foci of infection. the eradication of the transmission of wild-type poliovirus from the Americas can be achieved. Continued external financial support will be critical if the effort is to succeed. The prospect of poliomyelitis eradication in the Americas led the 41st World Health Assembly of WHO to adopt a resolution in May. 1988. to eradicate the indigenous transmission of wild-type poliovirus from the world by the year 2000.
The Jarisch-Herxheimer reaction in leptospirosis: possible pathogenesis and review, The importance of treating leptospirosis with penicillin is emphasized by two case reports and a review documenting the occurrence of the Jarisch-Herxheimer reaction (JHR) in patients with this bacterial infection. The JHR is significant both as a cause of morbidity and mortality and as an indication of the therapeutic efficacy of penicillin. The possible etiology of the JHR is discussed. and comparisons with the changes occurring in septic shock are made; a study of either condition facilitates the understanding of the other. Tumor necrosis factor is hypothesized to play a key role in both. Current treatment of the JHR consists of general clinical support. Specific measures such as oxpentifylline therapy may play a role in the future.
Neisseria lactamica meningitis following skull trauma, A woman developed meningitis due to Neisseria lactamica in association with a cribriform plate fracture. Cerebrospinal fluid antigen tests for Neisseria meningitidis were negative. The patient recovered with intravenous penicillin therapy. N. lactamica can be rapidly distinguished from N. meningitidis by the hydrolysis of ONPG (o-nitrophenyl-beta-D-galactopyranoside). In contrast to N. meningitidis and Neisseria gonorrhoeae. N. lactamica lacks virulence properties. As 100% of N. lactamica strains are susceptible to penicillin and all three previously described patients with N. lactamica meningitis have recovered with penicillin treatment. the reason for distinguishing the organisms in this context is primarily to prevent unnecessary anxiety and prophylaxis among contacts.
Four decades of shigellosis in Israel: epidemiology of a growing public health problem, Despite the improved standard of living in Israel. shigellosis remains a common disease. Examination of trends in the incidence of shigellosis in Israel between 1951 and 1987 showed a period of declining rates followed by an increase in the reported incidence beginning around 1969. This increase was mainly due to Shigella sonnei; rates of infection with Shigella flexneri remained relatively constant. Trends showed marked differences between age groups and between ethnic groups. In comparison. the rates in the United States--much lower than those in Israel--began to decline in the early 1950s and have remained low. The incidence in Israel is now about 20 times higher than that in the United States. Thus shigellosis remains a major and growing public health problem in Israel. a country that has enjoyed a dramatic improvement in basic sanitary services and infrastructure over the past few decades. This disturbing finding lends urgency to efforts to control the disease.
Cryptosporidium in asymptomatic children, Recent reviews state that cryptosporidiosis is a disease particularly of young children. but we have found the opposite age distribution. with no cases in children less than 5 years old. No Cryptosporidium species was detected in fecal samples obtained from 423 healthy preschool children. for a prevalence of less than 0.24%. When these results were combined with our previous data (from a study of diagnostic stool samples). the prevalence of Cryptosporidium among children less than 5 years of age in the Helsinki area was calculated to be less than 0.18%. The worldwide prevalence of Cryptosporidium among asymptomatic children is less than 0.5% if a few exceptional localities with high prevalences (which probably have a local explanation) are excluded from the calculations. Since the Helsinki area turned out to be no exception. the age distribution of symptomatic cryptosporidiosis also needs further study that would take into account simultaneous asymptomatic carrier rates and a significant local variation.
Human infection with B virus following a needlestick injury, A 26-year-old veterinary technician who became infected with B virus at the site of a needlestick injury is described. After the patient was treated with intravenous acyclovir. all cultures became negative for B virus and have remained so during treatment with oral acyclovir. The literature on infections due to B virus in humans is reviewed. and a detailed discussion of the various aspects of this simian herpesvirus is presented.
Relation of the pathogenesis of human immunodeficiency virus infection to various strategies for its control, This paper reviews functionally important insights into the pathogenesis of human immunodeficiency virus (HIV) infection. The major sequela of this infection is early and progressive involvement of the immune system. with widespread immune dysfunction. This pathogenetic feature has a major impact on strategies for control of the infection. The immunosuppression caused by the virus leads to higher levels of viral replication and enhanced potential for development or selection of variant viruses. including forms that are more virulent or even drug resistant. Therefore. control of HIV infection and disease may require antiviral agents and CD4 receptor competitors as well as recombinant DNA-derived lymphokines and subunit vaccine immunotherapies. To be successful. such therapies must work to counter infection in monocytes and nonlymphoid cells as well as in T4 lymphocytes. Because many limbs of the immune system are affected by HIV infection. the complexities of this pathogen can be unraveled only by the careful study of immune functions during the disease and of effective interventions to control infection and disease and to restore immune functions.
The English sweating sickness, with particular reference to the 1551 outbreak in Chester, During the 15th and 16th centuries in England. there were five epidemics of a disease characterized by fever and profuse sweating and associated with high mortality. This disease became known as the English sweating sickness. The first epidemic occurred during 1485 at around the time of Henry Tudor's victory at Bosworth Field. and the last took place during the reign of Edward VI in 1551. The disease tended to occur during the summer and early autumn. The relatively affluent male adult population. particularly the clergy. seemed to suffer the highest attack rates. and. except in one epidemic. the disease appears to have attacked only individuals native to England. Despite the reputation of the English sweating sickness as a disease with a high fatality rate. records of burials and wills in Chester suggest that the 1551 epidemic did not have a marked effect on the demographics of the population. The etiologic agent is still unknown. although an enterovirus seems to this author to be the most likely pathogen.
Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease, Each year in the United States. 30.000 to 40.000 infants are born congenitally infected with cytomegalovirus (CMV). and more than 9.000 of these children suffer permanent sequelae. The purpose of this workshop was to present and discuss current information on the epidemiology. diagnosis. treatment. and prevention of CMV disease in mothers and their infants. The participants concluded that congenital CMV disease is a significant public health problem that. to date. has been largely ignored. They also agreed that certain child-rearing practices. such as the common use of day-care centers and breast-feeding. have changed the epidemiology of CMV in the United States and that the next decade may bring an increase in congenital CMV disease in certain groups. Therefore. a national system for surveillance of congenital CMV disease was established; its goals are to characterize trends over time. to identify risk groups. and to lay the groundwork for evaluation of future intervention programs. In addition. the surveillance system will be used to educate the medical and lay communities about congenital CMV disease and to facilitate collaborative efforts in research.
Corneal ulcer caused by Pseudomonas pseudomallei: report of three cases, We report three cases of corneal ulcer caused by Pseudomonas pseudomallei. In all cases corneal trauma preceded the development of extensive ulcers. subconjunctival abscesses. and hypopyon. Treatment for a total of 8 weeks with topical and/or parenteral ceftazidime followed by amoxicillin-clavulanic acid produced resolution of infection in each case.
Surgical intensive care unit resource use in a specialty referral hospital: I. Predictors of early death and cost implications, The rationing of medical care prioritizes the need for early predictors of death in the surgical intensive care unit (SICU). We prospectively studied 100 consecutive SICU admissions. looking for predictors of early death in the SICU and the cost implications of these findings. Serial APACHE II scores on days 1. 3. and 5 were subjected to multinomial logistic regression analysis to determine significant predictors of death in the SICU on day 1. Survivors had significantly lower (p less than 0.05) mean day-1 APACHE II scores than had nonsurvivors (13.6 vs 22.1). Half of the patients with scores greater than 18 died. and all patients with scores on day 1 of 25 or greater died. Significant predictors of death on SICU day 1 were APACHE II scores. Acute Physiology Score. Glasgow Coma Score. creatinine level. and Chronic Health Evaluation Score. Forty-one patients had been transferred from community hospitals as a results of acute illness; this population accounted for two thirds of the deaths in the SICU. Ten of 18 nonsurvivors were predicted on day 1. with these patients incurring a total cost of approximately $1 million. If therapy had been modified on days 5. 10. or 15. the potential cost savings would have been $340.000. $240.000. or $140.000. respectively. Integration of the results of this study into the management decision-making process and treatment guidelines may reduce the cost of care in the SICU.
Irresectable hepatoma treated by intrahepatic iodized oil doxorubicin hydrochloride: initial results, In this study we describe the investigation and treatment of 14 patients with primary hepatocellular carcinoma. Patients were treated with intra-arterial infusion of iodized oil and doxorubicin hydrochloride. Five of these patients were alive after 1 year. Twelve patients showed a fall in alpha-fetoprotein. and in seven of these patients. the fall in alpha-fetoprotein was greater than 50%.
Alterations in circulating lymphocyte number and function after circulation through colorectal carcinomas, Thirty-six patients undergoing curative resection for colorectal cancer were studied to determine the effect of the tumor on lymphocytes circulating through it. In the venous blood draining the tumor. there was an increased percentage of natural killer (NK) cells (p = 0.001). no difference in overall NK cell function. and decreased T-lymphocyte activation (p = 0.035) and proliferation (p = 0.002) compared with the lymphocytes in the arterial blood supplying the tumor. There were no significant differences in the control group of 16 patients. Local effects of colorectal cancer may include the ability to down-regulate T and NK cell function while increasing the number of NK cells. Means of enhancing antitumor activity therapeutically in an adjuvant setting. possibly through the portal vein during surgery. need to be considered. especially in the light of the immunosuppressive effects of surgery.
Pylorus and antroseromuscular flap-preserving gastrectomy--a new type of reconstruction after subtotal gastrectomy for treatment of gastroduodenal ulcer: clinical and experimental study, To avoid motility disturbances after Billroth gastrectomy. the authors designed pylorus and antroseromuscular flap-preserving subtotal gastrectomy (PAFPG). Results showed that gastric motility and emptying time of dogs after PAFPG were close to normal. PAFPG was applied to 125 consecutive patients with gastroduodenal ulcers (gastric ulcer. 15 patients; duodenal ulcer. 94 patients; and combined ulcers. 16 patients) confirmed by barium examination and fibro-gastroendoscopy. All patients recovered smoothly. none of them had postoperative complication. Gastric acid output reduction rates were as follows: basal acid output. 85.05% +/- 8.13%; maximal acid output. 81.76% +/- 10.85%; peak acid output. 81.42% +/- 10.15%. The incidence of postoperative enterogastric reflux (endoscopically) and the concentration of cholic acids in gastric juice were significantly lower in patients after PAFPG than after Billroth I or II gastrectomy. Results suggest that PAFPG reduced gastric acid outputs definitely and overcame adverse motility consequences after Billroth I or II gastrectomy desirably.
Interleukin-6 and its relation to the humoral immune response and clinical parameters in burned patients, The cytokine interleukin-6. which has been shown to be increased in patients with burn injuries. is produced by activated monocytes and endothelial cells and has many in vitro activities. including stimulation of acute-phase protein synthesis in hepatocytes. immunoglobulin synthesis in B lymphocytes. and stimulation of growth of megakaryocytes. In 13 patients with a mean of 31% full-thickness burns. we studied the relation of serum interleukin-6 to clinical parameters and parameters of the acute-phase response and immunoglobulin production. Interleukin-6 was already elevated within hours after the injury was sustained. and it remained elevated for several weeks. All components of the acute-phase response were observed: fever. tachycardia. leukocytosis with an associated left shift. elevation of C-reactive protein and alpha 1-antitrypsin. and a decrease in albumin levels. In the second week after burn injury. immunoglobulin M levels peaked. followed by a prolonged elevation of immunoglobulin G levels. Thrombocyte counts initially decreased and rebounded to supranormal levels after 2 weeks. Interleukin-6 levels were positively correlated with acute-phase responses. We believe that the production of interleukin-6 induces the synthesis of acute-phase proteins. High interleukin-6 levels may also be an etiologic factor in the marked immunoglobulin response observed. Likewise. the relation between the megakaryocyte-promoting activity of interleukin-6 and the rebound thrombocytosis requires further investigation.
Management of anterior and posterior epistaxis, Management of epistaxis is directly related to the site of the bleeding. Anterior nosebleeds are the least dangerous and the most common. especially among children. Sinus disease. colds. allergies. abrupt temperature changes and dry heat produce fragile and hyperemic nasal mucosa that bleeds easily with nose blowing or mild abrasion. Anterior epistaxis can be reached easily and stopped by pinching the nostrils. applying silver nitrate cautery or lightly packing the anterior nose. Posterior epistaxis may be severe and may be more difficult to locate and control. Occurring more often in the elderly. posterior nosebleeds are frequently associated with hypertension. atherosclerosis and conditions that decrease platelets and clotting function. Visualization of the bleeding site is enhanced by proper positioning of the patient. use of topical vasoconstricting anesthesia and suctioning. Anterior and posterior nasal packing. hospitalization. antibiotics and close follow-up may be required to control posterior nosebleeds.
Hypopituitarism, The pituitary regulates the body's endocrine system. including the thyroid gland. adrenal cortex. ovaries and testes. through the release of numerous hormones. Pituitary function. in turn. is regulated through complex feedback loops involving the hypothalamus and the target endocrine glands. Hypopituitarism may result from multiple causes. including primary and metastatic cancer. ischemic and granulomatous disease. infection. developmental abnormalities and trauma. which may affect the gland itself (primary hypopituitarism) or the hypothalamus (secondary hypopituitarism). Depending on the anatomic lesion. patients with hypopituitarism may present with signs or symptoms of multiple endocrine abnormalities. such as hypothyroidism. adrenal insufficiency. diabetes insipidus. hypoglycemia. sexual dysfunction and growth retardation. A thorough clinical history. detailed examination. laboratory evaluation of endocrine function and radiographic views of the pituitary and sella turcica can suggest the diagnosis and etiology. Treatment. usually lifelong. may include hormone replacement and medical or surgical correction of the underlying disease.
Nongenital warts: classification and treatment options, Common. plantar and flat warts are the primary classes of nongenital warts. Although spontaneous remission does occur. all warts should be treated to avoid spreading. Common warts often develop in the periungual region of the fingers. This type of wart generally can be removed with cryotherapy. topical application of salicylic acid or occlusive taping. Plantar warts are found over pressure points of the heel or metatarsal heads. They are also treated with cryotherapy or salicylic acid. Flat warts are commonly seen on the dorsum of the hands or on the face. These warts are best treated with topical retinoids. Immunotherapies are being developed.
Dual diagnoses: psychiatric syndromes in alcoholism and drug addiction, Concomitant psychiatric illness and alcohol or drug addiction are difficult to diagnose and treat. Alcohol and drug problems are significantly underdiagnosed in medical and psychiatric populations. while psychiatric disorders may be underdiagnosed in alcohol- and drug-addicted patients. An understanding of addiction and psychiatric disorders is essential for successful treatment of the comorbidity of these disorders. Alcohol or drug addiction frequently produces significant psychiatric syndromes. which may resolve during periods of sobriety. The combination of addiction and established psychiatric disorders is less common.
Neuroleptic drug use in the nursing home: the impact of OBRA, In 1990 the new OBRA legislation affecting nursing home care went into effect. This legislation and the regulations written to interpret it introduce specific rules concerning the use of neuroleptic medication in the care of nursing home residents. This article examines this legislation and the new regulations. and reviews neuroleptic drug use. including appropriate indications. side effects and prescribing guidelines. Physicians who care for nursing home patients should be familiar with the regulations.
Comparison of rubidium-82 positron emission tomography and thallium-201 SPECT imaging for detection of coronary artery disease, The diagnostic performance of rubidium-82 (Rb-82) positron emission tomography (PET) and thallium-201 (Tl-201) single-photon emission-computed tomography (SPECT) for detecting coronary artery disease was investigated in 81 patients (52 men. 29 women). PET studies using 60 mCi of Rb-82 were performed at baseline and after intravenous infusion of 0.56 mg/kg dipyridamole in conjunction with handgrip stress. Tl-201 SPECT was performed after dipyridamole-handgrip stress and. in a subset of patients. after treadmill exercise. Sensitivity. specificity and overall diagnostic accuracy were assessed using both visually and quantitatively interpreted coronary angiograms. The overall sensitivity. specificity and accuracy of PET for detection of coronary artery disease (greater than 50% diameter stenosis) were 84. 88 and 85%. respectively. In comparison. the performance of SPECT revealed a sensitivity of 84%. specificity of 53% (p less than 0.05 vs PET) and accuracy of 79%. Similar results were obtained using either visual or quantitative angiographic criteria for severity of coronary artery disease. In 43 patients without prior myocardial infarction. the sensitivity for detection of disease was 71 and 73%. respectively. similar for both PET and SPECT. There was no significant difference in diagnostic performance between imaging modalities when 2 different modes of stress (exercise treadmill vs intravenous dipyridamole plus handgrip) were used with SPECT imaging. Thus. Rb-82 PET provides improved specificity compared with Tl-201 SPECT for identifying coronary artery disease. most likely due to the higher photon energy of Rb-82 and attenuation correction provided by PET. However. post-test referral cannot be entirely excluded as a potential explanation for the lower specificity of Tl-201 SPECT.
Dobutamine digital echocardiography for detecting coronary artery disease, To assess the value of dobutamine echocardiography for detecting coronary artery disease (CAD). 70 men (mean age 62 +/- 8 years) presenting for coronary angiography were prospectively studied. Dobutamine (2.5 to 40 micrograms/kg/min) was infused in 3-minute stages. Digital echocardiograms were recorded on-line at baseline. during low- and high-dose dobutamine infusion. and at recovery. An echocardiogram positive for CAD was defined as one showing a new wall motion abnormality induced by dobutamine. Compared with coronary angiography. the overall sensitivity of dobutamine echocardiography for detecting CAD was 86%. specificity 95% and accuracy 89%. The sensitivity for detecting 3-vessel CAD was 100%. 89% for 2-vessel and 69% for 1-vessel CAD. The accuracy of predicting multivessel disease by 2 methods was 71% and 84%. respectively. Heart rate at the echocardiographic ischemic threshold was lower in patients with 3- and 2-vessel CAD versus 1-vessel CAD (89 +/- 17. 95 +/- 18 and 118 +/- 18 beats/min. respectively. p less than 0.01); rate-pressure product was also lower in patients with 3- and 2-vessel CAD versus 1-vessel CAD (12.7 +/- 3.6. 13.7 +/- 2.8 and 18.9 +/- 44 x 10(3) beats/min x mm Hg. respectively. p less than 0.01). Heart rate was the most important physiologic determinant of ischemia induced by dobutamine. There were no major complications during the study. Thus. dobutamine digital echocardiography is an excellent test for identifying CAD and should be beneficial in patients unable to exercise.
Usefulness of esmolol in unstable angina pectoris. European Esmolol Study Group, Esmolol is a new cardioselective beta blocker with unique pharmacokinetic properties resulting in a half-life of only 9 minutes. The present multicenter. randomized. placebo-controlled study examined the hemodynamic and antiischemic effects of this compound given as an adjunctive to conventional medical therapy in 113 patients with unstable angina. Fifty-nine patients received esmolol and 54 received matching placebo infusions. Esmolol was titrated in a step-wise manner at dosages of 2 to 24 mg/min until a 25% reduction in the double product was achieved; thereafter. esmolol was continuously infused for up to 72 hours. Esmolol caused a significant and persistent decline in heart rate and blood pressure throughout the entire study period. Clinical events. such as development of acute myocardial infarction or the need for urgent revascularization. occurred in 3 esmolol compared with 9 placebo patients (p = 0.06). There was also a trend toward reduction of silent ischemia as judged by Holter monitoring (mean [+/- standard deviation] duration/patient/24 hours. 21 +/- 81 minutes in the esmolol and 35 +/- 128 minutes in the placebo groups). Esmolol-related adverse effects were mostly cardiovascular in origin and could be managed promptly by downward dose titration or cessation of drug infusion. Thus. esmolol appears to be a safe and effective drug for patients with unstable angina because it permits a large degree of flexibility in adapting the desired level of beta blockade to the patient's changing clinical presentation.
Effects of hemoperfusion during percutaneous transluminal coronary angioplasty on left ventricular function, The effect of autologous blood perfusion. delivered through an angiographic power injector. on alleviating left ventricular (LV) hemodynamic deterioration during percutaneous transluminal coronary angioplasty (PTCA) was examined. LV systolic and diastolic pressures. LV peak positive and peak negative first derivative of LV pressure (dP/dt). and ST-segment shift were recorded in 9 patients with and without hemoperfusion. Hemoperfusion resulted in an improved LV hemodynamic profile during balloon occlusion. as reflected in LV systolic pressure (127 +/- 14 vs 120 +/- 15 mm Hg. p = 0.01). LV end-diastolic pressure (17 +/- 14 vs 25 +/- 6 mm Hg. p less than 0.001). peak positive (1.237 +/- 240 vs 1.149 +/- 225 mm Hg/s. p less than 0.05) and peak negative (1.666 +/- 357 vs 1.485 +/- 385 mm Hg/s. p = 0.003) dP/dt. Hemoperfusion provides substantial protection for significant LV dysfunction induced by conventional PTCA in 1-vessel angioplasty and is a feasible option to protect against potential cardiovascular collapse in high-risk PTCA.
Detection of intracoronary fibrin degradation after coronary balloon angioplasty, Intracoronary thrombus formation may be involved in the pathogenesis of arterial closure after coronary angioplasty and may contribute to restenosis. It is hypothesized that. unlike markers of platelet activation and fibrin formation. D-dimer. a product of plasmin-mediated proteolysis of cross-linked fibrin. is not subject to significant catheter-induced artifact and could be used to study intracoronary fibrin degradation during angioplasty. No significant difference in D-dimer levels was noted in serial plasma samples obtained from an 8Fr arterial sheath and the wire lumen of an angioplasty balloon catheter. indicating that sampling through the catheter lumen did not induce artifactual D-dimer elevations. Translesion (proximal and distal to the lesion) coronary blood samples were collected in 31 patients undergoing elective coronary angioplasty pretreated with aspirin. dipyridamole and heparin. In 20 of those in whom translesion coronary samples for plasma D-dimer levels (mean +/- standard deviation) were collected before balloon dilation. there was no evidence of ongoing intracoronary fibrinolysis (proximal D-dimer levels. 289 +/- 145 ng/ml; distal. 299 +/- 156 ng/ml; difference not significant). After coronary angioplasty (n = 31). there was a relatively small. but significant (p less than 0.001) increase (45 +/- 71 ng/ml) in translesional D-dimer levels (proximal. 396 +/- 223 ng/ml; distal. 441 +/- 257 ng/ml). The results from this study suggest (1) D-dimer levels are not subject to significant catheter-induced artifact and may be useful for assessment of intracoronary fibrin metabolism. and (2) intracoronary degradation of fibrin can be detected after (but not before) routine coronary angioplasty despite pretreatment with antithrombotic therapy. presumably in response to balloon-induced arterial injury and fibrin formation.
Validation of continuous radionuclide left ventricular functioning monitoring in detecting silent myocardial ischemia during balloon angioplasty of the left anterior descending coronary artery, Silent myocardial ischemia has been inferred from transient ST-segment depression during continuous electrocardiographic monitoring. Recently. continuous ambulatory monitoring of left ventricular (LV) function using a radionuclide technique (VEST) has demonstrated episodes of significant silent LV dysfunction in the absence of electrocardiographic changes. To validate the demonstration of silent LV dysfunction with this technique. 12 men were studied during percutaneous transluminal coronary angioplasty. A total of 18 left anterior descending coronary artery balloon inflations were performed. Balloon inflations at 8 +/- 2 atm (4 to 10 atm) lasted 70 +/- 16 seconds. Seventeen of 18 inflations were associated with a decrease in LV ejection fraction greater than 0.10. Mean LV ejection fraction decreased from 0.53 +/- 0.08 to 0.28 +/- 0.11 (p less than 0.0001). In contrast. there was pain in only 10 inflations and ST-segment changes in 7. LV dysfunction was associated with a minimal increase in end-diastolic volume (4 +/- 3%. p less than 0.003). and a major increase in relative end-systolic volume (69 +/- 43%. p less than 0.001). These data suggest that continuous monitoring of LV function with the VEST can sensitively detect silent ischemic decreases in LV function occurring during angioplasty. and provide further validation of the use of this technique for detecting silent myocardial ischemia.
Hemodynamic and metabolic effects of venoarterial cardiopulmonary support in coronary artery disease, Coronary angioplasty was performed on 14 high-risk patients supported with venoarterial partial cardiopulmonary bypass. Hemodynamic. metabolic and physiologic parameters were monitored to assess the effect of cardiopulmonary support in conscious patients. Cardiopulmonary support caused a decrease in systolic (45 +/- 17 to 27 +/- 14 mm Hg. p less than 0.001). diastolic (23 +/- 12 to 14 +/- 8 mm Hg. p less than 0.005) and mean (29.7 +/- 13.2 to 18 +/- 9 mm Hg. p less than 0.001) pulmonary artery pressures. Aortic systolic (129 +/- 18 to 106 +/- 17 mm Hg. p less than 0.001). mean (89 +/- 19 to 84 +/- 19 mm Hg. p less than 0.05) and pulse (64 +/- 17 to 37 +/- 16 mm Hg. p less than 0.00001) pressures also decreased. Heart rate and aortic diastolic pressures were unchanged. End-systolic wall stress (122 +/- 48 x 10(3) to 96 +/- 44 x 10(3) dynes/cm2. p less than 0.001) and left ventricular end-diastolic diameter (5.7 +/- 0.8 to 5.5 +/- 0.9 cm. p less than 0.05) were reduced during partial cardiopulmonary bypass. After initiation of cardiopulmonary support. normal lactate extraction across the coronary circulation was diminished or converted to lactate production (38 +/- 23 to 2 +/- 29%. p less than 0.005). There was a marked reduction in hematocrit (41 +/- 4 to 28 +/- 5%. p less than 0.0001) and platelet count (259.000 +/- 57.600/ml to 145.900 +/- 46.000/ml. p less than 0.0001) after bypass. Cardiopulmonary bypass successfully supported all patients during balloon inflation. for an optimal angioplasty result.
Frequency and mechanism of bradycardia in cardiac transplant recipients and need for pacemakers, Orthotopic cardiac transplantation is occasionally complicated by unexplained bradyarrhythmias. Sinus node injury as a consequence of operation or acute rejection has anecdotally been linked to the development of bradycardia early after transplantation. These arrhythmias are empirically managed by pacemaker implantation. the indications for which remain poorly defined. This retrospective study examined the 20-year experience of our institution with bradyarrhythmias after transplantation to determine the predisposing factors and indications for pacemaker implantation. Forty-one of 556 patients in our cardiac transplant program (7.4%) received permanent pacemakers between 1969 and 1989. The predominant rhythm disturbances were junctional rhythm (46%). sinus arrest (27%) and sinus bradycardia (17%). Most patients were asymptomatic (61%). and presented in the early post-transplant period (73%). Four possible predisposing factors were evaluated: (1) graft ischemic time. (2) rejection history. (3) use of bradycardia-inducing drugs. and (4) anatomy of blood supply to the sinoatrial (SA) node. No significant differences existed between patients with and without pacemakers with regard to the first 3 variables. However. after transplantation angiograms showed that prevalence of abnormal SA nodal arteries was greater in patients with than without pacemakers (p less than 0.02). Pacemaker follow-up at 3. 6 and 12 months showed persistent bradycardia (60 to 90 beats/min) in 88. 75 and 50% of patients. respectively. The most common pacemaker complication (15%) was lead displacement at time of biopsy. These results suggest that disruption of the SA nodal blood supply may be an important predisposing factor in the development of bradycardias.
Ventricular function in the single ventricle before and after Fontan surgery, To better delineate the importance of ventricular function in patients with a single ventricle and assess its relation to outcome after the Fontan procedure. 47 patients with a single ventricle were studied. Ventricular ejection fraction was estimated by radionuclide angiocardiography. Before Fontan surgery. ejection fraction was 0.57 +/- 0.10 (mean +/- standard deviation). This differed significantly from the normal mean left ventricular ejection fraction of 0.68 +/- 0.09 (p less than 0.001) derived in our laboratory by radionuclide angiocardiographic methods. Age. ventricular morphology and the presence of pulmonary artery band or systemic to pulmonary artery shunts had no statistical relation to ventricular ejection fraction in patients with a single ventricle. Serial preoperative evaluation in 15 patients over 3.8 +/- 1.3 years revealed no significant change in ventricular ejection fraction; however. increased atrioventricular valve regurgitation was documented in 4 of these 15. Modified Fontan procedure was performed in 24 of the 47 study patients; 7 have died. 1 has undergone cardiac transplantation and 1 faces possible transplantation. No difference was noted in preoperative ejection fraction between survivors and nonsurvivors. Ventricular morphology. age at Fontan surgery and operative factors such as bypass and cross-clamp time were not related to functional outcome. Preoperative ejection fraction of 0.52 +/- 0.08 decreased to 0.39 +/- 0.11 (p less than 0.001) when evaluated 1.16 +/- 0.44 years after Fontan surgery. In patients with a single ventricle (1) ventricular ejection fraction is less than that of the normal systemic ventricle; (2) during childhood. ejection fraction is not related to age or ventricular morphology; and (3) ventricular ejection fraction frequently decreases after a Fontan repair.
Lamellar body number density and the prediction of respiratory distress, The determination of amniotic fluid lamellar body number density (LBND) has recently been shown to correlate well with other established indicators of fetal lung maturity. The authors have compared the LBND with a fetal lung phospholipid profile in predicting the clinical outcome in 52 well-documented cases. If a cutoff of 30.000/microL was used to indicate fetal lung maturity. there were no false-negative results for the LBND whereas there was one for the fetal lung profile. On the other hand. this cutoff resulted in 22 false-positive results for the LBND. whereas there were only 7 false-positive results by the fetal lung profile. The number of false-positive results by the LBND can be decreased by using a separate cutoff of less than 10.000/microL to indicate high risk for development of respiratory distress. while leaving the cutoff for predicting mature lung at 30.000/microL. This resulted in only four false-positive results for the LBND; each of these were from the same patients who also had false-positive results by the fetal lung profile. Care must be taken to ensure that the particle counter used is properly calibrated and that the appropriate cutoffs for both lung maturity and immaturity are used.
Clinical significance of histology and immunophenotype in childhood diffuse large cell lymphoma, To correlate the histologic subtype of diffuse large cell (DLC) lymphoma with immunophenotype. clinical features. and treatment outcome. 88 consecutively diagnosed children with this disease were studied. Of these cases. 42 (48%) were immunoblastic (IB). polymorphous subtype; 17 (19%) IB. plasmacytoid; 8 (9%) IB. clear cell; 6 (7%) IB. not otherwise specified; and 15 (17%) DLC-follicular center cell (DLC-FCC) type. Of 34 cases successfully phenotyped from paraffin sections. 13 were T cell and 9 were B cell; of the remaining cases. 8 were suggestive of T-cell lineage. 3 of B-cell lineage. and 1 of histiocytic differentiation. Although histologic subtype did not correlate with clinical features or outcome. it did correlate with immunophenotype among those cases for which lineage could be unequivocally assigned (5 of 18 IB vs. 4 of 4 DLC cases were B cell; P = 0.02) Immunophenotype was also correlated with stage of disease (11 of 13 T-cell vs. 3 of 9 B-cell cases had stage III-IV disease; P = 0.03). (Stage III includes all primary thoracic tumors; stage IV includes all with central nervous system and/or bone marrow involvement.) Significant prognostic features were clinical stage and era (thus type) of therapy (P less than 0.001). The authors conclude that most cases of large cell non-Hodgkin's lymphoma in children are of IB morphologic type. most frequently of T-cell lineage. and those with T-cell phenotype appeared to have more advanced disease.
Prognostic value of serum proteins synthesized by breast carcinoma cells, Several breast carcinoma cell lines or explants of such tumors. as well as examples of lactating or dysplastic breast tissue. synthesized three serum proteins (alpha 2-Zn-glycoprotein. alpha 1-antichymotrypsin. and alpha-lipoprotein) in vitro. These proteins were detected by immunoperoxidase techniques in 126 breast carcinomas that had been evaluated clinically for more than six years. Alpha-2-Zn-glycoprotein was present in 58% of the carcinomas. whereas alpha 1-antichymotrypsin was seen in 55% and alpha-lipoprotein in 52%. These markers showed a relationship with clinical outcome. Alpha-1-antichymotrypsin and alpha-lipoprotein were unfavorable determinants. whereas alpha 2-Zn-glycoprotein was detected in lesions with a favorable evolution. Taken individually. these markers have similar but rather weak associations with five-year survival rates; roughly 20% of patients in the "favorable" group died. compared with 33% in the "unfavorable" group. Alpha-2-Zn-glycoprotein in grade 1 tumors was a marker with marginally favorable significance. but alpha 1-antichymotrypsin significantly worsened the prognosis of grade 2 and 3 tumors. Furthermore. stratification of patients according to the number of positive unfavorable markers yielded striking results. Eight percent of patients with none of the unfavorable markers were dead at five years. compared with 55% of those whose lesions expressed three unfavorable markers.
Prognostic factors in esophageal squamous carcinoma. A study of histologic features, blood group expression, and DNA ploidy, The authors studied 69 squamous carcinomas of the middle or lower esophagus to evaluate prognostic factors. Clinical and histologic parameters that were evaluated included weight loss. esophageal obstruction at presentation. site. gross configuration. degree of tumor differentiation. vascular invasion. the status of resection margins. and stage. Blood group antigen (BGA) expression in the tumors was determined immunohistochemically and compared with blood type and antigen reactivity in adjacent normal mucosa. A loss of BGA expression was seen in 27 tumors. This finding was correlated with high stage but was not significantly linked to survival. DNA ploidy was determined by flow cytometry of paraffin-embedded tissues. Forty-one of 52 tumors were aneuploid. and 14 had two or more separate aneuploid populations. However. survival was not correlated with ploidy status. The degree of differentiation and stage of the tumors were the only two independently significant prognostic indicators in this study.
IgA-IgM nephropathy. A subgroup of primary mesangial glomerulonephritis, The renal biopsy material of Tampere University Central Hospital comprises 1992 renal biopsy specimens. accessioned during the years 1978-1989. Among these. there were three cases of mesangial glomerulonephritis with a peculiar type of immunofluorescent reactivity. Striking mesangial deposits of both IgA and IgM were found in glomeruli. whereas C3 deposits were absent or present in slight amounts. The light microscopic findings ranged from mild mesangial glomerulonephritis to more advanced forms of sclerosing glomerulopathy. Electron microscopic examination disclosed an increase of mesangial matrix. together with mesangial and paramesangial electron-dense deposits. Two of the patients had microscopic hematuria associated with proteinuria. and one had isolated proteinuria. The authors propose that this group of cases may represent a new subgroup of primary mesangial glomerulonephritis that has not been described previously. They differ immunohistologically from both IgA nephropathy and IgM nephropathy. and therefore could be designated as IgA-IgM nephropathy.
Immunocytochemical panel for the identification of malignant cells in serous effusions, The cytologic diagnosis of malignancy in serous effusions can be challenging. An immunocytochemical (ICC) panel using commercially available antibodies (to carcinoembryonic antigen [CEA]. epithelial membrane antigen [EMA]. B72.3. Leu-M1. cytokeratin [CK]. leukocyte common antigen [LCA]. S-100 protein. and vimentin) was applied to cell blocks fixed in methyl Carnoy's solution that were from 55 consecutive pleural. peritoneal. and pericardial fluid specimens. The results were correlated with data from clinical records and routine cytologic studies. Final cytologic diagnoses included 26 of adenocarcinoma and 1 of mesothelioma. The remaining 28 cases were considered to be benign (reactive) proliferations. EMA. CEA. B72.3. and Leu-M1 were present in 96%. 77%. 58%. and 42% of adenocarcinomas. respectively. These determinants were absent in the mesothelioma and the reactive effusions. although anti-CEA yielded strong background staining of inflammatory cells. The CK markers identified malignant cells in 93% of cases. but consistently stained mesothelial cells as well. Antivimentin strongly labeled mesothelial cells in all cases. with weak to absent staining of malignant cells. In 3 of 26 carcinoma cases (12%). the ICC panel identified malignant cells that were not recognized initially on routine cytologic examination. In 1 of 26 cases (4%). the panel was falsely negative. Use of this approach can improve the diagnostic accuracy of cytologic examination of serous fluids. The ICC panel is especially helpful when atypical mesothelial proliferation is present. or in cases that are clinically suspect for malignancy. but cytologically negative because there are only a few malignant cells. or those that are cytologically bland.
Mucocele-like tumors of the breast. Cytologic findings in two cases, Mucocele-like tumors of the breast originally were reported by Rosen in 1986 as benign lesions that histologically resembled colloid carcinoma of the breast. The authors document two cases of mucocele-like tumors to illustrate the difficulty in separating these lesions from colloid carcinoma on the basis of fine-needle aspiration biopsy. Cytologically. mucocele-like tumors contained abundant mucin. few clusters. and sheets of regular epithelium that lacked nuclear atypia. and they contained no intact single cells. The authors recommend open surgical biopsy when fine-needle aspiration biopsy findings in such cases are equivocal.
Arias-Stella reaction in fallopian tube epithelium. A light and electron microscopic study with a review of the literature, Most pathologists are familiar with the Arias-Stella reaction in the endometrium. because it is seen in approximately 25% of curettage specimens during early pregnancy. However. the Arias-Stella reaction is exceedingly rare in the fallopian tube. and may be confused with herpetic infection or malignancy. This may result in unnecessary therapy. The authors present a case of Arias-Stella reaction in the fallopian tube and discuss the differential diagnosis of this condition.
A survey of the health of homeless children in Philadelphia shelters, We conducted a random-sample survey of homeless children and their mothers residing in Philadelphia (Pa) shelters. One hundred forty-six families were included in the final sample. resulting in an 80% response rate. The aims of the survey were to characterize the child's current and past health status. to determine access to and use of medical services. and to determine the serum erythrocyte protoporphyrin levels and tuberculin skin test status of the children. In addition. psychological tests were administered to both child and parent to assess developmental level and psychological problems. Finally. detailed questions were asked concerning the reasons for the homeless condition. The important reasons for homelessness cited in the survey included physical abuse. substance abuse. disagreements with landlords. and poor living conditions. The children's health problems included a high incidence of reported accidents and injuries. burns. and lead toxicity; the parents suffered from depression. physical abuse. and substance abuse. School-aged children tended to have low scores on tests of expressive vocabulary and word decoding. and preschoolers seemed to be below age expectations in receptive vocabulary and visual motor skills. The findings of this study suggest that homeless children tend to score poorly on developmental and psychological tests and tend to sustain serious burns and accidents. Policy implications of the survey include suggestions for health screening. rehabilitation. and education.
Establishment of permanent renal tubule cell lines by infection with the wild-type and a thermosensitive mutant of the simian virus 40, This study summarizes the properties of rabbit renal tubule cell lines transformed by the simian virus 40 (SV40). By infection with the wild type SV40. it was possible to establish three different cell lines exhibiting the main functions of proximal (RC.SV1). thick ascending limb-distal (RC.SV2). and collecting (RC.SV3) tubules. Another cell line infected with a thermosensitive mutant of SV40 (RC.SVtsA58) was highly sensitive to arginine vasopressin when cells were cultured at the restrictive temperature of 39.5 degrees C. suggesting they derived from principal cells of the collecting tubule.
Aberrant epithelial cell growth in autosomal dominant polycystic kidney disease, Renal cyst enlargement in autosomal dominant polycystic kidney disease (ADPKD) is characterized by increased epithelial cell proliferation and fluid accumulation. Using monolayer epithelial cultures derived from individually microdissected human ADPKD cysts and immunolocalization studies in vivo. the roles of matrix and growth factors in aberrant ADPKD cell proliferation have been studied. Abnormal ADPKD basement membrane ultrastructure was associated with increased turnover of 35S-labeled heparan sulfate proteoglycans (HSPG) by comparison to normal renal tubule epithelia in vitro. Mitogenic assays demonstrated significant increase in 3H-thymidine incorporation into ADPKD epithelia grown on type I and type IV collagen by comparison to normal proximal straight tubules (PST). collecting ducts. and thick ascending limbs of Henle (TAL). Proliferation on laminin or fibronectin matrices was unchanged and immunolocalization of matrix proteins was polarized and restricted to basal membranes of both ADPKD cysts and renal tubule epithelia in vivo. ADPKD epithelia in vitro were hypersensitive to the mitogenic action of epidermal growth factor (EGF) and EGF immunoreactivity was detected in ADPKD cyst lining epithelia. in cyst fluid. and in conditioned media from confluent ADPKD cultures. suggesting an autocrine mechanism of growth regulation. In addition. inhibition of epithelial proliferation by transforming growth factor-beta (TGF-beta). which was 100% in normal renal tubule epithelia. was reduced to 41% in ADPKD epithelia.
Regulation of gene expression in renal compensatory growth, Compensatory renal hypertrophy is characterized by an increase in cell protein content. There are a number of different cellular mechanisms by which such an increase could be mediated. The relative contributions of transcriptional and posttranscriptional regulation of gene expression to the increase in constitutively expressed cellular proteins were examined in mouse kidneys undergoing compensatory growth following unilateral nephrectomy (UNI-NX). Over the 14-day study period. total protein per kidney increased by up to 37%. Northern blot analysis of the expression of the mRNAs for a number of genes associated with cell growth indicated that there was no significant increase in steady-state levels of these selected genes in nephrectomized compared with sham-operated animals. In vitro assays to measure transcriptional regulation of the same set of genes in compensatory growth showed no increase in the rate of transcription. However. transcription of the 18S ribosomal RNA gene was increased 24 hours after nephrectomy. Immunoblots of two representative proteins showed that the concentration of these proteins in total kidney protein remained constant in the different experimental groups. Since total protein increased. the concentration of these proteins in the hypertrophied kidney must have increased. Taken together. these data suggest that posttranscriptional mechanisms may account for the increase in at least some constitutively expressed proteins in cells undergoing compensatory growth.
Differences in "primary response" gene expression in renal compensatory hypertrophy and hyperplasia, The induction of a family of primary response genes (ie. genes whose transcription is not dependent on new protein synthesis) occurs within minutes after stimulation of quiescent 3T3 cells by phorbol esters and growth factors. A similar pattern of gene expression is seen in PC-12 pheochromocytoma cells induced to differentiate by nerve growth factor (NGF). suggesting that a common set of activating signals occur in different forms of cell growth. To determine whether the same "activation" process occurs in renal hypertrophy. we measured mRNA levels in mice subjected to uninephrectomy (UNX) or sham operation. Regenerative renal hyperplasia was induced by intraperitoneal folic acid (FA) injection with vehicle as control. Northern blots showed induction of these genes by FA with elevated mRNA levels persisting for up to 24 to 48 hours. UNX and sham operation demonstrated a slight and transient elevation of mRNA levels. with a prompt return to basal levels by 60 minutes.
Compensatory hypertrophy and adaptation in the cortical collecting duct, The cortical collecting duct (CCD) undergoes hypertrophy and functional adaptation following reduction of renal mass. The nature and mechanisms of these changes have been investigated using microperfusion of isolated CCD from rabbit remnant kidneys. By 1 week after reduction of renal mass. tubule hypertrophy and increased sodium transport are fully developed. The transport adaptations are specific or selective. since bicarbonate transport in these CCD is unchanged. Mineralocorticoids may play an important role in the hypertrophy and increased sodium transport. since plasma aldosterone increases early after reduction of renal mass. Also. adrenalectomy abolishes the changes in size and sodium transport. even with supplementation of aldosterone to unstressed physiologic levels. Epidermal growth factor also has immediate effects on CCD sodium transport; however. the direction of the effect is opposite--an inhibition of transport.
Role of ammonia in the induction of renal hypertrophy, Recent experiments from our laboratory have documented the importance of ammonia as a modulator of renal cell growth in vitro. Ammonia induces renal hypertrophy by increasing the rate of protein synthesis and decreasing the rate of protein degradation. These results have led to the hypothesis that an increase in renal ammoniagenesis contributes to renal growth in several seemingly unrelated clinical disorders. In chronic hypokalemia and metabolic acidosis. mitochondrial ammoniagenesis is stimulated directly. During protein loading. uninephrectomy. and diabetes mellitus. renal ammoniagenesis may be stimulated by an increase in single-nephron glomerular filtration rate (SNGFR).
Increased ammoniagenesis as a determinant of progressive renal injury, Loss of renal mass evokes increased ammoniagenesis in surviving nephrons. which in turn enables net acid excretion by the kidney. However. this compensatory increase in ammonia production in surviving nephrons triggers the alternative complement pathway. thereby instigating progressive tubulointerstitial injury. Ammonia has recently been identified as a stimulus to renal growth. Enhanced renal growth may serve as a forerunner for renal injury. The growth-promoting properties of ammonia may provide another mechanism through which augmented ammoniagenesis may underlie the enhancement of renal growth and injury observed in such models as the remnant kidney. hypokalemic nephropathy. high protein feeding. experimental diabetes nephropathy. and dietary deficiency of antioxidants.
The adverse impact of cyclosporine on serum lipids in renal transplant recipients, The extent to which cyclosporine (CsA) directly. or indirectly. influences serum lipid levels in renal transplant patients treated with multiple-drug immunosuppression protocols is unclear. Indeed. patients treated with CsA have reduced corticosteroid requirements. fewer acute rejection episodes. and other differences from patients receiving conventional immunosuppression that may reduce serum lipid levels. We studied patients treated with low-dose CsA. corticosteroids. azathioprine. and Minnesota antilymphocyte globulin ([ALG] n = 205) versus conventional (three-drug) immunosuppression (n = 368) and evaluated the impact of CsA. acute rejection episodes. and other clinical parameters on serum lipids. Fasting serum lipid levels from stable patients transplanted between 1976 to 1989 were studied at 3 (n = 573). 12 (n = 565). 26 (n = 55). and 52 (n = 521) weeks posttransplant using multivariate. linear regression analysis. The incidence of acute rejection episodes was reduced by CsA. but patients with fewer acute rejection episodes in the early posttransplant period had higher serum total cholesterol (increased by .33 +/- .12 mmol/L [13 +/- 5 mg/dL] and .27 +/- .12 mmol/L [10 +/- 5 mg/dL]. P less than 0.05. at 3 and 12 weeks. respectively) and low-density lipoprotein (LDL) (increased by .23 +/- .11 mmol/L [9 +/- 4 mg/dL] and .23 +/- .11 mmol/L [9 +/- 4 mg/dL]. P less than 0.05).
Preventability of emergent hospital readmission, To determine whether emergent readmissions within 30 days of discharge are potentially preventable. we prospectively studied all readmissions to the medical service of a university teaching hospital during a 4-month period. The 327 readmissions. including 42 patients who were readmitted more than once during the study period. accounted for 12% of medical admissions. Nearly 75% of readmissions were due to previously diagnosed medical conditions; complications of drugs or therapeutic procedures caused 29%. and patient compliance contributed to 11%. Three reviewers judged 28 (9%) readmissions to be potentially preventable. These 28 readmissions constituted 1% of all admissions to the medical service and did not result in any fatalities. indicating that the quality of care was generally very good. One third of the potentially preventable readmissions were thought to be related to medical system failures. one third to an unfulfilled hope that the patient would improve after discharge. and one third to other suboptimal judgements in evaluation or treatment. Of the 28 potentially preventable readmissions. 89% occurred within 10 days of discharge. We conclude that potentially preventable readmissions would nearly always be detected by review of readmissions within 10 days of discharge and that many may be amenable to systematic interventions such as standardized predischarge assessment and better coordination of post-discharge follow-up.
The chronic fatigue syndrome, The chronic fatigue syndrome (CFS) was formally defined in 1988 to describe disabling fatigue of at least 6 months' duration of uncertain etiology. Reports of CFS have emerged from the United States. Canada. the United Kingdom. Australia. New Zealand. Israel. Spain. and France. The disease primarily affects individuals between 20 and 50 years of age. and there is a preponderance of females. Although a triggering infectious illness is reported by most patients with CFS. there is no convincing evidence causally linking any currently recognized infectious agent to CFS. Multiple minor immunologic aberrations are frequent but inconsistent and of uncertain significance. There is no consistent evidence for myopathy or physical deconditioning. Depression is found in approximately 50% of CFS patients. with depression preceding the physical symptoms in half of the cases. No therapy has been proved effective in controlled clinical trials with prolonged follow-up. although antidepressants have not been formally evaluated. The long-term prognosis of patients with CFS has not been well studied. but CFS appears to be a disease of prolonged duration with considerable morbidity but no mortality. Further research into the pathogenesis and treatment of CFS is necessary.
An assessment of the biological capacity of a Sacramento Valley population of Aedes melanimon to vector arboviruses, Daily survivorship. duration of the gonotrophic cycle. absolute abundance and season-long relative abundance were estimated for Aedes melanimon in the Sacramento Valley of California in 1987 and 1988 using mark-release-recapture (MRR) techniques and by monitoring changes in the abundance and parity rate of the native population. One objective of these studies was to determine the extent to which A. melanimon was biologically capable of serving as a horizontal arbovirus vector. Daily survivorship was estimated to be 0.90 and 0.84 in MRR studies conducted in September 1987 and August 1988. 0.89 based on changes in the parity state and abundance of the native population in August 1988 and 0.82 using summer-long parity data in 1988. Gonotrophic cycle length (GCL) was estimated to be five days in three studies. Aedes melanimon densities were estimated to be approximately 1.000.000 and 15.000 females per hectare in September 1987 and August 1988 respectively. Parous A. melanimon females were collected on each sampling occasion from April to November 1988. suggesting that A. melanimon maintained a continuous presence in the study area throughout the summer. The results of these studies suggest that A. melanimon has the potential to be an efficient horizontal vector of western equine encephalomyelitis (WEE). based on high adult survivorship. short GCL. high abundance and a continuous presence across the summer. This supports the concept of a WEE transmission cycle in the Sacramento Valley involving Ae. melanimon as an important vector. Aedes melanimon also can be an efficient horizontal vector of California encephalitis virus (CE). though the importance of horizontal transmission to the maintenance of CE virus is unclear.
Positive response to sodium antimony gluconate administration in visceral leishmaniasis seropositive patients, In a prospective study conducted in Mymensingh district of Bangladesh. 1. 273 patients were assessed for the presence of visceral leishmaniasis (VL). Sodium antimony gluconate (SAG) was successfully administered to 715 patients with parasitologically confirmed infection. In the remaining 558. although there was clinical indication of VL. Leishmania donovani parasites could not be demonstrated. Administration of SAG in this group was on the grounds of the prevailing symptoms. exclusion of malaria and a positive direct agglutination test (DAT). Significant improvements in the clinical and hematological parameters were observed in 547 (98%) of the unconfirmed VL cases. On the basis of the parasitological findings or positive response to specific anti-Leishmania chemotherapy. the sensitivity and specificity of the DAT were 99.6% and 97.7% respectively. The results supported the reliability of DAT for diagnosis of VL at levels below that of parasitological detection.
Acridine orange detection of Plasmodium falciparum malaria: relationship between sensitivity and optical configuration, Blood samples collected from five volunteers participating in a P. falciparum infectivity trial were examined to determine the efficacy of the acridine orange technique. Several lens configurations were tested for efficiency in the diagnosis of malaria using this system. There was no significant difference in the sensitivity for detecting positive specimens or number of parasites among three lens configurations: a 50x long working distance objective (0.34 mm) with either a 10x ocular (total magnification 500x) or a 12.5x ocular (625x) and a 750x configuration using a 50x objective with a shorter working distance (0.24 mm). All three lens configurations were significantly better than the 1.000x configuration using a commonly available 100x oil immersion objective. The results achieved using this lens still exceeded the sensitivity of the thick blood film.
Myocardial perfusion as assessed by thallium-201 scintigraphy during the discontinuation of mechanical ventilation in ventilator-dependent patients, Patients who cannot be separated from mechanical ventilation (MV) after an episode of acute respiratory failure often have coexisting coronary artery disease. The authors hypothesized that increased left ventricular (LV) wall stress during periods of spontaneous ventilation (SV) could alter myocardial perfusion in these patients. Using thallium-201 (201TI) myocardial scintigraphy. the authors studied the occurrence of myocardial perfusion abnormalities during periods of SV in 15 MV-dependent patients (nine women. six men; aged 71 +/- 7 yr. mean +/- SD). Fourteen of these patients were studied once with 201TI myocardial scintigraphy during intermittent mechanical ventilation (IMV) and again on another day. after at least 10 min of SV through a T-piece. One patient was studied during SV only. Thirteen of 14 of the patients (93%) studied during MV had abnormal patterns of initial myocardial 201TI uptake. but only 1 patient demonstrated redistribution of 201TI on delayed images. The remainder of the abnormalities observed during MV were fixed defects. SV produced significant alterations of myocardial 201TI distribution or transient LV dilation. or both. in 7 of the 15 patients (47%). Four patients demonstrated new regional decreases of LV myocardial thallium concentration with redistribution of the isotope on delayed images. The patient studied only during SV also had myocardial 201TI defects with redistribution. Five patients (3 also having areas of 201TI redistribution) had transient LV dilation during SV.
Midazolam improves electrophysiologic recovery after anoxia and reduces the changes in ATP levels and calcium influx during anoxia in the rat hippocampal slice, Since blockers of excitatory transmission have been shown to reduce anoxic and ischemic neuronal damage. augmentation of inhibitory transmission by agents such as midazolam might have a similar protective effect. Rat hippocampal slices were maintained in vitro and used to determine whether and by what mechanism midazolam improves recovery of evoked responses after anoxia. The Schaffer collateral pathway in the slice was stimulated electrically. and an extracellular potential. the evoked population spike. was recorded from the CA1 pyramidal cells. which are postsynaptic. The slices were made anoxic by substituting artificial cerebrospinal fluid aerated with 95% nitrogen-5% carbon dioxide for fluid aerated with 95% oxygen-5% carbon dioxide. Percentage recovery was expressed as the amplitude of the evoked population spike 60 min after anoxia divided by its preanoxic amplitude. Protection in this model is defined as a significant (P less than 0.05) improvement in percentage recovery compared to the recovery of untreated slices. There was no recovery of the response recorded from CA1 pyramidal cells after 5 min of anoxia (4 +/- 2%) (mean +/- standard error of the mean [SEM]). Slices were treated with midazolam 10 min before. during. and 10 min after anoxia. Midazolam (1 microM) did not enhance recovery after anoxia when dissolved either in water (3 +/- 3%) or in dimethyl sulfoxide (DMSO) (1 +/- 1%). A higher concentration of midazolam (100 microM) did enhance recovery when dissolved in DMSO (27 +/- 7%) but not when dissolved in water (5 +/- 2%). To test whether prolonged pretreatment with midazolam dissolved in water would enhance recovery. slices were treated for 30 min prior to anoxia.
Sustained supraventricular tachyarrhythmias following coronary artery bypass surgery comparing mammary versus saphenous vein grafts, This retrospective study was designed to determine the incidence of sustained supraventricular tachyarrhythmias (SVTs) in patients undergoing coronary artery bypass grafting (CABG) with internal mammary artery (IMA) grafts. Group A. compared with those with saphenous vein grafts (SVG). Group B. Among 569 consecutive patients who underwent CABG surgery in the same institution. a total of 80 cases from Group A and 80 cases from Group B were selected for this study after application of exclusion criteria. Excluded from this study were the following: patients with preexisting or prior history of SVTs. significant left ventricular dysfunction (ejection fraction less than 40%). postoperative myocardial infarction. drug toxicity or electrolyte imbalance. and advanced chronic obstructive lung disease. Group A consisted of 63 men and 17 women and Group B consisted of 52 men and 28 women. All patients were monitored either in ICU or by telemetry for a period of three to six days after surgery and all had a predischarge 12-lead electrocardiogram. Both groups were fairly comparable in most of their clinical profile and number of grafts. The incidence of SVTs in Group A was 31% (25 of 80 patients) and in Group B was 24% (19 of 80 patients). Furthermore. the incidence of postoperative pericarditis was noted in 35% (28 of 80 patients) of Group A and in 19% (15 of 80 patients) in Group B. The authors conclude that male tobacco smokers of Group A tended to have a significantly higher incidence of postoperative pericarditis with a higher trend for postoperative SVTs than patients from Group B.
Systolic ejection murmurs in the elderly: aortic valve and carotid arteries echo-Doppler findings, Two-dimensional echographic and color Doppler studies of the heart and carotid arteries (CA) were performed in 45 patients greater than sixty-five years old without aortic stenosis. 23 with (Group 1) and 22 without (group 2) precordial ejection systolic murmur (SM). Aortic cusps thickening was found in 11 Group 1 (48%) and 2 Group 2 (9%) patients (p less than 0.001). Aortic root and aortic arch size were similar in the two groups. Maximum aortic flow velocity was significantly greater in Group 1 (200 60 cm/sec) than in Group 2 (120 20 cm/sec) (p less than 0.001). Left ventricular outflow systolic maximum velocity was similar in the two groups. A bilateral neck murmur was heard in 10/23 Group 1 patients (43%); in this group. patients with cervical SM had a greater maximum aortic flow velocity than those without cervical SM (230 + 60 cm/sec vs 172 + 32 cm/sec. p less than 0.001). In Group 1. 3 patients had a cervical SM louder on one neck side; only in these 3 patients were ipsilateral obstructive CA plaques found. A unilateral neck SM was heard in 4/22 Group 2 patients (18%); in these 4. ipsilateral obstructive CA were found. Conclusions: (1) in the elderly. precordial ejection SM is related to mild increase in maximum aortic flow velocity and thickening of aortic cusps; (2) in patients with precordial SM radiated to both neck sides. maximum aortic flow velocity tends to be more markedly increased; (3) in patients with precordial SM. a cervical SM louder on one neck side should suggest coexistent ipsilateral CA stenosis.
Chronic venous insufficiency in primary varicose veins evaluated by plethysmographic technique, Venous hemodynamics were evaluated by plethysmography in normal subjects and patients with venous disorders of the lower extremity. to clarify the pathophysiology of chronic venous insufficiency (CVI) due to primary varicose veins. Expelled volume during five active dorsiflexions of the feet and venous recovery time were calculated to evaluate muscle pump efficiency and valvular competence. Limbs with CVI due to primary varicose veins showed a higher expelled volume and a more shortened refilling time than limbs with simple varicosities. With application of tourniquets. the refilling time normalized in limbs with CVI. as well as in limbs with simple varicosities. These results indicate that a high degree of venous congestion in the distal part of the calf and valvular incompetence of the superficial vein system might cause CVI due to primary varicose veins.
Regional intravenous ketanserin and guanethidine therapy in Raynaud's phenomenon, The authors report the results of a study of 25 patients with Raynaud's phenomenon (primary. posttraumatic. and secondary to diffuse connective tissue diseases) treated with regional intravenous injections of guanethidine or ketanserin. These two drugs were chosen because of the different etiopathologic profiles of the conditions. All the patients showed a substantial clinical improvement with a remission of trophic lesions. Conditions secondary to connective tissue disorders did not demonstrate much improvement based on instrumental data alone. possibly because of the intrinsic limitations of the techniques used for evaluating peripheral blood flow. This specific type of pharmaceutical treatment appeared to be especially suitable for this disease owing to a combination of therapeutic efficacy and a substantial reduction in the total dosage for each patient.
Relationship between foot transcutaneous oxygen tension and ankle systolic blood pressure at rest and following exercise, To determine whether foot transcutaneous oxygen tension (TcPO2) and ankle systolic blood pressure (SBP) measure similar aspects of peripheral vascular occlusive disease (PVOD). the authors examined their relationship at rest and following treadmill exercise. Thirty-seven PVOD patients (mean age 69.2 +/- 0.8 years) rested supine for twenty minutes. followed by a progressive treadmill walking test at a constant speed of 2 mph. The initial grade was 0%; this increased 2% every two minutes until maximal claudication pain (n = 19) or until the occurrence of such limiting symptoms as volitional fatigue (n = 6). ST segment depression (n = 4). dyspnea (n = 3). multiple premature ventricular contractions (n = 2). and angina (n = 2). Patients then rested supine for fifteen minutes. Foot TcPO2 was recorded before. during. and after exercise. whereas ankle SBP was measured before and after exercise. At rest. a curvilinear relationship was found between foot TcPO2 and ankle SBP (foot TcPO2 = 41.89 + 0.22(ankle SBP) + 0.0005 (ankle SBP2); SEE = 9.2. R = 0.64. R2 = 0.41. p less than 0.001). In contrast. the relationship was stronger and more linear during recovery. particularly at the sixth minute (foot TcPO2) = 8.33 + 0.35 (ankle SBP); SEE = 13.6. R = 0.86. R2 = 0.73. p less than 0.001). At rest. foot TcPO2 and ankle SBP characterized different aspects of PVOD because they shared only 41% common variance. During recovery. they provided similar information because up to 73% of the variance was shared. It is concluded that foot TcPO2 should also be used to assess PVOD patients because unique information is obtained at rest and values can be recorded during exercise.
Transient pulsus alternans induced by isosorbide dinitrate: echocardiographic and hemodynamic evidence of reduced venous return--a case report, Transient pulsus alternans was induced by isosorbide dinitrate (ISDN) in a patient with postmyocarditis congestive heart failure under diuretic therapy. The severity and duration of pulsus alternans depended on the dose of ISDN. According to the echocardiographic and hemodynamic examinations. the superimposed preload reduction caused by ISDN combined with decreased blood volume owing to diuretic therapy most likely contributed to the development of pulsus alternans.
Cerebral hemodynamics in ischemic cerebrovascular disease, During the past decade. technological advances have made it possible to measure regional cerebral hemodynamics in individual patients. Studies performed with these techniques have demonstrated that the degree of carotid stenosis correlates poorly with the hemodynamic status of the ipsilateral cerebral circulation. The primary determinant of cerebral perfusion pressure and blood flow under these circumstances is the adequacy of collateral circulatory pathways. Since collateral circulation varies from patient to patient. there is no critical degree of carotid stenosis that consistently produces hemodynamic compromise of the cerebral circulation. It is. thus. time to abandon the concept of the hemodynamically significant carotid stenosis as it relates to the pathogenesis and treatment of cerebrovascular disease. Measurements of regional cerebral hemodynamics have provided new insight into the pathogenesis of transient ischemic attacks and generated some preliminary data on the prognostic and therapeutic importance of chronic reductions in regional cerebral perfusion pressure. Further investigations into the importance of hemodynamic factors in ischemic stroke can now be based on accurate assessment of cerebral (not carotid or vertebrobasilar) hemodynamics in the context of other coexisting epidemiological. clinical. hematological. and angiographic risk factors.
Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer, The serum and cerebrospinal fluid (CSF) of 8 women with ataxia. 6 of whom also had eye movement abnormalities believed to be opsoclonus. were found to contain a highly specific antineuronal antibody we call anti-Ri. Seven of the 8 women also had or developed cancer: carcinoma of the breast in 5. adenocarcinoma in an axillary lymph node in 1. and carcinoma of the fallopian tube in 1. Four patients presented with the neurological disorder; the cancer was diagnosed first in the other 4. Immunohistochemical studies using serum or CSF from all 8 patients revealed a highly specific antibody interaction with central nervous system neuronal nuclei but not with glial or other cells; the titer ranged from 1:5.000 to 1:320.000 in serum and from 1:2.000 to 1:16.000 in CSF. Biotinylated IgG from the patients' serum reacted with the tumors of 3 of 4 patients with anti-Ri antibody but not with breast cancers from patients without anti-Ri antibody. Immunoblots against cerebral cortex neuronal extracts identified protein antigens of 55-kd and 80-kd relative molecular mass. Serum titers by immunoblot ranged from 1:500 to more than 1:40.000 and CSF titers. from 1:10 to 1:2.000. The relative amount of anti-Ri was always higher in CSF than in serum. The antibody was not present in sera from normal individuals; patients with breast cancer without opsoclonus; other patients with opsoclonus; or patients with other paraneoplastic syndromes related to breast. ovarian. or small-cell lung cancer. We conclude that the presence of anti-Ri antibody identifies a subset of patients with paraneoplastic ataxia and eye movement disorders (opsoclonus) who usually suffer from breast or other gynecological cancer; the antibody when present is a useful marker for an underlying malignancy.
Abnormal cerebral glucose metabolism in long-term survivors of childhood acute lymphocytic leukemia, Chemotherapy and radiation treatment of the central nervous system may cause delayed neurotoxicity in children with acute lymphocytic leukemia. We evaluated 12 long-term survivors of childhood leukemia using [18F]fluorodeoxyglucose positron emission tomography. computed tomography scans. clinical neurological examinations. and neuropsychological tests. Regional cerebral metabolic rate for glucose (rCMRGlc) values for white matter were lower in the older long-term survivors (greater than 18 years old) treated with cranial radiation and intrathecal chemotherapy than in normal control subjects or survivors who had been treated with intrathecal chemotherapy alone. The ratio of white matter: cortex rCMRGlc values was lower than control values in the long-term survivors treated with cranial radiation and intrathecal chemotherapy. regardless of age. but not in those treated with intrathecal chemotherapy alone. By contrast. thalamic rCMRGlc values were lower than control values in older survivors regardless of treatment. and the ratio for thalamus:cortex rCMRGlc values was lower in all the treatment groups than in the control subjects. The highest rCMRGlc values were found in the youngest children. indicating an important effect of age on cerebral glucose metabolism. No neuropsychological deficits were identified in patients treated only with intrathecal chemotherapy; however. lower IQ scores were found in the long-term survivors who had been treated with cranial radiation and intrathecal chemotherapy. Treatment of the central nervous system with cranial radiation and intrathecal chemotherapy may cause prolonged alterations in white-matter and thalamic rCMRGlc. which may permit the identification and assessment of neurotoxicity in long-term survivors of acute lymphocytic leukemia by [18F]fluorodeoxyglucose positron emission tomography.
Cortical dysplasia in temporal lobe epilepsy: magnetic resonance imaging correlations, Cortical dysplasia has been documented in histological specimens surgically removed for treatment of refractory temporal lobe epilepsy. We studied 10 patients with cortical dysplasia and complex partial seizures who underwent temporal lobectomy. Magnetic resonance imaging revealed abnormalities in 5 of the patients who had microscopically detectable major abnormalities. Magnetic resonance imaging revealed an abnormal cortical-white matter architectonic pattern in 2 patients with moderate cortical dysplasia. In the remaining 3 patients. magnetic resonance imaging findings were unremarkable. These observations suggest that magnetic resonance imaging is sensitive in the detection of certain dysplastic lesions in temporal lobe epilepsy. Preoperative identification of these abnormalities by magnetic resonance imaging may permit early and optimal surgical treatment in patients with refractory epilepsy.
Calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome, We have tested 36 patients with the Lambert-Eaton myasthenic syndrome for serum antibodies to voltage-gated calcium channels by using an immunoprecipitation assay with [125I] omega-conotoxin-labeled voltage-gated calcium channels extracted from a human neuroblastoma cell line. SKN-SH. Forty-four percent of these patients had significant levels of antibody (30-1.466 pM) compared with healthy control individuals (less than 15 pM). The incidence of positive sera in patients without associated small cell lung carcinoma (61%) was greater than in those patients with small cell lung carcinoma (28%). Results correlated strongly with results obtained using voltage-gated calcium channels extracted from the small cell lung carcinoma line. MAR5. Anti-voltage-gated calcium channel antibody titers did not correlate with disease severity across individuals. but longitudinal studies in 2 patients receiving immunosuppressive therapy showed a clear inverse relation between antibody titer and an electromyographic index of disease severity. The incidence of positive sera among patients with other neurological disorders was not significant. but 8 of 12 patients with rheumatoid arthritis or systemic lupus erythematosus had raised titers (30-82 pM). We conclude that the antibodies detected in this assay are heterogeneous and that some of them are likely to be implicated in this disorder of neuromuscular transmission. The assay should prove useful as an additional diagnostic aid in patients with Lambert-Eaton myasthenic syndrome.
A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy, Although neuropeptides have been demonstrated to be hippocampal neuromodulators in laboratory animals. their role in human hippocampal physiology or pathophysiology remains to be defined. The concentrations of somatostatin. cholecystokinin octapeptide. vasoactive intestinal polypeptide. and dynorphin A 1-17 were determined in hippocampal tissue resected from patients with cryptogenic temporal lobe epilepsy. a common seizure disorder originating in or near the hippocampus. Control tissue was obtained from cadavera or epilepsy patients in whom the hippocampus was removed during the resection of temporal lobe tumors. Peptide determinations were performed on extracts of punch biopsy specimens taken from six different hippocampal regions. A significant decrease in immunoreactive somatostatin concentration was identified in the dentate gyrus and in region cornu ammonis 4 of cryptogenic temporal lobe epilepsy specimens. No significant changes were present in any other hippocampal region or in the levels of other peptides. In situ hybridization studies performed on cryostat sections from similar patients confirmed a marked loss of neurons expressing the somatostatin gene. which was restricted to the dentate hilus. The density of specific 125I-somatostatin binding to cryostat sections. as determined by semiquantitative in vitro autoradiography. was significantly increased in the dentate gyrus of the cryptogenic epilepsy patients. compared with tumor control specimens. We conclude that a loss of somatostatin-producing interneurons with an upregulation of dentate somatostatin receptors is a specific and characteristic element in the pathophysiology of human cryptogenic temporal lobe epilepsy.
Invasive treatment for coronary artery disease in the elderly, The widespread availability of coronary artery bypass grafting and percutaneous transluminal coronary angioplasty presents important treatment options for the older patient. The findings from a number of surgical series of coronary artery bypass grafting and percutaneous transluminal coronary angioplasty are summarized. Certain trends are evident. Perioperative mortality. cardiovascular morbidity. and other complications. while declining. remain somewhat higher in elderly patients. However. the impact of age alone is slight. In both coronary artery bypass grafting and percutaneous transluminal coronary angioplasty. complications are more closely correlated with the presence of serious concomitant disease. Long-term survival and pain relief after coronary artery bypass grafting are excellent in older patients. and percutaneous transluminal coronary angioplasty may be the treatment of choice in some elderly patients with coronary artery disease. As in younger patients. prolongation of survival should not be the exclusive goal. Rather. a focus on quality of life and freedom from dependency should be seriously considered.
Cytomegalovirus pneumonitis after cardiac transplantation, To evaluate the incidence and clinical features of cytomegalovirus (CMV) pneumonitis after cardiac transplantation. we identified 27 (16%) of 171 consecutive recipients in whom CMV pneumonitis was confirmed by strict diagnostic criteria. Cytomegalovirus pneumonitis occurred in 6 (30%) of 20 patients treated with azathioprine and prednisone. and 8 (25%) of 32 patients treated with azathioprine. cyclosporine. and prednisone. but only 13 (11%) of 119 patients treated with cyclosporine and prednisone. The incidence of CMV pneumonitis was not related to recipient preoperative CMV titers or to postoperative cardiac rejection. but there was a trend toward increased CMV pneumonitis in patients who received organs from CMV-positive donors. Mean onset of CMV pneumonitis was 2.9 +/- 1.6 (SD) months after transplantation. In the azathioprine-prednisone group. CMV was always associated with at least one other respiratory pathogen (Aspergillus. n = 5; Pneumocystis carinii. n = 2). In the two cyclosporine groups. CMV was either the sole respiratory pathogen (n = 9). or associated with P carinii (n = 11). Roentgenographically. diffuse bilateral hazy pulmonary opacities were present in 19 (70%) of 27 patients. but focal subsegmental opacity (26%). small pleural effusion (26%). and lobar consolidation (7%) were also observed. When bronchoscopy was performed. bronchoalveolar lavage was the most sensitive technique for detecting CMV (72%). whereas transbronchial biopsy (39%) and combined washings and brushings (33%) were relatively insensitive techniques. Respiratory failure and death occurred in 52% and 44%. respectively. of patients with CMV pneumonitis. In this population of immunocompromised hosts: (1) CMV pneumonitis. alone or with other respiratory pathogens. was a major cause of morbidity and mortality; (2) localized roentgenographic opacity did not exclude CMV pneumonitis; (3) bronchoalveolar lavage was the most sensitive bronchoscopic technique for detecting CMV pneumonitis.
A comparison of home glucose monitoring with determinations of hemoglobin A1c, total glycated hemoglobin, fructosamine, and random serum glucose in diabetic patients, We compared four objective measures of glycemic control (fructosamine. total glycated hemoglobin. hemoglobin A1c. and random serum glucose) with home glucose monitoring records in 17 diabetic patients followed up prospectively for 4 months. There was good overall correlation between all of these objective measures and weekly mean capillary glucose values. However. considerable scatter was seen in the data such that none of the glycated protein measurements was an ideal predictor of home glucose values. For example. all markedly elevated home glucose levels (greater than 11.1 mmol/L) were associated with elevated glycated protein levels. but moderately high blood glucose levels (8.3 to 11.1 mmol/L) were associated with one or more normal glycated protein values in some patients. Similar correlations were obtained whether glycemia was estimated by 1-week or 6-week home averages. Random serum glucose level also correlated with average home glucose level; however. there was wide fluctuation within individual subjects. All three glycated protein measurements (hemoglobin A1c. glycated hemoglobin. and fructosamine) appear equally useful as a supplement to home glucose monitoring in the assessment of glycemic control. Of the three types of glycated protein assays. fructosamine. with its advantage of speed and simplicity. may offer a more cost-effective alternative.
Pilocarpine treatment of salivary gland hypofunction and dry mouth (xerostomia), We studied the effects of pilocarpine hydrochloride. a para-sympathomimetic agent. on major salivary gland output and subjective responses in 31 patients with salivary hypofunction. Pilocarpine hydrochloride (5-mg capsules. three times daily) was given for 5 months and a placebo was randomly assigned for 1 month in a double-blind fashion. Objective measurements of major salivary gland output. subjective impressions of oral moisture. treatment-related side effects. and a number of physiologic measures were assessed monthly. Pilocarpine significantly increased salivary output in 21 of the 31 patients. Subjective improvement in the feeling of oral dryness. speaking. chewing. and swallowing were reported by 27 individuals. Side effects. while common. generally were mild and tolerable. There were no significant alterations in cardiovascular or other physiologic measures. We conclude that pilocarpine is an effective and safe treatment for salivary gland hypofunction and xerostomia in selected patients. The increase in major gland output provides beneficial natural secretions and relief of oral dryness.
Physicians' attitudes, beliefs, and practices regarding AIDS health care promotion, While there is now evidence that health-promoting education can be effective at reducing transmission of human immunodeficiency virus (HIV) infection. little is known of the role of the practicing physician in this process. We have surveyed 301 practicing physicians in Northeastern Ohio over a 2-year period and we have assessed their attitudes. beliefs. and practices regarding preventive education with particular reference to HIV. We have found that while the majority of physicians believe strongly that HIV prevention is important and that physicians should play a prominent role in education. the incorporation of such measures in their practice lags far behind other areas of health prevention. Positive educational behavior was correlated with direct experience with HIV-infected patients and postgraduate education on HIV infection.
The effects of low doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects. A randomized controlled trial, The potential antihypertensive effects after prolonged use of small doses of fish oils remain undefined. Therefore. we conducted a randomized. double-blind. controlled crossover study comparing low doses of n-3 fatty acid supplementation with n-6 fatty acids on blood pressure in 33 subjects with mild hypertension. After a 6-week stabilization period. subjects ingested either 2.04 g/d of n-3 fatty acids or safflower oil (4.8 g/d of linoleic acid) for 12 weeks. then crossed over to the alternative encapsulated oil for another 12 weeks. after a 4-week washout period. All antihypertensive drug therapy had been discontinued. For the combined data. there were significant reductions from pretreatment values for supine diastolic (-2.4 mm Hg) and sitting systolic (-4.1 mm Hg) blood pressure after fish oil; no significant changes occurred after safflower oil control. Compared with safflower oil. fish oil supplementation was associated with a statistically significant reduction in mean supine diastolic blood pressure of 3.7 mm Hg (95% confidence interval. -7.3 and 0.1). Sitting diastolic and mean arterial pressures showed a sequence effect; therefore. only the initial period was used in an analysis of their responses. There were significant decreases from pretreatment values for sitting diastolic (-4.4 mm Hg). mean arterial (-5.1 mm Hg). and systolic (-6.5 mm Hg) blood pressure after fish oil. The differences between groups after the 12-week period remained statistically significant for sitting diastolic and sitting mean arterial blood pressures. No adverse changes were noted in plasma levels of lipid-related measures.
Dietary lipid predictors of coronary heart disease in men. The Framingham Study, The relationship between dietary lipids and the 16-year incidence of coronary heart disease (CHD) morbidity and mortality was examined in two male cohorts. aged 45 to 55 years (n = 420) and 56 to 65 years (n = 393) from the Framingham Study. Dietary lipids were assessed through a single 24-hour recall at the initiation of follow-up in 1966 to 1969. In the younger cohort. there were significant positive associations between the incidence of CHD and the proportion of dietary energy intake from total fat and monounsaturated fatty acids. The proportion of energy intake from saturated fatty acids had a marginally significant positive association with CHD. The associations remained even after adjustment for cardiovascular disease risk factors. including serum cholesterol level. suggesting that their effects are at least partially independent of other established risk factors. In contrast to the younger cohort. none of the dietary lipids were associated with CHD in the older cohort. Dietary intervention for the prevention of CHD in younger men is supported by these findings.
The representation of the visual field in human striate cortex. A revision of the classic Holmes map, We have tested the accuracy of Gordon Holmes' retinotopic map of human striate cortex by correlating magnetic resonance scans with homonymous field defects in patients with clearly defined occipital lobe lesions. Our findings indicate that Holmes underestimated the cortical magnification of central vision. In a revised map of the human striate cortex. we expand the area subserving central vision and reduce the area devoted to peripheral vision. These changes bring the map of human striate cortex into agreement with data reported for closely related nonhuman primate species.
Computer-assisted videokeratography of corneal topography after radial keratotomy, We used computer-assisted videokeratography to compare the topographies of 32 corneas from 23 subjects after radial keratotomy with those of 47 normal corneas from 47 subjects controlled for age and preoperative keratometric and refractive power. Three ophthalmologists independently classified color-coded videokeratographs based on the color-coded pattern of dioptric power distribution and the cross-sectional shape. Corneas that had radial keratotomy exhibited a polygonal pattern not seen in normal eyes; this occurred in 59% of corneas. All normal corneas demonstrated a cross-sectional shape configuration that was steeper centrally than peripherally; 79% of corneas after radial keratotomy had a shape that was flatter centrally than peripherally. After radial keratotomy. the dioptric power increased from the center to the periphery (radius of approximately 4.6 mm) by 2.8 +/- 2.2 diopters (mean +/- SD). with a sharp inflection zone ("paracentral knee") 2.7 mm from the center; normal corneas showed a smooth decrease in power from the center to the periphery of 1.9 +/- 0.5 diopters.
Facial cleanliness and risk of trachoma in families, Trachoma is the leading infectious cause of blindness worldwide. and epidemiologic studies of factors that may increase the transmission of ocular Chlamydia trachomatis are needed. In two villages in a hyperendemic area of Central Tanzania. 472 (90%) of 527 preschool-aged children were examined for specific signs of unclean faces and presence of trachoma. The odds of trachoma were 70% higher in children with flies and nasal discharge on their faces. Other facial signs were not important. In large families. the odds of trachoma increased 4.8-fold if a sibling had trachoma and 6.8-fold if a sibling had trachoma and an unclean face. Health education strategies aimed at improving face washing need to target cleaning nasal discharge and keeping flies off children's faces.
Outflow facility and its response to pilocarpine decline in aging rhesus monkeys, Refractive error and total outflow facility were determined by Hartinger coincidence refractometry and two-level constant-pressure perfusion. respectively. in 17 rhesus monkeys. aged 5 to 29 years. Maximum accommodative response to corneal (iontophoretic) carbachol hydrochloride. baseline outflow facility. and the facility response to strong but submaximal intracameral doses of pilocarpine hydrochloride all declined with age. The correlation between accommodative response to carbachol and facility response to pilocarpine was slightly stronger than that between age and facility response. Since the ciliary muscle plays a major role in controlling both outflow facility and accommodation. and since histologic and videographic techniques demonstrate an age-related decline in rhesus ciliary muscle excursion induced by topical pilocarpine or electrical stimulation of the Edinger-Westphal nucleus. the present data support the hypothesis that an age-related decline in ciliary muscle mobility is associated. perhaps causally. with an age-related decline in facility and facility responsiveness to cholinergic drugs.
Indications for office radiographs, Radiology is an essential part of the family physician's office practice. Like most diagnostic tools. radiographs can provide valuable information. but they also have the potential to be abused. One of the first tasks in ensuring optimal use of any procedure is to establish criteria for proper patient selection. This article is a review of general and specific indications for office radiographs on both symptomatic and asymptomatic patients based on published expert consensus and studies that have examined indications for radiographs using clinical criteria. For symptomatic patients. indications are discussed for the following radiographs: extremities (traumatic and nontraumatic). skull. abdomen. chest. orbits. sinuses. facial bones. and spine. Indications for asymptomatic patients are discussed with specific attention to lumbosacral spine and chest radiographs. When appropriate indications are followed. the physician can avoid the problem of overuse and its consequent radiation and economic burdens. as well as the problem of underuse with its risk of incomplete evaluation.
Comparison of the effects of atenolol and nifedipine on glucose, insulin, and lipid metabolism in patients with hypertension, Various aspects of carbohydrate and lipid metabolism have been studied in two groups of patients with mild hypertension before and after four months of treatment with either nifedipine (n = 12) or atenolol (n = 12). Mean (+/- SEM) blood pressure fell to the same degree following treatment with either nifedipine (147 +/- 3/98 +/- 2 to 134 +/- 2/85 +/- 2 mm Hg) or atenolol (149 +/- 3/99 +/- 2 to 135 +/- 2/86 +/- 3 mm Hg). Circulating plasma glucose. insulin. and triglyceride concentrations were measured at hourly intervals from 8:00 AM to 4:00 PM. before and after breakfast (8:00 AM). and at lunch time (noon). The response to treatment was different in the two groups. Specifically. plasma glucose concentration were unchanged and insulin concentrations were higher in association with atenolol treatment. In contrast. nifedipine-treated patients had similar plasma insulin. but lower plasma glucose and triglyceride concentrations after four months of therapy. The changes in day-long plasma glucose and insulin responses suggested that resistance to insulin-stimulated glucose uptake had increased in association with atenolol treatment and decreased following nifedipine. This conclusion was supported in that measurement of insulin-stimulated glucose disposal showed a decrease in atenolol-treated patients and an increase in nifedipine-treated patients. Finally. plasma lipoprotein cholesterol concentrations did not change following atenolol therapy. whereas plasma high density lipoprotein cholesterol increased in association with nifedipine administration. These data show that changes in carbohydrate and lipid metabolism observed with treatment of mild hypertension can vary significantly as a function of the drug used. despite similar beneficial effects on blood pressure.
Interdependence of blood pressure and heart period regulation in mild hypertension, Blood pressure and heart period variability have been measured directly in 142 subjects with mild hypertension over 24 h. The variabilities have been expressed as the standard deviation of 2 min averages of all beats over 24 h. Baroreflex sensitivity was assessed in 102 subjects by the phenylephrine method. Blood pressure varies over a range of approximately 40% around the mean by day and by approximately 20% at night. The variability of blood pressure by day was inversely proportional to the sensitivity of the baroreflex (r = -0.33. P less than .001). while the variability of heart period was directly related to the sensitivity of the reflex (r = 0.27. P less than .01). Neither of these relationships was significant at night. An inverse relationship between heart period and blood pressure was shown by regression analysis of blood pressure and heart period averages over 24 h. The steepness of the slope of the heart period-systolic blood pressure relationship was strongly correlated with the baroreflex sensitivity (r = -0.55. P less than .001). suggesting that blood pressure variations are substantially buffered by changes in heart frequency. Thus. a more stable heart rate that results from an ineffective baroreflex is associated with a more variable systolic blood pressure.
Reduced vascular compliance as a marker for essential hypertension, In 38 patients with established essential hypertension and 32 age-matched normotensive control subjects proximal and distal arterial compliance were determined by computer-based assessment of the diastolic decay of a brachial arterial tracing and a modified Windkessel model of the circulation. In the hypertensive subjects compared to the normotensive subjects mean arterial pressure was 25% higher (P less than .001). systemic vascular resistance 23% higher (P less than .01). proximal compliance 19% lower (P less than .01). and distal compliance 72% lower (P less than .001). The reduction in distal compliance was highly age-dependent. In the youngest age range (45 to 54 years) little overlap appeared between hypertensive and normotensive groups. whereas in the oldest subjects studied (65 to 75 years) distal compliance was comparably low in the two groups. Thus. distal vascular compliance provides a sensitive and specific marker for the abnormal vasculature associated with hypertension and may be particularly useful in identifying the disease in young individuals with borderline blood pressure.
Altered noradrenergic projection to hypothalamus via baroreflex in spontaneously hypertensive rats, To determine whether noradrenergic projections to the posterior hypothalamus via baroreflex are altered in the hypertensive state. the extracellular norepinephrine (NE) content of the posterior hypothalamus was measured in both spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) after sinoaortic denervation (SAD) or sham operation. In WKY. blood pressure (BP) and extracellular NE content 24 h after SAD were significantly higher than those of sham-operated rats. Contrarily. SAD did not increase both BP and NE in the posterior hypothalamus of SHR. These results suggest that the noradrenergic pathway via the baroreflex is impaired in SHR. This mechanism may play an important role in the development and maintenance of hypertension in SHR.
Sodium regulation in the affinity of renal alpha 2-adrenoceptors for epinephrine in Sabra salt-sensitive and salt-resistant rats, Sodium ions markedly decreased in vitro renal alpha 2-adrenoceptor affinity for epinephrine in Sabra hypertensive (SBH) but not in normotensive (SBN) rats. Under these conditions. affinity of alpha 1-adrenoceptor for epinephrine was unchanged in SBH and SBN rats. If these data could be confirmed in vivo. the sodium ion. by acting as an inhibitor. could modify the effect of agonists on renal alpha 2-adrenoceptors in SBH rats. Conversely. the absence of sodium regulation in SBN rats might represent a genetically mediated change responsible for the resistance to the development of salt-induced hypertension.
Abnormal blood pressure response to exercise in borderline hypertension. A two year follow-up study, Twenty-eight men with borderline hypertension according to the World Health Organization criteria underwent maximal exercise testing. and then were followed for a two year period. The prevalence of abnormal blood pressure behavior during exercise was 53.58% (n = 15). During follow-up established hypertension developed in 63.33% (n = 10) of subjects with an abnormal blood pressure response to exercise. and only in 15% (n = 2) of subjects with normal blood pressure behavior. In predicting established hypertension development in a two year follow-up. maximal exercise testing has the following statistical values: sensitivity = 83.33%. specificity = 68.75%. accuracy = 75%. positive predictive value = 66.66%. negative predictive value = 84.61%.
Generation of intracellular signals by low density lipoprotein is independent of the classical LDL receptor, Low density lipoprotein cholesterol (LDL) and apolipoprotein B-100 (1 to 15 micrograms/mL) had no significant influence on the inositol-1.4.5-trisphosphate (InsP3) formation in vascular smooth muscle cells and fibroblasts. Low density lipoprotein cholesterol (15 micrograms/mL) induced an elevation of intracellular Ca2+ from 85 to approximately 210 nmol/L in vascular smooth muscle cells from rat aorta in the absence or in the presence of 15 micrograms/mL monoclonal antibodies against the classical low density lipoprotein receptor or in the presence of apolipoprotein B-100. Moreover. in both human cultured fibroblasts from normocholesterolemic individuals and from patients with familial hypercholesterolemia homozygote class 1. LDL induced a dose-dependent rise of free intracellular calcium and a biphasic change of intracellular pH. Since homozygote class 1 fibroblasts are classical LDL receptor negative. and as antibodies against this receptor. as well as apolipoprotein B-100. did not attenuate the LDL-induced elevation of cytosolic calcium. we conclude that LDL might modify vascular activity via the observed intracellular changes without involving the classical low density lipoprotein receptor.
The clinical heterogeneity of hypertension, More than the character of the blood pressure elevation. the cardiovascular risk profile should be the prognostic guide for antihypertensive therapeutic decision-making. Hypertension tends to occur in association with other risk factors which augment the risk and need to be considered in evaluating the hazard of hypertension. the urgency for treatment. and the choice of treatment. Elevated blood pressure is often accompanied by blood lipid abnormality. obesity. electrocardiograph (ECG) abnormality. glucose intolerance. and elevated fibrinogen and hematocrit. all of which enhance the risk of cardiovascular sequelae of hypertension. Hypertensive patients at particularly increased risk of cardiovascular events are those with an increased total/HDL-cholesterol ratio. ECG abnormality. impaired glucose tolerance. or the cigarette smoking habit. The risk of a cardiovascular event among hypertensive patients varies over more than a 10-fold range depending on the number of these coexistent risk factors. Multivariate risk formulations are available to allow a composite estimate of the joint conditional probability of a cardiovascular outcome in hypertensive patients with multiple risk factors. Since some antihypertensive agents can adversely affect blood lipids. glucose tolerance. or uric acid values. the risk profile must also be taken into account in choosing the optimal antihypertensive therapy. Also. hypertension is commonly associated with angina. myocardial infarction. left ventricular hypertrophy. stroke. or cardiac failure. These too must be taken under consideration in judging the urgency for treatment and the choice of agents. Thus. hypertension is best regarded as a component of a cardiovascular risk profile in implementing optimal therapy and in assessing its efficacy.
Angiotensin converting enzyme inhibitors, regional vascular hemodynamics, and the development and prevention of experimental genetic hypertension, During the development of hypertension in young spontaneously hypertensive rats (SHR) vascular resistance is increased. particularly in the renal circulation. and. to a lesser extent. in the splanchnic bed. Treatment with angiotensin converting enzyme inhibitors in young SHR reverses the renovascular abnormalities more effectively than simple vasodilators. suggesting that the resistance changes may depend on angiotensin II. Perindopril treatment during the development of hypertension causes a reduction in blood pressure as a result of a fall in total peripheral resistance. which persists long after treatment is stopped. These long-term effects can be prevented by replacing angiotensin during perindopril treatment. Not all organs share the long-term resistance changes following perindopril treatment. which are most marked in the renal. splanchnic. and cerebral circulations. The heterogeneous patterns of regional vascular resistance during the development and after prevention of hypertension with angiotensin converting enzyme inhibitors in SHR suggest that local factors. for example. angiotensin II related to the tissue renin-angiotensin system or local adrenergic activity. may be important in the genesis of high blood pressure in this genetic model.
Effects of perindopril on left ventricular hypertrophy, coronary blood flow, and mechanical properties of cardiac muscle in renovascular hypertensive rats, We studied the effects of perindopril on left ventricular hypertrophy. systemic and coronary hemodynamics. and mechanical cardiac performance in renovascular hypertensive rats (Goldblatt. two-kidneys. one-clip). Systemic and coronary hemodynamics. before and after carbochrome infusion. were assessed by radioactive microspheres injection via an atrial catheter in conscious rats. Mechanical performance was measured on isolated papillary muscle from the same animal. Twelve treated hypertensive rats were compared with 10 nontreated hypertensive rats and nine sham-operated normotensive rats of the same age. Perindopril treatment induced a complete control of blood pressure (mean blood pressure from 156 +/- 22 mm Hg in the untreated group to 100 +/- 24 mm Hg in the treated group (P less than .01). compared to 106 +/- 18 mm Hg in the sham group). This was associated with a nearly complete regression of left ventricular hypertrophy (left ventricular mass/body weight 2.26 +/- 0.38 mg/g in the treated group v 3.1 +/- 0.6 in the untreated group [P less than .01]. compared to 2 +/- 0.25 mg/g in the sham group [p = NS]). Minimal left ventricular coronary resistances after carbochrome were slightly higher in the hypertensive group compared both to sham and treated group. A reversal of impaired myocardial mechanical parameters towards control values was observed. except for some parameters of relaxation. We conclude that perindopril allows in this model a complete control of blood pressure. and a regression of left ventricular hypertrophy with normalization of coronary hemodynamics and contractile function.
Remodeling of heart and arteries by chronic converting enzyme inhibition in spontaneously hypertensive rats, Hemodynamic and structural changes of the heart and large arterial vessels were studied in normotensive and spontaneously hypertensive rats following 12 weeks administration of converting enzyme inhibitor (perindopril. 2 mg/kg daily by gavage). In both strains. a significant blood pressure reduction was observed. In normotensive rats. the hemodynamic changes involved significant increase in systemic arterial compliance whereas slight changes in left ventricular weight and aortic medial thickness were observed. In hypertensive rats. the increase in compliance was relatively small. whereas there was a major reduction in medial thickness. Furthermore. the reduction of the media thickness was much more pronounced than that of the left ventricular hypertrophy. The present results suggest that the cardiac and arterial changes observed following long term converting enzyme inhibition do not strictly parallel the blood pressure changes in hypertensive rats. Dissociation between cardiac and arterial changes may be observed.
Effects of the angiotensin I converting enzyme inhibitor perindopril on cerebral blood flow in awake hypertensive rats, As chronic hypertension shifts the lower limit of cerebral blood flow (CBF) autoregulation to higher pressure levels. we studied the effects of the angiotensin converting enzyme (ACE) inhibitor. perindopril on mean arterial pressure (mean BP). basal CBF. and CBF autoregulation in awake renovascular hypertensive (2 kidneys. 1 clip model) and spontaneously hypertensive rats (SHR). Blood pressure was measured via a chronically implanted arterial cannula and CBF by hydrogen clearance. Chronic renovascular hypertension. like spontaneous hypertension. caused a marked shift in the lower limit of CBF autoregulation but did not alter basal CBF. In SHR. acute administration of perindopril did not diminish CBF in spite of the fact that BP fell to a level below the lower limit of CBF autoregulation (determined by hypotensive hemorrhage). Chronic treatment of renovascular hypertensive rats with perindopril normalized BP and restored CBF autoregulation.
Angiotensin converting enzyme inhibition. Systemic and regional hemodynamics in rats and humans, The systemic and regional hemodynamic effects of angiotensin I converting enzyme inhibitors (ACEIs) have been investigated using different experimental methods (pulsed Doppler. radioactive microspheres). either in rats (normotensive NT or genetically hypertensive SHRs) or in humans (healthy volunteers or patients with congestive heart failure CHF). All ACEIs decreased systemic vascular resistance but the profile of their peripheral vasodilating properties was heterogeneous. ACEI-induced vasodilation primarily affected the kidney in rats and in humans and this effect was accompanied by a strong and consistent increase in renal blood flow. This occurred even at non-hypotensive doses in SHRs and CHF patients and resulted in a favorable redistribution of cardiac output towards the kidney. In the muscular vascular bed. ACEIs also decreased local vascular resistance in rats and in humans. whether normotensive or hypertensive. In humans. this vasodilation affected both the arterioles and the large conductance vessels. more markedly in CHF patients than in normotensive subjects. Muscular blood flow was increased and a favorable redistribution of cardiac output towards the muscle occurred. Cerebral blood flow in SHRs and carotid blood flow in humans were augmented. whereas hepatosplanchnic blood flow was increased in rats but not modified in humans. There was no major difference between the regional vasodilating profiles of the different ACEIs. but captopril was somewhat less active at the muscular level. In conclusion. ACEI-induced regional vasodilation is heterogeneous. preferentially affecting the kidney and the muscle. In the latter. both arterioles and large conductance vessels are dilated.
From tissue angiotensin converting enzyme inhibition to antihypertensive effect, The renin-angiotensin system (RAS) has long been regarded as a classical hormonal system. with angiotensin II (ANG II) being the circulating effector peptide. In recent years. evidence for additional RAS in various organs. including vascular wall. kidney. adrenal gland. heart. and brain. has been obtained. Drugs interfering with the RAS such as the converting enzyme (CE) inhibitors may. therefore. not only inhibit the plasma RAS but also inhibit these tissue RAS. Such a "tissue" RAS inhibition has been repeatedly demonstrated in animal experiments. and in some cases it correlated better with the cardiovascular actions of the CE inhibitors than did inhibition of plasma RAS. In the vascular wall. a local inhibition of ANG II synthesis may contribute not only to the reduction of vascular tone but also to the marked regression of media hypertrophy seen after CE inhibitor treatment. Vascular ANG II generation by CE appears to occur almost exclusively at the luminal surface of the endothelium. Locally formed ANG II may then contribute to the pool of circulating ANG II (endocrine ANG II) or feed back to adjacent cells without being transported by the blood (paracrine ANG II). Thus. CE inhibitors may not have to penetrate into deeper layers of the vascular wall to inhibit the vascular RAS. but may rather prevent the paracrine actions of locally generated ANG II.
Latrine ownership as a protective factor in inflammatory trachoma in Egypt, We investigated the association between inflammatory trachoma in children aged 1-5 and environmental and sociodemographic risk factors in a rural Nile Delta hamlet. Inflammatory trachoma clustered in households. emphasising the child-to-child nature of transmission in the hamlet. Multiple logistic regression analysis revealed three factors predicting inflammatory trachoma in children: the absence of a latrine in the household. school-age siblings with inflammatory trachoma. and additional same-age siblings (with or without disease) in the household. In the Egyptian setting the presence of pit latrines in all houses. even when full and unscreened. might result in a reduction in trachoma prevalence in this population from the current 49% to 35%. The construction of pit latrines may offer the simplest and most acceptable environmental method for reducing trachoma in this trachoma endemic area.
Dominant cone dystrophy starting with blue cone involvement, The results of ophthalmological and colour vision studies are reported on 13 patients from a family with a dominant cone dystrophy spanning seven generations. The onset of visual deterioration occurred in the third or fourth decade. In the early stages of the disease. when visual acuity is still close to normal. a severe defect in the blue sensitivity is already present. as measured by spectral sensitivity curves and other tests suitable for the detection of tritan defects. In our opinion this condition represents a distinct entity with autosomal dominant inheritance.
Use of orbital floor steroids in the management of patients with uniocular non-necrotising scleritis, Most cases of non-necrotising scleritis can be successfully treated with non-steroidal anti-inflammatory drugs. If these are ineffective. then high-dose systemic corticosteroids. with all their attendant side-effects. are usually required. We have used orbital floor injections of depot steroid in the management of nine patients with non-necrotising scleritis in an attempt to avoid the use of systemic steroids. or to allow the dose of steroids to be reduced while maintaining disease control. A temporary reduction in inflammation was achieved in all cases. which allowed the use of systemic steroids to be avoided altogether in two patients and delayed in the others. Non-steroidal anti-inflammatory drugs and systemic corticosteroids remain the mainstay of treatment for non-necrotising scleritis. but orbital floor injections may be a useful adjunct in certain cases.
Use of cyclosporin in the management of steroid dependent non-necrotising scleritis, Many patients with non-necrotising scleritis can be treated adequately with non-steroidal anti-inflammatory drugs or steroids. But. as many of them are young. treatment may present problems if they require high doses of steroids to control the scleral inflammation and then relapse when the dosage is reduced. Five such patients were treated with a combination of steroids and low-dose cyclosporin therapy. and in all cases the scleritis remained under control on a much lower dose of steroids than when steroids were used alone. Cyclosporin is therefore a useful drug in the management of younger patients dependent on high-dose steroids to control their scleral inflammation.
Lid lengthening by sclera interposition for eyelid retraction in Graves' ophthalmopathy, The efficacy of scleral grafts for eyelid lengthening in patients with thyroid related upper and/or lower lid retraction was evaluated in 62 consecutive patients with Graves' ophthalmopathy who underwent lid surgery in the last 3.5 years. Seventy-eight upper and 30 lower lids were lengthened by scleral interposition. A good or acceptable result was achieved in 50% of all operated upper lids after one procedure. This percentage increased to 75% after a second and to 77% after a third procedure. Persistent temporal retraction and nasal overcorrection were the major complications. In lower lid lengthening the success percentage was 90% after one operation. We conclude that scleral grafting for upper eyelid lengthening has no distinct advantage in comparison with other lengthening techniques. Scleral implants to lengthen lower lids are very effective.
Serological investigation of ocular toxoplasmosis, The limitations of serological assessment in toxoplasma infection of the eye are well recognised. but the predictive value of clinical examination is not defined. We undertook a prospective investigation into the role of clinical examination and of serological findings in cases of suspected toxoplasma infection of the eye by means of the dye test and multiple IgM assays. Seventy-four cases of retinal disease and 202 control patients were studied. Patients with retinal disease had a significantly higher incidence of toxoplasma seropositivity than the control group. This was because some patients with retinal disease had acquired the infection congenitally. Half the patients investigated for toxoplasmosis were seronegative. Possible explanations for these findings included misdiagnosis. clinical uncertainty. or. the use of serology testing in the confirmation of other diseases. An excess of IgM reactivity among the retinal disease group may indicate low level immunoglobulin-M production associated with an acute exacerbation of ocular toxoplasmosis. There is a need to consider invasive procedures in cases of ocular infection and for novel techniques to aid the diagnosis of toxoplasma retinochoroiditis.
Yellow mercuric oxide: a treatment of choice for phthiriasis palpebrarum, Thirty-five patients presenting with phthiriasis palpebrarum were all treated with a regimen of 1% yellow oxide of mercury ointment four times daily for 14 days. At the conclusion of treatment there was complete resolution of the signs and symptoms of the disease. No side effects due to the treatment were reported or detected. We have shown that 1% mercuric oxide ointment is both a safe and effective treatment for phthiriasis palpebrarum. We recommend it as the treatment of choice.
Vitrectomy, argon laser, and gas tamponade for serous retinal detachment associated with an optic disc pit: a case report, We report the case of a 9-year-old boy with a right optic disc pit and associated serous retinal detachment of the macula. This was treated by vitrectomy. endolaser. and gas tamponade as a primary procedure. which resulted in complete resolution. We review the literature and conclude that further reports of the management of this uncommon condition are required so that firmer guidelines on treatment can be established.
Expression of embryonic globins by erythroid cells in juvenile chronic myelocytic leukemia, Juvenile chronic myelocytic leukemia (JCML) is a rare hematopoietic neoplasia of early childhood with distinct hematologic and biochemical features. We studied the biologic properties and the globin synthetic profiles of JCML erythroid cells both in vivo and in vitro from a total of 24 patients. In these cases we observed the exuberant colony-forming unit-macrophage (CFU-M) colony growth. as reported previously. Furthermore. in contrast to previous reports. we found significant erythroid colony growth in most of our cases (average: 1.182 burst-forming unit-erythroid [BFUe] per 10(5) plated cells. range: 40 to 6.927). This growth was by and large erythropoietin-dependent and was not greatly influenced by other added cytokines. By several criteria all erythroid colony growth detected in vitro was derived from JCML progenitors. The globin synthetic profile of JCML erythroid cells showed high levels of fetal hemoglobin both in vivo and in vitro (gamma/gamma + beta: 53% to 94% in reticulocytes. 62% to 98% in BFUe-derived cells). In addition (in seven cases studied) we detected embryonic globins (epsilon and zeta) at the protein and messenger RNA level. a novel finding for primary leukemic cells. We speculate that the transformed erythroid cells in JCML harbor a trans environment supporting expression of developmentally earlier genes (fetal. embryonic). However. in contrast to other acute or subacute leukemias. JCML erythroid cells also have the ability to reach full maturation to the red cell level. thus allowing detection of this primitive program in vivo.
Characterization of the structure of the erythropoietin receptor by ligand blotting, Erythropoietin (Epo) regulates the growth and differentiation of erythroid cells by binding to a specific receptor. We characterized the native Epo receptor on erythroleukemia cell lines by ligand blotting. Solubilized cell membrane proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. transferred onto nitrocellulose. and probed with 125I-Epo. Specificity was demonstrated by inhibition of 125I-Epo binding by unlabeled excess Epo but not other peptide growth factors and by the cellular distribution of the Epo binding protein. A single membrane protein of 61 Kd +/- 4 Kd was sufficient to bind 125I Epo in both human (OCIM2. K562) and murine (GM979. Rauscher. DA-1) cell lines. This finding is consistent with the predicted size of the Epo receptor from the murine cDNA clone. However. chemical crosslinking of 125I-Epo to its receptor has identified two Epo binding proteins of 105 Kd and 85 Kd. This difference may occur because the receptor is size fractionated before Epo binding in the ligand blot. but after Epo binding in crosslinking studies. Ligand blotting demonstrates that the native Epo receptor is composed of a single 61-Kd Epo binding protein. and suggests the presence of additional proteins of 20 to 25 Kd that associate with the receptor after Epo binding.
Epithelial membrane glycoprotein PAS-IV is related to platelet glycoprotein IIIb binding to thrombospondin but not to malaria-infected erythrocytes, Glycoprotein (GP) IIIb (also termed GPIV or CD36) is an integral platelet membrane protein. and has been identified as a binding site for thrombospondin. collagen. and malaria-infected erythrocytes. PAS-IV is an integral membrane protein found in lactating mammary epithelial cells and capillary endothelial cells. The N-terminal sequence of PAS-IV is nearly identical to that of GPIIIb and monospecific anti-PAS-IV antibody reacts with GPIIIb. indicating that PAS-IV is structurally related to GPIIIb. In this study. human platelet GPIIIb and bovine epithelial PAS-IV were compared in terms of structural. immunologic. and functional characteristics. The two-dimensional tryptic peptide map of both intact and deglycosylated PAS-IV was highly similar but not identical to that of GPIIIb. PAS-IV and GPIIIb reacted to an equal extent with monoclonal antibodies OKM5 and OKM8 by enzyme-linked immunosorbent assay. GPIIIb bound to surface immobilized thrombospondin (TSP) in a concentration-dependent and saturable manner. with approximately 60% reduction in binding in the presence of EDTA. PAS-IV bound to TSP with similar characteristics except that maximum binding was consistently approximately 50% of that of GPIIIb and binding was not inhibited by EDTA. GPIIIb supported adhesion of Plasmodium falciparum-infected erythrocytes (PRBC) in a dose-dependent manner while no significant adhesion of PRBC to PAS-IV was observed. Our data demonstrate that while epithelial PAS-IV and platelet GPIIIb are structurally and immunologically related. there are significant differences in their functional properties. Whether this result is due to different posttranslational glycosylation modifications or that PAS-IV and GPIIIb represent a family of related cell adhesive protein receptors remains to be determined.
Characteristics of quinine- and quinidine-induced antibodies specific for platelet glycoproteins IIb and IIIa, Recent studies have shown that antibodies characteristic of quinine- and quinidine-induced thrombocytopenia sometimes recognize the platelet membrane glycoprotein (GP) complex IIb/IIIa in addition to their well known target. GPIb/IX. We have investigated the frequency with which drug-induced antibodies bind to GPIIb/IIIa and the nature of their target epitopes. In studies of sera from 13 patients sensitive to quinidine or quinine. we found that 10 contained IgG antibodies specific for both GPIb/IX and GPIIb/IIIa. two reacted with GPIb/IX alone. and one reacted with GPIIb/IIIa alone. In all cases. the presence of drug was required for binding of IgG to target GPs. By immunoabsorption. we found that each of five polyspecific sera contained at least two different antibodies. one reactive with GPb/IX and the other with GPIIb/IIIa. Further studies with eight drug-dependent antibodies (DDAb) specific for GPIIb/IIIa showed that three recognized the GPIIb/IIIa complex only. one recognized GPIIb alone. and three recognized GPIIIa alone. The eighth serum appeared to bind to both GPIIIa alone and to an epitope determined by the GPIIb/IIIa complex. The three antibodies specific for GPIIIa alone also reacted with GPIIIa deglycosylated with endo-H. and with the major (61 Kd) fragment obtained by chymotryptic digestion of GPIIIa but failed to react with reduced GPIIIa. These findings demonstrate that. in drug-induced. immunologic thrombocytopenia. the anti-platelet immune response is typically directed against epitopes on both GPIb/IX and GPIIb/IIIa. The three DDAb we studied that were specific for GPIIIa alone recognize epitopes resistant to chymotrypsin and endo-H treatment that are dependent on intrachain disulfide bonding.
Carrier detection in Wiskott-Aldrich syndrome: combined use of M27 beta for X-inactivation studies and as a linked probe, Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder with no clinical or immunologic abnormalities in carrier females. The defective gene has been localized to proximal Xp. Carrier females have nonrandom use of the X chromosome in granulocytes. lymphocytes. and monocytes. We have used the probe M27 beta. which detects both a variable number tandem repeat polymorphism and methylation differences between the active and inactive X chromosome. in the investigation of families referred for genetic counseling. M27 beta detects the locus DXS255. which is tightly linked to WAS. As the probe that is used for investigation of X-inactivation patterns is also linked to the disease locus. it is possible to assign phase in families where this could not be done by conventional use of linked probes. The mothers of four isolated male cases had nonrandom use of the X chromosome. A new mutation was identified in one family with two affected males.
'Role of bone marrow stromal cells in the growth of human multiple myeloma, We have verified the hypothesis that multiple myeloma (MM) may be disseminated by circulating clonogenic cells that selectively home to the bone marrow (BM) to receive the signal(s) leading to proliferation. terminal differentiation. and production of the osteoclast activating factors. Long-term cultures of stromal cells have been developed from the BM of nine patients with MM. These cells were mostly fibroblast-like elements. interspersed with a proportion of scattered macrophages and rare osteoclasts. BM stromal cells were CD54+. produced high levels of interleukin-6 (IL-6) and measurable amounts of IL-1 beta. and were used as feeder layers for autologous peripheral blood mononuclear cells (PBMC). After 3 weeks of cocultures. monoclonal B lymphocytes and plasma cells. derived from PBMC. developed and the number of osteoclasts significantly increased. Both populations grew tightly adherent to the stromal cell layer and their expansion was matched by a sharp increase of IL-6 and by the appearance of IL-3 in the culture supernatant. These data attribute to BM stromal cells a critical role in supporting the growth of B lymphocytes. plasma cells. and osteoclasts and the in vivo dissemination of MM.
Regulation of c-myc expression by granulocyte-macrophage colony-stimulating factor in human leukemia cells, Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates both the proliferation and functional properties of normal and leukemic myeloid cells via cell surface receptors. The postreceptor mechanisms for these two actions. and the extent to which they represent overlapping biochemical pathways. have not been fully clarified. We have examined the actions of GM-CSF on the expression of c-myc. an early response oncogene associated with the proliferative stimulus of growth factors. GM-CSF reduced the population doubling time of HL-60 leukemia cells from 32 hours to 25 hours. and. at concentrations that were correlated with mitogenicity. induced a rapid twofold increase in the level of c-myc mRNA. Nuclear runoff studies indicated that GM-CSF approximately doubled the transcription rate of c-myc by reversing the transcription attenuation that occurs at the exon 1-intron 1 junction. GM-CSF had no effect on the half-life of c-myc messenger RNA. The biochemical basis for the modulation of c-myc expression by GM-CSF was explored. GM-CSF treatment caused intracellular alkalinization of the cells as measured using the fluorescent probe 2'. 7-bis (2-carboxyethyl)-5(and-6) carboxyfluorescein (BCECF). The sodium channel blocker amiloride prevented the GM-CSF-induced change in pH. but did not affect the stimulation of c-myc transcription by GM-CSF. Agents that increase cellular cyclic adenosine monophosphate (cAMP) levels (prostaglandin E2 and cholera toxin) blocked the actions of GM-CSF on c-myc; however. these agents also reduced the basal level of c-myc expression. GM-CSF caused a rapid (5 minutes) and transient decline in cellular cyclic guanosine monophosphate (cGMP) levels. and a slower (30 minutes) and transient decrease in cellular cAMP levels. These observations are consistent with the hypothesis that the declines in cAMP and cGMP are associated with a stimulation of HL-60 proliferation. while previously reported manipulations that elevate cyclic nucleotides are related to an inhibition of HL-60 proliferation and the potentiation of differentiation.
Structure and expression of the cDNA encoding human neutrophil collagenase, We have isolated and characterized a 2.4-kb cDNA clone encoding human neutrophil collagenase (HNC). a member of the family of matrix metalloproteinases restricted to secondary granules within neutrophils. Partial amino acid sequence was used to deduce oligonucleotide probes. These probes were used to screen a human granulocyte cDNA library derived from messenger RNA (mRNA) from a patient with chronic granulocytic leukemia. Cell-free translation of RNA produced from the cDNA produced a 52-Kd protein that was recognized by anti-HNC antibody. The cDNA clone was sequenced and shown to encode a 467-residue protein whose sequence matched those regions currently known for HNC. The enzyme exhibits 58% homology to human fibroblast collagenase and has the same domain structure. It consists of a 20-residue signal peptide. and an 80-residue propeptide that is lost on autolytic activation by cleavage of an M-L bond. Other regions identified include the autolytic degradation site. the "cysteine switch" residue that is involved in latency and activation. and a putative zinc binding sequence. HNC has six potential N-linked glycosylation sites. The cDNA hybridized to a 3.4-kb mRNA in RNA from a patient with chronic granulocytic leukemia. but not to RNA from uninduced HL60 cells or HL60 cells that had been induced to undergo granulocytic or monocytic maturation with dimethyl sulfoxide or 12-O-tetradecanoylphorbol 13-acetate. respectively. These results parallel those seen with lactoferrin and transcobalamin I. two other secondary granule proteins.
Hereditary erythrocyte adenylate kinase deficiency: a defect of multiple phosphotransferases, Adenylate kinase (AK) modulates the interconversion of adenine nucleotides (AMP + adenosine triphosphate----2 ADP). We evaluated the fifth kindred with hereditary erythrocyte (RBC) AK deficiency. The proband had chronic hemolytic anemia. Her RBC had undetectable AK activity when measured spectrophotometrically. whereas those of her parents had half-normal AK activity. AK electrophoresis showed only AK-1 in the parents. The activities of pyruvate kinase and phosphoribosylpyrophosphate synthetase were decreased given the young age of the proband's RBC. Despite the absence of spectrophotometric AK activity. the proband's RBC were able to incorporate 14C-adenine into 14C-adenine nucleotides at 50% of the rate expected for her young RBC population. suggesting the possibility of an alternative pathway for the formation of ADP from AMP. Normal hemolysate had AMP:guanosine triphosphate (GTP) phosphotransferase activity. which produced ADP at 8% to 9% of the rate of AK (6.8 +/- 0.8 IU/mL RBC). AMP:GTP phosphotransferase activity was not detectable in the proband's or parent's hemolysates. These additional biochemical defects in the AK-deficient RBC further support the concept that AK deficiency per se may not cause hemolytic anemia. We propose that defects occur in multiple phosphotransferases in the AK-deficient RBC and that these other biochemical defects may produce deleterious lesions that promote the shortened RBC survival in AK deficiency.
Posttransfusion purpura due to an alloantibody reactive with glycoprotein Ia/IIa (anti-HPA-5b), A 38-year-old woman (JT) was diagnosed with posttransfusion purpura and significant posthysterectomy vaginal bleeding 9 days after the transfusion of 2 U of packed red blood cells. Analysis of JT's serum by a monoclonal antibody-antigen capture enzyme-linked immunosorbent assay method showed the presence of anti-HPA-5b (anti-Bra) antibodies directed against an epitope on platelet glycoprotein (GP) la of the GPIa/IIa complex. The patient's serum immunoprecipitated two proteins from 125I-labeled HPA-5b positive platelets that migrated under both nonreducing and reducing conditions on sodium dodecyl sulfate polyacrylamide gels at molecular weights characteristic of GPIa (150 Kd and 165 Kd. respectively) and GPIIa (120 Kd and 145 Kd. respectively). These bands were not precipitated when 125I-labeled HPA-5b negative platelets were used. Platelet typings performed on JT and her three children showed that the patient was HPA-5b negative and one of her children was HPA-5b positive. Platelets obtained from one of the donors who provided blood for the inciting transfusion also typed as HPA-5b positive. These findings demonstrate that posttransfusion purpura may be induced by antibodies directed against an alloantigenic epitope. namely HPA-5b (Bra). located on GPIa/IIa. Moreover. clinically significant bleeding can be associated with antibody reactions directed against this GP complex.
Importance of maternal history of non-insulin dependent diabetic patients, OBJECTIVE--To assess the family history of diabetes in non-insulin dependent diabetes mellitus with particular emphasis on parental phenotype. DESIGN--Family histories were obtained from an existing computerised database and supplemented by postal questionnaires. SETTING--Diabetic service of a provincial teaching hospital. SUBJECTS--A total of 1326 patients with non-insulin dependent diabetes who had been referred to diabetic clinics over the past 10 years and from whom data had been collected for inclusion in the database. of whom 347 had affected first degree relatives. Nineteen non-white patients were excluded because of the differential hereditability of the disease. and 230 (70%) patients with an affected first degree relative responded to the postal questionnaire. RESULTS--Mothers were implicated in significantly more cases than fathers in patients with a single affected parent: 125 mothers and 48 fathers from database; 82 mothers and 34 fathers from postal questionnaire; p less than 0.001 in both cases. CONCLUSIONS--Maternal influences seem to have an important role in the inheritance of non-insulin dependent diabetes.
Home nebulisers in childhood asthma: survey of hospital supervised use, OBJECTIVE--To review the management of and outcome in asthmatic children using home nebulisers under hospital supervision. DESIGN--Postal questionnaires sent to parents. SETTING--Paediatric departments of a children's hospital and a district general hospital. SUBJECTS--Parents of 93 asthmatic children who had been loaned home nebulisers for administration of bronchodilators with verbal instructions on their use. MAIN OUTCOME MEASURES--Drugs administered with nebuliser. side effects. frequency of hospital admission. and theoretical management of a severe attack. RESULTS--84 children took salbutamol and 37 received more than 10 mg a day during attacks; side effects were reported in 54 children. Parents of 16 children said that they would give another dose of bronchodilator rather than seek medical help if their child failed to respond to the first dose. Since being loaned nebulisers 65 children were admitted to hospital less frequently and 16 were not readmitted; over two thirds of parents thought that there had been a marked improvement in their child's asthma. CONCLUSIONS--Home nebulisers are valuable in childhood asthma. Excessive doses of bronchodilators may be given. however. and a weight related dose may be more appropriate. Parents should be given written as well as verbal instructions. especially regarding the management of severe attacks.
Delay to invasive investigation and revascularisation for coronary heart disease in south west Thames region: a two tier system, OBJECTIVES--To assess the accessibility of invasive investigation and revascularisation procedures in the management of coronary heart disease in a defined population in the South West Thames region over 10 years. and to audit the performance of both the NHS and the private sector. DESIGN--Analysis of all patient referrals to the regional cardiothoracic centres for coronary heart disease during 1979-88. SETTING--North West Surrey District Health Authority. which had a mean catchment population of 205.000 during the study period. The health district is one of the 13 in the South West Thames region. PATIENTS--823 patients aged 34-80 years with suspected coronary heart disease. 204 of whom were referred for private investigation and 619 were referred within the NHS. The NHS referrals were mainly to St Thomas's Hospital during 1979-83 and to St George's Hospital during 1984-8. MAIN OUTCOME MEASURES--Difference in time to investigation and intervention between the NHS and the private patients. RESULTS--After some variation in earlier years the mean (SD. range) waiting times from referral to cardiac catheterisation and then revascularisation increased progressively in NHS patients. to 115.8 (126.5. 22-482) days and 305.9 (164.4. 22-620) days respectively in 1988. There was no significant change over the 10 years in waiting times within the private sector. with a mean of 17.2 (18.2. 1-62) days to angiography and 22.8 (14.5. 2-152) days to surgery. Fifteen people on the NHS waiting list died of probable cardiac causes. No people on the private waiting list died. CONCLUSIONS--The performance of the NHS system in South West Thames region in response to emergency referral is adequate. The waiting time to routine investigation and revascularisation is prolonged and seems to be worsening despite increased investigative and surgical activity by the regional centre. The delays may subject NHS patients to unnecessary risk. which is not shared by private patients.
Neonatal screening strategy for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis, OBJECTIVE--To assess the effectiveness of a two tier neonatal screening strategy for cystic fibrosis. which combines estimation of immunoreactive trypsinogen followed by direct gene analysis in dried blood spot samples collected at age 5 days. DESIGN--Prospective study of two tier screening strategy. The first tier of testing immunoreactive trypsinogen concentration was measured in dried blood spot samples from neonates aged 4-5 days. In the second tier direct gene analysis to detect cystic fibrosis mutations deltaF508 and deltaI506 was performed in those blood spot samples which produced the highest 1% of immunoreactive trypsinogen values. Direct gene analysis was also performed on blood spot samples from infants with suspected or confirmed meconium ileus. regardless of the immunoreactive trypsinogen value. SETTING--The South Australian Neonatal Screening Programme. operating from the department of chemical pathology at Adelaide Children's Hospital. Subjects--All 12.056 neonates born in South Australia between December 1989 and June 1990. No selection criteria were applied. INTERVENTIONS--All infants found to have two recognised cystic fibrosis mutations on direct gene analysis were referred directly for clinical management. and those with one recognised cystic fibrosis mutation were recalled for a sweat test; their families were given genetic counselling. MAIN OUTCOME MEASURES--Direct or exclusion of cystic fibrosis by sweat testing of neonates identified as being at high risk of cystic fibrosis on screening and of those at minimum risk but whose subsequent clinical history raised suspicion about the disease. RESULTS--Of the 12.056 infants screened. 11.907 (98.8%) were reported as "cystic fibrosis not indicated" on the basis of low immunoreactive trypsinogen values. Of the 148 (1.23%) infants with raised immunoreactive trypsinogen values and one (0.008%) with meconium ileus. 132 (1.09%) were reported as cystic fibrosis not indicated. four (0.033%) were identified as having cystic fibrosis. and 13 (0.108%) were recalled for sweat testing after direct gene analysis for the presence of the deltaF508 and deltaI506 cystic fibrosis mutations. No cases of affected infants are known to have been missed to date. CONCLUSION--The strategy of measurement of immunoreactive trypsinogen followed by direct gene analysis is a highly specific neonatal screen for cystic fibrosis. requiring only 2.8 families to be contacted for every case of cystic fibrosis diagnosed.
Histopathology of multiple sclerosis lesions detected by magnetic resonance imaging in unfixed postmortem central nervous system tissue, Postmortem unfixed whole brains from 17 multiple sclerosis and 6 control cases were examined by magnetic resonance imaging (MRI) using a T2-weighted spin echo sequence and histology to determine the relationship between areas of abnormal MRI signal and underlying pathological change. In group 1. small MRI lesions and correspondingly small plaques. most of which were chronic. were detected histologically in 5 brains. In 4 brains there were more extensive areas of both abnormal signal and histological plaques which were more often active (group 2). However. in a further 5 brains extensive MRI abnormalities were observed when only small periventricular plaques were present histologically (group 3). Lesions in the hindbrain and cerebral grey matter were infrequently observed by MRI. The extensive MRI abnormalities seen in areas in which only small histological plaques were found may be the result of vascular permeability changes in the normal-appearing white matter surrounding plaques.
The natural history of multiple sclerosis: a geographically based study. 3. Multivariate analysis of predictive factors and models of outcome, A multivariate hierarchical analysis was used to assess the significance of several demographic and clinical factors in multiple sclerosis patients. We used the time to reach level 6 on the disability status scale (DSS) of Kurtzke as endpoint. Several factors at presentation were significantly associated with an adverse outcome including older age at onset. male sex. cerebellar involvement or insidious onset of a motor deficit as first symptom. Factors ascertained later which were associated significantly with a worse outcome. even after controlling for those previously mentioned. included persisting deficits in brainstem. cerebellar or cerebral systems. a higher frequency of attacks in the first 2 yrs after onset of disease. a short first interattack interval and higher DSS at 2 yrs and 5 yrs from onset. An analysis similar to multiple regression was used to generate predictive models which permit the calculation of the median time to DSS 6 for patients with a given set of covariates. The goodness of fit of these models to the data and their predictive accuracy are discussed.
The natural history of multiple sclerosis: a geographically based study. 4. Applications to planning and interpretation of clinical therapeutic trials, We used hypothetical entry criteria typical of those used in clinical therapeutic trials to determine the patients who would have been eligible among those followed in a clinic-based study of multiple sclerosis (MS) in London. Ontario. between 1972 and 1984. For these patients. we determined the observed frequency of deterioration by 1 point on the disability status scale (DSS) of Kurtzke. which is the most feasible and frequently used endpoint in clinical trials. We calculated the number of patients required for a randomized clinical trial to detect a significant result (alpha = 0.05) with 80% or 90% power based on the observed rate of deterioration. To assess the linearity of the DSS. we determined the frequency of progression and staying time at each level of the DSS. Overall the frequency of progression was lower and the staying times were longer at higher levels of disability. There was considerable intrapatient as well as interpatient variation in staying time. These data have major implications for the design and conduct of clinical therapeutic trials in MS.
Deficits in strategy application following frontal lobe damage in man, A quantitative investigation of the ability to carry out a variety of cognitive tasks was performed in 3 patients who had sustained traumatic injuries which involved prefrontal structures. All 3 had severe difficulties in 2 tests which required them to carry out a number of fairly simple but open-ended tasks over a 15-30 min period. They typically spent too long on individual tasks. All patients scored well on tests of perception. language and intelligence and 2 performed well on a variety of other tests of frontal lobe function. Explanations for their difficulty on the multiple subgoal tasks in terms of memory or motivational problems could be excluded. It is argued that the problem arose from an inability to reactivate after a delay previously-generated intentions when they are not directly signalled by the stimulus situation.
Basal temporal language area, Language interference was elicited by electrical stimulation of the dominant basal temporal region in 8 out of 22 cases and in none of 7 cases with subdural electrodes implanted over the nondominant temporal lobe. Language interference was elicited by stimulation of electrodes placed over the fusiform gyrus 3-7 cm from the tip of the temporal lobe. Electrical stimulation of the basal temporal language area produced a global receptive and expressive aphasia with speech arrest at high stimulus intensities. Other higher cortical function. for example copying complex designs or memory of nonverbal information was intact. in spite of the total inability to process verbal information. At lower stimulus intensities partial aphasias with a predominant receptive component occurred. Surgical resection of the basal temporal language area produces no lasting language deficit.
Periventricular lesions in the white matter on magnetic resonance imaging in the elderly. A morphometric correlation with arteriolosclerosis and dilated perivascular spaces, Magnetic resonance imaging (MRI) was performed postmortem on the brains of 40 patients aged over 60 yrs who had died from causes other than brain disease. Periventricular lesions of increased signal intensity on T2-weighted images. graded as moderate or severe. were found in 10% of the patients in the age group between 60 and 69 yrs. and in 50% between 80 and 89 yrs. Macroscopic and microscopic whole-brain sections were studied in 19 brain specimens (8 with normal white matter. 4 with moderate lesions and 7 with severe lesions of the white matter on MRI). The presence or absence of periventricular lesions on MRI correlated well with the severity of demyelination and astrocytic gliosis. Demyelination was always associated with an increased ratio between wall thickness and external diameter of arterioles (up to 150 microns). A variable degree of axonal loss in Bodian-stained sections was present in the white matter of all brains with demyelination. Dilated perivascular spaces were found and studied morphometrically in 9 brain specimens; their presence correlated strongly with corrected brain weight. but incompletely with demyelination and arteriolosclerosis. Our findings suggest that arteriolosclerosis is the primary factor in the pathogenesis of diffuse white matter lesions in the elderly. This is soon followed by demyelination and loss of axons. and only later by dilatation of perivascular spaces.
Ubiquitin-immunoreactive intraneuronal inclusions in amyotrophic lateral sclerosis. Morphology, distribution, and specificity, Antibodies to ubiquitin have been used to search for evidence of abnormal protein degradation in amyotrophic lateral sclerosis--motor neuron disease (ALS). Anterior horn cell ubiquitin-immunoreactive (IR) inclusions were present in all of 31 ALS cases but in none of 23 neurologically normal and in only 1 of 22 neurologically abnormal controls. These inclusions. which were present in familial and sporadic ALS cases. and in cases with dementia. took the form of dense rounded or irregular ubiquitin-IR cytoplasmic inclusions (dense bodies). or loosely arranged bundles ('skeins') of filamentous-appearing material. The presence of ubiquitin-IR inclusions corresponded to the pattern of selective neuronal vulnerability in ALS. although inclusions in pyramidal neurons of the motor cortex were infrequent and were noted in only a minority of cases. Ubiquitin-IR inclusions were more prevalent than Bunina bodies. The latter were present in 67% of ALS cases but were seldom labelled by antibodies to ubiquitin. Intraneuronal inclusions resembling Lewy bodies were present in 23% of ALS cases and were often identified by antibodies to ubiquitin. We conclude that the presence of ubiquitin-IR inclusions in lower motor neurons represents a characteristic pathological feature of ALS in its various clinical forms. Ubiquitin-IR inclusions in ALS differ from ubiquitinated inclusions in other neuronal degenerations in that they are not readily identified by antibodies to cytoskeletal proteins. They may represent accumulations of altered or abnormal neuronal proteins resistant to degradation via the ubiquitin proteolytic pathway.
Patterns of blood-brain barrier breakdown in inflammatory demyelination, The evolution of the changes in the blood-brain barrier (BBB) in chronic relapsing experimental allergic encephalomyelitis (CREAE). a model of immune-mediated demyelination. has been studied by magnetic resonance imaging (MRI); gadolinium-DTPA (Gd-DTPA) was used to detect BBB breakdown by both quantitative and qualitative techniques. Animals with acute EAE were examined for comparison. In animals with CREAE an approximately linear relationship was found between the mean number of lesions enhancing with Gd-DTPA seen per MRI slice and the severity of clinical disability at relapse. In addition. a direct relationship was seen between the duration of clinical relapse and the duration of enhancement with Gd-DTPA for lesions associated with the relapse. Lesions studied in animals having entered a progressive phase of disease showed the most sustained BBB breakdown. These observations suggest that BBB breakdown is important in the development of clinical signs in inflammatory demyelination. In CREAE. areas of focal enhancement with Gd-DTPA could usually be clearly defined at a time of clinical relapse. In slices free of focal lesions. no abnormal Gd-DTPA leakage could be detected using a quantitative method. In contrast. in acute EAE no focal lesions were visible. but significant leakage was detected by measurement. No change was found in T2 relaxation times in CREAE or acute EAE. The pattern of BBB breakdown in inflammatory demyelination evolves from a diffuse shortlived disturbance in acute EAE to a more focal and prolonged breakdown in animals with chronic relapsing and progressive disease. The broad similarities in the pattern of BBB breakdown seen in CREAE and multiple sclerosis support the hypothesis that the initial vascular changes in the human disease are due to inflammation which could be mediated immunologically.
Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis, It has been suggested that the degeneration of lower motor neurons in amyotrophic lateral sclerosis (ALS) is a transneuronal event. secondary to the loss of corticospinal and corticobulbar neurons. In an attempt to test this hypothesis. the cross-sectional areas of pyramidal cells in layer 5 of the foot and tongue areas of the precentral gyri were measured in 12 cases of the classical sporadic form of ALS. and in 10 control subjects. The areas of motor neurons in the hypoglossal nuclei and in the ventral horns of segment L4 of the spinal cord were also measured. The number of neurons per 20 microns section of ventral horn or hypoglossal nucleus provided a more reliable index of severity of lower motor neuron loss at the time of death than did a semiquantitative score derived from clinical observations. Cortical neurons and lower motor neurons were significantly smaller in the cases of ALS than in the controls. In the cortex this change included. but was not confined to. the largest neurons. These observations indicate that shrinkage precedes neuronal death. There was no correlation. positive or negative. between the numbers of surviving lower motor neurons and the mean sizes of pyramidal cells in layer 5 of the corresponding areas of the precentral gyri. The absence of such a correlation indicates that functionally related cortical and lower motor neurons probably degenerate independently. and not from a transsynaptic effect. Neuronal shrinkage has been observed in other diseases in which interconnected systems of neurons degenerate. The possible association of shrinkage with cytoskeletal degradation is discussed.
Hereditary ataxias and paraplegias in Cantabria, Spain. An epidemiological and clinical study, A clinical. genetic and epidemiological study of hereditary ataxias and paraplegias was conducted within a defined area (Cantabria) in Northern Spain from 1974 to 1986. The series comprised 48 index cases and 65 affected relatives. On prevalence day. 103 patients were alive. giving a prevalence of 20.2 cases per 100.000. There were 24 patients (18 families) with Friedreich's ataxia (FA). 12 (6 families) with early onset cerebellar ataxia (EOCA) differing from FA. 6 (3 families) with dominantly transmitted late onset cerebellar ataxia (LOCA). 11 with 'idiopathic' LOCA. 49 (9 families) with 'pure' hereditary spastic paraplegia (HSP). and 1 patient with congenital cerebellar ataxia. The prevalence found here is comparable with the highest figures described in previous surveys. This may in part be due to the great number of secondary cases in our series. A high frequency of parental consanguinity occurred in FA patients. 'pseudodominant' inheritance being observed in 1 family. The clinical features were those of classical FA except for later onset and slower course in 1 family. and retained tendon reflexes in the lower limbs in 2 cases. Such data indicate the need for modification of the essential criteria for the disease. EOCA included 4 patients with normoreflexic ataxia and 1 patient with ataxia and luteinizing hormone-releasing hormone deficiency. In addition. there were 7 patients from 2 unrelated families with a homogeneous syndrome characterized by autosomal recessive inheritance. cerebellar ataxia. retinitis pigmentosa and sensory neuropathy. This syndrome is therefore a well defined nosological entity to be added to the list of autosomal recessive mendelian phenotypes. The clinical picture of patients with LOCA was either a 'pure' cerebellar or a 'cerebellar-plus' syndrome. Genetic subgroups of 'pure' HSP were autosomal dominant type I in 5 families and type II in 2. and autosomal recessive in 2 families.
Experimental vitamin E deficiency in rats. Morphological and functional evidence of abnormal axonal transport secondary to free radical damage, Morphological and functional studies have been performed on experimental vitamin E deficient rats. The predominant morphological change was axonal dystrophy and degeneration in the rostral parts of the dorsal columns. particularly in the gracile fasciculi. The dystrophic changes comprised focal axonal swellings containing accumulations of normal and abnormal organelles which included tubulovesicular structures probably derived from the smooth endoplasmic reticulum. mitochondria. dense lamellar bodies. neurofilaments. multifascicular bodies and lysosomes. Similar but lesser changes were observed in distal peripheral nerves. The appearances suggested a disturbance of axonal transport with a defect of 'turnaround' in the distal axons. Studies on the axonal transport of endogenous acetylcholinesterase showed an impairment both of fast anterograde and retrograde transport. The changes were considered to be secondary to the lack of the antioxidant effect of vitamin E as the neurological deficits could be reduced by the concomitant dietary administration of the synthetic antioxidant ethoxyquin and were markedly aggravated by the administration of polyunsaturated fatty acids. It is suggested that the neurological syndrome produced by vitamin E deficiency could be the result of damage to the function of mitochondria and other intra-axonal membranous structures which would interfer both with fast anterograde transport and 'turnaround' and lead to a distal axonal degeneration.
The American Cancer Society National Prostate Cancer Detection Project. Findings on the detection of early prostate cancer in 2425 men, The American Cancer Society National Prostate Cancer Detection Project (ACS-NPCDP) is a multidisciplinary. multicenter effort to assess the feasibility of early prostate cancer detection by digital rectal examination (DRE). transrectal ultrasound (TRUS). and prostate specific antigen (PSA) assay. By June 1990. 2425 men not previously suspected of having prostate cancer had been examined in ten participating clinical centers according to the project protocol. Three hundred ninety-six men (16.3%) were recommended for biopsy on the basis of TRUS or DRE. An analysis of the results of 330 completed biopsies showed 52 cancers detected by DRE and/or TRUS. Forty-four (84.6%) of the men with cancer had positive TRUS examination results compared with 33 (63.5%) with positive DRE. Five additional cancers were discovered as a result of elevated PSA levels. The overall detection rate was 2.4% and this rate varied by age. The detection rate in men 55 to 60 years of age was 1.3% and this rose to 3.3% in men older than 65 years of age. The estimated sensitivity was significantly greater for TRUS compared with DRE (77.2% versus 57.9%; P less than 0.05). The estimated specificity of DRE was greater than that of TRUS (96.3% versus 89.4%; P less than 0.01). The positive predictive value (PPV) for the tests varied as a function of patient and disease characteristics. The overall PPV was 28.0% for DRE and 15.2% for TRUS. The occurrence of elevated PSA levels significantly increased the PPV of both TRUS and DRE. The majority of cancers detected were at early stages. These preliminary data suggest the feasibility of using these techniques to promote cancer control. but additional data and follow-up are needed to assess the significance of the results.
A pilot study of stanozolol for advanced breast carcinoma, Eighteen patients with advanced metastatic carcinoma of the breast who had been previously treated with other hormone therapy were treated with stanozolol in a pilot study to assess its efficacy and toxicity. In a heavily pretreated population of patients with advanced breast cancer. three patients (16.6%) had partial responses (PR) and five patients (27.7%) had stable disease (SD). Toxicity was far less than that expected with androgen therapy. Stanozolol should be investigated in large groups of patients to establish its role more fully in the management of metastatic breast carcinoma.
Activity of doxorubicin and cisplatin combination chemotherapy in patients with diffuse malignant pleural mesothelioma. An Italian Lung Cancer Task Force (FONICAP) Phase II study, Twenty-six symptomatic patients with diffuse malignant pleural mesothelioma (DMPM) were enrolled in a Phase II Italian Lung Cancer Task Force (FONICAP) study to assess the activity and toxicity of doxorubicin and cisplatin combination chemotherapy. The drug schedule was as follows; 60 mg/m2 of doxorubicin and 60 mg/m2 of cisplatin both given intravenously (IV) on day 1 every 3 to 4 weeks. Of the 24 evaluable patients. 6 objective partial responses (25%; 95% confidence limits. 9.77% to 46.71%) were observed. Twelve of 24 patients (50%). including 6 with no radiologic evidence of response. had a clinical improvement as demonstrated by an objective reduction of symptom or performance status scores along treatment. The overall median survival time was 10 months. Toxicity was mild and dose reductions or suspensions were not required. The combination of doxorubicin and cisplatin is effective and well tolerated. It might be considered for palliation of symptomatic patients with DMPM.
A phase II study of idarubicin in the treatment of measurable gastric cancer, Idarubicin is one of the new anthracycline analogues. It has a higher therapeutic index than either doxorubicin or daunorubicin in a variety of murine leukemias and solid tumors. The authors performed a multicenter Phase II trial of idarubicin in patients with advanced gastric cancer. Seventeen patients with measurable metastatic disease were entered into the trial and treated with idarubicin at a starting dose of 15 mg/m2. This dose was escalated or reduced according to toxicity. There were no documented responses. The dose-limiting toxicity was myelosuppression. These data did not compared favourably with the data on doxorubicin in the treatment of gastric carcinoma. A conclusion could not be reached on whether idarubicin has minimal activity in the treatment of gastric carcinoma.
Splenectomy does not correlate with length of survival in patients undergoing curative total gastrectomy for gastric carcinoma. Univariate and multivariate analyses, The relationship between splenectomy and survival time after curative total gastrectomy for advanced gastric cancer was examined by reviewing retrospectively data on 252 patients treated in our clinics between 1965 and 1985. One hundred three patients (40.9%) did not undergo splenectomy and 149 (59.1%) did. In patients subjected to splenectomy. advanced stages of the malignancy were more frequent and metastasis was noticed in 8.1% of splenic hilar lymph nodes and in 10.1% of the lymph nodes associated with the splenic artery. A univariate analysis revealed that the survival time of patients with splenectomy was significantly less than those for whom splenectomy was not done (P less than 0.05). In a subgroup of our patients stratified to adjust for the stage of disease. there was no significant difference between the survival rates. Subsequently. multivariate analysis using the Cox regression analysis adjusted for sex. age. and other covariates indicated that serosa invasion. lymph node metastasis. and tumor size were the most important prognostic factors. and there was no correlation whatever with splenectomy. Our findings rule out any relationship between splenectomy and length of survival time in patients undergoing curative total gastrectomy for advanced gastric cancer.
Postresection autopsy findings in patients with cancer of the main hepatic duct junction, Extensive resection of the bile ducts combined with hepatic resection is the procedure of choice for carcinoma of the main hepatic duct junction. Currently this procedure is done without great risk. and increasing long-term survival is now the issue. For this purpose. it is necessary to elucidate the biologic properties of the cancer to take reasonable measures. Autopsy findings of patients who died of recurrence may offer a reliable guide. Autopsy findings were studied in 14 patients: eight who had undergone curative resection and six who had received noncurative resection. Cancer recurred at the liver hilum with invasion into adjacent organs. Peritoneal dissemination and lymph node metastases were infrequent. These were common findings in both curative and noncurative resection groups. Cancer cells in the connective tissue of the hepatoduodenal ligament may play a major role in recurrence.
Ganglioside GM3:GD3 ratio as an index for the management of melanoma, This report evaluates the relevance of the ratio of the melanoma-associated ganglioside. GD3. and its precursor. GM3. to prognosis and management of Stage II disease. Tumor biopsy specimens from 42 melanoma patients were examined for the ratio and found that GD3 and GM3 constitute 80% of the total lipid bound sialic acids (LBSA) of melanoma. Although the ratio of GM3:GD3 in melanocytes. the progenitors of melanoma. is 19:1 (based on %LBSA). it ranged from 15:1 to 1:5 in tumor biopsy specimens. Patients are categorized into three groups based on their GM3:GD3 ratio (%LBSA) of tumor tissues as Group I (ratio ranged from 15:1 to 1.5:1) (10 of 42). Group II (1.4:1 to 1:1.4) (13 of 42). and Group III (1:1.5 to 1:5) (19 of 42). When the overall survival of patients from the onset of Stage II disease was evaluated among different groups. patients belonging to Group I survived significantly longer than patients of Group II (P = 0.02) and Group III (P = 0.01). Interestingly. Group III expressed immunogenic gangliosides (GD2. GM2. and O-AcGD3) better than the other groups and may benefit more from therapies targeted against these gangliosides antigens. The results of this study indicate that GM3:GD3 ratio is an unusual but well-defined biochemical criteria that may be useful for prognosis and therapeutic management of the disease. Therefore. we propose a routine analysis of the GM3:GD3 ratio of tumors excised after surgery. Screening the ratio is feasible since melanoma expresses a simple profile of gangliosides unlike other forms of cancer.
Immunohistochemical studies of blood group-related antigens in human superficial esophageal carcinomas, A total of 63 surgically resected esophageal carcinomas (including 49 superficial esophageal carcinomas) and histologically normal tissue adjacent to the superficial carcinoma (nontumorous epithelium) were examined immunohistochemically for the blood group antigens (BGA) A. B. H. Lewisa. Lewisb. Lewisx. and Lewisy. Deletion of an expected A. B or H antigen occurred in 12 (24.5%) of the 49 superficial carcinomas and three (21.4%) of the 14 advanced carcinomas. Incompatible expression of an unexpected A or B antigens occurred in only one case (1.6%) in the carcinoma. In the clinicopathologic study. there was a significant correlation between immunoreactivity of Lewisa and depth of cancer invasion (chi-square test. P less than 0.05). In the superficial carcinoma. there were significant correlations between immunoreactivity of Lewisx and lymph node status (chi-square test. P less than 0.05). immunoreactivity of Lewisy and prognosis (Z test. P less than 0.05). and incompatible expression of Lewisb for tumor against nontumorous epithelium and histologic variation (chi-square test. P less than 0.01). The functional significance of alternations in BGA expression that may be associated with oncogenesis is not clear. However. immunohistochemical determination of BGA may be a more advantageous marker to predict the patient's clinical course in superficial esophageal carcinoma.
Immunohistochemical study of childhood rhabdomyosarcomas and related neoplasms. Results of an Intergroup Rhabdomyosarcoma study project, The authors assessed a panel of immunohistochemical stains against 109 pediatric solid tumors. primarily rhabdomyosarcomas. under the auspices of the Intergroup Rhabdomyosarcoma Study. Fresh tumor tissue received from participating organizations was divided into portions that were either frozen or fixed in formalin. alcohol. or B5. Immunostaining was performed by the avidin-biotin complex method using monoclonal antibodies to desmin. neurofilaments. vimentin. cytokeratin. and leukocyte common antigen on cryostat sections. Tissue was also embedded in paraffin and stained with antimuscle-specific actin (MSA) and polyclonal antibodies to desmin. creatine kinase M subunit (CKM). myoglobin. and neuron-specific enolase (NSE). Antidesmin staining of cryostat sections was the most sensitive indicator of rhabdomyosarcoma (58 of 62 specimens positive). Results with this reagent in alcohol-fixed and formalin-fixed tissue were similar (46 of 56 positive versus 43 of 56 positive. respectively) and comparable with results with anti-MSA in formalin-fixed tissue (43 of 55 positive). However. the proportion of cells stained by antidesmin was higher in alcohol-fixed tissue than in formalin-fixed tissue. Staining with antimyoglobin and anti-CKM was much less satisfactory. with positivity rates of 17 of 37 and 11 of 57. respectively. in formalin-fixed rhabdomyosarcomas. Immunostaining of muscle markers revealed evidence of myogenesis in six undifferentiated sarcomas and in two sarcomas with inadequate histologic study on hematoxylin-eosin-stained sections. However. positivity was also noticed in samples of fibromatosis. Wilms' tumor. ectomesenchyoma. peripheral primitive neuroectodermal tumor. renal rhabdoid tumor. myositis ossificans. malignant fibrous histiocytoma. and embryonal sarcoma of the liver. The authors conclude that combined use of antidesmin and anti-MSA enhances the diagnosis of childhood sarcomas. especially when employed with other techniques such as electron microscopic study.
Significance of aberrant immunophenotypes in childhood acute lymphoid leukemia, Leukemic cells from 51 pediatric patients (younger than 18 years) diagnosed with acute lymphoid leukemia by standard morphologic and cytochemical methods were subjected to flow cytometric studies using a panel of monoclonal antibodies against T-cell (CD1. 2. 3. 4. 5. 7. 8). B-cell (CD10. 19. 20. 21). myeloid (CD13. 14. 15. 33). and HLA-DR antigens. Cases of "conventional" acute lymphoid leukemia (leukemic cells with a normal configuration of B-cell or T-cell differentiation antigens) were observed in 26 of 51 (51%) cases. whereas cases of "aberrant" acute lymphoid leukemia (cells with abnormal patterns of B-cell or T-cell antigens or with concomitant myeloid antigens) were noticed in 25 (49%) cases. Myeloid antigen-positive acute lymphoid leukemia was observed in the leukemic cells of eight (16%) individuals. No significant differences were observed between conventional and aberrant ALL in the distribution of sex. age. leukocyte count. hemoglobin concentration. platelet count. blast count. French-American-British (FAB) type. lymphadenopathy. organomegaly. rate or duration of remission. or survival. When only myeloid antigen-positive cases were compared with myeloid antigen negative-cases. no significant correlations were observed except for duration of first remission (myeloid antigen positive. 26+ +/- 22 months; myeloid antigen negative. 40+ +/- 18 months; P less than 0.001). and duration of survival (myeloid antigen positive. 27+ +/- 24 months; myeloid antigen negative. 62+ +/- 17 months; P = 0.001). These data suggest that pediatric patients with ALL blasts possessing myeloid antigens may represent a high-risk group for length of remission and survival.
Adrenal carcinoma presenting as a lesion resembling cutaneous angiosarcoma, A case is reported of adrenal carcinoma presenting as an angiosarcoma-like metastasis in the scalp. Adrenal carcinoma is a rare tumor. and it metastasizes to skin rarely. The authors discuss the features of this tumor that led to a diagnosis of angiosarcoma and the means by which such a metastasis may be distinguished from vascular tumors.
Quantitative determination of acid-labile DNA in cervical intraepithelial neoplasia, Using a modified Feulgen hydrolysis procedure and integrating microdensitometry. the acid-labile nuclear DNA in exfoliated cervical epithelial cells was quantified in a range of histologically confirmed cervical intraepithelial neoplasia (CIN). invasive cancer. and normal controls. The mean relative optical densities obtained for each sample group showed an increase from normal epithelium. through CIN grades. to invasive cancer. Although there was some overlap between groups. the difference in the overall mean values between the adjacent groups was statistically significant. The sensitivity of the test was 87.1% with a specificity of 99.2% and a predictive value of 99.5%. with no false negatives in the severe dysplasia and cancer groups. Quantitative data allows the threshold value to be altered to vary the sensitivity and specificity according to prevailing requirements. This suggests the possibility of using quantitative acid-labile DNA measurements to improve existing screening for cervical precancer.
Quality of life assessment. An independent prognostic variable for survival in lung cancer, Improved quality of life has long been the goal of cancer treatment. but only recently have investigators begun to include a systematic assessment of quality of life in clinical trials. The major interest for its inclusion in clinical trials has been to assess treatment outcome. An evaluation of the relationship between patient-rated quality of life and survival is reported in a homogeneous sample of patients with advanced metastatic lung cancer participating in a clinical trial. Under the Cox proportional-hazards model (with quality of life. marital status. and their interaction in the model). a statistically significant relationship was observed between initial patient-rated quality of life and subsequent survival. In addition. being married led to a significantly improved survival. These findings suggest that nonmedical factors. such as quality of life assessment and marital status. play a role in survival and that they should be evaluated and described as potential predictors of survival in cancer patients in clinical trials.
Malignant melanoma arising in a dermoid cyst of the ovary, Autopsy findings of primary malignant melanoma arising in an ovarian dermoid cyst in an 86-year-old woman are presented. The right ovary was replaced by a dermoid cyst. 14 x 9 x 9 cm in size. in which several nodular tumors with diameters less than 3.2 cm were localized. They comprised diffusely proliferating anaplastic cells with prominent nucleoli. Some of them contained melanin pigments in the cytoplasm. The tumor cells were positive for S-100 protein and ultrastructurally showed melanosomes. In addition. several benign pigmented lesions resembling dermal nevus. pigmented schwannoma. or cellular blue nevus were present in the dermoid cyst. one of which contained a malignant melanomatous component. Histologic transition between benign and malignant components and the presence of another small focus of atypical melanocytes in the benign lesion suggested that the malignant melanoma arose in close association with the previously existing benign pigmented lesions in the dermoid cyst.
Prognostic factors in multiple myeloma, The pretreatment characteristics of 265 multiple myeloma patients treated between 1977 and 1983 were evaluated as potential prognostic factors for survival. Patients whose diagnosis was based on bone marrow plasmacytosis (greater than 30%) were noticed to have poorer survival (P less than 0.001). Although classification of patients according to stage has traditionally been used to identify prognostic groups. differences in survival were noted only between Stage III and Stage I or II patients using one of two common staging systems. Multivariate analysis using Cox's proportional hazards model identified the following prognostic factors in order of importance: plasmacytosis (hazard ratio [HR] = 2.2. 95% confidence interval [CI] = 1.49 to 3.27). hypercalcemia (HR = 1.68. CI = 1.22 to 2.32). hypoalbuminemia (HR = 1.51. CI = 1.15 to 1.99). alkaline phosphatase (HR = 1.62. CI = 1.18 to 2.23). hyperuricemia (HR = 1.46. CI = 1.09 to 1.96). and renal insufficiency (HR = 1.48. CI = 1.08 to 2.04). All patients were followed from 2 to 7.5 years and 130 (49%) survived over 2 years. Logistic regression analysis demonstrated that hyperuricemia. hypoalbuminemia. renal insufficiency. plasmacytosis. gender. alkaline phosphatase. and hypercalcemia were significant predictors of 2-year survival. Knowledge of these factors could be of value in predicting prognosis and planning therapy in patients with multiple myeloma.
Hypertensive heart disease in blacks, Although blacks may differ from whites in the response of hypertension to therapy. present data do not suggest that potential racial differences in cardiac structural adaptation to hypertension by themselves mandate a difference in therapeutic strategy. The results of large racially mixed trials of therapy that monitor LV mass regression. such as the VA Cooperative Monotherapy Trial. will be of interest in this regard.
Socioeconomic status and morbidity and mortality in hypertensive blacks, Despite an overall limited range of social and economic opportunities in the recent past. blacks of lower socioeconomic status have experienced marked excesses in hypertension-related burdens compared with their more advantaged peers: the incidence. prevalence. and severity of hypertension and its end-organ sequelae increased with decreasing educational achievement and the 5-year mortality was two times higher for black hypertensives of lower than higher educational achievement under conditions of usual care in U.S. communities in the 1970s. The Stepped Care program of antihypertensive pharmacologic therapy of the HDFP reduced all-cause mortality by 19% for black hypertensive men and 28% for black women. The HDFP also eliminated the association of mortality with educational achievement; the favorable impact of the program was greatest in the group at highest risk. blacks of lowest socioeconomic status.
Coronary artery disease in blacks: past perspectives and current overview, It is difficult to draw strong conclusions from the available data. One must simply accept the fact that vital statistics show that cardiovascular disease is the most common cause of death among black Americans. Health care providers. policymakers. and funding agencies should use this information to develop preventive and therapeutic strategies to conquer this dreadful disease.
Coronary heart disease: black-white differences, Important features of the racial patterns in CHD at the present time are summarized in Table 15-10. Many of these conclusions follow inevitably from the economic disadvantage suffered by blacks. and the overwhelming importance of hypertension in this population. More knowledge is needed regarding the value of standard diagnostic tools in distinguishing noncoronary from coronary chest pain symptoms. A hard look is also needed at questions of access for blacks. particularly to angioplasty and thrombolytic therapy. There is additional growing evidence that the gains against CHD have been concentrated primarily among the educated and affluent. New strategies will need to be developed if we are to repeat the kind of gains against cardiovascular disease among blacks in the 1990s that were made in the 1970s and 1980s.
Prevention of adult heart disease beginning in childhood: intervention programs, Multiple strategies are available to affect children's cardiovascular health. From clinic-based high-risk counseling to broad-based school or community programs. intervention strategies are being developed and tested to find the most effective means of changing the risk factors of youth to assure a healthier future for our children. Since adoption of new behaviors is improved by consistent messages from multiple sources. a concerted effort is needed. The involvement of health professionals. educators. community organizations. industry. and government together will be important to support the adoption of healthy lifestyles for succeeding generations. Intervention through cardiovascular health promotion for school children may well be the future direction for preventive cardiology.
Prevention of coronary heart disease in black adults, Development of strategies to prevent CHD in blacks is impeded by the virtual absence of clinical trials demonstrating the feasibility and effectiveness of interventions in blacks. The wholesale generalization that interventions effective (or ineffective) in whites are similarly effective in blacks may risk the employment of worthless or even dangerous interventions in blacks. Using available epidemiologic data. a number of risk factors may be more important in blacks than whites by virtue of higher prevalence. increased relative risk. or both. These may include hypertension. lipoprotein (a). smoking. diabetes. and obesity. Thus. health agencies might emphasize these risk factors when developing preventive programs targeted at black populations. Prevention programs may best seek to prevent the onset of risk factors found highly prevalent in black communities. rather than the costly and side-effect-prone interventions to treat risk factors once established. Thus. there is a role for community-based as well as a high-risk approaches. The community-based approaches should seek to work with organizations such as churches. which traditionally play strong roles in the black community. Physicians treating black patients should be aware of the potentially different roles played by risk factors. and treat aggressively those individuals identified to be at high risk. Risk factor management should be emphasized. rather than reduced. in patients with already established CHD. CHD has been clearly shown to be preventable; both blacks and whites should benefit from specific interventions aimed toward this worthy goal.
Cardiomyopathy in blacks, The intent in this chapter has been to bring to general awareness the fact that myocardial dysfunction represents a significant proportion of cardiovascular disease affecting blacks; in particular. dilated cardiomyopathy is a new frontier in cardiology. which demands an aggressive approach. At present. the prognosis is not good in the majority of cases; despite the best medical therapy. most of those with cardiomyopathy are doomed to death within a few years after the onset of congestive heart failure. Many of these are young African-American men in the prime of their lives. Cardiac transplantation offers some hope from this desperate situation. but donor shortages as well as restrictive criteria for prospective recipients and socioeconomic constraints. which may deny many blacks the opportunity to receive a transplant. make this option less than ideal.
Risk factors and the natural history of coronary heart disease in blacks, Contrary to early impressions of blacks' relative immunity to CHD. it is now clear that African Americans experience greater mortality from CHD than whites. The natural history of CHD differs between blacks and whites in three important respects: First. greater prevalence of established risk factors among blacks suggests that they may be at greater risk for heart disease than their white counterparts. Second. health care seeking differences are evident between blacks and whites. leading to lower rates of identification of early disease and slower seeking of services for acute events. However. risk factor differences and health care seeking behaviors do not appear to account for all of the differences in the natural history of heart disease between the ethnic groups. such as survival rate differences during treatment. Economic factors appear to account for only a portion of these differences in risk factors and health care seeking. Beyond differences in risk factors and health care seeking. other. as yet undetermined. factors seem to be involved. These unknown influences could include physiologic. behavioral. and/or psychologic differences.
Heart disease in blacks of Africa and the Caribbean, Cardiovascular pathology in African and Afro-Caribbean blacks features three major conditions: hypertension. rheumatic heart disease. and the cardiomyopathies. Ischemic heart disease is as yet distinctly uncommon in these societies but the adoption of Western lifestyle and its inevitable risk factors for atherosclerosis makes it likely that coronary artery disease will emerge ultimately. Hypertension poses special problems in these regions--its prevalence rate is high both in rural and urban settings. its consequences devastating in its severity of target organ involvement. and its management strategy complicated by the high cost of drugs. poor patient compliance. and the lack of clinical resources for effective monitoring of detected and referred cases. Rheumatic heart disease remains an eminently preventable condition. The ultimate strategy lies in improving the quality of life in these communities through adequate housing. sanitation. and health education. and integrating primary prophylaxis into national health care programs to forestall the development of rheumatic fever. Cardiomyopathy poses the greatest challenge as its etiology remains elusive. Its dilated form has been linked with Toxoplasma and with Coxsackie B viruses. but hard evidence of a cause-effect relationship is still lacking.
Hypertension in blacks: clinical overview, Although the decline in stroke and other cardiovascular morbid and mortal events has been occurring since the 1940s. the steeper decline since 1968 has been attributed to improved hypertension awareness. treatment. and control. However. in spite of this encouraging trend from the population in general. surveys from the 1970s and our more recent survey from the Maryland Hypertension Program indicate that hypertension control among blacks remains unacceptably poor. particularly in view of the high prevalence. Of special concern are black men. who have the highest prevalence of any group and the poorest control rate (see Tables 6-1 through 6-4). According to Gillum and Gillum. "High rates of non-compliance with follow-up and drug therapy seriously compromised the efforts of community-wide programs. Indeed. non-compliance with therapeutic or preventive health advice is now the major barrier to effective hypertension control in the United States." Impediments to ideal hypertension control in black communities can be divided into three categories 1. Severity of hypertension in blacks. 2. Barriers related to the medical care system. including inadequate financial resources (see also Chapter 5). inconveniently located health care facilities. long waiting times. and inaccessibility to health education. specifically as it relates to hypertension. 3. Barriers related to the social. psychosocial. and sociopolitical environment. which include problems of underemployment. unemployment. racism. and strained racial relationships. In summary. one could say that. in spite of generally improved hypertension control in the United States. the group that has the worse problems (blacks. especially males) is not benefiting as much as the general population. The strategy for treating black patients with hypertension is little different from that applied to all other patients. However. consideration must be given to the patients' lifestyle. The cultural differences in diet especially must be taken into account. Finally. economic considerations must always be an important component in managing black hypertensive patients. For a detailed discussion of treatment alternatives. see Chapter 11.
The pathogenesis of hypertension: black-white differences, In summary. for reasons that are not clear. some persons seem to be extremely good at retaining sodium on a high-sodium diet or poor at excreting sodium on a high-sodium intake. This is more frequent in Western hemisphere blacks than in whites in the West or in blacks in Africa. These geographic/ethnic differences in sodium handling ability may be related to environmental factors or. more likely. to inherited differences in the ability to conserve sodium based on the evolutionary principle of survival fo the fittest for the ability to conserve sodium. The frequency of this salt-conserving (thrifty) genotype in Western hemisphere blacks may have been further increased as a consequence of severe selection pressures for survival based on the ability to conserve sodium during the slavery period of history in the West. One characteristic of the blood pressure control systems of Western hemisphere blacks is suppression of plasma renin activity without suppression of aldosterone production. In addition there is greater nephrosclerosis in blacks than whites and a more rapid decline in creatinine clearance with age. When more sodium is ingested than the kidneys are able to handle (excrete). there is a (transient) slight positive sodium balance; as a result sodium. chloride. and water are retained. resulting in an expansion of plasma volume (Fig. 7-3). The initial physiologic responses include (increased) secretion of atrial natriuretic peptides and the digitalis-like substance (natriuretic hormone). and inhibition of vasopressin and aldosterone secretion. The net effect is directly enhanced natriuresis and diuresis. and a reduction in plasma volume. with no significant effect on blood pressure. However. if there is a continuing tendency to sodium retention and volume expansion. the capacity of the aforementioned mechanisms to control plasma volume will be exceeded; then. the chronically elevated level of the digitalis-like substance will inhibit the sodium pumps in the arterial and venous smooth muscle cells and in the sympathetic neurons. The increased venous tone will help to reduce plasma volume directly by reducing central venous volume. Arterial tone will be increased by direct action of the digitalis-like substance on the arterial smooth muscle and. indirectly. via the hormone's action on the sympathetic neurons. Initially. of course. blood pressure will be maintained in the normal range (but will be labile) because of the compensating cardiovascular reflexes. Once the capacity of these reflexes to control blood pressure is exceeded. however. the blood pressure will begin to rise; this will induce a pressure natriuresis to help restore plasma volume to normal.(ABSTRACT TRUNCATED AT 400 WORDS).
Tibial cortical bone peg fixation in osteochondritis dissecans of the knee, Ten knees in nine patients with large. symptomatic osteochondritis dissecans lesions of the knee were treated by cortical bone peg fixation. The follow-up time averaged 2.9 years (range. 0.9-6.6 years). The average age was 19.5 years (range. 15-33 years). The knees were evaluated and rated clinically and roentgenographically. Magnetic resonance (MR) imaging of nine knees was obtained at the follow-up examination to evaluate lesion and bone peg incorporation. evidence of lesion loosening. and the articular cartilage. Eight good to excellent. one fair. and one poor result were obtained clinically. MR imaging showed 33% of knees had poor lesion cartilage and 44% had partial or poor lesion incorporation possibly consistent with loosening. Complications included four partial defect healings. one tibial donor graft-site fracture. and one bone peg loosening. Four symptomatic knees had follow-up arthroscopy at an average of 1.8 years postsurgery and findings included four loose bodies. one loose peg. one meniscal tear. and one symptomatic hypertrophic synovium. MR imaging was a useful tool in evaluating lesion stability. articular cartilage quality. lesion and bone peg incorporation. the menisci. and cruciate ligaments. Bone peg fixation of large osteochondritis dissecans defects of the knee offers a physiologic approach to treatment of this lesion in nearly skeletally mature or skeletally mature patients.
Porous-coated anatomic total knee arthroplasty. A prospective analysis comparing cemented and cementless fixation, The results of 26 cementless porous-coated anatomic (PCA) total knee arthroplasties (TKAs) were analyzed and compared to 25 cemented PCA TKAs. Identical prospective protocols were followed. The mean preoperative and postoperative knee scores at an average three-year follow-up interval (range. two to five years) were 59.6 and 81.5 for cementless knees compared to 57.6 and 80.4 for cemented knees. The difference was not statistically significant (p greater than 0.10). Blood loss was significantly higher in the cementless knees (p = 0.02). Radiolucent lines. loose beads. and tibial component subsidence were more frequent in cementless knees. No differences between cementless and cemented knees were observed in the femoral components. The PCA femoral components implanted without cement compare favorably to those implanted with cement. The PCA tibial and patellar components are more reliably secured with cement.
Residual functional deficit after partial fibulectomy for bone graft, The residual functional deficit caused by partial fibulectomy for bone graft was documented with subjective assessment and clinical and instrumented examination in ten patients. The donor leg often remained mildly symptomatic. Residual weakness occurred when the middle one third of the fibula was excised. However. mild discomfort. residual weakness. and laxity were not considered significant enough to discourage transplantation of large segments of the fibula. Postoperative therapy should emphasize muscular strength to minimize the functional deficit.
Profiles of spinal cord injury and recovery after gunshot injury, Prospective motor and sensory examinations were conducted on 135 patients with neurologic deficits caused by spinal cord injuries resulting from gunshot wounds. Annual follow-up motor and sensory examinations were conducted for 67 patients. The neurologic data (motor and sensory neurologic levels of injury. zone of injury. and completeness of lesion) were assessed in terms of the vertebral level of injury. region of injury. bullet caliber. direction of bullet entry. and whether the bullet penetrated the spinal canal. completely traversed the spinal canal. or entered and remained lodged in the spinal canal. Seventy-seven of the patients sustained complete lesions and 58 sustained incomplete lesions. Anatomically. 19.3% of the injuries were in the cervical region. 51.8% in the thoracic. and 28.9% in the thoracolumbar. In 93 cases. the neurologic level was at least one level higher than vertebral level of injury. Although twice as many individuals were shot from the back as from the front and from the left as from the right. the point of bullet entry did not appear to be related to the severity of the injury. At the annual follow-up examinations. 66.7% of the patients with complete lesions and 64.0% of the patients with incomplete lesions had no improvement in the neurologic level of injury. Nevertheless. there was a significant (p less than 0.0001) improvement in the American Spinal Injury Association motor index scores one year after injury.
Roentgenographic assessment in hallux valgus, Which simple roentgenographic angle should be used to assess medial (varus) deviation of the first metatarsal in cases of hallux valgus has been a topic of debate. Measurements were made from roentgenograms of 100 symptomatic feet in women with hallux valgus. These were compared with similar measurements obtained from symptomatic normal feet of women of a similar age distribution. The hallux valgus angle was associated with medial deviation of the first metatarsal measured by all three of the parameters defined and tested. i.e.. the intermetatarsal. metatarsus primus varus. and metatarsus omnis varus angles. Of these. the best measure was the intermetatarsal angle. which in the hallux valgus feet differed significantly from controls more than the other measurements. No evidence was found to support any concept of second metatarsal deviation from normal.
Surgical treatment of forefoot deformity with special reference to polyarthritis, Among 523 patients consecutively treated for forefoot pain and deformity. 64 had inflammatory arthritis. Most patients no longer had difficulties finding shoes that fit after the deformities were surgically corrected. Although about one half of the patients had some residual symptoms after treatment. 57 (89%) were satisfied with the operation. If the deformities are corrected early. joint resections can be avoided and toe function preserved.
Early mobilization of ankle fractures after open reduction and internal fixation, The effect of early mobilization and unrestricted weight bearing on final ankle motion in 51 operatively stabilized ankle fractures was prospectively investigated. Patients were treated with an ankle-foot orthosis (AFO) or a cast. Full weight bearing was unrestricted in both groups. Thirty-two fractures received an AFO and 19 received a cast. The follow-up period ranged from 2.3 to 66 months. with a median of eight months. At the final follow-up examination. the motion in the AFO-treated group was not functionally different from that of the cast-treated group. However. 72% of the patients treated in an AFO compared with 37% of patients treated in a cast had ankle dorsiflexion greater than 15 degrees (p = 0.014). No complications were directly related to the AFO. No loss of reduction occurred in any patient. The results of this series indicate that early motion of a fractured ankle treated operatively does not affect ankle motion. Early motion was not associated with increased morbidity or loss of reduction.
A study of function and residual joint stiffness after functional bracing of tibial shaft fractures, Ninety-eight diaphyseal tibial fractures were treated with custom made functional braces in 97 patients older than 14 years of age. The average follow-up period was 1.86 years. and 53 patients had more than two years' evaluation (average. 2.83 years). The majority of the patients did not have full range of movement in the ankle and subtalar joints when the brace was removed after fracture healing. Although the stiffness decreased with time. a significant number of patients were left with residual joint stiffness. At an average follow-up period of 1.86 years. 68.4% of the patients had normal ankle motion and 60% had normal inversion and eversion of the hindfoot. In patients with more than two years' evaluation. 75.5% had normal ankle movement and 71.1% had normal inversion and eversion of the foot. In the knee joint. the incidence of residual joint stiffness was small and the amount of stiffness was clinically insignificant. Patients with an abnormal walking pattern after fracture healing had a high incidence of ankle and subtalar joint stiffness.
Percutaneous cerclage wiring and interlocking nailing for treatment of torsional fractures of the tibia, A new method for treatment of torsional tibial fractures allows full weight bearing two days post-operatively. Percutaneous cerclage wiring (Gotzes method) is done after a manual anatomic reduction on a normal fracture table. followed by static interlocking nailing. Compared to other methods. no extensive exposure is necessary. which helps preserve the periosteal blood supply. These considerations. as well as an early axial pressure load and an almost absolute stability. might explain the roentgenographic and clinical evidence that bone healing with minimal callus formation occurs six to eight weeks postoperatively.
Biomechanical characteristics of interlocking femoral nails in the treatment of complex femoral fractures, Interlocking intramedullary (IM) nails allow more comminuted and proximal or distal femoral fractures to be successfully treated than previously possible with routine IM nailing. Autopsy specimens were prepared to evaluate the effectiveness of different locking mechanisms on fracture site stability. Grosse-Kempf (GK) and Brooker-Wills (BW) IM nails were inserted in anatomic specimen femurs with transverse fractures and 1-. 2-. and 3-cm defects. The femurs were loaded in four-point bending. and bending stiffness was calculated. The femurs were also loaded in torsion. and the amount of slippage between the nail and bone (at 10 Nm of applied torque) was measured. The GK nail. fully interlocked. had the lowest amount of rotational slip. followed by the BW and the GK noninterlocked nail. Bending stiffness was not significantly different for these IM nails.
Brucellosis complicating bilateral total knee arthroplasty, Infection after arthroplasty is a serious complication associated with a high incidence of morbidity. A 24-year-old woman developed brucella septic arthritis in both knees following bilateral total knee arthroplasty. This complication appears not to have been previously reported in the literature.
Osteoid osteoma. Diagnosis, localization, and treatment, The preoperative insertion of a needle under computed tomographic scan. performed under local anesthesia. is a convenient and important new way to localize the nidus in osteoid osteoma. It necessitates less bone removal. which should reduce the postoperative fracture rate. It should also help to locate the lesion during surgery. Some clinical points and previously unstressed pathologic findings are also discussed.
Peroneal nerve repair. Surgical results, Eleven patients had either repair (two) or nerve graft reconstruction (nine) of the common peroneal nerve or its superficial or deep divisions about the knee. The average follow-up period was 29.1 months. A good or excellent result was achieved in six (54.5%) patients. The results appeared best when direct nerve repair was possible or when a defect of 6 cm or less required grafting. Peroneal nerve exploration and repair or reconstruction as required seem indicated for known nerve disruption or unknown nerve continuity if there is no suggestion of continuing recovery by three to six months after the injury.
Continuous passive motion versus immobilization. The effect on posttraumatic joint stiffness, Management of intraarticular fractures is often complicated by joint stiffness long after bony healing has occurred. The following experiments provide biomechanical evidence for the effectiveness of CPM in maintaining joint function in stabilized articular injuries. The ankles of ten adolescent New Zealand white rabbits were penetrated by Steinmann pins to create an intraarticular injury. One limb of each animal was immobilized. and the contralateral limb was placed in a continuous passive motion (CPM) machine for three weeks. Joint stiffness of each ankle was quantified with an arthrograph before injury and after three weeks of treatment. Hindlimb volumes were recorded before injury and monitored at weekly intervals using a water-displacement method. Joint stiffness increased 2.6 times the preinjury levels in limbs that were immobilized for three weeks. There was no statistically significant increase in joint stiffness in ankles treated with CPM compared to preinjury values. The posttraumatic difference between the CPM-treated and immobilized limbs was highly significant; limb swelling was not affected by CPM.
Tetracycline labeling of the femoral head following acute intracapsular fracture of the femoral neck, The purpose of this study was to assess the utility of tetracycline hydrochloride (HCl) labeling of the femoral head following acute intracapsular fracture of the femoral neck to indirectly assess femoral head viability and vascularity. A standard labeling (1.5-3.0 g) and fixative protocol (70% ethanol) was used. The initial tetracycline dose was given in the emergency room. The time from last dose to bone sampling in the operating room ranged from six to 36 hours (average. 21.2 hours). There was no evidence of tetracycline deposition at the bone-osteoid interface in any of the femoral head specimens or the ipsilateral extracapsular greater trochanter control specimens. Sources of labeling failure are multifactorial: problems with label delivery to the patient. in vivo deposition of the label. and the fixation protocol.
Malignancy supervening on an intramedullary nail, A primary. malignant. fibrous histiocytoma of bone occurring in association with a Hansen Street intramedullary nail occurred in a 39-year-old man. The physical and chemical characteristics of materials. in relation to the generation of secondary neoplasia are reviewed. but the problem of coincidence is difficult to exclude.
Autograft and Leeds-Keio reconstructions of the ovine anterior cruciate ligament, This study compared the Leeds-Keio prosthesis with grafting of autogeneic patellar tendon for the reconstruction of the ovine anterior cruciate ligament under controlled conditions. Reconstructed knees from six sheep of each group were evaluated at 12. 26. and 52 weeks postreconstruction with respect to clinical assessment. gross pathology. mechanical properties. and histology. Although no difference in clinical assessment (anteroposterior draw. range of motion. and function) was noted between the prosthesis reconstruction and the autograft reconstruction. the prosthesis provided a higher strength initially. which remained relatively constant over the one-year study. However. prosthesis wear was observed. with up to 50% of Dacron fibers ruptured in some cases. Histologic sections indicated that in the ovine model. the Leeds-Keio prosthesis should be considered an artificial device and not a scaffold or stent that supports aligned collagenous growth. The autograft had low strength at 12 weeks. which increased over the study period. Despite acceptable clinical performance and adequate mechanical properties up to one year postimplantation. neither reconstruction approached the clinical or mechanical performance of the normal anterior cruciate ligament in the ovine model.
A new surgical classification system for shoulder-girdle resections. Analysis of 38 patients, A new. six-stage surgical classification system is described for shoulder-girdle resections for patients being treated by limb-sparing procedures for bone and soft-tissue tumors. The classification is based upon current concepts of oncological surgery. the structures removed. the type of resection performed. and the relationship of the resection to the glenohumeral joint. and it indicates the increasing surgical magnitude of the procedure. Data from 38 patients with an average follow-up period of 4.6 years (range. two to 8.4 years) were analyzed. Thirty-two tumors were in bone and six in soft tissue. Eighty-seven percent (33 of the 38 tumors) were malignant. Twenty-four lesions were located in the proximal humerus and 14 in the scapula. The system permitted classification of all shoulder girdle resections done in this study's institutions. The classification is proposed as a means of establishing a uniform terminology in the comparison of such data.
Arthroscopic treatment of massive rotator cuff tears. Clinical results and biomechanical rationale, Ten patients with painful. massive (greater than 5 cm). complete rotator cuff tears involving primarily the supraspinatus were treated with arthroscopic acromioplasty and rotator cuff debridement. All patients except one had normal active motion and strength preoperatively. All patients had roentgenographically normal acromiohumeral distance and an anterior-inferior acromial osteophyte. The goal was to obtain pain relief without loss of motion of strength. This was accomplished in all patients. This study shows that normal shoulder function is possible with a massive unrepaired tear of the rotator cuff. Normal function in the face of an unrepaired cuff tear can occur only if there is a balance of two important force couples. one in the coronal plane and the other in the transverse plane. This balance depends upon the functional integrity of the anterior cuff. the posterior cuff. and the deltoid. In patients whose cuff tears satisfy these anatomic and biomechanical criteria. the achievement of pain relief through arthroscopic debridement and decompression seems to be all that is necessary for normal pain-free function.
Rotator cuff pathology. Arthroscopic assessment and treatment, The results of 50 operative arthroscopies for impingement syndrome were reviewed. Preoperative arthrography was correlated with arthroscopic findings. which were pathologically graded. Results of arthroscopic surgery were assessed. Preoperative arthrography predicted 78% of the complete tears of the rotator cuff and only 25% of the partial tears. Of 40 shoulders followed for at least one year postoperatively. 87.5% had satisfactory results. Arthrography was not as reliable as arthroscopy in predicting partial tears of the rotator cuff. Arthroscopy permitted detailed intraarticular and subacromial visualization and classification of partial and complete tears of the rotator cuff. The early results of arthroscopic acromioplasty and debridement are comparable to those obtained with open operations.
Internal fixation of femoral neck fractures. A comparative biomechanical study of Knowles pins and 6.5-mm cancellous screws, In a comparative biomechanical study of the stability of experimentally produced femoral neck fractures fixed with Knowles pins or with 6.5-mm cancellous screws. 12 matched pairs of anatomic specimen femurs were divided into four groups of standardized osteotomies. One member of each matched pair was fixed with three or four 6.5-mm cancellous screws. whereas the other member was fixed with the same number of Knowles pins. Mechanical testing was performed on an Instron testing machine. There was no statistically significant difference in maximum load to failure or in fixed stiffness between the two methods of fixation. When examining maximum load to failure. three of either device provided fixation equivalent to four. Although there was a difference in absolute fixed stiffness between specimens fixed with three Knowles pins compared to four. when stiffness was expressed as a percentage of intact stiffness. there was no difference between any fixation group. From an analysis of the observed modes of failure and from calculations of the flexural rigidity provided by the devices. it is proposed that the quality of the trabecular bone of the femoral neck is a major factor in the experimental fixation of femoral neck fractures.
Newborn chemical exposure from over-the-counter skin care products, Human exposure to potentially toxic environmental chemicals is a major concern to our society. Over-the-counter (OTC) skin care products are a potential source of environmental chemical exposure to newborns. A prospective study was undertaken to define existing newborn bathing practices and quantitate environmental chemical exposure from OTC skin care products. One hundred-ninety six mothers of infants discharged from our newborn nursery were asked to respond to a questionnaire concerning newborn bathing practices and OTC skin care product usage. Complete questionnaires were returned by 23% of the mothers. The average newborn had 8 +/- 3 (+/- SEM) skin care products applied with the resultant exposure to 48 +/- 18 different environmental chemicals. Forty-seven percent of our respondents used a baby powder. The average one month old was bathed 4 times a week and was shampooed 3 times weekly. Seventy-eight percent of the respondents reported that their newborn had a rash but only 45% of those reporting a rash sought professional medical advice. Thirty-seven percent of the mothers reporting a rash made a change in bathing practice or product selection. In view of our findings. the human newborn is exposed to a large number of environmental chemicals thorough topical OTC preparations. The efficacy. transcutaneous absorption and potential toxicity of these products should be investigated.
The long term benefits of a comprehensive teenage pregnancy program, A comprehensive program was founded in 1982 to provide adolescents with prenatal and family planning care. The program's impact through its first five years of operation on medical aspects of pregnancy course and fetal outcome will be the subject of a separate report. This study examines subsequent maternal and infant health of the patients attending the program compared to a control group. Four hundred ninety-eight adolescents and their newborns attending the program's mother-baby family planning clinic from 1982 to 1989 (subject group) were compared to ninety-one adolescents and their newborns receiving postpartum family planning and pediatrics clinics from 1980 through 1989 (control group). Seventy-five percent of the subject group regularly attended mother-baby clinic. compared to 18% of the control group attending family planning and pediatric clinics (P less than or equal to .0001). The subject group experienced less maternal and infant morbidity. greater school attendance. graduation. employment. and contraceptive use than the control group (P less than or equal to .0001). Many parameters improved with each program year indicating continued wide acceptance of our program by area adolescents.
Enterobacter cloacae bacteremia in children: a review of 30 cases in 12 years, A review was performed of the 30 cases of pediatric Enterobacter cloacae (EBC) bacteremia which occurred at our institution during a 12-year period. These 30 cases represented 88% of all cases in which EBC was isolated by blood culture (four other instances were considered contaminants); the rate of isolation of this organism relative to all positive blood cultures was 0.6%. There were 14 patients less than 12 months of age. with 10 less than 2 months of age. Infection was nosocomially-acquired in 17 cases. At the time the positive blood culture was obtained. 5 patients were afebrile. and 8 patients (five immunocompromised) had been receiving parenteral antibiotic therapy to which the organism exhibited in-vitro sensitivity for at least 24 hours. EBC was a constituent of polymicrobial bacteremia in 6 cases; in 5 instances the associated organisms were also gram-negative bacteria. There were a total of 33 underlying medical conditions or foci of infection associated with EBC bacteremia identified in 27 patients. the most common of which were immune-deficiency state (17) and gastrointestinal tract lesions (6). There were 3 patients who died. EBC bacteremia is a relatively rare pediatric infection. It is commonly nosocomially-acquired. and afflicts children who are younger-aged or compromised by underlying medical problems.
Corticosteroid sensitivity and cross-sensitivity. A review of 18 cases 1967-1988, 506 patients were suspected of being allergic to corticosteroid medicaments in our clinic during the 22 years from 1967 to 1988. Patch tests were performed in these patients. Scratch tests. intradermal tests. and challenge tests were also carried out in some cases. 69 patients showed positive reactions to corticosteroid products (as is). 18 were allergic to the corticosteroid itself and 44 were sensitive to vehicle components or other active ingredients. In 7 cases. the allergen could not be detected. Patients who were allergic to corticosteroids were tested for their cross-sensitivity with our corticosteroid patch test series. Cross-reactions tended to occur between members of the same corticosteroid type. and some of the combinations of different corticosteroid types cross-reacted with each other. Corticosteroid-sensitive cases have increased in number during these 22 years. Corticosteroid sensitivity is not as rare as formerly thought.
Contact sensitization of mice to nickel sulphate and potassium dichromate, The ability of nickel sulphate and potassium dichromate to induce contact sensitization in mice has been investigated. Topical exposure of mice to 0.5% potassium dichromate in dimethylsulphoxide (DMSO) under occlusion resulted in specific contact sensitization in each of 7 experiments. Although sensitization to nickel sulphate under the same conditions was weak and somewhat variable. evidence for significant levels of contact allergy was obtained in 4 of 7 experiments. In addition. repeated topical application of both nickel sulphate and potassium dichromate in DMSO was found to result in the induction of lymphocyte proliferative responses in lymph nodes draining the site of exposure. These data indicate that epicutaneous exposure to both metal salts may cause specific contact sensitization in mice.
A quantitative structure activity/dose response relationship for contact allergic potential of alkyl group transfer agents, As part of the investigation of structure activity relationships in contact allergy. it has been shown that methyl transfer agents are capable of acting as skin sensitizers. This work has now been extended to a more general examination of alkyl transfer reactions. The modified single injection adjuvant test has been used to investigate the sensitization potential of C12. C16 and unsaturated C18 alkyl transfer agents. Dose responses to challenge and the patterns of cross-reactivity between these materials and methyl transfer agents have been studied. All alkyl transfer agents examined were potent sensitizers in the guinea pig. There was evidence of mutual cross-reactivity between all alkyl transfer agents examined (including methyl transfer agents). Analysis of the data in terms of a modified relative alkylation index showed evidence of an overload effect. The sensitization data has been accurately modelled using a mathematical equation. These results emphasize the possibilities for relating physicochemical parameters and skin sensitization potential. Further studies with alkyl transfer agents are in progress of amplify the observations and conclusions presented in this report. No in vitro model is available for the prediction of skin sensitization potential. Therefore an approach based on a model using physicochemical criteria is the most likely route to a reduced requirement for animal testing.
Contact and photocontact allergy to ketoprofen: clinical and experimental study, In the last 3 years. we have studied 10 patients with allergic reactions to topical ketoprofen. We have investigated the sensitization and irritant potential of the drug and the possibility of cross-reactivity with other aryl-propionic non-steroidal anti-inflammatory drugs (ibuproxam. ibuprofen. naproxen. fenoprofen. flubiprofen and tiaprofenic acid). 2 of our patients had contact dermatitis. and the other 8 photocontact dermatitis. One of our patients showed cross-reactivity between ketoprofen and ibuproxam on patch testing. In the photopatch tests. we observed cross-reactivity between ketoprofen and tiaprofenic acid in 2 patients. and cross-reaction between ketoprofen and ibuproxam and flurbiprofen in another case. Experimental studies. including human maximization and photomaximization tests. performed in 20 healthy volunteers. showed a complete absence of sensitization. 3 volunteers showed a marked irritant reaction to ketoprofen (20% pet.) during either maximization (2 cases) or photomaximization (1 case) tests. Although ketoprofen appears not to be a sensitizing agent in human volunteers. the fact that photosensitization to this drug seems to be quite common after topical use suggests that there are some local or individual factors. at present unknown. facilitating the development of allergy.
Sensitizing risk of butylated hydroxytoluene based on exposure and effect data, A national database on chemical products (the Danish Product Register (PROBAS) was searched for products containing butylated hydroxytoluene (BHT). As of March 1990. 440 products containing BHT were registered. The content of BHT was below 50 ppm in 66% of these products. Paints/lacquers (1- and 2-component) and hardeners for 2-component paints. glues. fillers. etc. make up the main categories. No positive reactions were seen in 1336 consecutive eczema patients patch tested with BHT. From the widespread use of BHT. it was considered that BHT could be regarded as a safe antioxidant in the normally used concentrations. The possibilities. limitations. and demands of product registration as exposure estimates are discussed.
Inhibitory effect of zinc oxide on contact allergy due to colophony, Contact allergy to a wound dressing with an adhesive mass consisting of colophony. zinc oxide and rubber (Mezinc) was studied in 179 patients with a history of eczema. 12 patients were found to be allergic to colophony. whereas only 4 of these patients also showed a positive patch test reaction to the wound dressing. 14 patients with verified moderate contact allergy to colophony were patch tested with adhesive mass (10%). Portuguese colophony (10%). zinc oxide (10%). purified resin acids (10%). and Portuguese colophony (10%). in combination with zinc oxide. Only 3 patients reacted to the adhesive mass. whereas all patients showed a positive patch test reaction to Portuguese colophony. A combination of zinc oxide (10%) with Portuguese colophony (10%) provoked a positive patch test reaction in only 5 of these 14 patients. An allergic reaction to abietic acid (90-95% purity) was found in 7 patients and to neoabietic acid (99 + %) in 3 patients. whereas no reactions to dehydroabietic (99 + %). isopimaric (99 + %) or levopimaric acids (98 + %) were found.
Contact allergy due to colophony (VII). Sensitizing studies with oxidation products of abietic and related acids, 9 oxidation products of abietic acid. dehydroabietic acid. and levopimaric acid were prepared synthetically to determine their sensitizing potential in guinea pigs. It was found that compounds with epoxy and peroxo groups in rings A and B had a notable sensitizing potential. The same result was found with 7-oxode-hydroabietic acid identified earlier in rosin (3) and a polar fraction obtained from commercial abietic acid. suggesting the presence of still unidentified oxidation products. Hydroxylation of rings A or B. or conversion to the methyl esters. considerably decreases the sensitizing potential. A model is presented underlining the importance of hydrophobic and polar domains. in addition to chemically reactive groupings. in the allergen. Insertion into the lipid bilayer may play an important role in contact sensitivity.
Phototoxicity due to Cachrys libanotis, After classification and identification of the plant. the alcoholic extract of Cachrys libanotis L. was analysed in order to identify the phototoxic agents. The substances responsible for photodermatitis were found to be 4 furocoumarins. of which 3 have been clearly identified. namely 5-methoxy-. 8-methoxy- and 5.8-dimethoxypsoralen. The structure of a 4th compound was not completely defined.
The nickel content of certain commercially available metallic patch test materials and its relevance in nickel-sensitive subjects, The nickel contamination of the metallic patch test substances from 3 commercial sources was estimated by atomic absorption spectrophotometry. Contamination was generally greatest in the cobalt patch test substances. To determine whether the levels of contamination encountered were sufficient to produce a false positive patch test. 20 nickel-sensitive patients were patch tested to various concentrations of free elemental nickel in aqueous solution. The level of nickel contamination was less than that required to produce a false positive patch test in our patients. but was at a level which could produce false positive reactions in subjects highly sensitive to nickel.
Cutting oil dermatitis on guinea pig skin (I). Cutting oil dermatitis and barrier cream, We assessed the effect of repeated application of cutting oil on 9 guinea pigs' skin by visual scoring and skin water vapour loss measurement. The visual scores (severity score) were significantly higher on skin treated with cutting oil (positive control) compared to untreated skin (negative control). The corresponding mean SVL values were also significantly higher. We also assessed the effect of 2 barrier creams on the 9 guinea pigs' skin treated with cutting oil. The visual scores on skin treated with either barrier cream were significantly higher than positive control skin. The corresponding mean SVL values on skin treated with either barrier cream were also higher (not statistically significant). It appeared that the 2 barrier creams did not confer protection against the irritant effect of the cutting oil. On the contrary. barrier creams appeared to exacerbate the irritant effect of cutting oil.
Minimum eliciting patch test concentration of thimerosal, Positive patch test reactions to thimerosal 0.1% pet. (40/690 subjects: 5.8%) were more common in younger age groups. in the allergic contact dermatitis group and in subjects who had used contact lens solutions. In the 40 thimerosal-positive patients. the minimum eliciting quantity of preservative was evaluated using different test concentrations: 0.05% and 0.01% pet. (patch testing) and 1:10.000 in saline (intradermal testing). Cross-reactions between thimerosal and other mercury compounds and sensitivity to thiosalicylic acid were also examined. The results of the investigation demonstrate that many of the reactions to 0.1% thimerosal are probably irritant. because only half the subjects studied had positive patch tests when allergen concentrations 5 to 10x lower than that conventionally used for patch testing. were utilized. In these subjects. the average strength of patch test reactions was higher. intradermal testing was more often positive and cross-reactions between mercurials more frequent. These data indicate that the optimal eliciting patch test concentration for studying thimerosal sensitivity is 0.05% pet.
Allergic contact dermatitis from eosin, Before 1960. eosin sensitivity was not rare and lipstick cheilitis was very common. We report 4 patients seen in 1988 and 1989 who were sensitized to eosin from topical bacteriostatic preparations. All 4 patients had positive patch tests to eosin. The allergen is probably an impurity rather than eosin itself.
Capsaicin enhances allergic contact dermatitis in the guinea pig, Guinea pigs were sensitized to dinitrochlorobenzene (DNCB) by the intracutaneous route and challenged epicutaneously on the flanks. The intensity of the allergic contact dermatitis was evaluated by inspection and palpation as well as by wet weight determination. With the purpose of diminishing tissue neuropeptides. and substance P in particular. the animals were treated with capsaicin either between induction and challenge. or before sensitization. In comparison with controls. the contact dermatitis was enhanced in both groups of animals treated with capsaicin.
Nickel-sulphate-induced contact dermatitis in the guinea pig maximization test: a dose-response study, Nickel sulphate is a sensitizer in guinea pigs. but the frequency of sensitization varies from study to study. The dose-response relationship for NiSO4.6H2O was evaluated in the guinea pig maximization test in this study. 6 intradermal (0.01%-3.0% aq.) and 6 topical (0.25%-10.0% pet.) concentrations were chosen for induction and NiSO4.6H2O 1% pet. was used for challenge. based on the absence of skin irritation in a pilot study. Blind reading was performed. A logistic dose-response model was applied to the challenge results. At 48 h. a linear relationship was obtained between the intradermal induction dose (but not topical dose) and the response. resulting in a maximum sensitization rate of 40% after 3% i.d. The reactivity disappeared at re-challenge 1 week later. Following a booster closed patch on day 35. using NiSO4 10% pet.. the animals were challenged with NiSO4 2% pet. and statistical analyses of 72-h readings revealed a non-linear dose-response relationship. giving a maximum response frequency of 40% after initial induction with NiSO4 3% i.d. and 2% topical.
Allergic contact dermatitis from Dittrichia viscosa (L.) Greuter, 9 cases of contact sensitivity to Dittrichia viscosa. mainly with an airborne pattern. are described. All patients reacted to the fresh leaf of the plant and to its ethereal extracts at 1 and 0.5% pet.. and some of them also to that at 0.1% pet. Positive reactions to Frullania dilatata. Laurus nobilis. some other members of the Compositae. and helenin were observed. suggesting the diagnosis of a sesquiterpene-lactone-induced allergic contact dermatitis.
Chlorhexidine gluconate and acetate in patch testing, Patch testing to chlorhexidine is usually performed with chlorhexidine gluconate aq. We report the results of 297 patients. almost all with leg ulcers. concomitantly tested with chlorhexidine acetate 1% aq. and chlorhexidine gluconate 1% aq. 39 patients had positive reactions to one of these compounds or to both. 36 positive reactions to the acetate were found. in contrast to 18 reactions to the gluconate. The reactions were considered relevant in 22 of 39 patients. since these patients had developed an eczema in an area where a chlorhexidine compound was used. and discontinuing the chlorhexidine compound resulted in improvement of the condition. In 10 of these 22 patients. the diagnosis would have been missed if the gluconate only had been used for testing. while the acetate failed to diagnose 2 patients. In 109 patients without leg ulcers. inconclusive patch test readings (i.e.. irritant reactions or weak positive reactions) were found in 17% with chlorhexidine acetate 1% aq.. compared to 5% with chlorhexidine gluconate 1% aq.. indicating a high degree of irritant potential of the acetate 1% aq. We consider that some positive reactions are lost if chlorhexidine gluconate 1% aq. only is used for patch testing. but that chlorhexidine acetate 1% aq.. on the other hand. is an unacceptably strong irritant. We therefore suggest that further testing with chlorhexidine acetate 1 and 0.5% aq. should be performed. in parallel with chlorhexidine gluconate 1% aq.. in order to establish appropriate test concentrations. We find that up to 13% of the leg ulcer patients in this study may be sensitized to chlorhexidine. and we recommend that the indications for the drug in leg ulcer patients should be reconsidered.
Vaccination despite thimerosal sensitivity, Thimerosal sensitivity is extremely common in Austria. being surpassed as a contact allergen only by nickel. This high incidence is still rising and is probably due to the frequent vaccinations which are performed in Austria. Most of the patch-test-positive patients had recently been immunized with thimerosal-containing vaccines. and no other obvious sources of exposure to thimerosal could be found. On retrospective questioning. 48 out of 50 patients had had no problems with their recent immunization; the 2 who reported massive local reactions had received their injections. against the recommendation of the manufacturer. subcutaneously. In a prospective study. 12 thimerosal-sensitized persons received their follow-up immunization at our department. and no side effects occurred. This enables us to conclude that sensitization had occurred through vaccines. but that those amounts of thimerosal delivered i.m. are not sufficient to elicit clinical symptoms. Patch-test positivity to thimerosal thus represents no contra-indication to i.m. immunization with thimerosal-containing vaccines.
Effect of antihypertensive drugs on insulin, glucose, and lipid metabolism, The close relationship between diabetes and hypertension has been recognized for decades. New information indicates that resistance to insulin action on glucose uptake in peripheral tissues is a common underlying mechanism in hypertension and diabetes. In prospective trials. the effects of antihypertensive agents on insulin sensitivity and lipoprotein metabolism have been evaluated. Both beta-blockers and thiazide diuretics worsen insulin resistance and deteriorate lipoprotein metabolism. Angiotensin-converting enzyme (ACE) inhibitors. Ca2(+)-channel blockers. and alpha-blockers are neutral or improve these factors. These data may explain the unexpectedly high incidence of the development of diabetes among treated hypertensives and the poor effect on risk for coronary heart disease in intervention trials.
Na+ transport in hypertension, Several different lines of argument lead to the conclusion that the Na+ ion is important in hypertension. These include dietary and epidemiological studies. studies on the isolated cells and tissues of hypertensive subjects. and the association of the genetic predisposition to hypertension with abnormalities of cellular Na+ handling. In isolated cells. the most convincing abnormalities have been shown in the Na+ pump. where there is also evidence of a circulating inhibitor of the pump in essential hypertension. although the nature of the agent is still uncertain. The genetic association between essential hypertension and Na+ transport is best represented by alterations in Na(+)-Li+ countertransport in hypertensive subjects and their near relatives. although interpretation is rendered more complex by the influence of nongenetic factors on this system. The demonstrated differences between hypertensive and nonhypertensive subjects in the cellular handling of Na+ have not been integrated into a totally convincing explanation of the ultimate mechanism of the condition. Attention has focused on the possible mechanisms whereby an increase in intracellular Na+ may increase the concentration of cytosolic Ca2+ in the vascular smooth muscle. which is presumed to be a necessary precondition to a chronically elevated peripheral vascular resistance.
Descriptive epidemiologic study of epilepsy syndromes in a district of northwest Tuscany, Italy, To evaluate the prevalence of epilepsy syndromes in a district in Northwest Tuscany (Vecchiano. 9.952 inhabitants) we identified all suspected cases (probable epilepsy) from several information sources: files of local doctors. prescriptions of antiepileptic drugs (AEDs). hospital files from the center for epilepsy at the University of Pisa. medical files from university and hospital departments in Pisa. and files of the school doctors and social workers in the district of Vecchiano. All persons suspected of having epilepsy were examined; 51 cases of epilepsy were found. i.e.. a prevalence rate of 5.1 in 1.000. During a previous study performed in the same district with the "house-to-house" method. a lower rate was found. Our study confirms that use of different epidemiologic investigational methods can produce different results.
History of epilepsy in Chinese traditional medicine, The first known document on epilepsy in China appeared in The Yellow Emperor's Classic of Internal Medicine. Huang Di Nei Ching. written by a group of physicians around 770-221 B.C. The description of epilepsy in this book and in many others later published was confined to generalized convulsive seizures. No documentation of absence or simple partial seizures was provided. The first classification of epilepsy. probably by Cao Yuan Fang in A.D. 610. listed five types of epilepsy: "Yang Dian." "Yin Dian." "Feng (Wind) Dian." "Shih (Wet) Dian." and "Lao (Labor) Dian." Later. other classifications named seizures after the cry of animals whose cry the "epileptic cry" resembled. or after "visceral organs" believed to be responsible for the seizures. The concept of partial versus generalized seizures. however. was not observed in any of these classifications. The treatment of epilepsy. based on principles of "Yin Yang Wu Xing." consisted of herbs. acupuncture. and massage.
Electroencephalographic correlations of extracranial and epidural electrodes in temporal lobe epilepsy, Thirty patients with medically intractable complex partial seizures of temporal lobe origin. but no structural abnormalities on neuroradiologic investigations. had both extracranial (scalp) and epidural EEG recordings. Fifteen patients (50%) had localized. unilateral. ictal. scalp EEGs. but one of these had bilateral independent temporal seizure onset according to epidural recordings. Of the 15 patients in whom scalp EEGs were non-localizing. 12 had well-localized epidural ictal EEGs. and 3 had multifocal or bilateral independent temporal ictal recordings. Epidural recordings provide information for determination of site of onset of temporal lobe seizures in selected patients.
Long-term ambulatory cassette EEG with sphenoidal recording in complex partial seizures, Long-term ambulatory cassette EEG with sphenoidal recording (A/EEG-SP) was performed in 51 patients. Group A comprised 31 patients with a clinical diagnosis of complex partial seizures (CPS). and group B comprised 20 patients suspected of having CPS. In group A. detection of temporal spikes was 27% by routine EEG (R/EEG). 72% by sphenoidal EEG (SP/EEG). 27% by A/EEG with temporal chain montage. and 91% by A/EEG-SP. The highest yield achieved by A/EEG-SP as compared with other EEG recordings was documentation of spontaneous seizures of temporal lobe origin. The detection rate of spontaneous seizures by A/EEG-SP was approximately 30%. and the focal or regional onset of seizures could be determined in 60% of patients. In group B. detection of temporal spikes was 11% by R/EEG. 18% by SP/EEG. and 30% by A/EEG-SP. Spontaneous seizures were recorded by A/EEG-SP in two patients (10%). Thus. A/EEG-SP was more effective than A/EEG in detecting interictal and ictal temporal discharges. and A/EEG-SP was superior to SP/EEG in documenting spontaneous seizures of temporal lobe origin.
Impact of the Children's Epilepsy Program on parents, A randomized controlled trial was conducted in Santiago. Chile to test the efficacy of the Children's Epilepsy Program. a child-centered. family-focused intervention developed and pilot tested in Los Angeles. CA. U.S.A.. using a counseling model for parents of children with seizure disorders to help them (a) deal with their anger. resentment. and grief related to the loss of a normal child; (b) increase their knowledge about caring for their child; (c) reduce anxieties related to having a child with a seizure disorder; and (d) improve their decision-making skills. All parents were pretested and then retested 5 months after the educational interventions. Parents in the experimental group (n = 185) and their children separately attended four 1 1/2-h sessions and then met together at the end of each session to share learning experiences. Comparison group parents (n = 180) and their children jointly attended three 2-h lecture sessions followed by question-and-answer periods. Although parents' overall knowledge of epilepsy was relatively high initially. it improved considerably in both comparison and experimental groups. With regard to anxiety. at the 5-month evaluation. experimental group parents and mothers in particular were more likely than control parents to state that they were less anxious (p less than 0.001). and their anxiety. as measured by the Taylor Manifest Anxiety scale. was significantly reduced (p less than 0.01).
Surgical versus medical treatment for epilepsy. I. Outcome related to survival, seizures, and neurologic deficit, We conducted a retrospective parallel longitudinal cohort study comparing surgical and medical treatment for epilepsy. The surgical group contained 201 patients treated with resective surgery for epilepsy in Norway since the first operation in 1949 until January 1988. The 185 control group patients treated medically only were closely matched for year of treatment. age at treatment. sex. seizure type. and neurologic deficit before treatment. There was no significant difference in survival between the two groups. The total monthly seizure frequency in the first and second year after operation and last year of registration (median 9 years) was significantly lower in the surgical group than in the control group (Mann-Whitney U test. two-tailed p less than 0.0001). The patterns were similar. with significant differences for subgroups with similar pretreatment status. such as seizure frequency. age. etiology and EEG-focality. Twenty-three and four-tenths percent (n = 40) of the surgically treated. and 2.9% of the controls had contracted neurologic deficits within 2 years after treatment. The difference was significant (chi square = 32.89. p less than 0.0001). Psychosis or permanent psychotic symptoms were reported in 6.7% (n = 11) of the surgically treated patients. and we suspect a higher proportion of psychotic development in the surgical group than in the control group. We conclude that surgical treatment for partial epilepsy is more successful than medical treatment in producing seizure reduction. provided the indications for operation exist. Surgical treatment produces more neurologic deficits than medical treatment (and possibly more psychiatric morbidity). and this factor must be weighed against the reduction in seizure frequency. The two treatments are equal for longterm survival.
Felbamate: a clinical trial for complex partial seizures, We performed a randomized. double-blind. three-period cross-over study of felbamate (FBM. 2-phenyl-1.3-propanediol dicarbamate: Carter-Wallace 554) in patients with complex partial seizures. Patients continued carbamazepine (CBZ) throughout the study and were observed in the hospital for the entire trial period. The entry criteria required at least six seizures in a 3-week baseline period (and no more than 1 week with a single seizure) with CBZ alone. Thirty subjects were randomized. Two left the study after randomization. 1 owing to seizure exacerbation. and 1 owing to hyponatremia. which may have been related to CBZ therapy. The daily dosage of 50 mg/kg (maximum 3.000 mg) FBM per day was well tolerated by all 28 patients who completed the study. Only mild adverse experience were observed during the trial. FBM reduced CBZ level (p less than 0.0001; 95% confidence interval -28%. -20%). There was no significant difference in seizure frequency between placebo and FBM periods (one-sided p = 0.172). but when a correction was made for the lower CBZ level noted during FBM periods. the data suggested a strong antiseizure effect of FBM.
Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group, During the past 7 years in Canada. more than 1.300 refractory epileptic patients have been treated with clobazam (CLB) by 104 adult and pediatric neurologists. Using a standard case report. 32 neurologists. who had each treated greater than or equal to 10 patients. provided retrospective data for 877 patients. The population had the following characteristics; the percentages of children and adults were 51 and 49%. respectively; 38% of the patients were mentally retarded; the percentages for single and multiple seizure type diseases were 46 and 54%. respectively; and adults had more complex partial seizures. whereas children had more atypical absence and myoclonic types. Before clobazam. patients received an average of 2 other antiepileptic drugs (AEDs) (range 0-5 AEDs). Average dose of CLB in children was 0.87 mg/kg per day (range 0.05-3.8 mg/kg per day) and in adults 30 mg/day (range 2.5-150 mg/day). Duration of CLB therapy ranged from a few days to greater than 4 years. with 40% being treated greater than 1 year. Using Kaplan-Meier curves. we found that 4 years after starting. 40-50% of patients continued CLB. More than 40% of patients with single seizure type had at least a 50% reduction in seizure frequency (improved). At least 60% of patients with multiple seizure type had improvement in one or more seizure types. and nearly 40% of the patients had all their seizure types improved. The seizure frequency for each seizure type. except tonic. was reduced greater than 50% in 40-50% of patients and by 100% in 10-30% of patients. Twenty percent stopped CLB for poor efficacy. 4% stopped for safety-related reasons including drug interactions. and 8% stopped for both reasons. Possible side effects (predominantly somnolence) were reported by 32%; however. in only 11% were the side effects sufficiently severe to cause discontinuation of medication. "Tolerance." leading to discontinuation of CLB. was reported for 9%. Patients treated with CLB for at least 1 year were generally maintained with CLB greater than 1 year. Thus. CLB is useful in refractory epilepsy of all types. suggesting that a monotherapy trial in less severe epilepsy is now desirable.
Effect of valproate on human cerebral glucose metabolism, We studied the effects of valproate (VPA) on local cerebral glucose metabolism (LCMRglc) in eight patients with partial seizure disorders and two with primary generalized epilepsy. Each patient had two positron-emission tomography (PET) scans with 18F-2-deoxyglucose (FDG). with. and without. VPA (mean level 52 mg/dl. range 30-127 mg/dl). Patients continued carbamazepine (CBZ) for both scans: serum concentrations were not significantly changed by VPA (CBZ range 5.4-12 mg/dl). Seven patients had the "without-VPA" scan first. Mean interval between PET scans was 75 days. Global CMRglc was decreased by 22% by addition of VPA (7.2 +/- 1.8 mg/100 g/min without VPA. 5.6 +/- 1.1 g/min with VPA. p less than 0.05. corrected). Thirteen regions of interest (ROIs) were analyzed in each hemisphere in each PET scan. Metabolic rates were significantly lower in 15 of 26 ROIs with VPA (p less than 0.05. corrected). VPA depresses cerebral metabolism to a greater degree than do CBZ and phenytoin (PHT) but less than does phenobarbital (PB). The metabolic effect may be related to the mechanism of action and have neuropsychological implications.
The social impact of asthma, While much research has examined the aetiology and treatment of asthma. little work has been done on its social impact. Yet asthma. like any disease. has a social as well as a medical dimension and it is increasingly being recognized that these two dimensions are interlinked. This paper describes a study into the social and personal impact of asthma on the lives of sufferers and their families. It shows that people are affected in many different ways: in employment. schooling. physical activities. social interaction. personal relationships and emotional well-being. All of the people interviewed had experienced some impact on their lives. albeit to varying degrees. The overall social impact was positively correlated with the severity of the asthma itself; this correlation was statistically significant in the case of adults and children under school age.
Medical students knowledge of HIV infection and AIDS. Members of the Association of University Teachers in General Practice, To evaluate the knowledge on infection with the human immunodeficiency virus (HIV) a questionnaire survey was carried out in West German medical students attending general practice courses. Lecturers of 19 medical schools agreed to participate and 1665 completed questionnaires were returned. The analysis of students' answers showed some remarkable deficiencies. The data suggest that teaching of this subject in medical school may be insufficient. General practitioners could possibly contribute to reaching a higher level of knowledge.
Prevalence and severity of morbidity among Gujarati Asian elders: a controlled comparison, Asian elders make relatively heavy use of health services: this may be due to higher levels of morbidity. but controlled comparisons have not been carried out. A comparison of the prevalence and severity of chronic diseases and use of health services of Asian and indigenous elders was made. A sample of 59 Gujarati Asians of mean age 62.9 years and 59 indigenous subjects of mean age 63.9 years of whom 42% (25 in each group) were female drawn from a general practice was studied. Asian subjects had a higher prevalence of diagnosed diseases. with the exception of chronic obstructive airways disease. but lower risk of falls and urinary incontinence. Asian subjects had higher life satisfaction scores and lower prevalence of depressed mood. Asian women were more likely to have had contact with primary care services. Both Asian men and women had more frequent hospital admissions. but similar levels of out-patient attendance. Body mass index. blood pressure and shoulder joint range of movement were similar for both Asians and the indigenous population. Asian subjects had significantly lower peak expiratory flow rates and hand grip strength. Asian elders have a higher risk of chronic diseases. but the impact of disease (indicated by life satisfaction. mood. and common disabilities) is less than among the indigenous population. Lower peak expiratory flow rates and grip strength among Asian elders are of concern since they may lead to premature arrival at age-related thresholds of physical capacity essential for independence in activities of daily living.
Asthma: a diagnostic and therapeutic challenge, Asthma is a disease needing urgent action. Morbidity and mortality are rising. despite advances in our understanding of asthma and in its treatment. The lifetime prevalence of asthma in children varies from 5 to 31%. depending on the defining criteria. and even when recent prevalence (occurring in the past two years) is examined. rates from 5 to 18% have been found. There is growing evidence which shows that signs of reversible airways disease occur in the elderly with even greater frequency and it is likely that at least 10% of the population will need asthma treatment at some stage of their lives; this means that well over five million people in the UK or 250 patients in each 'average' general practice list of 2500 merit the diagnosis of asthma at some stage of their lives. The fact that an average practice is likely to have diagnosed less than half that number clearly implies that asthma is first and foremost an under-diagnosed disease.
Effect of enteric pacing on intestinal motility and hormone secretion in dogs with short bowel, The present study was designed to examine the role of electrode position during retrograde pacing in dogs with short bowel syndrome and unsevered intact duodenum. In nine beagle dogs a subtotal resection of the small bowel and jejunoileostomy was performed. In five of these dogs. an isolated blind loop (jejunum) with preserved mesenteric connections was left in situ as an additional place for a stimulation electrode. Small intestinal motility and plasma levels of insulin. glucagon. gastrin. somatostatin. and glucose were examined during pacing of the residual jejunum or the isolated loop. respectively. compared with control experiments in the same dogs without pacing. During pacing of the loop a significant (P less than 0.05-0.01) decrease in the postprandial small intestinal motility index was observed combined with a significant (P less than 0.05) increase in plasma insulin levels. whereas the postprandial increase in glucagon. somatostatin. gastrin. and glucose levels was not different from that in controls. In contrast. pacing of the jejunum increased postprandial small intestinal motility index (less than or equal to 68%). whereas the levels of the four hormones and plasma glucose were not different from those in controls. The data suggest that in dogs with intact duodenum. pacing on an excluded loop is required to obtain the desired effect of reduced intestinal motility and improved anabolic pancreatic hormone secretion.
Scintigraphic measurement of regional gut transit in idiopathic constipation, In this study. total gut transit and regional colonic transit in patients with idiopathic constipation were measured scintigraphically. Eight patients with severe constipation were studied. none of whom had evidence of abnormal function of the pelvic floor. 99mTc-radiolabeled Amberlite resin particles (average diameter. 1 mm; Sigma Chemical Co.. St. Louis. MO) with a mixed meal were used to assess gastric emptying and small bowel transit; similar particles labeled with 111In were ingested in a coated capsule that dispersed in the ileocecal region. These were used to quantify colonic transit. Five healthy volunteers were also studied. Two patients showed delayed gastric emptying and two had slow small bowel transit. Seven of the eight patients had slow colonic transit. In five. delay affected the whole colon ("pancolonic inertia"); in two. transit in the ascending and transverse colon was normal. but solids moved through the left colon slowly. Mean colonic transit was also measured using radiopaque markers; this technique identified the patients with slow transit. as shown by measurements of overall colonic transit by simultaneous scintigraphy. However. estimated transit through the ascending and transverse colons was considerably shorter by the radiopaque marker technique. In conclusion. idiopathic constipation is characterized by either exaggerated reservoir functions of the ascending and transverse colons and/or impairment of propulsive function in the descending colon. Particle size may influence the result of regional colonic transit tests. Transit delays in other parts of the gut suggest that. in some patients. the condition may be a more generalized motor dysfunction.
Epidemiology of inflammatory bowel disease among U.S. military veterans, The Department of Veterans Affairs maintains a computerized patient treatment file that contains all records from veterans treated as inpatients in VA hospitals distributed throughout the United States. Using the patient treatment files from 1986 to 1989. the present study takes advantage of this large national data set to examine demographic and geographic associations of inflammatory bowel disease. Inflammatory bowel disease tended to affect predominantly female. white. and younger veterans. these trends being more marked in cases of Crohn's disease than ulcerative colitis. Hospital discharges secondary to both Crohn's disease and ulcerative colitis appeared to be more frequent in veterans from northern than southern parts of the United States. but did not show a seasonal variation different from the general pattern of all other diagnoses. The results in veterans confirm observations made in other studies and suggest that inflammatory bowel disease among different populations is modulated by similar pathophysiologic mechanisms and environmental risk factors.
Pharmacokinetics of oral and intravenous omeprazole in patients with the Zollinger-Ellison syndrome, The pharmacokinetics and pharmacodynamics of oral and IV omeprazole after a single dose were studied in 9 patients with the Zollinger-Ellison syndrome to determine whether the increased dose required to control gastric acid hypersecretion could be explained on the basis of altered pharmacokinetics. Each patient was studied both after receiving a single IV bolus of omeprazole (40 mg) and after receiving a single oral dose of omeprazole (80 mg). Intravenous and oral omeprazole doses were administered 1 week apart. Gastric acid secretion and plasma concentrations of omeprazole after drug administration were determined in each patient. The area under the plasma concentration curve. clearance. and volume of distribution after IV omeprazole administration and the area under the plasma concentration curve. peak plasma concentration. and time required to reach the peak after oral omeprazole administration were not different from those reported previously for normal subjects and patients with peptic ulcer disease. Mean (+/- SEM) bioavailability of oral omeprazole for all patients was 68% +/- 16%. which was similar to the bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability (20% +/- 8%) than the others. and their basal acid outputs were significantly higher than those of the other 7 patients. For all patients there was an inverse correlation between bioavailability and basal acid output (r = 0.76; P less than 0.02). The mean (+/- SEM) elimination half-lives of IV and oral omeprazole were not different (2.3 +/- 0.4 vs. 2.4 +/- 0.5 hours) but were significantly longer than those reported previously for normal subjects (P less than 0.02). The duration of action correlated with the elimination half-life of the drug (r = 0.87; P less than 0.003) and area under the plasma concentration curve (r = 0.72; P less than 0.03). The mean durations of action of IV and oral omeprazole were not significantly different (34 +/- 7.2 vs. 35 +/- 6.2 hours). It was concluded that altered pharmacokinetics do not account for the increased drug requirement of omeprazole in patients with the Zollinger-Ellison syndrome. In contrast to a previous study. the oral and IV omeprazole had the same duration of action. suggesting that intermittent bolus administration of parenteral omeprazole will obviate the need for continuous infusion of histamine H2-receptor antagonists in patients requiring parenteral antisecretory drugs. Furthermore. an IV dose every 12 hours controlled acid secretion in all patients. suggesting this as the recommended dose interval in patients requiring parenteral drug therapy.
Genetic characterization of the APC locus involved in familial adenomatous polyposis, Familial adenomatous polyposis is a rare disease inherited in a Mendelian dominant fashion. It is characterized by the occurrence of more than 100 adenomatous polyps in the large bowels of affected individuals. The genetic defect responsible for adenomatous polyposis resides at a locus called APC which has been localized to the long arm of human chromosome 5. In this study. the APC locus was mapped with respect to 11 markers known to map to this chromosomal segment. Linkage of APC to four of these markers had been previously reported. Three additional markers are shown here to be linked to APC. By multipoint analysis. the APC locus maps to an interval bounded by D5S49 and D5S58. The refined map of the APC locus and the new markers described here improve the informativeness and accuracy of the presymptomatic diagnosis of familial adenomatous polyposis.
Increased paracellular permeability in intrahepatic cholestasis induced by carmustine (BCNU) in rats, Carmustine [i.e.. 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU)] is a drug with cholestatic potency both in experimental animals and in humans. To study the mechanisms involved in the development of the hepatic lesions. early changes in liver function in rats pretreated with the drug were investigated. Dosages and sampling times that did not result in hepatocellular injury. as indicated by release of marker enzymes. were applied. In isolated perfused livers from pretreated rats. bile flow and maximal secretion rate of taurocholate were decreased. An increase in biliary [14C]sucrose clearance suggested enhanced permeability of the bile tract and was correlated with increased inorganic phosphate concentration in bile. To assess the contribution of paracellular and transcellular pathways of sucrose. [14C]sucrose access into bile was analyzed by biliary off-kinetics after omission of the radioactive marker from the perfusion medium. An improved method was developed to quantitate the permeability of the bile tract by applying the classical flow equation to the paracellular portion of biliary sucrose clearance. With this method it was shown that pretreatment of rats with BCNU resulted in an increase in both diffusion and convection of paracellular sucrose from perfusate into bile. Accordingly. the fast access of horseradish peroxidase from perfusate into bile was facilitated in isolated perfused livers of BCNU-treated rats. The results indicate that an increase in paracellular permeability is an early alteration that may contribute to the development of hepatotoxic lesions caused by BCNU. It is shown that inert solute clearance can be used to assess paracellular permeability if the paracellular fraction is determined.
The bentiromide test using plasma p-aminobenzoic acid for diagnosing pancreatic insufficiency in young children. The effect of two different doses and a liquid meal, The bentiromide test was evaluated using plasma p-aminobenzoic acid as an indirect test of pancreatic insufficiency in young children between 2 months and 4 years of age. To determine the optimal test method. the following were examined: (a) the best dose of bentiromide (15 mg/kg or 30 mg/kg); (b) the optimal sampling time for plasma p-aminobenzoic acid; and (c) the effect of coadministration of a liquid meal. Sixty-nine children 91.6 +/- 1.0 years) were studied. including 34 controls with normal fat absorption and 35 patients (34 with cystic fibrosis) with fat maldigestion due to pancreatic insufficiency. Control and pancreatic insufficient subjects were studied in three age-matched groups: (a) low-dose bentiromide (15 mg/kg) with clear fluids; (b) high-dose bentiromide (30 mg/kg) with clear fluids; and (c) high-dose bentiromide with a liquid meal. Plasma p-aminobenzoic acid was determined at 0. 30. 60. and 90 minutes then hourly for 6 hours. The dose effect of bentiromide with clear liquids was evaluated. High-dose bentiromide best discriminated control and pancreatic insufficient subjects. due to a higher peak plasma p-aminobenzoic acid level in controls. but poor sensitivity and specificity remained. High-dose bentiromide with a liquid meal produced a delayed increase in plasma p-aminobenzoic acid in the control subjects probably caused by retarded gastric emptying. However. in the pancreatic insufficient subjects. use of a liquid meal resulted in significantly lower plasma p-aminobenzoic acid levels at all time points; plasma p-aminobenzoic acid at 2 and 3 hours completely discriminated between control and pancreatic insufficient patients. Evaluation of the data by area under the time-concentration curve failed to improve test results. In conclusion. the bentiromide test is a simple. clinically useful means of detecting pancreatic insufficiency in young children. but a higher dose administered with a liquid meal is recommended.
Factors affecting the measurement of cholesterol nucleation in human gallbladder and duodenal bile, The study of cholesterol gallstone disease would be facilitated if the nucleation time of cholesterol crystals could be measured in duodenal bile and was correlated with nucleation occurring in vivo. Therefore. our aims were to determine (a) if nucleation time could be measured in duodenal bile. (b) the effect of bacteria. phospholipase. protease. and dilution on the measurement of nucleation time. and (c) the ability of nucleation time of duodenal bile to reflect changes occurring in vivo that promote the formation of gallstones and. therefore. the potential usefulness of nucleation time in predicting and studying the formation of gallstones. Gallbladder bile was obtained from 27 patients undergoing elective cholecystectomy and 19 patients undergoing diagnostic duodenal biliary drainage. Among the 14 bile samples collected by drainage that nucleated within 21 days. mean nucleation time was 6.3 +/- 2.8 days. The addition of inhibitors of phospholipase or protease prolonged nucleation time slightly. Bacteria were cultured from one bile sample at the time of collection and five samples at the time of nucleation. The addition of antibiotics had no effect on nucleation time. Dilution of bile collected at cholecystectomy to the concentration of duodenal bile prolonged nucleation time. In 4 of 5 obese patients receiving a very low calorie diet and predisposed to gallstones. the nucleation time in duodenal bile shortened. and the shortest nucleation times were associated with the formation of cholesterol crystals in vivo. Thus. measurement of nucleation time in duodenal bile may be useful in predicting and studying the formation of cholesterol gallstones.
Secretagogue response of azaserine-induced rat pancreatic acinar tumors in vivo, This study investigates digestive and lysosomal enzyme secretion of azaserine-induced pancreatic acinar carcinomas in response to cholecystokinin in rats. After 15-20 months of treatment. 95% of the animals developed pancreatic acinar carcinomas encompassing more than 90% of the tissue. In anesthetized rats basal trypsin output was significantly elevated in the tumor group despite diminished fluid secretion. There was a linear correlation between tumor size and basal amylase and trypsin secretion. Intravenous infusion of cholecystokinin (25 IDU.kg-1.h-1) induced a significantly lower secretion of fluid per gram pancreas. as well as decreased amylase and trypsin output. in the tumor group compared with the control group. Plasma amylase and lipase levels were significantly elevated in the tumor group under both basal and stimulated conditions. The output of the lysosomal enzymes beta-D-glucuronidase and alpha-D-glucosidase was significantly increased in the tumor group under background secretin infusion. Additional cholecystokinin infusion caused a sharp increase in glucuronidase output in this group with only minimal increase in controls. Glucosidase output increased similarly in both groups. Amylase. lipase. and trypsin tumor tissue concentrations were markedly reduced by 85%. 90%. and 87%. respectively. It was concluded that the decreased secretory response of digestive enzymes may result from decreased synthesis. lowered storage capabilities. and/or a decreased/increased responsiveness to cholecystokinin. Increased glucuronidase secretion may reflect an augmented cell turnover of malignant tissue.
Growth in adulthood after liver transplantation for glycogen storage disease type I, Continuation of linear growth late into the third decade of life is rarely observed. This report describes a 27-year-old man with delayed growth and sexual maturation secondary to glycogen storage disease type I who grew 5.3 cm after orthotopic liver transplantation. Sequential improvement in selected measures of metabolic control (blood glucose. lactate. and bicarbonate concentrations) and growth-promoting peptides (testosterone and insulinlike growth factor I) were documented after transplantation and before the increase in height. Potential increases in final stature may be present in adult patients with underlying metabolic disease and delayed skeletal maturation.
Use of azathioprine or 6-mercaptopurine in the treatment of Crohn's disease, The efficacy and safety of therapy with azathioprine/6-mercaptopurine was studied in 78 patients with Crohn's disease. Mean duration of therapy was 1.6 years; 52 patients were treated greater than or equal to 6 months. All patients were also on other antiinflammatory medications. Evaluations included self-assessment and physician's assessment of well-being. functional capacity. general clinical response. clinical activities indices (National Foundation for Ileitis and Colitis/International Organization for the Study of Inflammatory Bowel Disease and Harvey-Bradshaw). and achievement of specific therapeutic goals. General clinical condition improved in 70% of the patients. Median response time was 3 months. The average Harvey-Bradshaw score decreased 37% with therapy. and a decrease of greater than or equal to 30% occurred in 66% of the subjects. An overall 72% achievement rate for specified therapeutic goals included controlling refractory disease. 73%; corticosteroid "sparing." 76%; and lessening fistulization. 63%. Nine patients got worse despite therapy. Adverse effects requiring discontinuation of therapy occurred in 10%. whereas dosages were briefly lowered for mild side effects in another 10%. This study demonstrates the effectiveness and safety of azathioprine/6-mercaptopurine in the majority of selected patients with chronic. unremitting. or steroid-requiring Crohn's disease.
The nature of elder impairment and its impact on family caregivers' health and psychosocial functioning, This study assessed the nature of elder impairment and its impact on the health and psychosocial functioning of family caregivers. All caregivers were daughters or daughters-in-law living with an elderly parent. Contrary to expectations and previous research. no differences were revealed among caregivers of cognitively impaired. functionally impaired. and nonimpaired elderly relatives in terms of self-reported health or psychosocial functioning. Thus. other aspects of the caregiving context. such as familial generation. gender. and living arrangement. may affect caregiver health and psychosocial functioning more than the nature of the elder's impairment.
Carotid baroreceptor function in dogs with chronic norepinephrine infusion, Carotid baroreceptor function. the compliance of the carotid sinus wall. and the structure of the carotid artery were examined in dogs with elevated plasma norepinephrine (2.000-4.000 pg/ml) for 28 days. The dogs with high norepinephrine were normotensive (100 +/- 4.0 versus 98 +/- 4.0 mm Hg; p greater than 0.05) with bradycardia (65 +/- 4.0 versus 87 +/- 16 beats/min; p less than 0.05) compared with normal dogs in the conscious state. However. after pentobarbital anesthesia blood pressure was significantly higher in dogs with chronic norepinephrine infusion (165 +/- 6 mm Hg) compared with normal dogs (132 +/- 6 mm Hg). To assess baroreceptor sensitivity. multiunit carotid baroreceptor activity was recorded from the right carotid sinus nerve. and the carotid sinus wall compliance (sonomicrometers) was measured during nitroglycerin and phenylephrine injections. The threshold and saturation pressures increased from 96 +/- 3.9 to 117 +/- 4.2 mm Hg and from 145 +/- 4.3 to 171 +/- 5.7 mm Hg. respectively. in the normal dogs compared with the high norepinephrine dogs. The most striking differences were the marked increases in sensitivity of carotid baroreceptors (0.47 +/- 0.05 versus 1.99 +/- 0.45 spikes.sec-1.mm Hg-1; p less than 0.01) and maximum firing frequency of the baroreceptors (24 +/- 3.1 versus 48 +/- 4.4 spikes/sec; p less than 0.01). whereas the carotid sinus wall compliance was unchanged (0.014 +/- 0.003 versus 0.012 +/- 0.002 mm/mm Hg; p greater than 0.05). Similar alterations were observed using single fiber recordings. that is. an increase in threshold and saturation pressures and slope of baroreceptor units in dogs with elevated norepinephrine. The wall thickness and area of the carotid artery were determined. Both increased significantly (0.77 +/- 0.06 versus 1.30 +/- 0.12 mm and 9.0 +/- 0.8 versus 11.9 +/- 0.9 mm2; p less than 0.05) in dogs chronically infused with norepinephrine while the dry weight-to-wet weight ratio of left carotid artery tissue also increased from 26.0 +/- 0.73% to 29.0 +/- 0.57%. These studies indicate that 1) one of the possible mechanisms responsible for bradycardia in the conscious dogs with high norepinephrine is enhanced sensitivity of carotid baroreceptors; 2) the enhanced sensitivity of carotid baroreceptors is not due to a change in compliance of the carotid sinus wall; and 3) chronic elevation of norepinephrine causes hypertrophy or hyperplasia of the wall of the common carotid artery.
Role of anteroventral third ventricle and vasopressin in renal response to stress in borderline hypertensive rats, The borderline hypertensive rat is the first filial offspring of the spontaneously hypertensive rat and the Wistar-Kyoto rat. In response to acute environmental stress (air jet). the borderline hypertensive rat exhibits a diuretic response. whereas the parental strains exhibit an antidiuretic response (spontaneously hypertensive rat) or no change in urine flow rate (Wistar-Kyoto rat). This study sought to investigate the role of the periventricular tissue surrounding the anteroventral third ventricle and vasopressin release in the diuretic response of the borderline hypertensive rat to acute environmental stress. Sixteen-week-old borderline hypertensive rats who had consumed a 1% NaCl diet for 10-12 weeks were given either electrolytic lesions of the anteroventral portion of the third ventricle or sham lesions. When exposed to acute environmental stress 4 weeks later. the increase in volume of dilute urine seen in the sham-lesion rats was not observed in the lesion rats. Plasma vasopressin concentration was decreased by acute environmental stress in the sham-lesion rats (15.2 +/- 4.0 to 10.9 +/- 1.7 pg/ml. p less than 0.05) but was unchanged in the lesion rats (12.3 +/- 2.0 to 13.4 +/- 4.0 pg/ml). In a separate group of intact borderline hypertensive rats. a constant intravenous infusion of vasopressin prevented the diuretic response to acute environmental stress. The results suggest that acute environmental stress produces a diuresis in the borderline hypertensive rats via a decrease in plasma vasopressin concentration that is dependent on the integrity of the periventricular tissue of the anteroventral portion of the third ventricle.
Prevention of cold-induced increase in blood pressure of rats by captopril, To assess the possibility that the renin-angiotensin system may play a role in the development of cold-induced hypertension. three groups of rats were used. Two groups were exposed to cold (5 +/- 2 degrees C) while the remaining group was kept at 26 +/- 2 degrees C. One group of cold-treated rats received food into which captopril (0.06% by weight) had been thoroughly mixed. The remaining two groups received the same food but without captopril. Systolic blood pressure of the untreated. cold-exposed group increased significantly above that of the warm-adapted. control group within 4 weeks of exposure to cold. In contrast. chronic treatment with captopril prevented the elevation of blood pressure. Rats were killed after 4 months of exposure to cold. At death. the heart. kidneys. adrenal glands. and interscapular brown fat pad were removed and weighed. Although captopril prevented the elevation of blood pressure in cold-treated rats. it did not prevent hypertrophy of the kidneys. heart. and interstitial brown adipose tissue that characteristically accompanies exposure to cold. Thus. chronic treatment with captopril prevented the elevation of blood pressure when administered at the time exposure to cold was initiated. It also reduced the elevated blood pressure of cold-treated rats when administered after blood pressure became elevated. This suggests that the renin-angiotensin system may play a role in the elevation of blood pressure during exposure to cold.
Antihypertensive effects of an aromatase inhibitor in inbred salt-sensitive rats, Rats susceptible to the hypertensive effect of dietary salt (SS/Jr) have excess urinary 19-nordeoxycorticosterone compared with salt-resistant control rats (SR/Jr). 19-Nordeoxycorticosterone is a hypertensinogenic mineralocorticoid. but whether it contributes to the salt sensitivity of SS/Jr is unknown. This study sought to evaluate the contribution of 19-nordeoxycorticosterone to the salt sensitivity of SS/Jr by lowering its production with an aromatase inhibitor. 10-propargyl-androst-4-ene.3.17-dione (19-acetylenic-androstenedione. 19-AA). This aromatase inhibitor also preferentially inhibits nonaromatizing adrenal 19-hydroxylation. an essential step in the formation of 19-nordeoxycorticosterone. To test this hypothesis. inhibitor (120 mg) or vehicle pellets were implanted into male and female weanling SS/Jr at 42 days of age. A high salt diet (8% NaCl) was started and two additional pellets were implanted at 52 and 62 days of age. Systolic blood pressure was measured in all animals and urinary corticosteroids in males. Compared with vehicle. the inhibitor lowered blood pressure at 50 days of age (when it could first be measured) until 64 days of age in females and 71 days of age in males. Corticosterone and aldosterone levels were not different between 19-AA- and vehicle-treated SS/Jr. 19-Nordeoxycorticosterone levels. however. were mildly reduced with the inhibitor (0.05 less than p less than 0.10). After 28 days of high salt diet all 23 of the 19-AA-treated SS/Jr were alive. whereas almost one half of the control animals had died. These data demonstrate that 19-AA attenuates the hypertension in SS/Jr; this effect may be through reduction in 19-nordeoxycorticosterone production.
Chronic treatment with tin normalizes blood pressure in spontaneously hypertensive rats, We have reported that short-term treatment of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats with stannous chloride (SnCl2). which selectively depletes renal cytochrome P450. restores blood pressure to normal in young but not in adult SHR. and is without effect on blood pressure of either young or adult WKY rats. We report in the present study that chronic treatment with SnCl2. begun at age 5 weeks. prevented the development of hypertension in SHR over a period of 15 weeks at which time they were killed. Suspension of SnCl2 treatment after 8 weeks (i.e.. at age 13 weeks) did not result in return of blood pressure to hypertensive levels in SHR. Age-matched WKY rats were not affected by tin treatment. These findings provide additional evidence that administration of tin. which stimulates heme oxygenase. thereby producing depletion of cytochrome P450. restores blood pressure to normal levels in SHR.
Intracellular pH in human resistance arteries in essential hypertension, To investigate intracellular pH (pHi) in human resistance arteries in essential hypertension. vessels were obtained from small biopsies of skin and subcutaneous fat from 14 untreated patients. and the results were compared with those from 14 matched normotensive control volunteers. Segments of isolated resistance arteries were mounted in a myograph and loaded with the pH-sensitive fluorescent dye 2'.7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Fluorescence signals were monitored using a series of barrier filters and chromatic beam splitters. In this way both resting pHi and the changes in pHi observed during isometric contractions initiated by agonists could be recorded. Resting pHi was not different in vessels from hypertensive patients (hypertensive. 7.24 +/- 0.06 versus control. 7.25 +/- 0.04 pH units). The application of ethylisopropylamiloride (EIPA) and 4.4'-diisothiocyanatostilbene-2.2'-disulfonic acid (DIDS) demonstrated that both Na(+)-H+ exchange and bicarbonate-dependent membrane mechanisms contributed to pHi homeostasis but that neither system was overactive in hypertension (pHi change with EIPA in vessels from hypertensive versus control subjects was -0.11 +/- 0.02 and 0.13 +/- 0.03 pH units. respectively. and pHi change with DIDS in vessels from hypertensive versus control subjects was -0.097 +/- 0.05 and -0.091 +/- 0.03 pH units. respectively). The application of norepinephrine or 125 mM K+ solution induced contraction in the arterial segments with an accompanying fall in pHi. With norepinephrine this fall was significantly attenuated in vessels from hypertensive patients. These results fail to provide evidence for raised pHi in resistance arteries in human essential hypertension. and contrary to previous reports in circulating blood cells. Na(+)-H+ exchange is not overactive in the vessels of such patients.
High blood pressure due to alcohol. A rapidly reversible effect, The hypothesis that the action of alcohol on blood pressure is rapidly reversible and that its effect is therefore mainly due to very recent alcohol consumption was examined in this study. Five hundred and seventy-seven subjects were screened in an occupational survey. Alcohol consumption. documented with a 1-week retrospective diary was divided into two categories: "recent" and "previous" intake. Recent intake was defined as the amount consumed on days 1. 2. and 3 immediately preceding blood pressure measurement. Previous intake was defined as the amount consumed on days 4. 5. and 6 preceding blood pressure measurement. High recent alcohol intake significantly raised systolic and diastolic blood pressure in both men and women. Previous alcohol intake. however. did not appear to influence blood pressure. We conclude that the effect of alcohol on blood pressure appears to be predominantly due to alcohol consumed in the few days immediately preceding blood pressure measurement. with alcohol consumption before those few days exerting little effect on blood pressure.
Influence of hypertension and dietary copper on indexes of copper status in rats, The Dahl salt-sensitive rat was used to investigate the effect of hypertension on indexes of copper status and to determine the extent to which dietary manipulation of copper attenuated. or exacerbated. the rate of sodium chloride-induced hypertension. Weanling salt-sensitive rats were fed. in a 2 x 3 factorial design. one of six diets that contained one of three levels of copper (2.0 micrograms/g marginal. 12 micrograms/g adequate. or 50 micrograms/g supplemental) and either control (0.4%) or high (4%) levels of sodium. Diets were fed to the rats for 11 weeks. Rats fed the high sodium diets were characterized by high plasma copper concentrations and ceruloplasmin activities compared with their respective control sodium rats. The magnitude of the sodium-induced rise in plasma copper and ceruloplasmin was affected by dietary copper intake; however. dietary copper intake had no effect on the development of hypertension in the high sodium groups. These results suggest that altered copper metabolism is secondary. rather than primary. to the development of sodium chloride-induced hypertension in the salt-sensitive rat. Red blood cell superoxide dismutase activity was reduced in rats fed the low copper diets compared with the adequate and supplemented copper groups. At the lower levels of copper intake. sodium chloride-induced hypertension increased red blood cell superoxide dismutase activity in a manner consistent with the plasma copper and ceruloplasmin changes observed. However. at adequate or supplemental levels of dietary copper. red blood cell superoxide dismutase activity plateaued. suggesting possible saturation of copper at sites of hematopoeisis.
Sodium restriction in hypertensive patients treated with a converting enzyme inhibitor and a thiazide, When the function of the renin system is inhibited. blood pressure becomes more dependent on changes in sodium and water balance. Diuretics alone and sodium restriction alone are additive to converting enzyme inhibitor therapy. However. it is not known if these two ways of reducing sodium balance are additive in the presence of established converting enzyme inhibition. We therefore performed a double-blind crossover study of the effects of moderate sodium restriction in 21 patients with essential hypertension who were already being treated with the combination of a converting enzyme inhibitor and a diuretic. After 1 month of captopril (50 mg twice daily) and hydrochlorothiazide (25 mg once daily) therapy. with their usual sodium intake. average supine blood pressure was 147/96 +/- 5/3 (SEM) mm Hg 2 hours after treatment. Patients then reduced their sodium intake to around 80-100 mmol/day for the remainder of the study. After 2 weeks of sodium restriction. they entered a double-blind. randomized. crossover study of Slow Sodium (100 mmol sodium/day) compared with Slow Sodium placebo. while continuing sodium restriction and the above treatment. During the double-blind study. after 1 month of treatment with captopril (50 mg twice daily). hydrochlorothiazide (25 mg once daily). and Slow Sodium placebo. supine blood pressure 2 hours after treatment was 138/88 +/- 4/2 mm Hg (24-hour urinary sodium 104 +/- 11 mmol). After 1 month of captopril (50 mg twice daily). hydrochlorothiazide (25 mg once daily). and Slow Sodium tablets. supine blood pressure 2 hours after treatment was 147/91 +/- 5/2 mm Hg (p less than 0.05; 24-hour urinary sodium 195 +/- 14 mmol).
Suppression of rat deoxycorticosterone-salt hypertension by kallikrein-kinin system, Brown Norway kininogen-deficient rats had very low levels of plasma kininogens and lower levels of plasma prekallikrein. compared with those of normal rats of the same strain. Systolic blood pressure. determined by the tail-cuff method. of 5-week-old kininogen-deficient rats (106 +/- 0.4 mm Hg. n = 7) and the rate of systolic blood pressure increase with age were not different from those in normal rats. Weekly injections of deoxycorticosterone acetate (5 mg/kg s.c.) with 1% sodium chloride solution in drinking water after uninephrectomy at 7 weeks of age caused a gradual increase in the blood pressure of normal rats. reaching a plateau at 18 weeks of age. whereas that of deficient rats rose rapidly to 158 +/- 6 mm Hg 2 weeks after the start of treatment and continued to increase slightly. becoming significantly higher than normal rats at 8. 9. 10. 11. and 12 weeks of age (p less than 0.05 or 0.01). The levels of urinary prokallikrein and active kallikrein were slightly higher in deficient rats before deoxycorticosterone acetate-salt treatment but were not significantly increased after this treatment. whereas these levels in normal rats were increased 3.6- and 4.7-fold by this treatment. Urinary free kinin. collected from the ureter in untreated deficient rats. was below the detection limit. The plasma level of low molecular weight kininogen. the substrate of glandular kallikrein. was decreased in normal rats during the treatment. Continuous subcutaneous injection of aprotinin by an osmotic pump to normal rats induced significant increase in blood pressure. These results indicate that glandular kallikrein may play a suppressive role in deoxycorticosterone acetate-salt hypertension.
Norepinephrine overflow and renin pattern of the individual kidney in patients with unilateral renal artery stenosis, This study was performed to determine divided renal efferent sympathetic nerve activity from kidneys in seven patients with renin-positive. unilateral renal artery stenosis before and 30 minutes after an acute intravenous dose of 1.25 mg enalaprilat. Renal norepinephrine release was calculated from split renal plasma flow. venoarterial plasma concentration gradients across the kidney. and the fractional extraction of tritiated norepinephrine. All patients had unilateral renin secretion. the affected kidney increasing its plasma renin activity gradient 1.7-fold. whereas no statistically significant change was noted on the contralateral side in response to enalaprilat. Total norepinephrine release to plasma and norepinephrine plasma clearance (assessed by isotope dilution) were similar before and after administration of enalaprilat (approximately 400 ng/min and 1.0 l/min). despite a 26% fall in mean arterial pressure (from 125 mm Hg. p less than 0.01). Heart rate remained unchanged. After enalaprilat. norepinephrine venoarterial difference increased in the renin-secreting kidney (from 264 to 396. SED = 57 pg/ml. p less than 0.05). whereas it increased only slightly in the contralateral kidney (from 149 to 256. SED = 72 pg/ml. NS). Tritiated norepinephrine extraction fell approximately 25% (p less than 0.01) in both kidneys. Thus. renal norepinephrine spillover increased from 49 to 62. SED = 9 ng/min (NS) and from 81 to 129. SED = 17 ng/min (p less than 0.05) from the affected and the contralateral kidney. respectively. Hence. in this relatively small study in patients with renovascular hypertension. no evidence for increased renal nerve activity could be observed in the affected kidney. despite its marked renin production.
Dual hemodynamic mechanisms for salt-induced hypertension in Dahl salt-sensitive rats, Cardiac output. blood volume. total peripheral resistance. and renal blood flow were measured in awake salt-sensitive and salt-resistant Dahl rats on normal rat chow (1% NaCl) and on high salt (8% NaCl) diets. Rats were studied after 4. 8. and 46 weeks on a 1% NaCl diet and after 4 and 8 weeks on an 8% NaCl diet. Salt-sensitive rats on 8% NaCl for 4 weeks developed systolic hypertension; by 8 weeks they developed greater systolic and also diastolic hypertension. Salt-resistant rats on 8% NaCl remained normotensive throughout the studies. although renal resistance decreased (p less than 0.05). At 4 weeks. hypertension in salt-sensitive rats on 8% NaCl was caused by increased blood volume and cardiac output (p less than 0.05). with normal total peripheral resistance. At 8 weeks. hypertension was due to increased total peripheral resistance (p less than 0.05); cardiac output was below normal despite persistent elevation of blood volume (p less than 0.05). Salt-sensitive rats on 1% NaCl for 46 weeks were hypertensive. with elevated total peripheral resistance (p less than 0.05); cardiac output decreased (p less than 0.05). whereas blood volume remained unchanged. Salt-resistant rats on 1% NaCl remained normotensive with no charges in hemodynamics. Salt-sensitive rats on 8% NaCl for 4 weeks had an increase in renal vascular resistance but no significant change in nonrenal resistance or total peripheral resistance. The increased total peripheral resistance in salt-sensitive rats on 8% NaCl for 8 weeks and on 1% NaCl for 46 weeks was a reflection of increases of both renal and nonrenal vascular resistance.
Central hemodynamic observations in untreated preeclamptic patients, Reported central hemodynamics obtained with a Swan-Ganz pulmonary artery thermodilution catheter in preeclamptic patients show marked disparity. which has been interpreted to indicate a variable hemodynamic expression of the disease. However. the variability also may be due. at least in part. to the pharmacological treatment that most of the women studied received during Swan-Ganz measurements. To evaluate the effects of treatment on hemodynamics. we compared the results of Swan-Ganz measurements in 87 preeclamptic women who had received no treatment at all with those obtained in 47 preeclamptic women who had received various drugs and intravenous fluids. Control values were obtained in 10 normotensive pregnant volunteers. Measurements were performed between 25 and 34 weeks of gestation. The median (range) cardiac index in the untreated patients of 3.3 (2.0-5.3) l.min-1.m-2 was significantly lower than that in the treated patients of 4.3 (2.4-7.6) l.min-1.m-2 and in the normotensive pregnant women of 4.2 (3.5-4.6) l.min-1.m-2. The systemic vascular resistance index in the untreated group of 3.003 (1.771-5.225) dyne.sec.cm-5.m2 was significantly higher than that of 2.212 (1.057-3.688) in the treated and of 1.560 (1.430-2.019) dyne.sec.cm-5.m2 in the normotensive control group. The median (range) pulmonary capillary wedge pressure in the untreated group was 7 (-1-20) mm Hg and did not differ from that of 7 (0-25) mm Hg in the treated group. Variability of all hemodynamic variables was much lower in untreated than in treated patients.
Contribution of regional vascular responses to whole body autoregulation in conscious areflexic rats, We designed studies to evaluate the autoregulation response during volume expansion in three major circulation regions (intestine. kidney. and hind limb) during simultaneous determination of whole body autoregulation in conscious areflexic rats. Cardiac output was measured with chronically implanted electromagnetic flow probes on the ascending aorta. Regional blood flow velocity was measured with pulsed Doppler flow probes on the superior mesenteric (n = 7). left renal (n = 7). and right iliac (n = 7) arteries. Doppler flow probes were calibrated in situ in each rat to determine regional blood flow values. Neurohumoral reflex control of pressure was removed pharmacologically. and blood pressure and cardiac output were returned to resting control values with intravenous norepinephrine infusion. which was maintained at that constant level throughout the study. Hemodynamic changes were measured in response to blood volume expansion with infusion of 0.9 ml blood over 6 minutes. This small change in blood volume resulted in significant increases in vascular resistance of 15% in the whole body. 8% in the intestine. 18% in the kidney. and 15% in the hind limb. The pressure-flow slope. used as an index of autoregulation (slope = 0. perfect autoregulation; slope = 1. rigid vasculature). averaged 0.34 in the whole body. 0.52 in the intestine. 0.19 in the kidney. and 0.39 in the hind limb. When compared with the whole body. blood flow autoregulation was less in the intestine. greater in the kidney. and the same in the hind limb.
Role of vasopressin in salt-induced hypertension in baroreceptor-denervated uninephrectomized rabbits, To elucidate the contributions of renal. humoral. and arterial baroreceptor reflex components to salt-induced hypertension. we administered 10% NaCl intravenously for 10 days to sinoaortic-denervated rabbits with unilateral nephrectomy (n = 7). sinoaortic-denervated rabbits with intact kidneys (n = 7). and sham-operated sinoaortic-denervated rabbits with unilateral nephrectomy (n = 7). Serial changes in mean arterial pressure (MAP). heart rate. and blood pressure variability were recorded. In sinoaortic-denervated rabbits with unilateral nephrectomy. MAP increased significantly from 109 +/- 2 to 124 +/- 3 mm Hg (day 4) and remained elevated for the rest of the experiment. This elevation of MAP was accompanied by a reduction in the standard deviation of MAP. with significant elevations in plasma vasopressin. norepinephrine. and atrial natriuretic peptide concentrations and in sodium retention. In the other groups. there were no significant changes in these vasoactive hormones. In the sham-operated sinoaortic-denervated rabbits with unilateral nephrectomy. sodium retention was similar to that of sinoaortic-denervated rabbits with unilateral nephrectomy. Continuous infusion (1 microgram/kg/hr) of a V1 antagonist prevented the elevation of blood pressure and plasma norepinephrine. the accumulation of sodium. and the reduction of blood pressure lability. whereas a bolus injection (10 micrograms/kg) on day 4 reduced blood pressure from 128 +/- 3 to 115 +/- 2 mm Hg (p less than 0.005). These results imply that vasopressin plays a crucial role in the expression of salt-induced hypertension in rabbits with compromised baroreceptor and renal function.
Separate sex-influenced and genetic components in spontaneously hypertensive rat hypertension, Previous results from our laboratory indicated two major genetic components of spontaneously hypertensive rat (SHR) hypertension. an autosomal component and a Y chromosome component. Two new substrains. SHR/a and SHR/y. were developed using a series of backcrosses to isolate each of these components. The SHR/a substrain has the autosomal loci and X chromosome from the SHR strain and the Y chromosome from the Wistar-Kyoto (WKY) rat strain. The SHR/y substrain has only the Y chromosome from the SHR and autosomal loci and X chromosome from the WKY strain. Throughout these breeding programs parents were chosen at random without selection for blood pressure. Males of both substrains maintained blood pressures over 180 mm Hg. Comparisons of blood pressure in these new substrains with the original parental strains can be used to determine the relative proportions of each genetic component in hypertension. The Y chromosome component contributes 34 mm Hg. which is the difference between SHR/y male and WKY male blood pressure. The total autosomal component contributes 46 mm Hg. which is the difference between SHR/a male and WKY male blood pressure. The autosomal component is a sex-influenced trait; males in the SHR/a strain have significantly higher pressures than SHR/a females. Of the 46 mm Hg estimated for the autosomal component. 41 mm Hg is the result of these loci interacting with male phenotypic sex. This sex-influenced component is separate and distinct from the Y chromosome component.
Expression of brain natriuretic peptide gene in human heart. Production in the ventricle, To elucidate the expression of the brain natriuretic peptide gene in the human heart. we have measured brain natriuretic peptide mRNA levels in hearts using the Northern blot hybridization method. Brain natriuretic peptide mRNA was present with a size of approximately 0.9 kb in the ventricle as well as in the atrium. The brain natriuretic peptide mRNA level in the ventricle was 52% of that in the atrium. whereas the atrial natriuretic peptide mRNA level in the ventricle was approximately two orders of magnitude lower than that in the atrium. Taking atrial and ventricular weights into account. the total amount of brain natriuretic peptide mRNA in the ventricle represented 77% of that in the whole heart. These results demonstrate that most of brain natriuretic peptide mRNA occurs in the ventricle. in contrast with atrial natriuretic peptide mRNA. which is present mainly in the atrium. indicating that the ventricle is a major production site of brain natriuretic peptide.
Quinapril, an angiotensin converting enzyme inhibitor, prevents cardiac hypertrophy during episodic hypertension, Six control dogs. six dogs treated with 1.5 mg/kg b.i.d. quinapril. and six dogs treated with 8 mg/kg q.d. minoxidil underwent 6 hours daily of hindquarter compression for 9 weeks. Minoxidil significantly decreased baseline blood pressure (-17 mm Hg; p less than or equal to 0.01). whereas quinapril decreased baseline blood pressure 11 mm Hg but not significantly (p = 0.15). Hindquarter compression elicited blood pressure increases in all three groups (control +18. quinapril +13. minoxidil +19 mm Hg). After 9 weeks. left ventricular mass in control dogs increased 22% (p less than 0.004); a similar increase was seen in minoxidil-treated dogs (+22%. p less than 0.0001) but not in the quinapril-treated group (+4%. p less than 0.15). The increase in left ventricular mass in control dogs was concentric (increased epicardial volume only). whereas in the minoxidil group. the hypertrophy was eccentric (both epicardial and endocardial volumes increased). The minimal hypertrophy in the quinapril group was concentric (no change in epicardial. but a decrease in endocardial volume). Quinapril had little hypotensive effect. but prevented the development of left ventricular hypertrophy. whereas minoxidil did not prevent hypertrophy in spite of its hypotensive effect. The mechanism of this differential effect of direct vasodilation versus converting enzyme inhibition on left ventricular hypertrophy is not fully elucidated. The results with quinapril suggest that some antihypertensive agents may positively affect left ventricular hypertrophy in spite of the absence of a large effect on baseline blood pressure or on blood pressure reactivity.
Renin promoter SV40 T-antigen transgenic mouse. A model of primary renal vascular hyperplasia, Transgenic mice containing a ren-2 promoter T-antigen fusion construct (TAG+) develop renal vascular hypertrophy and hyperplasia associated with markedly suppressed renal renin mRNA. renal renin content. and plasma renin concentration. These animals are normotensive. In the present study. the renal and cardiovascular systems are characterized. revealing some surprising findings. Not only are the TAG+ mice normotensive in the face of pronounced renal pathology but also in the presence of an increase in plasma volume. These data raise interesting questions about blood pressure physiology and renal function of the TAG+ mice. Blood nitrogen urea of the TAG+ animal was markedly elevated and plasma creatinine level was in the normal range. indicating prerenal azotemia without renal failure. These findings are consistent with impaired renal perfusion with secondary volume expansion probably as the result of vascular hyperplasia. These transgenic animals provide a unique genetic model for studying the physiology of primarily renal vascular hyperplasia as well as blood pressure control in a low renin state.
Lateral parabrachial nucleus and angiotensin II-induced hypertension, The objective of this study was to determine if ablation of the lateral parabrachial nucleus (LPBN) would prevent angiotensin II-induced hypertension in rats. Thirteen male Sprague-Dawley rats were studied. Bilateral electrolytic lesions in the LPBN were produced in six rats; the remaining seven rats were subjected to sham lesion surgery only. All rats were instrumented with vascular catheters and housed in metabolism cages. Daily measurements during the 16-day protocol included arterial pressure. heart rate. water intake. urine output. and urinary sodium excretion. Periodically throughout the protocol depressor responses to ganglion blockade and to blockade of V1-type vasopressin receptors also were measured. The protocol was divided into three control-period days. 10 days of continuous (24 hr/day) angiotensin II infusion (10 ng/min i.v.). and three recovery-period days. There were no significant differences between the two groups of rats for any variable during the control period. During angiotensin II infusion. sham-lesion rats exhibited a progressive increase in arterial pressure and the depressor response to ganglion blockade and a decrease in urinary sodium excretion. No other variable was significantly changed. In rats with LPBN lesions. arterial pressure was significantly increased only on days 1 and 3 of angiotensin II infusion. No other variable was affected. It was concluded that ablation of the LPBN in rats prevented sustained hypertension during intravenous infusion of angiotensin II by interfering with neurogenic pressor mechanisms normally activated by the peptide.
Sympathetic neural control of vascular muscle in reduced renal mass hypertension, Vascular smooth muscle (VSM) transmembrane potentials (Em) were measured in situ in small branch arteries (150-300-microns o.d.). small branch veins (300-400-microns o.d.). arterioles (90-150-microns o.d.). and venules (80-250-microns o.d.) in the mesenteric and gracilis muscle and the arterioles and venules of cremaster muscle vascular beds in anesthetized rats with reduced renal mass hypertension (HT-RRM) and normotensive sham-operated RRM control rats. All rats were given a 4% NaCl diet for 2 weeks with water ad libitum. Relative to sham. HT-RRM mesenteric and gracilis arterial and venous vessels. but not the microvessels of the cremaster muscle bed. were less polarized during superfusion with normal physiological salt solution. Also relative to sham. hyperpolarization responses to local sympathetic neural (SNS) denervation with 6-hydroxydopamine were greater in mesenteric and gracilis small arteries. arterioles. veins. and venules but not in cremaster microvessels. The immediate (less than 5-minute) electrogenic depolarization response to local blockade of VSM Na(+)-K+ pump activity with 10(-3) M ouabain was similar between each respective HT-RRM and sham vessel pair in each vascular bed.
Effect of NG-monomethyl L-arginine on endothelium-dependent relaxation in arterioles of one-kidney, one clip hypertensive rats, Dose-response curves to topically applied acetylcholine. bradykinin. and nitroprusside were obtained by intravital microscopy in arcading arterioles of the spinotrapezius muscle of control (n = 9) and one-kidney. one clip hypertensive (1K1C) rats (n = 11) of 4 weeks' duration before and during superfusion with the specific inhibitor of nitric oxide formation NG-monomethyl L-arginine (LNMMA) (10(-4) M) and both LNMMA (10(-4) M) and indomethacin (2.8 x 10(-5) M). Resting arteriolar tone was higher in 1K1C rats than in controls. and vasodilation to acetylcholine and bradykinin. but not to nitroprusside. was reduced (p less than 0.05) in 1K1C rats compared with controls. LNMMA increased arteriolar tone (p less than 0.05) and inhibited the vasodilator responses to acetylcholine and bradykinin (p less than 0.05) in controls but not in 1K1C rats. LNMMA did not alter the response to nitroprusside in either group. Addition of indomethacin to LNMMA increased arteriolar tone and markedly reduced the response to bradykinin. but not to acetylcholine or nitroprusside. in both groups. These findings suggest that resting arteriolar tone is increased in 1K1C rats partially because of the decreased basal release or synthesis of nitric oxide. Responses to the endothelium-dependent vasodilators acetylcholine and bradykinin were attenuated in 1K1C rats. possibly because of changes in synthesis or release of nitric oxide for acetylcholine and of prostacyclin for bradykinin. because the response to the endothelium-independent vasodilator nitroprusside did not differ between the groups.
Hypertension-induced changes of platelet-derived growth factor receptor expression in rat aorta and heart, Hypertension-associated growth of vascular smooth muscle cells might be mediated in vivo by platelet-derived growth factor (PDGF). Our previous investigations in hypertensive rats failed to demonstrate changes in aortic steady-state mRNA levels of PDGF A or B chains. The current studies were performed to determine whether hypertension might affect the expression of PDGF receptors. We studied PDGF alpha- and beta-receptor gene expression by Northern analysis using human and rat cDNA probes. Studies of tissue distribution revealed that PDGF beta-receptor mRNA was most abundant in total aorta and aortic media. whereas the PDGF alpha-receptor mRNA was most abundant in the lung and was expressed at low levels in aortic tissue. Deoxycorticosterone acetate (DOCA)-salt hypertension induced a threefold increase in aortic steady-state PDGF beta-receptor mRNA levels. Aortic PDGF beta-receptor expression also was higher in spontaneously hypertensive rats (SHRs) when compared with age-matched normotensive Wistar-Kyoto (WKY) controls. Aortic PDGF alpha-receptor steady-state mRNA levels were unchanged in DOCA-salt hypertension and were expressed at similar levels in WKY rats and SHRs. Unlike the findings with aorta. cardiac PDGF beta- and alpha-receptor and PDGF B-chain expressions were unchanged in the DOCA-salt model and were decreased in SHRs. These findings indicate that hypertension can increase aortic steady-state mRNA levels for PDGF beta-receptor. They also indicate that tissue-specific expression of the genes of the PDGF ligand/receptor system are differentially regulated in hypertension.
Structural alterations of microvascular smooth muscle cells in reduced renal mass hypertension, Loss of microvessels (anatomic rarefaction) occurs in chronic reduced renal mass (RRM) hypertension and is mediated via structural degeneration of vascular smooth muscle (VSM) and endothelial cells. The purpose of the present study was to determine if structural changes occur in VSM cells of the microvessels that remain in the tissue of rats with chronic RRM hypertension. Samples of cremaster muscles were taken from normotensive control rats and rats with acute (3-7 days) and chronic (14-28 days) RRM hypertension (75% reduction in kidney mass with 4% NaCl loading). The samples were fixed in situ and processed for light and electron microscopy. Ultrastructural morphology of VSM cells in terminal arterioles of control animals was normal. Although VSM morphology in many microvessels of RRM hypertensive rats was also normal. some vessels exhibited structural changes that were not present in arterioles of the normotensive animals. The most striking change was the appearance of more extensive dense bodies anchoring the contractile filaments around the outer membrane of the cells. Extreme vasoconstriction was observed in some arterioles of RRM rats as long as 2 weeks after salt loading. Focal areas of VSM cell proliferation were evident. Many of the changes occurring in RRM were detected as early as 1 week after the onset of hypertension. These observations suggest that renal mass reduction-salt loading hypertension is associated with early structural and functional changes in the VSM cells.
Role of endothelium-derived relaxing factor in regulation of vascular tone and remodeling. Update on humoral regulation of vascular tone, In addition to preserving the permselectivity of the vascular wall and providing an antithrombogenic surface. the vascular endothelium contributes importantly to the regulation of vasomotor tone. Indeed. the endothelium participates in the conversion of angiotensin I to angiotensin II; the enzymatic inactivation of several plasma constituents such as bradykinin. norepinephrine. serotonin. and ADP; and the synthesis and release of vasodilator substances such as prostacyclin and the recently discovered endothelium-derived relaxing factor (EDRF). The diffusible EDRF released from the endothelium is nitric oxide or a substance closely related to it such as nitrosothiol. The endothelium also synthesizes and releases vasoconstrictive factors. including products derived from arachidonic acid metabolism and the recently discovered peptide endothelin. An increasing body of evidence from experimental and clinical studies indicates that EDRF and endothelium-derived contracting factors play an important role in vascular physiology and pathology. It has become apparent that the balance of these factors may be a major determinant of systemic and regional hemodynamics. Moreover. through generally opposite effects on growth-related vascular changes. contracting factors such as endothelin and relaxing factors such as EDRF also may be important determinants of the vascular response to injury in various disease states such as atherosclerosis and hypertension. It is clear that the vascular endothelium is a complex and dynamic organ. Understanding endothelium function in normal physiology and disease states is of potential clinical importance and should be the focus of future investigation.
Predictors of an increased risk of future hypertension in Utah. A screening analysis, A prospective study on 1.482 adult members of 98 Utah pedigrees was carried out to determine which variables may be associated with an increased risk of hypertension incidence. After an average of 7 years of follow-up. 40 individuals had been placed on antihypertensive medications to lower blood pressure. Baseline study variables included anthropometrics. clinical chemistry measurements of blood and urine. socioeconomic and lifestyle variables. and detailed erythrocyte ion transport and concentration measurements. Age (relative risk of 4.28 for a 2 SD difference. p less than 0.0001) and baseline systolic and diastolic blood pressures (relative risks of 3.55 and 3.52. respectively. both p less than 0.0001) had the strongest associations with hypertension incidence. Controlling for age and baseline blood pressure. the following age- and sex-adjusted variables were associated with an increased risk of future hypertension (relative risks for a 2 SD difference. all p less than 0.10): family history of hypertension (2.35); height (1.97); body mass index (2.31); abdominal girth (2.66); subscapular. suprailiac. and triceps skinfold thicknesses (2.79. 2.52. and 2.28. respectively); percent ideal body weight (2.63); log triglyceride concentration (2.02); plasma uric acid (2.16); inorganic phosphate (0.50); and passive erythrocyte sodium permeability (1.59). The final model.which included all of the age- and sex-adjusted variables (p less than 0.10) in a backward elimination logistic regression analysis. consisted of age (4.78). systolic blood pressure (2.91). subscapular skinfold thickness (2.21). height (1.92). uric acid (2.06). inorganic phosphate (0.50). and family history of hypertension (1.82). None of the ion transport or concentration measurements ws associated with an increased risk of hypertension.
Renal vascular response to sodium loading in sons of hypertensive parents, Studies of normotensive offspring of hypertensive parents offer the potential to identify inherited abnormalities that contribute to essential hypertension. We compared renal and systemic hemodynamic responses to saline infusion between normotensive sons of two hypertensive parents (SOHT) and sons of two normotensive parents (SONT) selected from the general population of Rochester. Minn. Hemodynamic measurements were performed after a week of low sodium intake (10 meq/day) and were repeated after a week of high sodium intake (200 meq/day). Despite being in the normotensive range. blood pressures in SOHT were higher than those in SONT during low sodium (124 +/- 3/85 +/- 3 versus 118 +/- 2/71 +/- 2 mm Hg. p less than 0.01) and high sodium (122 +/- 3/80 +/- 3 versus 112 +/- 2/70 +/- 2 mm Hg. p less than 0.05) conditions. Higher pressures in SOHT were associated with elevated systemic and renal vascular resistance. After a high sodium diet. renal vascular resistance in SOHT rose further during acute saline infusion. whereas systemic vascular resistance did not change. After a low sodium diet. this renal vasoconstrictor response to saline infusion in SOHT was not present. and renal vascular resistance fell to levels not different from SONT. Plasma renin activity. aldosterone. and atrial natriuretic peptide did not differ between SONT and SOHT. Circulating levels of norepinephrine were higher in SOHT. These data demonstrate a renal vasoconstrictor response to saline infusion in normotensive SOHT. which depends on prior sodium intake. This alteration in renal hemodynamics may represent an inherited abnormality related to the development of hypertension.
Irregular isoantibodies in the sera of patients undergoing chronic hemodialysis, We screened 89 patients undergoing chronic hemodialysis for irregular isoantibodies. Irregular isoantibodies were detected in six patients (6.7%). This is an extremely high percentage compared with previous reports. considering that the presence of irregular isoantibodies was estimated to be 2.91% in multiparas. in whom they were found most frequently. This may be due to the fact that hemodialysis patients often receive blood transfusions but it also suggests that hemodialysis per se may induce the production of irregular isoantibodies. The blood-group specificities of the irregular isoantibodies detected were anti-N. anti-Leb + anti-HI. anti-Lea + anti-Leb. anti-H and anti-I. anti-P1. anti-rh" (E). The majority of the cases with irregular isoantibodies were examined because of clinical problems during hemodialysis. Therefore. we checked for the presence of irregular isoantibodies before the induction of hemodialysis and every three to six months thereafter.
Renal hemodynamics, plasma amino acids and hormones after a meat meal in progressive nephron loss, Ten patients with chronic renal failure (GFR 29-97 ml/min). on free diets providing 1 g/kg B.W. of proteins. ingested an oral protein load (meat meal. 2 g/kg B.W.). GFR and RPF increased significantly over baseline with no change in filtration fraction. Within 30 min of the meal and for the next 3 h a statistically significant increase was observed in the plasma concentrations of the following amino acid groups: essential. non-essential. total. branched-chain. ketogenic. glycogenic. glycogenic and ketogenic. basic. acid. polar and non-polar. At 30 min the smallest increase was seen in acid and polar amino acids (6.7% and 7.6%. respectively). At 180 min the largest increase (78.8%) was seen for glycogenic and ketogenic amino acids and total plasma amino acids were 1.58 times baseline. After the meat meal plasma glucagon and insulin rose significantly. while growth hormone. plasma renin activity and aldosterone did not vary.
Cavitation potential of mechanical heart valve prostheses, Just like technical check valves. the function of mechanical heart valve prostheses may presumably also lead to cavitation effects during valve closure. Due to the waterhammer effect. cavitation may primarily occur in the mitral position leading to high mechanical loading of the valve itself and of corpuscular blood elements. Ten different types of commercial mechanical heart valves were investigated in the mitral position of a pulsatile mock loop. to detect cavitation thresholds under physiologically similar conditions by cinematographic techniques. Almost all these valve prostheses show cavitation up to a ventricular pressure gradient of 5000 mmHg/s. The threshold depends on valve type and size and is sometimes within the physiological range below 2000 mmHg/s. Visible cavitation bubbles with a diameter of up to 1.8 mm and a collapse time of less than 0.1 ms suggest that vapour cavitation may play an important role for material and blood damage in mechanical heart valve prostheses.
Mathematical modeling of antigen and immune complex kinetics during extracorporeal removal of autoantibody, The extracorporeal removal of circulating auto-antibodies by repeated plasma exchange or continuous lymph drainage is modeled by single-pool kinetics. Total amounts of antigenic determinants. k-valent antibodies and immune complexes are variables of the model. Factors influencing the course of therapy are included: production rate of antigen and antibody and their natural catabolism. This model can give useful formulae for clinical practice. The effect of treatment can be predicted from the relative depletion of antibody and the actual severity of the disease. Another formula shows how the changed catabolism of antigen after antibody binding can influence the amount of immune complexes. As an example. lymph drainage in myasthenia gravis is calculated using averaged data from three patients.
Synthesis of chondrocytic keratan sulphate-containing proteoglycans by human chondrosarcoma cells in long-term cell culture [published erratum appears in J Bone Joint Surg [Am] 1991 Sep;73(8):1274, Keratan sulphate is an integral component of the large aggregating proteoglycans of mature human articular cartilage. The keratan sulphate content of chondrocytic proteoglycans increases during maturation. and it is a useful marker of mature-type chondrocytic proteoglycans. Ordinarily. in cell culture. chondrocytes from non-neoplastic tissues dedifferentiate. diminish or cease to synthesize aggregating proteoglycans with the same amount of keratan sulphate as those formed in vivo. and do not maintain their in vivo phenotype. In tissue culture. this down-regulation of synthesis of keratan sulphate is irreversible. The study of the metabolism of mature human chondrocytes has been hampered by the absence of stable models. We report a cell-line. 105KC. derived from a human chondrosarcoma. that has maintained a stable proteoglycan phenotype during more than three years of culture. Analysis with immunofluorescence suggested that 105KC cells continued to synthesize keratan sulphate in long-term culture. Biochemical analysis demonstrated that 105KC cells maintained the production of chondrocytic large-aggregating proteoglycans and that keratan sulphate composed 13 per cent of their glycosaminoglycan content. To our knowledge. 105KC represents the first model to have maintained the post-fetal chondrocytic proteoglycan phenotype in stable culture. This study documents the feasibility of the development of mature chondrocytic cell-lines and sheds light on the biological characteristics of chondrosarcomas.
Fractures of the atlas, Thirty-four patients who had fractures of the atlas (the first cervical vertebra) were reviewed at an average follow-up of 4.5 years. Seventeen patients had bilateral fracture of the posterior arch of the first cervical vertebra. Eight were treated with immobilization in a cervical orthosis. with no long-term problems secondary to the injury. Nine of these patients had additional fractures in the first and second cervical vertebral complex. complicating the management of the fractures of the posterior arch. Two of the nine patients died. and the treatment of the other seven was dependent on the additional fractures. A second group of six patients had a fracture in the area of the lateral mass. with one fracture just anterior to or within the anterior portion of the lateral mass of the first cervical vertebra and a second fracture posterior to the lateral mass of the first cervical vertebra on the same side; resultant asymmetrical displacement of the lateral masses was seen on the open-mouth roentgenogram that was made for each patient. A third group of eleven patients sustained a Jefferson. or burst. fracture of the first cervical vertebra. These patients had either four fractures (two in the anterior arch and two in the posterior arch) or three fractures (one in the anterior arch and two in the posterior arch). Spreading of the lateral masses was relatively symmetrical on the open-mouth roentgenogram. Patients who had fractures with displacement of two to seven millimeters were treated with immobilization in a halo vest. Patients who had fractures with severe spreading of the lateral masses (more than seven millimeters) were treated with reduction of the lateral masses by axial traction until healing of the arch had occurred. No atlanto-axial instability was evident in any patient at follow-up.
Evaluation of degenerative lesions of the rotator cuff. A comparison of arthrography and ultrasonography, A prospective study was performed to determine the accuracy of arthrography compared with ultrasonography in the evaluation of thirty-two patients who had a degenerative lesion of the rotator cuff. Both tests were done preoperatively. and the condition of the rotator cuff was determined intraoperatively. Arthrography was accurate in the diagnosis of twenty-eight (87 per cent) of the thirty-two patients (twenty who had a full-thickness tear. seven who had a partial-thickness tear. and five who had an untorn rotator cuff and tendinitis). while ultrasonography was diagnostic in only twelve (37 per cent). In this specific population of patients. arthrography was found to be superior to ultrasonography.
Radiation therapy for aggressive fibromatosis. The Experience at the University of Florida, Twenty-nine patients (thirty sites) who had histologically confirmed aggressive fibromatosis were treated with radical courses of radiation at the University of Florida between March 1975 and February 1986. The minimum length of follow-up was two years; 76 per cent of the patients were followed for more than five years. Twenty-seven sites received doses of at least 5000 centigrays (one centigray equals one rad). Twelve patients were treated twice a day. Fourteen sites were treated with radiation postoperatively for known or presumed microscopic quantities of residual aggressive fibromatosis; in eleven. the disease was locally controlled. Sixteen sites were treated postoperatively for known grossly apparent residual disease; in fourteen. the disease was locally controlled. Over-all. aggressive fibromatosis was controlled in twenty-five (83 per cent) of the thirty sites. The six-year actuarial rate of local control was 79 per cent. The five local recurrences occurred at four. eleven. thirty-four. sixty-one. and sixty-eight months after the initiation of radiation therapy. Two of the five failures occurred in the high-dose radiation field in patients who were treated for grossly apparent disease. The remaining three failures occurred at the margin of the irradiated field in patients who were treated for assumed microscopic quantities of residual disease. There was no apparent difference in local control between patients who were treated for primary (previously untreated) aggressive fibromatosis and those who were treated after one or more recurrences. Comparison of the results of radiation therapy with published data on operative treatment shows that local control substantially improves with postoperative radiation therapy when operative margins are less than wide.
Treatment of the unstable intertrochanteric fracture. Effect of the placement of the screw, its angle of insertion, and osteotomy, We created unstable intertrochanteric fractures with a large posteromedial defect in eighteen pairs of fresh-frozen femora from cadavera. and used the femora to evaluate the stability of six combinations of treatment with sliding compression screws and sideplates. The variables that were tested were high (150-degree) angle plates compared with low (130-degree) angle plates. the position of the lag-screw in the femoral head and neck (in the center of the head as seen on both anteroposterior and lateral roentgenograms compared with posteroinferiorly). and whether or not medial cortical contact had been re-established with a limited osteotomy of the greater trochanter. The femora were loaded to the point of failure. The mode of failure. maximum load to failure. and bending rigidity of each method of fixation were measured. Of the six types of treatment. the use of a 150-degree-angle plate. position of the lag-screw in the center of the head as seen on both anteroposterior and lateral roentgenograms. and osteotomy of the greater trochanter resulted in the highest mean load to failure and the greatest rigidity. Over-all. re-establishment of medial cortical contact by means of an osteotomy of the greater trochanter significantly improved the mean load to failure and the rigidity of the fixation. The higher-angle plate. although more difficult to insert. increased the mean load to failure but had no effect on rigidity. The position of the lag-screw (in the center of the head as seen on both anteroposterior and lateral roentgenograms or posteroinferiorly) had no bearing on the mean load to failure. but it significantly affected the mode of failure.
The use of bone morphogenetic protein in the treatment of non-union in a canine model, A non-union model was established in the mid-part of the radial diaphysis in dogs. The non-union was treated with operative implantation of a carrier (guanidine-extracted. demineralized bovine bone or a polylactic acid polymer). alone or in combination with fractions that had been enriched in bone morphogenetic protein. All sites of treatment were examined radiographically and histomorphometrically at twelve weeks after implantation. Guanidine-extracted. demineralized bovine bone. alone or combined with fifteen milligrams of canine bone morphogenetic protein. failed to induce any healing of the non-union. When polylactic acid alone had been implanted. a small amount of reparative new bone was found in the defect at three months. When polylactic acid combined with fifteen milligrams of canine bone morphogenetic protein had been implanted. a significant increase in new bone formation was seen (p less than 0.03). compared with that seen in control animals. Trabecular bone bridged the gap between the proximal and distal fragments in all four specimens from the dogs that had received that treatment. In contrast. when polylactic acid combined with bovine bone morphogenetic protein had been implanted. significant reparative new bone was not found in the defect at three months.
A comparison of quality of life before and after arthroplasty in patients who had arthrosis of the hip joint, Quality of life before and one year after total hip arthroplasty was evaluated in fifty-six patients who had arthrosis of the hip joint. There were twenty-one men and thirty-five women. and the median age was sixty-five years (range. thirty to seventy-nine years). Before and after total hip arthroplasty. a functional assessment was done with the Charnley-Merle d'Aubigne scoring system. The patients assessed quality of life using the Nottingham Health Profile. In the comparison of quality of life before and after the arthroplasty. significant improvement was observed regarding pain (p less than 0.0001). energy (p less than 0.0001). sleep (p less than 0.0001). and social isolation (p = 0.001). Similarly. there was a significant reduction in the frequency of health-related problems pertaining to housework (p less than 0.0001). holidays (p less than 0.0001). hobbies (p = 0.0001). social life (p less than 0.0001). sexual function (p = 0.001). and family life (p = 0.0005). and among patients who were sixty-five years old or less and who worked at paid employment (p = 0.04). Quality of life after total hip arthroplasty was in close agreement with that of a healthy reference group of similar age and sex distribution. It was concluded that quality of life after total hip arthroplasty is improved considerably. The Nottingham Health Profile is a valuable tool in the evaluation of the result of. as well as the indicators for. total hip arthroplasty.
Clinical review 23: The use of the long-acting somatostatin analog octreotide in the treatment of gut neuroendocrine tumors, The SRIF analog octreotide (SMS 201-995) has been in clinical use for over 6 yr in the treatment of acromegaly and metastatic endocrine pancreatic and carcinoid tumors. The use of the analog in the treatment of acromegaly and TSH-secreting tumors is beyond the scope of this clinical review. Patient acceptance of the analog. given chronically by the sc route. has been excellent and side effects have been few with the exception of the development of gallstones. In endocrine pancreatic and carcinoid tumors the hypersecretion of hormones such as VIP. glucagon. and gastrin and the secretory products of carcinoid tumors (e.g. 5-hydroxytryptamine and tachykinins) and their clinical effects may be successfully blocked. This allows excellent palliation of such tumors and often enables the patients to return home and lead normal social lives. Initial hopes that long-term octreotide therapy would be an effective antitumor drug. reducing tumor growth. based on experimental animal models and human tumor cell lines. have not been born out in clinical practice. A reduction in gut tumor bulk due to octreotide. rarely or never occurs as a sustained phenomenon. Eventually a decrease in. and finally an absence of. clinical effectiveness occurs despite the reintroduction of other treatment modalities.
Pretreatment with betamethasone of patients with Graves' disease given radioiodine therapy: thyroid autoantibody responses and outcome of therapy, The effects of betamethasone on thyroid autoantibody responses and outcome of radioiodine therapy were determined over a period of 1 yr in a prospective randomized study of 40 patients with Graves' disease. Twenty patients were given placebo tablets. and 20 patients were treated with beta-methasone from 3 weeks before until 4 weeks after 131I therapy. At the time of inclusion in the study. the mean serum concentrations of TSH receptor antibodies. thyroid peroxidase antibodies. and thyroglobulin antibodies (TgAb) were increased in both groups. Three weeks of treatment with betamethasone reduced the thyroid peroxidase antibody and TgAb titers as well as the serum concentrations of thyroid hormones. A decrease in the TSH receptor antibody level was not statistically significant. After radioiodine therapy. transient increases in thyroid autoantibody levels were observed. The titers of the different antibodies generally changed in parallel. In some patients a detectable level of a given antibody was found only after the radioiodine treatment. and in two cases. TgAb did not appear at all. although the two other antibodies increased temporarily. Betamethasone delayed. but did not abolish. the 131I-induced antibody peaks. Betamethasone also caused a reduction in the total serum immunoglobulin G. a reduction which persisted throughout the study period. When the study ended. 17 patients given placebo and 9 patients given betamethasone (P less than 0.001) were receiving replacement therapy due to the development of hypothyroidism. These patients at this point in time had lower antibody levels than those not requiring T4. The results of this study demonstrate that betamethasone reduces and modifies the thyroid autoantibody responses as well as the outcome of radioiodine therapy in patients with Graves' disease. From a clinical point of view. these effects may be in opposite directions.
Enhanced left ventricular diastolic function in hyperthyroidism: noninvasive assessment and response to treatment, Hyperthyroidism is associated with a marked effect on the cardiovascular system. Despite enhanced resting ventricular systolic performance. thyrotoxicosis has been implicated as a primary cause of cardiomegaly. congestive heart failure. and decreased exercise tolerance. To further assess potential alterations in ventricular function we have noninvasively studied diastolic performance in nine newly diagnosed and untreated hyperthyroid patients. Parameters including diastolic flow velocities. isovolumic relaxation time (IVRT). and the rate of diastolic flow deceleration were compared to those of an age- and sex-matched control population. and then repeat determinations were made after beta-adrenergic blockade and again when the patients were chemically and clinically euthyroid. Before treatment the IVRT was 33.0 ms. which was significantly (P less than 0.005) shorter than the control value (57.9 ms) and in combination with other measures of diastolic function indicated enhanced left ventricular relaxation. beta-Adrenergic blockade slowed the resting heart rate from 97 to 80 beats/min (P less than 0.005) and partially normalized the rate of diastolic deceleration. but had no effect on the IVRT (33.8 ms). When patients were euthyroid. the IVRT was 51.7 ms. and other measures of diastolic performance were the same as those in controls. The current data assessing resting diastolic function in hyperthyroidism are similar to those previously reported for systolic function. Our findings of enhanced cardiac diastolic performance do not support the hypothesis that thyrotoxicosis is associated with compromised left ventricular function and suggest the possibility that the cardiac symptoms that accompany hyperthyroidism may be due to noncardiac mechanisms.
Acetylcholine regulates pancreastatin secretion from the human pancreastatin-producing cell line (QGP-1N), Studies were made of pancreastatin (PST) secretion from a human PST-producing cell line (QGP-1N) in response to various secretagogues. Cells with immunoreactivity for PST were observed in monolayer cultures of QGP-1N cells. Carbachol stimulated PST secretion and the intracellular Ca2+ mobilization concentration dependently in the range of 10(-6)-10(-4) M. The PST secretion and Ca2+ mobilization induced by carbachol were inhibited by atropine. The calcium ionophore (A23187) stimulated PST secretion. However. cholecystokinin and gastrin-releasing peptide did not stimulate either PST secretion or Ca2+ mobilization. Secretin also did not stimulate PST secretion. The glucose concentration in the culture medium had no effect on PST secretion. These results suggest that PST secretion is mainly regulated by acetylcholine through a muscarinic receptor. and that an increase in intracellular Ca2+ plays an important role in stimulus-secretion coupling in QGP-1N cells.
3 alpha-androstanediol glucuronide in virilizing congenital adrenal hyperplasia: a useful serum metabolic marker of integrated adrenal androgen secretion, To determine whether serum 3 alpha-androstanediol glucuronide (3AG) reflects the overall effect of integrated adrenal androgen secretion in the virilizing form of congenital adrenal hyperplasia (CVAH). circadian levels (0800. 1200. 1600. and 2000 h) of serum 3AG and 17-hydroxyprogesterone (17OHP) or 11-deoxycortisol (S). androstenedione (A). testosterone (T). and 24-h urinary 17-ketosteroids (17KS) were examined in seven patients (pts) with classical 21-hydroxylase deficiency (21OHD) and one pt with classical 11 beta-hydroxylase deficiency (11 beta OHD). Hormonal studies were conducted during the second day of dexamethasone (Dex) administration (2 mg/day). In five poorly controlled CVAH pts. including the 11 beta OHD pt. highly elevated baseline morning (AM) serum 17OHP or S as well as A levels. and elevated AM T levels in three pts decreased markedly in the evening (PM). while elevated serum 3AG showed no significant circadian changes; 17KS levels were markedly elevated for age. During Dex. moderately or slightly elevated AM 17OHP. A. or T in two to four pts with 21OHD decreased to the normal range in the PM. In the pt with 11 beta OHD. S. A. and T levels were suppressed. 3AG levels were modestly elevated or normal. without circadian changes. in these pts; 17KS levels were elevated or normal. In two other 21OHD pts. modestly elevated AM baseline 17OHP and A levels decreased in the PM; elevated AM T decreased in one pt in the PM; modestly elevated 3AG levels showed no circadian changes; 17KS levels were modestly elevated. During Dex. normal or slightly elevated serum steroids and 17KS levels were associated with normal or high normal 3AG levels without circadian changes. In one postpubertal female with 21OHD. modestly elevated AM baseline 17OHP levels decreased at 2000 h; normal A and T levels throughout the day and low normal 17KS were associated with slightly low 3AG levels. without circadian variation. During Dex treatment. normal 17OHP. A. T. and low 17KS levels were associated with low 3AG levels without circadian variation. In all pts as a group. an excellent correlation (r = 0.9) was found between either 0800 h or mean. or 2000 h serum 3AG levels and 17KS. In addition. AM and PM serum 3AG levels in five normal women were similar. We conclude that the high correlation between serum 3AG and urinary 17KS and the absence of a significant circadian variation in 3AG indicate that serum 3AG. regardless of sample time. is a useful metabolic index of integrated adrenal androgen secretion in CVAH.
Mitotane enhances cytotoxicity of chemotherapy in cell lines expressing a multidrug resistance gene (mdr-1/P-glycoprotein) which is also expressed by adrenocortical carcinomas, P-Glycoprotein (Pgp). product of the mdr-1 gene. is a 130- to 180-kDa plasma membrane phosphoglycoprotein which mediates multidrug resistance in cell culture by increasing efflux of the natural product chemotherapeutic agents. High levels of expression of mdr-1/Pgp are found in both the normal adrenal and adrenocortical cancers. By RNA in situ hybridization the expression in adrenocortical cancer is shown to be widely distributed. The present study demonstrates that decreased drug accumulation mediated by mdr-1/Pgp can be overcome by clinically achievable concentrations of mitotane (o.p'-DDD). The increase in drug accumulation with the addition of mitotane is due at least in part to a decrease in drug efflux and results in an increase in cytotoxicity when agents of the natural product class are used. This effect is observed in cells with a broad range of mdr-1/Pgp expression. including levels comparable to those found in most adrenocortical cancers. Similar increases in drug accumulation can be demonstrated in an unselected adrenocortical cancer cell line that expresses mdr-1/Pgp. The finding that multidrug resistance mediated by mdr-1/Pgp can be reversed by mitotane provides a rational basis for exploring the use of mitotane in combination with natural product chemotherapeutic agents in adrenocortical cancer.
Human plasma growth hormone (GH)-binding proteins are regulated by GH and testosterone, Possible regulation of GH-binding proteins (GH-BPs) in human plasma was examined. Eight children with isolated GH deficiency had a very low level of plasma GH-binding activity (10.2 +/- 1.1% of radioactivity). Under GH treatment the hormone binding to the high affinity BP (peak II-BP) increased in every patient to reach the mean value of 18.5 +/- 1.4%. In one patient. Scatchard plot analysis indicated that this increase was related to a higher binding capacity without any significant change in the binding affinity. A positive correlation existed between the GH-binding activity and insulin-like growth factor-I plasma levels. In nine boys with pubertal delay. the GH-specific binding to peak II-BP was normal (30.6 +/- 3.7% of radioactivity); it decreased significantly after testosterone treatment. In four boys with precocious puberty. the specific GH binding to peak II-BP was low (16.6 +/- 1.1%). It increased significantly to 21.6 +/- 1.1% of radioactivity after treatment with a LHRH analog. A negative correlation existed between plasma testosterone levels and GH binding to peak II-BP in boys presenting pubertal delay or precocious puberty. The high affinity GH-BP is regulated. and among the factors that play a role in this regulation. GH and testosterone have opposite effects.
Cyclic adenosine 3',5'-monophosphate responses to parathyroid hormone, prostaglandin E2, and isoproterenol in dermal fibroblasts from patients with familial benign hypercalcemia, Plasma concentrations of PTH are much lower for a given calcium or phosphorus level in patients with familial benign hypercalcemia (FBH. or familial hypocalciuric hypercalcemia) than in those with primary hyperparathyroidism; these and other data suggest that there might be tissue hypersensitivity to PTH in FBH. To test this hypothesis. we have used cultured dermal fibroblasts from abdominal skin biopsies of six patients with FBH and six age- and sex-matched controls as surrogate PTH-responsive tissues. Cells in 24-well plastic plates were exposed to vehicle. human PTH-(1-34) (10(-10)-10(-7) M). prostaglandin E2 (10(-6) M). or isoproterenol (10(-4) M) for 10 min in the presence of isobutylmethylxanthine. and cellular cAMP was determined by RIA. All cells responded to PTH with dose-dependent increases in cAMP. and all responded strongly to prostaglandin E2 and isoproterenol. There were no consistent or significant differences between control and FBH fibroblasts in maximal responses to the three agonists. and half-maximal stimulation was achieved with about 10(-9) M PTH in both normal and FBH cells. These data are not consistent with increased tissue sensitivity to PTH in FBH.
Effect of selenium supplementation in hypothyroid subjects of an iodine and selenium deficient area: the possible danger of indiscriminate supplementation of iodine-deficient subjects with selenium, Selenium and seleno dependent glutathione peroxidase (GPX) deficiency has been described in endemias of myxedematous cretinism. In northern Zaire. a selenium supplementation trial has been conducted. Beside correcting the GPX activity. two months of selenium supplementation was shown to modify the serum thyroid hormones parameters in clinically euthyroid subjects and to induce a dramatic fall of the already impaired thyroid function in clinically hypothyroid subjects. These results further support a role of selenium in thyroid hormone metabolism. In an iodine deficient area. this selenium deficiency could lead to opposite clinical consequences: protect the general population and the fetus against iodine deficiency and brain damage; and in turn. favour the degenerative process of the thyroid gland leading to myxoedematous cretinism.
Lipolytic and ketogenic fluxes in human hyperthyroidism, The effect of hyperthyroidism on lipolytic and ketogenic fluxes was determined by measuring simultaneously (stable isotope methodology) glycerol. nonesterified fatty acids (NEFA). and ketone body (KB) kinetics in euthyroid and hyperthyroid subjects. In the postabsorptive state hyperthyroid patients had normal concentrations of insulin and glucagon. but increased concentrations (P less than 0.01) and turnover rates (P less than 0.01) of glycerol. NEFA. and KB. The ratio of NEFA appearance rate to glycerol appearance rate was decreased in hyperthyroid subjects (2.34 +/- 0.23 vs. 3.15 +/- 0.22; P less than 0.05). indicating that intracellular cycling between triglycerides and fatty acids was increased. The percentage of NEFA flux used for KB production. calculated from NEFA disappearance rates and KB appearance rates. was increased in hyperthyroid patients (21.20 +/- 2.75% vs. 13.37 +/- 0.63%; P less than 0.05). suggesting a diversion during hyperthyroidism of hepatic fatty acid metabolism toward ketogenesis. However. when the plasma NEFA levels of control subjects were raised by the infusion of a triglyceride emulsion to levels comparable to those observed in hyperthyroid patients their percentage of NEFA flux used for ketogenesis rose to values slightly higher (26.30%) than those of hyperthyroid subjects. In conclusion. 1) hyperthyroidism results not only in increased lipolysis. but also in enhanced triglyceride-fatty acid cycling. which could contribute to the excessive energy expenditure; and 2) the increased KB production of hyperthyroid patients results more from an increase in NEFA availability than from a direct stimulation of hepatic ketogenesis.
Specificity of low dose fadrozole hydrochloride (CGS 16949A) as an aromatase inhibitor, CGS 16949A (fadrozole hydrochloride). a potent cytochrome P450-mediated steroidogenesis inhibitor. blocks aromatase at low doses. but other biosynthetic steps at higher concentrations. Recent studies demonstrated inhibition of C11-hydroxylase. corticosterone methyloxidase-II. and deoxycorticosterone to corticosterone conversion with this agent at some-what higher concentrations than those required for blockade of aromatase. Based upon phase I studies. we postulated that relatively selective inhibition of aromatase might be possible if sufficiently low doses of CGS 16949A were used. A phase II study in 54 postmenopausal women with metastatic breast cancer examined the effects of low dose CGS 16949A on estrogen. mineralocorticoid. and glucocorticoid secretion. Two dose schedules and two dose levels were chosen based upon our prior dose escalation protocol study. Plasma estrone. estradiol. and estrone sulfate as well as urinary estrone and estradiol fell equally with 1.8-4 mg CGS 16949A given either on a twice daily or three times daily dose schedule. Isotopic kinetic studies demonstrated an 84% decrease in the rate of conversion of androstenedione to estrone to 0.40 +/- 0.07% (patients receiving 1.8-4 mg CGS 16949A daily). With these three regimens. basal levels of aldosterone and cortisol did not change significantly over a 12-week period of observation. Clinical examination. plasma electrolytes. and urinary sodium/potassium ratios suggested no biological evidence of mineralo-corticoid deficiency. ACTH-stimulated cortisol concentrations. however. were blunted at each dose level compared to pretreatment values. Nonetheless. peak responses exceeded 550 nmol/L. or a basal to peak difference of 190 nmol/L or greater. in 97% of instances. This probably reflected inhibition of C11-hydroxylase. since basal and ACTH-stimulated levels of 11-deoxycortisol were increased in response to CGS 16949A. Androstenedione and 17 alpha-hydroxyprogesterone also exhibited an upward trend in response to drug treatment. ACTH-stimulated aldosterone levels were blunted to a greater extent than those of cortisol. probably as a reflection of corticosterone methyloxidase type II blockade. Overall. the results suggest that CGS 16949A. at doses of 1.8-2 mg daily. blocks aromatase effectively and does not produce clinically important inhibition of cortisol or aldosterone biosynthesis. Thus. this agent can probably be used safely without glucocorticoid or mineralocorticoid supplementation.
Serological diagnosis of HIV infection: practice and performance in western Europe, Current laboratory practice in testing for HIV antibodies in western Europe was investigated by means of a questionnaire addressed to the 12 EC countries and Finland. Norway. Sweden and Switzerland. Despite inevitable regional differences there was a fair degree of homogeneity in broad laboratory organisation and in the types of tests and confirmatory strategies used. The primary test is always some form of enzyme linked immunosorbent assay (ELISA). though a number of laboratories also use agglutination tests. Confirmation is by an ELISA of a different type. or by Western blot. or both. The size and workload of laboratories covered a wide range. It is suggested that laboratories doing only a small number of tests at infrequent intervals should take extra care in validating their results and should be closely monitored. Twelve of the 16 countries studied have a quality assurance scheme for monitoring laboratory performance. Participation is voluntary but is invaluable even for the largest laboratories. The results suggest that the standard of laboratory diagnosis is reasonably uniform throughout the region. which is not only important for the individual patient but means that epidemiological comparisons of data from different areas have at least a sound technical base.
Estimation of prevalence of Helicobacter pylori infection in an asymptomatic elderly population comparing [14C] urea breath test and serology, A non-invasive serological assay devised in this laboratory had a sensitivity and specificity of 100% as determined by culture and confirmed by histology in a group of 47 patients who had undergone endoscopy. The correlation between serology and the non-invasive [14C] breath test was very good. Only one of 24 culture positive patients was. while all 23 culture negative patients were. breath test negative. In a group of 46 healthy elderly persons. however. significant anomalies between serology and breath test were observed. Only 83% of the breath test negative persons were seronegative. while only 68% of the breath test positive persons were seropositive. These results can be explained in terms of age related atrophic gastritis and immune incompetence. causing reduced colonisation and decreased antibody production. respectively. These investigations suggest that non-invasive tests for H pylori infection may not be reliable in the elderly.
Neutropenia associated with X-linked agammaglobulinaemia, In a series of six cases of sex-linked agammaglobulinaemia neutropenia occurred as a presenting feature in four and during the presenting illness in the other two. The six patients all had low antibody titres and absent or low immunoglobulin concentrations with normal concentrations of T cells and absent B cells. The patients were all first seen with severe. acute infection. including septic abscesses and meningitis; neutropenia resolved as the infection and immunoglobulin deficiency were treated. Haematologists should be aware that neutropenia is a common association of infection in patients with immunoglobulin deficiency.
Comparative ferrokinetic study with initial and extended iron clearance models, Erythrokinetic studies were performed on 10 patients with chronic myelofibrosis and 11 patients with myelodysplasia (MDS). Values for plasma iron turnover. marrow iron turnover. and erythron transferrin uptake were derived using two ferrokinetic models. One entailed analysis of the extended plasma iron clearance over a number of days. the other comprised analysis of the initial plasma iron clearance during the first few hours of the study. A close correlation was found between the variables quantifying total erythropoiesis (marrow iron turnover and erythron transferrin uptake) in the two methodologies. Functional classifications produced by both models and based on the values for plasma iron turnover. marrow iron turnover. and erythron transferrin uptake were compared. Both models identified functional heterogeneity in the group with myelofibrosis and functional homogeneity within the MDS group. Each method produced comparable data on erythropoiesis. The main reason for analysing the extended plasma iron clearance is to differentiate levels of effective and ineffective erythropoiesis. The short analysis presents the practical advantages associated with a one-day study. This could be further enhanced if the level of effective erythropoiesis could be clearly defined.
Prognostic value of proliferative activity in lymph node metastases of patients with breast cancer, Whether the proliferative activity of distant metastases could be predicted by the proliferation in axillary lymph node metastases was investigated in 304 lymph nodes metastases of 52 patients with breast cancer who had not received adjuvant treatment. The standard deviation of the mean mitotic index (MI)--the average number of mitoses per field in 10 high power fields--was of the best prognostic valve in univariate survival analysis. None of the classic (volume % epithelium and stroma) or morphometric features (nuclear area. nuclear axis ratio. shape factors) provided significant results. In Cox regression analysis a multivariate combination of the mean MI. the SD of the mean MI. and the maximum MI emerged. which provided a satisfying means of differentiating patients with a good (68% survival) and a poor (28% survival) prognosis. Proliferation variables derived from axillary lymph node metastases of patients with breast cancer can predict the clinical course of distant metastases.
Spinous injury caused by a sea urchin, A bather on holiday in Kenya injured a finger on a spiny marine creature living on the sea bed. A skin biopsy specimen from the injured finger contained several black spines about 0.5 mm in diameter and up to 1.5 cm in length. Spines removed from the specimen were embedded in plastic resin to facilitate transverse sectioning. Light microscopical examination using crossed polarisers showed an ornate symmetrical structure brightly illuminated against a dark background. These features are characteristic of sea urchin (Echinoderm) spines which are composed of ornately formed calcite crystals covered by an epithelium. The spines of sea mice. on the other hand. are chitinous in nature; they are also much finer and lack the ornate symmetry of sea urchin spines.
Morbidity survey of post mortem room staff, A retrospective study of post mortem staff who had taken leave due to sickness was carried out over a 12 month period throughout England and Wales. Eight hundred and nineteen post mortem room personnel (representing a 57% response) replied to individual postal questionnaires regarding their sick leave of two days or more. for the period June 1985 to June 1986. Complete responses were available for 751. Post mortem room technical staff reported more mean days sickness per person (7.8) than either pathologists (1.6) or a control group of coroners' officers (3.9). The annual inception rate (frequency by spells) was also higher among technicians than the other two groups. Technical staff had more infectious disease (0.73 mean days of absence compared with pathologist (0.10) or coroners' officers (0.12] and more frequent absences due to cuts and lacerations.
Future applications of electronic thermography, The dental literature does not yet indicate the full range of facial thermographic findings in health and disease. Thermography is not useful in assessing some common dental problems. such as periapical granuloma. Promising reports. however. support its use in the diagnosis of neuralgias and atypical odontalgia. TMJ. nerve damage and repair after oral surgery. and in evaluating local dental anesthesia. Unfortunately. few if any of these studies were properly designed or conducted. limiting current attempts to define the value of thermography in dentistry. Until this situation resolves. ET of the face. for use in dentistry. can only be considered an investigational procedure. More research will clarify the precise contribution of thermography to dental problems.
Respiratory mucus hypersecretion (bronchorrhea): a case discussion--possible mechanisms(s) and treatment, The mechanism(s) underlying mucus hypersecretion (bronchorrhea) and the treatment of this condition are poorly understood. We have previously demonstrated that erythromycin inhibited mucus secretion from human airways and from secretory epithelial cells in vitro. We encountered a patient with airway obstruction marked by severe bronchorrhea. who previously had responded only to inhaled bronchodilators and high-dose prednisone. Many attempts to wean him from prednisone had failed. During the course of his disease. he had developed an IgG antibody to vasoactive intestinal peptide. had increased amounts of mucus secreted by his respiratory epithelial cells. and demonstrated hyperreactive airways as measured by methacholine challenge provocation test. Erythromycin was added to his therapy. The effect of erythromycin treatment was quite dramatic and included clinical and laboratory improvement. After a short trial of erythromycin. the patient tolerated low. every-other-day doses of prednisone. there was a significant reduction in the volume of his bronchorrhea. a major decrease in the epithelial mucins in his total expectorated mucus. complete inhibition of his airway hyperresponsiveness to inhaled methacholine. and significant reduction in the level of IgG antibody to vasoactive intestinal peptide. This response was specific for erythromycin since other antibiotics did not have any clinical. biochemical. or physiologic effects. We conclude that erythromycin may play a role in the treatment of patients with bronchorrhea and may have a steroid-sparing effect. Additional studies with larger numbers of patients are indicated.
Cockroach-allergen study: allergen patterns of three common cockroach species probed by allergic sera collected in two cities, Antigens/allergens of three common cockroach extracts. crude whole body extract of the American cockroach (CRa-A). crude whole body extract of the German cockroach (CRa-G). and crude whole body extract of the Oriental cockroach (CRa-O). were studied with crossed immunoelectrophoresis. crossed radioimmunoelectrophoresis. and Western blot analysis. Sera of cockroach-allergic patients with asthma. 10 from Chicago. Ill. (C group) and six patients from Lexington. Ky. (L group). were used; results were then compared with sera of control subjects with asthma. Qualitative differences in protein bands were noted among CRa-A. CRa-G. and CRa-O by crossed immunoelectrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Allergen bands on Western blot were analyzed for distribution by molecular weight (MW) with relative intensity scores. Results were compared by species and by geography. Two to 12 allergenic bands of variable MW (14 kd to greater than 116 kd) were identified by 13 of 16 individual sera from cockroach-allergic patients from all three extracts. CRa-A demonstrated 55 bands with an intensity score of 125; CRa-G. 58 bands with an intensity score of 100; and CRa-O. 51 bands with an intensity score of 108. Allergenic bands of CRa-A were identified by six sera of the C group and one sera of the L group. whereas bands of both CRa-G and CRa-O were noted by nine sera of the C group and four sera of the L group. All three species had an allergen band in MW range of 40 to 45 kd that reacted to most sera from cockroach-allergic patients with asthma.
Effective site of bronchodilation by antiasthma drugs in subjects with asthma, We studied the effective sites of airway response to atropine and fenoterol aerosols and to the intravenous injection of aminophylline in patients with stable and spontaneous asthma. by the simultaneous assessment of respiratory resistance (Rrs) and anatomic dead space (VD). Central airway response was determined by VD. and overall response was determined by Rrs. Peripheral airway response was inferred from Rrs when the change in VD was slight. Atropine (4 mg/ml) or fenoterol (0.4 mg/ml) was continuously inhaled during tidal breathing for 5 minutes. Inhalation of both atropine and fenoterol increased Grs (reciprocal of Rrs) (p less than 0.01) with a simultaneous increase in VD (p less than 0.01) in the patients with stable and spontaneous asthma. Fenoterol increased Grs more than did atropine at an equivalent increase in VD in patients with spontaneous asthma (p less than 0.05). Intravenous injection of aminophylline (250 mg) had no effect on either Grs or VD in patients with stable asthma. but it significantly increased Grs (p less than 0.01) without change in VD in patients with spontaneous asthma. These results suggest that the predominant sites of bronchodilation induced by inhaled atropine are the central airways. that those sites induced by intravenous injection of aminophylline are the peripheral airways. and that inhaled fenoterol dilates both the central and peripheral airways in subjects with asthma. Differences among clinically used bronchodilators on the effective sites may be considered in the treatment of bronchial asthma.
Human eosinophils are more toxic than neutrophils in antibody-independent killing, Eosinophils (EOSs) are implicated in damaging host tissues in diseases such as asthma and eosinophilic gastroenteritis. In the present study. we assessed the cytotoxicity of human EOSs from peripheral blood of patients with eosinophilia and from peritoneal fluid of patients undergoing continuous peritoneal dialysis and compared them to normal neutrophils. Cytotoxicity was measured by the release of 51chromium from cultured tumor cells and chicken erythrocytes. Both EOSs and neutrophils were separated on discontinuous Percoll gradients with greater than 95% purity. The granulocytes were activated by preincubation in an ice bath with phorbol myristate acetate and washed before incubation with the target cells. The EOSs lysed significantly more tumor cells (K562. Raji. and CEM lines) in an 18-hour assay than did neutrophils. and no significant difference was found between the peritoneal and blood EOSs. The EOSs were also much more efficient than neutrophils in lysing chicken erythrocytes when they were activated by granulocyte-macrophage colony-stimulating factor instead of phorbol myristate acetate. Cytolysis by EOSs is mediated by both oxidative and nonoxidative mechanisms. as indicated by experiments with cells from patients with chronic granulomatous disease. Thus. EOSs are much more cytotoxic than neutrophils and potentially much more damaging to patients with eosinophilia.
Late asthmatic responses after exercise challenge are reproducible, In this study the reproducibility of a late asthmatic reaction (LAR) after exercise challenge (EC) has been documented. Eighty-three hospitalized patients with asthma were challenged with exercise. The patients were examined according to a standardized protocol that comprised 8 minutes of bicycling at 90% of predicted heart rate. An LAR after EC was considered to have occurred when there was a fall in peak expiratory flow rate greater than or equal to 20% on three or more time points on the exercise day compared to corresponding clock time on a control day. According to these criteria. 11 patients (13.3%) experienced an LAR. Those patients were rechallenged 21 to 150 days after the first EC. without changing the therapy regimen of the patients. to study its reproducibility. Eight patients (73%) demonstrated a reproducible LAR after EC based on the criteria for a positive LAR. Although the LAR after EC was reproducible. the time points at which the LAR took place after the second EC differed from LARs after the first EC. Our results indicate that the LAR after EC occurs in a considerable number of patients with bronchial asthma and is quite reproducible.
Abnormal response to a human B cell growth factor in patients with common variable immunodeficiency (CVI), Patients with common variable immunodeficiency (CVI) generally fail to produce antigen-specific IgG. We have identified a lymphokine called high molecular weight B cell growth factor (HMW BCGF) that expands an IgG-producing subpopulation of B cells. The B cells from 15 of 16 patients with CVI evaluated in this study failed to proliferate to HMW BCGF. although they proliferated normally to another BCGF. low molecular weight BCGF (LMW BCGF). Nevertheless. 11 patients had more than normal numbers of B cells expressing HMW BCGF receptors. The HMW BCGF receptors on the B cells of three patients with CVI studied were the same molecular weight as the normal HMW BCGF receptor. Examination of B cells from four patients with CVI for intracellular signals produced in normal B cells after stimulation with HMW BCGF revealed that B cells from patients with CVI failed to developed significant increases in cyclic adenosine monophosphate or phosphoinositides after HMW BCGF stimulation. However. cytoplasmic phosphoinositides in the B cells from all four patients with CVI were already increased above what is observed in normal B cells before stimulation with HMW BCGF (either freshly isolated or Staphylococcus aureus Cowan I-activated B cell). Thus. the failure of B cells from patients with CVI to respond to HMW BCGF may be related to their abnormal activation in vivo. Since HMW BCGF expands a subpopulation of memory B cells. the inability of CVI B cells to respond to HMW BCGF may contribute to their abnormal secondary responses to antigens.
"Designer drugs"--a current perspective, Since the late 1970s. in an effort to quench the ever burgeoning appetite for pharmacological substances of abuse and to satiate their own need for profit. unscrupulous chemists have set up clandestine laboratories to produce and market new drugs for street sale. Using fairly common industrial chemicals. they have altered or modified preexisting controlled substances such as fentanyl. meperidine. mescaline. amphetamine. and phencyclidine. producing derivatives of these parent compounds that. up until 1986. were able to temporarily elude the guidelines of the Federal Controlled Substances Act due to their new and unique chemical structures. Unsuspecting users continue to use the drugs recreationally. This article will present a comprehensive review of these "Designer Drugs" looking at historical data. pharmacokinetics. treatment. abuse trends. and some of the more recent additions to the social pharmacopoeia.
Interpretation and clinical significance of the QRS axis of the electrocardiogram, The frontal plane QRS axis of the standard 12-lead electrocardiogram (ECG) is easily and accurately measured by the clinician. A simple method of estimating this axis is discussed. This axis is age-dependent. We reviewed the literature to determine if evidence exists of an association between an "abnormal" QRS axis and clinically significant myocardial disease. We also examined the literature for clinical correlation of a "normal" QRS axis with the absence of myocardial pathology. We found that although an abnormal QRS axis (falling outside the limits of +30 degrees and +90 degrees) occurs in a small number of normal individuals. its presence should prompt a thorough evaluation of all the parameters of the ECG to look for myocardial disease.
Making tympanocentesis [correction of tympanpanocentesis] easier, Tympanocentesis can be of great value in identifying the etiologic agent of acute otitis media. Unfortunately the trepidation with which clinicians approach this procedure may limit its application. This report of a method of tympanocentesis suggests a short-cut using instruments readily available in emergency departments and in many doctors' offices. The manuscript describes a means of stabilizing the needle in the middle ear during aspiration and details a simple method of handling middle ear aspirates which should ensure the viability of middle ear bacteria until they reach the laboratory.
The etiology of medical gridlock: causes of emergency department overcrowding in New York City, Overcrowding of emergency departments in New York City is the most apparent symptom of a crumbling health care system. There is a growing need for the care of a largely impoverished population suffering from an increasing prevalence of AIDS. substance abuse. and psychiatric disease. Institutions crippled by critical shortages of inpatient beds and nurses lack the resources to meet this rising demand. Although the epidemic of medical gridlock began in New York City. it is spreading rapidly to involve other areas of the country. Short-term efforts to resolve this crisis have thus far been unsuccessful. Long-range solutions are likely to be costly and may require a reconfiguration of societal health care priorities.
Axillosubclavian vein thrombosis: case report, Deep-vein thrombosis of the upper extremity. that is. axillosubclavian vein thrombosis. is a relatively rare and potentially overlooked diagnosis in the emergency department (ED). It can be the cause of significant morbidity and it may be life-threatening. Reported here is the case of a 23-year-old man who presented to the ED with left upper extremity pain and swelling. Venography confirmed the diagnosis of axillosubclavian vein thrombosis. Hospitalization and treatment with intravenous heparin led to a satisfactory recovery. The clinical presentation. predisposing factors. diagnosis. treatment. and complications of this rare entity are discussed.
Emergency department echocardiography in the diagnosis and therapy of cardiac tamponade, A 44-year-old male presented to the emergency department in shock with jugular venous distension and upper chest cyanosis. Superior vena cava syndrome was ruled out by computed tomography (CT scan). However. a large pericardial effusion was found on CT scan and confirmed by sonography. Pericardial tamponade was diagnosed by emergency physicians and sonography-guided pericardiocentesis was performed with marked improvement in symptomatology.
Effectiveness of nitrous oxide in a rural EMS system, Prehospital systems need a safe. effective analgesic agent for the treatment of patients suffering from pain. Recent studies have documented the efficacy of nitrous oxide in urban and rural settings. This study reviews the findings on 200 patients (157 trauma. 23 medical. 18 musculoskeletal problems) who received nitrous oxide during a 28-month period in a rural EMS system. Eighty-five percent of the patients reported pain relief. Only minor side effects were noted. Patient satisfaction was high. and there was no abuse noted among personnel.
The physical examination in acute cardiac ischemic syndromes, The physical examination in acute cardiac ischemia remains a valuable tool when done with skill. Ischemia without infarction alters cardiac function. and the physical examination yields findings that reflect these changes. Ischemia with infarction alters structure and function. resulting in physical findings that are usually more dramatic and of longer duration. sometimes permanent. Carefully done. the physical examination provides information that helps in management of the immediate course. predicts prognosis. and allows for better interpretation of cardiovascular tests. both invasive and noninvasive.
William Heberden and Myron Prinzmetal: angina pectoris, The most significant accounts of angina pectoris appeared in the medical literature separated by nearly two centuries. They were Heberden's initial description of classic angina and Prinzmetal's report of the variant form. Angina pectoris represents a transient myocardial oxygen deficiency. It is usually related to atherosclerotic coronary artery disease. but there are a number of less common etiologies. most notably aortic stenosis. Stable and unstable forms exist. with stable angina being further subclassified as being of one of four patterns: classic. variant. atypical. and angina equivalent.
Detection of cross-reactive idiotypes in the serum of patients with bullous pemphigoid, To further characterize the circulating antibasement membrane zone (antiBMZ) antibodies present in the sera of patients with bullous pemphigoid (BP). we have generated a mouse monoclonal anti-idiotypic antibody (antiId 3-17) specific for an IgG antiBMZ antibody. AntiId 3-17 is specific for an idiotype expressed on antiBMZ IgG in the serum of a patient with BP. and not expressed on pooled normal human IgG or IgG from patients with other autoimmune skin diseases. AntiId 3-17 binds to non-reduced. but not reduced. antiBMZ IgG on immunoblot. suggesting that the idiotype is composed of a conformational epitope expressed on native antibody. By a competitive inhibition ELISA. antiId 3-17 detects a cross-reactive idiotype (CRI) expressed in 18 of 50 (36%) of the sera of patients with BP. but in the sera of only 1 of 50 (2%) normal blood bank controls (p less than 0.001. Fisher's exact test) and 1 of 12 (8%) patients with pemphigus (p = 0.005). Thus. antiId 3-17 recognizes a public idiotype on a native antiBMZ antibody from a patient with BP. which is expressed in the sera of 36% of the unrelated patients with BP studied.
Characterization of pemphigus foliaceus antigen from human epidermis, Pemphigus foliaceus (PF) and its endemic form. Fogo Selvagem (FS). are characterized by subcorneal vesicles and pathogenic IgG autoantibodies directed against keratinocyte surface antigens. A major pool of FS antigen(s) remains bound to the insoluble epidermal envelope fraction. In this paper we demonstrate that this antigen(s) can be released from the envelope fraction by sonication. By immune precipitation four components can be detected. having molecular weights (MW) of 260. 80. 62. and 45 kD. The 260-kD component is lost by boiling or extraction with glycine HCl at pH 2.8. The major components appear to be the 80- and 62-kD poly-peptides. They chromatograph as a unit by gel filtration in 0.1% SDS. in the MW range of 115-120 kD. The FS antigen(s) appears to be cationic. forming insoluble complexes at low pH with SDS. and is labile to ammonium sulfate and freezing and thawing. It is unaffected by positive pressure concentration. 50% acetone precipitation. and reduction/alkylation. The FS antigen(s) is precipitated by all FS and nonendemic PF sera except those in complete clinical and serologic remission. The FS antigen(s) is also precipitated by 50% of pemphigus vulgaris but none of the bullous pemphigoid sera tested. All FS antigenic components are immunoprecipitated by IgG4 autoantibodies. but the IgG1 subclass from the same patients appear to immunoprecipitate only the 62-kD polypeptide. The FS antigen(s) is able to adsorb human autoantibodies against human desmoglein 1 (DG1). but not rabbit antisera against bovine DG1 or 2. This paper shows that physical stress. i.e.. sonication. may be able to solubilize sufficient FS antigen(s) from the epidermal envelope fractions for further chemical characterization. The relationship of these FS antigen(s) to other reported FS antigens is presently unknown.
Immunosuppressive effects of transforming growth factor beta: inhibition of the induction of Ia antigen on Langerhans cells by cytokines and of the contact hypersensitivity response, Recent reports show that transforming growth factor (TGF)-beta exerts a variety of immunosuppressive activities. The present study focuses on the effects of TGF-beta 1 on expression of Ia antigen by Langerhans cells. Although TGF-beta 1. in concentrations from 0.001 to 100 micrograms/ml. has no effect on constitutive expression of Ia antigen on these cells. the in vitro up-regulation of Ia antigen on the surface of LC by interleukin (IL)-1. tumor necrosis factor-alpha. interferon-gamma. IL-3. and granulocyte/macrophage-colony stimulating factor is inhibited by the concomitant addition of 1 microgram/ml TGF-beta 1. In contrast. TGF-beta 1 has no effect on the up-regulation induced by IL-2 or IL-6. In this report. the activity of TGF-beta closely resembles that of Cyclosporine A (CsA). Similar results are seen in vivo when either TGF-beta 1 (5 micrograms. intraperitoneally [ip]. daily on days 0-3) or CsA (1 mg. subcutaneously [sc]. twice daily on days 0-3) are given together with IL-2 (500 U. intraperitoneally [ip]. twice daily on days 1-3) or interferon-gamma (4.000 U. ip. twice daily on days 1-3). Given the important role of Ia expression in cell-mediated immune reactions. the effect of TGF-beta on contact sensitivity was next investigated. In doses of 5 micrograms. ip. daily on days 6-8. TGF-beta inhibits the expression of contact reactivity in animals sensitized on day 0 and challenged on day 7. In contrast. no effect is observed on the induction of contact sensitivity in mice given TGF-beta 1 on days--1 to 2. sensitized on day 0. and challenged on day 7. The possible importance of antagonism between TGF-beta and other cytokines. especially IFN-gamma. involved in the elicitation of contact hypersensitivity reactions is discussed.
Effect of glutathione depletion on sunburn cell formation in the hairless mouse, Cutaneous protection against ultraviolet B (UVB) radiation damage by endogenous glutathione (GSH) was evaluated in the epidermis of the hairless mouse by measuring the influence of GSH depletion on sunburn cell (SBC) formation. Cellular GSH exerts antioxidant effects and recent studies have suggested a role for oxygen radicals in the production of SBC. Hairless mice (Skh/h 1) received oral treatment with buthionine S.R-sulfoximine (BSO). an irreversible inhibitor of gamma-glutamylcysteine synthetase. to deplete cutaneous GSH; 4 d later their ears were exposed to UVB radiation. BSO treatment significantly reduced GSH levels in the epidermis to 10-15% of control levels. Twenty-four hours after UVB exposure. SBC counts in the ears of animals with and without BSO treatment were measured. and those exposed to UVB were found to have increased. Greater numbers of SBC were found in the ears of BSO-treated mice exposed to 15 or 20 mJ/cm2 UVB. than in non-BSO-treated mice exposed to the same UVB doses. At higher UVB doses. there were no statistically significant differences between the groups. The results show that endogenous GSH provides the epidermis with measurable protection against injury by low or moderate UVB doses.
Extracellular localization of human connective tissue mast cell granule contents, In early phases of cutaneous inflammation. connective tissue mast cell degranulation is associated with apparent secretion and externalization of immunoreactive chymotryptic serine proteinase. To determine whether this event is associated with structural evidence of granule externalization. we studied the sequential evolution of IgE-mediated hypersensitivity in vivo. as well as mast cell degranulation provoked by a variety of stimuli in cultured explants of human skin. By 1 min after intradermal antigen challenge with ragweed extract. mast cell degranulation was associated with apparent extrusion of intragranule constituents into the pericellular connective tissue. Similar features typified cultured skin explants exposed for 45 min to anti-IgE and other mast cell secretagogues (morphine sulfate. calcium ionophore A23187. compound 48/80. and substance P). Once externalized. granule constituents could be identified within the dermal matrix by their rounded contour and structural similarity to solubilized granule matrices remaining within actively secreting cells. These data indicate that externalization of connective tissue mast cell granule contents occurs early after secretagogue exposure. potentially accounting for infrequent documentation of this event in naturally occurring dermatoses. The ability to recognize externalized granule products at a morphologic level should facilitate the understanding of interactions between mast cell-derived mediators and target structures of the dermal microvasculature.
Induction of suppressor T cells and inhibition of contact hypersensitivity in mice by 12-O-tetradecanoylphorbol-13-acetate and its analogs, 12-O-tetradecanoylphorbol-13-acetate (TPA) and its analogs were surveyed for their abilities to modify contact hypersensitivity (CHS) responses in SENCAR mice. Sensitization of dorsal skin with 2.4-dinitrofluorobenzene (DNFB) and subsequent challenge of the ear 5 d later resulted within 24 h in ear swelling and increased vascular permeability (as measured by the extravasation of Evans Blue dye). Treatment of dorsal or ventral skin with TPA 4 times (application made every 3 or 4 d) prior to sensitization on the dorsum inhibited subsequent induction of CHS by DNFB challenge. Maximum suppression of CHS required sensitization at the site of TPA treatment. Suppression occurred over a narrow dose range of TPA (0.1-1.0 micrograms). and qualitatively correlated with the tumor incidences scored in an initiation-promotion multistage skin carcinogenesis experiment. Multiple applications (4x) of the promoters phorbol-12.13-dibenzoate (10 micrograms) and mezerein (2 micrograms) also suppressed CHS. whereas the non-promoter phorbol (20 micrograms) and the first stage tumor promoter 4-O-methyl TPA (20 micrograms) had no effect. Adoptive transfer of splenocytes isolated from mice pre-treated with TPA prior to DNFB sensitization inhibited the development of CHS in recipient mice that were sensitized and challenged with DNFB. but not oxazolone. Splenocyte preparations depleted of T lymphocytes prior to transfer could not suppress CHS in recipient mice. Conversely. suppressive activity was concentrated in splenocyte preparations depleted of adherent cells/monocytes. Collectively. these studies demonstrate that TPA treatment of murine epidermis prior to sensitization with hapten can inhibit subsequent hapten-dependent elicitation of CHS. This suppression is mediated in part by antigen-specific suppressor T cells. Furthermore. there is a qualitative correlation between the complete and second stage in vivo tumor-promoting activities of TPA and its analogs. and their abilities to inhibit CHS.
The autologous mixed epidermal cell-T lymphocyte reaction is elevated in psoriasis: a crucial role for epidermal HLA-DR+/CD1a- antigen-presenting cells, The objective of this study was to determine whether epidermal cells (EC) from psoriasis lesions and uninvolved skin could stimulate autologous T lymphocytes in the in vitro autologous mixed epidermal cell-T lymphocyte reaction (autologous MECLR). The functional role of antigen-presenting cell (APC) subsets was concurrently determined in this reaction. Mononuclear cells and purified T lymphocytes from peripheral blood of psoriasis patients showed a clear proliferative response to autologous unpurified epidermal cells from involved as well as uninvolved skin. The autologous mixed leukocyte reaction (MLR) was not elevated in psoriasis patients. In healthy controls and contact allergy patients. T-lymphocyte proliferation was not observed either in the autologous MECLR or in the autologous MLR. The level of proliferation in the autologous MECLR from psoriasis patients correlated to the number of epidermal cells that were added. To exclude the possibility that the observed proliferation in the autologous MECLR in psoriasis was due to the presence of epidermal T lymphocytes that were being stimulated and expanded in vitro. the stimulator EC were gamma irradiated (30 Gy) in some experiments. Preincubation of EC with cyclosporin A (CsA) significantly inhibited the autologous MECLR. The CsA-induced inhibition could be neutralized by the addition of fresh untreated EC to these cultures. This indicated that one of the modes of action of CsA in resolving psoriasis is. as some investigators have already shown. via inhibition of epidermal accessory cell function. In the autologous MECLR. APC from psoriasis skin could initiate this reaction. whereas APC from peripheral blood could not. This occurred in an MHC class II restricted fashion. Depletion experiments showed that Langerhans cells (HLA-DR+/CD1a+) were not the principal stimulators of autologous T lymphocytes in the MECLR. These results indicated that mainly HLA-DR+/CD1a- epidermal cells from psoriasis patients could stimulate autologous peripheral blood T lymphocytes in an MHC class II-restricted fashion.
Mediators, initiating the inflammatory response, released in organ culture by full-thickness human skin explants exposed to the irritant, sulfur mustard, Mediators released from injured human skin that initiate the inflammatory response have not been adequately identified. Organ culture of full-thickness skin explants enables us to do so. because injury to the skin can be made in vitro. eliminating the rapid leakage of serum and infiltration of leukocytes that occur in vivo. In our studies. the military vesicant sulfur mustard (SM) (10 microliters of a 0.01 to 1.0% dilution) was topically applied to injure the epidermis of the explant. Then. the explants were cultured in small Petri dishes. usually for 18 h at 36 degrees C. and the organ-culture fluids were assayed for various inflammatory mediators. We found that the culture fluids from SM-exposed and control explants contained similar amounts of angiotensin-converting enzyme. trypsin-like and chymotrypsin-like proteases. acid phosphatase. beta-glucuronidase. beta-galactosidase. lysozyme. deoxyribonuclease. ribonuclease. interleukin 1. and lactic dehydrogenase. However. the culture fluids from SM-exposed explants contained increased amounts of histamine and plasminogen-activating activity. and often prostaglandin E2. when compared to culture fluids from control explants. After 3 to 4 d in culture. full-thickness human skin explants. when exposed to 0.2% SM (but not when exposed to 1.0% SM). sometimes showed separation of the epidermis and increased collagenase activity (i.e.. hydroxyproline release). Thus. histamine (from local mast cells). and prostaglandin E2 and plasminogen-activating activity (probably from both mast cells and epidermal cells) are apparently involved in early mediation of the inflammatory response.
DNA damage in cultured human skin fibroblasts exposed to excimer laser radiation, Ultraviolet excimer lasers are being considered for use in a variety of refractive and therapeutic procedures. the long-term biologic consequences of which are unknown. The effect of sublethal doses of 193-nm laser radiation on cellular DNA was examined in cultured human skin fibroblasts. In contrast to 248 nm. treatments with the 193-nm laser radiation below 70 J/m2 did not cause significant pyrimidine dimer formation in the skin cells. This was indicated by the lack of excision repair activities (unscheduled DNA synthesis assay). and further demonstrated by direct analysis of pyrimidine dimers in DNA from irradiated cells. However. a low level of unscheduled DNA synthesis could be detected following irradiation at 193 nm with 70 J/m2. Both the 193-nm and 248-nm radiation were able to induce chromosomal aberrations. as indicated by a micronucleus assay. A dose-dependent increase in micronuclei frequency was observed 48 and 72 h after laser irradiation. These results indicate that exposure of actively replicating human skin fibroblasts to sublethal doses of either 193- or 248-nm laser radiation can result in genotoxicity.
Bullous pemphigoid antigen: cDNA cloning, cellular expression, and evidence for polymorphism of the human gene, A human epidermal keratinocyte lambda gt11 recombinant cDNA library was screened with a 0.45-kb cDNA that was generated by polymerase chain reaction (PCR) amplification of a segment of human bullous pemphigoid (BP) antigen mRNA. The screen yielded five clones. the largest one. pcBPA-4. being 2.3 kb in size. The pcBPA-4 cDNA hybridized in Northern analyses with an approximately 9-kb mRNA from cultured keratinocytes. whereas no hybridization signal was detected with RNA from human skin fibroblast. fibrosarcoma HT-1080 cells. or amniotic epithelial WISH cell cultures. Nucleotide sequencing of pcBPA-4 revealed an open reading frame encoding a putative polypeptide of 447 amino acids. This polypeptide showed 88% homology with corresponding mouse BP antigen sequences. and a region of it was identical to a segment in previously published human BP antigen sequences. The 2.3-kb cDNA isolated here was different from a previously published human BP antigen cDNA. in that the open reading frame coded for 264 additional amino acids at the carboxyl end of the putative polypeptide. Known human BP antigen amino acid sequences. compared with mouse sequences. were predicted to be moderately divergent with a unit of evolutionary period (UEP) of 4.5 millions of years (MY). Southern hybridizations suggested that the BP antigen gene (BPAG1) is present as a single copy in the human genome. Southern analyses also revealed the presence of a StuI restriction fragment length polymorphism that can be used for linkage analyses to study the inheritance of a particular BPAG1 allele and a heritable cutaneous disorder affecting the basement membrane zone. such as epidermolysis bullosa.
Epidermal Langerhans cells in myelodysplastic syndromes are abnormal, The myelodysplastic syndromes (MDS) represent clonal disorders of the hematopoietic stem cell that are associated with quantitative and qualitative disturbances of the peripheral blood cells and a high risk for the transition to overt leukemia. As epidermal Langerhans cells (LC) are bone-marrow-derived cells. we were interested to see whether they are altered in patients with MDS. Epidermal sheets were prepared from biopsies taken from the thighs of nine patients with MDS and five control persons and processed for immunoperoxidase staining of CD1a antigens. The density and morphology of CD1a+ cells (i.e.. LC) was evaluated by visual assessment as well as automatic image analysis. The density of LC was reduced in seven of nine patients (range. 30-75% of normal). whereas the morphology of LC appeared to be altered in all MDS patients in that the LC displayed large and bizarre cell bodies with only a few and often abnormally long dendrites. The HLA-DR expression by LC was not altered. as shown by double immunofluorescence staining of CD1a and HLA-DR antigens. Ultrastructurally. LC again appeared enlarged and often presented with bizarre nuclei. yet displayed no other abnormalities. Our findings suggest that LC are abnormal in MDS and might even indicate a more wide-spread involvement of the dendritic cell lineage in this syndrome.
Antigen-presenting cells in essential fatty acid-deficient murine epidermis: keratinocytes bearing class II (Ia) antigens may potentiate the accessory cell function of Langerhans cells, Essential fatty acid deficiency (EFAD) is a useful model for studying the role of (n-6) fatty acid metabolism in normal physiology. Because cutaneous manifestations are among the earliest signs of EFAD and because abnormalities in the distribution and function of tissue macrophages have been documented in EFAD rodents. we studied the distribution and function of Class II MHC (Ia) antigen-bearing cells in EFAD C57B1/6 mouse epidermis. Immunofluorescence studies revealed 1.9-9.6 (mean +/- SEM = 5.2 +/- 2.6) times more class II MHC (Ia) antigen-bearing epidermal cells in suspensions prepared from EFAD as compared to normal skin. Analysis of epidermal sheets demonstrated similar numbers of dendritic Ia+ and NLDC145+ cells in EFAD and normal epidermis. however. This discrepancy occurred because some keratinocytes in EFAD epidermal sheets expressed class II MHC (Ia) antigens. whereas keratinocytes in normal mouse epidermis did not. Two-color flow cytometry confirmed that all Ia+ cells in normal epidermis are Langerhans (Ia+ NLDC145+) cells. whereas Ia+ cells in EFAD epidermis are comprised of Langerhans cells and a subpopulation of keratinocytes (Ia+ NLDC145-). Similar levels of Ia antigens were expressed on EFAD and normal Langerhans cells. EFAD and normal epidermal cells were also compared in several in vitro assays of accessory cell function. Epidermal cells prepared from EFAD C57B1/6 mice present the protein antigen DNP-Ova to primed helper T cells more effectively than epidermal cells prepared from normal animals. EFAD epidermal cells are also more potent stimulators of T cells in primary and secondary allogeneic mixed lymphocyte-epidermal cell reactions than normal epidermal cells. The functional differences between EFAD and normal epidermal cells do not appear to result from increased cytokine release or decreased prostaglandin production by EFAD epidermal cells. In view of these findings and the observation that the antigen-presenting cell activity of EFAD epidermal cells correlates with the number of Ia+ keratinocytes in epidermal cell preparations. Ia+ keratinocytes (in the presence of Langerhans cells) may potentiate cutaneous immune responses in vitro and perhaps in vivo as well. These results also suggest that (n-6) fatty acids or metabolites of (n-6) fatty acids are involved in regulating the expression of class II MHC (Ia) antigens by keratinocytes in vivo.
Effect of sodium lauryl sulfate-induced skin irritation on in vitro percutaneous absorption of four drugs, The influence of irritant contact dermatitis on percutaneous penetration was investigated for four 14C-labeled compounds with diverse physicochemical properties: hydrocortisone (HC). indomethacin (IM). ibuprofen (IB). and acitretin (AC). Hairless guinea pigs were pretreated in vivo for 24 h with either 0.5% sodium lauryl sulfate (SLS) to induce irritant contact dermatitis or with water (controls). Twenty-four hours after pretreatment animals were sacrificed. Percutaneous penetration was then measured using in vitro diffusion cells and the removed (pretreated) skin. The following parameters were determined: cumulative amount of compound penetrated. steady state flux. lag time. and permeability coefficient. skin concentration per unit area. and the relative amount of drug remaining in the skin (as a percentage of the cumulative amount of compound penetrated through the skin). SLS pretreatment resulted in moderate irritant dermatitis in all animals and increased in vivo transepidermal water loss 4.5 times. Flux was increased in SLS-pretreated skin as compared with controls for all four compounds. with the greatest enhancement for hydrocortisone (HC) (5.9 times). followed by indomethacin (IM) (4.6 times). ibuprofen (IB) (3.9 times). and acitretin (AC) (3.4 times). Skin concentrations increased to a smaller degree from 1.6 times (IB) and 2.6 times (HC) to 3.4 times (IM). However. AC skin concentrations were not different between the two groups. Thus. percutaneous penetration parameters were equivocally influenced by SLS-induced irritation. Increased skin concentrations were paralleled by even higher increases in flux.
Detection of HIV-1 in epidermal Langerhans cells of HIV-infected patients using the polymerase chain reaction, Langerhans cells (LC) are bone marrow-derived. HLA-DR+. CD1a+. dendritic antigen-presenting cells found in stratified squamous epithelia. Within resident epidermal cells (EC). LC are the only cells expressing the CD4 antigen and are. therefore. a possible target for human immunodeficiency virus (HIV) infection. To date. conflicting results have been reported on the in vivo infection of LC by HIV. The aim of the present study was to investigate the presence of HIV-1 proviral DNA in epidermal LC of HIV-1-infected patients. EC suspensions were prepared from clinically normal skin of nine seropositive patients. Purified LC and LC-depleted EC were obtained by immunomagnetic separation and analyzed for the presence of HIV-1 proviral DNA by the polymerase chain reaction using primer pairs from different conserved regions (env and gag) of the HIV-1 genome. HIV-1 proviral DNA was detected in LC from seven of nine patients. LC-depleted EC fractions from the same nine patients were all negative. with the exception of one case. Altogether these results demonstrate that epidermal LC are infected by HIV-1 and constitute the only resident cell type in the epidermis harboring the virus. Further studies are. however. needed to demonstrate HIV replication in LC and to elucidate the functional role of LC in this infection.
The conversion of primaquine into primaquine-aldehyde, primaquine-alcohol, and carboxyprimaquine, a major plasma metabolite, Although efficacy and toxicity of primaquine (PQ) depend on bioconversion. the process is poorly understood. even for carboxyprimaquine (CPQ). the major plasma metabolite. Earlier work to clarify drug metabolism showed that PQ could be converted quantitatively into CPQ. in vitro. with human erythroleukemic K562 cells or nonleukemic bone marrow supplemented with calf serum. We have now found--using systems with serum only. as well as with K562. bone marrow. and adult or embryonic liver cells--that the bioconversion of the side chain of PQ involves a branched pathway with at least three separate enzymes and two derivatives other than CPQ. An oxidase activity in serum converted PQ first into a novel side chain aldehyde (Y). Aldehyde dehydrogenase transformed PQ-aldehyde into CPQ in cell-free systems and in K562. bone marrow. and adult liver cells. Embryonic hepatocytes or bone marrow treated with 1.3-bis(2-chloroethyl)-1-nitrosourea did not produce CPQ; instead. they made a metabolite (Xc) that we could synthetize via PQ-aldehyde and identify as PQ-alcohol. PQ-alcohol replaced CPQ as the final product whenever alcohol-dehydrogenase prevailed over aldehyde dehydrogenase. These enzymes operated in intact cells and controlled the biotransformation of PQ absolutely. Unless both dehydrogenase were absent. inhibited. or deprived of coenzyme. potentially cytotoxic PQ-aldehyde intermediate did not accumulate. Some of the unique tissues schizonticidal and gametocidal effects of PQ may depend on the distribution pattern and relative activities of PQ oxidase. aldehyde dehydrogenase. and alcohol dehydrogenase in human subjects and in parasites.
Effects of glycemic control on red cell deformability determined by using the cell transit time analyzer, There is considerable evidence that blood viscosity is greater than normal in diabetes. and decreased red blood cell deformability has been suggested as the cause. However. viscosity can be influenced by changes in the properties of blood proteins in addition to red cells. Direct interpretation of red cell filtrometry data in terms of deformability has been complicated by the interfering effect of white cells and platelets and clogging of micropores. We have thus used the cell transit time analyzer. a new filtrometric procedure that eliminates these complications and produces an individual red cell micropore transit time profile. to reassess diabetic red cell deformability. Samples from 26 patients with diabetes and an equal number of subjects without diabetes who served as controls were assayed by the cell transit time analyzer at 2 and at 4 cm hydrostatic pressure. Samples from patients with diabetes and controls were sex and age matched for daily runs. At 2 cm H2O. red blood cell transit time for the patients with diabetes was 2.73 +/- 0.05 milliseconds as compared with 2.67 +/- 0.05 milliseconds for controls (p not significant). The ratio of transit time for patients with diabetes to that of controls (Td/Tnd) was 1.03 +/- 0.01 (p less than 0.05. Wilcoxon) at 2 cm H2O and 1.02 +/- 0.01 (p not significant) at 4 cm H2O.
The Tromso Study: the positive predictive value of gamma-glutamyltransferase and an alcohol questionnaire in the detection of early-stage risk drinkers, Based on the measurement of gamma-glutamyltransferase and a questionnaire on frequency of alcohol intake. 338 early-stage risk drinkers were identified from more than 20.000 participants in a health survey programme. Two-thirds (225) of these subjects were questioned regarding their 'true' alcohol intake at the first consultation. Positive predictive values were calculated for true daily intake of 30 and 40 g alcohol d-1 for men (20 and 30 g alcohol d-1 for women) on the basis of gamma-glutamyltransferase activity and the response to a questionnaire. The positive predictive values for a risk intake of 30 g d-1 in men increased from 0.49 to 0.88. with increasing values for gamma-glutamyltransferase activity and increasing frequency of alcohol intake. The corresponding values for a risk intake of 40 g d-1 were 0.34-0.75. In women. increasing gamma-glutamyltransferase activity gave no increase in positive predictive values. The estimates for increasing frequency of alcohol intake were unreliable due to small numbers.
High frequency of asymptomatic visual field defects in subjects with transient ischaemic attacks or minor strokes, The hypothesis that asymptomatic visual field defects can be found in patients with carotid transient ischaemic attacks (TIA) or minor strokes was tested. Twenty-two consecutive male patients with TIA and 18 patients with minor strokes from the carotid artery territory were examined by perimetry. cerebral computerised tomography and regional cerebral blood flow. Asymptomatic visual field defects were found in many TIA and minor stroke patients. 29% (5/17) and 57% (8/14). respectively (NS). Eighty-five per cent (11/13) of the scotomas were solely or predominantly located in the upper part of the visual field (P = 0.008 for absolute defects and P = 0.03 for relative defects). We conclude that both carotid territory TIA and minor stroke patients have a high frequency of asymptomatic visual field defects. predominantly located in the upper part of the visual field.
Effects of felodipine ER and hydrochlorothiazide on blood rheology in essential hypertension--a randomized, double-blind, crossover study, The haemorheological effects of felodipine extended release (ER). a new dihydropyridine calcium antagonist. were compared with hydrochlorothiazide (HCTZ) in 28 mild to moderate hypertensives (18 men and 10 women. aged 30-70 years) in a randomized. double-blind. crossover trial. Antihypertensive drugs were gradually discontinued. Felodipine Er. 10 mg. was given once daily for 2 weeks. and after another wash-out period of 1 week. patients were switched to 25 mg HCTZ. once daily. and vice versa. Whole blood viscosity (BV) at three different shear stresses. haematocrit (Hct). plasma viscosity (PV). red blood cell (RBC) aggregation. RBC deformability. and fibrinogen were measured under standardized conditions 2.5 h after medication. and after 2 week of treatment (24 h post-dosing). Felodipine ER improved BV acutely. but not during treatment over a 2-week period. By contrast. HCTZ did not affect BV. but decreased RBC deformability 2.5 h after medication intake. After 2 weeks of treatment. the negative effect on RBC deformability had increased slightly. Furthermore. fibrinogen and PV were significantly elevated at this stage. In summary. felodipine ER did not improve blood rheology over a 2-week treatment period in this study. HCTZ exhibited marginal but significant negative effects on fibrinogen. PV and indices of RBC deformability. but not on RBC aggregation.
Interleukin-6 concentrations in the serum of patients with AIDS-associated Kaposi's sarcoma during treatment with interferon-alpha, Interleukin-6 (IL-6) levels were determined in the serum of 14 HIV-1-infected patients with Kaposi's sarcoma. 10 HIV-1-infected patients without symptoms. and 10 healthy male subjects. IL-6 levels were also determined in the serum of the 14 patients with Kaposi's sarcoma during treatment with high-dose human recombinant interferon-alpha (IFN alpha). Serum IL-6 levels were significantly higher in the patients with Kaposi's sarcoma than in the HIV-infected patients without symptoms and the controls. There was no consistent pattern of changes of IL-6 levels during IFN alpha treatment. These results support the view that IL-6 is a cytokine involved in the pathogenesis of AIDS-associated Kaposi's sarcoma. but appear to argue against an effect of IFN alpha on the production or release of IL-6 as an important mechanism of action of IFN alpha.
Apathetic thyrotoxicosis in adolescence, We here describe a case of apathetic thyrotoxicosis in a 16-year-old female subject who presented with a range of non-specific symptoms. Apart from a history of significant weight loss. there were no other signs or symptoms indicative of hyperthyroidism. The diagnosis was made incidentally upon thyroid function testing. and there was a prompt clinical response to anti-thyroid therapy. The diagnostic pitfalls of this unusual presentation in the young are highlighted. A history of weight loss and a clinical index of suspicion will lead to the diagnosis. which is readily confirmed biochemically.
Zinc sulphate therapy for Wilson's disease after acute deterioration during treatment with low-dose D-penicillamine, A 30-year-old woman with Wilson's disease was treated with low-dose D-penicillamine. After 12 days. treatment was changed to zinc sulphate because of severe neurological deterioration. The patient subsequently improved within a few days. During a follow-up period of 20 months. the effectiveness of therapy was evaluated by measuring copper and zinc levels in plasma and urine. and by 64Cu-loading tests. We conclude that sulphate therapy may be a satisfactory alternative. even when rapid deterioration occurs in the early stages of D-penicillamine treatment.
Cerebral blood flow changes in migraine: methods, observations and hypotheses, A number of basically different methods have been used in studies of the cerebrovascular changes which occur in migraine and each individual set of findings seems to be dependent on which method is used. One method on its own can only disclose a part of all the pathophysiological events. This review is an attempt to consider the capabilities of each method and to bring together the results from different studies on migraine in order to create a complete picture of the cerebrovascular changes which occur during the course of a migraine attack.
Neuroeffector functions of sensory fibres: implications for headache mechanisms and drug actions, The results of recent investigations designed to elucidate the neuroeffector functions of sensory fibres. the cause of migraine headache and the mechanism of action of antimigraine drugs are reviewed and discussed. Neurogenic inflammation (vasodilatation and neurogenic plasma extravasation) is one explanation for the development of headaches and the blood flow changes which occur during migraine headache. Numerous studies have recently been carried out on rats and guinea-pigs into the effects of antimigraine agents. including ergot alkaloids. sumatriptan and non-steroidal anti-inflammatory drugs (NSAIDs). on neurogenic plasma protein extravasation in the dura mater induced by electrical stimulation of trigeminal ganglia or systemic administration of capsaicin. It is known that the dura mater is able to produce headaches in man. Ergot alkaloids have been shown to block neurogenic inflammation via a C-fibre dependent neuronal mechanism. Sumatriptan appears to act fairly similarly although. whereas the ergot alkaloids are non-selective for either 5-hydroxytryptamine (5-HT; serotonin) receptors or 5-HT1. sumatriptan is selective for 5-HT1 receptors. The antimigraine action of NSAIDs may be via either an effect on blood vessels or an effect on the nerve fibre. The antimigraine effects of ergot alkaloids. sumatriptan and NSAIDs are discussed in the light of the common vasoconstrictor actions of these agents and knowledge that vasodilatation is apparently not responsible for migraine headache pain in most cases.
What is migraine? Controversy and stalemate in migraine pathophysiology, Theories of migraine pathophysiology have evolved from the realms of the supernatural into the scientific arena but their further evolution seems delayed by unproductive controversy about whether or not migraine is primarily a vascular or a neurological dysfunction. This conceptual deadlock needs to be transcended by thinking beyond the neural and vascular systems. and by identifying mechanisms that could affect both to produce the characteristic clinical phenomena of migraine. One theoretical model envisages 5-hydroxytryptamine (serotonin; 5-HT) as a link between the neural and vascular systems. with global alteration of serotonergic neurotransmission affecting not only these systems. but the gastrointestinal tract as well. with incidental reverberations on platelet function. Such altered serotonergic transmission might originate from altered 5-HT receptor dynamics. a molecular change in turn produced by genetic mechanisms. Recognition of the importance of 5-HT receptor function in migraine. most notably that agonists of 5-HT1 receptors abort acute migraine and that antagonists of 5-HT2 receptors prevent migraine. may lead to significant therapeutic advances. The possibility that the "trigeminovascular system" might be the end-stage mechanism that these serotonergic changes detonate to produce the painful reverberations of migraine headache is also important. Seeking ways to muffle these reverberations. or to insulate the system itself from the action of external influences (likely through further study of peptidergic transmission and receptors) might result in more drugs that will abort or prevent migraine.
A review of current drugs for migraine, The current treatments available for migraine are reviewed and may be classified into four basic types. (a) Identification and elimination of migraine trigger factors. which include stress. emotions. fatigue. certain foods and beverages. and certain medications such as oestrogen therapy. (b) Symptomatic treatment of individual attacks. This includes various non-steroidal anti-inflammatory drugs (NSAIDs). including aspirin and paracetamol. and ergotamine. dihydroergotamine and phenothiazines. Morphinomimetics. which are often given for migraine. should really be avoided. (c) Prophylactic treatment which is particularly recommended for patients averaging two or more severe migraine attacks per month. Useful drugs include: beta-adrenergic receptor blockers as first choice. e.g. propranolol. timolol. nadolol and metoprolol; 5-hydroxytryptamine blockers. e.g. pizotifen and methysergide; calcium channel blockers; dihydroergotamine; and NSAIDs. (d) Non-drug treatment which is best combined with identification and elimination of trigger factors. and the use of various relaxation techniques. These four treatment types are covered in some detail. however it is clear that none of them is ideal and side-effects present a problem. Clearly. the continued research and development of novel and specific drugs for migraine is vital.
Pharmacology of antimigraine drugs, The drugs used in migraine therapy can be divided into two groups: agents that abort an established migraine attack and agents used prophylactically to reduce the number of migraine attacks. Both groups have drugs that are specific for migrainous headaches and that are non-specific. and are used to treat the accompanying headache (analgesics). vomiting (anti-emetics). anxiety (sedatives and anxiolytics). or depression (antidepressants). The main drugs with specific action on migraine include ergot alkaloids (ergotamine. dihydroergotamine). agonists (sumatriptan) or partial agonists (methysergide) at a specific subtype of 5-HT1-like receptors. beta-adrenoceptor antagonists (propranolol. metoprolol). calcium antagonists (flunarizine) and anti-inflammatory agents (indomethacin). The pharmacological basis of therapeutic action of several of these drugs is not well understood. In the case of the ergot alkaloids and 5-HT1-like receptor agonists. however. it is likely that the antimigraine effect is related to the potent and rather selective constriction of the large arteries and arteriovenous anastomoses in the scalp and dural regions. In addition. these drugs inhibit plasma extravasation into the dura in response to trigeminal ganglion stimulation. but it is possible that this effect is related to the selective vasoconstriction in the extracerebral vascular bed. The selectivity of the pharmacological effects of these antimigraine drugs (constriction of the extracerebral arteries and arteriovenous anastomoses. poor penetration into the central nervous system and the absence of an antinociceptive effect even after intrathecal administration) strongly suggests that excessive dilatation in the extracerebral cranial vasculature. probably initiated by a neuronal event. is an integral part of the pathophysiology of migraine.
5-Hydroxytryptamine and the pathophysiology of migraine, 5-Hydroxytryptamine (5-HT; serotonin) has long been implicated in the aetiology of migraine but the evidence remains circumstantial and certainly not definitive. Numerous papers have reviewed the background which is briefly outlined here. Although the continued belief in the primary involvement of 5-HT in the genesis of a migraine attack has recently been questioned. many antimigraine drugs undeniably interact potently with 5-HT receptors. It can be argued. however. that their modest clinical benefit results from their pharmacological effects. be they mediated through 5-HT receptors or otherwise. independently of any pathophysiological involvement of endogenous 5-HT. Nevertheless. there seems convincing evidence that central release of 5-HT by various drug mechanisms causes migraine-like headache in migraineurs. It remains to be seen whether these drugs mimic the pathological event initiating the spontaneous migraine attack. Regardless of these considerations. the focus of research on 5-HT and migraine has proved to be enormously profitable over several decades. culminating recently in the identification of a novel. potentially important. antimigraine drug for the treatment of the acute attack. This drug. sumatriptan. is a selective cranial vasoconstrictor which mediates this effect by specifically activating a particular 5-HT1 receptor subtype. Undoubtedly a precise understanding of its clinical mechanism of action. which is currently being studied by a number of groups. will lead to a better understanding of the pathogenesis of migraine. Perhaps this in turn will help in finally determining whether migraine is a vascular disease and whether or not a disturbance of 5-HT is just epiphenomenal or is truly the primary initiating pathological event.
5-HT2 receptor antagonists and migraine therapy, 5-Hydroxytryptamine (5-HT; serotonin) has been implicated in the pathophysiology of migraine. and several drugs with potent 5-HT2 receptor blocking activity (methysergide. pizotifen. cyproheptadine and mianserin) have been recognized as being clinically effective in migraine prophylaxis. although the selective 5-HT2 receptor antagonist ketanserin (the principal agent used to identify 5-HT2 receptor-mediated actions) seems to be ineffective in migraine. Pizotifen is the most widely used 5-HT2 receptor antagonist in migraine prophylaxis. because of its superior efficacy compared with cyproheptadine. and because the incidence and severity of adverse effects with pizotifen is lower compared with methysergide and mianserin. These agents have additional antagonistic effects at histamine H1. muscarinic cholinergic. alpha 1-adrenergic. alpha 2-adrenergic and dopamine receptors. but drugs which are selective for these non-5-HT receptors appear to be of no benefit in migraine. Actions mediated by 5-HT2 receptors which could be of relevance to migraine comprise cranial vasoconstriction. increased cranial capillary permeability and platelet aggregation. and some central nervous system effects and neuroendocrine functions. Although pizotifen. cyproheptadine and mianserin are considered to be relatively specific for 5-HT2 receptors. these agents and methysergide all share a high affinity for 5-HT1C binding sites; ketanserin. however. has little affinity for these sites. thus activation of 5-HT1C receptors may be an important step in the pathogenesis of migraine. It is not yet known which 5-HT1C receptor-mediated actions of 5-HT are relevant to migraine. but some behavioural actions and cranial vasodilatation via release of endothelium-derived relaxing factor may be involved.
5-HT3 receptor antagonists and migraine therapy, Neuronal 5-hydroxytryptamine3 (5-HT3) receptors mediate the excitatory effects of 5-HT. They are located in pain- and nausea-modulating areas in the central nervous system and on C-fibre primary afferents in the peripheral nervous system. Consequently. these receptors mediate the painful and emetic effects of 5-HT. Selective and potent 5-HT3 receptor antagonists have been shown to block inflammatory and 5-HT induced and potentiated "vascular pain". Based on the hypothesis that 5-HT3 receptor antagonists may block neurogenic dural inflammation in the distribution area of the trigeminal nerve and. thus. could potentially prevent migraine (pain). four highly selective and potent 5-HT3 receptor antagonists have been tested in both the acute and prophylactic treatment of migraine. Unfortunately. except for a clear anti-emetic effect. none of these drugs has shown unequivocal efficacy in the treatment of migraine. This may be partly due to the complex (bell-shaped) dose-response relationship of these compounds. making exact titration of the correct dose difficult. Moreover. most 5-HT3 receptor antagonists have proved to be toxic in man on chronic administration thereby preventing further trials in migraine with adjusted doses. Short-term treatment for cytotoxic drug-induced emesis so far appears to be the only proven indication for 5-HT3 receptor antagonists.
Rationale for the use of 5-HT1-like agonists in the treatment of migraine, Migraine headache is thought to be associated with a dilatation of cranial blood vessels. particularly those in the dura mater. and an accompanying localized sterile inflammatory response. Sumatriptan is a highly selective 5-HT1-like receptor agonist which selectively constricts cranial blood vessels (including those in the dura mater). It also inhibits neurogenically-mediated plasma protein extravasation in the dura mater. Haemodynamic studies in anaesthetized animals have shown that sumatriptan selectively constricts the carotid arterial circulation and this effect appears to be restricted to an effect on carotid arteriovenous anastomoses. Sumatriptan has a much more selective pharmacological profile than ergot preparations which are also used in the acute treatment of migraine. The development of sumatriptan has been based on a vascular theory of migraine and its high degree of efficacy in the treatment of migraine strengthens the argument that dilatation of cranial blood vessels is the cause of vascular headache.
The clinical diagnosis of migraine: the beginning of therapy, Clear symptoms and signs are found in patients during severe migraine attacks. Diagnostic difficulties are encountered in eliciting this episodic clinical picture. A label of migraine. however. is only the beginning: factors that precipitate attacks. fears aroused in the migraineur and the failure. or partial efficacy. of acute and prophylactic therapy need also to be determined. If migraine is complicated by an additional headache. the analysis becomes more difficult. but the diagnosis still has to be accurate. This. however. is not always possible at the initial interview. A successful consultation should be more than just diagnostic; it is the beginning of treatment.
Clinical experience with oral sumatriptan: a placebo-controlled, dose-ranging study. Oral Sumatriptan Dose-defining Study Group, A double-blind. placebo-controlled multicentre study was carried out to evaluate the efficacy and tolerability of 100. 200 and 300 mg sumatriptan. a selective 5-hydroxytryptamine (5-HT)1-like receptor agonist. given in an oral dispersible form in the acute treatment of migraine attacks. A total of 1130 patients were recruited from 51 centres in eight countries and the efficacy results are presented from an interim analysis of 538 cases. Tolerability was evaluated in 227 patients. At 2 h. an improvement in headache severity from moderate or severe to mild or none was reported by 67% of patients who received 100 mg sumatriptan. 75% receiving 200 mg and 69% of patients receiving 300 mg sumatriptan. compared with 22% of patients who received placebo (P less than 0.001 all doses sumatriptan vs placebo). Adverse events were generally mild and transient. and appeared to be dose-related; the adverse event profile of 100 mg sumatriptan was similar to that of placebo. Overall. nausea/vomiting and "bitter taste" were the most common complaints. The proportion of patients withdrawn due to adverse events was similar in the placebo and 100 mg sumatriptan treatment groups (2% and 3%. respectively). It is concluded that 100 mg sumatriptan given orally is well tolerated with an anti-migraine efficacy comparable to that provided by the two higher doses.
Subcutaneous sumatriptan in the acute treatment of migraine. Sumatriptan International Study Group, Two double-blind. randomized. placebo-controlled multicentre studies were carried out to assess the efficacy and tolerability of subcutaneous (s.c.) injections of 1-3 mg and 1-8 mg sumatriptan. respectively. in the acute treatment of migraine. Data are presented from a total of 519 patients. In both studies. the primary endpoint of efficacy was a reduction in headache severity from severe or moderate to mild or no headache. All doses of sumatriptan were significantly more effective than placebo in relieving symptoms. and the response appeared to be dose-related; an effective response to treatment was achieved within 30 min in 73% of patients treated with 6 mg sumatriptan and 80% of patients treated with 8 mg sumatriptan s.c.. compared with 22% for placebo. Sumatriptan was well tolerated and the majority of adverse events were mild and transient. The most frequent complaint was irritation and pain at the site of injection. No changes in laboratory values were noted and ECG readings were unaltered by treatment. On the basis of these results. the 6 mg subcutaneous dose has been selected for further evaluation in large-scale studies.
Antibiotic availability and use: consequences to man and his environment, Antibiotics are the cornerstone of therapy for infectious diseases affecting people living worldwide. The ability of these agents to cure infections. with little if any harm to the host. has helped to propagate their designation as "miracle drugs". This idea has continued throughout the past four decades and into the present one. To a large extent. this concept has led to the inappropriate use of these agents. The consequence of this misuse affects not only the individuals taking antibiotics. but indirectly others who may subsequently need antibiotics. but find that the infecting pathogen is resistant. This phenomenon results from the strong selective environmental effect of these drugs for resistant bacteria. Resistant pathogens have emerged and spread worldwide. In response to this global health problem. the Alliance for the Prudent Use of Antibiotics was established. This international network of concerned prescribers and users aims to improve antibiotic use and eliminate inappropriate use worldwide. Prudent use of antibiotics will not only curtail health care costs and the potential side effects to the individual taking these drugs. but also diminish the wide ecologic effects leading to selection of antibiotic resistant forms of common disease-causing agents.
Prediction of prognosis in primary breast cancer by detection of a high molecular weight mucin-like antigen using monoclonal antibodies DF3, F36/22, and CU18: a Cancer and Leukemia Group B study, Three monoclonal antibodies (MAbs) (DF3. F36/22. CU18) were used to monitor expression of distinct epitopes present within a family of mucin-like. breast carcinoma-associated molecules. Primary tumor specimens from more than 190 stage II breast cancer patients were evaluated for expression of the high molecular weight antigens. With a median follow-up of 6 years. patients whose tumors exhibited high immunoperoxidase staining scores (greater than 50% positive cells) with MAb DF3 had a superior disease-free survival ([DFS] 56% +/- 6% v 37% +/- 5% at 6 years; P = .0088) and overall survival ([OS] 72% +/- 5% v 59% +/- 5% at 6 years; P = .025). Staining scores with the other two antibodies did not correlate with improved prognosis. For MAbs DF3 and CU18. patients whose tumors exhibited predominantly apical cellular reactivity patterns had improved DFS. although differences reached conventional levels of statistical significance only with MAb CU18. In multivariate analyses. the prognostic value of MAb DF3 staining was independent of other identified prognostic factors. Furthermore. the concordance between primary and axillary lymph node metastases staining with each MAb was 73%. 80%. and 85% for MAbs DF3. F36/22. and CU18. respectively. These results suggest that staining with MAb DF3 identifies a group of node-positive women with a relatively favorable prognosis. Expression of the DF3 mucin-like glycoprotein is related to better differentiation. and staining with MAb DF3 provides an accurate and objective estimate of clinical outcome independent of histopathologic evaluation.
Cyclophosphamide, methotrexate, and fluorouracil with and without doxorubicin in the adjuvant treatment of resectable breast cancer with one to three positive axillary nodes, In the attempt to improve current adjuvant results in patients with one to three positive axillary lymph nodes. in November 1981 we activated a prospective randomized study to assess the effectiveness of intravenous (IV) cyclophosphamide. methotrexate. and fluorouracil (CMF) for 12 courses versus CMF for eight courses followed by Adriamycin (doxorubicin; Farmitalia Carlo Erba. Milan. Italy) for four courses. The 5-year results were evaluated in a total of 486 patients entered into the study up to December 1987. CMF chemotherapy was delivered IV for a total of 12 courses when given alone and for eight courses when followed by four courses of Adriamycin. All drugs were recycled every 3 weeks. Rather than temporarily reducing doses. drug administration was delayed for 1 to 2 weeks in the face of myelosuppression on the planned day of treatment. After a median follow-up of 61 months. no significant differences were evident between the treatment groups in terms of relapse-free (CMF 74% v CMF followed by Adriamycin 72%) and total survival (CMF 89% v CMF followed by Adriamycin 86%). Drug treatments were fairly well tolerated and devoid of life-threatening toxicity. Present results. which were not influenced by menopausal status. indicate that Adriamycin given after CMF failed to improve treatment outcome over CMF alone. However. the role of Adriamycin in an adjuvant setting remains to be further clarified. Considering the good 5-year results achieved in this study at the expense of minimal toxicity. full-dose CMF remains. at present. the adjuvant chemotherapy of choice for patients with one to three positive nodes.
A randomized trial of carboplatin versus iproplatin in untreated advanced ovarian cancer, Between August 1984 and October 1987. 120 patients with stage IC to IV epithelial ovarian cancer were randomly assigned to receive carboplatin (400 mg/m2) or iproplatin (300 mg/m2) every 4 weeks as initial treatment. Stratification was made according to International Federation of Gynecology and Obstetrics (FIGO) stage and according to size of residual disease after surgery. Response was evaluated after six courses when patients were restaged. with laparoscopy or laparotomy in clinical complete responders or those with no assessable disease. Treatment was then stopped in surgically proven complete responders. Patients with partial (PR) or minor response (MR) received a further six courses of their original drug at a reduced dose (carboplatin 300 mg/m2. iproplatin 225 mg/m2). Patients with stable (SD). progressive (PD). or recurrent disease were treated with cyclophosphamide (1 g/m2). The response rates were 63% (95% confidence interval [CI]. 50% to 74%) for carboplatin and 38% (95% CI. 26% to 51%) for iproplatin. Fifteen patients were not assessable for response. The median survival was 114 weeks (95% CI. 82 to 233 weeks) for carboplatin patients and 68 weeks (95% CI. 48 to 82 weeks) for iproplatin patients (P = .008). The amount of residual disease after initial laparotomy was a prognostic factor for survival. Myelosuppression was the main toxicity and was greater with iproplatin. This study shows carboplatin to be more active than iproplatin in the treatment of ovarian cancer and less toxic. Few responses to cyclophosphamide occurred following either drug. implying resistance to the alkylating agent.
Postoperative treatment of nonmetastatic visible residual neuroblastoma: a Pediatric Oncology Group study, The Pediatric Oncology Group (POG) evaluated in a prospective study the hypothesis that patients who had localized. visible residual neuroblastoma without regional lymph node involvement after surgery (POG stage B) have a favorable prognosis when treated with moderate intensive chemotherapy. Eligible patients were initially treated with five courses of Cytoxan (cyclophosphamide; Bristol-Myers Squibb Co.. Evansville. IN) and Adriamycin (doxorubicin; Adria Laboratories. Columbus. OH) followed by surgery (CY/AD +/- surgery). Those patients not achieving a complete remission (CR) crossed over to five courses of cisplatin and teniposide (PL/VM) +/- surgery. Radiation therapy (XRT) was given to selected patients who still were not in CR after the crossover therapy. Of the 61 eligible patients. 38 (62%) patients achieved CR after CY/AD proven by clinical (31) or surgical (seven) evaluation. One (2%) patient in clinical partial remission (PR-C) entered CR without further therapy. Nineteen (31%) patients achieved CR with the following salvage therapies: surgery (five). PL/VM +/- surgery (five) followed by XRT (three) or autologous bone marrow transplant (ABMT) (one) and further courses of CY/AD +/- PL/VM instead of courses of PL/VM (five). The overall CR rate was 95% (58 of 61). Four patients had recurrence of the disease. The probability of being disease-free at 3 years after initial or salvage therapy was estimated at 84% (SE. 5%). The overall prognosis of children older than 1 year and younger than 1 year was similar (P = .26). If. however. the three remission deaths (all younger than 1 year) were censored. there was only one other failure in 32 children younger than one versus seven of 29 children older than 1 year (P = .018). These results confirm the excellent prognosis for patients with POG stage B neuroblastoma and indicate that most patients are curable with CY/AD +/- surgery. and those not achieving CR with this therapy are curable with alternate therapy.
Activity of esorubicin in recurrent malignant lymphoma: a Southwest Oncology Group study, A phase II trial of esorubicin (4' deoxydoxorubicin) was conducted by the Southwest Oncology Group in 88 assessable patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) at the time of first relapse. Esorubicin was administered at two dose levels: 25 mg/m2 for patients at risk for excessive myelosuppression. and at 30 mg/m2 for all others at 21-day intervals. Overall. 33 of 88 patients (38%) responded to treatment including three complete remissions (CRs; 3%) and 30 partial remissions (PRs; 34%). with the median duration of response lasting 6.2 months. Response rates did not differ significantly by histologic subtype: 31% of 26 patients with favorable NHL. 33% of 43 patients with unfavorable NHL. and 58% of 19 patients with HD. Twelve of 33 responding patients (36%) had relatively durable remissions lasting from 1 to more than 4 years. Leukopenia (less than 3.000 cells per microliter) was seen in 65 of 88 patients (74%) and was severe (less than 1.000 cells per microliter) in 20 of 88 patients (23%). Clinical signs or symptoms of congestive heart failure were not seen and the ejection fraction (EF) fell 10% to 20% in three patients. Esorubicin is an active agent in patients with NHL or HD at the time of first relapse.
Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia, Thirty-two patients with refractory acute myeloid leukemia (AML) received salvage therapy with a single course of mitoxantrone 6 mg/m2 intravenous (IV) bolus. etoposide 80 mg/m2 IV for a period of 1 hour. and cytarabine (Ara-C) 1 g/m2 IV for a period of 6 hours daily for 6 days (MEC). Eighteen patients were primarily resistant to conventional daunorubicin and Ara-C induction treatment; eight patients had relapsed within 6 months from initial remission; six patients had relapsed after a bone marrow transplantation (BMT) procedure. Overall. 21 patients (66%) achieved a complete remission (CR). two (6%) died of infection during induction. and nine (28%) had resistant disease. Age greater than 50 years was the only factor predictive for a significantly lower response rate (P = .03). The median remission duration was 16 weeks; the overall median survival was 36 weeks. Severe myelosuppression was observed in all patients resulting in fever or documented infections in 91% of patients. Nonhematologic toxicity was minimal. We conclude that the MEC regimen has significant antileukemic activity and acceptable toxicity in salvage AML. Its benefit in front-line AML therapy is being investigated.
Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens, Cyclophosphamide (CY) cardiotoxicity may be a lethal complication of bone marrow transplantation. Previous echocardiographic studies have reported that left ventricular dysfunction due to CY occurs in over 50% of patients undergoing transplantation. To evaluate the cardiotoxicity of new dosing protocols that included twice-daily rather than once-daily CY. 44 bone marrow transplantation patients were prospectively evaluated with serial ECGs and echocardiograms. Twenty-six patients received a once-daily lower-dose protocol (mean total 87 +/- 11 mg/kg). and 18 patients received a twice-daily higher-dose (mean total 174 +/- 34 mg/kg) CY regimen. In the higher-dose CY group. significant reductions in summed ECG voltage (-20%) (P less than .01) and increases in left ventricular mass index (LVMI) (+10%) (P less than .05) were detected in the first week following therapy. These changes resolved by the third week following CY and were significantly greater than the changes noted in the lower-dose group. However. left ventricular ejection fraction (EF) did not change significantly in either group. Five patients developed clinical cardiotoxicity (four. pericarditis; one. congestive heart failure); four of the five patients were in the higher-dose group (P = .14). Only a prior history of congestive heart failure or a baseline EF less than 50% was an independent correlate of clinical cardiotoxicity (P less than .05). Thus. dose-dependent cardiotoxicity following the use of CY for bone marrow transplantation is evident as reversible decreases in ECG voltage and increases in left ventricular mass. possibly reflecting myocardial edema or hemorrhage. However. systolic dysfunction is much less common with these new twice-daily dosing regimens when compared with earlier studies of high-dose once-daily CY.
Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation, The regimen-related toxicity (RRT) of a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) conditioning regimen (BuCy) was evaluated in 70 consecutive patients undergoing allogeneic bone marrow transplantation for hematologic malignancies. Patients were given toxicity gradings retrospectively in each of eight organ systems (cardiac. bladder. renal. pulmonary. hepatic. CNS. stomatic. and gastrointestinal) according to a recently developed RRT scale. A set of patient. disease. and treatment parameters (age. sex. diagnosis. Eastern Cooperative Oncology Group [ECOG] score. preconditioning liver function tests [LFT]. prior chemotherapy exposure. disease status. graft-versus-host disease [GVHD] prophylaxis. antimicrobial agent use. hematologic recovery. and severity of acute GVHD) was statistically analyzed to determine significant predictors of RRT. The most common significant organ toxicities were stomatic (87% of patients; 63% grades II to IV) and hepatic (83% of patients; 44% grades II to IV). Renal and gastrointestinal toxicities were not uncommon (35% and 27%. respectively) but were rarely serious (9% and 1% grades II to IV. respectively). Twelve patients developed grade III toxicities of the following systems: hepatic (seven). pulmonary (two). bladder (two). and CNS (one). Females had more frequent stomatitis (P = .04) and hepatic RRT (P = .004). Patients receiving methotrexate in their GVHD prophylactic regimen experienced more grade II to IV stomatitis (P = .04) and hepatic RRT (P = .04). The use of amphotericin B (P = .01) or prolonged antibiotic courses (P = .04) was associated with more grades II to IV hepatic RRT. In a multivariate analysis. only amphotericin B administration predicted grades II to IV hepatic RRT (P = .01). The incidence of acute GVHD was 49%. with 31% having grades II to IV GVHD. The estimated 2-year event-free survival (EFS) for the entire study group was 44%. The estimated 2-year EFS was 63% for standard-risk patients (acute leukemia in first remission and chronic myelogenous leukemia [CML] in first stable phase) and 24% for all others (high-risk patients). High-risk patients were at increased risk of disease recurrence and RRT. BuCy is an efficacious bone marrow transplant conditioning regimen for standard-risk patients with leukemia but has significant associated hepatic RRT.
Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a National Biotherapy Study Group trial, We conducted a multicenter. phase II trial of continuous-infusion recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells. Patients had advanced cancer. measurable disease. and a good performance level. Treatment included a 5-day continuous infusion of 18 x 10(6) IU/m2/d of rIL-2 followed by 1 day of rest. 4 days of leukapheresis to collect cells for in vitro augmentation of cellular cytotoxicity. and 5 more days of rIL-2 infusion with reinfusion of LAK cells for 3 successive days. Therapy was repeated after 2 weeks. There were 117 patients enrolled: 63% were males. with a median age of 51 years. Eighty-two percent were managed in oncology units. and 18% were in intensive care units. Six patients died within 1 month of initiating therapy. In renal cell carcinoma. the response rate was one of 31 patients (3%). with a median survival of 10.7 months. In melanoma. the response rate was four of 33 patients (12%). with a median survival of 6.1 months. For all other histologies. response rate was three of 53 patients (5%). with a median survival of 7.4 months. All responders were asymptomatic when therapy was initiated. This trial confirms the feasibility of administering continuous rIL-2 and LAK cells outside the intensive care unit environment. Antitumor activity in melanoma was similar to that seen in multicenter trials of bolus rIL-2 and LAK cells. Activity in renal cell cancer was disappointing.
Phase I study of recombinant human interleukin-3 in patients with bone marrow failure, Interleukin-3 (IL-3) is a T-cell-derived colony-stimulating factor (CSF) whose primary targets include relatively early. multipotential. hematopoietic progenitor cells. In this trial. we treated 24 patients with recombinant human IL-3 given by a daily 4-hour intravenous infusion for 28 days. The dose levels were 30. 60. 125. 250. 500. 750. and 1.000 micrograms/m2/d. At least three patients were entered at every dose level. Each participant suffered from bone marrow failure. with the underlying diagnosis being myelodysplastic syndrome (13 patients). aplastic anemia (eight patients). or aplasia after prolonged high-dose chemotherapy (three patients) for multiple myeloma. breast cancer. or acute myelogenous leukemia. Most patients tolerated therapy well. with the most frequent side effects being low-grade fever and headaches. Hematopoietic changes included modest increases in neutrophil counts (eight patients). eosinophil counts (six patients). platelet counts (three patients). and reticulocyte counts (two patients). An increase in blasts occurred in one patient who had refractory anemia with excess blasts in transformation and was reversible once IL-3 was discontinued. In addition. one patient with chronic myelomonocytic leukemia showed an increase in monocytes (and granulocytes). Progression to acute leukemia did not occur. Pharmacokinetic analyses showed a rapid clearance with a mean half-life of 18.8 minutes at the 60 micrograms/m2/d dose. and 52.9 minutes at the 250 micrograms/m2/d dose. Serum concentrations of 10 to 20 ng/mL of IL-3 were achievable at the 250 micrograms/m2/d dose. Our observations indicate that recombinant human IL-3 can be given safely at doses of 1.000 micrograms/m2/d or less. In addition. on the basis of preclinical data and the biologic activity observed in this study. further trials of this molecule. alone and in combination with other growth factors. are warranted in patients with pancytopenia.
A phase I trial of taxol given by a 6-hour intravenous infusion, Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result. the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond. and premedication with diphenhydramine. dexamethasone. and cimetidine was initiated. Early studies showed antitumor activity. especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol. as a 6-hour IV infusion every 21 days. without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction. which was easily controlled using routine measures. Myelosuppression was dose-limiting. but sporadic. with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias. requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer. one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.
Cancer risk notification: psychosocial and ethical implications, Basic and medical science investigations have identified a growing number of risk factors important in carcinogenesis. By communicating cancer risk information in medical practice. we have the potential to motivate high-risk individuals to adhere to cancer prevention and surveillance protocols. However. cancer screening and risk notification might have adverse psychologic and social consequences as well. In this review. we address the psychosocial and ethical implications of cancer risk notification. The literature on the psychosocial impact of cancer screening programs and programs for notifying workers exposed to occupational carcinogens is reviewed critically. In addition. we examine new concerns and responsibilities raised by the emerging field of cancer genetics. Suggestions for future research and for patient education are addressed.
Electrothrombosis of saccular aneurysms via endovascular approach. Part 1: Electrochemical basis, technique, and experimental results, Eleven experimental saccular aneurysms were created on the common carotid artery of swine. Between 3 and 15 days after creation of these aneurysms. they were thrombosed via an endovascular approach. using a very soft detachable platinum coil delivered through a microcatheter positioned within the aneurysm. This detachable platinum coil was soldered to a stainless steel delivery guidewire. Intra-aneurysmal thrombosis was then initiated by applying a low positive direct electric current to the delivery guidewire. Thrombosis occurred because of the attraction of negatively charged white blood cells. red blood cells. platelets. and fibrinogen to the positively charged platinum coil positioned within the aneurysm. The passage of electric current detached the platinum coil within the clotted aneurysm in 4 to 12 minutes. This detachment was elicited by electrolysis of the stainless steel wire nearest to the thrombus-covered platinum coil. Control angiograms obtained 2 to 6 months postembolization confirmed permanent aneurysm occlusion as well as patency of the parent artery in all cases. No angiographic manifestation of untoward distal embolization was noted. Due to the encouraging results of this research. this technique has been applied in selected clinical cases which are described in Part 2 of this study.
Isolated symptomatic cervical spinous process fracture requiring surgery. Case report, Isolated cervical spinous process fractures are common. but are usually considered to be inconsequential. Although such fractures may produce pain. complete recovery without residual symptoms is expected after conservative treatment. and neurological injury does not usually occur. The case of a patient with a persistently symptomatic C-2 spinous process fracture that required surgical treatment for pain relief is reported. A review of the pertinent literature illustrates with unusual clarity the interactions of social. political. and economic forces associated with this medical condition.
Retrograde suction decompression of an ophthalmic artery aneurysm using balloon occlusion. Technical note, A large ophthalmic artery aneurysm was ligated using a modification of the retrograde suction technique described by Batjer and Samson. Temporary proximal occlusion of the internal carotid artery was accomplished with a double-lumen balloon catheter. and distal occlusion was performed with a temporary clip. The aneurysm was collapsed by gentle aspiration through the distal lumen of the balloon catheter. This greatly facilitated dissection and clip ligation of the aneurysm.
Index for optimum ventricular catheter length. Technical note, The optimum length of a ventricular catheter to be placed in a particular patient may be difficult to determine when either intraoperative ultrasound is not available or considerable time has elapsed between the diagnostic computerized tomography scan and the operation. An index for estimating ventricular length based on the head circumference of the individual is described. This method was tested clinically and proved to be successful.
Cardiac performance indices during hypervolemic therapy for cerebral vasospasm, The effect of hypervolemic preload enhancement on cardiac performance was systematically analyzed in nine patients following aneurysmal subarachnoid hemorrhage. The patients ranged in age from 34 to 63 years. and none had a history of cardiac disease. Each patient underwent placement of a flow-directed balloon-tipped catheter and the following measurements were taken during hypervolemic therapy: pulmonary artery wedge pressure (PAWP). central venous pressure (CVP). cardiac index (CI). stroke volume index (SVI). and left ventricular stroke work index (LVSWI). After baseline measurements were recorded. hetastarch or plasmanate was infused intravenously at 300 cc/hr. Thermal output determination and pressures were measured every 15 minutes. The PAWP did not correlate in a statistically significant fashion with the CVP in the ranges recorded; however. a statistically significant correlation did exist between PAWP increases and increases in CI. SVI. and LVSWI (p less than 0.01). There was no statistical correlation between PAWP increases above 14 mm Hg and improvement in cardiac performance as evidenced by CI. SVI. and LVSWI measurements. It is concluded that CVP is an unreliable index of cardiac performance during hypervolemic therapy and that. in previously healthy individuals. a PAWP of 14 mm Hg is associated with maximum cardiac performance.
Stereotactic craniotomy in the resection of small arteriovenous malformations, Surgical resection of 10 obscure arteriovenous malformations (AVM's) was accomplished with craniotomy guided by computerized tomography (CT) or angiography and the use of the Brown-Roberts-Wells stereotactic frame. Stereotactic craniotomy was invaluable for resection of the following types of AVM's: 1) AVM's with a nidus less than 2 cm in diameter. 2) AVM's located in an eloquent area of the brain. and 3) AVM's located deep in the brain. Stereotactic localization of these AVM's on preoperative radiological studies provides a precise route to the nidus. often avoiding important areas of the brain. This series included six male and four female patients with a mean age of 32 years. All patients presented with an intracerebral hemorrhage. from which eight made a complete neurological recovery prior to surgery. Two AVM's were located on the cortex. three were found subcortically. and five were situated near the ventricles or in the deep white matter. As a guide. angiography was used in six cases and CT in four cases. In each instance. the study providing the best image of the AVM nidus was employed. Postoperatively. no neurological deficits were found in eight patients and. in the two patients with preoperative deficits. neurological improvement was observed after recovery from surgery. Postoperative studies revealed complete removal of the AVM in all patients. and all lesions were confirmed histologically. The authors conclude that stereotactic craniotomy provides the optimum operative approach for the localization and microsurgical resection of AVM's that are either obscure or located deep in the brain.
Screening for unruptured asymptomatic intracranial aneurysms in patients undergoing coronary angiography, In screening for unruptured asymptomatic intracranial aneurysms. an intracranial intra-arterial digital subtraction angiography (IA-DSA). posteroanterior view. was obtained in 72 consecutive patients who underwent coronary angiography for workup of angina pectoris. In cases where an aneurysm was suspected from IA-DSA. conventional intracranial angiography was obtained. Five asymptomatic unruptured aneurysms were detected in four of these cases. The aneurysms ranged from 4 to 16 mm in diameter. There were no complications associated with the coronary angiography nor with the additional intracranial IA-DSA. which required less than 5 minutes to perform in all cases. The value of performing intracranial IA-DSA in patients undergoing coronary angiography to screen for unruptured asymptomatic aneurysm is discussed. as is the possible racial differences in the frequency of aneurysms.
Primary angiosarcoma of the central nervous system. Study of eight cases and review of the literature, Angiosarcoma arising in the central or peripheral nervous system has rarely been reported. Eight patients with primary angiosarcoma of the central nervous system are described here; these included five males and three females ranging in age from 2 weeks to 72 years (mean 38 years). Of the eight neoplasms. six were located in the cerebral hemispheres and one was in the meninges; the site was unknown in the other. All patients underwent surgical resection. Five of the eight patients died. four within 4 months after surgery and one after 30 months. Two of the remaining three patients were 17 and 27 years old at the time of diagnosis and were alive at follow-up review 39 and 102 months after surgery. respectively. One patient was lost to follow-up monitoring. Microscopically. all eight tumors demonstrated a well-differentiated pattern with irregular vascular channels and intraluminal papillae; in addition. four showed poorly differentiated solid areas. Immunohistochemical staining of neoplastic cells to factor VIII-related antigen and Ulex europaeus agglutinin I was performed in five tumors and was focally positive in four. No correlation could be shown between the histological features and the growth and biological behavior of the tumors.
Carpal tunnel syndrome: surgical treatment using the Paine retinaculatome, The operative technique for the relief of carpal tunnel syndrome has remained controversial. This report presents the results of 445 patients or 577 hands operated on using a transverse technique that varies little from that described by Paine and Polyzoidis. The patients were followed for 9 months to 3 years. In addition to the data received from follow-up visits. a questionnaire was sent to each patient for evaluation of their results. All surgery was performed under local anesthesia. sometimes with intravenous supplement. Of the 445 patients. 313 had unilateral operations and 132 had bilateral operations at one sitting. Postoperatively. normal hand function was achieved in 59.4% of patients in 1 week or less. Of the 577 hands operated on. 535 (92.7%) exhibited satisfactory results from surgery. No patient required postoperative physical therapy or splinting. There were no injuries to the median nerve or any of its branches.
Transforming growth factor-alpha, epidermal growth factor receptor, and proliferating potential in benign and malignant gliomas, Surgical specimens from six benign and 16 malignant human gliomas were investigated immunohistochemically to correlate the degree of malignancy. the distribution of transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) receptor. and the potential for cell proliferation using monoclonal antibodies to TGF-alpha. EGF receptor. and Ki-67. Fourteen (88%) of the malignant gliomas and one (17%) of the benign gliomas were found to be positive for TGF-alpha. and 14 (88%) of the malignant gliomas and two (33%) of the benign gliomas expressed EGF receptor. The proliferation index with Ki-67 was 18.8% +/- 8.1% (mean +/- standard deviation) in malignant gliomas and 1.9% +/- 1.8% in benign gliomas. In general. cells positive for EGF receptor and Ki-67 were randomly distributed throughout the tumor tissue. and cells positive for TGF-alpha tended to be clustered without obvious relationship to areas of necrosis or blood vessels. In some tumors. cells positive for TGF-alpha. EGF receptor. and Ki-67 were associated in a focal distribution. The more frequent expression of TGF-alpha and EGF receptor in the highly proliferative malignant gliomas is compatible with a role for TGF-alpha and EGF receptor in the induction or stimulation of malignant gliomas.
In vivo SPECT quantitation of bone metabolism in hyperparathyroidism and thyrotoxicosis, Bone metabolism was assessed in vivo and noninvasively using quantitative SPECT. The effect of endocrine abnormalities on bone metabolism was studied in 27 patients with primary hyperparathyroidism (HPT) and 12 patients with thyrotoxicosis (TTX). Quantitative bone scintigraphy (QBS) values of 99mTc-MDP uptake were compared to normal values matched for sex and age. Bones with significantly increased QBS values indicating increased bone metabolism were identified in the two patient groups. Fifty-one percent of the bones in patients with HPT and 78% in patients with TTX showed significantly increased QBS values. Increase in bone metabolism was highest in the femoral shaft. Seven patients with HPT and five with TTX were successfully treated. Six patients with HPT and four patients with TTX showed significant decrease of bone metabolism with normal QBS values after three months. The results indicate that QBS can be used to evaluate bone metabolism and its response to treatment in individual bones in patients with endocrine abnormalities.
Pharmacokinetics, immune response, and biodistribution of iodine-131-labeled chimeric mouse/human IgG1,k 17-1A monoclonal antibody, Pharmacokinetics. immunogenicity. and biodistribution of a 131I-labeled mouse/human chimeric monoclonal antibody (C-17-1A) was studied in six metastatic colon cancer patients. Pharmacokinetics obtained from serum radioactivity or chimera concentration were identical after 5 mCi of 131I-C-17-1A with mean alpha half-lives of 17.6 +/- 2.3 and 19.7 +/- 2.9 and mean beta half-lives of 100.9 +/- 16.1 and 106.4 +/- 14.1 hr. respectively. HPLC analysis documented the monomeric chimeric 17-1A without evidence of immune complexes or free 131I. None of the patients developed antibody after 131I-chimeric 17-1A exposure. Radiolocalization occurred in known areas of disease greater than 4 cm in all patients. The half-life of total-body radioactivity was 58 +/- 7 hr by whole-body counts and 64 +/- 13 hr by urine measurements. Whole-body and bone marrow dose estimates ranged from 0.75-1.03 and 0.76-1.05 rad/mCi. respectively. These studies confirm the prolonged circulation and reduced immunogenicity of chimeric 17-1A versus murine 17-1A. Marrow radiation exposure using antibodies with prolonged circulation is a critical factor in planning for radioimmunotherapeutic applications.
Validation of in vivo receptor measurements via in vitro radioassay: technetium-99m-galactosyl-neoglycoalbumin as prototype model, Hepatic binding protein (HBP) is a hepatocyte-specific receptor for serum asialoglycoproteins. The receptor also recognizes a synthetic glycoprotein that has been developed as a radiopharmaceutical. technetium-99m-galactosyl-neoglycoalbumin (99mTc-NGA). This report describes the correlation between receptor parameters measured in vivo via kinetic modeling of 99mTc-NGA and those measured by in vitro radioassay of biopsied liver tissue. Eleven patients with diffuse hepatic disease underwent percutaneous liver biopsy followed by a 99mTc-NGA functional imaging study. In vivo measurements of HBP quantity Ro and forward binding rate constant kb obtained from the kinetic analysis of 99mTc-NGA liver and blood time-activity data were compared to total receptor quantity and the HBP-99mTc-NGA association constant KA as measured by Scatchard binding assay of the biopsied tissue. The correlation coefficients between in vivo and in vitro measurements were 0.73 (df = 8. p = 0.015) and 0.98 (df = 8. p less than 0.01) for Ro and kb. respectively. The in vivo measurements of HBP biochemistry via kinetic analysis of the radiopharmaceutical time-activity data reflect the average concentration and affinity of the receptor. This study further substantiates the validity of 99mTc-NGA as a quantitative probe for the HBP receptor.
In vivo use of a radioiodinated somatostatin analogue: dynamics, metabolism, and binding to somatostatin receptor-positive tumors in man, Somatostatin analogues. labeled with gamma-emitting radionuclides. are of potential value in the localization of somatostatin receptor-positive tumors with gamma camera imaging. We investigated the application in man of a radioiodinated analogue of somatostatin. 123I-Tyr-3-octreotide. which has similar biologic characteristics as the native peptide. The radiopharmaceutical is cleared rapidly from the circulation (up to 85% of the dose after 10 min) mainly by the liver. Liver radioactivity is rapidly excreted into the biliary system. Until 3 hr after injection. radioactivity in the circulation is mainly in the form of 123I-Tyr-3-octreotide. Thereafter. plasma samples contain increasing proportions of free iodide. Similarly. during the first hours after injection. radioactivity in the urine exists mainly in the form of the unchanged peptide. Thereafter. a progressive increase in radioiodide excretion is observed. indicating degradation of the radiopharmaceutical in vivo. Fecal excretion of radioactivity amounts to only a few percent of the dose. The calculated median effective dose equivalent is comparable with values for applications of other 123I-radiopharmaceuticals (0.019 mSv/MBq).
Evaluation of right ventricular regional perfusion with technetium-99m-sestamibi SPECT, To evaluate technetium-99m-sestamibi as a right ventricular perfusion imaging agent. 25 normal volunteers and 25 patients with suspected coronary disease were studied with both sestamibi and thallium-201 SPECT. All patients underwent cardiac characterization. Compared to thallium-201 images. visualization of the right ventricle was superior for sestamibi in all cases. After computer masking of the left ventricle. count profiles for each 6-mm right ventricular short-axis slice were extracted and plotted in a bull's-eye type polar map with images normalized to maximal right ventricular counts. On sestamibi right ventricular polar maps. 7 of 11 patients (64%) with right coronary stenosis had fixed or reversible inferior right ventricular defects. None of the 25 volunteers or patients without right coronary stenosis had right ventricular defects (true-negative rate = 100%). We conclude that sestamibi SPECT provides an accurate means to assess right ventricular regional perfusion. with data presentation and interpretation facilitated by the polar map display.
The selenium-75-homocholic acid taurine test reevaluated: combined measurement of fecal selenium-75 activity and 3 alpha-hydroxy bile acids in 211 patients, The recommended reference values for the selenium-75-homocholic acid taurine (75SeHCAT) test. used in the analysis of chronic diarrhea. were evaluated in 211 patients by comparing simultaneous measurements of 3 alpha-hydroxy bile acids and 75Se activity in daily collected stools. An initial evaluation in 11 patients showed that the fecal collection method. which allows inspection and additional analysis of stools. was equivalent to the abdominal retention method. Selenium-75-HCAT whole-body retention half-life (WBR50) was greater than 2.8 days in less than 10% of the patients with bile acid malabsorption and less than 1.7 days in less than 10% of the normals. We recommend that a 75SeHCAT WBR50 less than 1.7 days is abnormal. a WBR50 greater than 2.8 days is normal. and a WBR50 in the range 1.7-2.8 days is equivocal. which was the case in 48% (94/195) of the patients in this study.
Brain and brain tumor uptake of L-3-[123I]iodo-alpha-methyl tyrosine: competition with natural L-amino acids, SPECT studies with L-3-[123I]iodo-alpha-methyl tyrosine (IMT) were carried out in 10 patients with different types of brain tumors--first under fasting conditions (basal) and a week later during intravenous infusion of a mixture of naturally-occurring L-amino acids (AA load). An uptake index (UI) was calculated by dividing tissue count rates by the integral of plasma count rates. The UI decreased by 45.6% +/- 15.4% (n = 10. p less than 0.001) for normal brain and by 53.2% +/- 14.1% for gliomas (n = 5. p less than 0.01) during AA load compared to basal conditions. while two meningiomas and a metastasis showed only a minor decrease (23.9 +/- 5.7%. n.s.). Two pituitary adenomas could not be delineated on the SPECT scans. These data indicate that IMT competes with naturally-occurring L-amino acids for transport into normal brain and gliomas. Transport characteristics of IMT into tumors of nonglial origin appear to be different from those of gliomas. For both types of tumors. it is advisable to perform IMT-SPECT under fasting conditions.
The pharmacokinetics and biodistribution of technetium-99m(V)dimercaptosuccinic acid in an animal tumor model, This study used an established rabbit tumor model with squamous carcinoma to evaluate the pharmacokinetics and biodistribution of technetium-99m-(V)dimercaptosuccinic acid. A total of 54 rabbits were studied (25 with no tumor; 29 with tumor). Technetium-99m(V)dimercaptosuccinic acid had a bi-exponential blood clearance in rabbits with no tumors (28 and 325 min) and in rabbits with tumors (27 and 352 min). There was no significant difference (p greater than 0.05) in mean clearance times between the two groups and clearance appeared unaffected by tumor mass. Technetium-99m(V)dimercaptosuccinic acid had a bi-exponential cumulative urine excretion with no apparent difference in half-times between non-tumor and tumor rabbit groups (200 and 240 min. respectively). Technetium-99m(V)dimercaptosuccinic acid had a major organ biodistribution in rabbits which included bone. kidneys. bladder and the blood pool. The major route of excretion was via the urine. There was no significant difference (p greater than 0.05) in organ biodistribution between rabbits with no tumors and rabbits with tumors and there was no evidence of active uptake of technetium-99m(V)dimercaptosuccinic acid by either squamous carcinoma or inflammatory tissue.
Nuclear imaging analysis of human low-density lipoprotein biodistribution in rabbits and monkeys, We have evaluated the biodistribution of human low-density lipoprotein (LDL) radiolabeled with 99mTc or with 123I-tyramine cellobiose in rabbits and in rhesus monkeys. Biodistribution was assessed after intravenous injection of radiolabeled LDL by quantitative analysis of scintigrams. counting of excreta. and counting of tissues at necropsy. Both rabbits and monkeys showed lower renal uptake (123I:99mTc approximately 1:3. as regional percent injected activity corrected for physical decay) and excretion (1:2 to 1:4). but higher hepatic (1.5:1 to 2:1) and cardiac (1.7:1 to 4:1) uptake of 123I than of 99mTc. Adrenals were visualized in normolipemic animals with 123I-tyramine cellobiose-LDL but not with 99mTc-LDL. Hyperlipemic animals showed increased cardiac (up to six-fold) and decreased hepatic activity (by 50%-60%) of both radionuclides. We conclude that 123I-tyramine cellobiose-LDL is better suited than 99mTc-LDL for dynamic studies of LDL metabolism in vivo.
Localization and visualization of pulmonary emboli with radiolabeled fibrin-specific monoclonal antibody, Indium-111-labeled monoclonal antibody 64C5 specific for the beta-chain of fibrin monomer was used to image canine (n = 6) experimental pulmonary emboli (at least one barium-thrombin and one copper-coil induced clot per dog). Uptake of 111In-64C5 and 125I-control-DIG26-11 were compared in 10 clots (7 barium-thrombin and 3 copper-coil) identified in the lungs. There was no difference in the blood clearance of 111In-64C5 and 125I-DIG26-11. Uptake of 111In-64C5 (0.183 +/- 0.105. mean %ID/g) was greater than 125I-DIG26-11 (0.024 +/- 0.025) in pulmonary clots (p less than 0.001). Mean thrombus to blood ratios at 24 hr were 6.78:1 for 64C5 and 0.57:1 for DIG26-11. The clots visualized in vivo were larger (0.315 +/- 0.381 g) than clots not visualized (0.089 +/- 0.098). Negative images were recorded in three dogs with pulmonary emboli. injected with 111In-labeled control monoclonal antibody 3H3. These data suggest that 111In-labeled antifibrin can detect large pulmonary emboli in vivo.
Malignant transformation of a Hurthle cell tumor: case report and survey of the literature, Hurthle cell carcinoma is a relatively uncommon type of well-differentiated thyroid carcinoma. Its diagnosis has been controversial due to the difficulty in separating Hurthle cell adenoma from Hurthle cell carcinoma. thus the term Hurthle cell tumor is often used to describe both lesions. The present case of anaplastic giant-cell carcinoma in an 81-yr-old woman arose in a Hurthle cell tumor. This case illustrates the propensity of Hurthle cell tumor to undergo "malignant transformation" and argues for a more aggressive approach to such tumors.
Naloxone reverses pattern of obstruction of the distal common bile duct induced by analgesic narcotics in hepatobiliary imaging, It is widely known that narcotics. such as morphine. cause spasm of the sphincter of Oddi. increasing pressure in the common bile duct. This pharmacologic effect has been applied to hepatobiliary scintigraphy in patients with chronic cholecystitis or cholestasis to reducing the time required for a diagnostic study. However. this feature of narcotics could result in delayed or nonvisualization of the small bowel. simulating a distal common bile duct obstruction. in patients requiring parenteral narcotic analgesics who must undergo hepatobiliary scintigraphy. We report on three patients where administration of intravenous naloxone hydrochloride (Narcan). a narcotic antagonist. was helpful in distinguishing narcotic-induced spasm of the sphincter of Oddi from true obstruction of the common bile duct.
Dynamic acquisition with a three-headed SPECT system: application to technetium 99m-SQ30217 myocardial imaging, A method for SPECT data acquisition. "continuous repetitive rotation acquisition." was developed with a high-sensitivity three-headed SPECT system. The method was applied to the dynamic imaging of 99mTc-SQ30217. a new myocardial imaging agent. After acquisition and reconstruction of SPECT data every minute. projection images at arbitrary intervals were used for tomographic reconstruction to determine the best timing of SPECT imaging in 99mTc-SQ30217. Based on a comparison of several possible acquisition intervals. SPECT data acquisition within 9 min after injection is recommended because of high myocardial uptake (myocardium-to-lung ratio. 2.83 +/- 0.42 (mean +/- s.e.m.) at 3-6 min) and relatively low hepatic uptake (myocardium-to-liver ratio. 0.85 +/- 0.13 at 3-6 min). The rate constant of the clearance of 99mTc-SQ30217 from the myocardium obtained by SPECT was: k1 = 0.249 +/- 0.050 per min (average half-life = 2.8 min) and k2 = 0.012 +/- 0.004/min (average half-life = 58 min). The continuous repetitive rotation acquisition SPECT study appears useful for imaging SQ30217 with its rapidly changing myocardial distribution.
Procedures of choice in renal nuclear medicine, The uronephrologic applications of nuclear medicine have reached a stage of maturity where procedures of choice for many specific clinical problems can be identified. This review attempts to achieve this aim as objectively as possible. It must be emphasized that the opinions expressed here are those of the author and in many areas there may be a lack of consensus.
Monitoring, reentry, and relapse prevention for chemically dependent health care professionals, Monitoring and reentry programs for chemically dependent health care professionals are increasingly being recognized as important components of recovery efforts targeted at this population. Such monitoring and preventive programs should incorporate certain eligibility requirements. patient-monitoring program contracts. recovery maintenance activities and adjuncts. work-site assessments and reentry recommendations. random body fluid analysis. relapse management. and clear explanations of financial responsibility. Monitoring and reentry programs need to be fully integrated within the spectrum of resources available to health care professionals.
The preferential antagonism of pentylenetetrazole proconflict responses differentiates a class of anxiolytic benzodiazepines with potential antipanic action, With the use of the shock-induced suppression of water drinking in thirsty rats (Vogel's conflict paradigm) and the pentylenetetrazole-enhanced shock-induced suppression of drinking (proconflict paradigm) as animal models to test anxiolytic and antipanic agents. it was possible to distinguish two major classes of benzodiazepines (BZDs) and congeners on the basis of their antiproconflict index (ratio of anticonflict/antiproconflict potencies). Thus. typical low potency BZDs and congeners (diazepam. midazolam. zolpidem. alpidem) with anxiolytic/hypnotic properties have a low antiproconflict index (close to 1). whereas typical high potency BZDs (clonazepam. alprazolam. bretazenil) with reported antipanic properties have an antiproconflict index approximately 10-fold higher. The anticonflict and antiproconflict actions of BZDs with low or high antiproconflict indices are blocked by flumazenil but are potentiated differentially by the gamma-aminobutyric acid (GABA) reuptake blocker 1-2-[bis(trifluoromethyl)-phenyl]-methoxyethyl-1.2.5.6-tetrahydro-3- pyridine-carboxylic acid. Protracted administration of antianxiety and antipanic antidepressant drugs that do not act on GABAA receptors. directly. resulted in anticonflict and antiproconflict effects. However. the efficacy of these drugs is clearly inferior (20-30%) to that of BZDs. These data suggest that specific GABAA receptor subtypes mediate the pharmacological action of BZDs possessing low and high antiproconflict indices.
Tin(Sn+4)-diiododeuteroporphyrin; an in vitro and in vivo inhibitor of heme oxygenase with substantially reduced photoactive properties, Iodination of Sn-deuteroporphyrin (Ki = 0.185 microM) at positions C2 and C4 of the porphyrin ring results in an enhanced ability of the resulting derivative. Sn-diiododeuteroporphyrin. to inhibit (Ki = 0.069 microM) heme oxygenase activity in vitro. The potency of Sn-diiododeuteroporphyrin inhibition of bilirubin production in vivo is similar to that of Sn-protoporphyrin. but in vitro tests demonstrate that. when in solution with human serum albumin. Sn-diiododeuteroporphyrin is significantly (3-10 times. depending upon conditions) less photosensitizing than are Sn-protoporphyrin or Sn-mesoporphyrin. These findings demonstrate that halogenation of a suitable porphyrin macrocycle can substantially diminish photoactive properties of the compound whereas retaining its ability to act as a heme oxygenase inhibitor.
The novel competitive N-methyl-D-aspartate (NMDA) antagonist CGP 37849 preferentially induces phencyclidine-like behavioral effects in kindled rats: attenuation by manipulation of dopamine, alpha-1 and serotonin1A receptors, The novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849) was found to produce a phencyclidine (PCP)-like behavioral syndrome (ataxia. locomotion. stereotypies) in amygdala-kindled rats. whereas the amphetamine-like behavioral alterations of the syndrome (locomotion. stereotypies) were only infrequently seen in nonkindled rats. In dose-response experiments in kindled and nonkindled rats. behavioral effects were scored using a ranked intensity scale. and the behaviors and behavioural scores determined after CGP 37849 were compared with those determined after i.p. administration of the noncompetitive NMDA receptor antagonist dizocilpine maleate (MK-801). In kindled rats. 20 mg/kg of CGP 37849 produced about the same scores for hyperlocomotion and head weaving as 0.1 mg/kg of MK-801. Kindled rats exhibited higher behavioral scores than nonkindled rats. especially in the case of CGP 37849. The behavioral effects produced by CGP 37849 in kindled rats were almost indistinguishable from the PCP-like behavioral effects induced by MK-801. indicating that CGP 37849 indeed produces a PCP-like pattern of behavior in kindled rats. Hyperlocomotion and head weaving induced by CGP 37849 in kindled rats could be attenuated or totally prevented by pretreatment with ipsapirone. a partial agonist/antagonist at postsynaptic 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype. Furthermore. these behavioural effects were attenuated or blocked by the dopamine antagonist haloperidol and the alpha-1 adrenoceptor antagonist. prazosin. The data demonstrate that kindling induces a hypersensitivity to PCP-like behavioral effects of competitive and noncompetitive NMDA receptor antagonists. which could relate to the recent finding of increased function of NMDA receptors following kindling.
Enhanced antitumor activity in mice after administration of thermosensitive liposome encapsulating cisplatin with hyperthermia, The antitumor effect of cisplatin-(CDDP)-encapsulated thermosensitive large unilamellar liposome (ThLip) administration with hyperthermia (HT) was examined in mice bearing Meth A fibrosarcoma. The tumor Pt levels after ThLip administration were increased in response to HT. The targeting index was approximately 3. The antitumor activity of ThLip + HT. as measured by tumor growth delay or tumor weight inhibition. was larger than that of ThLip without HT or a solution with or without HT. The CDDP dose in ThLip + HT to give equivalent tumor growth delay in solution (40 micrograms/mouse) + HT was about 10 micrograms/mouse. and therefore the targeted drug delivery enhancement ratio was about 4. The ratio correlates with the targeting index. The blood urea nitrogen level. as an indicator of CDDP nephrotoxicity. was increased 7 days after the administration of ThLip (40 micrograms CDDP/mouse) with HT. However. this blood urea nitrogen level rise was independent of the activity enhancement by the liposome. These findings suggest that the HT combined CDDP delivery system using ThLip can decrease the effective CDDP dose. thereby increasing its therapeutic index.
Effects of different angiotensin-converting enzyme (ACE) inhibitors on ischemic isolated rat hearts: relationship between cardiac ACE inhibition and cardioprotection, We determined the relationship between cardiac angiotensin-converting enzyme (ACE) inhibition and anti-ischemic efficacy of several structurally different ACE inhibitors or their prodrug esters perfused through the isolated rat heart. Seven ACE inhibitors inhibited cardiac ACE to varying degrees due to differences in uptake during perfusion through nonischemic rat hearts. Zofenopril-sulfhydryl and fosinoprilic acid were the most effective of the free inhibitors. Among the prodrugs. zofenopril and S-benzoylcaptopril. hydrolyzed rapidly by cardiac esterase. were more effective than their component ACE-inhibitors. whereas fosinopril. ramipril and enalapril were poorly active. For studies in ischemic rat hearts. vehicle or drug treatment was initiated 10 min before a 25-min period of global ischemia and during a 30-min reperfusion period. Of five unesterified ACE inhibitors studied for anti-ischemic activity. only captopril and zofenopril-sulfhydryl were found to improve postischemic contractile function and reduce cell death in the isolated rat hearts. Fosinoprilic acid. ramiprilat and enalaprilat were not cardioprotective at high perfusion concentrations. despite the fact that nearly complete inhibition of cardiac ACE was achieved with all of the compounds studied. The S-benzoyl prodrugs of zofenopril-sulfhydryl and captopril were at least as potent as their component ACE inhibitors in reducing ischemic-reperfusion damage in the same model. Neither zofenopril nor captopril. however. had any effect on coronary flow before or after ischemia. Thus. it appears that the cardioprotective effects of zofenopril and captopril are independent of cardiac ACE inhibition or. at least. that ACE inhibition alone is not sufficient. Both captopril and zofenopril are sulfhydryl-containing compounds whereas the inactive compounds are not; and. thus. this group appears to be important in mediating their cardioprotective actions.
Oral contraceptives and coronary heart disease, In industrialized countries. coronary heart disease (CHD) is a major public health problem for both men and women. Preventive strategies for reducing the excessive mortality and morbidity associated with CHD involve the identification and modification of metabolic factors believed to be involved in the disease process. Three major areas of concern are lipid metabolism. carbohydrate metabolism and the hemostatic system. The steroid hormones contained in oral contraceptives (OCs) have been shown to interfere in all three areas. In many instances OCs have been shown to alter metabolic markers for CHD in directions associated with increased risk. Although evidence is lacking that such changes induce CHD in users of modern. low-dose OCs. it would be prudent to develop formulations with a minimal impact on metabolic risk markers. There is increasing evidence that many of the metabolic disturbances seen in CHD patients share a common origin. and the development of risk-free OCs is likely to require investigation into complex interrelationships.
Coronary heart disease risk markers in users of low-dose oral contraceptives, Seven combination oral contraceptives (OCs) were studied for their effects on glucose. insulin. triglyceride and lipoprotein concentrations. Subjects included 925 women using fixed-dose (monophasic) or variable-dose (triphasic) formulations and 418 premenopausal women not using OCs. The monophasics contained 150 or 250 micrograms of levonorgestrel. 500 or 1.000 micrograms of norethindrone or 150 micrograms of desogestrel as the progestin. Triphasic progestin doses were 50-125 micrograms of levonorgestrel or 500-1.000 micrograms of norethindrone. All the formulations increased the fasting serum triglycerides. No changes were seen in serum total cholesterol. The effects on serum lipoproteins depended on the progestin type and dose. Monophasics containing 500 micrograms of norethindrone or 150 micrograms of desogestrel lowered low density lipoprotein (LDL) cholesterol and increased high density lipoprotein (HDL) cholesterol. Monophasics containing levonorgestrel reduced HDL cholesterol. The triphasics did not affect LDL or HDL cholesterol but altered the balance of HDL subfractions. All the formulations caused a deterioration in glucose tolerance and insulin resistance and increased pancreatic insulin secretion. The greatest effects were seen with formulations containing levonorgestrel. The study showed that a reduction in the progestin dose and use of novel progestins can reduce the potentially adverse effects of OCs on metabolic risk markers for coronary heart disease.
Strategies for reducing cardiovascular risk in women, The major risk factors for coronary heart disease in women are much the same as in men. They include elevated cholesterol. hypertension. diabetes. cigarette smoking. severe obesity. a history of stroke and/or thromboembolic disease. and a family history of premature coronary heart disease. Diabetes appears to confer a greater risk and hypertension to have a lesser effect in women than in men. The obstetrician-gynecologist's role as primary care physician is important in terms of risk reduction counseling in areas that are amenable to change: diet. exercise and cigarette smoking. A fourth area. prescribing hormonal therapy. including oral contraceptives and hormone replacement. is the one risk reduction modality that is within the physician's control.
Complexion changes in oral contraceptive users. Results from a phase IV multicenter trial evaluating the safety and efficacy of ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, An open-label. phase IV. multicenter survey of obstetrician-gynecologists was conducted to evaluate the efficacy and safety of a low-dose monophasic oral contraceptive. ethynodiol diacetate. 1 mg. with ethinyl estradiol. 35 micrograms. Surveys from 983 community-based physicians reported on 6.382 women. Most patients did not experience "clinically noticeable complexion changes" (5.695/6.382. or 89.2%). Of the 687 patients with complexion changes. nearly three-fourths reported an improvement (501/687. or 72.9%). A follow-up questionnaire was sent to 127 respondents (18.6%) who reported worsening of the complexion; 70% of the questionnaires were returned. Most complexion worsening was of slight degree (63%). reported by the patient and not the physician (84% vs. 16%). and experienced during the first two to three months (84%). Although the literature includes many references to skin condition "improvement" on oral contraceptives. this report of a descriptive study gives clinicians as estimate of the incidence and severity of complexion changes in actual use.
Incidence of ovarian cyst formation in women taking ethynodiol diacetate, 1 mg, with ethinyl estradiol, 35 micrograms, A total of 7.759 women were treated with ethynodiol diacetate. 1 mg. with ethinyl estradiol. 35 micrograms (EDA 1 mg with EE 35 micrograms) in a field study involving 983 obstetrician-gynecologists evaluating the incidence of ovarian cyst formation. Six thousand three hundred eighty-two patients were evaluable; 1.377 could not be evaluated because of failure to meet inclusion criteria or inconsistent or incomplete data collection. Cysts were detected in 80 patients at the time of the final visit. Follow-up questionnaires were received on 61% of patients and confirmed the presence of 12 newly formed ovarian cysts in patients taking EDA 1 mg with EE 35 micrograms. Only three women required an operation for ovarian cysts; two women had functional ovarian cysts (one follicular and one luteal). and one had a neoplastic cyst (cystadenoma). Thus. the incidence of ovarian cyst formation requiring surgical intervention was 0.05% in women taking EDA 1 mg with EE 35 micrograms.
Hospital characteristics associated with adverse events and substandard care, To explore the epidemiology of adverse events (AEs). which were defined as injuries due to medical treatment. and that subset of AEs caused by negligence. we studied interhospital variation in these outcomes in a sample of 31.000 medical records drawn from a random selection of 51 hospitals in New York in 1984. We found a substantial variation in both AE rates (0.2% to 7.9%; mean. 3.2%) and the percentage of AEs due to negligence (1% to 60%; mean. 24.9%) among hospitals. Univariate analyses of AEs revealed that primary teaching institutions had significantly higher rates (4.1%) and rural hospitals had significantly lower ones (1.0%). The percentage of AEs due to negligence was lower in primary teaching (10.7%) and for-profit (9.5%) hospitals and was significantly higher in hospitals with predominantly (greater than 80%) minority patients who had been discharged (37%). These findings were corroborated by multivariate analysis. Our results suggest that AEs and negligence are not randomly distributed and that certain types of hospitals have significantly higher rates of injuries due to substandard care. These observations may represent an important improvement on existing measures of quality because they take into account the fact that some hospitals' populations may be at risk of suffering a poor outcome.
Diarrheal deaths in the United States, 1979 through 1987. A special problem for the elderly, OBJECTIVE.--Diarrhea is an important cause of death among young children in both developing and developed countries. but little is known about diarrheal death among adults. In this study. we examined trends in diarrheal deaths among all age groups in the United States. DESIGN/SETTING/PARTICIPANTS.--We reviewed national mortality data complied by the National Center for Health Statistics. Hyattsville. Md. which consists of information from all death certificates filed in the United States for the period 1979 through 1987. A death for which diarrhea was listed as an immediate or underlying cause was considered a "diarrheal death" and included in the analysis. RESULTS.--We found that 28.538 persons died of diarrhea cited as either an immediate or the underlying cause of death during the 9-year period. A majority of diarrheal deaths occurred among the elderly (older than 74 years of age. 51%). followed by adults 55 to 74 years of age (27%). and young children (younger than 5 years of age. 11%). For the elderly. adjusted risk factors for dying of diarrhea included being white. female. and residing in a long-term care facility. Only the elderly and young children had clear. distinct winter peaks of diarrheal deaths. suggesting that the diarrhea may. in part. be infectious in origin. CONCLUSION.--For the elderly. more directed studies of those at risk. such as nursing home residents. are needed to determine if oral rehydration therapy. vaccines. or other preventive measures might benefit this population.
Exaggerated radiation-induced fibrosis in patients with systemic sclerosis, Four patients with stable systemic sclerosis and limited skin involvement received radiation for the treatment of solid malignant neoplasms. Following localized irradiation. each patient developed an exaggerated cutaneous and internal fibrotic reaction in the irradiated areas. The surface area of fibrosis extended beyond the radiation portals employed. and the fibrotic process was poorly responsive to antifibrotic therapy. Three of the patients died of complications caused by fibrous encasement of internal organs. The extent and severity of postradiation fibrosis in these patients was distinctly unusual. These observations suggest that patients with systemic sclerosis are particularly susceptible to developing excessive radiation-induced fibrosis.
Diagnostic and therapeutic technology assessment. Vasoactive intracavernous pharmacotherapy for impotence: intracavernous injection of prostaglandin E1, The DATTA panelists consider PGE1 to be a useful addition to the family of vasoactive agents used to treat organic impotence. It is associated with fewer side effects than either papaverine or phentolamine. Although most patients can achieve an erection with PGE1. some will not. and the other vasoactive agents may be of benefit in these cases. Synergy has been demonstrated when papaverine and PGE1 are used together. and a combination of the two in reduced dosages may be effective in producing an erection with a reduction in side effects. Intracavernosal therapy should be prescribed and monitored by a urologist who is experienced in the treatment of impotence and who is able to treat any of the potential side effects. Whether long-term use of local injections will produce additional complications is yet to be determined.
Variations in length of stay and outcomes for six medical and surgical conditions in Massachusetts and California, OBJECTIVES.--To determine the extent to which interinstitutional variations in length of stay are explained by differences in patient characteristics and to determine whether patients in hospitals with shorter lengths of stay had worse outcomes. DESIGN.--We reviewed patients' medical records and surveyed patients between 3 and 12 months after hospital discharge using a questionnaire. SETTING.--Six teaching hospitals in California and Massachusetts. PATIENTS.--A cohort of 2484 selected patients who had been hospitalized for acute myocardial infarction or to rule out acute myocardial infarction. coronary artery bypass graft surgery. total hip replacement. cholecystectomy. or transurethral prostatectomy. Between 73% and 84% of the patients with each condition completed a follow-up questionnaire. OUTCOME MEASURES.--In-hospital complications. deaths. length of stay. functional status after hospital discharge. readmission. and patient satisfaction with hospital care were analyzed. RESULTS.--Significant interinstitutional differences in length of stay were noted for all conditions except rule-out acute myocardial infarction. Statistical adjustment for case-mix differences accounted for most of the interinstitutional differences in length of stay for total hip replacement but explained little of the differences in the other conditions. When we controlled statistically for other predictors. length of stay did not have a significant impact on deaths. functional status after hospital discharge. the probability of readmission. or patient satisfaction with hospital care. CONCLUSION.--More research is needed to determine the medical practices that are related to variations in lengths of stay. Routinely available outcome data may help preserve quality in the face of efforts to decrease costs by effecting more standardized practices of care.
Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials, A key principle for interpretation of subgroup results is that quantitative interactions (differences in degree) are much more likely than qualitative interactions (differences in kind). Quantitative interactions are likely to be truly present whether or not they are apparent. whereas apparent qualitative interactions should generally be disbelieved as they have usually not been replicated consistently. Therefore. the overall trial result is usually a better guide to the direction of effect in subgroups than the apparent effect observed within a subgroup. Failure to specify prior hypotheses. to account for multiple comparisons. or to correct P values increases the chance of finding spurious subgroup effects. Conversely. inadequate sample size. classification of patients into the wrong subgroup. and low power of tests of interaction make finding true subgroup effects difficult. We recommend examining the architecture of the entire set of subgroups within a trial. analyzing similar subgroups across independent trials. and interpreting the evidence in the context of known biologic mechanisms and patient prognosis.
Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis, This paper attempts to further delineate the similar pathobiologic mechanisms involved in the atherosclerosis and glomerulosclerosis processes. In particular. recent experimental data in models of both processes have focused on the roles of hypercholesterolemia and the monocyte/macrophage in propagating these lesions. In a nonimmune toxic glomerulopathy. chronic aminonucleoside nephrosis. our laboratory has demonstrated an important role for the glomerular macrophage. which is increased in number in temporal association with the onset of albuminuria. in propagating initial glomerular injury to glomerulosclerosis. In addition. a superimposition of dietary hypercholesterolemia further augments this heightened glomerular macrophage number and activates systemic macrophages. These data suggest a synergistic role between the hypercholesterolemia of nephrosis and the surge in glomerular macrophage number following initial glomerular injury in establishing a cascade of intercellular events that culminates in glomerulosclerosis. The intriguing histologic and immunohistochemical similarities between the evolving fatty streak in the atherosclerotic vessel wall and the progressive glomerular lesion leading to glomerulosclerosis suggest analogous pathobiologic mechanisms.
Physiopathology of plasma lipoprotein metabolism, The metabolism of plasma lipoproteins is under the regulation of several factors which involve apolipoproteins. lipid-modifying enzymes. lipid transfer proteins. and cell membrane receptors. The genes of most of these proteins have been defined and several mutants of these proteins also identified. Studies of these mutants have provided important new insights into the molecular basis of the abnormalities of lipoprotein metabolism and also a better understanding of the mechanisms involved in secondary dyslipoproteinemias inclusive of those occurring in renal disorders.
Beer versus mixed-drink consumption at fraternity parties: a time and place for low-alcohol alternatives, Blood alcohol concentration (BAC) measurements were taken of university students entering and exiting three fraternity parties: during each party. the rates of drinking beer and mixed drinks were monitored. The parties choose beer or mixed drinks to consume exclusively throughout the evening at no cost. Unbeknownst to the subjects. the following conditions were manipulated across successive parties: (1) at the first party (64 males and 43 females) the beer alternative had standard alcohol content (i.e.. 7% alcohol by volume). (2) at the second party (70 males and 48 females) the beer was a low-alcohol beer (3% alcohol) and (3) at the third party (53 males and 41 females) the partiers were randomly assigned to a regular alcohol content conditions of beer or mixed drinks or to a low-alcohol content condition (i.e.. 3% beer or mixed drinks made with 7/8-oz of distilled spirits). Since those assigned to the low-alcohol conditions did not consume more beverages than those in the regular alcohol conditions. a titration hypothesis was not supported and the exit BACs were significantly lower for partiers in the low-alcohol conditions. When females drank at the same rate as males. their exit BACs were significantly higher than those of males. Implications for DWI prevention are discussed.
Anticipated and subjective sensitivities to alcohol, The development and maintenance of alcohol use patterns may depend. in part. on differences between how an individual anticipates he will respond to alcohol and how he appears to others when he is drinking. Such differences may introduce bias in decisions regarding which activities are safe while under the influence of an intoxicating amount of alcohol. This study of 387 participants of the Colorado Alcohol Research on Twins and Adoptees project examined the interrelationships of anticipated. subjective and observer-judged sensitivity to a blood alcohol concentrations of about 0.1 g/dl (approximated by breath alcohol concentration). Differences among the sensitivity measures were dependent upon recent alcohol drinking history and individual differences in actual sensitivity (as observer-rated). The results were consistent with hypotheses that people with little drinking experience may overestimate how intoxicated they will be. that heavier drinkers may develop chronic tolerance to the intoxicating effects and that denial may play a role in both subjective and anticipated sensitivity.
Drinking patterns and drinking-related problems of Mexican-American husbands and wives, The present research builds on previous studies' findings of alcohol-related gender differences between Mexican-American men and women. through examination of drinking levels. norms and related problems within the context of marriage and family. A survey of husbands and wives in 206 married couples randomly selected from eligible households in East San Jose. California. was carried out. Highlights in our findings include significant gender differences in reports of drinking patterns. frequency of heavier drinking. tangible consequences of drinking and expectancies regarding alcohol. Most notably. correlations were found between husbands' and wives' quantity-frequency drinking measures. the frequency of heavier drinking. tangible consequences of drinking and expectancies regarding alcohol. Although men have higher levels of drinking and greater drinking-related problems. husbands' and wives' patterns are correlated with one another. These links between spouses' drinking-related variables have important implications for family prevention and education about alcohol use.
Differences in drinking patterns associated with migration from a Greek island to Melbourne, Australia: a study of sibships, Siblings (and their families) who have migrated from the Greek island of Levkada to Melbourne. Australia reported markedly lower alcohol consumption (n aged 25-74 = 846. reported consumption 16 g/d for men. 2 g/d for women) when compared with the siblings (and their family members) who stayed on the island (n = 498. 54 g/d for men. 16 g/d for women). Median time since migration exceeded 20 years. Of nonmigrants. 73% drank wine and 88% of these produced all they consumed. They drank wine regularly with the two main meals each day. Some migrants managed a kind of self-sufficiency by home-pressing bulk-purchased grapes. but commoner responses were to purchase beer or wine or to cease drinking alcohol. Migrants who drank wine consumed less than half as much as comparable nonmigrants. The prevalence of drinking on special occasions was not lower in migrants. nor were the amounts drunk. Drinking contexts continued to be those traditional within Greek culture. Among nonmigrant men self-rated health was positively associated with alcohol consumption. In this culture. which has traditionally made heavy use of alcohol and used it primarily as a food. the level and pattern of use changed markedly under changed circumstances--such as the loss of true self-sufficiency and an altered temporal pattern of daily life.
Adult self-esteem and locus of control as a function of familial alcoholism and dysfunction, This study examines self-esteem and locus of control in adult children of alcoholics. We assessed these measures in 195 professional adults in relation to alcoholism and functioning in the family of origin. Although the presence of parental alcoholism was not a predictor of significant differences in adult self-esteem or locus of control. familial dysfunction was reflected in significant differences in self-esteem. This suggests that parental alcoholism does not necessarily result in personality differences in adult children.
Women, alcohol and incest: an analytical review, This study examines the historical treatment of two phenomena that impact negatively on the lives of millions of women--incest and alcoholism--and explores the similarities in characteristics of alcoholic women and women with histories of incest. Prior to the early 1980s. incest histories were rarely mentioned in the literature on alcohol. Similarly. the literature on incest makes only passing references to alcohol abuse among adolescent and adult survivors. Hence. formal research comparisons between the alcoholic woman and the incest-surviving woman are lacking. The purpose of this study is not merely to illustrate the similarities between the alcoholic woman and the incest-surviving woman. but also to present a persuasive argument that multidisciplinary research efforts are essential in order to promote more effectively the identification. diagnosis and treatment of women who suffer both alcoholism and incest. To accomplish these goals. this study presents parallel reviews of (1) women and alcohol and (2) women and incest. then develops a comparative profile of the alcoholic woman and the incest-surviving woman. Additionally. the relatively sparse information on the alcoholic incest-surviving woman is reviewed. This study points to the need for further research in order to address the compelling question that emerges: Why do some incest-surviving women become alcoholic while others do not?.
Tinnitus, Tinnitus. a common complaint. reportedly affects more than 37 million Americans. Most often. it is associated with a sensorineural hearing loss in the high-frequency range. Tinnitus. however. is a symptom and not a disease. Complacency about this symptom complex may cause physicians to overlook a severe underlying pathologic process. Patients with unilateral tinnitus. pulsatile tinnitus. fluctuating tinnitus. or tinnitus associated with vertigo should undergo thorough assessment. including elicitation of a complete history. physical examination. and audiologic analysis. In many instances. treatment is effective. Masking of tinnitus. medical therapy. and biofeedback and counseling are some measures that have been used in the management of tinnitus.
T-cell reactivity to 38 kD insulin-secretory-granule protein in patients with recent-onset type 1 diabetes, Type 1 diabetes seems to be an autoimmune disease in which T cells have a substantial role. A possible target antigen was suggested by the proliferation of CD4 T cells from a newly diagnosed patient in response to a 38 kD polypeptide of the insulin-secretory-granule membrane. To see whether this reactivity is widespread at disease onset. we have generated T-cell lines in vitro from peripheral blood mononuclear cells of nineteen children of caucasoid origin with newly diagnosed type 1 diabetes and sixteen healthy controls matched for age and HLA antigens. The procedure involved two cycles of incubation with a rat beta-cell tumour subcellular fraction enriched in secretory granules and plasma membrane components. followed by a proliferation assay. Fourteen (74% [95% confidence interval 49-91%]) of the patients' cell lines showed a positive proliferative response on subsequent exposure to the islet-cell antigen preparation compared with only two (13% [2-38%]) of the controls (p = 3 x 10(-4); difference 61% [44-87%]). Two subjects who had high titres of islet-cell autoantibodies (ICA) without clinical diabetes produced responsive T-cell lines. Reactivity towards the 38 kD fraction of insulin-secretory-granule membranes was found only in patients (eight of ten responders tested; 95% CI 44-98%) and one ICA-positive non-diabetic subject. Detection of an ongoing autoimmune T-cell response might be useful diagnostically and could lead to prevention of diabetes through specific immunotherapy.
Effects of occupational therapy home service on patients with rheumatoid arthritis, Because there is little information about the efficacy of home occupational therapy. we decided to assess the effects of a home service on patients with rheumatoid arthritis. 105 patients aged 18-70 years. on stable medical therapy. were randomised to receive a 6-week comprehensive programme of occupational therapy (experimental group. 53 patients) or to receive no such treatment (control group. 52). At 6 weeks. control patients received the experimental regimen. and experimental patients were continued on treatment as needed up to 12 weeks. Outcomes were measured at baseline. 6. and 12 weeks with a global functional capacity score (functional score). At 6 weeks the functional score for the experimental group was significantly higher than that for the control group (mean difference = 8.1. 95% Cl 1.7 to 15.8. p = 0.012). Control patients at 12 weeks showed a similar improvement to experimental patients at 6 weeks. and between 6 and 12 weeks the experimental patients were stable. Occupational therapy leads to a statistically significant and clinically important improvement in function in patients with rheumatoid arthritis.
Alfuzosin for treatment of benign prostatic hypertrophy. The BPH-ALF Group, To assess the long-term efficacy and safety of alfuzosin. a selective alpha 1-adrenergic antagonist. 518 symptomatic patients with benign prostatic hypertrophy (BPH) were randomised to received either alfuzosin (daily dose 7.5-10 mg) or placebo for 6 months. Obstructive and irritative symptoms. assessed according to the Boyarsky scale. significantly improved in the alfuzosin group compared with the placebo group (p = 0.0004). Fewer patients in the alfuzosin group than in the placebo group dropped out due to lack of efficacy (6.8% vs 14.6%. p = 0.004) and the prevalence of spontaneous acute urine retention was lower in the alfuzosin group (0.4% vs 2.6%. p = 0.04). By 6 months. mean urinary flow rates had increased (p less than 0.05) and residual volume had decreased (p = 0.017) in the alfuzosin group. although the two groups were broadly similar with respect to increase in peak flow rate. The overall incidence of adverse events was similar in the two groups. which led to the withdrawal of 10.8% and 9.0% of patients. respectively. The findings emphasise the magnitude of the placebo response in symptomatic patients with BPH and show that treatment with alpha 1 adrenergic antagonist drugs provides long-lasting improvement in such patients.
The effect of insecticide-treated bed nets on mortality of Gambian children, Insecticide treatment of bed nets ("mosquito nets") may be a cheap and acceptable method of reducing the morbidity and mortality caused by malaria. In a rural area of The Gambia. bed nets in villages participating in a primary health-care (PHC) scheme were treated with permethrin at the beginning of the malaria transmission season. Additionally. children aged 6 months to 5 years were randomised to receive weekly either chemoprophylaxis with maloprim or a placebo throughout the malaria transmission season. We measured mortality in children in PHC villages before and after the interventions described. and compared this with mortality in villages where no interventions occurred (non-PHC villages). About 92% of children in PHC villages slept under insecticide-treated bed nets. In the year before intervention. mortality in children aged 1-4 years was lower in non-PHC villages. After intervention. the overall mortality and mortality attributable to malaria of children aged 1-4 in the intervention villages was 37% and 30%. respectively. of that in the non-PHC villages. Among children who slept under treated nets. we found no evidence of an additional benefit of chemoprophylaxis in preventing deaths. Insecticide-treated bed nets are simple to introduce and can reduce mortality from malaria.
Water source as risk factor for Helicobacter pylori infection in Peruvian children. Gastrointestinal Physiology Working Group, Helicobacter pylori infection is widespread among Peruvian adults by the age of 30. but the age at which children become infected. the prevalence of disease. and the role of socioeconomic status in the epidemiology of infection are not known. We used the 13C-urea breath test to study the prevalence of infection in 407 Peruvian children from Lima. aged 2 months to 12 years. from families of low and high socioeconomic status. Peruvian children acquire H pylori early in life and the number of infected individuals increases rapidly with age; overall prevalence was 48%. H pylori infection was independent of sex. but was highly correlated with socioeconomic status; prevalence of infection was higher among children from low-income families than among those from high-income families (56% vs 32%. p = 0.001). Children whose homes had external water sources were three times more likely to be infected than were those whose homes had internal water sources. Among families with internal water sources. there was no difference in H pylori infection associated with income. Children from high-income families whose homes were supplied with municipal water were 12 times more likely to be infected than were those from high-income families whose water supply came from community wells. The findings show that the prevalence of H pylori infection is high among young Peruvian children and that the municipal water supply seems to be an important source of infection among Lima children from families of both low and high socioeconomic status.
Administration of antidiuretic peptide (DDAVP) by way of suction de-epithelialised skin, Transdermal drug delivery seems a promising way of achieving complete. predictable absorption. but the epidermis is a barrier for most drugs. A new technique for transdermal drug delivery. in which a small patch of epidermis was removed. was tested in seven healthy volunteers by means of the antidiuretic peptide 1-deamino-8-D-arginine vasopressin (DDAVP). The epithelium of a small area of forearm skin (diameter 5 mm) was removed painlessly. and in a standard way. by a simple device operating at a present vacuum. DDAVP was given by way of improvised occlusive reservoirs. Plasma DDAVP concentration/time curves conformed closely with zero-order kinetics. which suggests that the bioavailability approached 100%. corresponding to that for direct intravenous infusion. Four volunteers were given DDAVP daily for 4 days by way of the de-epithelialised site; there were no signs that re-epithelialisation hindered permeation. All plasma DDAVP values substantially exceeded the lowest effective therapeutic concentration for patients with diabetes insipidus. The vacuum removal of the epithelium caused pronounced hyperaemia in the de-epithelialised dermis (assessed by laser doppler flow measurement); the hyperaemia persisted. unaffected by DDAVP. and may have contributed to the efficient permeation. The skin spot appeared normal at 6 weeks.
Bone-marrow transplantation for congenital erythropoietic porphyria, Congenital erythropoietic porphyria. a disorder of haem synthesis. is caused by uroporphyrinogen III synthase deficiency in bone-marrow normoblasts. Uroporphyrins and coproporphyrins accumulate and cause oxidative damage to cells exposed to sunlight. Uroporphyrin overproduction was greatly reduced and skin changes reversed in a girl who received a bone-marrow graft from an HLA-identical sibling at 10 years of age. The patient died 11 months after transplantation because of severe progressive pneumonitis and encephalopathy associated with cytomegalovirus infection. but the encouraging response up to 8 months after engraftment indicates a possible benefit of bone-marrow transplantation in the treatment of this rare but usually fatal inherited disease.
Lyme disease surveillance--United States, 1989-1990, Surveillance for Lyme disease (LD) was initiated by CDC in 1982 (1). and in January 1991. LD became nationally reportable (2). Forty-six states reported cases in 1989 and 1990 (Figure 1). but the occurrence in nature of the causative bacterium. Borrelia burgdorferi. has not been documented in all of these states. From 1982 through 1989. the annual reported number of cases of LD increased 18-fold (from 497 to 8803. respectively) and from 1986 through 1989. nearly doubled each year (Figure 2). The provisional total of 7997 cases for 1990 suggests a plateau in this trend of rapid annual increase. This report summarizes surveillance of LD during 1990 in Connecticut. Georgia. Michigan. Missouri. New Jersey. and Wisconsin.
Shigella dysenteriae type 1--Guatemala, 1991, On March 14. 1991. physicians at a hospital in Guatemala City reported to the Institute of Nutrition of Central America and Panama (INCAP) that a 2-year-old boy living in an orphanage in Guatemala City had been hospitalized with dysentery; stool cultures yielded Shigella dysenteriae type 1. Another child from the orphanage had recently died from dysentery. During March 18-21. two other young children from the orphanage were diagnosed with S. dysenteriae type 1. On March 21. health officials in Rabinal. in the department of Baja Verapaz. reported more than 100 cases of dysentery to the Division of Epidemiology and Disease Control of the Ministry of Health (MOH). This report summarizes the investigation of these outbreaks.
Predictors of event-free survival after balloon aortic valvuloplasty, BACKGROUND. Balloon aortic valvuloplasty was developed as an alternative to aortic-valve replacement in selected elderly patients with aortic stenosis. The use of this procedure is limited. however. by a high incidence of restenosis. METHODS. Between December 1985 and April 1989. valvuloplasty was performed in 205 patients. We evaluated 40 demographic and hemodynamic variables as univariate predictors of event-free survival by Cox regression analysis and identified independent predictors of event-free survival by stepwise multivariate analysis. RESULTS. Early hemodynamic results indicated a decrease in the peak transaortic-valve pressure gradient from 67 +/- 28 to 33 +/- 15 mm Hg after valvuloplasty and an increase in aortic-valve area from 0.6 +/- 0.2 to 0.9 +/- 0.3 cm2 (P less than 0.001 for both comparisons). The rate of event-free survival (defined as survival without recurrent symptoms. repeated valvuloplasty. or aortic-valve replacement) was 18 percent over the mean (+/- SD) follow-up period of 24 +/- 12 months (range. 1 to 47). Significant predictors of event-free survival included the left ventricular ejection fraction and the left ventricular and aortic systolic pressure before valvuloplasty. and the percent reduction in the aortic-valve pressure gradient; the pulmonary-capillary wedge pressure was inversely associated with event-free survival. Although the predicted event-free survival rate for the entire patient group was 50 percent at one year (95 percent confidence interval. 43 to 57 percent) and 25 percent at two years (95 percent confidence interval. 19 to 31 percent). the probability of event-free survival at one year varied between 23 and 65 percent when patients were stratified according to three independent predictors: the aortic systolic pressure. the pulmonary-capillary wedge pressure. and the percent reduction in the peak aortic-valve gradient. CONCLUSIONS. The most important predictors of event-free survival after balloon aortic valvuloplasty were related to base-line left ventricular performance. The best long-term results after valvuloplasty were observed among patients who would also have been expected to have excellent long-term results after aortic-valve replacement.
Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor, The transforming proteins of several DNA tumour viruses. including adenovirus E1a and simian virus 40 large T antigen. complex with the retinoblastoma (Rb) tumour-suppressor gene product. This requires regions in these viral proteins necessary for transformation and is thought to inactivate the growth-suppressing properties of the Rb protein by disrupting its interaction with cellular targets. Indeed. regions of Rb required to form a complex with E1a and large T antigen are often mutated in transformed cells. The level at which the Rb protein regulates proliferation is unknown. although one possibility is transcription. We have previously characterized a sequence-specific transcription factor. DRTF1. the activity of which is downregulated as embryonal carcinoma stem cells differentiate. DRTF1 is found in several discrete protein complexes (a. b and c) which are of different sizes but have the same DNA specificity. We now show that one of these also contains the Rb protein and. further. that the adenovirus E1a protein causes the dissociation of the Rb protein from this complex. This requires conserved regions 1 and 2 of E1a that are known to be required for efficient transformation. These results demonstrate that the Rb protein forms a complex with a DNA-bound transcription factor. and suggests that the Rb protein might act by regulating transcription.
The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests, A cross-sectional survey and subsequent longitudinal study among diabetic residents of Rochester. MN--The Rochester Diabetic Neuropathy Study (RDNS)--is population-based and uses quantitative. validated. and unique end points to detect. classify. and stage neuropathy. Nondiabetic persons. drawn from the same population. serve as controls. For patients 10 to 70 years old. the RDNS cohort is representative of diabetics living in Rochester. MN. We assessed reproducibility of tests used to characterize and quantitate severity of neuropathy in 20 diabetic subjects without neuropathy and with varying severities of neuropathy. Using intraclass correlation coefficient (rI) as a measure of test reproducibility. we found high rI (usually 0.9 or better) with small confidence intervals for the Neurologic Disability Score (NDS); weakness subset of NDS (W-NDS); vibratory and cooling detection thresholds (using computer-assisted sensory examination [CASE] IV); compound muscle action potentials; sensory nerve action potentials; and motor nerve conduction velocities. There was good agreement among three trained observers for NDS and the W-NDS.
Peripheral neuropathy in systemic lupus erythematosus, We studied 33 consecutive patients with systemic lupus erythematosus (SLE) for neuropathy by employing the Neuropathy Symptom Score (NSS). Neurological Disability Score (NDS). EMG and nerve conduction velocity (NCV) studies. and determinations of vibration thresholds (VT). Polyneuropathy defined as NCV abnormalities of two or more nerves occurred in seven patients (21%). Neuropathic symptoms showed a poor correlation with NCV and VT. while clinical neuropathic signs. VT. and NCV correlated with each other in most instances. When reporting frequencies of neuropathy in SLE. NCV studies should be used as a basis. NSS. NDS. and VT give additional quantifiable information and can be useful in the follow-up of patients and for evaluating the response to therapy.
Cerebrovascular complications after orthotopic liver transplantation: a clinicopathologic study, We analyzed 55 autopsy cases in 1.357 patients undergoing orthotopic liver transplantation at the University of Pittsburgh and found that 13 (23.6%) patients had intracranial bleeding. and five (9%) had infarcts. Eight patients had bleeding localized to one intracranial compartment: intracerebral hemorrhage (three patients); subarachnoid hemorrhage (three patients); and subdural hematoma (two patients). Five patients had combinations of multiple sites of bleeding: three with subarachnoid hemorrhage-intracerebral hemorrhage. one with subarachnoid hemorrhage-intracerebral hemorrhage-subdural hematoma. and one with subdural hematoma-intracerebral hemorrhage. Coexistent CNS infections (fungal or bacterial) were associated with hemorrhagic infarcts and intracerebral hemorrhage in four patients. Cerebral embolism and hemorrhagic infarction from bacterial endocarditis occurred in one patient. Five patients died of intracranial bleeding. Severe coagulopathy was the major cause of intracranial bleeding and was associated with systemic bleeding in 12 patients. Significant systemic or metabolic complications were present in all patients and masked the focal signs of the intracranial process in more than one half.
Clinical and electrodiagnostic features of X-linked recessive bulbospinal neuronopathy, We describe four men from two kinships affected with X-linked recessive bulbospinal neuronopathy. and one sporadic case. All developed postural tremor. weakness. and fasciculations. with onset from age 25 to 39 years. Weakness began in the pelvic girdle or hands. with dysphagia or dysarthria occurring years later in two. Sensory symptoms were present in only one. who also had diabetes mellitus. In contrast. sural nerve action potentials were small or absent in all. Needle EMG showed widespread chronic partial denervation with reinnervation. The characteristic twitching of the chin produced by pursing of the lips consisted of repetitive or grouped motor unit discharges. rather than fasciculations. Broader awareness of the distinctive features of bulbospinal neuronopathy will probably increase the frequency of its recognition. Diagnosis is important for purposes of providing a prognosis for affected men and genetic counseling for affected families.
HTLV-I-associated myelopathy endemic in Texas-born residents and isolation of virus from CSF cells, We report three Texas-born patients with spastic paraparesis and well-documented infection with HTLV-I. CSF examination showed moderate pleocytosis. protein elevation. and elevated IgG index. Oligoclonal bands were present in two patients. On MRI. one patient had frontal lobe lesions that were low intensity on T1- and high intensity on T2-weighted images. HTLV-I immunoblot studies of serum and CSF revealed reactivity to p19. p24. p53. gp46. or gp68 from all three patients. Titration studies of serum and CSF antibodies on ELISA and immunoblot assays indicated an intrathecal virus-specific response. HTLV-I-specific p19 antigen capture assay and polymerase chain reaction (PCR) demonstrated HTLV-I in lymphocyte cultures derived from each patient's peripheral blood mononuclear cells (PBMC) or CSF cells. Using HTLV-I- and HTLV-II-specific pol and gag primers. PCR studies of PBMC cells obtained directly from the patients demonstrated that the patients were infected with HTLV-I and not HTLV-II. These three cases are to our knowledge the only US cases in whom virus isolation from the CSF has been accomplished. Importantly. two patients may be the first US cases of myelopathy arising from endemic infection.
Cortical blindness and residual vision: is the "second" visual system in humans capable of more than rudimentary visual perception, We studied 12 patients with static cortical blindness to evaluate residual vision after destruction of area 17 and to assess the visual capacity of the subcortical "second" visual system in humans. In each case. the cause was bilateral infarction of the occipital lobes. Five patients had total blindness. and four had residual rudimentary vision (RRV). characterized by homonymous areas of light perception in the peripheral field and ability to detect moving objects. Only three patients had the ability to read; two of these had spared macular vision. and the other had spared left homonymous hemimaculae and spared temporal crescent. Neuroimaging and visual evoked potentials (VEPs) correlated with the extent of the visual dysfunction. Total destruction of area 17 bilaterally was associated with total permanent visual loss. The larger the amount of spared visual cortex. the better the vision. Positron emission tomography (PET) or single photon emission computed tomography (SPECT) demonstrated retained metabolic activity in islands of preserved area 17 in patients with some residual vision. VEPs were present in totally blind individuals. We conclude that. in humans. useful visual function is preserved only when a critical amount of area 17 is spared. The subcortical second system may participate in the generation of VEPs. but is incapable of conscious visual perception.
Behavioral state-specific changes in human hippocampal theta activity, Although there has been extensive examination of the behavioral and physiologic correlates of hippocampal theta activity in animals. the human literature consists of a single case study. We investigated the differential effects of four behavioral states on human hippocampal theta activity in 16 epilepsy surgery patients. Behavioral conditions included resting eyes closed (RC). resting eyes open (RO). eyes open with auditory word activation (AW). and eyes open with visuospatial activation (VS). Hippocampal theta activity decreased during both RO and VS compared to both RC and AW. There were reciprocal changes in delta activity. Comparisons of RO to VS and of RC to AW were nonsignificant. The results demonstrate state-specific changes in human hippocampal theta and are consistent with the animal literature that relates hippocampal theta to sensorimotor integration and forebrain volitional mechanisms.
An open-label trial of fluoxetine for obsessive-compulsive disorder in Gilles de la Tourette's syndrome, Obsessive-compulsive disorder (OCD) occurs commonly in association with Gilles de la Tourette's syndrome (GTS) and can be a major source of disability. Fluoxetine. a new antidepressant. has been effective for psychiatric patients with OCD. We conducted an open-label trial of fluoxetine (20 to 40 mg/d) for 32 GTS patients with OCD. After 1 week of treatment. six patients (16%) withdrew from the trial due to perceived lack of benefit. Data were analyzed for 26 patients (13 children and 13 adults) who were treated by a neurologist for 3 to 8 months. Following treatment. there was a significant reduction in scores on the Leyton Obsessional Inventory for both the adult and child groups. and 81% of patients reported a subjective improvement in obsessions and compulsions. Since fluoxetine was well tolerated. our findings indicate that the drug may be an effective agent for the treatment of OCD in GTS patients.
Primary progressive aphasia with focal neuronal achromasia, We describe the clinical. radiologic. neuropsychological. and neuropathologic features of a 69-year-old man with a 3-year history of progressive transcortical expressive aphasia. Neuropsychological testing showed progressive dysfunction of expressive language. Neuropathologic examination demonstrated focal cortical degeneration involving the left superior frontal gyrus. with swollen achromasic neurons and no evidence of Alzheimer's disease. Pick's disease. Creutzfeldt-Jakob disease. Lewybody disease. or other dementing disorders. This case adds to the known heterogeneity of the underlying pathology of patients with primary progressive aphasia.
Epidemiologic trends in multiple sclerosis in More and Romsdal, Norway: a prevalence/incidence study in a stable population, The western part of Norway has been a low-to medium-frequency area for multiple sclerosis (MS). The prevalence of definite/probable MS on January 1. 1961. was 24.3/100.000 in the county of More and Romsdal. western Norway. Based on the same diagnostic criteria. the prevalence of definite/probable MS increased to 75.4/100.000 on January 1. 1985. The average annual incidence rate increased from 1.94/100.000 in the period 1950-1954 to 3.78/100.000 from 1975-1979. Remitting MS in the younger age groups of both sexes increased the most. We consider this increase of MS to be due to alteration in exogenous factors as variation in genetic susceptibility cannot account for the increase in the stable western Norwegian population. The rise in prevalence/incidence over the last 20 to 25 years in western Norway supports the theory that MS is a disease influenced by exogenous factors that show variation over time.
Two-tiered DNA-based diagnosis of transthyretin amyloidosis reveals two novel point mutations, We analyzed 11 consecutive unrelated cases of polyneuropathy due to transthyretin amyloidosis. Direct sequencing of the promoter region. exons. and splice junctions revealed that each patient was heterozygous for a mutation: six patients had valine 30 substituted by methionine (V30----M; Portuguese-Japanese type). one had threonine 60 substituted by alanine (T60----A; Appalachian type). and two had serine 77 substituted by tyrosine (S77----Y; Illinois type). In addition. two patients had previously undescribed mutation: phenylalanine 33 substituted by leucine (F33----L) and phenylalanine 64 substituted by leucine (F64----L). From present information. the probands of these novel mutations do not exhibit any pathology that clearly distinguishes them from individuals with the other mutations. The mutations extend the range of mutations associated with amyloidotic polyneuropathy. In our 11 patients. the different mutations did not seem to correlate with distinct clinical phenotypes. We developed PASA assays (PCR amplification of specific alleles) for each of the five mutations. PASA can be used by any diagnostic laboratory that can perform PCR to rapidly detect any of the known mutations. The minority of samples with an undescribed mutation can be sent to a specialty laboratory for delineation of the mutation by direct genomic sequencing. The presently described combination of methods may have widespread utility in the diagnosis of genetic disease.
Alzheimer's disease with delusions and hallucinations: neuropsychological and electroencephalographic correlates, We longitudinally evaluated the neuropsychological functions. rate of progression. and waking EEG findings in 17 patients with probable Alzheimer's disease (AD) with delusions and hallucinations. and compared them with those of matched AD patients without delusions and hallucinations. AD patients with delusions and hallucinations had a more rapid rate of decline. as measured by the Mini-Mental State Examination. a specific defect in receptive language. and a greater frequency of aggression and hostility. Visual EEG analysis showed that these patients had a significantly greater proportion of moderately abnormal EEGs. and spectral analysis confirmed the increased amount of delta and theta activity. These data demonstrate that AD patients with delusions and hallucinations have a greater degree of cerebral dysfunction and a relatively focal neuropsychological defect. which may indicate a localized pathologic abnormality.
Factors influencing outcome of prednisone dose reduction in myasthenia gravis, We reviewed retrospectively 114 prednisone dose reduction attempts in 63 myasthenic patients. Dose reduction was considered successful if a patient remained asymptomatic for more than 1 year on no prednisone or a stable low dose of prednisone. Successful dose reduction attempts were more common in patients taking azathioprine. but thymectomy did not influence taper outcome. Slower rate of dose reduction and higher ending dose of prednisone improved the chance of success.
Repeat thymectomy in chronic refractory myasthenia gravis, Encouraged by recent results with "extended" thymectomy in the treatment of myasthenia gravis. we carried out repeat thymectomy in six patients with chronic. refractory disease who did not initially have extended thymectomy. All were completely disabled with longstanding myasthenia. Initial thymectomy (four transsternal. one transcervical. and one substernal) was carried out at a mean of 8.9 years previously (range. 5 to 18). There was no residual thymus observed with CT. but at repeat thymectomy. residual thymic tissue was present in five of six patients. Five patients significantly improved and four returned to full-time work. Mean prednisone dose declined from 51 mg to 18 mg/d. and mean pyridostigmine dose fell from 1.290 mg to 415 mg/d. No patient to date has had a complete remission. These results suggest that repeat thymectomy may benefit some patients with chronic disabling myasthenia gravis. especially when it is uncertain from a review of the operative report whether all thymic tissue was removed at the initial thymectomy.
Fermentable fibers and vitamin B12 dependency, Addition of the fermentable fiber pectin to a B12-deficient diet accelerates development of deficiency symptoms. This appears to be the result of changes in the intestinal bacteria that bind vitamin B12. interfere with enterohepatic circulation. and accelerate depletion of this vitamin.
The antenatal diagnosis of congenital heart disease using fetal echocardiography: is color flow mapping necessary, Doppler color flow mapping is widely used in fetal echocardiography. We studied the impact of color flow mapping on fetal cardiac diagnosess. Between January 1. 1989 and June 30. 1990. we performed 854 fetal echocardiograms on 776 fetuses. Color flow mapping was used in 45 of 48 fetuses diagnosed as having cardiac abnormalities. Scans were reviewed to assess how color flow mapping influenced the ultimate diagnoses. Color flow mapping was essential to the correct anatomical diagnoses in 13 fetuses (29%). helpful but not essential in 21 (47%). and added little to two-dimensional examination alone in 11 (24%). It was essential in determining the course and flow direction in the great vessels when outflow obstruction was present or with transposition. and it was helpful but not essential in locating small jets of atrioventricular valve regurgitation. It was not helpful when the anatomical abnormalities were clearly identified from two-dimensional examination alone. We conclude that color flow mapping is helpful in the delineation of anatomical diagnoses in three-quarters of cases of fetal heart disease. particularly when the great vessels are abnormal. It may speed examinations by directing pulsed Doppler sampling. We did not find it essential to the proper recognition of anatomically abnormal hearts.
Adverse infant outcomes associated with first-trimester vaginal bleeding, We assessed the association between first-trimester vaginal bleeding and singleton infant outcomes in a hospital-based population of 11.444 nondiabetic women. Low birth weight (LBW). shortened gestation. LBW at term. and neonatal death occurred more often in women reporting first-trimester bleeding than in those who never bled. These relationships remained statistically significant after adjusting for confounding factors. Women who experienced vaginal bleeding limited to the first trimester (N = 1174) had double the risk of delivering a preterm infant compared with those experiencing no bleeding (adjusted risk ratio = 2.0; 95% confidence interval 1.6-2.5). Bleeding limited to the first trimester was associated with a 1.6-fold risk of delivery of a term LBW infant (95% confidence interval 1.3-2.0). These results suggest that first-trimester vaginal bleeding is an important correlate of adverse infant outcomes.
Comparison of direct insertion of disposable and standard reusable laparoscopic trocars and previous pneumoperitoneum with Veress needle, A randomized prospective study was conducted to evaluate the ease of use and safety of direct insertion of laparoscopic trocars. Comparison of previous pneumoperitoneum by Veress needle insertion with direct insertion of the reusable conventional laparoscopic trocar and direct insertion of the disposable shielded trocar revealed minor complication rates of 22. 6 and 0%. respectively. No major complications occurred in this series of 200 patients.
A shoulder dystocia intervention form, The absence of a detailed note describing the maneuvers used to resolve shoulder dystocia often results in an inconsistent and counterproductive representation of the facts. Such a note should include exact times of events. a description of the maneuvers used. and an estimation of the traction forces exerted.
Sequential outpatient application of intravaginal prostaglandin E2 gel in the management of postdates pregnancies, A randomized blinded investigation was undertaken to determine the efficacy and safety of sequentially applied intravaginal prostaglandin E2 (PGE2) gel for accelerating cervical ripening in an outpatient setting in low-risk prolonged pregnancies. Fifty women with uncomplicated pregnancies at or beyond 41 weeks' gestation and Bishop scores below 9 received twice-weekly outpatient administration of gel containing 2.0 mg of PGE2 or placebo. Thirty nulliparas and 20 multiparas were enrolled. The PGE2 gel failed to improve cervical ripening over placebo. as judged by Bishop scores. There was no difference between the groups in gestational age on admission to the labor and delivery suite. number of gel applications. requirement for oxytocin. incidence of cesarean delivery. or neonatal outcome. Only two patients (4%) experienced regular uterine contractions after gel insertion; these subsided spontaneously in both. None of the subjects experienced labor. tetanic contractions. evidence of fetal distress. or any other side effects related to gel insertion. We conclude that PGE2 gel in this dosage may be used safely in an outpatient setting. but more frequent application or earlier initiation may be required to produce a clinical effect.
Complement activation in relation to development of preeclampsia, Six hundred eighty-five primigravidas followed as a series had complement activation evaluated by the formation of anaphylatoxins (C3a and C5a) and terminal C5b-9 complement complexes in venous blood. Samples for complement determinations were obtained four times during pregnancy. in pregnancy weeks 12-16. 20-24. 28-32. and 34-36. Seven of the women developed preeclampsia and one of them the syndrome of hemolysis. elevated liver enzymes. and low platelet count (HELLP syndrome). Eleven others with uncomplicated pregnancies were selected as a control group. Plasma samples were taken from these 18 women at delivery and 1 and 7 days after delivery. At delivery. plasma C5a levels were significantly greater in the preeclamptics than in controls. and four of the seven preeclamptics had elevated plasma C3a values compared with controls. One week after delivery. these plasma anaphylatoxins had returned to normal. Elevations of the anaphylatoxins could not be detected before the women developed clinical signs of preeclampsia. No alterations in terminal C5b-9 complement complexes could be observed in the women with preeclampsia. However. the women who developed HELLP syndrome had elevated plasma concentrations of C3a. C5a. and terminal C5b-9 complement complex at delivery. These values returned to the normal range 1 week after delivery. We conclude that complement activation in the systemic circulation does not occur early in pregnancy and that plasma concentrations of C3a. C5a. or terminal C5b-9 complement complex cannot be used as predictors of preeclampsia.
Radical hysterectomy morbidity in relation to age, The complications of radical hysterectomy in patients 65 years and older were compared with those in women younger than 65. There was no statistical difference in complication rates between the two groups. although the older women had a significantly higher incidence of preoperative medical problems. No surgical deaths occurred in either group. Our data indicate that selected older women can tolerate radical hysterectomy as well as younger ones.
Pattern of treatment failure following laser for cervical intraepithelial neoplasia: implications for follow-up protocol, In an effort to devise a rational protocol for the follow-up of patients who have had destructive treatment for cervical intraepithelial neoplasia (CIN). an analysis has been performed of treatment failures following laser therapy in 2130 women treated between 1980-1989. Of this group. 1253 women have been followed up for 3 years or more and 380 for 6 years or more. There have been 119 treatment failures (5.6%). of which 71% of the women had the second lesion detected during the first year of follow-up. 24% during the second year. 3.3% during the third year. and 1.7% during the sixth year. In 18% of these 119. the second lesion was detected colposcopically in the presence of negative cytology. There were two cases of microinvasion and one frankly invasive lesion following laser. all diagnosed during the second year of follow-up. Our data suggest that if the first year of follow-up includes at least one colposcopic examination. some second lesions will be diagnosed in the presence of negative cytology.
A randomized, double-blind, placebo-controlled, cross-over trial to assess the side effects of medroxyprogesterone acetate in hormone replacement therapy, Cyclic progestin therapy has been widely advocated as an adjunct to postmenopausal estrogen replacement therapy to reduce the risk of endometrial carcinoma. Acceptance of this approach. however. appears to have preceded detailed evaluation of possible adverse side effects of progestins that could result in patient noncompliance. We evaluated the nonmenstrual physical and psychological side effects of oral medroxyprogesterone acetate given in conjunction with transdermal estrogen in two groups of women with previous hysterectomy and oophorectomy. Twenty-four women with prospectively documented severe premenstrual syndrome (PMS) before surgery and 24 women with no such history of adverse premenstrual changes received transdermal estrogen 100 micrograms on days 1-25 and either oral medroxyprogesterone acetate 10 mg daily or an identical placebo (days 12-25) in a randomized. double-blind. cross-over design. Mood and physical symptoms were monitored prospectively. using daily self-ratings on the Daily Symptoms Checklist. The Beck Depression Inventory and Premenstrual Tension Self-Rating Scale were completed on day 24. At the study's completion. the patients were asked which treatment period they preferred. Paired comparisons did not reveal any significant differences. and preference for treatment was equally divided between medroxyprogesterone acetate and placebo. We conclude that addition of medroxyprogesterone acetate 10 mg/day for 14 days to cyclic transdermal estrogen therapy (days 1-25) produces no consistent adverse physical or psychological effects on women for one cycle of treatment. regardless of their PMS history.
Comparison of the effects of two viscoelastic agents, Healon and Viscoat, on postoperative intraocular pressure after penetrating keratoplasty, Sixty-two patients undergoing penetrating keratoplasty were randomized to receive Healon (1% sodium hyaluronate) or Viscoat (3% sodium hyaluronate and 4% chondroitin sulfate) as a means of maintaining the anterior chamber during surgery. Neither viscoelastic agent was irrigated from the eye at the end of the procedure. Intraocular pressures (IOPs) were measured at 4. 10. 24. and 72 hours postoperatively. For the Healon group. IOPs were 16.52. 23.50. 28.31. 23.27. and 16.03 mm Hg at baseline and at the four follow-up periods. respectively. For the Viscoat group. they were 19.10. 28.33. 23.48. 18.62. and 16.17 mm Hg at those points. respectively. IOPs were significantly elevated over baseline in the Healon group at 4. 10. and 24 hours. and in the Viscoat group at 4 and 10 hours. There were no statistically significant differences between the Healon and Viscoat groups at 4. 10. and 72 hours. At 24 hours. the Healon group had a mean pressure rise over baseline of 6.5 mm Hg. while the Viscoat group had returned to baseline levels (P = .02). We conclude that both Healon and Viscoat raise postoperative IOPs. but that Healon appears to elevate IOPs for a longer period after surgery than Viscoat.
Intraocular gas injection in the treatment of cornea-lens touch and choroidal effusion following fistulizing surgery, Five eyes with large choroidal detachments and flat anterior chambers following fistulizing surgery were treated with injection of perfluoropropane into the anterior chamber. In all cases the choroidal detachments resolved within 4 days. without the need for drainage. Three phakic eyes developed anterior capsular opacification in the area of contact between the gas bubble and the anterior capsule. Injection of perfluoropropane is recommended as a simple and effective approach to the management of choroidal detachments with flat anterior chamber in pseudophakic eyes and in cataractous phakic eyes.
Quantitative CW Nd:YAG pars plana transscleral photocoagulation in postmortem eyes, The effect of different types of burns and numbers of lesions on. and the role of initial pressure head in. the rate of aqueous outflow was studied in enucleated human and porcine eyes. Noncontact and contact CW Nd:YAG laser applied to human eyes 3 mm posterior to the limbus produced a 34% and 51% increase. respectively. in outflow as compared with controls (P = .01). In porcine eyes. outflow increased directly with the number of noncontact burns as well as with the amount of perfusion pressure. Our results suggest that intraocular pressure and outflow are functions of both the intensity of irradiation and the surface area treated. and that each individual pressure head may require an optimal pars plana area of treatment of therapeutic degree to lower pressure and yet prevent overfiltration and phthisis. Our results also suggest that there may be a passive transneuroepithelial and transscleral outflow component in clinical laser cycloablation and. therefore. a need to grade laser treatments in order to prevent visual loss through unnecessary injury.
Iontophoresis for eyelid anesthesia, Local anesthesia is appropriate for eyelid surgery. but patients fear the pain of injections. We evaluated iontophoresis of lidocaine for eyelid skin anesthesia to pinprick pain sensation in normal subjects. and prior to regional infiltration of the anesthetic agent in patients undergoing eyelid surgery. After iontophoresis of lidocaine hydrochloride 4% solution to one randomly chosen eyelid. pinprick skin sensation was tested in a double-masked manner. Subjective pain scores of 10 subjects were significantly less (P less than .008) on the iontophoresis treated eyelids (0.25) than on the untreated eyelids (2.55). Nine patients undergoing bilateral upper eyelid surgery had iontophoresis applied to one randomly chosen eyelid prior to the usual anesthetic injections. In this double-masked evaluation. patients reported significantly less pain (P less than .02) on the treated eyelids (1.4) than on the untreated eyelids (4.7). We conclude that iontophoresis is effective for achieving short-term. superficial anesthesia of eyelid skin.
Scleral fixation suture for dislocated posterior chamber intraocular lens, The posterior dislocation of an intraocular lens is a serious complication of extracapsular cataract extraction with implantation of a posterior chamber intraocular lens. We describe a method of repositioning and suturing such a lens. using pars plana techniques. The method we recommend has several advantages over previously described methods. including the use of radially oriented scleral fixation sutures.
Dental management of the patient with major depression, Major depression is a psychiatric disorder in which mood. thought content. and behavioral patterns are impaired for long periods of time. It is a common disorder. with an increasing prevalence among young adults. It may be associated with a disinterest in performing appropriate preventive oral hygiene techniques. a cariogenic diet. diminished salivary flow. rampant dental decay. advanced periodontal disease. and oral dysesthesias. Many medications used to treat the disease magnify the xerostomia and increase the incidence of dental disease. Appropriate dental management necessitates a vigorous preventive dental education program. the use of saliva substitutes and anticaries agents containing fluoride. and special precautions when prescribing or administering analgesics and local anesthetics.
Clinical, radiographic, and histologic study of endodontic treatment failures, One hundred fifty cases of endodontic treatment failures were studied clinically. radiographically. and histologically. Fifty-seven percent of the teeth were asymptomatic. Pain alone and/or associated with swelling was present in 21% of the teeth. There was no correlation between the size of periradicular rarefaction and the occurrence or severity of clinical signs and/or symptoms. Stainable bacteria were demonstrated in 69% of the teeth and were present mostly in the canal. The severity of periradicular inflammation was related to presence of stainable bacteria in the canal. Swelling and pain or a draining sinus tract was often associated with stainable bacteria inside the canal. The development of a radicular cyst associated with an endodontically treated tooth that has failed is not necessarily the cause of endodontic treatment failure.
Healing of periapical radiolucencies after nonsurgical endodontic therapy, Eighty-nine periapical radiolucencies treated by nonsurgical endodontic therapy were evaluated to better understand the healing rates of these lesions. After at least 3 months after treatment. radiographs revealed that 46.1% of the lesions had resolved. 48.3% had undergone partial resolution. 2.2% were unchanged. and 3.4% were larger. The average radiographic rate of repair was 3.2 mm2/mo. Less than 6 months after treatment. 17.6% of lesions demonstrated complete radiographic resolution. whereas 70.6% showed radiographic resolution at 12 months or longer.
Magnetic resonance imaging of canine salivary glands after ductal ligation and stimulation by pilocarpine, We performed magnetic resonance imaging in six dogs after submandibular ductal ligation on one side. followed by secretory stimulation with intraperitoneal injection of pilocarpine (5 mg/kg). On the images obtained after ductal ligation but before stimulation. there was no significant change in signal intensity on either side. After injection of pilocarpine the signal intensity of the ligated gland increased significantly (p less than 0.01) in T2-weighted images and nonsignificantly in inversion recovery images. and remained constant in T1-weighted images. Significant (p less than 0.01) volume increases of the glands after ligation and stimulation were measured for the T1. T2. and inversion recovery protocols. These findings likely reflect the retention of saliva caused by pilocarpine stimulation and the absence of drainage through the obstructed duct. The results indicate that the T2-weighted images obtained after pilocarpine stimulation may be useful for studying patients with disturbance of major salivary gland function and may provide an objective basis for the noninvasive diagnosis of unilateral stenosis.
Lyme disease. Difficulties in diagnosis and management [published erratum appears in Pediatr Clin North Am 1991 Oct;38(5):viii, LB is a multisystem illness caused by the spirochete B. burgdorferi. As with other spirochetal diseases. LB evolves in stages. Some manifestations are the result of persistent infection. whereas other symptoms are a consequence of immunologic changes secondary to the infection. Most disease manifestations are not specific to this illness. In addition. in endemic areas. almost 100% of the tick vector. the Ixodes species. are infected and the incidence rate of LB is as high as 1%. Because of these factors. the illness is overdiagnosed and overtreated. We have reviewed the current state of diagnosis and treatment of LB as well as questions that arise during the management of this illness.
Diagnostic dilemmas. Results of screening tests for congenital hypothyroidism, The natural history of congenital hypothyroidism has changed drastically since the institution of newborn screening in North America. Europe. and Japan. Before screening was available. diagnosis of this condition was often delayed. The IQ of 65% of all patients with congenital hypothyroidism was below 85. and 19% were profoundly retarded (IQ less than 15). In two large screening programs in which long-term IQ data are available. no child has tested below the IQ of 74. Furthermore. a comparison of affected children treated within the first month of life with matched controls demonstrated no significant difference in IQ scores between the two groups. Widespread screening has lead to the evaluation of over 7 million infants annually. This represents over 1200 fewer children with subnormal intelligence. and approximately 360 children annually who are saved from the effects of profound mental retardation. There is little doubt that newborn screening is one of the greatest advances in diagnosis and treatment of endocrine disease in the newborn period to occur in the past 20 years. However. even experienced screening programs are not perfect. so the practitioner must remain alert to the possibility of undiagnosed hypothyroidism presenting in infancy.
Diagnostic dilemma. The goiter, The incidence of goiters in children is about 4% to 5%. The first step in the evaluation is to decide whether the swelling indeed involves the thyroid. After careful examination. one determines if the thyroid is diffusely or focally enlarged. A solitary nodule merits an extensive workup because of the high rate of malignancy. The evaluation of a diffuse goiter proceeds after deciding if the patient is euthyroid. hypothyroid. or hyperthyroid. In most cases. the child is euthyroid and the diagnosis is either CLT or simple colloid goiter. Laboratory tests for thyroid function and antibodies usually make the diagnosis. The hypothyroid patient most likely has CLT. although drugs or goitrogens. dyshormonogenesis. and thyroid resistance are also possible. The hyperthyroid patient usually has Graves' disease. The incidence of malignancy of solitary thyroid nodules is 15% to 40%; therefore. evaluation must be sensitive enough not to miss cancer. Ultrasonography helps to delineate the anatomy and to reveal if the nodule is cystic. Radionuclide scans are useful. as warm or hot lesions are rarely malignant. Cold nodules require further investigation. and in most institutions. this amounts to open biopsy. Fine-needle aspiration may be used if the clinician and pathologist are experienced. With this aggressive approach to thyroid nodules. malignancies are given early treatment. The prognosis is good in most thyroid carcinomas.
An approach to the evaluation and treatment of microscopic hematuria, Persistent microscopic hematuria in children is most often benign or untreatable. The evaluation of microscopic hematuria in an otherwise healthy child need not require invasive and costly laboratory studies. The initial evaluation must look for signs of life-threatening causes of hematuria. i.e.. hypertension. edema. oliguria. or significant proteinuria. If these are absent. a stepwise evaluation is suggested. which includes microscopic examination of the urine for red blood cell casts. a test for proteinuria. serum creatinine. and serial follow-up. Renal biopsy may establish a diagnosis but rarely changes the treatment in a child with asymptomatic isolated microscopic hematuria.
Chemotherapy update, The administration of chemotherapy is one of the major forms of cancer treatment. Recent progress in the use of chemotherapeutic agents has evolved from an understanding of the basic mechanisms of tumor cell kinetics and the molecular and biochemical basis for individual and multidrug resistance patterns. These advances have led to the development of novel approaches to the administration of cancer chemotherapeutic agents. Nurses must remain knowledgeable about these concepts to understand the mechanisms underlying the administration of various combinations of cancer chemotherapy.
Update on antimicrobial agents, A variety of antimicrobial agents are currently in use to treat bacterial. fungal. and viral infections. Pharmacologic and microbiologic properties unique to the classes of drugs are reviewed in this article. Home parenteral antibiotics are an acceptable and efficacious way to treat certain infections and may lead to shorter hospitalizations. Knowledge of general drug characteristics. indications. and toxicities will help the nurse to manage effectively the patient receiving antimicrobial therapy.
Pharmacologic treatment of heart failure, An increased understanding of the pathophysiologic changes underlying CHF. advanced monitoring technology. and a wider array of drug therapy have improved the prognosis of patients with this disorder. These advances allow for greater individualization of therapy. improve patient compliance. and lower the incidence of undesirable side effects. Of course. with the increase in complexity of treatment choices comes the need for more knowledgeable practitioners who can select the most appropriate therapeutic approach. All practitioners also must make every effort to educate the patients about their disease. treatments. and necessary lifestyle changes so that optimal benefits can be realized.
Multiple drug therapy in the treatment of essential hypertension, Treatment for high blood pressure is aimed to prevent the excess morbidity and mortality associated with hypertension by reducing the blood pressure to acceptable levels and by improving the cardiovascular risk status. Antihypertensive medications can be selected that not only reduce blood pressure but also have beneficial effects in concomitant illness and neutral or positive effects on other cardiovascular risk factors. Multiple drug therapy offers not only the possibility of greater therapeutic efficacy than that achieved with single agents but also the possibility of reduced incidence of side effects through complementary actions. The antihypertensive regimen should be simple and acceptable to the patient to promote compliance. Nurses. along with physicians. have an integral role in the long-term management of hypertensive patients through education. counsel. and follow-up for blood pressure control and health promotion.
Pain management, Patients with pain are not a new phenomena. For centuries. the incidence of pain has been well-documented. Responsibility for pain management has not been a universal priority for health care providers; however. pain management must be considered an integral part of the nursing role. The health care system must facilitate the improved management of patient's pain. A better understanding of the factors that underpin the effective management of a patient's pain is necessary. In this article. the theoretical foundation and conceptual model used in the expansion of this knowledge is presented. Further. the physiologic and pharmacologic principles related to this patient care issue are discussed. Appropriate consideration of the nurse's significant part in the management of pain is emphasized.
Joint and systemic distribution of dialysis amyloid, Deposition of beta 2-microglobulin amyloid in the joints of dialysis patients is common and begins early in the course of treatment. but its pathogenic significance in the production of dialysis arthropathy is uncertain. The joints (hip. knee. shoulder. elbow. wrist. cervical and lumbar spine. sacroiliac joint) and systemic tissues of 19 autopsied patients who had undergone haemodialysis for between 6 and 231 months were examined histopathologically for the presence of beta 2-microglobulin amyloid; it was present in all joints examined. including those unassociated with radiological changes and those of patients who had been on haemodialysis alone for only 24 months. Osteoarticular beta 2-microglobulin amyloid deposits were also found in patients who had been treated mainly by continuous ambulatory peritoneal dialysis. Systemic amyloid deposition was only seen in patients who had been haemodialysed for more than 13 years and consisted of sparse tiny deposits in blood vessel walls.
Changing patterns in presentation and management of the Zollinger-Ellison syndrome in Northern Ireland, 1970-1988, The clinical features. diagnostic methods. management and survival in 16 cases of Zollinger-Ellison syndrome encountered in Northern Ireland between the years 1970 and 1988 are described. While the majority of patients in the first decade of the study period had surgical treatment. those presenting in the latter period have been managed with medical therapy in the form of H2-receptor antagonists or omeprazole. The increasing use of these agents seems to be altering the severe clinical features of this condition. reducing the indications for surgery and maintaining patients. with or without evidence of metastatic disease. in clinical remission.
The initial electrocardiogram in patients seen by a mobile coronary care unit, The advent of thrombolytic therapy for patients with suspected acute myocardial infarction has highlighted the importance of the initial electrocardiogram (ECG) in decision making. Thus we analysed the initial ECGs of 94 consecutive cases with suspected myocardial infarction who were seen within six hours after the onset of chest pain by a mobile coronary care unit. The study included 91 patients (three patients admitted twice) (61 male). aged 27-83 years (mean 60.5). Median time from onset of chest pain to arrival of the mobile coronary care unit was 75 minutes (range 15-345). and mean mobile coronary care unit response time was 12.3 +/- 7 (SD) minutes (range 5-45). The majority of cases (65 of 94. 69.1 per cent) were seen within two hours of the onset of symptoms. A final diagnosis of myocardial infarction was made in 48 of 94 (51.1 per cent) cases; 38 had unstable angina and eight other diagnoses. Of the 48 with myocardial infarction the initial ECG showed ST segment elevation in 37. ST depression and or T wave inversion in six. Q waves only in three and left bundle branch block in two. No patient with an initially normal ECG had a myocardial infarction. Thrombolytic therapy was given out of hospital to 33 of 38 patients with ST segment elevation. In seven patients with ST elevation (median delay time to intensive care 60 minutes). rapid resolution of ST segment elevation occurred following thrombolytic therapy and there was no significant elevation of cardiac enzymes. suggesting that the infarct had been aborted.
Pseudohypoparathyroidism: its phenotypic variability and associated disorders in a large family, Pseudohypoparathyroidism is a complex disorder of renal resistance to parathyroid hormone the mechanism of which is unclear. It is often associated with skeletal abnormalities and there may also be other hormonal defects. This is an extensive endocrinological investigation of five of six affected members in two generations of one family. The phenotypic variability of the syndrome is explored: four members had hypothyroidism; two had abnormal gonadal function; all five had abnormal prolactin response to TRH; one had abnormal hepatic response to glucagon infusion. All had normal hypothalamic-pituitary-adrenal axes. renal responsiveness to vasopressin and growth hormone responses to a variety of stimuli. Special note is made of oral pathology. and evidence of platelet aggregation abnormalities is presented which has not previously been described in the syndrome.
Microbiology and diagnosis of infections with Shigella and enteroinvasive Escherichia coli, The etiology of dysentery in Thailand and the existing methods of diagnosing infections with Shigella and enteroinvasive Escherichia coli (EIEC) are reviewed. The four Shigella species (S. dysenteriae. S. flexneri. S. boydii. and S. sonnei) are classically identified by culture of fecal specimens on selective media and testing of isolates for agglutination in species-specific antisera. DNA probes have been used to identify both lactose-fermenting and non-lactose-fermenting EIEC as well as Shigella isolates that do not agglutinate in antisera. These DNA probes are not necessary for the identification of Shigella if a competent bacteriology laboratory with shigella antisera is available. In Thailand Shigella and EIEC are isolated more often from children greater than 2 years of age than from younger children. The clinical illness associated with EIEC infections is similar to shigellosis. Fewer children with EIEC infections than with shigellosis. however. have occult blood in stool (36% vs. 82%) and more than 10 fecal leukocytes per high-power field (36% vs. 67%). Standard bacteriologic methods and testing of E. coli isolates for hybridization with the shigella/EIEC probe are currently the most sensitive means of diagnosing infections caused by these enteric pathogens. A more rapid method of identifying Shigella and EIEC infections in a situation where a bacteriology laboratory is not available will probably involve immunologic assays.
Shigellosis in Vietnam: seroepidemiologic studies with use of lipopolysaccharide antigens in enzyme immunoassays, The performance of enzyme immunoassays (EIAs) with use of O-antigen-containing lipopolysaccharides (LPSs) extracted with phenol-water from Shigella dysenteriae type 1. Shigella flexneri serotypes 1a-5b. and Shigella sonnei for determination of the serum antibody responses after onset of bacillary dysentery is reviewed. For the purpose of several studies. serum samples from a total of 175 Vietnamese and 47 Swedish patients. for whom Shigella species had been isolated from fecal specimens. were obtained at various intervals until less than or equal to 1 year after the onset of infection. Titers of antibodies in serum samples from infected patients were compared with those in serum samples from healthy control subjects; the combined control population of all studies comprised 426 Vietnamese and 154 Swedes. The sensitivity of the EIAs ranged from 78% to 100% for patients whose fecal culture was positive for Shigella. For diagnosis of S. flexneri. a species-specific but no serotype-specific assay based on LPS antigens is possible. Among Vietnamese patients the EIA with use of S. flexneri was sensitive and diagnostic only for children less than 3 years of age. most likely because healthy older Vietnamese children and adults have high titers of antibody to the O-antigens of S. flexneri. Among Swedish patients the same EIA was diagnostic for adults as well as children. Increased titers of IgA in the early phase and of IgG in the convalescent phase. as determined by EIA. were the best indicators of infection due to Shigella species.
Folk terminology for diarrhea in rural Bangladesh, Diarrhea. a descriptive term used in medical science for a variety of clinical diseases. denotes an illness that is categorized differently and known by numerous terms in various cultures. These diversified classifications and terminologies are based on the symptoms of diarrheal disorders. their perceived etiology. and their treatment. In Bangladesh. four types of illnesses with names derived from folk terminology have been identified for which the clinical symptoms resemble those of diarrhea. These include dud haga. which is due to ingestion of breast milk by infants; ajirno. which is due to overeating; amasha. a mucoid diarrhea; and daeria. which is severe watery diarrhea or cholera. Use of the word diarrhea in epidemiologic evaluations was discovered to be problematic; people confused this term with daeria. which accounted for only 5% of all episodes of diarrhea. The implications of such epidemiologic information for a large-scale program of oral rehydration therapy are also discussed.
The role of behavioral research in the prevention and management of invasive diarrheas, Reduction in the prevalence of invasive diarrheal diseases can be facilitated by the development of models for systematic examination of behavioral risk factors that are associated with these illnesses. These factors include insufficient use of health care services. noncompliance with treatment. unhygienic behaviors. employment of poor feeding practices for infants and young children. and inappropriate handling of foods. Information on conditions that facilitate or constrain appropriate behaviors will assist the development of programs for the prevention and management of invasive diarrheas.
The use of soap and water in two Bangladeshi communities: implications for the transmission of diarrhea, Efforts to reduce the incidence of diarrheal infections in which enteropathogens are endemic have focused on education about the importance of hand washing to interrupt transmission of such organisms. Since the effectiveness of health education depends on an understanding of the recipients' ideas and customs. we studied perceptions of cleanliness and the role of soap and hand washing in two poor Bangladeshi communities. one rural and one urban. We found that ideas about cleanliness generally are not based on germ theory; cleanliness is viewed in a larger. socioreligious context of purity vs. impurity. Washing serves both physical and spiritual needs and is performed according to defined patterns that may not effectively interrupt transmission of microorganisms. Soap is regarded as a cosmetic rather than an agent for removal of microorganisms.
Use of social science research to improve epidemiologic studies of and interventions for diarrhea and dysentery, The significance of dysentery has not been recognized in community-based programs for the management of diarrhea. Culturally sensitive methods of classification and algorithms for treatment of these diseases must be developed. Considered in this article is the manner in which ethnographic studies of diarrhea can contribute to descriptive epidemiologic data on diarrhea and dysentery and to procedures of health education and evaluation of interventions for the diseases. Indigenous terms for bloody diarrhea exist in many cultures. Local use of such terms must be carefully examined before they are incorporated in health education efforts and epidemiologic surveillance programs.
Social and behavioral factors in transmission and response to shigellosis, Biomedical approaches to shigellosis tend to emphasize unique etiologic and clinical features of the disease. e.g.. those related to the development of vaccines or case management. The biologic characteristics of the organism and sociocultural responses to it imply that it is unlikely that a purely technologic solution (vaccine) to shigellosis will be found soon. Infrastructural development (protected water supply and sanitary disposal of feces) may be too expensive to be feasible due to the economic. environmental. and demographic conditions in developing countries. Behavioral change to reduce the risk of transmission may be a more effective preventive strategy. Case management in developing countries will require prompt. appropriate action when symptoms of shigellosis occur. A general model of health-seeking behavior suggests patients' parents or guardians (anyone responsible for care of the child and for overseeing the child's health. e.g.. older siblings or grandparents) will take no action if the symptoms are not recognized or are perceived as normal or if the condition is not evaluated as serious or treatable. It is not necessary for patients' parents or guardians to learn about etiologic models from medical practitioners to behave in ways that will reduce the risk of infection or to seek effective treatment. For example. hand washing may be promoted on the basis of symbolism. Agreement between potential patients or their guardians and health care providers on signs of potentially severe disease may be enough to bring them into effective contact.
The lipopolysaccharide of Shigella bacteria as a virulence factor, The virulence factors of the lipopolysaccharide of Shigella species bacteria include the endotoxic activities of the lipid A component of the molecule and the ability of the polysaccharide chain--the core and the O-antigenic polysaccharide--to provide the bacterium with resistance to host defense mechanisms such as opsonization. phagocytosis. and intracellular killing. Structural features of the lipopolysaccharides of four Shigella species-S. dysenteriae. S. flexneri. S. boydii. and S. sonnei--are described.
Genetic and molecular basis of epithelial cell invasion by Shigella species, Bacteria that belong to the four species of the genus Shigella cause a dysenteric syndrome by means of their unique capacity to invade the human colonic mucosa. The various steps of invasion of epithelial cells are controlled by a 220-kilobase plasmid. Plasmid genes that encode for entry into cells through bacterium-directed phagocytosis have been identified. Among these. ipa genes encode four highly immunogenic polypeptides. The ability of intracellular bacteria to multiply subsequently in an efficient manner is attributable to their capacity to lyse phagocytic membrane with a plasmid-encoded contact hemolysin that also determines bacterial entry capacity. In a further step. bacteria that lie free within the cytosol spread intracellularly and infect adjacent cells by inducing rapid polymerization of actin or accumulation of actin. Another plasmid gene. icsA (virG). that encodes a 120-kDa outer-membrane protein accounts for this phenotype. Finally. intracellular shigellae kill host cells rapidly by means of an unknown mechanism that does not seem to involve production of Shiga toxin or Shiga-like toxin. The invasion genes are controlled by both positive and negative regulatory systems.
Shiga toxin: intestinal cell receptors and pathophysiology of enterotoxic effects, Shiga toxin is enterotoxic in rabbit small bowel and binds to the microvillus membrane (MVM). The toxin exhibits specificity for glycolipids possessing a terminal gal-alpha 1----4gal disaccharide. including the neutral glycolipid Gb3 in MVM. Gb3. which is developmentally regulated in the rabbit small bowel. is present in very low concentration until the animals reach day 16 of life. In older animals an increase in Gb3 content is paralleled by an increase in the ability of MVM to bind toxin. which also correlates with the fluid secretion response. Shiga toxin selectively binds to villus cells. which contain Gb3. and not to crypt cells. which do not express Gb3. Targeting of the villus cell by the toxin is consistent with physiologic studies that demonstrate inhibition of villus cell Na+ absorptive pathways. with no effect on crypt cell Cl- secretory mechanisms. These effects are sufficient to account for the enterotoxicity of Shiga toxin in the rabbit model.
Morphology of rectal mucosa of patients with shigellosis, Biopsy specimens of rectal mucosa from 46 consecutive patients with dysentery. from whom shigellae were isolated. were examined. On examination it appeared that the specialized epithelial cells overlying lymphoid follicles were the first to be damaged. and subsequently a vascular lesion led to detachment of epithelial cells. The vascular lesion was widespread in the lamina propria mucosae. Extensive ulceration was associated with invasion of epithelial cells by the organism. There was marked depletion of mucus and an increase in mitotic activity in the crypts. Abscesses of the crypts were rare. The only difference between patients from whom the Shiga bacillus was isolated and patients from whom other shigellae were isolated was a higher prevalence of epithelial cell detachment and luminal exudate. In patients who had been ill for greater than 1 week. cell damage of the crypts was associated with cell-mediated cytolysis. a release of cytotoxic substances from eosinophils and mast cells. and relative vascular insufficiency. all of which may contribute to persistence of dysentery.
Antimicrobial therapy for shigellosis, In controlled clinical trials. which were first performed with use of the sulfonamides. antimicrobial agents have been shown to shorten the duration of symptoms and lessen the excretion of pathogens during episodes of shigellosis. Not all antimicrobial agents that are active in vitro against Shigella are effective in vivo. and efficacy of an agent can only be assessed by properly conducted clinical trials. Resistance to both ampicillin and trimethoprim-sulfamethoxazole. the drugs of choice for the treatment of shigellosis. is now common among Shigella dysenteriae type I isolates in Africa and Asia and is increasing among isolates of other Shigella species. including Shigella sonnei in the United States. Nalidixic acid. the newer quinolones. and amnidocillin pivoxil are additional agents that have been found to be effective in controlled clinical trials. There is a need. however. for more data on the safety of the quinolones before they can be routinely administered to children. Newer agents that deserve evaluation include the orally administered to children. Newer agents that deserve evaluation include the orally administered second- and third-generation cephalosporins. which are highly active in vitro against most strains of Shigella.
Response to antimicrobial therapy for shigellosis in Thailand, Shigella species have been one of the most common causes of acute diarrhea in Bangkok. Thailand. The incidence of shigellosis increased steadily from 1984 to 1988. The majority of Shigella species isolated from specimens from patients with acute diarrhea in Bangkok in 1988 were resistant to both ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ). Shigella flexneri was the most commonly isolated organism and had the highest rate of resistance to ampicillin. chloramphenicol. TMP-SMZ. and tetracycline. The antimicrobial agents of choice for the treatment of shigellosis have been changed from ampicillin to TMP-SMZ and recently to the fluoroquinolones. We conducted a controlled study of norfloxacin that revealed its efficacy for eradication of Shigella species from the stool of both adults and children. The fluoroquinolones shorten the course of diarrhea. reduce the shedding of the organism. and prevent the spread of infection. No short-term adverse effects of the quinolones were observed in this study; however. its use among children should be restricted to treatment of severe shigellosis and the duration of treatment should be as short as possible.
Current practices for treatment of dysentery in rural Bangladesh, A rural area of Bangladesh with a population of 191.000 had 643 health care providers. of whom 324 (50%) practiced allopathic (Western) medicine. 152 (24%) were spiritualists. 109 (17%) were herbalists. and 58 (9%) were homeopaths. Two hundred eight (64%) of the allopaths had no formal training. and only 18 (6%) were graduates of medical school. In a community-based study of 480 children with bloody diarrhea and 480 children with nonbloody diarrhea. allopathic treatment was the most common care provided. Furazolidone and metronidazole were the two most commonly prescribed drugs. given to 26% and 23% of children. respectively. who were seen by a practitioner. Only 25% of children had received oral rehydration therapy. We conclude that in this region of Bangladesh care of acute diarrhea is provided mostly by private medical practitioners who have little or no training; that such care currently is largely irrational; and that the provision of rational care will require the development of simple algorithms that these practitioners can implement for treatment of this disease.
An auxotrophic live oral Shigella flexneri vaccine: development and testing, Through transduction. a wild-type strain of Shigella flexneri serotype Y (SFL1) was rendered auxotrophic and dependent on aromatic metabolites that are not available in mammalian tissues. Monkeys that were orally vaccinated with 10(11) bacteria of the transductant strain SFL114 remained healthy when challenged with 10(11) bacteria of wild-type strains of S. flexneri serotypes Y. 1b. and 2a. The safety and immunogenicity of SFL114 were next studied in volunteers who were given either 10(9) or 10(10) SFL114 bacteria orally. Mild intestinal discomfort that lasted for 1-2 days was reported by three (12%) of 25 volunteers given 10(9) live SFL114 bacteria and by 13 (54%) of 24 volunteers given 10(10) live SFL114 bacteria. A local intestinal secretory IgA response to the S. flexneri O-antigen was recorded. The in vitro and in vivo results suggest that the aroD transductant SFL114 possesses properties that are desirable in an oral live candidate vaccine.
O-specific side-chain toxin-protein conjugates as parenteral vaccines for the prevention of shigellosis and related diseases, Only indirect evidence has been cited to document that lipopolysaccharide-mediated virulence at the bacterial level and serum antibodies to the O-specific side chain of the lipopolysaccharide molecule may prevent shigellosis. Our proposed use of the B subunit of Shiga toxin as a carrier protein is based upon evidence (even more indirect) that serum antitoxin may reduce the severity of dysentery and diarrhea. Because animal models of disease may provide information inapplicable to the prediction of vaccine-induced protective immunity. we suggest that clinical trials in the population at risk should be started after successful completion of the safety and immunogenicity phases of vaccine development in laboratory animals and in the target population. Clinical studies of shigella vaccines are difficult because of the many causes of dysentery in a population with a high rate of intestinal disease.
Acanthamoeba and disinfection of soft contact lenses, The association between acanthamoeba keratitis and the use of soft contact lenses is firmly established. Despite alerts and warnings. education of eye-care professionals and patients. and identification of risk factors that are associated with the use of soft contact lenses. acanthamoeba keratitis remains a threat. It is presumed that in some cases. the soft contact lens is the vector by which Acanthamoeba is introduced to the cornea. This presumption has spurred concern regarding the efficacy of systems used for the disinfection of soft contact lenses in killing the organism. Many questions have been raised regarding the proficiency of disinfection. These have stemmed from a poor understanding of the interactions among soft contact lenses. soft contact lens paraphernalia. and Acanthamoeba. Another issue to be addressed is the need for standardized testing of the efficacy of contact lens disinfection systems against Acanthamoeba. Only through a concerted and focused effort by eye-care and other concerned health care professionals can these questions be answered.
In vitro evaluation of antimicrobial compounds for cysticidal activity against Acanthamoeba, Amebic keratitis presents a therapeutic dilemma because Acanthamoeba. unlike Naegleria. encysts in infected tissues. To date. the results of medical therapy have been disappointing. and the optimal medical regimen for acanthamoeba keratitis is yet to be defined. Clinical cure necessitates eradication of the encysted amebae with medications known to have ocular toxic effects in combination with surgical maneuvers. Antiinfective agents possessing in vitro cysticidal activity include paromomycin. neomycin. ketoconazole. natamycin. and ciclopirox olamine. but no agent has been shown to be uniformly effective against all isolates of Acanthamoeba. Treatment of amebic cysts with propamidine isethionate plus either paromomycin or neomycin has produced slightly additive cysticidal effects. Multiple factors. including the varied clinical presentation and the lack of standardized in vitro techniques for the assay of cysticidal activity. account for the lack of correlation between in vitro activity and in vivo efficacy.
Recent advances in the polymerase chain reaction, The polymerase chain reaction (PCR) has dramatically altered how molecular studies are conducted as well as what questions can be asked. In addition to simplifying molecular tasks typically carried out with the use of recombinant DNA technology. PCR has allowed a spectrum of advances ranging from the identification of novel genes and pathogens to the quantitation of characterized nucleotide sequences. PCR can provide insights into the intricacies of single cells as well as the evolution of species. Some recent developments in instrumentation. methodology. and applications of the PCR are presented in this review.
Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n, The sequence of a Pst I restriction fragment was determined that demonstrate instability in fragile X syndrome pedigrees. The region of instability was localized to a trinucleotide repeat p(CCG)n. The sequence flanking this repeat were identical in normal and affected individuals. The breakpoints in two somatic cell hybrids constructed to break at the fragile site also mapped to this repeat sequence. The repeat exhibits instability both when cloned in a nonhomologous host and after amplification by the polymerase chain reaction. These results suggest variation in the trinucleotide repeat copy number as the molecular basis for the instability and possibly the fragile site. This would account for the observed properties of this region in vivo and in vitro.
Effectiveness of nonsurgical treatment for idiopathic scoliosis. Overview of available evidence, To define further the effectiveness of nonsurgical therapy for idiopathic scoliosis. predefined criteria were established for selection and data retrieval from studies of therapy and natural history. and the results were synthesized quantitatively. Only studies of patients with no more than a 50 degree Cobb angle scoliosis were considered. Twenty-four reports were eligible. There was a fivefold proportion of failures among patients with scoliosis greater than 30 degrees at the start of therapy but no difference in progression between different kinds of nonsurgical therapies or between treated and untreated patients; these were the main findings of this quantitative analysis. These data cannot be used to prove the effectiveness or ineffectiveness of nonsurgical therapy for idiopathic scoliosis. and experimental controlled studies of different therapies seem to be justified both on ethical and scientific grounds. The findings of this overview can be used for their planning.
The effect of Luque segmental sublaminar instrumentation on the rib hump in idiopathic scoliosis, The change in back shape after Luque segmental sublaminar instrumentation was assessed in the frontal. sagittal. and transverse planes in 61 patients with adolescent idiopathic scoliosis using the Integrated Shape Investigation System (ISIS) and standard radiographic techniques. Luque instrumentation was found to be an effective method of correcting thoracic and thoracolumbar curves in the frontal plane with a 59% and 63% respective reduction in the size of the preoperative Cobb angle. Despite the frontal plane correction. however. the ISIS scan showed that of the 40 single thoracic curves. the rib hump was reduced in only 6 patients. was unchanged in 27 patients. and was worsened slightly in 7 patients. By contrast. thoracolumbar and lumbar curves were corrected in all three planes with a significant cosmetic improvement.
Progression of spondylolisthesis in children and adolescents. A long-term follow-up of 272 patients, The radiologic progression of spondylolisthesis during a long-term follow-up was studied in 272 children and adolescents. There were 134 girls and 138 boys. The mean age at the first visit was 14.3 years (girls. 13.8 years; boys. 14.9 years). The radiologic follow-up time was 14.8 years on average (range. 5-32). The operation was done in 190 patients younger than 20 years of age. Fusion in situ. using a posterior or posterolateral technique. had no statistically significant effect on progression. Surgically treated patients did not differ from conservatively treated patients. Ninety percent of the slip. on average. had already occurred at the first radiologic examination compared with the final amount of slip. More than 10% progression occurred in 62 patients. mainly within the first year postoperatively or after the first examination. Progression of the lumbosacral kyphosis and sinking of the vertebral body was noted in severe slips. Although female gender and dysplasia (spina bifida) at the lumbosacral junction were more frequent in severe slips. they statistically had no value in predicting progression. A wedge form of L5 or sacral rounding also had no prognostic value. These were secondary to the slip and expressed it but did not predict it. The only radiologic variable with predictive value of progression was the percentage amount of the primary slip. In age groups corresponding to the growth spurt in early puberty (girls. 9-12 years; boys. 11-14 years). there was a tendency to progress.
Radiologic progression of isthmic lumbar spondylolisthesis in young patients, In 311 patients (160 girls and women and 151 boys and men) with lumbar spondylolysis/spondylolisthesis 30 years of age or younger at diagnosis and with at least two separate examinations available. radiographs were evaluated retrospectively to estimate the magnitude of slip progression in relation to age and to search for possible prognostic factors of progression. The mean age at diagnosis was 16.2 years. and the mean observation time was 3.8 years. Nine patients (3%) had a slip progression (defined as an increase greater than or equal to 20%). The magnitude of progression per year was low (0.6%). No prognostic factors for progression were found.
Leg-length inequality in people of working age. The association between mild inequality and low-back pain is questionable, Leg-length inequality was measured from radiographs at the level of the vertices of the femoral heads in 247 men and women aged 35-54 years. Of these. 53 had never had any low-back problem. but they had considerable variation in leg-length inequality (mean SD. 5.5 +/- 4.1 mm; range. up to 20 mm). This group of symptom-free individuals did not differ from a group of 78 persons who had disabling low-back pain (LBP) during the previous 12 months (mean SD. 5.3 +/- 4.0 mm; range. up to 17 mm). The adjusted relative risks (odds ratios) of having LBP ever and of disabling pain during the last 12 months were 0.78 (95% confidence interval. 0.43-1.17) and 1.02 (0.68-1.38). respectively. for an increase of 5 mm in leg-length inequality. The results from this study make an association between mild leg-length inequality and LBP questionable.
Previous back pain and risk of developing back pain in a future pregnancy, Four hundred twenty-nine pregnant women who had back pain before pregnancy and 375 pregnant women with no previous back pain were followed at regular intervals from the 12th week of pregnancy until delivery; back-pain complaints were recorded. Overall . back pain occurred twice as often in the group with a back-pain history (period prevalence) (P less than 0.001). The point prevalence of back pain in weeks 12. 24. 30. and 36 was three times higher in the group who had had back pain before pregnancy indicating that pain was not only more prevalent but also lasted longer in that group. Women who had been pregnant previously tended to have an increased risk of back pain. and there was a statistically significant correlation between multiparity and longer periods of back pain (P less than 0.001). Young age increased the risk of back pain (P less than 0.001). Pain intensity was higher in the younger women during the first part of their pregnancies but not later on (P less than 0.05).
Disc degeneration and associated abnormalities of the spine in elite gymnasts. A magnetic resonance imaging study, The thoracolumbar spine was examined by magnetic resonance imaging (MRI) and the history of back pain was analyzed in 24 male elite gymnasts (age range. 19-29 years) and in 16 male nonathletes (age range. 23-36 years). Disc degeneration. defined as reduced disc signal intensity. was significantly more common in athletes (75%) than in nonathletes (31%). The gymnasts also had a higher incidence of other abnormalities of the thoracolumbar spine. and there was a significant correlation between reduced disc signal intensity and the other abnormalities among the gymnasts. There were also significant correlations between back pain and reduced disc signal intensity and abnormal vertebral configuration when the gymnasts run a high risk of developing severe abnormalities of the thoracolumbar spine. and they often have a history of back pain.
Posterior wiring without bony fusion in traumatic distractive flexion injuries of the mid to lower cervical spine. Long-term follow-up in 30 patients, Thirty-four patients with traumatic distractive flexion injuries in the mid to lower cervical spine were treated with posterior wire stabilization without bony fusion from January 1981 through May 1987. Fifteen had cord involvement. and nine had root involvement. Ten were neurologically intact. Thirty patients were followed for a mean of 38 months. Two neurologically intact patients had root deficits postoperatively. One patient was reoperated because of redislocation due to a spinous process fracture. Mean loss of lordosis was 7.5 degrees. Eight patients had a wire break at follow-up. but no case of late instability was observed. Sixteen patients had signs of spontaneous anterior interbody fusion at follow-up. and 11 patients had signs of posterior fusion. Twenty-four patients complained of late--but in most cases--minor pain. These results indicate that simple posterior wiring without bony fusion is a reliable method to obtain good immediate stability in traumatic distractive flexion injuries of the mid to lower cervical spine. The wires provide sufficient stability during the time of soft tissue healing.
Factors influencing 20-hour increments after platelet transfusion, The 20-hour posttransfusion platelet count determines transfusion policy for patients requiring platelet support. and yet factors influencing the 20-hour count have been poorly defined. The clinical factors influencing both the 1- and 20-hour corrected count increment (CCI). were studied in 623 human leukocyte antigen (HLA)-unmatched platelet transfusions in 108 patients. The 1- and 20-hour CCIs were highly correlated (r = 0.67. p less than 0.001). On average. the 20-hour CCI was 64 percent of the 1-hour CCI. Multiple linear regression analyses identified splenectomy. bone marrow transplantation. disseminated intravascular coagulation. administration of amphotericin B. palpable spleen. and HLA antibody grade as the major factors influencing the 20-hour posttransfusion CCI. Platelet-specific antibodies. number of concurrent antibiotics. clinical bleeding. and temperature did not significantly influence the 20-hour posttransfusion CCI. The 1-hour CCI was the only significant factor influencing the 20-hour CCI in a regression model containing the 1-hour CCI and the above factors. Thus. the same clinical factors exert a major influence on the CCI at both 1 and 20 hours after platelet transfusion. with no evidence that any factor has more influence at 20 hours after transfusion than at 1 hour.
IgA and IgM human immunodeficiency virus antibodies in weakly reactive or false-negative blood donors, Detection of antibodies to the human immunodeficiency virus (HIV) in recently infected donors is crucial to prevent the transmission of HIV infection via blood products. To determine whether specific antibodies of the IgA or IgM class are present as markers of recent infection in donor specimens that have borderline reactivity on routine enzyme immunoassay (EIA) screening. 15 specimens that were positive by immunoblot were tested for IgA and IgM HIV antibodies. All 15 had detectable IgA HIV antibodies. and 14 had IgM HIV antibodies. The 15 specimens were tested further. each by two independent laboratories. with nine licensed EIAs. Two of the nine EIAs found all 15 units positive in both laboratories; seven EIAs found 1 to 5 of the 15 units negative. for a total of 31 false-negative results. The results indicated a difference between the sensitivity of EIA kits using only anti-IgG reagents and of kits using multispecific reagents that react with IgG and other classes of antibody. In a modified procedure. the addition of enzyme-conjugated anti-IgA or anti-IgM to the kit's enzyme-conjugated reagent increased the optical density values of most false-negative specimens to the positive range. It was concluded that licensed kits vary in reactivity with IgA and IgM HIV antibodies and that sensitivity could be increased by improved detection of these classes of antibody.
Progressive platelet activation with storage: evidence for shortened survival of activated platelets after transfusion, Platelets are known to become activated during storage. but it is unclear whether such activation affects recovery or survival after platelet concentrate (PC) transfusion. With the use of flow cytometry to determine the percentage of platelets expressing the alpha-granule membrane protein 140 (GMP-140). a known adhesive ligand appearing on the platelet surface after activation. several studies were conducted. These investigations evaluated 1) the occurrence of significant platelet activation over time in PCs (n = 46) stored under standard blood bank conditions; 2) the correlation between platelet activation and platelet recovery in normal subjects after PC storage (n = 12). as assessed by the recovery of Indium-labeled platelets; and 3) the recovery of activated and unactivated platelets in thrombocytopenic cancer patients transfused with standard PCs (n = 11). It was determined 1) that an increasing duration of storage of PC was associated with increasing platelet activation as measured by the percentage of platelets expressing GMP-140. progressing from a mean of 4 +/- 2 percent (SD) on the day of collection to a mean of 25 +/- 8 percent by 5 days of storage: 2) that. in normal subjects. posttransfusion recovery of autologous platelets stored for 2 to 4 days and then labeled with In111 was inversely correlated with the percentage of activated platelets in the transfused PC (r = -0.55. p = 0.05); and 3) that. when thrombocytopenic patients were transfused with standard PCs. the recovery of the activated platelets in the transfused PCs averaged only 38 +/- 15 percent of the number predicted by the absolute platelet increment.
Oriental cholangiohepatitis: pathologic, clinical, and radiologic features, Oriental cholangiohepatitis. an endemic disease in Southeast Asia. is characterized by recurrent attacks of abdominal pain. fever. and jaundice. Pathologically. the intra- and extrahepatic ducts are dilated and contain soft. pigmented stone and pus. There is proliferation of bile ducts and infiltration of inflammatory cells along the periportal spaces and hepatic parenchyma. Localized intrahepatic segmental ductal stenosis may be present. especially in the lateral segment of the left lobe or posterior segment of the right hepatic lobe. The cause of the disease is not known. but associations with clonorchiasis. ascariasis. and nutritional deficiency have been suggested. Sonographic and CT findings include intra- or extrahepatic duct stones. dilatation of the extrahepatic duct with relatively mild or no dilatation of the intrahepatic ducts. localized dilatation of the lobar or segmental bile ducts. increased periportal echogenicity. segmental hepatic atrophy. and gallstones. Cholangiographic findings include bile duct stones; disproportionately severe dilatation of the extrahepatic ducts with mild or no dilatation of the intrahepatic ducts; and focal strictures. acute peripheral tapering. straightening. rigidity. decreased arborization. and an increased branching angle of the intrahepatic bile ducts.
Unidirectional joint communications in wrist arthrography: an evaluation of 250 cases, Although arthrographically demonstrable communications between various compartments of the wrist occur in older persons without symptoms. similar communications in younger persons may indicate clinically significant posttraumatic ligament tears and other pathologic processes. However. detection of communications varies depending on the arthrographic technique used. It has been claimed that if triple-compartment arthrography is not used in all patients. clinically significant unidirectional ligament tears may be overlooked. We determined the frequency and distribution of unidirectional intercompartmental communications. using a modification of techniques described in the literature. Separate injections of contrast material were made in sequence into the midcarpal. distal radioulnar. and radiocarpal joints of 250 consecutive patients. We found 38 unidirectional communications (17 lunotriquetral. nine scapholunate. three radial capsular. one ulnar capsular. six combined sites. and two indeterminate sites) between the midcarpal and radiocarpal joints. Nine unidirectional communications between the radiocarpal and distal radioulnar joints were found. Comparison of these results with the frequency and direction of unidirectional communications reported by others suggests that demonstration of communications depends on specific technical factors. such as which joint is injected first. the amount of contrast material used. and the delay between injections. This dependence on technical factors raises questions about the value of routine three-compartment wrist arthrography.
Normal splenic size in infants and children: sonographic measurements, The purpose of this study was to establish guidelines for normal splenic size at different ages by using a simple and reproducible sonographic method. Two hundred thirty patients. from neonate to 20-year-old. had sonography because of abdominal and/or pelvic problems unrelated to the spleen. Findings on sonograms of the liver and kidneys were normal in all cases. Splenic size was measured by obtaining a coronal view that included the hilum. while the patient was breathing quietly. The greatest longitudinal distance between the dome of the spleen and the tip (splenic length) was measured and correlated with age. height. and weight. The following guidelines are proposed for the upper limit of normal splenic length based on this simple. easy to use. one-measurement technique: splenic length no greater than 6.0 cm at 3 months. 6.5 cm at 6 months. and 7.0 cm at 12 months. 8.0 cm at 2 years. 9.0 at 4 years. 9.5 cm at 6 years. 10.0 cm at 8 years. 11.0 cm at 10 years. 11.5 cm at 12 years. 12.0 cm at 15 years or older for girls. and 13.0 cm at 15 years or older for boys. Twenty-two patients with known abnormalities of the spleen were randomly selected and their splenic lengths compared with the proposed guidelines; in each case. the length of the spleen exceeded the upper limit of normal for that age. Normal values of a single measurement of the greatest longitudinal diameter of the spleen. from the dome to the tip measured at the hilum in the coronal plane. were obtained in patients from newborn to 20 years old.
Differential diagnosis of head and neck lesions based on their space of origin. 2. The infrahyoid portion of the neck, The infrahyoid portion of the neck can be considered as a series of contiguous fascial planes and intervening spaces that lend themselves well to axial imaging. These spaces can serve as a basis on which to formulate differential diagnoses for diseases in this region. This pictorial essay describes the fascia and fascial spaces of the infrahyoid portion of the neck. The contents of each space. the common abnormalities affecting the space. and the characteristic displacements produced by disease in each space are reviewed.
Radiologic evaluation of the normal and diseased posterior cervical space, The posterior cervical space seen on cross-sectional imaging of the neck constitutes most of the posterior triangle seen on clinical examination. Although triangular anatomy relates best to the surface perspective of the clinician. a spatial approach to anatomy works better for the radiologist viewing axial images. The posterior cervical space is defined as the area in the posterolateral portion of the neck from the skull base to the clavicles deep to the sternomastoid and trapezius muscles but superficial to the prevertebral space. Its principal contents are fat. the spinal accessory nerve. and lymph nodes. We analyzed CT and MR images and clinical records of 63 patients known or suspected to have disease of the posterior cervical space to determine the imaging features that mark a lesion as originating in the posterior cervical space and the spectrum of diseases that arise there. Of the 63 patients in the study. four had clinical pseudomasses. nine had congenital lesions. 10 had inflammatory disease. six had benign tumors. and 34 had malignant tumors. A typical mass lesion of the posterior cervical space was centered within the fat of the space. between the deep and superficial layers of the deep cervical fascia. Characteristic displacements caused by a mass in the posterior cervical space included anteromedial displacement of the carotid space and posteromedial displacement of the prevertebral space. Our study shows that the differential diagnosis of lesions of the posterior cervical space reflects the normal contents of the space. and that diagnosis can thereby be predicted from knowledge of the normal anatomy and contents of the space.
Stenoses of vascular anastomoses after hepatic transplantation: treatment with balloon angioplasty, Vascular complications after liver transplantation include occlusion or stenosis at the sites of anastomosis in the hepatic artery. portal vein. and vena cava. From our experience with more than 600 liver transplants. vascular stenoses have been identified in 10 patients and treated by balloon angioplasty in nine. Three patients with hepatic artery stenosis and deteriorating graft function were treated by balloon angioplasty with a coaxial technique. A specially designed catheter facilitated a successful femoral artery approach. Portal vein stenoses in three patients resulted in portal hypertension. These were treated by balloon dilatation via transhepatic catheterization of the portal vein. Stenoses of the suprahepatic caval anastomosis were dilated in three patients with severe lower limb edema. Technical success was achieved in all three cases of hepatic artery stenosis with improvement in graft function. Recurrent stenoses in two patients were successfully treated with repeated dilatations. Portal hypertension resolved in two of three patients after portal venoplasty. Dilatation of a caval stenosis resulted in the resolution of leg edema in all three cases. Repeated dilatation was required in one case. No reduction in the portal venous pressure gradient occurred after venoplasty in one case. and an ultimately fatal caval thrombosis developed in one patient with caval stenosis before venoplasty could be performed. Our experience suggests that balloon angioplasty of arterial and venous stenoses complicating hepatic transplantation carries little risk and is a useful procedure for the treatment of these problems.
The prevalence of carcinoma in palpable vs impalpable, mammographically detected lesions, Concern over excessive numbers of false-positive mammograms. leading to unnecessary investigations and surgical interventions. has been cited as a barrier to mammographic screening for breast cancer. We compared the biopsy results from palpable vs impalpable. mammographically detected lesions from one experienced breast surgeon's practice from July 1980 through July 1989. Overall. there were 372 biopsies in 346 women. Of 143 biopsies for palpable abnormalities. 48 (34%) yielded a primary malignant lesion. The length of the palpable cancers averaged 3.7 cm (median. 2.8 cm). Sixteen (33%) of the 48 biopsies were in patients who had positive axillary lymph nodes. and five (10%) were in patients who had distant metastases at the time of biopsy. Of 229 biopsies for impalpable. mammographically detected lesions. 72 (31%) yielded a primary breast carcinoma. Excluding 34 carcinomas that had only calcifications. the length of the mammographically detected tumors averaged 2.0 cm (median. 1.5 cm). Eleven (15%) of the 72 biopsies were in patients who had positive axillary nodes. and none were in patients who had distant metastases at the time of biopsy. The positive predictive values (number of cancers detected divided by the number of biopsies recommended) were not significantly different when comparing biopsies indicated for palpable. clinically detected (34%) vs impalpable. mammographically detected (31%) abnormalities (p = .669). However. the mammographically detected cancers were smaller. more often noninvasive (32% vs 4%). less often associated with axillary metastases (15% vs 33%). and without distant metastases (0% vs 10%).
Thin-layer chromatography to monitor cholesterol gallstone dissolution by methyl tert-butyl ether, We describe a simple and inexpensive method of monitoring methyl tert-butyl ether (MTBE) dissolution of cholesterol gallstones with thin-layer chromatography (TLC) in 10 patients. TLC is a routine semiquantitative laboratory method that can be used to measure the cholesterol concentration present in the MTBE and bile mixture aspirated through the cholecystostomy catheter during gallstone dissolution. TLC is practical in the clinical setting because it can be used to determine if gallstone dissolution is occurring and when MTBE lavage is no longer effective. TLC is performed in the laboratory with routine material and is completed in 15 min. Each TLC measurement costs about $1. The procedure provides objective and specific chemical information on effectiveness and progression of gallstone dissolution. apart from the radiologic and sonographic studies. In our study. TLC signaled effective dissolution in the initial phase of gallstone dissolution by detecting large amounts of cholesterol in the MTBE and bile mixture even before a visible change in size or shape of the stone became apparent by transcatheter cholecystography or by sonography (six of 10 patients). Conversely. lack of cholesterol on TLC after 1 hr or more of MTBE infusion indicates that the stones are pigmented or contain substantial calcium. This means that dissolution with MTBE will be ineffective and that solvent infusion should be terminated. In those cases in which dissolution is progressing well. when TLC shows decreasing amounts of cholesterol in the effluent. only residual fragments insoluble to MTBE remain or the stone is sequestered from MTBE; at this point. solvent infusion should be discontinued or the catheter must be repositioned. Monitoring the rate of cholesterol dissolution by TLC provides important complementary information to cholecystography and sonography during gallstone treatment with MTBE.
Afferent loop syndrome: sonographic findings in seven cases, We studied the sonographic findings in seven patients in whom afferent loop obstruction was first detected by sonography. All seven subsequently were proved at surgery to have afferent loop syndrome. The causes of the obstruction included internal hernia (n = 3). cancer recurrence (n = 2). marginal ulcer (n = 1). and development of cancer at the anastomosis site (n = 1). In all cases. the dilated afferent loop was seen on sonography as a tubular structure in the upper abdomen crossing transversely over the midline. The distal end of the afferent loop could be traced toward the anastomosis. The probable cause of the syndrome was predicted on the basis of sonography in two of three patients with cancer at the anastomosis. Our experience suggests that afferent loop syndrome can be diagnosed sonographically on the basis of the detection. location. and shape of the dilated afferent loop.
Sonography of the cervix during the third trimester of pregnancy: value of the transperineal approach, Transabdominal sonography reliably depicts the cervix during the first and second trimesters of pregnancy. but cervical visualization becomes increasingly difficult as the third trimester progresses. To evaluate the possibility of using a perineal approach to bypass the fetus and image the cervix during the third trimester. we used transperineal sonography to image the cervix of 158 third-trimester patients in whom transabdominal visualization was inadequate. The internal os and upper cervix were successfully visualized on transperineal sonograms in all 158 patients. but the region of the external os was obscured by rectal gas in 22 (14%) cases. In some patients in whom the external portion of the cervix was obscured by bowel gas. the problem could be overcome by scanning with the patient in the lateral decubitus position or by rotating the patient. Transperineal sonography is an effective technique for imaging the cervix during the third trimester of pregnancy. allowing cervical visualization in most patients in whom transabdominal sonography of this area is unsuccessful.
Organic vs functional obstruction of the fallopian tubes: differentiation with prostaglandin antagonist- and beta 2-agonist-mediated hysterosalpingography and selective ostial salpingography, In order to determine the prevalence and cause of functional vs organic obstruction of the fallopian tubes. hysterosalpingography was repeated after pharmacologic manipulation with a prostaglandin antagonist (aspirin) and/or a beta 2-agonist (terbutaline) in 100 patients in whom the fallopian tubes did not fill with contrast medium on the initial hysterosalpingogram. Selective ostial salpingography was performed in those in whom the fallopian tubes did not fill on the second hysterosalpingogram. Patients referred from three infertility clinics were included in the study if they could be rescheduled for a second hysterosalpingogram after at least 1 week of preparation with aspirin. Hysterosalpingograms obtained after administration of aspirin showed normal filling in 21 of 100 patients with initially obstructed tubes; the tubes filled in four more patients after administration of terbutaline. Selective ostial salpingography opacified the tubes in another 36 patients in whom the tubes had so far failed to fill. On the basis of the radiographic appearance and sometimes laparoscopic observation. initial nonfilling was attributed to spasma and debris in 49 patients. submucosal fibroids in six. synechiae in three. salpingitis isthmica nodosa in two. and septated uterus in one. Hysterosalpingography. after pharmacologic manipulation with aspirin and/or selective ostial salpingography. revealed false-positive and functional tube obstructions in 61 of 100 patients. Moreover. the radiologic appearance improved categorization of organic obstructions.
MR examination of the knee: interpretation with multiscreen digital workstation vs hardcopy format, A multiscreen imaging workstation was compared with conventional hardcopy format for diagnostic interpretation of MR images of the knee. MR examinations from 30 patients were interpreted by two observers using film displayed both on a standard film panel alternator and an eight-screen digital workstation. Arthroscopic examination of these patients disclosed 30 meniscal tears and five anterior cruciate ligament tears in 28 patients. Two patients had normal arthroscopic examinations. The MR examinations were evaluated with a five-point confidence rating scale. Results were correlated with arthroscopic findings. and receiver-operating-characteristic curves were generated from these data. No significant difference was found between the areas under the receiver-operating-characteristic curves for film and digital display. The time required for image interpretation was greater when using the digital workstation than when using the film by a factor of approximately 2.7. Our data indicate that a multiscreen digital workstation can be used for interpreting MR examinations of the knee without impairment of diagnostic performance. but with increased time required for image interpretation when compared with radiographic film and a film panel alternator.
Normal and degenerated intervertebral disk: in vivo and in vitro MR imaging with histopathologic correlation, The components of the intervertebral disk serve two purposes. The hydrophilic matrix is contained by circumferential rings of fibrocartilage (outer anulus) and Sharpey's fibers. The gellike hydrophilic matrix acts as a cushion between the vertebral body endplates by providing an even distribution of axial and rotational compressive forces. The construction and integrity of the intervertebral disk are assessed well by MR. The purpose of this pictorial essay is to show the in vitro and in vivo MR appearances of the normal and degenerated disk. and to correlate these MR changes with their respective histopathologic findings.
Receptor function in heart failure, In patients with congestive heart failure. down-regulation of beta-adrenoceptors is present. probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy. beta 1-adrenoceptor density is markedly reduced. while beta 2-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to beta 2-stimulation. due to possible alterations in the beta-adrenoceptor/adenylate cyclase complex beyond the receptor. In some disease states. such as ischemic cardiomyopathy and mitral valve disease. there seems to be a concomitant reduction of the beta 1- and beta 2-adrenoceptor density. The finding of beta-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate beta receptors. and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity. such as forskolin. or that increase cyclic adenosine monophosphate degradation. such as the phosphodiesterase inhibitors. are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before beta-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the beta-adrenoceptor down-regulation. Studies testing whether beta-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.
Coupling between the heart and arterial system in heart failure, A number of experimental studies have demonstrated the optimal coupling between the ventricle and arterial load. under physiologic and pathologic circumstances. directed to produce maximal stroke work. We investigated matching of the ventricular properties. quantified by the slope of end-systolic pressure-volume relationship. with arterial load properties. expressed by the slope of end-systolic pressure-stroke volume relationship. In normal subjects. with ejection fraction of greater than or equal to 60%. ventricular elastance was nearly twice as large as arterial elastance. This condition affords maximal mechanical efficiency. In patients with moderate heart failure. with ejection fraction of 40-59%. ventricular elastance was almost equal to arterial elastance. This condition affords maximal stroke work from a given end-diastolic volume. In patients with severe heart failure. with ejection fraction of less than 40%. ventricular elastance was less than half of arterial elastance. which resulted in increased potential energy and decreased work efficiency. Ventriculoarterial coupling is normally set toward higher left ventricular work efficiency. whereas in patients with moderate cardiac dysfunction. ventricular and arterial properties are matched. in order to maximize stroke work at the expense of work efficiency. Neither the stroke work nor work efficiency is near maximum for patients with severe cardiac dysfunction.
Circulatory abnormalities and compensatory mechanisms in heart failure, Knowledge of the basic alterations of central hemodynamics in congestive heart failure has failed to explain many aspects of this important syndrome. Increasing attention has recently been paid to compensatory and adaptive mechanisms occurring after the initial insult. Thus. new insights have been gained into the pathophysiology of contraction of hypertrophied myocardium and changes of adrenergic receptors in the myocardium due to chronically increased cardiac sympathetic tone. The role of the renin-angiotensin-aldosterone system in early and advanced congestive heart failure has been further elucidated. and the role of the vasodilating atrial natriuretic peptide is undergoing further definition. New results further clarify the mechanisms leading to breathlessness and muscular fatigue in congestive heart failure. with emphasis shifting from the traditional concept of the importance of increased filling pressures to changes to the peripheral circulation and exercising muscles. Although progress has been made in understanding of the pathophysiology of congestive heart failure. many aspects are still poorly understood and await clarification.
Cardiovascular pharmacology of adrenergic and dopaminergic receptors: therapeutic significance in congestive heart failure, This review discusses the localization of adrenergic- and dopaminergic-adrenoceptors within the cardiovascular system and describes the cardiovascular and renal changes produced following the activation of these receptors by appropriate agonists. Whereas the role of alpha- and beta-adrenergic agents in the treatment of heart failure is well recognized. recent studies with dopamine (DA)-receptor agonists indicate that they offer a novel approach in the therapy of congestive heart failure. DA-adrenoceptor agonists reduce afterload by causing vasodilation and promote sodium excretion via direct activation of DA1-adrenoceptors located on renal tubules. Fenoldopam is a selective DA1-adrenoceptor agonist found to be effective in heart failure. It reduces afterload by causing peripheral vasodilation and produces natriuresis and diuresis. Dopexamine is a DA1- and beta 2-adrenoceptor agonist. and its efficacy in heart failure is due to its ability to provide mild inotropic support and cause a reduction in afterload. Ibopamine is a prodrug that is converted into its active metabolite. epinine. This compound activates primarily DA1- and DA2-adrenoceptors. It is effective in heart failure. and the mechanism progresses via DA1- and DA2-adrenoceptor-mediated reduction in afterload. Agonists of DA2-adrenoceptors reduce afterload by decreasing the release of norepinephrine and by reducing the levels of renin-angiotensin-aldosterone system. Since both of these systems are active in heart failure. ibopamine offers a rational approach for therapy. The present review addresses the concept of pharmacologic intervention in adrenergic and dopaminergic influence in the cardiovascular and renal systems to produce changes that are desirable for the pharmacotherapy of congestive heart failure.
Peripheral adaptations in congestive heart failure: a review, In congestive heart failure. peripheral adaptive mechanisms play a significant and largely underestimated role. In acute heart failure. sympathetic-mediated peripheral vasoconstriction together with chronotropic and inotropic actions serves to maintain perfusion pressure and blood supply to the vital organs. In chronic heart failure. activation of the renin-angiotensin system increases peripheral vascular resistance and arterial tone and decreases arterial compliance and vasodilator capacity. Endothelium-mediated. flow-dependent vasodilation is reduced as a consequence of reduced blood flow. Deconditioning renders the blood vessels incapable of dilating in response to increased flow. Simultaneously. reduced blood flow and inactivity are induced by deconditioning. with functional and structural consequences within the skeletal muscle. Exercise performance is limited by reduced overall blood flow. reduced conductance of the feeding arteries. elevated tone of the resistance vessels. reduced vasodilator capacity. impaired dissipation of heat from the working muscle. and functional and structural changes of the skeletal muscle due to underperfusion and inactivity. The adaptive mechanisms operate at different time scales. Under therapeutic intervention. their reversibility also follows different time constants. Restoration of the vasodilator capacity of the large arteries and of the abnormalities of skeletal muscle in heart failure requires time. Vasodilation with reduced pre- and/or afterload will retard progression of the superimposed ventricular dilation and hypertrophy. and therefore retard the progress of the disease. However. restoration of the peripheral blood flow and of organ function will require time. Restoration of the vascular compliance and of the full amplitude of adaptive flow-dependent vasodilation in the large arteries requires weeks or months. Similarly. restoration of functionally and morphologically altered skeletal muscle can be expected to be reversible over a longer time period.
Assessing drugs for the treatment of heart failure, The aims of treatment in patients with heart failure. as with any other condition. are to relieve symptoms and prolong life. A secondary objective is to do so at the lowest possible economic cost. When treatment of the cause of heart failure is possible--which usually means some form of surgery. but could include treatment of a primary disease. such as thyrotoxicosis--then this is obviously the treatment of choice. In patients for whom there is no such definitive treatment. a wide and increasing variety of drugs are available. When new antifailure drugs are to be developed there are therefore two problems: first. to ensure that they are more effective than placebo treatment. and second. to compare them with existing drugs. Both of these tests can present ethical difficulties. for it is unreasonable to withhold established effective treatment in order to conduct a placebo-controlled trial. and when drugs are being compared. it is unlikely that any new medication will be dramatically superior to an old one. The more effective the treatments already available. the harder it becomes to evaluate a new drug.
Ibopamine in chronic congestive heart failure: hemodynamic and neurohumoral effects, Ibopamine is a dopamine-like drug that shows mainly vasoactive properties. predominantly acting on dopamine1-(DA1-) and DA2-adrenoceptors. Ibopamine increases cardiac output. reduces peripheral vascular resistance. and increases renal blood flow. exerting a lesser effect on preload parameters. This hemodynamic improvement is also present even after relatively long-term treatment. There is no evidence of pharmacologic tolerance. In relation to DA2-activation. ibopamine modulates the neurohumoral consequences of heart failure with decreases in plasma renin activity and aldosterone and norepinephrine plasma levels. an effect that can be beneficial in the long-term treatment of heart failure patients.
Ibopamine in the treatment of heart failure, Efficacy and safety of a drug are essential criteria to be fulfilled before a new drug receives recommendation. This review focuses on the safety of ibopamine in the treatment of chronic heart failure. Ibopamine is a new. orally active drug with a predominant action on dopaminergic adrenoceptors. As a result. it reduces systemic vascular resistance. increases cardiac output. and increases renal flow. Ibopamine also modulates the neuroendocrine reflexes in heart failure; plasma renin activity and norepinephrine and aldosterone plasma concentrations are reduced. both immediately and during sustained administration. Ibopamine has proved to be safe in many thousands of heart failure patients during long-term therapy. This argues well for its use as an alternative or additive therapy in the treatment of patients with chronic heart failure.
Should cervical cytologic testing be augmented by cervicography or human papillomavirus deoxyribonucleic acid detection, Criticism of the Papanicolaou smear in the lay press and recent federal legislation regulating cytology laboratories indicate a need to reappraise cervical cancer screening programs. This study directly compares three potential screening tests. used alone or in combination. A total of 1012 women aged 18 to 35 years were screened by cytologic testing. cervicography. and hybridization for human papillomavirus deoxyribonucleic acid. with discrepancies being referred by the last two authors. After findings from the entire lower genital tract were combined. 116 women (11.5%) showed definite clinical abnormalities (either exophytic vulvovaginal condylomas or cervical squamous intraepithelial lesions). Another 72 (7.2%) had positive Southern blot hybridizations without accompanying viral expression. yielding a cumulative frequency for established disease or latent infection of 18.6%. When associated vulvovaginal condylomas are disregarded. final groupings with regard to cervical pathologic classification were: 23 high-grade and 71 low-grade squamous intraepithelial lesions. 164 cases of equivocal atypia (34 of which had detectable human papillomavirus deoxyribonucleic acid). and 754 cases with negative results (38 of which had detectable human papillomavirus deoxyribonucleic acid). Cervical screening tests were compared principally by plotting increasingly liberal recall criteria onto receiver operating characteristic curves (i.e.. graphs of true-positive results on the Y axis versus false-positive results on the X axis). Used individually. each screening test was valid. but none was substantially better than the others. No matter how liberal the recall criteria. no single test was able to detect all of the 23 definite precursors in this sample. Applying conventional recall criteria (i.e.. high- or low-grade lesion suspected). cytologic testing alone detected 12 high-grade squamous intraepithelial lesions (52.2%). at a cost of having to perform colposcopy in 8.7% of the sample. Combining all three tests and setting the end point as just a high-positive result by at least one test. 19 high-grade squamous intraepithelial lesions (83%) were detected. with a recall of 7%. Optimal test performance (96% sensitivity. 4% recall) would have been attained by recalling all patients with high-grade cytologic results or positive cervicography results. plus any patients with low-grade morphologic atypia in which hybridization detected an oncogenic human papillomavirus type. Our conclusions are as follows: (1) Cytologic detection rates are markedly improved by a second or third test; (2) increased screening costs could be offset by not recalling patients with minor lesions with no apparent potential for progression.
The fetal concentrating index as a gestational age-independent measure of placental dysfunction in intrauterine growth retardation, In previous work we have shown. using cordocentesis to obtain fetal blood. that fetuses with intrauterine growth retardation are hypoxic and suffer from in utero starvation of nutrients. In this study we have developed gestational age curves for fetal blood amino acids and carnitine that now allow the development of a new parameter. the fetal concentrating index. which is the numeric mean of the fetal/maternal ratio of six essential and nonessential concentrated amino acids. Our data have shown that this index does not vary with gestation in either normal pregnancies (1.83 +/- 0.42. mean +/- SD) or pregnancies with intrauterine growth retardation (1.46 +/- 0.38). but the index is markedly reduced in intrauterine growth retardation (p less than 0.001). These results suggest that. because cordocentesis has become very safe in experienced hands. cordocentesis to obtain the fetal concentrating index might ethically be obtained in cases of fetuses at risk for intrauterine growth retardation. to devise strategies for intervention before the onset of severe hypoxia and morphometric changes.
Stage IB squamous cell cancer of the cervix: clinicopathologic features related to survival, Three hundred forty-five patients with stage IB squamous cell carcinoma of the cervix were treated at the University of Michigan Medical Center from 1970 through 1985. The overall cumulative 5-year survival was 89%. The clinical characteristics included mean age 44.6 years. nulliparity 10%. married 93%. obese 38%. hypertension 32%. diabetes mellitus 5%. smoking 54%. symptoms of bleeding 68%. positive cytologic smear 83%. Lymph nodes were diseased in 45 of 261 (17%) with 26 unilateral (10%) and 19 bilateral (7%). Tumor differentiation showed: grade 1. 112 (33%); grade 2. 144 (42%); grade 3. 86 (25%). Factors that did not influence survival included age. presence or absence of positive cervical cytologic smear. the interval from previous papanicolaou smear. hypertension. smoking history. patient's blood type. and transfusion at radical hysterectomy. In all patients survival was significantly influenced by the following features: tumor classified as well differentiated (95%) or poorly differentiated (82%); tumor size less than 3 cm (91%) or greater than 3 cm (76%); negative lymph nodes (93%) or positive lymph nodes (61%). When three or fewer lymph nodes were involved. the survival was 79% compared with 33% when four or more lymph nodes were involved. In 213 patients undergoing radical hysterectomy the cumulative 5-year survival was significantly influenced by the amount of residual cervical disease: no residual disease. 100%; less than 50% penetration. 96%; greater than 50% penetration. 83%. Involvement of the lower uterine segment reduced survival to 73% compared with 95% when the lower segment was uninvolved. One hundred seventeen patients without angiolymphatic invasion had a 97% cumulative 5-year survival whereas 70 patients without disease in the lymph nodes but with angiolymphatic invasion had an 88% cumulative 5-year survival rate. A Cox model. multiple proportional hazard analysis was performed for all patients. and the factors that influenced survival included tumor grade. tumor size. presence of metastatic disease in the lymph nodes. and diabetes mellitus. In patients undergoing radiation therapy. the tumor grade and size were significant factors in survival. In patients undergoing radical hysterectomy. survival was influenced by the depth of cervical penetration and lower uterine segment involvement whereas the tumor grade. tumor size. patient's age. and removal of ovaries were not significant.
Hysterosalpingography with color Doppler ultrasonography, To assess the accuracy of the diagnosis of tubal occlusion with the use of color Doppler flow ultrasonography and hysterosalpingography. 129 infertile women were studied. All 129 women had the procedure performed with an ATL Ultramark 9 (Advanced Technology Laboratories. Bothel. Wash.) color Doppler ultrasonography machine. Eighty-five of the 129 women also had an additional study including x-ray hysterosalpingography and/or chromopertubation. Of these 85 women. 58 had pelviscopic examination with chromopertubation. The frequency of diagnosis of tubal occlusion was compared among the three methods. When results of ultrasonography-hysterosalpingography were compared with those of x-ray hysterosalpingography and/or chromopertubation. 69 of 85 (81%) studies showed agreement. and 50 of 58 (86%) ultrasonography-hysterosalpingography findings agreed with observations at chromopertubation. The frequency of comparable findings between x-ray hysterosalpingography and chromopertubation is 75%. These data suggest that ultrasonography-hysterosalpingography is at least as accurate as x-ray hysterosalpingography in diagnosing tubal occlusion. In addition. ultrasonography-hysterosalpingography is safer and more cost-effective than x-ray hysterosalpingography and chromopertubation.
Comparison of associated high-risk factors and perinatal outcome between symmetric and asymmetric fetal intrauterine growth retardation, This study compares associated high-risk factors and perinatal outcome between 273 symmetric and 445 asymmetric infants with intrauterine growth retardation. No differences were seen in 17 obstetric. medical. and environmental-behavioral high-risk factors between symmetric and asymmetric intrauterine growth retardation. In preeclampsia. the incidence of symmetric intrauterine growth retardation is higher than that of asymmetric intrauterine growth retardation. The timing of the interaction between the high-risk factor and the stage of gestation is more important than the specific high-risk factor in determining whether symmetric or asymmetric intrauterine growth retardation is produced. On comparison of perinatal outcome between the two groups. we concluded: (1) that the onset of symmetric intrauterine growth retardation occurs much earlier in the course of pregnancy than does asymmetric intrauterine growth retardation. (2) that more symmetric than asymmetric pregnancies with intrauterine growth retardation result in preterm delivery. (3) that the neonatal morbidity rate for symmetric intrauterine growth retardation is higher than that for asymmetric intrauterine growth retardation. and (4) that term symmetric infants with intrauterine growth retardation tend to have a lower mean birth weight and a higher incidence of small placentas than term infants with asymmetric intrauterine growth retardation.
Significance of oligohydramnios complicating pregnancy, Oligohydramnios is a serious complication of pregnancy that is associated with a poor perinatal outcome. Eighty pregnancies complicated by oligohydramnios constitute the basis for this retrospective study. Forty patients had premature rupture of the membranes; of these. outcomes were good in 25. Twelve of 14 fetuses with oligohydramnios and intrauterine growth retardation survived. None of the nine fetuses with severe renal anomalies lived. None of the twins with twin-twin transfusion and oligohydramnios survived. Six pregnancies with oligohydramnios and premature separation of the placenta were identified; all of these resulted in fetal or neonatal death during the second trimester.
Improved mammographic accuracy, Use of ancillary imaging studies to evaluate suspicious screening mammograms can improve their positive predictive value for detecting malignant lesions. In 1989 8181 screening mammograms were performed at the breast evaluation center at Memorial Hospital Medical Center in Long Beach. A total of 670 patients were called back for magnification views or ultrasonographic evaluation. and 92 of these patients underwent surgical biopsy. There were 42 cancers diagnosed. yielding an accuracy rate of 46%.
Conservative management of breast fibroadenomas, Is it conservative or radical management to excise all fibroadenomas of the breast. especially in women less than 30 years old? Once a definite diagnosis is established by physical examination. fine-needle aspiration cytologic testing. and mammography. is it prudent to monitor women with small fibroadenomas (less than 4 cm in diameter)? We reviewed 498 cases of biopsy-proved fibroadenomas and 17 cases of phyllodes tumors (by biopsy) seen at Los Angeles County/University of Southern California Medical Center from 1986 to 1989. Analysis of patient age and measured tumor size in 203 fibroadenomas and 10 phyllodes tumor specimens revealed similar ranges for both tumors. The mean values were 28.5 years and 2.3 cm for fibroadenomas and 44 years and 3.8 cm for phyllodes tumors. No cases of coincident carcinoma within a fibroadenoma or of metastatic malignant phyllodes tumors were present in this review. As an alternative to excising all breast tumors. cytologically diagnosed fibroadenomas can be monitored. because they have no intrinsic premalignant potential and tend to regress with time. All breast tumors that rapidly increase in size should probably be excised at any age.
Patient-controlled on-demand epidural fentanyl. A comparison of patient-controlled on-demand fentanyl delivered epidurally or intravenously, A prospective. open. clinical trial is described in which 20 patients having upper abdominal surgery were randomly allocated to receive fentanyl for postoperative analgesia by patient-controlled demand analgesic computer by either the epidural or intravenous route. Hourly pain. sedation and nausea scores were very similar in the two groups during the first 24 hours after surgery. What few differences there were favoured the epidural group. There was a highly significant difference in fentanyl consumption between the two groups. with the intravenous group demanding consistently more than twice as much as the epidural group.
Comparison of extradural and intravenous diamorphine as a supplement to extradural bupivacaine, The influence of route of administration (extradural as compared with intravenous) of diamorphine 0.5 mg/hour as a supplement to extradural bupivacaine (0.125% at 15 ml/hour) was investigated in two groups of 20 patients who underwent major abdominal gynaecological surgery. Significantly more patients in the intravenous group withdrew because of inadequate analgesia (p less than 0.05). Those in the extradural group were significantly more drowsy throughout the study (p less than 0.01). but no major side effects were encountered.
Propofol in short gynaecological procedures. Comparison of recovery over 2 days after anaesthesia with propofol or thiopentone as sole anaesthetic agent, Recovery was assessed over 48 hours after anaesthesia with propofol or thiopentone as sole anaesthetic agent in 36 unpremedicated gynaecological patients. Immediate recovery. as measured by the Steward scale. was shown to be quicker for the patients given propofol. At one hour postoperatively the thiopentone group showed impaired visual-motor coordination on the aiming test (p less than 0.01) and dexterity task (p less than 0.05). and a slowing of reaction time (p less than 0.01). Patients given propofol showed only an increase in reaction time (p less than 0.05). By 2 hours the thiopentone group showed impairment only in the aiming task (p less than 0.05). No further significant impairment was detected at 4. 24 or 48 hours. However. patients reported symptoms throughout the 48 hours indicative of residual drug effects. There was a substantial practice effect with some tests which may have obscured impairment. It can be argued therefore that the better recovery profile after propofol is still evident at 24 hours.
Peri-operative drug prescribing pattern and manufacturers' guidelines. An audit, Many patients admitted for surgery are receiving regular drug therapy. Adverse effects may occur. either as a result of these drugs being stopped suddenly or because staff are unaware of significant interactions between certain drugs and anaesthetic agents or techniques. This study aimed to find out how regular drug medication is actually given in the peri-operative period. In addition. pharmaceutical companies were contacted and asked for information about the effects of sudden withdrawal of their products and potential interactions with anaesthetic agents. We found that many drugs were omitted peri-operatively with potentially significant effects. Pharmaceutical companies do not seem to appreciate the importance of this problem and not all of them give clear recommendations relevant to practising anaesthetists.
Doxapram after general anaesthesia. Its role in stopping shivering during recovery, A group of patients who developed postoperative shivering after receiving inhalational anaesthesia were assigned. at random. to receive either doxapram or a placebo under double-blind conditions. A significantly higher proportion of patients stopped shivering after being given doxapram than after the placebo.
Resedation after bolus administration of midazolam to an infant and its reversal by flumazenil, A 4-month-old infant was sedated with bolus doses of midazolam. and after initial apparent complete arousal. became unresponsive and hypotonic. Administration of flumazenil enabled differentiation of a residual drug effect from an intracerebral event.
Myoclonic spasms after epidural diamorphine infusion, A case is presented in which myoclonus occurred after epidural diamorphine infusion. Reports of this phenomenon following other epidural drugs and possible mechanisms are discussed.
Minitracheotomy Seldinger--assessment of a new technique, A multicentre. prospective study of 26 patients was undertaken for the assessment of insertion of minitracheotomy tubes by the Seldinger technique. The technique of insertion is described. There were two misplacements. three blockages of the inserting Tuohy needle with fat. and six cases of difficulty in passing the minitracheotomy tube.
Evaluation of the Graseby PCAS. A clinical and laboratory study, The Graseby patient-controlled analgesia system was evaluated in the laboratory and in clinical use. The problems encountered with eight examples used to treat 510 patients are reported. Laboratory performance revealed the unit to be accurate at infusion volumes of 1 and 2 ml.
The laryngeal mask airway in children. A fibreoptic assessment of positioning, Clinical and fibreoptic assessment of the positioning of the laryngeal mask airway was performed in 100 children. Clinical observation indicated a patent airway in 98% and severe airway obstruction in 2% of cases. Perfect positioning. as judged by fibreoptic laryngoscopy. was found in 49% and the epiglottis was within the mask in 49%. Fibreoptic evidence of partial airway obstruction in 17% was not detected clinically.
Studies of delayed hypersensitivity responses in children in an industrialized region of Italy, The purpose of the present study was to evaluate the effects of chronic exposure to chemical pollutants on cell mediated immune responses in a pediatric population living in Priolo. an industrialized area of Italy. by means of skin test (Multitest CMI). The results suggest that children living in Priolo display significantly lower delayed type hypersensitivity (DTH) response than those seen in an age-matched and socioeconomically similar group of children living in Taormina. a nonindustrialized area. The lowered incidence of DTH scores in Priolo is not due to the number of positive skin test responses to individual antigens. but rather to the size of individual reactions.
Clinical and immunologic approach to patients with alleged environmental injury, Many of the challenging clinical evaluations facing today's practitioner and particularly today's allergist involve suspected hidden environmental exposure. not only to traditional allergens that induce classic symptoms of IgE-mediated disease. but to a wide range of simple chemicals encountered in trace amounts that may be associated with multisystemic symptoms including behavioral and neurologic manifestations. In the litigious social climate in which we live. the increased number of disability and personal injury claims and the ambiguous posturing by the legal profession often dictate a new set of diagnostic rules and norms. These must be considered by allergists and other practitioners in evaluating patients with polysomatic complaints allegedly due to trace environmental contaminants and with little or no identifiable pathology by gross or microscopic examination of tissues or laboratory data. These patients may have been declared totally disabled and may be seeking or receiving large amounts of personal injury compensation. Furthermore. they may be under "treatment" with multiple unproven diagnostic and therapeutic modalities and properly controlled challenge procedures may be necessary to prove or disprove the necessity for these diagnostic tests and therapies. With the ever increasing industrialization of our environment. it is likely that patients with these problems. who present for evaluation. will increase in number. It is therefore prudent for the practitioner to consider sound. comprehensive approaches to diagnoses and management of these conditions and above all to allay morbid fears of clinically relevant disease or immune system dysfunction based on results of isolated laboratory test findings.
Approaches to immunotoxicologic studies with emphasis on chemical-induced immunomodulation, Immunotoxicology has developed into a subdiscipline of toxicology in a tradition similar to other subdisciplines of toxicology. The use of experimental animals to determine the potential for chemicals to alter the structure and function of the immune system represents a significant part of this subdiscipline. This manuscript describes approaches to assessment of chemical-induced modification of immune status and key issues in interpreting the data for risk assessment.
Emphysema type in relation to silica dust exposure in South African gold miners, The relationship between silica dust exposure in gold mines and the type of emphysema was studied in a group of 1.553 white gold miners who had undergone autopsy examination between 1974 and 1987. Of particular interest was the contrast between centriacinar and panacinar emphysema as they relate to silica exposure and the presence of silicosis. Subjects with significant emphysema. that is. with an emphysema score of 30% or more. were classified as having predominantly panacinar or predominantly centriacinar emphysema. and compared to those without emphysema (emphysema score less than or equal to 10%). Of those who had significant emphysema (greater than or equal to 30%). 24% had predominantly panacinar. 43% predominantly centriacinar. and 33% were classified as mixed. The odds ratios (OR) for the association between each emphysema type and dust exposure (one unit of the cumulative dust index) were found to be statistically significant and of equal magnitude [1.019. with a 95% confidence interval (CI) of 1.005 to 1.033 for panacinar and 1.019 with a 95% CI of 1.007 to 1.031 for centriacinar emphysema]. In 163 nonsmokers insignificant panacinar emphysema was more common than centriacinar emphysema. The results indicate that a miner with 20 yr in high-dust occupations has a 3.5 (1.7;6.6) times higher odds of having a significant degree of emphysema at autopsy than a miner not in a dusty occupation. This is likely to be true of smoking miners only because there were only four nonsmokers with an emphysema score between 30 and 40%.
Energy balance in chronic obstructive pulmonary disease, A substantial number of patients with chronic obstructive pulmonary disease (COPD) suffer from gradual and significant weight loss during the natural course of their illness. The aim of this study was to determine the contribution of resting energy expenditure (REE) and energy intake (E-Intake) to weight loss in 80 patients with stable COPD: age (mean +/- SEM) 65 +/- 3 yr and FEV1 1.0 +/- 0.1 L. A total of 39 patients exhibited a continued weight loss in the previous year. REE measured with a ventilated hood system was significantly (p less than 0.005) higher in weight-losing compared to weight-stable patients when values were normalized for predicted metabolic rate (117 +/- 3 and 108 +/- 2%. respectively) or kg fat-free mass using bioelectrical impedance (FFM-BI): 35.0 +/- 0.8 and 31.8 +/- 0.6 kcal/kg. respectively). Normalized values of E-Intake were not significantly different between weight-losing and weight-stable patients. REE/FFM-BI correlated significantly with FEV1 (r = 0.22. p less than 0.05). maximal inspiratory mouth pressure (Plmax; r = 0.35. p less than 0.001). and E-Intake/FFM-BI (r = 0.48. p less than 0.001). Classification in three subgroups by severity of disease. (1) FEV1 greater than 35%. (2) FEV1 less than or equal to 35%. and (3) PaO2 less than 7.3 kPa. revealed a higher prevalence of weight loss in the more compromised groups and a significantly decreased (p less than 0.05) E-Intake in the hypoxemic patients.
Lung volume and distensibility in insulin-dependent diabetes mellitus, The effect of insulin-dependent diabetes mellitus on pulmonary function was studied in 22 diabetic nonsmokers (11 men) with a mean age of 40 yr (SE. 4 yr) and no history of cardiorespiratory disease. Exponential analysis of static pressure-volume data obtained during deflation of the lungs gave the exponent K. an index of pulmonary distensibility. In the diabetic subjects. mean values for total lung capacity. functional residual capacity. VC. and FEV1 were similar to predicted values. Diffusing capacity. K. and in K did not differ significantly from corresponding values in healthy subjects. The regression of in K on age was significant (R = 0.52; p less than 0.01) and similar to that obtained for 124 healthy subjects. The findings show that insulin-dependent diabetes mellitus does not affect pulmonary function. This study does not support the routine testing of lung function in otherwise well diabetic nonsmokers.
Nonhomogeneous lung emptying in cystic fibrosis patients. Volume history and bronchodilator effects, In spontaneous asthma after a deep inhalation (DI) obstruction occurs in direct proportion to disease severity. Since this has been associated with peripheral inflammation. which is present in cystic fibrosis (CF). we tested whether worsening obstruction after DI also occurs in CF in 12 patients. We assessed volume history effects by comparing isovolumic expiratory flows (Vmax) during forced exhalation begun at the end of tidal inspiration (partial P) with those begun at TLC (maximal M) to obtain M/P. As in asthma there was a correlation between M/P and FEV1 (% predicted; r = 0.64. p less than or equal to 0.03. n = 12). To control for a time dependency effect due to preferential emptying of fast compartments early in both the P and M maneuvers. we compared Vmax obtained from a first partial (P1) with a second (P2) obtained after inspiration to TLC and slow exhalation to the same starting volume as P1 (P2/P1). In contrast to asthma the P2/P1 was greater than the M/P and not related to disease severity. A further index of nonhomogeneous lung emptying was the relationship between M/P and the slope ratio at 70% TLC (r = -0.67. p less than or equal to 0.03). After isoetharine inhalation the M/P decreased (-0.12 +/- 0.12. p less than or equal to 0.01) but no change was apparent in P2/P1. indicating further increases in the degree of nonhomogeneity. We conclude that although volume history effects on M/P are similar in asthma and CF. this is due to a predominance of parenchymal hysteresis in the former and nonhomogeneity in the latter. which worsens with bronchodilator use.
Oxygen consumption is independent of changes in oxygen delivery in severe adult respiratory distress syndrome, We asked whether oxygen consumption is dependent on oxygen delivery in 17 patients who had severe adult respiratory distress syndrome (ARDS). 10 of whom had increased concentrations of plasma lactate. We determined oxygen consumption using analysis of respiratory gases while increasing oxygen delivery using blood transfusion. Oxygen consumption did not change after transfusion (from 227 +/- 83 to 225 +/- 82 ml/min. p less than or equal to 0.38). Oxygen delivery increased from 1.043 +/- 468 ml/min (24%. p less than or equal to 0.001). Even in the 10 patients who had increased concentration of plasma lactate and metabolic acidosis. oxygen consumption remained constant after increasing oxygen delivery (pretransfusion. 224 +/- 101 ml/min; post-transfusion. 225 +/- 99 ml/min; p less than or equal to 0.83). These data have more than 99% power of detecting a change in oxygen consumption of 20 ml/min after transfusion. Therefore. we conclude that directly measured oxygen consumption remains constant and independent of increases in oxygen delivery in our patients with severe ARDS. Because simultaneously determined oxygen consumption calculated from variables shared with the calculation of oxygen delivery yielded a dependent relationship. we speculate that finding dependence of calculated oxygen consumption on oxygen delivery may be the result of methodologic error.
Interaction of chemical and mechanical respiratory stimuli in the arousal response to hypoxia in sleeping dogs, The role of respiratory mechanoreceptor stimuli in the arousal response to hypoxia was studied in three trained dogs. The dogs breathed through a cuffed endotracheal tube inserted through a chronic tracheostomy. and resistive loads of 8 to 49 cm H2O/L/s were added to the expiratory circuit. Arterial O2 saturation (SaO2) was measured with an ear oximeter. and isocapnic progressive hypoxia was induced by a rebreathing technique. Arousal from sleep was determined by electroencephalographic and behavioral criteria. SaO2 at arousal from non-rapid eye movement (NREM) sleep increased progressively from 67.5 +/- 4.6% (mean +/- SEM). with no added resistance to 85.2 +/- 0.5% with the highest resistance (p less than 0.01). and from 60.6 +/- 0.6 to 81.6 +/- 0.4% during REM sleep (p less than 0.01). The added resistances also increased the steady-state (normoxic) level of alveolar PCO2 (PACO2). However. when PACO2 was increased to comparable levels by the addition of dead space rather than expiratory resistance to the breathing circuit. SaO2 at arousal from hypoxia was significantly lower than during expiratory resistive loading (p less than 0.05). We therefore conclude that mechanoreceptor stimuli arising from the ventilatory apparatus may contribute substantially to the arousal response to hypoxia.
Endogenous opiates modulate the postapnea ventilatory response in the obstructive sleep apnea syndrome, Defense of ventilatory homeostasis against recurrent hypercapnia. hypoxia. and acidosis resulting from apnea in obstructive sleep apnea syndrome (OSAS) is dependent on compensatory mechanisms operative between episodes of airway obstruction. This investigation was designed to examine whether endogenous opiate activity modulates the compensatory ventilatory response to apnea in OSAS. Polysomnography and quantitative measurement of tidal volume was performed in 12 patients with moderate to severe OSAS during a morning nap study before and after intravenous administration of 10 mg of naloxone. Apnea index was not significantly altered. There was a small but significant shortening of apneas (postnaloxone apnea duration. 91.2% of prenaloxone; p = 0.002 by ANOVA). Tidal volume of the first postapnea breath and minute ventilation extrapolated from the first two postapnea breaths. but not frequency. increased significantly after naloxone (postnaloxone first breath volume. 112.7% of prenaloxone value [p = 0.03]. with a similar increase for minute ventilation. 115.1% [p = 0.007]). The volume of the first postapnea breath was correlated with the duration of the previous apnea. both before (r = 0.59. p = 0.0001) and after naloxone. Despite this. analysis of covariance with apnea duration as the covariate confirmed a significant independent increase in postapnea breath volume after naloxone (p = 0.001). Naloxone also altered sleep architecture. increasing percent time awake during the study period (prenaloxone. 36.3 +/- 15.6%; postnaloxone. 56.7 +/- 22.4%; p = 0.0003) and decreasing total sleep time and percent time in Stage 1. Furthermore. naloxone increased continuity of awake periods (mean length of awake periods increased from 27.0 +/- 8.4 to 66.0 +/- 66.6 s after naloxone. p = 0.05).
Upper respiratory tract environmental tobacco smoke sensitivity, Some patients report rhinitis symptoms after exposure to environmental tobacco smoke (ETS). but objective assessments of this response have been lacking. Furthermore. the mechanism of this response is unknown. We assessed the frequency of ETS-related symptoms by administering a questionnaire to 77 healthy nonsmoking young adults who were participating in an unrelated study. Of the subjects 34% (26 of 77) reported one or more rhinitis symptoms (congestion. rhinorrhea. or sneezing) following ETS exposure. We then exposed 10 historically ETS-sensitive (ETS-S) and 11 historically ETS-nonsensitive (ETS-NS) subjects to 15 min of clean air followed by 15 min of sidestream tobacco smoke (CO concentration of 45 parts per million). At selected time points during these procedures we recorded symptoms. posterior nasal resistance. and spirometry and performed nasal lavages. ETS-S but not ETS-NS subjects reported significant (p less than 0.01) increases in nasal congestion. headache. chest discomfort or tightness. and cough following exposure to sidestream tobacco smoke. Rhinorrhea symptoms were greater and more prolonged in ETS-S subjects compared to ETS-NS subjects. Significant (p less than 0.01) increases in perception of odor and in eye. nose. and throat irritation occurred in both study groups. but ETS-S subjects reported significantly more nose and throat irritation. No significant changes in posterior nasal resistance occurred in the ETS-NS group but a significant increase occurred in the ETS-S subjects. with the resistance rising from 3.8 +/- 0.5 cm H2O/L/s (mean +/- SE) preexposure to a peak of 8.0 +/- 2.7 cm H2O/L/s 20 min after completion of the smoke exposure (p less than 0.001).
Influence of progressive and of transient hypoxia on upper airway resistance in normal humans, In order to evaluate the influence of hypoxia on upper airway patency. we measured the response of upper airway resistance (UAR) to progressive (P) normocapnic hypoxia (Rebuck's method) and transient (T) hypoxia (three to five breaths to 100% N2) in 11 normal men. Breath-by-breath inspiratory UAR was calculated at isoflow during exclusive nasal breathing. The UAR response to hypoxia was characterized by the changes in nasal resistance and pharyngeal resistance (PR) as a function of SaO2. mean inspiratory flow (VT/Tl). and changes in the end-expiratory lung volume (EELV) measured with an inductance vest. The ventilatory response to hypoxia was greater during T (-0.31 +/- 0.03 L/min/%SaO2; mean +/- SEM) than during P (-0.27 +/- 0.03 L/min/%SaO2. p = 0.05). UAR decreased as SaO2 decreased; this decrease was steeper during T than during P hypoxia (delta PR/%SaO2: 3.9 +/- 0.5 during P and 2.5 +/- 0.2 during T. p = 0.05). For the whole group. there was no difference in the slope of the decrease in UAR with increasing VT/Tl between the two hypoxic tests (delta PR/delta VT/Tl: -0.85 +/- 0.1 during P and -0.70 +/- 0.1 during T. p greater than 0.05). However. in four subjects. the slope of the relationship PR/VT/Tl during T remained steeper than during P. EELV increased as SaO2 decreased. with a greater increase during progressive than during transient hypoxia.
Time course of change in bronchial reactivity with an inhaled corticosteroid in asthma, The time course of change in FEV1. bronchial reactivity. and daily measures of asthma control (peak expiratory flow. symptoms. and beta 2-agonist inhaler use) was determined during 6 wk of treatment with inhaled budesonide. 800 micrograms twice a day. and for 2 wk following cessation of treatment in 40 asthmatic subjects in a double-blind. placebo-controlled. parallel group study. Histamine reactivity. expressed as the provocative dose of histamine causing a 20% fall in FEV1 (PD20). was measured at intervals during the 8 wk of the study. with more frequent measurements after the first and last dose of drug to provide a detailed profile of change at the start and end of treatment. The first dose of budesonide caused a small increase in median values of FEV1 (0.2 L) and PD20 (1.0 doubling dose of histamine). which was maximum at 6 h. There was a further increase in FEV1 and PD20 over the 6 wk in the budesonide group relative to placebo. the maximum increases (0.53 L. 3.4 doubling doses of histamine) being recorded 6 h after the last dose on Day 42. Following cessation of treatment. FEV1 and PD20 declined and PD20 returned to placebo values at 1 wk. Median PEF increased by 40 and 30 L/min in the morning and evening. respectively. with budesonide treatment. Symptom scores and beta 2-agonist inhaler use were lower in the budesonide group than the placebo group during treatment but tended to be similar (symptom scores) or higher (beta 2-agonist) in the 2 wk following cessation of treatment.
Effect of inhaled furosemide and bumetanide on adenosine 5'-monophosphate- and sodium metabisulfite-induced bronchoconstriction in asthmatic subjects, Inhaled furosemide. a high ceiling diuretic. inhibits bronchoconstrictor responses to sodium metabisulfite (MBS) and other indirect challenges by unknown mechanisms. Furosemide acts by inhibition of Na+/Cl- transport in renal tubules and may exert similar effects on asthmatic airways. To evaluate this hypothesis we compared the effects of nebulized furosemide with those of bumetanide. another high ceiling diuretic that inhibits Na+/Cl- transport. on bronchial challenge with adenosine 5'-monophosphate (AMP) and MBS in 16 asthmatic subjects. We also studied the effects of furosemide on histamine-induced bronchoconstriction in seven of these subjects. Nine subjects inhaled furosemide (30 mg) or placebo (P) 30 min before challenge with nebulized AMP (0.39 to 400 mg/ml). Seven returned for similar study with histamine (0.125 to 32 mg/ml). In another study. seven subjects inhaled bumetanide (2 mg) or P 5 and 30 min before AMP and MBS (0.3 to 80 mg/ml) challenge. The provocative concentration causing a 20% fall in FEV1 (logPC20) was calculated by linear interpolation of log dose-response curves. Furosemide (F) significantly attenuated responses to AMP: mean +/- SEM logPC20. 1.59 +/- 0.24 (geometric mean PC20 [GM]. 39.0 mg/ml) after F and 0.98 +/- 0.29 (GM. 9.5 mg/ml) after P (p less than 0.01). but it did not alter responsiveness to histamine: logPC20. 0.09 +/- 0.17 (GM 1.2 mg/ml) after F and 0.09 +/- 0.20 (GM. 1.2 mg/ml) after P.
Neutrophil retention in the lungs of patients with chronic obstructive pulmonary disease, In order to study neutrophil traffic in the lungs of humans. we harvested autologous neutrophils and radiolabeled them with indium-111 prior to reinjection. The passage of these [111In]neutrophils through the pulmonary vasculature was compared with that of [99mTc]erythrocytes in normal elderly subjects and in patients with chronic obstructive pulmonary disease (COPD). Neutrophil sequestration within the lungs of seven normal subjects. 10 min after reinjection. correlated with local erythrocyte transit times in the lungs (tau = 0.72. p less than 0.001). This relationship was lost in patients with COPD. In seven patients studied during an acute exacerbation of COPD. neutrophil retention was higher during the first passage through the lungs (mean. 22.0 SD 14.1%) compared with 14 patients studied when their condition was stable (16.3 SD 3.4%. p less than 0.001). or to the normal elderly subjects (13.7 SD 7.0%. p less than 0.001). In addition. the subsequent rate of neutrophil washout from the lungs was slower in patients with acute COPD (1.93 SD 0.66 x 10(-3)s1) than in those with stable disease (3.08 SD 1.8 x 10(-3)s-1. p less than 0.02). Neutrophil retention in the lungs correlated inversely with the extent of emphysema. assessed quantitatively by CT scanning (tau = 0.68. p less than 0.05). Thus. patients presenting with acute exacerbations of COPD have an increased neutrophil burden in the pulmonary vasculature with the potential for increased lung proteolysis.
Evidence that genetic emphysema in tight-skin mice is not caused by neutrophil elastase, Mutant tight-skin mice that had severe pulmonary emphysema were crossed with beige mice that contained neutrophils deficient in elastase activity. The resultant tight skin-beige cross mice were deficient in neutrophil elastase activity. yet they were still afflicted with the same degree of severe emphysema as the tight-skin mice. The results indicate that neutrophil elastase does not cause the emphysematous lesions found in tight-skin mice.
Snowmobile trauma: an eleven-year experience, Records of 88 patients with snowmobile injuries from 1977 to 1987 were reviewed to identify the types of trauma. Data collected included age. sex. method and degree of injury. use of safety attire. and risk factors. There were 77 males and 11 females. Seventeen (19.3%) were children under the age of 16. Poor driving judgment involved in the hitting of obstacles led to the majority of injuries. There were 106 fractures in 71 patients. Eighteen patients (25%) had more than one fracture. Eleven patients had loss of consciousness. Eighty-eight other injuries resulted for a total of 205 injuries. There were three fatalities. Results indicate that inexperience. prior use of alcohol. driver carelessness. excessive speed. and poor adherence to manufacturer recommendations were the leading contributors to the accidents.
Trauma center closure: effects on an adjacent trauma center, The effects of the closure of a busy trauma center on an adjacent university trauma hospital were analyzed. Significant increases were found in monthly volume (P less than .01) and frequency of penetrating injuries (P less than .05) and significant decreases in patients with insurance coverage (P less than .01) and numbers requiring intensive care (P less than .01). The authors conclude that trauma center closures have significant and measurable effects which influence allocation of scarce resources within remaining hospitals and generate pressures to transfer patients to overburdened public facilities. Transfers undermine continuity of care and education and further threaten the integrity of the trauma system.
Safety of triple lumen catheters in the critically ill, The authors performed this prospective study to determine the infection rate of triple lumen catheters (TLC) in their surgical intensive care unit (SICU) patient population. Patients who required a central venous line for the first time while in their SICU were studied. Those with preexisting catheter infections. bacteremias. and TLC reinsertions were excluded. TLC was placed through the internal jugular or the subclavian vein and all peripheral lines were removed. The distal port was used for parenteral nutrition and the other two ports were used for fluids and medications. Dressings were changed daily and blood cultures were obtained through each port of the TLC. At the time of catheter removal. blood. catheter tip. and the subcutaneous tract were cultured. Duration of catheterization was recorded. Eighty-six catheters were studied. The mean duration of catheterization was 6.2 days and the range was two to 23 days. Six of 86 (6.9%) catheter tip cultures were positive and the remaining 80 (93.1%) were negative. Two positive tips (2.3%) had negative blood cultures for two catheter infections (CIs). The remaining four catheters (4.6%) had associated bacteremias for four catheter sepsis (CS). The two catheter infections occurred among catheters indwelling for 10 days or less while the four cases of catheter sepsis occurred among catheters indwelling longer than 10 days. In conclusion. triple lumen catheters can be safely left in place for up to 10 days with minimal risk for bacteremia.
The utility of cardiac evaluation in the hemodynamically stable patient with suspected myocardial contusion, Myocardial contusion following isolated blunt thoracic trauma (BTT) remains a diagnostic and therapeutic dilemma. To identify the presence of cardiac abnormality following BTT. 123 hemodynamically stable patients were prospectively evaluated with serial electrocardiograms (ECG) and cardiac enzymes (total CPK and CPK-MB). Gated cardiac radionuclide angiography (MUGA) scans were performed within 48 hours following admission. Patients included in the study sustained significant thoracic trauma identified by physical findings or mechanism of injury. Sixty-three patients (51%) were identified with either abnormal ECG. or abnormal total CPK. CPK-MB. MUGA scan. or combination of the above. Thirty-seven patients (58.7%) manifested an ECG abnormality defined as ST-segment or T-wave abnormality. Twenty-two patients (34.9%) had total CPK value greater than or equal to 50 International Units (I.U.) or CPK-MB fractions greater than or equal to five per cent. MUGA scan was abnormal (right ventricular ejection fraction less than 40 per cent and/or wall motion abnormality) in 12 patients (19%). Eight patients with MUGA scan abnormality had normal ECG and/or normal total CPK. CPK-MB values. Evaluation of all patients up to six months revealed no mortality. malignant arrhythmias. or cardiac failure.
Spraying of aerosolized fibrin glue in the treatment of nonsuturable hemorrhage, In the present report. the authors describe the use of aerosolized fibrin glue (FG) to achieve hemostasis in patients with nonsuturable hemorrhage. The multicomponent FG was sprayed on bleeding tissues with a dual chamber spray head that allowed simultaneous application and mixing of fibrinogen and thrombin on the tissue surface. Sterile propellant gas was passed through tubing to the spray head and independently controlled. allowing for drying of the tissue surface immediately before FG application. This technique was found to be effective in achieving hemostasis of parenchymal organs. retroperitoneal surfaces. and skin graft donor sites. Additional potential applications of this technique include the control of hemorrhage from mediastinal and pleural surfaces.
Clostridial bacteremia: implications for the surgeon, Clostridial bacteremia is rare and has a variable presentation from asymptomatic to septic shock with disseminated intravascular coagulation (DIC). red cell hemolysis. and rapid death. In order to delineate the predisposing and prognostic factors in these patients. the authors reviewed 47 cases of clostridial bacteremia presenting over a seven year period at a major metropolitan teaching hospital. Predisposing factors included locally decreased oxidation reduction potential (Eh) in 43 per cent (including atherosclerosis. diabetes. and radiation therapy). systemic immunosuppression in 53 per cent (including alcohol abuse. chemotherapy. steroids. and malignancy). and a site of epithelial barrier disruption. The sites of clostridial invasion included: gastrointestinal tract (GI) (n = 22). pulmonary (n = 7). cutaneous (n = 7). undetermined (n = 7). and female genital tract (n = 4). Seven patients were found to have malignancy. Seventy-nine per cent of the blood culture isolates were histotoxic species (Clostridia perfringens and C. septicum). The overall mortality was 47 per cent. Significant differences between survivors and deaths included DIC. new onset renal failure. severe atherosclerotic disease. and age (P less than .05). The authors conclude that clostridial bacteremia is uncommon but highly lethal and may occur when decreased tissue Eh. systemic immunosuppression. and an epithelial barrier disruption are present. Poor outcome appears to be a reflection of advanced age. underlying illness. and presence of a histotoxic species.
Anatomy of the accident scene: a prospective study of injury and mortality, This study of the accident scene focuses on the effects of vehicular deformity and restraint devices on occupant injury. In 500 patients evaluated in a Level I trauma center. seatbelts significantly reduced the likelihood of individuals' requiring the trauma center (P less than 0.0001). Seatbelts also significantly reduced the mortality rate of those who were transported to the trauma center (P less than 0.04). Dashboard intrusion correlated with pelvic (P less than 0.001) and femur (P less than 0.03) fractures. closed head injuries (P less than 0.001). and intraabdominal injuries (P less than 0.02). Steering wheel deformity correlated with pelvic fractures (P less than 0.001) and closed head injuries (P less than 0.005). Windshield violation correlated with closed head injuries (P less than 0.014) and spinal fractures (P less than 0.03). Irreparable vehicles correlated with pelvic (P less than 0.0001) and femur fractures (P less than 0.01). closed head injuries (P less than 0.0001) and intra-abdominal injuries (P less than 0.0001). The authors conclude that a careful examination of the accident scene for specific mechanisms of injury can lead to better prehospital care. more rapid and consistent diagnosis of injury. and improved patient outcome. Further prospective studies should accumulate data that will improve prehospital care. alert physicians to possible injury. increase community awareness of injury prevention. and improve vehicle construction.
Survival after massive transfusions exceeding four blood volumes in patients with blunt injuries, The authors' experience with 29 patients with blunt injuries who sustained massive transfusions exceeding four blood volumes in the initial posttraumatic 12 hours was reviewed. The overall mortality was 62 per cent. Only one patient survived when the amount of transfusions exceeded 50 units. The most common bleeding sites were abdominal and pelvic. Half of the dead succumbed within the first 24 hours. Of those who died. seven died from brain injury. six from multiple organ failure (MOF). and five from uncontrollable bleeding. Initial shock was observed in 55 per cent of patients. The high mortality of patients with massive transfusions and MOF related to the duration of shock strongly promote the importance of initial volume resuscitation.
Diuretic drug use and the risk for hip fracture, OBJECTIVE: To test the hypothesis that use of thiazide diuretics prevents hip fracture and to study the risk for hip fracture associated with furosemide use. DESIGN: A case-control study. SETTING: Hospitals owned by a health maintenance organization in Washington. PATIENTS: Elderly patients (n = 462) hospitalized because of a hip fracture between 1977 and 1983 and an equal number of age- and sex-matched population-based control patients. MEASUREMENTS: Use of thiazide diuretics and furosemide was ascertained from medical records and computerized pharmacy records. The relative risk for hip fracture associated with diuretic use was calculated and adjusted for the potentially confounding effects of nursing home residence; previous hospitalizations; a history of stroke. alcoholism. or the organic brain syndrome; body weight; leg paralysis; and use of phenobarbital. corticosteroids. or other diuretics. Current and former users of diuretics were analyzed separately. MAIN RESULTS: The adjusted risk for hip fracture was 1.6 (95% CI. 1.0 to 2.5) for current thiazide users. The adjusted risk for hip fracture for current furosemide use was 3.9 (CI. 1.5 to 10.4). CONCLUSIONS: According to this study. use of thiazide diuretics did not protect against hip fracture and cannot be recommended for fracture prevention. Current furosemide use was also associated with hip fracture.
Intravascular ultrasound assessment of the renal artery, OBJECTIVE: To determine the feasibility and diagnostic value of catheter-based intravascular ultrasound imaging compared with angiography for visualizing renal artery structure. DESIGN: Renal artery images were obtained in patients with renal artery stenosis having percutaneous balloon angioplasty and in normal subjects by digital angiography and by a 20-MHz. mechanically driven. catheter-based. intravascular ultrasound imaging system. SETTING: A referral-based university hospital. PATIENTS: Four randomly selected normal subjects without known renal disease and four consecutive patients with known renal artery stenosis referred for percutaneous balloon angioplasty. INTERVENTIONS: Digital angiograms and intravascular ultrasound images of nine renal artery segments were obtained. In patients with renal artery stenosis. imaging was done before and after balloon angioplasty. MAIN RESULTS: Digital angiography and ultrasonography correlated closely in the determination of arterial lumen diameter (r = 0.81) and cross-sectional area (r = 0.83). However. ultrasonography provided structural information not shown by angiography. All normal arteries showed discrete intimal. medial. and adventitial wall layers by ultrasonography. In the five stenotic segments. angiography identified the cause of stenosis to be atherosclerosis in four patients and fibromuscular dysplasia in one patient. Ultrasound imaging. however. identified the disease process as atherosclerosis in three patients and as fibromuscular dysplasia in two patients. After renal angioplasty. ultrasonography identified three arterial dissections. only one of which was shown by angiography. CONCLUSIONS: These preliminary data indicate that catheter-based intravascular ultrasound imaging of the renal artery is feasible and correlates well with angiography in assessing renal artery size and also provides potentially important additional structural information that permits a better characterization of arterial pathology.
Adjuncts to thrombolysis for myocardial reperfusion, OBJECTIVE: To discuss adjunctive pharmacologic agents for acute myocardial infarction. to critique their initial effects in clinical trials. and to review their potential for improving the clinical conditions of patients with acute myocardial infarction. DATA SOURCES: Relevant studies reported from January 1985 to December 1990 were identified through a MEDLINE search of the English-language literature and through a manual search of the bibliographies of all identified articles. STUDY SELECTION: Peer-reviewed experimental and clinical studies evaluating the role of pharmacologic adjuncts to thrombolytic therapy in experimental models of coronary occlusion and clinical trials of patients with acute myocardial infarction were selected for review. DATA EXTRACTION AND SYNTHESIS: The data presented were abstracted by the investigators. Differences with a univariate P value of less than 0.05 were considered to be statistically significant. CONCLUSIONS: Current clinical data suggest that adjunctive pharmacologic therapy to thrombolytic agents should include aspirin. at least 160 mg administered as soon as possible after the onset of symptoms; intravenous heparin; and. in selected patients without contraindications. intravenous beta-blockading agents.
Insulin plus a sulfonylurea agent for treating type 2 diabetes, PURPOSE: To review the recent literature on the efficacy of combined insulin and sulfonylurea therapy in patients with type 2 diabetes. DATA SOURCES: Pertinent articles were obtained through an English-language MEDLINE search from 1979 to 1990 and from the references of these articles. STUDY SELECTION: We reviewed the studies in which patients with poorly controlled diabetes received insulin and a sulfonylurea agent and in which insulin treatment alone (usually given in conjunction with a placebo) was compared with insulin plus sulfonylurea therapy. DATA EXTRACTION: Pre- and post-treatment insulin doses. blood glucose levels. glycated hemoglobin values. C-peptide levels. and insulin levels were analyzed. Other data were analyzed separately. RESULTS OF DATA SYNTHESIS: Data from similar trials were compared. Data from concurrent trials were analyzed separately from data derived from cross-over trials. Weighted mean fasting blood glucose levels. glycated hemoglobin levels. insulin dosage. and fasting C-peptide concentrations were determined for insulin plus placebo and insulin plus sulfonylurea agent groups for both types of studies. In concurrent trials. the weighted mean post-treatment glycated hemoglobin level was 11.1% after insulin plus placebo compared with 10.0% after insulin plus a sulfonylurea agent. In cross-over trials. the corresponding values were 10.6% and 9.8%. CONCLUSIONS: Combination therapy with insulin and a sulfonylurea agent only slightly improved glycemic control in patients with type 2 diabetes. When a sulfonylurea agent was used. less exogenous insulin was needed. but fasting serum insulin levels were not different between the treatment groups. Such therapy did not produce nearly normal blood glucose concentrations and therefore should not be used in patients with poorly controlled type 2 diabetes receiving insulin.
Bronchoalveolar lavage cell data in 19 patients with drug-associated pneumonitis (except amiodarone) [published erratum appears in Chest 1991 Jun;99(6):1556, We examined bronchoalveolar lavage (BAL) cell data from 19 patients with a lung disorder presenting clinical. radiologic. functional. and course characteristics of drug-associated interstitial pneumonitis. In each of them. one of 13 different drugs was incriminated and no other cause was found. In one case due to bleomycin. a neutrophil and eosinophil alveolitis was present. In the other 18. the common denominator was a lymphocyte alveolitis. either pure (n = 6) or associated with neutrophilia (n = 5). eosinophilia (n = 3). or neutrophilia and eosinophilia (n = 4). In addition. in all patients. an inverted CD4/CD8 lymphocyte ratio was observed. In eight patients who underwent another BAL. lymphocyte alveolitis decreased but was persistent in two of them two to four months after cessation of treatment with the drug incriminated. whereas interstitial pneumonitis had resolved clinically. In five patients. after resolution of pneumonitis and after an almost normal BAL cell profile was obtained. resumption of treatment with the suspected drug for two to four weeks induced a rise in lymphocyte population in a third BAL. In conclusion. apart from one case of bleomycin lung. the most striking feature of drug-associated alveolitis in this series was expansion of lymphocyte population and imbalance in lymphocyte subsets. When a provocation test was performed. variations in alveolar lymphocyte levels paralleled withdrawal and readministration of the drug responsible for alveolitis. These data could be of value in diagnosing and understanding drug-induced lung disorders.
Cellular, immunologic and biochemical characterization of topical retinoic acid-treated human skin [published erratum appears in J Invest Dermatol 1991 Jun;96(6):814, Histologic and clinical improvement of sun-exposed skin following topical treatment with retinoic acid has been reported. Daily application of retinoic acid typically results within 2-5 d in an erythematous scaling reaction. which lessens with continued usage. The cellular. immunologic. and biochemical basis of this retinoid reaction and its role in the repair of photodamaged skin are not known. To investigate the retinoid reaction in man. we have treated non-sun-exposed skin with 0.1% retinoic acid cream (Retin-A. Ortho Pharmaceutical Corporation. Raritan. NJ) under occlusion for 4 d to induce erythema and then examined changes in 1) histology. 2) expression of cell-surface molecules. 3) the enzymes and second messengers of the phospholipase C/protein kinase C signal-transduction system. 4) levels of eicosanoids. and 5) levels of interleukin-1 protein and mRNA. These parameters were chosen for measurement both because they are indicators of epidermal function and previous studies suggest they may be responsive to retinoic acid treatment. Epidermal cell growth as judged by increased epidermal thickness and mitotic figures was significantly increased in retinoic acid-treated skin compared to vehicle-treated controls. Increased numbers of CD4+ T cells accompanied by prominence of dermal dendrocytes in the papillary dermis and focal keratinocyte expression of intercellular adhesion molecule-1 were observed in retinoic acid-treated biopsies. Phosphoinositide-specific phospholipase C activity and 1.2-diacylglycerol content were also elevated in retinoic acid-treated epidermis. Protein kinase C activity was reduced by one third in both the soluble and membrane fraction. suggesting down-regulation. Surprisingly. in view of the inflammatory nature of the retinoid reaction. no increases were observed in arachidonic acid. its metabolites. interleukin-1 alpha. or interleukin-1 beta. To examine the specificity of the retinoid reaction. subjects were treated with the irritant sodium lauryl sulfate. under conditions that resulted in a reaction clinically similar to that observed with retinoic acid. The histologic alterations induced by sodium lauryl sulfate were found to be indistinguishable from those induced by retinoic acid. These data indicate that. although a wide range of cellular and molecular alterations occur in retinoic acid-treated skin. these changes may not be necessarily specific or unique for retinoic acid.
Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis, The toxicity profiles of 7 disease modifying antirheumatic drugs (DMARD) (hydroxychloroquine. intramuscular (im) gold. D-penicillamine. oral gold. methotrexate (MTX). azathioprine and cyclophosphamide) were evaluated in 2.479 patients with rheumatoid arthritis consecutively enrolled at 5 centers in the Arthritis. Rheumatism and Aging Medical Information System (ARAMIS) program. Incidence rates for side effects are reported as events/1000 patient-years. Our descriptive study revealed an individual profile of prevalent toxicities for each drug. Oral gold was characterized by substantial lower gastrointestinal (GI) toxicity (diarrhea 391 events/1000 patient-years. loose bowel movement 148. lower abdominal pain 76). MTX by hepatotoxicity (47) while D-penicillamine had the only clinically significant incidence of altered taste (40). MTX users reported the most mucosal ulcers (87). followed by oral gold (76). im gold (55) and D-penicillamine (38). Rash was frequently seen with gold compounds and D-penicillamine. while upper GI toxicity was common with immunosuppressive agents. Cyclophosphamide had 48% discontinuations within 6 months. MTX had the lowest discontinuation rate in the first 6 months. but then showed little difference from im gold. A preliminary similarity index was developed to compare the toxicity profiles of various DMARD. Close similarities were found between toxicity profiles of im gold and D-penicillamine. and between azathioprine and MTX. Oral gold had a unique toxicity pattern. Knowledge of these different toxicity patterns can enable more appropriate selection of agents for particular patients.
Segregation analysis of the structural genes of the major fibrillar collagens provides further evidence of molecular heterogeneity in type II Ehlers-Danlos syndrome, Type II Ehlers-Danlos syndrome (EDS) is one of a group of disorders characterized by striking abnormalities of the soft connective tissues. The major fibrillar collagens (types I and III) found in these tissues have important stress-bearing functions and abnormal collagen could therefore account for the clinical features of this condition. We have used a number of restriction site dimorphisms. tightly linked to the structural genes of type I collagen (COL1A1 COL1A2) and type III collagen (COL3A1). to investigate the segregation of corresponding alleles in three pedigrees in which type II EDS was clearly inherited as a dominant trait. Discordant segregation of all three collagen genes was seen in a large pedigree that included 17 affected individuals with the typical phenotype of type II EDS. Thus mutations in neither type I nor type III collagen genes were responsible for the disease in this family. In a second small pedigree discordant segregation of the disease with both type I collagen loci was observed while the concordant segregation seen at COL3A1 could easily have arisen by chance (P = 0.5). The third pedigree was uninformative at all three collagen loci because of inability to discriminate between the parental alleles. These results suggest that there may be molecular heterogeneity of type II EDS since abnormalities of type I collagen have been described in other individuals phenotypically similar to those in our study.
Interleukin-6 activity in paired samples of synovial fluid. Correlation of synovial fluid interleukin-6 levels with clinical and laboratory parameters of inflammation, Paired synovial fluid (SF) samples obtained from the knees of 12 arthritis patients were studied to establish a relation between parameters of local inflammatory activity and SF interleukin-6 (IL-6) levels. Local disease activity was scored using joint temperature. swelling and pain as clinical parameters of inflammation. SF samples were assayed for laboratory parameters of inflammation such as leucocyte content. the percentage polymorphonuclear cells. the pH. and for immunoglobulin levels (IgG. IgM). SF IL-6 concentrations were determined using the B9-bioassay. Within individual patients the local activity of inflammation as measured using clinical parameters was found to be related to the local SF IL-6 level. When considering the total group of patients. a correlation (P less than 0.001) was found between the clinical parameters of local inflammation and the SF IL-6 levels. Furthermore. IL-6 levels were found to correlate with leucocyte counts (P less than 0.02). the percentage of polymorphonuclear cells (P less than 0.10). the pH value (P less than 0.01). but not with SF IgM and IgG concentrations.
Pyroelectric vidicon thermography and cold challenge quantify the severity of Raynaud's phenomenon, Thermographic images of the hands of patients with primary and secondary Raynaud's phenomenon and of a group of normal subjects. recorded before and after cold provocation using a pyroelectric vidicon thermal imaging system. showed differences in thermal distribution patterns that were characteristic of primary Raynaud's phenomenon (RP). scleroderma (RS) and normal. and were exaggerated by cold provocation. The responses to cold challenge. assessed by computing the mean temperature of the hand as it recovered from cold challenge and plotting these values against time to produce a rewarming curve. were also characteristic of the patient and the normal groups. and gave an indication of the severity of circulatory impairment. Methods are described for the simple numerical characterization of these parameters.
Primary Raynaud's phenomenon in early childhood, Three young children. aged 17 months. 26 months and 29 months. presented with primary Raynaud's phenomenon. One was treated with nifedipine. Raynaud's phenomenon is rare in children and as a result experience in its treatment limited. Previously reported cases of childhood Raynaud's are reviewed. and approaches to management discussed.
Isolated ACTH deficiency presenting with bilateral frozen shoulder, We describe a 55-year-old female who presented with a 1-year history of tiredness. depression and painful stiff joints. The most striking clinical abnormality was bilateral frozen shoulders. local corticosteroid treatment of which provided the first diagnostic clue. She was found to have profound diminution of plasma cortisol secondary to an isolated deficiency of ACTH. There was no obvious cause for this. Steroid replacement eradicated her lethargy within 3 months and evidence of frozen shoulders resolved completely.
Malignant melanoma in the 1990s: the continued importance of early detection and the role of physician examination and self-examination of the skin, Despite the exciting new techniques being developed to help diagnose early malignant melanoma. the current standard of care remains periodic examination of the skin. The combination of routine physician examination coupled with self-examination of the skin provides an opportunity for the identification of early malignant melanoma. Removal of such thin lesions can significantly reduce the ever-increasing mortality rate from this potentially serious form of cutaneous cancer.
Cytologic detection of colorectal cancer after administration of oral lavage solution, Whether malignant cells can be detected in the bowel movements induced by oral gut lavage solution administration was studied in patients with known colonic adenocarcinomas. The induced bowel movements were collected in 27 patients. nine of whom had cancer proven by anatomic pathologic examination. The cells present were recovered with a simple technique and stained by the Papanicolaou method. Malignant cells were identified in the stained preparations in all nine patients with cancer (100% sensitivity). and there were few false positives (94.5% specificity). The authors concluded that if additional studies with greater numbers of subjects confirm the reliability of this technique. a test may be developed that would be useful for either early detection or screening.
Elevated tissue concentrations of sialyl Lex-i in cancerous tissues compared with those in noncancerous tissues of various organs, Sialyl Lex-i (SLX) concentrations in the extracts of noncancerous and cancerous tissues of various human organs were determined by radioimmunoassay for detailed evaluation of SLX. Cancerous tissues had significantly elevated SLX concentrations compared with noncancerous tissues of various organs. Tissue SLX concentration of the cancerous part was significantly higher than that of the adjacent noncancerous part in the same tissue. There was no significant correlation between tissue SLX concentration and serum SLX level. Positive localization of SLX was clearly observed in such cancerous tissues by immunohistochemical study. although not in any noncancerous tissues. Each of the antigens: SLX. CA 19-9. carcinoembryonic antigen. and CA 125 showed a different distribution pattern in tissue concentration or localization in various organs. These results indicate that SLX may be a valuable cancer-associated antigen produced by malignant tissues. suggesting its clinical application as a tumor marker.
Clinicopathologic study of large cell anaplastic lymphoma (Ki-1-positive large cell lymphoma) among the Japanese, The clinical. prognostic. phenotypic. and genotypic findings of 30 patients with large cell anaplastic lymphoma (Ki-1-positive large cell lymphoma) were analyzed. There were 13 male and 17 female patients (male-female ratio. 0.8) whose ages ranged from 3 to 81 years of age (mean. 28 years of age; 67% of the patients younger than 30 years of age). The 5-year survival rate was 52%; this was better than that of other types of high-grade peripheral T-cell lymphoma. Histologic examination showed distinctive morphologic features such as tumor cell pleomorphism. sinus infiltration. fibrosis. partial lymph node involvement. sparing of B-cell regions. and occasional plasma cell infiltrates. Eighty percent of the cases were of T-cell phenotype. and others expressed neither B-cell nor T-cell markers. The tumors were frequently positive for a histocompatibility antigen (HLA-DR). CD25 (the interleukin-2 receptor). and epithelial membrane antigen. Rearrangements of the T-cell receptor beta gene were observed in nine of 13 cases (69%). These findings indicated that many of the tumors had the phenotype and genotype of activated T-cells. This study also showed that large cell anaplastic lymphoma has a survival figure intermediate between Hodgkin's disease and low-grade peripheral T-cell lymphoma.
Use of aspiration cytology and frozen section examination for management of benign and malignant thyroid nodules, Between January 1980 and December 1988. 161 patients underwent thyroidectomy with intraoperative frozen section consultation after fine-needle aspiration (FNA) of a thyroid nodule. The FNA were insufficient in 15 instances (9%) and in error in 39 (24%). In 15 cases. the incorrect aspiration diagnosis could have led to excessive surgery and in ten cases to delayed therapy if it had been the only guide for therapy. The diagnosis was deferred to permanent section analysis in 30 (19%) frozen sections. Twenty-two errors (14% of cases) were made in the interpretation of frozen section material. and in an additional 15 patients (9%). the diagnosis suggested (but deferred at frozen section) was in error. In one patient. this error could have led to more extensive surgery than necessary; in 21 patients. the frozen section error could have led to undertreatment. When frozen section results were combined with those of FNA. no therapeutically important false-positive diagnoses were made. In five patients. the combination of both FNA and frozen section results would not have identified a carcinoma which. in three cases. was a small occult papillary carcinoma not found in the index nodule.
Clinical significance of the expression of epidermal growth factor and its receptor in esophageal cancer, The epidermal growth factor receptor (EGFR) level in 56 esophageal cancer tissues was measured by 125I-EGF binding assay to elucidate its role in tumor progression. The survival rate of patients with high EGFR level (more than 50 fmol/mg protein) was significantly lower than that of patients with low EGFR level (less than 50 fmol/mg protein. P less than 0.01). although a correlation between EGFR level and the pathologic findings was not observed. The expression of EGF was examined immunohistochemically using anti-EGF monoclonal antibody in 100 esophageal cancer tissues; EGF-positive tumor cells were detected in 92.0%. The immunoreactivity of EGF was classified arbitrarily into four grades according to the number of stained tumor cells. The expression of EGF significantly correlated with the differentiation of esophageal squamous cell carcinoma (P less than 0.01. by chi-square test). The survival rate of patients with high EGF immunoreactivity (Grade 2 or 3) was much lower than in those with lower grade (0 or 1) tumors. (P less than 0.01). Patients with both high EGFR level and EGF immunoreactivity had a much worse prognosis than if both were low. Furthermore. the mitotic index was higher in groups with both high EGFR and EGF than if both were low (16.39 +/- 5.35 versus 6.90 +/- 3.31). These results suggest that EGF and EGFR in the autocrine system may play an important role in tumor progression in esophageal cancer and their expression could be of prognostic significance.
The possibility of diagnosing small pancreatic cancer (less than 4.0 cm) by measuring various serum tumor markers. A retrospective study, Comparative studies measuring various tumor markers such as SPan-1. CA 19-9. carcinoembryonic antigen (CEA). DUPAN-2. and elastase I were done in 74 patients with small pancreatic cancer including 23 cases of T1 pancreatic cancer (tumor size less than 2.0 cm) and 51 cases of T2 pancreatic cancer (tumor size between 2.1 to 4.0 cm). retrospectively. Although the mean value of these tumor markers in T1 and T2 pancreatic cancer were higher than those of the control cutoff levels. their sensitivities were different. In T1 pancreatic cancer. 13 of 23 cases (56.5%) of SPan-1 and 14 of 23 cases of (60.7%) of CA 19-9 had levels above normal. Although the numbers of patients were small. sensitivities of CEA. DUPAN-2. and elastase I were 30.8%. 22.2%. and 28.6%. respectively. In T2 pancreatic cancer. 41 of 51 cases (80.4%) of SPan-1 and 40 of 51 cases (78.4%) of CA 19-9 showed higher levels than normal. but only 46.9% of CEA. 40.0% of DUPAN-2. and 52.6% of elastase I were positive. The overall sensitivities in small pancreatic cancer (less than 4.0 cm) were 73% for SPan-1 and CA 19-9 but were less for CEA. DUPAN-2. and elastase I. These results indicate that even small pancreatic cancers release detectable pancreatic cancer-associated antigens in serum in more than 70% of cases. especially SPan-1 and CA 19-9. The measurement of these two tumor markers makes it possible to detect small pancreatic cancers after using imaging diagnostic procedures.
The malignant nature of papillary and cystic neoplasm of the pancreas, Two new cases of papillary and cystic neoplasm of the pancreas are reported. One patient was a 20-year-old woman with massive unresectable liver metastases. and the other was a 15-year-old boy. To study the natural history and malignant potential of this tumor. the English literature was reviewed to obtain an additional 56 cases. Clinical characteristics include pain and a mass in most patients. although many are found incidentally. Jaundice. hemoperitoneum. nausea. and vomiting are unusual findings. Most patients are treated by wide resection with good results. These tumors appear to be indolent. However. 16% of patients had major organ or blood vessel invasion. and 7% had liver metastases at some time during the course of their disease. illustrating the malignant nature of this tumor. Long-term follow-up is necessary to evaluate the efficacy of treatment. especially in the case of locally advanced and metastatic disease.
Multi-parameter flow cytometric quantitation of the expression of the tumor-associated antigen SM3 in normal and neoplastic ovarian tissues. A comparison with HMFG1 and HMFG2, SM3 is a monoclonal antibody that reacts with a peptide epitope in the core protein of polymorphic epithelial mucin. Multi-parameter flow cytometry was used to characterize the expression of SM3 and compare it with two related tumor-associated antigens. HMFG1 and HMFG2. in cell suspensions of 44 malignant ovarian tumors. 15 benign ovarian tumors. and 16 normal ovaries. Tumor-associated antigen expression was significantly higher in malignant ovarian neoplasms than in benign neoplasms (P less than 0.001 for all three antigens). SM3 was expressed more specifically in malignant than benign tumors but had a lower affinity than HMFG1 and HMFG2. Multi-parameter flow cytometric evaluation of a panel of monoclonal antibodies can be used to help in choosing the best antibody for immunohistochemistry. imaging. and eventually treatment of ovarian tumors.
Interrelationship between histopathologic characteristics of melanoma and estrogen receptor status, To evaluate whether the increase in disease-free survival and survival previously reported for women with melanomas with estrogen receptors (ER) was a reflection of the histopathology of the primary melanoma. the interrelationship of histopathologic characteristics of 143 patients with such tumors was examined. The ER was assayed in the primary tumor from 44 patients and in 99 metastatic deposits from the other patients. Tumor thickness. level of invasion. prognostic index. mitoses/mm2. ulceration. vascular invasion. necrosis. histologic grade. preexisting nevus. and predominant malignant cell type were examined. There was no relationship between ER presence and any histopathologic characteristic examined. irrespective of the tumor source (primary or metastatic). Examination of histopathologic characteristics as a function of sex and receptor status showed a slight but insignificant predominance of more well-differentiated. thinner tumors in women whose lesions were positive for the ER. These results suggest that the increased disease-free survival in patients with ER-positive lesions is not attributable to the pathologic characteristics of the primary tumor examined during this study.
A comparison of the clinical characteristics of first and second primary head and neck cancers. A population-based study, The clinical characteristics of 183 patients with second primary neoplasms in the head and neck region were compared with those of 20.598 patients with one primary tumor in the same region registered during the period 1973 to 1984 in the Surveillance. Epidemiology and End-Results Program. Second primary head and neck tumors were more likely to be diagnosed in a localized stage (47%) than if diagnosed as a single primary tumor (43%). but this difference was not significant. The tumor grade distribution was comparable in both groups. Using Cox proportional hazards modeling with age. sex. race. and stage as covariates. the median survival of patients with first and second head and neck cancer was identical (50 months). The survival of patients with localized second head and neck cancer was shorter than that of patients with single localized tumors (55 versus 102 months. P less than 0.026). Survival for regional tumors was similar (18 versus 21 months. not significant). The 84 second head and neck cancers in which the first head and neck cancer received radiation therapy (RT) had a median survival of 20 months; the 98 cases without prior RT had a median survival of 35 months. The high incidence of localized second cancers was probably due to the more intense surveillance. The worse survival in this group may be a result of prior RT or biologic characteristics of the tumor.
Natural history of vaginal intraepithelial neoplasia, The natural history of vaginal intraepithelial neoplasia (VAIN) was studied in 23 patients followed for at least 3 years with no treatment. The mean age of the patients was 41 years of age. A large proportion of the VAIN lesions (50%) were multifocal. and approximately one half of the lesions were associated with concomitant cervical or vulvar intraepithelial neoplasia. Progression to invasive vaginal carcinoma occurred in two (9%) cases. persistence of VAIN occurred in three (13%) cases. and regression of VAIN occurred in 18 (78%) cases. The risk for progression to invasive carcinoma emphasizes the significance of colposcopic examination of the vagina with directed biopsy specimens obtained from all lesions.
Solitary myeloma of the talus bone, Solitary myeloma can present as either extramedullary plasmacytoma or solitary plasmacytoma of bone (SPB). More than half of reported cases of SPB are localized to the spine. The rest include appendage long bones of the skeleton. pelvis. and skull. The first case of SPB (to the authors' knowledge) is reported involving the talus bone of the foot. Although approximately 50% of SPB patients progress to multiple myeloma in the first 3 years after diagnosis. aggressive local therapy is indicated because the median survival of patients with SPB is better than that for multiple myeloma.
A protocol for the safe administration of debrisoquine in biochemical epidemiologic research protocols for hospitalized patients, The genetically determined ability to metabolize the antihypertensive drug debrisoquine has been proposed as a genetic risk factor for primary carcinomas of the lung. To test this hypothesis. the metabolism of the drug was evaluated in a case control study. The subjects were characterized by their ability to metabolize debrisoquine after receiving a test dose of the drug followed by the collection of an 8-hour urine sample. They were classified by laboratory analysis into one of the following three groups: extensive. intermediate. and poor metabolizers. Poor metabolizers comprise 10% of the population and are unable to hydroxylate the drug. This group was expected to be at highest risk for deleterious effects from this medication. A protocol was created that included patient education and blood pressure monitoring to administer this medication safely to a group of patients with cancer who were already compromised. Although poor metabolizers showed a small decrease in systolic and diastolic blood pressure. no significant hypotensive episodes or clinical sequelae were observed in any of the groups. These data suggest that debrisoquine can be administered safely in a controlled clinical setting and will be useful for the characterization of lung cancer patients in biochemical epidemiology studies.
A randomized study of chemotherapy with procarbazine, vincristine, and lomustine with and without radiation therapy for astrocytoma grades 3 and/or 4, The authors undertook a controlled. prospective. randomized study of 171 patients with supratentorial astrocytoma grades 3 and/or 4 (classified according to Kernohan). All patients were given chemotherapy consisting of procarbazine. vincristine. and lomustine (CCNU) (PVC). Half of the patients received whole-brain irradiation (RT) to a dose of 5800 cGy in the tumor-bearing hemisphere and 5000 cGy in the contralateral hemisphere. After diagnosis of progressive tumor growth. patients received individual treatment. The endpoint of the study was time to progression. but cases were followed until the patients died. Median time to progression (MTP) for the whole randomized population was 21 weeks. Median survival time (MST) was 53 weeks; 18% of patients survived for 2 years or longer. Survival analysis showed that patients less than 50 years of age treated with PVC plus RT had significantly longer MTP (81 weeks) and MST (124 weeks) than all other patients. For patients less than 50 years of age treated with PVC alone. MTP was 21 weeks and MST was 66 weeks. For patients more than 50 years of age treated with PVC plus RT. MTP was 23 weeks and MST was 51 weeks; in the PVC group. MTP was 17 weeks and MST was 39 weeks. Age. Karnofsky index. areas of Grade 2. and absence of extensive necrosis in the tumor were significant prognostic factors in the univariate analyses. Patients less than 50 years of age treated with PVC plus RT had significantly longer survival (P = 0.037) when correcting for these factors in a multi-variate analysis.
What value is given to quality of life assessment by health professionals considering response to palliative chemotherapy for advanced cancer, A study was designed to obtain information on the importance of quality of life assessment (QL) during palliative chemotherapy. A questionnaire was answered by 542 health professionals (392 general practitioners. 20 specialist oncologists. and 130 oncology nurses). In both simulated patient situations and multiple-choice questions. all groups rated QL higher than other standard methods of assessment. General practitioners and oncologists appeared to weight the assessment criteria more equally than nurses who gave strong emphasis to QL. In the simulated patient situation. there was a small degree of interaction between QL and other assessment criteria. However. the analysis showed that QL was regarded as an independent variable and was considered to be the most important objective of palliative chemotherapy for advanced cancer.
A double-blind trial of tamoxifen plus prednisolone versus tamoxifen plus placebo in postmenopausal women with metastatic breast cancer. A collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic, This trial was conducted to determine if the reported superiority of tamoxifen (TAM) plus prednisolone (PRDLN) over TAM alone in postmenopausal women with metastatic breast cancer could be corroborated. A total of 326 patients were randomized on a double-blind trial to TAM (10 mg twice daily) plus placebo or TAM plus PRDLN (5 mg twice daily). Six patients (2%) were disqualified. Considering 256 patients with measurable or evaluable disease. objective responses were seen in 48 (38%) of 126 TAM patients and 61 (47%) of 130 TAM plus PRDLN patients (chi-square. P = 0.15). Considering all 320 evaluated patients. median time to disease progression was 11 months for TAM and 10 months for TAM plus PRDLN (log rank. P = 0.81). and median survival time was 35 and 32 months. respectively (P = 0.40). Covariate analyses showed no significant association between treatment and outcome. Weight gain and edema were significantly greater with TAM plus PRDLN. The addition of PRDLN to TAM is not advocated for the management of postmenopausal women with metastatic breast cancer.
No correlation between response and survival in patients with multiple myeloma treated with vincristine, melphalan, cyclophosphamide, and prednisone, A vincristine. melphalan. cyclophosphamide. and prednisone (VMCP) multi-drug regimen was used in 85 previously untreated patients with multiple myeloma (MM) (symptomatic Durie Stages II and III) until they became refractory. The prognostic significance of various pretreatment characteristics was evaluated in terms of therapeutic response (according to Southwest Oncology Group [SWOG] and Chronic Leukemia-Myeloma Task Force [TF] criteria) and survival. Therapeutic responses. obtained in 31.2% (SWOG) and 68.7% (TF) of patients. had a significant inverse correlation with myeloma cell mass. serum calcium. and bone status. Median survival time of Stage II and Stage III patients was 39 and 34 months. respectively. Serum B2 microglobulin greater than or equal to 6 micrograms/ml was the only variable correlating unfavorably with survival duration after multi-variate analysis (increased risk = 2.79). although therapeutic response as a time-dependent variable had no effect on survival. These data suggest no correlation between response and survival. partially because of inadequate response assessment criteria and partially because no existing treatment is curative (although current therapeutic approaches may prevent death from complications).
DNA ploidy analysis of effectiveness of radiation therapy for cervical carcinoma, Cellular DNA content from 30 patients with cervical carcinoma was determined using flow cytometry before and after radiation therapy (RT). The authors attempted to correlate changes in DNA content. tumor response to RT. and post-RT pathologic findings. Before RT. tumors from eight of 30 patients (26.7%) were diploid or near-diploid; tumors from 22 patients (73.3%) were aneuploid. After RT. diploid or near-diploid tumors were found in 23 patients (76.7%). and aneuploid tumors were observed in seven patients (23.3%). Aneuploidy disappeared in 15 of the patient tumors. and complete tumor response (CR) was observed in 13 of these 15 patients (86.7%). Pathologic examinations were negative in 12 of 15 cases and suspicious in one of 15 cases. Of the seven patients whose tumor aneuploidy did not change after RT. CR was observed in only two (28.7%). Pathologic examinations were positive in five of seven cases and suspicious in one of seven cases. The CR for the 22 patients with pre-RT aneuploid tumors was 15 of 22 (68.2%); the CR for the eight patients with pre-RT diploid tumors was two of eight (25%. P less than 0.01). From these data the authors conclude there is a direct correlation between DNA content and radiosensitivity in cervical carcinoma. Aneuploid tumors from these patients were more radiosensitive than diploid tumors. and they patients had a better clinical tumor response and improved pathologic findings.
Relationship between length and surface area of each segment of the large intestine and the incidence of colorectal cancer, In investigating the occurrence and clinical characteristics of diseases of the large intestine. particularly tumors. the number. distribution. and incidence of the lesions were compared between segments of the large intestine. If the distribution and incidence of lesions are correlated with the length or surface area of each segment. the incidence of lesions will be the same throughout the large intestine. If the lesions are unrelated to length or surface area. the factors that affect the occurrence of lesions must be determined and will be characteristic for each segment. However. the length and surface area of each segment of the large intestine and the ratios of each to both the total length and surface area of the large intestine are not clear. In this study the length and surface area of each segment of the large intestine were measured and calculated using the barium enema technique. and the incidence rates of cancer per unit length and surface area of each segment were determined and compared.
Medical management of obesity, Medical therapy for obesity is still unsuccessful in the majority of patients at five-year follow-up. Physicians should not become discouraged. however. because the number of successful participants in weight loss programs is increasing. An effective medical weight loss program requires five basic elements: (1) an effective means of caloric restriction. either a balance of fuel sources in patients who are less than 30% above ideal body weight. or a very-low-calorie diet in patients with obesity that is a significant threat to their health; (2) extensive nutritional instruction. to enable the patient to make wise food choices that are varied and palatable; (3) an individual exercise program sufficient to maintain the patient's goal weight on maintenance food; (4) behavioral modification. to allow patients to control their food consumption; and (5) a mechanism for continuing support. Now that low-fat diets and very-low-calorie diets allow effective means of safe and rapid weight loss. progress must be made in preventing weight regain. Obesity is a lifelong disease. with remissions followed by relapses. Long-term therapeutic success depends on the rapid reinstitution of therapy by a nonjudgemental support team when a relapse occurs.
Restoring nitrogen balance after burn injury, The metabolic response to burn injury is characterized by weight loss and marked protein wasting. This phenomenon is mediated hormonally. resulting in hypermetabolism. Energy expenditure increases linearly with the extent of burn injury. reaching a plateau of twice resting energy expenditure when 50% of the total body surface area is involved. It is therefore essential to minimize other factors that may further augment postburn catabolism. Occlusive dressings. a warm ambient environment. analgesics. and timely closure of the burn wound are all important therapeutic measures in this regard. Furthermore. it is imperative to institute early nutritional support in order to offset the negative metabolic effects of severe burn injury.
A randomized controlled trial of a 12-month course of recombinant human interferon-alpha in chronic delta (type D) hepatitis: a multicenter Italian study, To determine whether long-term therapy with recombinant interferon-alpha can improve the course of chronic delta hepatitis. 61 Italian patients with this disease were randomly assigned to receive either interferon-alpha-2b three times a week (5 MU/m2 for 4 mo and then 3 MU/m2 for another 8 mo) or no treatment. At the end of the 12-mo study. all patients were followed-up for 12 additional months. Normalization or decrease of more than 50% from baseline of serum ALT levels occurred in 42% of treated patients the fourth month of therapy. 26% the twelfth month and 3% the twenty-fourth month vs. 7%. 7% and 0%. respectively. in the control group. However. relapses occurred in 7 of 8 (87.5%) responders 1 to 10 mo (mean = 3.5 mo) after cessation of therapy. Liver biopsies were carried out at baseline and during the twelfth month of treatment. Histological improvement. mostly caused by decrease of portal inflammation. was observed in 57% of treated and 36% of untreated patients. Measures of antiviral activity (serum hepatitis delta virus RNA and intrahepatic hepatitis delta antigen) showed similar levels in treated and control patients. In treated patients the percentage of patients who were negative for HDV RNA never exceeded that of baseline. Although interferon-alpha in the dosage given in this study had no antiviral effect on patients with chronic hepatitis D. it reduced hepatic inflammation as measured by ALT levels. Whether a longer duration or reinstitution of interferon-alpha therapy would achieve long-term control of ALT levels and prevent chronic liver damage is not known.
Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes, To clarify the pathogenetic role of acetaldehyde in the development of alcoholic liver disease. genotyping of aldehyde dehydrogenase-2 genes was performed and the clinical features of the alcoholic liver disease patients with different genotypes were compared. Genotyping of aldehyde dehydrogenase-2 was performed in 47 patients with alcoholic liver disease using the polymerase chain reaction and slot-blot hybridization. Of the 47 patients with alcoholic liver disease. 40 were homozygous for the normal aldehyde dehydrogenase-2 gene and the remaining seven cases were heterozygous for the normal and mutant aldehyde dehydrogenase-2 genes. No homozygote was found for the mutant aldehyde dehydrogenase-2 genes. Daily alcohol intake was less than 100 gm in all heterozygotes without relation to the type of alcoholic liver disease. On the other hand. all but four patients homozygotic for the normal aldehyde dehydrogenase-2 gene drank more than 100 gm alcohol/day. The mean daily alcohol intake in the heterozygotes was significantly lower than that in the normal homozygotes. The incidence of alcoholic fibrosis tended to be lower in the heterozygotes than in the normal homozygotes (14.2% vs. 52.5%). On the other hand. the incidence of alcoholic hepatitis and/or cirrhosis tended to be higher in the heterozygotes than in the normal homozygotes. These results indicate that alcoholic liver disease develops even with moderate amounts of alcohol intake in heterozygotes of the aldehyde dehydrogenase-2 genes. in which acetaldehyde metabolism in the liver is impaired and liver damage in the heterozygotes is more severe than that in the normal homozygotes. suggesting that habitual drinkers who are heterozygotes of the aldehyde dehydrogenase-2 genes may be at high risk for alcoholic liver disease.
Primary biliary cirrhosis: relation between hepatic function and pulmonary function in patients who never smoked, We studied the relationship between selected variables of hepatic and pulmonary function in 47 patients with primary biliary cirrhosis. who were participating in a prospective study to assess sequential pulmonary function at yearly intervals. An additional 20 patients with primary biliary cirrhosis. who were liver transplant candidates awaiting transplantation. were studied. None of the 67 patients ever smoked cigarettes. Severity of primary biliary cirrhosis was characterized by histological stage and the Mayo risk score derived from a Cox regression model that used the following variables: serum bilirubin and serum albumin levels. age. prothrombin time and clinical severity of edema. Pulmonary function assessment included key variables describing expiratory airflow (forced expiratory volume in 1 sec divided by forced vital capacity) and efficiency of gas exchange (steady-state diffusing capacity for carbon monoxide). We found a significant relationship between histological stage of primary biliary cirrhosis and steady-state diffusing capacity (p = 0.02) and between the Mayo risk score for disease severity and steady-state diffusing capacity (p = 0.03). Progressive deterioration of steady-state diffusing capacity was associated with increasing severity of primary biliary cirrhosis. No relationship existed between pulmonary function and the presence of sicca complex or Sjogren's syndrome or the clinical manifestations of portal hypertension (e.g.. esophageal varices. ascites and splenomegaly). No significant relationship existed between expiratory airflow and severity of primary biliary cirrhosis. We conclude that in patients with primary biliary cirrhosis who have never smoked. a statistically significant relationship exists between the severity of the liver disease and the efficiency of gas exchange measured by steady-state diffusing capacity.
Epidermal growth factor-related transforming growth factors in the urine of patients with hepatocellular carcinoma, To characterize epidermal growth factor-related transforming growth factors in the urine of patients with hepatocellular carcinoma. gel filtration with Bio-Gel P-30 was performed in seven hepatocellular carcinoma patients and seven sex-matched and age-matched healthy controls. Distinct profiles of soft agar growth assay in the hepatocellular carcinoma patients and the normal controls were seen. Three peaks (A. B and C) in the urine were examined. Peak C in most hepatocellular carcinoma patients was higher than that in healthy controls. Similar profiles were detected with epidermal growth factor radioreceptor assay and cellular DNA synthesis assay. This result might indicate that transforming growth factors with low molecular weight were found in the urine of hepatocellular carcinoma patients. An exceptional HCC patient had an additional peak (A') that corresponded to the high molecular weight protein. We concluded that there were transforming growth factors with functional activity in the urine of patients with hepatocellular carcinoma.
Eosinophil cationic protein's role in human hepatic allograft rejection, Although it is known that eosinophils consistently infiltrate rejecting human liver allografts. their function is unknown. Infiltrating eosinophils can release a cytotoxic substance. eosinophil cationic protein. Furthermore. eosinophil cationic protein may be identified in biopsy specimens using immunoperoxidase staining of an eosinophil cationic protein-specific monoclonal antibody. To study a possible effector role of eosinophils in rejecting liver allografts. 38 serial allograft biopsy specimens from 12 patients with acute rejection. 54 biopsy specimens from 11 patients with allograft dysfunction caused by other causes and 22 biopsy specimens from 8 patients without allograft dysfunction were stained for extracellular eosinophil cationic protein. In addition. the absolute blood eosinophil counts and the portal tract eosinophil percent of the total number of portal tract inflammatory cells were tabulated in these patients until 30 days after transplantation. The blood absolute eosinophil count. portal tract eosinophil percent and incidence of positive extracellular eosinophil cationic protein staining were significantly increased in patients with rejection compared with patients with dysfunction from other causes (p less than 0.05 to 0.005. t test). Furthermore. each of these parameters predicted rejection with excellent sensitivity (75% to 92%) and specificity (91% to 100%). Of patients with rejection. 59% had significant elevation of all three parameters before or during rejection. and 92% had at least two parameters elevated. Conversely. of the patients with dysfunction from other causes. 0% had elevations of any parameter. The recognized cytotoxic properties of eosinophil cationic protein and its almost exclusive presence. along with eosinophils in the blood and allograft biopsy specimens of patients during acute rejection. support the role of the eosinophil as an effector cell in tissue injury during acute liver allograft rejection.
Human fetal hepatocytes respond to inflammatory mediators and excrete bile, Under strict observation of the ethical guidelines of the 1975 Declaration of Helsinki Human Research Committee. primary hepatocyte cultures were prepared from second-trimester fetal liver specimens. We have shown for the first time that fetal hepatocytes have the capacity to produce an acute-phase response on treatment with inflammatory mediators. Addition of interleukin-6 to the cultures resulted in strong induction of C-reactive protein and alpha-1-antichymotrypsin expression. whereas albumin expression was repressed. In contrast to interleukin-6. transforming growth factor-beta did not induce C-reactive protein expression. However. as in adult hepatocytes. fetal cells responded to transforming growth factor-beta by reduced albumin synthesis. We were able to show by virtue of fluorescein excretion into sealed clefts that fetal hepatocytes have the functional capacity to form bile. Our findings indicate that second-trimester hepatocytes can be regarded as fairly mature liver cells.
Systemic and splanchnic hemodynamic effects of molsidomine in rats with carbon tetrachloride-induced cirrhosis, Molsidomine. a long-acting vasodilator mainly used as an antianginal agent. was reported to decrease the portohepatic venous pressure gradient in patients with alcoholic cirrhosis. This study investigated the effects of linsidomine. the active metabolite of molsidomine. on systemic and splanchnic hemodynamics in rats with CCl4-induced cirrhosis using the microsphere technique. Compared with placebo-treated rats. linsidomine-treated animals were found to have a significant decrease in portal venous pressure (-18%. p less than 0.01) and in mean arterial pressure (-16%. p less than 0.01). smaller peripheral resistances (p less than 0.01). greater portal venous inflow (p less than 0.05). smaller splanchnic arteriolar resistances (p less than 0.01) and smaller protocol-lateral resistances (p less than 0.05). Cardiac output. hepatic arterial blood flow. portal blood flow and estimated hepatic blood flow were not significantly different between the two groups of animals. Linsidomine-treated rats exhibited a trend toward greater collateral blood flow compared with controls. but this difference was not significant. We conclude that linsidomine decreases portal venous pressure by reducing portocollateral resistances without affecting liver blood flow. These effects should be beneficial for patients with cirrhosis and portal hypertension.
Tissue distribution, quantitation and proliferation kinetics of fat-storing cells in carbon tetrachloride-injured rat liver, In this study. we have investigated the cell population kinetics of fat-storing cells in livers of rats intoxicated with CCl4. Fat-storing cells were identified in cryostat sections by immunoperoxidase staining of desmin. The peroxidase label was visualized using diaminobenzidine/hydrogen peroxide containing Ni2+ and Co(2+)-ions (Nico/diaminobenzidine method). In normal rats. we found 12.8 fat-storing cells/0.1 mm2 in periportal areas vs. 9.4 in pericentral fields. After one injection of CCl4. the number of pericentral cells increased gradually to reach a maximum of 39.4 cells/0.1 mm2 96 hr after injection. The desmin staining intensity of the pericentral fat-storing cells increased from 48 hr onward. At 72 to 120 hr. strongly stained cells were observed in pericentral areas and in bands of tissue between adjacent central veins. reminiscent of the connective tissue septa in fibrotic livers. In the periportal areas the number of fat-storing cells was not altered. After a second and third injection of CCl4. the number of cells increased further in the pericentral areas. When more than three injections were given. the pericentral fat-storing cell population reached a new steady state with the cell number being seven times higher than in control animals. Proliferation of fat-storing cells at different stages of CCl4 intoxication was studied by intravenous administration of 3H-thymidine. followed by combined desmin staining and autoradiography. Autoradiographical labeling of fat-storing cells was nearly absent in control animals and at 24 hr after a single CCl4 injection. At 48 to 96 hr. labeling indices of pericentral fat-storing cells were significantly higher than in control animals. with a maximum at 72 hr when 22.9% of the cells were labeled. After multiple injections of CCl4. labeling indices between 4.9% and 8.4% were found. We conclude that fibrogenesis is preceded by a strong expansion of the fat-storing cell population in the pericentral areas of the liver lobules and in bands of tissue between adjacent central veins. Local proliferation is an important mechanism underlying the expansion of this cell population.
Migraine--why and how a cortical excitatory wave may initiate the aura and headache, A large number of clinical and neurophysiological observations are reviewed that clearly indicate that the symptoms of migraine aura result from a spread of an excitatory wave along the cortex from a primary focus. This excitation may start as a consequence of information overload to a low threshold cortical area. The transient neuronal excitation is followed by a long-lasting period of reduced cortical flow. which involves a substantial component of active constriction of resistance vessels. even persisting for several hours during the headache phase. When the excitatory wave has reached and activated free pain fiber endings in sufficiently many cortical vessels. off-branching peripheral motor endings of these fibers may become activated via axon reflexes. These motor endings may be located in cortical microvessels or in small vessels around large dural vessels. This leads to a neurogenic inflammation in the vessel walls. experienced as headache by the sufferer. The wall of dural sinuses offers a rational explanation for the beneficial effect of most medications used in migraine.
5-Hydroxtryptamine1D receptor agonism predicts antimigraine efficacy, The interactions of four abortive anti-migraine agents and four prophylactic anti-migraine agents with 5-HT1D receptors in bovine brain were analyzed using radioligand binding techniques and adenylate cyclase assays. In bovine caudate. the affinities of abortive anti-migraine agents (i.e. 5-hydroxytryptamine. ergotamine. dihydroergotamine. sumatriptan) for 5-HT1D receptors range from 4.0-34 nM while the affinities of prophylactic anti-migraine agents (i.e. methysergide. amitriptyline. (-)propranolol. verapamil) range from 46-11.000 nM. In adenylate cyclase studies in bovine substantia nigra. all four abortive anti-migraine agents dose-dependently inhibit forskolin-stimulated adenylate cyclase activity. a biochemical effect mediated by 5-HT1D receptors. No agonist effect on cyclase activity is observed with the four prophylactic anti-migraine agents. These data support the hypothesis that abortive anti-migraine agents are 5-HT1D receptor agonists and that this effect may underlie their anti-migraine efficacy.
EEG and topographic frequency analysis in common and classic migraine, Electroencephalographic (EEG) changes occurring in patients with migraine have received much attention. However. almost equal number of reports indicate the predominance of normal and abnormal findings. We studied the EEG in symptom-free. otherwise healthy. unmedicated 18-28 year-old patients: 22 with common migraine. 20 with classic migraine. and 20 age-matched controls. The routine EEG findings in the three groups revealed mild non-specific slowing in 2 (9%). 3 (15%) and 2 (10%). respectively. Simultaneously. topographic EEG mapping and frequency analysis were performed in 13 consecutive patients with common migraine. 10 patients with classic migraine and 11 age-matched controls. EEG mapping showed minimal regional differences with lower power in the alpha range in patients with eyes closed. The peak alpha power. as well as its reactivity. were lower among patients than controls. This difference reached statistical significance only for patients with classic migraine versus controls in the left occipital region. Patients also had slightly faster peak alpha frequency. No frank right-left asymmetry was observed in the peak alpha power. neither among the controls. nor the patients. All the findings were rather minor. They may suggest some difference in the posterior background activity in the EEG in migraine patients as compared to the controls. but are not useful in differentiating migraine from non-migraine patients.
Atypical MRI findings of venous sinus thrombosis in pregnancy: clinical significance relating to episodic vascular headache, Two cases of headache during pregnancy were associated with MRI findings suggestive of venous sinus thrombosis. The findings. however. were atypical. and of uncertain clinical significance. Venous sinus thrombosis typically does not occur during the first and second trimesters (less than 10 percent of reported cases). Thus. these two cases are doubly unusual. The correct significance of these equivocal MRI findings of possible venous sinus thrombosis must be understood so that unnecessary and potentially harmful therapies are not employed. and so that appropriate management of what may otherwise be a typical vascular headache syndrome may be undertaken.
The efficacy of Polysporin First Aid Antibiotic Spray (polymyxin B sulfate and bacitracin zinc) against clinical burn wound isolates, Polysporin First Aid Antibiotic Spray (Burroughs Wellcome Co.. Research Triangle Park. N.C.) is a dry spray containing 200.000 units Aerosporin (polymyxin B sulfate) and 10.000 units bacitracin zinc. along with a propellant. Each 1-second spray delivers approximately 2300 units of polymyxin B sulfate and 115 units of bacitracin zinc. This study was designed to evaluate the efficacy of Polysporin Spray against various clinical isolates. Blood agar plates were inoculated with a pure culture of each isolate. Polysporin was then sprayed in an area approximately 30 mm in diameter. The area of inhibition was measured and recorded after 18 to 24 hours of incubation. A clear zone at least 20 mm in diameter with surrounding edges of growth indicated sensitivity. A zone less than 20 mm in diameter or growth over the whole plate indicated resistance. Three hundred fifty-three clinical isolates (202 gram positive and 151 gram negative) were tested. The results show that Polysporin inhibits the growth of all the gram-positive organisms. including methicillin-resistant strains of Staphylococcus. The gram-negative organisms were also sensitive to Polysporin Spray. with the exception of Serratia marcescens. Morganella morganii. and Proteus mirabilis. This study suggests that Polysporin First Aid Antibiotic Spray may be effective for wounds contaminated with gram-positive and some gram-negative organisms.
The bactericidal power of the blood and plasma of patients with burns, Patients with burns are unusually susceptible to bacterial infections. but so far there is no satisfactory explanation for this lack of resistance. Since resistance to infection involves many different mechanisms. examination of individual components of the immune system may not sufficiently explain the underlying reasons for increased susceptibility. The use of whole blood for antibacterial tests has the advantage that all the immune systems present in that fluid compartment can take part in the bactericidal effect. Tests with Klebsiella pneumoniae and Staphylococcus aureus showed no evidence that the bactericidal power of the blood and plasma of patients with burns was less than that of normal control plasma. This suggests that the solution to the problem of increased susceptibility to infection in patients with burns does not lie with the blood but must be looked for elsewhere.
Gasoline-induced contact burns, Gasoline contact may cause significant full-thickness burn injuries. Systemic complications may result from the absorption of hydrocarbons through the skin. Regional neuromuscular absorption may produce transient or even permanent impairment. It is vital that the physician be aware of the possible full-thickness injuries and complications that may result from cutaneous exposure to gasoline.
Self-inflicted burns: a ten-year retrospective study, In this 10-year retrospective survey of 2216 admissions to a regional burn center. 15 patients (0.67%) had self-inflicted burn wounds. The burns were serious. with a mean abbreviated burn severity index of 11.2. and eight patients died of their injuries. Nine patients had a documented history of psychiatric problems. seven of whom had undergone a previous psychiatric hospitalization. A psychiatric assessment was obtained for 12 patients immediately after self-immolation. and all but one had a major psychiatric disorder. Seven patients had major depression and four had chronic paranoid schizophrenia. Motives were assessed. both by chart review and by interview of five available survivors and of relatives of nonsurvivors. Fewer than half actually intended to kill themselves; equally important was the theme of attempting to control internal psychotic states.
Alcohol use and burn injury, Charts of 108 consecutive adult patients with flame burns of 20% to 70% total body surface area were reviewed to determine the incidence of acute alcohol intoxication and the likelihood that intoxicated patients were chronic alcohol abusers. to assess morbidity and mortality in the alcoholic patient with burns. and to characterize the intervention used in postdischarge treatment of the alcoholic patient with burns who survives. Twenty-seven percent of patients were acutely intoxicated at the time of injury. Evidence for chronic alcohol abuse was apparent in 90% of intoxicated patients. compared to only 11% of nonintoxicated patients (p = 0.0001). Alcoholic patients with burns not only had an overall mortality rate three times that of nonalcoholics (p = 0.001) but also died of smaller burns (p less than 0.05). Surviving alcoholic patients with burns required significantly more intravenous antibiotics and a longer hospitalization. Social service evaluation of use of alcohol was made in 84% of the cases of surviving intoxicated burn victims. Further intervention was undertaken in two thirds of these cases. usually involving an outpatient treatment program.
Grease burns at fast-food restaurants. Adolescents at risk, Intermountain Burn Center and Utah State Insurance Fund industrial records were reviewed to determine the incidence and consequences of grease burns among teenagers employed at fast-food restaurants. Burn center records reveal that 10 patients were admitted between 1977 and 1985. and that nine patients required surgery with mean burn care costs of $7389 per patient. State Insurance Fund records demonstrate that 81 grease-burn injuries were reported from 1982 through 1985. at an average burn care cost of $660 per patient. Causes of burn wounds included adding. filtering. or removing hot grease. dropping objects into hot grease. slipping on the floor. cleaning the grill or fryer. and splashing hot grease during cooking. Those treated as outpatients were off from work for as long as 10 days. These data identify an adolescent population at risk for work-related burn injury in fast-food restaurants.
Acquired progressive lymphangioma, Acquired progressive lymphangioma is rare and can histologically mimic well-differentiated angioendothelioma. In a 9-year-old boy with acquired progressive lymphangioma. we demonstrated that the neoplasm consists of at least a vascular component and a smooth muscle component. The presence of type IV collagen around many vascular channels suggests that an intermediate stage of differentiation between blood vessels and lymphatics may be present. Our findings indicate that acquired progressive lymphangioma is most likely a complex hamartoma composed of vascular channels and smooth muscle.
Giant neuroendocrine (Merkel cell) carcinoma of the skin, An 82-year-old woman had a dark red to purple tumor on the left buttock that had gradually enlarged during the last 5 years. Although routine histologic examination was not sufficient for diagnosis. neuroendocrine carcinoma was diagnosed by immunohistochemical and ultrastructural studies. Immunohistochemical-positive reactions to neurofilament. cytokeratin. neuron-specific enolase. and epithelial membrane antigen were noted. Electron microscopically. membrane-bound. dense core granules that yielded a positive uranaffin reaction and intermediate filaments in the perinuclear area were observed in the cytoplasm of most tumor cells. Desmosome-like structure between them was also found. Approximately 6 months after local excision. metastatic lesions developed in the regional lymph nodes and liver.
IgA pemphigus foliaceus with a clinical presentation of pemphigus herpetiformis, A patient with clinical features of herpetiform pemphigus of the foliaceus type had histologic findings consistent with pemphigus. Intercellular IgA deposits in a pattern like that of IgG in pemphigus were present. Circulating pemphigus-type IgA-class antibodies reacted first only with guinea pig and later in the disease also with monkey esophagus sections. IgG-class pemphigus antibodies were blocked by the IgA-class antibodies of this patient. In addition. the IgA-class pemphigus antibodies in this patient were blocked by the IgG-class pemphigus antibodies in tests on guinea pig and monkey esophagus. This indicates that the IgA-class antibodies in this patient were directed either to the same antigen as the IgG-class pemphigus foliaceus antibodies or to one that is close enough to it to give steric hindrance. The skin lesions responded poorly to systemic corticosteroid therapy. Dapsone therapy initially produced dramatic improvement. but the condition flared to the point that plasmapheresis. in addition to high doses of corticosteroids and cyclophosphamide. had to be used to control it.
Membranous lipodystrophy: primary idiopathic type, A 20-year-old woman had a pea-sized. tender subcutaneous nodule on the leg. Histopathologically. the panniculus showed multiple microcysts lined by membranes and light brown granules in the histiocytes. Histochemical studies of the membranes of the microcysts and the granules in the histiocytes indicated that they were composed of ceroid. Electron microscopy revealed that the membrane of the microcyst was composed of electron-dense areas of a regular 18.6 nm lamellar array and reticulated vacuolated areas suggestive of degenerating fat cells of unknown origin. Membranous lipodystrophy has been associated with many local and systemic diseases. but it may be idiopathic. as in our patient.
Evaluation of right ventricular early diastolic filling by cine nuclear magnetic resonance imaging in patients with hypertrophic cardiomyopathy, Numerous studies have established abnormalities in systolic and diastolic function of the left ventricle in hypertrophic cardiomyopathy. A consistent feature of this disease is reduced diastolic function of the left ventricle. but little information is available regarding right ventricular function in this disease. Cine nuclear magnetic resonance (NMR) imaging has been found to be effective for measuring right ventricular volumes and therefore was used to assess early diastolic filling of the right ventricle in patients with hypertrophic cardiomyopathy. Right ventricular time-volume curves were obtained from cine NMR images in 10 patients with hypertrophic cardiomyopathy and 8 normal subjects. Right ventricular volume was calculated with use of Simpson's algorithm at approximately 18 phases of the cardiac cycle and. from the curve. peak filling rate and filling fraction during the first third of diastole were determined. In patients with hypertrophic cardiomyopathy. peak filling rate tended to be less (176 +/- 46 vs. 305 +/- 50 ml/s. p less than 0.01) and filling fraction decreased (39.5 +/- 13.8 vs. 74.5 +/- 13.3%. p less than 0.01) in comparison with values in normal subjects. Thus. analysis of right ventricular time-volume curves obtained by using cine NMR imaging demonstrated diastolic dysfunction of the right ventricle in hypertrophic cardiomyopathy.
Identification of false positive exercise tests with use of electrocardiographic criteria: a possible role for atrial repolarization waves, Atrial repolarization waves are opposite in direction to P waves. may have a magnitude of 100 to 200 mu V and may extend into the ST segment and T wave. It was postulated that exaggerated atrial repolarization waves during exercise could produce ST segment depression mimicking myocardial ischemia. The P waves. PR segments and ST segments were studied in leads II. III. aVF and V4 to V6 in 69 patients whose exercise electrocardiogram (ECG) suggested ischemia (100 mu V horizontal or 150 mu V upsloping ST depression 80 ms after the J point). All had a normal ECG at rest. The exercise test in 25 patients (52% male. mean age 53 years) was deemed false positive because of normal coronary arteriograms and left ventricular function (5 patients) or normal stress single photon emission computed tomographic thallium or gated blood pool scans (16 patients). or both (4 patients). Forty-four patients with a similar age and gender distribution. anginal chest pain and at least one coronary stenosis greater than or equal to 80% served as a true positive control group. The false positive group was characterized by 1) markedly downsloping PR segments at peak exercise. 2) longer exercise time and more rapid peak exercise heart rate than those of the true positive group. and 3) absence of exercise-induced chest pain. The false positive group also displayed significantly greater absolute P wave amplitudes at peak exercise and greater augmentation of P wave amplitude by exercise in all six ECG leads than were observed in the true positive group.
Evaluation of antiarrhythmic drug effects with simultaneous analysis of single ventricular premature contractions, couplets and salvos, To improve the clinical value of ambulatory Holter electrocardiographic (ECG) monitoring as a tool of antiarrhythmic therapy control. a new statistical model was developed. In a patient group at increased risk of sudden cardiac death. the spontaneous variability of ventricular arrhythmias was assessed. with simultaneous consideration of single ventricular premature complexes. couplets and salvos. The study included 100 patients who suffered from coronary heart disease or idiopathic dilated cardiomyopathy and for whom greater than 30 ventricular premature complexes/h and couplets had been demonstrated on the last Holter ECG before the study. Between 3 and 12 Holter recordings were made for each patient in a drug-free state; the mean follow-up period was 260 days (maximum 1.403). The mean hourly values of the ectopic events (EE) were assessed separately for ventricular premature complexes. couplets and salvos. The spontaneous variability (SV) was calculated for single ventricular premature complexes. couplets and salvos as SV = log (EEday 2 + 0.01/EEday 1 + 0.01) and linked in one. two and three dimensions. Compared with the consideration of only one type of arrhythmia (one-dimensional model). the simultaneous use of two or three types of arrhythmia (two- or three-dimensional model) resulted in considerably lower reduction and aggravation rates as sufficient proof of drug effects. With control intervals up to 1 week. the one-dimensional model yielded reduction rates for ventricular premature complexes. couplets and salvos of -63%. -90% and -95%. respectively. In contrast. with the three-dimensional model. the rates were -28%. -72% and -88%. The corresponding aggravation values were +370. +1.114% and +2.189% versus +38%. +256% and +747%.
Reduction in defibrillator shocks with an implantable device combining antitachycardia pacing and shock therapy, Implantable defibrillators reduce the risk of sudden death in patients with malignant ventricular arrhythmias. but significant restriction in quality of life can occur as a result of frequent device activation. To determine if a device that provides both antitachycardia pacing and shock therapy can safely reduce the frequency of shocks after implantation. 46 consecutive patients undergoing initial implantation of a defibrillator were studied. In all patients. the implanted device provided antitachycardia pacing and shock therapy. Detected tachycardia characteristics and the results of therapy were stored in the device's memory. There were 42 men and 4 women. aged 26 to 71 years (mean 58.7 +/- 13.5). Left ventricular ejection fraction ranged from 13% to 67% (mean 32.2 +/- 13.4%) and 31 patients had experienced one or more episodes of cardiac arrest. Induced arrhythmias included sustained monomorphic ventricular tachycardia in 38 patients. nonsustained polymorphic ventricular tachycardia in 2 and ventricular fibrillation in 4. Over a total follow-up period of 255 patient-months (range 1 to 13. mean 6.1). 25 patients experienced spontaneous arrhythmic events. In 22 patients. 909 episodes of tachycardia were treated by antitachycardia pacing. which was successful on 840 occasions (92.4%). Acceleration of ventricular tachycardia by pacing therapy was estimated to have occurred 39 times. Syncope occurred once during pacing-induced acceleration of ventricular tachycardia. Forty-four episodes of tachycardia in seven patients were treated directly by shocks because of short tachycardia cycle length; 88% of all detected tachycardias were treated without the need for shocks. Four patients died from cardiorespiratory failure and one patient died suddenly without any detected tachyarrhythmia.
Results of balloon pulmonary valvuloplasty as a palliative procedure in tetralogy of Fallot, Balloon pulmonary valvuloplasty was attempted in 67 patients with tetralogy of Fallot at a median age of 5 months (range 0.03 to 52 months) for relief of cyanosis. In three patients. the valve could not be crossed and an aortopulmonary shunt was performed. In 35 patients. follow-up angiography was performed 3 to 30 months (average 12) after valvuloplasty. In 24 of these 35 patients (group A). the stenosis had been adequately palliated by valvuloplasty; the other 11 patients (group B) had required an aortopulmonary shunt 1 month (range 0 to 3 months) after valvuloplasty. The two groups were similar (p greater than 0.1) with respect to age at valvuloplasty. pulmonary anulus diameter. ratio of pulmonary artery to descending aorta diameter before valvuloplasty and interval to follow-up angiography. In contrast to patients in group B. patients in group A had a significant immediate improvement in systemic arterial oxygen saturation (p less than 0.01) and a significant increase in pulmonary anulus diameter at follow-up angiography (p less than 0.001). The growth of the branch pulmonary arteries was similar (p greater than 0.1) in the two groups. Among 42 patients who have had surgical correction. a transannular patch for right ventricular outflow tract reconstruction was used in 27 (64%); there was no difference between groups A and B with respect to its use. Eight patients died (three after repair) and death could not be directly attributed to valvuloplasty in any. Balloon valvuloplasty promotes growth of the pulmonary valve anulus and pulmonary arteries and is a useful alternative to an aortopulmonary shunt in patients with small pulmonary arteries or associated complex intracardiac defects.
Double-outlet right ventricle: morphologic demonstration using nuclear magnetic resonance imaging, Sixteen patients with double-outlet right ventricle. aged 1 week to 29 years (median 5 months). were studied with a 1.5 tesla nuclear magnetic resonance (NMR) imaging scanner. Two-dimensional echocardiography was performed in all patients. Thirteen patients underwent angiography. including nine who underwent subsequent surgical correction. Three patients underwent postmortem examination. Small children and infants were scanned inside a 32 cm diameter proton head coil. Multiple 5 mm thick sections separated by 0.5 mm and gated to the patient's electrocardiogram were acquired with a spin-echo sequence and an echo time of 30 ms. A combination of standard and oblique imaging planes was used. Imaging times were less than 90 min. The NMR images were technically unsuitable in one patient because of excessive motion artifact. In the remaining patients. the diagnosis of double outlet right ventricle was confirmed and correlated with surgical and postmortem findings. The NMR images were particularly valuable in demonstrating the interrelations between the great arteries and the anatomy of the outlet septum and the spatial relations between the ventricular septal defect and the great arteries. Although the atrioventricular (AV) valves were not consistently demonstrated. NMR imaging in two patients identified abnormalities of the mitral valve that were not seen with two-dimensional echocardiography. In one patient who had a superoinferior arrangement of the ventricles. NMR imaging was the most useful imaging technique for demonstrating the anatomy. In patients with double-outlet right ventricle. NMR imaging can provide clinically relevant and accurate morphologic information that may contribute to future improvement in patient management.
Junctional tachycardias: anatomic substrate and its significance in ablative procedures, The conduction system was studied by serial section in three patients with intractable supraventricular tachycardias originating from the atrioventricular (AV) junction who died suddenly. The three patients were a 6 month old girl (Case 1). a 5 month old boy (Case 2) and a 22 year old woman (Case 3). The latter had a pacemaker inserted after surgical ablation of the AV node. The heart was hypertrophied and enlarged in all. In Case 1. the AV node was partly within the central fibrous body and there was a left-sided AV bundle with acute necrosis in the summit of the ventricular septum. adjacent to the AV node and bundle. In Case 2. the coronary sinus was displaced cranially close to the central fibrous body. resulting in abnormality of the latter. with entrapment. distortion and division of the AV node and bundle into two distinct components within the central fibrous body. In Case 3. a left-sided AV node was connected to the atrial septum. The right AV node was completely interrupted by sutures and the penetrating and branching bundle and bundle branches were markedly fibrosed. In addition. the atrial septum and summit of the ventricular septum showed marked inflammatory reaction with fibrosis. which was more marked on the right ventricular side. Histologic examination of the conduction system in all three cases demonstrated congenital abnormalities of the AV junction that may be related to the tachycardia. These findings emphasize the need to carefully evaluate the atrial septum and AV junctional area. including the coronary sinus. before ablative procedures are undertaken.
Transcatheter embolization in the treatment of coronary artery fistulas, Seven patients with a coronary artery fistula underwent percutaneous transcatheter embolization (five were male and two female; the age range was 2 to 67 years [median 17]). Three patients were symptomatic. The left to right shunt ranged from 1.6 to 2.6:1. In six patients. the fistula was an isolated congenital anomaly; in one. it was acquired. The fistula arose from branches of the left (n = 5) and right (n = 2) coronary arteries and drained to the right ventricle (n = 2). right atrium (n = 2). coronary sinus (n = 1). pulmonary artery (n = 1) and a bronchial artery (n = 1). Different embolization techniques were used to occlude eight feeding arteries. The embolization materials included a detachable balloon (n = 3). coaxial embolization with platinum microcoils (n = 3). a combination of detachable balloon and microcoil (n = 1) and standard steel coils (n = 1). Satisfactory occlusion was achieved in six patients. In one case. the valve of the detachable balloon was damaged. resulting in early balloon deflation and a residual fistula. There were no associated complications in any patient. Follow-up investigation by Doppler ultrasound or coronary angiography 4 months to 4 years later showed that permanent occlusion was achieved in all six patients in whom embolization was initially successful. Transcatheter embolization should be considered the treatment of choice for coronary artery fistulas.
Limitation of no reflow injury by blood-free reperfusion with oxygenated perfluorochemical (Fluosol-DA 20%), This study was designed to assess the effects of blood-free reperfusion with oxygenated or unoxygenated intracoronary perfluorochemical (Fluosol-DA 20%) on myocardial perfusion and to determine its mechanism or mechanisms of limiting no reflow. Twenty-four dogs underwent 90 min of coronary occlusion followed by 210 min of reperfusion and were randomized to either: 1) blood-free reperfusion with intracoronary oxygenated perfluorochemical (20 ml/kg per min) for 20 min followed by blood reperfusion (n = 8); 2) intracoronary unoxygenated perfluorochemical administered as in those treated with oxygenated perfluorochemical (n = 8); and 3) blood reperfusion alone (control) (n = 8). Regional myocardial blood flow was serially determined and global myocardial perfusion was assessed by an intravenous injection of the fluorescent dye (thioflavin-S). Quantitative studies were performed to determine neutrophil infiltration and extent of endothelial injury. Hemodynamic variables were similar in all groups. The zone of impaired perfusion (thioflavin negative). expressed as a percent of the left ventricle. averaged 10 +/- 2%. 6 +/- 2% and 3 +/- 1%. in control and unoxygenated and oxygenated perfluorochemical groups. respectively (control versus oxygenated perfluorochemical p less than 0.004). The reduction in thioflavin-negative area with oxygenated perfluorochemical was associated with a notable recovery of endocardial blood flow (0.97 +/- 0.22 vs. control 0.39 +/- 0.08 ml/min per g; p less than 0.04) at 210 min of reperfusion. The number of capillaries plugged by neutrophils (per 200 capillaries) in thioflavin-negative areas was similar with both oxygenated (5.9 +/- 1.4) and unoxygenated perfluorochemical (5.4 +/- 0.8) treatment and was significantly less than that with the control group (18.9 +/- 3.2. p less than 0.003).
Effect of superoxide dismutase on infarct size and postischemic recovery of myocardial contractility and metabolism in dogs, The effects of superoxide dismutase treatment on infarct size. postischemic recovery of contractile function and tissue content of high energy phosphates were examined in a canine model of myocardial ischemia and reperfusion. Ischemia was induced by thrombotic occlusion of a coronary artery and reperfusion was achieved by intravenous thrombolysis. Average duration of ischemia was 90 min. Fifty closed chest anesthetized dogs were randomized to receive either superoxide dismutase (34.000 IU/min intravenously) or placebo. starting approximately 30 min before and continuing for 30 min into the reperfusion phase. Left ventricular ejection fraction and regional segmental shortening of the postischemic area were calculated from contrast angiograms after 4 h. 48 h and 1 week of reperfusion. Tissue content of high energy phosphates was determined from transmural biopsy after 4 h and 1 week. Infarct size was measured by planimetry of dye-stained heart slices. In the superoxide dismutase and placebo-treated groups. respectively. the mortality rate was 25% and 16%. collateral flow 20 +/- 10 and 23 +/- 18 ml/min per 100 g. area at risk 25 +/- 6% and 26 +/- 7% of the left ventricle and infarct size 28 +/- 19% and 36 +/- 27% of the area at risk. Multiple regression analysis failed to show any beneficial effect of superoxide dismutase treatment on infarct size. Left ventricular ejection fraction. regional segmental shortening of the postischemic area and tissue content of high energy phosphates recovered to a similar extent and at a similar rate in both treated and placebo groups up to 1 week after reperfusion. Thus. in this model of coronary occlusion and reperfusion superoxide dismutase treatment is of no benefit.
Quantitative relation between increased intrapericardial pressure and Doppler flow velocities during experimental cardiac tamponade, To establish whether a quantitative relation exists between pericardial pressure and respiratory variation in intracardiac blood flow velocities. a spontaneously breathing closed chest canine model of pericardial tamponade was created. In seven dogs. pericardial pressure was sequentially increased in stages from a mean of -4 +/- 1 to 10 +/- 2 mm Hg while aortic and pulmonary Doppler flow velocities. pleural pressure changes (respiratory effort). blood pressure and cardiac output were measured. The variation in the Doppler-detected peak transaortic velocity (AV) during inspiration (IV) increased linearly from -5 +/- 3% at baseline (pericardial pressure -4 mm Hg) to -32 +/- 9% at a pericardial pressure of 10 mm Hg [IVAV = -2 (pericardial pressure)--13.1; r = 0.78. p less than 10(-6)]. The inspiratory variation in the peak transpulmonary velocity increased from 13 +/- 3% at baseline to 71 +/- 19% at a pericardial pressure of 10 mm Hg. The inspiratory variation in the pulmonary Doppler peak velocity (IVPV) was dependent on both pericardial pressure and degree of respiratory effort [IVPV = 3.8 (pericardial pressure) + 2.6 (respiratory effort) + 10.9; r = 0.88. p less than 10(-8)]. Thus. quantitative relations exist between increases in intrapericardial pressure and increases in inspiratory variation of peak aortic and pulmonary flow velocities. Additionally. pulmonary artery flow velocity is influenced more than aortic velocity by intrathoracic pressure.
Experimental cardiac tamponade: a hemodynamic and Doppler echocardiographic reexamination of the relation of right and left heart ejection dynamics to the phase of respiration, A hallmark of cardiac tamponade is pulsus paradoxus. However. the exact mechanism of pulsus paradoxus and the relation of left and right ventricular ejection dynamics remain controversial. with some studies suggesting an inverse relation in ventricular filling and ejection and others citing a more important role for the effects of right heart ejection dynamics delayed by transit through the pulmonary artery bed. To specifically reexamine this issue. six sedated but spontaneously breathing dogs were studied during experimental cardiac tamponade with use of extensive hemodynamic instrumentation and Doppler methods. During cardiac tamponade. left ventricular systolic pressure decreased from 125.8 +/- 12.1 to 81.7 +/- 26.7 mm Hg (p less than 0.01) and cardiac output from 5.86 +/- 1.48 to 2.34 +/- 0.98 liters/min (p less than 0.001); mean pericardial pressure increased from -1.2 +/- 0.8 to 10.5 +/- 3 mm Hg (p less than 0.001) and pulsus paradoxus from 4.3 +/- 1.6 to 10.7 +/- 1.2 mm Hg (p less than 0.001) compared with baseline values. An inverse relation in left and right ventricular ejection dynamics that was very close to 180 degrees out of phase was seen throughout the respiratory cycle in multiple hemodynamic and Doppler variables including peak systolic pressures. aortic and pulmonary flow velocities and ventricular ejection times. Simultaneous recording of the transmitral pressure gradient provided indirect evidence that the ventricular ejection dynamics were directly related to changes in ventricular filling. However. the magnitude of ventricular pressure or output flow velocity for each respiratory cycle was variable. depending on the exact timing of filling and ejection in relation to the phase of respiration. Variation in left ventricular output due to changes in right ventricular output delayed by transit through the pulmonary vasculature was not recognized in any animal. It is concluded that in spontaneously breathing dogs with acute cardiac tamponade. peak ventricular pressures. ventricular ejection times and pulmonary and aortic flow velocities have an inverse relation that is very close to 180 degrees out of phase.
Positron emission tomography demonstrates that coronary sinus retroperfusion can restore regional myocardial perfusion and preserve metabolism, Positron emission tomography was used to image blood flow and metabolic tracers in risk zone myocardium after left anterior descending coronary artery occlusion during synchronized coronary venous retroperfusion. Six control and seven intervention open chest dogs had occlusion of the mid left anterior descending coronary artery. Synchronized retroperfusion commenced 25 min later. Flow tracers (rubidium-82 and nitrogen-13 ammonia) were injected retrogradely. Three hours after coronary occlusion. fluorine-18 (F-18) deoxyglucose uptake in the control and treatment groups was compared. At 200 min of occlusion. infarct size was assessed. Retrograde flow tracer uptake was observed in the risk zone in the seven intervention dogs. Fluorine-18 deoxyglucose uptake in the risk zone was increased in five of the six intervention dogs but was reduced in five of the six control dogs. The risk zone to normal zone F-18 deoxyglucose count ratio was higher in the intervention than the control group (1.13 +/- 0.39 vs. 0.59 +/- 0.51; p less than 0.05). The endocardial subsegment risk zone to normal zone F-18 deoxyglucose count ratio was also significantly higher in the intervention group. Percent infarction in the risk zone was 70% lower in the group treated with synchronized retroperfusion than in the control group (18.4 +/- 22.6% vs. 61.2 +/- 25.4%; p less than 0.02). Thus. positron emission tomography revealed that retroperfusion could deliver oxygenated blood and maintain metabolism in risk zone myocardium. Infarct size was limited to 30% of that of control. In acute closure of the left anterior descending coronary artery. synchronized retroperfusion might be considered for maintaining viability of the jeopardized myocardium if the artery cannot be reopened rapidly.
Synchronized coronary venous retroperfusion for support and salvage of ischemic myocardium during elective and failed angioplasty, To determine the safety and efficacy of synchronized coronary venous retroperfusion during brief periods of ischemia. 30 patients undergoing angioplasty of the left anterior descending coronary artery were studied. Each patient underwent a minimum of two angioplasty balloon inflations. Alternate dilations were supported with retroperfusion; the unsupported inflations served as the control inflations. Synchronized retroperfusion was performed by pumping autologous femoral artery blood by means of an electrocardiogram-triggered retroperfusion pump into the great cardiac vein through a triple lumen 8.5F balloon-tipped retroperfusion catheter inserted percutaneously from the right internal jugular vein. Clinical symptoms. hemodynamics and two-dimensional echocardiographic wall motion abnormalities were analyzed. Retroperfusion was associated with a lower angina severity score (0.8 +/- 1 vs. 1.2 +/- 1) and delay in onset of angina (53 +/- 31 vs. 37 +/- 14 s; p less than 0.05) compared with the control inflations. The magnitude of ST segment change was 0.11 +/- 0.14 mV with retroperfusion and 0.16 +/- 0.17 mV without treatment (p less than 0.05). The severity of left ventricular wall motion abnormality was also significantly (p less than 0.01) reduced with retroperfusion compared with control (0.7 +/- 1.4 [hypokinesia] vs. -0.3 +/- 1.6 [dyskinesia]). There were no significant changes in hemodynamics. except in mean coronary venous pressure. which increased from 8 +/- 3 mm Hg at baseline to 13 +/- 6 mm Hg with retroperfusion. Four patients required prolonged retroperfusion for treatment of angioplasty-induced complications. The mean retroperfusion duration in these patients was 4 +/- 2 h (range 2 to 7). In the three patients who underwent emergency bypass surgery. the coronary sinus was directly visualized during surgery and found to be without significant injury. There were no major complications. Minor adverse effects were transient atrial fibrillation (n = 2). jugular venous catheter insertion site hematomas (n = 4) and atrial wall staining (n = 1). all of which subsided spontaneously. Thus. retroperfusion significantly reduced and delayed the onset of coronary angioplasty-induced myocardial ischemia and provided effective supportive therapy for failed and complicated angioplasty.
Coronary venous retroperfusion support during high risk angioplasty in patients with unstable angina: preliminary experience, Synchronized coronary venous retroperfusion was used during coronary balloon angioplasty to support the ischemic myocardium of 20 patients with unstable angina and anatomy at high risk of a coronary event. Hemodynamics and left ventricular function were the major end points of the study. Coronary venous catheterization and retroperfusion were successfully performed in 15 patients. The target vessel was an unprotected left main artery in 2. left anterior descending artery in 10. left circumflex coronary artery in 1 and right coronary artery in 2 patients. A nonsupported balloon inflation (mean 44 +/- 13 s) was compared with a later retroperfusion-supported inflation (mean 145 +/- 21 s). Right anterior oblique left ventriculograms. aortic blood pressure. pulmonary artery pressure and thermodilution cardiac output were obtained before and during peak untreated and treated balloon inflations and on completion of angioplasty. All patients had either a baseline left ventricular ejection fraction less than 0.40 or greater than 40% of contracting myocardium estimated to be at risk for severe ischemia during angioplasty. The cardiac (liters/min per m2) and stroke work (g.m/m2) indexes decreased from mean baseline values of 2.5 +/- 0.52 and 52 +/- 15 to 1.7 +/- 0.47 and 27 +/- 12 (mean +/- SD). respectively. during nonsupported balloon inflations but decreased only to 2.1 +/- 0.52 (p less than 0.01 vs. nonsupported) and to 36 +/- 14 (p = 0.01 vs. nonsupported). respectively. during retroperfusion-supported inflations. Ejection fraction (n = 8) decreased from a baseline value of 55 +/- 13% to 27 +/- 7.3% during nonsupported inflations but only to 39 +/- 10% during retroperfusion-supported inflations (p = 0.01 vs. nonsupported). Regional wall motion (area change) in the ischemic (target) region was reduced from a baseline value of 49 +/- 17% to 11 +/- 16% during nonsupported inflations but only to 27 +/- 15% during retroperfusion-supported inflations (p less than 0.01 vs. nonsupported). All but two patients had a favorable hemodynamic response to retroperfusion. There were no serious adverse effects related to the procedures and no hospital deaths. It is concluded from this preliminary study that coronary venous retroperfusion appears to be safe. to provide hemodynamic support and to improve left ventricular function during angioplasty in patients with unstable angina and anatomy at high risk of a coronary event.
Percutaneous cooling of ischemic myocardium by hypothermic retroperfusion of autologous arterial blood: effects on regional myocardial temperature distribution and infarct size, The effects of synchronized coronary venous retroperfusion of cooled autologous arterial blood on regional myocardial temperature distribution and infarct size were studied in open chest dogs with 3.5 h of left anterior descending coronary artery occlusion. After 30 min of occlusion. the dogs were randomly assigned to one of three groups: 1) untreated control group (n = 5). 2) normothermic retroperfusion group (infusion temperature 32 degrees C) (n = 7). and 3) hypothermic retroperfusion group (infusion temperature 15 degrees C) (n = 7). Regional myocardial temperatures were measured by using needle-tipped thermistors stabbed in the 1) anterior wall distal to the occlusion site. 2) anterior wall proximal to the occlusion site. 3) left lateral wall. 4) posterior wall. and 5) right ventricular free wall. Rectal and pulmonary artery temperatures were also measured. In the hypothermic retroperfusion group. the anterior wall temperature decreased rapidly by 5 degrees C at 15 min of retroperfusion (p less than 0.05 vs. normothermic retroperfusion or untreated control groups). whereas the temperature at other sites decreased with a linear trend over time. Myocardial temperatures in the ischemic area (distal anterior wall) were generally lower than those in the other sites during the first 60 min of hypothermic retroperfusion and the largest intramyocardial temperature difference (3.6 degrees C) was found at 15 min after retroperfusion. Infarct size expressed as a percent of the risk area was significantly smaller in the hypothermic retroperfusion group (6.2 +/- 3.3%) than in the control (64.9 +/- 14%) or normothermic retroperfusion groups (24.1 +/- 6.7%).
Increased plasma endothelin-1 in the early hours of acute myocardial infarction, Endothelin is a novel endothelium-derived vasoactive peptide with potent vasoconstrictor action in the coronary bed; however. its possible contribution to myocardial ischemia and infarction is not known. Plasma endothelin-1 concentration was measured with use of a radioimmunoassay in serial venous samples from 22 patients over a 72 h period after acute myocardial infarction (14 patients with uncomplicated infarction [group I] and 8 patients with hemodynamic or ischemic sequelae [group II]). Twenty-two normal subjects and seven patients with stable angina served as the control subjects. Endothelin-1 levels in patients with stable coronary disease were not different from those of normal subjects (0.62 +/- 0.56 and 0.76 +/- 0.38 pg/ml. respectively). In group I. plasma levels of endothelin-1 rose sharply after myocardial infarction. reaching a peak of 4.95 +/- 0.78 pg/ml at 6 h after the onset of chest pain (p less than 0.05 compared with values in control subjects) and returning rapidly toward the normal range by 24 h. Patients with complicated infarction (group II) demonstrated a similar rapid increase in plasma endothelin-1 to a peak value of 8.29 +/- 1.95 pg/ml; however. plasma endothelin-1 remained elevated in these patients. becoming significantly different from values in group I at 48 and 72 h. There was no correlation between peak increases in creatine kinase and peak endothelin-1 in either group. suggesting that the stimulus for elevation of endothelin-1 was not myocardial necrosis itself. Furthermore. left ventricular ejection fraction did not correlate with the increase in endothelin-1 in group I patients. whereas there was a significant inverse relation between ventricular function and plasma endothelin-1 in group II.
The Marfan syndrome: abnormal aortic elastic properties, Aortic distensibility and aortic stiffness index were measured at the ascending aorta (3 cm above the aortic valve) and the mid-portion of the abdominal aorta from the changes in echocardiographic diameters and pulse pressure in 14 patients with the Marfan syndrome and 15 age- and gender-matched normal control subjects. The following formulas were used: 1) Aortic distensibility = 2(Changes in aortic diameter)/(Diastolic aortic diameter) (Pulse pressure); and 2) Aortic stiffness index = ln(Systolic blood pressure)/(Diastolic blood pressure)(Changes in aortic diameter)/Diastolic aortic diameter. Pulse wave velocity was also measured. Compared with normal subjects. patients with the Marfan syndrome had decreased aortic distensibility in the ascending and the abdominal aorta (2.9 +/- 1.3 vs. 5.6 +/- 1.4 cm2 dynes-1. p less than 0.001 and 4.5 +/- 2.1. vs. 7.7 +/- 2.5. cm2 dynes-1. p less than 0.001. respectively) and had an increased aortic stiffness index in the ascending and the abdominal aorta (10.9 +/- 5.6 vs. 5.9 +/- 2.2. p less than 0.005 and 7.1 +/- 3.1 vs. 3.9 +/- 1.2. p less than 0.005. respectively). Aortic diameters in the ascending aorta were larger in these patients than in normal subjects. but those in the abdominal aorta were similar in the two groups. Linear correlations for both aortic distensibility and stiffness index were found between the ascending and the abdominal aorta (r = 0.85 and 0.71. respectively). Pulse wave velocity was more rapid in the patients than in the normal subjects (11.6 +/- 2.5 vs. 9.5 +/- 1.4 m/s. respectively. p less than 0.01). Thus. aortic elastic properties are abnormal in patients with the Marfan syndrome irrespective of the aortic diameter. which suggests an intrinsic abnormality of the aortic arterial wall.
Evaluation of pulmonary venous flow by transesophageal echocardiography in subjects with a normal heart: comparison with transthoracic echocardiography, Nineteen normal subjects and five patients with atrial fibrillation underwent transesophageal and transthoracic echocardiographic studies to evaluate the normal pulmonary venous flow pattern. compare right and left pulmonary venous flow and assess the effect of sample volume location on pulmonary venous flow velocities. Best quality tracings were obtained by transesophageal echocardiography. Anterograde flow during systole and diastole was observed in all patients by both techniques. Reversed flow during atrial contraction was observed with transesophageal echocardiography in 18 of the 19 subjects in normal sinus rhythm. but in only 7 subjects with transthoracic echocardiography. Two forward peaks during ventricular systole were clearly identified in 14 subjects (73%) with transesophageal echocardiography. but in none with the transthoracic technique. The early systolic wave immediately followed the reversed flow during atrial contraction and was strongly related to the timing of atrial contraction (r = 0.78; p less than 0.001). but not to the timing of ventricular contraction. and appeared to be secondary to atrial relaxation. Conversely. the late systolic wave was temporally related to ventricular ejection (r = 0.66; p less than 0.001). peaking 100 ms before the end of the aortic valve closure and was unrelated to atrial contraction time. Quantitatively. significantly higher peak systolic flow velocities were obtained in the left upper pulmonary vein compared with the right upper pulmonary vein (60 +/- 17 vs. 52 +/- 15 cm/s; p less than 0.05) and by transesophageal echocardiography compared with transthoracic studies (60 +/- 17 vs. 50 +/- 14 cm/s; p less than 0.05). Increasing depth of interrogation beyond 1 cm from the vein orifice resulted in a significant decrease in the number of interpretable tracings.
Influence of exercise-induced myocardial ischemia on the pattern of left ventricular diastolic filling: a Doppler echocardiographic study, Previous studies using Doppler echocardiography to evaluate left ventricular diastolic filling have shown that myocardial ischemia induced by coronary balloon angioplasty or atrial pacing results in a decrease in the left ventricular inflow peak early (E) to peak atrial (A) velocity ratio. To investigate the effects of exercise-induced ischemia on Doppler-derived filling variables. 20 patients with coronary artery disease and exercise-induced electrocardiographic changes and regional wall motion abnormalities determined by two-dimensional echocardiography were evaluated and compared with 20 patients without evidence of exercise-induced ischemia. Doppler echocardiography was performed at rest and immediately after exercise before the resolution of exercise-induced wall motion abnormalities. Peak E and A velocities increased from rest to postexercise in both the ischemic and nonischemic groups. although the ischemic group demonstrated a greater increase in peak E velocity (from 68 +/- 15 cm/s at rest to 88 +/- 22 cm/s after exercise) than the nonischemic group (70 +/- 13 to 77 +/- 18 cm/s) (p less than 0.05 for the difference in response between groups). Accompanying these changes was a slight increase in the peak E/A velocity ratio in the ischemic group (1.04 +/- 0.28 at rest to 1.13 +/- 0.42 after exercise) versus a decrease in the nonischemic group (1.07 +/- 0.30 to 0.90 +/- 0.28) (p less than 0.05 intergroup difference).
Application of Doppler color flow imaging to determine valve area in mitral stenosis, This study was undertaken to examine whether Doppler color flow imaging could accurately estimate the valve area in mitral stenosis. Doppler color flow assessments were performed in both an in vitro model and in 30 patients with mitral stenosis undergoing cardiac catheterization. In the experimental Doppler study using a circuit model. color jet width correlated well with actual orifice diameter (r = 0.99). In the clinical Doppler study. the mitral valve orifice was assumed to be elliptic and the mitral valve area was calculated from the following equation: (pi/4) (a x b). where a = color jet width at the mitral valve orifice in the apical long-axis view (short diameter) and b = the width in the 90 degrees rotated view (long diameter). Mitral valve area was also determined by two-dimensional echocardiography and the pressure half-time method. and the results for all three noninvasive methods were compared with those obtained at cardiac catheterization. By Doppler color flow imaging. mitral valve area could be determined in all patients and there was a significant correlation between the Doppler jet and catheterization estimates of mitral valve area (r = 0.93). Valve area determined by two-dimensional echocardiography correlated well with catheterization measurements in 26 patients (r = 0.84). However. the area could not be determined in 4 (13%) of the 30 patients because of technical problems. Although there was a fair correlation between the valve area determined by the pressure half-time method and catheterization (r = 0.79). this method tended to overestimate valve area in patients with aortic regurgitation.
Injury due to uncontrolled acceleration of an electric wheelchair, Approximately 750.000 disabled individuals use electrical platform mobility aids (wheelchairs) for adaptive transportation. Because there are no mandatory standards for platform mobility aids and wheelchairs. these adaptive transportation aids are prone to potential design and maintenance problems. An injury caused by uncontrolled acceleration of a platform mobility aid is reported. Examination of the platform mobility aid identified a defect in its speed control regulator that has been subsequently corrected by the manufacturer.
Eating utensil foreign bodies of the esophagus, Large foreign bodies of the esophagus are uncommon. We report two unusual cases of eating utensil. esophageal. foreign bodies that occurred unintentionally following self-instrumentation of the oropharynx. The histories. radiographs. and clinical management of these cases are presented and discussed.
Delayed presentation of unstable cervical spine injury with minimal symptoms, Emergency physicians are less likely to suspect the presence of a severe or unstable cervical spine injury in patients who have been ambulatory since the traumatic episode. We present the case of a man with multiple cervical fractures and a 75% anterior subluxation of C6 and C7 who did not seek medical care for six weeks after falling from a height. Previous reports of delayed or occult cervical spine injuries are reviewed. Physicians must aggressively search for injuries whenever a history of neck pain is present or a strong mechanism of injury exists. even if the patient has been ambulatory for days or weeks following the injury.
Fatal nicotine ingestion, Nicotine is one of the most readily available and commonly abused drugs in modern society. However. serious or fatal overdoses of this agent are rare. We present a case of intentional fatal ingestion of nicotine alkaloid solution. This diagnosis may be elusive since nicotine is commonly qualitatively identified on urine toxicology screens. but is seldom quantified. Clinicians should be knowledgeable about the nature of this agent and its pathophysiologic presentations since recognition of the toxidrome is often necessary to make this diagnosis.
Fracture of the base of the little finger metacarpal: importance of the "ball-catcher" radiographic view, A case of fracture of the base of the little finger metacarpal is presented. These unusual fractures are not easily detected on the routine three-view "hand-series." Physicians should be aware of the AP oblique (Norgaard. or "ball-catcher's") view. which is helpful in detecting these fractures.
Ecology and epidemiology of zoonotic pathogens, The possibility that a perplexing febrile illness may represent a zoonotic infection should be explored. The history should include where the person has been. what he or she has done. what has been eaten and drunk. what contacts have occurred with vertebrates or arthropods in wild or domestic venues. and whether there has been exposure to unusual animal products. The preceding discussion emphasized. via some examples. mechanisms of spread as well as the physical and biologic conditions that enhance the probability of an encounter with a pathogen. From clues in the history and physical examination the appropriate diagnostic and therapeutic decisions can be made. These decisions may be life saving for the patient. and perhaps protect care providers and family from acquiring the same disease. Many of the infections mentioned in this article will be amplified in subsequent articles. which will deal with diseases encountered primarily in the United States.
Lyme disease, The rapid rate of increase in reported cases of Lyme disease exceeds that of any zoonotic disease. and the annual occurrence of cases is greater than the sum of all other tick-borne illnesses in the United States. This. in addition to the geographic spread of cases to most of the United States. has greatly heightened investigative interests in all aspects of Lyme disease and its control.
Emerging vector-borne infections, The principles that regulate the transmission of vector-borne infectious agents are briefly described. In particular. the circumstances that may lead to human exposure to various North American zoonoses are analyzed.
Elevated levels of endogenous IL-6 in systemic lupus erythematosus. A putative role in pathogenesis, Elevated spontaneous IgG production is characteristic of SLE. To identify the factors that support it. IL-6. a cytokine with an important role in the differentiation of IgG-secreting cells. was studied in SLE patients. Higher than normal levels of IL-6 were found. by a B9 assay. in sera of 63 of 70 patients (p less than 0.05). IL-6 was detected in 36 of 37 active SLE sera in higher titers (p = 0.009) than those for inactive SLE (n = 33). which were higher (p less than 0.05) than healthy controls (n = 15). IL-6 mRNA was detected in freshly isolated PBMC of 11 of 11 patients but not in normal PBMC. whereas IL-1 mRNA was detected only in patients with active disease. IL-6 activity was recovered from PBMC of four SLE patients. but not from four normal donors. By immunoperoxidase. IL-6 was detected in the cytoplasm of SLE monocytes and lymphocytes. When SLE PBMC were grown in short term cultures with no deliberate stimulation. expression of the IL-6 gene declined rapidly. Accordingly. the spontaneous production of IgG by SLE PBMC could be enhanced by exogenous IL-6. Spontaneous IgG production was diminished by 20 to 65% in the presence of neutralizing antibodies to IL-6. TNF-alpha. or IL-1. In contrast. neutralization of endogenous IL-4 increased production by approximately 40%. Anti-TNF-alpha treatment decreased IL-6 content of PBMC cultures. whereas anti-IL-4 augmented it. and exogenous IL-6 reversed anti-TNF-alpha effects on IgG production. Therefore. it is possible that the neutralization of TNF-alpha and IL-4 affected IgG production by modulating the synthesis/activity of IL-6. These results support the concept that SLE B cell hyperactivity is promoted by dysregulation of endogenous cytokines and suggest that IL-6. in particular. has an important pathogenic role.
Retinoic acid enhances IL-1 beta expression in myeloid leukemia cells and in human monocytes, We have examined the role of retinoic acid (RA). the biologically active metabolite of vitamin A. in expression of the IL-1 beta gene in the human myeloid leukemia cell line THP-1 and in human monocytes. Both protein kinase C-activating phorbol esters. e.g.. PMA. and LPS induce IL-1 beta expression in these cells. Physiologic RA concentrations alone were not able to induce any IL-1 beta production. but they strongly enhanced the PMA-induced IL-1 beta protein production and mRNA accumulation in both human monocytes and in THP-1 cells. Nuclear run-off analysis revealed that the enhancing effect was at the transcriptional level. RA also slightly potentiated LPS-induced IL-1 beta expression in THP-1 cells but not in human monocytes. These data suggest that RA can be a strong up-regulator of IL-1 production. but its strength varies depending on the nature of the activating signal.
Definition of an epitope and MHC class I molecule recognized by gag-specific cytotoxic T lymphocytes in SIVmac-infected rhesus monkeys, Infection of macaque monkeys with the simian immunodeficiency virus of macaques (SIVmac) results in disease similar to human AIDS. Therefore. the macaque monkey is proving to be an important model for testing the effectiveness of various AIDS vaccine approaches. A detailed analysis of the cellular immune responses is necessary for the evaluation of candidate vaccines. However. this has not been possible in macaques. due. in part. to the unknown nature of the MHC molecules that restrict their T lymphocytes. In our report we demonstrate that a particular MHC class I molecule involved in the rhesus monkey's effector T lymphocyte response to SIVmac is expressed at a high frequency in a colony of rhesus monkeys. SIVmac-infected monkeys that express this MHC class I molecule all develop CTL that are restricted by that molecule and recognize an identical nine amino acid epitope of the SIVmac gag protein. This MHC class I molecule has been defined as an HLA-A homolog by cDNA cloning and sequencing. It has also been expressed in an MHC class I-deficient cell line to demonstrate directly the cloned molecule's capacity to bind and present peptide Ag to CTL. These studies illustrate that AIDS virus-specific CTL can be characterized in detail in the rhesus monkey and lay the foundation for exploring novel approaches to AIDS virus vaccination in this species.
Alveolar macrophage activation in experimental legionellosis, Legionella pneumophila is a facultative intracellular parasite of alveolar macrophages. In vitro studies have shown that lymphokine-activated mononuclear phagocytes inhibit intracellular replication of L. pneumophila. To determine if recovery from legionellosis is associated with activation of alveolar macrophages in vivo to resist L. pneumophila. we studied an animal model of Legionnaires' disease. Rats were exposed to aerosolized L. pneumophila and alveolar macrophages were harvested during the recovery phase of infection. We compared these alveolar exudate macrophages with normal resident alveolar macrophages for the capacity to support or inhibit the intracellular growth of L. pneumophila. We also measured Ia expression as a marker of immunologic activation. and studied binding of bacteria. superoxide release. and the expression of transferrin receptors as potential mechanisms of resistance to L. pneumophila. For perspective on the specificity of these responses. we also studied alveolar exudate cells elicited by inhalation of heat-killed L. pneumophila. live Listeria monocytogenes. and live Escherichia coli. We found that alveolar exudate macrophages elicited by live L. pneumophila. but not heat-killed L. pneumophila. resisted the intracellular growth of L. pneumophila. Exudate macrophages in resolving legionellosis exhibited increased Ia expression. diminished superoxide production. and downregulation of transferrin receptors. Binding of L. pneumophila to exudate macrophages was indistinguishable from that to resident macrophages in the presence of normal serum. and augmented in the presence of immune serum. Alveolar exudate macrophages elicited by E. coli also inhibited growth of L. pneumophila. and exhibited a modest increase in Ia expression without change in transferrin receptors. Exudate cells induced by L. monocytogenes exhibited up-regulation of Ia without diminution of superoxide release. Alveolar cells harvested after inhalation of heat-killed L. pneumophila did not differ from resident alveolar macrophages in the expression of surface markers. These findings suggest that alveolar macrophages are immunologically activated in vivo to serve as effector cells in resolving legionellosis. and that live bacteria are required to induce this expression of immunity. The mechanism of resistance to parasitism by L. pneumophila may entail restriction of the intracellular availability of iron. but does not involve diminished bacterial binding or an augmented respiratory burst.
Experimental onchocerciasis in chimpanzees. Cell-mediated immune responses, and production and effects of IL-1 and IL-2 with Onchocerca volvulus infection, Nine of eighteen chimpanzees inoculated with infective third-stage larvae of Onchocerca volvulus developed patent infection with microfilariae in skin biopsies. In all infected chimpanzees the in vitro cellular reactivity to O. volvulus adult worm-derived Ag (OvAg) increased significantly after exposure to third-stage larvae. However. during prepatency the in vitro cellular responses to OvAg decreased gradually in subsequently mf positive (patent) animals. and returned with patency to values not different to those before infection. In non-patent chimpanzees cellular responses remained significantly higher than before infection. Stimulation of PBMC in vitro with bacterial Ag and mitogen did not show any differences between the experimental groups through 20 months p.i. The addition of exogenous IL-2 did not restore the impaired responses of PBMC to OvAg in patent animals. Exogenous IL-2 elicited an additive increase of the cellular response to OvAg in nonpatent. and a mitogenic effect to OvAg in patent animals. Selective depletion of adherent. suppressor/cytotoxic (CD8+). NK cells (CD16+) and the use of autologous serum had no effect on antigenic and mitogenic cellular responsiveness. OvAg-induced IL-2 production decreased after patency. whereas. IL-1 production was significantly greater in both patent and nonpatent than in control chimpanzees. In summary. these data demonstrate that experimental O. volvulus infection in chimpanzees stimulated a substantial cell-mediated immune response. In patent chimpanzees an OvAg-specific cellular hyporesponsiveness occurred before onset of patency. possibly due to decreased IL-2 production and responsiveness.
Trichophyton tonsurans allergen. I. Characterization of a protein that causes immediate but not delayed hypersensitivity, Fungal infections of skin or nails are extremely common and often caused by dermatophyte fungi of the genus Trichophyton. These fungi are unusual in that they can give rise to delayed hypersensitivity (DH) or immediate hypersensitivity (IH) responses. Recently. IH to Trichophyton tonsurans has been demonstrated in patients by skin tests. serum IgE antibody test (RAST). and positive nasal and bronchial challenges. To further investigate the immunology of Trichophyton. a 30-kDa T. tonsurans allergen was isolated by gel filtration and hydrophobic interaction chromatography. This protein. Tri t I. gave a single band on SDS-PAGE. and the 30 amino-terminal amino acids have been determined. Among patients with positive IH skin tests. 34 of 48 (71%) had IgG antibody and 26 of 48 (54%) had IgE antibody to Tri t I. Among those who had positive responses to both skin tests and RAST. 22 of 30 (73%) had IgE antibodies to Tri t I; thus. this protein represents a major allergen. Twelve clones of murine IgG mAb antibodies were produced. Two clones. 2F2-F7 and 6B11-C2. were found to define separate epitopes on Tri t I and were used to develop an immunometric assay for the quantitation of Tri t I. Twenty-three of 38 volunteers with a history of athlete's foot were found to have either IH and/or DH to Trichophyton mix and underwent further testing with purified Tri t I. Of the nine found to have IH to the mix. eight were sensitive to Tri t I. Seven of these eight had IgG and IgE antibodies to Tri t I. by Ag-binding RIA. and all were RAST positive to the unpurified extract. An additional 14 had either DH alone (n = 7) or a wheal and flare response followed by DH at 48 h (n = 7). Of these 14 who had DH responses to Trichophyton mix. only one showed DH to an equivalent quantity of purified Tri t I; among this group. none showed IH or serum IgE antibodies and only one had detectable IgG antibody to Tri t I. The results suggest that the majority of subjects with DH to Trichophyton are responding to a protein other than Tri t I and that the wheal that precedes DH reactions is some patients is not associated with IgE antibodies.
Body image dissatisfaction in homosexual and heterosexual males, A nonclinical sample of 43 homosexual and 32 heterosexual men completed two self-report inventories regarding weight. body satisfaction. eating attitudes. and behaviors. Subjects were also asked to select their current and ideal figures. the weight they felt would be most attractive to a potential partner. and the weight to which they would be most attracted in a potential partner from figures representing very thin to very heavy physiques. Heterosexual men were significantly heavier than homosexual men and desired a significantly heavier ideal weight. Although the current and ideal physiques selected by the homosexual and heterosexual men were almost identical. homosexual men were more likely to desire an underweight ideal. A heightened pursuit of thinness may place homosexual men at an increased risk for developing eating disorders.
Copper deficiency in a genetically hypertensive cardiomyopathic rat: electrocardiogram, functional and ultrastructural aspects, The effect of copper deficiency on cardiac function and structure was studied in a strain of rats (SHHS/Mcc-cp) known to develop cardiac failure as adults. Restriction of dietary copper (less than or equal to 1 mg/kg vs. 6 mg/kg in adequate diets) at weaning in both sexes for a 6-wk period produced cardiac hypertrophy. Male rats developed more severe copper-deficiency symptoms than their female counterparts. In both sexes of copper-deficient rats. there was an increase in cardiac length. width. free ventricular wall thickness and septum thickness. Electrocardiographic tracings revealed greater QRS height among male copper-deficient rats. Heart rate also was substantially reduced in this group. The increased volume of myocardium occupied by mitochondria in the copper-deficient male rats might result in increased electrical resistance that would increase the QRS height; hypertrophy or anemia also could be contributory. Some male copper-deficient rats had prolongation of the QRS in a bundle branch block pattern. Maximal rates of rise and fall for left ventricular pressure were reduced in male copper-deficient rats. The gross histology indicated that this type of heart failure was more concentric than eccentric. The copper-deficient male rat may serve as a useful model for studying the concentric cardiac hypertrophy that occurs in humans.
Vitamin B-6 requirements of elderly men and women, The vitamin B-6 requirements of 12 men and women over 60 y old were studied. The protocol consisted of a 5-d baseline period and four experimental periods during which the subjects successively received 0.003. 0.015. 0.0225 and 0.03375 mg of vitamin B-6/(kg body wt.d). Dietary protein was 1.2 or 0.8 g/(kg body wt.d). At 5- or 6-d intervals. xanthurenic acid (XA) after a 5-g L-tryptophan load and 4-pyridoxic acid (4-PA) in 24-h urine. erythrocyte aspartate aminotransferase activity coefficient (EAST-AC) and plasma pyridoxal-5'-phosphate (PLP) were measured. These measurements were abnormal during vitamin B-6 depletion but returned to normal during repletion. Men who ingested approximately 120 g protein/d required 1.96 +/- 0.11 mg of vitamin B-6 to normalize XA; women who ingested 78 g protein/d required 1.90 +/- 0.18 mg of vitamin B-6 to normalize XA. To attain normal levels of EAST-AC and 4-PA in men. 2.88 +/- 0.17 mg of vitamin B-6 were needed; to normalize PLP. 1.96 +/- 0.11 mg of vitamin B-6 were required. Women required 1.90 +/- 0.18 mg or more of vitamin B-6 to normalize these measurements. Vitamin B-6 requirements were not decreased in two of three subjects who ingested 54 g of protein daily. Thus. vitamin B-6 requirements of elderly men and women are about 1.96 and 1.90 mg/d. respectively.
Gastric inhibitory polypeptide and insulin responses to orally administered amino acids in genetically obese hyperglycemic (ob/ob) mice, The effects of oral administration of eight L-amino acids (alanine. arginine. cysteine. glycine. histidine. hydroxyproline. lysine and threonine) individually or as an amino acid mixture on plasma gastric inhibitory polypeptide (GIP). insulin and glucose concentrations were examined in 18-h fasted obese hyperglycemic (ob/ob) mice. At a dose of 5.4 mmol/kg body weight. arginine. cysteine. histidine and the amino acid mixture were equipotent in terms of increasing plasma GIP and insulin concentrations. Alanine. hydroxyproline and lysine also increased plasma GIP. but insulin concentrations were unchanged. In contrast. threonine failed to affect either GIP or insulin concentrations. There was no correlation between either the incremental or integrated GIP and insulin responses. and none of the amino acids administered affected circulating glucose concentrations. The results indicate that a range of essential and nonessential neutral and basic amino acids stimulate the release of GIP in ob/ob mice. However. GIP made only a modest contribution to the stimulation of insulin secretion following administration of amino acids in the presence of basal glycemia.
Prevention of the incidence of diabetes by dietary sorbose in nonobese diabetic mice, The effect of dietary sorbose on the prevention of the incidence of diabetes in the nonobese diabetic mouse was investigated in animals from 5 to 11 wk of age. When sucrose (200 g/kg diet) in the control diet was replaced by sorbose. body weight was significantly reduced. The blood glucose level also was lowered in mice fed sorbose. but the serum insulin level was unchanged. Glucose was not detected in the urine of mice fed the sorbose diet during the experiment. but some mice in the control group excreted glucose in urine. Relative weights of the heart. liver and left kidney were significantly higher in mice fed the sorbose diet vs. those fed the control diet. The results suggest that dietary sorbose would benefit patients with diabetes by lowering blood glucose and inhibiting urinary glucose excretion.
The value of a clinical definition for epidemic KS in predicting HIV seropositivity in Africa, Kaposi's sarcoma (KS) in African adults can present in endemic (non-HIV-related) and epidemic (HIV-related) forms. We evaluated the usefulness of a clinical case definition for epidemic KS in predicting HIV seropositivity. A total of 235 patients with KS presenting to the Uganda Cancer Institute from January 1. 1988 to March 31. 1990 were evaluated with history and physical examination. Symptomatic patients underwent chest radiography and upper gastrointestinal endoscopy. One hundred seventy-four patients (80%) underwent HIV ELISA testing with Western blot confirmation. The clinical case definition had a 91% sensitivity and a 95% specificity in predicting HIV seropositivity. Oral KS was the most sensitive specific site of involvement in predicting HIV seropositivity. The clinical case definition is useful in assessing patients to determine prognosis and likelihood of responding to aggressive therapy.
Analyzing laboratory marker changes in AIDS clinical trials, Repeated measurements of laboratory markers of immunologic or disease status. such as CD4 lymphocyte counts and HIV p24 antigen levels. can be important end points in comparative clinical trials. In this report. we consider comparison of treatment groups with respect to such markers. focusing on a distribution-free approach in which each participant's data are characterized by a single summary statistic. The summary statistics examined are (a) the slope of the least-squares regression of the marker. (b) the average of the last r measurements. and (c) the difference between the averages of the last r and the first s measurements. Under various models of marker time trends. these methods are compared with regard to statistical power. It is found that the slope is usually more efficient than the other two types of summaries. Adaptations for missing data are discussed and illustrated in an analysis of CD4 counts from a recent AIDS clinical trial.
Antibodies against defined carbohydrate structures of Candida albicans protect H9 cells against infection with human immunodeficiency virus-1 in vitro, In this study we raised antibodies against Candida albicans mannans of serotype A and B which comprise mannose alpha(1----2)-and mannose alpha(1----3)-linked residues. These antibodies inhibited human immunodeficiency virus type IIIB (HIV-IIIB) infection of H9 cells in vitro; 5 micrograms/ml of antibodies against mannan from serotype A and 10 micrograms/ml of antibodies against serotype B mannan were sufficient to inhibit infection by almost 100 and 85%. respectively. after an incubation period of 4 days. During a prolonged incubation period (8-12 days). the amount of HIV particles (as measured by reverse transcriptase activity in the culture medium) increased again in assays with antibodies raised against serotype B. but only little in assays containing antibodies against serotype A. Applying the Western blotting technique and a novel enzyme-linked immunosorbent assay system it was established that the antibodies reacted with the gp120 of HIV-1 exclusively. Immunofluorescence inspection using a confocal laser scanning microscope revealed that the gp120 protein is exposed on the outer surface of H9 cells where it is recognized by the anti-mannan antibodies. These results indicate that mannan residues of C. albicans can serve as antigens to raise neutralizing antibodies against HIV infection.
Protracted withdrawal syndromes from benzodiazepines, The benzodiazepine withdrawal syndrome is a complex phenomenon which presents serious difficulties in definition and measurement. It is particularly difficult to set out precise limits on its duration. Many withdrawal symptoms are a result of pharmacodynamic tolerance to benzodiazepines. some mechanisms for which are discussed. Such tolerance develops unevenly in different brain systems and may be slow to reverse. Withdrawal symptoms occurring in the first week after cessation of drug use tend to merge with more persistent symptoms that may last for many months. These prolonged symptoms do not necessarily constitute "true" pharmacological withdrawal symptoms. but are nevertheless related to long-term benzodiazepine use. Such symptoms can include anxiety. which may partly result from a learning deficit imposed by the drugs. and a variety of sensory and motor neurological symptoms. The protracted nature of some of these symptoms raises the possibility that benzodiazepines can give rise not only to slowly reversible functional changes in the central nervous system. but may also occasionally cause structural neuronal damage.
Pharmacologic aspects of benzodiazepine tolerance and dependence, Benzodiazepines. which are among the safest and most effective drugs. possess all the characteristic of abuseable compounds. Although there appear to be differences in potency among compounds and variations in sensitivity among individuals. benzodiazepines have clear reinforcing properties. Tolerance to the depressant effects of benzodiazepines is rapid. but tolerance to the anxiolytic effects develops slowly and to a limited extent. Although abusers use very high doses. most long-term users persist at daily doses in the low therapeutic range (10-20 mg of diazepam or its equivalent) without dose escalation. Physical dependence is a risk associated with long-term use. even at therapeutic doses. The withdrawal syndrome is mild at low doses. Continued self-administration of low therapeutic doses is maintained to alleviate withdrawal symptoms. The advances in the recent understanding of the molecular biology of the benzodiazepine receptor gives hope to the development of new anxiolytic compounds with less dependence liability than the present ones.
Benzodiazepines: a major problem. Introduction, Benzodiazepine use is prevalent. Moreover. benzodiazepine abuse. addiction. tolerance. and dependence occur commonly with benzodiazepine use. Confusion arises in assessing the nature and magnitude of benzodiazepine use and its consequences. Abuse. addiction. tolerance. and dependence occur in medical and nonmedical populations. but the studies do not clearly differentiate the benzodiazepine use between these two populations. The nonmedical use in medical populations is underestimated and underdiagnosed. The nonmedical use is also misdiagnosed in nonmedical populations as medical use. Clearer definitions and usage of the terms of abuse. addiction. tolerance. and dependence would result in accurate diagnosis and proper treatment of the disorders associated with benzodiazepine use. that is. anxiety and depressive disorders. alcoholism. and other drug addictions.
Benzodiazepines and the elderly. A review of potential problems, This article reviews the literature describing the extent of benzodiazepine use and abuse in the elderly and specific problems attendant upon this use. Unrecognized. undocumented use and abuse of psychoactive drugs is frequent in this population and can lead to serious problems with untreated dependence and withdrawal. The elderly appear to be more sensitive to the effects of benzodiazepines. both because of changed pharmacokinetics and pharmacodynamics with aging and because of altered postreceptor cerebral response. All problems identified with benzodiazepines such as dependence. withdrawal. and cognitive and psychomotor impairment are proportionally greater among the elderly. who can least afford these risks. Review of the literature leads to the conclusion that benzodiazepine prescribing for the elderly should be undertaken with the greatest caution and only with the recognition of all potentially disastrous effects.
Alprazolam and diazepam: addiction potential, Alprazolam and diazepam. the two most prescribed benzodiazepine anxiolytics in the United States. have potential for addictive use. The Drug Abuse Warning Network (DAWN) indicates they are the most mentioned benzodiazepines. and the National Household Survey indicates significant abuse of tranquilizers. Both drugs are rapidly absorbed and enter the brain tissue rapidly. leading to reinforcement. Alprazolam has a shorter half-life. which may lead to more withdrawal symptoms than diazepam. In experimental conditions. they are among the most reinforcing benzodiazepines. Each causes a withdrawal syndrome. but alprazolam withdrawal may be more severe and may occur after a shorter period of use. Adverse effects from their use are said to be rare. yet subtle negative consequences may be seen with some regularity. Alprazolam deserves special caution because of its relative newness. great popularity. reinforcing capabilities. relatively severe withdrawal syndrome. and reports of addiction and negative consequences of use.
Addiction to and dependence on benzodiazepines. Diagnostic confusion in clinical practice and research studies, Considerable confusion continues to surround basic concepts for abuse. addiction. tolerance. and dependence. Clinicians may be making decisions about prescribing these medications without clear definitions and distinctions. The terms are not equivalent in meaning and should not be used interchangeably in clinical application. Moreover. they may occur together or independently and are not etiologically related. Abuse is improper use outside the standard norms. Abuse implies a violation component and a control over the use of the drug. Addiction is a preoccupation with the acquisition and compulsive use of and a pattern of relapse to drugs is spite of adverse consequences. Pervasive to the criteria is a loss of control over drug use and a lack of volitional component in the drug use. In spite of problems in definitions. studies have clearly shown that abuse. addiction. tolerance. and dependence develop commonly in benzodiazepine use.
The dual-diagnosis patient in a psychiatric day treatment program: a treatment failure, This study was undertaken to determine the effectiveness of treating the dual-diagnosis patient in a standard psychiatric day treatment program. These patients. presenting with psychiatric disorder coexisting with alcohol and/or drug abuse. present a major problem in treatment because of their emotional fragility. their propensity to impulsive acting-out behaviors. and their adaptation to psychiatric symptomatology via self-medication with illicit drugs. Of the 24 dual-diagnosis patients admitted to our Day Treatment Center in 1988. 57% left treatment at or before 8 weeks following admission. as opposed to 21% of a nonsubstance abusing psychiatric control group. Their rate of absenteeism and suspensions for continuing abuse and infraction of the rules was four times that of the controls. In light of these data. it appears that these patients require highly specialized treatment strategies not generally available in a conventional psychiatric day hospital.
Altered states of consciousness therapy. A missing component in alcohol and drug rehabilitation treatment, Attaining altered states of consciousness is described as a basic human motive. The substance dependent population is distinguished from other populations because they pursue these states destructively by inappropriate use of alcohol and drugs. Despite a body of literature supporting the benefits of altered states of consciousness. alcohol and drug rehabilitation treatment programs fail to address this motive because of social disapproval. means-end confusion. and inadequate staff training. The authors maintain that Alcoholics Anonymous directs its members toward an altered state of consciousness called a spiritual awakening. which replaces the self-destructive pursuit of substance induced "highs." Failure to address patients' need for alternative methods of achieving altered states of consciousness is presented as part of the reason for relapse. An Altered States of Consciousness Therapy (ASCT) program is described that can be used to teach patients to consciously manipulate affect and cognition to achieve a new consciousness.
Alcohol and drug problems in Czechoslovakia, The authors describe the current drug and alcohol scene in Czechoslovakia. with references to historical developments. Drug abuse is divided into nine groups: from drugs most frequently abused (opiates and speed) to illegally cultivated hemp (hashish and marijuana). In 1985 there were 9.900 registered drug addicts and 720 are added to this number annually. There are approximately 15 nonregistered drug addicts for every registered one. In the consumption of alcoholic beverages. Czechoslovakia holds 13th place in the world (average annual per capita consumption is in the vicinity of 9.5 litres of 100% alcohol). In 1985 there were 239.385 registered alcoholics (of this number. 18.746 were women). In conclusion the authors describe the Czechoslovak system of treatment of addictions: detoxification departments. outpatient treatment. and institutional care. as well as treatment for prisoners and forced treatment. They also mention the effectiveness of these treatment programs.
Detoxification from benzodiazepines: schedules and strategies, Management of benzodiazepine (BZD) tolerance is divided into low- and high-dose withdrawal. Low-dose withdrawal includes patients who have received manufacturer-recommended doses of BZD on a daily basis for longer than 1 month. Gradual tapering of the BZD over 4 weeks on an outpatient basis is suggested. High-dose withdrawal includes patients who have been ingesting doses of BZD greater than the equivalent of diazepam 40 mg/d for longer than 8 months. It is recommended that the patients be tolerance tested with diazepam and. if tolerant. tapered off medication as inpatients at a rate of 10% per day. Triazolobenzodiazepines may be exceptions to these recommendations. Alprazolam should be titrated at a rate of 0.5 mg three times a day regardless of whether the patient is being tapered for low- or high-dose withdrawal.
Acute poisoning with bromofosmethyl (bromophos), One hour after suicidal ingestion of about 20 mL of a 38% solution of bromofosmethyl. CAS: 2104-96-3 (bromophos). a 52 year-old female was admitted to the hospital with extreme miosis. hypersalivation. hyperperistalsis and muscular fibrillation. Gastric lavage was performed and activated charcoal administered. Cholinergic symptoms were antagonized by repeated doses of 0.5 mg atropine. Because of the high dose of bromophos. hemoperfusion was performed with amberlite XAD4. The bromophos clearance during hemoperfusion was 95 mL/min (flow 200 mL/min). The patient received two doses of 500 mg obidoxime for recurrent muscular fibrillation. The further clinical course was uneventful. On day 4. the patient was transferred to a psychiatric ward because of persistent suicidality. In contrast to poisoning by most organophosphates. red blood cell acetyl cholinesterase was only minimally depressed but the plasma butyryl cholinesterase was initially decreased and normalized within a few days. The records of 25 patients reported to our Poison Control Center with ingestion of more than 1 g bromophos were also evaluated. The most frequent symptoms were miosis. hyperperistalsis. hypersalivation. agitation. nausea/vomiting and convulsions. Nine of the patients had no symptoms. Bromophos is relatively less toxic than its phosphate derivative. parathion.
Mass poisoning by sodium arsenite, An acute massive epidemic of arsenic poisoning in Argentina involved 718 subjects. Urine samples were obtained from 307. The 49 with urine arsenic 76-500 micrograms/dl and 12 with urine arsenic greater than 500 micrograms/dL received dimercaprol treatment. Symptomatology increased with the urine arsenic with increased diarrhea. vomiting and systemic symptoms at urine arsenic greater than 75 micrograms/dL.
Considerations for the treatment of ethylene glycol poisoning based on analysis of two cases, The clinical picture as well as the principles of treatment in ethylene glycol poisoning differ with the time after ingestion. These time-related differences are illustrated by two case reports. During the first hours of ethylene glycol poisoning. the patient suffers from drunkenness. vomiting and somnolence due to the intoxicant effect of ethylene glycol on the central nervous system. In the following hours a poisoning with glycolate and oxalate develops. with increasing acidosis. renal and brain damage. A patient admitted within a few hours of an overdose. with no or only slight metabolic acidosis. may be successfully treated with ethanol. If the serum concentration of ethylene glycol is very high. hemodialysis may be deferred until the necessary staff and equipment are available. If the patient is admitted with severe metabolic acidosis. hemodialysis must be started immediately. The need for ethanol administration during hemodialysis merits reevaluation.
Determination of serum acetaminophen in emergency toxicology: evaluation of newer methods: Abbott TDx and second derivative ultraviolet spectrophotometry, Newer methods for the determination of serum acetaminophen in emergency toxicology. the Abbott TDx immunoassay and second derivative ultraviolet spectrophotometry. were evaluated and compared to a high pressure liquid chromatographic procedure. The Abbott TDx immunoassay within-run and day to day precision yielded coefficients of variance below 2.7% and 7.2% respectively: Abbott TDx immunoassay results correlated well with those of high pressure liquid chromatographic in patient serums 15.0 to 333 mg/L acetaminophen; r2 = 0.954. n = 40. The Abbott TDx immunoassay assay was rapid. easy to perform. free of interferences from other drugs and exhibited no carryover from previous samples. The within run precision of the second derivative ultraviolet spectrophotometry method yielded coefficients of variance of less than 7.0%. Second derivative ultraviolet spectrophotometry results demonstrated good correlation with high pressure liquid chromatographic results in patient sera; r2 = 0.923. n = 40; however. performance deteriorated below 50.0 mg/L acetaminophen. Spectral interferences were noted at high concentrations of some drugs.
Management of oil of citronella poisoning, The management for ingestion of oil of citronella. an essential oil. has traditionally been rigorous. including dilution with milk or oil. and gastric lavage or emesis. taking care to prevent aspiration. Recently our Centre handled five oil of citronella poisonings and their outcomes led us to review our management protocol which had been based on information from standard poisoning texts. The source data used to determine the human toxicity of oil of citronella and the appropriate management of poisoning included a case report of a fatal ingestion of oil of citronella in a child. On scrutiny. however. the management of this poisoning included now out-moded techniques. giving rise to uncertainties in establishing the true cause of the child's death. Our own experiences indicate that advice given in standard texts based on poisoning cases managed with out-moded techniques should be carefully evaluated.
Pharmacists' poison prevention advice to the elderly, Up to 36% of childhood ingestions take place in grandparents' homes. We surveyed the 1544 registered pharmacists in the state of Nebraska by a mailed anonymous questionnaire concerning their poison prevention practices with the elderly. Of the 26% respondents. 75% always or usually gave older adults a choice of child-resistant containers but estimated that 65% chose non-child-resistant containers. Fifty-two percent reported that they asked older adults about children who could possibly ingest medications. and 59% reported that they had poison prevention material available. However. over 50% of pharmacists reported that they neither actively counseled nor handed out poison prevention material to the elderly. and only 9% reported that they specifically advise older adults about poison prevention. If all pharmacists targeted poison control education to the elderly. childhood poisoning by drugs could be reduced by one-third.
Comparative effects of thermal and surgical trauma on rat muscle protein metabolism, A modified intraperitoneal pool flooding technique. employing L-3H-tyrosine. was developed for measuring muscle protein synthetic rates following traumatic injury. Sufficient radiolabeled tyrosine was injected intraperitoneally to effect a six-fold increase in plasma tyrosine concentration (124-800 microM) resulting in constant. sustained specific radioactivities in plasma- and intracellular-free tyrosine pools. Localized vs systemic effects of thermal and surgical trauma on gastrocnemius muscle protein turnover were assessed 2 and 4 days postinjury. Thermal trauma increased total. myofibrillar. and sarcoplasmic muscle protein synthesis (44%) and protein degradation (300%). Conversely. surgical trauma decreased synthesis of total (24%). myofibrillar (14%). and sarcoplasmic (43%) muscle proteins without altering protein degradation. Short-term restriction of pair-fed controls did not affect either aspect of protein turnover.
Tumor regulation of hepatic glutamine metabolism, Fast-growing tumors are major glutamine consumers and may alter host glutamine metabolism to benefit the tumor. Previous studies from our laboratory have demonstrated that the liver switches from an organ of glutamine balance to one of glutamine release with progressive malignant growth. However. the regulation of this change is unclear. This study examined tumor modulation of hepatic glutamine metabolism by determining the activities of glutaminase. the principle enzyme of glutamine degradation. and glutamine synthetase. the principal enzyme of glutamine synthesis. Hepatic glutamine content was also determined. Rats with a fast-growing subcutaneous fibrosarcoma (TBR) and pair-fed controls were studied at 2 and 3 weeks after tumor or sham implantation. when the tumors comprised approximately 5% and 20% of total body weight. Arterial glutamine fell with progressive tumor growth (608 +/- 26 mumol/L in controls vs 494 +/- 15 in TBR. p less than 0.005) and was not attributable to a diminished food intake. Hepatic glutamine content was increased 45% (p less than 0.01) in tumor rats at 2 weeks due in part to a 35% fall in liver glutaminase activity. At 3 weeks. glutamine synthetase activity increased by 43% (0.58 +/- 0.07 mumol/mg of protein/hr in controls vs 0.83 +/- 0.04 in TBR. p less than 0.01) whereas glutaminase remained depressed (2.68 +/- 0.12 mumol/mg of protein/hr in controls vs 2.22 +/- 0.15 in TBR. p less than 0.05) and glutamine content fell compared to 2 week tumor-bearing rats. consistent with accelerated hepatic glutamine release. Tumors may alter liver glutamine metabolism by modulating hepatic enzyme activity in order to provide circulating glutamine for the growing malignancy.
Successful high-dose calcium treatment of aluminum-induced metabolic bone disease in long-term home parenteral nutrition, A patient who developed severe metabolic bone disease is presented. He had received long-term home parenteral nutrition (HPN) following extensive small bowel resection after mesenteric vein thrombosis. Bone disease caused by aluminum intoxication had components of osteomalacia and low-turnover osteoporosis. Aluminum was detected at the surface of mineralized bone and was elevated in the serum. resulting in a positive deferoxamine infusion test. One year of treatment with high doses of calcium (up to 24 mEq per day) significantly diminished the patient's bone pain. increased the serum levels of calcium. abolished aluminum deposits in the mineralized trabecula. improved bone formation. and increased trabecular bone volume as assessed by repeated histomorphometric analysis.
Hormonal and metabolic response to operative stress in the neonate, It is evident from this review that newborns. even those born prematurely. are capable of mounting an endocrine and metabolic response to operative stress. Unfortunately. many of the areas for which a relatively well-characterized response exists in adults are poorly documented in neonates. As is the case in adults. the response seems to be primarily catabolic in nature because the combined hormonal changes include an increased release of catabolic hormones such as catecholamines. glucagon. and corticosteroids coupled with a suppression of and peripheral resistance to the effects of the primary anabolic hormone. insulin.
Effect of glycine on medullary thick ascending limb injury in perfused kidneys, The addition of 2 mM glycine to the recirculating perfusate of isolated perfused rat kidneys almost completely prevented the severe morphological injury to tubular cells lining the medullary thick ascending limb (mTAL) that normally develops in this preparation. Glycine was similarly effective in reducing mTAL injury associated with hypoxic perfusion. indomethacin and amphotericin. Fractional reabsorption of sodium was increased with glycine. without any change in perfusate flow to the whole kidney and without consistent improvement in GFR. L-alanine demonstrated a similar though less pronounced cytoprotective action. but glutamine. cysteine. glutamate. cysteine plus glutamate. 1-serine and 4-aminoisobutyric acid all had little or no effect in preventing severe mTAL injury. The protective effect of glycine was unimpaired by the arginine analogue NG-monomethyl-l-arginine (L-NMMA). suggesting that the endothelial-derived relaxing factor. NO. was not involved. The action of glycine was not reduced by the addition of a substrate (benzoate) or a product (hippurate) of the glycine N-acyltransferase reaction. Glycine did not depress the respiration of dispersed mTALs prepared from rat kidneys. The cytoprotective effect of glycine in the mTAL of perfused kidneys. shared with l-alanine. appears to be relatively specific for these amino acids and probably unrelated to a diminution in cell work.
C-myc as an inducer of polycystic kidney disease in transgenic mice, In this study. a genetic model of polycystic kidney disease (PKD) has been produced in transgenic mice bearing the murine c-myc gene driven by the SV40 enhancer and the adult beta-globin promoter. These animals reproducibly develop PKD and die of renal failure. The phenotype appears to result from the overexpression of c-myc in the renal tubular epithelium and consequent abnormal cell proliferation. These transgenic mice represent a genetic model of PKD which bears similarities to human autosomal dominant PKD (ADPKD) with respect to renal morphology. renal functional alterations and dominant transmission. Study of these transgenic mice may offer valuable insights into the pathogenesis of PKD.
Significance of mononuclear phagocytes in IgA nephropathy, To clarify the significance of mononuclear phagocytes in IgA nephropathy. renal biopsied materials from 45 patients with the disease were examined by the indirect immunoperoxidase method using anti-human monoclonal antibodies and by ultrastructural peroxidase (PO) cytochemistry. The monoclonal antibodies were FMC32. S-100 (alpha). My4. and LeuM5 for detection of mononuclear phagocytes and HLA-DR for Ia antigens. Mesangial hypercellularity in IgA nephropathy was divided into three grades. The number of monocyte/macrophages per glomerulus differed significantly among the grade of mesangial hypercellularity. In the capillary lumen. monocytes were more numerous in the group with slight mesangial hypercellularity. By contrast. macrophages were often found in the Bowman's space and mesangial area of the glomeruli in the advanced group. In the renal interstitium. the number of monocyte/macrophages per 100 interstitial cells differed significantly among the degree of interstitial damage. and they were observed mainly around sclerotic glomeruli. Ultrastructural PO cytochemistry revealed infiltration of monocytes. exudate macrophages. and/or PO-negative macrophages. Clinicopathological study showed a relationship between the number of monocyte/macrophages per glomerulus and the number of glomerular crescents and the degree of proteinuria. The constancy of the percentage of exudate macrophages and polymorphonuclear leukocytes were observed irrespective of the grade of mesangial hypercellularity. On the other hand. the increasing percentage of PO-negative macrophages and decreasing percentage of monocytes were observed over the grade. These results suggest that mononuclear phagocytes might play an important role in the pathogenesis of mesangial hypercellularity. and irreversible glomerular damage and interstitial tissue injury in IgA nephropathy.
Lack of correlation between urea kinetic indices and clinical outcomes in CAPD patients, We examined the predictive value of urea kinetics for patient outcomes in CAPD by measuring dialysis index (DI; a means of quantifying CAPD dose using urea kinetics). KT/V and normalized protein catabolic rate (PCRN) on 222 occasions in 76 new patients at the time of starting CAPD and at subsequent six month intervals. We investigated how these indices altered with time and in relation to each other. and how they correlated with a wide range of subsequent patient outcomes. DI. KT/V and PCRN all tended to decrease with time on CAPD (P less than 0.0004. less than 0.0001 and 0.0005. respectively). DI and KT/V were highly correlated with each other (r = 0.89. P less than 0.0001) and both correlated with PCRN (r = 0.57. P less than 0.0001 and r = 0.60. P less than 0.0001. respectively). DI and KT/V both correlated inversely with subsequent values for serum creatinine (P less than 0.0001). urea (P less than 0.0002). potassium (P less than 0.02) and phosphate (P less than 0.002). and directly with bicarbonate (P less than 0.0001). PCRN correlated inversely with serum creatinine (P less than 0.0002) and directly with urea (P less than 0.0001) and with the number of blood transfusions received (P less than 0.03). None of these indices correlated with levels of hemoglobin. PTH. alkaline phosphatase or albumin. or with nerve conduction velocity or any other subsequent clinical outcomes including death. technique failure. hospital days. peritonitis rate and subjective indices of fatigue. pruritus and insomnia. We conclude that the urea kinetic model is predictive of some biochemical outcomes but not of clinical outcomes in CAPD patients.
Potential role of PFOB enhanced sonography of the kidney. I. Detection of renal function and acute tubular necrosis, Perfluorooctylbromide (PFOB) enhances the echogenicity of perfused tissues on sonography. Since PFOB is not filtered and is limited to the intravascular space. the particles are concentrated in the vasa rectae as they travel across the osmotic gradient. Because sonography has been unable to detect renal function. we aimed to determine whether sonography when aided by PFOB could detect and distinguish the normal from the abnormal osmotic gradient. The sonographer. unaware of rabbit assignment. imaged both kidneys in 17 rabbits before and 24 hours after the temporary occlusion of one of the renal arteries and then again after the infusion of up to 5 ml/kg of PFOB (N = 10) or saline (N = 7). Two normal rabbits were imaged before and after PFOB infusion and then again after i.v. furosemide. Without PFOB. the normal and impaired kidneys were indistinguishable. The echogenicity of the medulla which was darker than cortex in normal kidneys became brighter than cortex after PFOB (increased by 117% +/- 10%; P less than 0.01). PFOB. which was visible in the renal medulla on real-time sonography. produced an echogenic gradient that increased in brightness towards the papillary tip. Because the medulla of kidneys with ATN mildly increased in brightness after PFOB (increased by 40% +/- 7.8%; P less than 0.01). and because the echogenic gradient produced by PFOB was reversed (decreased in brightness towards the papillary tip). ATN kidneys were distinguished from normal kidneys in all 10 rabbits after 2.5 ml/kg PFOB. Medullary echogenicity produced by PFOB in normal kidneys was lost after furosemide.
Potential role of PFOB enhanced sonography of the kidney. II. Detection of partial infarction, Aside from its ability to assess flow velocity within vessels. color Doppler and gray-scale sonography cannot distinguish perfused from non-perfused tissues. In this study we evaluated whether Perfluorooctylbromide (PFOB). a sonographic contrast agent given i.v.. could aid sonography with this recognition. Partial renal infarction was produced by a 1 mm bead embolized in the right. the left. or both renal arteries of 20 normal rabbits. The sonographer. unaware of rabbit assignment. attempted to diagnose the infarct 24 hours later. All 20 rabbits were studied with gray-scale and color Doppler sonography. 10 before and after PFOB and 10 only after PFOB. Angiography and post-mortem examination were done for confirmation. Of the 20 kidneys evaluated before PFOB. the sonographer was unable to diagnose the 10 partial infarctions. Color Doppler identified five of the ten infarcted kidneys. but accurately localized the infarction in only two. Of the 40 kidneys evaluated after PFOB infusion. 20 scanned before and 20 scanned only after PFOB. all 20 partial infarctions were accurately diagnosed with both gray-scale and color Doppler. PFOB enhanced the echogenicity of perfused renal tissue allowing the easy detection of the unenhanced infarct. Because of the increased signal from vessels after PFOB. color Doppler displayed the entire vascular tree. allowing the detection of the truncated embolized branch. The ability of PFOB to enhance Doppler signals and the echogenicity of perfused tissues improved the diagnostic accuracy of sonography when used to detect partial renal infarctions.
Heterogeneity of immune complex-derived anti-DNA antibodies associated with lupus nephritis, The mechanisms responsible for the tissue injuries associated with lupus nephritis have not yet been well explained. We have investigated the characteristics of anti-DNA antibodies in circulating immune complexes (CIC) and in the deposits of renal glomeruli in patients with active lupus nephritis. The CIC-derived antibodies expressed anti-DNA idiotypes (Id) designated as 0-81 Id and NE-1 Id. and bound mainly to single-stranded DNA but never to glomerular basement membrane (GBM) antigens. On the other hand. the immunoglobulins (Ig) eluted from renal glomeruli of lupus patients reacted not only with DNA but also with GBM. proteoglycan. and heparan sulfate. The binding of glomeruli-deposited Ig was markedly low when GBM antigens were used after treatment with heparitinase. suggesting that some anti-DNA antibodies may bind directly to GBM antigens associated with heparan sulfate. and form in situ IC in renal glomeruli. It was also revealed that the renal eluates obtained after passing through GBM antigen-coupled Sepharose lost the binding ability with GBM but still retained DNA-binding and 0-81 Id activity. showing the participation of circulating IC-derived anti-DNA antibodies in the glomerular deposits. Theoretically there may be two mechanisms in the pathogenesis of lupus nephritis through the deposition of circulating IC and through in situ formation of anti-DNA IC in renal glomeruli. The diversity of histological features in lupus kidneys may be attributed to the heterogeneity of the mechanisms.
From Bright's disease to modern nephrology: Pierre Rayer's innovative method of clinical investigation, Pierre Rayer. in a day of purely descriptive medicine. devised a method for the scientific study of diseases affecting the kidney and urinary tract. He first assembled vivid illustrations of a wide range of disorders of the kidney found in specimens obtained at autopsy. The resulting Atlas won him widespread praise and is still often cited. His Treatise (Traite des Maladies des Reins et des Alterations de la Secretion Urinaire). in which he integrated data from pathological anatomy with urinary biology and clinical manifestations. was ahead of its time. Hence it was poorly understood and. like the work of many other innovators. was largely ignored. Nevertheless. his 2100 page Traite which begins with a description of his innovative and highly disciplined method of study. most unusual at this time. is by no means lacking in interest for today's nephrologists. Rayer's was a landmark contribution. affording. as it did. a comprehensive approach to the clinical problems of nephrology a century before the diseases themselves could be understood. Could a contemporary of Rayer tell that he was an inventor of scientific methodology before the proof of his rigorous demonstrations was carried out? That has been the achievement of clinical nephrology in the past forty years...one century later.
Activated (IL-2R+) intraglomerular mononuclear cells in crescentic glomerulonephritis, We recently reported evidence for the involvement of local cellular immune activation in the immunopathogenesis of human IgA nephropathy. particularly in cases of IgA disease featuring crescent formation. In the current study. using monoclonal antibodies. we investigated whether mononuclear cells bearing receptors for interleukin 2 (IL-2R+ MNC) were present within glomeruli or associated crescents in biopsies from patients with crescentic glomerulonephritis (greater than 60% crescents. N = 19). IgA disease with crescents (N = 9). or other types of proliferative glomerulonephritis with crescents (10 to 44%. N = 6). compared with normal control kidneys (N = 10). Biopsies were further classified into those showing active (cells. fibrin) (N = 15) or inactive (sclerosed) crescents (N = 19). to determine whether IL-2R+ MNC were particularly associated with active crescent formation. Few leucocytes were found within glomerular tufts of normal kidneys (2.4 +/- 0.7 cells/glomerular cross-section; mean +/- SEM). By contrast. in biopsies from patients with active crescentic glomerulonephritis. total intraglomerular tuft leucocytes were increased to 14.0 +/- 1.7 (P less than 0.01 vs. normal kidneys). largely due to increased numbers of intraglomerular monocytes (10.4 +/- 1.1. P less than 0.01) and T cells (3.7 +/- 0.6. P less than 0.01). Biopsies with active crescents also contained significantly increased numbers of intraglomerular tuft IL-2R+ MNC (4.0 +/- 0.7. 29% of total intraglomerular leucocytes). and there was a strong correlation between the numbers of intraglomerular IL-2R+ MNC and T cells (P less than 0.001).
Role of iron metabolism in absorption and cellular uptake of aluminum, The effect of iron status on aluminum (Al) absorption was investigated in this study in vivo using an animal model and in vitro using an intestinal mucosal cell line. In the in vivo model rats were rendered iron overloaded by intraperitoneal injection of iron dextran (5 mg/48 hr) or iron deficient by phlebotomy (2.5 to 3 ml blood/week). These rats. and normal controls. were then dosed with Al(OH)3 (40 mg/day) for 30 days. Urinary excretion of Al was significantly greater in the iron deficient group than in the other two groups throughout the study period. and brain Al at the end of the experiment was significantly increased in the iron depleted group (1.93 micrograms/g) and decreased in the iron overloaded group (0.73 microgram/g) compared with controls (1.42 micrograms/g). The brain Al levels in iron overloaded rats were no higher than those in normal rats that had not been dosed with Al(OH)3 (0.61 microgram/g). No significant differences were found in serum Al levels. In the in vitro experiments cultures of the rat intestinal cell line RIE1 were iron overloaded by addition of iron nitrilotriacetate (0.1 mM) or iron depleted with desferrioxamine (5 micrograms/ml) for 20 days prior to pulsing with Al transferrin (0.5 mg/ml) for 24 hours. Uptake of Al was significantly greater in the iron depleted cells (2.3 ng/micrograms cell DNA) than in iron overloaded (0.81 ng) or untreated (0.83 microgram) cells. These studies show that iron depletion markedly increases absorption and cellular uptake and suggest that susceptible individuals. such as renal failure patients. run an increased risk of toxicity if they are iron deficient.
Molecular basis of opsonic defect in immunodeficient children, Low serum mannose-binding protein (MBP) concentrations are associated with a common opsonic defect. Sequence analysis of the MBP gene in three children with recurrent infections. the opsonic defect. and low serum MBP concentrations showed a point mutation at base 230 of exon 1 causing a change of codon 54 from GGC to GAC. The replacement of glycine with an aspartic acid residue disrupts the fifth Gly-Xaa-Yaa repeat in the collagen-like domain of each 32 kD MBP peptide chain and probably prevents the formation of the normal triple helix. Study of sixteen members of the three families showed autosomal dominant co-inheritance of the mutation and low serum MBP concentrations.
Control of blood gas measurements in intensive-care units, The frequency of blood gas measurement in two adult intensive-care units was assessed for 7 months before and 12 months after introduction of a protocol of indications for such investigation. Demographic. diagnostic. outcome. and intervention data were collected prospectively. There were no differences in demographic characteristics. severity or type of illness. survival. or frequency of arterial or pulmonary artery catheter use between the two observation periods. but the frequency of blood gas analysis fell by 44% (p less than 0.001) after the protocol was introduced.
Long-term effects of vacuum and forceps deliveries, The long-term effects of vacuum and forceps deliveries are largely unknown. We determined the long-term outcome of instrumental deliveries in 52.282 infants born in Jerusalem between 1964 and 1972. For each individual. events at birth were related to results of an intelligence test and medical examination done at 17 years of age by the Israeli Defence Forces draft board. 1747 individuals were delivered by vacuum. 937 by forceps. 47.500 by spontaneous delivery. and 2098 by caesarean section. Crude data showed that mean intelligence scores at 17 were significantly higher (p less than 0.0001) in the vacuum and forceps deliveries groups than in the spontaneous-delivery group; however. after adjustment for confounding factors by stepwise multiple regression. these differences were no longer seen. Although the forceps-delivery group had functional impairment of feet. vision. and retina compared with the spontaneous-delivery group. and the vacuum-extraction group had impairment of the legs. differences were small. Our findings suggest that infants delivered by vacuum or forceps are not at risk of physical and cognitive impairment at 17 years of age.
Urinary incontinence among hospitalized persons aged 65 years and older--United States, 1984-1987, Urinary incontinence (the involuntary loss of urine so severe as to have social or hygienic consequences) affects at least 10 million persons in the United States. This problem is particularly common among persons aged greater than or equal to 65 years; in this age group. urinary incontinence is present in 15%-30% of community-dwelling (i.e.. not hospitalized or in long-term-care institutions) persons. 15%-34% of those hospitalized in acute-care institutions. and about 50% of all long-term-care institution residents. This report summarizes a study of urinary incontinence among persons greater than or equal to 65 years of age discharged from hospitals in the United States from 1984 through 1987.
Public Health Service report on fluoride benefits and risks, This report. "Public Health Service Report on Fluoride Benefits and Risks" is a summary of the findings. conclusions. and recommendations of Review of Fluoride Benefits and Risks: Report of the Ad Hoc Subcommittee on Fluoride of the Committee to Coordinate Environmental Health and Related Programs. published in February 1991. The full report was prepared by an ad hoc subcommittee of the United States Public Health Service's Committee to Coordinate Environmental Health and Related Programs (CCEHRP) at the request of the Assistant Secretary for Health. The full report can be obtained from the Public Health Service. Department of Health and Human Services.
Development of the light response in neonatal mammalian rods, The sensitivity to light is low in many neonatal mammals when compared with that in the adult. In human infants at one month of age. for example. the dark-adapted sensitivity for detection of large stimuli is 50 times lower than in the adult. and in rats the overall sensitivity of the neonatal retina is also low compared with the adult. This low sensitivity in the neonate has been attributed to a number of factors. but the possibility that the photoreceptors themselves might be an important limitation on the overall visual sensitivity has not so far been clearly established. Here we record the light response of single neonatal rat rods and find that the sensitivity is considerably lower than in the adult. The response to a single photoisomerization is normal in the neonate. and the sensitivity deficit can therefore be attributed to a low level of functional rhodopsin. Opsin. the protein component of rhodopsin. must be present in normal amounts. as the sensitivity can be restored to adult levels by treating the retina with 9-cis retinal. an active homologue of the native chromophore 11-cis retinal. The low sensitivity of photoreceptors in the neonate can therefore be attributed mainly to a low concentration of 11-cis retinal in the developing retina.
Spontaneous lactation is an adaptive result of pseudopregnancy, Lactation is almost exclusively associated with pregnancy and giving birth. Although lactation can be induced without a preceding pregnancy in some species. this requires exogenous hormones. artificially intense or extended suckling or both. Spontaneous lactation. lactation by females that have neither been pregnant nor experimentally manipulated. is extremely unusual among eutherians. Among nondomesticated animals. spontaneous lactation has been observed repeatedly only in the dwarf mongoose Helogale parvula. We report here spontaneous lactation by free-living dwarf mongooses using data on urinary oestrogen conjugate concentrations (n = 560. 65 females) and body weight (n = 3.096. 25 females) from a population in Serengeti National Park. Tanzania. We use demographic data from this population to demonstrate that spontaneous lactation. and thus the endocrine phenomena that induce it. increase the evolutionary fitness of lactating females.
Embryological and molecular investigations of parental imprinting on mouse chromosome 7, Mouse embryos with duplications of whole maternal (parthenogenetic and gynogenetic) or paternal (androgenetic) genomes show reciprocal phenotypes and do not develop to term. Genetic complementation has identified the distal region of chromosome 7 (Chr 7) as one of the regions for which both a maternal and paternal chromosome copy are essential for normal development. presumably because of the presence of imprinted genes whose expression is dependent on their parental origin. Embryos with the maternal duplication and paternal deficiency of distal Chr 7 are growth retarded and die around day 16 of gestation; the reciprocal paternal duplication embryos die at an unidentified earlier stage. We report here the incorporation of cells with the paternal duplication into chimaeras. resulting in a striking growth enhancement of the embryos. One gene located on mouse distal Chr 7 (ref. 5) is the insulin-like growth factor 2 (Igf2) gene. an embryonic mitogen. In embryos with the maternal duplication of distal Chr 7. the two maternal alleles of the Igf2 gene are repressed. The presence of two paternal alleles of this gene in many cells is probably responsible for the growth enhancement observed in chimaeras. We propose that there are other imprinted genes in this Chr 7 region. We also compare the imprinting of this subgenomic region with phenotypes resulting from the duplication of the whole parental genome in parthenogenones and androgenones.
Effect of contact lens biomicroscopy on the clarity of fluorescein angiography, To study the effect of contact lens fundus biomicroscopy on the clarity of subsequent fluorescein angiography. the authors compared the fluorescein angiogram from 20 eyes recently examined using a fundus contact lens with fellow control eyes. Saline solution was used to couple the lens to the cornea. In 15 (75%) of the 20 pairs of eyes studied. there was no difference in the fluorescein angiogram clarity between examined and control eyes. In five (25%) patients. there was a slight asymmetry in clarity between the examined and control eyes. but this did not affect the ability to interpret the angiogram. The results were verified by comparing the overall quality of the transit phase of the angiograms. The application of a fundus contact lens to the cornea using saline solution as a coupling agent does not adversely affect the clarity of subsequent fluorescein angiography.
Color Doppler imaging provides accurate assessment of orbital blood flow in occlusive carotid artery disease, Color Doppler imaging was used to evaluate the hemodynamics of the ophthalmic vasculature in a case of complete internal carotid artery occlusion. This procedure. which allows rapid. noninvasive imaging. showed a partial ophthalmic artery obstruction with absent flow in the central retinal artery. central retinal vein. and nasal posterior ciliary arteries. Although altered perfusion of the retinal vessels may be evaluated clinically. assessment of blood flow in the ophthalmic and ciliary arteries previously could be evaluated only indirectly by intravenous fluorescein angiography. The color Doppler imaging findings were confirmed by intravenous fluorescein angiography and carotid arteriography. Color Doppler imaging represents a noninvasive method to diagnose abnormal blood flow of the ophthalmic artery and its branches and to evaluate serial changes of the circulation in a noninvasive manner.
Chlorhexidine mouthwash-induced fixed drug eruption. Case report and review of the literature, Various adverse reactions including anaphylactic shock have already been reported after the topical application of chlorhexidine. This article reports for the first time a hypersensitivity reaction in the form of fixed drug eruption after the use of a mouthwash containing chlorhexidine. This report should bring an increased awareness of the possibility of systemic hypersensitivity reaction to chlorhexidine in a previously sensitized person. The report also will add fixed drug eruption to the list of skin hypersensitivity reactions caused by chlorhexidine.
Serum zinc levels in patients with burning mouth syndrome, The serum zinc levels were measured by atomic absorption spectrophotometry in 30 patients with burning mouth syndrome. (BMS) and in 30 control subjects with clinically healthy oral mucosa. The mean value of serum zinc levels in the patient group was found to be significantly lower (mean +/- SD = 12.13 +/- 1.40 mumol/L) than the mean value of serum zinc levels in the control group (mean +/- SD = 12.89 +/- 1.62 mumol/L; p less than 0.05). The number of subjects with serum zinc levels less than the minimum normal value (less than 11 mumol/L) was higher in the patients with BMS (30%) than in the control subjects (10%). These results suggest that in some patients low serum zinc levels may be associated with BMS. However. the number of patients with BMS was too small to allow definite conclusions.
An in vivo study of the use of a nonresorbable ceramic hydroxyapatite as an alloplastic graft material in periapical surgery, This study evaluated reactions to a hydroxyapatite after endodontic treatment and periapical surgery. Thirty-eight root canals in two Macaca speciosa monkeys were endodontically treated. Apicoectomy was then performed. leaving bony defects at the apex of each root. The defects were either packed with Durapatite ceramic crystals or allowed to fill with blood. Each animal received at least one dose of Procion red. a hard-tissue marking agent. After healing periods of 2 to 6 months. the apices were examined clinically. radiographically. and histologically. The ceramic material was well tolerated clinically with no gross evidence of inflammation or rejection. Histologically. the material was biocompatible. Healing of the experimental sites consisted of an initial investment of the apatite crystals in fibrous connective tissue followed by eventual replacement of the connective tissue with bone. Despite its excellent biocompatibility. the material appeared to retard osteogenesis by its physical presence. Although the ceramic eventually became entrapped in bone. without an intervening layer of connective tissue. there was a significantly greater amount of new bone in control sites.
Apicectomy: a comparative clinical study of amalgam and glass ionomer cement as apical sealants, Healing capacity after apicectomy was investigated in a randomized clinical study of 105 teeth apically sealed with either amalgam or glass ionomer cement. The results were evaluated clinically and radiographically after 1 year. The success rate was high for both materials: 91% for amalgam and 89% for glass ionomer cement. Contamination with moisture and blood adversely affected the outcome for both materials and was significantly more frequent in unsuccessful cases.
Cortical defects in the mandibular sulcus, Examination of 5366 dry mandibles at the Smithsonian Institution revealed three cases of unilateral lingual defects superior to the mandibular foramen. The differential diagnosis includes a neuroma. neurolemmoma. hemangioma. or aneurysm of the inferior alveolar artery. The clinical significance of a vascular neoplasm or aneurysm would be the likelihood of increasing the risk of injecting the anesthetic solution directly into a blood vessel.
Spinal cord stimulation for chronic, intractable pain: superiority of "multi-channel" devices, Spinal cord stimulation has evolved over the past 20 years into an easily implemented technique. with low morbidity. for the treatment of intractable. chronic pain in properly selected patients. We report our experience with a series of 62 patients implanted between 1983 and 1987. with percutaneous and laminectomy electrodes. and with single- and "multi-channel" (programmable. multi-contact) devices. Fifty had chronic. intractable low back and leg pain ("failed back surgery syndrome." lumbar arachnoid fibrosis). five had spinal cord injuries. and seven "peripheral" pathology or stump pain. Statistical analysis of these and other patient characteristics and technical factors was undertaken to identify predictors of outcome. All patients were interviewed by a disinterested third party at a mean of 2.14 years following implantation. A majority of patients reported at least 50% sustained relief of pain and indicated that they would go through the procedure again for the same result. There was corresponding improvement in ability to perform various everyday activities. and decrease in use of analgesics. Ten of 40 failed back patients who were disabled before the procedure returned to work postoperatively. Superposition of stimulation paresthesias upon a patient's topography of pain was found to be a statistically significant predictor of successful relief of pain. by linear regression methods. Univariate and multivariate analysis of patient characteristics and technical factors as predictors of outcome demonstrated significant advantages for female patients. and for patients implanted with "multi-channel" devices. With these devices. electrode geometries with central cathode(s) flanked by rostral and caudal anode(s) were favored disproportionately. Technical improvements in implanted spinal cord stimulation devices. in particular the development of multi-contact percutaneous electrode arrays and supporting programmable electronics. have significantly improved clinical results.
Prevalence of HLA-B27 in patients with back pain attending a pain clinic, 101 patients presenting to a pain clinic with low back pain were tested for HLA-B27 status. Eight (7.9%) of the patients were positive for HLA-B27. This prevalence is similar to that recorded in the general population and suggests that few patients referred to our clinic with back pain have undiagnosed spondyloarthropathies.
The analgesic effects of caffeine in headache, Caffeine is frequently added to mild analgesic preparations but its effect when used alone on pain has never been studied in humans. Using a double-blind placebo-controlled multiple crossover design. 53 patients with non-migrainous headaches were given placebo. acetaminophen. 2 doses of caffeine and 2 combinations of caffeine with acetaminophen. Caffeine appeared to have independent analgesic effects that were equivalent to acetaminophen and were still significant when statistical adjustments were made for prior caffeine consumption and caffeine's effects on mood.
Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model, While much evidence implicates substance P (SP). an endogenous neurokinin (NK). as a primary sensory transmitter of acute pain in mammalian spinal cord. its role in continuous (tonic) pain is less clear. Although glutamate is co-localized with SP in dorsal root ganglion neurons. its role in nociceptive processing is uncertain. While antagonists of NKs and excitatory amino acids (EAAs) have been found to be antinociceptive in some acute assays. they have not been tested against tonic pain. We hypothesize that: (1) NKs and EAAs contribute to signaling of tonic chemogenic nociception; and (2) interaction between NK and EAA systems is important in determining the perceived intensity of a continuous noxious stimulus. We therefore evaluated two NK antagonists ([D-Pro2.D-Trp7.9] SP (DPDT-SP. 0.26-6.6 nmoles. non-specific) and [D-Pro4. D-Trp7.9.10.Phe11]-SP(4-11) (DPDTP-octa. 1.6-12.3 nmoles. somewhat NK-1 selective]. as well as DL-2-amino-5-phosphonovalerate (DL-AP5. NMDA antagonist. 0.05-1 nmole) and urethane (a kainic acid (KA) antagonist at 2.5 mumoles) for antinociceptive activity in the mouse formalin model. Administered intrathecally (i.t.). DL-AP5 and both NK antagonists were significantly antinociceptive while urethane (2.5 mumoles) and naloxone (2.7 nmoles) were inactive. A50 values for mean % analgesia. nmoles/mouse i.t. (95% CLs) were: DPDT-SP. 1.1 (0.79-1.6); DPDTP-octa. 3.9 (2.4-6.1); DL-AP5. 0.29 (0.16-0.71). The antinociception associated with 1.3 nmoles of DPDT-SP was not reversed by co-administering 2.7 nmoles of naloxone. Co-administration of 0.1 nmoles of DL-AP5 with either 1.3 nmoles of DPDT-SP or 3.3 nmoles of DPDTP-octa did not lead to additive antinociception.
Effects of spinal kappa-opioid receptor agonists on the responsiveness of nociceptive superficial dorsal horn neurons, Spinal cord application of the kappa-opioid receptor agonists dynorphin (50 nmol) or (1S.2S)U-50.488H (0.19-1.9 mumol) produced changes in the excitability of some superficial dorsal horn nociceptive neurons. One-third of the cells exhibited expansion of their receptive fields as defined using mechanical stimuli following a spinal kappa agonist (dynorphin or U-50.488H); receptive field expansions were of the same order as those observed immediately after a conditioning electrical stimulus applied to a peripheral nerve. In addition. spinal U-50.488H produced changes in mechanical and thermal thresholds of the majority of superficial dorsal horn neurons. These changes were dose-dependent. Facilitation of responses occurred at lower doses and inhibition occurred primarily at higher doses. but these effects were not reversed by subsequent administration of naloxone. The data are consistent with the hypothesis that one action of increases in spinal dynorphin levels due to peripheral inflammation. tissue injury or nerve damage. is to contribute to enhanced neuronal excitability in superficial dorsal horn neurons.
The antinociceptive effects of anterior pretectal stimulation in tests using thermal, mechanical and chemical noxious stimuli, Four behavioural tests have been used to study the antinociceptive effects of electrical stimulation of the anterior pretectal nucleus (APtN) in the rat. The antinociceptive effects of stimulating this nucleus. which lies dorsally in the posterior diencephalon. have recently been studied extensively but always using briefly applied heat stimuli. It is reported here that APtN stimulation effectively inhibited responses to briefly applied noxious pressure and longer-lasting noxious chemical (formalin) stimuli. Although the tail-flick reflex to noxious heat was very potently depressed by APtN stimulation. responses to noxious heat in the hot-plate test were not. Three doses of morphine were also studied with each test and it was concluded that 15 sec of 35 microA r.m.s. current into the APtN was as effective as 3-5 mg/kg morphine s.c. in the rat.
Increased postoperative pain and consumption of analgesics following acupuncture, Acupuncture was given to patients before (preoperative-acupuncture group. PRE-ACU. n = 25) or after (postoperative-acupuncture group. POST-ACU. n = 25) operative removal of impacted mandibular third molars. Sixty patients did not receive acupuncture and participated as a control group (CG). All patients completed a questionnaire in order to characterize state tension and stress. degrees of neuroticism. extroversion. depression and psychosomatic disorders. We also recorded intraoperative discomfort and pain intensity. postoperative pain intensity and consumption of analgesics for 72 h. The PRE-ACU was significantly more tense following surgery and found the operative procedure more unpleasant than the other two groups. The PRE-ACU further rated intraoperative pain intensity higher than the CG and experienced higher pain intensity immediately postoperatively compared with POST-ACU and CG. Of the PRE-ACU patients 15/24 needed additional local anesthesia intraoperatively while none in the POST-ACU or CG requested extra lidocaine. Postoperatively patients in both PRE- and POST-ACU reported a higher total sum of pain scores (pain intensity) and the PRE-ACU consumed more analgesics compared with the CG. A significantly larger number of patients suffering from "dry socket" (a complication during wound healing) was found in both PRE- and POST-ACU compared with the CG. No correlation was found between assessed personality characteristics and reported postoperative pain/consumption of analgesics in any group and could thus not explain the observed differences between the groups. The reason for our unexpected "negative" findings is unclear but some hypothetical explanations are discussed.
L-tryptophan supplementation does not affect postoperative pain intensity or consumption of analgesics, Aiming at optimizing serotonin levels in endogenous pain-modulating systems. L-tryptophan supplementation pre- and postoperatively (2 g/day for 7 days) did not affect pain development or analgesic consumption after third molar surgery. Biological effects related to an increase in mood were observed. however. indicating transport of L-tryptophan to the central nervous system. The findings are discussed in relation to earlier reports on favorable effects of L-tryptophan on experimental pain in healthy subjects and in chronic pain patients.
Sex differences in the perception of noxious heat stimuli, This study compared pain perception in young male and female subjects. using experimental noxious heat stimuli. During 2 sessions. each of 40 subjects rated the magnitude of 120 heat stimuli. ranging from 45 degrees C to 50 degrees C. The study included a comparison of visual analogue and magnitude matching rating procedures. as well as a test of simulated analgesia. in which the range of stimuli presented during the 2 experimental sessions was shifted by 1 degree C. We found that females rated noxious heat stimuli as more intense than did males. independent of the gender of the experimenter or the type of rating scale. In addition. the data suggest that females discriminate among the painful heat intensities better than males. For example. female subjects showed significant between-session discrimination of noxious heat stimuli. while male subjects did not. and females produced steeper within-session stimulus-response functions than did males. These observed differences in nociceptive discrimination between males and females indicate that the sex-related variation in pain perception is probably related to sensory factors rather than differences in attitude or emotional response.
Epidemiology of pain in New Zealand, Information on the prevalence of pain in the general population has relevance for the allocation of health services and for understanding of chronic pain. In 1986 a sample of 1498 adults were interviewed using the Diagnostic Interview Schedule. Questions on pain were taken from the somatisation section of the interview schedule. These responses were used to determine the lifetime prevalence of pain in the urban population of New Zealand. The majority of subjects reported more than one life disrupting experience of pain. Pain was most common in the joints. back. head and abdomen. Women reported more pain than men. In general the prevalence of pain increased with age. however this was not true for headaches and abdominal pain. Most subjects related their pain symptoms to a physical cause.
Phantom-related phenomena after rectal amputation: prevalence and clinical characteristics, Phantom sensations are well known and almost inevitable sequels to limb amputation. whereas similar phenomena are only rarely described after rectum amputation (phantom rectum). Our study attempted to assess the frequency and character of phantom rectum. All surviving patients (n = 22). who had undergone abdominoperineal surgical resection of the rectum in the period 1980-1986 at our clinic. were interviewed by a standard questionnaire and underwent a physical examination. Sixty-eight per cent of the patients experienced a sensation of a missing rectum (phantom rectum). and in 27% of these or 18% of all patients this sensation was painful (phantom pain). The most common symptoms were sensations of flatus and/or faeces in a normal rectum. phantom flatus or phantom faeces. The phantom pains were described as either pricking and shooting or like haemorrhoids or hard stools that would rupture the rectum. Neither age. sex. preoperative pain. the Duke classification of the tumour nor the healing of the perineal wound seemed related to the likelihood of phantom rectum. The pathophysiological mechanisms underlying phantom-related phenomena following amputation have not yet been elucidated. This study describes a relatively unknown phantom-related clinical entity after amputation and may thus contribute to the understanding of this phenomenon.
Retinoid-mediated transcriptional regulation of keratin genes in human epidermal and squamous cell carcinoma cells, Vitamin A and other retinoids profoundly inhibit morphological and biochemical features of epidermal differentiation in vivo and in vitro. To elucidate the molecular mechanisms underlying the differential expression of epidermal keratins and their regulation by retinoids. we examined retinoid-mediated changes in total protein expression. protein synthesis. mRNA expression. and transcription in cultured human keratinocytes and in squamous cell carcinoma (SCC-13) cells of epidermal origin. Our studies revealed that the epidermal keratins. K5. K6. K14. and K16. their mRNAs. and their transcripts were diminished relative to actin as a consequence of retinoic acid (RA) treatment. The effects were most pronounced in SCC-13 and were detected as early as 6 hr post-RA treatment. with enhancement over an additional 24-48 hr. Repression was also observed when 5' upstream sequences of K14 or K5 genes were used to drive expression of a chloramphenicol acetyltransferase reporter gene in SCC-13 keratinocytes. Both cell types were found to express mRNAs for the RA receptors alpha and gamma. which may be involved in the RA-mediated transcriptional changes in these cells. The rapid transcriptional changes in epidermal keratin genes were in striking contrast to the previously reported slow transcriptional changes in simple epithelial keratin genes.
Inactivation of the Zfx gene on the mouse X chromosome [published erratum appears in Proc Natl Acad Sci U S A 1991 Jul 1;88(13):5937, ZFX. an X chromosome-linked gene encoding a zinc-finger protein. has previously been shown to escape X inactivation in humans. Here we report studies of the inactivation status of the homolog. Zfx. on the mouse X chromosome. We took advantage of both the preferential inactivation of the normal X chromosome in females carrying the T(X;16)16H translocation and the high degree of nucleotide sequence variation between the laboratory strain of mouse [corrected] and Mus spretus genomes. An EcoRV restriction fragment difference between laboratory strain of mouse [corrected] and M. spretus was detected after amplification of Zfx transcripts using the reverse transcription-polymerase chain reaction. Using this allelic variation. we assessed expression of the two Zfx genes in females carrying the T(X;16)16H translocation (from laboratory strain of mouse [corrected]) and an intact X chromosome (from M. spretus). Such females exhibit Zfx transcription from the active laboratory strain of mouse [corrected] chromosome but not from the inactive M. spretus chromosome. These results indicate that the mouse Zfx gene is subject to X inactivation.
Infection by mink cell focus-forming viruses confers interleukin 2 (IL-2) independence to an IL-2-dependent rat T-cell lymphoma line, The development of T-cell lymphomas in rodents infected with type C retroviruses has been linked to the generation of a class of envelope (env) recombinant viruses called mink cell focus-forming viruses (MCF viruses) in the preleukemic thymus. To determine whether infection by MCF viruses altered the growth phenotype of retrovirus-induced T-cell lymphomas. a Moloney murine leukemia virus-induced interleukin-2 (IL-2)-dependent rat T-cell lymphoma line (4437A) was infected with MCF-247. modified MCF-V33 (mMCF-V33). or NZB-xenotropic (NZB-X) virus. The effects of virus infection on the IL-2 dependence of these cells was examined by cultivating them in the absence of IL-2. After IL-2 withdrawal. the uninfected and NZB-X-infected cells went through a crisis period characterized by massive death. All the independently maintained cultures of MCF- and mMCF-V33-infected cells. on the other hand. became IL-2 independent without a crisis. All the polytropic virus-infected IL-2-independent cultures contained a population of cells that was polyclonal with regard to polytropic provirus integration. Over this polyclonal background each culture produced multiple clones of cells that were selected rapidly after IL-2 withdrawal. Furthermore. the resulting MCF- or mMCF-V33-infected IL-2-independent cells retained the expression of IL-2 receptor. These data show that MCF and mMCF-V33 viruses may alter the growth phenotype of a T-cell lymphoma line and suggest that their effect on cell growth may be due to the direct interaction of the MCF envelope glycoprotein with cellular components. perhaps the IL-2 receptor.
Immunization of simian immunodeficiency virus-infected rhesus monkeys with soluble human CD4 elicits an antiviral response, Since the CD4 molecule is a high-affinity cell-surface receptor for the human immunodeficiency virus (HIV). it has been suggested that a soluble truncated form of CD4 may compete with cell-surface CD4 for HIV binding and thus be of use in the therapy of AIDS. We have utilized the simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys to explore another possible therapeutic application of CD4 in AIDS--the use of recombinant soluble CD4 (rsCD4) as an immunogen. SIVmac-infected rhesus monkeys immunized with human rsCD4 developed not only an anti-human CD4 but also an anti-rhesus monkey CD4 antibody response. Coincident with the generation of this antibody response. SIVmac could not be isolated easily from peripheral blood lymphocytes and bone marrow macrophages of these animals. Furthermore. the decreased number of both granulocyte/macrophage and erythrocyte colonies grown from the bone marrow of these immunized monkeys rose to normal levels. These findings suggest that a modified human CD4 molecule serving as an immunogen might elicit an antibody response in man that could induce a beneficial therapeutic response in HIV-infected individuals.
Transmembrane domain length variation in the evolution of major histocompatibility complex class I genes, The fifth exons of major histocompatibility complex (MHC) class I genes encode a transmembrane domain (TM) that is largely responsible for class I antigen cell-surface expression usually through conventional hydrophobic amino acid-membrane interactions or. less often. through phosphatidylinositol linkage. In this report we show that Peromyscus leucopus. a Cricetidae rodent. has MHC class I genes (Pele-A genes) encoding three distinct sizes of TMs. Increases in TM lengths were due to tandem duplications of sequences similar to human hypervariable minisatellite repeats and the lambda chi site. We discerned remnants of a similar duplication event in comparable rodent and primate MHC class I genes. Furthermore. several duplications and deletions appear to have occurred independently in H-2. RT1. Pele-A. and ChLA genes in near-identical positions. Accumulated data suggests that sequences in the fifth exon of MHC class I genes may. therefore. constitute a mutational or recombinational hot spot that is mediated by minisatellite- and chi-like sequences imbedded within the coding region. The MHC class I genes may thus have recruited "selfish" DNA in their evolution to encode cell surface proteins. Expression of Pele-A genes was examined by the polymerase chain reaction (PCR) using oligonucleotide primers specific for exon 4 and 5 sequences. The PCR product sizes indicated that genes encoding each TM domain length are ubiquitously transcribed.
Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains, Mice homozygous for the viable Sl allele steel-Dickie (Sld) are sterile. severely anemic. and black-eyed white. The nature of the Sld mutation was investigated at the molecular level and was found to be due to a 4.0-kilobase intragenic deletion in mast cell growth factor (MGF) genomic sequences. providing conclusive evidence that Sl encodes MGF. As a consequence of this deletion. Sld is only capable of encoding a soluble truncated growth factor that lacks both transmembrane and cytoplasmic domains. Northern analysis indicates that Sld mRNA is expressed at approximately wild-type levels in adult tissues. and yeast expression studies suggest that the Sld protein is as biologically active as wild-type soluble MGF. These studies provide a molecular basis for explaining the Sld phenotype. a description of a germ-line mutation in the transmembrane and cytoplasmic domains of a membrane-bound growth factor. and in vivo evidence for the importance of membrane-bound forms of growth factors in mammalian development.
Characterization of the decay-accelerating factor gene promoter region, Decay-accelerating factor (DAF) expression modulates susceptibility of cells to autologous complement attack. To characterize the regulatory region controlling DAF gene transcription. genomic DNA extending from 815 base pairs (bp) upstream to approximately 4 kilobases downstream of DAF's AUG codon (designated +1) was cloned and sequenced. The 5' flanking sequence showed 59-76% G + C content (-355 to +1). at least one GC box(es) (-135 to -131). and variable length sequences (from -629 to -285) conforming to the motifs TCCTCC and TCn. Nuclease S1 digestions and primer extensions localized a major transcriptional start site to -82/-81. 38 bp downstream of a possible TATA variant. (A)TTTAA. In COS cell transfections. the sequence encompassing -815 to -67 functioned 2.5% as efficiently as the Rous sarcoma virus 3' long terminal repeat. but following deletion upstream of -355 its activity increased approximately 4-fold. Two octanucleotides exhibiting partial homology to phorbol 12-myristate 13-acetate (PMA) and cAMP responsive elements (PREs and CREs. respectively) were detected. and the respective modulators enhanced transcriptional efficiency 2- and approximately 10-fold. respectively. Thus. the DAF gene promoter (i) exhibits sequences resembling both conventional and unconventional transcriptional control elements. (ii) possesses a region with negative regulatory activity. and (iii) responds to PMA and cAMP induction presumably via PRE- and CRE-like enhancer elements.
Altered expression of insulin receptor types A and B in the skeletal muscle of non-insulin-dependent diabetes mellitus patients, The human insulin receptor exists in two isoforms. HIR-A and HIR-B. which are generated by alternative splicing of a primary gene transcript and differ by a 12-amino acid insertion sequence in the alpha-subunit. The two receptor isoforms bind insulin with different affinities and are differentially expressed in human tissues. We report here a tissue-specific alteration of the insulin receptor RNA splice pattern in non-insulin-dependent diabetes mellitus (NIDDM) patients. Whereas skeletal muscle of healthy individuals contains exclusively high-affinity HIR-A-encoding RNA. we consistently find low-affinity HIR-B RNA expression in NIDDM muscle tissue at levels similar to HIR-A.
Synchronous hippocampal bursting reveals network excitability defects in an epilepsy gene mutation, A mutation at the tottering locus (tg. recessive. on chromosome 8) stimulates noradrenergic locus coeruleus axon terminal outgrowth and predisposes the brain to generalized spike-wave epilepsy in the young mouse. In an isolated synaptic circuit studied in vitro. the hyperinnervated mutant hippocampal pyramidal neurons respond normally when individually activated; however. latent neuronal signaling defects emerge during synchronous network bursting. revealing two conditional excitability phenotypes: a voltage-dependent prolongation of a complex synaptic response. the paroxysmal depolarizing shift. and a beta-adrenoreceptor-linked attenuation of the afterhyperpolarization. In this target brain region. the tg locus transforms neuronal excitability without altering measured intrinsic membrane properties. indicating that gene control of inherited epileptic traits may be mediated in part by activity-dependent modulation of network behavior favoring synchronous neuronal firing.
Deletion of sequences upstream of the proteinase improves the proteolytic processing of human immunodeficiency virus type 1, Human immunodeficiency virus type 1 expresses structural proteins and replicative enzymes within gag and gag-pol precursor polyproteins. Specific proteolytic processing of the precursors by the viral proteinase is essential for maturation of infectious viral particles. We have studied the activity of proteinase in its immature form. as part of a gag-pol fusion protein. in an in vitro expression system. We found that deletion of p6*. the region in pol upstream of proteinase. resulted in improved processing of the precursor. A modified proteinase is released. but it functions less efficiently than wild type. Improved autoprocessing correlates with increased accessibility of the active site region in the polyprotein carrying the p6* deletion. Our results suggest that p6* is involved in the regulation of proteinase activation. perhaps as a region limiting the interaction of the active site and substrate binding domain with the remainder of the polyprotein. Release of p6* inhibition may be an activation step necessary for infectious particle maturation.
Localized cytosolic domains of the erythropoietin receptor regulate growth signaling and down-modulate responsiveness to granulocyte-macrophage colony-stimulating factor, Erythrocyte development in mammals depends in part upon the interaction of the glycopeptide hormone erythropoietin (EPO) with cell surface receptors on committed erythroid progenitor cells. Both this factor and an EPO receptor polypeptide previously have been cloned. yet little is presently understood concerning molecular mechanisms of receptor activation and signal transduction. To identify cytosolic receptor domains necessary for signaling. we have compared the activities of a series of deletionally mutated EPO receptor constructs by their expression in interleukin 3-dependent. myeloid FDC-P1 cells. EPO-induced growth was transduced efficiently in these cells by the full-length receptor (507 amino acids). and no measurable loss in activity resulted from the deletion of up to 111 carboxyl-terminal residues. In contrast. the deletion of 44 additional residues led to a dramatic loss (86.3% +/- 7.8%; mean +/- SD) in the ability of this receptor to mediate EPO-induced growth. thus indicating that residues between Gly-352 and Met-396 constitute a functionally critical cytosolic subdomain. Interestingly. the expression of full-length EPO receptors in FDC-P1 cells also led to a selective inhibition of normal proliferative responsiveness to the alternative hematopoietic factor granulocyte-macrophage colony-stimulating factor. Moreover. this inhibition was progressively reversed in forms of the EPO receptor in which distal cytosolic residues were sequentially deleted. These results suggest that EPO receptors normally may trans-modulate components in the pathway of granulocyte-macrophage colony-stimulating factor-induced proliferation and that this down-modulation. as exerted by intact EPO receptors. may play a role in promoting erythroid commitment during myeloid blood cell development.
Mouse platelet-derived growth factor receptor alpha gene is deleted in W19H and patch mutations on chromosome 5, The mouse W19H mutation is an x-ray-induced deletion of more than 2 centimorgans on chromosome 5 encompassing the white spotting mutation W (encoded by the Kit protooncogene). patch (Ph). and recessive lethal (l) loci. The platelet-derived growth factor receptor alpha gene (PDGFRA) like Kit encodes a transmembrane receptor tyrosine kinase. By using mouse-Chinese hamster somatic cell hybrids and haplotype analysis in interspecific backcross mice. mouse Pdgfra was mapped to chromosome 5 in tight linkage with Kit. Hybridization of a PDGFRA probe to DNAs from W19H/ + heterozygous mice and patch heterozygous mice. and their wild-type littermates. demonstrated deletion of Pdgfra. Pulsed-field gel electrophoresis indicated that Kit and Pdgfra are linked on a 630-kilobase Mlu I DNA fragment. Thus the W19H deletion removes at least two receptor tyrosine kinases and the results suggest Pdgfra as a candidate for the Ph locus.
Use of a rapid, efficient inoculation method to induce papillomas by cottontail rabbit papillomavirus DNA shows that the E7 gene is required, A simple inoculation method to induce papillomas efficiently with cottontail rabbit papillomavirus (CRPV) DNA is described. Using a jet injector. recombinant CRPV DNA is easily delivered to 100 or more sites per rabbit and induces typical epithelial papillomas in approximately 50% of those sites. Papillomas begin to form by 3 weeks and continue to develop for up to 7 weeks. a pattern similar to that reported following infection with intact virus. This system readily lends itself to investigation of viral gene function by delivering mutant viral genomes into an immunologically intact host. Two mutations in the E7 open reading frame were introduced into the complete CRPV genome and analyzed by this method. One was a frameshift mutation encoding just nine amino-terminal amino acids of the E7 protein; the other was an in-frame insertion mutation at position 9. Both E7 mutations were in a region of homology to the 300-kDa protein binding domain of adenovirus E1A protein. Neither mutant construct was able to induce papillomas. thereby demonstrating that the E7 gene participates in this biologic function. Exploitation of this approach. which demonstrates that a papillomavirus E7 gene is involved in the induction of papillomas in vivo. should permit detailed studies into molecular mechanisms involved in papilloma induction. malignant conversion. and host immune response. The high efficiency of papilloma induction with recombinant CRPV DNA suggests that the jet injector can also be used to study the biologic effects of other genetic elements in rabbits or in other species.
Genetic basis of X-Y chromosome dissociation and male sterility in interspecific hybrids, A high frequency of X-Y chromosome dissociation (95%) was found at first meiotic metaphase (MI) in spermatocytes of interspecific hybrids between laboratory mice. C57BL/6J (BL/6) and Mus spretus. compared with an X-Y dissociation frequency of only 3-4% in parental mice. The X-Y dissociation in F1 hybrids occurred before diakinesis rather than as a precocious dissociation at MI. The high X-Y dissociation was accompanied by spermatogenic breakdown after MI. resulting in male sterility. All F1 males were sterile and approximately half of the backcross males from fertile F1 females crossed with either BL/6 or M. spretus males were sterile. Male sterility was highly correlated with X-Y dissociation in both backcrosses. All of the mice with high X-Y dissociation were sterile and all of the males with low X-Y dissociation were fertile or subfertile. This correlation suggested that genetic divergence of the X-Y pairing region could contribute to the male sterile phenotype such that the BL/6 X chromosome would not pair with the M. spretus Y chromosome. The segregation of species-type alleles of amelogenin (Amelb and Amels). a distal X chromosome locus adjacent to the X-Y pairing region. was followed in backcross males that were analyzed for X-Y dissociation and sterility (we have used Amel as the designation for the mouse amelogenin locus; the current designation for this locus is Amg). A 95% concordance between Amelb with fertility and Amels with sterility was observed in backcrosses with BL/6. whereas the converse was observed in the backcross to M. spretus. These results imply that X-Y pairing plays an important role in male fertility and suggest that genetic divergence in X-Y pairing region between Mus species can contribute to the reproductive barriers between species and the process of speciation.
A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity, Epidemiological as well as biochemical evidence of recent years has established that a low plasma level of high density lipoprotein-cholesterol is a predictor for the risk of coronary artery disease. However. there is a heterogeneous group of rare familial disorders. characterized by severe high density lipoprotein deficiency. in which the predicted increased risk is not clearly apparent. One such disorder has been called fish eye disease to reflect the massive corneal opacification seen in these patients. In this report. we describe the biochemical and genetic presentation of two German fish eye disease homozygotes and their family members. Vertical transmission of a decrease in the specific activity of lecithin-cholesterol acyltransferase (EC 2.3.1.43) indicated that this enzyme was a candidate gene for harboring the defect responsible for this disorder. Direct sequencing of DNA segments amplified by the polymerase chain reaction (PCR) that encode the exons of the lecithin-cholesterol acyltransferase gene led to the identification of a homozygous mutation resulting in the substitution of threonine at codon 123 for an isoleucine residue in both individuals. Family analysis in an extended pedigree was used to establish a causal relationship between this mutation and the biochemical phenotype for fish eye disease. The homozygous presence of this mutation in two phenotypically homozygous members of an unrelated Dutch family with fish eye disease further supports this finding.
The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions, The TPR-MET oncogenic rearrangement was originally observed in an in vitro transformed human osteosarcoma cell line. Recently. we detected the expression of this rearrangement at very low levels in several cell lines derived from human tumors of nonhematopoietic origin using a highly sensitive method based on polymerase chain reaction amplification of the transcript. We report here the results of analysis of TPR-MET expression in cell lines derived from human gastric tumors and 22 biopsy samples of human gastric mucosa showing cancer or precursor lesions. The rearranged RNA was expressed in all four cell lines as well as in biopsy samples from 12 of the 22 patients. Overexpression of TPR-MET RNA in superficial gastritis lesions with hyperplasia of glandular neck cells suggests the possible involvement of this oncogene at an early stage of gastric tumorigenesis. Analysis of gastric biopsy samples for RAS gene mutations showed base substitutions occurring in the codon 12 region of Ki- and Ha-RAS genes in four cases. including two precursor lesions.
Structure-function relationships of the mouse inositol 1,4,5-trisphosphate receptor, The homotetrameric complex of inositol 1.4.5-triphosphate (InsP3) receptors displays a Ca2+ release activity in response to InsP3 molecules. Structure-function relationships of the mouse cerebellar InsP3 receptor have been studied by analyses of a series of internal deletion or C-terminal truncation mutant proteins expressed in NG108-15 cells. Within the large cytoplasmic portion of the InsP3 receptor. approximately 650 N-terminal amino acids are highly conserved between mouse and Drosophila. and this region has the critical sequences for InsP3 binding that probably form the three-dimensionally restricted binding site. The N-terminal region of each InsP3 receptor subunit also binds one InsP3 molecule. Cross-linking experiments have revealed that InsP3 receptors are intermolecularly associated at the transmembrane domains and/or the successive C termini. The interaction between the receptor subunit and InsP3 may cause a conformational change in the tetrameric complex. resulting in the opening of Ca2+ channels.
9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo, A new class of compounds. 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] [(RS)-FPMP] derivatives of purines. is described that has selective activity against a broad spectrum of retroviruses [including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)] but not other RNA or DNA viruses. This activity spectrum is completely different from that of the parental compounds. 9-[(2S)-3-hydroxy-2-phosphonylmethoxypropyl] [(S)-HPMP] derivatives of purines. which are active against a broad range of DNA viruses. The racemic (RS)-FPMP derivatives of adenine and 2.6-diaminopurine. termed (RS)-FPMPA and (RS)-FPMPDAP. respectively. are markedly more selective as in vitro antiretroviral agents than their 9-(2-phosphonylmethoxyethyl) (PME) counterparts. PMEA and PMEDAP. Also. (RS)-FPMPA and (RS)-FPMPDAP have a substantially higher therapeutic index in mice in inhibiting Moloney murine sarcoma virus-induced tumor formation and associated death and are markedly less inhibitory to human bone marrow cells than PMEA and PMEDAP. The diphosphate derivative of (RS)-FPMPA [(RS)-FPMPApp] is a potent and selective inhibitor of HIV-1 reverse transcriptase but not of HSV-1 DNA polymerase or DNA polymerase alpha. (RS)-FPMPApp. akin to PMEA diphosphate (PMEApp). acts as a DNA chain terminator. The DNA chain-terminating properties of PMEApp and (RS)-FPMPApp seem to be a prerequisite for acyclic nucleoside phosphonates to exhibit antiretrovirus (i.e.. anti-HIV) activity.
Reduction to homozygosity involving p53 in esophageal cancers demonstrated by the polymerase chain reaction, Loss of heterozygosity affecting chromosome 17p has been detected at high frequencies in a variety of human tumors. including cancers of the colon. breast. lung. and brain. One presumed target of these losses is p53. a tumor suppressor gene located on 17p. To our knowledge. loss of heterozygosity has not yet been reported at any locus. including p53. in human esophageal cancer. Moreover. current methods of detecting loss of heterozygosity depend on the availability of large amounts of high molecular weight DNA. making the study of small biopsy specimens or paraffin-embedded tissues problematic. We examined 52 primary human esophageal neoplasms for loss of heterozygosity affecting the p53 gene by using the polymerase chain reaction. Loss of one allele was detected in 52% of informative cases and was more common in squamous carcinomas than in adenocarcinomas. Southern blot analysis was used to confirm polymerase chain reaction-derived data. The identification of allelic loss in approximately half of the tumors analyzed supports the hypothesis that inactivation of p53 is involved in the pathogenesis of esophageal cancer.
Cloning and expression of the human vasoactive intestinal peptide receptor, Vasoactive intestinal peptide (VIP) is a neuroendocrine mediator found in the central and peripheral nervous system. Distinct subsets of neural. respiratory. gastrointestinal. and immune cells bear specific high-affinity receptors for VIP. which are associated with a guanine nucleotide-binding (G) protein capable of activating adenylate cyclase. A cDNA clone (GPRN1) encoding the human VIP receptor was identified in libraries prepared from the Nalm 6 line of leukemic pre-B lymphoblasts and the HT-29 line of colon carcinoma cells. The deduced 362-amino acid polypeptide sequence encoded by GPRN1 shares a seven-transmembrane-segment hydropathicity profile with other G protein-coupled receptors. Northern blot analyses identified a 2.7-kilobase transcript of the VIP receptor in Nalm 6 and HT-29 cells as well as in tissues from rat brain. colon. heart. lung. kidney. spleen. and small intestine. COS-6 cells transfected with GPRN1 bound 125I-labeled VIP specifically with a dissociation constant (Kd) of 2.5 nM. VIP--and less effectively secretin. peptide histidine isoleucine (PHI). and glucagon competitively displaced bound 125I-VIP from transfected COS-6 cells. with potencies in the order VIP greater than secretin = PHI much greater than glucagon. VIP stimulated adenylate cyclase activity in stably transfected Chinese hamster ovary K1 cells. inducing a 3-fold increase in the intracellular level of cAMP. When the antisense orientation of the VIP receptor clone was introduced into HT-29 cells. there was a 50% suppression of the specific binding of 125I-VIP and of the VIP-induced increase in cAMP level. relative to untransfected cells. The VIP receptor cloned exhibits less than or equal to 24% homology with other receptors in the same superfamily and thus represents a subset of G protein-coupled receptors for peptide ligands.
Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells, To determine whether mononuclear cell secretory products contribute to the changes in bone turnover that characterize the development of postmenopausal osteoporosis. we evaluated the effects of oophorectomy and subsequent estrogen replacement on the spontaneous secretion of interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) and on the phytohemagglutinin A-induced secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) from peripheral blood mononuclear cells. In 15 healthy premenopausal women who underwent oophorectomy. increases in GM-CSF activity were observed as early as 1 week after surgery. whereas elevations in IL-1 and TNF-alpha and in hydroxyproline/creatinine and calcium/creatinine ratios. two urinary indices of bone resorption. were detectable 2 weeks after the surgical procedure. Six of the oophorectomized women received no estrogen therapy after surgery and in these subjects hydroxyproline/creatinine and calcium/creatinine ratios plateaued 6 weeks postoperatively. and all three cytokines reached the highest levels 8 weeks after oophorectomy. when the study ended. In the remaining 9 women. who were started on estrogen replacement therapy 4 weeks after oophorectomy. decreases in the indices of bone resorption paralleled decreases in the secretion of the cytokines. with lower levels detected after 2 weeks of therapy. In the women who did not receive estrogen therapy. circulating osteocalcin. a marker of bone formation. increased beyond preoperative levels 8 weeks after oophorectomy. whereas in the estrogen-treated subjects osteocalcin remained unchanged in the entire study period. In 9 female controls who underwent simple hysterectomy. cytokine release and biochemical indices of bone turnover did not change after surgery. These data indicate that changes in estrogen status in vivo are associated with the secretion of mononuclear cell immune factors in vitro and suggest that alterations in the local production of bone-acting cytokines may underlie changes in bone turnover caused by surgically induced menopause and estrogen replacement.
Hyperalgesia induced in the rat by the amino-terminal octapeptide of nerve growth factor, Nerve growth factor (NGF) in the mouse submandibular gland undergoes cleavage of its amino-terminal octapeptide when salivation is induced by epinephrine. The significance of this event is uncertain; cleaved NGF demonstrates bioactivity and no function has been attributed to the octapeptide produced (NGF-OP; Ser-Ser-Thr-His-Pro-Val-Phe-His). Enzyme inhibition studies indicating structural relatedness of NGF-OP and bradykinin (BK) prompted us to determine whether NGF-OP would elicit BK-like actions. We found that like BK. NGF-OP induced a decrease in mechanical nociceptive threshold (i.e.. produced hyperalgesia) in the hairy skin of the rat. This effect was dose-dependent and sequence-specific; like BK it was attenuated by sympathectomy and indomethacin pretreatment. However. NGF-OP actions appeared to be distinct from those for BK in that tissue injury was required for NGF-OP to induce hyperalgesia. Furthermore. we found no evidence that NGF-OP bound to or activated BK receptors. Our data indicate that NGF-OP is a distinct mediator of hyperalgesia. We suggest that NGF-OP alters pain threshold in the injured target regions of NGF-responsive neurons.
Correlation of histology and drug response of human tumors grown in native-state three-dimensional histoculture and in nude mice, An in vitro histoculture system in which a native-state collagen-sponge gel supports the three-dimensional growth of tumor tissue has been recently developed that allows the culture and drug response assay for most every tumor type. Important features of the histoculture system include the maintenance of three-dimensional tissue architecture and the use of histological autoradiography to measure nuclear incorporation of [3H]thymidine as an endpoint. We describe in this report in vitro-in vivo correlations for drug response and tumor histology by using human tumor xenografts grown in the native-state three-dimensional histoculture system and as xenografts in nude mice. This comparison eliminates many of the confounding variables seen in most correlative clinical trials. Results demonstrate (i) a very high preservation of in vivo tissue architecture in vitro. (ii) an 86% accuracy in vitro of predicting drug resistance in vivo using suprapharmacologic doses of drugs in vitro. and (iii) an overall predictive frequency of drug resistance and sensitivity ranging from 53% for 5-fluorouracil to 78% for doxorubicin.
Development of a highly efficient expression cDNA cloning system: application to oncogene isolation, We developed an expression cDNA cloning system capable of generating high-complexity libraries with unidirectionally inserted cDNA fragments and allowing efficient plasmid rescue. As an application of this system. a cDNA library was constructed from an NIH 3T3 transformant induced by mouse hepatocellular carcinoma DNA. Transfection of NIH 3T3 cells by the library DNA led to the detection of several transformed foci from which identical plasmids with transforming ability could be rescued. Structure and sequence analysis of the cDNA clones revealed that the oncogene was created by recombinational events involving an unknown gene and the mouse homologue of the B-raf protooncogene. Detection of the same genetic rearrangement in independent primary transformants implied that generation of the oncogene occurred within the tumor rather than during DNA transfection or cDNA library construction. The high frequency at which clones were identified and the large sizes of some of the transforming cDNA inserts isolated suggest wide applicability of this mammalian expression cloning system for isolating cDNAs of biologic interest.
An influenza A virus containing influenza B virus 5' and 3' noncoding regions on the neuraminidase gene is attenuated in mice, Influenza A and B viruses have not been shown to form reassortants. It had been assumed that the lack of genotypic mixing between influenza virus types reflected differences in polymerase and packaging specificity. In this study. we show that an influenza A virus polymerase transcribes and replicates a chloramphenicol acetyltransferase (CAT) gene flanked by the nontranslated sequences of an influenza B virus gene. Although the transcription level of this CAT gene was several times lower than that of a CAT gene flanked by the homologous nontranslated sequences of an influenza A virus. we proceeded to construct a chimeric type A/B influenza virus. Using recombinant DNA techniques. a chimeric neuraminidase gene was introduced into the genome of influenza A/WSN/33 virus. The hybrid influenza A/B virus gene contained the coding region of the A/WSN neuraminidase and the 3' and 5' nontranslated sequences of the nonstructural gene of influenza B/Lee virus. The resulting chimeric virus formed plaques in Madin-Darby bovine kidney cells but replicated more slowly and achieved lower titers than wild-type influenza A/WSN/33 virus. The chimeric virus was attenuated for mice as indicated by a 400-fold increase in its LD50. Interestingly. the virus was greatly restricted in replication in the upper respiratory tract and partially restricted in the lungs. Animals infected with the transfectant virus were highly resistant to influenza virus challenge. It appears that this chimeric virus has many of the properties desirable for a live attenuated virus vaccine.
The retinoblastoma gene functions as a growth and tumor suppressor in human bladder carcinoma cells, The product of the human retinoblastoma gene (RB) is a nuclear phosphoprotein that is thought to function as a tumor suppressor. Mutations of RB frequently occur in human bladder carcinoma. To investigate the significance of the functional loss of this gene in bladder cancer. an RB expression plasmid (pBARB) under control of the human beta-actin promoter was transfected into the bladder carcinoma cell line HTB9. which lacks RB expression. Marker-selected transfectants that expressed RB protein were identified by immunoblotting and immunohistochemical staining. In selected clones. stable RB expression has persisted over 1 yr under standard culture conditions with 10% serum. However. RB expression caused major alterations of HTB9 growth properties both in vitro and in vivo. RB+ transfectants lacked the ability to form colonies in semi-solid medium. and their growth rate was significantly decreased in 3% serum. In addition. the tumorigenicity of these transfectants was markedly decreased. Tumors that formed in nude mice were much smaller and had a longer latency period but were indistinguishable microscopically from those produced by parental cells. Slower growing tumors were RB+. as measured by nuclear staining of their RB protein and by a normal RB protein pattern on immunoblots. These findings support the concept that the RB gene acts as both a growth and tumor suppressor in bladder cancer cells.
Cystic fibrosis gene expression is not correlated with rectifying Cl- channels, Cystic fibrosis (CF) involves a profound reduction of Cl- permeability in several exocrine tissues. A distinctive. outwardly rectifying. depolarization-induced Cl- channel (ORDIC channel) has been proposed to account for the Cl- conductance that is defective in CF. The recently identified CF gene is predicted to code for a 1480-amino acid integral membrane protein termed the CF transmembrane conductance regulator (CFTR). The CFTR shares sequence similarity with a superfamily of ATP-binding membrane transport proteins such as P-glycoprotein and STE6. but it also has features consistent with an ion channel function. It has been proposed that the CFTR might be an ORDIC channel. To determine if CFTR and ORDIC channel expression are correlated. we surveyed various cell lines for natural variation in CFTR and ORDIC channel expression. In four human epithelial cell lines (T84. CaCo2. PANC-1. and 9HTEo-/S) that encompass the full observed range of CFTR mRNA levels and ORDIC channel density we found no correlation.
The aging process: major risk factor for disease and death, Aging is the accumulation of changes responsible for the sequential alterations that accompany advancing age and the associated progressive increases in the chance of disease and death. Average life expectancies at birth in the developed countries are now approaching plateau values as the aging changes associated with the environment and disease near irreducible levels. The inborn aging process is now the major risk factor for disease and death after around age 28 in the developed countries and limits average life expectancy at birth to approximately 85 years. Future significant increases in average life expectancy--a rough measure of the healthy. productive life-span. i.e.. the functional life-span--in these countries will be achieved only by slowing the rate of production of aging changes by the aging process. Many theories have been advanced to account for the aging process. The free radical theory of aging is discussed briefly. The importance attached to increasing the functional life-span dictates that aging hypotheses be explored for practical means of achieving this goal while work continues toward a consensus on the cause(s) of the aging process. Efforts to further increase the functional life-span by conventional measures are now almost futile. whereas those directed toward slowing the aging process are just beginning. These new efforts show promise.
Identification and characterization of a cis-acting element that interferes with glucocorticoid-inducible activation of the mouse mammary tumor virus promoter, The rat hepatoma cell line M1.19 is stably infected by the mouse mammary tumor virus (MMTV). and the expression of the virus is induced by glucocorticoid treatment. However. in the 6.10.2 variant of M1.19. an increase in MMTV transcription is hardly detectable upon exposure to hormone. The mechanism of hormone-unresponsiveness in these cells has been unclear. In this study. we show that nuclear extract from 6.10.2 cells contains a specific DNA-binding activity that recognizes a sequence motif extending from positions -163 to -147 on the MMTV promoter. An oligonucleotide probe spanning this region binds a nuclear factor distinct from the glucocorticoid receptor. In vivo competition experiments. where increased amounts of a plasmid containing this element were transfected into 6.10.2 cells. showed a dose-dependent increase in hormonal inducibility of MMTV expression. Together. these results indicate that this sequence motif negatively modulates glucocorticoid-inducible activation of the MMTV promoter. Moreover. we have characterized a nuclear factor that preferentially binds to the coding strand of this element.
p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia, We have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies. including acute lymphoblastic leukemia. the major subtypes of non-Hodgkin lymphoma. and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direct sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsies; 17/27 cell lines) and its leukemic counterpart L3-type B-cell acute lymphoblastic leukemia (5/9). both of which also carry activated c-myc oncogenes. and (ii) B-cell chronic lymphocytic leukemia (6/40) and. in particular. its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases. only the mutated allele was detectable. implying loss of the normal allele. These results suggest that (i) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (ii) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (iii) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemic form L3-type B-cell acute lymphoblastic leukemia.
Mutation in a gene for type I procollagen (COL1A2) in a woman with postmenopausal osteoporosis: evidence for phenotypic and genotypic overlap with mild osteogenesis imperfecta, Mutations in the two genes for type I collagen (COL1A1 or COL1A2) cause osteogenesis imperfecta (OI). a heritable disease characterized by moderate to extreme brittleness of bone early in life. Here we show that a 52-year-old postmenopausal woman with severe osteopenia and a compression fracture of a thoracic vertebra had a mutation in the gene for the alpha 2(I) chain of type I collagen (COL1A2) similar to mutations that cause OI. cDNA was prepared from the woman's skin fibroblast RNA and assayed for the presence of a mutation by treating DNA heteroduplexes with carbodiimide. The results indicated a sequence variation in the region encoding amino acid residues 660-667 of the alpha 2(I) chain. Further analysis demonstrated a single-base mutation that caused a serine-for-glycine substitution at position 661 of the alpha 2(I) triple-helical domain. The substitution produced posttranslational overmodification of the collagen triple helix. as is seen with most glycine substitutions that cause OI. The patient had a history of five previous fractures. slightly blue sclerae. and slight hearing loss. Therefore. the results suggest that there may be phenotypic and genotypic overlap between mild osteogenesis imperfecta and postmenopausal osteoporosis. and that a subset of women with postmenopausal osteoporosis may have mutations in the genes for type I procollagen.
Hormone-regulated K+ channels in follicle-enclosed oocytes are activated by vasorelaxing K+ channel openers and blocked by antidiabetic sulfonylureas, Follicular oocytes from Xenopus laevis contain K+ channels activated by members of the recently recognized class of vasorelaxants that include cromakalim and pinacidil and blocked by antidiabetic sulfonylureas. such as glibenclamide. These channels are situated on the adherent follicular cells and are not present in denuded oocytes. Cromakalim-activated K+ channels are also activated by increases in intracellular cAMP. and cAMP-activated K+ channels are blocked by glibenclamide. Although cromakalim and cAMP effects are synergistic. cromakalim activation of K+ channels is drastically reduced or abolished by treatments that stimulate protein kinase C (e.g.. muscarinic effectors. phorbol esters). Gonadotropins. known to play an essential role in ovarian physiology. also activate cromakalim and sulfonylurea-sensitive K+ channels. Follicular oocytes constitute an excellent system for studying regulation of cromakalim-sensitive K+ channels that are important in relation to a variety of disease processes. such as cardiovascular dysfunction and asthma. as well as brain function.
Effect of acupuncture-point stimulation on diastolic blood pressure in hypertensive subjects: a preliminary study, Electrical stimulation of four specific acupuncture points (Liver 3. Stomach 36. Large Intestine 11. and the Groove for Lowering Blood Pressure) was examined in order to determine the effect of this stimulation on diastolic blood pressure in 10 subjects with diastolic hypertension. Subjects were randomly divided into two groups: (1) an Acu-ES group. which received electrical stimulation applied to the four antihypertensive acupuncture points. and (2) a Sham-ES group. which received electrical stimulation applied to non-acupuncture-point areas. A repeated-measures analysis of variance revealed a significant. immediate poststimulation reduction of diastolic blood pressure for the Acu-Es group versus the Sham-ES group. Further studies are needed to determine whether there are other acupuncture points. stimulation characteristics. or modalities that can enhance this treatment effect and whether the treatment effect can last for a clinically significant period of time.
Free bone graft reconstruction of irradiated facial tissue: experimental effects of basic fibroblast growth factor stimulation, A study was undertaken to evaluate the potential utility of basic fibroblast growth factor in the induction of angiogenesis and osseous healing in bone previously exposed to high doses of irradiation. Thirty New Zealand rabbits were evaluated by introducing basic fibroblast growth factor into irradiated mandibular resection sites either prior to or simultaneous with reconstruction by corticocancellous autografts harvested from the ilium. The fate of the free bone grafts was then evaluated at 90 days postoperatively by microangiographic. histologic. and fluorochrome bone-labeling techniques. Sequestration. necrosis. and failure to heal to recipient osseous margins was observed both clinically and histologically in all nontreated irradiated graft sites as well as those receiving simultaneous angiogenic stimulation at the time of graft placement. No fluorescent activity was seen in these graft groups. In the recipient sites pretreated with basic fibroblast growth factor prior to placement of the graft. healing and reestablishment of mandibular contour occurred in nearly 50 percent of the animals. Active bone formation was evident at cortical margins adjacent to the recipient sites but was absent in the more central cancellous regions of the grafts.
Microsurgical toenail transfer to the hand, Free nonvascularized toenail grafts have been used to reconstruct congenital or traumatic nail defects of the thumb or finger. Unfortunately. these transfers often result in deformity or atrophy. To avoid these undesirable results. microsurgical free vascularized toenail transfer was performed in 10 patients. 3 for congenital nail absence and 7 for traumatic nail defects. Patient age averaged 17 years (range 2 to 32 years). In contrast with previous reports. the whole big or second toenail complex without pulp was used in reconstruction. All 10 nails were successfully transferred with complete survival. No digits required reexploration. There were no donor- or recipient-site problems. Follow-up averaged 3 years. with a range of 14 months to 5 years and 4 months. Appropriate nail growth occurred in the congenital patients. No atrophy of the nail complex was found as long as sufficient bony support was present (9 of 10 cases). Whole free vascularized toenail transfers for reconstruction of congenital and traumatic nailbed defects achieve excellent aesthetic results while maintaining normal hand function.
Management of early human bites of the hand: a prospective randomized study, A prospective. randomized study was undertaken to determine if mechanical care of early human bites alone is sufficient therapy in the compliant patient or if prophylactic antibiotics (oral versus parenteral) are indicated. Beginning in June of 1985. patients presenting with human bites of the hand were entered into the study if (1) the bite was less than 24 hours old. (2) the patient was free of infection. (3) the bite did not penetrate the joint capsule. and (4) there was no injury to tendon. Forty-eight patients were ultimately segregated into one of three study groups after standardized ER mechanical wound care. Fifteen patients received an oral placebo. with 7 developing infection (46.7 percent). Sixteen patients received an oral antibiotic. and 17 patients received parenteral antibiotics. No infections were found in either of these latter groups. The results statistically substantiate that mechanical wound care alone is insufficient therapy. Oral antibiotics appear to be equal to intravenous antibiotics for prophylaxis. From a cost-benefit standpoint. vigorous cleaning. debridement. and coverage with a broad-spectrum oral antibiotic are adequate care for an uncomplicated bite in the compliant patient.
Immediate closure of traumatic upper arm and forearm injuries with the latissimus dorsi island myocutaneous pedicle flap, This paper reports the authors' experience with latissimus dorsi island pedicle flaps in the acute treatment of massive arm injuries. Seven patients with upper arm injuries and four patients with forearm injuries were treated with latissimus dorsi pedicle flaps. All cases involved massive soft-tissue loss and open fractures. Primary healing of wounds occurred without complications in 10 of 11 patients; the eleventh developed a wound infection. There were no instances of flap loss or vascular complications. This report compares and discusses surgical management options and details the importance of robust. immediate soft-tissue coverage for optimal functional recovery. Contrary to traditional thought. delay in definitive wound closure may be unnecessary when aggressive debridement is followed by acute flap closure.
The Tessier number 5 cleft: a report of two cases and a review of the literature, Two cases of facial clefts that fit the anatomic description of the rare Tessier number 5 cleft are presented and bring the total number of reported cases to 19. These cases and a review of the literature help define the soft-tissue course of the cleft from just medial to the oral commissure to the junction of the middle and lateral thirds of the lower eyelid. They also emphasize the role of axial CT scanning to define the bony cleft as one passing from just distal to the canine tooth to the orbital rim lateral to the infraorbital foramen. The widespread use of CT scanning and a thorough dental examination of these patients should provide more accurate diagnosis and classification of these clefts.
Primary cutaneous adenoid cystic carcinoma: a case report and review of the literature, A case of adenoid cystic carcinoma of the ear in a 67-year-old man is presented along with a review of the literature. Adenoid cystic carcinoma most commonly arises in the salivary glands. Primary cutaneous adenoid cystic carcinoma occurs principally in the scalp and chest. Perineural invasion is seen in at least half the cases and is associated with an increased recurrence rate. Treatment consists of wide local resection with tumor-free margins. Just over half the patients will develop recurrence. with long tumor-free intervals necessitating long-term follow-up. Distant metastases are rarely seen. Radiation therapy is not curative and should be reserved for palliation.
Toe-to-thumb transfer: a new technique, Our technique combines the advantages of two proven techniques of the wraparound flap and vascularized joint transfer while offering a more normal thumb. both functionally and cosmetically. Its advantages are as follows: 1. A more normal-looking thumb with good length 2. Preservation of motion through joint transfer 3. Maintenance of growth potential through transfer of vascularized epiphyses 4. Minimal donor-site morbidity.
Transverse lumbar flap for sacral bed sores, Over the last 30 months. we covered all the 21 cases of sacral pressure sores admitted to our section with the transverse lumbar flap. All the flaps survived. The rationale of the flap design. its technique. and complications are described. The advantages and the drawbacks of the flap are also described. One of the major principles of bed-sore flaps. i.e.. that the flap should be as large as possible. need not be adhered to.
Reconstruction of internal orbital fractures with Vitallium mesh, Trauma to the face frequently results in internal orbital fractures that may produce large orbital defects involving multiple walls. Accurate anatomic reconstruction of the bony orbit is essential to maintain normal appearance and function of the eye following such injuries. Autogenous bone grafts do not always produce predictable long-term support of the globe. Displacement and varying amounts of bone-graft resorption can lead to enophthalmos. This study examines the use of Vitallium mesh in the acute reconstruction of internal orbital defects. Fifty-four patients with 66 orbits underwent reconstruction of internal orbital defects with Vitallium mesh. Associated fractures were anatomically reduced and rigidly fixed. Forty-six patients and 57 orbits had adequate follow-up for analysis of results. The average follow-up was 9 months. with 85 percent of the patients followed 6 months or longer. There were no postoperative orbital infections. and none of the Vitallium mesh required removal. Large internal orbital defects can be reconstructed using Vitallium mesh with good results and little risk of infection. Vitallium mesh appears to be well tolerated in spite of free communication with the sinuses. Stable reconstruction of the internal orbit can be achieved and predictable eye position maintained without donor-site morbidity.
Chin disfigurement following removal of alloplastic chin implants, Insertion and subsequent removal of alloplastic chin implants is not an innocuous procedure. as commonly believed. Ten women. aged 23 to 62 years of age (mean 45 years) are reported in whom severe soft-tissue deformities were observed 6 months to 6 years (mean 32 months) after removal of their implants. Resulting deformities consisted of chin ptosis and bizarre soft-tissue pogonial bunching and dimpling in repose or on animation in 9 of the 10 patients (90 percent). Asymmetrical motion of the lower lip was noted by 5 of the 10 patients. Two patients complained of pain and tenderness over the soft-tissue pogonion. The "bizarre" soft-tissue chin deformities. once established. are virtually uncorrectable. Presently. we recommend serious consideration be given to performing an immediate osseous genioplasty in patients requiring removal of alloplastic chin implants to prevent the evolution of such abnormalities.
Combined (team) approach to hemangioma management: arteriography with superselective embolization plus YAG laser/sapphire-tip resection, Thirteen patients have been treated over a 2-year period utilizing a team approach between the radiology and surgical services. Initial diagnostic evaluation is directed at determining the size and anatomic extent of the hemangioma; clinical assessment of coagulation and hemodynamic status is also performed. Arteriography with superselective embolization precedes the surgical procedure. usually by 24 hours. The YAG laser with contact sapphire-tip scalpels is then utilized for resection and reconstruction of the hemangioma. Total removal of hemangioma was achieved in 9 of 13 patients. and partial or subtotal removal was achieved in the remainder. Blood loss and complications were minimal.
Early excision and skin grafting of selected burns of the face and neck, Since 1979. 16 patients with facial and neck burns have been treated with excision and skin grafting within the first 4 days of injury. The injuries were tangentially excised and immediately covered with split-thickness skin grafts. Detailed consecutive results are presented. The patients can be divided into three groups. Group 1 consisted of small subdermal or circumscribed deep dermal burns of the face (n = 8). Healing was quick. Some patients developed signs of overgrafting. As a late result. unevenness and discoloration were seen. Group 2 consisted of mixed deep dermal and subdermal burns of the face and neck (n = 5). Usually. minor areas had to be regrafted. Some patients developed hypertrophic scars at border areas. In the completely excised and grafted area. the skin was smooth. pliable. and discolored. Group 3 consisted mostly of subdermal burns of the face and neck (n = 3). The surgical trauma was significant. Small areas had to be regrafted. Ectropion and microstomia developed. It is concluded that in selected cases of deep dermal and subdermal burns. early excision and skin grafting will result in faster healing and less scarring than expectant treatment.
CT evaluation for pulmonary metastases in patients with extrathoracic malignancy, Computed tomography (CT) is clearly more sensitive than chest radiography or conventional linear tomography in the detection of pulmonary metastases. Routine chest CT scans may reveal peripheral nodules as small as 2-3 mm. and high-resolution CT may demonstrate lymphangitic carcinomatosis. Specificity remains a problem. but attention to clinical factors. such as the type of extrathoracic malignancy (ETM). epidemiology. patient age. and prior treatment. should be of assistance. CT is useful in the evaluation of an apparent solitary pulmonary nodule or an equivocal radiographic finding. For single or multiple nodules. CT is essential for planning invasive procedures such as biopsy or surgical resection. Routine CT scanning to screen for occult metastases is indicated only for patients with ETMs that have a high propensity for metastasizing to the lungs and for which detection of pulmonary metastases would influence therapy--bone and soft-tissue sarcomas. most pediatric tumors. choriocarcinoma. nonseminomatous testicular carcinoma. and possibly advanced melanoma. Future large prospective studies evaluating individual malignancies are needed to assess the impact on long-term survival of early detection of pulmonary metastases with CT.
Impact of section doubling on lesion contrast, Misregistration between section position and a feature of interest. such as a lesion. can result in loss of contrast on magnetic resonance images. Because the section direction typically has the poorest resolution. reduction of section misregistration can improve lesion contrast. Lesions occur at random sites; hence. to reduce misregistration. it is necessary to repeat imaging with a small amount of offset. This is impractical. Therefore. a reconstruction algorithm that yields offset sections was implemented. in which sections were produced with a zero- and a half-section shift. This algorithm was tested in 14 patients with multiple sclerosis. As expected. because of randomness associated with section placement relative to lesions. the half-shifted sections provided greater contrast as often as the zero-shifted sections. The combined set improved contrast significantly in 39% of lesions; improvement was greatest in lesions with lesser contrast. Signal-to-noise ratios were not affected by this process. which appears to be useful in magnetic resonance image reconstruction.
Occlusive peripheral vascular disease: a multicenter trial of fluorescence-guided, pulsed dye laser-assisted balloon angioplasty, Fluorescence-guided. laser-assisted balloon angioplasty was performed in 129 patients with iliac and femoropopliteal artery chronic occlusions (range. 0.5-50.0 cm; mean length. 9.9 cm) after failure of recanalization with standard guide-wire techniques. Laser recanalization and short-term angiographic success were achieved in 101 (72%) and 95 (68%) of 140 occlusions. respectively. Laser and balloon angioplasty failures were encountered in heavily calcified plaques or after perforations and dissections. Complications included perforations (19%). hematomas (5%). thromboses (4%). and distal embolizations (4%). Real-time fluorescence spectroscopy identified thrombus. white fibrous plaque. and media but could not avoid perforations in many cases because laser wire advancement outdistanced fluorescence sensing. Disruption of tissue by means of pressure transients and/or mechanical advancement occurred in at least 36% of lesions where the laser energy was insufficient (less than 0.4 J/cm) to ablate significant tissue. Integration of fluorescence guidance with pulsed dye laser ablation is feasible. but additional refinements are necessary to increase safety and efficacy.
New device for percutaneous fragmentation of pulmonary emboli, A new catheter system was designed for percutaneous fragmentation of large pulmonary emboli. The device consists of an impeller rotating at high speed at the center of a self-expandable basket at the tip of a 7-F catheter. The highly flexible catheter was able to reach all tested embolus sites in a glass model of the pulmonary arterial tree. Embolus fragmentation was quick and thorough. Particles in the effluent larger than 10 microns accounted for only about 9% of the treated embolus weight. Wall contact with the rotating impeller was not observed. The impeller-basket catheter promises to be a useful tool for percutaneous treatment of acute pulmonary embolism.
Echinococcus granulosus cysts in the liver: management with percutaneous drainage, Twenty-one hepatic Echinococcus granulosus cysts (maximal diameter. 7.5 cm +/- 4.0) in 12 patients were aspirated and irrigated with hypertonic (20%) saline under sonographic guidance. All patients had signs and symptoms of a hepatic mass caused by the cysts. which had a prominent fluid component that appeared anechoic or hypoechoic. with marked enhancement of back wall echoes. The amounts of cyst fluid aspirated and of hypertonic saline used were 190 mL +/- 240 and 120 mL +/- 90. respectively. Separation of the endocyst from the pericyst and nonviability of scoleces were observed in all cysts. Mean hospital stay was 4.0 days +/- 3.4. Serial sonographic examinations revealed high-level echoes in the cyst cavity (heterogeneous echo pattern). which ultimately became uniformly echogenic (pseudotumor). After follow-up of 14.0 months +/- 5.5. maximal cyst diameter decreased to 4.1 cm +/- 3.1 (P less than .001). One patient died of unrelated causes; the remaining 11 patients experienced relief of symptoms and a decrease in liver span.
Acute, subacute, and chronic myocardial infarction: quantitative analysis of gadolinium-enhanced MR images, The value of gadolinium enhancement to enable detection of infarcted myocardium at T1-weighted magnetic resonance (MR) imaging was assessed in 84 patients after acute myocardial infarction (AMI). Five healthy subjects served as controls. All patients underwent MR imaging before and 20 minutes after administration of gadopentetate dimeglumine. Contrast enhancement of normal myocardium varied 7% +/- 4 after administration of gadopentetate dimeglumine. Mean intensity ratio after gadolinium enhancement in group 1 (imaging less than 1 week after AMI). group 2 (imaging 1-3 weeks after AMI). and group 3 (imaging 3-6 weeks after AMI) was significantly higher than before gadolinium enhancement. In group 4 (imaging more than 6 weeks after AMI). no significant difference was observed. After gadolinium enhancement. the intensity ratio was abnormally increased in 82% of the MR examinations in group 1. in 62% of group 2. in 58% of group 3. and in 12% of group 4. Gadolinium enhancement improved visualization of myocardial infarction at MR imaging up to 6 weeks after onset of symptoms and had a maximal effect within 1 week after AMI.
Myocardial infarction: assessment with an intravascular MR contrast medium. Work in progress, The effect of a new intravascular magnetic resonance (MR) contrast medium (gadolinium diethylenetriaminepentaacetic acid [DTPA] polylysine) was evaluated in acute. subacute. and chronic myocardial infarctions in rats. Signal intensity (SI) was measured before and after intravenous administration of Gd-DTPA polylysine. Before administration of contrast material. chronic infarctions had lower SI than normal myocardium. With Gd-DTPA polylysine. three zones were identified in acute and subacute stages of myocardial infarction. but in the chronic stage. images demonstrated two zones. In acute and subacute infarctions. Gd-DTPA polylysine produced greater enhancement (over 60 minutes) in the peri-infarction zone than in the normal or infarcted myocardium. In chronic infarctions. Gd-DTPA polylysine had no discernible effect on the SI of the central infarction zone. Overall. it caused no significant hemodynamic effects. MR imaging with Gd-DTPA polylysine produced differential tissue enhancement in myocardial infarctions. which varied according to the age of the infarction.
Lung abscesses: US examination and US-guided transthoracic aspiration, Examinations with ultrasound (US) and US-guided transthoracic aspiration were conducted in 35 patients to enable diagnosis of lung abscesses. Thirty-three of the abscesses (94%) were demonstrated at US. while two lesions were not depicted. At US. lung abscesses were depicted as hypoechoic lesions with irregular outer margins and an abscess cavity that was manifested as a hyperechoic ring. Twenty-five abscesses (71%) had local adhesion to parietal pleura (lesion-pleura symphysis). US-guided transthoracic needle aspiration of fluid from the abscess cavity was performed successfully in 31 of 33 patients (94%). A total of 65 pathogens were isolated from 31 aspirates (41 anaerobes and 24 aerobes). not-withstanding the fact that 23 of the patients had been previously treated with antibiotics. Only two of 65 pathogens (3%) could be recovered from blood culture. seven (11%) from sputum culture. and two from bronchoalveolar lavage (3%). Two patients developed minimal pneumothorax. The authors conclude that US examination and US-guided transthoracic aspiration are useful and safe diagnostic methods of collecting specimens to enable accurate diagnosis of lung abscesses.
Variations in acromial ossification simulating infant abuse in victims of sudden infant death syndrome, A variation in ossification of the acromial process of the scapula is described. Postmortem radiographs. obtained in 78 infants who died of sudden infant death syndrome. showed an ossific opacity adjacent to the acromial process in 10 infants (13%). This finding was noted bilaterally in six patients and unilaterally in four patients. No two ossicles were identical. Histologically. no growth plate cartilage was evident between the bony structure and the acromion proper; therefore. this appeared to represent a "pseudoepiphysis." Superficially. this normal variation may appear similar to an acromial fracture resulting from infant abuse. However. a careful analysis of the findings of this normal variation should help prevent any confusion with inflicted injury.
Lobar emphysema: long-term imaging follow-up, In a retrospective study. the authors evaluated the initial and follow-up radiographs and ventilation perfusion (V/Q) scans of 12 boys and girls with lobar emphysema who were treated conservatively and were followed up for a median of 3 years (range. 6 months to 12 years). All 12 boys and girls underwent anteroposterior and lateral chest radiography at admission and at varying intervals thereafter. Ten patients underwent V/Q lung scanning; six of these procedures were performed within 4 weeks of initial radiography. Six patients underwent follow-up V/Q scanning. Thoracic computed tomography was performed in four patients at admission. In all 12 cases gradual improvement in symptoms was paralleled by improvements in serial chest radiographs and. in six cases. by improvements in V/Q scans. The affected lobe appeared to be less hyperinflated on follow-up radiographs. For those children who showed functional improvement. ventilation improved more than perfusion. as demonstrated on the V/Q scans. At initial radiography the adjacent "collapsed" lobe was seen to function well. suggesting that it was only compressed.
Transient white matter changes on MR images in children undergoing chemotherapy for acute lymphocytic leukemia: correlation with neuropsychologic deficiencies, The cranial magnetic resonance (MR) images of 25 children with acute lymphocytic leukemia (ALL) who were undergoing chemotherapy were retrospectively studied to determine the frequency of white matter changes and to analyze the significance of these observed changes in predicting subsequent neuropsychologic deficiencies. MR images showed transient white matter abnormalities in 17 of the 25 patients during consolidation therapy. Twelve of 20 children showed neuropsychologic deficits. There was no correlation between white matter changes and neuropsychologic deficits. In the subgroup of children under age 5 years at the time of diagnosis. 10 of 11 showed neuropsychologic deficits. and eight of 11 had white matter changes. Children under age 5 who undergo chemotherapy for ALL are at high risk to develop neuropsychologic deficiencies. Age at diagnosis is a reliable predictor of subsequent neuropsychologic deficits.
Dehiscent temporomandibular joint, The appearance of an acute effusion in a well-pneumatized temporal bone directs attention to the nasopharynx and skull base. Two patients are described in whom dehiscence of the temporomandibular joint allowed herniation of the contents of the joint posteromedically. where they obstructed the middle ear entrance of the eustachian tube. the protympanum. This is. to the authors' knowledge. a previously unreported cause of an acute middle ear and mastoid effusion.
Abnormal corpus callosum: a sensitive and specific indicator of multiple sclerosis, The authors investigated whether identification of corpus callosal (CC) involvement might increase the specificity of magnetic resonance (MR) imaging in differentiating multiple sclerosis (MS) from other periventricular white matter diseases (PWDs). They prospectively evaluated 42 patients with MS and 127 control patients with other PWDs. Ninety-three percent of the MS patients demonstrated confluent and/or focal lesions involving the callosal-septal interface (CSI). These lesions characteristically involved the inferior aspect of the callosum and radiated from the ventricular surface into the overlying callosum. CSI lesions were optimally demonstrated on sagittal long repetition time (TR)/short echo time (TE) images and frequently (45% of cases) went undetected on axial images. Only 2.4% of the control patients had lesions of the CC. The authors conclude that midsagittal long TR/short TE images are highly sensitive and specific for MS and that callosal involvement in MS is more common than previously reported.
Sacroiliitis: MR imaging findings, Magnetic resonance (MR) imaging was performed in seven asymptomatic volunteers and 17 patients with clinical and radiologic evidence of sacroiliitis. MR imaging findings were compared with those at computed tomography (CT) to determine the MR imaging appearance of the sacroiliac joint when normal and in sacroiliitis. The normal articulation was well depicted with MR imaging. Findings of sacroiliitis were identified in 20 sacroiliac joints (12 patients). MR imaging findings characteristic of sacroiliitis included abnormal cartilage signal intensity (95% of joints) and erosions (75% of joints) on T1-weighted images. Areas of increased intensity in the articulation (80% of joints) or in erosions (60% of joints) were seen on T2-weighted images. MR imaging was superior to CT for evaluation of cartilage and detection of erosions. Four sacroiliac joints (20%) and two patients (17%) with MR imaging findings of sacroiliitis were negative at CT. The authors conclude that MR imaging is a valuable method for detecting sacroiliitis. particularly when results of other imaging techniques are inconclusive.
Vertebral density distribution pattern: CT classification of patients undergoing maintenance hemodialysis, The authors performed densitometry of the vertebral bodies in 152 patients undergoing renal hemodialysis and histologically examined four vertebrae from cadavers. Bone mineral density (BMD) values were found to be potentially misleading because the vertebrae are often heterogeneous. and the BMD value is merely an average value from one region of interest. To overcome this problem. the authors designed a computed tomographic classification that divides vertebral density distribution patterns into the following five types: normal (type 1). osteopenia (type 2). diffuse osteosclerosis (type 3). spotty osteosclerosis (type 4). and central osteosclerosis (type 5). This classification may be useful in the evaluation of bone changes in patients undergoing hemodialysis. The type 5 pattern is thought to be strongly related to secondary hyperparathyroidism and was often seen in younger patients and women. Many patients with aluminum-induced osteopathy had type 2 patterns. with decreased BMD in cortical bone.
Ocular hazard of metallic fragments during MR imaging at 0.06 T, The hazard of magnetic resonance (MR) imaging at low field strength (0.06 T) was examined by using both in vitro and in vivo animal experiments. Ferromagnetic fragments. 0.25-2.2 mm in diameter. were placed in vitreous humor obtained from excised cow eyes and in rabbit eyes. The magnetic field strength at which motion occurred was measured for each fragment size. Two types of motion. rotation and translation. were observed. The authors found that fragments that could not be seen on plain radiographs did not appear to move enough to be a significant ocular hazard during MR imaging at a field strength of 0.06 T.
Human orthotopic small intestine transplantation: radiologic assessment, The authors describe the postoperative anatomy and review the radiologic examinations of five patients who underwent orthotopic small intestine or combined orthotopic liver and small intestine transplantation. Mucosal thickening of the transplanted intestine was demonstrated on the first postoperative contrast material-enhanced images and was due to submucosal edema. This resolved within 2 weeks in the long-term survivors. Bowel peristalsis appeared normal as early as 31 days after transplantation. Contrast-enhanced examinations of the intestine were useful to exclude surgical complications such as anastomotic leaks or strictures. but were insensitive for biopsy-proved cytomegalovirus enteritis or rejection.
Optimal technique for detection of gallstones at injection cholecystography: in vitro analysis, Injection cholecystography is often employed during invasive gallbladder procedures to determine the number of gallstones that are present. The authors undertook this study to define the optimal radiographic technique for performance of injection cholecystography. Condoms filled with 100 mL of contrast medium at four different iodine concentrations (30%. 15%. 7.5%. and 3.8% [wt/vol]) and containing up to five 4-mm-thick gallstones or a single 10-mm-thick gallstone were radiographed in a 20-cm-deep water bath by using four kilovolt peak settings (70. 80. 90. and 100 kVp). Images were read by three radiologists who were blinded to the radiographic technique. significantly (P less than .05) improved Decreasing iodine concentration significantly (P less than .05) improved detection of 4-mm-thick gallstones at a constant kilovolt peak setting. However. increasing the kilovolt peak setting while using the same concentration of contrast medium had no statistically significant influence on gallstone detectability. although radiologists did indicate a preference for the high-kilovolt peak technique. Results of the authors' experiments showed that for detection of small gallstones at injection cholecystography. use of a low-concentration contrast medium and a high kilovolt peak setting is the recommended radiographic technique.
In vitro cholesterol gallstone dissolution: comparison of methyl tert-butyl ether with three new ester solvents, The in vitro effectiveness of three new cholesterol gallstone solvents that have a potential for clinical use--ethyl propionate. isopropyl acetate. and n-propyl acetate--was compared with that of the well-known cholesterol solvent methyl tert-butyl ether (MTBE). Ten sets of matched gallstones were initially weighed. imaged with radiography and computed tomography (CT). and analyzed for content. One stone from each set was incubated in one of the four solvents at 37 degrees C. Solvents were changed at 30-minute intervals. The study was stopped either when the stones were completely dissolved or at the end of 7 hours. Any residual fragments were weighed. reimaged. and reanalyzed for content. There were no statistical differences between dissolution times of the stones in MTBE compared with those in the three new solvents. Ethyl propionate and n-propyl acetate appear to be as efficacious as MTBE in dissolving cholesterol stones and could be attractive alternatives for gallstone chemolysis.
Pseudomembranous colitis: CT evaluation of 26 cases, Pseudomembranous colitis (PMC) is an infectious colitis usually occurring as a complication of antibiotic use. The computed tomographic (CT) appearances of 26 patients with PMC were reviewed. Twenty-three patients demonstrated an abnormal bowel wall. with an average wall thickness of 14.7 mm (range. 3-32 mm); in three patients. bowel wall thickness was normal. Contrast material trapped between thickened folds corresponded to the broad transverse bands described on plain radiographs. Pancolonic involvement was seen in 13 cases. while seven patients had right-sided involvement only; three patients had bowel wall thickening limited to the rectosigmoid only. Although the CT appearance of PMC is not highly specific. the diagnosis may be suggested in the proper clinical setting.
Pseudomembranous colitis: sonographic features, The sonographic features of pseudomembranous colitis (PMC) are described in 13 patients and correlated with clinical. radiologic. and pathologic findings. At sonography. the wall of the entire colon was moderately to markedly thickened in all patients. The enlarged colon wall was most commonly shown as a wide band of heterogeneous medium echogenicity surrounded by a narrow hypoechoic layer. Pathologic correlations proved that the wide inner stratum represented severely edematous submucosa and mucosa. while the outer layer depicted the muscularis propria. Almost complete effacement of the lumen of the colon occurred secondary to the mural edema in 69% of the cases. The dearth of intraluminal gas combined with thickening of the colon wall and ascites facilitated excellent sonographic evaluation. The diagnosis of PMC is strongly suggested by the presence of these sonographic features in a patient with watery diarrhea and a history of antibiotic therapy.
Prevalence of simple adnexal cysts in postmenopausal women, This prospective study was performed with ultrasound (US) to determine the prevalence of unilocular. nonseptated adnexal cysts ("simple cysts") in healthy postmenopausal women and the relationship between cyst occurrence and both hormone replacement and length of time since onset of menopause. Transabdominal and transvaginal US were performed on 149 volunteers aged 50 years or older. Patients were classified according to hormone regimens (no hormones. unopposed estrogen. continuous daily estrogen and progesterone. and sequential estrogen and progesterone) and time since onset of menopause (less than 5 years. 5-10 years. and greater than 10 years). Simple adnexal cysts were found in 22 women with the aid of transvaginal and/or transabdominal US. yielding a relative frequency of 14.8% +/- 5.7% and a prevalence of 14.800 patients with cysts per 100.000 patients. No statistical relationship was found between cyst frequency and type of hormone replacement or length of time since onset of menopause.
Endometrial cysts: diagnosis with MR imaging, The value of 1.5-T magnetic resonance (MR) imaging in diagnosing endometrial cysts and differentiating them from other gynecologic masses was prospectively evaluated in 374 female patients with clinically suspected adnexal masses. A suggestive diagnosis of endometrial cyst was made when a cyst that was hyperintense on T1-weighted images exhibited homogeneous hyperintensity on T2-weighted images. A definitive diagnosis was made when a cyst that was hyperintense on T1-weighted images exhibited hypointense signal on T2-weighted images (shading) or when the lesion consisted of multiple hyperintense cysts on T1-weighted images (multiplicity) regardless of the signal intensity on T2-weighted images. Surgery was performed in 293 patients. and confirmation was obtained in 354 lesions. MR imaging enabled accurate diagnosis of 77 of 86 endometrial cysts and exclusion of the diagnosis of endometrial cyst in 263 of 268 other gynecologic masses with or without internal hemorrhage. The overall diagnostic sensitivity. specificity. and accuracy were 90%. 98%. 96%. respectively. MR imaging seems to be an acceptable diagnostic test on which clinical decisions can be based in selecting treatment.
Cervical carcinoma: MR imaging with an endorectal surface coil, Ten consecutive patients with biopsy-proved invasive cervical carcinoma underwent magnetic resonance (MR) imaging with both a standard body coil and with an endorectal surface coil. The endorectal coil provided a markedly improved signal-to-noise ratio. enabling the use of small fields of view; thus. the images had significantly improved in-plane resolution. The images were assigned an MR imaging stage based on the clinical staging system of the International Federation of Gynecology and Obstetrics. Vaginal wall. vaginal fornix. parametrium. and pelvic side-wall invasion by tumor were all well demonstrated. When compared with body coil images. the endorectal coil images provided increased anatomic detail and demonstrated tissue planes between tumor and normal structures that were not seen on the body coil images. This preliminary investigation indicates that use of an endorectal surface coil is a promising technique to obtain high-resolution images of the female genital tract. This technique has the potential to improve the accuracy of staging for cervical carcinoma.
Selective injection of contrast media: inflammatory effects on rabbit fallopian tubes, The inflammatory effects of fallopian tube catheterization and selective injection of seven contrast agents (ethiodized oil. diatrizoate meglumine 52%. diatrizoate meglumine 66%. iothalamate meglumine 60%. iopamidol. ioxitol. and ioxaglate) were evaluated in 88 rabbits. The contrast agent used was randomly selected and selectively injected after unilateral catheterization; the contralateral side was used for control. Pathologic inspection of right and left uteri with attached fallopian tubes and ovaries was done without knowledge of side of catheterization or duration of time since catheterization. The degree and location of inflammation were noted. Inflammation disappeared by 4 days in five of seven contrast agents. Iothalamate meglumine 60% and iopamidol required 2 weeks for disappearance of inflammation. Essentially no inflammation was associated at any time with ioxaglate. These findings suggest that all of these contrast agents would be clinically acceptable for direct injection into the human fallopian tube.
Deer stands: a significant cause of injury and mortality, Deer hunting is a popular recreational activity in the United States. Although the risks associated with firearms are well known. the hazards related to deer stands are not widely appreciated. From September 1982 through December 1989. there were 19 patients admitted to the Medical College of Georgia Hospital and Clinics for injuries sustained from falls related to deer stands. One death occurred. and six of the 18 survivors remain paralyzed. Data from 18 of these patients showed that 83% of these falls (15/18) were associated with hunter-constructed stands. Structural failure accounted for 39% (7/18) of the accidents; other causes included carelessness. falling asleep. and medical events. Four of the 19 patients (21%) had elevated blood alcohol levels on admission. Fracture of the spine and long bones accounted for the majority of the injuries. and seven of the 18 survivors (39%) were hospitalized for more than 4 weeks. Eight of the survivors (44%) remain permanently disabled. Deer-stand-related falls may result in significant long-term disability. expensive and lengthy hospitalization. and even death. A preventive approach to these injuries is paramount. and published guidelines for safety while hunting from deer stands should be followed.
Nonthermal surgical complications in burn patients, Patients with severe burn injuries are generally admitted to specialized units and managed by physicians who specialize in burn care. Complications requiring operative intervention and not directly related to the burn wound occur frequently but are easily overlooked. To determine the nature and frequency of these complications. we conducted a retrospective study of all burn cases in our burn unit over a 5-year period. Twenty-three of the 309 patients (7%) had 45 complications not related directly to the burn wound and required surgical intervention or consultation. The population with surgical complications was generally older (52 vs 42 years). more severely burned (36% vs 25% total body surface area). and had a higher mortality (44% vs 13%). Sixteen of the 23 patients with complications had a single surgical problem. while seven patients sustained multiple complications. In six of the 10 deaths. the surgical complication was believed to be either directly related or significantly contributory to the cause of death. Because the number of burn patients requiring surgical intervention is high. burn patients must be thoroughly examined for possible complications.
Effect of breast implants on mammography, We developed an experimental. reproducible method of evaluating the radiographic characteristics of breast implants in vitro using a mammographic phantom and a cadaver. Implant shells tested included smooth silicone. textured silicone. and silicone coated with polyurethane foam. Each type of shell was subsequently filled with saline. silicone gel. and peanut oil; the images were recorded radiographically. Textured silicone and smooth silicone shells minimally impair detection of artifacts. Polyurethane-coated shells are less radiolucent but allow visualization of some microcalcifications. Saline and silicone-gel-filled implants are radiopaque regardless of shell type. Textured silicone and smooth silicone shells filled with peanut oil are radiolucent and allow visualization of microcalcifications and most soft-tissue masses. These data demonstrate that radiolucent breast implants are possible. and further efforts are under way to achieve Food and Drug Administration approval for clinical testing.
Prenatal hepatitis B testing in a midsize southern city, Universal prenatal screening for hepatitis B in low-risk populations remains controversial. The purpose of this study was to characterize the obstetric population of the city/county hospital in a midsize southern city. A total of 2013 patients were screened for hepatitis B surface antigen and antibody between June 1988 and February 1990. with 1893 negative for both. 105 (5.2%) positive for surface antibody. and 15 (0.8%) positive for surface antigen. Only 25% of the patients with positive results of hepatitis B screening would have been identified by the 1984 Centers for Disease Control risk group criteria. and no other predictive features were identified. We conclude that universal prenatal screening for hepatitis B is indicated in low-risk populations because of the high prevalence and the lack of predictive features.
Haemophilus influenzae resistance in a community hospital, We prospectively tabulated all isolates of Haemophilus influenzae at DeKalb Medical Center from 1987 through 1989 to assess the occurrence of antibiotic resistance in patients of different ages. Of 325 total strains isolated. 24% produced beta-lactamase. rendering them resistant to ampicillin and amoxicillin. Antibiotic resistance was as common in patients older than age 60 (24%) as in younger patients (23%). Sensitivity testing by disk diffusion and microdilution techniques on 71 isolates (37 beta-lactamase-positive) showed uniform susceptibility to cefuroxime. cefotaxime. amoxicillin/clavulanate. cefaclor. and chloramphenicol. but three beta-lactamase-positive isolates were resistant to trimethoprim/sulfamethoxazole. The high rate of ampicillin resistance noted in elderly patients has implications for the choice of antimicrobial therapy for these infections.
External fistulas arising from the digestive tract, External abdominal fistulas that arise from the digestive tract are associated with high mortality and prolonged morbidity in terms of infection. malnutrition. and skin excoriation. Such external fistulas most commonly follow anastomotic leak after gastrointestinal surgery. We identified 58 patients seen over a 5-year period at the University of Louisville Hospitals because of external abdominal fistulas that arose from the stomach (8). duodenum (4). small intestine (26). colon (14). biliary tract (9). and pancreas (7). Fifteen patients had multiple fistulas and 32 had high-output fistulas (greater than 200 mL/day). Closure was achieved in 48 patients. and eight of the 10 patients whose fistulas remained open died. Overall mortality was 19%. Principles of management include control of infection. correction of fluid and electrolyte imbalance. nutritional support. proper wound care. and often operative intervention. Multiple staged operations over many months were particularly important in managing complex wounds with large abdominal wall defects and multiple fistulas. Fistula closure is the ultimate goal. and patience is important to achieve it.
Pleomorphic melanoma mimicking sarcoma, Malignant melanoma may display a wide variety of unusual morphologic patterns that simulate unrelated neoplasms. The diagnostic approach to such complex and morphologically divergent lesions requires thorough and extensive scrutiny not only by routine light microscopy. but also by immunohistochemical and ultrastructural evaluation. We have reported the case of a patient with a mass on the heel exhibiting complex morphology that illustrates the value of such a systematic approach.
Incidental detection of a microcystic adenoma of the pancreas, Cystic neoplasms of the pancreas are uncommon. The two major types of cystic pancreatic neoplasms are microcystic (serous) cystadenoma and mucinous cystic lesions (mucinous cystadenoma and mucinous cystadenocarcinoma). The two types differ substantially in the long-term mortality. Symptoms and signs do not distinguish between the two types. and small lesions are often asymptomatic. The neoplasms may be discovered during imaging procedures for unrelated complaints. Computerized tomography may suggest the diagnosis of microcystic adenoma or mucinous cystic neoplasm when the features are typical. but the final diagnosis must be established by surgical biopsy. Characteristic gross findings. light microscopic findings. and immunohistochemical staining patterns distinguish between the two types. When preliminary open biopsy confirms microcystic adenoma. extensive unnecessary surgery can be avoided.
Periumbilical pseudoxanthoma elasticum with systemic manifestations, We have reviewed the typical clinical manifestations of pseudoxanthoma elasticum and presented the case of a patient with involvement of the skin. eyes. and cardiovascular system. We suggest that patients with periumbilical lesions that might indicate pseudoxanthoma elasticum have. at minimum. a full physical examination with emphasis on the cardiovascular system and a complete ophthalmologic evaluation.
Enterobacter sakazakii bacteremia in an adult, We have reported a case of E sakazakii primary bacteremia in an elderly patient in whom evaluation failed to reveal a source of infection. This patient had an uneventful recovery after intravenous administration of a third-generation cephalosporin for 7 days followed by 1 week of oral ciprofloxacin. This excellent response supports the previous suggestion that agents more active against gram-negative bacilli should be considered. despite apparent susceptibility to less active agents. Since this case attests to the pathogenicity of this organism in adults. isolation of the organism from clinical specimens should not be dismissed as contamination.
Cardiac conduction manifestations of Reiter's syndrome, This study shows that conduction abnormalities may occur frequently in Reiter's syndrome of new onset or short duration. Since these conduction defects may be initially life threatening or may progress to life-threatening abnormalities. anyone with RS should be followed up. Because of the strong association between RS and HIV infection. we suggest HIV testing for all patients with RS. Anyone with RS should have an electrocardiogram. either to study symptoms or as a baseline if no symptoms exist.
Effects of acute, graded compression on spinal nerve root function and structure. An experimental study of the pig cauda equina, A well-controlled experimental model for analysis of compression-induced functional changes of the porcine cauda equina is presented. The model allows for electrophysiologic investigation of a variety of neurophysiologic changes induced by nerve root deformation. At an acute pressure threshold of 50-75 mm Hg. changes in both afferent and efferent conduction are induced. With higher compression pressure. a differential recovery in afferent and efferent conduction is seen.
Analysis and prevention of spinal column deformity following cervical laminectomy. I. Pathogenetic analysis of postlaminectomy deformities, Postlaminectomy deformities were simulated in the cervical or cervicothoracic spine by the use of a displacement incremental method based on finite-element analysis combined with composite material and spanning element theory. The simulation analyses revealed that the primary cause of postlaminectomy deformity was the resection of one or more spinous processes and/or posterior ligaments (ie. ligamenta flava. supraspinous. and interspinous ligaments). After their removal. the tensile stresses that were preoperatively distributed through the posterior ligaments were transferred to the facets. This led to an imbalance of the stresses on the spinal bodies. causing deformity. The gravitational center of the head determined whether the deformity would develop as a kyphosis or increasing lordosis. As the elastic modulus of the soft tissue composites (eg. end plates. ligaments. and facets) increased. a kyphotic deformity changed gradually from swan-neck deformity. to extreme kyphotic deformity with a large curvature. and finally to a straightening deformity. Progressive kyphotic deformity is found only in children.
Influence of the ultrasonic surgical aspirator on the dura and spinal cord. An electrohistologic study, The influence of the ultrasonic surgical aspirator on the dura and underlying spinal cord was examined. Spinal-cord-evoked potential was simultaneously recorded. In a test of identical time. the degree of influence on the dura. the pia mater. and the spinal cord increased according to the increase of energy of the ultrasonic surgical aspirator. With 60% energy at 20 seconds and 80% energy at both 10 and 20 seconds. spinal-cord-evoked potential showed wave changes. In light of these results. it is suggested that in using the ultrasonic surgical aspirator on the dura. the electrohistologic safety limit be set at 60% energy and the maximum time duration at one point less than 10 seconds.
The role of facet joint tropism and facet angle in disc degeneration, In this study. the relationship between facet geometry (joint angle and tropism) and disc degeneration was analyzed. Magnetic resonance imaging and computed tomographic scans of 46 subjects less than 50 years of age were evaluated. Magnetic resonance imaging was used to determine disc degeneration. and computed tomography was used to measure facet joint angles and determine tropism. Subjects with tropism had a significantly higher prevalence of disc degeneration at all three lumbar levels examined (L3-4. L4-5. L5-S1). The average facet angles increased from L3-4 to L4-5 and further to the L5-S1 level. There was no statistically significant relationship between the magnitude of the angle and the presence of disc degeneration at any of the three levels. It was concluded that the risk of disc degeneration is increased in the presence of facet joint tropism.
Back sprain in industry. The role of socioeconomic factors in chronicity, A minority of industrial-back-sprain claimants account for most of the cost of industrial back sprain: those whose disability persists into "chronicity". which is defined as 90 days or more off work. The data in this study demonstrate the effects of socioeconomic factors on chronicity. This analysis is based on State of Washington industrial insurance claims for back sprain. For both men and women. three socioeconomic factors significantly affect the risk of chronicity: age. wage. and the family status of being either widowed or divorced with no children. In addition. the Nam-Powers Socioeconomic Index is significant for men. Wage compensation ratio cannot be shown to be a factor in chronicity.
Prevalence of back pain in pregnancy, The prevalence of back pain was studied in 855 pregnant women who were followed from the 12th week of pregnancy. every 2nd week. until childbirth. The 9-month period prevalence was 49%. with a point prevalence of 22-28% from the 12th week until delivery. Because 22% of the women had back pain at the 12th week of the pregnancy. the 6-month incidence was 27%. Based on pain drawings. back pain was classified into three groups: In one group. pain was localized to the sacroiliac areas and increased as pregnancy progressed; in the other two groups. pain either decreased or did not change. respectively. True sciatica with a dermatomal distribution occurred in only 10 women (1%). Back problems before pregnancy increased the risk of back pain. as did young age. multiparity. and several physical and psychological work factors.
A controlled study of caudal epidural injections of triamcinolone plus procaine for the management of intractable sciatica, The management of sciatica due to lumbar nerve root compromise remains controversial. probably because few well-controlled studies of conservative management have been performed. This preliminary study assesses the efficacy of epidural injections of 80 mg triamcinolone acetonide plus 0.5% procaine hydrochloride in saline. administered via the caudal route. in a double-blind. placebo controlled trial with 1 year follow-up. Twenty-three patients were entered into the study: 12 received treatment and 11 placebo. The active group showed significant pain relief (P = 0.02) and a significant increase in mobility (P = 0.01) at 4 weeks. which resulted in improved quality of life (P = 0.02). At 1 year. subjective and objective measures improved in both groups. The improvement was greater in the actively treated group. but only the objective assessment (straight leg raise) was statistically significant.
Traumatic atlantoaxial dislocation without fracture of the odontoid, Four cases of atlantoaxial dislocation without fracture of the odontoid have now been reported in patients surviving significant trauma. Experience with these cases suggest the following: 1. Atlantoaxial dislocation is compatible with survival and minimal or no long-term neurologic effects. 2. Reduction of the dislocation by traction is possible and has not resulted in significant complications. but marked instability can be present. Close medical supervision and frequent radiographic evaluation is mandatory. During reduction. the weight and angle of traction applied is changed in each phase of reduction (distraction. realignment. release). After reduction. physician-controlled. gentle flexion-extension radiographs are used to assess stability. 3. Traction should be started with light weights. care being taken to avoid overdistraction. A maximum of 15 lb traction was required for reduction in the present case. 4. Posterior surgical fusion is usually necessary because of residual instability and/or incomplete reduction. as demonstrated by postreduction supervised. gentle flexion-extension radiographs and/or CT scan. 5. There may be a small number of patients who can be treated by immobilization alone if a completely stable. anatomic reduction is obtained with traction.
Evaluation of extracranial-to-intracranial bypass surgery using iodine 123 iodoamphetamine single-photon emission computed tomography, Eleven patients with occlusive cerebrovascular diseases were imaged with N-isopropyl-p-I-123 iodoamphetamine. Preoperative and postoperative single-photon emission computed tomography was performed in 10 patients undergoing extracranial-to-intracranial bypass procedures. New images were reconstructed from the two images obtained on the different days by superimposition and division in each pixel to get the ratio of cerebral perfusion change. All patients with bypass procedures had an increase in cerebral blood flow in the affected areas. and nine of 10 had an increase in cerebral blood flow in the contralateral cortex. There was no increase in cerebral blood flow in one case with no operation. Neither our procedure nor the results in this small series prove that recovery of function is due to an increase in blood flow. but we believe this is the case.
Posttraumatic intradiploic leptomeningeal cyst in an adult: case report, We report the case of an adult with a posttraumatic intradiploic leptomeningeal cyst that caused a circumscribed osteolytic skull lesion. Local pain. the only symptom of the lesion. regressed after surgery. Intradiploic leptomeningeal cysts must be distinguished from intradiploic arachnoid cysts. which are of congenital origin.
Facial nerve monitoring by monopolar low constant current stimulation during acoustic neurinoma surgery, Electrophysiological characteristics of monopolar low constant current stimulation. and evoked facial muscle responses to such stimulation. were evaluated in 34 cases of acoustic neurinoma. Our study. using stimulus parameters of 0.1-ms-duration pulse wave with 0.5-0.6 mA intensity. revealed that extent of spreading current depends on the current intensity. being about 1 mm from the electrode with 0.5-0.6 mA. and insulation of the electrode prevented the current from spreading through the cerebrospinal fluid. giving a reliable amount of current to the tissue. Evoked facial muscle responses to facial nerve stimulation in the internal auditory meatus and over the pons were analyzed and revealed the following: (1) The responses to stimulation in the internal auditory meatus showed no amplitude attenuation throughout the operation. (2) The responses to stimulation over the pons gradually decreased in amplitude as tumor dissection from the nerve proceeded. especially in large tumors. (3) Anatomical continuity of the nerve was obtained in 100% of small. 91.7% of medium. and 88.2% of large tumors. Our data show that monopolar low constant current stimulation is effective in obtaining the precise anatomical orientation of the facial nerve during tumor removal.
Histopathological studies of a new liquid embolization method using estrogen-alcohol and polyvinyl acetate. Experimental evaluations with a model of cortical arterial cannulation in the canine brain, This experimental report evaluates the histopathological effects of a new embolization method using estrogen-alcohol (E-A) and polyvinyl acetate solution (PVac) as tested on 21 mongrel dogs. Three other animals treated with normal saline served as controls. All agents were introduced through an isolated cortical artery. Estrogen-alcohol induced immediate occlusion of small vessels (less than 20 microns). and then progressive obstruction of larger ones (200-300 microns) within several days. Animals treated with PVac showed vascular obliteration (greater than 100 microns) and moderate chronic fibrosis. The effects of embolization using E-A followed by PVac were found to have the combined advantages of both materials. showing diffuse occlusion of the vascular network with less tissue reaction. Hyalinization of embolized vessels with extensive fibrosis occurred afterward. For 6 weeks there was no evidence of recanalization or foreign body giant cell reaction. This study shows that E-A and PVac are capable of producing vascular occlusions with only mild tissue reaction. Because they are easily controllable and have no adverse effects. they may be suitable for intravascular application in the central nervous system.
Resection of intrinsic tumors from nondominant face motor cortex using stimulation mapping: report of two cases, We report two right-handed patients who underwent resection of intrinsic glial tumors from the nondominant hemisphere. face motor cortex. Both patients underwent preoperative assessment with computed tomography and magnetic resonance imaging localizing the tumor in the inferior region of the Rolandic cortex. With the patients under general anesthesia and without muscular paralysis. the tumor volume was determined by intraoperative ultrasound and resective surgery accomplished with the aid of cortical and subcortical stimulation mapping techniques. Radical resection of the tumor from the face motor cortex was achieved in both patients. A transient contralateral facial weakness and apraxia were noted in each patient. and this resolved within 6 to 8 weeks following surgery. Removal of intrinsic tumors involving the nondominant face motor cortex may be safely achieved using brain mapping techniques to localize inferior Rolandic cortex and avoid resection of the hand motor cortex and descending subcortical motor pathways. Permanent disability will be prevented due to the bilateral representation of face motor function at the neocortical level. However. due to language localization in cortical zones contiguous with the dominant hemisphere. face motor cortex. we do not recommend resection of this region.
Serial angiography in a spontaneous dissecting anterior cerebral artery aneurysm, Intracranial dissecting aneurysms are uncommon. and little is known concerning the natural history of these lesions. In this paper we present a rare case of dissecting aneurysm of the anterior cerebral artery in which a true diagnostic sign of "double lumen" was demonstrated. Sequential changes in angiographic features shown on serial angiographic studies are described. and diagnosis is briefly discussed.
Intracranial metastasis of a choroid plexus papilloma originating in the cerebellopontine angle region: a case report, The authors present a rare case in which a choroid plexus papilloma originating in the left cerebellopontine angle region metastasized and formed a space-occupying lesion in the right temporal region. A 46-year-old woman with choked disks presented with two separate mass lesions in the right temporal and the left cerebellopontine angle regions. Magnetic resonance imaging exhibited the relationship between the tumors and the surrounding structures. To our knowledge. no case has been reported in which a choroid plexus papilloma originating in the cerebellopontine angle region formed a space-occupying lesion in the right temporal region.
Astrocytoma and associated arteriovenous malformation, A case is reported of a cerebral arteriovenous malformation occurring in continuity with an astrocytoma. Possible etiologies of this unusual association are discussed.
Single center experience of the effect of delayed function on outcome in retransplant recipients of cadaveric renal allografts, The incidence of DRF in the regraft study group was most commonly seen in patients with a historic high level of HLA sensitization. Primary NF was an immune mediated event seen in 63% of third regrafts. Delayed use of CyA with ALG induction coverage provides good graft survival with either double or triple maintenance therapy. Stricter patient selection for third transplants and aggressive clinical monitoring of the regrafted patient has provided a 1-year actuarial graft survival result of 88% at our transplant center.
Transplant aspiration cytology: applications to kidney and liver transplantations, In summary. cytologic monitoring of renal and liver transplants is a well established diagnostic procedure. The prime value of the FNAB relates to the posttransplantation perioperative period: the acute alterations in the transplant. such as acute rejection and the differential diagnoses. can be established in most cases. However. evaluation of vascular patterns of rejection. in particular chronic rejection. is impossible to obtain from the FNAB. A needle core biopsy is needed.
A randomized double-blind study of recombinant human erythropoietin in anaemic hemodialysis patients. Canadian Erythropoietin Study Group, This study suggests that both the quality of life and exercise capacity of anaemic hemodialysis patients is improved with EPO therapy. This was seen most convincingly in the dimensions of fatigue and physical symptoms. There was no difference in improvement in quality of life or exercise capacity between patients with a mean hemoglobin level of 102 g/L and those with a mean hemoglobin level of 117 g/L. There was an increase in diastolic blood pressure in the EPO-treated patients. especially those randomized to the high EPO group.
Arterial insufficiency in hemodialysis access procedures: correction by "banding" technique, Arterial insufficiency distal to an antecubital access is fortunately an infrequent but disturbing and often debilitating complication resulting in suboptimal access. During an 8 1/2-year period. 335 vascular access procedures were performed. 108 of which were antecubital brachiocephalic Gore-Tex conduits. Of these Gore-Tex conduits. 1.8% (2/108) had developed symptoms of vascular insufficiency 2 to 3 1/2 months after such access surgery. As previously published. arterial steal after the creation of an AV fistula could be corrected by the placement of an interposition Gore-Tex loop that would cure the problem and save the access. We have presented a procedure to correct a steal syndrome once a Gore-Tex conduit is already in place. Proximal banding and distal ligation with division of the cephalic vein below an end-to-side Gore-Tex loop is a simple surgical solution. It is not only curative but the procedure also maintains the existing Gore-Tex graft as a sustained avenue for access.
Dietary calcium supplementation as a treatment for mild hypertension, The blood pressure responses of 19 mildly hypertensive (diastolic blood pressure 90-104 mmHg) individuals to treatment with either 1200 mg of elemental calcium supplementation or placebo were assessed weekly in a 6-month randomized. double-blind. placebo-controlled crossover study. Both groups showed a decrease in blood pressure (calcium treated: 6 +/- 12 mmHg systolic. 7 +/- 7 mmHg diastolic; and placebo controlled: 9 +/- 14 mmHg systolic. 9 +/- 8 mmHg diastolic). Differences between the two groups were not significant (P greater than 0.1). There were no adverse effects to either treatment. This study does not support the hypothesis that dietary calcium supplementation is more effective than placebo in reducing blood pressure in mildly hypertensive individuals.
Converting the stress of medical practice to personal and professional growth: 5 years of experience with a psychodynamic support and supervision group, Medical practice is stressful. Although much of the burden comes from the content of the work. physicians' personalities and emotions contribute greatly. Few traditions or structures are available in the medical community to help physicians deal with this stress and prevent disillusionment and impairment. This article describes the 5-year evolution of a physician-support group that has provided supervision and psychodynamic insight. The key elements of the group's effectiveness are leadership. connecting work issues to personal dynamics. defusing defenses. and ensuring confidentiality. Competitiveness. mistakes. anger. difficult patients. death. fear of malpractice. and family-work tensions are issues that have been addressed. Psychodynamic supervision groups differ from peer-support groups and therapy groups. Psychodynamic supervision in support groups. as used in the supervision and training of pastoral counselors. offers a simple and powerful means to ease the burdens of medical practice and thus prevents disillusionment and subsequent impairment among physicians.
Adenocarcinoma of the stomach: a plea for early diagnosis, In the United States. early diagnosis and cure of gastric carcinoma remain elusive. Patients with this disease commonly have gastrointestinal symptoms that often go unexplained. Physicians give gastric carcinoma a low priority in their differential diagnosis and are unaware of the risk factors patients may have. Patients may have a normal upper gastrointestinal series. and fiberoptic gastroscopy is delayed. Patients with unexplained indigestion and abdominal pain. coupled with such risk factors for gastric carcinoma as national origin. diet. heredity. and previous subtotal gastrectomy for gastric ulcers. should be given the opportunity of esophagogastroduodenoscopy.
Post-transfusion purpura, Post-transfusion purpura is a complication of blood product transfusion in which the recipient produces antiplatelet antibodies resulting in severe thrombocytopenia. The typical patient is a multiparous woman who develops sudden severe purpura 1 week after receiving a transfusion of packed red cells or whole blood. Post-transfusion purpura should. however. be considered in any patient with thrombocytopenia following infusion of a blood product. Untreated. the disease can be fatal or cause serious morbidity. Treatment options include plasmapheresis. intravenous immunoglobulin. and corticosteroids. Platelet transfusion is usually unsuccessful.
Calcium antagonists: an overview, Calcium antagonists reduce the influx of calcium ions through the calcium channels. This causes a reduction in myocardial contractility or a fall in vascular resistance because of a lowering of vascular smooth muscle tone. Therefore. the net effect is a fall in blood pressure. The three major classes of calcium antagonists. the dihydropyridines. papaverine derivatives. and benzothiazepines. differ in molecular structure and their binding characteristics to the calcium channels. Furthermore. newer antagonists. particularly the dihydropyridines such as nicardipine. have a high affinity for vascular tissue and are highly selective for vascular smooth muscle. These compounds also have a favorable effect on hypertension mainly because of lowering of vascular resistance. In addition. they do not cause potentially negative metabolic effects on glucose or lipid levels and are generally well tolerated. Based on these findings. the Joint National Committee in the United States and the World Health Organization/International Society of Hypertension Committee on the Management of Mild Hypertension recommended the use of calcium antagonists as first-line treatment in hypertension.
Drug-induced modification of vascular structure: effects of antihypertensive drugs, It has long been realized that hypertension causes alterations in the peripheral vasculature. with the arterial wall becoming thicker and the lumen relatively smaller. This is particularly true in small resistance arteries. but larger vessels are also affected. The precise mechanisms remain to be determined. although it is highly likely that growth-promoting autacoids are involved as well as mechanical forces. Numerous studies of hypertension in animal models and a few in hypertensive humans have tried to establish the reversibility of these changes after successful lowering of blood pressure. Too few data are available to form firm conclusions. but thiazides and hydralazine-like vasodilators appear to have only a minimal effect on the vasculature. On the other hand. angiotensin-converting enzyme inhibitors are clearly effective. and alpha-blockers may be active. However. it is difficult to derive even tentative conclusions from the available information on calcium antagonists and beta-blockers. These results are discussed in the context of future therapeutic and investigative approaches.
Nicardipine and vascular hypertrophy, The effects of nicardipine administration on the morphology of coronary. renal. and pulmonary vascular trees were studied in spontaneously hypertensive rats (SHRs). Male 10-week-old SHRs received 1 mg/kg/day of nicardipine or vehicle orally for 12 weeks. Age-matched Wistar-Kyoto rats were used as normotensive reference animals. Blood pressure. heart weight. heart/body weight ratio. the area occupied by the medial layer. and area occupied by the vascular wall/area of lumen ratio increased significantly (p less than 0.001) in SHRs compared with normotensive Wistar-Kyoto rats. Nicardipine reduced blood pressure. as well as relative heart weight. the area occupied by vascular smooth muscle. and the area occupied by the vascular wall/area of lumen ratio. In addition. the size of laminae of smooth muscle of the pulmonary artery was reduced in nicardipine-treated SHRs; coronary artery branches were the most sensitive. The results of the study provide direct evidence that nicardipine reduces not only blood pressure but is also able to counteract the development of hypertension-dependent changes in the morphology of the cardiovascular system.
Heterogeneous interference of nicardipine, verapamil, and diltiazem with forearm arteriolar responsiveness to adrenergic stimulation in hypertensive patients, The interference of intraarterial nicardipine. verapamil. and diltiazem with the forearm vascular response to graded exogenous norepinephrine was evaluated in hypertensive patients. Nicardipine antagonized the vasoconstrictor effect of norepinephrine in a dose-dependent manner. whereas verapamil was ineffective. suggesting that functional alpha-adrenergic antagonism may participate in the vasodilatory and possibly the antihypertensive effect. Nicardipine also blunted the vasoconstriction to lower-body negative pressure and the action of angiotensin II administered intraarterially. Despite a comparable increase in basal forearm flow. verapamil was less potent than nicardipine in inhibiting vasoconstriction after both stimuli. Therefore nicardipine suppressed preferentially regional vascular reactivity. probably by blockade of the influx of extracellular calcium in response to receptor activation. because both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. At variance with both nicardipine and verapamil was potentiation of the responses to norepinephrine after the administration of diltiazem. Because intraarterial propranolol abolished that potentiating action and the local vasodilatation to isoproterenol was clearly reduced. diltiazem probably interfered also with beta-adrenergic receptor-mediated vasorelaxing mechanisms in human forearm arterioles. The data further stress the heterogeneity of calcium channel blockers in humans.
Controlled multicenter double-blind trial of nicardipine in the treatment of primary Raynaud phenomenon. French Cooperative Multicenter Group for Raynaud Phenomenon, Paris, France, A total of 69 patients with primary Raynaud phenomenon were included in a multicenter. randomized. double-blind. crossover. placebo-controlled trial to assess the efficacy of nicardipine. a new calcium channel blocker. The trial data were combined with a meteorological survey. Nicardipine significantly (p = 0.02) reduced the number of crises of Raynaud phenomenon but had no significant effect on the intensity of the crises. Mean overall improvement. assessed on a linear visual analog scale. was 21% (p = 0.018). but results for the cold-reactive hyperemia test were not significantly altered after nicardipine treatment. All side effects were mild. and their frequency only differed significantly (p less than 0.05) from that of placebo for edema and headache.
Effect of the calcium antagonist nicardipine hydrochloride on glucose tolerance and insulin secretion, The calcium antagonist nicardipine was administered to 42 patients at a dose of 60 or 120 mg/day for an average of 7.8 weeks to determine its effects on glucose tolerance and insulin secretion. Glucose tolerance and immunoreactive insulin levels were essentially unchanged by nicardipine regardless of the preexisting level of glucose tolerance. Mean systolic and diastolic blood pressures decreased in all patients. Concentrations of triglycerides decreased and high-density lipoprotein cholesterol levels increased significantly (p less than 0.05) in association with nicardipine administration. Therefore it is concluded that. regardless of the preexisting level of glucose tolerance. nicardipine exerted hypotensive effects without significant adverse effects on glucose tolerance or insulin secretion.
Nutrition epidemiology: how do we know what they ate, It is generally believed but difficult to prove that diet plays a role in the risk of various diseases. This paper reviews strengths and deficiencies of select diet-assessment methods used in epidemiologic studies with particular reference to their use in the study of osteoporosis. Direct observation or weighed food records are useful primarily as validation for less intrusive methods. Complete food history by interview or food diary (by self report) is expensive and time consuming. A 24-h diet recall obtained by a trained dietitian can provide accurate. quantitative information on recent intake but does not represent usual intake. Food frequency questionnaires provide better estimates of usual diet but are less quantitative and subject to problems of recall and seasonality. No method is universally the best. Lack of an expected diet-disease association may reflect exposure misclassification. inadequate statistical power. or limited range of the nutrients studied. Given the differences in diet-assessment methods. studies of dietary calcium and osteoporotic fracture have had surprisingly similar results.
Can colon cancer incidence and death rates be reduced with calcium and vitamin D, It was proposed in 1980 that vitamin D and calcium could reduce the risk of colon cancer. This assertion was based on the decreasing gradient of mortality rates from north to south. suggesting a mechanism related to a favorable influence of ultraviolet-induced vitamin D metabolites on metabolism of calcium. A 19-y prospective study of 1954 Chicago men found that a dietary intake of greater than 3.75 micrograms vitamin D/d was associated with a 50% reduction in the incidence of colorectal cancer. whereas an intake of greater than or equal to 1200 mg Ca/d was associated with a 75% reduction. Clinical and laboratory studies further support these findings. A nested case-control study based on serum drawn from a cohort of 25.620 individuals reported that moderately elevated concentrations of 25-hydroxyvitamin D. in the range 65-100 nmol/L. were associated with large reductions (P less than 0.05) in the incidence of colorectal cancer.
Calcium and carcinogenesis of the mammary gland, Effects of dietary calcium on mammary carcinogenesis in rats were investigated because of evidence that calcium counteracts the promotion of colon cancer by dietary fat and because experimental diets for rats normally contain higher amounts of calcium and vitamin D than do human diets. Our earlier experiments indicated that yields of tumors induced in young. Sprague-Dawley rats by 7.12-dimethylbenz(a)-anthracene (DMBA) were higher when dietary calcium. phosphate. and vitamin D were decreased. Results of an experiment in which dietary amounts of calcium. phosphate. and vitamin D were varied independently suggested that phosphate and vitamin D have interactive effects with calcium. Another experiment in which dietary vitamin D alone was varied provided evidence that higher amounts inhibited tumorigenesis in the presence of low amounts of calcium and phosphate but the results with a high-calcium and -phosphate diet were inconclusive. The findings suggest that low amounts of dietary calcium and vitamin D and high amounts of phosphate increase susceptibility to DMBA-induced mammary neoplasia.
Calcium-regulating hormones in hypertension: vascular actions, The vascular and potentially hypertensive actions of the calcium-regulating hormones 1.25-dihydroxychole-calciferol [1.25(OH)2D3]. parathyroid hormone (PTH). and calcitonin and related factors such as parathyroid hypertensive factor (PHF) and calcitonin gene-related peptide (CGRP) are discussed. 1.25(OH)2D3 has inotropic and calciotropic actions on isolated vascular tissue whereas PTH is a vasodilator. PHF. which has been reported in plasma of humans with essential hypertension and spontaneously hypertensive rats. has both pressor and calciotropic actions. Calcitonin is without vascular effects and CGRP is a potent vasodilator. It is concluded that several of the hormones responsible for maintaining Ca2+ homeostasis modulate vascular Ca2+ metabolism and force generating capacity. These substances may be long-term modulators of vascular function and play a role in the determination of peripheral vascular resistance.
Dietary Ca2+ prevents NaCl-sensitive hypertension in spontaneously hypertensive rats via sympatholytic and renal effects, NaCl-sensitive spontaneously hypertensive rats (SHR-S) were used to test the hypotheses that dietary Ca2+ supplementation 1) prevents NaCl-sensitive hypertension via a sympatholytic mechanism. and 2) increases diuretic and natriuretic responses to acute volume loading. SHR-S and control WKY rats were begun on one of four diets at age 8 wk: control. high NaCl. high Ca2+. or high NaCl and high Ca2+. In SHR-S. dietary Ca2+ supplementation prevented the NaCl-induced increases in blood pressure and plasma norepinephrine concentrations. the reductions in anterior hypothalamic norepinephrine stores and turnover. and the secondary increases in alpha 2 adrenoceptor number. Thus. Ca2+ prevented NaCl-sensitive hypertension in SHR-S by increasing noradrenergic input to the anterior hypothalamus. High-NaCl-fed SHR-S had impaired diuretic and natriuretic responses to an isotonic volume load; Ca2+ enhanced the ability of these animals to adjust fluid volume rapidly via diuresis and natriuresis. This alteration in renal function may contribute to the hypotensive effect of a high Ca2+ diet in NaCl-sensitive hypertension.
Calcium absorption efficiency and calcium requirements in children and adolescents, Optimizing bone mass of young adults is important in the prevention of osteoporosis in later life. To achieve maximal peak bone mass. dietary calcium and its absorption need to be sufficient for skeletal growth and consolidation and for obligatory losses in urine. feces. and sweat. Direct measurements of skeletal accretion. obligatory losses. and of dietary calcium and absorption in children and adolescents have either not been done or are incomplete. From the measurements available and from extrapolated data in adults. it appears likely that many children and adolescents are not absorbing sufficient calcium in relation to their intake to achieve maximal bone mass.
Dermal, intestinal, and renal obligatory losses of calcium: relation to skeletal calcium loss, Calcium balance is the difference between dietary calcium intake on the one hand and dermal. fecal. and urinary losses on the other. Bone is lost throughout adult life by at least three different mechanisms. Whether all these processes are affected by dietary calcium is at present unknown. In case they are not. dietary calcium intake should balance an adjusted value estimated as obligatory skeletal calcium loss minus obligatory external (dermal + intestinal + urinary) calcium loss. Such a correction would reduce estimated calcium allowances. To solve this question it is important. however. to ascertain whether obligatory bone loss is affected by dietary intake of calcium. ie. Can a high dietary calcium or calcium supplementation influence bone metabolism and reduce bone loss at all ages?.
Calcium supplementation and bone loss: a review of controlled clinical trials, The responsiveness of postmenopausal women to supplementation with calcium appears to depend on their menopausal age. In women who are within the first 5 y of menopause. bone loss from the radius is attenuated but not arrested by added calcium. The maximal effect appears to occur with supplement dosages of approximately 1000 mg elemental Ca/d. In contrast. the spine is unresponsive to supplementation with calcium even at higher doses in early postmenopausal women. In late postmenopausal women. bone loss from the radius is attenuated by increased calcium intake. Loss from the spine can be retarded by increasing calcium intake to the current recommended dietary allowance in older women with low usual calcium diets. The effect of supplementation with higher doses of calcium in this segment of the population is unknown. Finally. the effect of added calcium on hip density of postmenopausal women is not yet established.
Localization of nuclear matrix proteins (NMPs) in multiple tissue types with NM-200.4 (an antibody strongly reactive with NMPs found in breast carcinoma), Nuclear matrix proteins (NMP) are nonhistone proteins found in the nucleus of many eukaryotic cells. Furthermore certain NMPs are reported to be cell-type specific and expressed differentially by malignant cells. To study the specificity of NM-200.4 (an antibody reactive to NMPs extracted from cultured breast carcinoma cells of the T-47D line). cancers and benign tissues from multiple body sites were surveyed. All 17 breast carcinomas showed strong reactivity to tumor cell nuclei. Also nuclei from one of two lung carcinomas. a papillary thyroid carcinoma. an ovarian fibroma. and a lymphoma were strongly reactive. One leiomyosarcoma and a dermoid cyst were negative. Although 1 benign breast with duct hyperplasia showed moderate reactivity. only 1 of 10 benign breast biopsies without hyperplasia showed reactivity. Three of 4 skin biopsies. 2 liver biopsies. 6 of 9 kidney biopsies. and 5 of 10 gastrointestinal mucosal biopsies showed reactivity in benign nuclei. It is concluded that. although breast carcinoma nuclei showed the most consistent reactivity for NM-200.4. both benign and malignant nuclei from other body sites also show reactivity.
Differential expression of markers for endothelial cells, pericytes, and basal lamina in the microvasculature of tumors and granulation tissue, The structure and function of the tumor microvasculature is of great interest for cancer biology. diagnosis. and therapy. The distribution of endothelial cells. pericytes. and basal lamina in tumors is not well documented. In this study. the authors investigated the distribution of markers for these different components in a series of malignant human tumors and in human granulation tissue. both situations with extensive angiogenesis. Their results show a striking heterogeneity in the expression of markers for pericytes and endothelial cells between different tumors. but also within a single tumor lesion. To be able to distinguish between these two adjacent cell types decisively. all marker studies were carried out both on the light and the electron microscopical level and compared with staining results in granulation tissue of cutaneous wounds in healthy volunteers and of decubitus lesions. In granulation tissue of decubitus lesions. well-defined zones with increasing levels of maturation can be delineated. It was found that antibodies recognizing von Willebrand factor often failed to stain the tumor capillaries. Of the pericyte markers. alpha-smooth muscle actin was only locally expressed by pericytes in the tumor vasculature. whereas the high-molecular-weight melanoma-associated antigen. a chondroitin sulfate proteoglycan. stained the microvasculature broadly. Staining of the basal lamina components collagen type IV and laminin was. within the tumor. not restricted to the microvasculature. From their findings the authors conclude that 1) for the visualization of the tumor vasculature. antibodies recognizing endothelial markers. especially monoclonal antibodies PAL-E and BMA 120. are preferable to those recognizing pericytes or basal lamina; 2) within the microvasculature of tumors and granulation tissue. a heterogeneity of expression of endothelial and pericyte markers is observed; 3) during the formation of granulation tissue. all three microvascular components can be demonstrated already in the histologically earliest stage. suggesting not only an involvement of endothelial cells but also of pericytes and basal lamina in the initial steps of angiogenesis in wound healing.
Proliferation of normal breast epithelial cells as shown by in vivo labeling with bromodeoxyuridine, The proliferative activity of normal acinar and ductal breast epithelial cells was studied by in vivo labeling with 5-bromodeoxyuridine (BrdUrd) in 26 cases with concurrent breast carcinoma. The BrdUrd-labeled cells were recognized in histologic sections of paraffin-embedded tissue. using an anti-BrdUrd antibody and an immunoperoxidase reaction. The percentage of BrdUrd-labeled cells showed great variability for both acinar (0% to 2.66%; mean. 0.70%; standard deviation [SD]. 0.80%) and ductal cells (0% to 1.99%; mean. 0.51%; SD. 0.57%). The fraction of proliferating epithelial cells declined with the age of the patients and was significantly higher in premenopausal women (1.16% +/- 0.85% for acinar and 0.94% +/- 0.60% for ductal cells) as compared with the postmenopausal women (0.27% +/- 0.46% for acinar and 0.17% +/- 0.22% for ductal cells). P less than 0.01 for acinar and P less than 0.001 for ductal cells. respectively. In some patients. great variability in distribution of proliferating acinar and ductal cells among different lobules and ducts was observed. No difference was found in the number of proliferating acinar and ductal cells situated near or far from their corresponding tumors. No correlation was seen between cell proliferation of normal acinar or ductal cells and cell proliferation of the respective tumors.
Cytokeratin expression and vimentin content in large cell anaplastic lymphomas and other non-Hodgkin's lymphomas, The immunophenotypes of 74 malignant lymphomas (9 Hodgkin's disease. 19 low-grade B-cell. 20 high-grade B-cell. 8 T-cell. and 18 large cell anaplastic lymphomas [LCAL]) have been characterized with antibodies against leucocyte differentiation antigens. keratin. and vimentin. All the non-LCAL were CD45 positive and keratin negative. The LCALs had a more varied immunophenotype. with CD45 present only in 11 of 18 cases and keratin present in 5 of 18 of these rare lymphomas. The lymphoid origin of these latter cases was proven by gene rearrangement studies. All LCALs were CD30+. and. where tested. vimentin positive. Of four different vimentin monoclonal antibodies tested. V9 and MVI stained the highest number of lymphomas. Positive staining of tumor cells was seen in 61 of 71 cases. Vimentin-negative cases included Burkitt's as well as some follicular lymphomas.
Alterations in proteoglycan synthesis common to healing wounds and tumors, Wound healing and tumor stroma generation share several important properties. including hyperpermeable blood vessels. extravasation of fibrinogen. and extravascular clotting. In both. the deposits of fibrin gel serve initially as provisional stroma and later are replaced by granulation tissue. Proteoglycans (PG) are also important constituents of the extracellular matrix. but their composition and role in healing wounds and tumor stroma generation are poorly understood. The authors used immunohistochemical and biochemical methods to investigate the dermatan sulfate proteoglycan (DSPG) and chondroitin sulfate proteoglycan (CSPG) composition of healing skin wounds and solid tumors. By immunohistochemistry. the great majority of normal guinea pig and human dermis stained weakly for CSPG and strongly for decorin. In contrast. the granulation tissue of healing skin wounds and scars stained intensely for CSPG and weakly or not at all for decorin; however decorin staining was restored to normal intensity after digestion with chondroitin ABC lyase. suggesting that decorin antigenic sites had been masked by glycosaminoglycan (GAG) chains. Like wounds. the stroma of several carcinomas (line 1 guinea pig. human breast. colon. basal cell. and squamous) stained strongly for CSPG and weakly or not at all for decorin. but decorin staining developed after chondroitin ABC lyase digestion. Thus healing wounds and tumor stroma express a common pattern of altered PG staining. adding another to the properties these pathologic entities share. Proteoglycans extracted from healing wounds after in situ labelling with [35S] Na sulfate contained more CSPG than normal dermis with significantly longer GAG chains. Granulation tissue also synthesized more DSPG than normal skin. with greater heterogeneity and longer GAG chains. These alterations in PG synthesis correlate with the cell proliferation. migration. and collagen synthesis that accompany wound healing and may provide clues to the mechanisms responsible for both wound healing and tumor stroma generation.
Growth fraction estimation of malignant lymphomas in formalin-fixed paraffin-embedded tissue using anti-PCNA/Cyclin 19A2. Correlation with Ki-67 labeling, The immunohistochemical detection of PCNA/Cyclin. a nuclear protein associated with cell proliferation. represents a potentially useful tool for the study of tumor proliferative activity. Previous studies investigating the reactivity of anti-PCNA/Cyclin monoclonal antibody 19A2 have not clearly defined the population of proliferating cells with which 19A2 reacts in tissue sections. The authors describe a method for detection of PCNA/Cyclin in formalin-fixed. paraffin-embedded tissue using a routine biotin-streptavidin immunohistochemical system that employs an anti-IgM. mu-chain-specific second-stage antibody. The authors used this method to study the proliferative activity of 24 malignant lymphomas. consisting of 12 low-grade lymphomas (LGLs) and 12 intermediate-grade lymphomas (IGLs). and five reactive tonsils. 19A2 data was compared with Ki-67 labeling in frozen sections in the same group of cases. 19A2 provided easily detectable nuclear staining of proliferating cells with reactive cells demonstrating varying intensity of staining. this latter finding most likely due to the varying nuclear concentration of PCNA/Cyclin protein during the cell cycle. In tonsils. 19A2 reacted with germinal center cells and basal keratinocytes. In the malignant lymphomas. there was good correlation between 19A2 and Ki-67 data (r = 0.90. P less than 0.001). The subgroup of LGLs showed a mean PCNA/Cyclin of 26% and a mean Ki-67 of 28%. In the subgroup of IGLs. mean PCNA/Cyclin = 54% and mean Ki-67 = 59%. These results indicate that 19A2 detects a fraction of proliferating cells that is similar to that detected by Ki-67. ie. the growth fraction. and that 19A2 is a reliable marker of proliferative activity in uniformly handled. formalin-fixed. paraffin-embedded tissue.
The intratracheal administration of endotoxin and cytokines. I. Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS-, IL-1-, and TNF-induced inflammatory infiltrate, Endotoxin (LPS). one of the major proinflammatory constituents of the cell walls of gram-negative bacteria. induces alveolar macrophages to express interleukin-1 (IL-1) and tumor necrosis factor (TNF) messenger RNA (mRNA). peaking at 1 hour in vitro. Intratracheal injection of LPS induces IL-1 and TNF mRNA expression in vivo in whole-lung RNA preparations. Interleukin-1 mRNA is not constitutively detected. In the case of TNF. however. a constitutively-expressed hybridization band is noted at 1.6 kb. whereas the LPS-induced hybridization band is noted at approximately 1.95 kb. Intratracheal injection of LPS induces an intra-alveolar inflammatory reaction composed of a neutrophilic exudate. peaking at 6 to 12 hours. a monocytic exudate peaking at 24 hours. and a lymphocytic exudate peaking at 48 hours. as quantitated by bronchoalveolar lavage. Intratracheal injection of IL-1 recapitulates the kinetics and relative magnitudes of the acute neutrophilic and chronic monocytic and lymphocytic inflammatory sequence. Intratracheal injection of TNF also induces an acute intraalveolar neutrophilic exudate. but TNF is much less potent of an inflammatory stimulus than IL-1. The effects of recombinant IL-1 and TNF are not due to LPS contamination. as shown by abrogation of the cytokines' inflammatory activity by boiling. In conclusion. LPS induces IL-1 and TNF mRNA expression in vitro in alveolar macrophages and in vivo in pulmonary tissue. and intratracheal injection of IL-1 and TNF recapitulates the LPS-induced pulmonary inflammatory sequence. strongly supporting the hypothesis that these cytokines play an important in vivo role in the pathogenesis of gram-negative bacterial pneumonia.
Dilated rough endoplasmic reticulum and premature death in melanocytes cultured from the vitiligo mouse, It has been proposed that the selective melanocyte destruction in hair bulbs of the murine model for vitiligo (VIT) is instigated by either the local cutaneous environment or an innate melanocyte defect. To address this problem. the authors have isolated the melanocyte population from environmental influences by using cell culture technology and have observed reduced proliferation. specific cytologic abnormalities. and premature cell death in cultures of pure VIT melanocytes established from neonatal skin. Cultured VIT melanocytes manifest abnormal compartmentalization of melanosomes and some aberrant dihydroxyphenylalanine-positive structures. The most prominent abnormality observed in cultured VIT melanocytes when compared with the control C57BL/6J cells is a development in dilation of the rough endoplasmic reticulum (RER) that morphologically resembles the in vivo condition. Dilation of the RER can be exaggerated in VIT or induced in C57BL/6J melanocytes by the addition of Brefeldin A to cultures. Conversely the dilated RER cisternae characteristic of the VIT melanocyte can be reversed by inhibition of protein synthesis with cyclobeximide. Melanocyte cultures developed from heterozygote neonates. resulting from cross-breedings between the VIT and the C57BL/6J lines. also demonstrated extensive RER dilation along with only slightly reduced proliferation. The results in this report verify that the murine vitiligo melanocyte expresses an innate defect that affects the structure and presumably the function of the rough endoplasmic reticulum.
Expression of neu protein, epidermal growth factor receptor, and transforming growth factor alpha in breast cancer. Correlation with clinicopathologic parameters, The major objectives of this study were twofold: to determine 1) if growth factors or growth factor receptors were expressed similarly or differently in a clinically well-characterized group of breast cancer patients and 2) if these phenotypic characteristics were associated with any of the commonly used prognostic parameters. Formalin-fixed paraffin-embedded tumor tissue from 51 node-positive breast cancer patients were analyzed for the expression of neu. epidermal growth factor-receptor (EGF-R). and transforming growth factor alpha (TGF alpha) using immunoperoxidase staining. Positive membranous staining for neu was observed in 15 (29%) tumors. Over-expression of neu was observed in high-grade. estrogen-receptor-negative tumors (P less than 0.05). Epidermal growth factor receptor was expressed in 22 (43%) of the tumors analyzed and found to a greater degree in estrogen-receptor-negative and high-grade tumors (P less than 0.025). A significant correlation between neu and EGF-R expression was also noted. Tumors expressing membranous staining of neu had a greater than 70% chance of expressing EGF-R (P less than 0.01). Expression of TGF alpha was found in 68% of tumors and TGF alpha was detected in grade 1 and 2 tumor to a greater degree than EGF-R. The authors conclude that assaying tumors for these antigens may give additional phenotypic characteristics that can give further insight into the biology of breast cancer.
Endothelial cell damage by Walker carcinosarcoma cells is dependent on vitronectin receptor-mediated tumor cell adhesion, The transport of cancer cells from blood vessels to extravascular tissue is a critical step in metastasis. where endothelial cells and the vascular basement membrane act as barriers to cell traffic. Because endothelial injury can facilitate the metastasis of intravascular cancer cells in vivo. the authors have studied in vitro the free-radical-mediated endothelial damage caused by the rat Walker 256 carcinosarcoma (W256) cell after stimulation with 10(-6) mol/l (molar) phorbol ester. Here the authors have examined the hypothesis that W256 cell-mediated endothelial injury is dependent on adhesion between the effector and target cells. Attachment of phorbol 12-myristate. 13-acetate (PMA)-stimulated W256 cells to endothelial monolayers was increased 1.8 +/- 0.1-fold and damage (3H-2-deoxyglucose release from labeled endothelium) 1.4 +/- 0.1-fold after 4-hour pretreatment of the endothelium with 10 ng/ml recombinant human interleukin-1 alpha (rIL-1 alpha). Under various assay conditions. the release of 3H-2-deoxyglucose correlated directly with tumor cell adhesion (r = 0.98. P less than 0.005). In the presence of a polyclonal anti-vitronectin receptor antiserum. adhesion of stimulated W256 cells to rIL-1 alpha-treated monolayers was inhibited by 39% +/- 2%. and 3H-2-deoxyglucose release was inhibited by 53% +/- 13%. Immunoblot analysis and immunofluorescence flow cytometry demonstrated that the endothelial cells but not the W256 cells expressed vitronectin receptor (VnR) on their cell surface. The surface expression of VnR by endothelial cells was increased 1.9 +/- 0.1-fold after 4 hours' incubation with rIL-1 alpha. The authors conclude that W256 cell-mediated endothelial damage is dependent on cell adhesion. which. in turn. is partly regulated by the expression of VnR on the endothelial cell surface.
Declining frequency of neuroleptic malignant syndrome in a hospital population, OBJECTIVE: The authors investigated trends in the frequency of neuroleptic malignant syndrome at their center over a period of 8 years and assessed possible reasons for these trends. METHOD: They used previously defined operational criteria in conducting a prospective survey of cases of the syndrome among 2.695 neuroleptic-treated patients from Oct. 1. 1986. to Aug. 31. 1990. The frequency of neuroleptic malignant syndrome during this period was then compared with the frequency in a comparable period prior to October 1986. The investigators also assessed changes between the two periods in risk factors associated with the syndrome. including patients' mean age. sex ratio. diagnoses. and severity of illness; neuroleptic dosage. potency. and route of administration; concomitant use of lithium; and degree of agitation. RESULTS: Four cases of neuroleptic malignant syndrome were diagnosed during the more recent 47-month survey period. yielding a frequency of 0.15% +/- 0.05%. This represents a significant decline in the frequency of the syndrome from the estimate of 1.10% +/- 0.40% for the earlier survey period. Significantly fewer patients in the recent period had received intramuscular doses of neuroleptics. CONCLUSIONS: The frequency of neuroleptic malignant syndrome has declined significantly at this center. The decline appears to be attributable to increasing clinical awareness of the features of the syndrome. allowing early intervention and treatment. and to a reduction in risk factors. such as use of intramuscular neuroleptics.
Have general hospitals become chronic care institutions for the mentally ill, OBJECTIVE: Dramatic increases in lengths of stay for general hospital psychiatric patients in New York City in recent years have raised speculation that general hospitals are assuming a large responsibility for care of the chronically mentally ill. This study examines changes in utilization patterns and patient characteristics to assess whether such a trend is occurring. METHOD: The authors obtained discharge abstract data for all New York City general hospital adult psychiatric patients in 1985 and 1988 as well as utilization data from the public general hospital system for 1977-1989. Three measures of chronicity were chosen: hospital stays longer than 60 days. discharges to long-term care. and three or more admissions per year. Data on psychiatric diagnoses and comorbid diagnoses for chronically ill patients were also reviewed. RESULTS: The mean length of stay of psychiatric patients in general hospitals has increased substantially in recent years and nearly tripled in the public hospitals during 1977-1989. Between 1985 and 1988. citywide increases were due largely to a growing proportion of patients with very long stays. Patients with stays longer than 60 days accounted for 35% of all inpatient days in 1988. compared with 27% in 1985. Patients with chronic illness accounted for half of all days in 1988. compared with 38% in 1985. CONCLUSIONS: Although many factors have contributed to these trends. the leading cause has been reimbursement policies favoring short-term inpatient care. Improving accountability for community treatment programs will be the key to redirecting funding priorities and creating more appropriate alternatives for the chronically mentally ill.
Relationships between requests for psychiatric consultations and psychiatric diagnoses in long-term-care facilities, OBJECTIVE: The authors' objective was to investigate reasons for referral of elderly nursing home residents for psychiatric consultation and the relationship of these reasons for referral to psychiatric diagnoses. METHOD: They examined 197 nursing home residents consecutively referred to a consulting team in a university-affiliated mental health center. These patients represented all patients evaluated by the consulting team at six nursing homes over a 2-year period (Sept. 1. 1984. through Aug. 30. 1986). RESULTS: Reasons for referral were diverse but fell into seven broad clusters: behavioral problems; mood-related problems; consultations requested by involuntary treatment services. patients. physicians. or other referring agencies; psychotic features; physical signs; impaired activities of daily living; and other. Behavioral problems were most commonly cited and tended to be associated with dementia diagnoses. Mood-related reasons for referral were most strongly associated with diagnoses of affective disorders. and diagnoses of schizophrenia and adjustment disorder were each associated with two or more reasons for referral. However. reasons for referral were distributed widely across diagnostic groups and were relatively weak predictors of diagnoses. CONCLUSIONS: The results illustrate the variety of problems for which nursing home staff are willing to seek psychiatric consultation but emphasize the need for professional psychiatric evaluation to establish a diagnostic base on which treatment interventions can be built.
Technique for greatly shortening the transition from methadone to naltrexone maintenance of patients addicted to opiates, Acute methadone detoxification was induced by the intravenous administration of naloxone during simultaneous intravenous sedation with midazolam. a fully reversible short-acting benzodiazepine. in seven patients addicted to opiates. Within hours the patients tolerated full doses of naltrexone. This technique enables patients to transfer easily. quickly. and safely from methadone to naltrexone maintenance.
Quantitative electroencephalography: a report on the present state of computerized EEG techniques. American Psychiatric Association Task Force on Quantitative Electrophysiological Assessment, The American Psychiatric Association established the Task Force on Quantitative Electrophysiological Assessment in May 1989 to consider several questions of interest to psychiatrists. From the inception of techniques for quantitative electroencephalography (qEEG). the possibility was raised that it would substantially assist in the diagnosis of brain disorders. However. controversy exists over the scientific basis for such approaches and the training necessary for interpretation of computerized records. The task force's charge was to report 1) the present state of scientific knowledge about qEEG. 2) the role of qEEG in clinical psychiatric practice at the present time. 3) the training necessary for the use of qEEG techniques. and 4) the possible future of the technique in the study of mental disorders. The task force concluded that qEEG is particularly useful for the detection of abnormalities in slow waves. which are a feature of delirium. dementia. intoxication. and other syndromes involving gross CNS dysfunction. The ability of qEEG to help in the diagnosis of other disorders. such as schizophrenia or depression. is not yet established. Clinical replications and sharing of normative and patient data bases are necessary for the advancement of this field. Proper use of this technique requires extensive training in a center experienced in its use. Standards for training and for using the technology in psychiatry are urgently needed. This report was approved by the Board of Trustees in December 1990.
Tobacco industry scientific advisors: serving society or selling cigarettes, According to industry documents. the tobacco industry has executed a "brilliantly conceived" strategy to "creat[e] doubt" in the public's mind about whether cigarette smoking is in fact a serious cause of disease. A component of this strategy has been the funding of scientific research "into the gaps in knowledge in the smoking controversy." Grant review and selection are performed by a group of independent scientists. Knowledgeable observers believe that the existence of this research funding program in general. and the Scientific Advisory Board in particular. is intended by the industry to reinforce doubts in the public mind about the severity of the hazards posed by smoking. Because the Advisory Board has never taken a public stance against the industry's position that the causal relationship between smoking and disease remains unproven. I polled these scientists to determine whether they believed that smoking is a cause of lung cancer. Despite repeated opportunities. only four of 13 board members responded. all affirmatively; two others have expressed their judgment that smoking causes lung cancer in their professional publications. Thus. over half of the Board members. and the Board as a whole. have not gone on record as rejecting the industry's "party line." It might be hoped that the American scientists would follow the lead of the members of a similar body of scientists in Australia who have taken a strong and public stand against the industry position that smoking is not an established cause of disease.
A prospective study of hospitalization with gallstone disease among women: role of dietary factors, fasting period, and dieting, BACKGROUND: Dietary risk factors for the development of gallstones have not been clearly established. We analyzed data from a population-based prospective study to determine dietary risk factors for hospitalization with gallstone disease. METHODS: We evaluated the role of dietary constituents. fasting. and dieting on subsequent hospitalization with gallstone disease among 4.730 women. ages 25 to 74 years. who participated in the first follow-up of the first National Health and Nutrition Examination Survey. Baseline dietary variables were established through a 24-hour dietary recall and a medical history. Proportional hazards models were used to calculate the effects of dietary variables while controlling for baseline risk factors. RESULTS: After an average of 10 years follow-up. gallstone disease was confirmed by hospital records among 216 women who denied gallstone disease at the baseline examination. The hazard rate of hospitalization with gallstone disease increased with increasing overnight fasting period and with dieting. Intake of fiber showed a small protective effect. The effect of energy intake was significant only among women younger than age 50 years at baseline. Results were not affected by adjustment for known risk factors for gallstone disease or other dietary factors. CONCLUSION: A long overnight fasting period. dieting. and low fiber intake may increase the risk of hospitalization with gallstone disease.
Cervical cancer screening: who is not screened and why, BACKGROUND: The decline in death rates from cervical cancer in the United States has been widely attributed to the use of Papanicolaou (Pap) smears for early detection of cervical cancer. METHODS: Pap smear screening rates. beliefs about appropriate screening intervals and factors affecting screening were examined using 1987 National Health Interview Survey data. RESULTS: Results indicate that through age 69. Blacks are screened at similar or higher rates than Whites. Hispanics. particularly those speaking only or mostly Spanish. are least likely to have received a Pap smear within the last three years. Of women who had never heard of or never had a Pap smear. nearly 80 percent reported contact with a medical practitioner in the past two years. while more than 90 percent reported a contact in the past five years. Overall. the most frequently reported reason for not having a recent Pap smear was procrastinating or not believing it was necessary. CONCLUSIONS: Thus. in developing screening programs. Hispanics. particularly Spanish speakers. must be targeted. In addition. educational programs should target unscreened women who forego the test due to underestimating its importance. procrastination. or because their medical care provider did not suggest the procedure. Women must be intensively educated that Pap smears should be scheduled routinely to detect asymptomatic cervical cancer.
Does cigarette smoking have an independent effect on coronary heart disease incidence in the elderly, In order to evaluate the effects of cigarette smoking on coronary heart disease (CHD) in elderly persons in the Honolulu Heart Program. 1.394 men between ages 65 and 74 were followed during an average 12-year period for new cases of nonfatal myocardial infarction and fatal CHD. Incidence rates increased progressively in individuals classified at baseline as never. former. and current smokers. respectively. The absolute excess risk associated with cigarette smoking was nearly twice as high in elderly compared with middle-aged men.
Television viewing and obesity in adult females, We measured the relation between time spent watching television per week and obesity in 4.771 adult females. After controlling for age. education. cigarette smoking. length of work week. and weekly duration of exercise. females who reported three to four hours of TV viewing per day showed almost twice the prevalence of obesity (body fat greater than 30 percent). and those who reported more than four hours of TV watching per day showed more than double the prevalence of obesity. compared to the reference group (less than 1 hr/day). Part of the TV/obesity association was a function of differences in exercise duration among the four TV viewing categories.
Characteristics of a random sample of emergency food program users in New York: I. Food pantries, Food pantry users throughout New York State were studied and many demographic differences found between New York City and Upstate New York respondents. Seven percent of households had no income and median income as percent of the poverty level was 59 percent. Slightly more than 40 percent were spending over 60 percent of their incomes on housing. The data from this survey. the first in New York State to employ a random sampling design. demonstrate a sizable gap between household needs and available resources.
The use of direct mail to increase clinician knowledge: an intervention study, A probability sample of American general practitioner dentists. 40 years of age or older. in solo private practice. was the target of two direct mail interventions offered at two different times. to test whether knowledge regarding prophylaxis of patients at risk for infective endocarditis could be improved. Tests of knowledge were responses in a mail questionnaire to clinical vignettes. designed to elicit the content of antibiotic regimens used for patients at risk. The research design enabled detection of (1) the effect of the interventions; (2) the differences in their effect; (3) the attenuation of their effect; and (4) the effect of time. Where baseline knowledge was low. it was improved and did not rapidly disappear. Both mail interventions were equally effective. in most instances. and there was no attenuation of the interventions' effect and no effect of time on the control groups' knowledge over a 4 1/2 month period. The results suggest that it is possible to improve clinicians' knowledge of expert recommendations through direct mail intervention.
Serum amylase determination and blunt abdominal trauma, To determine the value of serum amylase sampling as an indicator of intra-abdominal injury. the records of 940 consecutive victims of blunt trauma were retrospectively reviewed. The sensitivity. specificity. and predictive value were poor in the determination of intra-abdominal injury. whether accompanied by craniofacial injury or not. It was concluded that routine serum amylase determination is of no value in the clinical management of the patient suffering blunt injury.
Intraoperative use of a 2-mm choledochoscope for the exploration of small bile ducts and the pancreatic duct, Intraoperative visualization of the biliary and pancreatic ducts can be difficult in a nondilated system. Very small extra- and intrahepatic bile ducts occasionally require visualization but do not admit the traditional 6.5-mm intraoperative flexible choledochoscope. We have prospectively examined the use of a 2-mm choledochoscope for the intraoperative evaluation of the biliary and pancreatic ducts in 36 patients. In 27 patients. the choledochoscope was advanced through the cystic duct stump for examination of the common bile duct following cholangiography. The scope was successfully passed into the cystic duct stump and into the common bile duct in 76 per cent of patients. Inability to pass the scope through the cystic duct was usually due to acute angulation of the cystic duct/common duct junction. In an additional five patients. intraoperative cholangiography revealed a filling defect in a very small duct. A choledochotomy was made and the 2-mm choledochoscope was used to exclude the presence of stones in a small bile duct. In four patients the choledochoscope was used during a Puestow procedure to visualize and help extract stones in the tail and head of the gland. No complications occurred in these patients due to the use of the choledochoscope. We conclude that the 2-mm choledochoscope aids in internal visualization of small intra- and extrahepatic bile ducts and the pancreatic duct. It may be useful as an adjunct to cholangiography in determining the nature of filling defects.
Decision for surgical management of perforation following endoscopic sphincterotomy, Duodenal perforation resulting from endoscopic sphincterotomy (ES) is a serious complication with a high mortality. Diagnosis is often problematic and the optimum treatment is controversial. Eight proven perforations occurred following 441 ES at University of Colorado Hospital. a rate of 1.8 per cent. Physical and laboratory findings were of little diagnostic value. whereas plain abdominal radiographs showed evidence of perforation in 86 per cent. All patients were operated on promptly after diagnosis of perforation. Delay in diagnosis of perforation beyond 24 hours in six patients was associated with a high morbidity and two deaths. Analysis of published series confirmed that delay in diagnosis and delay in operation after perforation were associated with a higher mortality rate than early diagnosis with or without operation. We recommend operative intervention in all patients with clinical evidence of perforation following ES.
The impact of colonoscopy on colorectal carcinoma, In an eight-year. ongoing study of 120 patients. 39 with carcinomas and 81 with adenomas. no patient has produced a new carcinoma despite a high incidence of metachronous adenomas. Colonoscopy can identify early carcinomas that can be resected for cure. In addition. colonoscopy can identify the adenomatous polyps and with polypectectomy prevent the progression to carcinoma. Colonoscopy is more accurate than air contrast barium enema. provides a tissue diagnosis. and allows polypectomy. When applied according to risk factors known to be cost effective. colonoscopy leads to earlier diagnosis and thus improved long-term survival.
Hypoxaemia after nebulised salbutamol in wheezy infants: the importance of aerosol acidity, The effect of nebulised iso-osmolar. preservative free. but acidic salbutamol solution was studied in 34 acutely wheezing infants aged 1-17 months. Transcutaneous oxygen pressure (TcPO2) and oxygen saturation (SO2) fell significantly during the first five minutes after nebulisation with further deterioration at 15-20 minutes. Ten of these infants were followed up for another two hours and showed slight improvement. Even after the second hour TcPO2 had not reached baseline values. Three months later the response to salbutamol and a placebo of equal acidity (pH 3.9) was studied in 11 infants from the same group. now free of symptoms. Lung function tests were included and showed no significant changes in specific conductance and volume corrected maximum expiratory flows (Vmax at functional residual capacity/thoracic gas volume). However. hypoxaemia occurred after the acidic placebo with a significant drop of TcPO2 (mean 0.9 kPa); SO2 decreased similarly but this did not reach significance. After salbutamol there was a further significant deterioration of mean TcPO2 (1.4 kPa) and of SO2. These results show that beside a possible pharmacological effect of salbutamol the acidity of the aerosol also induces hypoxaemia in infants.
Home monitoring of transcutaneous oxygen tension in the early detection of hypoxaemia in infants and young children, Twenty three patients (age range 0.5-40 months) with recurrent cyanotic episodes underwent physiological recordings. including transcutaneous oxygen tension (TcPO2) from a monitor modified for use at home (Kontron 821S). Of 69 episodes in which the arterial oxygen saturation (SaO2. Nellcor N200) was less than or equal to 80% for greater than or equal to 20 seconds and/or central cyanosis was present. the TcPO2 monitor alarmed (less than or equal to 20 mmHg or 2.67 kPa) in every episode. The pulse oximeter identified hypoxaemia in 62 out of 69 episodes. failing in seven episodes due to signal loss from movement artefact. In only seven of 69 episodes was there an accompanying apnoeic pause (greater than or equal to 20 seconds). and heart rate fell to less than or equal to 80 beats/minute in only five of 28 episodes in which an electrocardiogram was recorded. In 32 episodes in which SaO2 fell to less than or equal to 60%. the TcPO2 monitor alarmed after a median time interval of 16 seconds (maximum time interval 30 seconds). The TcPO2 monitor was then used in an uncontrolled trial at home in 350 patients at increased risk of sudden death and/or hypoxaemia. Indications for monitoring included apparent life threatening events or cyanotic episodes (n = 163). prematurity and prematurity related disorders (n = 86). and sudden unexpected death in one or more siblings (n = 122). The TcPO2 monitor detected cyanotic episodes at home in 81 patients. 52 of whom received vigorous stimulation and/or mouth to mouth resuscitation. Twenty one of these 52 patients had further hypoxaemic episodes documented in hospital with pulse oximetry.
Imaging in influenza A encephalitis, Two cases of influenza A encephalitis seen during an outbreak of influenza types A/England/427/88 (H3N2) and A/Taiwan/1/86 (H1N1) in December 1989 are described. In both children the encephalitis developed within three days of the respiratory symptoms and both became comatose within 48 hours. Virological studies showed that the patients had had a recent influenza A infection. Symmetrical localised hypodense lesions within the thalami and pons were demonstrated in both cases on computed tomography of the brain and striking findings in the pons in one case on magnetic resonance imaging. Influenza A encephalitis is not easy to recognise clinically and serological confirmation can only be made after 10 days. Imaging may provide evidence in the acute stage to support a diagnosis of influenza encephalitis during influenza outbreaks.
Occurrence, clinical manifestations, and prognosis of Guillain-Barre syndrome, In order to obtain more information on the incidence of Guillain-Barre syndrome and recent developments in its prognosis. we analysed the severity and prognosis of Guillain-Barre syndrome in children diagnosed and treated during the years 1980-6 throughout Finland. The criteria for Guillain-Barre syndrome were fulfilled in 14 boys and 13 girls. The mean annual number of cases of Guillain-Barre syndrome was thus 3.9. giving a mean annual incidence of 0.38/100.000 of population under 15 years of age (95% confidence intervals 0.25 to 0.56/100.000). The incidence of Guillain-Barre syndrome causing permanent neurological defects in children under 15 years of age was 1.4/10 million annually (95% confidence intervals 0.035 to 7.8/10 million). Our figures appeared to be one fourth to a half of that reported earlier in children and even lower than those in adults. Although there were no deaths among our patients. mortality from Guillain-Barre syndrome seems to have remained similar for the last 20 years despite current awareness of the possibility of cardiac arrest and respiratory failure.
Perinatal hepatitis B virus infection caused by antihepatitis Be positive maternal mononuclear cells, To investigate the infectivity of hepatitis B virus (HBV) from mothers to their newborn offspring. HBV-DNA in plasma and peripheral mononuclear cells from 28 antihepatitis Be positive. hepatitis B surface antigen positive carrier mothers was examined by a highly sensitive polymerase chain reaction/Southern hybridisation technique. HBV specific DNA was detected in three maternal mononuclear cell samples. but was absent in plasma. Two of four infants born to the three mothers with HBV-DNA positive mononuclear cells developed acute or fulminant hepatitis within three months after birth. Two infants were effectively prevented from infection with HBV by combined hepatitis B immunoglobulin/HBV vaccine administration. The 25 infants born to the HBV-DNA negative mothers were free of HBV infection within the next seven months to 3.5 years. These results suggest that latent infection with HBV in maternal mononuclear cells is responsible for perinatal HBV infection.
Cold agglutinins in haemophiliac boys infected with HIV, Eleven haemophiliac boys infected with HIV were screened for irregular red cell antibodies and were compared with nine haemophiliac boys who did not have antibodies to HIV. Seven (64%) of the children who had antibodies to HIV also had cold agglutinins. mostly of anti-I specificity. compared with one (11%) of those who did not have antibodies to HIV. The children with antibodies to HIV and cold agglutinins had a significantly increased mean IgM concentration. The presence of cold agglutinins was not correlated with T4 lymphocyte count. symptoms of HIV infection. serum beta 2 microglobulin concentrations. concentrations of IgG or IgA. or with the evidence of past infection with cytomegalovirus or Epstein-Barr virus.
Treatment of rheumatoid arthritis by extracorporeal photochemotherapy. A pilot study, In a 6-month pilot study of 7 patients with rheumatoid arthritis. we tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links lymphocyte DNA; the injured cells are reinfused into the patient. Prior experimental studies had indicated that this regimen produces an immune reaction against antigens on treated T cells. and a clinical trial in patients with cutaneous T cell lymphoma had been successful. The current study patients were treated monthly. on 2 successive days (or biweekly. later on). Between 12 and 16 weeks of therapy. there appeared to be a breakpoint. after which the joint counts and joint scores of 4 of the patients began to improve. In 3 of the 4 patients. these measures eventually diminished by a mean of 71% and 80% of baseline values. respectively. and there was variable improvement in less direct indicators of clinical response. The joint counts and scores of the fourth patient improved modestly (by 33% and 59% of baselines. respectively) but he required alternative therapy. and those of the remaining 3 study patients did not improve. Mean slopes for the joint counts were significantly different from zero after the apparent breakpoint (but not before). whether one examined the 4 apparent responders (P = 0.01) or the entire group of 7 patients (P = 0.01). After completion of therapy. there was also a delay. of 2-3 months. in the clinical deterioration of those patients who had improved. There was only 1 mechanical adverse effect--a single episode of transient hypotension in 102 treatment sessions--and no toxic effects.
The progression of erosion and joint space narrowing scores in rheumatoid arthritis during the first twenty-five years of disease, Erosions and cartilage destruction are nearly universal features in peripheral joints that have been chronically affected by rheumatoid arthritis. Scoring methods to measure the extent of these abnormalities in hands and wrists have been developed and have been thoroughly tested in several studies to establish their reproducibility. In this study. we utilized one of these scoring methods to examine the progression of radiologic damage as related to duration of disease. Two hundred ninety-two patients from 3 different participating centers in the Arthritis. Rheumatism. and Aging Medical Information System were included. Six hundred fifty films of the hands and wrists. obtained from 210 patients. were scored for erosions and joint space narrowing. The average annual rate of progression of the total radiologic score. which sums erosion and joint space abnormalities and has a maximum possible score of 314. was approximately 4 units per year over the first 25 years after onset; this progression was more rapid in the earlier years of disease and slightly slower in the later years. Data were insufficient to accurately determine the progression rate in disease of more than 25 years duration.
The impact of rheumatoid arthritis on the household work performance of women, We conducted a study to assess whether and to what degree household work disability exists in women with rheumatoid arthritis (RA) and to examine the role of health versus family and personal factors as predictors of household work disability. In addition. the participation of other family members and paid employees in household work was evaluated. One hundred forty-two women with RA and 58 female friends/neighbors completed questionnaires which assessed household work performance and health. family. and personal variables. Performance was measured in 4 ways: the current amount of time spent on household work. the proportion of the household work done. and the changes in time and proportion since just before the onset of RA. Functional status was measured via the Health Assessment Questionnaire. Pain. anxiety and depression. and general health perception were measured via the Arthritis Impact Measurement Scales. The results indicate that household work disability exists in women with RA. but is substantial only in women with moderate-to-severe disease. In families in which the wife/mother has moderate-to-severe RA. the other family members spend 7 hours more per week on household work than in control families. but there was no increase in the use of paid household employees. Health factors were the strongest predictors of household work disability. but family and personal factors also had significant effects. Household work disability in women with moderate or severe RA merits more attention because of the importance of household work to family functioning and the negative effects that changes in this area can produce.
Identification and characterization of opsonic fibronectin in synovial fluids of patients with active rheumatoid arthritis, A cofactor that selectively opsonizes particulate activators of the human alternative complement pathway and enhances their phagocytosis by human monocytes was identified in synovial fluids of patients with rheumatoid arthritis. The active material was present in fluids treated with protease inhibitors. was heat stable. and was unaffected by incubation with hyaluronidase. Chromatographic isolation of synovial fluid fibronectin by gelatin affinity and by immunoaffinity on antifibronectin monoclonal antibody BD4 yielded similar quantities of protein for each of 3 fluids. Synovial fluid proteins with the BD4 fibronectin epitope accounted for essentially all of the phagocytosis-enhancing activity and expressed this activity by opsonizing target activators. Additional chromatographic analyses of synovial fluid fibronectin with the BD4 epitope were carried out using Sepharose-bearing gelatin and 4 additional antifibronectin monoclonal antibodies. The opsonic materials were characterized as having 2 distinct fibronectin epitopes. which always mapped from the cell adhesive domain to the carboxyl-terminus of plasma fibronectin. but only rarely contained the gelatin binding domain.
PBC 95k, a 95-kilodalton nuclear autoantigen in primary biliary cirrhosis, We have identified a novel antinuclear antibody (ANA) in the sera of patients with primary biliary cirrhosis (PBC). Sera from 22 of 50 PBC patients stained the nuclei of HEp-2 cells in a pattern of 5-20 discrete dots. on indirect immunofluorescence. Typically. the titers were higher than 1:1.280. This staining pattern was seen in only 4 of 1.240 ANA-positive samples from patients with other connective tissue diseases. and in none of the ANA-positive sera from 49 patients with other liver diseases. Sera which stained the nuclear dots bound a 95-kd polypeptide in immunoblots of HeLa nuclei and in immunoprecipitates of 35S-methionine-labeled HeLa extracts. Affinity-purified antibodies from the 95-kd protein reproduced the nuclear dot immunofluorescence staining pattern. demonstrating that this polypeptide is located in the nuclear dots. ANA of this type. therefore. occur in 44% of patients with PBC. and they appear to be specific for PBC. These antibodies bind a 95-kd protein that is discrete and is scattered throughout the nucleus.
Autosomal dominant arthropathy in a French family, We studied a French family in which 18 adult members had destructive arthropathy and enthesopathic changes. In 16 patients. the diagnosis was verified radiologically. and in the 2 other patients. the clinical history was consistent with familial arthropathy. The disease predominantly affects the wrists. fingers. shoulders. and peripheral entheses. and its onset occurs after age 18. Genetic transmission is autosomal dominant. with 100% penetrance. and is not related to the HLA system. The clinical and radiologic features are strikingly similar in all patients in successive generations and different branches of the genealogic tree. and this suggests monogenic transmission.
The clinical and health status of patients with recent-onset rheumatoid arthritis, This study was designed to document the clinical and health status of patients with recent-onset rheumatoid arthritis (RA). Three groups were studied: 108 patients who had had RA for greater than 1 year (established RA group). 313 patients who had had RA for less than or equal to 1 year (recent-onset RA group). and 188 healthy friend of the patients with recent-onset RA (no RA group). Clinical status was measured using tender joint count. erythrocyte sedimentation rate. and overall physician assessment. Health status was measured using the physical. psychological. pain. and arthritis impact scores of the Arthritis Impact Measurement Scales. Scores on all clinical and health status measures indicated substantial disease effects in the group with recent-onset RA. For most of these measures. effect size analysis indicated that clinical and health status impacts in the recent-onset RA group were similar in magnitude to those found in the groups with more established disease. with scores in both groups being substantially different from those found in the no RA group. These results document the magnitude of the clinical and health status impacts in recent-onset RA. They lend support to recent arguments advocating aggressive therapy earlier in the course of this frequently disabling disease.
Neutrophil chemotactic factors in synovial fluids of patients with Lyme disease, We examined synovial fluid samples from 14 patients with Lyme arthritis for the presence of neutrophil chemotactic factors. Thirteen of the synovial fluids stimulated chemotaxis of normal human neutrophils. The chemotactic activity was heat-sensitive and was not inhibited by antibody to C5a or antibody to interleukin-8. or by a competitive inhibitor of the chemotactic peptide f-Met-Leu-Phe. A culture supernatant of Borrelia burgdorferi also contained neutrophil chemoattractants. Chromatography demonstrated that the chemoattractants in the synovial fluid samples were different from those in the B burgdorferi culture supernatant. One of the major chemotactic factors in Lyme disease synovial fluid had a calculated molecular weight of 13.900. We conclude that a novel. host-derived chemoattractant is present in the synovial fluid of patients with Lyme disease.
SWR mice are resistant to collagen-induced arthritis but produce potentially arthritogenic antibodies, SWR mice are resistant to collagen-induced arthritis but produce antibodies to type II collagen. To determine if these antibodies have arthritogenic potential. serum from collagen-immunized mice was concentrated and passively transferred to DBA/1 mice. The recipients developed severe arthritis within 72 hours. To evaluate the role of complement. SWR mice were bred with congenic inbred B10.D2/oSn (complement deficient) and B10.D2/nSn (complement normal) mice. Collagen-immunized (SWR x B10.D2/nSn)F1 mice had high levels of C5 and were susceptible to arthritis. while (SWR x B10.D2/oSn)F1 mice were deficient in C5 and were resistant to arthritis.
Leukaemia of novel gastrointestinal T-lymphocyte population infected with HTLV-I, In a 72-year-old man with watery diarrhoea and leukocytosis the proliferation of abnormal cells was studied in specimens obtained by endoscopic biopsy of the gastrointestinal tract. Flow cytometry of leukaemia cells revealed a monoclonal expansion of "double-negative" (CD4-. CD8-) cells bearing T-cell receptor (TCR) alpha beta products. Southern blotting confirmed monoclonal integration of HTLV-I. A novel T-cell subset of double-negative TCR alpha beta cells in the gastrointestinal tract in adult man may be a target for HTLV-I infection.
Comprehensive primary health care antiepileptic drug treatment programme in rural and semi-urban Kenya. ICBERG (International Community-based Epilepsy Research Group), A programme of antiepileptic treatment in a rural and semi-urban region in Kenya was assessed. Patients with generalised tonic-clonic seizures were treated according to one of two simple drug protocols. Health workers screened cases reported by key informants in the community. From the 529 patients identified by health workers as having active seizures 302 patients aged 6-65 years were recruited by a psychiatrist for therapy with carbamazepine or phenobarbitone. Treatment was supervised largely by primary health workers. and the programme was monitored by a research team. which assessed the effectiveness of treatment. Of the 249 patients who completed the study. 53% became seizure-free in the second 6 months of therapy. and another 26% had substantially (50% or more reduction) fewer seizures than in the 6 months before therapy. The similarity of these findings to those obtained in newly diagnosed patients in the developed world. the low drop-out rate. the low rate of withdrawal due to adverse effects. and the acceptable compliance with therapy indicate that health workers can monitor therapy adequately. Most patients had had several years of delay before starting therapy for their epilepsy. yet they responded well--a finding that does not support the suggestion that the disorder becomes intractable if not treated early.
Diagnostic x-ray procedures and risk of leukemia, lymphoma, and multiple myeloma [published erratum appears in JAMA 1991 Jun 5;265(21):2810, Exposure to diagnostic x-rays and the risk of leukemia. non-Hodgkin's lymphoma (NHL). and multiple myeloma were studied within two prepaid health plans. Adult patients with leukemia (n = 565). NHL (n = 318). and multiple myeloma (n = 208) were matched to controls (n = 1390). and over 25.000 x-ray procedures were abstracted from medical records. Dose response was evaluated by assigning each x-ray procedure a score based on estimated bone marrow dose. X-ray exposure was not associated with chronic lymphocytic leukemia. one of the few malignant conditions never linked to radiation (relative risk [RR]. 0.66). For all other forms of leukemia combined (n = 358). there was a slight elevation in risk (RR. 1.17) but no evidence of a dose-response relationship when x-ray procedures near the time of diagnosis were excluded. Similarly. patients with NHL were exposed to diagnostic x-ray procedures more often than controls (RR. 1.32). but the RR fell to 0.99 when the exposure to diagnostic x-ray procedures within 2 years of diagnosis was ignored. For multiple myeloma. overall risk was not significantly high (RR. 1.14). but there was consistent evidence of increasing risk with increasing numbers of diagnostic x-ray procedures. These data suggest that persons with leukemia and NHL undergo x-ray procedures frequently just prior to diagnosis for conditions related to the development or natural history of their disease. There was little evidence that diagnostic x-ray procedures were causally associated with leukemia or NHL. The risk for multiple myeloma. however. was increased among those patients who were frequently exposed to x-rays.
A prospective evaluation of glucose reagent teststrips in the prehospital setting, Reagent teststrip determination of blood glucose has been shown to be accurate for hospital and home testing and is commonly used in prehospital care despite the lack of studies in this arena. This prospective. multicenter study examines the ability of glucose reagent teststrips to detect hypoglycemia when used under field conditions compared with simultaneously drawn control samples for laboratory glucose determination. Also examined was the accuracy of the teststrips in the laboratory glucose range less than or equal to 200 mg/dL. One hundred eighty-one pairs of data were analyzed. Hypoglycemia was defined as laboratory glucose less than or equal to 60 mg/dL. The teststrips correctly identified 31 of 33 patients in this range (sensitivity = 94%). and 125 of 148 patients without hypoglycemia (specificity = 85%). The two false negative readings were 70 and 90 mg/dL. Reagent teststrips were within +/- 40 mg/dL of the laboratory value in 70% of cases. The correlation coefficient (Spearman r) between teststrip and laboratory glucose in the range less than or equal to 200 mg/dL was .80. Using teststrip readings of 90 mg/dL or less as a measure of hypoglycemia yields 100% sensitivity with a specificity of 57%. We conclude glucose reagent teststrips are a useful adjunct for use in the prehospital setting and may be valuable for the detection of hypoglycemia.
Hemodynamically stable upper gastrointestinal bleeding, This article is a prospective evaluation of 38 patients presenting to an emergency department (ED) with hematemesis but who were otherwise hemodynamically stable. Four patients were admitted. only one because of the development of hemodynamic instability. Thirty-three patients were discharged; on follow-up there was no evidence of major morbidity or mortality. Two patients were lost to follow-up. one who left against medical advice and one who lived in a county outside the service area of our hospital. Patients with hematemesis can be safely discharged from the ED after observation for 6 hours if they: (1) lack orthostatic vital sign changes; (2) lack associated significant underlying disease; (3) have a hemoglobin concentration greater than 10 gm/dL; (4) are less than 60 years of age; and (5) are thought to be reliable and compliant.
Eye injuries with metal missiles presenting to an emergency center: a three year study, The authors retrospectively evaluated 33 eye injuries due to metal missiles in 31 patients presenting to our emergency center over the last 3 years. Injuries occurred most frequently when the patients were grinding metal or working on their cars. The type of metal involved in the injury often dictates the type of ophthalmic reaction that will occur. A discussion of intraocular metallic foreign bodies with an emphasis on electroretinograms and metal analysis is presented.
The contribution of impurities to the acute morbidity of illegal drug use, Although emergency physicians treat many patients who use illegal drugs. little is known about the relative toxicities of the abused drug versus those that result from drug impurities and additives. Although case reports suggest significant contribution of contaminants to the morbidity and mortality of street drugs. most physicians' clinical experience and a comprehensive review of the clinical and forensic science literature demonstrate that impurities and additives play only a minor role in the majority of drug-related emergency department presentations. The strengths and weaknesses of several of the currently available drug abuse information data bases are reviewed. and qualitative information concerning the scope of contaminants that have been reported in preparations of cocaine. heroin. and phencyclidine is presented. More research is needed in this area. and a closer liaison between law enforcement. forensic scientists. and emergency physicians should be developed.
The diagnosis and initial management of the fractured mandible, Mandibular fractures are the second most common facial fracture. The usual causes are interpersonal violence and motor vehicle accidents (MVA). Nearly all cases present to an emergency department for initial management. They are rarely life-threatening injuries and must assume low priority in the initial assessment and management of the severely traumatized patient. Following any resuscitation and exclusion of other significant injuries. a clinical and radiologic diagnosis of the facial injuries should be undertaken including assessment of the fractured mandible. Initial therapy should be directed at temporary immobilization and pharmacologic treatment. followed by referral for appropriate definitive care.
Use of whole bowel irrigation in an infant following iron overdose, An 11-month-old. 11-kg infant presented to the emergency department after ingesting 130 to 150 mg/kg of elemental iron. Emesis was induced twice and the child was lavaged throughout a 4-hour period with some tablet return. An abdominal radiograph after gastrointestinal decontamination showed at least 16 whole iron tablets remaining in the stomach. Serum iron drawn 2 hours postingestion was 46.7 mumol/L. Blood glucose was 7.7 mmol/L and white blood count was 21.800 mm3. Despite a second lavage 8 hours postingestion. a large number of whole tablets were visualized in the stomach per radiograph. Whole bowel irrigation with polyethylene glycol electrolyte lavage solution (Golytely. Braintree Laboratories. Inc. Braintree. MA) was begun via nasogastric tube 14 hours after the ingestion. Serial abdominal radiographs showed tablet movement out of the stomach within 4 hours after initiating whole bowel irrigation. This case demonstrates the safety and efficacy of WBI in an infant when conventional gastrointestinal decontamination has failed.
Histopathological validation of high frequency epicardial echocardiography of the coronary arteries in vitro, The accuracy and reliability of measurement of coronary artery dimensions and detection of atherosclerotic lesions by high frequency epicardial echocardiography were compared with histopathological results. Ten pressure perfused human hearts were examined in vitro with a 10 MHz (Diasonics) transducer and a 7.5 MHz (Vingmed/Sonotron) transducer. There was close agreement between ultrasound and pathological measurements of coronary artery luminal diameter. Qualitative changes in wall structure such as diffuse wall thickening and calcification were readily identified; however. the resolution of the transducers was not high enough accurately to measure wall dimensions in normal coronary arteries. Coefficient of variation measurements for intra and inter observer variability (5.2% and 6.9% respectively) showed excellent reproducibility. The technique was accurate in identifying atherosclerotic lesions. imaging arteries distal to an occlusion. locating deeply sited arteries. and identifying complete obliteration of an artery. Intraoperative video playback and transducer miniaturisation may minimise problems caused by cardiac movement and restricted access. With these developments intraoperative assessment of coronary artery disease may become a real possibility.
Influence of physical exercise on serum digoxin concentration and heart rate in patients with atrial fibrillation, Heart rate and serum digoxin concentration in eight patients with atrial fibrillation were studied at rest and during exercise when initial serum digoxin concentrations were zero and at low and high therapeutic values. Eight patients with ischemic heart disease and in sinus rhythm were studied for comparison. Though the serum digoxin concentration decreased significantly during exercise. the absolute reduction in heart rate was the same at rest and during exercise in patients with atrial fibrillation. Compared with the control patients in sinus rhythm. the heart rate in patients with atrial fibrillation was not adequately controlled during exercise by any serum digoxin concentration tested despite a reduction in heart rate with increasing digoxin concentration. The effects of digoxin on heart rate regulation in atrial fibrillation are complex and include direct effects on the myocardium as well as indirect effects mediated by modulation of the autonomic nervous system; the present results indicate that the drug is not displaced from the target organs by decreasing serum concentrations during exercise. In atrial fibrillation. because the demands on the filter function of the atrioventricular node are highly unphysiological. the effect of digoxin on heart rate during exercise is not adequate.
Jugular venous 'a' wave in dilated cardiomyopathy: sign of abbreviated right ventricular filling time, OBJECTIVE--To study the mechanisms underlying the high venous pressure often seen in patients with dilated cardiomyopathy. DESIGN--Retrospective and prospective examination of the pattern of flow in the superior vena cava. cardiac echo-Doppler studies. and recordings of the jugular venous pulse. SETTING--A tertiary referral cardiac centre. PATIENTS PARTICIPANTS--23 patients with dilated cardiomyopathy. all with functional mitral and tricuspid regurgitation. RESULTS--Two patterns of venous pulse were seen: a dominant 'a' wave and 'x' descent. with systolic flow in the superior vena cava (group 1. n = 11). and a dominant 'v' wave with 'y' descent and diastolic flow in the superior vena cava (group 2. n = 12). A comparison of group 1 and group 2 showed: age (mean (SD] 58 (12) v 61 (6) years. left ventricular end diastolic dimension 7.0 (0.7) cm in both groups. right ventricular short axis 3.3 (0.6) v 3.6 (0.5) cm and long axis 7.3 (0.5) v 7.1 (0.7) cm. and duration of tricuspid regurgitation 350 (65) v 370 (50) ms. The RR interval (550 (100) v 680 (80) ms) and right ventricular filling time (150 (30) v 290 (50) ms) were significantly shorter in group 1. In all patients in group 2 right ventricular filling time was more than 200 ms with separate E and A waves on the tricuspid Doppler echocardiogram. while in all group 1 patients it was less than 200 ms with a single summation peak. In nine patients in group 1. the right ventricular filling time was limited by prolonged tricuspid regurgitation and in the remaining two by prolonged isovolumic relaxation time (215 (80) ms). so that it was consistently significantly less than that of the left ventricle. CONCLUSION--In patients with dilated cardiomyopathy. right ventricular filling time may be so short that it limits stroke volume. Such patients can be recognised by a dominant 'a' wave on the jugular venous pulse. Patients in whom the right ventricular filling time was longer showed a dominant 'v' wave. Both groups can present as "congestive heart failure".
Balloon dilatation of restrictive interatrial communications in congenital heart disease, An adequate interatrial communication is necessary for survival in several forms of congenital heart disease. Three children are presented in whom blade atrial septostomy proved either technically impossible or failed to achieve adequate interatrial communication. In all three an adequate communication was obtained by a balloon dilatation technique similar to that used for pulmonary valve dilatation. In one critically ill infant with mitral atresia the procedure was life saving.
Isovolumic relaxation sound: a new class of added heart sound, An early diastolic sound in a patient with apical left ventricular disease is reported. Pulsed Doppler echocardiography showed blood flow within the left ventricular cavity during the isovolumic relaxation period whose peak flow velocity was synchronous with the onset of this diastolic sound. Because it occurred before filling started it could not have been either a third or fourth heart sound. It must thus represent a distinct and apparently unrecognised class of diastolic sound.
Further evaluation of collagen shields as a delivery system for 5-fluorouracil: histopathological observations, Collagen shields are a potential delivery system for antifibroblast drugs such as 5-fluorouracil after filtration surgery. To determine whether collagen shields produce histologic evidence of inflammation when implanted subconjunctivally. shields were implanted into four rabbit eyes and six guinea pig eyes and retained for 7 or 14 days. Two rabbit eyes and two guinea pig eyes served as controls. Seven days after implantation in the rabbit eyes foreign-body giant cells were present at the surface of the shield. and early deposition of connective tissue was evident around the shield. The inflammatory response at 14 days was similar but more intense. In the guinea pig eyes the collagen shields induced substantially less inflammation. and there was marked shield degradation at 14 days. The results suggest that the inflammatory response in rabbits may be species specific and that collagen shields may be of value as a drug-delivery system for antifibroblast drugs in other species.
Four-snip procedure for involutional lower lid entropion: modification of Quickert and Jones procedures, Involutional lower lid entropion results from a faulty lower lid retractor complex. lid laxity and overriding of preseptal orbicularis fibres on the tarsal and pretarsal fibres. The author describes the anatomy of the lower lid and presents a four-snip procedure for correcting this condition in which the Quickert and Jones techniques are combined.
Efficacy of polyacrylamide vs. sodium hyaluronate in cataract surgery, A prospective randomized study was conducted in 137 patients who underwent cataract surgery and implantation of a polymethylmethacrylate intraocular lens with either polyacrylamide (Orcolon) (68 patients) or sodium hyaluronate (Healon) (69 patients) as the viscoelastic material. Both viscoelastics were aspirated at the end of surgery. Patients were examined before surgery and 1 and 14 days after surgery. Endothelial cell counts were obtained before surgery and 3 months after surgery in 34 patients (16 in the polyacrylamide group and 18 in the sodium hyaluronate group). There were no reports of a flat or shallow anterior chamber intraoperatively in either group. There was no statistically significant difference between the two groups in the incidence of corneal edema or iritis on any visit or in endothelial cell loss. Although there was a significant reduction in intraocular pressure across postoperative visits for the overall sample. there was no significant difference in pressure between the polyacrylamide and sodium hyaluronate groups. The results indicate that no untoward effects on corneal edema. endothelial cell count. iritis or intraocular pressure are to be expected when polyacrylamide is used as an aid to cataract surgery.
Pregnancy outcome among native Indians in Saskatchewan, OBJECTIVE: To determine the difference in pregnancy outcome between native Indians and the provincial population in Saskatchewan. DESIGN: Retrospective analysis of data collected from all birth and death registration forms. SETTING: Saskatchewan. MAIN OUTCOME MEASURES: Incidence of low birth weight and rates of stillbirth and of neonatal and infant death. RESULTS: The neonatal death rate was higher in the Indian population than in the provincial population during the study period; the difference between the two groups in the rate decreased markedly after 1982. The rates of stillbirth and infant death were also higher among the Indians. and the difference persisted during the study period. The incidence of low birth weight and the rate of stillbirth were highest in the youngest and oldest maternal groups in the provincial population; however. the pattern was markedly different among the Indians. teenaged mothers having the best outcomes. CONCLUSION: Further studies are needed to determine the relation between maternal age and fetal outcome among native Indians.
Diminished tolerance of prehypertrophic, cardiomyopathic Syrian hamster hearts to Ca2+ stresses, Although abnormal myocardial calcium homeostasis in the cardiomyopathic hamster (CMH) has been documented in the hypertrophic stage of the disease. the Ca2+ tolerance before the hypertrophic stage has not been investigated. We studied isovolumic contractile function in response to a variety of Ca2+ stresses including increases in perfusate [Ca2+] (Cao). the Ca2+ channel agonist Bay K 8644. and alpha- or beta-adrenergic agonists of isolated perfused hamster hearts from 24-45-day-old male CMH. BIO 14.6 strain. and age- and sex-matched F1B strain controls. The coronary flow at a constant perfusion pressure did not differ between two groups at baseline or after any Ca2+ stress. At a Cao of 1.0 mM. neither end-diastolic pressure (EDP) nor developed pressure (DP) nor half relaxation time (RT1/2) during stimulation at 1-3 Hz differed between the two groups; as Cao was increased up to 10 mM. CMH hearts showed a lower threshold for the occurrence of a Ca2+ overload profile: EDP and RT1/2 increased to a greater. and DP to a lesser. extent in CMH than in control hearts. To determine whether calcium influx via Ca2+ channels mediates the lower threshold for Ca2+ overload in CMH hearts. we measured resting pressure and scattered laser light intensity fluctuation (SLIF) in unstimulated hearts. Prior studies have shown that SLIF is generated by microscopic tissue motion caused by diastolic spontaneous sarcoplasmic reticulum Ca2+ release and that SLIF amplitude reflects the extent of cell and sarcoplasmic reticulum Ca2+ loading. The Ca(2+)-dependent increase in resting pressure in unstimulated hearts was highly correlated with an increase in SLIF. and this relation was steeper in CMH than in control hearts. CMH hearts also showed a reduced threshold for the occurrence of a Ca2+ overload profile in response to the adrenergic receptor agonists and the Ca2+ channel agonist during electrical stimulation in a Cao of 2.0 mM: maximum DP achieved with each agonist was significantly less and the dose-response curves to each agonist were shifted leftward in CMH versus control hearts. In CMH hearts EDP began to increase at a significantly lower concentration of each agonist. and the maximum extent of increase in EDP in response to all agonists was significantly enhanced compared with control hearts. In response to beta-adrenergic or Ca2+ channel agonists. neither resting pressure nor SLIF in unstimulated hearts increased in control or in CMH hearts. In contrast. in response to alpha-adrenergic stimulation. both SLIF and resting pressure increased to a greater extent in CMH than in control hearts.(ABSTRACT TRUNCATED AT 400 WORDS).
Effect of reduced blood flow on alpha 1- and alpha 2-adrenoceptor constriction of rat skeletal muscle microvessels, Adrenergic constriction of skeletal muscle arterioles. particularly small terminal arterioles. is opposed by decreased blood flow or increased metabolic rate. Our previous studies indicate that neural constriction of large arterioles. which have both postjunctional alpha 1- and alpha 2-adrenoceptors. is mediated by alpha 1-receptors; small arterioles depend on alpha 2-receptors. Also. alpha 2. but not alpha 1. constriction is reduced by acidosis. Differential sensitivity of alpha 1 versus alpha 2 constriction to metabolic signals such as H+ may underlie the sensitivity of arteriolar adrenergic constriction to metabolic inhibition. To examine this hypothesis. we studied the effect of reduced perfusion on alpha 1- versus alpha 2-mediated constriction of large arterioles and venules. Intravital microscopy of rat cremaster skeletal muscle was used to obtain concentration-response curves for phenylephrine (alpha 1-agonist) and UK-14.304 (alpha 2-agonist). Thirty percent reduction in cremasteric artery flow by venous outflow obstruction had no effect on baseline diameter. indicating no effect on "intrinsic tone." Reduced perfusion also had no effect on arteriolar or venular sensitivity to phenylephrine or venular sensitivity to UK-14.304 but significantly attenuated arteriolar response to UK-14.304. To examine a possible mechanism for the selective inhibition of alpha 2 constriction by acidosis. we determined the effect of acidosis on the partial alpha 1-agonist St587. Like alpha 2 constriction. St587-mediated constriction of arterioles was reduced during acidosis and was attenuated by nifedipine.
A cellular mechanism for impaired posthypoxic relaxation in isolated cardiac myocytes. Altered myofilament relaxation kinetics at reoxygenation, Single. isolated rat ventricular myocytes were made hypoxic for 10 minutes and then reoxygenated. During hypoxia. there was a marked abbreviation of the mechanical twitch. without a decrease in its amplitude. Immediately after reoxygenation. both the time to peak shortening and the duration of relaxation were markedly prolonged. and they remained prolonged for 10-50 minutes. The alterations in contraction and relaxation were not associated with any change in the time course of either the transmembrane action potential or the cytosolic calcium transient. as recorded with the fluorescent probe indo 1. Intracellular pH. measured with a fluorescent probe (carboxyseminaphthorhodofluor). showed an acid shift during hypoxia and an alkaline rebound immediately after reoxygenation. The time courses of intracellular pH and contraction duration were not parallel during hypoxia or reoxygenation. and simulation of the alkaline pH shift by lowering PCO2 or superfusing NH4Cl (in the absence of exposure to hypoxia) did not quantitatively reproduce the prolongation of relaxation seen after reoxygenation. The prolongation of contraction after reoxygenation could be overridden by the beta-adrenergic agonist isoproterenol or the nonenzymatic phosphatase butanedione monoxime. We conclude that delayed relaxation after reoxygenation exists at the single cell level and is due to an alteration of the properties of the myofilaments. Intracellular pH is not the primary mediator of this alteration. We speculate that alteration of intracellular inorganic phosphate or covalent modification of the myofilaments might be involved.
Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes, To determine whether endothelin-1 (ET-1) induces hypertrophy of cardiomyocytes. the effects of ET-1 on the expression of muscle-specific genes and a proto-oncogene. c-fos. in cultured neonatal rat cardiomyocytes were examined by Northern blot analysis. ET-1 (10(-7) M) induced about twofold to fourfold increases in the gene expression of myosin light chain 2. alpha-actin. and troponin I after 6 hours. which continued up to 24 hours. The ET-1-induced increases in mRNA levels for these muscle-specific genes were dose dependent (10(-9) to 10(-7) M). Run-on transcriptional assay showed that the changes in mRNA level for three muscle-specific genes were regulated. at least in part. at the transcriptional level. 12-O-Tetradecanoylphorbol 13-acetate (TPA). a potent protein kinase C activator. and the Ca2+ ionophore ionomycin also increased mRNA levels of three muscle-specific genes. ET-1. TPA. and ionomycin similarly induced the expression of c-fos after 30 minutes. which returned to an undetectable level after 6 hours. ET-1 remarkably and dose-dependently stimulated accumulation of total inositol phosphates in cardiomyocytes. Morphometrical evaluation showed that ET-1 significantly increased surface area of cardiomyocytes without cell proliferation. ET-1 also dose-dependently stimulated the synthesis of protein and DNA. which was unaffected by the L-type calcium channel blocker nicardipine. These data suggest that ET-1 induces hypertrophy of cardiomyocytes associated with the induction of muscle-specific gene transcripts through the possible involvement of protein kinase C activation or intracellular Ca2+ mobilization.
Regional changes in hemodynamics and cardiac myocyte size in rats with aortocaval fistulas. 1. Developing and established hypertrophy, The effects of a large arteriovenous fistula on left and right ventricular hemodynamics and cardiac myocyte size were examined in adult rats at 1 week and 1 month after surgery. Cardiac output. left ventricular function. and right ventricular function were evaluated before obtaining isolated myocytes for cell size measurements. Average heart weight increased 35% at 1 week and 86% at 1 month in rats with fistulas. In general. myocyte hypertrophy was due to a proportional increase in length and width (length/width ratio remained constant). This change was more evident in the large hearts from rats with 1-month fistulas. At both the 1-week and 1-month intervals. the hypertrophic response of right ventricular myocytes was slightly greater than that observed in the left ventricle or interventricular septum. Left ventricular systolic pressure and dP/dtmax were significantly reduced at 1 week but returned to normal after 1 month of overloading. Left ventricular end-diastolic pressure was increased approximately fivefold and twofold at 1 week and 1 month. respectively. Right ventricular systolic pressure and dP/dtmax were increased at both intervals examined. We conclude that severe volume overloading from a large aortocaval fistula in the rat is characterized by 1) depressed left ventricular function at 1 week followed by a large compensatory hypertrophy and near normal function at 1 month. 2) right ventricular pressure overload. and 3) changes in myocyte shape that resemble normal physiological growth.
Regional changes in hemodynamics and cardiac myocyte size in rats with aortocaval fistulas. 2. Long-term effects, Regional changes in hemodynamics and cardiac myocyte size were examined in adult rats 5 months after creating a large aortocaval fistula. At that time. cardiac output. left and right ventricular pressures. and left and right ventricular dP/dtmax were measured. Subsequently. isolated cardiac myocytes were collected from the left ventricle. right ventricle. and septum for cell size measurements. Compared with sham-operated controls. percent dry weight was reduced in the liver and kidney but was unchanged in the lung. Heart rate. left ventricular systolic pressure. left ventricular dP/dtmax. and systolic aortic pressure were not changed in rats with fistulas. However. cardiac output. stroke volume. left ventricular end-diastolic pressure. and all measured parameters in the right ventricle were significantly increased. Mean cell volume and the ratio of heart weight to body weight were both elevated 92%. Cell volume. cell length. and cross-sectional area increased significantly in each heart region examined. Hypertrophy was more pronounced in cells from the right ventricle and the endomyocardium of the left ventricle. The percentage of cells with mononucleation or binucleation was not changed in any heart region of rats with fistulas. In summary. despite evidence of renal and hepatic congestion. most indexes of cardiac function were normal or elevated 5 months after creation of a large volume-overload-induced hypertrophy. Data from isolated cardiac myocytes suggested that cellular hypertrophy. rather than hyperplasia. was responsible for the increased cardiac mass.
Effects of acidic fibroblast growth factor on normal and ischemic myocardium, We sought to determine the effects of acidic fibroblast growth factor (FGF) on ischemic and normal myocardium and to determine whether direct application of acidic FGF to the heart could promote angiogenesis. Eighteen dogs underwent placement of an ameroid constrictor on the left anterior descending coronary artery (LAD). Three weeks later. a left internal mammary artery (IMA) pedicle was positioned over the LAD territory. with a sponge saturated with acidic FGF (n = 12) or saline (n = 4) interposed between the pedicle and the heart. Polytetrafluoroethylene fiber or collagen I sponges were used to deliver the acidic FGF. Weekly angiography of the IMA was performed in all dogs. but significant IMA to coronary collaterals were not demonstrable in any dog. Eight dogs had histological evidence of subendocardial infarction in the LAD territory (five acidic FGF. three control. p = NS). Striking smooth muscle cell hyperplasia was present in arterioles and small arteries exclusively in areas of subendocardial infarction in all of the acidic FGF-treated dogs but in none of the control dogs (p less than 0.05). Noninfarcted myocardium appeared normal in all dogs. In two additional dogs. ameroid constrictors were not placed on the LAD. such that acidic FGF-treated sponges were placed on normally perfused myocardium of the LAD territory. Histological evaluation of those hearts revealed normal myocardium. without evidence of myocardial infarction or smooth muscle cell hyperplasia. Thus. when acidic FGF is delivered to the myocardium via an epicardial sponge in dogs whose coronary flow is compromised. acidic FGF does not cause an angiogenic response in viable myocardium but causes vascular smooth muscle cell hyperplasia in areas subjected to ischemic injury.
Renal carnitine concentration decreases in endotoxic dogs, BACKGROUND AND METHODS: Renal cortical and serum carnitine concentrations were studied in seven anesthetized beagle dogs in which acute circulatory collapse was induced by an iv injection of Escherichia coli endotoxin. 0.5 mg/kg given over 15 mins. Four controls received normal saline. RESULTS: The endotoxin injection resulted in cardiac depression. renal hypoperfusion. acidosis with a decrease in urinary output. and hematuria. Arterial and renal venous free carnitine concentrations increased significantly in endotoxemia during the 5-hr experiment. but remained low and unchanged in the controls. Circulating acyl-carnitine concentrations underwent no essential changes in either group. Total. free. and acyl-carnitine concentrations decreased in endotoxic renal tissue. CONCLUSIONS: These data suggest that endotoxemia decreases carnitine concentrations in the renal cortex. but increases free carnitine concentrations in the circulation.
Right ventricular function assessed by thermodilution technique during apnea and mechanical ventilation, OBJECTIVES: To evaluate strategies for thermodilution-based measurement of cardiac output and right ventricular (RV) ejection fraction and to assess the effects of controlled mechanical ventilation in patients. Furthermore. to compare strategy-associated reproducibility with reference values obtained during long-term apnea. DESIGN: Crossover trial in patients; reference values from apneic animals. SETTING: University ICU and physiology laboratory. PATIENTS: Six consecutive male ICU patients (48 to 70 yrs) after major abdominal vascular surgery. Animals: two adult female sheep. INTERVENTIONS: Three ventilatory rates (8. 16. and 24 cycles/min) and 15-sec periods of apnea were selected for measurements in patients. In animals. continuous apnea was achieved with extracorporeal CO2 removal and apneic oxygenation. MEASUREMENTS: Measurements were performed using an appropriate pulmonary artery catheter and an ejection fraction/cardiac output computer prototype. The thermal indicator was injected automatically at four defined points of the ventilatory cycle. but triggered manually during apnea. MAIN RESULTS: At 8 cycles/min. there was a wide mean range of cyclic variable modulation. with a coefficient of variation of 11.6% and 23.2% for cardiac output and RV ejection fraction. respectively. Allowing for ventilatory phase or changing from 8 to 16 cycles/min reduced errors by half. Combining both procedures resulted in a coefficient of variation of 4.7% and 6.6% for cardiac output and RV ejection fraction. respectively. The best coefficient of variation values obtained during 15 secs of apnea in patients approached those variations in experimental apnea (coefficient of variation of 2.1% and 4.5% for cardiac output and RV ejection fraction. respectively). CONCLUSIONS: At low ventilatory rates. best results are achieved by averaging four phase-selected measurements. One-point measurements were less accurate and random point measurements less reproducible.
Statistical modeling of prognostic indices for evaluation of critically ill patients, OBJECTIVE: To identify the most predictive association of variables from the usual indices of severity of illness by statistical objective analysis. DESIGN: Logistic regression analysis of the different variables of the most important indices. SETTING: A general critical care medicine group practice in a university hospital. PATIENTS: A total of 630 critical care patients age 12 to 87 yrs were evaluated. The most important indices of severity of illness and the corresponding variables were recorded and the patient's course was followed for 3 months after ICU admission. MEASUREMENTS AND MAIN RESULTS: One of our hypotheses was that the inclusion of an excessive number of variables to obtain the most common prognostic indices of mortality in critical care patients results in an underestimation of mortality and a redundancy of prognostic information. We performed a logistic regression analysis using the variables of the currently used indices of critical care prognosis: Acute Physiology Score. Simplified Acute Physiology Score. Acute Physiology Score-II. and Mortality Prediction Model. This mathematical approach resulted in a model of five variables: organ system failure. blood glucose. serum calcium. serum prothrombin activity. and serum osmolality. The score obtained from this model gave accurate prognostic criteria:sensitivity 91.2% and specificity 90%. using a cutoff point of 0.7; sensitivity 86% and. specificity 94%. using a cutoff point of 0.5. CONCLUSIONS: Our results show that suitable statistical management of the discriminant prognostic variables allows reduction of the number of variables of the severity indices currently used. obtaining five more predictive variables.
Risk factors for the misdiagnosis of pneumothorax in the intensive care unit, OBJECTIVE: To identify risk factors predisposing to the misdiagnosis of pneumothorax in the ICU. DESIGN: A prospective case series investigation. SETTING: A medical ICU service of a military referral hospital. PATIENTS: All adult medical ICU patients were evaluated during a 12-month period. Of 464 admissions. 28 (6%) were found to have acquired a pneumothorax during their medical ICU stay. INTERVENTIONS: Nineteen (67.9%) patients with pneumothorax were diagnosed correctly on initial presentation of their pneumothorax. The remaining nine (32.1%) patients' pneumothoraces were misdiagnosed at initial presentation. MEASUREMENTS AND MAIN RESULTS: Tension pneumothorax occurred more frequently in patients with an initially misdiagnosed pneumothorax (33.3%) than in patients with pneumothoraces that were correctly diagnosed during their medical ICU stay (5.3%) (p less than .06). Thirteen variables chosen prospectively were examined using a chi-square statistic. The following four variables occurred statistically more often in nine patients with an initially misdiagnosed pneumothorax: a) mechanical ventilation required at the time of the development of pneumothorax (p less than .05); b) an atypical radiographic location of the pneumothorax (p less than .05); c) altered mental status exhibited at the time of pneumothorax presentation (p less than .05); and d) development of pneumothorax after peak physician staffing hours (p less than .02). CONCLUSIONS: Certain medical ICU patients appear to be at higher risk for the initial misdiagnosis of pneumothorax. Familiarity with factors predisposing to this problem should allow for a higher index of suspicion for the diagnosis of pneumothorax in critically ill patients and possibly improve the early detection of pneumothorax.
Transanal electrostimulation for fecal incontinence: clinical, psychologic, and manometric prospective study, A prospective study was carried out to analyze the clinical. psychologic. and manometric short-term results of transanal electrostimulation (TES) in the treatment of fecal incontinence. Fifteen patients underwent TES. An initial clinical and manometric assessment was carried out before and 1 month after the procedure. A psychologic evaluation was also performed by means of interviews and appropriate tests. Early improvement of symptoms was noted in 10 patients. The nonresponders were women with gross daily incontinence to solid stool. At anal manometry. resting tone and rectal sensation remained unchanged. whereas a significant increase of voluntary contraction was observed following TES (from 48 +/- 26 to 59 +/- 39 mm Hg. P = 0.03). Psychologically. TES led to a significant decrease of both latent and paranoid anxiety related to symptoms (P = 0.02). At a clinical reassessment 6 months later. one of the nonresponders became continent after a further course of TES. In conclusion. TES is well accepted by the patients. is followed by positive emotional response. and. by improving striated sphincter function. seems to be effective in the treatment of partial fecal incontinence.
Prognostic factors in colorectal carcinoma treated by preoperative radiotherapy and immediate surgery, The clinicopathologic staging of colorectal cancer is the subject of recent debate. We studied morphologic variables in a series of tumors resected from 284 patients. Half had been prospectively. randomly allocated to receive a 4-day schedule of preoperative pelvic radiotherapy followed by immediate surgery. There was a significant (P less than 0.01) difference in the distribution of tumors of various histopathologic grades between irradiated (XS) and unirradiated (S) patients and borderline differences in the predictive values of venous spread. tumor grading. and local spread. However. these differences were less marked in 180 tumors examined by one review pathologist. They were thought to be due to misinterpretation of changes induced by radiotherapy. No differences were detected in the distribution of tumors of various sizes and Dukes' stage in the XS and S groups. The review pathologist recorded a borderline (P = 0.049) difference in the distribution of tumors of various CEA staining patterns between the XS and S groups. In a Cox regression model. Dukes' staging remained the most important predictive variable for survival and pelvic recurrence in the XS and S groups. Dukes' staging was apparently unchanged by this schedule of preoperative radiotherapy. but Broders' grading may be unreliable. Any new clinicopathologic staging system for colorectal cancer should record when preoperative radiotherapy is delivered. More studies of radiotherapy effects are required.
Investigation of colonic prostaglandins in carcinogenesis in the rat colon, Large bowel carcinoma was induced in rats by injecting MNNG intrarectally. and changes in the large bowel mucosa prostaglandin (PG) with time were determined. The PGE2 levels of the colonic mucosa in a control group were 20.9 +/- 9.7 (pg/mg total protein) at 5 weeks. 25.5 +/- 9.7 at 10 weeks. 26.5 +/- 18.1 at 20 weeks. and 34.8 +/- 12.7 at 40 weeks. The PGE2 levels in the MNNG-treated group were 44.7 +/- 6.2 at 5 weeks. 43.1 +/- 14.9 at 10 weeks. 70.1 +/- 23.4 at 20 weeks. and 79.7 +/- 54.1 at 40 weeks. The intrinsic PGE2 levels of the noncancerous mucosa were thus significantly higher for the MNNG group than for the control group at all weeks. At 40 weeks. the PGE2 levels of cancer lesions were significantly high compared with those of the noncancerous area. In the cancerous lesions. 6-keto-PGF1 alpha and PGF2 alpha decreased and TXB2 increased significantly at 40 weeks. The observations demonstrated that PGE2 was implicated as a promoter in the development and proliferation of carcinoma in MNNG-induced large bowel carcinogenesis in rats.
Temporal changes in the occurrence of hemorrhoids in the United States and England, Although numerous etiologic risk factors have been proposed. the pathogenesis of hemorrhoids remains unknown. The present investigation assesses the temporal distribution of hemorrhoids as depicted by physician visits. hospital discharges. and surgical procedures to provide further insight into potential etiologic risk factors. The analysis was based on five data sources: from the United States. the National Disease and Therapeutic Index (NDTI). the National Hospital Discharge Survey (NHDS). and the Commission on Professional Hospital Activities (CPHA); from England and Wales. the Morbidity Statistics from General Practice (MSGP) and the Hospital In-patient Enquiry (HIPE). Results demonstrated a consistent decline in all data sources from the United States. The decrease occurred in males and females similarly and was most striking in those aged 45-64 years. Physician visits and hospital discharges for hemorrhoids in England and Wales likewise declined although the decrease was not as dramatic. The consistency of the temporal distributions among the two countries. as well as among the different sources. suggests that the observed decline may. in fact. reflect an overall decrease in the occurrence of hemorrhoidal disease.
Aseptic colon resection by an invagination technique. Experimental study on dogs, A new aseptic colon resection by an invagination technique is presented. The bowel to be resected is invaginated down into the healthy intestine. and the anastomosis is sutured in one layer of continuous suture before transection by a diathermy wire. placed in the intestinal lumen via the anus. Sections of bowel that cannot be invaginated. e.g.. because of a tumor. are first removed by transection between pairs of cable ties. which close the lumen. Twenty dogs were operated on without receiving prophylactic antibiotics. In 10. the intestine was transected between cable ties. An imprint. taken from the anastomosis and subcutis. was cultured. The bacterial count at the anastomosis exceeded 100 in only three cases; in the subcutis. this was the case in one dog. One wound infection developed. Serial barium enemas at 1. 2. 3. and 4 weeks revealed no anastomotic leakage. One early death because of a total anastomotic dehiscence was encountered. and two dogs were killed because of wound dehiscence and anastomotic stricture. respectively. It is concluded that. in dogs. the method is easily and safely performed. but further experimental studies are needed.
Use of photodynamic therapy in the palliation of massive advanced rectal cancer. Phase I/II study, Photodynamic therapy (PDT) is a relatively new form of cancer therapy utilizing a photosensitizer such as hematoporphyrin derivative. We conducted a pilot study to determine the efficacy of its use in palliating advanced rectal cancer. to determine toxicity. and to establish objective outcome criteria. Six patients with very advanced. usually recurrent rectal cancer were treated with PDT after being photosensitized with Photofrin II. A protocol was established to measure clinical and radiologic response to therapy. A new intraluminal delivery system was incorporated. Five patients had both clinical and radiologic responses to therapy. In two patients we observed such significant responses that they cannot be accounted for on a photobiologic basis alone. One patient developed a significant sunburn after discharge. There was no major toxicity of bleeding or sepsis even at maximum doses (200 J/cm2). We are confident that PDT has a role to play in rectal cancer and speculate as to future applications.
Effects of diclofenac sodium on intestinal anastomotic healing. Experimental study on the small intestine of rabbits, To study the possible effects of diclofenac sodium on intestinal anastomoses. 48 rabbits were submitted to surgery consisting of two single-layer ileal anastomoses performed with separate propylene 5-0 sutures. The animals were divided at random into two groups (test and control). The animals in the test group were given intramuscular injections of diclofenac sodium at the dose of 3 mg/kg body weight at 24-hour intervals. and the control animals were given injections of an identical amount of 0.9 percent saline. The animals were sacrificed on the 3rd. 7th. and 14th postoperative days for macroscopic evaluation of the peritoneal cavity and of the anastomoses. tensile strength measurement. hydroxyproline determination. and histopathologic examination. The following results were observed: anastomotic dehiscence followed by peritonitis and death in five test animals (20.83 percent) and no control animals; decreased anastomotic tensile strength on the 7th day in test animals (P less than 0.05); delayed acute inflammatory response and onset of fibroblast proliferation in the test group; and similar hydroxyproline levels in both groups. On the basis of the results obtained. we conclude that diclofenac sodium had a negative effect on intestinal anastomotic healing.
Multiple luteinizing hormone/chorionic gonadotropin receptor messenger ribonucleic acid transcripts, It has previously been shown that multiple messenger RNA (mRNA) species can be identified in gonadal tissues by probes specific for the LH/CG receptor. Here we show that the sizes and relative abundancies of gonadal LH/CG receptor transcripts are quite variable between such closely related species as rat and mouse. These patterns of LH/CG receptor mRNAs are yet different from that observed in human embryonic kidney 293 cells that have been transfected with a cDNA encoding for the rat luteal LH/CG receptor. In spite of the diversity in the number and sizes of LH/CG receptor mRNA transcripts. however. our data also show that the size of the cell surface receptor expressed in these three cells/tissues is identical. We further show that the most abundant LH/CG receptor mRNA present in MA-10 cells. a clonal strain of cultured Leydig tumor cells. is a 1.2 kilobase transcript which encodes for a truncated version of the LH/CG receptor corresponding to the extracellular hormone-binding domain. It does not appear. however. that this transcript is translated into a functional protein.
Differential regulation of the insulin-like growth factors (IGF-I and -II) and IGF binding proteins during malnutrition in the neonatal rat, Insulin-like growth factor (IGF)-I and -II are known to play a major role in fetal and early postnatal growth. The IGF binding proteins (IGFBPs) are thought to be important in modulating the actions of the IGFs. In this paper. the effect of malnutrition in the neonatal rat on serum IGFs and IGFBPs and hepatic IGFBP messenger (m) RNA was examined. Control (C) dams (n = 9) were allowed ad libitum intake. whereas restricted (R) dams (n = 9) were limited to 50% of ad libitum intake throughout lactation. which results in decreased milk production and malnutrition of pups suckling on restricted dams. A subset of pups were cross-fostered from the R-dams to the C-dams from days 15-19 postpartum (PP) to investigate the effect of nutritional repletion (refed). Pups were killed on days 8. 12. 15. and 19 PP and liver and blood collected. Serum IGF-I and -II concentrations were measured by RIA after acid-chromatography to remove IGFBPs. Serum IGFBPs were characterized by Western ligand blot. Hepatic mRNA for IGFBP-1. -2. and -3 were determined by northern analysis. Body weight (BW) of R-pups was significantly less than C-pups by day 10 PP (P less than or equal to 0.05). and mean BW at day 19 was 56% of the C-pups. Refeeding from days 15-19 resulted in a significantly greater rate of growth vs. R-pups (3.2 vs. 0.9 g/day). and mean BW of refed pups at day 19 PP was 75% of C-pups. Malnutrition caused a significant reduction in both serum IGF-I and -II after day 12 PP. while causing an elevation in serum IGFBP-2. IGFBP-1 and IGFBP-2 mRNA expression were not significantly affected at days 8 and 12. but were elevated in livers of day 15 and 19 pups. Malnutrition caused a delay in the development shift from IGFBP-2 to IGFBP-3. which normally occurs between day 15 and 19 in the rat. Refeeding raised serum IGF-I and -II levels to those found in the C-pups and a trend toward normalization of IGFBP profiles. In conclusion. IGFs and IGFBPs are differentially regulated during neonatal malnutrition. The decrease in IGF peptide and induction of IGFBP-1 and -2 may provide protective mechanisms by inhibiting growth during malnutrition.
Early hypothyroidism in rats causes increased adult testis and reproductive organ size but does not change testosterone levels, The role of thyroid hormones in the testis is unclear. although recent evidence indicates they may be important for testicular development. Here we describe a novel method for increasing adult testicular size in the rat by induction of transient hypothyroidism during neonatal life. Rats were treated with a reversible goitrogen. 6-propyl-2-thiouracil from birth to day 25 when treatment was stopped. allowing return to a euthyroid state. At days 90. 135. 160. and 180. wt and DNA content of the testis. epididymis. ventral prostate. seminal vesicle. and those of some nonreproductive organs were determined. as well as serum levels of testosterone (T) and thyroid hormones. Despite decreased body wts in 90-day and older 6-propyl-2-thiouracil-treated rats. testis wt was increased by 40% and 60% at 90 and 135 days. respectively; maximal increase (80%) occurred at 160 days. These wt increases were accompanied by proportional changes in DNA content. Significant enlargements were also seen in other reproductive organs. but they occurred after a time lag and were smaller in magnitude. Interestingly. serum T levels showed no increase at any age. Weight and DNA content of nonreproductive organs. like body wts. were less than controls at all ages but thyroid hormone levels were normal. Thus. transient hypothyroidism in neonatal rats is associated with lasting enlargements in the ultimate size of testis and other reproductive organs in the adult. These changes are not related to excess T levels. The results indicate early critical influences of thyroid hormones on growth and development of the reproductive system and suggest an experimental model for inducing lasting enlargements in testis and reproductive organs. The model may also be useful for studying regulation of reproductive growth and final size.
Increased sperm production in adult rats after transient neonatal hypothyroidism, In the preceding paper it was shown that transient neonatal hypothyroidism induced by treatment of rats from birth to day 25 with the goitrogen 6-propyl-2-thiouracil (PTU) is associated with increases in testis wt and DNA content of up to 80% during adulthood. The testis changes were accompanied by similar. though less marked. increases in the wt and DNA content of epididymis and accessory organs. The purpose of this study was to assess sperm production in these enlarged testes and measure changes in sperm reserves in the epididymis. Testes and epididymides were obtained from control rats or rats given PTU from birth to day 25 (designated "treated") at 90. 135. 160. and 180 days of age. Daily sperm production (DSP). efficiency of sperm production (DSP/g testis). and epididymal sperm reserves were measured in all animals. Compared to controls. DSP of the treated rats was increased by 83%. 86%. 136%. and 132% at 90. 135. 160. and 180 days. respectively. Thus. in the treated rats. DSP. like testis wt. plateaued at day 160. In addition. efficiency of sperm production was increased by 15%-30% at all ages in treated animals. Epididymal sperm reserves were also increased in treated rats at all ages. but the correlation between DSP and epididymal sperm reserves was weak. Sperm motility and concentration in caudal epididymal fluid of adult males treated from birth to day 25 with PTU were normal. These males were fertile and sired litters in which pup wt and pup number were normal. These results indicate that neonatal hypothyroidism in rats is associated not only with increased testis size but also with increased efficiency of sperm production. resulting in increases in DSP of up to 140% in these animals during adulthood. Maximal sperm production is reached at 160 days of age in treated rats (compared to 100 days in controls). coinciding with the attainment of final testicular size. This system represents the first experimental model in which such large increases in sperm production can be produced. The neonatal PTU treatment does not appear to impair fertility or alter sperm characteristics when these animals become adults and may be a useful system with which to study factors which normally regulate sperm production.
Cation-induced restoration of insulin action in insulin-desensitized HTC cells, Insulin desensitization of amino acid uptake in HTC cells was induced by preincubation with 4 or 10 micrograms/ml insulin. Insulin binding after desensitisation was decreased by both insulin concentrations due to a 45-49% decrease in insulin receptor numbers. Desensitization with 4 micrograms/ml insulin increased the ED50 for half-maximal stimulation of amino acid uptake from 19.5 +/- 9.2 ng/ml in control cells to 84.0 +/- 8.3 ng/ml (P less than 0.0001). It also decreased the maximal insulin response of amino acid uptake from 1.40 +/- 0.10 to 1.14 +/- 0.10 nmol/mg protein. indicating the production of a mild postreceptor defect. Desensitization with 10 micrograms/ml insulin completely abolished this insulin response. When cellular receptors were down-regulated with 4 micrograms/ml insulin and restimulated with insulin in the presence of 0.03 mM ruthenium red (RR) or 10 mM Ca2+. both the insulin response and insulin binding were increased. Insulin binding was restored to levels comparable to those observed in control cells by an increase in receptor affinity. The ED50 of amino acid uptake decreased to 20.5 +/- 7.3 ng/ml insulin in the presence of RR and to 42.2 +/- 8.9 ng/ml in the presence of 10 mM Ca2+ (both P less than 0.0001 from down-regulated cells). In addition. the maximal insulin response increased from 1.14 +/- 0.10 to 1.40 +/- 0.10 and 1.45 +/- 0.10 nmol/mg protein. respectively. Preincubation with 10 micrograms/ml insulin prevented the effect of RR and Ca2+ on the recovery of insulin responses. These experiments suggest that insulin-desensitized cells undergo a progressive loss of their insulin response and that RR and Ca2+ provide useful reagents to investigate the mechanisms of this process because they can counteract the decrease in insulin response by increasing receptor affinity and receptor-effector coupling.
High activity of low-Michaelis-Menten constant 3', 5'-cyclic adenosine monophosphate-phosphodiesterase isozymes in renal inner medulla of mice with hereditary nephrogenic diabetes insipidus, Our previous studies on microdissected kidney tubule segments indicate that the failure of vasopressin (VP) to increase cAMP content in collecting ducts of mice with hereditary nephrogenic diabetes insipidus (NDI mice) is due to abnormally rapid cAMP catabolism via cyclic-3'.5'-nucleotide phosphodiesterases (PDE). Furthermore. the VP-stimulated cAMP accumulation can be restored by addition of PDE isozyme-specific inhibitors. To elucidate the biochemical basis of the NDI syndrome. we analyzed PDE activities in extracts from inner medullary tissues of NDI mice and from control mice separated with the use of ionex fast protein liquid chromatography on a Mono-Q column. In extracts of inner medullary tissues from either control or NDI mice. the low Michaelis-Menten constant (Km) cAMP-PDE activity specific for cAMP as a substrate (cAMP-PDE) was eluted from a Mono-Q column with linear sodium acetate gradient as peak 3 at Na-acetate concentration (0.75-0.93 M) and was well separated from fractions containing the Ca(2+)-calmodulin sensitive PDE. The cAMP-PDE activity in peak 3 was significantly higher in NDI mice (greater than delta + 100%) than in controls. The sensitivity to effect of cAMP-PDE isozyme-specific inhibitors. rolipram and cilostamide. indicates that peak 3 consists predominantly (approximately 75%) of the rolipram-sensitive PDE-IV isozyme and a minor portion (approximately 25%) of cilostamide-sensitive PDE-III isozyme in both control and NDI mice. Higher activity of PDE-IV in NDI mice was due to 2.4 times higher apparent maximum velocity compared to controls. whereas the apparent Km for cAMP was not different. Our results show that low Km cAMP-PDE activities. predominantly PDE-IV. are higher in inner medulla of NDI mice. We suggest that the higher activity of PDE-IV. and to a lesser degree perhaps also PDE-III. accounts for rapid cAMP hydrolysis. which prevents the increase of cAMP generated in the response to VP in collecting ducts of NDI mice.
Growth of human breast cancer cell lines is inhibited by the somatostatin analog BIM23014, Somatostatin has been shown to lower plasma levels of various hormones and growth factors involved in regulation of the growth of human breast cells. In the present study we examined the ability of the somatostatin octapeptide analog BIM23014 to modulate the in vitro growth of five human breast cell lines: HBL100. Hs578T. MDAMB231. T47D. and MCF7. BIM23014 inhibited the growth of the two steroid-dependent cell lines. MCF7 and T47D. in a dose-related manner. This inhibitory effect was only observed when MCF7 and T47D cells were cultivated in medium containing steroid-depleted serum. The growth of a MCF7 variant capable of growth in serum-free medium was also inhibited by BIM23014. indicating that serum factors are not required for this inhibition. In the serum-free medium. the addition of estradiol before or during treatment with BIM23014 abolished its inhibitory effects on cell growth. The studies including time course. competitive inhibition. and cross-linking of iodinated BIM23014 to its receptor revealed a specific binding on MCF7 cells and showed a single 57.000 mol wt protein band in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. These results support the hypothesis that BIM23014 inhibits the growth of steroid-receptor positive cells of human breast cancers through its own receptor in estradiol-free conditions.
Selective depletion of macrophages prevents pituitary-adrenal activation in response to subpyrogenic, but not to pyrogenic, doses of bacterial endotoxin in rats, The mechanisms by which bacterial endotoxin [lipopolysaccharide (LPS)] stimulates the hypothalamo-pituitary-adrenal axis (HPAA) have not been elucidated. The present study was designed to investigate the involvement of macrophages in plasma ACTH and corticosterone responses to LPS administration in rats using selective in vivo macrophage depletion. Intraperitoneal administration of subpyrogenic doses of LPS to normal rats resulted in elevated plasma ACTH and corticosterone concentrations. measured 2 h later. The response showed a remarkable steep dose relationship. with minimal effective doses between 0.5-1.5 micrograms (ACTH) and 0.5 micrograms or less (corticosterone)/kg BW. Plasma PRL. LH. and catecholamine (norepinephrine. epinephrine) levels were not significantly changed under the conditions used. Only at 6 h after LPS administration was a small elevation of norepinephrine noted. To deplete macrophages. rats were injected with liposomes encapsulated with dichloromethylene diphosphonate (Cl2MDP). Histochemical (acid phosphatase) and immunocytochemical techniques (monoclonal antibodies to rat macrophages coded ED1 and ED3) were applied to examine the efficiency of macrophage elimination by the Cl2MDP liposomes in cytospins of peritoneal exudates and in sections of the liver and spleen. Since cells of the macrophage lineage are considered to be the main source of IL-1 in the circulation. we also measured circulating levels of immunoreactive interleukin-1 beta (IL-1) concentrations in control and Cl2MDP liposome-treated rats by the use of a newly developed RIA. Reduced numbers of macrophages were seen in peritoneal lavages of Cl2MDP liposome-treated animals. whereas the morphological appearance and numbers of mast cells. granulocytes. and T-cells were unaffected. Similarly. macrophages were effectively eliminated in the spleen. mesenteric lymph nodes. and liver. as inferred from the reduction of macrophage staining in these organs. Plasma IL-1 concentrations could only be detected in response to a pyrogenic (2.5 mg/kg. iv) and not to a subpyrogenic (0.025 mg/kg. ip) dose of LPS. The increase in plasma IL-1 concentrations in response to the pyrogenic dose of LPS. reaching levels of 20-40 ng/ml in control rats. was blunted in animals treated with the Cl2MDP liposomes. Macrophage depletion by Cl2MDP liposomes did not affect either resting plasma corticosterone levels or the corticosterone response to ether exposure. At subpyrogenic doses of LPS. plasma ACTH and corticosterone responses were completely prevented by macrophage depletion. In contrast. at pyrogenic doses of LPS. plasma ACTH and corticosterone responses were not significantly affected by depleting macrophages. These data demonstrate that activation of the HPAA by a subpyrogenic dose of LPS is macrophage dependent. However. macrophage-independent mechanisms mediate activation of the HPAA in response to a pyrogenic dose of LPS.
Down-regulation of messenger ribonucleic acid and protein levels for estrogen receptors by phorbol ester and calcium in MCF-7 cells, Treatment of MCF-7 cells. a human mammary carcinoma cell line. with phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] or calcium ionophore (A23187) was associated with striking effects on levels of estrogen receptor (ER) mRNA. specific binding of 17 beta-[3H]estradiol [( 3H]E2). and immunoreactive ER. TPA (10(-7) M) caused a time-dependent reduction of ER mRNA which was below the level of detection after 9 h. Similar effects of TPA appeared at levels of specific binding of [3H]E2 as well as immunoreactive ER. In contrast. TPA induced an increase in mRNA for beta-actin. Incubation of MCF-7 cells with increasing concentrations of TPA (10(-11)-10(-7) M) was associated with biphasic effects on ER mRNA and proteins. Levels of immunoreactive progesterone receptors (PR) were induced by E2 (10(-9) M) in a time-dependent manner. In the presence of TPA (10(-7) M). where ER levels were suppressed. no induction of PR was observed. Removal of TPA (10(-7) M) after 10 h (ER mRNA) or 22 h (ER proteins) of treatment was associated with a continued suppression of both mRNA and protein levels during the entire incubation period (48 h). Treatment with A23187 (2 x 10(-7) M) also caused a time-dependent down-regulation of levels of ER mRNA and proteins. These effects occurred somewhat more slowly than those of TPA. Levels of beta-actin mRNA were not changed by this treatment. These results indicate that changes in estrogen sensitivity are mediated by calcium-dependent protein kinases in human mammary carcinoma MCF-7 cells.
Triiodothyronine-receptor complex in rat brain: effects of thyroidectomy, fasting, food restriction, and diabetes, In vitro saturation analysis combined with quantification of T3. by an isotopic equilibrium technique or RIA. were used to examine the effects of thyroidectomy. fasting. diabetes. and food restriction on T3 concentration and specific binding in cerebral cortex and cerebellum. Fasting and food restriction did not affect the T3 binding parameters in the brain areas studied. Both thyroidectomy and diabetes were accompanied by a reduction in T3 content in nuclei from both cerebral cortex and cerebellum. but a decrease in T3 binding sites was only observed in both brain areas of diabetic animals. No significant differences in the binding affinity values among the experimental groups were seen. The diabetes-induced decrease in T3 content and receptor number were completely reversed by insulin treatment. Studies with fractionated nuclei from cerebral cortex and cerebellum showed that diabetes resulted in a reduction in T3 content and the number of receptors in glial nuclei from both brain areas. Although T3 content was also decreased in neuronal nuclei. the receptor concentration in these nuclear preparations did not change in concentration or affinity under the same conditions. These observations indicate that glial cells. not only have T3-binding characteristics similar to those of neuronal cells. but the T3 receptor number is decreased in the diabetes state.
Evidence that pretranslational and translational defects decrease serum insulin-like growth factor-I concentrations during dietary protein restriction, Dietary protein restriction causes GH resistance and decreases serum insulin-like growth factor-I (IGF-I) concentrations. To determine whether pretranslational or translational defects are involved in the decline of serum IGF-I concentrations during protein restriction. we measured hepatic IGF-I mRNA abundance together with the serum IGF-I peptide response to exogenous GH after 1 week of protein restriction (5% casein in diet; P5) in hypophysectomized rats. We compared these responses with those of hypophysectomized rats fed a protein-sufficient diet (15% casein in diet; P15) and given exogenous GH. A single injection of rat GH (200 micrograms/100 g BW) produced a comparable IGF-I mRNA increment in both groups (at 6 h. 7.8 +/- 1.1 arbitrary units in P5 vs. 8.2 +/- 1.1 in P15). but failed to raise serum IGF-I normally in the P5 group (at 6 h. 90 +/- 15 ng/ml in P5 vs. 216 +/- 63 in P15; P less than 0.01). The post-GH decline of the 7.5-kilobase (kb) IGF-I mRNA abundance was faster in P5 than in P15 animals. In another experiment in intact rats subjected to protein restriction. injections of pharmacological doses of rat GH (400 micrograms/100 g BW.day) for 1 week restored liver IGF-I mRNA abundance to normal without normalization of serum IGF-I (403 +/- 91 vs. 713 +/- 53 ng/ml; P less than 0.01). Our data suggest that 1) the machinery involved in the transcription of the liver IGF-I gene is intact in protein-restricted rats. because these animals retain the ability to muster normal IGF-I mRNA responses to high doses of exogenous GH; 2) the stability of the 7.5-kb IGF-I mRNA is probably decreased by the protein restriction. as suggested by the faster decline of the 7.5-kb transcript in P5 than in P15 hypophysectomized rats; and 3) the discrepancy between normal liver IGF-I mRNA abundance and low serum and liver IGF-I peptide concentrations suggests that translational stalling of the IGF-I mRNAs or increased serum IGF-I clearance is involved in the low serum IGF-I concentrations during dietary protein restriction.
Receptor-mediated endocytosis of an extracellular steroid-binding protein (TeBG) in MCF-7 human breast cancer cells, Previous studies suggested that an extracellular steroid-binding protein. testosterone-estradiol-binding globulin (TeBG). can enter a variety of cells. Experiments were conducted to determine whether uptake of TeBG occurs by nonspecific fluid phase endocytosis or via a specific receptor-mediated process. In human breast carcinoma cells (MCF-7) maintained on serum-free medium. exposure to radiolabeled TeBG resulted in cellular uptake. which reached a plateau by 6 h and could be inhibited 80% by competition with unlabeled TeBG. Uptake was temperature dependent with cell-associated radioactivity at 37 C being 1.6-fold higher than at 4 C. Subsequent exposure of cells to pronase resulted in release of the cell-associated TeBG by 88% and 44% at 4 C and 37 C. respectively. After transfer to media devoid of TeBG. approximately 35% of cell-associated radioactivity was release into the medium at 37 C; it was not possible to distinguish whether this was released from the cell surface or from inside the cell. Investigation of the localization of TeBG-gold complexes by electron microscopy revealed that TeBG first binds to the plasmalemma. Within 15 min label appears in receptosomes. which fuse to form multivesicular endosomes. By 1 h all label is observed in multivesicular endosomes and lysosomes. most of which are in the Golgi zone. Localization of the internalized radioactivity using classical cell fractionation techniques showed it appears in a symmetrical band exhibiting the same buoyant density as the lysosomal marker acid phosphatase. The observations reported here show that: 1) TeBG binds to MCF-7 cells; 2) some of the bound TeBG is taken up via a mechanism with all the characteristics of receptor-mediated endocytosis; and 3) within these cells TeBG is localized in endosomes and lysosomes.
Thyroid hormone increases muscle/fat glucose transporter gene expression in rat skeletal muscle, The enhancement of metabolic rate by thyroid hormone in target tissues is accompanied by increased glucose utilization. which in skeletal muscle and many other tissues is regulated at the level of membrane transport. To elucidate the role of thyroid hormone as a regulator of glucose transport in skeletal muscle. we have examined its effects on the expression of the muscle/fat (insulin-regulatable) glucose transporter. a distinct glucose transporter isotype whose expression is limited to insulin-sensitive tissues and which appears to be the major glucose transport protein in skeletal muscle. Treatment of hypothyroid rats with L-T3 (T3; 100 micrograms/100 g BW.day for 6 days) increased the abundance of the muscle/fat glucose transporter protein in crude membranes from hindlimb muscle. assessed by immunoblotting. to 145 +/- 8% of the control value in animals fasted for 17-20 h before death and to 159 +/- 16% of the control value in animals fed ad libitum (mean +/- SE). In purified plasma membranes. this effect of thyroid hormone was greater (208 +/- 23% and 219 +/- 13% of control in fasted and fed animals. respectively). Similar increases were found in an intracellular membrane fraction. Levels of muscle/fat glucose transporter mRNA were also increased in hindlimb muscle from the T3-treated rats. to 261 +/- 17% and 316 +/- 23% of control values in fasted and fed animals. respectively. In contrast. the erythroid glucose transporter protein and its mRNA. which are only weakly expressed in skeletal muscle but strongly expressed in brain. were not substantially increased by T3 treatment in either tissue. In experiments comparing hypothyroid. euthyroid. and chronically T4-treated animals. muscle/fat glucose transporter protein and mRNA abundance in skeletal muscle were also found to be dependent on thyroid status. Thyroid hormone may. thus. be an important regulator of the muscle/fat glucose transporter in skeletal muscle.
Evidence for a defect in growth hormone-releasing factor signal transduction in the dwarf (dw/dw) rat pituitary, Dwarf (dw/dw) rats exhibit a 40% reduction in body growth. isolated GH deficiency (less than 5% of normal pituitary content). and a decreased number of pituitary somatotrophs (15-20% of normal). Since GH-releasing factor (GRF) stimulates GH synthesis and secretion and somatotroph proliferation. and its effects are probably mediated by cAMP. we have assessed GH secretion and cAMP production in dw rat pituitaries in response to various GH secretagogues. Dispersed pituitary cells from dw rats were less sensitive (2.5-fold) to stimulation of GH secretion by GRF and showed a 25% reduction in the maximal GH response even after normalization of their reduced GH content. Intracellular cAMP was elevated 63-fold over basal levels in normal cells after 4 h in response to maximal GRF stimulation. but only 1.9-fold in dw cells. and even larger differences between the groups were found at earlier time points. The GH responses of dw cells to exogenous cAMP. however. were indistinguishable from normal. Forskolin. a direct stimulator of adenylate cyclase. elicited comparable maximal GH and cAMP responses. but an increased ED50. in dw cells. Activation of GS alpha by cholera toxin showed an increased ED50 and reduced GH and cAMP responses in dw cells. and marked decreases in these responses were observed in response to prostaglandin E1. Phorbol ester stimulation resulted in a reduced maximal GH response in dw cells without a change in sensitivity. These results provide evidence for a defect in the GRF signal transduction pathway associated with a decreased ability of GS alpha to stimulate adenylate cyclase in dw rat somatotrophs that may be causally linked to their GH deficiency.
Biological effects of sex hormone-binding globulin on androgen-induced proliferation and androgen metabolism in LNCaP prostate cells, The effects of purified human sex hormone-binding globulin (SHBG) on androgen-sensitive cell proliferation were examined using a human prostatic cell line (LNCaP-FGC). Cells were grown for 5 days in medium supplemented with 10% charcoal-dextran-stripped human serum (10% CDHuS) and various concentrations of 5 alpha-dihydrotestosterone (DHT). In 10% CDHuS. without SHBG. the proliferative response of these cells to androgens was typically biphasic. At low androgen concentrations. cell yields were increased in a dose-dependent manner. reaching maximal levels at 0.3 nM DHT. However. at high androgen concentrations. cell proliferation was inhibited. Addition of purified human SHBG to the medium reduced the effectiveness of DHT on both phases of the proliferative response in a dose-dependent manner. These effects of SHBG appeared to be due primarily to the high affinity binding of DHT by SHBG. Proliferative responses induced by the synthetic androgen methyltrienolone (R1881). which binds poorly to SHBG. were not affected by added SHBG. Furthermore. analysis of the protein binding of DHT revealed that cell proliferation correlated best with the concentration of DHT not bound to SHBG. The presence of SHBG in the medium also altered the uptake and metabolism of DHT. LNCaP-FGC cells rapidly metabolized DHT to a polar glucuronidase-sensitive conjugate of DHT. In 10% CDHuS. LNCaP-FGC cells conjugated virtually all of the added DHT during the 5-day experiment. However. in medium containing SHBG. the SHBG-bound DHT remained unconjugated; more than 90% of the DHT initially bound to SHBG was present in the medium at the end of the experiment as unconjugated DHT. Uptake of radiolabeled DHT by cells was also inhibited by SHBG. In summary. these experiments provide evidence that 1) SHBG-bound DHT is not a signal for DHT-induced cell proliferation and 2) SHBG inhibits the uptake and metabolism of DHT by LNCaP-FGC cells.
Effects of hyperthyroidism on rat liver glutathione metabolism: related enzymes' activities, efflux, and turnover, The effect of hyperthyroidism on liver glutathione (GSH) metabolism was studied in fed rats after the administration of 0.1 mg T3/kg body wt. for 1-3 consecutive days. T3-calorigenesis resulted in elevated rates of O2 consumption by the liver. together with higher lipid peroxidative processes and GSH depletion. compared to the euthyroid state. The study of the enzymes related to GSH metabolism revealed no significant changes in the activity of glutathione peroxidase and glutathione reductase. with decreases (27-41%) in the activity of glutathione-S-transferases and marked elevation (133%) in that of gamma-glutamyl transferase. 3 days after T3 treatment. At this experimental time. the activity of the NADPH generating enzyme glucose-6-phosphate dehydrogenase was enhanced by 84% in the liver of T3-treated rats. compared to that in the controls. In these conditions. the canalicular efflux of GSH was not altered by T3. whereas net and fractional rates of sinusoidal GSH efflux were enhanced by 86% and 288%. respectively. The latter effect of hyperthyroidism was found in parallel with an enhancement in sinusoidal lactate dehydrogenase and protein release. suggesting that loss of GSH might be related to a permeabilization of the hepatocyte plasma membrane. Liver GSH turnover assessed after a pulse of [35S]cysteine resulted in a 209% increase in the fractional turnover rate in hyperthyroid rats over controls. under steady state conditions for both hepatic GSH pools. leading to a 62% enhancement in the respective turnover flux. Data suggest that the elevation in the sinusoidal GSH efflux from the liver and in the hepatic capacity to degrade the tripeptide are major mechanisms leading to GSH depletion in the liver of T3-treated rats. As the increased GSH use is not balanced by the elevation in GSH synthesis. a lower steady state level of GSH is attained in the liver.
Salmon calcitonin prevents cyclosporin-A-induced high turnover bone loss, Cyclosporin-A (CsA) has greatly influenced the outcome of organ transplantation and has also been effective in the treatment of many autoimmune diseases. Unfortunately. it has deleterious effects on bone remodelling. causing a high turnover bone loss. with bone resorption exceeding bone formation. Salmon calcitonin (SCtn) has been shown to inhibit bone resorption in high turnover states such as Paget's disease and postmenopausal osteoporosis. In an attempt to attenuate the high turnover bone remodelling caused by CsA alone. we studied the bone mineral effects of CsA in combination with SCtn in male Sprague-Dawley rats. Group A (n = 20) received vehicle as control. group B (n = 20) received CsA (15 mg/kg BW) by daily gavage and SCtn vehicle sc. group C (n = 20) received SCtn (1.3 IU/kg BW) daily sc and CsA vehicle. and group D (n = 20) received a combination of CsA and Ctn daily. as described above. Rats were bled weekly for determination of circulating biochemical bone parameters. Eight rats from each group were killed on day 14 (short term). and the remaining rats were killed on day 28 (long term). Tibiae were removed for bone histomorphometry after death. which revealed a reduction of trabecular bone volume and an increase in osteoclast number induced by CsA alone. These changes were significantly attenuated by the combination of CsA and SCtn to resemble the histomorphometry of the control group. The inhibition of osteoclast number by SCtn is the most plausible mechanism by which the combination therapy attenuates the high turnover bone loss induced by CsA alone.
Hypohydration does not impair skeletal muscle glycogen resynthesis after exercise, The purpose of this investigation was to examine the effects of moderate hypohydration (HY) on skeletal muscle glycogen resynthesis after exhaustive exercise. On two occasions. eight males completed 2 h of intermittent cycle ergometer exercise (4 bouts of 17 min at 60% and 3 min at 80% of maximal O2 consumption/10 min rest) to reduce muscle glycogen concentrations (control values 711 +/- 41 mumol/g dry wt). During one trial. cycle exercise was followed by several hours of light upper body exercise in the heat without fluid replacement to induce HY (-5% body wt); in the second trial. sufficient water was ingested during the upper body exercise and heat exposure to maintain euhydration (EU). In both trials. 400 g of carbohydrate were ingested at the completion of exercise and followed by 15 h of rest while the desired hydration level was maintained. Muscle biopsy samples were obtained from the vastus lateralis immediately after intermittent cycle exercise (T1) and after 15 h of rest (T2). During the HY trial. the muscle water content was lower (P less than 0.05) at T1 and T2 (288 +/- 9 and 265 +/- 5 ml/100 g dry wt. respectively; NS) than during EU (313 +/- 8 and 301 +/- 4 ml/100 g dry wt. respectively; NS). Muscle glycogen concentration was not significantly different during EU and HY at T1 (200 +/- 35 vs. 251 +/- 50 mumol/g dry wt) or T2 (452 +/- 34 vs. 491 +/- 35 mumol/g dry wt). These data indicate that. despite reduced water content during the first 15 h after heavy exercise. skeletal muscle glycogen resynthesis is not impaired.
Rapid orocecal transit in chronically active persons with high energy intake, Although chronic physical activity by humans can raise energy requirements and energy intake severalfold above sedentary levels. whether these increases alter digestive strategy remains unknown. To investigate this possibility. food passage rate (mouth-to-large intestinal lactulose transit) and absorption (xylose) were compared in a cross section of young men chosen to represent a wide range of daily physical activity and food intake. In 20 men (energy intake 1.272-5.342 kcal/day). resting mouth-to-cecum transit was faster in high caloric consumers (r = -0.69. P less than 0.01). In contrast. xylose absorption (n = 26; measured either as urinary xylose excretion or integrated breath H2 production from the sugar) was unrelated to food intake. Dietary fiber intake was uncorrelated with energy intake. This apparent human digestive strategy of rapid transit across the gut absorptive surface. without a sacrifice in absorption. parallels the adaptations made by several animal species similarly faced with increased energy demand at constant fiber intake. We therefore conclude that the hyperphagia of chronic exercise in humans may be linked with significant gastrointestinal adaptations.
Changes in insulin response to glucose after exercise training in partially pancreatectomized rats, The effects of exercise training on glucose-stimulated insulin secretion (GSIS) were studied in male Sprague-Dawley rats made mildly to severely diabetic by partial pancreatectomy. Exercise trained (10 wk treadmill; T) and untrained (Unt) rats were grouped according to posttraining fed-state hyperglycemia as follows: T less than 200 and Unt less than 200 (glucose concn less than 200 mg/dl). T 200-300 and Unt 200-300 (glucose concn 200-300 mg/dl). and T greater than 300 and Unt greater than 300 (glucose concn greater than 300 mg/dl). After exercise training. hyperglycemic glucose clamps were performed in awake rats by elevation of arterial blood glucose concentration 126 mg/dl above fasting basal levels for 90 min. Exercise training significantly increased muscle citrate synthase activity. Prevailing hyperglycemia was reduced during the 10-wk exercise training period in all T rats with fed-state glucose concentrations less than 300. and only 53% of Unt rats in these groups had reduced glycemia. GSIS was significantly higher in T less than 200 [2.4 +/- 0.7 (SD) ng/ml at 90 min] than in Unt less than 200 (1.5 +/- 0.3). A similar response was found for T 200-300 (1.1 +/- 0.3 ng/dl) vs. Unt 200-300 (0.7 +/- 0.1) but not T greater than 300 (0.36 +/- 0.2) vs Unt greater than 300 (0.44 +/- 0.05). Sham-operated control rats had insulin concentrations of 6.6 +/- 1.6 ng/ml at the 90th min of the clamp. Acute exercise reduced fed-state glycemia in rats with mild-to-moderate (less than 300 mg/dl) diabetes.
Stimulation of glucose transport in skeletal muscle by hypoxia, Hypoxia caused a progressive cytochalasin B-inhibitable increase in the rate of 3-O-methylglucose transport in rat epitrochlearis muscles to a level approximately six-fold above basal. Muscle ATP concentration was well maintained during hypoxia. and increased glucose transport activity was still present after 15 min of reoxygenation despite repletion of phosphocreatine. However. the increase in glucose transport activity completely reversed during a 180-min-long recovery in oxygenated medium. In perfused rat hindlimb muscles. hypoxia caused an increase in glucose transporters in the plasma membrane. suggesting that glucose transporter translocation plays a role in the stimulation of glucose transport by hypoxia. The maximal effects of hypoxia and insulin on glucose transport activity were additive. whereas the effects of exercise and hypoxia were not. providing evidence suggesting that hypoxia and exercise stimulate glucose transport by the same mechanism. Caffeine. at a concentration too low to cause muscle contraction or an increase in glucose transport by itself. markedly potentiated the effect of a submaximal hypoxic stimulus on sugar transport. Dantrolene significantly inhibited the hypoxia-induced increase in 3-O-methylglucose transport. These effects of caffeine and dantrolene suggest that Ca2+ plays a role in the stimulation of glucose transport by hypoxia.
Effect of vasoconstriction on longitudinal distribution of pulmonary vascular pressure and volume, We used an improved version of the low-viscosity bolus method to evaluate longitudinal (arterial-to-venous) differences in the sensitivity of the dog lung lobe vasculature to selected vasoconstrictor stimuli. including hypoxia. and serotonin. histamine. and norepinephrine infusions. This method revealed a bimodal distribution of local vascular resistance vs. cumulative vascular volume under the zone 3 conditions studied. Our interpretation of the two modes of relatively high resistance is that they correspond to high resistance per unit volume segments of the arteries and veins upstream and downstream from the relatively low resistance per unit volume capillary bed. Thus an increase in the height of the upstream and downstream modes of the resistance distribution suggests constriction in small arteries and veins. respectively. Horizontal displacement of the modes along the cumulative volume axis suggests changes in the distribution of volume among the arteries. veins. and capillary bed. By use of these criteria. the results are consistent with the concept that each of the vasoconstrictor stimuli studied had a different longitudinal response pattern. Hypoxia constricted mainly small arteries. whereas serotonin constricted small and large arteries. Histamine constricted large and small veins. and norepinephrine constricted large and small veins and arteries.
Effect of inspiratory muscle fatigue on breathing pattern during inspiratory resistive loading, The purpose of this study was to determine whether induction of either inspiratory muscle fatigue (expt 1) or diaphragmatic fatigue (expt 2) would alter the breathing pattern response to large inspiratory resistive loads. In particular. we wondered whether induction of fatigue would result in rapid shallow breathing during inspiratory resistive loading. The breathing pattern during inspiratory resistive loading was measured for 5 min in the absence of fatigue (control) and immediately after induction of either inspiratory muscle fatigue or diaphragmatic fatigue. Data were separately analyzed for the 1st and 5th min of resistive loading to distinguish between immediate and sustained effects. Fatigue was achieved by having the subjects breathe against an inspiratory threshold load while generating a predetermined fraction of either the maximal mouth pressure or maximal transdiaphragmatic pressure until they could no longer reach the target pressure. Compared with control. there were no significant alterations in breathing pattern after induction of fatigue during either the 1st or 5th min of resistive loading. regardless of whether fatigue was induced in the majority of the inspiratory muscles or just in the diaphragm. We conclude that the development of inspiratory muscle fatigue does not alter the breathing pattern response to large inspiratory resistive loads.
Metabolic and work efficiencies during exercise in Andean natives, Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives from the Andes than in lowlanders. In exploring how this was achieved. we found that. for a given work rate. Quechua highlanders at 4.200 m accumulated substantially less lactate than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon. known as the lactate paradox. was entirely refractory to normoxia-hypoxia transitions. In lowlanders. the lactate paradox is an acclimation; however. in Quechuas. the lactate paradox is an expression of metabolic organization that did not deacclimate. at least over the 6-wk period of our study. Thus it was concluded that this metabolic organization is a developmentally or genetically fixed characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work. which is also advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally. minimizing the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per metabolic power input); this was evident at all work rates but was most pronounced at submaximal work rates (efficiency approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs. metabolic power input did not extrapolate to the origin. it was concluded 1) that exercise in both groups sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was downregulated in Andean natives by thus far unexplained mechanisms.
Recovery after intense chronic stimulation: a physiological study of cat's fast muscle, Adult cats were used to study the recovery of muscles that had become altered by long-term electrical stimulation. Chronic activation was delivered to the deafferented common peroneal nerve (no pain. no reflexes). and contractile properties were measured for peroneus longus muscle. After 4 wk of great daily amounts of treatment at moderately high pulse rates (30-40 Hz delivered during 50% of daily time). the peroneus longus became considerably weaker. demonstrated a longer time course of twitches and a slower rate of rise of tetanic force. and became less fatigable. Furthermore. its twitch-to-tetanus ratio decreased. and there was no longer any depression of electromyogram (EMG) amplitude during fatigue tests. After 4 wk of subsequent rest it was found that 1) twitch speed and maximum tetanic force had returned to nearly normal values. 2) fatigue resistance showed some return toward normal but was still significantly enhanced. and 3) no significant recovery had yet occurred of the altered twitch-to-tetanus ratio. the abolished EMG depression. or the slowed rate of rise of tetanic tension. During the poststimulation recovery period. the progressive increase of isometric twitch speed was not promoted by the administration of small daily amounts of high-rate stimulation (100-Hz bursts). The results support the conclusions that 1) the time course of recovery differs among physiological properties. 2) the EMG and force reactions that occur during a fatigue test are not strongly coupled. as demonstrated by the alterations of their relationship during poststimulation recovery. and 3) in cat's fast muscles. there is still no evidence for rate-specific effects of chronic stimulation on isometric twitch speed.
Exercise endurance and arterial desaturation in normobaric hypoxia with increased chemosensitivity, We studied whether exercise endurance under normobaric hypoxia can be enhanced by increasing hypoxic ventilatory sensitivity with almitrine bismesylate (ALM). On both ALM and placebo (PL) days. resting subjects breathed a hypoxic gas mixture (an inspired O2 fraction of 10.4-13.2%). which lowered resting arterial O2 saturation (SaO2) to 80%. After 15 min of rest there was a 3-min warm-up period of exercise at 50 W (light) on a cycle ergometer. followed by a step increase in load to 60% of the previously determined maximum power output with room-air breathing (moderate). which was maintained until exhaustion. With PL. SaO2 decreased rapidly with the onset of exercise and continued to fall slowly during moderate exercise. averaging 71.0 +/- 1.8% (SE) at exhaustion. With ALM. saturation did not differ from PL during air breathing but significantly exceeded SaO2 with PL. by 3.4% during resting hypoxia. by 4.0% at the start of exercise. and by 5.9% at exhaustion. Ventilation was not affected by ALM during air breathing and was slightly. although not significantly. increased during hypoxic rest and exercise. ALM was associated with an increased heart rate during room air breathing but not during hypoxia. Endurance time was 20.6 +/- 1.6 min with ALM and 21.3 +/- 0.9 min with PL. During hypoxic exercise. the potential benefit of greater saturation with ALM is apparently offset by other unidentified factors.
Splanchnic sympathetic nerve activity and circulating catecholamines in the hyperthermic rat, The mechanisms responsible for the initial rise in splanchnic vascular resistance with environmental heating are controversial. and those responsible for the subsequent fall in splanchnic resistance in the severely hyperthermic animal are unknown. Thus we examined the effect of environmental heating on plasma catecholamine concentration. splanchnic sympathetic nerve activity (SNA). and select blood chemistries. In one study. 25 male Sprague-Dawley rats (270-300 g) were assigned to one of five groups on the basis of their core temperature (Tc. 37. 39. 41. 43. or 44 degrees C) at death. Heart rate (HR). mean arterial pressure (MAP). and Tc were monitored during heat stress under alpha-chloralose anesthesia (12.5 mg.ml-1.h-1). At each predetermined Tc. an aortic blood sample was drawn and analyzed for mean plasma concentration of norepinephrine (NE). epinephrine (E). Na+. K+. and lactate. From 41 to 43 degrees C. NE and E rose significantly. and the animals became hyperkalemic and lactacidemic. In a separate study. we quantitated SNA from the greater splanchnic nerve during heat exposure of artificially respired animals anesthetized with pentobarbital sodium (50 mg/kg). MAP. splanchnic SNA. and Tc were recorded. Tc was elevated from 37.0 +/- 0.12 to 41.3 +/- 0.18 degrees C in 70 min by increase of ambient temperature to 38 degrees C in an environmental chamber. Splanchnic SNA was 54 +/- 8 spikes/s at a Tc of 37 degrees C and increased significantly as Tc exceeded 39 degrees C (P less than 0.05).
Pulmonary vascular reactivity in Fischer rats, We previously reported that Fischer (F) rat lungs developed more extensive injury when challenged with oxidants than age-matched Sprague-Dawley (SD) rat lungs. We now describe a reduced pulmonary vascular response to alveolar hypoxia and angiotensin II (ANG II) in F compared with SD rats. The comparative studies were performed with isolated lungs perfused with salt solution or blood. catheter-implanted awake rats. and isolated main pulmonary arterial rings. Isolated lungs from F rats perfused with either blood or salt solution had reduced vasoconstriction in comparison with lungs from SD rats when exposed to alveolar hypoxia or challenged with ANG II. Instrumented awake F rats had a smaller mean increase in total pulmonary vascular resistance (PVR) than SD rats (35 vs. 94 mmHg.min.l-1. P less than 0.05) when challenged with 8% oxygen. The contractile response of isolated pulmonary artery but not thoracic aortic rings to KCl and ANG II was reduced in F compared with SD rats. In addition. F rats exposed to 4 wk of hypobaric hypoxia developed less pulmonary hypertension and right ventricular hypertrophy (when corrected for the hematocrit) than SD rats. We conclude that the oxidant stress-sensitive inbred F rat strain is characterized by a lung vascular bed that is relatively unresponsive to vasoconstricting stimuli. The mechanism underlying this genetic difference in lung vascular control remains to be defined.
Energy state and vasomotor tone in hypoxic pig lungs, To evaluate the role of energy state in pulmonary vascular responses to hypoxia. we exposed isolated pig lungs to decreases in inspired PO2 or increases in perfusate NaCN concentration. Lung energy state was assessed by 31P nuclear magnetic resonance spectroscopy or measurement of adenine nucleotides by high-pressure liquid chromatography in freeze-clamped biopsies. In ventilated lungs. inspired PO2 of 200 (normoxia). 50 (hypoxia). and 0 Torr (anoxia) did not change adenine nucleotides but resulted in steady-state pulmonary arterial pressure (Ppa) values of 15.5 +/- 1.4. 30.3 +/- 1.8. and 17.2 +/- 1.9 mmHg. respectively. indicating vasoconstriction during hypoxia and reversal of vasoconstriction during anoxia. In degassed lungs. similar changes in Ppa were observed; however. energy state deteriorated during anoxia. An increase in perfusate NaCN concentration from 0 to 0.1 mM progressively increased Ppa and did not alter adenine nucleotides. whereas 1 mM reversed this vasoconstriction and caused deterioration of energy state. These results suggest that 1) pulmonary vasoconstrictor responses to hypoxia or cyanide occurred independently of whole lung energy state. 2) the inability of the pulmonary vasculature to sustain hypoxic vasoconstriction during anoxia might be associated with decreased energy state in some lung compartment. and 3) atelectasis was detrimental to whole lung energy state.
Effects of lower limb unloading on skeletal muscle mass and function in humans, A model to simulate effects of microgravity on skeletal muscle mass and function in humans has been developed. Unilateral lower limb unloading that allowed ankle. knee. and hip joint mobility was conducted in six healthy men by suspending one lower limb and having the subjects walk on crutches. They performed maximal unilateral concentric or eccentric quadriceps actions at different angular velocities before and after 4 wk of suspension and after 4 days and after 7 wk of uncontrolled recovery. Peak torque (PT) and angle-specific torque (AST) were measured. Muscle cross-sectional area (CSA) and radiological density (RD) of the thigh were assessed by means of computerized tomography. Concentric and eccentric PT and AST across speeds decreased (P less than 0.05) by 22 and 16%. respectively. in response to unloading. At 4 days of recovery PT (-11%) and AST (-7%) were still lower (P less than 0.05) than before. Muscle CSA and RD decreased (P less than 0.05) by 7 and 6%. respectively. After 7 wk of recovery PT. AST. CSA. and RD had returned to normal. The control limb showed no changes over the experimental period except for a 6% decrease (P less than 0.05) in RD. It is suggested that this human model of unloading could serve to simulate effects of microgravity on skeletal muscle mass and function because reductions in muscle mass and strength were of similar magnitude to those produced by bed rest.
Chest radiograph changes after cardiopulmonary bypass in children, To determine the spectrum of pediatric chest radiograph changes after cardiopulmonary bypass. 98 children (mean age = 5.9 yr. range 4 wk-16 yr) were studied for 3 days postoperatively. Daily A-P radiographs were evaluated for atelectasis. cardiomegaly. pleural effusions. diaphragmatic elevation. mediastinal widening. and pulmonary infiltrates. The overall incidence of atelectasis was 82%. with left lower lobe atelectasis the most common (64%). Right upper lobe atelectasis occurred in 35% of patients. far more common than in the adult. Radiographic changes were then compared with independent variables including patient weight. age. duration of bypass. and fluid balance by multiple linear regression. Pleural effusion correlated with patient weight and duration of bypass. Diaphragmatic elevation correlated with patient weight. Cardiomegaly correlated with patient age. Net fluid balance was a poor predictor of postoperative chest radiograph changes. We conclude that radiographic changes are common after cardiopulmonary bypass in children. that the overall incidence is not markedly different from adults. and that right upper lobe atelectasis occurs more frequently in children.
Obliterations of the proximal subclavian artery: to bypass or to anastomose, A clinical series has been analysed to determine which of two similar. extrathoracic "extraanatomic" methods of treating proximal blocks of the subclavian artery is the superior option. From 1975 until 1988 direct carotid-subclavian anastomosis was used in 32 patients and carotid-subclavian bypass in 19. There were no statistically significant differences for the probability of postoperative survival (p less than 0.877 Breslow; p less than 0.774 Mantel). intraoperative blood loss or the duration of anaesthesia. Those patients who had undergone subclavian artery repair had a significantly longer survival than those following carotid bifurcation endarterectomy (p less than 0.002 Breslow. p less than 0.0002 Mantel). As patients with subclavian lesions have a reasonable life-expectancy. they may possibly experience late complications of their vascular repair. Therefore it seems important to select the most durable operation. and direct carotid subclavian anastomosis has a significantly greater patency rate than bypass (p less than 0.006 Breslow. p less than 0.006 Mantel). Patients with preoperative symptoms of cerebrovascular insufficiency had a lower probability of survival than those with upper extremity claudication. although this did not reach statistical significance (p less than 0.205 Breslow; p less than 0.198 Mantel).
A modified technique of pre-operative aortography to demonstrate the complete arterial tree of the lower limb, One hundred consecutive aortograms were studied to establish the efficacy of conventional arteriography in demonstrating distal vessels and the pedal arch. The standard technique was modified by using a long injection time. a large volume of contrast material (iopamidol 370). prolonged filming and multiple exposures of the feet. On the basis of these examinations each limb was classified as having aorto-iliac disease (18 limbs). superficial femoral disease (103 limbs). combined segment disease (28 limbs) or generalised disease (51 limbs). Calf and ankle arteries were seen in 196 of the 200 limbs (98%). Patency of the pedal arch was established in 184 (92%). Fourteen percent of the group of patients with combined segment disease did not have their pedal arch visualised and this group contained most of the examination failures. This modified method of aortography can demonstrate the entire arterial tree from the aorta to the foot in 92% of limbs with symptomatic chronic atherosclerotic disease. This allows the majority of peripheral vascular reconstructions to be planned and performed without the need for intra-operative arteriography.
The "ultraperipheral" revascularization in arteriosclerotic obstruction of tibial vessels. Experimental study, In arteriosclerotic obstruction of the main tibial arteries. the tibial collateral vessels are usually patent. and about 70% of these arteries are potentially suitable for surgical revascularization. The present study aimed at investigating the practical feasibility of a selective revascularization procedure on these tibial muscular arteries (ultraperipheral revascularization). Six lower limbs amputated at thigh level for arteriosclerotic gangrene with complete obstruction of the main tibial arteries. were studied: the tibial collateral muscular vessels showed patency in 65% of cases. The authors propose a surgical technique for the revascularization of these peripheral vessels with the use of a vascular prosthesis. The "post-operative" angiographic studies showed that revascularization of these peripheral muscular arteries was possible.
Takayasu's disease and atherosclerosis, The aortic arch syndrome characterised by diminished or absent pulses in the arteries arising from the aortic arch has many etiologies. such as syphilitic aortitis. dissection of the aorta. atherosclerosis and Takayasu's arteritis. The diagnostic criteria of Takayasu's arteritis often do not mention histological investigations. We observed a case of an aortic arch syndrome. presenting as a classical case of Takayasu's arteritis but caused by a severe form of atherosclerosis.
Internal mammary artery subclavian vein fistula following internal jugular vein catheterization. A case report and review of the literature, We have recently treated a patient with an arteriovenous fistula that developed after a right internal jugular vein catheterization. The patient was found to have a pulsatile hematoma and a bruit five days after removal of a temporary pacemaker catheter. Digital subtraction arteriography documented a fistula between the right internal mammary artery and subclavian vein. The fistula was surgically repaired via the cervical route. To our knowledge. an arteriovenous fistula between the internal mammary artery and subclavian vein has not been previously described as a complication of a percutaneous internal jugular vein catheterization.
Strut fracture after Greenfield filter placement, We present the unusual event of strut fracture of a Greenfield filter. This being an extremely rare complication. we postulate a possible cause of fracture and present a review of literature.
Impaired autoregulation of glomerular capillary hydrostatic pressure in the rat remnant nephron, In the present micropuncture study. the autoregulation of glomerular capillary hydrostatic pressure (PG) in Munich-Wistar rats 24 h after 75% nephrectomy (Nx) or sham operation (Sh) was investigated. The effect of varying renal perfusion pressure (RPP) on paired determinations of directly measured PG was evaluated in glomeruli of nephrons in which distal fluid delivery was present (unblocked). Autoregulation of PG in Sh glomeruli with unblocked tubules occurred at RPP values between 99.5 +/- 1.0 and 132.1 +/- 1.0 mmHg. In contrast. in Nx glomeruli with unblocked tubules PG increased by 0.32 +/- 0.07 mmHg/mmHg increase in RPP over this same range of RPP (P less than 0.0001). To determine whether enhanced prostaglandins synthesis was responsible for the altered regulation of PG in Nx glomeruli. we repeated the micropuncture measurements in a setting of prostaglandin synthesis inhibition. Although prostaglandins synthesis inhibition did not affect the autoregulation of PG in Sh glomeruli. it did normalize the autoregulatory capacity for PG of Nx glomeruli with unblocked tubules. Thus. acute Nx is associated with a significant loss of the autoregulatory capacity for PG and this impairment appears to be related to a prostaglandin-mediated alteration of the responsiveness of the vascular effector site for autoregulation.
Sarcoplasmic reticulum-associated cyclic adenosine 5'-monophosphate phosphodiesterase activity in normal and failing human hearts, Sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was examined in microsomes prepared from the left ventricular myocardium of eight heart transplant recipients with end-stage idiopathic dilated cardiomyopathy and six unmatched organ donors with normal cardiac function. At cAMP concentrations less than or equal to 1.0 microM. sarcoplasmic reticulum-associated cAMP phosphodiesterase activity was functionally homogeneous. cAMP phosphodiesterase activity was inhibited competitively by cGMP (Ki = 0.031 +/- 0.008 microM) and the cilostamide derivative OPC 3911 (Ki = 0.018 +/- 0.004 microM). but was essentially insensitive to rolipram. Vmax and Km were 781.7 +/- 109.2 nmol/mg per min and 0.188 +/- 0.031 microM. respectively. in microsomes prepared from nonfailing hearts and 793.9 +/- 68.9 nmol/mg per min and 0.150 +/- 0.027 microM in microsomes prepared from failing hearts. Microsomes prepared from nonfailing and failing hearts did not differ with respect to either the ratio of cAMP phosphodiesterase activity to ATP-dependent Ca2+ accumulation activity or the sensitivity of cAMP phosphodiesterase activity to inhibition by OPC 3911. These data suggest that the diminished inotropic efficacy of phosphodiesterase inhibitors in failing human hearts does not result from changes in the level. kinetic properties. or pharmacologic sensitivity of sarcoplasmic reticulum-associated cAMP phosphodiesterase activity.
Interleukin 4 suppresses the spontaneous growth of chronic myelomonocytic leukemia cells, We studied the effects of IL-4 on the spontaneous proliferation of chronic myelomonocytic leukemia (CMMoL) cells in vitro. IL-4 (100 U/ml) suppressed the spontaneous DNA synthesis by approximately 50% in 5 of 8 cases examined. IL-4 (100 U/ml) also inhibited the spontaneous colony formation by CMMoL cells in a methylcellulose culture by 50-97% in all of the 10 cases in which spontaneous colonies were formed. This IL-4-mediated suppression of the growth of CMMoL cells was completely abolished by the addition of anti-IL-4 neutralizing antibodies. The spontaneous CMMoL colonies were substantially suppressed by the addition of either anti-IL-6 or anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) antibodies to the colony assay system: the addition of both anti-IL-6 and anti-GM-CSF antibodies resulted in greater than 80% inhibition of the colony formation by CMMoL cells. On the other hand. none of anti-IL-1-beta. anti-granulocyte-CSF. anti-macrophage-CSF. or anti-tumor necrosis factor-alpha antibodies affected the CMMoL colony formation. In the supernatants from 24-h cultures of CMMoL cells. high levels of IL-6 and GM-CSF were demonstrated in 9 of 9 and 2 of 9 cases examined. respectively. IL-4 (100 U/ml) almost completely inhibited the secretion of IL-6 and GM-CSF by CMMoL cells. These observations suggest that IL-4 suppresses the spontaneous proliferation of CMMoL cells by inhibiting their production of IL-6 and/or GM-CSF. both of which could act in vitro as an autocrine growth factor for CMMoL cells.
Immunoregulation in onchocerciasis. Functional and phenotypic abnormalities of lymphocyte subsets and changes with therapy, To help define the immunoregulatory defects in patients with onchocerciasis. flow cytometric analysis of circulating lymphocyte subpopulations was performed in parallel with functional assays. No significant differences in CD4/CD8 ratios were seen when microfilariae-positive individuals from Guatemala were compared with Guatemalan controls. However. the infected individuals had significantly increased numbers of circulating CD4+CD45RA+ lymphocytes (mean 38.3%) when compared with controls (mean 16.0%). Coexpression of the activation marker HLA-DR was significantly increased on CD4+ cells from infected individuals. In contrast. no up-regulation of HLA-DR was seen on CD8+ or CD19+ cells. At 1 year after initiation of treatment with semiannual doses of the microfilaricide ivermectin. there were significant increases (P less than 0.05) in the percentage of CD4+CD45RA- cells. the percentage of CD4+HLA-DR+ cells. and mitogen-induced lymphokine production (IL-2. IL-4). Despite these changes. parasite-specific IL-2 and IL-4 production which had been undetectable before treatment did not manifest itself even by the 2-yr follow-up. Defects in the T-cell activation pathway in Onchocerca volvulus-infected individuals may thus exist at several independent points; a state of parasite antigen-specific tolerance appears to remain even after the relative reversal of other generalized immunoregulatory defects.
An acquired antithrombin autoantibody directed toward the catalytic center of the enzyme, Antibody inhibitors against human thrombin are rare and have remained poorly characterized. We report the case of a 40-yr-old patient who developed a potent thrombin inhibitor revealed by mild bleeding symptoms and marked prolongation of most laboratory clotting times. After two years of evolution. he died from cerebral hemorrhage. The inhibitor. a polyclonal IgG. was associated with hematological and immunological criteria of autoimmune disorder. Antithrombin IgG was isolated from the patient's plasma by protein A- and thrombin-affinity chromatography. Fab fragments inhibited amidolytic activity of alpha thrombin. and thrombin-thrombomodulin catalyzed protein C activation with a Ki of approximately 10(-8) M in a noncompetitive manner. Alpha to gamma conversion of thrombin resulted in a moderate loss of affinity for the inhibitor. Upon complex formation of thrombin with staphylocoagulase or alpha 2-macroglobulin (alpha 2M). inhibition was decreased by two orders of magnitude and acquired an apparent competitive character. In Western blot experiments. the antibody reacted with active alpha-thrombin. did not react with chloromethylketone-inhibited thrombin and reacted with a lower affinity with iPr2P-thrombin. The inhibitor did not block thrombin binding to benzamidine-. heparin-. or fibrin-Sepharose. but displaced proflavin from its complex with thrombin. Taken together. these results indicate that the patient's autoantibody recognized a conformational structure which includes. at least in part. the apolar binding site adjacent to the catalytic site of thrombin.
Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts, Expression of the two sarcomeric actins. alpha-skeletal and alpha-cardiac. is regulated in the rodent heart in response to developmental. hormonal. and hemodynamic stimuli. Little is known in man. except that both isogenes were found to be coexpressed in three adult ventricles. In this report. we investigated the isoactin mRNA composition in ventricles from 21 control patients (4 fetal. 5 juvenile. 12 adult) and from 15 patients undergoing cardiac transplantation (5 idiopathic dilated cardiomyopathies. 5 ischemic myopathies with myocardial infarcts. 5 diverse etiologies) by two different and complementary techniques: RNA dot blot analysis with specific cDNA probes. and primer extensions with an oligonucleotide common to alpha-cardiac and alpha-skeletal actins. In the case of dot blot analysis. quantification of each isoform was performed by using as standards RNA transcripts obtained from cloned human alpha-actin sequences. and the total amount of sarcomeric actin mRNA was evaluated as a function of total poly(A+)RNA. We found that both isogenes are always coexpressed. and that the isoactin pattern changes during development. In utero and in neonatal hearts. alpha-skeletal actin mRNA represents less than or equal to 20% of sarcomeric actins. it increases to 48 +/- 6% during the first decade after birth and becomes the predominant isoform of adult hearts (60.4 +/- 8.5%). The 15 adult failing hearts exhibited the same isoactin pattern as the control ones (62.84 +/- 11.06%). and there was no difference in expression between patients with dilated cardiomyopathy or ischemic heart disease. These observations demonstrate that cardiac development in man. in contrast to rodent heart. is characterized by an up-regulation of the skeletal actin gene. the expression of which does not change in hypertrophied and failing hearts. and suggest that the actin and myosin heavy chain families are independently regulated in human heart.
The rapid and reversible activation of a calcium-independent plasmalogen-selective phospholipase A2 during myocardial ischemia, Recent studies have demonstrated the existence of two members of a novel family of calcium-independent plasmalogen-selective phospholipases A2 in mammalian myocardium (Wolf. R. A.. and R. W. Gross. 1985. J. Biol. Chem. 260:7295-7303; and Hazen. S. L.. D. A. Ford. and R. W. Gross. 1991. J. Biol. Chem. 266:5629-5633). To examine the potential role of these calcium-independent phospholipases A2 in mediating membrane dysfunction during early myocardial ischemia. the temporal course of alterations in phospholipase A2 activity during global ischemia in Langendorf perfused rabbit hearts was quantified and compared with traditionally accepted markers of myocytic ischemic injury and anaerobic metabolism. We now report that membrane-associated calcium-independent plasmalogen-selective phospholipase A2 activity increased over 400% during 2 min of global ischemia (P less than 0.01). was near maximally activated (greater than 10-fold) after only 5 min of ischemia. and remained activated throughout the entire ischemic interval examined (2-60 min). Activation of membrane-associated plasmalogen-selective phospholipase A2 after 5 min of myocardial ischemia was rapidly reversible during reperfusion of ischemic tissue. Both the activation of phospholipase A2 and its reversibility during reperfusion were temporally correlated to alterations in myocytic anaerobic metabolism. Furthermore. activation of membrane-associated phospholipase A2 was essentially complete before electron microscopic evidence of cellular damage. Collectively. these results identify dynamic alterations in calcium-independent plasmalogen-selective phospholipase A2 activity during myocardial ischemia which precede irreversible cellular injury and demonstrate that activation of plasmalogen-selective phospholipase A2 is amongst the earliest biochemical alterations in ischemic myocardium.
Binding domains of stimulatory and inhibitory thyrotropin (TSH) receptor autoantibodies determined with chimeric TSH-lutropin/chorionic gonadotropin receptors, We examined the relative effects of thyrotropin (TSH) and TSH receptor autoantibodies in the sera of patients with autoimmune thyroid disease on three TSH-lutropin/chorionic gonadotropin (LH/CG) receptor extracellular domain chimeras. Each chimera binds TSH with high affinity. Only the chimera with TSH receptor extracellular domains ABC (amino acids 1-260) had a functional (cAMP) response to thyroid stimulatory IgG. The chimeras with TSH receptor domains CD (amino acids 171-360) and DE (amino acids 261-418) were unresponsive. The lack of response of the chimera with TSH receptor domains DE was anticipated because it fails to transduce a signal with TSH stimulation. unlike the other two chimeras. A different spectrum of responses occurred when the TSH-LH/CG chimeras were examined in terms of autoantibody competition for TSH binding. IgG with TSH binding-inhibitory activity when tested with the wild-type TSH receptor also inhibited TSH binding to the chimera with TSH receptor domains DE. Dramatically. however. these IgG did not inhibit TSH binding to the chimera with TSH receptor domains CD. and had weak or absent activity with the chimera with TSH receptor domains ABC. Chimeras with TSH receptor domains ABC and DE were equally effective in affinity-purifying IgG with thyroid-stimulatory and TSH binding-inhibitory activities. Nonstimulatory IgG with TSH binding-inhibitory activity inhibited the action of stimulatory IgG on the wild-type TSH receptor. but not with the chimera containing TSH receptor domains ABC. In summary. TSH receptor autoantibodies and TSH bind to regions in both domains ABC and DE of the TSH receptor extracellular region. Stimulatory and inhibitory TSH receptor autoantibodies. as well as TSH. appear to bind to different sites in domains ABC. but similar sites in domains DE. of the receptor. Alternatively. TSH and the different TSH receptor antibodies bind with differing affinities to the same site in the ABC region.
Contributions of [Ca2+]i, [Pi]i, and pHi to altered diastolic myocyte tone during partial metabolic inhibition, Ischemia may cause increased or decreased distensibility of the left ventricle. but the cellular mechanisms involved have not been clarified. We examined the possible contributions of changes in intracellular inorganic phosphate. pH. and Ca2+ concentrations to altered diastolic function in cultured myocytes subjected to partial metabolic inhibition. Paced cultured embryonic chick and adult rabbit ventricular myocytes superfused with 20 mM 2-deoxyglucose (2DG) exhibited an increase in end-diastolic intracellular free calcium concentration ([Ca2+]i) and an upward shift in end-diastolic cell position. These results indicate that glycolytic blockade increases diastolic and systolic calcium in paced ventricular myocytes. and that this elevated diastolic calcium influences the extent of diastolic relaxation. In contrast. paced ventricular myocytes superfused with 1 mM cyanide (CN) exhibited a similar increase in end-diastolic [Ca2+]i but a decrease in end-diastolic cell position and amplitude of motion. Although changes in ATP contents were similar in both groups (2DG. -29.9%; CN. -40.1%). alterations of intracellular pH and inorganic phosphate concentrations were different. In 2DG-treated cells. pHi did not decrease significantly (7.18 +/- 0.04 to 7.12 +/- 0.11. n = 14) but in the CN group it decreased markedly within 6 min (7.18 +/- 0.04 to 6.76 +/- 0.11. n = 11. P less than 0.01). Intracellular inorganic phosphate decreased slightly in the 2DG group (-14.8%. NS) but increased in cells exposed to CN (45.7%. P less than 0.02). We conclude that while a prominent increase in diastolic [Ca2+]i occurs in rapidly paced ventricular myocytes exposed to either inhibitors of glycolysis or oxidative phosphorylation. the effects of this increase in [Ca2+]i on diastolic distensibility may be influenced by intracellular accumulation of metabolites that decrease the sensitivity of myofilament to [Ca2+]i.
Spectrin Rouen (beta 220-218), a novel shortened beta-chain variant in a kindred with hereditary elliptocytosis. Characterization of the molecular defect as exon skipping due to a splice site mutation, The molecular defect responsible for the shortened beta-spectrin chain variant. spectrin Rouen. was identified by analysis of cDNA and genomic DNA of affected individuals after amplification by the polymerase chain reaction. Peripheral blood reticulocyte RNA was transcribed into cDNA and amplified using primers corresponding to the 3' end of beta-spectrin cDNA. Agarose gel electrophoresis of cDNA amplification products from affected individuals revealed the expected band of 391 bp as well as a shortened band of 341 bp. Nucleotide sequencing of the shortened cDNA amplification product revealed that the sequences corresponding to the penultimate exon of the beta-spectrin gene (exon Y) were absent. This result was confirmed by hybridization of a Southern blot of amplification products with a labeled probe specific for exon Y. Nucleotide sequencing of the proband's amplified genomic DNA corresponding to this region of the beta-spectrin gene revealed a mutation in the 5' donor consensus splice site of the intron downstream of the Y exon. TGG/GTGAGT to TGG/GTTAGT. in one allele. We postulate that this mutation leads to the splicing out or skipping of exon Y. thus producing a shortened beta-spectrin chain. To our knowledge. this is the first documented example of exon skipping as the cause of a shortened beta-spectrin chain in a case of hereditary elliptocytosis. The exon skip results in the loss of the 17 amino acids of exon Y and creates a frameshift with the synthesis of 33 novel amino acids prior to premature chain termination 14 residues upstream of the normal carboxy terminus of the beta-spectrin chain. giving a mutant beta-spectrin chain that is 31 amino acids shorter than the normal chain.
Pharmacologic modulation of picryl chloride-induced contact dermatitis in the mouse, A biphasic response of ear swelling was observed 2 h and 24 h after application of the antigen to picryl chloride-sensitized Balb/c mice. A platelet-activating factor (PAF) antagonist. BN 52063. or the anti-inflammatory drug. betamethasone. applied topically or injected subcutaneously. inhibited in a dose-dependent fashion the antigen-induced increase in ear thickness observed after 24 h. In addition. BN 52063 and betamethasone presented a synergistic effect when administered in vivo simultaneously and subcutaneously. Indomethacin administered subcutaneously at the time of the antigen challenge significantly potentiated the early swelling phase and inhibited the late one. In contrast. the inhibitors of histamine and serotonin. ketotifen and methysergide. respectively. modulated mostly the early. and to a lower extent the late phase when administered at the time of antigen challenge. In contrast. none of these drugs inhibited the late phase reaction when administered 4 h after the antigen. A significant eosinophil and mononuclear-cell ear infiltrate was observed following topical application of the antigen. a phenomenon that was markedly reduced by either BN 52063 or betamethasone. These results demonstrate the effectiveness of PAF antagonists. either alone or in association with glucocorticosteroids. in experimental CD. the modulation of the infiltration of eosinophils and mononuclear cells possibly explaining part of the inhibitory action of these drugs.
Constitutive expression of multiple growth factor genes by melanoma cells but not normal melanocytes, In a panel of metastatic melanoma cell lines we found steady-state mRNA transcripts for multiple growth factors including basic fibroblast growth factor (bFGF). platelet-derived growth factor (PDGF)-A. PDGF-B. transforming growth factor (TGF)- beta 1. TGF- alpha. melanoma growth-stimulating activity (MGSA). interleukin (IL)-1 alpha. and IL-1 beta but not insulin-like growth factor (IGF)-1 or IGF-2. Expression of growth factor genes was constitutive because prior to RNA extraction melanoma cells were maintained in a chemically defined culture medium free of exogenous growth factors. Each of four cell lines had an individual pattern of expression of either two. four. five. or seven growth factors; however. all cell lines shared expression of the bFGF gene. Two strains of normal melanocytes expressed TGF- beta 1 but not bFGF. PDGF. TGF- alpha . or MGSA mRNA at detectable levels. We tested growth-modulatory effects of the growth factors most frequently expressed by melanoma cells (bFGF. TGF- alpha. TGF- beta. PDGF). None of these stimulated melanoma cell growth consistently. whereas exogenous. acid-activated TGF- beta inhibited melanoma growth at concentrations greater than 10 ng/ml. suggesting that bioactive TGF- beta may represent a physiologic growth inhibitor. Neither neutralizing antisera to PDGF or TGF- alpha nor a monoclonal antibody to the epidermal growth factor (EGF)-receptor inhibited melanoma cell growth. Our results indicate that multiple growth factors are expressed simultaneously and constitutively by melanoma cells but not normal melanocytes in culture. Expression of bFGF is a common feature underscoring the significance of bFGF as an autocrine factor for melanoma cells as described earlier. Secreted PDGF and TGF- alpha are apparently not involved in or not essential for autocrine growth stimulation of melanoma cells.
Increased IL-6 production by monocytes and keratinocytes in patients with psoriasis, Interleukin-6 (IL-6) is a multifunctional inflammatory cytokine that is produced by monocytes and keratinocytes upon stimulation. Because psoriasis is a skin disease characterized by a hyperproliferative activity of keratinocytes and an inflammatory infiltrate. in the present study IL-6 production of monocytes and keratinocytes of patients with psoriasis was investigated. Peripheral blood mononuclear cells (PBMC) derived from psoriatics. atopics. and healthy controls were incubated for 24 h and. subsequently. supernatant IL-6 activity was measured using an IL-6-dependent hybridoma cell line (B9). Compared to controls and atopics. PBMC of psoriatics produced significantly increased amounts of biologically active IL-6. These findings were also confirmed by Western blot analysis using a specific antiserum directed against IL-6. Moreover. when the sera of the same patients were tested for IL-6 activity. sera of psoriatics contained significantly elevated amounts of circulating IL-6 in comparison to samples from atopics and healthy controls. In contrast to normal or uninvolved skin. keratinocytes in psoriatic lesions were remarkably positive for IL-6 as detected by immunohistochemistry and in situ hybridization. In addition. IL-6 also was found to induce its own synthesis and release by monocytes. These findings indicate that keratinocytes and monocytes in psoriasis are activated to produce increased amounts of IL-6. which may be one of the mediators involved in the regulation of both local and systemic inflammatory reactions occurring in skin diseases such as psoriasis.
Cicatricial pemphigoid antigen differs from bullous pemphigoid antigen by its exclusive extracellular localization: a study by indirect immunoelectronmicroscopy, Several components of the dermal-epidermal junction (DEJ) bear the name of the autoimmune bullous disease in which they are involved. The epidermolysis bullosa acquisita (EBA) antigen. a component of anchoring fibrils. and the bullous pemphigoid (BP) antigen. a component of hemidesmosomes (HD) with a molecular weight of 220-240 kD. have been well characterized. In contrast. there is little data known about the cicatricial pemphigoid (CP) antigen. No differences between CP and BP have been reported when sera of patients were studied by Western immunoblotting. Findings of a study of sera from 8 patients with CP by indirect immunoelectron microscopy (IEM) on normal human skin are reported. Saponin (0.1% 10 mn) was used as a permeabilizing agent of cytomembranes and saponin-treated skin samples were compared to saponin-untreated skin samples. Four sera from patients with BP. one from a patient with EBA. and three from healthy donors served as controls. The CP sera produced a similar staining of DEJ on both saponin-treated and saponin-untreated skin samples: immune deposits were localized over the lamina densa and the lower part of the lamina lucida clearly separated from the cytoplasmic membrane of keratinocytes. in regularly spaced clumps. The BP sera produced an intense staining of DEJ only on saponin-treated skin samples: immune deposits were observed on the cytoplasmic attachment plaque of the HD; on saponin-untreated skin samples. BP sera produced only a faint staining of the extracellular part of HD. Finally. as expected the EBA serum appeared on the lower part of the lamina densa and anchoring fibrils. and no DAB deposits were observed with the serum of healthy donors. This data indicated that CP antigen is different than BP antigen by its exclusive extracellular localization. It may be a component of anchoring filaments.
Local suppression of contact hypersensitivity in mice by a new bifunctional psoralen, 4,4',5'-trimethylazapsoralen, and UVA radiation, Although psoralens plus UVA radiation (320-400 nm) have been widely used for the treatment of dermatologic diseases. the toxic effects of these agents have led investigators to develop new photochemotherapeutic compounds. One such compound is 4.4'.5'-trimethylazapsoralen (TMAP). a new bifunctional molecule. The purpose of this study was to examine the immunologic side effects of repeated treatment of C3H mice with TMAP plus UVA radiation. During this treatment. the number of ATPase+. la+. and Thy-1+ dendritic epidermal cells greatly decreased in the treated site. despite the lack of phototoxicity. The reduction in the number of detectable cutaneous immune cells was accompanied by a decrease in the induction of contact hypersensitivity to dinitrofluorobenzene applied to the treated skin. an impairment in the antigen-presenting activity of draining lymph node cells. and the presence of suppressor lymphoid cells in the spleen of unresponsive mice. Treatment with UVA radiation alone also reduced the number of ATPase+. Ia+. and Thy-1+ cells in the skin. but did not cause any detectable alterations in immune function. This implies that morphologic alterations in these cells do not necessarily indicate loss of function. Thus. although TMAP in combination with UVA radiation is not overtly phototoxic. it is highly immunosuppressive in mice.
Upper keratinocytes of psoriatic skin lesions express high levels of NAP-1/IL-8 mRNA in situ, In order to better understand the factors regulating disease promotion and activity in psoriasis (PS). we searched for the in situ expression of mRNA for various cytokines in long-standing PS skin lesions. Specific hybridization with a NAP-1/IL-8 anti-sense RNA probe was keratinocyte associated and yielded strong and specific signals exclusively in the upper layers of the lesional epidermis. but not in uninvolved skin from psoriatic patients or normal skin from non-psoriatics. Interestingly. NAP-1/IL-8 transcripts were focally clustered in a spotty pattern predominantly between the tips of elongated papillae. but were absent in the lower epidermal region and the dermal compartment. We consistently failed to detect appreciable numbers of TNF-alpha and/or IL-6 mRNA-containing cells in psoriatic lesions. These results support the notion that IL-8. rather than IL-6. is an important disease-promoting cytokine in PS. In view of the known in vitro and in vivo effects of IL-8. it is conceivable that this substance greatly contributes to the major pathologic changes seen in psoriatic skin. i.e.. keratinocyte hyperproliferation and leucocyte infiltration. In this case. local pharmacologic down-regulation of NAP-1/IL-8 activity could be a promising therapeutic strategy in PS.
Protooncogene (C-Myc) expression in the infiltrating cells of lesional skin from patients with systemic lupus erythematosus, Polyclonal activation of lymphocytes due to an unknown cause is considered to be one of the most important findings of systemic autoimmune disorders including systemic lupus erythematosus (SLE). In order to confirm the expression of the C-Myc protooncogene in lesional skin. tissue specimens from SLE were examined by the histo in situ hybridization method and a histochemical method using a specific antibody reactive with C-Myc related products. Twenty-two cases of SLE. six cases of DLE. one case of lupus erythematosus profundus. two cases of lichen planus. and five skin specimens from healthy volunteers were selected for the examination. In the SLE group. further comparative examination of diseased skin and normal skin from the same patient. and of diseased skin in an active stage and a stable stage in the same SLE patient with renal involvement. were carried out. In most of the active SLE cases. protooncogene expression had apparently increased as compared with the expression in the groups of inactive and treated SLE. active DLE. active lichen planus. and those with healthy skin. Even in normal-appearing skin from active SLE without other organic failure. the protooncogenes were not expressed very strongly.
Stereographic and stereometric study of sebaceous gland hyperplasia in rabbit pinnas induced by topically applied substances, Tetradecane (TD). testosterone (TS). and dimethyl sulfoxide (DMSO) were separately inuncted on rabbit pinnas once a day; the pinnas were biopsied on days 1. 3. 7. and 28. Untreated pinnas and squalane-treated pinnas were used as controls. Three-dimensional images of sebaceous glands were reconstructed from their serial histologic sections using a computer-image analysis system. By stereometry. the sebaceous gland volumes gradually increased during the course of treatments with TS and DMSO. whereas the volumes of TD-treated sebaceous glands increased. reached the maximum on day 7. and then decreased. The acinus number was increased by all the substances. the DMSO-treated sebaceous glands on day 28 showing the largest number of acini. The volumes of individual acini increased until day 28 with TS treatment. whereas with TD and DMSO treatments they increased. reached the maximum on day 7. and then decreased. Stereographically. each untreated control sebaceous gland was composed of 20-30 pear-shaped acini. On day 28. acini of TS-treated sebaceous glands were swollen and ovoid in shape. DMSO-treated sebaceous glands resembled a bunch of grapes. and acini of TD-treated sebaceous glands were widely scattered and showed globular swelling arising from an elongated tube. Hyperplastic responses of sebaceous glands are quite different according to substances applied topically.
Detection of human immunodeficiency virus-DNA and RNA in the skin of HIV-infected patients using the polymerase chain reaction, The presence of HIV genomic-associated nucleic acids (DNA and RNA) within biopsies of normal-appearing skin and various skin lesions obtained from a group of 33 HIV-infected patients was investigated by using the polymerase chain reaction (PCR). In order to define the localization (dermal vs. epidermal) of HIV. the PCR was carried out separately on the dermis and the epidermis in 21 of the specimens. Altogether. HIV-DNA and HIV-RNA were detected. respectively. in 89% and 47% of the specimens included in this study; both DNA and RNA were detected more frequently in the dermis (90% and 43%. respectively) than in the epidermis (62% and 5%. respectively). No correlation could be established between the presence of HIV genomic material. the nature (normal-appearing vs. diseased) of the skin specimen studied. and the clinical or biologic severity of HIV infection. as evidenced by the CDC stage classification and the number of peripheral CD4+ cells. It seems. therefore. that the HIV is very frequently present within the skin during the course of HIV infection; however. its precise cellular localization and pathologic significance await further investigation.
Biologic and protective properties of the 69-kDa outer membrane protein of Bordetella pertussis: a novel formulation for an acellular pertussis vaccine, A combination of the 69-kDa outer membrane protein and filamentous hemagglutinin (FHA). both isolated from lymphocytosis promoting factor (LPF; pertussis toxin) minus mutants of Bordetella pertussis. is protective in the mouse intracerebral challenge potency (Kendrick) test. A combination of the same 69-kDa protein and LPF is approximately 15 times less effective. These data suggest that. surprisingly. the 69-kDa protein in tandem with FHA is the most relevant combination for mouse protection; consequently such a combination may be a more suitable acellular pertussis vaccine candidate than the LPF/FHA combinations. which have never been satisfactorily protective in the mouse test. Preparation of samples of the 69-kDa protein of acceptable protective quality remains difficult. Attempts were made to screen the most suitable batches of the preparations by exploiting some recently discovered properties of the 69-kDa protein: the characteristic chromatofocusing pattern of the protein. the affinity for lymphocytes. and the ability to bind to nicotinamide adenine dinucleotide. None of these tests was able to replace the mouse intracerebral challenge potency test for final quality assessment.
Recombinant outer surface protein a from Borrelia burgdorferi induces antibodies protective against spirochetal infection in mice, The outer surface protein A (OspA) of Borrelia burgdorferi was isolated in its native form from strains ZS7 and B31 and as a recombinant protein from strain ZS7. Amino acid sequence analysis of internal peptides of native OspA (strain ZS7) revealed identity with the sequence deduced from the OspA gene. Repeated immunization of C57BL/6 and C.B-17 mice with any of the three OspA structures resulted in the generation of monospecific hyperimmune sera reactive with both native and recombinant OspA. Upon transfer of immune sera specific for either native OspA (strain B31) or recombinant OspA (strain ZS7) but not of those reactive with the recombinant 41-kDa flagellin-associated antigen. severe combined immunodeficient (SCID) mice were completely protected against infection with strain ZS7. The finding that monoclonal antibodies to OspA and to OspB but not to non-outer surface spirochetal structures such as flagellin. p20. p65. and p70 conferred protection in SCID mice makes OspA (and possibly OspB) a promising candidate vaccine against Lyme disease.
The zinc-reversible antimicrobial activity of neutrophil lysates and abscess fluid supernatants, There is some evidence to suggest that microbial growth inhibition may occur in chronic abscesses. A substance perhaps responsible for this phenomenon is calprotectin. a neutrophil cytoplasmic protein that inhibits microbial growth and that belongs to a class of proteins often having specific binding sites for zinc. In the present study. the suppressive effects of either human or mouse neutrophil lysates on Candida albicans growth were found to be completely reversed by micromolar quantities of zinc but not by iron or other trace elements. Similarly. supernatants of exudates from experimental abscesses in mice or from clinical specimens of abscesses in humans markedly inhibited the proliferation of C. albicans. and this effect was also completely reversed by zinc. A protein complex characteristic of calprotectin was identified in the abscess fluids. Preparations of the neutrophil growth-inhibiting protein. containing predominantly calprotectin. were shown to have zinc-binding activity by a dialysis technique. These findings suggest that the major mechanism of C. albicans growth inhibition by abscess fluids is through competition for zinc by a cytoplasmic protein apparently released from dying neutrophils.
Treatment of Mycobacterium avium-intracellulare complex infection in beige mice with free and liposome-encapsulated streptomycin: role of liposome type and duration of treatment, Current treatments for Mycobacterium avium-intracellulare complex (MAC) infections are generally ineffective. Thus. the potential of free or liposome-encapsulated streptomycin to treat acute MAC infection was investigated in beige mice. Free streptomycin administered intramuscularly 5 days a week (150 mg/kg) was effective in the liver. spleen. and lungs. At 4 weeks. liposome-encapsulated streptomycin. administered intravenously in weekly doses (15 mg/kg). reduced the colony-forming units in the liver and spleen by about the same extent as a 50- to 100-fold higher dose of free drug. With 4 weekly injections of liposomes. the colony-forming units in the liver and spleen were lower by 2.4 and 2.9 log units. respectively. compared to untreated controls. even by the end of 12 weeks. The effects of unilamellar and multilamellar liposomes were similar. These observations suggest that liposome encapsulation not only targets streptomycin to infected cells but also increases the residual activity of the drug.
Exposure to human immunodeficiency virus (HIV) type I indicated by HIV-specific T helper cell responses before detection of infection by polymerase chain reaction and serum antibodies [corrected] [published erratum appears in J Infect Dis 1991 Oct;164(4):832, A healthy individual at risk for human immunodeficiency virus type 1 (HIV-1) infection was studied longitudinally for 19 months for evidence of exposure to and infection with HIV. Peripheral blood mononuclear cells (PBMC) were tested at 1. 5. 13. 16. and 19 months for T helper (Th) cell function by in vitro-generated proliferation and interleukin-2 production in response to four synthetic peptides corresponding to env of HIV. PBMC were also tested for proviral DNA using gag primers by the polymerase chain reaction (PCR) at 0. 5. 10. 13. 16. and 19 months. HIV serology by ELISA and p24 antigen and Western blot analyses were done on samples taken at 0. 1. 5. 10. 13. 16. and 19 months. The results indicated that both Th cell tests were positive during months 5-19. In contrast. the PCR and all serologic assays were negative except for month 19. when the assays became positive. These results. based on the longitudinal study of one individual. showed that the Th cell tests can reveal exposure to HIV-1 antigens several months before evidence of viral infection is detected. even by PCR.
Comparison of cervical, urethral, and urine specimens for the detection of Chlamydia trachomatis in women, Cervical. urethral. and first void urine (FVU) specimens from 937 women were tested for Chlamydia trachomatis by culture or EIA to determine the most sensitive combination of tests and specimens. For cervical and urethral specimens the prevalence of infection by culture or confirmed EIA was 7.2% (67/937) at either site. 6.8% (64/937) at the cervix. and 4.3% (40/937) at the urethra. Of 67 specimens. 37 (55.2%) yielded a positive test from both the cervical and urethral swabs. Three (4.5%) of the 67 infections were only at the urethra and none were only in FVU. Only 37.3% (25/67) of all positive women had a positive FVU. The most sensitive combination was cervical swab culture and EIA. which detected 95.5% (64/67) of the infections. a substantial increase over culture only (76.1%) or EIA of the cervical swab (79.1%). The testing of urethral and FVU specimens apparently offers only minimal advantage over testing of cervical specimens only for chlamydia.
Global distribution of a variant of the circumsporozoite gene of Plasmodium vivax, The global distribution of a newly described variant of the Plasmodium vivax circumsporozoite (CS) gene was determined by genetic analysis of wild isolates. Whole blood specimens were collected on filter paper from patients infected with P. vivax in South America. West Africa. and the Indian subcontinent. P. vivax DNA was released from the filter paper samples. and the CS gene was amplified by polymerase chain reaction and analyzed for genetic variation. Amplified DNA was probed with oligonucleotide probes that hybridize with the predominant CS repeat region (PV210) and the variant CS repeat region (PV247) of P. vivax. The PV247 variant was found in all three geographically diverse areas. In addition. five of six consecutive patients studied had simultaneous infection with both the predominant and variant forms of P. vivax. These findings suggest that a single-epitope vaccine based on the predominant CS domain is unlikely to be protective on even a regional basis.
The cost of home air-fluidized therapy for pressure sores. A randomized controlled trial, BACKGROUND. Recurrent pressures sores are a serious problem that often cause chronically ill patients to be hospitalized. We hypothesized that home air-fluidized bed therapy may be a safe and effective way to treat these patients. thus avoiding the costs of hospitalization. METHODS. One hundred twelve patients with 3rd or 4th stage pressure sores were randomly assigned to 36 weeks of either (1) home air-fluidized bed therapy that included the services of a visiting nurse specialist as long as the patient had 3rd or 4th stage sores. or (2) conventional therapy. RESULTS. Compared with patients in the control group. patients receiving air-fluidized bed therapy spent fewer days in the hospital (11.4 days vs 25.5 days. P less than .01) and used fewer total inpatient resources. as reflected both in charges ($13.263 vs $25.736. P less than .05) and in Medicare DRG and physician payments ($6.646 vs $12.131. P less than .05). Total resources used (inpatient and outpatient) were lower for patients treated with air-fluidized bed therapy. but the difference was not statistically significant. Clinical outcomes were similar. CONCLUSIONS. Home air-fluidized bed therapy is safe. reduces hospitalizations. is no more costly than alternative therapy. and allows the patients to receive their needed care in a more desirable. nonhospital setting.
Syphilis screening in primary care, BACKGROUND. Reported cases of early syphilis have increased dramatically since 1987. Screening high-risk patients has been advocated as an intervention strategy to control the syphilis epidemic. METHODS. This study determined the prevalence of previously unrecognized positive syphilis serologies among patients at an urgent care center. Two hundred sixty-five patients treated empirically for gonorrhea were screened. RESULTS. Two patients had positive serology; both were previously treated for syphilis and had no evidence of recurrent infection. The yield from screening the study population was 0. CONCLUSIONS. Serologic diagnosis of syphilis is not reliable or cost effective in groups with a very low prevalence of disease. Routine screening for syphilis in asymptomatic high-risk patients may not be indicated in all primary care settings.
Preventive practices for adult cardiovascular disease in children, BACKGROUND. Differences between family practitioners and pediatricians regarding appropriate interventions for cardiovascular disease prevention in pediatric patients have been described by national surveys of physicians in the two specialties. the purpose of the study reported here was to determine whether similar differences existed in a more complete sample from a confined geographical area in which local standards of care might influence physicians practicing in the locale. METHODS. Members of the Southwestern Ohio Society of Family Physicians and the Cincinnati Pediatric Society were surveyed by questionnaire about their attitudes and practices concerning cardiovascular risk factors in children. The response rate was greater than 70% in each specialty group. RESULTS. Differences in the diagnosis and treatment of hypercholesterolemia were detected: (1) pediatricians screened patients at younger ages and used lower cutoff points for diagnosis (5.0 vs 5.5 mmol/L [192 vs 211 mg/dL]); and (2) family physicians were more likely to treat with medication (57% vs 5%). whereas pediatricians referred hypercholesterolemic patients to specialists more often (71% vs 19%). Both family physicians and pediatricians mislabeled blood pressures at the age-specific 90th percentile as normal (21% and 14%. respectively); this occurred more commonly with younger patients. Blood pressure was the risk factor most often measured. but smoking was the risk factor that received the most counseling by physicians in both specialties. CONCLUSIONS. Both family physicians and pediatricians reported feeling inadequately prepared to counsel lifestyle changes. and ranked obesity. smoking. and cholesterol as topics of greatest interest for continuing medical education courses. Physicians in both specialties did not routinely update family history of cardiovascular disease during well-child visits.
Late onset Krabbe's leukodystrophy: a report of four cases, Four cases of late-onset Krabbe's leukodystrophy had varying clinical features. One sibling became wheelchair-bound while another leads an active working life. The computed tomography (CT) scan of a third patient showed occipital demyelination with contrast enhancement identical to that seen in an adrenoleucodystrophy. The fourth was the only patient with peripheral neuropathy. All patients had enzyme activity comparable to the classic infantile-onset form.
The motor response to sequential apomorphine in parkinsonian fluctuations, Fifteen patients with Parkinson's disease and levodopa-induced motor fluctuations. were studied with repeated injections of apomorphine using two protocols to explore possible changes in the duration of motor response. One involved different interdose intervals; in the other. doses were given when the motor effects induced by the previous dose had just worn off. No significant change in the duration of motor response to sequential subcutaneous apomorphine with either protocol was found. The results suggest that rapid changes in receptor sensitivity during repeated intermittent dopaminergic stimulation do not contribute to the pathogenesis of Parkinsonian motor fluctuations.
Arthroscopic surgery for treatment of closed lock, This study evaluates the first 51 consecutive cases treated for limitation of mandibular movement due to closed lock. Eighty joints (22 unilateral. 29 bilateral) were treated with arthroscopic surgery. The mean follow-up was 29.4 weeks. with a range of 6 to 77 weeks. These results showed an immediate improvement after arthroscopy followed by a more gradual improvement during the next 6 months. with a plateau in improvement thereafter. All cases. unilateral and bilateral. generally reached the same level of opening.
Early diagnosis of osteoarthrosis of the temporomandibular joint: correlation between arthroscopic diagnosis and keratan sulfate levels in the synovial fluid, The role of osteoarthrosis (OA) and proteoglycan degradation in the pathogenesis of temporomandibular joint (TMJ) disorders has not been well established. The orthopaedic literature has demonstrated that proteoglycan degradation plays a significant role in the pathology of many joints. The purpose of this investigation was to determine if levels of immunoreactive keratan sulfate (an important component of cartilage proteoglycans) present in synovial fluid aspirates from TMJs correlated with arthroscopically demonstrated OA. Temporomandibular joint arthroscopy was performed on 25 joints in 20 patients and synovial fluid aspirates were obtained just prior to the insertion of arthroscopic cannulas. The results showed that synovial fluid aspirates from joints that arthroscopically demonstrated OA had significantly higher levels of keratan sulfate than synovial fluid aspirates from those joints that showed no evidence of OA (NON-OA). This study gives support to the theory that the pathogenesis of OA of the TMJ is similar to that of chondromalacia of other synovial joints. The combination of TMJ arthroscopy and synovial fluid analysis is an important model that can be used for investigation of the pathogenesis of TMJ disorders.
Cervical spine fractures and maxillofacial trauma, Cervical spine fractures are a serious complication of maxillofacial trauma because of the high potential for mortality and neurologic morbidity. This study reviewed 563 patients with facial fractures treated by the Division of Oral and Maxillofacial Surgery at a level I trauma center and identified 11 concomitant cervical spine fractures (2.0%). These patients were almost exclusively male (91%). white (100%). between 20 and 35 years of age (64%). involved in a motor vehicle accident (91%). with a concomitant mandibular fracture (91%). The examination. diagnosis. and management of patients with cervical spine injuries are discussed.
Facial nerve injuries associated with orthognathic surgery: a review of incidence and management, While facial nerve injuries associated with both extraoral and intraoral orthognathic surgery are rare. the results of such an injury can be devastating to the patient. A review of the literature shows that the majority of such injuries fall into the first-. second-. and third-degree injury categories. Prevention cannot be stressed enough; however. early recognition of an injury with prompt electrodiagnostic testing can assist with determining prognosis and treatment planning. When close observation is indicated. a variety of medical therapies have been suggested. For more severe injuries. nerve repair and facial reanimation have been reported.
Central arteriovenous malformations of the maxillofacial skeleton: case report, Central arteriovenous malformation of the maxillofacial skeleton. though rare. is a well-documented entity. Past treatments have usually included some form of surgical intervention. Surgical resection as an attempt to cure has been effective but costly. ie. in relationship to patient morbidity and hospital expenditures. A case of vascular malformation is presented in which selective angiography and embolization as a primary treatment were used rather than ablative surgery. The patient tolerated the procedures well. with complete resolution of bleeding.
Dose response characteristics of hypertonic saline dextran solutions, In an effort to find the best hypertonic saline-dextran solution (HSD) for prehospital use. 33 chronically catheterized sheep were bled using a fixed pressure shock model (50 mm Hg x 2 hours) and resuscitated with 4 ml/kg of HSD solution (2-minute bolus). In the first set of experiments colloid was varied and sodium chloride was held constant. as 7.5% NaCl was paired with either 0%. 6%. or 12% dextran 70. A dose-response relationship existed. with cardiac output increasing 20% with each sequential dextran 70 concentration. Mean arterial blood pressure was higher in animals that were resuscitated with either the 7.5% NaCl/6% dextran 70 or 7.5% NaCl/12% dextran 70 solution (p less than 0.05). Using the optimal dextran 70 concentration from the first set of experiments (i.e.. 12%). solute was varied in a second set of experiments comparing 0.9%. 3.8%. 7.5%. or 10% NaCl/12% dextran 70. Again. dose-response features were demonstrated. as cardiac output increased as a function of NaCl concentration. However. this response plateaued with the 7.5% NaCl concentration and no advantage was obtained by increasing the NaCl concentration to 10%. We conclude that a 4-ml/kg bolus of 7.5% NaCl/12% dextran 70 solution may be a more effective form of therapy than those previously evaluated. This new solution is now being included in our ongoing clinical trials.
Are CT scans for head injury patients always necessary, The study reported here sought to identify a group of adult head injury patients in whom computerized axial tomographic (CT) scans were not necessary. The study was limited to patients 18 years of age and older with a history of minor head injury who remained neurologically stable for 20 minutes after arrival at the trauma center. maintained a Glasgow Coma Scale score of at least 13. and had no clinical evidence of basal skull fracture. These patients had a uniformly good neurologic prognosis. The CT scan did not have any prognostic or therapeutic implications. Of a total of 348 patients studied. 12 had an abnormal CT scan with no neurologic deficits or sequelae. and all of them had an uneventful hospital discharge without readmission. It appears that a routine CT scan for minimal head injury patients is an inefficient use of personnel and equipment which may add to the ever increasing financial burden on trauma centers.
AAST organ injury scale: correlation of CT-graded liver injuries and operative findings, The Organ Injury Scaling Committee of the AAST recently published a consensus classification of splenic. hepatic. and renal injuries (J Trauma. 29:1664. 1989). The hepatic injury scale (HIS). based on parenchymal laceration and intrahepatic hematoma. includes grades 1 to 6. representing the least to most severe injury. This study classifies liver injuries by findings at celiotomy. correlates operative findings with transfusion requirements and method of management of liver injury. and relates preoperative CT to anatomic findings at laparotomy. Thirty-seven patients with blunt liver injury were evaluated by abdominal CT with and without intravenous contrast and then underwent celiotomy. Increasing operative HIS correlated well with increasing severity of injury as measured by transfusions and operative management. Thirty-one CT grades did not correlate with operative findings (84%). Four patients had intrahepatic hematomas that were not discovered at operation. Twelve lacerations were graded too high by CT and 15 too low. Of these 15. ten CT scores were at least two grades lower than operative findings. Injuries around the falciform ligament occurred in three of the low misclassifications. One patient with intrahepatic hematoma developed hepatic artery pseudoaneurysm. We conclude that the HIS readily characterizes operative findings of hepatic lacerations and that increasing operative grade correlates well with transfusion requirements and operative management. CT can define intrahepatic hematomas. but does not correlate well with hepatic lacerations. Extreme caution is required when using CT alone to define "minimal" liver injury for prospective management of blunt trauma victims.
The spectrum of abdominal injuries associated with the use of seat belts, Several recent reports have described abdominal injuries occurring as a result of seat belt use. raising concerns about seat belts as an agent of injury in motor vehicle crashes. The purpose of this study was to characterize the distribution of abdominal injuries after motor vehicle crashes in belted and unbelted patients admitted to trauma centers. The mortality was higher in unbelted than belted patients (7% vs. 3.2%. respectively. p less than 0.0001). Unbelted patients also had significantly more frequent and more severe head injuries (50.0% vs. 32.9%. respectively. p less than 0.001). The incidence of abdominal injury was equal in both unbelted patients (13.9%). but the spectrum of organs injured was different in the two groups. Gastrointestinal tract injuries (stomach. small bowel. colon and rectum) were significantly more frequent in belted vs. unbelted patients (3.4% vs. 1.8%. respectively. p = 0.001). The frequency of liver and spleen injuries was the same in both groups. This study demonstrates that in patients admitted to trauma centers after motor vehicle crashes. belted and unbelted patients have an equal incidence of abdominal injury. but belted and unbelted patients have a different spectrum of injuries. Hollow viscus injuries are more common in belted crash victims. Seat belt use was associated with significantly fewer head injuries and deaths. Physicians evaluating trauma victims after motor vehicle crashes should be aware of the fact that the types of abdominal injuries may vary substantially depending on seat belt use.
Trauma patients return to productivity, Economic issues threaten the development of a national trauma system. Much work has focused on the cost of trauma care; little has been done to define society's long-term economic return. We asked three questions about high cost trauma patients: (1) Do they survive?. (2) Do they continue to require expensive care?. and (3) Do they return to productivity? Of 6.129 consecutive trauma admissions. 114 had hospital charges over $100.000 (mean = $143.000). 102 (89.5%) were discharged alive. and 10 (8.8%) were lost to followup. Ninety-two patients or families were interviewed at least 1 year (mean = 2.6 year) after discharge. There were 88 survivors and 4 deaths (3.5%). Of the 88 survivors 73% had no limitation of ADLs. 67% received rehabilitation. 58% were still improving. and 37% were involved in litigation. Five survivors (5.7%) were confined to a nursing home. 48 (54.5%) had returned to productivity (RTP). 35 (39.8%) were unemployed. and five of these still require medical therapy. We conclude: (1) The majority of high cost patients survive (89.5%) and return to productivity (54.5%); (2) the severity of injury predicts survival but not return to productivity; and (3) the RTP rate may be increased by addressing nonmedical need.
Transesophageal echocardiographic examination of a patient with traumatic aortic transection from blunt chest trauma: a case report, Traumatic aortic disruption is an injury associated with high mortality. Early recognition. diagnosis. and surgical repair are important in order to salvage patients with this injury. We report a case in which transesophageal echocardiography. a rapid. minimally invasive diagnostic technique. was used to identify an acute disruption of the proximal descending aorta in a patient with blunt chest trauma.
Triple-contrast CT scans in penetrating back and flank trauma, Triple-contrast CT scanning (3-CT) is a diagnostic modality that has been introduced recently for the work-up of patients with penetrating injuries to the back or flank. Triple-contrast CT consists of giving oral. intravenous (IV). and rectal contrast medium. Our hypothesis was that this test is an accurate predictor of the absence of a retroperitoneal injury requiring surgical repair. We prospectively enrolled 88 clinically stable patients who sustained penetrating wounds to the back or flank. Seventy-eight received a diagnostic peritoneal lavage (DPL) before 3-CT. The scans were classified according to the risk of a retroperitoneal injury requiring repair. Patients who did not go to the operating room (OR) were observed for 48 hours. Of 88 patients entered. nine had high-risk scans. five of these patients underwent exploratory laparotomy. two of whom had significant injuries. Seventy-nine patients had non-high-risk scans. Seventy-seven were observed without complication. and two were explored for positive DPL. with no significant lesion found. The negative predictive value of a low- or moderate-risk 3-CT scan is 100% +/- 11%.
Decrease in renal vascular resistance in University of Wisconsin solution preserved kidney transplants, Renal vascular resistance was compared in 2 groups of renal grafts: group 1-16 kidneys perfused with University of Wisconsin solution and group 2-16 kidneys perfused with Euro-Collins solution. Both groups had comparable donors and recipient criteria. Renal blood flow was measured by a miniaturized pulsed Doppler probe fixed on the graft renal artery. Renal vascular resistance was calculated either according to the formula: renal vascular resistance (mm. Hg/ml. per second) = systemic arterial pressure (P)/renal blood flow or through the renal vascular resistive index (RVRI): RVRI = systolic flow velocity - diastolic flow velocity/systolic flow velocity = (S-D)/S. Renal vascular resistance estimation seems to be more contributory than renal blood flow in assessment of renal graft reperfusion disorders. Our results show that University of Wisconsin solution seems to preserve intrarenal arterial caliber better with a decrease in intrarenal vascular resistance. thus. allowing for a higher arterial graft perfusion flow.
Simple tests to determine urinary risk factors and calcium oxalate crystallization in the outpatient clinic, We developed 2 simple and rapid tests for measurement of constituent concentrations and the stone-forming tendency of urine in the outpatient clinic. The concentrations of urinary constituents of calcium. magnesium. phosphorus. uric acid and oxalic acid were measured using 2 types of simple colorimetric tests (vial and quantitative filter types). The intensity of the color developing after a given interval was compared with a color standard of 4 levels. The results obtained using the colorimetric test were slightly lower in value than but significantly correlated with those obtained with standard measurements. The second test measured the crystal-forming ability of urine. A 10 ml. urine sample was pipetted into 4 vials that each contained different concentrations of oxalic acid and calcium. After a given interval the turbidity in each vial was compared with a control (0 mg. oxalic acid and calcium). If turbidity occurred in urine with low concentrations of oxalic acid and calcium the sample had a large tendency for crystals to form.
Extramural ambulatory urodynamic monitoring during natural filling and normal daily activities: evaluation of 100 patients, Conventional urodynamic tests are short and performed under nonphysiological circumstances. The introduction of ambulatory urodynamic tests is a promising improvement of our diagnostic abilities with respect to these disadvantages. To test the value of our ambulatory urodynamic method we evaluated 100 patients with urinary incontinence and/or voiding problems by both diagnostic methods. Pre-classification according to medical history was compared with the urodynamic diagnosis obtained from the conventional and extramural ambulatory monitoring methods. and the combination of both techniques in patients with urinary incontinence. The conventional method showed no abnormalities in 32% of the patients. compared to only 3% with the ambulatory method. The conventional method confirmed pre-classified stress incontinence in 36% of the patients. compared to only 14% by extramural ambulatory monitoring. Combining both methods. pre-classified stress incontinence was confirmed in 43% of the patients. Pre-classified urge incontinence was confirmed in 47%. 59% and 84%. and pre-classified mixed incontinence was confirmed in 23%. 29% and 55% of the patients using the conventional. extramural ambulatory monitoring and combination methods. respectively. An over-all correlation with the pre-classification in the incontinence group was found in 34% with the conventional method and 43% with extramural ambulatory monitoring. Combining both diagnostic tools showed a correlation with the pre-classification in 67% of the patients. These results show the promising impact of ambulatory urodynamic testing in the near future.
Transureteroureterostomy with cutaneous ureterostomy: a 25-year experience, We reviewed 67 patients who underwent transureteroureterostomy with cutaneous ureterostomy for benign (32) and malignant (35) disease in regard to the indications for and complications of the procedure. The most common complications included urine leakage at the ureteroureterostomy. stomal stenosis and calculus formation. Renal function improved or remained stable in 75% of the patients. Transureteroureterostomy with cutaneous ureterostomy is a viable alternative diversion technique in a select group of patients.
Transvaginal ultrasonography and urodynamic evaluation after suspension operations: comparison among the Gittes, Stamey and Burch suspensions, Radiological and ultrasonographic imaging enables the objective determination of bladder neck position and movement in stress urinary incontinence. Postoperative results were evaluated in 60 patients after Burch colposuspension (29) or bladder neck suspension according to the Gittes (18) or Stamey (13) method. No differences in continence rates were noted 3 months postoperatively (Gittes 83%. Stamey 85% and Burch 93% of the patients). Late results were assessed by urodynamic evaluation and transvaginal ultrasonography. The largest decrease in continence rate was observed after the Gittes procedure (44% of the patients continent. mean followup 14.7 months). in comparison with the Stamey (69% continent after 34.6 months) and Burch (86% continent after 30.5 months) procedures. Urodynamic parameters showed no significant differences for the 3 groups. Transvaginal ultrasonography did not indicate a correlation between absolute resting or stress position of the bladder neck and continence. The main factor concerning continence was the rotation angle and descent of the bladder neck during stress. Our data indicate that transvaginal ultrasonography is a safe and reliable method to evaluate the postoperative outcome for stress urinary incontinence.
Urinary tract malformations in identical twins, We describe 3 sets of twins with discordance for urological malformations. Zygosity was documented by HLA and blood group typing. It is suggested that evaluation of the identical twin of an affected patient should include the entire urinary tract because of the potential for different lesions.
An unusual complication of high dose infusion computerized tomography in a patient with a continent diversion, We describe a myelodysplastic woman with a Kock continent ileal reservoir who suffered parastomal herniation of the pouch following high dose infusion computerized tomography. Prophylactic indwelling catheterization in patients with continent diversion undergoing procedures that induce significant diuresis or involve prolonged distension of the reservoir is probably indicated.
Kock pouch procedures: continuing experience and evolution in 135 cases, Between April 1985 and January 1989. 135 consecutive patients underwent construction of a Kock pouch (to the skin in 72 patients. a urethral pouch in 45. an ileorectal pouch in 10 and a hemi-Kock pouch augmentation cystoplasty in 8). The operative mortality (30 days) rate was 4.4%. There were 16 early complications (12.4%) leading to 14 reoperations (11%). with a followup of 6 to 60 months. After Kock pouch to the skin. the late complication rate was 26.1% in the Kock-Skinner technique group and 7.4% in the simplified technique group. and 94.2% of the patients were continent. After a urethral Kock pouch daytime continence was achieved in 93% of the patients within 2 months and nighttime dryness was noted in 65% within 3 months. After an ileorectal Kock pouch all patients were continent day and night. as were those after hemi-Kock pouch augmentation. although 5 of the latter patients required intermittent catheterization.
Inhibition of prostatic tumor cell proliferation by suramin: alterations in TGF alpha-mediated autocrine growth regulation and cell cycle distribution, Suramin is a trypanocidal drug that has generated recent interest as an antineoplastic agent because of its ability to inhibit the binding of growth factors to their cell surface receptors. Our studies. and others. suggest that the androgen-independent human prostatic carcinoma cell lines PC3 and DU145 proliferate via autocrine growth mechanisms mediated by transforming growth factor alpha (TGFa) and its receptor. the epidermal growth factor (EGF) receptor. The present studies were designed to evaluate the ability of suramin to inhibit PC3 and DU145 proliferation by interfering with TGFa-mediated autocrine growth. Suramin induced a dose-dependent reduction of prostatic tumor cell proliferation which was reversed by removal of suramin from the culture medium. 3H-thymidine release studies showed that suramin had little direct cytotoxicity to either cell line. These findings suggest that the effects of suramin are mediated by cytostatic. rather than cytotoxic. mechanisms. Suramin also interfered with TGFa-mediated growth mechanisms. Specifically. suramin reduced the specific binding of TGFa to PC3 and DU145 cells. Additionally. the inhibitory effect of suramin on DU145 was reversed by cultivation of cells in the presence of excess TGFa. Further investigations revealed that suramin increased the percentage of cells in the S phase of the cell cycle for both cell lines. These studies show that the inhibitory effect of suramin on PC3 and DU145 cell growth is mediated. in part. by alteration of TGFa-mediated autocrine growth mechanisms and cell cycle kinetics.
Vesicoureteral reflux in the adult. V. Unilateral disease, We studied 37 patients with primary unilateral vesicoureteral reflux to compare medical (17) and surgical (20) management. Medical management consisted of observation and antimicrobial therapy as needed. During followup (mean 84.6 months) none of the patients in either management group had a significant decrease in total renal function. worsening of hypertension or progression of stone disease. The surgically treated group had a higher incidence of pyelonephritis preoperatively (75% versus 13%) but during followup these infections developed in only 10% of the surgical patients and in 13% of the medically managed group. The primary indication for surgical correction of unilateral reflux in adults is a history of pyelonephritis in patients in whom antibiotic prophylaxis has been unsuccessful or in women of childbearing age.
Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle, The majority of cases of impotence are associated with vascular risk factors such as diabetes. hypercholesterolemia. hypertension and smoking. These factors induce impairment of endothelium-dependent relaxation of blood vessels in man and in experimental animals. In this study the effects of hypercholesterolemia on the reactivity of rabbit corpus cavernosum smooth muscle strips to endothelium-dependent and endothelium-independent agents were investigated. New Zealand White rabbits (n = 14) were randomly divided into control and treatment groups. The control group (n = 7) received a regular diet while the treatment group (n = 7) was fed a diet of 0.5% cholesterol and 4% peanut oil for 10 weeks. Animals were then sacrificed and the corporal tissue studied in organ chambers for isometric tension measurement. Tissue was contracted with phenylephrine and concentration-dependent relaxation to acetylcholine. in the presence and absence of indomethacin. and to nitroprusside were examined. Blood level of cholesterol in the cholesterol-fed group was significantly higher compared to the control group. Contractions to phenylephrine were similar in both groups. Hypercholesterolemia. however. inhibited relaxation to acetylcholine but did not alter relaxation to nitroprusside. a cyclic guanosine monophosphate (cGMP)-dependent. direct smooth muscle dilator. Indomethacin enhanced the relaxations to acetylcholine in both control and cholesterol-fed groups but did not correct the difference in the relaxation to acetylcholine between both groups. It is concluded that hypercholesterolemia impairs endothelium-mediated relaxation of rabbit corpus cavernosum smooth muscle. The mechanism for the endothelial dysfunction does not appear to involve alteration in cyclooxygenase products of arachidonate or the cGMP-dependent relaxation of corporal smooth muscle. Impairment of endothelium-dependent relaxation of corporal smooth muscle may contribute to the pathophysiology of impotence associated with hypercholesterolemia in man.
A controlled study of low and high volume anesthetic jelly as a lubricant and pain reliever during cystoscopy, To evaluate the influence of the volume of 2% lidocaine jelly as an anesthetic during cystoscopy 241 men and women received either 11 or 20 ml. jelly intraurethrally in a randomized. double-blind fashion. Pain was recorded on a visual analogue scale by the patient and on a 3-level scale by the physician. The pain scores according to the visual analogue scale were significantly higher in the patients given 11 ml. jelly than in those given 20 ml. when all patients in the study were analyzed. There was no significant difference in the visual analogue scale between the 2 treatments in women but a significant difference was noted in men. although in men older than 55 years the difference was not statistically significant. There was general agreement between the visual analogue scale results and the physician scores but the visual analogue scale procedure was more sensitive in detecting differences between treatments. It is suggested that approximately 11 ml. 2% lidocaine jelly is the appropriate volume for women and 20 ml. is the appropriate volume for men during cystoscopy but that the lower volume of jelly may be sufficient in older men.
Treatment options for ureteral calculi: endourology or extracorporeal shock wave lithotripsy, Two therapeutic methods. endourology and extracorporeal shock wave lithotripsy (ESWL). can be used in the treatment of ureteral calculi. In a retrospective analysis during a 2-year period 236 patients treated with endourological procedures and 71 who underwent ESWL with a Siemens Lithostar were analyzed as to the success rate. effectiveness quotient. complication rate and hospitalization. The mean stone size was 1.12 cm. in the endourology group and 1.03 cm. in the ESWL group. Complete removal of all stone fragments was achieved in 93.6% of the patients treated endourologically and without retreatment. In the ESWL group success was obtained in 90.1%. with an 11.2% retreatment rate. The retreatment rate was higher (25.0%) for calculi in the mid ureter. The group treated endourologically had a better success rate and no retreatment was necessary. On the other hand. the group treated with ESWL had a shorter hospitalization and a lower complication rate. Followup ranged from 11 to 60 months (mean 48 months) in the endourology group and 7 to 29 months (mean 11 months) in the ESWL group. These observations showed that in situ ESWL therapy with the Siemens Lithostar device is the method of choice for upper ureteral stones. Lower ureteral calculi should be treated endoscopically. Mid ureteral stones larger than 1 cm. had better results with endoscopic procedures and those smaller than 1 cm. had better results with ESWL.
Characterization of prostate cancer, benign prostatic hyperplasia and normal prostates using transrectal 31phosphorus magnetic resonance spectroscopy: a preliminary report, We assessed the ability of 31phosphorus (31P) transrectal magnetic resonance spectroscopy to characterize normal human prostates as well as prostates with benign and malignant neoplasms. With a transrectal probe that we devised for surface coil spectroscopy we studied 15 individuals with normal (5). benign hyperplastic (4) and malignant (6) prostates. Digital rectal examination. transrectal ultrasonography and magnetic resonance imaging were used to aid in accurate positioning of the transrectal probe against the region of interest within the prostate. The major findings of the in vivo studies were that normal prostates had phosphocreatine-to-adenosine triphosphate (ATP) ratios of 1.2 +/- 0.2. phosphomonoester-to-beta-ATP ratios of 1.1 +/- 0.1 and phosphomonoester-to-phosphocreatine ratios of 0.9 +/- 0.1. Malignant prostates had phosphocreatine-to-beta-ATP ratios that were lower (0.7 +/- 0.1) than those of normal prostates (p less than 0.02) or prostates with benign hyperplasia (1.1 +/- 0.2. p less than 0.01). Malignant prostates had phosphomonoester-to-beta-ATP ratios (1.8 +/- 0.2) that were higher than that of normal prostates (p less than 0.02). Using the phosphomonoester-to-phosphocreatine ratio. it was possible to differentiate metabolically malignant (2.7 +/- 0.3) from normal prostates (p less than 0.001). with no overlap of individual ratios. The mean phosphomonoester-to-phosphocreatine ratio (1.5 +/- 0.5) of prostates with benign hyperplasia was midway between the normal and malignant ratios. and there was overlap between individual phosphomonoester-to-phosphocreatine ratios of benign prostatic hyperplasia glands with that of normal and malignant glands. To verify the in vivo results. we performed high resolution magnetic resonance spectroscopy on perchloric acid extracts of benign prostatic hyperplasia tissue obtained at operation and on a human prostatic cancer cell line DU145. The extract results confirmed the differences in metabolite ratios observed in vivo. We conclude that transrectal 31P magnetic resonance spectroscopy can characterize metabolic differences between the normal and malignant prostate.
The ability of systematic transrectal ultrasound guided biopsy to detect prostate cancer in men with the clinical diagnosis of benign prostatic hyperplasia, Multiple directed and systematic ultrasound guided biopsies of the prostate were performed in 73 men with the clinical diagnosis of benign prostatic hyperplasia (BPH). Seven men (10%) had prostate cancer. Of the 67 patients with benign biopsies 40 underwent subsequent transurethral prostatectomy and 2 (5%) had prostate cancer. Multiple directed and systematic biopsies of the prostate detected 78% of the nonpalpable prostate cancers diagnosed in the study population. Radical prostatectomy was performed in all 9 men with prostate cancer: there were 3 small organ-confined tumors. 5 large organ-confined tumors and 1 stage C tumor with 1 focus of microscopic capsular penetration. Our results suggest that multiple directed and systematic ultrasound guided biopsies are capable of detecting low volume nonpalpable prostate cancer in men with BPH. However. the exact indication for pre-treatment ultrasound guided biopsy of the prostate in men with symptomatic BPH remains unclear. It may be that use of this modality is most appropriate for patients undergoing pharmacological therapy or balloon dilation of BPH rather than for those undergoing transurethral prostatectomy.
Anesthesia-free in situ extracorporeal shock wave lithotripsy of ureteral stones, Stones in the proximal. mid and distal ureter in 375 consecutive patients were treated with extracorporeal shock wave lithotripsy (ESWL) in a technically unmodified Dornier HM3 lithotriptor without regional or general anesthesia. Adequate followup was available in 162 patients with proximal. 62 with mid and 146 with distal ureteral stones. The fraction of patients with stone-free ureters within 3 months after ESWL was 96. 97 and 97%. respectively. Of all patients only 13 (3.6%) had residual stones or fragments in the ureter after 3 months. The average number of ESWL sessions was 1.34 for all patients. and 1.36. 1.45 and 1.38 for those with proximal. mid and distal ureteral stones. respectively. A ureteral catheter with saline irrigation was used whenever it was possible to insert a ureteral catheter. Only 15 stones were pushed up to the kidney during catheterization and all other stones were treated in situ. There were more retreatments in patients in whom the stone had not been bypassed by a catheter at the initial ESWL session. During at least 1 treatment session 238 patients had a ureteral catheter with the tip above the stone. Approximately half of all patients were treated after only premedication with pethidine and diazepam. and cutaneous half of all patients were treated after only premedication with pethidine and diazepam. and cutaneous anesthesia with an anesthetic cream containing lidocaine-prilocaine (for proximal and mid ureteral stones). Small supplements of pethidine and diazepam were given to the other patients during the ESWL session. In situ ESWL of ureteral stones as described is a convenient. efficient and attractive procedure that. applied in a consequent manner. theoretically might result in a successful outcome in up to 98% of the patients.
The impact of obesity on left ventricular mass and geometry. The Framingham Heart Study, OBJECTIVE.--To determine the relationship of varying degrees of obesity with left ventricular mass and geometry. DESIGN.--Survey. SETTING.--Population-based epidemiologic study. PARTICIPANTS AND METHODS.--M-mode echocardiograms. which were adequate for estimation of left ventricular mass. were obtained in 3922 healthy participants of the Framingham Heart Study. Measured height and weight were used to calculate body-mass index. a measure of obesity. RESULTS.--Body-mass index was strongly correlated with left ventricular mass. After adjusting for age and blood pressure. body-mass index remained a strong independent predictor of left ventricular mass. left ventricular wall thickness. and left ventricular internal dimension (P less than .01 for all). Body-mass index was associated with prevalence of echocardiographic left ventricular hypertrophy. particularly in subjects with a body-mass index exceeding 30 kg/m2. CONCLUSIONS.--Obesity is significantly correlated with left ventricular mass. even after controlling for age and blood pressure. The increase in left ventricular mass associated with increasing adiposity reflects increases in both left ventricular wall thickness and left ventricular internal dimension.
A multivariate analysis of risk factors for preeclampsia, OBJECTIVE.--To determine. in a multivariate analysis. risk factors for preeclampsia that could be observed early in pregnancy and to establish whether these risk factors are different for nulliparas and multiparas. DESIGN.--A case-control study of preeclampsia. SETTING.--Women who gave birth at Northern California Kaiser Permanente Medical Centers in 1984 and 1985. PARTICIPANTS.--Preeclamptic cases (n = 139) were determined from discharge diagnosis of severe preeclampsia and by confirmation of blood pressures and proteinuria from medical records. Controls (n = 132) were randomly selected women who had no discharge diagnosis of any hypertensive disorder of pregnancy and who had no evidence of hypertension or proteinuria from medical record review. MAIN VARIABLES EXAMINED.--Medical records were abstracted for information regarding maternal age. race. previous pregnancy history. family medical history. socioeconomic status. employment during pregnancy. body mass. and smoking and alcohol consumption. RESULTS.--Multiple logistic regression analyses confirmed that case patients were more likely than control patients to be nulliparous (adjusted odds ratio [OR]. 5.4; 95% confidence interval [Cl]. 2.8 to 10.3) and that preeclampsia in a previous pregnancy greatly increased the risk in a subsequent one (adjusted OR. 10.8; 95% Cl. 1.2 to 29.1). However. regardless of parity. preeclamptic women were also more likely to be of high body mass (adjusted OR. 1.7; 95% Cl. 1.2 to 6.2). to work during pregnancy (adjusted OR. 2.1; 95% Cl. 1.1 to 4.4). and to have a family history of hypertension (adjusted OR. 1.7; 95% Cl. 0.92 to 3.2). Having a previous history of a spontaneous abortion was protective but only in multiparous women (adjusted OR for multiparas. 0.09; 95% Cl. 0.02 to 0.48). In contrast. being black was a significant risk for preeclampsia but only in nulliparous women (adjusted OR for nulliparas. 12.3; 95% Cl. 1.6 to 100.8). CONCLUSIONS.--There are a number of risk factors for preeclampsia that may be determined early in a woman's pregnancy. Multiparas and nulliparas share certain risk factors but not others. A cohort investigation is needed to determine the ability of these risk factors to predict who develops preeclampsia.
Tubal sterilization and subsequent ectopic pregnancy. A case-control study, OBJECTIVE--To assess the relative risk of ectopic pregnancy associated with postpartum or interval tubal sterilization. DESIGN--Case-control study using a comparison group of women of reproductive age at risk of pregnancy. SETTING--Group Health Cooperative of Puget Sound. a health maintenance organization based in Seattle. Wash. organization based in Seattle. Wash. PARTICIPANTS--Cases were 249 enrollees diagnosed as having an ectopic pregnancy between October 1. 1981. and September 30. 1986. Controls were 835 randomly selected enrollees matched to cases on age and county of residence. MEASUREMENTS--Information on interval sterilization history was obtained from interviews. examination of medical records. automated hospitalization files and a previously validated algorithm. A logistic regression model was used to estimate relative risks (RRs) for sterilized women compared with women using other types of or no contraception at the reference date. RESULTS--Controlling for age. county. race. smoking. income. gravidity. and prior use of a Dalkon Shield intrauterine device. the risk of ectopic pregnancy in women who had undergone interval sterilization was 3.7 (95% confidence interval [CI]. 1.7 to 8.0) times that of women currently using oral contraception and 2.8 (95% CI. 1.5 to 5.5) times that of women currently using barrier contraceptive methods. Use of interval sterilization was associated with a risk of ectopic pregnancy similar to that of women using intrauterine devices (RR. 0.8; 95% CI. 0.4 to 1.7) and a risk lower than that of women who were not using contraception (RR. 0.2; 95% CI. 0.1 to 0.3). The corresponding RRs associated with postpartum sterilization were lower: 1.2 (95% CI. 0.3 to 3.9). 0.9 (95% CI. 0.3 to 2.8). 0.3 (95% CI. 0.1 to 0.8). and 0.1 (95% CI. 0.0 to 0.2). respectively. CONCLUSION--Tubal sterilization provides some protection against extrauterine as well as intrauterine pregnancy. It is likely that postpartum sterilization can be a safe alternative to all types of temporary contraception in terms of risk of ectopic pregnancy. while some types of interval sterilization may lead to an increased risk. in comparison with use of oral contraceptives or barrier methods.
Racial variations in the prevalence of primary open-angle glaucoma. The Baltimore Eye Survey, OBJECTIVE.--To compare the prevalence of primary open-angle glaucoma between black and white Americans. DESIGN. SETTING. AND PARTICIPANTS.--The design was a population-based prevalence survey of a noninstitutionalized black and white population aged 40 years or older from the eastern and southeastern health districts of Baltimore. Md. A multistage random sampling strategy was used to identify 7104 eligible participants. of whom 5308 (2395 blacks. 2913 whites) received an ophthalmologic screening examination. Those with abnormalities were referred for definitive diagnostic evaluation. MAIN OUTCOME MEASURE.--Primary open-angle glaucoma was defined based on evidence of glaucomatous optic nerve damage. including abnormal visual fields and/or severe optic disc cupping. and was independent of intraocular pressure. MAIN RESULTS.--Age-adjusted prevalence rates for primary open-angle glaucoma were four to five times higher in blacks as compared with whites. Rates among blacks ranged from 1.23% in those aged 40 through 49 years to 11.26% in those 80 years or older. whereas rates for whites ranged from 0.92% to 2.16%. respectively. There was no difference in rates of primary open-angle glaucoma between men and women for either blacks or whites in this population. Based on these data. an estimated 1.6 million persons aged 40 years or older in the United States have primary open-angle glaucoma. CONCLUSIONS.--Black Americans are at higher risk of primary open-angle glaucoma than their white neighbors. This may reflect an underlying genetic susceptibility to this disease and indicates that additional efforts are needed to identify and treat this sight-threatening disorder in high-risk communities.
Results of the Massachusetts Model Systems for Blood Cholesterol Screening Project, OBJECTIVE.--To evaluate the effectiveness of a model blood cholesterol screening program. DESIGN.--Principal components included physician education. community-based screenings. and follow-up. A lay or professional educator provided counseling and referral advice. Half of the subjects with high blood cholesterol levels received a reminder to see their physician. SETTING.--135 sites in four Massachusetts communities. PARTICIPANTS.--10.428 adults. Males. the young. the poor. the less educated. and minorities were underrepresented. MAIN OUTCOME MEASURES.--Referral completion rates. blood cholesterol changes. RESULTS.--51.5% of those referred had visited their physicians within 2 to 4 months. increasing to 65.6% within 6 to 12 months. Older age (odds ratio [OR]. 1.17 per additional decade). more education (OR. 1.17 per additional level). higher blood cholesterol levels (OR. 1.19 per additional 0.51 mmol/L). previous knowledge of level (OR. 1.34). and receiving a reminder (OR. 1.24) were significantly associated with greater likelihood of referral completion. whereas the type of educator providing counseling was not. Physicians had remeasured the blood cholesterol level of 76% of those seen. given dietary counseling to 70%. and prescribed medication to 15%. Significant changes in dietary fat were reported by both compliers and noncompliers with advice to follow up with their physicians. Six months after screening. blood cholesterol levels were 3.6% lower in noncompliers. 4.4% lower in compliers not taking cholesterol-lowering medications. and 8.8% in compliers taking such medications. CONCLUSIONS.--An effective. community-based blood cholesterol screening program can attract diverse populations and can result in most participants with high levels following up with their physicians. making dietary changes. and lowering their cholesterol levels. Additional strategies may be needed to attract underrepresented groups and to reduce the apparent overuse of cholesterol-lowering medications.
Bedside diagnostic blood testing. Its accuracy, rapidity, and utility in blood conservation, OBJECTIVE.--Bedside diagnostic testing utilizing microchemistry instruments potentially offers physicians the opportunity to evaluate urgent blood test results rapidly and reliably using only drops (250 microL) of whole blood. The use of microchemistry technology may also represent an essential component of a blood conservation program in acutely ill patients. We tested the hypothesis that a microchemistry instrument would have important advantages in the intensive care unit. including rapid turnaround time. decreased iatrogenic blood loss. and the provision of accurate analyte results. DESIGN.--One-year prospective. random-sample comparative study. SETTING.--A tertiary. acute care. 1000-bed university teaching hospital and a 450-bed university-affiliated community hospital. PATIENTS.--Blood samples from 850 patients were analyzed. RESULTS.--There were strong correlations (for pH. R2 = .97; PCO2. R2 = .97; PO2. R2 = .99; sodium. R2 = .83; potassium. R2 = .94; chloride. R2 = .90; glucose. R2 = .98; and hematocrit. R2 = .92) when paired samples were analyzed simultaneously in the laboratory comparing the microchemistry instrument and currently accepted clinical laboratory instruments. There were significant correlations (for pH. R2 = .91; PCO2. R2 = .94; PO2. R2 = .97; sodium. R2 = .91; potassium. R2 = .86; chloride. R2 = .91; ionized calcium. R2 = .82; glucose. R2 = .96; and hematocrit. R2 = .75) but increased variability occurred in some analyte results when samples were first analyzed in the intensive care unit (using the microchemistry instrument) and then transported to the laboratory in the routine fashion for "stat" determinations. CONCLUSIONS.--The multichannel microchemistry instrument provided accurate analyte determinations when compared with accepted clinical laboratory instruments. Significant savings of time and blood were also realized by the use of a microchemistry instrument in the intensive care unit. Bedside microchemistry may provide clinically important advantages in emergency departments. operating rooms. and neonatal. pediatric. coronary. adult medical and surgical. trauma. and burn intensive care units.
Alpha-blocker therapy of hypertension. An unfulfilled promise, For various reasons. the alpha 1-receptor blocker prazosin has been used infrequently as initial therapy for hypertension. The introduction of additional agents of this class with properties different from prazosin provides slower onset of action. which should reduce the degree of first-dose and postural hypotension and a longer duration of action. which allows for once-a-day dosage. A summary of the published data on efficacy. side effects. and special properties of this class of agents indicates that they will probably be used more extensively. particularly because of their ability to improve lipid and glucose-insulin metabolism.
Nutritional supplementation, psychosocial stimulation, and mental development of stunted children: the Jamaican Study, There is little unequivocal evidence that nutritional supplementation of undernourished children has a beneficial effect on their mental development. The effects of nutritional supplementation. with or without psychosocial stimulation. of growth-retarded (stunted) children aged 9-24 months were assessed in a study in Kingston. Jamaica. 129 children from poor neighbourhoods were randomly assigned to four groups--control. supplemented only. stimulated only. and supplemented plus stimulated. A group of matched non-stunted children (n = 32) was also included. The supplement comprised 1 kg milk-based formula per week for 2 years. and the stimulation weekly play sessions at home with a community health aide. The children's development (DQ) was assessed on the Griffiths mental development scales. Initially the stunted groups' DQs were lower than those of the non-stunted group. and those of the control group declined during the study. increasing their deficit. Stimulation and supplementation had significant independent beneficial effects on the children's development. Estimates of the supplementation effect ranged from 2.2 (95% confidence limits-1.4. 5.7) for the hand and eye subscale to 12.4 (5.4. 19.5) for the locomotor subscale and those for the stimulation effect from 6.4 (2.8. 10.0) for hand and eye to 10.3 (3.3. 17.3) for locomotor. The treatment effects were additive. and combined interventions were significantly more effective than either alone. These findings suggest that poor mental development in stunted children is at least partly attributable to undernutrition.
Impairments, disabilities, and handicaps of very preterm and very-low-birthweight infants at five years of age. The Collaborative Project on Preterm and Small for Gestational Age Infants (POPS) in The Netherlands, The Project On Preterm and Small for gestational age infants (POPS) was started in the Netherlands in 1983 to investigate the relation between prenatal/perinatal factors and mortality/morbidity in very preterm and very-low-birthweight infants. Of the 1338 liveborn infants (less than 32 weeks and/or less than 1500 g) 966 were enrolled in the five-year (chronological age) follow-up programme; 96% of these children were assessed during a home visit. The overall outcome was expressed as impairments. disabilities. and handicaps according to World Health Organisation criteria. Of the assessed children. 13% had a disability and 14% were handicapped. which are much higher frequencies than those found in the general population. Handicaps were due mainly to abnormalities of neuromotor function. mental development. or language and speech development. Compared with the handicap frequency in the same cohort at two years of age. a more favourable outcome at five years of age was seen in 10%. and a less favourable outcome in 7% of the children. The findings show that most of those high-risk children survived without handicap or serious disability at preschool age.
Comparison of ribavirin and placebo in CDC group III human immunodeficiency virus infection. Spanish Ribavirin Trial Group, To assess the efficacy and safety of ribavirin in patients with human immunodeficiency virus (HIV) infection a multicentre. placebo-controlled. prospectively randomised trial was conducted in CDC group III HIV-infected individuals between February. 1988. and October. 1989. Mean treatment time was 39 weeks (range 6-52); 152 individuals were enrolled. of whom 133 could be evaluated. The two treatment groups were similar at baseline and 66% of all subjects had intravenous drug abuse as the main risk factor for HIV infection. Ribavirin was given at a dose of 15 mg/kg daily by mouth (average daily dose 1000 mg). 9 of 67 patients in the placebo group (13.4%) progressed to CDC Groups IVA. C1. or D vs 6 of 66 (9%) in the ribavirin group. Progressions to group IVC2 were 7 (10.4%) and 9 (13.6%). respectively. These differences are not statistically significant. There were no clinically or statistically significant differences in CD4 cell counts. total lymphocytes. total white cells. or CD4/CD8 ratios between the two groups during treatment. and no clinically important side-effects were noted.
Seasonal variations in fibrinogen concentrations among elderly people, Mortality and morbidity in elderly people are higher in winter than in summer months. with seasonal variations in rates of both fatal and non-fatal myocardial infarction and stroke. To identify factors that might contribute to the excess winter frequency of cardiovascular disease in the elderly. we studied 100 subjects aged 75 and over who lived in either their own homes or in sheltered or residential accommodation. Each person was visited each month for one year. body and environmental temperatures were noted. and cardiovascular risk factors were measured. 32 subjects withdrew from the study. Significant seasonal effects were found for fibrinogen. plasma viscosity. and HDL cholesterol (p less than 0.003. Bonferroni adjustment). Plasma fibrinogen concentrations showed the greatest seasonal change and were 23% higher in the coldest six months compared with summer months. Fibrinogen was significantly (p less than 0.05) and negatively related to core body temperature and all measures of environmental temperature. Those living in institutions had greater changes in plasma fibrinogen than those living in the community. The seasonal variation in plasma fibrinogen concentration is large enough to increase the risk of both myocardial infarction and stroke in winter.
Radial growth plate injury in a female gymnast, Radial growth plate injury is a cause of wrist pain in female gymnasts. The mechanism of injury and its relationship to dowel grips. now standard gymnastic equipment. are considered. An athlete's response to a treatment approach emphasizing moderation and protection is described.
Metabolic rate, not percent dehydration, predicts rectal temperature in marathon runners, This study was designed to determine the factors predicting the post-race rectal temperature in marathon runners. Post-race rectal temperatures of 30 recreational runners (maximum oxygen consumption (VO2max) = 58.3 +/- 5.9 ml O2.kg-1.min-1; mean +/- SD) who completed a 42.2 km marathon at 75.8% (+/- 9.3%) VO2max were measured and related to their levels of dehydration (percent mass loss). their running velocities (km.h-1). and their estimated absolute metabolic rates (1 O2.min-1) for different segments of the 42.2 km race. The influence of certain anthropometric variables was also determined. Percent mass loss during the race (2.5 +/- 1.4%). post-race rectal temperatures (38.9 +/- 0.6 degrees C). and rates of sweat loss (1.0 +/- 0.3 1.h-1) were low. There was no statistical relationship between percent mass loss and post-race rectal temperature. Post-race rectal temperatures were significantly related to the metabolic rates for the full 42.2 km and for the last 21.1 and 6 km of the race. and to the average running velocity for the last 6 km (P less than 0.05 and P less than 0.01). Average sweat rates were related to metabolic rates for 42.2 km and for the last 6 km of the race (P less than 0.05) but were unrelated to running velocity. We conclude that metabolic rate sustained during the latter section of the race. and not the level of dehydration. is the principal determinant of the post-race rectal temperature in marathon runners.
Use of graded exercise to evaluate physiological hyperreactivity to mental stress, Physiological hyperreactivity (i.e.. response in excess of metabolic requirements) to mental stress has been implicated in the etiology of coronary heart disease. This study evaluated potential hyperreactivity of cardiovascular. pulmonary. and biochemical variables to mental stress. Thirty healthy males. 19-36 yr. performed a mental arithmetic task and cycle ergometry at three powerloads. Linear regressions were calculated for each of 17 dependent variables during exercise. with oxygen uptake (VO2) serving as the independent variable. Ten variables were significantly correlated (P less than 0.003) with VO2 during exercise and. therefore. were predicted at the VO2 observed during the arithmetic task. The actual level of each variable observed during the arithmetic task was compared with the level predicted from the exercise by paired t-tests. Heart rate. systolic and diastolic blood pressure. rate-pressure product. minute ventilation. respiratory frequency. and respiratory exchange ratio were significantly greater (7-32%. P less than 0.005) during the arithmetic task than predicted from the exercise at an equivalent VO2. Plasma cortisol and serum lipid variables were not useful for evaluating hyperreactivity. Results demonstrated that graded aerobic exercise can serve as a reference for evaluating physiological hyperreactivity to mental stress for a group of ten variables which were significantly correlated with VO2 during graded exercise.
The effects of shoes on the torsion and rearfoot motion in running, Excessive pronation is accepted as a good indicator for various running injuries. The least amount of pronation takes place when running barefoot. The latest investigations show that this is connected to a large torsional movement between forefoot and rearfoot which can be influenced by the shoe sole construction. The shoes which are in use among runners in track and field are basically of two types. running shoes (in general torsionally stiff) and spikes (torsionally flexible). The possibly varying effect of these shoes on the shoe/foot motion in running is not known. The purpose of this investigation was therefore to show whether the pronation angle and the torsion angle differ when running barefoot. with spikes. and with running shoes (forefoot touchdown. N = 9 left and right). A film analysis provided the angular movements of the lower leg. rearfoot. and forefoot as well as pronation and torsion in the frontal plane. The results show that at touchdown the torsional movements with both shoe types are quite different from those of running barefoot. With shoes. the torsion angle is reduced back to zero--with running shoes more than with spikes--and the pronation angle is increased beyond the barefoot values (P less than 0.01). In order to reduce the risk of injury. both shoe types should be improved--the running shoes with respect to torsion and the spikes with respect to pronation.
Rocky Mountain spotted fever--United States, 1990, In 1990. state health departments reported 649 cases of Rocky Mountain spotted fever (RMSF) to CDC. a 7.6% increase from the 603 cases reported in 1989. The incidence rate was 0.26 per 100.000 persons. Of the 649 cases. 292 (45.0%) and 101 (15.6%) were reported from the South Atlantic and the West South Central regions. respectively.
Differences in the use of procedures between women and men hospitalized for coronary heart disease, BACKGROUND AND METHODS. Previous studies at individual hospitals have reported differences in the use of major diagnostic and therapeutic procedures for women and men with coronary heart disease. To assess whether these differences can be generalized. we performed retrospective analyses of coronary angiography and revascularization (coronary-artery bypass surgery or percutaneous transluminal coronary angioplasty) in women and men hospitalized for coronary heart disease in 1987. using abstract data on 49.623 discharges in Massachusetts and 33.159 discharges in Maryland. We used multiple logistic regression to estimate the adjusted odds of the use of a procedure. controlling for principal diagnosis. age. secondary diagnosis of congestive heart failure or diabetes mellitus. race. and insurance status. RESULTS. The adjusted odds of undergoing angiography were 28 percent and 15 percent higher for men than for women in Massachusetts and Maryland. respectively (95 percent confidence intervals for the odds ratios. 1.22 to 1.35 and 1.08 to 1.22). The respective adjusted odds of undergoing revascularization were 45 percent and 27 percent higher for men than for women (95 percent confidence intervals. 1.35 to 1.55 and 1.16 to 1.40). Because these differences could be related to differing thresholds for hospital admission. we performed a second analysis limited to patients with diagnosed acute myocardial infarction (11.865 discharges in Massachusetts and 6894 discharges in Maryland). a group in which all patients would be expected to receive hospital care. The male-to-female odds ratios in both states remained similar in magnitude and were statistically significant for angiography and revascularization. CONCLUSIONS. These findings demonstrate that women who are hospitalized for coronary heart disease undergo fewer major diagnostic and therapeutic procedures than men. These differences may represent appropriate levels of care for men and women. but it is also possible that they reflect underuse in women or overuse in men. Further study should assess the cause of these differences and their effect on patients' outcomes.
Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators, BACKGROUND. Despite the fact that coronary artery disease is the leading cause of death among women. previous studies have suggested that physicians are less likely to pursue an aggressive approach to coronary artery disease in women than in men. To define this issue further. we compared the care previously received by men and women who were enrolled in a large postinfarction intervention trial. METHODS. We assessed the nature and severity of anginal symptoms and the use of antianginal and antiischemic interventions before enrollment in the 1842 men and 389 women with left ventricular ejection fractions less than or equal to 40 percent after an acute myocardial infarction who were randomized in the Survival and Ventricular Enlargement trial. RESULTS. Before their index infarction. women were as likely as men to have had angina and to have been treated with antianginal drugs. However. despite reports by women of symptoms consistent with greater functional disability from angina. fewer women had undergone cardiac catheterization (15.4 percent of women vs. 27.3 percent of men. P less than 0.001) or coronary bypass surgery (5.9 percent of women vs. 12.7 percent of men. P less than 0.001). When these differences were adjusted for important covariates. men were still twice as likely to undergo an invasive cardiac procedure as women. but bypass surgery was performed with equal frequency among the men and women who did undergo cardiac catheterization. CONCLUSIONS. Physicians pursue a less aggressive management approach to coronary disease in women than in men. despite greater cardiac disability in women.
Effect of very low birth weight and subnormal head size on cognitive abilities at school age, BACKGROUND. We tested the hypothesis that very-low-birth-weight (less than 1.5 kg) infants with perinatal growth failure whose head size is not normal by eight months of age (corrected for prematurity) have significantly poorer growth and neurocognitive abilities at school age than very-low-birth-weight children with a normal head size at eight months. We also hypothesized that these differences would persist even after control for major neurologic impairment and perinatal and sociodemographic risk factors. METHODS. We have followed a cohort of very-low-birth-weight children since their birth during the period 1977 to 1979. At eight to nine years of age 249 children were evaluated with a neurologic examination and tests of intelligence; receptive and expressive language skills; speech. reading. mathematics. and spelling aptitude; visual and fine motor abilities; and behavior. Ages were corrected for premature birth. RESULTS. Among these 249 very-low-birth-weight children. head size was subnormal (less than the mean -2 SD for age) at birth in 30 (12 percent). at term in 57 (23 percent). and at eight months in 33 (13 percent). As compared with the 216 children with normal head sizes. the 33 children with subnormal head sizes at the age of eight months had significantly lower mean birth weights (1.1 vs. 1.2 kg) and higher neonatal risk scores (71 vs. 53) and at the age of eight years had a higher incidence of neurologic impairment (21 percent vs. 8 percent) and lower IQ scores (mean verbal. 84 vs. 98). Even among the children without neurologic abnormalities. a subnormal head size at eight months of age was predictive of poorer verbal and performance IQ scores at eight years of age; lower scores for receptive language. speech. reading. mathematics. and spelling; and a higher incidence of hyperactivity. In multiple regression analyses to control for socioeconomic and neonatal risk factors. intrauterine growth failure. birth weight. and neurologic impairment. a subnormal head size at eight months of age had an independently adverse effect on IQ and on scores for receptive language. speech. reading. and spelling. CONCLUSIONS. In very-low-birth-weight infants. perinatal growth failure. as evidenced by a subnormal head circumference at eight months of age. is associated with poor cognitive function. academic achievement. and behavior at eight years of age.
Relation between malpractice claims and adverse events due to negligence. Results of the Harvard Medical Practice Study III, BACKGROUND AND METHODS. By matching the medical records of a random sample of 31.429 patients hospitalized in New York State in 1984 with statewide data on medical-malpractice claims. we identified patients who had filed claims against physicians and hospitals. These results were then compared with our findings. based on a review of the same medical records. regarding the incidence of injuries to patients caused by medical management (adverse events). RESULTS. We identified 47 malpractice claims among 30.195 patients' records located on our initial visits to the hospitals. and 4 claims among 580 additional records located during follow-up visits. The overall rate of claims per discharge (weighted) was 0.13 percent (95 percent confidence interval. 0.076 to 0.18 percent). Of the 280 patients who had adverse events caused by medical negligence as defined by the study protocol. 8 filed malpractice claims (weighted rate. 1.53 percent; 95 percent confidence interval. 0 to 3.2 percent). By contrast. our estimate of the statewide ratio of adverse events caused by negligence (27.179) to malpractice claims (3570) is 7.6 to 1. This relative frequency overstates the chances that a negligent adverse event will produce a claim. however. because most of the events for which claims were made in the sample did not meet our definition of adverse events due to negligence. CONCLUSIONS. Medical-malpractice litigation infrequently compensates patients injured by medical negligence and rarely identifies. and holds providers accountable for. substandard care.
A double-blind trial of a 16-hour transdermal nicotine patch in smoking cessation, BACKGROUND. The use of nicotine chewing gum combined with psychological support improves the success rate in quitting smoking. We studied the safety and efficacy of a transdermal nicotine patch in smoking cessation. METHODS. We conducted a double-blind randomized study comparing the effects of a 16-hour nicotine patch (15 +/- 3.5 mg of nicotine in 16 hours) with those of a placebo patch. Of the 289 smokers (207 women and 82 men) enrolled in the study. 145 were treated with nicotine patches and 144 with placebo patches for 16 weeks. RESULTS. Rates of sustained abstinence were significantly better with active treatment than with placebo: 53. 41. 24. and 17 percent of those in the nicotine-patch group were abstinent after 6. 12. 26. and 52 weeks. respectively. as compared with 17. 10. 5. and 4 percent of those in the placebo-patch group (P less than 0.0001). Only two subjects with the nicotine patch and one with the placebo patch had to withdraw from the study because of side effects. CONCLUSIONS. The nicotine skin patch proved to be safe and effective. as demonstrated by a higher rate of abstinence than with placebo. However. the absolute rate of abstinence after one year was only 17 percent. which is lower than the rate in studies that have combined the use of nicotine chewing gum with behavioral therapy.
Visual outcome in pseudophakic eyes with clinical cystoid macular edema, Thirty-nine eyes with clinical cystoid macular edema (CME) following extracapsular cataract extraction and intraocular lens (IOL) implantation were reviewed retrospectively. Chronic CME. defined as clinically symptomatic CME persisting more than 6 months. developed in 14 of the 39 eyes (36%): in 5 of the 7 (71%) eyes in which vitreous loss occurred and anterior chamber IOLs were implanted; and in 9 of 32 (28%) eyes in which no complications occurred and posterior chamber IOLs were implanted. The mean duration between diagnosis and last follow-up visit was 34 months. Only 4 of the 14 eyes (29%) with chronic CME achieved a visual acuity better than 20/40. Vitreous loss did not affect long-term visual prognosis.
Determination of maximal incision length for true small-incision surgery, We studied induced astigmatism in cadaver eyes to determine how small a limbal incision must be to avoid a long-term corneal flattening induced by limbal incisions along the meridian of the incision. We performed scleral pocket incisions (2.0 to 5.5 mm in 0.5-mm increments) on 12 fresh human cadaver globes. recessing the incisions 0.5 mm to simulate the natural wound sliding that causes corneal flattening. We found that with increasing incision length there was a nearly linear increase in corneal flattening. The maximal incision length that minimized induction of corneal flattening in excess of 0.25 diopters was 3.0 mm.
Early visual rehabilitation following keratoplasty using a single continuous adjustable suture technique, We measured postkeratoplasty visual acuity. refraction. retinoscopy. keratometry. and corneal topography in 105 patients. in 33 of whom an adjustable continuous technique had been used. and in 72 of whom a standard technique (in which the continuous suture was not adjusted) had been used. In the eyes in which the sutures were adjusted (within 6 weeks following surgery). acuity improved (preadjustment mean. 20/205; postadjustment mean. 20/100). and astigmatism decreased (preadjustment mean. 8.41 diopters; postadjustment mean. 2.22 D). Visual acuity and astigmatism in the control group were unchanged at the same point after surgery.
Surgical management of corneal perforation with expanded polytetrafluoroethylene (Gore-Tex), We report a series of six patients with spontaneous corneal perforations successfully treated with a temporary graft of expanded polytetrafluoroethylene (Gore-Tex) until a definitive penetrating keratoplasty could be performed. Two other patients had a paralimbic perforation treated with an artificial lamellar Gore-Tex graft. No infection or extrusion developed. and the artificial graft kept the anterior chamber tight in all cases. Gore-Tex appears to be a safe and effective material for use in treating acute central and peripheral corneal perforation.
Outpatient dacryocystorhinostomy, We report 105 dacryocystorhinostomy procedures in 87 patients performed on an outpatient basis. Seventy-six patients received local. and 29 received general. anesthesia. The patients left the hospital an average of 2.6 hours after surgery. but 14 were admitted after surgery--9 immediately. and 5 after some delay. primarily for epistaxis. There were no serious complications related to the outpatient nature of the surgery. The success rate was 94%. We conclude that outpatient dacryocystorhinostomy is successful. well accepted by patients. and safe. provided that inpatient care facilities are readily available should they be needed.
Long-term placement of silastic nasolacrimal tubes, We retrospectively reviewed the complication rate associated with silastic tube intubation in the treatment of congenital and acquired obstructions of the lacrimal system in 82 patients with a follow-up of 3 to 66 months. Complications included tube prolapse. extrusion or breakage. punctal erosion. conjunctival irritation. intranasal discomfort. and tube inspissation with mucoid debris ("dirty tubes"). The rate was highest in the first 3 months (41%); it decreased to less than 10% after 6 months. Based on these findings. we recommend that silastic nasolacrimal tubes be regarded as semi-permanent devices which may safely be left in place for years.
Canalicular stenosis following probing for congenital nasolacrimal duct obstruction, A canalicular stenosis was identified in 29 of 66 (44%) children and 35 of 80 (44%) lacrimal drainage systems undergoing silicone intubation for congenital nasolacrimal duct obstruction. having previously had unsuccessful probings. The stenoses were equally divided between boys and girls and between right and left sides. There was no significant difference in age at the time of probing. number of prior probings. or age at intubation between children with and without canalicular stenosis. Stenoses may be congenital or acquired as a result of faulty probing. Any child undergoing a second lacrimal procedure after a failed probing should be evaluated for evidence of a canalicular stenosis. If a stenosis is present. a silicone stent should be placed to try to salvage the canaliculus.
Methylene blue stain guiding layered excision in Mohs' micrographic surgery, Resection of a continuous layer of tissue by means of Mohs' micrographic surgery is problematic at several periorbital sites. We describe a technique in which methylene blue is used to identify instances of incomplete specimen removal and thus facilitate subsequent complete removal.
Choroidal thickness in primary glaucoma, A and B scan echography does not allow to measure separately the thickness of the three ocular layers. retina. choroid and sclera. This. however. is possible by radiofrequency signals. 48 eyes of normal subjects and 21 eyes of patient suffering from chronic glaucoma with ocular hypertension from 30 to 45 mm Hg were examined. The thickness of the retina and sclera was equal in the two groups. whereas the thickness of the choroid in the glaucomatous eyes showed an increase of 20% as compared with normal eyes.
Combined cytochemical detection of Muller-cell-specific enzyme activity and permeability tracers, A combination of cytochemical methods in one tissue section was studied in order to detect the contribution of Muller cells to the blood-ocular barrier. Applications are shown for the detection of Muller cells and peroxidatic enzymes. The following advantages of the present method were demonstrated: superior sensitivity of glucose-6-phosphatase (G6Pase) activity. which allows the detection of these cells even in the coagulated retina. The reaction products showed no deleterious change after a subsequent reaction. These factors. and the contrasting reaction products of G6Pase and the enzymatic tracers (especially those of horseradish peroxidase) allow the distinction of Muller cells and the functional barrier site.
Setting the optimal erythrocyte protoporphyrin screening decision threshold for lead poisoning: a decision analytic approach, Erythrocyte protoporphyrin (EP) was introduced in the 1970s as an inexpensive screening test for lead poisoning. As greater knowledge of lead poisoning has accumulated. the recommended EP level at which further evaluation for lead poisoning should be initiated has been lowered from greater than or equal to 50 micrograms/dL to greater than or equal to 35 micrograms/dL. The purpose of this study was to evaluate the utility of this EP threshold. A receiver operator characteristic curve was constructed to assess the relationship between the true-positive rate and false-positive rate of EP at various decision thresholds. The receiver operator characteristic curve was constructed with data from the second National Health and Nutrition Examination Survey from 1976 to 1980. which included 2673 children 6 years of age or younger who had both blood lead and EP level determinations. Decision analysis was then used to determine the optimal EP decision threshold for detecting a blood lead level greater than or equal to 25 micrograms/dL. The receiver operator characteristic curve demonstrated that EP is a poor predictor of a blood lead level greater than or equal to 25 micrograms/dL. At the currently recommended EP decision threshold of 35 micrograms/dL. the true-positive rates and false-positive rates of EP are 0.23 and 0.04. respectively. As a result of the inadequate performance of EP screening for lead poisoning. when the prevalence of lead poisoning is greater than 8%. there is no EP decision threshold that optimizes the relationship between the cost of screening normal children and the benefit of detecting lead-poisoned children. Erythrocyte protoporphyrin measurement is not sufficiently sensitive to be recommended uniformly as a screening test for lead poisoning.
A physicians's guide to preventing tobacco use during childhood and adolescence, Physicians who care for children can and should help patients avoid the use of tobacco. Physicians are well aware of the health hazards associated with tobacco use. inasmuch as smoking is the chief. single cause of premature mortality in this country. Each day. more than 3000 children in the United States begin to use tobacco. Physicians who care for children have patients at vastly different stages of intellectual and social maturity. Both the theory and practical details of tobacco-related interventions differ among infants. children. and adolescents. The physician is in a unique position to intervene in the early stages. Anticipatory guidance--the practice of providing counsel regarding potential problems--is a key part of health care for the young. If physicians provide messages about tobacco use that are appropriate to the patient's age and developmental stage. the potential for broad public health impact is great. Based on a series of clinical trials. the National Cancer Institute developed a manual to assist physicians in helping their patients stop smoking. The recommendations in this manual include four physician activities that begin with the letter A (four A's): Ask. Advise. Assist. and Arrange follow-up. For physicians who treat children. a fifth A. Anticipatory guidance. is added.
Sweden's experience in reducing childhood injuries, Why does Sweden have the lowest childhood injury rate of any country in the world? The answer lies in a combination of factors including the special characteristics of Swedish society and an energetic 35-year campaign. Contributing societal characteristics are a small. relatively homogeneous. health conscious. law-abiding population that values children. Key factors in the campaign have been support of trauma surveillance systems and injury prevention research. ensuring safer environments and products through legislation and regulation. and a broad-based safety education campaign using coalitions of existing groups. Emulating the strategies used in the Swedish campaign would markedly reduce the number of US children killed. injured. and disabled from trauma.
Surfactant proteins and anti-surfactant antibodies in sera from infants with respiratory distress syndrome with and without surfactant treatment, The presence of surfactant protein antigenemia and of surfactant protein antibodies was determined in serum from surfactant-treated and control infants with respiratory distress syndrome who were enrolled in a prospective randomized clinical trial. The surfactant used for treatment (surfactant TA) contained surfactant proteins (SPs) B and C and no SP-A. Enzyme-linked immunosorbent assays (ELISAs) that identify surfactant-associated proteins and ELISAs that identify IgG or IgM directed against surfactant proteins were used to investigate sera from these infants obtained prior to treatment. at 1 week of age. and at 2 months of age. There were no significant differences between average values in the surfactant-treated and control groups at each time period. However. in the control group. averaged results from ELISAs that identify SP-A and that identify IgM antibodies to SP-A or to SP-B. C showed significant differences between pretreatment sera and sera obtained at 1 week of age. No significant differences were noted in averaged results for IgG. Positive ELISA values were more frequently found in the control group than in the surfactant-treated group with regard to SP-A. and IgM against SP-A and SP-B. C in sera from neonates at 1 week of age. No positive ELISA values were found in sera from infants at 2 months of age. It is concluded that some patients with severe respiratory distress syndrome presumably leak surfactant proteins into the circulation and that this induces transient low titers of IgM antibody. This occurrence is decreased with surfactant treatment. Surfactant treatment may reduce leak of surfactant proteins into the vascular space by reducing lung damage.
Readmissions of children with diabetes mellitus to a children's hospital, The characteristics of children with diabetes readmitted to Children's Hospital during a 5-year period. 1984 to 1989. were compared with those characteristics of new-onset patients admitted for stabilization and education and to outpatients in the Children's Hospital diabetes program to determine which characteristics were associated with patients who were readmitted. Changes in the frequency of readmissions were examined to determine whether the introduction of a diabetes team and a program that emphasizes the importance of ensuring that patients at risk of readmission consistently received insulin injections resulted in a reduction of readmissions. Readmissions occurred more frequently in patients who were black (71% compared with 38% of new-onset patients and 31% of outpatients) (P less than .001). from one-parent homes (56% compared with 27% of new-onset patients and 24% of outpatients) (P less than .001). and without third-party insurance (45% compared with 18% of new-onset patients and 15% of outpatients) (P less than .001). Readmissions were very common at 14 to 15 years of age (39% of readmissions vs 18% of outpatients) and very uncommon in children younger than age 9 (6% of readmissions vs 27% of outpatients) (P less than .001). Fewer readmissions for ketoacidosis occurred in the summer than in any other season (P less than .05). Readmissions fell by 47% over the 5-year period while new-onset patients increased by 85%. The reduction in frequency of readmissions was due to fewer readmissions for ketoacidosis and fewer readmissions in blacks. in patients from one-parent homes. and in patients without third-party insurance.
North American Symptomatic Carotid Endarterectomy Trial. Methods, patient characteristics, and progress, Fifty North American centers have combined to evaluate the benefit of carotid endarterectomy in randomized patients who have experienced symptoms related to arteriosclerotic stenosis of the carotid artery and who have received either best medical therapy alone or best medical therapy plus carotid endarterectomy. The outcome events are nonfatal and fatal stroke or death. A three-tier system identifies and adjudicates the type. severity. and location of each stroke and the cause of any death. Data about patients submitted to carotid endarterectomy outside the trial are compiled at the Nonrandomized Data Center at the Mayo Clinic. Between December 27. 1987. and October 1. 1990. 1.212 patients were randomized. 596 to medical therapy. 616 to carotid endarterectomy. Cross-over from the medical to the surgical arm has been low (4.2%). Patients eligible for the trial. but not randomized totaled 1.044; their characteristics were similar to those randomized so that. for the type of symptomatic patient in this study. our conclusions about the benefit of carotid endarterectomy can be generalized. Patients excluded by medical criteria totaled 679. Another 1.591 had carotid endarterectomy. but either lacked the disease under study. were asymptomatic. or received inadequate investigation to meet entry criteria. We set sample size at 1.900 patients. with continuing enrollment. The Monitoring Committee reviews at intervals the confidential analyses performed on the groups with moderate (30-69%) and severe (70-99%) stenosis. Stopping rules will be invoked for one or both groups if unequivocal benefit or harm is identified.
Fourier analysis of the cerebrovascular system, We performed Fourier analysis of the middle cerebral artery blood flow velocity waveform envelope in 14 normal subjects (group A) and 15 patients. of whom five had arteriovenous malformations (group B). five had cerebral vasospasm (group C). and five had arterial hypertension (group D). Measurements were obtained under conditions of normocapnia. hypercapnia. and hypocapnia. The Fourier coefficients measured in the first five harmonics of the Doppler waveforms of group A were used as the reference baseline and were compared with the coefficients found in the other three groups. Group B showed significantly lower Fourier coefficients. while groups C and D showed higher coefficients (p less than 0.05). The elevation of the Fourier coefficients occurred in an alternating pattern in group C and a decremental pattern in group D. This distinction was attributed to possible differences in the underlying pathophysiological processes. The degree of vascular distensibility of the cerebral arterioles. inferred from the shape of the Fourier analysis curves. was compared in all four groups. Vascular distensibility was characterized as abnormal in arteriovenous malformations. vasospasm. and arterial hypertension. Fourier coefficients may be better indicators of cerebrovascular abnormalities than mean blood flow velocity in hypertension and pulsatility index in arteriovenous malformations. vasospasm. and hypertension.
Detection of paradoxical cerebral echo contrast embolization by transcranial Doppler ultrasound, Contrast echocardiography has been shown to be a sensitive method for detecting patent foramen ovale in embolic stroke. implying paradoxical embolization. However. not all two-dimensional echocardiographic studies are of diagnostic quality. and direct evidence for paradoxical cerebral embolization remains lacking. We addressed these problems by simultaneously using transcranial Doppler ultrasound and contrast echocardiography to compare relative sensitivity and concordance in the detection of right-to-left vascular shunting. Forty-six patients with stroke. transient neurologic defect. or question of atrial septal defect underwent study at rest and during Valsalva strain. Two-dimensional echocardiography detected shunting in 26% at rest and 15% during Valsalva strain. whereas transcranial Doppler study returned rates of 41% and 41%. respectively. Concordance was 82% and 75%. respectively. Discordant studies almost always had evidence of paradoxical contrast embolization by transcranial Doppler and intermediate findings by two-dimensional echocardiography. Transcranial Doppler is a sensitive. unambiguous technique for the detection of anatomic substrates and target organ involvement in patients suspected to have paradoxical cerebral embolization.
Effect of elevated plasma norepinephrine on electrocardiographic changes in subarachnoid hemorrhage, We compared electrocardiographic abnormalities and plasma norepinephrine concentrations in 40 patients with subarachnoid hemorrhage within the first 24 hours. at 72 hours. and after 1 week. In 20 patients with high plasma norepinephrine concentrations within the first 24 hours. sinus tachycardia (p less than 0.02) and negative T waves (p less than 0.01) were more frequent than in the 20 patients with normal plasma norepinephrine concentrations. After 72 hours. only sinus tachycardia (p less than 0.03) was found with increased frequency in the 26 patients with high plasma norepinephrine concentrations. Although 24 patients had high plasma norepinephrine concentrations after 1 week. we found no differences in the frequency of electrocardiographic abnormalities compared to patients with normal plasma norepinephrine. However. QTc prolongation. U waves. ST depression. and arrhythmias were found with similar frequency in patients with both high and normal plasma norepinephrine concentrations. We conclude that. with the exception of sinus tachycardia and negative T waves. electrocardiographic changes in patients with subarachnoid hemorrhage do not depend on elevated plasma norepinephrine concentrations.
Headache in transient or permanent cerebral ischemia. Dutch TIA Study Group, We studied headache features in 3.126 patients with acute cerebral or retinal ischemia. Headache occurred in 18% of these patients (in 16% of all patients with transient ischemic attacks. in 18% of patients with reversible ischemic neurologic deficits. and in 19% of patients with minor strokes) and was mostly continuous in all types of attacks. Headache was present in 16% of patients with monocular visual symptoms. The occurrence of headache was not related to the mode of onset. mode of disappearance. or duration of the attack. Patients with headache more often were known to have heart disease. Headache was less frequent in patients with small deep infarcts. who were more often hypertensive. and in patients with infarcts in the anterior circulation; headache was more frequent in patients with cortical infarcts and in patients with infarcts in the posterior circulation. Patients with a relevant small deep infarct on computed tomographic scan and accompanying headache relatively often reported symptoms compatible with cortical ischemia. such as language disorders or a visual field defect. We conclude that headache is a frequent accompanying symptom in patients with acute cerebral and retinal ischemia and that the occurrence of headache is partly related to the underlying cause of the ischemic lesion.
Bilateral anterior cerebral artery infarction resulting from explosion-type injury to the head and neck, A 43-year-old woman suffered a blast-type injury to the head and neck. She subsequently developed bilateral internal carotid artery occlusion and bilateral anterior cerebral artery infarction not demonstrated by magnetic resonance imaging scan 24 hours after the explosion. but confirmed by a second scan 8 days after the explosion. In patients with blast-type injury to the head and neck who develop coma with a nonfocal neurological exam. the possibility of bilateral carotid artery occlusion and bilateral ischemic infarction should be considered.
Thrombocytopenia possibly caused by structurally related third-generation cephalosporins, Thrombocytopenia is defined as a decrease in the platelet count to less than 100 x 10(9)/L and it is the most commonly reported drug-induced blood dyscrasia. Heparin is the most commonly reported cause of drug-induced thrombocytopenia with a reported incidence between one and ten percent. Thrombocytopenia induced by cephalosporins has been reported but is relatively rare. This report does not completely document that two third-generation cephalosporins caused platelet counts to fall less than 100 x 10(9)/L in the patient described but there was no other explanation available. Platelet counts began to fall with the institution of third-generation cephalosporins and began to rise when these agents were stopped. In order to document that thrombocytopenia was induced by the third-generation cephalosporins a rechallenge would have been necessary; this was not considered to be safe in this patient. A review of the literature is presented describing similar cases of cephalosporin-induced thrombocytopenia.
Mesalamine in ulcerative colitis, Sulfasalazine has been used for many years in the management of ulcerative colitis. As many as 20 percent of patients treated with it experience intolerable adverse effects usually attributed to its sulfapyridine component. The other active component is 5-aminosalicylic acid (5-ASA); the only 5-ASA enema preparation currently available in the U.S. is mesalamine (Rowasa. Reid-Rowell) containing 5-ASA 4 g in 60 mL. In clinical trials. mesalamine has proved efficacious in treating refractory cases of distal ulcerative colitis. proctitis. and proctosigmoiditis. Because of its high cost compared with more conventional treatment modalities. it should be reserved for cases that are either refractory or intolerant to conventional treatment.
The postantibiotic effect: a review of in vitro and in vivo data, The term postantibiotic effect (PAE) refers to a period of time after complete removal of an antibiotic during which there is no growth of the target organism. The PAE appears to be a feature of most antimicrobial agents and has been documented with a variety of common bacterial pathogens. Several factors influence the presence or duration of the PAE including the type of organism. type of antimicrobial. concentration of antimicrobial. duration of antimicrobial exposure. and antimicrobial combinations. In vitro. beta-lactam antimicrobials demonstrate a PAE against gram-positive cocci but fail to produce a PAE with gram-negative bacilli. Antimicrobials that inhibit RNA or protein synthesis produce an in vitro PAE against gram positive cocci and also produce a PAE against gram-negative bacilli. In vitro methods used to determine the PAE include colony counts. optical density. and measurement of adenosine triphosphate in bacteria. The exact mechanisms by which antimicrobials induce the PAE have not been clearly delineated. Animal studies reveal in vivo PAEs in accordance with PAEs obtained in vitro for most organism/antimicrobial combinations. The clinical relevance of the PAE is probably most important when designing dosage regimens. The presence of a long PAE allows aminoglycosides to be dosed infrequently; the lack of an in vivo PAE suggests that beta-lactam antimicrobials require frequent or continuous dosing. Important questions remain to be answered concerning the PAE.
Is there a reliable index of glomerular filtration rate in critically ill patients, Assessment of renal function in critically ill patients is important for appropriate individualization of dosage regimens and nutrition. but is complicated by a high incidence of acute renal failure (ARF). The most common cause of ARF in intensive care unit (ICU) patients is hypoperfusion. Other causes of ARF include intrinsic injury. nephrotoxicity. and postrenal obstruction. ARF is associated with a decreased glomerular filtration rate (GFR). reduced or maintained urine output (nonoliguric renal failure). and alterations in other commonly obtained urinary indices. Twenty-four-hour or shorter urinary creatinine clearance studies may overpredict GFR as creatinine is both filtered and secreted. The use of serum creatinine in empiric predictive equations is impaired in ICU patients because of decreases in creatinine production due to immobilization and malnutrition or increases in creatinine production due to catabolic illnesses. Adjustment of empiric methods by employing lean body weight. ideal body weight. or corrected serum creatinine values has not been evaluated against uncorrected values in this population. but is routinely performed in clinical practice. Inulin and radiolabeled substances are not practical for routine clinical use and may overpredict GFR in ARF due to backleak of large molecular-weight substances through the tubules. Comparative clinical trials have shown essentially equivalent performance of empiric methods relative to 24-hour urinary creatinine clearance in adults. No studies have compared these methods to a reference method for determination of GFR. Until conclusive data become available. clinicians should cautiously compare results from at least two independent methods of assessment to estimate renal functional impairment in ICU patients.
Physician follow-up of a community cholesterol-screening project, We report the results of physician follow-up of a group of community cholesterol-screening participants with hypercholesterolemia two years after the initial screening. Of 443 participants in a 1987 screening program. 51 (12%) had a cholesterol greater than the program cutoff of 7.16 mmol/L (277 mg/dL). In 1989. follow-up data from office records review and patient questionnaires were available on 48 (94%) of the 51 participants. Forty-three participants (90%) had consulted with a physician as advised. Twenty-five participants (66%) of the charts reviewed) had lipid profiles performed subsequent to the 1987 screening. Of the 43 participants consulting their physicians. twenty-six (60%) were prescribed a lipid-lowering regimen. Twenty-two were prescribed diet alone. fourteen also received prescriptions for medication. and two were advised to exercise more. Thirty subjects had had cholesterol levels checked in 1989. two years after the screening program. This group experienced an average decrease of 1.32 mmol/L (51 mg/dL). but several confounding factors may have contributed to this 16%-mean decline in cholesterol. Men were underrepresented throughout the screening and follow-up process. This community cholesterol-screening project in a small rural community achieved a high physician follow-up rate.
Laboratory differences in cervical cytology, This prospective study was designed to determine if there is a difference in reporting endocervical cells in Papanicolaou smears among laboratories used by an urban. academic family practice. A review of the literature found no studies comparing Papanicolaou smear results among laboratories with respect to the presence of endocervical cells. In this study. three laboratories evaluated a total of 140 Papanicolaou smears from women aged 16 to 83 (mean = 33.8) for endocervical cells. The presence of endocervical cells was reported for 88 smears (62.9%) ranging from 42/83 (50.6%) to 21/23 (91.3%) among laboratories. Results of an analysis of variance revealed a statistically significant difference in the frequency of reporting endocervical cells (p less than .001) among the laboratories. Analysis of covariance controlling for effects of several factors known to influence the outcome of Papanicolaou smears (age. days since last menstrual period. method used to obtain smear. and experience of clinician obtaining smear) failed to explain this difference.
Aspirin in transient ischemic attacks and minor stroke: a meta-analysis, An overview analysis of seven randomized controlled trials testing the effectiveness of aspirin in the treatment of patients with transient ischemic attacks and minor strokes was performed. A total of 6409 patients from the seven trials was entered in the analysis; 2182 patients received only aspirin; 1598 patients received an aspirin-combination regimen with either sulfinpyrazone or dipyridamole; and 2629 subjects received a placebo. Aspirin alone produced an 18% decrease in all strokes and cardiovascular deaths. The pooling of studies examining aspirin-combination regimens and the larger grouping of studies of aspirin and aspirin-combination regimens led to more striking results. Indeed. significant risk reductions were observed for three of the four outcomes. namely. total deaths. total strokes. and total strokes and cardiovascular deaths. with odds ratios ranging from 0.59 to 0.78. Suggestive. albeit more modest. results were obtained when examining the impact of these regimens on total cardiovascular mortality. The same tendencies have also been observed in three previously published meta-analyses.
Methicillin-resistant Staphylococcus aureus (MRSA) bacteriuria in nursing home-residents, Methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly common in nursing homes in the United States. It can cause serious infections and is difficult to eradicate once it becomes established in an institution. We report three representative cases of MRSA bacteriuria occurring in residents of a skilled nursing facility that experienced an outbreak of MRSA beginning in 1988. The clinical options available in such cases are described. and the research methods that should be used to answer important clinical questions arising from the presence of MRSA bacteriuria in long-term care settings are outlined.
Gonorrhea care in a clinic for low-income patients, There are few studies from family practice offices summarizing experience with culture-proven gonorrhea. Seventy-nine such cases were identified over a six-year period in a family practice model office in Gainesville. Florida. a rate of 5.8 cases per 10.000 patient visits. Ninety-six percent of the patients in the study had limited financial resources by insurance classification. The most commonly recognized presentations in men were complaints of discharge or dysuria or both. Nine (15%) of the women gave a history of contact with a person said to have a sexually transmitted disease. but none of the men did. Of the 62 women. gonorrhea was found on routine cervical culture in only two (3%). 38 (61%) had pelvic pain. and 40 (65%) had discharge as an initial complaint. Fifty-one of the patients (88%) reported symptomatic improvement with treatment. and seven (12%) reported no improvement by the treatment. Post-treatment gonorrhea cultures were positive in two (3%). negative in thirty-three (42%). not done in seventeen (22%). and twenty-seven of the patients (34%) did not return for scheduled follow-up. Difficulties in treating patients with gonorrhea in this population appeared to be largely related to problems with patient follow-up.
A new algorithm for the diagnosis of polycythemia, A new algorithm for the diagnostic evaluation of erythrocytosis is presented. This algorithm is based on principles of decision-making analysis and on the pathophysiology of erythrocytosis. The initial task is to identify smokers. because of the high probability that they have "smoker's" polycythemia. The current diagnostic criteria for polycythemia vera may be insufficient when the probability of disease is low but may be too rigorous when the probability of disease is high.
Laryngeal cancer: diagnosis, treatment and speech rehabilitation, Cancer of the larynx occurs most often in men between 50 and 70 years of age. Cigarette smoking and alcohol are responsible for more than 75 percent of cases. Hoarseness is the most common presenting complaint. If hoarseness persists for more than two weeks. laryngoscopy is indicated. Clinical staging utilizes direct laryngoscopy. esophagoscopy and bronchoscopy to exclude synchronous malignancies. The five-year cure rate. with preservation of voice and glottic function. is as high as 90 percent if the lesions of the vocal cords are found in an early stage. Total laryngectomy is required for more extensive disease. Speech rehabilitation has been revolutionized by tracheoesophageal speech techniques.
Caring for older patients with high blood pressure, Hypertension. a major risk factor for cardiovascular disease. is common in older patients. Optimal selection of antihypertensive therapy in the elderly requires consideration of the unique risks. physiology and concomitant illnesses in this age group. Since the U.S. population is aging rapidly. appropriate management of hypertension in older patients is likely to remain an important concern.
Making sense of dysfunctional uterine bleeding, Dysfunctional uterine bleeding is abnormal vaginal bleeding originating in the uterus and caused by a hormonal mechanism. Other sources and causes of vaginal bleeding should be considered before the diagnosis is established. Dysfunctional uterine bleeding is diagnosed on the basis of the history and physical examination. supported by other investigations. particularly endometrial sampling. An appropriate management plan can be developed for each patient. depending on the ovulatory state. endometrial thickness and reproductive phase. as well as the quantity and duration of bleeding.
Management of snakebite, Patients who have been or may have been bitten by a snake should receive prompt and careful clinical and laboratory evaluation. Fang marks. pain and swelling are characteristic of pit viper envenomation. Although no therapy is universally accepted. a number of treatment plans appear to be effective. If envenomation has occurred. intravenous administration of antivenin and/or surgical excision or incision should be carried out without delay. Prompt transferral to a medical facility is the most appropriate first-aid measure. If transportation is unduly delayed. immediate linear incision and suction may be of value.
Usefulness of early versus late programmed ventricular stimulation in acute myocardial infarction, To determine the influence of timing on the prognostic value of programmed ventricular stimulation after acute myocardial infarction (AMI). 32 patients were studied on day 19 (early study) and again on day 36 (late study) after AMI using up to 3 extrastimuli. At the early study. sustained monomorphic ventricular tachycardia (VT) was induced in 12 patients (38%). sustained polymorphic VT in 8 (25%). nonsustained monomorphic VT in 1 (3%). nonsustained polymorphic VT in 1 (3%) and no inducible arrhythmia in 10 (31%). At the late study. sustained monomorphic VT. nonsustained monomorphic VT and nonsustained polymorphic VT were induced in 8 patients (25%) each. and no inducible arrhythmia in 8 (25%). Of the 12 patients who had inducible sustained monomorphic VT at the early study. 7 had noninducibility of sustained monomorphic VT at the late study. Of the 20 patients who had noninducibility of sustained monomorphic VT at the early study. 3 had inducible sustained monomorphic VT at the late study. During the follow-up period (mean +/- standard deviation 21 +/- 8 months). there were 2 sudden cardiac deaths and 3 occurrences of sustained VT. Univariate analysis revealed both inducibilities of sustained monomorphic VT at the early study (p = 0.045) and at the late study (p less than 0.001) to be predictive of sudden cardiac death or clinical occurrence of sustained VT. However. inducibility of sustained monomorphic VT at the late study had a higher sensitivity (100%). specificity (89%). positive predictive value (63%) and negative predictive value (100%) than at the early study (80. 70. 33 and 95%. respectively).
Relation of left ventricular volume and function over one year after acute myocardial infarction to infarct size determined by technetium-99m sestamibi, Twenty patients with a first acute myocardial infarction (AMI) (15 anterior. 5 inferior) who received successful reperfusion therapy underwent tomographic imaging with technetium-99m (Tc-99m) sestamibi and radionuclide ventriculography at discharge. 6 weeks. and 1 year after AMI. Patency of the infarct-related artery after reperfusion (thrombolysis. 8 patients; coronary angioplasty. 12 patients) was confirmed by angiogrpahy in all patients. Tc-99m sestamibi perfusion defect at discharge (a measure of infarct size) was quantitated using previous methods and expressed as a percentage of the left ventricle (28 +/- 19%. range 0 to 59%). This perfusion defect size correlated closely with ejection fraction at discharge (r = -0.87). 6 weeks (r = -0.81) and at 1 year (r = -0.78. all p less than 0.0001). Perfusion defect size at discharge also correlated closely with end-systolic volume index at discharge (r = 0.71. p less than 0.0005). 6 weeks (r = 0.63. p less than 0.005) and at 1 year (r = 0.76. p less than 0.0001). Perfusion defect size at discharge did not correlate significantly with end-diastolic volume index at discharge or at 6 weeks. but did correlate at 1 year (r = 0.66. p less than 0.005). There was no significant group change in end-systolic or end-diastolic volume indexes from discharge to 1 year later. although 7 patients had definite individual changes in end-diastolic volume index (3 increased and 4 decreased). There was no relation between defect size and late changes in end-systolic volume index. but there was a weak correlation between defect size and late changes in end-diastolic volume index (r = 0.42. p = 0.07).
Percutaneous transluminal angioplasty of aortocoronary venous bypass grafts and effect of the caliber of the grafted coronary artery on graft stenosis, The influence of morphologic parameters on the recurrence of stenosis after percutaneous transluminal coronary angioplasty of 49 stenoses in aortocoronary venous bypass grafts of 41 patients was investigated. Vessel dimensions were measured quantitatively. Angioplasty was successful in 46 stenoses (94%) of 38 patients (93%). In 35 patients (92% of successfully treated patients) with 42 stenoses. control angiography was performed after a mean interval of 189 +/- 186 days. In 9 patients (26%). 9 stenoses (21%) had recurred. The diameter of the grafted coronary artery distal to the anastomosis was significantly smaller in grafted arteries with than without recurrent stenoses (1.92 +/- 0.52 vs 2.45 +/- 0.50 mm; p less than 0.01). Recurrence also correlated with the ratio between graft diameter and coronary artery diameter greater than 1.35 (p less than 0.02) and with the stenosis length greater than 10 mm before angioplasty (p less than 0.01). Graft age. graft diameter and stenosis location in the graft had no significant influence on recurrence. Thus. the diameter of the grafted coronary artery and the length of the critical stenosis are parameters for recurrence after angioplasty of graft stenoses and should be considered in the selection of patients for this intervention.
Effects of a multidimensional cardiopulmonary rehabilitation program on psychosocial function, The effects of participation in a structured. outpatient cardiac rehabilitation program on psychosocial function after acute myocardial infarction or coronary artery bypass surgery. or both. were evaluated prospectively in 141 patients who were married or living with "a significant other" (89% men. mean [+/- standard deviation] age 63 +/- 9 years old). Forty-one patients who were participants in a 3-month cardiac rehabilitation program were compared with 100 patients who did not participate in a formal program. On average. patients in both groups were well educated. older Caucasians who had minimal cardiac dysfunction (New York Heart Association class I or II). Patients in the 2 groups were not different at baseline in sociodemographic or clinical characteristics or in any of the dependent measures of anxiety. depression. psychosocial adjustment to illness or marital adjustment. Six months after initial testing. patients who attended cardiac rehabilitation were significantly less anxious (F[1.139] = 5.09. p = 0.03). less depressed (F[1.139] = 8.39. p = 0.004). had better psychosocial adjustment (F[1.139] = 5.87. p = 0.02). and were more satisfied with their marriages (F[1.139] = 8.6. p = 0.004) than nonparticipants. The findings support the effectiveness of group cardiac rehabilitation for this subgroup of patients in facilitating their psychosocial recovery after an acute cardiac event.
Efficacy and safety of intravenous sotalol for termination of paroxysmal supraventricular tachycardia. The Sotalol Versus Placebo Multicenter Study Group, A double-blind. placebo-controlled. crossover. multicenter study was conducted to study the efficacy and safety of a single intravenous dose of sotalol (1.5 mg/kg over 10 minutes) in achieving normal sinus rhythm in paroxysmal supraventricular tachycardia (SVT) lasting greater than or equal to 15 minutes. Patients were randomized to either sotalol or placebo as initial treatment. and if the SVT was not terminated a crossover was performed after 20 minutes. A total of 43 patients were enrolled. 38 of whom with spontaneous (n = 14) or induced (n = 24) SVT were analyzed for sotalol efficacy. Most patients (n = 27) had atrioventricular (AV) nodal reentrant tachycardia. and an important subgroup (n = 11) had circus movement tachycardia. using an accessory pathway for retrograde conduction. The number of patients converting to sinus rhythm as a result of the initial treatment was significantly higher in the sotalol group than in the placebo group. for spontaneous (p less than 0.005) as well as for induced tachycardia (p less than 0.001). Sinus rhythm was achieved within 30 minutes in 83% of all patients who received sotalol as the first drug. compared with 16% of the patients first receiving placebo (p less than 0.0001). For sotalol safety analysis. 42 patients were included. A total of 37 patients received sotalol. 19 as the first treatment. and 18 as the second treatment. while 25 patients received placebo. A total of 15 possible adverse effects were reported. occurring in 10 patients with sotalol versus 4 with placebo. The only severe side effect (hypotension) necessitating termination of drug administration occurred with placebo. No proarrhythmic effects were observed.
Left ventricular diastolic filling alterations in normotensive young adults with a family history of systemic hypertension, To characterize the cardiovascular consequences of a history of hypertension in first-degree relatives in normotensive young adults. 72 normotensive (diastolic blood pressure [BP] less than 90 mm Hg) healthy volunteers (age 18 to 30 years) were studied with 2 dimensionally guided M-mode echocardiography. pulsed Doppler echocardiography. and 2-hour automated BP monitoring. Of the 72 subjects. 19 (12 men and 7 women) had a family history of hypertension and were compared with 19 subjects without a family history of hypertension who were matched for systolic BP and gender. There were no detectable differences in 2-hour average BP. left ventricular (LV) mass or wall thickness. or echocardiographic systolic functional indexes between subjects with and without a family history of hypertension. Doppler-derived diastolic functional indexes demonstrated more prominent late diastolic filling in subjects with a family history of hypertension. Late diastolic transmitral flow time and flow velocity integral were greater (132 +/- 24 vs 117 +/- 17 ms. p less than 0.05; and 2.5 +/- 0.7 vs 1.9 +/- 0.5 cm. p less than 0.01. respectively). To measure possible gender-related effects of a family history of hypertension. the men and women were analyzed separately. The 12 men with a family history of hypertension had greater peak late (40 +/- 0.9 vs 31 +/- 0.8 cm/s. p less than 0.02) and ratio of late-to-early (0.64 +/- 0.19 vs 0.46 +/- 0.10. p less than 0.01) transmitral flow velocities and greater late transmitral flow velocity integrals (2.6 +/- 0.8 vs 1.9 +/- 0.5 cm. p less than 0.05) than the matched male control subjects.
Effect of bisoprolol on blood pressure and arterial hemodynamics in systemic hypertension, Blood pressure. heart rate. common carotid and brachial arterial hemodynamics using pulsed Doppler flowmetry and pulse wave velocity determinations were evaluated using a double-blind crossover design versus placebo in 14 patients with sustained essential hypertension treated by the selective beta 1 blocking agent bisoprolol. Blood pressure and heart rate significantly decreased after bisoprolol. whereas no significant change occurred in the diameter. the blood flow and in the vascular resistance of the carotid and brachial circulations. Pulse wave velocity significantly decreased in the brachioradial and the carotid femoral areas. The decrease in the latter was -1.6 +/- 0.8 m/s with bisoprolol and -0.06 +/- 0.80 m/s with placebo (p = 0.001). Brachial artery compliance significantly increased from 117 +/- 49 to 205 +/- 84 cm4 x dynes-1 x 10(9) (p = 0.001). indicating that the antihypertensive effect of beta 1 blockade is associated with an improvement in the viscoelastic properties of the brachial artery wall.
Difference in mortality between patients treated with captopril or enalapril in the Xamoterol in Severe Heart Failure Study, The double-blind. placebo-controlled. multinational trial Xamoterol in Severe Heart Failure randomized 290 patients treated with captopril and 217 treated with enalapril to xamoterol or placebo. At the end of the 100-day follow-up period. the cumulative probability of survival in patients with coronary artery disease or with dilated cardiomyopathy decreased in the captopril group (90.3%) when compared with the enalapril group (97.2%). The excess mortality in the captopril group could not be related to the indexes of the severity of heart failure. such as baseline exercise duration. functional class. cardiothoracic ratio. ejection fraction or dose of diuretic drugs. Furthermore. the excess in mortality was seen in all subsets of patients examined as well as across countries. Examination of the dosing regimen used. however. suggests that insufficient daily dosage of captopril or the inadequate schedule of administration. or both. might be responsible for different degrees of angiotensin-converting enzyme inhibition between the enalapril and captopril groups and hence for the difference in mortality. It is important in future clinical trials to determine to what extent complete circadian angiotensin-converting enzyme inhibition is necessary to provide the full benefit of this therapy in heart failure.
Determinants of one-year outcome from balloon aortic valvuloplasty, Balloon aortic valvuloplasty (BAV) has been a therapeutic alternative treatment for severe symptomatic aortic stenosis. Previous studies have been unable to predict 1-year outcome because of limited acute and follow-up clinical. invasive and echocardiographic data. The purpose of this study was to predict long-term outcome based on comprehensive data obtained at the time of valvuloplasty and at 3 and 6 months after the procedure. Of 170 consecutive patients undergoing BAV. 108 (mean age 78 years) were at least 1 year from their procedure. Prospective clinical. micromanometer hemodynamic. digital ventriculographic and echocardiographic/Doppler data were collected at baseline and immediately after the procedure. Echocardiographic data were also obtained at 3 and 6 months. With use of Cox model analysis. major events (defined as cardiac death [n = 30]. aortic valve replacement [n = 21] or repeat BAV [n = 13]) were predicted by advanced age. baseline heart failure class. and baseline echocardiographic-determined diastolic left ventricular diameter. Only baseline left ventricular ejection fraction proved to be a significant predictor of cardiac death (p = 0.002) in a multivariate model. Absolute values after BAV (stroke work. first derivative of left ventricular pressure. valve area. end-systolic volume. Fick cardiac output. transvalvular gradient) and acute changes measured by catheterization or echocardiography did not provide additional predictive information over that of post procedure ejection fraction. Similarly. echocardiographic valve area and transvalvular gradient at 3 months added no further prognostic data. With an ejection fraction greater than or equal to 45% (n = 63). cardiac survival at 1 year was 80%. irrespective of age. sex. congestive heart failure class or severity of coronary artery disease.
Effects of handrail support on claudication and hemodynamic responses to single-stage and progressive treadmill protocols in peripheral vascular occlusive disease, Because handrail support reduces the energy cost of treadmill walking. claudication and hemodynamic responses of patients with peripheral vascular occlusive disease should also be affected. Furthermore. the reliability of the test results may be reduced unless the same pressure is applied to the handrails over repeated tests. The effect of handrail support on claudication and hemodynamic responses. and on their reliability. were examined during single-stage (2 mph. 12% grade) and progressive (2 mph. 0% grade with 2% increase every 2 minutes) treadmill protocols. Ten patients with stable disease performed both protocols 3 times. separated by 1 week. with and without handrail support. Claudication pain distance and maximal walking distance were greater (p less than 0.05) when handrail support was permitted. and they increased (p less than 0.05) over repeated tests of each protocol. No increase was noted over the tests without support. The responses and reliability of foot transcutaneous oxygen tension. ankle systolic pressure and ankle/brachial systolic pressure index after exercise to maximal tolerable pain were not affected by handrail support. Because claudication distances were altered. it is concluded that handrail support should not be allowed when assessing claudicants. unless balance cannot otherwise be maintained.
Nutrient balance in humans: effects of diet composition, The purpose of this study was to examine the effect of alterations in diet composition on energy expenditure and nutrient balance in humans. Eight adults (three men. five women) ate a high-carbohydrate (60% of calories from carbohydrate) and a high-fat (60% of calories from fat) diet for 7 d each according to a randomized. crossover design. Six subjects were studied for an additional week on a mixed diet (45% of calories from fat). For each subject. total caloric intake was identical on all diets and was intended to provide the subject's maintenance energy requirements. All subjects spent days 3 and 7 of each week in a whole-room indirect calorimeter. Diet composition did not affect total daily energy expenditure but did affect daily nutrient oxidation by rapidly shifting substrate oxidation to more closely reflect the composition of the diet. These results show that diet composition can affect substrate oxidation without producing measurable effects on total energy expenditure.
Carbohydrate intake and body mass index in relation to the risk of glucose intolerance in an elderly population, The association between the intake of carbohydrates. body mass index (BMI). and the 4-y incidence of impaired glucose tolerance and diabetes mellitus (glucose intolerance) was investigated in elderly men and women aged 64-87 y. In 1971 the baseline population consisted of 175 normoglycemic subjects. During the follow-up period (1972-1975) an oral glucose-tolerance test (OGTT) was carried out annually. In univariate analyses. baseline BMI and the habitual intake of carbohydrates and pastries. as determined from a cross-check dietary history. were positively associated with the incidence of glucose intolerance. The habitual intake of legumes was inversely related to the incidence of glucose intolerance. These results could not be explained by potential confounding factors such as age. gender. alcohol use. energy intake. prescribed diet. medication use. and comorbidity. These results suggest that energy balance and the use of carbohydrate-rich foods are related to the development of glucose intolerance in an elderly population.
Relative effectiveness of milks with reduced amounts of lactose in alleviating milk intolerance, The relative effectiveness of five milk products with various levels of lactose reduction [0%. 50%. 80% (#1). 80% (#2). and 95%] was evaluated in six subjects with lactose malabsorption. Breath hydrogen was measured for 4 h after consumption of 300 mL of each product in a single-blind. randomized design. The mean +/- SEM maximum breath-hydrogen rise (ppm) after the 0%. 50%. 80% (#1). 80% (#2). and 95% lactose-reduced (LR) milks was 31 +/- 6. 7 +/- 3. 5 +/- 3. 5 +/- 2. and 8 +/- 3. respectively. The difference between whole milk and the LR milks was statistically significant (P less than 0.05) but there was no difference between any of the LR milks. Whole milk provoked symptoms in most subjects whereas 95% LR milk produced none. Only one of six subjects reacted to the 50% and 80% LR milks. The results suggest that a 50% level of lactose reduction in milk may be adequate to relieve the signs and symptoms of milk intolerance in the majority of healthy adults with lactose malabsorption.
Total and subcutaneous adipose tissue in women: the measurement of distribution and accurate prediction of quantity by using magnetic resonance imaging, Total and subcutaneous adipose tissue in seven lean and seven obese women were quantified using magnetic resonance imaging (MRI). The distributions of adipose tissues along the body were closely correlated: subcutaneous with total. both within and between lean and obese groups. Lean women had proportionally less adipose tissue in the lower thorax and upper abdomen than did obese women. Reducing the number of MRI scans from 17 to 4 did not increase the residual SD of predicted body adipose tissue (2.9 percent) when body density was used as the reference measure. MRI gave an estimate of total-body adipose tissue significantly closer to the value for fat percent produced when the results from five other techniques (skinfold thickness. underwater weighing. 40K whole-body counting. isotopic water dilution. and tetrapolar bioelectrical impedance) were averaged than when any other technique was used alone. MRI-determined percent body adipose tissue in women is close to. and proportional to. estimates derived by underwater weighing.
Estimating energy requirements in burned children: a new approach derived from measurements of resting energy expenditure, We examined the determinants of resting energy expenditure (REE) in 127 observations in 56 burned children. Predicted basal energy expenditure (PBEE). body surface area (BSA). and body weight correlated significantly with REE (r2 = 0.76). Days postburn and burn size (% BSA burned) only accounted for 21%. and 24% of the variation in the elevation in REE above PBEE. The single most powerful predictor of REE was PBEE (REE = 1.29 x PBEE); addition of other variables did not improve the prediction. When our recently described activity factor of 1.2 for burn patients is used. the data predict that the average energy requirement to maintain energy balance is 1.55 x PBEE. which is significantly lower than commonly used recommendations. especially for larger burns. The energy required to ensure that 95% of patients achieve energy balance was (1.55 x PBEE) + (2.39 xoff+PBEE0.75). approximately equal to 2 x PBEE. Because the equations presented are derived from measurements of energy expenditure. they represent the most valid approach to estimating energy requirements.
Alcohol intake in relation to diet and obesity in women and men, We studied relations between alcohol intake. body mass index. and diet in 89.538 women and 48.493 men in two cohort studies. Total energy increased with alcohol consumption (partial r = 0.11. P less than 0.001). and carbohydrate intake decreased from 153 g/d in abstainers to 131 g/d in women drinking 2.5.0-49.9 g alcohol/d. The decrease in carbohydrate intake was due mainly to decreased sugar consumption with higher alcohol intake (partial r = -0.05. P less than 0.001). reflecting decreased energy consumption from sources excluding alcohol. In men total energy increased with alcohol consumption (partial r = 0.19. P less than 0.001). from 7575.6 (abstainers) to 9821.5 kJ/d (greater than 50 g alcohol/d). Energy intake excluding alcohol varied little with alcohol intake (partial r = 0.003. P = 0.48) but sucrose intake decreased with higher alcohol intake. These data suggest that calories from alcohol were added to energy intake from other sources in men. and that in women. energy from alcohol intake displaced sucrose. The consumption of candy and sugar is inversely related to alcohol intake. raising the possibility that it is related to appetite for alcohol.
Effects of a very-low-calorie diet and physical-training regimens on body composition and resting metabolic rate in obese females, Sixty-nine obese females received 90 d of a liquid diet providing 2184 kJ/d in clinical trials. Groups were diet only (C). diet plus endurance exercise (EE). diet plus weight training (WT). or diet plus endurance exercise and weight training (EEWT). Changes in body weight. percent fat. fat weight. and fat-free mass were not different between groups. Declines in resting metabolic rate (RMR) were approximately 7% to approximately 12% of baseline values with no differences among groups. A significant increase in work capacity (approximately 16%) was shown for EEWT. Strength index showed declines of approximately 6% for C and EE and gains of approximately 3% and approximately 10% for EEWT and WT. respectively. These clinical trials did not show advantages of any exercise regimen over diet alone for weight loss. body-composition changes. or declines in RMR. Improvements in work capacity were limited and strength improved in groups that participated in strength training.
Effect of supplementary feeding on recovery from mild to moderate wasting in preschool children, Three-month recovery rates from moderate wasting (less than 90% weight-for-length) were compared in 6-24-mo-old children in four Guatemalan villages that had been randomly assigned to receive a moderate (Atole) or low (Fresco) energy supplement. The recovery rate (Rr) in the Atole villages was 12% higher than in the Fresco villages (P less than 0.05). This effect was above all due to the children in the Atole villages who consumed greater than or equal to 10% of the daily recommended dietary intake of energy (RDI) from the supplement (high-Atole group) and whose total energy intake (including home diet) was 10.5% of the RDI higher than a comparable high-Fresco group with low supplemental energy intake. All those in the high-Atole group whose wasting was due to malnutrition recovered. Much of this recovery (range 29-52%) was due to the increased supplementation. This proportion rose after potential confounding variables were controlled for.
Effects of a soy-protein beverage on plasma lipoproteins in children with familial hypercholesterolemia, The effects of soy protein (35% of protein energy) given as a beverage and those of cow-milk proteins were investigated on plasma lipoprotein concentrations in children with familial hypercholesterolemia (FH). Subjects were randomly assigned to either the soy-protein or cow-milk-protein experimental period. with subsequent crossover after a washout period. each period lasting 4 wk. Diets were planned to provide 20% energy as protein. 28% as fat (polyunsaturated:monounsaturated:saturated fatty acids. 1:3:3) and less than 200 mg cholesterol/d. No changes were observed in either plasma cholesterol. low-density-lipoprotein cholesterol. or apolipoprotein concentrations. However. the soy beverage significantly reduced the concentrations of triglyceride and very-low-density-lipoprotein cholesterol (P less than 0.05) and significantly increased the concentrations of high-density-lipoprotein cholesterol (HDL-C) and HDL3-C (P less than 0.04 and P less than 0.03. respectively). These results indicate that the administration of soy protein may induce clinically beneficial effects in children with FH.
Apparent decreased risk of invasive bacterial disease after heterologous childhood immunization, To investigate the possibility that there might be an increased risk of heterologous invasive bacterial disease after routine childhood immunization with measles. mumps. and rubella vaccine live; diphtheria and tetanus toxoids and pertussis vaccine; and oral poliovirus vaccine live. a case-control study was conducted within the Kaiser Permanente Northern California pediatric population. Contrary to the premise. an apparent protective effect against invasive bacterial disease was detected after all childhood vaccinations. However. when adjustment was made for frequency of well-care visits and day-care attendance. no significant relationship was seen between receipt of routine childhood immunizations and risk of invasive heterologous bacterial disease for any individual vaccine. although a statistically significant protective effect was detected within 1 or 3 months after the receipt of any vaccine. Since a decreased risk of invasive bacterial disease was also noted to be related to the receipt of routine well-child pediatric care. other preventive health care measures may be responsible for the apparent immunization protective effect.
DTP immunization and susceptibility to infectious diseases. Is there a relationship, A two-part study was carried out in Alaskan Native children to evaluate the potential risk of invasive bacterial disease and the occurrence of minor illnesses after immunization with diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP). First. a case-control comparison was performed with 186 children who had invasive Haemophilus influenzae type b or Streptococcus pneumoniae disease (cases) and 186 healthy controls matched for sex. region of residence. birth date. and number of DTP immunizations. The proportion of cases and controls immunized in the 30-day period before onset of disease for cases or reference date for controls was identical. suggesting no association with DTP immunization. In a second analysis. the occurrence of any illness. particularly infectious diseases. in 104 study subjects was compared for the period 30 days before and after 377 DTP immunizations. The rate of illness before immunization was 53%. and after immunization. 43%. again suggesting no causative effects from DTP immunization. Despite the high rates of invasive bacterial disease and nearly compete DTP immunization status in this population. no consistent relationship could be demonstrated between DTP immunization and susceptibility to infectious diseases.
Effects of obesity on aerobic fitness in adolescent females, Obesity impairs performance in most athletic events. but the influence of increased body fat on cardiopulmonary function has not been clearly delineated. An understanding of the fatness-fitness relationship is important in the optimal design of exercise programs for obese subjects. In this study. 27 adolescent females with body fat levels ranging from normal to gross obesity were evaluated to determine the impact of adiposity on physiologic factors during maximal and submaximal treadmill walking. Increased skinfold measures correlated significantly with absolute maximal oxygen uptake throughout the range of body fat levels (r = .72). and oxygen consumption per kilogram of body weight and treadmill endurance time both declined as fatness increased (r = -.49 and -.42. respectively). Obesity did not affect submaximal walking economy. These findings indicate that increased fat levels are associated with increased cardiopulmonary exercise capacity. but that functional fitness declines because of the inert load created by excess body fat. Therefore. therapeutic exercise programs for obese adolescents are best designed to increase caloric expenditure and decrease body fat rather than to improve aerobic fitness.
Seasonal variation in growth during growth hormone therapy, Seasonal variation in growth of normal children has been well described. although the mechanism by which it occurs has not been elucidated. The growth of 52 growth hormone-deficient children treated with synthetic human growth hormone was analyzed. A similar seasonal variation was observed. with mean (+/- SEM) peak growth occurring in the summer (8.2 +/- 0.3 cm/y) and winter (7.7 +/- 0.2 cm/y). and trough growth occurring in the autumn (6.9 +/- 0.3 cm/y). Forty-seven percent of subjects grew minimally during the autumn. and only two children showed peak growth in that season. Individual variations between maximal and minimal growth seasons amounted to 3.5 +/- 0.3 cm/y. The seasonal pattern was statistically significant for the group as a whole. for the prepubertal subgroup. and for the boys. The variation persisted when the first year of treatment was excluded to avoid bias of the initial growth spurt. The season of onset of therapy did not affect total growth during the first year. The demonstration of a seasonal pattern in growth of these children suggests that the seasonal variation may be mediated by peripheral rather than central factors. Paired clonidine-provoked growth hormone levels and an integrated concentration of 24-hour growth hormone levels and serum levels of insulinlike growth hormone I measured in a control group of normally growing children were also analyzed and showed no seasonal variation. This further suggests that peripheral rather than central factors are responsible for the seasonal variation in children's growth.
Injuries and poisonings in out-of-home child care and home care, As part of a national telephone survey regarding health events associated with out-of-home child care. data regarding poisonings and injuries were collected. Of 171 reported poisonings. none occurred during out-of-home child care. The rate of injury during out-of-home child care was 1.69 per 100.000 child-hours compared with 2.66 for home care. Overall injury rates were slightly higher for children who attended out-of-home child care than for those who do not. This occurred because children who attended out-of-home child care had a higher injury rate during home care than did the children who did not attend out-of-home child care at all. Although out-of-home child care may carry an increased risk of infectious disease relative to home care. it does not appear to carry an increased risk of injury and. in fact. may confer a lower risk.
A longitudinal study of birth weight and being overweight in late adolescence, A total of 33.413 infants born in Jerusalem between 1964 and 1971 were followed up at 17 years of age by matching computerized database files. A logistic regression model was used to estimate the odds ratios for being overweight at 17 years of age for 500-g birth weight categories from less than 2500 g to 4500 g or greater. Information on the ethnic origin. paternal education. birth order. maternal age. and area of residence at birth was available. and these factors were used as possible confounders. The adjusted odds ratios for being overweight (greater than or equal to 90th percentile; body mass index greater than 24.6 kg/m2) and severely overweight (greater than or equal to 97th percentile; body mass index greater than 27.8 kg/m2) at 17 years of age was elevated for the three birth weight categories above the normal reference category of 3000 to 3499 g. with an estimate of 2.16 and 2.30 for male subjects with a birth weight greater than 4500 g and 2.95 and 4.39 for female subjects. The data suggest that higher birth weights correlate strongly with being overweight in late adolescence independently of other factors considered. However. the predictive power of this association is poor.
The effect of low-dose dopamine infusion on cardiopulmonary and renal status in premature newborns with respiratory distress syndrome, To study the effects of infusion of low doses of dopamine hydrochloride on cardiopulmonary and renal status in premature newborns with respiratory distress syndrome. 49 newborns were randomly assigned to three groups: group 1 (18 patients) received no dopamine and was the control group; group 2 (16 patients) was infused with a dose of dopamine measuring 1.0 micrograms/kg of body weight per minute for 72 hours; and group 3 (15 patients) was infused with a dose of dopamine measuring 2.5 micrograms/kg of body weight per minute for 72 hours. Birth weights. gestational ages. post-natal ages. and cardiopulmonary status of all groups at the start of the study were comparable. Continuous infusion of these low doses of dopamine for 3 days after birth did not significantly improve levels of blood gases. acid-base balance. or clinical outcome. In newborns with systemic hypotension. dopamine improved cardiovascular status and caused early return of blood pressure to the normal range. Infusion of low doses of dopamine produced mild to moderate natriuresis and insignificant increases in glomerular filtration rate and urine volume.
Effect of necrotizing enterocolitis on urinary epidermal growth factor levels [published erratum appears in Am J Dis Child 1991 Sep;145(9):982, The pattern of urinary epidermal growth factor/creatinine levels in necrotizing enterocolitis was examined in 75 infants (in 28 infants the diagnosis of necrotizing enterocolitis was considered; 47 infants were studied for effect of surgery or nutrition on epidermal growth factor levels). There was a consistent and significant increase in epidermal growth factor/creatinine values at the time of diagnosis of necrotizing enterocolitis compared with baseline values. Epidermal growth factor levels in infants without necrotizing enterocolitis and in early nutrition remained unchanged. These results suggested that urinary epidermal growth factor/creatinine levels may differentiate stage II and III necrotizing enterocolitis from stage I disease. The increased epidermal growth factor/creatinine levels may be related to the absorption into the circulation of preexisting gastrointestinal tract epidermal growth factor through damaged tissue or to increased synthesis by the gastrointestinal tract in response to the injury caused by necrotizing enterocolitis.
Predictors of neurodevelopmental outcome following bronchopulmonary dysplasia, In infants with bronchopulmonary dysplasia. the influence of the severity of their pulmonary disease on neurodevelopmental outcome is unknown. Neurodevelopmental outcomes at a mean age of 36 months were assessed in 27 premature subjects who had bronchopulmonary dysplasia. Subjects had a mean birth weight of 940 g (range. 540 to 1690 g) and a mean gestational age of 27 weeks (range. 25 to 31 weeks). The duration of mechanical ventilation ranged from 22 to 128 days. and the duration of requirement of supplemental oxygen ranged from 34 to 1033 days. No significant correlations were found between duration of mechanical ventilation or oxygen therapy and overall neurodevelopmental outcome. In contrast. cranial ultrasound findings of intracranial hemorrhage and/or periventricular echodensity related specifically to poorer cognitive outcome. By age 3 years. severity of bronchopulmonary dysplasia is not a sufficient predictor of neurodevelopmental outcome. Intracranial hemorrhage and periventricular echodensity continue to be important predictors.
Pediatric endoscopic retrograde cholangiopancreatography, Endoscopic retrograde cholangiopancreatography (ERCP) was performed 42 times in 38 patients aged 14 months to 20 yr at Children's Hospital of Pittsburgh from 1982 to 1990. The adult side-viewing duodenoscope. Olympus JF1T. was used for all procedures. Intravenous sedation was used in 68% of the patients. whereas general anesthesia was employed in the remainder. Visualization of the appropriate ductal system was accomplished in 35 patients (92%). No therapeutic maneuvers were performed at endoscopy. Eleven of the 22 patients with ductal abnormalities underwent surgical treatment. based on the ERCP findings. The only complication encountered was mild pancreatitis in three patients (8%). all with a history of pancreatitis. We conclude that ERCP is a safe. useful procedure in the evaluation of children with pancreaticobiliary disorders. and in the identification of surgically correctable lesions in 29% of those patients.
Percutaneous transhepatic choledochoscopic electrohydraulic lithotripsy for common bile duct stones: experience in four high-risk patients, Choledochoscopic electrohydraulic lithotripsy was applied through a percutaneous transhepatic approach in four high-risk patients with common bile duct stones that were not extractable by duodenoscopic means. All stones were fragmented and removed from three patients. but one patient died from bronchopneumonia before ductal clearance could be achieved. The procedure was well tolerated. without any complication. The major disadvantage is the multiple maneuvers required and the prolonged hospital stay. Percutaneous transhepatic choledochoscopic electrohydraulic lithotripsy provides a safe and effective alternative for nonoperative treatment of common bile duct stones in high-risk patients when the duodenoscopic approach fails.
Accumulation of glycoprotein in the Golgi apparatus of hepatocytes in alcoholic liver injuries, To clarify the role of the hepatocytic Golgi apparatus in the accumulation of proteins in the hepatocytes of alcoholic liver disease. changes in the Golgi apparatus in human and experimental alcoholic liver injuries were analyzed. Immunoelectron microscopically. transferrin. one of the secretory glycoproteins from the liver. was retained in the smooth endoplasmic reticulum and Golgi apparatus of the hepatocytes in both human and rat alcoholic liver injuries. Biochemically. transferrin content in the Golgi fraction was clearly high in the rats with alcoholic liver injury. Desialo-glycoproteins were found in the serum of rats with alcoholic liver injuries. These results suggested that the glycosylation and secretion of hepatic glycoproteins in the Golgi apparatus were impaired in alcoholic liver injury. These abnormalities in the Golgi apparatus function may be important for the development of alcoholic liver injury.
Lectin-reactive patterns of markedly elevated serum alpha-fetoprotein in patients with chronic active hepatitis, Four cases of chronic hepatitis associated with high serum levels of alpha-fetoprotein (AFP) without hepatocellular carcinoma are reported. All showed transient elevations of serum AFP. with peak levels of 13.500. 8.000. 4.450. and 3.000 ng/ml shortly after aggravation resulting from liver function tests. Liver biopsies revealed severe parenchymal damage in all the cases with piece-meal necrosis. bridging necrosis or bridging fibrosis. In two of four cases. there was a lobular distortion. AFP stain by an immunoperoxidase method showed a positive result in surviving hepatocytes. Lectin affinity electrophoresis of AFP in the four cases. together with an additional 12 patients with chronic hepatitis and cirrhosis and 44 patients with hepatocellular carcinoma. all having AFP levels above 1.000 ng/ml. revealed that the chronic hepatitis patients had a benign pattern of AFP bands. in contrast with the pattern of hepatocellular carcinoma with increased proportions of lentil lectin-reactive AFP-L3 and/or erythroagglutinating phytohemagglutinin-reactive AFP-P4. indicating that the analysis of lectin reactivity of AFP has a great value in differentiating the benign and malignant conditions with increased serum levels of AFP above 1.000 ng/ml.
Effect of octreotide (SMS 201-995) on meal-stimulated pancreatic secretion in three patients with external pancreatic fistula, Octreotide (SMS 201-995) is a long-acting somatostatin analogue that inhibits both basal and secretin-cholecystokinin-stimulated pancreatic secretion. This study assesses the effect of this compound on pancreatic secretion induced by ordinary meals. Three patients with stable secretion of pure pancreatic juice from high output pancreatic fistula were studied. In all three. meal ingestion caused a marked and prolonged increase in pancreatic juice flow. and in bicarbonate and protein output. The subcutaneous injection of 50 micrograms octreotide before meals almost totally prevented (by about 90%) this increase. The inhibitory effect of octreotide on postprandial pancreatic secretion appeared soon. and persisted for the duration of the study period (8 h).
Self-Administered Alcoholism Screening Test: a comparison of conventional versus computer-administered formats, The equivalence of paper-and-pencil-administered and computer-administered versions of the Self-Administered Alcoholism Screening Test (SAAST) was investigated with alcoholic inpatients and nonalcoholic psychiatric outpatients. When the two formats were administered in counterbalanced order. total score mean differences were nonsignificant. In addition. mean differences on a short-form version were also nonsignificant. Equivalence was also determined by comparing the two formats in terms of classification agreement (i.e.. classification of subjects into alcoholic and nonalcoholic categories). Agreement between the two formats was 95% in both the total score and short-form versions. Implications of these results as well as the advantages and disadvantages of using computer-administered alcoholism screening tests are discussed.
Male physical aggression as a function of alcohol intoxication and frustration: experimental results and methodological considerations, Forty-five undergraduate students were assigned to either an Alcohol. a Placebo. or a Control group. The alcohol dose was 0.80 g of 100% alcohol/kg body weight. Subjects were informed that they could win a sum of money depending on the performance of a partner. They then supervised the partner over a series of trials on a visual scan test and could influence the partner by either giving an uncomfortable electric shock (aggressive alternative) or a comfortable vibration (nonaggressive alternative) at each incorrect response from the partner. Both alternatives were said to be equally instrumental in reaching the goal of winning the money and both could be varied in intensity on a 10-point scale and without limits in terms of duration. Aggression was measured as number of aggressive responses chosen. and in terms of intensity and duration. Nonaggression was measured in terms of intensity and duration. Intoxicated subjects did not increase their aggression but all groups chose significantly more nonaggressive responses and did so with higher intensity and duration. Frustration did not significantly affect these types of responding. Results are discussed in terms of methodological considerations and the importance of using realistic experimental paradigms is stressed. Also. theoretical implications are discussed.
The effects of progressive abstinence from alcohol on red blood cell proton NMR relaxation times and water content, Red blood cell proton relaxation times T1 and T2 were measured in samples from chronic alcoholic patients abstinent for varying periods from 1 week to over 6 months. T1 and T2 were elevated in the early stages of abstinence and declined to the values of controls after 8 weeks. Changes in the water content of the red blood cells and the mean corpuscular volume paralleled these changes but were more closely associated with T2. It is suggested that T1 and T2 may reflect different aspects in water content and free-to-bound ratio of water. The significance of these findings is discussed in the context of changes previously observed in the brains of alcoholic patients. and in rats fed a diet supplemented with alcohol for 6 months.
The metabolism of ethyl esters of fatty acids in adipose tissue of rats chronically exposed to ethanol, The concentration of ethyl esters of fatty acids as well as the activity of the enzyme synthesizing these esters (fatty acid ethyl ester synthase) were determined in adipose tissue of rats ingesting ethanol (9-16 g/kg body weight/day) for different periods of time. After 10 and 17 weeks of ethanol exposure about 300 nmol of ethyl esters of oleic. palmitic. stearic. and linoleic acids were found per gram adipose tissue. The ethyl esters disappeared after 1 week of abstinence. Closer analyses. using radioactive ethanol. revealed a half-life of the esters of less than 24 hr. The bulk of the esters was found in a membrane preparation of isolated adipocytes. Hormone-sensitive lipase hydrolyzed emulsified ethyl oleate as efficiently as that of trioleoylglycerol. but in mixed ethyl oleate/trioleoyl glycerol particles the hydrolysis of ethyl oleate was slower. suggesting a decreased accessibility. Synthase activity was found in adipose tissue from rats not exposed to ethanol. It doubled after 10 and 17 weeks of ethanol and decreased with a half-life of at least a week after abstinence. It was concluded that ethyl esters of fatty acids are formed in rat adipose tissue as previously shown in other tissues. They seem to be stored mainly in membranous parts of the adipocytes. Synthase activity is induced by ethanol. The elevated activity has a longer half-life. and may be useful as an indicator of alcohol abuse.
Typical patterns and cost of alcoholism treatment across a variety of populations and providers, This paper presents data on the utilization of alcoholism treatment services in three populations of insurance enrollees: enrollees covered by the insurance plan of a large midwestern manufacturing firm. 1981-1987 (N = 1.425); enrollees of the California Health Insurance Plan of the Public Employees Retirement System. 1974-1976 (N = 766); U.S. government civilian employees enrolled with the Aetna Insurance Company. 1980-1983 (N = 1.697). The average age of the treated alcoholics in these three groups ranged from 37 to 51. Between two-thirds and three-quarters were male. Inpatient alcoholism treatment services were more frequently used than outpatient. with inpatient admissions averaging between 1.2 and 1.5 per person. For enrollees of the midwestern manufacturing firm. total alcoholism treatment costs averaged $4.665 per person (December 1985 dollars). The influence of insurance plan coverage and other factors on utilization patterns is discussed.
Effect of chronic ethanol treatment and selective breeding for sensitivity to ethanol on calcium release induced by inositol trisphosphate or ethanol from brain and liver microsomes, Our previous work showed that ethanol increases the resting intracellular free calcium concentration (CAi) in synaptosomes and releases calcium from an inositol trisphosphate (IP3)-insensitive calcium store of brain microsomes. In this report. we investigated the effects of chronic ethanol treatment and selective breeding for hypnotic sensitivity to ethanol on IP3 and ethanol-stimulated calcium release from brain and liver microsomes. Chronic ethanol treatment did not alter IP3-stimulated calcium release from brain microsomes or ethanol-stimulated calcium release from brain or liver microsomes. Chronic ethanol treatment increased the spontaneous release of calcium from brain but not liver microsomes. In microsomes isolated from cerebellum or cerebral cortex of long-sleep (LS) and short-sleep (SS) mice. ethanol and IP3 released calcium in a concentration dependent manner. The amount of calcium released by ethanol and IP3 was larger in microsomes isolated from cerebellum than microsomes from cerebral cortex. However. the amount of calcium released by ethanol and IP3 did not differ between the two lines in either brain area. These results do not support the idea that the hypnotic effects of ethanol are due to ethanol-induced calcium release from a nonmitochondrial intracellular calcium store in brain tissue. The development of ethanol tolerance and dependence also does not appear to be associated with altered ability of ethanol to release calcium from non-mitochondrial intracellular stores; however. effects of chronic ethanol exposure on spontaneous release of intracellular calcium could alter neuronal function in ethanol dependence.
Effect of prenatal exposure to ethanol on the cell cycle kinetics and growth fraction in the proliferative zones of fetal rat cerebral cortex, Prenatal exposure to ethanol produces profound changes in the number of neurons in the mature cortex. These changes in neuronal number may reflect ethanol-induced disturbances in early developmental processes. that is in the proliferation of neuronal precursors. Hence. the present study examined the effect of ethanol on cell proliferation in the two neocortical proliferative zones. the ventricular zone (VZ) and subventricular zone (SZ). From gestational day 5 to 21. pregnant rats were fed an ethanol diet (6.7% v/v). pair-fed an isocaloric control diet. or fed chow and water. Pregnant rats were given a series of one to nine injections of bromodeoxyuridine (BrdU). After immunohistochemical processing. the ratio of cells in each proliferative zone that were labeled with BrdU to the total population was determined. The portion of the population that was cycling (growth fraction). the total length of the cell cycle. and the length of the S-phase of the cell cycle were calculated for VZ and SZ cells. Exposure to moderate levels of ethanol has markedly different effects upon the two neocortical proliferative zones. In the VZ. the length of the total cell cycle was significantly greater in ethanol-treated rats than in controls; however. the growth fraction and the length of the S-phase were unaffected by ethanol. In contrast. in the SZ. the growth fraction was significantly greater in ethanol-treated rats. but ethanol had no effect on the length of the total cell cycle or of the S-phase. These differences may underlie the ethanol-induced abnormalities in neuronal generation.
Acute ethanol intoxication suppresses E. coli lipopolysaccharide enhanced glucose utilization by hepatic nonparenchymal cells, During infection or endotoxemia. the immune system is activated and its energy needs increase. Alcohol (ETOH) intoxication on the other hand suppresses the immune system and increases susceptibility to infection. Since the liver is the primary site both for metabolism of ETOH and detoxification of bacterial lipopolysaccharides (LPS). this investigation was directed at studying the effect of acute ETOH intoxication on the LPS-induced enhancement of in vivo glucose utilization in different types of hepatic cells. Rats were given an intravenous (IV) injection of ETOH followed by a constant infusion for 7 hr to maintain blood alcohol levels at about 175 mg/dl. E. coli LPS was administered IV at 4 hr and in vivo glucose utilization by the different types of liver cells was estimated 3 hr later using the 14C-2-deoxyglucose technique. Hepatocytes (HP). Kupffer (KC). and endothelial cells (EC). as well as the sequestered polymorphonuclear leukocytes (PMN). were separated from the liver by collagenase-pronase digestion followed by centrifugal elutriation and Ficoll-Hypaque density gradient centrifugation. The number of PMN in the liver was increased several-fold 3 hr after LPS administration. The presence of ETOH did not inhibit the LPS-induced neutrophil migration into the liver. ETOH depressed the LPS-induced increase in glucose uptake in both EC and KC by 50 to 80%. respectively. It also reduced the LPS-induced increase of plasma tumor necrosis factor activity by 80%. ETOH alone did not produce any significant changes in the parameters studied.
Effects of protein size on the rate of import of the precursors of aldehyde dehydrogenase and ornithine transcarbamylase into rat liver mitochondria, It is known that a signal peptide is required for the import of a protein into mitochondrial matrix. It is also known that a signal peptide can be attached to any protein and allow it to be imported. We recently reported that the rate of import of rat liver mitochondrial aldehyde dehydrogenase precursor was slower than that of ornithine transcarbamylase precursor (Wang TTY. Farres J. and Weiner H. Arch Biochem Biophys 272. 440-449. 1989). It was not known if the difference in the rate of import was related to the fact that the mature portion of aldehyde dehydrogenase is larger (500 amino acids compared with 322 amino acids) or because the signal peptides were different. We further showed that treatment of the mitochondria with alcohols caused an inhibition of the import of the precursor of aldehyde dehydrogenase but not that of ornithine transcarbamylase. In the present study we constructed chimeric proteins that contained the signal peptide from one precursor protein and the mature portion from the other. We found that the rate of import was related to the overall size of the precursor protein. Consistent with this observation was finding that a truncated aldehyde dehydrogenase precursor. which contained 317 amino acids. was imported more rapidly than was the authentic precursor. Consistent with this finding was the fact that butanol caused the inhibition of only the large precursor proteins. Thus. it appears that size of the protein being imported is a major determinant of the rate at which a precursor protein is imported into mitochondria.
Physical exercise after alcohol intake: effect on plasma catecholamines and lymphocytic beta-adrenergic receptors, The combined effects of alcohol intoxication and intense physical exercise on the adrenergic system were studied in eight healthy male volunteers. Ethanol (0.8 g/kg body weight) was administered perorally to bring about a mean serum concentration of 21 mmol/liter (0.1%); each subject also participated in an identical control session without alcohol. Acute alcohol intake alone did not change the concentrations of plasma adrenaline or noradrenaline or the density. affinity. and functioning (ability to mediate catecholamine-stimulated production of cAMP) of lymphocytic beta-adrenergic receptors. In contrast. acute ergometer exercise brought about an approximately 10-fold increase of plasma adrenaline and noradrenaline concentrations. a 2- to 3-fold increase of beta-adrenergic receptor density and an enhancement of isoproterenol-stimulated cAMP production. Alcohol intake immediately before the ergometer exercise did not modify these changes. In conclusion. acute physical exercise activates the human adrenergic system. with an increase of both plasma catecholamines and lymphocytic beta-adrenergic receptors. Moderate alcohol intoxication does not affect exercise-induced alterations of these parameters.
Binding of anti-acetaldehyde IgG antibodies to hepatocytes with an acetaldehyde-phosphatidylethanolamine adduct on their surface, We have previously shown that antibodies raised against acetaldehyde adducts of protein cross-react with an acetaldehyde adduct of dioleoylphosphatidylethanolamine. N-ethyl-dioleoylphosphatidylethanolamine. when the latter is incorporated into hexagonal phase phospholipid micelles. In the present study we demonstrate that these same IgG antibodies cross-react with N-ethyl-dioleoylphosphatidylethanolamine when this adduct is incorporated into the surface of hepatocytes. Hapten-specific IgG antibodies were purified from the sera of rabbits sensitized to an albumin-acetaldehyde conjugate that had been reduced with sodium cyanoborohydride (N-ethyl-RSA). The N-ethyl-RSA was coupled to an Affi-Gel-10 column to affinity purify the IgG. Liposomes containing N-ethyl-dioleoylphosphatidylethanolamine were fused with isolated hepatocytes. the affinity purified primary IgG antibodies were added. then fluorescein-conjugated second antibodies were added. and antibody binding to hepatocytes was measured by flow cytometry. The fluorescence of these hepatocytes was significantly greater (p less than 0.01) than control hepatocytes prepared with (1) pre-immune primary IgG antibodies with fluorescein-conjugated second antibodies. (2) no primary antibody but with fluorescein-conjugated second antibodies. and (3) no fluorescein-conjugated second antibodies.
Does the presence of a measurable blood alcohol level in a potential organ donor affect the outcome of liver transplantation, The widespread application of hepatic transplantation has created a tremendous demand for donor organs. An assessment of donor parameters is thought to be important in selecting good donors; however. the criteria utilized have not been standardized. This study was performed to determine the effect of a measurable donor blood alcohol level on graft survival. Fifty-two patients who underwent orthotopic liver transplantation at the University of Pittsburgh were included in the study. Twenty-five patients received liver grafts from donors having a blood alcohol level between 0.04 and 0.4 g/l with a mean of 0.17 g/l. Twenty-seven patients received a liver graft from a donor who had no measurable blood alcohol. There were no differences between these two groups of donors regarding the time of initial hospitalization until the time of donation. Graft failure within the first 30 days was 24% for those receiving an organ from an alcohol-positive donor as compared with 22.2% in those receiving an organ from an alcohol negative donor. The recipient mortality rate was 16% and 11%. respectively. No relationships between the donor blood alcohol level and organ performance. frequency of primary graft nonfunction. or number of episodes of acute cellular rejection were evident. Based upon these data. the presence of a measurable blood alcohol level in a donor should not mitigate against organ donation.
Acetaldehyde dehydrogenase (Ahd-2)-associated DNA polymorphisms in mouse strains with variable ethanol preferences, The genotype-dependent response of mice to ethanol has been well documented. Cytosolic acetaldehyde dehydrogenase (ALDH-2) increases in some strains while decreasing in others with ethanol treatment. Further work suggests that the mRNA for ALDH-2 (Ahd-2 mRNA) levels are altered following ethanol feeding in a strain-dependent fashion. This report identifies differences in Ahd-2 at the genomic DNA level among different strains of mice. Restriction fragment length polymorphisms (RFLPs) associated with the Ahd-2 locus were found for the restriction enzymes EcoRI. HindIII. Pst I and Rsa I. The mouse strains included in this study could be categorized into two groups based on their overall Ahd-2 associated DNA banding patterns. Strains C57BL/6J. C57BL/6J*. C57BL/10J and BALB/c form group 1 while strains C3H/HeJ. C3H/HeSnJ. 129/ReJ. Csb. SW and DBA/2J form group 2. With the exception of BALB/c. group 1 represents alcohol preferring strains while group 2 are alcohol avoiding strains. Additional work will be required to determine the physiological significance (if any) of these RFLPs and their possible relationship to ethanol preference and avoidance.
Choice of anesthetic technique for needle localized breast biopsy, General anesthesia has been recommended to increase the accuracy and safety of needle localized biopsy (NLB). The authors' NLB experience was reviewed to determine whether the method of anesthesia affected accuracy. yield. complication rate. or cost. All biopsies were performed in a standard operating room using either local anesthesia (Group 1. n = 14). local anesthesia with an anesthesiologist present (Group 2. n = 14). or general anesthesia (Group 3. n = 10). The mean operative times were 54. 59. and 56 minutes for Groups 1. 2. and 3. respectively. In groups 1 and 2. 100 per cent of the specimen radiographs showed the target lesion had been excised. although one biopsy was indeterminate. Among Group 3 two target lesions could not be identified on specimen radiographs and one was indeterminate. There was one malignancy in Group 1 compared with four malignancies in Group 2 and two in Group 3. The average hospital bill was $1.172 for Group 1. $1.418 for Group 2. and $1.488 for Group 3. Anesthesiologists' fees added an additional $224 to Groups 2 and 3. NLB can be performed using local anesthesia without sacrificing accuracy or yield. increasing operative time. or increasing complication rate; the cost is significantly less than with general anesthesia.
Radiologic recommendation for breast biopsy on screening mammography reports, Radiologic reports on screening mammography findings often obligate breast biopsy. Ready recommendation for biopsy of nonpalpable lesions imaged by x ray is a conservative radiologic policy but is unsettling for patients and creates an imperative bind for surgeons. Like the decision to send the patient with right lower quadrant abdominal pain home rather than to the operating room. the diagnosis that requires clinical confidence and precision is nonappendicitis. Noncancer of the breast is a similar diagnosis that can usually be made on clinical and mammographic findings rather than passing such patients through to invasive diagnosis. A series of 84 patients was referred for needle localization of nonpalpable mammographically detected lesions called suspicious on screening examination. Of these 84 patients. new radiographic reports reinterpreting the findings without biopsy were written on the original mammogram in 15 patients. This is a cancellation rate of 21 per cent. In 69 patients needle localization was carried out with the finding of cancer in 28 per cent. compared with the national average of 15 per cent. This higher than average yield caused concern whether any unbiopsied cancers had been followed. and a review of these patients was undertaken. In the log of patients referred for needle localization. the prereading by the mammographer performing the needle localization was recorded in advance of biopsy confirmation. and specificity proved to be 94 per cent and sensitivity 96 per cent. Of the cancers that were detected. 39 per cent were proven in patients older than 50 years.
Mammographic guidewire localization of nonpalpable breast lesions, Guidewire-directed biopsy is the predominant method of evaluating nonpalpable breast lesions detected by mammography. It is an accurate and safe procedure for obtaining a histologic evaluation of abnormal tissue. leading to early diagnosis and improved survival rates. This report reviews 526 needle localizations and biopsies of nonpalpable breast lesions performed in two community hospitals over a 39-month period and compares early results with those achieved in the last 13 months of the study. This review indicates that as experience in using this modality increased. the cancer detection rate increased and the percentage of invasive cancers decreased. The percentage of cancers detected in the final 13 months of the study (19%. Group II) was higher than in the first 26 months of the study (13%. Group I). Although microcalcifications were found in 24 per cent of the mammograms leading to a diagnosis of cancer. they did not prove to be a reliable indicator of malignancy in this study.
Multiple, giant fibroadenoma, Multiple. giant fibroadenomas are histologic and clinical variants of "juvenile" or "giant" fibroadenomas. These tumors are rare and occur mainly in adolescent and young adult black females. The individual lesions are well encapsulated with a histologic pattern primarily of the "juvenile" type. although cases of the "adult" type have been reported. A high incidence of recurrence is noted upon local excision. although this may decrease as the patient becomes older. Management options include local excision with reconstruction. reduction mammoplasty. and simple mastectomy with reconstruction. A case is described of this condition with review of the literature.
Anatomic location and variety of nonmalignant neck masses seen in surgical practice, During a 10-year interval. 189 patients. comprised of 121 females and 68 males ranging in age from 1 to 98 years. were surgically treated for nonmalignant neck masses. Nonmalignant neck masses were located in the thyroid or submaxillary gland in 60 per cent of these patients. Thyroid adenoma. reactive cervical nodes. and mixed tumor of the submaxillary salivary glands represented the three most commonly occurring nonmalignant pathologic conditions in this series. When stratified by age and sex. thyroid abnormalities. specifically thyroid adenoma. occurred most often in females of all ages. In males. reactive nodes were usually seen before 40 years of age; thereafter. tumors of the submaxillary salivary gland predominated. Most studies of nonmalignant neck masses indicate that reactive nodes are the most common condition in patients of all ages. Thyroid conditions were seen most frequently in this group of patients. The probable explanation is a tertiary referral pattern to surgeons. Patients with nonsurgical conditions were. presumably. identified and managed earlier and not referred further. and therefore did not appear in this group of patients.
Intrarectal sonography. A new technique for the assessment of rectal tumors, Preoperative staging of rectal tumors provides a selective therapeutic approach. Twenty-three patients were evaluated with prospective intrarectal sonography. Endosonography identified all 21 rectal lesions. Two patients with previous rectal carcinoma had no evidence of recurrence. Thirteen of 17 patients (76%) with rectal carcinoma were correctly staged by endosonography. A submucosal leiomyosarcoma and pararectal arachnoid cyst were correctly identified. Preoperative assessment of lymph node status was accurate in five of ten patients (50%). Results of preoperative digital rectal examination predicting rectal wall involvement correlated with pathologic findings in 11 of 15 patients (73%). Intrarectal sonography is an important staging technique for preoperative evaluation of rectal wall invasion and guides appropriate surgical intervention.
Screening for dementia and investigating its causes, OBJECTIVE: To examine. from the perspective of primary care physicians. the value of mental status findings and ancillary tests in diagnosing dementia or its causes. DATA SOURCES: Studies identified using MEDLINE and bibliographies of pertinent articles. STUDY SELECTION: Selection based on availability of information on specific findings or tests. the criterion standard used to confirm diagnoses. the disease spectrum. and the richness of the reported data. DATA EXTRACTION: Data collected on sensitivity and specificity. In many cases. the originally reported data are re-analyzed to illustrate the usefulness of alternative cut-off values or to answer specific clinical questions. Likelihood ratios estimated to summarize test results. DATA SYNTHESIS: Probability of dementia is greatly reduced (likelihood ratio. 0.06 to 0.2) when either normal serial 7s. 7-digit span. 3-item recall. or clock drawing test results are obtained; abnormal results only moderately increase the odds of disease. Low (less than or equal to 20). intermediate (21 to 25). or high (greater than or equal to 26) scores on the Mini-Mental State Examination (MMSE) increase (likelihood ratio greater than or equal to 8.2). have little effect (likelihood ratio. 1.3 to 2.4). or decrease (likelihood ratio. 0.06 to 0.1) the odds of disease. The usefulness of tests to investigate the cause of dementia varies depending on the pretest probability of the specific condition. CONCLUSIONS: Several useful methods exist to screen for cognitive impairment. and clinicians need to be familiar with the strengths and limitations of their preferred screening methods. In investigating the cause of dementia. routinely obtaining a VDRL test. cerebral imaging studies. serum cobalamin level. or folate level is unwarranted.
Thyroid cancer: a lethal endocrine neoplasm, This conference focuses on the controversies about managing thyroid cancer. emphasizing the possibility that the treatment of patients with potentially fatal thyroid cancer may be improved. Although the mortality rate from thyroid cancer is low. it is the highest among cancers affecting the endocrine glands (excluding the ovary). Exposure to radiation during childhood in the 1930s and 1940s increased the incidence of but not the mortality from thyroid cancer. because these tumors are mainly papillary cancers developing in young adults. These rates may change as the exposed cohort ages. Risk factors that increase mortality include older patient age and the growth characteristics of the tumor at diagnosis. the presence of distant metastases. and cell type (for example. the tall-cell variants of papillary cancer. follicular cancer [to be distinguished from the more benign follicular variant of papillary cancer]. medullary cancer. and anaplastic cancer). Local metastases in lymph nodes do not seem to increase the risk for death from papillary cancer. but they do increase the risk for death from follicular and medullary cancer. In the latter. mortality is decreased by the early detection and treatment of patients with the familial multiple endocrine neoplasia syndrome 2a. There are excellent tumor markers for differentiated cancer of the parafollicular and of the follicular cells (serum calcitonin and serum thyroglobulin levels. respectively). Measuring the calcitonin level allows early diagnosis of familial medullary cancer. whereas measuring the thyroglobulin level. although useful only after total thyroidectomy. allows early recognition of recurrence or metastases of papillary or follicular cancer. Initial surgery. protocols for follow-up. and the use of radioiodine for the ablation of any residual thyroid and the treatment of metastatic cancer are discussed. Because these tumors resist currently available chemotherapy regimens. possible ways to increase the effectiveness of radioiodine therapy are considered as are new approaches to treatment.
CD4 count and the risk for death in patients infected with HIV receiving antiretroviral therapy, OBJECTIVE: To investigate the relation between CD4 count and the immediate hazard of dying in patients receiving zidovudine (azidothymidine [AZT])-based antiretroviral therapy. SETTING: A research hospital that recruits patients from the entire United States. DESIGN: Retrospective analysis of a cohort of patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex participating in long-term zidovudine-based antiretroviral protocols. PATIENTS: Fifty-five patients with human immunodeficiency virus (HIV) infection and either AIDS or severe AIDS-related complex who were followed for as many as 4 years while they received antiretroviral therapy. MEASUREMENTS: CD4 counts were measured. MAIN RESULTS: Ten patients are known to be alive and 1 was lost to follow-up. Of the 44 patients who are known to have died. the CD4 range was known within 6 months of death in 41. All but 1 of these 41 assessable deaths occurred in patients whose CD4 counts were known to have fallen below 50 CD4 cells/mm3 (P less than 10(-10)). The hazard of dying in the cohort ranged from 0 deaths/patient-month (95% CI. 0 to 0.008 deaths/patient-month) in patients with 200 or more CD4 cells/mm3 to 0.07 deaths/patient-month (CI. 0.050 to 0.094 deaths/patient-month) in patients with fewer than 50 CD4 cells/mm3. For the patients who died and whose cases were assessable. the mean of the last three CD4 counts obtained before death was 7.7 CD4 cells/mm3 (CI. 0.9 to 63.3 cells/mm3). The median survival of patients once their CD4 counts fell below 50 CD4 cells/mm3 was 12.1 months (CI. 7.2 to 19.4 months). CONCLUSIONS: In a carefully followed cohort treated with zidovudine-based antiretroviral therapy. nearly all deaths occurred in patients with fewer than 50 CD4 cells/mm3. These findings may have implications in the monitoring of patients with AIDS and in the use of CD4 count as a clinical trials end point for the antiretroviral therapy of HIV infection.
Assessment of competency: the role of neurobehavioral deficits, We present a practical set of guidelines for assessing competency in patients with cognitive deficits due to neurologic disorders such as stroke. head injury. Alzheimer disease. and multi-infarct dementia. Our focus is the evaluation of cognitive processes underlying the ability to make competent decisions. with an emphasis on the identification of areas of preserved function that may be used to bypass intellectual deficits. The assessment of the cognitive processes underlying competency involves a series of steps designed to evaluate attention. language. memory. and frontal lobe function. The examiner must first show that the patient has an adequate level of attention for participation in the further testing of specific cognitive functions; second. that the patient is able to comprehend relevant instructions. retain information long enough to evaluate it in relation to relevant recent and remote experiences. and express his or her wishes; and finally. that the patient has sufficiently intact judgment and awareness. The examiner must determine whether the patient's preserved cognitive abilities are sufficient for him or her to make an adequate judgment in relation to the specific question being asked. If cognitive function is found to be significantly impaired. the examiner should do a detailed assessment for the presence of compensatory abilities that can be used to bypass the deficits. For example. the examiner should assess whether patients who cannot speak are still able to express their wishes by pointing. using gesture. or even by drawing pictures. Unless such an assessment has been done. patients should not be considered incompetent.
Laser uvulopalatoplasty in treatment of habitual snoring, Velopharyngeal sonorous snoring is best treated with uvulopalatopharyngoplasty (UPPP). To reduce surgical risks and minimize the morbidity. a simplified carbon dioxide laser uvulopalatoplasty (LUPP) was performed under local anesthesia. Among a total of 146 patients who had a LUPP performed. there was no significant bleeding or postoperative episodes of asphyxia. The procedure was well tolerated even by those patients with strong vomiting reflexes. The operation time was halved. as was the convalescence. Two patients (1.4%) developed scarring with nasal obstruction. but the impact of factors other than the laser approach itself seemed to be the cause. By scored questionnaires the effect on snoring. family complaints. and daytime somnolence was evaluated in two comparable random groups of patients. Sixty-three patients had LUPP procedures. and 37 had UPPP. The short-term results showed that about 90% of the patients considered themselves essentially improved as regarded snoring and that most patients felt more alert. irrespective of the surgical method used.
Inhibition of bacterial adherence by nasopharyngeal secretions, The role of secretory immunoglobulin (Ig) A in nasopharyngeal secretions in the adherence of Streptococcus pneumoniae and Hemophilus influenzae to nasopharyngeal epithelial cells was investigated in vitro. The adherence was remarkably reduced by treating bacteria with nasopharyngeal secretions. and the antiadhesive activity was significantly greater in nasopharyngeal secretions having secretory IgA antibody activity against bacteria than in those having no activity. Noticeable changes were not observed in the antiadhesive activity caused by absorption of IgG from nasopharyngeal secretions. Results suggest that secretory IgA in nasopharyngeal secretions is related to bacterial adherence and adds to the prevention of nasopharyngeal infections.
Middle ear pressures of children with otitis media with effusion, Middle ear (ME) pressures were measured in 30 children with chronic otitis media with effusion (OME) transtubally with the use of a catheter pressure transducer (Mikro-tip. PC-330F). They were found to range from 40 to -185 mm H2O. the average being mildly negative (-54.33 +/- 59.04 mm H2O). About two thirds of these children had pulsating changes of ME pressure; the range of the pressure change was between 10 and 50 mm H2O. The ME pressure tended to be lower in ears with serous effusion than in those with mucoid effusion. but there was no significant difference between them.
Auditory nerve compound action potentials and brain stem auditory evoked potentials in patients with various degrees of hearing loss, Click-evoked compound action potentials recorded in normal-hearing patients through a monopolar electrode placed on the intracranial portion of the eighth nerve were compared with the responses recorded in patients with high-frequency hearing loss or with high- and low-frequency hearing losses. That multiple peaks appear in the compound action potential in patients with hearing loss implies that click sounds elicit successive and separated volleys of neural excitation in the ascending auditory pathway. whereas click sounds in patients with normal hearing mainly give rise to a single volley of neural activity. This difference in the pattern of auditory nerve activity might explain why there are often multiple peaks in the brain stem auditory evoked potentials in patients with hearing loss and that the peaks are often less well-defined than peaks in patients with normal hearing.
Muscle rehabilitation: its effect on muscular and functional performance of patients with knee osteoarthritis, Muscle function and functional performance are limited in patients with osteoarthritis (OA). Although aerobic exercise can increase aerobic power and reduce fatigue. it does not appear to improve muscle function. The purpose of this study was to demonstrate the effect of a muscle rehabilitation program on muscle strength. endurance. speed. and function for patients with OA of the knees. Fifteen men (67.6 +/- 6.1 years) with OA of the knees underwent a four-month exercise program. three times per week. Muscle strength. endurance. and speed were 50% less in OA patients than in controls. After rehabilitation. there was a significant increase in strength (35%). endurance (35%). and speed (50%). Deficiencies and improvements in the muscles were greater at longer muscle lengths. Increases in muscle function were associated with decreased dependency (10%). difficulty (30%). and pain (40%). The average increase in all measured parameters was 10% and 25% after two and four months of rehabilitation. respectively. Improvements were sustained for eight months after rehabilitation. The muscle rehabilitation program was designed specifically to improve function; the improved muscle function was translated into improved functional performance.
Treatment of open-skin wounds with electric stimulation, A randomized double blind multi-center study of electric stimulation compared with sham units enrolled 59 patients (67 wounds) with open wounds of pressure. vascular and surgical etiology at nine sites. The 14-week study consisted of a four-week phase. randomized. parallel-group. double blind. sham stimulation controlled group comparing effectiveness and tolerance of electric and sham stimulation of open wounds. Patients with wounds not completely closed at the end of the four weeks were allowed to cross over to actual treatment. After four weeks of treatment. the electric stimulation group showed a 56% decrease in size with only a 33% decrease in size with sham treatment. Available data suggest that pulsed electric stimulation should be considered by health care practitioners as an adjunct for treating open wounds.
Carpal tunnel syndrome, subclinical median mononeuropathy, and peripheral polyneuropathy: common early complications of chronic peritoneal dialysis and hemodialysis, Nerve conduction velocity studies were done in median. ulnar. and peroneal nerves. one time each in 46 patients who had been on chronic peritoneal dialysis or hemodialysis for varying lengths of time. Only six patients had normal findings; 37 had peripheral polyneuropathy (15 had isolated polyneuropathy; 22 had median nerve dysfunction in addition); 16 had subclinical median mononeuropathy (14 with polyneuropathy. two without); and nine had overt carpal tunnel syndrome (eight with polyneuropathy. one without). Abnormalities were present in seven of the 11 patients studied after one year of dialysis and in 19 of the 24 patients studied after two years of dialysis. Seventeen patients studied after five years of dialysis all had polyneuropathy. Nine patients studied after seven years of dialysis all had median nerve dysfunction. Abnormalities were as common with peritoneal dialysis as with hemodialysis. Nerve dysfunction was independent of the disease underlying renal failure. the side of the dialysis access shunt. and the presence or absence of osteodystrophy. Dialysis patients need frequent nerve conduction studies from the onset of dialysis to identify carpal tunnel syndrome early and to avoid irreversible nerve damage.
Shoulder limitation in juvenile rheumatoid arthritis, One hundred consecutive children with juvenile rheumatoid arthritis (JRA) were evaluated for shoulder dysfunction. Shoulder arthritis was virtually absent in all 45 children with pauciarticular onset JRA. Twenty of 40 children (50%) with polyarticular JRA and 12 of 15 (80%) with systemic onset JRA had shoulder involvement characterized by pain or restricted passive range of motion (PROM). Ninety-five percent of those with shoulder arthritis had bilateral involvement. Children with systemic onset were likely to have shoulder disease within 2.5 years of onset and to have more severely limited PROM. Children with polyarticular onset developed shoulder arthritis any time during the course of their disease. With either type of onset. internal rotation was the most commonly and severely limited motion. followed by abduction. Clinicians treating children with JRA should carefully monitor pain and examine both rotational and planar components of shoulder motion.
Nonpharmacologic treatment of periodic leg movements in sleep, The effects of a 30-minute stimulation of the dorsiflexors of the feet and toes before bedtime were investigated in eight patients with periodic leg movements in sleep (PLMS). None were taking medications at the time of the investigation. All subjects were treated with the EMS-250 Neuromuscular Stimulator. which has a maximum output per channel of 1.5mA and a frequency of 47Hz. Stimuli were delivered via a pulse train (on for 1.5sec and off for 1.8sec). A single all-night polysomnogram after this stimulation showed that all patients responded to stimulation. with reduction of leg movements from an average pretreatment PLMS index of 44.6 per hour to a posttreatment PLMS index of 14 per hour (p less than .01). Nocturnal leg movements were primarily reduced during the non-REM sleep. Multiple indices of sleep continuity did not change significantly. although there was a trend toward better sleep consolidation.
Gait characteristics of obese children, The gait patterns of ten obese and ten normal-weight. prepubertal children were evaluated to provide objective data for a weight status comparison. Temporal and kinematic analyses were conducted on representative gait cycles at three speeds of walking: slow. normal. and fast. Subjects were filmed by two phase locked cameras. one each in the sagittal and frontal planes. operating at a speed of 50 frames per second while the subjects traversed a 10-m walkway in one direction. Obese subjects displayed longer cycle duration (p less than .001). lower cadence (p less than .001). lower relative velocity (statures/sec. p less than .001). and longer stance period (sec. p less than .001) than normal-weight subjects at all speeds. Other temporal differences included gait asymmetry and greater stride width for the obese. all pointing to a slower. more tentative normal speed and problems encountered when walking at speeds other than normal. Greatest instability was evidenced at the slow speed of walking. Joint angle displacement data showed a largely invariant pattern among speeds for most joints studied and similar patterns for both study groups. Normal-weight subjects displayed more consistent patterns of rotation at all joints and speeds. and for the hip and knee joints. there was greater total excursion that favored increased flexion. Obese subjects displayed a more flat-footed weight acceptance period in early stance and a greater external rotation (out-toeing) of the foot at all phases of the gait cycle.
Immobilization impairs recovery after spinal cord injury, The effect of immobilization on motor recovery was studied in adult rats after subtotal spinal cord section. Anesthetized rats underwent three-quarter section of the cord. sparing the left lateral funiculus. After surgery. half the rats were placed in immobilization tubes for three to four weeks; the others were allowed free mobility. Hindlimb motor function was graded at various times in the two groups. In contrast to the marked recovery observed in mobile animals. the immobilized rats with similar cord lesions showed no significant motor recovery during the period of immobilization. Immobilized rats without cord lesions showed minimal transient deficits. In conclusion. hindlimb activity appears to be a necessary condition for motor recovery after subtotal spinal cord injury.
Discourse analyses with closed head injured adults: evidence for differing patterns of deficits, To better characterize the verbal impairments of higher level closed head injured (CHI) adults. we used narrative stories to longitudinally sample their discourse abilities. Stories were analyzed at the levels of intersentential cohesion and story grammar. Two differing patterns of deficits that emerged are described. In the first. a CHI subject demonstrated excessive verbalization characterized by poorly organized. but task-appropriate. content. In the second. a CHI subject demonstrated fair to good organization but little appropriate content. Prognostically. the presence of appropriate. although disorganized. content was an early indication that the subject was able to appreciate potential relationships of characters in the stimulus picture. The second pattern represented a more severe cognitive dysfunction. This subject's attempts at stories. although well organized. were merely elaborate descriptions of the picture. Discourse analyses appear to be well suited for the assessment of CHI adults.
Behavioral treatment of dizziness secondary to benign positional vertigo following head trauma, Benign positional vertigo (BPV) represents a challenge to rehabilitation due to the subjective nature of the complaint of dizziness. frequent failure of pharmacologic intervention. and complicating psychologic factors. Behavioral therapy was used to treat a 26-year-old woman who complained of debilitating dizzy spells after mild head injury sustained in a motor vehicle accident. During a three-week baseline period before treatment. the patient reported a weekly average of 48 dizzy spells. which prevented participation in independent activities and kept her homebound and psychologically distressed. Nine-week behavioral treatment included biofeedback-assisted relaxation training. psychologic counseling. gaze-fixation practice. desensitization exercise. and generalization training. This protocol has been used successfully to train aviators to combat vertigo and nausea in flight. Our regimen included hourly recording of physical activity. notation of frequency of dizzy spells. and use of behavioral methods during nine weeks. The patient reported 90% reduction in dizzy spells and full resumption of independent activities including driving and athletics. Results are discussed in the context of behavioral problems associated with BPV and application of behavioral methods to the complaint of dizziness.
Substance use and receipt of treatment by persons with long-term spinal cord injuries, The purpose of this study was to assess the rate of self-reported substance use. consequent problems. perceived need for treatment. and receipt of treatment by persons with long-term spinal cord injury (SCI). Information was obtained from 86 persons with traumatic SCI who were between 13 and 58 years of age at injury. cognitively intact. injured more than two years earlier. English speaking. and recruited from two SCI organizations. The mean age of the sample was 39.5 years at recruitment: 69% were men. Participants reported substance use information across four periods covering six months before injury to an average of 13 years after injury. All participants reported use of substances with abuse potential at some time in their lives; the time of greatest use was injury to six months before first interview. The duration of this period ranged from 18 months to 43 years. Problems resulting from substance use were reported by 70%; more than half (52%) the sample reported problems during this postinjury period. Sixteen percent of the sample believed they needed treatment at some time; the time of greatest perceived need was in the period after injury. Treatment for substance abuse was received by 7%. Problems attributable to abuse of both prescription and nonprescription medication were reported. suggesting the importance of close monitoring of substance-use patterns in persons with SCI who are prescribed sedating or narcotic medications. Timely assessment of problems related to substance use and provision of treatment services to persons with traumatic injury are indicated to prevent a potential dual disability.
Behavioral and demographic predictors of suicide after traumatic spinal cord injury, Among people with spinal cord injuries. death from suicide is two to six times more prevalent than in the general population. To determine if individual characteristics and behaviors present during rehabilitation can identify high-risk individuals. records of 5.200 spinal cord injured patients admitted to the Rocky Mountain Regional Spinal Injury System were reviewed. Of 489 deaths. 9% were due to suicide. They were compared with a control group of equal size. matched on age. gender. and injury level. The two groups differed significantly on postinjury despondency; expressions of shame. apathy. and hopelessness; and preinjury family disruption (p less than .01). They also differed on alcohol abuse. active involvement in the injury. preinjury depression or despondency. destructive behavior. and one aspect of etiology (p less than .05). Discriminant analysis yielded a predictive model that correctly classified 81% of the suicide group and 79% of the control group. Many of the demographic predictors identified in this study are similar to those reported in the scientific literature. However. when combined with specific behavioral characteristics manifested during rehabilitation. they comprise an array of variables that permits development of a clinical model for predicting suicide among persons with spinal cord injuries.
Developing anxiety-reduction procedures for a ventilator-dependent pediatric patient, This study evaluated two strategies to reduce anxiety behaviors which interfered with the daily tracheostomy care and ventilator maintenance of an eight-year-old ventilator-dependent boy. A multiple-baseline design (across ventilator and tracheostomy procedures) was used to evaluate the effectiveness of an information-only procedure and combined relaxation and cognitive distraction procedures. Partial-interval recording was used to measure heart rate. disruptive mouth noises. and demands and complaints to staff members. The patient's behavior did not change during a no-intervention baseline or during the information-only condition. Cognitive distraction and relaxation procedures were introduced. first during ventilator checks and then during tracheostomy care; corresponding decreases in heart rate. mouth noises. and demands and complaints were noted. Gains were maintained at one year follow-up. Results suggest that information alone may not effectively reduce anxiety behaviors for some ventilator-dependent patients unless additional anxiety-reduction procedures are implemented.
Carpal tunnel syndrome: objective measures and splint use, One hundred five adults with carpal tunnel syndrome (CTS) were studied to assess the efficacy of a neutral-angle wrist splint. and to identify criteria for splint referral. Ten observations before and after treatment were analyzed with descriptive and inferential statistics. After splint use. 67% of the subjects reported symptom relief. T-test comparison of sensory latency of values before and after treatment indicated improvement for the total group. Chi-square and t-tests failed to reveal significant differences between relief and no-relief groups for gender. affected hand. presence of concomitant conditions. duration of symptoms before treatment. age. length of time between pretreatment and posttreatment nerve conduction testing. initial nerve latency of motor and sensory fibers. or the difference between pretreatment and posttreatment sensory latencies. A significant difference was found for motor latency; the relief group improved and the no-relief group deteriorated. Data suggest that splinting is most effective if applied within three months of symptom onset. Those with damage to the wrist structures or median nerve were least responsive to splinting.
The motor control assessment: an instrument to measure motor control in physically disabled children, The Motor Control Assessment has been developed as a research tool for the assessment of motor skills in physically disabled children. In tests of concurrent validity it was found to be highly correlated with the results of the Physical Abilities Chart (Pearson coefficient = .96). and satisfactorily correlated with ranking of motor ability assigned using the clinical judgment of physiotherapists (Spearman rank coefficients = .63 to .97 in diagnostic subgroups). Estimates of both interrater and intrarater reliability were also high. with intraclass coefficients above .95.
Rocker-soled shoes and walking distance in patients with calf claudication, Calf claudication is the major clinical manifestation of peripheral vascular occlusive disease in a significant number of patients. Although claudication causes substantial patient disability. most patients are treated conservatively because of the risks of surgical therapy and the uncertain efficacy of drug therapy. It was hypothesized that rocker-soled shoes would decrease the work of the plantar flexors and therefore increase walking distance in patients with calf claudication. To test this hypothesis. walking distances in patients with calf claudication using rocker-soled shoes and a placebo shoe insert were compared. Rocker-soled shoes significantly increased both the total distance walked and the distance at which patients were initially bothered by symptoms by 77m (37%. p less than .0005) and 89m (91%. p = .003). respectively. It was concluded that rocker-soled shoes may reduce disability in patients with calf claudication by increasing walking distance.
Reliability of peak physiological responses during wheelchair ergometry in persons with spinal cord injury, This study examined the test-retest reliability of peak physiological responses during wheelchair ergometry (WE) in individuals with spinal cord injury (SCI). Seven wheelchair dependent subjects. two with paraplegia (T10-11 and T11-12 lesions) and five with quadriplegia (all with C6-7 lesions). were given two incremental exercise tests to volitional fatigue on separate occasions within a one-week period. Each subject wheeled his or her personal wheelchair. which was mounted on a set of frictionless rollers with side-mounted flywheels. Metabolic and cardiorespiratory responses were continuously monitored by means of an automated metabolic measurement cart interfaced with an electrocardiograph. Statistical analysis revealed no significant differences (p greater than .05) between the mean values of the two test trials for six peak values. Reliability coefficients (p less than .01) were: oxygen uptake (0.98). heart rate (0.97). ventilation volume (0.96). respiratory exchange ratio (0.91). oxygen pulse (0.96). and ventilatory equivalent for oxygen (0.88). The investigators concluded that these six physiological responses in subjects with SCI undergoing WE are highly reliable. and that these variables can be used in the objective prescription. monitoring. and evaluation of exercise rehabilitation programs for individuals with SCI.
Myocardial and aerobic requirements for an upper body exerciser: implications for cardiac rehabilitation, To assess the cardiorespiratory. hemodynamic. and electrocardiograph (ECG) responses to an upper body exercise device. we studied ten cardiac men (mean age +/- SD = 58.0 +/- 6.5 years) who performed three five-minute exercise bouts at metronome settings of 20. 50. and 80 clicks per minute. Operation of the device involved shuttling a plastic buoy on two 6-m waxed ropes between two persons. Aerobic requirements were generally appropriate for arm training. corresponding to mean values of 5.3. 7.0. and 10.1 ml.kg-1.min-1 at the three progressive metronome settings. Perceived exertion (Borg. 6 to 20 scale) at these work rates was 8.3. 10.4. and 14.6. whereas average heart rate and systolic blood pressure responses were 77. 85. and 114 beats.min-1 and 145. 158. and 175 mmHg. respectively. Continuous ECG monitoring during upper body exercise revealed no significant ST-segment depression or serious arrhythmias. The device appears to be a safe and effective complement to a cardiac exercise training program.
Paralysis of the trapezius: a case report, A patient was referred to physical therapy for exercises to the right shoulder secondary to a peripheral nerve injury involving the spinal accessory nerve. A treatment program was designed to accommodate for lack of upward scapula rotation. which is necessary for elevation of the upper extremity above shoulder level. During the course of two and a half years of care. a variety of associated problems were encountered. There was no apparent nerve regeneration. and the patient was left with limited mobility of the affected upper extremity.
Serum hyaluronate level as a predictor of radiologic progression in early rheumatoid arthritis, Increased serum levels of hyaluronate (HA) have been found in patients with rheumatoid arthritis (RA). This probably reflects increased leakage of HA from the inflamed joints into the circulation. In a prospective study of 40 patients with early RA. we evaluated the relationship of serum HA to clinical. laboratory. and radiologic parameters of disease activity. The patients were followed for 12 months; all had active disease at study entry. We confirmed the previous finding of higher serum HA concentrations in RA patients compared with healthy controls. At study entry. the patients' serum HA levels correlated positively with clinical and laboratory parameters of acute inflammation. Despite marked clinical improvement during therapy with second-line drugs. the serum HA levels increased during the followup period. At the end of 1 year. these levels correlated with the radiologic progression of joint lesions. whereas they showed a less pronounced correlation with clinical or laboratory parameters of inflammation. We conclude that. in early RA. serum HA levels may reflect ongoing joint destruction and may even predict subsequent joint damage.
Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Results of a followup study, The association between HLA-DR antigens and rheumatoid arthritis (RA) was investigated in a well-characterized cohort of RA patients who were followed from the beginning of the disease (mean followup 6 years). The frequencies of HLA-DR antigens in patients with possible or probable RA (n = 49) were similar to those in controls. In patients with definite RA (n = 134). the frequencies of DR1. DR4. and DRw53 were increased. whereas the frequencies of DR2. DR3. DRw6. DRw13. and DRw52 were decreased. compared with controls. Comparison of HLA-DR frequencies in patients with definite RA subclassified according to the severity of the disease at the end of the followup period revealed a difference only in the frequency of DR4. which was increased in patients with progressive RA (59.2%) compared with those who had mild RA (34.8%). Further analysis showed that. compared with DR4-negative RA patients. DR4-positive patients had more swollen joints. higher scores on the Ritchie articular index. the Health Assessment Questionnaire. and the Steinbrocker functional classification. more radiologic abnormalities. and more use of second-line drugs. Also. the rate of progression of radiologic abnormalities. functional classification. and use of second-line drugs was higher in DR4-positive patients. We conclude that DR4 is associated with a more severe disease course. and is a prognostic marker in early RA.
Subclass distribution and size of human IgA rheumatoid factor at mucosal and nonmucosal sites, Elevated serum levels of IgA. IgA1. and IgA2 rheumatoid factors (RF) were demonstrated by enzyme-linked immunosorbent assay in 69%. 73%. and 36%. respectively. of 100 patients with rheumatoid arthritis (RA). whereas fewer than 5% of 100 healthy donor sera contained elevated levels of these RFs. In serum samples from 125 controls with 4 different chronic diseases (systemic lupus erythematosus. ankylosing spondylitis. bronchial asthma. and polyarteritis nodosa). levels of IgA-. IgA1-. and IgA2-RF were found to be increased in 7%. 7%. and 8%. respectively. Comparison of RF levels in samples of serum. synovial fluid (SF). and saliva from RA patients indicated local production of both IgA-RF subclasses in salivary glands and in synovial tissue. Significant positive correlations were found between levels of IgA-RF subclasses in SF and serum. but not in serum and saliva or in SF and saliva. Fractionation of serum. SF. and saliva from patients with RA (by high performance liquid chromatography under acidic conditions) demonstrated that both IgA subclasses with RF activity occur mainly in fractions that also contain IgM. The results of this study show that 1) IgA-RF in serum and SF is mainly of IgA1 subclass. 2) both IgA-RF subclasses are produced locally in salivary glands and in synovial tissue. 3) the production of both IgA-RF subclasses at mucosal and nonmucosal sites is independent from each other. and 4) both IgA-RF subclasses occur predominantly in polymeric form in serum. SF. and saliva in RA patients.
Expression of large quantities of rheumatoid factor major cross-reactive idiotype in the serum of adults with seropositive rheumatoid arthritis, We quantified rheumatoid factor cross-reactive idiotype (RF-CRI) in whole serum from RF+ rheumatoid arthritis (RA) patients. using an inhibition enzyme-linked immunosorbent assay which is not affected by the presence of IgG. Serum from 16 RF+ RA patients contained 2-252 micrograms/ml RF-CRI (geometric mean */divided by SD 20.8 */divided by 5.2). while serum from 11 normal adults contained 1-16 micrograms/ml RF-CRI (geometric mean */divided by SD 3.9 */divided by 2.3). Serum from 8 of the RF+ RA patients contained RF-CRI at concentrations more than 2 standard deviations above the geometric mean in the normal subjects (greater than 21 micrograms/ml). Our results indicate that some RF+ RA patients express high concentrations of RF-RCRI and immunoglobulin molecules that express the RF-CRI may not be RF.
The GERI-AIMS. Reliability and validity of the arthritis impact measurement scales adapted for elderly respondents, We adapted the Arthritis Impact Measurement Scales (AIMS) for use with frail elderly respondents. The new instrument. called the GERI-AIMS. generates both generic and arthritis-specific impairment scores. to control for comorbid conditions that are commonly found in an older population. An analysis of scores obtained on 438 elderly persons (mean age 76) indicated that more than half of the total disability measured by the generic GERI-AIMS scores is related to arthritis. The GERI-AIMS scales have standardized-item alpha levels greater than 0.70 and correlate well with clinical measures of arthritis severity. Information gained by using the GERI-AIMS has important public policy implications. insofar as information on both generic and disease-specific functional impairment is needed to establish priorities for basic research. epidemiologic. and intervention studies.
Development of a disability measurement tool for juvenile rheumatoid arthritis. The Juvenile Arthritis Functional Assessment Report for Children and their Parents, Two questionnaires were developed for measuring disability due to juvenile rheumatoid arthritis (JRA). one based on patient reports and one on parent reports. These questionnaires were termed the Juvenile Arthritis Functional Assessment Report for Children (JAFAR-C) and for Parents (JAFAR-P). The questionnaires were administered to 72 JRA patients ages 7-18 years and to their parents. Respondents rated the patient's recent ability to perform 23 activities. Patient reports and parent reports were found to correlate highly with each other and with an objective assessment performed by therapists. Questionnaire scores did not correlate significantly with the age of the patient. The JAFAR appears to be a convenient. reliable. and valid measure of disability in patients with JRA.
Prognostic value of VEPs in young children with acute onset of cortical blindness, Visual evoked potentials (VEPs) were recorded in 32 children (ages 4 months to 5 years) who were clinically diagnosed as being cortically blind. None of the children had visual or neurologic abnormalities prior to the precipitating insult which included surgery (N = 15). trauma (N = 3). infectious disease (N = 5). hypoxia (N = 3). and other causes (N = 6). VEPs were recorded during the acute stage of cortical blindness in all children and were repeated in 24 of them. Either flash or pattern stimulation was used. depending upon the age and visual status of the child. All but one of the children who had normal flash VEPs while cortically blind. recovered normal visual function. All patients with abnormal VEPs had permanent visual impairment or blindness and all but one of those with absent VEPs remained blind. The recovery period was highly variable. ranging from 5 days to 3 years. Thus. flash VEPs recorded during the period of blindness were useful in predicting visual outcome. regardless of etiology. Repeat studies using pattern VEPs were valuable in monitoring recovery in many of these patients.
Terminal axon pathology in infantile neuroaxonal dystrophy, In order to clarify the pathogenesis of infantile neuroaxonal dystrophy. ultrastructural studies of the terminal and nonterminal axons of motor and autonomic nerves in muscle and skin. of which structures are much simpler than those of the central nervous system. were performed in 5 patients affected by infantile neuroaxonal dystrophy. The primary lesion was located in the axon terminal; the majority of terminal axons were dystrophic with tubulo-membranous profiles. while there were only a few dystrophic axons in the nonterminal axons. According to these findings. it is logical to consider that interruption of axonal transport at the site of the "turnaround" process is a cause of dystrophic change of the terminal axon in infantile neuroaxonal dystrophy.
Ictal 99mTc-HMPAO SPECT in alternating hemiplegia, 99mTc-hexamethylpropylenamine oxime (99mTc-HMPAO) single-photon emission computed tomography (SPECT) was performed in a patient with alternating hemiplegia during 2 episodes of the disease. The regional cerebral blood flow patterns correlated with the clinical manifestations during both episodes. Hyperperfusion of the contralateral hemisphere was suggested by asymmetric 99mTc-HMPAO uptake. whereas symmetric 123I-N-isopropyl-p-iodoamphetamine uptake was detected during the interictal period. The results suggested that alternating hemiplegia in infants represents an atypical manifestation of epilepsy. despite the lack of paroxysmal electroencephalographic abnormalities during the episodes. 99mTc-HMPAO SPECT appears to be a useful method for detecting transient regional cerebral blood flow alterations during paroxysmal events because the tracer is rapidly available for emergencies and retains a fixed distribution for 5-8 hours. sufficient time to allow for SPECT acquisition.
Defect in fatty acid oxidation: laboratory and pathologic findings in a patient, The clinical. laboratory. and pathologic findings in a patient with a previously undescribed deficiency in fatty acid oxidation are summarized. The patient had a fatal defect in fatty acid metabolism profoundly affecting heart. skeletal muscle. liver. and kidney. Oxidation of palmitate was 38-51% of controls. Complementation assays demonstrated that the patient's fibroblasts complemented fibroblast lines from all known defects in fatty acid oxidation except long-chain acyl-CoA dehydrogenase deficiency. Urine and serum carnitine profiles also were indicative of a defect in the oxidation of long-chain substrate; however. the palmitoyl-CoA dehydrogenase activity was actually increased. This finding indicates that the patient had a defect that was distinct from. but possibly related to. long-chain acyl-CoA dehydrogenase deficiency. This patient demonstrates the laboratory and pathologic findings in defects in fatty acid oxidation and how they differ from those in Reye syndrome.
Long-term L-carnitine treatment in isovaleric acidemia, A 5-year-old girl with isovaleric acidemia was treated with long-term L-carnitine and no supplemental glycine. Clinical and laboratory data are presented. Following diagnosis and treatment at age 2 years. the frequency of acute exacerbations of metabolic acidosis was reduced and she resumed normal growth and development. L-carnitine supplementation and protein restriction may be sufficient for effective therapy of isovaleric acidemia.
Neonatal asphyxia: vulnerability of basal ganglia, thalamus, and brainstem, Two infants who suffered acute intrapartum asphyxia resulting in severe neonatal encephalopathy are described. Although computed tomography revealed no abnormalities. magnetic resonance imaging documented unequivocal lesions in the thalamus. basal ganglia. parasagittal cortex. brainstem tectum. and midline cerebellum in one patient and in the basal ganglia and parasagittal cortex in the other. Thus. magnetic resonance imaging was more sensitive than computed tomography in detecting acute brain damage after neonatal asphyxia and may become an important tool in improving our understanding of the relationship between adverse perinatal events. neonatal encephalopathy. and neurologic morbidity.
Dendritic and synaptic pathology in mental retardation, Histologic changes in brains from mentally retarded patients are often subtle and may be limited to abnormalities in the dendritic and synaptic organization of the cerebral cortex. Special methods may be necessary for their demonstration. This review summarizes data on dendritic and synaptic pathology in human mental retardation syndromes. Findings in humans are compared to those in animal models that are of relevance to human disorders. Both in humans and in animal models there is evidence that development modifies the observed changes and that findings differ depending on the developmental age at which the tissue is studied.
Serial visual evoked potentials and outcome in term birth asphyxia, Birth asphyxia is a major cause of neonatal mortality and morbidity. It remains difficult to predict accurately neurologic outcome among survivors. particularly infants with moderate hypoxic-ischemic encephalopathy. Visual evoked potential (VEP) is a reproducible measure of cortical function and reflects acute changes in central nervous system status secondary to asphyxial insult. We performed serial VEPs on 36 term infants with documented birth asphyxia to investigate the relationship between VEPs and neurodevelopmental outcome at 18 months of age. Fourteen infants were neurologically intact at subsequent examination; all had normal VEPs during the first week of life. Twenty-two infants had died or were significantly handicapped at 18 months of age; 20 had abnormal VEPs persisting beyond day 7 of life. Abnormal VEPs accurately predicted abnormal outcome (100%) and were both sensitive (91%) and specific (100%). In 20 infants who were classified as moderately asphyxiated according to the criteria of Sarnat and Sarnat. even greater accuracy. sensitivity. and specificity (all 100%) were observed. VEPs demonstrate good correlation with neurodevelopmental outcome in term infants with birth asphyxia and provide accurate prognostic information useful in the clinical management of these infants.
Vitamin B6 and valproic acid in treatment of infantile spasms, Twenty patients with infantile spasms were treated with high doses of vitamin b6. valproic acid. or both. Three of 13 patients (23%) treated initially with high doses of vitamin B6 demonstrated a definite reduction in seizures; 2 patients had no improvement on electroencephalography. Vitamin B6 therapy alone was continued in a single patient (8%) who remained seizure-free during the 15-month follow-up period. Initial treatment with vitamin B6 and valproic acid improved the electroencephalogram significantly more (P less than 0.05) than initial vitamin B6 treatment alone. The group which had valproic acid added to vitamin B6 therapy had significantly fewer seizures (P less than 0.05) and better electroencephalograms (P less than 0.01) than did the group treated initially with vitamin B6 alone. There were no significant differences among the group treated initially with vitamin B6. the group treated initially with valproic acid. and the group in which valproic acid was substituted for vitamin B6. ACTH was more effective in abolishing seizures than was valproic acid or vitamin B6 and valproic acid. ACTH had an excellent effect on seizures in 86% of patients who did not respond well to vitamin B6. valproic acid. or both; however. many of these patients had later recurrence of infantile spasms. The combination of vitamin B6 and valproic acid is effective and safe in the treatment of infantile spasms.
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys, 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the in vitro replication of a number of retroviruses. including HIV-1 and HIV-2. simian immunodeficiency virus (SIV). simian AIDS-related virus (SRV). feline immunodeficiency virus (FIV) and Moloney murine sarcoma virus (MSV). PMEA causes a dose-dependent suppression of the induction of anti-SIVmacgp120 antibodies in SIV mac-infected rhesus monkeys. Complete suppression of anti-SIVmacgp120 antibodies was achieved in SIV-infected animals treated with PMEA at 2 x 10 or 2 x 5 mg/kg per day for 29 days. No toxic side-effects were noted during this treatment period. Antibodies against SIVmac gp120 appeared 1-2 weeks after PMEA treatment was stopped. but the antibody titre reached in these animals was significantly lower than in the SIVmac-infected animals who had not been treated with PMEA. Our data strongly suggest that PMEA should be pursued for its potential in the treatment of AIDS and other retrovirus infections.
Differences in clinical course in zidovudine-treated asymptomatic HIV-infected men associated with T-cell function at intake, Declining CD4+ T-cell numbers and anti-CD3-induced T-cell responsiveness are prognostic markers for progression of HIV infection. We investigated the effect of long-term (2-year) zidovudine treatment on these immunological markers in a group of nine asymptomatic p24-antigenaemic men. five of whom progressed to AIDS. A group of 10 untreated HIV-infected men. five of whom progressed to AIDS. was studied as a control. At intake. 1 year before the start of treatment. CD4+ T-cell numbers in the groups were not significantly different. However. at that time progressors already exhibited an extremely low anti-CD3-induced T-cell responsiveness compared with non-progressors. In all people T-cell responsiveness and the number of CD4+ T-cells had improved 6 months after the start of zidovudine treatment. However. CD4+ T-cell numbers were not persistently elevated. and restoration of T-cell responsiveness was of only short duration. Our results show that zidovudine treatment in the asymptomatic phase of HIV infection did not result in a sustained improvement in T-cell function. Furthermore. they suggest that differences in clinical course among zidovudine-treated asymptomatics may be caused by heterogeneity of this group with respect to T-cell functional capacity at the start of treatment.
Attitudes of health-care workers towards AIDS at three Dutch hospitals, A questionnaire survey was held among 938 doctors and 2304 nurses to assess their attitudes toward AIDS and the influence of their concern about the occupational risks involved. The response was 65 and 72%. respectively. The results suggest that in treating patients with actual or possible HIV infection. in non-invasive procedures many doctors and nurses often take too many precautions. whereas in invasive procedures doctors often take too few. A minority of the respondents were in favour of testing all patients. The majority felt that patients in the high-risk groups should be tested. The percentage in favour of anonymous testing was considerably higher among the doctors than among the nurses. Most of the doctors and nurses were concerned about contagion by patients. This concern had a negative influence on their attitudes toward AIDS. Factual information alone does not suffice to dispel excessive concern. In training and educating medical personnel. attention should be devoted to cognitive as well as emotional aspects.
Evidence of marked sexual behavior change associated with low HIV-1 seroconversion in 149 married couples with discordant HIV-1 serostatus: experience at an HIV counselling center in Zaire, To determine the effect of an HIV-1 counselling program on 149 married Zairian couples with discordant HIV-1 serology. the rates of HIV-1 seroconversion and reported condom utilization have been observed during 382.4 person-years of follow-up (minimum follow-up time per couple of 6 months). Before determination of HIV-1 serostatus and counselling. less than 5% of these couples had ever used a condom. One month after notification of HIV-1 serostatus and counselling. 70.7% of couples reported using condoms during all episodes of sexual intercourse. At 18 months follow-up. 77.4% of the 140 couples still being followed reported continued use of condoms during all episodes of sexual intercourse. At the time of notification of HIV-1 serostatus. 18 couples experienced acute psychological distress. Home-based counselling by trained nurses resolved these difficulties in all but three couples who subsequently divorced. Intensive counselling following notification of HIV-1 serostatus led to low rates of HIV-1 seroconversion (3.1% per 100 person-years of observation) in Zairian married couples with discordant HIV-1 serostatus who voluntarily attended an HIV counselling center.
Sexual risk behavior among heterosexual intravenous drug users: ethnic and gender variations, We analyzed the relationship of ethnicity and gender to high-risk sexual behavior among 457 male and female heterosexual intravenous drug users (IVDUs) interviewed in street and clinic settings in San Francisco. Over two-thirds said they never used condoms. More of the black respondents had not been enrolled in treatment. White IVDUs were more likely to report 10 or more partners. anal sex. and a steady drug-injecting partner; black respondents more often reported prostitution. More men said they never used condoms. and more women said they engaged in prostitution. These high-risk sexual behaviors were significantly and independently associated with ethnicity or gender when other sociodemographic variables were held constant. Sexual risk reduction for IVDUs. focusing on condom use. needs to be expanded to reach non-injecting partners. Intervention is critical for the black community. where a high proportion of IVDUs have steady non-injecting partners.
HIV-2 infection in an American, HIV-2 is endemic in West Africa but rare elsewhere. In the USA there have been 18 reported cases of HIV-2 infection; most identified people have been West Africans. We recently diagnosed the first case of HIV-2 infection in a native-born US citizen. a woman whose serum was found to be reactive to anti-HIV-1 enzyme immunoassay (EIA) when she attempted to donate blood in 1986. Although both HIV-1- and HIV-2-specific EIAs were reactive. the anti-HIV-2 Western blot (WB) was positive. while the anti-HIV-1 WB was positive or indeterminate on different occasions. Synthetic peptide testing was reactive for HIV-2 but not HIV-1. HIV-2 DNA was detected using the polymerase chain reaction procedure. Although she had travelled to West Africa. it is unclear how she became infected with HIV-2.
Immunocytochemical determination of antigen and epitope specificity of HIV-1-specific B cells in lymph-node biopsies from HIV-1-infected individuals, Knowledge about B-cell dysfunction and HIV-specific antibody production is necessary for the understanding of both HIV-1-related immunopathology and the (vaccine-induced) humoral immunity involved in protection against AIDS. This paper describes the application of recently developed methods to detect epitope specificity of B cells in lymph-node biopsies with antigen-enzyme conjugates. Cryosections of five lymph-node biopsies from HIV-1-infected individuals and four control tissues were stained with a panel of HIV-1 antigen-enzyme conjugates: recombinant HIV-1 proteins (gp 160. gp 120 and p24). labelled with peroxidase. and synthetic peptides representing neutralizing epitopes from gp120 and gp41. labelled with alkaline phosphatase. Antibody-forming cells (AFCs) were detected in all the HIV-1-infected biopsies with gp160. gp120 and/or p24. in numbers up to 350 per section. AFCs producing specific antibodies against peptide 101 (SP 101). representing the neutralizing epitope 586-608 of gp41. were detected in one patient. These techniques allow correlation of in vivo function of B cells with lymph-node pathology. clinical stage of the disease and serological data. Their potential for the elucidation of HIV-related immunopathogenesis and the development of vaccines is discussed.
HIV-2 infection in hospitalized patients in Bissau, Guinea-Bissau, During 11 months in 1989-1990. 1009 consecutive hospitalized adult patients admitted to the medical wards of the National Hospital in Bissau were interviewed. examined clinically. and tested for antibodies to HIV-1 and HIV-2. The prevalence of HIV-2 infection was 20.4% (206 out of 1009) and of HIV-2-associated AIDS 4.4% (44 out of 1009). HIV-2 infection was more frequent in women (25%. 110 out of 440) than in men (16.9%. 96 out of 569). HIV-1 infection was diagnosed in one patient only. and one patient (with AIDS) had reactivity to both HIV-1 and HIV-2. Among HIV-2-seropositive patients. AIDS was demonstrated in 21.3% and AIDS-related symptoms (not fulfilling the AIDS criteria) in 19.4%. The frequency of AIDS-associated symptoms was significantly higher in HIV-2-seropositive patients than in seronegative patients. The clinical profile of the HIV-2-associated AIDS cases was very similar to that described in HIV-1-associated AIDS cases in Africa. Seven out of 51 patients fulfilling the clinical criteria for AIDS were HIV-seronegative. The World Health Organization (WHO) clinical case definition for AIDS in Africa had a specificity of 99% and a positive predictive value of 86%. Tuberculosis was more common in HIV-2-seropositive patients (6.3%) than in HIV-2-seronegative patients (2.2%). A history of blood transfusion was a significant risk factor for HIV-2 infection. HIV-2 infection and AIDS are public health problems in Guinea-Bissau.
Knowledge of AIDS among secondary school pupils in Bagamoyo and Dar-Es-Salaam, Tanzania, We assessed knowledge of AIDS among pupils in selected schools in Tanzania in August 1989. Four hundred and eight-one pupils from four randomly selected secondary schools. two from Dar-Es-Salaam (a city) and two from Bagamoyo (a semi-rural town). were interviewed using a structured questionnaire. Of these. 476 (99.0%) had heard of AIDS. and 447 (92.9%) were able to mention spontaneously at least one sexually transmitted disease (STD). of whom 374 (83.7%) mentioned AIDS. Knowledge was found to increase with age and tended to be higher among women in Dar-Es-Salaam than in Bagamoyo. These data suggest that communication channels directed at women in rural areas should be strengthened. While knowledge of sexual transmission of HIV was generally high. and prevalence of reported misconceptions about modes of transmission was very low. knowledge of non-sexual means of transmission (transfusions. injections. vertical) was lacking. Although 80% of pupils mentioned reduction of number of sexual partners as a means of AIDS prevention. only 22% mentioned condom use. and less than 5% reported that they had ever used a condom. Future research should concentrate on means of promoting sexual behavior change. the ultimate aim of any AIDS prevention strategy.
The reliability of self-reported sexual behaviour, The quality of data collected by surveys of sexual behaviour may be subject to sources of error involving reliability. validity. and non-participation bias. A preliminary study of sexual behaviour. including perception of risk for HIV infection. knowledge of HIV transmission and attitudes towards AIDS. was conducted in a genitourinary medicine clinic. The sample comprised 767 patients attending clinic over a 3-month period; comparisons were made between different methods of data collection (questionnaires and interviews) and between responders and non-responders. High levels of agreement were found between questionnaire and interview. Some sexual behaviours were more frequently reported at interview. No significant differences were found between responders and non-responders to either questionnaire or interview.
Mortality trends in Abidjan, Cote d'Ivoire, 1983-1988, To assess changes in mortality in Abidjan since the development of the AIDS epidemic. we compared official city mortality statistics and hospital fatality rates in 1983. before AIDS was recognized in Abidjan. with those in 1988. Review of records in the city's major hospitals showed that fatality rates (deaths per 1000 admissions) in adult medical patients increased by 54% between 1983 and 1988. with increases of 106 and 98% in men 20-29 and 30-39 years of age. respectively. and 199 and 42% in women of the same age ranges. Mortality rates in surgical patients showed little change. while in children they declined. Over the same period. official mortality statistics for the city showed reduced mortality rates in children and women 20-29 years of age. but an increase in mortality rates of 54% in men 20 years of age and older. and of 28% in women aged 30 years and older. HIV infection may be a major cause of the increased adult mortality documented in hospital and city records. and jeopardizes improved survival from preventive measures such as maternal and child health services.
High antibody titres in mice with polymethylmethacrylate nanoparticles as adjuvant for HIV vaccines, The aim of the present study was to determine the effect of polymethylmethacrylate (PMMA) nanoparticles as adjuvants for an HIV-2 whole-virus vaccine in mice. The data clearly revealed that PMMA nanoparticles induced 10-100-fold higher antibody titres than aluminium hydroxide or an aqueous vaccine control preparation as measured by enzyme-linked immunosorbent assay. Moreover. the high antibody titres obtained with PMMA as adjuvant appeared to be stable for between 10 and 20 weeks after immunization. In contrast. the titres of the control preparations. fluid or aluminium hydroxide formulations. decreased after 10 weeks.
Risk of transfusion-associated HIV transmission in Kinshasa, Zaire, Between 5 March and 12 April 1990. we assessed transfusion practices and the risk of transfusion-associated HIV transmission in all the hospitals and medical centres in Kinshasa. Zaire. Of the 733 hospitals and medical centres surveyed. 62 (8.5%) transfuse blood. Of 3741 units of blood transfused in February 1990. 1045 (27.9%) were not screened for HIV infection. Eighteen out of 62 centres (29%) received HIV test kits on a regular basis. Twenty of the centres (32.3%) recorded HIV test results. Major blood group cross-matching was done by 9.7% (six out of 62) of the centres. Bacteriological results indicated contamination in 17% (four out of 23) of stocked blood units. 6.4% (four out of 62) of solutions for disinfections. and 22% (13 out of 59) of sterilized instruments (possessed by 59 centres only). Transfusion practices in Kinshasa are associated with considerable health risks. The establishment and appropriate supervision of HIV screening facilities should be integrated into primary health-care programmes in order to increase safe transfusions in Kinshasa.
Plasma endothelin in human essential hypertension, Plasma endothelin immunoreactivity was measured in normal controls. in mild essential hypertensive patients with no antihypertensive treatment. in moderate to severe hypertensives whose blood pressure was controlled by treatment. and in moderate to severe hypertensives whose blood pressure was not controlled by treatment. Endothelin immunoreactivity levels in plasma in the four groups were similar. but had a positive correlation with blood pressure in hypertensives although not in normotensives. The concentration in plasma of both C-terminal and N-terminal atrial natriuretic peptide also had a positive correlation with blood pressure in these hypertensive patients. We conclude that if plasma immunoreactive endothelin levels represent the result of endothelial production of endothelin. in absence of changes in catabolism of the peptide. essential hypertensive patients do not appear to have increased production of endothelin.
Effects of substance P on norepinephrine release from vascular adrenergic neurons in spontaneously hypertensive rats, This study was performed to investigate the role of substance P in the vascular adrenergic transmission in hypertension. In perfused mesenteric vasculatures prepared from spontaneously hypertensive rats (SHR. 7 to 10 weeks old) and age-matched Wistar-Kyoto rats (WKY). we have examined the effects of substance P on vascular responsiveness as well as on norepinephrine release from the vascular adrenergic neurons. In preliminary studies with normotensive Wistar rats. pressor responses and endogenous norepinephrine release during electrical nerve stimulation were inhibited by substance P in a dose-dependent manner. However. vasoconstrictor responses to exogenous norepinephrine were not affected by the peptide. In SHR. the stimulation-evoked pressor responses and norepinephrine release were enhanced compared with WKY. Alternatively. the suppression of these responses by substance P was significantly less in SHR than in WKY. These results demonstrate that substance P could have a modulatory effect on noradrenergic activity and cause a decrease in stimulation-evoked norepinephrine release from the vascular adrenergic neurons. The attenuated reduction of pressor responses and norepinephrine release by substance P in SHR might suggest insufficient regulation of vascular adrenergic transmission by the peptide in hypertension.
Are angiotensin converting enzyme inhibition and aldosterone antagonism equivalent in hypertensive patients over fifty, The effects of inhibiting angiotensin converting enzyme with perindopril and aldosterone with spironolactone were tested in hypertensive patients over fifty. Accordingly. 75 patients with mild hypertension aged 50 to 70 were randomly divided into three groups for a double-blind 8 week comparison of the actions of placebo. 4 to 8 mg/day perindopril. and 37.5 to 75 mg/day spironolactone. Side-effects caused one patient to withdraw from placebo and one from spironolactone treatment. Mean blood pressure rose by 2.4 mm Hg after placebo but dropped by 7.4 and 8.6 after perindopril and spironolactone (P less than .01). Placebo. perindopril. and spironolactone did not alter blood glucose or plasma potassium. but induced. respectively. variations of -0.09. 0. and +0.34 mmol/L in cholesterol (P = .04). and -0.02. -0.05. and +0.27 mmol/L in triglycerides (P less than .01). After the three treatments. changes in angiotensin converting enzyme activity averaged -1. -6. and -1 mU/mL (P less than .01). in active renin -2. +18. and +28 pg/mL (P less than .01). and in aldosterone. +15. +8. and +95 pg/mL (P less than .01). Placebo. perindopril. and spironolactone did not alter microalbuminuria. but reduced urinary kallikrein activity by 0.9. 1.8. and 5.4 mU/mmol creatinine (P = .04). Although short-term administration of spironolactone raised renin and aldosterone markedly and lipids moderately (possibly because of volume contraction). the present results show that perindopril and spironolactone are both safe and effective for treating hypertension at the age of 50 or older.
Assessment of quality of life by patient and spouse during antihypertensive therapy with atenolol and nifedipine gastrointestinal therapeutic system, To evaluate differences in efficacy. safety. and quality of life. 394 male patients with mild-to-moderate hypertension were randomized to receive 20 weeks of either atenolol or nifedipine gastrointestinal therapeutic system (GITS) in a multicenter double-blind trial. A four-week placebo washout was followed by 8 weeks of titration and 12 weeks of maintenance therapy. Quality-of-life evaluation included clinical assessments by the patient and parallel take-home assessments by patient and spouse. Blood pressure was controlled equally in both groups. The total incidence of adverse reactions was similar in both groups. but a greater percentage of nifedipine GITS patients withdrew due to peripheral edema. Patients completing 20 weeks of therapy demonstrated a more favorable quality-of-life profile (P less than .05) for nifedipine GITS over atenolol in psychosocial (P less than .01). well-being (P less than .05). general affect (P less than .05). emotional ties (P less than .01). emotional control (P less than .05). vitality (P less than .05). and leisure (P less than .05) scores. Treatment differences were particularly pronounced for patients over 50 years of age and were not fully detectable until after 14 weeks of therapy. Deterioration in quality of life was associated with withdrawal. Spouses of younger patients receiving atenolol reported deterioration in sexual satisfaction as compared to spouses of patients taking nifedipine GITS (P less than .02). Thus age. length of trial. and third-party observation are important factors in quality-of-life assessment. Comparison of adverse reactions provides an incomplete measure of how well a drug is tolerated. In contrast. findings indicate that even subtle CNS-mediated effects on mood and well-being can be detected by quality-of-life evaluation.
What is the role of the central nervous system in mineralocorticoid hypertension, The importance of the central nervous system (CNS) in the development of mineralocorticoid hypertension has been well documented. Type I receptors in adrenalectomized rats are concentrated in the hippocampus. amygdala. lateral septum. and hypothalamus. particularly in the periventricular regions. areas known to be or suspected of being important in the regulation of ACTH release. arousal. fluid and fluid osmolality equilibrium. and the maintenance of normal blood pressure. In the rat. ablation of the AV3V area and central. but not peripheral. sympathectomy prevent the development of DOCA-salt hypertension. The continuous intracerebroventricular (icv) infusion of aldosterone in rats or dogs at doses which do not affect the blood pressure when administered subcutaneously (sc) produces significant increases in resting blood pressure. In rats this effect is dose dependent. blocked by the concomitant icv infusion of prorenone. an aldosterone antagonist. and enhanced. but not completely dependent upon renal mass reduction and excess salt consumption. The icv infusion of RU28318. a selective mineralocorticoid antagonist. at doses which are ineffective when administered sc. inhibits the development of hypertension produced by the sc infusion of aldosterone or deoxycorticosterone. as well as that produced by the oral administration of a licorice derivative and of a high salt diet in the Dahl S/JR rat. It is assumed that this effect is mediated through the mineralocorticoid receptor because it is inhibited by mineralocorticoid antagonists and because the icv infusion of RU26988. a selective glucocorticoid agonist. has no effect. The concomitant icv infusion of corticosterone. which is thought to be the primary ligand of the brain mineralocorticoid receptor. antagonizes the effect of icv infusion of aldosterone.
Role of endogenous endothelin in the development of hypertension in rats, To further elucidate the pathophysiologic role of endogenous endothelin (ET). we have studied the chronic effect of anti-ET gamma-globulin on the development of hypertension in spontaneously hypertensive rats (SHR) and stroke prone SHR (SHR-SP) for three weeks. In neither SHR nor SHR-SP did repetitive bolus injection of anti-ET gamma-globulin suppress the rise in blood pressure. The present data suggest that endogenous ET is not likely to play a key role in the development of hypertension. although ET may induce a local vasoconstriction at the injured vascular wall.
Immunohistological demonstration of intermediate trophoblast in the diagnosis of uterine versus ectopic pregnancy: a retrospective survey and results of a prospective trial, Immunohistological demonstration of human placental lactogen (hPL) in non-villous. mononuclear intermediate trophoblastic cells may be of routine diagnostic value. when chorionic villi are absent in endometrial curettings from patients suspected of miscarriage of an intrauterine pregnancy. The histological presence and distribution of hPL was investigated in endometrial curettings from 90 patients studied retrospectively (47 had ectopic pregnancies. 14 miscarriages. and 29 legal abortions). and a consecutive. prospective series of 50 patients (40 had miscarriages and 10 had ectopic pregnancies) without chorionic villi in their endometrial curettings. Non-specific background staining was not a problem. The retrospective survey disclosed that hPL was a highly sensitive marker of intrauterine pregnancy (sensitivity = 0.98). In the prospective series. the predictive value of positive staining for hPL for intrauterine pregnancy was 1.00. and the sensitivity of hPL. as an indicator of uterine gestation. was 0.62. In absence of specific hPL-staining. the risk of ectopic pregnancy was about 50%. The immunohistochemical demonstration of hPL is a useful tool for identifying patients who are suspected of having had a miscarriage. but for whom evidence in the form of chorionic villi in endometrial curettings is lacking.
The use of Histoacryl for episiotomy repair, Histoacryl-tissue adhesive (B. Braun Melsungen AG W. Germany) was used in place of skin sutures (2/0 chromic catgut. Ethicon Ltd. Edinburgh. Scotland) for episiotomy repair in a group of 20 women. This group was compared with two groups of women undergoing first and repeat episiotomy. Variables analysed included pain in the episiotomy site. pain while walking. sitting. sleeping. lying down. breast-feeding. micturating and defaecating. The Histoacryl group was superior with regard to all the variables. This simple. new method can reduce pain and inconvenience for patients. especially following the first delivery.
Gastric cancer in Scotland: changing epidemiology, unchanging workload, OBJECTIVE--To determine the changes in incidence of and mortality from gastric cancer in Scotland between 1978 and 1987 and in the operative workload in Lothian between 1979 and 1988. DESIGN--Analysis of national incidence statistics for gastric cancer derived from the Scottish national cancer registry. deaths from gastric cancer recorded by the registrar general for Scotland. and Lothian surgical audit data. SETTING--Scotland and Lothian Health Board area. PATIENTS--Patients in Scotland with gastric cancer during 1978 to 1987 inclusive; patients in Scotland with gastric cancer recorded on their death certificate as cause of death during 1978 to 1987; patients who had an operation in Lothian for gastric cancer during 1979 to 1988. MAIN OUTCOME MEASURES--Changes in incidence of and mortality from gastric cancer in Scotland from 1978 to 1987 and in the number of operations performed for gastric cancer in Lothian from 1979 to 1988. RESULTS--Mortality from gastric cancer in Scotland fell by about 25% over the 10 years. The incidence and standardised incidence of gastric cancer showed a marginal decline of about 9%. The differences in trends between incidence and mortality were significant (p less than 0.05). CONCLUSIONS--This study shows that the surgical workload associated with gastric cancer is not declining. This is because the incidence has remained almost static. which may be due to the relative increase in the numbers of older people in the population. who are at greater risk of developing gastric cancer. Gastric cancer should not be regarded as a disease in decline. Incidence and workload should determine resources allocated to this disease rather than mortality statistics.
Rapid one step urine test for human chorionic gonadotrophin in evaluating suspected complications of early pregnancy, OBJECTIVE--To determine the ability of a sensitive one step urine test to detect human chorionic gonadotrophin in women with suspected complications of early pregnancy. DESIGN--Test on women presenting to accident and emergency department with gynaecological problems over six months. Results were validated using a quantitative assay for human chorionic gonadotrophin in serum and urine. SETTING--Accident and emergency department and gynaecology wards of a university teaching hospital. SUBJECTS--130 unselected women. MAIN OUTCOME MEASURES--Detection of human chorionic gonadotrophin by one step test. presence of ectopic pregnancy. and results of quantitative analysis of chorionic gonadotrophin in serum and urine. RESULTS--79 women had a positive urine test result and 51 a negative result. All 12 women with ectopic pregnancy had a positive test result. although urinary concentration varied from 191 IU/l to 47.800 IU/l. Only one woman. who had a faintly positive result. was found not to be pregnant on subsequent examination. The sensitivity and negative predictive values of the urine test were 100% respectively. 33 women were sent home from the accident and emergency department with normal clinical findings after a negative urine test result. All these women had undetectable concentrations of chorionic gonadotrophin in matched samples of urine and serum. CONCLUSIONS--A simple. rapid one step test for chorionic gonadotrophin should be available for the initial evaluation of emergency gynaecological problems. The additional cost of the test is offset by not admitting those patients whose clinical findings are normal and who have a negative urine test result and by reducing the number of women requiring quantitative assays of chorionic gonadotrophin.
Rationalising the management of swallowed coins in children, OBJECTIVE--To assess the management of swallowed coins in children and identify aspects that could be improved. DESIGN--Study of records of three hospital departments for 1986-90. SETTING--Accident and emergency. radiology. and operating theatre departments in a children's hospital. SUBJECTS--50 children reported to have ingested coins. MAIN OUTCOME MEASURES--Radiological investigations performed. position of coin. symptoms of child. and surgical intervention. RESULTS--50 children were recorded to have swallowed coins during 1986-90. Five children had only chest radiography. five only abdominal radiography. and 40 had both. A coin was detected in the oesophagus in 15 children. six of whom had symptoms. and below the cardia in 26. none of whom had symptoms; no coin was seen in nine children. Eleven children had further abdominal radiographs despite the absence of gastrointestinal symptoms; one child had a coin removed from the stomach. CONCLUSIONS--Children are being unnecessarily exposed to radiation and surgical intervention. and a consensus on management of swallowed coins is needed. Most children require only a single chest and neck radiograph.
Decline in ischaemic heart disease in Iceland and change in risk factor levels, OBJECTIVE--To monitor trends in mortality and morbidity due to ischaemic heart disease and compare these with observed levels of risk factors from population surveys. DESIGN--Analysis of trends in death rates from ischaemic heart disease in Iceland compared with expected rates computed from population surveys. Risk factor levels together with beta factors obtained from Cox's regression analysis were used to compute expected death rates. Trends in morbidity due to acute myocardial infarction were assessed and secular trends in dietary consumption compared with trends in cholesterol concentrations. SETTING--Reykjavik. Iceland (total population 250.000; over half the population live in Reykjavik). SUBJECTS--12.814 randomly selected residents in the Reykjavik area aged 45-64 (6623 men. 6191 women; 72% and 80% of those invited). MAIN OUTCOME MEASURES--Age adjusted rates of myocardial infarction and deaths from ischaemic heart disease. Expected risk from risk factor levels (smoking. total serum cholesterol concentration. systolic blood pressure) at each unique survey visit. RESULTS--Mortality from ischaemic heart disease has decreased by 17-18% since 1970. During 1981-6 the myocardial infarction attack rate in men under 75 decreased by 23%. A decrease occurred in the level of all three major risk factors after 1968. The fall in the serum cholesterol concentration coincided with a reduction in consumption of dairy fat and margarine. The calculated reduction in risk for the age group 45-64 was about 35%. which was closely similar to the observed decrease in mortality due to ischaemic heart disease in that age group. CONCLUSION--The reduction in mortality from ischaemic heart disease was substantially due to a decreased incidence of myocardial infarction and could be attributed largely to the reduction in risk factors.
Open access clinic providing HIV-I antibody results on day of testing: the first twelve months, OBJECTIVES--To determine the sociodemographic profile. risk category. and prevalence of HIV-I infection among people attending a clinic providing counselling. medical advice. and results of HIV-I antibody testing on the day of consultation; to determine the stage of infection and peripheral blood CD4 cell count among attenders with detectable HIV-I antibodies. DESIGN--Analysis of prospectively collected data for the 12 months from March 1989. SETTING--Same day testing clinic run by the HIV/AIDS team at an urban teaching hospital. PATIENTS--561 consecutive people choosing to attend and proceeding to HIV-I testing. RESULTS--The demand for the service caused it to run to capacity within six months. The median age of those attending was 28 years and 65% (364 patients) were male. The overall prevalence of HIV-I infection was 3.9% (22 patients). The greatest prevalence was in men reporting their primary risk as homosexual contact (11.9%. 13/109). The median CD4 cell count in the 22 patients who had detectable HIV-I antibodies was 0.31 x 10(9) cells/l (normal range 0.5 x 10(9)/l to 1.2 x 10(9)/l). Twenty of these patients were asymptomatic (Centers for Disease Control stages II or III). 14 had CD4 cell counts below 0.5 x 10(9)/l. CONCLUSIONS--There is a recognisable demand for a service providing rapid results of HIV-I antibody testing in this setting. The overall seroprevalence of 3.9% is comparable with the 5.8% reported from freestanding clinics in the United States. Most patients with HIV-I antibodies detected in this way are asymptomatic but could benefit from early medical intervention because of low CD4 cell counts.
Role of interstitial therapy in the treatment of liver cancer, Conventional palliative management of inoperable focal hepatic tumours remains unsatisfactory. Interstitial techniques such as cryotherapy. alcohol injection. low power laser hyperthermia and interstitial radiotherapy offer alternative approaches. Cryotherapy is an effective and precise technique for inducing tumour necrosis. It can only be performed at laparotomy making it relatively invasive and retreatment impractical. Alcohol is cheap and can be injected percutaneously. However. inhomogeneous distribution produces imprecise and nonreproducible lesions. Low power laser hyperthermia produces precise and reproducible areas of necrosis that are roughly spherical in shape. At present. this technique is most effective for small tumours. Interstitial radiotherapy remains the least evaluated of all the interstitial techniques. Unlike cryotherapy and low power laser hyperthermia. the biological effect of ethanol injection and interstitial radiotherapy cannot be monitored in real time by ultrasound. With the exception of cryotherapy. all methods can be applied percutaneously with low morbidity and mortality. None of these techniques is established. but they may offer the prospect of cure in cases where all areas of tumour can be positively identified and fully treated. However. in most instances the intention is to control the growth of relatively small discrete volumes of tumour within the hepatic parenchyma.
Steroid receptors in breast cancer, Recent advances in steroid receptor structure and function now indicate that oestrogen binds to the oestrogen receptor (ER) molecule at a specific site. denoted region E. This allows binding of the oestrogen-ER complex to DNA via cysteine residues in region C of the ER molecule. which tetrahedrally co-ordinate zinc. This modulates transcription and stimulates cell growth. A number of newly discovered growth factors are also regulated by ER. as is the progesterone receptor. Steroid receptor concentrations in tissues can now be measured on smaller tissue samples using enzyme immunoassay or on cells obtained by fine needle aspiration using monoclonal antibody technology. The prognostic value of steroid receptor is limited. but still constitutes the best marker for predicting response to endocrine therapy. The role of steroid receptors in selecting patients for adjuvant therapy is discussed.
Insights gained from the management of problematical anal fistulae at St. Mark's Hospital, 1984-88, Twenty-four (3.6 percent) patients with problematical anal fistulae out of 671 with anal fistulae were analysed to assess the reasons for their recurrences and ultimate outcome. Thirteen patients (group A) had recurrent fistulae despite two definitive attempts at surgery at this hospital (median number of previous procedures before referral to this hospital was two. range 0-7; median number of definitive procedures at this hospital was three. range 3-4). In five of these patients. the reason for recurrence was missed primary (four cases) or secondary tracks (one case) at earlier operations. Five patients required multiple operations related to the use of setons. Eleven other patients (group B) required colostomy construction. eight because of severe perianal sepsis. two because of complex fistulae. and one for postrectal dermoid. Fistula healing occurred ultimately in all patients in group A after a median of 14 months (range 4-38 months). In group B. fistula healing occurred in eight patients after a median of 7.5 months (range 2-55 months) after colostomy construction. Only one patient has had a proctectomy. and five still have their colostomy. Of the other 18 patients. continence is normal in 14. there is mucus leakage in two. flatus incontinence in one and faecal incontinence in one. In conclusion. persistent attempts to resolve anal fistulae in difficult cases are frequently successful in the long term and result in good continence.
Risks of leaving the gallbladder in situ after endoscopic sphincterotomy for bile duct stones, There is controversy concerning the subsequent clinical course of patients whose gallbladder is left in situ following successful endoscopic removal of stones from their common bile ducts. A total of 191 patients (median age 76 years) were reviewed between 12 and 100 months (mean 38 months) after endoscopic sphincterotomy. Ten patients (5.2 per cent) had symptoms requiring cholecystectomy which was uneventful. nine in the first year. Cholangitis at presentation or failure to fill the gallbladder by endoscopic retrograde cholangiography were not helpful in identifying these patients. Forty-nine (25.6 per cent) patients died during the review period from non-biliary pathology (usually cardiovascular). Elective cholecystectomy is not required in elderly patients with symptomatic bile duct stones if the common bile duct can be cleared of stones after endoscopic sphincterotomy.
Combined surgical and interventional radiological approach for complex benign biliary tract obstruction, In patients with complicated high benign biliary strictures surgical technique alone cannot exclude the possibility of recurrent problems. and hepatic atrophy/hypertrophy. portal hypertension and intrahepatic stones may all complicate surgical management. A multidisciplinary approach to these complex cases. which minimizes the need for repeated surgical interventions. has been pursued. Roux-en-Y hepaticojejunostomy was performed and an extended limb of the jejunum brought to the abdominal wall to allow access for later radiological intervention. Over a 30-month period 58 biliary-enteric anastomoses for benign disease were performed. Seventeen of these 58 patients were managed using the combined approach. Ten of these 17 patients had complex postcholecystectomy strictures and seven had strictures resulting from inflammatory disease. hepatic resection or congenital problems. A new classification of results of management of bile duct strictures is proposed. Seven patients were classified as 'excellent'. six 'good'. two 'fair' and two 'poor'. Results were obtained at a mean follow-up of 16 months and it seems likely that in some patients major surgical reinterventions were avoided.
Primary sclerosing cholangitis: surgical options, prognostic variables and outcome, The natural history of primary sclerosing cholangitis (PSC) is poorly defined and its management remains controversial. Forty-eight symptomatic patients (median age 39 years. range 8-67 years; 30 male) with PSC were reviewed retrospectively. Thirty patients had inflammatory bowel disease. Four patients (8 per cent) developed or had an associated malignancy. Twenty-one (44 per cent) died; overall 5 year actuarial survival was 30 per cent. Twenty-three patients had 27 non-transplant related biliary operations (16 patients specifically for PSC) of whom 12 died. Serum bilirubin was the only parameter to improve after biliary surgery. Seventeen patients (35 per cent) underwent orthotopic liver transplantation (OLT) of whom nine are currently alive (1 year projected survival of 55 per cent). Previous biliary surgery correlated with a poor outcome (P less than 0.0001) after OLT. Being male. presence of cirrhosis. duration of symptomatic disease (greater than 3 years) and a serum bilirubin level greater than 100 mumol/l at presentation. were independently associated with a poor outcome (P less than 0.05). These data provide evidence that PSC is a progressive disease and conventional surgical options have little influence on the outcome. Previous biliary surgery adversely affects outcome following OLT. For progressive liver disease. liver transplantation should be considered the treatment of choice.
Effects of relief of biliary obstruction on mononuclear phagocyte system function and cell mediated immunity, Obstructive jaundice causes depression of immune system function but it is unclear at present how rapidly immune function recovers after relief of biliary obstruction. To address this issue. we studied 218 Sprague-Dawley rats with common bile duct obstruction. Mononuclear phagocyte function. cell mediated immune function. portal-systemic shunt fraction. liver function tests. and liver histology were evaluated in normal (sham) rats. obstructed rats. and at weekly intervals after relief of biliary obstruction. Hepatic uptake of radiolabelled bacteria was 82 per cent in sham rats and 66 per cent in rats 21 days after CBD obstruction (P less than 0.05). Phagocytic activity returned to normal within 7 days after choledochoduodenostomy. Cell mediated immunity. measured by skin graft rejection. was significantly prolonged in the obstructed group (P less than 0.05) but had returned to normal 7 days after biliary diversion. Return of hepatocellular function. as measured by liver function tests. paralleled recovery of immune function. This study demonstrates prompt recovery of the immune system after internal biliary drainage for obstructive jaundice. This finding is in contrast to previous studies that demonstrated persistent immune suppression months after biliary diversion. These data may have implications concerning the usefulness of internal biliary drainage before surgery in patients with obstructive jaundice.
Treatment of oesophageal perforation: a multivariate analysis, Perforation of the oesophagus was retrospectively analysed in 59 patients. Cause and extent of perforation. localization. quality of the oesophageal wall and therapeutic modes were subjected to univariate analysis. The perforations of the intrathoracic oesophagus (39) were also subjected to multivariate analysis. Perforation of the cervical oesophagus is seldom lethal and can be adequately treated conservatively in the majority of cases. Perforations of the intrathoracic oesophagus can be divided into two groups. with or without simultaneous perforation of the parietal pleura. The optimal treatment for the group with pleural perforation seems to be resection of the oesophagus and secondary reconstruction. although primary closure is indicated in selected early cases. Perforations of the intrathoracic oesophagus confined to the mediastinum can be adequately treated conservatively in most patients. Perforation of the intra-abdominal oesophagus should be treated like any other intra-abdominal visceral perforation. by closure or diversion. even if this results in resection of the oesophagus.
Preoperative localization of parathyroid tumours does not reduce operating time, Accurate preoperative localization of abnormal parathyroid glands might be expected to result in a reduction in operating time. To test this hypothesis the duration of surgery was recorded in a consecutive series of 50 patients who underwent neck exploration after preoperative localization by thallium-201 and technetium-99m subtraction scanning and were found to have parathyroid tumours. A total of 34 patients had accurate localization by the scan. and these patients had a median operating time of 90 min. When the tumour had not been localized before operation. the median operating time was not significantly different (80 min). Accurate preoperative localization of parathyroid tumours does not reduce operating time.
Breast cancer in elderly women: a Cancer Research Campaign trial comparing treatment with tamoxifen and optimal surgery with tamoxifen alone. The Elderly Breast Cancer Working Party, Three hundred and eighty-one women with operable breast cancer aged over 70 years were randomly allocated to 40 mg tamoxifen daily and optimal surgery or to tamoxifen alone. At a median follow-up of 34 months there was no demonstrable difference in survival rate or in quality of life between the two treatment groups. More patients treated with tamoxifen alone had a subsequent change of management and this was usually an operation for local treatment failure. This progression to surgery has not been shown to be disadvantageous and the study will continue. Informed consent for randomization was difficult to obtain. leading to the exclusion of eligible patients. and it is therefore proposed to include non-randomized patients in a total cohort study.
In situ venous valve construction, A technique of in situ deep venous valve construction based on vein wall intussusception is described. The technique has been used to construct a size-matched. autogenous valve in the femoral vein of the dog. Forty-one valves have been constructed. Immediately after construction. all 41 were patent at ascending phlebography and Harvey's test showed them to be competent. Descending phlebography demonstrated competence in 38 valves. Hydrostatic testing was performed on 27 valves in the vertical position at pressure gradients in the range 0.2-250 cmH2O. Of these. 24 valves were fully competent. Six valves were studied at intervals between 1 and 112 days after construction. All six were competent by Harvey's test and five were competent at descending phlebography. There was no evidence of thrombosis in any valve. This technique may be suitable for replacement of deep venous valves in patients with the calf pump failure syndrome caused by deep venous reflux.
Comparison of duplex ultrasonography and venography in the diagnosis of deep venous thrombosis, Sixty-five patients with suspected deep venous thrombosis (DVT) in 68 limbs were entered consecutively into a study to compare venography with duplex ultrasonography scanning. Both tests were performed on 64 limbs. venography being contraindicated in four. Overall. duplex scanning correctly identified 86 per cent of DVTs diagnosed on venography and correctly excluded 80 per cent with negative venograms. Nearly all errors arose in the diagnosis of calf DVT. In the femoral vein duplex scanning had a specificity of 100 per cent and a sensitivity of 95 per cent. In addition. duplex scanning provided data on the limb not undergoing venography. Of 55 limbs that underwent bilateral duplex scanning. five had thrombus in the femoropopliteal segment and a negative contralateral venogram. In addition. three Baker's cysts were diagnosed. Duplex scanning can be used in patients in whom venography is contraindicated and may also provide information about the contralateral limb. We regard femoropopliteal duplex scanning as sufficiently accurate that treatment can be initiated on the basis of the scan. Duplex scanning should replace venography as the standard method of diagnosing femoropopliteal DVT; radiographic studies should now be required only when the scan result is in doubt.
Limitations of ultrasonography in surveillance of small abdominal aortic aneurysms, The repeatability. observer bias and instrument bias of aortic diameter measurement by ultrasonography. were investigated in ten patients with small (3-6 cm by computed tomography) infrarenal abdominal aortic aneurysm. The repeatability of maximum aortic diameter measurement by ultrasonography was much better for anterior-posterior than transverse diameter. with coefficients of repeatability 3.0-7.5 mm and 10-15 mm respectively. The repeatability of suprarenal aortic diameter measurement was poor. Surprisingly. maximum diameter using ultrasonography was larger than that using computed tomography. the difference being least for anterior-posterior measurements. At best a single. experienced observer. using the same instrument may provide aortic diameters using ultrasonography accurate to within 5 mm. but more commonly such aortic diameter is only accurate to within 8 mm.
Haemodynamic significance of incompetent calf perforating veins, A total of 149 consecutive unselected patients (221 limbs) who presented with signs and symptoms of chronic venous problems (varicose veins with or without ankle oedema. skin changes and leg ulcers) have been studied by clinical examination. ascending deep to superficial venography. Doppler ultrasound and ambulatory venous pressure measurements. Of the limbs. 180 (82 per cent) had varicose veins without obstruction in the deep veins or reflux in the popliteal or femoral veins while 41 (18 per cent) had deep venous disease. Of the 180 limbs with 'primary' varicose veins 110 (60 per cent) did not have incompetent calf perforating veins (group A) while 70 (40 per cent) did (group B). On the basis of the ambulatory venous pressure after calf muscle exercise and the refilling time. the incompetent calf perforating veins of limbs in group B belonged to three subgroups of different haemodynamic significance. In 20 limbs (30 per cent) they were found to be of no haemodynamic significance. in 25 (35 per cent) of moderate haemodynamic significance and in 25 (35 per cent) of major haemodynamic significance. The last were. on clinical examination. indistinguishable from limbs with deep venous disease although they had patent deep veins with competent popliteal valves.
Preoperative evaluation of the cardiac patient for noncardiac surgery, In summary. obtaining a comprehensive patient history is a critical part of the diagnostic and risk stratification process of the patient with cardiac disease undergoing non-cardiac surgery. Many of the factors associated with perioperative cardiac morbidity are treatable and early and aggressive management appears to have beneficial effects on morbidity and mortality rates.
Histopathologic validation of angioscopy and intravascular ultrasound, BACKGROUND. To establish a histopathologic basis for angioscopic and ultrasound image interpretation we studied 70 postmortem human arterial segments in vitro. METHODS AND RESULTS. We used 7- to 9-French fiber-optic angioscopes and 20- to 30-MHz intravascular ultrasound imaging catheters. Three observers assigned an angioscopic and ultrasound image classification to each vessel segment. The image and histological classification categories were then compared. The sensitivity. specificity. and accuracy of both methods separately or in combination for normal vessels were each greater than or equal to 95%. The predictive value was better for angioscopy than for ultrasound due to incorrect ultrasound interpretations of normal anatomy in the presence of thrombus. For stable atheroma the sensitivity. specificity. and accuracy of the individual methods were each greater than 90%. However. both angioscopy and ultrasound had classification errors in that disrupted atheroma was identified and classified as stable atheroma. Consequently. the predictive value was 74% for angioscopy and 78% for ultrasound. For disrupted atheroma the sensitivities for angioscopy and ultrasound were only moderate (73% and 81%. respectively). whereas the specificity. accuracy. and predictive value were each high (greater than 90%). For thrombus detection. the specificity. accuracy. and predictive value were high (greater than 93%) for each method. The sensitivity of angioscopy was 100%. However. sensitivity was lower for ultrasound (57%) due to false-negative interpretation of laminar clots in normal vessels and an inability to distinguish disrupted or stable atheroma from intraluminal thrombus. CONCLUSIONS. Contingency analyses showed that each imaging method alone or combined had significant agreement with the results obtained from histology (p less than 0.001). When assessing all cases in which angioscopy and ultrasound were concordant. there was a 92% agreement with the histological classification.
Metabolic basis of primary hypercholesterolemia, BACKGROUND. Hypercholesterolemia is a well-established risk factor for coronary heart disease. However. the mechanisms underlying hypercholesterolemia. elevated low density lipoprotein (LDL) in particular. are not well understood. To determine these mechanisms. we studied LDL kinetics in a group of men with primary hypercholesterolemia. METHODS AND RESULTS. LDL kinetics in 134 middle-aged men with high-risk levels of LDL cholesterol (more than 160 mg/dl) were compared with kinetics in 16 men with borderline high-risk levels of LDL cholesterol (120-159 mg/dl) and 14 men with heterozygous familial hypercholesterolemia (FH). Patients with primary hypercholesterolemia (non-FH) were further divided into moderate hypercholesterolemia (LDL cholesterol. 160-210 mg/dl; n = 108) and severe hypercholesterolemia groups (LDL cholesterol. more than 210 mg/dl; n = 26). Four factors contributed to increasing LDL cholesterol concentrations above the borderline range to moderately elevated levels: 37 patients had no increase in LDL apolipoprotein (apo) B levels but had abnormally high LDL cholesterol-to-apo B ratios; 14 patients had very low fractional catabolic rates (FCRs) for LDL. similar to FH patients; 35 patients had FCRs for LDL in the borderline range but high production rates for LDL; and 22 patients had a high flux of LDL (high production rates and high FCRs). In general. patients with severe hypercholesterolemia resembled those with moderate LDL elevations. except that their LDL particles were enriched with cholesterol. CONCLUSIONS. Data from the present study reveal that there are several distinct patterns of LDL metabolism responsible for primary hypercholesterolemia. These patterns can serve as the basis for further investigation to determine the molecular defects responsible for each pattern.
HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men, BACKGROUND. We investigated the association of cholesterol concentrations in serum high density lipoprotein (HDL) and its subfractions HDL2 and HDL3 with the risk of acute myocardial infarction in 1.799 randomly selected men 42. 48. 54. or 60 years old. METHODS AND RESULTS. Baseline examinations in the Kuopio Ischaemic Heart Disease Risk Factor Study were done during 1984-1987. In Cox multivariate survival models adjusted for age and examination year. serum HDL cholesterol of less than 1.09 mmol/l (42 mg/dl) was associated with a 3.3-fold risk of acute myocardial infarction (95% confidence intervals [CI]. 1.7-6.4). serum HDL2. cholesterol of less than 0.65 mmol/l (25 mg/dl) was associated with a 4.0-fold risk of acute myocardial infarction (95% CI. 1.9-8.3). and serum HDL3 cholesterol of less than 0.40 mmol/l (15 mg/dl) was associated with a 2.0-fold (95% CI. 1.1-4.0) risk of acute myocardial infarction. Adjustments for obesity. ischemic heart disease. other cardiovascular disease. maximal oxygen uptake. systolic blood pressure. antihypertensive medication. serum low density lipoprotein cholesterol. and triglyceride concentrations reduced the excess risks associated with serum HDL. HDL2. and HDL3 cholesterol in the lowest quartiles by 52%. 48%. and 41%. respectively. Additional adjustments for alcohol consumption. cigarettes smoked daily. smoking years. and leisure time energy expenditure reduced these excess risks associated with low HDL. HDL2. and HDL3 cholesterol levels by another 26%. 24% and 21%. respectively. CONCLUSIONS. Our data confirm that both total HDL and HDL2 levels have inverse associations with the risk of acute myocardial infarction and may thus be protective factors in ischemic heart disease. whereas the role of HDL3 remains equivocal.
Relation of arteriographically defined coronary artery disease to serum lipoprotein particles mapped with monoclonal antibodies, BACKGROUND. This study was designed to investigate the relation of a molecular analysis of apolipoprotein B (apoB)-containing atherogenic lipoprotein particles to coronary artery disease (CAD) in middle-aged men. METHODS AND RESULTS. Two groups of men were studied. The first consisted of 97 patients with angiographically documented CAD (greater than 50% stenosis of at least one coronary artery). The second group consisted of 145 subjects without symptomatic CAD. who served as controls. In both groups. measurements were obtained for total cholesterol level. triglyceride level. cholesterol contents in apoB- and nonapoB-containing particles (LpB. LpnonB). total apoB and apolipoprotein AI (apoAI levels). lipoprotein particles recognized by monoclonal antibodies anti-apoB (LpBL3. LpBL5. LpBL7) and anti-apoAI (LpAI-2GII). Taking into account age. body mass index. hypertension. diabetes. smoking habits. and drug consumption. the analysis showed that the mean levels of cholesterol were identical in both groups but differed when cholesterol content in LpB and LpnonB subfractions were assessed. thus reflecting an increase in the low density fraction and a decrease in the high density fraction. respectively. This was confirmed by an increase in total apoB and a decrease in total apoAI. Measurements of LpBL3. LpBL5. LpBL7. and LpAI-2GII particles also discriminated between the two groups. After adjustment for cholesterol content in LpnonB particles. a difference in total apoB was no longer significant between groups. whereas LpBL3. LpBL5. and LpBL7 levels remained significantly higher in CAD patients. CONCLUSIONS. The measurement of separate concentrations of apoB in different particles may permit a more-accurate assessment of CAD risk than measurements of total apoB levels.
Racial (black-white) differences in serum lipoprotein (a) distribution and its relation to parental myocardial infarction in children. Bogalusa Heart Study, BACKGROUND. The value of lipoprotein (a) [Lp(a)] in the prediction of coronary artery disease risk very early in life remains to be established in different racial groups. METHODS AND RESULTS. Serum Lp(a) distribution and its relation to parental histories of myocardial infarction were examined in 2.438 children (8-17 years old) from a biracial community. Parental myocardial infarction was used as a surrogate measure of future risk of disease in the offspring. Lp(a) levels averaged 1.7-fold higher in blacks than in whites (p less than 0.0001). A small but significant sex difference (females greater than males. p less than 0.05) was seen in both races. Race was the only independent variable that contributed appreciably (9%) to the variability of Lp(a) in serum. White children with parental myocardial infarction (n = 90) had increased levels of Lp(a) compared with those without parental myocardial infarction (22.4 versus 17.1 mg/dl. p less than 0.01). Furthermore. among white children. the prevalence of parental myocardial infarction was higher in those with Lp(a) levels of more than 25 mg/dl than in those with values of 25 mg/dl or less (9.5% versus 5.4%. p less than 0.01). In contrast. the relation of Lp(a) to parental myocardial infarction was not seen in black children. No associations were observed between parental myocardial infarction and serum levels of any of the lipids or lipoprotein cholesterol classes in children of either race. CONCLUSIONS. Serum Lp(a) levels may prove valuable in the assessment of coronary artery disease risk early in life among white populations. These findings also emphasize the need to evaluate the atherogenic potential of Lp(a) in different racial groups.
Prospective evaluation of the risk of bacteremia associated with transesophageal echocardiography, BACKGROUND. Transient bacteremia may lead to endocarditis in patients with significant valvular lesions. METHODS AND RESULTS. Because transesophageal echocardiography selects a patient population with a high prevalence of valvular lesions. we prospectively evaluated the risk of transient bacteremia associated with transesophageal echocardiography in 49 patients. Blood cultures were obtained immediately before transesophageal echocardiography and at 5. 10. and 20 minutes after the start of the procedure. For each culture. 30 ml venous blood was obtained and 10 ml was inoculated into each of an Isolator tube. Septi-chek bottle. and a nonvented Trypticase soy broth bottle. Broth cultures were incubated for 14 days. Blood from the Isolator tube was plated onto appropriate media for recovery of bacteria and fungi. Two patients were excluded from analysis because the final two sets of blood cultures could not be obtained. Among the remaining 47 study patients. two preprocedure control blood cultures were positive. and two of 141 subsequent cultures were positive. All isolates were considered contaminants. Thus. we found no significant bacteremia due to pathogenic oral flora during transesophageal echocardiography (0%; 95% CI. 0.0-7.5%). CONCLUSIONS. Although recommendations for antimicrobial prophylaxis for transesophageal echocardiography should be individualized for each patient. many patients may not require antimicrobial prophylaxis.
Effects of drive train stimulus intensity on ventricular refractoriness in humans, BACKGROUND. The strength-interval relation between the intensity of premature stimulus and the ventricular effective refractory period (VERP) has been well characterized. The effects of variation in the intensity of the basic drive train stimuli (S1) on VERP are not as well defined. This relation was studied in 44 patients undergoing clinically indicated electrophysiological study. METHODS AND RESULTS. The outputs of two stimulus isolation units were connected in parallel. allowing the intensity of S1 to be varied independently of intensity of the extrastimulus (S2). To prevent confounding effects from cycle length change. continuous overdrive pacing was performed for 3 minutes before each measurement of VERP. The effect of S1 intensity on VERP was assessed in 24 patients with S2 intensity kept constant at twice threshold. VERP shortened from 232 +/- 19 msec at an S1 intensity of 1.5 times threshold to 219 +/- 20 msec at 5 mA and 211 +/- 19 msec at 10 mA (p less than 0.0001 for baseline versus 5 mA and for 5 mA versus 10 mA). Autonomic blockade with atropine and propranolol blunted but did not completely eliminate this effect. To assess whether the effect of S1 intensity on VERP was independent of S2 intensity. S2 strength-interval curves were generated in 10 patients at low (1.5 times threshold) and high (10 mA) S1 intensities. All portions of the strength-interval curve were shifted to the left by an increase in S1 intensity. The time course of change in VERP after an abrupt increase in S1 intensity was assessed in an additional 10 patients. VERP changed slowly. requiring 18 +/- 28 seconds to shorten by 2 msec and 64 +/- 46 seconds to decrease by 10 msec after a change in S1 intensity from 1.5 times threshold to 10 mA. In a final group of 10 patients. VERP was measured using an eight-beat drive train and a 4-second intertrain interval. With this more conventional protocol. VERP shortened by 14 +/- 8 msec with an increase in S1 intensity from 1.5 times threshold to 10 mA. CONCLUSIONS. Increasing S1 intensity results in clinically significant. progressive shortening of VERP in man. This effect is independent of S2 intensity. The prolonged time course of the change in VERP after an increase in S1 intensity and the attenuation of this effect by autonomic blockade are consistent with stimulation of sympathetic nerve terminals and catecholamine release as a result of intense stimulation.
Electrogram patterns predictive of successful catheter ablation of accessory pathways. Value of unipolar recording mode, BACKGROUND. Transcatheter electrical ablation has been used in the treatment of arrhythmias. and most experience has been obtained by ablating the normal atrioventricular conduction system. Less information is available on ablation of atrioventricular accessory pathways. METHODS AND RESULTS. Catheter ablation of overt accessory pathways was attempted in 135 patients with 142 distinct pathways. including 21 right parietal or anteroseptal. 47 posteroseptal. and 74 left lateral pathways. We sought to identify the type and value of electrophysiological parameters associated with successful ablation outcome. For this purpose. the unipolar recording mode was used in addition to bipolar anterograde and retrograde parameters. With a mean follow-up of 16 +/- 6 (mean +/- SD) months. fulguration was successful in eliminating preexcitation in 129 patients (96%). including all seven with two distinct accessory pathways. The first ablation attempt was successful in 110 patients. and two or more attempts were performed in 25 patients. Bipolar electrograms associated with success of fulguration showed a shorter atrioventricular conduction time (40 +/- 13 versus 53 +/- 17 msec. p less than 0.0001) and an earlier main ventricular deflection relative to delta wave onset (-1.7 +/- 10 versus 5 +/- 7 msec. p less than 0.001) than electrograms associated with unsuccessful outcome. The only parameter dealing with retrograde conduction (i.e.. ventriculoatrial conduction time during reciprocating tachycardia) was not predictive (86 +/- 17 versus 93 +/- 17 msec). Neither was the atrial to ventricular electrogram amplitude ratio. Two unipolar parameters were found to be predictive of successful outcome: 1) The three different patterns PQS. P-QS. P-rS of unipolar waves recorded at the annulus were associated with respective success rates of 97%. 78%. and 55% (p less than 0.001). 2) Intrinsic deflection timing occurred -4 +/- 8 and 6 +/- 7 msec relative to delta wave onset in successful attempts and in failures. respectively (p less than 0.001). Logistic regression analysis revealed a single independent factor predictive of success. the unipolar pattern (p = 0.03). with an odds ratio of 7:1 (PQS pattern versus P-rS pattern). In the group of 18 patients who underwent a first unsuccessful but second successful attempt. comparison of electrograms revealed no difference in the ventriculoatrial conduction time but a significant improvement in anterograde parameters and unipolar pattern distribution. CONCLUSIONS. Some distinctive electrogram patterns concerning anterograde conduction are associated with success of accessory pathway fulguration. The unfiltered unipolar recording mode (PQS pattern) contributes significantly to optimizing the accuracy of accessory pathway localization.
Coronary capillaries in patients with congestive cardiomyopathy or angina pectoris with patent main coronary arteries. Ultrastructural morphometry of endomyocardial biopsy samples, BACKGROUND. The coronary microvasculature may be abnormal even in the presence of angiographically normal epicardial arteries. Abnormalities of small coronary vessels have been invoked as a cause of angina. METHODS AND RESULTS. To quantitatively evaluate the morphology of capillaries in patients with idiopathic dilated cardiomyopathy (DCM) or the syndrome of angina and small vessel disease (SVD). we performed electron microscopic morphometry of capillaries in right ventricular biopsy samples taken from 32 patients. Ten had angina. normal epicardial coronary arteries. and evidence for SVD; 12 had DCM; and 10 had normal hearts. In patients with DCM. the ratio of microvessels to myocytes was not different than that of controls (0.49 +/- 0.06 versus 0.51 +/- 0.05). Mean cross-sectional areas of the capillaries (lumen plus wall) and lumen were significantly greater than those of controls (45.3 +/- 15.1 versus 22.7 +/- 8.3 micron 2. p less than 0.001; 17.6 +/- 6.9 versus 11.6 +/- 6.2 micron 2. p less than 0.05. respectively). Fibrous content of the myocardium. as assessed by quantitative light microscopy. was significantly increased (16.3 +/- 3.3% versus 5.0 +/- 2.4%. p less than 0.001). In contrast. in patients with SVD. the capillary-to-myocyte ratio was reduced (0.33 +/- 0.08. p less than 0.001). Although mean cross-sectional areas of the entire capillary (32.4 +/- 19.7 micron 2) and the lumen (8.9 +/- 7.8 micron 2) were not statistically different than those of controls. there was an absence of capillaries less than 15 micron 2 in cross-sectional area. and the frequency distribution of the lumen area was skewed to the left. Swollen endothelial cells frequently encroached upon the lumen. There was a mild increase in fibrous content (9.5 +/- 3.7%. p less than 0.05). CONCLUSIONS. Enlarged capillaries and a normal ratio of capillaries to myocytes appear to be features of DCM. Of the patients with SVD. there was both a relative lack of capillaries and capillary lumen narrowing from swollen endothelium. These changes may induce ischemia and angina and may result in mild fibrosis.
Comparative effects of pacing-induced and balloon coronary occlusion ischemia on left ventricular diastolic function in man, BACKGROUND. Effects of pacing-induced and coronary occlusion myocardial ischemia on left ventricular (LV) function have been compared only in anesthetized dogs. Diastolic properties of the same LV anterior wall segment were therefore compared in 12 patients with single-vessel proximal left anterior descending coronary artery stenosis at rest. immediately after 7 +/- 1.2 minutes of pacing. and at the end of a 1-minute balloon occlusion of coronary angioplasty (CO). METHODS AND RESULTS. Shifts of the diastolic LV pressure-length relation. derived from simultaneous tip-micromanometer LV pressure recordings and digital subtraction LV angiograms. were used as an index of regional diastolic LV distensibility of the anterior wall segment. Immediately after pacing. LV end-diastolic pressure rose from 13.5 +/- 3.5 to 23.8 +/- 7.0 mm Hg (p less than 0.01 versus at rest) without a significant change of the LV end-diastolic volume index (83.1 +/- 18.9 versus 88.4 +/- 16.5 ml/m2). percentage systolic shortening (%SS) of the ischemic segment fell from 40.1 +/- 10.6% to 25.2 +/- 8.6% (p less than 0.01). and the diastolic LV pressure-radial length (P-RL) plot of the ischemic segment was shifted upward by 7.1 +/- 5.0 mm Hg for portions of the plot that overlapped with the diastolic LV P-RL plot at rest. At the end of CO. LV end-diastolic pressure rose to 20.8 +/- 7.8 mm Hg (p less than 0.01 versus at rest) and the LV end-diastolic volume index rose to 95.6 +/- 16.3 ml/m2 (p less than 0.05 versus at rest. p less than 0.05 versus after pacing). Ejection fraction and %SS of the ischemic segment fell respectively from 76.6 +/- 6.8% to 46.6 +/- 11.4% (p less than 0.01 versus at rest. p less than 0.01 versus after pacing) and from 40.1 +/- 10.6% to 6.4 +/- 8.6% (p less than 0.01 versus at rest. p less than 0.01 versus after pacing). The diastolic LV P-RL plot of the ischemic segment was shifted upward by 3.1 +/- 2.3 mm Hg for portions of the plot that overlapped with the diastolic LV P-RL plot at rest. This upward shift at the end of CO was significantly smaller (p less than 0.05) than that immediately after pacing. At the end of CO. a correlation (p less than 0.03) was observed for the ischemic segment between %SS and upward shift of the diastolic LV P-RL plot. CONCLUSIONS. The upward shift of the diastolic LV P-RL plot. which was used as an index of decreased regional diastolic LV distensibility. was larger immediately after pacing than at the end of CO. Persistent systolic shortening of ischemic myocardium seems to be a prerequisite for a decrease in diastolic distensibility of the ischemic segment because of the higher %SS of the ischemic segment immediately after pacing. and because of the correlation at the end of CO between the upward shift of the diastolic LV P-RL plot and %SS of the ischemic segment.
Effectiveness of recombinant desulphatohirudin in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits, BACKGROUND. The effectiveness of balloon angioplasty is limited by a restenosis rate of approximately 30%. Recombinant desulphatohirudin (r-hirudin [CGP 39393]) has been found to be highly effective in preventing acute platelet-rich thrombosis after deep arterial injury as compared with heparin. METHODS AND RESULTS. This study evaluated the effect of intravenous r-hirudin. a selective inhibitor of thrombin. on restenosis after balloon angioplasty in 29 rabbits. Focal femoral atherosclerosis was induced by air desiccation endothelial injury followed by a 2% cholesterol diet for 1 month. At angioplasty (2.5-mm balloon with three 60-second. 10-atm inflations 60 seconds apart). the rabbits received heparin (150 units/kg bolus. n = 16) or r-hirudin (1 mg/kg bolus followed by infusions of 1 mg/kg for the first hour and 0.5 mg/kg for the second hour. n = 13). Angiograms performed before and after angioplasty and before death were analyzed quantitatively by a blinded observer. Rabbits were killed 2 hours (n = 14) or 28 days (n = 15) after angioplasty. Femoral arteries were fixed in situ by perfusion of 10% formaldehyde at 100 mm Hg. The mean luminal diameter of the arteries with successful angioplasty (greater than or equal to 20% increase in luminal diameter) in rabbits treated with heparin (n = 8 arteries) increased from 1.18 +/- 0.29 mm before angioplasty to 1.86 +/- 0.24 mm immediately after angioplasty (p less than 0.001) and decreased to 0.94 +/- 0.69 mm (p = 0.0004) at 28 days after angioplasty. In rabbits treated with r-hirudin (n = 11 arteries). the mean luminal diameter increased from 1.14 +/- 0.17 mm before angioplasty to 1.68 +/- 0.20 mm immediately after angioplasty (p less than 0.001) and decreased to 1.37 +/- 0.47 mm (p = 0.01) at 28 days after angioplasty. The mean reduction in luminal diameter by angiography was less in the r-hirudin-treated group than in the heparin-treated group (0.30 +/- 0.33 versus 0.92 +/- 0.61 mm. p = 0.01). Blinded planimetric analysis of stained histological sections of the femoral arteries also showed less cross-sectional area narrowing by plaque in rabbits treated with r-hirudin compared with those treated with heparin (22 +/- 16% verus 48 +/- 29%. p = 0.01). Both groups had similar numbers of arteries with histological evidence of balloon-induced plaque tear (12 of 13 versus 13 of 15). CONCLUSIONS. Rabbits receiving r-hirudin at the time of experimental balloon angioplasty had significantly less restenosis by angiography and by quantitative histopathology than rabbits receiving heparin.
Chronic beta-adrenoceptor blockade prevents the development of beta-adrenergic subsensitivity in experimental right-sided congestive heart failure in dogs, BACKGROUND. The reductions of myocardial beta-adrenergic receptor density and responsiveness to catecholamines in congestive heart failure are associated with excessive sympathetic stimulation. The purpose of this study was to determine whether the myocardial changes could be prevented by beta-receptor blockade. METHODS AND RESULTS. We administered the oral beta-receptor blocking agent nadolol (40 mg/day) to dogs during an early stage of experimental right heart failure and to sham-operated dogs for 5 weeks. Animals receiving no nadolol were studied concurrently. Nadolol treatment did not prevent right ventricular hypertrophy or elevated concentrations of plasma norepinephrine that occurred in right heart failure. nor did it affect the decrease in myocardial norepinephrine content and norepinephrine uptake activity. suggesting that the hemodynamic stress imposed on the right ventricle of dogs with right heart failure was similar regardless of the presence or absence of beta-receptor blockade. Resting heart rate. right atrial pressure. aortic pressure. cardiac output. right ventricular dP/dt. and left ventricular dP/dt and dP/dt/P measured 5 days after discontinuation of nadolol did not differ significantly from those without nadolol treatment in either right heart failure or sham-operated animals. Sham-operated dogs also showed no changes in myocardial beta-receptor or adenylate cyclase activity after nadolol treatment. However. nadolol treatment prevented the reduction of myocardial beta-receptor density and attenuated the decrease in the cardiac beta-adrenergic sensitivity that occurred in right heart failure. CONCLUSIONS. Excessive sympathetic stimulation may play an important role in the development of beta-receptor downregulation and beta-adrenergic subsensitivity in right heart failure.
Ventricular tachycardia after in vivo DC shock ablation in dogs. Electrophysiologic and histologic correlation, BACKGROUND. DC shock catheter ablation for the treatment of ventricular tachycardia (VT) may induce VT episodes that disappear within days. METHODS AND RESULTS. A 30-J cathodal shock was delivered to the endocardial left ventricular wall in 15 closed-chest dogs. All dogs had VT during the first day after ablation. Eleven of these dogs were studied on the first day. Extensive epicardial and endocardial activation mapping in vivo. in Langendorff-perfused hearts. and in tissue blocks in a tissue bath localized the site of origin of VT to subendocardial Purkinje fibers in a border zone surrounding the central necrotic ablation lesion. Intracellular recording showed that this zone consisted of a subendocardial superficial layer (SSL) of cells with abnormal characteristics. a resting membrane potential (RMP) of -58 +/- 11 mV (mean +/- SD). and an action potential amplitude (APA) of 61 +/- 20 mV. In addition. the steepness of phase 0 of the action potential was markedly reduced. In three dogs abnormal automaticity was found in a very small area. Immediately below the SSL. cells were normal with an RMP of -78 +/- 5 mV and an APA of 107 +/- 8 mV. Histology confirmed a thin SSL with edematous and necrotic cells. hemorrhage. and infiltration. The other four dogs were studied at 1 week after ablation when VT was absent. Microelectrode impalement in the SSL was either impossible or showed nearly normal action potential characteristics. Histological examination showed a markedly thickened fibrotic subendocardial layer at places where impalement was impossible. Normal subendocardium was found in other areas of the border zone. CONCLUSIONS. Our results indicate that VT after DC shock ablation originates from cells with abnormal automaticity in the superficial subendocardial border zone around the central ablation lesion. Within 1 week edematous and necrotic cells in this border zone are replaced by a fibrotic layer. and this transition is associated with the disappearance of VT.
Protein C activation following coronary artery occlusion in the in situ porcine heart, BACKGROUND. Activated protein C. the body's natural anticoagulant. may play a role in protecting the heart during and following an occlusion of the left anterior descending coronary artery (LAD) in the porcine heart. METHODS AND RESULTS. Infusion of 1 unit thrombin over 30 seconds into the LAD of juvenile pigs produced a prolongation of the Xa clotting time (153 +/- 14%) in blood drawn from the anterior interventricular vein (AIV). The action of the anticoagulant was blocked by a polyclonal immunoglobulin G antibody directed against porcine activated protein C. A brief (30 seconds) occlusion of the LAD induced a similar prolongation of the Xa clotting time (138 +/- 11%). which was also blocked by the polyclonal antibody. To determine whether activated protein C helps sustain the heart during and following a 2-minute occlusion. three groups of pigs were studied: 11 controls. six receiving activated porcine protein C. and nine receiving a monoclonal antibody (HPC4) that blocks protein C activation. Relative to the controls. HPC4-treated animals recovered function. as measured by the maximum time derivative of left ventricular pressure and segmental shortening. more slowly and were not able to sustain this recovery. Animals receiving activated protein C recovered more quickly and sustained this recovery. CONCLUSIONS. These data indicate that an ischemic insult induces rapid activation of protein C in the coronary microcirulation and that blocking this activation impairs recovery.
Canine myocardial creatine kinase isoenzymes after chronic coronary artery occlusion, BACKGROUND. Creatine kinase (CK) exists as three cytosolic isoenzymes. CK-MM. CK-MB. and CK-BB. and one mitochondrial isoenzyme. Animal and human observations suggest that the CK-MB content of myocardium is dynamic and may increase in response to ischemia. but the response of the myocardial CK system to chronic coronary artery occlusion is not well-defined. METHODS AND RESULTS. We measured serial changes in myocardial total CK. percent CK-MB. and percent CK-BB before and 3 weeks after coronary artery occlusion in 17 pentobarbital-anesthetized dogs. Tissue biopsies were obtained from the left anterior descending (LAD) coronary artery myocardium. the right coronary artery (RCA) myocardium. and the circumflex coronary artery myocardium at baseline and 3 weeks after LAD occlusion (n = 6). RCA occlusion (n = 5). and no coronary artery occlusion (n = 6). Tissue samples were assayed for total CK. percent CK-MB. and percent CK-BB. Samples were also examined by electron microscopy for evidence of ischemic myopathy. Total myocardial CK activity did not change over 3 weeks. Percent CK-MB increased significantly in the tissue supplied by the occluded artery (4.1-fold in dogs with LAD occlusion and 6.7-fold in dogs with RCA occlusion). Percent CK-BB did not change. Dogs with LAD occlusion had ultrastructural evidence of myopathic fibers interspersed with normal fibers in the LAD myocardium. Dogs with RCA occlusion had no ultrastructural evidence of myopathic fibers in the RCA myocardium. CONCLUSIONS. Chronic coronary artery occlusion causes a pronounced change in the canine myocardial CK system that is limited to the tissue supplied by the occluded coronary artery. These biochemical alterations do not correlate with any cellular ultrastructural changes. Myocardial CK-MB content is dynamic. varies geographically within the heart. and increases rapidly after coronary artery occlusion.
Preconditioning causes improved wall motion as well as smaller infarcts after transient coronary occlusion in rabbits, BACKGROUND. A brief coronary occlusion before a more prolonged occlusion results in less myocardial infarction than the longer occlusion alone. However. the effects of this preconditioning on recovery of systolic function after coronary occlusion have not been determined. METHODS AND RESULTS. Ultrasonic crystals implanted in rabbit myocardium measured segment length in the distribution of a branch of the left coronary artery that was fitted with a snare occluder. Rabbits were randomly allocated to either nonpreconditioned or preconditioned groups. Rabbits in the latter group underwent preconditioning with a 5-minute coronary occlusion followed by 10 minutes of reperfusion. Then the coronary artery was occluded for 20 minutes in all rabbits. after which it was allowed to reperfuse for 90 minutes. The hearts were then excised. and infarct size was measured by staining with triphenyltetrazolium chloride. During coronary occlusion. all hearts except one demonstrated either akinesis or paradoxical bulging. Five minutes after release of the 20-minute occlusion. active shortening had returned in the preconditioned rabbits and averaged 27.9 +/- 16.6% of baseline shortening. At the same time. paradoxical lengthening persisted in nonpreconditioned rabbits (-15.5 +/- 19.8% of baseline). By the end of the 90-minute reperfusion period. segment shortening averaged 40.1 +/- 8.4% of baseline in preconditioned rabbits and only 6.2 +/- 12.0% in nonpreconditioned rabbits (p less than 0.05). Infarct size as a percentage of risk area was significantly smaller in preconditioned rabbits as well (3.0 +/- 1.6% versus 28.8 +/- 7.0%. p less than 0.002) and likely accounted for the improved shortening. CONCLUSIONS. We conclude that a brief coronary occlusion before a more prolonged occlusion results in not only reduced infarct size but also significantly better recovery of systolic function.
Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart, BACKGROUND. Preconditioning (5 minutes of ischemia followed by 10 minutes of recovery) renders the heart very resistant to infarction from subsequent ischemia. This study tests whether adenosine receptors might mediate preconditioning protection. METHODS AND RESULTS. We examined the effect on infarct size of pretreatment with either of two adenosine receptor antagonists in both control and preconditioned in situ rabbit hearts. Hearts underwent 30 minutes of regional ischemia plus 3 hours of reperfusion. and infarct size was measured with tetrazolium. Infarct size averaged 39% of the zone at risk in controls but only 8% in preconditioned hearts. Preconditioned and nonpreconditioned hearts receiving either blocker had infarcts not different in size from the controls. A 5-minute intracoronary infusion of adenosine was as effective as 5 minutes of ischemia in protecting parabiotically perfused isolated hearts against infarction from a 45-minute ischemic insult. Similarly. intracoronary infusion of N6-1-(phenyl-2R-isopropyl)adenosine. an A1-selective adenosine receptor agonist. at a dose that delayed conduction but did not dilate the coronary vessels. also limited infarct size. The protection disappeared when we reduced the coronary concentration of drug by intravenous infusion of adenosine. indicating that cardiac rather than peripheral receptors were involved in the protection. CONCLUSIONS. We conclude that adenosine released during the preconditioning occlusion stimulates cardiac A1 receptors. which leaves the heart protected against infarction even after the adenosine has been withdrawn.
Activation of cardiac sympathetic afferents during coronary occlusion. Evidence for reflex activation of sympathetic nervous system during transmural myocardial ischemia in the dog, BACKGROUND. Left ventricular sympathetic afferent nerves are located mainly in superficial epicardial layers. Reflex excitatory responses mediated by sympathetic afferent nerves have been observed during myocardial ischemia in cats and humans but not in dogs. Previous canine studies have induced ischemia by occlusion of a coronary artery. Extensive collateral circulation in the canine heart may limit ischemia of epicardial layers during simple coronary occlusion. resulting in little stimulation of sympathetic afferent nerves and minimal reflex excitatory responses. METHODS AND RESULTS. In anesthetized dogs with sinoaortic and vagal deafferentation. we determined whether reflex sympathoexcitatory responses mediated by sympathetic afferents occurred during transmural myocardial ischemia. Reflex sympathoexcitation was quantitated by direct recording from either efferent renal (n = 20) or cardiac (n = 5) sympathetic nerves. Responses of arterial pressure and efferent sympathetic nerve activity were measured during simple occlusion of the anterior descending artery (LAD alone) and during LAD occlusion with a circumflex stenosis (LAD + CIRC). This circumflex stenosis was adjusted to abolish coronary vasodilator reserve without reducing basal flow. We observed significantly greater reflex increases in renal (32 +/- 5%) and cardiac (58 +/- 15%) nerve activity during LAD + CIRC than during LAD alone (14 +/- 6% and 8 +/- 7%. respectively). Reflex changes in renal nerve activity during LAD + CIRC were abolished by interruption of cardiac sympathetic afferent pathways (n = 5). In eight experiments. myocardial blood flow was measured during the two coronary occlusions. These experiments confirmed that LAD + CIRC elicited more transmural ischemia in the LAD distribution than did LAD alone. However. these experiments also revealed that LAD + CIRC elicited endocardial ischemia in the circumflex distribution. In five additional experiments. regional sympathetic deafferentation of the posterior left ventricle by epicardial application of 88% phenol along the atrioventricular groove had no significant effect on renal nerve responses to LAD + CIRC (36 +/- 5% increase before phenol versus 31 +/- 3% increase after phenol). These results indicate that endocardial ischemia in the circumflex distribution did not contribute to the reflex increases in nerve activity that were noted during LAD + CIRC. CONCLUSIONS. Reflex sympathoexcitation mediated by cardiac sympathetic afferents can be elicited in dogs. However. these responses are significant only during ischemia that is transmural and involves the superficial epicardial layers of the left ventricle.
Reversible and irreversible elongation of ischemic, infarcted, and healed myocardium in response to increases in preload and afterload, BACKGROUND. Left ventricular aneurysm formation after myocardial infarction (MI) has been associated with elongation of infarcted tissue in response to wall stress. Such elongation most commonly occurs in acutely infarcted or partially healed regions during the early post-MI period; however. recent reports have indicated that mature (15-week-old) healed infarct regions also undergo elongation after stress. METHODS AND RESULTS. To assess factors contributing to post-MI left ventricular aneurysm formation. we subjected isolated strips (n = 50) of rabbit myocardial tissue from acutely ischemic (noninfarcted left ventricular). acutely infarcted (24 hours after MI). and healed infarct (3 and 15 weeks after MI) regions to a range of loading conditions and measured the reversible and irreversible length changes that occurred. The isolated strips were repetitively stretched for 1 hour at 4 Hz to impose cyclical physiological peak and resting stresses of 2.0 and 0.2 g/mm2. During a second hour. either peak stress ("afterload") or resting stress ("preload") was tripled. and the increase in strip length (strain) was measured. During a third hour. peak and resting stresses were returned to the initial values to assess the reversibility of length changes occurring during increased load. Elongation was expressed as the increase in natural strain from the first hour. Increasing afterload caused similar irreversible length increases of 4-5%/hr in acutely infarcted and 3- and 15-week-old healed infarct strips; acutely ischemic tissue length increased by 7.4%/hr (p less than 0.05 versus acutely infarcted tissue and scars). Increasing preload in acutely ischemic and acutely infarcted tissue caused a reversible length increase of less than 1%/hr. (Scar strips were not tested for the effect of preload.) CONCLUSIONS. Since an irreversible length increase may represent an early event in aneurysm formation. our results suggest that 1) afterload increases are more likely to lead to aneurysm development than preload increases. 2) acutely ischemic tissue is the most vulnerable to increased afterload. and 3) for a given wall stress level. healing scar tissue is as susceptible to irreversible length changes as is acutely infarcted tissue. The observation that even mature post-MI scar elongated in response to increases in afterload implies that long-term pharmacological management of afterload in post-MI patients may be beneficial in preventing tissue elongation and aneurysm formation and that factors that increase wall stress (e.g.. hypertension and exercise stress) have the potential to promote aneurysm formation in healed infarct scars.
Neutrophil accumulation in ischemic canine myocardium. Insights into time course, distribution, and mechanism of localization during early reperfusion, BACKGROUND. We have previously demonstrated that chemotactic factors released from the ischemic canine myocardium peak early during reperfusion and that they elicit neutrophil adherence reactions in vitro that are dependent on the CD18 glycoprotein family. In this study we investigated the hypothesis that neutrophil localization in ischemic canine myocardium in vivo occurs over a similar time course during early reperfusion and involves a CD18-dependent mechanism. METHODS AND RESULTS. We occluded the circumflex coronary artery for 1 hour in acute. open-chest dogs. followed by reperfusion for 1. 2. 3. or 4 hours. Regional myocardial blood flow was determined using radiolabeled microspheres. and localization was traced using technetium-99m-labeled autologous neutrophils. In the first hour of reperfusion. neutrophil localization occurred preferentially within the subendocardial region and was inversely related to flow. Neutrophil localization diminished across the ischemic myocardium from endocardium to epicardium but remained negatively related to flow in the midmyocardial region. Regardless of flow. little neutrophil localization occurred in the subepicardial region. Neutrophil localization was greatest in the first hour of reperfusion and diminished thereafter. By 4 hours of reperfusion. the rate of localization was markedly attenuated relative to 1 hour. Dogs given anti-CD18 monoclonal antibody R15.7 (1 mg/kg i.v.) before occlusion underwent 1 hour of occlusion followed by 1 hour of reperfusion. When compared with 1-hour reperfusion controls. the R15.7-treated dogs demonstrated significant attenuation of neutrophil localization in the subendocardial region. CONCLUSIONS. These data support the concepts that rapid neutrophil localization during reperfusion occurs within regions of previous myocardial ischemia and that neutrophils preferentially localize within the subendocardial region. The rate of neutrophil localization is greatest within the first hour after the initiation of reperfusion. and localization is. at least in part. CD18 dependent. Therapies directed against neutrophil-mediated reperfusion injury should be initiated with these considerations in mind.
Effect of ST segment measurement point on performance of standard and heart rate-adjusted ST segment criteria for the identification of coronary artery disease, BACKGROUND. Recent reports critical of the performance of heart rate-adjusted indexes of ST depression during exercise electrocardiography have used J-point rather than ST segment measurements. However. no standard exists for the optimal time after the J-point at which to measure ST segment deviation. METHODS AND RESULTS. To assess the effect of ST segment measurement position on performance of standard exercise electrocardiographic criteria. the delta ST segment/heart rate (delta ST/HR) index. and the ST segment/heart rate (ST/HR) slope for the detection of coronary artery disease. the exercise electrocardiograms of 50 clinically normal subjects and 80 patients with known or likely coronary disease were analyzed using ST depression measured at both the J-point and at 60 msec after the J-point (J + 60). A positive exercise electrocardiogram by standard criteria. defined as 0.1 mV or more of additional horizontal or downsloping ST depression at end exercise. had a specificity of 96% when ST depression was measured at either the J-point or J + 60. There was no difference in sensitivity of standard electrocardiographic criteria at J + 60 and J point (both 59%. p = NS). However. at matched specificity of 96%. the delta ST/HR index and ST/HR slope calculated using ST depression at J + 60 were significantly more sensitive (90% and 93%) than when calculated using J-point depression (64% and 61%. each p less than 0.001). Comparison of areas under respective receiver operating characteristic curves confirmed the superior performance of J + 60 as opposed to J-point measurements for both the delta ST/HR index (0.98 versus 0.89. p = 0.006) and the ST/HR slope (0.96 versus 0.87. p = 0.007) and also demonstrated modestly improved overall test performance for standard electrocardiographic criteria using J + 60 measurements (0.88 versus 0.82. p = 0.001). CONCLUSIONS. Use of J-point measurements significantly degrades performance of heart rate-adjusted indexes of ST depression but has less effect on standard criteria.
Hemodynamic and neurohormonal effects of clonidine in patients with preganglionic and postganglionic sympathetic lesions. Evidence for a central sympatholytic action, BACKGROUND. Clonidine. a partial presynaptic and postsynaptic alpha-adrenoceptor agonist. has been shown to lower blood pressure in normal subjects but not in tetraplegics; however. the mechanisms of this action have not been elucidated. METHODS AND RESULTS. The hemodynamic and hormonal basis of the hypotensive action of clonidine was investigated in tetraplegics with complete cervical spinal cord transection and preganglionic sympathetic denervation. in patients with unilateral brachial plexus injury and postganglionic sympathetic denervation. and in normal subjects. In normal subjects. the fall in blood pressure after clonidine infusion was accompanied by a reduction in cardiac output that was predominantly due to a fall in stroke volume and in heart rate. The lack of fall in blood pressure. cardiac output. and stroke volume in tetraplegics indicates that these effects are exerted at a supraspinal level and require intact descending sympathetic pathways. After clonidine infusion. digital skin vasodilatation occurred in normal subjects. in the innervated but not the denervated limb of patients with unilateral brachial plexus injury. and in tetraplegics. indicating that this response is due to the central sympatholytic effect of clonidine. Plasma norepinephrine was much lower in tetraplegics compared with normal subjects. and after clonidine infusion. it fell substantially in normal subjects alone. Plasma renin activity did not change. Bladder stimulation in tetraplegics resulted in a rise in blood pressure and vasoconstriction in digital skin vessels. The inability of clonidine to significantly reduce or abolish the pressor and digital vasoconstrictor responses after bladder stimulation in tetraplegics indicates that clonidine does not exert a major effect on spinal preganglionic neurons or peripheral presynaptic alpha 2-adrenoceptors. CONCLUSIONS. Therefore. clonidine is a suitable drug for use in analyzing the central supraspinal levels of control in varying circulatory disorders. such as hypertension and postural hypotension.
Ankle arthrodesis with vertical Steinmann's pins in rheumatoid arthritis, Many techniques for ankle arthrodesis have been described but some of them are not applicable in patients with severe rheumatoid arthritis (RA) who have also developed osteopenia and decreased bone density. A technique utilizing two longitudinally placed Steinmann's pins to fixate and align the joint was used in five patients with severe RA and is described here. Results showed a 100% fusion rate and patient satisfaction over an average follow-up time of six years. This ankle arthrodesis technique was found to be applicable in arthritic patients with osteopenia and decreased bone density caused by RA.
Conservative treatment of Grade III acromioclavicular dislocations, Twenty-two patients with Grade III acromioclavicular (AC) joint dislocations were treated nonoperatively and evaluated by questionnaire. physical exam. and isokinetic strength and endurance testing. The mean follow-up time was 2.6 years (range. six months to 7.7 years). Patients returned to work an average of 2.1 weeks after injury. All of the patients were right-handed; 14 injured their dominant right AC joint whereas eight injured their nondominant left side. Isokinetic muscle testing was used to evaluate the strength and endurance of both shoulders in all 22 patients. Strength was measured as peak torque for shoulder flexion. extension. internal and external rotation. abduction. and adduction at 400 degrees per second. Internal and external rotation testing was also evaluated at 60 degrees per second. Endurance was measured at 400 degrees per second for flexion. extension. and internal and external rotation. The strength and endurance levels of the injured shoulders were comparable to the noninjured side. Although discomfort levels were low. long range follow-up reports reveal discomfort appearing with increased intensity of activity.
The effect of capsular venting on glenohumeral laxity, Anesthetized shoulders are frequently stable against forces applied during drawer and sulcus tests. even though the shoulder muscles are inactive and do not contribute to stability. This passive stability is also evident in the glenohumeral joints of anatomic specimens. The translational laxity of anatomic specimen shoulders was measured. and it was demonstrated that this laxity was substantially increased when air was admitted into the capsule. Eight shoulders. aged 57-87 years. including six contralateral pairs. were analyzed using a six degrees-of-freedom force transducer and a six degrees-of-freedom spatial tracker. Capsules were vented by admitting air ad libitum through an 18-gauge needle. Venting reduced the force necessary to translate the humeral head with respect to the glenoid fossa by an average of 15.3 N (55%) for anterior forces. 10.8 N (43%) for posterior forces. and 19.0 N (57%) for inferior forces. It is likely that passive stability will also be diminished by a similar mechanism in patients with intact but excessively lax capsules. The principle of limited joint volume should be considered and tested when investigating glenohumeral stability.
Use of bipolar endoprosthesis and bone grafting for acetabular reconstruction, Reconstruction operations for severe acetabular defects using bone grafting and a bipolar hemiarthroplasty retrospectively reviewed in 81 hips between 1983 and 1985. The most common indication was failed total hip arthroplasty. Bone grafts consisted of cancellous bone. bone blocks. and wafer-type grafts used singly or in combination. The follow-up period was 12 to 36 months postoperatively (mean. 16 months). There were 22 perioperative complications (27%) and 13 postoperative complications (16.7%). A majority of hips showed some graft resorption and component migration that worsened with time. There were four graft failures with subluxation of the component. one prosthesis dislocation. and one component disassembly. Ten hips had revision (13.3%) for a variety of reasons. Nevertheless. clinically. most patients (83%) believed the procedure had improved their condition. Reconstruction for severe acetabular defects can be achieved successfully using this technique. but long-term follow-up evaluation is needed to fully assess the role of this procedure in relation to other available options.
Osteonecrosis of the femoral head. A prospective randomized treatment protocol, Conservative treatment versus core decompression for cases of osteonecrosis (ON) of the femoral head was prospectively reviewed in 36 patients. A preoperative evaluation of the patients' history. physical examination. Harris Hip Score. roentgenograms. computed tomography. bone scan. magnetic resonance imaging. and measurement of the intraosseous pressure was used to grade the level of ON according to a rating system developed by Ficat. Hips were randomized to core decompression or conservative treatment groups. Fifty-five hips in 36 patients were randomized (29 surgical and 26 conservative). When success was gauged by Harris Hip Scores for Stage I hips. treatment was successful for seven of ten (70%) operatively treated hips and one of five (20%) non-operatively treated hips. Among Stage II hips. treatment was successful for five of seven (71%) decompressed hips and none of seven conservatively treated hips. Successful treatment was accomplished in eight of 11 hips (73%) and one of ten hips (10%) in decompression and conservative groups. respectively. for Stage III hips. Stages 0 and IV had groups too small for comparison. Less successful results were seen if roentgenographic criteria of success were used. Survival analysis showed more favorable results with surgical treatment. Core decompression produced better results than conservative treatment in the early stages of ON.
Arthrodesis of the ankle and subtalar joints, The late reconstruction of a complex nonunion of the distal tibial metaphysis. the ankle. or the subtalar joint was undertaken in five patients through a posterior surgical approach and the application of a blade plate into the os calcis. This technique was preferred as a salvage operation when the surrounding soft tissue envelope was compromised by the initial injury. previous surgical procedures. or infection. Each of the cases was notable for a segmental bone loss. an infected nonunion. or a collapse of the talar body. In the presence of a major soft tissue defect. the internal fixation was accompanied by the application of a microvascular free flap. The postoperative assessment of the posterior arthrodesis with the blade plate fixation was at an average of 33 months. Using a modification of the Boston Children's Hospital ankle scoring system. a preoperative and postoperative assessment was made. The criteria included an objective rating system based on the intensity of pain. the cessation of drainage. the degree of independent ambulation. and the roentgenographic documentation of union. The average preoperative score was 13 (range. 8-16). After arthrodesis. the average score was 44 (range. 40-48). with three patients rated excellent and two rated good.
Nonunion and pseudarthrosis of fracture healing. A histopathologic study of 95 human specimens, Forty-one human tissue specimens from fracture nonunions in extraarticular locations demonstrated a spectrum of clefts at the site of nonunion ranging from tiny microscopic spaces within the soft tissue of the nonunion to dominant clefts that completely separated the ends of the fracture. These latter specimens were examples of frank pseudarthrosis. The soft tissues lining the large clefts were often considerably eroded. Pseudarthrosis of fracture healing may be a late manifestation of more mobile nonunions that progressively tear apart. Fifty-four additional nonunion or pseudarthrosis specimens from former intraarticular fractures demonstrated the same sequence of changes occurring in 24 of the cases. However. 30 of the intraarticular fractures demonstrated no tissues of a fibrous nonunion. which could indicate that in such locations pseudarthrosis may exist from the date of the original fracture.
Chondroblastomalike extraskeletal chondroma, An unusual extraskeletal tumor occurring in the right thumb of a 44-year-old man exhibited histologically a chondroblastomalike appearance. The tumor was characterized by dense proliferation of chondroblastic cells admixed with a few multinucleated giant cells of osteoclast type. The patient had no evidence of local recurrence or metastasis three-and-a-half years after a simple excision.
Intracortical osteosarcoma. A case report, Intracortical osteosarcoma (IO) is the rarest form of osteosarcoma. A 19-year-old man had one of these lesions in the upper diaphysis of the femur. Microscopically. IO was a well-differentiated osteosarcoma with an osteoblastic histologic pattern. The typical location in the diaphysis and the peculiar histologic and roentgenographic findings with intracortical origin clearly separate this entity from conventional osteosarcomas as well as periosteal and parosteal osteosarcomas. IO are lytic neoplasms confined to the cortex of the diaphysis with a benign roentgenographic appearance. but are included in the differential diagnosis of benign tumors.
Tissue reaction to collagen-coated porous hydroxyapatite, To give tenacity to high porosity (80%-90%) hydroxyapatite (HA) and to make a stronger bone substitute. a collagen-coated porous HA (C-HA) was prepared. and its compressive strength was examined. By implanting C-HA into the femoral condyle of adult rabbits. the capacity for new bone formation and foreign-body reactivity were quantitatively compared with those of HA alone. The compressive strength of C-HA was 4.3 times greater than HA. At four weeks after implantation. the mean areal ratio of the newly formed bone in the C-HA block in each rabbit was 9.9%. which was somewhat less than the 13.7% in the HA block; the mean number of multinucleated giant cells (MGC) per visual field at x25 in the C-HA-implanted specimens in each rabbit was 14.4. significantly larger than the 6.1 in the HA specimens. However. 12 weeks after C-HA implantation. the areal ratio of new bone increased to 32.7%. the number of MGC decreased to 9.4. and the differences compared to the values in HA cases. 31.5% and 6.8. disappeared. These results showed that C-HA is mechanically stronger than HA and that there is no difference between HA and C-HA in capacity for new bone formation or foreign-body reaction.
Absorption, biocompatibility, and fixation properties of polylactic acid in bone tissue: an experimental study in rats, The absorption. biocompatibility. and fixation properties of self-reinforced (SR) poly-L-lactic acid (PLLA) and poly-DL-lactic acid (PDLLA) were investigated in cancellous bone in 56 rats. Osteotomies of the distal femur were operatively fixed with cylindrical implants made of SR-PLLA and SR-PDLLA/PLLA (40 PDLLA:60 PLLA). The follow-up times were one. three. six. 12. 24. 36. and 48 weeks. Roentgenographic. microradiographic. histologic. histomorphometric. and oxytetracycline-labeling studies were done. Histologically. there was no evidence of inflammation or foreign-body reaction in the bony tissues. Histomorphometric analysis showed that absorption in the SR-PDLLA/PLLA implant was faster than in the SR-PLLA implant. Absorption started peripherally in the implants and continued with subsequent replacement by new bone. At 48 weeks the implant was completely surrounded by a layer of new bone. The SR-PLLA and SR-PDLLA/PLLA implants were visible in all specimens during the 48-week follow-up period. Ninety-five percent of the osteotomies were consolidated. Implants made of SR polylactic acid in rats proved to be biocompatible and slowly absorbable. and they possessed sufficient mechanical properties for fixation of osteotomies.
The use of bone grafts and alloplastic materials in cranioplasty, Trephination dates from prehistoric neolithic times (10.000-7000 B.C.) and is the oldest operation known. Cranioplasty with bone allografts dates from the Stone Age Celts. Through the millennia. generations of surgeons have tried bone autografts. allografts. and rarely xenografts for cranioplasty but abandoned these in favor of alloplastic metals and plastics. most recently methylmethacrylate. Disillusionment with bone cranioplasty has followed the recurrent experience that orthotopic transplantation of bone to skull is almost invariably accompanied by a striking propensity for resorption. Resorption coupled to new bone formation is the usual process of remodeling. A unique acellular nonosteoclastic resorption. antedating invasion of the graft by osteoprogenitor cells and unrelated to the remodeling. characterizes the initial response of bone placed in a skull bed. This previously undescribed resorption in the skull likely represents passive diffusion of mineral from an altered matrix (calciolysis) and varies directly with the degree the graft is denatured by processing. There is the least amount of resorption in the fresh autograft and the most in autoclaved or chemically treated frozen or freeze-dried grafts. Remodeling of this diminished template occurs centripetally from skull defect margins through osteoconductive mechanisms only. Marrow-poor skull with thin diploe provides few osteoprogenitor cells that slowly. incompletely remodel the reduced graft over years.
Revision arthrodesis for tibiotalar pseudarthrosis with fibular onlay-inlay graft and internal screw fixation, Pseudarthrosis after failed tibiotalar arthrodesis was successfully treated surgically in nine of 11 patients between 1980 and 1987. The indication for the initial attempted arthrodesis was traumatic arthrosis in seven patients. traumatic arthrosis with osteonecrosis of the talus in two patients. degenerative arthrosis in one patient with cavovarus foot (Charcot-Marie-Tooth). and myelodysplasia with progressive valgus deformity of the foot and ankle in one. The surgical technique planned for revision arthrodesis provided firm coaptation of tibia to talus with internal fixation that maintained the foot at right angles to the tibia with the forefoot in neutral position. Seven feet in 11 patients were treated using a transfibular approach that allowed excision of fibrous tissue and sclerotic bone. decortication of the media malleolus. fixation of the tibia to the talus with cancellous screws. and onlay/inlay fibular graft. Of the remaining four patients. one was treated with medial compression plate. a second was treated using an anteromedial cortical graft. a third was treated by a combination of sliding anteromedial corticocancellous graft and tibiotalar compression screw. and a fourth was treated with tibiotalar compression screw. Clinical and roentgenographic union occurred in nine of 11 patients. One patient developed a painless. fibrous union and one patient with persistent pseudarthrosis had myelodysplasia and severe valgus deformity and required amputation. Adequate exposure was possible through the transfibular approach to provide cancellous bone opposition. to excise the pseudarthrosis membrane and sclerotic bone. and to remove necrotic segments of the talus. In addition. supplemental bone graft. internal fixation. and postoperative cast immobilization were also helpful in obtaining union.
Treatment of nonunion by percutaneous injection of bone marrow and demineralized bone matrix. An experimental study in dogs, Successful treatment of nonunited fractures remains a major clinical challenge. Because bone marrow and demineralized bone matrix (DBM) are capable of stimulating osteogenesis. experiments were designed to test the effectiveness of bone marrow or DBM or both when injected percutaneously into a canine nonunion model. Six-millimeter segmental defects were created in the midtibial diaphysis of 24 adult mongrel dogs and held distracted by external fixation. For comparative purposes. a 0.5-mm osteotomy was created in five dogs. Five weeks later. the 6-mm defects were injected with either saline. autogeneic marrow. DBM powder. a composite of bone marrow and DBM. or treated by open grafting techniques with autogenic cancellous bone. Healing of the defect was evaluated roentgenographically. biomechanically (three-point bending). histologically. and biochemically 13 weeks postsurgery. Marrow and DBM stimulated defect healing. However. the combination of bone marrow with DBM produced a synergistic response in the defect. which was greater than the sum of either marrow or DBM alone. Healing in the composite-grafted dogs was comparable to those treated by standard cancellous bone grafting. These data suggest that percutaneous injection of bone marrow and DBM may be a potential alternative that offers numerous advantages over standard open grafting techniques in the treatment of fractures with nonunited defects.
Salvage of nonunion following ankle arthrodesis for failed total ankle arthroplasty, Revision operations for nonunion following total ankle arthrodesis for total ankle arthroplasty (TAA) were reviewed in ten patients. Operations averaged 2.0 years after prior arthrodesis attempts and featured external fixation in seven. internal fixation in one. percutaneous pin fixation in one. and cast immobilization only in one. Bone graft was used in seven. Union was achieved in 78%. The one complication was an infection in a patient with prior sepsis. The results were considered excellent in three. good in one. fair in three. and poor in two of the nine patients with adequate follow-up evaluation (average. 7 years). Despite successful arthrodesis. residual symptoms were common because of factors such as hindfoot degenerative arthritis and malalignment.
Ankle fusion, Multiple techniques for ankle arthrodesis have been described. A transfibular lateral approach between the sural nerve and the lateral branch of the superficial peroneal nerve is utilized. This permits excellent visualization of the ankle joint so that correction of the deformity can readily be achieved under direct visualization. Eighteen ankle fusions carried out through a transfibular approach were reviewed. The fusion site was stabilized with two or more 6.5-mm AO screws. No bone graft was utilized. The follow-up period was from six to 48 months. Ages of the patients ranged from 21 to 68 years. The postoperative regimen was six weeks nonweight-bearing in a short-leg cast. followed by weight bearing in a short-leg cast until union occurred. All fusions but one healed with an average period of 14 weeks of immobilization. No patient experienced wound healing difficulty or disruption of a superficial nerve. The authors believe that this is a simple technique that permits excellent visualization through a safe internervous interval. good bone apposition. rigid interfragmentary fixation and does not require the use of bone graft.
Transarticular cross-screw fixation. A technique of ankle arthrodesis, Many techniques of ankle arthrodesis have been described. Failure rates of up to 40% have been reported in the past. In this study. a technique for internal fixation of ankle fusions was employed using transarticular crossed-screw fixation. This provides bony coaptation. compression. and immobilization necessary for reliable union. Thirty-five patients had ankle arthrodesis with this technique of internal fixation and 12 patients had ankle fusions with Charnley compression arthrodesis. Follow-up evaluation averaged two years. The fusion rate was 100% (35 fusions of 35 attempts) with the transarticular crossed-screw technique and 83% (ten fusions of 12 attempts) with compression arthrodesis.
Ankle arthrodesis with an anterior tension plate, The incidence of complications associated with arthrodesis of the ankle has remained high. especially in wound complications and infections. A new method to achieve arthrodesis of the ankle that utilizes an anterior surgical approach and an anterior tension plate was assessed in 17 patients. This method transforms the potentially deforming force of the tendoachilles into a compressive and corrective force and facilitates realignment of the ankle in all planes. Also. dissection and subperiosteal elevation is minimized while soft tissue coverage of the hardware is maximized. Whereas the predominant preoperative diagnosis was posttraumatic degenerative joint disease. others included failed ankle arthroplasty. failed arthrodesis. and a fixed equinus deformity. A solid arthrodesis was achieved in 82% of the patients. Although complications occurred and two patients required reoperations. there were no problems with respect to wound healing or infection. which is a marked contrast to other series. This technique is recommended as a simple. safe. and effective method to achieve an arthrodesis of the ankle joint.
Ankle arthrodesis. A comparison of an arthroscopic and an open method of treatment, An arthroscopic technique and an open technique with malleolar ostectomy for ankle arthrodesis is described and compared. Internal fixation with compression across the tibiotalar joint was utilized for both methods using either 6.5-mm or 7.0-mm cannulated screws. The indications. advantages. results. and complications of these two fusion techniques in 33 patients are reported. Arthroscopic arthrodesis was performed in 17 patients. using open arthrotomy and malleolar ostectomy in 16. The mean time to arthrodesis for patients having the procedure arthroscopically was 8.7 weeks (range. six to 14 weeks). compared to 14.5 weeks in the open arthrotomy group (range. eight to 26 weeks; p less than 0.004). Despite differences in patient selection for each of the two groups. it was concluded that disabling ankle arthritis for certain patients may be more appropriately managed with arthroscopic arthrodesis than by arthrotomy and malleolar ostectomy. utilizing similar methods of internal fixation.
An overview of ankle arthrodesis, Arthrodesis of the ankle can result in a painless. normal walking gait. However. complications in ankle arthrodesis can be major. and can occur when anatomy. deformity. or bony deficiency is not properly addressed. Nonoperative treatment should always be considered first. and. if possible. an open or arthroscopic ankle debridement can provide significant pain relief. Arthrodesis should be considered after conservative treatment fails. Infections. deformity. sensory deficiencies. and bony defects require special consideration. The use of bone graft and internal or external compression will enhance the likelihood of a successful arthrodesis.
Pharmacokinetics of esmolol in children, The pharmacokinetics and concentration-response relationships of intravenous esmolol were investigated in 20 children undergoing indicated cardiac electrophysiologic testing. A loading dose of 600 micrograms/kg was infused for 2 minutes. An infusion of esmolol was initiated and dosage was titrated until beta-blockade occurred. Serial esmolol blood samples were obtained for pharmacokinetic analysis. Non-compartmental pharmacokinetic analysis of the data revealed the following parameter estimates (mean +/- SD): volume of distribution at steady state. 2.0 +/- 1.4 L/kg; total body clearance. 321.2 +/- 238.8 ml/kg/min; and terminal elimination half-life. 4.5 +/- 2.1 minutes. There was a significant correlation between mean esmolol concentrations and mean percentage of reductions of mean arterial pressures and heart rates at each sample time (p less than 0.001). The doses of esmolol required for beta-blockade (mean +/- SD. 535 +/- 180 micrograms/kg/min) in children were considerably higher than those typically used in adults. Esmolol should prove useful in children in the acute management of cardiac arrhythmias and hypertension.
Assessment of systemic effects of different ophthalmic beta-blockers in healthy volunteers, Systemic beta-blockade after single doses of ophthalmic beta-blockers (one drop in each eye) was investigated in healthy volunteers in two randomized. double-blind. crossover. placebo-controlled studies. beta-Blockade was evaluated by displacement of the bronchodilator (specific airway conductance). positive chronotropic (heart rate). and tremorogenic (finger tremor amplitude) dose-response curve for inhaled isoproterenol. In study 1. 0.5% betaxolol. 0.6% metipranolol. and 0.5% timolol were tested in 16 subjects. Compared with placebo. all beta-blockers resulted in a significant systemic beta-blockade (p greater than 0.05); the increasing order of potency was betaxolol. metipranolol. and timolol. In study 2. 2% butylamino-phenoxy-propanol-acetate (BPPA; a noncardioselective but topically oculoselective drug) and 1% timolol were investigated in 12 subjects. Placebo and BPPA showed no differences (p greater than 0.05). whereas timolol resulted in a significant beta-blockade (p less than 0.05). Topical oculoselectivity is an important aspect of drug safety of beta-blocking eyedrops. Measure of tremor is appropriate to evaluate beta 2-blockade.
Effect of caffeine on ibuprofen analgesia in postoperative oral surgery pain, Recent studies have demonstrated that caffeine acts as an analgesic adjuvant when combined with acetaminophen. aspirin. or their mixture. Our objective was to determine whether similar enhancement of analgesia could be demonstrated when caffeine is combined with ibuprofen. On a double-blind basis. a single oral dose of ibuprofen (50. 100. or 200 mg). a combination of ibuprofen. 100 mg. with caffeine. 100 mg. a combination of ibuprofen. 200 mg. with caffeine. 100 mg. or placebo was randomly assigned to 298 outpatients with postoperative pain after the surgical removal of impacted third molars. With a self-rating record. subjects rated their pain and its relief hourly for 8 hours. All active treatments were significantly superior to placebo. and the caffeine effect was significant for every measure of analgesia. Relative potency estimates indicated that the combination was 2.4 to 2.8 times as potent as ibuprofen alone. The combination also had a more rapid onset and longer duration of analgesic action. The analgesic adjuvancy of caffeine clearly extends to combinations with nonsteroidal anti-inflammatory drugs other than acetaminophen or aspirin.
A cross-sectional study of platelet cyclic AMP in healthy and hypertensive pregnant women, 1. Platelet activation in vivo occurs in healthy pregnant women and is more marked in women with preeclampsia. During pregnancy platelets have also been shown in vitro to be less susceptible to the inhibitory effects of prostacyclin. The cyclic nucleotide cyclic AMP has a key role as an inhibitory second messenger in platelets and mediates the inhibitory effects of prostacyclin. 2. We have studied cyclic AMP in relation to platelet behaviour in healthy pregnant women in the third trimester and in women with pregnancy-induced hypertension and pre-eclampsia. Non-pregnant young women were used as controls. 3. Pharmacological agents which increase levels of cyclic AMP were significantly less effective as inhibitors of platelet activation during pregnancy. but there was no difference between the healthy and hypertensive pregnant subjects. 4. Basal platelet cyclic AMP levels were the same in all three groups. However. the production of cyclic AMP in response to a range of adenylate cyclase stimulators was reduced during pregnancy. but again there was no difference between healthy and hypertensive pregnant subjects. 5. The reduction in platelet cyclic AMP levels in pregnancy occurred not only with those adenylate cyclase stimulators which operate via surface receptors. but also on direct stimulation of the enzyme with forskolin. 6. The most likely explanation of these observations is a reduction in the ability of the platelet adenylate cyclase enzyme to respond to stimulation of the third trimester of pregnancy. The consequent reduction in formation of the inhibitory second messenger cyclic AMP may in part be responsible for platelet activation in vivo during pregnancy. There does not appear to be a further difference in platelet cyclic AMP production in hypertensive pregnant women.
Glutathione depletion during experimental damage to rat skeletal muscle and its relevance to Duchenne muscular dystrophy, 1. The release of glutathione has been studied in comparison with the release of creatine kinase from isolated rat soleus muscles subjected to certain forms of experimental damage. 2. Excessive electrically stimulated contractile activity or treatment of muscles with the mitochondrial inhibitor. 2.4-dinitrophenol. induced a substantial release of both creatine kinase and glutathione and a reduction in the total glutathione content of the muscle. The time course of this release and depletion indicates that the efflux of the two molecules is not directly related and that a reduction in muscle glutathione content does not occur before cytosolic enzyme release. 3. 2.4-Dinitrophenol-stimulated release of creatine kinase was significantly reduced by the omission of external calcium from the incubation media. but glutathione release and depletion was relatively unaffected by this. Deliberate elevation of the muscle intracellular calcium content with the calcium ionophore. A23187. induced a substantial loss of creatine kinase. but had no significant effect on the release of glutathione. 4. Muscle biopsies from patients with Duchenne muscular dystrophy were found to have an elevated content of glutathione and an equivalent protein-thiol content compared with control subjects. 5. We conclude that. although release of glutathione from skeletal muscle occurs after excessive contractile activity or inhibition of mitochondrial metabolism. this is not a key step in the damaging processes leading to cytosolic enzyme release. neither is it relevant to the ongoing damage to skeletal muscle which occurs in patients with Duchenne muscular dystrophy.
Increased symptoms of hypoglycaemia in the standing position in insulin-dependent diabetes mellitus, 1. To test the hypothesis that patients with insulin-dependent diabetes mellitus perceive the symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position. we assessed symptoms of hypoglycaemia. as well as heart rate and plasma noradrenaline and adrenaline concentrations. in both positions during hyperinsulinaemic glucose clamps on three occasions in seven patients. 2. Plasma glucose concentrations were clamped at 5.0 mmol/l (90 mg/dl) and 5.0 mmol/l on one occasion. at 5.0 mmol/l and 3.9 mmol/l (70 mg/dl) on another occasion. and at 5.0 mmol/l and 2.8 mmol/l (50 mg/dl) on yet another occasion. 3. During euglycaemia there was no effect of position on the symptom panels used to assess the symptomatic response to hypoglycaemia. However. at the plasma glucose concentration of 2.8 mmol/l. total (P less than 0.003) and neurogenic (P less than 0.005). but not neuroglycopenic. hypoglycaemic symptom scores were higher with the patients in the standing than in the lying position. Increments in total hypoglycaemic symptom scores. over those during the corresponding euglycaemic phase. were 5 +/- 2 in the lying position and 11 +/- 2 in the standing position (means +/- SEM. P less than 0.01). 4. Thus patients with insulin-dependent diabetes mellitus perceive symptoms of hypoglycaemia to a greater extent when they are in the standing position than when they are in the lying position because of enhanced neurogenic symptoms.
Measurement of tumour protein synthesis in vivo in human colorectal and breast cancer and its variability in separate biopsies from the same tumour, 1. A method is described for measuring the rates of protein synthesis in vivo in human colorectal and breast tumours by the intravenous injection of L-[1-13C]leucine as a 'flooding dose'. 2. The incorporation of isotope into colorectal tumour protein was measured in six patients. whose tumours were biopsied after the injection. Fractional rates of protein synthesis were calculated from the enrichment of leucine in protein and the average free leucine enrichment in plasma. The range of rates obtained was 17.2-33.9%/day. with a mean rate (+/- SEM) of 22.5 +/- 2.6%/day. 3. Tumour protein synthesis rates were also measured in 15 patients with breast cancer. The range of rates obtained was 5.3-15.9%/day. with a mean rate (+/- SEM) of 10.3 +/- 0.8%/day. These rates are significantly lower than those obtained with colorectal tumours (P less than 0.001). 4. In 9 of the breast cancer patients. protein synthesis was measured in multiple random biopsies taken from the same tumour. The mean (+/- SEM) difference between the highest and lowest rates in biopsies from the same tumour was only 1.1 +/- 0.3%/day. Only 13% of the variation in protein synthesis between separate tumours could be explained by sampling error because of variation within the tumour itself. the remainder being genuine variation between individual tumours.
Cardiopulmonary exercise responses after single lung transplantation for severe obstructive lung disease, The purpose of this study was to characterize cardiovascular and ventilatory responses to exercise in single lung transplantation (SLT) recipients with nonseptic. severe obstructive lung disease (SLT-OB). We also investigated whether the hyperinflated native lung in SLT-OB recipients could limit normal increases in tidal volume by mechanically constraining the transplanted lung. resulting in ventilation-perfusion imbalance in the lung graft. Data from six SLT-OB recipients (five women. one man) and six age-matched SLT recipients (two women. four men) with severe interstitial lung disease (SLT-IN) were compared. Resting arterial O2 and CO2 tensions were normal and comparable between the SLT groups. Spirometry results were reduced but comparable between SLT groups. Total lung capacity was significantly larger in patients with SLT-OB than in patients with SLT-IN. Diffusion capacity was not different between SLT groups when differences in alveolar volume were accounted for. Quantitative perfusion to the lung graft was comparable between the SLT groups. but quantitative ventilation was greater in patients with SLT-OB than in patients with SLT-IN. Maximum exercise capacity following SLT-OB was decreased. but was comparable to that of SLT-IN recipients. None of the SLT-OB recipients reached predicted maximum minute ventilation and only one experienced mild arterial O2 desaturation. suggesting peripheral muscle abnormalities from corticosteroid use and deconditioning as limiting factors rather than a ventilatory limitation. Tidal volumes at end exercise in the SLT-OB recipients were normal. Our quantitative lung scan and exercise testing data suggest that ventilation-perfusion imbalance and resulting gas exchange abnormalities from lung graft constraint and compression do not occur at rest or with exercise after SLT for obstructive lung disease.
Collagenase and collagenase inhibitors in bronchoalveolar lavage fluids, Collagenase. collagenolytic activity and tissue inhibitor of metalloproteinases were evaluated in bronchoalveolar lavage from 25 patients with hypersensitivity pneumonitis and four control subjects. Patients were followed between two and three years. after which they were classified as "healed." "improved." or "worsened." In control samples. immunoreactive collagenase was not detected. The enzyme was present in four of seven patients who healed. six of ten patients who improved. and four of eight patients who worsened. There was no relationship between the presence or absence of BAL collagenase or its concentration and the evolution of the disease. Latent collagenolytic activity was detected only in 5 of the 14 patients who displayed immunoreactive collagenase. Regarding collagenase inhibitor. TIMP was present in BAL fluid from all patients and normal subjects. Although the highest values were found in two cases who healed or improved. there was not a statistically significant difference among the three groups of patients. neither between patients nor control subjects. These findings suggest that at least in HP. the presence of collagenase. collagenolytic activity. or TIMP in BAL fluid is not associated with the prognosis of the disease.
Breathing during sleep in patients treated for obstructive sleep apnea. Nasal CPAP for only part of the night, To determine whether long-term NCPAP therapy influences severity of sleep disordered breathing during the second part of a night when NCPAP is applied for only the first four hours of sleep. we studied 21 patients with OSA receiving NCPAP therapy for 253 +/- 41.6 days. Results from polysomnography for the period after withdrawal from NCPAP (night B) were compared to the corresponding period of sleep prior to initiation of NCPAP therapy (night A). There was no significant change in RDI from night A (53.9 +/- 8.6) to night B (28.7 +/- 3.3). but maximal apnea length diminished from 55 +/- 2.9 s to 40 +/- 2.9 s (p less than 0.05). Whereas daytime Po2 and the amplitude of desaturations during sleep remained equal. overall oxygenation during sleep improved slightly (mean SaO2 night A = 90.6 +/- 0.9 percent; night B = 92.8 +/- 0.5 percent; p less than 0.05). Differences between nights A and B were more prominent the more severe sleep apnea had been prior to treatment and could not be explained by weight loss. There was strong correlation between improvements in oxygenation measurements and the daily time of NCPAP use. In conclusion. we found a subgroup of OSA patients receiving long-term NCPAP therapy with less disturbed ventilation during sleep following use of NCPAP for only the first part of the night. but in the majority of patients. sleep disordered breathing off NCPAP remained unchanged.
Excess mortality in critically ill patients with nosocomial bloodstream infections, To determine the excess mortality attributable to hospital-acquired bloodstream infections. we applied the acute physiology and chronic health evaluation (APACHE) II classification to 34 critically ill patients with this complication. The study included primary bloodstream infections. defined by a positive blood culture at least three days after hospitalization. in the absence of any other apparent source of infection. The most frequent blood isolates included Staphylococcus aureus (39 percent). Gram-negative rods (24 percent). and Candida albicans (15 percent); the spectrum of blood isolates suggested that most infections were related to intravascular catheters. In a control group of intensive care unit patients (n = 384). the death rate predicted by APACHE II was similar to the observed death rate (35.3 vs 37.8 percent). In a subgroup of control patients (n = 34). chosen for APACHE II scores that matched the patients with bloodstream infections. predicted and observed death rates were also similar (53.1 vs 52.9 percent). For patients with bloodstream infections. however. observed mortality (82.4 percent) significantly exceeded the predicted value (54.1 percent. p = 0.025). We conclude that critically ill patients who develop nosocomial bloodstream infections are at greater risk of death than patients with comparable severity of illness without this complication. The difference between the observed and predicted death rates. 28 percent. represents the excess mortality associated with bloodstream infection in critically ill patients.
Inhaled verapamil-induced bronchoconstriction in mild asthma, Methacholine challenges were performed in ten subjects with mild asthma at 2 h before and 20 min after placebo or 5. 10. 20. 40. 80. and 160 mg of inhaled verapamil given in a single-blind randomized crossover manner on different days. While verapamil did not have a bronchodilator effect. the 10-mg dose modestly increased the concentration of methacholine required to decrease FEV1 by 20 percent (PC20). The mean (+/- SEM) increase in PC20 from baseline was 2.1 +/- 0.2 times baseline after 10 mg of verapamil. compared to 1.1 +/- 0.1 times baseline after placebo (p less than 0.001). Unexpectedly. bronchoconstriction (greater than 10 percent decrease in FEV1) associated with cough or wheezing was observed in seven of ten subjects at doses of 20 mg or more. This adverse effect was not related to the osmolarity of the nebulized solutions. Thirty minutes before a standardized exercise challenge. 13 subjects inhaled placebo. 10 mg. or the highest dose of verapamil tolerated during the methacholine study (20 to 160 mg) in a double-blind randomized crossover manner. The exercise challenge was aborted in three subjects because of bronchospasm that occurred after administration of the higher dose. The mean (+/- SEM) maximum change in FEV1 after exercise in the ten subjects completing all three regimens of treatment was -17.1 +/- 4.0 percent after placebo. -12.7 +/- 4.3 percent after 10 mg (p less than 0.05). and -6.4 +/- 3.6 percent after the highest dose (p less than 0.05). We conclude that increasing the dose of verapamil above 10 mg did not provide greater benefit but. paradoxically. induced bronchoconstriction in most of the subjects. Because of this potential bronchoconstrictor effect. high doses of oral or intravenous verapamil should be used with caution in asthmatic subjects.
Exercise testing and left main coronary artery stenosis. Can patients with left main disease be identified, Exercise testing is commonly used to evaluate patients with coronary artery disease who have serious anatomic characteristics. To study the characteristic exercise test variables in patients with left main coronary artery disease. the computerized data base of the Hungarian Institute of Cardiology Exercise Test Laboratory was used. Among 2.378 patients who had undergone a supine bicycle exercise test and who had abnormal coronary angiographic results. 65 patients with significant (greater than 50 percent diameter narrowing) stenosis of the left main coronary artery were found. The 65 patients were subgrouped according to their previous history and other vessel involvement. Nine patients had isolated left main coronary artery disease and no myocardial infarction (group 1); 28 patients had left main coronary artery stenosis and another diseased vessel but no prior myocardial infarction (MI) (group 2); and 28 patients had left main coronary artery disease. another diseased vessel. and a prior MI (group 3). For comparison. the 27 patients selected to be the control group (group C) had no history of MI but had significant stenosis of both the left anterior descending and the left circumflex arteries. Exercise time. calculated oxygen consumption. maximal work load. time to ST depression. prevalence of ST segment depression. and maximal ST depression were similar in the groups. Maximal heart rate and double product were higher in group 1. but we could find no single variable or group of variables characteristic of left main coronary artery disease.
Coronary vasospasm secondary to labetalol in a patient with aortic dissection, A 66-year-old hypertensive woman presented with epigastric and scapular pain on the basis of type 3 aortic dissection. Appropriate therapy with a combined alpha-adrenergic and beta-adrenergic antagonist agent prevented further ongoing dissection and amelioration of symptoms. On day 5. an episode of coronary vasospasm occurred presumably due to beta-blockade with unopposed alpha-adrenergic activity.
Asymptomatic cor triatriatum incidentally revealed by computed tomography, We report a case of asymptomatic cor triatriatum in a 75-year-old man in whom the anomaly was incidentally revealed by computed tomography (CT). To our knowledge. this patient is the oldest case reported and the only such case in which the anomaly was demonstrated by CT.
Ventricular tachycardia originating from the right ventricular free wall in a patient with an old myocardial infarction, A 64-year-old woman with right ventricular infarction had ventricular tachycardia (VT) with left bundle-branch block morphology. Pace-mapping during sinus rhythm and the earliest ventricular potential during VT suggested that the VT originated in the inflow-inferior site of the right ventricular free wall.
Late variation in ventricular function after myocardial infarction, To assess the possible role of variables not related to early infarct artery reperfusion in predicting late changes in ventricular function after infarction. paired early (mean 6.6 +/- 3.5 days after admission) and late (12.7 +/- 7.0 months later) cross-sectional echocardiograms from 54 infarction survivors were retrospectively reviewed. Ejection fraction was calculated from digitized biapical echocardiographic views on a graphics tablet. Changes of 0.10 or more in LVEF were correlated with 23 clinical variables. By stepwise regression analysis. Q-wave infarction and low early LVEF independently predicted late improvement in function. Early high LVEF and interval infarction were the only independent predictors of late declines in function. Overall. when patients were indexed by early left ventricular systolic function. a pronounced late "regression to the mean" was noted with initially high values tending to fall and low values to rise (r = -0.44. p less than 0.001). This effect must be accounted for in any acute intervention trial in myocardial infarction. The occurrence of Q-wave infarction does not exclude late improvement in ventricular function.
Respiratory illness in nonsmokers chronically exposed to tobacco smoke in the work place, We evaluated CO levels as an index of cigarette smoke in the work place and analyzed diary entries on respiratory symptoms. eye irritation. chest colds and lost days from work due to respiratory illness in 40 passive smokers (nonsmokers chronically exposed to tobacco smoke in the work place) and 40 control subjects (nonsmokers not exposed to tobacco smoke in the work place) matched for age and gender. Passive smokers experienced greater CO levels during the workday. Also they reported significantly more cough. greater phlegm production. more shortness of breath. greater eye irritation. more chest colds and more days lost from work due to chest colds than control subjects. Nonsmoking workers and their employers are likely to incur significant financial loss because of missed workdays due to illnesses resulting from exposure to second-hand tobacco smoke.
Increased incidence of type II diabetes mellitus in Mexican Americans, OBJECTIVE: To determine whether Mexican Americans have an increased incidence of non-insulin-dependent (type II) diabetes mellitus relative to non-Hispanic whites. Currently. no study has reported on the incidence of this disorder in Mexican Americans. RESEARCH DESIGN AND METHODS: We determined the 8-yr incidence of type II diabetes in 617 Mexican Americans and 306 non-Hispanic whites who participated in the San Antonio Heart Study. a population-based study of diabetes and cardiovascular disease. Forty Mexican Americans (6.5%) and 6 non-Hispanic whites (2%) developed type II diabetes. as defined by World Health Organization criteria. The age-adjusted ethnic odds ratio (OR; Mexican Americans/non-Hispanic whites) for diabetes incidence was 8.13 (95% confidence interval [C1] 1.10-59.9) in men and 3.62 (95% CI 1.37-9.55) in women. We adjusted for age. sex. ethnicity. body mass index. and level of educational attainment with multiple logistic regression analyses. RESULTS: Mexican Americans continued to show a statistically significant increase in diabetes incidence (OR 2.72. 95% CI 1.02-7.28). Obesity and age were also positively related to diabetes incidence in this analysis (P less than 0.001). In addition. subjects with at least some college education had a lower incidence of diabetes than those with less than a high school education (OR 0.51. 95% CI 0.26-0.99). CONCLUSIONS: The incidence of type II diabetes in Mexican Americans is greater than in non-Hispanic whites. a difference that is not explained by ethnic differences in obesity. age. or level of educational attainment.
Effect of antecedent glucose control on cerebral function during hypoglycemia, OBJECTIVE: The incidence of both severe and asymptomatic hypoglycemia is increased threefold in intensively treated diabetic patients. To examine whether this reflects cerebral adaptation to low blood glucose levels. we investigated the effect of preceding glycemic experience on hormonal. EEG. and evoked potential responses to experimentally induced hypoglycemia with the slow-fall clamp. RESEARCH DESIGN AND METHODS: Three groups were examined: well-controlled diabetic patients and patients with insulinoma (group 1). poorly controlled diabetic patients (group 2). and nondiabetic subjects (group 3). RESULTS: The glucose threshold for epinephrine release was lower in group 1 (2.3 +/- 0.1 vs. 3.0 +/- 0.3 and 3.1 +/- 0.1 mM. P less than 0.02). and the peak epinephrine response was reduced (1.29 +/- 0.36 vs. 5.48 +/- 1 and 5.62 +/- 1.2 nM. P less than 0.01) compared with groups 2 and 3. whereas symptoms were not perceived until a lower blood glucose level had been reached (2.0 +/- 0.2 vs. 3.3 +/- 0.4 and 2.6 +/- 0.2 mM. P less than 0.01). Other counterregulatory responses were similarly delayed and diminished. In contrast. EEG changes that were compatible with hypoglycemia were detected in all subjects in group 1 (blood glucose 1.9 +/- 0.1 mM) but in only two in group 2 and none in group 3. despite similar blood glucose nadirs. CONCLUSIONS: The glycemic threshold for hormonal responses to hypoglycemia falls in individuals with intensively treated diabetes or insulinomas. but these patients are more likely to develop EEG abnormalities during hypoglycemia. This disparity helps explain the increased vulnerability of intensively treated patients to severe hypoglycemia.
Association of cigarette smoking with diabetic retinopathy, OBJECTIVE: To determine whether cigarette smoking is associated with the incidence and progression of diabetic retinopathy. RESEARCH DESIGN AND METHODS: Younger-onset diabetic subjects who had been diagnosed at less than 30 yr of age and taking insulin (n = 1210) and a random sample of older-onset diabetic subjects diagnosed at greater than or equal to 30 yr of age (n = 1780) were selected. Baseline examinations were conducted on 996 younger- and 1370 older-onset subjects. Incidence of retinopathy was based on 138 younger-onset and 154 older-onset insulin-taking subjects and 321 older-onset non-insulin-taking subjects who were free of retinopathy at baseline. Progression of retinopathy was based on 530 younger-onset and 418 older-onset insulin-taking subjects and 486 older-onset non-insulin-taking subjects with less than proliferative diabetic retinopathy at baseline. RESULTS: Baseline smoking history was categorized by status (nonsmoker. ex-smoker. current smoker) and pack-years smoked while diabetic. Retinopathy was documented by stereoscopic fundus photography. In univariate analyses. the only significant association was between pack-years and progression to proliferative diabetic retinopathy in older-onset insulin-taking subjects (P less than 0.01). After controlling for known risk factors for the incidence and progression of retinopathy. pack-years smoked was borderline significant (P = 0.052) in predicting incidence of retinopathy in younger-onset subjects. Smoking was not associated with incidence in older-onset subjects or with progression or progression to proliferative diabetic retinopathy in any of the groups. CONCLUSIONS: Smoking is not likely to be an important risk factor for diabetic retinopathy.
Relationship of metabolic control and body weight to hypercholesterolemia in NIDDM patients with apolipoprotein E4, OBJECTIVE: We previously reported that non-insulin-dependent diabetes mellitus (NIDDM) patients with apolipoprotein E4 (apoE4) are more susceptible to hypercholesterolemia. The purpose of this study was to clarify whether metabolic control or body weight is related to hypercholesterolemia in NIDDM patients with apoE4. RESEARCH DESIGN AND METHODS: Two hundred forty NIDDM patients with apoE4 or apoE3/3 who had either hypercholesterolemia or normolipidemia were studied. ApoE phenotypes were determined by isoelectric focusing method. RESULTS: The apoE4-carrying NIDDM patients with hypercholesterolemia (n = 39) showed significantly higher fasting plasma glucose (8.4 vs. 7.2 mM. P less than 0.05). HbA1 (9.3 vs. 8.1%. P less than 0.05). and percentage of ideal body weight values (116 vs. 102%. P less than 0.01) than the apoE4-carrying NIDDM patients with normolipidemia (n = 26). whereas there was no significant difference in their levels between the apoE3/3-carrying NIDDM patients with hypercholesterolemia (n = 47) and normolipidemia (n = 128). CONCLUSIONS: In addition to our previous finding. this study indicates that hypercholesterolemia in apoE4-carrying NIDDM patients may be more closely related to poor metabolic control and increased percentage of ideal body weight.
Telematic transmission of computerized blood glucose profiles for IDDM patients, OBJECTIVE: To improve the analysis of self-monitoring of blood glucose (SMBG) and its communication between patients and physicians by a telematic transmission of computerized SMBG and to study the consequences of its use on glucose control of insulin-dependent diabetic (IDDM) patients. RESEARCH DESIGN AND METHODS: A prospective randomized crossover trial with two 3-mo periods. one with SMBG recorded on traditional booklets (booklet period) and another with computerized SMBG transmitted to a central data base through a telematic network (telematic period). comprised the study. During the latter phase. patients could receive computerized SMBG analysis on individual terminals connected to the telephone network (Minitel system). Blood glucose recordings and HbA1c were measured at inclusion and end of each period. Eleven pairs of IDDM patients on intensified insulin therapy were randomized within each pair to start with the telematic period (group A) or the booklet period (group B). RESULTS: Telematic transmissions were successful (less than 1% failure rate). Although initial HbA1c was low (6.7%). it declined during the telematic period (delta = -0.41%) compared with the booklet period (delta = +0.37%. P = 0.05). The percentage of low (less than 3.3 mM) blood glucose values correlated with HbA1c changes during the telematic period (r = 0.714. P = 0.0014) but not the booklet period. The patients favored the telematic tool to analyze SMBG. CONCLUSIONS: Telematic transmission of SMBG is feasible. It can improve SMBG analysis and perhaps glucose control. therefore offering a new way of communication between diabetic patients and their physicians.
Color discrimination and accuracy of blood glucose self-monitoring in type I diabetic patients, OBJECTIVE: To determine the importance of color discrimination ability regarding accuracy in the self-monitoring of blood glucose. RESEARCH DESIGN AND METHODS: Two hundred two insulin-dependent (type I) diabetic patients performed the Fansworth-Munsell 100-hue test and a second group of 159 type I diabetic patients performed a new Dusseldorf 26-hue test. Error scores in both tests were compared with error scores of patients' self-monitoring of blood glucose measurements with Chemstrip Haemoglucotest 20-800 strips. RESULTS: Color discrimination ability decreased with age. diabetes duration. and presence of retinopathy. It was independent of the degree of glycemia and accuracy of self-monitoring of blood glucose. CONCLUSIONS: Impaired color vision by itself is no reason to abandon self-monitoring of blood glucose with visually read strips.
Reproducibility of glucose and insulin responses to mixed meal in type II diabetic patients, OBJECTIVE: The reproducibility of glucose and insulin responses to a mixed meal were studied in 24 consecutive non-insulin-dependent (type II) diabetic patients. the diet of which matched the tested diet. Patients received their usual treatment throughout the study. RESEARCH DESIGN AND METHODS: A standardized diet was followed for 3 days. and responses were measured on the 2nd and 3rd days. Glucose and insulin responses were studied after lunches with the 180-min positive area under the curve. and were analyzed with paired t test and Pearson's linear regression. RESULTS: Glucose responses did not vary (217 +/- 50 vs. 217 +/- 38 min x mM. NS) and were significantly correlated (r = 0.64. P less than 0.01). Insulin responses did not vary (35.224 +/- 5768 vs. 35.305 +/- 7779 min x pM. NS) and were strongly correlated (r = 0.83. P less than 0.001). CONCLUSIONS: These results suggest that glucose and insulin responses to a test meal are reproducible in type II diabetic patients.
von Willebrand factor and endothelial abnormalities in diabetic microangiopathy, We briefly summarize current knowledge on 1) the abnormalities of von Willebrand factor (vWF) as an indicator of endothelial cell (EC) dysfunction in diabetes and 2) the modifications induced in the growth of cultured ECs by high glucose in the incubation media. A MEDLINE search (1986 through Sept. 1989) was performed to update previous relevant references on vWF and ECs in healthy and diabetic subjects. Main data in the literature and personal contributions were scrutinized. Study quality. information. and relevance to the subject were assessed. vWF is synthesized and stored mainly in ECs. Its plasma levels are increased in diabetic microangiopathy but are not influenced by circulating glucose. insulin. or growth hormone. nor do they acutely affect platelet function in diabetes. Supraphysiological concentrations of glucose inhibit the replication of cultured ECs from large vessels via different possible mechanisms but appear to stimulate pathways involved in the activation of capillary ECs. vWF is a possible marker of EC damage in diabetes. and prospective studies will ascertain its role as a predictor for the development of microangiopathy. The possible dichotomy in the response of cultured ECs from large and small vessels to high glucose in the culture media may help explain some of the lesions observed in the walls of arteries and capillaries in diabetes.
Plasma catecholamine responses to hypoglycemia in children and adolescents with IDDM, OBJECTIVE: The goal of this study was to assess whether children and adolescents with insulin-dependent diabetes mellitus (IDDM) have decreased catecholamine responses to insulin-induced hypoglycemia as has been reported in adults and to explore the pathogenesis of the decreased response in terms of possible relationships to autonomic neuropathy or hyperinsulinism. RESEARCH DESIGN AND METHODS: A before-and-after trial on the effects of 3 days of intensive insulin therapy was conducted on 60 subjects with IDDM (age 15.4 +/- 2.6 yr. duration of diabetes 7.8 +/- 3.5 yr). The control group consisted of 5 children with non-growth hormone-deficient short stature (age 14.8 +/- 3.2 yr). Hypoglycemia was induced with an intravenous insulin bolus (0.15-0.75 U/kg) after insulin withdrawal and 3 days of intensive insulin therapy in diabetic subjects on an inpatient basis to assess the role of hyperinsulinism in suppressing the catecholamine response to hypoglycemia. Control subjects were studied once and received an insulin bolus of 0.1 microU/kg. Autonomic neuropathy was assessed by computerized assessment of the basal R-R variation during inspiration and expiration and the pancreatic polypeptide response to hypoglycemia. RESULTS: Basal plasma catecholamine levels were lower in diabetic subjects after intensive insulin therapy than in control subjects (P = 0.008). The peak and incremental catecholamine responses after insulin withdrawal and intensive insulin therapy in IDDM subjects were significantly decreased compared with control subjects (P less than 0.001). Peak catecholamine responses to hypoglycemia in IDDM were decreased after intensive insulin therapy (P = 0.002). This was particularly true in those with plasma glucose nadir levels of less than 2.2 mmol (P less than 0.001). The diminished catecholamine responses were primarily due to decreased peak epinephrine responses after intensive insulin therapy compared with insulin withdrawal (P = 0.011). There were no significant correlations between the catecholamine response to hypoglycemia and age. duration of diabetes. pancreatic polypeptide. or R-R interval. CONCLUSIONS: These results suggest that children and adolescents with IDDM after insulin withdrawal have diminished catecholamine response to hypoglycemia compared with control subjects and indicate that short-term intensive insulin therapy diminishes this response further. Thus. hyperinsulinism may play a role in suppressing the catecholamine response to hypoglycemia. There is no evidence for a clinical or subclinical role of autonomic neuropathy to explain the altered catecholamine responses.
Low-glycemic index foods improve long-term glycemic control in NIDDM, OBJECTIVE: To compare high- and low-glycemic index (GI) diets in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: Sixteen subjects with well-controlled NIDDM and normal lipid profile. 10 of whom continued oral hypoglycemic medication. participated in the study. A diet that emphasized low-GI foods (e.g.. porridge. pasta) was compared with a high-GI diet (e.g.. processed cereals. potatoes). The GI of the low-GI diet was 15% lower than the high-GI diet (77 +/- 3 vs. 91 +/- 1) but otherwise similar in macronutrient composition and fiber. as determined by a 4-day weighed record. The diets were instituted under instruction from a dietitian who visited subjects at home on a weekly basis. Body weight was maintained within 1-2 kg. RESULTS: Glycemic control was improved on the low-GI diet compared with the high-GI diet (statistically significant findings. P less than 0.05). Mean glycosylated hemoglobin at the end of the low-GI diet was 11% lower (7.0 +/- 0.3%) than at the end of the high-GI diet (7.9 +/- 0.5%). and the 8-h plasma glucose profile was lower (area under the curve above fasting 128 +/- 23 vs. 148 +/- 22 mmol.h-1.L-1. respectively). Mean fasting plasma glucose. total cholesterol triglycerides. and lipoproteins did not show important differences. CONCLUSIONS: A low-GI diet gives a modest improvement in long-term glycemic control but not plasma lipids in normolipidemic well-controlled subjects with NIDDM.
Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians, OBJECTIVE: We wanted to determine whether obesity. abdominal fat distribution. and physical inactivity act similarly and independently as risk factors for noninsulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) in Hindu and Muslim Asian Indians. African-origin Creoles. and Chinese Mauritians. RESEARCH DESIGN AND METHODS: We examined a population-based random cluster sample of 5080 adult subjects from the Indian Ocean island of Mauritius. Glucose tolerance was assessed with a 75-g oral glucose tolerance test and World Health Organization criteria. RESULTS: Univariate data and multiple logistic regression models indicated that age. family history of diabetes. body mass index (BMI). waist-hip ratio (WHR). and physical inactivity conveyed similar risk for NIDDM (and IGT) in each ethnic group. After adjusting for all other factors. Hindu ethnicity conferred additional risk for NIDDM (but not IGT) in men. but in women there were no clear ethnic differences. Although BMI and WHR were independently significant risk factors. WHR conveyed relatively stronger risk for NIDDM than BMI in women. whereas the converse was true in men. For ethnic groups combined. the independent odds ratios for IGT associated with moderate and low physical activity scores (relative to high) were 1.56 and 1.71 (P less than 0.05). respectively. in men and 1.32 and 1.69 (P less than 0.05) in women. In subjects with asymptomatic NIDDM diagnosed during the survey. the independent odds ratios were 1.96 and 2.00 (P less than 0.05) in men and 1.73 and 2.70 (P less than 0.05) in women. CONCLUSIONS: These data indicate that BMI. abdominally distributed fat. and physical inactivity are important independent risk factors for both IGT and NIDDM in diverse ethnic groups. Attributable risk fractions for Mauritius suggest that populationwide modification of levels of these risk factors could potentially result in substantially lower occurrence of NIDDM (and IGT). Such interventions should be attempted in high-risk populations.
Lipoprotein(a) levels in black and white children and adolescents with IDDM, OBJECTIVE: To examine the relationship between levels of lipoprotein(a) [Lp(a)]. diabetes. and glycemic control in white and black nondiabetic control and insulin-dependent diabetic (IDDM) children and adolescents. fasting blood analyses were conducted on a subject sample drawn from referral-based diabetes and endocrine clinics and a primary-care general pediatric clinic. RESEARCH DESIGN AND METHODS: Thirty-six white and 16 black children with IDDM who volunteered to participate in this study were compared with 30 white and 42 black nondiabetic control children. RESULTS: Lp(a) protein levels were significantly higher (P less than 0.05) in both groups of black children compared with whites (black vs. white nondiabetic children 6.8 +/- 0.95 vs. 3.1 +/- 0.68 mg/dl and black vs. white diabetic children 7.5 +/- 1.52 vs. 3.0 +/- 0.64 mg/dl). Lp(a) protein levels directly correlated with the level of glycosylated hemoglobin (r = 0.46. P less than 0.01) in white diabetic children but not in black diabetic children. Well-controlled white diabetic children (n = 12. glycosylated hemoglobin less than 10%) had a mean Lp(a) protein level of 1.4 +/- 0.3 mg/dl compared with poorly controlled white diabetic children (n = 10. glycosylated hemoglobin greater than 13%) whose mean Lp(a) protein level was 5.7 +/- 1.7 mg/dl (P less than 0.01). CONCLUSIONS: We conclude that circulating levels of Lp(a) protein are increased in hyperglycemia. A genetically determined elevated level of Lp(a) is a risk factor for atherosclerotic disease in white and Asian adults. Elevated Lp(a) should be investigated as an independent risk factor for atherosclerotic disease in IDDM. It could prove to be an additional mechanism for the development of diabetic complications in selected populations.
Decrease of lipoprotein(a) with improved glycemic control in IDDM subjects, OBJECTIVE: Recently. lipoprotein(a) [Lp(a)] has been identified as a major risk factor for coronary heart disease. There are few data available on the influence of metabolic control on plasma Lp(a) concentrations in subjects with insulin-dependent diabetes mellitus (IDDM). a group at high risk for coronary heart disease. RESEARCH DESIGN AND METHODS: We examined the effects of improved metabolic control on plasma lipid and lipoproteins and Lp(a) concentrations in 12 subjects before and after 21 days of tight metabolic control. RESULTS: Glycosylated hemoglobin declined from 8.4 to 6.9% (P less than 0.001). and Lp(a) declined from 29.7 to 27.1 mg/dl (P = 0.022). There were no significant differences in total. low-density lipoprotein. or high-density lipoprotein cholesterol. although the decline in triglyceride concentrations were borderline statistically significant. The distribution of apolipoprotein(a) isoforms in IDDM patients was not unusual. and the apolipoprotein(a) isoform phenotypes did not change with improved metabolic control. Lp(a) concentrations were also significantly higher than in a population-based control group of nondiabetic subjects from the San Antonio Heart Study. CONCLUSIONS: Although the number of subjects was small and the degree of improvement in metabolic control was modest. the results suggest that improved metabolic control may decrease the risk of coronary heart disease mediated by Lp(a) in IDDM.
Health, life, and automobile insurance characteristics in adults with IDDM, OBJECTIVE: To determine whether people with insulin-dependent diabetes mellitus (IDDM) were compromised in their access to insurance. RESEARCH DESIGN AND METHODS: A case-control study of 158 people with IDDM and 158 nondiabetic siblings matched for age and sex was conducted to evaluate the health. life. and automobile insurance characteristics and history of people with IDDM. RESULTS: Health insurance coverage (yes/no) among the IDDM and sibling control subjects was similar. More than 90% of the IDDM and control respondents had insurance through a private third-party source. and this insurance did not differ by type of plan. coverage. or premium. However. Medicare coverage was more common among the IDDM subjects and was associated with the presence of severe diabetic complications. IDDM subjects were also more likely to have been denied a health insurance policy by an insurer than were the control subjects (23 vs. 1%. P less than 0.001). Similarly. there was no difference between the IDDM and sibling control subjects in the number who had a life or automobile insurance policy. However. life and automobile insurance refusal was much more frequent among the IDDM respondents. more so for life (55 vs. 0%. P less than 0.001) than for automobile (12 vs. 4%. P less than 0.05) insurance. CONCLUSIONS: These results suggest that access to insurance is severely compromised for people with IDDM. Although most of those with IDDM are able to find some form of insurance. it is evident that on average they must go to extra lengths to find it. These data and a changing insurance environment emphasize the need to reexamine. as a society. the importance of insurance for people with chronic disease. particularly IDDM.
Differential effect of diabetes education on self-regulation and life-style behaviors, OBJECTIVE: To examine the effect of diabetes education on self-regulation and life-style behaviors. RESEARCH DESIGN AND METHODS: Participants in an outpatient diabetes education program completed a protocol measuring several self-care behaviors and glycemic control at entry (n = 165) and 6 (n = 124) and 12 (n = 89) mo after the program. RESULTS: Improvement was noted at 6 mo for most self-care behaviors and glycemic control. At 12 mo. lower glycosylated hemoglobin levels were maintained (P less than 0.001) without increases in perceived hypoglycemia. Improvement was not maintained for those self-care behaviors that require change in life-style. i.e.. diet and exercise. However. self-care behaviors that allow patients to self-regulate their glycemic control--self-monitoring of blood glucose and insulin dose self-adjustment--were improved at 12 mo over preprogram levels (P less than 0.001). Frequency of insulin self-adjustment continued to increase during the period between follow-ups. CONCLUSIONS: The findings suggest that diabetes education is effective in promoting self-regulation behaviors. although it has less effect on traditional regimen behaviors such as diet and exercise.
Elevated cholesteryl ester transfer protein activity in IDDM men who smoke. Possible factor for unfavorable lipoprotein profile, OBJECTIVES: To determine the effect of cigarette smoking on the activity of cholesteryl ester transfer protein (CETP) and high-density (HDL). low-density (LDL). and very-low-density (VLDL) lipoproteins in insulin-dependent diabetic (IDDM) men with microvascular complications. RESEARCH DESIGN AND METHODS: We performed a case-control study in a referral-based diabetes clinic on a sequential sample of 9 cigarette-smoking and 12 nonsmoking IDDM men with microvascular complications and 12 nonsmoking control men. CETP activity was determined in each serum with an isotope assay with exogenous cholesteryl ester-labeled LDL and HDL. The method is independent of the endogenous lipoprotein present in serum. RESULTS: The HDL-cholesterol (VLDL and LDL) ratio was lower in the smoking diabetic men than in the other groups (P less than 0.05 vs. the nonsmoking diabetic men and P less than 0.01 vs. the control subjects). CETP activity was 70% higher in the smoking diabetic men than in the control subjects (P less than 0.01) and 30% higher than in the nonsmoking diabetic men (P less than 0.05). The HDL-cholesterol (VLDL and LDL) ratio and the apolipoprotein A-I-B ratio were inversely correlated to CETP activity in the diabetic patients (r = -0.52. P less than 0.02 and r = -0.45. P less than 0.05. respectively). CONCLUSIONS: CETP activity is increased in cigarette-smoking IDDM men with microvascular complications. High CETP activity may contribute to the unfavorable lipoprotein profile in these patients.
Double-blind evaluation of efficacy and tolerability of metformin in NIDDM, OBJECTIVE: To test the efficacy and tolerability of metformin. RESEARCH DESIGN AND METHODS: An 8-mo double-blind placebo-controlled parallel-group trial was performed at University hospital diabetic clinics on 60 patients with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone. Metformin was administered and built up to a maximum dosage of 1 g three times daily. RESULTS: Mean HbA1 fell from 11.7 +/- 0.4 to 10.3 +/- 0.4% (means +/- SE) on metformin but rose from 11.8 +/- 0.4 to 13.3 +/- 0.4% on placebo (P less than 0.001). Final mean fasting blood glucose was 5.1 mM lower with metformin than placebo (P less than 0.001). No other biochemical variable differed significantly. and weight did not change. A favorable glycemic response was not restricted to the obese. The mean final dosage of metformin was 1.7 +/- 0.1 g and was well tolerated. CONCLUSIONS: Metformin achieved a 23% lower mean HbA1 than placebo without weight gain or significant unwanted effects.
Controlled study of biofeedback-assisted relaxation in type I diabetes, OBJECTIVE: The effect of biofeedback-assisted relaxation was tested in a randomized trial in 18 adults with insulin-dependent (type I) diabetes. RESEARCH DESIGN AND METHODS: Pretreatment and posttreatment blood glucose values and insulin dosages in the group trained for 10 wk in biofeedback-assisted relaxation were compared with those in the untrained group. RESULTS: Significantly lower average blood glucose levels. percentage of fasting blood glucose levels at target. and percentage of glucose values greater than 11.2 mM were observed in the trained group at posttest compared with the untrained group. CONCLUSIONS: These differences could not be explained by increases in insulin. It is suggested that stress management be considered as an adjunct to the medical management of people with type I diabetes.
Effects of alpha-glucosidase inhibition on meal glucose tolerance and timing of insulin administration in patients with type I diabetes mellitus, OBJECTIVE: Miglitol. an alpha-glucosidase inhibitor. delays absorption of carbohydrates. This study was undertaken to determine the potential of this agent as an adjunct to insulin in the treatment of diabetes. RESEARCH DESIGN AND METHODS: Twelve nonobese patients with insulin-dependent (type I) diabetes mellitus were randomly selected from the outpatient diabetes clinic. The patients were made euglycemic with the Biostator. and postprandial hyperglycemia was determined under the following conditions: protocol 1. subcutaneous injection of insulin (13 +/- 1 U) given 60 min before the meal. with insulin dosages determined by the Biostator; protocols 2 and 3 same as protocol 1 but with insulin given at the time of meal ingestion; protocols 4 and 5 same as protocol 1 but with insulin given 30 min before the meal. Miglitol (100 mg) was administered in protocols 2 and 4 and placebo in protocols 3 and 5. RESULTS: When insulin was given 30 min before the meal with miglitol (protocol 4) or placebo (protocol 5). plasma glucose increased from 4.94 +/- 0.16 to 5.94 +/- 0.55 mM and from 5.11 +/- 0.22 to 8.22 +/- 0.72 mM. respectively (P less than 0.01). When insulin was given at the time of the meal with miglitol (protocol 2) or placebo (protocol 3). plasma glucose increased from 5.44 +/- 0.27 to 7.77 +/- 0.5 mM and from 5.72 +/- 0.22 to 10.83 +/- 0.77 mM. respectively (P less than 0.01). When insulin was given 60 min before the meal (protocol 1). plasma glucose initially decreased from 5.61 +/- 0.38 to 4.33 +/- 0.33 mM and then increased to 6.94 +/- 0.66 mM after the meal.
Kelly West Lecture. Primary prevention of type II diabetes mellitus, A useful paradigm for developing a public health strategy for combating chronic diseases consists of three phases: observational epidemiological studies. first cross-sectional and then prospective; intervention trials; and. finally. public health action. Although the field of cardiovascular epidemiology is well advanced into the third phase. i.e.. public health action. the field of diabetes epidemiology is at least a generation behind and has only recently entered the phase of prospective observational studies. Part of the reason for this lag may be that. unlike cardiovascular disease. non-insulin-dependent (type II) diabetes has not been traditionally viewed as an epidemic. thereby detracting from a sense of urgency about the disease. Although this perspective may be appropriate for white populations. data from around the world make it increasingly apparent that type II diabetes has indeed reached epidemic proportions in non-white populations. Prospective studies are needed to firmly establish risk factors on which public health actions can be confidently based. Although anthropometric and metabolic risk factors such as obesity. body fat distribution. and circulating glucose and insulin concentrations are becoming well established as risk factors for type II diabetes. much less is known about behavioral risk factors. These latter risk factors are especially important because they are often amenable to public health action. There are preliminary data suggesting that decreased physical activity and increased fat consumption may be behavioral risk factors for diabetes. Decreased total energy intake. reflecting either low levels of physical activity or an intrinsically low metabolic rate. perhaps genetic in origin. may also be a diabetes risk factor. Unlike the field of cardiovascular epidemiology. in which there is already a critical mass of intervention trials on primary prevention. such trials are essentially nonexistent in the field of diabetes epidemiology; they are urgently needed. Although the notion of a single gene causing diabetes is clearly simplistic. there is a reasonable expectation that genetic markers can be identified that would be useful in screening for genetic susceptibles. at least in selected predisposed populations. Such markers could then be used to identify target populations for primary-prevention trials and public health action. Although primary-prevention trials should not be deferred until genetic markers are available. these two research paths may someday converge and genetic markers may come to play an important role in screening individuals as part of a comprehensive public health strategy. Numerous trial designs should be considered for testing hypotheses about the primary prevention of type II diabetes. These include single risk factor. multiple risk factor. and factorial designs.(ABSTRACT TRUNCATED AT 400 WORDS).
Infant feeding in Finnish children less than 7 yr of age with newly diagnosed IDDM. Childhood Diabetes in Finland Study Group, OBJECTIVE: We studied associations between the type of feeding in infancy and the incidence of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: We studied 103 newly diagnosed diabetic children less than 7 yr of age and 103 age- and sex-matched population-based control children in a countrywide study. Results: The risk of IDDM was decreased (P less than 0.05) among children breast-fed for at least 7 mo (odds ratio [OR] 0.45. 95% confidence interval [CI] 0.24-0.85) or exclusively breast-fed for at least 3 (OR 0.33. 95% CI 0.13-0.84) or 4 (OR 0.43. 95% CI 0.22-0.84) mo. Also. children who were greater than or equal to 4 mo old at the time of introduction of supplementary milk feeding had a lower risk of diabetes (OR 0.48. 95% CI 0.26-0.91). CONCLUSIONS: The protective effects of a long duration of breast-feeding and a late introduction of dairy products on the risk of IDDM remained significant after adjusting for the mother's education.
The challenge of translating scientific knowledge into improved diabetes care in the 1990s [editorial, The problems associated with translating scientific knowledge into improved diabetes care are formidable but solvable. The American public has already made important changes in its health-related behavior. Millions of people have stopped smoking cigarettes. and many people have changed other behaviors to reduce their risk of cardiovascular disease and cancer. Many of the changes required to improve the quality of diabetes care in the 1990s will involve significant changes in our society's health-care policies and its health-related values and behaviors. Such changes. although often difficult to bring about. have the potential to have a profound and lasting impact on the health of our society. Many patients with diabetes have already implemented new care practices such as self-monitoring of blood glucose and multiple insulin injection regimens. As better technology and more evidence for the efficacy of rigorous blood glucose control become available. they will also be translated into practice. Diabetes care can be improved but to do so significant scientific and societal resources will have to be brought to bear on the problem of understanding and influencing the health-related behavior of people with diabetes and the health-care professionals and institutions providing care for them.
Risk factors for NIDDM in white population. Paris prospective study, Risk factors for non-insulin-dependent diabetes mellitus (NIDDM) were assessed in a population of 5042 middle-aged white men. initially nondiabetic. who were followed 3 yr. The subjects were participants in the Paris Prospective Study I. Sixty-three subjects developed diabetes during the follow-up. Plasma glucose concentration in the years before the occurrence of the disease was a major risk factor. Subjects with normal glucose tolerance but elevated fasting plasma glucose exhibited a similar risk of developing NIDDM as did subjects classified as having impaired glucose tolerance on the basis of 2-h postload glucose. In a multiple logistic regression. a high fasting plasma insulin concentration and a low 2-h plasma insulin concentration after a glucose load in association with a high body mass index were independent predictors of conversion to NIDDM from impaired glucose tolerance. Previously. this result had been found only in Nauruans. Pima Indians. and Japanese. This demonstrates for the first time in a white population that a high fasting and low 2-h insulin concentration is predictive of conversion to NIDDM from impaired glucose tolerance.
1,2-diacylglycerol content and its fatty acid composition in thoracic aorta of diabetic rats, These experiments were conducted to determine 1.2-diacylglycerol (DAG) in the thoracic aorta obtained from streptozocin-induced diabetic rats because 1.2-DAG is assumed to be a second messenger associated with phosphoinositide metabolism. After preincubation for a 25-min stabilization. 1.2-DAG content in isolated thoracic aortas 4 and 8 wk after streptozocin injection was significantly decreased by 42 and 31%. respectively. compared with age-matched control rats on 10-min norepinephrine stimulation (10(-5) M). However. 4 wk of daily insulin injection after 4 wk of untreated diabetes significantly shifted 1.2-DAG toward normal levels. Analysis of its fatty acid composition showed a significant difference between control and diabetic rat aortas at both 4 and 8 wk. In particular. the percentage of arachidonate. a precursor of eicosanoids. decreased. Such alteration in the fatty acid profile in diabetic rat aortas was inhibited by insulin treatment. 1.2-DAG content in the 8-wk diabetic group was also significantly decreased by 33% compared with control in the absence of norepinephrine. whereas 1.2-DAG content was lower than in the presence of norepinephrine in both the control and diabetic groups. Cholesterol. triglyceride. and phosphatidylcholine content in diabetic rat aortas was lower than control. Lower levels of 1.2-DAG in the thoracic aorta from diabetic rats were observed in the presence and absence of norepinephrine. suggesting that a defect in 1.2-DAG production may be associated with abnormalities of vascular smooth muscle responsiveness by agonists. as described previously.
Risk of diabetes in siblings and other relatives of IDDM subjects, The risk of insulin-dependent diabetes mellitus (IDDM) was examined in siblings of an unselected population (n = 194) of newly diagnosed diabetic individuals less than 30 yr old. From 1 July 1984 to 30 June 1987. diabetic subjects (proband) identified within a geographically defined area of southern Wisconsin were studied. IDDM occurred among siblings of probands in 13.5% of families and was associated with proband age at diagnosis. The highest risk was found for diabetic subjects less than 10 yr old at diagnosis (P = 0.04). We did not find an association between sibling IDDM and proband sex. HLA-DR3/4. duration of symptoms. or ketosis at diagnosis. In addition. the odds ratio (OR) for the association of IDDM in the proband with IDDM in parents and second- and third-degree family members was examined by case-control methodology. Diabetic subjects were matched to two types of control subjects (friends and general population) by age stratum and sex. The OR for IDDM was not increased significantly if parental IDDM or non-insulin-dependent diabetes mellitus (NIDDM) was reported. However. there were very few parents with diabetes among diabetic or control subjects. In 6.4% of diabetic subjects. one parent had IDDM. 54% of whom were fathers. In 4.3% of diabetic subjects. one parent had NIDDM. and 57.1% of these were fathers. The OR for IDDM was significantly increased if second- and/or third-degree relatives had IDDM (OR diabetic subjects vs. general population 2.33 [P less than 0.05)] or NIDDM (OR diabetic subjects vs. friends 2.05 [P less than 0.01]).
Persistent reversal of diabetes by transplantation of fetal pig proislets into nude mice, Facing the limited availability of human adult and fetal pancreases. fetal pig proislets (pancreatic islet precursors) were investigated in view of several inherent advantages. Six litters of fetuses of mean +/- SE gestational age 75 +/- 3 days were obtained from commercially available farm pigs. Pancreatic tissue was gently digested with collagenase. then a 10-day culture was performed. During culture. fetal proislets showed no insulin response to glucose alone but a significant response to glucose plus theophylline. The insulin content per microgram of DNA in the cultured proislets continuously increased. Histological examination by immunoperoxidase staining showed that. apart from single insulin- and glucagon-positive cells. there were no discrete islets in the pancreatic tissue and the cultured proislets. Diabetes was induced with streptozocin (STZ) in eight nude mice 3-4 wk after proislet transplantation and in another eight nude mice without transplantation. During the initial week. blood glucose levels of mice in both groups increased rapidly. The mean +/- SE peak value of blood glucose levels in the transplanted group was 20.4 +/- 2.0 mM and was 20.1 +/- 1.3 mM in the group without transplantation. Simultaneously. body weight decreased from 29.5 +/- 0.7 to 21.5 +/- 0.9 g and from 27.9 +/- 0.7 to 19 +/- 1 g in the groups. respectively. Afterward. blood glucose levels of mice in the transplanted group gradually decreased. and normoglycemia was achieved in all mice within 50 +/- 13 days after injection of STZ. i.e.. 74 +/- 13 days after transplantation. The group without transplantation persistently maintained blood glucose levels greater than 16.7 mM.
Liver and kidney tissue membranes as tissue markers for nonenzymatic glycosylation, We investigated the relationship of serum protein glycosylation to peripheral tissue membrane glycosylation. We studied 27 Sprague-Dawley rats and induced diabetes in 20 of them. Blood glucose levels were treated in 10 of the diabetic animals with daily subcutaneous insulin. After 8 wk. liver and kidney tissue was removed. purified membranes were prepared. and the percentage of glycosylated membrane protein was determined for the liver and kidney membranes by boronate-affinity methods. The percentage of glycosylated membrane protein for both liver and kidney tissue was found to correlate significantly with the glycemic state of the animal as assessed with glycosylated serum albumin. total glycosylated serum proteins. and glycosylated hemoglobin determinations (P less than 0.001 for each glycosylated protein parameter). In addition. the percentage of glycosylated membrane protein in the liver tissue correlated significantly with the measured level in the corresponding kidney tissue (r = 0.78. P less than 0.001). To identify the nature of the glycosylated membrane proteins. boronate-affinity methods were used to separate the glycosylated and nonglycosylated membrane proteins. It was determined that two major glycosylated protein bands exist for the liver membrane (78.000 and 58.700 Mr) and four for the kidney membranes (ranging from 48.700 to 74.000 Mr). The ultrastructural location and identification of these glycosylated membrane proteins are not known. This study demonstrates that measurement of clinical glycemic state. as reflected in glycosylated blood protein parameters such as glycosylated serum albumin and glycosylated hemoglobin. correlates significantly with ongoing tissue membrane accumulation of glucose.
Transplantation of purified islet cells in diabetic rats. I. Standardization of islet cell grafts, A standardized procedure was developed for the preparation of rat islet cell grafts with selected cell number and composition. After collagenase digestion of pancreases and elutriation of tissue fragments. islets were isolated and dissociated. and cells were purified by autofluorescence-activated cell sorting. Approximately 30% of the initial beta-cell mass was lost during digestion and elimination of small mostly exocrine particles. Fifty percent was recovered in isolated islet preparations and 30% in the purified beta-cell suspensions of greater than 95% purity and viability. Sorting according to cellular flavin adenine dinucleotide content discriminated islet beta-cells from islet endocrine non-beta-cells. fibroblasts. leukocytes. and exocrine cells. Purified endocrine islet cell grafts were prepared by aggregating 10(6) pure beta-cells with or without 8 x 10(5) pure endocrine non-beta-cells. In contrast to intact islets. the purified aggregates were devoid of nonendocrine and damaged cells. Intraportal implantation of a pure beta-cell graft rapidly and permanently normalized the diabetic state of streptozocin-administered animals. The standardized preparation of purified beta-cell grafts allows us to address several metabolic and immunological questions concerning islet cell transplantation in diabetes.
Transplantation of purified islet cells in diabetic rats. II. Immunogenicity of allografted islet beta-cells, This study examines whether the survival of allografted rat islet beta-cells is influenced by the presence of other pancreatic donor cells. Grafts (RT1u/l) of different cellular composition were intraportally transplanted in streptozocin-induced diabetic rats (RT1n/n). All grafts corrected the diabetic state within 3 days. Implants of freshly isolated islets contained various endocrine and nonendocrine cell types; they became diffusely infiltrated within 1 wk and were completely destroyed within 2 wk. A 4-day culture period did not lead to major changes in the cellular composition of the islets or in their survival as allograft. Islet cell aggregates prepared after islet dissociation and cell purification were less acutely infiltrated and less rapidly rejected. Aggregates composed of sorted MHC class II-negative cells maintained basal normoglycemia in 3 of 5 recipients for 5 wk but only in 1 of 5 for 20 wk. Aggregates of purified islet beta-cells remained relatively free of diffuse infiltrations during the 1st wk and preserved the normalized state in 7 of 13 recipients for 5 wk; after 20 wk. 6 of 13 were still aglucosuric. but 40% of the implants were diffusely infiltrated and depleted of insulin. Reaggregation of purified islet beta-cells with purified islet endocrine non-beta-cells promoted their long-term survival as allograft: 11 of 13 recipients of mixed islet endocrine cells maintained normal basal glycemia over 20 wk; their implants contained relatively constant insulin reserves and remained virtually devoid of diffuse infiltrations. These results demonstrate that techniques aiming at the elimination of surface MHC class II-positive cells are less successful in preparing rat islet allografts of low immunogenicity than methods of positive cell selection. Pure islet beta-cells are immunogenic as an allograft but illicit a milder and less-acute immune attack than undissociated islet tissue. Nonendocrine and damaged islet cells are suspected of enhancing the rapidity and intensity of the cytotoxic reaction. Survival of allografted beta-cells is markedly prolonged by the presence of islet endocrine non-beta-cells within the graft. The mechanisms underlying this effect have not yet been elucidated; they may involve immune and metabolic interactions of the endocrine non-beta-cells. We conclude that purification of islet endocrine cells represents a new and powerful method for preparing insulin-producing allografts that can survive in hosts without pharmacological immunosuppression.
Transplantation of purified islet cells in diabetic rats. III. Immunosuppressive effect of cyclosporin, This study examined the effect of cyclosporin on the survival of islet beta-cell allografts in streptozocin (STZ)-induced diabetic rats. At a daily oral dose of 5 mg/kg. the agent prevented the rejection of isolated islets. provided they were little contaminated by other pancreatic tissue. The immunosuppressive effect rapidly disappeared after discontinuation of the drug. except when the donor tissue had been pretreated to reduce its nonendocrine content. All recipients of cultured and selected islets maintained a normalized state for greater than 15 wk beyond the 5-wk drug course; this was not the case for shorter periods of treatment. A long-term beneficial effect was also observed in all recipients of purified islet beta-cell grafts. which reversed without treatment in half of the cases. Cyclosporin markedly reduced the mononuclear cell infiltration in each type of islet beta-cell allograft; aggregates of mixed endocrine islet cells were kept virtually infiltration free. Conditions with minimal initial infiltration were associated with long-term graft survival without the need for continuous pharmacological immunosuppression. We conclude that a short-term cyclosporin treatment can induce long-term survival of allografted islet beta-cells. provided the grafts are only slightly contaminated by nonendocrine elements. In rodents. sufficient immunosuppression was achieved by circulating cyclosporin levels of 100-400 ng/ml. Higher concentrations were cytotoxic for cultured islet beta-cells and islet non-beta-cells. A 5-wk treatment with the immunomodulator ciamexone also resulted in long-term survival of purified beta-cell allografts but not of cultured islets.
Preventive maintenance of the aging heart, Coronary heart disease (CHD) is the major cause of mortality in the elderly. Important risk factors include hypercholesterolemia. systolic and diastolic hypertension. cigarette smoking. hyperglycemia. and obesity. Elderly patients with existing CHD should be treated aggressively to control these risk factors. along with other medical therapies to treat myocardial ischemia. For elderly patients without recognized CHD. however. a more conservative approach is recommended and includes behavioral interventions when appropriate and pharmacologic therapy for higher risk patients with persistent. uncontrolled risk factors.
Unique aspects of respiratory disease in the aged, Chronic obstructive pulmonary disease (COPD) is a common problem in the elderly. often resulting in reduced pulmonary capacity and serious functional disability. Contrary to commonly-held medical opinion. COPD often has a significant reversible component in the older patient and thus offers an excellent opportunity for successful treatment. Smoking cessation is the single most important measure to manage COPD. In addition. treatment with inhaled bronchodilators and corticosteroids. pulmonary rehabilitation programs. home oxygen therapy. and various preventive strategies are practical components for reversing COPD-induced dysfunction.
In-office mental status testing: a practical guide, Elderly patients with dementia often first come to the attention of their primary medical care providers. Evaluation of cognitive functioning is an important part of the diagnostic work-up. since dementia is a disorder defined by problems of mental or cognitive abilities. Mental status examination in the physician's office can provide diagnostically valuable information and prove useful for determining the need for referral for formal neuropsychological testing. This article briefly describes the cognitive changes associated with dementia and explains proper administration and interpretation of the Mini-Mental State Examination. a quantitative screening test of cognitive function.
Prospective clinical and manometric study comparing pneumatic dilatation and sublingual nifedipine in the treatment of oesophageal achalasia, A study was carried out in 30 patients affected by a mild or moderate degree of oesophageal achalasia to compare the clinical and manometric effects of sublingual nifedipine and pneumatic dilatation. Sixteen patients were dilated twice with Rider-Moeller dilators and 14 were treated with sublingual nifedipine 10-20 mg 30 minutes before meals. A manometric evaluation was performed before and six months after starting treatment. The clinical evaluation (according to Vantrappen's criteria) was performed every three months for a mean follow up of 21 months. In both groups of patients a significant (p less than 0.001) fall in lower oesophageal sphincter pressure was observed after treatment and excellent or good clinical results were observed in 75% of dilated patients and in 77% of patients treated with nifedipine. One patient could not tolerate nifedipine. No complications were observed after dilatation. It is concluded that longterm treatment with sublingual nifedipine and pneumatic dilatation are equally effective in the treatment of oesophageal achalasia of mild or moderate degree.
Monitoring of upper oesophageal sphincter pressure in children, In children technical limitations of upper oesophageal sphincter manometry have restricted investigation to the pull through technique under sedation. In this study we have used an adapted sleeve manometric technique for upper oesophageal sphincter monitoring in unsedated children and determined the influence of the state of arousal on upper oesophageal sphincter pressure. Twenty six children aged 3 to 42 months (median 17.5 months). who were referred for evaluation of oesophageal motor function. were studied with dual sleeve manometric assemblies which monitored upper and lower oesophageal sphincter pressures simultaneously. Pharyngeal. oesophageal body. and gastric pressures were also monitored with seven perfused side holes. Recordings were made for four hours after a meal and were technically successful in 24 children. The child's state of arousal was scored every 12th minute as follows: (A) resting. eyes closed. (B) resting. eyes open. (C) moving but comfortable. (D) restless and uncomfortable. (E) crying. In 67% of the 12 minute samples the children showed good adaptation to the procedure (arousal states A to C). There was a highly significant difference in upper oesophageal sphincter pressure between each of the arousal states (p less than 0.0001). being lowest in category A at (mean (SD) 18.1 (10.3) mmHg and highest in category D 55.7 (13.2) mm Hg. Abrupt changes in the state of arousal were associated with equally abrupt changes in upper oesophageal sphincter pressure. The state of arousal of unsedated children has an important influence on upper oesophageal sphincter pressure. It is essential that this factor is controlled for in any studies of upper oesophageal sphincter tone in children. The sleeve technique is capable of monitoring upper oesophageal sphincter motility for prolonged periods in unsedated children.
Peptic ulcer disease: absence of antibodies stimulating the histamine sensitive adenylate cyclase of gastric mucosal cells, The possible presence of parietal cell stimulating antibodies was examined in sera from 57 patients with relapsing ulcer disease. The sera were obtained at the time of symptomatic relapse and all patients had ulcers confirmed by endoscopy. A sensitive assay based on adenosine 3':5' cyclic monophosphate (cAMP) production in isolated porcine gastric mucosal cells was used as a measure. cAMP production increased up to four hours of incubation and was histamine responsive; an approximately 20-fold increase was found with histamine 10(-4) mol/l. Sera from both patients and healthy control subjects showed some inhibitory effect on basal cAMP production compared with incubation in medium only. whereas immunoglobulin preparations had a weaker non-specific effect. No stimulation was found when the patients' sera and immunoglobulins (up to a concentration of 6 mg/ml) were examined. These results suggest that gastric acid hypersecretion in duodenal ulcer disease is not an effect of histamine receptor stimulating antibodies. The data thus argue against a recent hypothesis that severe chronic ulcer disease in some patients has an autoimmune origin.
Diagnostic value of measurement of serum type I procollagen carboxy terminal peptides in patients with scirrhous carcinoma of the stomach, We have evaluated the radioimmunoassay for type I procollagen carboxy terminal peptide (type I C-peptide). which is liberated from type I procollagen during its conversion to collagen. in the serodiagnosis of scirrhous carcinoma of the stomach. The mean (SD) serum concentration of type I C-peptide in 39 normal subjects was 41.7 (19.7) ng/ml. The mean serum values and the positive ratio of type I C-peptide in 11 patients with stages II and III scirrhous carcinoma of the stomach were 91.2 (41.9) ng/ml and 54.5%. respectively. In 10 patients with other types of gastric carcinoma. the mean type I C-peptide values were not significantly different from the normal value. Serum type I C-peptide values reflected the clinical course of scirrhous gastric carcinoma in five patients who underwent either operation or chemotherapy. The measurement of serum type I C-peptide concentrations could provide a useful way of diagnosing and monitoring scirrhous carcinoma of the stomach.
Jejunal permeability to water and electrolytes in patients with chronic intrahepatic hypertension: evidence for a role of aldosterone, Acute prehepatic portal hypertension induces intestinal secretion in animal models. In the course of chronic liver disease. however. these changes are not observed. despite higher portal pressures than those found in experimental studies. Eight patients without diarrhoea and with chronic alcoholic liver disease were examined for evidence of increased jejunal secretion; their suprahepatic wedge pressure was raised from 21 to 45 mmHg (mean 34.6 mmHg). Jejunal perfusion with a triple lumen catheter and a proximal occluding balloon was used to study net flows of water and chloride as well as net and unidirectional flows of sodium and potassium. No statistical difference in intestinal flows of water and electrolytes was noted between cirrhotic patients and control subjects after infusion with a 30 mmol/l glucose solution. Infusion with a 30 mmol/l mannitol solution resulted in a lower absorption of water. Na. K. and Cl than with the glucose solution. A higher rate of Na secretion was observed in cirrhotic patients than control subjects after infusion with 30 mmol/l mannitol (p less than 0.01). In addition. the rate of Na secretion was higher in cirrhotic patients than in control subjects (p less than 0.05). There was no correlation between the net flow of Na and the suprahepatic wedge pressure. A second perfusion with a 30 mmol/l glucose solution was given 75 minutes after a bolus injection of spironolactone (400 mg). Net flows of Na and Cl were lower in cirrhotic patients than in control subjects (p less than 0.05) because of a lower absorption of Na. Patients with gradually developing portal hypertension have moderate jejunal secretions of H2O and electrolytes which we assume are partly masked by increased absorption resulting from hyperaldosteronism. In contrast to animal models. this mechanism may be part of the jejunal adaptation to permeability in acute portal hypertension.
'Low sodium' diuresis and ileal loss in patients with ileostomies: effect of desmopressin, Patients with ileostomies show an early diuresis when sodium restricted; this. together with an obligatory ileal sodium loss. predisposes them to severe salt and water depletion. The role of arginine vasopressin in this circumstance and whether it is natriuretic. or antinatriuretic. is unclear. There is also controversy over its likely effect on small bowel fluid reabsorption. We have examined the effect of the non-pressor (V2) synthetic vasopressin analogue 1-deamino-8-D-arginine (desmopressin) on renal and ileal sodium and water excretion in ileostomy patients during acute adaptation to a low sodium diet. Patients were studied on two separate occasions (nonrandomised) with and without the administration of desmopressin (0.75 micrograms intramuscular. three times a day). In eight subjects without desmopressin there was pronounced diuresis on the first low sodium day. associated with a fall in renal sodium excretion and no change in ileal output or composition. In five (of the original) subjects with desmopressin there was pronounced antidiuresis. no change in renal sodium excretion. and no change in ileal output or composition. In both studies rises in plasma renin activity and salivary aldosterone concentration lagged behind the early decline in renal sodium excretion. We have confirmed the phenomenon of 'low sodium' diuresis after sodium restriction in ileostomy patients and shown that it can be prevented by desmopressin. Desmopressin has no direct or indirect effect on renal sodium excretion or ileal fluid and electrolyte loss in humans.
Total orthotopic allogeneic small bowel transplantation in rats: effect of allograft irradiation combined with cyclosporine-A therapy, Rejection and graft versus host disease are prominent features in small bowel allotransplantation in rats. Cyclosporine treatment of the recipient and irradiation of the donor were used to circumvent these phenomena in the WAG to brown Norway rat model. Irradiation of the donor with five or 10 Gy did prevent graft versus host disease but resulted in a more vigorous rejection of small bowel allografts in untreated recipients (mean (SEM) survival times of 11.5 (0.4) (n = 8) and 7.5 (0.9) (n = 11) days respectively. versus 16.6 (2.6) days (n = 17). p less than 0.01). Cyclosporine treatment of the recipient (25 mg/kg on days 0. 1. 2. 4. and 6 after transplantation) led to a mean (SEM) survival time of 38.3 (8.5) days (n = 10); 20% of the animals developed graft versus host disease. Combined with 5 Gy donor pretreatment. a similar survival was obtained without occurrence of graft versus host disease. However. cyclosporine treatment combined with 10 Gy led to a significant shortening of graft survival (23.1 (6.8) days. n = 9). These results suggest that although irradiation is very effective in preventing graft versus host disease. high dosages may accelerate rejection either by making the graft more vulnerable to rejection or by completely removing the immuno-suppressive effect of graft versus host disease.
Fluticasone propionate in Crohn's disease, Fluticasone propionate. a topically active corticosteroid of low systemic bioavailability after oral administration. has been used in a pilot study for the treatment of mild and moderately active Crohn's disease. Twelve patients received oral fluticasone propionate for three weeks. and the effects were monitored using the Crohn's disease activity index and by 111In granulocyte scanning. assessing inflammation from scan appearances. four day faecal excretion of radioactivity. and whole body excretion of radioactivity. All patients completed the trial. No serious side effects were reported. There was a significant fall in Crohn's disease activity index values over the three week treatment period (193 (84) v 122 (51). p less than 0.01). 111In leucocyte scan images were improved (seven patients) or unchanged (five patients). There was a significant fall in excretion of injected radioactivity calculated from whole body data (28 (21)% v 14 (0.7)%. p less than 0.05). There were no changes in plasma cortisol values. either basal or synacthen stimulated. Fluticasone propionate is a promising therapeutic agent for Crohn's disease that offers the possibility of controlling inflammation without inducing systemic corticosteroid side effects and which merits evaluation in a double blind trial versus conventional corticosteroids.
Abdominal distension in female patients with irritable bowel syndrome: exploration of possible mechanisms, Abdominal distension is a common but little understood symptom of the irritable bowel syndrome. The authenticity of the symptom was confirmed by appreciable increases in girth measurement during the day in 20 patients with the irritable bowel syndrome compared with 20 control subjects. Objective corroboration of this finding was shown in the group with the irritable bowel syndrome by a highly significant increase in lateral abdominal 'profile' on computed tomography. Previously postulated mechanisms for distension--namely. retention of gas. depression of the diaphragm. and excess lumbar lordosis--were excluded by the radiological findings. Voluntary protrusion of the abdomen produced a completely different pattern on computed tomography to that observed in the irritable bowel syndrome. These observations suggest that abdominal distension may be related to changes in motility or tone of gastrointestinal smooth muscle.
Human papillomavirus type 16 DNA in anal cancers from six different countries, An association between anal squamous cell carcinoma and human papillomavirus (HPV) type 16 DNA has been documented in the UK. If HPV type 16 is an important aetiological factor in the development of this tumour it would be expected to occur in anal cancer tissues from other parts of the world. In this study a series of 173 anal squamous cell carcinoma tissue samples from five centres around the world have been examined by DNA hybridisation for HPV type 16 DNA sequences. HPV type 16 DNA was found in 50 of 173 (29%) of these. The prevalence of HPV associated anal squamous cell carcinoma was significantly lower in tissue from India and South Africa than in the Swiss. Polish. or Brazilian samples. HPV associated anal squamous cell carcinoma does occur in other countries and further investigations of the prevalence of these tumours in association with other HPV types are required.
Natural history of hepatic haemangiomas: clinical and ultrasound study, Hepatic haemangiomas are the most common benign tumours of the liver and commonly present as incidental findings on sonographic examination of the abdomen. Since little is known of the natural course of these tumours. we performed a clinical and sonographic follow up of 123 haemangioma patients. Our prospective study investigated clinical and sonographic findings in 158 haemangiomas for periods of 12 to 60 months. Ninety nine haemangiomas measured less than 2 cm and had an echogenic pattern; 40 were between 2 cm and 5 cm with a mainly echogenic structure; 19 measured greater than 5 cm and showed a mixed echo pattern. At the first examination only eight patients. all with giant haemangiomas. presented symptoms which could be attributed to the tumour. During follow up only one haemangioma changed in shape and size. One patient who was symptom free at the first examination experienced right upper abdominal quadrant pain during follow up. No deterioration occurred in any of the patients with symptoms at the first examination. and all had a satisfactory quality of life. No complications arose during the follow up period. This study shows that in adults haemangiomas remain stable in size and echo patterns rarely change. Only haemangiomas greater than 5 cm may cause symptoms. Prolonged clinical and sonographic follow up of small and medium sized haemangiomas is not warranted.
Comparison of hemostasis with two high-flux hemocompatible dialysis membranes, Eight adults with chronic renal failure were dialyzed using polyacrylonitrile (AN 69) or polysulfone (PS) membranes with a high (HHR) or low (LHR) continuous non-fractionated heparin regimen--a total of either 90 or 50 IU/kg body weight. With the HHR. for a mean anti-Xa (aXa) activity of around 0.40 IU/ml. no plasma activation of coagulation was observed; fibrinopeptide A (FPA) was in agreement with the residual blood volume (RBV) and the state of the bubble trap. especially with the PS membrane. With the LHR. for a mean aXa below 0.21 IU/ml. there was only moderate activation of coagulation. The PS membrane gave different results from the AN 69 membrane. RBV values on the HHR and aXa being lower on both the HHR and LHR. with FPA values being regularly lower on the LHR. The decrease in plasma beta-TG on the LHR was more marked with the PS than with the AN 69 membrane due to loss on dialysis or adsorption. as shown by the arterio-venous difference. The increase in plasma PF4 was related to the effect of heparin. However. there was no platelet activation. On the LHR. platelet count and intraplatelet beta-TG and PF4 levels remained very stable. The two high-flux membranes were very hemocompatible and require only low doses of heparin. but the dialyzer with AN 69 membrane need its geometry improving.
Encapsulated hepatocytes for controlling hyperbilirubinemia in Gunn rats, Hepatocytes encapsulated in an alginate-polylysine-membrane were used to lower bilirubin levels in hyperbilirubinemia. The animal model was the Gunn rat. The microencapsulated hepatocytes were implanted intraperitoneally. 15 x 16(6) microencapsulated hepatocytes from Wistar rats lowered the bilirubin from 14 mg/100 ml to 6 mg/100 ml after 20 days. 15 x 10(6) microencapsulated hepatocytes from Sprague-Dawley rats lowered the bilirubin levels from 8 mg/100 ml to 5 mg/100 ml. They were as effective as free Sprague-Dawley hepatocytes. 12 x 10(6) Guinea pig hepatocytes. whether encapsulated or free. lowered the bilirubin from 9.36 mg/100 ml to 4.37 mg/100 ml.
Impaired efficacy of selective LDL-apheresis in primary biliary cirrhosis, Low-density lipoprotein apheresis (LDL-apheresis) was done with either cascade filtration (DF) or dextran sulfate cellulose adsorption (DSC) in a patient with primary biliary cirrhosis who developed severe dyslipidemia associated with cholestasis and accumulation of lipoprotein-X (LP-X). The extracorporeal treatment was initially performed weekly. and resulted in a sharp drop in total cholesterol from 1038 to 430 mg/dl. During the next four months the patient was treated every 10-15 days. and pre-apheresis cholesterol levels were maintained between 438 and 505 mg/dl. until an orthotopic liver transplantation was successfully performed. With semi-selective DF a mean 47.1% of total cholesterol was removed per procedure compared to 30.0% with DSC. although the volume of treated plasma was 38.0 vs 49.9 ml/kg body weight. The changes in plasma cholesterol levels during DSC and DF showed that the kinetics of cholesterol removal were similar with both techniques. but the efficacy differed; DF removed both LDL and LP-X from plasma. whereas DSC selectively lowered the LDL content. Cascade filtration may therefore be considered as a first-choice treatment for patients with LP-X accumulation due to cholestasis.
Vibrio vulnificus septicemia in Korea: clinical and epidemiologic findings in seventy patients, We studied the clinical characteristics and the epidemiology of primary septicemia associated with Vibrio vulnificus in 70 patients. All patients came from the western and southern coastal areas of Korea. Most cases (96%) occurred during the summer months. in men (96%). and in persons 40 or more years of age (90%). The illness of 46 patients (66%) began with septicemia. often within 2 days of the consumption of raw seafood. Forty-seven patients (67%) had preexisting hepatic disease. and 49 (70%) had a history of alcoholism. Of the 70 patients. 45 (79%) died. The cutaneous lesions that were present on admission in 64 patients (91%) appeared on the legs in 51 of the cases. V. vulnificus was isolated from the blood of 65 patients tested and from the skin lesions of 51 of 55 patients tested. The histopathologic findings differed according to the clinical stage of lesions. Because V. vulnificus septicemia is a highly fatal disease. persons with liver disease or alcoholism should avoid eating or handling raw seafood.
Inverse relation between density of nevi and terminal cutaneous hair. Study of male volunteer subjects and patients enrolled in a dysplastic nevus syndrome registry, Terminal hair density was graded at seven sites in 19 male patients enrolled in a dysplastic nevus syndrome (DNS) registry and in 22 matched control subjects. An inverse relation between density of nevi and terminal hair for all sites combined was observed for both patients and control subjects (p = 0.0001. regression analysis). In addition. the registry patients had significantly less terminal cutaneous hair overall (p = 0.007. Wilcoxon rank sum test) compared with the controls.
Treatment of lichen planus with acitretin. A double-blind, placebo-controlled study in 65 patients, Sixty-five patients with lichen planus were included in a multicenter trial of acitretin. At the end of an 8-week placebo-controlled. double-blind phase. a significantly higher number of patients treated with 30 mg/day acitretin (64%) showed remission or marked improvement compared with placebo (13%). Furthermore. during the subsequent 8-week open phase. 83% of previously placebo-treated patients responded favorably to acitretin therapy. Typical retinoid adverse reactions were present in all patients on active drug. Laboratory studies did not show any clinically significant changes. This study shows that acitretin is an effective and acceptable therapy for severe cases of lichen planus.
A double-blind, vehicle-controlled study of clobetasol propionate 0.05% (Temovate) scalp application in the treatment of moderate to severe scalp psoriasis, The efficacy and safety of clobetasol propionate 0.05% scalp application was evaluated in 378 patients with moderate to severe scalp psoriasis in a double-blind vehicle-controlled parallel group study. After 2 weeks of twice-daily applications. 81% receiving active drug versus 22% receiving vehicle had clearing of 50% or greater. Complete clearing was seen in 26% with active drug and 1% with vehicle. Local side effects were primarily burning or stinging in 11% and 10% of patients treated on an active or a vehicle regimen. respectively. The morning cortisol levels of 168 patients were checked at baseline and again after 2 weeks of drug therapy. Subnormal morning plasma cortisol values were seen in 5% of the patients receiving active drug and in 5% receiving vehicle; 13% of those taking active drug versus 5% taking vehicle had a 50% or greater decrease in morning cortisol at the 2-week visit compared with baseline values. Clobetasol propionate 0.05% scalp application appears to be a safe and an effective treatment for scalp psoriasis.
Topical treatment of multiple actinic keratoses of the face with arotinoid methyl sulfone (Ro 14-9706) cream versus tretinoin cream: a double-blind, comparative study, In a double-blind. randomized. within-patient comparative study. the efficacy and tolerability of Ro 14-9706 (an arotinoid methyl sulfone) in the treatment of actinic keratoses was compared with that of tretinoin (all-trans-retinoic acid). A total of 25 patients with more than three lesions on each side of the face completed the study. All patients applied each agent twice daily for 16 weeks as a 0.05% cream to opposite sides of the face. The number of actinic keratoses in each treatment area was counted before treatment and at weekly intervals. The mean percent decrease in the number of actinic keratoses was 37.8% for areas treated with Ro 14-9706 and 30.3% for areas treated with tretinoin. Each of these decreases was significantly different from baseline (p less than 0.01). but not from each other. Ro 14-9706 was better tolerated; local inflammation was slight or absent in most patients. whereas tretinoin caused severe erythema in 50% and severe scaling in 23% of patients.
Alopecia totalis: is treating nonresponder patients useful, The purpose of this study was to assess the effectiveness of different treatments in patients with alopecia totalis or universalis who did not respond to sensitizing therapies. Twenty-six patients. who had been receiving sensitizing therapy for at least 1 year without any response. were randomly assigned to receive the following treatments: topical 10% cyclosporine in oily solution (eight patients). PUVA (eight patients). and intravenous thymopentin (ten patients). None of them had any acceptable regrowth after at least 6 months of treatment. Our results suggest that other treatments are not useful in patients with 100% hair loss who fail to respond to sensitizing therapies.
Chemotherapy-induced acral erythema, Chemotherapy-induced acral erythema has been described in association with several different chemotherapy regimens. We review the literature on this topic and suggest that different mechanisms may be responsible for the clinically heterogeneous array of acral changes.
Flashlamp-pumped pulsed dye laser for port-wine stains in infancy: earlier versus later treatment, Twelve children. 6 to 30 weeks of age (average 14.9 weeks). with port-wine stains of the head and neck were treated with the flashlamp-pumped pulsed dye laser at 585 nm and 450 microsecond pulse duration. Ten of 12 patients (83%) showed more than 50% lightening of their port-wine stains after 2.9 treatment sessions (2.9 +/- 1.4 [+/- standard deviation]). Forty-five percent of the patients demonstrated 75% or more lightening of their lesions after a mean of 3.8 treatments (+/- 1.6). No lesions in this group cleared completely after a mean of 2.8 treatments. Treated skin was identical in texture to normal skin in all patients. There was no evidence of depressed scars. atrophy. hyperpigmentation. or hypopigmentation in the treated areas. These results indicate that pulsed dye laser treatment of port-wine stains can be undertaken safely in infancy.
Survival in a residential home: an eleven-year longitudinal study, The length of survival and various risk factors were studied utilizing 408 residents (141 men. 267 women) of a large residential home. The subjects. aged 68 years or more at entry. admitted between 1978 and 1983. were physically independent. continent. and non-diabetic. They were followed until December 31. 1988. by which time 78% had died. The multivariate proportional hazard analysis showed the following entry variables to have the indicated effects on relative mortality rate ratios: 5-years' higher age (+10%. NS). persistent bacteriuria (+13%. NS). abnormal ECG (+26%. NS). current smoking (+63%. P less than 0.01). mildly impaired mobility (+96%. P less than 0.001). higher levels of in-study systolic pressure in 10-mm Hg steps (-4%. NS). higher entry serum cholesterol in 1-mmol/L steps (-7%. NS). and higher hematocrit in 5% steps (-14%. P less than 0.02). Female sex was associated with a +25% (NS) rate ratio; socioeconomic status and body weight were without effect. These data highlight the relative importance of specific factors associated with survival of persons within retirement homes and indicate that: (1) the presence of mild impairment of mobility at entry is by far the strongest predictor of early death; (2) smoking and lower hematocrit also exert important adverse effects; and (3) certain "risk factors". ie elevated systolic blood pressure and serum cholesterol. have a minimal protective effect. if any. in this age group.
Osteoporosis in late life: does health locus of control affect psychosocial adaptation, Osteoporosis. a metabolic bone disease most prevalent in older adults. is a major public health problem. Although management of osteoporosis through diet. exercise. and medication has improved. little is known about the psychosocial consequences of this disabling disease. In an attempt to identify patient characteristics that would provide physicians with insight into appropriate management styles for older osteoporotics. we assessed 103 patients with osteoporosis for their health locus of control (HLOC) orientation. We examined the relationship between HLOC and patient outcomes after participation in the Duke University Preventive and Therapeutic Program for Osteoporosis (DUPATPO) to determine whether HLOC was associated with functioning after program participation. More specifically. we asked whether internal or external HLOC was associated with decreases in depression. psychiatric symptoms. and stress symptoms. or with increases in self-esteem. exercise. and disease knowledge. We have shown in our earlier work (Gold et al. J Am Geriatr Soc 1989; 37:417) that program participation is associated with improved functioning in older adults. We now asked whether knowledge of a patient's HLOC would help predict these improvements. A comparison group (ie. older osteoporotics who did not participate in DUPATPO) was also assessed for HLOC to examine the possible association between HLOC and health behaviors regardless of the DUPATPO intervention. Our findings indicate that HLOC provided little useful information regarding patient outcomes. Although improvements were seen in the mental health of program participants. no association between these improvements and HLOC could be found.
The management of geriatric hypertension in health maintenance organizations, OBJECTIVE: To evaluate the quality of medical care received by Medicare enrollees with hypertension in health maintenance organizations (HMOs) compared to that received by a similar group of elderly hypertensives in a fee-for-service (FFS) setting. DESIGN: A quasi-experimental design was used to study an historical cohort of newly evaluated hypertensive patients over a 2-year period. SETTING: Medicare HMO and FFS practice settings. PARTICIPANTS: Eight Medicare HMOs and 87 FFS primary care physicians in the same communities were selected. A sample of 685 elderly hypertensive patients was studied. 336 in FFS settings and 349 in HMOs. MEASUREMENTS AND MAIN RESULTS: An expert panel of physicians selected standards of care for the management of geriatric hypertension. and medical records were reviewed. The results showed significant differences (P less than 0.01) in recording medications (94.5% HMO versus 88% FFS) and smoking histories (75.8% HMO versus 64.7% FFS). checking orthostatic blood pressures (9.5% HMO versus 3.3% FFS). performing funduscopy (44.4% HMO versus 27% FFS). completing cardiac examinations (90.8% HMO versus 79.8% FFS). and obtaining chest x-rays (72.8% HMO versus 64.3% FFS. P less than 0.05). Treatment and follow-up were similar between the two groups. except that FFS hypertensives were more likely to have medications adjusted and electrolytes ordered. CONCLUSIONS: The results suggest that elderly hypertensives in HMOs received equal or better quality of care for most criteria compared to elderly hypertensives in FFS settings.
Adverse reactions to amantadine prophylaxis of influenza in a retirement home, OBJECTIVE: Controversy exists about the safety of following the recommendation of the Immunization Practice Committee of the Centers for Disease Control that nursing home residents be given amantadine prophylaxis during influenza outbreaks. This study was undertaken to define the incidence of adverse reactions to amantadine in the elderly and to identify risk factors for side effects. DESIGN: A retrospective cohort study. SETTING: A retirement home which offered amantadine prophylaxis to its residents during a presumed influenza outbreak. PARTICIPANTS: Of the 96 elderly residents. 79 accepted the offer of amantadine prophylaxis. MAIN OUTCOME MEASURES: Attributable adverse health outcomes as assessed by chart review. RESULTS: 41% of the people receiving amantadine had attributable adverse reactions. of which 22% were classified as severe. Severe adverse reactions were associated with residence in the assisted living section of the facility (P = 0.002). a greater number of underlying diagnoses (P = 0.009). congestive heart failure (P = 0.02). and high serum creatinine (P = 0.02). A person with none of these risk factors had a 7% chance of having a severe adverse outcome compared to a 70% chance for someone with all four risk factors. CONCLUSION: The findings raise concern that the prophylactic administration of amantadine to all elderly residents of nursing and retirement homes may be associated with a high incidence of unacceptable reactions. particularly among less healthy residents.
Behavioral complications of drug treatment of Parkinson's disease, A variety of neuropharmacologic agents. including anticholinergic drugs. amantadine hydrochloride. levodopa. selegiline. bromocriptine. and pergolide. are now available for the treatment of Parkinson's disease. Of patients treated with dopaminergic agents. 30% develop visual hallucinations. 10% exhibit delusions. 10% have euphoria. 1% have mania. 10% to 15% experience increased anxiety. 15% have confusional periods. and a few exhibit altered sexual behavior. Anticholinergic drugs have a greater tendency to produce confusional states than dopaminergic compounds. Elderly patients and those with underlying dementia are most likely to have untoward side effects with anti-parkinsonism treatment. Dosage reduction is the optimum management strategy. although anti-psychotic agents may be necessary in patients with delusions. and lithium may help control drug-induced mania. Dopaminergic agents share the property of stimulation of D2 dopamine receptors. and this action may play an essential role in mediating their neuropsychiatric effects.
Treatment of severe male-factor infertility with high concentrations of motile sperm by microinsemination in embryo cryopreservation straws, A microinsemination technique was evaluated for treating our program's most severe cases of male-factor infertility. Oocytes were inseminated with high concentrations of motile sperm (1 to 9 x 10(6)/ml) in 10 to 150 microliters within embryo cryopreservation straws. Fertilization was obtained in 20 of 29 (69%) couples treated by this technique. In the 15 patients in which only embryos generated from the straw technique were transferred. 7 clinical pregnancies resulted (46.7% per transfer). The implantation rate for couples receiving embryos from the straw technique only (12/58; 20.7%) compared favorably to that observed for other cases treated during this same time period with regular insemination techniques (111/766; 14.5%). Clinical pregnancy rates per transfer for IVF-ET. TET. and PROST were 33.0% (1/3). 0% (0/2). and 60.0% (6/10). respectively. The percentage of polyploidic embryos was significantly lower (P less than 0.0001) for male-factor patients treated by the straw technique with high sperm concentrations than for non-male-factor patients treated during this same time period with standard sperm concentrations. Normal births have resulted from straw inseminations with 3.4 x 10(6) and ongoing pregnancies with 5.0 x 10(6) motile sperm/ml. The results of this study suggest that some cases of male-factor infertility can be successfully treated by insemination with high concentrations of motile sperm in embryo cryopreservation straws. A technique of centrifuging sperm in straws was also developed to concentrate the entire fraction of washed sperm into 10 microliters. Further development of this technique may allow treatment of more severe cases of oligo/asthenospermia by microinsemination with high concentrations of motile sperm than is presently possible with standard washing techniques.
The effect of cryopreservation on the development of S- and G2-phase mouse embryos, The survival rate and development of four-cell-stage mouse embryos frozen and thawed in S phase versus G2 phase was compared. Significantly more G2-phase than S-phase embryos survived freezing and thawing. In both groups. disruption of the zona pellucida. fusion of blastomeres. and dispersion of chromosomes were occasionally observed after thawing. Cryopreservation resulted in a longer delay in cleavage from the four- to the eight-cell stage of S (about 5 hr)- and G2-phase embryos (about 3 hr) compared to unfrozen controls. The number of frozen embryos which developed to the blastocyst stage was reduced compared to controls. and in the case of S-phase embryos. formation of the blastocyst cavity was also delayed. However. the average number of cells in the experimental and control embryos was similar. No increased incidence of chromosome abnormalities was seen. Our results suggest that freezing embryos in G2 is superior to freezing in S phase.
Major alteration of the pathological phenotype in gamma irradiated mdx soleus muscles, Two thousand rads of gamma irradiation delivered to the lower legs of ten day old normal and x-chromosome linked muscular dystrophy (mdx) mice caused significant inhibition of tibial bone and soleus muscle fiber growth. In the irradiated mdx solei. there was a major loss of muscle fibers. lack of central nucleation. and some endomysial fibrosis. These features were caused by a failure of regeneration of muscle fibers due to impaired proliferative capacity of satellite cells. Gamma irradiation transforms the late pathological phenotype of mdx muscles. so that in one major aspect (muscle fiber loss) they resemble muscles in Duchenne muscular dystrophy. However. extensive endomysial fibrosis which is another characteristic feature of Duchenne muscular dystrophy did not develop. This experimental model could be useful for the functional investigation of possible beneficial effects of therapeutic interventions in mdx dystrophy.
Cytomegalovirus preferentially infects a monocyte derived macrophage/microglial cell in human brain cultures: neuropathology differs between strains, Cytomegalovirus (CMV) has been shown through pathologic examination to infect many cell types of the brain; however. neuropathology specific for CMV has been difficult to prove in the absence of classic cytomegalic cells or demonstration of CMV antigens. In an effort to further understand CMV infection of brain tissue. a human brain cell aggregate system was infected with several strains of CMV. Different neuropathologic changes were observed that were related to CMV strain and multiplicity of infection. These changes were consistent with those considered characteristic for human immunodeficiency virus (HIV) infection. including a nodular and multinucleated giant cell formation. By electron microscopy. only a few cells throughout the aggregates demonstrated intranuclear virions. These cells were identified by ultrastructural morphology as either monocyte derived macrophages or microglial cells (M/M). Antigen expression was observed in these cells with and without neuropathologic changes. Infection progressed in either a diffuse fulminant manner or a more focal cell to cell spread. These studies demonstrate that CMV selectively infects M/M in normal human brain cultures and suggests differences in neuropathology based on multiplicity of infection and strain variation.
Infection of human neural cell aggregate cultures with a clinical isolate of cytomegalovirus, Human neural cell aggregate cultures were prepared from dissociated fetal brain tissue and maintained in rotation culture. After 35 days in culture. aggregates had the histologic appearance of dense. immature. neural cells in a tightly packed neuropil. Electron microscopy revealed ultrastructural features suggestive of immature neurons and neuroglia. In addition. neuron-specific enolase and glial fibrillary acidic protein associated with radial glial cells were detected within the aggregates by immunoperoxidase staining. When infected with a laboratory-adapted strain of cytomegalovirus (CMV). [AD169]. cells containing large. bizarre. nuclei and CMV-induced intranuclear inclusion bodies were dispersed throughout the aggregates at 16 days postinfection. In situ hybridization using a CMV-specific DNA probe and electron microscopy confirmed the presence of virus sequences as well as virus particles at histologic sites of cytopathology. In sharp contrast. aggregate cultures infected with a CMV strain recovered from the retina of an acquired immune deficiency syndrome (AIDS) patient with CMV retinitis and encephalitis displayed distinct foci of cytopathology at 23 days postinfection. a pattern not observed in CMV [AD169]-infected aggregates. Our findings suggest that human neural cell aggregates represent a a promising multicellular non-neoplastic culture system in which to study the replication of human neurotropic viruses within neural tissue.
Ubiquitin in motor neuron disease: study at the light and electron microscope, Several neurodegenerative diseases. including motor neuron disease (MND). are characterized by formation of abnormal cytoskeleton-derived inclusions which contain ubiquitin (Ubq). We have studied the distribution of Ubq in 26 cases of MND with light and electron microscopic immunocytochemistry. Ubiquitin-positive inclusions were found in neurons of anterior horns in most cases of amyotrophic lateral sclerosis (ALS) but were not present in other forms of MND. Ubiquitin immunoreactivity was observed in 10-15 nm intraneuronal filaments. which were not stained by antibodies to neurofilaments. and on dense bodies of dystrophic neurites throughout the neuropil of anterior horns and pyramidal tracts. Data analysis showed a trend toward lower percentage of Ubq-positive neurons in cases with longer duration of illness or lower number of neurons. A high percentage of Ubq-positive inclusions occurred in cases with an aggressive clinical course. suggesting that ubiquitination takes place at early stages of the disease.
Neurofilament distribution is altered in the Mnd (motor neuron degeneration) mouse, Motor neuron degeneration (Mnd) is a genetic neurodegenerative disease of the mouse that is characterized by a progressive increase in motor dysfunction. moving from hind to fore limbs. leading to paralysis. An immunocytochemical analysis of the neurofilament distribution in spinal motor neurons in Mnd mice from all stages of the disease. including the presymptomatic. was performed using antibodies to different neurofilament subunits with different degrees of phosphorylation. Perikarya that stained with antibodies to phosphorylated neurofilaments were present in Mnd and control spinal cords. but the number of stained perikarya in Mnd was not significantly different from controls. There was a marked redistribution of neurofilaments within the cytoplasm of some motor neurons in Mnd cords. In Mnd but not controls. the immunoreaction product appeared marginated. leaving areas in the cytoplasm absent of immunostaining. These areas were observed in all stages of the disease. but less predictably in presymptomatics. Both the size of the areas and the number of motoneurons containing these areas appeared to increase with the severity of the disease. The number of anterior horn neurons in the hind limb region of lamina IX in spinal segment L4 of Mnd was lower than in controls. suggesting there is a loss of neurons in Mnd.
Guidelines for the care of children and adolescents with HIV infection. Immunologic considerations in pediatric HIV infection, The pervasive effect of HIV infection on the immune system requires that the clinician be alert to the variety of immunologic abnormalities that can result from this disease. The tests described in this section provide guidelines for testing the HIV-infected child. Additional information on immunologic evaluations in the child with indeterminate HIV infection status can be found in the article on ambulatory care.
Postmenopausal hormone replacement with a combination estrogen-progestin regimen for five days per week, A group of 15 postmenopausal women who had not recently received estrogen replacement were enrolled in a study during which they received 0.625 mg of conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate daily from Monday through Friday of each week for six months. No treatment was given on the weekend. Endometrial biopsy specimens at the end of therapy revealed minimal growth of glands and stroma and a low mean mitosis count. Of the 12 women who completed the trial. 5 were completely amenorrheic. and only 4 of the 15 bled beyond the second month of treatment. Of those four. two spotted for only a few days. In the 12 women who completed the trial there was a significant increase in high density lipoprotein cholesterol and a nonsignificant lowering of low density lipoprotein cholesterol. The results of this study indicate that comparative trials between this regimen and one in which the two drugs are given daily for seven days a week are warranted.
Oral contraceptives and breast cancer. Cause and effect, Case-control studies dealing with breast cancer and oral contraceptives (OCs) were reviewed against a background of currently accepted rules for conducting and interpreting epidemiologic research. There is a strong consensus that OCs have not increased the risk of breast cancer in women over age 45. even when they have been used for long periods. The controversy is confined to studies of cancer diagnosed in young women. Although an effect of duration of OC use has been observed in some studies. there is neither a latency period nor an effect from recent or current use. There is no obvious relationship to the type of pill and no consistent effect of the dose of estrogen. The effect. if it exists at all. is not confined to any specific subgroup; it has not been related to age at starting OCs. It has been observed in only a few studies. some of which were subsequently discounted. Others have shown no effect or have suggested a reduced risk of breast cancer with increasing duration of use. None of the studies purporting to show an effect of OCs have controlled for the potential confounding effects of duration of lactation. induced abortion. recent pregnancy or a history of diseases that are associated both with reduced use of OCs and reduced risk of breast cancer. Most have inappropriately controlled for benign breast disease. There is an urgent need for a reanalysis of existing studies to take these factors into account. The lack of consistency and the potential for bias and confounding argue strongly against concluding. at this time. that there is a causal relationship between OCs and breast cancer.
Discordance of mullerian agenesis in monozygotic twins. A case report, With the case described here there have been six reported cases of discordance of mullerian development in monozygotic twins. The etiology of the disorder remains obscure. Although a genetic basis may exist in some cases. it could not be demonstrated in any of the six cases.
A study of the status of clinical cancer research in the United States (1990), This study has confirmed a continuing decrease in the quality and quantity of young physicians entering academic careers in clinical oncology research. defined as cancer research requiring a clinician-patient interaction. Two major contributing factors were identified: the training programs and the research environment. The primary problems for the trainees were the financial insecurity of embarking on an academic career and the poor academic status of their role models in clinical cancer research. The problems regarding the environment of academic oncology and oncology research relate primarily to the strong and widespread perception that grant proposals for clinical oncology research are at a competitive disadvantage with proposals for cancer research in the laboratory. The study results yielded two basic recommendations. The first recommendation is to improve training for clinical cancer research and to implement unique funding mechanisms for trainees. Because physicians devote 3-10 years to clinical training. a minimum of 10 years of clinical research is needed for a clinician to compete effectively as a principal investigator in the R01 and P01 grant areas. The second recommendation is to develop peer review mechanisms that allow clinical research proposals to compete within a pool restricted to proposals in this category. The consensus in the study was that when programs in clinical research and laboratory research are in competition. the clinical proposals have a lower success rate. The problem appears to rest with the fact that the reviewers are frequently from disciplines other than clinical research and. more importantly. that clinical research proposals fare badly in competition against laboratory research proposals even when they are reviewed by appropriate peers. Implementation of this recommendation will require development of a clinical oncology research study section in the Division of Research Grants at the National Institutes of Health to review R01 grant proposals for innovative clinical cancer research. providing an academic environment that would enable the clinical investigator. through increased success in obtaining grants. to be a positive role model for the young physician/scientist.
Breast cancer in men: aspects of familial aggregation, Familial aggregation of breast cancer in males was investigated in a population-based case-control study. Cases were ascertained from 10 Surveillance. Epidemiology. and End Results Program registries in the United States between 1983 and 1986. Controls were identified by random-digit dialing and from lists of Medicare recipients. The relative odds of developing breast cancer were similar in men with affected paternal and maternal relatives and in men with affected mothers and sisters. The risk increased with the number of affected relatives. The relative odds of developing breast cancer were greater in men with first-degree relatives who developed their mammary neoplasm before the age of 45 than in men with older first-degree affected relatives; the enhancement of risk in men with an affected sister was greater in those under age 60 than in older men. These results are similar to those observed by others in studies of breast cancer in women.
Randomized trial of cyclophosphamide, doxorubicin, and vincristine versus cisplatin and etoposide versus alternation of these regimens in small-cell lung cancer, Between April 1985 and May 1988. we conducted a randomized study comparing two standard chemotherapy regimens with the same regimens given on an alternating basis in patients with small-cell lung cancer. The patients were randomly assigned to receive cyclophosphamide at a dose of 800 mg/m2 intravenously (IV) on day 1. doxorubicin at 50 mg/m2 IV on day 1. and vincristine at 1.4 mg/m2 IV on day 1 (CAV); cisplatin at 80 mg/m2 IV on day 1 and etoposide at 100 mg/m2 IV on days 1. 3. and 5 (PE); or CAV alternating with PE (CAV/PE). Each regimen was repeated every 3-4 weeks. Three hundred patients were entered in the study. and 288 of them were eligible for analysis (97 for CAV. 97 for PE. and 94 for CAV/PE). The response rates for PE (78%) and CAV/PE (76%) were significantly higher than the rate for CAV (55%). while the complete response rates were similar (14%. 16%. and 15%. respectively). Nine (23%) of 39 patients who failed to respond to the initial CAV regimen responded to PE when they were crossed over. In contrast. only one (8%) of 13 patients responded to CAV after failing to respond to the PE regimen. suggesting that these two regimens were partially non-cross-resistant. The response duration on CAV/PE was significantly longer than that with CAV (P = .004). The survival time with CAV/PE (11.8 months) was superior to that with CAV (9.9 months) (P = .027) or that with PE (9.9 months) (P = .056). In patients with limited disease. the survival in the alternating arm was significantly superior to the survival in the CAV arm (P = .014) or the survival in the PE arm (P = .023). The toxic effects were acceptable in all three chemotherapy regimens. These results favor the alternating chemotherapy over either standard chemotherapy. such as CAV and PE. although the differences are not dramatic.
Preneoplastic alterations in nuclear morphology that accompany loss of tumor suppressor phenotype, Alterations of nuclear shape are frequently observed in tumor cells. but the genes controlling these changes and the stage in the neoplastic process at which they occur are unknown. We have studied nuclear shape changes in chemically immortalized. nontumorigenic Syrian hamster embryo cell clones that had either retained (supB+) or lost (supB-) the ability to suppress the tumorigenic phenotype when they were hybridized with a tumor cell line (BP6T). Quantitative morphometric analysis of the nuclei of cells from each of two pairs of supB+/supB- variants indicated that the nuclei of supB- cells were significantly more out of round than those of their corresponding supB+ clones. These data indicate that modification of nuclear structure may represent an early. preneoplastic event in multistep chemical carcinogenesis and that loss of a tumor suppressor gene function may regulate alterations in nuclear morphology.
Intracellular gastrin in human gastrointestinal tumor cells, Flow cytometry and immunohistochemical analyses of the human gastric adenocarcinoma cell line MKN45G identified an intracellular peptide recognized by an anti-gastrin-17 (G17) antiserum but not by an anti-cholecystokinin-specific antiserum. Staining was not associated with the parental line MKN45. of which MKN45G is a clonal variant. The MKN45G cell line had elevated in vitro growth in serum-free medium in which the proliferation of MKN45G cells but not MKN45 cells was reduced to 58% of the control value by treatment with a rabbit anti-G17 antiserum. This inhibition of proliferation was reversed by preabsorbing the antiserum with excess G17. Disaggregated primary human gastric and colorectal tumors were screened for gastrin immunoreactivity by flow cytometry. and 6 of 28 colorectal and 8 of 22 gastric tumors had greater than 20% positively staining cells.
Penetrating carotid injuries--a wartime experience, Thirty-nine patients with penetrating carotid injuries were treated between 1975 and 1987. All were war victims. On admission 27 (69%) had no neurologic deficit (group I). 8 (20.5%) had a mild neurologic deficit (group II). and 4 (10.5%) had a severe deficit (group III). Repair was undertaken in 38 of 39 (97.5%) patients. and carotid ligation was performed in 1 case (2.5%). Associated injuries were found in 25 (65%) patients. All patients survived. At the time of discharge all group I and II patients had a normal neurologic examination. One patient in group III recovered completely. whereas two had significant improvement. One patient remained unchanged. We conclude that repair should be attempted in all patients with carotid injuries who are seen early (less than 120 minutes) after the accident.
Spontaneous thrombosis of iatrogenic femoral artery pseudoaneurysms: documentation with color Doppler and two-dimensional ultrasonography, Two-dimensional ultrasonography and color Doppler were used over an 18-month period for the diagnosis and management of femoral artery pseudoaneurysms in six patients with pulsatile groin masses found after catheterization. A diagnosis of pseudoaneurysm was made when color Doppler demonstrated pulsatile systolic flow into echolucent masses. One patient underwent surgical repair of a symptomatic pseudoaneurysm after the initial Doppler study. Serial color Doppler studies were performed in five subjects. all of whom showed resolution of flow after a mean of 18 days (range 7 to 42). Despite an absence of flow. one patient underwent surgical drainage of persistent hematoma. After a mean interval of 233 days (range 84 to 552) all patients have remained free of other complications or symptoms related to the pseudoaneurysm. This experience suggests that urgent surgical repair is not required in all cases of small iatrogenic pseudoaneurysms. and that asymptomatic patients can be safely followed with serial color Doppler examinations.
Systemic hypertension alters vasomotor function in experimental vein grafts, Hypertension is an established risk factor for atherosclerosis. a disease that is important in the pathophysiology of vein graft failure. Hypertension can also alter arterial vasoreactivity. The vasomotor function and histologic characteristics of autogenous vein grafts in hypertensive rabbits were assessed in this study. Hypertension was induced in 13 male New Zealand white rabbits by use of the Goldblatt one clip two kidney method. The right carotid artery was divided and bypassed with the reversed right external jugular vein 7 days later in these animals and in 13 normotensive controls. Blood pressure and renal function were assessed serially. and all the grafts were harvested after 28 days. Three grafts in each group were examined by light microscopy. The responses of the remaining grafts to norepinephrine. histamine. serotonin. and angiotensin II were determined in vitro under isometric tension. Endothelium-dependent relaxation to acetylcholine and calcium ionophore (A23187) was assessed in precontracted grafts. The mean arterial pressure was significantly increased after the Goldblatt procedure was performed. Intimal hyperplasia was observed in both groups. but the grafts in the hypertensive groups showed increased adventitial and medial fibrosis and a reduced number of vasa vasora. The grafts in the hypertensive rabbits were hypersensitive to all agonists as indicated by a significant reduction in their median effective dose values. and their maximal responses to all agonists were also significantly reduced. No graft relaxed in response to acetylcholine. and whereas precontracted grafts in normotensive rabbits had a maximal relaxation of 24% +/- 6% of precontraction with A23187. this was absent in the grafts in the hypertensive rabbits. The results suggest that angiotensin-induced hypertension may adversely affect vein graft patency by inducing hypersensitivity to physiologically important agonists and reducing the effect of receptor-independent endothelium-derived relaxation on vasomotor tone.
Temporary closure of the abdominal wall by use of silicone rubber sheets after operative repair of ruptured abdominal aortic aneurysms, Management of patients after operative repair of abdominal aortic aneurysms can be further complicated if primary closure of the abdominal wall cannot be technically accomplished or is associated with profound increases in intraabdominal and peak inspiratory pressures. We recently treated five patients with ruptured abdominal aortic aneurysms and one patient with a ruptured thoracoabdominal aneurysm whose abdominal incisions had to be closed with a Dacron reinforced. silicone sheet. All patients were hemodynamically unstable either at admission to the hospital or became so during operation. Four patients required the insertion of a silicone rubber sheet at the primary operation because of massive retroperitoneal hematoma or edema of the bowel wall or both. Incisions in two patients were closed primarily. but the patients required reexploration and secondary closure with silicone rubber sheets because of the development of marked increases in peak inspiratory pressures. intraabdominal pressures. and decreased urinary output. Four of the six patients subsequently underwent successful removal of the silicone rubber sheets with delayed primary closure of the abdominal wall. and two others died before removal. The patient with the ruptured thoracoabdominal aneurysm died on postoperative day 20 because of pulmonary sepsis but had a healed abdominal incision. The three surviving patients have been discharged. A silicone rubber sheet may be necessary for closure of the abdominal wall after repair of ruptured abdominal aortic aneurysm in patients where primary abdominal wall closure is impossible or where it results in compromise in respiratory or renal function.
Urinary cotinine measurement in patients with Buerger's disease--effects of active and passive smoking on the disease process, Although Buerger's disease is known to be closely related to smoking. no objective analysis of the smoke-associated problems has been performed. In this study. cotinine. the major metabolite of nicotine. was used as a sensitive marker to measure levels of active smoking and the exposure of nonsmokers to tobacco smoke because it has a relatively long half-life and because cotinine levels can be determined by noninvasive means in urine. According to urinary cotinine levels. 40 patients with Buerger's disease were classified as (1) smokers: those with urinary cotinine levels above 50 ng/mg creatinine; (2) passive smokers: those with levels between 10 and 50 ng/mg creatinine; and (3) nonsmokers who did not experience noticeable passive smoking: those with levels below 10 ng/mg creatinine. There were 10 smokers. 9 passive smokers. and 21 nonsmokers. The course of the disease. after the initial treatment at our hospital. was studied retrospectively. Seven of the 10 smokers. none of the 9 passive smokers. and 4 of the 21 nonsmokers experienced aggravation of the disease. Of the four nonsmokers who experienced aggravation. three had still been smokers and one had been exposed to tobacco smoke in the workplace at the time of relapse. There was a significant difference in the aggravation rate between the smokers' group and the other two groups. Among the smokers. the seven patients whose conditions worsened showed significantly higher cotinine levels than the three remaining patients who were in the stage of remission.
Intermittent claudication as a manifestation of silent myocardial ischemia: a pilot study, One hundred consecutive patients with intermittent claudication were screened noninvasively with electrocardiography chest wall mapping stress test and transcutaneous aortovelography during bicycle ergometry. Electrocardiographic chest wall stress testing indicated three-vessel coronary disease in 25 patients and left anterior descending plus circumflex (left main stem equivalent) disease in seven. In these 32 patients transcutaneous aortovelography demonstrated a decrease in stroke distance (an index of cardiac stroke volume) (median. -28%; 90% range. +5% to -48%). and coronary angiography confirmed the presence and severity of the disease. The claudication distance ranged between 50 and 250 meters. After myocardial revascularization or medical therapy a significant increase occurred in the stroke distance after exercise (median. +20; 90% range. +40% to -25%); also a significant increase in the postexercise pressure index and a reduction in the recovery time (p less than 0.01). No change occurred in the ankle/pressure index at rest. Twelve patients were able to walk without being limited by claudication; 15 reported improvement with a two to tenfold increase in claudication distance. No change occurred in three. The results indicate that silent myocardial ischemia is a common finding in patients with intermittent claudication. It produces left ventricular dysfunction and a decrease in stroke volume leading to a large fall in ankle pressure and early onset of claudication during exercise. Niltrates and myocardial revascularization tend to reverse this.
A prospective study of aspirin use and primary prevention of cardiovascular disease in women, OBJECTIVE. The aim of the study was to examine prospectively the association between regular aspirin use and the risk of a first myocardial infarction and other cardiovascular events in women. DESIGN. Prospective cohort study including 6 years of follow-up. SETTING. Registered nurses residing in 11 US states. PARTICIPANTS. US registered nurses (n = 87.678) aged 34 to 65 years and free of diagnosed coronary heart disease. stroke. and cancer at baseline. Followup was 96.7% of total potential person-years of follow-up. MAIN OUTCOME MEASURES. Incidence of myocardial infarction. stroke. cardiovascular death. and all important vascular events. RESULTS. During 475.265 person-years of follow-up. we documented 240 nonfatal myocardial infarctions. 146 nonfatal strokes. and 130 deaths due to cardiovascular disease (total. 516 important vascular events). Among women who reported taking one through six aspirin per week. the age-adjusted relative risk (RR) of a first myocardial infarction was 0.68 (95% confidence interval [CI]. 0.52 to 0.89; P = .005). as compared with those women who took no aspirin. After simultaneous adjustment for risk factors for coronary disease. the RR was 0.75 (95% CI. 0.58 to 0.99; P = .04). For women aged 50 years and older. the age-adjusted RR was 0.61 (95% CI. 0.45 to 0.84; P = .002) and the multivariate RR was 0.68 (95% CI. 0.50 to 0.93; P = .02). We observed no alteration in the risk of stroke (multivariate RR = 0.99; P = .94). The multivariate RR of cardiovascular death was 0.89 (P = .56) and of important vascular events was 0.85 (P = .12). When examined separately. the results were nearly identical for the subgroups who took one through three and four through six aspirin per week. Among women who took seven or more aspirin per week. there were no apparent reductions in risk. CONCLUSIONS. The use of one through six aspirin per week appears to be associated with a reduced risk of a first myocardial infarction among women. A randomized trial in women is necessary. however. to provide conclusive data on the role of aspirin in the primary prevention of cardiovascular disease in women.
Outbreak of group A streptococcus septicemia in children. Clinical, epidemiologic, and microbiological correlates, OBJECTIVE. To determine the epidemiologic. clinical. and microbiological features of group A streptococcus septicemia in children. DESIGN. A descriptive series of 34 cases over an 11-year period from 1980 through 1990. SETTING. An academically affiliated tertiary-care pediatric hospital. the principal referral center for the state of Colorado and surrounding states. PARTICIPANTS. Thirty-four patients with positive blood cultures for group A streptococcus (33 medical records were available). MAIN OUTCOME MEASURES. Yearly incidence and clinical features of cases; microbiological features of isolated organisms. RESULTS. There was a significant increase (P = .01) in the incidence of group A streptococcus bacteremia over an 11-year period. with 14 (41%) of these cases occurring in 1989 and 1990. Patients had a rapidly progressing illness. usually without preceding pharyngitis. The prominent M and T types were 1 (4) and 12 (4). Eleven (73%) of the 15 strains produced pyrogenic exotoxin B that significantly correlated with production of proteinase. CONCLUSION. There appears to be an increase in group A streptococcus bacteremia in children that is associated with a strain phenotype that suggests a change in organism virulence.
Promoting cancer prevention activities by primary care physicians. Results of a randomized, controlled trial, BACKGROUND. Previous interventions to promote performance of cancer prevention activities have largely targeted physicians in university-based practices. METHODS. We randomly assigned 40 primary care physicians in community-based practices to either (1) Cancer Prevention Reminders. computer-generated lists of overdue screening tests. and smoking and dietary assessment and counseling. supplemented by cancer education materials; or (2) controls. For each physician. we reviewed a random sample of 60 medical records for data about screening test. assessment. and counseling performance during 12-month preintervention and intervention periods. We calculated performance scores as percentage compliance with American Cancer Society and/or National Cancer Institute recommendations. Multiple regression analyses provided estimates of incremental differences in performance scores between intervention and control groups. RESULTS. Controlling for preintervention performance levels. significant incremental differences in performance scores between intervention and control groups (P less than .05) were achieved for nine maneuvers: stool occult-blood test. +14.5; rectal examination. +10.5; pelvic examination. +11.8; Papanicolaou's smear. +30.7; breast examination. +8.7; smoking assessment. +10.2; smoking counseling. +17.3; dietary assessment. +12.3; and dietary counseling. +13.9. Increments for sigmoidoscopy and mammography were not significant. CONCLUSION. Computerized reminders can significantly increase physicians' performance of cancer prevention activities in community-based practices.
A statewide early defibrillation initiative including laypersons and outcome reporting, Rapid delivery of defibrillatory shocks increases survival in patients with cardiac arrest. The automated external defibrillator interprets cardiac rhythms and delivers electrical shocks. permitting appropriate defibrillation by persons with minimal training. California initiated a program for early defibrillation by basic emergency medical technicians. using manual or automated external defibrillators. and by public safety personnel (fire fighters. peace officers. and public lifeguards). using automated external defibrillators. The program includes a system for reporting outcomes statewide. In the first 46 months under this program. 1487 patients received defibrillatory shocks; 1009 (68%) of these patients had witnessed ventricular fibrillation. Of the latter group. 191 were discharged from the hospital. representing 19% of those with witnessed ventricular fibrillation and 13% of all patients who had had shocks applied. California also implemented a framework of training and medical direction for defibrillation by laypersons using automated external defibrillators. Early defibrillation by basic emergency medical technicians and public safety personnel. encouraged by appropriate regulatory changes. results in gratifying survival rates.
Septic reactions to platelet transfusions. A persistent problem, OBJECTIVE. To determine the medical and laboratory characteristics of bacteremia secondary to transfusion of microbiologically contaminated platelet concentrates. DESIGN. Febrile transfusion reactions were prospectively monitored over 42 months. Units involved in reactions were evaluated with Gram's stain and culture tests. SETTING. Comprehensive cancer center. PATIENTS. Patients receiving platelet transfusions for thrombocytopenia secondary to bone marrow failure. RESULT. Seven cases of transfusion-associated sepsis were observed. Multidonor platelet products stored for 5 days resulted in an incidence of sepsis five times higher than those stored for 4 days or less (P less than .01). Investigation indicates that contamination most likely occurred at the time of blood collection. Clinically. septic reactions were associated with greater temperature elevations (average increase. 2.0 degrees C) than febrile reactions to sterile products. CONCLUSIONS. Contamination of platelet concentrates remains a significant clinical problem. Septic episodes may be reduced by transfusion of platelets with shorter storage intervals.
Molecular mechanisms of tubulointerstitial hypertrophy and hyperplasia, Adult kidneys. which are principally composed of tubulointerstitium. do not normally regenerate or expand their working pool of functional cells at a very high rate. Loss of kidney tissue. however. can lead to some compensatory renal enlargement. The catalytic forces initiating such exchanges have not been fully articulated by current experimental endeavors. Increasing evidence. nevertheless. does suggest that factors other than simple changes in renal hemodynamics may be involved in this process. Different cellular elements in the tubulointerstitial microenvironment probably modulate changes in tubular enlargement or size through a complex cytokine network. Autocrine and paracrine stimulation of enlargement by different local growth factors also seem to play a pivotal role. After binding to cellular receptors. these factors activate signal transduction pathways resulting in expression of immediate early genes. which by themselves can synchronize the expression of subsequent genes through the medium of transacting factors. The renal enlargement response can also be modified by endocrine hormones that can activate such genes directly and/or stimulate other adjunctive processes. like receptor expression for the regional binding of growth factors. Furthermore. renal enlargement is under negative feedback of inhibitory factors like TGF beta. It is possible. for example. that special genes exist which are only expressed to arrest enlargement. It has been further suggested that activation of the Na+/H+ antiporter is a common denominator in renal enlargement. Recent findings. however. indicate that the activation of this antiporter is not always necessary. and might rather be a parallel event rather than a key phenomena in tubular enlargement. G0/G1 transition of tubular cells seems to involve similar factors in tubular hypertrophy and hyperplasia. The factors which are responsible for the final determination of the enlargement pattern (hypertrophy vs. proliferation) are unknown. The separation between hypertrophy and hyperplasia. although suggested by striking differences in cellular regulation. may be somewhat artificial. since responses leading to tubular enlargement also exist in circumstances where hyperplasia and hypertrophy are combined events. Recently it has been proposed that growth factors stimulate gluconeogenesis in proximal tubular cells producing hyperplasia. whereas factors inhibiting gluconeogenesis might induce hypertrophy. Whether the common pathway message of this intriguing hypothesis is correct still requires further validation.(ABSTRACT TRUNCATED AT 400 WORDS).
Mechanisms of tubulointerstitial fibrosis, With regard to tubulointerstitial fibrogenesis we are left with a variety informational gaps regarding nearly all aspects of this clinically important process. Table 2 summarizes a generalized version of fibrogenesis based primarily on investigations in other organs. Extrapolation of data obtained with other fibrogenic systems is useful. but only in so far as it motivates us to adapt and test many of the experimental principles within in the context of the kidney. This begins with a comprehensive examination of the in vivo state. the establishment of adequate animal models. and the dissections of the process in vitro. Key areas for the future are the characterization of the signals involved. the cellular responses to these signals. and the variations in interactions produced by differing inciting fibrogenic conditions.
Oncogene expression and oral cancer, Cancer of the oral cavity remains a major problem in the United States as well as in many other countries. some of which record as much as 30% of all their cancers to be in the oral region. Despite numerous advances in the fields of epidemiology and etiology. little is known of the molecular basis of oral cancer. Advances in the field of oncogenes have produced a tool to study the different stages of carcinogenesis. including transition from premalignant to malignant stages. These strategies have direct relevance to oral cancer where the premalignant stage is well defined. Preliminary studies into the expression and function of oncogenes suggest abnormalities including individual and multiple amplification of three or more types of these genes. This review briefly describes the concept of oncogenes. and their possible role in the development of neoplasia and specifically on studies in oral cancer.
Adenosquamous carcinoma of the pancreas: a clinicopathologic study, A total of eight patients with adenosquamous carcinoma of the pancreas were studied clinicopathologically. Histochemical and immunohistochemical studies were also done. The 8 patients were composed of 4 men and 4 women with a mean age of 56 years. which was 9 years younger than for other pancreatic carcinoma. The site of origin and size of the tumors were similar to those of usual pancreatic carcinoma. Histopathologically. all eight tumors showed an abrupt transition between adenocarcinoma and squamous cell carcinoma. Squamous cell carcinoma was located at the periphery of the tumors. Histochemistry and immunohistochemistry disclosed a different nature for both components. The cumulative 1-year survival rate of the 8 patients was 21.4%. compared to 42.1% of 72 with adenocarcinoma of the pancreas. The survival curve of the 8 patients with adenosquamous carcinoma was significantly less favorable than that of 36 patients with well-differentiated adenocarcinoma of the pancreas. These facts support the view that squamous cell carcinoma in adenosquamous carcinoma of the pancreas is squamous cell metaplasia of the pre-existing adenocarcinoma. The clinical course of adenosquamous carcinoma of the pancreas was unfavorable.
Major amputations done with palliative intent in the treatment of local bony complications associated with advanced cancer, Palliative amputations were performed on 11 patients (7 men. 4 women) with disseminated disease to control local bony complications. The average patient age was 54 years (range 14-78 years). The primary diseases were melanoma/sarcoma (seven patients) and carcinoma (four patients). All had pain; eight had intractable pain that could not be controlled by analgesics. All 11 patients had additional severe local complications. which included recurrent pathological fracture (4). sepsis (2). hemorrhage (2). radiation necrosis (2). and iliofemoral thrombosis secondary to tumor (1). Previous attempts of palliation had been made in all 11 patients. and 8 had undergone previous operative procedures (5 had undergone two or more) prior to amputation. Three anterior hemipelvectomies. five posterior hemipelvectomies. two hip disarticulations. and one forequarter amputation were performed. All patients survived the surgery. and there were no intraoperative complications. All patients received dramatic relief of pain. Postoperative complications included two cases of flap necrosis and two infections; all resolved satisfactorily. The six patients who were nonambulatory before surgery ambulated postoperatively. and two eventually ambulated with a prosthesis. Six of 11 patients survived 1 year or longer. with a median postoperative survival period of 13 months (average 16 months). Although major amputations are viewed at times as offering little to already-compromised patients. they can improve dramatically the quality of life in selected patients.
Aggressive malignant hemangiopericytoma in the neck, Hemangiopericytomas are rare vascular tumors. one fourth of which occur in the head and neck. These lesions are characteristically slow growing and slow to metastasize. We describe an otherwise healthy patient with a hemangiopericytoma on the left side of his neck that metastasized to his chest wall within 3 months after the tumor was first observed. The metastasis occurred while the patient was receiving radiation therapy. The patient died soon afterward. This case illustrates the aggressive malignant potential of hemangiopericytomas.
Open biopsy without wound closure for skeletal neoplasms, During the past several years. the indications for limb salvage in musculoskeletal neoplasms have been expanded. As a result. interest in the topic of diagnostic biopsy has been renewed. Post biopsy hematoma formation and the iatrogenic spread of cancer cells has led to universally accepted guidelines for biopsy technique. These include meticulous hemostasis and wound closure. A technique of open biopsy without wound closure in which the biopsy site in a long bone with contained neoplasm remains open and hematoma allowed to drain into the dressings is outlined. A discussion of the theoretical advantages and disadvantages of this technique is presented.
Elevated serum gastrin levels in patients with gastric cancer, Elevated plasma gastrin levels have been found in patients with colorectal cancer. We measured fasting serum gastrin levels in control subjects (n = 12). patients with gastric cancer (n = 43). and patients with carcinoma of the esophagus (n = 55). Serum gastrin levels were significantly higher in patients with gastric cancer compared to normal controls (P less than 0.005) and those with esophageal cancer (P less than 0.05). This information may add to our understanding of the pathogenesis of gastric cancer.
Colorectal cancer patients with high risk of hematogenous metastasis: correlation with CEA levels in peripheral and draining venous blood during the period of operation, Correlations between carcinoembryonic antigen (CEA) levels of peripheral (p) and draining (d) venous blood during the period of operation. and pre- and post-operatively detected hematogenous metastases were examined in 78 patients with colorectal cancer. The metastases were found in 28 patients (HM group). but not found in the other 50 patients (non-HM group). The mean values (43 and 198 ng/ml) and positive rates (61 and 96%) greater than 5 ng/ml of p- and d-CEA levels in the HM group were significantly higher than those (6 and 14 ng/ml. and 22 and 48%. respectively) in the non-HM group. The differences (mean 184 ng/ml and positive rate 49%) of d-CEA levels between both groups were more significant than those (39 ng/ml and 30%) of p-CEA levels. The mean value (155 ng/ml) and positive rate (82%) greater than 5 ng/ml of the gradient between d- and p-CEA levels (d-p CEA gradient) in the HM group were significantly higher than those (8 ng/ml and 34%) in the non-HM group. These results suggest that patients with a high risk of hematogenous metastases are more effectively checked by the determination of d-CEA levels and d-p CEA gradient than of p-CEA levels. and that they are patients with positive d-CEA and d-p CEA gradient levels.
Prospective analysis of masticatory function following lateral mandibulotomy, Based on clinical impressions and subjective reports by patients. it is generally accepted that a loss of mandibular continuity will result in decreased masticatory function while preserving continuity will result in maintenance of masticatory function. Surprisingly. there is a paucity of well controlled studies objectively evaluating masticatory function to support these statements. The purpose of this study was to objectively evaluate masticatory function in a patient who underwent surgical resection for cure of a tonsillar carcinoma where a lateral mandibulotomy was used. Masticatory performance and swallowing threshold were assessed using a 0.5 gm frito as the test food substance and a sieve analysis. The subject was evaluated pre and post surgery and post prosthetic rehabilitation. When compared with pre surgery function. masticatory function and swallowing threshold were maintained and enhanced with prosthetic treatment 1 year post surgery. Maintenance of mandibular continuity did have functional merit for the subject studied.
Efficacy of vitamin A in reducing preschool child mortality in Nepal, Community trials of the efficacy of vitamin A supplementation in reducing preschool childhood mortality have produced conflicting results. To resolve the question. a randomised. double-masked. placebo-controlled community trial of 28.630 children aged 6-72 months was carried out in rural Nepal. an area representative of the Gangetic flood plain of South Asia. Randomisation was carried out by administrative ward; the vitamin-A-supplemented children received 60.000 retinol equivalents every 4 months and placebo-treated children received identical capsules containing 300 retinol equivalents. After 12 months. the relative risk of death in the vitamin-A-supplemented compared with the control group was 0.70 (95% confidence interval 0.56-0.88). equivalent to a 30% reduction in mortality. The trial. which had been planned to last 2 years. was discontinued. The reduction in mortality was present in both sexes (relative risk for boys 0.77; for girls 0.65). at all ages (range of relative risks 0.83-0.50). and throughout the year (0.76-0.67). The reduction in mortality risk was not affected by acute nutritional status. as measured by arm circumference. Thus. periodic vitamin A delivery in the community can greatly reduce child mortality in developing countries.
Prediction of lymph node involvement in breast cancer by detection of altered glycosylation in the primary tumour, Axillary lymph node metastases at the time of diagnosis of breast cancer is the most accurate predictor of long-term prognosis. However. in patients treated by conservative surgery lymph node status often remains unknown. We have investigated the relation between changes in glycosylation of primary breast cancer cells. as judged by lectin binding. and the presence of axillary lymph node metastases. In a 24-year retrospective study. paraffin-embedded sections of 373 primary breast cancers were stained for the binding of Helix pomatia lectin (HPA). There was a strong association between HPA binding and presence of lymph node metastases. but no association with tumour size. histological grade. S-phase fraction. or patient age at diagnosis. This relation was confirmed by multiple regression analysis (in both survival and relapse free survival models) in which the prognostic significance of HPA binding was lost once nodal status had been introduced into the models. Life tables calculated for lymph-node positive versus lymph-node negative and HPA staining versus non-staining patients were almost identical over 15 years of follow-up. We propose that HPA recognises a glycoprotein that is associated with metastasis (to axillary lymph nodes and elsewhere) and poor prognosis in breast cancer. HPA binding to paraffin sections of primary tumour could aid difficult treatment decisions by providing an additional assessment of staging and likely long-term patient prognosis.
PUVA and cancer: a large-scale epidemiological study, There is concern about the long-term carcinogenic effects of psoralen and ultraviolet A radiation (PUVA) therapy for treatment of skin disorders. A study of 4799 Swedish patients (2343 males. 2056 females; mean age at first treatment 45.3 years. range 6-93; mean follow-up 6.9 years males. 7.2 years females) who received PUVA between 1974 and 1985 showed a dose-dependent increase in the risk of squamous cell cancer of the skin. Male patients who had received more than 200 treatments had over 30 times the incidence of squamous cell cancer found in the general population. Significant increases (p less than 0.05) were also found in the incidences of respiratory cancer in males and females. pancreatic cancer in males. and kidney and colonic cancer in females. This study confirms previous reports of a dose-dependent increase in the incidence of squamous cell cancer in patients treated with PUVA.
Correlates of vestibular evaluation results during the first year of life, Prenatal and perinatal correlates of abnormal auditory brainstem responses in neonates have been studied extensively. In contrast. vestibular function during the first year of life has received sparse attention. Using a specially modified vestibular test battery. 65 infants (17 low-risk. 48 high-risk) were initially evaluated during their first 6 months of life. Results revealed normal vestibular function in 46 infants (13 low-risk. 33 high-risk) and abnormal findings at either 3 or 6 months in 19 infants (4 low-risk. 15 high-risk). Correlations between vestibular results and variables such as auditory brainstem response results. birth history. and postnatal course in the neonatal intensive care unit were analyzed statistically. While some differences were mildly significant. none were highly significant. The lack of significant correlation between abnormal auditory brainstem response and vestibular results is of particular interest.
Headshake versus whole-body rotation testing of the vestibulo-ocular reflex, The vestibulo-ocular reflex (VOR) is usually evaluated by whole-body rotary chair oscillation in darkness. but is limited to ambulatory patients. In order to develop a portable method of VOR assessment. eye movements from 10 normal subjects were studied under three conditions: 1. whole-body rotary chair oscillation in the dark and in the light with a head mounted blank field. 2. passive head-on-body rotation in the light with a blank field. and 3. active head-on-body rotation in the light with a blank field. The influence of visual fixation. neck rotation. and volition on VOR gain was to be assessed. Head oscillations were maintained at 0.5 and 1.0 Hz. 50 degrees/s peak velocity. Mean VOR gains with blank field testing were indistinguishable from those obtained in darkness during whole-body rotation. In addition. there were no significant differences in the mean gain between whole-body. passive head rotation or active head rotation. Two vestibulopathic patients (absent calorics bilaterally and oscillopsia) were also studied to illustrate potential clinical utility of the methods. Rotations under all conditions revealed low but variable gains. The evaluation of the VOR in the light with a blank visual surround and passive or active head rotation is a potentially useful clinical method of bedside assessment of the VOR.
Efficacy of feedback training in long-standing facial nerve paresis, An efficacious treatment has not been available to patients with aberrant regeneration of the facial nerve as a result of Bell's palsy or after acoustic neuroma excision. This prospective controlled trial examines the efficacy of electromyographic feedback versus mirror feedback as treatment strategies for patients suffering from long-standing (18 months minimum) facial nerve paresis. Twenty-five patients were randomly assigned to electromyography with mirror feedback or mirror feedback alone. Seven rural patients who did not undergo treatment served as controls. At 0. 6. and 12 months. facial motor function was objectively quantified by linear measurement of facial movement. visual assessment of voluntary movement. and electrical measurement of facial nerve response to maximal stimulation. Statistically significant improvements were noted in both electromyography and mirror-feedback groups with respect to symmetry of voluntary movement (P less than .03) and linear measurement of facial expression (P less than .01). The positive results of this controlled trial demonstrate that feedback training in combination with a structured home rehabilitation program is a clinically efficacious treatment for patients with facial nerve paresis.
Primary ciliary dyskinesia and the middle ear, The middle ear cavity and the eustachian tube contain a well-functioning mucociliary clearance system. To learn more about the importance of this mucociliary clearance. we studied patients with primary ciliary dyskinesia. in whom mucociliary clearance is absent. Thirty-six patients were investigated by means of a questionnaire; in 16 of these patients. otological and audiological studies could be performed. In patients with primary ciliary dyskinesia. a discrepancy was found between subjective ear complaints and the actual middle ear function. Moreover. it appeared that for the middle ear system. mucociliary clearance is of importance only in the first 3 decades of life. With aging. however. a deficient mucociliary clearance system in the middle ear and eustachian tube can be fully compensated for.
Transoral approach to the upper cervical spine, The transoral approach to pathology of the upper cervical spine is logical. but it is seldom used due to concerns about exposure and infection. The authors report on 16 consecutive patients requiring exposure from clivus through C3 for pathology. including spinal cord compression by rheumatoid pannus. craniovertebral anomalies. and tumor. Exposure was obtained using a Dingman mouth gag and soft palate retraction with silicone rubber sheeting. A horizontal "H" incision was made in the posterior pharyngeal wall creating three layers. closed separately. with attention to a watertight closure of the final mucosal layer. In no case was it necessary to divide the mandible. tongue. soft palate. or uvula. There were no deaths. wound breakdowns. infections. or persistent cerebrospinal fluid leakage. Patients with neurological indications improved postoperatively. and all tumors were grossly resected. Combined otolaryngology/neurosurgical exposure and treatment of pathology involving the upper cervical spine via the transoral approach is safe and effective. Functional results have been excellent. and no major complications were encountered.
Future directions of laser phototherapy for diagnosis and treatment of malignancies: fantasy, fallacy, or reality, A new and highly promising adjunctive modality for the diagnosis and therapy of malignancies is under development using lasers and tumor targeting dyes. To reach the eventual goal of clinical treatment. several current "fantasies and fallacies" regarding laser applications in medicine must be identified and their problems clearly outlined. A multidisciplinary scientific approach is also required to enable the clinical practicality of this laser targeting approach. Many new dyes and laser wavelengths are being tested to improve specific tumor uptake and/or retention. lower systemic toxicity. increase tissue penetration. and identify fluorochromes with synergistic properties to further enhance laser tumoricidal effects. Rapid technological advancements in magnetic resonance imaging may now provide an extremely sensitive way to detect and monitor laser-tissue effects. and allow efficient interstitial laser phototherapy of deep and sometimes inaccessible tumors. The current and future prospectives of the emerging field of laser phototherapy are described.
Enhanced maternal mortality surveillance--North Carolina, 1988 and 1989, Despite dramatic declines in maternal mortality in North Carolina since the late 1940s. public health officials have continued to characterize the magnitude of and risk factors for maternal death in that state (1.2). In 1989 and 1990. the State Center for Health and Environmental Statistics enhanced its surveillance for maternal mortality by computer-matching birth and fetal-death records with the death certificates of females who had died in 1988 and 1989. This report summarizes the findings of this enhanced surveillance for 1988 and 1989.
A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction, BACKGROUND. The independent contributions of subfractions of high-density lipoprotein (HDL) cholesterol (HDL2 and HDL3) and apolipoproteins in predicting the risk of myocardial infarction are unclear. Prospective data are sparse. but HDL2 is widely believed to be a more important predictor than HDL3. METHODS. Blood samples were collected at base line from 14.916 men (ages. 40 to 84 years) who were participants in the Physicians' Health Study. After five years of follow-up. plasma samples from 246 men with new myocardial infarction (case subjects) were analyzed together with specimens from 246 men matched to them for age and smoking status who had not had a myocardial infarction. RESULTS. The levels of total cholesterol and apolipoprotein B-100 were significantly associated with an increased risk of myocardial infarction (data on levels of low-density lipoprotein cholesterol were unavailable). Both HDL cholesterol and HDL2 levels were associated with a substantially decreased risk of myocardial infarction. but the HDL3 level was the strongest predictor; the relative risk was 0.3 (95 percent confidence interval. 0.2 to 0.6) for those in the fifth of the group with the highest HDL3 levels. as compared with the fifth with the lowest levels. The benefit of a higher HDL cholesterol level was most pronounced among those with lower total cholesterol levels. Levels of apolipoprotein A-I and apolipoprotein A-II were also associated with decreased risk. However. the levels of HDL subfractions and apolipoproteins did not add significantly to the value of a multivariate model that included the ratio of total to HDL cholesterol in predicting myocardial infarction. whereas that ratio remained a significant independent predictor of risk. After adjustment for other risk factors. a change of one unit in the ratio of total to HDL cholesterol was associated with a 53 percent change in risk (95 percent confidence interval. 26 percent to 85 percent). CONCLUSIONS. This study underscores the importance of HDL cholesterol in predicting the risk of myocardial infarction and demonstrates protective effects of both the HDL3 and HDL2 subfractions of HDL cholesterol. We found little or no predictive value for the levels of apolipoproteins A-I. A-II. and B or HDL subfractions after conventional risk factors and the ratio of total to HDL cholesterol were considered.
Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma, BACKGROUND. The presence of airway inflammation even in mild asthma points to the potential value of antiinflammatory therapy. We compared the effect of an inhaled corticosteroid. budesonide. with that of an inhaled beta 2-agonist. terbutaline. in the long-term treatment of newly detected asthma. METHODS. We studied 103 patients (29 male and 74 female patients 15 to 64 years old) in whom asthma had appeared within the previous year. The patients were randomly assigned in blinded fashion to two treatment groups: one to receive 600 micrograms of inhaled budesonide twice a day. and the other to receive 375 micrograms of inhaled terbutaline twice a day. The study period was two years. RESULTS. After six weeks of treatment. the patients treated with budesonide tolerated inhaled histamine better than the patients treated with terbutaline (a difference of one doubling dose step. P less than 0.001). and the difference was sustained. Patients' diaries kept during the first three months of the study and during the last month of the first and second years showed budesonide to be more effective than terbutaline in improving peak expiratory flow in the morning (average increase from the pretreatment value. 32.8 liters per minute for budesonide vs. 4.8 liters per minute for terbutaline; P less than 0.001) and in the evening (P less than 0.01). Budesonide was also more effective in reducing the symptoms of asthma (P less than 0.01) and the use of supplemental beta 2-agonist medication (P less than 0.01). Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective. whereas only one dropped out of the budesonide group. The adverse reactions to both treatments were few and mild. CONCLUSIONS. Antiinflammatory therapy with inhaled budesonide is an effective first-line treatment for patients with newly detected. mild asthma. and it is superior to the use of terbutaline in such patients.
Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group, BACKGROUND. Thrombotic thrombocytopenic purpura is an uncommon disease with a high mortality rate even with current treatment. The cause of the syndrome and its optimal treatment are unknown. Although both plasma exchange and plasma infusion have been useful treatments. it is not clear which is superior. In this report we describe a prospective randomized trial comparing plasma exchange with plasma infusion for the treatment of thrombotic thrombocytopenic purpura. METHODS. One hundred two patients with thrombotic thrombocytopenic purpura were randomly assigned to receive either plasma exchange or plasma infusion with fresh-frozen plasma on seven of the first nine days after entry into the trial. The total volume of plasma received by patients undergoing plasma exchange was three times that received by patients undergoing plasma infusion. All the patients also received aspirin and dipyridamole. The outcomes in the two groups were compared at the end of the first treatment cycle (day 9) and after six months. RESULTS. At the end of the first treatment cycle patients receiving plasma exchange had a higher rate of response as defined by an increase in the platelet count (24 of 51 patients) than those who received plasma infusion (13 of 51. P = 0.025). Of the 51 patients treated with plasma exchange. 2 died. whereas 8 of the 51 patients who received plasma infusion died (P = 0.035). After six months the outcome in the plasma-exchange group was still superior. with a response observed in 40 of 51 patients. whereas 25 of 51 patients in the plasma-infusion group responded (P = 0.002). Eleven patients in the plasma-exchange group died. as did 19 patients in the plasma-infusion group (P = 0.036). The overall mortality was 29 percent. CONCLUSIONS. Plasma exchange is more effective than plasma infusion in the treatment of thrombotic thrombocytopenic purpura.
Mortality rates and population density of tsetse flies correlated with satellite imagery, Tsetse flies are a major constraint on animal production in about 10 million km2 of Africa through their transmission of animal trypanosomiasis. Up to 25 million people are at risk from human trypanosomiasis. or sleeping sickness. Tsetse research has been concentrated on the factors that control the distribution and abundance of these vectors and the means by which their numbers can be reduced. Eradication successes in some countries are insignificant compared with the continental scale of the problem and the long-term reduction in the area infested by tsetse has been negligible. We report here that the mortality rates of tsetse from sites in both West and East Africa. the size of male and female tsetse (related to the mortality rate of the parental female population) along a north-south transect in West Africa. and the abundance of two species of tsetse over the northern half of Cote d'Ivoire. are significantly correlated with data from meterological satellites. This information could be used to predict both the mortality rate and the abundance (key determinants of disease transmission potential) of tsetse over very large areas of the continent and to produce maps of high risk areas of disease transmission for the African trypanosomiases and. by implication. for many other vector-borne diseases.
AIDS against the rest of the world [news, The spread of AIDS through heterosexual contact in Asia and Africa has reached truly epidemic proportions. The rest of the world should take notice while there is time.
Defective acidification of intracellular organelles in cystic fibrosis, The phenotype of cystic fibrosis (CF) includes abnormalities in transepithelial transport of Cl- (refs 1-5). decreased sialylation and increased sulphation and fucosylation of glycoproteins. and lung colonization with Pseudomonas. It is not apparent how these abnormalities are interrelated. nor how they result from loss of function of the CF gene-encoded transmembrane regulator (CFTR). We have previously shown that that the pH of a secretory granule is regulated by the vesicular conductance for Cl- (ref. 11). Here we find defective acidification in CF cells of the trans-Golgi/trans-Golgi network. of prelysosomes and of endosomes as a result of diminished Cl- conductance. Sialytation of proteins and lipids is reduced and ligand traffic altered. These abnormalities can result from defective acidification because vacuolar pH regulates glycoprotein processing and ligand transport. The CF phenotype is similar to that of alkalinized cells and acidification-defective mutatants.
Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy, X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease. being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families. with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium. because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.
Structure of recombinant human rheumatoid arthritic synovial fluid phospholipase A2 at 2.2 A resolution, Phospholipases A2 (PLA2s) may be grouped into distinct families of proteins that catalyse the hydrolysis of the 2-acyl bond of phospholipids and perform a variety of biological functions. The best characterized are the small (relative molecular mass approximately 14.000) calcium-dependent. secretory enzymes of diverse origin. such as pancreatic and venom PLA2s. The structures and functions of several PLA2s are known. Recently. high-resolution crystal structures of complexes of secretory PLA2s with phosphonate phospholipid analogues have provided information about the detailed stereochemistry of transition-state binding. confirming the proposed catalytic mechanism of esterolysis. By contrast. studies on mammalian nonpancreatic secretory PLA2s (s-PLA2s) have only recently begun; s-PLA2s are scarce in normal cells and tissues but large amounts are found in association with local and systemic inflammatory processes and tissue injury in animals and man. Such s-PLAs have been purified from rabbit and rat inflammatory exudate. from synovial fluid from patients with rheumatoid arthritis and from human platelets. Cloning and sequencing shows that the primary structure of the human s-PLA2 has about 37% homology with that of bovine pancreatic PLA2 and 44% homology with that of Crotalus atrox PLA2. The human s-PLA2 is an unusually basic protein. yet contains most of the highly conserved amino-acid residues and sequences characteristic of the PLA2s sequenced so far. Here we report the refined. three-dimensional crystal structure at 2.2 A resolution of recombinant human rheumatoid arthritic synovial fluid PLA2. This may aid the development of potent and specific inhibitors of this enzyme using structure-based design.
Insect paralysis by baculovirus-mediated expression of a mite neurotoxin gene, Female mites of the species Pyemotes tritici inject an extremely potent venom into their insect prey that causes muscle-contraction and paralysis. These mites are able to paralyse insects 150.000 times their size and their venom is effective in a broad range of insect species. A toxin (TxP-I) associated with the mite venom apparatus causes immediate muscle-contractive paralysis when injected into insects but not mice. In this report. we describe the cloning. sequencing and expression of a complementary DNA (Tox-34) encoding TxP-I. Insect cells infected with a recombinant baculovirus (vEV-Tox34) expressing Tox-34 secrete three polypeptides related to TxP-I which cause paralysis on injection. Larvae infected with vEV-Tox34 become paralysed during infection. thus reflecting the potential application of this toxin gene in insect biocontrol methods. The toxin gene expression system will also allow further exploration of the neurophysiological basis of its insect-specific effects.
Famine: a perspective for the nutrition community, Famine is a nasty turn of events that intrudes on the world's consciousness from time to time. Pictures of starving people and acutely malnourished children. rampant disease. a rising death toll. and massive suffering in some far-off land move many among us to contribute to famine relief. shocked by the paradox of famine in a world "awash in grain". Those who think about it appreciate that famine is related to poverty. that it is often triggered by climatic instability. and that it is both an instrument and tragic by-product of political conflict. But few know very much about famine beyond such fleeting insights. Even fewer are aware that the collective response to famine is woefully deficient. Just as we in the nutrition community had to fight long and hard to get malnutrition onto the development agenda as an explicit concern of public policy. so we and others like us are going to have to labor hard again to do the same for famine. This paper is an attempt to crystallize the issues involved.
Laser photocoagulation for stage 3+ retinopathy of prematurity, Twenty-two infants with "threshold" stage 3+ retinopathy of prematurity (ROP) were entered into a prospective. randomized clinical trial to compare the efficacy of transscleral cryotherapy versus laser photocoagulation delivered by the indirect ophthalmoscope. Eighteen infants have been followed for at least 3 months. Fifteen of 16 eyes randomized to laser and 9 of 12 eyes randomized to cryotherapy showed regression. The results suggest that laser therapy is as effective as cryotherapy in the treatment of ROP (P = 0.285).
Peripheral vision screening for driving in retinitis pigmentosa patients, The authors evaluated the test protocols used most frequently to screen the peripheral visual field of driving applicants to determine whether they are suitable for detecting peripheral field loss in patients with retinitis pigmentosa (RP). The peripheral vision tests available on the Keystone View Tester and the Titmus Vision Tester were administered to 23 subjects with RP. 3 subjects with Type 2 Usher's syndrome. and 1 subject who was a partially affected carrier of X-linked recessive RP. The subjects had varying degrees and types of visual field loss. Tests were administered using the standard protocol of the State of Illinois. which is a standard procedure used by state licensing bureaus nationwide. Results demonstrate that the screening protocols use stimulus conditions that are primarily sensitive only to appreciable field losses and examine locations that typically lie within an RP patient's remaining visual field rather than at locations that characteristically are scotomatous. The authors suggest that the current test protocols could determine peripheral field impairment more accurately by assessing additional locations in the visual field. and by introducing a background field and/or by reducing the luminance of the test targets.
Long-term outcome after corneal transplantation. Visual result and patient perception of success, Snellen acuity. reading line. and keratometry were measured in a cohort of 60 patients at 2 or more years after penetrating keratoplasty was performed. Patients were asked to complete a questionnaire to elicit information on their perceptions of visual function and the success of the procedure. Using preferred correction. a Snellen acuity of 6/18 or better was achieved by 65%. and a reading line of N8 or better was achieved by 57% of index grafts. Thirty-eight percent had more than 5 diopters (D) of astigmatism in the graft. Approximately 75% of patients reported satisfaction with their graft (satisfaction being associated with better acuity in the grafted eye than the other eye). graft clarity. and a perceived improvement in lifestyle. Dissatisfaction appeared to be associated with graft failure and problems with contact lens wear. The findings have implications for patient selection for corneal transplantation and for the measurement of outcome.
Autosomal dominant crystalline dystrophy, A black woman was identified with a tapetoretinal degeneration with sparkling intraretinal crystals. retinal pigment epithelial and choroidal atrophy. night blindness. color vision abnormalities. and paracentral scotomas. This constellation of findings is most consistent with the diagnosis of Bietti's crystalline dystrophy. Eight other family members were identified with intraretinal crystals similar to those seen in the proband but in varying degrees of progression. Transmission electron microscopy of circulating lymphocytes in several patients demonstrated crystals and granular osmophilic material of unknown composition contained within abnormal lysosomes. These crystals are similar in appearance and location to those seen in cholesterol ester storage disease. This family demonstrates an autosomal dominant inheritance pattern. as well as other differences from classic Bietti's crystalline dystrophy. The authors. therefore. suggest that this new entity be named autosomal dominant crystalline dystrophy.
Glaucoma after pediatric lensectomy/vitrectomy, Glaucoma after pediatric cataract surgery. once well recognized. now occurs only rarely after modern lensectomy/vitrectomy. The authors performed directed glaucoma evaluations of 34 eyes of 26 children. Based on intraocular pressures of 26 mmHg or greater. glaucoma was diagnosed in 8 (24%) eyes of 7 (27%) children. Glaucoma was found more commonly among children followed more than 60 months and was diagnosed up to 105 months after surgery. Typically. the glaucoma was open angle and asymptomatic. Four children had had previously normal pressures recorded. With longer follow-up. it is likely that more children will be diagnosed with glaucoma after lensectomy/vitrectomy procedures. The authors believe such patients should be followed as glaucoma suspects for the rest of their lives.
Increased preferential optic disc asymmetry in ocular hypertensive patients compared with control subjects, The authors determined asymmetrical differences in optic disc cupping and pallor between the right and left eyes of 57 control subjects and 75 patients with ocular hypertension. Photogrammetry was used to measure the optic disc cup. and computerized image analysis was used to measure the optic disc pallor for the total disc and its quadrants. Generally. for control and ocular hypertensive eyes. the median values of cupping and pallor were significantly larger in the left eye than in the right. except for depth in the inferior quadrant (right eye minus left eye = 9.3%. P = 0.000) and pallor in the nasal quadrant (right eye minus left eye = 21.3%. P = 0.01). which were preferentially larger in the right eye than in the left in ocular hypertensive eyes. Ocular hypertensive eyes also showed a greater difference between the right and left eyes compared with control eyes for inferior depth (P = 0.06) and nasal pallor (P = 0.02). Detection of optic disc differences as a sign of ocular hypertension between the right eye and the left should evaluate the inferior and nasal quadrants of the disc.
Device drug delivery to the eye. Collagen shields, iontophoresis, and pumps, External devices have been used to enhance drug delivery. This article reviews the role of collagen shields. iontophoresis. and pumps used to deliver ophthalmic medications. Collagen shields have been used to deliver drugs and promote corneal epithelial healing. Presoaked collagen shields deliver many drugs to the eye as well as or better than traditional methods such as frequent topical therapy or subconjunctival injection. The efficacy of drug delivery by collagen shields was demonstrated in animal models of graft rejection and bacterial keratitis. Iontophoresis uses an electrical current to carry an ionized drug across tissue. Transcorneal iontophoresis delivers high concentrations of a drug to the anterior segment of the eye. Transscleral iontophoresis bypasses the lens-iris diaphragm and produces adequate vitreous levels. Pumps deliver fluid to the eye for extended periods of time via a tube with its distal opening in the conjunctival sac. corneal stroma. anterior chamber. or vitreous cavity. Clinical acceptance of the collagen shield for drug delivery to the anterior segment is better than iontophoresis or pumps. probably because the collagen shield is simpler and more convenient to use.
Role of depressive illness in the outcome of treatment of temporomandibular joint pain-dysfunction syndrome, The aim of this study was to assess the role of a depressive illness in the outcome of the treatment of patients with temporomandibular joint pain-dysfunction syndrome. One group was considered psychiatrically normal and the other had a concurrent depressive illness. The latter group was subdivided equally to produce three treatment groups: one undergoing occlusal splint therapy. one receiving antidepressant medication. and the third having a combination of occlusal splint and antidepressant therapy. The results showed clearly that there was a significant difference in response in the nonpsychiatric and combined-therapy depressed groups in comparison with the two depressed groups treated either with occlusal splint or with antidepressant therapy. The combined therapy led to resolution of the painful problem and the depression. whereas the single therapies were only partly successful in relieving the pain-dysfunction syndrome. The preexisting duration of this painful problem did not influence the response to therapy.
Human papillomavirus DNA types in squamous cell carcinomas of the head and neck, Previous studies have found variable evidence suggestive of a role for human papillomavirus (HPV) in squamous cell carcinoma of the head and neck. In this study 49 cases of primary verrucous or squamous cell carcinoma from patients referred to a regional medical center were examined initially by Southern blot hybridization to detect HPV types 2. 6. 11. 13. 16. 18. and 32. Approximately 60% of carcinomas from certain head and neck sites. particularly the floor of the mouth. tongue. pharynx. piriform sinus. and larynx. were positive for episomal viral DNA of HPV-6. -11. -16. or -18. HPV DNA was found in some multiple tumors from separate sites of the same patient. Integration of viral DNA into the host cell chromosome was likely in a minority of the positive carcinomas. and no novel HPV DNA types were indicated by the hybridization analyses. Subsequently. DNA remaining from 30 of the carcinomas was examined by a more sensitive polymerase chain reaction amplification assay for DNA of HPV-6. -11. -16. and -18. Twenty-seven of the samples were positive for one or more HPV DNA types. with all positive carcinoma samples containing oncogenic HPV-16 or -18 DNAs. Almost all the patients examined were of the middle to older age group with a history of tobacco use. Although HPV infection of oral mucosa may be a frequent occurrence. a possible role for HPVs in the multifactorial etiology of head and neck carcinogenesis merits further epidemiologic investigation.
Human immunodeficiency virus infection of fibroblasts of dental pulp in seropositive patients, Presence of human immunodeficiency virus (HIV) within noninflamed human dental pulps was documented by polymerase chain reaction assays in 11 of 12 pulps from HIV-seropositive patients. The purpose of the present study was to determine the cellular location of HIV in vivo within these tissues by means of in situ hybridization. Results of the in situ hybridization indicated HIV within fibroblasts of the pulp. These results are especially relevant because fibroblasts lack the CD4 receptor thought necessary for in vivo infection with HIV. These results suggest the fibroblast as a possible reservoir for HIV in the body.
Contrast enhancement as an aid to interpretation in digital subtraction radiography, An initial study was performed to demonstrate the feasibility of pseudocolor contrast enhancement technique in digital subtraction radiography (DSR). DSR is an electronic image processing technique that has been shown to be of greater diagnostic value in the detection of small periodontal bone lesions than conventional radiography. Pseudocolor enhancement involves selectively assigning a unique color to each shade of gray present in a black-and-white subtracted image. Two image enhancement techniques were developed and tested in a phantom system consisting of extracted teeth set in blocks of plaster mixed with sawdust to simulate trabecular bone. It was found that experimentally induced periodontal lesions were more readily detected by the average clinician in both types of enhanced subtraction images than unenhanced subtractions. Furthermore. both enhancement techniques were of significantly greater diagnostic value for lesions smaller than 1.0 mm (p less than 0.001). The technique that colored an isolated area of interest was significantly more diagnostic at all depths tested (p less than 0.001 at 0.5 and 1.0 mm. and p less than 0.05 at 0.5 mm). Contrast enhancement may be a significant aid to the average clinician for the interpretation of DSR and the detection of small periodontal defects.
Psoriatic involvement of the temporomandibular joint. Literature review and report of two cases, An unusual case of bilateral psoriatic involvement of the temporomandibular joints with severe ankylosis is reported. A second case describing the typical destructive changes more commonly reported is presented for comparison.
Antibody response to outer membrane of noncapsulated Haemophilus influenzae isolated from the nasopharynx of children with pneumonia, In a prospective study aimed at determining the etiology of community-acquired pneumonia in children nasopharyngeal cultures and paired serum samples were obtained from 336 consecutive children ages 6 weeks to 15 years with pneumonia. 167 hospitalized and 169 outpatients. Results regarding Haemophilus influenzae are reported here. Blood cultures obtained from 127 of the hospitalized patients did not yield growth of H. influenzae. H. influenzae was isolated from the nasopharynx of 88 children. Seventy-three strains were noncapsulated. 2 were type b. 2 were type f and 11 were not serotyped. Paired serum samples were available from 38 children with growth of noncapsulated H. influenzae in the nasopharynx as the only potential pathogen. Sixteen of them responded with significant increases in serum antibodies against outer membrane preparations prepared from their own nasopharyngeal isolates. Thirty-eight age- and sex-matched control children with pneumonia without growth of H. influenzae in the nasopharynx served as controls. Sera from each control patient were tested for antibodies against two strains of noncapsulated H. influenzae. Of those. 4 had significant increases in antibodies against one or both outer membrane preparations. The increases in serum antibodies against the outer membrane of noncapsulated strains of H. influenzae indicate that this organism might be a cause of pneumonia in some children.
Prospective comparison of the immune response of infants to three Haemophilus influenzae type b vaccines, The antibody response to three Haemophilus influenzae type b vaccines was examined in 134 infants 17 to 22 months of age. Sera were collected from each subject before and 1 month after vaccination with either purified H. influenzae type b capsular polysaccharide (polyribosyl-ribitol phosphate (PRP] or one of two protein-conjugated vaccines (PRP-D or HbOC). Comparison of the two conjugate vaccines revealed that HbOC produced an antibody response greater than or equal to 1.0 micrograms/ml in 96% compared with 72% who were vaccinated with PRP-D (P less than 0.05). The isotype distribution of the antibodies produced by the two vaccines was similar. While all of the vaccines resulted in higher concentrations of anticapsular IgG1 than IgG2. the IgG1:IgG2 ratio was significantly higher in subjects immunized with HbOC. The IgG1:IgG2 ratio was similar in subjects immunized with PRP or PRP-D. The clinical significance of these observations remains to be determined.
Safety and immunogenicity of a Haemophilus influenzae type b conjugate vaccine in a high risk American Indian population [published erratum appears in Pediatr Infect Dis J 1991 May;10(5):369], The safety and immunogenicity of a Haemophilus influenzae type b polysaccharide conjugate vaccine linked to the outer membrane protein complex of Neisseria meningitidis (Hib-OMP) were evaluated among Apache and Navajo infants and children. One dose of the Hib-OMP was given to 42 children who were from 12 and 60 months of age. Ninety-two infants 6 to 8 weeks old were given one dose of Hib-OMP at the time of enrollment. A subsequent dose of the vaccine was given 2 months later and a third dose was offered between 12 and 15 months of age. All of the 12- to 60-month-old children achieved a protective antibody concentration (greater than 1 microgram/ml) 1 month postvaccination. Among the 6- to 8-week-old infants only 11% of the Apaches and 8% of Navajos had a protective anti-PRP antibody concentration prevaccination. One month post vaccination 68% of the Apaches and 69% of the Navajos had protective anti-PRP antibody concentrations. One month after the second immunization 67% of the Apaches and 75% of Navajos had protective anti-PRP concentrations. Among the infants that received the third (booster) immunization (N = 28) 74% had protective anti-PRP antibody titers just before the booster immunization. One month after the booster immunization all of the infants had protective concentrations of anti-PRP antibody. We conclude that the Hib-OMP is safe and highly immunogenic among Apache and Navajo infants and children.
Efficacy in infancy of oligosaccharide conjugate Haemophilus influenzae type b (HbOC) vaccine in a United States population of 61,080 children. The Northern California Kaiser Permanente Vaccine Study Center Pediatrics Group, The efficacy of the HbOC conjugate Haemophilus influenzae type b vaccine was evaluated in a study population of 61.080 infants in the Northern California Kaiser Permanente Medical Care Program. Between February. 1988. and June. 1990. the HbOC vaccine was given as part of a three-dose series at 2. 4. and 6 months of age to 20.800 infants. The study population included children with a well-care visit at a study center during the first 6 months of life. There were 25 cases of Haemophilus influenzae type b disease in the study population: 22 in unvaccinated children and 3 in children who received only one dose of HbOC vaccine. The efficacy of the full three-dose series was evaluated by several methods: a primary analysis comparing fully vaccinated children with unvaccinated children from 7 to 18 months of age; a stratified exact analysis adjusted for age and seasonality; and a case-control analysis which further adjusted for known risk factors. The efficacy of three doses of vaccine was 100% with the lower bound of the 95% confidence interval for the three analyses at 68. 71. and 64%. respectively. There were no cases of disease resulting from two doses of HbOC vaccine yielding an estimate of 100% efficacy (95% confidence interval. 47 to 100) for two doses of HbOC vaccine. However. for children who had received only one dose of HbOC vaccine. vaccine efficacy was estimated to be 26% and the possibility that one dose of HbOC vaccine had no efficacy could not be excluded.
Diarrhea in children newly enrolled in day-care centers in Houston, Diarrhea is a common illness among children in day-care centers (DCC). We hypothesized that the incidence of diarrhea was greater among children in their first 1 or 2 months after enrollment in a DCC than in any subsequent period in day care. We followed 442 children younger than 2 years of age enrolled in 13 randomly selected DCCs for the occurrence of diarrhea during a 14 1/2-month period. Parents completed standardized baseline questionnaires and research nurses visited the DCC twice weekly to record the occurrence of diarrhea and to collect stool specimens. Incidence rates. rate ratios. chi square statistics and 95% confidence intervals were calculated for crude and stratified analyses. The diarrheal incidence rate of 4.4 cases/child-year in the first 4 weeks in the centers was significantly (rate ratio. 1.6; confidence interval. 1.3 to 2.1; P less than 0.01) higher than the 2.7 cases/child-year incidence rate of diarrhea in subsequent weeks. The effects of gender. ethnicity. age. DCC size. previous DCC attendance and season were examined and did not account for the association observed between recent enrollement and risk of diarrheal illness. Rotavirus was identified in 18% of cases of diarrhea. but no association was seen with recent enrollment in DCC. A significantly higher incidence of diarrhea occurred in males compared with females (P less than 0.002) and in younger children (P less than 0.001) compared with older children. Diarrhea is common in children in DCCs and occurs significantly more frequently in children during their first 4 weeks in a DCC.
Chronic fatigue in children: clinical features, Epstein-Barr virus and human herpesvirus 6 serology and long term follow-up, During a 2-year period. 23 patients (14 girls. 9 boys) with chronic fatigue were referred to the Pediatric Infectious Disease Clinic of a tertiary care center. representing 19% of all out-patients seen in that clinic during that time. The median age was 14 years and the median duration of symptoms before referral was 6 months; 65% had missed at least 2 weeks of school and 30% required a home tutor. There were few positive physical findings and no elevation of white blood cell count (median. 7000/mm3) or erythrocyte sedimentation rate (median. 5 mm/hour). Twenty-five percent had no evidence of Epstein-Barr virus infection. 15% had current or recent infection and 60% had past infection; 33% of the latter had detectable antibody to early antigen but the titers were low. Human herpesvirus 6 titers in 8 patients were similar to those in age- and sex-matched controls. Of 17 patients contacted after a median of 26 months. 76% reported definite improvement. although 38% of these still experienced occasional symptoms. In this referral population chronic fatigue was a common presenting complaint. was associated with marked degrees of dysfunction and bore no relationship to Epstein-Barr virus or human herpesvirus 6 infection. In most children the disorder was self-limited. although a minority were persistently or severely affected.
Sensitivity and specificity of daily tracheal aspirate cultures in predicting organisms causing bacteremia in ventilated neonates, The sensitivity of daily tracheal aspirates in predicting neonatal bacteremia was ascertained from 48 of 354 ventilated neonates who became septic during a 4-year period. Fourteen babies (designated Group A) had a positive blood culture on the first day of life; 28 infants (Group B) and 6 infants (Group C) had bacteremia beyond the first day. Group C infants became septic as a result of intraabdominal pathology. Pathogens isolated from blood were correlated with those from preceding daily tracheal aspirates. The overall sensitivity of tracheal cultures in predicting results of blood cultures was 81% (Group A. 71%; Group B. 93%; Group C. 50%). The specificity of daily tracheal aspirates was ascertained from 28 of 50 ventilated infants who were nonseptic and had negative blood cultures during a 6-month period. Only 18 had consistently sterile tracheal aspirates (specificity. 64%). The mean number of days of intubation was 6.6 for the 10 false positive and 3.6 for the 18 true negative. Because of low positive predictive value (0.26) the role of daily tracheal aspirate culture is limited to providing early information regarding potential pathogens when sepsis occurs rather than to identify babies who are going to become septic.
Successful immunization of infants at 6 months of age with high dose Edmonston-Zagreb measles vaccine. Cite Soleil/JHU Project Team, A group of 2097 Haitian infants 6 to 11 months of age were randomized to receive Schwarz or Edmonston-Zagreb strain measles vaccines containing 10- to 500-fold more vaccine viral particles than standard potency vaccines. No unusual adverse reactions were noted. Edmonston-Zagreb vaccines were more effective than equivalent doses of Schwarz vaccines as measured by the proportion of vaccinated children with measles antibody concentrations greater than or equal to 200 mIU/ml 2 months after vaccination and the persistence of antibody at 18 to 24 months of age. High titer Edmonston-Zagreb vaccine administered at 6 months of age induced antibody concentrations greater than or equal to 200 mIU/ml in 83% of infants by plaque reduction neutralization and 93% of infants by enzyme-linked immunosorbent assay with high rates of antibody persistence at 12 to 24 months of age. The World Health Organization recommends high titer Edmonston-Zagreb measles vaccines for routine use at 6 months of age in areas where measles is an important cause of mortality in young infants.
Comparison of antigenuria after immunization with three Haemophilus influenzae type b conjugate vaccines, The incidence of antigenuria was documented after vaccination of 75 children 15 to 60 months of age with one of three Haemophilus influenzae type b conjugate vaccines. PRP-D (ProHIBiT). PRP-T and HbOC (HibTITER). Unconcentrated and concentrated urine was tested on the first. third. fifth and seventh days after vaccination. Antigenuria occurred on Day 1 in 100% of PRP-D. 43% of PRP-T and 12% of HbOC recipients. The percentages of children excreting antigen on Day 3 were 95. 17 and 8%; on Day 5 they were 36. 4 and 12%; and on Day 7 they were 14. 0 and 18% for PRP-D. PRP-T and HbOC. respectively. The difference in the occurrence of antigenuria resulting from each vaccine was statistically significant on Day 1 and for PRP-D compared with PRP-T or HbOC on Day 3. It is important for clinicians to be aware of the frequency with which antigenuria occurs after these vaccines so that appropriate therapeutic decisions can be made.
Health benefits of aerobic exercise, Regular aerobic exercise has significant cardiovascular benefits. including a reduction in incidence of and mortality from coronary artery disease--probably because of positive effects on blood lipid levels and blood pressure. Aerobic exercise can also be an important adjunct to a weight-loss program. Many persons who continue an exercise program do so because of its positive mental benefits. including reduction in anxiety and depression and modulation of stress levels. Aerobic exercise has a place in the management of diabetes. pregnancy. and aging. The problems associated with aerobic exercise are minimal compared with its benefits.
Management of hypertension. Useful nonpharmacologic measures, Hypertension is a chronic problem commonly seen by primary care physicians. Inadequate treatment may result in significant morbidity and even death. Therefore. all patients with hypertension or at risk for hypertension should be educated about nonpharmacologic measures to control blood pressure. Weight reduction and sodium restriction are cornerstones of nonpharmacologic management of hypertension. Although studies of the effects of aerobic exercise on blood pressure are not well designed. data confirm the value of such exercise. Relaxation therapy has been shown to lower blood pressure. but effects may be transient. Potassium and calcium supplementation has lowered blood pressure. but because study results are contradictory. the exact clinical criteria for use of such supplements have not been determined. Vegetarians have lower blood pressure than nonvegetarians. but no specific dietary components (eg. fiber. fat) have been documented as the beneficial factors. Because of its significant pressor effect. alcohol should be avoided by hypertensives. A low-fat diet is recommended to decrease cardiovascular risk and assist in weight control.
Sepsis and septic shock. Deadly complications that are on the rise, Most patients are already hospitalized when sepsis and septic shock develop. and in spite of therapy. at least 50% die. Although newer therapeutic agents are being evaluated. current management consists of antibiotics. fluids for volume resuscitation. inotropic agents. and surgery for septic foci. Greater emphasis on preventive measures is recommended.
Avoiding the blanket approach to insomnia. Targeted therapy for specific causes, A systematic approach to the common complaint of insomnia usually results in a specific clinical diagnosis with clear therapeutic implications. Use of effective treatment strategies tailored to the situation can make treating insomnia a gratifying experience instead of a frustrating one.
How much testing is needed after myocardial infarction, Both physicians and patients should be encouraged by the tremendous progress made in the clinical care of patients with heart disease during the last 20 years. However. the number of invasive and noninvasive tests is vast. so they need to be applied judiciously. using a reasonable set of clinical principles to recognize the needs of the individual patient. In the case of myocardial infarction. one of the most important prognostic factors is left ventricular systolic function. which is commonly measured by the ejection fraction. This measurement can be made with a left ventriculogram. radionuclide ventriculogram. or two-dimensional echocardiogram. the choice depending on individual circumstances.
The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines, Human cervical carcinoma cell lines that were either positive or negative for human papillomavirus (HPV) DNA sequences were analyzed for evidence of mutation of the p53 and retinoblastoma genes. Each of five HPV-positive cervical cancer cell lines expressed normal pRB and low levels of wild-type p53 proteins. which are presumed to be altered in function as a consequence of association with HPV E7 and E6 oncoproteins. respectively. In contrast. mutations were identified in the p53 and RB genes expressed in the C-33A and HT-3 cervical cancer cell lines. which lack HPV DNA sequences. Mutations in the p53 genes mapped to codon 273 and codon 245 in the C33-A and HT-3 cell lines. respectively. located in the highly conserved regions of p53. where mutations appear in a variety of human cancers. Mutations in RB occurred at splice junctions. resulting in in-frame deletions. affecting exons 13 and 20 in the HT-3 and C-33A cell lines. respectively. These mutations resulted in aberrant proteins that were not phosphorylated and were unable to complex with the adenovirus E1A oncoprotein. These results support the hypothesis that the inactivation of the normal functions of the tumor-suppressor proteins pRB and p53 are important steps in human cervical carcinogenesis. either by mutation or from complex formation with the HPV E6 and E7 oncoproteins.
Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education, Characteristic lesions in mice hemi- or homozygous for the X-linked mutation scurfy (sf) include lymphohistiocytic proliferation in the skin and lymphoid organs. Coombs' test-positive anemia. hypergammaglobulinemia. and death by 24 days of age. The role of the thymus in the development of fatal lymphoreticular disease in the scurfy mouse was investigated. Neonatal thymectomy doubles the life span of scurfy mice. moderates the histologic lesions. and prevents anemia. despite the continued presence of high levels of serum IgG. Animals bred to be nude and scurfy (nu/nu; sf/Y) are viable. fertile. and free of scurfy lesions. Bone marrow from scurfy mice can reconstitute lethally irradiated. H-2-compatible animals but does not transmit scurfy disease. We conclude. from these data. that scurfy lesions are mediated by T lymphocytes that mature in an abnormal (sf) thymic environment.
The glucocorticoid hormone signal transduction pathway in mice homozygous for chromosomal deletions causing failure of cell type-specific inducible gene expression, Wild-type newborn mice are characterized by the ability of certain liver-specific genes encoding various enzymes and mapping on different chromosomes to respond to glucocorticoid induction. Newborn mice homozygous for deletions at and around the albino locus on chromosome 7 fail to develop this competence for hormone-inducible gene expression even through they do show normal constitutive expression of the same genes. Studies of the glucocorticoid hormone signal transduction pathway reported here show identical expression of glucocorticoid receptor mRNA and protein in deletion homozygotes and normal littermates. Furthermore. the receptor interacts normally with the 90-kDa heat shock protein hsp90. Elevated glucocorticoid hormone levels in newborn deletion homozygotes. most likely resulting from their stressed condition. provide an explanation for the reduced binding activities of receptors reported previously. The elimination of receptors and hormones as direct targets of the chromosomal deletion effects suggests that the failure of inducible gene expression might reside in defective competence of the affected structural genes to respond to the hormonal stimulus.
Stimulation of a Ca(2+)-dependent protein kinase by GM1 ganglioside in nerve growth factor-treated PC12 cells, We have investigated the ability of exogenous gangliosides to modulate nerve growth factor (NGF) signal transduction in PC12 cells. The effects of exogenous ganglioside GM1 on multiple protein kinase activities were assayed by analyzing site-specific serine phosphorylation of tyrosine hydroxylase (TyrOHase) by two-dimensional phosphopeptide mapping. In the presence of NGF. exogenous GM1 (1-10 microM) increased 32P incorporation into TyrOHase phosphopeptide T2. a Ca2+/calmodulin-dependent protein kinase substrate whose phosphorylation is not normally affected by NGF treatment. In the absence of NGF. GM1 treatment had no significant effects on TyrOHase phosphorylation. The removal of extracellular Ca2+ or blockade of dihydropyridine-sensitive Ca2+ channels prevented the GM1-induced increases in 32P incorporation into phosphopeptide T2. Exogenous GM1 also potentiated K+ depolarization-induced increases in the phosphorylation of TryOHase. These results suggest that the stimulatory effects of exogenous GM1 ganglioside on NGF actions may be due to its ability to potentiate a Ca(2+)-dependent signaling pathway.
Nerve growth factor rapidly stimulates tyrosine phosphorylation of phospholipase C-gamma 1 by a kinase activity associated with the product of the trk protooncogene, Nerve growth factor (NGF) promotes the survival and differentiation of specific populations of neurons. The molecular mechanisms by which cells respond to NGF are poorly understood. but two clues have emerged recently. First. NGF rapidly stimulates tyrosine phosphorylation of several unidentified proteins in the NGF-responsive pheochromocytoma cell line PC12 [Maher. P. (1988) Proc. Natl. Acad. Sci. USA 85. 6788-6791]. Second. the protein-tyrosine kinase encoded by the protooncogene trk (p140trk). a member of the receptor class of tyrosine kinases. becomes activated and phosphorylated on tyrosine after NGF treatment of PC12 cells [Kaplan. D. R.. Martin-Zanca. D. & Parada. L. F. (1991) Nature (London) 350. 158-160]. We now report that NGF rapidly induces tyrosine phosphorylation of phospholipase C-gamma 1 (PLC-gamma 1). and we present evidence that the responsible tyrosine kinase is either p140trk or a closely associated protein. Treatment of responsive cells with NGF elicited phosphorylation of PLC-gamma 1 on tyrosine and serine. PLC-gamma 1 immunoprecipitated from NGF-stimulated cells was phosphorylated in vitro by coprecipitating protein kinase activity. and the phosphorylations occurred principally on tyrosine. The responsible kinase could be depleted from cellular lysates by antibodies specific for p140trk. This procedure also depleted a 140-kDa protein that normally coprecipitated with PLC-gamma 1 and became phosphorylated on tyrosine in vivo in response to NGF. Analysis of tryptic peptides from PLC-gamma 1 indicated that the residues phosphorylated in vitro by p140trk-associated kinase activity were largely congruent with those phosphorylated in vivo after NGF treatment. Our findings identify PLC-gamma 1 as a likely substrate for the trk-encoded tyrosine kinase. and they provide a link between NGF-dependent activation of p140trk and the stimulation of intracellular second messenger pathways.
Hypoxia-inducible nuclear factors bind to an enhancer element located 3' to the human erythropoietin gene, Human erythropoietin gene expression in liver and kidney is inducible by anemia or hypoxia. DNase I-hypersensitive sites were identified 3' to the human erythropoietin gene in liver nuclei. A 256-base-pair region of 3' flanking sequence was shown by DNase I protection and electrophoretic mobility-shift assays to bind four or more different nuclear factors. at least two of which are induced by anemia in both liver and kidney. and the region functioned as a hypoxia-inducible enhancer in transient expression assays. These results provide insight into the molecular basis for the regulation of gene expression by a fundamental physiologic stimulus. hypoxia.
CD4 peptide-protein conjugates, but not recombinant human CD4, bind to recombinant gp120 from the human immunodeficiency virus in the presence of serum from AIDS patients, Sera from human immunodeficiency virus-positive (HIV+; Walter Reed stage 6) individuals inhibit the interaction between recombinant human CD4 and recombinant gp120 from HIV (rCD4 and rgp120. respectively). thereby interfering with the ability of soluble rCD4 to block infection with HIV or rCD4-toxin conjugates to kill HIV-infected cells. In this report we demonstrate that the inhibitory activity of such sera is caused primarily by anti-gp120 antibodies that do not recognize the CD4 interaction site on gp120. To circumvent the problem of inhibition. we have generated a construct containing a peptide of CD4 (residues 41-84) conjugated to ovalbumin (three to five peptides per molecule). This multivalent conjugate binds to rgp120 and binding is not inhibited by antibodies in HIV+ sera.
Generation of a nested series of interstitial deletions in yeast artificial chromosomes carrying human DNA, We have generated a nested series of interstitial deletions in a fragment of human X chromosome-derived DNA cloned into a yeast artificial chromosome (YAC) vector. A yeast strain carrying the YAC was transformed with a linear recombination substrate containing at one end a sequence that is uniquely represented on the YAC and at the other end a truncated long interspersed repetitive element (LINE 1. or L1). Homologous recombination between the YAC and the input DNA resulted in a nested series of interstitial deletions. the largest of which was 500 kilobases. In combination with terminal deletions that can be generated through homologous recombination. the interstitial deletions are useful for mapping and studying gene structure-function relationships.
Vascular endothelial cell growth factor (VEGF) produced by A-431 human epidermoid carcinoma cells and identification of VEGF membrane binding sites, A distinct family of endothelial cell mitogens that are homologous to platelet-derived growth factor has recently been identified. Unlike other known endothelial cell mitogens. these vascular endothelial cell growth factors (VEGFs) are secreted and appear to act specifically on endothelial cells. We have purified VEGF 2083-fold to apparent homogeneity from protein-free culture medium conditioned by A-431 human epidermoid carcinoma cells. This A-431-derived VEGF was characterized as a homodimer composed of 22-kDa subunits with an N-terminal sequence that was similar to VEGFs produced by human HL-60 leukemic and U-937 histiocytic lymphoma cells. A-431 VEGF was used to identify specific and saturable binding sites for VEGF on human umbilical vein endothelial cells (HUVEC). By affinity cross-linking. VEGF-binding site complexes of 230. 170. and 125 kDa were detected on HUVEC. VEGF specifically induced the tyrosine phosphorylation of a 190-kDa polypeptide. which was similar in mass to the largest binding site detected by affinity cross-linking.
A "public" T-helper epitope of the E7 transforming protein of human papillomavirus 16 provides cognate help for several E7 B-cell epitopes from cervical cancer-associated human papillomavirus genotypes, We have identified a major T-cell epitope. amino acids 48-54 (DRAHYNI. in one-letter code) in the E7 open reading frame protein of human papillomavirus (HPV) type 16. Lymph node cells from mice immunized with synthetic peptides containing DRAHYNI proliferated and produced interleukin when challenged in vitro with peptide or whole HPV-16 E7 fusion protein. The T epitope was recognized in association with all five major histocompatibility complex class II I-A and I-E alleles tested. Synthetic peptides consisting of DRAHYNI linked to major B-cell epitopes on the E7 molecule formed immunogens capable of eliciting strong antibody responses to HPV-16 E7. The T epitope could provide help for the production of antibody to several B epitopes simultaneously. including a B epitope of HPV-18 E7 protein. Mice immunized with a peptide containing DRAHYNI and B epitope and. at a later date. infected with recombinant vaccinia E7 virus. displayed secondary antibody responses to E7. Because E7 has a role in cell transformation and is the most abundant viral protein in HPV-associated neoplastic cervical epithelial cells. the data have implications for vaccine strategies.
Mechanisms of plasma membrane protein degradation: recycling proteins are degraded more rapidly than those confined to the cell surface, Plasma membrane proteins of intact mouse 3T3 fibroblasts and H4-II-E-C3 hepatoma cells were separated into two groups based on their compartmentation between the cell surface and an intracellular compartment accessible at 20 degrees C but not at 0 degrees C. One group was derivatized at 0 degrees C with sulfosuccinimidyl 2-(biotinamido)ethyl-1.3-dithiopropionate but not at 20 degrees C. The second group was derivatized at 20 degrees C as well as at 0 degrees C. Derivatized proteins were isolated from 35S-labeled cells on streptavidin/agarose and resolved by two-dimensional PAGE. With few exceptions. pulse-chase experiments revealed that those proteins confined exclusively to the cell surface turned over slowly (t1/2. greater than 75 h). while those bimodally compartmentalized between the cell surface and the 20 degrees C accessible compartment were degraded more rapidly (t1/2. less than 31 h). These observations suggest a mechanism to explain the varied metabolic stability of plasma membrane proteins in which the half-life of each protein is determined by the proportion of time spent in the endocytic compartment.
Functional complementation of ataxia-telangiectasia group D (AT-D) cells by microcell-mediated chromosome transfer and mapping of the AT-D locus to the region 11q22-23, The hereditary human disease ataxia-telangiectasia (AT) is characterized by phenotypic complexity at the cellular level. We show that multiple mutant phenotypes of immortalized AT cells from genetic complementation group D (AT-D) are corrected after the introduction of a single human chromosome from a human-mouse hybrid line by microcell-mediated chromosome transfer. This chromosome is cytogenetically abnormal. It consists primarily of human chromosome 18. but it carries translocated material from the region 11q22-23. where one or more AT genes have been previously mapped by linkage analysis. A cytogenetically normal human chromosome 18 does not complement AT-D cells after microcell-mediated transfer. whereas a normal human chromosome 11 does. We conclude that the AT-D gene is located on chromosome 11q22-23.
Population dynamics of natural antibodies in normal and autoimmune individuals, We have measured the quantities of naturally occurring autoantibodies in the serum of normal. unmanipulated individuals. These changes over time following broad-band complex dynamical patterns that are similar in mouse and man. The patterns more likely reflect the network architecture of the natural antibody repertoire. regulating the activation and decay of individual clones. The temporal changes of both disease-specific and nonspecific autoantibodies are consistently modified in autoimmune individuals.
Lumbar disc disease and stenosis, In recent years MR has been the major advancement in the imaging of lumbar disc disease. Its advantages include multiplanar imaging. excellent resolution. and absence of ionizing radiation. Although CT remains an efficient and accurate method of evaluating the spine. we currently recommend MR imaging as the best initial examination. Myelography with follow-up CT scans should be reserved for specific patients in whom additional information is needed after MR images or CT scans.
Thoracic disc disease and stenosis, Disc herniation and stenosis in the thoracic spine are relatively uncommon compared with their occurrence in the cervical or lumbar spine. They are usually degenerative. although trauma may be an aggravating or initiating factor. The clinical presentation includes local and/or radicular pain with or without signs and symptoms of cord dysfunction. Radicular pain may be secondary to mechanical compression or vascular impingement. MR imaging is the best way to define the specific abnormality as well as the effect on the adjacent spinal cord. CT after myelography may be useful as well. especially in those patients in whom there is involvement of the posterior ligamentous and osseous structures of the thoracic spinal canal. MR imaging may finally reveal the true incidence of thoracic disc herniation.
Cervical stenosis, spondylosis, and herniated disc disease, While IntCECT is still considered by many to be the optimal modality in cervical spine imaging. it is the most invasive of the techniques considered here. MR imaging may have nearly equivalent diagnostic capability in many cases of degenerative disc and spine disease. The value of unenhanced CT essentially is limited to the demonstration of bony changes. In the evaluation of radiculopathy. either MR imaging or IvCECT is useful for the initial screening and may be the only study needed. MR imaging is the study of choice for diseases of the spinal cord. With continuing progress in MR capability. IntCECT is shifting more toward a supplemental or confirmatory role. A rigid neurodiagnostic algorithm for this common radiologic problem is not possible. Rather. each step of the diagnostic process is influenced by the individual patient. Specific patient characteristics may affect the selection of an imaging modality. Modification of routine studies. such as use of gadolinium or oblique MR imaging. may be indicated in some patients. Finally. because of the high prevalence of asymptomatic disc and spine changes. knowledge of clinical findings is essential in the accurate interpretation of anatomic findings.
Spinal trauma, Spinal trauma is classified according to the mechanism of injury and the presence or absence of stability. A variety of imaging modalities. including radiography. conventional tomography. computed tomography. and magnetic resonance imaging are available for assessment of the injured spine. This article discusses the role of these various methods in evaluating osseous. ligamentous. and neural damage. Common injuries are described at the upper and lower cervical. thoracic. and thoracolumbar regions.
Surgery for ventricular septal defect, Of 255 patients undergoing closure of ventricular septal defect (VSD). 48% were younger than 2 years. 59% had associated cardiac and 26% non-cardiac abnormality. 13% had multiple. and only 29% isolated VSD. VSD was closed via the left ventricular apex in seven cases. without increased morbidity or mortality. The three early and six late deaths occurred in patients with complicated defects. Pulmonary vascular occlusive disease caused four deaths (1 early. 3 late). At follow-up (mean c. 3. range 1-11 years). 79% of the patients were well. 10% had cardiac symptoms and 7.5% had symptoms from associated noncardiac anomalies. Reoperation for significant residual VSD was required in 12 cases (4 single and 8 multiple VSD). Complete. pacemaker-requiring A-V block was found in four patients (none with simple VSD closure). It is concluded that 1) concomitant cardiac and non-cardiac lesions are common in VSD. 2) mortality is closely related to such lesions and to pulmonary vascular occlusive disease. 3) the latter is a rare. but real cause of death. 4) left ventricular approach need not increase mortality or morbidity. 5) significant residual VSD is rare after single. but common in multiple VSD. and 6) risk of complete A-V block after simple VSD closure is very low.
Elective coronary artery bypass surgery without homologous blood transfusion. Early results with an inexpensive blood conservation program, Restriction of donor blood transfusions in cardiac surgery should reduce risks of infective contamination and antigenicity. We report a systemic. simple and inexpensive blood conservation program used for 121 consecutive patients who underwent elective coronary artery bypass surgery without need for homologous blood transfusion. The left internal mammary artery was grafted in all cases. in addition to saphenous vein grafts. Autologous. heparinized blood was removed intraoperatively. pre-bypass. and returned to the patient at conclusion of the extracorporeal circulation. The volume remaining in the oxygenator and the tubing set was returned without cell processing or hemofiltration. Using the hard-shell cardiotomy reservoir from the heart-lung machine. autotransfusion of the shed mediastinal blood was continued hourly up to 18 hours after surgery. The mean postoperative mediastinal bleeding was 551 +/- 206 ml. of which 505 +/- 218 ml was autotransfused. No re-exploration for bleeding was required and no homologous red-cell transfusions were given. Five patients each received 1-2 units of fresh frozen plasma because of prolonged bleeding time. Morbidity was low and mortality nil. At discharge the mean hemoglobin was 12.0 +/- 1.4 g/dl and the hematocrit 36.0 +/- 4.2%.
Systemic and pulmonary circulatory effects of protamine following cardiopulmonary bypass in man, The cardiovascular effects of protamine were studied in 19 men with normal left ventricular function undergoing primary myocardial revascularization. Protamine was given over 120 sec after termination of cardiopulmonary bypass. Arterial and pulmonary pressures. aortic blood flow. central venous pressure. heart rate and electrocardiogram were continuously registered. Pulmonary capillary wedge pressure was recorded at the times of maximal hemodynamic response. The systolic arterial pressure fell from 116 to 66 mmHg about 60 sec after the start of protamine infusion. but spontaneously began to rise after a few seconds. reaching 90% of pre-protamine levels at 126 sec. No inotropic drugs or volume infusion were given. At about 2 min. the mean pulmonary artery pressure rose from 16.3 to 26.2 mmHg and the central venous pressure from 7.0 to 11.4 mmHg. The heart rate and cardiac output were almost unchanged throughout. Systemic hypotension and pulmonary hypertension are suggested to represent true side effects of protamine or protamine/heparin complex. When left ventricular function is good. the hypotension reverses without treatment. Volume infusion may indeed precipitate right heart failure when the pre-load effect is added to the subsequent protamine-induced pulmonary hypertension.
Early results of aortic valve replacement with or without concomitant coronary artery bypass grafting, Early results of aortic valve replacement were reviewed in 962 unselected patients. 659 without concomitant coronary bypass surgery (AVR group) and 303 with combined valve replacement and coronary artery bypass grafting (AVR + CABG). The early (less than 30-day) mortality was 4.6% in the AVR. and 5.9% in the AVR + CABG group. Multivariate analysis showed coronary artery stenoses and NYHA functional class to be independent predictors of early mortality in the AVR group. and the number of distal anastomoses as the strongest predictor in AVR + CABG. The incidence of peroperative technical complications in the cases with fatal outcome was 27% in the AVR and 6% in the AVR + CABG group. The incidence of myocardial injury (new Q wave or evidence of increased enzyme leakage) was 11% in AVR and 21% in AVR + CABG. Independent predictors of postoperative myocardial injury were aortic cross-clamp time. year of surgery. coronary artery stenoses and NYHA class in AVR and aortic cross-clamp time and year of surgery in AVR + CABG. The study suggests that coronary artery disease increases risk in aortic valve replacement with or without CABG. Replacement should be undertaken before endstage of the disease (NYHA IV). with CABG if significant coronary disease is present. and in multivessel disease the number of distal anastomoses should be restricted in order to shorten aortic cross-clamp time.
Continuous vectorcardiography in cardiac surgery: natural course of vector changes and relationship to myocardial oxygen uptake, Continuous vectorcardiography was registered before and during the first 18 hours after cardiac surgery in 53 patients. QRS vector changes (QRS-VD) occurred during the operation. but no further changes were observed postoperatively. The ST vector (ST-VM) increased during the operation. and a further slight increase occurred postoperatively. Perioperative myocardial infarction occurred in three patients. Their ST-VM was higher than the average in patients without myocardial infarction. while QRS-VD did not differ from the average pattern. Twelve other patients were studied in pacemaker-induced moderate tachycardia. QRS-VD increased in proportion to heart-rate changes (rs median = 0.93. p less than 0.01). QRS-VD also correlated with myocardial oxygen uptake (rs median = 0.62. p less than 0.05). The ST-VM responses were not uniform. The data suggest that vectorcardiogram variables can provide information related to myocardial energy metabolism.
Visceral and peripheral tissue perfusion after cardiac surgery, Visceral and peripheral tissue perfusion and oxygenation were studied in ten patients in the early phase after coronary artery bypass grafting. Visceral perfusion was assessed indirectly. by determining gastric intramucosal pH. As parameters of peripheral tissue perfusion and oxygenation. subcutaneous tissue PO2 (PscO2). transcutaneous PO2 (PtcO2). PtcO2 index (PtcO2/PaO2). laser-Doppler skin red-cell flux (RCF) and fingertip temperature (Tft) were recorded in the upper extremity. Central haemodynamics. rectal temperature and blood gases were also measured. The inspired oxygen concentration was maintained at 30 v/v%. Gastric intramucosal pH declined progressively during the first 3 hours in the intensive care unit. reached its minimum at 5 hours and thereafter slowly increased. The peripheral vascular bed was shut down on admission to the ICU. as indicated by low values of PscO2. PtcO2. PtCO2 index. RCF and Tft. These parameters began to rise after the next 2-4 hours and peaked by the end of the 8-hour study period. indicating complete opening of the peripheral vascular bed.
Granulated sugar treatment of severe mediastinitis after open-heart surgery, Fifteen cases of mediastinitis developing after 1.164 open-heart operations (incidence 1.3%) were analyzed. Closed mediastinal irrigation was used as primary therapy in ten cases and led to complete healing in five. Granulated sugar treatment was given primarily to four patients and to five others after failure of closed mediastinal irrigation. The sugar treatment was successful in six patients with hospital stay averaging 91.6 +/- 8 days. The three other patients in this group died before discharge from hospital. During 22-month follow-up there was no recurrence of mediastinitis in the granulated sugar group. but reoperation was necessitated by sternal fistula in two of the patients with closed mediastinal irrigation. Granulated sugar treatment is effective in refractory. severe mediastinal infections.
Revascularization of infarcted vs. viable myocardium. Effects on symptoms, physical performance and global/regional left ventricular function, Symptoms. physical performance and global vs. regional left ventricular (LV) function were reviewed in 25 patients with postinfarction anterior-apical akinesia and minor dyskinesia who subsequently underwent revascularization of all graftable stenotic vessels. The observed postoperative improvement in functional NYHA capacity and physical performance was not related to significant change in any systolic or diastolic variable of global LV function. 'Nonspecific postoperative septal hypokinesia' developed in most cases. The regional ejection fraction showed slight (nonsignificant) mean increase in the infarcted apex and low anterior wall supplied by the left anterior descending artery. but marked increase in the noninfarcted lateral wall supplied by the left circumflex branch. Hearts with grafted left circumflex artery showed on average lower preoperative and postoperative ejection fraction in the lateral wall than did hearts without such grafting. but the rise in regional ejection fraction was significant only after left circumflex grafting. The clinical response to coronary artery surgery is attributed mainly to functional improvement of non-infarcted myocardium. Revascularization of viable myocardium occurs directly via bypass grafts. but collateral vessels may also contribute.
Revascularization of infarcted myocardium. Effect on myocardial perfusion assessed with quantified Tl-201 SPECT technique, Myocardial perfusion was studied in 21 patients before and after revascularization of all graftable stenotic vessels following post-infarction anteroapical akinesia and minor dyskinesia. At preoperative and late postoperative evaluation. perfusion abnormalities in identified sectors were quantified with two methods. one (Q1) assessing the extent and the other (Q3) the severity of abnormal perfusion. The preoperative scores with both methods indicated permanent myocardial perfusion defects in all 21 patients and reversible defects. indicating myocardial ischemia. in 16 with Q1 and 14 with Q3. After bypass grafting there was overall reduction of myocardial perfusion defect and of abnormality scores: Notably. 13/21 patients (62%) had decreased permanent myocardial defect score. reflecting reactivation of 'hibernating myocardium'. The findings indicated that obstructed but graftable vessels supplying myocardium with loss of contractile function should be bypassed. since flow contribution to distant. viable myocardium is probable via preserved collateral circulation. This should be particularly relevant for the LAD. because of that artery's septal branches.
The receptor for ciliary neurotrophic factor, Although neurotrophic factors were originally isolated on the basis of their ability to support the survival of neurons. these molecules are now thought to influence many aspects of the development and maintenance of the nervous system. Identifying the receptors for these neurotrophic factors should aid in identifying the cells on which these factors act and in understanding their precise mechanisms of action. A "tagged-ligand panning" procedure was used to clone a receptor for ciliary neurotrophic factor (CNTF). This receptor is expressed exclusively within the nervous system and skeletal muscle. The CNTF receptor has a structure unrelated to the receptors utilized by the nerve growth factor family of neurotrophic molecules. but instead is most homologous to the receptor for a cytokine. interleukin-6. This similarity suggestes that the CNTF receptor. like the interleukin-6 receptor. requires a second. signal-transducing component. In contrast to all known receptors. the CNTF receptor is anchored to cell membranes by a glycosyl-phosphatidylinositol linkage.
Human ultrasonic speech perception, Bone-conducted ultrasonic hearing has been found capable of supporting frequency discrimination and speech detection in normal. older hearing-impaired. and profoundly deaf human subjects. When speech signals were modulated into the ultrasonic range. listening to words resulted in the clear perception of the speech stimuli and not a sense of high-frequency vibration. These data suggest that ultrasonic bone conduction hearing has potential as an alternative communication channel in the rehabilitation of hearing disorders.
Does ventricular dysfunction occur during liver transplantation, In conclusion. we believe that ventricular dysfunction occurs infrequently during liver transplantation. except for the very short period of "cardioplegia" of the heart on reperfusion in some patients. There is no evidence that prolonged cardiac dysfunction is a common problem during liver transplantation. Understanding the physiologic changes that occur during liver transplantation should allow the anesthesiologist to correct many factors that might otherwise cause hemodynamic instability.
Ventricular dysfunction does occur during liver transplantation, Ventricular dysfunction. then. does indeed occur during liver transplantation. particularly at the time of reperfusion. Pulmonary embolism contributes to right ventricular and right atrial encroachment on left-heart filling. and paradoxical embolism may occur. Pericardial effusions. tricuspid regurgitation. hypothermia. and the release of substances. particularly potassium from the donor liver. may further contribute to compromises in ventricular function. Proper monitoring and appropriate treatment. however. lead to successful operative outcomes in most cases.
Impaired suppression of plasma norepinephrine during head-down tilt in patients with congestive heart failure, Neurohumoral activation is present in congestive heart failure and may contribute to vasoconstriction in this syndrome. The mechanisms leading to and maintaining neurohumoral activation in long-standing congestive heart failure are as yet undefined. The present study addresses the possibility that baroreceptor-mediated suppression of plasma norepinephrine may be abnormal in patients with long-standing congestive heart failure. Eight normal subjects and 12 patients with long-standing congestive heart failure were studied during 15 minutes of 30 degrees head-down tilt. There were no significant changes in heart rate or arterial blood pressure in either group during these maneuvers. In normal subjects. plasma norepinephrine declined from 257 +/- 38 pg/ml at control to 208 +/- 39 pg/ml during head-down tilt (p less than 0.005). Plasma norepinephrine was elevated in the patients with congestive heart failure. 475 +/- 189 pg/ml. and did not change during head-down tilt. These observations suggest that baroreflex loading maneuvers. which in this study included increased central blood volume and hydrostatic effects on the sinoaortic baroreceptor. do not suppress increased plasma norepinephrine in patients with long-standing congestive heart failure. Impaired baroreflex responsiveness could therefore contribute to either the generation or maintenance of high plasma norepinephrine in this syndrome.
Effect of antireceptor antibodies in dilated cardiomyopathy on the cycling of cardiac beta receptors, A substantial proportion of patients with dilated cardiomyopathy have circulating autoantibodies directed against the cardiac beta-adrenoceptor. These antireceptor antibodies inhibit both ligand binding to membrane beta-receptors and isoproterenol-sensitive adenylate cyclase. The functional consequences of antibody-receptor interactions were further studied by examining their influence on beta-adrenoceptor cycling. Sera from eight patients with cardiomyopathy induced a loss of beta-receptors from the surface of cardiac myocytes consistent with internalization. This loss was inhibited by concanavalin A. suggesting that receptor sequestration preceded internalization but was unaffected by the cytoskeleton inhibitors colchicine and cytochalasin. In cell-free preparations. serum-induced desensitization of beta-receptors was prevented by heparin but not the inhibitor of protein kinase A; this is consistent with a requirement for receptor phosphorylation by the beta-receptor kinase. In contrast to isoproterenol-mediated endocytosis. beta-receptors internalized under the influence of cardiomyopathic sera do not recycle to the plasma membrane. These results indicate that antireceptor antibodies in human dilated cardiomyopathy induced downregulation by interfering at several steps in the cycling of beta-receptors. These effects would contribute to the reported decline in beta-receptor responsiveness in cardiomyopathic myocardium.
Modulation of catecholamine cardiomyopathy by allopurinol, It has been suggested that cardiac injury by catecholamines may be the result of coronary constriction leading to ischemic damage. Allopurinol (ALLO) has been shown to reduce the extent of myocardial necrosis in various systems. Hence the possibility that ALLO might limit norepinephrine (NE) injury was tested. Rabbit hearts were infused with NE (3 micrograms/min/kg) for 90 minutes. with or without ALLO (50 micrograms/min/kg). Control specimens infused with saline solution plus ALLO were also prepared. Hearts were excised 48 hours later and studied as isovolumic isolated heart preparations. Peak systolic pressure. coronary flow. and myocardial oxygen consumption were significantly reduced in the hearts infused with NE but not in the NE + ALLO hearts. Myocardial adenosine triphosphate and glycogen concentrations were 29% and 26% lower in the NE hearts compared with control hearts. These reductions were absent in the NE + ALLO group. Moreover. rates of creatine phosphokinase and lactic dehydrogenase release were sharply elevated in the NE hearts but not in those also given ALLO. These findings are consistent with the changes observed histologically. The amount of myocardial damage was less in the ALLO + NE group compared with the NE group (p less than 0.02). This appears to be the first report to demonstrate that ALLO reduces myocyte damage by NE. Possible mechanisms include decreased free radical production. scavenging of free radicals. and preservation of the adenine nucleotide pool. Because xanthine oxidase activity is absent in the rabbit. the latter two mechanisms are more likely explanations for the findings.
Cardiac function and metabolism after chronic alcohol consumption: adaptation, reversibility, and effects of verapamil, Hamsters were fed 50% alcohol instead of drinking water for up to 42 weeks (average serum alcohol levels were 0.12 +/- 0.06 gm/dl during the 42 weeks). One group of hamsters (28 weeks) was given verapamil 3 days before they were killed. Two groups were withdrawn from alcohol acutely (3 days before they were killed) at 14 and 28 weeks. High-energy phosphate compounds were studied in isolated hearts with 31P-MRS standardized by freeze clamping the tissue. Hemodynamics of the heart were monitored throughout the study. After 7 and 14 weeks of alcohol ingestion. developed pressure and the phosphorylation potential were depressed in the hearts of chronically treated hamsters. At 28 and 42 weeks developed pressure increased but was significantly below baseline values; however. the phosphorylation potential and [pH]i returned to baseline values at 28 and 42 weeks. Throughout the 7 to 42 weeks of alcohol ingestion the alcohol-treated hamsters had a significantly higher end-diastolic pressure as compared with control animals. Withdrawal of alcohol (3 days before the hamsters were killed) reversed the depression of developed pressure and the phosphorylation potential. Acute administration of verapamil (therapeutic dose 3 days before they were killed) to hamsters given alcohol for 28 weeks reversed the depressed hemodynamic values. Overall the data suggest an adaptation of the heart to continuing alcohol consumption. which was related to normalization of the phosphorylation potential and [pH]i and partial alleviation of functional depression.
Left ventricular mass in childhood dilated cardiomyopathy: a possible predictor for selection of patients for cardiac transplantation, To determine the relationship of left ventricular hypertrophy (as assessed by mass) to symptoms and cardiac function in chronic childhood dilated cardiomyopathy. 17 long-term survivors (12 asymptomatic. 5 symptomatic) were studied at a median follow-up of 6.25 years (1.25 to 16.8 years). Left ventricular mass. dimension. wall stress. and contractility (relationship between velocity of circumferential fiber shortening and end-systolic wall stress) were assessed by echocardiography. These data were compared to measurements at the onset of disease. At follow-up. mass decreased significantly from the onset in the asymptomatic patients but remained elevated in the symptomatic patients (101 +/- 35 gm/m2 to 54 +/- 12 gm/m2. p = 0.001; 122 +/- 55 gm/m2 to 198 +/- 115 gm/m2. p = 0.23. respectively). Shortening fraction and contractility were both significantly lower in the symptomatic group compared with the asymptomatic group at follow-up (shortening fraction = 21 +/- 7% vs 29 +/- 5%. p = 0.02; contractility = -0.24 +/- 0.14 circ/sec vs -0.05 +/- 0.11 circ/sec. p = 0.01). Follow-up wall stress was slightly higher in symptomatic patients compared with asymptomatic patients. Three symptomatic patients had progressive hypertrophy and either died or required transplantation. Higher left ventricular mass is associated with the presence of symptoms. depressed contractility. and slightly higher wall stress. Persistence or progression of hypertrophy may be a poor prognostic sign in survivors of childhood dilated cardiomyopathy. Measurement of mass may be useful to indicate the necessity for closer follow-up to select patients for cardiac transplantation before hemodynamic decompensation.
Dependency of the pulsed Doppler-derived transmitral filling profile on the sampling site, In previous reports that evaluated pulsed Doppler transmitral filling. the sampling site has varied; we examined the effect of the sample volume location on Doppler measurements. Studied were 97 patients: 58 with normal echocardiograms. 20 with mitral regurgitation. and 19 with miscellaneous cardiac diseases. Transmitral filling was recorded at the mitral anulus and at the left atrial and left ventricular (LV) sides of the mitral tips. As the sample volume was moved from the mitral anulus to the LV side. the peak velocity and time-velocity integral of early diastole increased (40.6 +/- 13.8 versus 59.0 +/- 19.0 cm/sec. 5.26 +/- 1.65 versus 8.35 +/- 2.37 cm; p less than 0.001) as did those of late diastole (48.7 +/- 11.5 versus 57.5 +/- 17.0 cm/sec. 3.48 +/- 0.97 versus 4.59 +/- 1.39 cm; p less than 0.001). The late-to-early diastolic peak velocity and time-velocity integral ratios and the late-to-total diastolic time-velocity integral ratio decreased (1.33 +/- 0.51 versus 1.06 +/- 0.41. 0.71 +/- 0.24 versus 0.58 +/- 0.19. 0.40 +/- 0.09 versus 0.36 +/- 0.08; p less than 0.001). The dependency of these indices on the sampling site was in the same degree in all three groups. However. the peak filling rate normalized to mitral stroke volume (4.71 +/- 1.43 versus 4.63 +/- 1.32 l/sec; p = NS) was not influenced by the sample volume location; thus this parameter may be more reliable for assessing LV filling.
Intravascular ultrasound imaging of human coronary arteries after percutaneous transluminal angioplasty: morphologic and quantitative assessment, An intravascular ultrasound catheter system was used in patients to assess the effect of percutaneous transluminal coronary angioplasty. In 14 out of 16 patients. the intravascular ultrasound catheter could be successfully advanced to the site of a previous dilatation. Qualitative assessment of the cross-sectional images revealed intimal thickening and an increase of ultrasound reflectance and calcification at atherosclerotic coronary arteries. A disruption of the obstructing plaque and evidence for local dissections (11 of 14 cases) were observed after angioplasty. The quantitative comparison between angiography and the ultrasound measurement showed a close correlation for vessel sites distant to the dilatation (r = 0.91 for vessel diameter; r = 0.86 for luminal area; p less than 0.001). After angioplasty. the quantitative evaluation of the dilated area was possible in 11 cases. The correlation of angiographic and sonographic measurements of these segments was good for the assessment of the vessel diameter (r = 0.82. p less than 0.001). but poor for the determination of the luminal area (r = 0.48. p = 0.10). This difference reflected the complex morphology of the vessel lumen after angioplasty. which would be better assessed by the cross-sectional sonographic technique than by contrast angiography. The intravascular imaging of coronary arteries provides a new and unique method to obtain information on the plaque morphology and composition. and to assess the local effects of interventional procedures and their complications.
Adenosine thallium 201 myocardial perfusion scintigraphy, Pharmacologic coronary vasodilation as an adjunct to myocardial perfusion imaging has become increasingly important in the evaluation of patients with coronary artery disease. in view of the large number of patients who cannot perform an adequate exercise test or in whom contraindications render exercise inappropriate. Adenosine is a very potent coronary vasodilator and when combined with thallium 201 scintigraphy produces images of high quality. with the added advantages of a very short half-life (less than 10 seconds) and the ability to adjust the dose during the infusion. which may enhance safety and curtail the duration of side effects. The reported sensitivity and specificity of adenosine thallium 201 scintigraphy for the detection of coronary artery disease are high and at least comparable with imaging after exercise or dipyridamole administration.
Mixed venous oxygen saturation as a guide to tissue oxygenation and prognosis in patients with acute myocardial infarction, The relation of mixed venous oxygen saturation and the cardiac index to tissue oxygenation and prognosis was investigated in 119 patients with acute myocardial infarction. There was a positive correlation between mixed venous oxygen saturation and the cardiac index in 97 survivors and 22 nonsurvivors. but a significantly lower mixed venous oxygen saturation level at the same level of cardiac index was observed in nonsurvivors compared with survivors. Results of multivariate analysis with mixed venous oxygen saturation and the cardiac index indicated that only mixed venous oxygen saturation was significantly related to survival and to hyperlactacidemia. Oxygen delivery to tissues declined significantly in nonsurvivors because of a lower cardiac index and a lower hemoglobin concentration in these patients than in survivors. However. at the same level of oxygen delivery to tissues. nonsurvivors had a significantly higher rate of oxygen consumption leading to a correspondingly greater decrease in mixed venous oxygen saturation. suggesting that a greater increase in oxygen demand was also observed in nonsurvivors than in survivors. Thus mixed venous oxygen saturation after acute myocardial infarction is a better predictor of hyperlactacidemia and survival than the cardiac index. and this may be associated with an increased oxygen demand and an impaired oxygen transport system in seriously ill patients.
Single-photon emission computed tomographic thallium imaging with adenosine, dipyridamole, and exercise, Stress thallium imaging is a sensitive technique for detecting coronary artery disease. particularly in those patients with multivessel disease. Single-photon emission computed tomography (SPECT) is superior to planar imaging; because of improved image quality and lack of overlap between normal and abnormal segments. SPECT has greater ability to detect diseased arteries. The inherent three-dimensional nature of the data presentation suggests the feasibility of quantifying the extent of myocardium at risk. Pharmacologic stressors such as adenosine and dipyridamole allow imaging with thallium (and probably other perfusion agents) even in patients who are not candidates for exercise testing or who cannot achieve adequate levels of exercise. Studies suggest that adenosine has unique advantages for use with SPECT perfusion imaging with a high degree of accuracy. In our experience the sensitivity of detecting one-vessel disease is higher with adenosine-thallium imaging than in exercise SPECT thallium imaging. The degree of coronary hyperemia is greater and the duration of action is shorter with adenosine than with dipyridamole.
Use of adenosine echocardiography for diagnosis of coronary artery disease, Two-dimensional echocardiography combined with exercise is sensitive and specific in the detection of coronary artery disease (CAD) by demonstrating transient abnormalities in wall motion. Frequently. however. patients cannot achieve maximal exercise because of various factors. Pharmacologic stress testing with intravenous adenosine was evaluated as a means of detecting CAD in a noninvasive manner. Patients with suspected CAD underwent echocardiographic imaging and simultaneous thallium 201 single-photon emission computed tomography during the intravenous administration of 140 micrograms/kg/min of adenosine. An increase in heart rate. decrease in blood pressure. and increase in double product were observed during adenosine administration. Initial observations revealed that wall motion abnormalities were induced by adenosine in areas of perfusion defects. The adenosine infusion was well tolerated. and symptoms disappeared within 1 to 2 minutes after termination of the infusion. Therefore preliminary observations suggest that adenosine echocardiography appears to be useful in the assessment of CAD.
Adenosine in myocardial perfusion imaging using positron emission tomography, Because of its unique ability to demonstrate the metabolic consequences of myocardial ischemia. positron emission tomography (PET) is extremely valuable in assessing myocardial viability. PET imaging can identify the myocardial segments that are likely to improve after revascularization and may be more sensitive and specific for the detection of coronary artery disease compared with thallium perfusion imaging. Adenosine has several advantages over dipyridamole as a pharmacologic stress agent for use with PET. It produces maximal vasodilation in a significantly greater percentage of patients. is a more potent coronary vasodilator. and its very short half-life may be ideal for use with the very short half-life radioactive tracers used in PET. When combined with metabolic studies. adenosine may be useful for the assessment of patients who received thrombolytic therapy for an acute myocardial infarction.
Effect of cardiopulmonary support on regional and global left ventricular function during transient coronary occlusion, The ability of extracorporeal cardiopulmonary support (CPS) to unload the left ventricle and reduce ischemic dysfunction during transient coronary occlusion was studied in 10 anesthetized dogs. Three serial 60-second circumflex coronary artery occlusions were performed with CPS initiated only during the second occlusion. CPS significantly reduced preocclusion systolic blood pressure. blood pressure x heart rate double-product. circumflex blood flow. left ventricular end-diastolic pressure (LVEDP). peak negative dP/dt. and left ventricular systolic thickening. Circumflex occlusion caused changes in LVEDP and left ventricular wall thickening that were similar regardless of the presence or absence of CPS. These data suggest that CPS unloads the left ventricle during myocardial ischemia but does not prevent regional or global myocardial dysfunction.
Reliability of echocardiography in the diagnosis of anomalous origin of the left coronary artery from the pulmonary trunk, Previous studies have indicated that the definitive diagnosis of anomalous origin of the left coronary artery from the pulmonary trunk (ALC) should be made by cardiac catheterization and angiography. This study evaluates echocardiography (two-dimensional. pulsed Doppler. and color flow mapping) as a method to establish the diagnosis of ALC. To diagnose ALC. a modified parasternal short-axis view was used to demonstrate continuity of the ALC with the pulmonary trunk and to detect the retrograde flow through the ALC into the pulmonary trunk. Absence of these imaging characteristics ruled out ALC. From June 1985 to January 1990. 16 patients who presented with or had previously had a dilated poorly contracting left ventricle were prospectively assessed by echocardiography to rule out ALC. Four patients had ALC (age 2 to 120 months. mean +/- 1SD = 32 +/- 59) and 12 patients (age 1 to 192 months. mean +/- 1SD = 57 +/- 80) had myocardiopathy. Two other patients with known ALC were evaluated by an observer unaware of the diagnosis. All coronary anatomy was confirmed by angiography. surgery. or autopsy. The correct diagnosis of coronary anatomy was obtained by echocardiography in all instances without false positive or false negative diagnosis of ALC. Three infants underwent surgical repair of ALC based only on the echocardiographic diagnosis. Echocardiography can be used to establish the diagnosis of ALC. Therefore surgical repair can be undertaken in some critically sick infants based on the echocardiographic diagnosis alone.
Anomalous origin and course of coronary arteries in adults: identification and improved imaging utilizing transesophageal echocardiography, Anomalous origin of a coronary artery is rare. but may represent a clinically significant abnormality. since some anomalies are associated with myocardial ischemia. infarction. and sudden death. Diagnosis may elude routine screening procedures. and even when an anomalous vessel is identified angiographically. it may be difficult to delineate its true course on the basis of angiography alone. The purpose of this study was to determine whether transesophageal echocardiography (TEE) is of value in making the diagnosis and outlining the course of anomalous coronary arteries. Five adult patients with anomalous origin of a coronary artery were studied by monoplane TEE and selective coronary angiography. Transthoracic echocardiography (TTE) was also performed in four of these five patients. Anomalous coronary ostia were visualized in four of five patients utilizing TEE. but in none of four patients by TTE. A proximal segment of the anomalous coronary vessel was identified in all five patients by TEE. and in only two of four patients by TTE. TEE images were consistently of superior diagnostic quality. TEE is a valuable tool for the echocardiographic identification of anomalous coronary arteries. and is superior to TTE in adult patients.
Assessment of the extent of jeopardized myocardium during acute coronary artery occlusion followed by reperfusion in man using technetium-99m isonitrile imaging, We tested the feasibility of technetium-99m methoxyisobutyl isonitrile (Tc-MIBI) imaging for delineating jeopardized myocardium during acute coronary occlusion and reperfusion in man. This new perfusion agent was injected in 25 patients during elective percutaneous transluminal coronary angioplasty (PTCA) of a single-vessel left anterior descending (LAD) coronary artery stenosis. Distinct perfusion defects were present on "occlusion" images but not on "open vessel" images obtained 20 to 24 hours later in 21 patients (84%). The extent and severity of perfusion defects were significantly smaller in patients with distal versus proximal LAD occlusions (3.4 +/- 1.2 versus 5.2 +/- 1.5 segments; p less than 0.001). The only factor that was significantly related to the presence or absence of such "ischemic" perfusion defects was the absence or presence of visible collateral vessels to the LAD (p less than 0.03). The site of occlusion. presence of wall motion abnormalities. or occlusion time did not influence the results significantly. Thus the myocardial area at risk could be visualized and quantitated by Tc-MIBI imaging even after occlusion times as short as 15 seconds. but functioning collateral vessels are capable of protecting jeopardized myocardium in this setting.
Low-energy catheter electrical ablation for sustained ventricular tachycardia, Catheter electrical ablation using a relatively low level of energy--40 to 100 joules--was attempted in 12 consecutive patients with drug-refractory sustained ventricular tachycardia (VT). They had 19 monomorphic VTs. and ischemic heart disease was found as the underlying heart disease in one. nonischemic heart disease was found in nine. and no structural heart disease was seen in two patients. Electrical discharge was delivered at the site of the earliest endocardial activation in 17 VTs. and at the slow conduction area in two VTs. Among 19 VTs in 12 patients. 12 VTs (63%) in seven patients (58%) were successfully ablated and became noninducible during electrophysiologic study. There were no major complications. but transient atrioventricular block occurred in one patient and transient friction rub occurred in another. Delivered electrical energy and the time interval between the local electrogram and the surface QRS did not correlate with the clinical outcome of the procedure. However. "excellent" pace-mapped QRS morphology was obtained from the site of earliest activation or from the slow conduction area in 9 of 12 VTs in the successful cases but in only one of seven VTs in the unsuccessful cases. Low-energy catheter electrical ablation seems to be a satisfactory therapeutic procedure compared with the conventional method that uses an energy level of 200 joules or higher.
Patients with a high defibrillation threshold: clinical characteristics, management, and outcome, Of 125 patients prepared to receive implantable cardioverter-defibrillators (ICDs) with the patch-patch configuration of the difibrillating electrodes. 23 (18%) had high (greater than or equal to 25 joules) defibrillation thresholds (DFTs). These patients had lower left ventricular ejection fractions (27 +/- 12 vs 34 +/- 13; p less than 0.03) and a higher incidence of previous heart surgery (47% vs 19%; p less than 0.01) than patients with normal DFTs but did not differ in age. type of heart disease. incidence of concomitant heart surgery. or use of antiarrhythmic medication. Defibrillators were implanted in 18 of these 23 patients. 12 during the initial surgery and six after repeat DFT testing 2 weeks later. After 22 +/- 11 months of follow-up. four patients with ICDs died (two suddenly. and two of nonsudden cardiac causes). Two patients without ICDs died of nonsudden cardiac causes. Appropriate shocks were received by five patients (29%) including both who died suddenly later. A high DFT may be more common than previously stated. It is associated with poor ventricular function and previous heart surgery. Repeated DFT testing may be useful in some patients. A high DFT does not preclude successful ICD shocks. but other therapies may provide better results.
Hemodynamic effects and tolerability of intravenous amiodarone in patients with impaired left ventricular function, Acute hemodynamic effects and tolerability of intravenous amiodarone. 5 mg/kg administered over 5 minutes. were compared in patients with coronary artery disease and either a normal (left ventricular [LV] ejection fraction greater than or equal to 45%. n = 10. group N) or impaired LV function (ejection fraction less than 45%. n = 9. group L). Amiodarone reduced systemic vascular resistence and LV and aortic pressures in both groups (13%. 18%. and 13%. respectively [group N]. and 15%. 17%. and 15%. respectively [group L]) over the short term. Heart rate initially increased (18%. group L. and 10% group N). but was followed by a late 6% decrease in group N only. and by a progressive reduction in contractility (Vmax). together with a rise in LV end-diastolic pressure (19% and 38%. respectively [group N] and 17% and 58%. respectively [group L]; all values p less than 0.05 versus control). Coronary flow increased significantly by 20% (group N) and 31% (group L). but only during amiodarone administration. accompanied by a 26% and 25% reduction in myocardial oxygen extraction in groups N and L. respectively. Stroke work decreased in both groups (20% [group N] and 19% [group L]. p less than 0.05 versus control). In contrast. cardiac output only improved (10%) in patients with impaired ventricular function. Significant side effects did not occur. Thus relatively high dosages of intravenous amiodarone are well tolerated and improve cardiac pump function in patients with an impaired. but not with a normal cardiac function. However. the tendency to increase LV end-diastolic pressures necessitates careful monitoring in patients in whom preexisting LV filling pressure may be elevated.
Outcome of patients who were admitted to a new short-stay unit to "rule-out" myocardial infarction, For emergency room patients with a low probability of acute myocardial infarction. we established a new short-stay coronary observation unit. a 2-bed nonintensive care unit with telemetry monitoring adjacent to the emergency room. Of 512 consecutive admissions to the coronary observation unit. 425 (83%) were discharged home without evidence of acute myocardial infarction or serious complications (mean length of stay. 1.2 days; median length of stay. 1 day); 87 (17%) were transferred to other hospital beds. The rate of acute myocardial infarction was 3%. No deaths and only 1 serious complication occurred in the coronary observation unit. At 6 month follow-up. the cardiac survival rate was 99% for patients sent home directly from this unit. It is concluded that the coronary observation unit is safe and adequate for ruling out acute myocardial infarction in a defined subset of patients. Short-stay units. however. encourage early discharges which. when premature. may miss patients who are at risk of having complications shortly thereafter. Strategies such as mandatory but expeditious predischarge stress testing to encourage early but not premature discharge may augment the efficiency of coronary observation units.
Beneficial effect of long-term beta blockade after acute myocardial infarction in patients without anterograde flow in the infarct artery, Previous studies have shown that long-term survival after acute myocardial infarction (AMI) is improved by beta-adrenergic blockade and anterograde flow in the infarct artery. This study was done to assess the influence of beta blockade on mortality in survivors of AMI without anterograde flow. Over 9.5 years. 113 subjects (87 men and 26 women. aged 26 to 66 years) with AMI and no anterograde flow in the infarct artery and no disease of the other arteries were medically treated for 48 +/- 28 (mean +/- standard deviation) months. Forty-six patients received long-term beta blockade (group I). whereas 67 did not (group II). The groups were similar in age. sex. cardioactive medications. left ventricular performance and infarct artery. Of the 46 group I subjects. 1 (2%) died of cardiac causes; in contrast. 20 (30%) of the group II patients died of cardiac causes (p = 0.007 compared with group I). Thus. in survivors of AMI without anterograde flow in the infarct artery. mortality is markedly reduced by long-term beta blockade.
Diurnal variations of neurocardiac rhythms in acute myocardial infarction, To determine the diurnal pattern of cardiac autonomic tone in acute myocardial infarction (AMI). this study examined the power spectrum of heart rate (HR) variability in 24 patients during a single 24-hour segment within 4 days of AMI. Patients were nonrandomly allocated to a group (n = 14) without autonomic drugs and to a group (n = 10) already receiving beta blockers at the time of AMI. With use of autoregressive modeling. the power spectrum of HR variability was computed from continuous 1-hour electrocardiographic segments recorded at equally spaced intervals; 7 to 8 A.M.. 3 to 4 P.M.. and 11 to 12 P.M. All patients were supine. awake and pain free during recordings. There were no differences in HR. HR variance or the low-frequency peak power (0.06 to 0.1 Hz) from one temporal sequence to another. For the patients not taking beta blockers. the high-frequency peak power (0.2 to 0.36 Hz) or vagal component increased significantly from 3 P.M. to 11 P.M. (28 +/- 11 to 45 +/- 20 beats/min2.Hz-1. p less than 0.01). There was a significant decrease in the low- to high-frequency peak power and area ratios from 3 P.M. to 11 P.M. All power spectral parameters in the patients taking beta blockers remained unchanged over 24 hours. There was significantly heightened vagal modulation of sinus node activity in those receiving beta blockers. especially at 7 A.M. and 3 P.M. The data suggest that under steady-state wakeful conditions in the early recovery phase after an AMI. vagal tone is more pronounced during the late evening hours with a possible shift to relative sympathetic dominance during early morning and midafternoon hours.
Early prediction of acute myocardial infarction from clinical history, examination and electrocardiogram in the emergency room, The possibility of early prediction of acute myocardial infarction (AMI) was assessed in 7.157 consecutive patients coming to our emergency room during a 21-month period with chest pain or other symptoms suggestive of AMI. Of these patients 921 developed an AMI during the first 3 days in the hospital. Of the 4.690 patients admitted to hospital. 1.576 (34%) had a normal admission electrocardiogram. and 90 of these (6%) developed AMI. Of 1.964 patients with an abnormal electrocardiogram without signs of acute ischemia (42% of those admitted). 268 (14%) developed AMI. and 563 (51%) of 1.109 patients with acute ischemia on the electrocardiogram (24%) developed AMI. All patients were prospectively classified in the emergency room on the basis of history. clinical examination and electrocardiogram into 1 of 4 categories. according to the initial degree of suspicion of AMI. Of 279 admitted patients judged to have an obvious AMI (6% of the 4.690). 245 (88%) actually developed AMI; of 1.426 with a strong suspicion of AMI (30%). 478 (34%) developed one; of 2.519 with a vague suspicion of AMI (54%). 192 (8%) developed one; and of 466 with no suspicion of AMI (10%). 6 (1%) developed one. Thus. only a low percentage of the patients with a normal initial electrocardiogram or a vague initial suspicion of AMI developed a confirmed AMI.
Usefulness of severity of myocardial ischemia on exercise testing in predicting the severity of myocardial ischemia during daily activities, To determine the relation between myocardial ischemic indexes on exercise testing and on ambulatory Holter recording. 60 patients with stable coronary artery disease who exhibited an ischemic response to both testing procedures were studied. All patients performed a Bruce protocol exercise test and underwent 24-hour Holter recording within 2 weeks without antianginal medications. Mean exercise duration was 7.4 +/- 2.8 minutes. mean heart rate at 1-mm ST depression was 118 +/- 20 beats/min and mean maximal ST depression during exercise was 2.2 +/- 1 mm. During Holter recording the average number of ischemic episodes was 4.7 +/- 2.6 per patient. mean duration of daily ischemia was 62 +/- 54 minutes. mean maximal ST depression was 3.2 +/- 1.3 mm and average heart rate at 1-mm ST depression was 93 +/- 17 beats/min. Overall. the correlations between ischemic indexes on both testing procedures were very weak (mean r2 = 0.054). The only exercise variable that had a significant correlation (p less than 0.05) with all Holter variables was heart rate at 1-mm ST depression. yet it correlated very weakly (0.064 less than or equal to r2 less than or equal to 0.125) with most Holter covariates and had a better correlation (r2 = 0.256) only with average heart rate at 1-mm ST depression during Holter. Thus. ischemic indexes on exercise testing cannot accurately predict ischemic indexes on ambulatory Holter recording in patients with stable coronary artery disease who exhibit ischemic changes on both tests.
Systemic neurohumoral activation and vasoconstriction during pacing-induced acute myocardial ischemia in patients with stable angina pectoris, To identify the effect of myocardial ischemia on systemic neurohormones and vascular resistance. 32 untreated. normotensive patients with coronary artery disease underwent incremental atrial pacing until angina. Arterial and coronary venous lactate and arterial values of catecholamines and angiotensin II were determined at control. at maximal pacing rates. and at 1. 2. 5 and 30 minutes after pacing. Based on pacing-induced ST-segment depression (greater than or equal to 0.1 mV) or myocardial lactate production. or both. patients were selected as ischemic (n = 25) or nonischemic (n = 7). Baseline clinical and hemodynamic data were comparable. During pacing. chest pain was similar (20 ischemic vs 7 nonischemic patients). Also. hemodynamic measurements were comparable. except for contractility. which did not improve. and left ventricular end-diastolic pressure. which significantly increased in ischemic patients. Moreover. during ischemia arterial pressures increased significantly (13%) and systemic resistance increased from 1.470 +/- 60 (control) to 1.632 +/- 76 dynes.s.cm-5 5 minutes after pacing (p less than 0.05) in ischemic but not in nonischemic patients. Pacing did not affect neurohormones in nonischemic patients. In contrast. norepinephrine in ischemic patients increased significantly from 1.7 +/- 0.2 (control) to 2.6 +/- 0.3 (maximal pacing) and to 3.0 +/- 0.4 nmol/liter (1 minute after pacing). whereas angiotensin II levels increased from 6.2 +/- 1.4 (control) to 9.3 +/- 2.1 pmol/liter (1 minute after pacing. p less than 0.05). Epinephrine only increased during maximal rates (0.9 +/- 0.1 vs 0.6 +/- 0.1 nmol/liter at control. p less than 0.05). Thus. myocardial ischemia activates circulating catecholamines and angiotensin II. accompanied by systemic vasoconstriction.
Frequency of low serum high-density lipoprotein cholesterol levels in hospitalized patients with "desirable" total cholesterol levels, Because the National Cholesterol Education Program guidelines suggest that levels of total serum cholesterol less than 5.17 mmol/liter (200 mg/dl) are "desirable." we performed a retrospective observational analysis to determine the prevalence of coronary artery disease (CAD) in patients with total cholesterol less than 5.17 mmol/liter (200 mg/dl) and the prevalence of total cholesterol less than 5.17 mmol/liter (200 mg/dl) in patients with CAD by angiography. Cholesterol levels less than 5.17 mmol/liter (200 mg/dl) were found in 1.084 of 2.535 patients (42%) having cholesterol measured on hospital admission; 690 of these 1.084 (64%) had CAD. These patients were mostly men. had a family history of premature CAD. and 60% (414 of 690) had high-density lipoprotein (HDL) cholesterol less than 0.90 mmol/liter (35 mg/dl). In a separate group of patients defined from the same admission population but having angiographically established CAD. 32% (424 of 1.197) had a total cholesterol less than 5.17 mmol/liter (200 mg/dl). 59% of whom (252 of 424) had HDL less than 0.90 mmol/liter (35 mg/dl). An analysis of persons admitted electively for angiography (to exclude any effects of hospitalization per se on serum lipids) revealed a similar proportion of persons with total cholesterol less than 5.17 mmol/liter (200 mg/dl) (35%). CAD (82%). and HDL less than 0.90 mmol/liter (35 mg/dl).
Epicardial mapping in patients with "nodoventricular" accessory pathways, Some patients with electrophysiologic features suggesting nodoventricular fibers have been shown to have right parietal atrioventricular (AV) accessory pathways with decremental conduction properties intraoperatively. The experience with 11 patients (7 women and 4 men. mean age +/- standard deviation 25 +/- 5 years) who had electrophysiologic features consistent with a nodoventricular pathway and who underwent operative correction was reviewed. At electrophysiologic study. all patients had absent or minimal preexcitation in sinus rhythm. During atrial pacing and extrastimulus testing. maximal preexcitation with left bundle branch block morphology developed and the AH and AV intervals progressively prolonged. Preexcited tachycardia was initiated in all patients (AV reentrant tachycardia in 10 patients and AV node reentrant tachycardia in 1 patient). At operation all patients had a right parietal accessory pathway demonstrated. Intraoperative mapping demonstrated the earliest site of ventricular activation during anterograde preexcitation to be at the midanterior right ventricle. consistent with insertion of these pathways into the right bundle branch system. in 7 patients. The ventricular insertion was at the AV groove in 4 patients. in keeping with the typical Wolff-Parkinson-White syndrome. Retrograde conduction over the pathway was not demonstrated in any patient. Two patients had evidence of a second accessory AV pathway in the left paraseptal region. Operative AV node ablation was electively performed in 2 patients without affecting preexcitation in either case. In 1 of these patients. accessory pathway conduction was temporarily abolished by ice mapping in the right anterolateral AV groove.
Time-motion reconstruction of mitral leaflet motion from two-dimensional echocardiography in mitral valve prolapse, To assess the contributions of mitral leaflet billowing and exaggerated systolic mitral anular expansion to posterior motion of mitral leaflets recognized as mitral valve prolapse (MVP) by M-mode echocardiography. time-motion reconstructions of the anteroposterior displacement of points equally spaced along the anterior and posterior mitral leaflets were derived by computer-assisted analysis of 2-dimensional echocardiograms. Late or holosystolic posterior displacement of mitral leaflets. greater than or equal to 2 mm. occurred in the reconstructions from 24 of 24 (100%) patients with MVP with leaflet billowing and in 20 of 24 (83%) patients with MVP without leaflet billowing compared with 4 of 35 (11%) age-sex matched normal adults (both p less than 0.0000002). Posterior motion of the posterior mitral leaflet in time-motion reconstruction was significantly less with respect to the posterior end of the mitral anulus than with respect to the chest wall in patients with nonbillowing MVP (1.6 +/- 1.9 vs 2.7 +/- 1.6. p less than 0.02). but not in those with leaflet billowing (3.6 +/- 1.8 vs 3.9 +/- 1.8. p = not significant). because anular expansion contributed importantly to MVP in the former but not in the latter group. Thus. M-mode echocardiographic patterns of MVP reflect the separate but interacting effects of distinct abnormalities of mitral anular and leaflet dynamics.
Radiation exposure of pediatric patients and physicians during cardiac catheterization and balloon pulmonary valvuloplasty, Thermoluminescent dosimeters were applied to various areas of 61 pediatric patients and physicians to measure radiation doses during routine cardiac catheterization and during 4 cases of balloon pulmonary valvuloplasty. Radiation doses were measured during chest roentgenography. fluoroscopy and cineangiography. Average skin dose to the chest was 121 microGy during chest x-ray. 5.182 microGy during catheterization and 641 mGy during valvuloplasty. For the eyes. thyroid and gonads of the patients. the exposure during routine catheterization was equal to 0.4. 6 and 0.2 chest x-rays. respectively. Radiation dose of the operator was 3 microGy for the eyes and 6 miCroGy in the thyroid. About 56% of the operator's dose could be reduced by thyroid shields. and 80% by lead aprons. The assistant received only 1 microGy outside the thyroid shield. Therefore. we have concluded that the patients' dose during routine catheterization is largely based on our experimental results. but the dose is acceptable based on the risk factor analysis. The skin dose to the right lateral chest of the patient during valvuloplasty is extremely high. perhaps as high as the equivalent of 1.000 chest x-rays. Besides the clinical benefits of valvuloplasty. the long-term radiation-related hazards to the patient should be carefully monitored.
Ability of high-intensity ultrasound to ablate human atherosclerotic plaques and minimize debris size, To investigate whether high-intensity ultrasound can destroy atherosclerotic plaques while sparing the normal arterial wall. 279 normal human aortic sites and 119 fibrous and 193 calcified plaques. obtained from 24 necropsies. were insonified in a water tank. at 20 kHz and at 5 different power intensities. ranging from 68 W/cm2 (P1) to 150 W/cm2 (P5). These intensities were associated with a total excursion of the ultrasound irradiation apparatus tip from 90 to 268 microns. respectively. Time to perforate normal aortic sites and fibrous and calcified plaques was recorded at each intensity. There was no difference in perforation time between normal aortic sites and fibrous and calcified plaques when high-power levels (P2 to P5) were used. However. at the lowest power (P1). perforation time for the normal aortic wall was significantly longer than for fibrous and calcified plaques: 30 +/- 18 seconds (166 observations). 14 +/- 7 seconds (p less than 0.001) (78 observations) and 12 +/- 8 seconds (p less than 0.001) (115 observations). respectively. When perforation times for normal vessel wall versus fibrous plaque and normal vessel wall versus calcified plaque from the same necropsy specimen were compared in a pairwise manner. the results were: 29 +/- 13 vs 16 +/- 7 (p less than 0.001) (48 paired observations) and 26 +/- 9 vs 10 +/- 5 seconds (p less than 0.001) (55 paired observations). respectively. Regardless of whether paired or unpaired comparison was applied. no significant difference was found in perforation time between fibrous and calcified plaques. The debris did not differ in size as measured separately for normal sites and fibrous and calcified plaques by a computer-interfaced Channelizer and Coulter Counter system.
House-fire and drowning deaths among children and young adults, House fires and drownings remain frequent causes of pediatric and young adult mortality and morbidity. yet have received less attention than other causes of injury to the young. To investigate the gender. racial and socio-economic components of these problems. as well as the contribution of chronic disabilities. all deaths in a single state over a 7-year period in the birth through 24-year-old population were studied. Females and males overall had no appreciable differences in house-fire mortality. Females from birth through age 4 were more at risk. however. than older females of dying in house fires. but did not appear at more risk than males of the same age. Nonwhite males under age 4 were much more at risk than white males. Nonwhite females compared similarly to white females. both in the birth through 4-year age range. as well as in the overall population studied. Males had more drowning deaths overall than females. with most of the difference attributable to a large male predominance in the 15- through 24-year age group. Furthermore. males in this age group were much more likely to drown than were younger males. Both males and females in this age group were at particular risk if they had a past history of seizures. No other gender or racial differences could be determined. either in the overall population or in the separate age groups. except in victims greater than 4 years of age many more deaths were found in the lower three socio-economic quintiles than in the higher two.
Pedestrian fatalities. The Metropolitan Dade County experience, 1984-1988, The case files of the Dade County Medical Examiner Department of Metropolitan Dade County were used to study pedestrian fatalities. Epidemiologic data are correlated and compared with those of other studies.
Use of orthopantomographs in forensic identification, Radiographs of the head region were used for identification of 17 victims during an 11-year period in the Department of Forensic Medicine. University of Turku. Finland. Examinations resulted in positive identification of 10 victims. Proof of identity of four people was based on exclusion identifications. In one case. comparable information supporting the identity was achieved. Due to insufficient ante- and postmortem material. two individuals remained unidentified by radiological methods. The use of orthopantomography in identification is recommended because it enables visualization of the structures of the jaws and related areas on a single radiograph.
Autoerotic death. A definition, A definition of autoerotic death is suggested that restricts the use of this term to accidental deaths that occur during individual. usually solitary. sexual activity in which a device. apparatus. or prop that was employed to enhance the sexual stimulation of the deceased in some way caused unintended death. The case of the autoerotic asphyxial death of a 48-year-old man is reported in order to demonstrate the application of this definition.
Sexual asphyxia in siblings, We present an accidental autoerotic asphyxiation of a 24-year-old man. Further investigation revealed that 18 years earlier. his brother. then 13. had been found dead. hanging in the family bathroom. Although that death had been ruled a suicide. reevaluation of the death scene indicates that this was also an autoerotic asphyxiation. This is the first reported case of sexual asphyxia involving siblings.
Can the nephrologist prevent dialysis-related amyloidosis, The pathogenesis of dialysis-related amyloidosis is still poorly understood. Therefore. preventive measures can be proposed at present only on the basis of retrospective studies and hypothetical considerations. Two main solutions may be recommended. namely an effective dialytic removal of beta 2-microglobulin (beta 2-M). which is the protein precursor of dialysis amyloid. and the avoidance of bioincompatibility-associated phenomena such as those induced by dialysis membranes and endotoxins. Promising new imaging techniques such as computed tomography (CT) scan. nuclear magnetic resonance (NMR). and scintigraphy with specific tracers for amyloid may be helpful to evaluate the long-term results of different treatment schedules. including various strategies of renal replacement therapy.
Differentiation between renal allograft rejection and cyclosporine toxicity: a clinicopathological study, The differentiation between cyclosporine nephrotoxicity (CyN) and acute rejection (AR) still remains a matter of intensive research. In a retrospective study over the last 2 years. we assessed the clinical and histopathological data of 43 episodes of renal dysfunction in 39 renal transplant recipients immunosuppressed with cyclosporine (CyA). Ten episodes (23.2%) were identified as AR and 10 (23.2%) as acute CyN; in six cases (13.9%). signs of both AR and CyN were found. Fever (80%). oliguria (50%). and edema (50%) were prominent features in AR. but not in CyN. Renal blood flow was higher in the nephrotoxicity group and for corresponding degree of renal dysfunction. Significant hyperuricemia (greater than 8 mg/dL) was a prominent finding in CyN (80%) and to a lesser extent in AR (20%). The helper to suppressor cell ratio in the peripheral blood remained stable or slightly decreased in all cases with CyN. but increased in 70% of the cases with AR. CyN was associated with significantly higher whole blood CyA levels (P less than 0.005) and there was a positive correlation between plasma creatinine and CyA levels during the nephrotoxicity episodes (P less than 0.02). Diffuse mononuclear cell infiltrate was observed in 90% of the biopsies with AR and only in 20% with CyN (P less than 0.005). Concerning the extent of the tubular lesions. no significant differences were observed between the two groups. In contrast. vascular lesions such as arterial endothelial proliferation (P less than 0.05). hyalinosis (P less than 0.05). and glomerular capillary thrombi (P less than 0.05) were more commonly seen in nephrotoxicity biopsies.
Severe neurologic toxicity induced by cyclosporine A in three renal transplant patients, Cyclosporine A (CyA) is a potent immunosuppressive agent that is used in organ transplantation and in a variety of immunological diseases. It has a variety of adverse side effects. some of which can be serious and even life-threatening. CyA-associated neurotoxicity is generally mild. consisting of fine tremor. However. more complex neurologic abnormalities. including motor spinal cord and cerebellar syndromes. have rarely been described in bone marrow and liver transplant patients. Renal transplant patients have been spared from such CyA-induced toxicity. In this report. three renal transplant patients are described who developed complex and severe neurologic toxicity in the setting of therapeutic blood levels of CyA. which was completely reversible on discontinuation of the drug. No patient had a prior history of neurological or psychiatric dysfunction and there was no evidence of known psychoactive substance abuse. The toxicity was manifested as flaccid hemiparesis in one and dementia in a second patient. The third patient developed a previously unreported Guillain-Barre-like syndrome consisting of an ascending motor neuropathy. One patient developed reversible lesions involving the cerebral white matter. Whereas similar complex neurologic syndromes have been confined to patients who are intensely immunosuppressed. often debilitated. and have toxic levels of the drug. these three patients serve to emphasize that complex neurotoxicity can occur in stable patients who have therapeutic levels of CyA. Given the use of CyA in an ever-expanding list of disease processes. an appreciation of these potential neurologic syndromes is of paramount importance. At present. CyA-induced neurologic disease remains a diagnosis of exclusion.
Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses, To clarify the risk factors for chronic renal failure in idiopathic IgA glomerulonephritis (IgA-GN). we performed a dual study on 282 patients using both standard univariate statistical methods and the multivariate regression model of Cox. During a follow-up ranging from 1 to 36 years. with a mean of 8 years. 18% of the patients (50/282) had gone into chronic renal failure (CRF). with 18 of them in end-stage renal disease (ESRD) (6%). The univariate comparison of patients with CRF versus patients without CRF showed multiple risk factors: mainly arterial hypertension. an amount of proteinuria. nephrotic syndrome. a high level of serum IgA. presence of HLA-B35 antigen. and the intensity of most pathological lesions on light microscopy. The actuarial survival rate for a normal renal function (serum creatinine less than 135 mumol/L [1.5 mg/dL]) was 84% at 10 years and 64% at 20 years. The multivariate study allowed the isolation of only four risk factors with a significant effect on survival rate. These were the amount of proteinuria. the global optical score on first renal biopsy. the presence of an initial hypertension. and the presence of the HLA-B35 antigen. From these results. the probability of renal survival for individual patients may be calculated and a high-risk subgroup defined. Our data confirm the greater usefulness of multivariate over univariate statistical analyses in finding risk factors for CRF in IgA-GN.
Hemothorax as a complication following percutaneous renal biopsy, Percutaneous renal biopsy is a routine procedure with a low complication rate. We report a patient who developed shock and respiratory distress secondary to hemothorax following a fluoroscopically guided biopsy.
Nontuberculous mycobacterial peritonitis during continuous ambulatory peritoneal dialysis: case report and review of diagnostic and therapeutic strategies, Nontuberculous mycobacteria (NTM) are responsible for an increasing proportion of mycobacterial disease. Peritonitis due to NTM is an unusual but treatable complication of continuous ambulatory peritoneal dialysis (CAPD). Its presentation is similar to that of typical bacterial peritonitis. but special culture techniques are required to avoid a delay in diagnosis. Successful treatment depends on early catheter removal. drainage of fluid collections. and appropriate use of antimicrobial agents. We report a case of Mycobacterium fortuitum peritonitis in a patient undergoing CAPD. and review all previously reported cases. Diagnostic and therapeutic strategies are summarized based on available literature.
The fate of aggregated immunoglobulin A injected in IgA nephropathy patients and healthy controls, Organ uptake of IgA-containing immunologically active material was studied in humans by intravenous (IV) injection of 131I-labeled heat-aggregated human secretory IgA (HAS-IgA) in nine patients affected by primary IgA nephropathy and 10 normal volunteers. Aggregated secretory IgA was found to be removed almost exclusively by the liver. The peak activity in liver was reached at 21.1 minutes (range. 18 to 26 minutes) in patients and 19 minutes (range. 14 to 22 minutes) in controls. The rate of increase of liver radioactivity was found to be significantly slower in patients (with a mean slope of 5.0; range. 3.4 to 7.1 v 7.6. 5.6 to 11.4; P less than 0.02). The mean liver to precordium ratio at the peak time was significantly lower in patients (mean value. 2.3; range. 1.9 to 3.1) compared with controls (mean value. 3.3; range. 2.4 to 4.0) (P less than 0.02). These data confirm the pivotal role of the liver in the removal of aggregated IgA in humans and the defective clearance capacity of this test probe in IgA nephropathy patients.
Recombinant human erythropoietin to correct uremic bleeding, Recombinant human erythropoietin may improve hemostasis of uremic patients by correcting anemia. However. a complete correction of renal anemia carries the risk of hypertension. encephalopathy. thrombosis. and hyperkalemia. Our aim was to establish the minimum level of packed cell volume (PCV) achieved with recombinant human erythropoietin that corrects the prolonged bleeding time in uremia. Twenty patients with chronic renal failure. anemia. and very prolonged bleeding time (greater than or equal to 15 minutes) were randomly allocated to erythropoietin or no specific treatment. The initial dose of erythropoietin was 50 U/kg intravenously (IV) three times a week. Every 4 weeks. the dose was increased by 25 U/kg until a normalization of bleeding time was achieved. Erythropoietin at a dose ranging from 150 to 300 U/kg/wk induced an increase in PCV to a range of 27% to 32% in all patients but one. and normalized bleeding time in all patients. A significant negative correlation (r = 0.898. P less than 0.001) was found between PCV and bleeding time measurements. Erythropoietin also significantly (P less than 0.01) increased values for red blood cell (RBC) distribution width (basal. 11.3 +/- 0.6; 12 weeks. 13.1 +/- 1.3). Platelet count and platelet function parameters did not significantly change. In untreated patients. no changes were recorded in all the parameters considered. These results establish in a controlled fashion that erythropoietin shortens bleeding time of uremic patients and indicate that a partial correction of renal anemia is enough to normalize bleeding time.
The comprehension of nephrology in America a century ago, In America 100 years ago. the leading clinician pathologists had an understanding of nephrology comparable to that in Europe. Emphasis was on clinical observations devoid of modern clinical laboratory assistance. but verified or disproved at autopsy. The clinician often functioned as the pathologist for his own patients. and although microscopy had been introduced a few decades earlier and many had the benefit of some training in Germany or elsewhere in Europe. diagnostic capabilities remained limited. Renal physiology and pathophysiology were at best embryonic in the United States and elsewhere. The frequency and severity of medical renal diseases maintained the interest of some of the most astute physicians of the late 19th century; however. they had to remain frustrated by their inadequate diagnostic and. especially. therapeutic ability.
Taurine levels in plasma and blood cells in patients undergoing routine maintenance hemodialysis, We compared taurine levels in plasma. erythrocytes. platelets. lymphocytes. and granulocytes from 11 normal adults and 11 maintenance hemodialysis (MHD) patients immediately before and following a routine hemodialysis treatment. Taurine concentrations were elevated in plasma predialysis. as compared with normal subjects (90 +/- 16 [SEM] v 54 +/- 2 mumol/L [1.1 +/- 0.2 v 0.7 +/- 0.03. mg/dL]). but decreased with a dialysis treatment (to 34 +/- 3 mumol/L [0.4 +/- 0.04 mg/dL]). Erythrocyte taurine levels tended to be higher in MHD patients predialysis (1.2 +/- 0.2 v 0.7 +/- 0.1 nmol/10(9) cells. P less than 0.05 where P less than 0.025 is significant) as compared with controls; erythrocyte taurine was increased after dialysis (to 1.8 +/- 0.3 nmol/10(9) cells. P less than 0.006). In contrast. platelet taurine concentrations in MHD patients were lower than normal predialysis (18 +/- 2 v 27 +/- 2 nmol/10(9) cells) and declined further during the dialysis procedure (to 14 +/- 1). Granulocyte and lymphocyte taurine levels were not different in MHD patients. as compared with normal adults. either before or after dialysis. The observed differences in blood cell taurine content (expressed per 10(9) cells) could not be explained by variation in cell volumes among the groups examined. Thus. both chronic renal failure and a routine hemodialysis treatment produce changes in cell and plasma taurine levels that tend to be specific for the individual cell type.
Ascorbic acid supplements in patients receiving chronic peritoneal dialysis, Ascorbic acid supplements are commonly prescribed to patients with end-stage renal disease receiving peritoneal dialysis. To establish the need for ascorbic acid supplements. we evaluated seven chronic peritoneal dialysis patients during a supplement-free (phase I) period. and while receiving oral ascorbic acid (0.57 mmol/d [100 mg/d]) (phase II). Because of a proposed interaction with vitamin B6. patients were additionally supplemented with pyridoxine HCl (59.6 mumol/d [10 mg/d]) (phase III). Plasma levels and dialysate removal rates of total ascorbic acid and plasma pyridoxal-5-phosphate (PLP) were measured at the end of each phase. During phase I. plasma ascorbic acid levels (normal. 45 to 57 mumol/L [0.8 to 1.0 mg/dL]) declined slightly from 74 +/- 11 mumol/L (1.3 +/- 0.2 mg/dL) to 62 +/- 11 mumol/L (1.1 +/- 0.2 mg/dL) (P less than 0.02) at the end of the third week. and then remained stable to the end of the fourth week. Plasma ascorbic acid levels were no different in patients with or without residual renal function. With the addition of vitamin C supplements. plasma ascorbic acid levels increased by 45% of the baseline value at the end of phases II (P less than 0.001). The dialysate removal rate of ascorbic acid was 0.28 +/- 0.03 mmol/d (50 +/- 6 mg/d) at the end of phase I. and increased by 57% of the baseline value at the end of phases II (P less than 0.001). However. the peritoneal clearance of ascorbic acid remained unchanged during all phases the study. Pyridoxine depletion or repletion had no effect on plasma ascorbic acid levels (P greater than 0.05).
Detection of aneuploidy involving chromosomes 13, 18, or 21, by fluorescence in situ hybridization (FISH) to interphase and metaphase amniocytes, Fluorescence in situ hybridization (FISH) with chromosome-specific probes has been applied to detection of numerical aberrations involving chromosomes 13. 18. and 21 in metaphase and interphase amniocytes. High-complexity. composite probes for chromosomes 13. 18. and 21 were used as hybridization probes for this study. These probes were constructed as chromosome-specific libraries in Bluescribe plasmids and are designated pBS-13. pBS-18. and pBS-21. Elements of these probes bind at numerous sites along the target chromosome and. when detected fluorescently. stain essentially the entire long arm of the target chromosome. The target chromosome number (i.e.. the number of chromosomes of the type for which the probe was specific) was correctly determined in 20 of 20 samples in which metaphase spreads were analyzed and in 43 of 43 samples in which interphase nuclei were analyzed; all of these studies were conducted in blind fashion. These results suggest the utility of FISH with composite probes for rapid detection of numerical aberrations in metaphase and interphase amniotic cells.
Twinning and mitotic crossing-over: some possibilities and their implications, Mitotic crossing-over does occur in man and is much more frequent and important than generally assumed. Its postzygotic occurrence before an embryo differentiates into MZ twins is theoretically predicted to have disrupting effects on genomic imprinting and cis-acting sequences. with consequences ranging from early lethality to MZ twin discordance. Some predictions are at odds with classical views on twinning and include a high discordance rate of MZ twins for some genetic diseases. A review of MZ twin discordance and an attempt at explaining some of the data lead one to hypothesize both the existence of a sex differences in the rate of mitotic crossing-over and the impossibility for crossed X chromosomes to undergo inactivation. The close interrelationship of twinning and midline malformations further suggests a major role of mitotic crossing-over in the induction of the twinning process itself. The model can be tested with molecular methods and provides a new approach for the gene mapping of so-called multifactorial diseases and of rarer disorders with apparently irregular inheritance.
delta-Aminolevulinate dehydratase deficient porphyria: identification of the molecular lesions in a severely affected homozygote, delta-Aminolevulinate dehydratase deficient porphyria. a recently recognized inborn error of heme biosynthesis. results from the markedly deficient activity of the heme biosynthetic enzyme. delta-aminolevulinate dehydratase (ALA-D). The four homozygotes described to date with this disorder have remarkably distinct phenotypes. ranging from a severely affected infant with failure to thrive to an essentially asymptomatic 68-year-old male. To investigate the molecular nature of the lesions causing the severe infantile-onset form. total RNA was isolated from cultured lymphoblasts of the affected homozygote. RNA was reverse-transcribed to cDNA. and the 990-bp ALA-D-coding region was amplified by the PCR. Heterozygosity for an RsaI RFLP within the ALA-dehydratase-coding region permitted identification of the paternal and maternal mutant alleles prior to sequencing. The maternal mutation (designated G133R). a G-to-A transition of nucleotide 397. predicted a glycine-to-arginine substitution at residue 133 at the carboxyl end of the highly conserved zinc-binding site in the enzyme subunit. The G133R mutation created a PstI site and permitted the confirmation and rapid detection of this lesion in amplified genomic DNA from maternal relatives. The paternal mutation. a G-to-A transition of nucleotide 823. predicted a valine-to-methionine substitution of residue 275 (designated V275M). This mutation was confirmed in genomic DNA from family members by the competitive PCR technique. Both missense mutations. which occurred at CpG dinucleotides. resulted in the synthesis of enzyme subunits such that the activity of the homooctameric enzyme was markedly reduced. thereby causing the severe infantile-onset phenotype in the affected homozygote.
The gene for Treacher Collins syndrome maps to the long arm of chromosome 5, Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development. the features of which include conductive hearing loss and cleft palate. We have studied 12 unrelated TCS families with multiple affected individuals for linkage to five chromosome 5 markers. There is strong evidence demonstrating linkage to three of these markers. Multipoint linkage analysis places the mutation causing TCS in the interval between the gene for the glucocorticoid receptor and the anonymous marker D5S22. with a maximum multipoint lod score of 9.1.
Complementation and maternal effect in insulin-dependent diabetes, The marker association segregation chi-square (MASC) method was applied to a sample of 416 Caucasians affected with insulin-dependent diabetes mellitus (IDDM). for which information on the parental and sibship status was available. as well as HLA typing. We show that the model which best explains all the observations assumes a cis or trans complementation of two tightly linked genes within the HLA region. an additional maternal effect. and other familial factors. The HLA molecule corresponding to the complementation of Arg52(+) and Asp57(-) has been recently proposed as explaining susceptibility to IDDM. However. this hypothesis does not account for the overall observations made on the HLA marker in IDDM patients and their relatives. The MASC method may also be applied to evaluate the risk for relatives of an affected individual (the "index"). For example. the risk for a sib depends not only on the parental status and on the number of HLA haplotypes he shares with the index. but also on which haplotype the index himself inherited from his mother and father.
DRB genotyping supports recessive inheritance of DR3-associated susceptibility to insulin-dependent diabetes mellitus, The mode of inheritance of HLA-associated susceptibility to insulin-dependent diabetes mellitus was investigated by the antigen genotype frequency among patients method in a white Caucasian population and a North Indian Asian population. DR genotypes were determined by DRB/DQB RFLP analysis. In white Caucasians. simple recessive and simple additive inheritance of a single HLA-associated disease susceptibility allele were rejected (P less than .025 and P less than 10(-6). respectively). The data were compatible with a three-allele model of disease susceptibility. In North Indian Asians. simple additive inheritance was rejected (P less than 10(-6)). The observed genotype frequencies were compatible with a single DR3-associated disease susceptibility allele which is inherited recessively. These data show that study of DR genotypes in populations of different ethnic origins may further the understanding of inherited susceptibility to insulin-dependent diabetes mellitus.
Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies, Becker muscular dystrophy (BMD) often results from in-frame mutations of the dystrophin gene that allow production of an altered but partially functional protein. To address potential structure-function relationships for the various domains of dystrophin. we examined both the dystrophin gene and protein in 68 patients with abnormal dystrophin. Eighty-six percent of BMD patients with dystrophin of altered size have deletions or duplications. and the observed sizes of dystrophin fit well with predictions based on DNA data. Deletions within the amino-terminal domain I tended to result in low levels of dystrophin and a more severe phenotype. The phenotypes of patients with deletions or duplications in the central rod domain were more variable. This region can be divided into three portions based on differences in clinical presentations of patients. Deletions around exons 4553 were most common and generally caused typical BMD; however. phenotypic variability among patients with similar mutations suggests that epigenetic and/or environmental factors play an important role in determining the clinical progression. In contrast. deletions or duplications in the proximal portion of this domain tended to cause severe cramps and myalgia. Finally. loss of the middle of this region probably causes a very mild phenotype. as only one such patient was found and his only symptom was elevated serum creatine phosphokinase levels.
Compensatory growth in fibrotic lung injury, We induced severe left-sided lung fibrosis by the unilateral endobronchial instillation of paraquat (1.0 mg/kg) into the left lungs of adult Fischer 344 male rats. Growth of the contralateral lung as well as its proliferative activity were measured 6 or 14 days later. Whereas the left lung underwent severe fibrosis and shrinkage with more than 85% reduction in lung volume. the right lung more than doubled in size. In addition. there was a significant increase in total protein content. DNA content. and DNA synthesis. We conclude that unilateral lung injury resulting in ipsilateral fibrosis and loss of parenchyma is associated with compensatory growth of the contralateral lung.
Case report: dextran-induced acute anuric renal failure, Acute renal failure is an infrequent adverse reaction following the administration of dextran-40. We report a case of anuric acute renal failure in a 59-year-old female following the administration of 90 gm of dextran-40 and radiocontrast. An increased risk secondary to radiocontrast-induced ischemia is discussed in relationship to the pathogenesis of the dextran-induced acute renal failure. In addition. plasmapheresis is demonstrated to be of potential therapeutic benefit.
Isolation of dengue virus with a human promonocyte cell line, In October-November. 1988 there was an outbreak of dengue fever in the Kaoshiung area of southern Taiwan. We collected 100 serum samples from 96 patients at the onset of their fever for virus cultures and identification. A human promonocyte cell line (HL-CZ) established in our laboratory was used and proved to be susceptible for dengue virus propagation. Type 1 dengue virus in the HL-CZ cell culture was identified by immunofluorescence tests using monoclonal antibodies. and also by hemagglutination tests with goose red blood cells. The density of the virus particles. as measured by sucrose gradient ultracentrifugation. ranged from 1.186 to 1.224 g/ml. The virus yield from this cell culture is comparable with that from the C6/36 mosquito cell line. There was a significant correlation between the antibody responses tested with Western dot blots and hemagglutination inhibition techniques.
Age specific patterns of change in the dynamics of Wuchereria bancrofti infection in Papua New Guinea, Results of a longitudinal study of the age-specific dynamics of Wuchereria bancrofti infection in a community of East Sepik Province. Papua New Guinea (PNG) are described. Microfilarial (mf) density and serum levels of W. bancrofti phosphorylcholine-containing antigen (PC-Ag) in individuals were used as indirect measures of adult worm burden. These parasitological data were collected from 126 subjects greater than 4 years of age at two time points. 12 months apart. prior to the administration of the antifilarial drug diethylcambamazine (DEC). No significant changes in levels of mf density were observed for the study population between these two time points. However. significant changes in the levels of circulating PC-Ag were noted in subjects less than or equal to 20 years of age. but not in subjects greater than 20 years of age. between these two time points. The apparent shorter half life of circulating PC-Ag compared to that of mf makes antigenemia a more sensitive measure of the dynamics of adult worm populations. These data are discussed in terms of a basic mathematical model describing the dynamics of adult worm populations in relation to their life expectancy and attrition of larvae during establishment. Consideration of these data in the context of this simple immigration/death model suggests that the differences observed in patterns of change in intensity of infection between subjects less than or equal to 20 years old and those greater than 20 years old may be consistent with the acquisition of resistance to superinfection with increasing age.
Serological evaluation of the macrofilaricidal effects of diethylcarbamazine treatment in bancroftian filariasis, An Mr 200.000 phosphorylcholine-containing antigen (PC-Ag) of predominantly adult worm origin was found in the sera of humans infected with Wuchereria bancrofti. This paper describes results of a longitudinal study of changes in levels of PC-Ag in response to diethylcarbamazine (DEC) therapy as measured by two-site immunoradiometric assay (IRMA) and Western blotting. One hundred thirty-two residents of a bancroftian filariasis-endemic area of Papua New Guinea (PNG) were treated with a 72 mg/kg dose of DEC. A macrofilaricidal effect was seen with this dose of DEC as 34% of the treated subjects had localized side effects and long-term decreases in microfilariae (mf) counts were observed 12 months after treatment. The PC-Ag levels were reduced to 72%. 52%. and 51% of pretreatment values at 21 days and at six and 12 months after treatment. These decreases. observed by IRMA. were specifically associated with loss of the Mr 200.000 PC-Ag detected by immunoadsorption and Western blotting. From drug treatment data. the maximum half-life of PC-Ag in circulation was calculated to be 50 days. assuming a first-order decay process. This maximum half-life indicates that persistent antigenemia observed in the majority of treated subjects could only result from the survival of adult worms. In the absence of methods to directly demonstrate W. bancrofti adult worms. detection of serum PC-Ag levels provides a sensitive indirect measure of the dynamics of adult worm populations. This serological measurement may be useful in optimizing the macrofilaricidal and therapeutic effects of DEC and in assessing the macrofilaricidal action of new antifilarial drugs and immunological interventions.
Leishmaniasis in Bahia, Brazil: evidence that Leishmania amazonensis produces a wide spectrum of clinical disease, One hundred fourteen Leishmania isolates from patients with different clinical forms of leishmaniasis in the State of Bahia. Brazil. were characterized by indirect radioimmune binding assay using specific monoclonal antibodies (serodeme analysis). Seventy-five of these isolates were also analyzed by enzyme electrophoresis. based on 11 enzyme loci; parasite species were compared. according to their characteristic zymodemes. to those of WHO Leishmania reference strains. All isolates could be classified into one of three species: Leishmania amazonensis (n = 40). L. braziliensis (n = 39) or L. chagasi (n = 35). The most interesting information obtained from this study is the realization that L. amazonensis is capable of producing a wide spectrum of disease in humans. Infection with this parasite was associated with many different clinical presentations. including cutaneous leishmaniasis [CL] (20/49 cases). mucocutaneous leishmaniasis [MCL] (5/13 cases) and. of special note. visceral leishmaniasis [VL] (11/46 cases). as well as four cases of post kalaazar dermal leishmaniasis [PKDL]. In situ tissue parasite characterization. by immunoperoxidase assay and employing anti-L. amazonensis amastigote monoclonal antibodies. confirmed the infection with this species in two cases of CL. one case of DCL. one case of MCL and one case of PKDL. Our results also demonstrate the difficulty of parasite differentiation based on clinical grounds. since at least L. amazonensis infection can be associated with all types of leishmanial diseases. and different Leishmania species may be associated with indistinguishable clinical presentations. Since leishmanial parasites may vary in their biological behavior or in their response to treatment. it is important that their identification be made by reliable methods.
Resistance to chloroquine by Plasmodium vivax in Irian Jaya, Indonesia, Evidence of emerging resistance to chloroquine by Plasmodium vivax is described from Irian Jaya (Indonesian New Guinea). Sixteen of 24 residents in the village of Arso PIR II taking supervised weekly chloroquine prophylaxis (5 mg base/kg) had asexual parasitemia with P. vivax at least once during eight weeks of surveillance. An American working in the same village developed symptomatic P. vivax parasitemia despite chloroquine prophylaxis. Five days after therapy with 600 mg chloroquine base. the asexual parasitemia in the American increased 40-fold. but cleared after treatment with 1.500 mg chloroquine base. Serum samples were not available from many of the cases. but six local residents and the American had serum levels of chloroquine in excess of the ordinarily suppressive 15 ng/ml at the time of their asexual parasitemias (16-70 ng/ml). The weekly 300 mg base tablet of chloroquine. which has been the standard for prophylaxis against malaria for more than 40 years. was not effective against P. vivax in Arso PIR. Irian Jaya.
Comparison of antimalarial efficacy of alpha, beta, and alpha/beta arteether against Plasmodium cynomolgi B infection in monkeys, The blood schizontocidal activity of alpha and beta arteether has been compared with that of alpha/beta arteether (a 30:70 mixture of alpha and beta isomers). which is a fast-acting blood schizontocide undergoing phase I clinical trials at the Central Drug Research Institute. Both beta and alpha/beta arteether have comparable activity and are curative at a dose of 5 mg/kg for 3 days against blood-induced Plasmodium cynomolgi B infection in the rhesus monkey; alpha arteether alone is slightly less active. with a 50% cure rate at the above dose.
Polyclonal B-lymphocyte stimulation in human malaria and its association with ongoing parasitemia, To study the polyclonal B-lymphocyte stimulation or activation (PBA) phenomenon in human malaria. the numbers of immunoglobulin (G. A. and M)-secreting cells in the peripheral blood. serum levels of immunoglobulins. and the presence of antibodies directed against the DNA-autoantigen were evaluated in Plasmodium falciparum- and P. vivax-infected individuals. Individuals chronically exposed to the risk of infection or non-immune subjects who contracted malaria during first visits to endemic areas were studied. Numbers of immunoglobulin-secreting cells (IgSC) were increased dependent upon ongoing parasitemia. Levels of IgG and the anti-DNA activity were also augmented in malarious individuals from the endemic area. Study of the kinetics of PBA done in treated patients showed that PBA decreased during treatment and disappeared 5-15 days after the start of chemotherapy.
Weight control after vertical banded gastroplasty for morbid obesity, Vertical banded gastroplasty is a common method of treating morbid obesity. Several physical. behavioral. economic. and psychologic factors are believed to affect its efficacy. In this study. 100 consecutive patients received a 4.5-cm circumference band. while a second 100 consecutive patients were given a 5.0-cm circumference band. One year after surgery. with a follow-up of 97.5%. neither the patient's stoma size nor their preoperative occupation. economic status. or mental health significantly affected the patient's weight loss. which averaged 27% of their original weight. Postoperative eating behavior. however. dramatically affected weight loss. Among the patients who lost less than 20% of their original weight. 25% drank large volumes of caloried liquids. while 75% ate large amounts of soft foods. Patients with banded gastroplasties must "use" their operation to lose weight.
Bypass grafting to the popliteal artery in limbs with occluded crural arteries, Intraoperative completion angiograms of 47 femoropopliteal bypasses in limbs with occluded crural arteries were reviewed to identify the angiographic determinants of early outcome. Of 28 limbs in which the foot vessels were available for analysis. only 2 (7%) had an intact pedal circulation. and 18 limbs demonstrated no crural arteries suitable for distal reconstruction. The overall cumulative patency rate was 51% with a 76% limb salvage rate at 12 months. All seven grafts performed onto a popliteal artery segment of less than 8 cm occluded in the early period. The status of crural and foot arteries and the number of collaterals did not correlate well with early patency. Limbs with no patent crural artery that were analyzed in the poor angiographic runoff group. according to our previously reported classification. demonstrated relatively higher patency rates than the other subgroups with poor runoff. In cases where angiography demonstrates a poor runoff for distal revascularization. popliteal bypass with occluded crural arteries might achieve acceptable patency rates.
The Allen Brown shunt: a useful option for vascular access, This study analyzes the performance of 273 Allen Brown arteriovenous shunts inserted in the thigh and anastomosed to the superficial femoral artery and either the superficial femoral vein or the long saphenous vein. The median duration of shunt function was 9 weeks (range: 0 to 175 weeks). A significantly longer median function time of 22 weeks was found in patients who had had more than five previous access procedures (p less than 0.02). No other independent variable affecting shunt function time was identified. There were 84 complications (56 due to infection) and 2 deaths in the series. The infection rate was not improved by the use of perioperative antibiotics. with most infections occurring more than 6 weeks after insertion. Since the complication rate for Allen Brown shunts was no greater than that reported for subclavian catheters. and their function no less reliable than that reported for Quinton-Scribner shunts. the Allen Brown shunt is a useful option for short- and medium-term vascular access. It may also be useful for longer-term access in the patient in whom failure of multiple previous access procedures has occurred.
Effect of bile diversion and sphincterotomy on gallbladder muscle contractility and gallstone formation, Feeding prairie dogs a diet rich in cholesterol induces gallstone formation that is preceded by a sustained decrease in gallbladder smooth muscle contractility. Sphincterotomy is known to prevent gallstone formation in cholesterol-fed prairie dogs. Experiments were designed to determine whether the effect of sphincterotomy is a consequence of hepatic bile diversion. and whether bile diversion prevents the altered contractility. Following sham operation. surgical biliary enteric bypass. or sphincterotomy. prairie dogs were fed a high-cholesterol or a regular diet. Gallbladder muscle contractility and the presence of crystals and stones were determined. In sham-operated animals. the cholesterol diet induced a decrease in gallbladder muscle contractility and caused the formation of cholesterol gallstones. In animals with bile diversion and sphincterotomy. the effects of cholesterol feeding were reduced or prevented. Thus. these procedures may prevent stone formation by preventing a reduction in gallbladder contractility. Contractility was depressed in animals with bile diversion fed a regular diet. compared with animals with a sham operation fed a regular diet. The mechanism for this depression may differ from that induced by the cholesterol diet. Diversion. and perhaps sphincterotomy. impairs gallbladder filling. Thus. gallbladder muscle is not stretched and does not contract against a load. This could result in a "disuse atrophy." If the results from our study apply to humans. sphincterotomy may reduce stone formation by preventing the effects of lithogenic bile on gallbladder muscle contractility and by enhancing the ability of the muscle to empty the lithogenic bile.
Insulinopenia as a risk factor in hepatectomy and its resolution by intraportal insulin administration, Insulopenia is a possible risk factor in hepatectomy. especially since insulin has been recognized to have a significant hepatotrophic effect. In the current study. insulinopenic patients were defined as those who showed abnormally low insulinogenic indexes (less than 0.6) on the oral glucose tolerance test. compared with those in 22 normal volunteers (1.16 +/- 0.57. mean +/- SD). The insulinogenic index represents the ratio of the cumulative enhancement of immunoreactive insulin (IRI) to the glucose level (delta IRI/delta glucose). Surgical outcomes were studied retrospectively in 17 insulinopenic patients who underwent hepatic resections from January 1987 to July 1988. Six of 10 patients in the major hepatic resection group showed postoperative complications. 5 of whom experienced hepatic failure resulting in hospital death. By contrast. all seven patients in the minor resection group tolerated the operations. From August 1988. intraportal insulin was prospectively administered as a posthepatectomy management technique to nine patients. eight of whom were diagnosed as insulinopenic. These patients all tolerated major hepatic resections including four hepatic vascular exclusion procedures with veno-venous bypass. In conclusion. the current study indicates that insulinopenic patients are high-risk candidates for major hepatic resection and that intraportal insulin administration has a beneficial effect on the postoperative management of these patients.
Hydroxyethyl starch macromolecule and superoxide dismutase effects on myocardial reperfusion injury, Myocardial reperfusion injury may be due to biophysical changes (e.g.. endothelial cell junctional separations). as well as biochemical mechanisms (e.g.. oxygen free radical activity). Superoxide dismutase (SOD). a free radical scavenger. may be effective in reducing chemical injury. Fractions of hydroxyethyl starch (HES-Pz). a large macromolecule. have been shown to decrease microvascular permeability associated with reperfusion-induced biophysical alterations. A comparison of SOD to HES-Pz was performed using a canine model of 1-hour left anterior descending coronary artery (LAD) clamping followed by 24 hours of reperfusion. Amounts of the test solution equal to 10% of the dog's blood volume were administered intraatrially to the animals just before release of the LAD clamp. Six dogs received Ringer's lactate. 7 were given 600.000 IU of SOD. 13 received 6% HES-Pz. and 9 were given SOD and HES-Pz. The ratio of infarct to area at risk was 20 +/- 3% in the control dogs receiving Ringer's lactate. 16 +/- 4% in animals receiving SOD alone (p = NS). 6 +/- 3% in dogs receiving HES-Pz alone (p less than 0.05). and 8 +/- 3% in dogs given a combination of SOD and HES-Pz (p less than 0.05). HES-Pz alone and with SOD significantly reduced reperfusion injury. although addition of SOD to HES-Pz did not have an additive effect. Appropriate-sized macromolecules may act by reducing ischemia-induced microvascular permeability.
Dexmedetomidine prevents epinephrine-induced arrhythmias through stimulation of central alpha 2 adrenoceptors in halothane-anesthetized dogs, Since alpha 2-adrenergic agonists have important effects on the adrenergic system that have recently been applied to the anesthetic setting. we investigated the effect of stimulation of alpha 2 adrenoceptors on epinephrine-induced arrhythmias in halothane-anesthetized dogs. The arrhythmogenic threshold for epinephrine was determined during halothane anesthesia in the presence of dexmedetomidine. a selective alpha 2 agonist. and L-medetomidine. a stereoisomer of medetomidine that lacks alpha 2-agonist activity. Dexmedetomidine increased the arrhythmogenic threshold for epinephrine in a dose-dependent manner during halothane anesthesia. At the highest dose of dexmedetomidine. 0.5 microgram.kg-1.min-1. there was a three-fold increase in both the arrhythmogenic dose of epinephrine and the plasma epinephrine concentration that was reached at this dose. On the other hand. L-medetomidine over the same dose range did not effect the arrhythmogenic dose of epinephrine. Atipamezole. a central alpha 2 antagonist that crossed the blood-brain barrier. blocked the antiarrhythmic action of dexmedetomidine. L-659.066 a peripheral alpha 2 antagonist that does not penetrate the blood-brain barrier. did not affect the antiarrhythmic action of dexmedetomidine. Thus. dexmedetomidine's antiarrhythmic effect on epinephrine-induced arrhythmias during halothane anesthesia appears to be mediated at least in part by stimulation of central alpha 2 adrenoceptors.
Effects of anemia on pulse oximetry and continuous mixed venous hemoglobin saturation monitoring in dogs, The accuracy of pulse oximetry (for pulse hemoglobin oxygen saturation [SpO2]) and mixed venous oximetry (for mixed venous hemoglobin oxygen saturation [SvO2]) was assessed during progressive normovolemic anemia in dogs. Splenectomized mongrel dogs under general anesthesia were monitored with a three-wavelength pulmonary artery oximeter catheter (10 dogs) and a pulse oximeter (11 dogs). Data were collected while fractional inspired oxygen concentration (FIO2) was varied from 1.00 to 0.05 in seven steps. The dogs then underwent isovolemic hemodilution. and the FIO2 was again varied. This sequence continued until data no longer could be obtained. The accuracy of each device was assessed by determining the bias (the average difference between the continuous monitor oximeter and the bench oximeter) and the precision (the standard deviation of the difference). For the three-wavelength Oximetrix catheter (for hemoglobin oxygen saturation denoted here SoxO2). the overall bias (SoxO2 - SvO2) and precision were -0.7 +/- 8.6% for the 193 data points. The accuracy as assessed by bias and precision for SoxO2 was similar for hematocrits of 40-15%. (Bias +/- precision was 2.1 +/- 5.7% for hematocrits greater than 40%. and -1.1 +/- 7.5% for hematocrits of 15% to 19%). At hematocrits between 10 and 14%. the precision worsened to 12%. and for hematocrits less than 10% the bias +/- precision was -11.5 +/- 11.8%. The overall SpO2 accuracy was 0.2 +/- 7.6% for 178 points. The pulse oximeter's accuracy was similar. down to hematocrits of 10%. Below 10%. the bias and precision worsened to -5.4 +/- 18.8%.
Recovery of costal and crural diaphragmatic contractility from partial paralysis, Since the two muscles (costal and crural) that constitute the diaphragm are separate and histologically different. their individual recovery pattern from neuromuscular blockade also may be different. Therefore. we studied the recovery of force and shortening in the in vivo diaphragm from atracurium-induced neuromuscular blockade in seven pentobarbital anesthetized dogs to assess segmental differences. Transdiaphragmatic pressure (Pdi). shortening of costal and crural segments. integrated electromyogram (EMG). and tidal volume (VT) were measured during spontaneous breathing. After atracurium had reduced VT to 30% of control. breathing parameters were followed until recovered to 90% of control values. In addition. force-frequency curves generated by supramaximal tetanic stimuli of the phrenic nerve were measured. Recovery times for tidal Pdi. tidal EMG. tidal shortening. low-frequency shortening. and twitch Pdi were twice as fast as for VT (40 +/- 4 min). reflecting a slower rate of recovery of accessory inspiratory muscles. High-frequency recovery was typically slower than that of VT. During tidal breathing and tetanic stimulation. costal and crural shortening recovered simultaneously. On the other hand. comparison between costal and crural by analysis of pressure-shortening relationships showed a segmental difference (crural shortened 30% more than costal at the same Pdi). which implied reduced afterload on the crural segment. However. since shortening and pressure were linearly related during paralysis and recovery. measurements of Pdi alone can accurately reflect changes in contractile mass when heterogeneity and afterload are controlled.
The relationship among canine brain temperature, metabolism, and function during hypothermia, Cerebral protection by hypothermia is commonly attributed to cerebral metabolic suppression. However. at temperatures below 28 degrees C. the relationship of temperature to cerebral metabolic rate of oxygen consumption (CMRO2) has not been well characterized. Accordingly. the relationship between brain temperature and CMRO2 was determined in eight dogs during cooling from 37 to 14 degrees C while the EEG was continuously monitored. Cardiopulmonary bypass was initiated and control measurements were made at 37 degrees C during anesthesia with nitrous oxide 50-60% inspired and morphine sulfate 2 mg.kg-1 intravenously (iv). Upon cooling to 27 degrees C. the nitrous oxide was discontinued and the morphine was antagonized with naloxone 2 mg iv. Measurements were repeated at 27. 22. 18. and 14 degrees C and in four dogs again at 37 degrees C after nitrous oxide 50-60% had been reestablished at 27 degrees C along with administration of morphine sulfate 2 mg.kg-1. For each temperature interval. the temperature coefficient (Q10) for CMRO2 was calculated (Q10 = CMRO2 at x degrees C divided by CMRO2 at [x - 10] degrees C). Between 37 and 27 degrees C the Q10 was 2.23. but between 27 and 14 degrees C the mean Q10 was doubled to 4.53. With rewarming to 37 degrees C. CBF and CMRO2 returned to control levels. and brain biopsies revealed a normal brain energy state. During cooling. the EEG developed burst suppression at or below 22 degrees C. With further cooling. the periods of suppression increased; however. burst activity continued in seven of eight dogs even at 14 degrees C.
Anemia in pediatric day-surgery patients: prevalence and detection, A prospective study was conducted to determine the prevalence of anemia in pediatric day-surgery patients. and a single-blinded study was conducted to evaluate the anesthesiologist's capability to detect preoperative anemia clinically. The subsequent management of children with anemia was noted. During the preoperative examination the anesthesiologist completed a questionnaire and predicted the preoperative hemoglobin concentration based on the history and physical examination. The preoperative hemoglobin concentration was measured for all of the patients. but the results were withheld until after completion of the questionnaire. Documentation was complete in 2.649 patients. and these comprised the final study group. Fourteen patients (0.5%) were anemic (hemoglobin concentration less than 100 g/l). but of these. only 5 had been predicted to be anemic based on clinical examination. Seven of these 14 anemic patients were less than 1 yr of age. Only 2 of the anemic patients had surgery postponed. and 1 of these also had a respiratory infection. Forty-four patients were incorrectly predicted to be anemic (i.e.. their actual hemoglobin concentration was greater than 100 g/l). We conclude that in our patients. anemia is rare but is more likely to occur in those less than 1 yr of age. The presence of mild degrees of anemia does not alter the decision to proceed with day surgery. The anesthesiologists participating in this study could not reliably detect anemia clinically.
A comparison of the caffeine halothane muscle contracture test with the molecular genetic diagnosis of malignant hyperthermia, Malignant hyperthermia (MH) is currently diagnosed by the caffeine-halothane contracture (CHC) test. In a previous study. this test was used to establish linkage between the human gene for MH susceptibility and the ryanodine receptor (RYR) gene. The current study extends the genetic linkage analysis to a large French-Canadian kindred. In this family. genetic linkage between RYR and MH genes was not demonstrable using the currently recommended limits of normal for the CHC test in the identification of MH-susceptible individuals. With CHC test threshold limits below those currently recommended. however. complete linkage between the RYR and MH genes was seen. Comparisons of CHC test results with genetic linkage studies will increase the diagnostic accuracy of both tests as well as generate new insights into the biology of MH.
Normal parathyroid hormone responses to hypocalcemia during cardiopulmonary bypass, To determine whether the calcium-magnesium-parathyroid hormone-calcitriol (vitamin D) axis responds appropriately to the hypocalcemia that routinely follows initiation of cardiopulmonary bypass (CPB). we measured blood ionized calcium (CaI). total calcium (CaT). total magnesium (MgT). ultrafilterable magnesium (MgI). total protein. intact parathyroid hormone (PTH). and calcitriol concentrations at eight defined time points in 28 patients undergoing elective cardiac surgery. With the onset of CPB. CaI decreased from 1.14 +/- 0.02 to 0.91 +/- 0.03 mM. P less than 0.05) (n = 17). and then gradually returned to a normal value by the time of separation from CPB (0.98 +/- 0.01 mM). CaT. MgI. MgT. and total protein concentrations declined significantly upon initiation of CPB and remained depressed thereafter. PTH initially decreased upon initiation of CPB (from 50 +/- 8 to 24 +/- 9 pg/ml. n = 9. P less than 0.05). remained inappropriately decreased during the early phases of CPB. and then gradually increased to maximal concentrations in response to hypocalcemia (103 +/- 15 pg/ml) before emergence. Calcitriol concentrations (n = 8) were unchanged during surgery. Based on these initial results. which suggested an association between hypomagnesemia and the slow PTH response to hypocalcemia. measurements were repeated in 10 additional patients. to whom magnesium (Mg) (1 g MgSO4 in two separate intravenous doses) was administered. Mg administration neither altered the PTH response to ionized hypocalcemia nor hastened the return of CaI to normal.
Optimum concentration of bupivacaine for combined caudal--general anesthesia in children, Caudal epidural anesthesia has become widely accepted as a means of providing postoperative pain relief and intraoperative supplementation to general anesthesia for children. To determine the best concentration of bupivacaine for combined general-caudal anesthesia in children. 122 children aged 1-8 yr scheduled for outpatient inguinal herniorrhaphy were randomized to receive. in a double-blind fashion. caudal anesthesia with bupivacaine in one of six concentrations (0.125. 0.15. 0.175. 0.2. 0.225. or 0.25%). After incision. a programmed reduction in inspired halothane resulted. if tolerated by the subject. in an inspired halothane concentration of 0.5% 10 min after incision. End-tidal halothane concentration at hernia sac ligation for subjects receiving 0.175% bupivacaine (0.55 +/- 0.03%) was less than that for subjects receiving 0.15% bupivacaine (0.75 +/- 0.05%; P less than 0.05). Subjects receiving 0.175% bupivacaine also were discharged earlier from the postanesthesia care unit (PACU) (27 +/- 1 min) than were subjects receiving 0.15% bupivacaine (38 +/- 5 min; P = 0.05). Children receiving greater than or equal to 0.2% bupivacaine tended to complain more of leg weakness after surgery; however. the difference did not reach statistical significance (39 of 67 vs. 16 of 47; P = 0.057). The incidence of complaints of leg weakness and paresthesia was positively correlated with bupivacaine concentration (r = 0.706; P = 0.05). Subjects receiving 0.125% bupivacaine had higher pain scores on arrival to the PACU than did those receiving 0.2% bupivacaine (P = 0.05); there were no other differences in pain scores.
A comparison of the analgesic and respiratory effects of epidural nalbuphine or morphine in postthoracotomy patients, This randomized. double-blind study compared the analgesic and respiratory effects of lumbar epidural morphine 5 mg. nalbuphine 10 mg. and nalbuphine 20 mg in repeated doses in patients after thoracotomy; the first dose was administered intraoperatively. Pre-and postoperative monitoring included continuous pulse oximetry. respiratory inductance plethysmography. and repeated arterial blood gas analysis. Postoperatively. visual analogue pain scores. somnolence scores. respiratory rate. and arterial blood gases were determined for 16 h. Preoperatively. episodes of apnea were common during sleep but were not associated with low hemoglobin oxygen saturation or increased arterial carbon dioxide tension (PaCO2). During sleep. some otherwise normal patients had increased PaCO2. and 2 of 15 patients had episodes of hemoglobin oxygen saturation of less than 90%. Postoperatively. 1 and 2 h after arrival in the recovery room. patients who received morphine had lower pain scores than did those who received nalbuphine 10 or 20 mg (P less than 0.05). All 6 patients who received morphine had satisfactory analgesia. Two of 4 patients who received nalbuphine 10 mg and all 5 who received nalbuphine 20 mg were withdrawn from the study because of inadequate analgesia (morphine vs. nalbuphine 10 mg. not significant; morphine vs. nalbuphine 20 mg. P less than 0.01). Two patients who received morphine had persistently increased PaCO2 postoperatively. Two patients who received morphine had episodes of apnea and slow respiratory rate. which were most frequent 6 h after arrival in the recovery room. We conclude that lumbar epidural nalbuphine does not provide adequate analgesia after thoracotomy.
Correlation of emergency health care use, 911 volume, and jail activity with welfare check distribution, STUDY OBJECTIVES: The purpose of this study was to examine the relationship among emergency health care use. 911 call volume. and jail admissions with the timing of the distribution of General Assistance. Aid to Families With Dependent Children. and Minnesota Supplemental Aid welfare checks. DESIGN: This was a retrospective study analyzing previously collected census and welfare check distribution data. SETTING: The data used in this study were obtained from the Hennepin County Medical Center. the Hennepin County jail and alcoholic receiving center. and Department of Economic Assistance. INTERVENTIONS: The daily census for the years 1986 through 1988 in the Hennepin County Medical Center emergency department. ED resuscitation room. pediatric ED. crisis intervention center. urgent care center. and alcoholic receiving center was obtained. The numbers of daily ambulance runs. nonelective hospital admissions. Hennepin County 911 calls. and Hennepin County jail admissions for the same years also were obtained. Means for each day of the month were computed across the 36 months of observation. These data were correlated with the number of days elapsed since the monthly issuance of the General Assistance. Aid to Families With Dependent Children. and Minnesota Supplemental Aid welfare checks. MEASUREMENTS and MAIN RESULTS: There were significant correlations between the number of days after distribution of the checks and the average values of the census of the alcoholic receiving center (r = -.96. P less than .00001). the ED (r = -.80. P less than .0001). ambulance runs (r = -.68. P less than .0001). 911 calls (r = -.45. P = .01). jail admissions (r = -.45. P = .01). nonelective hospital admissions (r = -.44. P = .01). and the crisis intervention center visits (r = -.39. P = .03). CONCLUSIONS: The findings suggest that scheduling and staffing practices of various emergency service areas in Hennepin County reflect patient load variation associated with time of welfare check distribution. Systematic variation of time or amount of welfare could lead to improved distribution and reduction of emergency services demand.
Limitations of open-chest cardiac massage after prolonged, untreated cardiac arrest in dogs, STUDY OBJECTIVES: Open-chest cardiac massage is an effective method of resuscitation if instituted within 15 minutes of normothermic cardiac arrest that has failed to respond to ongoing closed-chest CPR efforts. The usefulness of invasive forms of CPR after various periods of untreated cardiac arrest is less certain. This study was performed to determine the effectiveness of open-chest resuscitation after prolonged periods of untreated cardiac arrest. SETTING AND DESIGN: Prospective. controlled laboratory investigation using an animal model of cardiac arrest. Open-chest cardiac massage initially was compared to standard closed-chest compression CPR. The efficacy of open-chest CPR then was evaluated after ten and 40 minutes of untreated ventricular fibrillation. TYPE OF PARTICIPANTS: Twenty mongrel dogs (24 +/- 1 kg). MEASUREMENTS AND MAIN RESULTS: After 20 minutes of untreated ventricular fibrillation. open-chest resuscitation was significantly better than closed-chest efforts for the production of coronary perfusion pressure (58 +/- 14 vs 2 +/- 1 mm Hg; P less than .05) and initial resuscitation success (five of five vs one of five; P less than .03). Open-chest cardiac massage was equally effective for initial resuscitation if begun after ten or 20 minutes of untreated ventricular fibrillation (five of five vs five of five). but if untreated ventricular fibrillation continued for 40 minutes prior to instituting open-chest massage. no resuscitation benefit was found (none of five; P less than .005). There were marked differences in 24-hour survival depending on the length of time untreated cardiac arrest continued prior to instituting open-chest resuscitation efforts. After 20 minutes of ventricular fibrillation. initial resuscitation was successful with open-chest massage. but long-term survival was poor. CONCLUSION: Open-chest cardiac massage did not produce long-term survival if untreated cardiac arrest persisted for 20 or more minutes prior to invasive resuscitation efforts.
Serum glucose after intraperitoneal infusion of 5% dextrose solution, STUDY OBJECTIVE: This study investigated the use of intraperitoneal (IP) glucose infusion as a therapy for hypoglycemia. DESIGN: Randomized. placebo-controlled. crossover design. with each animal serving as its own control. SETTING: Laboratory investigation. TYPE OF PARTICIPANTS: Seven female New Zealand White rabbits with a mean weight of 3.7 kg. INTERVENTIONS: Each animal was subjected to three experiments separated by a four-day period. After baseline measurements. the following interventions were undertaken: Control day. no treatment; placebo day. 10 mL/kg 0.9% normal saline solution IP; and treatment day. 10 mL/kg 5% dextrose solution IP. MEASUREMENTS AND MAIN RESULTS: Serial serum glucose levels were obtained. Compared with control and placebo. the mean absolute serum glucose value of the treatment group was significantly higher beginning at ten minutes after intervention and continuing until conclusion of the study at 30 minutes. For these time points. the mean increase in serum glucose levels (percent change) of the treatment group compared with the control group was as follows: ten minutes. 15.5 mg/dL (0.86 mmol/L) (11%). P less than .01; 15 minutes. 20.6 mg/dL (1.14 mmol/L) (14%). P less than .01; 20 minutes. 36.5 mg/dL (2.03 mmol/L) (26%). P less than .001; and 30 minutes. 34.7 mg/dL (1.93 mmol/L) (24%). P less than .001. CONCLUSION: Glucose instilled into the peritoneal cavity of rabbits is absorbed rapidly into the systemic circulation.
Prevalence of HIV antibody in a noninner-city university hospital emergency department, STUDY HYPOTHESIS: To determine the prevalence of antibody to human immunodeficiency virus (HIV) in trauma and nontrauma patients not identified as having known HIV infection in a noninner-city university teaching hospital emergency department. and to determine the frequency with which treating emergency physicians are knowledgeable of patients' risk factors for HIV infection. POPULATION: ED patients between 18 and 59 years old with injuries that met trauma center triage criteria or with nontrauma-related illness who had blood drawn for physician-requested laboratory tests and for whom an extra aliquot of blood was available for HIV antibody testing. METHODS: All serum samples were first tested for antibody to HIV by enzyme-linked immunosorbent assay. If positive. the specimen was retested. All repeatedly reactive specimens were analyzed by Western blot test. The treating physician completed a questionnaire regarding the patient's illness and risk factors for HIV infection after the patient's care was completed. RESULTS: Two of 100 major trauma patients (confidence interval. 0% to 5%) and seven of 100 nontrauma patients (confidence interval. 2% to 12%) had antibody to HIV. The seropositive rate by age and clinical group varied from 0% to 12.5%. with the highest rates in the 30- to 39-year-old group of nontrauma patients. The difference in proportions of seropositivity between the sexes was not statistically significant. Physicians obtained information regarding homosexual or bisexual behavior. IV drug use. and hemophilia from 52% of the nontrauma patients and only 17% of trauma patients. None of 30 trauma patients for whom data were available and only two of the 100 nontrauma patients gave a history of any high-risk behavior. CONCLUSION: Although the sampling technique we used has limitations. the prevalence of HIV infection in our noninner-city ED is similar to that recently reported from inner-city EDs. This is in contrast to previous reports of low rates of HIV infection among ED patients in nonurban settings. Physician assessment of risk factors was incomplete in the majority of our patients. Patients rarely acknowledged any high-risk behavior. It is essential that emergency health care workers take maximum diligence to prevent exposure to blood and other body fluids from all ED patients.
Median frequency--a new parameter for predicting defibrillation success rate, STUDY HYPOTHESIS: Current American Heart Association guidelines recommend immediate defibrillation of ventricular fibrillation. When this is unsuccessful. there are no guidelines to help determine the optimum time at which to defibrillate after the administration of an alpha-adrenergic agonist. Previous studies have shown that the median frequency of the ventricular fibrillation ECG signal correlates with myocardial perfusion during CPR. We hypothesized that median frequency could predict the success of defibrillation and thus accurately determine the most appropriate time at which to defibrillate during ventricular fibrillation. STUDY POPULATION: Twenty-two mixed-breed swine weighing more than 15 kg were studied. METHODS: Ventricular fibrillation was induced electrically. and the ventricular fibrillation ECG signal was analyzed using fast Fourier analysis. After ten minutes of ventricular fibrillation. mechanical CPR was begun. After three minutes of CPR. the animals received one of three alpha-adrenergic agonists and CPR was continued. Defibrillation was attempted three and one-half minutes after drug administration. The average median frequency 20 seconds before defibrillation was calculated. Sensitivity and specificity of median frequency with respect to defibrillation success were determined. RESULTS: A median frequency of 9.14 Hz had a sensitivity of 100% and a specificity of 92.31% in predicting the results of defibrillation in this model. CONCLUSION: The median frequency may serve as a valuable parameter to guide defibrillation therapy during ventricular fibrillation.
The effects of positive end-expiratory pressure on respiratory resistance in patients with the adult respiratory distress syndrome and in normal anesthetized subjects, We investigated the effects of positive end-expiratory pressure (PEEP) upon respiratory resistance during mechanical ventilation in 21 subjects anesthetized for surgery (normal subjects) and in 11 patients with the adult respiratory distress syndrome (ARDS). We measured tracheal pressure (Ptr) near the end of the endotracheal tube through a 1.5-mm ID catheter and airflow (V) at 0. 5. and 10 cm H2O PEEP (normal subjects) and at 0. 5. 10. 15. and 20 cm H2O PEEP (patients with ARDS). We computed respiratory system static elastance (Estrs). maximal (Rrsmax) and minimal (Rrsmin) inspiratory resistance by the end-inspiratory occlusion method during constant-flow inflation. Rrsmin represents the ohmic respiratory resistance. whereas Rrsmax is Rrsmin plus the additional respiratory impedance caused by the stress adaptation phenomena of the respiratory system tissues and to time constant inhomogeneities between lung units (pendelluft). The difference (Rrsmax - Rrsmin) has been termed DRrs. We also computed expiratory resistance (Rrsexp) at preselected volume (50% of expiration; Rrsexp50) and flow (0.3 L/s; Rrsexp0.3) using the equation: Rrsexp = (Pelrs(t) - Ptr(t]/Flow(t). where elastic recoil pressure (Pelrs) at time t was computed as:Estrs . V(t) + PEEP. in which V(t) is the volume above end-expiratory volume at time t. We found that (1) at PEEP 0. expiratory resistances (Rrsexp50: 7.38 +/- 1.92 versus 5.35 +/- 1.97 cm H2O.L-1.s) and DRrs (3.08 +/- 1.9 versus 1.66 +/- 0.77 cm H2O.L-1.s) were significantly higher in the ARDS group than in the normal group.
The effect of obliterative bronchiolitis on breathing pattern during exercise in recipients of heart-lung transplants, The more rapid and shallow ventilation pattern seen during exercise in patients with obstructive and/or restrictive lung disease has been attributed by some investigators to the effects of vagal afferents from intrapulmonary receptors. Recipients of heart-lung transplants (HLTR) offer a unique opportunity to test this hypothesis since they have denervated lungs and may develop obliterative bronchiolitis after organ rejection. We thus compared the ventilation responses to incremental bicycle ergometry of five HLTR with relatively normal pulmonary function (HLTR-N) and four with bronchiolitis obliterans (HLTR-O). We compared the slopes of the linear portion of the tidal volume versus inspired minute ventilation relationship of both groups. The rate of rise of tidal volume (VT) (slope of VT versus VI) was greater in HLTR-N (0.31 +/- 0.004) than in HLTR-O (0.023 +/- 0.007) (p less than 0.05). This corresponded to a slower increase in respiratory rate (RR) (slope of RR versus Vl/cm) in HLTR-N (0.055 +/- 0.005) than in HLTR-O (0.083 +/- 0.019) (p less than 0.01). Furthermore. values for VT. inspiratory time (TI). and duty cycle (TI/Ttot) measured during exercise at the VT break point were all significantly lower in the HLTR-O than in HLTR-N. We also evaluated the ability of HLTR with lung disease to regulate their ultimate level of ventilation during maximal exercise.
The destructive index and early lung destruction in smokers, The destructive index (DI). a measure of alveolar septal damage and emphysema. has been proposed as a sensitive index of lung destruction that closely reflects functional abnormalities. especially loss of elastic recoil. To better understand the progression of lung destruction in smokers. we studied the contribution of its principal components: breaks in the alveolar septa (DIb) and the presence of emphysematous spaces (DIe). and compared them to the mean linear intercept (Lm) and DI as originally described. To do this we employed lungs obtained at autopsy from non-smokers and smokers. Lungs were selected by emphysema score (ES) so that all cases were emphysema free (nonsmokers and seven smokers) or had minimal emphysema (nine smokers; ES = 5). Of these indices. only DIb was significantly increased in the lungs of smokers: 17.8 +/- 1.2 versus 12.4 +/- 1.6. p less than 0.05. We also investigated the regional distribution of destruction by comparing results in upper and lower lobes. DIe. but not DIb. was significantly increased in upper lobes of smokers. These data support the notion that increases in DI in the lungs of smokers that occur before increases in Lm or ES reflect the presence of alveolar septal breaks and highlight the importance of alveolar septal destruction as a precursor to the development of airspace enlargement in the lungs of cigarette smokers.
Idiopathic pulmonary fibrosis. Abnormalities in the bronchoalveolar lavage content of surfactant protein A, Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung characterized by an inflammatory infiltrate. alveolar type II cell hypertrophy and hyperplasia. and ultimate parenchymal scarring. The phospholipid composition of the surface-active material recovered by bronchoalveolar lavage (BAL) is abnormal in this disease. In the present study we have extended the analysis of surfactant components in IPF to include the major surfactant-associated protein. surfactant protein A (SP-A). SP-A has been reported to be essential for the formation of tubular myelin. to facilitate the adsorption of phospholipid to the air/liquid interface. and to stimulate uptake and inhibit secretion of surfactant in vitro. The BAL of 25 normal volunteers and 42 patients with interstitial lung disease (ILD) was analyzed for surfactant protein A content by ELISA and for phospholipids. The changes in BAL components were correlated to histopathologic markers at open-lung biopsy. clinical status. and survival. The total phospholipid (PL) recovered at lavage was reduced in patients with IPF relative to normal volunteers (p less than 0.0005). In addition. the percentage of phosphatidyl-glycerol (% PG) was decreased in patients with IPF (p less than 0.0001). whereas the percentage of phosphatidylcholine that was saturated was not altered. The content of surfactant protein A in lavage was reduced. even when normalized for the total amount of surface-active material recovered (SP-A/PL) (p less than 0.007). The reduction in SP-A was not specific to IPF but also occurred in other interstitial lung diseases.
The role of platelet-activating factor in the pulmonary response to inhaled bacterial endotoxin, Quantitative morphometric analyses were carried out on animals subjected to aerosols of bacterial endotoxin (LPS) to further define the role of platelet-activating factor (PAF) in the development of pulmonary injury. Hamsters were exposed to either saline aerosol or dilute aerosols of LPS (4 micrograms/m3) for standard lengths of time. Within each aerosol exposure group. animals were further subdivided into groups receiving either the PAF receptor binding antagonist. RP 48740. or saline injections. LPS inhalation resulted in decreased fixed lung volume. increased sequestration of polymorphonuclear leukocytes and platelets in pulmonary capillaries. increased type I epithelial and endothelial cellular volumes. increased cellular interstitium. and increased endothelial pinocytotic vesicles. Treatment with RP 48740 either attenuated or abolished the ability of inhaled LPS to induce these structural alterations. The PAF antagonist also inhibited LPS-induced increases in pulmonary capillary permeability. It is concluded that PAF is one of the major injury-promoting mediators released upon inhalation exposure to environmentally realistic concentrations of bacterial endotoxin. A major but not exclusive target of this mediator is the pulmonary vascular endothelium.
Smoking and symptom effects on the curves of lung function growth and decline, Numerous studies have examined the natural time course of human lung function growth and decline throughout life. In most of these studies the investigators used statistical models that required a priori assumptions concerning the underlying form or structure of the lung function data. thus introducing possible biases. In this study we used recently developed nonparametric regression (spline) techniques to describe the evolution of lung function measures with age. This procedure yields an optimally fitted smooth curve through the data and estimates of the process velocity and does not require assumptions concerning the underlying shape of the data curves. The lung function growth-velocity curves are used to estimate the age of growth cessation. This technique was applied to the FVC. FEV1. and the FEV1/FVC ratios of 1.295 females and 1.230 males who were tested in at least one of the first nine surveys of the Tucson epidemiologic study of airway obstructive diseases. Data were analyzed stratified according to gender. smoking status. and respiratory symptoms or diseases. The results indicate large differences between the fitted FEV1 and FEV1/FVC smoothed curves of the various subgroups compared with asymptomatic nonsmokers. These differences were most pronounced in the adult symptomatic smokers. who had higher rates of lung function loss that also began at earlier ages. for both sexes. No significant differences were observed between asymptomatic and symptomatic nonsmokers. most likely because of the reduced number of symptomatic nonsmokers. particularly among the males.
Morphologic changes in lungs of anesthetized sheep following intravenous infusion of recombinant tumor necrosis factor alpha, Tumor necrosis factor alpha (TNF alpha) is a monokine released in response to endotoxin and has been suggested as a primary mediator of endotoxic shock. We have recently demonstrated that infusion of recombinant human tumor necrosis factor alpha (rTNF alpha) into sheep elicits a physiologic response in the lung that closely resembles endotoxemia. The present study examines the morphologic changes that accompany these alterations in pulmonary physiology. Five anesthetized. open-chest sheep received 0.01 mg/kg of protein (2.24 x 10(7) U rTNF alpha/mg) intravenously over 30 min. Lung biopsy tissue for light and electron microscopy was obtained from random lobes 7.5. 15. 30. 60. 120. 180. and 240 min after beginning the infusion. Pulmonary (Ppa) and systemic arterial pressures. cardiac output. and peripheral blood leukocyte number and differential counts were monitored throughout the study. Three control animals were treated in a similar manner but received either saline (n = 1) or rTNF alpha denatured by boiling for 30 min (n = 2). rTNF alpha caused an early increase in Ppa and peripheral blood leukopenia. Light microscopy revealed a threefold increase in the number of granulocytes per 100 alveolar profiles by 30 min and a fivefold increase by 2 h. From 60 min. increased alveolar wall thickness. red cell congestion. and peribronchovascular edema were apparent; from 2 h. there was increased cellularity of the alveolar walls and mononuclear cell infiltration of perivascular connective tissue. Electron microscopy revealed damage to alveolar Type I and II pneumonocytes and progressive endothelial injury from 30 min.
Nonspecific bronchial reactivity in asthmatic children depends on severity but not on age, Bronchial reactivity to inhaled methacholine was measured by the steady-state tidal breathing method in asthmatic children aged 1 to 17 yr. The children were divided into three clinical groups according to their minimal therapeutic requirements: mild asthma. children requiring infrequent treatment with inhaled beta-agonists (81 patients); moderate asthma. children requiring daily preventive treatment with either cromolyn sodium or slow-release theophylline (67 patients); and severe asthma. children requiring daily preventive treatment with oral or inhaled steroids (34 patients). They were also divided into three age groups: from 1 to 6 yr. tested by using bronchial provocation with tracheal auscultation (BPTA) to determine the methacholine concentration causing wheezing (PCW); and from 7 to 11 yr and 12 to 17 yr. using lung function testing to determine the concentration causing a 20% fall in FEV1 (PC20). For the whole group the mean level of bronchial reactivity to methacholine correlated inversely with the severity of bronchial asthma according to the minimal drug requirements (p less than 0.0001) and was similar over the whole age range (p less than 0.9965) for each severity grouping. In the older children the difference between moderate and severe asthma was not significant. but this may have been a result of the effect of corticosteroids in the severe group. We concluded that age has no significant effect on the methacholine response in asthmatic children over a wide age range.
Effect of cold air on the bronchial response to inhaled histamine in patients with asthma, We measured the concentration of inhaled histamine required to reduce the FEV1 by 20% (PC20) in seven asthmatic patients immediately following the inhalation of warm air (mean temperature +/- 1 SD. 21.1 +/- 1.1 degrees C) and following cold air inhalation (-10.2 +/- 5.0 degrees C). Patients breathed either warm or cold air for 10 min before 30-s challenges with doubling concentrations of aerosolized histamine that were nebulized while the subject breathed warm air. Before histamine inhalation minute ventilation (VI) was 8.41 +/- 1.38 L/min breathing warm air and 7.86 +/- 0.97 L/min breathing cold air. Respiratory heat exchange (RHE) was 0.25 +/- 0.05 kcal/min with warm air and 0.24 +/- 0.03 kcal/min with cold air. The PC20 obtained following cold air breathing (0.48 +/- 4.63 mg/ml) was lower than that following warm air breathing (0.85 +/- 4.60 mg/ml; p less than 0.02). We conclude that breathing cold air increases the bronchial reactivity to inhaled histamine in asthmatic patients.
Cholinergic mechanisms involved with histamine hyperreactivity in immune rabbit airways challenged with ragweed antigen, The present study examines the effects of aerosolized ragweed antigen (RAg) on tracheal (TSM) and bronchial (BSM) smooth muscle contraction in rabbits actively immunized with RAg. Airway segments were isolated 48 h after aerosol challenge with either saline or RAg. and airway contractile responses to histamine were measured. Histamine remained a weak agonist in TSM segments after RAg challenge. In contrast. BSM responsivity to histamine was significantly increased after RAg challenge as evidenced by a parallel shift to the left (i.e.. Fslope = 3.2; degrees of freedom (df) = 1.224; p = NS and Felev = 19.4; df = 1.225; p less than 0.001) of the mean dose-response relationship. In sham-immunized rabbits. the BSM contractile responses to histamine were similar after aerosol challenge with either RAg or normal saline. After the BSM segments were treated with 10(-6) M atropine. there was no significant difference in histamine reactivity between the RAg- and saline-challenged groups. The augmented BSM contractile response to histamine was only partially inhibited in the presence of either tetrodotoxin or hexamethonium. We conclude that 48 h after a single in vivo exposure to antigen in immune rabbits. the airway contractile responses to histamine in vitro are increased in BSM but not in TSM and that the mechanism of the augmented contractile responses in BSM likely involves the facilitated neural release of acetylcholine from both preganglionic and postganglionic sites.
Antigen-induced mediator release in primates, We examined the release of bronchoactive mediators into the airways of allergic primates during the acute response to specific antigen inhalation. Twelve adult male cynomolgus monkeys (Macaca fascicularis) with a naturally occurring respiratory sensitivity to inhaled Ascaris suum extract were anesthetized and intubated for each study. Respiratory system resistance (Rrs) and dynamic lung compliance (CLdyn) were measured before and after antigen inhalation. and the release of mediators into the airways was assessed by bronchoalveolar lavage (BAL). BAL samples were concentrated approximately 5-fold before quantitation of LTC4 and PGD2 by RP-HPLC and radioimmunoassay and histamine by a fluorometric assay. Antigen inhalation resulted in a 40-fold increase in BAL levels of i-LTC4 (1.5 +/- 0.7 to 41.6 +/- 12.7 ng. p less than 0.01). a 10-fold increase in i-PGD2 (2.4 +/- 0.9 to 25.9 +/- 5.5 ng. p less than 0.01). and a 20-fold increase in BAL histamine (1.0 +/- 1.5 to 21.4 +/- 2.3 micrograms. p less than 0.01). Dexamethasone (n = 7) inhibited the antigen-induced increase in BAL i-LTC4 (71 +/- 6%. p less than 0.01) and i-PGD2 (52 +/- 8%. p less than 0.05) while weakly inhibiting histamine release (43 +/- 10%). Indomethacin (n = 7) had a variable effect on i-LTC4 levels (6 +/- 51%). strongly inhibited i-PGD2 (88 +/- 9%. p less than 0.01). and had no effect on histamine release (25 +/- 8%). Pretreatment with iodoxamide tromethamine significantly blocked the release of each mediator. but mepyramine. an H1 antagonist. had no effect on mediator release.
Ventilation-perfusion mismatch after methacholine challenge in patients with mild bronchial asthma, To investigate the effects of methacholine (MTH) challenge on spirometry. lung mechanics. respiratory gases. and ventilation-perfusion (VA/Q) distributions. 16 subjects 16 to 58 yr of age with stable mild asthma (FEV1. 92 +/- 5% [SEM] predicted; FEF25-75. 71 +/- 7% predicted; respiratory system resistance (Rrs) at 4 Hz. 4.6 +/- 0.4 cm H2O/L-1 s; PaO2. 88 +/- 3 mm Hg; AaPO2. 23 +/- 3 mm Hg) were recruited. Baseline VA/Q distributions were unimodal and relatively narrow in 12 patients and modestly bimodal in the other four. The dispersion of pulmonary blood flow (log SD Q) was slightly enlarged (0.71 +/- 0.09) and that of ventilation (log SD V) was normal (0.57 +/- 0.04) (normal range. 0.3 to 0.6); an index of overall VA/Q heterogeneity (DISP R-E*) was also mildly abnormal (5.3 +/- 0.8) (normal values less than 3.0). After MTH challenge. FEV1. FEF25-75. and PaO2 fell (to 62 +/- 3 and 35 +/- 3% predicted. and to 71 +/- 1 mm Hg. respectively). whereas Rrs (p less than 0.001 each). minute ventilation (p less than 0.02). heart rate (p less than 0.01). and AaPO2 increased (p less than 0.001). VA/Q relationships mildly to moderately worsened (log SD Q increased to 0.98 +/- 0.04 [p less than 0.01]. log SD V to 0.79 +/- 0.04. and DISP R-E* to 9.8 +/- 0.6 [p less than 0.001 each]). Qualitatively. the pattern of blood flow distribution was broadly unimodal in 13 patients and modestly bimodal in three. of whom only one had a bimodal baseline distribution.
A direct correlation of the resolution of pseudophakic cystoid macular edema with acetazolamide therapy, We report the case of a patient with pseudophakic cystoid macular edema whose visual acuity improved promptly with oral administration of 500 mg of acetazolamide extended-release capsules BID for two weeks. However. vision worsened again within two weeks of discontinuation of the treatment. On resumption of acetazolamide therapy for three weeks. and its slow withdrawal during the following three weeks. the macular edema eventually resolved. and vision returned to normal. Our observation provides a direct correlation of the resolution of pseudophakic cystoid macular edema with acetazolamide therapy and shows the importance of tapering the doses of this regimen.
Adenocarcinoma: an unusual presentation, A young pregnant woman had facial swelling in the upper nasal region. This was initially considered to be lymphedema in view of a history of past severe facial acne. A biopsy was done when the lesion progressed; the specimen showed adenocarcinoma. This responded well to radiotherapy. the favorable response being maintained for more than 24 months.
Sympathetic ophthalmia associated with anterior chamber intraocular lens implantation, We describe a rare case of sympathetic ophthalmia associated with intracapsular cataract extraction and anterior-chamber intraocular lens implantation. This occurred three months after an immediate postoperative complication of pupillary block. flat anterior chamber. and wound dehiscence with one of the lens haptics dissecting into the subconjunctival space. Both eyes developed granulomatous panuveitis. which partially responded to medical treatment. Removal of the anterior-chamber intraocular lens and pars plana vitrectomy resulted in control of the uveitis with significant visual improvement. A pathologic examination of material from the anterior chamber and vitreous showed lymphocytes. histiocytes. and pigment cells contributing to the diagnosis of sympathetic ophthalmia. To the best of our knowledge. this is the first report of an intraocular lens implicated as a cause of sympathetic ophthalmia.
A case of progressive cone dystrophy with marked asymmetry in the fundus, In those with progressive cone dystrophy. affected patients have similar lesions bilaterally. We examined a patient with progressive cone dystrophy who had a bull's-eye lesion OD and choroidal vascular atrophy OS.
Long-term effects of cyclophosphamide and colchicine treatment in Behcet's disease, We assessed the long-term effects of cyclophosphamide and colchicine on visual prognosis and attack frequency in 64 patients with Behcet's disease who were studied in two separate groups between the years of 1976 and 1989. No statistically significant positive changes in visual acuity or attack frequency which might be attributed to the treatment could be shown when the period of treatment was compared with the period after treatment.
Punctate inner choroidopathy and its differential diagnosis, The diagnosis of chorioretinal diseases largely depends on their clinical presentation rather than etiologic or systemic investigations. We report on a patient whose examination revealed a peculiar fundus pattern. almost completely different from disorders such as multifocal choroiditis. presumed ocular histoplasmosis. myopic degeneration. acute multifocal placoid pigment epitheliopathy. vitiliginous chorioretinitis. and punctate outer retinal toxoplasmosis. It resembled punctate inner choroidopathy. described by Watzke in 1984.
Delayed diagnosis of diabetic retinopathy in black and Hispanic patients with diabetes mellitus, We examined 51 black and 35 Hispanic consecutive patients with noninsulin-dependent diabetes mellitus from similar socioeconomic backgrounds who were evaluated initially for diabetic retinopathy. The mean ages were 58 years for the Hispanics and 53 years for the blacks (P greater than .05). Sixty-five percent of the Hispanics were women. as were 68.6% of the blacks (P greater than .05). The mean duration between the diagnosis of the diabetes mellitus and the initial diagnosis of the retinopathy was 11.5 years for the Hispanics and 12.2 years for the blacks (P = .671). The percentage of patients with severe diabetic retinopathy (preproliferative or proliferative) at the time of initial diagnosis was 42.9% for the Hispanics and 37.3% for the blacks (P greater than .10). Although no significant differences were found between the two groups. the high percentage of patients in both groups (42.9% and 37.3%) with severe diabetic retinopathy at the time of initial presentation suggests that earlier patient referral from primary-care physicians and better patient education about the need for earlier eye examinations should be encouraged in these two groups.
Tinnitus suppression by cochlear implants, The beneficial effects of cochlear implants on tinnitus have been noted in several studies. but few detailed appraisals of the phenomenon have been made. Six patients fitted with the UCSF/Storz cochlear implant device were studied. The effects of use of the implant device on tinnitus were monitored. and suppression of tinnitus was tracked throughout periods of stimulation and poststimulation. Tinnitus was effectively suppressed in five of six patients with the device on and with noise input. and reduction of perceived tinnitus loudness occurred in four of six with the device on but without acoustic input to the speech processor. Unilateral stimulation frequently resulted in bilateral tinnitus suppression. These studies reveal that profound tinnitus suppression is obtained by patients using their cochlear implants. Further work is required to quantify the optimal mode of stimulation. but these findings suggest that tinnitus sufferers may ultimately benefit from development of electrical stimulation tinnitus suppression devices.
Effects of preoperative electrical stimulability and historical factors on performance with multichannel cochlear implant, We investigated the relationship between results of preoperative transtympanic electrical promontory stimulation. duration of deafness. postoperative implanted psychophysical results. and postoperative speech and speech sound recognition as indicated by a battery of five tests. Our subjects were 10 patients implanted with the Cochlear Corporation multielectrode implant. 1 year postimplantation. with a minimum of 17 active electrodes programmed in the bipolar + 1 mode. The results indicated that preoperative promontory thresholds. the slope of the threshold function. and the duration of auditory deprivation are excellent predictors of postoperative speech and speech sound recognition in the auditory (processor alone) mode. These results have significant implications for patient selection and counseling.
Abolition of optokinetic afternystagmus by aminoglycoside ototoxicity, We studied optokinetic afternystagmus in eight subjects with loss of or impairment of vestibular function due to ototoxic antibiotics. We found that the initial amplitude. the time constant. and the slow-phase cumulative eye position of optokinetic afternystagmus were significantly reduced in the patients. Slow-phase cumulative eye position most reliably distinguished our patients' responses from those of a normal group.
Polarized light examination and photography of the skin, Light reflected from skin has two components: regular reflectance. or "glare" arising from the surface. and light backscattered from within the tissue. The regular reflectance contains the visual cues related to surface texture. whereas the backscattered component contains the cues related to pigmentation. erythema. infiltrates. vessels. and other intracutaneous structures. Unlike the backscattered component. regular reflectance preserves the plane of polarization of polarized incident light. Thus. viewing skin through a linear polarizer. under linearly polarized illumination. separates the two components of tissue reflectance. Thirty patients were examined and photographed in this manner. When the planes of polarization are parallel. images with enhanced surface detail are obtained. When the planes are orthogonal. wrinkles and surface detail disappear. and an enhanced view of vasculature and pigmented lesions is obtained. Simple. clinically useful techniques are presented.
Cigarette smoking and flap and full-thickness graft necrosis, The association between cigarette smoking and necrosis of flaps and full-thickness grafts was analyzed in 220 patients. Review of a series of 916 flaps and full-thickness grafts revealed 44 patients in whom some degree of tissue necrosis occurred. These patients with necrosis were age and gender matched with 176 controls randomly selected from the remaining 872 patients. Current high-level smokers. that is those smoking one or more packs per day. had necrosis develop approximately three times more frequently than never smokers. low-level smokers (less than one pack per day). or former smokers (95% confidence interval. 1.2 to 8.2). Former smokers (relative risk. 1.4; 95% confidence interval. 0.6 to 3.2) and low-level smokers (relative risk. 1.1; 95% confidence interval. 0.2 to 6.1) were at a negligible increased risk for necrosis that was not significantly different from never smokers. Once tissue necrosis developed. the median percent of the visible flap or graft tissue that necrosed was approximately threefold greater among current smokers (regardless of the number of packs per day smoked) than never smokers.
'Irritants' increase the response to an allergen in allergic contact dermatitis, We studied the effect of "irritants" on the response to an allergen in 15 patients. Dilutions of allergens were applied in duplicate. and 24 hours later they were removed and sodium lauryl sulfate (11 subjects) or anthralin (dithranol) (four subjects) was applied for a further 24 hours to one set of patches. Control dilutions of irritants alone were applied. Responses were measured objectively at 72 hours. The response to both allergen and irritant was greater than to either alone. Doses of allergen. which did not produce a response when applied alone. produced a response when an irritant was added. Irritants therefore increase the allergic contact dermatitis response and may explain the presence of contact dermatitis in patients with negative patch tests.
Hendersonula toruloidea and Scytalidium hyalinum. Review and update, Hendersonula toruloidea and Scytalidium hyalinum are opportunistic organisms that can produce tinea pedis. tinea manuum. and tinea unguium. These infections. which clinically mimic those caused by dermatophytes but are caused by nondermatophyte agents. are correctly called dermatomycoses. When examined microscopically with potassium hydroxide. the agents of these disorders resemble those of dermatophytosis. showing narrow. septate. branching hyphae. It. therefore. becomes important to culture samples taken from sites with these tineas on cycloheximide-free agars even if they are potassium hydroxide-positive to rule out nondermatophyte mycoses. Correct identification becomes imperative since neither H toruloidea nor S hyalinum responds to conventional therapy. We review these diseases with emphasis on clinical appearance and differentiation from dermatophytosis. We also report four cases of S hyalinum infection of the nail or feet.
Verification of a new clinicopathologic staging system for colorectal adenocarcinoma, Rectal adenocarcinoma is said to have a poorer outcome than colon adenocarcinoma when compared on the basis of Dukes' staging. However a new staging system. determined by a multivariate analysis of 147 patients with rectal adenocarcinoma. has revealed three other variables significantly related to outcome. Therefore this study analyzed the authors' experience with colonic carcinoma during the same time period as they had studied for rectal carcinoma to determine whether the new staging system is valid for colon carcinoma as well. and. if so. to compare the outcome of patients with colon and rectal carcinoma on the basis of this new staging. A total of 603 patients with 611 colonic adenocarcinoma were operated on at the University of Chicago Medical Center between 1965 and 1981. Two hundred seventy-nine adenocarcinomas (45.7%) were located proximal to the splenic flexure and 332 (54.3%) were located between the splenic flexure and the rectosigmoid. Four hundred sixty-two patients underwent segmental colectomy. 46 subtotal colectomy. 26 total colectomy. 18 proctocolectomy. 5 abdominal-perineal resection. 1 appendectomy. while 20 had local excision of the tumor through colotomy and 25 had permanent diverting stoma as the only procedure. The operative mortality rate was 6.1% in the whole group. but was only 2.7% in the group of potentially curable patients. Complete follow-up was obtained in all patients. To validate a previous staging system for Dukes' B and C rectal adenocarcinoma. the authors investigated the correlation between 5-year survival for colonic carcinoma patients and all relevant variables that they had considered potentially meaningful in the previous study with rectal adenocarcinoma. The resulting multivariate analysis using Cox regression showed that the four variables found previously to be significantly related to outcome for rectal adenocarcinoma patients (stage. race. tumor morphology. and vascular and/or lymphatic microinvasion) were the only four variables significantly (p less than 0.05) associated with outcome for colonic adenocarcinoma patients. In addition. by using the results of their previous staging system for rectal adenocarcinoma patients. they 'predicted' the 5-year survival rates of the colon adenocarcinoma patients. divided in 16 staging subgroups. In subgroups of at least 15 patients. the rectal staging system predicted the outcome to within 1 to 6 percentage points of the observed outcome of the colonic adenocarcinoma patients. Thus this study validates this staging system. incorporating stage. race. tumor morphology. and microinvasion to predict 5-year survival rate more accurately than Dukes' staging alone for both colon and rectal adenocarcinoma.(ABSTRACT TRUNCATED AT 400 WORDS).
Diagnosis and management of retroperitoneal soft-tissue sarcoma, Retroperitoneal soft-tissue sarcomas are locally invasive tumors that remain occult for long periods and grow quite large due to the abdominal cavity's remarkable ability to accommodate these slowly expanding masses with a paucity of attendant symptoms. An open biopsy is required to establish diagnosis definitively. Despite improved imaging techniques and preoperative and intraoperative patient management. resectability has not changed significantly in the past 20 years. Even with an aggressive operative approach. only one half the tumors can be resected completely. and of those. more than 90% recur locally and result in the death of the patient. The addition of adjuvant radiotherapy or chemotherapy has not altered this pattern of local failure. in contrast to promising results with extremity soft-tissue sarcoma. Because of the rarity of these tumors. there is an urgent need to establish a national retroperitoneal sarcoma registry and to form cooperative intergroup studies to evaluate. treat. and apply innovative multimodality combination therapies to these otherwise lethal tumors.
Management and long-term outcome of aortic dissection, All 163 patients admitted to one institution between 1975 and 1988 with aortic dissection were reviewed. Type I and type II patients received grafting of the ascending aorta. with an intraoperative mortality rate of 11%. For type III dissection. management was medical in 53 patients. while 19 required surgery for aortic rupture or expansion. with an intraoperative mortality rate of 11%. The 9- or 10-year survival rates were 29%. 46%. and 29% for types I. II. and III respectively. Of 135 patients with primary aortic dissection. 17 (13%) required subsequent aortic surgery. Cause of late death was other cardiovascular disease in 38%. rupture of another aortic segment in 18%. sudden death in 24%. and other medical conditions in 21%. Although operative therapy for types I and II dissections and reserving operation for selected type III dissections provides acceptable long-term survival. careful follow-up is necessary due to concurrent cardiovascular disease and residual aortic disease.
Plasma gastrin and cholecystokinin response after pylorus-preserving pancreatoduodenectomy with Billroth-I type of reconstruction, Plasma gastrin and cholecystokinin (CCK) responses were measured after a pancreatoduodenectomy (PD) using the Billroth-I type reconstruction combined with distal partial gastrectomy (standard PD) and combined with preservation of the pylorus and the duodenal bulb (PPPD). Six unoperated patients. 4 men and 2 women. were studied as control subjects. Basal plasma levels of gastrin were significantly higher in controls than in patients who had a standard PD (p less than 0.05) and gastrin responses to a meal were also blunted in these patients. In contrast basal and postprandial levels of gastrin after PPPD were significantly higher than these found in patients with standard PD (p less than 0.05). Postprandial gastrin response after PPPD were similar in pattern to these found in controls. Integrated gastrin release after PPPD was less than that of the control but was significantly greater than that in patients with standard PD. Basal plasma levels of CCK in the patients after the standard PD were significantly lower than in controls and significantly higher postprandial levels of CCK were found after PPPD compared to standard PD (p less than 0.05). However integrated CCK from 0 to 120 minutes were not significantly different between PPPD and standard PD groups. Based on these observations concerning hormonal release of gastrin and CCK. preservation of the stomach and the duodenal bulb appears to be a more physiologic reconstructive procedure than the standard PD. In addition the operation probably has more beneficial effect on the injured pancreas in time.
Report of the Council on Scientific Affairs: ultrasonic imaging of the heart: report of the Ultrasonography Task Force, The use of ultrasonography in cardiology has progressed so dramatically that not only is anatomic information available but information can also be derived about cardiac hemodynamics. Applications range from intravascular ultrasonic imaging of coronary atherosclerosis to predictions of the severity of fetal valvular pulmonic stenosis detected in utero. We reviewed cardiac ultrasonography as utilized in B-mode imaging. pulsed and continuous-wave spectral Doppler. and Doppler color flow mapping. We reviewed specialized areas. including stress echo for wall motion analysis. valvular and congenital heart disease applications. and new applications in intraoperative. transesophageal. contrast echography. coronary imaging. and fetal echocardiography. Finally. future applications of quantitative flow mapping and intraluminal and interventional ultrasonography were considered along with the required technological advances.
Human immunodeficiency virus infection among Peace Corps volunteers in Zaire. No evidence for unusual modes of transmission, A prospective study of US Peace Corps volunteers (PCVs) serving in Zaire. central Africa. was undertaken to determine the risk of human immunodeficiency virus (HIV) and hepatitis B virus infection in an acquired immunodeficiency syndrome-aware expatriate population living in an area of high endemicity for both diseases. Of the 338 PCVs who served in Zaire between October 1985 and May 1988. 282 (83%) were enrolled. representing 7776 volunteer-months of service. Analyses of serum samples for HIV and hepatitis B virus were performed on enrollment and at completion of service. All PCVs received extensive education and counseling regarding HIV and acquired immunodeficiency syndrome throughout their stay in Zaire. There were no documented seroconversions to HIV among 282 PCVs who lived in Zaire for periods ranging from 1 to 81 months. with a mean length of stay of 27.4 months. Of the 14 (6.2%) of 226 PCVs tested who had at least one positive serologic marker for infection with hepatitis B virus. none was documented to have seroconverted during service. During the study period. the rate of all sexually transmitted diseases among PCVs in Africa decreased from 131 to 68 per 1000 study population per year. and there were 52 cases of confirmed malaria among volunteers in Zaire. These data suggest that the risk of acquiring infection with HIV or hepatitis B virus in PCVs in Zaire is very low. and there is no evidence for unusual modes of transmission.
Effects of a very-low-calorie diet on long-term glycemic control in obese type 2 diabetic subjects, We tested the hypothesis that the use of a very-low-calorie diet (VLCD) in combination with behavior modification would promote long-term glycemic control in obese type 2 diabetic subjects. Thirty-six diabetic subjects were randomly assigned to a standard behavior therapy program or to a behavior therapy program that included an 8-week period of VLCD. The behavior therapy group consumed a balanced diet of 4200 to 6300 J/d throughout the 20-week program. The VLCD group consumed a balanced diet of 4200 to 6300 J for weeks 1 to 4. followed by a VLCD (1680 J/d of lean meat. fish. and fowl) for weeks 5 to 12. The VLCD group then gradually reintroduced other foods during weeks 13 to 16 and consumed a balanced diet of 4200 to 6300 J/d for weeks 17 to 20. Thirty-three of the 36 subjects completed the 20-week program and the 1-year follow-up. Use of the VLCD produced greater decreases in fasting glucose at the end of the 20-week program and at 1-year follow-up and greater long-term reductions in HbA1. The VLCD group also had greater weight losses at week 20. but weight losses from pretreatment to 1-year follow-up were similar in the two treatment groups. The improved glycemic control with the VLCD appeared to be due to increased insulin secretion. but further research is needed to confirm this.
QRS interval fails to predict coronary disease incidence. The Framingham Study, The Framingham Study cohort of 5209 white men and women was examined to determine the long-term incidence of manifestations of new coronary heart disease as a function of QRS interval on subjects' baseline electrocardiograms (recorded at the 9th biennial examination). Over 18 years of follow-up. age-adjusted incidence of myocardial infarction. angina pectoris. and coronary death appeared unrelated to baseline QRS prolongation in both sexes. by Cox regression. Subjects with left bundle-branch block fared no worse than those with right pattern. These relations held whether or not subjects with baseline electrocardiographic abnormalities other than intraventricular block were excluded from consideration. In sum. QRS duration is an unimportant predictor of coronary disease in this Framingham population.
Iodine 131-labeled metaiodobenzylguanidine scintigraphy and biochemical analyses in suspected pheochromocytoma, Detection of abnormal catecholamine levels and localization of tumor mass are important factors in the diagnosis and treatment of pheochromocytoma. Iodine 131-labeled metaiodobenzylguanidine scintigraphy was performed in 64 patients with suspected pheochromocytoma if their urinary catecholamine levels were borderline or elevated. or if the clinical suspicion for pheochromocytoma was high in spite of normal urinary catecholamine determinations. The 131I-metaiodobenzylguanidine scans were evaluated for abnormal localization of tracer. Twenty-four-hour urine collections were analyzed for vanillylmandelic acid. homovanillic acid. dopamine. epinephrine. and norepinephrine. Thirty of the 64 patients had pheochromocytomas. The 131I-metaiodobenzylguanidine scan had a sensitivity and a specificity of 88%. The 24-hour urine vanillylmandelic acid and norepinephrine measurements had the best sensitivity (97%). while the vanillylmandelic acid and homovanillic acid measurements had the best specificity (91%). In patients in whom the vanillylmandelic acid measurement and the 131I-metaiodobenzylguanidine scan were normal. no pheochromocytomas were found. In patients in whom the vanillylmandelic acid measurement and 131I-metaiodobenzylguanidine scan were abnormal. a pheochromocytoma was always present. The 131I-metaiodobenzylguanidine scan often documents the presence or absence of a pheochromocytoma and provides localization of the tumor in the preoperative evaluation of these patients.
Improved detection and referral of patients with diabetic retinopathy by primary care physicians. Effectiveness of education, We studied the effect of a 4-hour course in recognition and management of diabetic retinopathy on the ability of nonophthalmologist physicians to detect and to appropriately refer patients with sight-threatening diabetic retinopathy. Participants completed a written examination covering case management and performed a total of 340 dilated ophthalmoscopic examinations on selected patients before and 2 weeks following the teaching session. Accuracy of ophthalmoscopy was assessed by comparison with standardized grading of fundus photographs. Scores on the written examination increased from a mean of 49% to 78% correct. The likelihood of failing to detect and appropriately refer patients with proliferative or preproliferative retinopathy decreased from 60% to 15%. Similarly. for patients with maculopathy. the likelihood of failure to detect and to appropriately refer decreased from 83% to 15.6%. These data suggest that education may significantly improve the ability of nonophthalmologists to detect and to appropriately refer patients who are at risk for vision loss.
The treatment of mild hypertension study. A randomized, placebo-controlled trial of a nutritional-hygienic regimen along with various drug monotherapies. The Treatment of Mild Hypertension Research Group, There is no consensus for the optimal treatment program for individuals with mild hypertension. including whether treatment should emphasize life-style changes alone. such as weight loss. reduction of sodium and alcohol intake. and increased physical activity. or whether it should also include a pharmacologic component. The dilemma is accentuated by the availability of many drugs from different classes to lower blood pressure. To study the relative efficacy and safety of a combination of pharmacologic and nutritional-hygienic intervention compared with nutritional-hygienic intervention alone. a double-blind. controlled clinical trial was initiated. Nine hundred two men and women with mild hypertension (average blood pressure. 140/91 mm Hg) were randomized to receive nutritional-hygienic intervention plus one of six treatments: (1) placebo; (2) diuretic (chlorthalidone); (3) beta-blocker (acebutolol); (4) alpha 1-antagonist (doxazosin mesylate); (5) calcium antagonist (amlodipine maleate); or (6) angiotensin-converting enzyme inhibitor (enalapril maleate). After 12 months. weight loss averaged 4.5 kg. urinary sodium excretion was reduced by 23%. and reported leisure-time physical activity was nearly doubled. Systolic and diastolic blood pressure in the group given nutritional-hygienic intervention alone (placebo) were reduced by 10.6 and 8.1 mm Hg. respectively. For participants in the five groups receiving antihypertensive medication in addition to nutritional-hygienic treatment. blood pressure reductions were significantly greater than those achieved with nutritional-hygienic treatment alone (range. 16 to 22 mm Hg for systolic and 12 to 14 mm Hg for diastolic blood pressure). Although differences among treatment groups in certain dimensions of quality of life. self-reported side effects. plasma lipid levels. and biochemical measures were observed. no consistent pattern in the differences was noted. Nutritional-hygienic therapy is an effective first-step treatment for persons with mild hypertension. and significant additional blood pressure lowering with minimal short-term side effects can be achieved by adding one of five different classes of antihypertensive agents.
Niacin revisited. A randomized, controlled trial of wax-matrix sustained-release niacin in hypercholesterolemia, Two hundred one male and female subjects. aged 20 to 70 years. with elevated low-density lipoprotein cholesterol values (in the 75th to 95th percentiles). participated in a randomized. controlled. double-blind study using a new form of niacin (Enduracin). which employs a wax-matrix vehicle for sustained release. Four niacin treatment groups (daily doses of 2000. 1500. 1250. and 1000 mg) were compared with placebo- and diet-treated controls to determine side-effect profile and optimal range of efficacy. The groups given 2000 and 1500 mg demonstrated significant reductions in values of low-density lipoprotein cholesterol (-26% and -19.3%. respectively). total cholesterol (-18.4% and -13.3%). and total cholesterol-high-density lipoprotein cholesterol ratio (-20.4% and -19.4%) when compared with diet- and placebo-treated controls. Smaller improvements were seen in high-density lipoprotein cholesterol and triglyceride levels. Blood chemistry monitoring indicated that reduction in low-density lipoprotein cholesterol level strongly correlated with an increase in baseline levels of some enzymes for niacin-treated subjects. The improved side-effect profile of the wax-matrix form of niacin was particularly notable. The dropout rate due to side effects was only 3.4% and was coupled with good medication compliance.
Dyslipidemia in veterans. Multiple risk factors may break the bank, The National Cholesterol Education Program guidelines for treatment of high cholesterol levels especially target patients who have multiple risk factors for coronary heart disease. Veterans have an increased prevalence of smoking. are predominantly male. and may have higher rates of other risk factors than other groups; therefore. they may require more aggressive screening and treatment for dyslipidemias. To assess the prevalence of cardiac risk factors. current cholesterol screening practices. and the potential impact of the National Cholesterol Education Program guidelines on the Veterans Affairs health care system. we reviewed 185 randomly selected charts of outpatients who were actively receiving follow-up at the Denver (Colo) Veterans Affairs Medical Center. The patients had an average age of 58.3 years and 99.5% were male. Of these patients. 60% had a serum cholesterol level checked within the last 999 days. Nearly all patients (84%) had two or more risk factors noted. The mean cholesterol level was 5.85 mmol/L (226 mg/dL). with 72% of patients having levels above 5.20 mmol/L (200 mg/dL) and 36.1% having levels above 6.20 mmol/L (240 mg/dL). Of patients who had their cholesterol level checked. 69% (77/111) would require lipoprotein analysis by National Cholesterol Education Program guidelines (cholesterol. greater than or equal to 6.20 mmol/L [greater than or equal to 240 mg/dL] or 5.15 to 6.20 mmol/L [200 to 239 mg/dL] with two or more risk factors). yet only 16% (12/77) had lipoprotein analyses done. Extrapolating from these data. the Denver Veteran Affairs Medical Center. which cares for 28.000 patients. has more than 19.000 patients who would need lipoprotein analysis to meet current guidelines. Full evaluation and subsequent treatment of dyslipidemias in veterans would require tremendous financial and manpower commitments.
Drivers with untreated sleep apnea. A cause of death and serious injury, Three patients with untreated sleep apnea fell asleep while driving and caused serious automobile accidents. One person died. another became permanently paraplegic. and the three patients with sleep apnea were seriously injured in these crashes. This sequela of sleep apnea is not surprising. since subjects with sleep apnea may be poor drivers with a high accident rate and a high incidence of "near-miss" vehicular incidents. Because drivers with untreated sleep apnea may cause a large number of preventable automobile accidents. physicians have specific duties involving these drivers. First. physicians must try to identify impaired drivers with sleep apnea before they have an accident; routinely asking patients about loud snoring and hypersomnolence may help identify these impaired drivers. Second. physicians must consider the diagnosis of sleep apnea when examining patients who fall asleep while driving. Next. physicians must warn their patients with sleep apnea about the risks of driving with untreated sleep apnea. Finally. physicians must treat any seriously impaired driver with sleep apnea and keep these patients from driving until they can receive successful treatment.
Importance of the placenta and cord in the defense of neurologically impaired infant claims, Verdicts in favor of the defense were delivered in all 12 cases tried to a conclusion in which the placenta and/or cord was available for examination and was found to be abnormal or diseased and in which testimony was provided by a placental pathologist. The St Paul (Minn) Fire and Marine Insurance Company recommends that placenta/cord specimens be retained in cases where the mother is at high risk. the fetus/newborn has certain high-risk characteristics. and/or the placenta appears to be grossly abnormal. If a claim is made against the health care providers. the specimens can subsequently be examined by a placental specialist for possible trial testimony. The placenta may well be the key to a solid defense for these cases in the courtroom.
Examination of the early conceptus, The pathologist encounters the early. first-trimester conceptus as a product of spontaneous or surgical abortion or as a specimen from ectopic. usually tubal. gestation. In the vast majority of cases of spontaneous abortion. the embryo/fetus has been dead for 1 week to several weeks and is most often lost in the process of uterine emptying; the placenta. accordingly. stands as the main "witness" of the abortive process. The fact of embryonic/fetal death is established and dated through an interpretation of gross and microscopic changes in the villous stroma. including its vessels and the embryonic erythrocytes therein. Elective abortions performed for social reasons occasionally yield abnormal findings that suggest gestations otherwise destined to eventual spontaneous abortion. Other therapeutic abortions are indicated by abnormal sonographic or cytogenetic findings that may be correlated with the morphologic features of the evacuated conceptus. Cytogenetic abnormalities correlate to a high degree with embryonic growth disorganization and with early death. usually before the fetal stage (30 mm) is reached. Adequate sampling of the placenta. its membranes. and of the embryo/fetus is recommended. For cytogenetic studies. clean. viable specimens must be obtained; these are most often required in cases of habitual abortion.
Abnormal scleral collagen in nanophthalmos. An ultrastructural study, Ten patients with bilateral nanophthalmos underwent sclerectomies for uveal effusion. Ultrastructural examination of the sclera revealed abnormal collagen in seven patients. Four showed dramatic fraying of the collagen fibrils into fine filaments 2 to 3 nm in diameter. In three of these cases and three other cases without fraying. there were foci of 10- to 35-nm small collagen fibrils. some appearing to arise by splitting of otherwise normal collagen fibrils. In areas of fraying. elastic fibers were absent. All patients had a wider range of collagen diameters than did control subjects. The youngest patient with fraying also had Hallermann-Streiff syndrome. In three patients. no collagen abnormality was found. The clinical feature correlating best with the presence of abnormal collagen was an extremely small eye. since the three patients without collagen abnormality had the largest eyes (range of anteroposterior diameters. 19.2 to 20.3 mm). Nanophthalmos appears to result from several distinct defects.
Intraocular gentamicin toxicity [letter, The catastrophic effects of inadvertent intraocular injection of gentamicin can be difficult to distinguish from vascular occlusive disease. particularly ophthalmic artery obstruction. Diffuse vitreous haze and shallow retinal detachment were described by Brown et al in a study of the short-term and long-term effects of a 10-mg dose of intravitreal gentamicin in adult macaque monkeys. An earlier study by Peyman et al demonstrated a vitreal reaction in rabbits with high doses of intravitreal gentamicin. Vitreal haze and shallow retinal detachment appear to be important findings that distinguish gentamicin toxicity from ophthalmic artery occlusion. but. to our knowledge. they have not been described in humans.
Improved visualization of macular hole lesions with laser biomicroscopy, We have developed instrumentation to improve the visualization of fine vitreoretinal structures at the macula during slit-lamp biomicroscopy. The instrument. mounted on a slit-lamp microscope. used a green helium-neon laser to deliver a narrow beam. 15 micron(s) in width and 2 mm in length. The intersection of the laser slit with the ocular structures was viewed at an angle. as in conventional slit-lamp biomicroscopy. The instrument was used to examine patients with idiopathic macular holes or cysts. The results indicated that the new illumination was superior due to the narrow width of the beam. the enhanced brightness. and the monochromacy in green. which reduced background scatter. These advantages allowed for visualization of fine retinal structures that are difficult to detect with conventional slit-lamp biomicroscopy. The findings in patients with idiopathic macular hole demonstrated that the operculum was located approximately 500 micron(s) anterior to the surrounding retina and moved minimally. This suggested that the operculum may be supported by partially detached posterior vitreous cortex. and that a macular hole is the result of tangential traction followed by axial traction caused by a contracted and detached cortical vitreous gel.
Vitreous photography with a +90-diopter double aspheric preset lens vs the El Bayadi-Kajiura preset lens, Two fundus lenses. a 90-diopter preset lens and a 58.6-diopter El Bayadi-Kajiura lens. were compared. The lenses were evaluated with regard to their optics. magnification. field of view. and photographic usefulness in photographing the posterior vitreous. The 90-diopter lens provided a wider field of view but lower magnification. Both lenses permitted high-quality vitreous photographs through the slit lamp. but the 90-diopter lens allowed photographs to be taken through small pupils and some lens opacities.
Cellular and humoral anticorneal immune response in corneal transplantation, Immunologic responses play a role in the rejection process of corneal transplants. Both histocompatibility antigens and tissue-specific antigens may be potential targets for such an immune response. To identify relevant responses. the humoral immune response against corneal tissue and the cellular immune response against one specific corneal protein were determined in patients before and after corneal transplantation. The results were compared with known risk factors for corneal transplantation. but no correlations were observed. A conversion from negative to positive in cellular immune response against the cornea-specific protein was seen in patients who had experienced an inflammatory episode during the time interval between measurements. The anticorneal protein response may therefore be the result of an intraocular inflammatory response. but not a prognostic factor to help predict the patients at risk for rejection.
Prevalence of lens opacities in surgical and general populations, The distribution and prevalence of lens opacities were examined and compared among three general population-based groups and a group that underwent cataract surgery. The population-based groups comprised subjects from the Framingham Eye Survey. the National Health and Nutrition Examination Survey. and the study of watermen in Maryland. Comparison among these groups revealed similar frequencies of lens opacities among age groups. with slightly higher rates for older individuals in the watermen study population. Comparison between the watermen and the surgical groups revealed that. of lenses with opacities. posterior subcapsular cataracts were present in a far greater percentage of surgery cases (60.6%) than in general population cases (5.3%). These findings confirm the generally held clinical belief that posterior subcapsular opacities are disproportionally represented in the surgical population and suggest that they cause more significant visual disability than do other types of cataracts.
In vivo prevalence of azidothymidine (AZT) resistance mutations in an AIDS patient before and after AZT therapy, In order to examine the in vivo prevalence of AZT resistance mutations in AID patients after long-term therapy we amplified. by polymerase chain reaction (PCR). a 654 bp pol gene fragment from peripheral blood mononuclear cell DNA samples from a patient before. and 19 months after. the start of AZT therapy. PCR products from each sample were cloned and 9 clones from each sample were sequenced. Seven of 9 clones from the post-AZT sample. but none from the pre-AZT sample. contained an amino acid substitution (Thr215 to Tyr) requiring two nucleotide changes within the same codon (ACC to TAC). This change had previously been shown by Larder and Kemp (Science. 246:1155-1158. 1989) to correlate with partial AZT resistance of virus isolates. In colony hybridizations using synthetic oligonucleotides corresponding to the mutant and wild-type sequences. 22 of 22 clones from the pre-AZT sample hybridized only to the wild-type probe while 21 of 26 clones from the post-AZT sample hybridized only to the mutant. Clinically. this patient remains well. indicating that while Tyr215 may be the first amino acid substitution leading to resistance. it alone does not appear to have significantly influenced the clinical status of this patient.
Vaccine protection against HIV-2 infection in cynomolgus monkeys, The aim of this study was to determine if protection against an infectious human immunodeficiency virus type 2 (HIV-2) challenge could be obtained in cynomolgus macaques by active immunization using whole killed virus vaccine. Four monkeys were immunized with killed HIV-2SBL-6669. two of them with five intramuscular (im) injections of viral preparation containing 100 or 300 micrograms protein emulsified in incomplete Freund's adjuvant (IFA) and the two remaining received four im injections of 25-50 micrograms viral protein in iscoms. Each of the four vaccinated cynomolgus monkeys. along with four unvaccinated controls. were challenged intravenously two weeks after the last booster with approximately 100 animal infectious doses (ID50) of live HIV-2SBL-6669. All four immunized monkeys developed antibodies to HIV-2 envelope and core proteins before challenge exposure to HIV-2. but only the two animals vaccinated with virus in IFA developed detectable neutralizing antibodies. The two monkeys immunized with killed virus in IFA have shown no evidence of infection nine months after challenge with live virus. When blood and lymph node cells from these animals were transfused into naive cynomolgus monkeys. the recipients remained free of infection. In contrast. virus was recovered repeatedly in all nonimmunized animals and in the two animals immunized with iscom-associated viral antigens. which had a low content of envelope gp125 antigen. The demonstration of vaccine-induced protection against HIV-2 in a nonhuman primate raises hope for effective immunization against HIV infections in humans as well.
Characterization of an HIV-1 isolate displaying an apparent absence of virion-associated reverse transcriptase activity, In characterizing a group of independent human immunodeficiency virus (HIV-1) isolates. we noted that certain isolates had anomolously low levels of virion-associated reverse transcriptase activity. In an attempt to understand the basis of this phenomenon. we examined in detail one such isolate. HIV-1G. We found correctly processed forms of the viral reverse transcriptase in virions as well as processed forms of other viral proteins. suggesting that viral proteins are both expressed and properly processed. We have detected a nuclease activity associated with the outer face of the HIV-1G envelope. This nuclease degrades the DNA product generated during the reverse transcription assay. The nuclease activity is more sensitive to mild protein denaturation than is the viral reverse transcriptase. and it is stimulated by the presence of Ca2+. The amount of virion-associated nuclease activity relative to reverse transcriptase activity varies between virus isolates and can vary also for one isolate during virus spread through a culture. The origin of the nuclease activity is unknown but is presumed to be cellular. The variability in amount of nuclease activity may reflect variability in the interaction of the virus with different cellular components during maturation.
p17 and p17-containing gag precursors of input human immunodeficiency virus are transported into the nuclei of infected cells, Subcellular localization of input human immunodeficiency virus type 1 (HIV-1) gag proteins was determined in infected H9 and Jurkat tat cells. Infected cells were fractionated at intervals. and the proteins in cell fraction were identified by immunoblotting using pooled sera from acquired immunodeficiency syndrome (AIDS) patients and monoclonal antibodies. Cycloheximide was added at 0 time to prove that the proteins detected were not nascent ones. Gag proteins p55. p41. p39 (in the most essential relative concentrations). and p17 were found in the cell nuclei for at least 4 h after infection. However. p24 was not found in the cell nuclei and was accumulated in the nuclear washing buffer. The data presented confirm the presence of karyotypic signal at the N terminus of p55 gag precursor. The potential role of nuclear localization of gag precursor is discussed.
Production of a nef-specific monoclonal antibody by the use of a synthetic peptide, Monoclonal antibodies have been generated against a synthetic peptide of the nef protein of human immunodeficiency virus type 1 (HIV-1) in order to further characterize the biochemical and functional nature of this protein and its role in the control of HIV-1 transcriptional regulation. Earlier studies indicated nef to be a negative regulatory factor for viral transcription. whereas more recent studies report evidence against this original hypothesis. Nef is a protein of 206 amino acids of approximately 27 kD in most HIV-1 isolates; however. in some other isolates a truncated form of 124 amino acids has been described. A peptide sequence of six amino acids. corresponding to a region of the nef protein exhibiting high-sequence homology to thymosin alpha 1 protein. has been synthesized by Merrifield solid-phase methodology. This peptide is coded by a sequence located upstream to the stop codon described in some HIV-1 isolates and then is maintained in both complete and truncated forms of the nef protein. F14.11 is a nef peptide-specific monoclonal antibody (IgG2a/k) exhibiting the ability to recognize natural nef protein in either radioimmunoassay. radioimmunoprecipitation assay. or immunocytochemical analysis. Since F14.11 is able to identify nef protein in the cytoplasm of lymphocytes from HIV-infected seronegative subjects it may prove useful in monitoring the expression of nef during the silent HIV-1 infection.
Detection of proviral sequences in saliva of patients infected with human immunodeficiency virus type 1, Single samples of saliva collected from 20 human immunodeficiency virus type I (HIV-1) seropositive patients were tested by the polymerase chain reaction for HIV-1 proviral sequences using primers from the long terminal repeat (LTR). gag. and env regions of the virus. Proviral sequences were detected in the saliva of 50% of the patients. Sequential samples of saliva. collected at four different times. from each of six additional patients led to the detection of proviral sequences in 100% of the patients. Since. however. the detection of HIV-1 required not only the highly sensitive polymerase chain reaction. but also multiple samples. it appears that under ordinary circumstances infected cells are present in saliva in low numbers. Although this may explain the lack of transmission of HIV-1 by casual contact through the salivary route to household members and health-care workers. the presence of infected cells in the saliva of a high percentage of patients argues for avoidance of sexually intimate situations involving prolonged and repeated contact with saliva.
Zones of differential sensory block during extradural anaesthesia, We have measured spinal segmental levels of anaesthesia to light touch (LT). pinprick (PP) and cold temperature discrimination (TE) during 2% lignocaine extradural anaesthesia in 22 patients. to determine if zones of differential sensory block develop during extradural anaesthesia and. if so. the extent to which TE extends beyond PP or LT levels and how age affects differential block. The median thoracic dermatomal levels were 4.5 for LT. 2.0 for PP and 2.0 for TE. Zones of differential sensory block developed within 5 min of extradural injection of local anaesthetic. and persisted for the next 55 min. In all instances. PP extended more cephalad than LT. and TE extended above PP levels. There were no differences in the extent of zones between the two groups of patients with mean ages of 28 and 48 yr. Thus. during extradural anaesthesia. sympathetic denervation extended one to two spinal segments above the sensory levels of LT and PP anaesthesia. age (28 vs 48 yr) affected neither the cephalad extent nor the width of zones of differential block. and PP levels of anaesthesia were closer to presumed levels of sympathetic block than were LT levels.
Antagonism of the hypnotic effect of midazolam in children: a randomized, double-blind study of placebo and flumazenil administered after midazolam-induced anaesthesia, In a randomized. double-blind study. we administered placebo and flumazenil to 40 healthy Chinese boys. aged 3-12 yr. undergoing circumcision. The children received midazolam 0.5 mg kg-1 orally for premedication and 0.5 mg kg-1 i.v. during induction. After operation the patients were given 0.1 ml kg-1 of a blinded solution followed by 0.05 ml kg-1 min-1 until either they awoke or the 10-ml ampoule of solution was empty. Efficacy of antagonism of midazolam was assessed by times to eye opening and self identification. modified Steward coma scale. a post-box toy completion-time ratio and qualitatively by an independent observer. The difference between flumazenil and placebo was both clinically and statistically different in the first 2 h. Children receiving flumazenil awoke approximately four times faster and identified themselves nearly three times sooner; 65% of this group could complete the post-box toy at 10 min. compared with none of the placebo group. There were no cases of resedation. but one child did not awaken for 30 min after i.v. administration of flumazenil 1.0 mg. The mean total dose of flumazenil administered was 0.024 (SD 0.019) mg kg-1. Flumazenil rapidly antagonized midazolam-induced hypnosis in children and was associated with minimal change in cardiorespiratory variables.
Possible involvement of inositol-lipid metabolism in malignant hyperthermia, Alpha-adrenoceptor stimulation may induce malignant hyperthermia (MH) in vivo. Consequently. we have investigated the effects of the alpha-adrenoceptor agonist phenylephrine and. for comparison. the effects of the beta-adrenoceptor agonist isoproterenol on inositol-lipid metabolism of malignant hyperthermia susceptible (MHS) and healthy control (MHN) swine. The experiments were performed on electrically stimulated (frequency 0.2 Hz) trabeculae isolated from the right ventricles of the hearts of MHS and MHN animals. After labelling with [3H]inositol for 6 h. different inositol phosphates were measured by high pressure liquid chromatography. including inositol 1-phosphate. inositol 1.4-bisphosphate. inositol 1.3.4-trisphosphate. inositol 1.4.5-trisphosphate (1.4.5-IP3) and inositol 1.3.4.5-tetrakisphosphate. After stimulation with isoproterenol. the inositol phosphate content did not increase or vary between muscle from MHS and MHN animals. In contrast. all inositol phosphates increased after stimulation with phenylephrine in both muscle types. the effects being greater in MHS than in MHN. especially as regards 1.4.5-IP3 content. As 1.4.5-IP3. a presumed second messenger. has been shown to mobilize intracellular calcium. it is concluded that an enhanced alpha-adrenergic response is involved in the development of MH.
Diagnostic and management dilemmas in a patient with tracheal trauma, A patient with a foreign body penetrating the neck and chest was found to have physical signs which were consistent with serious tracheal injury and included a large movement of air through the lower part of the neck. The subsequent management of the patient and the difficult problem of securing an airway are described. At operation. the tracheal damage was found to be less severe than anticipated and the observed air flow was a result of penetration of the foreign body into the pleural cavity. The management of the patient is discussed and the potential for misinterpretation of the physical signs in this type of trauma is emphasized.
Epidermal cytokines and their roles in cutaneous wound healing, Cytokines are small proteins or glycoproteins which are synthesized and secreted by a variety of cell types. Through binding to specific receptors on target cells. these hormone-like products regulate many normal cell activities. including growth and differentiation. migration and immune functions. Within the epidermis. keratinocytes are the major source of cytokines along with melanocytes and Langerhans cells. In response to a variety of injurious stimuli. including ultraviolet irradiation and cutaneous wounding. epidermal keratinocytes may release a number of these regulatory molecules which can then interact directly with receptors on inflammatory cells. Epidermal cytokines can therefore play an important role in the wound-healing process by recruiting polymorphs and monocytes and in encouraging deposition of extracellular matrix proteins by fibroblasts. Keratinocytes can themselves respond to keratinocyte-derived cytokines by dividing and migrating over the wound surface before differentiating into a new stratified epidermis. This review presents the evidence of the production of cytokines by human keratinocytes and their role in the healing of skin wounds.
Protein kinase C activity in normal and psoriatic cells: cultures of fibroblasts and lymphocytes, Protein kinase C (PKC) activity was measured in cultures of fibroblasts from biopsies of the involved and uninvolved skin of seven patients with psoriasis and from the skin biopsies of nine normal controls. PKC activity was significantly increased (P less than 0.005) in the particulate fraction of fibroblasts obtained from the involved areas of skin (450 +/- SEM 89 pmol/mg protein/3 min) and the uninvolved skin (394 +/- 94 pmol/mg protein/3 min) in psoriasis as compared to that of controls (103 +/- 24 pmol/mg protein/3 min). The soluble fraction of PKC activity was comparable in controls and in the fibroblasts obtained from involved areas and not significantly different from the values in fibroblasts from uninvolved skin. PKC activity was also measured in the soluble and particulate fractions of lymphocytes from 13 patients with psoriasis and from 14 normal controls. The PKC activity did not differ in the lymphocytes of patients with psoriasis from the controls in either the cytosolic or the membrane fractions. The increase in PKC activity as expressed at the membrane level of psoriatic fibroblasts may be related to an increase in sensitivity of these cells to hormones or growth factors involved in the regulation of their growth.
Neuropeptides in skin disease: increased VIP in eczema and psoriasis but not axillary hyperhidrosis, The neuropeptides vasoactive intestinal polypeptide (VIP). substance P and somatostatin were studied in skin biopsies from patients with eczema. psoriasis and axillary hyperhidrosis. VIP concentrations were elevated in skin affected by eczema and psoriasis. whereas substance P and somatostatin levels did not differ from controls. There was a higher concentration of VIP. but not of substance P or somatostatin. in normal axillary skin when compared to adjacent trunk skin. with abundant VIP-containing fibres surrounding eccrine sweat glands. The VIP concentration was unchanged in skin affected by axillary hyperhidrosis. VIP may increase local blood flow in eczema and psoriasis. but does not appear to play a role in axillary hyperhidrosis.
Malignant melanoma occurring in those aged under 30 in the west of Scotland 1979-1986: a study of incidence, clinical features, pathological features and survival, The study population consisted of the 95 patients who presented with cutaneous malignant melanoma in the west of Scotland between 1979 and 1986 and who were aged under 30 at the time of diagnosis. Over this 7-year period. 1299 melanomas were diagnosed in all age groups in this geographical area. increasing in incidence by 82% from 135 in 1979 to 246 in 1986. The proportion of melanomas diagnosed before the patients' thirtieth birthday remained constant at 6%. None were diagnosed in the under-15 age-group. and none developed on giant congenital naevi. Forty-two of the 95 melanomas (44%) in the under-30 group developed on a small naevus present either from birth or early childhood. These melanomas were thicker than those apparently developing on normal skin. but once controlled for tumour thickness and sex the presence of a pre-existing naevus did not affect 5-year survival. The overall 5-year survival was 76% with poorer survival associated with thicker tumours and male sex. This study suggests that small early onset naevi may have a higher potential for post-pubertal malignant change than has been previously recognized.
Measurement of involved surface area in patients with psoriasis, Three methods of measuring the surface area of the involved skin were compared in 10 patients with psoriasis. Using the rule of nines. four untrained observers estimated the average extent of psoriasis as 20. 14. 23 and 33% of the body surface area. Measuring the area of tracings of plaque outlines using image analysis gave a mean involved surface area of 9% and image analysis of whole body photographs gave a mean value of 7%. We conclude that untrained observers using the rule of nines will overestimate the extent of psoriasis and that image analysis of whole body photographs is comparable to that of traced outlines.
Computer-assisted image analysis of skin surface replicas, Using a rubber-based dental impression material. negative surface impressions were made of demarcated areas of skin and prepared as dry specimens for scanning-electron microscopy. Electron micrographs were taken at low magnification and. using a programmed computer-assisted image analyser. it was possible to represent quantitatively the topography of that particular body site according to the degree of circularity of the various geometric subunits. This technique was most applicable to skin topography with a reliable geometrical pattern of triangles and squares. a feature of hair-bearing surfaces in general and in particular. the antecubital fossa. Using standardized trauma of various types the origin of skin surface markings were found to be located in the dermis. The technique was applied to the healing of experimental trauma produced by tape stripping. the resolution of clinical eczema and a comparison of steroid-treated and untreated tape-stripped skin.
The relationship between plasma psoralen concentration and psoralen-UVA erythema, The plasma 8-methoxypsoralen (8-MOP) concentration was measured in 60 patients commencing psoralen photochemotherapy (PUVA). At the time of blood sampling each patient was phototested using a series of 10 exposures to UVA. The resulting erythema was measured objectively 72 h after irradiation and dose-response curves for psoralen-UVA erythema were constructed. Although the dose of 8-MOP was calculated according to body weight. patients receiving 30 mg of 8-MOP had a significantly lower mean plasma concentration than those receiving higher doses. There was no significant correlation between plasma 8-MOP concentration and minimal phototoxic dose. either estimated visually or calculated from the dose-response curves. However the slope of the dose-response curve showed significant correlation with plasma 8-MOP concentration. The variation between patients in the rate of increase of the erythemal response. but not the variation in threshold sensitivity. can be explained by difference in plasma psoralen concentration.
Naevocytic naevi with vascular-like spaces, Fourteen cases of naevocytic naevi with anastomising lacunae suggestive of vascular spaces are reported. The cells lining these lacunae were consistent with naevus cells. being positive for vimentin and S100 protein and negative for factor VIII-related antigen and Ulex europaeus I. The cells were not surrounded by laminin or type IV collagen. We suggest the formation of these vascular-like spaces may be due to defective production or increased degradation of components of the basement membrane with a consequent lack of cohesion.
The role of the right hemisphere in emotional communication, Previous research has established that patients with right hemisphere damage (RHD) are impaired in the comprehension of emotional prosody and facial expression. There are several explanations for this impairment. It may reflect defective acoustic and visuospatial analysis. disruption of nonverbal communicative representations. or a disturbance in the comprehension of emotional meaning. In order to examine these hypotheses. we asked RHD patients. left hemisphere damaged patients (LHD) and normal controls (NC) to judge the emotional content of sentences describing nonverbal expressions. and sentences describing emotional situations. We found that RHD subjects performed normally in their ability to infer the emotion conveyed by sentences describing situations. However. RHD patients were impaired in relation to both LHD and NC in the capacity to judge the emotional content of sentences depicting facial. prosodic. and gestural expressions. suggesting a disruption of nonverbal communicative representations.
Absence of both auditory evoked potentials and auditory percepts dependent on timing cues, An 11-yr-old girl had an absence of sensory components of auditory evoked potentials (brainstem. middle and long-latency) to click and tone burst stimuli that she could clearly hear. Psychoacoustic tests revealed a marked impairment of those auditory perceptions dependent on temporal cues. that is. lateralization of binaural clicks. change of binaural masked threshold with changes in signal phase. binaural beats. detection of paired monaural clicks. monaural detection of a silent gap in a sound. and monaural threshold elevation for short duration tones. In contrast. auditory functions reflecting intensity or frequency discriminations (difference limens) were only minimally impaired. Pure tone audiometry showed a moderate (50 dB) bilateral hearing loss with a disproportionate severe loss of word intelligibility. Those auditory evoked potentials that were preserved included (1) cochlear microphonics reflecting hair cell activity; (2) cortical sustained potentials reflecting processing of slowly changing signals; and (3) long-latency cognitive components (P300. processing negativity) reflecting endogenous auditory cognitive processes. Both the evoked potential and perceptual deficits are attributed to changes in temporal encoding of acoustic signals perhaps occurring at the synapse between hair cell and eighth nerve dendrites. The results from this patient are discussed in relation to previously published cases with absent auditory evoked potentials and preserved hearing.
Free and supported stance in Parkinson's disease. The effect of posture and 'postural set' on leg muscle responses to perturbation, and its relation to the severity of the disease, Upright stance and its reflex control were studied in parkinsonian patients and in age-matched normal subjects. They stood unperturbed on a force-measuring surface (static conditions). or were displaced by movement of a supporting platform (dynamic conditions). During quiet stance the following variables were analysed. with eyes open or closed: position of the centre of foot pressure (CFP). average sway area. length of sway path. amplitude and distribution of tonic leg muscle EMG activity. Perturbations of stance were induced by toe-up or toe-down rotations. and by backward or forward translations of the platform. Amplitude of short. medium and long-latency EMG responses to displacement were measured in the tibialis anterior (TA) and in the three heads of the triceps surae (TS) muscle. The perturbations were produced during both free and supported stance (holding onto a stable structure). under which condition normal subjects suppress medium and long-latency responses. Under static conditions. the only significant finding in parkinsonians was represented by a shift in the position of the CFP. This was correlated with the severity of the disease (Webster scale). the less affected patients being shifted backwards and the more affected patients forwards. with respect to normals. Under dynamic conditions. the reflex responses to perturbations of free stance were similar in both groups. Only the medium-latency burst of gastrocnemius lateralis and the long-latency burst TA evoked by TS stretch were larger in parkinsonians. The amplitude of these responses. as well as of all the others. was not related to the Webster score. Within the patients' group. a relationship between position of CFP and area of EMG burst was found for both medium and long-latency TA responses evoked by forward translation and toe-up rotation. respectively. Under supported conditions. the capability to suppress all medium and long-latency muscle responses to any perturbation was lost or impaired in the parkinsonians. The degree of impairment was unrelated to the position of the CFP. but was significantly related to the severity of the disease. The suppression to 40% (supported/nonsupported). of TA response to toe-down rotation is proposed as the point of separation between normals and parkinsonians. The forward projection of the CFP. occurring in the severe stages of the disease. and the increase in amplitude of some responses to perturbations of free stance might be a compensatory adaptation to the anomalous upright posture.(ABSTRACT TRUNCATED AT 400 WORDS).
The longstanding MS lesion. A quantitative MRI and electron microscopic study, Important questions remain unanswered about the sequence of events leading to progressive and ultimately irreversible tissue damage in MS. This study was designed to investigate the pathological characteristics of. and function of. the blood-brain barrier within longstanding MS lesions using quantitative and Gd-DTPA enhanced MRI techniques. The ultrastructural appearances of postmortem lesions from a single. separate case of MS have been correlated with the MRI findings. Both MRI and ultrastructural analysis revealed considerable heterogeneity in the chronic lesions: some are 'closed' with no detectable extracellular water. but most are 'open' and show expansion of the extracellular space to as much as 87% of tissue area. This variable expansion probably results from differing degrees of axonal loss. Evidence of blood-brain barrier damage was found in only 17% of lesions. was less severe than that seen in acute lesions. and may result from repeated previous inflammatory insults. The findings imply progressive axonal loss in lesions as they age. It is possible that this loss is related to clinical progression of the disease.
Eye movement behaviour of patients with cerebral microangiopathy and macroangiopathy in simple visual detection tasks, Patients with cerebral microangiopathy (n = 17). acute and chronic left hemisphere (LH) stroke (n = 18. n = 21) and normal controls (n = 41) were studied in 2 simple visual detection tasks. one with predictable. the other with unpredictable targets. Eye movements were registered by means of infrared light reflections (pupil-corneal reflection method); the points of visual fixation were continuously calculated by a microprocessor system. Patients with cerebral microangiopathy showed primarily difficulties in holding attention. as reflected by pathologically short durations of gaze on target. frequent unsuccessful anticipations and a high overall number of fixations. In contrast. acute LH stroke patients were characterized by a deficit in shifting attention. as reflected by prolonged latencies and long search durations due to many intervening search fixations. By means of a nonparametric discriminant analysis procedure. about 90% of patients with microangiopathy and about 80% of acute LH stroke patients were reliably distinguished from normal controls. The differences between these two patient groups were most pronounced in the simpler task with predictable targets. Among those patients discriminated from normals. about 96% were correctly reclassified as belonging either to the microangiopathy or to the acute LH stroke group on the basis of their abnormal eye movement variables alone.
Stereopsis after unilateral anterior temporal lobectomy. Dissociation between local and global measures, In man. an impairment in stereopsis may occur following damage outside the occipital lobes. If local and global stereopsis can be dissociated. this may imply that different mechanisms mediate these functions. We tested 44 patients with unilateral anterior temporal lobe excisions and 23 normal control subjects on two tasks. In the local stereopsis task. subjects indicated which of two pins varying in disparity between 4 and 512 s of arc was closer. Results showed no threshold impairment in any group. In the global stereopsis task. random-dot stereograms varying in binocular correlation were presented in random order. and subjects indicated if the squares perceived in depth were in front of or behind the screen. At binocular correlations between 50% and 70%. left and right temporal lobectomy resulted in a deficit. which was more marked following right-sided excisions. These results are concordant with earlier work (Ptito and Zatorre. 1988). and with other evidence of a right hemisphere superiority in treating binocular depth information. Moreover. the fact that global stereopsis is impaired in the presence of intact local stereopsis suggests that closely related but not identical mechanisms are involved. and fits the notion that there is a hierarchical organization of the visual pathways originating in the striate cortex leading into temporal cortex. Global stereopsis would thus be mediated in temporal lobe areas that receive information about local disparities from more posterior regions.
Altered corticospinal projections to lower limb motoneurons in subjects with cerebral palsy, The projections of cortical neurons activated by transcranial magnetic stimulation to the motoneurons of lower limb muscles were examined in 22 normal subjects and 14 subjects with cerebral palsy (CP). In normal subjects. magnetic stimulation produced strong facilitation of tibialis anterior (TA) motoneurons. but little or no facilitation of soleus (SOL) motoneurons. This differential facilitation of TA and SOL motoneurons was observed at all stimulus sites on the scalp and all stimulus intensities at which responses could be elicited. In subjects with CP. magnetic stimulation produced almost equal facilitation of TA and SOL motoneurons. This could not be explained by differences in the excitability of the respective motoneuron pools. It is postulated that the projections from the motor cortex to spinal motoneurons are altered in CP. These abnormal projections may contribute to the impairment of voluntary movements experienced by these subjects.
Transcortical aphasia. Importance of the nonspeech dominant hemisphere in language repetition, While a relative preservation of repetition in acute transcortical aphasia (TA) has usually been associated with the functional integrity of the speech dominant (left) perisylvian area. recent amytal data (Bando et al.. 1986) have suggested a fundamental role of the nondominant (right) hemisphere in language repetition. The neuroradiological correlates of repetition were studied in a consecutive series of 21 patients with acute TA. A similar frequency of either perisylvian or extraperisylvian pathology was found. In 2 patients with perisylvian pathology. the injection of amytal in the hemisphere contralateral to the lesion abolished repetition. Positron emission tomography (PET) in another patient revealed marked hypometabolism over the entire left cortical mantle ipsilateral to a basal ganglia lesion. suggesting that preserved repetition was carried out by right hemisphere structures. This was confirmed in a second patient with left extraperisylvian pathology. in whom a second lesion in the right hemisphere resulted in impaired repetition. These findings suggest that the spared contralateral hemisphere may subserve residual repetition in some transcortical aphasic patients with a lesion within or outside the speech-dominant perisylvian area.
Hemisphere asymmetry in decision making abilities. An experimental study in unilateral brain damage, Thirty control subjects and 60 unilateral brain-damaged patients. 30 with left hemisphere (LH) damage and 30 with right hemisphere (RH) disease. underwent a disjunctive 4-choice reaction time study. Speed of reaction (as defined by the reciprocal of reaction time (RT). movement time (MT) and total response time (TRT] and accuracy of response (as represented by the sum of errors in selecting the correct response key) were investigated comparatively as a function of side of lesion and of performance on Raven's Coloured Progressive Matrices (PM47). In contrast to movement speed (1/MT). reaction speed (1/RT) as well as total response speed (1/TRT) showed a lesion effect independent of side of damage. Conversely. accuracy was differentially impaired. LH damage being associated with a significantly higher number of errors. Speed and accuracy had different relationships with the performance on the PM47 in the two hemisphere groups. Speed was affected in parallel with changes in PM47 performance both in the LH and in RH groups. whereas accuracy was altered only in LH patients. It was concluded that speed of motor reaction is affected by unilateral brain lesions irrespective of their side. whereas decision making processes. as expressed by accuracy of response. seem to be specifically impaired by LH damage.
Language functions in progressive supranuclear palsy, Language functions were studied in 6 patients with clinically diagnosed progressive supranuclear palsy who conformed to the characteristic pattern of 'subcortical dementia'. Dysarthria. reading difficulties and disturbances of handwriting were present in all patients. Some patients showed additional deficits including visual dyslexia. constructional dysgraphia and an increased rate of self-corrections and misnamings in object confrontation naming. In most instances. the naming errors referred to an object visually similar to the target object. suggesting that visual misperception is the major cause of the naming disorder. It is concluded that a variety of language impairments may develop secondary to other neurological and neuropsychological changes in progressive supranuclear palsy.
Cortical control of reflexive visually-guided saccades, Reflexive visually-guided saccade triggering may be facilitated or inhibited by the cerebral cortex. To study this control. saccades made towards suddenly appearing visual targets (saccade task) or away from them (antisaccade task) were recorded electro-oculographically in 45 patients with limited unilateral cerebral infarction. Lesions affected (1) the superior part of the angular gyrus (area 39 of Brodmann) in the posterior parietal cortex (PPC). (2) the dorsolateral prefrontal cortex (PFC) (area 46 of Brodmann). (3) the frontal eye field (FEF). or (4) the supplementary motor area (SMA). As these 4 types of lesions were located either in the right or the left cerebral hemisphere. patients were divided into 8 groups. Saccade latency. in the saccade task. and the percentage of errors (misdirected saccades made towards the visual target). in the antisaccade task. were compared in each group of patients with the values of 20 control subjects. In the saccade task. saccade latency was significantly increased bilaterally in the right PPC group. In the left PPC group. the increase in latency was less marked. and significant only for saccades made contralaterally to the lesion. In the different frontal groups. latency was unchanged or only slightly increased. These results confirm that the main area facilitating the triggering of reflexive visually-guided saccades is located in the PPC. in or near the superior part of the angular gyrus. The difference between right and left parietal lesions could be due to the predominance of the right hemisphere in the control of these saccades. In the antisaccade task. the percentage of errors was significantly increased bilaterally in both PFC groups compared with the control group and also to the FEF and SMA groups. These results suggest that the PFC is the main area in the cerebral hemisphere inhibiting reflexive visually-guided saccades.
Ovarian cancer screening in asymptomatic postmenopausal women by transvaginal sonography, From November 1987 to January 1991. 1300 postmenopausal women underwent screening with transvaginal sonography (TVS). Women eligible for screening were all asymptomatic with no known ovarian tumors. Ovarian volume was calculated using the prolate ellipsoid formula. and a value in excess of 8.0 cm3 was considered abnormal. Ovarian abnormalities were detected in 33 women (2.5%). and 27 underwent exploratory laparotomy. Ovarian tumors were noted in all 27 patients. including 2 primary carcinomas and 14 serous cystadenomas. The two women with ovarian carcinomas had normal results of pelvic examinations and normal serum CA-125 levels. Both women had Stage I disease. and are alive and well after conventional therapy. TVS was time efficient. easy to perform. and well-accepted by patients. Currently. there are more than 3000 patient years of follow-up in the screened population. and there have been no deaths due to ovarian cancer. A multi-institutional trial to determine the efficacy of TVS as a screening method for ovarian cancer is indicated.
Hyperfractionated radiation therapy in brain stem tumors. Results of treatment at the 7020 cGy dose level of Pediatric Oncology Group study #8495, Between May 1986 and February 1988. 57 patients were accrued to the second dose level of a Phase I/II Pediatric Oncology Group (POG) study exploring the use of hyperfractionated radiation therapy (HRT) in children with high-risk brain stem tumors. Local fields were treated with fraction sizes of 117 cGy given twice daily. with a minimum interfraction interval of 6 hours. to a total dose of 7020 cGy in 60 fractions over 6 weeks. Information regarding clinical status during HRT was available for 55 patients (44 [80%] improved. 6 remained stable. and 5 deteriorated). Results of initial and follow-up computed tomography (CT) scan and/or magnetic resonance imaging (MRI) were available for review for 52 patients. One patient had a complete response (CR) to treatment. 3 had a partial response (PR) (more than 50% response). and 40 remained stable. for a total response rate (CR + PR + stable) of 77%. Median time to disease progression was 6 months. Median survival time was 10 months. Survival rate was 39.6% (standard error [SE] = 6.6%) at 1 year and 23% (SE = 5.8%) at 2 years. Complications of treatment included an enhanced skin reaction in six patients and otitis media and/or externa in nine. One patient bled into tumor shortly after completion of HRT. and three had intralesional necrosis. Five patients continued taking steroids for protracted periods in the face of improved clinical and/or radiologic findings. Complications related to the use of steroids included opportunistic infections. impaired glucose tolerance. hypertension. osteoporosis. and significant mood changes. In no patient was there evidence of any late injury attributable to HRT. When compared with results of treatment with HRT at a lower dose level (6600 cGy). there appears to be a trend toward improved survival at 7020 cGy despite a less favorable patient population at the higher dose level. A second dose escalation to 7560 cGy in 60 fractions over 6 weeks has been implemented as planned.
A pilot study of neoadjuvant chemotherapy with 5-fluorouracil and cisplatin with surgical resection and postoperative radiation therapy and/or chemotherapy in adenocarcinoma of the esophagus, Fifteen patients with potentially resectable adenocarcinoma of the esophagus were treated with two cycles of preoperative chemotherapy with 5-fluorouracil (5-FU) and cisplatin (DDP). Response to chemotherapy was evaluated by comparative barium swallow. computerized chest tomography. esophagoscopy. and change in clinical symptomatology. Eleven patients (73%) were resected. two (13%) were explored and found inoperable. and two (13%) were not subjected to surgery (one because of death related to toxicity and one due to progressive disease). Ten of eleven patients (91%) had gross residual tumor. One patient (9%) had residual microscopic disease only. One patient (7%) had complete clinical responses (CCR). five (33%) had partial clinical response (PCR). and nine (60%) had no response (NR). Five of 15 patients (or 45% of resected patients) remain free of disease. Median survival time was 18.47 months for all patients and 23.83 months for resected patients.
Prognostic factors of alveolar rhabdomyosarcoma in childhood. An International Society of Pediatric Oncology study, Pretreatment characteristics of 57 patients with alveolar rhabdomyosarcoma (RMS) registered by the International Society of Pediatric Oncology (SIOP) between January 1975 and December 1983 were identified to perform a prognostic factor study. Living status and disease-free survival (DFS) time were assessed for all patients on January 1. 1988. By multi-variate analyses. lymph node involvement (P = 0.0003) and tumor invasiveness (P = 0.007) were identified as the most significant covariates correlated with survival. A model including N stage (P = 0.001) and age (P = 0.03) was selected for predicting DFS rates. Children between 5 and 10 years of age had better DFS rates than those younger than 5 years of age or those older than 10 years of age. The authors suggest a prognostic classification that could allow treatment to be adjusted according to clinical staging.
Severe 5-fluorouracil toxicity secondary to dihydropyrimidine dehydrogenase deficiency. A potentially more common pharmacogenetic syndrome, This study describes the inheritance of a defect in pyrimidine catabolism and its association with drug-induced toxicity in a patient receiving 5-fluorouracil (FUra) as adjuvant chemotherapy for breast carcinoma. The study population included the affected patient (proband). nine of her blood relatives. and seven healthy volunteers. The activity of dihydropyrimidine dehydrogenase (DPD). the initial enzyme of pyrimidine (and FUra) catabolism. in peripheral blood mononuclear cells was measured in each subject by a specific radiometric assay using FUra as the substrate. The proband had no detectable DPD activity. When enzyme levels in the proband and relatives were compared with that in controls. an autosomal recessive pattern of inheritance was demonstrated. This is the third patient with severe FUra toxicity secondary to an alteration in pyrimidine catabolism and the second from our clinic population suggesting that the frequency of this genetic defect may be greater than previously thought. Monitoring DPD activity may be important in the management of patients experiencing severe toxicity secondary to FUra chemotherapy.
Transition of Ki-67 index of uterine cervical tumors during radiation therapy. Immunohistochemical study, Histopathologic and Ki-67-staining features of cancer cells were investigated in biopsy specimens before and during radiation therapy in 29 patients with cervical squamous cell carcinoma. No morphologic changes were observed up to doses of 540 cGy. A few intact cancer cells remained up to doses of 2700 cGy. Moderate changes in the cancer cells were noticed in patients who received 900 cGy or more. i.e.. multinuclei. swollen nuclei and cytoplasms. and prominent large nucleoli. At doses of 1800 cGy or greater. many cancer nests had severely damaged cancer cells with features such as cytolysis. karyolysis. karyorrhexis. pyknosis. and bizarre giant cells. There was no mitosis in the cells of patients who received doses greater than 1800 cGy. The Ki-67-positive cancer cells showed diffuse nuclear-stainings and dot-stainings before radiation therapy. Radiation doses more than 900 cGy changed the staining pattern of the Ki-67 antibody; large irregular spot-stainings and ring-stainings were observed predominantly. The Ki-67 index initially increased with the radiation dose; the mean Ki-67 indices before radiation therapy and at radiation doses of 180 cGy. 540 cGy. and 900 cGy were 41%. 50%. 63%. and 68%. respectively. The indices decreased when the dose was increased further. and they were 39% and 20% at doses of 1800 cGy and 2700 cGy. respectively. Possible explanations. including recruitment of quiescent cells. for the change in Ki-67 staining are discussed.
Comparison of estrogen receptor and epidermal growth factor receptor content of primary and involved nodes in human breast cancer, Estrogen receptors (ER) and epidermal growth factor receptors (EGFR) in the tumor cells of breast cancer tissues (primary tumors) and metastatic lymph nodes (involved nodes) were analyzed by immunocytochemical study in 19 patients; 12 were ER positive. and seven were ER negative. Microscopic study was used to determine the percentage of positive cells and the staining index. The percentage of EGFR-positive cells and the EGFR staining index were higher in the ER-negative primary tumors than ER-positive primary tumors. In ER-positive cases. both the number of ER-positive cells and ER content per cell was less in the involved nodes than in the primary tumors. whereas the number of EGFR-positive cells and EGFR content per cell was greater in affected nodes. On the other hand. in the ER-negative cases the number of EGFR-positive cells and EGFR content per cell remain almost unchanged between the primary tumors and involved nodes. The authors supposed a probability. in this study. that estrogen may exert inhibitory action on EGFR production through binding to ER.
The prognostic significance of glial fibrillary acidic protein staining in medulloblastoma, Histologic and immunohistochemical properties of 53 medulloblastomas were analyzed with regard to clinical features and survival rate. No correlation was found between survival rate and histologic features of the tumor. such as desmoplastic reaction. number of mitoses. hemorrhages. necrosis. endothelial proliferation. glomerular arrangement. calcifications. rosettes. or oligodendroglial cells. However 82% of the patients with positive glial fibrillary acidic protein (GFAP) staining in numerous tumor cells survived more than 5 years; only 30% survived that long if their tumor cells were GFAP negative (P = 0.0093). This significant difference was not related to the mode of therapeutic protocol used. The authors suggest that GFAP staining may be a useful prognostic tool in medulloblastoma.
Epipodophyllotoxin-related leukemia. Identification of a new subset of secondary leukemia, Thirty-seven children and adults who developed acute nonlymphocytic leukemia after the administration of chemotherapy that included etoposide or teniposide for a variety of hematologic and solid malignancies were identified. The secondary leukemia that occurred in these patients could be distinguished from the secondary leukemia that occurs after treatment with alkylating agents by the following: a shorter latency period; a predominance of monocytic or myelomonocytic features; and frequent cytogenetic abnormalities involving 11q23. Patients receiving an epipodophyllotoxin are at risk for developing secondary leukemia that has features distinct from the syndrome of secondary leukemia associated with alkylating agents.
Breast cancer metastatic to the eye is a common entity, Breast cancer metastatic to the eye is a common entity occurring in up to 30% of women with metastatic disease. The prevalence of this lesion is not appreciated because of the dominant clinical picture of metastases occurring in other organs. The diagnosis should be suspected in any women with a history of breast cancer and any visual symptoms. particularly metamorphopsia and scotomata. A thorough ophthalmologic evaluation. aided by ultrasonography. computed tomography. or magnetic resonance scanning. usually confirms the diagnosis. Early treatment with radiation therapy can alleviate symptoms and control local disease. The recognition and treatment of this disorder is important in maximizing the quality of life in patients with metastatic breast cancer. especially because newer treatment regimens prolong survival and thereby increase the chances for ocular metastasis.
Breast cancer with bone-only metastases. Visceral metastases-free rate in relation to anatomic distribution of bone metastases, The medical records of 82 patients with breast cancer with bone-only metastases were reviewed. According to the distribution of the metastases by bone scan at the time they were first documented. the patients were divided into three groups: Group A (patients who had bone metastases exclusively cranial to the lumbosacral junction). Group B (patients who had bone metastases exclusively caudal to the junction). and Group C (patients who had bone metastases both cranial and caudal to the junction). Group A had a significantly higher visceral metastases-free rate than Groups B or C. Serial bone scans and radiographs of Group A patients revealed that bone lesions cranial to the junction rarely developed into visceral metastases and that bone lesions extending caudal to the junction frequently developed into visceral metastases. These results indicate that the presence of bone metastases caudal to the lumbosacral junction is predictive of visceral metastases.
Ploidy in invasive colorectal cancer. Implications for metastatic disease, A retrospective study was performed to determine the ploidy of superficial (above muscularis propria) and deep (below muscularis propria) biopsy specimens from the primary colorectal cancer of 88 patients with Dukes Stage C2 and D colorectal tumors. The ploidy of lymph node and liver metastases was compared with that of the superficial and deep specimen from the corresponding primary tumor. Among the tumors studied. 78% exhibited nondiploid stemlines. In 19% of the tumors. the ploidy of the superficial biopsy differed from that of the deep biopsy. Among these discordant tumors. all of the deep biopsy specimens corresponded in ploidy to the liver metastases. whereas most of the superficial specimens were similar in ploidy to the lymph node metastases. Our observations suggest that measurement of a single site may not be sufficient to detect nondiploid stemlines within a tumor. They also suggest that measurement of deeper parts of invasive tumors may be more reflective of the phenotype of distant metastases than measurement of superficial specimens.
Cancer incidence in Norwegian Seventh-Day Adventists 1961 to 1986. Is the cancer-life-style association overestimated, Standardized incidence ratio for cancer in Norwegian Seventh-Day Adventists compared with the general population was not significantly different from unity (men 91. women 97). Persons converting late in life had a higher incidence than those converting at an earlier age. Respiratory cancers (standardized incidence ratio [SIR] 59. 95% CI = 36 to 91) and cancers with an unspecified site (SIR 53. 95% CI = 25 to 97) were rarer and cancer of the uterine corpus (SIR 164. 95% CI = 109 to 237) was more common in Seventh-Day Adventists before the age of 75 years. Inclusion of all registered Seventh-Day Adventists regardless of religious activity and the relatively low cancer incidence rates in the Norwegian population could contribute to the nonsignificant result with regard to total cancer. Main etiologic factors in cancer development in Norway should be sought in areas where Seventh-Day Adventists do not differ from the general population.
A cohort study of stomach cancer in a high-risk American population, Demographic. smoking and dietary information was obtained from a cohort of 17.633 white American men. largely of Scandinavian and German descent. who responded to a mailed questionnaire in 1966. After 20 years of follow-up. 50% to 90% increases in mortality from stomach cancer (75 deaths) were found among foreign-born. their children. and among residents of the North Central states. An association was seen with low educational attainment and laboring or semiskilled occupations. primarily among immigrants and their children. Risk was evaluated in subjects who regularly smoked cigarettes (RR = 2.6. 95% CI = 1.1 to 5.8). A significant dose-response trend was observed. with subjects who smoked 30 or more cigarettes per day having more than a five-fold increased risk compared with those who never smoked. Elevated risks were also found for pipe smoking and smokeless tobacco use. but not for alcohol consumption. Analysis of dietary consumption of nine food groups revealed no significant associations with stomach cancer. However. total carbohydrate intake and a few individual food items (salted fish. bacon. cooked cereal. milk. and apples) were associated with increased risk. The findings of this prospective study of a high-risk population add to the limited evidence relating tobacco consumption to stomach cancer risk and suggest clues to ethnic. geographic. and dietary risk factors.
Epidural fentanyl does not influence intravenous PCA requirements in the post-caesarean patient, Forty ASA physical status I or II patients scheduled for elective Caesarean delivery were studied to determine the effect of epidural fentanyl on post-Caesarean delivery analgesic requirements as administered by intravenous patient-controlled analgesia (PCA). Following delivery of the infant. under epidural anaesthesia with lidocaine 2% with 1/200.000 epinephrine. patients were randomly assigned to receive either 10 ml of preservative-free normal saline via the epidural catheter or 100 micrograms of fentanyl with 8 ml preservative-free normal saline in a double-blinded fashion. On arrival in the post-anesthesia recovery room (PAR). patients were provided with intravenous PCA meperidine 12.5 mg every eight minutes as needed. Patients were visited at intervals over the next 24 hr to determine if any differences in narcotic requirements. demands for narcotics. or severity of pain were noted. No differences were observed in any values between the groups. It is concluded that a single bolus of epidural fentanyl does not provide an advantage for postoperative pain relief in this patient population.
Haemodynamic considerations in the management of patients with subarachnoid haemorrhage, Cerebral vasospasm occurs. following subarachnoid haemorrhage. in the majority of patients and is accompanied by cerebral ischaemia in 30%. The objectives of this article are to review (1) the effects of subarachnoid haemorrhage and vasospasm on cerebral blood flow (CBF); (2) the effects of induced hypotension and hypocapnia on CBF in these patients; (3) current therapy for cerebral ischaemia from vasospasm. The medical literature was searched using Index Medicus; for the period 1983-90 this search was done on a computer with the CD-ROM version of Index Medicus. Silver Platter. Papers were selected on the basis of validity and applicability to clinical practice; animal studies are included when human data is lacking. Cerebral vasospasm may decrease cerebral blood flow. disturb autoregulation and place the patient at risk for delayed cerebral ischaemia. Intraoperative induced hypotension and hypocapnia can decrease CBF further. although effects of either on outcome have not been evaluated. Calcium antagonists are effective for both the prevention and the treatment of delayed cerebral ischaemia. Of the mechanical treatments. systemic-arterial hypertension has the firmest scientific foundation. although this is frequently combined with haemodilution and blood volume expansion. There is a need for randomized clinical trials to assess the efficacy of these latter treatments.
Idiopathic orthostatic hypotension, midodrine, and anaesthesia, A patient with idiopathic orthostatic hypotension receiving chronic oral midodrine therapy required anaesthesia for coronary artery bypass grafting. A perioperative infusion of phenylephrine was substituted for midodrine. an alpha-2 agonist. enabling hypotension resulting from low systemic vascular resistance to be controlled easily. Anticipated adrenergic receptor denervation hypersensitivity was noted. The only significant perioperative problem was one episode of syncope from orthostatic hypotension during the reambulation period.
The stratification of cardiac surgical procedures according to use of blood products: a retrospective analysis of 1480 cases, The use of blood products in 1480 consecutive cases of adult cardiac surgical procedures over a period of 15 mth was studied retrospectively using the database of the Department of Anaesthesia of the Institut de Cardiologie de Montreal. Use of blood products was compared in patients having (1) coronary artery bypass grafting. (2) valvular surgery. (3) or a combination of 1 and 2. First operations were compared with reoperations. Overall. the use of homologous blood products was greatest in patients of Group 3. intermediate in patients of Group 2. and smallest in patients of Group 1. Reoperations were associated with an increase in intraoperative transfusion of packed red blood cells. but postoperative chest drainage was similar to first operations. When all blood products (packed red blood cells. fresh frozen plasma and platelets) were taken into consideration. patients undergoing primary CABG or valve surgery were the least exposed to homologous blood donors (five and six units transfused respectively). Repeat CABG was associated with an intermediate exposure to homologous blood products (eight units). Finally. primary and repeat combined procedures. and repeat valve surgery were associated with the greatest exposure to foreign blood products (10. 13 and 10 units respectively). The data presented in this study provide a rational basis for stratification of procedures according to the expected use of blood products. particularly in view of future studies which may be planned to examine the efficiency of blood conservation strategies.
A prospective trial of intrauterine insemination of motile spermatozoa versus timed intercourse, STUDY OBJECTIVE: The efficacy of intrauterine insemination (IUI) of selected motile sperm. DESIGN: Prospective randomized sequential alternating cycle trial comparing IUI with luteinizing hormone (LH)-timed intercourse. SETTING: Clinical infertility service. PATIENTS: Couples selected included unexplained infertility (n = 73). cervical mucus hostility (n = 24). moderate semen defect (n = 110). and severe semen defect (n = 78). Two hundred eighty-five couples undertook 600 IUI cycles and 505 LH-timed intercourse. RESULTS: Overall. IUI was slightly more effective than LH-timed intercourse with a pregnancy rate of 6.2% versus 3.4% per cycle. When individual categories were considered only. IUI for severe semen defect was significantly better (5.6% versus 1.3%. P less than 0.05). The first IUI cycle was more effective when compared with both subsequent IUI cycles and the initial LH-timed cycle. Overall. 74% (27/37) of IUI pregnancies occurred in the first cycle. CONCLUSIONS: Compared with LH-timed intercourse. IUI provided little or no improved expectation of pregnancy but was beneficial in couples with severe semen defect. The occurrence of pregnancy was limited per cycle and confined essentially to the initial cycle of treatment. Continued IUI is considered to be unrewarding.
Sperm motility index: a new parameter for human sperm evaluation, OBJECTIVE: The study was performed to evaluate the correlation between sperm motility index. a novel parameter of semen quality. and routine semen analysis parameters by microscopic evaluation. DESIGN: Sperm motility index was measured by an electro-optical device. the Sperm Quality Analyzer (United Medical Systems Inc.. Santa Ana. CA). Human semen samples covering the whole span of qualities were analyzed prospectively and simultaneously by both methods. SETTING: Samples were collected from patients referred to university hospital infertility clinics. PATIENTS. PARTICIPANTS: Nine hundred sixty-eight semen samples of 812 patients and healthy men were analyzed. MAIN OUTCOME MEASURE(S): Sperm motility index is a measurement of optical density fluctuations caused by motile cells; therefore. a positive correlation was anticipated between its values and semen motility parameters. RESULTS: Sperm motility index values demonstrated statistically significant correlation with motile cell concentration. total cell concentration. and percent motile cells. They were also shown to reliably represent semen quality assessment obtained by two experienced andrologists. CONCLUSIONS: The sperm motility index provides a reliable and objective reflection of semen motility parameters and quality.
Reproductive outcome after microsurgery for proximal and distal occlusions in the same fallopian tube, The reproductive outcome after microsurgery for both proximal and distal occlusions in the same fallopian tube has been reported in only small numbers of women. Our case series is in agreement with other series and shows that microsurgery for correction of both proximal and distal occlusions in the same fallopian tube yields only modest fertility and may predispose to ectopic tubal pregnancies.
Effects of fibrin sealant on tubal anastomosis and adhesion formation, The results of the present study suggest that there is no difference in adhesion formation and PR after tubal anastomosis using sutures or fibrin sealant. It appears that the use of fibrin sealant is associated with decreased incidence of ectopic pregnancy.
Magnetic resonance imaging of the adrenal gland in women with late-onset adrenal hyperplasia, To determine the presence of structural abnormalities of the adrenal in late-onset adrenal hyperplasia. four consecutive patients were studied by MRI before beginning glucocorticoid replacement therapy. Three women were diagnosed as 21-hydroxylase deficient late-onset adrenal hyperplasia by a 17-OHP level greater than 1.000 ng/dL 30 minutes after acute adrenal stimulation. and one patient was diagnosed as 11-hydroxylase deficient late-onset adrenal hyperplasia when her 11-deoxycortisol level was threefold the upper 95th percentile of normal. Two patients with 21-hydroxylase deficient late-onset adrenal hyperplasia had normal adrenal glands on MRI. Another 21-hydroxylase deficient late-onset adrenal hyperplasia patient was noted to have a 2.5 x 3.3-cm left adrenal nodule. which had been documented some 4 years earlier on CT scan and had not changed in size during that interval. This patient was 40 years of age when the diagnosis of late-onset adrenal hyperplasia was established. The patient with 11-hydroxylase deficient late-onset adrenal hyperplasia demonstrated a diffuse enlargement of the left adrenal gland consistent with hyperplasia. with no focal lesions. In conclusion. although patients with late-onset adrenal hyperplasia may often demonstrate nodular or diffuse adrenocortical hyperplasia on MRI. not all patients with endocrinologically evident disease demonstrate such abnormalities. consistent with a lesser degree of ACTH stimulation compared with women with classical congenital adrenal hyperplasia.
Semen quality in varicocele patients is characterized by tapered sperm cells, We used a retrospective case-control study design to compare sperm morphology in 50 varicocele patients and 50 patients with idiopathic infertility. Cases and controls were matched for the percentage of motile sperm and total sperm number per ejaculate. Varicocele patients had significantly more tapered sperm (36% +/- 3% versus 15% +/- 2%) and significantly fewer oval sperm (41% +/- 3% versus 47% +/- 2%). There was no significant difference between cases and controls in any other morphological type.
Luteal phase defect in habitual abortion: progesterone in saliva, OBJECTIVE: To re-evaluate the occurrence of luteal phase defect (LPD) in habitual abortion and to determine the value of salivary progesterone (P) assay in its diagnosis. DESIGN: Prospective study on patients with a history of at least three consecutive miscarriages. SETTING: Departments I and II of Obstetrics and Gynecology. University Central Hospital of Helsinki. Helsinki. Finland. PATIENTS: Forty-six patients (27 primary and 19 secondary aborters) and 12 healthy control women without a history of abortion. RESULTS: Eight patients (17.4%. 5 primary and 3 secondary aborters) exhibited a delay of greater than 2 days in endometrial maturation during two consecutive cycles. whereas in 38 patients (82.6%) endometrial maturation corresponded to the actual cycle day. Salivary P showed a distinct ovulatory rise. but no statistically significant differences were evident between patients (with or without LPD) and healthy control women. CONCLUSIONS: An endometrial maturation defect may be a factor in 17.4% of patients with habitual abortion. but this cannot be detected by salivary P assay.
Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium, OBJECTIVE: The role of natural killer (NK) cells in the decreased cellular immunity of women with endometriosis was investigated. DESIGN. SETTING. PATIENTS: Thirty-four women were investigated prospectively before a CO2-laser laparoscopy for infertility and/or pain at the University Hospital Gasthuisberg. Endometriosis was scored blindly. MAIN OUTCOME MEASURE: The cytotoxicity. directed against the endometrium. was mediated by NK cells because this cytotoxicity could be removed by treating the effector cells with the NK-specific anti-Leu-11b monoclonal antibody. Consequently. we evaluated prospectively in those women the lymphocyte-mediated cytotoxicity toward NK sensitive (K562-assay) and autologous endometrial target cells. RESULTS: The NK activity (K562-assay) and the cytotoxicity against autologous endometrial cells were similarly decreased in women with endometriosis and correlated with the severity of the disease. Using heterologous effector cells. the decreased chromium release in women with endometriosis was less pronounced but still present. CONCLUSION: The decreased cytotoxicity to endometrial cells in women with endometriosis is mainly because of a defect in NK activity but is also partially because of a resistance of the endometrium to NK cytotoxicity.
Relaxin levels in ovum donation pregnancies, STUDY OBJECTIVE: To investigate the relative contributions of the corpus luteum (CL) and the placenta to the circulating levels of relaxin during pregnancy. PATIENTS: Forty-one patients in whom pregnancy had been achieved by ovum donation. RESULTS: Relaxin was not detected in the serum of 36 patients; in the remaining 5. although it was detectable. the levels were markedly reduced when compared with those in normal pregnancies. CONCLUSION: These results demonstrate that the CL is essential for the maintenance of normal circulating levels of relaxin during pregnancy.
The prognostic value and significance of preclinical abortions in in vitro fertilization-embryo transfer programs, Preclinical abortions occur in natural conceptions as well as in in vitro fertilization-embryo transfer (IVF-ET) cycles. Nevertheless. although known. this entity is ill defined. OBJECTIVE: The purpose of this study was to propose a classification of these pregnancies on the basis of pathophysiological evidence and to evaluate their future clinical impact. DESIGN: Of 970 IVF-ET cycles. 114 cycles (11.7%) terminated in preclinical abortions. Abortions were divided according to peak beta human chorionic gonadotropin (beta-hCG) values into chemical abortions (52%) occurring 2 weeks after ET with beta-hCG values not higher than 21 mIU/mL and peri-implantation abortions (47%) terminating spontaneously 4 weeks after ET; the latter had higher beta-hCG values for a longer period of time but without any sonographic evidence of gestational sac. No woman in the two groups needed curettage. RESULTS: After a chemical abortion. the pregnancy outcome had better ongoing pregnancy rates (24.7%) in comparison with the 17% achieved in the total IVF-ET cycles. CONCLUSIONS: It is concluded that these two groups most probably have different pathophysiological backgrounds and concomitantly different future clinical impacts.
The effect of female antisperm antibodies on in vitro fertilization, early embryonic development, and pregnancy outcome, STUDY OBJECTIVE: To evaluate the extent to which human in vitro fertilization-embryo transfer (IVF-ET) alleviates immunological infertility. DESIGN: Retrospective. SETTING: In vitro fertilization program. PATIENTS: Thirty-three patients with positive antisperm antibodies undergoing 50 cycles of IVF-ET in which maternal serum was replaced by 5 mg/mL of bovine serum albumin (BSA) comprised the study group. Seventy-one patients with tubal infertility served as controls. In 50 of these. medium was supplemented with 7.5% maternal serum. and 21 were assigned to BSA substitution. RESULTS: Percentage of fertilization in the study group was significantly lower (41 +/- 31; mean +/- SD) than that of controls with maternal serum (77 +/- 15) and BSA (76 +/- 22). Early embryonic quality. as assessed by percentage of cleavage and morphological grading. was found to be inferior in patients with antisperm antibodies. The percentage of advanced embryos (greater than or equal to 4 blastomeres) at the time of transfer was 42 +/- 39 in the study group. compared with 65 +/- 23 and 75 +/- 35 for maternal serum and BSA controls. respectively. Percentage of morphologically favorable embryos (grades 1 and 2 in a 1 to 5 grading system) was 49 +/- 31 in the study group. compared with 78 +/- 35 and 74 +/- 23 for the controls. Percentage of clinical pregnancy was somewhat lower in the study group (12.5%) than in controls with either maternal serum (18%) or BSA (19%). CONCLUSIONS: Antisperm antibodies may have an adverse effect on fertilization and early embryonic development. Female immunological infertility may not be completely alleviated by IVF-ET.
In vivo and in vitro maturation of human oocytes: effects on embryo development and polyspermic fertilization, OBJECTIVE: To compare the effects of in vivo and in vitro maturation of human oocytes. DESIGN: Women (n = 60) undergoing follicular stimulation for in vitro fertilization. using long-course analog therapy to suppress endogenous luteinizing hormone (LH). were randomly allocated to a short (34 hour) or long (39 hour) delay between human chorionic gonadotropin (hCG) administration and oocyte retrieval. Each patient's oocytes were divided into two groups that were either inseminated immediately or after 5 hours. RESULTS: The incidence of polyspermic fertilization was highest in oocytes inseminated immediately after a short hCG/oocyte retrieval interval (17/100) and was significantly (P less than 0.05) reduced by preincubation and/or a long hGG/oocyte retrieval interval. Fertilization rates were higher with 39 hours than with 34 hours in vivo maturation (84.2% versus 76.8%; P less than 0.05). The incidence of delayed fertilization was reduced by extending the hCG/oocyte retrieval interval (short. 12.9%; long. 3.9%; P less than 0.001). CONCLUSIONS: Extension of the in vivo maturation time increased fertilization rates and eliminated the requirement for preinsemination incubation. allowing simplification of laboratory procedures.
Assessing the denominator problem in community-oriented primary care, Determination of health care needs is an essential cornerstone of community-oriented primary care (COPC). Many physicians. lacking research resources. may generalize their own patient registry data to the community. But practice populations are likely to differ significantly from community populations. This study compared demographics. health status. and medical care utilization in a sample of 990 elderly living in the community and 250 elderly patients registered at the St. Elizabeth Hospital Family Health Center in Youngstown. Ohio. The community survey and patient registries were comparable on key demographic characteristics. But statistically significant differences were observed for functional status and a number of chronic medical conditions. Comparisons of symptomatology. use of health aides. subjective health status. depression. and stress produced no significant differences. Overall health care utilization patterns were similar. The elderly family health center patients were more representative of the non-institutionalized elderly in the community than expected. And although the clinical significance remains uncertain. these findings suggest that this practice sample may be used with caution for COPC planning. But considerably more research must be undertaken in a variety of practice settings before the use of practice populations for COPC planning is widely applied.
Culture, illness, and the biopsychosocial model, Family medicine has appropriated the biopsychosocial model as a conceptualization of the systemic interrelationships among the biological. the psychological. and the social in health and illness. For all its strengths. it is questionable whether this model adequately depicts the centrality of culture to the human experience of illness. Culture (as meaning system) is not an optional factor that only sometimes influences health and illness; it is prerequisite for all meaningful human experience. including that of being ill. A more adequate model of the relationship between culture and illness would demonstrate the preeminence of culture in the experience of illness among all people. not just members of "exotic" cultures; would view healers as well as patients as dwellers in culture; would incorporate the role of culture as meaning system in linking body. mind. and world; and would promote the significance of the cultural context as a resource for research and therapy.
Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth, The authors have established a long-term tissue culture cell line (BON) derived from a metastatic human carcinoid tumor of the pancreas. The cells have been in continuous passage for 46 months. Tissue culture cells produce tumors in a dose-dependent fashion after SC inoculation of cell suspensions in athymic nude mice. BON tumors. grown in nude mice. are histologically identical to the original tumor; they possess gastrin and somatostatin receptors. synthesize serotonin and chromogranin A. and have a doubling time of approximately 13 days. The antiproliferative effects of the long-acting somatostatin analogue. SMS 201-995 (300 micrograms/kg. t.i.d.). and 2% alpha-difluoromethylornithine on BON xenografts in nude mice were examined. Tumor size was significantly decreased by day 14 of treatment with either agent and at all points of analysis thereafter until the animals were killed (day 33). In addition. tumor weight. DNA. RNA. and protein contents were significantly decreased in treated mice compared with controls. Establishment of this human carcinoid xenograft line. BON. provides an excellent model to study further the biological behavior of carcinoid tumors and the in vivo effect of chemotherapeutic agents on tumor growth.
Effects of Vibrio cholerae recombinant strains on rabbit ileum in vivo. Enterotoxin production and myoelectric activity, Previous studies have identified the effects of Vibrio cholerae and its enterotoxin. choleragen (CT A+B+). on the myoelectric activity of rabbit ileal loops in vivo. The response was defined as the migrating action potential complex. the single ring contraction that propels luminal contents aborad. In this study the same rabbit model is used to assess whether migrating action potential complex activity or fluid output is induced by recombinant strains of V. cholerae that produce no subunit of cholera toxin (CT A-B-) or only by the inactive binding subunit (CT A-B+). Three live strains were studied: El Tor wild-type N16961 (CT A+B+) and recombinant strains CVD106 (CT A-B+) and JBK70 (CT A-B-). Controls received sterile culture broth. Migrating action potential complex frequency in animals inoculated with CT A+B+ was significantly increased compared with that in all other experimental groups (P less than 0.01). Fluid output was also increased in animals inoculated with CT A+B+ compared with fluid output in all other groups (P less than 0.05). Migrating action potential complex frequency and fluid output in rabbits given CT A-B+ or CT A-B- did not differ from activity in controls. How these recombinant strains induce diarrhea is unknown. but the mechanism may involve bacterial colonization or production of an unknown toxin.
Abnormal esophageal motility. An analysis of concurrent radiographic and manometric findings, The findings of concurrent esophageal videofluoroscopy and manometry in 15 patients with major disturbances of esophageal motor function were evaluated and the data were analyzed from a fluid mechanical perspective. Each of 153 fluoroscopic barium swallow sequences was analyzed on a swallow-by-swallow basis. Two distinct pressure domains were identified: intrabolus pressure and pressure within a bolus-free contracting esophageal segment. Analyses in terms of these pressure domains showed specific and consistent correlations between the radiographic and manometric findings. Radiography was insensitive to contractions occurring in esophageal segments devoid of bolus fluid. whereas manometry was insensitive to contractions that did not occlude the lumen. It is concluded that using fluid mechanical principles of bolus transport allows meaningful comparison of esophageal motility as recorded by radiography and intraluminal manometry. However. the inherent limitations in the range of physical phenomena recorded by each modality make these techniques complementary for evaluating esophageal motor function.
Regional esophageal distribution and clearance of refluxed gastric acid, Regional differences in the esophageal distribution and clearance of refluxed gastric acid was studied in seven asymptomatic volunteers and seven patients with reflux esophagitis. Intraluminal pH was recorded for 3 postprandial hours from the distal. middle. and proximal esophagus on two separate occasions (with subjects in upright and supine positions). With the subjects in a supine position. about half of the acid reflux episodes reached the proximal esophagus in patients as well as in controls. This percentage decreased to 25% in patients and 29% in controls when they were upright. In both groups. the pH drops in the distal esophagus were significantly greater than in the proximal esophagus for both the supine and upright positions. In both patients and controls. a 4-5-fold greater acid exposure occurred in the distal esophagus. than in the proximal esophagus. In both patient and control groups. acid exposure time. as well as the number of reflux episodes in the distal esophagus. were significantly greater than that of the proximal esophagus (P less than 0.05). Spontaneous acid clearance time in the distal esophagus was significantly longer than that of the proximal esophagus in both positions (P less than 0.05) for both subject groups. In conclusion. regional differences exist in the exposure of the esophageal mucosa to refluxed gastric acid. These regional differences are more pronounced when subjects are upright than supine. Regional differences also exist in esophageal acid clearance. with clearance taking longer in the distal esophagus than in the proximal esophagus. The net effect of these phenomena is that acid exposure time in the distal esophagus is greater than that in the remainder of the esophagus.
Ion transport abnormalities in rectal suction biopsies from children with cystic fibrosis, Abnormalities in transepithelial electrolyte transport in cystic fibrosis rectum were analyzed by short-circuit current measurements on 11 control subjects and 11 subjects with cystic fibrosis in a modified Ussing chamber. As judged by the amiloride-sensitive component of the short-circuit current. electrogenic sodium absorption appeared unmodified in cystic fibrosis. In contrast. the short-circuit current response to specific stimuli of both cyclic adenosine monophosphate (cAMP)- and calcium-mediated chloride secretion was drastically altered in all of the cystic fibrosis biopsy specimens examined. Stimulation of the cAMP pathway by 8-bromo cAMP or forskolin resulted in a sustained increase in short-circuit current in control tissues (+ 2.51 +/- 0.63 microA/cm2) but in a slight change in the opposite direction in cystic fibrosis (-0.56 +/- 0.49 microA/cm2; P less than 0.05). Carbachol. a calcium-linked secretagogue. provoked a transient increase in short-circuit current in all of the control tissues (peak response. + 26.69 +/- 3.63 microA/cm2) but a transient change in the opposite direction in 6 of 11 cystic fibrosis tissues (-12.46 +/- 4.64 microA/cm2; P less than 0.05). In 2 of 11 patients with cystic fibrosis. however. a significant but subnormal and transient increase in short-circuit current was observed (+ 2.62 +/- 0.04 microA/cm2; P less than 0.05). whereas in 3 of 11 patients with cystic fibrosis a transient change in the opposite direction (-9.83 +/- 2.20 microA/cm2; P less than 0.05) was followed by a small and transient increase (+ 2.89 +/- 0.83 microA/cm2; P less than 0.05). Using the calcium-mediated secretory response therefore. patients with cystic fibrosis could be divided into two categories: a major population showing defective anion secretion but active cation secretion and a subclass (including three siblings) showing residual but subnormal anion secretion. The easy accessibility of rectal samples and the inversed direction of the cAMP- or calcium-provoked short-circuit current is of considerable advantage in the diagnosis of cystic fibrosis.
Increased Na(+)-H+ exchange in jejunal brush border membrane vesicles of spontaneously hypertensive rats, The spontaneously hypertensive rats and their genetically matched controls. Wistar-Kyoto. serve as models of essential hypertension. The present study was undertaken to determine whether brush border membrane vesicles obtained from jejunal enterocytes of spontaneously hypertensive rats show increased Na(+)-H+ exchange as part of a generalized membrane disorder. Brush border membrane vesicles were prepared from the jejunum of adult spontaneously hypertensive rats and Wistar-Kyoto rats using an Mg2+/ethylene glycol tetraacetic acid precipitation method. Uptake of 22Na by these vesicles was found to be into an osmotically sensitive intravesicular space rather than mere binding. Initial Na+ uptake by brush border membrane vesicles was greater in spontaneously hypertensive rats than in Wistar-Kyoto rats (P less than 0.05). Higher total and amiloride-sensitive Na+ uptake in spontaneously hypertensive rats occurred in the presence of an outwardly directed pH gradient. and uptake became statistically similar to that of Wistar-Kyoto rats in the absence of a pH gradient. Moreover. amiloride-insensitive Na+ uptake under an outwardly directed pH gradient did not differ significantly between the two groups. The enhanced Na(+)-H+ activity in spontaneously hypertensive rats is not due to altered membrane permeability to protons. as is shown by acridine orange-quenching studies. Kinetic studies for amiloride-sensitive Na+ uptake showed a greater Vmax in spontaneously hypertensive rats compared with Wistar-Kyoto rats (1.46 +/- 0.05 vs. 1.08 +/- 0.08 nmol.mg protein-1.7 s-1) but the Km values were similar in the two groups. These finding. along with similar findings previously reported in vascular smooth muscle and renal tissue of SHR. strongly suggest that an increased Na(+)-H+ exchange is related to the development of hypertension.
Cell type-dependent effect of phospholipid and cholesterol on bile salt cytotoxicity, The effect of phosphatidylcholine and cholesterol on bile salt-induced cytotoxicity was investigated. Experiments were performed in both human erythrocytes and cultured CaCo-2 cells. a model system for gastrointestinal epithelium. Hemolysis induced by 50 mmol/L sodium-taurocholate was reduced by both lecithin and cholesterol in a concentration-dependent manner. Cholesterol was 10 times more effective than phosphatidylcholine. Addition of only small amounts of the sterol to phosphatidylcholine/taurocholate solutions eliminated all cytotoxicity. The protective influence of cholesterol is probably mediated through a direct effect on the membrane. Incubation of erythrocytes with a cholesterol/taurocholate mixture greatly increased the cholesterol content of the membrane. With respect to sensitivity to bile salts and the protective effect of lecithin. CaCo-2 cells behaved very similar to erythrocytes. However. cholesterol failed to have any cytoprotective effect when used in combination with taurocholate or phosphatidylcholine/taurocholate solutions. Interestingly. at relatively high concentrations of cholesterol (cholesterol saturation index greater than 1.0). the sterol even increased cytotoxicity. This correlated with a cholesterol-induced shift of phosphatidylcholine from micelles to vesicles. which normally occurs in supersaturated model and human bile. The different sensitivity of the two cell types to the effect of cholesterol on bile salt damage might be caused by the difference in lipid membrane composition. In conclusion. CaCo-2 cells represent a physiologically more relevant model system to study bile cytotoxicity than erythrocytes. When extrapolated to gallbladder epithelial cells. these results could be relevant for the pathogenesis of gallstone disease. The increased cytotoxicity might be the signal by means of which supersaturated bile induces mucin hypersecretion by gallbladder epithelial cells.
Intraductal mucin-hypersecreting neoplasms of the pancreas. A clinicopathologic study of eight patients, Intraductal mucin-hypersecreting neoplasms of the pancreas with extreme dilatation of the main duct were studied in eight patients. They included five men and three women. aged 47-85 years. Five patients had a history of symptoms mimicking pancreatitis; four developed steatorrhea and/or diabetes. At endoscopic retrograde pancreatography. five patients showed an open ampulla filled with mucin. and six patients showed patchy filling defects in the ectatic main duct. Morphological examination showed extreme dilatation of the entire pancreatic duct in six patients and its tail segment in two patients. The duct segments filled with viscous mucin were lined by well-differentiated mucin-secreting cells. forming papillary foldings and occasionally showing cellular atypia. None of the patients had invasive tumor or metastasis. Six patients whose lesions were resected are alive and doing well (mean follow-up. 5.5 years). It is concluded that intraductal mucin-hypersecreting neoplasm is a pancreatic tumor with favorable prognosis. Because it shares many features with intraductal papillary neoplasm. a common pathogenesis of these pancreatic tumors is suggested.
Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia, A 20-year-old woman with abetalipoproteinemia underwent orthotopic liver transplantation for cirrhosis. affording access to her liver and small intestine for study. Before transplantation. her plasma apolipoprotein B concentration was less than 1 mg/dL according to enzyme-linked immunosorbent assay. whereas after transplantation her plasma apolipoprotein B concentration was 76 mg/dL (all apolipoprotein B-100). Apolipoprotein B content was reduced in her intestine and liver compared with normal and cirrhotic controls. Cultured hepatocytes from the patient's explanted liver secreted a 1.006 g/mL less than or equal to d less than or equal to 1.063 g/mL lipoprotein rich in apolipoprotein E and a 1.063 g/mL less than or equal to d less than or equal to 1.21 g/mL lipoprotein containing apolipoproteins E and A-I with no immunodetectable apolipoprotein B in the culture medium. Normal hepatocytes secreted very low-density lipoprotein and low-density lipoprotein containing apolipoprotein B-100. Abetalipoproteinemic intestinal apolipoprotein B messenger RNA concentration was 4-5-fold higher than control values. However. the patient's liver apolipoprotein B messenger RNA level was one fifth that of control normal and cirrhotic liver. Analysis of the patient's intestinal and hepatic apolipoprotein B messenger RNA for posttranscriptional stop-codon insertion revealed normally edited transcripts. These results suggest that apolipoprotein B is synthesized as the product of a normally edited messenger RNA transcript. but not secreted. in abetalipoproteinemia.
Relationship between insulin sensitivity, insulin secretion and glucose tolerance in cirrhosis, Hepatic insulin extraction is difficult to measure in humans; as a result. the interrelationship between defective insulin secretion and insulin insensitivity in the pathogenesis of glucose intolerance in cirrhosis remains unclear. To reassess this we used recombinant human C-peptide to measure C-peptide clearance in cirrhotic patients and controls and thus derive C-peptide and insulin secretion rates after a 75-gm oral glucose load and during a 10 mmol/L hyperglycemic clamp. Cirrhotic patients were confirmed as insulin-insensitive during a euglycemic clamp (glucose requirement: 4.1 +/- 0.1 mg/kg/min vs. 8.1 +/- 0.5 mg/kg/min; p less than 0.001). which also demonstrated a low insulin metabolic clearance rate (p less than 0.001). Although intolerant after oral glucose. the cirrhotic patients had glucose requirements identical to those of controls during the hyperglycemic clamp (cirrhotic patients: 6.1 +/- 1.0 mg/kg/min; controls: 6.3 +/- 0.7 mg/kg/min). suggesting normal intravenous glucose tolerance. C-peptide MCR was identical in cirrhotic patients (2.93 +/- 0.16 ml/min/kg) and controls (2.96 +/- 0.24 ml/min/kg). Insulin secretion was higher in cirrhotic patients. both fasting (2.13 +/- 0.26 U/hr vs. 1.09 +/- 0.10 U/hr; p less than 0.001) and from min 30 to 90 of the hyperglycemic clamp (5.22 +/- 0.70 U/hr vs. 2.85 +/- 0.22 U/hr; p less than 0.001). However. with oral glucose the rise in serum C-peptide concentration was relatively delayed. and the insulin secretion index (secretion/area under 3-hr glucose curve) was not elevated. Hepatic insulin extraction was reduced both in fasting and during the hyperglycemic clamp (p less than 0.001).
Acidosis protects against lethal oxidative injury of liver sinusoidal endothelial cells, The purposes of this study were to determine the pH dependence of lethal endothelial cell injury during oxidative stress and the pH dependence of those cellular mechanisms proposed to result in endothelial cell killing. Oxidative stress was produced in rat liver sinusoidal endothelial cells with H2O2 (5 mmol/L). Cell survival was dependent on the extracellular pH. Indeed. after 180 min of incubation with H2O2. cell survival was only 27% at pH 7.4. 45% at pH 6.8 (p less than 0.05) and 62% at pH 6.4 (p less than 0.05). Despite improved cell survival at pH 6.4 compared with pH 7.4. the magnitude of ATP hydrolysis and glutathione depletion was similar. In contrast to cell survival. lipid peroxidation as measured by malondialdehyde generation was increased twofold at pH 6.4 compared with pH 7.4. A rapid and profound loss of the mitochondrial membrane potential occurred during oxidative stress at pH 7.4 that was delayed at pH 6.4 (0.3% vs. 20% of the initial value at 30 min. p less than 0.0001). After 60 min of incubation with H2O2. NAD(P)H oxidation was greater at pH 7.4 than at pH 6.4 (100% vs. 64%. p less than 0.05). The results indicate that the protective effect of acidosis against cell death during oxidative stress is associated with the inhibition of NAD(P)H oxidation and delayed loss of the mitochondrial membrane potential. Acidosis appears to maintain organelle and cell integrity during oxidative stress by influencing the redox status of NAD(P)H.
Replacement of cholesterol gallstones by murideoxycholyl taurine gallstones in prairie dogs fed murideoxycholic acid, The effect of two hydrophilic bile acids. murideoxycholic acid (3 alpha.6 beta-dihydroxy-5 beta-cholanoic acid) and ursodeoxycholic acid. on cholesterol and bile acid metabolism and hepatic pathology and gallstone composition was studied in the prairie dog. Cholesterol gallstones were induced by feeding a diet containing 1.2% cholesterol for 75 days. The animals were divided into six groups. and gallstone regression was studied as follows: groups 2 and 5. chow plus 0.2% cholesterol; groups 3 and 6. chow plus 0.2% cholesterol plus 0.15% ursodeoxycholic acid; groups 4 and 7. chow plus 0.2% cholesterol plus 0.15% murideoxycholic acid. Animals in groups 2 to 4 were killed after an additional 6 wk; animals in groups 5 to 7 were killed after an additional 12 wk. Gallstone dissolution did not occur in any group. The gallstones in groups 2. 3. 5 and 6 were typical cholesterol aggregates. as determined by polarized light microscopy and Fourier transform infrared spectrometry. The gallstones of the murideoxycholic acid group were large. solitary. dark stones that appeared radiopaque under 22 kVp x-ray examination. Scanning electron microscopy showed that in these stones the cholesterol crystals had been replaced by an amorphous material. both within the stone and on the stone surface. Chemical analysis indicated that at the end of 12 wk the calcium/sodium salt of the taurine conjugate of murideoxycholic acid (murideoxycholyl taurine) comprised 70% of the stones; protein. cholesterol and small amounts of other bile salts were also present. In vitro studies confirmed the insolubility of the sodium and calcium salts of murideoxycholyl taurine. These studies indicate that the hydrophilic bile acids. murideoxycholic acid and ursodeoxycholic acid. did not achieve gallstone dissolution under the conditions used. In the animals fed murideoxycholic acid. an insoluble calcium salt of murideoxycholyl taurine replaced cholesterol as the major constituent of gallbladder stones. This is the first example of an insoluble dihydroxy taurine-conjugated bile acid; administration of the unconjugated bile acid induced precipitation of a kind of gallstone not previously reported. The final result was transformation of cholesterol stones to bile salt stones.
Clinical significance of two forms of IgM antibody to hepatitis delta virus, Separation of 7-8 S and 19 S forms of serum IgM antibodies to the hepatitis delta virus by rate-zonal centrifugation was carried out on serum from 24 patients with hepatitis delta virus infection: 4 patients with acute. self-limited hepatitis; 5 patients with hepatitis delta virus superinfection progressing to chronicity; and 15 patients with chronic hepatitis delta virus. The high molecular weight IgM form (19 S) was predominantly detected in acute hepatitis delta virus cases. whereas the low molecular weight (7 S) form was found in chronic hepatitis delta virus cases. The serological profile of these two forms of IgM antibody to hepatitis delta virus was investigated in serial samples from five patients with acute hepatitis delta virus superinfection that evolved to chronic hepatitis delta virus. We found that. in the acute stage of the disease. the 19 S form was predominant. whereas 6 mo later a predominance of 7-8 S IgM was observed. These results suggest that IgM antibody to hepatitis delta virus antibody forms are different in acute and chronic hepatitis delta virus infection and that their detection only helps in differentiating an acute infection from a chronic infection but not a hepatitis delta virus-hepatitis B virus-HBV coinfection from hepatitis delta virus superinfection in the acute stage of the disease.
Persistence of hepatitis B viral DNA after serological recovery from hepatitis B virus infection, Chronic hepatitis B virus infection is a major medical problem worldwide. Apart from HBsAg carriers. hepatitis B virus has also been identified in some HBsAg-individuals with or without antibodies to viral antigens. The molecular mechanisms underlying hepatitis B virus persistence in HBsAg-individuals are unresolved. however. To identify a possible genetic basis for viral persistence. we cloned the viral genome from the liver of a patient serologically immune to hepatitis B virus infection. DNA sequence analysis of the complete viral genome identified numerous mutations in all viral genes. Analysis of the biological effects of these mutations revealed three major findings: a low level of HBsAg synthesis. absence of HBeAg production and a defect terminating viral replication. These data suggest that mutations accumulating during the natural course of hepatitis B virus infection may be a mechanism underlying viral persistence in HBsAg-individuals. presumably through escape from immune surveillance.
Specificities of serum alpha-fetoprotein in HBsAg+ and HBsAg- patients in the diagnosis of hepatocellular carcinoma, Serum alpha-fetoprotein level is often elevated in patients with chronic liver disease and patients with hepatocellular carcinoma. One of the most difficult problems frequently encountered in practice is differentiating hepatocellular carcinoma from chronic liver disease. This study investigated the specificity and predictive value positive of serum alpha-fetoprotein at various levels in the diagnosis of hepatocellular carcinoma. using 54 patients with histologically proven hepatocellular carcinoma and 200 patients with chronic liver disease (40 patients with chronic active hepatitis and 160 patients with cirrhosis) as nontumor controls. Among 254 patients. 170 (66.9%) were HBsAg+. A wide range of overlap (from 0 to 6.400 ng/ml) in the distribution of serum alpha-fetoprotein levels between hepatocellular carcinoma and chronic liver disease patients was observed mainly among HBsAg+ patients. In contrast. the overlapping range of serum alpha-fetoprotein levels between HBsAg- patients with hepatocellular carcinoma and chronic liver disease was remarkably narrow (from 0 to 200 ng/ml). Therefore the specificity and predictive value positive of alpha-fetoprotein at a given level were significantly lower in HBsAg+ than in HBsAg- patients. especially when alpha-fetoprotein was between 25 and 200 ng/ml. The specificities of alpha-fetoprotein at 200 ng/ml and 400 ng/ml in HBsAg+ patients were 79.8% and 91.5%. respectively. whereas these specificities were both 100% in HBsAg- patients. The predictive values positive at 200 ng/ml and 400 ng/ml in HBsAg+ patients were 53.6% and 72.5%. respectively. in contrast to 100% at both levels in HBsAg- patients. The serum alpha-fetoprotein level. which showed a predictive value positive of 95% in HBsAg+ hepatocellular carcinoma patients. was 3.200 ng/ml. whereas that in HBsAg- hepatocellular carcinoma patients. was 200 ng/ml. We conclude that serum HBsAg status should be considered when serum alpha-fetoprotein is measured as an independent test to diagnose hepatocellular carcinoma. and suggest that regular serum alpha-fetoprotein determination may be more useful in HBsAg- patients with chronic liver disease for the early diagnosis of hepatocellular carcinoma than in HBsAg+ patients.
Expression of androgen receptor mRNA in human hepatocellular carcinomas and hepatoma cell lines, The expression of androgen receptor messenger RNA in hepatocellular carcinomas and hepatoma cell lines was studied using Northern-blot analysis and the complementary DNA-polymerase chain reaction method. Androgen receptor messenger RNAs were detected (although in low levels) in both hepatocellular carcinoma tissues and noncancerous tissues of the liver in all eight cases we studied. except for the tumor sample of one case. None of the hepatoma cell lines studied. however. expressed detectable levels of androgen receptor messenger RNA except for the SK-HEP-1 hepatoma cell line.
Current problems in haematology. 2: Hereditary spherocytosis, Hereditary spherocytosis is a relatively common haematological disorder and will be encountered by all haematologists. The abundance of new information. dealing principally with molecular and genetic aspects of pathophysiology. is beginning to have implications for its investigation and management. While these advances have not yet exerted a large influence at therapeutic level. the promise of such advents as prenatal diagnosis make this an exciting field to watch.
Routine histological compared with immunohistological examination of bone marrow trephine biopsy specimens in disseminated neuroblastoma, The ability to detect infiltration in bone marrow biopsy specimens from patients with disseminated neuroblastoma was assessed by immunohistological and routine histological methods. Frozen cores from 33 staging procedures were tested with UJ13A and UJ127.11. Immunopositive tumour cells were found in 10 of 17 staging procedures in which tumour was detectable by routine histological methods. Positive cells or stromal material were also found in eight of 12 staging procedures in which distorted architecture and fibrosis. but no obvious tumour. had been noted. Paraffin wax embedded cores from 29 of the same staging procedures were tested with antibodies against neurone specific enolase and neurofilament. Only a single core reacted with anti-neurofilament antibody. Neurone specific enolase positive cells or stromal material were found in nine of 15 staging procedures in which obvious tumour was detectable. Although these immunohistochemical techniques proved inferior to routine histology in their ability to detect obvious tumour. the demonstration of immunopositive stromal tissue which was not frankly malignant supports the view that distorted. fibrotic marrow may reflect persistence of neuroectodermal tissue and justifies its distinction from normal marrow when reporting the response to treatment.
Method for auditing turnround time in histopathology related to user requirements, Histopathology audit schemes have concentrated on the accuracy of diagnosis or the standard of technical work. The most appropriate measure of specimen report time for histopathology was assessed. The simplest method is to calculate the mean or median number of days from receipt of specimens to issue of report. but this takes no account of clinical practice. An alternative approach is to compare the laboratory's performance with the clinicians' requirements. Clinicians were invited to complete a questionnaire specifying the reporting times they required subdivided by tissue type. clinical suspicion of malignancy. and bed occupancy of the patient. The questionnaire showed that there were distinct differences in clinicians' requirements. The turnround time for each category of specimen was calculated and expressed in three ways. The traditional method of quoting a median value showed very few differences among the categories. A comparison of the department's performance with the clinicians' requirements. using an arbitrary cut-off point of satisfying at least 80% of the clinicians' most stringent requirements or an achievement index. however. provided useful information for refining laboratory priorities.
Analysis of adhesion molecules in the immunopathogenesis of giant cell arteritis, To explore the role of adhesion molecules in mediating mononuclear cell localisation. development of the granulomatous reaction. and cell mediated damage to the arterial wall in giant cell arteritis. 17 temporal artery biopsy specimens were examined. Eleven showed the histological features of giant cell arteritis and six showed no evidence of arteritis. All were examined for the expression of LFA-3. ICAM-1 and its receptor LFA-1. and HLA-DR. Temporal arteries with early features of arteritis. as well as histologically unaffected skip areas. showed a regional induction of ICAM-1 expression. but not HLA-DR. on smooth muscle cells of the media. ICAM-1 expression was detected in areas where a clinically important mononuclear cell infiltrate had not yet developed. In more florid cases of giant cell arteritis there was an additional widespread induction of ICAM-1 expression on intimal myofibroblasts. Strong expression of ICAM-1. HLA-DR. and LFA-3 was found on macrophages. epithelioid cells. and giant cells comprising the granulomatous lesion. The pattern of expression of these adhesion molecules suggests that they have a role in leucocyte traffic into the vascular lesion as well as in mediating the intercellular interactions which constitute the granulomatous response.
Value of quantitative nucleolar features in the preoperative cytological diagnosis of follicular neoplasias of the thyroid, Nucleolar prevalence. size. and outline were investigated on cytological material from cold thyroid nodules obtained by fine needle aspiration. The percentage of nucleolated nuclei in follicular adenoma (32 cases) was less than in follicular carcinoma (26 cases). In adenoma most nuclei contained one nucleolus. and nuclei with two or more nucleoli were less common than in carcinoma where most cases showed the highest nucleolar diameter values. There was some overlap between adenomas and carcinomas. however. when the mean of the 10 largest values of the major nucleolar diameter was considered. In follicular carcinoma the percentage of marginated nucleoli--that is. those touching the nuclear membrane--was. in general. greater than 20%; in adenoma the values were equal to or lower than 16%. The overlap index showed that the percentages of marginated nucleoli and nucleolated nuclei are the two best discriminatory features between adenoma and carcinoma.
Helicobacter pylori and ABO blood groups, A serological study was carried out to assess the prevalence of antibodies to Helicobacter pylori and compare it with the distribution of ABO blood groups. Serum samples from 402 healthy blood donors were tested with an IgG enzyme linked immunosorbent assay. There was no difference in blood groups between those who were seropositive and those who were seronegative. which suggests that blood group O is not a risk factor for acquiring H pylori infection.
Anticardiolipin antibodies in leptospirosis, The clinical course and serology of 16 cases of leptospirosis in an area with an unusually high endemic infection rate were studied to gain further insight into the pathology of the secondary immune phase that is typical of the disease. IgG anticardiolipin antibody concentrations were measured by immunoassay and found to be increased in eight serologically confirmed cases with severe complicated disease. compared with eight patients with relatively uncomplicated leptospirosis who had IgG anticardiolipin concentrations within the control reference range. This previously unreported association suggests that leptospira may induce vascular endothelial injury in severe cases and expose crypt antigens or induce conformational change of cell surface phospholipids. Leptospirosis may provide a model for an infective origin of some cases of the antiphospholipid syndrome.
Cachexia and tumour necrosis factor-alpha in cytomegalovirus infection, Although cachexia is a common feature of cytomegalovirus infection. little is known about its cause. To explore any contributory role that tumour necrosis factor-alpha (TNF) might have the serum concentrations of TNF in eight patients who developed CMV disease after liver transplantation were investigated. All patients exhibited pronounced and long lasting increases in TNF serum concentrations. Increased endogenous TNF concentrations were associated with weight loss and anorexia. In contrast. liver transplant recipients without CMV disease showed no weight loss.
Variations in the prevalence and extent of periodontitis, A national survey of employed adults showed a decrease in the extent and severity of periodontal disease in comparison with findings from earlier studies. Using data from that survey. this report evaluates the association of socioeconomic factors--race. education. income and dental insurance. as well as most recent dental visit--with the prevalence and extent of periodontal disease. Periodontitis was more prevalent and usually more extensive in persons who are black. have less education or had not seen a dentist in three or more years. Having dental insurance was not associated with better periodontal health.
Managing aphthous ulcers: laser treatment applied, The recurrent aphthous ulcer is a common oral ulcerative condition. Therapies are pharmaceutical in nature. remain palliative and do not alleviate pain. Carbon dioxide laser therapy was used to treat a minor form of the ulcer (canker sore); the laser therapy reduced or eliminated the pain and inflammation with normal wound healing.
Constipation--some provocative thoughts [editorial, Constipation is a collective term with different definitions and manifestations. In the present communication. I hope to shed light on the pathogenesis. investigation. and treatment of these manifestations. The levator ani is the principal muscle of defecation; together with anorectal reflex actions. it conducts the act of defecation. Strainodynia is the term I give to excessive and exhaustive straining at defecation. Band strainodynia has normal stool character but elevated rectal neck pressure due to the presence of a fibrous band in the rectal neck. Diet strainodynia presents with lower stool weight and frequency than normal; the internal anal sphincter is fibrous. The stools in levator strainodynia have been repeatedly obstructed at defecation due to levator dysfunction. Idiopathic oligofecorrhea or infrequent defecation was studied in 146 patients. Three stages could be identified: the deep and the everted intersphincteric groove and the cone anus. Fecoflowmetry is introduced as a new method for investigating anorectal disorders. It measures the defecated volume per time unit. and provides quantitative as well as qualitative data concerning the act of defecation. Changes in the fecal flow parameters or curve configuration from normal point to a defecation disorder.
Practice patterns and costs of hospitalization for upper gastrointestinal hemorrhage, We conducted an observational study at three hospitals in Boston to examine the patterns of practice and the costs involved in the medical management of noncirrhotic. upper gastrointestinal bleeding. A total of 111 patients were identified and studied: 42 from hospital 1. 38 from hospital 2. and 31 from hospital 3. There were no significant differences in the management of the patients. except for the more frequent use of upper gastrointestinal radiography at hospital 3 and the more frequent use of cimetidine at hospital 2. Only a small percentage (3-7%) of patients required surgery. and overall mortality (0-8%) was low. The average cost of hospitalization. determined by using the New England Medical Center cost model. was calculated for direct costs ($3.180). The majority of costs incurred were for hospital bed or intensive care unit stay (63%) and transfusion of blood products (14%). with costs for physicians' services (9%). endoscopy (2%). and upper gastrointestinal radiography (1%) accounting for only a small percentage. This study demonstrates remarkable similarity in practice patterns and resource utilization at three different hospitals and provides data on the actual costs involved in hospitalization for noncirrhotic. upper gastrointestinal hemorrhage.
Early gastric cancer: a clinicopathologic study, We report our experience. between 1973 and 1989 of 302 patients with gastric cancer in a Dutch general hospital. In 144 (47.7%) of them gastric resection was performed. Twenty-eight patients had early gastric cancer (EGC) (9.3% of the entire series and 19.4% of the resected specimens). Multicentricity of EGC was noted in 3 patients (10.7%). The incidence of EGC decreased slightly during consecutive 8-year intervals. There were 16 men and 12 women (mean age 64 and 66 years. respectively). Standard biphasic contrast radiographic studies of the upper gastrointestinal tract diagnosed or suggested malignancy in all but one patient. Endoscopy with directed biopsy diagnosed malignancy in all patients. Twenty-one lesions (67.7%) were localized to the antral region. Type IIc was most frequent (38.7%). There were 21 intestinal-type and 10 diffuse-type EGC by the Lauren classification. The incidence of intestinal-type EGC decreased during two consecutive 8-year periods. All type I and IIa lesions were of the intestinal type. whereas all diffuse-type EGCs were either type IIc or III. Lymph node metastasis was observed in 9.7% of the lesions. The incidence of lymph node metastasis increased from 0% in mucosal cancer to 20% in submucosal cancer. The overall 5-year survival rate was 91.3%: (diffuse type 100% and intestinal type 85.7%). The 5-year survival rate was 100% in mucosal cancer and 81.8% in submucosal cancer.
Prolonged gastric pH monitoring in responder and nonresponder duodenal ulcer patients: response to placebo and to H2-blocker administration, We evaluated the circadian pattern of gastric acidity by prolonged intraluminal pHmetry in 15 "responder" and 10 "nonresponder" duodenal ulcer patients after nocturnal administration of placebo. ranitidine. and famotidine. Acidity was measured during predefined periods under the different drug regimens in the two groups of subjects. and a comparison was performed both within and between groups. With placebo. significantly lower median 24-h pH values were detected in patients with resistant ulcer than in responders (1.13 versus 1.63). On the contrary. no statistical difference was detected between the two groups during any time of day after administration of either ranitidine or famotidine. Within each group. no significant difference was noted between the two different H2-blockers. Thus. our data suggest that patients with resistant duodenal ulcer display an increased gastric acidity in control conditions but a "normal" response to administration of antisecretory drugs.
Preoperative diagnosis by enteroclysis of unsuspected closed loop obstruction in medically managed patients, Initial observation and evaluation of patient progress have reduced the number of operative interventions in the management of small intestinal obstruction. The differentiation of simple mechanical from strangulating obstructions has remained difficult. Strangulation is not an invariable component of a closed loop obstruction. We report 27 patients with small bowel obstruction initially managed nonsurgically. in whom enteroclysis 2-8 days after admission demonstrated unsuspected closed loop obstruction. In 25 of the 27 patients. subsequent surgery confirmed the radiologic diagnosis: all the obstructed loops were viable and there was no operative mortality. Our experience suggests that the early performance of enteroclysis should be considered in patients with small bowel obstruction undergoing a trial of nonoperative management.
Budd-Chiari syndrome in Israel: predisposing factors, prognosis, and early identification of high-risk patients, In twenty-seven patients with venography-documented Budd-Chiari syndrome (BCS). underlying diseases included polycythemia vera (nine patients). membranous occlusion of the inferior vena cava (three). and cirrhosis (two). In only nine patients did the syndrome occur in the absence of any predisposing factor. All patients with a membranous web were relatively young (mean age 29 years) and were born in Morocco. With regard to prognosis. three groups could be delineated. Eight patients formed a rapidly progressive group. with mean survival from first symptom of only 4.3 weeks. and were characterized mainly by their relatively advanced age and minimal enlargement of the spleen.
Echo Doppler duplex scanner and color in the study of portal hypertension, In the present state of the art. the Doppler duplex scanner provides much information about portal hypertension and its associated pathology. liver cirrhosis. hepatic malformations. vascular or avascular structures. hepatic transplants. and ascites. Its usefulness for experimental studies. providing new insight into the pathophysiology of this disease. has been proven. It is limited by the subjectivity of the conclusions. and by its poor feasibility in fat patients and those with excessive abdominal gas. However. the noninvasive nature of Doppler and its relative low cost make it a useful first step in the evaluation of portal hypertension.
Depressed adenoma of the stomach. Conceptual review and study of five cases, Depressed gastric adenoma is a recently featured lesion. distinguished by a depression in the gastric mucosa. with histologic changes of conventional adenomatous polyp. We observed five cases of depressed gastric adenoma. one of them associated with a peptic ulcer. another with a gastric stump. and yet another with an early gastric carcinoma. None of the cases was detected clinically by radiology or endoscopic study. Endoscopically. this lesion stimulates a peptic ulcer at a re-epithelialization stage or an early carcinoma of the depressed type. Histologically. all the cases showed dysplastic changes of varying degrees. with a relevant risk of malignancy. A similarity is shown to other lesions described in the gastric mucosa.
Maximal activity of phosphate-dependent glutaminase and glutamine metabolism in septic rats, The activity of phosphate-dependent glutaminase and glutamine metabolism by tissues known markedly to utilize or synthesize glutamine (or both) were studied in rats made septic by cecal ligation and puncture technique and compared with the same measures in rats that underwent sham operation (laparotomy). Blood glucose level was not markedly different in septic rats. but lactate. pyruvate. alanine. and glutamine levels were markedly increased. Conversely. blood ketone body concentrations were significantly decreased in septic rats. Both plasma insulin and glucagon levels were markedly elevated in response to sepsis. The maximal activity of phosphate-dependent glutaminase was decreased in the small intestine. increased in the kidney and mesenteric lymph nodes. and unchanged in the liver of septic rats. Arteriovenous concentration difference measurements across the gut showed a decrease in the net glutamine removed from the circulation in septic rats. Arteriovenous concentration difference measurements for glutamine showed that both renal uptake and skeletal muscle release of the amino acid were increased in response to sepsis. whereas measurements across the hepatic bed showed a net uptake of glutamine in septic rats. Enterocytes isolated from septic rats exhibited a decreased rate of utilization of glutamine and production of glutamate. alanine. and ammonia. whereas lymphocytes isolated from septic rats showed an enhanced rate of utilization of glutamine and production of glutamate. aspartate. and ammonia. It is concluded that. during sepsis. glutamine uptake and metabolism are enhanced in renal and lymphoid tissue but decreased in that of the small intestine. with increased rates of release by skeletal muscle; however. the liver appears to utilize glutamine in septic rats.
Adenylate cyclase activity in various components of the sarcoplasmic reticulum: a cytochemical study of ventricular biopsies from diseased human hearts, Localization of adenylate cyclase (ACLase) activity was studied in biopsies of diseased human myocardium by means of electron microscopic cytochemistry. Five right and seven left ventricular biopsy specimens were obtained from patients with idiopathic dilated (3 cases) and hypertrophic (3 cases) cardiomyopathies. various acquired (3 cases) and congenital (1 case) heart diseases. and other heart diseases (2 cases). Catecholamine-stimulated ACLase activity was assessed relative to the fine structure of cardiocytes. The most intense ACLase activity was found in the sarcoplasmic reticulum (SR). but activity was also present in the sarcolemma. The enzyme activity was present in a wide morphologic spectrum of components of the SR. including junctional SR of internal and peripheral coupling (12 cases). free SR in association with myofibrils (6 cases). and free SR in association with mitochondria (5 cases). ACLase activity in junctional SR in the human myocardium resembles the findings in hearts of other mammalian species. The enzyme activity in human myocardial SR may represent a local regulatory function of the ACLase-cyclic AMP-phosphodiestrerase system in the SR components.
Continuous subcutaneous octreotide infusion: dose-response relationships between metabolic effects and octreotide clearance in patients with insulin-dependent (type 1) diabetes, Octreotide (Sandostatin). a potent and long-acting octapeptide analogue of somatostatin. exhibits variable metabolic effects in type 1 diabetes. We have postulated that interindividual variability in octreotide metabolism could be responsible in part for the differences in metabolic responses reported in previous clinical studies. To this end. we determined plasma levels and MCR of octreotide during 24-hour continuous SC infusion (low dose. 200 micrograms; high dose. 400 micrograms) in nine female. C peptide-negative patients with type 1 diabetes. The metabolic effects of the analogue were assessed by measuring serum glucose. free insulin. glucagon. GH. and PP levels before and at 1- to 2-hour intervals during each dose of the analogue or control (0.9% saline solution) infusion in a single-blind randomized manner. Mean daytime (0800-0000 hours) and bedtime (0000-0800 hours) serum glucose levels decreased significantly (p less than 0.05 to 0.02) during analogue therapy compared with control. Mean serum free insulin levels were significantly (p less than 0.02) greater during octreotide infusion compared with control. despite the similar daily insulin requirements. Both doses of the analogue effectively suppressed 24-hour GH by 50%. glucagon by 50%. and PP by 80%. Steady-state octreotide levels varied considerably among patients (low. mean +/- SEM). 1000 +/- 101. range 638 to 1375 pg/ml; high. mean 1940 +/- 147. range 1032 to 2462 pg/ml). Although mean MCR values were similar with both doses. we observed greater interindividual variability (low. mean 2.45 +/- 0.30. range 1.31 to 3.78 ml/kg/min; high. mean 2.36 +/- 0.19. range 1.68 to 3.48 ml/kg/min).
Cardiac resuscitation by extracorporeal circulation after failure of conventional CPR, After cardiac arrest. return of cardiac function and effective circulation are contingent on prompt restoration of myocardial blood flow. Because conventional closed-chest CPR has limited hemodynamic efficiency. we investigated venoarterial ECC utilizing peripheral vascular access as an alternative for cardiac resuscitation. Ventricular fibrillation was induced in domestic pigs by alternating current delivered to the endocardium of the right ventricle. Conventional closed-chest CPR was begun after 10 minutes. In each instance. precordial compression and external defibrillation failed to restore a viable rhythm. ECC was begun at 15 minutes at an average flow rate of 183 ml/kg/min. In each of eight animals. sinus rhythm was restored. In six of these eight animals. spontaneous circulation was reestablished after an average interval of 152 minutes. When epinephrine was administered concomitantly with ECC in an additional eight animals so as to maintain mean aortic pressure between 60 and 100 mm Hg. sinus rhythm and spontaneous circulation were reestablished in each pig after an average of only 23 minutes. The effects of ECC in conjunction with epinephrine were then compared with those of conventional precordial compression in conjunction with epinephrine (sham ECC). In contrast to ECC. which successfully resuscitated each of five animals. none of five sham ECC-treated animals was resuscitated by continued precordial compression and maximal doses of epinephrine (p less than 0.01). We conclude that ECC in conjunction with epinephrine emerges as a highly effective experimental intervention for resuscitation when conventional techniques of precordial compression and external defibrillation fail to reverse cardiac arrest.
Importance of bile acid structure in amelioration of griseofulvin-induced murine protoporphyric hepatopathy, This study investigated the effects of bile acid structure on griseofulvin-induced murine hepatopathy and explored the mechanism(s) of cholestasis in this model of protoporphyria. Mice were fed pulverized chow with cholate. chenodeoxycholate. or ursodeoxycholate. with or without griseofulvin. After 1 to 4 weeks. bile flow. bile acid excretion and composition. biliary protoporphyrin excretion. hepatic protoporphyrin contents. liver histology. and griseofulvin plasma concentrations were determined. Additionally. bile acid absorption was measured. Griseofulvin induced a progressive increase in liver weight. hepatic protoporphyrin content. and histopathologic evidence of cholestasis. Biliary protoporphyrin excretion increased and pigmented gallbladder microliths developed. Bile flow and bile acid excretion fell in relation to liver weight but not in relation to body weight. Cholic acid augmented biliary protoporphyrin excretion. markedly reduced hepatic protoporphyrin content. and obviated the development of intrahepatic biliary thrombi. Ursodeoxycholate and chenodeoxycholate both reduced biliary protoporphyrin excretion. This was associated with bile acid compositional changes. particularly a fall in cholic acid. Although histopathologic abnormalities were not altered. these bile acids reduced hepatic protoporphyrin contents. Bile acid treatments with griseofulvin all increased bile flow and bile acid excretion relative to controls. but differences in the relationship of bile flow to bile acid structure on protoporphyrin disposition. They document biliary excretion as the principal mode of cholic acid amelioration of griseofulvin-induced hepatopathy. They also suggest distinctive roles for griseofulvin and protoporphyrin in the generation of the cholestasis.
Growth hormone-enhanced lipolysis in the spontaneously diabetic BB rat, Responsiveness to lipolytic agents and glycerol output from rat adipocytes is altered by the diabetic process. We have confirmed reports that preincubation is required for growth hormone-induced lipolysis in isolated fat cells. Isolated fat cells were prepared from the epididymal fat pads of normal and spontaneously diabetic BB Wistar rats (weight. 250-400 gm) and their nondiabetic littermates by collagenase digestion. Lipolysis was measured by glycerol release after sequential perifusion with buffer alone. bovine growth hormone 1 microgram/ml. buffer alone. and epinephrine. 0.5 mumol/L. In each case isolated fat cells from control. nondiabetic. and spontaneously diabetic rats were perifused under two conditions. with and without preincubation with bovine growth hormone. Isolated fat cells from control and nondiabetic rats did not respond to bovine growth hormone without preincubation. When preincubation with bovine growth hormone. response in control rats increased from nonpreincubated glycerol values of 4.9 to 13.5 nmol glycerol released/10(6) cells/min. In contrast to controls. non-preincubated isolated fat cells from spontaneously diabetic rats that were stimulated with 1 microgram/ml bovine growth hormone went from 18.0 to 42.6 nmol of glycerol released/10(6) cells/min. No preincubation was necessary in spontaneously diabetic rats. In addition. in all situations in which preincubation or the diabetic state enhanced lipolysis with growth hormone. similar enhancement was seen with epinephrine. For nondiabetic rats both preincubated and nonpreincubated isolated fat cells respond minimally to bovine growth hormone. In conclusion. preincubation with bovine growth hormone is not required to elicit lipolysis in perifused isolated fat cells from spontaneously diabetic BB rats.
Cardiovascular risk factors in young snuff-users and cigarette smokers, We studied cardiovascular risk factors in 21 young men who were habitual snuff-users. and compared them with the same risk factors in 18 non-tobacco-users and 19 cigarette smokers of the same age and body mass index. Both snuff-users and smokers showed increased levels of alcohol and coffee consumption and a decreased level of physical exercise compared to non-users. Both groups of tobacco-users showed increased serum insulin levels compared to the control group at similar blood glucose concentrations. In contrast to the smokers. snuff-users showed no significant elevation of diastolic blood pressure. haemoglobin concentrations. white cell count. serum cholesterol or triglyceride levels. Snuff users had higher plasma fibrinogen levels than non-users (P = 0.07). The use of snuff by young men appears to have less impact than smoking on cardiovascular risk factors. with the possible exception of elevated serum insulin and plasma fibrinogen levels.
Lovastatin therapy in heterozygous familial hypercholesterolaemic patients: effect on blood rheology and fibrinogen levels, Thirteen heterozygous familial hypercholesterolaemic patients were treated with lovastatin for 1 year. and were investigated for the effect on lipid profile. blood rheology and fibrinogen levels. A significant dose-dependent reduction in serum levels of total and LDL-cholesterol. Apo B and the ratio of total cholesterol to HDL-cholesterol was noted. Improvement in red blood cell filterability and an increase in fibrinogen levels were also observed. We conclude that the hypocholesterolaemic effect of lovastatin in familial hypercholesterolaemia is accompanied by changes in blood rheology. While some of these haemorheological changes may be considered beneficial. others may be regarded as unfavourable. The net effect of lovastatin therapy on the coronary risk of familial hypercholesterolaemic patients warrants further investigation.
Coffee, coronary heart disease and mortality in middle-aged Swedish men: findings from the Primary Prevention Study, The effect of coffee consumption on the incidence of coronary heart disease (CHD) was studied prospectively in a population sample of 6765 men aged 51-59 years at baseline during the period 1974-1977. and free of myocardial infarction (MI) prior to the screening. During a 7.1-year follow-up there were 230 non-fatal myocardial infarctions. 169 coronary deaths and 478 deaths from all causes. Among men who were smokers at baseline there was no relationship between either non-fatal MI or death from CHD. and coffee consumption. Among non-smokers. a weak but far from significant trend towards an increasing incidence of CHD in heavy consumers of coffee was observed. There was an inverse relationship between mortality from all causes and coffee consumption.
Pitfalls in the diagnosis of drug smuggler's abdomen, Narcotics "body packing" can be detected in abdominal X-rays by the ring shadow caused by air trapped in the packs. In a series of 82 cases admitted for abdominal X-ray in Helsinki. Finland. in 1982 through 1988. we encountered 9 (11.0%) true positives. 3 (3.6%) false positives. and 1 (1.2%) false negative. The false positives were due to the constipation often associated with the narcotics abuse. The false negative X-ray diagnosis was attributable to an inexperienced radiologist. False negatives may also be associated with packets containing marijuana. packs with few wrappings. aluminum-foil coated packs. and machine-packed narcotics. Searching for trapped air in radiographs. repeated X-raying by an experienced radiologist. use of computed tomography. or combined urinary drug screening may be applied to diminish false findings and to avoid unnecessary arrest for the purpose of fecal screening over several days.
Fentanyl-related deaths: demographics, circumstances, and toxicology of 112 cases, Since 1979. the potent narcotic analgesic fentanyl and its analogs have been synthesized in clandestine laboratories and sold as heroin substitutes. At least 112 overdose deaths have been associated with their use. In this study. toxicology data. autopsy findings. and coroners' investigative reports were reviewed in order to construct a profile of the typical fentanyl overdose victim and to identify any factors that might heighten the risk of death from fentanyl use. The "typical" fentanyl overdose victim was 32.5 +/- 6.7 years of age (range. 19 to 57 years). male (78%. compared with 22% female). and Caucasian (50%. compared with 29% Hispanic. 20% Black. and 0.9% Asian). With the exception of his or her age. the typical fentanyl overdose victim is quite similar to the typical heroin user. Nearly all the deaths (94%) occurred in California. yet within the state they were widely distributed throughout 17 counties and 44 cities. Pulmonary edema and congestion and needle puncture sites were consistent postmortem findings. No preexisting medical conditions were identified as possible risk factors. Although most of the fentanyl victims had a prior history of intravenous drug use. morphine or codeine were not commonly found. which suggests that the victims had little or no opiate tolerance. Ethanol was present in 38% of the cases and is thought to be a significant risk factor. Mean fentanyl concentrations in the body fluids were quite low: 3.0 +/- 3.1 ng/mL (0.3 +/- 0.31 micrograms/dL) in blood and 3.9 +/- 4.3 ng/mL (0.39 +/- 0.43 micrograms/dL) in urine. measured by radioimmunoassay. Although the potency of the analogs and the purity of street samples varies considerably. it is probably the general availability of the drug rather than the potency of a particular analog that determines the incidence of overdose deaths.
Effects of the Taser in fatalities involving police confrontation, Sixteen deaths associated with the use of the Taser were examined. All involved young males who had a history of abuse of controlled substances; all but three were under the influence of cocaine. phencyclidine [phenylcyclohexylpiperidine (PCP)]. or amphetamine. All were behaving in a bizarre or unusual fashion which necessitated calling the police. The cause of death was an overdose of drugs in eleven. gunshot wounds in three. heart disease and Taser shock in one. and an undetermined cause in one. All were considered to be under the influence of PCP by the police at the time of the incident. All were unarmed. which was the reason a Taser was used instead of a more lethal weapon. The conclusion reached after evaluation of these cases is that the Taser in and of itself does not cause death. although it may have contributed to death in one case.
Effect of heroin in decomposing tissues on the development rate of Boettcherisca peregrina (Diptera, Sarcophagidae) and implications of this effect on estimation of postmortem intervals using arthropod development patterns, Larvae of the flesh fly Boettcherisca peregrina (Robineau-Desvoidy) were reared on the tissues of rabbits to study the effects of heroin on the development rates of this species. The rabbits were given 6. 12. 18. and 24 mg of heroin by cardiac puncture. From Hours 18 to 96. larvae feeding on tissues containing heroin (as morphine) developed more rapidly than those feeding on tissues from the control. The time required for pupation was significantly greater for colonies fed on tissues from heroin-dosed rabbits than for the control colony. The differences observed in the rates of development were sufficient to alter postmortem interval estimates based on larval development by up to 29 h and estimates based on pupal development by 18 to 38 h.
A simple histochemical technique for the identification of gunshot residue, Alizarin red S (ARS) is a commonly used organic dye useful in the histologic identification of calcium deposits. ARS also forms colored reaction products with other metal ions. including barium and lead. which are present in primer residue. In histochemical studies. ARS is shown to identify primer residues from several manufacturers as well as primer residue deposited in tissue. either experimentally or in close-range gunshot wounds. This can be easily accomplished with routine histologic techniques. ARS does not stain gunpowder residue. tattoo pigment. melanin. graphite. india ink. or anthracotic pigment.
A practical technique for the fabrication of transparent bite mark overlays, A quick. inexpensive. and accurate technique for generating transparent overlays. using office photocopy machines. for use in bite mark case analysis is presented. The critical step in the fabrication process involves determination of the accuracy of the product produced by the photocopy machine. A reliable method for making such a determination is discussed.
Fatal taxine poisoning from yew leaf ingestion, A case of fatal taxine poisoning from the ingestion of yew leaves by a young college man is reported. The toxicity of the plant is discussed. and the limited medical literature is reviewed.
Finding of a bullet in the cervical column of a body hit by a train, This case is about the finding of a body of an unidentified male of approximately 70 years of age who was hit by a train. During the carrying out of the corresponding autopsy and after the radiological tests for posterior odontological identification. a foreign body of a cylindrical-cone shape. identical to that of a bullet. was found lodged between the first and second cervical vertebrae. During dissection of the neck. a bullet was found. When the ballistic test was carried out. it was ascertained that the bullet was from a cartridge of 7.92 by 57-mm Mauser caliber. manufactured in Spain in 1936. This ammunition corresponds to that used during the Civil War in Spain (1936-1939). After the identification of the body. it was proved that the bullet was the result of a war wound. However. the victim had been unaware of the existence of the bullet. which had remained in his body for 50 years.
Determination of postmortem interval by arthropod succession: a case study from the Hawaiian Islands, A postmortem interval of 34 to 36 days was established for remains recovered on the island of Oahu. Hawaii. based on interpretations of patterns of arthropod succession on the remains. This interval was primarily based on the presence of adult specimens of Philonthus longicornis (family Staphylinidae). mature larvae of Piophila casei (family Piophilidae). and empty puparial cases of Chrysomya rufifacies (family Calliphoridae). Species and developmental stages of two additional Coleoptera species and three additional Diptera species were also present. which was consistent with the estimated interval. although not definitive.
Entrapment of a cat in a new-style pet food container, Although many regulations exist to protect human consumers from hazardous products. there are no comparable safeguards for products intended for pet use. The authors describe a case in which a new-style cat food container presented a hazard to pets.
Risk factors for second cancers of the upper respiratory and digestive systems: a case-control study, A case-control study of determinants of multiple cancers of the upper respiratory and digestive system (URDS) was conducted using a patient cohort-nested design. We analyzed demographic and risk factor information and clinical variables related to the index cancer for 85 cases of multiple cancers and 170 controls matched on sub-site of the index cancer of the case and date of hospital admission. Follow-up information for the control group was used to infer the person-years-at-risk for the cohort of 1977 patients. URDS cancer patients experienced a 10.7 times (95% confidence interval: 8.5-13.2) higher risk of additional related cancers than the general population. Although controls had cancers of the same sites as those of cases and thus. strongly tobacco and alcohol-related. there were marked residual effects for these two risks factors. In addition. characteristics related to the extension and clinical course of the index cancer were strongly associated with the patient's risk of developing additional cancers.
Reliability of interviewer and subject assessments of nevus counts in a study of melanoma, Several types of data are presented concerning the reliability of counting or estimating the density of nevi (moles). a major risk factor for melanoma. using methods typically employed in epidemiologic studies. First. interviewer-derived counts of nevi on the arm produced estimates of inter-observer. inter-subject. temporal and random variability. and their interactions. Second. interviewer-derived arm counts and respondent self-reports of whole body nevus density were compared. Finally. we compared male and female cases and controls with respect to their reported rates of having a relative with a malignant mole. Overall. the intra-observer reliability ranged from 55 to 81%. and was better for observers with more experience. The correlation between the interviewer counts and respondents' self-reported estimates was 0.41. The data on malignant moles in relatives suggest higher reporting rates in male cases and lower reporting in male controls relative to their female counterparts. but there is little difference by sex in the reporting of one's own nevus density.
Collinear nutrients and the risk of colon cancer, The relationship between colon cancer risk and the relative contributions of fat and caloric intake are assessed. A lack of consensus exists regarding the role of each of these dietary factors in the development of colon cancer. This lack of agreement originates from the high correlations between the nutrients. as well as the manner in which researchers treat these dietary variables in their analyses. Four proposed methods are evaluated which attempt to address the collinearity problem in nutritional epidemiology: (1) exclude one or more collinear variables. (2) use the proportion of calories consumed attributable to each dietary component. (3) use a regression-adjustment approach to purge the collinearity correlated nutrients. and (4) ridge regression. Diagnostic tests are reported which assess the degree of collinearity on data collected for a case-control study of colon cancer conducted in Utah between 1979 and 1983. Using logistic regression analyses. we apply each of these methods to case-control data. We find that the risks associated with fat and caloric consumption are extremely sensitive to a priori analytic decisions made by epidemiologist about the underlying collinearity problem.
Targeting, dosimetry, and radioimmunotherapy of B-cell lymphomas with iodine-131-labeled LL2 monoclonal antibody, Sixteen patients with non-Hodgkin's lymphoma were infused with 6.2 to 58.2 mCi (0.2 to 3.9 mg) doses of radioactive iodine (131I)-labeled LL2 immunoglobulin G (IgG) or F(ab')2. in order to study antibody distribution. pharmacokinetics. dosimetry. toxicity. tumor targeting. and therapy. LL2 is a murine IgG2a monoclonal antibody (MAb) reactive with B cells and non-Hodgkin's B-cell lymphoma. In a series of five assessable therapy patients. doses as small as 30 mCi 131I-LL2 IgG or F(ab')2 resulted in tumor responses (two partial remissions. two mixed and minor responses. and one no response). while one patient receiving diagnostic doses as low as 6.2 mCi showed a partial remission for 1 year and a complete remission after a second low radiation dose. No acute toxicities were noted. and only myelotoxicity accompanied therapeutic doses. with grade IV marrow toxicity seen in three of seven patients receiving total doses of about 50 mCi. Dosimetry calculations showed spleen and tumor dose rules of about 4.6 cGy/mCi. which was three to four times the dose to other organs. Despite the administration of relatively low doses of LL2 (0.2 to 3.9 mg). 82% of 60 known extrasplenic lymphoma sites were imaged. Serum clearance showed an average distribution half-life (T1/2) of 2.1 hours and an elimination T1/2 of 32.0 hours. The average total-body clearance T1/2 was 43 to 45 hours. LL2's antigenic target does not appear to be shed in high amounts into the circulation. Three of eight patients having at least two injections showed a human antimouse antibody response. These patients may have been presensitized to animal protein. An interesting observation in this study was the marked drop in circulating B lymphocytes after the administration of radioiodinated LL2 or anticarcinoembryonic antigen MAbs. suggesting that this is a nonspecific radiation effect and not necessarily related to the binding of MAb to normal B cells.
Cyclic-alternating versus response-oriented chemotherapy in small-cell lung cancer: a German multicenter randomized trial of 321 patients, To test whether alternating chemotherapy is a favorable treatment modality in small-cell lung cancer (SCLC). 334 patients were randomized to receive either fixed cyclic-alternating treatment with ifosfamide/etoposide (IE). cyclophosphamide. doxorubicin. and vincristine (CAV). or response-oriented treatment with IE therapy up to maximal response and subsequently an immediate switch to CAV. In both arms. six cycles were given in 3-week intervals. After chemotherapy. patients with limited-stage disease received chest irradiation with 45 Gy. Prophylactic cranial irradiation with 30 Gy was applied to all complete responders. No maintenance therapy was given to patients with complete response. Minimum follow-up was 2 years. Of 321 assessable patients. the overall response rate was 70% for cyclic alternating and 77% for response-oriented treatment. Complete remission (CR) rates were 26% versus 26%. The median survival times were 9.7 months for cyclic-alternating versus 10.7 months for response-oriented treatment; the 2-year survival rates were 11% versus 9%. In limited-stage disease (LD) patients. there was a median survival of 12.5 months versus 12.3 months and a 2-year survival rate of 21% versus 18%. In extensive-stage disease (ED) patients. median survival was 8.5 versus 9.1 months. and the 2-year survival rate 3% versus 4%. From these results. we conclude that the cyclic-alternating treatment according to the hypothesis of Goldie et al has no advantage in comparison to a sequential treatment strategy with an immediate switch to a second-line protocol at the time no further response to first-line therapy is seen. Our major aim in the treatment of SCLC is to administer an active regimen at any time during the course of treatment regardless of whether sequential or alternating therapy is used.
A phase II study of weekly 24-hour infusion with high-dose fluorouracil with leucovorin in colorectal carcinoma, Twenty-two patients with advanced colorectal carcinoma were enrolled in this study. Ten patients had received prior chemotherapy that included the combination of fluorouracil (5-FU) and leucovorin (LV). All patients required subcutaneous port insertion and portable external infusion pumps to allow outpatient treatment. 5-FU (2.600 mg/m2) was administered concurrently with LV (500 mg/m2) over 24 hours of continuous infusion. The mean steady-state plasma concentration of 5-FU was 10 mumol/L (range. 7 to 14 mumol/L). The 5-FU dose was based on our previous phase I study. in which maximum-tolerated dose (MTD) of 5-FU was determined to be 2.600 mg/m2 in combination with a fixed dose of LV at 500 mg/m2. The treatment was repeated weekly. Twenty-two patients received a total of 560 courses of treatment. Eleven instances of grade 2-3 toxicity were observed: diarrhea (five). stomatitis (three). hand/foot syndrome (three). The overall objective response was 45% (10 of 22) and among previously untreated patients was 58%. Three of the responders achieved complete response (CR). with lung and liver as the metastatic sites. The median duration of survival for the previously untreated patients was not reached at 22 months. and was 10 months for the previously treated patients. These results suggest that short-term infusional therapy of 5-FU and LV in patients with advanced metastatic colorectal cancer generates acceptable toxicity. with equivalent or superior survivability in previously treated and untreated patients versus alternative methods of administration of the two agents.
Initial clinical study of indium-111-labeled clone 110 anticarcinoembryonic antigen antibody in patients with colorectal cancer, A murine monoclonal antibody directed against carcinoembryonic antigen (CEA) was labeled with indium-111 (111In) by means of a benzylisothiocyanate derivative of diethylenetriamine penta-acetic acid (DTPA) and used for clinical radioimmunodetection studies. Twenty-one patients having a history of surgically resected colorectal cancer and rising serum CEA levels suggestive of tumor recurrence were studied. Patients were infused over 20 minutes with 5. 10. or 20 mg of the monoclonal antibody labeled with 5 mCi of 111In. The mean radiochemical purity was greater than 96%. No toxicity was seen. The stability of the radiolabel on antibody in patient serum was demonstrated by high-performance liquid chromatography (HPLC). sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) with autoradiography. and immunoprecipitation for up to 96 hours after infusion. Tumor sites were identified in 20 of 21 patients. Sites of antibody accumulation in 20 patients were confirmed as tumor either by resection at laparotomy (16 patients) or fine-needle biopsy (four patients). Nine patients who had the identified lesion resected or irradiated showed return of the serum CEA antigen level to normal or near normal values. In the absence of high levels of circulating CEA (greater than 500 ng/mL). the disappearance of radioactivity from patient serum demonstrated first order elimination kinetics. with a mean half-life of 38 hours. The serum half-life was not affected by the dose of antibody administered or by serum CEA titers below 500 ng/mL. Despite a mean liver uptake of 18% injected dose (ID) 24 hours after administration. hepatic metastases were easily visualized as areas of increased uptake of radioactivity. Radioimmunodetection of recurrent colorectal cancer. not detected by computed tomographic (CT) scans. appears achievable with this agent. This may allow successful clinical intervention in selected patients.
A phase II study of high-dose continuous infusion interleukin-2 with lymphokine-activated killer cells in patients with metastatic melanoma, Thirty-three patients with metastatic melanoma were treated in a phase II study with an intravenous continuous infusion (IVCI) of interleukin-2 (IL2) given with lymphokine-activated killer (LAK) cells. The dose of IL2 was the optimal priming dose for LAK-cell induction. followed by the maximally tolerated LAK-cell dose that could be given by an IVCI schedule as determined by a previous phase I trial. The CI schedule was chosen for evaluation because of a postulated reduction in toxicity with the possibility of administering a more prolonged IL2 infusion and because greater rebound lymphocytosis and LAK-cell generation had been reported using this dose and schedule. The 33 patients were similar in age. performance status. and sites of disease to those treated in previous IL2 trials. All patients were assessable for response and toxicity. One patient (3%) achieved a partial response of 10 months duration. There were no other clinically significant responses. Significant toxicity included hypotension requiring pressors (45%). dyspnea (36%). renal insufficiency (24%). hepatic dysfunction (66%). and cardiac arrhythmias (18%). These toxicities reversed with cessation of the infusion. There were four deaths during the first 30 days of treatment. three from infection (one related to central line. one related to LAK cells. one related to tumor). and one from tumor-related hemorrhage. Toxicity was unexpectedly high and at least comparable to that seen in previous studies using a high-dose IV bolus schedule of IL2. When comparing the IVCI schedule with high-dose bolus IL2 to LAK cells in nonrandomized but sequential studies in patients with advanced melanoma. it appears that CI IL2 is less efficacious.
A phase II trial of intraperitoneal cisplatin and etoposide as salvage treatment for minimal residual ovarian carcinoma, We conducted a phase II study of intraperitoneal (IP) cisplatin (CDDP) and etoposide (VP-16) as salvage therapy in patients with ovarian cancer who had persistent disease or who had relapsed after primary systemic chemotherapy and had residual disease of less than 2 cm. Two hundred eleven courses of IP chemotherapy consisting of CDDP 200 mg/m2 and VP-16 350 mg/m2 were administered. All patients received intravenous (IV) thiosulfate protection. Treatment was given once every 4 weeks for a median of six cycles. Twenty-four of 37 assessable patients were clinically free of disease at the end of treatment (normal physical exam. computed tomographic [CT] scan. CA-125 and peritoneal cytology); one patient had a partial response. Ten of these 24 patients consented to reexploration at the end of treatment. and nine were in pathologic complete remission. while one patient had positive peritoneal washings as her only evidence of persistent disease. The median survival of the 37 patients was 26 months from the first day of IP treatment and 51 months from diagnosis. The major toxicity was myelosuppression. with median nadir WBC. granulocyte. and platelet counts of 2.400. 684. and 134.000/mm3. respectively. There was no cumulative renal damage. hypomagnesemia. or chemical peritonitis. We conclude that IP CDDP and VP-16 can produce pathologic complete remissions when used as a second-line regimen for patients with ovarian cancer who have received systemic cisplatin-based therapy and have less than 2 cm disease.
Carboplatin, doxorubicin, and cyclophosphamide versus cisplatin, doxorubicin, and cyclophosphamide: a randomized trial in stage III-IV epithelial ovarian carcinoma, One hundred sixty-four patients with stage III-IV epithelial ovarian carcinoma were randomized to receive cisplatin (CDDP) 50 mg/mq. doxorubicin 45 mg/mq. and cyclophosphamide 600 mg/mq (PAC) or carboplatin 200 mg/mq. doxorubicin 45 mg/m2. and cyclophosphamide 600 mg/mq (CAC). To administer equitoxic doses at each cycle. the drug dosages were adjusted according to the hematologic toxicities experienced after the previous course; 44.7% of CAC and 21.1% of PAC patients required a dosage reduction at the second course (P = .002). Neither CAC nor PAC caused any clinically relevant neuro-nephrotoxicity; however. CDDP was administered with hydration and forced diuresis. while carboplatin was administered by rapid intravenous (IV) infusion. After six cycles. response rates were superimposable: 62.5% and 66.6% for CAC and PAC. respectively; pathologic complete responses (pCRs) were 16.7% for CAC and 23.2% for PAC; among patients with more than 2 cm residual disease. PAC induced more pCRs than CAC (eight of 52 or 15.4% v one of 42 or 2.4%. P = .07). Median survivals and progression-free survivals (PFSs) were 22.6 and 13.2 months for PAC. and 23.1 and 15.5 months for CAC. respectively; these differences are not significant. In conclusion. this trial demonstrates that equitoxic doses of PAC or CAC result in a similar response rate. PFS. and survival.
Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research, In this prospective randomized study. first-line treatment with the combination of cisplatin (P) and etoposide (E) was compared with the standard cyclophosphamide. methotrexate. and fluorouracil (CMF) combination in 140 patients. Complete remissions were obtained in 11% of 65 assessable patients on CMF and in 12% of 65 assessable patients on PE. Complete plus partial remission rates were 48% on CMF and 63% on PE (P = .08). Time to progression (median. 32 v 31 weeks). duration of response (48 v 39 weeks). and survival (75 v 76 weeks) were not different. Hematologic toxicity was significantly higher with PE. and gastrointestinal side effects were frequent with this treatment. This study demonstrated that the PE combination is effective as front-line chemotherapy. As far as response rate is concerned. a trend of superiority over CMF was observed. which was of borderline significance. Due to the lack of survival advantage and to toxicity. this combination is not recommended for routine clinical use. However. its high level of activity should be taken into account for further research.
Rescue of experimental intrathecal methotrexate overdose with carboxypeptidase-G2, The carboxypeptidase G class of enzymes rapidly hydrolyze methotrexate (MTX) into the inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. This study evaluated the use of carboxypeptidase-G2 (CPDG2) as a potential intrathecal (IT) rescue agent for massive IT MTX overdose. The CSF pharmacokinetics of MTX with and without CPDG2 rescue was studied in adult rhesus monkeys (Macaca mulatta) using a nontoxic IT 5 mg dose (equivalent to 50 mg in humans). Without CPDG2 rescue. peak CSF MTX concentration was 2.904 +/- 340 mumol/L. Within 5 minutes of administration of 30 U IT CPDG2. CSF MTX concentrations decreased greater than 400-fold to 6.55 +/- 6.7 microM. Subsequently. groups of three monkeys received either 25 mg IT MTX (equivalent to 250 mg in humans) followed by 150 U IT CPDG2 or 50 mg IT MTX (equivalent to 500 mg in humans) followed by 300 U IT CPDG2. All animals survived without neurotoxicity. Our studies suggest that CPDG2 may prove to be an important addition to the currently recommended strategy for the management of IT MTX overdose.
Cytarabine and neurologic toxicity, Cytarabine is an effective drug in the treatment of certain hematologic malignancies and its common toxicities are myelosuppression and gastrointestinal disturbance. In the past decade. neurotoxicity has been an increasingly recognized cytarabine effect. Intrathecal (IT) cytarabine may result in myelopathy that is incompletely reversible. Combined IT drug and cranial irradiation may lead to necrotizing leukoencephalopathy. Intravenous (IV) therapy may cause a peripheral neuropathy that varies greatly in its severity. The high IV cytarabine doses now commonly used can cause seizures. cerebral dysfunction. or an acute cerebellar syndrome with an incidence up to 14%. Patient age (greater than 60 years) appears to be the most important risk factor. but drug dose/schedule. cumulative drug dose. renal and hepatic dysfunction. and concomitant use of neurotropic antiemetic agents may also influence the risk of neurotoxicity. A better understanding of the pathophysiology and pharmacology of such cytarabine-induced neuronal injury will allow this drug to be used with greater efficacy and safety.
Interleukin-2 toxicity, Because of the ability of interleukin-2 (IL-2) to support the proliferation and activation of numerous types of immunocompetent cells and to support the survival of adoptively transferred lymphocytes. there has been considerable interest in its use in the immunotherapy of malignancies. While studies to date have indicated that IL-2 has activity against some malignancies. considerable toxicity has also been observed. Careful prescreening and selection of patients and appropriate management of toxicity can minimize adverse outcomes. Studies of IL-2 effects have provided intriguing evidence of interactions of the immune/cytokine system with the neuroendocrine. cardiovascular. and other systems. Studies in animal models have demonstrated the central role of an intact immune system in mediating many toxicities of IL-2. Several adverse effects of IL-2 appear to be mediated by other cytokines whose production is induced by IL-2. Studies into the pathogenesis and manifestations of IL-2 toxicity have offered the hope of developing less toxic approaches to IL-2 therapy. Several lessons from the IL-2 experience are likely to be applicable in the clinical development of other cytokines.
Anti-carcinoembryonic antigen immunoscintigraphy (technetium-99m-monoclonal antibody BW 431/26) and serum CEA levels in patients with suspected primary and recurrent colorectal carcinoma, This study comprises a total of 141 patients with suspected primary and recurrent colorectal carcinomas. in whom immunoscintigraphy with 99mTc-Mab BW 431/26 was performed. Whole-body scans were done 5.5 hr and SPECT imaging of the abdominal region was done at 6 and 24 hr postinjection of 1100 MBq 99mTc-labeled Mab (1 mg). In the course of primary tumor identification (n = 65). sensitivity of anti-CEA immunoscintigraphy was 95%. specificity 91%. In the diagnosis of early recurrences (n = 76). immunoscintigraphy was the method of choice to clarify the problem (sensitivity 94%; specificity 86%). Overall sensitivity of immunoscintigraphy in patients with suspected colorectal carcinomas and early recurrences was 95%. specificity 88%. Human anti-mouse antibodies were found in 29% (80% predominantly anti-isotypic. 20% predominantly anti-idiotypic). In contrast to anti-CEA immunoscintigraphy. the results of serum CEA levels were rather disappointing. Only 18 out of the 43 surgically verified primary colorectal carcinomas and 17 out of 32 patients with recurrences showed elevated serum CEA levels. In our clinical experience with this 99mTc-labeled anti-CEA antibody. immunoscintigraphy can play an important role in the identification of early colorectal recurrences and in postoperative colorectal cancer patients it should be performed in cases with unclear transmission computed tomography.
Indium-111-labeled B72.3 monoclonal antibody in the detection and staging of breast cancer: a phase I study, Sixteen patients with primary breast cancer were studied with a pancarcinoma monoclonal antibody B72.3. an IgG1 molecule directed against tumor-associated glycoprotein (TAG-72) present in several tumors. Five millicuries of 111In was used to label 0.2 mg (six patients). or 2 mg (six patients). or 20 mg using the site-directed bifunctional DTPA method (at carbohydrate moiety). Digital. planar. and SPECT images were obtained at 2. 48. 72 and 96 hr when possible. HAMA levels were obtained before the Mab infusion and at 1. 3. and 6 wk postinfusion. Fourteen of 14 known primary breast lesions were detected by imaging (100% sensitivity). Two fibrocystic lesions were negative. Seven of 14 patients had lymph node metastases by histologic methods. but all were missed by radioimmunoscintigraphy. Tumor uptake of Mab ranged 0.00054%-0.0038% of the ID/g. The tumor-to-normal breast tissue ratio was 4.3 +/- 0.91 (mean +/- s.e.m.). Lymph nodes localization of 111In-B72.3 by tissue analysis was similar for tumor-bearing and normal nodes (0.0039 +/- 0.0023 versus 0.0025 +/- 0.0019). Pharmacokinetics revealed mean plasma half-life of 33.3-41.2 hr for the different doses. There was no statistical difference between any of the pharmacokinetic parameters of different doses. HAMA was positive only in 17% of the patients. The study suggests that this antibody has 100% sensitivity for primary breast cancers. but very poor detection rate of metastatic lesions in axillary lymph nodes; thus making it of questionable value in the initial staging process of this disease.
Assessment of myocardial damage in dilated-phase hypertrophic cardiomyopathy by using indium-111-antimyosin Fab myocardial scintigraphy, For the detection of myocardial cell damage. an 111In-antimyosin Fab study was carried out on seven patients (Group A) in the dilated phase of hypertrophic cardiomyopathy. seven patients (Group B) with dilated cardiomyopathy. and eight control patients (Group C). Imaging was done 48 hr after intravenous injection of 74 MBq of 111In-antimyosin Fab. Myocardial antimyosin uptake was visually graded as 0. +1. +2 or +3. A score of +2 or +3 was considered positive. The heart/lung ratio of antimyosin uptake (antimyosin index) also was determined. Antimyosin uptake was positive in seven (100%). nine (90%) and no (0%) patients in Groups A. B. and C. respectively. The antimyosin index in Groups A and B was 2.46 +/- 0.49 and 2.04 +/- 0.24. respectively. findings were significantly higher than that in Group C (1.51 +/- 0.13) (p less than 0.01). Positive biopsy findings were noted in only two patients in Group A. Thus. antimyosin uptake was increased in dilated phase hypertrophic cardiomyopathy and dilated cardiomyopathy. which suggests ongoing necrotic changes in these patients.
The comparison of 2-18F-2-deoxyglucose and 15-(ortho-123I-phenyl)-pentadecanoic acid uptake in persisting defects on thallium-201 tomography in myocardial infarction, The myocardial uptake of glucose and fatty acids into 201Tl redistribution defects were studied in 32 patients with myocardial infarction by tomography using 2-18F-2-deoxyglucose (FDG) and 15-(ortho-123I-phenyl)-pentadecanoic acid (oPPA). A total of 1153 segments were analyzed. 408 (35%) of which showed a persistent thallium-defect in stress-redistribution images. Of the segments with a decreased 201Tl uptake in these redistribution tomograms. 50.5% had a decreased uptake of both FDG and oPPA; in 21.8% FDG as well as oPPA uptake was within normal range. Normal FDG uptake but decreased oPPA uptake was detected in 17.4%. whereas 10.3% of the segments had normal oPPA uptake but decreased FDG uptake (chi-square test. p less than 0.001). A significant correlation of FDG and oPPA uptake (r = 0.51) was found in the segments with persistent 201Tl defect. Thus. a substantial fraction of persistent thallium-defects after healed myocardial infarction exhibit FDG as well as oPPA uptake. probably due to residual fatty acid metabolism in partially ischemic regions.
Insular carcinoma: a distinct thyroid carcinoma with associated iodine-131 localization, Insular carcinoma. once considered a poorly-differentiated thyroid cancer. has been reclassified as a distinct thyroid neoplasm. Since this neoplasm is composed of follicular epithelial cells. it may concentrate radioiodide (131I) making postoperative 131I imaging for detection of metastases and radiotherapy possible. A 20-yr review of 35 cases diagnosed as anaplastic or undifferentiated thyroid carcinoma at this medical center revealed five patients with insular carcinoma. Four patients showed postoperative 131I localization and received therapeutic doses of 131I. Three of the four showed extrathyroidal 131I localization in neoplastic lesions. In one patient. the resolution of metastatic lesions by magnetic resonance and 131I imaging suggests that 131I may have an important therapeutic role in this aggressive neoplasm.
Multiple swallow test for the quantitative and qualitative evaluation of esophageal motility disorders, Esophageal motility was evaluated from the analysis of six consecutive swallows. A sum image was generated comprising the representative information of an entire study. Calculation of emptying rates and characterization of the bolus behavior was performed from the sum image and the single swallow data. In 86 patients investigated. liquid and solid-phase studies showed a remarkable variation of single swallow data in normals (relative variation coefficient for liquid: 10%. solid: 14%). which were even higher (p less than 0.001) in patients with disorders (liquid: 31%. solid: 25%). As sum images compensate for this intra-individual variation. false-positive (liquid: 16%. solid: 25%) or negative single swallow findings (liquid: 36%. solid: 27%) are reduced. Qualitative analysis of condensed sum images provided characteristic image patterns representing different pathophysiologic aspects. Since the method introduced better discriminates between normal and pathologic function. it may enhance diagnostic accuracy.
Use of technetium-HMPAO to demonstrate changes in cerebral blood flow reserve following carotid endarterectomy, Cerebral perfusion through stenosed internal carotid arteries is usually maintained by autoregulation. However. flow reserve may be reduced. suggesting hemodynamically significant stenosis. and such reduction should be improved by carotid endarterectomy. This concept was studied in 20 subjects with unilateral internal carotid artery stenosis (major stenosis greater than or equal to 70%. minor stenosis less than or equal to 50%). Thirteen had experienced recent transient ischemic attacks and seven had no definite focal symptoms. Subjects underwent Tc-HMPAO cerebral SPECT during acetazolamide dysautoregulation before and after internal carotid endarterectomy. Nine (45%) had perfusion defects that improved after surgery. suggesting surgery had improved cerebral flow reserve. Seven had defects that did not improve after surgery. Four had worsened or new defects after surgery. suggesting perioperative infarcts. The relatively large proportion of patients with improved cerebral blood flow reserve after surgery suggests that this technique may have a significant role to play in assessing which patients might benefit from carotid endarterectomy.
Bone marrow dosimetry in rats using direct tissue counting after injection of radio-iodinated intact monoclonal antibodies or F(ab')2 fragments, Normal rats were injected intravenously with 131I- and 125I-labeled intact murine and chimeric mouse-human monoclonal antibodies directed against carcinoembryonic antigen or with the corresponding F(ab')2 fragments. At different times after injection. individual animals were killed and radioactivity of blood and major organs. including bones and bone marrow. was determined. Ratios comparing radioactivity concentration in different tissues with that of bone marrow were calculated and found to remain stable during several effective half-lives of the antibodies. Mean bone marrow radioactivity was 35% (range. 29%-40%) of that of blood and 126% (range. 108%-147%) of that of liver after injection of intact Mabs or F(ab')2 fragments. In nude rats bearing human colon carcinoma xenografts producing carcinoembryonic antigen. relative bone marrow radioactivity was slightly lower than that in normal rats.
Single-dose subcutaneous iodine-131-iodohippurate for determination of renal plasma flow, Subcutaneous administration of a single dose of 131I-iodohippurate was used for determination of renal plasma flow (RPF) in 20 subjects during water diuresis. Slow release of tracer (200 microCi) permitted serial clearance measurements over 5 hr that were compared to standard. constant infusion. PAH clearance (mean 379.5 +/- 34.9 ml/min/1.73 m2. range 50.9 to 696.3 ml/min/1.73 m2). RPF(Isotope) was 424.9 +/- 30.3 ml/min/1.73 m2 (range 144.4 to 746.5 ml/min/1.73 m2) and highly correlated with RPFPAH (r = 0.883. p less than 0.0001). This technique permits prolonged studies of renal plasma flow under steady-state conditions without constant infusion.
Evaluation of housestaff physicians' preparation and interpretation of sputum Gram stains for community-acquired pneumonia, OBJECTIVE: To evaluate the preparation and interpretation of sputum Gram stains by housestaff physicians in the assessment of patients with community-acquired pneumonia. DESIGN: A prospective. multicenter study. SETTING: Two university-affiliated hospitals in Pittsburgh. PATIENTS: Ninety-nine cases of clinically and radiographically established pneumonia occurring in 97 patients. Diagnostic test assessment: Housestaff and microbiology personnel prepared a Gram stain for each case of pneumonia. Housestaff assessed the presence and identity of a predominant microbial organism on the slides they prepared. Two senior staff microbiologists. blinded to patient and preparer. evaluated all slides for preparation. sputum purulence. and identification of the predominant organism. Two reference standards were used to assess the sensitivity. specificity. and predictive values of housestaff's Gram-stain interpretations: 1) senior staff microbiologists' determinations of the microbes present using the slides without benefit of culture results. and 2) the etiologic agent derived from results of sputum culture. blood culture. or serology. MEASUREMENTS AND MAIN RESULTS: Housestaff physicians completed a Gram stain in 58% of the pneumonia episodes. Gram stains were not made in 42% of cases. primarily because patients were unable to produce sputum. Fifteen percent of housestaff's smears were judged inadequately prepared. compared with 3% for the laboratory personnel (p less than 0.01). Housestaff obtained purulent sputum samples significantly more often than did nursing personnel (58% versus 38%; p less than 0.01). Housestaff's Gram stains were 90% sensitive for detecting pneumococcus. with a 50% false-positive rate. The sensitivity of the Gram stain was less for identification of Haemophilus influenzae than for identification of Streptococcus pneumoniae. A single antimicrobial agent was chosen as initial therapy for 50% of the patients in whom housestaff identified a predominant organism. compared with 30% in whom a predominant organism was not identified (p less than or equal to 0.05). CONCLUSIONS: Although housestaff obtained purulent sputum samples more frequently than did nursing personnel. they made systematic errors in the preparation and interpretation of Gram-stained slides. Housestaff physicians should receive formal training in the preparation and interpretation of Gram stains; the specific defects elucidated in this study warrant special attention.
Prognostic significance of marked leukocytosis in hospitalized patients, STUDY OBJECTIVE: To identify the prognostic significance of marked neutrophilic leukocytosis (MNL). defined as white blood cell (WBC) count of greater than or equal to 25.000/microL and greater than or equal to 80% mature neutrophils by differential count. in hospitalized patients. DESIGN: A central laboratory computer identified all consecutive patients with MNL in a one-month period. After exclusion of outpatients. neonates. and patients with hematologic malignancies or incomplete records. the remaining patients were studied and followed until discharge or death. SETTING: Inpatient services of a 988-bed tertiary care teaching hospital. PATIENTS: 72 inpatients with MNL. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Associated conditions and hospital mortality were recorded. Potentially confounding or contributing variables. including age. sex. intensive care unit stay. infection. acidosis. uremia. malignancy. hemorrhage. surgery or invasive procedure. peak WBC count. and duration of MNL. were examined by multivariate analysis with mortality as the outcome variable. Overall hospital mortality was 29% in study patients. A higher peak WBC count (p = 0.0046). increasing age (p = 0.0058). MNL duration of greater than one day (p = 0.025). and lack of associated invasive procedures (p = 0.04) were jointly significant in the prediction of mortality in MNL patients. CONCLUSIONS: The results confirm the impression of poor outcome associated with MNL and validate the use of MNL data in indices of severity of illness and as a prognostic marker for hospitalized patients regardless of underlying disease.
A target-based model for increasing influenza immunizations in private practice. Genesee Hospital Medical Staff, OBJECTIVE: To measure the impact of a population-based tracking system on influenza immunization rates. DESIGN: Thirteen practices with 45 physicians were randomized to a control and two intervention groups. SETTING: Private practices. PATIENTS: All patients aged 65 years and over who were seen in participating physicians' practices within the preceding two years. INTERVENTION: In both intervention groups influenza immunization rates for physicians were recorded weekly as cumulative percentages of their target populations. using a specially prepared poster. In addition. postcard reminders were sent to all the patients in one of the intervention groups. MEASUREMENTS AND MAIN RESULTS: Immunization rates in the two intervention groups were 30% higher than in the control group; the control group immunized 50% (2.405/4.772) of its target population. while the poster and poster/postcard groups immunized 66% (1.420/2.149) and 67% (2.427/3.604). respectively. CONCLUSION: A population-based strategy that monitors performance can significantly improve rates of influenza immunization in private practices.
Cholesterol screening in the emergency department, OBJECTIVE: To determine the feasibility of providing cholesterol screening in the emergency department (ED) and to determine compliance with follow-up recommendations. DESIGN: A prospective observational study. SETTING: The Ambulatory Care and Treatment Section of the George Washington University Medical Center ED. PATIENTS/PARTICIPANTS: All patients seen in the Ambulatory Care and Treatment Section of the ED who were 18 years of age or older and who were residents of the metropolitan Washington. D.C.. area were eligible to participate. During the six-month study period. 660 patients were asked to participate and 539 (82%) agreed. INTERVENTIONS: Fingerstick cholesterol measurements were performed on all participants. Participants who had elevated cholesterol levels. as determined by the National Cholesterol Education Program guidelines. were scheduled for a six-week follow-up visit in the Lipid Research Clinic. where repeat fingerstick cholesterol measurements were performed. Those participants with elevated cholesterol levels were instructed to follow up with their primary care physicians. Compliance with follow-up was assessed by a telephone contact four months after the initial ED visit. MEASUREMENTS AND MAIN RESULTS: Of the 539 participants. 100 (19%) were found to have elevated cholesterol levels. Fifty-three (53%) returned for the six-week follow-up visit. Of the 53 who returned. 7 (13%) had normal and 46 (87%) had elevated cholesterol levels. Of the 46 participants with elevated cholesterol levels. 15 (33%) reported four months after their ED visit that they had received further follow-up care. CONCLUSIONS: Cholesterol screening in the ED is feasible. but compliance with follow-up is less than desirable.
Utilization of hospital resources by alcoholic and nonalcoholic patients: a prospective study, OBJECTIVE: To measure any difference in the utilization of hospital resources between alcoholic patients and nonalcoholic patients (controls) in a department of internal medicine. DESIGN: Prospective comparative study. Alcoholics were identified as patients with Michigan Alcoholism Screening Test (MAST) scores of greater than or equal to 8. Controls were defined as patients with MAST scores of less than or equal to 4. and matched with alcoholics for sex. age. and time of admission. The length of stay. as well as several indicators of utilization of diagnostic and therapeutic procedures. was used for the comparison of resource utilization. SETTING: General wards of internal medicine of a 1.000-bed city and teaching hospital in Lausanne. Switzerland. PARTICIPANTS: One hundred and three alcoholic patients and 103 controls aged 20-75 years. admitted from September 1. 1988. to March 18. 1989. RESULTS: Alcoholics had the same lengths of stay (16 days). durations of intravenous infusions (six days). and durations of bladder catheterization (one day). Statistically nonsignificant differences were found between alcoholics and nonalcoholics regarding the charges for routine laboratory examinations [693 vs. 734 Swiss francs (Sfrs)]. antibiotic therapies (218 vs. 145 Sfrs). and x-ray procedures (568 vs. 774 Sfrs; p = 0.06). The average number of electrocardiograms (two vs. five; p less than 0.005) and the duration of intensive care unit (ICU) stay (one vs. two days; p less than 0.05) were significantly lower for alcoholics than for controls. A total hospital charges index was also lower for alcoholics than for controls (11.900 Sfrs vs. 12.800 Sfrs). but not significantly. CONCLUSION: The authors' results suggest that alcoholics do not use more hospital resources per admission than do nonalcoholics. Moreover. alcoholics tend to use less frequently some procedures. such as the ICU. electrocardiography. and x-ray examinations. Several hypotheses are developed to explain these results in relation to those of previous studies. which showed more use of medical care by alcoholics than by nonalcoholics.
Ventricular arrhythmias in children with an apparently normal heart, Ventricular ectopy occurs frequently in normal children. In the presence of a normal heart. these arrhythmias. including asymptomatic. nonsustained ventricular tachycardia. carry a benign prognosis and are not associated with sudden. unexpected death. However. complex ventricular arrhythmias frequently indicate the presence of underlying cardiac disease; patients with such arrhythmias must undergo an appropriately thorough evaluation before decisions regarding prognosis and the need for therapy can be made.
Comparison of morphine and methadone for prevention of postoperative pain in 3- to 7-year-old children, A randomized. double-blind. prospective study was performed to determine the effects of perioperative administration of morphine or methadone on postoperative analgesic requirements and pain scores in 35 children aged 3 to 7 years undergoing major surgery. After a standardized induction of anesthesia. methadone or morphine. 0.2 mg/kg. was blindly administered. and supplemental doses were titrated to achieve comfort in the recovery room. Pain was assessed during the next 36 hours with a combination of validated behavioral and self-report measures. Patients in the methadone group required fewer supplemental opioid analgesic drugs during the next 36 hours. and reported lower pain scores. No patient had prolonged emergence from anesthesia. and no patient required naloxone or postoperative ventilatory assistance. No major adverse events occurred. We conclude that perioperative intravenous administration of methadone is an effective. inexpensive. and technologically simple means for providing prolonged analgesia for children after surgery.
Cardiovascular and antiarrhythmic effects of esmolol in children, This prospective study evaluated the cardiovascular and antiarrhythmic effects of esmolol. an intravenous beta-blocker with an extremely short half-life. Twenty patients (aged 2 to 16 years) underwent diagnostic electrophysiologic studies at rest and during beta-blockade induced with esmolol. An initial dose of 600 micrograms/kg was infused for 2 minutes and followed by an infusion of 200 micrograms/kg per minute. The dosage was increased by 50 to 100 micrograms/kg per minute every 5 to 10 minutes until a reduction of greater than 10% in either heart rate or mean blood pressure was seen. The dosage required to achieve beta-blockade ranged from 300 to 1000 micrograms/kg per minute (mean 550 micrograms/kg per minute). Electrophysiologic effects included a decrease in the rate of sinoatrial node discharge and delay in conduction through the atrioventricular node. There was no effect on His-Purkinje conduction. Atrial and ventricular effective refractory periods were unchanged. In six patients with supraventricular tachycardia. esmolol prevented induction of tachycardia in four and slowed the rate of the tachycardia in two. In four patients with ventricular tachycardia. clinical findings were improved in three and unchanged in one. Heart rate and blood pressure returned to near baseline values 10 minutes after the esmolol infusion was stopped. Adverse ventricular electrophysiologic effects were observed in two patients with biopsy evidence of myocarditis. No other adverse effects were seen. We conclude that the effects of esmolol in children are similar to those of other beta-blockers and that it is useful in the evaluation and management of pediatric tachyarrhythmias. The weight-adjusted dosage required to induce beta-blockade in children is larger than the adult dosage. and the effects of esmolol dissipate rapidly.
Near normalization of adolescent height with growth hormone therapy in very short children without growth hormone deficiency, Ten prepubertal children with stature at or below the 1st percentile for height and without growth hormone deficiency received 0.3 U recombinant growth hormone per kilogram daily for 2 years before puberty. Their growth velocity increased from 4 +/- 0.3 cm/yr before treatment to 10.7 +/- 0.6 and 8.8 +/- 0.6 cm. respectively. during the first and second years of treatment. and then remained at 5.7 +/- 0.7 cm the year after the end of growth hormone administration. This resulted in a near normalization of adolescent height. Bone maturation paralleled chronologic age. and therefore the expected final height of the children increased by approximately 10 cm. Administration of growth hormone induced a reversible hyperinsulinemia. with moderate and transient changes in glucose metabolism. A prospective. randomized study. including an untreated cohort. will be needed to confirm the effects on final height and to determine the magnitude of the response in familial short stature.
Intellectual outcome in children with maple syrup urine disease, We report a controlled study of intellectual outcome in 16 children with maple syrup urine disease (MSUD) that compares the outcome of MSUD diagnosed after symptoms became apparent with that of MSUD diagnosed prospectively and in unaffected siblings and parents. The mean IQ (+/- SD) score in the children with classic MSUD was 78 +/- 24; however. there were two discrete groups: one with normal IQ (greater than 84) whose MSUD had been diagnosed at a mean age of 3.5 days and a second group. with IQ below normal. whose MSUD was diagnosed at a mean of 10 days of age. Affected children treated presymptomatically had higher IQ scores than their affected siblings treated when their disease was symptomatic. Multiple regression analysis indicated that the important influences on IQ were age at the time of diagnosis and long-term metabolic control; control at the time of testing also might have affected performance. The mean score of unaffected siblings was 92 +/- 5 and the mean parental IQ was 83 +/- 9. The mean IQ scores of children with variant MSUD. 97 +/- 4. was similar to that of their parents. 103 +/- 6. This study was not longitudinal and thus could not identify subtle developmental learning problems. We conclude that early and meticulous treatment of MSUD can result in intellectually normal children.
Hypercalciuria in children severely affected with osteogenesis imperfecta, To investigate our impression that hypercalciuria is relatively common in children with osteogenesis imperfecta. we performed a retrospective study of data accumulated from our pediatric population with this skeletal disorder. Children with osteogenesis imperfecta (17 girls. 30 boys; mean (+/- SD) age 7.8 +/- 4.6 years; range 0.7 to 16.8 years) had undergone detailed inpatient evaluation of mineral homeostasis during periods of clinical stability and controlled dietary calcium intake. Hypercalciuria was found in 36% of the patients and averaged (+/- SEM) 6.1 +/- 0.3 mg/kg per 24 hours (0.15 +/- 0.01 mmol/kg per 24 hours) or 392 +/- 28 mg/gm of creatinine (1.10 +/- 0.07 mmol calcium/mmol creatinine) in the group with hypercalciuria. There were no statistically significant differences in age. gender. or dietary calcium intake (per kilogram of body weight) between the normocalciuric and hypercalciuric children. However. the group with hypercalciuria was shorter than the normocalciuric group and had a greater lifelong fracture rate. When patient height z scores were regressed against urinary calcium levels. a significant negative correlation was found in the group with hypercalciuria (r = -0.76; p less than 0.001). Although serum alkaline phosphatase activity was lower in the group with hypercalciuria. no difference was found between groups with regard to serum levels of calcium. phosphate. magnesium. creatinine. immunoreactive parathyroid hormone. or osteocalcin. The groups were also similar with respect to both their total body mineral density. as determined by dual-photon absorptiometry (n = 17). and their static indexes of bone formation and resorption. as assessed histomorphometrically with iliac crest specimens (n = 19). We conclude that hypercalciuria occurs frequently in children with osteogenesis imperfecta. and that its magnitude appears to reflect the severity of the skeletal disease.
Effects of rat cytomegalovirus infection on immune functions in rats with collagen induced arthritis, The effect of rat cytomegalovirus (CMV) infection on immune function was studied in rats with collagen induced arthritis. an experimental model of autoimmunity targeted to cartilage and previously shown to be greatly augmented in severity by rat CMV. Rat CMV infection induced an early (7 to 14 day). 2.5-fold increase in circulating B cells (SIgG+) which was associated with moderate increases in the titers of serum IgG antirat type II collagen antibody. A significantly increased skin test reactivity (p less than 0.025) to rat type II collagen was detected at Day 14 and followed a small increase in numbers of W3/25+ T-helper cells in peripheral blood noted at Day 8. A 3-fold expansion of OX8+ peripheral lymphocytes. occurring maximally at Day 8. was tentatively identified as a natural killer cell population by functional 51Cr-release assays. Our data indicate that rat CMV augmentation of collagen induced arthritis is associated with a generalized but modest increase in immune reactivity towards rat type II collagen and with significant alterations of peripheral lymphocyte subsets.
Rheumatoid factor detection in the unaffected first degree relatives in families with multicase rheumatoid arthritis, Rheumatoid factor (RF) was assayed in 354 unaffected first degree relatives from 59 families with multicase rheumatoid arthritis (RA). using both the latex test and ELISA for different RF isotypes. The association between HLA and presence of RF was also analyzed. In all. 39% of the relatives were positive for at least one class of RF compared to 7% positive for latex. There were no differences between the sexes in these rates. There were significant excess rates of HLA-DR4 in RF positive when compared to the RF negative relatives. The HLA-DR4 frequency in these RF positive RA negative individuals is similar to that observed in series of RA positive patients. Thus HLA status did not usefully discriminate between RA positive and RA negative but RF positive individuals in these families.
Inability to interpret toxic salicylate levels in patients taking aspirin and diflunisal, Diflunisal. a nonsteroidal antiinflammatory drug. is not metabolized to the free salicylate moiety. but yields serum salicylate levels. We describe 2 patients who unexpectedly had toxic range serum salicylate levels while taking diflunisal and aspirin for rheumatoid arthritis. Diflunisal is measured by standard salicylate assays. a fact not widely appreciated. Serum salicylate levels by these assays cannot be used to determine salicylate toxicity when a patient is taking both aspirin and diflunisal. High pressure liquid chromatography can be used to distinguish true salicylate toxicity from interference with diflunisal.
Intramuscular gold therapy is associated with long survival in patients with rheumatoid arthritis, To investigate whether the premature death of patients with rheumatoid arthritis (RA) was associated with intramuscular (im) gold treatment or side effects due to gold. a sample of 573 adult patients with RA treated at hospital for the first time during 1961-66 was retrospectively studied for the duration and side effects of im gold treatment as well as death and causes of death. By 1989 a total of 251 patients had died. Gold treatment was not associated with premature death. On the contrary. longterm gold treatment was associated with a high survival rate. Secondary amyloidosis was diagnosed in 28 out of 63 patients. who had gold associated renal disease and who died.
Serum immunoglobulin levels in systemic lupus erythematosus: the effects of age, sex, race and disease duration, To determine whether factors other than disease activity influence immunoglobulin levels in patients with systemic lupus erythematosus (SLE). the effect of age. sex. race. and duration of disease on serum IgG and IgM levels in 170 patients with SLE were investigated. Serum IgM and IgG levels did not differ between men and women. while IgM levels were higher in whites. Serum IgG levels did not vary with age or duration of SLE. In contrast. serum IgM levels were negatively correlated with both age (r = -0.236; p = 0.002) and duration of SLE (r = 0.248; p = 0.001). and demonstrated a U-shaped age relationship. being higher in children and older patients. These patterns of immunoglobulin expression in patients with SLE contrast with those exhibited in populations of healthy individuals. suggesting that the immunoregulatory disturbances of SLE predominate over the normal mechanisms regulating levels of IgM and IgG.
Selective removal of anti-DNA and anticardiolipin antibodies by adsorbent plasmapheresis using dextran sulfate columns in patients with systemic lupus erythematosus, The effect of adsorbent plasmapheresis using dextran sulfate columns on anti-DNA and/or anticardiolipin antibodies (aCL) in 6 patients with systemic lupus erythematosus (SLE) was studied by multicenter clinical trials. The titers of anti-DNA (RI assay). IgG anti-dsDNA (ELISA). IgG and/or IgM anti-ssDNA. (ELISA). and IgG aCL (ELISA) significantly decreased or normalized after 4 treatments of plasmapheresis during a 2 to 4 week period. A patient with SLE with recurrent abortion and aCL who was successfully treated by adsorbent plasmapheresis is reported. We expect that adsorbent plasmapheresis will be an influential treatment for patients with not only SLE but aCL syndrome.
Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa, We attempted to define the most effective treatment for polyarteritis nodosa and Churg-Strauss angiitis. with a prospective. randomized. multicenter trial of cyclophosphamide in conjunction with corticosteroids and plasma exchanges. compared to corticosteroids and plasma exchanges. A total of 71 patients who fulfilled clinical. histological and/or arteriographic diagnostic criteria were randomly designated to receive either prednisone and plasma exchanges (group A. n = 39) or cyclophosphamide. prednisone and plasma exchanges (group B. n = 32). The end points of the study were control of the disease (recovery and remission) and death. Upon study entry clinical and laboratory features did not differ in the 2 groups. Treatment was stopped in 19 patients because of ineffectiveness in 10 (9 in Group A) and side effects in 9 (8 in Group B). Initial control of the disease was similar in both groups. At 5 years. 27 patients had completely recovered and 14 patients were in clinical remission. The cyclophosphamide-prednisone-plasma exchange association was beneficial in preventing relapses during longterm followup. Nineteen deaths were reported during the followup period. There was no difference between the 10 year cumulative survival rates of the 2 groups (respectively. 72 and 75%). Thus. the association of cyclophosphamide with corticosteroids and plasma exchanges reduced the incidence of relapses and improved the quality of the clinical response to therapy.
Transient chondrocyte nonresponsiveness to insulin-like growth factor-1 upon H2O2 exposure is not related to IGF receptor damage, We have shown that for anatomically intact murine cartilage. insulin-like growth factor-1 (IGF-1) is the major anabolic stimulus. Using an experimental arthritis model. we found that cartilage from an arthritic joint could not be stimulated in vitro with IGF-1. This nonresponsiveness was not caused by a generalized disturbance of chondrocyte metabolism since forskolin. an activator of adenylate cyclase. could stimulate cartilage from arthritic joints. To investigate whether hydrogen peroxide may cause IGF-1 nonresponsiveness. we exposed normal murine cartilage to H2O2 in vitro as well as in vivo. We found that cartilage. in which chondrocyte proteoglycan synthesis was inhibited due to H2O2 action in vitro. showed a normal response to IGF-1 after 24-h tissue culture. A time dependent but full recovery was found. In contrast. cartilage which was longterm exposed to H2O2 in vivo after injection of amidated glucoseoxidase (aGO) showed only a moderate IGF-1 response. This lack of total recovery was not due to chondrocyte death or to retained aGO producing extra H2O2 during tissue culture. Further studies with isolated bovine chondrocytes revealed that H2O2 did not damage the IGF-1 receptor. Binding of radiolabelled IGF-1 to H2O2 treated chondrocytes was unimpaired. Our data indicate that H2O2 inhibits chondrocyte proteoglycan synthesis via a mechanism not related to disturbance of IGF-1 signalling. Transient chondrocyte IGF-1 nonresponsiveness found after H2O2 exposure is not related to IGF receptor damage. and contrasts with the complete nonresponsiveness found in arthritic cartilage.
Knee osteoarthritis and physical functioning: evidence from the NHANES I Epidemiologic Followup Study, Although osteoarthritis (OA) is common among adults. little is known about its long-term impact on physical function. Therefore. in a cohort of 2.884 adults aged 45 years or older. [National Health and Nutrition Examination Survey I (NHANES I 1971-1975)] we examined the association of baseline radiographic knee OA and difficulty in physical functioning 10 years later (NHANES I Followup Study 1982-1984). In sex specific analyses. after controlling for age. race and length of followup. persons with radiographic knee OA were more likely than persons without knee OA to report difficulty with physical functioning. particularly for activities involving mobility. transfer and instrumental activities of daily living. However. the association of knee OA with physical functioning was influenced by the radiographic grade of OA and knee pain at NHANES I. suggesting that disease severity and pain are important in anticipating difficulties with physical functioning in persons with knee OA.
Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study, Disseminated soft-tissue sarcomas are a group of uncommon malignancies generally treated in a uniform manner. This study questioned the impact of schedule on response rate and toxicity in patients with metastatic soft-tissue sarcoma treated with the two-drug combination doxorubicin and dacarbazine. Patients were randomly assigned to receive either bolus therapy with doxorubicin at a dose of 60 mg/m2 and dacarbazine at a dose of 750 mg/m2 intravenously on day 1 (118 patients) or infusional therapy with doxorubicin at 60 mg/m2 and dacarbazine at 750 mg/m2 delivered by continuous intravenous infusion for 96 hours on days 1-4 (122 patients). Chemotherapy was to be repeated every 3 weeks. A unique feature of this cooperative group protocol was a provision for surgical resection of residual disease in patients with a partial response or with stable disease following chemotherapy. Similar overall response rates (17% in both treatment arms) and complete response rates (5% in both treatment arms) were observed. For patients receiving bolus therapy. the median response duration was 19.6 months for those in complete remission and 6.6 months for those in partial remission. For patients receiving infusional therapy. the median response duration was 12.6 months for those in complete remission and 9.3 months for those in partial remission. Examination of dose intensity received when combining treatment arms revealed a weak doxorubicin dose-response relationship. There was no difference in median survival times between the two treatment arms (bolus therapy. 10.6 months; infusional therapy. 10.5 months; logrank P = .97). Analysis of toxic effects favored infusional therapy. Significant reductions in cardiac toxicity (all events. P = .04; clinical events. P = .01) and nausea and emesis (P = .04) were seen in infusional therapy. Of 47 patients eligible for cytoreductive surgery following chemotherapy. 12 received surgery. and of those 12. eight were rendered disease free. The use of a 96-hour continuous intravenous infusion of doxorubicin-dacarbazine was comparable therapeutically with bolus dosing of these two agents and was better tolerated by the patients.
Lysis of autologous melanoma cells by tumor-infiltrating lymphocytes: association with clinical response, Tumor-infiltrating lymphocytes (TILs) can be grown in vitro in medium containing interleukin-2 (IL-2). In clinical trials at the Surgery Branch of the National Cancer Institute. patients with metastatic malignant melanomas were treated with IL-2 plus the adoptive transfer of autologous TILs. At the time of treatment. TILs were assayed for in vitro lysis of fresh autologous and allogeneic melanoma cells and Daudi cells. Patients were evaluated for clinical response 4-8 weeks later. Lysis of autologous tumor cells by TILs was significantly higher for responding than for nonresponding patients. Tumor cells from responding and nonresponding patients were equally sensitive to lysis by allogeneic lymphokine-activated killer (LAK) cells. There was no difference between TILs from responding and nonresponding patients for lysis of LAK-sensitive Daudi cells. which was low in most cases and demonstrated that TIL lysis of autologous tumor cells was not due to LAK cells. The observed association of autologous tumor cell lysis by TILs with clinical response suggests that the development of culture methods to optimize lysis of autologous tumors may lead to increased response rates using this TIL treatment regimen.
Occurrence of p53 gene abnormalities in gastric carcinoma tumors and cell lines, We explored the state of the p53 gene in gastric cancer. Using one or more methods. we examined 15 specimens from primary carcinomas (14 tumors. one cell line). five cell lines derived from metastases. and seven paired samples of nonmalignant gastric mucosa. Sequence analyses of complementary DNA containing the entire p53 gene open reading frame demonstrated abnormalities in one of five samples from primary tumors and in all five samples from metastases. The single cell line derived from a primary carcinoma had no abnormality of the gene. The six abnormalities included four point mutations. one base-pair deletion resulting in a frame shift. and a 24 base-pair deletion caused by an intronic point mutation (as determined by sequence analysis of genomic DNA). Four of the six mutations mapped to regions highly conserved among species or involved in simian virus 40 T-antigen binding. Restriction fragment length polymorphism studies confirmed that chromosome 17p allelic deletions occur only in a minority of primary tumors. but that they may occur more frequently in metastases. Northern blotting and ribonuclease protection assays detected only a fraction of the p53 gene abnormalities detected by sequencing. Our findings indicate that mutations of the p53 gene are relatively rare in primary gastric tumors but appear to be relatively frequent in cell lines derived from metastatic lesions. Our results may help in understanding the molecular events associated with progression and metastasis in gastric carcinoma.
A follow-up study of colonic epithelial proliferation as a biomarker ina Native-American family with hereditary nonpolyposis colon cancer, A 7-year follow-up study of colonic mucosa proliferation markers was conducted on members of a Native-American family with hereditary nonpolyposis colon cancer. Reproducibility of a tritiated thymidine autoradiography assay for labeling indexes during this 7-year biologically significant time frame was established. A good correlation between tritiated thymidine and a newer technique. bromodeoxyuridine immunoperoxidase staining. was seen. No confounding effect could be attributed to standard colon preparation. On average. both baseline and follow-up values for epithelial proliferation were within the accepted normal range. The presence of essentially normal labeling indexes among colon cancer patients and their high-risk offspring suggests the possibility of the significant effect of dietary factors in reducing proliferation. Such factors may account for the low risk of colon cancer that characterizes the Native-American population in the American Southwest.
Hemodialysis with cuprophane membrane modulates interleukin-2 receptor expression, Chronic dialysis patients have several indices of immune deficiency. We examined the hypothesis that the biocompatibility of dialysis membranes may influence the ability of lymphocytes to express interleukin-2 (IL-2) receptors on their surface. a key event in cellular immune response. We investigated the potential role of the dialysis membrane in eight chronic hemodialysis patients. The study design was a cross-over study using cuprophane and polymethylmethacrylate (PMMA) membranes. Chronic dialysis with new cuprophane membrane leads to an increase in baseline expression of the two subunits of IL-2 receptors. IL2R alpha (p55. CD25) and IL-2R beta (p70). in peripheral blood mononuclear cell (PBMC). However. Phytohemagglutinin (PHA) stimulation of PBMC harvested after two weeks of dialysis with cuprophane membrane showed a markedly decreased expression of high affinity IL-2 receptors. These findings are reversed when patients were dialyzed with a PMMA membrane which is also associated with minimal complement activation. The increased expression of IL-2 receptor subunits are reproduced in vitro by direct contact of PBMC with cuprophane membrane and by the addition of the anaphylatoxin C5a. This study confirms the participation of lymphocytes in the complex blood-membrane interactions that occurs during dialysis; the results may be relevant to observations of immune deficiency in dialysis patients.
Diagnostic significance of hypocomplementemia [editorial, Hypocomplementemia is an important marker for the presence of IC-mediated disease and can be used to assess disease activity. However. in interpreting the clinical significance of hypocomplementemia. the following must be kept in mind: 1) There are numerous non-immunologic conditions that also can cause hypocomplementemia. Furthermore. some of these conditions can cause a multisystem disease that. along with the hypocomplementemia. can closely resemble an IC-mediated systemic vasculitis. Furthermore. these nonimmunologic conditions that lower serum complement levels can complicate the course of patients with inactive IC-mediated disease. spuriously indicating that the disease is active. The most relevant of these differential diagnostic problems are listed in Table 2. 2) There are a few conditions (for example. pregnancy) that can raise serum complement levels. thereby possibly obscuring the presence of a disorder (such as. active SLE) that is lowering complement levels. 3) There are some conditions that might be expected to lower serum complement levels. because of their effect on protein metabolism. but do not. Nephrotic syndrome. and moderately poor nutrition are examples. All of these factors should be considered when interpreting results of serum complement levels in a given patient.
Increased plasma prorenin but not renin after bilateral ureteral ligation in dogs, Plasma prorenin is normally higher than renin and usually changes in response to the same stimuli. In dogs. plasma prorenin and renin disappear after bilateral nephrectomy. indicating that both are of renal origin. It has been proposed that prorenin may mediate tissue renin systems via its reversible intrinsic renin-like activity. The renin-angiotensin system has been implicated in the changes in renal function that occur with bilateral ureteral obstruction. but plasma prorenin has not been investigated. We therefore studied the effect of 48-hour bilateral obstruction on plasma prorenin in two groups of dogs: one was volume expanded (N = 5). while the other group (N = 6) was euvolemic. Plasma prorenin concentration increased fourfold in both groups. angiotensinogen increased twofold. while plasma renin activity was unchanged. Following release of obstruction. plasma renin fell slightly while prorenin and angiotensinogen remained elevated. There was a positive relationship between plasma prorenin and renin before (r = 0.63. P less than 0.05) and after (r = 0.76. P less than 0.01) obstruction. Post-obstruction. ERPF and GFR were subnormal but filtration fraction was maintained; the higher the ERPF and GFR the higher the plasma prorenin post-obstruction (r = 0.83. P less than 0.01 and r = 0.77. P less respectively; N = 11). These results show that impairment of renal function during bilateral obstruction is associated with an increase in plasma prorenin but not renin. Nonetheless. there is a positive relationship between plasma prorenin and renin both pre- and post-obstruction. Thus. preferential impairment of clearance of prorenin relative to renin may occur during bilateral obstruction.
Beta 2-microglobulin kinetics in end-stage renal failure, The kinetics of beta 2-microglobulin (beta 2m) were studied in five anephric or anuric hemodialysis patients. Human beta 2m was isolated from peritoneal dialysate using ion-exchange and gel chromatography and radiolabeled with 125I. Patients were injected with 10 microCi labeled beta 2m. In one study (N = 4). plasma activity was measured over 72 hours. In a second study (N = 4). patients received low-flux dialysis 24 hours after injection and high-clearance dialysis (Bellco BL655) at 48 hours. Plasma activities were fitted to a three-compartment. variable volume model. Endogenous beta 2m levels (radioimmunoassay) were 56 +/- 6 mg/liter. The beta 2m distribution volume was 12.7 +/- 2.0 liter (0.20 +/- 0.03 liter/kg) and the non-renal clearance was 3.0 +/- 0.4 ml/min. The generation rate. 9.9 +/- 1.7 mg/hr (0.16 +/- 0.04 mg/kg/hr). was similar to that measured in subjects with normal renal function. The three compartment model derived from the turnover data gave an adequate fit of the arterial concentrations of endogenous and exogenous beta 2m during low-flux (nil beta 2m clearance) and high-clearance (beta 2m clearance of 19 ml/min) dialysis. Simulations based on this model indicate that extracorporeal treatment can at best remove about 50% of weekly production. These results suggest that beta 2m production is not increased in dialysis patients. that there is substantial non-renal beta 2m clearance. and that the amount of beta 2m that can be removed by extracorporeal therapy is therefore limited.
Involvement of thromboxane A2, leukotrienes and free radicals in puromycin nephrosis in rats, Thromboxane A2 (TXA2). leukotrienes (LTs) and free radicals are considered to be possible mediators in the induction of glomerular injury and proteinuria. In this study. we examined the involvement of these three mediators and the protective effect of simultaneous inhibition of all three in puromycin aminonucleoside (PAN) nephrosis in rats. A single intraperitoneal injection of PAN (100 mg/kg) induced massive proteinuria and enhanced production of TXA2 and LTs from arachidonic acid in renal cortical slices and renal glomeruli. and increased malondialdehyde levels in plasma. urine and renal cortex. Oral administration of CV-6504(HCl) (3 to 20 mg/kg/day. for 1 to 2 weeks). a novel treble inhibitor of TXA2 synthetase. 5-lipoxygenase and lipid peroxidation. dose-dependently attenuated PAN-induced proteinuria and the increases in these three mediators. Any single specific inhibitor (CV-4151. a TXA2 synthetase inhibitor; AA-861. a 5-lipoxygenase inhibitor; or CV-3611. a radical scavenger) or a combination of two inhibitors showed no or only a slight antiproteinuric effect. but the combination of all three inhibitors significantly reduced PAN-induced proteinuria. These results suggest that. these three mediators may be involved in the pathogenesis of PAN nephrosis and that CV-6504(HCl). which can simultaneously inhibit all three. may be a useful therapeutic agent for nephrosis.
Identification of a low molecular weight inhibitor of osteoblast mitogenesis in uremic plasma, A low molecular weight inhibitor of cartilage sulfation has been detected in the plasma of dialysis patients. Preliminary studies of this inhibitor have suggested that it may have a role in decreasing bone mass. possibly by suppressing bone cell proliferation. Since the in vitro bioassay of crude sulfation inhibitor preparations is relatively nonspecific. we investigated whether there might also be an inhibitor of osteoblast mitogenesis in uremic plasma. We fractionated plasma and plasma ultrafiltrates from dialysis patients by gel filtration chromatography and looked for inhibition of mitogenesis in cultured osteoblasts. Material from fractions with a molecular weight range of 750 to 900 inhibited osteoblast mitogenesis. The inhibitory effect. however. could be overcome with serum or insulin-like growth factor-I. suggesting that the mechanism of inhibition was not growth factor dependent. Further characterization of the inhibitor revealed that it was not a peptide or a polar lipid. We conclude that uremic plasma contains a bone cell mitogenic inhibitor which may have a role in regulating bone remodeling in adults and bone growth in children.
Proto-oncogene expression in peripheral blood mononuclear cells in IgA nephropathy, We have investigated the expression of proto-oncogenes in mononuclear cells obtained from patients with IgA nephropathy using a RNA hybridization technique. Patients with IgA nephropathy expressed more c-myc. c-raf. c-fos. and c-jun proto-oncogene RNA than did normal controls. However. no significant expression of c-N-ras. c-mos or c-myb genes was found in the mononuclear cells of these patients. When the amount of urinary protein excretion was used as an indicator of disease activity (greater than 1 g/day). a positive correlation was found between c-myc. c-raf. c-fos. and c-jun expression and urinary protein excretion (P less than 0.01). The expression of these genes correlated also with the serum IgA concentration (P less than 0.01). IgA immune complex (P less than 0.01). and histopathological changes in renal tissues obtained from patients with IgA nephropathy (P less than 0.01). The results of this survey suggest that abnormally regulated proto-oncogene expression in mononuclear cells may play an important role in the progression of IgA nephropathy and may be useful as an indicator of disease activity and/or prognosis.
Elevated circulating levels of interleukin-6 in patients with chronic renal failure, In a previous study. we demonstrated the presence of circulating interleukin-1 (IL-1) in long-term dialyzed patients and that of tumor necrosis factor alpha (TNF alpha) in both long-term and not yet dialyzed uremic patients. In the present study. we attempted to determine the respective influence of hemodialysis (HD) and uremia on the plasma level of interleukin-6 (IL-6). which shares several biological properties with IL-1 and TNF alpha. including the induction of the acute phase response of the inflammatory process. Forty-eight patients with end-stage renal failure. including 32 long-term HD patients and 16 chronic uremic patients undergoing their first dialysis session. were tested for plasma IL-6 using both biological and immunoreactive assays. Plasma IL-6 activity was significantly increased in patients with chronic renal failure (P less than 0.001) compared to its level in normal individuals. No difference was observed. however. between long-term and not yet dialyzed patients. In the patients with the most pronounced IL-6 activity. immunoreactive IL-6 levels between 60 and 150 pg/ml were detected. A monoclonal antibody (mAb) against human IL-6 inhibited the activity of plasma in the IL-6 bioassay. and a close correlation existed between the biological activity of IL-6 and its immunoreactive level. No change in plasma IL-6 was detected during the course of the first dialysis as well as subsequent sessions. Likewise. no influence of the nature (cellulosic or synthetic polyacrilonitrile) of the dialysis membrane equipping the dialyzer was observed.
The DQw7 allele at the HLA-DQB locus is associated with susceptibility to IgA nephropathy in Caucasians, The frequencies of the MHC class II HLA-DR and DQ alleles in 36 Caucasian patients with IgA nephropathy (IgAN) were analyzed by RFLP analysis and allele specific oligonucleotide (ASO) probing of specifically amplified genomic DNA. The class II alleles HLA-DR4 (52.7%) and DR5 (30.5%) were increased in the patient group compared to 1103 UK Caucasoid controls. but these increases were not statistically significant. However. there was a significant increase in the HLA-DQw7 allele frequency (71%) (c = 27.8%. chi 2 = 29.2. P less than 0.001. Relative Risk = 6.17). This can be explained by linkage disequilibrium between the DQw7 allele at the DQB1 locus and DRB1 genes of some DR4 and all DR5 haplotypes. The polymorphic portion of the DQ alpha chains from DR4. DQw7 and DR5. DQw7 haplotypes differ but they have identical DQ beta chains. DNA encoding DQw7 allele at the DQB1 locus was sequenced in two patients and was identical to that previously published. We conclude that the DQw7 allele at the DQB1 locus is strongly associated with susceptibility to IgAN in Caucasians.
Glomerular hypertension in renovascular hypertensive patients, Split intrarenal hemodynamics in stenotic and contralateral kidneys of unilateral renovascular hypertension (RVH) were estimated by Gomez's formulae. Forty patients with essential hypertension and 40 patients with RVH were studied. Split para-amino hippurate and inulin clearances were measured by ureteral catheterization as indexes for effective renal plasma flow and glomerular filtration rates. allowing the estimation of intrarenal hemodynamics such as afferent arteriolar resistance (RA). efferent arteriolar resistance (RE) and glomerular hydrostatic pressure (PG) in each kidney. Normal values of intrarenal hemodynamic parameters were obtained in 24 normotensive subjects without ureteral catheterization. assuming each kidney had the half function of both kidneys. Systemic mean arterial pressure did not differ between essential and renovascular hypertension (141 +/- 3 vs. 148 +/- 3 mm Hg). Effective renal plasma flow and glomerular filtration rates were decreased in the stenotic kidney of RVH (98 +/- 8. 24 +/- 2 ml/min/m2). while increased in the contralateral kidney (195 +/- 11. 48 +/- 2). compared with the right kidney of essential hypertension (162 +/- 8. 33 +/- 1). Although effective renal plasma flow rate was not different from normal (191 +/- 8). glomerular filtration rate was significantly higher in the contralateral kidney of RVH than in normal (38 +/- 1). RA was elevated due to the stenotic lesion in the stenotic kidney (28.500 +/- 1.900 dyns.sec.cm-5). while the elevation in the contralateral kidney (10.800 +/- 600) was less than in the right kidney of essential hypertension (14.900 +/- 1.200). RE (5.800 +/- 300) in both kidneys of RVH was higher than in the right kidney of essential hypertension (4.500 +/- 200).
Ribosome and free amino acid content in muscle during hemodialysis, Patients (N = 8) with chronic renal failure and uremia treated with hospital hemodialysis were in a pilot study investigated before and after a single hemodialysis session. The extracorporeal dialysis circuit was flushed regularly with saline to avoid clotting and the use of heparin. Percutaneous skeletal muscle biopsies were taken before and after the dialysis to determine the content of free amino acids together with the concentration and size distribution of ribosomes before and after dialysis. After dialysis the alanine concentration in muscle decreased by 20% (P less than 0.05). while all other amino acids were unaffected. The total ribosome concentration per mg of DNA decreased by 31% (P less than 0.01) and the relative proportion of polyribosomes by 7% (P less than 0.05) after the dialysis compared to predialytic values. All individual plasma amino acids decreased during the dialysis procedure except for threonine and arginine. which were unaltered. and leucine and isoleucine. which increased. The decline in ribosome and polyribosome content together with the changes in amino acid levels indicate a low capacity for protein synthesis and increased catabolism in muscle of hemodialyzed patients.
Circulating anti-entactin antibodies in patients with glomerulonephritis, Sera from 305 consecutive patients in a renal biopsy series were analyzed for the presence of anti-entactin antibodies by ELISA. Of these patients. 59% had primary glomerulonephritis. 21% had secondary glomerulonephritis. while 20% had other nephropathies (noninflammatory conditions like amyloidosis. diabetic nephropathy. nephrosclerosis. etc.). Forty-one of these patients (13.4%) were positive for IgG/IgM antibodies against entactin: 60% of them had primary glomerulonephritis. 35% had secondary glomerulonephritis. while the remaining 3 patients had other nephropathies. Fifteen (70%) of the 23 patients with primary glomerulonephritis had proliferative glomerulonephritis (PGN). whereas 13 (87%) of the 15 patients with secondary glomerulonephritis were due to systemic connective tissue diseases (SCTD): 7 due to SLE. 4 due to SLE like SCTD and two due to other SCTD. There was a peak of incidence corresponding to the group aged 18 to 30 years. A majority of these patients (12 of the total 17) had primary glomerulonephritis and were associated with nephrotic or subnephrotic grade proteinuria. poorly or nonresponsive to immunosuppressive treatment and associated. in several cases. with progressive deterioration of renal function. In addition. there was a tendency to another peak in the age group 51 to 60 years. Most of these patients (6 of the total 8) had glomerulonephritis secondary. mainly. to SLE or SLE like SCTD with milder degree of proteinuria and better preserved renal functions. Anti-entactin antibodies were not found in certain glomerulonephritides like IgA nephropathy and those secondary to systemic vasculitides and in control subjects (healthy subjects. and patients with a variety of non-renal disorders including inflammatory diseases).
Effect of low concentrations of ozone on inhaled allergen responses in asthmatic subjects, The relation between inhalation of ambient concentrations of ozone and airway reactivity to inhaled allergens may be important in asthma. since both agents can produce inflammatory changes in the airways. Seven asthmatic patients (mean age 40 [SD 13] years). with seasonal symptoms of asthma and positive skin tests for ragweed or grass. took part in a study to investigate whether exposure to low concentrations of ozone potentiates the airway allergic response. The patients were studied during 4 separate weeks in the winter. In each week there were 3 study days: on days 1 and 3 methacholine challenges were carried out; and on day 2 the subject received one of four combined challenges in a single-blind design--air breathing followed by inhalation of allergen diluent (placebo); ozone followed by inhalation of allergen diluent; air followed by allergen; or ozone followed by allergen. The ozone concentration was 0.12 ppm during 1 h of tidal breathing at rest. and allergens were inhaled until the forced expiratory volume in 1 s (FEV1) had fallen by 15% (PC15). There were no significant differences in baseline FEV1 after exposure to ozone but PC15 was significantly reduced when allergen was preceded by ozone inhalation: the mean PC15 after air was 0.013 (SD 0.017) mg/ml compared with 0.0056 (0.0062) mg/ml after ozone (p = 0.042). Thus. low ozone concentrations. similar to those commonly occurring in urban areas. can increase the bronchial responsiveness to allergen in atopic asthmatic subjects. This effect does not seem to be the result of changes in baseline airway function.
Improvement of cyclosporin absorption in children after liver transplantation by means of water-soluble vitamin E, Many childhood recipients of liver transplantation require massive doses of cyclosporin to achieve therapeutic blood concentrations of the drug. The impaired absorption of this strongly lipophilic drug may be due to reduced intestinal absorptive area. suboptimal mixing of the drug with hepatobiliary secretions. or residual cholestasis. Improvement of cyclosporin absorption was sought by means of oral coadministration of d-alpha-tocopheryl-polyethylene-glycol-1000 succinate (TPGS). a water-soluble form of vitamin E which can form micelles. 25 mg/kg daily of TPGS was given to six paediatric liver transplant recipients and one young adult with severe hepatobiliary graft-vs-host disease after bone-marrow transplantation. who required 29-136 mg/kg cyclosporin daily to achieve therapeutic cyclosporin blood concentrations. Five responded; the oral cyclosporin dose could be reduced by 40-72% within 2 months. In addition. intravenous cyclosporin was stopped in two of the responders. In the two non-responders the cyclosporin doses at entry were similar to those in the responders after TPGS treatment. Oral cyclosporin absorption tests correctly predicted the outcome of treatment in three responders and one non-responder tested. Treatment with TPGS to enhance cyclosporin absorption might be a useful way of reducing the high cost of immunosuppression in paediatric liver transplant recipients.
Effect of glutathione aerosol on oxidant-antioxidant imbalance in idiopathic pulmonary fibrosis, Idiopathic pulmonary fibrosis (IPF) is characterised by alveolar inflammation. exaggerated release of oxidants. and subnormal concentrations of the antioxidant glutathione in respiratory epithelial lining fluid (ELF). Glutathione (600 mg twice daily for 3 days) was given by aerosol to 10 patients with IPF. Total ELF glutathione rose transiently. ELF oxidised glutathione concentrations increased. and there was a decrease in spontaneous superoxide anion release by alveolar macrophages. Thus. glutathione by aerosol could be a means of reversing the oxidant-antioxidant imbalance in IPF.
Cranioplasty, vertebral body replacement, and spinal fusion with tobramycin-impregnated methylmethacrylate, A prospective analysis of cranioplasty. vertebral body replacement. and spinal fusion using tobramycin-impregnated methylmethacrylate in 65 patients is presented. Cranioplastic methacrylate (1 packet) was mixed with 1.2 g of powdered tobramycin and placed into the desired location. The polymer was irrigated with bacitracin until it became solid. All patients received prophylactic medication with intravenously administered nafcillin and cephalosporin perioperatively and for 48 hours postoperatively. The follow-up time ranged from 7 to 57 months (mean. 32.2 months). Serum tobramycin levels remained below 0.5 microgram/ml in all patients tested. regardless of the time interval. Blood urea nitrogen and creatinine levels remained within normal limits in all patients. and there has been no nephrotoxicity or ototoxicity. There has been 1 infection among the 65 patients (1%) to date. It occurred in a patient who had a previously treated local infection. Cranioplasty. vertebral body replacement. or spinal fusion with tobramycin-impregnated methylmethacrylate is safe and may reduce the incidence of infection.
Open surgery assisted by the neuronavigator, a stereotactic, articulated, sensitive arm, A new computed tomographic-stereotactic device that translates the operating point onto preoperative computed tomographic (CT) images. the Neuronavigator. has been developed. We have applied this system to various neurosurgical procedures to examine its usefulness. The system consists of a 6-joint sensing arm and a 16-bit personal computer. It projects the location of the arm tip onto a corresponding CT slice with a cursor that guides the surgeon toward the intracranial target during open surgery. The system also projects the location of the tip onto angiograms. and when used in conjunction with echography or a transcranial Doppler (TCD) flow meter. the surgeon's ability to navigate is enhanced. Sixty-eight patients underwent operation with the Neuronavigator. The navigation system worked as the core of a multimodal three-dimensional data base that proved to be useful during surgery. The maximum detection error was 2.5 mm. which was considered sufficient for open microsurgery. It also proved useful in designing the position of a craniotomy. in targeting deep-seated mass lesions. and in tracing the tumor edge. which had been identified on a CT scan. When the angiogram was combined with the navigator. it became easy to identify key vessels within a small operating field. The system was also combined with a TCD flow meter. This combination makes it possible to translate the measuring point of the TCD directly into CT coordinates. improving the precision of location of the TCD probe. The Neuronavigator combines various diagnostic images into one database and effectively guides the surgeon during surgery.
Brain tumor resection aided with markers placed using stereotaxis guided by magnetic resonance imaging and computed tomography, In the operative resection of brain tumors. defining and locating edges of deep-seated tumors or those with indistinct color and consistency can be difficult. This report presents a simple yet precise. alternative method. using the basic Brown-Roberts-Wells or Cosman-Roberts-Wells stereotactic frame. for placement of visual markers to aid in tumor resections. The method can also be extended to the Leksell system. Using routine computed tomographic scanning or magnetic resonance imaging after stereotactic frame application. multiple points along tumor edges were used as target points. In the operating room. standard techniques were used for the skin incision. removal of the bone flap. and opening the dura. At each target point. after opening the dura and using stereotactic coordinates and equipment. a microbiopsy forceps was used to place "micropatties" (each with a string tail) or small catheters with pledgets or catheter tips located at tumor edges. After removing the arc. the tumor resection was accomplished in a conventional nonstereotactic manner by simply following string tails or catheters to the tumor. Gross tumor edges were determined from positions of actual patties or catheter tips. These simple but accurate techniques offer the possibility of tumor resections under stereotactic guidance with equipment readily available to most neurosurgeons. The fidelity of marker placement is also maintained in relation to tumor edges despite shifts in the tumor and/or brain as cystic areas are drained or large amounts of the tumor are resected.
Measurements of regional cerebral blood flow and blood flow velocity in experimental intracranial hypertension: infusion via the cisterna magna in rabbits, Cerebral blood flow velocity. as measured in the intracranial segment of the internal carotid artery by transcranial Doppler sonography via the transorbital route. and regional cerebral blood flow and volume in corresponding cortical areas. as measured by the hydrogen clearance technique. were recorded for eight New Zealand White rabbits subjected to infusion via the cisterna magna to elevate intracranial pressure. In the lower range of autoregulation. that is. at perfusion pressures between 80 and 40 mm Hg and even lower. the changes in cerebral blood flow velocity and cerebral blood flow showed a strong correlation (0.86) under conditions of standard pCO2 (PaCO2 = 35 +/- 2 mm Hg). Autoregulation was exhausted at 40 mm Hg. and the cerebrovascular resistance was minimal. Below this perfusion pressure. the cerebral blood flow and volume dropped sharply. whereas the cerebrovascular resistance gradually increased. indicating that. despite the maximally dilated resistance vessels. intracranial hypertension causes vascular resistance to increase. possibly via blocking of the venous outflow. Our results confirmed that noninvasive and easily (even at bedside) applicable measurements of changes in cerebral blood flow velocity could be a substitute for the cumbersome and expensive isotope measurements of cerebral blood flow in patients with intracranial hypertension.
Millipore analysis of valvular fluid in sterile valve malfunctions, Malfunctions of sterile shunts may result from valvular dysfunction. The cerebrospinal fluid shunt valves of 14 patients were excised during surgery for sterile shunt malfunctions. In 6 patients. the malfunction was due specifically to a valve malfunction. Cerebrospinal fluid from each valve was passed through a millipore filter. which was then stained using either hematoxylin and eosin or periodic acid-Schiff. The stained millipore filters were examined by a neuropathologist who was unaware of the cause of the shunt malfunction. Although inflammatory cells were detected in all cases. the patients with valve malfunctions were found to have numerous macrophages and giant multinucleated reactive cells within their valves. while cerebrospinal fluid from valves that had been removed during shunt revisions for reasons other than a malfunctioning valve contained only rare mononuclear cells or macrophages. No valve contained erythrocytes. fibrinous matter. neural or glial tissue. or choroid plexus. The possible causes of valve malfunction. including infection and allergic reactions. are discussed. All patients did well after simple replacement of the valve.
Arachnoid cyst of the cerebellopontine angle manifesting as contralateral trigeminal neuralgia: case report, A case of an arachnoid cyst in the cerebellopontine angle manifesting as contralateral trigeminal neuralgia is presented. Decompression and excision of the lesion resulted in total relief of symptoms. The possible causes of contralateral trigeminal neuralgia are briefly reviewed. and the surgical treatment of this entity is discussed.
Dissecting aneurysms of the posterior inferior cerebellar artery, The authors present three cases of dissecting aneurysms of the posterior inferior cerebellar artery (PICA). A literature search revealed only three previous cases. Analysis of these six cases showed a unique clinical picture. Three patients developed subarachnoid hemorrhage. and the other three had ischemia. All patients complained of occipital headache or neck pain. regardless of the initial symptoms. Heralding episodes were recorded in four cases. Angiography showed a characteristic fusiform dilatation of the PICA and a narrowing proximal to and distal to the lesion. Various surgical treatments were performed in five cases. Intraoperative observation showed a sausage-like swelling of the PICA or one of its branches with various discoloration depending on the age of the intramural clot. The outcomes were favorable.
Transoral crossbow injury to the cervical spine: an unusual case of penetrating cervical spine injury, The complexity of missile injuries to the cervical spine has increased as the technology that causes these injuries has become more sophisticated. Management requires adaptation of conventional neurosurgical approaches to the cervical spine in an effort to limit neurological deficit and establish stability. We report an unusual case of a 19-year-old man who suffered transoral penetration of the cervical spine by an arrow released by a crossbow at close range.
Mild cognitive impairment in the elderly: predictors of dementia, We conducted full diagnostic evaluations. including a comprehensive cognitive assessment battery. of a group of 32 elderly subjects with a clinically identified mild cognitive impairment and a group of 32 age-matched and education-matched normal subjects. The mildly impaired subjects performed significantly more poorly than the controls on tests of recent memory. remote memory. language function. concept formation. and visuospatial praxis. Follow-up evaluations of cognitive status 2 years later revealed clinically detectable cognitive decline relative baseline in 23 (72%) of the mildly impaired subjects. Several of the objective psychological tests accurately discriminated at baseline between the decliners and nondecliners in the mildly impaired group. Among the 20 mildly impaired subjects with no complicating conditions. 16 exhibited cognitive deterioration between baseline and follow-up. These results suggest that most elderly subjects with mild cognitive deficits. as determined by clinical evaluation and objective psychological testing. will manifest the progressive mental deterioration characteristic of dementia and that psychometric predictors can be used to distinguish between benign and more significant underlying disorders in mildly impaired elderly subjects.
Cerebrospinal fluid protein and opening pressure in idiopathic intracranial hypertension (pseudotumor cerebri), We studied the relationship between the CSF protein concentration and the degree of elevation of the CSF opening pressure in 177 patients with idiopathic intracranial hypertension (pseudotumor cerebri). There was no linear correlation between the CSF protein and opening pressure. In addition. low CSF protein (less than 20 mg/dl) was present in only 26% of the patients. Our findings fail to confirm previous reports of an inverse relationship between the CSF opening pressure and CSF protein as well as low CSF protein in these patients.
Diagnostic value of video-EEG polysomnography, To investigate the diagnostic value of video-EEG polysomnography (VPSG). we reviewed our experience in 122 patients with suspected parasomnias who underwent one or two nights of VPSG. Of 86 patients without known epilepsy. VPSG provided useful diagnostic information for 41 (69%) of those with a history of prominent motor activity during sleep and for 11 (41%) of those with a history of minor motor activity during sleep. Two children and one adult with clinical histories suggestive of sleep terrors had unequivocal partial seizures during VPSG. Of 36 patients with known epilepsy. VPSG was useful diagnostically in 28 (78%). VPSG is superior to standard polysomnography for the evaluation of parasomnias because of the increased capability to identify and localize EEG abnormalities and to correlate behavior with EEG and polysomnography. VPSG may also be a suitable alternative to intensive inpatient monitoring for some patients with known or suspected epilepsy who have frequent undiagnosed nocturnal spells.
Transcranial magnetic stimulation in patients with epilepsy, We studied the effects of transcranial magnetic stimulation (TMS) applied in trains of 8- to 25-Hz stimuli on electroencephalographic epileptiform activity on eight patients being evaluated for epilepsy surgery. We performed the stimulation with a round water-cooled stimulation coil held flat on the scalp and centered over different positions of the International 10-20 System. We were unable to trigger seizures or induce epileptiform discharges arising from the epileptic focus in any of the eight patients with any of the stimulation protocols. However. we induced a partial motor seizure from the contralateral hemisphere to the exclusive temporal focus in the only patient stimulated with 100% maximal intensity. Precautions have to be taken when applying rapid TMS to patients because of the risk of seizure induction. Our results do not support the view that TMS specifically activates the epileptic foci.
Patterns of postictal cerebral blood flow in temporal lobe epilepsy: qualitative and quantitative analysis, We used single-photon emission computed tomography (SPECT) to study postictal cerebral blood flow (CBF) in 51 patients with temporal lobe epilepsy. There were 78 seizures studied. 77 by early postictal injection of Tc-99m HMPAO (delay from seizure onset = 4.3 +/- 4.5 min) and one by ictal injection. Increased focal temporal lobe uptake. predominantly confined to the anteromesial region. was present in 83% and declined rapidly over 5 minutes. Reduced activity in the lateral temporal lobe accompanied the mesial increase in 80% of studies. extending over much of the ipsilateral hemisphere and closely associated with the degree and extent of postictal EEG slow waves. These patterns enabled correct seizure localization by blinded analysis in 69% (31/45) of the patients with a unilateral EEG focus. The remainder showed bilateral or no changes. One of six patients with bitemporal EEG foci had unilateral perfusion changes. The positive predictive value for the correct localization of a unilateral focus by postictal SPECT was 97% (31/32). Postictal CBF imaging with SPECT can be used to support noninvasive electrographic localization and may decrease the need for invasive electrode studies.
Neuropsychiatric aspects of psychogenic status epilepticus, We studied 20 patients with continuous repetitive psychogenic seizures simulating status epilepticus. Most patients received intravenous doses of multiple anticonvulsants. Our definition used for status epilepticus was that of Delgado-Escueta et al. at least 30 minutes of repetitive seizures without regaining consciousness. Nineteen of 20 patients were young women. all but one under 40 years of age. Sixteen of these patients had a history of childhood seizures. In over 50% of patients. seizures continued until respiratory arrest and intubation occurred. Thorough neuropsychological testing and psychiatric interview were done after cessation of the acute episode. Long-term outcome and prognosis depended on definitive psychiatric diagnosis. Repetitive psychogenic seizures simulating status epilepticus are not uncommon. and such patients may incur serious iatrogenic complications from treatment for status epilepticus. Appropriate management and long-term prognosis may be determined by the type and severity of the underlying psychiatric disorder.
Beta-receptor sensitivity in autonomic failure, We examined the cardiovascular. plasma norepinephrine (NE). and plasma renin (PRA) responses to isoproterenol infusion in patients with autonomic failure and in normal subjects. Slopes of the blood pressure response/dose relationships were more negative in patients with multiple system atrophy and pure autonomic failure (PAF) than in normal subjects. consistent with impaired baroreflex modulation. A shift to the left in patients with PAF suggests beta-adrenergic receptor supersensitivity. In normal subjects. the increase in plasma NE and PRA was proportional to the log of the plasma isoproterenol level. Isoproterenol infusion did not increase plasma NE or PRA in either patient group despite a reduction in mean blood pressure. Reflexive cardiovascular and renal mechanisms appear to play a role in eliciting the plasma NE and PRA responses to isoproterenol infusion in normal subjects.
Complex partial status epilepticus of extratemporal origin: report of a case, A 28-year-old woman with no history of seizure was 7 months pregnant when she developed a prolonged complex partial status epilepticus (CPSE) organized in recurrent complex partial seizures of occipital origin. which was ascertained by the presence of elementary visual hallucinations and nystagmus heralding the attacks. EEG demonstrated recurrent seizures starting from the right occipital area. This especially refractory case of CPSE resolved after treatment with antiepileptic drugs and termination of pregnancy by cesarean section.
Idazoxan treatment in progressive supranuclear palsy, To confirm the preliminary report that increases in norepinephrine neurotransmission improve motor performance. we administered the investigational drug idazoxan (IDA) to nine patients with progressive supranuclear palsy (PSP) according to a double-blind crossover protocol. There were seven women and two men. whose mean age was 70 years and mean duration of illness 4 years. All had an advanced parkinsonian syndrome. supranuclear ocular motor palsies. and poor responses to dopaminergic drugs. During administration of 40 mg tid of IDA. the total score and the motor subscale score of the United Parkinson's Disease Rating Scale significantly decreased. Features that improved most included mobility. balance. gait. and measures of digital dexterity. There were no significant changes in any measure during placebo administration. Corticobulbar manifestations and eye movements were not significantly improved during treatment. Side effects of IDA included transient hypertension. tachycardia. action tremor. flushing. and sweating. but none was so severe that any patient withdrew from the study. Among the few attempted treatments of PSP. IDA is the first medication shown in a double-blind study to improve aspects of motor function.
Predictive testing for Wilson's disease using tightly linked and flanking DNA markers, We studied DNA polymorphisms for five new chromosome 13 markers in 52 Wilson's disease (WD) families from Europe. North America. and the Middle East. There was significant evidence for linkage between the Wilson's disease locus (WND) and all the marker loci. Multilocus linkage analysis. using a genetic linkage map established from reference pedigrees. suggested that WND is most likely between D13S31 and D13S59. at distances of 0.4 and 1.2 centimorgans. respectively. Our results suggest that the chromosomal location of the Wilson's disease gene is the same in all families from the populations studied. This evidence and the availability of many close. flanking. and polymorphic DNA markers make possible accurate and informative testing of potential carriers and WD homozygotes in families with at least one previously affected child. An advantage of a genetic linkage test over other laboratory methods for prediction of genotype in WD is that a reliable diagnosis can be made at a much earlier stage in life. including prenatally. In addition. DNA testing can be used in place of an invasive liver biopsy procedure to confirm a diagnosis in patients with borderline serum ceruloplasmin levels. Presymptomatic identification will also allow therapeutic intervention to prevent symptoms before irreparable liver or neurologic damage occurs. We describe the implementation of prenatal and preclinical diagnosis for two families with WD.
Age-specific differences in the relationship between oral contraceptive use and breast cancer, Nearly all studies have suggested that the use of oral contraceptives (OC) is not associated with the aggregate risk of breast cancer diagnosed in women aged 20-54. Because of age-specific differences in the breast cancer-parity relationship and because of age-specific differences in other breast cancer risk factors. the Centers for Disease Control reexamined data from the Cancer and Steroid Hormone Study to assess whether OC use has different effects on the risk of breast cancer at different ages of diagnosis. This was a population-based case-control study conducted in eight geographic areas in the United States during 1980-1982. In these data. the relationship between the risk of breast cancer and OC use appeared to vary by age at diagnosis. Among women aged 20-34 years at diagnosis or interview. those who had ever used OC had a slightly increased risk of breast cancer (odds ratio 1.4. 95% confidence interval 1.0-2.1) when compared with women of the same ages who had never used OC. Among these women. there were no trends of increasing or decreasing risk with any measure of OC use. Among women aged 35-44 years. there was no association between OC use and breast cancer. Among women aged 45-54 years. those who used OC had a slightly decreased risk of breast cancer (odds ratio 0.9. 95% confidence interval 0.8-1.0). Among these women. the risk estimates decreased significantly with increasing time since first and last use. Although the slightly increased risk estimates for the youngest women are compatible with findings by other investigators. the decreased risk estimates for the oldest women have not been described in as many studies. Available data provide no reasons for changes in prescribing practices or in the use of OC as related to breast cancer risk.
Serum inhibin levels in polycystic ovary syndrome: effect of insulin resistance and insulin secretion, Insulin resistance is common in women with the polycystic ovary syndrome. We investigated the relationship between insulin resistance and the serum inhibin concentration in a group of 19 women with polycystic ovary syndrome and eight control subjects at different phases of the menstrual cycle. Insulin resistance was measured by the frequently sampled intravenous glucose tolerance test. and inhibin was measured by a specific radioimmunoassay. Insulin sensitivity (mean +/- SE) was significantly reduced in the polycystic ovary syndrome group compared with controls: reduced insulin sensitivity 46.7 +/- 5.0 min-1/(nmol/mL). normally insulin-sensitive 106.6 +/- 11.7 min-1/(nmol/mL) (P less than .01). The women with polycystic ovary syndrome had inhibin levels (126 +/- 15.2 microLEq/mL) comparable to those found during the early follicular phase of the control group (117 +/- 22.1 microLEq/mL). but significantly lower than late follicular phase (259 +/- 25.6 microLEq/mL) or luteal phase (448 +/- 91.8 microLEq/mL) levels in the control group. No association was found between the degree of insulin resistance and the inhibin concentration. which remained unaltered over a 3-hour period despite maximal stimulation of endogenous insulin secretion. The inhibin concentrations in polycystic ovary syndrome may reflect impaired follicular maturation. Inhibin secretion is not acutely affected by insulin secretion in normal or in hyperandrogenic women.
Oral magnesium successfully relieves premenstrual mood changes, Reduced magnesium (Mg) levels have been reported in women affected by premenstrual syndrome (PMS). To evaluate the effects of an oral Mg preparation on premenstrual symptoms. we studied. by a double-blind. randomized design. 32 women (24-39 years old) with PMS confirmed by the Moos Menstrual Distress Questionnaire. After 2 months of baseline recording. the subjects were randomly assigned to placebo or Mg for two cycles. In the next two cycles. both groups received Mg. Magnesium pyrrolidone carboxylic acid (360 mg Mg) or placebo was administered three times a day. from the 15th day of the menstrual cycle to the onset of menstrual flow. Blood samples for Mg measurement were drawn premenstrually. during the baseline period. and in the second and fourth months of treatment. The Menstrual Distress Questionnaire score of the cluster "pain" was significantly reduced during the second month in both groups. whereas Mg treatment significantly affected both the total Menstrual Distress Questionnaire score and the cluster "negative affect." In the second month. the women assigned to treatment showed a significant increase in Mg in lymphocytes and polymorphonuclear cells. whereas no changes were observed in plasma and erythrocytes. These data indicate that Mg supplementation could represent an effective treatment of premenstrual symptoms related to mood changes.
Release of tumor necrosis factor alpha by human peritoneal macrophages in response to toxic shock syndrome toxin-1, We examined the release in vitro of tumor necrosis factor-alpha (TNF-alpha) by peritoneal macrophages and peripheral blood monocytes following incubation with toxic shock syndrome toxin-1 (TSST-1). We obtained peritoneal macrophages from 22 women at laparoscopy and peripheral blood monocytes from four healthy women during both the midfollicular and midluteal phases of the menstrual cycle. The samples were incubated for 24 hours at 37 C with 10(-2)-10(4) ng/mL of TSST-1 or 10(4) ng/mL of bacterial endotoxin. Tumor necrosis factor-alpha activity was determined with a bioassay using an actinomycin D-sensitized WEHI-164 murine fibrosarcoma cell line. Twenty-four-hour incubation with TSST-1 resulted in a dose-dependent release of TNF-alpha by both peritoneal macrophages (maximal response 554 +/- 97 U of activity) and peripheral blood monocytes (maximal response 478 +/- 81 U of activity). We observed enhanced TNF-alpha release by peritoneal macrophages from women with endometriosis. compared with those without endometriosis. at a concentration of 10(4) ng/mL of TSST-1 (704 +/- 134 versus 354 +/- 103 U of activity; P less than .05). These data support the theory that the metabolic and physiologic derangements of perimenstrual toxic shock syndrome may be partially mediated by TNF-alpha released by peritoneal macrophages as a result of exposure to TSST-1.
Transvaginal sonography of the endometrium in postmenopausal women, The purposes of this study were to compare transvaginal sonographic scanning of the uterus and endometrium with histology obtained by endometrial biopsy or curettage and to determine whether the sonographic technique might be useful in the evaluation of postmenopausal women. Eighty postmenopausal women were studied. Of these. 65 were asymptomatic (38 on no hormone therapy and 27 on hormone replacement). Fifteen women underwent evaluation because of postmenopausal bleeding. In both groups. endometrial thickness of 4 mm or less as depicted by sonography correlated well with endometrial characteristics of decreased estrogen stimulation. However. in women with measured endometrial thickness between 5-8 mm. proliferative endometrium could not be distinguished from hyperplastic endometrium or. in one case. low-grade carcinoma. Large polyps and invasive carcinoma with myometrial extension were easily recognized.
Morbidity and vaginal tubal cautery: a report and review, Vaginal tubal sterilization was once the procedure of choice for interval sterilization. This technique fell out of favor in part because of a perceived increase in morbidity over the evolving laparoscopic techniques. Complications should be minimized by the advent of routine antibiotic prophylaxis and improved operating techniques that allow shorter procedure times. We retrospectively reviewed 240 vaginal tubal sterilization procedures performed by a single physician. Long-term follow-up (more than 5 years) was available in over half the study group (52%). Half of all operations were completed in 12 minutes or less. with an average time of 14.5 minutes. The planned vaginal procedure was completed in all but two cases. both of which required laparotomy secondary to dense adhesions. Median estimated blood loss was 20 mL. No postoperative infection was encountered. These data suggest that vaginal tubal sterilization may still be a safe alternative for interval sterilization.
Oxytocin augmentation of labor and perinatal outcome in nulliparas, Recent pharmacologic observations in vivo suggest the use of a lower starting dose (0.5-0.1 mU/minute) of oxytocin and a longer interval between dose augmentations (30-60 minutes) than previously advocated. In this study. a high-dose oxytocin protocol was used to augment nonprogressive labor in normal nulliparous women. The rate of oxytocin infusion started at 6 mU/minute and was increased by 6 mU/minute every 15 minutes to a maximum dose of 40 mU/minute. Charts were reviewed of 1080 nulliparous women for whom the principles of active management of labor were followed and delivery occurred between March 1. 1986 and December 31. 1988. Four hundred fifty-six who required oxytocin augmentation in labor were compared with 624 who did not receive oxytocin. There were no statistically significant differences in birth asphyxia or perinatal morbidity.
Influence of maternal body habitus and glucose tolerance on birth weight, Many physicians believe that macrosomia is a hallmark of a pregnancy complicated by glucose intolerance. Because the prevalence of obesity is increased among women with gestational diabetes. fetal overgrowth may be attributable at least in part to maternal obesity. We studied 2069 black. Latina. Chinese. and white mother-infant pairs to determine the interaction between maternal body habitus. maternal glucose homeostasis. and certain indices of fetal growth. Chinese women had a significantly higher serum glucose 1 hour after administration of 50 g glucose (136.6 +/- 32.7 mg/dL) than any of the other three ethnic groups. Black women had a significantly lower value for glucose (114.8 +/- 28.2 mg/dL) than either Chinese or Latina women (124.9 +/- 31.4 mg/dL). Results for Latina and white women (121.5 +/- 26.2 mg/dL) were not significantly different. Body mass index (BMI) was used to classify the subjects. The regression coefficient for the entire sample indicated a modest association of glucose with increased birth weight when maternal BMI was controlled. The BMI of the Chinese infants had a significant association with higher concentrations of glucose after administration of 50 g glucose. Maternal body habitus should be considered a major confounder in studies of the relationship of maternal glucose tolerance and infant birth weight.
Maternal left ventricular dimension in pregnancies complicated by fetal growth retardation, Previous studies using two-dimensional chest radiographs have found a significant correlation between prematurity. fetal growth retardation. and the size of the maternal heart. Accordingly. we evaluated maternal left ventricular size and function by M-mode echocardiography near the end of gestation in 42 women with suspected fetal growth retardation and in 79 women whose pregnancies were normal. No significant differences were found between the two groups. implying that maternal left ventricular size and function is adequate in pregnancies complicated by "idiopathic" fetal growth retardation.
Relationship between antepartum cocaine abuse, abnormal umbilical artery Doppler velocimetry, and placental abruption, We performed serial umbilical artery Doppler flow velocimetry studies on 314 women and grouped them according to history of antepartum cocaine abuse. placental abruption with antepartum cocaine abuse. preterm labor with antepartum cocaine abuse. preterm labor without antepartum cocaine abuse. and controls without preterm labor or antepartum cocaine abuse. Analyses excluded twin gestation. diabetes. and hypertension. The overall incidence of deliveries at or before 36 weeks was 28% (31 of 112). Thirteen (12%) of the infants were small for gestational age (SGA) and 33 (29%) were low birth weight (LBW). Almost all subjects with a history of cocaine abuse had normal systolic-diastolic ratios (S/Ds). All patients with abruption had abnormal S/Ds. as did 14 of 64 subjects who had preterm labor and a history of cocaine abuse. No abnormal S/Ds were found in the women with preterm labor or in controls. Among cocaine-abusing women. there was a significant correlation between placental abruption and abnormal S/Ds (P less than .05) and between abnormal S/Ds and the incidence of preterm birth and SGA and LBW infants.
No evidence of hearing loss due to fetal acoustic stimulation test, The fetal acoustic stimulation test is used increasingly for fetal assessment. To evaluate the possibility of acoustic trauma. 465 children who had been exposed to vibroacoustic stimulation in utero were screened at 4 years of age for high-frequency hearing loss. A hand-held audiometer with test tones at 25 dB for 1000 and 4000 Hz was used because responses at this level indicate hearing within normal limits for middle and high frequencies. Thirty-one children failed the test. Failure to respond was followed by inspection of the ear canal for wax. tympanometry. and reflex measurement to assess the tympanic membrane. middle ear. and eustachian tube. Hearing was retested across the full frequency range using conventional audiometric technique. and referral for otolaryngologic examination and treatment was made if necessary. The causes of hearing loss were impacted wax in 12. current or recent upper respiratory tract infection with eustachian tube dysfunction and middle ear effusion in 15. and unresolved middle ear effusion after treatment with antibiotics for otitis media in two. Profound bilateral sensorineural hearing loss of unknown origin was found in one and slight bilateral gently sloping hearing loss in another. Retesting of all children with conductive hearing loss indicated that hearing had returned to normal after treatment. None of the children showed evidence of hearing loss.
Dose- and age-dependent ectopic pregnancy risks with intrauterine contraception, Analyses of randomized trials of copper intrauterine devices (IUDs) substantiate three hypotheses: 1) Ratios of ectopic to total pregnancies conceived during copper IUD use did not differ among devices; 2) pregnancy rates per 1000 woman-years varied inversely with copper surface area; and 3) ectopic pregnancy rates consequently varied inversely by copper surface area. Randomized trials also demonstrated that progestin-only IUDs had a markedly higher ratio of ectopic to total pregnancies. 171 per 1000. than did copper IUDs. at 39 per 1000 (P less than .001). Ectopic pregnancy rates per 1000 woman-years with progestin-only IUDs varied inversely with dose. notably for levonorgestrel-releasing devices. In a large United States IUD cohort study. ectopic pregnancy ratios of copper IUDs varied significantly (P less than .05) with age. as they do in the general population. Copper and non-medicated IUDs in the United States and the United Kingdom had age-specific ectopic pregnancy ratios six times those of non-contraceptors in the United States population during 1970-1978. The estimated rate of ectopic pregnancy for users of IUDs having 200 mm2 of copper was four-tenths that of non-contraceptors in the United States during 1970-1978. For users of devices with 350 mm2 or more of copper. ectopic pregnancy rates were one-tenth those of non-contraceptors. Rates for users of devices releasing 65 micrograms/day of progesterone are estimated to have been 50-80% above those of non-contraceptors. Devices releasing 20 micrograms/day of levonorgestrel have had ectopic pregnancy rates estimated to be 0.1 of those of non-contraceptors. Most IUDs protect against ectopic pregnancy.
The role of hCG in regulation of the thyroid gland in normal and abnormal pregnancy, There is strong evidence that at least some forms of hCG can interact with and stimulate the thyroid both in vitro and in vivo. Changes in thyroid tests are sufficiently common in normal pregnancy for us to regard them as physiologic. The evidence that hCG is the agent responsible for these changes remains largely circumstantial but is now supported by an increasing body of evidence from laboratory studies. Trophoblastic tumors secrete variant forms of hCG that can stimulate the thyroid. but we do not know if they have any role in the extreme examples of thyroid stimulation encountered in normal pregnancy. Preparations of hCG from pregnancy urine bind to thyroid membranes from a wide variety of species. but they do not activate adenylate cyclase in all assay systems. The enzyme in human thyroid cells or membranes is. at best. only weakly stimulated by hCG. There are ample in vitro data that hCG can stimulate the thyroid. but studies using human thyroid cells have yielded conflicting results. The most direct evidence comes from the study of thyroid tests in normal pregnancy. In early pregnancy. when hCG concentrations are highest. free thyroid hormones are increased and serum TSH concentration is decreased. An inverse correlation exists between serum hCG and TSH concentrations. but hCG generally correlates poorly with individual thyroid tests. An activity in pregnancy serum related to hCG is able to stimulate FRTL-5 cells and may account for the changes in thyroid function observed in pregnancy. Structural considerations. along with data from biologic assays and sensitive thyroid function tests. suggest that hCG has significant thyroid-stimulating activity. This information suggests that the thyroid may be under dual control from both hCG and TSH in early pregnancy.
Protective efficacy of neonatal Bacillus Calmette-Guerin vaccination against tuberculosis, This matched case-control study was performed in two hospitals in Bangkok to evaluate the protective efficacy of neonatal Bacillus Calmette-Guerin (BCG) vaccination in Thai children and to find factors that might explain the reported variation in estimates of the protective efficacy of BCG. Cases were defined as children 3 months to 14 years of age who had tuberculosis and controls consisted of one to four children who were born in the same year and had the same district of residence as the case. A matched analysis with a variable number of controls per case was performed on 75 cases and 207 controls. Conditional logistic regression was performed to adjust for the potential confounding effects of household tuberculosis exposure and socioeconomic status. Forty-eight percent of cases had nonrespiratory tuberculosis. Laboratory-confirmed evidence for tuberculosis was found in 48% of cases. The adjusted protective efficacy of neonatal BCG vaccination was 83% (95% confidence limits. 35%. 96%). It was 96% (95% confidence limits. 66%. 100%) when only 36 matched sets of laboratory-confirmed cases were analyzed. Subgroup analyses and literature reviews indicated that the accuracy of tuberculosis diagnosis. types of tuberculosis. duration after vaccination and household tuberculosis exposure contribute to variation in the reported protective efficacy of neonatal BCG vaccination.
Multiple site blood cultures in the initial evaluation for neonatal sepsis during the first week of life, We present the first investigation that examines the usefulness of multiple site blood cultures in the initial evaluation for neonatal sepsis during the first week of life. Two sets of blood cultures (1 aerobic and 1 anaerobic bottle/set; BACTEC. NR 6A/7A) from different sites were obtained from 460 inborn infants who were evaluated for possible sepsis. From 0.5 to 1 ml of blood was inoculated into each blood culture bottle. In 18 infants the use of multiple site blood cultures yielded important information. In 8 of these neonates bacteremia was confirmed whereas in 10 cases contamination from skin flora was documented. We could identify no instances in which the delay in antibiotic therapy while the second set of blood cultures was obtained contributed to an adverse outcome. We conclude that multiple site blood cultures are useful in the initial evaluation for suspected sepsis during the first week of life.
Perspectives on human response to health and illness, Nursing's domain has been defined as the diagnosis and treatment of human responses to health problems. yet debate rages over what "human responses" are. Without clear meanings for this and other terms used in nursing. the profession cannot claim that its practice is scientifically based. nor can it share that base among disciplines.
A donor splice mutation and a single-base deletion produce two carboxyl-terminal variants of human serum albumin, At least 35 allelic variants of human serum albumin have been sequenced at the protein level. All except two COOH-terminal variants. Catania and Venezia. are readily explainable as single-point substitutions. The two chain-termination variants are clustered in certain locations in Italy and are found in numerous unrelated individuals. In order to correlate the protein change in these variants with the corresponding DNA mutation. the two variant albumin genes have been cloned. sequenced. and compared to normal albumin genomic DNA. In the Catania variant. a single base deletion and subsequent frameshift leads to a shortened and altered COOH terminus. Albumin Venezia is caused by a mutation that alters the first consensus nucleotide of the 5' donor splice junction of intron 14 and the 3' end of exon 14. which is shortened from 68 to 43 base pairs. This change leads to an exon skipping event resulting in direct splicing of exon 13 to exon 15. The predicted Venezia albumin product has a truncated amino acid sequence (580 residues instead of 585). and the COOH-terminal sequence is altered after Glu-571. The variant COOH terminus ends with the dibasic sequence Arg-Lys that is apparently removed through stepwise cleavage by serum carboxypeptidase B to yield several forms of circulating albumin.
Calcium and cAMP activate different chloride channels in the apical membrane of normal and cystic fibrosis epithelia, The genetic disease cystic fibrosis (CF) causes decreased Cl- transport in several epithelia. cAMP-dependent regulation of apical membrane Cl- channels is defective in CF airway epithelia; as a result. CF epithelia fail to secrete Cl-. In contrast. Ca(2+)-stimulated Cl- secretion is intact in CF airway epithelia and thus has the potential to bypass the CF Cl- secretory defect. For a Cl- channel to govern Cl- secretion. it must be located in the apical membrane. To specifically investigate apical membrane Cl- channels. we studied cells grown on permeable filter supports and measured Cl- currents across the apical membrane. We found that Ca2+ and cAMP activate different Cl- channels in the apical membrane. (i) Ca(2+)-activated Cl- channels were present in the apical membrane of airway but not in intestinal epithelia. (ii) cAMP- but not Ca(2+)-activated Cl- channels were defective in CF airway epithelia. (iii) Ca(2+)- but not cAMP-activated Cl- channels were blocked by 4.4'-diisothiocyanato-2.2'-stilbenedisulfonate. (iv) Ca(2+)- and cAMP-activated apical channels had different anion permeabilities. (v) An increase in both second messengers produced an additive increase in Cl- current. These results also explain the puzzling observation that Ca(2+)-stimulated Cl- secretion is defective in CF intestine: the Ca(2+)-activated Cl- channels that could circumvent the Cl- secretory defect in CF airway are missing from the apical membrane of intestinal epithelia.
Fibroblast cell interactions with human melanoma cells affect tumor cell growth as a function of tumor progression, It is known from a variety of experimental systems that the ability of tumor cells to grow locally and metastasize can be affected by the presence of adjacent normal tissues and cells. particularly mesenchymally derived stromal cells such as fibroblasts. However. the comparative influence of such normal cell-tumor cell interactions on tumor behavior has not been thoroughly investigated from the perspective of different stages of tumor progression. To address this question we assessed the influence of normal dermal fibroblasts on the growth of human melanoma cells obtained from different stages of tumor progression. We found that the in vitro growth of most (4 out of 5) melanoma cell lines derived from early-stage radial growth phase or vertical growth phase metastatically incompetent primary lesions is repressed by coculture with normal dermal fibroblasts. suggesting that negative homeostatic growth controls are still operative on melanoma cells from early stages of disease. On the other hand. 9 out of 11 melanoma cell lines derived from advanced metastatically competent vertical growth phase primary lesions. or from distant metastases. were found to be consistently stimulated to grow in the presence of dermal fibroblasts. Evidence was obtained to show that this discriminatory fibroblastic influence is mediated by soluble inhibitory and stimulatory growth factor(s). Taken together. these results indicate that fibroblast-derived signals can have antithetical growth effects on metastatic versus metastatically incompetent tumor subpopulations. This resultant conversion in responsiveness to host tissue environmental factors may confer upon small numbers of metastatically competent cells a growth advantage. allowing them to escape local growth constraints both in the primary tumor site and at distant ectopic tissue sites.
1H NMR study of renal trimethylamine responses to dehydration and acute volume loading in man, We have used volume-localized 1H NMR spectroscopy to detect and measure changes in medullary trimethylamines (TMAs) in the human kidney in vivo. Localized water-suppressed 1H spectra were collected from a volume of interest located within the renal medulla by using a stimulated echo-based localization scheme. The principal resonances in the medullary 1H spectrum were residual water (4.7 ppm). lipid (0.9-1.4 ppm). and TMAs (3.25 ppm). The TMA line width was 7-15 Hz before filtering. and the signal-to-noise ratio was 40:1. In four normal volunteers. 15 hr of dehydration led to a significant increase in urine osmolality and decrease in body weight and an increase in medullary TMAs. A subsequent water load [20 ml.(kg of body weight)-1] caused a transient water diuresis. a return to euvolemic body weight. and a significant reduction in medullary TMAs within 4 hr. These results suggest that TMAs may play an osmoregulatory role in the medulla of the normal human kidney.
A cell cycle-responsive transcriptional control element and a negative control element in the gene encoding DNA polymerase alpha in Saccharomyces cerevisiae, Transcription of the POL1 gene of Saccharomyces cerevisiae. which encodes DNA polymerase alpha. the DNA polymerase required for the initiation of DNA replication. has previously been shown to be cell cycle regulated. To understand how the POL1 gene senses cell cycle position. we have investigated the cis-acting elements that respond to the factors that govern cell cycle progression. In this report we demonstrate that a region of 54 nucleotides containing the repeated element ACGCGT. which conforms to an Mlu I restriction endonuclease recognition site. contains all information necessary for transcriptional activation and cell cycle responsiveness. Although oligonucleotides lacking either one or both of the repeated Mlu I sites can function as an upstream activating sequence. the presence of at least one Mlu I site stimulates expression and. moreover. is absolutely essential for cell cycle regulation. A synthetic oligonucleotide corresponding to a 19-base-pair sequence in the POL1 promoter containing one Mlu I site can function as an autonomous cell cycle-responsive upstream element (upstream activation sequence) with temporal regulation indistinguishable from that previously described for the POL1 gene. Thus. the Mlu I site is an essential part of a cis-acting element responsible for the observed periodic activation. This sequence differs from previously defined cell cycle-responsive transcriptional control elements in the yeast HO endonuclease and histone genes. We also present evidence for a negative regulatory element in the 5' flanking region of the Mlu I upstream activation sequence.
Alu-primed polymerase chain reaction for regional assignment of 110 yeast artificial chromosome clones from the human X chromosome: identification of clones associated with a disease locus, Over 400 yeast artificial chromosome (YAC) clones were isolated from the human X chromosome. and 110 of these were assigned to regions defined by chromosome translocation and deletion breakpoints. Polymerase chain reaction using Alu primers was applied to YAC clones in order to generate probes. to identify overlapping clones. and to derive "fingerprints" and sequence data directly from total yeast DNA. Several clones were identified in regions of medical interest. One set of three overlapping clones was found to cross a chromosomal translocation implicated in Lowe syndrome. The regional assignment of groups of YAC clones provides initiation points for further attempts to develop large cloned contiguous sequences. as well as material for investigation of regions involved in genetic diseases.
Determination of the c-MYC DNA-binding site, The carboxyl terminus of the protein encoded by the c-MYC protooncogene has similarity to the helix-loop-helix family of DNA-binding proteins and recognizes a six-nucleotide-long DNA sequence. We have used in vitro-translated c-MYC protein to further define its DNA-binding specificity. The hexanucleotide originally identified is necessary for DNA binding by c-MYC. but not sufficient; the c-MYC target site is a 12-nucleotide-long palindrome. This site is present within regulatory regions of genes that are expressed during cell growth. Point mutations within the helix-loop-helix motif of c-MYC abolish DNA-binding and transforming activities. indicating that c-MYC acts as a DNA-binding protein to transform cells. c-MYC may transform cells by activating transcription of genes required for cell division.
Islet-specific T-cell clones from nonobese diabetic mice express heterogeneous T-cell receptors, Nonobese diabetic (NOD) mice spontaneously develop a T-cell-mediated autoimmune disease that is similar in many respects to insulin-dependent diabetes mellitus in humans. T-cell clones that specifically recognize pancreatic islet cell antigens can be derived from NOD mice. and most of these have been diabetogenic upon transfer to healthy recipients. We report herein the sequences of the T-cell receptor alpha and beta chains from four NOD-derived. islet-specific clones. The sequences are quite heterogeneous--in the junctional regions. specifically--so there seems to be little hope for treating this disease with specific anti-T-cell receptor reagents. This result contrasts with the strikingly restricted junctional region sequences reported for the receptors on clones derived from mice with experimental allergic encephalomyelitis. another T-cell-mediated autoimmune disease. We discuss possible explanations for this difference.
Evidence for non-V3-specific neutralizing antibodies that interfere with gp120/CD4 binding in human immunodeficiency virus 1-infected humans, Total anti-gp120 antibodies (total anti-gp120 Abs) were purified from a pool of four human immunodeficiency virus-positive (HIV+) sera by affinity chromatography on a gp120SF2-Sepharose column and exhibited both type- and group-specific neutralizing activities. To dissect the epitope specificity of the group-specific neutralizing antibodies. CD4 attachment site-specific antibodies (CD4-site Abs) were isolated from total anti-gp120 Abs by using a CD4-blocked gp120SF2-Sepharose column. The CD4-site Abs exhibited group-specific neutralizing activities. Another approach to dissecting type- and group-specific neutralizing activities of total anti-gp120 Abs was to separate the third variable region (V3)-specific antibodies (V3-region Abs) from non-V3-region-specific antibodies (non-V3 Abs). The results indicated that V3-region Abs exhibited type-specific neutralizing activities. whereas non-V3 Abs exhibited group-specific neutralizing activities. By comparing the neutralizing activities of V3-region Abs to those of non-V3 Abs. we concluded that V3-region Abs are more effective than non-V3 Abs in neutralizing a specific HIV isolate. Collectively. this study indicates that group-specific neutralizing anti-gp120 antibodies are specific for the CD4 attachment site.
Tissue injury caused by deposition of immune complexes is L-arginine dependent, Nitric oxide (NO.). a free radical that is generated from L-arginine by stimulated endothelial cells. neutrophils. activated macrophages. and other cell types. reacts with superoxide anion (O2.-) to form peroxynitrite. which itself may be tissue toxic or can then react further to form the highly reactive and toxic hydroxyl radical (HO.). Because vascular injury produced by tissue deposition of immune complexes is linked to formation of toxic products derived from activated neutrophils. we have assessed whether immune complex-induced injury of rat lung and dermal vasculature is arginine dependent. The arginine analogue. NG-monomethyl-L-arginine (N-MeArg). which blocks NO. formation. protects against immune complex-induced vascular injury in rats. The protective effects of N-MeArg are reversed by the presence of L-arginine but not D-arginine. Additionally. in the absence of N-MeArg. injury is enhanced by the presence of L-arginine but not by D-arginine. Protection by N-MeArg is not associated with diminished recruitment of polymorphonuclear leukocytes. Bronchoalveolar lavage fluids from animals undergoing immune complex deposition in lung contain the decomposition products of NO.--namely. nitrite and nitrate. In the presence of N-MeArg these products are greatly diminished. These data suggest that immune complex-induced injury of rat lung and skin is L-arginine dependent. These data also suggest that in vivo metabolic products of L-arginine. such as NO(.). are directly or indirectly linked to immune complex-induced tissue injury.
Purification of parathyroid hypertensive factor from plasma of spontaneously hypertensive rats, Parathyroid hypertensive factor (PHF) is a newly described hypertensive factor that may be related to elevation of blood pressure in 30-40% of North American essential hypertensive patients. PHF is also found in several animal models of hypertension. including spontaneously hypertensive rats. and deoxycorticosterone acetate salt hypertensive rats. Plasma collected from spontaneously hypertensive rats (SHR) was used in the present study for purification of PHF. Plasma was dialyzed at a molecular mass cutoff of 1 kDa. and then ultrafiltered at a molecular mass cutoff of 5 kDa. PHF activity. as determined by bioassay (characteristic delayed hypertensive response in normotensive rat) was retained in the fraction that was greater than 1 kDa and less than 5 kDa. Dialyzed and ultrafiltered SHR plasma was fractionated by molecular-exclusion chromatography. either with Bio-Gel P-6 liquid chromatography. or TSK 2000 SW HPLC. The biological activity was detected in a discrete region corresponding to a molecular mass of 2.5-3 kDa. When the molecular-exclusion fraction was subsequently fractionated by reverse-phase HPLC. biological activity was located in a single discrete peak. which did not occur in plasma from normotensive rats prepared in a similar manner. The biologically active fraction of PHF was inactivated by trypsin; this and its UV spectrum indicate the presence of a peptide structure.
Radiologic evaluation of aortic dissection, The radiologic assessment of patients suspected of having an aortic dissection must be based on an understanding of the treatment options and how these are to be employed in any clinical setting. The appropriate selection and timing of imaging studies is crucial. The diagnosis of dissection must be quickly confirmed. other diseases that mimic dissection must be excluded. and the type and extent of dissection must be established so that appropriate therapy can be instituted. Although computed tomography. magnetic resonance (MR) imaging. and echocardiography greatly enhanced the ability to evaluate the aorta by noninvasive means. aortography remains the examination of choice for defining the vascular anatomy. especially when surgical intervention is considered. MR imaging may become the primary examination for the initial and subsequent evaluation of acute and chronic dissections as MR angiographic techniques improve and changes are made in monitoring equipment to allow the safe examination of acutely ill patients.
Small hepatocellular carcinoma treated with percutaneous ethanol injection: MR imaging findings, Fifty-seven magnetic resonance (MR) imaging examinations were obtained at 0.5 T in 19 patients before and after percutaneous ethanol injection (PEI) for 23 hepatocellular carcinoma (HCC) lesions less than 3.5 cm in diameter. Seventeen patients also underwent MR imaging 6 months after completion of therapy. In 11 patients. computed tomography was performed before and after treatment. After PEI. fine-needle biopsy specimens were obtained in all cases. Before treatment. HCC lesions had low signal intensity on T1-weighted images in 13 cases. had the same signal intensity as normal liver parenchyma in six. and had high signal intensity in four; all 23 tumors had high signal intensity on T2-weighted images. After treatment and at 6-month follow-up. all 21 lesions that contained no malignant cells at fine-needle biopsy had high signal intensity on T1-weighted images and had low signal intensity on T2-weighted images. The remaining two HCC lesions in which tumor necrosis was not achieved with PEI displayed a different MR pattern. since the residual neoplastic tissue showed no change in signal intensity on either T1- or T2-weighted images. The authors conclude that MR imaging may be useful for evaluating the effectiveness of PEI in achieving tumor regression.
Malignant hepatic tumors: P-31 MR spectroscopy with one-dimensional chemical shift imaging, To determine the clinical feasibility and applicability of phosphorus-31 magnetic resonance (MR) spectroscopy and to assess its potential for characterization of human hepatic tissue. one-dimensional chemical shift imaging (CSI) was performed in 37 patients with various malignant hepatic neoplasms (30 metastases from a variety of primary tumors and seven hepatocellular carcinomas) and seven healthy volunteers. Tumors were grouped according to the percentage of the analyzed section that was occupied by tumor: less than 50% (group A) or more than 50% (group B). In group B. all phosphomonoester/beta-adenosine triphosphate ratios were significantly higher than normal (P less than .001). Hepatocellular carcinomas and metastases from various primary neoplasms could not be differentiated on the basis of spectral characteristics and metabolite ratios. Limitations of one-dimensional surface coil CSI prevented separation of spectra of small tumors and tumors deep within the liver parenchyma from spectra of normal liver parenchyma.
Common bile duct and intrahepatic stones: results of transhepatic electrohydraulic lithotripsy in 50 patients, Percutaneous. transhepatic. intracorporeal. electrohydraulic shock wave lithotripsy was performed in 50 patients after failure of endoscopic treatment (n = 43) or directly in patients with a strictured hepaticojejunostomy (n = 7). Twenty-seven patients had common bile duct stones; 23. intrahepatic stones. Three steps were used: A transhepatic bilicutaneous fistula was created. a wide communication between the bile duct and the gut was established. and contact shock wave lithotripsy was performed under endoscopic guidance. Afterward. 46 patients were free of stones. In four patients with diffuse intrahepatic lithiasis. only 75% of stones could be cleared. Severe complications. seen in 11 patients (hemobilia necessitating transfusion [n = 6]. bile duct perforation resulting in cholangitis [n = 3]. acute pulmonary edema [n = 1]. and hemothorax [n = 1]). were fatal in four patients; all occurred early in the study. The authors modified their technique by dilating the biliary tract in two sessions 3 days apart. waiting 6 days for the tract to mature. and then introducing the cholangioscope directly through the skin. significantly reducing complications and mortality (P less than .005).
Low-dose high-resolution CT of lung parenchyma, To evaluate the efficacy of low-dose high-resolution computed tomography (HRCT) in the assessment of lung parenchyma. three observers reviewed the scans of 31 patients. The 1.5-mm-collimation. 2-second. 120-kVp scans were obtained at 20 and 200 mA at selected identical levels in the chest. The observers evaluated the visualization of normal pulmonary anatomy. various parenchymal abnormalities and their distribution. and artifacts. The low-dose and conventional scans were equivalent in the evaluation of vessels. lobar and segmental bronchi. and anatomy of secondary pulmonary lobules. and in characterizing the extent and distribution of reticulation. honeycomb cysts. and thickened interlobular septa. The low-dose technique failed to demonstrate ground-glass opacity in two of 10 cases (20%) and emphysema in one of nine cases (11%). in which they were evident but subtle on the high-dose scans. These differences were not statistically significant. Linear streak artifact was more prominent on images acquired with the low-dose technique. but the two techniques were judged equally diagnostic in 97% of cases. The authors conclude that HRCT images acquired at 20 mA yield anatomic information equivalent to that obtained with 200-mA scans in the majority of patients. without significant loss of spatial resolution or image degradation due to linear streak artifact.
Endometrial thickness after menopause: effect of hormone replacement, Ultrasound (US) images of the pelvis were evaluated in 112 asymptomatic postmenopausal women to investigate the normal range of endometrial thickness (double-layer measurement) and the effect of hormone replacement on these measurements. Twenty-one patients (19%) had endometrial thickness greater than 0.8 cm. One patient. with an endometrial thickness of 2.5 cm. had endometrial carcinoma. Consideration of the known actions of estrogen and progestogen on the endometrium led the authors to believe that the clinical significance of an endometrium measuring more than 0.8 cm depends on the patient's hormonal status. Among asymptomatic postmenopausal women with an endometrial thickness between 0.8 and 1.5 cm. those receiving unopposed estrogen or continuous estrogen and progestogen need to undergo dilatation and curettage (D&C) or biopsy and those receiving no hormones or receiving sequential estrogen and progestogen should be encouraged to undergo D&C or biopsy. If a patient in one of the latter two groups is unwilling to undergo an invasive procedure. then US examination at 3-month intervals is acceptable. Any patient with endometrial thickness of at least 1.5 cm should undergo histologic diagnosis. regardless of symptoms or hormone status.
Ureteral jets in healthy subjects and in patients with unilateral ureteral calculi: comparison with color Doppler US, Color Doppler ultrasound was used to image the ureteral jets in 17 healthy subjects and 26 patients with ureteral calculi proved with intravenous urography. In patients with ureteral calculi. three patterns of ureteral jets were seen: no detectable urine flow from the symptomatic side (12 patients). low-level continuous flow from the symptomatic side (four patients). and periodic ureteral jets on the symptomatic side that were not significantly different from ureteral jets of healthy subjects (10 patients). Of the 12 patients with high-grade obstruction on urograms. 11 had ureteral jets significantly different from those of healthy subjects (either no detectable ureteral jets or continuous low-level jets on the symptomatic side). Only three of the 11 patients with low-grade obstruction or nonobstructing stones had ureteral jets that were different from those of healthy subjects. It is concluded that analysis of ureteral jets with color Doppler can enable detection and qualitative determination of the degree of ureteral obstruction in many patients with unilateral ureteral calculi.
Autourethrography, "Autourethrography." a technique of retrograde urethrography in which the patient injects the contrast material. was used on 22 patients. The results of the study were compared with the results of nonemergency retrograde urethrography performed on 22 patients during an earlier 1-year period. The following observations of the autourethrography group were made. Patient tolerance was enhanced. with less discomfort and anxiety. There was no extravasation of contrast material outside the urethra. compared with extravasation in three of 22 patients (14%) in the control group for whom conventional techniques were used. Retrograde opacification of the posterior urethra was achieved in 20 of 22 patients (91%) in the autourethrography group. compared with 13 of 22 patients (59%) in the control group. Radiation exposure to the examining radiologist was eliminated. Autourethrography is a technique that has important benefits for both the radiologist and the patient.
Air in the temporomandibular joint fossa: CT sign of temporal bone fracture, Temporal bone fractures can be difficult to detect clinically and radiographically. Air is sometimes present in the glenoid fossa of the temporomandibular joint (TMJ) at computed tomography (CT) of acute basilar skull fractures. This study evaluated TMJ fossa air as a sign of temporal bone fracture. Initial CT scans of the head in 114 patients with a diagnosis of basilar skull fracture at discharge were retrospectively reviewed. TMJ fossa air was present in 23 of 114 patients (20.2%) and was bilateral in three patients. Only temporal bone fractures were significantly (P less than .001) associated with TMJ fossa air. Temporal bone fractures were observed at CT in 23 of 26 cases of TMJ fossa air. but in three of 26 cases. TMJ fossa air was the only CT sign of clinically apparent temporal bone fractures. TMJ fossa air is associated with acute temporal bone fracture and may be the only CT sign of an otherwise inconspicuous temporal bone fracture.
MR evaluation of CNS tumors: dose comparison study with gadopentetate dimeglumine and gadoteridol, In phase II and III trials of gadoteridol (Gd-HP-D03A). a new nonionic. low-osmolar contrast agent. 40 patients with intracranial neoplasms underwent magnetic resonance (MR) imaging with experimental doses of 0.05-0.3 mmol/kg. Fifteen patients also underwent contrast studies with the standard dose (0.1 mmol/kg) of gadopentetate dimeglumine. Both gadopentetate dimeglumine and gadoteridol appear to have a similar effect when given in equal doses (0.1 mmol/kg. n = 5). Lesion enhancement and delineation were better at higher experimental doses (0.2 or 0.3 mmol/kg. n = 7) and worse at a lower experimental dose (0.05 mmol/kg. n = 3). Quantitative analysis of 10 lesions examined with identical imaging protocols revealed a directly proportional relationship (r = .975) between lesion contrast ratio and dose over a range of 0.05-0.3 mmol/kg. Phantom experiments support the clinical results. Improved enhancement. detection. and delineation of central nervous system (CNS) neoplasms resulting from increased injected doses of gadoteridol have the potential to be clinically significant and may justify the possibly higher cost of increased contrast material dosage. Lower doses may not be adequate for the evaluation of most CNS tumors.
Developing spinal column: gadolinium-enhanced MR imaging, Enhancement characteristics of the normally developing spinal column were examined in magnetic resonance (MR) images obtained in 58 children aged 7 days to 9 years. With a 1.5-T imager. short-repetition-time spin-echo images were obtained before and after the administration of 0.1 mmol/kg gadopentetate dimeglumine. Enhancement of normal bone marrow was seen in all patients aged less than 7 years; it was marked only in patients aged less than 2 years. Enhancement of normal cartilage. seen in all patients aged less than 1 1/2 years. may be the most striking feature of enhanced MR images of the infant spine. Enhancement of both bone marrow and cartilage in children appears to be due to the unusual prominence of vasculature. associated with permeability of the capillary endothelium and a plentiful extravascular space. Although marked and diffuse enhancement of vertebral bodies in adults is often thought to indicate a pathologic marrow state. caution must be used before the same criteria are applied to children.
Vacuum phenomenon simulating meniscal or cartilaginous injury of the knee at MR imaging, In five patients undergoing magnetic resonance imaging of the knee after athletic injuries. the authors identified a vacuum phenomenon that simulated medial meniscal or joint compartment cartilaginous abnormality. A cadaveric knee was injected with air. and the findings were re-created. The presence of air or gas between the articular surfaces of the tibia and femur can simulate meniscal or cartilaginous injury.
CT-guided fixation of sacral fractures and sacroiliac joint disruptions, Open reduction and internal fixation (ORIF). the currently preferred method for treatment of unstable posterior pelvic and sacral fractures. has two significant disadvantages: the need for blind placement of the fixation screws and the occurrence of high complication rates. Advantages of computed tomographic (CT)-guided sacral fixation include direct visualization of the course of the screws and absence of significant complications. Eight patients with unstable but reducible sacral fractures or sacroiliac joint (SIJ) disruptions (seven unilateral and one bilateral) underwent CT-guided sacral fixation with use of the standard orthopedic A-O. 7.0-mm-diameter cannulated screw system. The guide pin was positioned across the fracture or SIJ by using depth and angulation measurements derived from the scout CT scans. After confirmation of the position of the pin with CT. the screw tract was drilled. and the cannulated screw was placed into position. Radiographic and clinical follow-up (5-9 months) showed healing with no significant complications in all eight patients. CT-guided sacral fixation is a safe alternative to ORIF in patients with reducible unstable pelvic fractures.
Three-port perineal sparing technique, The records were reviewed of 103 patients with low-lying pelvic malignancies irradiated with a skin-sparing technique involving use of a pair of anteroposterior-posteroanterior opposed ports and a direct perineal port. Patients had rectal. anal. cervical. vaginal. urethral. or vulvar cancer. Use of a special lead compensator allowed the three beams to be applied perpendicularly to the surface. while delivery of a homogeneous dose to the pelvis and perineum was maintained. Skin dose with this method was greatly reduced compared with that delivered with simple opposing or four-port techniques. in which irradiation is tangential to the surface at the perineum. Acute perineal skin irritation was assigned a grade between 0 and 3. with grade 0 representing the least amount of irritation. All patients were in the grade 0 or grade 1 category. Patients treated for low-lying rectal carcinoma showed no increase in perineal recurrences when compared with historic control subjects. Use of this approach allowed delivery of adequate doses to the pelvis and perineum and a definite decrease in local toxic effects. and local control was not compromised.
Technique for US-guided fallopian tube catheterization, Various catheter techniques guided with fluoroscopy and ultrasound (US) have been developed to assist conception by opening fallopian tubes. The authors present a simplified US-guided technique with which they were able to catheterize a fallopian tube consistently and rapidly in 15 of 17 attempts by using a prototype catheter system that is in general use for sperm or embryo transfer.
New device for CT-targeted percutaneous punctures, A device for computed tomography (CT)-guided percutaneous punctures that is not affixed to the patient and can be used even when the gantry is tilted was developed and tested. In initial patient examinations. the device was accurate within 1.0 mm of the predetermined target point. Experience so far has involved retrobulbar anesthesia and puncture of intervertebral disk space.
Patellofemoral joint: evaluation during active flexion with ultrafast spoiled GRASS MR imaging, An ultrafast spoiled gradient-recalled acquisition in the steady state pulse sequence was developed that permits multiple images to be obtained at a temporal resolution suitable for examining the patellofemoral joint during active flexion. This pulse sequence was used to perform kinematic magnetic resonance imaging of patellar alignment and tracking in five healthy subjects and seven patients with a provisional clinical diagnosis of abnormal patellofemoral joints.
Clinical experience with aztreonam for treatment of infections in children, The in vitro activity. pharmacokinetics. bactericidal activity. and tissue penetration of aztreonam suggest that it may play a role in therapy for serious gram-negative bacterial infections in children. Several thousand children throughout the world received aztreonam during open or comparative clinical trials for treatment of infections including pyelonephritis. bacteremia. meningitis. skeletal infection. pneumonia. and peritonitis. Cure rates have ranged from 92% to 100%. with relapses seen mainly in children with obstructive renal lesions and those with infections caused by Salmonella. A comparative trial of aztreonam for treatment of neonatal sepsis showed it to be at least as effective as amikacin for this infection. Aztreonam yielded clinical results comparable to those of conventional combined therapy for pulmonary infection in patients with cystic fibrosis. Adverse effects in pediatric trials have been uncommon; fever. diarrhea. or rash occurred in less than 2% of treated children. Reversible laboratory abnormalities have occasionally been noted. On the basis of these data. aztreonam is considered an appropriate alternative agent for the treatment of serious gram-negative bacterial infections in neonates and children. Further comparative clinical trials will delineate specific indications.
Aztreonam versus gentamicin for short-term prophylaxis in biliary and gastric surgery, Short-term antibiotic prophylaxis was studied in 80 patients undergoing biliary or gastric surgery. The patients were randomized to receive 1 g of aztreonam or 80 mg of gentamicin intravenously 30 minutes before surgery and 8 and 16 hours after surgery. Of samples taken from the abdominal cavity for bacteriologic study. 53% were culture positive. Wound infections developed in two (4.5%) of 44 patients receiving aztreonam and in seven (19.4%) of 36 patients treated with gentamicin. Staphylococcus epidermidis and Enterobacter species were isolated from sites of wound infection in the aztreonam group; Escherichia coli (two isolates). Pseudomonas aeruginosa (two isolates). Enterobacter species. Klebsiella species. Enterococcus faecalis. and Aeromonas hydrophila were isolated from the gentamicin group. Our data indicate that aztreonam is safe and effective for the prevention of infections following biliary and gastric surgery.
Shigellosis in Kentucky, 1986 through 1989, A marked increase in the number of cases of shigellosis was reported in Kentucky in 1988. To examine reasons for this increase. we reviewed the 389 cases of shigellosis reported from 1986 through 1989. Ninety-three percent (285/305) of cases due to known species were due to Shigella sonnei. Sixty-two percent (243/389) of cases occurred in children less than 10 years of age. The annual incidence for blacks (6.8 cases per 100.000) was nearly four times that for whites (1.8 per 100.000). The increased number of cases in 1988 was due to outbreaks in five areas of the state. which accounted for 85% (200/234) of the cases. Three of the five outbreaks involved day-care centers. The primary mode of transmission appeared to be person-to-person; there was no evidence of a common source of infection from food or water. To prevent future outbreaks. cases of shigellosis need to be reported promptly to ensure appropriate investigation and control by local health departments.
Antibodies to Epstein-Barr virus in patients with chronic fatigue, To clarify the role of Epstein-Barr virus (EBV) infection and the value of EBV antibody testing in evaluating patients with chronic fatigue. we studied 200 consecutive patients with chronic fatigue (mean duration. 9 years). Complete EBV serologic panels were obtained for 154 patients. 35 (23%) of whom met serologic or clinical criteria for chronic or reactivated EBV infection. We compared these patients with chronic EBV infection (CEBV cases) to 35 age- and sex-matched patients who were selected from the same cohort of fatigued patients but who did not meet the criteria (CEBV control subjects). We found few differences between groups in demographic characteristics. clinical features. and symptoms; CEBV cases were more likely to meet criteria for the proposed chronic fatigue syndrome (14% vs 0%). and to report that they suffered from an influenza-like illness at the onset of their fatigue syndrome (34% vs 12%). that they lost their job because of their fatigue (37% vs 11%). and that their fatigue was improved by recreational activity (26% vs 3%). Physical examination and laboratory testing showed few abnormalities in either group. Psychiatric morbidity was common in both groups. including mood disorders (63% of CEBV cases vs 54% of CEBV controls). anxiety (11% vs 9%) and somatization disorder (9% in each group). We conclude that EBV serologic patterns have little clinical usefulness in evaluating patients with chronic fatigue.
Diagnostic and prognostic importance of comparing the initial to the previous electrocardiogram in patients admitted for suspected acute myocardial infarction, Two hundred fifty-eight patients were admitted to the hospital for suspected acute myocardial infarction. Electrocardiograms recorded on admission (initial ECG) and the most recent available electrocardiogram recorded before admission (previous ECG) were compared to determine whether changes from the previous to initial ECG predicted acute myocardial infarction or complications of coronary artery disease. Initial ECGs were classed as either positive or negative. with positive indicating either infarction. injury. ischemia. strain. left ventricular hypertrophy. left bundle branch block. or paced rhythm. Negative ECGs were those that did not include any of the positive criteria. Positive and negative ECGs were subgrouped as showing change or no change from previous ECG. We found that patients with a negative initial ECG that had changed from the previous ECG had a 2.1 times greater risk for requiring interventions than those patients whose ECGs were unchanged. We also found that patients with a positive initial ECG that had changed from the previous ECG had a greater risk for interventions (2.0 times). complications (2.6 times). life-threatening complications (4.2 times). and acute myocardial infarction (6.6 times) than the sum of patients in all other ECG categories. We conclude that change is a useful predictor for interventions in patients with negative initial ECGs and a useful predictor for interventions. complications. and acute myocardial infarction in patients with positive initial ECGs.
Advantages of an immunohistochemical estrogen receptor assay, Immunohistochemical and biochemical assays for estrogen and progesterone receptors were done on 20 breast carcinomas. and results were correlated with various histologic features. The slide-based immunohistochemical technique demonstrated several distinct advantages relative to the tissue homogenization required by the traditional biochemical assay. With the use of frozen tissue sections. the immunohistochemical technique permitted direct visualization of antireceptor binding to tumor cells. Receptor staining of reactive stroma. necrotic tumor. and intermingled benign parenchyma was easily distinguished from receptor staining of the actual carcinoma. This separation is not possible with the biochemical assay. In addition. in situ and invasive components and different morphologic subtypes were evaluated independently. Receptor content of the most aggressive portion of the neoplasm is likely to have the greatest clinical relevance and prognostic significance. Careful correlation of histochemical scores with biochemical assay concentrations is needed to permit the application of this technique to patients entering cancer treatment protocols.
Application of estrogen receptor immunocytochemical assay to aspirates from mammographically guided fine needle biopsy of nonpalpable breast lesions, The importance of hormone receptors in the management and prognosis of breast cancer is well established. but difficult to apply to the growing numbers of very small breast cancers being detected. To assess the feasibility of applying estrogen receptor immunocytochemical assay (ER-ICA) to cytologic specimens. we prospectively studied 100 patients who had fine needle aspiration biopsy (FNAB) of mammographically detected nonpalpable breast lesions. All 100 patients also had surgical excision of these nonpalpable lesions immediately after cytologic aspiration. Twenty malignancies were ultimately diagnosed by histology; 17 of them had been cytologically diagnosed. Using specific monoclonal antibody for estrogen receptor. we applied ER-ICA to cytologic preparation of 15 malignant neoplasms with sufficient cellular material available for the assay. Positive immunostaining was demonstrated in nine cases. No ER expression was seen in six cases. Immunocytochemical assay was also done on frozen tissue of the corresponding surgically removed tumors. with 86.6% concordance between the two results. This study is the first to demonstrate that ER-ICA can be effective in assessing hormone receptor content of mammographically directed cytologic aspirates.
Breast cancer screening in a biracial community: the Charleston tricounty experience, Breast cancer remains a major cause of death among women in South Carolina. Mammography. breast self-examination. and clinical breast examination are effective methods for early detection and subsequent mortality reduction. The Tricounty Breast Cancer Screening Survey assessed knowledge of these methods and recommendations among 503 women in the Charleston area. While 57% of all respondents reported performing breast self-examination at least once per month. 13% of blacks and 6% of whites reported that they do not know how to perform the procedure. Clinical breast examinations within the past year were reported by 69%. yet 11% of blacks and 4% of whites reported that they had never had the examination. More than one third (40%) of all 503 women reported ever having had a mammogram. and 22% reported having had one within the past year. However. 18% of the blacks and 5% of whites reported never having heard of the procedure. The major barriers to mammography appear to be the belief that women do not need regular mammograms and the lack of recommendations by their physicians. Survey results support the need for educating women about what the procedures are. the importance of using them regularly. and the means to comply with them.
Shotgun injuries in pediatric patients, Firearms. particularly high-powered automatic weapons. injure progressively younger children in urban environments. At Arkansas Children's Hospital. 32 children have been admitted for gunshot wounds in 12 years. Air guns (3). handguns (19). and shotguns (10) caused the injuries. Shotgun wounds occurred during hunting accidents (2). flights from houses (3). and mistaken identity in the home (5). usually by family members (5). All victims of shotgun wounds were boys; seven were black. Their ages ranged from 6 to 20 years. Two injuries involved the abdomen. one the flank. one the chest. one the axilla. and five the legs. Accidental discharge of a weapon at close range caused extensive multisystem damage and long-term sequelae. Most of the wounds could have been avoided with the use of common sense and simple measures to identify the person within the household.
Mediastinal involvement by alveolar rhabdomyosarcoma: evaluation with computerized tomography, We have reported a case of alveolar rhabdomyosarcoma with mediastinal involvement occurring in a 15-year-old boy. Computerized tomography revealed an anterior mediastinal mass with internal mammary nodal involvement. which had metastasized from a tumor of the abdominal wall musculature. When making the differential diagnosis of a mediastinal mass with concurrent distant soft tissue and muscle involvement in an adolescent. rhabdomyosarcoma should be considered.
Hemorrhagic cardioembolic stroke: is anticoagulation absolutely contraindicated, Hemorrhagic cerebral embolism should not be considered an absolute contraindication to immediate low-dose systemic anticoagulation. Low levels of anticoagulation may give some protection from recurrent embolism while minimizing the risks of intracranial bleeding. Until further studies are available. these decisions must be made on a case-by-case basis. supported by limited scientific information.
Endoscopic palliation of tracheobronchial malignancies, The prognosis for tracheobronchial tumours remains poor. Most patients can be offered only palliation. When the main symptom is breathlessness or refractory haemoptysis from a large airway tumour endoscopic treatment may be very effective. Over the last decade most attention has focused on the neodymium YAG laser. This often produces dramatic effects but has some important limitations. In the last few years better techniques for stenting and intrabronchial radiotherapy (brachytherapy) have also been developed. This article discusses the range of techniques now available and aims to help clinicians decide which patients may benefit from referral to centres providing these techniques.
Hut lung: a domestically acquired pneumoconiosis of mixed aetiology in rural women [published erratum appears in Thorax 1991 Jul;46(7):544, A form of pneumoconiosis in rural African women termed "Transkei silicosis" has been thought to be due to silica particles inhaled while they are hand grinding maize between rocks. Twenty five women were studied who were considered to have this condition according to the following criteria: rural domicile. radiographic and lung biopsy evidence of pneumoconiosis. no exposure to mining or industry and no evidence of active tuberculosis. They were assessed for radiological. pathological. physiological and bronchoalveolar lavage fluid features. Potential aetiological factors were assessed by determining levels of exposure to respirable quartz and non-quartz containing dusts and smoke in rural dwellings during maize grinding and cooking. Most of the women were symptomless. Radiological findings ranged from a miliary pattern to extensive fibrosis resembling progressive massive fibrosis. Histological features included simple "anthracosis" in 12. anthracosis with macules in six. and mixed dust fibrosis in seven. Cell numbers and their proportions in lavage fluid were normal. More than 60% of macrophages were heavily laden with inorganic inclusions. Respirable quartz concentrations and calculated cumulative time weighted exposures were below those recommended for industry during grinding with sandstone (100% quartz) and they were even lower during grinding with dolerite containing no quartz despite the presence of an appreciable amount of quartz in the ground maize. Total respirable dust and smoke concentrations were greater than the recommended safe levels. Three women had no exposure to maize grinding. It is concluded that the inhalation of non-quartz containing dust and smoke from biomass fuelled fires is more important in the aetiology of this condition than exposure to quartz dust. The term "hut lung" may be more appropriate.
Silicosis in a Himalayan village population: role of environmental dust [published erratum appears in Thorax 1991 Jul;46(7):544, The Himalayan villages of Chuchot Shamma and Stok were surveyed because silicosis had been suspected from the radiographs of some of the inhabitants. The villages are agricultural. and Chuchot is exposed to frequent dust storms. Chest radiographs of villagers aged 50-62 were assessed blind by two independent observers using ILO criteria. In Chuchot five of seven men and all of the nine women examined showed varying grades of silicosis. compared with three of 13 men and seven of 11 women in Stok. which lies 300 metres higher and is exposed to fewer dust storms. The difference in prevalence of silicosis between the two villages was significant. as was the differences between men and women. Three patients from the village adjoining Chuchot were later found to have radiological evidence of progressive massive fibrosis. A necropsy on a man in a neighbouring village in the Indus valley showed classical silicosis in a hilar lymph node. Chemical analysis of the inorganic dust in the lung showed that 54.4% was elemental silicon [corrected]. This was similar to the silicon [corrected] content of dust samples collected from houses in Chuchot. which included particles of respirable size. X-ray microanalysis showed that quartz formed 16-21% of the inorganic lung dust. This study suggests that silicosis is common among the older inhabitants of these Himalayan villages. The dust exposure is clearly environmental and not industrial. Further studies are needed to define the extent and severity of silicosis in this community and to examine possible preventive measures.
Deaths in adults with notified pulmonary tuberculosis 1983-5, For a study of fatality in pulmonary tuberculosis in England and Wales. a sample (n = 1222) of patients notified in 1983 as having tuberculosis confined to the lungs was selected and their mortality up to the time of finishing chemotherapy calculated. During that time 158 patients died. a case fatality of 12.9%. Stratification by age and radiographic extent of disease confirmed these as important predictors of death. Comparison with a referent population showed that the all cause mortality among people with pulmonary tuberculosis was 10 times greater than that of the age and sex matched general population. This ratio fell with increasing age and with extent of disease. Coefficients derived from a logistic regression analysis allowed probability of death during chemotherapy of patients with pulmonary tuberculosis to be estimated.
Effects of inhaled budesonide on spirometric values, reversibility, airway responsiveness, and cough threshold in smokers with chronic obstructive lung disease, Inhaled corticosteroids are known to reduce respiratory symptoms and airway responsiveness in allergic patients with asthma. The aim of the present randomised. double blind study was to assess the effect of eight weeks' treatment with inhaled budesonide in non-allergic smokers with chronic obstructive lung disease. Twenty four subjects (23 male) entered the study. Their ages ranged from 40 to 70 (mean 57) years. with a mean of 35 (range 9-80) pack years of smoking; the mean FEV1 was 53% (range 32-74%) predicted and geometric mean PC20 (histamine concentration causing a 20% fall in FEV1) 0.96 (range 0.07-7.82) mg/ml. After a two week washout. single blind. placebo period. 12 patients were allocated to treatment with budesonide 1600 microgram/day and 12 to placebo for eight weeks. The only additional drug to be taken was ipratropium bromide "if needed." Twenty one patients completed the study. 10 in the budesonide group and 11 in the placebo group. The standard deviation of the difference between duplicate measurements of PC20 histamine and citric acid cough threshold made two weeks apart was below one doubling dose step. There was a significant reduction in dyspnoea in the budesonide group. but otherwise no change in symptom scores or use of ipratropium bromide over the eight weeks of treatment within or between the two groups. No significant differences in spirometric values. peak expiratory flow. PC20 histamine. or citric acid cough threshold were found between the groups. Although differences were not significant. some of the changes showed a trend in favour of budesonide. Whether a longer observation period would show a significant influence of inhaled corticosteroids in patients with chronic obstructive lung disease remains to be determined.
Long survival after excision of a primary malignant melanoma of the oesophagus, A woman who had a large primary malignant melanoma of the oesophagus. with evidence of submucosal invasion and several local metastases. underwent resection two years after the onset of retrosternal pain and has survived for 12 years with no recurrence.
Molecular aspects of immune recognition of cytomegalovirus, The studies discussed in this presentation have shown that CD8 T lymphocytes have a primary role in conferring resistance to MCMV in the immunocompetent BALB/c mouse. In the presence of selective CD8 deficiency. however. other mechanisms. apparently mediated by the CD4 T-cell subset. contribute in a compensatory fashion to antiviral immunity. The protective CTL response to MCMV. at least in BALB/c mice. is elicited by a single epitope encoded by the major ie 1 and expressed in protein pp89. The epitope itself contains 18 amino acids. only five of which are the minimum for CTL recognition. Substitutions within a nonapeptide sequence that is part of the pp89 epitope identified two positions that are critical for TCR binding by clone IE1 CTLs. Polyclonal CTLs. in contrast. respond to either the native nonapeptide or any of the substituted variants that were tested. which suggests a certain degree of degeneracy in the specificity of the physiologic immune response.
Agranulocytosis associated with enalapril, An 83-year-old patient developed agranulocytosis following six months of enalapril 10 mg/d. The patient also had received verapamil for three years. Upon discontinuation of both drugs the white blood cell count was rapidly restored. Cases of agranulocytosis due to angiotensin-converting enzyme inhibitors. mainly captopril. have been previously described. We could. however. find no single case associated with verapamil. This. and the very long exposure of the patient to verapamil. support the assumption that this life-threatening complication might have been caused by enalapril.
Antimicrobial prophylaxis in coronary bypass surgery: a critical appraisal, The literature has been examined to assess the optimal prophylactic antimicrobial regimen for patients undergoing coronary bypass surgery. Antimicrobial surgical prophylaxis should be based on the two main potential pathogens. Staphylococcus epidermidis and S. aureus. It is unclear whether the prophylactic use of antimicrobials can or should be guided by in vitro antimicrobial susceptibility testing; data from well-performed clinical trials should be evaluated. The data fail to demonstrate consistently a significant difference within the cephalosporin class of antimicrobials with regard to prevention of infectious complications. Although it does not reach statistical difference. the trend with respect to efficacy appears to be cefuroxime. then cefamandole. and then cefazolin. The lack of significant difference among antimicrobials suggests an institution-individualized approach to the selection of the optimal antimicrobial for prophylaxis. For our facilities we recommend the following regimen: cefazolin sodium 1-2 g iv q8h for two days. There are not enough data at this time to recommend less than two days of antimicrobial prophylaxis for this type of surgery. In addition. aminoglycosides provide no added benefit when added to cephalosporins.
Quinapril: a new second-generation ACE inhibitor, Quinapril is a new non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. The drug undergoes hepatic hydrolysis into its major active diacid metabolite. quinaprilat. and two minor inactive metabolites. On a weight basis quinaprilat is three times as potent an ACE inhibitor as quinapril. Approximately 60 percent of an oral dose of quinapril is absorbed. In contrast with captopril. the absorption of quinapril is unaffected by food. Peak serum concentrations of quinapril and quinaprilat are achieved within one and two hours. respectively. Approximately 61 percent of an orally administered dose is excreted in the urine. principally as quinaprilat. The elimination half-life of quinaprilat is three hours. but is prolonged up to 11 hours in patients with renal dysfunction. Quinapril dose reduction is recommended in patients with a creatinine clearance of 0.50 mL/sec or less. In the elderly the elimination of quinaprilat is reduced and correlates well with renal function. In patients with cirrhosis the hydrolysis of quinapril to quinaprilat is impaired resulting in lower plasma quinaprilat concentrations and up to a two-fold increase in quinapril half-life. Quinaprilat has a strong binding capacity to tissue ACE allowing for once-daily dosing. The recommended starting dose for quinapril is 20 mg/d. The nature and incidence of adverse reactions to quinapril are similar to those of enalapril and captopril. Quinapril's antihypertensive efficacy is equal to that of captopril and enalapril. A small number of patients with congestive heart failure (CHF) have been treated with quinapril. Preliminary data indicate that quinapril is an equally effective therapeutic alternative to presently available ACE inhibitors in the treatment of CHF.
Idarubicin: a second-generation anthracycline, Because of its in vitro activity in leukemic cell lines and Phase I studies of acute leukemia. Phase II and III clinical trials with idarubicin hydrochloride were conducted in patients with acute lymphocytic leukemia or acute nonlymphocytic leukemia. In the Phase III comparative trials between the combinations of idarubicin and cytarabine and daunorubicin hydrochloride and cytarabine. the idarubicin/cytarabine combination resulted in significantly greater complete remission rates and longer overall survival in two of three studies conducted in the US. As a result. the Food and Drug Administration approved intravenous idarubicin with a Class 1A rating in September 1990 for use in combination with other antileukemic drugs (e.g.. cytarabine) for the treatment of acute myelogenous leukemia in adults. The recommended dose of idarubicin is 12 mg/m2 daily for three days by slow intravenous injection in combination with cytarabine. Although idarubicin causes myelosuppression similar to that described with daunorubicin. the incidence of cardiotoxicity in animal models is lower. Idarubicin also has the advantage of oral administration. but the oral formulation of the drug remains investigational. The use of idarubicin in pediatric patients also remains to be established.
Fludarabine: a review, The new fluorinated adenine analog. fludarabine. has been tested for efficacy in many tumor types over the past ten years. Two other similar nucleoside analogs are currently available for commercial use. Cytarabine is used principally as an antileukemic agent. and vidarabine as an antiviral. Unlike vidarabine. fludarabine is resistant to deactivation by adenosine deaminase. Data from Phase I and II trials suggest that fludarabine is potentially effective in a number of leukemias. including acute lymphocytic leukemia. acute nonlymphocytic leukemia. and chronic lymphocytic leukemia (CLL). Unfortunately. the doses required to achieve adequate response in the acute leukemias (greater than 75 mg/m2) were above the maximum tolerated dose. resulting in intolerable granulocytopenia. thrombocytopenia. and a life-threatening neurotoxic syndrome. In CLL: however. the dose required to achieve a satisfactory response is well within tolerated limits. Long-term survival statistics are not yet available. but historical perspective strongly correlates response to other agents with increased survival times. Toxicities seen at dose regimens of 15-40 mg/m2/d for five consecutive days include somnolence. metabolic acidosis. confusion. fatigue. nausea. vomiting. increase in serum creatinine and aminotransferase concentrations. and pulmonary and hepatic abnormalities. Mild to severe hematologic toxicity has been observed at all dose levels.
The role of corticosteroids in infants and children with bacterial meningitis, Bacterial meningitis continues to be a cause of substantial morbidity in infants and children. Hearing impairment is the most common sequela of this disease. Corticosteroids have been used in an attempt to reduce the incidence of meningitis-induced hearing loss. Some studies have demonstrated a decrease in the incidence of hearing impairment in patients treated with cefuroxime plus dexamethasone compared with cefuroxime alone. Similar data are lacking for other frequently used antibiotics. Based on these studies. the use of dexamethasone should be considered in infants and children greater than two months of age with suspected bacterial meningitis. Critical issues including the timing of steroid initiation in relation to antibiotic therapy and the appropriate antibiotic-corticosteroid regimen must be addressed. Studies should be performed to define the exact role of corticosteroids in the treatment of bacterial meningitis. Until additional data are available. we recommend the use of dexamethasone in pediatric patients older than two months of age with bacterial meningitis.
Clonal immunoglobulin gene rearrangement in the infarcted lymph node syndrome, The authors report a case of complete lymph node infarction in which a specific etiology could not be determined by morphologic or immunophenotypic studies; however. clonal rearrangement of the immunoglobulin gene was demonstrated by Southern blot hybridization of DNA extracted from the necrotic tissue. A subsequent lymph node biopsy later was diagnosed as malignant lymphoma. using morphologic. immunophenotypic and genotypic criteria. Identical clonally rearranged bands were present in DNA from both the infarcted nodal and the subsequent tissue biopsies. In the setting of lymph node necrosis. gene rearrangement studies may provide diagnostic information concerning clonality. even if morphologic and immunophenotypic studies are indeterminate for a lymphoproliferative process.
Parvovirus B19 infection of the fetus. Histology and in situ hybridization, Fetal tissues from 16 spontaneous abortions. two terminations. and one perinatal death. 18 of which were associated with maternal human parvovirus B19 infection. were examined for B19 infection by histology and in situ hybridization using a digoxigenin-labeled B19-DNA probe. In 15 spontaneous abortions and one termination. erythroblasts with intranuclear inclusions (lantern cells) reacted with B19-DNA by in situ hybridization. No internal or external fetal malformations were observed. Because 13 (86.7%) spontaneous abortions with lantern cells occurred between the 20th and 28th weeks of gestation. it is postulated that B19 infection may be a particular threat to the fetus during this stage of gestation.
Anaplastic thyroid carcinoma. Immunocytochemical study of 32 cases, To study the histogenesis of and determine the most useful markers for diagnosing anaplastic thyroid carcinoma (ATC). 32 cases. including 2 with numerous osteoclast-like cells. were stained with a battery of antibodies to epithelial (keratin. epithelial membrane antigen [EMA]. carcinoembryonic antigen [CEA]). mesenchymal (vimentin. desmin. muscle-specific actin [MSA]. Factor VIII-related antigen [FVIII:RAg]). endocrine (thyroglobulin. calcitonin. chromogranin [Cg]). lymphocytic (leukocyte common antigen [LCA]). histiocytic (alpha-1-antitrypsin [alpha 1AT]. alpha-1-antichymotrypsin [alpha 1AChy]. KP1). melanocytic (HMB-45). and Schwann cell (S-100 protein) markers. Five tumors were associated with papillary carcinoma. In one of these cases. a morphologic continuum between the well-differentiated carcinoma and the ATC was visualized by their positive immunostaining for both vimentin and keratin. thus supporting the hypothesis that the latter tumor originated from the former. Twenty-five (78.1%) tumors expressed keratin. 10 (31.3%) reacted for EMA. and 3 (9.4%) expressed CEA. confirming the epithelial nature of this neoplasm. Reactivity for thyroglobulin was seen in a small number of cells in five (15.6%) thyroglobulin was seen in a small number of cells in five (15.6%) ATCs. Because all of the cases that expressed keratin also stained positively for EMA. CEA. or thyroglobulin. it is believed that keratin is the most useful epithelial marker for diagnosis of ATC. A lack of reactivity for calcitonin and Cg indicates that these tumors are not derived from C cells. as has been proposed by some authors. Reactivity for KP1 (CD68). a monoclonal antibody that reacts with a macrophage-associated antigen. occurred in the osteoclast-like cells but not in the anaplastic tumor cells. This finding. together with negative keratin staining of the osteoclast-like cells. indicates that these cells are not epithelial in nature and therefore should be considered reactive rather than neoplastic. Thirty tumors (93.8%) expressed vimentin. 15 (46.9%) marked for alpha 1AChy. 11 (34.4%) exhibited alpha 1AT. and 11 (34.4%) expressed S-100 protein. Because all of these markers can be seen in a wide variety of tumors of different histogeneses. they have no value in the diagnosis of ATC. Although immunostaining for FVIII:RAg. desmin. and MSA was negative in all of these tumors. these markers can help to differentiate between ATCs and some soft tissue sarcomas with which they can be confused.
Comparative immunohistochemical staining for desmin and muscle-specific actin. A study of 576 cases, Muscle-specific actin (MSA) and desmin are considered to be sensitive and specific markers for muscle differentiation. The authors compared staining patterns for these markers in 576 samples of normal. reactive. and neoplastic tissues. The standard avidin-biotin-peroxidase complex technique was performed with the use of two commercial antibodies against MSA (HHF35; Enzo Biochemical. Inc.. New York. NY) and desmin (DER11; DAKO Corporation. Santa Barbara. CA). respectively. on consecutive paraffin-embedded tissue sections from these cases. Both MSA and desmin were found in all 80 normal muscle samples. Although MSA appeared diffusely in all vascular smooth muscle samples. desmin was demonstrated focally in vascular smooth muscle cells in 100 of 196 samples. MSA but not desmin always was found in myoepithelial cells (25 samples). pericytes (286 samples). and decidual cells (7 samples). Among 76 cases of myofibroblast-containing lesions. 14 and 54 were found to have desmin and MSA. respectively. MSA and desmin were found in 4 of 4 cardiac rhabdomyomas. 34 of 34 rhabdomyosarcomas. and 5 of 6 leiomyomas. Among 22 leiomyosarcomas. 7 displayed either MSA or desmin and 7 showed both markers. In general. more tumor cells showed staining for MSA than desmin. but the reverse was true in some cases. Tissue fixed in Zenker's solution seemed to show a significant decrease in MSA immunoreactivity. but no significant change for desmin staining was observed. None of the 154 normal tissues and 22 benign nonmyogenic tumors expressed MSA or desmin. Among 133 malignant nonmyogenic tumors. positive staining for both desmin and MSA was found in 3 of 8 cases of glioblastoma multiforme. 1 of 10 malignant schwannomas. and 1 of 14 malignant fibrous histiocytomas; staining for only MSA was found in 3 of 14 malignant fibrous histiocytomas. 1 of 10 malignant schwannomas. 6 of 6 fibromatoses. 1 of 1 mammary myofibroblastoma. and 1 of 7 malignant mesotheliomas; and staining for desmin only was seen in 1 of 7 malignant mesotheliomas.(ABSTRACT TRUNCATED AT 400 WORDS).
Expression of a polymorphic epithelial mucin antigen defined by the monoclonal antibody BC2 in ovarian carcinoma. Use of the BC2 antibody for the detection of micrometastases, The BC2 monoclonal antibody. which binds to an epitope on the peptide backbone of polymorphic epithelial mucin. was tested immunohistochemically for reactivity with epithelial ovarian carcinoma. This epitope was expressed in 90 of 91 malignant ovarian tumors; in 88% of these. more than 50% of the tumor cells expressed the epitope. In 94% of the positive tumors. the epitope was expressed on the cell membrane; in 56%. cytoplasmic expression was evident; and in 39%. secreted extracellular antigen was detected. Differences were not clearly discernible between dissimilar histotypes with respect to the percentage of cells expressing antigen and antigen localization. Thirteen of 19 benign ovarian cystadenomas also expressed the epitope. but staining was weak and restricted to the luminal surface of the cell membrane. A blind retrospective immunohistochemical analysis of all second-look laparotomy biopsy specimens from 20 patients also was performed. All four patients in whom microscopic disease was detected by standard pathologic assessment had BC2-positive metastases. Of seven patients in whom recurrent disease subsequently developed despite negative pathologic findings. four had biopsy specimens containing BC2 antigen-positive adenocarcinoma-like cells. Of the nine patients with negative results on operation and no recurrence. one had biopsy specimens containing BC2 antigen-positive adenocarcinoma-like cells. Mesothelial cells. although typically negative. expressed the epitope in one biopsy specimen. necessitating caution in the interpretation of positive cells. The BC2 antibody is reactive with most epithelial ovarian carcinomas and appears to be a useful tool for the detection of micrometastases.
Comparison of monoclonal immunocytochemical and immunoenzymatic methods for steroid receptor evaluation in breast cancer, The production of monoclonal antibodies against estrogen receptor (ER) and progesterone receptor (PR) has permitted the development of the enzyme immunoassay (EIA) and immunocytochemical assay (ICA) for steroid receptor determination. The results obtained with these two techniques. using the same monoclonal antibodies. were compared in a large series of breast carcinomas (187 for ER and 100 for PR). The correlation between these methods was significant for ER (rs = 0.54) and PR (rs = 0.55) (P less than 0.001) but was lost when the receptor concentrations determined by EIA were less than or equal to 15 and less than or equal to 30 fmol/mg protein for ER and PR. respectively. When these values are considered as cutoffs. the concordance between the two methods was 84.5% for ER and 73% for PR. An analysis of discordant results revealed that low epithelial cellularity generally was present in ICA-positive. EIA-negative specimens. whereas only focal positivity with ICA. or positivity of only normal peripheral mammary ducts and lobules. frequently was found in ICA-negative. EIA-positive tumors. In conclusion. there is good correlation between the results obtained by EIA and ICA methods for detection of ER and PR. The authors suggest that biochemical and histochemical methods for steroid receptors could be considered complementary and used together for the analysis of breast cancer.
Immunocytochemical analysis of progesterone receptors in breast cancer, Breast cancer specimens from 116 patients were assayed for the presence of progesterone receptor (PR). with the use of a highly specific monoclonal antibody and the peroxidase-antiperoxidase technique on cryostat and permanent sections. Results were compared with those obtained by the conventional PR determination by dextran-coated charcoal (DCC) assay; they were in concordance in 90% of cryostat sections and 85% of paraffin-embedded tissue. The sensitivity and specificity of the PR immunocytochemical assay (PR-ICA) were 91% and 89% for frozen sections and 83% and 89% for permanent sections. respectively. The immunostained slides also were evaluated for several semiquantitative features. including staining intensity. heterogeneity of staining. and the proportion of positive tumor cells. A statistically significant correlation was found between the percentage of tumor cells stained with the PR immunocytochemical technique and the PR-cytosol levels (P less than 0.05). These results suggest that the PR-ICA is an effective tool in the evaluation of PR content in breast cancer and can be applied in paraffin as well as frozen sections. This technique provides excellent morphologic detail. as well as tissue localization for PR. It also offers an alternative for assessment of PR when fresh tissue is not available for conventional hormone receptor analysis. The immunocytochemical assay can be performed easily at community hospitals. Because it requires only a small amount of tissue. PR-ICA is an ideal method for analyzing specimens of insufficient size for the DCC assay. This technique also is suited to the evaluation of fine-needle aspiration biopsy specimens.
Automated procedure for dewaxing and rehydration of paraffin-embedded tissue sections for DNA flow cytometric analysis of breast tumors, Flow cytometric DNA analysis of paraffin-embedded tumors is an important diagnostic and prognostic tool in clinical pathology. The technique is limited. however. by the time-consuming multistep procedure for dewaxing and rehydrating tissue. The authors developed an automated procedure to complete the dewaxing and rehydration of tissue using a routine histologic tissue processor with a 24-hour timer. This technique provided excellent tissue recovery and reproducible DNA histograms comparable to those obtained by manual methods. Subsequently. the authors analyzed the DNA content of 93 paraffin-embedded breast cancer tissues. The automation of a significant portion of the routine processing required for paraffin-embedded tissue makes cytometric DNA analysis a more practical procedure in the laboratory.
Correlation between visual clues, objective architectural features, and interobserver agreement in prostate cancer, Three pathologists evaluated a number of designated architectural features to assign grades to 41 cases of well- to moderately differentiated adenocarcinoma. and their opinions were compared. The consensus opinion was obtained and evaluated against objective measurements of glandular architecture that were obtained by morphometric techniques. The observers agreed on gland size. gland uniformity. and the number of glands per field in only 49%. 31%. and 39% of cases. respectively. There were significant differences in the Gleason grades assigned by observers. Paired matching of individual Gleason grades showed agreement among observers in 44% (18 of 41). 56% (23 of 41). and 75% (31 of 41) of cases. respectively. This level of interobserver disagreement occurred even though cases with predominant patterns were selected carefully and those with variable patterns were excluded. A direct relationship appears to exist between increasing Gleason grade and increasing glandular variability. and there is an inverse relationship between Gleason grade. gland lumen area. and the number of glandular nuclei. as assessed by a group of pathologists.
Diagnostic problems in tissues previously sampled by fine-needle aspiration, Unusual tissue changes in needle tracts after fine-needle aspiration were studied in two specimens. One specimen. a 3.0 x 2.5 cm mesenteric nodule. was found six days after a nondiagnostic transabdominal fine-needle aspiration of a retroperitoneal mass. At frozen-section examination. the nodule had proliferating spindle-shaped cells interspersed with adipocytes that raised the possibility of well-differentiated liposarcoma. On permanent sections. however. there was fat necrosis and reactive spindle-shaped cells that immunohistochemically were consistent with myofibroblasts. In the second case. a needle tract was noted in breast tissue on which a biopsy was performed two days after a cytologic diagnosis of carcinoma. The 0.4-mm-wide tract contained neutrophils. foamy histiocytes. and clumps of intact. atypical epithelial cells without a desmoplastic or elastotic component. Aside from these epithelial cells. nothing in the biopsy specimen suggested invasive carcinoma. The cells were identical to those from a comedocarcinoma present in the biopsy and mastectomy specimens. These two cases provide examples of pitfalls that may arise during the examination of biopsy specimens obtained after fine-needle aspiration.
Composite lymphoma. A clinicopathologic analysis of nine patients with Hodgkin's disease and B-cell non-Hodgkin's lymphoma, Nine patients had composite lymphoma in which Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) involved the same anatomic site. Two of these patients had relapses of their tumors. In one. the initial biopsy specimen contained follicular and diffuse large cell NHL with unclassifiable HD. but the relapse showed diffuse large cell NHL with nodular sclerosis HD. In the other patient. both biopsy specimens showed follicular mixed NHL; the HD component in the initial biopsy specimen was nodular sclerosis. whereas. at relapse. it had the appearance of interfollicular HD. In the remaining seven patients. the HD component was subclassified as nodular sclerosis (three specimens) or mixed cellularity (three specimens). or it was unclassifiable (one specimen). The NHL component was categorized as diffuse large cell (two specimens). diffuse large cell immunoblastic (two specimens). follicular and diffuse large cell (one specimen). diffuse mixed small and large cell (one specimen). and lymphocytic lymphoma of intermediate differentiation (modified Rappaport classification) (one specimen). Paraffin section immunoperoxidase studies were done on the NHL component in eight patients (nine specimens) and on the HD component in six patients (seven specimens). In each of these. the NHL component was leukocyte common antigen (LCA) positive and Leu-M1 negative. In addition. the neoplastic cells were L26 positive and UCHL-1 negative. indicating a B-cell phenotype. In five of seven immunophenotyped cases. Reed-Sternberg (RS) and Hodgkin's (H) cells from the HD areas were Leu-M1 positive and LCA negative. reflecting an immunophenotype that is typical of non-lymphocyte-predominant HD. In two specimens. the malignant cells were negative for Leu-M1 and LCA (with positive internal controls). Composite lymphomas composed of HD and NHL are unusual. and cases of coexistent HD of the non-lymphocyte-predominant subtype and NHL are even less common. The results of the current study and a review of the literature indicate that this phenomenon usually involves a B-cell NHL that coexists with HD. perhaps further suggesting a close relationship between the malignant cells of HD (RS and H cells) and B lymphocytes.
The predictive value of bone marrow morphologic characteristics and immunostaining in primary (AL) amyloidosis, The authors previously demonstrated that bone marrow plasmacytosis in primary (AL) amyloidosis may be monoclonal or polyclonal. However. the clinical implications of the degree of plasmacytosis and its clonality have not been studied. The authors evaluated 62 patients with AL amyloidosis. 40 of whom had monoclonal medullary plasma cells. There was complete concordance between the light chain class of the plasma cells in the monoclonal cases and that of the circulating paraprotein in the 22 cases associated with a paraprotein. The remaining 22 patients had polyclonal plasma cells. although a paraprotein was detected in 6. The degree of plasmacytosis was significantly higher among patients with monoclonal plasma cells and correlated inversely with length of survival. The authors' findings indicate that the quantitation of bone marrow plasma cells in AL amyloidosis by immunoperoxidase studies may predict the clinical course.
Amphotericin B lipid complex therapy of experimental fungal infections in mice, The amphotericin B lipid complex (ABLC). which is composed of amphotericin B and the phospholipids dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol. was evaluated for its acute toxicity in mice and for its efficacy in mice infected with a variety of fungal pathogens. ABLC was markedly less toxic to mice when it was administered intravenously; it had a 50% lethal dose of greater than 40 mg/kg compared with a 50% lethal dose of 3 mg/kg for Fungizone. the desoxycholate form of amphotericin B. ABLC was efficacious against systemic infections in mice caused by Candida albicans. Candida species other than C. albicans. Cryptococcus neoformans. and Histoplasma capsulatum. ABLC was also efficacious in immunocompromised animals infected with C. albicans. Aspergillus fumigatus. and H. capsulatum. Against some infections. the efficacy of ABLC was comparable to that of Fungizone. while against other infections Fungizone was two- to fourfold more effective than ABLC. Against several infections. Fungizone could not be given at therapeutic levels because of intravenous toxicity. ABLC. with its reduced toxicity. could be administered at drug levels capable of giving a therapeutic response. ABLC should be of value in the treatment of severe fungal infections in humans.
Antiviral activities of 5-ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide and related compounds, A series of novel compounds. 5-alkynyl-1-beta-D-ribofuranosylimidazole-4- carboxamides. have been identified as broad-spectrum antiviral agents. 5-Ethynyl-1-beta-D-ribofuranosylimidazole-4- carboxamide (EICAR). the most potent congener of the group. showed antiviral potency about 10- to 100-fold greater than that of ribavirin. Similar in spectrum to ribavirin. EICAR was particularly active (50% inhibitory concentration. 0.2 to 4 micrograms/ml) against poxviruses (vaccinia virus). togaviruses (Sindbis and Semliki forest viruses). arenaviruses (Junin and Tacaribe viruses). reoviruses (reovirus type 1). orthomyxoviruses (influenza A and B viruses). and paramyxoviruses (parainfluenza virus type 3. measles virus. subacute sclerosing panencephalitis virus. and respiratory syncytial virus). EICAR was also cytostatic for rapidly growing cells (50% inhibitory concentration. 0.2 to 0.9 microgram/ml). EICAR inhibited vaccinia virus tail lesion formation at doses that were not toxic to the host. EICAR is a candidate antiviral drug for the treatment of pox-. toga-. arena-. reo-. orthomyxo. and paramyxovirus infections.
Killing of nongrowing and adherent Escherichia coli determines drug efficacy in device-related infections, Antimicrobial therapy of device-related infections often fails. despite the in vitro susceptibility of the infecting strain. Therefore. alternative laboratory-based in vitro tests are required to predict the outcome. Fleroxacin. ciprofloxacin. aztreonam. and co-trimoxazole were tested against Escherichia coli ATCC 25922 in vitro and in the tissue-cage animal model. The importance of early treatment was evaluated by starting the drugs either 30 min before or 4. 12. and 24 h after bacterial challenge. Results were compared with the in vitro drug efficacy against nongrowing and adherent Escherichia coli ATCC 25922. The alternative in vitro tests correlated highly with the outcome in the tissue-cage animal model. In the prophylaxis group (drug given 30 min before bacterial challenge). co-trimoxazole was less efficacious than the other three drugs (P less than 0.001). In delayed treatment. ciprofloxacin showed the highest cure rate. It was also more potent than the other drugs against nongrowing and adherent E. coli ATCC 25922. The efficacies of aztreonan. fleroxacin. and ciprofloxacin dropped significantly (P less than 0.01) when the time interval between bacterial challenge and the start of treatment was delayed to greater than 4 h. These data emphasize (i) the need for proper timing of prophylaxis in patients undergoing implant surgery. and (ii) the possibility of successful treatment of established device-related infections with drugs which kill not only growing but also nongrowing and adherent bacteria.
Loracarbef versus cefaclor in the treatment of urinary tract infections in women, In a double-blind. prospective. randomized study. 108 college women with acute urinary tract infections were treated for 7 days with either loracarbef (LY163892) at 200 mg once daily (n = 53) or cefaclor at 250 mg three times daily (n = 55). The cure rates at 5 to 9 days after treatment in the loracarbef and cefaclor groups were 96 and 90%. respectively. Both loracarbef and cefaclor are safe. well tolerated. and effective in the treatment of urinary tract infections in women.
Activities of various macrolide antibiotics against Mycobacterium leprae infection in mice, We evaluated the activities of several macrolide antibiotics against M. leprae infections in mouse footpads. Erythromycin and azithromycin were inactive. while both roxithromycin and clarithromycin were found to be consistently active and. in fact. bactericidal. By both methods. clarithromycin was found to be superior to roxithromycin. a finding which. at least in part. may be a consequence of the higher levels of clarithromycin at the site of infection.
Multicenter evaluation of the in vitro activities of three new quinolones, sparfloxacin, CI-960, and PD 131,628, compared with the activity of ciprofloxacin against 5,252 clinical bacterial isolates, The in vitro activities of three new quinolones (sparfloxacin. CI-960. and PD 131.628) were compared with that of ciprofloxacin against 5.252 routine clinical aerobic and facultatively anaerobic bacterial isolates. Overall. CI-960 was the most active drug in vitro (MIC for 90% of the strains tested. 0.13 micrograms/ml); ciprofloxacin and sparfloxacin were the least active (MIC for 90% of the strains tested. 1.0 micrograms/ml). All three new quinolones. but particularly CI-960 and PD 131.628. exhibited significantly greater activity than ciprofloxacin against enterococci and staphylococci.
Liposome-entrapped ampicillin in the treatment of experimental murine listeriosis and salmonellosis, The tissue distribution of ampicillin entrapped in liposomes was studied in normal noninfected mice and showed that ampicillin concentrated mostly in the liver and spleen. Liposomate ampicillin was significantly more effective than free ampicillin in reducing splenic and hepatic bacterial counts in C57BL/Ka nude mice chronically infected with Listeria monocytogenes EGD. It was also significantly more effective than free ampicillin in reducing mortality in C57BL/6 mice acutely infected with Salmonella typhimurium C5. Comparison of the results with those previously obtained in the same experimental models with the same amounts of ampicillin bound to polyisohexylcyanoacrylate nanoparticles showed that liposomes were more effective than nanoparticles (M. Youssef. E. Fattal. M. J. Alonso. L. Roblot-Treupel. J. Sauzieres. C. Tancrede. A. Omnes. P. Couvreur. and A. Andremont. Antimicrob. Agents Chemother. 32:1204-1207. 1988) in targeting ampicillin to the spleen but were less effective than nanoparticles in targeting ampicillin to the liver and reducing mortality in acute salmonellosis.
Effects of air pollution on adult pulmonary function, We conducted a study in three representative areas of Beijing to determine respiratory health effects of indoor and outdoor air pollution. In August 1986. we measured the lung function of 1.440 adults who were 40-69 y of age and who had never smoked. Forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1.0) were adjusted for height. sex. and age. Outdoor ambient air pollution measurements from the World Health Organization Global Air Pollution Monitoring Station were very different in the three study areas; the annual mean concentrations of sulfur dioxide (SO2) in residential. suburban. and industrial areas were 128. 18. and 57 micrograms/m3. respectively. and annual mean concentrations of total suspended particulate matter (TSPM) were 389. 261. and 449 micrograms/m3. respectively. Coal was most frequently used for domestic heating in the residential (92%) and suburban (96%) areas compared with the industrial area (17%). Heating with coal was associated with a reduced FEV1.0 (-91 +/- 36 ml) and FVC (-84 +/- 41 ml). Living in the residential area was associated with an additional reduction in FEV1.0 (-69 +/- 34 ml) and FVC (-257 +/- 37 ml). After we adjusted for age. height. and sex. an inverse linear association was found between In outdoor SO2 (or TSPM) concentration and FEV1.0 and FVC in subjects who had and had not used coal stove heating. Regression analysis results showed that a per-unit increase in In SO2 (TSPM) concentration (microgram/m3) could result in a 35.6 (131.4) ml reduction in FEV1.0 and a 142.2 (478.7) ml reduction in FVC.
Acute health effects from community exposure to N-propyl mercaptan from an ethoprop (Mocap)-treated potato field in Siskiyou County, California, A 145-acre potato field adjacent to Dorris. California. was treated with ethoprop (Mocap) to control nematodes. Ethoprop releases n-propyl mercaptan. a highly odorous and volatile gas. as a degradation product of the pesticide. An epidemiological investigation was undertaken by the California Department of Health Services because community residents sought medical attention for odor-related illness. Elevated health effects were found among those who reported smelling a strong odor (n-propyl mercaptan has a characteristic onion-like odor). In a logistic regression analysis. the most highly elevated 6-wk health effect incidence risks. expressed as odds ratios (ORs) adjusted for age. sex. and current cigarette smoking status. were for headache (OR = 5.08). diarrhea (OR = 3.80). runny nose (OR = 5.31). sore throat (OR = 3.58). burning/itching eyes (OR = 5.64). fever (OR = 3.59). hay fever attacks (OR = 3.50). and asthma attacks (OR = 6.0). Based upon these elevated health effects. it is recommended that human exposures to n-propyl mercaptan be minimized to the extent practicable.
Biological markers in chromium exposure assessment: confounding variables, An estimated two million tons of chromate production waste pollution has caused a major environmental and public health concern in Hudson County. New Jersey. As part of an occupational exposure assessment. urinary and red blood cell (RBC) chromium measurements were performed on 52 state employees who worked either near a contaminated site or elsewhere. Samples were collected so as to minimize contamination. and they were analyzed using sensitive techniques. These workers also completed a questionnaire that addressed potentially important third variables. Individual analyses suggested that exercise. drinking beer. past employment in chromium-related occupations. and diabetic status had an important effect on urinary chromium levels. These variables were entered into a regression model and were all found to be significant predictors of urinary chromium level (p less than .10). Some variables were also examined for their influence on RBC chromium level. but none had a measurable effect.
Functional results of muscle flap closure for sternal infection, The morbidity and mortality of infection after median sternotomy have been substantially reduced with the advent of treatment by wide sternal resection and muscle flap closure. A study was performed comparing the cardiorespiratory function of 13 such patients before and after operation as well as with a control group of 15 patients who underwent similar procedures without complication. The groups were comparable in preoperative pulmonary function. though more patients in the study group had evidence of chronic lung disease. Patients were studied 2 to 39 months after the original procedure. Late postoperative pulmonary function test results. exercise tolerance. and oxygen uptake were not significantly different between the groups. and pulmonary function test results were unchanged in those patients who were tested preoperatively. We conclude that muscle flap reconstruction for sternal infection can be expected to give good long-term functional results. Exercise tolerance and pulmonary function may not differ from a control group of cardiac surgical patients. despite the altered composition of the chest wall. Patients with chronic lung disease may be more prone to have this complication.
Multiple pulmonary microemboli complicating pneumonectomy, Pulmonary embolism is widely recognized to complicate abdominal and lower limb orthopedic surgical procedures. but in comparison. it is seldom recognized to hamper the postoperative progress of patients after thoracic operations. We present 4 patients in whom multiple pulmonary emboli developed after pneumonectomy. 2 of whom were treated successfully. We discuss the mostly atypical presentation and the physiological and clinical consequences. and also suggest a mode of management.
Intrathoracic goiter: approaching the posterior mediastinal mass, The surgical management of posterior mediastinal goiters can pose considerable technical difficulty. We illustrate a method of sterile spoon extraction that can facilitate the cervical or limited cervicomediastinal approach to these lesions.
Intraoperative transesophageal echocardiography for pulmonary embolectomy without cardiopulmonary bypass, This case report describes a patient with massive pulmonary embolism and acute circulatory failure in whom transesophageal echocardiography permitted the diagnosis of thrombi in the main pulmonary truncus and in the right branch and guided intraoperatively the surgical embolectomy performed under simple venous inflow occlusion because of a contraindication to heparin administration. Transesophageal echocardiography seems to be a very helpful technique to diagnose promptly massive pulmonary embolism and a very useful tool at the time of operation to guide the embolectomy.
Mediastinal emphysema secondary to dental restoration, Barotrauma due to oral procedures. although widely reported in dental publications. is rarely discussed in the medical literature. We report the case of a 42-year-old woman with mediastinal emphysema after a mandibular restoration and discuss management of this complication.
Triiodothyronine-enhanced left ventricular function after ischemic injury, Hypothyroidism is associated with profound left ventricular dysfunction. Brain-dead organ donors and patients undergoing cardiopulmonary bypass are chemically hypothyroid with significantly reduced circulating free triiodothyronine (T3). To test the hypothesis that T3 enhances left ventricular function in a hormonally deficient environment. a total of 36 healthy New Zealand White rabbit hearts were studied using a modified Langendorff preparation with Krebs-Henseleit perfusate and intra-ventricular balloon. In 9 normal rabbit hearts a cumulative dose-response curve with logarithmically increasing doses of T3 was obtained. The vehicle solution for T3 dissolution served as control (n = 9). Left ventricular function was assessed from peak developed pressure at baseline and after T3 administration. Triiodothyronine had no effect in normal hearts on peak developed pressure or end-diastolic pressure. In 18 rabbits. the acute effect of T3 administration after ischemia was investigated. Preischemic left ventricular function was measured to serve as baseline. and hearts were subjected to 37 degrees C global ischemia. Triiodothyronine (n = 9) or vehicle (n = 9) was infused during reperfusion. and left ventricular peak developed pressure was measured at 30 and 60 minutes of reperfusion. Recovery of function (expressed as percent return of left ventricular peak developed pressure) was significantly improved within 15 minutes of reperfusion (65.0% +/- 2.1% versus 80.2% +/- 4.1%) and remained significantly improved throughout the reperfusion period (p less than 0.05 by analysis of variance). These data suggest that although T3 possesses no inotropic properties. it significantly improves postischemic left ventricular function. The rapidity of the functional improvement suggests that these effects may be due to plasma membrane-mediated mechanisms.
Permanent transfemoral pacemaker insertion after repair of congenital heart disease, In certain patients with anomalies of systemic venous connection. traditional transvenous pacemaker lead insertion may not be technically feasible. We report the use of the femoral venous approach to insert a permanent pacemaker in a patient with congenital heart disease who had undergone two previous cardiac operations and had persistent anomalies of the superior systemic venous circulation. We recommend that the femoral venous approach be considered in select patients requiring permanent pacing.
Mechanical cardiac valvular prostheses, Mechanical cardiac valvular prostheses currently enjoy a 60% to 40% market-share advantage over tissue prostheses in the United States and worldwide. Only the Starr-Edwards caged Silastic (Dow Corning) ball. Medtronic-Hall. St. Jude Medical. and Omniscience valves remain available in the United States. Although each valve has certain advantages and disadvantages. no design has achieved functional mechanical perfection. Late follow-up of valve-related complications from the literature favors the St. Jude Medical and Medtronic-Hall valves.
Complete repair of atrioventricular septal defect, We report our experience with 103 consecutive children who underwent repair of complete atrioventricular septal defect between 1971 and 1990. Ninety-one patients were less than 18 months old (mean age. 6.2 months; mean weight. 5.8 kg) and were repaired using deep hypothermia and circulatory arrest. There were 15 perioperative deaths. Twelve patients were older (mean age. 40.2 months; mean weight. 18.9 kg) and were repaired using moderate hypothermia and cardiopulmonary bypass. There were two perioperative deaths. Repairs were performed with the single-patch technique. Four younger patients required repeat repair to control residual mitral regurgitation. Two of the older children required late reoperation to replace one or both atrioventricular valves. Three younger children underwent pulmonary artery banding initially; 1 died after complete repair. Three older children underwent initial pulmonary artery banding; 2 died at definitive repair. and the survivor required pulmonary artery reconstruction. which was repeated subsequently. Since 1977 our policy has been to perform primary definitive repair whenever possible. Two patients died late from unrelated causes. At the most recent follow-up the majority of patients had no or minimal symptoms. We continue to advocate primary definitive repair whenever possible using the single-patch technique in symptomatic patients with complete atrioventricular septal defect.
Cardiopulmonary bypass and thyroid function: a "euthyroid sick syndrome", The purpose of this prospective study was to define the effect of cardiopulmonary bypass on the concentrations of thyroid hormones and metabolites. Blood samples were obtained from 14 patients preoperatively. at specific times throughout cardiopulmonary bypass. and serially to 24 hours postoperatively. Thyroid-stimulating hormone. thyroid-binding globulin. total thyroxine. triiodothyronine (T3). and reverse T3. an inactive metabolite of thyroxine. were measured by radioimmunoassay. Free T3 was assayed by equilibrium dialysis. Values of total T3 and free T3. the active hormone. were significantly depressed (75% and 50%. respectively) up to 24 hours after bypass (p less than 0.05). Reverse T3 demonstrated a greater than fourfold rise at 8 and 24 hours postoperatively (p less than 0.05). Thyroid-binding globulin was decreased at all sampling times (p less than 0.05). Thyroid-stimulating hormone. thyroxine. and free thyroxine levels remained within normal ranges at all sampling times. These results indicate that cardiopulmonary bypass simulates the "euthyroid sick syndrome" as seen in severely burned patients and critically ill patients. which is characterized by depression of T3 and free T3 concentrations with a concomitant increase in reverse T3 levels and normal concentrations of thyroid-stimulating hormone. thyroxine. and free thyroxine. The hemodynamic effects of primary hypothyroidism are well established. These data provide further support for investigational trials of intravenous administration of T3 in the prevention or treatment of low cardiac output syndrome after cardiopulmonary bypass.
Effect of lung contusion on pulmonary hemodynamics, Our purpose was to examine changes in pulmonary hemodynamics for patients with pulmonary contusion. Pulmonary vascular resistance index (PVRI) and shunt fraction were calculated from standard measurements in 25 traumatized patients. The percent of lung volume injured. measured as air-space filling disease (ASF). was quantitated from computed tomograms using a previously described technique. The amount of reactive pulmonary vasoconstriction per unit of injury (PVRI/ASF) identified 3 groups of patients: 5 were reactors (PVRI/ASF greater than 15). 10 were weak-reactors (PVRI/ASF = 5 to 15). and 10 were nonreactors (PVRI/ASF less than 5). In the reactor group PVRI increased as the size of contusion (ASF) increased (r = 0.99). In weak-reactors PVRI also increased with the size of contusion (r = 0.93). but the slope was less pronounced. In both groups shunt fraction did not rise above 0.31. In the nonreactors. PVRI remained normal while shunt fraction increased with the extent of injury (r = 0.95). These results indicate that pulmonary vasoconstriction often occurs after pulmonary contusion. The vasoconstriction most probably represents a compensatory mechanism to limit perfusion of traumatized parenchyma. thereby minimizing increases in shunt fraction. Some patients (nonreactors) not demonstrating this response have unchecked increases in shunt fraction. This insight into the hemodynamic sequelae of pulmonary contusions may enhance our ability to provide optimal care for patients suffering from this injury.
Excess mortality among 3302 patients with 'pure' anxiety neurosis, The survival probability and causes of death before the age of 70 years were analyzed among 3302 inpatients with "pure" anxiety neurosis in Stockholm County. Sweden. who were tracked in case registries by means of automated record linkage during a 14-year period. When all patients with other psychiatric diagnoses and substance abuse were excluded. and marital status controlled for. there was a significant excess of deaths due to verified and undetermined suicides. ie. nearly one third of all deaths. These unnatural deaths preempted any excess in natural causes before the age of 70 years. such as cardiovascular disease. Treatment policy with regard to the use of anxiolytic drugs was not found to influence mortality. We concluded that the risk of suicide in inpatients before the age of 70 years with anxiety disorders may be as high as that in persons with depression or other diagnoses who require inpatient care.
No linkage between D2 dopamine receptor gene region and schizophrenia, The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance. we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score. less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However. they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia. such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.
Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism, The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and non-alcoholic subjects. In a blinded experiment. DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (lambda hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd [binding affinity] and Bmax [number of binding sites]) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele. in whom a high association with alcoholism was found. the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover. a progressively reduced Bmax was found in subjects with A2/A2. A1/A2. and A1/A1 alleles. with subjects with A2/A2 having the highest mean values. and subjects with A1/A1. the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.
Alcoholism and alleles of the human D2 dopamine receptor locus. Studies of association and linkage, The association of the A1 allele of the D2 dopamine receptor gene with alcoholism was examined by comparing 32 unrelated white alcoholics with 25 unrelated white controls and by analysis of 17 nuclear families in multigenerational pedigrees of alcoholics in whom the A1 allele was segregating. All subjects had structured psychiatric interviews. Clinical assessment and genotyping were carried out independently. Thirteen (41%) of the 32 alcoholics carried the A1 allele compared with three (12%) of the 25 controls. The association with the A1 allele was significant when controls were compared with a subset of 10 alcoholics with severe medical problems (60% vs 12%). but not less severe cases. However. regardless of clinical severity or subtype. there was no evidence of linkage or cosegregation of the A1 allele and increased susceptibility to alcoholism in informative pedigrees. The possible association in the general population without linkage in families may be explained either by chance variation in our small samples or a modifying effect of the A1 allele that increases severity. Further study of the role of the D2 receptor gene in alcoholism is warranted.
Influence of anesthesiology residents' noncognitive skills on the occurrence of critical incidents and the residents' overall clinical performances, The authors examined residents' clinical performances in five anesthesiology departments in U.S. teaching hospitals. The data were organized by daily use of the Clinical Anesthesia System of Evaluation. which categorizes and quantifies the narrative comments of faculty. The study was designed to identify predictor categories (particular performance characteristics of residents) for the residents' overall performances and their scores in handling critical incidents (those incidents that could or would have caused significant morbidity or mortality had faculty not intervened). More than 9.000 comments made by 163 faculty about 45 residents were analyzed. Residents' noncognitive skills that were predictors of overall performance were Conscientiousness. Management. Confidence. Critical Incidents. and Knowledge. Conscientiousness and Composure predicted two-thirds of the variability in critical incidents' scores. Path analysis verified causal relationships between the hypothesized predictors and critical incidents. For the residents studied. inadequate noncognitive performance in some areas was a powerful (p less than .0005) predictor of overall clinical performance and was related to the occurrence of critical incidents.
Intestinal absorption of calcium and calcium metabolism in patients with essential hypertension and normal renal function, Several abnormalities of calcium metabolism have been described in patients with essential hypertension. and they have been linked to the pathogenesis of hypertension. Intestinal calcium absorption has been shown to be decreased in rats with spontaneous hypertension. but it has not been studied in patients with essential hypertension. In these studies we have for the first time measured intestinal absorption of calcium (using oral and intravenous administration of 47Ca). along with other parameters of calcium metabolism. in 14 patients with essential hypertension and normal renal function and in 16 normal subjects. There was no difference in serum total or ionized calcium. serum phosphorus. parathyroid hormone (PTH). 25-hydroxyvitamin D (25(OH)D). 1.25-dihydroxyvitamin D (1.25(OH)2D). and 24.25-dihydroxy-vitamin D(24.25(OH)2D) among hypertensives and normotensives. The urinary excretion of calcium. on the other hand. was greater in hypertensive than in normotensive subjects (195 +/- 33 v 107 +/- 13 mg/24 h. P less than .05). There was also no difference in intestinal absorption of calcium after 2 and 24 h among hypertensives and normotensives. When hypertensive patients were stratified according to plasma renin activity (PRA) we found that patients with low PRA had higher intestinal absorption of calcium at 2 h (23 +/- 2.9 v 18 +/- 0.6%. P less than .05) but not at 24 h. Serum total and ionized calcium. PTH. and 1.25(OH)2D were not different between patients with low and those with normal-high PRA. The major derangement of calcium metabolism in patients with essential hypertension is hypercalciuria. This abnormality is more pronounced in patients with low PRA. and it may lead to increased vitamin D-dependent intestinal absorption of calcium.
Neurohumoral and metabolic effects of short-term dietary NaCl restriction in men. Relationship to salt-sensitivity status, Published observations suggest that not everyone benefits from severe dietary NaCl restriction. since blood pressure responses appear heterogeneous and adverse metabolic effects may occur. We studied the cardiovascular. neurohumoral. and metabolic effects of 7 day periods of 20 v 200 mEq/day NaCl diets in 27 men. Twelve subjects were salt sensitive (SS). defined as mean intraarterial pressure (MAP. mm Hg) during high NaCl greater than or equal to 5% above MAP on low NaCl. Eleven subjects were salt resistant (SR). defined as MAP during the low NaCl phase greater than or equal to MAP during the high NaCl phase. The SR subset had a tendency to greater neurohumoral activity. assessed by changes in mean values for plasma norepinephrine (NE. P = .12) and plasma renin activity (PRA. P less than .001) on the low v high NaCl diet. In SR subjects the low v high NaCl diet also raised mean values for creatinine (P = .03). uric acid (P = .001). and low density cholesterol (LDL-C. P = .03). but not fasting insulin (P = .15). In SS subjects. the low v high NaCl diet did not raise NE (P = .35). although the PRA was greater (P = .002). Among SS subjects. mean values for uric acid (P = .005) and insulin (P = .02) were greater during the low v high NaCl phase. while creatinine (P = .15) and LDL-C (P = .67) were not different. The data suggest that severe. short-term NaCl restriction can be undesirable. especially in SR subjects. since potentially adverse neurohumoral and metabolic changes are not counterbalanced by the benefits of a lower MAP.
Influence of environmental temperature on the blood pressure of hypertensive patients in Montreal, To assess the influence of environmental temperature on blood pressure. we analyzed 42.813 readings of systolic and diastolic blood pressures in recumbent and upright positions in 2.000 hypertensive patients in our clinic in correlation to noon temperature and mean daily temperature in Montreal. The sample comprised 860 men and 1140 women with an average age of 55 years. Analysis of variance showed highly statistically significant negative correlations for all blood pressure values between different noon temperature. as well as mean daily temperature. groups. The greatest difference for systolic blood pressure was 7 mm Hg. and for diastolic blood pressure it was 3 mm Hg. within the -24 degrees C to 27 degrees C temperature range. The same relationship between blood pressure and different environmental temperatures was also seen when the blood pressure recordings were divided between temperature below 0 degree C and above 0 degree C. ie. within the winter or summer months. This environmental effect may have a clinically significant impact because thermosensitivity appears to be related to hypertension.
Isolated T-wave abnormalities and evaluation of left ventricular wall motion after nifedipine for severe hypertension, Rapid reduction of blood pressure by vasodilators in severe hypertensives has been associated with T-wave inversion. The significance of these changes in the absence of chest pain or other manifestations of ischemia is not known. To determine if these T-wave inversions are due to myocardial ischemia. we obtained electrocardiograms and left ventricular wall motion studies (2-D echocardiography) before and 1 h after rapid blood pressure reduction with nifedipine in 23 severe hypertensives. One hour after 10 mg nifedipine blood pressure was markedly reduced from 189 +/- 6/117 +/- 3 (mean +/- SE) to 151 +/- 5/91 +/- 3 mm Hg (P less than .001). New T-wave inversions developed in 6 of 23 (26%) subjects. but blinded evaluation of 2-D echocardiograms revealed no new wall motion abnormalities. Wall motion score. which at pretreatment was abnormal in 11 of 23 patients. improved significantly after nifedipine from 1.4 +/- 0.1 to 1.2 +/- 0.1 (P less than .05). Therefore. rapid and marked reduction of blood pressure with nifedipine is accompanied by a high incidence of asymptomatic T-wave inversions which are not accompanied by left ventricular wall motion abnormalities. suggesting that significant myocardial ischemia did not occur.
Hypoperfusion of cerebral cortex in renal hypertensive rats, Morphometric and physiological measurements in the parietal cortex of rats with 2-kidney-1-clip renal hypertension and their normotensive controls indicated a 23% increase in capillary bed volume accompanied by a 32% reduction in the rate of cortical blood flow in the renal hypertensive animals. From these measures. we estimated an 83% increase in the duration of blood transit through the cortical capillary network of renal hypertensive rats. a new expression of altered microvascular function in the brain of this hypertensive model. The rate of glucose utilization in the cerebral cortex of renal hypertensive animals was not different from that observed for normotensive animals. Thus. for capillary networks in cerebral cortex of renal hypertensive rats. we demonstrated markedly reduced rates of perfusion independent of tissue metabolic factors. despite expansion of capillary bed volume.
Parathyroid hypertensive factor, a circulating factor in animal and human hypertension, A new circulating hypertensive factor (parathyroid hypertensive factor; PHF) was shown to exist in the plasma of spontaneously hypertensive rats (SHR) but not in that of normotensive rats. PHF produced a delayed increase in blood pressure with a peak response at 45 min (bolus injection) or 60 to 90 min (continuous infusion). This increase in blood pressure was coupled with an in vitro increase in calcium uptake in rat tail artery with a similar time course. The involvement of calcium in the mechanism of action was supported by the inhibitory effect of calcium antagonists on the vascular action of PHF. Furthermore. PHF increased the intracellular free calcium concentration in cultured smooth muscle cells from rat tail artery. Parathyroidectomy and parathyroid transplant experiments indicated the parathyroid origin of PHF. A culture of parathyroid glands from SHR. but not from normotensive rats. produced in the medium a factor which has the same biological property and HPLC retention time as plasma PHF. A novel cell type was described in the parathyroid gland of SHR. but not normotensive rats. and the percent of these cells correlated significantly with plasma PHF level and blood pressure. In some hyperparathyroid patients. plasma PHF and hypertension were found. both of which disappeared after surgical removal of the parathyroid gland. In both animal models and human studies. PHF seems to be associated with low or normal plasma renin and salt-sensitive type of hypertension.
Fibrinogen Kyoto II, a new congenitally abnormal molecule, characterized by the replacement of A alpha proline-18 by leucine, A new case of heterozygous dysfibrinogenemia characterized by an amino acid replacement in the NH2-terminal region of the fibrin alpha-chain was found in a 27-year-old woman with a bleeding problem. Her one-stage prothrombin time and activated partial thromboplastin time were slightly prolonged. and the purified fibrinogen from this patient had a markedly prolonged thrombin or reptilase time. Release of fibrinopeptides A and B was normal. but the polymerization of fibrin monomers was impaired. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the purified fibrinogen under the reduced condition showed no abnormalities in the apparent molecular weights of its three chains. Reverse-phase high performance liquid chromatography (HPLC) of the lysylendopeptidase-cleaved purified A alpha-chains showed a decrease in one peptide compared with the normal amount and the appearance of an abnormal peptide peak. These peptides were treated with thrombin and further separated on HPLC. Amino acid sequence analysis of the abnormal peptide indicated that A alpha proline-18. the second residue from the NH2-terminus of the fibrin alpha-chain. was replaced by leucine. The synthetic peptide Gly-Pro-Arg-Pro inhibited both thrombin- and reptilase-induced fibrin aggregation. but Gly-Leu-Arg-Pro showed little or no inhibition under the same conditions. The discovery of this abnormal fibrinogen supports the findings that A alpha proline-18 is important as part of the polymerization site in the NH2-terminus of the fibrin alpha-chain. The propositus' mother had the same abnormal fibrinogen. This unique inherited abnormal fibrinogen was designated as fibrinogen Kyoto II.
In vitro production of granulocyte-macrophage colony-stimulating factor in aplastic anemia: possible mechanisms of action of antithymocyte globulin, Various abnormalities of lymphokine production have been described in patients with aplastic anemia. To determine if abnormal production of hematopoietic growth factors could contribute to the process of aplastic anemia we studied the in vitro production of human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) by phytohemagglutinin (PHA)- and antithymocyte globulin (ATG)-stimulated peripheral blood lymphocytes from 29 patients with aplastic anemia and 15 normal controls. GM-CSF production in response to 1% PHA was seen in nearly all samples (43 of 44) and similar amounts of GM-CSF were produced by patients with aplastic anemia and normal controls. Production of GM-CSF by ATG-stimulated lymphocytes was seen in 7 of 23 patients with aplastic anemia (30%); two of these patients also demonstrated low-level spontaneous production of GM-CSF. Production of GM-CSF in response to ATG was also seen in 2 of 11 normal controls (18%) and barely detectable spontaneous production of GM-CSF was seen in both. Biologically active IL-3 could also be detected in PHA- or ATG-stimulated peripheral blood mononuclear cells in several patients and normal controls. Our results indicate that lymphocytes from patients with aplastic anemia can be stimulated in vitro to produce normal quantities of GM-CSF. suggesting that impaired potential for production of T-cell derived hematopoietic growth factors is unlikely to account for the marrow hypoplasia seen. In several patients overproduction of GM-CSF was observed. consistent with the notion that some patients with aplastic anemia may have circulating activated T cells. We also demonstrate that ATG can stimulate the production of growth factors such as IL-3 and GM-CSF. supporting the role for ATG in stimulating hematopoiesis.
A VH clonal deficit in human immunodeficiency virus-positive individuals reflects a B-cell maturational arrest, A major feature of human immunodeficiency virus (HIV) infection is disordered B-cell function. which paradoxically includes both pathologic overactivity (elevated serum antibodies. lymphadenopathy. and increased risk for lymphoma) and underactivity (impaired antibody immunity. particularly to bacterial polysaccharide antigens). B-cell immune dysfunction contributes significantly to HIV-related morbidity and also represents an obstacle to eventual definitive treatment by anti-HIV immunization. Our laboratory has recently identified in normal B-cell populations certain VH gene subfamilies with a developmentally regulated pattern of utilization. In particular. B cells bearing rearranged VH3L were rare in the germinal center but uniformly abundant in the blood and lymphoid mantle zone. We used this index gene subfamily as a clonal criterion for the pattern of B-cell development in lymphocytes of HIV-positive individuals. In a series of 19 HIV-positive subjects. a striking deficit of VH3L B cells was observed; in contrast. none of the 16 normal subjects showed this abnormality. Other VH subfamilies (VH1N. VH4/6. and VH5N) were unaffected in the HIV-positive patients. This VH3L clonal deficit and other recent phenotype and histopathologic findings suggest that the general B-cell dysfunction in HIV is due to a discreet maturational arrest at the germinal center stage.
Expression of the c-myc proto-oncogene in multiple myeloma and chronic lymphocytic leukemia: an in situ analysis, The c-myc gene plays a pivotal role in mediating the competence state for cell cycle transversion. This biologic role is in contradiction to reports of elevated expression of the gene in multiple myeloma. a tumor with restricted self-renewal capacity. To more clearly define the role of this gene in plasma cells of myeloma patients. c-myc messenger RNA (mRNA) and/or oncoprotein expression were semiquantitatively analyzed on the single cell level in 19 cases of multiple myeloma. among them 1 biclonal case and 1 case with coexistent chronic lymphocytic leukemia (CLL). Performing anti-sense/mRNA in situ hybridization. mature c-myc gene transcripts were detected in 92% (12 of 13) of cases and could definitely be attributed to the plasma cells by our study. The number of Ki 67-positive plasma cells actively passing the cell cycle was less than 1% and independent of c-myc gene expression. However. because the presence of the 152-c-MYC epitope was correlated to extent of marrow plasmacytosis (r = .64; P = .043) and content of plasmablasts (P = .09). the c-myc gene might serve a function different from proliferative activity. but also associated with tumor cell mass. In CLL cells (21 of 22 cases) and their benign counterparts. ie. bone marrow and peripheral blood lymphocytes. the anti-sense/c-myc mRNA hybridization signals remained below the threshold considered as cutpoint between negative and positive. The low amounts of c-myc transcripts were correlated to neither stage of disease (P = .52) nor lymphocyte counts (P = .24). Because the numbers of peripheral blood lymphoma cells were independent of tumor mass and of c-myc gene transcripts expressed. peripheral blood lymphocytosis might more likely reflect homing processes than proliferative activity in CLL.
Philadelphia-negative (Ph-) chronic myeloid leukemia (CML): comparison with Ph+ CML and chronic myelomonocytic leukemia. The Groupe Francais de Cytogenetique Hematologique, To better understand the Philadelphia-negative (Ph-) chronic myeloid leukemia (CML) and its relationships with Philadelphia-positive (Ph+) CML and chronic myelomonocytic leukemia (CMML). a study was undertaken by the Groupe Francais de Cytogenetique Hematologique. Thirty-five Ph- CML patients were investigated and compared with 55 chronic phase Ph+ CML and 100 CMML patients. There were 12 M-BCR positive (M-BCR+) and 23 M-BCR negative (MBCR+) patients. No clinical or biologic differences were found between Ph+ and Ph-. M-BCR+ patients. In the Ph- group. M-BCR+ and M-BCR- patients differed significantly in age (47.7 +/- 6.6 v 67.0 +/- 6.1 years. respectively; P = .001). leukocytosis (153.4 +/- 135.1 v 58.5 +/- 37.7 10(9)/L. P = .002). relative monocytosis (1.8% +/- 1.2% v 5.6% +/- 1.4%. P = .048). absolute basophilia (8.5 +/- 9.7 v 0.9 +/- 1.5 10(9)/L. P = .001). percentage of immature myeloid precursors (IMP) in peripheral blood (29.0% +/- 9.5% v 15.3% +/- 8.1%. P = .001). and percentage of erythroblasts in bone marrow (BM) (6.5% +/- 3.5% v 14.6% +/- 3.6%. P = .001). Karyotypic abnormalities other than the Ph chromosome occurred in 0 of 12 M-BCR- at diagnosis and 7 of 23 M-BCR- Ph- CML (P = .033). None of the 13 investigated BCR- patients had detectable BCR/ABL transcripts using polymerase chain reaction (PCR) and none had an N-RAS mutation. Cytologic findings showed a marked morphologic difference between M-BCR+ and M-BCR- patients. especially in the monocytic lineage. Dysmyelopoietic features in CMML and M-BCR- patients were very similar. and the differences were of quantitative order only. Using four criteria (monocytosis. percentage of IMP. basophilia. and percentage of erythroblasts in BM). patients could be divided into typical and atypical CML and this classification correlated well with molecular findings. We conclude that. while Ph-. M-BCR+. and Ph+ CML are identical diseases. Ph-. M-BCR- CML. and CMML have many similarities and might be only different aspects of a same entity.
Effects of hydroxyurea on hemoglobin F and water content in the red blood cells of dogs and of patients with sickle cell anemia, A rationale for clinical trials of hydroxyurea (HU) treatment in sickle cell disease is that the agent increases red blood cell (RBC) fetal hemoglobin content. However. an additional effect of HU is to raise the mean corpuscular volume (MCV). To investigate the action of HU in a species that makes no electrophoretically distinguishable fetal hemoglobin. we treated dogs with the drug and compared their response to that of five patients with sickle cell anemia. Both dogs and patients had an increase in MCV. but the effect of HU treatment on the mean corpuscular hemoglobin concentration (MCHC). density. and water content of the RBCs differed in the two species. The dog RBCs became low in MCHC. high in ion and water content. and low in mean density. Thus. HU can raise MCV and lower MCHC without influencing fetal hemoglobin synthesis. A different pattern was seen in the sickle cell patients during HU treatment. Although the MCV of their RBCs increased. there was no change in MCHC. ion content. or mean density. A notable change in the sickle cell patients' blood was that two subpopulations of cells were nearly eliminated during HU treatment; the hypodense reticulocyte fraction and the hyperdense fraction that contains irreversibly sickled cells. These findings lead us to suggest that trials of HU in sickle cell disease must recognize the possibility that any beneficial effect of this agent might be due not only to an increase in hemoglobin F alone. but perhaps also to the associated increase in MCV or the altered RBC density profile.
Rapid increase in red blood cell density driven by K:Cl cotransport in a subset of sickle cell anemia reticulocytes and discocytes, We have previously demonstrated that young normal (AA) and sickle cell anemia (SS) red blood cells are capable of a volume regulatory decrease response (VRD) driven by a K:Cl cotransporter that is activated by low pH or hypotonic conditions. We now report on the characteristics of young SS cells (SS2. discocytes) capable of rapid increase in density in response to swelling. We have isolated cells with high VRD response (H-VRD) and low VRD response (L-VRD) cells by incubation and density-gradient centrifugation under hypotonic conditions. Comparison of these cells in patients homozygous for hemoglobin (Hb)S indicated that H-VRD cells have 91% more reticulocytes (P less than 9 x 10(-9) than L-VRD cells. 25% less HbF (P less than 5.5 x 10(-5). 106% more NEM (N-methylmaleimide)-stimulated K:Cl cotransport activity (P less than 2 x 10(-4). and 86% more volume-stimulated K:Cl cotransport activity (P less than 1.8 x 10(-3). H-VRD and L-VRD cells have similar G-6-PD and Na+/H+ antiport activity. In agreement with the reduced percent HbF in H-VRD cells. F cells (red blood cells that contain fetal Hb) are depleted from the H-VRD population; however. F reticulocytes are enriched in the H-VRD population to the same extent as non-F reticulocytes. which suggests that both F and non-F reticulocytes have a similar initial distribution of volume-sensitive K:Cl cotransport activity but that it may be more rapidly inactivated in F than in S reticulocytes. We find that H-VRD cells consist of 20% reticulocytes (or 79% of all reticulocytes in SS2) and 80% more mature cells. This study demonstrates the role of K:Cl cotransport in determining red blood cell density. the heterogeneity of K:Cl cotransport activity in reticulocytes. and the capacity for rapid change in the density of reticulocytes with high K:Cl cotransport activity. We speculate that the H-VRD population may be more susceptible to generation of dense and irreversibly sickled cells.
Characterization and localization of Plasmodium falciparum surface antigens on infected erythrocytes from west African patients, The malaria-induced surface antigens on Plasmodium falciparum-infected erythrocytes from West African patients were characterized by agglutination of infected cells by human sera. surface immunofluorescence of live infected cells. inhibition of cytoadherence to C32 melanoma cells by human sera. immunoelectron microscopy (immunoEM). and immunoprecipitation. In a nonimmune individual. serum antibody reactivity to surface antigens of infected cells was acquired during convalescence. as tested by all five methods. and was generally parasite isolate-specific. By contrast. adult hyperimmune West African sera reacted with many isolates. including isolates from geographically distinct regions. A quantitative correlation was established between agglutination and surface immunofluorescence assay titers. and between surface immunofluorescence assay and immunoEM reactivity. suggesting that a single antigen or a set of coexpressed antigens is being detected. Surface iodination of infected cells identified trypsin-sensitive high M. antigens in the sodium dodecyl sulfate extract. All sera tested that agglutinated infected cells also immunoprecipitated these antigens. The same surface antigens were immunoprecipitated by the homologous convalescent serum as by adult sera. By immunoEM these antigens were localized exclusively at the knob-like protrusions of infected cells. where they may participate in adherence to vascular endothelium.
Expression of a foreign gene in cats reconstituted with retroviral vector infected autologous bone marrow, A Moloney murine leukemia virus based retroviral vector was used to transfer the bacterial neomycin resistance gene (neoR) into feline hematopoietic cells. We reconstituted four cats that had been lethally irradiated with autologous bone marrow that had been infected with the N2 or SAX retroviral vector. Bone marrow cells from all four cats expressed the neoR gene 30 days posttransplant and three of four cats still had the neoR gene and a low level of drug resistant colony-forming unit granulocyte-macrophage after more than 200 days. Two of the four cats unexpectedly developed diabetes mellitus 90 days posttransplantation. The expression of a foreign gene in cats. albeit at a low level. demonstrates that retroviral vectors can be used for gene transfer in noninbred large animal species and may be useful for gene therapy of humans. The development of diabetes mellitus in two of the subjects emphasizes the value of animal models for the study of possible deleterious effects of retroviral vector-mediated gene transfer.
Asymmetrically primed selective amplification/temperature shift fluorescence polymerase chain reaction to detect the hemoglobin constant spring mutation, Hemoglobin (Hb) Constant Spring is an alpha-thalassemic hemoglobinopathy that is a major cause of severe alpha-thalassemia in Southeast Asians. The difficulty of diagnosing Hb Constant Spring using standard electrophoretic methods has led to interest in DNA-dependent diagnostic methods. The methods developed have had to contend with the high degree of homology of the alpha 2-globin gene (the site of the Hb Constant Spring mutation) and the alpha 1-globin gene. We have developed a single reaction polymerase chain reaction-based method that uses asymmetric priming and a temperature shift to accomplish dual ends. selective amplification of alpha 2 but not alpha 1 DNA and discrimination of normal and Hb Constant Spring alpha 2 genes by allele-specific fluorescence polymerase chain reaction. Advantages of this method over previous approaches include avoiding radioisotopes. precluding the need for electrophoresis. and serving as its own control for successful amplification. It is readily applicable to routine diagnosis. population screening. and prenatal diagnosis.
Effective natural interferon-alpha therapy in recombinant interferon-alpha-resistant patients with hairy cell leukemia, To explore the relationship between anti-interferon-alpha (anti-IFN-alpha) antibodies and loss of clinical responsiveness to IFN-alpha treatment. we examined sera from 59 patients with hairy cell leukemia who responded to therapy with recombinant IFN-alpha-2a (rIFN-alpha-2a). During the first 2 years of therapy. 10 patients developed rIFN-alpha-2a-neutralizing and 15 rIFN-alpha-2a-binding antibodies. Nine of the 59 initially responding patients became resistant to rIFN-alpha-2a and suffered a relapse of the disease at 7 to 24 months of treatment. All nine relapsing patients tested positive for both neutralizing and binding antibodies with titers above 400 INU/mL. while none of the antibody-negative patients relapsed. Six patients with detectable binding antibody titers below 400 INU/mL continued to respond to treatment. By measuring the IFN kinetics and the levels of the IFN-induced Mx-homologous protein in mononuclear cells after a single injection each of rIFN-alpha-2a and nIFN-alpha the IFN antibodies of eight of the nine resistant rIFN-alpha patients were found to be highly specific for rIFN-alpha-2a. Therefore. these eight patients were switched to natural IFN-alpha (nIFN-alpha) therapy at doses of 3 million IU. three times a week. All eight patients responded to treatment with nIFN-alpha. achieving durable objective responses similar to those obtained previously with rIFN-alpha-2a. These data clearly demonstrate that rIFN-alpha antibody-positive patients can effectively be treated with nIFN-alpha.
Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as a chemosensitizer, Verapamil was evaluated as a chemosensitizer for reversing multidrug resistance in multiple myeloma both in vitro and in clinical trials. Bone marrows from 59 myeloma patients in relapse were evaluated for several resistance parameters: expression of p-glycoprotein (MDR1). doxorubicin (Adriamycin) and vincristine sensitivity. and the ability of added verapamil to reduce resistance to the cytotoxic agents. We found that verapamil was capable of sensitizing myeloma cells that exhibited resistance to doxorubicin and vincristine in vitro. but did not enhance sensitivity of cells that were drug sensitive (P less than .001). Myeloma cells expressing MDR1 immunohistochemically tended to be more doxorubicin resistant in vitro than MDR1-negative cells. In the clinical trials. 22 patients with myeloma refractory to vincristine-Adriamycin-dexamethasone (VAD) were treated with VAD plus high-dose intravenous verapamil (Ve). Among the 22 patients treated with VAD/Ve. five achieved a partial remission (23%). The median relapse-free survival for the VAD/Ve responders was 5.4 months and their overall survival from the start of VAD/Ve was better than that of the nonresponders. Among the subset of 10 patients whose myeloma cells were MDR1 positive. four responded clinically (40%). whereas none of five patients with MDR1-negative myeloma cells achieved remission with VAD/Ve. We also observed that myeloma cells from three of four VAD/Ve clinical responders exhibited in vitro chemosensitization with verapamil. whereas in vitro verapamil chemosensitization was seen in only one of six clinical nonresponders. Our observations demonstrate that clinical reversal of multidrug resistance can be achieved in some patients with VAD-refractory myeloma with the use of verapamil. In addition to their value in drug development. in vitro tests of MDR1 expression and of chemosensitizers plus cytotoxic drugs on the patients' bone marrow myeloma cells may identify patients who will respond clinically to chemosensitizer-containing regimens. We anticipate that chemosensitizer regimens capable of inhibiting multidrug resistance will play an increasing role in the treatment of hematologic malignancies. including B-cell neoplasms such as multiple myeloma and the non-Hodgkin's lymphomas.
Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single-center study of 22 cases, Twenty-two children with hemophagocytic lymphohistiocytosis were treated with a chemotherapy regimen consisting of VP16-213. corticosteroids. and intrathecal methotrexate. A sustained clinical and biologic complete remission was obtained in 15 children and a partial remission in one child; six children died early of opportunistic infection (n = 4) or of disease progression (n = 2). Of the 16 children who were placed in first remission. 10 received maintenance chemotherapy alone. while six underwent bone marrow transplantation (HLA matched in five. HLA mismatched in one). Of the children who received chemotherapy alone. only two are in long-term remission after cessation of treatment. The remaining eight patients relapsed after a mean period of 5.4 months (range 2 to 8 months). Further treatment using the same regimen induced second remissions of short duration; death occurred after a median period of 2.3 months (range 0.5 to 6 months). A total of nine patients received allogeneic bone marrow transplantation (BMT). Among the six children transplanted in remission. four are in long-term unmaintained remission. 1 to 6 years after HLA-matched BMT. However. the relapse that occurred in one patient 1 year post BMT is difficult to interpret because the donor. the patient's 5-year-old sister. also developed the disease 1 year later. An HLA-nonidentical BMT resulted in unmaintained remission for 1 year. with autologous hematologic reconstitution followed by disease relapse. HLA-nonidentical BMT failed in three other patients with active disease at time of transplant. The poor long-term results of chemotherapy alone justify the use of related HLA-matched BMT in complete remission.
Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1, Murine IgM monoclonal antibody STRO-1 identifies a cell surface antigen expressed by stromal elements in human bone marrow (BM). STRO-1 binds to approximately 10% of BM mononuclear cells. greater than 95% of which are nucleated erythroid precursors. but does not react with committed progenitor cells (colony-forming unit granulocyte-macrophage [CFU-GM]. erythroid bursts [BFU-E]. and mixed colonies [CFU-Mix]). Fibroblast colony-forming cells (CFU-F) are present exclusively in the STRO-1+ population. Dual-color cell sorting using STRO-1 in combination with antibody to glycophorin A yields a population approximately 100-fold enriched in CFU-F in the STRO-1+/glycophorin A+ population. When plated under long-term BM culture (LTBMC) conditions. STRO-1+ cells generate adherent cell layers containing multiple stromal cell types. including adipocytes. smooth muscle cells. and fibroblastic elements. STRO-1+ cells isolated from LTBMC at later times retain the capacity to generate adherent layers with a cellular composition identical to that of the parent cultures. The STRO-1-selected adherent layers are able to support the generation of clonogenic cells and mature hematopoietic cells from a population of CD34+ cells highly enriched in so-called long-term culture-initiating cells. We conclude that antibody STRO-1 binds to BM stromal elements with the capacity to transfer the hematopoietic microenvironment in vitro.
Development of a novel 1,25(OH)2-vitamin D3 analog with potent ability to induce HL-60 cell differentiation without modulating calcium metabolism, We describe several novel analogs of the seco-steroid 1.25(OH)2-vitamin D3[1.25(OH)2D3] and their effects on differentiation and proliferation of HL-60 human myeloid leukemic cells in vitro as well as their effects on calcium metabolism in vivo. The 1 alpha-25(OH)2-16ene-23yne-26.27F6-vitamin D3 is the most potent analog reported to date. having about 80-fold more activity than the reference 1.25(OH)2D3 for inhibition of proliferation and induction of differentiation of HL-60 cells. Also. this analog decreased RNA expression of MYC oncogene in HL-60 by 90% at 5 x 10(-10) mol/L. Intriguingly. intestinal calcium absorption and bone calcium mobilization mediated in vivo by 1 alpha-25(OH)2-16ene-23yne-26.27F6-D3 was found to be markedly (15-fold) less than that of 1.25(OH)2D3. In addition. 1 alpha-25(OH)2D3 bound to 1.25(OH)2D3 receptors of both HL-60 and intestine more avidly than did 1 alpha-25(OH)2-16ene-23yne-26.27F6-D3. This novel analog may open up new therapeutic strategies for several hematopoietic. skin. and bone abnormalities and may provide a new tool to understand how vitamin D3 seco-steroids induce cellular differentiation.
Blunted erythropoietin production and decreased erythropoiesis in early pregnancy, After decreasing in the first trimester of pregnancy. the total red blood cell mass increases in the second and third trimesters to peak at term at about 120% to 125% of nonpregnant values. but how this is brought about by changes in the rate of erythropoiesis is not known. We evaluated erythropoiesis by measuring serum transferrin receptor (TfR) levels in 406 women during normal pregnancy (N = 317). at delivery (N = 63). or in the early postpartum (N = 27). Despite the presence of the placenta and the frequent occurrence of iron deficiency. TfR levels remained low in the first two trimesters and increased in the third trimester and at delivery. To explain why erythropoiesic activity was relatively low in early pregnancy. we also measured serum immunoreactive erythropoietin (Epo) in relation to the degree of anemia. There was a very strong correlation between serum TfR and Epo levels in the entire group (r = .59. P less than .0001) as well as in each period of pregnancy. Epo levels remained low for the degree of anemia and did not correlate with hematocrit in the first two trimesters. but recovered afterwards. In the early postpartum. Epo production and erythropoiesis were normal. We conclude that: (1) erythropoiesis is decreased in the first part of pregnancy but increases afterwards; and (2) blunted Epo production in early pregnancy could be responsible for that observation.
CD63/Pltgp40: a platelet activation antigen identical to the stage-specific, melanoma-associated antigen ME491, CD63 is a 53-Kd lysosomal membrane glycoprotein that has been identified as a platelet activation molecule. The current study presents evidence that CD63 and Pltgp40. a platelet membrane glycoprotein identified in this laboratory. are the same molecule and that CD63/Pltgp40 is identical to the well-characterized. stage-specific melanoma-associated antigen ME491. Identity of CD63 and Pltgp40 was demonstrated by immunoprecipitation and sequential immunodepletion studies. which showed that the anti-Pltgp40 monoclonal antibody (MoAb) H5C6 and an anti-CD63 MoAb CLB/Gran 12 recognized the same 40- to 55-Kd platelet glycoprotein. In addition. the anti-CD63 MoAb specifically recognized immunoaffinity-purified Pltgp40. Amino acid sequences obtained from NH2-terminal and tryptic fragment peptides of Pltgp40 were used to generate complementary DNA (cDNA) probes using the polymerase chain reaction (PCR) technique. A 386-bp cDNA probe partially encoding CD63/Pltgp40 and a full length cDNA probe were 100% identical to the corresponding sequence of ME491. Antibodies H5C6 and CLB/Gran12 immunoprecipitated a 30- to 60-Kd heterodisperse glycoprotein from G361 melanoma cells. as had previously been reported for antibodies recognizing ME491. These data. taken together with the extensive homology recently reported between ME491. the Schistosoma mansoni membrane antigen SM23. CD37. the tumor-associated antigen CO-029. and the target of an antiproliferative antibody-1. suggest that CD63 is a member of a new family of related molecules.
Establishment in culture and characterization of a strain with mast cell and monocytic properties from the bone marrow of a child with diffuse cutaneous mastocytosis, Bone marrow was isolated from a child with congenital mastocytosis. Upon prolonged in vitro culture. initially in the presence of interleukin-3 (IL-3). a population of relatively large fusiform. strongly adherent cells grew out plus a subpopulation of smaller nonadherent cells. The morphology of the adherent cells was not typical of fibroblasts. epithelial cells. nor of standard hematopoietic cell types. whereas the morphology of the nonadherent cells resembled mast cells. Neither cell type required the presence of IL-3 nor a feeder layer of fibroblasts for continued growth. Attempts to isolate the two populations were unsuccessful. This cell strain comprised of both cell populations has been termed human bone marrow-derived mastocytosis cells (HBM-M). These cells were found to possess some of the cytochemical. ultrastructural. and surface phenotypic features of degranulated mast cells. They reacted with the mast cell marker. monoclonal antibody YB5.B8. but not with the basophil specific monoclonal antibody Bsp-1 and released the inflammatory mediators histamine. leukotriene C4. prostaglandin D2. and platelet-activating factor constitutively. This release was not potentiated by immunologic- or nonimmunologic-activating stimuli. In addition. they exhibited cytochemical and surface phenotypic features of monocytes. Our results indicate that a population of abnormal proliferative cells exist in the marrow of this patient; that these cells may be responsible for the patient's pronounced systemic proliferation of mast cells and the associated symptoms; and that the cell's mast cell. monocyte properties may be indicative of a common bone marrow-derived mast cell/monocyte precursor.
Characterization of a receptor for interleukin-5 on human eosinophils and the myeloid leukemia line HL-60, Interleukin-5 (IL-5) promotes the growth and differentiation of human eosinophils and may regulate the selective eosinophilia and eosinophil activation seen in certain diseases. Radiolabeled recombinant human IL-5 (hIL-5) was used to characterize the IL-5 receptor present on normal human eosinophils and on the myeloid leukemia line HL-60. which can be induced to differentiate into eosinophilic cells. Binding studies with eosinophils and HL-60 cells grown under alkaline conditions demonstrated similar high-affinity binding sites for hIL-5 on both cell types with kd values of approximately 400 pmol/L. The binding observed was specific in that it was not inhibited by hIL-3. human granulocyte-macrophage colony-stimulating factor. or hIL-2. Binding studies with a number of other human cell lines. including a B-lymphoma line. and with lymphocyte and neutrophil preparations were also performed. but IL-5 receptors were not detectable on these cells. The number of hIL-5 receptors on HL-60 cells could be correlated with its propensity to differentiate towards an eosinophilic cell type. Expression of hIL-5 receptors on HL-60 cells was upregulated by butyric acid under alkaline conditions. downregulated by hIL-3. virtually eliminated by dimethyl sulfoxide and hIL-5. while hIL-2 had no detectable effect. One major 125I-hIL-5-crosslinked complex of 75 to 85 Kd in Mr was detected on HL-60 cells using crosslinking agents giving a molecular mass of 55 to 60 Kd for the hIL-5 receptor itself. Studies using cellular autoradiography showed that IL-5 receptors were evenly distributed on eosinophils but that receptor distribution on HL-60 cells was noticeably heterogeneous. Eosinophils were the only cells in slides prepared from peripheral blood that had detectable levels of IL-5 receptors in agreement with the specific action of IL-5 on the human eosinophil lineage.
Antiproliferative and differentiative effects of recombinant interleukin-4 on a granulocyte colony-stimulating factor-dependent myeloblastic leukemic cell line, The effect of recombinant human interleukin-4 (IL-4) on a granulocyte colony-stimulating factor (G-CSF)-dependent human myeloblastic leukemic cell line. OCI-AML1a. was investigated. IL-4 suppressed the clonogenic cell growth in methylcellulose culture. inhibited the uptake of 3H thymidine in a dose-dependent manner at 5 to 100 U/mL. and consequently suppressed the growth of clonogenic cells in short- and long-term suspension cultures. In addition. IL-4 markedly increased the number of adherent cells. These adherent cells were alpha-naphthyl-butyrate (alpha-NB) esterase-positive and showed macrophage-like appearance. increased expression of CD14. CD11b. CD23. and Ia. and significantly decreased clonogenicity. On the other hand. nonadherent cells growing in suspension showed only slight increase in proportion of alpha-NB esterase-positive or monocyte/macrophage-like cells and increased CD23 expression by an addition of IL-4. The clonogenicity of the nonadherent cells was not significantly influenced by IL-4. By addition of the media conditioned by OCI-AML1a cells in the presence of IL-4. the clonogenic cells growth of OCIAML1a cells was suppressed and adherent cells were markedly increased. The suppressive and differentiative effects on OCI/AML1a cells of the conditioned media and IL-4 itself were almost completely abolished by anti-IL-4 antibody. Furthermore. the neutralizing antibodies against transforming growth factor-beta 2 (TGF-beta 2). tumor necrosis factor-alpha (TNF-alpha). or IL-6 did not influence the effect of recombinant IL-4. Taken together. IL-4 was shown to suppress the growth and induce differentiation toward adherent macrophage-like cells of the G-CSF-dependent myeloblastic cell line. The effect of IL-4 may be direct. and not secondary via inducing production of other cytokines such as TGF-beta. TNF-alpha. or IL-6 by leukemic cells.
Expression of 5'-nucleotidase (CD73) related to other differentiation antigens in leukemias of B-cell lineage, Ecto-5'nucleotidase (5'NT; CD73) expression was studied with a monoclonal antibody (7G2) and a radiochemical assay and compared with the expression of other antigens in B-cell-lineage leukemias on cells from 100 leukemic patients and two cell lines. A B-cell origin was confirmed by the expression of CD19 and HLA-DR. Four stages of B-cell leukemias were defined: stage I (pro-B) as CD10-. cytoplasmic mu- (c mu-). surface Ig- (sIg-); stage II (cALL) as CD10+/c mu-/sIg-; stage III (pre-B) as CD10+ or -/c mu+/sIg-; and stage IV (B) as CD10-/c mu-/sIg+. A linear correlation was found between immunohistochemical and radiochemical determination of 5'NT (r = .86). 5'NT expression was low in T-cell leukemias and stage I. high in stages II and III. and low again in stage IV of B-cell leukemias. 5'NT expression was not related to c mu. CD20. CD21. CD22. CD34. and terminal deoxynucleotidyl transferase (TdT) expression. but was significantly related to CD10 and inversely related to kappa/lambda expression. However. the 5'NT activity in CD10+ leukemias (stages II and III) shows a very wide range. Within the group of CD10+ leukemias no differences were detected between 5'NT+ and 5'NT- cells in their expression of other B-cell antigens. We conclude that the place of 5'NT in leukemias corresponding to early stages of B-cell development has been characterized. 5'NT is expressed in CD10+ stages and decreases before the expression of sIgs. Future studies should make clear whether a high expression of this enzyme in CD10+ stages is a normal maturation phenomenon or a malignant phenomenon.
Peritoneal fluid and plasma levels of human macrophage colony-stimulating factor in relation to peritoneal fluid macrophage content, The peritoneal fluid (PF) of women with infertility (especially in the presence of endometriosis) contains increased numbers of leukocytes. 90% to 95% of which are macrophages. The high numbers of peritoneal macrophages presumably result from an influx of blood monocytes into the peritoneum. and/or from local proliferation of peritoneal macrophages. Once in the peritoneal cavity. monocytes differentiate into tissue macrophages. Mononuclear phagocyte proliferation and differentiation are influenced by different cytokines. including macrophage colony-stimulating factor (M-CSF). The purpose of this study was to determine the relationship of M-CSF levels in human PF and plasma to the macrophage content. and to the patient diagnoses. Mean concentrations of PF M-CSF were higher than plasma levels (2.44 +/- 0.13 v 0.95 +/- 0.06 ng/mL. respectively). The mean concentrations of plasma M-CSF did not differ in samples from women of different diagnostic groups (normal. peritoneal adhesions. endometriosis. inactive pelvic inflammatory disease. uterine fibroids. and idiopathic infertility). but the PF concentration was slightly higher in normal women. The absolute (total) amount of PF M-CSF in normal women was lower than in those of the other diagnostic groups. The total amount of PF M-CSF in all women correlated closely with the total number of peritoneal macrophages. The tubal patency status (open versus closed) did not influence the plasma and PF concentrations of M-CSF. nor the PF absolute amount of M-CSF. The PF M-CSF may have come from peritoneal macrophages. fibroblasts. mesothelial cells. or endothelial cells. PF M-CSF may play important roles in the proliferation and/or the differentiation of peritoneal mononuclear phagocytes.
An insertional frameshift mutation of the beta-spectrin gene associated with elliptocytosis in spectrin nice (beta 220/216), Spectrin Nice (beta 220/216) is a spectrin variant associated with a shortened beta chain found in a patient with elliptocytosis. The shortened beta chain (beta' chain) appeared as an additional band of approximately 216 Kd on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was defective in its ability to be phosphorylated. There were increased amounts of spectrin dimers in crude spectrin extracts from the propositus and the association constant of spectrin dimer self-association was decreased. There was an associated increase of the alpha I 74-Kd fragment from the alpha chain after partial trypic digestion of spectrin. To identify the underlying molecular defect. we analyzed cDNA for beta spectrin obtained by polymerase chain reaction amplification of reverse-transcribed reticulocyte messenger RNA from peripheral blood of the propositus. DNA sequencing of individual as well as pooled subclones showed that two extra bases (GA) are inserted in codon no. 2046 in one allele of the beta-spectrin gene. The insertion results in a frameshift mutation and generates an aberrant C-terminus truncated by about 4 Kd. consistent with the estimated size of the beta' chain observed. By allele-specific oligonucleotide hybridization. the insertion was shown to be present in the propositus and absent in his parents. confirming a previous proposal that it is a de novo mutation. The determination of the location of the mutation in spectrin Nice points to specific regions of the beta-spectrin chain where phosphorylation may occur. A model is proposed to describe the interaction between the alpha- and beta-spectrin chains and to explain the effects of the mutation found in spectrin Nice on the trypsin digestion pattern of its associated alpha chain.
Congenital heart disease in Down's syndrome: two year prospective early screening study, OBJECTIVE--To determine the effectiveness of clinical examination. chest radiography. and electrocardiography compared with echocardiography in detecting congenital heart disease early in the life of children with Down's syndrome. DESIGN--Prospective two year screening survey. SETTING--Regional paediatric cardiology service. Northern Ireland. PATIENTS--81 newborn infants with Down's syndrome born in Northern Ireland between November 1987 and November 1989. INTERVENTIONS--Clinical examination. chest radiography. and electrocardiography soon after birth followed by cross sectional Doppler echocardiography. MAIN OUTCOME MEASURES--Diagnostic ability of clinical examination. radiography. and electrocardiography compared with echocardiographic findings. RESULTS--34 babies had congenital heart disease detected by echocardiography (13 had atrioventricular septal defects. seven secundum atrial septal defects. six a solitary patent ductus arteriosus. five isolated ventricular septal defects. and three combinations of heart defects). Individual examination methods were insensitive (the sensitivity of clinical examination was 0.53. of radiography 0.44. and of electrocardiography 0.41) but highly specific (the specificity of clinical examination was 0.94. of radiography 0.98. and of electrocardiography 1.0). although sensitivity improved when the three techniques were combined (the sensitivity was 0.71. the specificity 0.91). CONCLUSION--Echocardiography performed early in life can detect congenital heart disease that might otherwise be missed. Early detection may help prevent complications such as pulmonary vascular disease that may adversely affect the outcome of cardiac surgery.
Rifampicin prophylaxis for throat carriage of Haemophilus influenzae type b in patients with invasive disease and their contacts, OBJECTIVE--To determine rates of colonisation with Haemophilus influenzae type b among household contacts of children with invasive H influenzae type b disease; compliance among medical staff with recommendations for use of rifampicin prophylaxis; and effects of rifampicin treatment in H influenzae type b colonisation of patients and contacts. DESIGN--Prospective study of patients and their household contacts. SETTING--Royal Children's Hospital (the major paediatric hospital) in Victoria. Australia. with catchment population of 4.2 million. including 300.000 children aged under 5 years. SUBJECTS--234 patients (age range 6 weeks to 8 years) with 235 episodes of all types of invasive H influenzae type b disease admitted during 1988-9 and their contacts. MAIN OUTCOME MEASURES--Positive cultures of H influenzae type b from throat swabs taken at admission and six weeks subsequently; recording of rifampicin prophylaxis. RESULTS--The percentage of patients with positive throat cultures fell from 69% (33/48) on day 1 of admission to 9% (4/47) after three days' treatment; at six weeks' follow up 32% (32/99) of patients who had not received rifampicin and 8% (5/61) who had. had positive throat cultures. Among household contacts. 33% (62/190) of children and 7% (25/359) of adults were colonised. and the colonisation rates were similar in contacts of patients with all types of H influenzae type b disease. Rifampicin prophylaxis was indicated in 85 families; in 34% it was not prescribed at all for contacts and in 41% not as recommended. The colonisation rates at follow up were significantly less in siblings given rifampicin (12%. 9/78). particularly in families in which all members were treated (3%). than in those in which they were not (36%) (odds ratio 21.5; 95% confidence interval 3.0 to 103.4). CONCLUSIONS--The rate of throat colonisation with H influenzae type b was similar among siblings of children with all types of invasive H influenzae type b disease. Colonisation in contacts can be reduced by rifampicin prophylaxis. but some contacts remained colonised or were recolonised by the time of follow up. Medical staff complied poorly with current recommendations for rifampicin prophylaxis. which reduces its intrinsically limited value in preventing H influenzae type b disease.
Audit of outpatients: entering the loop, OBJECTIVE--To develop and test a method for routine data collection to observe current practice in outpatient pain clinics. DESIGN--Prospective questionnaire survey completed by consultants on each patient seen during October 1989 to May 1990. SETTING--Outpatient pain clinics of five teaching and five district general hospitals in Scotland and northern England. MAIN OUTCOME MEASURES--Number of new referrals and their source. and characteristics of pain at presentation. RESULTS--4354 forms were completed by 21 consultants over 29 weeks. corresponding to 2241 patients. of whom 981 were new referrals. The proportion of consultations at which new referrals were seen varied among the 10 clinics from 15% to 34%. The difference could not be accounted for by type of hospital. Sources of new referrals varied widely between the clinics (for example. range 22% to 78% for general practitioner referrals). as did new referrals by the type of pain (range 10.8% to 55.2% for low back pain. 10.5% to 32.5% for pain associated with surgery). However. these differences in types of patients seen could not be accounted for by variations in referral patterns among clinics. Problems identified in performing an audit of outpatients included the difficulty of obtaining firm diagnoses. the need for a method to link successive patient contacts. and the complexity of the presenting problem in many patients. CONCLUSIONS--It is possible to collect data for audit routinely in outpatient clinics. Observation of current practice in the clinics suggested possible unmet need or inappropriate management. which may require changes in practice.
Quickscan: Doppler ultrasound emulation of angiography--its value prior to arteriography in peripheral vascular disease, The prevalence of peripheral vascular disease demands a quick. reliable. non-invasive technique for initial assessment. We have devised a new method which combines the two physical principles that (1) Doppler shift is proportional to blood velocity and (2) blood velocity is inversely proportional to arterial cross-section with the ability to track probe position using a non-contacting method. An image of the probe track and any arterial narrowing is shown superimposed on an outline of the patient. Pressure measurement. scan and graphics with final report take about 20 minutes. The accuracy of this system in peripheral vascular disease was evaluated. Thirty-one patients underwent quickscan (QS) and arteriography within an average time of 7 days. Abdominal aorta. common iliac-common femoral. superficial femoral and popliteal artery segments were graded independently as normal. significant stenosis (greater than 50% of diameter) or occluded by both techniques. Of 197 segments. QS correctly assessed 106 normal. 22 stenosed and 28 occluded segments. Four equivocal angiographic stenoses were normal on QS and three severe stenoses were graded occlusion. Fifteen segments on angiography and five on QS were not assessed. For the iliac and superficial femoral artery segments. sensitivity and specificity averaged 77% and 86%. respectively. for all grades. Aortic statistics were invalid (only one significant lesion). Six out of eight popliteal occlusions were correctly diagnosed by QS. but no popliteal stenoses were detected out of six shown on arteriography. Low numbers may contribute to this discrepancy but an improved popliteal scanning method may be necessary. We find initial QS an invaluable aid to direct percutaneous angiography and to indicate potential sites for angioplasty.
Duplex sonography in splenomegaly, The aetiology of splenomegaly is seldom clear from either clinical or imaging assessment of the spleen. In the majority of cases sonographic assessment of the spleen produces a homogeneous enlargement of variable echodensity. but with very poor correlation with pathology. A study has been undertaken to assess the Doppler characteristics of the splenic artery in splenomegaly. excluding cases of portal hypertension in an attempt to provide further diagnostic information. Duplex assessment of 18 normal subjects and 10 patients with splenomegaly due to five different causes was undertaken. Analysis of waveform. peak frequency and pulsatility index were compared and failed to demonstrate any significant change. In the normal subject there is a broad systolic spectrum related to the tortuosity of the splenic artery. with persistence of forward flow throughout diastole. a reflection of the low peripheral resistance of the spleen. In splenomegaly the broad systolic spectrum is unchanged. since vessel tortuosity persists. Pathological and physiological assessment of the spleen in splenomegaly shows that a low resistance circulation persists. explaining maintenance of the diastolic flow pattern in splenomegaly. Increased blood flow to the spleen in splenomegaly occurs either as a result of an increase in vessel diameter or an increase in flow velocity. or a variable combination of the two which does not seem to be governed by specific pathology. An increase in peak frequency in some cases reflected some increase in flow velocity but provided no useful correlation. Analysis of the pulsatility index supported the above findings without adding further information.
Automated measurement of tumour extent in patients with colorectal liver metastases from X-ray computed tomography, Tumour burden is a significant prognostic factor in patients with colorectal liver metastases. and can be staged according to percentage hepatic replacement (PHR). but accurate measurements of PHR are difficult to obtain. We have used an automated computerized technique to isolate tumour and measure PHR from computed tomography images of 22 patients. Tumour identification was achieved by establishing local histogram-based thresholds at liver-tumour boundaries displaying clear bimodal histogram distributions. There was a significant association between measured PHR and independent visual estimates of PHR stage defined in quartiles (p less than 0.001). When the measured value of PHR differed from the PHR stage. the visual estimate was always higher. The accuracy of PHR measurement was assessed on stimulated liver computed tomography images. It seems likely that visual estimates of PHR from computed tomography images tend to overestimate tumour extent. The automated technique is probably more accurate and will be useful for assessing and monitoring patients.
Quantitative magnetic resonance imaging in cervical carcinoma: a report on 30 cases, T1 and T2 relaxation times were calculated. before radiation therapy. in 30 patients with cervical carcinoma. Eight healthy young women were submitted to magnetic resonance imaging (MRI) to determine T1 and T2 times of the normal cervix. Magnetic resonance imaging was repeated. in 22 patients. during radiation therapy and at follow-up. During treatment and follow-up. patients with complete tumour response showed a significant T1 reduction compared with the pre-treatment values. With persistence of palpable or visible tumour. T1 times showed a small decrease during therapy. and a marked increase at subsequent examinations. The results suggest that the modifications of T1 times. during radiation therapy and follow-up. could be considered as a useful discriminant between patients with differing tumour response.
Assessment of the psychological impact of a breast screening programme, In order to assess the psychological effect of mammographic screening. questionnaires (which included psychometric tests) were sent to 750 women at invitation and. 6 weeks after screening. to 420 women normal after the first mammograph. to 240 women normal after special assessment. and to 68 women normal after open biopsy. Increasing degree of the investigation was associated both with increasing frequency of breast self examination (10% were practising breast self-examination at least once a week before screening compared with 24% for women after special assessment and 35% of women who had had an open biopsy (p less than 0.001)). and with greater confidence that any malignancy in the breast would have been found. Psychometric scores showed no increase of general levels of anxiety or depression in the screened groups. For anxiety. percentages abnormal were 5. 4. 2 and 6 for the four groups. respectively. and for depression the percentages abnormal were 5. 4. 4 and 6. respectively; 10% of screened women were more anxious about having breast cancer as a result of the screening. At least 10% of women proceeding to open biopsy of benign lesions require professional counselling and support. Psychological ill effects were not detected by the psychometric test among women who did not proceed to this final investigation. Behavioural changes did suggest a raised awareness or fear of potential cancer among the screened population.
Stage distribution of breast cancer: a basis for the evaluation of breast screening programmes, Stage at presentation can be predictive of future mortality rates. A change in stage distribution will be indicative of the effect of a programme. All registrations for 1985 aged over 50 years were staged from case notes and. to assess whether a stage drift is already occurring. cases that presented in 1975 were also staged. The accuracy and completeness of the Wessex Cancer Register for this particular cancer was assessed and further sources of registration identified. There was a significant difference between 1975 and 1985 stage distributions. If the Southampton and Salisbury service achieves the same success as the Gavleborg County trials. 4.61 deaths will be prevented at 5 years for each annual cohort of cases. For individual breast screening programmes. effectiveness is better monitored by analysis of stage distribution than of mortality rates.
Ovarian ablation failures by radiation: a comparison of two dose schedules, Sixty Chinese breast cancer patients underwent ovarian irradiation with one of two dose schedules: 12 Gy/4 fractions/4-6 days or 14 Gy/4 fractions/4-6 days. The ovarian ablation failure rates were 14% and 0% respectively in patients above 40 years of age. The overall ablation failure rate in younger patients was unacceptably high at 35%. The significance of the findings is discussed.
Characterisation of inflammatory cells associated with "idiopathic retroperitoneal fibrosis", During ureterolysis in a patient with "idiopathic retroperitoneal fibrosis". fresh samples of peri-ureteric and peri-aortic tissue were obtained. An abdominal CT scan confirmed the peri-aortic distribution of the inflammation associated with advanced abdominal aortic atherosclerosis. Histology confirmed the presence of fibrosis and a variable chronic inflammatory cell infiltrate. Monoclonal antibodies were used to identify the inflammatory cells. B and T lymphocytes were present with the majority of T lymphocytes of the T helper phenotype. The majority of lymphocytes and macrophages and most vascular endothelial cells were HLA-DR positive. Ki67 and BerH2 staining was found in B cells and T helper cells. indicating that these cells were proliferating and activated. These findings compare with the characterisation of inflammatory cells associated with "inflammatory aneurysms" and with the inflammatory cells present in the spectrum of inflammation seen as a complication of advanced atherosclerosis--conditions known as "chronic peri-aortitis". It is suggested that our findings support the view that idiopathic retroperitoneal fibrosis represents clinical chronic peri-aortitis seen in an undilated aorta.
Value of the patient's case history in diagnosing urinary incontinence in general practice, What is the value of the case history in diagnosing urinary incontinence in general practice? A total of 103 women with urinary incontinence presented to their general practitioner (GP) and underwent a standard history-taking. physical examination and urodynamic testing. The urodynamic diagnoses were analysed against symptoms and symptom complexes. Symptoms of stress incontinence in the absence of symptoms of urge incontinence had a sensitivity of 78%. specificity of 84% and predictive value of 87%. Symptoms of urge incontinence in the absence of symptoms of stress incontinence excluded genuine stress incontinence. Information on age. parity. enuresis. nocturia. frequency. urgency. cystocele. prolapse and hysterectomy did not contribute to a correct diagnosis. It was concluded that urodynamics are unnecessary in most women presenting with urinary incontinence in general practice.
Urethral pressure and power generation during coughing and voluntary contraction of the pelvic floor in healthy females, A probe which permits continuous measurement of the related values of pressure and cross-sectional area in the female urethra was used to provide a quantitative description of the adjunctive occlusive forces in terms of pressure and power (mWatt) generation. Measurements were carried out at the bladder neck. midurethrally and distally in the urethra in 30 healthy women during coughing and squeezing. Statistically significant variations were found in pressure and power generation between the 3 sites of measurement both during coughing and squeezing. Power generation and the pressure increase were significantly greater during coughing than during squeezing along the entire length of the urethra. The presence of a dynamic active closure mechanism was demonstrated at the bladder neck in addition to that located midurethrally. This bladder neck mechanism is thought to be due to the vagino-levator sling system (the urethral supports).
Assessment of the long-term results of subtrigonal phenolisation, Long-term follow-up was conducted on 97 patients who had undergone subtrigonal phenolisation for detrusor instability. bladder hypersensitivity. detrusor hyper-reflexia or interstitial cystitis. The procedure failed to alleviate lower urinary tract dysfunction in 57% of patients; it had an unsustained benefit in 24% and long-term success was experienced by only 19%. It was most effective in the hypersensitive bladder of unknown cause. The incidence of complications (17%) suggests that the procedure should only be undertaken if more invasive measures are the only available alternative. and the possibility of these complications should be explained to the patient.
Clinical experience with subcutaneous urinary diversion: new approach using a double pigtail stent, Short-term results in 8 patients with ureteric obstruction and hydronephrosis who underwent subcutaneous urinary diversion show this procedure to be a simple and useful method of urinary diversion for uraemic cancer patients. This method has the additional advantage of avoiding the complications and social implications of other methods of palliative treatment.
Prostatic specific antigen related to clinical status 1 to 14 years after radical retropubic prostatectomy, Serum prostatic specific antigen (PSA by Tandem-R immunoassay) was measured in 190 patients after radical prostatectomy for prostate cancer. Serial measurements were made in all patients operated on in the past 3 years; 131 had undetectable levels and 59 had levels in the detectable range. Only 10% of the patients with undetectable PSA following surgery had seminal vesical involvement or positive lymph nodes. None of the patients with undetectable PSA have had clinical recurrence within the 41 months of mean follow-up. In 14 patients who had PSA serially measured since surgery. detectable levels were found within 6 months of operation and 7 of these patients had clinical progression within 2 years; 39 patients had detectable PSA after radical prostatectomy with no clinical evidence of recurrence. Biopsy of the anastomosis was performed in 11 patients with isolated detectable PSA after surgery and local recurrence was established in 4. PSA was detectable later in the follow-up of 45 patients operated on before the PSA assay became available but the date when PSA actually became detectable is not known. A relatively new method of estimating that date and constructing a corresponding Kaplan Meier curve is presented. PSA is an effective marker for monitoring patients after radical prostatectomy as it often detects early persistent disease in patients with detectable measurements 6 months post-operatively or recurrent disease in patients with later rising levels.
Experience with penile fractures in Saudi Arabia, Seven patients with penile rupture were treated surgically within a 9-month period. All were operated on as emergencies. with successful results. except in 1 case which was associated with urethral rupture. Sexual performance was satisfactory in 6 of 7 cases.
Influence of local recurrence on survival: a controversy reviewed from the perspective of soft tissue sarcoma, The relationship between local recurrence and survival has been examined using the example of soft tissue sarcomas of the extremities. Studies that appear to indicate that local recurrence does not jeopardize survival are shown to have been inappropriately analysed. to have inadequate patient numbers. or both. A survival deficit due to local tumour recurrence cannot be excluded on present data. and clinical decisions regarding conservative versus radical surgery will therefore continue to involve an element of value judgement.
Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil, Ischaemia is a common clinical event leading to local and remote injury. Evidence indicates that tissue damage is largely caused by activated neutrophils which accumulate when the tissue is reperfused. If the area of ischaemic tissue is large. neutrophils also sequester in the lungs. inducing non-cardiogenic pulmonary oedema. Ischaemia reperfusion injury is initiated by production of reactive oxygen species which initially appear responsible for the generation of chemotactic activity for neutrophils. Later. once adherent to endothelium. neutrophils mediate damage by secretion of additional reactive oxygen species as well as proteolytic enzymes. in particular elastase. Therapeutic options for limiting ischaemia reperfusion injury include inhibition of oxygen radical formation. pharmacological prevention of neutrophil activation and chemotaxis. and also the use of monoclonal antibodies which prevent neutrophil-endothelial adhesion. a prerequisite for injury.
Endothelial cell seeding, Endothelial cell seeding is a technique that has developed over the past 15 years in response to the need for a high performance synthetic vascular graft. This review details our present knowledge of seeding and examines the various problems that have hampered its introduction into clinical practice.
Intraoperative localization of colorectal cancers using radiolabelled monoclonal antibodies, Radiation detectors may allow the intraoperative localization of small cancer deposits following administration of radiolabelled tumour-associated antibodies. This technique was evaluated in 16 patients with colorectal tumours (14 cancers. one adenoma. one lipoma) with the 111In-labelled monoclonal antibody (MAb) ICR2 which recognizes the tumour-associated epithelial membrane antigen (EMA). At operation counting was carried out (3 x 20 s per site) using a hand-held radiation probe over the primary lesions and any palpable lymph nodes in the mesocolon. The tumour to normal colon (T/NC) ratio of counts recorded at operation was more than 1.5:1 in eight of the 14 patients with cancer (mean(s.d.). 1.54(0.41):1) and 0.91:1 and 1.06:1 respectively in the two patients with benign tumours. Node to normal colon ratios were higher in lymph nodes containing metastases. The uptake of radiolabelled antibody (T/NC ratio) was higher in EMA-expressing cancers than in those not expressing the target antigen (mean(s.d.). 2.45(0.65):1 versus 1.40(0.20):1. P = 0.019). An abdominal tumour model was also developed. Radioactively filled containers of 0.5-10 ml representing tumour deposits were suspended in a tank of 111In solution representing the background activity found in normal tissues. The ratio of radioactivity in the 'tumour' to that of background varied from 2:1 to 8:1. The 'tumour' was considered to be detectable if the mean counts recorded over the 'tumour' exceeded the mean of counts recorded over background by three standard deviations. At a ratio of 2:1 only 'tumours' greater than 5 ml could be detected with a sodium iodide probe and those over 10 ml could be detected with a cadmium telluride (CdTe) probe. At a ratio of 8:1. 'tumours' of 0.5 ml could be detected with either probe. At all ratios and counting periods the NaI probe was more sensitive than the CdTe.
Suture technique affects perianastomotic colonic crypt cell production and tumour formation, Suture line recurrence is an important cause of failure after potentially curative resection for colonic carcinoma. Our aim was to determine whether suture technique affected the incidence of perianastomotic tumours in experimentally induced colonic cancer. Sprague-Dawley rats were randomized into three groups. A 1 cm longitudinal colotomy was repaired with four interrupted 6/0 polypropylene monofilament sutures. using either a transmural technique (n = 18) or a seromuscular technique (n = 18). Control animals (n = 18) had a sham laparotomy. All animals received nine. weekly. subcutaneous injections of azoxymethane (total dose 90 mg/kg) starting 6 weeks after laparotomy. Surviving animals were killed 32 weeks after laparotomy. Five animals from each group were given intraperitoneal bromodeoxyuridine (100 mg/kg) 1 h before being killed. At death. perianastomotic tumours occurred more frequently in animals with transmural sutures than in either controls or those with seromuscular sutures. This difference was associated with a greater mucosal bromodeoxyuridine crypt cell labelling index in the transmural suture group. We conclude that a transmural anastomotic suture technique promotes the development of experimental perianastomotic colonic tumours.
Anismus in patients with normal and slow transit constipation, This study examined differences in anorectal function. with particular reference to anismus. which might explain why some patients with intractable constipation have slow and others have normal whole gut transit times. Twenty-four patients were studied; 13 with slow transit (all female. median age 32 years. range 16-52 years) and 11 with normal transit (eight women. three men. median age 37 years. range 21-60 years). Videoproctography with synchronous sphincteric electromyography and anorectal manometry was performed. There were no differences between the two groups. suggesting that slow transit constipation is not secondary to any abnormality in anorectal function and may therefore be a primary disorder of colonic motility. There was no correlation between electromyographic evidence of anismus (pelvic floor contraction on defaecation) and the ability of the patient to evacute the rectum or symptoms of obstructed defaecation. Electromyography findings alone can be misleading and should be related to proctographic evidence of incomplete rectal evacuation before functional anismus can be said to be present.
Evaluation of diagnostic peritoneal lavage in suspected penetrating abdominal stab wounds using a dipstick technique, The total protein content (g/l) and white blood cell count (cells/mm3) diagnostic peritoneal lavage was assessed using a urine dipstick in 46 patients with suspected penetrating abdominal stab wounds and equivocal physical examination. Those patients with a protein content greater than or equal to 1 g/l and white blood cell count of greater than 500 cells/mm3 were submitted to laparotomy while those with lower values underwent observation and repeat physical examination. In all. 26 patients had a positive lavage and significant injuries were found in 23 of these. Of 18 patients with a negative lavage. 17 were managed successfully without operation while one patient died from complications related to central venous catheterization. In two patients the lavage results were equivocal. One underwent a negative laparotomy and the remaining patient recovered uneventfully. The test has a 100 per cent sensitivity and 86 per cent specificity and provides an accurate. cheap. and rapid means of diagnosis of intra-abdominal injury in penetrating trauma.
Autologous transfusion: an alternative to transfusion with banked blood during surgery for cancer, Autologous blood transfusion in surgery for cancer has been avoided because of the metastatic potential of reinfused malignant cells. This study determined whether viable tumour cells remain in the red cell concentrate after separation and whether blood transfusion filters remove these tumour cells before reinfusion. Units of banked blood were inoculated with tumour cell lines: breast cancer SKBr3; colon cancer COLO 320; lymphoma Daudi; erythroleukaemia K562. After processing with the Cell Saver. aliquots of the red cell concentrate and waste saline wash were examined for tumour cells and cultured. Tumour cells from all four cell lines were identified in the red cell concentrate but not in the waste saline wash. All the cell lines except Daudi grew from the red cell concentrate. Experiments on two of the cell lines (SKBr3 and COLO 320) were performed in which the red cell concentrate was either unfiltered (control) or filtered with SQ40S blood transfusion filter or RC100 leucocyte depletion filter. Both cell lines were present in the control samples and after filtration with SQ40S filters. and cells from these samples grew normally in culture. No tumour cells were evident after filtration with the RC100 filters and no growth of either cell line was found after 1 week in culture. The Cell Saver in combination with RC100 filters may be suitable for use during the surgical treatment of malignant disease.
Paget's disease of the nipple, A total of 48 women with Paget's disease of the nipple (nipple eczema containing Paget cells but without a palpable lump) presented to one surgeon over a 13-year period. Temporary healing of the nipple eczema occurred in six patients. In all. 21 of 34 patients with in situ (DCIS) or invasive ductal carcinoma had mammographic abnormalities. Treatment was by simple mastectomy (37 cases). cone excision of the nipple-areola complex (ten cases) and tamoxifen (one case). DCIS was found in 45 operative specimens (96 per cent); eight had associated invasion. The DCIS was predominantly large cell solid/comedo in type and was multifocal in seven cases (19 per cent). At a median (range) follow-up of 56 (18-96) months. four of the ten patients treated by cone excision have developed a local recurrence. two of these patients have also developed metastases. Two of the 37 patients who underwent mastectomy developed loco-regional recurrences; both had invasive foci at their first operation and remain disease free at 8 years. We no longer feel that cone excision is appropriate treatment.
Comparison of adverse reactions to whole-virion and split-virion influenza vaccines in hospital personnel, OBJECTIVE: To compare the adverse effects. particularly generalized aching. of a trivalent. inactivated whole-virion vaccine (WVV) and split-virion vaccine (SVV) for influenza in hospital personnel. DESIGN: Recipient-blinded study; first-time vaccinees were randomly assigned to receive either of the vaccines from one manufacturer in the 1989-90 influenza season. Subjects were asked to complete a symptom questionnaire during the 48 hours after immunization. SETTING: Annual influenza program for staff of a tertiary care children's hospital. PARTICIPANTS: Volunteers were sought among approximately 2200 members of the hospital staff. Of the 358 vaccinated for the first time. 333 (93%) returned the questionnaire. RESULTS: During the 48 hours after vaccination 13% of the SVV recipients reported generalized aching. as compared with 26% of the WVV recipients (p less than 0.01). Also. the SVV group reported fewer visible local reactions and more transient arm soreness. but the actual differences between the two groups were small. The occurrence of mild symptoms was equally common in the two groups (local reactions in at least 70% of cases. systemic reactions in at least 33%). In each group 1% of the subjects reported missing work because of the vaccination. CONCLUSIONS: The use of SVV reduces the rate of the most objectionable of the common adverse effects of influenza vaccination. Therefore. as with children. it might be more acceptable to health care workers than the current use of WVV.
Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin. Evidence of major therapeutic activity in the anaplastic variants of these neoplasms, Forty-five patients with metastatic neuroendocrine tumors were treated with a regimen of etoposide 130 mg/m2/d for 3 days plus cisplatin 45 mg/m2/d on days 2 and 3. Both drugs were given by continuous intravenous infusion. Among 27 patients with well-differentiated carcinoid tumors or islet cell carcinomas. only two partial objective tumor regressions were observed (7%). Among 18 patients prospectively classified as having anaplastic neuroendocrine carcinomas. however. there were nine partial regressions and three complete regressions. an overall regression rate of 67%. For anaplastic disease. the median duration of regression was 8 months (range to 21 months). Tumor response was unrelated to primary site. endocrine hyperfunction. or prior therapy experience. The median survival of all patients with anaplastic tumors was 19 months; this seemed favorable when considering the small experiences with these rare tumors reported in the literature. Toxicity. which was severe for most patients. consisted primarily of vomiting. leukopenia. thrombocytopenia. anemia. alopecia. and neuropathy. The anaplastic neuroendocrine tumor is strongly responsive to therapy with combined etoposide and cisplatin. Patients with undifferentiated carcinomas. originating in typical neuroendocrine tumor sites (small and large bowel. pancreas. and stomach) or of unknown origin. who have consistent histologic findings by light microscopy should be evaluated for this possibility with appropriate immune staining or electron microscopy.
Continuous infusion 5-fluorouracil plus weekly cisplatin for pancreatic carcinoma. A Mid-Atlantic Oncology Program study, Fifty-six previously untreated patients with biopsy-proven. locally advanced or metastatic and measurable adenocarcinoma of the pancreas were treated with the combination of a protracted intravenous infusion of 5-fluorouracil (5-FU) and low dose weekly bolus cisplatin administered continuously for 10 weeks followed by a 2-week rest period. The objective response rate was 16% with two patients (4%) achieving a complete response (confidence intervals. 8% to 29%). The median survival time for all treated patients was 5.8 months; however. 26% of all patients were alive at 1 year. Both median survival time and the proportion alive at 1 year exceed that of prior reports involving large patient groups. possibly due to better patient selection.
Responsiveness of patients with advanced ovarian carcinoma to tamoxifen. A Gynecologic Oncology Group study of second-line therapy in 105 patients, One hundred five patients with Stage III or IV epithelial ovarian cancer whose disease had persisted or recurred after primary surgery and first-line chemotherapy were given tamoxifen (20 mg orally twice daily) and evaluated for response. Eighteen percent of the patients responded: 10% demonstrated a complete response (CR) and 8% showed a partial response (PR). Thirty-eight percent of the patients had short-term disease stabilization. CR had a median duration of 7.5 months. with the longest lasting 17 months. For patients with PR or stable disease. the median duration of response was 3 months (maximum duration. 9 months). When estrogen receptors of tumor tissue from patients demonstrating CR were evaluated. eight of nine (89%) had elevated estrogen receptor levels. This contrasts with patients who had stable or progressive disease as only 59% of them had measurable estrogen receptors (P = 0.16).
Characterization of estrogen receptor in human gastric cancer, Estrogen receptors (ER) were examined in cytosol. nuclear potassium chloride (KCl) extractable fraction. and nuclear KCl unextractable fraction by the dextran-coated charcoal adsorption method in various gastric cancer tissue. The overall ER-positive rate in the cytosol and nuclear fraction was 19.2%. The maximum binding site (Bmax) was 36.0 to 175.0 fmol/mg of protein. and the dissociation constant (Kd) was 0.6 to 1.6 X 10(-9) in cytosol fraction. In the nuclear fraction. Bmax was 7.5 fmol/mg of DNA and Kd was 2.3 X 10(-9). Estrogen receptors were characterized in cytosol protein. In cytosol. the estrogen (E2)-ER complex was sedimented at approximately the 5S and 8S regions by 5% to 20% linear sucrose gradient centrifugation. A steroid specificity study of ER showed the presence of an binder in gastric cancer tissue. In conclusion. these results that gastric cancer tissue has E2 binding sites with the same biochemical characteristics as in breast cancer and endometrial cancer strongly suggest the hormonal dependency of gastric cancer.
The role of second-look surgery in the management of advanced germ cell malignancies, The need for second-look surgery after chemotherapy in children with advanced germ cell tumors is controversial. particularly when levels of the tumor markers alpha-fetoprotein (AFP) or beta-human chorionic gonadotropin (beta HCG) are elevated at diagnosis. The authors evaluated the outcome of second-look surgery in relationship to tumor marker status in 27 patients with Stage III to IV disease who had completed four courses of chemotherapy. Markers were elevated at diagnosis in 19 patients. After chemotherapy. markers normalized in 12 of these patients. Second-look surgery confirmed complete response (CR) in these 12 patients. two of whom had residual masses on computed tomography (CT) scan (mature teratoma and necrotic tumor). The AFP decreased but did not normalize in seven patients; five had residual disease at second look and the other two later developed measurable disease. Of the eight patients with normal AFP at diagnosis. second look confirmed clinical CR in four. The other four patients had CT evidence of residual masses: surgery showed necrotic tissue in two cases. mature glial elements in one. and mature teratoma with glial elements in one. Thus second-look surgery added no information for treatment planning in children with elevated tumor markers at diagnosis and might best be reserved for patients without tumor markers at diagnosis and residual masses on CT scan. and those with persistent elevation of tumor markers and potentially resectable residual disease. Because of the possibility of small amount of residual tumor. second-look surgery may also be useful in patients whose markers normalize but who have residual masses on CT scans.
Regression of hepatic metastases from gastrointestinal leiomyosarcoma after hepatic arterial chemoembolization, Two patients with gastrointestinal leiomyosarcoma metastatic to the liver were treated by hepatic chemoembolization with cisplatin and polyvinyl sponge followed by hepatic arterial infusion of vinblastine. Effective palliation in terms of durable tumor regression was achieved in both patients after two chemoembolization-infusion procedures. These results suggest that regional therapy may offer new hope for the subset of sarcoma patients who have liver metastases resistant to combination systemic chemotherapy.
Prognostic factors in papillary carcinoma of the thyroid, In a retrospective study of 119 patients. followed for 1 to 30 years after treatment of a papillary carcinoma of the thyroid. the authors searched for possible prognostic factors of the risk of recurrence. Microcarcinomas. anaplastic tumors and Hurthle cell carcinomas were excluded from the study. In a univariate analysis. age (greater than 45 years). sex (male). loss of histologic differentiation. size (greater than 3 cm). presence of carcinomatous lymphangitis. extrathyroid extension. and presence of metastasis at diagnosis were associated with a higher recurrence rate; type of growth and multifocality were not significant. In a multivariate analysis (logistic regression). age. size. and carcinomatous lymphangitis were significant predictors for women. whereas metastasis at diagnosis and cystic growth were significant for men.
C-erbB-2 oncogene protein in in situ and invasive lobular breast neoplasia, Lobular carcinoma in situ (LCIS) has uncertain malignant potential; biologic markers that will identify patients at risk for a poor clinical outcome have been sought actively. Amplification of the c-erbB-2 protooncogene has been correlated with poor prognosis in invasive mammary carcinoma. and immunohistochemical evaluation for expression of the oncogene protein has been correlated with gene amplification. The authors retrospectively evaluated 62 cases of lobular neoplasia for expression of the c-erbB-2 gene product on formalin-fixed. deparaffinized sections. using two monoclonal anti-erbB-2 (p185) antibodies (c-neu Ab3 and m-erb) and one polyclonal anti-erbB-2 antibody (pAb 1) by the avidin-biotin-peroxidase method. All 62 cases were negative with the pAb 1 antibody; one of 62 cases was weakly positive with the c-neu Ab3 in a membranous pattern. Expression of c-erbB-2 gene product was identified on adjacent invasive ductal carcinoma in one case and in adjacent ductal carcinoma in situ in another. None of 15 cases if infiltrating lobular carcinoma was positive with either of the two anti-c-erbB-2 antibodies. Strong positivity was found on benign epithelium in one case. demonstrating epitheliosis. In summary. evidence of expression of the c-erbB-2 gene product was found in one of 57 cases of LCIS and none of 15 cases of invasive lobular carcinoma. This suggests that. in contrast to reported data concerning intraductal and invasive ductal carcinoma. c-erbB-2 oncogene amplification and/or overexpression does not play a significant role in the progression of lobular breast neoplasia.
Growth patterns and prognosis of submucosal carcinoma of the esophagus. A pathologic study, Sixteen cases of esophageal carcinoma invading the submucosa were analyzed in terms of growth patterns. Seven were classified into the massively penetrating (down growth) type. four into the superficially spreading (spreading growth) type. and five into the unclassified type. In the down growth type. the ratio of the submucosal area to the total (mucosa and submucosa) area was more than 0.2 (one fifth). and in the others that ratio was less than 0.2. The down growth type is characterized by a tendency toward elevated lesions. a high incidence of vessel invasions and lymph node metastasis. and a poor prognosis after surgery. Lymphatic and/or vascular invasions were recognized in six of seven cases. and the 5-year survival rate was 0%. In contrast. the spreading growth and unclassified types was characterized by superficial lesions. a low incidence of vessel invasions and lymph node metastasis. and a favorable prognosis. In only one with the spreading growth type was there lymphatic invasion. Three of the four with the spreading growth type survived over 5 years. and the other one with the spreading growth type and all of five with the unclassified type are alive without recurrences 15 to 52 months after surgery. Thus. growth patterns reflect well the prognosis of the submucosal carcinoma of the esophagus.
Enhancement of tumor-associated glycoprotein-72 antigen expression in hormone-related ovarian serous borderline tumors, The immunoreactivity of monoclonal antibody (MoAb) B72.3 with ovarian serous tumors of borderline malignancy from 44 women who were pregnant. were on hormone medication containing a progestin. or were known to be in the secretory phase of the menstrual cycle. was compared with that of similar tumors of 32 patients who were not known to be in any of these three categories. All 76 borderline tumors expressed the tumor-associated glycoprotein (TAG-72) recognized by MoAb B72.3. Striking staining differences (P less than 0.0001) were observed between the hormone-related and the nonhormone-related tumors. Differences were also noticed between the staining of tumors from pregnant patients and that of previous. persistent. or recurrent tumors of the ipsilateral or contralateral ovaries when the same patients were not pregnant. Tumor MoAb B72.3 reactivity increased with progressive gestational age and fell to lower levels at term and during the postpartum period. Although it has been suggested by cell culture studies. enhanced TAG-72 expression in human tumors under hormonal stimulation has not been described before.
Flow cytometric DNA content analysis in neuroendocrine carcinoma of the lung. Correlation with survival and histologic subtype, The DNA content of 53 primary and locally metastatic pulmonary neuroendocrine carcinomas was retrospectively determined by flow cytometric analysis of nuclei released from paraffin-embedded tissues and compared with histologic subtypes and clinical survival. Forty-one percent (9 of 22) of tumors classified as well-differentiated neuroendocrine carcinoma (WDNC) were aneuploid. In contrast. 85% (17 of 20) of small cell neuroendocrine carcinoma (SCNC). and 73% (8 of 11) of intermediate cell neuroendocrine carcinoma (ICNC) were aneuploid. DNA content was not a significant independent predictor of patient survival within each histologic subtype (P greater than 0.05 for all subtypes). Yet. when all cases were examined as a single group. diploid cases showed better clinical survival than cases with DNA aneuploidy (P less than 0.02). However. the survival advantage for diploid DNA content did not quite achieve statistical significance when only cases of limited stage disease were analyzed (0.10 greater than P greater than 0.05). Histologic subtype was also a prognostic indicator. with WDNC cases showing a significantly longer survival than either SCNC (P less than 0.05) or ICNC (P less than 0.02). for those cases with limited-stage disease. These results indicate information on clinical staging and the histologic subtype are important parameters to compare with DNA content analysis in determining independent prognostic factors in neuroendocrine or small cell carcinoma of the lung.
Clinicopathologic features and prognostic significance of duodenal invasion in patients with distal gastric carcinoma, Clinicopathologic features and prognostic significance of duodenal invasion were studied in a retrospective study on 593 patients who underwent gastrectomy for adenocarcinoma in the antrum. The patients were grouped into three. according to the histologic extent of duodenal invasion: Group A (80 patients). obvious invasion beyond the pyloric ring; Group B (61 patients). invasion up to the pyloric ring; and Group C (452 patients). no evidence of duodenal invasion. Five-year survival rates in Groups A. B. and C were 7.9%. 31.6%. and 57.6%. respectively (P less than 0.001). Cox's regression analysis showed that duodenal invasion is an independent prognostic factor in cases of a gastric antrum carcinoma. Gastric cancer with duodenal invasion (Groups A and B) most often was infiltrative and the incidence of serosal invasion. lymphatic and vascular invasion. and lymph node metastasis was high. Duodenal invasion was direct through submucosal or subserosal layers or through submucosal lymphatics.
Monomorphous histiocytoma in a child. Report of a case with ultrastructural features suggestive of dendritic cell differentiation, The authors describe a rapidly growing soft tissue tumor of predominantly histiocytic composition in an 8-year-old child. The tumor cells were identified as elements of the mononuclear phagocyte system by histologic. histochemical. immunologic. and electron microscopic study. Despite the presence of a minor fibroblastic component. the tumor did not conform to established criteria for a diagnosis of malignant fibrous histiocytoma. Formation of frequent desmosome-like intercellular junctions raised the possibility of dendritic reticulum cell differentiation. since the latter cells seem to be the only elements of the mononuclear phagocyte system that display such specialized cell junctions. The results of immunostaining were discrepant with those reported for normal dendritic reticulum cells. but the currently available information makes it doubtful that the entire neoplastic spectrum of dendritic cell differentiation can currently be diagnosed in surgical pathology.
Down's syndrome and mixed acute leukemia in infants, The routine use of panels of monoclonal antibodies has been complementary to the French-American-British (FAB) leukemia classification. and has unmasked the occurrence of mixed acute leukemia (myeloid-lymphoid). It is widely accepted that children with Down's syndrome (DS) have a high incidence of acute leukemia. There is an extensive body of literature emphasizing the cytogenetic findings in these children. However. information as to the immunophenotype is often limited to the lymphoid surface determinants. The authors report two children with DS whose leukemic blasts were studied with a panel of 17 monoclonal antibodies (myeloid. lymphoid. and megakaryocytic) by flow cytometric examination and were classified as biphenotypic acute leukemia. The blast population coexpressed myeloid and T-cell surface markers. The lymphoid origin was ruled out on the basis of negative terminal deoxynucleotidyl transferase and molecular analysis demonstrating germline configuration for the JH and beta TCR genes.
Comparison of long-term survival of 1986 consecutive patients with breast cancer treated at the National Cancer Institute of Milano, Italy (1971 to 1972 and 1977 to 1978), Long-term survival of 1986 consecutive patients with infiltrating duct carcinoma of the breast treated at the National Cancer Institute of Milano (Italy) in two periods of time (1971 to 1972 and 1977 to 1978) was comparatively evaluated to verify if the evolving concepts in the management of breast cancer had an impact on survival. The authors found that 10-year survival of our patients increased from 59.4% of the first period of time to 65% of the second (P = 0.005). Both node-negative (N-) and node-positive (N+) patients had an improvement of survival rates at 10 years of the same magnitude: 6.8% and 5.9% respectively. Taking into consideration both the maximum diameter of the primary tumor and the status of axillary nodes it was found that in (1) both N- and N+ patients with a primary tumor of no more than 2 cm in greatest diameter. the improvement of survival was not statistically significant; and (2) both N- and N+ patients with a primary greater than 2 cm in maximum diameter had a better chance of survival in the second time period.
Exercise echocardiography in the detection of anthracycline cardiotoxicity, Twenty long-term survivors of childhood cancer underwent exercise echocardiography to evaluate possible late anthracycline-induced cardiac toxicity. Ten patients ages 10 to 20 years had received anthracyclines. and ten patients ages 8 to 27 years had not received anthracyclines as part of their medical regimen. Both groups had normal cardiac function at rest. Patients who had not received anthracyclines had a greater increase in M-mode shortening fraction (P less than 0.005). velocity of circumferential fiber shortening (P = 0.05). and Doppler aortic peak flow velocity (P = 0.01) than patients receiving anthracyclines. There were no significant differences in work performed. or increase in heart rate or blood pressure with exercise between the groups. These results suggest that subtle abnormalities in myocardial function exist which become apparent only after exercise in survivors of childhood cancer who have received anthracyclines and have normal resting cardiac function.
A method for estimating catechol estrogen metabolism from excretion of noncatechol estrogens, The relationship of catechol estrogen metabolism to disease has seldom been investigated because of analytic difficulties. Estradiol (E2) and estrone (E1) are oxidized simultaneously at either ring A or ring D. and the rate of catechol estrogen formation (r2) is reciprocally related to the rate of 16 alpha-hydroxylation (r3). The rate of ovarian estrogen production (X10) can be summarized as to metabolic outcome: X10 = r10 + r2 + r3 + r(u). where r10 is the loss of E1 and E2 in urine. and ru is the fecal and urinary loss of unknown oxidative products. Assuming a constant r(u) between subjects: constancy of the X10 concentration between subjects during similar menstrual cycle phases. In the absence of xenobiotics. r2 x r3 are reciprocally interrelated: r2 x r3 = K (an oxidation constant whose limiting factor is the biologically available estrogen at the cell surface). To the extent that r10 approximates estrogens available for cellular metabolism. the rate of catechol estrogen metabolism may be determined from (Formula; see text) From published data K = 12.4 +/- 0.8 of the standard error of the mean. Pearson correlation coefficients between actual and estimated catechol estrogen excretion in groups of subjects ranged from 0.61 to 0.97 (median. 0.88). This method has been useful for clinical investigation of the relationship of catechol estrogen metabolism to disease until better methods to measure catechol estrogen directly are available.
Childhood cancer among the Polynesian population, From June 1981 through June 1989. 95 Polynesian children were seen for initial care of malignancy at the Princess Mary Hospital for Children (PMHC). The incidence of malignancy in the Polynesian populations served. the histology of the malignancies. and the outcome of therapy were reviewed and compared with 185 non-Polynesian (non-P) patients seen during the same period. Incidence figures for Polynesians and non-P were similar. but histologic patterns differed. showing an increased occurrence of leukemia. particularly nonlymphoblastic leukemia. an increased occurrence of bone tumors. and a decreased incidence of central nervous system tumors for Polynesians. Survival for Polynesian children with acute lymphoblastic leukemia was worse than for non-P. Survival in all other disease categories was similar.
Reduction in injection pain using buffered lidocaine as a local anesthetic before cardiac catheterization, Previous reports have suggested that pain associated with the injection of lidocaine is related to the acidic pH of the solution. To determine if the addition of a buffering solution to adjust the pH of lidocaine into the physiologic range would reduce pain during injection. we performed a blinded randomized study in patients undergoing cardiac catheterization. Twenty patients were asked to quantify the severity of pain after receiving standard lidocaine in one femoral area and buffered lidocaine in the opposite femoral area. The mean pain score for buffered lidocaine was significantly lower than the mean score for standard lidocaine (2.7 +/- 1.9 vs. 3.8 +/- 2.2. P = 0.03). The pH adjustment of standard lidocaine can be accomplished easily in the catheterization laboratory before injection and results in a reduction of the pain occurring during the infiltration of tissues.
Coronary arteriography in patients with dextrocardia, Coronary arteriography is described in a patient with dextrocardia and situs inversus totalis. Six cases of coronary arteriography in dextrocardia were reviewed from the literature. and 3 other cases were reported from the authors' institutions. In 9 of the 10 patients. coronary arteriography was performed without difficulty using standard Judkins or Sones catheters. Angiographers encountering patients with dextrocardia may use standard coronary arteriographic techniques with a few subtle modifications.
Accordion effect in tortuous right coronary arteries during percutaneous transluminal coronary angioplasty, Coronary spasm and intimal dissection are well-known complications of coronary angioplasty with potentially serious consequences. Their treatments are different and need to be instituted quickly to prevent vessel closure. We report two cases of mechanical deformation caused by the angioplasty hardware masquerading as dissection or spasm during coronary angioplasty of tortuous native right coronary arteries.
Accordion right coronary artery: an unusual complication of PTCA guidewire entrapment, The contour of the epicardial coronary vessels may change considerably during coronary angioplasty. We report the extreme and unique "accordion-like" wrinkling of the mid right coronary artery as a result of distal guidewire entrapment during coronary angioplasty. Recognition of this artifact and its treatment may prevent further complications of coronary angioplasty.
Subacute bilateral coronary ostial stenoses following cardiac catheterization and PTCA, Accelerated coronary ostial stenosis is an infrequent late complication of coronary artery catheter instrumentation during aortic valve surgery. PTCA. or coronary angiography. We report the first case of bilateral coronary artery ostial stenoses developing after cardiac catheterization and right coronary artery PTCA. In patients with worsening angina following cardiac catheterization or PTCA. accelerated ostial stenoses should not be over-looked in the differential diagnosis.
Lack of evidence for small vessel disease in a patient with "slow dye progression" in the coronary arteries, A patient with chest pain of recent onset. suggestive for angina pectoris. was referred for diagnostic coronary angiography. which showed the typical phenomenon of "slow dye progression" in the absence of any significant coronary artery stenosis. While intracoronary Doppler measurements confirmed the extremely slow blood flow velocity. the coronary flow reserve and the calculated coronary blood flow proved to be within normal range. The present findings suggest that. in contrast with a previous hypothesis. the phenomenon of slow dye progression may not always be due to a microvascular cause. Epicardial artery disease. as suggested by the marked coronary artery ectasia. may be linked to the slow dye progression and predispose to coronary artery thrombosis.
Coronary focal ectasia formation following percutaneous transluminal angioplasty, Focal ectasia of the right coronary artery developed following percutaneous transluminal angioplasty. Operative intervention was not deemed necessary. No restenosis was found on repeat coronary angiography. Five-yr follow-up was associated with a benign course.
In vivo thrombus formation on a guidewire during intravascular ultrasound imaging: evidence for inadequate heparinization, We present a case in which thrombus formation on a guidewire was visualized during intravascular ultrasound imaging despite the administration of 10.000 units of heparin sulfate prior to the procedure. Gross thrombus formation was confirmed upon removal of the guidewire. The activated clotting time was found to be 191 s. suggesting heparin resistance. This report graphically illustrates the potential thrombogenicity associated with intravascular guidewire manipulation during procedures such as intravascular ultrasound imaging and percutaneous transluminal coronary angioplasty. Moreover. this case suggests that adequate heparinization should be routinely verified by measuring the activated clotting time prior to introducing a guidewire into the arterial system.
Simplified formula for the calculation of mitral valve area: potential inaccuracies in patients with tachycardia, A simplified formula (cardiac output/[transvalvular pressure gradient]1/2) has been proposed as an alternative to the Gorlin equation for determining valve area in patients with mitral stenosis. This study was done (a) to assess the relationship between the results of the simplified formula and those of the Gorlin equation in patients with mitral stenosis and (b) to determine the clinical characteristics most likely to be associated with a disparity between the 2 formulae. In 96 patients with mitral stenosis. the disparity between the 2 formulae was greater than 0.2 cm2 in 43 (45%) and greater than or equal to 0.35 cm2 in 21 (22%). The results of the simplified formula were especially likely to be disparate from those of the Gorlin equation in those whose heart rates were greater than 100 beats/minute. Thus. in the patient with mitral stenosis. the simplified formula should be used with caution and cognizance of its potential inaccuracy. particularly if the patient is tachycardic.
Angioplasty of long or tandem coronary artery lesions using a new longer balloon dilatation catheter: a comparative study, To determine whether or not a new 3 cm long angioplasty balloon was more effective in treatment of long (15-25 mm) or tandem (less than 25 mm overall length) coronary lesions. 44 consecutive patients with suitable lesions were alternately assigned to treatment with shorter. standard. 2 cm length. or long. 3 cm balloons. Primary success of PTCA was achieved in 95%. Those treated with long balloons required fewer inflations (3.3 +/- 1.5 vs. 5.7 +/- 2.1. P = .0001) and showed fewer moderate or severe intimal dissections of the lesions (4/22 vs. 12/22. p = .028). The use of 3 cm PTCA balloons in long or tandem lesions appears to be efficacious and less likely to cause dissections than shorter. 2 cm length devices.
Rapid thrombus dissolution by continuous infusion of urokinase through an intracoronary perfusion wire prior to and following PTCA: results in native coronaries and patent saphenous vein grafts, Even with aspirin and heparin therapy. thrombus present prior to or forming after percutaneous transluminal coronary angioplasty (PTCA) results in significant complications. We report on 33 patients who were treated with continuous infusion of Urokinase through an intracoronary perfusion wire for 24 hr because of visible intracoronary thrombus. Seventeen native vessels (9 pre-PTCA and 8 post-PTCA) and sixteen saphenous vein grafts (12 pre-PTCA and 4 post-PTCA) were treated. All vessels were patent at the time of perfusion wire placement. Complete thrombus resolution. successful PTCA and sustained patency was seen in 31 of 33 patients. One native vessel treated post PTCA (originally occluded) re-occluded. One saphenous vein graft treated prior to PTCA showed improvement in thrombus but distal embolization with balloon inflation occurred. No significant complications related to the intracoronary infusion technique were observed. In conclusion. rapid lysis of intra-coronary thrombus can be accomplish safely using this technique and can result in improved PTCA outcome.
Coronary angioplasty using new 6 French guiding catheters, Coronary angioplasty (PTCA) was performed with specially constructed 6-French guiding catheters with an internal lumen of 0.051 inches. In 154 patients these guiding catheters were used in a variety of configurations in conjunction with miniature balloon-on-a-wire dilatation catheters in 1.5 to 3.5 mm sizes to perform PTCA. Overall patient success was 94%. PTCA was attempted in 24 totally occluded arteries with a success rate of 83% and 174 stenoses with a success rate of 97%. 6 French guiding catheters can be used to successfully perform PTCA.
The effect of treatment with ventilating tubes on language development in preschool children with otitis media with effusion, The effect of bilateral tube insertion on language development was studied in a randomized controlled trial of 43 preschool children with persistent bilateral otitis media with effusion (OME). Improvement in language scores was observed in both the treatment and non-treatment groups. There was a minor difference in favour of the treatment group which did not reach statistical significance. Although there is a growing consensus that otitis media with effusion can have negative effects on language development in young children. it has not yet been proved that this effect can be reversed by treatment with ventilating tubes.
The influence of exercise-induced temperature elevations on the auditory brain-stem response (ABR), The influence of exercise on the auditory brain-stem response (ABR) was examined in 16 healthy volunteers (8 female and 8 male). Ipsilateral ABR recordings were obtained before and after exercise on a bicycle ergonometer. The rise of body temperature so generated was 0.5-2.1 degrees C (mean. 1.3 degrees C) as measured in the contralateral external auditory meatus. Latencies of waves III and V (but not wave I) were found to be significantly lower immediately post-exercise (P less than 0.01). The temperature relations of the latency of wave V are described by the regression equation: Latency (ms) = 11.06-0.146 x temp. (degrees C). (The effects on amplitude were not significant. nor were male/female differences.) It is suggested that exercise hyperthermia could be an appropriate model for the evaluation of the ABR in fever.
Impedance measurement in divers during a scuba-diving training programme, An assessment of the strain on the tympanic membrane caused by diving was performed using impedance measurement of the middle ear in 21 untrained young men going through a scuba-diving training programme (scuba. self-contained under-water breathing apparatus). Tympanometry was carried out just before and after diving. The divers made 104 dives between them (median 5 each. range 2-7) at depths from 2 to 12 m (median 6 m). The results showed a significant increase in middle ear compliance on diving. The increase in compliance was significant at different depths. was transient. and fell to the initial level between the dives. We conclude that the strain exerted on the tympanic membrane and middle ear from barotrauma due to diving results in a reversible impairment of the recoiling capacity of the elastic fibrils of the tympanic membrane. This transient increase in compliance. we think. is the first measurable change in elasticity of the tympanic membrane. If barotrauma continue the changes could be irreversible.
Tympanometry in the detection of hearing impairments associated with otitis media with effusion, The monitoring of children with otitis media with effusion ties up considerable resources in audiology departments. Impedance audiometry is frequently used when investigating these children. It has been shown to be highly sensitive in detecting middle ear effusion. but its value in identifying those children with a significant hearing impairment secondary to this is in question because of the wide range of hearing impairments possible with a type B tympanogram. This study quantified the sensitivity and specificity of impedance audiometry in detecting a hearing impairment greater than or equal to 25 dB HL due to otitis media with effusion. The subjects were 285 children of whom 20% had hearing thresholds greater than or equal to 25 dB HL. A peaked tympanogram (types A or C) virtually eliminated the possibility (98% confidence) of such a hearing impairment. A flat type B tympanogram was satisfactorily sensitive (93%) in detecting a hearing impairment. but non-specific (76%). The positive predictive value was 49%. i.e. 51% of ears with this type of tympanogram had hearing within acceptable limits. Assuming that a sensorineural impairment has been excluded and a population is being monitored for hearing impairment associated with otitis media with effusion. it is suggested that the presence of a peaked tympanogram indicates normal hearing. whereas those children with a flat tympanogram would require their hearing to be evaluated. Increased use of impedance audiometry to monitor children with otitis media with effusion would reduce the number requiring full pure-tone audiometry with a subsequent reduction in the workload of an audiology department.
The prevalence of hearing impairment amongst Maori schoolchildren, A survey of hearing amongst a population of Maori schoolchildren in the eastern North Island of New Zealand has demonstrated a high prevalence of hearing impairment. Out of 194 children undergoing audiometry an impairment of 20 dB or greater at 0.5. 1.2 and 4 kHz was found in the worse hearing ear in 29% and in the better hearing ear in 12%. Comparison with a similar survey done in the same valley in 1977 revealed an apparent reduction in the prevalence of hearing loss and the prevalence of otitis media. This improvement appears to be due to a reduced prevalence of otitis media. An unexpected finding was that at least 2% of the children had a bilateral sensorineural hearing impairment.
Carcinoembryonic antigen and head and neck cancer, Carcinoembryonic antigen (CEA) concentrations were determined in the sera of 45 patients with a head and neck squamous cell carcinoma and of 13 controls. In 13 patients serial CEA measurements were made during the follow-up period. In 38% of the patients the serum CEA level was slightly elevated (greater than or equal to 2.5 ng/ml). Only 13% of the patients had clearly elevated CEA levels (greater than 5 ng/ml). CEA levels were significantly higher in patients with advanced. e.g. stage IV. disease but a correlation between serum CEA concentration and prognosis was not found. Patients who smoked had significantly higher serum CEA levels than non-smoking patients. In the serial determinations slight CEA elevations could be found in only 50% of patients with tumour recurrence. Combined with the data from the literature we conclude that serum CEA determination is not useful in predicting the outcome in patients with a head and neck squamous carcinoma.
Metastatic carcinoma in the neck: a clinical, radiological, scintigraphic and pathological study, This study was undertaken to compare clinical evaluation of the neck with 99mTc(v) DMSA planar scintigraphy and computerized tomography (CT) in patients with head and neck carcinoma. Twenty-six patients were studied and in all but one the neck was previously untreated. A total of 31 neck dissections were performed and the specimens examined histopathologically. CT was approximately as accurate (71%) as clinical examination (68%) and more accurate than 99mTc(v) DMSA planar scintigraphy (48%) in predicting which necks contained metastatic carcinoma. Overall. 13% of necks had their staging correctly changed by 99mTc(v) DMSA scintigraphy compared with 10% for CT. Although scintigraphy upstaged 13% of clinically N0 necks compared to 6% for CT. it was less sensitive and specific than either clinical examination or CT. 99mTc(v) DMSA planar scintigraphy has no role to play in the investigation of patients with metastatic carcinoma to include the clinically N0 neck.
The persistence of symptoms in patients with globus pharyngis, A follow-up study of 104 patients with globus sensation was performed by postal questionnaire. All were asked to complete the Eysenck Personality Questionnaire (EPQ) and a 12-item Throat Symptom Questionnaire. Seventy-two of these patients were sent a follow-up General Health Questionnaire (GHQ). Replies were received from 89 patients (86%). 68 females and 21 males. a mean of 31 months after initial presentation. The feeling of something stuck in the throat had disappeared completely in 27% of patients. but only 4% were never aware of the throat. Throat symptoms showed a reduction with increasing age. but not with increasing interval since presentation. The 15 patients initially treated with antacid therapy had significantly greater dyspepsia scores at review than untreated patients. but no other difference was found between the two groups. GHQ scores showed a small but significant reduction over time. Of EPQ parameters. only the lower lie score in female patients showed any significant difference on repeat testing. Those with persistently high throat scores had significantly lower EPQ lie scores and a trend towards higher GHQ scores at follow-up. None of the psychological parameters measured at the first interview was found to be of prognostic significance. We conclude that. although there is a reduction in occult psychiatric morbidity in patients with the globus sensation over time. underlying personality traits remain stable and that there is a remarkable persistence of pharyngeal symptoms.
The objective assessment of nasal patency, Nasal patency was measured by five techniques in 24 subjects and the results compared. In addition three pulmonary parameters were measured as well as height and weight. Nasal resistance to airflow measured by active anterior rhinomanometry was found to be highly correlated with peak nasal inspiratory flow rate. Other correlations were also noted. Peak nasal inspiratory flow was itself highly correlated with pulmonary peak expiratory flow rate as well as with several other parameters. The possible reasons for these correlations are discussed in terms of fluid mechanics.
Antroscopy in outpatient management: a prospective study, Antroscopy has an established role in the diagnosis of maxillary sinus disease; however. its role in overall patient management requires clarification if it is to be widely adopted as an outpatient procedure. This study examined 100 consecutive attenders to an antroscopy clinic and monitored their diagnosis and management plan both before and after antroscopy. Diagnosis was altered or added to in 79% of cases and management in 73% of cases. The trend after knowledge of antroscopic findings was towards more medical treatment and less surgical intervention. Such a change would clearly have significant resource implications. While computed tomographic scanning time is limited. outpatient sinus endoscopy can be used as an intermediate investigation. with only selected patients going forward to be more comprehensively investigated.
Fasting gastric pH and its relationship to true hypochlorhydria in humans, Abnormally low rates of gastric acid secretion (hypochlorhydria) are associated with bacterial overgrowth. enteric infection. and with hypergastrinemia and an increased risk of gastric neoplasms. In the present study. we evaluated the ability of fasting gastric juice pH measurements to detect true hypochlorhydria. True hypochlorhydria was defined as a peak acid output in response to a maximally effective stimulant of acid secretion that was below the lower limit of normal for 365 consecutive healthy subjects. In these healthy subjects. average basal pH was 2.16 +/- 0.09 in men and 2.79 +/- 0.18 in women. In 109 consecutive experiments in 28 subjects with true hypochlorhydria. fasting gastric pH averaged 7.44 +/- 0.11 in men and 7.65 +/- 0.33 in women. Fasting pH exceeded the upper 95% confidence limit of normal (5.09 in men and 6.81 in women) in 102 of the 109 experiments (94%). Thus. fasting pH measurement was a sensitive method for diagnosing bona fide hypochlorhydria.
Double-blind randomized multicenter study comparing Maalox TC tablets and ranitidine in healing of duodenal ulcers, The efficacy of ranitidine 150 mg twice daily and Maalox TC three tablets four times daily were compared in patients with endoscopically confirmed duodenal ulcer. Seventy-nine patients were randomly allocated to double-blind. double-dummy treatment. stratified for smokers. Endoscopy was repeated after four weeks. Those unhealed continued treatment for a further two weeks before final endoscopy. Per protocol analysis in 53 patients showed ulcer healing rates at week 4 and at weeks 4 and 6 combined of 78 and 89% on Maalox TC. and of 81 and 91% on ranitidine. respectively. The same analysis gave overall healing rates of 81% in smokers and 100% in nonsmokers. irrespective of treatment. Both treatments provided early ulcer pain relief. Diarrhea was a commoner side effect in patients on Maalox TC. The study showed Maalox TC and ranitidine were equally effective in healing duodenal ulceration.
Hepatocellular carcinoma. A worldwide problem and the major risk factors, Male sex. age. cirrhosis. and HBsAg are the major risk factors for hepatocellular carcinoma (HCC). The geographic distribution of HCC is highly uneven. such that three distinct incidence areas are recognized. To clarify the reason(s) for this geographic variability of HCC. the risk factors in each incidence area were assessed. In parallel with the geographic distribution of HCC. HBsAg prevalence was highest in both HCC patients and in general population in Africa and Asia. where mothers of HCC patients are frequently HBsAg-positive. suggesting that hepatitis B virus hyperendemicity and perinatal infection account for the high HCC incidence in these areas. Cirrhosis. which is found on autopsy in 80% of the cases of HCC patients worldwide. is the most prevalent risk factor for HCC in areas where hepatitis B virus infection is less common. However. HBsAg carriage adds to the HCC risk carried by cirrhosis and explains the higher incidence of HCC in cirrhotics from Africa and Asia as well as elsewhere. Available data suggest that chronic HCV infection is a risk factor for cirrhosis and HCC. HBV vaccination should decrease HCC incidence rates worldwide; however. HCC prevention in regions where HBsAg carriage is infrequent may also require prevention of the other causes of cirrhosis in order for HCC rates to decline.
Hepatocyte proliferation in stepwise development of experimental liver cell cancer, Cell proliferation is the most central and key phenotypic property of cancer including hepatocellular carcinoma. Hepatocyte proliferation is central not only at the late steps in carcinogenesis. the cancer. but at the earliest known step. initiation. Compensatory or regenerative hepatocyte proliferation is essential to initiation with chemical carcinogens but primary hyperplasia is ineffective. During promotion. hepatocyte proliferation is the major change seen as clonal proliferation to generate nodules occurs. During progression. autonomous hepatocyte proliferation balanced by cell loss makes its appearance. This continues in a balanced fashion with only a slight excess of proliferation over loss until the earlier steps in malignancy at which time the balance is disrupted.
[35S]methionine interaction with rat liver tRNA and effect of chemical carcinogens, The interaction of [35S]methionine with hepatic tRNA in normal. carcinogen-treated. and partially hepatectomized rats was studied. tRNA was preferentially labeled following [35S]methionine (1.6 mCi. 25 mg/kg body wt) administration by intraperitoneal injection. The extent of [35S]methionine-tRNA interaction was impaired by partial hepatectomy and by conditions having a carcinogenic potential.
Physiology and pathophysiology of colonic motor activity (2), The basic motor function of the colon is to mix and knead its contents. propel them slowly in the caudad direction. hold them in the distal colon until defecation. and provide a strong propulsive force during defecation. Infrequently. it also produces mass movements in the proximal colon. These motor functions are achieved in most species by three different types of contractions: the individual phasic contractions that include the short- and long-duration contractions. organized groups of contractions that include the migrating and nonmigrating motor complexes. and special propulsive contractions (giant migrating contractions). The spatial and temporal patterns of all of these contractions are controlled by myogenic. neural. and chemical control mechanisms. The individual phasic contractions are highly disorganized in time and space in the colon. For this reason. they are effective in mixing and kneading and slow distal propulsion. The underlying cause of the disorganization of short duration contractions is the irregularity in the frequency and waveshape of colonic electrical control activity and its phase unlocking throughout the colon. The individual contractions in many species occur in cyclic bursts called contractile states. At least in some species. these contractile states exhibit mostly caudad and sometimes orad migration. However. there are also nonmigrating or randomly migrating contractile states in the colon. These two patterns of contractile states are called colonic migrating motor complexes and colonic nonmigrating motor complexes. respectively. The giant migrating contractions provide the strong propulsive force for defecation and mass movements. The neural control of colonic contractions is organized at three levels--enteric. autonomic. and central. The enteric nervous system contains cholinergic and peptidergic neurons and plays a major role in the control of colonic contractions. The autonomic nerves. the vagi. pelvic. lumbar colonic. hypogastric. and splanchnic nerves. seem to continuously monitor the state of the colon and provide a modulatory input when necessary. These nerves play a major role in the reflexive control of colonic motor function. The voluntary input from the central nervous system coordinates the motor activity of the colon. rectum. anal canal and sphincters for orderly evacuation of feces during defecation. The role of acetylcholine. nonadrenaline. and the yet to be completely identified nonadrenergic. noncholinergic neurotransmitter. possibly VIP. in the control of contractions is fairly well established. Besides these. there are several other peptides and chemicals that are localized in the colonic wall; their physiological roles remain unknown. Colonic motor activity has been studied in several disease states. The findings have not always been consistent.(ABSTRACT TRUNCATED AT 400 WORDS).
The critically ill neonate in the emergency department, Recognition of the high-risk mother and fetus is an essential component of resuscitation if it is to be organized. accurate. and successful. Although many high-risk factors put the neonate in jeopardy. the first responder or ED physician can plan the initial approach to resuscitation by knowing the answer to three questions: (1) Is there particulate meconium in the amniotic fluid? (2) Is the fetus/baby premature? and (3) Is a multiple gestation pregnancy expected? Although the ABCs (airway. breathing. circulation. chemical) of resuscitation adequately describe the parameters essential for adequate resuscitation. they do not relate to the actions necessary to accomplish this feat; therefore. it is important for participants in neonatal resuscitation to remember the acronym SOS--suction. oxygen. stimulation. Even infants with moderate depression (occasional respiratory effort) will generally respond to brief suctioning of the airway. 100% oxygen. and vigorous stimulation. If SOS is ineffective. PPV must be administered without hesitation. Resuscitation of the newborn is not a simple procedure. but rather a dynamic process involving continuous evaluation. action. and reassessment before. during. and after the actual resuscitation. A specially trained resuscitation team of physician. nurse. and respiratory therapist interacting in a dynamic evaluation approach is ideal but not practical for most community hospitals. Each hospital must develop its own protocol and train and maintain its resuscitation personnel. If each member of the team is prepared to take over in the absence of the others. neonatal resuscitation will remain fast. organized. and accurate.
Advances in pediatric emergency department procedures, Pediatric procedures in the Emergency Department typically involve techniques for stabilization. evaluation. and treatment of the child. This article considers indications and techniques for vascular access. lumbar puncture. arterial lines. pulse oximetry. and urine collection. Multiple routes of medication administration and pain management modalities also are reviewed.
Cocultures: a new lead in embryo quality improvement for assisted reproduction, One of the contributory causes to poor PRs in assisted reproduction has been the decreased viability of transferred embryos and the transfer of four-cell embryos into an environment that naturally would be receptive only to 5-day-old blastocysts. In this paper. we have reviewed our own work and that of others on the role of tubal ampullary cells (cocultures) to mimic the in vivo environment to bring about improved embryo quality and an increased number of blastocysts for replacement in IVF patients. The establishment. maintenance. and behavior of human tubal cell lines is first presented. followed by their use as cocultures for fertilization and cleavage of embryos. The mode of action. specificity. and cryopreservation of ampullary cells are also discussed. The currently available results of pregnancies after cocultures are presented together with future aspects of research that are necessary to refine the coculture system. The ultimate aim is to mimic in vivo conditions in vitro. so that at least the PRs of assisted conception can be parallel to normal fecundity in the human. Therefore. a very attractive future includes the freezing of blastocysts generated from coculture. thawing. and replacing them in natural cycles.
Fallopian tube catheterization and recanalization under ultrasonic observation: a simplified technique to evaluate tubal patency and open proximally obstructed tubes, OBJECTIVE: To test a sonoscopic technique developed for transvaginal catheterization and recanalization of the fallopian tube. DESIGN: In a feasibility study. catheterization was performed with the use of laparoscopic control. Patients with bilateral proximal tubal obstruction underwent fallopian tube recanalization under ultrasonic observation. SETTING: This study represents patients evaluated for primary or secondary infertility at Humboldt University Hospital. PATIENTS. PARTICIPANTS: Proximal tubal obstruction had been diagnosed on previous hysterosalpingogram and with laparoscopy. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Tubal patency was assessed by hydrotubation under ultrasonic observation. RESULTS: Transvaginal catheterization was successful in 31 (91.2%) of the 34 tubes. In 19 patients with proximal tubal obstruction. patency of both or at least one tube was achieved in 16 (84.2%) women. Five (31.6%) of 16 patients successfully recanalized were found to have an intrauterine pregnancy at a 6-month follow-up interval. CONCLUSION: This catheterization technique should be investigated for possible use in diagnostic schedule early in the evaluation of the infertile patient. Also. the transvaginal recanalization of proximally obstructed tubes calls into question the application of microsurgical treatment of a selected group of patients.
Reliability of transvaginal ultrasound in detecting first trimester pregnancy abnormalities, OBJECTIVE: To evaluate the reliability of transvaginal ultrasound (US) and human chorionic gonadotropin (hCG) levels in detecting early abnormalities and predicting outcome of pregnancy. PATIENTS: One hundred thirty-two patients were studied. of which 113 had an intrauterine pregnancy and 19 had an ectopic pregnancy (EP). RESULTS: In 78 with singleton normal pregnancies. US revealed a normal crown-rump length. heart motion. and hCG levels between 1.000 to 107.000 mIU/mL. Of 16 patients with small crown-rump length. heart motion present. and normal hCG levels. 6 aborted and 10 reached term. Thus. 6 of 84 (7.14%) singleton with fetal heart motion aborted. Thirteen with small crown-rump and absent heart motion also aborted. All 8 with an empty gestational sac aborted. In 8. transvaginal US detected four twins. two triplets. and two quadruplets. whereas hCG was not discriminative. Transvaginal US revealed an empty uterus in 19 patients with an EP. whereas serum hCG varied between 37 and 10.500 mIU/mL. CONCLUSION: A fetal crown-rump length compatible with gestational age and fetal heart motion seen by transvaginal US can predict a term pregnancy in greater than 90% of patients.
Human chorionic gonadotropin rise in normal and vanishing twin pregnancies, OBJECTIVE: The purpose of the study was to describe and to compare the rate of rise of human chorionic gonadotropin (hCG) in vanishing twin and normally progressing twin pregnancies during the first trimester. DESIGN: All patients with twin pregnancies between 1985 and 1989 were prospectively studied. Human chorionic gonadotropin was measured one to three times per week between days 12 and 52 after luteinizing hormone (LH) surge or day of hCG administration (day 0). Pelvic ultrasound (US) was performed weekly beginning on day 24. SETTING: The study was performed at Rush-Presbyterian-St. Luke's Medical Center in an academic private practice setting of the Section of Reproductive Endocrinology and Infertility. Department of Obstetrics and Gynecology. PATIENTS: Forty patients who conceived after treatment of infertility and who had two gestational sacs on US examination were included in the study after the following criteria were met: (1) both sacs progressed to exhibit a fetal pole and (2) day of LH surge and/or day of hCG administration was known. MAIN OUTCOME MEASURE: The rate of rise of hCG was slower in vanishing twin pregnancies than in normally progressing twin gestations for the entire time period studied (P less than 0.05). RESULTS: A vanishing twin occurred in one third of the twin pregnancies. Forty-six percent of these losses occurred after fetal heart activity had been established. CONCLUSIONS: Vanishing twin phenomenon occurred in a large proportion of twin pregnancies in this infertility population. Fetal heart activity was not a reliable predictor of continuing fetal viability in early twin gestations. Vanishing twin conceptions were characterized by a slower rate of rise of hCG than normally progressing twin pregnancies.
Are there antiendometrial antibodies in sera of women with endometriosis, STUDY OBJECTIVE: To identify and characterize the antiendometrial tissue specific antibody response in endometriosis patients. DESIGN: Retrospective. SETTING: Industrial research laboratory. PATIENTS: Twenty untreated women with laparoscopically diagnosed endometriosis. 10 healthy women without symptoms of endometriosis. 12 women in whom laparoscopy failed to yield evidence of endometriosis. 10 healthy men. and 4 individuals with elevated titers of serum antinuclear antibodies. RESULTS: Several immunological methods have been employed including immunofluorescence. hemagglutination. enzyme-linked immunoabsorbent assays. and protein blotting. Contrary to reports in the literature. results of these analyses have failed to demonstrate the presence of detectable levels of antiendometrial immunoreactivity in sera from patients with endometriosis. CONCLUSION: The association of endometrial autoimmunity with endometriosis remains to be established.
Failed in vitro fertilization of human oocytes: a cytogenetic analysis, OBJECTIVE: To investigate possible causes of in vitro fertilization (IVF) failure. DESIGN: A retrospective cytogenetic study of human oocytes divided into four groups or. alternatively. into two groups according to fertilization rates and whether the patients became pregnant or not. Two additional groups included oocytes in which there was no or only partial fertilization. SETTING: Primary treatment of infertility in an institutional practice. PATIENTS. PARTICIPANTS: Two hundred fifty-three inseminated-unfertilized oocytes from 87 women entering the IVF program because of tubal. unknown. and male infertility. Immunological infertility was excluded. INTERVENTIONS: Ultrasound-guided transvaginal follicular aspiration. MAIN OUTCOME MEASURE(S): Planned after data collection. RESULTS: The rate of chromosome anomalies did not show any significant difference among the four groups established according to the fertilization rate and between pregnant and nonpregnant patients. Independently. our data identified male factor as responsible for 41%. chromosome anomalies 19.3%. oocyte immaturity 11.8%. and unknown etiology 41% of fertilization failures (based on analysis of 161 oocytes). CONCLUSIONS: Fertilization rate and pregnancy outcome after IVF are not related to the incidence of oocyte chromosome anomalies.
Clomiphene citrate-induced gamete intrafallopian transfer with diagnostic and operative laparoscopy, STUDY OBJECTIVE: To examine the efficacy of clomiphene citrate (CC) gamete intrafallopian transfer (GIFT) with operative laparoscopy. DESIGN: Retrospective. SETTING: Private office and outpatient surgical center. PATIENTS: Sixty-two patients who were to undergo diagnostic and operative laparoscopy as part of their infertility evaluation underwent concomitant CC-stimulated GIFT. Any significant pelvic pathology was treated in conjunction with the GIFT procedure. RESULTS: The average number of oocytes retrieved per laparoscopy was 3.4 and an ongoing pregnancy rate (PR) of 24.6% was attained. Endometriosis. pelvic adhesive disease. and myoma were treated laparoscopically in conjunction with the GIFT procedure. CONCLUSION: Clomiphene citrate-induced GIFT in conjunction with diagnostic and operative laparoscopy results in an acceptable ongoing PR without significantly interfering with any operative laparoscopy procedure required.
Platelet-activating factor in sperm from fertile and subfertile men, STUDY OBJECTIVE: To examine the proposed role of platelet-activating factor (PAF) as a mediator of sperm function first by quantitating the concentration of PAF in sperm and second by incubating sperm with PAF and assessing the change in sperm motion parameters with a computerized motion analysis system. DESIGN: Retrospective. case-control study. SETTING: University hospital urology clinic. PATIENTS: Concentrations of PAF were measured in sperm from 6 randomly chosen normal donors and 8 asthenozoospermic patients. The change in sperm motion parameters was assessed in sperm from 10 randomly chosen normal donors and 7 asthenozoospermic patients. RESULTS: Platelet-activating factor concentrations were significantly higher (P less than 0.05) in spermatozoa from asthenozoospermic patients (149 +/- 18.0 fmol/10(6) sperm) than in sperm from normal donors (91.9 +/- 13.0 fmol/10(6) sperm). Exogenous PAF did not enhance the percent motility of precapacitated or capacitated sperm from either patients or donors. and computerized semen analysis revealed no enhancement of sperm motion parameters in asthenozoospermic patients after addition of PAF to either precapacitated or capacitated sperm. CONCLUSION: Platelet-activating factor does not appear to have therapeutic value as a means of enhancing sperm motility.
The correlation between sperm cell morphology and fertilization after zona pellucida slitting in subfertile males, OBJECTIVE: This work was undertaken to evaluate the correlation between sperm cell morphology and fertilization after zona pellucida slitting in subfertile males. DESIGN: Twenty-two couples who failed at least one in vitro fertilization attempt because of lack of oocytes fertilization underwent a zona-slitting micromanipulative procedure. A total of 245 oocytes were retrieved and inseminated by three different modes: 151 oocytes underwent micromanipulation. 2 were damaged. and the remaining 149 inseminated by the husband's sperm (group A). Fifty-five oocytes were not manipulated and inseminated by the husband's sperm (group B). and 39 oocytes were not manipulated and inseminated by a donor sperm (group C). RESULTS: Fertilization rates were 26.8%. 5.5%. and 53.8% in groups A. B. and C. respectively. and differed significantly between group A and group B. The cleavage rates were lower for oocytes fertilized by the husband's sperm (48.6%) than that obtained by donor (90%). suggesting a sperm factor contributing to this phenomenon. The procedure was most efficient in patients with a total motile sperm count after preparation of greater than or equal to 5 million and with either normal sperm morphology or defects localized to the acrosome or tail region only. Sperm with nuclear morphological abnormalities demonstrated a marked reduction in fertilization potential. CONCLUSION: It is concluded that the zona-slitting technique enhances fertilization of severely subfertile sperm. and its efficacy is affected by sperm morphology and a threshold concentration of motile cells.
Failure of intrauterine insemination in a refractory infertility population, Intrauterine insemination by itself for multiple and/or severe infertility factors had no benefit over cervical cap with whole ejaculate or coitus in this study. The PRs for IUI and cervical cap with whole ejaculate or coitus were similar and low. suggesting that IUI by itself has limited. if any. utility in enhancing PRs in this type of infertility population. Couples attempting IUI should be advised about the low probability of achieving pregnancy. Ovulation stimulation and/or heterologous donor insemination. IVF. or gamete intrafallopian transfer may be beneficial therapeutic options.
Effect of hemostatic agents in canine gastric serosal blood vessels, The efficacy of various sclerotherapeutic agents in the control of acute bleeding. via subserosal injection. was assessed in 10 dogs. Blood flow rate (BFR) from severed gastric serosal vessels (diameter. 1.6 to 2.2 mm) was measured for 3 min (ml/min) for a control group and the agent used. The agents tested were 5 ml of normal saline (NS). 5 ml of 3% hypertonic saline (HS). 5 ml of 1:10.000 epinephrine in NS. 5 ml of 1:10.000 epinephrine/HS. 5 ml of 1:20.000 epinephrine/HS. 2 ml of old thrombin "cocktail" (thrombin. cephapirin + 1% tetradecyl). and 2 ml of fresh thrombin cocktail (total seven). One agent was tested per dog; there were one to two dogs in each subgroup. All of the agents showed significant reduction in BFR (except old thrombin) when compared with BFR of control vessels. The reduction ranged from 30% to more than 75% after 1:10 epinephrine/HS. Complete hemostasis was achieved in up to 47% of vessels using 1:20 epinephrine/HS. Overall. the epinephrine solutions achieved the best results. No systemic effects were observed with the use of any of the agents. Histological studies showed that epinephrine caused mild tissue damage. whereas the cocktail caused significant tissue necrosis. This serosal vessel model permits comparison of the effectiveness of each agent; however. clinical extrapolation to mucosal vessels in a patient and the long-term histological changes are not known.
Minute lesions of the rectum and sigmoid colon in patients with Crohn's disease, Sigmoidoscopy with a spray of 0.1% indigocarmine was performed on 20 patients with Crohn's disease whose main lesions were located proximal to the transverse colon and on 10 age-matched healthy volunteers. Minute lesions such as apthoid lesions. areas of erythema. and small ulcers were found in 90% of patients with Crohn's disease and in 0% of healthy volunteers (p less than 0.001). Among the minute lesions. aphthoid lesions were found in the highest incidence (85%). It was difficult to determine the presence of aphthoid lesions without the spray of indigocarmine. which facilitated detection. Histologically. granulomas were found in 15% of patients with Crohn's disease. Aphthoid lesions were not associated with superficial erosions and lymphoid follicles. The presence of aphthoid lesions in the rectum and sigmoid colon would be a strong indication of the presence of Crohn's disease.
Limited benefit of atropine as premedication for colonoscopy, A prospective double-blind trial was performed comparing atropine (0.5 mg) by slow intravenous administration to placebo as premedication for colonoscopy. to assess the possible beneficial effects of this vagolytic agent on the performance and safety of the procedure. A total of 77 patients was randomly assigned to receive atropine (38 patients) or placebo (39 patients) before colonoscopy in conjunction with our standard initial medications for conscious sedation (meperidine. 0.4 mg/kg and midazolam. 0.03 mg/kg). Total procedure time was 31 min for the atropine group and 35 min for the placebo group (p greater than 0.05). and there was no overall difference in the total amount of intra-procedural medications required. No statistically significant differences were observed relative to the number or severity of vagal episodes. and neither the endoscopist nor the patients noted any differences in the ease or tolerance of the procedure (p greater than 0.05). Although these results fail to demonstrate a significant benefit of atropine when given routinely as premedication for colonoscopy. this study does not rule out the potential usefulness of atropine in counteracting vagal episodes when they occur.
Endoscopic biopsy technique for acquiring larger mucosal samples, Biopsies of the esophagus. stomach. and intestine are most often obtained using the traditional advance-and-close method with flexible endoscopes by extending an open forceps several millimeters beyond the endoscope tip to sample the mucosa. all under direct vision. We developed an alternative "turn-and-suction" endoscopic biopsy technique that permits the acquisition of larger mucosal samples. The biopsy forceps is advanced into the lumen. opened. and withdrawn backward until it is flush with the endoscope tip. Next. the endoscope tip is turned gently into the wall while air is suctioned from the lumen. and the biopsy forceps is very slightly advanced and then closed. usually without direct visualization. After straightening the endoscope tip. the biopsy is obtained by withdrawing the forceps and avulsing a superficial mucosal sample. By using this new method. we have safely taken over 10.000 biopsies without complications in endoscopic surveillance research protocols in patients at risk for gastrointestinal cancer. To compare the sizes of biopsies obtained with these two techniques. histologic sections of 341 mucosal samples from 12 patients with chronic ulcerative colitis were studied retrospectively. The mean greatest length of biopsy sections using the traditional technique was 4.72 mm. and using our new technique was 7.35 mm (56% longer). The turn-and-suction endoscopic biopsy method is best applied when flat mucosa is randomly sampled to seek microscopic pathologic changes that are not visible endoscopically. and may be advantageous for various non-histologic research analyses of gastrointestinal mucosa which are limited by tissue quantity.
Endoscopic ultrasound in pancreatic tumor diagnosis, In a prospective study from 1988 to 1990. 132 patients with suspected pancreatic tumor were examined with endoscopic ultrasound (EUS). transabdominal ultrasound (US). computed tomography (CT). and ERCP. The final diagnosis of 102 pancreatic tumors of different origin (76 malignant and 26 inflammatory tumors) and the exclusion of a pancreatic tumor in 30 patients was made by operation (N = 47). puncture (N = 36). autopsy (N = 3). or follow-up of a mean of 51 weeks (N = 46). Sensitivity and specificity in pancreatic tumor diagnosis were significantly higher for EUS (99% and 100%) than for US (67%/40%) and CT (77%/53%) and equal to ERCP (sensitivity 90%). This was even more obvious in small pancreatic tumors of 3 cm and less. However. as with the other imaging procedures. EUS was not able to differentiate reliably malignant from inflammatory pancreatic masses (accuracy 76% for malignancy and 46% for focal inflammation). From analysis of the endosonographic pattern of pancreatic tumors. no consistent morphologic features were identified which could have been specifically attributed to malignant or inflammatory masses. Our results show that EUS is superior to US and CT and equal to ERCP in pancreatic tumor diagnosis. In contrast to the indirect evidence obtained by ERCP. EUS provides direct visualization of tumor size and shape in almost all patients examined. Thus. EUS should be considered early in the evaluation of patients with suspected pancreatic tumors.
Sexual headaches: case report, review, and treatment with calcium blocker, A case is reported in which a patient with sexual and orgasmic headaches was treated successfully with a calcium channel blocker. diltiazem. To the best of our knowledge. this is the first case of successful treatment of sexual headaches with calcium channel blockers reported in the English medical literature. The literature on sexually related headaches is reviewed. and classification. evaluation. differential diagnosis. pathophysiology. differential diagnosis. and treatment of sexual headaches are discussed.
Plasma and saliva levels of PGI2 and TXA2 in the headache-free period of classical migraine patients. The effects of nicardipine, The levels of Prostacyclin (PGI2) and Thromboxane A2 (TXA2) were assayed simultaneously (RIA) in the plasma and saliva of 9 patients suffering from classical migraine attacks. The assays were done during an attack-free period. In relation to the control group we observed a significant decrease in the plasma levels of PGI2 together with a sharp increase in TXA2 in saliva. When the patients were treated with nicardipine. a calcium antagonist. the TXA2 increase in saliva did not occur. These results suggest both a systemic and local effect in the classical migraine attacks. We explain and discuss our results by referring to the PGI2: TXA2 equilibrium system. Nicardipine action might be related to its ability to reduce the calcium entry into the cell induced by thromboxane.
Jolt accentuation of headache: the most sensitive sign of CSF pleocytosis, We prospectively examined the clinical signs of 54 febrile patients associated with recent-onset headache. They underwent lumbar puncture (LP) on suspicion of meningitis. The relation of each sign to cerebrospinal fluid (CSF) pleocytosis was estimated. Among 34 patients with pleocytosis. 33 had jolt accentuation (sensitivity: 97.1%). while only 5 of them had neck stiffness or Kernig's sign. Among 20 patients without pleocytosis. 12 had no jolt accentuation (specificity: 60%). We found jolt accentuation to be the most sensitive sign of CSF pleocytosis. If jolt accentuation is noted in a febrile patient associated with recent onset headache. the CSF should be examined even in the absence of neck stiffness or Kernig's sign.
Weaning from mechanical ventilation: current controversies, As an acute episode of respiratory failure resolves for the patient who is receiving mechanical ventilation. the sometimes difficult task of resuming spontaneous ventilation begins. The resumption of spontaneous ventilation. commonly referred to as weaning. is often difficult for the patient with preexisting lung disease. The purpose of this article is to explore the current controversies related to weaning patients from mechanical ventilation. Patients with chronic obstructive pulmonary disease are used as examples. providing the background for understanding weaning in difficult cases. Weaning is conceptualized as a process of three phases: preweaning. weaning. and extubation. Important considerations during each phase are examined.
Predictors of physical functioning after a cardiac event, An increased understanding of the factors that promote or hinder patients' return to optimal activity levels after a cardiac event is necessary to help them achieve this goal. Accordingly. the purpose of this study was to examine psychologic resources. depression. physical recovery. and illness severity for their relationships with subjective and objective physical functioning (exercise data). A correlational survey design was used to assess patients' (n = 46) illness responses 9 weeks after the cardiac event. Patients also participated in a symptom-limited exercise test. The findings suggested that the individual's return to greater activity levels after a cardiac illness was associated with less depression and illness severity. and higher levels of objective physical functioning. physical recovery. and self-esteem. Further. patients' objective physical functioning was associated not only with greater subjective physical functioning but also with greater levels of physical recovery and mastery.
Early histological and ultrastructural changes in medullary fracture callus, Light and electron microscopic studies of early changes in the medullary callus of a fracture of the rib in rabbits revealed the loss of normal architecture of the marrow and the disappearance of blood vessels in the region of high cellular density adjacent to the fibrin clot; the enlargement and transformation of capillary and venous endothelial cells in the region of low cellular density adjacent to the normal. uninjured marrow; the appearance of polymorphic mesenchymal cells throughout the medullary callus; and the appearance of osteoblasts and new-bone formation by twenty-four hours after the fracture. The meaning of these morphological changes is not clear. However. the spatial relationship between the various cells suggests the possibility that the transformed endothelial cells. reticular cells. and polymorphic mesenchymal cells may be interrelated and may either be osteoblast progenitor cells or may in some way lead to the appearance of osteoblasts in the early callus.
The revascularization of healing flexor tendons in the digital sheath. A vascular injection study in dogs, The role of revascularization in the nutritional support of repair of the flexor tendons is not completely understood. To explore the extent to which intrasynovial flexor tendons revascularize after transection and suture. a vascular injection study was carried out in a canine model. The tendons to the second and fifth digits of the forepaw in twelve adult mongrel dogs were transected and repaired. There were twenty-four experimental tendons and twenty-four normal tendons. The limb was placed in a polyurethane shoulder-spica cast. and the paw was treated with immediate protected passive mobilization. At three. seven. ten. seventeen. and twenty-eight days. the animals were killed and the major arteries supplying both the paw that had been operated on (left) and the contralateral normal paw (right) were injected with 200 milliliters of India ink. Segments of repaired and normal tendons were then clarified by a modified Spalteholz technique. The normal tendons demonstrated a well developed mesotenon that provided vascularization of the proximal portion of the flexor digitorum profundus tendon. A consistent three-cubic-millimeter avascular intrasynovial portion of tendon was noted. Distally. vessels arose from the vinculum breve. supplying the terminal twenty millimeters of tendon substance. In the experimental tendons. longitudinal and transverse clarified sections showed consistent revascularization of the site of repair by proximal vessels in the absence of ingrowth of peripheral adhesions. Vessels in the epitenon progressively extended for a distance of ten millimeters. through normally avascular regions. to reach the site of repair by the seventeenth postoperative day. Intratendinous vessels about the site of repair consistently originated from surface vessels. rather than from extensions of pre-existing intratendinous vessels. New vessels penetrated all areas. including the normally avascular volar segments of tendon. irrespective of previous topical zones of avascularity. Proximal vascular plexi were characterized by large tortuous vessels with frequent circuitous branches. More distal vessels had a longitudinally oriented. feathery appearance.
Formation of bone in tibial defects in a canine model. Histomorphometric and biomechanical studies, The histomorphometric. material. and structural properties of the reparative tissue and bone that formed in a two-millimeter tibial defect in dogs were determined at two. four. eight. and twelve weeks after the operation. At two weeks. the tibial defect was filled mainly with undifferentiated connective tissue. After two weeks. the relative proportion of undifferentiated connective tissue decreased and the amount of bone progressively increased throughout the twelve weeks. New bone formed primarily by intramembranous ossification. with a small degree of endochondral ossification. At twelve weeks. bone occupied 62 per cent of the defect. The calcium content of the reparative tissue increased between four and eight weeks and then. at twelve weeks. reached a plateau of 77 per cent that of normal cortical bone. Anisotropy of the new bone that formed in the defect increased from 13.8 per cent to 26 per cent. and the mean width of the trabecular bone increased 27 per cent between the eighth and twelfth weeks. Maximum torque and torsional stiffness increased between two and eight weeks and then. by twelve weeks. the values leveled off at 44 and 29 per cent of the values for intact bone. Indentation stiffness increased between the fourth and twelfth weeks; at twelve weeks. it was 22 per cent of the stiffness of normal cortical bone. Indentation stiffness increased 283 per cent between eight and twelve weeks. despite insignificant changes in calcium content. amount of new bone. non-osseous space. water content. or volume of trabecular bone during this time. This change in indentation stiffness did correlate with increases in anisotropy of the new bone between eight and twelve weeks.
The initiation of failure in cemented femoral components of hip arthroplasties, We studied 16 femora retrieved at post-mortem from symptomless patients who had a satisfactory cemented total hip arthroplasty from two weeks to 17 years earlier. with the aim of delineating the initial mechanisms involved in loosening. Only one specimen showed radiographic evidence of loosening; the other 15 were stable to mechanical testing at 17.0 Nm of torque. In all 16 specimens. the cement-bone interface was intact with little fibrous tissue formation. By contrast. separation at the cement-prosthesis interface and fractures in the cement mantle were frequent. The most common early feature was debonding of the cement from the metal. seen at the proximal and distal ends of the prosthesis. Specimens which had been in place for longer also showed circumferential fractures in the cement. near the cement-metal interface. and radial fractures extending from this interface into the cement and sometimes to the bony interface. The most extensive cement fractures appeared to have started at or near sharp corners in the metal. or where the cement mantle was thin or incomplete. Fractures were also related to voids in the cement. The time relationship in this series suggested that long-term failure of the fixation of cemented femoral components was primarily mechanical. starting with debonding at the interface between the cement and the prosthesis. and continuing as slowly developing fractures in the cement mantle.
Revision total hip arthroplasty for aseptic failure. A review of 276 cases, The results of 276 cemented revision total hip arthroplasties performed for aseptic failure between 1977 and 1986 have been reviewed. The mean time between revision and review was 75 months (range 30 to 144). Of 220 cases available for review. 159 were assessed clinically and radiographically. and 32 by postal questionnaire. Eighteen hips required further revision. 12 for loosening. two for sepsis. two for persistent pain. and one each for fracture and recurrent dislocation. A further six hips were radiologically and symptomatically loose. Pain was mild or absent in 83%. Over half were able to walk a mile or more; 70% flexed more than 70 degrees; 15% had a flexion deformity. but in only 7% was this more than 10 degrees. The mean Harris hip score was 74. Survival at five years was 95% and at 10 years. 77%.
Anteromedial osteoarthritis of the knee, Medial tibial plateaux excised during 46 unicompartmental arthroplasties for osteoarthritis were collected and photographed. The anterior cruciate ligament was intact in all joints. In every case the cartilage and bone erosion was centred anteriorly on the plateau and the posterior cartilage was intact. The site of the lesion and the intact state of the cruciate ligaments taken together explain why varus deformity was observed only in the extended knee. and why the deformity was correctable and had not become fixed. Failure of the anterior cruciate ligament may allow the erosion to extend posteriorly. producing fixed varus deformity and leading to degeneration of the lateral compartment. Anteromedial osteoarthritis is a distinct clinicopathological entity; its radiographic features enable it to be diagnosed from lateral radiographs; its anatomical features render it suitable for treatment by unicompartmental arthroplasty.
Neovascularisation of the meniscus with angiogenin. An experimental study in rabbits, Angiogenin. a potent blood vessel inducing protein. was implanted into experimentally injured menisci of 75 New Zealand white rabbits. Localised neovascularisation occurred in 52% of the angiogenin-treated animals. and in 9% of the controls. Neovascularisation induced by angiogenin may enhance healing of injuries within the poorly vascularised meniscal fibrocartilage. and improve the results of meniscal repair.
Fractures of the carpal scaphoid. A critical study of the standard splint, The effect of the position of splintage on displacement of fractures of the waist of the scaphoid was studied during operations and in cadavers. We found that these fractures were best splinted in neutral or slight palmar flexion with no ulnar deviation. Providing the wrist was not ulnar deviated. the position of the thumb had no effect on displacement.
The cubital tunnel and ulnar neuropathy, The anatomy of the cubital tunnel and its relationship to ulnar nerve compression is not well documented. In 27 cadaver elbows the proximal edge of the roof of the cubital tunnel was formed by a fibrous band that we call the cubital tunnel retinaculum (CTR). The band is about 4 mm wide. extending from the medial epicondyle to the olecranon. and perpendicular to the flexor carpi ulnaris aponeurosis. Variations in the CTR were classified into four types. In type 0 (n = 1) the CTR was absent. In type Ia (n = 17). the retinaculum was lax in extension and taut in full flexion. In type Ib (n = 6) it was tight in positions short of full flexion (90 degrees to 120 degrees). In type II (n = 3) it was replaced by a muscle. the anconeus epitrochlearis. The CTR appears to be a remnant of the anconeus epitrochlearis muscle and its function is to hold the ulnar nerve in position. Variations in the anatomy of the CTR may explain certain types of ulnar neuropathy. Its absence (type 0 CTR) permits ulnar nerve displacement. Type Ia is normal and does not cause ulnar neuropathy. Type Ib can cause dynamic nerve compression with elbow flexion. Type II may be associated with static compression due to the bulk of the anconeus epitrochlearis muscle.
Seasonal variation in the incidence of congenital talipes equinovarus, A review of 77 neonates who presented with congenital talipes equinovarus over a seven-year period revealed an increase in the condition amongst babies born in the winter quarter. This finding was particularly apparent among the less severe cases of club-foot. Possible reasons for this seasonal variation are discussed.
Ultrasonography in transient synovitis and early Perthes' disease, We used ultrasonography to examine 36 children suffering from transient synovitis and 12 children with early Perthes' disease. Widening of the joint space was revealed by ultrasonography in all affected hips with either disease. In the patients with transient synovitis. capsular distension was attributed to synovial effusion. while in the patients with Perthes' disease it was produced by thickening of the synovial membrane. Neither capsular distension nor thickening of the joint cartilage was seen in the contralateral normal hip in the patients with transient synovitis. but they were common in early Perthes' disease. Ultrasonography may provide significant diagnostic clues to differentiate early Perthes' from transient synovitis.
Transverse ligament rupture and atlanto-axial subluxation in children, We report four children aged two to nine years with traumatic tears of the transverse ligament of the atlas and atlanto-axial subluxation. This is extremely rare in this age group since trauma usually causes a skeletal rather than a ligamentous injury. The injuries resulted from falls or motor vehicle accidents. with considerable delay in diagnosis. Flexion radiographs showed atlas-dens intervals (ADI) of 6. 7. 8 and 13 mm; all four patients were treated by posterior fusion at C1-C2 after the failure of conservative treatment. In one child with quadriparesis and a fixed ADI of 13 mm. transoral anterior resection of the odontoid was performed before the fusion. Diagnosis of this traumatic lesion requires a high level of suspicion. Conservative treatment is likely to fail; surgical stabilisation is indicated.
The diagnosis of reflex sympathetic dystrophy using an algometer, Thirty-three patients with reflex sympathetic dystrophy were studied prospectively to ascertain the pressure-pain threshold of affected and unaffected limbs. The affected side had a lower threshold which was found to be statistically significant. In all 18 patients with upper limb involvement. the pain threshold was reduced on the affected side. but this applied to only 11 of the 15 with leg involvement. This difference may be because patients with lower limb symptoms had been referred later in the course of the syndrome. We showed by repeated tests that after an average of 49 days there was a slow return to normality. The estimation of pressure-pain thresholds may help in the earlier diagnosis of reflex sympathetic dystrophy.
A locking nail for fractures of the humerus, We reviewed 19 patients treated for upper arm fractures using Seidel's locking nail system. which allows for early function after operation. The overall results were good with no cases of pseudarthrosis. infection or radial nerve palsy. All the patients regained full shoulder movements with no evidence of rotator cuff lesions.
Axial movement and tibial fractures. A controlled randomised trial of treatment, Diaphyseal fractures of the tibia in 80 patients were treated by external skeletal fixation using a unilateral frame. either in a fixed mode or in a mode which allowed the application of a small amount of predominantly axial micromovement. Patients were allocated to each regime by random selection. Fracture healing was assessed clinically. radiologically and by measurement of the mechanical stiffness of the fracture. Both clinical and mechanical healing were enhanced in the group subjected to micromovement. compared to those treated with frames in a fixed mode possessing an overall stiffness similar to that of others in common clinical use. The differences in healing time were statistically significant and independently related to the treatment method. There was no difference in complication rates between treatment groups.
Inserting the distal screws in a locked femoral nail, We describe a simple method of inserting the distal screws in a locked femoral nail. The method requires no aiming device and no assistant. The only equipment needed is a 3 mm Kirschner wire and an air drill.
Subcutaneous sarcoma. A population-based study of 129 patients, We reviewed 129 patients with subcutaneous sarcoma diagnosed from 1964 to the end of 1985 in a population-based series of sarcoma cases from southern Sweden. The annual incidence was 0.4 per 100.000. comprising 32% of all soft-tissue sarcomas of the extremities or the trunk wall. Compared to deep-seated sarcomas. subcutaneous tumours were half the size at diagnosis. more common in the lower leg and foot. more often malignant fibrous histiocytoma. and of a lower grade of malignancy. None of the low-grade and only 7% of the high-grade tumours recurred locally after wide local excision without radiotherapy. The cumulative five-year survival for all 129 patients was 80%. Multivariate analysis identified only high grade of malignancy and the size of the tumour (greater than 5 cm) as independent prognostic factors. We conclude that systemic or local adjuvant therapy is not generally indicated for subcutaneous sarcoma because of the good prognosis and low local recurrence rate after wide excision.
Observer variation in the radiographic classification of ankle fractures, We recorded inter- and intra-observer variations in the classification of ankle fractures by the Lauge Hansen and Weber systems. Radiographs of 94 patients were classified independently by four observers. The observer variation was calculated by kappa statistics. which corrects the obtained values for the agreement expected by chance. There was an acceptable level of agreement for the overall classification into both systems. For the staging of supination-adduction and supination-eversion fractures in the Lauge Hansen system the agreement was poor. The results indicate that future classification systems should be subject to reliability analysis before they are accepted.
Dermatographism and cold-induced urticaria, Dermatographism and cold-induced urticaria are two common physical urticarias. Traditional treatment with antihistamines has been somewhat effective in alleviating symptoms; however. the sedative side effects of the agents pose problems. Results of treatment with the new low-sedating H1 antihistamines have been encouraging.
Therapeutic effects of cetirizine in delayed pressure urticaria: clinicopathologic findings, Cetirizine. a peripheral H1 antagonist. was administered to patients with delayed pressure urticaria in a double-blind. placebo-controlled. crossover study. Efficacy in reducing pressure-induced wheals and flares was evaluated. Histologic changes were also assessed with the skin window technique in weight-induced wheals. Results showed a statistically significant reduction in weight-induced wheal area (p less than 0.01) after cetirizine therapy; this improvement was accompanied by a concomitant reduction in eosinophil recruitment as demonstrated by the skin window technique (p = 0.0029). Subsequently. 14 patients with delayed pressure urticaria underwent biopsy before and after 3 weeks of cetirizine therapy to evaluate the drug's histologic effects. A blinded observer performed the histologic studies. Weight-induced lesions showed a mixed inflammatory infiltrate. primarily polymorphonuclear (neutrophils and eosinophils). whereas the unchallenged skin sites were normal. Cell counts from pressure-induced lesions showed a significant reduction in eosinophils after cetirizine treatment.
Eosinophil infiltration: effects of H1 antihistamines, This article reviews the contribution of cell-mediated inflammatory responses to the immediate immunoglobulin E-dependent allergic reaction. Apparently eosinophils play an important part in the pathogenesis of allergic reactions. Some new H1 antihistamines may also have non-H1-mediated antiinflammatory properties. In two double-blind. placebo-controlled. crossover studies of allergic and normal subjects. we showed that oral cetirizine. at dosages of 10 and 20 mg/day. significantly inhibited wheal-and-erythema reactions induced by grass pollen. 48/80. histamine. platelet-activating factor acether. and N-formyl-methionyl-leucyl-phenylalanine. In the first study. cutaneous eosinophil migration was significantly inhibited by cetirizine at pollen and 48/80 skin test sites (61%. p less than 0.01. and 53%. p less than 0.01. respectively). although no change was observed at histamine skin test sites. Inhibition of neutrophil accumulation was also observed at pollen and 48/80 sites (41%. p less than 0.1. and 31%. p less than 0.1. respectively). Monocyte accumulation was not affected by cetirizine. In the second study. cetirizine suppressed the eosinophil influx induced by pollen. platelet-activating factor. 400 ng. and platelet-activating factor. 40 ng (63%. p less than 0.001; 58.5%. p less than 0.001; and 57.8%. p less than 0.01. respectively). This inhibition was effective 2 hours after challenge and persisted through hours 4. 8. and 24. N-Formyl-methionyl-leucyl-phenylalanine induced a weak eosinophil accumulation that was inhibited by cetirizine.
Atopic dermatitis: new therapeutic considerations, Atopic dermatitis is a genetically determined inflammatory condition in which the primary defect is expressed in one or more hematopoietic cells that infiltrate the skin. It is a multifactorial disease with inflammation triggered by a variety of factors. Among these. atopic dermatitis has been experimentally induced and reproduced by emotional-stress interviews and food challenges only. The inflammatory events of atopic dermatitis appear to initiated by mast cells. but eosinophils. monocytes. and T lymphocytes (predominantly CD4) also are present in lesions. The secondary effects of inflammation are a dry. brittle stratum corneum and pruritus. causing excoriation and a lichenified epidermal layer resulting from chronic rubbing. Therapeutic approaches to atopic dermatitis may be directed at several points in the evolution of the disease. Agents including emollients are needed to preserve and restore the stratum corneum barrier. and effective antipruritics are required to reduce the self-inflicted damage to the involved skin. Various other agents may be needed to antagonize mediators or cytokines and to inhibit cytokine expression and release from lesional. immune-effector cells. Likewise. new phosphodiesterase inhibitors. calcium-active agents. and antiallergic drugs may be used to reduce the quantity and pathologic functioning of inflammatory infiltrating cells in the skin.
Identification of soybean dust as an epidemic asthma agent in urban areas by molecular marker and RAST analysis of aerosols, From 1981 to 1987. 26 outbreaks of asthma have occurred in the city of Barcelona. Spain. affecting a total of 687 subjects and causing 1155 emergency room admissions. Assays of urban aerosols collected with high-volume samplers between October 1986 and May 1989 have indicated that soybean dust originating from harbor activities (and not traffic or industrial pollution) is the causal agent for these epidemics. Soybean particulates in the filters have been characterized from the composition of the alcohol fraction. namely. campesterol. stigmasterol. beta-sitosterol. n-triacontan-1-ol. and n-dotriacontan-1-ol. constituting a series of aerosol components correlated with the epidemiologic data. This result has also been confirmed by immunochemical assay of specific soybean allergens. The concentration of these sterols in the air corresponds to a 24-hour average level of soybean dust in the order of 25 micrograms/m3 on epidemic days. These results suggest the advisability of monitoring soybean dust in air particulates of populated areas surrounding soybean storage or processing plants. The techniques presented here afford a simple way for the recognition of soybean dust in aerosols containing high concentrations of organic pollutants of traffic or industrial origin.
Immunotherapy decreases antigen-induced eosinophil cell migration into the nasal cavity, We investigated the effect of immunotherapy (IT) on eosinophil (EOS) migration into the nasal cavity after nasal provocation with ragweed antigen and during seasonal exposure. In the first study. three groups of subjects participated: one group with no treatment (N = 19). one group with 10 months of IT. reaching maintenance at 2 micrograms of Amb a I (antigen E) (N = 15). and one group with 22 months of IT. reaching maintenance at 24 micrograms of Amb a I (N = 10). The percent of EOSs in nasal lavages performed during December before and 24 hours after nasal challenge with ragweed extract was determined. No significant difference between groups existed before challenge. The no treatment group demonstrated a significant increase in the percent of EOSs from 26% to 69.5% (p less than 0.008). whereas the treated groups demonstrated no significant change. In the second study. 45 patients were divided into four groups based on maintenance dose in micrograms of Amb a I and duration of treatment: (1) no treatment (N = 15). (2) 1 year at 2 micrograms (N = 13). (3) 2 years at 2 micrograms (N = 11). and (4) 3 years at 24 micrograms (N = 9). Nasal mucosal brushings were done during the ragweed season. A significantly smaller percentage of EOSs in 3-year IT-treated individuals was obtained compared to the control group (18 versus 8.4; p less than 0.04). The smaller dose of IT. regardless of duration. did not reveal a reduction compared to that in the no-treatment group.
The pathophysiology of rhinitis. V. Sources of protein in allergen-induced nasal secretions, Allergic rhinitis is characterized by a profuse rhinorrhea in addition to paroxysms of sneezing. nasal congestion. and pruritus. To define better the sources of nasal secretion produced during rhinitis. nasal allergen challenges were performed on nine atopic subjects with seasonal rhinitis. A single dose of allergen was sprayed into one side of the nose. and nasal lavages were collected bilaterally for 7 hours. Nasal lavages were assayed for protein (total protein. albumin. lactoferrin. and lysozyme) and mediator (histamine and prostaglandin D2) content. Protein concentrations increased and remained elevated above baseline levels in both ipsilateral and contralateral secretions for up to 3 hours after allergen challenge. The proportion of albumin relative to total protein (the albumin percent) increased on the ipsilateral side. whereas the relative proportions of lactoferrin and lysozyme (the lactoferrin percent and lysozyme percent) increased on the contralateral side. Prostaglandin D2. but not histamine. increased selectively on the ipsilateral side. These data suggest that the ipsilateral protein secretory response is due to allergen-induced mast cell mediator release causing increased vascular permeability. whereas the contralateral protein secretory response is primarily a reflex-induced glandular secretion.
Differences in clinical and immunologic reactivity of patients allergic to grass pollens and to multiple-pollen species. II. Efficacy of a double-blind, placebo-controlled, specific immunotherapy with standardized extracts, The IgE response of patients only allergic to grass pollens differs from response of patients allergic to multiple-pollen species. The IgE immunoblots to orchard-grass pollens confirmed that polysensitized patients had more proteins revealed than patients only allergic to grass pollens. To determine if both groups of patients present a different response toward specific immunotherapy (IT). a double-blind. placebo-controlled study was performed in 70 patients. Patients receiving the active treatment had a rush IT with either a standardized orchard grass-pollen extract or with a standardized mixed-pollen extract prepared. depending on the sensitivity of the patients. The maintenance dose was defined as that dose effective in grass-pollen IT in previous experiments. The same equipotent maintenance dose was administered for all pollen species. Symptom-medication scores during the pollen season and nasal challenge with orchard grass-pollen grains demonstrated that grass pollen-allergic patients had a significantly improved efficacy by comparison to placebo treatment. whereas polysensitized patients had a nonsignificant improvement. Serum grass-pollen IgG was significantly increased after IT in both treated groups. This study demonstrate that the response toward specific IT differs in patients only allergic to grass pollens by comparison to polysensitized patients.
The distribution of bronchial responsiveness to histamine and exercise in 527 children and adolescents, The aim of the study was to describe the bronchial responsiveness to inhaled histamine and exercise in a randomly selected group of 527 children and adolescents from Copenhagen. aged between 7 to 16 years. The distribution of the bronchial responsiveness was described as (1) the provoking concentration that causes a 20% reduction in FEV1 (2) the dose-response slope (DRS). that is. the linear slope of the dose-response curve. and (3) reduction in FEV1 after 6 minutes of exercise on a treadmill. The distribution of the concentration that causes a 20% reduction in FEV1 in the responsive range was not significantly different from a unimodal distribution. although the findings were skewed toward the less responsive end of the range (p greater than 0.05). The subjects with asthma represented a subgroup within the responsive distribution tail rather than a separate distribution peak. In asymptomatic individuals. the values of DRS were distributed symmetrically on a logarithmic scale. The deviation from normal was such that the standard deviation only slightly underestimated the "normal" range. The distribution of the bronchial response to exercise was found to be significantly different from a normal distribution. However. a significant relationship was found between the bronchial response to inhaled histamine and exercise (p less than 0.0001). We conclude that there is a log-normal distribution of the bronchial response to inhaled histamine in a random sample of children and adolescents.
Review of clinical studies on cholesterol-lowering response to soy protein, Experiments on animals have shown that soybean protein has hypocholesterolemic and antiatherogenic properties. In human beings. substitution of soy protein for dietary animal protein or addition of soy protein to the diet lowers total and low-density-lipoprotein cholesterol levels in individuals with hypercholesterolemia. Reductions of 20% or more have been obtained with diets high in protein (about 20% of total energy) and relatively low in fat. Triglycerides are also decreased. particularly in subjects with hypertriglyceridemia. but soy-protein diets appear to have little effect on high-density-lipoprotein cholesterol levels. Responses are similar in men and women. but may be greater in younger than in older subjects. The hypocholesterolemic effect is thought to be mainly attributable to the protein itself rather than to nonprotein components of soy-protein preparations. The mechanism of action is not known. and it may not be possible to explain the observed effects in human beings and in experimental animal models by the same mechanism. Although the hypocholesterolemic response to dietary soy protein has been observed by a number of European research groups. substitution of soy protein for animal protein in North American diets has generally had little effect. for reasons that are still not clear.
Soy protein in relation to human protein and amino acid nutrition, The nutritional value of processed soy protein (isolated soy proteins and soy-protein concentrates) in human protein and amino acid nutrition is evaluated on the basis of a review of studies of growth and nitrogen balance in infants. children. adolescents. and adults. Findings show that well-processed soy-protein isolates and soy-protein concentrates can serve as the major. or even sole. source of protein intake and that their protein value is essentially equivalent to that of food proteins of animal origin. The importance of the sulfur amino acid content of soy protein for practical human nutrition is also examined from nitrogen-balance data. Under conditions of an anticipated normal usage of soy protein. methionine supplementation is not only unnecessary but may even be undesirable for young children and adults. However. for newborns. the data suggest that modest supplementation of soy-based formulas with methionine may be beneficial. Soy proteins have also been found to be of good quality to include in hypocaloric diets for weight reduction in obese subjects. Finally. the data indicate that soy proteins are well-tolerated and of good acceptability.
Increasing use of soyfoods and their potential role in cancer prevention, The United States produces approximately half of the world's soybeans. Although most of what is produced is used as animal feed. soy-protein products (eg. soy-protein flour. concentrates. and isolates) are used extensively by the food industry. primarily for their functional characteristics. such as emulsification. During the past decade. however. there has been a marked increase in the use of both traditional soyfoods. such as tofu and soymilk. and second-generation soyfoods. products which generally simulate familiar American dishes. Recently. attention has focused on the possible role of soybean consumption in reducing cancer risk. Soybeans contain. in relatively high concentrations. several compounds with demonstrated anticarcinogenic activity. Two of these compounds--protease inhibitors and phytic acid--have traditionally been viewed as antinutrients. The scientific community has begun to appreciate the potential importance of nonnutritive dietary compounds (phytochemicals) in foods such as soybeans. Dietitians need to become more aware of the phytochemical content of foods and the possible effect of phytochemicals on health and disease.
Prevalence of dementia in the 'oldest old' of a Dutch community, OBJECTIVE: To estimate the prevalence rate of dementia in subjects 85 years of age and over. DESIGN: A two-phase design with the Mini-Mental State Examination (MMSE) in the screening phase and the Geriatric Mental State Schedule (GMS) in the diagnostic phase. SETTING: Community survey including subjects in residential care. SUBJECTS: All (n = 1.259) inhabitants of Leiden. The Netherlands. aged 85 years and over on December 1. 1986. First phase participation rate was 71% (17% dropout due to death); second phase participation rate was 82%. MAIN OUTCOME MEASURE: DSM-III diagnosis of dementia without further specification of the etiology of the dementia. RESULTS: An overall prevalence rate of 23% (95% C.I.: 19%-26%) was found. This included 12% mild dementia. 7% moderate and 4% severe dementia. The prevalence rate was higher among women (24%) than among men (18%). It increased with age from 19% (95% C.I.: 16%-22%) in the group of 85-89 years to 32% (95% C.I.: 26%-39%) in the group of 90-94 years to 41% (95% C.I.: 25%-58%) in the 95+ group. CONCLUSION: A fifth of the 85+ and a third of the 90+ population suffer from dementia with an indication that half of the 95+ population is affected. With the expected steep rise in the number of the oldest old. dementia will stay a major health problem in the near future.
Pelvic muscle exercise for stress urinary incontinence in elderly women, PURPOSE: To compare pelvic muscle exercise to pharmacologic treatment of stress urinary incontinence. the most common cause of urine leakage reported by community-living elderly women. SUBJECTS: Convenience sample of 157 community-living women. aged 55 to 90 years. after completion of a comprehensive diagnostic evaluation. METHODS: Eighty-two subjects were randomly assigned to the exercise protocol (with a 34% attrition rate). Pelvic muscle exercises were taught and monitored for 6 months. Phenylpropanolamine hydrochloride was given to the other group in a dose of 50 mg a day. increasing to 50 mg twice a day. MAIN RESULTS: Treatment outcomes (subjective improvement. self recorded frequency of wetting) were equally satisfactory in both groups. The response to exercises was as good in 5 months as in 6. It was also as good when the minimum recommended number of exercises per day was 80 as when it was 125. CONCLUSIONS: Among those completing the protocol. pelvic exercises were beneficial in reducing stress incontinence. and the benefit was comparable to that produced by phenylpropanolamine.
Influences of dietary restriction on immunity to influenza in aged mice, Our previous studies of the immune response of aged mice inoculated with influenza A virus revealed age-related decreases in antigen-specific cytotoxic T-lymphocyte function (CTL). T-cell proliferation. IL-2 production. antigen presentation. and antibody production. Because dietary restriction (DR) of rodents has been shown to extend maximum life span. delay the onset of tumors. and improve many immunologic parameters in aged animals. we tested the effect of such a regimen on the immune response to the influenza virus. We report that DR significantly inhibited the age-related decline in antigen presentation and T-cell proliferation. It also reduced the decline in antibody production to the virus. This is the first demonstration of improved immunity to an actual infectious agent resulting from DR. The improvement appears to be on a number of levels and to reflect more than one operative mechanism.
Hyperdiploidy and trisomy of chromosome 15 in peritoneal macrophages of hyperimmune, older Swiss mice, Chromosome analysis was carried out in resident and exudate peritoneal macrophages and. also. in bone marrow cells of groups of mice either immunized with ovalbumin in complete Freund's adjuvant and challenged with the antigen. or stimulated with the irritant thioglycollic acid. Labeling of the phagocytic cells with colloidal carbon showed that dividing cells in the peritoneal cavity of experimental mice are resident macrophages. Also shown was an increase in number of hyperdiploid metaphases in hyperimmune. older mice but not in the young ones. Statistical analysis showed these differences to be significant. G-banding of hyperdiploid cells of hyperimmune older mice showed trisomy of chromosome 15 in several metaphases analyzed. The absence of hyperdiploid metaphases in the bone marrow cells of hyperimmune mice and in exudate macrophages of mice that received the irritant thioglycollic acid suggests that hyperdiploidy occurs in resident macrophages in the peritoneal cavity but not in their precursors in the bone marrow. These results raise some questions such as. hyperimmune older mice resident macrophages being prone to hyperdiploidy and trisomy of chromosome 15.
Causes and correlates of recurrent falls in ambulatory frail elderly, To determine causes and clinical correlates of recurrent falls in ambulatory frail elderly people. we evaluated 70 recurrent fallers and 56 nonfallers (mean age = 87 years) from two long-term care facilities. Evaluations included a detailed history. physical examination. performance-oriented mobility assessment. and laboratory studies. Primary causes including stroke. parkinsonism. blindness. drug-related hypotension. and arthritis were established for the most recent fall in 51 (73%) fallers. Eighteen fallers (26%) had multiple conditions that could not be prioritized for their contribution to the fall. Fallers were more often women. were functionally more impaired. and were taking more medications than nonfallers. Specific diseases did not distinguish fallers from nonfallers. Fallers of both sexes took more steps to turn 360 degrees. could not stand up from a chair without pushing off. had a higher prevalence of antidepressant use. and had impaired position sensation. These easily obtained clinical variables characterized nearly three-quarters of ambulatory elderly nursing home residents with a history of recurrent falls.
Dementia: case ascertainment in a community survey, The three-stage East Baltimore Mental Health Survey. conducted in 1981 as part of the Epidemiological Catchment Area Program. provided an opportunity to assess the prevalence of dementia and specific dementing disorders in a community-based. cross-sectional sample of the population. From the 3.841 households originally sampled. 810 individuals were selected for clinical psychiatric evaluation. Forty-one individuals were given a provisional diagnosis and referred to Stage 3 for differential diagnosis. with 32 individuals completing this evaluation. Thorough clinical evaluation of these cases resulted in an overall prevalence of dementia of 4.5% in those 65 years of age and older. The prevalence of specific dementing disorders was Alzheimer's disease (AD) (2.0%). Multi-Infarct Dementia (MID) (2.0%) and Mixed Dementia (MD) (0.5%). Prevalence increased with age for all dementias: Non-Whites had higher rates of dementia than Whites; females had higher rates of AD while males had higher rates of MID; and the prevalence of AD increased with increasing education. whereas the prevalence of MID decreased with increased education. Although this study includes only a small number of cases. necessitating some caution in interpreting the results. these figures do represent an estimate of the prevalence of severe dementing disorders and provide a basis for further community study.
Blood pressure, pulse, and neurohumoral responses to nitroprusside-induced hypotension in normotensive aging men, In order to assess the effects of age on blood pressure. pulse. and neurohumoral responses to hypotensive stress. we infused nitroprusside into healthy young and old men until mean arterial blood pressure was reduced 20% from basal. Elderly subjects were much more sensitive to nitroprusside. Pulse increases in response to this hypotensive stress were markedly reduced in the elderly. but renin. vasopressin. and norepinephrine responses were not different between young and old. We conclude that cardioacceleration. one of the primary defenses against hypotension. is impaired with age. However. neurohumoral responses to hypotension are intact in the elderly.
Cancer mortality, aging, and patterns of comorbidity in the United States: 1968 to 1986, Cancer is often reported as contributing to the risk of noncancer causes of death. The age variation of these reports was studied using U.S. data on all causes of death listed on death certificates for 1968 to 1986. The occurrence of cancer as a nonunderlying cause of death increased with age and was higher for treatable and slowly growing tumor types. These patterns persisted even if the cancer manifested changes in occurrence. Nonunderlying occurrences were highest in the 85 to 94 age group and were correlated with cancer survival. This suggests increased importance of cancer as a cause of death and a comorbid condition among oldest-old persons. The high rate of occurrence as an associated cause of death suggests that if life expectancy increases due to declines in circulatory and other chronic disease mortality. cancer could become the preeminent cause of death in the United States.
Relationship of cyclosporine A-mediated inhibition of clonal deletion and development of syngeneic graft-versus-host disease, We have described a strain-specific graft-vs-host disease (GVHD)-like syndrome in syngeneic mouse radiation chimeras that developed in two of seven strains tested after cyclosporine A (CsA) therapy. It has been suggested. recently. that autoreactive T cells that develop as a result of CsA treatment may result from inhibition of clonal deletion and could be responsible for the development of this disease. To test this hypothesis. TCR expression. as a measure of tolerance induction. was analyzed in a series of syngeneic radiation chimeras (inducible and noninducible for syngeneic GVHD). with and without CsA treatment. Clonal deletion. as assessed by anti-TCR V beta chain mAb. appeared to occur normally in strains of mice inducible for syngeneic GVHD. Conversely. animals in which T cells bearing self-reactive TCR could be detected. did not develop the disease. This discrepancy did not appear to be due to a generalized difference in the effects of CsA on the various strains of mice used. as the effects of the drug (i.e.. decreased mitogen responsiveness. inhibition of thymocyte maturation. etc.) appeared similar in all strains tested. Therefore. the development of CsA-induced autoreactive T cells as assessed by V beta TCR expression showed strain variation that did not correlate with the induction of syngeneic GVHD and suggested that other mechanisms may be involved in the development of this autoimmune phenomenon.
Defective immune adherence and elimination of hepatitis B surface antigen/antibody complexes in patients with mixed essential cryoglobulinemia type II, Mixed essential cryoglobulinemia type II (monoclonal Ig/polyclonal IgG) is characterized by systemic vasculitis caused by the deposition of circulating immune reactants that include the monoclonal component. Such reactants may include immune complexes (IC) formed from exogenous Ag. IC binding to E C receptor type 1 appears to play a role in transport and buffering of such IC (immune adherence: IA). To define the mechanisms responsible for immune deposition. 7 patients with cryoglobulinemia type II (IgM kappa/polyclonal IgG) and 14 normal volunteers were injected i.v. with hepatitis B surface Ag/antibody complexes. Two minutes after injection. only 19.4% (mean) of the circulating complexes were bound to E in patients as compared with 63.1% in normal subjects. This IA correlated directly with C4 and inversely with the IgM rheumatoid factor (RF) titer. Disappearance of IC was faster in patients (mean elimination rate: 15.7%/min) than in normal subjects (9.3%). In vitro experiments demonstrated that C depletion. interference with IC opsonization by monoclonal IgM RF. and decreased binding of opsonized IC in the presence of monoclonal RF are each associated with decreased IA. These observations suggest that. in patients with cryoglobulinemia type II. monoclonal IgM RF and low C contribute to reducing IA of circulating IC that might be rapidly trapped in tissues. resulting in injury.
IgG3 production in MRL/lpr mice is responsible for development of lupus nephritis, MRL/Mp-lpr/lpr (MRL/lpr) mice spontaneously develop lethal glomerulonephritis (GN) similar to human lupus nephritis. associated with the expression of lymphoproliferation gene lpr. To examine whether a particular IgG subclass is responsible for development of GN in these mice. first quantitative analysis of IgG subclasses in serum and in kidney eluates was performed. Although IgG2a was the dominant subclass in serum throughout the lifespan of mice. the IgG3 level in kidney eluates was three times higher than that of IgG2a at the 16 wk of age. which is the time of onset of development of severe GN. In sera of the 12-wk-old mice. half of the IgG3 was in immune complex form. whereas IgG2a in this form was only 17% of the total amount. Second. cyclosporin A. which ameliorates GN in MRL/lpr mice despite autoantibody production. was found to reduce serum IgG3 and mRNA levels. associated with the revision of cationic shift of the serum IgG3 spectrotype seen in isoelectric focusing. Third. among the hybrid mice with non-autoimmune-prone C3H/HeJ-lpr/lpr (C3H/lpr) mice. MRL/lpr x (MRL/lpr x C3H/lpr) F1. in which the genetic background for GN is likely segregated. the mRNA level for IgG3 correlated well with the degree of glomerular lesion. These findings indicate that production of IgG3 in MRL/lpr mice is one of the major factors responsible for development of GN in these mice. and that this is due to the genetic background of the MRL strain.
Administration of IL-7 to normal mice stimulates B-lymphopoiesis and peripheral lymphadenopathy, Normal mice were injected with IL-7 (500 ng. twice daily) for various periods of time up to 6 days and the cellularity and phenotypic composition of the thymus. spleen. lymph node. and bone marrow was assessed. After 6 days of treatment. significant increases in the cellularity of the spleen. lymph node. and bone marrow were observed which returned to the normal range within 6 days after cessation of treatment. After 3 days of IL-7 treatment. increased numbers of B220+/surface(s) IgM- bone marrow cells were observed. After 6 days of treatment. these numbers were still further increased and a significant population of B220+/sIgM- cells were observed in the spleen. The numbers of c mu+/sIgM- cells were also increased in the IL-7-treated mice. Analysis of the expression of B220 and BP-1 on the sIgM- bone marrow cells revealed that the B220+/BP-1+ population was dramatically increased after IL-7 treatment and the size of the B220+/BP-1- population did not differ from control mice. The pre-B cell numbers declined rapidly after the cessation of IL-7 treatment. After 6 days of IL-7 treatment. a twofold increase in the number of B cells in the spleen and lymph node was observed. The B cell numbers declined to normal values within 6 days after the cessation of IL-7 administration. In the spleens of the IL-7-treated mice. there was a significant increase in the number of B cells with an immature phenotype (e.g.. sIgMhi/sIgDlo. decreased levels of Ia and FcR expression). The numbers of CD8+ and CD4+ T cells were also increased in the lymph node and spleen of the IL-7-treated mice. These numbers declined to normal levels after the cessation of IL-7 treatment.
Site-directed mutagenesis of the region around Cys-241 of complement component C2. Evidence for a C4b binding site, We probed the functional significance of the region around Cys-241 in human C2 by testing the hemolytic activity of a series of mutant rC2. Mutant C2 cDNA were constructed by oligonucleotide-directed site-specific mutagenesis and expressed transiently in COS cells. Wild-type rC2 had threefold higher specific hemolytic activity than native serum C2. Substitution of Gly. Ala. or Ser for Cys-241 resulted in a slightly. but significantly. increased activity. In addition. I2 had no effect on the activity of these mutant C2. Substitution of Lys for Gln-243 increased the hemolytic activity by more than two-fold. Increased activity in all cases was due to slower decay rates of the C3 convertase. Finally. substitution of Leu or Ala for Asp-240 or Ser-244. respectively. resulted in more than 100-fold decrease of hemolytic activity. The results suggest that residues 240 to 244 of human C2 represent an important structural determinant of the C4b binding site of C2a. They also confirm that Cys-241 is the residue responsible for the increased activity of C2 reacted with I2.
Eosinophil activation on biologic surfaces. Production of O2- in response to physiologic soluble stimuli is differentially modulated by extracellular matrix components and endothelial cells, Production of O2- in response to FMLP. TNF. IFN-gamma. platelet activating factor. LPS. substance P. and PMA by human eosinophils in suspension and in contact with polystyrene ELISA plastic (PL) or biologic surfaces was studied. Monolayers of human endothelial cells (HEC) or PL coated with FCS. fibronectin. laminin. collagen types I and IV. fibrinogen. or fibrin were used as biologic surfaces. Only PMA and FMLP stimulated O2- generation by eosinophils in suspension. Eosinophils residing on HEC monolayers. either untreated or treated with LPS. were unresponsive to all stimuli except PMA. PMA induced O2- generation by eosinophils on all surfaces; FMLP on all surfaces but HEC monolayers; TNF and platelet-activating factor only on PL. fibrinogen. and fibrin; LPS and substance P only on PL. PMA was equally effective on eosinophils on surfaces and in suspension. whereas the effect of FMLP was greater on eosinophils on surfaces than on eosinophils in suspension. IFN-gamma was ineffective on any of the surfaces tested. These results indicate that biologic surfaces may profoundly affect the ability of eosinophils to respond with a respiratory burst to physiologically relevant soluble stimuli. the effect varying according to the nature of both the stimulus and the surface. Since the respiratory burst generates products of oxygen reduction that are toxic to several tissue components. it follows that biologic surfaces may modulate eosinophil-induced tissue injury.
Lipophosphoglycan masks recognition of the Leishmania donovani promastigote surface by human kala-azar serum, Markedly elevated titers of anti-leishmanial antibodies are a hallmark of kala-azar. We investigated the role played by the lipophosphoglycan (LPG) in determining the reactivity of kala-azar serum with the surface of Leishmania donovani promastigotes. In assays performed with liver parasites there was negligible agglutination or fluorescent staining of LPG-bearing promastigotes by kala-azar serum. but strong reactivity in both assays with the use of an L. donovani mutant strain (R2D2) that lacks surface expression of LPG. Immunoprecipitation of lysates of 125I surface-labeled promastigotes indicated that kala-azar serum has reactivity with several surface proteins common to both the wild-type and R2D2 strains. and no reactivity with surface proteins unique to R2D2. Although direct ELISA showed that kala-azar serum recognizes purified promastigote LPG. inhibition ELISA suggested that such recognition is based solely upon reactivity with the normally unexposed core-anchor region of the molecule. We conclude that the poor reactivity of kala-azar serum with the surface of L. donovani promastigotes is caused by its lack of recognition of the exposed phosphodisaccharide repeat units of LPG. which in turn effectively mask the surface molecules that are recognized by kala-azar serum antibodies.
Molecular characterization of the mouse mannose-binding proteins. The mannose-binding protein A but not C is an acute phase reactant, Mannose-binding proteins play a role in first line host defense against a variety of pathogens. We report the molecular cloning of two mouse mannose-binding proteins designated A and C based on their close identity with their rat homologues. The deduced amino acid sequence of the mouse mannose-binding proteins. as with rat and the human forms. have an NH2 terminus that is rich in cysteine that stabilizes a collagen alpha helix followed by a carboxyl- terminal carbohydrate binding domain. We further show that the mouse mannose-binding protein A mRNA. as with the human. is induced like the acute phase reactant serum amyloid P protein. yet the expression of mouse mannose-binding protein C mRNA is not regulated above its low baseline level. The expression of both mannose-binding proteins A and C mRNA is restricted to the liver under basal and stress conditions.
Specific adoptive immunotherapy mediated by tumor-draining lymph node cells sequentially activated with anti-CD3 and IL-2, Lymph nodes (LN) draining progressively growing tumors contain tumor-sensitized but not fully functional preeffector lymphocytes. These cells could acquire therapeutic efficacy and be expanded upon sequential culture with anti-CD3 mAb for 2 days followed by incubation in IL-2 for 3 days. Using the weakly immunogenic MCA 106 and MCA 205 murine sarcomas. we have further defined conditions of this anti-CD3/IL-2 activation with which preeffector cells differentiated into immune effector cells. In vitro activation and expansion of effector cells required sequential but independent stimulation with anti-CD3 and IL-2 because the simultaneous presence of both anti-CD3 and IL-2 at either stage did not enhance the efficacy of activation. Generation of effector cells by this two-stage activation was critically dependent on the optimal concentrations of anti-CD3 (1.0 microgram/ml) and IL-2 (2-10 U/ml). However. these conditions were not optimal for inducing the greatest cellular proliferation. In adoptive immunotherapy experiments. although the transfer of anti-CD3/IL-2-activated cells alone could mediate the regression of established metastases. the concomitant administration of IL-2 enhanced the in vivo activity of these cells. More importantly. tumor regression mediated by the anti-CD3/IL-2-activated cells was found to be immunologically specific. The specificity was determined by the tumor that stimulated the preeffector cell response. In spite of their in vivo antitumor effects. the anti-CD3/IL-2-activated tumor-draining LN cells did not exhibit detectable in vitro cytotoxicity against the tumor target in the 4-h 51Cr-release assay. In mice bearing progressive tumor. draining LN contained most preeffector cells. Some preeffector cells were also detected in the spleen whereas mesenteric LN did not demonstrate any reactivity. In kinetics studies. sensitization of preeffector cells in the draining LN occurred between 4 to 6 days after tumor inoculation. As the tumor progressed. the presence of preeffector cells declined gradually suggesting a tumor-induced suppression. These results define the conditions whereby tumor-draining LN cells could be stimulated. in the absence of tumor Ag. to develop into specific therapeutic effector cells. Our findings also raise the possibility of using similar approaches for isolating immune effector cells from cancer patients for adoptive immunotherapy.
The effect of an elemental diet with and without gluten on disease activity in dermatitis herpetiformis, Elemental diets are reported to decrease activity of patients with dermatitis herpetiformis. We tested the hypothesis that gluten. given in addition to an elemental diet. is responsible for the intestinal abnormalities. cutaneous immunoreactant deposition. and skin disease activity in dermatitis herpetiformis. At entry eight patients with dermatitis herpetiformis. who were consuming unrestricted diets. were stabilized on their suppressive medications at dosage levels that allowed individual lesions to erupt. Six patients were then given an elemental diet plus 30 of gluten for 2 weeks. followed by the elemental diet alone for 2 weeks. Conversely. two patients received an elemental diet alone for 2 weeks followed by an elemental diet plus gluten during the final 2 weeks. Small bowel biopsies. skin biopsies. and clinical assessments were done at 0. 2. and 4 weeks. Suppressive medication dose requirement decreased over the 4 weeks by a mean of 66%. Six of eight subjects significantly improved clinically during the gluten-challenge phase of the elemental diet and all were improved at the end of the study. The amount of IgA in perilesional skin did not change significantly. but the amount of C3 increased in five of seven evaluable subjects after gluten challenge. Circulating anti-gluten and anti-endomysial antibodies were not significantly affected by the diets. All subjects completing evaluable small bowel biopsies (seven of seven) demonstrated worsening of their villus architecture (by scanning electron microscopy and intraepithelial lymphocyte counts) during gluten challenge and improvement (six of six subjects) after 2 weeks of elemental dietary intake. We conclude that 1) there is a significant improvement in clinical disease activity on an elemental diet. independent of gluten administration. 2) small bowel morphology improves rapidly on an elemental diet. and 3) complement deposition but neither IgA deposition nor circulating antibody levels correlate with gluten intake. It seems likely that dietary factors other than gluten are important in the pathogenesis of the skin lesions in dermatitis herpetiformis.
Immunocytochemical analysis of the cellular infiltrate in primary regressing and non-regressing malignant melanoma, Spontaneous regression occurs in a small proportion of malignant melanomas. and it is important to understand the processes involved in its induction as this may give a guide to future therapies for this disease. We have examined 36 primary malignant melanomas (19 regressing. 17 non-regressing) and identified the cellular phenotypes and activation states of the cells infiltrating regressing and non-regressing primary melanomas by immunochemistry. We have found a significantly increased number of CD3-positive cells and an increased ratio of CD4/CD8-positive cells infiltrating regressing compared to non-regressing tumors. In addition. the expression of the interleukin 2 receptor. an activation marker for T cells. was increased. However. there were no significant differences in class II MHC. CD1. intercellular adhesion molecule 1 (ICAM1). or melanoma-associated differentiation-antigen expression in these tumors. These data are consistent with melanoma regression being induced by activated CD4 T cells and do not seem to be related to the differentiation markers we have examined on these tumors.
Examination of tetrachlorosalicylanilide (TCSA) photoallergy using in vitro photohapten-modified Langerhans cell-enriched epidermal cells, Lymphocytes from BALB/c mice photosensitized in vivo to tetrachlorosalicylanilide (TCSA) were investigated to determine whether they could be stimulated to proliferate when cultured with Langerhans cell-enriched cultured epidermal cells (LC-EC) photohapten-modified in vitro with TCSA + UVA radiation. Cultured LC-EC were photohapten-modified in vitro by irradiation in TCSA-containing medium using a 1000-watt solar simulator equipped with filters to deliver primarily UVA radiation (320-400 nm). Lymphocytes from TCSA-photosensitized mice were incubated with LC-EC that had been treated in vitro with 0.1 mM TCSA and 2 J/cm2 UVA radiation (TCSA + UVA). Responder lymphocytes demonstrated a significant increase in their blastogenesis response compared to lymphocytes that were incubated with LC-EC irradiated with UVA prior to treatment with TCSA (UVA/TCSA) or with LC-EC that had received no treatment. Lymphocytes from naive mice or mice photosensitized with musk ambrette (MA) demonstrated a significantly lower response to LC-EC modified with TCSA + UVA. indicating the specificity of the response. Maximum blastogenesis response was achieved when LC-EC were treated with 0.1 mM TCSA and a UVA radiation dose of at least 0.5 J/cm2. Epidermal cells depleted of LC by treatment with anti-Ia antibody plus complement or by an adherence procedure were unable to stimulate this blastogenesis response. Epidermal cells treated in vitro with TCSA + UVA demonstrated enhanced fluorescence compared to control cells. The fluorescence observed was not restricted to any specific epidermal cell type; however. fluorescence microscopy studies revealed that dendritic Ia-positive cells. presumably LC. were also TCSA fluorescent. Flow cytometry showed that Ia-positive epidermal cells demonstrated the greatest UV fluorescence when treated with TCSA + UVA compared to both cells irradiated with UVA and subsequently treated with TCSA and untreated cells. This is consistent with the enhanced antigen presentation capability of TCSA + UVA treated LC-EC. which leads to the conclusion that LC photohapten-modified in vitro with TCSA + UVA demonstrate enhanced TCSA fluorescence and are capable of stimulating lymphocytes from TCSA photosensitized mice in an antigen-specific manner.
Steady-state mRNA levels of collagens I, III, fibronectin, and collagenase in skin biopsies of systemic sclerosis patients, Total RNA was extracted from skin biopsies of nine patients suffering from systemic sclerosis (SSc). Steady-state mRNA levels of collagen alpha 1(I) and alpha 1(III). collagenase. fibronectin. and beta-actin were studied using specific cDNA probes and compared to those of 12 sex- and age-matched healthy individuals. There was a more than three-fold elevation of collagen I mRNA levels in SSc skin compared to controls. No difference was found. however. for collagen III. collagenase. and fibronectin mRNA levels in SSc and control biopsies. The selective increase of collagen alpha 1(I) mRNA levels indicates a specific alteration of fibroblast metabolism in scleroderma. Analysis of mRNA levels in skin biopsies might not only offer a direct approach to the understanding of the pathophysiology of SSc. but also facilitate the monitoring of fibrotic activity in SSc patients during therapeutic trials.
Expression of 1,25-dihydroxyvitamin D3 receptors in normal and psoriatic skin, Increasing evidence suggests an immunoregulatory function of the potent steroid hormone 1.25-dihydroxyvitamin D3 (1.25(OH)2D3) which has been successfully applied for treatment of psoriasis. The skin is both a site of production and a target of 1.25(OH)2D3. In vitro. 1.25(OH)2D3 inhibits proliferation and stimulates differentiation of keratinocytes. We investigated the in situ expression of vitamin D-receptors (VDR) in normal and psoriatic skin by immunochemical methods. The VDR were visualized using the monoclonal antibody (MoAb) 9A7g to the VDR and the labeled avidinbiotin technique. Immunoreactivity was consistently confined to nuclei in all skin biopsies. In normal skin specimens (n = 10) VDR antigens were expressed in keratinocytes of all epidermal layers (except those of the stratum corneum) and in cells of the epidermal appendages. Double labeling experiments with MoAb to cluster-defined antigens indicated that melanocytes and approximately 75% of Langerhans cells exhibit 1.25(OH)2D3 receptors in normal skin biopsies (n = 5). Depending on their localization in skin compartments 42-62% of CD11b+ positive macrophages and 45-75% of CD3+ T lymphocytes expressed VDR. Non-lesional psoriatic skin specimens (n = 8) revealed nearly identical staining patterns. Lesional psoriatic skin specimens (n = 8) exhibited a significant increase of VDR expression both in basal and suprabasal epidermal layers as measured by computer-assisted morphometry and showed a remarkable change of the immune cell pattern: the densitity and proportion of VDR positive T lymphocytes and macrophages were higher in the epidermal and the perivascular papillary loop compartment. These in vivo findings strongly support the hypothesis that 1.25(OH)2D3 modulates immune response and cell proliferation/differentiation in human skin.
Activation of collagen gene expression in keloids: co-localization of type I and VI collagen and transforming growth factor-beta 1 mRNA, Untreated. clinically active keloids were examined as model system to study the spatial expression of extracellular matrix and transforming growth factor-beta 1 (TGF-beta 1) genes in fibrotic skin diseases. In situ hybridizations localized active expression of type I and VI collagen genes to the areas containing an abundance of fibroblasts and apparently representing the expanding border of the lesions. Within this zone. microvascular endothelial cells also expressed the type I collagen genes. as evaluated by simultaneous use of in situ hybridization for collagen gene expression and immunolocalization for factor VIII-related antigen. a marker for endothelial cell differentiation. Slot-blot hybridizations of RNA isolated from this zone suggested that the expression of type I and IV collagen genes was selectively enhanced. as compared to type III collagen gene expression. TGF-beta 1 protein and mRNA were also detected in areas active in type I and type VI collagen gene expression. indicating that TGF-beta 1 gene is transcribed and the corresponding protein is deposited in areas of elevated collagen gene expression. including microvascular endothelial cells. We conclude that the initial step in the development of fibrotic reaction in keloids involves the expression of the TGF-beta 1 gene by the neovascular endothelial cells. thus activating the adjacent fibroblasts to express markedly elevated levels of TGF-beta 1. as well as type I and VI collagen genes.
Specific nucleotide sequence of HLA-C is strongly associated with psoriasis vulgaris, The association of specific HLA-C nucleotide sequences with psoriasis vulgaris was investigated in 75 Japanese patients by the polymerase chain reaction method. followed by slot-blot hybridization using two specific oligonucleotide probes. The synthesized nucleotide primers were C180P. 5'-GACCGGGAGACACAGAAGTACAAG-3' (coding for amino acid residues 61 to 68 of the alpha 1 domain of the HLA-C molecule) and C243PR. 5'-GCTCTGGTTGTAGTAGCCGCG-3' (residues 82 to 88). respectively. The amplified sequence detected with the probe C208A (5'-AGGCACAGGCTGACCGA-3'). including the coding region for alanine at position 73. was significantly increased in frequency in the patients compared with the healthy individuals (81% versus 48%. relative risk = 4.7. chi 2 = 15.3. p less than 0.0001). This specific nucleotide sequence is common to Cw6 and Cw7. but some other HLA-C alleles including Cw4 and C blank (Cx52) also proved to have this sequence. It is suggested that alanine at position 73 of HLA-C molecules can be a good marker for psoriasis vulgaris and that this residue may play an important role in determining susceptibility to this disease.
Identification of basement membrane zone antigens defined by antibodies that react to both the epidermal and dermal side of 1 M sodium chloride split skin, Some individuals have basement membrane zone (BMZ) antibodies that react to both the epidermal and dermal side of skin split with 1 M NaCl. To examine the significance of this combined staining pattern. we tested sera from 185 different. sequential. patients with BMZ antibodies for reactivity to normal human skin split with 1 M NaCl. Six sera (3.2%) stained both the epidermal and dermal sides of split skin. 173 (93.5%) stained only the epidermal side. and 6 (3.2%) only the dermal side. All six sera with a combined staining pattern yielded the same pattern when tested with three different specimens of skin. indicating that this pattern is reproducible. By immunoblot analysis. five (83%) of the six combined staining sera reacted to a 160-kD antigen present only in epidermal extracts of normal skin. one reacted in addition to a 230-kD epidermal antigen. and one did not react to either epidermal or dermal extracts. In contrast. five (83%) of the six sera with dermal staining reacted to a 290-kD antigen present only in dermal extracts. Eighteen (90%) of twenty representative epidermal staining sera reacted to a 230-kD epidermal antigen and seven (35%) sera (five with the 230-kD antibody and two without) also reacted to the 160-kD epidermal antigen. Affinity purified antibody to the 160-kD antigen defined by combined staining sera reacted to the BMZ of normal human skin. These results indicate that the combined staining pattern on 1 M NaCl split skin is due to the presence of a distinctive antibody response directed predominantly to a 160-kD BMZ antigen located on the epidermal side of the split skin and to an as yet unidentified BMZ antigen located on the dermal side.
Correlation between dermal interstitial immunoglobulin G and hypergammaglobulinemia, The diffuse dermal immunofluorescence (DDIF) observed in human skin biopsies that is produced by fluorochrome-conjugated antisera reactive with human immunoglobulin G (IgG) has commonly been viewed in the past as an artifact of direct immunofluorescence microscopy. However. it has been our belief that DDIF. which has been observed in 14% of the biopsies processed in our laboratory. might represent an in vivo phenomenon of excess unbound dermal interstitial immunoglobulin G reflective of elevated serum IgG levels. To examine this hypothesis. we carried out a blinded prospective study of the frequency of DDIF in two groups of age- and sex-matched patients that differed with respect to the presence or absence of serum hypergammaglobulinemia (gamma globulin greater than 2.5 mg/100 ml). The subjective intensity of DDIF and the fluorescein-isothiocyanate (FITC) conjugated anti-human IgG antibody titer at which point DDIF disappeared were both compared with serum gamma globulin levels. Also. the amount of IgG that could be extracted from biopsy specimens by an overnight phosphate-buffered saline (PBS) elution procedure was quantified by solid-phase immunoassay. We noted a trend of increased DDIF intensity with increasing serum gamma globulin levels. In addition. there was a relatively weak but significant positive correlation between DDIF endpoint titers and serum gamma globulin levels (p = 0.05. r = 0.429). The strongest positive statistical correlation observed in the study was between the quantities of IgG that could be eluted from skin biopsies and serum gamma globulin levels (p = 0.01. r = 0.599). These findings suggest that DDIF is a true biologic phenomenon reflective of elevated serum gamma globulin levels and demonstrate that simple overnight elution of unbound dermal IgG can unmask the presence of disease-related. specifically-bound IgG.
Randomized, cross over study to assess patient preference for an acoustically modified hearing aid system, It seems reasonable to postulate that if a patient has a hearing impairment at particular frequencies. selective amplification at those frequencies would be an advantage. Attempts have been made in the laboratory to show that when this is done scores on various audiometric tasks will improve. Whether such laboratory benefit will be preferred by patients in their daily life is another matter. Despite a lack of knowledge on this subject. modifications are frequently made to a hearing aid system in the expectation that this will improve auditory performance and hence be preferred by the patient. The most common modifications made to an ear level aid in the British National Health Service are adjusting the tone control and venting the ear mould with the aim of emphasizing the higher frequencies. A randomized crossover study was carried out in 83 first time hearing aid users with a mild to moderate hearing impairment to assess whether a hearing aid at the 'H' tone setting and with a 2 mm vented mould would be preferred by those with a more marked high frequency impairment. BE series aids were used so that any findings could be directly translated to NHS practice. No consistent preference for the modified system was identified when patients were subgrouped according to the overall slope (0.5 to 4 kHz) of their audiogram. However. when the slope between 0.25 and 1 kHz. which corresponds to the real ear effect of these modifications. was analyzed patients with a slope at these frequencies preferred the high-tone emphasis system (p less than 0.005).
Nasal endoscope in posterior epistaxis: a preliminary evaluation, The findings of a preliminary. prospective evaluation of the role of endoscopy in the management of adult posterior epistaxis are presented. A cohort of patients managed by the endoscopic technique was compared with a control group managed by the traditional methods of nasal packing or epistaxis balloons. The endoscope allowed visualization and direct treatment of previously undiagnosed posterior bleeding points. Patients managed by the endoscopic technique had a significantly shorter duration of in patient stay than those managed by traditional methods.
Non-Hodgkin's lymphoma involving the tonsil: an immunohistochemical study, Twenty-one patients with non-Hodgkin's lymphoma involving the palatine tonsil were studied in an attempt to relate pathological data to clinical outcome. Eleven tumours were classified as low-grade and ten as high-grade on morphological criteria. The results of immunohistochemical investigations are presented; all tumours but one were of B-cell origin. None of the pathological factors studied were found to be useful prognostic indicators.
Arytenoidectomy and posterior cordectomy for bilateral abductor paralysis, Twelve patients with bilateral fixed vocal cords seeking decannulation of their tracheostomies were subjected to endoscopic correction of the compromised airway. They all had arytenoidectomy associated with posterior cordectomy whether as a primary or secondary stage procedure. Decannulation was achieved in all patients using the technique described.
Primary treatment of cancer of the larynx, Analysis of 3.445 cases of cancer of the larynx with a follow-up of 99.8 per cent shows that over a period in which the survival has improved neither the modality of the treatment nor the severity of the cancer has changed. Improved survival may be due to socioeconomic factors or an improvement in the quality of treatment.
Chondrosarcoma of the parapharyngeal space, Chondrosarcoma is rarely found arising in the head and neck region. An unusual case arising in the parapharyngeal space in a male is reported and the differential diagnosis. pathology and treatment are discussed.
Aberrant central venous catheter complicating radical neck dissection, Abnormal migration of central venous catheters is especially common in the case of long lines inserted via the antecubital fossa. A case is described of internal jugular vein migration of a central venous catheter complicating an ipsilateral radical neck dissection.
Improved detection of hypotension by automated noninvasive blood pressure monitoring, This study was undertaken to determine whether the use of automated noninvasive blood pressure monitoring altered the frequency of detection of intraoperative hypotension. We retrospectively reviewed 1.861 anesthetic records from a period in 1987. when blood pressure was obtained manually by auscultation. We compared the records from 1987 with 1.716 anesthetic records from 1989. when automated blood pressure monitors were used universally. The incidences of hypotension requiring vasopressor therapy were determined during the two periods and compared using Student's two-tailed t test. The data revealed that the incidence of detected hypotension increased from 2.4 to 5.2% with the use of automated blood pressure monitors (P less than 0.00002). We conclude that at our hospital the use of automated noninvasive blood pressure monitors increases the incidence of detection of intraoperative hypotension as compared with the use of manual blood pressure measurement.
A prospective comparison of neuropsychologic performance of children surviving leukemia who received 18-Gy, 24-Gy, or no cranial irradiation, To compare the late neuropsychologic toxicities of CNS prophylaxis for childhood acute lymphoblastic leukemia (ALL). longitudinal assessments were performed on three groups of patients: those who received repeated courses of moderate-dose (1 g/m2) intravenous (IV) and intrathecal methotrexate (IT MTX) without cranial irradiation (MTX group. n = 26). those who received IT MTX and 18 Gy cranial irradiation (18-Gy group. n = 23). and those who received IT MTX and 24 Gy cranial irradiation (24-Gy group. n = 28). All patients were free of CNS leukemia at diagnosis and had remained in continuous. complete remission 5 to 11 years (median. 7.4 years) following CNS prophylaxis. An analysis of serial intelligence quotient (IQ). achievement. and neuropsychologic studies revealed no significant influence of either age at CNS prophylaxis or CNS prophylaxis group on any neuropsychologic outcome measure. After adjusting for changes in IQ test versions that were necessitated by advancing patient age. no statistically significant declines in Verbal. Performance. or Full Scale IQs were noted for the three CNS treatment groups. However. comparisons of group means masked declines in individual children; 22% to 30% of children exhibited a clinically significant deterioration (greater than or equal to 15 points) in uncorrected IQ values over the study period. Female sex was associated with an increased risk of deterioration in Verbal IQ. but we were unable to identify risk factors associated with other declines in intellect and achievement. The inability to reliably predict individual patients at risk for clinically significant neuropsychologic toxicities on the basis of age at diagnosis or specific method of CNS prophylaxis suggests that other etiologic factors must be explored as the basis for these changes. such as ecologic factors and chemotherapy during the continuation phase of treatment.
Interleukin-2 and lymphokine-activated killer cells in 15 children with advanced metastatic neuroblastoma, A phase II trial using interleukin-2 (IL2) and lymphokine-activated killer (LAK) cells was carried out in an attempt to treat children with end-stage neuroblastoma. Fifteen patients (median age. 7 years) were enrolled in the study. Twelve were in relapse after massive chemotherapy and autologous bone marrow transplantation (ABMT). and three had a primary refractory disease after conventional chemotherapy. IL2 was administered as an 18 x 10(6) IU/m2/d continuous infusion. One course consisted of a double 5-day treatment period separated by a 6-day break. Cytapheresis to harvest LAK progenitor cells was performed during the rest period. After a 4-day in vitro culture. LAK cells were reinjected during the second cycle of therapy. A phenotypic and functional analysis of immunologic parameters was conducted along with the therapeutic protocol. Toxicity was significant with two toxic deaths (cardiotoxicity and respiratory distress). The reinfusion of large amounts of LAK cells was clearly involved in one case. but this particularly severe toxicity has to be related to the patient's status (ie. heavy pretreatment). No significant clinical response was seen. The immunologic monitoring showed phenotypic and functional modifications in these patients before initiation of treatment and an unexpected absence of evolution of these parameters during IL2 therapy. Although the origin of these immune dysfunctions is not clear. they could be involved in the failure of IL2 therapy. Future studies of IL2 therapy in neuroblastoma should be undertaken earlier in the course of the disease.
Cisplatin and fluorouracil chemotherapy does not yield long-term benefit in locally advanced head and neck cancer: results from a single institution, Fifty-one patients with locally advanced head and neck cancer were treated with three cycles of cisplatin at 100 mg/m2 followed by 5-day continuous infusion fluorouracil (5-FU) at 1.000 mg/m2/d as induction chemotherapy. Subsequent local therapy consisted of surgery for patients with resectable disease and/or radiotherapy. Three cycles of adjuvant chemotherapy were administered to patients with partial response (PR) or complete response (CR) to induction chemotherapy. Twenty-two patients (43%) had a clinical CR that was pathologically confirmed in 12 patients (24%). and 24 patients (47%) had a PR for an overall response rate of 90%. Local therapy included surgery in 24 patients (47%) and radiotherapy alone in 22 patients (43%). Adjuvant chemotherapy was administered to 32 patients (63%) frequently at great dose reduction. At a median follow-up of 90 months. the median survival is 22 months (95% confidence interval. 15 to 36 months). and the 5-year survival is 25%. with only five patients known to be alive and disease-free at this time. The median time to progression is 14 months. with 29 patients (57%) having documented progression of their head and neck cancer and eight (16%) having progression of a second neoplasm. Seven patients died of intervening medical events. This high incidence of second malignancies supports the continued investigation of chemoprevention for patients in CR. Despite the known high response rates achieved with cisplatin and 5-FU induction chemotherapy. the overall poor survival data reported here should lead to a thorough reexamination of the frequent administration of this regimen in the community.
A phase I-II trial of induction chemotherapy with carboplatin and fluorouracil in locally advanced head and neck squamous cell carcinoma: a report from the UCL-Oncology Group, Belgium, Eighty-three patients (median age. 56 years and Karnofsky performance status greater than or equal to 70) were treated with carboplatin (Carbo) and fluorouracil (5Fu) for stage III and IV head and neck squamous cell carcinoma (HNSCC). 5Fu (1 g/m2/d) was administered from day 1 to 4 by continuous infusion. Carbo was given on day 1 and. in order to evaluate its maximum-tolerated dose (MTD). the dose level was progressively increased from 250 mg/m2 to 450 mg/m2. The effectiveness of this association and its potential role in local control were also evaluated. Three patients received Carbo at a dose of 250 mg/m2. 13 received 300 mg/m2. one received 330 mg/m2. 12 received 350 mg/m2. six received 375 mg/m2. 26 received 400 mg/m2. 18 received 420 mg/m2. and four received 450 mg/m2. Two (13 of 83) or three courses (64 of 83). repeated every 4 weeks. were administered. The overall (primary tumor and node) response and complete response (CR) rates were 33% and 14%. respectively. For primary tumor. the response rate (RR) was 57% with 32% CR and 18% pathologic complete response (PCR); the RR was higher for patients with oropharyngeal tumor (76%. P = .037) and for patients treated with Carbo greater than or equal to 350 mg/m2 (65%. P = .02); the tumor size (T1 + T2 v T3 + T4) was a good prognostic factor for RR (90% v 46%. P = .001). CR (65% v 20%. P less than .001). and PCR (45% v 8%. P less than .001). For nodes. the RR was 33% with 11% CR. Grade 3-4 neutropenia and thrombocytopenia were experienced by 17% and 28% of the patients treated with 420 mg/m2 of Carbo and by 50% of the patients treated with 450 mg/m2. The MTD can be fixed at 420 mg/m2 and the proposed dose at 400 mg/m2. Thirty-eight patients were treated with surgery plus radiotherapy. 33 with radiotherapy alone. and seven with surgery alone. The median follow-up is 12 months. The 18-month disease-free survival (DFS) is 78% for overall complete responders and 39% for the others (P = .04). There is no primary tumor recurrence among the 12 patients with a primary tumor PCR treated by radiotherapy alone for tumor control (median follow-up. 17.3 months). The association of Carbo-5Fu is a safe induction chemotherapy regimen for HNSCC. The proposed dose of Carbo for future treatment is 400 mg/m2.(ABSTRACT TRUNCATED AT 400 WORDS).
CHLVPP chemotherapy with involved-field irradiation for Hodgkin's disease: favorable results with acceptable toxicity, Patients with Hodgkin's disease who were previously untreated with chemotherapy received the chlorambucil. vinblastine. procarbazine. and prednisone (CHLVPP) regimen plus limited involved-field radiation therapy for treatment of Hodgkin's disease through the Nebraska Lymphoma Study Group. One hundred patients. 87 with newly diagnosed Hodgkin's disease and 13 who relapsed after receiving previous radiation therapy. were treated with this regimen between 1982 and 1989. Complete remissions (CRs) were obtained in 88 of 100 patients (88%). and there have been a total of eight relapses. The overall 3-year failure-free survival was 76%. with good-prognosis patients (ie. Karnofsky performance status greater than or equal to 80) having a 3-year failure-free survival of 87%. Toxicity with this regimen was minimal. with neutropenic fevers reported in 13% of the patient population. moderate alopecia in 5%. and mild to moderate nausea and vomiting in 11% of the patients. As primary induction therapy for Hodgkin's disease. CHLVPP is an effective regimen with a high patient acceptance profile.
Comparison of cyclophosphamide, doxorubicin, and vincristine with an alternating regimen of methotrexate, etoposide, and cisplatin/cyclophosphamide, doxorubicin, and vincristine in the treatment of extensive-disease small-cell lung carcinoma: a Mid-Atlantic Oncology Program study, An alternating regimen for the treatment of extensive-disease small-cell lung cancer (SCLC) was compared with standard treatment with cyclophosphamide. doxorubicin. and vincristine (CAV) in 170 patients. Overall severity of toxicity was similar in both arms. with four toxic deaths in each arm (4.7%). Response results were also similar. with 54% complete and partial responses with the standard regimen and 53% complete and partial responses with the alternating regimen. Median survival time was 6.9 months with the standard regimen and 9.2 months with the alternating regimen (P = .078). The 2-year survival rate was 1.2% for the standard regimen and 4.7% for the alternating regimen. Survival benefit for treatment with the alternating regimen reached statistical significance only in those subsets of patients with poorer prognosis (male sex. performance status 3. liver metastases. bone marrow metastases. and oat cell histologic subtype).
Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity, We have previously demonstrated that individualized dosing of etoposide (VP16) by 72-hour infusion is feasible and that the extent of leukopenia is a function of plasma concentration. pretreatment WBC (WBCp). albumin (ALB). performance status (PS). and bone marrow function (based on transfusion requirements). In the current study. 45 patients were randomized between a fixed dose of VP16 (125 mg/m2/d) versus individualized dosing to a target WBC nadir (WBCN) of 1.700/microL. The total dose was increased by an average of 22% in the latter patients (459 +/- 130 mg/m2 v 375 mg/m2. P = .002). This was associated with a decrease in both the mean WBCN (1.510 +/- 950 v 2.500 +/- 1.420/microL. P = .013) and in the variability of the WBCN (P = .039). The VP16 clearance (mL/min) was not correlated with body surface area. Partial responses were observed in one patient each with hepatoma and non-Hodgkin's lymphoma. We conclude that pharmacologically based dosing may be a means of increasing dose intensity without increasing the incidence of life-threatening toxicity due to a decrease in variability around a target WBC.
Socioeconomic status and cancer survival, Survival data from eight Cancer and Leukemia Group B (CALGB) protocols were examined for patients with lung cancer (N = 961). multiple myeloma (N = 577). gastric cancer (N = 231). pancreatic cancer (N = 174). breast cancer (N = 87). and Hodgkin's disease (N = 58). After accounting for differences in survival rate attributable to type of cancer. initial performance status. age. and 14 other protocol-specific prognostic indicators. the additional predictive value of socioeconomic status (SES) was evaluated. Race (white v non-white) was not a significant predictor of survival time. but income and education were. People with lower annual incomes (below $5.000 per year in the years 1977 to 1981) and those with lower educational level (grade school only) showed survival times significantly shorter than those with higher income or education. respectively. These survival differences were associated with. but could not be fully explained by. severity of disease at initial presentation. SES continued to exert a small but significant impact on cancer survival. even after controlling for all known prognostic variables. Economically and educationally disadvantaged cancer patients may require treatment programs that include education about treatment and compliance. even after an initial diagnosis is made and treatment is initiated. Because SES is related to survival independent of all known prognostic variables. it should be included in the data bases of clinical trial groups to provide a more accurate test of the effectiveness of new therapies.
Histological grading and bromodeoxyuridine labeling index of astrocytomas. Comparative study in a series of 60 cases, The histological grade and the bromodeoxyuridine (BUdR) labeling index of 60 astrocytomas of "ordinary" cell types (fibrillary. protoplasmic. gemistocytic. and anaplastic astrocytomas and glioblastomas) were compared to determine whether the grading system reflects the proliferative potential of the tumors. The tumor grade was based on the presence or absence of four criteria (nuclear abnormalities. mitosis. necrosis. and vascular endothelial proliferation): Grade 1. no criterion. Grade 2. one criterion. Grade 3. two criteria; and Grade 4. three or four criteria. The BUdR labeling index. or percentage of S-phase cells. was calculated in paraffin-embedded tumor sections after in situ labeling by intraoperative intravenous infusion of BUdR. 200 mg/sq m. Exponential regression analyses showed a positive correlation between the histological grade and labeling index (r = 0.88. p less than 0.001) that was stronger than the correlations between log labeling index and age (r = 0.55. p less than 0.001) and between grade and age (r = 0.55. p less than 0.001). These results indicate that the histological grading system reflects the proliferative potential of "ordinary" astrocytomas.
Evaluation and treatment of atlas burst fractures (Jefferson fractures), Although several large series of atlas fractures have been reported recently. none has concentrated on the evaluation and treatment of atlas burst fractures (Jefferson fractures). The treatment of this fracture is challenging. Its diagnosis may easily be missed due to concerns about associated trauma and absence of neurological signs. In addition. the open-mouth anteroposterior x-ray study. which is usually pathognomonic for the diagnosis. is often inadequate or not obtained. In order to clarify the diagnosis and treatment of this disorder. 17 cases of Jefferson fracture treated between 1982 and 1989 at the Louisiana State University Affiliated Hospitals are presented. The diagnosis was delayed in three patients because of a low index of suspicion and inadequate x-ray films. Four patients were noted to have unstable Jefferson fractures. all of these had an associated Type II odontoid fracture and were treated with occiput-C-2 wiring and fusion. The remainder of the patients had stable Jefferson fractures and were managed with Minerva jackets or rigid collar stabilization. No significant complications related to the treatment of the Jefferson fracture occurred in this series. One patient died from associated injuries; however. the remaining patients enjoyed an excellent long-term result with the acquisition of spinal stability and the resolution of subjective complaints.
Possible roles of basic fibroblast growth factor in the pathogenesis of moyamoya disease: an immunohistochemical study, Prominent features of moyamoya disease are fibrocellular thickening of the intima and enhanced angiogenesis. The pathogenesis of moyamoya disease is. however. unknown. Basic fibroblast growth factor (FGF) is an angiogenic factor as well as a potent mitogen for a number of cell types including vascular endothelial and smooth-muscle cells. In order to test the possibility that basic FGF takes part in the pathogenesis of moyamoya disease. the authors tested for the presence of this factor using a mouse monoclonal antibody against human recombinant basic FGF. The surgical specimens studied included two sections of the superficial temporal artery (STA) and four samples of dura mater from four patients with moyamoya disease. Surgical specimens were obtained from three patients with other diseases as control tissue. Sections of the STA obtained from the patients with moyamoya disease showed strong basic FGF immunoreactivity in endothelial and smooth-muscle cells. while control sections had only faint and scattered immunoreactivity. All sections of the dura mater obtained from the patients with moyamoya disease also revealed more intense immunohistochemical staining of basic FGF in meningeal and vascular cells than did control sections. These observations indicate that the amount of basic FGF is increased in the tissues of patients with moyamoya disease; thus. basic FGF may play an important role in the pathogenesis of moyamoya disease.
Cross-resistance patterns in ACNU-resistant glioma sublines in culture, Three ACNU-resistant clones (R1. R3. and R12) were isolated from 9L rat glioma cells under selection pressure of ACNU in vitro. The authors have investigated the mechanisms of resistance and characteristics of these clones at the cellular level by studying cross-resistance patterns to chemical and physical agents. Although these resistant sublines showed complete cross-resistance to methyl-chloroethylnitrosourea (MCNU). no cross-resistance was observed for other alkylating agents. while each of the resistant sublines showed partial cross-resistance to structurally dissimilar toxic agents (vinblastine. Adriamycin. and VP-16). No difference in ACNU uptake was observed between 9L and R3 cells. and resistance patterns among alkylating agents suggested that the mechanism of ACNU resistance was specific to bifunctional nitrosoureas. Based on a transport study. this multidrug resistance could be explained by reduced intracellular uptake of these drugs. but there seemed little possibility that membrane P-glycoprotein. which usually is observed in typical multidrug-resistant cells. was expressed in these ACNU-resistant cells because enhanced drug efflux was not found in ACNU-resistant sublines. Significant collateral sensitivity to L-asparaginase indicated that ACNU might disturb the asparagine synthetic pathways by its mutagenic action. The increased level of total glutathione in the resistant sublines may be one mechanism of radiation or ACNU resistance.
Coronary vasospasm following subarachnoid hemorrhage as a cause of stunned myocardium. Case report, A patient with subarachnoid hemorrhage was found to have electrocardiographic abnormalities resembling an acute myocardial infarction as well as left ventriculographic findings of cardiac dysfunction. These cardiac abnormalities resolved following surgical clipping of the aneurysm and the patient recovered well from the operation. She died 2 months later from cancer and a postmortem examination at that time revealed no evidence of myocardial necrosis. In this report. the authors discuss coronary vasospasm and reversible postischemic "stunned myocardium." a condition that has not been considered previously in relation to subarachnoid hemorrhage.
Cervical paraganglioma with subsequent intracranial and intraspinal metastases. Case report, Paragangliomas. tumors derived from the extra-adrenal paraganglion system. have commonly been found in the retroperitoneum. abdomen. mediastinum. skull base. and neck. Rare intraspinal cases have included involvement of the cauda equina and filum terminale. and a recent case has been reported of thoracic cord paraganglioma with metastasis to the cauda equina. The authors present the case of a patient with a cervical paraganglioma who underwent subtotal resection followed by postoperative irradiation; she subsequently developed multiple intracranial and intraspinal metastases 7 months following the first decompression procedure.
Identification of the proximal neck of giant paraclinoidal aneurysms. Technical note, Introduction of a double-lumen Swan-Ganz balloon catheter into the parent artery facilitated precise identification of the proximal neck in two giant paraclinoidal aneurysms. Reduction of the flow rate as low as possible and positioning of the patient's head were the most important factors in this procedure.
Management of oral submucous fibrosis: a conservative approach, Three hundred twenty-six patients with oral submucous fibrosis were divided into two groups and treated either with conventional submucosal injections of steroids and hyaluronidase. or with topical vitamin A. steroid applications. and oral iron preparations. The results were compared. The conventional treatment with injections was found to be hazardous. whereas the conservative treatment was found to be safe. Both treatments were purely palliative.
Sonography and scintigraphy in the diagnosis of diseases of the major salivary glands, This is a prospective study of 73 patients with diseases of the major salivary glands. The sonographic diagnosis could be confirmed by the course of the disease and/or the histologic result after operation in 67 (93%). In 29 patients. salivary gland scintigrams also were carried out. There was a tendency for signs of hypervascularization to be seen in patients with acute inflammation and reduction or loss of function in the presence of a chronic inflammation of the salivary glands. Scintigraphy did not provide diagnostic information on tumors of the salivary glands with regard to the type and location. with the exception of the Warthin's tumor. In selected cases it adds additional information. especially in functional therapy control.
A comparison of profile changes between ramus and anterior mandibular subapical osteotomies in class III Chinese patients, The purpose of this study was to compare cephalometrically the differences in soft-tissue profile changes produced by intraoral ramus and anterior subapical osteotomies for the treatment of Chinese patients with class III malocclusion. Thirty-seven Chinese adults whose class III malocclusion was treated either with an intraoral ramus (group A) or an anterior subapical (group B) osteotomy were selected for the study. Serial lateral cephalograms taken presurgically (T1) and at least 6 months postrentention (T2). showed marked improvement in the soft-tissue profile in both groups. Although the percentage response of soft- to hard-tissue movement was similar at lebrale inferius. the response at soft-tissue point B was found to be statistically less in group B than in group A (P less than .05). Although the correlation between the upper lip response to mandibular ramus setback in group A was weak (r = 0.11). there appeared to be a relatively strong correlation between posterior movement of the upper lip and the magnitude of the lower segmental setback (r = 0.65). The differences in soft- to hard-tissue response with the two osteotomy procedures appear to vary with those reported in whites. This study emphasizes the need for different prediction ratios of soft- to hard-tissue movement in different racial types.
Serum sialic acid levels in patients with oral and maxillofacial malignancy, Serum sialic acid levels were measured using the thiobarbituric acid method in 80 healthy subjects and in 40 patients with benign and 61 with malignant tumors in the oral and maxillofacial region. It was shown that the cancer group had statistically higher sialic acid levels than control group and the group with benign disease (P less than .05). but no significant difference was noted between the normal control group and the patients with benign tumor (P greater than .05). Serum sialic acid levels were significantly higher in the patients with stages III and IV cancer than in those individuals with stage I and II cancer. but no differences were seen between stages I and II. and between stages III and IV cancer patients (P greater than .05). There was also no difference when considering the anatomic site of the malignant lesion. Furthermore. during the serial sialic acid determination in cancer patients before and following treatment. the sialic acid levels usually declined with remission of the disease and increased with recurrence. metastasis. or a poor prognosis. We conclude from this study that the sequential measurement of sialic acid level is particularly useful in monitoring patients with oral cancer. and sialic acid may prove to be a valuable tumor marker in oral and maxillofacial malignancy.
Development of an in vitro temporomandibular joint cartilage analog, A method of producing an in vitro cartilage tissue analog by traditional organ culture methods in an animal model is presented. The resultant tissue analog had the clinical appearance and characteristics of the temporomandibular joint disc. Development of such an analog for in vivo autografting could provide an alternative to present methods for disc repair.
Effect of chitosan on lingual hemostasis in rabbits, Bleeding times were measured for bilateral (15 mm x 2 mm) tongue incisions in 14 New Zealand white rabbits. Using a randomized. blinded experimental design. one incision in each animal was treated with chitosan and the other was treated with control vehicle without chitosan. Extraoral bleeding and coagulation times were also measured for each animal preoperatively. postoperatively. and prior to killing to verify normal bleeding parameters and to evaluate possible systemic effects associated with topical application. Comparison of lingual incisions receiving the experimental substance versus those receiving control solution showed enhanced hemostasis manifested by a 32% (P less than .05) decrease in bleeding time.
Current chemotherapy of head and neck cancer, This article reviews the results of over 50 published trials testing the use of chemotherapy in patients with squamous cell carcinoma of the head and neck. Among the trials using chemotherapy before standard surgery and/or radiotherapy in stage III and IV disease. none has shown an improvement in survival compared with surgery and/or radiotherapy alone. In these studies. the survival at 3 to 5 years has been generally 40% to 50%. Several trials using chemotherapy after standard therapy. however. have reported survival benefits of 10% to 20%. suggested that further evaluation of classic adjuvant chemotherapy in this disease is warranted. Among studies in recurrent head and neck cancer. the most effective chemotherapy regimens appear to be variations of the program consisting of cisplatin followed by a 5-day infusion of 5-fluorouracil. Nevertheless. median survivals in recurrent disease remain short. generally 5 to 10 months.
A ganglion of the temporomandibular joint: a case report, Ganglion cysts of the TMJ are rare and accurate preoperative diagnosis is not usually made. although theoretically this might be possible with arthrography. Treatment of the condition is surgical but. if a positive diagnosis can be made. a period of conservative management could be attempted if the cyst is not excessively painful or surgery is contraindicated for any reason.
Methylmercury blocks N- and L-type Ca++ channels in nerve growth factor-differentiated pheochromocytoma (PC12) cells, Effects of methylmercury (MeHg) on whole-cell Ba++ currents in rat pheochromocytoma (PC12) cells were examined. Based on biophysical characteristics and sensitivity to omega-conotoxin GVIA and dihydropyridine agonists and antagonists. voltage-activated Ba++ currents (IBa) in PC12 cells were mediated by N- and L-type Ca++ channels. Addition of MeHg (10 microM) to the extracellular solution caused a rapid and complete block of current carried by 20 mM Ba++. The rate of block of IBa by MeHg increased in a concentration-dependent manner between 1 and 20 microM. Increasing the frequency of stimulation from 0.1 to 0.4 Hz facilitated block of IBa by MeHg. A 2-min application of 10 microM MeHg in the absence of stimulation also reduced IBa by approximately 80%. Thus. block of IBa by MeHg is not state-dependent. Additionally. MeHg blocked IBa when the membrane holding potential was -40. -70 and -90 mV. indicating that both N- and L-type Ca++ channels are blocked by MeHg. Block of IBa by MeHg was voltage-dependent at a membrane holding potential of -40 mV. but not at holding potentials of -70 and -90 mV. Decreasing the extracellular concentration of Ba++ ([Ba++]e) from 20 mM to 10 mM increased the magnitude of block by MeHg from 45.6 to 77.3%. Increasing [Ba++]e to 30 mM caused no further antagonism of block. Block of IBa by MeHg was not reversed by washing with MeHg-free solution. The ionic permeability of PC12 cell Ca++ channels was Ca++ = Sr++ greater than Ba++. In the presence of MeHg. all three divalent cations were equally permeant.
The antinociceptive effects of spinally administered neuropeptide Y in the rat: systematic studies on structure-activity relationship, Neuropeptide Y (NPY) is a 36-amino-acid. C-terminal amidated peptide that is found in bulbospinal pathways and can inhibit the release of the primary afferent C-fiber neurotransmitter. substance P. Based on these observations. the present studies examined the possible antinociceptive effects of this peptide and several NPY fragments after intrathecal administration in rats prepared with chronic intrathecal catheters. In the 52 degrees C hot plate test. NPY produced a dose-dependent elevation in the nociceptive threshold with a median effective dose of 1.1 nmol. The ordering of fragments' activity was: NPY greater than NPY16-36 greater than or equal to NPY19-36 greater than or equal to NPY14-36 greater than or equal to NPY18-36 much greater than NPY1-36-OH = NPY18-36-OH = 0. In the paw pressure test. NPY was not active. even at the highest doses examined (median effective dose greater than 20 nmol). whereas the C-terminal fragments retained their potency and produced significant increases in the pressure required to evoke escape (NPY18-36: median effective dose = 18.7 nmol). The rank ordering of activity in the paw pressure test was: NPY19-36 greater than or equal to NPY14-36 greater than or equal to NPY18-36 greater than or equal to NPY16-36 much greater than NPY = NPY18-36-OH = 0. Peptide YY. human pancreatic polypeptide and avian pancreatic polypeptide behave similarly to NPY.
Impaired endothelium-dependent relaxation in isolated thoracic aorta of rats with daunomycin-induced nephrosis, A single i.v. injection of daunomycin (10 mg/kg) into rats produced severe proteinuria and hypercholesterolemia without atherosclerosis on the 20th and 40th days after the treatment. However. these changes were not observed on the 5th day. No change in systolic blood pressure was seen through the 40-day experimental period. Relaxation to acetylcholine. A23187 and nitroprusside was examined in aortic rings precontracted with phenylephrine (3 x 10(-6) M). Acetylcholine-induced relaxation was significantly attenuated in the nephrotic rats on the 20th and 40th days. in comparison to the control animals. In aortic rings taken from control and nephrotic rats on the 40th day. removal of the endothelium or treatment with methylene blue (10(-5) M) completely abolished the relaxation induced by acetylcholine (10(-5) M). In addition. acetylcholine (10(-5) M) induced a transient increase in the aortic cyclic GMP and this increase was completely abolished by removal of the endothelium. In the preparations of nephrotic rats on the 20th and 40th days. the cyclic GMP levels stimulated by acetylcholine (10(-5) M) were decreased to about 50% in comparison to their respective control. A23187 also evoked diminished relaxation in nephrotic rats on the 20th and 40th days. However. on the 40th day after the treatment. the effects of nitroprusside in relaxing the aorta and in elevating the cyclic GMP level in the aorta were not altered by nephrosis. In addition. the nitroprusside-induced relaxation and cyclic GMP accumulation were not affected by removal of the endothelium. These results indicate that endothelium-dependent relaxation is attenuated with the development of nephrosis.
Beneficial effects of yohimbine on posthypoxic recovery of cardiac function and myocardial metabolism in isolated perfused rabbit hearts, The present study was undertaken to elucidate the possible actions of yohimbine on cardiac function and metabolism in the hypoxic and subsequently reoxygenated myocardium. For this purpose. rabbit hearts were perfused for 20 min under hypoxic conditions. followed by 45 min reoxygenated perfusion. and their functional and metabolic alterations with and without yohimbine treatment were examined. Hypoxia induced cessation of cardiac contractile force. rise in resting tension and depletion of tissue high-energy phosphates. which were poorly recovered by subsequent reoxygenation. Hypoxia also induced release of creatine kinase and ATP metabolites from perfused hearts and increases in tissue calcium and sodium contents. which were further enhanced upon subsequent reoxygenation. When hypoxic hearts were treated with 3 to 30 microM yohimbine. several beneficial effects were observed in a concentration-dependent manner. This included enhancement of posthypoxic recovery of contractile function and suppression of the hypoxia- and reoxygenation-induced rise in resting tension. Hypoxia/reoxygenation-induced release of ATP metabolites was inhibited and restoration of myocardial high-energy phosphates enhanced. Inhibition of reoxygenation-induced rise in tissue calcium and sodium and creatine kinase release were also noted. The findings suggest that suppression of transmembrane flux of ions. substrates and enzymes during hypoxia/reoxygenation plays a role in the posthypoxic functional and metabolic recovery. Yohimbine (3-30 microM) significantly depressed the maximal stimulus frequency the left atria could follow. These results suggest a close relationship between depression in the maximal driving frequency of atria and enhancement of the posthypoxic contractile and metabolic recovery of perfused hearts.
Interrelation of analgesia and uterine activity in women with primary dysmenorrhea. A preliminary report, The interrelation between uterine activity and pain from primary dysmenorrhea has been of interest for many years. Objective studies of uterine activity during non-steroidal antiinflammatory drug therapy have supported the assertion that uterine activity causes pain and that reducing that activity leads to pain reduction. Unfortunately. those studies could not refute the counter-assertion that reductions in uterine activity come about because of reduced pain through central analgesia and not by direct pharmacologic action. In an effort to clarify this question. a small number of women were studied using intrauterine pressure recording and analysis to evaluate objective changes in uterine physiology during transcutaneous electrical nerve stimulation (TENS) therapy for dysmenorrhea. The preliminary studies indicated that despite successful subjective therapy with TENS. intrauterine pressure parameters remained steady or showed signs of worsening. These findings indicate that TENS provides pure analgesia by an alteration of the body's ability to receive or perceive the pain signal rather than by a direct uterine effect. It appears that the reduction in uterine activity seen in objective drug studies represents direct drug action rather than a change from reduced pain through central analgesic effects.
Results of a preventive program for congenital toxoplasmosis, All pregnant women followed during the period 1982-87 were screened for toxoplasmosis. and 35 patients had documented seroconversion or doubtful toxoplasmosis titers. One patient opted for pregnancy termination. The remaining were followed with a protocol that included serial ultrasound examinations and prophylactic antibiotic treatment of the mother and neonate. No fetal abnormalities related to congenital toxoplasmosis were found. All the infants had negative toxoplasmosis test titers at birth; at follow-up only one was found to have developed a subclinical infection. at 2 months of age. Our data suggest that antiparasitic treatment during pregnancy for those at risk for Toxoplasma infection may reduce the transmission rate.
Surgical treatment of endometriosis at the time of gamete intrafallopian transfer, Gamete intrafallopian transfer (GIFT) was performed on 77 women with endometriosis in 92 cycles with or without concomitant laser therapy or electrofulguration of endometriosis. The pregnancy rates were 45% for laser cases. 25% for electrofulguration cases and 36.4% for GIFT only. The pregnancy rate for stage III endometriosis was 53% versus 14% and 47% for stages II and I. respectively. Although there was a trend toward an increased pregnancy yield with active therapy. no statistically significant difference was achieved. The postoperative fecundity in patients not conceiving with GIFT was poor for all the groups.
Auscultation with an esophageal stethoscope. A new test for pneumoperitoneum, Auscultation for the tympanic sound characteristic of developing pneumoperitoneum during insufflation of the abdomen at laparoscopy was performed with an esophageal stethoscope. Such auscultation detected pneumoperitoneum as soon as or sooner than did the other. standard methods to which it was compared. This test requires no additional maneuvers beyond those routine in standard laparoscopic and anesthetic procedures. providing a useful adjunctive test for pneumoperitoneum acquisition.
Direct sequencing from touch preparations of human carcinomas: analysis of p53 mutations in breast carcinomas, A new technique for characterizing somatic mutations in very small samples of cellularly heterogeneous human cancer tissue was developed and tested using mutations in the p53 gene in breast carcinomas as a model system. The technique combines touch preparation of specimens to obtain homogeneous clusters of carcinoma cells free of normal cells with a nested pair of polymerase chain reaction (PCR) amplifications of DNA to increase the amount of target gene sequence sufficiently to permit direct sequencing of the p53 gene. Touch preparations of fresh or previously frozen tissue from human adenocarcinomas derived from several organs were stained. and clusters of 10-50 malignant cells were transferred by pipette into microfuge tubes for PCR amplification. Exons 5-9 of the p53 gene. which contain the major mutational hot spots associated with most human cancers. were sequenced by the following steps: 1) two rounds of PCR amplification using DNA Taq polymerase and two sets of oligonucleotide primers. the second set being nested within the segment amplified by the first set and having attached T7 and SP6 phage promoter sequences. 2) transcription of the amplified DNA sequences with T7 and SP6 RNA polymerases. and 3) dideoxy sequencing of single-stranded RNA transcripts with reverse transcriptase and with additional oligonucleotide primers to achieve specificity for this unique region of the genome. The utility of this approach is illustrated by our success in detecting and analyzing point mutations in cell clusters from four of 11 primary adenocarcinomas of the human breast.
Phase I/II study of cyclophosphamide, doxorubicin, fluorouracil, and leucovorin for treatment of metastatic adenocarcinoma, Leucovorin enhances the cytotoxicity of fluorouracil (5-FU) in patients with colorectal cancer and may increase the efficacy of combination chemotherapy regimens containing 5-FU. To determine the maximum tolerated dose of 5-FU with leucovorin for use in combination with cyclophosphamide and doxorubicin. we conducted a phase I/II trial in 20 patients. The doses of leucovorin (200 mg/m2 on days 1-5). cyclophosphamide (500 mg/m2 on day 1). and doxorubicin (40 mg/m2 on day 1) were held constant. while the dose of 5-FU was escalated in cohorts of patients beginning at 150 mg/m2 on days 1-5. Cycles were repeated every 3 weeks. Significant mucositis. diarrhea. and myelosuppression were infrequently observed in patients receiving up to 250 mg/m2 5-FU on days 1-5. In contrast. at a dose of 300 mg/m2 on days 1-5. three of six patients had granulocyte count nadirs of less than 500/microL during the first cycle of therapy. and two of these three had platelet counts of less than 25.000/microL. In addition. two patients treated at this dose had significant mucosal toxic effects. and three had insufficient recovery to permit a second course by day 22. Among 14 patients with assessable breast cancer. there were one complete and nine partial responses (response rate 71%). Leucovorin modulation of 5-FU can be safely incorporated into combination chemotherapy with cyclophosphamide and doxorubicin and provides a highly active regimen for treatment of metastatic breast cancer. Further study will be required to determine whether the addition of leucovorin significantly enhances the activity of this regimen.
A prospective analysis of a two-year experience using computed tomography as an adjunct for cervical spine clearance, The role of CT scanning as an adjunct to plain roentgenograms of the cervical spine was reviewed in acutely injured blunt trauma patients. Following institution of a protocol to evaluate the cervical spine in all blunt trauma patients. 179 patients underwent CT scanning of their cervical spine. This was performed for patients whose x-ray findings were positive. for patients with plain x-ray films suggestive of a pathologic condition. for patients with plain x-ray films that did not reveal all of the cervical vertebrae. and for patients who had persistent pain or neurologic deficits despite normal plain x-ray films. Of 123 patients not able to have their cervical spine cleared by normal roentgenograms. 93% were cleared within 24 hours of admission based on CT scans. There were no missed injuries in this setting. A false-positive rate of 28% and a false-negative rate of 1.5% were found for plain roentgenograms. Computed tomographic scans detected 98% of the injuries in our study and when combined with a three-view plain x-ray series of the cervical spine. 100% of cervical spine injuries were detected. Computed tomographic scanning as an adjunct to plain x-ray films of the cervical spine is a highly accurate and expedient modality to clear the cervical spine of blunt trauma patients.
Reappraisal of emergency room thoracotomy in a changing environment, The efficacy of resuscitative emergency room thoracotomy (ERT). particularly in blunt injury. has been questioned. Wide application of the procedure may not be cost effective. The risk of exposure and lethal infection to medical personnel during ERT is considerable. For the past decade. the policy at this institution has been to perform ERT on all moribund patients sustaining penetrating torso injury and all patients sustaining blunt injury with any evidence of cardiac electrical activity. To evaluate whether such a liberal policy is currently justified. the charts of all patients undergoing ERT over a 4-year period were reviewed. One hundred twelve patients underwent ERT; 24 (21%) sustained penetrating injury. 88 (79%) blunt injury. The overall survival rate was 1.8%. Penetrating injury had a 4.2% survival and blunt injury 1.1%. No patients with CPR initiated at the scene and required throughout transport survived. In those patients with both blood pressure and spontaneous respirations present in the field. survival rate was 11.8%. Survival rate in patients manifesting sinus rhythm or ventricular fibrillation upon arrival at the ER was 6.4%. No survivors were noted among patients coming to the hospital with an idioventricular rhythm or asystole. The total hospital charges for patients undergoing ERT exceeded reimbursement by $59.565. Screening for HIV and hepatitis could be documented in only two patients; both were negative. Liberal performance of ERT has dismal results. incurs monetary loss. and affords a greater potential for exposure to lethal infection. Emergency room thoracotomy is justified only when vital signs or a resuscitatible cardiac rhythm are present in the field or ER and deteriorate shortly before thoracotomy.
Liver lacerations--a marker of severe but sometimes subtle intra-abdominal injuries in adults, Experience with conservative management of solid viscus injuries from abdominal trauma in children has produced the impetus for a similar management in adults. To explore the implications of such a policy. we reviewed the records of 82 patients with hepatic injuries noted at laparotomy. Indications for laparotomy were positive findings on diagnostic peritoneal lavage (DPL) or CT scan. or a history of penetrating trauma. The liver injuries were graded according to severity: grade I. 19 patients; grade II. 20 patients (low severity = LS); grade III. 14 patients; grade IV. 6 patients (high severity = HS). Twenty-three injuries were not classified by the operating surgeon. Of the 53 patients with blunt hepatic trauma. 23 (43%) had concomitant injuries that required operative intervention. Twenty-nine patients had penetrating liver injuries. Fourteen (48%) had associated injuries requiring intervention. Patients most likely to have nonoperative management. those with grade I and grade II liver injuries (LS). comprised 48 of the total. In this subgroup there were 26 (54.2%) associated injuries requiring operative intervention. Shock could not be used as a factor to differentiate patients not requiring operative intervention. Nineteen of the LS patients requiring operative intervention secondary to associated injury were never in shock. In adult trauma victims positive DPL findings secondary to minor hepatic injuries that might not require operative intervention serve as a marker for associated injuries that do require operation. The risk of nonoperative management of hepatic injuries based upon radiologic diagnosis is not the result of complications from the hepatic injury.
Elective intrahospital admissions versus acute interhospital transfers to a surgical intensive care unit: cost and outcome prediction, After a decade of intense fiscal scrutiny. appropriate utilization of intensive care resources remains controversial. In particular. the financial impact of patients transferred to a tertiary surgical intensive care unit (SICU) from a community hospital (interhospital) is unknown. especially when compared with elective (intrahospital) SICU admissions admitted from the tertiary center itself. We prospectively studied outcome and costs in 82 consecutive tertiary SICU admissions. Half were transferred acutely from community hospitals and half were transferred from within the hospital or postoperatively. Severity of illness (APACHE II) was scored on day 1. at the same time of the day (9:00-10:00 AM) and by one attending surgeon (BCB). Acute transfer patients had a significantly elevated mortality (36%) when compared with elective admissions (12%) (p less than 0.05). When stratified by APACHE II score. acute transfers had twice the mortality for equivalent APACHE II scores (p less than 0.05). Acute transfer patients with APACHE II scores greater than 19 had an 89% mortality; those nonsurvivors cost $128.652 each. From these results we conclude the following: (1) Acute transfer patients have a significantly elevated mortality when compared with elective intrahospital admissions with equivalent APACHE II day-1 scores; (2) patients transferred acutely to tertiary SICUs are significantly more costly. irrespective of outcome; (3) admission source (elective vs. acute transfer) should be seriously considered when evaluating patient outcome and cost in a SICU.
Coalition on trauma--trauma prevention and trauma care: presidential address, Trauma Association of Canada, Injury is the leading cause of death in persons under 40 years of age. The cost to society financially and in nonmonetary terms is enormous. For a successful assault on this major health epidemic. a cooperative effort between those involved in the development of prevention strategies and those involved in the care of the injured patient must develop. For our society to accept some of these prevention strategies. the rights of the community as a whole will have to be allowed to prevail over the rights of the individual. To facilitate this process. a National Advisory Committee on Injury in Canada needs to be formed. Its mandate will be to develop a set of national objectives on injury morbidity and mortality. to establish a national trauma registry. and to implement specific programs--a strategic plan. Only through a coalition of efforts between all groups involved with injury can we hope to lower the prevalence of injury in Canada.
Is outcome worse in a small volume Canadian trauma centre, The minimum number of seriously injured patients required to maintain clinical competence and achieve acceptable clinical competence in a single trauma centre is unknown. It has been suggested that the probability of survival is improved in hospitals treating greater than 200 trauma patients annually. We sought to determine if probability of survival was lower in our small volume centre. Between 1986 and 1989. 752 (522 male. 230 female; average age. 36 years) trauma patients were admitted to our institution. The major mechanism of injury was blunt (89%). All patients underwent trauma severity scoring. Trauma Score. Injury Severity Score. and a Revised Trauma Score were used to derived the probability of survival by the TRISS method. The mean Injury Severity Score was 23.3 and the mean Trauma Score was 13.2. The overall mortality rate was 15.8%. The Z statistic demonstrated no significant difference between actual and predicted deaths for the 4-year period or for any individual year (range. -1.05 to 1.26. p greater than 0.05). The M statistic was 0.753. We conclude that. despite fewer trauma patient admissions (less than 200 per year). comparable clinical results can be achieved by surgeons dedicated to trauma management.
Chest trauma in a Canadian urban setting--implications for trauma research in Canada, The trauma registry at the Montreal General Hospital was reviewed to provide basic epidemiologic data on chest trauma in Canada and to compare these data with the minimal data available in the literature. Chest trauma in multiply injured patients resulted in higher Injury Severity Scores (ISSs) than the average. This was reflected in higher mortality for patients with chest trauma. The majority of injuries were caused by blunt trauma. Less than 9% of patients admitted to the hospital required thoracotomy for thoracic vascular and cardiac trauma. Outcome (measured by mortality) was better than that predicted from the literature based on admission ISS. The etiology of trauma in this Canadian setting and the resulting injury profiles were substantially different from those obtained from the predominantly American epidemiologic data available in the literature. This suggests the need for gathering more Canadian population-based trauma data for the planning of trauma prevention and care in this country.
Unintentional carbon monoxide-related deaths in the United States, 1979 through 1988, OBJECTIVE. To describe the epidemiology of recent unintentional carbon monoxide poisoning deaths in the United States. DESIGN. Descriptive analysis of carbon monoxide-related deaths in the United States from 1979 through 1988. based on death certificate reports compiled by the National Center for Health Statistics. POPULATION STUDIED. All US deaths. 1979 through 1988. RESULTS. We reviewed data from 56.133 death certificates that contained codes implicating carbon monoxide as a contributing cause of death. Of these. 25.889 were suicides. 210 were homicides. 15.523 were associated with severe burns or house fires. and 11.547 were classified as unintentional. The number of unintentional deaths decreased steadily by about 63 deaths per year. from 1513 in 1979 to 878 in 1988. The highest death rates occurred in winter and among males. blacks. the elderly. and residents of northern states. Motor vehicle exhaust gas caused 6552 (57%) of the unintentional deaths; 5432 (83%) of these were associated with stationary automobiles. CONCLUSIONS. The rate of unintentional death from carbon monoxide poisoning is decreasing. This may be attributable to improvements in automobile pollution control systems and improved safety of cooking and heating appliances. Prevention programs should target young drivers. males. and the elderly.
Morbidity following acute irritant inhalation in a population-based study, STUDY OBJECTIVE. To estimate the incidence of and risk factors for morbidity due to inhalation of respiratory irritants. DESIGN. Six-month case series of inhalational exposures reported to a poison control center with follow-up. structured interviews of subjects. SETTING. A regional poison control center providing 24-hour telephone consultation to health professionals and the public. PATIENTS. Consecutive sample of 683 inhalation cases. with interviews of 323 subjects. MEASUREMENTS AND MAIN RESULTS. Moderate to severe irritants accounted for 160 (50%) of the inhalational exposures in interviewed subjects. Persistent symptoms lasting 14 days or longer were reported by only 20 (6%) of the subjects. Irritant exposure was a statistically significant risk factor for acute respiratory symptoms (relative risk [RR] = 1.7; 95% confidence interval [Cl]. 1.4 to 2.1) but was unrelated to persistent symptoms. Preexisting lung conditions (RR = 2.4; 95% Cl. 1.4 to 4.2) and cigarette smoking (RR = 1.7; 95% Cl. 1.3 to 2.2) were both statistically significant risk factors for persistent symptoms. CONCLUSIONS. Symptomatic inhalational exposures due to irritants are frequent in reports from poison control centers. Residual morbidity was uncommon and did not appear to be statistically related to the degree of irritant exposure. Host-related factors may be better predictors of ongoing morbidity after inhalational exposure.
The environment and the lung. Changing perspectives, The focus of public health concern and research in regard to environmental lung diseases has changed across the century. Illustrative agents include radon. indoor asbestos. environmental tobacco smoke. acidic aerosols. and oxidant gases. Tremendous progress has been made in understanding and preventing environmental lung diseases. However. we remain concerned about adverse consequences of breathing polluted outdoor and indoor air. In the persistent concerns about adverse effects of polluted air on the lung. a new emphasis is pervasive; the focus has shifted from avoiding clinical disease among highly exposed individuals to protecting the population from an unacceptable burden of risk. The technique of quantitative risk assessment has become increasingly important for characterizing the safety of environmental agents. The resulting emphasis on the final risk projection and attendant uncertainties may overly emphasize gaps in our knowledge.
Epidemiologic analysis of warfare. A historical review, Although warfare is thought to be responsible for high and increasing levels of morbidity and mortality in the modern era. little comparative epidemiologic research is available on the subject. Most research on past wars has been carried out for purposes of military planning. The present report provides an overview of the direct health impacts of various wars on military and civilian populations during the last 200 years. Risk factors for injury and death are analyzed. Changes in weaponry. military strategy. and medical services are found to modify the health effects of warfare.
Conservative management of intraductal carcinoma (DCIS) of the breast. Collaborating NSABP investigators, Seventy-six patients with intraductal carcinoma (DCIS) of the breast have been observed for 83 months (range 50-141) following treatment by lumpectomy (L) only (21). L and breast irradiation (XRT) (27). or mastectomy (28). All represented examples of DCIS retrieved after pathologic examination of a much larger cohort of patients with stage I and II invasive breast cancer enrolled in NSABP protocol 6. Local breast recurrences were similar for women with DCIS and those from this cohort at a similar period of follow-up with invasive cancer treated by L only (43% vs. 39%) and L + XRT (7% vs. 10%). The presence of moderate/marked comedonecrosis was suggestively related to local breast recurrence (P = .07). This latter was significantly reduced for patients receiving post L XRT (P = .01). All local breast recurrences in this study and 29 of 31 recorded by others occurred at or close to the site of extirpation of the index cancer minimizing multicentricity as a contraindication for the conservative surgical treatment of DCIS. Survival rates which were similar for patients with DCIS regardless of form of local treatment were better than that observed for negative node patients with invasive cancer enrolled in protocol 6. Thus. DCIS is a less. not more. ominous disease than invasive cancer. This and other features of its natural history indicate that it would be a contradiction to treat invasive cancer but not DCIS conservatively.
Pancreatoduodenal carcinoma: a clinicopathologic study of 304 patients and immunohistochemical observation for CEA and CA19-9, A total of 304 patients with pancreatoduodenal carcinoma were studied clinicopathologically and immunohistochemically in order to clarify features of carcinoma of four different sites of origin; carcinoma of the ampulla of Vater (Am). the distal common bile duct (DCBD). the head of the pancreas (PH). and the extra-ampullary duodenum (Du). The mean greatest diameter of 87 PH was 3.5 cm compared with 2.7 cm of 149 Am and 2.7 cm of DCBD. Histopathologically. 40% of Am were papillary adenocarcinoma. while about half of DCBD. PH and Du were tubular adenocarcinoma. PH invaded lymphatic (85%). vascular (62%). and perineural (95%) spaces and metastasized lymph nodes (72%) more frequently than Am (77%. 35%. 24%. 50%). DCBD (47%. 61%. 65%. 45%). and Du (76%. 29%. 35%. 65%). respectively. More than 50% of PH invaded the resected margins. whereas in only 2% of Am. the surgical margins were affected by malignant cells. Immunohistochemically. PH was more frequently positive for both carcinoembryonic antigen (CEA) (98%) and carbohydrate antigen (CA) 19-9 (91%) than Am (83%. 62%). DCBD (94%. 58%). and Du (56%. 11%). respectively. The stromal staining type of CEA and CA 19-9 was more frequently seen in PH (27%. 44%) than in Am (9%. 31%). DCBD (11%. 8%) and Du (0%. 0%). showing a more dedifferentiated nature of PH. The cumulative 3-year survival rate of 87 patients with PH (15%) was worse than that of 149 with Am (42%. P less than 0.001). of 51 with DCBD (25%) and of 17 with Du (58%. P less than 0.001). The survival curve of 87 with PH was worse than that of 51 with DCBD. of 149 with Am (P less than 0.001) and of 17 with Du (P less than 0.001). Cox regression analysis. using eleven profound prognostic variables. revealed that venous invasion. perineural infiltration. surgical margin. and histopathologic type were profound prognostic factors. Pancreatic carcinoma has a more dedifferentiated histopathologic nature. showing a more aggressive growth and fares worse than Am. DCBD. and Du.
Carcinoma of the pancreas: a personal experience with 100 cases, One hundred patients with pancreatic cancer were evaluated between March 1981 and December 1989. This study showed that 61 were not candidates for definitive surgery because of nonoperability (28 patients) or nonresectability (33 patients). An additional 25 patients had cancers that were unresectable because of metastases (13 patients) or local spread of disease (12 patients) discovered at laparotomy. Fourteen patients had resectable cancers. Ten were treated by total pancreatectomy. three by distal pancreatectomy and one by pancreatoduodenectomy (Whipple). There were two operative mortalities. The median patient survival time was 20.5 months. Two patients survived 5 years. Five patients are alive at 3. 14. 18. and 47 months. Palliative surgical procedures performed in 18 patients included 10 biliary bypasses. 9 gastrojejunostomies. and 6 T-tube placements. This was associated with an operative mortality rate of 11%. The median survival time was 5 months. Other palliative measures included endoscopic placement of biliary and pancreatic stents (47 patients. 2.7% mortality rate). endoluminal radiation therapy. interstitial radiation therapy and external beam radiation therapy. The median survival time of patients so treated was 4.5 months.
Radical hysterectomy with lymphadenectomy for treatment of early stage cervical cancer: clinical experience of 278 cases, This study includes 278 cases of stage I and II cervical cancer subjected to radical hysterectomy and lymphadenectomy. The clinical experience of 278 cases is reviewed. Of these cases. 215 were in stage I. and 63 were in stage II. Intraoperative complications occurred at a rate of 9.7% and involved injuries to the great vessels. lower urinary tract. nerves. and rectum. Operative mortality was found to be 0.3%. Postoperative complications were observed in 20.1% of patients. Fistulae were observed in 8 (2.8%) patients. The overall survival rate was 83.8%. The 5-year survival rates for stages IA. IB. IIA. and IIB were 100.0%. 87.9%. 71.0%. and 64.0%. respectively. Pelvic lymph node metastases varied from 0% for stage IA to 40.0% for stage IIB and paraaortic involvement varied from 0% for stage IA to 50.0% for stage IIB. Radical surgery seems to be the treatment of choice for patients with early invasive cervical cancer.
Angiolymphoid hyperplasia with eosinophilia (Kimura's disease): report of a large-sized lesion, Angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon lesion with a predilection for skin of the head and neck region. It usually presents as one or a few smooth-surfaced nodules which are often asymptomatic. Histologically the nodules reveal two components: abnormal proliferating vessels and a cellular infiltrate consisting of lymphocytes and eosinophils. involving both the dermis and the subcutaneous tissue. A case is presented of an unusually large recurrent lesion on the scalp.
The role of extrapleural pneumonectomy in malignant pleural mesothelioma. A Lung Cancer Study Group trial, Malignant pleural mesothelioma is usually a fatal cancer for which operation has been the mainstay of treatment because chemotherapy and radiation are relatively ineffective. The choice of operation for malignant pleural mesothelioma remains controversial. Extrapleural pneumonectomy has been advocated because it allows complete removal of gross tumor and can be associated with long-term survival. To evaluate extrapleural pneumonectomy. we conducted a prospective multiinstitutional trial in patients with biopsy-proved previously untreated malignant pleural mesothelioma. Criteria for extrapleural pneumonectomy were (1) potentially completely resectable unilateral disease by computed tomography scan. (2) predicted postresection forced expiratory volume in 1 second greater than 1 L/sec. and (3) no other major medical problems. Patients who were not candidates for extrapleural pneumonectomy had a more limited operation with or without adjuvant therapy or had nonsurgical treatment. From September 1985 to June 1988 83 eligible patients (64 male. 19 female) were entered. The mean age for all patients was 59.7 years. Only 20 of the 83 patients (24%) underwent extrapleural pneumonectomy. Three of these 20 patients (15%) died postoperatively. The recurrence-free survival was significantly longer for the patients undergoing extrapleural pneumonectomy than for the other two groups (p = 0.03). but there was no difference in overall survival among the three groups. In univariate analyses. epithelial versus sarcomatoid and mixed histologic findings and platelet count less than 400.000 were associated with a better overall survival (p = 0.02). and performance status (Karnofsky less than 80) was predictive of recurrence (p = 0.02). In a multivariate analysis. histologic findings. sex. age. extrapleural pneumonectomy. weight loss. and performance status all had no significant impact on survival. Extrapleural pneumonectomy was associated with a greater likelihood of relapse in distant sites than were limited operation and nonsurgical treatment. We conclude that (1) only a small proportion of all patients with malignant pleural mesothelioma are candidates for extrapleural pneumonectomy. (2) extrapleural pneumonectomy carries a significant operative mortality and does not seem to improve overall survival compared with more conservative forms of treatment. (3) extrapleural pneumonectomy alters the patterns of relapse. and (4) factors previously thought to have an impact on survival in other series did not affect outcome in this trial.
Effects of dynamic cardiomyoplasty on left ventricular performance and myocardial mechanics in dilated cardiomyopathy, We tested the hypothesis that dynamic cardiomyoplasty produces beneficial changes in the functional mechanics of the dilated. failing left ventricle. Chronic dilated cardiomyopathy was induced in seven mongrel dogs by rapid ventricular pacing (260 beats/min) for 3 to 4 weeks. After completion of the induction period. dynamic cardiomyoplasty was performed with the left latissimus dorsi muscle. paced synchronously with the R waves of the electrocardiogram (Medtronic SP1005). Instruments included an aortic flow probe. a left ventricular Millar pressure catheter. and piezoelectric sonomicrometric crystals on the left ventricle for measurements of wall thickness and minor and major axis dimensions. Data were obtained with the stimulator off and on. Statistical comparisons were made with Student's t test for paired data. Dynamic cardiomyoplasty increased the cardiac output of the failing heart (966 +/- 124 versus 1166 +/- 112 ml/min; p less than 0.01). Systolic shortening of both minor and major axis dimensions increased (3.1 +/- 0.3 versus 4.7 +/- 0.3 mm. p less than 0.01. and 4.6 +/- 0.3 versus 7.3 +/- 0.9 mm. p less than 0.05. respectively). Left ventricular end-diastolic pressure decreased by 16% (18 +/- 1 versus 15 +/- 1 mm Hg. p less than 0.01). Although skeletal muscle contraction increased the pressure development in the left ventricular chamber. mean systolic wall stress was diminished by concomitant changes in left ventricular dimensions (116.144 +/- 11.530 versus 101.268 +/- 7464 dynes/cm2. p less than 0.05). At end-systole. wall thickness increased (11.8 +/- 1.1 versus 12.7 +/- 1.1 mm. p less than 0.01). minor axis dimension decreased (51.3 +/- 1.4 versus 49.2 +/- 1.8 mm. p less than 0.01). and major axis dimension also decreased (85.6 +/- 3.3 versus 79.0 +/- 2.3 mm. p less than 0.05). Our detailed evaluation of left ventricular chamber mechanics suggests that dynamic cardiomyoplasty may have a role in ameliorating the functional and mechanical derangements associated with progression of dilated cardiomyopathy both by augmenting cardiac performance and by diminishing determinants of myocardial oxygen consumption. (All values are expressed as mean +/- standard error of the mean.).
Comparison of the aortic homograft and the pulmonary autograft for aortic valve or root replacement in children, To assess late results of aortic homograft and pulmonary autograft valves implanted into the left ventricular outflow tract of children. we reviewed the case histories of 146 patients 18 years of age or younger who underwent aortic valve or root replacement between November 1964 and April 1990. One hundred three patients (mean. 12 +/- 3.9 years) received an aortic homograft and 43 (mean. 14 +/- 4.1 years) had their own pulmonary valve transferred to the aortic position. There were 54 valve and 49 root replacements with homografts and 36 valve and seven root replacements with autografts. Hospital mortality rate was 15.5% (16 patients) in the homograft group and 11.6% (five patients) in the autograft group. Survivors were followed up for a total of 867 (homograft) and 297 (autograft) patient-years. The late mortality rate was 16.7% (1.9% per patient-year) for patients with homografts and 13.2% (4.4% per patient-year) for patients with autografts. whereas the incidence for reoperation per patient-year was 2.9% and 2.0%. respectively. At 15 years actuarial rates for homografts and autografts for freedom from reoperation were 54% +/- 8.1% and 68% +/- 11.1%; freedom from endocarditis. 97% +/- 2.4% and 75% +/- 10.2%; and freedom from any complication. 41% +/- 6.5% and 50% +/- 10.3%. Valve degeneration occurred in 19 homografts (2.2% per patient-year). whereas there was no definite instance of primary tissue failure among the pulmonary autografts. This experience would indicate that either the homograft or the autograft valve can be used with acceptable results in children. However. the pulmonary autograft gives better long-term performance and. if growth potential is realized. may be the ideal valve substitute in children.
Preservation of aortic valve in type A aortic dissection complicated by aortic regurgitation, Two hundred fifty-two patients underwent operation for type A aortic dissection at Stanford University Medical Center from 1963 to 1987 and Duke University Medical Center from 1975 to 1988. Sixty-seven percent had an acute type A dissection and 33% had a chronic type A dissection. In addition to repair or replacement of the ascending aorta. 121 patients (48%) required an aortic valve procedure. Valve resuspension was performed in 46 (39 acute type A and 7 chronic type A). with an operative mortality rate of 13% +/- 5% (+/- 70% confidence limits). and aortic valve replacement in 75 (36 acute type A and 39 chronic type A). with an operative mortality rate of 20% +/- 5% (p = not significant versus resuspension). The operative mortality rate for patients requiring only repair or replacement of the ascending aorta was 32% +/- 4%. Indications for valve replacement included coexistent (nonacute) aortic valve disease. Marfan's syndrome. annuloaortic ectasia. and cases in which successful resuspension could not be accomplished. The overall actuarial survival rate for all patients was 59% +/- 3% (+/- 1 standard error of the mean). 40% +/- 4%. and 25% +/- 5% at 5. 10. and 15 years. respectively. Survival rates at these same times for patients with valve resuspension were 67% +/- 8%. 52% +/- 10%. and 26% +/- 19%. respectively; for patients who required aortic valve replacement. these survival rates were 70% +/- 5%. 39% +/- 8%. and 21% +/- 11%; finally. patients who received only an ascending aortic procedure had survival probabilities of 51% +/- 5%. 37% +/- 6%. and 23% +/- 6% (p = not significant versus resuspension versus aortic valve replacement). Multivariate analysis showed advanced age (p less than 0.001). previous cardiac or aortic operation (p less than 0.001). more preoperative dissection complications (p = 0.002). and earlier operative date (p = 0.038) to be the only significant. independent factors that increased the likelihood of early or late death. The type of aortic valve procedure (resuspension versus aortic valve replacement versus none) was not a significant predictor of mortality. Two of 46 patients with valve resuspension required late aortic valve replacement (freedom from aortic valve replacement: 100% and 80% +/- 13% at 5 and 10 years. respectively). as did 4 of 75 patients with initial aortic valve replacement (freedom from repeat aortic valve replacement: 98% +/- 2% and 73% +/- 13%. respectively).(ABSTRACT TRUNCATED AT 400 WORDS).
Human T-cell lymphotropic virus type I sequences detected by nested polymerase chain reactions are not associated with multiple sclerosis, The hypothesis that human T-cell lymphotropic virus type I (HTLV-I) infection is associated with multiple sclerosis (MS) was tested by using primers specific to gag and pol regions of HTLV-I in an analysis that used polymerase chain reactions. No amplification of DNA from patients with MS was detected with primers for either region. After application of a more sensitive scheme with use of nested primers. however. half the samples. including patients with MS and normal control subjects. were found to contain pol DNA sequences. No sequences related to the HTLV-I gag region were detected among patients with MS by using nested primers. Sequences of the amplified HTLV-I pol genomes were determined. Regardless of their origin (MS or normal control). the pol region sequences were similar to HTLV-I sequences reported by other investigators. We conclude that HTLV-I does not have a distinct association with MS. but HTLV-I-related sequences. although in extremely low copy number. may be present in human genomes.
Adrenergic regulation of lipolysis in a patient with lipoatrophy of the upper body, A patient with lipoatrophy of the upper body had laboratory evidence of increased activity of the adrenergic nervous system. Because the adrenergic nervous system is important in the regulation of lipolysis. studies were performed to determine whether lipolysis of the upper body was ongoing in this patient and whether pharmacologic reduction of activity of the adrenergic nervous system would affect lipolysis of adipose tissue. Release of free fatty acids from systemic and forearm adipose tissue was measured before and after the administration of guanfacine hydrochloride. Forearm adipose tissue. although decreased in quantity. was found to release normal amounts of free fatty acids. Systemic and forearm release of free fatty acids decreased after 3 days of treatment with guanfacine. These results suggest that lipoatrophy of the upper body in some patients may be mediated through dysfunction of the adrenergic nervous system. These findings also emphasize the potential for heterogeneous responses of adipose tissue to hormonal regulatory factors.
Functioning insulinoma--incidence, recurrence, and long-term survival of patients: a 60-year study, For the 60-year period from 1927 through 1986. we assessed the incidence. recurrence. and long-term survival among all Mayo Clinic patients with histologically confirmed functioning insulinoma. With use of the complete medical record system at Mayo and the comprehensive epidemiologic data base of residents of Olmsted County. Minnesota. we found 224 patients in whom an initial pancreatic exploration at Mayo had confirmed the presence of insulinoma. The median age (and range) of these patients at surgical diagnosis was 47 (8 to 82) years. and 59% were female patients. During the study period. eight cases of insulinoma occurred among residents of Olmsted County; their age and gender distributions were similar to those of the total cohort. The incidence of insulinoma among residents of Olmsted County increased during the study period to a stable level during the last 2 decades of 4 cases per 1 million person-years. For the total cohort. 7.6% had multiple endocrine neoplasia type I (MEN I). and 5.8% had malignant insulinoma. The risk of recurrence was greater among patients with MEN I (21% at 10 and 20 years) than in those without MEN I (5% at 10 years and 7% at 20 years). Although survival of the total cohort was not significantly impaired. it was significantly worse than expected for patients with malignant insulinoma (29% versus 88% expected at 10 years postoperatively). We conclude that insulinoma is less rare than previously suspected. After successful surgical removal. the long-term risk of recurrent insulinoma is relatively high in patients with MEN I; for patients with benign disease. the long-term survival is normal.
The course of peptic ulcer disease, Peptic ulcer disease usually has periodic exacerbations and remissions. Pain can disappear without total healing of the ulcer crater and can be absent when an ulcer is present. Changes in the incidence of ulcer disease have been noted in recent years. Genetic predisposition. infection with H. pylori. and the use of anti-inflammatory drugs are involved in causation. Stress; the use of alcohol. tobacco and caffeine; and other diseases have been implicated as etiologic factors. Ulcer pain has a recognizable pattern. but the symptoms can be variable. particularly in older people and in patients taking ulcerogenic medications. The familiar complications of hemorrhage. perforation. and obstruction still occur. and nonulcer dyspepsia has not been fully explained. Duodenal ulcers have a disturbing tendency to return; new therapeutic approaches offer hope.
Psychologic factors associated with peptic ulcer disease, Peptic ulcer disease provides an excellent model for the study of mind-body interactions in the pathogenesis and course of an illness. Early psychodynamic explanations of the role of personality factors in the evolution of peptic ulcer disease have been supplemented in recent years by more scientifically based studies on the role of stress and coping ability. Multiple psychosocial variables have confounded the outcome of many of these studies. Yet. a clear need and guidelines exist for the comprehensive medical and psychosocial evaluation and treatment of patients with peptic ulcer disease. Concomitant psychiatric assessment and management. including psychotherapeutic and psychopharmacologic approaches. for those patients with refractory symptoms or ongoing psychiatric symptoms carried out in close collaboration with primary caregivers will significantly decrease overall morbidity and mortality.
Acid secretion and suppression, Hydrochloric acid is involved in the causation of peptic ulcer. but the exact role has not been defined. Suppression of acid secretion is associated with ulcer healing. The acid secreting cell is the parietal cell. which possesses a proton pump in the secretory membrane; morphologic changes accompany and facilitate the active secretion of hydrochloric acid. Stimulation of acid secretion occurs by three major pathways. which utilize acetylcholine. histamine. and gastrin. The predominant effects of histamine are mediated by adenylate cyclase. whereas those of gastrin and acetylcholine involve cytosolic calcium. There is a complicated arrangement of receptors and pathways that culminate in the activation of the proton pump. The parietal cell is influenced by neurocrine. hormonal. and paracrine mechanisms. Peptides join the more familiar neurotransmitters in affecting the parietal cell. Somatostatin is present in the gut and acts to decrease acid secretion. The hormone gastrin is released. in a feedback fashion. when the antrum is alkalinized. Most stimuli of acid secretion are blocked by H2-antagonists. Inhibitory hormones are released when acid arrives in the intestine. Inhibition of acid secretion can be achieved by influencing the parietal cell at the level of histamine. gastrin. and muscarinic receptors. The proton pump itself can be blocked by drugs that inhibit the final phase of acid secretion.
Peptic ulcer disease in children, Primary duodenal ulcer disease occurs in children of all ages. but is most often seen in those over 10 years. As in the adult. it often pursues a chronic course. Primary gastric ulcer is seen in children under 6 years. is more unusual. and does not tend to recur. Stress ulcers are seen most often in infants and in critically ill children and are asymptomatic until the complications of hemorrhage or perforation appear. Drug-related ulcers are being seen more frequently as the use of nonsteroidal anti-inflammatory agents increases. With the use of new therapeutic agents. management has been simplified and surgical intervention has become a rarity. Helicobacter pylori is now a recognized cause of antral gastritis and ulceration in the child.
Zollinger-Ellison syndrome, As clinical experience with patients with ZES has grown. increasing recognition has been made of the broad spectrum of symptoms associated with gastrinomas. Diarrhea and acid-induced esophageal injury have taken their place alongside chronic peptic ulcer disease as indications for screening for gastrinoma. Diagnostic testing should begin with fasting serum gastrin levels and should include intravenous secretin infusion if fasting serum levels of gastrin are nondiagnostic and the patient is not found to be hypochlorhydric. Tumor localization is critical to aid in the identification of patients with potentially curable localized disease. Preoperative evaluation utilizing CT scanning with intravenous contrast should be done early and should be supplemented by other imaging modalities as necessary. Exploratory laparotomy. including a thorough examination of the duodenum and perhaps intraoperative ultrasound. should be performed in all patients with sporadic gastrinoma who lack evidence of extensive metastatic disease on preoperative evaluation. By utilizing this approach. it is likely that at least 20% of patients with ZES can be cured. With the availability of the highly effective H(+)-K(+)-ATPase inhibitor omeprazole. excellent control of symptoms related to gastric acid hypersecretion can be expected. Patients with unresectable gastrinoma may thus avoid potentially morbid antisecretory surgery and be managed with a fairly simple medical regimen. Further developments in the chemotherapeutic management of these patients with unresectable disease should be forthcoming in the future.
Gastroesophageal reflux disease, Gastroesophageal reflux disease. usually manifested by frequent heartburn. occurs in approximately 10% of our adult population. The presence of a hiatal hernia is usually associated with. but does not necessarily cause. LES dysfunction. allowing acid reflux to produce esophageal and aerodigestive symptoms. The mucosa can be extensively damaged and. ultimately. a columnar lining. termed Barrett's esophagus. a premalignant condition. can develop. Treatment with H2-antagonists has been nirvana to some patients. but has proved only partially helpful to others. Adjunctive agents may increase relief and may help heal erosive esophagitis in some patients. but side effects and cost limit their use. Maintenance therapy with full doses is required. as the relapse rate for this chronic condition is high. Omeprazole temporarily heals almost everyone with otherwise resistant GERD. but it is currently used only on a short-term basis unless surgery. eminently successful in well-selected patients. is contraindicated.
Management of bleeding ulcers, Hemorrhage is a common complication of peptic ulcer disease and is increased in frequency and severity with aspirin and NSAID use. A variety of clinical and endoscopic factors associated with an increased mortality rate from ulcer bleeding have been identified. the most important of which are presentation in shock and ongoing or recurrent bleeding after routine resuscitative measures. After hemodynamic stabilization. the goal of therapy is to diminish the chance that an ulcer will continue to bleed or will rebleed. Currently. this is best achieved by one of several endoscopic interventions in carefully selected patients. The most effective endoscopic techniques for decreasing the risk of ulcer rebleeding are multipolar electrocoagulation. heater probe thermal coagulation. and injection therapy in patients with active bleeding or a visible vessel in the ulcer base. Injection therapy may be used alone or in combination with either of the other two techniques. The major impact of therapeutic endoscopy appears to be a reduction in the number of emergent operations necessary to control hemorrhage. The mortality of emergent surgery for bleeding ulcer is prohibitive. and any means of reducing the need for surgery is likely to have a beneficial effect on survival.
Diet and nutrition in ulcer disease, In this era of H2-inhibitors. the available evidence does not support the need to place peptic ulcer disease patients on restrictive diets. The major goal of diet is to avoid extreme elevations of gastric acid secretion and the direct irritation of gastric mucosa. In view of this. only slight modifications in the patient's usual diet are recommended. Table 1 depicts a sample menu for chronic peptic ulcer disease. Frequent milk ingestion as previously prescribed is not encouraged. This is owing to the transient buffering effect and significant gastric acid secretion effect of milk. The fat content of milk has no influence on these effects. Spices. in particular black pepper. red pepper. and chili powder. may produce dyspepsia. One study shows red chili powder to have no detrimental effect on duodenal ulcer healing. It has also been proposed that daily pepper ingestion may have a beneficial adaptive cytoprotective response. While still controversial and under evaluation. peptic ulcer patients should avoid any spice that causes discomfort. especially during exacerbation of peptic disease. Currently. studies indicate that it is prudent to avoid alcohol. This is especially true for the concentrated forms. such as 40% (80 proof) alcohol. Coffee should be avoided on the basis of its strong acid secretagogue property. Coffee can induce dyspepsia. Whether noncoffee caffeine-containing beverages (tea. soft drinks) induce peptic ulcer is unknown. but they are acid secretion stimulators. Decaffeinated coffee has an acid stimulating effect as well. It is reasonable to have peptic ulcer patients restrict decaffeinated coffee and all caffeine-containing beverages. There appears to be no evidence to restrict dietary fiber. Some fiber-containing foods may possess factors that are protective against ulcer disease. According to the Mayo Clinic Diet Manual. previously recommended small frequent feedings have not been shown to be more effective than three meals per day in the treatment of chronic peptic ulcer disease. This reference cites authorities advising against extra feedings because of increased acid secretion and unnecessary complication of eating patterns. However. some patients claim to be relieved of symptoms with more frequent feedings. especially during acute phases. Citric acid juices may induce reflux and cause discomfort in selective patients. Stomach distention with large quantities of food should be discouraged. Although there is now little role for dietary therapy. one should note that bland and ulcer diets probably are not detrimental to most persons if they are used for a short time and may have some psychological benefit.(ABSTRACT TRUNCATED AT 400 WORDS).
Medical treatment of peptic ulcer disease, Our understanding of PUD and its treatment has improved dramatically during the past 15 years. During this time. many new effective drugs have been approved by the FDA. and possibly even more potent and effective therapies are now being evaluated. The H2-blockers. sucralfate. and antacids heal over 90% of duodenal ulcers in 6 to 8 weeks. and H2-blockers heal about 80% of gastric ulcers by 8 weeks and over 90% by 12 weeks. The new. more potent pump blockers (omeprazole) promise to be even more effective drugs. even for the healing of patients who are taking NSAIDS. However. the potential hazards of marked. long-term acid suppression must still be evaluated. Maintenance therapy with H2-blockers or sucralfate. ideally used for patients who would otherwise have frequent symptomatic recurrences of duodenal ulcer disease or who have had complications. reduces the relapses. especially symptomatic relapses. Maintenance therapy with H2-blockers also seems to reduce the recurrences of GUD. but this use has not yet received FDA approval. Elimination of H. pylori infection with antibiotics may prove to reduce recurrent ulcer disease and negate the need for maintenance therapy. Colloidal bismuth subcitrate alone. which suppresses but does not eradicate H. pylori infection. seems to be an effective ulcer drug and may even reduce the rate of early recurrences. Effective ulcer therapy. especially if it prevents recurrent disease. may reduce the complications of PUD. but this expectation has yet to be established. The use of prophylactic cytoprotective prostaglandins (misoprostol) reduces the incidence of NSAID-induced GUD.
Surgical treatment of peptic ulcer disease, Elective surgery for peptic ulcer disease has diminished significantly over the past 15 years. However. emergency surgery has not shown a decline. Some series have even reported an increase in hospitalizations and operations for hemorrhage. The appropriate surgical procedure for peptic ulcer disease must be tailored to the specific needs of the individual patient. During emergency operations for hemorrhage from duodenal ulcer. we recommend suture ligature of the bleeding vessel and vagotomy-pyloroplasty for high-risk patients. or vagotomy-antrectomy for the lower-risk patient. Bleeding gastric ulcers should be resected. if possible. For massive hemorrhage from stress ulceration requiring surgery. near-total or total gastrectomy should be performed. Perforated duodenal ulcers are best managed by closure and a definitive ulcer operation. such as vagotomy-pyloroplasty. Perforated gastric ulcers are best excised but may be simply closed if conditions do not favor resection. In these situations. biopsy should be performed. We recommend truncal vagotomy-antrectomy for patients presenting with obstruction. Vagotomy (truncal or proximal gastric) with drainage is an acceptable alternative in this situation. For patients with intractable ulcer disease or for those who are noncompliant. proximal gastric vagotomy is the preferred operation. However. other operations may need to be considered. depending on the specific situation. Recurrent ulceration needs appropriate work-up to determine the possible cause. Although patients with ulcer recurrence initially may be placed on medical treatment. about 50% will require reoperation. The most effective procedure for peptic ulcer disease is truncal vagotomy-antrectomy. which has a recurrence rate of less than 1%. The procedure with the least morbidity and the fewest undesirable side effects is proximal gastric vagotomy. Ulcer recurrence after proximal gastric vagotomy or truncal vagotomy-pyloroplasty is in the range of 10% to 15%.
Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis, A few patients remain severely affected by atopic dermatitis into adult life despite treatment with systemic steroids. azathioprine. and photochemotherapy. 33 patients took part in a double-blind. placebo-controlled. crossover study to assess the efficacy and safety of cyclosporin (5 mg/kg per day) in adults with severe refractory atopic dermatitis. Treatments were given for eight weeks each with one group (n = 16) receiving placebo followed by cyclosporin and another (n = 17) receiving cyclosporin and then placebo. Disease activity. extent of disease. sleep and itch. topical steroid use. and adverse events were assessed every two weeks. Both extent and activity of dermatitis were significantly improved (p less than 0.001) as were subjective measures of disease. 20 patients receiving cyclosporin reported adverse events compared with 8 taking placebo. although no patient required withdrawal from the study. Cyclosporin therapy led to an increase in the mean serum urea. creatinine. and bilirubin concentrations. although only the rise in bilirubin was significant (p = 0.001). Our results confirm that cyclosporin is a safe and effective short-term treatment for severe. refractory atopic dermatitis.
Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation, Severe interstitial pneumonitis in 2 marrow-transplant recipients was associated with human herpesvirus-6 (HHV-6) infection. The virus was repeatedly detected in respiratory specimens from 1 patient. and HHV-6-infected cells were shown in lung tissue from both patients by immunohistochemical staining. The infected cells were primarily intra-alveolar macrophages. although infected lymphocytes were seen. HHV-6 should be considered as a cause of unexplained lung disease in marrow-transplant recipients and other immunocompromised patients.
Pulse sounds and measurement of diastolic blood pressure in children, Controversy exists over the value of measuring diastolic blood pressure (BP) in children. and over whether this should be measured at Korotkoff's fourth phase (K4) or fifth phase (K5) of pulse sounds. We measured diastolic BP in 3012 randomly selected Finnish children aged 6-18 years in 1980. and in 2885 of the same individuals in 1983 and 2500 in 1986. BP was measured with a standard mercury sphygmomanometer in 1980 and 1983. and with a random-zero sphygmomanometer in 1986. K4 was consistently absent in 187 individuals (3.2%) in 1980 and 1983. and in 155 individuals (6.2%) in 1986. K5 was absent in only 34 individuals (0.6%) in 1980/83 and 5 (0.2%) in 1986. The difference between mean K4 and K5 diastolic BP varied from 6.5 to 9.2 mm Hg depending upon age. K4 and K5 BPs showed good correlation in all age groups. Reliable and repeatable BP measurements in all age groups of children are best achieved with K5 as the indicator of diastolic BP.
Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion, Intramuscular and intravenous gammaglobulin treatment for hypogammaglobulinaemia is often associated with systemic adverse reactions in some patients. Subcutaneous infusions of gammaglobulin are usually given at a slow rate. To assess the safety of home treatment with subcutaneous gammaglobulin. rapid infusions (34-40 ml/h) given by small portable pumps were used to treat twenty-five patients with hypogammaglobulinaemia. Fifteen patients had previously had adverse reactions to intramuscular or intravenous gammaglobulin treatment. After the patients had been taught how to use the pumps during 6 months of treatment in hospital. in which they initially received 100 mg of an intramuscular gammaglobulin preparation/kg per week. they went on to use the pumps at home or at work. So far. the patients have given themselves 3232 rapid subcutaneous infusions (2308 in home therapy). A median pre-infusion serum IgG concentration of 8.1 g/l resulted after 6 months of treatment. There were only 30 (0.93%) mild systemic adverse reactions; there were fewer reactions with subcutaneous gammaglobulin than with previously given intramuscular injections (n = 21. p less than 0.001) or intravenous infusions (n = 9. p less than 0.001) in this group of patients. Overall. the patients spent 0.2 days a year in hospital due to respiratory tract infections. The findings show that the method for subcutaneous administration is very easy to learn and is appreciated by the patients; moreover. the infusions can be given much faster than previously reported without any pronounced local reaction.
Progestagen supplementation of exogenous oestrogens and risk of endometrial cancer, The favourable effects of exogenous progestagen on the endometrium are well known. but have not been adequately quantified with respect to endometrial cancer. The benefits of progestagen need to be weighted against its possible untoward effects on the risk of breast cancer and cardiovascular disease. A population-based case-control study of endometrial cancer was undertaken to evaluate the benefits of progestagen use. 158 incident cases were identified between 1985 and 1987 among women aged 40-64 years who were residents of King County. Washington. Detailed interviews were conducted and the responses were compared with those of 182 controls selected by random telephone digit dialling. The risk of endometrial cancer among women who had used unopposed oestrogen for more than 3 years was over five times that of women who had used no hormones (relative risk [RR] 5.7. 95% confidence interval [Cl] 2.5-12.8). whereas those who had also used a progestagen for at least six months of that time had an RR of only 1.6 (95% Cl 0.6-3.9). The RR differed according to days per month that progestagen was used: 2.4 (0.6-9.3) for progestagen use of less than 10 days per month versus 1.1 (0.4-3.6) for use of 10 or more days per month. These results provide additional evidence that the use of progestagen for 10 or more days per cycle can reduce the excess risk of endometrial cancer associated with long-term postmenopausal oestrogen use.
Antibodies to hepatitis C virus in autoimmune liver disease: evidence for geographical heterogeneity, To resolve conflicting reports about the occurrence of antibodies against hepatitis C virus (HCV) in patients with autoimmune chronic active hepatitis (AI-CAH). sera from UK and Italian patients were tested with the original anti-HCV assay (Ortho) and a novel anti-HCV assay (UBI) based entirely on synthetic HCV peptides. 28 (60%) of 47 Italian patients with type-1 AI-CAH were anti-HCV-positive by Ortho ELISA. 25 of whom were also strongly positive by the UBI assay. 15 (60%) of 25 UK patients with type-1 AI-CAH were HCV-positive by Ortho ELISA but only 2 were positive by the UBI assay. Similarly. 29 (88%) of 33 Italian patients with type-2 AI-CAH. but 0 of 10 UK patients. were very strongly anti-HCV-positive with the UBI assay. Italian patients with AI-CAH appear to have a high frequency of genuine exposure to HCV. whereas seropositivity by the Ortho HCV ELISA in UK patients is likely to represent a false-positive result. These findings indicate important geographical and/or genetic influences in autoimmune liver disease among different populations.
High fecundity of amenorrhoeic women in embryo-transfer programmes, There is uncertainty over whether the steady decline in human fertility with increasing maternal age is due to quality of the oocyte or of the endometrium. To clarify the issue age-related implantation and pregnancy rates in two embryo-transfer programmes were examined in relation to embryo quality and type of menstrual cycle. In both the UK and the US programmes rates were higher in previously amenorrhoeic (acyclic) women than in eugonadal women. irrespective of age and number of embryos replaced. Oocyte quality. as determined by age of oocyte donor. in-vitro growth of embryo. and proportion of defective embryos in culture. did not contribute to the difference. nor did type of cycle during therapy. If a uterus that has not been subjected to regular menstrual cycles is a favourable factor. a period of induced amenorrhoea might be beneficial for infertile women.
Body composition in ballet dancers measured by total body electrical conductivity, The purpose of this study was to describe the body composition of adolescent and young adult ballet dancers using total body electrical conductivity (TOBEC). We studied 112 female and 33 male dancers. The mean ages were 15.0 +/- 2.0 and 18.7 +/- 3.1 yr for females and males. respectively. The mean percent body fat (PBF) values were 20.1 +/- 3.6% for the females and 14.5 +/- 4.2% for the males. Age and pubertal development were not significantly related to PBF in the females. Age and pubertal status were significantly inversely related to PBF in the males. There was no difference in dance history. percent body fat. and abdominal/hip or waist/hip ratios in eumenorrheic vs amenorrheic dancers. Estimated calorie intake indicated that dancers with menstrual abnormalities had lower calorie intake than those with normal menses. This is the largest group of ballet dancers whose body composition has been studied. Our PBF measurements are higher than in previous reports using hydrodensitometry. which may have underestimated body fat by not accounting for the increased bone density in the lower extremities of dancers. Our data suggest that previous measurements of PBF in dancers are underestimates; these new data challenge our concept of PBF values in dancers.
The effects of acute moderate exercise on leukocyte and lymphocyte subpopulations, The extent and duration of changes in circulating leukocyte and lymphocyte subpopulations. cortisol. and catecholamines were examined in 12 women who walked 45 min at 60% VO2max in a laboratory setting. A two-factor. 2 x 6 design with repeated measures on both factors was utilized. The first factor was condition (exercise and rest). and the second factor was time (six points of measurement over a 24-h period). with treatment order counterbalanced. The 45-min walk. in comparison with rest in a seated position. was associated with a significant but moderate leukocytosis and lymphocytosis immediately following the walk. The leukocytosis was still evident after 3 h of recovery and was primarily due to a neutrophilia. The change in lymphocyte count. relative to baseline levels and the control condition. lasted less than 1.5 h. with an increase in the natural killer (CD16 and/or CD56) and cytotoxic T cell component (CD3 and CD16 and/or CD56) (NKCT) representing approximately two-thirds of the lymphocytosis and T cells (CD5) the other third. A significant decrease in the CD4:CD8 ratio was seen. with cytotoxic/suppressor (CD8) cells increasing and helper/inducer (CD4) cells demonstrating little change in comparison with baseline. This seems to have been due to a subpopulation of CD8 (low density antigen) cells. probably natural killer cells. The 45-min walk had no effect on plasma cortisol and epinephrine levels relative to the rest condition but was associated with a moderate increase in norepinephrine.
Culture methods to evaluate central venous catheter sepsis, Sepsis is a frequent complication of central venous catheters. but the diagnosis of catheter sepsis is not always clear-cut. A variety of culture methods is available to determine catheter-related septicemia. Each method has advantages and disadvantages for the clinician to consider. This article reviews qualitative. quantitative. and other culture methods applicable to both blood and the device.
Acquired immunodeficiency syndrome--Dade County, Florida, 1981-1990, In the United States. the impact of the epidemic of acquired immunodeficiency syndrome (AIDS) has been most substantial in urban areas. In addition. AIDS has differentially affected racial/ethnic minority groups. This report characterizes the epidemiology of AIDS through 1990 in Dade County (which includes incorporated Miami). Florida (1990 population: 1.937 million). an urban area with a diversity of racial/ethnic groups and cultures. The findings in this report are based on surveillance data from CDC's AIDS Public Information Data Set and from the Florida Department of Health and Rehabilitative Services' (HRS) AIDS Program.
Use of folic acid for prevention of spina bifida and other neural tube defects--1983-1991, Neural tube defects--including spina bifida. anencephaly. and encephalocele--are common. serious birth defects that are important causes of infant mortality and disability. Women in the United States who have had a pregnancy resulting in an infant or fetus with a neural tube defect have a 2%-3% risk for having another pregnancy resulting in an infant or fetus with a neural tube defect (i.e.. a recurrence) The British Medical Research Council (MRC) Vitamin Study Group recently reported the results of a randomized prevention trial that indicated that daily oral supplementation with folic acid before conception and during early pregnancy substantially reduces the recurrence of neural tube defects. This report summarizes the findings of that study and provides recommendations for supplementation with folic acid to prevent the recurrence of neural tube defects.
Cholera--New York, 1991, Through June 26. 1991. cholera has been reported from seven countries in the Western Hemisphere: Brazil. Chile. Colombia. Ecuador. Mexico. Peru. and the United States. In the United States. a total of 14 confirmed cases of epidemic-associated cholera have been reported among persons in Florida (one) (1). Georgia (one) (2). New Jersey (eight) (1). and New York (four). This report summarizes information regarding the four cases reported in New York and describes a new laboratory procedure used to confirm the vehicle of transmission in this outbreak.
Imported dengue--United States, 1990, In 1990. 102 cases of suspected imported dengue were reported to CDC from 24 states and the District of Columbia. Of these. 24 (22%) cases (from 14 states and the District of Columbia) were serologically or virologically confirmed as dengue. The dengue serotype was identified by virus isolation in two of these cases. Fifty-five of the suspected cases were serologically negative for dengue. and the laboratory diagnosis of 23 remained undetermined because convalescent serum samples were not submitted. Travel histories were available for 22 of the 24 persons with confirmed dengue. Eight cases were acquired in Oceania. six in the Caribbean. six in Asia. and one each in Mexico and Peru.
Involvement of thin afferents in carpal tunnel syndrome: evaluated quantitatively by argon laser stimulation, The thin afferent nerves were tested quantitatively by determining the thresholds of warmth and pricking pain to argon laser stimulation and by measuring the brain potentials related to pricking pain. In 27 patients with electrophysiologically verified carpal tunnel syndrome these parameters were measured from fingers 3 and 5 on both hands. All patients had had sensory symptoms ranging from 3 months to 25 years. Both the thresholds were elevated (P less than 0.05) at finger 3 compared to measurements from finger 5. and compared to finger 3 in a group of 39 controls. Four patients with symptoms for more than 7 years had thresholds below the control values. The power of the pain-evoked brain potentials elicited from finger 3 was lower (P less than 0.05) compared to finger 5. and compared to the control group (P less than 0.01). No correlations were found between the measured parameters and the clinical electrophysiological investigation. The findings support previous assumptions that chronic low-force compressions cause impairment of intraneural microcirculation. and hence can affect the function of the thin afferents.
A technique for needle localization in paraspinal muscles with cadaveric confirmation, Invasive electromyography (EMG) of the paraspinal muscles is useful in clinical and research settings. No technique for localization of the needle in specific fascicles has been validated. Recent descriptions of the segmented innervation of the multifidus imply that such a technique would add greatly to the EMG determination of root level of a radiculopathy. We have developed a technique for localization which relies on palpation of bony structures and needle insertion at certain angles and depths. The technique was evaluated by injecting latex dye in 199 locations in 13 cadavers. Dissection demonstrated that the technique was accurate in 91 of 112 injections into specific fascicles of the multifidus (originating from different spinous processes). 39 of 43 injections into the longissimus. and 35 of 44 injections into the iliocostalis. Certain types of errors would not have occurred with the aid of EMG in vivo. When these are added to the correct injections. accuracy improves 97%. 93%. and 82%. respectively. The technique described here should be useful for kinesiological studies. biopsies and injections. as well as for the EMG confirmation of a radiculopathy.
Age-related changes and tissue distribution of parvalbumin in normal and dystrophic mice of strain 129 ReJ, In murine muscular dystrophy. hindlimb muscle contains a functionally defective thiol protease inhibitor (TPI) which has been implicated in the onset and progression of the disease in mice. More recently. this protease inhibitor has been identified as parvalbumin. a calcium binding protein. In this study. a polyclonal antibody against mouse muscle parvalbumin was used to study the concentration and distribution of this protein in normal and dystrophic male mice at various ages. Immunodetection assays were used to screen extracts of hindlimb. forelimb. brain. heart. lung. liver. and kidney in 60-day-old normal and dystrophic male mice for parvalbumin content. Parvalbumin was detected in relatively high amounts in both hindlimb and forelimb muscle extracts. while much lower concentrations were detected in brains of normal and dystrophic animals. No parvalbumin was detected in the lung. liver. heart. or kidney extracts using the immunoassay. With aging. the parvalbumin concentration in hindlimb muscle of normal mice remained fairly constant for 90 days. whereupon the level increased at 120 days. In contrast. the parvalbumin concentration in hindlimb muscle of dystrophic mice decreased steadily with age to about 22%% of normal animals at 120 days. The parvalbumin content was also reduced in dystrophic brain.
Association between tumor necrosis factor-alpha and disease progression in patients with multiple sclerosis, BACKGROUND. Cachectin. or tumor necrosis factor-alpha (TNF-alpha). is a principal mediator of the inflammatory response and may be important in the pathogenesis and progression of multiple sclerosis. an inflammatory disease of the central nervous system. METHODS. In a 24-month prospective study. we used a sensitive enzyme-linked immunosorbent assay to determine levels of TNF-alpha in cerebrospinal fluid and serum in 32 patients with chronic progressive multiple sclerosis and in 20 with stable multiple sclerosis and 85 with other neurologic diseases. An attempt was made to relate TNF-alpha levels with the degree of disability of the patients with multiple sclerosis and with their neurologic deterioration during the 24 months of observation. RESULTS. High levels of TNF-alpha were found in the cerebrospinal fluid of 53 percent of the patients with chronic progressive multiple sclerosis and in none of those with stable multiple sclerosis (P less than 0.001). TNF-alpha was detected in the cerebrospinal fluid of 7 percent of the controls (P less than 0.01) with other neurologic disease. In patients with chronic progressive multiple sclerosis. mean TNF-alpha levels were significantly higher in the cerebrospinal fluid than in corresponding serum samples (52.41 vs. 11.88 U per milliliter; range. 2 to 178 vs. 2 to 39; P less than 0.001). In these patients. cerebrospinal fluid levels of TNF-alpha correlated with the degree of disability (r = 0.834. P less than 0.001) and the rate of neurologic deterioration (r = 0.741. P less than 0.001) before the start of the study. Cerebrospinal fluid levels also correlated with the increase in neurologic disability after 24 months of observation (r = 0.873. P less than 0.001). CONCLUSIONS. These data provide evidence of intrathecal synthesis of TNF-alpha in multiple sclerosis and suggest that the level of TNF-alpha in cerebrospinal fluid correlates with the severity and progression of the disease. Our results suggest that TNF-alpha may reflect histologic disease activity in multiple sclerosis and could be used to monitor outcomes or responses to therapy.
Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure, BACKGROUND. Increased gamma-aminobutyric acid (GABA) neurotransmission has been implicated in the pathogenesis of hepatic encephalopathy. The mechanism by which GABA-ergic activity is increased in hepatic failure is unclear. but recent studies in animals with encephalopathy due to fulminant hepatic failure suggest that GABA-ergic neurotransmission may be increased by the presence of elevated concentrations of benzodiazepine agonists such as diazepam and N-desmethyldiazepam. METHODS AND RESULTS. Samples of frontal cortex were obtained at autopsy from 11 patients with hepatic encephalopathy who died of acetaminophen-induced fulminant hepatic failure and 8 patients who died of cardiovascular disease or trauma. None of the 19 patients had received benzodiazepines while hospitalized. Chromatographic analyses of extracts of these samples revealed 4 to 19 peaks representing substances that inhibited the binding of a radiolabeled imidazobenzodiazepine ([3H]flumazenil) to its receptors. Several of these peaks had retention times corresponding to those of known 1.4-benzodiazepines. Ultraviolet- and mass-spectroscopic analysis confirmed that two of these peaks represented diazepam and N-desmethyldiazepam. The patients who died of fulminant hepatic failure could be divided into two groups: six who had had significantly elevated brain concentrations (2-fold to 10-fold higher than normal) of substances inhibiting the binding of [3H]flumazenil and five who had normal concentrations. CONCLUSIONS. Brain concentrations of substances inhibiting the binding of [3H]flumazenil to its receptors are increased in some patients with hepatic encephalopathy due to fulminant hepatic failure. The origin of these substances is unknown. but these findings provide a rational basis for trials of benzodiazepine-receptor antagonists in the management of this disorder.
Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes, Marfan syndrome (MFS). one of the most common genetic disorders of connective tissue. is characterized by skeletal. cardiovascular and ocular abnormalities. The incidence of the disease is about 1 in 20.000. with life expectancy severely reduced because of cardiovascular complications. As the underlying defect is unknown. MFS diagnosis is based solely on clinical criteria. Certain phenotypic features of MFS are also shared by other conditions. which may be genetically distinct entities although part of a clinical continuum. Immunohistochemical studies have implicated fibrillin. a major component of elastin-associated microfibrils. in MFS aetiology. Genetic linkage analysis with random probes has independently localized the MFS locus to chromosome 15. Here we report that these two experimental approaches converge with the cloning and mapping of the fibrillin gene to chromosome 15q15-21. and with the establishment of linkage to MFS. We also isolated a second fibrillin gene and mapped it to chromosome 5q23-31. We linked this novel gene to a condition. congenital contractural arachnodactyly. that shares some of the features of MFS. Thus. the cosegregation of two related genes with two related syndromes implies that fibrillin mutations are likely to be responsible for different MFS phenotypes.
Partial sequence of a candidate gene for the Marfan syndrome, Fibrillin is a large (relative molecular mass 350.000) glycoprotein which can be isolated from fibroblast cell cultures and is a component of the microfibrils that are ubiquitous in the connective tissue space. The microfibrils of the suspensory ligament of the lens as well as the elastic fibre microfibrils of the blood vessel wall are composed of fibrillin. The ocular and cardiovascular manifestations of the Marfan syndrome are consistent with a defect in the gene coding for a structural constituent of these connective tissues. Immunohistological experiments have recently implicated fibrillin microfibrils in the pathogenesis of the Marfan syndrome. Genetic linkage data localizing the Marfan gene to chromosome 15 and the in situ hybridization of fibrillin complementary DNA to 15q21.1 together support fibrillin as a candidate Marfan gene. As a first step towards investigating the function of fibrillin in the architecture and development of connective tissues and its relationship to the Marfan syndrome. we report the cloning and partial sequencing of fibrillin cDNA.
Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene, Marfan syndrome is an inherited disorder of connective tissue manifested in the ocular. skeletal and cardiovascular systems. It is inherited as an autosomal dominant with high penetrance. but has great clinical variability. Linkage studies have mapped the Marfan locus to chromosome 15q15-21.3. There have been no reports of genetic heterogeneity in the syndrome. Following the identification of fibrillin (a glycoprotein component of the extracellular microfibril). immunohistopathological quantification of the protein in skin and fibroblast culture. and examination of fibrillin synthesis. extracellular transport. and incorporation into the extracellular matrix (D. M. Milewicz. R.E.P.. E. S. Crawford and P. H. Byers. manuscript in preparation) have demonstrated abnormalities of fibrillin metabolism in most patients. A portion of the complementary DNA encoding fibrillin has been cloned and mapped by in situ hybridization to chromosome 15. Here we report that the fibrillin gene is linked to the Marfan phenotype (theta = 0.00; logarithm of the odds (lod) = 3.9) and describe a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. We thus implicate fibrillin as the protein defective in patients with the Marfan syndrome.
Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease [published erratum appears in Nature 1991 Aug 8;352(6335):547, The human prion diseases. Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler syndrome (GSS). are neurodegenerative diseases that are unique in being both infectious and genetic. Transmission of both diseases and the animal spongiform encephalopathies (for example. scrapie and bovine spongiform encephalopathy) to experimental animals by intracerebral inoculation with brain homogenates is well documented. Despite their experimental transmissibility. missense and insertional mutations in the prion protein gene are associated with both GSS and familial CJD. demonstrating that the human familial cases are autosomal dominant diseases. More than 80% of CJD cases occur sporadically. however. and are not known to be associated with mutations. Here we report that 21 of 22 sporadic CJD cases and a further 19 of 23 suspected sporadic CJD cases are homozygous at the polymorphic amino-acid residue 129; 51% of the normal population are heterozygous at this site. We argue that homozygosity predisposes towards sporadic CJD and that this directly supports the hypothesis that interaction between prion protein molecules underlies the disease process.
Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6, Wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene. Although the normal roles of tumour suppressor genes are still largely unknown. it seems that they could be involved in promoting cell differentiation as well as in mediating growth arrest by growth-inhibitory cytokines. Hence. the abrogation of wild-type p53 expression. which is a common feature of many tumours. could eliminate these activities. We have now tested this notion by restoring the expression of p53 in a murine myeloid leukaemic cell line that normally lacks p53. The use of a temperature-sensitive p53 mutant allowed us to analyse cells in which the introduced p53 had either wild-type or mutant properties. Although there seemed to be no effect on differentiation. the introduction of wild-type p53 resulted in rapid loss of cell viability in a way characteristic of apoptosis (programmed cell death). The effect of wild-type p53 was counteracted by interleukin-6. Thus products of tumour suppressor genes could be involved in restricting precursor cell populations by mediating apoptosis.
The effect of glaucoma filtering surgery on corneal endothelial cell density, Corneal endothelial cell counts were obtained preoperatively and 3 months postoperatively in 46 eyes undergoing glaucoma filtering surgery. Average central endothelial cell loss in eyes without postoperative iridocorneal touch was 1.6%. In eyes with iridocorneal touch (Spaeth's grades 1 and 2). the average cell counts decreased by 7.1% and 9.3%. respectively. The average loss for combined grades 1 and 2 (8.1%) approached statistical significance (P +/- .06). The average loss in two patients with corneolenticular touch (Spaeth's grade 3) was greater than 50%. These findings suggest that early postoperative iridocorneal touch is unlikely to lead to corneal compromise in most eyes. but that corneolenticular touch can result in severe endothelial cell loss.
A prospective evaluation of anterior retinal cryoablation in neovascular glaucoma, We report a prospective evaluation of the effect of anterior retinal cryopexy on 62 eyes with neovascular glaucoma. Pain was relieved and anterior chamber inflammatory reaction regressed dramatically in 95%. Iris neovascularization was reduced or regressed in 93.5%. Control of intraocular pressure was clinically significant in 82.3% 1 year after the procedure. especially in patients with pretreatment pressures less than 40 mm Hg on maximal medical therapy. Anterior retinal cryopexy is recommended in eyes with media opacities and as a preliminary procedure for filtering surgery in eyes with neovascular glaucoma.
Pseudophakic malignant glaucoma in a child, We report a pseudophakic malignant glaucoma attack in the early postoperative period in the normal eye of an 8-year-old child who had undergone extracapsular cataract extraction with posterior chamber (modified Sinskey type) intraocular lens implantation for congenital zonular cataract. Intensive antiglaucoma medical therapy did not resolve the glaucoma. but vitreous aspiration and anterior chamber reformation proved successful.
Repair of the severely contracted socket with meshed skin graft and semi-rigid conformer, Nine severely contracted sockets were reconstructed using a meshed skin graft in conjunction with a semi-rigid conformer-stent. Particularly useful following unsuccessful surgery with mucosal grafting. or in cases where for some reason mucosal grafts cannot be obtained. this technique is superior to current procedures utilizing nonmeshed split-thickness skin grafts.
Nd:YAG cyclophotocoagulation: outcome of treatment for uncontrolled glaucoma, We reviewed the records of 35 patients (35 eyes) treated with Nd:YAG cyclophotocoagulation for uncontrolled glaucoma and followed for 6 to 36 months or until treatment was declared a failure (loss of light perception. or intraocular pressure (IOP) greater than 21 mm Hg). The mean pretreatment intraocular pressure was 37.9 mm Hg (range. 20 to 61 mm Hg). The total energy in the initial treatment session ranged from 50.4 to 372.4 J (191.7 +/- 66.3 J). After the treatment. the mean IOP was 21.2 mm Hg (range. 0 to 53 mm Hg). The Kaplan Meier survival analysis demonstrated that failures occurred throughout the follow-up period and that the majority of patients required further intervention or lost all vision if followed long enough. Visual outcome was not correlated with energy used. Eleven eyes (31%) lost two or more lines of acuity or lost all light perception. These findings suggest that Nd:YAG cyclophotocoagulation may control IOP but cannot always save vision.
Maintaining nearly physiologic intraocular pressure levels prior to tying the sutures during cataract surgery reduces surgically-induced astigmatism, We sought to determine whether maintaining nearly physiologic levels of intraocular pressure (IOP) before the final tying of sutures in cataract surgery can help minimize postoperative-induced astigmatism. We compared the postoperative astigmatic decay curves of two similar groups of 18 patients who had undergone cataract surgery. in one of which IOP had been maintained at 17 mm Hg prior to the final tying of sutures. and in the other of which the eyes were hypotonus (3 mm Hg) at this point. Initial with-the-rule cylinder change was significantly less and astigmatic decay occurred earlier in the former group.
Magnetic resonance imaging of intraocular tamponades, The efficacy of proton magnetic resonance imaging in differentiating vitreous from C3F8 gas and silicone oil tamponades. and in detecting fresh hemorrhages and condensed vitreous was tested in rabbits in vivo. The results suggest that this imaging method could provide a useful alternative to ultrasonography. especially in eyes with opaque media.
Orbital exenteration with eyelid sparing: indications, technique, and results, Of 22 orbital exenterations performed from January 1980 to December 1989. 16 were performed by an eyelid-sparing technique. and six were allowed to heal by spontaneous granulation. Reviewing these procedures. we conclude that the eyelid-sparing method is indicated mainly for advanced primary orbital malignancies and for certain secondary orbital malignancies such as orbital extension of uveal melanoma. conjunctival melanoma. and conjunctival squamous cell carcinoma. It is not usually applicable to orbital invasion of malignant eyelid tumors such as basal cell carcinoma and sebaceous gland carcinoma. Advantages of the eyelid-sparing method are more rapid healing and earlier fitting of a prosthesis.
Response of argon laser trabeculoplasty with varying anterior chamber anatomy, We studied one randomly selected eye of 50 consecutive primary open-angle glaucoma patients treated with argon laser trabeculoplasty to assess response differences as functions of anterior chamber anatomy and refraction. We found no significant differences related to these variables. and thus conclude that argon laser trabeculoplasty may be performed successfully in patients with crowded angles as long as the trabecular meshwork can be visualized.
Bacterial resistance, Pathogenic bacteria remain adaptable to an increasingly hostile environment and a wider variety of more potent antibiotics. Organisms not intrinsically prepared for defense have been able to acquire resistance to newer antimicrobial agents. Chromosomal mutations alone cannot account for the rapid emergence and spread of antibiotic resistance. It has been established that plasmids and transposons are particularly important in the evolution of antibiotic-resistant bacteria. Plasmid- or transposon-mediated resistance provides the bacteria with pre-evolved genes refined to express high-level resistance. In particular. transposons can transfer these resistance determinants in diverse bacterial species. and nature provides in humans and animals large intestinal reservoirs in which such communications are facilitated. Antibiotic therapy exerts selection pressures on bacteria. Eradication or marked reduction in the populations of susceptible organisms promotes the overgrowth of intrinsically resistant strains and favors those resistant as a result of favorable chromosomal mutations or via plasmids or transposons. In our hospitals. where antibiotic consumption continues to increase. the nosocomial flora consists of many resistant bacteria. and infections acquired in the nosocomial setting are now far more severe than their community-acquired counterparts. There is convincing evidence that infection control measures must take into further consideration the contribution of the hospital worker as carrier and mediator of antibiotic resistance.
Management of soft tissue wounds associated with type III open fractures, The orthopedist's goals are to prevent wound infection. expedite fracture healing. and restore optimal function. The importance of the soft tissue envelope to fracture healing is well recognized. In spite of continual research concerning wound repair. we remain at a loss to define precisely what starts the wound healing process and what ultimately stops it. In this article. we consider the basic science of wound repair. the effects of the patient's nutrition and volume status. soft tissue wound dressing options. soft tissue transfers. and specific recommendations.
Does hyperbaric oxygen have a place in the treatment of osteomyelitis, There are several specific mechanisms by which HBO restores normal cellular processes that are compromised by hypoxia. or by which HBO augments bactericidal events. All of these are potentially applicable to. and beneficial for. the osteomyelitis patient. At the University of Texas Medical Branch. we find that early osteomyelitis is usually amenable to appropriate medical and surgical therapy. Adjunctive HBO is generally reserved for treatment of advanced stages of osteomyelitis (3B and 4B). In addition. HBO is occasionally used when patient circumstances dictate suppression of osteomyelitis rather than definitive treatment. Our clinical impression is that HBO has a beneficial effect on treatment outcome in these selected patients. Fault-free clinical studies are difficult to perform in this complex and varied patient population. Several studies have suggested a beneficial effect with the addition of adjunctive hyperbaric oxygen to usual osteomyelitis treatment regimens. whereas other clinical studies have failed to demonstrate such a benefit. No study has shown any harmful effect of adjunctive HBO on the outcome of osteomyelitis treatment. We hope that clinical researchers will continue to address this question. despite the research design problems inherent in the osteomyelitis population.
Diagnosis and management of the infected total joint arthroplasty, The preoperative diagnosis of the infected orthopedic implant is complicated by lack of a single precise test to forewarn patient and surgeon of the presence of microorganisms. Given the overall limitation of accuracy of preoperative diagnosis to approximately 80% when 111In scanning. preoperative aspiration. and ESR are considered. it would seem prudent to approach each revision surgery with the possibility in mind of subclinical sepsis as the cause for failure of the implant. The essentials of surgical technique including thorough debridement of the wound and removal of all existing foreign bodies. especially including PMMA bone cement. are critical to minimizing the risk for occurrence or persistence of sepsis. Although the use of antibiotic impregnated bone cement may enhance the treatment of orthopedic sepsis. the data available to date lead to the conclusion that two-stage revision surgery in the face of known sepsis remains the cornerstone of surgical therapy for the infected implant. along with aggressive and rational antibiotic treatment. The surgeon is offered the following guidelines in the management of the septic total hip arthroplasty. 1. Preoperative evaluation including ESR. 111In WBC scan. and aspiration for culture and sensitivity (fluoroscopically guided for the hip) will produce on average approximately 80% accuracy. 2. Intraoperative cultures at the time of revision surgery should be obtained prior to administration of systemic antibiotics; three tissue specimens (hip capsule. femoral membrane. acetabular membrane) should be submitted for culture and sensitivity determination. 3. Careful debridement of the surgical site of granulation tissue and all foreign bodies (e.g.. PMMA) should be performed within the limits of patient safety to maximize the likelihood of success.
Management of total knee arthroplasty infection, The treatment of infected total knee arthroplasty represents the most difficult form of revision surgery. Successful salvage of this complication can be accomplished only by extensive investment of surgical and infectious disease efforts in eradicating the infection. A two-stage reimplantation procedure for treating this condition has been the most successful functional option and should be utilized whenever possible to definitively eradicate the infection and ensure good function of the knee joint. It is the procedure of choice for younger healthy patients who can medically tolerate the protocol. Other options may be necessary as the medical condition of the patient dictates. Initial debridement with antibiotic suppression and antibiotic suppression alone have yielded limited successful results but can be accomplished only in a small number (23%) of patients.
Detection and treatment of brucellosis by screening a population at risk, Brucellosis presents a difficult diagnostic challenge in view of its protean manifestations. multiple organ involvement and variable clinical course. The purpose of the present study was to determine whether active screening of a population at risk. identified through index cases. would enhance the detection rate of brucellosis and improve treatment. During a 1-month period all 98 individuals sharing risk factors with 4 diagnosed symptomatic cases of brucellosis in one Bedouin town in southern Israel were approached and 86 agreed to undergo screening. Symptomatic brucellosis was found in 8 (9%) of the screened population and an additional 5 (6%) asymptomatic individuals were found to be seropositive. These 13 were followed for 12 months. All symptomatic cases were treated and cured. Of the 5 asymptomatic seropositive individuals 2 showed a further elevation of Brucella antibody titers. One became symptomatic. was treated and was cured. This screening program provided 53% of all reported cases from the Bedouin town during the entire year of the study. Screening a population at risk increased the detection rate of brucellosis and improved the treatment.
The effect of walking with an assistive device and using a wheelchair on school performance in students with myelomeningocele, An alternating-condition. single-subject research design was used to examine the effect of ambulation on three measures of school performance in three students with myelomeningocele. The subjects. aged 9. 10. and 15 years. had a physiological cost index greater than 1.00 beats per meter when walking with crutches or a walker. Subjects propelled a wheelchair at school for 5 days. ambulated with crutches or a walker for 5 days. and propelled a wheelchair for an additional 5 days. Performance in reading fluency. visuomotor accuracy. and manual dexterity was assessed at the end of each school day. Results were graphed and analyzed using the two-standard-deviation band method. All subjects had significantly lower visuomotor accuracy scores during the assistive-device ambulation phase than during the wheelchair phases. Performance in manual dexterity during the assistive-device ambulation and wheelchair phases varied among the subjects. Reading fluency was not affected by method of mobility. The results suggest that the high energy cost of walking may have a negative effect on certain aspects of the subjects' school performance. [Franks CA. Palisano RJ. Darbee JC. The effect of walking with an assistive device and using a wheelchair on school performance in students with myelomeningocele.
A comparison of the results following oromandibular reconstruction using a radial forearm flap with either radial bone or a reconstruction plate, Fifteen cases of oromandibular reconstruction using a radial osteocutaneous flap were compared with 16 in which the mandible was replaced with a reconstruction plate and a forearm flap was used for intraoral lining. All cases involved oral cancer; most had been irradiated. Nine survived in each group. Complications included one infected nonunion in addition to two bone exposures in the bone group. compared with three cases of plate exposure and two bone exposures in the plate group. Functional results were similar in both. but osteointegrated implants were possible only in the patients receiving bone. Cosmesis seemed somewhat better in the plate group. Donor-site problems were common but minor. and long-term forearm function was slightly reduced in both groups. Although the sample sizes were small. the reconstruction plate together with a radial forearm flap appeared to provide effective reconstruction following composite resection. However. we would not recommend this for the younger patient or in benign disease.
Reconstruction of the lower lip and chin with the composite radial forearm-palmaris longus free flap, Four cases of total lip and chin reconstruction are presented. In three. the composite radial forearm-palmaris longus free flap was used for reconstruction. In the fourth case. the palmaris longus was separated from the flap but still used as a lower lip sling. In all cases. the entire lower lip and the soft tissue of the chin were reconstructed in one stage. All patients healed primarily. and the three who underwent radiotherapy tolerated it without complications. Lip seal and speech were good. and there was no problem with drooling. Postoperative results emphasize the importance of respecting the aesthetic unit of the lower lip and chin.
Microsurgical free-tissue transfer in the elderly patient, During the 5-year period from July of 1984 to July of 1989. we performed 94 free-tissue transfers in 92 patients over the age of 50 whom we arbitrarily defined as "elderly." There were 32 patients in the age range between 50 and 59 years. 40 patients aged between 60 and 69 years. and 20 patients aged between 70 and 79 years. Seventy-one flaps were utilized for head and neck reconstruction. and 23 flaps were used in reconstruction of the trunk and extremities. There was 1 total flap loss. for a flap viability rate of 99 percent (93 of 94). Postoperative complications were classified into surgical (technical) and medical categories. There were 14 major surgical complications (15 percent) and 13 significant postoperative medical problems (14 percent). The majority of these complications occurred in head and neck cancer patients in the age group between 60 and 69 years. who had significant underlying medical problems and were preoperatively classified as ASA 3. There were 5 postoperative deaths. for a mortality rate of 5.4 percent (5 of 92 patients).
Preservation of skeletal muscle in tissue transfers using rat hindlimbs, Replantation of major extremities after long periods of ischemia can lead to viable replants in many cases. but functional restoration is often poor owing to fibrosis of the muscle. In this study. maximum hypothermic time in tissue transfers containing skeletal muscle using hindlimbs of Lewis rats preserved in 4 degrees C Euro-Collins solution was investigated. After preserving midthigh amputated legs in this solution for 6. 9. and 12 hours. the legs were transplanted to other inbred rats using microsurgical technique. and 1 week later. gastrocnemii were obtained to analyze ATP. ADP. and AMP using high-performance liquid chromatography. The values were compared with those for healthy legs. nonischemic operated control legs. and legs preserved in the same manner for 6. 9. and 12 hours. Histologic and serologic examinations were conducted. ATP values of the 9-hour preservation group resumed those of the nonischemic operated control group. with the values of the 12-hour preservation group remaining at 61 percent. Histologically. focal necrosis. hyaline degeneration. and regeneration processes were the most characteristic manifestations in the muscles transplanted after cold ischemia of 12 hours. It was concluded that skeletal muscle could be preserved for 9 hours in 4 degrees C Euro-Collins solution.
Arterial T and Y grafts, Presented is the use of an autogenous arterial T graft for the salvage of a thrombosed arterial end-to-side anastomosis. The T-graft concept also offers the possibility of replacing a segment of artery in patients with arterial vessel wall defects. stenosis. obliteration. or disease during free latissimus dorsi or scapular flap transfer. The arterial T graft is harvested from the axilla and consists of segments of the subscapular. circumflex scapular. and thoracodorsal arteries. The large diameter of these vessels offers a good match with the arteries of the lower leg and forearm. The arterial Y graft consists of the same arteries and is used as an interpositional graft to revascularize two distal vessels from one proximal vessel.
Divided nevus of the eyelid, The two-stage surgical treatment of an adult female patient who presented with a congenital divided nevus of the left upper and lower lid is described.
A simple technique for closure of a palatal fistula using a conchal cartilage graft, A simple technique for closure of a palatal fistula using a conchal cartilage graft as a substitute for nasal lining flaps is reported. This graft simplifies the repair of the palatal fistula and protects the suture line of the oral covering flaps from recurrence.
Combined vascularized fibula and peroneal composite-flap transfer for severe heat-press injury of the forearm, A free combined vascularized fibula and peroneal composite flap was transferred to the forearm in a patient with a severely damaged forearm following a heat-press injury. The operative technique. postoperative management. and subsequent clinical course are described. and the advantages of this method are outlined. Not only can the fibula now be used as a free vascularized bone graft in simple bone defects. but further applications. such as a combined fibula and peroneal composite flap. can be employed in the treatment of severely damaged forearms.
Liver damage in long-term anticonvulsant therapy: a serological and histological study, The prevalence of liver damage in patients receiving long-term anticonvulsant therapy was determined. using a new marker of liver disease. the serum F protein concentration. Abnormal serum F protein concentrations were detected in 50 per cent of 34 patients receiving anticonvulsant therapy. A retrospective analysis of post-mortem liver samples showed common histological abnormalities in three out of seven patients who had died whilst receiving anticonvulsant therapy. These changes were not seen in control patients. We suggest that chronic anticonvulsant therapy may cause significant hepatocellular damage.
Function of the homeodomain protein GHF1 in pituitary cell proliferation, Mutations that cause pituitary dwarfism in the mouse reside in the gene encoding the transcription factor growth hormone factor 1 (GHF1 or pit1). These dwarf mice (dw and dwJ) are deficient in growth hormone (GH) and prolactin (PRL) synthesis and exhibit pituitary hypoplasia. suggesting a stem cell defect. With antisense oligonucleotide technology. a cell culture model of this genetic defect was developed. Specific inhibition of GHF1 synthesis by complementary oligonucleotides led to a marked decrease in GH and PRL expression and to a marked decrease in proliferation of somatotrophic cell lines. These results provide direct evidence that the homeodomain protein GHF1 is required not only for the establishment and maintenance of the differentiated phenotype but for cell proliferation as well.
Demonstration that CFTR is a chloride channel by alteration of its anion selectivity, Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) generates adenosine 3'.5'-monophosphate (cAMP)-regulated chloride channels. indicating that CFTR is either a chloride channel or a chloride channel regulator. To distinguish between these possibilities. basic amino acids in the putative transmembrane domains were mutated. The sequence of anion selectivity of cAMP-regulated channels in cells containing either endogenous or recombinant CFTR was bromide greater than chloride greater than iodide greater than fluoride. Mutation of the lysines at positions 95 or 335 to acidic amino acids converted the selectivity sequence to iodide greater than bromide greater than chloride greater than fluoride. These data indicate that CFTR is a cAMP-regulated chloride channel and that lysines 95 and 335 determine anion selectivity.
Effect of deleting the R domain on CFTR-generated chloride channels, The cystic fibrosis transmembrane conductance regulator (CFTR). which forms adenosine 3'.5'-monophosphate (cAMP)-regulated chloride channels. is defective in patients with cystic fibrosis. This protein contains two putative nucleotide binding domains (NBD1 and NBD2) and an R domain. CFTR in which the R domain was deleted (CFTR delta R) conducted chloride independently of the presence of cAMP. However. sites within CFTR other than those deleted also respond to cAMP. because the chloride current of CFTR delta R increased further in response to cAMP stimulation. In addition. deletion of the R domain suppressed the inactivating effect of a mutation in NBD2 (but not NBD1). a result which suggests that NBD2 interacts with the channel through the R domain.
Epidemiology of subarachnoid hemorrhage in Finland from 1983 to 1985, The age-standardized incidence of subarachnoid hemorrhage was 33/100.000/yr among Finnish men and 25/100.000/yr among Finnish women. Subarachnoid hemorrhage represented 11% of all strokes detected during 1983-1985 in the community-based stroke register in three areas of Finland. Age-standardized mortality from subarachnoid hemorrhage was 18/100.000/yr among men and 12/100.000/yr among women aged 25-74 years. representing in men 22% and in women 23% of all deaths from stroke in the register. The case-fatality rate of subarachnoid hemorrhage was high: 35% among men and 33% among women within 2 days after the onset of the stroke attack and 48% in men and 46% in women at 1 month. Our findings suggest that the incidence and mortality of subarachnoid hemorrhage in Finland are among the highest worldwide. although differences in criteria. study methods. and classification procedures reduce the comparability of studies from different countries. The occurrence of subarachnoid hemorrhage in our present study is also higher than that previously reported in this country. We believe that this is more likely due to changes in diagnostic classification and improvements in detection of the disease than to a real increase in the morbidity and mortality of subarachnoid hemorrhage.
Role of platelet function in symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage, To evaluate the role of platelet function in the pathogenesis of cerebral vasospasm. we compared sequential changes of platelet aggregability and beta-thromboglobulin and thromboxane B2 concentrations in blood samples from the internal jugular and peripheral vein of 13 patients with aneurysmal subarachnoid hemorrhage. Platelet function in blood from the internal jugular vein tended to be enhanced during days 0-1 but recovered to the normal range during days 2-4. After day 5. platelet function showed various patterns depending on the presence of symptomatic vasospasm. In patients without symptomatic vasospasm. sequential changes were relatively minor. with normal or slightly high values. Patients with symptomatic vasospasm already showed high platelet aggregability during the early stage of vasospasm. The concentration of beta-thromboglobulin increased several days after the onset of vasospasm. reaching 80 ng/ml or more in patients with a poor prognosis. Two of the five patients with symptomatic vasospasm showed markedly high concentrations of thromboxane B2 after day 8. These results suggest that vasospasm activates platelets and promotes aggregability and that the resulting increased tendency for thrombus formation may affect the patient's prognosis during the advanced stage.
Reduction of central nervous system ischemic injury in rabbits using leukocyte adhesion antibody treatment, Activated leukocytes appear to be directly involved in ischemic central nervous system injury. A surface glycoprotein (CD18) on the leukocyte is required for endothelial adherence and subsequent function and can be blocked with leukocyte adhesion antibody treatment. We used two animal models to determine the efficacy of anti-CD18 antibody treatment in preserving neurologic function after central nervous system ischemia. We gave a dose of 1 mg/kg anti-CD18 to treatment rabbits 30 minutes before inducing irreversible ischemia in the brain with intraarterial microspheres or in the spinal cord using reversible aortic occlusion. Treatment with anti-CD18 produced a significant reduction in neurologic deficits in the reversible spinal cord model. but not in the irreversible microsphere model. This protective effect supports the active role of leukocytes in central nervous system reperfusion ischemic injury and offers potential for future therapy.
Effect of antihypertensive therapy on focal stroke in spontaneously hypertensive rats, Spontaneously hypertensive rats subjected to focal cerebral ischemia develop larger infarcts than normotensive rat strains. To determine whether antihypertensive therapy decreases infarct volume in hypertensive rats. 60 13-week-old animals were treated with 20 mg/kg hydralazine added daily to the drinking water for 1.5. 6. 10. or 16 weeks and then subjected to focal cerebral ischemia by tandem right common carotid artery and middle cerebral artery occlusion. Blood pressure in the treated groups was substantially lower than that in untreated groups after 1 week of hydralazine therapy and remained lower for the entire treatment period in all four experiments. Mean infarct volume in spontaneously hypertensive rats treated for 10 (p = 0.02) or 16 (p = 0.005) weeks. but not 1.5 or 6 weeks. was significantly less than that in the untreated controls. The percentage reduction of infarct volume in animals treated for 10 and 16 weeks was similar. This study demonstrates that antihypertensive therapy decreases infarct volume in hypertensive rats subjected to focal cerebral ischemia. This treatment effect appears to be dependent on the duration of therapy. and the magnitude of the treatment effect seems to plateau by 10 weeks of therapy.
Effects of U74006F on multifocal cerebral blood flow and metabolism after cardiac arrest in dogs, Lipid peroxidation reactions during reperfusion after cardiac arrest may contribute to postischemic cerebral hypoperfusion. which in turn can contribute to permanent neurological dysfunction. We designed this study to determine whether the aminosteroid U74006F. a putative inhibitor of lipid peroxidation. mitigates cerebral multifocal hypoperfusion after cardiac arrest. We used our established dog model of ventricular fibrillation cardiac arrest (no blood flow) of 12.5 minutes. reperfusion by cardiopulmonary bypass of less than or equal to 5 minutes. and control of extracerebral variables during 4 hours postarrest. Cerebral blood flow was monitored by the stable xenon computed tomography method. Changes in cerebral oxygen consumption were obtained from mean blood flow values of coronal slices and the cerebral arteriovenous (sagittal sinus) oxygen content difference. A treatment group (n = 5) received U74006F starting with reperfusion (1.5 mg/kg i.a. plus 1.5 mg/kg i.v.) and three additional (graded) doses over 4 hours (total dose 4.5. 7.5. or 14.5 mg/kg). The U74006F-treated group showed the same postarrest transient hyperemia and protracted hypoperfusion in terms of global (computed tomography slice). regional. and local (multifocal) cerebral blood flow values and the same global cerebral oxygen consumption pattern as a concurrent control group (n = 5). At 1-4 hours postarrest. in both groups there was mismatching of global cerebral oxygen consumption. which reached baseline values. in relation to global cerebral blood flow and oxygen delivery. which remained at 50% of baseline. We conclude that treatment with U74006F after prolonged cardiac arrest causes no deleterious side effects and does not seem to alter multifocal postarrest cerebral blood flow and oxygen consumption.
Captopril improves neurologic outcome from incomplete cerebral ischemia in rats, We investigated the effects of the angiotensin-converting enzyme inhibitor captopril on neurologic outcome in a rat model of incomplete cerebral ischemia. Twenty male Sprague-Dawley rats were anesthetized with 70% nitrous oxide in oxygen and fentanyl (10 micrograms x kg-1 i.v. bolus. 25 micrograms x kg-1 x hr-1 i.v. continuous infusion). Animals in group 1 (n = 10) received no angiotensin-converting enzyme inhibitor while animals in group 2 (n = 10) were given 10 mg x kg-1 i.v. captopril 30 minutes prior to the ischemic period. Ischemia was produced by unilateral carotid artery ligation and hemorrhagic hypotension to 35 mm Hg for 30 minutes. Body temperature. arterial blood gases. and arterial pH were maintained constant. Neurologic outcome was evaluated every 24 hours for 3 days using a graded deficit score (0. normal; 18. stroke-related death). On the third day after ischemia. captopril significantly improved neurologic outcome (median deficit score = 4) compared with controls (median deficit score = 18) (p less than 0.05). These results suggest that reduced angiotensin II levels or increased tissue kinin concentrations may decrease ischemic brain injury.
Magnesium sulfate reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in rats, We induced experimental delayed cerebral vasospasm by the intracisternal injection of greater than 0.5 ml blood in 30 rats. Seventy-two hours later the basilar artery was exposed via the transclival approach and photographed at high-power magnification through an operating microscope. We then evaluated the effect of topical (n = 30) and intravenous (n = 20) magnesium sulfate on the spastic artery by computerized image analysis. A greater than 50% reduction in baseline diameter of the basilar artery was observed in the rats subjected to subarachnoid hemorrhage compared with the 10 controls (p less than 0.0001). Intravenous magnesium sulfate dilated the spastic artery to approximately 75% of the baseline diameter in control rats (p less than 0.0001). Topical magnesium sulfate caused dramatic dilation of the basilar artery in both the control and the subarachnoid hemorrhage groups to near 150% of the baseline diameter in the controls (p less than 0.001). All rats receiving intravenous magnesium sulfate reached therapeutic plasma levels of the ion. Hemodynamic effects were mild and immediately reversible upon cessation of magnesium sulfate administration. We suggest that magnesium has a role in the treatment of subarachnoid hemorrhage-induced vasospasm in humans.
Effects of perinatal stroke on striatal amino acid efflux in rats studied with in vivo microdialysis, We used in vivo microdialysis to determine the impact of a focal hypoxic-ischemic insult on striatal amino acid efflux in the immature brain. Microdialysis probes were inserted into the right striatum of postnatal day 7 rats. To induce hypoxic-ischemic injury. the right carotid artery was ligated and the animals were exposed to 8% oxygen for 2.5 hours (n = 22). Rats exposed to ligation alone (n = 10) or hypoxia alone (n = 8) and untreated controls (n = 17) were also studied. Two hours after probe insertion. a 30-minute baseline microdialysis sample was obtained. After arterial ligation. two additional baseline samples were collected. Five more samples were collected over the next 2.5 hours (in 8% oxygen or room air). Eight amino acids (glutamate. aspartate. taurine. glutamine. alanine. serine. glycine. and asparagine) were consistently detected in dialysates using a high-performance liquid chromatography assay with electrochemical detection. In untreated controls. amino acid efflux did not change over 4 hours. During hypoxia-ischemia. efflux values fluctuated widely. with marked intra-animal and interanimal variability. Efflux peaks for each amino acid were defined as values greater than the highest control mean value plus two standard deviations. Glutamate efflux peaks (greater than 7 pmol/min compared with 2 pmol/min at baseline) were detected in no controls and in eight hypoxic-ischemic rats (p = 0.006. Fisher's two-tailed exact test). Taurine efflux peaks (greater than 75 pmol/min compared with 10 pmol/min for controls at baseline) were detected in 10 hypoxic-ischemic rats and one control (p = 0.01) and in seven of the eight animals in which glutamate efflux peaks occurred (p = 0.006).
Evaluation of the red cell storage lesion after irradiation in filtered packed red cell units, Packed red cell units (n = 10) were filtered and divided equally. One-half unit from each donor was irradiated (x) (3500 cGy). On Days 0. 14. 28. and 42. ATP. K+. Na+. lactate dehydrogenase (LDH). plasma-free hemoglobin (PFH). and pH were determined. The reduction in ATP was greater in the irradiated than the nonirradiated (y) units by Day 42 (mean x-y: -70. p = 0.0005). The increase in K+ was greater in the irradiated than nonirradiated units on Days 14. 28. and 42 (mean x-y: 17-20. p = 0.0001). Decrease in pH and increases in LDH and PFH were significant (p less than 0.05) on Day 42 only. K+ increases added only 1.7 to 2.0 mmol per unit. a difference felt to be clinically insignificant. The changes noted in ATP. pH. LDH. and PFH are significant but minimal on Day 42 and imply that viability changes would also be minimal. These biochemical data support the storage of irradiated units for at least 28 days.
Blood warming: current applications and techniques, Active blood warming is a recent practice and arises out of conflicting needs. On the one hand. the safety and preservation of blood require refrigerated storage and delivery up to the moment of transfusion. On the other hand. modern methods of very rapid transfusion in resuscitation would cause clinically dangerous hypothermia if unmodified. ice-cold blood were to be so transfused. These needs must be reconciled in the interest of adequate patient care--hence the need for blood warming. Nevertheless. blood warming creates risks of its own and should not be used without justifying clinical indications. Within limits that extend somewhat above normal body temperature. the application of heat does no harm to stored RBC. a fact that is not reflected in current standards for blood warmers. Bearing in mind the human tendency to "stretch" standards and the fallibility of mechanical devices. caution is always wise. But perhaps the time has come for reconsideration of the present upper limit of 38 degrees C. Many varieties of blood warmers are available in the US. but none at this time is based on electromagnetic activity. The most common systems now in use are in-line warmers. most of which are not adequate for the type of rapid-transfusion systems currently available. Countercurrent in-line blood warmers and the method of rapid warm saline admixture can both be used successfully for rapid. massive transfusions. Blood warming is seldom necessary or desirable for elective transfusions at conventional rates. even for patients with cold autoagglutinins.
Characterization of tumor hypoxia by 31P MR spectroscopy, Tumor hypoxia is of considerable importance to the oncologist in selecting and optimizing cancer therapy. because hypoxia can determine the effectiveness of various therapies. The relationship between tumor hypoxia and tumor bioenergetics. assessed by 31P MR spectroscopy. is examined to determine whether 31P MR spectroscopy can be clinically useful to measure or characterize tumor hypoxia. Work with experimental tumors has suggested that several different types of hypoxia may exist and that 31P MR spectroscopy cannot be used to characterize all types. Metabolic hypoxia is the level of hypoxia that results in mitochondrial impairment in cells. and it is associated with declining cellular bioenergetic status. which can be measured by enzymatic assay of adenosine triphosphate (ATP). Because 31P MR spectroscopy is sensitive to levels of ATP. it is potentially sensitive to metabolic hypoxia in vivo and may provide a rapid and noninvasive technique for characterizing metabolic hypoxia in tumors. Radiobiologic hypoxia is the level of hypoxia that results in attenuated cell death due to radiation. because radiotoxicity is directly related to tissue levels of oxygen. Radiobiologic hypoxia of tumors thus has more impact on choice of therapy. yet the relationship between metabolic hypoxia and radiobiologic hypoxia remains to be elucidated. An analysis of published data suggests that 31P MR spectroscopy is directly sensitive to metabolic hypoxia in tumors. but it is only indirectly sensitive to radiobiologic hypoxia in tumors. Therefore. 31P MR spectroscopy may be unable to quantify the cell fraction of a tumor that has radiobiologic hypoxia. However. preliminary data suggest that MR spectroscopy may prove useful for determining the effectiveness of therapeutic interventions designed to manipulate radiobiologic hypoxia in tumors or for monitoring the kinetics of tumor reoxygenation after treatment.
Lobular carcinoma in situ of the breast: clinical, pathologic, and mammographic features, Lobular carcinoma in situ (LCIS) was diagnosed in 165 surgical specimens (119 patients) at our institution between 1974 and 1987. LCIS was seen more often in younger women (mean age. 49 years) than other breast carcinomas were (mean age. 58 years). Sampling of a single breast revealed multifocal disease in 70% (96/138). When both breasts were sampled. bilateral foci were found in 50% (41/82). Of 165 breasts with foci of LCIS. 37% (61/165) had simultaneously occurring invasive cancers in the same breast. Direct mammographic-pathologic correlation of foci of LCIS was possible in 73 breasts (67 patients). Microcalcifications were an indication for biopsy in 49% (20/41) of breasts with a mammographic abnormality. but were a nonspecific finding often found in tissues adjacent to foci of LCIS. The mammogram was normal in 44% (32/73) of breasts with foci of LCIS. The mammograms of patients with LCIS and those from a group of age-matched control subjects were compared by using a modified form of Wolfe's criteria and the percentage of fibroglandular elements. LCIS was seldom found in an N1 breast (1% vs 29%) or in a breast with less than 25% of its parenchymal area occupied by fibroglandular density (3% vs 33%). Compared with the control group. breasts with LCIS had more than 50% fibroglandular density (85% vs 45%) and a much higher frequency of the DY pattern (56% vs 36%). More fibroglandular density was seen in the LCIS group at all ages. Postmenopausally. the frequencies of the DY pattern and fibroglandular density greater than 50% in LCIS patients were nearly double those in the control group. LCIS patients have disease of the entire breast parenchyma. characterized by multifocality and bilaterality of various forms of lobular disease. Their mammograms reveal a higher rate of the DY pattern and higher percentages of fibroglandular or parenchymal density than those of age-matched controls. In LCIS patients. persistence of the DY pattern. or large amounts of fibroglandular density postmenopausally supports the concept that mammographically dense breasts are a marker for increased cancer risk in women 50 years old and older.
Gadopentetate dimeglumine-enhanced chemical-shift MR imaging of the breast, Standard T1-weighted MR images enhanced with gadopentetate dimeglumine show relatively minimal enhancement of breast lesions due to the high background signal from fat in the breast. Strongly enhancing lesions may become isointense relative to the fat signal and become invisible or indistinct after contrast administration. Fat-suppressed chemical-shift imaging (CSI) combined with administration of gadopentetate dimeglumine improves lesion detection and characterization in other areas of the body where a strong lipid signal is present. We evaluated this technique in the breast. Twenty patients with mammographic lesions were studied with standard unenhanced T1- and T2-weighted images and enhanced T1-weighted images. as well as with CSI before and after administration of gadopentetate dimeglumine. The series were ranked independently for border and matrix characteristics. The border was assessed for a smooth. irregular. or spiculated margin. The matrix or internal substance was evaluated for visibility and type of enhancement. homogeneous or inhomogeneous. The enhanced CSI images were superior to all other images in the depiction of border and matrix characteristics. Of 20 patients. a corresponding mass was detected on MR in 14. In two of the 14 patients. the lesion was seen only in the enhanced CSI images. Chemical-shift artifacts on enhanced T1-weighted images obscured border detail in several cases. Enhanced CSI improves visualization of breast lesions as compared with conventional MR imaging with or without enhancement. The enhanced CSI technique produces differential enhancement between glandular tissue and lesions while suppressing the signal from fat. This improves the visualization of border and matrix characteristics and depicts lesions that otherwise might be obscured.
Abdominal desmoids: CT findings in 25 patients, Desmoids are histologically benign but locally aggressive fibrous tumors. Although overall they are rare lesions. they are a common manifestation of Gardner syndrome. We retrospectively reviewed clinical records and CT scans of 25 patients with abdominal desmoids. The number. location. and CT characteristics of the lesions were recorded for each patient. Tumors were solitary in 72% of patients and multiple in 28%. Fifty percent were located in the abdominal wall. 41% in the mesentery. and 9% in the retroperitoneum. More than two thirds of the lesions had well-defined borders. with the remainder displaying an infiltrative outer margin. The majority of tumors had attenuation values equal to (47%) or greater than (41%) the attenuation of muscle on contrast-enhanced CT scans. Complications attributable to the desmoid were commonly detectable on CT (hydronephrosis occurred in 36% and small-bowel obstruction in 20%). Our results detail the spectrum of CT findings and complications caused by abdominal desmoids.
Biliary lithotripsy: correlation between gallbladder contractility before treatment and the success of treatment, We perform biliary lithotripsy without adjuvant chemolitholytic agents. and therefore fragment clearance depends solely on the gallbladder's ability to evacuate its contents. We studied 205 patients to determine if gallbladder contractility before biliary lithotripsy is a predictor of treatment results and rate of fragment clearance. Percentage gallbladder contraction was calculated from the fractional difference in the sonographically measured gallbladder volumes before and after a fatty meal. Seventy-six patients (37%) were free of stones and fragments. and 129 patients (63%) had residual fragments at comparable follow-up intervals. Statistical analysis showed a significant difference in gallbladder contractility before biliary lithotripsy between the fragment-free group and the residual-fragment group (p = .008). Stone burden before treatment showed no significant difference between the groups (p = .074). but the number of stones was significantly less in the fragment-free group (p = .022). In the fragment-free group. a poor correlation (r = .047) was found between the percentage gallbladder contraction and the rate of fragment clearance. These data indicate that contractility of the gallbladder before treatment correlates with overall success of biliary lithotripsy but is not a predictor of the speed of fragment clearance.
Diagnosis of portal vein thrombosis: value of color Doppler imaging, This study was undertaken to determine the accuracy of color Doppler imaging in the diagnosis of portal vein thrombosis. Two hundred fifteen patients were studied with color Doppler imaging to determine patency of the main portal vein. Sonographic findings were confirmed in 75 patients. aged 19 to 66 years. Correlation with angiography was obtained in 13 patients. and surgical correlation was obtained in the remaining 62. Nine patients had portal vein thrombosis on the basis of these gold standards. Sonograms were classified as showing either patency or thrombosis. depending on the ability to show color flow within the main portal vein. Agreement between sonography and angiography or surgery was found in 69 patients (61 patent. eight thrombosed). One patient with a patent portal vein at sonography was found to have a thrombosed vessel at surgery. whereas five patients without portal venous flow at sonography had patent vessels at angiography (one patient) or surgery (four patients). Overall sensitivity and specificity for detection of portal vein thrombosis were 89% and 92%. with an accuracy of 92%. a false-negative rate of 0.11. a negative predictive value of 0.98. and a positive predictive value of 0.62. We postulate that the majority of errors in our study occurred in vessels that. although patent. had only sluggish flow. which could not be resolved because of technical limitations. We conclude that color Doppler imaging is a valuable screening procedure for the assessment of portal vein patency. If the sonogram shows a patent portal vein. no further studies are required. However. a lack of demonstrable flow does not always indicate thrombosis. and other imaging studies should be performed for confirmation.
Diagnosis and staging of hepatocellular carcinoma: comparison of CT and sonography in 36 liver transplantation patients, Radiologic studies are important in the detection of hepatocellular carcinoma and the selection of patients for partial liver resection. liver transplantation. or palliation. We retrospectively studied 36 patients with hepatocellular carcinoma who were examined with both CT and sonography before undergoing hepatic transplantation. Pathologic findings of the entire resected liver were correlated with results of imaging studies before transplantation. Parenchymal lesions were shown by sonography in 29 cases (81%) and by CT in 34 cases (94%). Although CT was more sensitive than sonography was. both CT and sonography frequently failed to depict reliably the size of tumor or the exact number of tumor nodules as determined pathologically. Pathologic findings showed vascular invasion in 19 cases (53%). whereas CT showed invasion in 11 cases (31%) and sonography showed it in only six (17%). Nodal metastasis to the porta hepatis was found in four patients; CT correctly showed two cases (three false-positive) and sonography correctly showed one case. Intrahepatic ductal dilatation was seen in eight patients on CT but was not identified on sonography. We conclude that CT is more accurate for identifying and staging hepatocellular carcinoma. but both CT and sonography frequently fail to depict the extent (size and number of lesions) of disease. especially when underlying cirrhosis is present.
Retroperitoneal fibrosis, Retroperitoneal fibrosis is idiopathic in two thirds of cases and is found most commonly as an isolated fibrotic plaque centered over the lower lumbar spine and entrapping one or both ureters. It has been postulated that the fibrosis in the idiopathic cases results from a hypersensitivity reaction to antigens leaking into the retroperitoneum from atheromatous plaques in the aorta or common iliac arteries. In the remaining one third of cases. causes include ergot-derivative drugs. retroperitoneal hemorrhage or urine extravasation. and a desmoplastic response to a variety of tumors. In up to 15% of cases. associated fibrotic processes are found elsewhere in the body. Although the disease is imaged best with CT or MR. neither of these techniques can be used to differentiate benign from malignant plaques. Histologically. the disease is characterized in its early stages by inflammatory cells and edema in a loose collagen network. The mature plaque is composed of dense fibrous tissue with minimal cellular infiltration. This progression is important as it influences MR signal characteristics.
Abnormalities of the seminal tract causing infertility: diagnosis with endorectal sonography, Endorectal sonography. developed primarily for use in the diagnosis and staging of prostatic carcinoma. should be the first imaging technique used in the evaluation of an infertile man with low semen volume in whom either a hypoplastic or obstructed seminal tract is suspected. Endorectal sonography allows visualization of the seminal vesicles. which are otherwise difficult to examine. We used endorectal sonography to evaluate six young men. five of whom were being evaluated for azoospermia and infertility. One patient had no identifiable seminal vesicle on either side. Four patients had unilateral absence of the seminal vesicles. Of these four. three had a sonographically normal-appearing seminal vesicle on the contralateral side. and the fourth had an obstructed system contralaterally. The sixth patient had a hypoplastic system on the left and an obstructed system on the right. The delineation of an obstructed or agenetic seminal vesicle and seminal tract on endorectal sonography allows decisions to be made regarding treatment and prognosis.
John Caffey Award paper. Avascular necrosis: early MR imaging and histologic findings in a canine model, To examine the early MR and histologic changes of avascular necrosis. we surgically devascularized the distal femur of adult beagle dogs and performed short TR/short TE MR imaging and histologic examinations. MR showed increasing areas of low signal. and histologic examination showed changes of fat necrosis. inflammatory infiltrate. and fibrocytic and bony repair. These processes were divided into four stages. Stage 1 is seen in the first days after surgery and consists of homogeneous high signal on MR and only subtle histologic changes of early fat necrosis. Stage 2. seen by 7 days after surgery. shows linear low-signal areas within the high-signal marrow on MR and fat necrosis and an inflammatory infiltrate on histologic sections. Stage 3. seen by 16 days after surgery. shows patchy low signal occupying more of the marrow on MR with a fibrocytic infiltrate on histologic sections. Stage 4. seen by 23 days after surgery. shows a more homogeneous low and intermediate signal on MR and histologic findings of more organized fibrocytes and the onset of new bone formation. Using this model. we have proved that MR imaging can show marrow changes as soon as 1 week after the onset of avascular necrosis. Whereas MR imaging showed a progression of increasing areas of low signal. the histologic findings seen during this time were diverse. including inflammatory infiltration (a previously unreported finding). fat necrosis. and fibrocytic and osseous repair.
Preoperative evaluation of osteosarcoma: value of gadopentetate dimeglumine-enhanced MR imaging, Decisions regarding the surgical approach in osteosarcoma require accurate assessment of tumor extent. In order to determine whether enhancement with gadopentetate dimeglumine could add clinically significant information to that available with unenhanced MR imaging. 21 patients with osteosarcoma underwent preoperative MR imaging. T1- and T2-weighted spin-echo MR images obtained before and after administration of IV gadopentetate dimeglumine were evaluated to determine the conspicuity of marrow and soft-tissue extent of tumor. including tumor involvement of major neurovascular bundles and adjacent joints. MR results were correlated with tumor margins found at surgery. In some instances. use of gadopentetate dimeglumine obscured differentiation of tumor from normal marrow or tumor infiltration into perineurovascular fat. and tumor extension through pseudocapsule could not be differentiated from peritumoral edema after contrast administration. Contrast enhancement did assist in differentiation of intraarticular tumor from effusion; however. synovial invasion could be identified on unenhanced T1-weighted images by loss of synovial fat and cortical disruption. These results indicate that gadopentetate dimeglumine does not assist in defining tumor margins of osteosarcoma.
Soft-tissue sarcoma: MR imaging vs sonography for detection of local recurrence after surgery, To determine the value of MR and sonography in detecting local recurrences of soft-tissue sarcomas after surgery. 26 MR and sonographic studies performed in 21 patients were reviewed retrospectively. Recurrences were confirmed histologically in 12 (46%) of 26 studies. The MR images and sonograms were obtained within 1 month of each other. The findings were classified as recurrence. no recurrence. or indeterminate. Sonography was instrumental in guiding fine-needle aspiration biopsy of impalpable lesions. In two cases. the findings on sonography were indeterminate. In both of these cases. the sonograms had been obtained soon after surgery (at 2 and 4 months). The sensitivity and specificity in the detection of local recurrences were 83% and 93%. respectively. for MR and 100% and 79%. respectively. for sonography. These differences were not statistically significant. We conclude that MR and sonography appear to be equally useful in the detection of local recurrences of soft-tissue sarcomas. sonography can be used for routine follow-up and in guiding needle biopsies. sonography may be more difficult to interpret than MR during the early postoperative period. and MR should be used if sonography is inconclusive.
Carotid duplex sonography: bisferious pulse contour in patients with aortic valvular disease, Characteristic systolic and diastolic pulse contours occur in the carotid Doppler waveforms of patients with aortic valvular disease that have not previously been described in publications concerning carotid duplex sonography. The purpose of this study was to evaluate the presence and characterize the nature of these carotid duplex waveform abnormalities in patients with known aortic valve disease and to correlate these changes with the severity of valve dysfunction. The study group consisted of 26 patients with aortic regurgitation or combined aortic regurgitation and aortic stenosis. Duplex studies were retrospectively reviewed by two radiologists for the presence of two systolic peaks. and for the presence of diastolic reversal of flow direction. This pattern of two systolic peaks. characteristic of aortic regurgitation. is called bisferious from the Latin "twice beating." Aortic regurgitation was graded by echocardiography as mild. moderate. or severe by the cardiologists reviewing the examination. A group of 20 age-matched patients without aortic valvular disease were similarly assessed. The bisferious pattern was demonstrated in 13 (50%) of 26 patients. Five (19%) of 26 patients had significant reversal of diastolic flow. Four patients were studied both before and after aortic valve replacement. Three had bisferious wave contours preoperatively; two of these also had diastolic reversal of flow. The fourth patient had retrograde flow in diastole without systolic contour abnormality. Postoperatively. all carotid waveforms were normal. None of the duplex waveforms in the control group demonstrated characteristic systolic or diastolic abnormalities. The bisferious waveform and retrograde diastolic flow are Doppler patterns associated with aortic valvular disease. These patterns are reversible after aortic valve replacement. While echocardiography remains the study of choice in the evaluation of suspected valvular dysfunction. up to one third of patients with aortic regurgitation may not have a detectable murmur. Therefore. identifying these patterns on carotid duplex examinations may provide clinically useful information and serve as a clue to previously unsuspected cardiovascular disease.
Does intensive glycemic control in diabetic pregnancies result in normalization of other metabolic fuels, Intensive treatment of insulin-dependent diabetes mellitus during pregnancy often normalizes plasma glucose levels. However. it is unclear whether this adversely affects other metabolic fuels that are essential to normal fetal growth and development. Metabolic studies were conducted after the subjects ingested a standardized mixed meal during each trimester in 7 normal and 15 insulin-dependent diabetic pregnant women. The latter were treated with continuous subcutaneous insulin infusion or multiple injections. which were adjusted to achieve strict glucose control throughout pregnancy. Insulin. alanine. branched-chain amino acids. triglycerides. free fatty acids. and ketones were measured every 15 to 30 minutes before a standardized breakfast and for 150 minutes after the breakfast. Patients with insulin-dependent diabetes mellitus were studied while they received their unusual insulin dosages. Fasting glucose levels (87 +/- 7 mg/dl) and glucose levels 150 minutes after the meal (112 +/- 11 mg/dl) were near normal. However. normoglycemia was achieved at the expense of increased plasma insulin levels (area under insulin response curves. p less than 0.01. vs nondiabetic curves). Nevertheless. fasting and post-prandial plasma branched-chain amino acids. alanine. and free fatty acids were similar in both groups. Fasting cholesterol. triglyceride. and ketone levels were also normalized. We conclude that normalization of circulating amino acids and lipids in conjunction with correction of hyperglycemia may contribute to favorable outcomes in infants of intensively treated diabetic mothers.
The enhanced production of placental interleukin-1 during labor and intrauterine infection, The purpose of this study was to determine the effect of labor and chorioamnionitis in interleukin-1 production by human placenta. We studied the activity of the placenta to produce interleukin-1 with an enzyme immunoassay by culturing tissue blocks. The placental tissue obtained after labor produced a larger amount of interleukin-1 than placental tissue obtained before labor. All the placental tissues produced more interleukin-1 beta than interleukin-1 alpha. The placentas with labor and chorioamnionitis produced about seventeenfold more interleukin-1 than placentas with labor only. We immunohistochemically identified interleukin-1--producing cells in the placenta and found that syncytiotrophoblasts produced both interleukin-1 alpha and interleukin-1 beta. while Hofbauer cells produced only interleukin-1 beta. In vitro analysis of the trophoblast activities to produce interleukin-1 revealed that microbial byproducts enhanced interleukin-1 production. possibly inducing accumulation of interleukin-1 receptor-positive cells at the sites of inflammation. In addition to stimulation of prostaglandin biosynthesis and labor. the placental interleukin-1 may act as an inflammatory mediator. leading to systemic and local changes at fetomaternal interface and activating fetomaternal immune systems against intrauterine infection.
Arterial blood flow velocity waveforms of the pelvis and lower extremities in normal and growth-retarded fetuses, Serial measurements of femoral artery flow velocity waveforms were made at specified intervals of 3 to 4 weeks from 15 to 20 weeks of gestational age to 35 weeks and 1- to 3-week intervals thereafter until delivery in 12 normal fetuses (group 1A) with pulsed Doppler ultrasonography. The pulsatility index of the femoral artery increased linearly with advancing gestation in all 12 fetuses; this was associated with reverse diastolic flow velocity waveforms. In 30 other normal fetuses (group 1B) whose gestational ages ranged between 16 and 38 weeks (mean +/- SD. 29.5 +/- 5.6 weeks). the femoral artery flow velocity waveforms were analyzed with the external iliac artery. internal iliac artery. and umbilical artery waveforms. No significant difference was observed between the pulsatility index of the external iliac artery and that of the femoral artery (mean +/- SD. 3.7 +/- 1.1 vs 3.7 +/- 1.1). The pulsatility index of the internal iliac artery was significantly higher than that observed in the umbilical artery (mean +/- SD. 1.27 +/- 0.28 vs 1.12 +/- 0.23). The femoral and umbilical artery velocity waveforms also were determined in 20 fetuses with intrauterine growth retardation (group 2). whose gestational ages ranged between 24 and 36 weeks (mean +/- SD. 31 +/- 3.4 weeks). Abnormal femoral artery pulsatility index was recorded in two fetuses who died. Absent or reverse flow of the umbilical artery was recorded in 10 fetuses; four of them died. and four others manifested fetal distress or required admission to the neonatal intensive care unit or both. These preliminary data suggest that the femoral artery pulsatility index cannot be used as an indicator of adverse fetal outcome. whereas absent or reverse flow of the umbilical artery seems to be better correlated with adverse fetal outcome.
The influence of contamination of culture medium with hepatitis B virus on the outcome of in vitro fertilization pregnancies, Heat-inactivated human serum is added to the culture medium used for in vitro fertilization and other forms of assisted conception. Because one batch of pooled serum contained hepatitis B virus. an epidemic occurred among women participating in the treatment program. Seventy-nine women had serologic proof of hepatitis B infection. This incident gave the opportunity to study the effect of hepatitis B virus on pregnancy outcome and the newborn. The situation is unique because the preimplantation embryo was exposed to hepatitis B virus or the pregnancy was complicated by a (sub)clinical infection. Twenty-four women were or became pregnant while having an acute hepatitis B infection. Five pregnancies ended in abortion. The remaining 19 pregnancies ended in the birth of 24 children. No evidence for any harmful effect of exposure to hepatitis B virus in the embryonic or fetal period on the newborn could be found.
The effect of the inhibition of prostaglandin synthesis on renal blood flow in fetal sheep, Treatment with prostaglandin synthesis inhibitors has been associated with oligohydramnios in the fetus. The presumed mechanism is a reduction in fetal renal blood flow. We examined the effect of meclofenamate administration on renal blood flow in chronically catheterized fetal sheep during normoxia and during moderate and severe hypoxia. Ten fetal sheep were made hypoxic twice at least 4 days after surgery: once in the presence and once in the absence of meclofenamate infusion. Renal blood flow and combined ventricular output were measured with radioactive microspheres. Prostaglandin synthesis blockade with meclofenamate caused no significant change in blood pressure. combined ventricular output. renal blood flow. or renal vascular resistance in either the normoxic or hypoxic animals. These data challenge the contention that prostaglandin activity protects the renal vascular bed of the fetus from vasoconstriction during hypoxia and they also do not support the hypothesis that prostaglandin synthesis inhibition causes oligohydramnios through reduction of fetal renal blood flow.
Subserosal adenomyosis: a possible variant of pelvic endometriosis, A total of 128 patients with adenomyosis were examined clinically and histologically to investigate the pathogenesis of subserosal adenomyosis. In this study 15 (11.7%) cases were classified as subserosal adenomyosis on the basis of localization of heterotopic endometrial tissues that consisted of glands and stroma. These were subclinical and incidental. The uterus was not enlarged in this type of adenomyosis. Distribution of the ectopic tissues and the patients' mean age at the time of the hysterectomy suggest that subserosal adenomyosis may develop as a variant of pelvic endometriosis.
Histologic study of endometriosis and examination of lymphatic drainage in and from the uterus, Histologic study of endometriosis and investigation of lymphatic drainage in and out of the uterus were conducted to obtain more information on the histogenesis of endometriosis. Endometriosis is a disease originating from the normal endometrium. specifically from its basal layer. Internal endometriosis (adenomyosis) is caused mainly by direct invasion of the endometrium into the spaces located in the connective tissue of the muscle layer. Serous and ovarian types of endometriosis are frequently found together with adenomyosis. Endometrial fragments in vessels are detected in 4.5% of cases of endometriosis. Observation of serial sections proved that serous endometriosis is caused mainly by continuous or semicontinuous invasion of the tunica muscularis spaces primarily from adenomyosis lesions and partly from the endometrium. Confirmation of lymph flow into the ovary from the uterine body strongly suggests that ovarian endometriosis arises as a consequence of vascular (lymphatic) transport of endometrial fragments from adenomyosis lesions. serous endometriosis lesions. or the endometrium.
Secondary mullerian system and endometriosis, The pathogenesis of endometriosis is controversial. The two principal histogenetic theories are (1) metastases of endometrial tissues to an ectopic location (metastatic theory) and (2) metaplastic development of endometrial tissue at the ectopic site (metaplastic theory). Studies on the development of the coelomic cavity and the mullerian duct. as well as expression of CA 125 during the fetal period and in the adult. strongly suggest that coelomic epithelium-related tissues and mullerian-derived epithelia of the adult have a shared embryologic ancestry. Many manifestations of mullerian-directed metaplasia suggest that tissues derived from the coelomic epithelium and its accompanying mesenchymal cells. referred to as the "secondary mullerian system." have the potentiality to differentiate into mullerian-directed epithelium and stroma. This metaplastic potentiality of the secondary mullerian system constitutes a basic concept in the pathogenesis of endometriosis.
Twin delivery: influence of the presentation and method of delivery on the second twin, To ascertain the perinatal mortality and morbidity in the second twin as related to its presentation and method of delivery. we reviewed the data on 578 sets of twins delivered from 1980 to 1987 and included 397 sets in whom both twins were greater than or equal to 1000 gm. without lethal anomalies. and in whom the first twin presented as a vertex. The perinatal outcome comparing twin A (all vertex) with twin B (vertex or nonvertex) with cesarean section or vaginal delivery was analyzed. No statistically significant difference in perinatal mortality or morbidity was found in comparing the nonvertex second twin delivered vaginally or by cesarean section. The one perinatal death and significant perinatal morbidity occurred in infants weighing less than 1500 gm or at less than 32 weeks' gestational age. It is concluded that vaginal delivery. irrespective of the position of the second twin. is valid in selected cases as long as fetal weight is greater than 1500 gm and the gestational age is greater than or equal to 32 weeks.
Cigarette smoking during pregnancy in relation to placenta previa, To evaluate the relationship between cigarette smoking and the occurrence of placenta previa. we used interview and medical record data to conduct a case-control analysis of 69 placenta previa cases and 12.351 controls. The unadjusted relative risk estimate of placenta previa for women reported to have "ever smoked" during pregnancy relative to nonsmoking mothers was 1.9 (95% confidence interval. 1.2 to 3.0). The risk rose after adjusting for potential confounders (odds ratio. 2.6; 95% confidence interval. 1.3 to 5.5). In contrast to a previous report. the duration of smoking was not an independent risk factor for placenta previa. These results suggest that cigarette smoking during pregnancy is a determinant of placenta previa. Carbon monoxide hypoxemia. which is one possible mechanism for this association. may result in compensatory placental hypertrophy. Placentas with increased surface areas are more likely to cover the cervical os. causing placenta previa.
Ten years after cryosurgical treatment of cervical intraepithelial neoplasia, From 1974 to 1977 we treated 96 patients for grade 2 or 3 cervical intraepithelial neoplasia with cryotherapy. They were monitored for 10 to 14 years with an attendance rate of 98%. Treatment resulted in cure in 92%. Nine patients had persisting lesions. and three patients had a recurrent lesion. The last recurrence was diagnosed 6.7 years after cryotherapy.
The association between human papillomavirus deoxyribonucleic acid status and the results of cytologic rescreening tests in young, sexually active women, We examined the utility of cytologic rescreening tests in women who had positive test results for human papillomavirus deoxyribonucleic acid but who were diagnosed as having benign conditions at cytologic testing. One hundred twenty-five Papanicolaou smears from women who were screened for human papillomavirus deoxyribonucleic acid were sent routinely to a private laboratory for diagnoses. These slides were then reviewed independently by two pathologists who were blinded to the human papillomavirus deoxyribonucleic acid results. The effects of cytologic rescreening in cases of both positive and negative human papillomavirus deoxyribonucleic acid were assessed by calculating z scores. Cervical intraepithelial neoplasia was diagnosed in 40% by pathologist A and in 20% by pathologist B of the human papillomavirus-positive subjects compared with none diagnosed by the private cytology laboratory (z = 3.09. p less than 0.005 and z = 1.98. p less than 0.05. respectively). No significant differences were found in the human papillomavirus-negative group. We conclude that cytologic rescreening in human papillomavirus deoxyribonucleic acid-positive women who were initially diagnosed as having benign cytologic results will yield a significant proportion of cases of cervical intraepithelial neoplasia.
Screening in ovarian cancer, Ovarian cancer will affect 20.000 American women this year and some 13.500 will die of the disease. Most patients will have stage III or IV disease at the time of diagnosis. Because ovarian cancer may be initially without symptoms. attempts have been made to develop screening tests that would lead to an early diagnosis. Two tests. serum CA 125 and pelvic ultrasonography. have been suggested by some to be accurate enough to be included in yearly screening for ovarian cancer. Although further testing of these techniques is encouraged. data to date do not justify yearly screening with CA 125 or pelvic ultrasonography in all women.
Elective versus emergency cesarean hysterectomy cases in a residency program setting: a review of 129 cases from 1984 to 1988, A retrospective study was performed to compare elective versus emergency cesarean hysterectomy in a residency program. We noted the following statistically significant differences between emergency and elective cases: (1) Estimated blood loss (mean +/- SD) for emergency and elective cases was significantly different at 1495 +/- 772 and 875 +/- 396 ml (p = 0.001). (2) Operative time in emergency cases was significantly longer than in elective cases (105 +/- 38 vs 83 +/- 27 minutes. p = 0.003). (3) The incidence of transfusion was 68% in our emergency cases and 14.6% in the elective series (p less than 0.05). (4) Febrile morbidity in our series was 40% in emergency cases and 18.3% in elective cases (p less than 0.05). Our series was comparable to previous series reported. Our experience suggests that cesarean hysterectomy can be performed safely in a residency training program when done as an elective procedure in the well-prepared patient.
Nerve growth factor receptor expression in peripheral and central neuroectodermal tumors, other pediatric brain tumors, and during development of the adrenal gland, Nerve growth factor (NGF) is important to the survival. development. and differentiation of neurons. Its action is mediated by a specific cell surface transmembrane glycoprotein. nerve growth factor receptor (NGFR). In this study. NGFR expression by human fetal and adult adrenal medullary tissue. peripheral nervous system (PNS) neuroectodermal tumors (neuroblastoma. ganglioneuroblastoma. ganglioneuroma). pediatric primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS). and CNS gliomas was examined by an immunohistochemical technique. Sixty-nine tumors in total were probed in this manner. Nerve growth factor receptor immunoreactivity was confined to nerve fibers and clusters of primitive-appearing cells in the fetal adrenal. and to nerve fibers and ganglion cells of the adult adrenal medulla; adrenal chromaffin cells were negative. In PNS neuroectodermal tumors. there was NGFR expression in tumor cells of 6 of 11 neuroblastomas and 6 of 6 ganglioneuroblastomas or ganglioneuromas. Thirteen of thirty-five CNS PNETs showed NGFR positivity. In most CNS PNETs. NGFR was restricted to scattered single or small groups of cells. but two tumors with astroglial differentiation showed much more extensive immunoreactivity. Most astrocytomas (11 of 14) and all ependymomas (3 of 3) were intensely NGFR positive.
Immunoreactive transforming growth factor alpha is commonly present in colorectal neoplasia, Surgical specimens from 19 patients with invasive colorectal cancers and 12 specimens of normal mucosa from the same patients were examined immunohistochemically for the production of the immunoreactive (IR-) transforming growth factor (TGF)-alpha and IR-epidermal growth factor (EGF) with an anti-TGF-alpha monoclonal antibody (MAb) OAL-MTG01 and anti-EGF MAb KEM-10. Immunoreactive TGF-alpha was detected in 16 (84.2%) of 19 colorectal cancers. In contrast. there was no IR-TGF-alpha in the gland cells of normal mucosa. Immunoreactive EGF was detected in 7 (36.8%) of 19 colorectal cancers and 1 (8.3%) of 12 cases of normal mucosa. The production of both IR-TGF-alpha and IR-EGF in colorectal cancer did not differ by histologic type and Dukes' stage. Immunoreactive TGF-alpha was detected at significantly higher incidence than IR-EGF in colorectal cancer. These results indicate that IR-TGF-alpha should prove valuable as a possible tumor marker in colorectal cancers. and it may be very useful in understanding the biology of colorectal cancer.
Development of complex atherosclerotic lesions in pigs with inherited hyper-LDL cholesterolemia bearing mutant alleles for apolipoprotein B, The development of atherosclerotic lesions was studied in pigs aged 4 to 54 months with inherited hyperlow-density lipoprotein (LDL) and hypercholesterolemia (IHLC pigs). These pigs bear the Lpb5 and Lpu1 mutant alleles for apolipoproteins B and U and demonstrate spontaneously elevated cholesterol levels. due primarily to elevated LDL. By 1 year of age. IHLC pigs exhibited focal lesions in the major coronary. iliac. and femoral arteries that were composed of macrophage-derived from cells and smooth muscle cells. Peripheral arterial lesions were more fibrous than those found in the coronaries. By 2 years of age. complicated stenotic lesions containing fibrous caps. necrotic cores. cholesterol clefts. granular calcium deposits. and neovascularization deep within the lesion were common in the major coronary vessels. Peripheral vascular lesions were more smooth muscle cell-rich and fibrotic. By 3 years of age. neovascularization was observed throughout the intimal lesion. and hemorrhage and rupture were common. The extent of complicated lesion formation correlated with both the degree and duration of hypercholesterolemia. with the most stenotic lesions observed in the coronary arteries of the oldest animals having the highest cholesterol levels. Thus IHLC pigs with mutant apolipoproteins B and U develop complicated atherosclerotic plaques that closely resemble advanced atherosclerotic lesions found in humans.
Expression of immunoreactive E-cadherin adhesion molecules in human cancers, E-cadherin (E-CD). a Ca(2+)-dependent adhesion molecule. plays a major role in the maintenance of intercellular junctions in normal epithelial cells in most organs. The expression of E-CD in human carcinoma samples (esophagus. stomach. and breast) was investigated using immunohistochemical staining. which was performed on surgical specimens using a monoclonal antibody for human E-CD. E-cadherin was strongly expressed in all normal epithelium examined. However E-CD expression in primary tumors of esophagus (11 of 15: 73%). stomach (5 of 20: 25%). and breast (9 of 20: 45%) was reduced. and 68% of these (esophagus: 8 of 11. stomach: 4 of 5. breast: 5 of 9) displayed heterogeneous E-CD expression. In some tumor cells with reduced E-CD expression. E-CD molecules were located in the cell cytoplasm. These results indicate that there are human cancer cells in which E-CD-related intercellular adhesion is impaired.
Subcellular distribution and life cycle of Epstein-Barr virus in keratinocytes of oral hairy leukoplakia, The authors investigated the life cycle of Epstein-Barr virus (EBV) in keratinocytes of oral hairy leukoplakia by combining immunohistochemistry. DNA in situ hybridization. and lectin histochemistry with electron microscopy. Diffuse-staining components of the EBV early antigen complex (EA-D). EBV 150-kd capsid antigen (VCA). EBV membrane antigen (gp350/220). and double-stranded DNA were labeled with monoclonal antibodies. An EBV-DNA probe was used to locate EBV DNA. Wheat-germ agglutinin (WGA) was employed to distinguish Golgi-associated compartments. The authors found EBV proteins and EBV DNA only in keratinocytes with apparent viral assembly. In situ hybridization showed EBV DNA in free corelike material and in electron-dense cores of mature nucleocapsids. Monoclonal antibodies to nonspecific double-stranded DNA attached to the same structures and to marginated chromatin. Components of EA-D were dispersed throughout the nuclei but accumulated near condensed chromatin and in 'punched-out' regions of the chromatin. Epstein-Barr virus 150-kd capsid antigen was found only in the nuclei. where it appeared preferentially on mature nucleocapsids. As yet unexplained arrays of intranuclear particles that remained unlabeled with all EBV-specific probes reacted intensely with an antiserum against common papillomavirus antigen. Gp350/220 was detectable in various cellular membrane compartments and was highly concentrated on EBV envelopes in peripheral Golgi-associated secretory vesicles. It was less abundant on the extracellular EBV. indicating that viral membrane antigen partly dissociates from the mature virus. Combined lectin-binding histochemistry and electron microscopy demonstrated for the first time that EBV is processed in the Golgi apparatus. which eventually releases the virus by fusion with the plasma membrane. These results provide insight into the biologic events that occur during complete EBV replication in vivo.
Cardiac myofibroblasts express alpha smooth muscle actin during right ventricular pressure overload in the rabbit, A number of changes occur in contractile proteins and mechanical performance of the heart within 2 weeks of right ventricular pressure overload in 8- to 12-week-old rabbits. These changes are accompanied by increases in collagen concentration and the ratio of type I to type III collagen. The purpose of the present study was to evaluate the evolution of these connective tissue changes morphologically and to characterize the interstitial cells that might be responsible. The myocardium is infiltrated by mononuclear inflammatory cells 2 days after banding. accompanied by focal myocyte necrosis. By 7 days. the inflammatory infiltrates subside and the damaged myocytes seen at 2 days are replaced by new collagen and a population of spindle-shaped cells. with ultrastructural features of myofibroblasts. A significant proportion of these cells contain alpha smooth muscle actin by immunohistochemical analysis. At 14 days. there is a large increase in stainable collagen with complex remodeling and reduplication of the collagen fiber network of the interstitium. Alpha smooth muscle actin-containing myofibroblasts persist. but their immunoreactivity appears reduced compared with day 7. The authors hypothesize that the interstitial fibroblasts that acquire smooth-muscle-like features in this model play a critical role in the heart's response to severe and sudden mechanical stress and are at least partly responsible for the changes in connective tissue that occur as a result of pressure overload in this model.
Intratumoral T lymphocytes from small cleaved follicular center cell lymphomas show unrestricted T-cell receptor alpha-chain variable region gene usage, The relationship between the reactive T cells and neoplastic B cells of follicular center cell lymphomas is unclear. It is not known whether the T cells are recruited nonspecifically by the neoplastic B cells or are responding through the T-cell antigen receptor (TCR). to tumor-related antigen(s). This question was addressed by polymerase chain reaction analysis of TCR alpha chain variable (V) region gene expression in intratumoral T lymphocytes from three cases of small cleaved follicular center cell lymphoma. In all three cases studied. the tumor-associated T cells showed unrestricted expression of all 18 alpha-chain V region genes. These findings imply that the T cells admixed with the neoplastic B cells of small cleaved follicular center cell lymphomas are not recruited based on TCR recognition of a single or limited number of tumor-related antigens.
Macrophage-tropic variants of SIV are associated with specific AIDS-related lesions but are not essential for the development of AIDS, The importance of macrophage infection for the development of acquired immune deficiency syndrome (AIDS) was investigated. Molecularly cloned simian immunodeficiency virus (SIV)mac239 replicates very poorly in cultured macrophages yet it causes AIDS in rhesus monkeys. Three of five rhesus monkeys that died with AIDS following SIVmac239 infection showed no disease manifestations directly associated with macrophage infection. such as encephalitis and granulomatous interstitial pneumonia. Simian immunodeficiency virus recovered from the peripheral blood of these three animals at or near the time of death replicated very poorly if at all in cultured macrophages. and tissues taken at autopsy showed little or no infection of macrophages by immunohistochemical staining. However two of the five rhesus monkeys that died with AIDS following SIVmac239 infection displayed a characteristic SIV-related meningoencephalitis and/or granulomatous pneumonia. lesions associated with macrophage infection. Simian immunodeficiency virus recovered from the peripheral blood of these two animals near the time of death replicated extremely well in cultured macrophages. indicating the emergency of macrophage-tropic variants in vivo. Furthermore tissues taken at autopsy from these two showed many infected macrophages by immunohistochemical staining. These results indicate that AIDS and death can occur without obvious involvement of macrophage infection. However the presence of macrophage-tropic viral strains appears to influence the disease course and disease manifestations.
Unexpected immunoreactivities of intermediate filament antibodies in human brain and brain tumors, Immunoreactivities of 35 different monoclonal antibodies (MAbs) that detect intermediate filaments were studied systematically on serial cryostat sections of 14 well-defined human gliomas (five astrocytomas. three oligodendrogliomas. six glioblastomas) and on normal brain. Glial fibrillary acidic protein (GFAP). vimentin. desmin. neurofilaments. and broad-specificity keratin MAbs. as well as MAbs that recognize several or only single keratin polypeptides. were used. Unexpected reactivities were surprisingly frequent. As these may lead to diagnostic confusion and misinterpretation on this material. the authors investigated these phenomena more thoroughly. Four major sources of artifactual staining were found: 1) positive staining attributable to the rabbit gamma G immunoglobulins used in the alkaline phosphatase anti-alkaline phosphatase technique; 2) certain desmin and keratin MAbs cross-reacted with astrocytic glia and with other brain-specific epitopes; 3) technical difficulties; 4) some MAbs directed against neurofilaments and keratins showed unexpected reactivities only on individual anaplastic gliomas. The implications of these findings for intermediate filament typing of neuropathologic material are discussed.
Activated monocytes and granulocytes, capillary nonperfusion, and neovascularization in diabetic retinopathy, Capillary occlusions are characteristic features of the early diabetic retinopathy and are presumed to initiate neovascularization. Activated leukocytes can cause microvascular occlusions and cell damage by release of cytotoxic products. To explore the role of leukocytes in capillary occlusion. nonperfusion. and neovascularization of diabetic retinopathy. a rat model was used. in which a diabetic state was induced by alloxan. Retina flat preparations were differentially stained for monocytes and granulocytes. Capillary occlusion. nonperfusion. and neovascularization were assessed microscopically in the center. midperiphery. and periphery of the retina. In contrast to control retinas. 2- to 9-month diabetic rats showed many capillary occlusions by leukocytes. especially monocytes. endothelial cell damage. extravascular macrophage accumulation. and tissue damage. The percentage of activated monocytes and granulocytes in the circulating blood of diabetic rats was greatly increased. and areas of capillary 'loss' and neovascularization in the retina coincided with sites of extravascular leukocytes. The authors' results suggest a potential role of monocytes and macrophages in the pathogenesis of diabetic retinopathy.
Correlates of psychiatric distress among wives of hemophilic men with and without HIV infection, OBJECTIVE: The authors' objectives were 1) to examine symptoms of depression. anxiety. and anger-hostility among the wives of men with hemophilia. a major risk group for AIDS. and 2) to identify psychosocial characteristics of the women and/or their husbands that were associated with elevated distress in the women. METHOD: Thirty-six women married to men with hemophilia were studied; the husbands of 17 of these women were HIV-seropositive. The men were drawn from the population of adults with hemophilia residing in a 24-county region of western Pennsylvania. Measures of wives' psychiatric symptoms were obtained. as were measures in three psychosocial domains: predispositional sociodemographic characteristics. psychosocial stressors. and husbands' strategies for coping. RESULTS: The psychiatric symptoms of the women did not differ as a function of their husbands' serostatus or across subgroups defined according to stages of HIV infection or clinical severity of hemophilia. Instead. other factors--perceptions of personal risk of AIDS. husbands' use of particular coping styles with respect to HIV infection. and the experience of other life events--were the principal correlates of psychiatric distress. CONCLUSIONS: HIV infection acted primarily as an indirect source of stress for these women. mediated by other psychosocial characteristics of both the women and their HIV-seropositive husbands. Mental health interventions for caregivers of HIV-seropositive individuals should target the identified psychosocial correlates of psychiatric distress.
Disturbances of hypothalamic-pituitary-adrenal axis functioning during ethanol withdrawal in six men, OBJECTIVE: Excessive exposure to glucocorticoids can have neurotoxic effects. The behavioral. cognitive. and neurochemical changes observed following the cessation of heavy drinking. therefore. may be associated with disturbances of the hypothalamic-pituitary-adrenal (HPA) axis. To investigate HPA axis disturbances during the ethanol withdrawal syndrome. the authors examined diurnal changes in plasma cortisol in six alcohol-dependent men following the abrupt discontinuation of alcohol intake. METHOD: Plasma cortisol concentrations were quantified every 30 minutes for 24 hours in the early stage (1 day after cessation) and the middle to late stage (3 days after cessation) of the ethanol withdrawal syndrome as well as after the resolution of acute symptoms (8 days or more after cessation). RESULTS: Plasma cortisol concentrations were almost twice as high during acute withdrawal as they were following recovery. The duration of the cortisol diurnal cycle on the first day of withdrawal was negatively correlated with the severity of withdrawal. CONCLUSIONS: There is a marked activation of the HPA axis associated with the ethanol withdrawal syndrome. The authors hypothesize that this activation may account for some of the signs and symptoms of acute and subacute withdrawal. They discuss the potential long-term physiological effects of the episodic increases in cortisol associated with repeated episodes of ethanol withdrawal. The alterations in cortisol rhythmicity during early withdrawal may also have clinical implications.
Cost offset from a psychiatric consultation-liaison intervention with elderly hip fracture patients, OBJECTIVE: The authors hypothesized that psychiatric liaison screening of elderly patients with hip fractures would shorten the average length of hospital stay and increase the proportion of patients who returned home after discharge. METHOD: The study was performed at Mount Sinai Medical Center in New York and Northwestern Memorial Hospital in Chicago. The subjects were 452 patients 65 years or older who were consecutively admitted for surgical repair of fractured hips. During a baseline year the patients received traditional referral for psychiatric consultation. During the experimental year all the patients at Mount Sinai and the patients on one Northwestern Unit were screened for psychiatric consultation. RESULTS: The patients who received psychiatric liaison screening had a higher consultation rate than those who received traditional consultation. The rates of DSM-III disorders in the experimental year were 56% at Mount Sinai and 60% at Northwestern. The mean length of stay was reduced from 20.7 to 18.5 days at Mount Sinai and from 15.5 to 13.8 days at Northwestern. resulting in reductions in hospital costs ($647/day) of $166.926 and $97.361. respectively. Fees generated from Medicare service delivery could have paid for the $20.000 psychiatric intervention cost at each site. There was no difference. however. between the two years in the discharge placement of patients. CONCLUSIONS: Admission psychiatric liaison screening of elderly patients with hip fractures results in early detection of psychiatric morbidity. better psychiatric care. earlier discharge. and substantial cost savings to the hospital.
Manic syndrome in AIDS, A manic syndrome in eight patients with AIDS is described. On the basis of clinical. neuropsychological. laboratory. magnetic resonance imaging. and epidemiological evidence. the authors suggest that the manic syndrome was secondary to HIV infection. The patients also developed concomitant cognitive impairment.
Decrease in resting metabolic rate during abstinence from bulimic behavior, Among eight normal-weight bulimic women studied during 1 week of binge eating and vomiting and 7 weeks of abstinence without weight loss. resting metabolic rate and T3 and T4 levels fell significantly during abstinence. These data suggest that a physiological consequence of binge eating and vomiting is an increase in metabolic rate. in part due to increased thyroid hormone activity.
Controlled trial of Giardia lamblia: control strategies in day care centers, BACKGROUND: Strategies for control of Giardia lamblia in day care differ in numbers of children treated and in costs to parents and day care operators. The effectiveness of these strategies has not been systematically evaluated. METHODS: We conducted a prospective randomized controlled trial comparing three strategies for control of Giardia in infant-toddler day care centers: Group 1. exclusion and treatment of symptomatic and asymptomatic infected children; Group 2. exclusion and treatment of symptomatic infection only; Group 3. exclusion and treatment of symptomatic infection. treatment of asymptomatic infection in the center. The study included 31 day care centers with 4180 child-months of observation. Giardia prevalence was determined before intervention and 1. 2. 4. and 6 months later; new infants and toddlers were tested on admission. RESULTS: Initial Giardia prevalences were 18% to 22% in the three groups. Giardia was identified in 10.5% of 676 new infants and toddlers entering study day care centers during the 6-month follow-up. Giardia prevalences by intervention group were 8%. 12%. and 7% at 1 month. and 7%. 8%. and 8% at 6 months. CONCLUSIONS: The stricter intervention resulted in greater cost in terms of child day care and parents' work days lost. but did not result in significantly better control of Giardia infections in this day care environment.
Measles vaccination coverage among Latino children aged 12 to 59 months in Los Angeles County: a household survey, A high rate of measles transmission has occurred in Los Angeles County since 1987. To determine measles vaccination coverage among Latino preschoolers. the group at highest risk of measles during this period. a cluster survey was conducted among Latino households with children aged 12 to 59 months. Of 279 children enrolled. 240 (86%. 95% confidence interval = 81% to 91%) reportedly had received the measles vaccine. Measles vaccination coverage among Latino preschoolers in Los Angeles County is insufficient to halt measles transmission within this subpopulation.
Low-level air pollution and upper respiratory infections in children, Effects of low-level air pollution were studied in one polluted city and two reference cities in northern Finland by comparing the frequency of upper respiratory infections over a 12-month period in 1982 as reported by parents of children ages 14 through 18 months (n = 679) and 6 years (n = 759). A similar comparison was carried out between children living in the more polluted and less polluted areas of the polluted city. The annual mean and the greatest half-hour concentrations of sulfur dioxide (23 and 807 micrograms/m3). particulates (31 and 291 micrograms/m3). nitrogen oxides (15 and 160 micrograms/m3). and hydrogen sulfide (2 and 177 micrograms/m3) in the polluted city were mainly due to industrial sources. In the reference cities. air pollution was produced mainly by traffic and heating. Adjusted odds ratios (OR) for one or more upper respiratory infections of residents in the polluted city vs those in the reference cities were 2.0 (95% confidence interval [CI] = 1.3-3.2) in the younger age group and 1.6 (95% CI = 1.1-2.1) in the older age group. Within the polluted city. OR calculated for living in more vs less polluted areas were 2.0 (95% CI = 1.0-4.0) in the younger and 1.6 (95% CI = 1.0-2.7) in the older children. The present results suggests that. for children. air pollution can be hazardous in concentrations lower than those recorded in earlier studies from Britain and central Europe. The synergistic effect of sulfur dioxide. particulates. nitrogen oxides. hydrogen sulfide. and other pollutants may be a contributing factor.
Attitudes toward abortion among parents of children with cystic fibrosis, BACKGROUND: DNA prenatal diagnosis for cystic fibrosis (CF) has been available for parents of affected children since late 1985. METHODS: Using anonymous questionnaires. we surveyed 395 parents of children with CF at 12 New England CF centers with regard to 12 maternal or family situations and 11 fetal characteristics; 271 (68%) responded. RESULTS: The majority supported legal abortion in the first trimester for all 23 situations; 58% would abort for severe mental retardation (MR). 40% would abort for a genetic disorder leading to death before age five years. 41% for a child bedridden for life. 35% for moderate MR. 20% for CF and 17% for a severe incurable disorder starting at age 40 years. Few would abort for a disorder starting at age 60 years. for genetic susceptibility to alcoholism or for sex selection. Variables most strongly related to abortion for CF were attitudes of spouse. respondent's siblings. and CF doctor toward abortion for CF as well as infrequent attendance at religious services. CONCLUSIONS: Prenatal diagnosis may not reduce substantially the number of CF births to parents of CF children because most do not accept abortion for CF.
Infant diet and salmonellosis, BACKGROUND: The Island of Guam has experienced a high incidence of infant salmonellosis for a number of years (age-specific incidence rate of approximately 3700 cases per 100.000 infants in 1984). Interviews of case parents suggested that the use of high-iron infant formula was associated with this problem. METHODS: A case-control study was conducted to test this hypothesis. Information on feeding practices and a variety of medical and socioeconomic factors was collected for 78 laboratory-confirmed Salmonella-case infants and 167 control infants. RESULTS: Case infants were less likely to have been breast-fed (odds ratio [OR] = 9.15; 95% confidence interval [CI] = 2.71-30.9) and more likely to have been fed infant formula with an iron content of 10 mg/L or greater (OR = 2.96; 95% CI = 1.24-7.08) than were control infants. CONCLUSIONS: Although the precise means by which infants are most commonly exposed to Salmonella bacteria remain obscure. breast-feeding apparently protects against the development of physician-diagnosed clinical salmonellosis. while the feeding of high-iron infant formula has the opposite effect.
Perioperative maternal and neonatal acid-base status and glucose metabolism in patients with insulin-dependent diabetes mellitus, Maternal and neonatal acid-base status and glucose metabolism were studied in 20 patients with insulin-dependent diabetes mellitus (group 1) undergoing elective cesarean section under lumbar epidural anesthesia. All patients were given glucose/insulin infusion before delivery. Fifteen healthy patients with iatrogenic hyperglycemia (group 2) and 15 healthy euglycemic patients (group 3) served as controls. Results were expressed as mean +/- 1 SE and were analyzed using analysis of variance and chi 2 analysis at P less than 0.05. No significant differences were seen at delivery either in maternal arterial and neonatal umbilical venous and arterial blood acid-base status or in neonatal Apgar scores among the three groups. Patients in groups 1 and 2 had larger blood glucose concentrations than those in group 3 (P = 0.01). Diabetic mothers and their neonates had a 25%-50% reduction in pyruvate concentration in maternal venous. and neonatal umbilical venous and arterial blood compared with that in the other two groups (P = 0.001). Postpartum neonatal hypoglycemia (less than 30 mg/dL) developed in seven of the group 1 neonates (P = 0.05). Thus. epidural anesthesia in diabetic women is associated with normal acid-base status in the mother and in the neonate. The data also show an increased incidence of neonatal hypoglycemia and altered maternal and neonatal glycolysis in patients with diabetes mellitus.
Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation, Ninety-six women undergoing laparoscopic tubal ligation were randomized to receive intravenously either 0.2 or 0.4 microgram/kg of dexmedetomidine. 60 micrograms/kg of oxycodone. or 250 micrograms/kg of diclofenac for postoperative pain in a double-blind study design. The study drugs were administered in the recovery room for moderate or severe pain and were repeated until pain subsided or disappeared. In the group receiving diclofenac. 83% of the patients required analgesic supplementation with morphine. This contrasted (P less than 0.01) with 33% of the patients receiving either oxycodone or the higher dose of dexmedetomidine. After the first dose of oxycodone was injected. the visual analogue scale for pain (0%-100%) was reduced from 58% to 33%. whereas corresponding pain relief was only achieved after the third injection of 0.4 microgram/kg of dexmedetomidine. Repeated doses of 0.2 microgram/kg of diclofenac or dexmedetomidine did not reduce the visual analogue scale value by more than 17%. More sedation was seen with the higher dose of dexmedetomidine than with either diclofenac or oxycodone (P less than 0.001). Both doses of dexmedetomidine decreased heart rate when compared with diclofenac (P less than 0.001). In the group given 0.4 microgram/kg of dexmedetomidine. 33% of the patients required atropine for bradycardia. The authors conclude that after laparoscopic tubal ligation. intravenously administered dexmedetomidine relieves pain and reduces opioid drug requirement but is attended by sedation and a high incidence of bradycardia.
Effect of prior anesthetic solution on epidural morphine analgesia, The quality and duration of analgesia and incidence of side effects following epidurally administered morphine after cesarean section are highly variable. Two suggested sources of this variability are prior use of epinephrine-containing solutions. which may enhance both analgesia and side effects of morphine. and prior use of 2-chloroprocaine. which may inhibit epidural morphine analgesia. To examine these proposed sources of this variability we performed two studies. In the first. designed to test epinephrine's effect. 30 women underwent testing for epidural catheter tip location with injection of 2-chloroprocaine. followed by either 0.5% bupivacaine alone or 0.5% bupivacaine with 5 micrograms/mL epinephrine for epidural anesthesia. Inclusion of epinephrine with bupivacaine decreased the bupivacaine dose needed to achieve a T-4 sensory block by 24% (P less than 0.05). but did not alter analgesic duration or the incidence of side effects of epidural morphine (5 mg). In the second study. designed to test the effect of 2-chloroprocaine. 30 women received 7 mL of either 2% 2-chloroprocaine or lidocaine for epidural catheter testing. followed by 0.5% bupivacaine for epidural anesthesia. Compared to lidocaine testing. 2-chloroprocaine decreased the duration of epidural morphine analgesia (median 16 h with 2-chloroprocaine vs 24 h with lidocaine; P less than 0.05) without altering the incidence of side effects. The authors conclude that addition of epinephrine to local anesthetic does not increase the incidence of side effects or the analgesic effect from epidurally administered morphine. 2-Chloroprocaine. even when administered in small doses remote to the time of morphine injection. interferes with the duration of epidural morphine analgesia.
Differential effects of intrathecal midazolam on morphine-induced antinociception in the rat: role of spinal opioid receptors, The antinociceptive effects of an intrathecally administered benzodiazepine agonist midazolam. alone and in combination with morphine. were examined in the rat by using the tail-flick test. The duration of antinociceptive effect produced by midazolam was significantly less (P less than 0.05) than that produced by morphine. Low doses of midazolam (10 micrograms) and morphine (10 micrograms) produced a synergistic effect in prolonging antinociceptive effect. However. at higher doses (20 or 30 micrograms). these drugs reduced the extent of antinociception produced by each other. Naloxone administration prevented antinociception produced by these drugs. indicating interactions between midazolam and opioid receptors. Midazolam had dual effects on the binding of opioid ligands to the spinal opioid receptors. At low dose. it potentiated the displacement of [3H]naloxone by morphine. At higher doses. midazolam inhibited the binding of opioid ligands to their spinal receptors in the following order: kappa greater than delta greater than mu. These results indicate that differential antinociceptive effects of midazolam on morphine-induced antinociception involve interaction of this benzodiazepine with spinal opioid receptors.
Comparison of continuous epidural bupivacaine infusion plus either continuous epidural infusion or patient-controlled epidural injection of fentanyl for postoperative analgesia, We compared the postoperative epidural analgesia provided by the continuous epidural infusion of bupivacaine supplemented with patient-controlled injection (PCA) of epidural fentanyl with that provided by a continuous infusion of bupivacaine supplemented with a continuous epidural infusion of fentanyl. Our patient population comprised 16 ASA physical status I or II patients undergoing laparotomy with a midline incision under general anesthesia combined with bupivacaine epidural analgesia. Post-operatively. a continuous epidural infusion of bupivacaine (0.1 mg.kg-1.h-1) was combined with epidural fentanyl given by either (a) PCA (15-micrograms bolus with a lockout interval of 12 min. n = 8) or (b) continuous infusion (1 microgram.kg-1.h-1. n = 8). In the case of inadequate pain relief in the latter group. the fentanyl infusion rate was increased by 10 micrograms/h. Analgesia evaluated by a visual analogue pain score and by a verbal pain score was similarly effective in both groups. The sedation score was also similar in both groups. The total dose of epidural fentanyl administered during the first 24 h was significantly lower in the PCA group than in the continuous infusion group (405 +/- 110 micrograms vs 1600 +/- 245 micrograms. P less than 0.001). The dose of fentanyl given during each 4-h interval ranged between 40 and 160 micrograms in the PCA group and 251 and 292 micrograms in the continuous infusion group. Clinically detectable respiratory depression was not observed in either group. In conclusion. epidural administration of 0.1 mg.kg-1.h-1 bupivacaine combined with fentanyl provides effective postoperative analgesia with a total dose of fentanyl required that is lower when fentanyl is administered by epidural PCA rather than by continuous epidural infusion.
Contributions of peritoneal lavage enzyme determinations to the management of isolated hollow visceral abdominal injuries, STUDY OBJECTIVE: To determine the role of lavage amylase (LAM) and lavage alkaline phosphatase (LAP) in the identification of intraperitoneal hollow visceral injuries. DESIGN: Retrospective. SETTING: Level I trauma center. city/county institution. TYPE OF PARTICIPANTS: Patients with hollow visceral organ injury following major blunt or penetrating trauma whose diagnostic peritoneal lavage was negative by lavage red blood cell and lavage white blood cell were negative. MEASUREMENTS AND MAIN RESULTS: Fifty-one patients with injury isolated to one or more hollow visceral structures underwent diagnostic peritoneal lavage; 28 were positive based on aspirate. lavage red blood cell count (greater than 100.000/mm3). or lavage white blood cell count (greater than 500/mm3). Of the remaining 23 patients. each of 11 with isolated small bowel injury had LAM greater than or equal to 20 IU/L and six of these had LAP levels greater than or equal to 3 IU/L. All six patients with colon injury and two of the patients with gallbladder injury had LAM less than 20 IU/L and LAP less than 3 IU/L. CONCLUSIONS: In patients with hollow visceral injury and otherwise normal diagnostic peritoneal lavage. elevation in LAM is highly specific for isolated small bowel injury. Lavage enzyme determinations appear unhelpful in the detection of colonic injury. We recommend routine enzyme determinations of lavage effluent as a marker for isolated small bowel injury.
Evaluation of liver function tests in screening for intra-abdominal injuries, STUDY OBJECTIVES: To determine the utility of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) in predicting intra-abdominal injury in blunt trauma patients. DESIGN: Descriptive review of 309 blunt trauma admissions during study period. SETTING: A 1.000-bed Level I trauma center in a major metropolitan area. TYPE OF PARTICIPANTS: Consecutive adult blunt trauma admissions to the trauma service. INTERVENTIONS: Serum levels of study enzymes were measured at initial evaluation and subsequent hospitalization. Results of all intra-abdominal evaluations were recorded. MAIN RESULTS: Significantly greater numbers of patients with SGOT and/or SGPT elevated to more than 130 IU/L had associated intra-abdominal injuries as compared with patients with enzyme elevations of less than 130 IU/L (52% versus 8%). All 18 patients with liver injuries had one or both enzymes elevated to more than 130 IU/L. Higher enzyme levels were more frequently associated with liver injury. CONCLUSIONS: Elevation of serum levels of the study enzymes is a marker for intra-abdominal injury. Levels in excess of 130 IU/L are relative indicators of abdominal computed tomography scan. Levels of less than 130 IU/L are unlikely to be associated with liver injury.
Injuries from tire and wheel explosions during servicing, STUDY OBJECTIVE: To evaluate injuries from tire and wheel explosions that occur during servicing. DESIGN: Retrospective analysis of all injury reports from the National Highway Traffic Safety Administration. the Occupational Safety and Health Administration. and the Insurance Institute for Highway Safety. RESULTS: For the period of 1978 through 1987. there were 694 reported injuries from explosions during tire servicing; 143 of them were fatal. resulting mainly from truck tires. Because the three data sources used different methods for case finding and covered different time periods. the actual number of such injuries was probably greater. Head injuries accounted for 78% of the deaths and 24% of nonfatal injuries. The proportion of injuries occurring during tire inflation declined from 51% in 1978 to 33% in 1987 (P less than .05). Fatal injuries involving single-piece rim wheels increased during the 1980s as multipiece rim wheels were phased out by the trucking industry. CONCLUSIONS: Exploding truck tires and wheel rims cause serious injuries. The use of safety cages during inflation as required by a 1980 Occupational Safety and Health Administration standard appears to have reduced injuries during truck tire inflation. The use of helmets during servicing may further reduce serious injuries.
A prospective study of the impact of helmet usage on motorcycle trauma, STUDY OBJECTIVE: To determine the effect of the use of a motorcycle helmet on reducing the mortality. morbidity. and health care costs resulting from motorcycle crashes. DESIGN: A prospective. multicenter study of all eligible motorcycle crash victims. SETTING: The emergency departments of eight medical centers across the state of Illinois. including representatives from urban. rural. teaching. and community facilities. TYPE OF PARTICIPANTS: All motorcycle crash victims presenting less than 24 hours after injury for whom helmet information was known. Data were collected from April 1 through October 31. 1988. MEASUREMENTS AND MAIN RESULTS: Fifty-eight of 398 patients (14.6%) were helmeted. and 340 (85.4%) were not. The nonhelmeted patients had higher Injury Severity Scores (11.9 vs 7.02). sustained head/neck injuries more frequently (41.7 vs 24.1%). and had lower Glasgow Coma Scores (13.73 vs 14.51). Twenty-five of the 26 fatalities were nonhelmeted patients. By logistic regression. the lack of helmet use was found to be a major risk factor for increased severity of injury. A 23% increase in health care costs was demonstrated for nonhelmeted patients (average charges $7.208 vs $5.852). CONCLUSION: Helmet use may reduce the overall severity of injury and the incidence of head injuries resulting from motorcycle crashes. A trend toward higher health care costs was demonstrated in the nonhelmeted patients.
Outcome of patients with blunt trauma transferred after diagnostic or treatment procedures or four-hour delay, STUDY OBJECTIVE: This study was conducted to assess the outcome of patients suffering multiple injuries from blunt trauma who were transferred to a Level I trauma center for definitive care after special diagnostic or treatment procedures (DTPs) or after a simple delay of four hours at a primary receiving hospital. DESIGN: Retrospective review of aeromedical registry data and clinical chart review. MEASUREMENTS: Aeromedical trauma transfers made during a four-year period were studied. The TRISS method was used to determine predicted survivals for DTP patients. patients transferred after a four-hour delay. and patients transferred promptly. RESULTS: The observed survival for 469 aeromedically transferred patients with blunt trauma was the same as that predicted by TRISS analysis (394 vs 392.5). Survival for 86 patients with DTP was also the same as predicted (62 vs 61.6). Outcomes for nonDTP patients and for 92 patients experiencing a delay in transport of four hours or more were also the same as predicted. CONCLUSION: Early versus delayed decision to transfer patients with blunt trauma did not appear to influence overall outcome. These data suggest that minor delays in recognizing the need to transfer patients with blunt injuries to a trauma center for definitive care may be offset by rapid. skilled transfer and highly specialized trauma care and support the hypothesis that regional trauma center care after initial evaluation and resuscitation elsewhere can be effective even when the timing of transfer is not ideal.
An evaluation of pulse oximetry in prehospital care, STUDY OBJECTIVES: We performed this study to evaluate the accuracy of pulse oximetry oxygen saturation (SpO2) against direct measurements of arterial oxygen saturation (SaO2) in the field. DESIGN: Prospective. cross-sectional. paired measurements of SpO2 against SaO2. SETTING: This evaluation was done in the prehospital setting. INTERVENTIONS: A pulse oximeter with digital probe was used to measure SpO2 in 30 patients. Arterial blood gases were drawn in the field while the pulse oximeter was in use. and oxygen saturation (HbO2) was measured by CO-oximetry. MAIN RESULTS: There was no significant difference between SpO2 (94.6 +/- 5.4%) and HbO2 (94.9 +/- 5.1%) (P = .495. beta less than .2). There was a strong correlation between SpO2 and HbO2 (r = .898). The bias between SpO2 and HbO2 was -0.3. with a precision of 2.4. When SpO2 was 88% or more. HbO2 was 90% or more in every case. Mean carboxyhemoglobin was 1.3 +/- 0.9%. and mean methemoglobin was 0.9 +/- 0.3%. There was no significant difference between the pulse oximeter heart rate and the ECG heart rate (P = .223. beta less than .2). CONCLUSION: We conclude that pulse oximetry is sufficiently accurate to be useful in the field when SpO2 is more than 88%. It is potentially useful in patients with clinical signs of acute hypoxemia and in patients receiving interventions that may produce acute hypoxemia. Further work is needed to evaluate the accuracy of pulse oximetry in the settings of elevated carboxyhemoglobin. methemoglobin. and very low saturations.
Efficacy and safety of prehospital rewarming techniques to treat accidental hypothermia, STUDY OBJECTIVE: Evaluation of inhalation rewarming and peripheral rewarming for reducing the body core temperature afterdrop and accelerating rewarming rates. DESIGN: Prospective. randomized human experimentation. SETTING: Physiology laboratory with cooling during ice water immersion and rewarming in rescue sleeping bags in a windy. cold (2 C) air environment. Type of participants: Eight experimental subjects who were cooled to clinical hypothermia (35.0 C). rectal or esophageal temperature (Tr or Te). MEASUREMENTS AND MAIN RESULTS: Afterdrop was characterized as minimum Tr and Te plus recovery time to the Tr and Te levels at the onset of rewarming. Rewarming rates 30 and 60 minutes after maximum afterdrop for Tr and Te were measured. By analysis of variance. inhalation rewarming and peripheral rewarming evaluated separately or in combination did not significantly influence afterdrop duration. afterdrop recovery. or rewarming rates. CONCLUSION: With no physiological benefit and hazards identified (inhalation rewarming burning the face. peripheral rewarming eliminating carbon monoxide equal to 300 to 600 ppm). inhalation rewarming and peripheral rewarming are not recommended for the prehospital treatment of mild hypothermia.
Continuous intravenous infusion fentanyl for sedation and analgesia of the multiple trauma patient, Fentanyl is an attractive agent for analgesia in the emergency department. Its use in this setting has been limited to IV bolus administration. We report successful sedation. muscle relaxation. and analgesia of a multiple trauma patient with fentanyl IV bolus and continuous infusion in the ED.
Comparison of an aggressive (U.S.) and a less aggressive (Canadian) policy for cholesterol screening and treatment, OBJECTIVE: To determine the point at which adverse quality-of-life effects engendered by an aggressive cholesterol-lowering strategy dictate the use of a less aggressive approach. DESIGN: Decision analysis was used to compare the effects of the National Cholesterol Education Program (NCEP) guidelines. an aggressive program. with those of the Canadian Task Force on the Periodic Health Examination (CTF) guidelines. a more conservative program. Quality-adjusted life expectancy was calculated for a theoretical cohort of middle-aged men treated according to each program using Markov cohort analysis. MEASUREMENTS: Guidelines were applied to the population of the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). under the assumption that cholesterol levels had the distribution of the age- and sex-matched general population. Outcomes were calculated using a three-state (health. coronary heart disease. and death) Markov model. State transition probabilities were calculated using bivariate (age and cholesterol) proportional hazards and logistic regression functions. MAIN RESULTS: The result was a "toss-up"; the number of expected quality-adjusted life years was similar for both programs at all time intervals. although the conservative program was consistently slightly favored. The result was very sensitive to the disutility of dietary therapy (threshold value. 0.0014 compared with the baseline estimate of 0.02) but was also affected by the time frame of the analysis and the rate at which adverse effects of treatment decline. CONCLUSIONS: Even small disutilities associated with treatment may outweight the benefits of aggressive cholesterol-lowering strategies. Research should be directed toward measuring these disutilities and finding ways to reduce their size. Incorporation of the disutility of treatment into policy formulation may result in less interventionist and less costly policies.
Biologic response modifiers in primary immunodeficiency disorders, OBJECTIVE: To propose a new classification for the primary immunodeficiency disorders and to review potential therapeutic applications of biologic response modifiers in these disorders. DATA SOURCE: Relevant articles were identified through a search of MEDLINE using the following indexing terms: primary immunodeficiencies (and subclassifications). and human immunomodulators (and subclassifications). STUDY SELECTION: Articles were critically reviewed and included if relevant. DATA SYNTHESIS: The primary immunodeficiency disorders are classified according to functional abnormalities. specifically. abnormalities in early cellular maturation. differentiation. regulatory cell function. enzymatic function. and cytokine responses. Such a classification clarifies the potential role of biologic response modifiers in primary immunodeficiency disorders. Intravenous gammaglobulin and histamine-2 (H2)-receptor blockers modify regulatory cell function; retinoids modify abnormal cellular differentiation. gene transfer and enzyme replacement can be applied in disorders characterized by specific functional gene abnormalities; and interferons modify abnormal cytokine responses. Interleukin-2. thymic hormones. transfer factor. and levamisole appear to affect multiple functional defects. CONCLUSIONS: Biologic response modifiers are currently important ancillary tools in the treatment of immunodeficiency disorders. and their therapeutic role will become even more important in the future. Multi-center cooperative trials of new and existing agents are needed to fully define their roles and efficacy in the treatment of these disorders.
High-level resistance to cefotaxime and ceftazidime in Klebsiella pneumoniae isolates from Cleveland, Ohio, Two isolates of Klebsiella pneumoniae possessing both TEM-1 and SHV-2 beta-lactamases were isolated from patients at the Cleveland Clinic in 1988. The beta-lactamases were discriminated and identified by using substrate hydrolysis data and an isoelectric focusing procedure in which the gel was overlaid with beta-lactamase inhibitors.
MICs and MBCs of chemotherapeutic agents against Renibacterium salmoninarum, The efficacies of 21 chemotherapeutic agents for controlling bacterial kidney disease were evaluated. The bactericidal and/or bacteriostatic effects of these drugs were tested against 11 Renibacterium salmoninarum strains with different origins. The most effective compounds displaying both bacteriostatic and bactericidal activity for all the isolates were tetracycline and erythromycin. with MICs ranging from less than 0.62 to 10.95 micrograms/ml for tetracycline and from less than 0.62 to 5.47 micrograms/ml for erythromycin. Whereas tetracycline showed identical MICs and MBCs. erythromycin showed bactericidal effects at concentrations of 5.47 to 21.87 micrograms/ml. Similarly. cefazolin and tiamulin proved to be very effective bactericidal compounds against the majority of R. salmoninarum isolates. with MBCs for 90% of the strains tested of 21.87 and 10.95 micrograms/ml. respectively. Neither nitrofuranes. quinolones. nor sulfonamides showed inhibitory effects on the growth of the strains.
Lack of ciprofloxacin ototoxicity after repeated ototopical application, The possible side effects of ototopically applied ciprofloxacin on inner ear function were investigated. The hearing function of pigmented guinea pigs was evaluated by daily frequency-specific evoked response audiometry after repeated application of the drug to both ears. Ciprofloxacin appeared to have no statistically significant effect on the hearing thresholds of the experimental animals.
Role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents, We studied the role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents. beta-Lactamase-positive strains were more resistant than beta-lactamase-negative strains to amoxicillin. ampicillin. and ticarcillin (P less than 0.05). With penicillin G. piperacillin. imipenem. and six cephalosporins. the susceptibility levels were similar for both beta-lactamase-positive and -negative strains. By using spectrophotometric and microbiological assays. the beta-lactamase from three strains hydrolyzed ampicillin. amoxicillin. penicillin G. cloxacillin. and. partially. cephalothin. Ticarcillin and piperacillin were partially hydrolyzed in the microbiological assay. There was no activity against five other cephalosporins or imipenem. Isoelectric focusing of the enzyme showed a pI of 8.8. Tazobactam was the best inhibitor of the enzyme. followed by clavulanic acid. sulbactam. and cefoxitin. while EDTA and p-chloromercuribenzoate had no activity. All beta-lactamase-positive strains became susceptible to amoxicillin and ampicillin with 1 micrograms of clavulanic acid per ml. With the same inhibitor. there was a reduced but significant effect for ticarcillin but no effect for penicillin G or piperacillin. Sulbactam had no effect and tazobactam was effective only at 2 micrograms/ml on amoxicillin and ampicillin. The beta-lactamase of C. jejuni seems to be a penicillinase with a role in resistance for only amoxicillin. ampicillin. and ticarcillin.
Mercuric reductase activity and evidence of broad-spectrum mercury resistance among clinical isolates of rapidly growing mycobacteria, Resistance to mercury was evaluated in 356 rapidly growing mycobacteria belonging to eight taxonomic groups. Resistance to inorganic Hg2+ ranged from 0% among the unnamed third biovariant complex of Mycobacterium fortuitum to 83% among M. chelonae-like organisms. With cell extracts and 203Hg(NO3)2 as the substrate. mercuric reductase (HgRe) activity was demonstrable in six of eight taxonomic groups. HgRe activity was inducible and required NADPH or NADH and a thiol donor for optimai activity. Species with HgRe activity were also resistant to organomercurial compounds. including phenylmercuric acetate. Attempts at intraspecies and intragenus transfer of HgRe activity by conjugation or transformation were unsuccessful. Mercury resistance is common in rapidly growing mycobacteria and appears to function via the same inducible enzyme systems already defined in other bacterial species. This system offers potential as a strain marker for epidemiologic investigations and for studying genetic systems in rapidly growing mycobacteria.
Interface-area-to-volume ratio of interstitial fluid in humans determined by pharmacokinetic analysis of netilmicin in small and large skin blisters, Human pharmacokinetics of netilmicin during multiple dosing were studied in serum and in the fluid of skin blisters with two different ratios of interface area to fluid volume. The kinetics in the blisters followed the serum concentration-time curve with a delay but with a similar elimination half-life of 2.4 h. The kinetics in the 40-microliters blisters followed closely the theoretically calculated concentrations of the peripheral compartment of a two-compartment model. In contrast. the concentrations in the 120-microliter blisters increased less rapidly. lower peaks were achieved. and concentrations decreased with a significantly longer delay. A very similar area-specific flow or clearance rate of 1.6 microliters.h-1.mm-2 was calculated for the interface area between the serum compartment and either the small or large blisters. The observed rapid mass transfer between serum and blister fluid suggests similar oscillations of concentrations in serum and in small interstitial fluid compartments.
Comparative in vitro antibacterial activity of sparfloxacin (AT-4140; RP 64206), a new quinolone, The in vitro activity of sparfloxacin (AT-4140; RP 64206). a new fluoroquinolone. was compared with those of 10 other agents against 1.222 clinical isolates. Sparfloxacin and ciprofloxacin were the most active quinolones against members of the family Enterobacteriaceae and nonfermenting gram-negative bacilli; sparfloxacin had superior activity against gram-positive cocci in comparison with the activities of ciprofloxacin and the other quinolones tested (norfloxacin. lomefloxacin. and pefloxacin). Among the inhibited strains. several were resistant to the tested beta-lactam antibiotics or to aminoglycosides. The activity of sparfloxacin was not influenced by the medium that was used; lowering of the pH to 5 had a marked effect on the MICs for two strains each of Enterobacter cloacae and Pseudomonas aeruginosa and one strain each of Escherichia coli and Staphylococcus aureus; the MBC of sparfloxacin was within 1 to 2 dilution steps of the MIC for the strains that were tested.
Steady-state pharmacokinetics of intramuscular imipenem-cilastatin in elderly patients with various degrees of renal function, We studied the concentrations in plasma and pharmacokinetics of imipenem and cilastatin in elderly patients (greater than 65 years old) who had various degrees of renal function and who were hospitalized with soft tissue infections. Three groups of patients received imipenem-cilastatin (500/500 mg) intramuscularly every 12 h: group I consisted of eight patients with a creatinine clearance (CLCR) of greater than 50 ml/min (range. 51 to 84 ml/min; mean. 65.8 ml/min); group II consisted of three patients with a CLCR of 20 to 50 ml/min; and group III consisted of two patients with a CLCR of less than 20 ml/min. Imipenem and cilastatin concentrations were measured at steady state on day 5. Mean peak and trough plasma imipenem concentrations were 5.28 +/- 1.78 and 1.43 +/- 0.76 micrograms/ml in group I. 6.25 +/- 0.78 and 2.50 +/- 0.00 micrograms/ml in group II. and 14.3 +/- 0.71 and 6.85 +/- 1.06 micrograms/ml in group III. respectively. Mean peak and trough plasma cilastatin concentrations were 11.8 +/- 2.85 and 0.31 +/- 0.43 microgram/ml in group I. 15.5 +/- 2.48 and 2.03 +/- 2.05 micrograms/ml in group II. and 24.5 +/- 6.72 and 10.7 +/- 5.94 micrograms/ml in group III. respectively. Mean imipenem AUCss (area under the concentration-time curve over a dosage interval at steady state) values were 38.7 +/- 7.9 micrograms.h/ml for group I. 52.3 +/- 7.3 micrograms.h/ml for group II. and 143.7 +/- 11.9 micrograms.h/ml for group III. Mean cilastatin AUCss values were 45.6 +/- 12.5 micrograms.h/ml for group I. 93.8 +/- 51.2 micrograms.h/ml for group II. and 217.5 +/- 57.8 micrograms.h/ml for group III.
Biological comparison of wild-type and zidovudine-resistant isolates of human immunodeficiency virus type 1 from the same subjects: susceptibility and resistance to other drugs, We used a viral endpoint dilution assay to show changes in the proportion of zidovudine (azidothymidine; AZT)-resistant viruses within a heterogeneous mixture of human immunodeficiency virus type 1 (HIV-1) quasispecies isolated from patients on long-term AZT therapy. Several HIV-1 isolates. which could replicate in 10 microM AZT. were susceptible to both 2'.3'-dideoxycytidine and a novel cytosine analog BCH-189. in which a sulfur atom replaces the 3' carbon of the pentose ring. In certain instances. cross-resistance was seen with 3'-didehydro-2'.3'-dideoxythymidine. Although most strains of AZT-resistant HIV-1 displayed reduced susceptibility to 3'-azido-2'.3'-dideoxyuridine. two strains were identified for which this was not the case.
Effect of low-level and intermittent minocycline therapy on the growth of Mycobacterium leprae in mice, We evaluated the minimal concentrations of minocycline in the diet and in serum required to inhibit the growth of seven Mycobacterium leprae isolates in mice. Minocycline concentrations of 0.01 and 0.04% in the diet. which resulted in levels in serum of less than or equal to 0.17 and 0.51 microgram/ml. respectively. were consistently and completely inhibitory. Even 0.004% dietary minocycline (levels in serum. less than or equal to 0.08 microgram/ml) partially inhibited five of these strains. while 0.001% minocycline was consistently inactive. For five of these isolates. minocycline at a concentration of 0.04% in the diet given 3 days (Monday. Wednesday. Friday) and 1 day weekly completely inhibited the growth of M. leprae. and minocycline given even 1 day monthly was partially inhibitory for three of these five M. leprae isolates.
Surgical options in 424 patients with primary breast cancer without systemic metastases, Mastectomy was dictated by medical considerations in about 40% of 424 consecutive patients who had invasive breast cancer with no evidence of systemic metastases. Half of the women considered suitable for local excision of the breast cancer followed by radiotherapy (conservation) elected to have mastectomy. and intraoperative findings dictated mastectomy in about 20% of those electing conservation. Consequently. conservation was accomplished in about one quarter of those treated for breast cancer. Younger rather than older women more frequently expressed the desire for breast conservation.
The role of tagged red blood cell imaging in the localization of gastrointestinal bleeding, The records of 162 patients who underwent technetium-99m-tagged red blood cell scans for the localization of gastrointestinal hemorrhage were studied. Ninety-eight scans were read as positive. with bleeding sites determined by a radiologist. Forty-six patients had a definitive diagnosis made by other means. Tagged scans accurately localized the site of bleeding in only 52% of cases. Analysis of the value of these tagged scans in predicting a subsequent positive angiogram indicated that there were 14 positive and 12 negative angiograms of 26 positive scans. Of the nine patients with negative scans who underwent arteriography. the arteriogram was positive in five. These data suggest that tagged red blood cell scanning is a poor diagnostic technique for the localization of gastrointestinal bleeding. and its use as a screening tool before angiography is questionable.
Prognosis of symptomatic duodenal adenomas in familial adenomatous polyposis, The frequent association between familial adenomatous polyposis and duodenal tumors is increasingly recognized. yet many patients do not benefit from adequate diagnosis and follow-up of upper gastrointestinal polyps. A retrospective review of 14 patients with duodenal tumors associated with familial adenomatous polyposis was undertaken to assess the impact of early diagnosis by screening asymptomatic patients. Six of eight patients presenting with symptoms suggesting duodenal disease had invasive cancer. Four of these six patients died after surviving a mean of 13 months after diagnosis. In contrast. none of the six patients diagnosed after screening with upper gastrointestinal endoscopy has had invasive carcinoma. Early diagnosis and long-term surveillance of asymptomatic patients with familial adenomatous polyposis affords the opportunity to diagnose and treat duodenal tumors at an early stage. thereby. avoiding the dismal prognosis once invasive cancer has developed.
A growing spectrum of surgical disease in patients with human immunodeficiency virus/acquired immunodeficiency syndrome. Experience with 120 major cases, One hundred twenty major general surgical procedures were performed on 88 adult patients harboring the human immunodeficiency virus. Fifty-eight (48%) of the procedures were performed on patients who fulfilled the criteria for acquired immunodeficiency syndrome. The patients were predominantly male (94%). Single risk factors included homosexuality (73% of cases). intravenous drug abuse (8%). and previous blood transfusions (8%). Four patients (5%) had multiple risk factors; risk factors were denied by seven patients (8%). The mean age at surgery was 41.6 years (range. 22 to 67 years). Surgical conditions that rarely affect the population without the human immunodeficiency virus presented diagnostic challenges. Altered physiologic responses to even routine conditions were observed. Thirty-day morbidity rates for emergency (group A) and elective (group B) procedures were 19% and 9%. respectively. This included seven surgical deaths (13%) in group A and one in group B (2%). Patients undergoing 92 of 112 procedures (82%) not associated with surgical mortality were followed up. Patients who were dead at follow-up had mean procedure-survivals of 19 weeks (group A) and 21 weeks (group B) for 33 procedures. Those who remained alive had a mean procedure-survival of 86 weeks for 59 procedures. No single prognosticator could be correlated with outcome. although the combination of hypoalbuminemia with a history of opportunistic infection(s) was associated with short survival. Emergency and elective procedures can be performed in the patient with human immunodeficiency virus/acquired immunodeficiency syndrome with acceptable morbidity and mortality. Procedures are indicated to extend patient life or to improve quality of life.
Pharmacokinetics of cefazolin applied topically to the surgical wound, Topical application of antibiotics is used in the prophylaxis of postoperative surgical infections. However. whether topically applied antibiotics remain primarily in the surgical wound fluid or are systemically absorbed is uncertain. The pharmacokinetics of topically applied cefazolin were studied in a canine model that allowed simultaneous determination of serum and wound fluid antibiotic concentrations. Topical administration of cefazolin resulted in high antibiotic concentrations in the wound fluid for prolonged periods and rapid systemic absorption. Bioavailability after topical administration was 95%. Within 1 hour. the serum concentrations after topical administration equaled the serum concentrations after intravenous administration. and the concentration time curves declined in parallel. In wound fluid. the mean time above the susceptibility break point minimum inhibitory concentration after topical administration of cefazolin was 5.76 hours compared with the estimated time above the minimum inhibitory concentration of 2.55 hours after intravenous administration.
A century of alcoholism conferences: unchanging themes, Modern conferences on alcoholism receive research papers and stimulate multidisciplinary discussion. but this is not new. similar events took place 100 years ago. The published proceedings of Chester's conference of 1895 are reviewed and compared with recent conferences. Subjects then included alcohol's effect on the foetus. particular facets of women's drinking and increased availability in grocer's shops. the young and evaluation of educational programmes. alcohol in the workplace. long term control studies on alcoholics. laboratory studies on reaction time. attitude of the popular press. effects of restrictions in outlets and hours and lessons to be learnt from such in Scotland. and political and legislative remedies including evidence from Scandinavia. A full knowledge of earlier research and experience may modify current thinking and prevent simple repetition of previous endeavour.
A three-sample test of a masked alcohol screening questionnaire, The study tested an expanded version of a masked alcohol screening instrument developed by Wallace and Haines [Use of a questionnaire in general practice to increase recognition of patients with excessive alcohol consumption. British Medical Journal 290. 1949-1953 (1985)]. The alcohol subscales include the CAGE. consumption. trauma. medical advice. past problems. and present problems with alcohol. There is preliminary evidence of the construct validity and reliability of the Health Screening Survey (HSS). As expected the HSS was sensitive in known populations of alcoholics (0.96; 0.95) correctly identifying at least 95% of the alcoholic patients recruited from two treatment centers. Specificity was adequate with identified nonalcoholics (0.80; 0.70). It was also sensitive in a community primary care sample. correctly classifying 78% of the subjects meeting DSM-III criteria for alcohol abuse and/or dependence. There were gender differences in the validity of the subscales in the community sample with alcoholic males more likely to report problems on the questionnaire than alcoholic females. Based on results. the HSS was revised to improve validity.
Alcohol consumption in young adults in the rural communities of Spain, In the spring of 1987. the patterns of alcohol consumption in 1.886 young people (14-30 years old) from the rural communities (less than 10.000 inhabitants) of Castile and Leon (Spain) were analysed. 64.1% of the young adults took alcoholic drinks at least once a week. while 24.4% were 'daily' consumers. Beer (56%) was the preferred drink. followed by gin (22.4%) and wine (21.3%). The age of starting to drink was close to 16 years old and the alcohol intake per capita was 19 g/day. Both frequency and intake were higher among males and at weekends. The main reported reason for drinking was 'because I like its taste' (39.1%). The results confirm the common consumption of alcoholic drinks among Spanish young adults. the establishment of beer as the preferred drink and the more extensive consumption of alcohol by males and at weekends.
In vivo pharmacology of DuP 753, A review of the in vivo pharmacology of DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biphen yl-4- yl)methyl]imidazole. potassium salt) is presented. In the pithed rat. DuP 753 exerted a selective and competitive inhibition of the pressor response to angiotensin II (AII). In conscious normotensive rats. DuP 753 inhibited the AII-induced aldosterone secretion and drinking response. DuP 753 lowered blood pressure in conscious normotensive rats pretreated with furosemide but not in untreated normotensive rats. Unlike saralasin. DuP 753 given intravenously did not cause pressor response. In conscious renal hypertensive rats (RHRs). a high renin model. DuP 753 decreased blood pressure with an intravenous ED30 of 0.78 mg/kg and an oral ED30 of 0.59 mg/kg. The antihypertensive efficacy of DuP 753 in RHRs was similar to that of captopril. In DOCA hypertensive rats. a low renin model. DuP 753 did not lower blood pressure. In conscious 18- to 21-week-old spontaneously hypertensive rats (SHRs). DuP 753 given orally or intravenously reduced blood pressure dose-dependently and did not alter heart rate at these doses. The acute antihypertensive efficacy of DuP 753 was greater than that of captopril in SHRs. In contrast. DuP 753 and captopril given orally at 10 mg/kg/day for 15 days in SHRs caused a similar decrease in blood pressure. Bilateral nephrectomy but not inhibition of prostaglandin synthesis abolished the antihypertensive effect of DuP 753 in SHRs. Our study. therefore. indicates that DuP 753 is an orally active. nonpeptide. selective. and competitive AII receptor antagonist lacking agonism. It appears that there is a relationship between basal renin level and the acute antihypertensive effect of DuP 753 in rats. Further. our results suggest that the renin-angiotensin system plays a significant role in the control of blood pressure in conscious SHRs.
Characterization of the renal microvascular effects of angiotensin II antagonist, DuP 753: studies in isolated perfused hydronephrotic kidneys, The renal microvascular effects of DuP 753. an orally active imidazole angiotensin II (ANG II) receptor antagonist were assessed directly in isolated perfused hydronephrotic rat kidneys. Unilateral hydronephrosis was induced to facilitate direct visualization of renal microvessels. Hydronephrotic kidneys were perfused in vitro and microvessel diameters were measured by automated computer-assisted image processing. The administration of 0.3 nmol/L ANG II decreased afferent arteriolar (AA) and efferent arteriolar (EA) diameters by 34 +/- 3% (from 17.9 +/- 0.6 to 11.9 +/- 0.6 microns. P less than .001. n = 11) and 28 +/- 3% (from 17.1 +/- 1.3 to 12.3 +/- 1.3 microns. P less than .001. n = 11). respectively. The subsequent administration of 0.1. 1.0. and 10 mumols/L DuP 753 reversed ANG II-induced vasoconstriction of the AA by 39 +/- 10%. 81 +/- 8%. and 103 +/- 9%. and of the EA by 22 +/- 7%. 51 +/- 6%. and 87 +/- 13%. respectively. These observations indicate that DuP 753 completely blocks both the renal afferent and efferent arteriolar actions of ANG II. In light of the pathogenetic role of ANG II in mediating the deranged renal hemodynamics associated with hypertension. congestive heart failure. and some forms of renal insufficiency. our findings provide a theoretical framework for future studies assessing the potential therapeutic applicability of DuP 753 in reversing ANG II-mediated renal vasoconstriction.
Effects of DuP 753 on renal function of normotensive and spontaneously hypertensive rats, This study examined the effects of a new. orally-active. nonpeptide angiotensin II (AII) receptor antagonist. 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4- yl)methyl] imidazole. DuP 753. on renal function of anesthetized. volume-expanded Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). and in a group of euvolemic Munich-Wistar (MW) rats. Plasma renin activities were similar and averaged 4.4 +/- 0.7 and 4.3 +/- 1.4 ng AI/mL.h. respectively. in the SHR and WKY rats. In WKY rats (n = 15). DuP 753 (2 or 10 mg/kg. intravenously) had no effect on urine flow. sodium excretion. renal blood flow (RBF). or glomerular filtration rate (GFR). Fractional excretion of lithium (FELi) rose from 32 +/- 5 to 40 +/- 4% of the filtered load and arterial pressure decreased slightly from 129 +/- 2 to 122 +/- 2 mm Hg. In SHR (n = 9). urine flow fell 24%. and FELi and RBF increased by 27% and 30%. respectively. after 2 mg/kg DuP 753. but sodium excretion. GFR. and arterial pressure were not significantly altered. A higher dose of DuP 753 (10 mg/kg; n = 8) reduced arterial pressure. urine flow. and sodium excretion in the SHR. RBF increased 34%. while GFR and FELi were not significantly altered. Similar effects were seen in SHR (n = 11). given an equivalent antihypertensive dose of captopril (20 mg/kg). In euvolemic MW rats in which plasma renin activity was elevated to 18.8 +/- 3.3 ng AI/mL.h. DuP 753 (2 mg/kg. n = 7) increased RBF. urine flow. and sodium excretion. while mean arterial pressure and GFR were unaltered.
Angiotensin II receptor antagonist markedly reduces mortality in salt-loaded Dahl S rats, We investigated the effect of blockade of the renin-angiotensin system (RAS) on morbidity and hypertension in salt-loaded Dahl salt-sensitive (Dahl S) rats. Six-week-old male Dahl S rats (n = 198) were fed a high sodium diet (8% NaCl) for 10 weeks. One group of rats (n = 91) was treated with 30 mg/kg/day of the nonpeptide angiotensin II receptor antagonist. DuP 753. whereas the control group (n = 107) was left untreated. Blood pressure rose steeply in both groups. reaching levels above 200 mm Hg by week 6. DuP 753-treated animals were less hypertensive than controls between weeks 3 and 5 of the study. but had similar blood pressure before and after that time. Although the angiotensin II antagonist had only a transient effect on blood pressure it markedly prolonged survival. After 10 weeks. 68.3% of rats receiving DuP 753. but only 30.1% of controls. were still alive (P less than .0001). Higher morbidity in controls than in DuP 753-treated rats was also suggested by body weights. Following 6 weeks of high salt diet. untreated rats progressively lost weight while DuP 753-treated animals maintained a steady body weight. These results show that the angiotensin II receptor antagonist DuP 753 greatly enhanced survival in salt-loaded Dahl S rats although it reduced blood pressure only transiently. Our data are consistent with a contribution of the RAS to morbidity in this model of hypertension.
Predicting left heart failure after a myocardial infarction: a preliminary study of the value of echocardiographic measures of left ventricular filling and wall motion, Heart failure occurs from both systolic and diastolic dysfunction. To determine whether simple Doppler echocardiographic measures of left ventricular filling could improve upon the ability of systolic function to predict heart failure after infarction. patients with acute myocardial infarction were studied within the first 36 hours by Doppler and two-dimensional echocardiography. Forty-eight patients who did not have heart failure before the Doppler echocardiographic study and who did not have myocardial revascularization. moderate or severe mitral regurgitation. or other complications during recovery were monitored for 6 months or to the onset of heart failure (n = 10). The univariate predictors of heart failure were age (p less than 0.05). anterior infarction (p less than 0.05). early diastolic peak filling velocity (p = 0.05). filling velocity with atrial systole (p less than 0.05). the ratio of these velocities (p less than 0.001). the percentage of filling with atrial systole (p less than 0.001). and the wall motion score index (p less than 0.001). However. the only independent predictors of heart failure by use of multivariant stepwise logistic regression analysis were the wall motion score index (p less than 0.05) and either the ratio of early and late peak filling velocities (p less than 0.001) or the percentage of filling with atrial systole (p less than 0.001). The combined use of a measure of systolic function and measures of the relative contribution of atrial systole to ventricular filling were useful predictors in identifying patients likely to develop subsequent heart failure after myocardial infarction.
Reference systems in echocardiographic quantitative wall motion analysis with registration of respiration, Registration of respiration allows analysis at the end-expiratory phase and may thus favor the use of the fixed-reference system versus the floating-reference system in echocardiographic quantitative wall motion analysis. Analysis is performed on two-dimensional echocardiograms of 44 normal subjects. 38 patients with anterior myocardial infarction. and 17 patients with posterior myocardial infarction. Two different models for wall motion analysis are applied. each using the fixed-reference system and the floating-reference system. respectively. In patients with anterior myocardial infarction. the fixed-reference system indicates severe wall motion abnormalities at the anterior. septal. and apical walls. whereas the floating-reference system indicates less severe wall motion abnormalities almost equally at every wall. In patients with posterior myocardial infarction. the fixed-reference system indicates severe wall motion abnormalities at the posterior wall. whereas the floating-reference system indicates less severe wall motion abnormalities almost equally at every wall. These findings indicate that the fixed-reference system is superior to the floating-reference system in quantification of wall motion of end-expiratory two-dimensional echocardiograms.
Intraventricular blood flow during isovolumetric relaxation and diastole in hypertrophic cardiomyopathy, Forty patients with hypertrophic cardiomyopathy were investigated by Doppler echocardiography for intraventricular blood flow abnormalities. None had a bundle branch block. The patients were recruited on the basis of the presence of at least one of four different types of abnormal left ventricular blood flow movements during systole. isovolumetric relaxation. and diastole (time after mitral valve opening). The abnormal blood flow patterns were composed of the following: (1) systolic left ventricular outflow and midventricular obstruction in 20 of 40 and in 6 of 40 patients. respectively; (2) retrograde isovolumetric relaxation flow (IVRFretro; mean velocity. 0.7 +/- 0.3 m/sec). that is. flow toward the apex of the left ventricle. in 28 of 40 patients; (3) antegrade isovolumetric relaxation flow (IVRFante; mean velocity. 1.6 +/- 1.0 m/sec). that is. flow toward the left ventricular outflow tract. in 3 of 40 patients; and (4) diastolic antegrade flow (DFante; mean velocity. 0.9 +/- 0.3 m/sec). that is. flow opposite to mitral inflow. in 10 of 40 patients. There were significantly fewer patients with asymmetric septal hypertrophy (group 1) than with apical hypertrophic cardiomyopathy (group 2) showing DFante (1/29 versus 9/11. p less than 0.01). IVRFretro and DFante revealed higher velocities in patients with marked left ventricular asymmetric hypertrophy than in those with mild hypertrophy. Thus. in hypertrophic cardiomyopathy and especially in patients with marked asymmetric hypertrophy. there are different types of abnormal intraventricular blood flow movements during isovolumetric relaxation and disatole. This phenomenon is probably caused by asynchronous relaxation of the asymmetrically distributed. hypertrophied myocardium. DFante is more often observed in the apical cardiomyopathy than other forms of hypertrophic cardiomyopathy probably attributable to apically localized left ventricular cavity obliteration.
Respective timing of maximal color Doppler jet areas and of peak velocity of jets in left-sided valvular lesions: clinical implications, Time intervals between the R wave of the electrocardiogram and maximal dimension of jet areas of color Doppler and the R wave of the electrocardiogram and peak velocity of valvular jets of continuous-wave Doppler were compared by use of paired and correlative studies for a group of 55 patients with a total of 71 left-sided lesions. Mean values of both time intervals. mean difference. and its standard error were equal to zero for stenoses. Time intervals of 71% for mitral stenosis and 52% for aortic stenosis did not differ by more than 0.01 second; correlation coefficients were 0.96 for mitral stenosis and 0.85 for aortic stenosis. For regurgitations. differences in mean values and a mean difference with a standard error were found but remained unsignificant. However. the percentage of differences in time intervals below or equal to 0.01 second decreased to 35 for aortic regurgitation and 13 for mitral regurgitation. which showed the widest 95% range of differences. Correlation coefficients were 0.84 for the aortic regurgitation and 0.33 for mitral regurgitation. Thus the close relationship of time intervals suggests that standardized timing of area measurements at peak velocity is feasible for stenoses and remains under consideration for aortic regurgitation. Timing of measurements should remain empiric for mitral regurgitation.
Anomalous papillary muscle producing dynamic left ventricular outflow tract obstruction, A patient with a dynamic left ventricular outflow murmur was shown to have an anomalous anterolateral papillary muscle by transthoracic and transesophageal two-dimensional Doppler echocardiography. High late systolic outflow velocity and systolic anterior motion were demonstrated in the lateral outflow tract near the anomalous muscle. suggesting a role for the Venturi effect. This is the first confirmation by Doppler echocardiography of an anomalous papillary muscle contributing to abnormal left ventricular hemodynamics.
Urea monitoring during dialysis: the wave of the future. A tale of two cities, The National Cooperative Dialysis Study (NCDS) suggested that the removal of small molecules controls the adequacy of the dialysis prescription. and it would seem appropriate that renal units regularly carry out formal urea kinetic modeling to ensure that the adequacy of dialysis is provided. Current methods of calculating Kt/V (urea) are complex and require the accurate measurement of dialyzer urea clearance and calculation of the volume of distribution of urea. This may be done by the direct measurement of total urea removed or by the use of computer programs that examine plasma urea and weight changes over time. Both methods have inherent problems. and this has stimulated the search for easier "bedside" formulas for the calculation of Kt/V. These newer formulas involve examination of the percentage reduction in blood urea concentration during hemodialysis. Two such formulas were examined and applied to 78 patients undergoing hemodialysis in two centers. One center routinely carried out formal urea kinetic modeling; the other did not. In the first center. it was found that the majority of patients were receiving more dialysis than necessary to achieve Kt/V (urea) = 1 when the latter was judged by those formulas. This suggested the possibility of time savings. with considerable implications for cost efficiency. In the second center. the majority of patients required more dialysis. It was concluded that intermittent formal urea kinetic modeling tends to overshoot the necessary prescription to allow for occasional "imperfect" dialyses and also that it is impossible to base dialysis prescriptions on routine pre-dialysis blood work and a "feel" for patients' needs.
The potential of a microencapsulated urease-zeolite oral sorbent for the removal of urea in uremia, Although successful in reducing urea levels. the use of oral microcapsules containing a urease-silica adduct and a zirconium phosphate ion exchanger result in a number of problems. including a negative calcium balance. In this study. it is demonstrated that the use of microcapsules containing a urease-zeolite preparation may be a potential route to urea removal. The use of zeolite ion exchangers. and zeolite W in particular. can alleviate the problems encountered with zirconium phosphate. Unlike zirconium phosphate. zeolite W is nonselective toward calcium ions and is stable at the high pH found in the intestinal tract. Zeolite W. when present in the sodium form. has a high ammonium capacity of 3.6 mEq NH4+/g zeolite under simulated intestinal conditions; its reactivity to ammonium is also higher. The application of enzyme envelopes to zeolite particles is a novel immobilization procedure that does not involve the use of colloidal silica and can reduce the amount of ingested material by as much as 25%. The current in vitro study shows that cellulose acetate butyrate microcapsules. containing a urease-zeolite preparation. remove up to 80% of urea in less than 1 hour. These microcapsules can be dried and retain activity when sealed in a jar at 4 degrees C.
Thrombolytic treatment in acute myocardial infarction: neutrophil activation, peripheral leucocyte responses, and myocardial injury, OBJECTIVE--To examine early leucocyte responses and neutrophil activation in acute myocardial infarction treated by streptokinase and to relate the findings to coronary recanalisation and indices of myocardial damage in order to provide further information about the role of neutrophils in the evolution of injury. DESIGN--Group analysis of paired blood samples. obtained before streptokinase treatment and one hour after it. and of three indirect measures of myocardial injury: left ventricular ejection fraction. QRS score. and peak creatine kinase. SETTING--The coronary care unit of a district general hospital. PATIENTS--39 patients with acute myocardial infarction who underwent paired blood sampling (before streptokinase and one hour after streptokinase) and cardiac catheterisation 5 (3-8) days later. END POINTS--Changes in peripheral white cell and neutrophil counts and plasma elastase one hour after streptokinase infusion. Comparison of these variables in patients with and without patency of the infarct related coronary artery. Correlations between these variables and indirect measures of myocardial injury. RESULTS--Neutrophil activation. as reflected by plasma elastase. increased sharply one hour after streptokinase. Total white cell and neutrophil counts also increased. Changes tended to be more pronounced in patients with patency of the infarct related artery. though the trend was not statistically significant. Neutrophil activation before streptokinase was unrelated to indirect indices of myocardial injury but only one hour after streptokinase a weak negative correlation with left ventricular ejection fraction had developed. Peripheral neutrophil responses showed a similar relation to ejection fraction and also correlated with peak creatine kinase and QRS score. CONCLUSIONS--Thrombolytic treatment in acute myocardial infarction is associated with an abrupt reactive neutrophil response which provides an early measure of injury. It is also associated with neutrophil activation. probably in response to coronary recanalisation and myocardial reperfusion. Activated neutrophils are recognised as mediators of reperfusion injury in experimental infarction and the data in the present study provide preliminary evidence of a similar pathogenic role in the clinical setting.
Aging, autonomic function, and the perception of angina, OBJECTIVE--To determine the effects of age and autonomic function on the perception of angina. DESIGN--Prospective evaluation of the relations between anginal perceptual threshold. autonomic function. and systolic blood pressure in patients with symptomatic coronary artery disease. Statistical analysis was by non-parametric techniques. SETTING--Cardiology departments of a district general hospital and a post-graduate teaching centre. SUBJECTS--82 non-diabetic men with typical exertional angina and coronary artery disease confirmed by arteriography (n = 64) or a history of Q wave infarction (n = 18). MAIN OUTCOME MEASURES--Age. anginal perceptual threshold. autonomic function. and blood pressure. Anginal perceptual threshold was defined as the time from onset of 0.1 mV ST depression to the onset of angina during treadmill stress testing. Autonomic function was measured as the ratio of peak heart rate during the Valsalva manoeuvre to the minimum rate after release. RESULTS--Anginal perceptual threshold showed a weak but significant correlation with age. with older patients tending to have a longer interval between the onset of ST depression and the onset of angina. Comparison of patients in the upper and lower quartile age ranges showed a difference of 50 seconds between median threshold measurements. Blood pressure and heart rate responses to the Valsalva manoeuvre also correlated with age. but neither variable correlated with the anginal perceptual threshold. CONCLUSIONS--In non-diabetic men with coronary artery disease the perception of angina tends to deteriorate with advancing age. The mechanism is unclear but is not attributable solely to alterations in blood pressure or autonomic function.
Angiotensin converting enzyme inhibitors and magnesium conservation in patients with congestive cardiac failure, OBJECTIVE--To investigate whether angiotensin converting enzyme inhibitors reduce diuretic induced magnesium excretion in patients in congestive cardiac failure. DESIGN--Cohort analytic study. SETTING--A London district general hospital. SUBJECTS--Thirty four patients with chronic congestive cardiac failure caused by ischaemic heart disease or cardiomyopathy selected consecutively from inpatients under the care of two consultant cardiologists. Nineteen patients (group 1) on diuretics alone were compared with 15 patients (group 2) taking diuretics plus either enalapril or captopril. All drug regimens were stable for at least three months before the study. Patients with impaired renal function (plasma creatinine greater than 120 mumol/l) were excluded. INTERVENTIONS--An intravenous loading dose of magnesium sulphate was given to minimise the variability in baseline magnesium state. MAIN OUTCOME MEASURE--Total urine magnesium excretion and creatinine clearance in 24 hour urine collections. RESULTS--Plasma magnesium was similar in the two groups. However. 24 hour urine magnesium excretion was significantly lower in group 2 than in group 1. Furthermore. creatinine clearance was also significantly lower in group 2 and correlated strongly with magnesium excretion. There was no such relation in group 1. There was no difference in fractional clearance of magnesium between groups. CONCLUSION--Angiotensin converting enzyme inhibitors have an important magnesium conserving action. possibly via their effect on glomerular filtration rate.
Intracardiac mobile thrombus and D-dimer fragment of fibrin in patients with mitral stenosis, OBJECTIVE--To investigate the relation between intracardiac thrombus and blood coagulability in patients with mitral stenosis. DESIGN--Prospective study. Cross sectional echocardiography and plasma concentrations of the D-dimer fragment of fibrin were used concurrently to detect intracardiac thrombus in patients with mitral stenosis. SETTING--Department of Medicine. National Cardiovascular Centre. Osaka. Japan. PATIENTS--63 patients with mitral stenosis. None of them had been receiving any anticoagulants or antiplatelet agents. MAIN OUTCOME MEASURES--Plasma concentrations of D-dimer in patients with a mobile intracardiac thrombus. those in patients with a non-mobile intracardiac thrombus. and those in patients without an intracardiac thrombus. RESULTS--A mobile intracardiac thrombus was found in 10 patients and a non-mobile thrombus in eight. The remaining 45 patients had no intracardiac thrombi. Plasma concentrations of D-dimer in the 10 patients with a mobile thrombus were all greater than 300 ng/ml (mean 983.3. 95% confidence interval 498.9 to 1467.7 ng/ml) and they were significantly higher than those in the patients with a non-mobile thrombus (226.2. 33.6 to 418.8 ng/ml) and the patients without an intracardiac thrombus (147.2. 110.4 to 184 ng/ml). CONCLUSIONS--A high plasma concentration of D-dimer seemed to reflect a hypercoagulable intracardiac state and may be a helpful indicator of the possible presence of mobile intracardiac thrombus in patients with mitral stenosis.
Familial Ebstein's anomaly: a report of six cases in two generations associated with mild skeletal abnormalities, In a family of 11 persons in three generations six had Ebstein's anomaly. Five of the six showed mild skeletal anomalies--that is. restricted finger extension. with or without limitation of larger joints. and externally rotated little toes. Two other members of the family had the skeletal features without Ebstein's anomaly. The findings suggest a dominantly inherited syndrome of Ebstein's anomaly and skeletal abnormalities. The four female patients were all mildly affected whereas three of the four male patients were severely affected.
Influence of racial origin on admission rates of patients with suspected myocardial infarction in Birmingham, All patients with suspected myocardial infarction admitted to hospital in four Birmingham health districts were studied to test the hypothesis that Asian patients would be overrepresented and Caribbean patients underrepresented compared with the indigenous population. One thousand four hundred and ninety six patients had a final diagnosis of myocardial infarction or severe angina pectoris. The relative risk of admission for Asian men compared with white men aged 45-64 years was 2.65 (95% confidence interval 2.20 to 3.19) and the risk for Asian men was high for both myocardial infarction and ischaemia when analysed separately. The relative risk of admission for Caribbean men compared with white men was 0.53 (95% CI 0.33 to 1.20). The relative risk for Asian women compared with white women in the same age group was 2.58 (95% CI 1.68 to 3.96). but this was due to an excess of admissions diagnosed as ischaemia rather than infarction in the Asian women. For Caribbean and white women the risk of admission was the same. although significantly fewer Caribbean women were admitted with myocardial infarction. The study was undertaken in 1986-87 and population data had to be derived from the 1981 census. The resident population changed in those five years and so the results were recalculated making allowances for these changes in the health districts involved. Based on these data the admission rate for Asian men with suspected myocardial infarction aged 45-64 was nearly twice that for white men (1.8): the relative risk of admission for Asian men compared with white men was 2.04 (95% CI 1.53 to 2.18).
Outcome of extensive coronary artery dissection during coronary angioplasty, A total of 32 (3.6%) patients of 880 undergoing coronary angioplasty during a nine year period at one hospital had extensive dissection (defined as a dissection extending beyond the limits of the dilated angioplasty balloon) in the coronary artery in which the angioplasty procedure was performed. Two (6.25%) of the 32 patients (both of whom were undergoing angioplasty because of unstable angina that was refractory to medical treatment) died as a consequence of the coronary artery dissection. Twelve (38%) needed immediate coronary artery bypass surgery and 11 (34%) had a myocardial infarction. which in four was minor in extent. During follow up. 20 of the 32 patients were successfully managed by medical treatment; only two needed further angioplasty procedures. There were no late deaths. Extensive coronary artery dissection is a serious complication of coronary angioplasty. with a high early mortality and a high incidence of infarction and requirement for bypass surgery. None the less. patients with extensive dissection who are free from the manifestations of acute ischaemia at the end of the procedure can be managed conservatively and have a good immediate and medium term outlook. Attempts should be made to stabilise extensive dissection during coronary angioplasty so that surgical intervention can be delayed or avoided altogether if possible.
North Carolina's dominant progressive foveal dystrophy: how progressive is it, We studied 34 family members at risk of having dominant progressive foveal dystrophy of Lefler. Wadsworth. and Sidbury (also called North Carolina macular dystrophy) and found 17 to be affected. Fifteen of these affected subjects were observed over at least a 10-year period for evidence of progressive macular degeneration. Only one subject showed objective evidence of progressive deterioration in only one eye. Our findings further substantiate that this dystrophy generally has a stable course. contrary to its original description.
Emmetropisation, squint, and reduced visual acuity after treatment, In a sample of children used to assess the value of optical correction of hypermetropia from the age of 6 months the refraction of the most hypermetropic meridian frequently became less than 3.5 D as the children grew. When this occurred. the incidence of squint was significantly less (p less than 0.001) and the last known acuity after treatment was significantly better (p less than 0.001) than when it did not. This process of emmetropisation appears to have been impeded by the consistent wearing of hypermetropic spectacle correction from the age of 6 months.
Comparison of retrobulbar and periocular injections of lignocaine by computerised tomography, Ten patients undergoing cataract surgery were given a local anaesthetic with lignocaine solution which was mixed with iohexol contrast medium. The location of the needle and the substance injected was determined by computerised tomography following retrobulbar or periocular anaesthesia. The retrobulbarly inserted needles were within the muscle cone. directed towards the optic foramen. The periocular needles were outside the muscle cone. tangentially along the orbital floor or pointing slightly upwards. After the retrobulbar injection the contrast medium was seen within the cone immediately after the injection and outside the cone as early as 3 minutes after the injection. With the periocular technique. however. diffusion of the anaesthetic in the opposite direction (that is. into the muscle cone) was rapid. The contrast medium was identified inside the muscle cone 2 minutes after the injection. Compression with an intraocular pressure reduction device after both of these techniques prevented exophthalmos. It is concluded that retrobulbar-like anaesthesia can also be induced by an appropriate periocular technique.
Relation between nicotine intake and Alzheimer's disease, OBJECTIVE--To study the association between Alzheimer's disease and nicotine intake through smoking. DESIGN--Population based case-control study. SETTING--City of Rotterdam and four northern provinces of The Netherlands. SUBJECTS--198 patients with early onset Alzheimer's disease. 198 controls matched for age and sex. and families of 17 patients in whom Alzheimer's disease was apparently inherited as an autosomal dominant disorder. MAIN OUTCOME MEASURES--Age of onset of dementia. relative risk of Alzheimer's disease. RESULTS--89 of 193 patients with Alzheimer's disease had a history of smoking compared with 102 of 195 controls. Among the patients and controls with a family history of dementia. smoking was significantly less common in those with dementia (40/95 with dementia v 55/96 controls; relative risk 0.35; 95% confidence interval 0.16 to 0.78). The risk of Alzheimer's disease decreased with increasing daily number of cigarettes smoked before onset of disease (relative risk 0.3 in those smoking greater than 21/day v 1 in non-smokers). In six families in which the disease was apparently inherited as an autosomal dominant disorder. the mean age of onset was 4.17 years later in smoking patients than in non-smoking patients from the same family (p = 0.03). CONCLUSIONS--These findings suggest an inverse association between smoking and Alzheimer's disease. although smoking cannot be advocated for other health reasons. We speculate that nicotine may have a role in the aetiology of both Alzheimer's disease and Parkinson's disease.
Intra-articular distension and steroids in the management of capsulitis of the shoulder, OBJECTIVE--To determine whether there is any synergistic effect in the administration of intraarticular steroids with distension in the management of early capsulitis of the shoulder. DESIGN--Prospective randomised trial of three treatments--namely distension only. steroid only. and steroid with distension. SETTING--Academic department of orthopaedic and accident surgery at Queen's Medical Centre. Nottingham. SUBJECTS--47 patients (30 women) with capsulitis affecting 50 shoulders. INTERVENTIONS--Three intra-articular injections into the shoulder given at six week intervals by the same technique. MAIN OUTCOME MEASURES--Passive range of abduction. forward flexion. and external rotation; results of shoulder dynamometry measuring work done and torque produced; pain levels at rest and with resisted movement. RESULTS--All patients reported improvement during the study. Analysis of the mean improvements in abduction and forward flexion showed these to be significantly greater in the steroid with distension and steroid only groups than in the distension only group (mean improvements in abduction (degrees/week (95% confidence interval)) 4.3 (3.4 to 5.2). 3.4 (2.4 to 4.5). and 1.0 (-0.8 to 2.8) in the three groups respectively; mean improvements in flexion (degrees/week (95% confidence interval)) 3.6 (3.2 to 4.0). 3.3 (2.3 to 4.3). and 1.5 (0.5 to 2.5) respectively). Shoulder dynamometry failed to show a significant difference among the treatment groups. No severe complications occurred as a result of the injections. but two patients reported facial flushing related to the use of steroids. CONCLUSION--Intra-articular steroid injections have a useful role in the outpatient management of early capsulitis.
Twenty five years of case finding and audit in a socially deprived community, OBJECTIVE--To evaluate audit and case finding (whole population care) in a community over 25 years. DESIGN--Contemporary screening for and audits of care of chronic disease and risk factors; retrospective review of computerised practice records; and comparisons of mortality and social indices with neighbouring communities. SETTING--One general practice in Glyncorrwg. West Glamorgan. SUBJECTS--1800 people registered with the practice in 1987 and 558 people who died from 1964 to 1987. whose records had been retained. MAIN OUTCOME MEASURES--Detection of high blood pressure. smoking. airways obstruction. obesity. diabetes. and alcohol problems in adults aged 20-79; prevalence of smoking in this population and in hypertensive and diabetic groups; age standardised mortality ratios in relation to indices of social deprivation. RESULTS--In the population aged 20-79 (1207 patients) 249 (21%) had peak expiratory flow rate less than 50% of expected value or which improved by 15% or more with an inhaled beta agonist. 207 (17%) had body mass index at or over 30 kg/m2. 118 (10%) had untreated mean arterial pressures greater than 159/104 mm Hg (three readings). 80 (7%) (65 (16%) men. 15 (4%) women) had recognised alcohol problems. and 35 (3%) had diabetes. The proportion of men aged 20-64 who said they smoked fell from 61% (290/476) in 1968-70 to 36% (162/456) in 1985 whereas that of women who smoked was unchanged (43%. 187/436 v 42%. 190/448 respectively). In 116 screened hypertensive patients group mean blood pressure fell from 186/110 mm Hg before treatment to 146/84 mm Hg at 1987 audit. as did the proportion of smokers (56% v 20%). but body mass index and total cholesterol concentration showed no significant change. In 34 diabetic patients mean blood pressure and the proportion of smokers fell (171/93 mm Hg v 155/81 mm Hg; 44% v 12%). The age standardised mortality ratio in 1981-6 was lower than in a neighbouring village without a developed case finding programme (actual to expected deaths less than 65 = 21 to 22 in Glyncorrwg. 48 to 30 in control village). CONCLUSIONS--Whole population care through organised case finding and audit is feasible but only with a labour intensive approach combining accessibility. flexibility. and continuity. as well as a planned and structured approach. which requires substantial expansion of staff numbers and assiduous recording. It may reduce risks for at least some high risk groups. Despite their shortcomings the available data are consistent with the hypothesis that whole population care helps reduce mortality. Incentives in the new contract. which encourage the uncritical development of structured process. may diminish health outputs.
Irrationality in the management of breast cancer. I. The staging system, The historic development of breast cancer staging began early in the 20th century with the simple concept of early localized disease. spread to regional nodes. and the presence of distant metastases. This last group often was divided into patients with advanced but perhaps still curable locoregional disease and incurable patients with distant metastases. As increasing numbers of prognostic factors were recognized. efforts were made to incorporate them into the staging systems to combine patients with similar prognosis into the same stages. These attempts resulted in the development of four classifications. namely. the Columbia. Manchester. International. and American tumor-node-metastasis (TNM) staging systems. Although many benefits of staging were reported. the most important was that of permitting valid comparisons between different treatments and different institutions. Many success-limiting factors were noticed during the developmental years. and even though the TNM system has been accepted. numerous speakers and authors present their staged data in a confusing and ambiguous manner. Recommendations are made that would permit clarification of presentations to general medical audiences along with recognizable statistical validity.
A combination trial of human lymphoblastoid interferon and bestrabucil (KM2210) for adult T-cell leukemia-lymphoma, Both human lymphoblastoid interferon (HLBI) and bestrabucil. the conjugate of chlorambucil and beta-estradiol. have antitumor activity against adult T-cell leukemia-lymphoma (ATLL). Because an in vitro study showed that these two agents combined had a synergistic antiproliferative effect on MOLT-4 and WI-38VA13 cell lines. the authors evaluated the clinical efficacy of this combination in a pilot study with a poor-risk group of ATLL patients. The patients were treated daily with 6 x 10(6) IU of HLBI subcutaneously and 100 mg of bestrabucil orally. In patients with lymphoma-type ATLL or hypercalcemia. prednisolone also was given daily. Of 12 patients suitable for evaluation. nine had partial responses. one had a minor response. and two had no response. All five patients with skin infiltration and both patients with hypercalcemia responded. A history of prior chemotherapy did not affect the response rate. The time to clinical response was 3 to 16 days (median. 11 days) after initiation of treatment. The response duration was 4 to 108+ weeks (median. 9 weeks). but all patients except one relapsed. even during continuing treatment. No serious side effects were observed. Although the response rate with this combination treatment was high. the response duration was short. and other treatments would have to be added to achieve control of this aggressive disease.
Drug-related pulmonary toxicity in non-Hodgkin's lymphoma. Comparative results with three different treatment regimens, Pulmonary toxicity may complicate the treatment of non-Hodgkin's lymphoma (NHL). The possible drug-related cause of pulmonary toxicity was investigated retrospectively in 207 NHL patients treated between 1981 and 1988 with three regimens containing cyclophosphamide with and without methotrexate or bleomycin: methotrexate. calcium. leucovorin. bleomycin. doxorubicin. cyclophosphamide. vincristine. and dexamethasone (m-BACOD) (n = 134); methotrexate. calcium. leucovorin. doxorubicin. cyclophosphamide. vincristine. and dexamethasone (m-ACOD) (n = 43); or cyclophosphamide. doxorubicin. vincristine. and prednisone (CHOP) (n = 30) chemotherapy. These regimens contained the same drugs and were administered in the same schedule; the regimens differed primarily in the addition of bleomycin or methotrexate. Pulmonary toxicity occurred in 24 of 134 (18%) m-BACOD-treated and in six of 43 (14%) m-ACOD-treated patients (P = 0.65). Chest radiography revealed diffuse pulmonary infiltrates in 16 (67%) and six (100%) of the m-BACOD-treated and m-ACOD-treated patients with pulmonary toxicity. respectively. None of the CHOP-treated patients had pulmonary toxicity. The clinical features of pulmonary toxicity and the amount of chemotherapy administered before it occurred did not differ in patients treated with m-BACOD or m-ACOD. although the toxicity tended to be more severe in the m-BACOD group. Open lung or transbronchial biopsies done in six (38%) of the m-BACOD-treated and three (50%) of the m-ACOD-treated patients with pulmonary infiltrates revealed nonspecific pneumonitis compatible with drug-related toxicity. In summary. these results showed that pulmonary toxicity during m-BACOD and m-ACOD therapy occurred with similar frequency and clinicopathologic features. This suggested that bleomycin was not responsible uniquely for the pulmonary toxicity in m-BACOD-treated patients. That pulmonary toxicity was not observed in patients treated with CHOP suggested that methotrexate may play an important role in the pathogenesis of the pulmonary toxicity.
High-dose carmustine and autologous bone marrow reinfusion in the treatment of refractory or relapsed small cell lung carcinoma, Fourteen patients with small cell carcinoma of the lung in relapse or with disease refractory to chemotherapy were treated with carmustine (BCNU) at doses of 600 to 1000 mg/m2 intravenously followed by autologous bone marrow transplantation. All patients previously were treated with cyclophosphamide. doxorubicin. vincristine. and etoposide. Seven of the 14 patients responded to the high-dose BCNU (50% response with 95% confidence limits ranging from 23% to 77%). Three patients had a complete response. and four had a partial response. Regrowth of tumor occurred within 60 days of treatment in the responding patients. Death occurred in six patients before the recovery of the platelet count to 50.000 cells/microliters. Although the response rate was high. the toxicity was excessive. In the dosage range of 600 to 1000 mg/m2 in heavily pretreated patients. BCNU is not recommended. but additional investigation may be warranted in patients with central nervous system metastases who previously were treated with radiation therapy.
Adjuvant intraperitoneal chromic phosphate therapy for women with apparent early ovarian carcinoma who have not undergone comprehensive surgical staging, Forty-nine women with apparent Stage I and II ovarian carcinoma received intraperitoneal phosphate 32 as the only adjuvant therapy after primary surgery. In addition to bilateral salpingo-oophorectomy. 40 (82%) had analysis of peritoneal cytology. and 35 (71%) underwent omentectomy. Random peritoneal biopsies and retroperitoneal lymph node sampling were not done in any of these patients. The overall and disease-free survival rates were 86% and 75%. respectively. with no significant differences by stage. histologic grade. histologic type. or low-risk versus high-risk subsets recognized in patients who received comprehensive surgical staging. Seven (58%) of 12 patients had lymph node metastasis as the first site of recurrence. including two of three with late recurrences. Significant morbidity related to intraperitoneal chromic phosphate (32P) occurred in one (2%) woman. These results emphasize the need for comprehensive surgical staging of women with apparent early ovarian carcinoma to aid in the selection of appropriate initial adjuvant therapy.
Statin immunolocalization in human brain tumors. Detection of noncycling cells using a novel marker of cell quiescence, Surgical specimens of 35 human brain tumors were examined with a novel monoclonal antibody. S-44. immunoreactive to statin. a nuclear protein specifically expressed in quiescent (noncycling) G0-phase cells. Benign tumors typically were statin positive with labeling indices (LI) between 22% and 96%: acoustic schwannomas (n = 3. mean = 29.9 +/- 19.4%); meningiomas (n = 4. mean = 59.0 +/- 15.1%); pituitary adenomas (n = 3. mean = 79.9 +/- 28.2%). and an epidermoid cyst (41.0%). By contrast. the statin LI of 18 of 24 (75%) malignant brain tumors was less than or equal to 2%: medulloblastomas (n = 7. mean = 0.3 +/- 0.2%); anaplastic astrocytomas (n = 3. mean = 1.6 +/- 2.7%); glioblastomas (n = 10. mean = 10.3 +/- 14.4%); metastatic carcinomas (n = 3. mean = 3.0 +/- 4.6); and a germinoma (0.2%). The vascular endothelium among diverse tumors typically was statin positive. All 21 tumors with a statin LI less than 10% were malignant. and all nine tumors with a statin LI greater than 40% were benign. The statin LI of benign tumors (n = 11. mean = 55.1 +/- 26.7%) was significantly higher than that of the malignant tumors (n = 24. mean = 5.2 +/- 10.5%. P less than 0.001). The absence of statin expression is a new way to determine the malignancy of human brain tumors. The statin LI may be useful to guide the prognosis and treatment of individual patients. The mechanisms that control statin expression are important in therapy seeking to shift the proliferating. cycling cells to the quiescent. G0 compartment.
Basic fibroblast growth factor and somatomedin C in human medulloepithelioma, Two published cases of medulloepithelioma. a rare malignant pediatric brain tumor composed of a mixture of primitive neuroepithelium and its differentiated neuronal and glial descendants. were examined by immunohistochemical staining for the presence of growth factors. From a panel of antibodies. those identifying basic fibroblast growth factor and insulin-like growth factor I. formerly known as somatomedin C. were strongly immunoreactive within the neuroepithelial cell population of the tumors. Immunoblots of purified recombinant basic fibroblast growth factor and insulin-like growth factor I showed antibody specificity without cross-reactivity. In controls. immunostaining of tissue sections was abolished by preabsorption of primary antibodies with the appropriate growth factor polypeptide antigen. Preabsorption with inappropriate growth factor did not reduce the intensity or alter the distribution of staining. The congruent histologic patterns of immunoreactivities suggest that more than one type of growth factor may be produced by the neuroepithelial component of medulloepithelioma. These growth factors may stimulate proliferation and differentiation of tumor cells by autocrine molecular mechanisms.
Nuclear DNA content, tumor cell aggregation, and metastatic events in patients with poorly differentiated adenocarcinoma of the stomach, Data on 100 patients who had undergone resection for poorly differentiated adenocarcinoma of the stomach with serosal invasion were examined to assess the prognostic significance of the DNA distribution pattern in relation to the histologic tumor cell aggregation pattern. DNA distribution patterns were classified into low and high ploidies and tumor cell aggregation patterns were classified into free-cell. small nest. and large nest types. The rates of high ploidy in the free-cell. small nest. and large nest types were 23.1%. 48.0%. and 66.7%. respectively. with a significant increase according to the degree of aggregation. The high ploidy group and large nest type had a higher incidence of lymphogenous and hematogenous metastasis than the low ploidy group and free-cell type. respectively. DNA ploidy had no prognostic value for the free-cell type of tumor. but differences in prognosis and the incidence of metastasis between the DNA ploidies were evident in the nest-forming type. Aneuploid tumors consisting of a poorly differentiated adenocarcinoma were those with nest formation. from the standpoint of histologic structure and metastatic behavior. The DNA analysis of poorly differentiated adenocarcinomas was of prognostic value. especially in the nest-forming type.
A clinicopathologic study of lymphoid neoplasias associated with human immunodeficiency virus infection in Italy, The clinicopathologic features of 45 human immunodeficiency virus (HIV)-infected patients (mainly intravenous drug users [IVDU]) with lymphoid neoplasias seen from September 1984 through July 1990 at an Italian cancer center are reviewed. Thirty-five had systemic non-Hodgkin's lymphoma (NHL). and ten had Hodgkin's disease (HD). Histologically. 27 NHL cases were intermediate grade (five cases) or high grade (22 cases. 14 of the small noncleaved cell type). according to the Working Formulation. Eight NHL cases. including four anaplastic large cell (ALC) BerH2 (CD30)-positive lymphomas. were in the miscellaneous group. Immunohistologic and/or gene rearrangement analysis showed the B-cell origin of 20 of the 24 NHL cases studied. At presentation. 71% of NHL patients had advanced stages (Stage III or IV). and 85% had extranodal disease (predominantly gastrointestinal tract and marrow). Of the 23 patients evaluable for treatment. only seven had a complete clinical response after lymphoma therapy; the median survival of 34 evaluable patients was 22 months after the diagnosis of NHL. Fifteen patients died; most deaths were attributable to progressive lymphoma and opportunistic infections. As with NHL. advanced disease. extranodal involvement. aggressive histologic findings. and poor response to therapy were also observed in patients with HD. This study shows that lymphoid neoplasias occurring in Italian IVDU with HIV infection and those previously reported in North American homosexual men with HIV infection share similar clinicopathologic features. However. some features such as the absence of history of Kaposi's sarcoma at diagnosis. the lack of detection of primary brain and rectal NHL. and the occurrence of B-cell ALC BerH2 (CD30)-positive NHL were observed uniquely in this series of patients.
Pleomorphic xanthoastrocytoma. Ultrastructural, immunohistochemical, and DNA cytofluorometric study of a case, A case of right frontal pleomorphic xanthoastrocytoma that occurred in a 7-year-old boy is reported clinicopathologically. The patient underwent surgery on September 29. 1988. Histologic diagnosis of pleomorphic xanthoastrocytoma was made because. in addition to the unique pleomorphic histologic features. positive glial fibrillary acidic protein in immunohistochemical staining and characteristic ultrastructural features. i.e.. cytoplasmic intermediate fibrils and lipid vacuoles. basal lamina. and abundant reticulin networks were demonstrated. The DNA cytofluorometric analysis of the nuclei of the tumor cells disclosed the main mode to be diploid with polyploid classes (4. 8. 16. and 32C) without any aneuploidy. Despite the presence of many pleomorphic nuclei. DNA histogram of the tumor disclosed very few DNA synthetic cells indicating a biologically inactive nature of the tumor. The patient is still alive and totally asymptomatic 20 months postoperatively.
Pattern of cell kinetics in colorectal mucosa of patients with different types of adenomatous polyps of the large bowel, It is generally accepted that adenomatous polyps represent the natural precursor of many colorectal malignancies. The sequence. however. which leads from a normally appearing mucosa to cancer is complex and involves many steps. including a hyperproliferative mucosa with an upward expansion of the replicative compartment. The current study evaluates cell replication in normal colorectal mucosa of patients with adenomatous polyps of various types and relates the observed findings to the main clinical and morphologic features of adenomas. Forty-four patients with polyps and 27 controls entered the study. Samples of colorectal mucosa were taken at endoscopy and cell replication was evaluated with a standard autoradiographic procedure. Cell replication was expressed as labeling index (LI). in the whole crypt and in each of the five longitudinal compartments in which the crypts were divided. Total LI and LI per crypt compartment were significantly higher (P less than 0.02 and P less than 0.01. respectively) than in controls. There was no appreciable difference of LI values between patients with single or multiple. tubular or tubulovillous. small or large adenomas. but in all of these subgroups LI was significantly higher than in controls. In conclusion. in normally appearing colorectal mucosa of patients with adenomatous polyps there was a significant increase of cell replication and a marked upward expansion of the proliferative zone; these changes were more evident in the left colon and in the rectum. Finally. cell replication did not seem to be related to the number of polyps. to the most common histotypes. or to the pattern of recurrence.
Familial juvenile polyposis coli and colorectal cancer, A 40-year-old mother and her 7-year-old son underwent colectomy for polyposis coli. Both colectomy specimens contained predominantly juvenile polyps. The mother's specimen also had numerous tubular adenomas and one 5-cm severely dysplastic villous adenoma without invasive carcinoma. Foci of adenomatous change in juvenile polyps were present in the son's specimen. The histologic features of both cases suggest a sequence of change from juvenile polyps to adenomatous polyps to cancer.
First heterotransplantation of a human carcinoid tumor into nude mice, The first successful heterotransplantation of a human carcinoid tumor into nude mice is reported. CSH. a voluminous hepatic metastasis of a primary bronchial carcinoid tumor (CSB) was resected and transplanted into three irradiated nude (Swiss-nu/nu) mice both by subcutaneous (SC) and intramuscular (IM) routes; the success rate was five of six. Heterotransplanted tumors took 4 to 5 months to appear in the mice and 1 month to attain a width of 0.5 cm. Both human and mouse tumors (named CSH-SC and CSH-IM) were studied by light and electron microscopy. They were Grimelius-positive. neuron-specific enolase-positive. and bombesin-negative by immunocytochemistry. Furthermore. CSH-SC cells presented characteristic (pear-shaped. rod-shaped. or tadpole-shaped) neurosecretory granules. Although CSB and CSH were slightly serotonin positive by immunocytochemistry. only a few serotonin-positive cells were found in CSH-SC and none in CSH-IM. suggesting partial loss of differentiation or an increase in serotonin catabolism during transplantation.
Climbing and the older athlete, Climbing may be considered appropriate for the older athlete. The requisites. cardiovascular and musculoskeletal fitness. can be attained through training; the skills can be acquired through schools or guide services. Inherent risks can enhance the enjoyment. The motivational psychology for climbing usually reflects positive qualities and attitudes toward life and the environment. With good health. the recreation of climbing can be enjoyed well into the seventh decade of life. Climbing may not be for everyone. but the physical and physiologic benefits. as well as the challenges. are available to the older athlete.
Golf for the mature athlete, Golf is a different sport from all others discussed in this issue in one important aspect: Almost all of its practitioners play more. rather than less. as they mature. A great many of them play better. too. This additional play and skill can be highly satisfying to the participants; however. it puts them at risk for a number of overuse syndromes directly caused by the motion requirements of golf. In addition. the repetitive nature of the activity can exacerbate pre-existing and age-related orthopedic pathology as well. There is no substitute for attention to the preplay aspects of golf (warm-up. flexibility. and strengthening).
The senior tennis player, Mature athletes playing tennis can sustain both acute and chronic injuries. A number of the injuries are related to a gradual loss of flexibility and strength. Much of this is reversible with properly directed conditioning and rehabilitative programs.
Swimming and the older athlete, Swimming is an organized. fast-growing sport and competitive swimmers are now found in abundance in all age groups. Including those athletes who do not compete in formal events (masters swimming program) and those participating in outside events (long-distance. channel swimming. triathlons. and so on). it may be one of the largest participant sports in this country. Injuries to the elite collegiate competitive swimmers have been well-documented. Considerations and injuries to the masters-level swimmer closely mirror those found in the younger athlete. but these injuries reflect the impact of tissue aging (degenerative disease). The preparticipation history and physical examination become more important. We are hopeful that this article will contribute to greater safety and enjoyment among all older swimmers.
Running and the older athlete, The beneficial effects of regular. aerobic exercise are well documented. Regular running fulfills the criteria for such a program. Because of the stresses incurred secondary to its impact loading. however. injuries are common. The biological changes that accompany aging can lead to a whole gamut of overuse injuries. To reduce these stresses. proper preparation. clothing. running shoes. training surfaces. and training techniques are recommended.
Exercise participation after menopause, Who should exercise? What exercises should be performed and with what frequency and duration? What benefits can be expected from such exercises? These are some of the questions frequently asked of physicians who care for elderly and post-menopausal patients. Data are conflicting. but significant conclusions can be drawn that will help provide the answers to these questions. This article is written to guide physicians' recommendations to their patients regarding postmenopausal exercise.
Athletic participation after myocardial revascularization. Possibilities and benefits, Exercise after open heart operation is not only possible but highly desirable. Training increases the efficiency of exercise and therefore decreases myocardial work for any given level of activity. Even before sternal and incisional healing is complete the patient may become physically active. Almost every patient can improve his or her level of fitness safely by following simple guidelines. Exercise treadmill testing is the basis for assessing exercise capacity in cardiac patients. Upper-body exercise is not adequately emphasized in most exercise programs.
Influence of erythropoietin treatment on urea kinetic parameters in hemodialysis patients, Urea kinetic parameters were studied by means of dialysate collection in 8 stable hemodialysis patients before and after treatment with recombinant human erythropoietin (r-HuEPO). in order to investigate the impact of a rising hematocrit (Ht) on dialyzer performance and nutritional status. After 6 months. the average in vivo dialyzer urea clearance had fallen from 152 to 132 ml/min and consequently Kt/V values had become undesirably low in most of the patients in whom the relatively short dialysis regimens had been kept unchanged. There was also a significant decrease of protein intake. As a result of both changes there was only a moderate increase of predialysis mean blood urea concentration. These findings indicate that after correction of anemia by r-HuEPO dialyzer performance decreased. The concomitant decrease of protein intake seems to contrast to the improved general physical condition and appetite as indicated in the questionnaires. Although body weight remained the same. there might have been a tendency to avoid protein consumption with maintained total calory intake as a result of slight underdialysis. Therefore. in individual cases dialysis prescriptions may need reconsideration when Ht levels rise after r-HuEPO administration. especially in short dialysis regimens.
Uremic polyneuropathy: a clinical and electrophysiological study in 135 short- and long-term hemodialyzed patients, Twenty neurophysiological parameters were employed to evaluate the presence and the degree of peripheral neuropathy (PNP) in a cohort of 135 patients (pts) on regular dialysis treatment (RDT) for 2 to 184 months. The 135 pts were divided into 3 groups according to the duration of RDT (group I: 52 pts with less than 5 yrs; group II: 46 pts 5 to 10 yrs; group III: 37 pts 10 to 15 yrs). Each group was then divided into two subgroups according to age (less or more than 47 yrs) to evaluate the influence of age on PNP. Correlations of electrophysiological parameters with some biochemical parameters (urea. creatinine. PTH) were looked for. The presence of clinical PNP was evaluated according to the Bolton classification: in group I. 50% of pts have mild PNP; in group II. 45.7% of pts have mild PNP; in group III. 81.1% have mild. 10.8% have moderate and 2.7% of pts have severe PNP. In as many as 84.4% of the 135 pts at least one of the 20 parameters studied had abnormal values and in 63% two or more parameters were abnormal. Of 20 parameters evaluated separately in the 3 groups only three showed abnormal mean values: sural nerve latency in all 3 groups; sural nerve Sensory Conduction Velocity (SCV) and peroneal nerve Max. Motor Conduction Velocity (MCV) in group III. Five parameters referring to ulnar nerves and two referring to the sural nerve were significantly more impaired in the group of pts with the longest duration of RDT and in this group the impairment was more severe in older patients.
Hypersensitivity reactions during hemodialysis related to the use of acetate dialysate. A case report, A patient developed a hypersensitivity reaction two weeks after being put on hemodialysis with acetate dialysate. The reactions appeared exclusively during hemodialysis and were relieved immediately after its termination. These allergic manifestations disappeared with substitution of bicarbonate for acetate dialysate and reappeared upon rechallenge with acetate dialysate. The rest of the dialysis materials were excluded as possible causes of allergy by scheduled dialysis sessions with varying materials. Acetate dialysate is implicated as the cause of allergy reaction in this case.
Shoulder ultrasound in dialysis related amyloidosis, Ultrasonographic changes around the shoulder joint were compared in ten symptomatic patients with dialysis related amyloid (DRA) and seventeen patients without symptoms. All patients had been on long-term (greater than 7 years) hemodialysis (HD). Three control groups were used: 8 predialysis patients. 10 continuous ambulatory peritoneal dialysis (CAPD) and 9 HD patients who had been on dialysis for less than two years. Dry bodyweight. sex. handedness. length of hemodialysis and fistula side were not significantly different between the study groups. Proven amyloid patients were significantly older than other groups (p less than 0.001). Parameters assessed included cross-sectional area of long head of biceps tendon (LHB). diameter of supraspinatus tendon (SS). and general features (bursae. deposits) around the joint. Results demonstrated significant differences in all parameters in patients with symptomatic amyloid compared with other long-term patients: [SS: 7.4 mm +/- 0.7. mean +/- SEM. vs 5.1 +/- 0.2 (right. R). p = 0.001; 6.7 +/- 0.7 vs 4.9 +/- 0.2 (left. L). p = 0.01. LHB: 140.0 mm2 +/- 11.1 vs 79.6 +/- 5.1 (R). p less than 0.001; 114.5 +/- 10.5 vs 80.8 +/- 5.4 (L). p = 0.004. Bursae: 5 vs 1 (patients). p = 0.006]. Compared with controls changes in the amyloid group were less marked though in most cases still significant. There was no significant difference between control groups nor between controls and asymptomatic long-term HD patients in any parameter. We conclude that shoulder ultrasound may have a role in identifying patients with dialysis related amyloid. Serial measurements may also help to elucidate the pathogenesis of the tendon changes.
No causal relationship between transdermal scopolamine and seizures: methodologic lessons for pharmacoepidemiology, Because of case reports suggesting that use of transdermal scopolamine might be associated with the subsequent development of seizures. a retrospective cohort study was performed with computerized Medicaid claims data. Patients receiving transdermal scopolamine were compared with patients receiving diphenhydramine. meclizine. prochlorperazine. and promethazine. A four-fold increased risk of seizures after transdermal scopolamine use was observed in the claims data. However. this was not supported by the primary medical records. All patients who had seizures after using transdermal scopolamine either had seizures before receiving the drug as well or did not really suffer from seizures. The original finding appeared to be the result of the use of transdermal scopolamine for "dizziness. rule out seizures"; the ICD-9-CM coding system does not include "rule out" diagnoses. Thus these data do not confirm the existence of an association between seizures and the use of transdermal scopolamine. In addition. this study demonstrates the usefulness of pharmacoepidemiology studies in documenting drug safety and the importance of obtaining primary medical records when performing pharmacoepidemiologic studies with claims data.
Enalapril effects on alcohol intake and other consummatory behaviors in alcoholics, Animal studies suggest that angiotensin-converting enzyme inhibitors decrease alcohol intake. In a double-blind crossover study 42 normotensive alcoholics (36 men and six women) aged 24 to 65 years. consuming 8.2 +/- 2.3 (mean +/- SD) standard alcoholic drinks per day. were randomized to enalapril. 10 mg/day (n = 20) or 20 mg/day (n = 22). and placebo for 4 weeks. They monitored their daily alcohol intake and attended biweekly assessments. but no other treatment or advice was given. Compliance and alcohol intake were verified objectively. Mean daily alcoholic drinks were not significantly different during 10 mg/day enalapril (mean +/- SEM. 7.5 +/- 0.5). and its placebo (7.2 +/- 0.5). but both decreased from baseline (8.1 +/- 0.5; both p less than 0.05). Similarly. mean daily drinks during 20 mg/day enalapril (6.8 +/- 0.6) and its placebo (7.2 +/- 0.4) was not significantly different. but both were lower than baseline (8.3 +/- 0.5; both p less than 0.01). Fourteen (64%) of the patients taking 20 mg/day enalapril decreased alcohol intake from placebo by an average of 21% (range. 1.6% to 78.3%). Self-ratings of interest. desire. craving. and liking for alcohol also decreased from baseline during enalapril and placebo treatments. but the effects of both were similar. Plasma renin activity increased. compared with placebo. after 10 mg/day enalapril (from 0.3 +/- 0.2 [mean +/- SD] to 1.9 +/- 1.5 ng/L/sec) and after 20 mg/day enalapril (from 0.4 +/- 0.3 to 2.8 +/- 4.0 ng/L/sec) (both p less than 0.05). Blood pressure decreased within a normotensive range. compared with placebo. with 10 mg/day enalapril (by 6.0 and 8.5 mm Hg systolic and diastolic blood pressures) and 20 mg/day enalapril (by 7.7 and 5.0 mm Hg. respectively). Side effects were few and mild. No patient characteristic or drug effect correlated with changes in alcohol intake. There were no significant variations in nonalcoholic beverages. cigarette smoking. or body weight. These results indicate that enalapril does not alter alcohol intake in normotensive alcoholics with normal plasma renin activity. Studies with higher doses of enalapril in humans may be limited by increased frequency and severity of side effects.
Physiological disturbances in hypoglycaemia: effect on subjective awareness [editorial, Deficiencies in the release of glucagon and adrenaline during hypoglycaemia in diabetic patients are associated with a high frequency of severe hypoglycaemic episodes. These have been attributed to a resulting inability to increase hepatic glucose output acutely. A more important consequence may be reduced awareness of impending hypoglycaemia. Such hypoglycaemia unawareness is related to. but not entirely explained by. diminished sympathetic activity. perhaps due to failure to activate the sympathoadrenal system until a lower blood glucose level is achieved. The patient's subsequent failure to act appropriately would then be due to impaired cerebral function preventing the perception of sympathoadrenal activation during the more severe hypoglycaemia. Unawareness of moderate hypoglycaemia is common in diabetic patients. Autonomic neuropathy probably accounts for only a few cases of hypoglycaemia unawareness and other factors which are potentially important include duration of diabetes. glycaemic control. insulin species. and the degree and frequency of hypoglycaemia. Further research is required to discover both the pathophysiological mechanisms of. and the treatment needed to reverse or prevent. the abnormality.
Effects of dietary Ca2+ on erythrocyte Na(+)-transport systems in spontaneously hypertensive rats, 1. The purpose of this study was to determine the effect of dietary Ca2+ intake on blood pressure and erythrocyte Na+ transport in spontaneously hypertensive rats. 2. Spontaneously hypertensive rats and Wistar-Kyoto rats were fed diets with three different Ca2+ contents. 0.1% (low-Ca2+ diet). 0.6% (normal-Ca2+ diet) and 4.0% (high-Ca2+ diet). between 6 and 20 weeks of age. At 20 weeks of age. the levels of erythrocyte Na+ efflux. as well as Na+ and K+ contents in erythrocytes. were measured. 3. On the low-Ca2+ diet. spontaneously hypertensive rats showed an enhancement of hypertension. Conversely. on the high-Ca2+ diet. they showed an attenuation of the increase in blood pressure. Spontaneously hypertensive rats had a lower erythrocyte Na+ content and increased activity of the Na+ pump at higher levels of dietary Ca2+. Passive Na+ permeability and Na(+)-K+ co-transport were similar in spontaneously hypertensive rats on the low-. normal- and high-Ca2+ diets. There were no significant differences in blood pressure and in Na+ pump activity in WKY on the three different diets. 4. It is concluded that dietary Ca2+ might affect the regulation of blood pressure in spontaneously hypertensive rats by changing the activity of Na+ pump in the cell membrane.
Posturally induced microvascular constriction in patients with different stages of leg ischaemia: effect of local skin heating, 1. Skin microcirculation was investigated in 12 asymptomatic subjects and 76 patients. grouped according to their ankle-to-brachial systolic blood pressure index. in order to evaluate to what extent posturally induced microvascular constriction is dependent on the stage of leg ischaemia at different local skin temperatures. 2. Skin microcirculation was assessed in the supine and sitting position by using laser Doppler fluxmetry at unheated skin temperature and at 36 degrees C. and transcutaneous oximetry at 37 degrees C and 44 degrees C. 3. Skin perfusion and oxygenation diminished with decreasing ankle-to-brachial systolic blood pressure index. In healthy control subjects. perfusion and oxygenation were reduced when changing from the supine to the sitting position. but were enhanced in patients with severe leg ischaemia (ankle-to-brachial systolic blood pressure less than 30%). indicating disturbed posturally induced vasoconstriction. 4. Increasing the local skin temperature resulted in a higher perfusion and masked the posturally induced vasoconstriction in healthy subjects. In patients with severe leg ischaemia. however. perfusion was unaltered by the temperature increase. apparently because the microvessels were already maximally dilated. The induction of reactive hyperaemia produced no additional increase in perfusion or oxygenation. 5. It is concluded that posturally induced microvascular constriction in the skin is disturbed in patients with severe leg ischaemia (ankle-to-brachial systolic blood pressure index less than 30%). Disturbed microvascular constriction upon dependency was also seen in healthy subjects after local skin heating. This suggests that posturally induced vasoconstriction is mainly regulated by local mechanisms.
Circulatory adaptation to orthostatic stress in healthy 10-14-year-old children investigated in a general practice, 1. The magnitude and time course of circulatory adaptation to active standing were investigated in healthy premenarchic girls and boys (n = 24; 10-14 years old) by non-invasive measurement of heart rate and continuous finger blood pressure (Finapres). 2. Four subjects (two girls. two boys) showed presyncopal symptoms after 4-9 min of free standing. 3. In the 20 non-fainting subjects. changes in blood pressure and heart rate upon standing did not differ between girls (n = 10) and boys (n = 10). In the initial phase of standing (first 30 s) systolic and diastolic blood pressures dropped by 22 +/- 14 (mean +/- SD) and 16 +/- 7 mmHg. respectively. at 8 +/- 2 s. Blood pressure subsequently recovered and showed an overshoot in all subjects. The transient drop in blood pressure was accompanied by an increase in heart rate of 40 +/- 7 beats/min. These characteristic transient changes were not observed with passive head-up tilt. During the early steady-state phase (2 min). systolic blood pressure was similar to the supine value and diastolic blood pressure rose by 11 +/- 5 mmHg. Heart rate increased by 25 +/- 11 beats/min. In six of the subjects (three girls. three boys) the increase in heart rate exceeded 30 beats/min (postural tachycardia). Little further changes were observed during prolonged (10 min) standing.
Comparison of the electrical properties of arterial smooth muscle in normotensive rats and rats with deoxycorticosterone acetate-salt-induced hypertension: possible involvement of (Na(+)-K(+)-Cl-) co-transport, 1. Hypertension was induced in male Sprague-Dawley rats by left unilateral nephrectomy and deoxycorticosterone acetate--salt administration. After 5 weeks. arterial systolic blood pressure was significantly elevated in these animals (191.5 +/- 6.0 mmHg. mean +/- SD. n = 17) compared with age-matched. unoperated control animals (134.0 +/- 4.2 mmHg. n = 8. P less than 0.001). 2. The membrane potential of femoral artery vascular smooth muscle measured in vitro was -55.1 +/- 6.3 mV (mean +/- SD. n = 154) for normotensive and -50.8 +/- 5.7 mV (n = 82) for hypertensive animals. The difference in membrane potential was significant (P less than 0.001). 3. The relationship between the log of the extracellular K+ concentration and membrane potential was nonlinear over the extracellular K+ concentration range 2.5-20 mmol/l. and showed a small positive shift with hypertension. 4. Tenfold reductions in the extracellular concentrations of Na+ or Cl- resulted in a membrane potential hyperpolarization in vascular smooth muscle from normotensive animals (4.9 +/- 2.0 mV. n = 13 and 12.1 +/- 1.3 mV. mean +/- SD. n = 14. respectively). In vascular smooth muscle from hypertensive animals. the hyperpolarization in low-Na+ media was significantly increased to 12.2 +/- 2.6 mV (mean +/- SD. n = 5). but that in low-Cl- media was unaffected (2.7 +/- 1.6 mV. n = 6). 5. The loop diuretic. bumetanide (10 mumol/l). hyperpolarized the membrane potential in vascular smooth muscle from both normotensive and hypertensive rats. but not in low-Na+ or low-Cl- media.
Increased plasma cholecystokinin levels and small gall bladders in adult patients with cystic fibrosis, 1. In patients with cystic fibrosis. abnormalities in plasma cholecystokinin level and gall-bladder emptying may contribute to the development of maldigestion and gall-stones. 2. Therefore. we have measured plasma cholecystokinin levels and gall-bladder volumes before and after ingestion of a standard breakfast in eight adult patients with cystic fibrosis and in eight normal control subjects. 3. In the patients with cystic fibrosis basal (2.8 +/- 0.4 pmol/l; P less than 0.05. t-test) and maximum post-prandial (5.7 +/- 0.5 pmol/l; P less than 0.05. t-test) plasma cholecystokinin levels were significantly higher than those in the control subjects (1.9 +/- 0.1 pmol/l. and 4.5 +/- 0.2 pmol/l. respectively). On the other hand. integrated plasma cholecystokinin secretion in response to the meal was similar (t-test. P = 0.4 versus control subjects). The increased plasma cholecystokinin levels in the patients with cystic fibrosis were accompanied by reduced gallbladder volumes in both the basal (7.8 +/- 2.1 cm3 versus 20.9 +/- 2.3 cm3 in control subjects; P less than 0.005. t-test) and the post-prandial state (2.2 +/- 1.0 cm3 versus 4.8 +/- 0.8 cm3 in control subjects; P = 0.06. t-test). Gall-bladder emptying in the patients with cystic fibrosis was well preserved (70 +/- 7% versus 78 +/- 9% in control subjects; P = 0.4. t-test). 4. In comparison with normal control subjects. patients with cystic fibrosis have an increased basal plasma cholecystokinin level and a reduced gall-bladder volume. whereas post-prandial gall-bladder emptying and plasma cholecystokinin secretion are not significantly different.
Pilonidal disease: 25 cases treated by the Dufourmentel technique, Twenty-five patients with pilonidal disease were treated by the Dufourmentel technique between 1984 and 1989. In this series. 18 patients (72 percent) were women and 7 (28 percent) were men (mean age. 24 years); hospital stay averaged 4 days. There were no recurrences and no reports of surgical wound infection. Diagnosis was confirmed histologically in all cases.
Squamous-cell carcinoma of the anal canal: management with combined chemo-radiation therapy, Twenty patients with squamous-cell carcinoma of the anal canal received combined chemo-radiation therapy as their primary treatment. There were 18 women and two men with a mean age of 63 years (range. 34-91 years). The mean follow-up was 34 months (range. 6-62 months). Anal margin cancers and adenocarcinomas were excluded. Fourteen of 20 patients treated had a complete response. There were six local failures: three with residual disease at the end of treatment and three with recurrent disease at a later date. Of the three with residual disease. one underwent abdominoperineal resection and two received salvage therapy (one with chemo-radiation and one with radiation alone). All three patients with recurrent disease were treated with abdominoperineal resection. All six were disease free at the end of the study. Of the 14 patients with complete local response. one presented with liver metastases 19 months later. Sixteen patients (80 percent) were alive at the end of the study. and 19 patients (95 percent) had no evidence of disease. These data add support for salvage therapy in the treatment of patients with residual disease following initial chemo-radiation therapy. Salvage options for patients with squamous-cell carcinoma of the anus who fail the Nigro protocol will be discussed.
Lectin staining of neoplastic and normal background colorectal mucosa in nonpolyposis and polyposis patients, A lectin histochemistry approach was adopted for comparative assessment of a colon cancer risk. Binding of Ulex europaeus agglutinin-I (UEA-I). peanut agglutinin (PNA). Griffonia simplicifolia agglutinin-II (GSA-II). and Dolichos biflorus agglutinin (DBA) was investigated in tumor and background tissue from a total of 34 adenoma and 44 cancer patients and compared with reaction patterns in control and familial adenomatous polyposis (FAP) patients. Adenoma patients with UEA-I positive rectal mucosa were found to have a 33.3 percent familial history of large bowel cancer. which was significantly higher (P less than 0.05) than the respective 4.0 percent figure for patients with negative rectal mucosa. In the cancer patients. an even stronger correlation was noted. with a 63.2 percent UEA-I positive family history association being recorded. as opposed to 4.0 percent in the negative rectal mucosa patients (P less than 0.01). Thus. the results suggest that. apparently. normal rectal background mucosa of individuals genetically at high risk for colon and rectal cancer demonstrates a specific lectin binding ability similar to that of FAP patients and that the simple method using UEA-I staining of rectal biopsy specimens can be of practical use in identification of high-risk colorectal cancer.
DNA ploidy pattern of flat adenomas of the large bowel, In an attempt to clarify the nature of "flat adenomas." DNA content was measured by means of microspectrophotometry. Thirty-nine flat adenomas (FA). 13 with mild. 22 with moderate. and 4 with severe atypia. were collected for this study. In FA. diploidy (D). polyploidy (P). and aneuploidy (A) were found 100. 0. and 0 percent in mild atypia. 41.9. 4.5. and 54.5 percent in moderate atypia. and 0. 0. and 100 percent in severe atypia. respectively. It is assumed that FA have a much higher malignancy potential than previously expected since. histologically. benign-appearing FA with moderate atypia have already contained malignant DNA patterns. In particular. those more than 5 mm in diameter show aneuploidy in 80 percent. These data suggest that FA with moderate atypia play an important role in the pathogenesis of small colonic carcinomas.
Assessment of the defunctioning efficiency of the loop ileostomy, The defunctioning efficiency of the loop ileostomy has been assessed using a radioisotope and dye technique. The median defunctioning capacity in patients without episodes of fecal discharge per rectum (n = 18) was 99.99 percent and was not affected by body position or the formation of a dependent stoma. In patients (n = 4) who passed fecal material per rectum but who had no stomal retraction. the median defunctioning efficiency was 99.99 percent. and continued fecal discharge was considered to be due to mucopurulent secretion from active distal disease. In patients who passed fecal material per rectum and also had a retracted stoma (n = 4). the defunctioning efficiency was significantly reduced (median = 84.70 [31.2-99.10 percent; P less than 0.01]). owing to the overspill into the distal limb. Two patients underwent stomal revision. with an improvement in defunctioning efficiency to 99.99 percent.
Use of the optical urethrotome knife in the treatment of a benign low rectal anastomotic stricture, Several methods of treatment for benign anastomotic strictures following anterior resection have been described. Surgical intervention in terms of re-exploration and excision of the stricture or the formation of a permanent colostomy will be accompanied by substantial morbidity. The dilatation of these strictures without direct vision may not be safe. We describe a simple method of treating benign rectal anastomotic stricture using an optical urethrotome knife under direct vision. This technique affords an accurate incision of the stricture to increase the size of the lumen. thereby relieving obstruction.
Colonoscopically guided tube decompression in Ogilvie's syndrome, Ogilvie's syndrome (pseudo-obstruction of the colon) may result in gangrene and perforation of the colon if not effectively treated. Colonoscopic decompression and endoscopically guided rectal tube placement were employed to treat five patients with this syndrome who had failed medical therapy. All patients tolerated the procedure well and required no further treatment.
Characterization of an insulin-like growth factor binding protein (IGFBP-4) produced by the B104 rat neuronal cell line: chemical and biological properties and differential synthesis by sublines, A previous report from our laboratory described an approximately 30 kilodalton (kDa) insulin-like growth factor binding protein (IGFBP) that inhibited the binding of insulin-like growth factor I (IGF-I) by its receptor and was secreted by a subline of the B104 rat neuronal cell line. To better understand the biology of this IGFBP. it was purified from media conditioned by these B104 cells. and the chemical and biological properties of the protein were examined. The IGFBP existed as a 24 kDa form and a 28 kDa form when the conditioned media were analyzed by ligand blot. Deglycosylation studies indicated the 28 kDa species was the N-linked glycosylated form of the 24 kDa IGFBP. Multiple forms at both mol wts were found using two-dimensional electrophoresis. suggesting that there were posttranslational modifications in addition to glycosylation. The amino acid sequence of the 12 amino-terminal residues was identical to that of rat IGFBP-4. Increased synthesis of IGFBP-4 by the subline contrasted with neglible production by other B104 cells. Blot hybridization with rat IGFBP-4 complementary DNA showed differential expression of a 2.6 kilobase transcript among B104 cell lines that correlated with quantities of IGFBP-4 secreted in media. The difference persisted even when the cells were xenografted into athymic nude mice. Purified IGFBP-4 inhibited the binding of [125I]IGF-I by its receptor and blunted stimulation of [3H]thymidine incorporation by IGF-I. These findings suggest a role for IGFBP-4 in neural cell function and indicate the B104 cell lines may be a useful model for further examination of IGFBP-4 biology.
Insulin acutely suppresses parathyroid hormone second messenger generation in UMR-106-01 osteoblast-like cells: differential effects on phospholipase C and adenylate cyclase activation, Insulin modifies the effects of PTH on osteoblast-like cells. However. the basis for this effect is unknown. In bone and kidney cells. the effects of PTH on cellular function are mediated by second messengers generated through both the phospholipase C and adenylate cyclase systems. Therefore. we examined the effects of insulin on PTH second messenger generation in UMR-106-01 rat osteoblastic osteosarcoma cells. PTH produced a rapid. transient increase in intracellular free calcium concentration ([Ca2+]i) which was maximal at 30 sec and was only minimally reduced in the absence of extracellular calcium. Inositol-triphosphate (IP3) production was increased in parallel. PTH stimulation of [Ca2+]i was concentration-dependent from 0.5-1.000 nM. with half-maximal stimulation at approximately 50 nM PTH. A 30-sec exposure to 50 nM PTH produced 32% and 23% increases in IP1 and IP3 production. respectively (both P less than 0.05). Although insulin alone did not significantly alter basal [Ca2+]i. a 1-min exposure to 1-100 nM insulin produced a concentration-dependent suppression of the PTH-stimulated transient increase in [Ca2+]i and IP3 generation. 100 nM insulin decreased 50 nM PTH stimulation of [Ca2+]i and IP3 levels by 84% (P less than 0.02) and 80% (P less than 0.001). respectively. Preexposure to insulin also decreased PTH stimulation of intracellular cAMP levels. but to a lesser degree. A 1-min exposure to 100 nM insulin produced a 32% (P less than 0.01) decrease in PTH-stimulated cAMP generation. but lower insulin concentrations were without significant effects. These results demonstrate that in UMR-106-01 cells. insulin suppresses PTH stimulation of second messengers generated through both the phospholipase C and adenylate cyclase systems. but has a more marked effect on the former.
Photoaffinity labeling of rat type I iodothyronine deiodinase, The photoreactive compound p-nitrophenyl-2-diazo-3.3.3-trifluoropropionate (PAL) was coupled to [125I]rT3. T4. or T3 and incubated with liver and kidney microsomes of hypo-. hyper-. or euthyroid rats to identify the type I iodothyronine deiodinase. Various substrates or inhibitors of the enzyme. including rT3. T4. T3. 6-n-propylthiouracil (PTU). and iopanoic acid. were used as competitors to establish the specificity of protein labeling. The PAL derivatization enhanced the behavior of T4 and T3 as substrates for the type I enzyme. No specific labeling of microsomal proteins was observed with either rT3 or T4-PAL. presumably due to deiodination of the labeled compound. In contrast. T3-PAL labeled a 27-kDa band. the presence of which paralleled thyroid status. The labeling of only this protein was blocked by either substrates or enzyme inhibitors in a dose-dependent fashion. with a rank order of potency predicted by the activity of such compounds in type I enzyme assays. The specific nature of these competitions provides further evidence that this 27-kDa protein. identified in previous studies using N-bromoacetyl [125I]T3 or -T4. contains the active site of the rat type I deiodinase. This is in agreement with the mol wt of the rat type I deiodinase deduced from the recently identified cDNA coding for this protein.
In vivo regulation of the activity of the two promoters of the rat acetyl coenzyme-A carboxylase gene, The acetyl-coenzyme-A carboxylase (ACC) gene contains two promoters: promoter I (PI) and promoter II (PII). Depending upon which promoter is active. two classes of ACC mRNA are formed. The physiological significance of the presence of two promoters in the gene is not clear at this time. However. this question can be indirectly approached by examination of their expression patterns under different physiological conditions. We have examined the activities of these two promoters under different physiological conditions by means of primer extension analysis. Under normal conditions. the Wistar rat. fed standard chow ad libitum. expresses only basal levels of PI in white adipose tissue and PII in the liver. Starvation leads to the virtual disappearance of transcriptional products from these promoters. When fatty acid synthesis is stimulated by refeeding a fat-free diet to starved rats. both PI and PII are activated in the liver; however. in white adipose tissue. only PI. not PII. is responsive to this nutritional induction. On the other hand. in streptozotocin-diabetic rats. in which the activity of both promoters in both tissues is depressed. the administration of insulin quickly induces PI in adipose tissues. but has no significant effect on either of the promoters in the liver. During the weaning transition. the increase in hepatic lipogenesis is accompanied by activation of PI and PII when the pups are weaned onto a fat-free diet. Weaning onto a standard chow causes only a slight increase in PII. During the lactation period. profound alterations occur in the metabolism of the lipogenic tissues. In the lactating rat mammary gland only PII is active. and its activity is increased throughout lactation. reaching a plateau by day 7. Concomitantly. all ACC gene activity is completely shut off in the adipose tissue. while in the liver. PII. the only promoter active. is affected only minimally. The fat accumulation of the genetically obese Zucker rats is largely due to an abnormally high hepatic lipogenesis. In the obese Zucker rat (fa/fa). the level of expression of PII is similar to that in its lean siblings; however. PI is constitutively expressed at high levels. comparable to those in the Wistar rat that has been subjected to the starvation/refeeding induction. These studies demonstrate that the in vivo transcriptional control of the dual promoter rat ACC gene is a highly regulated and tissue-specific process.
Tissue-specific regulation of alpha 1B, beta 1, and beta 2-adrenergic receptor mRNAs by thyroid state in the rat, Steady state levels of the mRNAs for alpha 1B. beta 1- and beta 2-adrenergic receptors (alpha 1BAR. beta 1AR. beta 2AR) were quantified by DNA excess solution hybridization assays in the heart. lungs. and liver of rats. Tissues for RNA extraction were obtained from euthyroid and thyroidectomized rats and from thyroidectomized rats treated with a single dose of thyroxine. Thyroidectomy resulted in significant decreases in beta 1AR and beta 2AR mRNAs in heart and lung and alpha 1BAR mRNA in liver. whereas the levels of beta 2AR mRNA in liver and alpha 1BAR mRNA in heart and lung were significantly increased. All these changes were reversed within 20 hours of a single s.c. injection of 1 mg/kg thyroxine. These findings indicate for the first time that thyroid state regulates mRNA levels for adrenergic receptors. and that this regulation is tissue- and receptor-specific. The changes in adrenergic receptor mRNAs correlate with and probably underlie the well documented. thyroid-dependent changes in the cellular densities and physiological reactivities of adrenergic receptors.
Adrenocorticotropin-releasing factor down-regulates glucocorticoid receptor expression in mouse corticotrope tumor cells via an adenylate cyclase-dependent mechanism, Anterior pituitary POMC transcription and peptide release are negatively regulated by glucocorticoids and stimulated by CRF. Although pretreatment of corticotrope cells with CRF markedly inhibits subsequent glucocorticoid effects. the mechanism of this action is unclear. We have thus used a mouse corticotrope tumor (AtT20) cell line. to examine the effects of CRF on glucocorticoid receptor (GR) messenger RNA levels and on GR capacity/nuclear translocation. GR mRNA levels were measured by solution hybridization/S1 nuclease protection. and both total cell binding and nuclear binding were determined with [3H]dexamethasone ([3H]DEX). CRF treatment of AtT20 cells led to a rapid time-dependent decrease in GR mRNA levels which preceded a dose- and time-dependent decrease in GR binding capacity. Scatchard analysis showed a single class of high affinity binding sites (GR) in both control and CRF-treated cultures. and a decrease in the total number of GR after CRF treatment. The relative proportion of nuclear vs. cytoplasmic localized [3H]DEX-bound GR did not differ between control and CRF-treated cultures. indicating that CRF does not interfere with GR nuclear translocation. To investigate whether CRF regulates GR expression through the adenylate cyclase system. as it does POMC. AtT20 cells were treated with either forskolin or 8-bromo-cAMP. and specific nuclear GR binding was determined. Both drugs mimic the CRF-induced decrease in GR binding. and in addition forskolin decreased GR mRNA levels; in contrast. forskolin had no effect on GH3 cell GR levels. These results suggest that CRF can decrease the cellular concentration of GR. and thus potentially the response to glucocorticoids. through the same mechanism by which it stimulates anterior pituitary POMC expression.
Molecular heterogeneity and cellular localization of carboxypeptidase H in the islets of Langerhans, The intracellular distribution and molecular heterogeneity of carboxypeptidase H was studied in rat insulinoma tissue and isolated islets of Langerhans by a combination of immunohistochemical. ultrastructural. subcellular fractionation. and immunoblotting analyses. Immunofluorescence microscopy of islets demonstrated the presence of carboxypeptidase H in both insulin-containing B cells and glucagon-containing A cells. Quantitative ultrastructural analyses of islet B cells indicated that the enzyme was concentrated in mature insulin secretory granules. clathrin-coated condensing granules. and to a lesser extent the Golgi apparatus. Carboxypeptidase H activity was localized principally to secretory granule subfractions of insulinoma tissue. where it was present for the major part (70%) as a form which is readily solubilizable at pH values prevailing in the granule interior (5.5). This species migrated as a diffuse band of 53-57 kilodaltons (kDa) on immunoblot analysis using antisera raised against the purified native enzyme. In contrast. the insoluble form which was associated with the granule membrane at pH 5.5. migrated as a relatively compact band of 55-57 kDa. Carboxypeptidase H activity was also present in subcellular fractions which contained Golgi membranes together with elements of the endoplasmic reticulum. and in a low density secretory granule fraction which may represent immature granules. The enzyme in these compartments. like the granule membrane species. migrated as a compact 55-57 kDa band on immunoblots. Two-dimensional electrophoretic immunoblot analysis of secretory granules suggested that both membrane and soluble forms of the enzyme were glycoproteins and that the terminal glycosylation was similar in both instances. Antiserum raised against the deduced C-terminal 11 amino acids of the cloned carboxypeptidase H sequence recognized the 55-57 kDa membrane component in granules but did not react with the 53-57 kDa soluble species. A major difference between the soluble and membrane forms therefore appears to be a structural modification or proteolytic removal of the C-terminal domain in the trans-Golgi or early secretory granule compartment. The concept that proteolysis is involved is further supported by the observation that the relative proportion of the high and low mol wt forms of the enzyme in different subcellular fractions correlated with that of proinsulin and insulin. respectively. The membrane association of the 55-57 kDa form of carboxypeptidase H is disrupted at pH values of 9 and is dependent on ionic strength. This further suggests that the C-terminus of the protein may have an important role in the sorting or concentration of the enzyme in vesicular elements of the regulated pathway of secretion.
The activity of 22-oxacalcitriol in osteoblast-like (ROS 17/2.8) cells, 22-Oxacalcitriol (OCT). a synthetic vitamin D analog. can mimic the ability of 1.25-dihydroxyvitamin D3[1.25-(OH)2D3] to differentiate leukemia and skin cells. to enhance the immune response and to suppress PTH secretion. but has much less calcemic activity. The mechanism for this selective action is not understood. OCT has been shown to have a diminished ability to mobilize calcium from bone in vivo. but in vitro findings are contradictory. Little is known about the effect of OCT on bone forming cells. Therefore. the present studies were designed to investigate the actions of OCT at the molecular level in the osteoblast-like cell line. ROS 17/2.8. 3H-OCT was bound to the vitamin D receptor (VDR) in intact cells at the same rate as 3H-1.25-(OH)2D3. As previously found for 1.25-(OH)2D3. the time course of specific binding of OCT was biphasic. with an initial plateau at 1 h and a further increase from 2-8 h. Scatchard analysis demonstrated that exposure to 3H-1.25-(OH)2D3 increased VDR from 24 fmol/mg protein at 2 h to 85 fmol/mg protein at 8 h. Exposure to 3H-OCT increased VDR from 22 to 76 fmol/mg protein. indicating that OCT is also capable of up-regulating the VDR in ROS 17/2.8 cells. In contrast to the lower affinity of OCT for VDR reported for chick intestine and HL-60 cells. the Kd for OCT in intact ROS 17/2.8 cells was identical to that for 1.25-(OH)2D3. The effect of OCT on osteocalcin secretion and alkaline phosphatase (ALP) activity in ROS 17/2.8 cells was also determined. Pretreatment for 24 h with either 1.25-(OH)2D3 or OCT resulted in a dose-dependent enhancement of osteocalcin secretion. A 2-fold stimulation by both compounds was observed with 10(-7)M. ALP activity was measured after a 72-h incubation with 10(-7)M 1.25-(OH)2D3 or OCT. Both compounds increased ALP activity to the same extent. Stimulation by OCT of VDR levels. ALP activity. and osteocalcin secretion were inhibited by the addition of 5 microM cycloheximide. indicating that these actions of OCT require new protein synthesis. Thus. OCT. like 1.25-(OH)2D3. up-regulates the vitamin D receptor. stimulates osteocalcin secretion. and increases ALP activity in ROS 17/2.8 cells. suggesting that the analog may be as active as 1.25-(OH)2D3 in stimulating bone formation in vivo. The low activity of OCT in mobilizing calcium from bone in vivo does not appear to be due to an inability of this compound to act on osteoblasts.
Acute phosphate depletion dissociates hormonal stimulated second messengers in osteoblast-like cells, The acute effect (24 h) of either phosphate depletion or phosphate surfeit on hormonal stimulated signal transduction systems was studied in the osteoblastic cell line UMR-106. Elevation of intracellular Ca2+ ([Ca2+]in). induced by different calciotropic hormones (PTH. prostaglandin E2. endothelin) was blunted by acute phosphate depletion. whereas at high inorganic phosphate (Pi) concentrations the rise in [Ca2+]in was augmented. Basal [Ca2+]in was not altered by either Pi depletion or Pi excess. The effect of acute phosphate depletion on hormonal mediated [Ca2+]in rise was not observed in the absence of extracellular Ca2+ suggesting that under these conditions. the release of Ca2+ from intracellular stores. is not affected. Also. nonhormonal calcium entry pathways such as depolarization-activated calcium channels or protein kinase C-activated Ca2+ channels were not affected by acute phosphate depletion. cAMP accumulation in the cells. either through receptor or nonreceptor-mediated mechanisms. increased under low Pi conditions and decreased as Pi concentration in the culture media was progressively increased from 0 to 2 mM during 24 h of incubation. Changes in Pi concentration had no effect on basal cAMP generation by the cells. The facilitative effect of acute Pi depletion on agonist-induced cAMP accumulation could be demonstrated in both the presence and absence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.2 mM). PTH receptor binding assessed with [Nle8 Nle18 Tyr34] bovine PTH (1-34) NH2 was not altered by phosphate depletion. We conclude that exposure of osteoblasts to different Pi environments modulates the second messenger responses to hormones in a reciprocal fashion so that acute phosphate depletion down-regulates [Ca2+]in signals while augmenting cAMP generation and vice versa. Inasmuch as bone resorption processes can be modulated by Ca2+ and cAMP the data presented herein suggest that the altered bone resorptive response to calciotropic hormones (e.g. PTH). under surfeit or deficit of phosphate. is mediated by changes in [Ca2+]in and cAMP.
Enhanced gastric mucosal haemostasis after upper gastrointestinal haemorrhage, An endoscopic technique for the measurement of gastric mucosal bleeding time has been developed to study gastric haemostasis in patients with acute upper gastrointestinal haemorrhage. The relation of gastric mucosal bleeding time to skin bleeding time and nonsterodial anti-inflammatory drug usage was examined in 61 control patients and in 47 patients presenting with bleeding peptic ulcers or erosions. Gastric mucosal bleeding time was shorter in patients with haemorrhage (median 2 minutes. range 0-5 minutes) than in the control group (median 4 minutes. range 2-8 minutes) (p less than 0.001). Skin bleeding times were similar in the two groups (medians 4 minutes in patients with haemorrhage and 4.5 minutes in controls). In 21 patients with haemorrhage who were taking non-steroidal anti-inflammatory drugs. the median gastric mucosal bleeding time (2.5 minutes. range 1.0-5.0 minutes) was similar to that in 26 patients with haemorrhage not associated with these drugs (2.0 minutes. range 0.0-5.0 minutes). These results show that gastric mucosal haemostasis is accelerated in response to haemorrhage in the upper gastrointestinal tract. even in patients taking nonsteroidal anti-inflammatory drugs. This enhanced gastric haemostasis probably reflects a local protective response to minimise blood loss from the bleeding lesion.
Endoscopic fine needle aspiration cytology in the diagnosis of gastro-oesophageal and colorectal malignancies, In a prospective study we compared the diagnostic accuracy of endoscopic fine needle aspiration cytology with that of brush cytology and forceps biopsy in relation to gross tumour pattern and site in 265 confirmed consecutive cases of malignancy of the oesophagus. stomach. colon. and rectum. Aspiration cytology gave the highest diagnostic accuracy (94%). which was significantly better than that of brush cytology (84.9%) and biopsy (87.2%) (p less than 0.005). The difference was mainly related to tumour pattern. When compared to brush cytology and biopsy aspiration cytology was significantly better in submucosal tumours (92.9% v 7.1% and 14.3%. p less than 0.001); in infiltrative malignancies (95.8% v 90.1% and 78.9%. p less than 0.01). and in ulceronecrotic malignancies (90.9% v 36.4% and 45.4%. p less than 0.05). In polypoid malignancies there was a significant trend (p less than 0.05) in favour of forceps biopsy. with a diagnostic yield of 100% compared with 95% for aspiration cytology and 93.3% for brush cytology. The accuracy of the different techniques was not significantly related to the site of the tumour. The cumulative accuracy of aspiration cytology and biopsy was significantly better than that of biopsy and brush cytology (98.5% v 90.9%. p less than 0.005). Aspiration cytology was diagnostic in 21 of 24 lesions that were negative with both brush cytology and biopsy. There were no false positive cytology or histology results. We conclude that aspiration cytology is a simple. safe. and reliable technique with a high diagnostic yield and is of particular value in submucosal. infiltrative. and ulceronecrotic tumours.
Impaired intestinal barrier function measured by differently sized polyethylene glycols in patients with chronic renal failure, The intestinal mucosa plays a fundamental role as the site for absorption of nutrients. and as an important barrier from potentially harmful agents in the intestinal lumen. Little is known of the permeability properties of the intestinal mucosa in uraemic patients. The intestinal permeability to differently sized polyethylene glycols (PEGs; range 326-1254 daltons) was studied in nine patients with chronic renal failure (24 hour endogeneous creatinine clearance 5-24 ml/minute). The maximum 24 hour urinary recovery of PEGs was decreased in the uraemic patients but relatively more of the larger than the smaller PEGs were found in these patients. The results suggest a reduced urinary recovery of PEGs caused by renal dysfunction but also a relatively increased intestinal permeability to larger PEGs in the uraemic patients.
Flow cytometric analysis of peripheral blood lymphocytes in ulcerative colitis and Crohn's disease, Using two colour immunofluorescence with fluorescein isothiocyanate and phycoerythrin labelled monoclonal antibodies. multi-parameter flow cytometry was used to examine the antigenic characteristics of peripheral blood lymphocytes in whole blood of patients with ulcerative colitis and Crohn's disease who were not taking immunosuppressive drugs. The numbers of CD4+ and CD8+ lymphocytes in patients with ulcerative colitis and Crohn's disease remained unchanged so that the CD4/CD8 ratio was the same as that of normal control subjects. In Crohn's disease there were many activated T cells (CD3+. CD25+). Although natural killer cells in active Crohn's disease were lower than in normal control subjects. cytotoxic T lymphocytes. as defined by CD3+. CD16+. did not differ in patients with inflammatory bowel disease compared with normal control subjects. For B cell subsets. there were differences in Leu-1+ B cells. Leu-8+ B cells. Fc epsilon R+B cells (Leu-16+. Leu-20+). and activated B cells (Leu-12+. Leu-21+) between patients with inflammatory bowel disease and normal control subjects. These differences are compatible with local activation of B cells in the inflamed colon.
More accurate diagnosis of irritable bowel syndrome by the use of 'non-colonic' symptomatology, The criteria now used in an attempt to distinguish irritable bowel syndrome from organic gastrointestinal disease rely almost entirely on symptoms of colonic origin. 'Non-colonic' symptoms. however. arising either from elsewhere in the gut or of a more general nature. are common in irritable bowel syndrome and may have even better diagnostic potential. The prevalence of these non-colonic features was assessed in 107 patients with the irritable bowel syndrome and 295 subjects with other gut disorders. Gastrointestinal type non-colonic symptoms are useful in differentiating irritable bowel syndrome from inflammatory bowel disease but. with the exception of early satiety. are not helpful when there is gastro-oesophageal or biliary disease. More general 'non-colonic' features. such as lethargy and backache. are much commoner in irritable bowel syndrome than in all the organic gastrointestinal diseases studied and have good discriminant function. Multiple logistic regression analysis identified certain features that had a particularly significant independent risk for irritable bowel syndrome. Those were lethargy (relative risk 6.7). incomplete evacuation (RR 5.2). age under 40 (RR 2.1). backache (RR 2.0). early satiety (RR 1.8). and frequency of micturition (RR 1.8). These relative risks can be multiplied together to give an overall risk when more than one of these features is present in a patient. Until a diagnostic test is available more confident diagnosis of irritable bowel syndrome can be achieved by identifying symptoms that have good discriminant function. The results of this study indicate that the non-colonic features of irritable bowel syndrome may be especially valuable in this respect.
Exocrine pancreatic function in children with coeliac disease before and after a gluten free diet, This study was designed to determine the extent of pancreatic insufficiency in untreated coeliac disease and whether pancreatic secretion is impaired after a prolonged gluten free period. Three groups of patients were studied: group A comprised 44 patients. mean (SD) age 4.0 (3.1) years. with coeliac disease and total or subtotal atrophy of the intestinal mucosa; group B comprised 67 patients. mean age 4.4 (3.0) years. with coeliac disease but with normal morphology of the intestinal villi (after 12.9 months of a gluten free diet); group C comprised 49 control subjects. mean age 3.2 (3.0) years. with normal jejunal histology. In all subjects exocrine pancreatic function was determined by the secretin-caerulein test; bicarbonate concentration and lipase. phospholipase. and chymotrypsin activity were measured after an intravenous injection of secretin 1 clinical unit (CU) + caerulein 75 ng/kg body weight. Faecal chymotrypsin concentration was also assayed. No significant difference was found between values of the duodenal output of pancreatic enzymes and bicarbonate obtained in the three groups; however. 10 of 44 untreated coeliac patients showed tryptic or lipolytic activity. or both. below the normal limit for our laboratory. The mean value of the faecal chymotrypsin concentration was significantly lower in untreated than in treated coeliac patients (p less than 0.0001) or in control subjects (p less than 0.0001). It is concluded that untreated coeliac patients may have pancreatic deficiency independent of a decrease in enterohormone release. No primary or secondary pancreatic insufficiency was found in coeliac patients where the intestinal mucosa had returned to normal.
Combination of cimetidine and alginic acid: an improvement in the treatment of oesophageal reflux disease. Cooperative Oesophageal Group, A new chewable tablet containing cimetidine 200 mg and alginic acid 500 mg. at a dosage of one tablet four times daily. was compared in a 12 week randomised study with the standard dosage of cimetidine (400 mg four times daily) in the management of oesophageal reflux disease. The dose of cimetidine continued unchanged throughout the study but the dose of the combination drugs could be increased after six weeks to two tablets four times a day if response was unsatisfactory. A total of 312 patients had data suitable for analysis. Sixty three per cent of those on the combination tablet completed the study without increasing their dose - that is taking cimetidine equivalent to half the standard dosage used in the control group. The improvement in heartburn symptoms was significantly greater in the combination group than in the group taking full dose cimetidine. There were no significant differences between the treatment groups in healing and improvement of the appearances of oesophagitis after 12 weeks. and healing rates were as expected from previous studies. The addition of alginic acid to cimetidine in this fixed combination tablet is an improvement in symptomatic treatment of oesophageal reflux disease.
Primary malignant melanoma of the oesophagus: case report and review of surgical pathology, Primary malignant melanoma of the oesophagus is both a rare presentation for melanoma and a cause of oesophageal neoplasm. It accounts for less than 0.1% of all primary oesophageal neoplasms. It was first recognised as a primary tumour by de la Pava et al who showed the presence of melanocytes within oesophageal mucosa. This case report includes a review of the surgical pathology. Even though it is a rare lesion it must be considered as a cause of polypoidal oesophageal lesions as both its diagnosis and treatment can present problems. It is usually fatal within one year.
Issues, goals, and guidelines in selecting first-line drug therapy for hypertension, Modern antihypertensive therapy is enriched by an explosion in drug development that makes available increasingly specific agents whose effects have advanced our understanding of pressor mechanisms. This and other research into hypertensive mechanisms has defined the clinical. pharmacological. and endocrinologic heterogeneity of human hypertension. The sum of these developments is a greatly enhanced ability to identify curable and definable causes of hypertension and to pathophysiologically stratify the remaining cases of essential hypertension. Modern treatment can be much more specific than before. When long-term drug therapy is indicated. the regimen is more likely to achieve a primary goal for each patient. that is. the fewest possible drugs in the smallest amount and in lowest frequency. Two clinically quantifiable mechanisms for long-term arteriolar vasoconstriction can be identified within the spectrum of human hypertension. The first. renin-mediated vasoconstriction. is directly related to the plasma renin level. The second. sodium-volume-related vasoconstriction. is marked by a reciprocally subnormal renin level and involves abnormal sodium retention and calcium transport. A baseline renin-sodium profile can identify the pressure of one of these two forms of vasoconstriction and therefore is the key for the diagnosis of the two curable disorders that fully express one of the two pressor mechanisms--renovascular hypertension and primary aldosteronism. Renovascular hypertension. more common than once thought. is often cured by angioplasty. It is important to diagnose these curable forms before beginning long-term drug therapy. The renin-sodium profile. used in conjunction with serum potassium and creatinine measurements. is valuable not only in screening patients for curable forms. but also for stratifying the remainder according to the pathophysiological vasoconstrictor mechanism that underlies the hypertension. Converting enzyme inhibitors or beta-blockers are. by themselves. often effective in correcting the hypertension of high- or medium-renin patients. whereas calcium antagonists. diuretic agents. or alpha-blockers alone are most effective against the low-renin form of vasoconstriction. In the large midzone of renin values. if monotherapy fails. a rational basis for combined antirenin-antisodium volume therapies can be developed.
Antihypertensive drug use. Trends in the United States from 1973 to 1985, Hypertension. a major public health problem. often requires drug therapy. We examined trends in outpatient antihypertensive drug use in the United States from 1973 to 1985. The numbers of prescriptions and the diagnostic and drug treatment information were obtained from the National Prescription Audit (Ambler. Pa. IMS America. 1985) the National Disease and Therapeutic Index (Ambler. Pa. IMS America. 1985). ongoing surveys of pharmacies. and office-based physicians. We adjusted drug-use data for the fact that several antihypertensive drugs also have other uses. During the study period. the annual numbers of prescriptions for treatment of hypertension progressively increased from 128.1 to 208.6 million. an average change of 5% per year. In 1973. the three leading classes of antihypertensive drugs were thiazide diuretic agents. peripheral neuronal inhibitors. and central alpha-adrenergic receptor stimulators. By 1985. the thiazide drugs were still the leader. followed by beta-adrenergic receptor blockers and potassium-sparing diuretic drugs. The use trends presented are consistent with surveys indicating increased drug therapy of hypertension from 1960 to the present.
Traditional first-line therapy. Overview of medical benefits and side effects, When diuretic-based stepped care was first advocated for the treatment of hypertension. there were fewer classes of antihypertensive medication than there are today. In 1984. the third Joint National Committee on Detection. Evaluation. and Treatment of High Blood Pressure (JNC) for the first time suggested an alternative initial treatment with a beta-blocker in selected hypertensive patients. and the fourth JNC report has recommended the alternatives of calcium channel blockers or angiotensin converting enzyme inhibitors for step-one therapy as well. However. only the diuretic drugs and beta-blockers have been shown to reduce cardiovascular morbidity and mortality in prospective. long-term. controlled trials. Moreover. 30 years' experience with diuretic agents and 20 years' experience with beta-blockers have defined the advantages. disadvantages. and potential side effects of these drugs more precisely than is possible for newer agents. The diuretic drugs and beta-blockers remain excellent choices in the management of hypertension.
Angiotensin converting enzyme inhibitors. Present and future, The angiotensin converting enzyme (ACE)-inhibiting agents have emerged with the diuretic agents. beta-adrenergic receptor-blocking agents. and calcium antagonists as therapeutic options for major consideration during the initial treatment of hypertensive patients. These compounds antagonize a potent pressor mechanism underlying hypertensive disease. The ACE inhibitors curtail the generation of the potent octapeptide angiotensin II; in addition. degradation of the potent vasodilator bradykinin is inhibited. Hemodynamically. ACE inhibitors reduce arterial pressure through a decreased total peripheral resistance that is unassociated with reflex stimulation of the heart or expansion of intravascular volume. The arteriolar dilation accounting for the decreased vascular resistance seems to occur in each target organ of the disease. Unlike the direct-acting smooth muscle vasodilators or adrenergic inhibitors. ACE inhibitors dilate the efferent as well as the afferent glomerular arterioles and thereby reduce glomerular hydrostatic pressure and renal filtration fraction. even though renal blood flow and glomerular filtration rate are preserved. The ACE-inhibiting compounds not only reduce left ventricular afterload in hypertension but also diminish cardiac mass and wall thicknesses. The mechanism(s) for some of these actions have not yet been defined precisely. but they undoubtedly involve the autocrine/paracrine actions of the renopressor system and their effects in the cellular biologic events of vascular smooth muscle and the cardiac myocyte. It seems plausible and exciting that the "more local" renin-angiotensin systems will be exploited by those ACE inhibitors yet to be synthesized. which will result in new applications for this class of pharmacological agents.
alpha 1-antagonists in the treatment of hypertension, A number of agents are now available to treat hypertension. One relatively new class of agents is the selective alpha 1-inhibitors. which have distinct advantages over earlier nonselective alpha-adrenergic receptor-blocking agents. Three alpha 1-inhibitors are reviewed in this article: prazosin. terazosin. and doxazosin. These alpha 1-inhibitors are similar in chemical structure and pharmacological action. alpha 1-Inhibitors lower blood pressure by reducing vascular tone in resistance and capacitance vessels. alpha 1-Inhibitors are similar in effectiveness in blood pressure lowering to other commonly used antihypertensive agents like the thiazide diuretic drugs and beta-blockers. which are efficacious as monotherapy in lowering pressure. as initial agents. or in combination with other antihypertensive agents in multidrug therapeutic regimens. alpha 1-Inhibitors are associated with a reasonably low incidence of serious adverse effects and are essentially free of any adverse metabolic effects. alpha 1-Inhibitors have been shown to beneficially effect blood lipids in several studies. The favorable lipid effect makes alpha 1-inhibitors especially appropriate to use in diabetic hypertensive and other patients with elevated serum lipid levels. The beneficial lipid effects may enhance the ability of alpha 1-inhibitors to prevent coronary heart disease. an outcome that has been difficult to demonstrate in thiazide-based trials.
Calcium channel blockers. Potential medical benefits and side effects, Calcium channel blockers are recently developed antihypertensive drugs. In terms of mechanisms of action. their specificity is not so well established as that of angiotensin converting enzyme inhibitors but is better understood than that for diuretics or adrenergic-inhibiting drugs. Calcium channel blockers were originally developed for treatment of angina but were found to lower arterial pressure as well. Three of them are now in wide use in the United States; their therapeutic spectrum in regard to type of hypertension is broad. Sublingual nifedipine has replaced intravenously administered vasodilators as immediate treatment of severe hypertension. and all three drugs. given orally. have been shown to be effective in mild. moderate. and severe hypertension. The three drugs available in this country are verapamil. diltiazem. and nifedipine. Pharmacological studies have shown that verapamil has the most negative chronotropic and inotropic effects of the three. with nifedipine producing the most vasodilation and having the potential for causing reflex tachycardia. Actually in practice. these various pharmacological differences have proved to have less significance than previously thought. and the drugs seem to have about equal antihypertensive effectiveness. Comparisons of calcium entry blockers with other drugs have shown them to be equally effective in whites as propranolol but more effective in blacks. Responsiveness appears to be related. as well. to pretreatment plasma renin activity and age. Thus. the antihypertensive effect is directly related to age and inversely related to plasma renin activity. The side effects mostly relate to vasodilation. reflex tachycardia. palpitations. headache. and edema; they are not frequent. and the drugs are well tolerated.
Choosing initial therapy for hypertension. A personal view, With numerous safe and effective antihypertensive drugs now available. the clinician should no longer choose only diuretic agents or beta-adrenergic receptor blockers (beta-blockers) as initial therapy. Five classes of agents. including angiotensin converting enzyme inhibitors. beta-blockers. calcium entry blockers. peripheral alpha 1-adrenergic receptor blockers. and thiazide diuretic agents. are all appropriate monotherapy in properly selected patients. The choice depends on efficacy. side effects. demography. comorbidity. dosage schedule. cost. mechanism of drug action. and the pathophysiology of the patient's hypertension. Extensive data are now available that will assist the clinician in choosing an agent that has the greatest probability of success without the need for extensive biochemical or hemodynamic evaluation.
Alternatives to traditional first-line antihypertensive treatment: unresolved questions and therapeutic dilemmas. A personal approach, The best antihypertensive regimen for use in patients with mild-to-moderate hypertension has not been determined. When nonpharmacological treatment of hypertension fails. initial drug treatment with diuretic drugs. sympatholytic agents (including beta-adrenergic receptor blockers). or vasodilators will result in satisfactory blood pressure control. However. each of these therapies has effects that are independent of their antihypertensive activity and that should be considered before a selection is made for initial therapy. The adverse effects of diuretic agents and beta-adrenergic receptor-blocking drugs on plasma lipid profiles may diminish the beneficial effects of blood pressure reduction. On the other hand. the hypocholesterolemic effect of alpha-adrenergic receptor antagonists. the potential cardioprotective effect of angiotensin converting enzyme inhibitors. and the salutary effects of calcium channel blockers on left ventricular function are responses that would support the use of vasodilatory therapy. Vasodilating antihypertensive drugs may be more beneficial than "standard" therapy and should be considered for the initial treatment of newly diagnosed hypertensive patients.
Economic considerations that influence health policy and research, Cardiovascular conditions account for more medical costs than any other diagnostic category in the United States. Increasingly. economic constraints will shape policy related to health care and research. Hypertension is the most common cardiovascular condition. and despite low unit health care costs. the aggregate costs are considerable. However. the unit and aggregate costs of the complications of hypertension are fourfold greater and. in this economic perspective. aggressive approaches are warranted to prevent complications. Treatment and research strategies should be identified that could have considerable potential economic impact. Several strategies are suggested as a prospective guide to policy development. Economic considerations will be important and should be incorporated in the planning of hypertension care and research.
Implications for research and policy in the treatment of hypertension. Medical considerations, Hypertension. or high blood pressure. is a disease and a risk factor. Cardiovascular risk is directly proportional to the level of blood pressure. Current therapeutic approaches include the classical medical model of detection. evaluation. and drug treatment of high-risk patients who have elevated blood pressure and also a less-well-studied population approach that seeks to manipulate environmental variables in large groups of subjects to reduce blood pressure and subsequent cardiovascular risk. Future research should center on more precise delineation of cardiovascular risk. evaluation of alternative environmental manipulations to reduce blood pressure. enhanced understanding of the pathophysiological mechanisms of hypertension. better matching of antihypertensive drug therapy to pathophysiology. development of new drugs that not only lower blood pressure but also provide additional benefits with minimal side effects. and finally. investigations to further our understanding of the behavioral aspects of the physician-patient encounter. as well as studies on compliance and other issues that influence therapeutic outcome.
The National Heart, Lung, and Blood Institute Workshop on antihypertensive drug treatment. The benefits, costs, and choices. Implications for research, Selected portions of the workshop's closing discussion are summarized. Major ongoing clinical trials of antihypertensive drug treatment are described. Some recommendations offered by workshop participants for future research directions are summarized.
Blood pressure (systolic and diastolic) and risk of fatal coronary heart disease, Among the 356.222 men screened for the Multiple Risk Factor Intervention Trial who had no history of hospitalization for heart attack at entry. more than 2.000 coronary deaths occurred during 6 years of follow-up. With this large data set. detailed cross-tabulations clearly and simply showed the strong graded relation between blood pressure and coronary heart disease death. This risk gradient was evident in each of five age groups ranging from 35 to 57 years and for levels of diastolic blood pressure ranging from less than 75 mm Hg to greater than 115 mm Hg. Systolic blood pressure was more strongly associated with coronary heart disease death than was diastolic blood pressure. and isolated systolic blood pressure elevation was found to be an important risk factor in these middle-aged men. The risk of coronary death was increased among hypertensive men who had elevated serum cholesterol levels or who smoked cigarettes. Because less than 10% of hypertensive men had cholesterol levels in the lowest quintile (below 182 mg/dl) and were nonsmokers. a multi-intervention approach for the large majority of hypertensive persons is clearly indicated. Risks of death were also substantially increased among those hypertensive men who already had end-organ damage. emphasizing the importance of early treatment to prevent such damage. These findings have implications for the design of prevention trials and clinical practice. as it is clear that systolic as well as diastolic blood pressure should be considered in treating hypertensive patients. Additionally. treatment goals should be directed at preventing not only death but many other morbid events. clinical and subclinical. that are associated with elevated blood pressure and that are preventable with appropriate treatment.
Antihypertensive drug therapy and survival by treatment status in a national survey, The National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study. an investigation of a cohort originally examined during the period 1971-1975. provided an opportunity to assess the frequency of antihypertensive drug therapy in the United States during the period 1982-1984. For most age-sex-race subgroups. the frequency of medication use during 1982-1984 was higher than that observed during 1976-1980 based on the NHANES II. In the interval 1982-1984. diuretic agents were the most frequent medications prescribed (47% of drugs prescribed). and beta-blockers were second (17%). At the time of the initial survey in 1971-1975. participants had their blood pressures measured and a history of diagnosis and treatment of hypertension ascertained. Follow-up for vital status was 93% complete by 1984 (average length of follow-up. 9 years). In white men and women aged 50 years and older. the relative risk of death increased steadily. from those with elevated blood pressure (systolic blood pressure greater than or equal to 160 mm Hg or diastolic blood pressure greater than or equal to 95 mm Hg) but no history of hypertension to those treated for hypertension but whose blood pressure was still elevated. Regardless of history or treatment. those with an elevated blood pressure had about a 25-30% excess risk of death. Evidence from these national studies shows a high frequency of antihypertensive drug therapy in 1982-1984 and suggests the importance of adequate blood pressure control for optimal survival.
Effect of risk status on treatment criteria. Implications of hypertension trials, When deciding whether to treat a patient with hypertension. clinicians must balance the benefit of treatment against its adverse effects. In the absence of an interaction. the multiplicative model of risk implies that the absolute benefit of treatment is related to the underlying risk of an adverse outcome. Thus. each additional risk factor multiplies the absolute benefit of treating hypertension. Analyses of data from subgroups in clinical trials of hypertension treatment suggest that this model is usually valid. In contrast. the adverse effects of treatment are usually unrelated to other risk factors. Thus. the cutoff point for treatment differs in different individuals: setting a single treatment threshold and goal for the entire population is not appropriate. Patients who are at high absolute risk because of prior coronary artery disease or other risk factors have a greater potential absolute benefit. and such patients deserve a low threshold and goal. such as a diastolic blood pressure of 90 mm Hg. Conversely. persons at low risk. such as white women without other risk factors. do not require such aggressive management.
Potential impact of exclusion criteria on results of hypertension trials, Recent trials of antihypertensive therapy. including the Veterans Administration trials. the Hypertension Detection and Follow-up Program. the Multiple Risk Factor Intervention Trial. the Australian Mild Hypertension Trial. and the British Medical Research Council Trial. are reviewed with a particular emphasis on the criteria leading to the exclusion of potentially eligible participants. The observation of all-cause and cause-specific mortality rates in the group ultimately selected to participate in the trial is suggested as an index to the general applicability of trial results. Because end-point rates are fundamental for determining sample size. substantial reduction in these end-point rates by patient exclusion should be taken into account by the trial design. Some recent trials may have generated end-point-event rates so low that the power of the trial to detect reasonable treatment effects was substantially reduced. Future trials should attempt to take this important factor into account at the design stage.
Socioeconomic status in the epidemiology and treatment of hypertension, The association of socioeconomic status (SES). as indexed by educational achievement. with the prevalence. prognosis. and efficacy of treatment of hypertension in the Hypertension Detection and Follow-up Program (HDFP) was reviewed. The prevalence of hypertension varied inversely with SES during the screening program initiated to identify HDFP eligibles in 14 communities in 1973-1974. There was a strong inverse gradient of 5-year all-cause mortality with SES among the hypertensive participants referred to usual care in the HDFP. The association of mortality with SES among hypertensive subjects was eliminated by the HDFP stepped-care program. A large portion of the efficacy of the HDFP was associated with in-trial blood pressure control. Inasmuch as these results are generalizable to the nation. a large fraction of hypertension-associated morbidity and mortality in the United States was related to lower SES in the 1970s. before widespread implementation of programs resulting in increased awareness. treatment. and control of hypertension.
Nonpharmacological therapy of hypertension. Commentary on diet and blood pressure, The use of dietary measures as sole therapy for hypertension has generated much enthusiasm and is supported by epidemiological and anecdotal data but is not substantiated by long-term controlled trials. Dietary measures should be effective in preventing the rise in blood pressure with age in civilized populations. but there are no firm data to substantiate this hypothesis. However. some data do suggest that weight loss and sodium restriction may benefit the drug-treated hypertensive patient. There are strong reasons to consider the use of nonpharmacological measures for the treatment of mild hypertension. Mild hypertension is ubiquitous. Some population subsets have a prevalence of mild hypertension approaching 40%. based on one blood pressure determination. for individuals older than 50 years. Even if the true prevalence is closer to 15%. this is a high proportion of the population in need of drug therapy. If a change in lifestyle could reduce the need for drug therapy by a respectable percentage. then an enormous number of individuals could be spared the necessity of taking antihypertensive medication.
Genetic factors in autoimmune thyroid disease analyzed by restriction fragment length polymorphisms of candidate genes, Possible genetic effects on the development of autoimmune thyroid disease were studied by analysis of restriction fragment length polymorphisms (RFLPs) of candidate genes. Peripheral blood leukocyte DNA was obtained from 65 caucasian patients with Graves' disease. 63 caucasian patients with Hashimoto's thyroiditis. and 65 caucasian controls. RFLP analysis was carried out on genomic DNA. using probes for DR beta. DQ alpha. DQ beta. DP alpha. DP beta. T-cell receptor TCR alpha. and thyroid peroxidase. The methodology allowed HLA-DR and DQ typing and provided information on specific RFLP patterns related to T cell receptor (TCR)alpha. DP alpha and -beta. and -beta. and thyroid peroxidase. HLA-DR3 frequency was significantly increased in patients with Graves' disease. as reported previously by others. but neither DNA-derived subtype of DR3 was differentially increased. HLA-DQw2 was also present in increased frequency because of its linkage disequilibrium with HLA-DR3. It is uncertain whether the primary susceptibility is with DQ. DR. or another nearby locus. Susceptibility was not related in these studies to genetic loci recognized in these studies involving DQ alpha. DP. TCR. or thyroid peroxidase. A significant linkage disequilibrium between DR3 and a specific DX alpha RFLP was observed in Graves' disease. but is believed to be representative of a generalized linkage disequilibrium between DR3 and DX alpha. rather than a specific abnormality in Graves' disease. Previous studies indicating association with specific TCR RFLPs could not be reproduced. The relative risk for carriers of HLA-DR3 subtype A in this study was 7.37-fold. RFLP analysis offers the possibility of investigating linkage in a variety of candidate genes as well as established genetic relationships for potentially important subtypes. While the significant relationship with HLA-DR3/DQw2 was reconfirmed. the involvement of other genes or haplotypes could not be established.
The incidence of thyroid stimulating blocking antibodies during the hypothyroid phase in patients with subacute thyroiditis, The etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain. although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses. It has been suggested that nonimmune processes are involved in SAT patients who have negative autoantibody titers. The disease has a variable course; although it is self-limited in most cases. some patients develop transient hypothyroidism. and others do not during the recovery period. The present study was performed to evaluate the occurrence of TSH receptor antibody (TRAb). measured by RRA (TSH binding inhibitor). TRAb measured by stimulation assay (thyroid-stimulating antibody). and TRAb measured by blocking assay [TSH-blocking antibody (TSH-BAb)] activity in 68 patients with SAT who had negative autoantibody titers. The patients were divided into 2 groups: group I. 31 patients who developed hypothyroidism during the recovery period; and group II. 37 patients who remained euthyroid during recovery. Positive immunoglobulin activity occurred in about 20% of group I patients during follow-up. but in only 3% of group II patients. About 20% of group I patients developed positive TSH-BAb activity and were hypothyroid. requiring exogenous hormone therapy for 1.2-3.5 yr. whereas hypothyroidism was relatively transient in group I patients who had negative TSH-BAb activity (2-6 months). Although increased TSH-BAb activity may account for hypothyroidism in some patients with SAT. the precise mechanism for the development of transient hypothyroidism in SAT remains enigmatic.
Androgen resistance associated with a mutation of the androgen receptor at amino acid 772 (Arg----Cys) results from a combination of decreased messenger ribonucleic acid levels and impairment of receptor function, Analysis of the nucleotide sequence of the coding segment of the androgen receptor gene in a patient (N105) with the receptor-negative form of complete testicular feminization has revealed a single substitution (CGC----TGC) at nucleotide 2476. This alteration results in the conversion of an arginine at amino acid 772 to a cysteine. Introduction of this mutation into an androgen receptor cDNA and transfection of the mutant cDNA into COS cells result in the production of a receptor protein with an alteration in the apparent Kd of ligand binding (3 nM) compared to that of the normal androgen receptor (0.5 nM). The mutant receptor protein predicted for patient N105 also demonstrates thermal instability of ligand binding that is not associated with quantitative or qualitative changes in the immunoreactive androgen receptor protein. When assayed in cotransfection experiments using a mouse mammary tumor virus-chloramphenicol acetyl transferase reporter system. the N105 receptor protein appears to be about a tenth as active as the control receptor. These functional characteristics do not appear sufficient to account for the phenotype of complete testicular feminization and do not explain the profound deficiency of androgen receptor in cultured skin fibroblasts. Quantitative S1 nuclease protection assays reveal that the level of androgen receptor mRNA in fibroblasts from patient N105 is markedly reduced. These results suggest that the phenotype in patient N105 is due to two effects of the nucleotide substitution at residue 2476: the replacement of a crucial amino acid (772) in the hormone-binding domain that impairs the function of any receptor molecules formed and a decrease in the level of androgen receptor mRNA.
Regional differences in adrenoreceptor status of adipose tissue in adults and prepubertal children, The relative anatomical distribution of adipose tissue in central (abdominal) vs. peripheral (extremity) depots is highly correlated with the risk of adiposity-related morbidities. such as hypertension. cardiovascular disease. and diabetes mellitus. In adults. comparisons of the functional status of plasma membrane adrenergic receptors indicate that abdominal adipocytes are more responsive to the lipolytic action of beta 1-adrenergic agonists. while gluteal adipocytes are more responsive to the antilipolytic action of alpha 2-adrenergic agonists. To determine whether such regional differences in adipocyte adrenoreceptor status are present before puberty. we obtained needle biopsy samples of abdominal and gluteal sc adipose tissue in the post-absorptive state from 13 prepubertal children and 47 adults of varying body compositions (obese vs. lean). Lipolysis rates were measured in the basal state and in the presence of 10(-7) M norepinephrine (a mixed alpha- and beta-adrenergic agonist) and 10(-7) M isoproterenol (a beta-adrenergic agonist). In children. there were no significant regional differences in either the basal rate of lipolysis or the responses to adrenergic lipolytic and antilipolytic stimuli. In lean and obese adults. gluteal sc adipose tissue was strikingly more responsive to antilipolytic alpha-adrenergic stimulation (P less than 0.0001) and less responsive to lipolytic beta-adrenergic stimuli (P less than 0.005) compared to abdominal tissue. Abdominal sc adipocytes from children had a significantly lower rate of basal lipolysis (P less than 0.01) and were more responsive to alpha 2-adrenergic (antilipolytic) stimuli (P less than 0.05) than abdominal adipocytes in adults. These results suggest that peripubertal endocrine changes may mediate the striking regional differences in adrenoreceptor status of adult adipose tissue. and that a decrease in the preponderance of alpha 2-receptors (antilipolytic) in abdominal adipose tissue may account in part for the relative loss of central vs. peripheral fat that occurs during puberty.
Routine inferior petrosal sinus sampling in the differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome: early recognition of the occult ectopic ACTH syndrome, The clinical. biochemical. and radiographic features of ectopic ACTH-dependent Cushing's syndrome are often indistinguishable from those of pituitary ACTH-dependent hypercortisolism (Cushing's disease). We prospectively evaluated 29 patients with ACTH-dependent hypercortisolism by means of bilateral inferior petrosal sinus ACTH sampling with ovine CRH (oCRH) stimulation. Patients with Cushing's disease (n = 20). had a maximal basal inferior petrosal sinus to peripheral ACTH ratio (IPS:P-ACTH) of 11.7 +/- 4.4 (+/- SE) from the dominant IPS. which increased to 50.8 +/- 18.3 after oCRH administration. Bilateral IPS sampling was necessary to correctly identify patients with Cushing's disease. since the maximal basal nondominant IPS:P-ACTH was less than 2.0 in over 50% of the patients and remained less than 2.0 after oCRH administration in one third. In contrast. patients with occult ectopic ACTH-secreting neoplasms (n = 9) had maximal basal IPS:P-ACTH of 1.2 +/- 0.1 that did not change after oCRH administration. Occult ectopic ACTH-secreting neoplasms were found in 7 of 9 patients from 0.4-14 yr after the recognition of Cushing's syndrome. and 4 of these patients had intermittent hypercortisolism with prolonged periods of remission. Selective endobronchial lavage for ACTH correctly localized a radiologically occult ACTH-secreting bronchial carcinoid in 1 patient. and magnetic resonance imaging identified a similar neoplasm in a patient with a normal chest computed tomographic scan. Basal ACTH and urinary free cortisol excretion were significantly higher in patients with ectopic ACTH than in those with Cushing's disease. but overlap existed between groups. High dose dexamethasone suppression testing inaccurately classified 24% of patients. and radiological imaging of the pituitary and adrenal glands was misleading. The occult ectopic ACTH syndrome is a common form of ACTH-dependent hypercortisolism that cannot be distinguished from Cushing's disease with routine clinical studies. The accurate differential diagnosis of ACTH-dependent Cushing's syndrome requires bilateral inferior petrosal sinus ACTH sampling with oCRH stimulation.
Octreotide stimulates insulin-like growth factor binding protein-1 (IGFBP-1) levels in acromegaly, Insulin-like growth factors (IGFs) circulate in a complexed state with several binding proteins (BPs). Of these. IGFBP-1 is regulated by hormonal and nutritional factors. The somatostatin analogue. octreotide. has been used to effectively control hypersomaototropism in acromegaly. IGFBP-1 levels were measured by RIA in 17 acromegalic patients receiving octreotide. Serum hormone sampling was conducted hourly for 8 hr periods. Among 13 octreotide responders. mean pre-treatment basal GH. IGF-1. and IGFBP-1 levels were 19 +/- 5 micrograms/L. 1021 +/- 168 micrograms/L. and 36 +/- 8 micrograms/L respectively. One month following octreotide treatment. an acute subcutaneous injection (100 micrograms) maximally attenuated GH to 3 +/- 0.6 microgram/L (18% of control. P less than 0.03) and IGF-1 to 467 +/- 75 micrograms/L (46% of control. P less than 0.008) after 4 hrs. IGFBP-1 levels. however. were stimulated to 95 +/- 16 micrograms/L (297% of control. P less than 0.003) during the same time period. A significant increase in IGFBP-1 levels occurred within 2 hrs (158% of baseline. P less than 0.03). and was sustained until the 7th hr following injection. Insulin. a known suppressor of IGFBP-1. did not change during this time. Among the 4 octreotide non-responders. mean basal IGFBP-1 levels were 42 +/- 4 micrograms/L. and 4 hrs following octreotide administration IGFBP-1 was 40 +/- 7 micrograms/L. Octreotide induced a dynamic inverse relationship between circulating GH and IGFBP-1 levels (r = -0.73. P less than 0.001). The absence of IGFBP-1 changes in octreotide non-responders and the non-suppression of insulin in octreotide responsive patients. suggest a direct GH-mediated mechanism of IGFBP-1 regulation in octreotide treated patients with acromegaly. IGFBP-1 may be another useful marker in evaluating the response of acromegaly to octreotide treatment in patients who experience clinical benefit but equivocal GH and IGF-1 attenuation.
Expression of intrahepatic hepatitis D viral antigen in chronic hepatitis D virus infection, To elucidate the biological importance of intrahepatic hepatitis D virus antigen. its expression was correlated with biochemical and histological inflammatory activity in 98 biopsy specimens from 68 patients seropositive for total antibody to the virus. Seventy five specimens were positive for intrahepatic nuclear antigen for HDV antigen accompanied by cytoplasmic HDV antigen in only one biopsy specimen. This group had significantly higher serum transaminase activities and inflammatory activity than the remaining cases that were negative for HDV antigen. Among the group positive for HDV antigen. there was no correlation between the proportion of hepatocytes containing HDV antigen and either serum transaminase activity or histological inflammatory indices. In 22 HDV antigen positive patients who had follow up biopsy specimens taken at a median of two years. the proportion with cirrhosis increased from 36% to 73%. Serum transaminase activities remained the same during this period. but the proportion of HDV antigen positive cells dropped. Follow up of 51 patients showed that 21 died or underwent liver transplantation within three years. The absence of an association between intrahepatic HDV antigen expression and progression of histological liver damage does not support the view that HDV is directly cytopathic to hepatocytes. Immune mediated mechanisms may have a role in the pathogenesis of chronic liver disease related to HDV infection.
Detection of hepatitis B virus pre-S1 and pre-S2 determinants in paraffin wax embedded liver tissue: importance of reagents used, The presence of pre-S polypeptides in paraffin wax embedded liver sections from the biopsy specimens of 15 hepatitis B surface antigen (HBsAg) seropositive patients (five with chronic persistent hepatitis (CPH). four with chronic active hepatitis (CAH). four with cirrhosis and two "healthy" HBsAg carriers) was investigated using monoclonal antibodies directed to distinct epitopes on pre-S1 (18/7 and TO 606) and pre-S2 (5535 and Q 19/10). Pre-S1 was found in 13 cases when MA 18/7 was used but in only one specimen when TO 606 was used. Pre-S2 was detected in all the biopsy specimens with 5535 and in eight samples with Q 19/10. Mild enzymatic digestion annulled the staining of all monoclonal antibodies but Q 19/10. No association was observed between pre-S polypeptide expression and hepatitis B virus (HBV) replication or disease severity. Pre-S polypeptides can be detected readily in paraffin wax embedded material but the results obtained largely depend on the monoclonal antibodies used.
Expression of neural cell adhesion molecule (NCAM) isoforms in neuroblastoma, A comparative study on the expression of the neural cell adhesion molecule (NCAM) in human neuroblastoma cell lines and tissues was undertaken. NCAMs are a family of closely related cell surface glycoproteins involved in cell-cell interactions. Using antibodies that recognise distinct epitopes on NCAM. their presence was shown in neuroblastoma. but these studies do not yield any information on the specific NCAM isoforms associated with the tumour. Western and Northern blot analyses were therefore carried out to characterise the NCAM isoforms in this neuroectodermal tumour. Western blot studies using the monoclonal antibody ERIC-1 showed that all human neuroblastoma cell lines tested expressed the 140 and 120 kilodalton isoforms of NCAM in their desialo state. Some of the cell lines also expressed NCAM-180. The data are corroborated by Northern blotting where a transcript of 7.4 kilobase pairs was identified only in lines expressing NCAM-180; the 6.7 and 5.4 kilobase pair transcripts coding for 140 and 120 kilodalton isoforms. respectively. were present in all the cell lines tested. The NCAM isoforms identified in neuroblastoma were also different from those found in adult and fetal brain tissue. suggesting that aberrations are expressed in the molecule during tumorigenesis.
Role of mesothelial cells in peritoneal antibacterial defence, Whether phagocytosis of Staphylococcus aureus by polymorphonuclear neutrophils. monocytes. and peritoneal macrophages takes place when the staphylococci are adherent to monolayers of human mesothelial cells in the absence of opsonins was investigated. Adherence of S aureus to mesothelial monolayers increased significantly when the bacteria were opsonised with pooled human serum. but phagocytosis by polymorphonuclear neutrophils and monocytes occurred independently. Phagocytosis by peritoneal macrophages. however. was only marginal. Pretreatment of polymorphonuclear neutrophils with inhibitors of cellular metabolism and motility reduced their phagocytic capacity. These results indicate that the surface of mesothelial cells provides favourable conditions for the elimination of staphylococci in the peritoneal cavity. Phagocytic motility seems to be important in surface phagocytosis. The inability of peritoneal macrophages to phagocytise staphylococci adherent to the mesothelial cells suggests that they contribute little to the antibacterial defence of the peritoneal membrane of patients receiving peritoneal dialysis.
Detection of Borrelia burgdorferi in patients with Lyme disease by the polymerase chain reaction, Borrelia burgdorferi. the causative agent of Lyme disease. was detected in patients' serum by DNA amplification using the polymerase chain reaction (PCR). B burgdorferi was pelleted from serum samples by centrifugation (10.000 x g for 10 minutes) and lysed by treatment with ammonium hydroxide (100 degrees C for 15 minutes). Two pairs of "nested" PCR primers complementary to the gene encoding a major outer surface protein (OSP A) of B burgdorferi were used in DNA amplification under standard PCR conditions (Perkin-Elmer Cetus). Two out of five patients with erythema migrans. the characteristic primary skin lesion associated with early Lyme disease. were positive by the PCR. This method could form the basis of a useful routine laboratory test in those cases of early Lyme disease where conventional serological testing commonly yields equivocal or false negative results.
Cyanotic congenital heart disease: dynamics of oxygen uptake and ventilation during exercise, The presence of intracardiac shunts dissociates the right and left circulations. making dynamic coupling of cellular and pulmonary gas exchange inefficient or impossible. As a result. patients may have profound changes in arterial blood gases and prolongation of adaptation and recovery even with low levels of physical activity. Because the exercise-induced symptoms in patients with cyanotic congenital heart disease have bases apart from heart failure. assignment of a New York Heart Association functional class may be misleading if not erroneous. Dr. Jane Somerville recommends the "Ability Index" shown in Table 1.
The adult with congenital heart disease: cardiac catheterization as a therapeutic intervention, The adult with congenital heart disease who undergoes cardiac catheterization at the present time is most likely to have complex heart disease and is left with clinically important sequelae or residual defects. ventricular dysfunction or arrhythmias. Residual defects such as paravalvular leaks. coronary fistulas and pulmonary artery narrowings may be corrected with transcatheter techniques. Patients with simple forms of congenital heart disease (for example. atrial septal defect. patent ductus arteriosus. aortic valve stenosis. pulmonary valve stenosis) will go to the catheterization laboratory for treatment. not diagnosis. Certain lesions previously considered benign (for example. patent foramen ovale) may require definitive interventional therapy to reduce the risk of stroke from paradoxic embolism.
Congestive heart failure symptoms in patients with preserved left ventricular systolic function: analysis of the CASS registry, The clinical characteristics and long-term survival of 284 patients from the Coronary Artery Surgery Study (CASS) registry data base who had moderate to severe congestive heart failure symptoms and a left ventricular ejection fraction greater than or equal to 0.45 were studied. A control group consisting of registry patients with an ejection fraction greater than or equal to 0.45 who did not have heart failure was used for comparison. Patients who had heart failure were older and more likely to be female and to have a higher incidence of hypertension. diabetes and chronic lung disease than registry patients who did not have heart failure. As a group. patients with heart failure had more severe angina and were more likely to have had a prior myocardial infarction than were registry patients without heart failure. At 6 year follow-up. 82% of patients in the heart failure group survived compared with 91% of patients in the control group (p less than 0.0001). Multivariate analysis using the Cox proportional hazards model identified the following independent predictors of mortality: regional ventricular systolic dysfunction. number of diseased coronary arteries. advanced age. hypertension. lung disease. diabetes. increased left ventricular end-diastolic pressure and heart failure symptoms. Among patients with heart failure. the 6-year survival rate of those who had three-vessel coronary artery disease was 68% compared with 92% for the group without coronary artery disease. However. the 6-year survival rate for patients with heart failure who underwent surgical revascularization of diseased coronary arteries was not significantly improved compared with that of patients treated medically.
Efficacy and safety of a short-term (6-h) intravenous infusion of dopexamine in patients with severe congestive heart failure: a randomized, double-blind, parallel, placebo-controlled multicenter study, Dopexamine hydrochloride is a new synthetic catechol that offers a unique profile of adrenergic and dopaminergic activity. In this multicenter. parallel design. placebo-controlled study. 45 patients with functional class III or IV chronic congestive heart failure were randomized to receive a placebo infusion or one of three different doses of dopexamine. After a 2-h dose titration sequence. patients received a 6-h constant dose infusion. During this 6-h period. dopexamine was infused at rates of 1. 2 and 4 micrograms/kg body weight per min in the low. intermediate and high dose groups. respectively. In patients receiving high dose infusion. dopexamine produced a 78% increase in cardiac index associated with a 43% decrease in systemic vascular resistance and 24% increase in heart rate (p less than 0.05 vs. placebo for all three variables). There was a trend (p = NS) toward a moderate increase in cardiac index at low and intermediate doses. In patients randomized to receive dopexamine. right atrial. systemic arterial. pulmonary artery and pulmonary capillary wedge pressures showed minimal change from baseline and did not differ statistically from the placebo response. Very few patients developed adverse reactions related to dopexamine. although five patients randomized to receive high dose and three patients randomized to receive intermediate dose dopexamine required dose reduction because hemodynamic variables exceeded arbitrary safety limits or the patients developed symptoms related to the study medication. dopexamine in higher doses effectively increases cardiac index in association with a reduction in systemic vascular resistance. Additional clinical studies are indicated to evaluate the merits of dopexamine in comparison with other inotropic and vasodilator medications.
Diagnostic value of transesophageal compared with transthoracic echocardiography in infective endocarditis, To compare the diagnostic value of transesophageal and transthoracic echocardiography in infective endocarditis. paired transesophageal and transthoracic echocardiograms were obtained prospectively for 66 episodes of suspected endocarditis in 62 patients. Echocardiographic results were compared with the presence or absence of endocarditis determined by pathologic or nonechocardiographic data from the subsequent clinical course. All echocardiograms were interpreted by an observer told only that the studies were from patients in whom the diagnosis of endocarditis was suspected. The diagnosis of endocarditis was eventually made in 16 of the 66 episodes of suspected endocarditis (14 by pathologic and 2 by clinical criteria). In 7 of 16 transthoracic and 15 of 16 transesophageal echocardiograms. endocarditis was diagnosed at a probability level of "almost certain." giving a sensitivity of 44% and 94%. respectively (p less than 0.01). For the remaining episodes. 49 of 50 transthoracic and all transesophageal studies yielded normal results. giving a specificity of 98% and 100%. respectively. This study suggests that transesophageal echocardiography is highly sensitive and specific for the diagnosis of infective endocarditis and significantly more sensitive than transthoracic echocardiography. Although echocardiography cannot rule out endocarditis. the high diagnostic sensitivity of transesophageal echocardiography results in a low probability of the disease when the study yields negative results in a patient with an intermediate likelihood of the disease.
Left atrial spontaneous echo contrast: a clinical and echocardiographic analysis, The clinical and echocardiographic variables related to left atrial spontaneous echo contrast were prospectively evaluated in a consecutive series of 400 patients undergoing transesophageal echocardiography with a 5-MHz single plane transducer. Left atrial spontaneous echo contrast was found in 75 patients (19%) and was significantly associated with atrial fibrillation. mitral stenosis. absence of mitral regurgitation. increased left atrial dimension and a history of suspected embolism. Seventy-one (95%) of the patients with spontaneous echo contrast had atrial fibrillation or mitral stenosis. Anticoagulant therapy had no significant association with spontaneous echo contrast. Multivariate analysis in 89 patients with mitral stenosis or mitral valve replacement showed that spontaneous echo contrast was the only independent predictor (p = 0.03) of left atrial thrombus or suspected embolism. or both. In 60 patients with atrial fibrillation of nonvalvular origin. spontaneous echo contrast (p = 0.01) and age (p = 0.03) were the only independent predictors of left atrial thrombus or suspected embolism. or both. It is concluded that left atrial spontaneous echo contrast is 1) a common finding in patients undergoing transesophageal echocardiography. 2) associated with conditions favoring stasis of left atrial blood. and 3) a marker of previous thromboembolism in patients with nonvalvular atrial fibrillation and those with mitral stenosis or mitral valve replacement.
Myocardial ischemia during daily activities: the importance of increased myocardial oxygen demand, The role of increased myocardial oxygen demand in the pathophysiology of myocardial ischemia occurring during daily activities was evaluated in 50 patients with coronary artery disease and exercise-induced ST segment depression. Each patient underwent ambulatory electrocardiographic (ECG) monitoring for ST segment shifts during normal daily activities and symptom-limited bicycle exercise testing with continuous ECG monitoring. All 50 patients had ST depression greater than or equal to 0.1 mV during exercise. A total of 241 episodes of ST depression were noted in the ambulatory setting in 31 patients; only 6% of these were accompanied by angina pectoris. Significant (0.1 mV) ST depression during ambulatory monitoring was preceded by a mean increase in heart rate of 27 +/- 12 beats/min. Patients with ischemia during daily activities developed ST depression earlier during exercise (7.9 +/- 4.4 vs. 14.2 +/- 6.4 min. p less than 0.001) and tended to have significant ECG changes at a lower exercise heart rate and rate-pressure product than did those without ST depression during ambulatory monitoring. In the 31 patients with ischemia during daily activities. the mean heart rate associated with ST depression in the ambulatory setting was closely correlated with the heart rate precipitating ECG changes during exercise testing (r = 0.74. p less than 0.001).
Interactive effects of ST-T wave abnormalities on survival of patients with coronary artery disease, Previous studies have documented a reduced survival time in patients with an electrocardiographic (ECG) ST-T wave abnormality. This study was designed to determine the clinical. hemodynamic and angiographic correlates of this observation. Data from 9.731 patients undergoing cardiac catheterization from 1976 through 1986 were analyzed; 5.531 had severe (greater than 70%) obstruction of at least one major coronary artery. 1.706 had mild (10 to 69%) obstruction and 2.494 had no obstruction. Of the patients with severe obstruction. 2.536 were treated medically and 2.995 were treated by surgical revascularization. Patients with an ST-T abnormality had more clinical risk factors (including older age and greater prevalence of diabetes mellitus. hypertension and prior myocardial infarction) and greater left ventricular dysfunction (including higher end-diastolic pressure and ventricular volume. reduced ejection fraction and greater prevalence of contraction abnormality) than did those without this ECG pattern. Survival time was significantly (p less than 0.01) reduced in subsets of patients with an ST-T abnormality and with severe or mild coronary artery disease; in those without coronary disease. ST-T changes did not correlate with reduced survival. Stepwise regression analysis was applied to each group to determine the independent predictors of 5-year survival. In patients with severe disease or no disease. an ST-T abnormality was not chosen as an independent predictor of 5-year survival; in the group with mild disease. ST-T changes were an independent predictor of reduced survival. Thus. the independent impact of an ST-T abnormality on survival is dependent on the severity of underlying coronary artery disease.
Hypertrophic cardiomyopathy characterized by marked hypertrophy of the posterior left ventricular free wall: significance and clinical implications, This report describes a subgroup of 17 patients with hypertrophic cardiomyopathy and an unusual and distinctive pattern of left ventricular hypertrophy characterized on echocardiography by marked thickening of the posterior left ventricular free wall and virtually normal or only modestly increased ventricular septal thickness. This distribution of hypertrophy often created a distinctive pattern of "inverted" asymmetry of the posterior wall relative to the septum. The thickness of the posterior wall was 20 to 42 mm (mean 25). while that of the basal ventricular septum was only 12 to 24 mm (mean 17). The left ventricular outflow tract was narrowed because of anterior displacement of the mitral valve within the small left ventricular cavity. Systolic anterior motion of the mitral valve was present in 16 of the 17 patients. The patients ranged in age from 13 to 54 years (mean 31) at most recent evaluation; most (11 of 17. 65%) were severely symptomatic and had experienced important symptoms early in life (before age 40). The condition of only 4 of these 11 patients improved with medical therapy over an average follow-up period of 9 years; however. 6 of the 7 patients who had unsuccessful medical treatment and underwent operation with mitral valve replacement (5 patients) or ventricular septal myotomy-myectomy (1 patient) experienced symptomatic benefit from surgery. The subgroup of patients described in this report underscores the morphologic and clinical diversity that exists within the overall disease spectrum of hypertrophic cardiomyopathy. Characteristically. the patients were young. severely symptomatic and demonstrated evidence of outflow obstruction and an "inverted" asymmetric pattern of posterior free wall left ventricular hypertrophy.
Effects of a meal on hemodynamic function at rest and during exercise in patients with hypertrophic cardiomyopathy, Many patients with hypertrophic cardiomyopathy experience postprandial exacerbation of their symptoms. The vasodilation associated with eating may be deleterious in hypertrophic cardiomyopathy. especially during exercise. To examine the hemodynamic effects of a meal in hypertrophic cardiomyopathy. 11 patients were studied with invasive hemodynamic monitoring during exercise testing in the fasting state and 45 min after a 740 kcal (3.100 J) meal. The meal induced a decrease in systemic vascular resistance index at rest (mean +/- SD. -17 +/- 14%). increases in mean right atrial (31 +/- 21%). mean pulmonary artery (14 +/- 14%) and mean pulmonary capillary wedge (17 +/- 14%) pressures and an increase in cardiac index (18 +/- 10%) due to an increased heart rate without any significant change in stroke volume. During postprandial exercise. heart rate. rate-pressure product. cardiac index and cardiac filling pressures were higher than during fasting exercise and one patient had a decrease in exercise blood pressure compared with the fasting test. Five patients with postprandial exacerbation of symptoms in everyday life had a lesser increase in systemic arterial pressure and stroke volume during both exercise tests and a smaller increase in cardiac index after the meal than did the six patients without postprandial symptom exacerbation. suggesting more severe cardiac disease. It is concluded that patients with hypertrophic cardiomyopathy have an abnormal hemodynamic response to food. in which stroke volume fails to increase and pulmonary capillary wedge and pulmonary artery pressures increase. These adverse changes persist during postprandial exercise and may predispose to exertional collapse in certain patients.
Differential effects on right ventricular function of transient right, left anterior descending and left circumflex coronary occlusions during percutaneous transluminal coronary angioplasty, Right ventricular function was studied by means of a thermodilution catheter before. during and after percutaneous transluminal angioplasty of the proximal right (group 1. n = 8). left anterior descending (group 2. n = 8) or left circumflex (group 3. n = 8) coronary artery. All patients had evidence of myocardial ischemia. with single-vessel disease affecting the proximal segment of one of the three major coronary arteries; no patient had had a previous myocardial infarction and all had normal cardiac function at baseline study. Cardiac index decreased during balloon inflation. Mean pulmonary artery pressure was unaffected in group 1 but increased in group 2 (from 19 +/- 5 to 31 +/- 11 mm Hg. p less than 0.01) and in group 3 (from 19 +/- 2 to 22 +/- 5 mm Hg. p less than 0.05). Right ventricular ejection fraction decreased from 62 +/- 9% to 52 +/- 10% (p less than 0.01) in group 1 and from 64 +/- 7% to 44 +/- 10% (p less than 0.005) in group 2. and returned to normal within 2 min after balloon deflation in both groups. In group 3. right ventricular ejection fraction was unchanged during balloon inflation (58 +/- 5% at baseline. 58 +/- 9% at 60 s. p = NS). Therefore. brief occlusion of the proximal segments of the left anterior descending or right coronary artery results in marked alteration of right ventricular performance that is probably caused by right ventricular free wall ischemia in the right coronary group and by the concomitant effects of septal ischemia and increased right ventricular afterload in the left anterior descending artery group.
Influence of contrast media on thrombus formation during coronary angioplasty, The influence of contrast media on thrombus formation during percutaneous transluminal coronary angioplasty was assessed in 124 consecutive patients undergoing coronary angioplasty and receiving either ionic (n = 57) (Group I) or nonionic (n = 67) (Group II) contrast medium. The presence of thrombus was assessed by qualitative analysis of angiograms in identical pre- and postangioplasty projections by four observers who had no knowledge of other data. Quantitation of stenosis severity before and after angioplasty and qualitative analysis of lesion eccentricity and complexity and of the presence of dissection were also performed. Although the baseline clinical characteristics of the two groups (including presenting syndromes and procedural and angiographic variables) did not differ. more patients in Group II than Group I developed new thrombus during coronary angioplasty (18% vs. 4%. p less than 0.02). In particular. patients with a presenting syndrome of recent myocardial infarction or rest angina. or both. and patients with an eccentric coronary plaque were more likely to develop new thrombus if they received nonionic than if they received ionic contrast medium (p less than 0.05). Patients with new thrombus formation and patients with thrombus present both before and after angioplasty had a high incidence of acute procedural complications (36% and 23%. respectively). Patients in Groups I and II had a similar incidence of ischemic events during follow-up.
Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure: demonstration in human subjects and verification in a paced canine model of ventricular failure, Although enhanced sympathetic tone is a well recognized component of the autonomic profile characteristic of congestive heart failure. the contribution of parasympathetic withdrawal to this autonomic imbalance is less well described. The technique of spectral analysis of heart rate variability provides a dynamic map of sympathetic and parasympathetic tone and was thus used to define the nature of sympathetic-parasympathetic interactions in humans with idiopathic dilated cardiomyopathy and in a paced canine model of congestive heart failure. Humans with cardiomyopathy were found to have an augmentation of the sympathetically mediated low frequency area of the power density spectrum. Parasympathetic withdrawal was demonstrated by significant reductions in the parasympathetically mediated high frequency area (p less than 0.05) and the ratio of high to low frequency areas (p less than 0.01). Administration of atropine to normal subjects resulted in a significant reduction in the high frequency area (p less than 0.05) and the high/low frequency area ratio. both of which decreased within the range noted in patients with congestive heart failure. Administration of isoproterenol in normal subjects led to an augmentation of the low frequency area but to only a small decrease in the high/low frequency area ratio. Induction of congestive heart failure in a paced canine model resulted in alterations in the autonomic profile that resembled those seen in humans with ventricular failure. The prominent high frequency region of the spectrum at baseline. indicating a predominance of parasympathetic tone. was absent after the evolution of congestive heart failure. and there was a marked augmentation of the low frequency region of the spectrum.
Imaging of myocardial infarction in dogs and humans using monoclonal antibodies specific for human myosin heavy chains, The use of three different monoclonal antibodies specific for human ventricular myosin heavy chains in the visualization of the location and extent of necrosis in dogs with experimental acute myocardial infarction and in humans is described. Using a classic immunohistochemical method or ex vivo analysis of heart slices in dogs with acute myocardial infarction subjected to intravenous injection of unlabeled antimyosin antibodies or antimyosin antibodies labeled with indium-111. it was observed that all antibody fragments specifically reached the targeted necrotic zone less than 2 h after antibody injection and remained bound for up to 24 h. In a limited but significant number of cases (5 of the 12 humans and 11 of 43 dogs). it was possible to image the necrotic zone in vivo as early as 2 to 4 h after antibody injection. In other cases. individual blood clearance variations retarded or even prevented in vivo necrosis detection. Higher antimyosin fixation values were obtained in the necrotic zones in dogs with a rapid blood clearance relative to that of the other dogs. It is concluded that antimyosin antibodies always reached necrotic areas within 2 h. If blood clearance was rapid. in vivo imaging of the necrotic area was possible 2 to 6 h after necrosis. even in humans. In some cases. however. uncontrolled individual variations in the timing required for sufficient blood clearance hampered this rapid in vivo detection of myocardial necrosis.
Effect of peripheral cardiopulmonary bypass on left ventricular size, afterload and myocardial function during elective supported coronary angioplasty, Although cardiopulmonary bypass support has been increasingly used for high risk coronary angioplasty. few data exist regarding its effects on left ventricular function. Accordingly. in 20 patients changes in left ventricular size. afterload and myocardial function were assessed by continuous hemodynamic monitoring and simultaneous two-dimensional echocardiography during cardiopulmonary bypass-supported high risk angioplasty. The cross-sectional left ventricular area during bypass support remained unchanged during diastole. whereas during systole it decreased (from 29.6 +/- 11.4 to 27.6 +/- 10.4 cm2. p less than 0.05). Global left ventricular function expressed as fractional area change remained unchanged from baseline to bypass support but decreased during balloon inflation (from 0.27 +/- 0.11 to 0.17 +/- 0.09. p less than 0.001). The end-systolic meridional wall stress decreased during bypass support (from 141 +/- 75 to 110 +/- 58 x 10(3) dynes/cm2. p less than 0.02). Regional myocardial function was assessed by a wall motion score (0 = normal. 1 = hypokinesia. 2 = akinesia and 3 = dyskinesia). Regions supplied by a stenotic (greater than or equal to 50% diameter) vessel deteriorated during bypass support (score from 0.9 +/- 0.8 to 1.06 +/- 0.8. p less than 0.01). whereas regions supplied by a nonstenotic vessel did not. Regions supplied by the target vessel deteriorated further during balloon inflation (score from 0.7 +/- 0.6 to 1.7 +/- 0.75. p less than 0.001). Thus. although left ventricular size and global function remain unchanged and afterload decreases during bypass support. myocardial dysfunction in regions supplied by a stenotic vessel may occur. Furthermore. regional and global left ventricular dysfunction still occur with angioplasty balloon inflation during cardiopulmonary bypass support.
Transesophageal Doppler echocardiography of pulmonary venous flow: a new marker of mitral regurgitation severity, Pulmonary venous flow varies with different cardiac conditions. Flow patterns in response to mitral regurgitation have not been well studied. but flows may vary enough to differentiate among different grades of regurgitation. Accordingly. pulmonary venous flow velocities were recorded in 50 consecutive patients referred for outpatient (n = 26) or intraoperative (mitral valve repair; n = 24) echocardiographic examination for mitral regurgitation. Recordings were made of right and left upper pulmonary veins with pulsed wave Doppler transesophageal echocardiography. Mitral regurgitation was graded from 1+ to 4+ by an independent observer using transesophageal color flow mapping. The results of cardiac catheterization performed 5 weeks earlier in 43 of the patients were also graded for mitral regurgitation by an independent observer. Pulmonary venous flow patterns. the presence of reversed systolic flow and peak systolic and diastolic flow velocities were compared with the severity of mitral regurgitation indicated by each technique. Of the 28 patients with 4+ regurgitation by transesophageal color flow mapping. 26 (93%) had reversed systolic flow. The sensitivity of reversed systolic flow in detecting 4+ mitral regurgitation by transesophageal color flow mapping was 93% and the specificity was 100%. The sensitivity and specificity of reversed systolic flow in detecting 4+ mitral regurgitation by cardiac catheterization were 86% and 81%. respectively. Discordant flows were observed in 9 (24%) of 38 patients; the left vein usually showed blunted systolic flow and the right showed reversed systolic flow. In 22 intraoperative patients. there was "normalization" of pulmonary venous systolic flow after mitral valve repair in the postcardiopulmonary bypass study compared with the prebypass study after the mitral regurgitant leak was corrected.
Predictive accuracy of electrophysiologic localization of accessory pathways, Operative ablation of accessory pathways depends critically on preoperative localization when technical limitations preclude complete intraoperative mapping. To assess the accuracy of localization. 345 patients undergoing operative ablation were studied; 316 (91.6%) had a single accessory pathway and 29 (8.4%) had multiple accessory pathways. The electrophysiologic study was diagnostically complete and accurate in 294 patients (93%) with a single accessory pathway and 19 (61%) with multiple accessory pathways. A left lateral accessory pathway was most accurately localized with excellent sensitivity (99%) and positive predictive value (98.5%). Diagnostic errors occurred in 33 patients because of 1) incorrect localization (n = 16). 2) failure to detect a second pathway (n = 9). and 3) diagnosis of a second pathway not verified intraoperatively (n = 8). Multiple pathways were more prevalent in the group with errors (33.3% vs. 5.8%. p = 0.0001). as were unidirectional pathways (48.5% vs. 24.3%. p = 0.003). It is concluded that preoperative localization of accessory pathways is sufficiently accurate to allow intraoperative mapping to be brief and focused.
Doppler echocardiography of fetal ductus arteriosus constriction versus increased right ventricular output, A prospective longitudinal study from 121 examinations of 41 normal pregnant women showed that fetal ductal flow velocities increased with gestational age. These normal data were compared with data in three groups of fetuses with altered ductal flow velocities: 22 fetuses (mean gestational age 31.3 weeks) had ductal constriction due to maternal indomethacin treatment; 10 fetuses (mean gestational age 27.9 weeks) had been exposed to terbutaline. a positive inotropic agent and 14 fetuses (mean gestational age 33.3 weeks) had hypoplastic left heart syndrome. In normal fetuses maximal systolic. mean and end-diastolic ductal flow velocities increased linearly (p less than 0.0001). The pulsatility index did not change (mean +/- 2 SD: 2.46 +/- 0.52). Fetuses with ductal constriction had higher maximal. mean and end-diastolic flow velocities and a significantly lower pulsatility index than did normal fetuses (1.25 +/- 0.76; p less than 0.0005). Six of 10 fetuses of the terbutaline group and 8 of 14 fetuses with hypoplastic left heart syndrome had increased maximal flow velocity. but normal or only mildly elevated mean flow velocity. The pulsatility index in fetuses during terbutaline therapy and with hypoplastic left heart syndrome was significantly higher than in normal fetuses (3.11 +/- 0.46 and 3.09 +/- 0.7. respectively. vs. 2.46 +/- 0.52; p less than 0.0005). Fetal ductal waveform analysis was necessary to distinguish fetal ductal constriction from increased right ventricular output. These measurements may be helpful in the diagnosis of left-sided outflow obstruction and assessment of fetal hemodynamic data.
Early surgical closure of a large ventricular septal defect: influence on long-term growth, The pre- and postoperative growth patterns of 52 otherwise normal infants undergoing primary surgical closure of a large ventricular septal defect before 7 months of age were reviewed. Serial measurements of weight. length and head circumference were compiled for all patients preoperatively and in 46 long-term survivors and were expressed as Z scores (in standard deviations from the mean for age and gender). By the time of surgery at a mean age of 0.33 year. the mean weight. length and head circumference Z scores of all 52 infants were -2.9. -0.9 and -0.6. respectively. and were all significantly below normal (p less than 0.001). At a mean age of 5.7 years. the mean weight. length and head circumference Z scores of 35 patients of normal birth weight were normal or varied only marginally from those of the reference population (-0.4. -0.1 and +0.5. respectively; p less than 0.02. p greater than 0.05 and p = 0.008. respectively) and did not differ significantly in any variable from those of 44 normal siblings. However. among 11 infants with a low birth weight. all three variables remained abnormal at long-term follow-up when compared with the reference population (-1.7. -1.7 and -0.9. respectively; p less than 0.001 for each) and 22 normal siblings (p less than or equal to 0.008).
Double-inlet single left ventricle: echocardiographic anatomy with emphasis on the morphology of the atrioventricular valves and ventricular septal defect, The echocardiographic anatomy of double-inlet single left ventricle was studied in 57 patients. aged 1 day to 27 years (mean 6 years); the variables examined included morphology. size and function of the atrioventricular (AV) valves and ventricular septal defect and their relation to pulmonary stenosis. aortic stenosis and aortic arch obstruction. The visceroatrial situs was solitus and the heart was in the left side of the chest in all 57 patients. A d-loop ventricle was present in 21 patients and an l-loop ventricle in 36. The great arteries were normally related (Holmes heart) in 8 patients and transposed in 49. In all hearts. the right AV valve was anterior to the left AV valve. In 53 patients. the tricuspid valve (right valve in d-loop and left valve in l-loop) was closer to and had attachments on the septum. The tricuspid valve straddled the outflow chamber in eight patients. No significant difference was noted in the mean AV valve diameter when comparing mitral and tricuspid valves within the same group or between the groups with a d- or l-loop ventricle. The right AV valve diameter had a significant direct correlation with the aortic valve diameter and the size of the ventricular septal defect regardless of ventricular loop. Both AV valves were functionally normal in 34 patients. Among patients with AV valve dysfunction. the tricuspid valve tended to be stenotic in patients with an l-loop ventricle and regurgitant in patients with a d-loop ventricle. Mitral valve dysfunction was uncommon. The ventricular septal defect (46 patients) was separated from the semilunar valves in 24 patients (muscular defect) and adjacent to the anterior semilunar valve as a result of hypoplasia or malalignment. or both. of the infundibular septum (subaortic defect) in 19 patients. Multiple defects were present in three patients. The defect was unrestrictive in 26 patients. restrictive in 23 and could not be evaluated in 8. Pulmonary artery banding had been performed in 8 of the 26 patients with an unrestrictive defect and in 10 of the 23 patients with a restrictive defect. Only 4 of 19 subaortic defects compared with 16 of 24 muscular defects were restrictive. The size of the defect was significantly correlated with the measured pressure gradient. Among patients with transposition. only 2 of 13 with pulmonary stenosis had a restrictive ventricular septal defect compared with 15 of 30 without pulmonary stenosis. In patients with transposition. the defect size was significantly smaller when coarctation was present.
Transesophageal real-time echocardiography in infants and children with congenital heart disease, Transesophageal echocardiography using Doppler color flow mapping with both single plane transverse and longitudinal pediatric probes was performed in 127 infants and children both intraoperatively and postoperatively. The 127 patients ranged in age from 1 day to 18 years (mean 37 months) and in weight from 2.4 to 45 kg (mean 13.2); 157 studies were successfully performed (100% of attempted) with no complications. Transesophageal two-dimensional echocardiography combined with pulsed wave Doppler ultrasound and color flow mapping provided detailed morphologic as well as physiologic information. with additional information provided overall in 56% of the cases. Typical limitations of single-plane transverse imaging were overcome using a prototype longitudinal-axis pediatric probe. Both left and right ventricular outflow tracts. distal pulmonary arteries and all of the interventricular and atrial septa were visualized. Assessment of surgical repair intraoperatively as well as assessment postoperatively for cardiac function. residual intracardiac shunts. residual valvular sequelae and other hemodynamic events was important and easily performed in an otherwise inaccessible patient. Transesophageal echocardiography in infants and in small children is a valuable "noninvasive" imaging technique that offers important additional and complementary information.
Effect of long-term enalapril therapy on cardiopulmonary exercise performance in men with mild heart failure and previous myocardial infarction, Forty-one men with documented myocardial infarction greater than 6 months previously were randomized to long-term (48 weeks) therapy with placebo or enalapril on a double-blind basis. All patients were receiving concurrent therapy with digitalis and a diuretic drug for symptomatic heart failure (functional class II or III). The mean age was 64 +/- 7.3 years and no patient suffered from exertional chest pain. Patients underwent maximal cardiopulmonary exertional chest pain. Patients underwent maximal cardiopulmonary exercise testing to exhaustion on an ergometer cycle nine times over the course of 48 weeks. Gas exchange data were collected on a breath by breath basis with use of a continuous ramp protocol. In the placebo group (n = 21). the mean (+/- SD) peak oxygen consumption (VO2) at baseline was 18.8 +/- 5.2 versus 18.5 +/- 5.5 ml/kg per min at 48 weeks (-1.4%. p = NS). In the enalapril group (n = 20). the corresponding values were 18.1 +/- 3.1 versus 18.3 +/- 2.6 ml/kg per min (+2.8%. p = NS). The mean VO2 at the anaerobic threshold for the placebo group at baseline study was 13.1 +/- 3.5 versus 12.8 +/- 2.1 ml/kg per min at 48 weeks (-2.2%. p = NS). The corresponding values for the enalapril group were 11.8 +/- 2.3 versus 11.8 +/- 2.4 ml/kg per min (+1.4%. p = NS). The mean total exercise duration in the placebo group at baseline study was 589 +/- 153 versus 620 +/- 181 s at 48 weeks (+5.4%. p = NS).
Pharmacokinetic analysis of coronary venous retroinfusion: a comparison with anterograde coronary artery drug administration using metoprolol as a tracer, Plasma and myocardial tissue concentrations of metoprolol were studied in ischemic and nonischemic areas of 22 pigs after 90 (n = 19) and 16 (n = 3) min of left anterior descending coronary artery occlusion. Group A (n = 6) received simultaneous intravenous metoprolol (0.2 mg/kg body weight) and tritium-labeled (3H)-metoprolol (0.2 mg/kg) retrogradely into the coronary vein. In group B (n = 5). metoprolol and 3H-metoprolol were administered in the same way. but at half the volume to study the influence of derived coronary venous pressure on the myocardial concentration of drug. In group C (n = 3). metoprolol was given retrogradely and saline solution was infused into the left anterior descending artery before induced death to wash out metoprolol from the coronary veins. To rule out a possible influence of the development of myocardial necrosis on drug distribution. metoprolol was retroinfused after 1 min of arterial occlusion in three pigs (group D). In group E (n = 5). metoprolol (0.2 mg/kg) was infused anterogradely into the left anterior descending artery. Peak plasma concentration was significantly higher after intravenous infusion of metoprolol (1.188 +/- 503 nmol/liter) than after coronary venous infusion (417 +/- 155 nmol/liter; p less than 0.001). In groups A and B. the nonischemic myocardial concentration of metoprolol was 250 to 300 pmol/g. whether the drug was infused intravenously or into the coronary vein. Coronary venous retroinfusion. however. resulted in a substantial accumulation of metoprolol in the ischemic myocardium. In group A pigs. subendocardial myocardial concentration was 16.800 +/- 7.774. mid-myocardial 39.590 +/- 18.043 and subepicardial 57.143 +/- 29.030 pmol/g (mean +/- SE). The ischemic myocardial concentration in pigs from group B was somewhat less pronounced. probably secondary to a lower coronary venous pressure (15 +/- 3 mm Hg) with the lower volume of infusion (6.1 +/- 0.3 ml) in group B compared with 32 +/- 5 mm Hg with a 14 +/- 1 ml infusion in group A. Coronary artery anterograde administration resulted in myocardial ischemic and nonischemic zone drug concentrations similar to those observed after retroinfusion into the coronary vein. With both modes of administration. there was a transmyocardial gradient from a somewhat lower drug concentration in the subendocardium. toward an increasing level in the mid-myocardium. to the highest concentration in the subepicardial zone of the ischemic myocardium. Coronary venous retroinfusion resulted in pronounced drug accumulation in the ischemic myocardium. The derived coronary venous pressure during infusion influenced the concentration of drug.(ABSTRACT TRUNCATED AT 400 WORDS).
Coronary venous retroinfusion of deferoxamine reduces infarct size in pigs, The efficacy of coronary venous retroinfusion of the iron chelator deferoxamine was studied in 24 pentobarbital-anesthetized open chest pigs with a 60 min occlusion of the left anterior descending coronary artery followed by 3 h of reperfusion. Eight retrogradely treated pigs were given 10 mg/kg body weight of deferoxamine by way of the anterior interventricular vein and eight systemically treated pigs received the same doses of deferoxamine intravenously. Drug infusions lasted for 5 min. beginning 15 min before reperfusion. Eight control pigs received systemic intravenous saline solution. Myocardial area at risk and necrotic area were assessed by the monastral blue dye and the triphenyltetrazolium chloride staining method. respectively. There were no significant differences in hemodynamics or regional myocardial function (sonomicrometry) among the groups. Infarct size expressed as percent of risk area was 73.9 +/- 13.5% in the control group. 70.6 +/- 16.4% in the systemically treated group and 48.5 +/- 21.4% (p less than 0.05) in the retrogradely treated group. In conclusion. deferoxamine significantly reduced infarct size after coronary occlusion only when given regionally by way of the coronary vein. Because there was no significant hemodynamic effect caused by deferoxamine infusion. it is suggested that this drug prevents postischemic reperfusion injury by a direct cardioprotective effect.
Cardioplegia by way of the coronary sinus for valvular and coronary surgery, Retrograde coronary sinus perfusion has recently reemerged as an attractive means of delivering cardioplegic solutions during open heart procedures. In patients undergoing aortic valve or aortic root surgery. there is no evidence that coronary sinus cardioplegia results in a better myocardial protection than that achieved with the use of standard methods of anterograde cardioplegia delivery. However. the retrograde approach provides distinct technical advantages that might favor its use as an alternative to direct coronary ostial cannulation. In select subgroups of patients undergoing coronary bypass procedures. there is a growing body of evidence that the coronary sinus route may be more effective than the anterograde route because of its superior capacity to ensure homogeneous distribution of cooling and cardioplegia in myocardial areas supplied occluded arteries. The well established safety of coronary sinus cardioplegia in the clinical setting further justifies its inclusion among techniques for ensuring adequate myocardial preservation during surgically induced ischemic arrest.
Antigenemia in the diagnosis and monitoring of active cytomegalovirus infection after liver transplantation, In 45 liver transplant recipients. the value of weekly monitoring of cytomegalovirus (CMV) antigenemia for early diagnosis of active CMV infection was compared with serology and rapid viral isolation. Active CMV infection occurred in 23 patients. The sensitivities of the antigenemia assay and serology (of blood) and rapid viral isolation (from blood or urine) were 96%. 96%. 57%. and 70%. respectively. First diagnostic results of these methods were obtained a median of 25. 36. 31. and 49 days. respectively. after transplant. CMV infection was symptomatic in 20 patients; antigenemia was present at the onset of disease in 13 of these. Maximum CMV antigenemia levels were higher in patients with severe disease than in those with mild or asymptomatic infection. CMV antigenemia is a sensitive. early. quantitative marker of active CMV infection after liver transplantation.
Simultaneous administration of two human-rhesus rotavirus reassortant strains of VP7 serotype 1 and 2 specificity to infants and young children, Two rotavirus vaccine strains representing VP7 serotypes 1 and 2 derived by reassortment between a rhesus rotavirus master strain. MMU18006. and either of two human rotavirus strains were administered simultaneously to infants and young children to assess potential interactions between strains. Children were observed in a day care setting for 10 days after vaccine administration for clinical symptoms. evidence of vaccine transmission. and patterns of viral shedding. Serum and local antibody responses were measured. The ratio of input virus strongly influenced the amount of each strain recovered from the child. Regardless of dose of virus administered. the neutralizing antibody response to the VP7 glycoprotein. the serotype determinant. was diminished in a bivalent preparation compared with a monovalent vaccine. Additional strategies must be sought to induce immunity against the multiple serotypes of human rotavirus before broad immunity will be established.
Application of hepatitis B virus (HBV) DNA sequence polymorphisms to the study of HBV transmission, Short sequences in hypervariable regions of the hepatitis B virus (HBV) genome can be used to identify different strains. providing a novel approach to the study of HBV transmission. The nucleotide sequence in positions 2551-2650 (1:EcoRI site) was determined for serum HBV DNA from 96 Chinese children living in Hong Kong and from 38 of their parents. HBV DNA was extracted and sequenced after amplification with the polymerase chain reaction. using as primers oligonucleotides corresponding to two conserved sequences. Among 82 unrelated children. 32 HBV DNA variants were present. One sequence was present in 33 children and 31 variants were found among the other 49. Siblings within each of nine families had the same variant; in three families siblings had different variants. Six of the eight fathers and 28 of the 30 mothers had HBV DNA sequences identical to those of their offspring. A total of 34 variants were found among the 134 individuals. The hypothesis of random assortment of sequences in parents and children was rejected (P less than .00005). Thus. this new approach proves the occurrence of intrafamilial transmission of HBV among Chinese.
Development of cross-reactive antibodies to plasminogen during the immune response to dengue virus infection, The four serotypes of dengue virus (a mosquito-borne flavivirus) cause an acute febrile illness (dengue fever) or a more prolonged illness with plasma leakage resulting in hypovolemia (dengue hemorrhagic fever). Hemorrhage may accompany either. Epidemiologic data suggest a role for dengue antibodies in pathogenesis. Computer analysis revealed a 20-residue region of similarity in amino acid sequence between the dengue type 4 envelope glycoprotein (E) and a family of clotting factors. including plasminogen. the prime mediator of fibrinolysis. By use of synthetic peptides in ELISA. E antibodies that potentially bind plasminogen were detected in 75% of 40 Thai patients acutely infected with dengue virus type 1. 2. 3. or 4. Plasminogen cross-reactivity of dengue antibodies was shown to be specific for the related sites in E and plasminogen. The dengue E sequence with similarity to plasminogen is largely conserved within the currently known flavivirus E sequences. However. 15 Thai patients hospitalized for illness caused by Japanese encephalitis virus (a flavivirus not associated with hemorrhage) did not develop plasminogen-cross-reactive antibodies. and this finding correlated with failure of Japanese encephalitis virus antibodies to bind to the plasminogen-cross-reactive site in E.
Intercontinental spread of a multiresistant clone of serotype 23F Streptococcus pneumoniae, Isolates of serotype 23F Streptococcus pneumoniae with high levels of resistance of penicillin have been commonly recovered in Spain for more than a decade. Recently penicillin-resistant serotype 23F S. pneumoniae strains were also isolated from children attending a day-care center in Cleveland. A number of Spanish and Cleveland isolates were compared by electrophoretic analysis of penicillin-binding protein (PBP) profiles and DNA restriction endonuclease cleavage profiles of the PBP 2X and 2B genes amplified with the polymerase chain reaction and by multilocus enzyme electrophoresis. All strains were identical by these criteria. The findings demonstrate that the Spanish and Cleveland isolates are clonally related and suggest that this antibiotic resistant clone of serotype 23F S. pneumoniae has spread intercontinentally from Spain to the United States.
Quantitative culture of bronchoalveolar lavage from patients with anaerobic lung abscesses, The study of anaerobic infections of the lung is usually limited to the use of invasive techniques such as transtracheal aspiration (TTA) to avoid contamination by oral flora. Bronchoalveolar lavage (BAL) has been used successfully in the study of the etiology of pneumonia in immunocompromised patients. This study evaluated the role of the quantitative culture of BAL in the diagnosis of lung abscess. Four episodes of lung abscess in three patients were studied. and the results of quantitative culture of BAL were compared with those of the standard technique of TTA. Nineteen anaerobic bacterial species were recovered from the BAL fluid. all but one at concentrations greater than 10(3) cfu/ml. Culture of BAL fluid yielded 18 of 22 of the isolates cultured from TTA. including 12 of 16 of the anaerobic bacteria. This study suggests that quantitative culture of BAL fluid may be useful in the bronchoscopic evaluation of lung abscess.
Comparative safety, tolerance, and pharmacokinetics of amphotericin B lipid complex and amphotericin B desoxycholate in healthy male volunteers, Amphotericin B lipid complex (ABLC). a lipid complex formulation of amphotericin B. and amphotericin B desoxycholate (AB) were compared for safety. tolerance. and pharmacokinetics in two groups of eight healthy male volunteers. After a 1-mg test dose. study drug was infused at 0.1. 0.25. and 0.5 mg/kg; the 0.5-mg/kg dose was not given to subjects receiving AB. ABLC caused few acute adverse effects except for mild somnolence (drowsiness) in six volunteers. In addition. three of eight ABLC recipient had asymptomatic. transient serum transaminase elevations that resolved spontaneously. The AB recipients experienced more acute side effects. but only one had a mild shaking chill: three of eight also experienced sleepiness. No significant changes in vital signs. electrocardiogram. oximetry. pulmonary function. or clinical status were observed in either group. Due to its increased estimate volume of distribution and estimated clearance. ABLC yielded decreased amphotericin B levels and area under the serum concentration versus time curve relative to AB.
Diagnosis of human African trypanosomiasis and visceral leishmaniasis based on the detection of anti-parasite-enzyme antibodies, A sensitive diagnostic assay for parasitic infections based on the detection of anti-enzyme antibodies is presented. All serum antibodies produced in response to parasite antigens are immobilized via their Fc domain on matrix-bound protein G. Incubation of the immobilized antibodies with saturating amounts of parasite extract results in the binding of all recognized antigens. including those directed against a specific and readily measurable enzyme. The amount of bound enzyme is proportional to the anti-enzyme antibody concentration in the serum. The application of this principle is demonstrated for the diagnosis of both human African trypanosomiasis and visceral leishmaniasis by the detection of antibodies against parasite acid phosphatases.
Lipoprotein composition and HDL particle size distribution in women with non-insulin-dependent diabetes mellitus and the effects of probucol treatment, To further characterize the spectrum of potentially atherogenic disturbances in lipoprotein composition in non-insulin-dependent diabetes mellitus (NIDDM). we have studied a subset of women with NIDDM before and after treatment with the lipophilic lipid-lowering drug probucol (1 gm day). which we have shown corrects certain compositional abnormalities these women share with subjects who have hypercholesterolemia. Before treatment. the NIDDM group had a somewhat higher plasma triglyceride level (154 +/- 58.3 mg/dl. vs control. 80.0 +/- 21 mg/dl [mean +/- SD]; p less than 0.025) than controls but their cholesterol and high-density lipoprotein cholesterol (HDL-C) levels did not differ from control levels. A number of significant disturbances. however. were present in the surface and core lipid composition of their lipoproteins. Although the cholesterol content of NIDDM low-density lipoprotein (LDL) was similar to that of controls. its content of sphingomyelin and phosphatidylinositol plus phosphatidylserine and sphingomyelin-to-lecithin ratio all were significantly reduced. Moreover. their very-low-density lipoprotein (VLDL) and HDL2 tended to have reduced amounts of free (unesterified) cholesterol (FC) relative to lecithin. and their HDL2 and HDL3 tended to be triglyceride enriched. Probucol therapy resulted in significant decreases in total plasma cholesterol (-15%). FC (-28%). HDL-C (-22%). and triglyceride (-16%) and in apoproteins A-I. B. and E (apo A-I. B. and E). without changing diabetic control (before probucol: hemoglobin A1. cholesterol. 10.7% +/- 2.7%; after probucol: 10.9% +/- 3.0%).
Glomerular hemodynamic effects of dietary polyunsaturated fatty acid supplementation, Dietary supplementation with polyunsaturated fatty acids (PUFAs) has been shown to alter the course of experimental renal disease. Although hemodynamic factors such as glomerular hypertension are felt to be important in the progression of renal disease. the effects of dietary PUFA supplementation on glomerular hemodynamics are unknown. The present investigation. therefore. was designed to evaluate the glomerular hemodynamic effects of dietary PUFA supplementation in normal rats. Male Sprague-Dawley rats were fed standard chow supplemented with either 20% (wt/wt) fish oil (FO) as a source of omega-3 PUFAs. 20% sunflower oil (SO) as a source of omega-6 PUFAs. or 20% coconut oil (CO) as a control diet. Micropuncture studies were performed after 4 to 6 weeks of dietary supplementation. Compared with CO rats. SO rats did not demonstrate any changes in glomerular hemodynamics. However. rats supplemented with FO demonstrated significant (p less than 0.05) increases in both single nephron glomerular filtration rate and single nephron plasma flow. These hemodynamic changes were not associated with alterations in glomerular capillary hydraulic pressure or the glomerular ultrafiltration coefficient. The increase in SNPF was primarily the consequence of a 37% reduction (p less than 0.05) in efferent arteriolar resistance. Thus dietary FO supplementation resulted in glomerular hyperfiltration and hyperperfusion. These hemodynamic actions may have important consequences in determining the effect of omega-3 PUFAs on the course of experimental and clinical renal disease.
Clearance and synthesis rates of beta 2-microglobulin in patients undergoing hemodialysis and in normal subjects, Retention of beta 2-microglobulin in patients undergoing hemodialysis is associated with a beta 2-microglobulin-derived amyloidosis. Removal of beta 2-microglobulin by renal replacement therapy has been proposed for the prevention of this amyloidosis. Currently. however. data on the beta 2-microglobulin synthesis rate in patients undergoing hemodialysis are scarce. and consequently it remains speculative how much removal would be necessary to counterbalance synthesis. The plasma kinetics of iodine 131-labeled beta 2-microglobulin were therefore examined in 11 patients with anuria who were undergoing long-term hemodialysis. Five healthy persons served as controls. Kinetic modeling of the plasma curves showed that the data fitted a two-pool model (r2 greater than 0.96) consisting of a rapid 2 to 4 hour distribution phase followed by a less steep curve. described by the plasma (metabolic) clearance (Clp). Synthetic rates were calculated from Clp and the beta 2-microglobulin steady state plasma concentration (plus beta 2-microglobulin removal during hemodialysis in the case of high flux hemodialysis). The results showed a significantly higher Clp in normal controls as compared with patients undergoing hemodialysis (65.5 +/- 12.8 ml/min (mean +/- SD) versus 3.4 +/- 0.7 ml/min). In contrast. the beta 2-microglobulin synthesis rate in the patient group (3.10 +/- 0.79 mg/kg/day) was not significantly different from that of normal controls (2.40 +/- 0.67 mg/kg/day). which was due to markedly elevated beta 2-microglobulin plasma concentrations in the patients (37.6 +/- 14.1 mg/L vs 1.92 +/- 0.27 mg/L). These findings suggest that the presence of end-stage renal disease does not have a significant impact on the beta 2-microglobulin generation rate. The degree of accumulation of beta 2-microglobulin in patients undergoing hemodialysis seems to depend on the loss of renal excretory function.
Carotenoids and liposoluble vitamins in liver cirrhosis, The role played by carotenoids. retinol and tocopherol in quencing oxidative cellular damage and combatting tumor growth is well documented. but little is known about their activity in human liver cirrhosis (LC). where oxidative damage and tumoral complications are common-place. We investigated 59 patients with LC of different etiology on admission to hospital and compared them with 32 healthy controls. matched for age and sex. Nutritional (cutaneous skinfolds. creatinine-height index) and serum parameters were determined; of these. alpha- and beta-carotene. cryptoxanthin. lycopene. retinol and alpha-tocopherol were detected by an high-performance liquid chromatographic (HPLC) technique. devised in our laboratory. which afforded an accurate and simultaneous resolution of all six compounds. The results point to a significant reduction in almost all the vitamin factors in LC. as well as in total serum lipids. In consequence. the ratio tocopherol/total serum lipids remains almost unchanged: 2.45 +/- 0.08 (m +/- se) in controls and 2.34 +/- 0.16 in patients. The effects of age. sex. nutritional habits. alcohol. malnutrition and the severity of the disease were also evaluated in relation to the vitamin-factor levels. It is suggested that the reduced levels observed in LC patients are due to a number of factors including portal hypertension and lymphatic circulation impairment. and it is concluded that thorough screening and improved diet are beneficial in the follow-up of LC.
Interpretation of unusual wounds caused by firearms, The interpretation of the range of fire of gunshot wounds requires coordination of information and observations from the autopsy surgeon. scene investigator. and laboratory analyst. Opinions based on incomplete information often lead to misinterpretation of the wound. The effects of interposed targets such as clothing. windows. and body parts are discussed. Case examples are given for interposed targets that cause confusing patterns and even lead to misidentification of the points of entrance and exit of the projectile in the body. The splitting of tissue in areas of bony prominence can be mistaken for evidence of discharge of a firearm at close range.
Comparison of insect species associated with decomposing remains recovered inside dwellings and outdoors on the island of Oahu, Hawaii, A comparison of insects collected from 35 cases of decomposing remains on the island of Oahu. Hawaiian Islands (14 from indoor situations and 21 from outdoors). yielded a total of 22 species of insects in 3 orders and 12 families. Of these. five species were recovered in both indoor and outdoor situations. Remains recovered indoors had a greater variety of Diptera larvae associated with them. while remains discovered outdoors had a greater variety of Coleoptera species present. Some species of insects were restricted to remains discovered indoors. while others were found only associated with remains in outdoor situations. Knowledge of the species of insects associated with different habitats may serve to provide information concerning the history of the remains.
Alcohol addiction of methamphetamine abusers in Japan, Fifty-eight methamphetamine (MAMP) abusers were surveyed to demonstrate the types of nature of MAMP abuse. In-depth interviews using psychophysiological techniques assessed the subjects to be truthful or deceptive about their abuse histories. Research diagnostic criteria determined the subjects clinical symptoms. The results show that three factors characterize MAMP abuse: significant correlation was found between the years of abuse; the manifestation of somatic or mental disorders or both. and alcohol (Alc) addiction. MAMP abusers who were nondrinkers or light drinkers developed a tendency to dislike Alc after MAMP abuse. while there was no change in Alc consumption in heavy drinkers. The findings suggest that the combined abuse of MAMP and Alc aggravates somatic and mental disorders and that Alc plays an important role in the fatal effect of MAMP. especially from small doses. This provides support for the synergistic effects between MAMP and Alc. Coadministration of MAMP and Alc appears to produce long-acting and more complicated changes in the brain's neurotransmitter function.
Cerebral tissue pulmonary embolization due to head trauma: a case report with immunohistochemical confirmation, Pulmonary embolization of cerebral tissue as the result of severe head trauma is an uncommon. if not rare. phenomenon. and few cases have been reported in the literature. The authors discuss the case of a 51-year-old male who died six days after suffering extensive head trauma in a motor vehicle collision. At autopsy. white-gray emboli were found in several subsegmental pulmonary arteries. The results of histologic examination with the hematoxylineosin stain gave the impression that the emboli were necrotic cerebral tissue; however. routine special stains for neural tissue produced inconclusive results. Immunohistochemical staining of the emboli with monoclonal mouse anti-human neurofilament protein (Dako Corp.. Carpinteria. California) confirmed the cerebral nature of the emboli. To the authors' knowledge. this is the first reported case of pulmonary embolization of cerebral tissue confirmed by immunohistochemistry.
Individualization and enamel histology: a case report in forensic anthropology, The cranium of a native Indian child about six years old was found in 1979 near Taseko River. British Columbia. Canada. While the remains matched the report of a child missing for eight years in terms of race. age at death. locale. and elapsed time since death. the cranium and dentition were basically unidentifiable because of the claimed lack of medical or dental history. There was no dental work. and the parents were unknown or dead. We report the presence. in the dental enamel of the primary and secondary dentition. of stress markers. termed striae of Retzius. whose locations correspond well with anecdotal reports and recently discovered medical records which describe the timing of specific episodes of stress. The enhanced probability of personal identification from dental histological stress markers is evaluated.
Alexithymic characteristics and metabolic control in diabetic and healthy adults, Diabetes has long been identified as a disease with possible psychological components. Alexithymia--an inability to express emotions verbally. operational thinking. and a lack of fantasy life--is found in a high proportion of psychosomatic patients. We therefore tested the hypothesis that diabetics would be more alexithymic than controls. In addition. the lack of awareness of affect was hypothesized to have negative consequences for the management of diabetes. as reflected in metabolic glucose control (HbA1). The number of emotion words produced in six imaginative (Thematic Apperception Test) stories was used as the measure of alexithymia. with few words reflecting alexithymic characteristics. Diabetics were found to be significantly more alexithymic than controls. Further. fewer emotion words (alexithymia) was associated with poorer metabolic control. These data suggest that alexithymic characteristics may interfere with a diabetic's ability to manage their illness. and support previous research showing that the suppression of emotions can lead to a difficulty in regulating glucose levels.
A short plasma exchange protocol is effective in severe myasthenia gravis, Plasma exchange has been reported to be a successful therapeutic procedure for the treatment of severely compromised myasthenic patients. but the optimal regimen in terms of costs or clinical benefit has not so far been determined. We have investigated the efficacy of a short plasmapheresis protocol of two exchanges 1 day apart in a series of 70 patients with severe forms of myasthenia gravis. Patients were evaluated before and 7 days after the first exchange. A positive outcome was observed in 70% of the plasma exchange cycles performed. Disease severity did not seem to be a negative prognostic factor for the efficacy of this short protocol. which was well tolerated by patients. In only 1 case were major side-effects observed. In spite of its short duration. the exchange treatment plus concomitant immunosuppressive drug therapy was not followed by early clinical deterioration.
Assessment of proliferative potential in gliomatosis cerebri, The proliferative potential of neoplastic cells in two cases of gliomatosis cerebri was investigated by a combined staining technique. a one-step silver colloid method for nucleolar organizer region-associated protein (AgNOR) and immunohistochemistry for fibrillary acidic protein (GFAP). The neoplastic cells in the two cases had an abnormal shape and showed positive GFAP immunostaining in their cytoplasm. The numbers of AgNORs were counted in central and peripheral lesions of the neoplastic field in each case. The mean AgNOR scores in neoplastic cells were almost the same as those of nonneoplastic astrocytes in both the central and the peripheral lesions. These values were almost equal to the AgNOR score of low-grade gliomas. These findings indicate that gliomatosis cerebri has an invasive character in the central nervous system and often shows a malignant tendency. but its proliferative potential is significantly lower than that of high-grade gliomas.
Transepithelial transport of HIV-1 by intestinal M cells: a mechanism for transmission of AIDS, This study was designed to determine whether human immunodeficiency virus type 1 (HIV-1) might enter the host by penetrating epithelial barriers through antigen-transporting M cells in lymphoid follicle-associated epithelia. Interaction of HIV-1 with epithelial cells was examined using mucosal explants from Peyer's patches of mice and rabbits. HIV-1 adhered to the luminal membranes of M cells of both species. and was endocytosed and delivered to intraepithelial spaces containing lymphocytes and macrophages. These observations suggest that M cells. which are numerous in the human rectal mucosa. may efficiently deliver HIV-1 to target cells in mucosal lymphoid tissue. and that such transport may contribute to sexual transmission of AIDS.
HIV-1 proviral copy number in blood mononuclear cells from AIDS patients on zidovudine therapy, The effect of treatment with 400-1.200 mg/day of zidovudine (ZDV) on HIV DNA concentrations in patient peripheral blood mononuclear cells (PBMCs) was studied in six patients during a 5- to 14-month period of therapy. HIV DNA was measured in PBMCs at intervals using a recently developed quantitative polymerase chain reaction assay. The amount of HIV DNA ranged from 2.000 to 40.000 copies of provirus per microgram of cellular DNA. The HIV provirus copy number showed little change with time in five patients. and increased and then remained constant in one patient. Thus. prolonged treatment with ZDV does not decrease the levels of HIV DNA in PBMCs.
Norepinephrine response in early HIV infection, Norepinephrine response to a cold pressor test was investigated in 95 homosexual men in a longitudinal study of human immunodeficiency virus (HIV) infection. The baseline data obtained from 76 HIV+ and 19 HIV- subjects are included in this report. After the insertion of a venicatheter and following a 30 min rest. subjects immersed one of their hands in ice water for 2 min. and serial blood samples were obtained for the determination of catecholamine levels. The results show that the norepinephrine response in HIV+ subjects compared to that of HIV- subjects was blunted. Examination of the responses using linear and quadratic orthogonal polynomials suggested that these differences between the two groups were primarily a function of their rate of increase in norepinephrine levels. It was observed also that in HIV+ subjects. norepinephrine level peaked earlier than that in HIV- subjects. The data suggest that autonomic dysfunction is present in the early stages of HIV infection.
Transfusion-associated AIDS cases in Europe: estimation of the incubation period distribution and prediction of future cases, European data on transfusion-associated (TA) AIDS cases reported by December 31. 1989 have been analyzed using both parametric and nonparametric methods. Parametric estimates of the median incubation period of TA AIDS in adults vary from 6.5 to 11 years according to the type of distribution assumed (Weibull or gamma) and the latest year of diagnosis included (1987 or 1988). The latter finding may reflect a lengthening of the incubation period due to increasing treatment of HIV-infected patients prior to the development of AIDS. It is predicted that. by the end of 1991. between 2.000 and 3.000 cases of AIDS will have been diagnosed in Europe among adults infected by transfusion between 1978 and 1985 (when systematic screening of donated blood was introduced in most western countries). It is not possible. however. to predict how many further cases may arise among those transfused more recently in countries in which screening was introduced at a later date.
An evaluation of the polymerase chain reaction in HIV-1 seronegative men, The apparent detection of human immunodeficiency virus (HIV-1) DNA by the polymerase chain reaction (PCR) in seronegative individuals has been the subject of great concern. In this study. 324 seronegative participants in the San Francisco Men's Health Study were evaluated for evidence of infection using a PCR testing algorithm with multiple amplifications targeting different regions of the HIV-1 genome. While most PCR reactions were negative. 8.6% of the specimens showed weak reactivity with one or more primer sets. However. all were negative with at least one primer set and no definitively positive specimens were identified. This study addressed the possibility that some of these PCR reactions might represent latent infection or abortive exposure. leaving residual integrated DNA. rather than false-positive reactions. The frequency of such reactions was determined in homosexual men who have been at risk for HIV-1 infection and in exclusively heterosexual men who have little or no past exposure. The results demonstrate an identical frequency and distribution of equivocal PCR reactions in both populations. Assuming that there is minimal HIV-1 infection among seronegative heterosexual men in San Francisco. we conclude that PCR testing does not provide evidence for a reservoir of occult HIV-1 infection in seronegative homosexual men.
Long acting drug combinations in rheumatoid arthritis: a formal overview, We compared the benefits and risks of combinations of long acting antirheumatic drugs with those of the same drugs used singly in the treatment of rheumatoid arthritis. We searched the literature through MEDLINE (1966-89). Index Medicus (1956-65). Excerpta Medica (1982-89). Science Citation Index (1982-89). and bibliographic review of located articles. Of a total of 341 citations. we identified 7 prospective trials that specifically addressed the stated purpose. We independently assessed the quality of the selected trials. using published methodological criteria and summarized the effect of treatment on arthritis activity and the incidence of side effects. The trials we evaluated tested various drug combinations. Because of deficiencies in methods and reporting. only 3 trials had sufficient quality to yield strong or moderately strong evidence. None conclusively demonstrated benefit of a drug combination: 2 suggested such benefit. including 1 also suggesting increased toxicity; the 3rd suggested only increased toxicity. The other 4 trials yielded weak evidence to support both increased efficacy and toxicity. The advantages of any antirheumatic drug combination remain unproven. Because these advantages are likely to be modest. they can only be shown in rigorously designed trials enrolling large numbers of patients. Methods and reporting of antirheumatic drug trials should be standardized to allow combining of study results.
Methotrexate in rheumatoid arthritis: effects on disease activity in a multicenter prospective study, One hundred and twenty-three patients with rheumatoid arthritis (RA) who successfully completed a randomized trial comparing oral methotrexate (MTX) to auranofin enrolled in a longterm prospective study of oral MTX. Of the 91 patients who completed 24 months of therapy. a significant (p = 0.0001) improvement was noted compared to baseline in all clinical disease variables and the Westergren erythrocyte sedimentation rate (ESR). Marked improvement occurred in 94 (76%) and 98 (80%) of the patients in the joint pain/tenderness index and joint swelling index at the last evaluable visit (mean 26 months). Of the 77 patients with an elevated ESR at baseline. 29 (38%) patients normalized it (less than 20 mm/h) while receiving therapy (p less than 0.01). A significant reduction in prednisone dose was also seen. Adverse events occurred frequently but were generally mild in severity. Twenty-seven patients (22%) withdrew during the study. Four (3%) withdrew due to lack of efficacy. and 6 (5%) because of adverse experiences. The overall probability of continuing therapy in the study for 48 months was projected at 72%. This large prospective study supports the observation of earlier smaller studies that MTX is an effective drug in the treatment of RA.
Low dose prednisone does not affect calcium homeostasis or bone density in postmenopausal women with rheumatoid arthritis, To assess whether low doses of prednisone produce generalized alterations in skeletal homeostasis in rheumatoid arthritis (RA). indices of calcium metabolism and bone mineral density (BMD) were measured in 22 women with RA treated without or with prednisone (6.6 mg daily). Ionized and total calcium concentrations. intact parathyroid hormone (PTH) and osteocalcin levels were comparable in the 2 groups. BMD measurements in the lumbar spine. and proximal femur sites including the femoral neck. Ward's triangle. and trochanteric region were not significantly different in patients with RA treated without or with prednisone. In our experience low dose prednisone did not adversely affect indices of mineral metabolism. or bone density in RA.
Specificity, sensitivity and diagnostic predictive value of selected laboratory generated autoantibody profiles in patients with connective tissue diseases, We tested the hypothesis that the application of 5 laboratory generated serologic profiles facilitates the interpretation of individual autoantibodies in connective tissue diseases without loss of specificity. sensitivity or diagnostic predictive value. The predetermined laboratory generated autoantibody profiles were analyzed in 423 sera from patients with clinically diagnosed connective tissue diseases. All sera positive for one or more autoantibodies to a selected panel of nuclear antigens could be segregated into one of 5 profiles. The distribution of individual autoantibodies and profiles in the sera of patients with various connective tissue diseases were compared in terms of their respective diagnostic predictive value and sensitivity. The application of these profiles improved the sensitivity and diagnostic predictive value of these tests when compared to individual autoantibodies without loss of specificity. thus aiding clinical interpretation.
Changes in levels of antibodies against the 70 kDa and a polypeptides of the U1RNP complex in relation to exacerbations of systemic lupus erythematosus, In order to investigate whether disease exacerbations of systemic lupus erythematosus (SLE) are accompanied or preceded by changes in antibody levels against the U1RNA associated 70 kDa and A polypeptides. we prospectively collected plasma specimens from 71 patients with SLE. We compared changes in anti-70 kDa/anti-A levels. measured by ELISA using cloned antigens. with changes in levels of anti-dsDNA and total IgG. Measurable levels of anti-70 kDa (n = 10) and/or anti-A antibodies (n = 6) were detected during 10 exacerbations. Four of the 10 exacerbations with a measurable level of anti-70 kDa antibodies were preceded by a significant rise in anti-70 kDa levels. 2 by a significant fall. while levels of anti-70 kDa did not change in the remaining 4 cases. Only one of the 6 exacerbations with detectable anti-A antibody levels was preceded by a significant rise in anti-A antibodies. while levels did not change before exacerbation in the other 5 cases. Six of the 10 exacerbations were preceded by a significant rise in anti-dsDNA; in 4 cases levels of anti-dsDNA did not change before exacerbation. In contrast to anti-dsDNA. no relation was found between changes in levels of anti-70 kDa/anti-A and changes in disease activity. Significant changes in levels of anti-70 kDa/anti-A. occurring in 6 cases. were accompanied by parallel changes in total IgG in 5 of these 6. We conclude that. in contrast to anti-dsDNA. serial measurement of levels of anti-70 kDa/anti-A is not useful for monitoring disease activity or predicting disease exacerbations in SLE.
Detection of circulating endothelial antigen, In order to determine whether endothelial cell antigens are detectable in serum from patients with rheumatic disease characterized by vascular involvement. we developed an ELISA using a monoclonal antibody directed against a 92.000 molecular weight endothelial cell specific antigen designated E92. Sera were assayed from 191 patients and 34 healthy controls. E92 was undetectable or present in very low concentrations in healthy controls and was elevated in most patients with an active rheumatic disease. Our results indicate that circulating endothelial antigens are present in rheumatic vascular syndromes and may provide a measure of endothelial cell function.
Supravital staining of cells in noninflammatory synovial fluids: analysis of the effect of crystals on cell populations, Leukocyte differential counts are rarely performed on synovial fluids (SF) with low leukocyte (WBC) counts as they have been difficult to do with standard Wright stains. We performed SF analysis including supravital (SV) stains for differential counts on 100 consecutive relatively noninflammatory synovial fluids defined as any SF with less than 2.000 cells/mm3. SV stains gave clear cellular morphology. Monocytes were the most prominent cells in all noninflammatory synovial fluids. Thirty-eight fluids were found to have crystals (monosodium urate (MSU) in 15. calcium pyrophosphate dihydrate (CPPD) in 5. CPPD plus apatite-like crystals in 9. apatite-like clumps alone in 8 and lipid liquid in 1). WBC counts. percentages of polymorphonuclear (PMN) and absolute PMN counts were greatest in fluids with MSU or CPPD crystals. Fluids with apatite-like clumps alone tended to have the lowest WBC counts. The presence of WBC over 500 cells/mm3. over 20% PMN and absolute PMN counts over 250 cells/mm3 should encourage a careful search for crystals. especially MSU. in noninflammatory synovial fluids.
Clinical usefulness of amitriptyline in fibromyalgia: the results of 23 N-of-1 randomized controlled trials, Twenty-three double blind. randomized. multiple crossover trials (N-of-1 RCT) of amitriptyline were conducted in patients with fibromyalgia. The benefit of amitriptyline was assessed using a symptom questionnaire and count of tender points. To assess the usefulness of the method. the proportion of trials that provided a definite answer was examined. Completing the trial resulted in reaching a high degree of confidence in the final management decision in 74% of trials. In 35% of trials. results led to discontinuation of the drug which otherwise would have been continued indefinitely. The drug benefit. if present. was evident within first 2 weeks of therapy. We concluded that these results support the feasibility and usefulness of N-of-1 RCT in rheumatology practice.
Giant cell arteritis presenting as limb claudication. Report and review of the literature, Upper limb claudication and pulselessness is an uncommon presentation of giant cell arteritis (GCA). often resulting in delayed diagnosis. We describe such a case diagnosed by angiography. in which a temporal artery biopsy showed classic GCA. despite the absence of local signs or symptoms. A review of 26 similar cases revealed that in 81% of patients where the only manifestation of GCA was upper limb findings. temporal artery biopsy yielded positive findings. Steroid therapy clinically improved 24/26 patients. These findings suggest that a consideration of temporal artery biopsy early in the investigation will hasten diagnosis and appropriate therapy.
Stryker frame gantry modification for extracorporeal shock wave lithotripsy to circumvent positioning problems, From July 1986 through December 1989. 45 patients with renal or biliary calculi were treated on a Dornier HM3* lithotriptor using a Stryker frame gantry modification. The modification was necessary due to inability to position the patients in the standard gantry. The situations that required nonstandard positioning techniques included stones in the distal or mid ureter. renal transplant. gallbladder or common bile duct. and unusual body habitus. such as myelomenigocele. bilateral lower extremity amputations and children with stones. Positioning with adequate focus of the shock wave was achieved in 87% of the patients and fragmentation was achieved in 89%. The Stryker frame gantry modification is an excellent method to circumvent positioning problems with the Dornier HM3 lithotriptor. extending lithotripsy capability to patients who might otherwise not be candidates.
The use of local anesthesia in second generation extracorporeal shock wave lithotripsy: eutectic mixture of local anesthetics, Extracorporeal shock wave lithotripsy (ESWL&) can be painful. Of our population of patients treated with a Siemens Lithostar device 51.4% needed intravenous analgesia. A eutectic mixture of local anesthetics. a hydrophylic cream containing 25 mg. lidocaine and 25 mg. prilocaine per gm.. proved to be effective for local analgesia. Therefore. we investigated its effectiveness during ESWL. With randomized. double-blind application the eutectic mixture of local anesthetics and placebo were evaluated in 83 patients according to the percentage of patients who required intravenous analgesia during ESWL. Of 40 patients treated with the eutectic mixture of local anesthetics 12 (30%) needed supplementary fentanyl citrate. compared to 23 of 43 (53%) placebo treated patients. Although there is no statistical significance (p = 0.32). the eutectic mixture of local anesthetics does decrease pain during ESWL and it should be particularly useful for patients in whom intravenous analgesia is contraindicated.
Equivalence of mobile and fixed lithotriptors for upper tract stones, Although mobile renal lithotripsy appears to be a cost-efficient method for a urologist to treat patients at the local hospital the quality issue has been raised with occasional use of a mobile lithotriptor. We reviewed 4.278 kidneys in 3.900 patients treated by 129 urologists using a mobile Dornier HM3 and a mobile Medstone lithotriptor at 21 mobile sites in 6 upper midwest states during 3 1/2 years. These results were compared with those in 524 kidneys in 480 patients treated by our fixed Medstone lithotriptor. After the procedure auxiliary treatments were needed in 3% of the patients treated with the mobile units and 2% of those treated with the fixed unit. The rate in 2 large published series was approximately 9%. The retreatment rates were 5% with the mobile lithotriptors and 6% with the fixed (reported average 16%). and the over-all stone-free rates at 3 months were 69% and 68% (versus 66%). Of note. the mobile units were as effective as the fixed unit against difficult stones. A mobile lithotriptor with a constant support staff that is used 1 or 2 times per month by many trained urologist will perform as well as fixed lithotriptor used regularly by a small unvarying staff of trained urologists.
Particle shedding and migration from silicone genitourinary prosthetic devices, Of 26 patients undergoing revision of genitourinary prostheses the surrounding reactive fibrous capsule was biopsied in 25 and the draining lymph nodes also were biopsied in 4. The prostheses included 16 inflatable and 14 flexible penile devices. and 10 artificial urinary sphincters. Tissue was examined by light and transmission electron microscopy. X-ray microanalysis was done on intracellular and extracellular foreign material from each specimen. Silicone was found in 18 of the 25 periprosthetic specimens and in all 4 lymph nodes. Foreign body granulomas were identified in 14 of these 29 specimens. Examination of new and explanted versions of each prosthesis by scanning electron microscopy revealed free particles of silicone or silicates on the surface of most devices. Pitting and microfissuring were seen on a few of the new devices and on nearly all of the used ones. Thus. genitourinary prostheses shed silicone particles that can be found in the fibrous capsule and draining lymph nodes.
Treatment of pharmacological priapism with phenylephrine, Pharmacological prolonged erections or priapism due to anesthesia were treated in 36 patients with intracorporeal injections of phenylephrine. Detumescence was obtained rapidly in every case and no marked side effect was reported. Considering the possible toxicity of other adrenergic agents. phenylephrine is strongly recommended in the treatment of priapism.
The surgical treatment of chordee without hypospadias in men, During a 2-year period we treated 26 young men for chordee without hypospadias. Many of these patients had straight erections as children but a ventral curvature developed as they achieved puberty. We describe the anatomical findings and discuss the possible cause for the development of this anomaly. Surgical therapy begins with a circumcising incision and reflection of the skin to expose the shaft of the penis. The corpus spongiosum containing the urethra was mobilized by resecting the dysgenetic tissue in the dartos and Buck's fascia layers. In 1 patient this dissection was sufficient to straighten the penis but in the remaining 25 the penis was not straight. In those patients we mobilized the dorsal bundle of vessels and nerves. and removed 1 or several ellipses of tunica albuginea to equalize the lengths of the ventral and dorsal aspects of the corpora cavernosa. The corpus spongiosum usually is elastic and the curve almost never is caused by shortness of the urethra. which stretches to fit the straightened penis. In 24 of the 26 patients the curvature was resolved with 1 operation. while 2 needed a second procedure.
Transrectal ultrasonography in stage A prostate cancer: detection of residual tumor after transurethral resection of prostate, To evaluate the ability of transrectal ultrasonography to detect residual cancer in the prostate gland after transurethral resection in patients with stage A cancer. we studied 38 patients with stage A disease (11 stage A1 and 27 stage A2) in whom transrectal ultrasonography was done at least 3 weeks after resection. Each patient underwent radical prostatectomy. and residual cancer was present in 97% of the specimens (peripheral zone cancer in 95% and transition zone cancer in 61%). At sonography we identified hypoechoic areas suggestive of cancer in 10 patients (26%). In the pathological specimen residual cancer was present at the hypoechoic area in 8 of these cases (positive predictive value 80%). In a retrospective review of the sonograms we identified 25 hypoechoic lesions greater than 5 mm. in diameter. including 15 that corresponded to cancer in the radical prostatectomy specimens (positive predictive value 60%). Granulomas due to the transurethral resection were found in 92% of the radical prostatectomy specimens but none appeared hypoechoic on ultrasound. A total of 103 separate cancers was identified in the whole mount step sections of the radical prostatectomy specimens (2.7 cancers per patient). Of the 103 separate cancers 54 were less than 0.1 cc in volume and none of these could be identified in the retrospective review of the sonograms. 37 were 0.1 to 1.0 cc and 5 of these (14%) appeared hypoechoic. and 12 were greater than 1.0 cc and 10 of these (83%) appeared hypoechoic. Hypoechoic lesions greater than 5 mm. in diameter in the transition zone proved to be cancer in 47% of the cases. while 88% of similar lesions in the peripheral zone proved to be cancer. We conclude that suspicious-appearing hypoechoic lesions suggestive of cancer. whether in the peripheral zone or the transition zone. should be biopsied before expectant management of stage A prostate cancer is considered. Transrectal ultrasonography is useful for restaging after transurethral resection and for evaluating the extent of residual cancer in stages A1 and A2 prostate cancer.
Traumatic disruption of the ureteropelvic junction managed by ileal interposition, The use of ileal interposition in the management of a patient with delayed diagnosis of traumatic disruption of the ureteropelvic junction is presented. The unusual presentation of this problem. potential options in reconstructing the ureter and successful outcome are discussed.
Ureteronephroscopic marsupialization of obstructing peripelvic renal cyst, Flexible ureteronephroscopy has been used for numerous therapeutic applications in the upper urinary tract. We report a case of a large peripelvic renal cyst causing obstruction to the ureteropelvic junction. which was treated by incising the wall of the cyst into the renal pelvis with the ureteronephroscope.
Effects of sensitization on female guinea pig urinary bladder function: in vivo and in vitro studies, Although bladder inflammation is known clinically to produce a variety of symptoms including urgency. frequency. and pain. there are only a few experimental studies that directly relate bladder inflammation with urodynamic and functional alterations. We have used the sensitized guinea pig model to study the effects of inflammation on micturition parameters. cystometry. and in vitro bladder contractility. This model depends on the allergic response of the bladder mucosa to ovalbumin. an otherwise non-irritative agent. as an antigen. In vivo exposure of the bladder to ovalbumin via urethral catheterization induced a prompt and marked increase in the number of micturitions in antigen-sensitized guinea pigs. Ovalbumin had no effects on the micturition parameters in the control group. Using in vivo cystometry. intravesical exposure to ovalbumin induced a significant decrease in both the pressure at which micturition was induced. and the volume at which micturition was induced. Ovalbumin had no effect on cystometric parameters of the control animals. In vitro exposure of whole-bladder preparations to ovalbumin induced a significant contractile response only in the bladders isolated from the sensitized guinea pigs. The responses of the isolated bladders to field stimulation and bethanechol were identical for bladders from both sensitized and control animals. In conclusion. exposure of the bladder to ovalbumin in the sensitized animal induced an increase in the frequency of micturitions and a decrease in the pressure and volume at which micturition was induced. Thus. intravesical exposure of the bladder mucosa to a substance that the bladder has been sensitized to can induce alterations in micturition that are consistent with the clinical symptoms of "urgency and frequency".
Nerve growth factor, nerve grafts and amniotic membrane grafts restore erectile function in rats, In an effort to reduce complications arising from radical pelvic surgery. an improved technique for restoration of autonomic innervation has been developed. The ability of nerve growth factor (NGF) alone or in combination with interposition nerve grafts. as well as the use of fetal amniotic membrane as an alternative growth matrix to enhance regeneration of ablated cavernous nerves were investigated in rats. Rats with ablated cavernous nerve displayed little or no penile erection. either in response to direct electrical stimulation or to an estrous female rat. A step wise improvement in electrically induced erections was observed by NGF alone. nerve graft alone. and the combination of NGF and nerve graft. Restoration of sexual behavior followed the same pattern obtained with electrical stimulation. Furthermore. the use of neonatal amniotic membrane as an alternative nerve growth matrix enhanced both electrically stimulated erection and mating behavior. These results suggest that the use of NGF and appropriate grafting materials can facilitate autonomic nerve regrowth and potentially reduce the morbidity of surgically induced nerve injuries.
Injury to the pre-pubertal vas deferens. I. Histological analysis of pre-pubertal human vas, There is very little information in the literature on the development of the human vas deferens. Therefore. the age at which the pre- or para-pubertal vas deferens becomes large enough for a vasovasostomy to be technically feasible is unknown. To determine the age or degree of sexual maturity at which a microscopic vasovasostomy is technically feasible. we collected surgical or autopsy vasa from 34 young males over a three year period. and correlated vasal size to age and Tanner stage (degree of sexual maturity ranging from 1-childhood to 5-adult). The specimens were embedded and sectioned transversely in glycol methacrylate. Using image analysis. the total transverse area and diameter. and luminal area and diameter was determined for each specimen. Surprisingly. there was no change in vasal size from birth up through 11 years. From age 15 years and on. the vas was adult in size. The vas develops to adult size between Tanner stages 2 and 3. The average external and luminal diameters of pre-midpuberty specimens (Tanner stages 1 and 2) were 1.0 and 0.19 (mm.) and the diameters of post-midpuberty specimens were 2.1 and 0.43 (mm.). respectively. These results suggest that. in the event of a recognized iatrogenic injury to the vas deferens after midpuberty. a repair by a traditional microsurgical vasovasostomy is possible. If the vas is injured before midpuberty it may be technically difficult to repair by traditional microsurgical methods.
Changes in bladder function in the one year spontaneously diabetic BB rat, Micturition characteristics and in vitro urinary bladder function were investigated in insulin-treated spontaneously diabetic BB rats and age-matched non-diabetic controls one year after the onset of diabetes. BB rats weighed less than controls and were hyperglycemic. Diabetic rats consumed larger volumes of water and excreted larger volumes of urine than controls. The frequency of micturitions and the mean volumes of urine excreted per micturition were significantly increased in BB rats compared to age-matched controls. Associated with the micturition changes in the BB rats were significant increases in bladder body mass. Contractile responses of strips from bladder bodies and bases were measured in response to nerve stimulation. carbachol. phenylephrine. ATP. and KCl. No significant differences between controls and diabetics were found in the absolute contractile responses of bladder body strips to nerve stimulation. carbachol. ATP. or KCl. However. if the data were transformed to correct for the increases in tissue mass in the diabetics. there were significant decreases in the responses of bladder body strips from BB rats to carbachol. ATP. and KCl. but not to nerve stimulation. Even after transformation. there were no differences in the responses of bladder base strips to carbachol. phenylephrine. or KCl. The data indicate that significant changes in micturition characteristics are evident one year after the onset of diabetes in the spontaneously diabetic BB rat. These changes are slow in development. since they are absent six months after the onset of diabetes. The changes in micturition and bladder strip contractility are qualitatively similar to. but quantitatively modest in comparison with those caused by streptozotocin-induced diabetes mellitus. The quantitative differences are probably attributable to an ameliorative effect of the insulin received by the BB rat.
Microcomputers and prevention of drug abuse, In recent years. the psychological treatment of drug addiction has been dominated by an emphasis on learning theory and an interest in minimal and self-administered treatment. The computer provides the consummate medium for bringing these components together. This paper reports on two computer-assisted learning programs. one for the prevention of relapse in former heroin users and the other for the promotion of controlled drinking in early-stage problem drinkers. The need for this type of technology is supported by mounting evidence that drug and alcohol misusers prefer self-help to psychotherapy and that most addicts who manage to overcome their addiction do so on their own.
Activation by extracellular nucleotides of chloride secretion in the airway epithelia of patients with cystic fibrosis, BACKGROUND. Cystic fibrosis is characterized by abnormal electrolyte transport across the epithelia of the airways. In particular. there is excessive sodium absorption and deficient chloride secretion. Drugs that block excessive sodium absorption may provide clinical benefit in cystic fibrosis. but there are no available therapeutic agents to improve chloride secretion. In vitro studies in cultured human-airway epithelia indicate that triphosphate nucleotides (ATP and UTP) induce chloride secretion through apical-membrane purinergic receptors. METHODS. We tested the ability of nucleotides to induce chloride secretion in vivo in 9 normal subjects and 12 patients with cystic fibrosis by measuring responses of nasal transepithelial potential difference (PD) to superfusion of nucleotides. Changes in transepithelial bioelectric properties and the permeability of the apical membrane to chloride in response to extracellular (apical) UTP were determined with ion-selective microelectrodes in cultured nasal epithelia. RESULTS. ATP and UTP induced chloride secretion in vivo in both groups. At their maximal effective concentrations of 10(-4) M. ATP and UTP were more effective chloride secretagogues in the patients with cystic fibrosis (mean [+/- SE] change in PD. -19.8 +/- 1.4 mV and -15.0 +/- 1.7 mV. respectively) than in the normal subjects (-6.9 +/- 0.6 mV and -8.1 +/- 0.9 mV. respectively). Microelectrode studies established that extracellular UTP stimulated a larger increase in PD and chloride secretory current in epithelial cells from patients with cystic fibrosis than in cells from normal subjects. by actions localized to the apical membrane. CONCLUSIONS. Extracellular nucleotides are effective in vivo chloride secretagogues in the nasal epithelia of patients with cystic fibrosis. The equipotency of ATP and UTP suggests that the effect is mediated by P2 nucleotide receptors. Selected nucleotides. such as UTP or nucleotide analogues. should be investigated as therapeutic agents for lung disease in cystic fibrosis.
The use of angioplasty, bypass surgery, and amputation in the management of peripheral vascular disease, BACKGROUND. Percutaneous transluminal angioplasty has been adopted widely as a treatment for patients with peripheral vascular disease of the lower extremities. However. the effect of this procedure on the overall management of peripheral vascular disease and on the outcomes of patients has not been clearly delineated. In particular. it is not known whether angioplasty has replaced other treatments for peripheral vascular disease. METHODS. To assess the extent to which angioplasty is used and the associated changes in the surgical management of peripheral vascular disease of the lower extremities. we used data on hospital discharges in Maryland to identify all angioplasty procedures. peripheral bypass operations. and lower-extremity amputations performed for peripheral vascular disease in Maryland hospitals between 1979 and 1989. RESULTS. We estimated that from 1979 to 1989 the annual rate of percutaneous transluminal angioplasty for peripheral vascular disease of the lower extremities. adjusted for age and sex. rose from 1 to 24 per 100.000 Maryland residents (P less than 0.0001 by linear regression). Despite this increase in the use of angioplasty. the adjusted annual rate of peripheral bypass surgery also rose substantially. from 32 to 65 per 100.000 (P less than 0.001). whereas the adjusted annual rate of lower-extremity amputation remained stable at about 30 per 100.000. Total charges for hospitalizations during which a peripheral revascularization procedure was performed increased from $14.7 million in 1979 (in 1989 dollars) to $30.5 million in 1989. CONCLUSIONS. In Maryland. the adoption of percutaneous transluminal angioplasty for peripheral vascular disease of the lower extremities has been associated with an increase in the use of peripheral bypass surgery and with no decline in lower-extremity amputations. These results could be due to increased diagnosis of peripheral vascular disease. expanded indications for procedural interventions. or an increased number of repeat procedures performed in patients with peripheral vascular disease of the lower extremities.
Measurement of sound, The measurement of sound involves the analysis of frequency. intensity. and temporal dimensions of acoustic signals. Each dimension of sound can be related directly to clinically observed phenomena. Frequency information. measured in Hz. can be extracted from pure-tone and complex stimuli. Intensity represents the physical energy of a signal and is described by using the decibel scale--a logarithmic scale of ratios. Temporal characteristics of sound include duration. phase. and repetition rate. In the analysis of human hearing sensitivity. the middle ear system and its impedance characteristics also must be considered. In this article. we have reviewed some major principles of sound and have presented a series of practical clinical applications. Such principles as these help to predict and explain frequency of laryngeal tones. middle ear mechanics. ear canal resonance. real-ear measurements of hearing aids. the Articulation Index. hearing loss. understanding of speech in quiet and in noise. and the relation between hearing and speech.
Basic hearing tests, This article contains a discussion of pure-tone and speech audiometry as these measures relate to primary audiologic evaluation of hearing. The scientific foundation underlying the development of stimulus-specific standards for normal hearing. test materials. and methods for basic tests are included. A rationale for test administration. masking. and interpretation of results is presented.
Behavioral audiometry, Behavioral audiometry is based on observation of overt responses to controlled auditory stimuli. as contrasted with electrophysiologic procedures. which involve electrophysiologic monitoring or direct recording of the bioelectric correlates of the original signal. When reinforcement is added to the behavioral procedures. the infant or young child provides highly reliable responses. and it is possible to test most infants 6 months of age and older with these procedures. The combination of both behavioral and electrophysiologic procedures can resolve most clinical questions regarding the auditory function of young infants and children.
Basic principles and clinical applications of tympanometry, This article presents an overview of tympanometric measures using a 226-Hz probe tone. with an additional focus on complex admittance measures at 678 Hz and an introduction to multiple frequency tympanometry. Basic principles underlying all admittance measures are presented. The clinical implementation and interpretation of tympanometry is discussed.
Acoustic reflex measures in audiologic evaluation, Measurement of the acoustic-stapedius reflex is useful in the diagnosis of certain otologic diseases. The anatomy and physiology of the middle ear muscles and the acoustic reflex arc are reviewed for normal and pathologic ears. The application of acoustic reflex measures to clinical diagnosis is illustrated by a series of case studies.
Central auditory function, Central auditory disorders in children and adults have become more widely recognized in patients seen by otolaryngologists and audiologists. This article briefly defines those clinical entities. discusses the historic background of testing. and describes current and future test approaches to assessment of central auditory disorders.
Pseudohypacusis, This article provides the basis for the techniques and interpretation of audiologic tests useful in evaluation of the patient with pseudohypacusis. Differences between the childhood and adult forms of the problem are discussed. The indications for currently popular conventional and special tests are presented. These include both behavioral and electrophysiologic measures for assessing auditory function.
Hearing compensation evaluation, Compensation claims for hearing loss are increasing. Physicians and audiologists supply necessary information regarding probable cause and amount of loss for evaluating these claims. Compensable hearing loss can arise from several sources. The principal activity has been claims based on industrial noise exposure. Compensation evaluation is considered as a consequence of noise-induced hearing loss. but the evaluation procedure is applicable regardless of the cause of hearing loss.
Occupational hearing conservation, Chronic exposure to high-intensity noise can produce permanent hearing loss. the amount of which depends on noise intensity. temporal and spectral characteristics. and the length of exposure. OSHA regulates workplace noise exposure in accordance with the Hearing Conservation Amendment of 1983. When noise levels equal or exceed an 85 dBA time-weighted average (TWA). the employer is required to provide annual audiometric screening. When noise levels exceed 90 dBA TWA. the worker's exposure must be reduced by engineering methods. administrative changes. or personal hearing protectors. If a worker demonstrates a standard (significant) threshold shift (10 dB or greater increased average hearing threshold at 2. 3. and 4 kHz in either ear) that is attributed to noise. the worker's exposure must be further reduced by one of the aforementioned methods.
Hearing aid evaluation and fitting, Although many patients with hearing loss benefit from medical or surgical intervention. the vast majority have noncorrectable hearing disorders for which rehabilitation through amplification is indicated. There are three goals for the application of hearing aids: (1) to amplify normal conversational speech to levels that are maximally understandable to the patient; (2) to help the patient hear other environmental sounds; and (3) to assist in the educational or habilitative process for those children who sustain hearing loss prior to language and speech development. In addition. there are certain issues that require medical consideration when a wearable device is placed in the ear. This article describes current hearing aid technology; reviews its benefits. limitations. and application for typical patients; discusses the medical aspects of hearing aid fitting; and describes new hearing aid technology on the horizon.
Aural rehabilitation, Aural rehabilitation involves a complete evaluation of the communication deficits and needs of the hearing-impaired patient as well as the provision of counselling and therapy. This article describes listening-assistive devices. speech production. and audiovisual training. Issues related to educational placement and tinnitus also are reviewed.
Vestibular testing in hearing loss, The basic electonystagmography battery (saccade. gaze. position. caloric tests. and spontaneous nystagmus) are described along with rotational testing and dynamic posturography. Emphasis is placed on interpretation. relative benefits. and limitations as an aid in diagnosis.
Applying the theory of reasoned action to AIDS risk behavior: condom use among black women, This study tested hypotheses regarding attitudinal and normative influences on intentions to use condoms. a practice that would reduce women's risk of sexually transmitted HIV infection. Participants were 103 sexually active unmarried black women undergraduates at an inner-city commuter university. in an area with a high rate of reported AIDS cases among women. Consistent with the theory of reasoned action. multiple regression analysis on women's anonymous responses to a mailed survey revealed that those who registered more favorable attitudes toward condoms and those who perceived subjective norms more supportive of condom use reported firmer intentions to use condoms in the next three months. Key behavioral beliefs related to attitudes centered on the adverse effects of condom use on sexual enjoyment. Key normative influences were respondents' sexual partners and mothers. However. women's own attitudes were a stronger determinant of intentions to use condoms than were their perceptions of normative influences. particularly among women with above-average AIDS knowledge. The results suggest that the theory of reasoned action provides a potentially useful conceptual framework for interventions to change a key AIDS risk behavior among women.
Uncertainty in illness theory: a replication of the mediating effects of mastery and coping, The purpose of this investigation was to replicate a test of the mediating functions of mastery and coping and to determine whether the relationships found in the initial test of the model would hold with a sample more heterogenous than the original sample. One hundred women receiving treatment for gynecological cancer participated in the investigation. Of the 14 relationships in the model. only 5 replicated significant paths and had overlapping confidence intervals. Two moderators were proposed to explain the differences between the initial and replication tests of the model and to improve the specificity of the theory.
Pain reduction interventions during neonatal circumcision, The purpose of this study was to determine the effect of some noninvasive pain reduction interventions on pain in 121 neonates undergoing unanesthetized circumcision. Subjects were randomly assigned to one of six groups: classical music. intrauterine sounds. pacifier. music and pacifier. intrauterine sounds and pacifier. or control (no nurses present and no pain reduction interventions used). Physiological variables that were monitored were heart rate. rhythm. dysrhythmias. blood pressure. transcutaneous oxygen (tcpO2). rate pressure product. and behavioral state. measured during 14 circumcision steps. Over the 14 steps. 42% of the heart rates. 78% of the systolic blood pressures (SBP). 30% of the diastolic blood pressures (DBP). and 81% of the tcpO2 pressures were abnormal. Few significant differences were found among any of the steps. SBP and DBP differed significantly between groups during two of the noninvasive steps; and tcpO2 differed significantly during six steps.
Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide, Although the CD4 molecule is the principal cellular receptor for the human immunodeficiency virus (HIV). several CD4-negative cell lines are susceptible to infection with one or more HIV strains. These findings indicate that there are alternate modes of viral entry. perhaps involving one or more receptor molecules. Antibodies against galactosyl ceramide (galactocerebroside. or GalC) inhibited viral internalization and infection in two CD4-negative cell lines derived from the nervous system: U373-MG and SK-N-MC. Furthermore. recombinant HIV surface glycoprotein gp120 bound to GalC but not to other glycolipids. These results suggest a role for GalC or a highly related molecule in HIV entry into neural cells.
Rules of language, Language and cognition have been explained as the products of a homogeneous associative memory structure or alternatively. of a set of genetically determined computational modules in which rules manipulate symbolic representations. Intensive study of one phenomenon of English grammar and how it is processed and acquired suggest that both theories are partly right. Regular verbs (walk-walked) are computed by a suffixation rule in a neural system for grammatical processing; irregular verbs (run-ran) are retrieved from an associative memory.
A component of calcium-activated potassium channels encoded by the Drosophila slo locus, Calcium-activated potassium channels mediate many biologically important functions in electrically excitable cells. Despite recent progress in the molecular analysis of voltage-activated K+ channels. Ca(2+)-activated K+ channels have not been similarly characterized. The Drosophila slowpoke (slo) locus. mutations of which specifically abolish a Ca(2+)-activated K+ current in muscles and neurons. provides an opportunity for molecular characterization of these channels. Genomic and complementary DNA clones from the slo locus were isolated and sequenced. The polypeptide predicted by slo is similar to voltage-activated K+ channel polypeptides in discrete domains known to be essential for function. Thus. these results indicate that slo encodes a structural component of Ca(2+)-activated K+ channels.
Identification of profilin as a novel pollen allergen; IgE autoreactivity in sensitized individuals, A complementary DNA encoding a pollen allergen from white birch (Betula verrucosa) that was isolated from a pollen complementary DNA library with serum immunoglobulin E from a birch pollen-allergic individual revealed significant sequence homology to profilins. The recombinant protein showed high affinity to poly-L-proline. Immunoglobulin E antibodies from allergic individuals bound to natural and recombinant birch profilin and also to human profilin. In addition. birch and human profilin induced histamine release from blood basophils of profilin-allergic individuals. but not of individuals sensitized to other plant allergens. The structural similarity of conserved proteins might therefore be responsible for maintaining immunoglobulin E antibody titers in type I allergy.
Differentiation of 3T3-L1 fibroblasts to adipocytes induced by transfection of ras oncogenes, Mammalian 3T3-L1 cells differentiate into adipocytes after continuous exposure to pharmacological doses of insulin or physiological doses of insulin-like growth factor I (IGF-1). Expression of transfected ras oncogenes led to differentiation of these cells into adipocytes in the absence of externally added insulin or IGF-I. Cells transfected with normal ras genes or the tyrosine kinase trk oncogene did not differentiate. Transfection with a dominant inhibitory ras mutant resulted in inhibition of differentiation. Exposure of untransfected 3T3-L1 cells to insulin stimulated formation of the active Ras.GTP complex. These observations indicate that Ras proteins participate in signal transduction pathways initiated by insulin and IGF-I in these cells.
Endothelium-dependent contraction and relaxation of the human and canine internal mammary artery: studies on bypass graft vasospasm, The internal mammary artery (IMA) is the preferred conduit for coronary artery bypass graft because of superior late patency. However. IMA vasospasm may contribute to myocardial ischemia and early postoperative morbidity. To investigate mechanisms of vasospasm. we compared the reactivity of human and canine IMA segments in vitro to agonists known to release endothelium-derived contracting factor and endothelium-derived relaxing factor. Rings (4 mm in length) of human and canine IMA were studied in organ chambers. Human and canine vascular smooth muscle exhibited comparable contraction to norepinephrine (maximum = 7.55 +/- 0.63 gm and 6.4 +/- 0.90 gm. respectively) and relaxation to sodium nitroprusside. Human and canine IMAs exhibited comparable endothelium-derived relaxing factor-mediated relaxations to acetylcholine (human) and methacholine (canine). Human and canine IMA also exhibited comparable endothelium-dependent contraction to hypoxia (to 173.3% +/- 8.1% and 178.9% +/- 16.0% of initial prehypoxic tension; means +/- SEM; n = 12). Endothelium-dependent contraction to hypoxia in human and canine IMA could be attenuated by NG-monomethyl-L-arginine (10(-6) mol/L). a competitive inhibitor of L-arginine metabolism (n = 9 and n = 10 for human and canine; p less than 0.05). These studies establish that the canine is an appropriate model for study of human IMA vascular reactivity and that hypoxia can induce the release of an L-arginine-dependent. endothelium-derived contracting factor in the human and canine IMA. In vivo. the release of endothelium-derived contracting factor in response to hypoxemia may be cause of IMA vasospasm.
Enhanced interstitial fluid adenosine attenuates myocardial stunning, Reversible myocardial dysfunction associated with transient ischemia has been termed the stunned myocardium. Because exogenous adenosine has been shown to protect the ischemic myocardium. we hypothesized that augmentation of endogenous adenosine levels would attenuate myocardial stunning. To induce stunning. anesthetized dogs were subjected to 15 minutes of ischemia (left anterior descending artery occlusion) followed by 60 minutes of reperfusion. Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA; 5 mg/kg/hr). an adenosine deaminase inhibitor. was used to augment adenosine levels. The effect of EHNA on interstitial fluid (ISF) adenosine levels. coronary blood flow. and regional systolic wall thickening was compared with that of an untreated group (n = 8). EHNA increased preischemia ISF adenosine levels threefold and was associated with a corresponding increase in coronary blood flow. EHNA administration did not alter preischemia systolic wall thickening. Although ISF adenosine increased fourfold during ischemia in the untreated group. ISF adenosine increased nearly sixtyfold above preischemia values in the EHNA-treated group and remained elevated throughout reperfusion. Postischemic regional function was enhanced significantly in the group treated with EHNA. These data show that adenosine deaminase inhibition increased ISF adenosine levels and attenuated myocardial stunning. Metabolic manipulation of myocardial ISF nucleoside levels may be beneficial in limiting postischemic myocardial dysfunction.
Effects of distention and short-term grafting on vasoreactivity in rabbit external jugular veins, The relative effects of distention. intraluminal pressure. and wall tension on venous smooth muscle and endothelial cell function were examined in 40 external jugular veins from New Zealand white rabbits. Vein grafts (n = 5) were interposed in the common carotid artery and explanted after 10 minutes. Distended veins were inflated in vitro with modified Krebs' solution at 37 degrees C for 10 minutes at pressures of either 20 mm Hg (D-20; n = 5) or 80 mm Hg (D-80; n = 5). Externally supported veins (ES-80; n = 5) were inflated at 80 mm Hg pressure. but distention was prevented by covering with a 3 mm internal diameter polytetrafluoroethylene sleeve. Bradykinin-induced in vitro maximal tension was attenuated significantly in vein grafts (0.13 +/- 0.04 g) and D-80 rings (0.27 +/- 0.07 g) compared with D-20 rings (1.20 +/- 0.14 g). ES-80 rings (0.99 +/- 0.13 g). or nondistended control rings (n = 40; 1.19 +/- 0.10 g; p less than 0.001). The attenuation in contraction in the vein graft and D-80 groups was nonspecific (i.e.. similar results were obtained with respect to other smooth muscle agonists). Contractile function was inversely associated with wall tension. the product of pressure and radius (r2 = 0.7438; p = 0.06). In contrast. there were no differences in endothelium-dependent or endothelium-independent relaxation among the five groups. It is concluded that. in this experimental system. (1) venous smooth muscle function is significantly attenuated after short-term in vitro distention or grafting although endothelial function is largely preserved. and (2) the decrement in contraction is due to elevated wall tension.
Hepatic failure and coma after liver resection is reversed by manipulation of gut contents: the role of endotoxin, Despite significant improvements in the surgical care of patients. hepatic failure after extensive liver resection continues to be associated with a high morbidity and death. We postulated that hepatic failure after liver resection was related to gut-derived endotoxemia. Rats were randomized to receive oral gavage twice daily with one of the following preparations: (1) 0.9% saline; (2) neomycin sulfate and cefazolin; (3) cholestyramine; (4) lactulose. After 7 days of gavage. animals underwent either a two-thirds partial hepatectomy or sham operation. At time 0 (preresection). 10. 20. and 30 hours after resection. aortic blood was obtained for determination of ammonia. glutamine. and endotoxin levels. In selected animals. portal vein or inferior caval blood was obtained simultaneously with the aortic sample to evaluate the glutamine and ammonia exchange across the intestine and hind limb. Germ-free rats also underwent a partial hepatectomy or sham operation. and blood was obtained for glutamine and ammonia exchange at 0 and 20 hours after resection. Hepatectomy in the saline-pretreated rats resulted in a sixfold increase in plasma glutamine. increased uptake of glutamine and release of ammonia by the gut. increased release of glutamine by the hind-limb. and a high mortality rate. Pretreatment with agents that altered gut contents reduced the endotoxemia. maintained normal glutamine and ammonia levels. and reduced the mortality rate. Germ-free rats had a similar response to that seen in treated animals. Altering the gut contents in this model reduced the level of endotoxemia. blunted the catabolic response. and enhanced survival.
Relation between p53 overexpression and established prognostic factors in breast cancer, The nuclear phosphoprotein p53 is expressed in all normal cells and appears to function in cell cycle regulation. Abnormally high levels of the protein are found in many different types of cancer. In breast carcinoma overexpression of p53 is associated with point mutations within highly conserved regions of the p53 gene. These altered genes encode stable p53 proteins that can be detected by standard immunohistochemical techniques unable to detect rapidly degraded wild-type protein. The level of p53 expression in 184 primary breast cancer specimens was assessed by immunohistochemical analysis and related to the following established prognostic factors for breast cancer: age. stage. metastatic involvement. concentration of estrogen and progesterone receptors. proliferative index. and HER-2/neu overexpression. Fifty (27%) of these primary breast cancer specimens had widespread overexpression of p53. Highly significant associations were found between p53 overexpression and late stage. metastatic spread. and low concentration of progesterone receptors. The presence of elevated levels of mutant p53 may itself be a prognostic factor in human breast cancer and activation of this oncogene may be important in the ability of a tumor to metastasize.
Vasoactive intestinal polypeptide inhibits c-myc expression and growth of human gastric carcinoma cells, Vasoactive intestinal polypeptide (VIP) is a gut neuroendocrine polypeptide that increases cyclic adenosine monophosphate (cAMP) production in cells with VIP receptors. Some gastrointestinal cancer cells possess functional receptors for VIP; however. the role of VIP in regulation of growth of gastric cancer cells has not been determined. The purpose of this study was to determine whether VIP and other agents that increase cAMP regulate growth of a human gastric cancer cell line (AGS) and whether these agents regulate expression of c-myc proto-oncogene. which is required for cell proliferation. We measured levels of cAMP by radioimmunoassay. and we used Northern blot analysis to examine c-myc messenger RNA expression. Cell-growth studies were carried out in media supplemented with 3% serum. and cells were counted with a Coulter counter. We found that VIP significantly increased cAMP production of AGS cells in a dose-dependent manner. whereas secretin. glucagon. and peptide histidine methionine (PHM) did not stimulate cAMP production. Exogenous cAMP (8-bromo-cAMP) inhibited AGS cell growth in a dose-dependent manner. VIP acted synergistically with either isobutylmethyl-xanthine or forskolin to inhibit AGS cell proliferation. The increased c-myc expression. which was induced by serum. was inhibited by simultaneous treatment with VIP and isobutylmethyl-xanthine. We have found that AGS cells have specific. functional VIP receptors (activation of which are negatively correlated with cell growth) and that the mechanism by which VIP acts to inhibit cell growth appears to be due. in part. to cAMP-dependent regulation of c-myc proto-oncogene expression.
Pentoxifylline restores intestinal microvascular blood flow during resuscitated hemorrhagic shock, We studied the intestinal microvascular blood flow responses to hemorrhage and resuscitation with pentoxifylline by in vivo video microscopy. Male Sprague-Dawley rats were hemorrhaged to 50% of baseline mean arterial pressure for 45 minutes and then blindly randomized to receive pentoxifylline (25 mg/kg bolus + 0.2 mg/kg/minute) or an equivalent volume of saline plus return of shed blood and an additional bled volume of Ringer's lactate solution. Hemorrhage caused intestinal microvascular blood flow to decrease to 10% to 15% of baseline values. In the control group. resuscitation restored cardiac output and mean arterial pressure to baseline values. but intestinal microvascular blood flow remained at 30% of baseline values. In contrast. addition of pentoxifylline to the resuscitation regimen resulted in an immediate hyperemic response with an increase in intestinal microvascular blood flow to significantly greater than baseline values followed by return to baseline. Arteriolar dilation was not responsible for the improvement in flow implicating improved flow dynamics between erythrocytes. granulocytes. and vascular endothelia within the microcirculation. We conclude that addition of pentoxifylline to resuscitation from hemorrhagic shock restores intestinal microvascular blood flow.
Pretreatment with a nontoxic derivative of endotoxin induces functional protection against cardiac ischemia/reperfusion injury, We hypothesized that low-dose pretreatment of an intact animal with a nontoxic derivative of endotoxin. monophosphoryl lipid A (MPL). would induce protection against cardiac ischemia/reperfusion (I/R) injury. The purposes of this study were to investigate whether MPL pretreatment would induce functional protection against cardiac I/R injury. to delineate the temporal induction of protection. and to examine antioxidant enzyme induction as a mechanism of protection. Rats were administered a 5 mg/kg dose of MPL at 2 hours and 24 hours before a 25-minute. global. 37 degrees C ischemic insult followed by reperfusion (modified Langendorff). At 40 minutes of reperfusion. ventricular function was assessed (ventricular balloon; developed pressure. rate of contraction. rate of relaxation). Hearts from rats pretreated with MPL 24 hours before isolation exhibited preservation of ventricular function (p less than 0.05). After I/R. hearts from rats pretreated with MPL 24 hours before isolation had increased (p less than 0.05) catalase activity compared to saline pretreated controls and rats pretreated with MPL 2 hours before isolation. We conclude that (1) pretreatment with MPL induces functional protection against cardiac I/R injury. (2) protection (not evident at 2 hours) is maximal at 24 hours. suggesting enzyme induction. and (3) increased catalase activity correlates with the functional protection.
Aneurysm or occlusive disease--factors determining the clinical course of atherosclerosis of the infrarenal aorta, Atherosclerosis of the infrarenal aorta results in distinct clinical entities--aortoiliac occlusive disease (AOD) and abdominal aortic aneurysm (AAA). Although loss of collagen has been implicated in AAA. collagen accumulation plays a role in AOD. In vivo collagen-gene expression can be assessed using complementary DNA for collagen types I and III alpha-chains. The purpose of this study is to compare total collagen (type I + III) and collagen types I and III messenger RNA in AAA. AOD and normal aorta. Specimens were collected from the infrarenal aorta during operation for AOD (n = 7). AAA (n = 7). autopsy. or organ procurement (normal; n = 7). Northern transfer analysis of total RNA was used to compare mRNA levels for type I and III collagen. After preliminary extraction. specimens were hydrolyzed for hydroxyproline analysis used to calculate total collagen (type I + III). Relative levels of type I (pro-a1[1]) mRNA were greater in both AOD (0.77 +/- 0.35) and AAA tissue (0.94 +/- 0.24; p = 0.6) than in normal aorta (0.02 +/- 0.03). Type III (pro-a1[III]) mRNA levels were also greater in AOD (2.52 +/- 0.19; p = 0.09) and AAA tissue (3.15 +/- 1.3) than in normals (0.97 +/- 0.47). Total collagen concentration was increased in AOD (45.6% +/- 3.1% dry weight; p less than 0.05) but not AAA tissue (27.8% +/- 4%) when compared to normal aorta (34.7% +/- 2.3%). Collagen type I and III gene expression is greater in older. diseased aorta. yet collagen accumulated only in AOD. This implies a similar synthetic response in both AOD and AAA. Thus. proteolytic degradation in AAA appears to determine collagen content and possibly the clinical course of the atherosclerotic process.
Diltiazem administration after crystalloid resuscitation restores active hepatocellular function and hepatic blood flow after severe hemorrhagic shock, Studies have shown that active hepatocellular function is depressed after hemorrhagic shock. despite crystalloid resuscitation. It is also known that calcium antagonists produce various beneficial effects on cell and organ function after ischemia and shock. However. it remains unknown whether such agents have any salutary effects on the depressed active hepatocellular function and hepatic blood flow in a nonheparinized model of trauma and hemorrhage. To study this. rats underwent a midline laparotomy (trauma-induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximum bleedout was returned in the form of Ringer's lactate. They were then resuscitated with four times the volume of shed blood with Ringer's lactate over 60 minutes. during and after which diltiazem (400 micrograms/kg body weight) was infused intravenously over 95 minutes. Active hepatocellular function (Vmax and Km) was determined with an in vivo indocyanine green clearance technique. Effective hepatic blood flow (EHBF) was determined by Fick principle and corrected by the indocyanine green extraction ratio. Hepatic microvascular blood flow (HMBF) was measured by laser Doppler flowmetry. Results indicate that Vmax. Km. EHBF. and HMBF decreased significantly at 1.5 and 4 hours after resuscitation. Diltiazem infusion restored the depressed Vmax. Km. EHBF. and HMBF and prevented the occurrence of hepatic edema. Thus. diltiazem may be a useful adjunct in the treatment of trauma and severe hemorrhage even in the absence of blood resuscitation.
Capsaicin-sensitive nerves mediate esophageal mucosal protection, The esophageal mucosa is exposed to damaging agents both by ingestion and reflux. Using our in vivo rabbit model of esophagitis. we have observed that acute luminal exposure (within 1 to 5 minutes) to potentially harmful agents. such as acid. bile. or ethanol. induces a rapid increase in mucosal blood flow; whereas prolonged exposure (10 to 60 minutes) results in mucosal injury and ablation of blood flow. We have also shown that capsaicin-sensitive mucosal afferent nerves can modulate esophageal blood flow. These findings led us to hypothesize that the reactive increase in blood flow induced by luminal agents represents a mechanism of protection mediated by capsaicin-sensitive nerves. The objective of these experiments was to determine if luminal capsaicin. a specific probe for visceral afferent nerves. could both preserve mucosal blood flow and protect against ethanol injury. Rabbits were subjected to luminal instillation of 50% ethanol with or without 1% capsaicin. Blood flow was measured with microspheres at baseline and after 2 and 10 minutes. Rabbits exposed only to ethanol developed severe mucosal injury coincident with near ablation of mucosal blood flow. In contrast. rabbits exposed to ethanol with capsaicin showed protection of the epithelium with a sixfold increase in mucosal blood flow. We conclude that capsaicin-sensitive nerves in the esophagus are local effectors of mucosal protection by virtue of preserving blood flow.
Insights into the mechanisms of defective antigen presentation after hemorrhage, Although hemorrhage depresses macrophage antigen presentation (AP). a critical component in eliciting an antigen-specific immune response. it is not known which particular step in macrophage AP (i.e.. uptake. ingestion. catabolism. or presentation of degraded antigens to T cells) is defective. To study this. C3H/HeN mice were bled to an arterial mean blood pressure of 35 mm Hg. maintained for 60 minutes. and then adequately resuscitated. Peritoneal and splenic macrophage cultures were prepared 2 and 24 hours after hemorrhage. Macrophage AP capacity was measured by coculturing macrophages with the T-helper cell clone D10.G4.1. To gain information about macrophage ability to digest the specific antigen conalbumin. lysosomal activity was bypassed by use of chemically denatured conalbumin peptides. To study macrophage ability to present conalbumin peptides. macrophages were fixed and D10.G4.1 proliferation in response to fragmented conalbumin was determined. AP of native conalbumin by peritoneal macrophages and splenic macrophages was depressed (p less than 0.05) by 50% (peritoneal macrophages) and 55% (splenic macrophages) 2 hours and 57% (peritoneal macrophages) and 35% (splenic macrophages) 24 hours after hemorrhage. In contrast. presentation of conalbumin peptides was only slightly decreased. In addition. the ability of fixed peritoneal macrophages and splenic macrophages to present conalbumin peptides was similar in hemorrhaged and sham mice. Because bypassing of macrophage lysosomal activity with degraded native antigens prevented the suppression of AP. the results suggest that hemorrhage-induced suppression of AP is not caused by a reduced macrophage capacity to present antigenic peptides but by decreased antigen catabolism by macrophages.
Use of transcutaneous oxygen tension, arterial oxygen saturation, and respiratory resistance to assess the response to inhaled methacholine in asthmatic children and normal adults, Respiratory resistance (Rrs6). transcutaneous oxygen tension (PtcO2). and oxygen saturation (SaO2) were measured during methacholine challenge in 15 asthmatic children and six normal adults. During bronchoconstriction. induced by a wide range of inhaled methacholine concentrations (0.5-256 g/l). the rise in Rrs6 was reflected by a fall in PtcO2 in all subjects. Although there was a significant mean fall in SaO2 at maximum bronchoconstriction there was no consistent relation between changes in SaO2 and Rrs6. The inhaled dose of methacholine causing a 40% increase in Rrs6 (PD40Rrs6) and a 20% fall in PtCO2 (PD20PtcO2) was calculated for each subject. There was no significant difference in mean PD40Rrs6 and PD20PtcO2. and the relation between the two was similar in the asthmatic children and the normal adults. It was therefore concluded that the measurement of PtcO2. but not SaO2. during methacholine challenge can be used for the assessment of bronchial responsiveness. and that it could prove particularly useful for children too young to cooperate with lung function tests.
Current trends in tuberculosis mortality in England and Wales, To determine current trends in mortality from tuberculosis according to age the published data on notification and deaths from tuberculosis from 1974 to 1987 have been analysed. The ratio of deaths to notifications per year was assessed over this period as a measure of case fatality from tuberculosis. The mean annual decline in the ratio for each age group was as follows: 0-14 years 6.7% (95% confidence interval 4.00 to 9.6%). 15-34 years 1.4% (-0.2 to 3.0%). 35-54 years 4.5% (2.2 to 6.9%). 55-74 years 2.8% (1.8 to 3.7%). and 75+ years 3.2% (2.1 to 4.2%). Because the incidence of disease in the 75+ group has declined much more slowly than in the rest of the population and because the size of this age group has increased in relation to the other groups. the overall annual mortality from tuberculosis has declined by only 0.13% (95% CI -1.3 to 1.3%). The total number of deaths from tuberculosis declined from 996 in 1974 to 430 in 1987. whereas deaths in the 75+ age group remained relatively constant at around 200 a year.
Radiation associated malignant pleural mesothelioma, Malignant pleural mesothelioma of epithelial type developed in a 24 year old woman. 20 years after radiotherapy for Hodgkin's disease. This case and a review of published cases indicate that radiation may induce malignant mesothelioma.
Adjuvant therapy in early breast cancer, Breast cancer is the most common malignancy in women. Screening mammography can detect cancer in its early stages. when it is potentially curable. Adjuvant chemotherapy is of major benefit in node-positive patients. It is also beneficial in certain node-negative patients with a high risk of breast cancer recurrence; these patients should be identified and offered adjuvant therapy or enrolled in a clinical trial.
Disulfiram: a guide to clinical use in alcoholism treatment, One option for helping chronic alcoholics remain sober is disulfiram therapy. Patients who take disulfiram develop a sensitivity to alcohol. resulting in unpleasant reactions to even small amounts of alcohol. When it is used as part of a comprehensive program for alcoholics who wish to remain sober. disulfiram can be an effective treatment aid.
Periodontal disease and the family physician, Periodontal disease can be divided into two categories: gingivitis (inflammation of the soft tissue) and periodontitis (destruction of the alveolar bone). Swelling. erythema. bleeding and gingival recession are common signs of gingivitis. However. most patients with gingivitis are asymptomatic. When patients complain of tooth pain and mobility. they already have severe periodontal disease. Dental loss secondary to periodontal disease may result in inadequate mastication. impaired phonetics and loss of self-esteem. Patients should be counseled that good oral hygiene and regular dental examinations can prevent periodontal disease.
Ulnar tunnel syndrome, The ulnar tunnel syndrome is a relatively uncommon condition resulting from compression of the ulnar nerve as it passes through the loge de Guyon. or ulnar tunnel. in the wrist. The syndrome may cause weakness and atrophy of the intrinsic hand muscles and loss of sensation in the ulnar nerve distribution of the hand. The most common cause of ulnar tunnel syndrome is chronic occupational trauma. either from pressure exerted over the hypothenar eminence by a tool or from the use of the heel of the hand as a hammer. Nonoccupational etiologies include congenital. inflammatory. neoplastic. vascular. metabolic. degenerative and traumatic disorders. Diagnosis often requires neurophysiologic evaluation. in addition to a careful history and physical examination. Conservative treatment aimed at protecting the ulnar tunnel from trauma frequently is effective. Occasionally. surgical decompression of the ulnar tunnel is required.
Office dermatologic testing: the scabies preparation, Patients with scabies may present with urticarial. eczematous or excoriated papules. eczematous patches or. occasionally. nodules. It is often difficult to differentiate scabies from eczema. folliculitis. drug eruption or lichen planus. The classically described burrows are often not seen. The scabies preparation. as described in this article. will aid in making the proper diagnosis.
Prevention of sports-related eye injury, Sports-related eye injury is an important cause of vision loss. Many eye injuries can be prevented through the supervision of play. the enforcement of game rules and the use of eye protective devices. State-of-the-art eye protective devices incorporate highly impact-resistant optical material. usually polycarbonate lenses. in a sturdy frame. Protective devices are available for use in racquet sports. baseball. basketball. football. ice hockey and other sports.
Temper tantrums, Temper tantrums are a normal response to anger and occur commonly in the child between one and four years of age. They arise from the child's thwarted efforts to exercise mastery and autonomy. Tantrums occur more frequently in the active. determined child who has abundant energy. Parenting practices that may encourage tantrums include inconsistency. unreasonable expectations. excessive strictness. overprotectiveness and overindulgence. Boredom. fatigue. hunger or illness may reduce the child's tolerance for frustration. Management consists of teaching the parents to understand the underlying meaning of tantrums and to modify parental behaviors that may perpetuate or accentuate the problem. Temper tantrums are best handled by ignoring the outburst. offering nurturance to the child after the tantrum has subsided and helping the child learn to express negative feelings in more acceptable ways.
Nonpharmacologic treatment of urinary incontinence, Standard therapy for urinary incontinence often includes pharmaceutical agents that carry a risk of side effects or interactions with other drugs. As an alternative. several nonpharmacologic management approaches are available. Scheduled voiding regimens are effective for patients who have uninhibited detrusor contractions. even when cognitive impairment is present. In motivated patients. pelvic muscle exercise is effective for stress incontinence. These methods are safe and inexpensive. and studies indicate that they can be as effective as or more effective than pharmaceutical agents. Other nonpharmacologic approaches to management include biofeedback techniques and electrical stimulation therapy.
Collateral circulation as a marker of the presence of viable myocardium in patients with recent myocardial infarction, The relationship between the presence of viable myocardium and the extent of coronary collateral circulation to the infarct area was evaluated in 20 patients with a recent anterior myocardial infarction who had complete obstruction of the left anterior descending coronary artery. The viability of myocardial tissue was assessed by exercise thallium-201 myocardial scintigraphy. and the collateral circulation was angiographically evaluated by means of a collateral index ranging from 0 to 3. Patients were divided into two groups according to the presence (group 1. n = 10) or absence (group 2. n = 10) of viable myocardium in the perfusion territory of the infarct-related artery. The collateral index in group 1 was 2.5 +/- 0.5 (SD). which was significantly higher than the 0.7 +/- 0.8 in group 2. These findings indicate that the presence of ischemic but viable myocardium is intimately related to the development of collateral circulation in patients with myocardial infarction. and the existence of well-developed collateral channels predicts the presence of viable myocardium in the infarct area.
Percutaneous transluminal angioplasty involving internal mammary artery grafts, With the increasing use of the internal mammary artery as the conduit of choice in coronary bypass surgery. it is anticipated that an expanding patient population will have stenosis. usually at the site of internal mammary-to-coronary artery anastomosis. In our series 31 patients underwent dilatation at either the site of anastomosis (24). the native coronary artery beyond the anastomosis (4). or both (3) with no mortality. myocardial infarction. or need for emergency coronary artery bypass surgery. Angiographic and clinical success was achieved in 28 patients (90%). There were two internal mammary artery dissections with both patients requiring elective coronary bypass surgery. Of the patients in whom dilatation was successful. 22 (79%) have been followed for longer than 6 months and 19 (86%) have had sustained functional improvement at a mean of 35 months after angioplasty. One patient is to undergo repeat coronary bypass surgery. No patient has had a myocardial infarction or died during follow-up. Although percutaneous transluminal coronary angioplasty of the internal mammary artery has inherent difficulties because of the anatomic characteristics of the vessel. it can be performed with a high degree of primary success and a low incidence of complications and can provide long-term clinical improvement.
Smoking and the risk of first acute myocardial infarction, When analyzing risk factors for first acute myocardial infarction in the Copenhagen City Heart Study. a large prospective population study of 20.000 men and women. smoking was found to influence risk significantly in a dose-dependent manner. the risk increasing 2% to 3% for each gram of tobacco smoked daily. Risk was particularly associated with inhalation. the risk for inhalers being almost twice that of noninhalers. No difference in risk could be demonstrated between various types of tobacco (pipe. cigar/cheroots. or plain and filtered cigarettes). The risk seemed associated with current smoking only. inasmuch as the duration of the smoking habit was not important. Ex-smokers had the same risk as those who had never smoked regardless of duration of smoking and time elapsed since quitting. Relative excess risk was significantly higher in female smokers than in male smokers. and daily alcohol intake appeared to have some protective effect on the risk of first acute myocardial infarction among heavy smokers.
Comparative effect of heparin treatment with and without strenuous exercise on treadmill capacity in patients with stable effort angina, It has recently been demonstrated that treadmill capacity and collateral circulation improve as a result of exercise with heparin pretreatment in patients with effort angina. In the present study. we assessed whether heparin alone is effective in increasing treadmill capacity in 14 patients with effort angina. Patients were randomly assigned to one of two treatment arms: (1) group A--20 treadmill exercise periods with standard Bruce protocol twice a day for 10 days with heparin (5000 IU intravenously) pretreatment (seven patients) or (2) group B--10 injections of heparin calcium (10.000 IU subcutaneously) once a day for 10 days (seven patients). In group A. total exercise time was increased from 6.9 +/- 1.2 (SD) to 9.9 +/- 1.9 minutes (p less than 0.0005). as was the maximal double product. from 21.700 +/- 3.500 to 27.000 +/- 4.800 mm Hg/min (p less than 0.05). The double product at the onset of angina was also increased by 34% (p less than 0.05). and the double product at which ST depression (0.1 mV) first appeared was 22% (p less than 0.05) greater after treatment. In contrast. in group B. all of the above-mentioned parameters of treadmill capacity remained unchanged. These data indicate that heparin does not serve as an angiogenic factor by itself. but that it potentiates the ischemia-derived angiogenic factor.
Electrophysiologic and anatomic characteristics of ventricular tachycardia induced at the right ventricular outflow tract but not at the apex, The site of ventricular stimulation is an important variable in the initiation of ventricular tachycardia (VT) by programmed ventricular stimulation. Among 169 patients studied consecutively. 17 (10%) had ventricular tachycardia induced by programmed electrical stimulation from the right ventricular outflow tract but not from the apex. Fourteen of these 17 patients had had prior myocardial infarction (12 had inferior. and two had both inferior and anterior myocardial infarction). two had a dilated cardiomyopathy. and one had a localized cardiomyopathy. Fourteen patients had echocardiograms suitable for analysis. Of these. 12 had posterior/inferior ventricular wall motion abnormalities located at the base of the heart. The ventricular effective refractory periods from the right ventricular outflow tract and right ventricular apex were 237 +/- 4 and 244 +/- 5 msec. respectively (p less than 0.05. mean +/- SEM). Induced VT had a cycle length of 229 +/- 4 msec and had the morphology of right bundle branch block in 12 patients. of left bundle branch block in three patients. and had both morphologies in two patients. In 14 patients the axis was superior. VT was initiated with two extrastimuli in 15 patients and with burst right ventricular pacing in two patients. Similar pacing techniques with identical pacing intervals did not induce VT at the right ventricular apex in 14 of these 17 patients. Further. among the 15 patients whose VT was induced at the right ventricular outflow tract with two extrastimuli. neither burst pacing (n = 13) nor two extrastimuli introduced at faster paced rates (n = 12) induced VT at the right ventricular apex.
Concealed rhythms by double ventricular parasystole, Electrocardiograms taken from 11 patients in sinus rhythm with ventricular ectopic rhythms from two different foci were analyzed to find the number of sinus beats. S. between the ectopic rhythms (S values). Three out of 11 patients had the S values typical for concealed ectopic rhythms. One of them had concealed bigeminy of 2n-1 form that occasionally shifted to 2n form. Following the shift. S values of 2n-1 form were always achieved by the occurrence of double ventricular ectopic rhythms in succession. Concealed trigeminy of 3n and 3n-2 form was seen in the other two patients. Double ventricular ectopic rhythms had bizarre abnormal QRS complexes of two different morphologies and were inscribed in opposite directions. Ectopic rhythms in each case had parasystolic characteristics. These observations suggest bifocal automaticity as a mechanism for bidirectional ventricular tachycardia.
Relationship of echocardiographic, shunt flow, and angiographic size to the stretched diameter of the atrial septal defect, Stretched diameter of the atrial septal defect (ASD). measured by balloon sizing. is generally used as a guide to the selection of the size of the device utilized for transcatheter closure of the ASD. Balloon sizing is a cumbersome procedure and sometimes requires the use of very large size balloon catheters. Several methods of assessment of ASD size. namely. echographic. pulmonary-to-systemic flow ratio (Qp:Qs). and angiographic measures. were undertaken in a group of 16 patients. aged 7 months to 45 years (median. 4.5 years). who were being evaluated for transcatheter closure of ASD; the results were compared with the stretched diameter. Although the echographic size of the ASD (9.9 +/- 4.1 mm. mean +/- SD) is similar (p greater than 0.1) to the angiographic size (7.9 +/- 2.5 mm). it is much smaller (p less than 0.01) than the stretched diameter (16.1 +/- 5.3 mm). When the relationship between various measures of ASD was examined. although the Qp:Qs ratio and angiographic size have a significant (p less than 0.05) correlation with the stretched diameter (r = 0.55 and 0.54. respectively). the echo diameter has the best correlation coefficient. r = 0.82. p less than 0.001. The stretched diameter can be estimated by the equation: 1.05 x echo + 5.49 mm. It is concluded that the echographic diameter is a useful adjunct in the estimation of the stretch ASD diameter. which in turn can be used in the selection of the size of the device for transcatheter occlusion of the ASD.
The ventilatory threshold: method, protocol, and evaluator agreement, To evaluate the effects of different methods of detection. exercise modes. protocols. and reviewers on oxygen uptake (VO2) at the ventilatory threshold (ATge). 17 men with heart disease (mean age 59 +/- 6 years) and six healthy men (mean age 60 +/- 11 years) underwent six exercise tests on different days. Each subject performed three treadmill tests (Bruce. Balke. and ramp) and three bicycle ergometer tests (50 W/stage. 25 W/stage. and ramp) in random order. The ventilatory threshold was determined for each of the six exercise tests by three independent. blinded reviewers by means of graphic plots of three commonly used methods of determination: (1) changes in the ventilatory equivalents for VO2 and VCO2. (2) changes in end-tidal oxygen and carbon dioxide pressures. and (3) the intersection of the slope of VCO2 and VO2 (V slope). The largest variability in the ATge was observed with changes in the exercise protocol. The greatest absolute (ml/min) and percentage differences in oxygen uptake at the ATge as a result of changes in protocol. method of determination. and observers were 336 (36%). 125 (12%). and 70 (7%). respectively. The overall intraclass correlation coefficient for VO2 at the ATge among the three reviewers was 0.60 and among the three protocols was 0.85 (p less than 0.01). The V slope method of detection had consistently good agreement among reviewers and was least affected by the protocol. The variance in the ATge (excluding intersubject and error variance) accounted for by differences in protocol. method. and reviewer was 82%. 14%. and 4%. respectively.
Pathophysiology of isolated systolic hypertension in elderly patients: Doppler echocardiographic insights, Systemic hemodynamics were evaluated with aortic pulsed wave Doppler echocardiography in 79 elderly subjects with isolated systolic hypertension participating in the Systolic Hypertension in the Elderly Program (SHEP) and were compared with the values in 39 normal age-matched subjects. Cardiac output was elevated (4.50 +/- 1.13 L/min versus 3.94 +/- 1.12 L/min. p less than 0.05) in patients with isolated systolic hypertension in comparison with values in normal elderly subjects. Systemic vascular resistance did not differ between both groups (2140 +/- 536 dyn.sec/cm-5 versus 2011 +/- 553 dyn.sec/cm-5. p = NS). The mean acceleration of blood during left ventricular ejection was similar in patients with isolated systolic hypertension in comparison with normals (12.6 +/- 5.6 m/sec2 versus 11.5 +/- 3.5 m/sec2. p = NS). Patients with isolated systolic hypertension had significantly decreased arterial compliance. as measured by the stroke volume-to-pulse pressure ratio (0.77 +/- 0.26 cm3/mm Hg versus 1.11 +/- 0.30 cm3/mm Hg. p less than 0.0001). The prevalence of aortic and mitral regurgitation as well as valvular and annular calcification did not differ between analyzed groups. Isolated systolic hypertension in elderly patients appears to be multifactorial. with reduced arterial compliance and increased cardiac output both playing a role.
A critical review of the relationship between impaired fibrinolysis and myocardial infarction, To explore the relationship between impaired fibrinolysis and myocardial infarction. we conducted a literature search and reviewed the published data. The results indicate that myocardial infarction has a significant influence on fibrinolytic activity and that impaired fibrinolysis is more frequent in patients who have had a myocardial infarction than in healthy control subjects. Prospective cohort studies indicate that tests for global fibrinolytic activity are not of prognostic value for first or recurrent myocardial infarction. However. high levels of plasminogen activator inhibitor and low levels of tissue plasminogen activator activity were associated with an increased risk of reinfarction in survivors of a first myocardial infarction. Whether this relationship between impaired fibrinolysis and reinfarction is causal or coincidental is unclear. There is evidence that impairment of fibrinolytic activity is more marked in patients with myocardial infarction who have minimal coronary atherosclerosis than in those who have marked atherosclerosis. suggesting that impaired fibrinolytic activity might be of pathogenetic importance in this small subgroup of patients.
Percutaneous coronary mid-infra-red laser angioplasty, A pilot study was performed to determine the safety and efficacy of coronary pulsed mid-infra-red laser angioplasty. The laser was coupled with a novel 2.0 mm multifiber catheter consisting of 37 optical fibers of 150 microns each arranged concentrically around a 0.018-inch central lumen and a soft leading tapered distal tip to maintain coaxial alignment and position plaque in front of fibers. The laser was operated at 500 millijoules/pulse. 3.5 Hz. and 250 microseconds/pulse. Twenty-three patients with stenosis or occlusion of the left anterior descending or right coronary artery were selected for laser treatment. In three patients the catheter could not be positioned against the obstruction. In the 20 remaining patients laser angioplasty increased the diameter of the lumen from 0.3 +/- 0.3 mm to 1.4 +/- 0.3 mm and reduced the stenosis from 91 +/- 8% to 57 +/- 10%. In three patients "stand-alone" laser treatment was sufficient. In 17 patients balloon dilatation further reduced the stenosis to 20 +/- 18%. In two patients who had previously undergone unsuccessful balloon angioplasty with high inflation pressure. laser angioplasty allowed subsequent successful dilatation with low inflation pressure. There were no deaths. perforations. dissections. or arrhythmias. One patient had abrupt reclosure 24 hours after the procedure. Spasm occurred in four patients. and six patients had chest sensations during laser emission. Thus mid-infra-red pulsed coronary laser angioplasty is safe and effective for recanalization of stenosed and totally occluded arteries. The efficacy may be sufficient for "stand-alone" laser treatment. The technique may improve the efficacy of balloon angioplasty in cases of unsuccessful primary dilatation.
Acute effects of intravenous nicardipine on hemodynamics and cardiac function in patients with a healed myocardial infarction and no evidence of congestive heart failure, Acute effects of intravenous nicardipine (10 micrograms/kg) on systemic hemodynamics and cardiac function were evaluated in 17 patients with a healed myocardial infarction and no evidence of congestive heart failure. Mean New York Heart Association functional class was 1.6 +/- 0.5 (mean +/- standard deviation). Aortic systolic pressure (p less than 0.001) and left ventricular end-diastolic pressure decreased (10 +/- 3 to 8 +/- 3 mm Hg. p less than 0.01). and systemic vascular resistance decreased significantly (p less than 0.001). whereas pulmonary and right atrial pressure and pulmonary arteriolar resistance did not change. Cardiac and stroke indexes showed biphasic changes. Although positive and negative maximal rate of left ventricular pressures decreased significantly (p less than 0.05 and p less than 0.01. respectively). they did not change significantly when aortic systolic pressure was corrected. There was a significant inverse correlation between the negative rate of left ventricular pressure/aortic systolic pressure before nicardipine infusion and its maximal percent increase after infusion (r = -0.56. p less than 0.05). indicating a beneficial effect on diastolic relaxation in patients with impaired diastolic function. Our data show that a low dose (10 micrograms/kg) of intravenous nicardipine exerts a favorable effect on impaired diastolic function. but depresses left ventricular pump function with much less effect on right heart circulation.
Safety and efficacy of percutaneous transluminal coronary angioplasty in patients with left ventricular dysfunction, The risks and long-term outcome after 845 elective percutaneous transluminal coronary angioplasties (PTCA) in patients with left ventricular (LV) dysfunction (ejection fraction less than or equal to 40%) were examined. Procedural results were compared with 8.117 consecutive procedures in patients with ejection fractions greater than 40%. The patients with LV dysfunction were older (63 vs 60 years. p less than 0.01). had a greater incidence of prior myocardial infarction (84 vs 45%. p less than 0.001). prior bypass surgery (39 vs 21%. p less than 0.001). 3-vessel disease (62 vs 33%. p less than 0.001). and class IV angina (48 vs 41%. p less than 0.01) than the control group. Angiographic success was lower (93 vs 95%. p less than 0.01). and overall procedural mortality was increased ( 4 vs 1%. p less than 0.001) in the study group. Emergency surgery rates were identical (2%). No significant difference was found in rates of nonfatal Q-wave myocardial infarction (2 vs 1%). At mean follow-up of 33.5 months. 15% of the patients with LV dysfunction required late bypass surgery. 27% underwent repeat PTCA. and 59% were angina free. Actuarial survival at 1 and 4 years was 87 and 69%. respectively. Cox regression analysis identified 3-vessel disease. age greater than or equal to 70 years. class IV angina and incomplete revascularization as correlates of long-term mortality. These data suggest that PTCA may be an effective treatment for coronary artery disease in patients with LV dysfunction.
Stunned left ventricular myocardium after exercise treadmill testing in coronary artery disease, Myocardial stunning (postischemic ventricular dysfunction) occurs in dogs after coronary stenosis following treadmill exercise. Less data are available in humans regarding development of stunned myocardium after exercise. Regional wall motion changes were evaluated in 22 patients with known coronary artery disease using 2-dimensional echocardiography and exercise treadmill testing. Wall motion was scored as 1 = normal. 2 = hypokinetic. 3 = akinetic. 4 = dyskinetic. At least 1 left ventricular segment with normal resting function developed an increase in wall motion score at 15 or 30 minutes compared with values at rest. The wall motion score in the midportion of the ventricular septum increased from 1.0 at rest to 1.6 (p less than 0.004) at 30 minutes after exercise; the basal inferior wall score worsened from 1.0 at rest to 1.9 (p less than 0.01) at 30 minutes after exercise. Coronary angiographic data in these patients revealed that left anterior descending narrowing correlated best with left ventricular septal wall motion abnormalities. whereas right coronary artery and circumflex narrowing best correlated with inferior and posterior wall motion abnormalities. Eight normal adult volunteers with no history of myocardial ischemia also underwent 2-dimensional echocardiography and exercise testing. No wall motion abnormalities were observed at any time after exercise. The present study suggests that in patients with coronary artery disease. exercise treadmill testing may induce regional wall motion abnormalities of the left ventricle that persist greater than or equal to 30 minutes after exercise. an observation consistent with the phenomenon of stunned myocardium.
Left ventricular shape as a determinant of functional mitral regurgitation in patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy, The relation between left ventricular (LV) shape and functional mitral regurgitation (MR) was evaluated in 39 patients with congestive heart failure. Heart failure was due to coronary artery disease in 23 patients (group I) and to idiopathic dilated cardiomyopathy in 16 (group II). LV shape was quantitated based on the ratio of LV major-to-minor axis and LV sphericity index calculated at end-systole and end-diastole. In group I. 9 patients had angiographic evidence of MR and 14 did not. In group II. 10 patients had MR and 6 did not. Within each group. there were no differences between patients with and without MR with regard to LV chamber volume and regional segmental wall motion abnormalities. In both groups. however. a significant difference was observed between patients with and without MR with respect to end-systolic and end-diastolic LV shape indexes. In group I. the end-systolic major-to-minor axis ratio was lower in patients with (1.42 +/- 0.04) than without (1.72 +/- 0.05) MR (p less than 0.001). Similar differences were observed in group II (1.41 +/- 0.06 vs 1.69 +/- 0.04) (p less than 0.01). In group I. the end-systolic sphericity index was also greater in patients with (0.32 +/- 0.02) than without (0.25 +/- 0.01) MR (p less than 0.02). Similar differences were observed in group II (0.37 +/- 0.03 vs 0.26 +/- 0.01) (p less than 0.02). These data indicate that in patients with severe heart failure. functional MR is present in those who manifest a more spherical LV cavity.
Effects of immunosuppressive therapy in biopsy-proved myocarditis and borderline myocarditis on left ventricular function, Twenty patients with decreased left ventricular (LV) function and endomyocardial biopsy-proved myocarditis (9 patients) or borderline myocarditis (11 patients) were studied to determine whether these 2 histologic subsets of patients with inflammatory heart disease differed in their response to a 6- to 8-week course of immunosuppressive therapy. All patients received a regimen of prednisone. 1.0 mg/kg/day. and azathioprine. 1.5 mg/kg/day. followed by repeat endomyocardial biopsy and reevaluation of LV function. LV function improved significantly in the group with borderline myocarditis. as assessed by LV stroke work--end-diastolic volume ratio (0.26 +/- 0.17 to 0.54 +/- 0.31 kg.m.ml-1. p less than 0.02). heart rate corrected velocity of circumferential shortening (0.49 +/- 0.30 to 0.80 +/- 0.29 circ.s-1. p less than 0.05). and LV ejection fraction (0.30 +/- 0.15 to 0.47 +/- 0.13. p less than 0.05). LV end-diastolic and end-systolic volume indexes also decreased significantly from 129 +/- 40 to 94 +/- 38 (p less than 0.05) and 90 +/- 37 to 49 +/- 26 ml (p less than 0.02). respectively. No significant change in these indexes of LV function or volume occurred in the myocarditis group. Whereas salutory improvements in cardiac output and filling pressures were found in both groups. objective improvement in LV function assessed by complementary indexes of contractility was greatest in the borderline myocarditis group. It is concluded that short-term immunosuppressive therapy improves LV contractile function and appears to be associated with regression of ventricular dilatation in patients with borderline myocarditis to a greater extent than patients with myocarditis.
Left ventricular filling abnormalities in asymptomatic morbid obesity, Indexes of left ventricular (LV) diastolic filling were measured by pulse Doppler echocardiography in 16 asymptomatic morbidity obese patients presenting for bariatric surgery and were compared with an age- and sex-matched lean control population. No patient had concomitant disorders known to affect diastolic function. All patients had normal systolic function. LV wall thickness and internal dimension were measured in order to calculate LV mass. Fifty percent of morbidly obese patients had LV diastolic filling abnormalities as assessed by the presence of greater than or equal to 2 abnormal variables of mitral inflow velocity. The ratio of peak early to peak late (atrial) filling velocity was significantly decreased in obese compared with control patients (1.16 +/- 0.26 vs 1.66 +/- 0.30. p less than 0.001). The peak velocity of early LV diastolic filling was significantly reduced in obese patients (75 +/- 15 vs 98 +/- 19 cm/s. p less than 0.001). The atrial contribution to stroke velocity as assessed by the time-velocity integral of late compared with total LV diastolic filling was significantly increased in obese patients (36 +/- 7 vs 27 +/- 4%. p less than 0.001). Obese patients had significantly increased LV mass (214 +/- 45 vs 138 +/- 37 g. p less than 0.001). even when corrected for body surface area (95 +/- 16 vs 76 +/- 16 g/m2. p less than 0.002). However. increased LV mass did not correlate with indexes of abnormal diastolic filling in obese patients. These data suggest that abnormalities of diastolic function occur frequently in asymptomatic morbidly obese patients and may represent a subclinical form of cardiomyopathy in the obese patient.
Changes in body weight, body composition, and energy intake in women fed high- and low-fat diets, The effects of a 20%-fat diet (LF) on total body weight. lean body weight. and adiposity were studied in 18 premenopausal women with body mass index (BMI) of 18-44. Subjects were fed a 37%-fat (HF) control diet for 4 wk followed by the LF diet for 20 wk. Total body weight. lean body weight. and fat weight were measured at the end of the HF and LF dietary periods by hydrostatic weighing. Despite adjustments in energy intake to maintain weight throughout the study. subjects exhibited a 2.8% decrease in total body weight (P less than 0.0006). an 11.3% decrease in fat weight (P less than 0.0001). and a 2.2% increase in lean body weight (P less than 0.0149) by the end of the LF period. Similar changes were observed in obese (BMI greater than 30) and non-obese women (BMI less than 30). By the end of the LF period. energy intake had increased significantly in comparison with the HF diet (119% of the HF intake. P less than 0.0001). Results could not be explained by changes in daily activity levels and suggest that macronutrient composition plays a role in energy requirements for weight maintenance.
Fluoxetine's effect on weight loss in obese subjects, Forty-five obese subjects with a mean weight of 102.9 kg and a body mass index (in kg/m2) of 37.6 were randomly assigned to a fluoxetine-diet group (n = 23) or a placebo-diet group (n = 22) for 52 wk. At week 29. 14 subjects on fluoxetine who completed the study attained their maximum weight loss of 12.4 kg. an amount significantly greater than the maximum weight loss of 4.5 kg for the 16 on placebo who completed the study. The fluoxetine group's significantly greater mean weight loss continued through week 45. However. those on fluoxetine regained a mean of 4.2 kg from their lowest weight (P less than 0.001) whereas the placebo group did not. By the end of the study. each group weighed significantly less than they did at baseline (fluoxetine: -8.2 kg; placebo: -4.5 kg; P less than 0.05) although the difference between groups was no longer significant (P greater than 0.05). Several factors were considered as possible causes for the regain with fluoxetine.
Effect of dietary menhaden oil on normal growth and development and on ameliorating mucosal injury in rats, We evaluated the effects of menhaden oil on growth and development of the small intestinal mucosa in growing rats and on the progression and resolution of methotrexate-induced mucosal injury in the rats. One study compared effects of diets containing 10% safflower oil(SO). 9% SO and 1% menhaden oil (MO). 10% MO. or 9% MO and 1% SO on mucosal growth and development for 125 d. In another study. animals fed the 10% MO or the 10% SO diet for 5 wk were subjected to subcutaneous methotrexate injections for 3 consecutive days. Feeding rats a diet containing large amounts of menhaden oil resulted in lower prostaglandin E2 and leukotriene B4 synthesis and lower sucrase activities. Indicators of mucosal mass after methotrexate-induced injury were significantly improved in both the jejunum and ileum at 3 and 10 d after methotrexate administration. Our data suggest that dietary menhaden oil stimulates mucosal regeneration after methotrexate-induced injury.
Proline metabolism in adult male burned patients and healthy control subjects, Postabsorptive proline flux. oxidation. and endogenous biosynthesis were determined in five severely burned intensive-care-unit patients (mean age 27 y) and in six healthy. young-adult control subjects. Continuous primed. intravenous. 160-min. dual stable-isotope-tracer infusions of L-[1-13C]proline and L-[methyl-2H3]leucine were used in conjunction with measurement of plasma proline concentration and 24-h urinary hydroxyproline output. Burn patients. compared with normal individuals. demonstrated a doubling in proline and leucine flux (P less than 0.01 for both findings). a threefold enhancement of proline oxidation (P less than 0.05). a trend toward decreased proline synthesis. and a 37% reduction in plasma proline concentrations (P less than 0.05). Further. the injured group. unlike the control group. was in a distinct negative body proline balance. as proline oxidation greatly exceeded endogenous proline biosynthesis (P less than 0.01). These studies indicate that significant proline deficits may evolve during the postabsorptive period in severely burned patients and that an exogenous supply of proline might benefit the nitrogen economy of the traumatized patient.
Zinc deficiency. A public health problem, Zinc deficiency occurs in individuals and populations whose diets are low in sources of readily bioavailable zinc such as red meat. and high in unrefined cereals that are rich in phytate and dietary fibers. Dietary zinc deficiency was described nearly three decades ago among the poor of the Middle East. It is now known to occur in children and adolescents from widely diverse areas including Egypt. Iran. Turkey. China. Yugoslavia. Canada. and the United States; and among pregnant women from Iran. Turkey. the United Kingdom. Australia. and the United States. Major manifestations include retarded growth and development and an increased incidence of pregnancy complications. Other manifestations may include suppressed immunity. poor healing. dermatitis. and impairments in neuropsychological functions. Precise information as to the numbers of people affected by dietary zinc deficiency is not available. Even so the nature of diets associated with zinc deficiency suggests that mild deficiency is common in some populations.
Paleonephrology and reflux nephropathy. From the 'big bang' to end-stage renal disease, Urinary tract infections. in association with ureteral reflux or dysperistalsis. may lead to invasive renal parenchymal infection and residual scarring (reflux nephropathy). Such infections in infants are often not diagnosed during the acute phase. Late sequelae of reflux nephropathy include hypertension. proteinuria. or chronic renal failure. The latter may eventuate in the subset of patients with urinary tract infection and unilateral reflux extending to a solitary kidney or bilateral reflux. Proteinuria may herald the inexorable progression of glomerular sclerosis in patients destined to progress to end-stage renal disease. despite the absence of further recurrences of urinary tract infections. The mechanism of progression is probably similar to that occurring in other forms of chronic. diffuse parenchymal renal disease. which all have similar alterations in glomerular hemodynamics (an increase in glomerular capillary flow. pressure. and filtration). The consequent hyperfiltration per nephron may be related to the level of dietary protein intake or to some derivative of the protein load. Hyperfiltration appears to recapitulate the presumed renal hemodynamic response to the relatively high level of episodic meat consumption by paleolithic hunter-gatherers. A prudent therapeutic intervention in children with progressive reflux nephropathy may be a proportional reduction in protein intake.
Immunization response varies with intensity of acute lymphoblastic leukemia therapy, Twenty-four children receiving maintenance chemotherapy for acute lymphoblastic leukemia were given booster doses of tetanus-diphtheria combined toxoids. One month later. 19 of the 24 children were given Haemophilus influenzae B oligosaccharide-cross-reacting material conjugate vaccine. Following immunization. all patients had protective antibody titers against tetanus. 92% had protective antidiphtheria titers. and 84% had protective titers against H influenzae. Preimmunization titers. postimmunization titers. and response to immunization varied according to the intensity of therapy. There was no correlation with duration of therapy or quantitative hematologic values in the peripheral blood. These observations support the recommendation that children treated for acute lymphoblastic leukemia should be immunized against H influenzae B.
Immunogenicity of tetravalent rhesus rotavirus vaccine administered with buffer and oral polio vaccine, Between January and November 1989. we studied 174 infants aged 6 to 16 weeks in a randomized clinical trial to (1) determine the immunogenicity of a single dose of tetravalent rhesus rotavirus vaccine (RRV-TV) when administered with three different buffer regimens: no antacid buffer and small-volume (2.5-mL) and large-volume (30-mL) antacid buffer; and (2) examine the potential interference of RRV-TV on the immune response to oral polio vaccine. Immunogenicity of RRV-TV. measured as a fourfold rise in antibody titers to rotavirus. was similar in the groups receiving small- and large-dose buffer (45% and 49%. respectively) and significantly less in the group that received RRV-TV alone (23%). Administration of RRV-TV with oral polio vaccine did not significantly interfere with the neutralization response of oral polio vaccine poliovirus serotypes 1. 2. or 3. and overall. 29%. 87%. and 24% of the infants had a fourfold rise in titer to each serotype. respectively.
Transfusion therapy in neonates, Infants. particularly those who were very small premature neonates. are among the most common of all patient groups to undergo extensive transfusion. It is estimated that approximately 300.000 neonates undergo transfusions annually. Most infants who undergo transfusion are exposed to multiple blood donors. and although each exposure poses only a small risk. the potential for adverse effects of multiple transfusions is not variable. and based on scanty scientific information. For the most part. controlled scientific studies have not been performed to clearly establish the indications for the transfusion of blood components to neonates. Considering these limitations. guidelines are offered for the transfusion of red blood cells. platelets. and neutrophils into neonates.
Use of infant walkers. Board of Trustees, American Medical Association, Infant walkers are used by many parents because of the convenience they provide in keeping children occupied. Unfortunately. parents may develop a false sense of security that leads to diminished vigilance over the safety of their infant. Although most injuries that result from walkers are minor. serious trauma from head injuries. lacerations. and burns does occur occasionally. The American Medical Association recommends that physicians counsel parents on the risk of injury that can occur from the use of infant walkers and inform parents that these devices do not either promote bipedal ambulation or offer a substitute for careful parental supervision.
Low serum calcium and high parathyroid hormone levels in neonates fed 'humanized' cow's milk-based formula, We previously suggested that "late" neonatal hypocalcemia is related to a low calcium-phosphorus ratio of current cow's milk-based formula compared with human milk. However. there are no longitudinal studies of ionized calcium and parathyroid hormone concentrations in neonates receiving formulas with varying Ca/P ratios. Sixty-nine term neonates were studied through 2 weeks of age. and formula-fed neonates were randomized at birth to receive formula with molar ratios of 0.9. 1.2. or 1.4. Serum phosphate concentrations on days 2 and 6 of age were higher. and ionized calcium levels lower on days 6 and 14. in formula-fed vs human milk-fed neonates. Serum intact parathyroid hormone level increased between days 2 and 6 in formula-fed neonates compared with a decrease in human milk-fed neonates. Serum parathyroid hormone level on day 6 correlated with phosphorus intake among formula-fed neonates. No differences were noted in serum mineral or hormone levels among formula-fed groups. We speculate that the lowering of serum ionized calcium concentrations in neonates fed a modern "humanized" cow's milk formula may be a factor in late neonatal hypocalcemia.
Choledocholithiasis in cirrhotic patients: is endoscopic sphincterotomy the safest choice, Of the 18 endoscopic sphincterotomies performed on 18 cirrhotic patients for choledocholithiasis. a mortality rate of 16.6% was registered. However. this figure can be limited to 6.6% if we take only successful sphincterotomies (15/18. 83.3%) into account. After closely reviewing relevant literature. it would appear that operative mortality in comparable cases is much higher. We therefore recommend that endoscopic sphincterotomy. despite higher mortality rates when compared to the general population. should be the initial choice of management of choledocholithiasis in cirrhotic patients.
Preoperative and intraoperative fine needle aspiration cytology of pancreatic lesions, The aim of the present study was to describe our experience from 1976 through 1988 with fine needle aspiration (FNA) cytology of pancreatic lesions in 90 patients. Fine needle aspirations were performed preoperatively under ultrasound guidance (USG) in 46 patients. under computed tomographic guidance (CTG) in seven patients. and intraoperatively in 37 patients. Based on histologic. cytologic. and clinical findings. final diagnoses were reached in 80 patients. of whom 62 had malignant pancreatic disease (MPD) and 18 had benign pancreatic disease (BPD). The accuracy of cytologic diagnoses was verified by histologic. cytologic. and clinical findings. In 62 patients with MPD. the cytologic findings suggested malignancy in 54 patients. suspected malignancy in five. and did not reveal malignancy in three patients. Among 18 patients with BPD. all of the cytologic findings were reported as benign. The sensitivity. specificity. positive and negative predictive values. and diagnostic accuracy for intraoperative FNA cytologic results were 96%. 100%. 100%. 91%. and 97%. respectively. and for USG FNA cytologic results were 94%. 100%. 100%. 78%. and 95%. respectively. No complications followed the procedure. Conclusions: Both transabdominal percutaneous imaging-guided and intraoperative FNA cytology of pancreatic lesions are simple. safe. and highly accurate methods in differentiation of benign from malignant pancreatic lesions.
Prognostic implications of the localization of carcinoma in the head of the pancreas, Between 1974 and 1989. 411 patients with pathologically and anatomically proven carcinoma of the head of the pancreas underwent endoscopic retrograde cholangiopancreatography (ERCP). According to the localization of the tumor. these patients were divided into those with a cranially. centrally (periductally). caudally. or indeterminately localized tumor. In cranially localized tumors. extrahepatic metastases and vessel invasion were absent or resectable in 53% and 46%. respectively. The tumor was resectable in 41% of cases. If a patient with a cranially localized tumor could not be operated curatively for secondary reasons. the prognosis was better than for tumors with another localization. If there was unresectable vessel invasion and the tumor was not resectable. the 0% survival rate was reached at 33 months. Of the curatively operated patients. 26% were alive at 36 months after the start of complaints. Of the centrally or periductally localized tumors. there were no liver metastases in 73%. Extrahepatic metastases and vessel invasion were absent or resectable in 57% and 53%. respectively. The tumor was resectable in 48% of cases. If there was unresectable vessel invasion or the tumor was unresectable. the 0% survival rate was reached after 18 months. These tumors have maximal chances at curative resection. Of the curatively operated patients. 31% were alive at 36 months after the start of complaints. In caudally localized tumors. there were liver metastases in 59%. unresectable other abdominal metastases in 93%. unresectable vessel invasion in 91%. and the tumor was unresectable in 96%. In patients with an unresectable vessel invasion or an unresectable tumor. the 0% survival rate was reached after 33 months; 3% of these patients were operated curatively. Indeterminately localized tumors had liver metastases in 77%. unresectable extrahepatic metastases in 90%. unresectable vessel invasion in 95%. and the tumor was unresectable in 91%. Only one of the 44 patients (2%) could be operated curatively.
Small bowel length in Crohn's disease, The length of the small intestine in patients with Crohn's disease who are referred for surgery has not been well studied. In this report. 25 patients with Crohn's disease who were being operated on for the first time had their small intestine measured at the time of surgery. The mean length of small intestine in this group was 501 cm. which was not different from a group of patients without Crohn's disease who were being operated on for other problems. In the group of patients with Crohn's disease. as well as the entire group. there was a correlation between increasing height and longer small bowel length. No other parameters investigated. including weight. surface area. age. sex. and duration of disease. correlated with bowel length. The results of this study are somewhat encouraging to patients with Crohn's disease. since these patients do not start off with a shortened bowel prior to surgery.
Pill-esophagitis caused by nonsteroidal antiinflammatory drugs, A case of meclofenamate-induced pill-esophagitis is reported. and the relevant literature is reviewed. The role of posture. amount of fluid chaser. esophageal obstruction or dysmotility. drug formulation. physical and chemical properties of the drug. and concomitant ingestion of alcohol. as well as the diagnosis and management of such cases. are discussed.
Screening for colon malignancy with colonoscopy, Screening of asymptomatic individuals for colon malignancy has been advocated for the past 20 yr in the hopes of reducing colon cancer mortality. Although sigmoidoscopy is an important element of current screening recommendations. the sensitivity of this test in asymptomatic subjects has never been studied. The purpose of this study was to determine the prevalence and location of polyps and cancers in an asymptomatic population by performing full colonoscopy. We wished to assess the sensitivity of screening flexible sigmoidoscopy to 60 cm by determining how many patients with adenomas or cancer had "index" adenomatous polyps in the distal 60 cm. One hundred five healthy male outpatients. over 50 yr old. with negative examinations for occult blood in stools and no prior history of colon pathology. had full colonoscopy. Careful examination of the distal 60 cm was performed. followed by a full colon examination to the cecum. Forty-three patients (41%) had adenomatous polyps. and only 19 of these patients had an index adenomatous polyp in the distal 60 cm. Therefore. the sensitivity of sigmoidoscopy was 44%. The prevalence of adenomas increased with age. Patients were assigned to one of three groups based on the findings in the distal 60 cm. Group 1 (n = 65) had no polyps in the distal 60 cm. but 18 of these patients (28%) had adenomatous polyps in the proximal colon. Among 21 patients with only hyperplastic polyps in the distal 60 cm (group 2). six patients (29%) had proximal adenomas. In group 3. eight of 19 patients (42%) with adenomas in the distal 60 cm also had proximal adenomatous polyps. We conclude that adenomatous polyps are common in asymptomatic men who have negative tests for fecal occult blood. Sigmoidoscopy to 60 cm had a sensitivity of only 44% in this patient population. suggesting that this is an insensitive test for the detection of patients with adenomatous polyps.
Upper gastrointestinal lesions in elderly patients presenting for endoscopy: relevance of NSAID usage, The occurrence of upper gastrointestinal disease and the relevance of nonsteroidal antiinflammatory drug (NSAID) usage were documented in 511 consecutive patients (321 women. 190 men) over 70 yr old. referred for upper gastrointestinal endoscopy in a district general hospital. The findings were benign esophageal disease (43%). normal (15%). gastric ulcer (11.5%). and duodenal ulcer (11%). Gastric ulcers were more common in women taking NSAIDs (25%) than in NSAID abstainers (7%) p less than 0.001 and male NSAID users (8%) p less than 0.001. Esophagitis and esophageal stricture were not influenced by NSAID usage. but gastric erosions were more common (10% vs. 3%) p less than 0.01. Of 142 patients receiving NSAIDs. 41% presented with hemorrhage. compared with 20.5% of NSAID abstainers (p less than 0.001). Hemorrhage was as common in aspirin takers (15 of 33. 45%) as in standard-dose NANSAID takers (43 of 109. 39%). even though 86% were taking 300 mg of aspirin per day or less. In elderly patients. esophageal disease is common. NSAID use. even low-dose aspirin. is associated with an increased risk of hemorrhage. In females. NSAID usage is associated with gastric ulcer.
Malaria in travelers in Rhode Island: a review of 26 cases, PURPOSE: We reviewed our experience with malaria in two community hospitals in Rhode Island from 1986 to 1990. RESULTS: Twenty-six patients with malaria were identified. Fifteen patients were immigrants who had acquired malaria while visiting their country of origin. particularly West Africa. Fever was present in 67% of cases and gastrointestinal complaints were prominent in 26%. Individuals with a past history of malaria could accurately distinguish current malarial infections from other febrile illnesses. Two patients developed cerebral malaria. Plasmodium falciparum was identified in 77% of the cases. CONCLUSIONS: Malaria is an important diagnosis that United States physicians must consider in the medical evaluation of returning travelers. A significant increase in the number of cases of P. falciparum acquired in East Africa has been reported in recent years. P. falciparum infection must be rapidly diagnosed and treated since delays may result in complications of malaria that may lead to death. Mefloquine is currently recommended by the Centers for Disease Control for prevention of malaria in travelers visiting countries endemic for chloroquine-resistant malaria. This change may alter the epidemiology of malaria in the United States in the future.
Activation of the host response in human Plasmodium falciparum malaria: relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels, PURPOSE: Hemostatic alterations and elevated tumor necrosis factor/cachectin (TNF alpha) serum levels may contribute to the pathogenesis of organ complications in human Plasmodium falciparum malaria. Therefore. we examined whether altered protein C (PC) and thrombin-antithrombin III (TAT) plasma levels correlated with TNF alpha serum concentrations. parasitemia. and the clinical course of human P. falciparum malaria. PATIENTS AND METHODS: Forty-seven patients with P. falciparum malaria were evaluated prospectively before and during antiparasitic therapy. TNF alpha serum levels were determined by immunoradiometric assay. PC and TAT plasma antigen by enzyme-linked immunosorbent assay. and PC and PC inhibitor-1 (PCI-1) activity levels by functional tests. Cultured endothelial cells were incubated with serum from four patients with malaria and from healthy control subjects and then assayed for procoagulant activity. Northern blot hybridization was used to detect tissue factor mRNA. RESULTS: In vivo. TNF alpha serum concentrations were elevated (median: 38.6 pg/mL; n = 47) while plasma levels of PC (antigen 55.4%; activity 39.0%; n = 47) and PCI-1 (0.56 U/L) were decreased in almost all patients before antiparasitic treatment. At the same time. TAT concentrations were high. These alterations correlated significantly (p less than 0.01) both with the severity of the disease (as defined by organ impairment) and with the number of circulating parasitized erythrocytes. Low PCI-1 activity correlated with low PC activity (p less than 0.001) and antigen (p less than 0.05) levels. The plasma level of coagulation factor IX. another vitamin K-dependent protein. was not significantly changed. In vitro. incubation of endothelial cells with patient serum (severe P. falciparum malaria) increased both endothelial cell procoagulant activity and cytoplasmic tissue factor mRNA levels. CONCLUSION: Elevated levels of TNF alpha and TAT. decreased plasma levels of anticoagulant PC. and the induction of procoagulant activity in endothelial cells by patient serum indicate a shift in the balance of hemostatic activity towards a procoagulant state in P. falciparum malaria. The alterations in TNF alpha. TAT. and PC levels may be a response to infection. since they correlate with parasitemia and are reversed during antiparasitic treatment.
Infection of Anopheles darlingi fed on patients with Plasmodium falciparum before and after treatment with quinine or quinine plus tetracycline, Anopheles darlingi fed on eight falciparum malaria patients with gametocytes before and after treatment with quinine sulfate or quinine sulfate plus tetracycline became infected. Quinine and quinine plus tetracycline had no apparent sporontocidal or gametocytocidal effect on late stage immature and mature gametocytes. Plasmodium falciparum gametocytes are persistent and infected mosquitoes for up to 21 days after patients were treated with quinine plus tetracycline. Sporogonic development was similar for groups of mosquitoes fed before and after patients were treated with these schizontocides. The percentages of infected mosquitoes that developed salivary gland infections were also similar for groups of mosquitoes fed before and after treatment. Twenty-four hours after treatment with 45 mg of primaquine phosphate. falciparum malaria patients were not infective to An. darlingi.
Conserved and variant epitopes of target antigens of transmission-blocking antibodies among isolates of Plasmodium falciparum from Malaysia, Monoclonal antibodies (MAbs) directed against different epitope regions on three sexual stage-specific gamete surface proteins of Plasmodium falciparum. Pfs 25. Pfs 230. and Pfs 48/45. were used to study the genetic diversity of these epitopes among fresh isolates of P. falciparum from Malaysia. using immunofluorescence microscopy (IFA). Among 45 Malaysian isolates. one epitope of Pfs 25. designated region I. showed evidence of variable reactivity with MAbs among different isolates; the Pfs 25 epitope. region II. was universally recognized by MAbs in all isolates. Two apparently distinct epitope regions of Pfs 230 were defined by MAbs. one of which was universally recognized by MAbs among the 45 isolates; the other was conserved in all but three isolates. The epitope regions of gamete-surface protein Pfs 48/45. designated regions I. IIa. IIb. IIc. III. and IV. were examined for reactivity by IFA in 33 isolates. Epitope regions I. IIb. III. and IV were conserved in all isolates; regions IIa and IIc existed in variant forms.
Cellular proliferative responses in squirrel monkeys immunized with recombinant and synthetic Plasmodium vivax circumsporozoite peptides, The role of circulating peripheral blood momonuclear cells (PBMC) in mediating protective immunity was examined during an immunization trial in Saimiri monkeys. Three engineered constructs representing different but overlapping regions of the circumsporozoite (CS) protein of Plasmodium vivax were used to immunize the Saimiri monkeys. Monkeys were randomly placed into three immunization groups: rPvCS2. rPvCS3. and LCV3 (representing three different but overlapping portions of the P. vivax CS protein) and two control groups: an alum adjuvant control group and an unimmunized control group. Collections of PBMC were made throughout the study at weeks 0. 2. 8. challenge (week 16). and two weeks after challenge. Proliferative responses to all immunogens and pokeweed mitogen were measured in all monkeys. Fourteen of 18 monkeys immunized with either rPvCS2 or rPvCS3 responded on the day of challenge to the appropriate immunogen with a stimulation index less than 2. Immunization with LCV3. which represents the repeat region only. elicited a specific response in only one monkey. However monkeys in both control groups also responded to rPvCS2 and rPvCS3. regardless of immunization. suggesting the presence of epitopes in rPvCS2 and rPvCS3 capable of associating with differing MHC antigens. Furthermore. the frequency of these cells in the periphery was increased by immunization. as demonstrated by a greater number of responding monkeys in the rPvCS2 and rPvCS3 immunized groups.
Resistance to antimalarials by Plasmodium falciparum in Arso PIR, Irian Jaya, Indonesia, Between 1987 and 1990. susceptibility of Plasmodium falciparum to chloroquine and to Fansidar was measured in vivo in 151 volunteers using the standard 7-day test. All volunteers lived in Arso PIR. Irian Jaya. A 25 mg/kg dose of chloroquine base was administered over a three-day period to 92 volunteers positive for P. falciparum rings (greater than 10 rings/200 white blood cells). Fifty volunteers (54%) showed results consistent with resistance. Twenty-nine were classified RII. and 21 RIII. In November 1989. a single curative dose of Fansidar was administered to 59 volunteers divided among three groups with 18 months. four years. and life-long exposure to endemic malaria. The proportion of volunteers in each group still positive for P. falciparum on day 7 of followup was 54%. 0%. and 14%. respectively. Thus. immune status profoundly effected clinically response to Fansidar. Standard in vitro microtests were also performed on parasites from 11 volunteers against chloroquine. amodiaquine. quinine. pyrimethamine/sulfadoxine. and and mefloquine. Nine of ten isolates showed in vitro growth consistent with resistance to chloroquine. Tests with other drugs showed few isolates with results considered indicative of susceptibility. Arso PIR has a severe drug resistance problem.
Characterization and classification of leishmanial parasites from humans, wild mammals, and sand flies in the Amazon region of Brazil, Ninety-four leishmanial isolates from the Brazilian Amazon Region (Amapa. Amazonas. Para. and Rondonia) were identified and classified using specific monoclonal antibodies and an indirect radioimmunoassay (serodeme analysis); eighty-two were also characterized by enzyme electrophoresis (zymodeme analysis). the results of which were subjected to a numerical phenetic analysis. Six isolates from humans (3). Didelphis marsupialis (1). Lutzomyia olmeca nociva (1). and Lu. reducta (1) showed reactivity patterns and isoenzyme profiles similar to those obtained with the Leishmania amazonensis reference strains. and were identified as this species. Eighty-six stocks were classified as members of the L. braziliensis complex; of these. 61 were L. guyanensis or variants. which presented three serodeme subtypes. but whose isoenzyme profiles were all similar to the reference strain. A total of 15 isolates were distinguished as L. braziliensis or variants and were classified into five serodeme subtypes. The isolate from Psychodopugus davisi appeared. from the numerical analysis. to be a distinct parasite species. Ten isolates showed reactivity patterns and isoenzyme profiles similar to those obtained with the L. naiffi reference strain. A parasite isolated from Ps. claustrei appeared to be different from all reference strains by both techniques. and was classified as probably being a new species. The importance of these results with respect to the taxonomic status of the New World Leishmania. and their implications for both clinical and epidemiologic data are discussed.
Characterization of Leishmania colombiensis sp. n (Kinetoplastida: Trypanosomatidae), a new parasite infecting humans, animals, and phlebotomine sand flies in Colombia and Panama, Characterization of Leishmania colombiensis sp.n. is presented. which on the basis of biological and molecular criteria. appears to be a new member of the L. braziliensis complex. A total of nine isolates of the new parasite were made in Colombia and Panama between 1980 and 1986: two from human cases of cutaneous leishmaniasis. six from phlebotomine sand flies. and one from a sloth. Although most closely related to L. lainsoni. L. colombiensis sp.n. is clearly distinguishable from other members of the genus by its reactivity with monoclonal antibodies. isoenzyme electrophoresis. and restriction endonuclease fragment patterns of kinetoplast DNA (k-DNA).
Evaluation of a monoclonal-antibody based antigen assay for diagnosis of Wuchereria bancrofti infection in Egypt, Conventional methods for diagnosis of Wuchereria bancrofti infection are insensitive and often impractical because of the need for night blood collections. A sensitive and specific antigen detection assay has been developed for W. bancrofti. which is based on a monoclonal antibody (AD12) that binds to a repeated epitope on a 200 kDa adult worm excretion product present in sera from infected humans. The only formal evaluation of this assay to date was performed with sera from India. In the present study. we have evaluated the performance of the AD12 antigen assay in two laboratories with sera collected in endemic and non-endemic areas in Egypt. Antigen was detected in 57 of 59 (97%) sera from microfilaremic subjects. and in 22 of 139 asymptomatic and amicrofilaremic subjects who reside in a highly endemic area. Antigen titers were significantly correlated with microfilaria counts (r = 0.41. P less than 0.01). Filarial antigen was not detected in most sera from amicrofilaremic subjects with clinical filariasis. Comparative antigen test results obtained from laboratories in Cairo and St. Louis agreed in 170 of 173 sera tested. Filarial antigen was not detected in sera from Egyptians with no history of residence in filaria-endemic areas. Specifically. nonendemic sera from patients with other parasitic infections (schistosomiasis. fascioliasis. ascariasis. etc.) were uniformly negative in the assay. We conclude that the AD12 filarial antigen assay is sensitive and specific for W. bancrofti infection in Egypt.
Vaccine effect of intact metacestodes of Taenia crassiceps against T. taeniaeformis infection in rats, Wistar rats inoculated intraperitoneally with 10 viable metacestodes of Taenia crassiceps without adjuvant once on day 0 showed strong resistance to challenge with 200 eggs of T. taeniaeformis on day 30. When rats were killed one month after challenge. there were 80.4% and 46.1% reductions in the number of cystic and total metacestodes of T. taeniaeformis in the liver. respectively. When five rats were killed 16 months after challenge. they showed almost complete immunity against the challenge. with 99.4% and 91.1% reductions in the number of cystic and total metacestodes. respectively. There were only a few degenerated. pin-point metacestodes of T. taeniaeformis in the liver of all five rats; one harbored one cystic metacestode as well. However. there were no such reductions in rats injected initially with cyst fluid antigens of T. crassiceps with Freund's complete adjuvant. An additional experiment was carried out using 500 eggs of T. taeniaeformis in order to confirm the vaccine effect against higher egg dose. There were 96.6%. 87.9%. 83.9%. and 79.3% reductions in the number of cystic metacestodes in rats initially inoculated with 10 viable. 10 formalized. and 10 frozen metacestodes. and injected with sodium deoxycholate-solubilized metacestode antigens. respectively. It is strongly suggested that rats singly dosed with 10 viable or non-viable. intact metacestodes of T. crassiceps without adjuvant became highly resistant to challenge infection with eggs of T. taeniaeformis. which resulted in almost no cystic metacestode establishment.
The response to chemotherapy of serum Mycobacterium leprae-specific antigen in multibacillary leprosy patients, We have examined the Mycobacterium leprae phenolic glycolipid-I (PG-I) antigen levels in the sera of 45 multibacillary leprosy patients commencing chemotherapy. The PG-I antigen levels correlated with the bacterial and morphological indices. but not with the serum IgM anti-PG-I antibody levels. Antigen levels were significantly higher in patients with diffuse skin infiltration. but did not vary significantly with other parameters reflecting the duration and extent of untreated disease. The PG-I antigen levels in 27 patients examined serially decreased consistently over the first year of multidrug therapy.
Isoflurane impairs the function of ischemic myocardium in acutely but not in chronically instrumented dogs, To compare the effects of isoflurane on ischemic myocardium in acutely and chronically instrumented animals. 12 mongrel dogs were monitored with electromagnetic or Doppler ultrasonic flow transducers and hydraulic occluders around the left circumflex coronary artery. pressure transducers in the left ventricle. and heparin-filled catheters in the descending aorta. Regional function of normal and ischemic myocardium was assessed by sonomicrometry. The hemodynamic effects of isoflurane (2% inspired concentration) were more pronounced in the acutely than in the chronically instrumented dogs. Decreases in mean arterial pressure (-47% +/- 5% in the acute and -22% +/- 4% in the chronic preparation. P less than 0.01). left ventricular contractility (-51% +/- 6% and -33% +/- 4%. P less than 0.01). and coronary perfusion pressure (-59% +/- 6% and -12% +/- 9%. P less than 0.01) were more distinct in the acutely instrumented animals. Although the reduction of regional function during isoflurane anesthesia was similar in normal myocardium in both preparations (-33% +/- 4% acute and -34% +/- 6% chronic preparation. not a significant difference). an exaggerated dysfunction was observed in the ischemic myocardium of the acutely instrumented dogs (-66% +/- 2% and -30% +/- 4%. P less than 0.01). It is concluded that acutely instrumented dogs respond to the hemodynamic effects of isoflurane. resulting in ischemic myocardial dysfunction. significantly more than do chronically instrumented dogs.
Effects of atracurium and pancuronium on the oculocardiac reflex in children, The authors compare the effect of two muscle relaxants. atracurium and pancuronium. on the bradycardia resulting from the oculocardiac reflex during eye surgery for strabismus in children. Two groups. each composed of 15 children. received either pancuronium or atracurium during strabismus operations. Heart rate and rhythm were observed at several points during the operations. and the changes that occurred in the two groups were compared. We found that the incidence and severity of the bradycardia. the incidence of dysrhythmias. and the need for atropine administration were significantly greater in the atracurium group than in the pancuronium group.
Clinical and metabolic responses to different types of premedication, Clinical and metabolic responses to three types of premedication were studied in ASA physical status I patients given any one of the following: (a) 0.5 mg of atropine and 50 mg of meperidine given intramuscularly plus an oral placebo tablet (n = 14). (b) 10 mg of oral diazepam and an intramuscular placebo (2 mL NaCl. concentration = 0.9) (n = 14). or (c) oral and intramuscular placebo (n = 14). Based both on subjective estimates (tiredness. fear. anxiety. dryness of mouth) and. especially. on metabolic responses (energy expenditure. oxygen consumption). oral diazepam appears to be superior to the combination of an opiate (meperidine) plus an anticholinergic (atropine). Atropine plus meperidine significantly increased energy expenditure above predicted values (2061 +/- 365 vs 1714 +/- 361 kcal/24 h. P = 0.004). calculated using the Harris-Benedict equation. based on sex. weight. height. and age. as well as increased oxygen consumption above levels seen with diazepam premedication (160 +/- 29 vs 137 +/- 17 mL.min-1. m-2). These findings indicate an iatrogenic stress factor induced by premedication with atropine plus meperidine.
Alfentanil infusion for postoperative pain: a comparison of epidural and intravenous routes, The efficacy of intravenous (iv) and epidural infusions of alfentanil for postoperative pain relief was investigated in 24 patients (ASA physical status 1-2) who were scheduled for abdominal hysterectomy. The patients were allocated randomly to receive either epidural or iv alfentanil. In both groups. a loading dose of 15 micrograms.kg-1 was administered. followed by a constant rate infusion of 18 micrograms.kg-1.h-1 alfentanil for 20 h. Both routes provided similar degrees of analgesia; however. analgesia occurred earlier in the intravenously treated group (P less than 0.03). Mean plasma alfentanil concentrations (Cps) varied between 42 and 82 ng.ml-1 in the iv group and 23 and 68 ng.ml-1 in the epidural group. with higher concentrations in the iv group for the first 60 min only (P less than 0.01). Cps increased with infusion time. suggesting accumulation of alfentanil. After infusion ended. pain recurred at the same time in both groups. whereas the alfentanil Cps still were greater than 45 ng/ml. Postoperative epinephrine concentrations decreased after 60 min of infusion (P less than 0.02). whereas. after 6 h. cortisol levels decreased to preoperative values. Norepinephrine concentrations decreased only slightly. The only clinically meaningful effect on vital signs that occurred was an abrupt reduction of respiratory rate after the iv loading dose. PaCO2 increased to the same extent in both groups during the first 15 min only. The incidence of opioid-related side effects was similar in both groups. These results suggest that the iv and epidural routes were equally effective for providing postoperative pain control and controlling the postoperative response to surgical stress.
Flumazenil antagonism of midazolam-induced ventilatory depression, Flumazenil. a benzodiazepine antagonist. reliably reverses midazolam-induced sedation; however. its effect on respiratory depression has not been established completely. Twelve healthy volunteers received sufficient midazolam (0.13 +/- 0.01 mg.kg-1 mean +/- SE) to render them unresponsive to verbal command; they then received flumazenil 1.0 mg or placebo (flumazenil vehicle) in a randomized. double-blind fashion. Ventilatory drive was measured before and after administration of midazolam. as well as 3. 30. 60. and 120 min after administration of flumazenil or placebo. Seven to 30 days later. the study was repeated. with subjects receiving placebo or flumazenil (whichever they had not received during their first trial). Midazolam caused significant decreases in the slope of the CO2 response (-29 +/- 5%; P less than 0.005); minute ventilation (VE) at end-tidal CO2 tension (PETCO2) = 46 mmHg (-28 +/- 4%; P less than 0.001). and tidal volume at PETCO2 = 46 mmHg (-44 +/- 4%; P less than 0.005). Three minutes after intravenous administration of flumazenil 1.0 mg. VE46 and tidal volume increased to 108 +/- 6% and 105 +/- 6%. respectively. of their premidazolam values; at the same time after administration of placebo. VE46 and tidal volume remained significantly depressed (between groups. P less than 0.005 for each variable). Thirty minutes later. these variables did not differ between groups. probably because the effects of flumazenil and midazolam were diminishing.
The use of immobilized protamine in removing heparin and preventing protamine-induced complications during extracorporeal blood circulation, Heparin. currently used in extracorporeal blood circulation procedures. may lead to hemorrhagic complications. Protamine. used for reversal of heparin-induced anticoagulation at the end of such procedures. can cause adverse hemodynamic responses. To prevent both types of complications. we have developed a reactor device containing immobilized protamine (i.e.. a protamine bio-reactor) that can be placed at the distal end of the circuit. thus providing simultaneous extracorporeal heparin removal and protamine treatment. In preliminary in vivo studies involving dogs at a blood flow of 100 ml/min. the bio-reactor removed about 50% of the administered dose of heparin (i.e.. 100 units/kg) in 10 min. While rapid injection of protamine in dogs anticoagulated with heparin produced a transient and significant (P less than 0.005) decreases in systemic arterial blood pressure (-39.5 +/- 9.2 mmHg). cardiac output (-1.59 +/- 0.23 L/min). and mixed venous oxygen saturation (-7.5 +/- 1.3%) and increases in pulmonary artery systolic (+12.7 +/- 4.4 mmHg) and diastolic pressures (+10.0 +/- 3.6 mmHg). the use of the protamine bio-reactor did not elicit any statistically significant change in any of the variables measured. Hemolysis was not significant. as reflected by a statistically insignificant change of the animals' red blood cell counts. hematocrits. and total hemoglobin values. In addition. hemolytic complement was found to be reduced only by 10% in animals with the protamine bio-reactor. whereas it was reduced rapidly by 20% in animals receiving intravenous protamine administration and progressively by 20% in control animals with a sham reactor that contained no protamine. Furthermore. the use of the protamine bio-reactor also significantly reduced the protamine-induced transient thrombocytopenic and granulocytopenic responses. The white blood cell counts and platelet counts decreased to 87.7 +/- 7.5 and 83.3 +/- 5.0% of baseline. respectively. in dogs with the protamine bio-reactor compared to 35.5 +/- 14.3 and 32.1 +/- 8.1% of baseline in dogs receiving intravenous protamine. The protamine bio-reactor may provide a unique means to simultaneously control both heparin- and protamine-induced complications.
Regional cerebral blood flow following resuscitation from hemorrhagic shock with hypertonic saline. Influence of a subdural mass, After severe hemorrhage. hypertonic saline restores systemic hemodynamics and decreases intracranial pressure (ICP). but its effects on regional cerebral blood flow (rCBF) when used for resuscitation of experimental animals with combined shock and intracranial hypertension have not been reported. We compared rCBF changes (by radiolabeled microsphere technique) after resuscitation from hemorrhage with either 0.8 or 7.2% saline in animals with and without a right hemispheric subdural mass. We studied 24 mongrel dogs anesthetized with 0.5% halothane and 60% nitrous oxide. In group 1 (n = 12). hemorrhage reduced mean arterial pressure (MAP) to 45 mmHg for 30 min. In group 2 (n = 12). ICP was increased and maintained constant at 15 mmHg. whereas hemorrhage reduced MAP to 55 mmHg for 30 min (cerebral perfusion pressure [CPP] approximately 40 mmHg in each group). After the 30-min shock period. 6 animals in each group received one of two randomly assigned resuscitation fluids over a 5-min interval: 1) 7.2% hypertonic saline (HS; sodium 1.232 mEq.l-1. volume 6.0 ml.kg-1); or 2) 0.8% isotonic saline (SAL; sodium 137 mEq.l-1. volume 54 ml.kg-1). Once fluid resuscitation began. ICP was permitted to vary independently in both groups. Data were collected at baseline (before subdural balloon inflation in group 2). midway through the shock interval (T15). immediately after fluid infusion (T35). and 60 and 90 min later (T95. T155). In groups 1 and 2. ICP was significantly less in animals resuscitated with HS compared to those receiving SAL (P less than 0.05).
Effect of maternal immunotherapy on immediate skin test reactivity, specific rye I IgG and IgE antibody, and total IgE of the children, The effect of specific immunotherapy during pregnancy was studied in 14 children. 3 to 12 years after delivery. Fourteen additional children from the same allergic mothers. in whom immunotherapy was not given during the pregnancy. served as controls. The immediate skin test response to grass allergens of the children of mothers given immunotherapy. Levels of rye I IgG and total IgE were lower in the sera of children born to mothers who received immunotherapy (not statistically significant) than their control cohorts. Paired cord blood and maternal blood samples drawn at delivery showed similar levels of rye I IgG. indicating that blocking antibody freely crosses the placenta. This evidence indicates that immunotherapy during pregnancy may have an inhibitory effect on immediate skin reactivity to grass allergens in some of the offspring. Whether tolerance to other allergens can be induced in children by maternal immunotherapy remains to be determined.
Analysis of house dust mite-specific IgE, IgG4, and IgG antibodies during immunotherapy in asthmatic children, House dust mite (Dermatophagoides pteronyssinus. DP) specific IgE. IgG4. and IgG antibodies were analyzed by Western blotting in 18 asthmatic children during the course of 2-years' allergen-specific immunotherapy. Although more than 50 protein bands could be identified in the crude mite extracts by SDS-PAGE. only eight of them elicited both IgE and IgG4 antibodies in most patients. The molecular weights were 110. 60. 55. 43. 33. 27. 16. and 14 kD. respectively. No antibodies against new antigens were induced after immunotherapy. There was a significant correlation between the intensity of reactive bands of Western blotting and RAST. IgG4 antibody was increased in 72% (13/18) of patients. but the simultaneous change in IgE varied. Analysis of allergen-specific IgE and IgG4 antibodies by Western blotting may provide a useful tool for evaluation of clinical response to immunotherapy.
Comparison of three pretreatment protocols to prevent anaphylactoid reactions to radiocontrast media, Three pretreatment regimens were compared for prevention of anaphylactoid reactions in 149 patients who previously had reacted to radiocontrast media (RCM) administration. From 1976 to 1980. 52 patients were treated with 50 mg of oral prednisone 13. 7. and 1 hour before and 50 mg intramuscular diphenhydramine 1 hour before procedures (group I). From 1980 to 1984. 48 patients received 300 mg oral cimetidine one hour before procedure in addition to the other regimen (group II). From 1984 to 1989. 49 patients received the three drugs and 25 mg oral ephedrine one hour before procedures (group III). Previous reactions were similar in each group. consisting of urticaria and/or angioedema in all patients. hypotension in some (groups I. 5; II. 6; III. 4). and wheezing in two (group I). Readministration of RCM was intraarterial (groups I. 18; II. 20; III. 20) or intravenous. Generalized reactions upon readministration of RCM occurred in 4 (8%) of group I and 3 (6%) of both groups II and III. All reactions consisted of urticaria and/or angioedema. were mild. and required no specific treatment. In a separate group of ten patients whose previous reactions to RCM were life threatening (shock). pretreatment was accompanied by a provocative dosing regimen. Two patients (20%) experienced systemic reactions that resulted in termination of the procedure. All our pretreatment regimens were equally effective; however. we favor a more comprehensive pretreatment protocol (regimen III) based upon our lack of demonstrated adverse effects and a possible therapeutic advantage as reported by other investigators.
Growth and the nutritional status of nonsteroid-dependent asthmatic children, Nonsteroid dependent children were evaluated to determine the effect of asthma on growth and nutritional status. No significant differences were observed for the growth of asthmatics and control groups. In addition. dietary records indicated asthmatics met or exceeded the recommended daily allowance for total calories and nutrients.
The function of lung and blood neutrophils in patients with the adult respiratory distress syndrome. Implications for the pathogenesis of lung infections, Pulmonary infections are a frequent cause of morbidity and mortality in patients with the adult respiratory distress syndrome (ARDS). but the reason is uncertain. Because neutrophils are important for lung defense and are found in increased numbers in the bronchoalveolar lavage fluid of patients with ARDS. we compared the functional activities of neutrophils obtained from lavage fluid and pulmonary artery blood of 28 patients shortly after the onset of ARDS. The lavage fluids contained 81.3 +/- 9.9% neutrophils. of which more than 95% were viable by vital dye exclusion. and the total protein concentrations were increased (98.8 +/- 98.5 mg/dl). The production of superoxide anion and hydrogen peroxide by the neutrophils in lavage fluid was significantly impaired compared with simultaneously tested pulmonary artery and normal neutrophils. and the microbicidal activity of the lavage neutrophils for Staphylococcus aureus was significantly impaired. The migration of alveolar neutrophils in response to a variety of stimuli was markedly reduced as compared with both pulmonary artery and normal neutrophils. The alterations in superoxide anion production and chemotaxis could be reproduced by exposure of normal neutrophils to oxidants (glucose:glucose oxidase). but not to other mediators that have been found in ARDS lavage fluids. Although the pulmonary artery neutrophils from the same patients had impaired production of superoxide anion and hydrogen peroxide. their microbicidal activity and chemotactic responses were normal. These findings indicate that the function of alveolar neutrophils is impaired in the lungs of patients with ARDS. This could contribute to the high incidence of pulmonary infections in these patients.
Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome, Tumor necrosis factor (TNF) was measured antigenically and functionally in serum and bronchoalveolar lavage fluid (BAL) of patients with ARDS and those at high risk for ARDS. Of 22 patients with ARDS. 14 had sepsis or serious infection as the major clinical predisposition. and 10 of 20 high-risk patients had sepsis or serious infection. Mean levels of TNF in serum of patients with ARDS and high risk showed a trend toward elevation but were not significantly higher than mean serum levels in normal subjects. Mean levels of TNF in BAL of ARDS patients (242 +/- 126 pg/ml) were significantly higher than in normal subjects (9 +/- 5 pg/ml). p less than 0.05. Antigenic levels of TNF were undetectable in approximately half the patients with ARDS or the high-risk state. Levels of TNF in BAL appeared to be highest in the first day of ARDS. There appeared to be no relationship between levels of TNF in serum or BAL and subsequent mortality. However. serum levels of TNF were significantly higher in septic patients than in nonseptic patients. whereas this difference was not apparent in BAL. These results show that functional and antigenic elevations of TNF are present in BAL and perhaps in serum of patients with ARDS or with the high-risk state.
Measurement of urinary desmosine by isotope dilution and high performance liquid chromatography. Correlation between elastase-induced air-space enlargement in the hamster and elevation of urinary desmosine, The accuracy of methods employed to measure the elastin-specific crosslinks. desmosine (DES) and isodesmosine (IDES). has been called into question because contaminants in the urine may cause elevated values. In the present study urine samples were spiked with a known amount of [14C]DES and refluxed in 6 N HCl. Sephadex G-15 chromatography of the hydrolyzed urine employed to remove contaminants. DES and IDES were quantified by high performance liquid chromatography (HPLC) as well as by amino acid analysis. The amount of isotope recovered was used to determine losses during the overall procedure and the isotope dilution to calculate the amounts of endogenous DES and IDES originally present in the urine. Because similar values were obtained by both methods. the more rapid HPLC method was used for all succeeding analyses. In one experiment. the DES amounts in urine collected from hamsters for 3 days after intratracheal treatment with human neutrophil elastase (300 micrograms) or porcine pancreatic elastase (300 micrograms) were 0.212 +/- 0.012 (mean +/- SEM. two measurements on a single pool) and 0.816 +/- 0.005 (two measurements) microgram per hamster per day. respectively. Urine from control hamsters had a mean value of 0.074 +/- 0.008 (eight measurements) microgram per hamster per day. The HNE- and PPE-treated hamsters had mean linear intercept values of 119 and 159% of control values. respectively. giving a positive correlation between increase in airspace size and elevation of urinary DES.
Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial, Twenty-seven newly diagnosed patients with idiopathic pulmonary fibrosis (IPF) who were previously untreated for IPF were enrolled in a prospective. double-blind. randomized. placebo-controlled study to compare the therapeutic effect of combined prednisone/azathioprine (n = 14) with prednisone plus placebo (n = 13). Prednisone was started at 1.5 mg/kg/day (not to exceed 100 mg/day) for the first 2 wk followed by a biweekly taper to a maintenance dose of 20 mg/day. Azathioprine was administered at a daily dose of 3 mg/kg (not to exceed 200 mg/day). The patients tolerated the use of azathioprine well with few associated side effects. Changes in lung function at 1 yr. as measured by resting alveolar-arterial oxygen difference P[A-a]O2. FVC. and single breath diffusing capacity for carbon monoxide (DLCOSB). were all somewhat better in the azathioprine/prednisone group compared with the prednisone alone group. although none of these comparisons were statistically significant. Six of 14 (43%) patients randomized to prednisone plus azathioprine died during the 9-yr follow-up period. compared with 10 of 13 (77%) patients randomized to prednisone plus placebo. A Cox model survival analysis shows a nonsignificant but potentially large survival advantage for azathioprine/prednisone (hazard ratio 0.48. with 95% confidence interval increasing from 0.17 to 1.38). When adjusted for age. the survival advantage of azathioprine/prednisone becomes marginally significant (hazard ratio 0.26. with 95% confidence interval increasing from 0.08 to 0.88; p = 0.02 by large sample approximation. p = 0.05 by randomization test). We conclude that combined prednisone and azathioprine is a safe and possibly effective regimen for the treatment of IPF.
Prospective study of pulmonary function and lung cancer, The role of pulmonary function as an independent predictor of lung cancer risk was studied in a community-based cohort of 6.317 Japanese-American men who were aged 45 to 68 at the time of examination. After a follow-up period of about 22 yr. 172 incident cases of lung cancer were identified. The percentage of the predicted FEV1 was inversely related to lung cancer (p value for trend = 0.01) after adjustment for age and cigarette smoking history. The subjects in the lowest quartile of pulmonary function (% predicted FEV1 less than 84.5) had a relative risk of 2.1 (95% confidence interval = 1.3 to 3.5) for lung cancer compared with subjects in the highest quartile (% predicted FEV1 = 103.5+). For the 84 cases with a squamous or small cell histologic type of lung cancer. the subjects in the lowest quartile had a relative risk of 2.5 (95% Cl = 1.2 to 5.6) compared with subjects in the highest quartile of pulmonary function. For the 84 patients with lung cancer whose tumors were located within 4 cm of the pulmonary hilum. the subjects in the lowest quartile had a relative risk of 4.0 (95% Cl = 1.7 to 9.7). The results suggest that impaired pulmonary function in a community-based population is a predictor of lung cancer.
Repeatability of histamine bronchial challenge and comparability with methacholine bronchial challenge in a population of Australian schoolchildren, To measure the repeatability of the bronchial challenge test and the comparability of histamine and methacholine as provoking agents. we studied a population sample of children and conducted histamine bronchial challenge tests on each of 3 consecutive days followed by a methacholine bronchial challenge on the fourth day. Bronchial responsiveness was measured using the rapid inhalation method. A total of 393 children had satisfactory bronchial challenge data for all 4 days. The measurements derived from the dose-response curve were the PD20 FEV1. which was measured as the provoking dose causing a 20% fall in FEV1. and the dose-response slope (DRS). which was measured as the percentage fall in FEV1 at final dose/total dose administered. Children who had a PD20 FEV1 were categorized as having bronchial hyperresponsiveness (BHR). The percentage of children with BHR each day was between 7 and 11. One-third of the children with BHR reacted only to histamine or methacholine. The within-subject range for histamine PD20 FEV1 values compared with methacholine suggested that histamine and methacholine are not directly comparable bronchial challenge agents. The dose-response slope values. which could be obtained for all children. had slightly better repeatability than PD20 FEV1 values. Because DRS values obtain data for the entire sample. have good repeatability. and are equally repeatable in children with normal responsiveness or bronchial hyperresponsiveness. they should prove more useful than PD20 FEV1 values for measuring bronchial responsiveness in populations.
Assessment of airway responsiveness in infants with cystic fibrosis, We compared the responses of cystic fibrosis (CF) (N = 14) and normal (N = 14) infants with inhaled methacholine. Airway function was assessed by forced expiratory flows at functional residual capacity (Vmax FRC) generated by the rapid compression technique. and methacholine responsiveness was quantitated as (1) TC: the threshold concentration to decrease Vmax FRC by 2 SD from baseline; (2) PC50: the provocative concentration to decrease Vmax FRC by 30%; and (3) SPC30; the slope of the dose-response curve between TC and PC30. There were no significant differences in age between CF and normal infants (16 +/- 8 versus 17 +/- 5 months. p greater than 0.3); however. the CF infants were shorter (74 +/- 10 versus 81 +/- 5 cm. p less than 0.05). had lower absolute Vmax FRC (241 +/- 103 versus 374 +/- 113 ml/s. p less than 0.001). and tended to have lower percentage of predicted flow values (87 +/- 13 versus 111 +/- 34%. p less than 0.10). Comparison of the indices of airway responsiveness revealed no difference in logTC; however. the CF infants had smaller. more negative values for logPC30 (-0.76 +/- 0.52 versus -0.22 +/- 0.53. p less than 0.02) and steeper slopes to their dose-response curves (logSPC30. 2.42 +/- 0.45 versus 1.88 +/- 0.74. p less than 0.025). Indices of airway responsiveness correlated significantly with baseline Vmax FRC (% of predicted). After the influence of baseline flow upon airway responsiveness was accounted for by multiple linear regression analysis. there was a tendency for CF infants to be more responsive than control infants.
Short-term effect of albuterol, delivered via a new auxiliary device, in wheezy infants, In a double-blind. placebo-controlled study. the response of lung function to albuterol. topically administered by a metered-dose inhaler (MD) through a baby-adapted auxiliary device. was evaluated in 36 wheezy infants (1.6 to 25.2 months of age; median 8.1 months). The auxiliary device contains an air chamber of 350 ml and two low-resistant valves separating the inspiratory from the expiratory line. After baseline lung function measurements by infant whole-body plethysmography. the patients were randomly assigned to inhale either three times two puffs albuterol (100 micrograms/puff) or three times two puffs placebo at 5-min intervals. Changes in the degree of pulmonary hyperinflation. estimated by thoracic gas volume (TGV) and/or in the degree of bronchial obstruction. estimated by thoracic gas volume (TGV) and/or in the degree of bronchial obstruction. estimated by airway conductance (Gaw). were measured at 5-min intervals for up to 30 min. TGV and Gaw were expressed as standard deviation scores (SDS) of values predicted. and patients improving TGV and/or Gaw more than 2 SD were considered responders. In comparison with placebo. a significant percentage improvement in TGV (by the mean 26 to 53%) and a significant percentage improvement in Gaw (by the mean 34 to 51%) could be found in the active treatment groups. The study documents the usefulness of a new auxiliary device for the administration of aerosolized bronchodilators to wheezy infants.
Dissimilarity in methacholine and adenosine 5'-monophosphate responsiveness 3 and 24 h after allergen challenge, Bronchial hyperresponsiveness (BHR) to methacholine and adenosine 5'-monophosphate (AMP) was studied in 15 allergic asthmatic patients before and 3 and 24 h after allergen challenge with house dust mite (HDM). Subjects attended the clinic on 3 consecutive days. On the first day a control solution was inhaled. and methacholine or AMP challenge was performed 3 h later. The next day HDM was inhaled. and 3 and 24 h later methacholine or AMP challenge was performed again. There were no significant difference in FEV1 baseline value between any of the study days. PD20 HDM. percentage decrease in FEV1. and AUC for both the EAR and LAR were not significantly different in the methacholine and AMP studies. After HDM challenge. PC20 methacholine decreased significantly from a geometric mean (+/- SEM) starting value of 1.39 +/- 0.63 mg/ml to 0.30 +/- 0.78 mg/ml (p less than 0.001) at 3 h and to 0.22 +/- 0.75 mg/ml (p less than 0.001) at 24 h. The magnitude of the decrease in PC20 methacholine at 3 h correlated with the severity of the late asthmatic reaction (LAR) as measured by the percentage fall in FEV1 and area under the curve (AUC) (r = -0.60 and r = 0.55; p less than 0.05). A significant decrease was observed in the PC20 AMP at 3 h. from a geometric mean value of 12.2 +/- 0.96 mg/ml after challenge with the control solution to 4.47 +/- 0.99 mg/ml (p less than 0.05) after HDM challenge.
Transient airway cooling modulates dry-air-induced and hypertonic aerosol-induced bronchoconstriction, Airflow-induced bronchoconstriction (AIB) may be initiated in asthmatic patients by inhaling dry air during eucapnic hyperventilation or exercise. Hypertonic aerosol-induced bronchoconstriction (HIB) also occurs in these patients. but it differs from AIB by exhibiting a faster time course. Although AIB and HIB probably increase airway fluid osmolality. only AIB is associated with airway cooling. In light of the similarities between our canine model and human AIB. we examined peripheral airway responses to dry air and hypertonic aerosol challenge. Specifically. we studied the magnitude and time course of these responses in an in situ. isolated. perfused lobe in which airway temperature was independently controlled. At body temperature. HIB peaked immediately after challenge. whereas transient airway cooling during aerosol challenge delayed HIB. In contrast. airway cooling attenuated AIB but did not alter its time course. Hypocapnia- and histamine-induced responses were not affected by airway cooling. suggesting that smooth muscle function was not impaired. To the extent that the mechanisms producing AIB in dogs and in humans are similar. our results suggest that (1) changes in airway fluid osmolality initiate AIB. (2) AIB = HIB + Cooling. and (3) exercise-induced asthma results from an imbalance between an excitatory pathway stimulated by airway drying and an inhibitory pathway initiated by airway cooling.
Late-phase asthmatic reaction to inhaled allergen is associated with early recruitment of eosinophils in the airways, To determine whether a link exists between the recruitment of inflammatory cells in the airways and the development of the late-phase asthmatic reaction. we studied with bronchoalveolar lavage 54 asthmatic patients either at baseline (10 patients) or 4 h (11 patients). 24 h (13 patients). and 72 h (20 patients) after allergen inhalation challenge. Among the patients studied 4 h after allergen challenge. five were known to have a late-phase asthmatic response and showed a significant increase in the number and percentage of eosinophils in bronchoalveolar lavage compared with either patients without late-phase response (p less than 0.05) or unchallenged patients (p less than 0.01). Both the number and the percentage of eosinophils in bronchoalveolar lavage were also increased (p less than 0.05) in patients without a late-phase asthmatic reaction studied 24 h but not in those studied 4 h after allergen challenge. The numbers and the percentages of macrophages. neutrophils. or lymphocytes did not differ significantly among the different groups of patients. Of the patients studied 4 and 24 h after allergen challenge. only those with a late-phase asthmatic response showed an increased airway responsiveness to methacholine 1 h before bronchoalveolar lavage. We conclude that the development of the late-phase asthmatic response to allergen inhalation challenge and the allergen-induced increase in airway responsiveness are associated with an early recruitment of eosinophils in the airways.
Flow resistance in patients with chronic obstructive pulmonary disease in acute respiratory failure. Effects of flow and volume, The flow and volume dependence of the total resistance of the respiratory system (Rrs) was investigated in six mechanically ventilated patients with chronic obstructive pulmonary disease (COPD) using a simple. rapid method. Isovolume Rrs-flow (V) relationships obtained at different inflation volumes (range 0.1 to 1 L) fitted (p less than 0.001) the following function: Rrs = a/V + b + cV. where a. b. and c are constants. The term "a/V" in this equation represents the hyperbolic decrease in thoracic tissue resistance with increasing flow; the term "cV" represents the linear increase in airway resistance with increasing flow. Rrs initially decreased with increasing V because at low flow the weight of the a/V was greater than that of the cV. At higher flow. however. cV became predominant and hence Rrs tended to increase. At an inflation volume of 0.5 L. minimum Rrs occurred at average inflation flow of 1.28 L/s. At low flow. Rrs increased progressively with increasing inflation volume; at inflation V greater than 1 L/s. the highest values of Rrs were obtained at low inflation volumes. The flow and volume dependence of Rrs implies that. for comparative purposes. measurements of Rrs should be standardized to a fixed inflation flow and volume.
Sustained improvement in gas exchange after negative pressure ventilation for 8 hours per day on 2 successive days in chronic airflow limitation, Negative pressure ventilation (NPV) was applied for 6 to 8 h/day for 2 consecutive days in 13 patients with severe airflow limitation and chronic respiratory failure. After cessation of NPV. the mean arterial blood gases were improved in 10 patients. and this improvement was sustained for the nex 2 days in eight patients. for 3 days in seven patients. and was still present in four patients on the fourth day. Respiratory muscle strength improved in all patients. but there was no relationship between the increase in strength and sustained improvement in gas exchange. Ventilation and respiratory pattern were unchanged in all patients. but the mean VD/VT fell and VA rose while the VO2 and VCO2 fell. The ventilatory responses to hypoxia and hypercapnia increased in patients who demonstrated sustained improvement in blood gases. The mechanism underlying the sustained improvement in gas exchange following NPV is not clear but is likely multifactorial.
Constant-flow insufflation prevents arterial oxygen desaturation during endotracheal suctioning, In mechanically ventilated patients. disconnection from the ventilator and endotracheal suctioning can induce major arterial oxygen desaturation resulting from apnea. changes in inspired oxygen fraction. and decrease in lung volume. The aim of this study was to test the efficacy of a simple method of delivering oxygen and maintaining lung volume during this process. Our study was conducted in two parts. In the first part. constant-flow insufflation of oxygen (CFI) was used in seven patients ventilated for acute respiratory failure (PaO2/FlO2 = 347 +/- 33 mm Hg) as a means of maintaining arterial oxygenation during apnea and disconnection from the ventilator. CFI was administered via a modified endotracheal tube in which small capillaries allowed delivery of a high-velocity jet flow near the tracheal end of the tube during disconnection from the ventilator. In comparison to apnea alone. CFI prevented a fall in arterial oxygen tension (16 +/- 7 mm Hg during CFI versus 117 +/- 27 during apnea. after 90 s of disconnection in the two situations. p less than 0.001). whereas it did not reduce the development of hypercapnia. The efficacy of CFI resulted both from the injection of oxygen into the trachea and from the maintenance of positive alveolar pressure induced by air entrainment (mean 10.4 +/- 1.1 cm H2O). preventing a fall in lung volume usually occurring after disconnection (+338 +/- 88 ml during CFI versus -344 +/- 64 ml during apnea. p less than 0.01). In the second part of the study CFI was used to prevent arterial oxygen desaturation induced by endotracheal suctioning.
Evolution of nocturnal oxyhemoglobin desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg, We studied 31 clinically stable chronic obstructive pulmonary disease (COPD) patients with a PaO2 greater than or equal to 60 mm Hg using polysomnographic sleep study at baseline (between 1983 and 1986) and at a mean follow-up time of 42.5 months to examine the evolution of rapid-eye-movement (REM) sleep nocturnal oxyhemoglobin desaturation (NOD). Arterial blood gases and spirometry measured at baseline and follow-up were compared with mean nocturnal SaO2 and to other REM sleep SaO2 parameters. We postulated that the onset of NOD would be seen most frequently in those patients with marked derangements of lung mechanics and greater longitudinal deterioration in arterial blood gases. Eight of the subjects developed REM-NOD on follow-up polysomnography. The appearance of REM-NOD was not related. or only minimally so. to initial PaO2. PaCO2. or mean nocturnal SaO2. Upon follow-up. however. the onset of NOD was always associated with deterioration of daytime PaO2 and PaCO2. mainly in those patients with the most severe baseline derangement of spirometry (lung mechanics). On the other hand. one group showed equivalent deterioration in daytime PaO2 and a stable PaCO2 but had less severely deranged baseline mechanics and demonstrated a fall in mean nocturnal SaO2 only. The findings in this latter group indicate that the development of NOD is not purely a result of decreasing daytime PaO2. We conclude that the onset of REM-NOD is mainly related to a severe derangement of lung mechanics with deterioration of resting awake gas exchange (progressive hypoxemia. hypercarbia. and worsening airflow).
Effect of hypercapnia on total pulmonary resistance during wakefulness and during NREM sleep, We investigated the effect of different levels of hypercapnia on total pulmonary resistance (RL) in 13 subjects ranging from nonsnorers with low RL to snorers with high RL and dynamic narrowing of the upper airway during inspiration. Added CO2 was adjusted to achieve a steady-state increase in PETCO2 of +2. +4. or +6 mm Hg. RL was measured at peak inspiratory flow (RLpf). at maximal resistance within breath (RLmax). and at 10 equally spaced points within inspiration in several trials. During wakefulness. hypercapnia was associated with decreased RLmax. During steady state +6 mm Hg hypercapnia. RLmax decreased by 30% (p less than 0.01). During NREM sleep. low levels of hypercapnia did not affect RL. However. +6 mm Hg hypercapnia was associated with decreased RLmax in six of eight subjects (p = 0.07). especially in subjects with high RLmax during room air breathing. The effects of hypercapnia on RLpf paralleled its effect on RLmax. We concluded that (1) the decrease in RL during awake hypercapnia suggests an increase in upper airway dimensions and stiffness. (2) the absence of increased RL during low level NREM hypercapnia (despite the increase in inspiratory flows and collapsing pressures) also suggests an increase in upper airway dimensions and stiffness. and (3) upper airway dilating muscles appear to be recruited in a coordinated fashion with inspiratory muscles in normal humans during NREM sleep. The implications of these findings in patients with obstructive sleep apnea are not clear at this point.
Oral mucosal stimulation modulates intensity of breathlessness induced in normal subjects, Patients with chronic obstructive pulmonary disease (COPD) often report an increase in breathlessness when they breathe through a mouthpiece. We hypothesized that stimulation of receptors in the oral mucosa modulates the sensation of breathlessness. We studied 10 normal naive volunteers in whom breathlessness was induced by having them breathe for 4 min with an inspiratory resistive load (18 cm H2O/L/s) while breathing was stimulated by CO2 inhalation (end-tidal PCO2 maintained at 55 mm Hg). Initially. subjects breathed with a tight-fitting face mask and inspiratory flow was displayed on a storage oscilloscope. In subsequent trials. the subjects were asked to match this trace. which controlled ventilation and the pattern of breathing. Subjects performed eight trials. four with the tight-fitting mask only (M) and four with a mouthpiece and the mask (MM). M and MM were alternated; the initial condition was chosen at random. Following each of the trials. subjects rated the intensity of their breathlessness by choosing a number from a modified Borg scale. On the average. subjects were more breathless while breathing with the mask and mouthpiece than with the mask alone (mean ratings of breathlessness 6.6 +/- 1.1 and 5.6 +/- 1.8 units. p less than 0.01). Six subjects repeated the protocol on 2 additional days: 1 day with inhalation of warm (34 degrees C). humidified air and 1 day after topical application of 4% lidocaine to the oral mucosa. Both these interventions abolished the differences in breathlessness between mask and mouthpiece and mask alone. We conclude that afferent information from oral mucosal stimulation influences the intensity of breathlessness.
Structural changes in the airways of sensitized brown Norway rats after antigen challenge, The purpose of this study was to quantitate the structural changes in the airways of sensitized rats after repeated challenge with aerosolized antigen and to examine the relationship between these changes and alterations in responsiveness to methacholine (MCh). We studied 28 Brown Norway rats that were actively sensitized to ovalbumin (OA). Responsiveness to aerosolized MCh was quantitated as the concentration of MCh required to double pulmonary resistance (EC200 RL). The EC200 RL was determined before and 1 and 5 days after three inhalational challenges with OA (n = 17) or saline (n = 11) at 5-day intervals (on Days 14. 19. and 24 after sensitization). Responsiveness to MCh increased after OA; EC200 RL fell from 1.71 to 0.71 mg/ml at 1 day (p less than 0.01) and 0.87 mg/ml at 5 days (p less than 0.02) after OA but did not change after saline challenge. Formalin-fixed lungs from a sample of OA-challenged (n = 12) and saline-challenged (n = 6) animals were paraffin embedded. and 5-microns sections were stained with hematoxylin-phloxin-saffron. Cross-sectional areas of the airway wall and smooth muscle (ASM) were determined for all intrapulmonary membranous airways. There was an approximately twofold increase in the quantity of airway smooth muscle in airways of OA-challenged animals compared with saline-challenged control animals. Airway wall area did not change significantly. There was a correlation (r = 0.618. p less than 0.05) between the quantity of ASM in large airways (basement membrane length 2.00 to 2.99 mm) and change in responsiveness to MCh.
Three-dimensional upper airway computed tomography in obstructive sleep apnea. A prospective study in patients treated by uvulopalatopharyngoplasty, The success of uvulopalatopharyngoplasty in treating obstructive sleep apnea varies considerably. Some of this variability may be accounted for by differences in the site of upper airway narrowing. To determine whether preoperative awake upper airway and soft tissue volumes predict the response to uvulopalatopharyngoplasty. preoperative awake computed tomograms (CT) of the upper airway were performed on 60 consecutive patients with symptomatic obstructive sleep apnea. Tracings were made from the CT scans of upper airway. tongue. and soft palate. Computer software was used to determine the cross-sectional area and volume of the upper airway. tongue. and soft palate. Patients underwent overnight polysomnograms before and 3 months after uvulopalatopharyngoplasty. Tongue volume was larger (p less than 0.02) and both upper airway to tongue volume (p less than 0.0005) and oropharynx to soft palate volume ratios (p less than 0.01) were smaller in obese patients. A good response to uvulopalatopharyngoplasty as defined by a postoperative apnea index of less than 5 apneas/h or a reduction in apnea index greater than or equal to 50% was seen in 50 patients (83%). Patients who had a good response had a smaller oropharyngeal cross-sectional area (p less than 0.01). a smaller upper airway volume (p less than 0.05). a smaller upper airway to tongue volume ratio (p less than 0.01). and a smaller oropharynx to soft palate volume ratio (p less than 0.05). Obese patients with obstructive sleep apnea have larger tongues and smaller upper airways relative to tongue and soft palate size. Patients with smaller upper airways. particularly relative to tongue and soft palate size. have a good response to uvulopalatopharyngoplasty.
Benign familial neonatal convulsions: evidence for clinical and genetic heterogeneity, The gene for autosomal dominant "benign" familial neonatal convulsions. a transient. primary epilepsy of infancy. has recently been assigned to chromosome 20q. To determine whether this disorder is genetically heterogeneous. we performed linkage analysis in two previously unreported pedigrees with benign familial neonatal convulsions in which clinical heterogeneity was evident. There were 14 affected persons in the first family. and none had seizures (febrile or afebrile) after the age of 2 months. The second family had 13 affected individuals and 2 obligate carriers; seizures frequently did not remit until 6 to 24 months. febrile convulsions occurred in at least 2 patients. apparent audiogenic seizures occurred in 4 patients. and 1 individual had refractory epilepsy until late adolescence. Linkage studies with the chromosome 20 markers D20S19 and D20S20 were performed in both families. The resulting data favored linkage of the disease and marker loci in Family 2 by a maximum odds ratio of 45:1 at 6% recombination. In Family 1. however. the odds were greater than 20.000:1 against linkage at 10% recombination or less. We conclude that the syndrome of benign familial neonatal convulsions is clinically and genetically heterogeneous. Further study will be necessary to clarify the relationship between phenotype and genotype in this disorder.
Cold-induced brain edema and infarction are reduced in transgenic mice overexpressing CuZn-superoxide dismutase, It has been proposed that oxygen-derived radicals. superoxide in particular. are involved in the alteration of blood-brain barrier permeability and the pathogenesis of brain edema following trauma. ischemia. and reperfusion injury. Using transgenic mice that overexpress the human gene for copper-zinc-superoxide dismutase. we studied the role of superoxide radicals in the blood-brain permeability changes. edema development. and delayed infarction resulting from cold-trauma brain injury. At 2 hours after a 30-second cold injury. cerebral water and Evans blue contents were reduced. respectively. from 80 +/- 0.2% and 132.7 +/- 12.9 micrograms/gm of dry weight for nontransgenic mice to 78.5 +/- 0.3% and 87.1 +/- 9.9 micrograms/gm of dry weight for transgenic mice. Infarction. as measured by 2.3.5-triphenyltetrazolium chloride staining. was reduced by 52% in transgenic brains. These data indicate that an increased level of superoxide dismutase activity in the brain reduces the development of vasogenic brain edema and infarction. Superoxide radicals play an important role in the pathogenesis of these lesions in cold-traumatized brain.
The erythrocyte-type glucose transporter in blood vessels of primary and metastatic brain tumors, We previously demonstrated that brain microvessels have a high density of the erythrocyte-type glucose transporter and suggested this could be used as a marker of cells with "occluding" junctions. Now. we have studied by immunocytochemistry the tissue distribution of the glucose transporter in a variety of primary and metastatic human brain tumors with a monoclonal antibody to the glucose transporter of human erythrocytes. Microvessels in normal brain tissue distant from the tumor. and in brain surrounding the tumor. immunostained strongly for the glucose transporter. Microvessels in primary and metastatic tumors. however. lacked glucose transporter immunoreactivity. Only in the relatively benign juvenile cerebellar astrocytomas was glucose transporter immunoreactivity retained in some of the tumor microvessels. Because a high glucose transporter density is a marker of vessels with barrier properties. our results indicate that the vast majority of brain tumor microvessels do nc. have an intact blood-brain barrier.
Coculture with autologous myotubes of cytotoxic T cells isolated from muscle in inflammatory myopathies, T-cell lines were expanded from muscle of 10 patients with polymyositis. 5 with inclusion body myositis. 5 with dermatomyositis. and 5 with other muscle diseases. All cell lines uniformly expressed T-cell antigens. but not natural killer cell or B-cell antigens. The proportion of helper (CD4+) and cytotoxic (CD8+) T cells in the expanded lines was variable and showed no correlation with the diagnosis. Sixteen cell lines (6 polymyositis. 4 inclusion body myositis. 5 dermatomyositis. 1 other muscle disease) consisted predominantly of CD8+ T cells. None of these lines displayed natural killer-like cytotoxicity but all were capable of lectin-dependent cytotoxicity. Three of 6 polymyositis. 1 of 4 inclusion body myositis. and 1 of 5 dermatomyositis lines showed low but statistically significant cytotoxicity against autologous myotubes (6 to 27% specific 51Cr release; effector-target ratio. 20:1). The results demonstrate that functionally competent cytotoxic T cells can be expanded from muscle affected by inflammatory myopathies and are consistent with the hypothesis that some cytotoxic T cells recognize an autoantigen on myotubes. Further studies of this experimental system may define the molecular mechanism of T cell-mediated muscle fiber injury and may help to identify the relevant antigens.
Altered excitatory and inhibitory amino acid receptor binding in hippocampus of patients with temporal lobe epilepsy, We examined binding to excitatory amino acid and inhibitory amino acid receptors in frozen hippocampal sections prepared from surgical specimens resected from 8 individuals with medically refractory temporal lobe epilepsy. The excitatory receptors studied included N-methyl-D-aspartate (NMDA). strychnine-insensitive glycine. phencyclidine. and quisqualate. The inhibitory receptors studied were gamma-aminobutyric acid type A (GABAA) and benzodiazepine. Excitatory and inhibitory amino acid receptor binding were differentially altered in the patients with temporal lobe epilepsy in comparison to 8 age-comparable autopsy control subjects. and changes in receptor binding were regionally selective in four areas. Binding to phencyclidine receptors associated with the NMDA channel was reduced by 35 to 70% in all regions in the hippocampi of the patients. In contrast. binding to the NMDA recognition site and its associated glycine modulatory site was elevated by 20 to 110% in the cornu ammonis (CA) 1 area and dentate gyrus of the hippocampus of the patients. Binding to these sites was unaffected in area CA4. Binding to the quisqualate-type excitatory amino acid receptor was unchanged in all regions except the stratum lacunosum moleculare CA1. where it was increased by 63%. GABAA and benzodiazepine receptor binding was reduced by 20 to 60% in CA1 and CA4. but unchanged in dentate gyrus. The data indicate that excitatory and inhibitory amino acid receptors are altered in the hippocampus of patients with temporal lobe epilepsy.
Temporal relationships between plasma and cerebrospinal fluid pharmacokinetics of levodopa and clinical effect in Parkinson's disease, We studied the pharmacokinetics of levodopa and its metabolites in plasma and ventricular cerebrospinal fluid in 4 parkinsonian patients with indwelling Ommaya reservoirs placed at the time of previous adrenal-medullary to caudate nucleus transplantation. Cerebrospinal fluid levodopa levels were 11.9% of those in plasma. Motor performance and dyskinesia correlated more closely with the time course of the appearance of levodopa in the ventricular cerebrospinal fluid than with the plasma levodopa concentration and did not correlate with plasma 3-O-methyldopa or cerebrospinal fluid 3-O-methyldopa or homovanillic acid. Our data confirm that the wearing off of the levodopa effect in patients with advanced Parkinson's disease is a function of drug concentration in the central nervous system.
Central sleep apnea and arterial compression of the medulla, We report a 5-year-old with central sleep apnea associated with compression of the medulla oblongata by abnormal looping of the left vertebral artery. The magnetic resonance imaging findings raise the possibility that compression of the respiratory center by an aberrant vertebral artery might cause central sleep apnea.
Leg-length discrepancy: effect on the amplitude of postural sway, The purpose of this study was to investigate whether leg-length discrepancy (LLD) influences a person's standing balance as measured by the amplitude of his/her postural sway. Twenty volunteers between the ages of 20 and 32 participated. Eleven individuals with no measurable LLD constituted the control group. The experimental group consisted of nine individuals with at least a 9.5mm LLD. Each subject stood barefoot on a force platform with their feet together. Center-of-pressure data were collected at a rate of 10Hz for 12.8 seconds while the subjects stood with their eyes opened and again with their eyes closed. The amplitude of each person's postural sway in the medial-lateral and anterior-posterior directions was calculated from the center-of-pressure data. The results of the study showed that no significant difference existed between the experimental and control groups. There was. however. a significant difference (p less than .05) between the conditions of eyes opened and closed. These results indicate that individuals with an LLD do not have more postural sway than those without an LLD.
Treadmill gait retraining following fractured neck-of-femur, The rehabilitation outcome of two methods of gait retraining. was studied in 40 elderly women who had fractured the neck-of-femur. Twenty control subjects received conventional gait retraining. and 20 experimental subjects participated in a treadmill gait retraining program. Rehabilitation outcome was determined by temporal-distance gait parameters and mobility level (house-bound. limited. or unlimited). Muscle strength and range of movement of the lower limb were measured. Previously reported predictors of poor outcome (age. prefracture mobility. admission from sites other than own home. availability of caring person. type of ambulatory aid. presence or absence of senile dementia. and number of concomitant medical diseases) were recorded. Subjects were assessed on admission to the gait retraining program and at discharge from hospital. A 3 x 2 chi-square analysis on discharge mobility level showed the mobility level of the treadmill group to be significantly (p less than .05) higher than the mobility level attained by the control group. Analysis of variance showed no significant differences between the two groups at either assessment time. However. a significant increase in within-group variance from admission to discharge (p less than .01) was noted. and this led to the analysis of a subgroup containing six pairs of subjects matched for number of predictors of poor outcome.
Postural differences between asymptomatic men and women and craniofacial pain patients, A forward head position and rounded shoulders have been implicated in the development or perpetuation of craniomandibular disorders. Since women seek treatment for these problems more frequently than men. postural differences may account for the increased incidence of symptoms in women. The purposes of this study were (1) to compare the sagittal head and shoulder posture of asymptomatic men and women and (2) to compare the posture of asymptomatic and symptomatic women to determine differences in sagittal plane posture. Subjects were 20 asymptomatic men and women volunteers and nine consecutive women patients presenting for evaluation and treatment of craniomandibular pain. The subjects were compared using a valid. reliable. computer-assisted slide digitizing system called the Postural Analysis Digitizing System (PADS). Asymptomatic men and women did not differ in the postural characteristics associated with craniomandibular disorders. Sagittal posture does not appear to be a gender-related factor in these disorders. Symptomatic women. however. do display these postural characteristics to a greater extent than asymptomatic women. Evaluation and treatment of postural dysfunction should be included in the management of these patients.
Children with traumatic head injury: morbidity and postacute treatment, The purpose of this paper was to describe pediatric head trauma and the factors that affect the extent. characteristics. and postacute service needs of functional limitations resulting from head trauma. Data are presented on 4.870 children who survived head injuries and who were enrolled in the National Pediatric Trauma Registry during 1985 to 1988. The sample excluded 349 children who died and 151 children who had impairments before injury. More than 50% of the surviving children sustained extracranial injury in addition to head injury. and this occurrence was related to age and mechanism of injury. Although 78% of the children were discharged from acute care without obvious impairments. 787 had one to three impairments. and 286 had four or more impairments. Discharge to rehabilitation or extended care facilities depended on the number and type of resulting impairments.
Analysis of auditory comprehension performance in individuals with severe aphasia, This research compared the performance of 20 individuals with global and mixed nonfluent aphasia across the four auditory comprehension subtests of the Boston Diagnostic Aphasia Examination (Word Discrimination. Body Part Identification. Commands. and Complex Ideational Material) and across the six subcomponents of the Word Discrimination Subtest (objects. actions. letters. colors. forms. and numbers). As expected. group means revealed severely reduced performance which was equally observable across all auditory comprehension tasks. To determine whether individual subjects demonstrated a pattern of consistently reduced performance for auditory comprehension tasks. z-scores and chi-square statistics were also calculated for each subject and task. The individuals with global aphasia demonstrated a greater number of statistically significant z-scores than was expected by chance. This was not true for the subjects with mixed nonfluent aphasia. Results of this research indicate that although as a group individuals with global aphasia may demonstrate consistently reduced auditory comprehension. when considered on an individual basis. this group may comprise a somewhat divergent population with respect to the configuration of preserved and impaired auditory comprehension skills.
Quantitative cervical flexor strength in healthy subjects and in subjects with mechanical neck pain, Although weakness of anterior cervical muscles is postulated to contribute to persistent neck pain in patients with mechanical neck pain. quantitation of weakness has never been reported. We compared anterior cervical muscle strength in 30 subjects with mechanical neck pain and in 30 asymptomatic control subjects. Testing was performed with the subject supine. chin retracted. and neck flexed. Assessment was made using a hand-held dynamometer with head held at the midline and with rotation left and right within a pain-free range. Analysis with Wilcoxon scores showed that patients with neck pain had significantly less (p less than .05) strength (N.Kg-1) in all three positions than controls (1.16 +/- 0.49 vs 1.71 +/- 0.42. sagittally; 1.01 +/- 0.52 vs 1.47 +/- 0.41. rotation left; .99 +/- 0.46 vs 1.43 +/- 0.43 rotation right; neck pain vs control. respectively.) This weakness and its role in persistent neck pain should be recognized. The efficiency and effect of cervical muscle strengthening in treatment of chronic neck pain should be further defined.
Predictors of intracranial carotid artery atherosclerosis. Duration of cigarette smoking and hypertension are more powerful than serum lipid levels, The effect of cigarette smoking on intracranial internal carotid artery atherosclerosis (ICAS) was studied by obtaining cigarette smoking histories and data on other potential predictors. including serum lipid estimations. for consecutive patients undergoing carotid arteriography. The duration of cigarette smoking was the most significant independent predictor of the presence of ICAS. Other independently significant predictors of ICAS were hypertension. diabetes mellitus. and current systolic blood pressure. The interaction of diabetes and duration of smoking was a significant negative predictor. In patients for whom serum lipid values were available. lower levels of apolipoprotein A-I were associated with a higher risk of having ICAS. However. the effect of apolipoprotein A-I as a predictor of the presence of ICAS was far outweighted by the effects of duration of smoking and hypertension.
Correlative angiographic and pathologic findings in the diagnosis of ulcerated plaques in the carotid artery, We determined the accuracy of angiography in the diagnosis of internal carotid ulcers by comparing the angiographic reports with the pathologic findings in 36 endarterectomy specimens. Eighteen of these specimens had microscopic ulcerations. and the observer with the highest accuracy rate read 12. of which ten were ulcerated. These results revealed a sensitivity of 56%. a specificity of 89%. and an overall accuracy of 61% for angiography. The ulcers were classified into types A. B. and C to assess the interobserver agreement rate among three readers. This resulted in a 4% interobserver agreement among a total of 75 ulcers. Because of the high interobserver disagreement and the poor correlation between angiographic and pathologic findings in the surgical specimens. we conclude that the diagnosis of carotid artery ulceration by angiography is not reliable.
Acquired immunodeficiency syndrome. Cerebrospinal fluid findings in patients before and during long-term oral zidovudine therapy, Fifty-two patients with acquired immunodeficiency syndrome were enrolled in this study to evaluate the relationship between cerebrospinal fluid (CSF) zidovudine concentrations and neurologic and human immunodeficiency virus (HIV) culture findings. Paired HIV-CSF culture and neurologic measurements were available in 30 and 45 patients. respectively. Twenty-nine patients were assessable for zidovudine CSF concentrations. Patients underwent lumbar puncture and neurologic testing before and after 8 weeks or more of oral zidovudine therapy (600 to 1500 mg/d). After 8 weeks of therapy. the frequency of HIV isolation from CSF cultures was unchanged. Significant neurologic improvement by examination was noted in 61.5% (32/52) of the patients. The median CSF zidovudine concentration among 29 patients was 0.047 mg/L (range. 0.015 to 0.198 mg/L). No correlation between CSF zidovudine concentration. cumulative dose. or HIV isolation from CSF and persistence or resolution of neurologic symptoms or signs was observed. The mechanisms by which zidovudine improves neurologic function are unclear and appear unrelated to direct clearance of virus from CSF.
Rate of CD4 decline and neuropsychological performance in HIV infection, This study examined the relationship between performance on a battery of neuropsychologic tasks and rate of CD4 lymphocyte decline in 47 gay or bisexual men infected with the human immunodeficiency virus type 1. Subjects were volunteers for a longitudinal study of the human immunodeficiency virus infection and were not selected because of neuropsychiatric symptoms. Subjects were at all stages of illness. although most were asymptomatic. Faster rates of decline in percent CD4 lymphocyte were related to poorer performance on measures of memory and reaction time. This relationship was independent of stage of illness and CD4 level at the time of neuropsychologic examination. and was not due to medication effects. The rate of percent CD4 lymphocyte cell loss is associated with and may represent a risk factor for the development of the human immunodeficiency virus-related neurobehavioral deficit.
Epidemiology of myasthenia gravis in Denmark. A longitudinal and comprehensive population survey, The incidence of myasthenia gravis (MG) was found to be constant in calendar time. The mean annual incidence rate was 4.4 per million population. Age- and sex-specific incidence rates disclosed a bimodal appearance for both sexes. with a peak age at onset located in the early-onset group and another peak for late onset of MG. Early onset of MG appeared 10 years later for male individuals than for female individuals. whereas the peak for late onset of MG was located at the same age for both sexes. It is suggested that the separation between early onset and late onset of MG should be at the age of 50 years for both sexes. rather than at 35 to 40 years as accepted in most studies. The prevalence of MG has increased in time. On January 1. 1988. the point prevalence rate was 77 per million population (female subjects. 96. and male subjects. 57). This reflects an improvement in prognosis despite the fact that life expectancy was found to be significantly lower for MG patients than that of the sex- and age-matched population. The factors causing increased mortality were found to be operative throughout the duration of the disease. Maximum severity of disease was reached within 2 years from onset in 78% of the cases. and more than 50% of all MG-related deaths occurred during the same period. In the course of MG. 70% of all patients experience generalized muscular weakness. and 30% to 40% also suffer from respiratory problems.
Cognitive neuropsychology. Resolving enigmas about Wernicke's aphasia and other higher cortical disorders, Cognitive neuropsychology is a young branch of neuroscience whose ancestral influences include a rich pool of experimental (eg. cognitive. psychology). theoretical (eg. epistemology). and clinical (eg. neurology. neuropsychology) disciplines. An essential principle of cognitive neuropsychology is that disorders of higher cortical functions can be understood in terms of breakdowns of one or more information-processing modules. Each module is the most basic element of intelligence that can be defined based on current knowledge. This approach is a refinement of-not a fundamental departure from-the 19th-century "localizationist" view of language disorders. Wernicke's aphasia. for example. classical attributed to a single cognitive deficit (loss of word sounds). is shown in this review to require damage to multiple distinct information-processing modules. Cognitive neuropsychology provides the tools for the type of fine-grained analyses of behavior that are needed to capitalize on recent advances in neuroimaging techniques. including the development of more sophisticated models of brain-behavior relationships.
Broca's aphasia following damage to Wernicke's area. For or against traditional aphasiology, Classic aphasiology has been challenged by studies that have employed cranial computed tomography to test predicted anatomic-behavioral correlations. We treated a patient who developed a classic Broca's aphasia but whose computed tomographic scan revealed damage to Wernicke's area. thus seeming to contradict the principles of traditional aphasiology. However. subsequent information obtained by magnetic resonance imaging. intracarotid amobarbital (Amytal) testing. and electrophysiologic studies. including cortical stimulation. demonstrated that the brain-behavior correlations in this patient can be understood in terms of the formulations of traditional aphasiology.
Enkephalinase: a physiologic neuroimmunomodulator detected in the synovial fluid, Enkephalinase (endopeptidase 24.11) is a metallopeptidase that is able to cleave not only neuropeptides and hormones but also immune mediators. The enzyme was quantified in synovial fluid obtained from 36 swollen joints. Its concentration correlated with the synovial fluid cell count. mainly the polymorphonuclear cells and lymphocytes. and with the erythrocyte sedimentation rate. No statistically significant difference in enkephalinase levels was demonstrated between the groups of patients with rheumatoid arthritis. seronegative spondylarthropathy. microcrystalline arthritis. or osteoarthritis. The presence of enkephalinase in the synovial fluid could reflect the intensity of the inflammatory process. or it could represent a physiologic regulator of inflammation and pain within the joint.
Definition, incidence, and clinical description of flare in systemic lupus erythematosus. A prospective cohort study, The course of systemic lupus erythematosus (SLE) is characterized by exacerbations (or flares) and remissions of disease activity. As part of an ongoing prospective cohort study. 3 disease activity indices. the physician's global assessment. the Lupus Activity Index. and the University of Toronto SLE Disease Activity Index. have been recorded. at least quarterly since 1987. on 185 SLE patients. We developed a definition of SLE flare and a description of its clinical epidemiology. Disease flare was defined as a change of greater than or equal to 1.0 in the physician's global assessment of disease activity (measured on a 0-3 scale) from the previous visit or from a visit within the last 93 days. Of the 185 patients. 98 (53%) had greater than or equal to 1 flare; the total number of flares was 146. The incidence of flare was 0.65 per patient-year of followup. The median time from the first study visit to a flare was 12 months. Flares were frequently characterized by constitutional symptoms. musculoskeletal involvement. cutaneous involvement. and decreasing levels of C3 and C4. At the time of flare. the mean University of Toronto SLE Disease Activity Index score increased by 3.0 and the mean Lupus Activity Index score (modified to omit the physician's global assessment) increased by 0.26. Overall. 44.8% of the flares prompted a change in treatment. Patients who experienced flares fulfilled more of the SLE criteria at entry and had been followed up for a longer duration after entry into the study. compared with those who did not have flares.
Methotrexate versus azathioprine in the treatment of rheumatoid arthritis. A forty-eight-week randomized, double-blind trial, We conducted a double-blind. randomized trial comparing azathioprine (AZA) and methotrexate (MTX) in the treatment of patients with rheumatoid arthritis in whom parenteral gold and/or D-penicillamine treatment had been unsuccessful. Patients were randomly assigned to receive either AZA (100 mg daily) or oral MTX (7.5 mg weekly). After 8 weeks. the dosage was increased depending on the clinical improvement. Sixty-four patients were followed up for 48 weeks (33 AZA. 31 MTX). Comparison of values at week 24 with baseline values revealed significant improvement in 12 of 13 disease variables in the MTX group and in 6 of 13 in the AZA group. Comparison between the 2 treatment groups at 24 weeks. by area-under-the-curve analysis. showed significantly more improvement in the MTX group in terms of the swollen joint count. pain score. erythrocyte sedimentation rate. C-reactive protein level. hemoglobin level. thrombocyte level. and disease activity score. A significant overall clinical improvement (disease activity score) was found in 7 of 20 patients treated with AZA and 18 of 30 patients treated with MTX after 24 weeks of therapy. and in 6 of 12 AZA-treated patients and 19 of 25 MTX-treated patients after 48 weeks. The number of withdrawals due to side effects was significantly higher in the AZA group. After 48 weeks. only 12 patients from the AZA group (36%). but 25 from the MTX group (81%). were still using the initial drug. These results demonstrate MTX to be superior to AZA in the treatment of rheumatoid arthritis. with a more rapid clinical improvement which is sustained after 1 year. accompanied by a lower rate of serious adverse reactions.
Endothelin, an endothelial-dependent vasoconstrictor in scleroderma. Enhanced production and profibrotic action, The vascular endothelium is an important functional unit in the regulation of the vascular and perivascular environment. Various chemical and physical stimuli mediate an endothelial-dependent vasoconstriction through the release of endothelial soluble factors. such as the recently recognized endothelium-derived vasoconstrictor peptide called endothelin. The presence of circulating endothelin and the effect of cold exposure on plasma endothelin levels were investigated in patients with scleroderma and in healthy control subjects. Radioimmunoassay demonstrated a mean +/- SD plasma level of 10.7 +/- 7.3 pg/ml in the patients (n = 19) and 3.7 +/- 2 in the control subjects (n = 16) (P less than 0.005). These levels were also assessed in 5 control subjects and 5 scleroderma patients before and after 30 minutes of total body cooling (to 15 degrees C). The endothelin level did not change significantly in either group; however. 2 scleroderma patients showed a significant increase after cooling. The effects of endothelin on fibroblast proliferation and collagen synthesis were evaluated in order to assess the impact of released endothelin on the interstitium. A significant mitogenic effect and a collagen synthesis-enhancing effect. which were dose-dependent. were seen. The strong. characteristically prolonged. vasoconstrictor activity coupled with the profibrotic effect demonstrated here make it likely that disturbances in the control of endothelin production can contribute to the pathogenesis of scleroderma.
Occupation, income, and education as independent covariates of arthritis in four national probability samples, The strong associations between education level and prevalence and severity of arthritis have recently been investigated. with some suggestion that the relationships might be causal. Data from 4 national probability samples were analyzed. in which occupation and income were measured currently and prior to the development of arthritis. These data indicate that previous studies overestimated the strength of the association between schooling and arthritis because income and. especially. occupation were not analyzed as separate covariates. The overestimate appears to be especially high for persons currently employed. for men. and for persons employed in dangerous jobs. Health policy strategies directed toward reducing arthritis rates require not simply a focus on education. but the additional socioeconomic status dimensions of income and occupational safety and health.
The laryngeal mask airway in children, The laryngeal mask airway was used in 200 children during a variety of surgical procedures. Some problem with the use of the device was encountered in 47 cases (23%). but in only five cases (2.5%) were the problems serious enough to warrant abandonment of its use. A clear airway was ultimately achieved in 191 children. Downfolding of the epiglottis over the laryngeal inlet was identified in eight out of 24 patients where flexible laryngoscopy was performed. clinically all these had unobstructed airways. The mask was used in 16 children with known airway problems. It is concluded that the size 2 laryngeal mask airway can be successfully used within the weight range 6-30 kg.
Escherichia coli bacteriuria and contraceptive method, We evaluated the effects of contraceptive method on the occurrence of bacteriuria and vaginal colonization with Escherichia coli in 104 women who were evaluated prior to having sexual intercourse. the morning after intercourse. and 24 hours later. After intercourse. the prevalence of E coli bacteriuria increased slightly in oral contraceptive users but dramatically in both foam and condom users and diaphragm-spermicide users. Twenty-four hours later. the prevalence of bacteriuria remained significantly elevated only in the latter two groups. Similarly. vaginal colonization with E coli was more dramatic and persistent in users of diaphragm-spermicide and foam and condoms. Vaginal colonization with Candida species. enterococci. and staphylococci also increased significantly in diaphragm-spermicide users after intercourse. We conclude that use of the diaphragm with spermicidal jelly or use of a spermicidal foam with a condom markedly alters normal vaginal flora and strongly predisposes users to the development of vaginal colonization and bacteriuria with E coli.
Monosialoganglioside in subarachnoid hemorrhage [published erratum appears in Stroke 1991 Jul;22(7):957, We studied 119 patients with disturbance of consciousness following subarachnoid hemorrhage. due mostly to verified aneurysm rupture. admitted to five Italian neurosurgical departments over 18 months. Level of consciousness as assessed by score on the Glasgow coma Scale ranged from 8 to 14 before the beginning of treatment; level of consciousness was assessed again 7. 14. and 21 days later. Patients were randomly allocated to treatment with monosialoganglioside or placebo according to a double-blind experimental design. The two treatment groups were homogeneous at entry with regard to the main clinical parameters. Both groups improved. but the rate and degree of improvement were greater in the monosialoganglioside-treated group. The difference was significant on days 14 (p = 0.04) and 21 (p = 0.02). Our results seem to confirm the hypothesis that monosialoganglioside reduces brain edema and provides nonspecific neuronal membrane protection.
Cardiac function in aneurysmal subarachnoid haemorrhage: a study of electrocardiographic and echocardiographic abnormalities, Electrocardiographic (ECG) changes are reported frequently after subarachnoid haemorrhage (SAH). The aim of this study was to investigate the functional significance of ECG changes by echocardiographic assessment of cardiac function. Forty-five patients with intracranial aneurysms were studied. All patients had a 12-lead ECG and a two-dimensional echocardiogram. After patients with an history of chronic cardiac disease (n = 4) were excluded. only four patients were found to have wall motion abnormalities. These patients had only minor ECG abnormalities. but severe neurological dysfunction. Conversely. patients with other ECG abnormalities including the deep inverted T waves associated usually with SAH. had normal echocardiograms. We conclude that the ECG is not an accurate predictor of myocardial function after SAH and that myocardial dysfunction is related more closely to severity of neurological condition.
Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells, The purposes of this study were to examine the biologic effects of the engagement of the interleukin-7 receptor (IL-7R) with recombinant human interleukin-7 (rhIL-7) in immunophenotypically distinct T-lineage acute lymphoblastic leukemia (ALL) blasts and to elucidate the biochemical nature of the IL-7R-linked transmembrane signal in rhIL-7-responsive T-lineage ALL blast populations. In the absence of costimulants. rhIL-7 stimulated the in vitro proliferation and colony formation of freshly isolated leukemic blasts from six to eight T-lineage ALL patients with a mean plating efficiency of 196 +/- 53 (background subtracted) colonies/10(5) blasts plated. Stimulation of T-lineage ALL blasts with rhIL-7 resulted in markedly enhanced tyrosine phosphorylation of six distinct phosphoproteins with molecular weights of 57. 72. 98. 123. 150. and 190 Kd. and induced a rapid increase in the production of inositol-1.4.5-trisphosphate (Ins-1.4.5-P3). which was inhibitable by the tyrosine-specific protein kinase inhibitor genistein. but not by the serine/threonine-specific protein kinase C inhibitor H7. Similarly. rhIL-7 stimulated Ins-1.4.5-P3 production in CEM-1.3 T-lineage ALL cells and this stimulation was inhibitable by the tyrosine-specific protein kinase inhibitors genistein and herbimycin A. but not by H-7. Thus. the transmembrane signal triggered by engagement of the IL-7R is intimately linked to a functional tyrosine-specific protein kinase pathway and stimulates the phosphoinositide (PI) turnover and proliferation of T-lineage ALL blasts. The presented data confirm and extend previous studies on the expression of functional IL-7R on T-lineage ALL blasts and support the hypothesis that IL-7 may play an important regulatory role in the biology of T-lineage ALL.
Differentiation in B-precursor acute lymphoblastic leukemia cell populations with CD34-positive subpopulations, B-precursor acute lymphoblastic leukemia bone marrow specimens that contained subpopulations of cells with immunophenotypes corresponding to early (CD34) and late (CD20) and (CD22) stages of normal B-cell differentiation were studied. Subpopulations of cells were isolated according to immunophenotype and then analyzed by both a clonogenic assay and molecular genetic methods. Clonal equivalence of the early and late immunophenotypic subpopulations was confirmed for each case by the demonstration of identical lg gene rearrangements. The in vitro colony-forming assay consistently showed a growth advantage for the CD34+ subpopulations over the CD34- subpopulations. CD34 mRNA was detected readily in these isolated precursor cells. When two specimens in which virtually all of the leukemia cells were CD34+ and CD34+CD20+ and CD34+CD22+ subpopulations were also present the CD34 mRNA was limited to the cells without the late-stage differentiation antigens on their surface. Furthermore. the c-myb mRNA was found only in the subpopulations that also contained CD34 mRNA. Our results show that a limited program of differentiation reminiscent of normal B-cell development may be present in this leukemia.
Autoantibody activity of immunoglobulins isolated from B-cell follicular lymphomas, Previous work with monoclonal Igs (MIgs) has demonstrated that a high proportion of paraproteins bind to self-antigens such as the Fc fragment of IgG. Ii blood group antigens. cytoskeleton proteins. DNA. and myelin-associated glycoprotein (MAG). Recent work in CLL indicates that CD5+ B lymphocytes are frequently committed to production of autoantibodies. We have examined the antibody specificity of MIgs derived from the tumor cells of 31 different patients with CD5- B-cell lymphomas. Our results indicate that the tumor cells from 8 of these 31 patients (25.8%) express Igs with autoantibody activity. In two cases antibody activity was multispecific. In four cases. antibody activity was exclusively directed against the Fc fragment of IgG. whereas the two other cases bound to both Fc fragment of IgG and nuclear antigens. Most non-Hodgkin's lymphomas (NHL) are derived from CD5- B cells. These results indicate that like CLL. NHL also express Igs that frequently have autoantibody activity.
Induction of HL60 cell differentiation by tiazofurin and its analogues: characterization and efficacy, Among inducers of myeloid differentiation for leukemic cells. tiazofurin is of special interest because its mechanism of action is known; it inhibits inosine monophosphate dehydrogenase and thus decreases the guanine nucleotide pool. Reported here are three aspects of tiazofurin induction of myeloid differentiation in HL60 human acute promyelocytic leukemia cells. First. inductive efficacy was evaluated for analogues ara-tiazofurin. xylo-tiazofurin. and selenazofurin. for dinucleotide anabolites thiazole-4-carboxamide adenine dinucleotide (TAD) and selenazole-4-carboxamide adenine dinucleotide (SAD). and for a phosphodiesterase-resistant TAD analogue. beta-methylene TAD. The results showed that the parent compounds are more effective inducers than the dinucleotide derivatives and that the selenazole analogues are more effective inducers than the thiazole compounds. Second. HL60 cell induction by tiazofurin was shown to be synergistic with that produced by the antiviral agent ribavirin. Finally. tiazofurin was found to induce expression of a phosphatidylinositol-specific phospholipase C-sensitive Fc gamma-receptor III (FcRIII) on HL60 cells. a feature consistent with neutrophilic. but not monocytic. differentiation.
Erythropoiesis in Fanconi's anemia, Fanconi's anemia (FA) is an autosomal recessive condition in which greater than 90% of the homozygotes develop aplastic anemia. To determine the relation between erythroid progenitors and clinical status. blood and marrow mononuclear cells were cultured in methyl cellulose with erythropoietin. plus other hematopoietic growth factors. and growth in normal oxygen (20%) was compared with growth in low. physiologic oxygen (5%). Peripheral blood cultures were performed from 24 patients. and marrows from six. Patients were classified into six clinical groups. Group 1: Severe aplasia. transfused; one patient; no erythroid progenitors. Group 2: Severe. transfused. androgen unresponsive; one patient; no blood burst-forming units-erythroid (BFU-E). Group 3: Androgen responsive; eight patients. with decreased blood BFU-E. Group 4: Aplastic. about to start treatment; two patients; below normal numbers of colony-forming units-erythroid (CFU-E) and BFU-E. Group 5: Stable. with mild anemia. and/or thrombocytopenia. and/or macrocytosis; seven patients; with below normal numbers of blood BFU-E. Group 6: Hematologically normal; five patients; blood BFU-E low normal to normal. One marrow had normal numbers of CFU-E and BFU-E. Incubation in 5% oxygen doubled CFU-E and BFU-E only in the patients with close to normal or normal growth in 20% oxygen. Hemin and interleukin-3 increased growth slightly in those cultures where there was some growth with erythropoietin alone. Our data show that there is a correlation between current clinical status and in vitro erythropoiesis. Cultures of erythroid progenitors may also be useful predictors of hematologic prognosis in FA. although our follow-up period is too short to prove this hypothesis.
Expression of interleukin-4 receptors on early human B-lineage cells, Interleukin-4 (IL-4) regulates multiple stages of the antigen-dependent phase of B-cell development. However. its precise role in regulating B lymphopoiesis in bone marrow is not as well defined. We examined whether surface IgM- normal and leukemic human B-cell precursors (BCP) expressed IL-4 receptors using biotinylated IL-4. Constitutive expression of IL-4 receptors was detected on both normal and leukemic BCP. A higher percentage of normal BCP (82% +/- 15%) expressed IL-4 receptors compared with leukemic BCP (44% +/- 8%). Using mean fluorescent intensity as an indicator of receptor level on the IL-4 receptor positive cells. normal (91 +/- 41) and leukemic (44 +/- 37) BCP expressed comparable numbers of receptors. IL-4 induced the expression of CD23 on 30% of the leukemic BCP cases examined. IL-4 induced CD23 on surface IgM+ fetal bone marrow lymphoid cells but not on the surface IgM- normal BCP. despite the presence of detectable receptors on the surface IgM- cells. IL-4 did not stimulate proliferation of normal BCP. nor could it enhance the effect of recombinant IL-7 or low molecular weight B-cell growth factor. However. IL-4 increased the expression of surface IgM and surface Ig kappa on in vitro differentiated pre-B cells. Our collective results identify no role for IL-4 in the proliferation of normal or leukemic BCP. but identify a role in the enhancement of surface Ig expression during pre-B to B-cell differentiation.
Detection of lymphomatous bone marrow involvement with magnetic resonance imaging, We reviewed magnetic resonance (MR) staging examinations of 98 patients with malignant lymphoma who failed other therapy and were under evaluation for bone marrow transplantation. MR scan results were compared with blind posterior iliac crest aspirations and biopsies. Images of vertebral. pelvic. and femoral marrow were obtained using a standard T1-weighted. short repetition time (TR). short time to echo (TE) (TR700/TE22). spin-echo (T1-SE) method in 92 patients and short TI inversion recovery (STIR) technique (TR1.500/TE36/TI100) in all. On standard T1-SE sequence. normal marrow is bright due to the predominance of marrow fat. and tumor is dark. With STIR images. water containing tumor has a very high signal intensity in a dark (fat suppressed) background. Thirteen patients had positive MR scans and marrow biopsies. whereas 49 had negative MR scans and biopsies. Of 36 discordant MR/histology results. 10 had positive biopsies and negative MR exams; eight of these had microscopic infiltration (less than or equal to 5%) with tumor. MR detected marrow tumor either in the crests or elsewhere in 25 of 75 (33%) patients with negative study biopsies. We could confirm marrow involvement in 15 of these 25 (60%) by clinical methods. Therefore. up to one third of the patients evaluated with routine biopsies may have occult marrow tumor detectable by MR exam. In patients with negative marrow biopsies. especially those with Hodgkin's disease or intermediate to high-grade non-Hodgkin's lymphomas. MR scans found focal lesions distant from the crests. Biopsy better detected lower grade microscopic involvement. We conclude that optimal marrow staging of lymphoma patients incorporates both biopsy and MR imaging.
Detection of minimal residual disease in T-cell acute lymphoblastic leukemia using polymerase chain reaction predicts impending relapse, After achieving remission. approximately one-third of patients with T-cell acute lymphoblastic leukemia (T-ALL) relapse due to the resurgence of residual leukemic cells that cannot be detected in remission by morphologic methods. Thus. the early detection of residual disease is highly desirable to monitor the efficacy of therapy. or to institute an alternative mode of therapy. Toward this aim. we have examined the applicability of polymerase chain reaction (PCR) amplification in the detection of minimal residual disease (MRD) in bone marrow samples from patients with T-ALL in morphologic remission. Two different approaches were taken to identify leukemic clone-specific sequences that could be used as targets for PCR amplification. The first technique used T-cell receptor-delta (TCR-delta) gene rearrangements that were sequenced directly after PCR amplification of leukemic DNA. This method was successful in generating clone-specific probes for 76% of T-ALL patients screened. An alternative method was used to clone and sequence a TCR-beta chain gene from leukemic cells to generate a specific probe. The PCR assays that we used were specific for each patient's leukemic clone. and were capable of routinely detecting one leukemic cell in 10(4) normal cells. Using these sensitive PCR-based assays. we found no evidence for persistence of the leukemic clone in any of the bone marrow samples from four T-ALL patients who are in long-term (3.9 + to 8.1 + years) remission. In contrast. we detected residual disease in clinical remission samples from two patients who subsequently relapsed. In one patient. where we had appropriate samples. we observed a dramatic expansion of the leukemic clone 3 months before clinical relapse. These results suggest that PCR-based assays for detection of MRD in T-ALL patients have great potential in predicting impending relapse. and in determining the efficacy of the anti-leukemic therapy. These methods may also allow the identification of long-term survivors.
Human interleukin-7 induces proliferation of neoplastic cells from chronic lymphocytic leukemia and acute leukemias, The biologic effects of interleukin-7 (IL-7) and the expression of specific IL-7 membrane receptors on isolated neoplastic cells from previously untreated patients with chronic lymphocytic leukemia as well as acute leukemias were investigated in vitro. Leukemic cells were incubated for up to 6 days with various concentrations of IL-7 (0.01 to 2.000 U/mL). Neoplastic cells of the T- or B-phenotype from chronic as well as from acute leukemias proliferated in a dose-dependent manner. Cells from acute myeloid leukemias also proliferated in response to IL-7. An optimal proliferative effect was achieved between 96 and 120 hours with 200 U/mL IL-7. Combinations of IL-7 with IL-2 and tumor necrosis factor-alpha showed an additive effect on [3H]TdR incorporation. IL-7 binding assays gave a value of approximately 33 to 180 high-affinity (kd approximately 20 pmol/L) binding sites/cell and approximately 241 to 3.280 low-affinity (kd approximately 600 pmol/L) binding sites/cell. Receptor expression correlated with the proliferation in response to IL-7. These data indicate that IL-7 can induce proliferation of relatively mature tumor cells. and that this effect is not restricted to the lymphoid lineage.
Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for relapsed non-Hodgkin's lymphoma: blood and bone marrow progenitor growth studies. A phase II Eastern Cooperative Oncology Group Trial, Sixteen patients with relapsed non-Hodgkin's lymphoma underwent autologous bone marrow transplantation and infusion of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). Treatment consisted of involved-field radiotherapy. cyclophosphamide 60 mg/kg/d intravenously (IV) for 2 days. and fractionated total body irradiation (1.200 cGy). Autologous bone marrow was thawed and infused IV. followed 3 hours later by the first infusion of IV rhGM-CSF 11 micrograms/kg/d over 4 hours. Infusions of rhGM-CSF were continued daily until either both neutrophil count exceeded 1.500/microL and platelet count exceeded 50.000/microL. or until 30 days after marrow re-infusion. Toxicities encountered were mild and included fever. chills. hypertension. alopecia. rash. diarrhea. stomatitis. myalgias. and synovial (knee) effusions. Neutrophil recovery greater than 500/microL occurred a median of 14 days (range. 9 to 30 days) after marrow infusion. significantly earlier than in a comparable group of historic controls who recovered counts at a median time of 20 days (range. 12 to 51 days) (P = .00002). Median time to self-sustaining platelet counts greater than 20.000/microL was 23.5 days (range. 12 to 100 days). comparable with the historic group (P = .38). One bacteremia (central venous catheter exit site infection with Staphylococcus epidermidis) and one local infection (Giardia lamblia in stool) occurred. Patients received a median of 11.4 (range. 4.4 to 20.2) x 10(4) colony-forming unit granulocyte-macrophage (CFU-GM) progenitors per kg. Stem cell progenitors CFU-GM. CFU-granulocyte. erythroid. monocyte. megakaryocyte (CFU-GEMM). and burst-forming unit-erythroid (BFU-E) were detected in the bone marrow as early as 7 days after marrow re-infusion. and increased in proportion to peripheral blood counts. but by 30 to 60 days still remained much lower than before transplant. Neutrophils transiently decreased in 13 of 16 patients (median decrease. 42%) within 24 to 72 hours of discontinuing rhGM-CSF infusions. These data suggest that rhGM-CSF therapy enhances neutrophil recovery by forcing stem cells to produce mature elements at an enhanced rate but may not affect marrow stem cell and early progenitor population sizes.
Bone density in women receiving depot medroxyprogesterone acetate for contraception [published erratum appears in BMJ 1991 Jul 27;303(6796):220, OBJECTIVE--To determine if the use of the injectable contraceptive depot medroxyprogesterone (DMPA). which reduces ovarian oestrogen production. is associated with changes in bone density. DESIGN--Population study. DMPA users were compared with two control groups selected from larger population studies and individually matched for several putative determinants of bone density (age. race. body mass index. and years of oestrogen deficiency). Controls and DMPA users were matched without prior knowledge of their bone density measurements. SETTING--Teaching hospital and community family planning clinics. SUBJECTS--30 current users of DMPA with a minimum five years' previous use. 30 premenopausal controls. and 30 postmenopausal controls. MAIN OUTCOME MEASURE--Lumbar spine and femoral neck bone mineral density assessed by dual energy x ray absorptiometry. RESULTS--Compared with premenopausal controls matched for age. race. and body mass index. DMPA users had significantly reduced bone density in the lumbar spine (mean difference 7.5% (95% confidence interval 1.9% to 13.1%). p = 0.002) and in the femoral neck (6.6%. (0.8% to 12.3%). p = 0.007). Compared with postmenopausal controls matched for body mass index and duration of oestrogen deficiency. DMPA users had greater bone density in the lumbar spine (8.9% (4.3% to 13.5%). p = 0.001). but in the femoral neck the difference in bone density was less (4.0% (-0.4% to 8.5%). p = 0.04). CONCLUSIONS--Women using DMPA have bone density values intermediate between those of normal premenopausal and postmenopausal controls; thus. the degree of oestrogen deficiency induced by DMPA may have an adverse effect on bone density.
Eating disorders in young adults with insulin dependent diabetes mellitus: a controlled study, OBJECTIVE--To determine the prevalence of clinical eating disorders and lesser degrees of disturbed eating in young adults with insulin dependent diabetes and a matched sample of non-diabetic female controls. DESIGN--Cross sectional survey of eating habits and attitudes in diabetic and non-diabetic subjects. SETTING--Outpatient clinic catering for young adults with diabetes; community sample of non-diabetic women drawn from the lists of two general practices. SUBJECTS--100 patients with insulin dependent diabetes (54 women and 46 men) aged 17-25 and 67 non-diabetic women of the same age. MAIN OUTCOME MEASURES--Eating habits and eating disorder psychopathology were assessed by standardised research interview adapted for the assessment of patients with diabetes (eating disorder examination). Glycaemic control was assessed by glycated haemoglobin assay. RESULTS--In both non-diabetic and diabetic women disturbed eating was common. and in diabetic women the degree of disturbance was related to control of glycaemia. Twenty of the diabetic women (37%) had omitted or underused insulin to influence their weight. This behaviour was not restricted to those with a clinical eating disorder. None of the men showed any features of eating disorders. and none had misused insulin to influence their weight. CONCLUSIONS--There was no evidence that clinical eating disorders are more prevalent in young women with diabetes than in non-diabetic women. Nevertheless. disturbed eating is common and is associated with poor control of glycaemia. and the misuse of insulin to influence body weight is also common in young women with diabetes.
Does plasma cholesterol concentration predict mortality from coronary heart disease in elderly people? 18 year follow up in Whitehall study, OBJECTIVE--To explore the extent to which the relation between plasma cholesterol concentration and risk of death from coronary heart disease in men persists into old age. DESIGN--18 year follow up of male Whitehall civil servants. Plasma cholesterol concentrations and other risk factors were determined at first examination in 1967-9 when they were aged 40-69. Death of men up to 31 January 1987 was recorded. SUBJECTS--18.296 male civil servants. 4155 of whom died during follow up. MAIN OUTCOME MEASURES--Cause and age of death. Cholesterol concentration in 1967-9 and number of years elapsed between testing and death. RESULTS--1676 men died of coronary heart disease. The mean cholesterol concentration in these men was 0.32 mmol/l higher than that in all other men (95% confidence interval 0.26 to 0.37 mmol/l). This difference in cholesterol concentrations fell 0.15 mmol/l with every 10 years' increase in age at screening. The risk of raised cholesterol concentration fell with age at death. Compared with other men cholesterol concentration in those who died of coronary heart disease was 0.44 mmol/l higher in those who died aged less than 60 and 0.26 mmol/l higher in those aged 60-79 (p = 0.03). For a given age at death the longer the gap between cholesterol measurement and death the more predictive the cholesterol concentration. both for coronary heart disease and all cause mortality (trend test p = 0.06 and 0.03 respectively). CONCLUSION--Reducing plasma cholesterol concentrations in middle age may influence the risk of death from coronary heart disease in old age.
Hemodynamic monitoring: a technology assessment. Technology Subcommittee of the Working Group on Critical Care, Ontario Ministry of Health, OBJECTIVE: To review catheterization of the right side of the heart according to technical capability. diagnostic accuracy. range of possible uses. therapeutic impact. benefit to patient outcome and impact on health care workers. DATA SOURCES: MEDLINE was searched for English-language articles published since 1962. Additional references were selected from the bibliographies of identified articles. STUDY SELECTION: Nonrandomized trials and retrospective reviews were included because of a paucity of randomized controlled trials. DATA EXTRACTION AND SYNTHESIS: After a review of the data on hemodynamic monitoring by the subcommittee members. guidelines were developed through the use of the nominal group and Delphi consensus-gathering techniques. CONCLUSIONS: The use of catheterization of the right side of the heart for hemodynamic monitoring should be reserved for tertiary and secondary care hospitals. which are adequately staffed by physicians and nurses well versed in the use of such monitoring. Future research should be directed at determining whether the use of hemodynamic monitoring will improve outcomes among patients. especially those with myocardial infarction. septic shock or pulmonary edema.
Differential effects of thromboxane A2 synthase inhibition, singly or combined with thromboxane A2/prostaglandin endoperoxide receptor antagonism, on occlusive thrombosis elicited by endothelial cell injury or by deep vascular damage in canine coronary arteries, In open-chest dogs. cyclic flow reductions (CFRs. 5.1-6.6/hr in controls; n = 24) caused by platelet deposition/dislodgment at sites of endothelial cell injury in critically stenosed left anterior descending coronary arteries (59% flow reduction) were attenuated to the same extent either by single thromboxane A2 (TXA2) synthase inhibition (0.31 mg/kg i.v. ridogrel; CFR. 0.16 +/- 0.16/hr; n = 6; p less than 0.05) or by a comparatively modest degree of TXA2/prostaglandin endoperoxide receptor antagonism on top of TXA2 synthase inhibition (5 mg/kg i.v. ridogrel; CFR. 0.22 +/- 0.1/hr; n = 10; p less than 0.05). By contrast. occlusive thrombosis on deep vascular damage elicited by intraluminal stimulation (150-microA anodal constant current) in nonpreconstricted canine coronary arteries (time to occlusion. 237.1 +/- 13.9 minutes; n = 7; incidence of occlusion within 300 minutes. six of seven experiments) was not affected by platelet cyclooxygenase inhibition (5 mg/kg i.v. acetylsalicylic acid; n = 7). single TXA2 synthase inhibition (1.25 mg/kg i.v. ridogrel; n = 7). or single TXA2/prostaglandin endoperoxide receptor antagonism (10 mg/kg + 10 mg/kg/hr i.v. sulotroban for 300 minutes; n = 5). However. such an occlusive thrombus formation was significantly reduced by combined TXA2 synthase/prostaglandin endoperoxide receptor inhibition (5 mg/kg i.v. ridogrel; time to occlusion greater than 300 minutes. n = 7; incidence of occlusion within 300 minutes. one of seven experiments; p less than 0.05). This study reveals 1) a differential efficacy of TXA2 synthase inhibition. singly or combined with TXA2/prostaglandin endoperoxide receptor antagonism. depending on the extent of the vessel wall lesion triggering thrombosis and the size of the thrombus required to obstruct the vascular lumen and 2) a significant synergism in preventing occlusive thrombosis of extensively damaged coronary arteries between strong TXA2 synthase inhibition and comparatively modest TXA2/prostaglandin endoperoxide receptor antagonism with ridogrel.
Contribution of endogenous endothelin to the extension of myocardial infarct size in rats, Pathophysiological roles of endogenous endothelin have been studied from the viewpoint of its contribution to the extension of myocardial infarct size. A monoclonal antibody against endothelin 1 (AwETN40) suppressed changes induced by endothelin 1 and endothelin 2 but did not modify those by endothelin 3 in vivo or in vitro. Effects of AwETN40 on myocardial infarct size were investigated. Coronary ligation (1 hour) and reperfusion (24 hours) in rats caused infarction in 35% of the left ventricle. Repetitive or single administration of AwETN40 reduced the infarct size; an intravenous injection of 22.5 mg/kg of the antibody 5 minutes after coronary occlusion or 5 minutes before reperfusion reduced the size by 38% or 31% of the control. respectively. Plasma and tissue endothelin 1 and plasma big endothelin 1 in rats were measured at various stages after occlusion. Plasma endothelin 1 showed a fourfold increase 10 minutes after reperfusion (from 1.02 to 3.96 pg/ml) and had returned to the control value after 8 hours. Plasma big endothelin 1 showed changes similar to those of plasma endothelin 1. No significant changes in plasma endothelin 2 and endothelin 3 were observed. Cardiac tissue contained seven times as much endothelin 1 as the control value 1 hour after reperfusion (4.59 versus 33.1 pg/g tissue). and a high concentration (13.2 pg/g tissue) was maintained even after 48 hours. We concluded that an increase in endogenous endothelin 1 plays an important role in the extension of myocardial infarct size.
Intrarenal hemodynamics in patients with essential hypertension, Intrarenal hemodynamics were estimated clinically in essential hypertension. Two-week studies were performed in 30 patients with essential hypertension who were given a regular sodium diet in the first week and a sodium-restricted diet in the second week. Intrarenal hemodynamic parameters such as afferent arteriolar (preglomerular) resistance. efferent arteriolar resistance. and glomerular hydrostatic pressure were calculated from renal clearances and plasma total protein concentration measured on the last day of the regular sodium diet. Calculations were based on Gomez's equations with the assumption that the gross filtration coefficient of glomerular capillaries was normal. The increase in afferent arteriolar resistance (8.100 +/- 500 dyne.sec.cm-5) was significantly correlated with an elevation in mean arterial pressure (120 +/- 2 mm Hg). whereas glomerular pressure (56 +/- 1 mm Hg) and efferent arteriolar resistance (2.500 +/- 100 dyne.sec.cm-5) remained normal. The renal function curve (pressure-natriuresis relation) was drawn by plotting urinary sodium excretion on the y axis as a function of mean arterial pressure on the x axis. both of which were measured on the last 3 days of each week. The extrapolated x intercept (107 +/- 2 mm Hg) of the renal function curve was strongly correlated in a 1:1 fashion with the sum of the arterial pressure drop from the aorta to the renal glomeruli plus the opposing pressures against glomerular filtration at glomeruli (r = 0.7. p less than 0.001) on the regular sodium diet. suggesting that the difference between mean arterial pressure on the regular sodium diet and the extrapolated x intercept represented the effective filtration pressure across the glomerular capillaries on the regular sodium diet.
Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure, In addition to the circulating renin-angiotensin system. recent data demonstrate the existence of tissue renin-angiotensin systems that may be important in cardiovascular homeostasis. However. the relative activities of the circulating and tissue renin-angiotensin systems have not been examined previously in pathophysiological states. such as congestive heart failure. The present study was performed to examine the status of plasma and tissue angiotensin converting enzyme (ACE) activities in compensated experimental heart failure induced by coronary artery ligation in the rat. Three groups of male Sprague-Dawley rats were examined: 1) nonoperated rats (NO. n = 5). 2) sham-operated rats (SO. n = 5). and 3) heart failure rats (HF. n = 11). Rats were studied an averaged of 85 days postoperatively. In HF animals. plasma renin concentration and serum ACE activities were not different compared with NO and SO control animals. Cardiac ACE activity was 50% greater in the right ventricle than the interventricular septum in NO and SO rats. Both right ventricular and interventricular septal ACE activity increased approximately twofold in HF animals as compared with NO and SO groups (p less than 0.05). In contrast. pulmonary. aortic. and renal ACE activities were not altered in HF rats compared with control animals. A positive correlation existed between the histopathological size of myocardial infarction and the level of right ventricular ACE activity (r = 0.75. p less than or equal to 0.05). Such a relation between infarct size and either serum or noncardiac tissue ACE activities was not observed.
Differential effects of transforming growth factor-beta 1 and phorbol myristate acetate on cardiac fibroblasts. Regulation of fibrillar collagen mRNAs and expression of early transcription factors, Cardiac fibroblasts are responsible for synthesis and deposition of fibrillar collagen types I and III. Transforming growth factor-beta 1 (TGF-beta 1) has been proved to increase collagen biosynthesis in various systems. both in vivo and in vitro. We have investigated the effect of TGF-beta 1 on collagen gene expression in cultured cardiac fibroblasts and have compared this effect with that of a mitogenic agent. phorbol myristate acetate (PMA). The regulation of collagen types I and III gene expression was examined by using cDNA probes to rat alpha 2 (I) and mouse alpha 1 (III) procollagens. Quiescent cultured cardiac fibroblasts from rabbit heart were treated with TGF-beta 1 (10-15 ng/ml) and PMA (200 ng/ml). After 24 hours of treatment with TGF-beta 1. the abundance of mRNA for pro-alpha 2 (I) and pro-alpha 1 (III) collagens was increased by 112% (p less than 0.001) and 97% (p = 0.05). respectively. in treated fibroblasts compared with untreated cells. However. PMA-treated cells showed an opposite response: a 42% (p = 0.01) decrease in mRNA levels for pro-alpha 2 (I) collagen was observed. Immunofluorescent staining of cardiac fibroblasts in culture with anti-type I collagen antibody showed that alterations in mRNA levels led to altered collagen synthesis: cellular collagen was relatively increased in TGF-beta 1-treated cells and significantly diminished in PMA-treated cells. The abundance of mRNA for pro-alpha 1 (III) collagen was not affected by PMA treatment.
Inhibitory effects of procainamide on sympathetic nerve activity in humans, In experimental animals. procainamide causes hypotension and reductions in efferent vasoconstrictor sympathetic outflow that may result from ganglionic blockade or central nervous system sympathetic inhibition. To test the hypothesis that procainamide decreases sympathetic nerve activity (SNA) in humans. we recorded postganglionic SNA in seven normal subjects in the baseline state and during infusions of procainamide HCl at 50 mg/min (loading) and 8 mg/min (maintenance). At the end of the loading infusion. mean arterial pressure (MAP) had decreased from 88.5 +/- 2.4 (mean +/- SEM) to 81.5 +/- 3.2 mm Hg (p less than 0.05). central venous pressure from 6.7 +/- 0.7 to 5.4 +/- 0.9 mm Hg (p less than 0.05). forearm vascular resistance (FVR) from 28 +/- 4.8 to 22.3 +/- 5.1 resistance units (p less than 0.05). and SNA from 259 +/- 47 to 94 +/- 26 units/min (p less than 0.05). These changes persisted during the maintenance infusion. Increased levels of SNA. FVR. and MAP provoked by the cold pressor test were reduced significantly by intravenous procainamide. In eight other subjects. intravenous procainamide HCl (15 mg/kg at 50 mg/min) caused dose-dependent inhibition of SNA that reversed as blood concentrations fell during drug washout. To determine if procainamide causes direct vasodilation. in nine subjects. graded infusions were delivered into the brachial artery at doses that produced no systemic effect. Ipsilateral FVR tended to increase during local intra-arterial infusion of procainamide. These data show that intravenous procainamide causes hypotension. vasodilation. and sympathetic withdrawal. Vasodilation does not result from a direct vasorelaxant effect of the drug.
Cardiovascular neural regulation explored in the frequency domain, A consistent link appears to exist between predominance of vagal or sympathetic activity and predominance of HF or LF oscillations. respectively: RR variability contains both of these rhythms. and their relative powers appear to subserve a reciprocal relation like that commonly found in sympathovagal balance. In this respect. it is our opinion that rhythms and neural components always interact. just like flexor and extensor tones or excitatory and inhibitory cardiovascular reflexes. and that it is misleading to separately consider vagal and sympathetic modulations of heart rate. In humans and experimental animals. functional states likely to be accompanied by an increased sympathetic activity are characterized by a shift of the LF-HF balance in favor of the LF component; the opposite occurs during presumed increases in vagal activity. In addition. LF oscillation evaluated from SAP variability appears to be a convenient marker of the sympathetic modulation of vasomotor activity. Although based on indirect markers. the exploration in the frequency domain of cardiovascular neural regulation might disclose a unitary vision hard to reach through the assemblage of more specific but fragmented pieces of information.
Left cardiac sympathetic denervation in the therapy of congenital long QT syndrome. A worldwide report, BACKGROUND. Long QT syndrome (LQTS) is a congenital disorder accompanied by a high incidence of sudden cardiac death. beta-Adrenergic blockade is the therapy of choice. and it is successful in 75-80% of patients. For those in whom cardiac events (syncope or cardiac arrest) are not prevented by beta-blockade. experimental studies suggest that left cardiac sympathetic denervation (LCSD) may be useful. METHODS AND RESULTS. We identified 85 LQTS patients worldwide who underwent LCSD. and we provide here the first large-scale evaluation of its efficacy. The time interval between the first cardiac event and LCSD and the follow-up period after LCSD were similar (5.6 +/- 6.1 versus 5.9 +/- 5.7 years). The mean age of the patients at surgery was 20 +/- 13 years. LCSD was followed by highly significant (p less than 0.0001) decreases in the number of patients with cardiac events (from 99% to 45%). in the number of cardiac events per patient (from 22 +/- 32 to 1 +/- 3). and in the number of patients with five or more cardiac events (from 71% to 10%). There were seven sudden deaths (8%). and the 5-year survival rate was 94%. The marked reduction in the incidence of tachyarrhythmic syncope suggests that LCSD has also reduced the risk for sudden death in this high-risk population. CONCLUSIONS. The present findings demonstrate that for LQTS patients who continue with syncope or cardiac arrest despite the use of beta-blockers. LCSD is a very effective therapy.
Left ventricular thrombus in anterior acute myocardial infarction after thrombolysis. A GISSI-2 connected study, BACKGROUND. Streptokinase reduces the incidence of left ventricular thrombosis after acute myocardial infarction. However. it is unknown whether a similar effect can be obtained with different thrombolytic agents and whether subcutaneous calcium heparin can have an additional efficacy. METHODS AND RESULTS. To compare the effects of two different thrombolytic agents combined or not with heparin on the incidence and features of left ventricular thrombi and their related embolic events. we performed a GISSI-2 ancillary echocardiographic study (the first echocardiogram obtained within 48 hours of symptoms onset and the second before hospital discharge) that enrolled 180 consecutive patients (mean age. 63 +/- 11 years. 142 men) with a first anterior acute myocardial infarction. Patients were randomized into four groups of treatment: recombinant tissue-type plasminogen activator (rt-PA) (n = 47). rt-PA plus heparin (n = 45). streptokinase (n = 39). and streptokinase plus heparin (n = 49). Left ventricular thrombosis was observed in 51 of 180 patients (28%). No significant differences were found concerning the incidence of thrombi in the four treatment groups. Mural shape of left ventricular thrombi was found more frequently than the protruding shape (71% versus 29% at the first examination. 64% versus 36% at the second). particularly in heparin-treated patients (93% versus 7% at first examination. 70% versus 30% at the second). Only one embolic event (0.5%) occurred during the hospitalization. CONCLUSIONS. We conclude that 1) the rate of left ventricular thrombi does not differ in patients with acute myocardial infarction treated either with streptokinase or rt-PA. 2) subcutaneous heparin. when begun 12 hours after intravenous thrombolysis. does not appear to further reduce the occurrence of thrombi but seems to influence the shape of left ventricular thrombi. and 3) during the predischarge period. embolic events are rare in patients treated by thrombolysis.
Post-myocardial infarction mortality in patients with ventricular premature depolarizations. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Pilot Study, BACKGROUND. Among survivors of acute myocardial infarction. frequent and repetitive ventricular premature depolarizations (VPDs) detected on ambulatory monitoring contribute independently to the risk of all-cause mortality and sudden death. Apart from the beta-blockers. no antiarrhythmic drug has been reliably demonstrated to reduce mortality among patients with VPDs. A pilot study was undertaken to gather data to aid in the design of a multicenter trial of amiodarone for the reduction of mortality from cardiac arrhythmias in such patients. METHODS AND RESULTS. Seventy-seven patients with acute myocardial infarction within the previous 6-30 days and 10 or more VPDs/hr or one or more runs of ventricular tachycardia on 24-hour electrocardiographic recording were randomized in a double-blind fashion in a 2:1 amiodarone-to-placebo ratio. The loading dose was 10 mg/kg/day for 3 weeks. The maintenance dose was 300-400 mg/day with reductions at 4-month intervals in response to VPD suppression. excessive plasma levels. or toxicity. VPD suppression at 1 week and 2 weeks was 63% and 85%. respectively. on amiodarone and 17% and 27%. respectively. on placebo. Apart from thyroid-stimulating hormone elevation and skin reactions. no side effects occurred more frequently with amiodarone. The study drug was stopped for side effects or noncompliance in 35% of amiodarone patients and 34% of placebo patients. Patients were followed for a maximum of 2 years (mean. 20 months). Arrhythmic death or resuscitated ventricular fibrillation occurred in two of 48 amiodarone patients (6%) and four of 29 placebo patients (14%). whereas the rates of all-cause mortality were five of 48 (10%) and six of 29 (21%). respectively. CONCLUSIONS. Amiodarone. in moderate loading and maintenance dosages with adjustments in response to plasma levels. VPD suppression. and side effects. results in effective VPD suppression and acceptable levels of toxicity.
Predictors of first discharge and subsequent survival in patients with automatic implantable cardioverter-defibrillators, BACKGROUND. Two hundred eighteen patients were evaluated in a two-phase approach (time to first appropriate discharge. survival after discharge) to identify factors that may be related to maximal benefit derived from use of an automatic implantable cardioverter-defibrillator (AICD). METHODS AND RESULTS. One hundred ninety-seven patients survived implantation of AICD. with or without concomitant cardiac surgery. One hundred five patients had an AICD discharge associated with syncope. presyncope. documented sustained ventricular tachycardia or fibrillation. or sleep at 9.1 +/- 11.1 months after implantation. Patients survived 23.8 +/- 18.0 months after AICD discharge. Left ventricular dysfunction (p = 0.008 for ejection fraction less than 25%) was associated with earlier AICD discharge and shortened survival after AICD discharge (p = 0.008 for ejection fraction less than 25%; p = 0.01 for New York Heart Association functional class III and IV). beta-Blocker administration (p = 0.006) and coronary bypass surgery (p = 0.06) were associated with later AICD discharge. Coronary bypass surgery (p = 0.035) but not beta-blockers was associated with more prolonged survival after AICD discharge. CONCLUSIONS. These data suggest that a relatively easy algorithm can be applied to predict which patient will benefit most from AICD implantation.
Regression of left ventricular hypertrophy in hypertensive heart transplant recipients treated with enalapril, furosemide, and verapamil, BACKGROUND. This prospective study was designed to examine whether left ventricular (LV) hypertrophy of the denervated transplanted heart may be reversed by medical therapy and. if so. to investigate the time course of this process and its effect on exercise capacity. myocardial function. and cardiac hemodynamics. METHODS AND RESULTS. Ten hypertensive heart transplant recipients with LV hypertrophy were evaluated before therapy with enalapril plus furosemide alone or combined with verapamil. at initial blood pressure (BP) control and after 3. 6. 9. and 12 months. using 24-hour noninvasive ambulatory BP monitoring. M-mode and two-dimensional echocardiography. and supine bicycle ergometry. Average 24-hour systolic and diastolic BP declined from 158 +/- 10 and 104 +/- 7 mm Hg to 129 +/- 9 and 84 +/- 10 mm Hg at initial BP control (p less than 0.005 and p less than 0.025. respectively) and total peripheral resistance from 1.687 +/- 177 to 1.376 +/- 122 dyne.sec.cm-5 (p less than 0.025). remaining normal thereafter. Exercise capacity remained unchanged during the study. LV mass. mass-to-volume ratio. and end-diastolic septal plus posterior wall thickness decreased progressively from 211 +/- 30 g. 2.49 +/- 0.62 g/ml. and 25.7 +/- 2.6 mm to 184 +/- 26 g. 2.22 +/- 0.46 g/ml. and 22.5 +/- 1.9 mm after 3 months (all p less than 0.025) and to 174 +/- 25 g. 2.07 +/- 0.38 g/ml. and 21.5 +/- 1.5 mm after 6 months (all p less than 0.005). remaining unaltered at 9 and 12 months. A correlation was found between the decrease in average 24-hour mean BP and LV mass after 3 months of antihypertensive therapy (r = 0.71. p less than 0.05). Systolic meridional wall stress. LV end-diastolic and stroke volume. ejection fraction. and cardiac output remained unchanged throughout the observation period. CONCLUSIONS. The results indicate that regression of LV hypertrophy is induced by effective antihypertensive therapy in the denervated transplanted heart. The extent of decrease in average 24-hour BP appears to be the main determinant for the extent of reduction in LV mass. LV afterload as characterized by systolic meridional wall stress. LV size and pump function. and physical exercise capacity of the transplant patients are not influenced by the therapeutic regimen chosen in this study.
Intraoperative transesophageal Doppler color flow imaging used to guide patient selection and operative treatment of ischemic mitral regurgitation, BACKGROUND. Intraoperative transesophageal Doppler color flow imaging (TDCF) affords the opportunity to assess mitral valve competency immediately before and after cardiopulmonary bypass (CPB). The purpose of this study was to assess the utility of TDCF to assist in the selection and operative treatment of ischemic mitral regurgitation (MR). METHODS AND RESULTS. Two hundred forty-six patients undergoing surgery for ischemic heart disease were prospectively studied. All had preoperative cardiac catheterization. Catheterization and pre-CPB TDCF were discordant in their estimation of MR in 112 patients (46%). Compared with patients in whom both techniques agreed in estimation of MR. patients with discordance in MR were more likely to have had unstable clinical syndromes at the time of catheterization (79% versus 40%. p less than 0.05) or to have received thrombolytics (16% versus 8%. p less than 0.05). Pre-CPB TDCF resulted in a change in the operative plan with respect to the mitral valve in 27 patients (11%). Because less MR was found by TDCF than catheterization. 22 patients had only coronary bypass grafting when combined coronary bypass and mitral valve surgery had been planned. Because more MR was found by TDCF than catheterization. five patients had combined coronary bypass and mitral valve surgery when coronary bypass alone had been planned. Unsatisfactory results noted by TDCF following mitral valve surgery in five patients resulted in immediate corrective surgery. Cox regression analysis identified residual MR at the completion of surgery to be an important predictor of survival (chi 2 = 21.4) after surgery--more important than patient age (chi 2 = 8.3) or left ventricular ejection fraction (chi 2 = 5.3). CONCLUSIONS. These results indicate that TDCF is useful in guiding patient selection and operative treatment of ischemic MR and that in such patients. intraoperative TDCF should be performed routinely.
Blood platelet count and function are related to total and cardiovascular death in apparently healthy men, BACKGROUND. Experimental animal and clinical studies indicate that blood platelets have an important role in atherosclerosis and formation of thrombi. Prospective studies presenting evidence of an association between blood platelet count and cardiovascular mortality have not been performed. METHODS AND RESULTS. From 1973 to 1975. blood platelets were counted. and their responsiveness to aggregating agents was studied in healthy middle-aged men. The aim was to assess the possible association between these variables and coronary heart disease. At 13.5 years of follow up. a significantly higher coronary heart disease mortality was observed among the 25% of subjects with the highest platelet counts. Platelet aggregation performed in a random subsample (150 of the 487 men). moreover. revealed that the 50% with the most rapid aggregation response after ADP stimulation had significantly increased coronary heart disease mortality compared with the others. These associations could not be explained by differences in age. lipids. blood pressure. or smoking habits. CONCLUSIONS. The present study is the first to present conclusive. prospective evidence of an association between platelet concentration and aggregability and long-term incidence of fatal coronary heart disease in a population of apparently healthy middle-aged men.
Hemodynamics and coronary blood flow during exercise after coronary artery bypass grafting with internal mammary arteries in children with Kawasaki disease, BACKGROUND. Saphenous vein grafts (SVG) and internal mammary artery (IMA) grafts have been used for coronary artery bypass grafting. In adult patients with bypass grafting for atherosclerotic coronary artery disease. IMA grafts have been reported to have long-term patency; however. results are conflicting on whether the graft is sufficient to meet increased myocardial oxygen demand during exercise. There have been no studies on hemodynamics and blood flow during exercise after bypass grafting with IMA in pediatric patients with Kawasaki disease. METHODS AND RESULTS. We studied 17 pediatric patients with Kawasaki disease (average age. 7.5 +/- 3.1 years). who underwent coronary artery bypass grafting with the IMA. The average number of coronary artery bypass grafts was 2.1 +/- 0.7/patient. For all patients. the left IMA was anastomosed to the left anterior descending coronary artery; for eight patients. the right IMA was also anastomosed to the right coronary artery. In addition. 11 SVGs were used. The postoperative patency rates after 1 month were 100% with the IMA graft and 91% with SVG. One year after the operation. the patency rates were 100% with IMA and 50% with SVG. Hemodynamics during exercise were measured with a bicycle ergometer. and coronary sinus blood flow was measured by the continuous thermodilution method in six patients. The relation between delta LVEDP (the difference between left ventricular end-diastolic pressure at rest and during exercise) and delta SVI (the difference between the stroke volume index at rest and during exercise) was analyzed. Four of six patients had reduced cardiac function before operation (delta LVEDP. positive; delta SVI. negative). However. after the operation. all patients demonstrated improvements in cardiac function during exercise (delta LVEDP. positive; delta SVI. positive). Coronary sinus flow per left ventricular mass increased after operation from 70 +/- 46 to 87 +/- 56 ml/min at rest (p less than 0.05) and from 139 +/- 118 to 183 +/- 150 ml/min during exercise (p less than 0.05). CONCLUSIONS. In conclusion. this study reveals improvements in both hemodynamics and coronary blood flow during exercise after coronary artery bypass grafting with IMA grafts in pediatric patients with Kawasaki disease.
Electrode system influence on biphasic waveform defibrillation efficacy in humans, BACKGROUND. Several clinical studies have demonstrated a general superiority of biphasic waveform defibrillation compared with monophasic waveform defibrillation using epicardial lead systems. To test the breadth of utility of biphasic waveforms in humans. a prospective. randomized evaluation of defibrillation efficacy of monophasic and single capacitor biphasic waveform pulses was performed for two distinct nonthoracotomy lead systems as well as for an epicardial electrode system in 51 cardiac arrest survivors undergoing automatic defibrillator implantation. METHODS AND RESULTS. The configurations tested consisted of a right ventricular-left ventricular (RV-LV) epicardial patch-patch system. an RV catheter-chest patch (CP) nonthoracotomy system. and a coronary sinus (CS) catheter-RV catheter nonthoracotomy system. For each configuration. the defibrillation current and voltage waveforms were recorded via a digital oscilloscope to measure defibrillation threshold voltage. current. resistance. and stored energy. Biphasic waveform defibrillation proved more efficient than monophasic waveform defibrillation for the epicardial RV-LV system (4.8 +/- 4.1 versus 6.7 +/- 4.9 J. p = 0.047) and the nonthoracotomy RV-CP system (23.4 +/- 11.1 versus 34.3 +/- 10.4 J. p = 0.0042). Biphasic waveform defibrillation thresholds were not significantly lower than monophasic waveform defibrillation thresholds for the CS-RV nonthoracotomy system (15.6 +/- 7.2 versus 20.0 +/- 11.5 J. p = 0.11). Biphasic waveform defibrillation proved more efficacious than monophasic waveform defibrillation in 13 of 20 patients (65%) with RV-LV epicardial patches. 10 of 15 patients (67%) with an RV-CP nonthoracotomy system. and nine of 16 patients (56%) with an RV-CS nonthoracotomy system. CONCLUSIONS. Biphasic pulsing was useful with nonthoracotomy lead systems as well as with epicardial lead systems. However. the degree of biphasic waveform defibrillation superiority appeared to be electrode system dependent. Furthermore. for a few individuals. biphasic waveform defibrillation proved less efficient than monophasic waveform defibrillation. regardless of the lead system used.
Differences in electrophysiological substrate in patients with coronary artery disease and cardiac arrest or ventricular tachycardia. Insights from endocardial mapping and signal-averaged electrocardiography, BACKGROUND. Many studies have combined patients with hemodynamically well-tolerated ventricular tachycardia (VT) and those with cardiac arrest (CA) as a single. homogenous group. Recent studies suggest that these two groups have different electrophysiological substrates and responses to therapy. Most of these studies. however. enrolled patients with a variety of cardiac diagnoses. METHODS AND RESULTS. We used signal-averaged electrocardiography (SAECG) and endocardial catheter mapping to define the electrophysiological substrate in patients with coronary artery disease and VT or CA and correlate the results of the two methods. We also examined the usefulness of SAECG in CA patients to differentiate those with inducible arrhythmias from those who are noninducible. VT patients were more likely to have had a prior myocardial infarction (p = 0.0005) and to have inducible arrhythmias (p = 0.0001) than were CA patients. The induced arrhythmias in patients who presented with VT was VT in more than 90% of cases. whereas in CA patients. polymorphic ventricular tachycardia (PMVT) accounted for one third of induced arrhythmias. Mean filtered QRS duration was longer (135 versus 120 msec) and the terminal QRS voltage was smaller (20 versus 34 microV) in VT than in CA patients (p less than 0.01). Sixty-three percent of CA patients and 87% of VT patients had abnormal SAECG (p = 0.001). VT patients had more extensive endocardial abnormalities and more abnormal (53% versus 40%. p = 0.002). fractionated (8% versus 3%. p = 0.02). late (17% versus 8%. p = 0.0003). and late abnormal or fractionated (14% versus 4%. p = 0.0001) sites than CA patients. VT patients had a greater duration of the longest electrogram (129 versus 109 msec. p = 0.0006) and total endocardial activation time (68 versus 54 msec. p = 0.009). Among CA patients. those with induced VT had more extensive substrate than did those with induced PMVT and were similar to VT patients with induced VT. Among CA patients. the trend for more patients with inducible VT (77%) or PMVT (55%) than noninducible patients (47%) to have an abnormal SAECG did not reach statistical significance (p = 0.14). The positive and negative predictive values of an abnormal SAECG were 77% and 44%. respectively. CONCLUSIONS. VT patients have more extensive endocardial substrate than CA patients. which translates into greater and more frequent SAECG abnormalities. Among CA patients. there are significant differences in substrate between patients with induced VT and those with induced PMVT. SAECG is not useful in differentiating CA patients who have inducible VT or PMVT from those who do not.
Suppression of eicosanoid biosynthesis during coronary angioplasty by fish oil and aspirin, BACKGROUND. Percutaneous transluminal coronary angioplasty (PTCA) is an acute. localized stimulus to platelet and vascular function. Periprocedural cardiovascular complications are reduced by moderate-dose aspirin (ASA). presumably due to inhibition of thromboxane (TX) A2. METHODS AND RESULTS. Excretion of TXA2 and prostacyclin (PGI2) metabolites in urine increased during PTCA. Pretreatment for 3 days with either moderate- (325 mg/day) or low-dose (80 mg/day) ASA inhibited the increase in both eicosanoids. Pretreatment for 3 weeks with fish oil (10 g/day) only partially suppressed TXA2. Formation of trienoic eicosanoids and accumulation of omega-3 fatty acids in platelet membranes confirmed fish oil ingestion. Although basal PGI2 was not inhibited. the PTCA-related increment was suppressed. CONCLUSIONS. PTCA results in an acute. transient alteration of eicosanoid biosynthesis consistent with accelerated platelet-vascular interactions. Pretreatment for 3 days with moderate or low doses of ASA suppresses TXA to a similar extent during PTCA. and their effects on acute cardiovascular complications of this procedure are likely to be comparable. It is unlikely that even prolonged pretreatment with fish oil can substitute for the platelet inhibitory action of ASA during PTCA. Suppression of PGI2 may contribute to the residual acute periprocedural complication rate in patients taking ASA.
Abnormal vascular responses to supine exercise in hypertrophic cardiomyopathy, BACKGROUND. Exercise hypotension has been documented in hypertrophic cardiomyopathy. It is not the result of an inability to augment cardiac output but instead relates to an inappropriate and exaggerated decrease in systemic vascular resistance at high work loads. METHODS AND RESULTS. To enable us to examine the behavior of the peripheral vasculature during exercise. 103 consecutive patients underwent maximal symptom-limited supine bicycle exercise with measurement of forearm blood flow. A minimum reduction of 12% from the basal value was defined as a normal response based on the study of 25 normal controls. In the patients. two patterns of forearm blood flow were observed. Sixty-four patients had an appropriate reduction in forearm blood flow of 40 +/- 16% from resting flow. In 39 patients. the forearm blood flow either failed to decrease or increased with exercise by 45 +/- 105% of the resting value. Patients with an abnormal forearm vasodilator response were younger (31 +/- 13 versus 46 +/- 14 years). and more of them had a family history of hypertrophic cardiomyopathy and sudden death than did those with a normal vasoconstrictor response (16 of 39 versus eight of 64). Left ventricular end-diastolic cavity dimensions were smaller in those with an abnormal forearm blood flow response. but other clinical. echocardiographic. and arrhythmic variables were similar. To assess the relation of abnormal peripheral vascular responses to erect exercise blood pressure response. patients underwent treadmill exercise testing with careful monitoring of systolic blood pressure response. Thirty-eight patients had significant exercise hypotension with failure of the systolic blood pressure to increase during progressive exercise (n = 6) or an abrupt decrease in systolic blood pressure (20-60 mm Hg) from the peak value (n = 32); 65 patients had a normal exercise blood pressure response. but 18 of these patients had an oscillation in systolic blood pressure of 10 mm Hg or more early in the recovery phase. Thirty-one of 39 patients with an abnormal forearm blood flow response demonstrated exercise hypotension during the erect exercise testing. and the remaining eight patients had a normal exercise blood pressure response; however. five of these eight had abnormal oscillations in blood pressure during recovery (r = 0.61. p less than 0.001). CONCLUSIONS. The relation of abnormal peripheral vascular responses to exercise hypotension confirms the observation of hemodynamic instability in patients with hypertrophic cardiomyopathy. The finding of abnormal vascular responses in patients known to be at increased risk (young age and a family history of hypertrophic cardiomyopathy and sudden death) suggests that hemodynamic mechanisms may be important in the occurrence of sudden death in hypertrophic cardiomyopathy.
Diminishment of respiratory sinus arrhythmia foreshadows doxorubicin-induced cardiomyopathy, BACKGROUND. The development of a microcomputer-based device permits quick. simple. and noninvasive quantification of the respiratory sinus arrhythmia (RSA) during quiet breathing. METHODS AND RESULTS. We prospectively and serially measured the radionuclide left ventricular ejection fraction and the RSA amplitude in 34 cancer patients receiving up to nine monthly bolus treatments with doxorubicin hydrochloride (60 mg/m2). Of the eight patients who ultimately developed symptomatic doxorubicin-induced congestive heart failure. seven (87.5%) demonstrated a significant decline in RSA amplitude; five of 26 subjects without clinical symptoms of cardiotoxicity (19.2%) showed a similar RSA amplitude decline. On average. significant RSA amplitude decline occurred 3 months before the last planned doxorubicin dose in patients destined to develop clinical congestive heart failure. CONCLUSION. Overall. RSA amplitude abnormality proved to be a more specific predictor of clinically significant congestive heart failure than did serial resting radionuclide ejection fractions.
Clinical characteristics of nonfatal myocardial infarction among individuals on prophylactic low-dose aspirin therapy, BACKGROUND. The influence of prophylactic low-dose aspirin on the clinical characteristics of subsequent nonfatal myocardial infarction was examined in the Physicians' Health Study. a randomized. double-blind placebo-controlled trial of alternate-day aspirin (325 mg) among 22.071 US male physicians. METHODS AND RESULTS. During 60.2 months of follow-up. 342 incident cases of nonfatal myocardial infarction were confirmed (95.2% of all reports): 129 on aspirin and 213 on placebo (p less than 0.00001). Despite this statistically extreme reduction in occurrence of a first nonfatal infarction attributable to aspirin. there were no significant differences in the size. location. electrocardiographic features. or postinfarction left ventricular ejection fraction between the aspirin and placebo groups. Furthermore. among those undergoing angiography. there were no differences in the distribution or number of coronary vessels obstructed. CONCLUSIONS. These data indicate that chronic platelet inhibition with alternate-day aspirin therapy reduces the risk of a first myocardial infarction but does not appear to have a significant effect on the clinical characteristics of events that are survived. This finding may result from a direct effect of aspirin or from an aspirin-induced shift in infarction severity. Regardless of mechanism. these clinical observations suggest that treatment decisions for acute infarction patients should be made independently of a history of aspirin use.
Impact of impinging wall jet on color Doppler quantification of mitral regurgitation, BACKGROUND. In clinical color Doppler examinations. mitral regurgitant jets are often observed to impinge on the left atrial wall immediately beyond the mitral valve. In accordance with fluid dynamics theory. we hypothesized that a jet impinging on a wall would lose momentum more rapidly. undergo spatial distortion. and thus have a different observed jet area from that of a free jet with an identical flow rate. METHODS AND RESULTS. To test this hypothesis in vivo. we studied 44 patients with mitral regurgitation--30 with centrally directed free jets and 14 with eccentrically directed impinging wall jets. Maximal color jet areas (cm2) (with and without correction for left atrial size) were correlated with mitral regurgitant volumes. flow rates. and fractions derived from pulsed Doppler mitral and aortic forward flows. The groups were compared by analysis of covariance. Mean +/- SD mitral regurgitant fraction. regurgitant volume. and mean flow rate averaged 37 +/- 17%. 3.06 +/- 2.65 l/min. and 147 +/- 118 ml/sec. respectively. The maximal jet area from color Doppler imaging correlated relatively well with the mitral regurgitant fraction in the patients with free mitral regurgitant jets (r = 0.74. p less than 0.0001) but poorly in the patients with impinging wall jets (r = 0.42. p = NS). Although the mitral regurgitant fraction was larger (p less than 0.05) in patients with wall jets (44 +/- 20%) than in those with free jets (33 +/- 15%). the maximal jet area was significantly smaller (4.78 +/- 2.87 cm2 for wall jets versus 9.17 +/- 6.45 cm2 for free jets. p less than 0.01). For the same regurgitant fraction. wall jets were only approximately 40% of the size of a corresponding free jet. a difference confirmed by analysis of covariance (p less than 0.0001). CONCLUSIONS. Patients with mitral regurgitation frequently have jets that impinge on the left atrial wall close to the mitral valve. Such impinging wall jets are less predictable and usually have much smaller color Doppler areas in conventional echocardiographic views than do free jets of similar regurgitant severity. Jet morphology should be considered in the semiquantitative interpretation of mitral regurgitation by Doppler color flow mapping. Future studies of the three-dimensional morphology of wall jets may aid in their assessment.
Combination balloon-ultrasound imaging catheter for percutaneous transluminal angioplasty. Validation of imaging, analysis of recoil, and identification of plaque fracture, BACKGROUND. We investigated the hypothesis that an ultrasound transducer positioned within an angioplasty balloon could be used to perform quantitative assessment of arterial dimensions before and after percutaneous transluminal angioplasty (PTA) and to identify certain mechanical alterations consequent to PTA. including vascular wall recoil and the initiation of plaque fractures. METHODS AND RESULTS. A combination balloon-ultrasound imaging catheter (BUIC) that houses a 20-MHz ultrasound transducer within and halfway between the proximal and distal ends of an angioplasty balloon was used to perform PTA in 10 patients with peripheral vascular disease. Each PTA site was also evaluated before and after PTA by standard (nonballoon) intravascular ultrasound (IVUS) technique. In eight patients in whom satisfactory images were recorded with the BUIC before PTA. luminal cross-sectional area (XSA) of stenotic sites (0.10 +/- 0.01 cm2) did not differ significantly from measurements of XSA by IVUS (0.09 +/- 0.01 cm2. p = NS). Likewise. minimum luminal diameter (Dmin) measured by BUIC (0.34 +/- 0.02 cm) was similar to that measured by IVUS (0.33 +/- 0.01 cm. p = NS). In nine patients in whom satisfactory images were recorded with the BUIC after PTA. XSA measured by BUIC (0.29 +/- 0.03 cm2) did not differ significantly from XSA measured by IVUS (0.30 +/- 0.03 cm2. p = NS). Dmin measured by BUIC after PTA (0.57 +/- 0.02 cm) was also similar to Dmin measured by IVUS (0.57 +/- 0.03 cm. p = NS). After PTA. XSA and Dmin measured immediately after deflation were significantly less than balloon XSA and diameter at full inflation. indicating significant elastic recoil of the dilated site. For the nine patients in whom post-PTA images were satisfactory for quantitative analysis. including four patients in whom recoil was 39%. 46%. 50%. and 61%. percent recoil measured 28.6 +/- 7.2%. Finally. plaque fractures were identified on-line in six of 10 patients (60%); in each case. initiation of plaque fracture was observed at inflation pressures of 2 atm or less. CONCLUSIONS. The results of this preliminary human investigation indicate that an ultrasound transducer positioned within an angioplasty balloon can be used to perform quantitative and qualitative analyses of lumen-plaque-wall alterations immediately preceding. during. and immediately after PTA in patients with peripheral vascular disease.
Effects of milrinone on left ventricular remodeling after acute myocardial infarction, BACKGROUND. Left ventricular remodeling after an acute myocardial infarction may result in progressive left ventricular dilation that may be associated with increased mortality. We studied the effects of the phosphodiesterase inhibitor milrinone on left ventricular remodeling after acute myocardial infarction. METHODS AND RESULTS. Rats (n = 90) were randomized to undergo either left coronary artery ligation or sham operation. Three weeks after surgery. rats received either no treatment or milrinone. which was continued until 2 days before the rats were killed. Ninety days after the initial surgery. hemodynamic measurements were made before and after volume loading. The rats were killed. the hearts were removed. and passive pressure-volume curves were obtained. The hearts were fixed at a constant pressure and analyzed morphometrically. Compared with untreated infarcted rats. milrinone-treated infarcted rats had a lower left ventricular end-diastolic pressure (1.7 +/- 0.4 versus 4.3 +/- 1.4 mm Hg. p less than 0.05). a lower left ventricular volume (1.25 +/- 0.20 versus 2.37 +/- 0.30 ml/kg. p less than 0.001) and a lower left ventricular wall stress index (1.3 +/- 0.2 versus 1.7 +/- 0.1. p less than 0.05). Left ventricular chamber stiffness was higher in milrinone-treated infarcted rats than in untreated infarcted rats. Milrinone had no cardiac effect on uninfarcted animals. CONCLUSION. Chronic milrinone therapy after acute myocardial infarction improves cardiac hemodynamic indexes and attenuates progressive left ventricular dilation.
Antithrombotic therapy for deep arterial injury by angioplasty. Efficacy of common platelet inhibition compared with thrombin inhibition in pigs, BACKGROUND. Platelet-thrombus formation is a complication of arterial wall deep injury by balloon angioplasty that may lead to acute arterial occlusion and may contribute to restenosis. METHODS AND RESULTS. Because common platelet-inhibitor drugs with a heparin bolus (100 units/kg) may be effective in inhibiting platelet-thrombus formation after arterial angioplasty. these were compared with a bolus of heparin alone (control). the specific thrombin inhibitor hirudin (1.0 mg/kg). and saline (hirudin control) in normal pigs after angioplasty of the common carotid arteries. In the presence of deep arterial wall injury (injury exposing the media). indium-111-labeled platelet deposition (x 10(6)/cm2) was 68.8 +/- 12.3 and 48.1 +/- 16.9 in the control animals. This was significantly reduced by pretreatment with low-dose aspirin (1 mg/kg/day). by high-dose aspirin (20 mg/kg/day) plus dipyridamole. and especially by thrombin inhibition with hirudin. Treatment regimens with aspirin alone (20 mg/kg/day). dipyridamole alone. or sulfinpyrazone were ineffective. Likewise. the incidence of mural thrombosis was 75% and 80% in deeply injured arteries of controls and was significantly reduced to 46% with aspirin plus dipyridamole. 25% with low-dose aspirin. and 0% with hirudin. The incidence of mural thrombosis was unchanged with high-dose aspirin (69%). dipyridamole (90%). or sulfinpyrazone (92%). This mural thrombosis could not be identified by angiography. In the presence of mild injury (deendothelialization). platelet deposition was low (less than 10 x 10(6)/cm2. a single layer) and was not changed by any therapy. including hirudin. CONCLUSIONS. These therapies do not affect platelet adhesion to deeply or mildly injured artery. These data suggest a greater role for thrombin inhibition than with thromboxane or cyclooxygenase inhibition in the pathogenesis of platelet-rich mural thrombosis after deep injury during angioplasty. Antithrombotic therapy for arterial thrombosis by thrombin inhibition appears promising.
Anatomy of the tricuspid annulus. Circumferential myofibers as the structural basis for atrial flutter in a canine model, BACKGROUND. Little anatomic information is available on the annular myocardium. This study was conducted to determine the anatomic substrate for atrial flutter due to circus movement around the tricuspid annulus in the Y-shaped incision canine model of atrial flutter. METHODS AND RESULTS. We studied photographs of the annular myocardium serial histological sections. made in either of three different planes. and compared these with photographs of the intact and blocked gross heart specimens. We found that the annulus is the most caudal region of the atrial wall. The epicardial aspect of the annulus abuts the ventricular septum or the aortic root in the medial region; in other regions. it is covered by the fat of the coronary sulcus. Its endocardial aspect is delimited by the tricuspid leaflets inferiorly and by the pectinate muscle bundles superiorly. except in the medial region where the pectinate muscle bundles are absent. The annular myocardium is bilaminated. A continuous subepicardial circumferential lamina is the most prominent and is robust in the anterior. lateral. and posterior regions. but it attenuates to a fine muscular connection in the medial region. Myofibers of its superior border merge with the pectinate muscle bundles or are admixed in the medial region with myocardium at the base of the medial atrial wall. Its inferior border makes little contact with the annulus fibrosus about the ring; however. in the medial region. these myofibers insert into fibrous tissue superior to the septal leaflet. A discontinuous. subendocardial perpendicular lamina contains myofibers that descend from the atrium; most of these myofibers insert into the annulus fibrosus about the ring. but the lamina is absent in the anteromedial region. CONCLUSIONS. We conclude that the continuous circumferential lamina provides the anatomic substrate for circus movement of excitation in this model.
Optimal right ventricular filling pressures and the role of pericardial constraint in right ventricular infarction in dogs, BACKGROUND. Previous studies have reported an important role for right ventricular function in the pathophysiology of the low cardiac output state that can accompany right ventricular infarction. Some studies have suggested that right ventricular distensibility impairs right ventricular filling and stroke output; others have demonstrated that the pericardium can mediate depressed left ventricular filling and stroke output. METHODS AND RESULTS. To determine the role of pericardial constraint and optimal volume loading in an experimental model of right ventricular wall infarction. six mongrel dogs were studied before and after right ventricular wall infarction and after volume loading. The pericardium was then opened in two phases. In the first phase. the pericardium was opened partially to allow the atria to distend freely. and in the second phase. the pericardium was opened completely. The animals were preinstrumented with two sets of piezoelectric crystals attached to the right ventricular free wall. one in the infarct and the other in the noninfarct territory. Left ventricular size was estimated by left ventricular crystals on the anterior wall of the left ventricle. Right ventricular and left ventricular Millar catheters were used to assess intracavitary pressure. and a flat balloon was used to assess intrapericardial pressure. Right ventricular infarction reduced cardiac output by 23% and stroke volume by 30%. End-diastolic segment length and transmural pressure of the left ventricle decreased. Volume loading restored cardiac output to baseline values and was mediated by a significant increase in end-diastolic length in the noninfarct territory. This was achieved by increasing right ventricular end-diastolic pressure from 9 +/- 2 to 16 +/- 3 mm Hg (p less than 0.01). Partial opening of the pericardium mediated significant increases in both end-diastolic segment lengths of the left ventricle and the noninfarct territory. Left ventricular end-diastolic pressure decreased slightly by 3 mm Hg (p = NS). Complete opening of the pericardium increased cardiac output and stroke volume and mediated a significant decrease in right and left ventricular end-diastolic pressures. Left ventricular transmural pressure and end-diastolic segment lengths of the left ventricle and the noninfarct territory increased. Left ventricular diastolic pressure-segment length relations were shifted upward by right ventricular infarction. A partial opening of the pericardium shifted this relation downward in all animals. and complete opening of the pericardium shifted the relation rightward and further downward. CONCLUSIONS. Cardiac output is restored to baseline values by volume loading sufficient to increase the right ventricular diastolic pressure to 16 +/- 3 mm Hg. Evidence of pericardial constraint was observed and appears to be mediated by an atrioventricular interaction in addition to the direct ventricular interaction.
Instantaneous hyperemic flow-versus-pressure slope index. Microsphere validation of an alternative to measures of coronary reserve, BACKGROUND. The instantaneous hyperemic flow-versus-pressure (i-HFVP) slope index is a new method of assessing maximal coronary conductance and can be used as an alternative to conventional measures of coronary reserve. The i-HFVP slope index is determined by measuring the slope of the linear diastolic segment of the relation between instantaneous aortic pressure and hyperemic coronary flow. METHODS AND RESULTS. To validate the i-HFVP slope index as a measure of maximal coronary conductance. we compared this method with a microsphere-derived measurement of maximal coronary conductance (m-HFVP slope index) by determining the slope of the least-squares regression line of the data points for coronary flow during maximal hyperemia and four or five steady-state alterations of aortic pressure in 43 dogs (open-chest. anesthetized preparations) with or without coronary stenoses. The i-HFVP slope index demonstrated no dependence on heart rate. left ventricular end-diastolic pressure. or mean aortic pressure and was highly reproducible within the groups studied (intraclass correlation coefficient. 0.86 for normal arteries. 0.87 for stenotic arteries. and 0.93 for combined groups; for all coefficients. p less than 0.001). The i-HFVP slope index was significantly decreased in the presence of a stenosis (10.3 +/- 3.9 for normal arteries versus 3.6 +/- 1.6 for stenotic arteries. p less than 0.001) as was the transmural m-HFVP slope index (8.9 +/- 4.6 for normal arteries versus 5.3 +/- 3.1. p less than 0.01). Of special importance. the i-HFVP slope index measurement for normal arteries was not significantly different from the transmural and subendocardial m-HFVP slope index measurements (10.3 +/- 3.9 versus 8.9 +/- 4.6 and 9.2 +/- 5.7. respectively). For stenotic arteries. the i-HFVP slope index measurement was also not significantly different from the transmural and subendocardial m-HFVP slope index measurements (3.6 +/- 1.6 versus 5.3 +/- 3.1 and 4.1 +/- 2.3. respectively). The i-HFVP slope index correlated best with subendocardial m-HFVP slope index measurements (correlation coefficient. 0.57; p less than 0.001). When the 95% confidence intervals for the transmural (or subendocardial) m-HFVP slope index in normal arteries were compared with the i-HFVP slope index values. the latter demonstrated a systematic trend to overestimate the m-HFVP slope index. In the presence of a stenosis. this effect was minimized. and the slope values were nearly identical. CONCLUSIONS. The i-HFVP slope index correlates most closely with subendocardial coronary conductance; the index is a hemodynamically independent measure of coronary reserve that is reproducible over a broad range of aortic pressures; and the methodology is applicable to an intact circulation in experimental preparations and may with future developments also prove useful in humans.
Detection and localization of prolonged epicardial electrograms with 64-lead body surface signal-averaged electrocardiography, BACKGROUND. Prolonged. fractionated ventricular electrograms often are detectable after myocardial infarction and are a marker for an arrhythmia-prone state. QRS late potentials detected on the body surface with signal-averaged electrocardiography (SAECG) are thought to arise from the diseased tissue that generates prolonged ventricular electrograms and as such are also a marker for arrhythmias. A limitation of the current SAECG technique is that recordings are obtained from only three bipolar lead pairs. Because late potentials probably arise from multiple small sources in the heart. more extensive sampling of the body surface may contribute additional information to the SAECG. The present study investigates the additional sensitivity of SAECG using 64 body surface leads in detecting prolonged epicardial electrograms and examines its use in determining the epicardial location of prolonged electrograms. METHODS AND RESULTS. Dogs were studied before and 5-10 days after either lateral left ventricular (n = 13) or right ventricular (n = 8) myocardial infarction. Greater prolongation of signal-averaged QRS duration was detected with 64-lead SAECG (postinfarction QRS duration. 100.3 +/- 16.3 msec) than with three-lead SAECG (postinfarction QRS duration. 89.4 +/- 10.1. p = 0.0005). Nineteen of the 21 dogs (90%) had prolonged epicardial electrograms detected over the infarct. The correlation between epicardial electrogram duration and signal-averaged QRS duration calculated from individual leads was much better for 64-lead SAECG (r = 0.88. p less than 0.0001) than for three-lead SAECG (r = 0.53. p = 0.01). and the difference was most marked in cases with longer electrogram durations (more than 100 msec). Local late potential maxima on the thorax after lateral left ventricular infarction were located to the left and inferior compared with those after right ventricular infarction (p = 0.006). CONCLUSIONS. SAECG with more extensive recording from the body surface using 64 leads detects greater QRS prolongation than three-lead SAECG. and the longer QRS durations detected correspond to the duration of prolonged epicardial electrograms. Body surface location of late potentials corresponds to the epicardial location of the prolonged electrograms. This application of body surface mapping techniques to SAECG may permit more sensitive detection of arrhythmia-prone states and may aid in identifying arrhythmia sources.
Effects of vascular runoff on myointimal hyperplasia after mechanical balloon or thermal laser arterial injury in dogs, BACKGROUND. Clinical evidence suggests that poor vascular runoff reduces the long-term success rate of femoral angioplasty procedures. The purpose of this experimental study was to examine myointimal hyperplasia of dog femoral arteries after balloon denudation. thermal laser arterial injury. or sham operation in normal and reduced vascular runoff conditions. METHODS AND RESULTS. Before mechanical balloon injury or transluminal heated laser probe motion. the peripheral vascular runoff of dogs was reduced by ligating the femoral artery below its three distal side branches. decreasing the femoral flow rate from 114 +/- 9 to 52 +/- 5 ml/min (mean +/- SEM). Endothelial denudation with a predominantly intact elastic internal membrane and circumferential structural changes in the media were noted by light microscopy 1 hour after balloon injury. Focal completely necrotic lesions of intima and media were found 1 hour after thermal laser arterial injury. After 8 weeks. the maximal thickness of neointima plus media of the site of previous intervention was greater after balloon injury (0.45 +/- 0.03 mm) and thermal laser injury (0.54 +/- 0.03 mm) than after sham operation (0.40 +/- 0.01 mm; p less than 0.001) in normal runoff dogs. Reduced vascular runoff augmented myointimal hyperplasia both in the balloon-injured and thermally damaged arteries; the wall thickness increased from 0.45 +/- 0.03 to 0.93 +/- 0.10 mm and from 0.54 +/- 0.03 to 0.65 +/- 0.05 mm. respectively (p less than 0.001). The neointimal and medial wall area of the balloon-injured arteries contributed 48% to the area encompassed by the external elastic membrane compared with an 81% portion when vascular runoff was reduced (p less than 0.01). A 47% neointimal and medial wall area was found in thermally injured arteries with normal runoff compared with 63% after runoff reduction (p less than 0.05). CONCLUSION. This study suggests that hemodynamic factors associated with poor vascular runoff play an important role in extending myointimal hyperplasia independent of method and severity of the arterial injury during angioplasty.
Cardiac epinephrine synthesis. Regulation by a glucocorticoid, BACKGROUND. The heart can synthesize epinephrine. Homogenates of rat heart. which contain the enzymes phenylethanolamine N-methyltransferase (PNMT) and nonspecific N-methyltransferase (NMT). methylate norepinephrine to form epinephrine. The cardiac atrium contains primarily PNMT and the cardiac ventricle contains both PNMT and NMT. METHODS AND RESULTS. Rats were given the glucocorticoid dexamethasone at doses ranging from 0.2 to 20 mg/kg. Twenty-four hours later. cardiac atria. ventricle. skeletal muscle. and adrenal had increases in PNMT activity to as much as 230% of baseline. NMT activity was unchanged. Longer-term treatment with 1 mg/kg dexamethasone daily for 12 days increased cardiac PNMT activity about fivefold and also increased atrial epinephrine levels. Dexamethasone did not alter ventricular epinephrine levels but increased levels of both PNMT and catechol-O-methyltransferase. the major catabolic enzyme for epinephrine. After dexamethasone treatment. greater volumes of anti-PNMT antiserum were needed to decrease PNMT enzymatic activity. indicating that dexamethasone treatment resulted in greater amounts of PNMT and did not just activate existing PNMT molecules. Denervation of the masseter muscle of rats by unilateral superior cervical ganglionectomy markedly diminished tissue norepinephrine and epinephrine levels but had no effect on masseter PNMT or NMT levels. We have previously shown that chemical sympathectomy with 6-hydroxydopamine increases cardiac PNMT levels. These findings suggest that PNMT is an extraneuronal enzyme in both cardiac and skeletal muscle. CONCLUSIONS. Glucocorticoids have several cardiovascular effects. including increased cardiac output and blood pressure. Enhanced cardiac epinephrine synthesis may mediate some of these glucocorticoid effects.
Epidemiology and natural course of idiopathic nephrotic syndrome, The term "idiopathic nephrotic syndrome" is poorly defined and is used to refer to a variety of glomerular lesions. This article seeks to clarify the situation by considering the case for treating minimal-change nephropathy. focal and segmental glomerulosclerotic lesions. and mesangioproliferative lesions with predominantly IgM deposition as separate disease entities. In children. nephrotic syndrome has a pattern different from that in adults. in whom a wider pathogenetic spectrum is seen. There is support for the use of prospective clinicopathological data as the basis of identifying those patients with nephrotic syndrome who will progress to end-stage renal failure. Very heavy. persisting proteinuria is one marker of such progression and is also an indicator of metabolic complications. such as cardiovascular disease. which further increase the risks of mortality and morbidity in this group of patients.
Treatment of adult idiopathic nephrotic syndrome with cyclosporin A: minimal-change disease and focal-segmental glomerulosclerosis. Collaborative Group of the French Society of Nephrology, Two open studies were conducted to determine the efficacy and tolerance of cyclosporin A (CyA. Sandimmun) 5 mg/kg/day. Sixty-four patients received CyA as monotherapy. and efficacy was assessed at three months; in 48 other patients. CyA was given with prednisone 12-15 mg/kg/day. and efficacy was assessed at six months. Of these 112 patients. 14 withdrew prematurely because of adverse events or other reasons. and a further nine patients were excluded for protocol violation. The remaining 98 patients were considered valid for the evaluation of efficacy (52 with minimal-change disease [MCD] and 46 with focal-segmental glomerulosclerosis [FSGS]; 37/98 were steroid-dependent [SD]. and 61/98 were steroid-resistant [SR]). The remission:failure rate depended on histology (36:16 in MCD. 11:35 in FSGS) and steroid response (25:12 in SD. 22:39 in SR). The rate of remission was highest in SD MCD (71%) and lowest in SR FSGS (20%; chi square = 18.6. p less than 0.001). Tolerance was assessed by serum creatinine and. in 36 cases. by repeat renal biopsy at six to 42 months. Serum creatinine was remarkably stable in MCD. Rising creatinines were observed mostly in cases of SR FSGS. particularly those who had pretreatment interstitial lesions; this was considered due to both an increase of interstitial lesions and progression of the glomerular lesions of FSGS.
Safety and tolerability of cyclosporin A (Sandimmun) in idiopathic nephrotic syndrome. Collaborative Study Group of Sandimmun in Nephrotic Syndrome, The safety and tolerability of cyclosporin A (CyA. Sandimmun) in idiopathic nephrotic syndrome were analyzed in 661 patients enrolled in 10 clinical studies. The majority had minimal-change nephropathy (MCN. 34%) or focal-segmental glomerulosclerosis (FSGS. 33%). The safety experience covered 435 patient years of CyA exposure. The initial CyA dose averaged 5 mg/kg/day in adults and 6 mg/kg/day in children. and was further titrated according to efficacy or adverse reactions. Relevant CyA-induced renal dysfunction occurred almost exclusively in patients (mostly FSGS) who had abnormal baseline renal function. Renal tolerability was better in patients who had complete remission of nephrotic syndrome than in those who did not respond to treatment. However. in the latter. the risk was still relatively low if CyA treatment was stopped after three to four months of treatment. Sixty-nine patients had a renal biopsy performed after one to three years of continuous CyA therapy. and CyA-associated nephropathy. especially interstitial fibrosis. was seen in a few of these patients. Kidney biopsies may therefore be advisable in MCN patients treated successfully for one to two years and in whom further CyA therapy is indicated. Hypertension occurred in approximately 10% and was usually well controlled with conventional antihypertensive therapy. There were a few infectious complications. but the course of these was not unusual. Malignancies developed in five patients. including Hodgkin's lymphoma in two. Overall. adverse reactions resulted in CyA treatment discontinuation in 7.4% of patients. half of them because of renal dysfunction.
Aortic-carotid artery pressure differences and cephalic perfusion pressure during cardiopulmonary resuscitation in humans, OBJECTIVE: Animal studies have shown an aortic-carotid artery pressure difference during cardiopulmonary resuscitation (CPR). which compromises cerebral perfusion. This pressure difference is most marked with prolonged CPR and can be abolished with administration of high doses of epinephrine. To better understand the mechanism of cerebral blood flow during CPR in humans. we determined the aortic-carotid artery pressure difference. the cephalic perfusion pressure (the carotid artery-jugular vein pressure difference). and thoracic inlet venous "valving" (the central venous-jugular vein pressure difference). while administering standard doses of epinephrine. DESIGN: Prospective study with randomization as to which side the carotid artery was catheterized. SETTING: The resuscitation room of a large urban hospital's emergency department. PATIENTS: Fifteen adults in normothermic. nontraumatic prehospital cardiac arrest treated according to Advanced Cardiac Life Support guidelines. including administration of 1 mg epinephrine iv every 5 mins. INTERVENTIONS: The descending aorta. cervical common carotid artery. internal jugular vein. and central venous system were catheterized. Pressures were recorded during standard CPR for 5 mins after administration of 1 mg epinephrine iv. MEASUREMENTS AND MAIN RESULTS: Most patients received CPR for greater than 20 mins before the first epinephrine dose and for greater than 45 mins before pressure recording as described above. There was no significant difference between aortic and carotid artery compression and relaxation phase pressures. The mean +/- SD compression central venous-jugular vein pressure difference was 22.1 +/- 15.0 mm Hg. and the mean cephalic perfusion pressure was 20.8 +/- 19.5 mm Hg. CONCLUSIONS: There is no clinically important aortic-carotid artery pressure difference during human CPR using the standard dose of epinephrine. even with prolonged CPR. Despite carotid artery patency and thoracic inlet venous valving. the cephalic perfusion pressure is low during CPR in humans.
Accuracy of a mixed venous saturation catheter during acutely induced changes in hematocrit in humans, OBJECTIVE: To determine the accuracy of in vivo mixed venous hemoglobin saturation (Svo2) measurements with a fiber optic thermodilution catheter during acute changes in hematocrit. DESIGN: Comparison of fiberoptic in vivo Svo2 values with in vitro Svo2 values obtained with a multiwavelength spectrophotometer. SETTING: Operating room in a university hospital. PATIENTS: Six consecutive patients who are Jehovah's Witnesses. MEASUREMENTS AND MAIN RESULTS: Before and after each step of hypervolemic hemodilution and after every 500 mL of blood loss. blood gases were analyzed and hemodynamic. hemoglobin. hematocrit. and in vitro and in vivo Svo2 measurements were made. Hematocrit values were measured in the range of 40% to 18%. Plotting all in vivo Svo2 values (n = 74) against the in vitro Svo2 measurements obtained during the entire study period gives r2 = .86. The accuracy of in vivo Svo2 measurements was not affected by changes in hematocrit or cardiac output. The Svo2 catheter value at the beginning of the study differed from the in vitro Svo2 value by -0.86 +/- 2.56% and at the end of the study period of 8 to 10 hrs by 0.71 +/- 3.04%. CONCLUSIONS: The accuracy of the studied fiberoptic continuous measuring Svo2 system was not affected by changes in hematocrit or cardiac output. No significant drift in the in vitro Svo2 measurements was observed.
Reduced alveolar macrophage production of tumor necrosis factor during sepsis in mice and men, BACKGROUND AND METHODS: Tumor necrosis factor (TNF) has been implicated as a major humoral mediator of sepsis and endotoxin shock. TNF is secreted by cells of the reticuloendothelial system. including alveolar macrophages. Alveolar macrophage TNF production has been postulated to play a pathogenetic role in the development of adult respiratory distress syndrome (ARDS) in sepsis. To evaluate alveolar macrophage production of TNF during sepsis and endotoxin shock. we studied the effects of sepsis and/or in vivo lipopolysaccharide on the in vitro production of TNF by pulmonary alveolar macrophages. Human pulmonary alveolar macrophages were obtained by bronchoalveolar lavage from six septic and five nonseptic patients. cultured in the presence or absence of lipopolysaccharide (1 ng/mL). and assayed for TNF activity in a bioassay using fibroblast lysis. A murine model of sepsis was also utilized to study pulmonary alveolar macrophage TNF production under more controlled conditions. Normal mice were given ip injections of either lipopolysaccharide or saline. After 2 hrs. pulmonary alveolar macrophages were obtained and cultured in saline or various concentrations of lipopolysaccharide (0.001 to 10 micrograms/mL). RESULTS: There was no difference in baseline TNF activity. expressed as per cent lysis at 1:10 dilution. between pulmonary alveolar macrophages from control and septic patients (35.7 +/- 5.5% vs. 24.4 +/- 9.3%. respectively) (p greater than .05). However. when stimulated with lipopolysaccharide in vitro. the pulmonary alveolar macrophages from nonseptic patients produced significantly (p less than .01) more TNF (82.8 +/- 3.6%) than did pulmonary alveolar macrophages from patients with the septic syndrome (35.2 +/- 3.8%). Similar findings were obtained using the murine sepsis model. The baseline TNF activity in pulmonary alveolar macrophages from control mice was 22.9 +/- 7.0% (mean +/- SEM) and from lipopolysaccharide-injected mice was 26.8 +/- 3.3% (p greater than .05). Stimulation with 1 ng/mL lipopolysaccharide in vitro produced an increase in TNF activity in both groups. but the increase was greater in the control mice (68.1 +/- 5.7%) than in the lipopolysaccharide-injected mice (47.5 +/- 5.3%) (p less than .01). When the murine pulmonary alveolar macrophages were stimulated with higher concentrations of lipopolysaccharide (0.1 to 10 micrograms/mL). pulmonary alveolar macrophages from lipopolysaccharide-injected mice produced less than 25.5% of the TNF produced by pulmonary alveolar macrophages from control mice. CONCLUSIONS: These studies indicate that sepsis and endotoxin injection result in a rapid decrease in the ability of pulmonary alveolar macrophages from both humans and mice to produce and secrete TNF in response to lipopolysaccharide. We speculate that a downregulation of TNF production or of macrophage responsiveness to lipopolysaccharide has occurred. These results suggest that sustained TNF production by macrophages is not required for lung injury in sepsis.
Platelet activating factor-induced shock and intestinal necrosis in the rat: role of endogenous platelet-activating factor and effect of saline infusion, BACKGROUND AND METHODS: The mechanism of ischemic bowel necrosis induced by platelet-activating factor is unclear. Since intestinal hypoperfusion is observed after platelet-activating factor injection. we hypothesized that mesenteric vasoconstriction is the mechanism of bowel injury. The present study investigated the effects of saline infusion on platelet activating factor-induced bowel necrosis and its mechanism. Male Sprague-Dawley rats were divided into four groups: group A consisted of sham-operated rats; group B received platelet-activating factor (1.5 micrograms/kg iv); group C received platelet-activating factor and saline (0.097 mL/min iv); group D received platelet-activating factor and WEB 2086 (platelet-activating factor antagonist). RESULTS: Saline infusion largely reversed platelet activating factor-induced hypotension. hemoconcentration. and reduction of the superior mesenteric arterial blood flow. Saline infusion also ameliorated platelet activating factor-induced bowel injury. although a mild-to-moderate degree of necrosis still developed focally. In addition. saline prevented the platelet activating factor-induced increase in intestinal platelet-activating factor production. Saline also prevented the increase in intestine leukocyte number. as estimated by myeloperoxidase activity. CONCLUSIONS: Saline infusion is an effective treatment for platelet activating factor-induced shock and intestinal necrosis. However. focal bowel injury is still observed. suggesting that other factors besides hemodynamic changes contribute to the development of tissue injury. We also showed that. in vivo. platelet-activating factor stimulates its own synthesis via a positive feedback loop. which could be blocked by intravascular volume expansion with saline.
Trans-hydroxyl group configuration on carbons 2 and 3 of glucose. Responsible for acute inhibition of myo-inositol transport, Cultured neuroblastoma. cerebral microvessel endothelial. and retinoblastoma cells were used to examine the mechanism of acute inhibition by D-glucose of myo-inositol uptake. Acute exposure of the cells to 30 mM D-glucose caused a significant decrease in Na(+)-dependent myo-inositol uptake in all three cell types. The effect of D-glucose to acutely inhibit myo-inositol uptake was dependent on the extracellular glucose concentration and was not reversed by sorbinil. 2-Deoxy-D-glucose (30 mM). 3-O-methyl-D-glucose (30 mM). and cytochalasin B (100 microM) did not acutely inhibit myo-inositol uptake. These data suggest that the hydroxyl groups on carbons 2 and 3 of D-glucose. which in a Haworth projection appear trans to each other. are important for inhibitory activity. Other monosaccharides (30 mM) having a similar 2.3-trans-diol configuration. L-glucose. D- and L-fucose. D- and L-galactose. D- and L-xylose. and D-arabinose. all to varying degrees significantly inhibited myo-inositol uptake. In all cases. the L-isomers were more potent inhibitors of myo-inositol uptake than the corresponding D-isomers. Monosaccharides (30 mM) having hydroxyl groups on carbons 2 and 3 in a cis configuration. D-mannose. L-rhamnose. D-allose. and D-ribose. did not acutely inhibit myo-inositol uptake. Replacing the hydroxyl group with a fluorine on carbons 2 or 3 of D-glucose negated its inhibitory activity of myo-inositol uptake. In contrast. replacing the hydroxyl group with a fluorine on carbon 6 of D-glucose did not block its inhibition of myo-inositol uptake.
Insulin and glucose levels and prevalence of glucose intolerance in pedigrees with multiple diabetic siblings, Hyperinsulinemia may be an early inherited marker for a defect in insulin action that subsequently results in glucose intolerance and non-insulin-dependent diabetes mellitus (NIDDM). To examine the role of hyperinsulinemia in individuals at high genetic risk for NIDDM and determine the prevalence of impaired glucose tolerance (IGT) and newly diagnosed diabetes in members of NIDDM pedigrees. we studied 310 members of 16 pedigrees ascertained for greater than or equal to 2 NIDDM siblings. Nondiabetic members of all pedigrees were examined by 75-g oral glucose tolerance test with fasting and 1-h insulin levels. Participants had height and weight recorded. Spouses of pedigree members (n = 88) served as control subjects. The spouse control subjects were older and slightly more obese than the undiagnosed pedigree members. The prevalence of IGT was 14.8% in spouses and 7.7% in pedigree members. and NIDDM was present in 11.3% of spouses and 2.3% of previously undiagnosed pedigree members. However. neither spouses nor pedigree members differed significantly from published age-specific prevalence rates for IGT or newly diagnosed NIDDM. Insulin and glucose levels were examined in pedigree members with normal glucose tolerance (NGT). Fasting insulin levels were not significantly different between spouses and NGT pedigree members. However. after adjustment for age. weight (body mass index). and sex. NGT pedigree members had higher 1-h insulin levels and higher fasting and 1-h glucose levels than spouses. These differences were also evident when pedigree members with at least 1 affected (NIDDM or IGT) parent were compared with spouses with no family history of diabetes.
Importance of insulin in subjective, cognitive, and hormonal responses to hypoglycemia in patients with IDDM, Not all episodes of hypoglycemia are recognized as such by diabetic patients. suggesting that it is possible for them to adapt to a low blood glucose level. although the mechanism involved is not known. The aim of this study was to examine whether insulin has an effect. independent of blood glucose. on the subjective. cognitive. and hormonal responses to hypoglycemia. Nine patients with insulin-dependent diabetes mellitus (IDDM) participated in three hyperinsulinemic glucose-clamp studies. After 60 min at 4.5 mM. blood glucose was randomized to be 1) maintained at 4.5 mM for 240 min. 2) lowered to 2.8 mM for 180 min followed by 60 min at 2 mM with an insulin infusion rate of 40 mU.m-2.m-1. and 3) fitted to the same protocol as 2 but with an infusion rate of 120 mU.m-2.min-1. Symptoms and awareness of hypoglycemia (100-mm visual analogue scales). cognitive function. and counterregulatory hormone levels were assessed every 30 min. There were no subjective or cognitive changes during the euglycemic study. Awareness and hypoglycemic symptoms (hunger. facial flushing. trembling. and sweating) were attenuated by the higher insulin infusion rate (P less than 0.05 and P less than 0.01. respectively). Cognition was significantly impaired after 60 min at 2.8 mM (P less than 0.001) and deteriorated further when the blood glucose level was lowered to 2 mM (P less than 0.01). Levels of cortisol (P less than 0.01) and growth hormone (P less than 0.05) but not epinephrine were suppressed by the higher insulin infusion rate.
Prediction and prevention of IDDM--1991, Although we can now identify some nondiabetic individuals who will subsequently develop clinical insulin-dependent diabetes mellitus (IDDM). our ability to predict subsequent clinical IDDM is far from perfect. In this article. we discuss the status of knowledge regarding the natural history of preclinical IDDM and discuss. especially in relation to predicting IDDM. the genetic. immunologic. and metabolic components of the IDDM disease process.
Abnormalities of cognitive functions in IDDM revealed by P300 event-related potential analysis. Comparison with short-latency evoked potentials and psychometric tests, The possible influence of diabetes on the higher mnestic and cognitive functions has been investigated. The P300 wave latency. an endogenous electrophysiological event. was explored and compared with the multimodal short-latency evoked potential (EP) recordings (visual [VEP]. brainstem auditory [BAEP]. and median and tibial nerve somatosensory EPs [mSEP and tSEP. respectively]) and psychometric test measures in 16 insulin-dependent diabetic (IDDM) patients. in 16 age- and (IDDM) sex-matched nondiabetic subjects. and in a large normal reference population. The age of subjects. the duration of IDDM. and the metabolic control of patients were taken into account. P300 values were significantly increased in IDDM versus matched control subjects (P less than 0.001). and 3 patients showed values above the reference value range. Abnormal VEP recordings were present in 1 of 16 patients. BAEP in 3 of 16. mSEP in 7 of 16. and tSEP in 6 of 16. Digit-span backward test results were significantly (P less than 0.02) modified in the diabetic cohort. There was no tendency for anomalies of P300. short-latency EPs. and psychometric test values to be contemporarily present. except in 1 patient. Electrophysiological or psychometric abnormalities were not clearly correlated with the duration of IDDM or the degree of short-term metabolic control. These findings give evidence that 1) higher cognitive functions may be affected in diabetes as documented by P300 analysis and short-term memory tests. 2) endogenous electrophysiological analysis highlights neuropsychological changes not detectable by psychometric tests. 3) an alteration of evoked potentials was present in half of the IDDM subjects studied. and 4) anomalies of the CNS are patchily distributed in diabetes.
Nutrition and somatomedin. XXVII. Total and free IGF-I and IGF binding proteins in rats with streptozocin-induced diabetes, Impaired growth in diabetic humans occurs despite increased growth hormone and normal insulinlike growth factor I (IGF-I). Because IGF-I circulates complexed to binding proteins (BPs). we asked whether diabetes-related changes in IGF BPs could be associated with alterations in free unbound IGF-I--presumably the active form. Rats were given streptozocin (STZ) in increasing doses to produce graded severity of diabetes. IGF BP-1 and BP-3 were measured by ligand blotting. total IGF-I was determined by radioimmunoassay after separation from BPs by isocratic high-performance liquid chromatography (HPLC) at pH 3.9. and free IGF-I was estimated operationally as immunoreactivity with molecular weight equal to native IGF-I after HPLC at pH 7. Animals given 36 mg/kg STZ exhibited a glucose level of 9.74 mM and impaired weight gain. with little alteration in IGF BPs or total or free IGF-I. In contrast. animals given 72 mg/kg STZ (glucose level 24.64 mM and weight loss) had insignificant changes in total IGF-I and BP-3 but a 300% increase in BP-1 and a 50% fall in free IGF-I (both P less than 0.005). With 144 and 288 mg/kg STZ. animals had further metabolic decompensation and weight loss. with progressive fall in BP-3 and rise in BP-1; total and free IGF-I fell to 10-20% of control (both P less than 0.001).
Relative hypersecretion of proinsulin in rat model of NIDDM, The plasma ratio of proinsulin to insulin is raised in individuals with non-insulin-dependent diabetes mellitus (NIDDM). Increased secretion of proinsulin relative to insulin is thought to be the cause. although differential changes in clearance have not been ruled out. This study was conducted in a rat model of NIDDM. 90% pancreatectomized (Px) rats. to investigate the pathophysiology of this observation. Proinsulin storage and secretion were assessed with high-performance liquid chromatography separation of the insulins and the proinsulins. followed by quantification of the peaks by insulin radioimmunoassay. In Px rats. the relative proportion of proinsulin in pancreas extracts was twice that of control (sham-operated) rats (15.6 +/- 1.4 vs. 8.3 +/- 1.4%. P less than 0.01). Samples obtained from the portal vein during in vitro pancreas perfusion also had an elevated proinsulin fraction (Px. 10.3 +/- 3.0; sham. 3.0 +/- 0.6%; P less than 0.006). In summary. 90% Px rats share many pathophysiological features with NIDDM. including loss of normal proinsulin homeostasis. Our results suggest that chronic hyperglycemia causes an intrinsic change in beta-cells that is characterized by the increased storage and secretion of proinsulin.
Insulin pulses less effective than continuous insulin in inhibiting PEPCK mRNA levels stimulated by cAMP and dexamethasone in perifused hepatoma cells, Hepatic glucose production is stimulated in vitro twice as effectively by pulsatile as by continuous glucagon. given equivalent time-averaged doses. Efficacy studies of pulsatile insulin have yielded conflicting results. In the rat hepatoma cell line H-4-II-E-C3. insulin rapidly (t1/2 15 min) inhibits transcription of the gene and lowers mRNA levels for the gluconeogenic enzyme. PEPCK via a receptor-mediated process. We attached H-4-II-E-C3 cells to Cytodex-3 microcarriers and used a perifusion column system to test whether pulsatile insulin is more or less effective than equivalent time-averaged doses of continuous insulin. PEPCK transcription was induced by inclusion of cAMP analogue 8-(4-chlorophenyl-thio)-cAMP (0.1 mM) and dexamethasone (0.5 microM) in the perifusion medium. Three columns were exposed either to continuous. pulsatile. or no insulin. After 3 h. total nucleic acid was extracted. and mRNA(PEPCK) was measured with a sensitive-solution hybridization assay. Continuous insulin inhibited PEPCK expression in a dose-dependent fashion with EC50 1 x 10(-11) M. Equivalent time-averaged amounts of insulin delivered as pulses achieved significant inhibition but less effectively than continuous insulin. The apparent EC50 for pulsatile insulin increased from 2 x 10(-11) M to 5 x 10(-11) M as the oscillatory period was raised from 5 to 20 min. respectively. These observations suggest that insulin-mediated inhibition of PEPCK gene transcription is diminished by a pulsatile mode of administration in marked contrast to the pulse enhancement demonstrated for glucagon-mediated hepatic glucose production.
Sulindac causes regression of rectal polyps in familial adenomatous polyposis, In familial adenomatous polyposis. sulindac-induced polyp regression has been reported by several authors. In this study. the goal was to confirm these results by a randomized. placebo-controlled. double-blind crossover study in 10 patients with rectal polyps that had been previously treated by colectomy and ileorectal anastomosis. Patients received sulindac. 300 mg/day. or placebo during two 4-month periods separated by a 1-month wash-out phase. One patient was not compliant and was excluded. With sulindac. the authors observed a complete (6 patients) or almost complete (3 patients) regression of the polyps. With placebo. the authors observed an increase (5 patients). no change (2 patients). and a relative decrease (2 patients) in the number of polyps. The difference between sulindac and placebo was statistically significant (P less than 0.01). In biopsy specimens of polyps and normal rectal mucosa of 6 patients. the authors conducted an immunohistochemical study of the cellular proliferation index using the Ki 67 monoclonal antibody (Ki 67 index). at the beginning and at the end of each treatment period. They were not able to show a sulindac-induced modification of the Ki 67 index. The authors conclude that sulindac is effective in inducing the regression of rectal polyps in familial adenomatous polyposis.
Hypertrophic smooth muscle in the partially obstructed opossum esophagus. Excitability and electrophysiological properties, Partial obstruction of the opossum esophagus leads to thickening of the circular muscle. hypertrophy of smooth muscle cells. and diminution of the extracellular space. The pharmacological and electrophysiological properties of this hypertrophied muscle were studied. Carbachol produced phasic and tonic contractions of the circular muscle. The EC50 for tonic contractions was greater for hypertrophied than for normal muscle (21.1 +/- 3.9 mumol/L vs. 4.8 +/- 2.2 mumol/L; P less than 0.05). The resting membrane potential difference of hypertrophied muscle (-50.8 +/- 0.2 mV) was similar to that of normal muscle (-50.0 +/- 0.2 mV). Electrical stimulation of intrinsic nerves in the normal muscle produced a hyperpolarization followed by a depolarization of smooth muscle membrane potential. Hypertrophied muscle responded either with an attenuated hyperpolarization or no hyperpolarization. both of which were followed by a depolarization. The space constant in the long axes of the hypertrophied circular muscle cells was greater than normal (4.4 +/- 0.2 mm vs. 3.4 +/- 0.1 mm; P less than 0.001). The threshold potential for initiation of action potentials was more negative for hypertrophied (-43.2 +/- 0.4 mV) than for normal circular muscle (-41.6 +/- 0.2 mV; P less than 0.005). These data indicate that alterations in neuromuscular function accompany the hypertrophy of esophageal smooth muscle.
Immunohistochemical characterization, distribution, and ultrastructure of lymphocytes bearing T-cell receptor gamma/delta in inflammatory bowel disease, Phenotypic characterization and distribution of gamma/delta T lymphocytes in the intestinal mucosa were investigated in ulcerative colitis and Crohn's disease by immunohistochemistry. The ratio of delta(+) cells to CD3(+) cells in the intraepithelial space of colon was decreased in Crohn's disease (13%) and strikingly decreased in ulcerative colitis (8%) compared with the control (36%). Delta(+) cells in the lamina propria were also decreased. particularly in the distal ileum of Crohn's disease (4%). compared with the control (15%). On the contrary. the cells gathered at the severe inflammatory sites with other inflammatory cells. including beta(+) cells. and were densely distributed in the T-cell zone around lymphoid follicles. Phenotypic characterization showed that delta(+) lamina proprial lymphocytes of colon were mainly CD4(-)CD8(-) in the control (80%) and Crohn's disease (59%). However. in ulcerative colitis. CD4(-)CD8(-) delta(+) lymphocytes were rarely found (3%). This reflects the difference of immunologic background between the two diseases. Immunoelectron microscopically. these cells in inflammatory bowel disease were rich with vesicular structures in cytoplasms. whereas those in the control group contained electron-opaque granules. The decrease and the morphological change may be closely related to the weakness of mucosal defense.
Quality of life after proctocolectomy. A comparison of Brooke ileostomy, Kock pouch, and ileal pouch-anal anastomosis, Recent work has shown that patients undergoing proctocolectomy and ileal pouch-anal anastomosis experience a better quality of life than those undergoing proctocolectomy and Brooke ileostomy. To assess whether the improvement with the pouch is due to the absence of a stoma or the preservation of fecal continence. functional and performance activities were assessed in 406 patients with Brooke ileostomies (stoma present. incontinent). 313 with Kock pouches (stoma present. continent). and 298 with ileal pouch-anal anastomoses (stoma absent. continent). All patients underwent proctocolectomy for ulcerative colitis or familial adenomatous polyposis. After adjusting for age. sex. diagnosis. attitude towards the operation. dietary satisfaction. and ability to work. the likelihood of an impact on performance was estimated for the three types of operation using logistic regression analysis. Patients with ileal pouch-anal anastomoses had fewer restrictions in sports and sexual activities than those with Kock pouches (P less than 0.05). whereas those with Kock pouches in turn had fewer restrictions in these activities but more restrictions in travel than those with Brooke ileostomies (P less than 0.05). In contrast. performance in the categories of social life. recreation. work. and family was similar between groups. It is concluded that both the presence of a stoma and fecal incontinence impair the quality of life after proctocolectomy. Ileal pouch-anal anastomosis. which avoids both stoma and incontinence. offers the best quality of life between the three operations studied.
Apolipoprotein synthesis in normal and abetalipoproteinemic intestinal mucosa, The genetic disease abetalipoproteinemia is characterized by a total absence of apolipoprotein B-containing lipoproteins from plasma. A presumed synthetic defect in apolipoprotein B synthesis was thought to be responsible for this disorder. The present study quantitates apoprotein B synthesis and apolipoprotein B messenger RNA levels in duodenal mucosa from normal patients and four patients with abetalipoproteinemia. After in vitro [3H]leucine incorporation. small intestinal biopsy specimens from three of four patients with abetalipoproteinemia synthesized immunoprecipitable apolipoprotein B of identical mobility (on sodium dodecyl sulfate gel electrophoresis) to normal apolipoprotein B. In abetalipoproteinemia. the apolipoprotein B content of intestinal mucosa by radioimmunoassay was 15% of normal mucosal values. whereas apolipoprotein B messenger RNA quantitation showed 3-20-fold increased levels compared with normal mucosa. In one patient. smaller-molecular-weight fragments of apolipoprotein B were immunoprecipitated from duodenal biopsy specimens. The synthesis rates and messenger RNA levels of two other chylomicron apoproteins (apolipoprotein A-I and apolipoprotein A-IV) were found to be reduced by 50%. These results show the synthesis of immunologically recognizable apolipoprotein B48 in abetalipoproteinemia. The significance of mucosal apolipoprotein B content in abetalipoproteinemia is discussed in terms of factors controlling apolipoprotein B synthesis in normal mucosa and in abetalipoproteinemia.
The effects of benzodiazepine-receptor antagonists and partial inverse agonists on acute hepatic encephalopathy in the rat, Two benzodiazepine-receptor partial inverse agonists (Ro 15-4513. Ro 15-3505) and one benzodiazepine-receptor antagonist (flumazenil) were administered to rats with hepatic encephalopathy due to acute liver ischemia. Significant improvement (P less than 0.002) of both the clinical grade of hepatic encephalopathy and the electroencephalographic abnormalities was observed after administration of the benzodiazepine-receptor partial inverse agonists: comatose rats with no spontaneous righting reflex regained consciousness immediately after injection of the drug. Only slight improvement in clinical hepatic encephalopathy grade was seen after administration of 25 mg/kg of flumazenil. The present data strongly support a role of increased gamma-aminobutyric acid-ergic tone in the pathogenesis of acute hepatic encephalopathy and provide a rationale for trials of benzodiazepine-receptor partial inverse agonists to restore consciousness in hepatic encephalopathy in humans in the near future.
Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes 1, 2, and 3, The purpose of these experiments was to determine whether chronic dietary iron overload causes impairment of hepatic mitochondrial and/or microsomal calcium sequestration. Experimental iron overload was produced by feeding three groups of rats a chow diet supplemented with 3.0% (wt/wt) carbonyl iron for up to 8 weeks achieving graded increases in hepatic iron concentrations ranging from 1360 to 3170 micrograms/g. At low levels of iron overload. there were no changes in mitochondrial oxidative metabolism or calcium sequestration. whereas at moderate and high degrees of iron loading. both of these parameters were significantly reduced. In contrast. there were significant decreases in microsomal cytochrome P450 levels and microsomal calcium sequestration at all three levels of iron loading. These abnormalities occurred at hepatic iron concentrations at which the authors have previously found evidence of hepatic organelle lipid peroxidation. These alterations in organelle calcium sequestration may impair intracellular calcium homeostasis in the liver and contribute to subsequent cellular injury.
Inhibition of prostaglandin synthesis fails to prevent gallbladder mucin hypersecretion in the cholesterol-fed prairie dog, Gallstone formation in the cholesterol-fed prairie dog is preceded by an increase in mucin secretion by the gallbladder epithelium. and mucin hypersecretion is believed to promote cholesterol gallstone formation by accelerating the nucleation of cholesterol monohydrate crystals. Some studies have suggested that gallbladder mucin hypersecretion is mediated by increases in gallbladder prostaglandin synthesis. but other observations are difficult to reconcile with this view. An organ culture technique was used to measure mucin secretion in normal prairie dog gallbladder in response to exogenous prostaglandins and agents that increased or decreased endogenous prostaglandin production. Incubation with indomethacin produced a concentration-dependent inhibition of endogenous prostaglandin synthesis with virtually complete inhibition at 10(-5) mol/L indomethacin. However. indomethacin had no effect on gallbladder mucin secretion at concentrations as high as 10(-5) mol/L. and significant inhibition of mucin secretion was only found at 10(-4) mol/L indomethacin. a concentration that also produced a significant increase in lactate dehydrogenase release from cultured explants. Incubation of gallbladder explants with the calcium ionophore A23187 significantly stimulated endogenous prostaglandin synthesis in a concentration-dependent manner. increasing synthesis of prostaglandins E and F to as much as 278% +/- 20% and 335% +/- 21% of basal values. respectively; however. the same concentrations of A23187 did not stimulate mucin secretion. Incubation of gallbladder explants in the presence of exogenous prostaglandin E2 or prostaglandin F2a in concentrations as high as 10(-6) mol/L also did not stimulate mucin secretion. Prairie dogs fed a lithogenic 1.2% cholesterol diet showed a significant increase in gallbladder mucin secretion after 1 week (117.5 +/- 10.2% of control. P less than 0.05). and 4 of 5 had formed cholesterol monohydrate crystals after 3 weeks. Long-term treatment with indomethacin. 1.2 mg.kg-1.day-1. failed to inhibit gallbladder mucin hypersecretion (129.2 +/- 10.7% of control after 1 week) or cholesterol monohydrate crystal formation (3/5) in cholesterol-fed prairie dogs. Furthermore. incubation of explants with 10(-5) mol/L indomethacin failed to prevent in vitro mucin hypersecretion in cholesterol-fed animals. These findings suggest that prostaglandins do not regulate gallbladder mucin secretion in the prairie dog. and it is unlikely that increases in gallbladder prostaglandin synthesis are responsible for mediating gallbladder mucin hypersecretion during cholelithiasis in the prairie dog.
Effect of oral propranolol administration on azygos, renal and hepatic uptake and output of catecholamines in cirrhosis, Circulating catecholamines are increased in cirrhosis with portal hypertension. and increase further after propranolol. In 23 cirrhotic patients. plasma norepinephrine and epinephrine were determined in an artery. the azygos vein. the right renal vein and a hepatic vein before and after an oral 80-mg dose of propranolol. Baseline azygos and renal venous norepinephrine levels were significantly higher than arterial norepinephrine levels (+20%. p less than 0.005; and +28%. p less than 0.001. respectively). Hepatic venous norepinephrine and all venous epinephrine values were below the arterial values (all p less than 0.05). After propranolol intake. arterial norepinephrine and epinephrine increased (+16%. p less than 0.01; and +93%. p less than 0.001. respectively). Significant increases in norepinephrine and epinephrine were found in azygos and renal veins (all p less than 0.01). whereas hepatic venous norepinephrine and epinephrine remained unchanged. Azygos and hepatic blood flow decreased after propranolol intake (-27%. p less than 0.05; and -16%. p less than 0.01. respectively). Azygos spillover of norepinephrine (an estimate of locally released norepinephrine delivered to the circulation) and clearance of epinephrine remained unaltered. Hepatointestinal clearance showed no significant change for norepinephrine. but showed a borderline-significant decrease for epinephrine (-23%. p = 0.08). Our results show a net production of norepinephrine in the prehepatic splanchnic area drained through superior portalsystemic collaterals and in the kidneys. The increase in circulating catecholamines after propranolol intake is probably due to a combination of further enhancement of sympathetic activity and a decrease in catecholamine degradation.
Detection of fibronectin receptor in sera: its clinical significance as a parameter of hepatic fibrosis, Pooled sera collected from cirrhotic patients was fractionated by affinity chromatography with a fibronectin receptor monoclonal antibody against the beta-subunit of fibronectin receptor. Eluates were assayed using Western immunoblotting. The relative mobility of the protein reactive with fibronectin receptor antibody was nearly identical to that of the beta-subunit of fibronectin receptor. confirming that fibronectin receptor is present in human serum. Serum levels of the beta-subunit of fibronectin receptor were analyzed by sandwich enzyme-linked immunosorbent assay in patients with various liver diseases. The serum level of fibronectin receptor (micrograms/ml) was significantly higher in patients with chronic hepatitis (inactive. 2.59 +/- 0.04; active. 3.45 +/- 0.13). cirrhosis (4.77 +/- 0.30). alcoholic liver disease (2.96 +/- 0.16) and hepatocellular carcinoma (4.71 +/- 0.49) than in normal subjects (2.11 +/- 0.08). Strong positive correlation was observed between serum levels of fibronectin receptor and histological findings. particularly in the degree of hepatic fibrosis. Immunohistochemical studies with fibronectin receptor antibody revealed that the beta-subunit of fibronectin receptor was present on the plasma membrane of hepatocytes and sinusoidal lining cells in the normal liver and was increased in fibrotic areas and on the plasma membrane of hepatocytes and sinusoidal lining cells of fibrotic liver. The serum level of fibronectin receptor in patients with chronic liver diseases may therefore be a useful marker of hepatic fibrosis.
Prognosis of unresectable hepatocellular carcinoma: an evaluation based on multivariate analysis of 90 cases, A multivariate analysis of data from 90 patients with unresectable hepatocellular carcinoma was performed using Cox's regression model to identify factors possibly affecting their prognoses. Thirty-one patients underwent arterial anticancer chemotherapy. and the remaining 59 patients received transcatheter arterial embolization with anticancer agents. Four of 27 variables tested for all the patients (i.e.. encapsulation [p less than 0.05]. gross appearance of hepatocellular carcinoma [p less than 0.01]. clinical stage [p less than 0.01] and therapy [p less than 0.01]) were found to be prognostically significant. Five of 27 variables tested were prognostically significant for the transcatheter arterial embolization group; they were an extension rate of hepatocellular carcinoma (p less than 0.01). encapsulation (p less than 0.01). alpha-fetoprotein (p less than 0.01). prothrombin time (p less than 0.01) and serum sodium (p less than 0.01). Regression equations were used to describe a prognostic index. A prognostic index was defined as the regression equation derived from the results of a total of 90 patients; PI-1 = eY. where PI-1 = prognostic index 1 Y = 1.549 (gross appearance of hepatocellular carcinoma - 1.344) + 0.778 (encapsulation - 1.622) + 0.818 (clinical stage - 1.800) + 1.760 (therapy - 1.344) and prognostic index 2. the regression equation derived from the results of the transcatheter arterial embolization group of patients; PI-2 = eY. where PI-2 = prognostic index 2 Y = 1.210 (extension rate of hepatocellular carcinoma - 1.576) + 1.179 (encapsulation - 1.475) + 0.0001277 (alpha-fetoprotein - 1420.792) -0.039 (prothrombin time - 72.237) - 0.214 (serum sodium - 138.427).
Binding and internalization of transforming growth factor-beta 1 by human hepatoma cells: evidence for receptor recycling, Cellular processing of 125I-labeled transforming growth factor-beta 1 was investigated in the human hepatoma cell lines Hep G2 and Hep 3B. Binding of 125I-transforming growth factor-beta 1 to cell surface receptors was specific. saturable and calcium-independent. Both cell lines exhibited a single class of high-affinity (Kd = 2.2 x 10(-10) mol/L) binding sites (4.5 x 10(3) for the Hep G2 cell; 1.5 x 10(3) for the Hep 3B cell) for both human and porcine transforming growth factor-beta 1. Binding was temperature dependent. time dependent and pH dependent. Cell-bound 125I-transforming growth factor-beta 1 was removed by brief exposure to acidic medium (pH less than 4) but was converted into an acid-resistant state rapidly after shifting the cells to 37 degrees C. Spontaneous dissociation of bound ligand over a 6 hr period at 4 degrees C was less than 10%. Disuccinimidyl suberate was used to covalently label 125I-transforming growth factor-beta 1 to cell-surface binding sites. Labeling of the ligand/receptor complexes was inhibited by unlabeled transforming growth factor-beta 1 but was unaffected by other growth factors. The radiolabeled complexes showed approximate molecular weights of 280.000. 85.000 and 65.000 when run on reducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cell-bound 125I-transforming growth factor-beta 1 was internalized and degraded at 37 degrees C. and the products were released into the medium as trichloroacetic acid-nonprecipitable radioactivity. The lysosomotropic base chloroquine and the carboxylic ionphore monensin inhibited degradation and release of 125I-labeled products from the cells.
In vitro fragmentation of gallstones: comparison of electrohydraulic, electromagnetic and piezoelectric shockwave lithotripters, To compare the fragmentation efficiency of three different shockwave systems. 63 human gallstone triplets were disintegrated in vitro using an electrohydraulic (MPL 9000. Dornier). an electromagnetic (Lithostar Plus. Siemens) and a piezoelectric (Piezolith 2300. R. Wolf) lithotripter. Since each stone triplet was obtained from the same gallbladder. the concrements of one such set were identical in physicochemical parameters. According to the maximal diameter. the calculi were divided into group A (6 to 15 mm) and group B (16 to 30 mm). Shockwave application was terminated when residual fragments measured 4 mm or less. Forty-five triplets were fragmented at energy settings mainly used in clinical treatment of patients with gallbladder stones (MPL 9000: 20 kV; Lithostar Plus: setting 9 (maximal); Piezolith 2300: setting 3). The fragmentation endpoint was achieved in group A (n = 3 x 36) with the Piezolith 2300 after median 150 (range = 50 to 500) pulses and with the Lithostar Plus after 150 (50 to 750) pulses compared with 500 (50 to 1.500) pulses using the MPL 9000 (p less than 0.01). In group B (n = 3 x 9) the Lithostar Plus (median = 750. range = 250 to 1.250 pluses) required fewer discharges than the Piezolith 2300 (1.250. 250 to 2.500 pulses; p less than 0.05) and the MPL (1.500. 500 to 1.600 [upper limit] pulses; p less than 0.01).
Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant Sprague-Dawley rat, The hepatic transport of bile acid conjugates was studied in the Eisai hyperbilirubinuria rat. a Sprague-Dawley mutant rat with conjugated hyperbilirubinemia. Serum bile acid levels were increased. bile acid-independent bile flow was decreased and biliary glutathione concentrations were markedly decreased in the Eisai hyperbilirubinuria rat. Biliary excretion of sulfobromophthalein was markedly impaired and almost no glutathione conjugate was excreted in the bile of the Eisai hyperbilirubinuria rat. Biliary excretion of lithocholate-3-O-glucuronide and lithocholate-3-sulfate in the Eisai hyperbilirubinuria rat was markedly delayed. whereas that of lithocholate was only slightly delayed. After [14C]chenodeoxycholate infusion (1 mumol/min/100 gm for 60 min). the increases in bile flow and biliary excretion of isotope in the Eisai hyperbilirubinuria rat were not so prominent as those observed in control rats. and the glucuronide of chenodeoxycholate. which constituted about 15% of biliary chenodeoxycholate in control rats. was not observed in the Eisai hyperbilirubinuria rat. Initial uptake of lithocholate and its glucuronide and sulfate by isolated hepatocytes was not impaired in the Eisai hyperbilirubinuria rat; the profiles of cytosolic bile acid binding proteins in Eisai hyperbilirubinuria rat liver were identical to those in control liver. These data indicate that the Eisai hyperbilirubinuria rat has excretory impairment of organic anions. bile acid glucuronide and sulfate and that it has characteristics very similar to those of the hyperbilirubinemic mutant Wistar rats TR- and GY.
Minor contribution of hepatocytes to collagen production in normal and early fibrotic rat livers, Hepatocyte contribution to hepatic collagen production in vivo was estimated in rats. based on the fact that ornithine is used for protein synthesis in the liver as arginine after conversion by way of the urea cycle only by hepatocytes. From rats given a mixture of [14C] ornithine and [3H]arginine. hepatic collagen and serum albumin were obtained. The hepatocyte contribution was calculated from the 14C and 3H in arginine purified from collagen and albumin by high performance liquid chromatography. The contribution was less than 10% of total collagen production in normal and early fibrotic livers induced by a single dose of carbon tetrachloride or dimethylnitrosamine. We conclude that hepatocytes may play a minor role in collagen production in normal and early fibrotic rat livers.
Dopamine beta-hydroxylase deficiency. A genetic disorder of cardiovascular regulation, Dopamine beta-hydroxylase (DBH) deficiency is a genetic disorder in which affected patients cannot synthesize norepinephrine. epinephrine. and octopamine in either the central nervous system or the peripheral autonomic neurons. Dopamine acts as a false neurotransmitter in their noradrenergic neurons. Neonates with DBH deficiency have had episodic hypothermia. hypoglycemia. and hypotension. but survivors sometimes cope relatively well until late childhood when overwhelming orthostatic hypotension profoundly limits their activities. The hypotension may be so severe that clonic seizures supervene. Most currently recognized patients are young or middle-aged adults. The diagnosis is established by the observation of severe orthostatic hypotension in a patient whose plasma norepinephrine/dopamine ratio is much less than one.
Renal arteriolar diameters in spontaneously hypertensive rats. Vascular cast study, The relation between the arteriolar diameters and hypertensive glomerulosclerosis was studied by using microvascular casts and histological evaluation. Spontaneously hypertensive rats 4 weeks of age were divided into three groups: nontreated. captopril (40 mg/kg/day)-treated. and trichlormethiazide (1 mg/kg/day) with hydralazine (20 mg/kg/day)-treated. Wistar-Kyoto rats served as controls. At 6 weeks old. the captopril-treated rats showed a lower blood pressure and a larger afferent arteriolar diameter compared with the control rats. At 20 weeks old. the nontreated group exhibited hypertension and a lower arteriolar diameter ratio (afferent to efferent. 0.89 versus 1.22 in control group) because of afferent constriction and efferent dilatation. seen equally in the outer and inner cortexes. Glomerulosclerosis was accentuated only in the inner cortex of the nontreated group (score. 63 versus 29 in control group). In the two treated rat groups. the blood pressure was reduced and arteriolar diameter ratios were similar to those in the control group (1.18 and 1.26). The sclerosis score in the trichlormethiazide with hydralazine-treated rats (score. 26) was lower than in the nontreated rats but not the captopril-treated rats (score. 36). These results indicated that 1) in the hypertensive rats. despite a reduced diameter ratio. glomerulosclerosis was more severe in the inner cortex; 2) two therapies reduced blood pressure and reversed the arteriolar changes. but a decrease in glomerulosclerosis was seen only in the trichlormethiazide with hydralazine-treated rats; and 3) for development of glomerulosclerosis. factors other than hemodynamics may be important in addition to intraglomerular pressure.
Abnormal platelet and lymphocyte calcium handling in prehypertensive rats, We have reported that the basal and stimulated cytosolic free calcium concentrations [( Ca2+]i) are elevated in platelets isolated from 12-14-week-old spontaneously hypertensive rats (SHR) as compared with normotensive Wistar-Kyoto (WKY) rats. To determine whether altered cell calcium metabolism precedes the development of overt hypertension. we measured [Ca2+]i under resting and stimulated conditions in blood platelets and thymic lymphocytes isolated from 4-week-old prehypertensive SHR and WKY rats. Blood pressure was similar in both groups (SHR 95 +/- 8 versus WKY rats 92 +/- 7 mm Hg). Basal [Ca2+]i in platelets was higher in SHR than WKY rats (63.4 +/- 3.9 versus 54.8 +/- 3.1 nM. p less than 0.003). Also the [Ca2+]i response to thrombin was greater in SHR than WKY rats in both the presence and absence of extracellular calcium. For lymphocytes. although no difference was detected in basal [Ca2+]i. the concanavalin A-induced peak [Ca2+]i was higher for SHR than WKY rats in both calcium-containing and calcium-free media. These results suggest that agonist-stimulated calcium influx and calcium discharge from intracellular stores are enhanced in both platelets and lymphocytes of 4-week-old SHR. We conclude that abnormalities in calcium metabolism in two different cell types precede the development of overt hypertension in the SHR.
Platelet-free calcium and vascular calcium uptake in ethanol-induced hypertensive rats, This study examined the effect of moderate ethanol intake on systolic blood pressure. platelet cytosolic free calcium. aortic calcium. and rubidium-86 uptake in Wistar-Kyoto rats. Twelve Wistar-Kyoto rats. aged 6 weeks. were given 5% ethanol in drinking water the first week followed by 10% ethanol in drinking water for the next 6 weeks. Twelve control animals were given regular tap water. Systolic blood pressure in the ethanol-treated rats was significantly higher (p less than 0.05) than that in controls after 1 week and remained higher throughout the study. At 13 weeks of age. platelet cytosolic free calcium and calcium uptake by aortas were significantly higher (p less than 0.001) in ethanol-treated animals as compared with those in controls. Ethanol intake did not affect aortic ouabain-sensitive 86Rb uptake. The in vitro effect of ethanol on calcium-45 and 86Rb uptake was also investigated in aortas of untreated Wistar-Kyoto rats at 13 weeks of age. In vitro ethanol (2.5-20 mmols/l) did not significantly affect 45Ca and 86Rb uptake in rat aortas. The increases in systolic blood pressure. platelet cytosolic free calcium. and vascular calcium uptake suggest that increases in cytosolic free calcium and calcium uptake mechanisms are associated with ethanol-induced hypertension.
Human astrocytes contain two distinct angiotensin receptor subtypes, The ability of angiotensin peptides to stimulate prostaglandin release and raise intracellular calcium levels by activating a phosphoinositide-specific phospholipase C was assessed in three human astrocytoma cell lines (CRTG3. STTG1. and WITG2). The addition of angiotensin II to CRTG3 cells resulted in a dose-dependent release of prostaglandin E2 and prostacyclin. the production of inositol 1.4.5-trisphosphate. and the mobilization of intracellular calcium. Angiotensin-(1-7). previously considered to be an inactive metabolite of angiotensin II. was as potent as angiotensin II for prostaglandin release but did not activate phospholipase C or mobilize intracellular calcium. In contrast. angiotensin-(2-8) caused only a slight increase in prostaglandin release. even though it was as effective as angiotensin II in augmenting inositol 1.4.5-trisphosphate production and calcium mobilization. Moreover. neither the release of prostaglandins in response to angiotensin II or angiotensin-(1-7) nor the mobilization of intracellular calcium in response to angiotensin II required extracellular calcium. Angiotensin II and angiotensin-(1-7) caused the release of prostaglandins from all three human astrocytoma cell lines. but changes in the level of intracellular calcium in response to angiotensin II only occurred in CRTG3 cells. Although previous studies have provided evidence for angiotensin receptor subtypes on the basis of selectivity of antagonists or signal transduction mechanisms. these data suggest that human astrocytes contain multiple angiotensin receptor subtypes on the basis of their response to different angiotensin heptapeptides--angiotensin-(1-7) and angiotensin-(2-8).
Sodium and volume sensitivity of blood pressure. Age and pressure change over time, Salt sensitivity has been implicated in the age-related increase in blood pressure. We studied the reproducibility of a rapid method for assessing sodium sensitivity and resistance of blood pressure as well as the effect of age on this phenomenon. Blood pressure after volume expansion with 2 l intravenous saline (0.9%) over 4 hours was compared with that after 1 day of 10 mmol sodium chloride intake and 3 and 40 mg oral doses of furosemide. Normal and hypertensive subjects (n = 28) were studied twice within a year. Cross-sectional observations of the effect of age were made from studies in 230 hypertensive and 430 normotensive subjects. Longitudinal observations of blood pressure change over time were made 10 or more years after categorization of sodium responsivity in 31 subjects. The blood pressure response was reproducible in 28 subjects studied twice (r = 0.56. p less than 0.002). Four subjects changed salt-responsiveness status and six were indeterminate on restudy. Sodium sensitivity of blood pressure increased significantly with increasing age in the entire population (n = 660. r = -0.38. p less than 0.001). The relation was more striking in hypertensive subjects (n = 230. r = -0.31. p less than 0.001) in whom a progressive increase in salt sensitivity with decades was seen than in the normotensive group (n = 430. r = -0.19. p less than 0.01) in whom salt sensitivity was not observed until the sixth decade. Salt-sensitive subjects had a significantly greater increase in systolic (p less than 0.001) and diastolic (p less than 0.01) pressure over time than those who were salt-resistant. Salt sensitivity is a reproducible phenomenon that is related to the age-associated increase in blood pressure characteristic of industrialized societies. In addition. salt sensitivity can be shown to be a predictor of subsequent. age-related blood pressure increase.
Prevalence of Type A behavior in untreated hypertensive individuals, Type A behavior has been associated with coronary heart disease as well as high cholesterol and smoking. major risk factors for coronary heart disease. but the data indicating a similar association with hypertension are inconsistent. Since past studies have usually based hypertension on a single blood pressure assessment or have often included treated hypertensive patients. this inconsistency is not surprising. The current study compared the prevalence of Type A behavior (assessed by Rosenman's structured interview) between 109 untreated hypertensive subjects and 109 age-. sex-. ethnic-. and occupation-matched normotensive subjects. Hypertension status was based on five repeated assessments over a 5-month period. Results indicated that Type A behavior is more prevalent in untreated. mildly hypertensive employed individuals than occupationally matched normotensive subjects. Type A component analysis confirmed the importance of hostility and certain vigorous voice stylistics in predicting cardiovascular conditions. These findings. taken together with the evidence linking Type A behavior with high cholesterol and cigarette smoking. further support the view that this behavior pattern is associated with increased risk of coronary heart disease.
Polyamines, vascular smooth muscle, and deoxycorticosterone acetate-salt hypertension, This study was performed to determine if an alteration in vascular polyamine contents is associated with the development of deoxycorticosterone acetate-salt hypertension. The effects of chronic administration of alpha-difluoromethylornithine. a specific irreversible inhibitor of ornithine decarboxylase and thus polyamine biosynthesis. on vascular polyamine contents. structure. and function as well as the development of hypertension was studied. Control and deoxycorticosterone acetate-salt rats received either tap water or a drinking solution containing alpha-difluoromethylornithine for 6 weeks. during which period systolic blood pressures were recorded. Vascular reactivity studies were performed on rings of aorta and tail artery. Medial thickness. vessel weight. and vascular polyamine contents were also assessed in these arteries. alpha-difluoromethylornithine treatment had no significant effect on either systolic blood pressure or vascular structure. function. and polyamine contents of control animals. The elevation in blood pressure and the increase in medial thickness. ring weight. and vascular polyamine contents as well as altered vascular reactivity observed in deoxycorticosterone acetate-salt rats was significantly attenuated by alpha-difluoromethylornithine treatment. These results are the first to demonstrate that vascular polyamine contents are elevated in the deoxycorticosterone acetate-salt rat and that chronic alpha-difluoromethylornithine treatment prevents the rise in vascular polyamines as well as the elevation in blood pressure and attendant changes in the vasculature. Thus. the increase in vascular polyamines may comprise a critical link between the initiating stimuli and the alterations in vascular structure and function implicated in the pathogenesis of deoxycorticosterone acetate-salt hypertension.
Questionnaire versus clinical interview in the diagnosis of headache, A self-administered questionnaire based on the operational diagnostic criteria of the International Headache Society (IHS) was evaluated in a cross-sectional epidemiological survey of headache disorders. A clinical interview was used as index of validity. Seven hundred and thirteen subjects were included. Sensitivity. specificity. predictive value. and chance-corrected agreement rate for the diagnosis of migraine was 51%. 92%. 50% (PVpos). 93% (PVneg). and 0.43 respectively. Corresponding values for episodic tension-type headache were 43%. 96%. 95% (PVpos). 46% (PVneg). and 0.30; and for chronic tension-type headache 14%. 100%. 100% (PVpos). 97% (PVneg). and 0.24. It is concluded that a questionnaire is not a satisfactory tool in diagnosing headache disorders according to the IHS criteria. The methods of data collection seem to have significant influence on the results. Caution in handling data obtained by means of subjective statements is advocated.
First clinical study of the selective 5-HT3 antagonist, granisetron (BRL 43694), in the acute treatment of migraine headache, Granisetron (BRL 43694). a selective 5-HT3 receptor antagonist. was assessed as acute therapy for the first time in migraine patients. In an open pilot study 7 migraine attacks were treated in 6 patients. All but 1 patient experienced marked and rapid relief from the headache. and nausea and vomiting were rapidly resolved in the 6 cases where these symptoms accompanied the attack. No side effects were recorded. Development of granisetron for migraine was suspended during the study for extraneous reasons.
Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium, The effects of oral Magnesium (Mg) pyrrolidone carboxylic acid were evaluated in 20 patients affected by menstrual migraine. in a double-blind. placebo controlled study. After a two cycles run-in period. the treatment (360 mg/day of Mg or placebo) started on the 15th day of the cycle and continued till the next menses. for two months. Oral Mg was then supplemented in an open design for the next two months. At the 2nd month. the Pain Total Index was decreased by both Placebo and Mg. with patients receiving active drug showing the lowest values (P less than 0.03). The number of days with headache was reduced only in the patients on active drug. Mg treatment also improved premenstrual complaints. as demonstrated by the significant reduction of Menstrual Distress Questionnaire (MDQ) scores. The reduction of PTI and MDQ scores was observed also at the 4th month of treatment. when Mg was supplemented in all the patients. Intracellular Mg++ levels in patients with menstrual migraine were reduced compared to controls. During oral Mg treatment. the Mg++ content of Lymphocytes (LC) and Polymorphonucleated cells (PMN) significantly increased. while no changes in plasma or Red Blood Cells were found. An inverse correlation between PTI and Mg++ content in PMN was demonstrated. These data point to magnesium supplementation as a further means for menstrual migraine prophylaxis. and support the possibility that a lower migraine threshold could be related to magnesium deficiency.
Anger and hostility in tension-type headache, A battery of standardized psychometric tests was administered to a group of 47 episodic tension-type headache sufferers and 47 headache-free controls. Compared to controls. headache subjects showed higher levels of anxiety. depression. and anger/hostility. The groups did not differ significantly on a measure of anger expressed toward persons or objects. but headache subjects showed significantly greater levels of suppressed anger. The results provide objective data that are in general agreement with predictions derived from psychosomatic theories about the interrelationships among anxiety..
The disappearance of the "cold patch" in recovered migraine patients: thermographic findings, In a previous paper we suggested that the vascular cold patch may be a useful prognostic index to followup migraine patients. Considerable criticism against our contention has been raised by Swerdlow and Dieter (Headache 29:562-568. 1989. ref. 1). who claim that the cold patch constitutes a "fixed geography" of the vasculature of migraine patients. In the present paper we replicate and extend our previous findings reporting the results of facial thermography in a sample of 246 consecutive migraine patients. Of these the 206 exhibiting a typical cold patch or a significant asymmetry in the forehead thermal dissipation were admitted to prophylactic treatment (beta blocker or calcium channel blocker). The thermography was performed at entry in the study and after six months of active treatment. The clinical outcome was compared to the thermographic findings. The patients were subdivided in three classes on the basis of the clinical outcome. Among the 136 patients who experienced complete or substantial relief from headache the cold patch disappeared or markedly improved in 85% of the cases. In the 46 patients with partial relief the thermogram showed an improved pattern in 48% of cases. most of the time of smaller extent than in the previous class. In 24 patients we observed no clinical improvement. Among these the thermogram remained unchanged in 85% of cases. Taken together these findings corroborate our previous suggestion that thermography is useful to monitor the clinical course of the disease. One additional suggestion from the present data is that thermography closely parallels the clinical course so as to represent a useful criterion for the decision of discontinuing the therapy.
Activation of pain fibers to the internal carotid artery intracranially may cause the pain and local signs of reduced sympathetic and enhanced parasympathetic activity in cluster headache, Several clinical and circulatory physiological observations indicate that the internal carotid artery (ICA) with proximal pial and orbital-periorbital branches. as well as external carotid vessels adjacent to the orbital region. are involved in the autonomic symptoms of an attack of cluster headache. Evidence is presented here that an activation of pain fibers innervating the intracranial segment of ICA may cause not only the retroorbital pain of an attack but also. via the mechanical effect of a neurogenic inflammation in the vessel wall. the local symptoms of a sympathetic defect and. via a reflex are to the parasympathetic pathway along the greater superficial petrosal nerve. the local symptoms from glands and vessels of parasympathetic discharge. Dilation of the intracranial ICA due to activation of this parasympathetic pathway may aggravate pain. Possible mechanisms behind such a local pain fiber activation are discussed.
EMG activity in pericranial muscles during postural variation and mental activity in healthy volunteers and patients with chronic tension type headache, EMG activity was recorded over frontalis. temporalis and trapezius muscles in a supine position. a standing position and during a mental task in 32 female patients suffering from chronic tension-type headache and in 20 healthy volunteers. Measurements in patients were made before and after biofeedback therapy. All EMG levels were on average significantly higher in patients than in controls. 62.5% of patients had at least one abnormal EMG level. but only 34% were beyond the normal range. if 1 muscle and 1 recording condition was considered. EMG levels were not correlated with headache severity. anxiety or response to biofeedback treatment. It is therefore suggested that pericranial EMG activity is not pathogenetic in chronic tension type headache. but merely one of several pathophysiologic changes. that are produced by a central dysfunction.
The impact of cigarette smoking on headache activity in headache patients, The present study was designed to explore the relationship between cigarette smoking and headache activity in a sample of patients presenting for treatment. Subjects completed various self-report measures and monitored headache activity four times per day over a 4-week period. Analyses revealed that smokers experienced greater weekly peak headache intensity. and reported higher levels of depression and general physical symptoms. Among smokers. nicotine content of the preferred brand was associated with mean headache index and weekly headache-free days. as well as depression and anxiety scores. Daily smoking rate and pack-year history were related to level of general physical symptoms only. Thus. both smoking status and the nicotine content of the preferred cigarette appear to adversely impact headache activity. Further. smokers who are more anxious or depressed may increase their headache activity via their preference for higher nicotine-content cigarettes. These results are discussed in the context of possible mechanisms underlying these effects. and implications for the clinical management of headache suffers who smoke.
Hair transplantation in advanced male pattern alopecia. The role of incisional slit grafting, The technique of incisional slit grafting is described and discussed. The results of the use of this technique for hair transplantation in patients with Norwood Type VII or advanced alopecia are reported.
Partial-thickness wedge and advancement flap for upper lip repair, Reconstruction of upper lip defects demands careful attention in order to reconstitute both normal function and normal appearance. These defects may involve mucosa. orbicularis oris muscle. skin. vermilion. or any combination of these structures. We will describe five cases in which there were defects created by Mohs micrographic surgery and present the concept of partial-thickness wedge in combination with a flap to repair these wounds.
Practical phlebology. Sclerotherapy of large veins, A practical. step-by-step guide for the sclerotherapy of large varicose veins is offered. First. an orientation regarding the place of sclerotherapy and surgery in the total treatment of varicose veins is given. with a practical clinical classification of varicose veins. This is followed by a detailed discussion of patient education before sclerotherapy. material to be used with recommended concentrations. injection technique. compression after sclerotherapy. instructions to the patient after injection. and procedures at subsequent visits.
Raising the root. A look at orthodontic extrusion, A simple technique using bonded wires to establish anchorage and an attachment to a tooth requires a minimum of special materials or advanced skills in orthodontics. The bonded wire stabilizes the anchor unit and avoids any adverse tooth movement.
How finishing affects glass ionomers. Results of a five-year evaluation, At least four cervical erosion/abrasion lesions were restored with glass ionomer materials in 30 patients. Some restorations were finished in 15 minutes. and some were finished 24 hours after placement. No significant differences were found after five years.
A survey of emergency department communicable disease reporting practices, A group of physicians. nurses. and administrators at all 11 hospitals in the District of Columbia were interviewed to elucidate each hospital emergency department's (ED) system for patient and public health notification of the diagnosis of legally reportable communicable diseases. The hospitals' reporting systems were divided into two groups. Three hospitals (27%) had reporting systems that were centered in the emergency department (EDS). Eight hospitals (73%) had disease reporting systems that depended primarily on extradepartmental personnel (HBS) for disease reporting. The EDS outperformed the HBS in several key areas of system performance. Greater attention needs to be paid by ED directors to assuring that their hospital's system is as accurate as possible and fulfills their jurisdiction's legal requirements for communicable disease reporting.
Inability of patients to self-diagnose wound infections, At the time of follow-up wound inspection or suture removal. 433 patients were questioned about signs of wound infection. Patients' answers were compared to evaluations by medical examiners. Patients frequently failed to recognize infection and signs of inflammation. When asked if wound infection was present. patients' false positive diagnostic rate was only 8%. but the false negative diagnostic rate was 48%. Medical examiners diagnosed wound infection in 21 wounds. and patients correctly identified their infections in only 11 of these cases. These results indicate that for the population studied. patients cannot be expected to recognize infection in their own wounds using verbal or printed instructions. Clinical investigators of wound healing should not use patient-reported data about wound infection that is obtained by telephone interview or other means.
Adrenal pheochromocytoma presenting with persistent abdominal and flank pain, Pheochromocytoma is classically associated with paroxysms of headache and hypertension. Its presentation. however. may be more varied and subtle. We present a case of an adolescent female who complained of right upper quadrant and flank pain. A right adrenal pheochromocytoma was diagnosed and subsequently removed. The pertinent literature is discussed.
Blow-out fractures: a review, Blow-out fractures are a relatively common injury seen in the emergency department (ED). The diagnosis is based on clinical grounds. but defined radiographically. For the emergency physician. it is important to recognize the associated signs and symptoms in order that the diagnosis not be missed. Once the diagnosis is made. appropriate referrals need to be made. This article reviews diagnostic criteria. both clinical and radiographic. as well as an ED treatment protocol for blow-out fractures.
Post-triathalon delirium [clinical conference, This is a case presentation of acute delirium in a previously healthy man. It was originally discussed during Morbidity and Mortality Conference at The George Washington. Georgetown Residency Program in Emergency Medicine. December 1989.
Inhibition of antigen-driven proliferative responses and enhancement of antibody production during infection with Brugia pahangi, Long standing Brugia pahangi infections in seven dogs. restricted to one rear limb popliteal lymph node and its afferent ducts. were monitored with regard to proliferative responses and antibody production specific for a PBS extract of B. pahangi (BpA) by cells from infected and uninfected lymph nodes and by PBL. Five of 10 dogs were negative for proliferative responses to BpA in node cells from infected limbs. yet they had positive PBL responses. and another was negative in both node cells and PBL. Production of BpA-specific antibody was detected in cultures of node cells from infected limbs of 9 of 10 dogs. but only in two cultures of node cells from uninfected limbs and not at all in PBL cultures. Three dogs with responsive node cells produced the least amount of anti-BpA antibody in culture. Injections of B. pahangi adult worm excretory/secretory products (ES). totaling 1 mg over 48 h. into the limb of the original infections in seven dogs. resulted in inhibition of Ag-driven proliferation by cell populations previously responsive to BpA. There was a loss of PBL responsiveness by all but one infected dog and a loss of node cell response by the two dogs previously responsive in infected and uninfected nodes. This loss of responsiveness lasted at least 28 days in three dogs. There was no evidence of suppression of responses to mitogens either before or after ES injection. In contrast. BpA-specific antibody production was greatly increased in node cells from infected limbs injected with ES. Similar injections into the uninfected limbs of two infected dogs produced no change of proliferative responses or of antibody production in the uninfected node. These results indicate that ES can modulate immune cell. Ag-driven proliferation. and simultaneously enhance antibody production in previously infected nodes. This may promote parasite survival by inhibiting cellular attack based on delayed-type hypersensitivity while directing immune responses toward production of antibodies that are less damaging to the adult helminth.
Treatment of murine B cell lymphoma with bispecific monoclonal antibodies (anti-idiotype x anti-CD3), It has previously been reported that T lymphocytes can be targeted by using bispecific antibodies consisting of anti-target antibody and anti-CD3. In the present study. a bispecific mAb was developed by somatic hybridization of mouse hybridomas. one producing a mAb against the Id determinant of the mouse B cell lymphoma 38C13 and the other a mAb against a polymorphic determinant on murine CD3. The bispecific antibody. anti-38C13 x anti-CD3. is bi-isotypic (IgG1 x IgG2a) and was purified by ion exchange and affinity chromatography. The dual specificity of the hybrid hybridoma-produced mAb could be demonstrated by flow cytometry. the induction of T cell proliferation. the induction of IL-2 secretion by polyclonal T cells. and redirected lysis of the relevant target cells. The hybrid (bi-isotypic) Fc part of the bispecific antibodies was nonfunctional in FcR-dependent redirected lysis. In vivo studies demonstrate that this bispecific mAb could efficiently target T cells towards the tumor cells. resulting in long term survival and cure of the lymphoma.
Cloning and in vitro expression of a melanoma-associated antigen immunogenic in patients with melanoma, The purpose of this study was to identify human melanoma-associated Ag (MAA) that are immunogenic in patients. because these molecules may be useful immunogens to implement active specific immunotherapy. To this end. an expression cDNA library constructed from the human melanoma cell line A375 was screened with sera from patients with melanoma. A 1029-bp cDNA (designated D-1) was isolated. Its nucleotide sequence showed no significant homology with viral and mammalian sequences stored in GE-NETYX. cDNA D-1 hybridized to a 2.0-kb mRNA species from human melanoma. neuroblastoma. erythroleukemia. B lymphoid. and T lymphoid cell lines but not from a renal carcinoma cell line. PBL. and cultured skin fibroblasts. The D-1 clone produced a fusion protein that displayed a significantly higher reactivity with sera from patients with melanoma than from healthy controls. Furthermore. D-1 fusion protein induced in mice antibodies that immunoprecipitated a 50-kDa component from cultured human melanoma cells. The structural properties of D-1 MAA are different from those of previously described MAA. These results suggest that the approach we have applied may be useful to identify novel MAA expressed by melanoma cells. Furthermore. the immunogenicity of recombinant D-1 protein suggests that it may be a valuable immunogen to implement active specific immunotherapy in patients with melanoma. if additional experiments show that it has the appropriate tissue distribution.
Subpopulations of B cells in germinal centers. III. HJ6, a monoclonal antibody, binds globoside and a subpopulation of germinal center B cells, To identify surface Ag uniquely expressed on human germinal center B cells. we produced a mouse mAb. HJ6. When tonsillar lymphocytes were examined. HJ6 did not label T cells and labeled only about half of PNA+ B cells that were HK23-. HJ6 did not label mononuclear cells from peripheral blood. splenocytes. and any of 29 cell lines including 23 B cell lines. This binding pattern of HJ6 was very similar to that of a mAb named 5B5. It was shown previously that 5B5 bound a glycolipid named CTH (CD77) and its Ag was expressed on HK23- PNA+ tonsillar lymphocytes and Burkitt's lymphoma cell lines. Despite the similarity. HJ6 differed from 5B5: HJ6 did not stain Burkitt's lymphoma cell lines and stained PNA+ tonsillar lymphocytes in the presence of a large concentration of galactose. When its binding to isolated glycolipids was studied. HJ6 was found to bind globoside and Forssman Ag and not to other glycolipids including CTH. When its binding to neutral glycolipids extracted from tonsillar lymphocytes was studied. HJ6 bound only globoside; Forssman Ag was not detected in tonsillar lymphocytes. Taken together. we conclude that globoside is a B cell Ag expressed on a subpopulation of germinal center B cells.
Intravascular IL-8. Inhibitor of polymorphonuclear leukocyte accumulation at sites of acute inflammation, IL-8 has been characterized primarily as a polymorphonuclear leukocyte (PMN) chemoattractant and proinflammatory mediator. Recently. we have reported that [Ala-IL-8]77 is secreted by activated cultured human endothelial cells and can function as a potent inhibitor of PMN adhesion to these monolayers. The pathophysiologic relevance of this in vitro observation was examined by determining the effects of intravascular or extravascular administration of IL-8 on PMN emigration at sites of acute inflammation in the skin of NZW rabbits. An i.v. bolus of [Ala-IL-8]77 (12 micrograms/kg) produced a marked and selective reduction of circulating PMN within 3 min. which returned toward preinjection levels within 30 min. and subsequently exceeded this level. A similar response was observed for circulating radiolabeled PMN. and gamma-scintigraphy determined that the lungs were the primary site of leukosequestration. During the 30- to 150-min interval after i.v. infusion of [Ala-IL-8]77. PMN emigration into acute inflammatory sites. elicited by various chemoattractants or cytokines. was significantly reduced. as judged histologically and quantitated with 51Cr-labeled PMN and myeloperoxidase measurements. Intravenous administration of [Ser-IL-8]72 yielded similar results. This inhibitory effect of i.v. IL-8 was transient and reinducible and did not reflect a suppression of the responsiveness of circulating PMN to chemoattractants. Intradermal injections of [Ala-IL-8]77 or [Ser-IL-8]72 induced dose-dependent PMN accumulation. which also was significantly reduced by i.v. administration of either form of IL-8. These results indicate that i.v. IL-8 can function as a PMN-directed leukocyte adhesion inhibitor and suggest that local secretion of IL-8 by activated endothelium may differentially modulate leukocyte-endothelial interactions at sites of acute inflammation.
Differentiation-inducing cytokine P48 exists in a membrane-associated form, P48 is a recently described 48-kDa differentiation-inducing cytokine isolated from the culture medium of the human leukemia line Reh. P48 induces differentiation and cytolytic activity in the promyelocytic cell line HL-60. and stimulates the release of TNF-alpha and IL-1 from peripheral blood monocytes. In further studies designed to examine the biosynthesis and function of P48. surface immunofluorescence flow cytometry analysis as well as 125I surface labeling and immunoprecipitation. revealed the presence of P48 on the surface of Reh cells. Triton X-114-treated Reh cells were partitioned into detergent and aqueous phases and separated by SDS-PAGE. Western blot analysis revealed that P48 partitioned exclusively into the detergent phase. suggesting an integral membrane association. Reh cells fixed with paraformaldehyde. but not K562 or P815. were able to stimulate the release of TNF-alpha from peripheral blood monocytes in a manner similar to that of secreted P48. Isolated plasma membranes from Reh cells could also stimulate TNF-alpha release. This TNF-alpha-releasing activity could be removed from detergent solubilized Reh membranes by immunoaffinity chromatography on an anti-P48 column. This study suggests that. in addition to being secreted into the culture medium. P48 is expressed on the surface of Reh cells in a biologically active form. The membrane form of P48 may be 1) a final maturation step before secretion or 2) a cell membrane-associated form that may be analogous to the membrane forms of TNF-alpha and IL-1.
Purified Fc epsilon R+ bone marrow and splenic non-B, non-T cells are highly enriched in the capacity to produce IL-4 in response to immobilized IgE, IgG2a, or ionomycin, Non-B. non-T cells from spleen and bone marrow cells produce IL-4 in response to cross-linkage of high affinity receptors for Fc epsilon R or Fc gamma RII. and to treatment with calcium ionophores. Cells bearing high affinity Fc epsilon R constituted 1 to 2% of non-B. non-T cells of spleen and of total bone marrow cells from naive donors. In mice whose immune systems had been polyclonally activated by injection with anti-IgD antibodies or had been infected with Nippostrongylus brasiliensis larvae. the frequency of Fc epsilon R+ cells in splenic non-B. non-T cells was also 1 to 2% but in bone marrow from anti-IgD-injected mice donors the frequency was approximately 5%. Cell sorting experiments revealed that all of the capacity to produce IL-4 in response to immobilized IgE or IgG2a or to ionomycin was found in the Fc epsilon R+ fraction. Among the Fc epsilon R+ spleen cells from naive donors. the frequency of IL-4-producing cells was 1/20 to 1/40 whereas in mice that had been injected with anti-IgD or infected with N. brasiliensis. the frequency of IL-4 producing cells in the Fc epsilon R+ population was approximately 1/5.
Generation and specificity of monoclonal anti-idiotypic antibodies against human HIV-specific antibodies. I. Cross-reacting idiotopes are expressed in subpopulations of HIV-infected individuals, In this study we have generated monoclonal anti-idiotypic antibodies against human monoclonal and polyclonal anti-HIV antibodies in seropositive sera. A human anti-gp41 mAb (H2. IgM kappa) was used to immunize BALB/c mice and to prepare hybridoma anti-antibodies that react with H2 and not with normal human IgM. Similar monoclonal anti-antibodies were made in BALB/c mice immunized with Ig fraction prepared from a pool of HIV-seropositive sera. Both kinds of anti-idiotypic antibodies reacted with antibodies in pools of seropositive sera and with individual seropositive sera but not with normal human Ig or seronegative sera. The Id-positive Ig from single donors were isolated on two different anti-Id immunoabsorbents and shown to bind to p24 and gp120. respectively. The detection and isolation of idiotypically cross-reactive human anti-HIV antibodies from seropositive donors demonstrated. for the first time. the existence of shared Id expressed by antibodies against HIV Ag. The utility of cross-reacting anti-idiotypic antibodies as tools to dissect the network regulation of the anti-viral immunity in AIDS is discussed.
Natural killer cell cytolytic granule-associated enzymes. I. Purification, characterization, and analysis of function of an enzyme with sulfatase activity, An enzyme with sulfatase activity has been isolated from the granules of a rat NK leukemia cell line. CRNK-16. The enzyme has been purified from crude preparation. with a specific activity of 52 nmol/min/mg of protein. by DEAE ion exchange and Con A-Sepharose affinity chromatography. resulting in a specific activity of 230 nmol/min/mg of protein. The molecular mass of the purified enzyme was estimated to be 40 kDa by gel filtration chromatography at pH 7.4. but the enzyme had the ability to complex to molecular masses of greater than 300 kDa at low pH when crude granule extract was used as the starting sample. suggesting that it associates with other granule components. The enzyme was determined to be an arylsulfatase by its ability to (a) hydrolyze p-nitrophenyl sulfate (Km = 26.0 mM) and p-nitrocatechol sulfate (pNC sulfate) (Km = 1.1 mM) and (b) be inhibited by sulfite (Ki = 6.0 x 10(-7) M). sulfate (Ki = 1 x 10(-3) M). and phosphate (Ki = 4 x 10(-5) M) in a competitive manner. The pH optimum for enzymatic activity was determined to be 5.6. The role of this enzyme in cytolytic function was investigated by examining the effect of its substrates and inhibitors on granule- and cell-mediated lysis. pNC sulfate was shown to cause a dose-dependent inhibition of target cell lysis by isolated cytolytic granules (complete inhibition at 12.5 mM). Sulfite induced an incomplete inhibition (50% at 1 mM). whereas phosphate was essentially without inhibitory effect. Sulfate. on the other hand. altered lytic activity in a biphasic manner. inasmuch as it induced an inhibition of lysis at high concentrations and an increase of lysis at low concentrations. Cell-mediated lysis was inhibited by pNC sulfate in a dose-dependent fashion at concentrations greater than 2.5 mM. with nearly complete inhibition at 50 mM. Sulfate also altered the lytic activity by intact cells in a biphasic manner. although the effect was much less pronounced. Sulfite and phosphate caused only a 30% inhibition of lytic activity. These results suggest that the sulfatase enzyme is involved in NK cytolytic function. presumably at the lethal hit stage.
Dietary taurine content and feline reproduction and outcome, The reproductive performance and the outcome of the kittens was determined for female cats fed 0. 0.01. 0.02 or 0.05% taurine. Reproductive performance and outcome in the 0.02% group was substantially better than in the 0 and 0.01% groups but not as good as in the 0.05% group. Kittens in the 0.05% group had higher body weights and brain weights at birth and at 8 wk after birth than did kittens in the other groups. The concentration of taurine in milk was much higher in females fed 0.05% taurine (approximately 1.9 mmol/L) compared with females fed 0.02% taurine (approximately 0.55 mmol/L) or females fed 0 or 0.01% taurine (approximately 0.2 mmol/L). The concentration of taurine in tissues and fluids of adult females. newborn kittens and 8-wk-old kittens in the 0.05% group was significantly higher than in all other groups. In general. the concentration of taurine in tissues and fluids of the 0.02% group were not significantly different than in the 0 or 0.01% groups. with the exception of 8-wk-old kittens. in which several values. including retina and five brain regions. were significantly higher than in the 0 and 0.01% groups. These results indicate that the postnatal supply of taurine in the mother's milk had a greater impact than the intrauterine environment on the taurine concentration of the offspring in the 0.02% group; this amount of dietary taurine is still insufficient for a normal reproductive performance and resulted in significantly smaller taurine concentrations in adults and offspring.
Kinetics of rat peripheral nerve, forebrain and cerebellum alpha-tocopherol depletion: comparison with different organs, Forty-two 60-d-old rats were fed a vitamin E-deficient diet for up to 8 wk and the kinetics of alpha-tocopherol depletion were measured in nervous tissue and various organs. In most tissues examined. including the sciatic nerve but not the cerebellum. the disappearance was biphasic. suggesting the existence of two pools of vitamin E. In forebrain the disappearance was poorly biphasic. After an 8-wk period of vitamin E deprivation. forebrain. cerebellum. sciatic nerve endoneurium. liver. heart. muscle. testes and serum vitamin E concentrations were 51. 64. 65. 10. 20. 20. 40. and 19%. respectively. of initial values.
Effect of dietary deficiency and supplementation with all-rac-alpha-tocopherol on hepatic content in rats, We studied the effect of dietary deficiency and supplementation with vitamin E in the form of all-rac-alpha-tocopherol in relation to the content of alpha-tocopherol in parenchymal and nonparenchymal liver cells. The cells were isolated by centrifugal elutriation from rats fed diets containing normal. low or high amounts of vitamin E. The parenchymal cells contained about 90% of total hepatic alpha-tocopherol content in rats fed a nonpurified diet (reference group). However. the Kupffer and the endothelial/stellate cells contained four and two times more alpha-tocopherol. respectively. than the parenchymal cells per milligram of cell protein. When the rats were deprived of vitamin E for 8 wk. the content of alpha-tocopherol in parenchymal cells was reduced to 30% of values obtained from rats fed the nonpurified diet. and nonparenchymal cells contained very low levels of alpha-tocopherol (less than 5% of reference values). A diet enriched in vitamin E resulted in a sixfold increase in the content of alpha-tocopherol in parenchymal cells but in small changes in nonparenchymal cells compared to the reference diet. Accordingly. the parenchymal cells may have storage capacity for alpha-tocopherol. The light mitochondrial and microsomal fractions contained high amounts of alpha-tocopherol. These fractions were subdivided by density gradient centrifugation to examine the alpha-tocopherol content in different cell organelles. The lysosomes and the Golgi apparatus were found to contain high levels of alpha-tocopherol. whereas peroxisomes contained small amounts.
Rumen succinate production may ameliorate the effects of cobalt-vitamin B-12 deficiency on methylmalonyl CoA mutase in sheep, When lambs were fed a cobalt-deficient whole barley diet there was a rapid and massive increase in rumen succinate concentrations. Within 2 d of feeding the Co-deficient diet. the rumen succinate concentrations rose 200-fold and peaked at a level 1000-fold higher than that in Co-sufficient controls. Rumen propionate concentrations decreased. suggesting that an alteration in the balance between succinate- and propionate-producing microorganisms had occurred. The rumen succinate can be absorbed and thus may lead to elevated plasma succinate concentrations in Co-deficient animals. whether fed barley or grass. Thus. the absorbed succinate can at least partially overcome the effect on gluconeogenesis of a decreased activity of methylmalonyl CoA mutase induced by Co-deficiency. These findings suggest that impaired propionate metabolism may not be the primary metabolic defect in ovine Co-deficiency.
Cerebral Doppler studies in the fetus and newborn infant, The goal of developing reliable commercial Doppler systems for measuring vessel diameter and velocity changes during the cardiac cycle appears to be near. Reaching this goal would enable us to obtain volume-flow information continuously. In animal experiments. continuous measurements of Doppler velocity. pressure. and flow add important insights into hemodynamic measurements. Incorporating Doppler methods in microcirculatory research could also provide a link between the microcirculatory and the macrocirculatory hemodynamic research. Although Doppler methods have been validated. Doppler findings in clinical research (using commercial systems) must be considered at best to reflect qualitative circulatory alterations indicating directions of change. Because of inherent technologic limitations and considerable intersubject and intrasubject variability. direct extrapolation of the numeric findings from one study to the other can lead to misleading conclusions. The Doppler results are also influenced by measurement conditions and equipment settings. However. Doppler-derived information can be used as an adjunct to clinical management in many of the diseases discussed above. As with any physiologic variable. serial measurements probably are of greater value than single measurements. With continued improvement in technology. Doppler methods hold promise of becoming an important adjunct in cerebral hemodynamic monitoring in perinatal-neonatal intensive care units.
Mumps outbreak in a highly vaccinated population, From October 1988 to April 1989. a large mumps outbreak occurred in Douglas County. Kansas. Of the 269 cases. 208 (77.3%) occurred among primary and secondary school students. of whom 203 (97.6%) had documentation of mumps vaccination. Attack rates were highest for students attending junior high school (8.0%). followed by high school (2.0%) and elementary school (0.7%). A retrospective cohort study conducted at one junior high school with an attack rate of 12.9% did not find age at vaccination or type of vaccine received (single or combined antigen) to be risk factors for vaccine failure. Students vaccinated more than 4 years before the outbreak appeared to have a higher attack rate than those vaccinated more recently (relative risk (RR) = 4.3; 95% confidence interval (CI) = 0.6. 30.0); however. this association did not exist when risk was evaluated based on number of vaccine doses received. Students who had documentation of receiving only one dose of vaccine were at greater risk than those who had received two doses (RR = 5.2; 95% CI = 1.0. 206.2). Overall. vaccine effectiveness among Douglas County junior high school students was estimated to be 83% (95% CI = 57%. 94%). These data suggest that mumps vaccine failure and the failure to vaccinate have contributed to the relative resurgence of mumps observed in the United States since 1986. The recent change in immunization policy to recommend a two-dose schedule of measles-mumps-rubella vaccine should help reduce the occurrence of mumps outbreaks in highly vaccinated populations.
Epidemiology of hemolytic-uremic syndrome in Canadian children from 1986 to 1988. The Canadian Pediatric Kidney Disease Reference Centre, OBJECTIVE: To define the epidemiologic features of childhood hemolytic-uremic syndrome (HUS) on a national level in Canada. to determine the proportion of patients in whom Escherichia coli O157:H7 was isolated from stools. and to examine risk factors for more severe HUS. DESIGN: From January 1986 to December 1988. patients with HUS were reported prospectively to the Canadian Pediatric Kidney Disease Reference Centre. a national registry for pediatric renal disorders. or were identified retrospectively through a medical records search at participating institutions. SETTING: All children's hospitals in Canada and the children's wards of general hospitals in Canadian cities with populations greater than 350.000. PATIENTS: Two hundred twenty-six children. including 126 girls. MEASUREMENTS AND MAIN RESULTS: The average annual incidence of HUS in children younger than 15 years was 1.44 per 100.000; the peak age-specific incidence was 3.11 per 100.000 younger than 5 years. The incidence of HUS varied by region; the risk of HUS in Alberta was 2.9 times that in Ontario (p less than 0.0001). Of the 169 patients whose stools were screened. E. coli O157:H7 was isolated in 87 (51%). Risk factors for prolonged dialysis or death included young age. seizures. elevated white blood cell count at admission to hospital. and shorter. more severe prodromal illness. The rate of dialysis was higher in female patients (55% vs 39%; p = 0.02). CONCLUSIONS: HUS is relatively common in Canadian children younger than 5 years. and is strongly associated with E. coli O157:H7 infection. Reasons for the striking regional variation in the incidence of HUS and for the increased rate of dialysis in female patients are unexplained and deserve further investigation.
Mass screening in Japan increased the detection of infants with neuroblastoma without a decrease in cases in older children, Analysis of data from the Kanto-Ko-Shin-Etsu Branch of the Japan Children's Cancer Registry revealed that mass screening for neuroblastoma increased the detection of cases in infants younger than 1 year from about 25% before screening to about 50%. and the percentage of neuroblastomas among all pediatric cancers almost doubled. from approximately 10% to 19.3%. However. when the cases found on screening were subtracted. the numbers after the onset of mass screening were similar to those before screening. It is likely that neuroblastoma mass screening has identified a unique type of tumor. which may not be recognized without mass screening. rather than that it has contributed to the earlier diagnosis of tumors in older children.
Immunologic studies in Turner syndrome before and during treatment with growth hormone. The Dutch Growth Hormone Working Group, Immunologic studies of 14 girls with Turner syndrome were done before and during treatment with biosynthetic growth hormone (GH). Compared with control subjects. the patients before treatment had a decreased CD4/CD8 ratio and an increased number of cells bearing the natural killer cell marker CD16; serum immunoglobulin levels were within the normal range. During GH treatment some of the girls had a slight reduction in the percentage of CD20+ B cells. but we observed no impairment of B lymphocyte function as demonstrated by the normal in vivo antibody response to the primary antigen Helix Pomatia hemocyanin. administered 6 months after the start of GH treatment. The number of CD16+ natural killer cells returned to normal. Although the number of children with thyroid antibodies increased from two before treatment to five after 1 year. no conclusion about an adverse effect of GH is warranted. because the phenomenon might be part of the natural course of the disease. We conclude that girls with Turner syndrome have minor changes in some immunologic measurements and that GH treatment resulted in some alterations that have no effect on immune function.
Screening for glucose-6-phosphate dehydrogenase deficiency as a preventive measure: prevalence among 1,286,000 Greek newborn infants, We evaluated the Greek screening program for glucose-6-phosphate dehydrogenase (G6PD) deficiency. which was incorporated into the existing national phenyketonuria (PKU) screening program to identify infants with G6PD deficiency and eliminate the induction of acute hemolytic crisis by informing the families about the extrinsic factors that G6PD-deficient patients should avoid. Between 1977 and 1989. 1.286.000 infants were screened. The fluorescent spot test was used on samples extracted from dried blood spots. Abnormal fluorescence due to G6PD deficiency (severe or partial) was found in 3.14% of the samples (1 in 22 males and 1 in 54 females). The sensitivity of the test for homozygosity and hemizygosity was 100%. In heterozygosity the test identifies only subjects who have considerably diminished enzyme activity. The test is inexpensive when added to the PKU screening program ($0.90 US per test). We believe that screening a population for G6PD deficiency is justified if the incidence of the deficiency in the population is high and the clinical manifestations serious. The fluorescent spot test is recommended because it is reliable. easy to perform. and inexpensive. The test must be performed within a fortnight from sampling. and the cards must not be exposed to high temperature or humidity.
Reduction in tumor burden allowing partial nephrectomy following preoperative chemotherapy in biopsy proved Wilms tumor, During the last 6 years a treatment protocol of radiographic staging along with percutaneous biopsy to establish a histological diagnosis has been used in 37 patients with Wilms tumor. Combination chemotherapy was given for 4 to 6 weeks before definitive surgical resection. In 9 patients tumor shrinkage was sufficient to permit preservation of a portion of the affected kidney(s). In stage V disease partial nephrectomy was accomplished in 5 patients. In 4 additional patients with unilateral disease downstaging also allowed partial nephrectomy. The radiological and histological changes that allowed this limited surgery are analyzed and compared.
Extended followup of bilateral Wilms tumor: results of the National Wilms Tumor Study, The long-term survival of patients with synchronous bilateral Wilms tumor is not well defined. Retrospective review of 185 patients registered with the National Wilms Tumor Study from January 1974 to July 1986 with stage V tumors suggests that the long-term outcome remains good. Over-all survival is 83%. 73% and 70% at 2. 5 and 10 years. respectively. Unfavorable histology. age at diagnosis and the most advanced stage of the individual tumors remain the most important prognostic variables. No significant difference in survival was noted between patients undergoing initial surgical resection of the tumor and those managed with initial tumor biopsy followed by chemotherapy with or without radiotherapy and subsequent surgical resection. Survival does not appear to be compromised by attempting to conserve native renal function with renal-sparing operations.
The binding and functional properties of voltage dependent calcium channel receptors in pediatric normal and myelodysplastic bladders, The present study was designed to compare the binding and functional properties of calcium channel receptors in normal and myelodysplastic bladders. Normal bladders were obtained from children with vesicoureteral reflux undergoing ureteral reimplantation. Myelodysplastic bladder specimens were obtained from patients undergoing bladder augmentation. The functional studies included agonist (calcium chloride) dose response experiments and the determination of apparent antagonist dissociation constants for various calcium channel antagonists. The receptor binding studies were performed using the ligand (+)-3H-PN200-110 (specific activity 86.6 Ci./mmol.). The mean maximal response of myelodysplastic bladders to calcium ions was 31% less than normal bladders (p greater than 0.05). The mean EC50 for calcium mediated isometric tension and the mean -log antagonist dissociation constant values of nifedipine. diltiazem and verapamil were similar in normal and myelodysplastic bladders. The radioligand receptor binding studies demonstrated that the equilibrium dissociation constant of (+)-3H-PN200-110 in myelodysplastic bladders was 4-fold greater than in normal bladders. The density of dihydropyridine binding sites in myelodysplastic and normal bladders was similar. Our study demonstrated that the pathophysiology of the poorly compliant hyperreflexic bladder is not related to up regulation of dihydropyridine calcium channel receptors or alterations in the response of detrusor muscle to calcium ions. The relative abundance of calcium channel receptors in the normal and myelodysplastic bladders. and the regulation of detrusor contraction by calcium ions suggest that calcium channel receptors have a meaningful role in detrusor function.
The use of intravesical oxybutynin chloride in children with neurogenic bladder, Intravesical oxybutynin chloride was administered to 10 children with neurogenic bladder (myelomeningocele in 9 and imperforate anus in 1) and urinary incontinence refractory to regimens of intermittent catheterization and oral anticholinergic medication. Therapy consisted of instillation of 5 mg. crushed oxybutynin chloride in 10 cc sterile saline twice daily. Of the children 5 (50%) became completely dry day and night. 3 (30%) achieved daytime continence alone. and 2 did not improve clinically and remained in diapers. Urodynamic study revealed increases in bladder capacity up to 335% over baseline and decreases of maximum filling pressures to 63%. No local or systemic side effects were noted. Surgical bladder augmentation was avoided in those who clinically responded to this therapy.
Seromuscular enterocystoplasty in rats, Enterocystoplasty is commonly used in clinical practice. Many of its undesirable effects. that is infections. stones. mucus production. absorption of urinary components into the blood stream and risk of cancer. result from the intestinal mucosa lining the urinary tract. We report on the feasibility of creating an enterocytoplasty with a seromuscular colonic segment that acquires a transitional epithelial lining. Augmentation enterocystoplasty was performed in 51 male. 500 gm.. Sprague-Dawley rats with a 1.82 cm.2 patch of left colon from which the mucosa had been stripped. The serosal surface was used as lining for the enterocystoplasty. The intestinal patch and the bladder capacity at known pressure were measured at operation and at sacrifice. The histology of the enterocystoplasty was studied in detail following sacrifice. Of the animals 40 survived without significant complications and were sacrificed at a mean postoperative time of 30 days (range 5 to 80 days). In the remaining 11 rats a bladder stone developed but it did not seem to affect the outcome of the experiment. The size of the patch could be measured in 22 rats: it was 1.82 cm.2 (standard deviation +/- 0.86) at operation and 2.30 cm.2 (standard deviation +/- 1.1) at sacrifice. In none of the rats did the patch decrease in size. The bladder capacity at a known pressure (mean 17 cm. water) could be measured in 26 animals: it was 2.35 ml. (standard deviation +/- 0.65) at operation and 5.18 ml. (standard deviation +/- 1.19) at sacrifice. Histological analysis was done in 40 rats. In all cases the serosal surface was lined with transitional epithelium. there was no fibrosis or inflammation and the structure of the muscular layer of the bowel remained intact. The earliest growth of uroepithelium in the serosal surface of the bowel was noted at 5 days. This model suggests that the seromuscular enterocystoplasty can be constructed successfully in the rat model. The seromuscular intestinal patch does not shrink. The bladder capacity increases and histology shows a uroepithelial lining of the augmentation.
Bladder augmentation in patients with neurogenic bladder and vesicoureteral reflux, Current treatment of noncompliant neurogenic bladder associated with significant vesicoureteral reflux that is refractory to intermittent self-catheterization and anticholinergic therapy includes bladder augmentation coupled with a procedure to eliminate reflux. Antireflux surgery is often difficult in such a clinical setting. The diseased and thickened detrusor makes reimplantation into the bladder difficult. and successful reimplantation into the intestinal component is tricky and time-consuming. Augmentation alone was done in 14 patients with significant vesicoureteral reflux in the face of a noncompliant. high pressure neurogenic bladder. No effort was made to correct reflux surgically because. in theory. reflux is secondary to abnormal bladder pressure. Of the 13 patients who have had adequate evaluation with postoperative cystograms 12 no longer have reflux. The reflux in the remaining patient has improved from grade IV to grade II. Postoperative cystometric examination in 12 patients demonstrated low pressure and adequate volume. Correction of bladder dynamics alone reversed the reflux. Conversely. persistence of reflux postoperatively is an indication that augmentation has not successfully returned the bladder to a low pressure reservoir. Our experience indicates that antireflux procedures are not routinely needed in this group of patients.
Rubber-specific IgE in children with spina bifida, We attempted to determine the prevalence and clinical significance of rubber-specific IgE in a prospective case control study of 32 preoperative children with spina bifida. compared with 45 outpatient controls and 35 age-matched preoperative controls without spina bifida. A latex-specific radioallergosorbent test was positive in 11 of the 32 spina bifida patients (34%). compared with 1 (2%) and 4 (11%) of the respective controls (p less than 0.05). Within the spina bifida group 5 of 11 antibody-positive patients had a history of rubber-associated. intraoperative or otherwise idiopathic allergic episodes and 1 of 21 antibody-negative patients gave such a history (p = 0.012). Children with spina bifida have a significantly greater likelihood than controls of having IgE specific for rubber antigens. In addition. the presence of rubber-specific IgE is associated with a higher frequency of rubber-associated. intraoperative or idiopathic allergic reactions.
Sequential renography and renal function in Brown-Norway rats with congenital hydronephrosis, Animal models may be helpful to gain insight into the long-term functional outcome of the hydronephrotic kidney. Inbred Brown-Norway rats frequently have kidneys with a delayed urine outflow. In 26 male rats 99mtechnetium-diethylenetriaminepentaacetic acid (Tc-DTPA) furosemide renography was performed to assess the presence and degree of obstruction. and the contribution of each kidney to the total glomerular filtration rate. The total glomerular filtration rate was measured as the plasma clearance of 51chromium-ethylenediaminetetraacetic acid. The measurements were first done at the age of 3 months. and repeated at ages 6. 10 and 15 months. From the renography curve we derived an obstruction score ranging from 0 (minimum) to 10 (maximum) based on the time to peak. the 99mTc-DTPA accumulation at 15 minutes and the furosemide response. Kidneys were classified as normal. obstructed or equivocal. At the first renography 21 kidneys were normal. 8 were equivocal and 23 were obstructed. The total obstruction score of the next 3 renographies indicated that 29 units were normal. 14 were equivocal and 9 were obstructed. Two groups of rats with unilateral hydronephrosis (hydronephrotic kidney-1 and hydronephrotic kidney-2) were selected based on the total obstruction score of all 4 renographies. These groups were compared with rats with 2 normal kidneys. The hydronephrotic kidney-1 rats had an obstruction score indicating equivocal obstruction. while the obstruction score of the hydronephrotic kidney-2 rats indicated obstruction. During the 15 months of followup the presence of a unilateral hydronephrotic kidney with an obstruction score indicating obstruction did not affect the contribution of the hydronephrotic kidney to the total glomerular filtration rate. or the total glomerular filtration rate. We conclude that the obstruction score of a hydronephrotic kidney in rats may change considerably with time. In cases in which renography suggested the permanent presence of ureteral obstruction the glomerular filtration rate remained stable. Thus. renal functional criteria did not indicate obstruction. In Brown-Norway rats a hydronephrotic kidney is able to maintain a normal glomerular filtration rate during at least 50% of the normal lfie span.
Radionuclide diuresis pyelography, Radionuclide diuresis renography continues to be relied upon as a major diagnostic tool to differentiate obstructive and nonobstructive hydronephrosis. Controversy continues to exist with respect to methodology and interpretation of intermediate obstructive patterns. In this study radionuclide diuresis pyelography was performed in 11 renal units with hydronephrosis and a pre-existing percutaneous nephrostomy tube in place. The procedure consisted of the introduction per kidney of 20 muc./kg. 99mtechnetium-diethylenetriaminepentaacetic acid and sterile saline as a bolus into the renal pelvis via a percutaneous nephrostomy tube to produce a volume equal to the capacity of the hydronephrotic system. The kidney was monitored with a gamma camera and computer system. Furosemide (0.3 mg./kg.) was injected intravenously halfway into a 40-minute study. The time/activity curves thus generated were relatively independent of the cortical transport phase. The 2 types of curves were accelerated and constant. Analysis of these pyelogram curves revealed a strong correlation between the presence of an accelerated clearance rate response to furosemide and hydronephrosis without obstruction in 5 of 6 renal units. A constant clearance rate response to furosemide correlated with the presence of obstruction in 4 of 5 units. These observations may indicate that diuretic pyelogram curve dynamics may reflect not only the presence or absence of obstruction but also the ability of the hydronephrotic kidney to respond to the diuretic. More experience must be accumulated to determine the conditions under which diuresis pyelography may become useful clinically.
Diuretic Doppler sonography in postnatal hydronephrosis, Renal resistive indexes were measured by Doppler sonography in 12 children undergoing other standard diagnostic studies to evaluate hydronephrosis. Measurement of renal resistive indexes was modified by prior placement of a bladder catheter. oral hydration and administration of 1 mg./kg. furosemide after baseline measurement. Renal resistive indexes were again measured at 10 and 30 minutes after diuretic. While diuretic administration had no measurable influence on 10 nonobstructed kidneys. the elevated 10-minute post-diuretic renal resistive indexes recorded in 10 obstructed kidneys differed significantly from the indexes recorded in the nonobstructed group (p less than 0.001). The highest elevations in renal resistive indexes were recorded in nonpaired kidneys. which included 7 of the 10 kidneys in the obstructed group. In the 3 unilaterally obstructed kidneys the 10-minute post-diuretic renal resistive indexes did not differ significantly. However. renal resistive indexes in these kidneys increased at least 15% over baseline readings after diuretic administration. Diuretic Doppler sonography appears to be another useful method for differentiating functionally significant hydronephrosis from nonobstructive hydronephrosis in children.
The morphometric histopathology of undescended testes and testes associated with incarcerated inguinal hernia: a comparative study, The underlying injury to undescended testes may be hormonal. a transient perinatal form fruste of hypogonadotropic hypogonadism characterized by blunting of the surge in gonadotropins normally seen at age 60 to 90 days. Ischemia is the underlying injury to testes associated with incarcerated inguinal hernias. To determine if the histopathology of these 2 injuries is different histomorphometric analyses were performed on semithin microscopic sections of biopsies of 21 control testes. 17 undescended testes and 13 intrascrotal testes associated with incarcerated inguinal hernias. The infants in all groups were 30 to 120 days old. The results showed that. as in previous studies. undescended testes at this age are characterized by hypoplasia of Leydig cells. normal germ cell counts and defective maturation of gonocytes into adult dark spermatogonia. In contrast. testes associated with incarcerated inguinal hernias were characterized by hyperplasia of Leydig cells. reduced germ cell counts and normal maturation of gonocytes into adult dark spermatogonia. One might conclude that the underlying injury of undescended testes. presumably the blunted surge of gonadotropins. causes a primary hypoplasia and hypofunction of Leydig cells. which in turn causes a secondary defect in transformation of gonocytes into spermatogonia. In contrast. ischemia may primarily cause a tubular epithelial lesion leaving the hypothalamic-pituitary-gonadal axis intact and allowing normal transformation of gonocytes into spermatogonia. Reduced gonadotropins and ischemia appear to produce distinctly different primary and secondary pathophysiological effects on the testes.
Does compensatory testicular enlargement predict monorchism, In 37 boys 3 years old or younger with an impalpable testis the length and volume of the normally descended testis were measured. In 12 boys who had surgically proved monorchism the descended testis length and volume exceeded 2 cm. (mean 2.22) and 2 cc. respectively. This represented significant compensatory enlargement of the descended testis compared to the descended testis in 19 boys with normal sized (mean 1.51) or 6 boys with atrophic (mean 1.78) impalpable undescended testes. Histological examinations revealed that in no case in which the descended testis was greater than 2 cm. long was there histological evidence contralaterally of normal. recognizably abnormal or dysgenetic testicular tissue. In these patients compensatory descended testis enlargement with testis length exceeding 2 cm. (2 cc volume) defined monorchism.
Effectiveness of trigonoplasty to treat primary vesicoureteral reflux, Among the surgical procedures to treat vesicoureteral reflux trigonoplasty is a conservative technique that preserves the integrity of the vesicoureteral junction. Since its introduction in 1984 by Gil Vernet it gained only little attention in small series. Between 1986 and 1989 we performed trigonoplasty in 51 children 4 months to 13 years old. of whom 47 had primary vesicoureteral reflux. Our study includes 44 patients who have sufficient followup and 69 refluxing units. Reflux was grade II in 25 units. grade III in 39 and grade IV in 5. Patients were arbitrarily divided into 2 age groups: less than (13) and greater than (31) 3 years old. All children underwent standard preoperative assessment. The operation. with technical modifications (absorbable sutures in all cases and muscular incision added in 12). was performed after failed conservative treatment in all patients except 5 who were operated on at diagnosis. Surgery was successful in 97.7% of the patients and in 92.3% of the children less than 3 years old. The only recurrence was noted on 1 side of a 2-year-old child who had had grade IV bilateral reflux. Considering that reimplantation threatens the integrity of the vesicoureteral junction and endoscopic injections still have unclear side effects. indications for trigonoplasty can be extended to higher grades of reflux if ureteral tapering is not required and a sufficient intramural length of ureter can be obtained.
A novel technique for reconstruction of the abdominal wall in the prune belly syndrome, There is currently widespread enthusiasm for abdominal wall reconstruction in patients with the prune belly syndrome. We have devised an operation that appears to offer some advantages over those proposed by Ehrlich and Randolph. The technique preserves the umbilicus. and thickens and strengthens the anterior abdominal wall. By narrowing the waist. it also produces a better cosmetic appearance. After full thickness resection of a varying amount of skin from the central abdomen. the anterior wall is sutured in double-breasted fashion. thus. preserving all vascularization and the umbilicus. Since 1969 we have successfully performed this procedure on 9 prune belly patients including 1 girl. The results were excellent in terms of duration and cosmetic appearance.
M inverted V glansplasty: a procedure for distal hypospadias, Minimal hypospadias is a commonly encountered anomaly. Duckett's innovative meatoplasty and glanuloplasty (MAGPI) procedure has become a standard operation for the correction of these lesions. Although usually successful. the complication of meatal retraction has been recognized at times after a MAGPI. The M inverted V glansplasty was designed to address the factors leading to meatal retraction and the abnormal glans shape sometimes seen after the MAGPI. The M inverted V glansplasty derives its name from the initial M-shaped incision that reconfigures during the course of the procedure into an inverted V. Of 16 boys followed for more than 2 months after an M inverted V glansplasty 14 have achieved good results. The remaining 2 cases had a definite degree of meatal retraction but because of the meatal and glanular relationships they have a good cosmetic result. The technique. its indications and its limitations are described.
Distal hypospadias repair by urethral sliding advancement and Y-V glanuloplasty, Different techniques are available today for repairing distal (coronal and subcoronal) hypospadias but none is universally recommended. We developed the technique of a distal urethral advancement glanuloplasty operation that is specifically intended for distal hypospadias repair even with mild chordee. Mobilization of the distal urethra is performed for 1.0 to 1.5 cm. after subcoronal circumcision and a deep Y-shaped incision of the glans. The mobilized urethra is dorsally split and slid forward to the tip of the dart of the glans previously prepared. Glanuloplasty is performed using the 2 lateral flaps of glans tissue. From January 1987 to December 1989 we used this technique in 74 cases of distal hypospadias with mild or no chordee (patient age 18 months to 9 years. mean 3.5 years). A transurethral catheter was left indwelling for 3 to 4 days. Hospitalization time was 5 (plus or minus 1.5) days. Results after 4 to 40 months of followup are encouraging cosmetically and functionally. All patients were cured. In 3 cases (4%) meatal stenoses occurred requiring meatotomy and in 8 boys meatal dilations were performed on an outpatient basis. In 1 case (1.3%) a fistula developed. which was subsequently repaired without further complications. This operation may be successfully used in most cases of distal hypospadias. with a low complication rate and excellent cosmetic results. It also may be used if mild chordee is present. thus reducing the indications for flip-flap urethroplasty in those cases when meatal advancement procedures may not be effective.
Abdominoperitoneal approach to management of the high, short vagina in the adrenogenital syndrome, We describe a combined transtrigonal. abdominoperineal approach to the surgical management of the female pseudohermaphrodite with the adrenogenital syndrome and a high. short vagina. Most of our patients had undergone previous clitoral reduction surgery and. therefore. clitoral shaft skin was not available for exteriorization of the vagina. Our operation involves partial mobilization of the vagina through an inverted U flap from the perineum followed by detachment from the urogenital sinus from above by splitting the trigone. Exteriorization is accomplished by mobilizing 2 lateral skin flaps from the perineum and joining them with the inverted U flap to reach the vagina. Cosmetic results have been excellent. although anastomotic stenosis occurred in 1 young infant.
Renal blood flow measurements using radioactive microspheres in a porcine model with unilateral vesicoureteral reflux, Renal blood flow was studied in Yorkshire pigs with surgically created unilateral vesicoureteral reflux using radionuclide labeled microspheres. The contralateral. nonrefluxing kidney served as a within-subject control and a group of nonoperated pigs without reflux served as an additional control group. Unilateral reflux did not change the distribution of whole renal blood flow between the refluxing and nonrefluxing kidneys. In addition. reflux had only minor effects upon the distribution of blood flow to cortical regions within the kidneys.
Urinary levels of renal tubular enzyme N-acetyl-beta-D-glucosaminidase in relation to grade of vesicoureteral reflux, Elevated urinary levels of the renal tubular enzyme N-acetyl-beta-D-glucosaminidase (NAG) have been shown to be associated with tubular damage. To determine whether urinary levels of NAG would be abnormal and/or vary with the severity of vesicoureteral reflux. bladder urine was obtained from 31 children without reflux and 32 children with various grades of reflux. Nonrefluxing controls were obtained from children undergoing evaluation for a history of infection. hematuria or voiding abnormality. Patients with evidence of obstruction. neuropathic bladder dysfunction. urinary tract infection or renal failure were excluded. Bladder (32 cases) and ureteral (5 cases) urine from children with reflux was obtained at cystography or at antireflux surgery. Control and reflux patients were not significantly different with regard to sex or age. The mean urinary NAG level in nonrefluxing control patients was 10.63 IU/mg. (range 0.94 to 26.61. standard error of mean 0.43). Mean urinary NAG for all patients with reflux was 16.47 IU/mg. (range 2.85 to 52.02. standard error of mean 0.9). Two children with intrarenal reflux had urinary NAG levels of 52 and 48 IU/mg. Urinary NAG levels are elevated with higher grades of reflux and this relatively simple assay may have clinical usefulness in the assessment of tubular dysfunction associated with reflux.
Quantification of vascular graft seeding by use of computer-assisted image analysis and genetically modified endothelial cells, Current methods for the evaluation of retention of endothelial cells seeded on vascular grafts are limited by the inability to specifically identify and quantitate seeded cells on a long-term basis. To address this problem we developed a method of quantification of graft surface coverage using genetic labeling of endothelial cells combined with computer-assisted image analysis. Rabbit aortic endothelial cells were transduced with a marker gene (lac-Z) and seeded on polytetrafluoroethylene grafts. After histochemical staining in which the genetically labeled cells turn blue. computer-assisted image analysis was used to measure the percentage of graft surface covered by the seeded cells. The utility of the method was evaluated by using it to assess the effect on graft coverage of seeded cell density and by precoating with fibronectin. Quantification of surface area coverage was automated and reproducible both between scans and between observers. Use of this method allowed the determination of a linear correlation between cell density in the seeding suspension and graft coverage (r2 = 0.93. p less than 0.0001). The method also permitted confirmation of the positive contribution of fibronectin coating to graft coverage by seeded cells: 73% coverage coated versus 8% coverage uncoated (p less than 0.0001). The ability of this method to specifically identify genetically marked endothelial cells and their progeny makes it attractive for use in studies targeted at optimization of graft coverage in vivo.
Septic complications after cardiac catheterization and percutaneous transluminal coronary angioplasty, Septic complications after cardiac catheterization and percutaneous transluminal coronary artery angioplasty are distinctly uncommon. However. we have recently treated nine patients with sepsis and life-threatening complications after cardiac catheterization alone or after catheterization and subsequent percutaneous transluminal coronary angioplasty. The common denominator in all patients was either repeat puncturing of the ipsilateral femoral artery or leaving the femoral artery sheath in for 1 to 5 days after the procedure. Two patients died as a direct result of their septic complications. One death occurred in a patient in whom bacterial endocarditis with congestive heart failure developed. and the other patient had a large retroperitoneal hematoma that became secondarily infected. Infected aneurysms that were successfully treated developed in three patients. Our study suggests that colonization of the needle tract by skin flora predisposes to septic complications if repeat arterial punctures are required or if a femoral artery sheath is left in place for more than 24 hours. Patients in whom sepsis develops after these procedures should be initially treated with antibiotics effective against gram-positive organisms. CT scanning or angiography should be considered for patients with persistent sepsis. septic emboli. and abdominal or flank pain. Infected aneurysms require resection or ligation because of the propensity of these aneurysms to rupture.
Clinical significance of aortic graft dilation, To determine if there is a relationship between aortic graft dilation and graft complications. 443 serial ultrasound studies performed on 106 patients were analyzed. Of 443 studies. 243 were done retrospectively on 59 patients from 3 to 144 months (mean. 38 months) after graft implantation. Forty-seven additional patients were studied prospectively. with direct measurement of external graft diameter after aortic clamp release. Subsequent ultrasound examinations at 3. 6. 9. and 12 months and then annually (n = 200) were routinely performed. Mean follow-up was 12 months (range. 3 to 48). Knitted double velour Dacron prostheses were used in all cases reported in this study. This cohort was culled from our ongoing graft surveillance program. which includes grafts of other materials and manufacturers. Comparison of the manufacturer's recorded box size with follow-up ultrasound measurements in all cases demonstrated a mean increase in graft diameter of 3.7 mm (23%). Little dilation occurred after 1 year. In 47 patients with direct graft diameter measurements taken after declamping. an immediate mean increase of 1.7 mm (11%) was noted. Dilation was not related to surgical indication (aneurysm vs occlusive disease) or hypertension. Analysis of the 10% segment of the series with the greatest dilation (mean. 39%) did not demonstrate a predilection for graft complications. No significant dilation was noted in the single cases encountered of femoral and iliac anastomotic aneurysms and perigraft seroma. Although dilation of knitted Dacron grafts is to be anticipated. no association between graft dilation and graft complications was found in this series.
Transverse versus longitudinal arteriotomy: an experimental study in dogs, An arteriotomy is a commonly used surgical technique. Either a transverse or a longitudinal incision can be made. but no study has been done to determine if one technique results in more stenosis or flow disturbance than the other. Six-millimeter arteriotomies were made on the carotid and femoral arteries of six dogs. Transverse arteriotomies were made on the right. and longitudinal arteriotomies were made on the left. Four weeks later the vessels were reexplored. Duplex scanning was used to assess the amount of turbulence at each arteriotomy. Afterward. latex casts of the arteries were made to determine the percent stenosis caused by each arteriotomy. The mean percent stenosis associated with transverse arteriotomies was 10.5% (+/- 4.4%). versus 22.8% (+/- 9.4%) for the longitudinal arteriotomies. (p = 0.001. matched t test). No difference in the amount of turbulence associated with each technique was demonstrated. A longitudinal arteriotomy results in significantly greater stenosis than does a transverse arteriotomy. Unless there is a specific indication for a longitudinal arteriotomy. a transverse arteriotomy should be used.
Renovascular hypertension: predicting surgical cure with exercise renography, Renal artery stenosis with resultant renovascular hypertension has attracted clinical attention because the disease is potentially curable and because numerous diagnostic and therapeutic modalities compete for clinical acceptance. An exercise-mediated disturbance of renal hippurate transport was recently described. and has been implicated as having a role in nephrogenic fixed hypertension. To predict the final course of renovascular hypertension before operation we carried out a prospective study with the goal of verifying the predictive value of exercise hippurate scintigraphy. The study was to test the hypothesis that patients with disturbance of renal hippurate transport (pathologic renogram) induced by exercise would have stabilized hypertension and would continue to be hypertensive after operation. Thirty-one patients with hypertension who had unilateral or bilateral renovascular stenosis documented on angiography were referred to rest and exercise hippurate scintigrams before operation. The results of the examinations at rest served as standard and were compared with the exercise scintigrams. In 19 of the 31 (61%) patients a disturbance of transrenal hippurate transport evolved during exercise. whereas 12 (39%) patients failed to respond to exercise with altered hippurate kinetics. Twenty-six patients went on to renovascular operations; five had percutaneous transluminal angioplasty. Revascularization results differed markedly when the blood pressure response of patients with positive results on exercise (abnormal) and patients with negative results on exercise (normal) were compared. Ten of 12 patients with hypertension who had normal exercise renograms were cured. In comparison. blood pressure values were little influenced by therapy in patients with an abnormal response. where 17 of 19 patients continued to have hypertensive disease after therapy.
Peripheral arterial occlusion in infants--a report of two cases treated conservatively, The occlusion of major arteries in newborns is usually associated with catheterization of the umbilical vessels. It occurs very rarely instead as a primary disorder. and the cause is still unclear. We present two new cases of newborns with this type of disease. which were resolved with the only medical treatment. The literature is reviewed. and the usefulness of the different diagnostic procedures is discussed.
Celiomesenteric anomaly and aneurysm: clinical and etiologic features, The development of aneurysmal disease involving the rarely encountered celiomesenteric anomaly is extremely unusual. Aneurysmal disease of the celiac or superior mesenteric arteries is itself an extremely uncommon finding. accounting for less than 10% of all visceral artery aneurysms. The existence of aneurysmal disease involving a celiomesenteric anomaly has been alluded to only briefly in two previous clinical reports. We review the case of a young woman with aneurysmal disease involving a common celiomesenteric trunk. The patient underwent excision of the aneurysm with successful vascular reconstruction. Although extremely unusual. the development of this extremely rare lesion can be predicted on the basis of specific etiologic theories. Variations in the patterns of embryologic formation of the visceral arteries account for the development of celiomesenteric anomalies. whereas atherosclerosis. medial degeneration. and infection lead to the development of most visceral aneurysms. Surgical treatment of celiac or mesenteric aneurysms is almost always indicated. Awareness of potential vascular anomalies and patterns of collateral circulation are necessary for appropriate surgical intervention.
The choice between surgical resection and radiation therapy for patients with cancer of the esophagus and cardia: a retrospective comparison between two treatments, The choice of treatment for patients with cancer of the esophagus and cardia is controversial. Since overall survival is poor. the most important aim of treatment should be improvement of the main complaint: the inability to eat. In a retrospective analysis of 265 patients. referred to the University Hospital in Leiden. The Netherlands. comparisons were made between palliative effects of surgical resection (N = 92) and irradiation (N = 128). Several methods of comparing surgery with irradiation are possible: (1) all surgical patients vs. all irradiated patients; (2) only those surgical patients who survived the operation (N = 70) vs. all irradiated patients (N = 128); and (3) survivors after resection (N = 70) vs. only those irradiated patients treated with "curative" radiation (N = 62). Analysis of prognostic factors showed that in both surgical and irradiated patients. the only statistically significant factor was the (dis)ability to eat. Criteria to be considered to make individual recommendations for either treatment are presented.
Melanoma tumor vaccine: five-year follow-up, For many years. various melanoma vaccines have been employed. This is a unique melanoma vaccine in that it is a subcellular tumor homogenate and no adjuvants have been added. This vaccine has been given to 129 stage I and 61 stage II melanoma patients. All were followed at least 5 years and had 87.5% and 63.9% 5-year survival rates. respectively. Sixty-four stage I males and 65 stage I females had 84% and 90% 5-year survival rates. respectively. We saw no difference between those with or without lymph node dissection. Thirty-six stage II males and 25 stage II females had 66.7% and 60% 5-year survival rates. respectively. Of stage II patients. 23 had only one positive node. 22 had two to four positive nodes. and 9 had five or more positive nodes with 69%. 63%. and 55% 5-year survival rates. respectively. Large published series were used as historical controls [6.27.28]. and significant differences were noted when compared to our stage II patients (P = 0.001)--those with two to four positive nodes (P = 0.03). and those with five or more positive nodes (P = 0.04). We conclude that there is a significant increase in survival for these stage II patients. at high risk of recurrence. receiving a tumor homogenate vaccine. This vaccine warrants further analysis. development. and use in a phase III randomized clinical trial.
A myocutaneous flap for closure of upper arm amputations for uncontrolled axillary tumors, Tumor spread or recurrence in the axilla is usually treated with nodal dissections. At times disease recurrence is uncontrolled. causing significant morbidity including pain. bleeding. lymphedema. and neurologic symptoms. Previously. forequarter amputation has been the treatment for this problem. resulting in a significant cosmetic and functional deficit. This report describes a novel myocutaneous flap that can be used to cover soft tissue defects after major disarticulations of the upper extremity. The deltoid myocutaneous flap has been used to successfully treat three patients with uncontrolled tumors in the axilla and preserve the shoulder structures to lessen the functional deficit.
Indwelling subclavian catheters and a visit with the "pinched-off sign", Percutaneously inserted indwelling subclavian vein silastic catheters have revolutionized the administration of chemotherapeutic agents. Complications associated with insertion of such lines have always included bleeding. pneumothorax. haemothorax. arterial cannulation. and catheter displacement. Recently a patient receiving 5-fluorouracil and folinic acid for 11 months for small bowel carcinoma experienced a catheter fracture with distal segment embolization in the right atrium. A literature survey revealed 13 cases where mechanical shearing forces on the catheter caused by compression of the catheter between the clavicle and first rib were thought to be the cause for this complication. Interestingly all cases involved patients receiving chemotherapy. Radiologically. potential candidates for catheter fracture can be identified by the pinched-off sign with bending and pinching of the catheter at the thoracic inlet. Recommendations are for more lateral insertions of such percutaneously placed catheters and if the pinched-off sign is seen. then said catheters should be followed radiologically and probably should not remain in situ for longer than 6 months.
Primary breast lymphoma, Primary breast lymphoma (PBL) is a rare tumor of the breast. Three cases of PBL are being described. All three cases achieved remission following biopsy. chemotherapy. and/or radiotherapy. The literature is extensively reviewed with emphasis on true incidence of PBL and survival rates.
Prospective evaluation of vertical banded gastroplasty as the primary operation for morbid obesity, Our previous experience with vertical (nonbanded) gastroplasty proved disappointing because of unsatisfactory maintenance of weight loss. Vertical banded gastroplasty seemed to be an attractive alternative operation because it provided an externally reinforced (banded) stoma that would not enlarge over time. In this study. our aim was to determine prospectively the results of vertical banded gastroplasty used as a primary. weight-reducing procedure in patients with morbid obesity. Seventy consecutive patients with morbid obesity (mean weight. 139 kg). all of whom had obesity-related complications. underwent vertical banded gastroplasty and prospective follow-up. The hospital mortality was nil. and substantial morbidity occurred in 3% (two patients). Long-term achievement and maintenance of satisfactory weight loss. however. were variable. The median weight loss at 1 year after operation was 36.7 kg or 48% of excess body weight. At 3 years postoperatively. however. weight loss was only 32.4 kg or 40% of excess body weight. and only 38% of patients had achieved and maintained a weight loss of 50% or more of their preoperative excess body weight. Vertical banded gastroplasty caused major changes in eating habits. and many patients were unable to eat red meat or untoasted bread; moreover. approximately 30 to 50% of patients continued to vomit once or more per week. Despite theoretically attractive advantages as a weight-reduction operation. vertical banded gastroplasty does not seem to be the optimal procedure for most patients with morbid obesity.
Associative anomia: dissociating words and their definitions, A 60-year-old woman. in whom magnetic resonance imaging and single photon emission computed tomography confirmed the presence of chronic damage to the left temporal lobe. had pure anomia with sparing of other language and cognitive functions. She could independently access lexical knowledge (words) and semantic knowledge (word definitions). We postulate that her anomia was due to a failure to associate lexical and semantic knowledge.
Systemic adjuvant therapy in women with resected node-negative breast cancer, Currently. the role of adjuvant systemic therapy in women with node-negative breast cancer is being determined. Several studies of adjuvant hormonal therapy and adjuvant chemotherapy have demonstrated a moderate reduction in the risk of recurrence in the treated patients. With relatively limited follow-up. however. overall survival has not improved with use of adjuvant therapy. The use of prognostic factors to select those patients at highest risk for relapse is an active area of oncologic research. The decision to recommend adjuvant therapy necessitates assessment of the probability of recurrence. the expected reduction of risk with adjuvant therapy. the toxic effects of therapy. and the influence of treatment on the patient's overall quality of life.
The porcine model for the understanding of thrombogenesis and atherogenesis, The hypothesis originated by Carl Rokitansky a century ago that thrombosis contributes substantially to atherosclerosis has been rekindled by accumulating experimental and clinical evidence. On the basis of our experience with the experimental porcine model. several important biologic determinants of thrombosis have been identified. The degree of vascular injury seems to be the primary determinant of the thrombotic response. In addition. hemodynamic shear stress and the presence of the von Willebrand factor have important roles in the process of thrombosis. Although there is little evidence that thrombosis is a factor in the initiation of spontaneous. or naturally occurring. atherosclerosis. substantial evidence suggests that thrombosis has an essential role in the progression of spontaneous atherosclerosis and also in the early pathogenic process of the syndromes of accelerated atherosclerosis-namely. heart transplant atherosclerosis. vein graft disease. and coronary restenosis after angioplasty. Advances in the understanding of vascular injury and of the interactions of blood cells with the vascular wall have allowed development of new experimental antithrombotic strategies and subsequent clinical applications in the prevention of these vascular diseases.
Prospective randomised trial of povidone-iodine, alcohol, and chlorhexidine for prevention of infection associated with central venous and arterial catheters, More than 90% of all intravascular device-related septicaemias are due to central venous or arterial catheters. To assess the efficacy of cutaneous antisepsis to prevent catheter-associated infection. we prospectively studied three antiseptics for disinfection of patients' central venous and arterial catheter insertion sites in a surgical intensive care unit. 668 catheters were randomised to 10% povidone-iodine. 70% alcohol. or 2% aqueous chlorhexidine disinfection of the site before insertion and for site care every other day thereafter. Chlorhexidine was associated with the lowest incidence of local catheter-related infection (2.3 per 100 catheters vs 7.1 and 9.3 for alcohol and povidone-iodine. respectively. p = 0.02) and catheter-related bacteraemia (0.5 vs 2.3 and 2.6). Of the 14 infusion-related bacteraemias (4 due to contaminated infusate or catheter hub. 10 due to infected catheters). 1 was in the chlorhexidine group and 13 were in the other two groups (odds ratio 0.16. p = 0.04). We conclude that use of 2% chlorhexidine. rather than 10% povidone-iodine or 70% alcohol. for cutaneous disinfection before insertion of an intravascular device and for post-insertion site care can substantially reduce the incidence of device-related infection.
Torsades de pointes ventricular tachycardia and terodiline, We report five patients (four women. one man; mean age 74 years. range 55-87) taking terodiline who had torsades de pointes ventricular tachycardia associated with prolongation of the QT interval. The QT interval was normal before the introduction of terodiline in three patients and returned to normal after terodiline withdrawal in four. Atrioventricular conduction disturbance or bradycardia were evident in all patients. Terodiline should be prescribed with caution to elderly patients.
Metabolic disorder as early consequence of simian immunodeficiency virus infection in rhesus macaques, To establish whether the high plasma glutamate and low acid-soluble thiol (mainly cysteine) concentrations previously found in patients with HIV-1 infection are a consequence of the infection or a risk factor for its development. a closely related animal model. rhesus and fascicularis macaques infected with simian immunodeficiency virus (SIVmac251). was studied. The 23 infected macaques had significantly lower mean plasma thiol and higher glutamate concentrations than 18 uninfected controls (p less than 0.001). The changes were apparent by 1 week after infection. Thus. abnormal plasma glutamate and thiol concentrations are. at least in this model. a direct and early consequence of the retroviral infection.
Argon laser-assisted anastomoses in medium-size vessels: one-year follow-up, Laser-assisted anastomosis of medium-size vessels can be performed with satisfactory short-term patency. This study was undertaken to evaluate patency and structural integrity up to 1 year. An argon laser was used to make bilateral femoral arteriovenous anastomoses in 12 dogs compared to conventional suture method in another 8 dogs. These anastomoses were evaluated for patency and aneurysm formation at 1 hour; 1. 2. 4. and 8 weeks; and 12 months after surgery. All anastomotic sites were patent and without aneurysmal change or luminal narrowing at all harvesting intervals. Histologic examination revealed that within 1 month laser anastomotic sites were almost completely healed and without intimal hyperplasia. In suture anastomoses. foreign-body reaction remained evident up to 1 year. Use of the argon laser for medium size vessel anastomoses resulted in excellent patency without aneurysm formation or intimal hyperplasia even in the long term. These data suggest promising clinical applications.
Wavelength dependence of pulsed laser ablation of calcified tissue, Pulsed laser ablation of calcified biological tissue was studied at several wavelengths in the near-ultraviolet. visible. near- and mid-infrared regions of the spectrum. The primary tissue model was bovine shank bone. while human arterial calcified plaque and normal human artery wall were also studied at selected wavelengths for comparison. Laser irradiances were on the order of MW/mm2. fluences ranged up to 1000 mJ/mm2. and repetition rates varied between 0.3-10 Hz. Spot sizes on the tissue surface ranged from 150 to 850 microns. Laser craters made with wavelengths between lambda = 295 nm and lambda = 375 nm and in the lambda = 3 microns region exhibited the highest quality ablation with clean. sharp cuts following closely the spatial contour of the incident beam. Craters drilled with visible wavelengths between lambda = 450 nm and lambda = 590 nm were generally larger than the incident laser beam spot. irregular in shape and often surrounded by large flakes of tissue debris. Ablation fluence thresholds increased with wavelength through the visible wavelengths and into the mid-infrared. but dropped to their lowest values near lambda = 3 microns. Fluence thresholds obtained with the tissue under a 1 mm depth of saline were approximately twice air thresholds. Ablation yields also varied with wavelength. probably due to increased scattering in the visible region. and were the same under saline as in air.
Fluorescence localization of early colonic cancer in the rat by hematoporphyrin derivative, Laser excitation of hematoporphyrin derivatives (HPD) localizing in tumors of the tracheobronchial tree and bladder is useful in the identification and treatment of those tumors. A comparable utility for HPD in the endoscopic localization of colonic tumors may be possible. In this study the ability of HPD to identify 1.2 dimethylhydrazine (DMH) induced colon cancer in rats is evaluated. A total of 111 rats were studied with HPD. Sixty-nine rats received weekly injections of DMH (20 mg/kg) and 42 received injections of the vehicle alone. Twenty-four hours after the intravenous injection of 5 mg/kg of HPD. 18 DMH-induced tumors were identified by visual fluorescence using excitation by either a blue light (390-436 nm) or an argon laser (488 and 514 nm). This represented 100% of the visually or microscopically detected tumors. Seventy-five fluorescent areas were noted that did not contain evidence of cancer. The majority (63) of false positive areas contained lymphoid follicles. All but 2 false positive areas (73/75. 97%. p less than .001) were seen in DMH-treated animals. suggesting that they were an artifact of DMH treatment. HPD fluorescence did not identify microscopic dysplasia. We conclude that HPD fluorescence is an effective method of identifying early colonic cancer and may have a potential clinical role in patients at high risk for colorectal cancer.
Excimer laser ablation of fibrocartilage: an in vitro and in vivo study, To date. lasers have found only limited applications in orthopedics. We employed a 308 nm XeCl excimer laser for ablation of fibrocartilage. in order to investigate the feasibility of excimer laser assisted meniscectomy. Experiments were conducted both in vitro and in vivo. For the in vitro study. human menisci. obtained during surgery and autopsy. were irradiated via a 600 microns core fiber at radiant exposures ranging between 20 mj/mm2 and 80 mj/mm2. at 20 Hz. Ablation rate measurements and histological analysis of the samples were performed. The ablation rates were found to range from 3 microns/pulse to 100 microns/pulse depending on the radiant exposure and/or the applied pressure on the fiber delivery system. Thermographic analysis was also performed during pulsed excimer as well as CW Nd:Yag and CW CO2 laser irradiation. Temperatures were lower for excimer laser (Tmax less than 65 degrees) than CW ND: Yag (Tmax less than 210 degrees) or CW CO2 (Tmax less than 202 degrees) laser. For the in vitro study. medial meniscectomy was performed in 15 rabbits with the excimer laser and a CW Nd:Yag laser in the right and left knee respectively. Excimer laser irradiation was performed at 70 mj/mm2. Nd:Yag irradiation was performed via a 600 microns core fiber at power outputs between 20 to 40 W for 10 and 20 seconds duration. The healing response to injury was investigated by histological analysis of the menisci after 1 day. 1. 2. 4. and 8 weeks following the laser procedure. Excimer laser treated menisci showed less inflammatory reaction and noticeable repair with minimal inflammatory response.
Trends in traumatic spinal cord injury--New York, 1982-1988, In the United States. injuries resulting from falls are the most common type of injury among persons greater than or equal to 65 years of age. and most spinal cord injuries (SCIs) among persons in this age group are caused by falls. SCI. with its resultant paralysis. is one of the most catastrophic and devastating medical conditions. Previous studies have characterized the epidemiology of SCI. This report describes changes in the reported incidence of SCI in New York during 1982-1988.
Assessment of broadcast media airings of AIDS-related public service announcements--United States, 1987-1990, Television and radio public service announcements (PSAs) are an integral part of acquired immunodeficiency syndrome (AIDS) public information campaigns. This report summarizes an assessment of airings of AIDS PSAs in the United States during October 1987-December 1990 that were produced by CDC's "America Responds to AIDS" (ARTA) campaign and other groups.* The assessment used data obtained from Broadcast Advertisers Reports (BAR) of the Arbitron Company.
Multistate outbreak of Salmonella poona infections--United States and Canada, 1991, During June and July 1991. more than 400 laboratory-confirmed infections with Salmonella poona occurred in 23 states and in Canada. This report describes several investigations that indicated this was a large nationwide outbreak related to consumption of cantaloupes.
Pseudo-outbreak of infectious mononucleosis--Puerto Rico, 1990, From September 11 through October 7. 1990. 57 persons (including outpatients. inpatients. and staff) at a community hospital in Puerto Rico had laboratory-confirmed infectious mononucleosis; however. investigation determined that test results may have been misinterpreted. This report describes the investigation of this pseudo-outbreak by the Puerto Rico Department of Health (PRDH) in October 1990.
County data on alcohol-related mortality--United States, Although estimates of alcohol-related mortality (ARM) have been determined for the United States and selected states. the magnitude of ARM ahs not been well defined for smaller geographic areas. To provide additional geographically specific data. the Alcohol Epidemiologic Data System of the National Institute on Alcohol Abuse and Alcoholism recently released a reference manual for ARM in U.S. counties (County Alcohol Problem Indicators). The manual provides information for 3107 counties for 1979-1985 using both underlying and multiple cause-of-death information. This report summarizes data sources. methods. and applications for the manual.
Update: cholera--Western Hemisphere, and recommendations for treatment of cholera [published erratum appears in MMWR Morb Mortal Wkly Rep 1991 Oct 4;40(39):679, Epidemic cholera appeared in Peru in January 1991 and subsequently spread to Ecuador. Colombia. Chile. Brazil. Mexico. and Guatemala. Cholera can be a severe. life-threatening illness but is highly preventable and easily treated; however. few health-care practitioners in the United States have experience identifying and treating cholera. This report provides an update on cholera in the Western Hemisphere and provides recommendations on the clinical diagnosis and treatment of cholera in the United States.
Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-N1. Papilloma Study Group, BACKGROUND. We earlier reported that patients with recurrent respiratory papillomatosis responded to six months of treatment with lymphoblastoid interferon alfa-n1. Because another study of patients treated for one year with leukocyte interferon alfa-n3 found that the growth rate of papillomas was slowed in the first six months but returned to base line during months 7 through 12 despite persistent interferon treatment. we now report the long-term results in our original study patients who were followed for a median of four years after the original one-year crossover study. METHODS. After the patients in our study had completed the first study year. their physicians could continue or recommence treatment with lymphoblastoid interferon alfa-n1 in a dose of either 2 MU per square meter of body-surface area per day or 4 MU per square meter every other day. The extent of disease was measured by endoscopy when clinically indicated. RESULTS. Data on late-follow-up were obtained for 60 of the 66 patients. There were 22 complete remissions and 25 partial remissions; 13 patients had no response. The median duration of the complete remissions was 550 days. and 15 patients continued to be in complete remission. The median duration of partial remissions was 400 days and seven patients were still in partial remission. Thirteen of 28 patients responded to a second course of interferon after an interruption in treatment of at least one month. The rate of response in the 11 of 53 patients who had neutralizing antibody to interferon was the same as in the patients without the antibody. CONCLUSIONS. Patients with severe recurrent respiratory papillomatosis may have a sustained or repeated response to treatment with lymphoblastoid interferon alfa-n1. We recommend that patients with recurrent respiratory papillomatosis who require surgery every two to three months be given a six-month trial of interferon alfa-n1.
Prevention of HIV-2 and SIVsm infection by passive immunization in cynomolgus monkeys, Infection of macaques with simian immunodeficiency virus (SIV) and human immunodeficiency virus type 2 (HIV-2) are useful models for studies of immunotherapy and vaccination against HIV as well as for testing of antiviral drugs. Vaccine research showing protective immunity in immunized monkeys has indicated that it will be possible to develop a vaccine for prevention of human HIV infection. although many hurdles remain. The design of an HIV vaccine would be helped if the basis of the protective immunity could be elucidated. Passive immune prophylaxis offers a means to determine the relative role of antibodies in protection against infection. We have studied whether a transfer of antibodies can prevent HIV-2 and SIVsm (SIV of sooty mangabey origin) infection in cynomolgus monkeys. Sera with high antibody titres were collected. heat-treated and injected into naive animals 6 h before challenge with 10-100 monkey-infectious doses of live homologous virus. All control animals treated with normal monkey serum (n = 6) or no serum (n = 39) became infected by the challenge virus. whereas five out of seven animals pretreated with antibody-containing serum at a dose of 9 ml kg-1 resisted infection. Thus passively transferred antibodies can protect against a low-dose lentivirus challenge in a nonhuman primate.
Jaw pain and tenderness levels during and after repeated sustained maximum voluntary protrusion, Eight normal male volunteers performed 4 repeated sustained voluntary isometric protrusive jaw muscle contractions of 25. 50. 75 and 100% of maximum effort. Each contraction was sustained until maximum pain tolerance was reached. and all 4 contractions were completed within a single 120-min experimental period. A 30-min rest period followed each sustained contraction. The following measurements were made before and 1. 2. 3. and 7 days after the experiment: (1) superficial masseter and anterior temporalis muscle pain threshold; (2) maximum active pain-free jaw opening and lateral excursion; and (3) current overall jaw pain level. None of these measurements showed any significant post-experimental changes. Contrary to common clinical belief. these results suggest that in healthy male subjects. significant jaw pain and tenderness following repeated sustained isometric protrusion efforts are difficult to induce.
Electromyographic recordings of low back pain subjects and non-pain controls in six different positions: effect of pain levels, Surface electromyographic (EMG) activity recordings of bilateral paraspinal muscle tension were measured twice on 20 non-pain controls and on 46 low back pain subjects (21 individuals with intervertebral disk disorders and 25 subjects with unspecified musculoskeletal backache) during 6 positions: standing. bending from the waist. rising. sitting with back unsupported. sitting with back supported. and prone. Back pain subjects were measured during both low pain and high pain states. Results revealed a non-significant trend for all subjects. regardless of diagnosis. to have higher paraspinal muscle tension levels on the second (or high pain) assessment. A significant diagnosis by position interaction was observed which was similar to the interaction in our previous study which employed only a single measurement session. Analysis of simple main effects revealed this to be due to control subjects during the standing position having lower EMG levels than the back pain groups. and intervertebral disk disorder subjects having higher EMG levels than the other groups during the supported sitting position. As in our previous study. diagnosis was found to be a clinically significant factor. in that controls had much fewer clinically abnormal readings than back pain patients. The lack of a significant effect for pain state is congruent with findings in the headache literature. The importance of clearly defined diagnostic categories in low back pain research and the utility of measuring subjects in various positions is discussed. as are possible explanations for lack of significant pain state findings.
Deep brain stimulation: a review of basic research and clinical studies, Deep brain stimulation for pain control in humans was first used almost 30 years ago and has continued to receive considerable attention. Despite the large number of clinical reports describing pain relief. numerous studies have indicated that the results of these procedures vary considerably. In addition. many neurosurgeons find the procedures unpredictable. and considerable disagreement still exists regarding important issues related to the technique itself. This review gives an historical overview of the relevant basic and clinical literature and provides a critical examination of the clinical efficacy. choice of stimulation sites. parameters of stimulation. and effects on experimental pain. Finally. we give suggestions for future research that could more definitively determine the usefulness of deep brain stimulation for pain control.
Thermographic observations on rats with experimental neuropathic pain, Infrared thermographic images were obtained from the plantar hind paws of rats with an experimental nerve injury that produces signs of neuropathic pain. Thermograms confirmed that the experimental neuropathy produces signs resembling those of patients with neuropathic pain. The hind paws on the nerve-damaged side were abnormally hot. abnormally cold. or apparently normal 8-16 days post injury. a variability that is seen clinically in neuropathic pain patients. Abnormally cold hind paws became warm as soon as the injured sciatic nerve was transected. indicating that the underlying vasoconstriction was mediated by neural impulse activity. Xylazine (Rompun). a sympatho-inhibitory alpha 2-adrenoceptor agonist that normally increases cutaneous temperature. caused the hind paw on the control side to warm. as anticipated. while causing paradoxical cooling of abnormally hot hind paws. and even of 'normal temperature' paws on the nerve-injured side. These findings shed light on possible mechanisms underlying abnormal deviations of skin temperature as a symptom of nerve injury. The findings also attest to the usefulness of the experimental animal model of neuropathic pain and of the thermographic method.
Modulation of neuropathic pain behavior in rats by spinal disinhibition and NMDA receptor blockade of injury discharge, When a peripheral nerve is severed. damaged sensory fibers emit a barrage of impulses that lasts for many seconds. or even several minutes ('injury discharge'). We have shown in rats that local anesthetic blockade of this discharge suppresses autotomy (a behavioral model of neuropathic pain). Correspondingly. mimicking prolonged injury discharge with electrical stimulation. especially of C-fibers. increased autotomy. These data support the hypothesis that injury discharge plays a role in the triggering of neuropathic pain. The mechanism of triggering autotomy was investigated using intrathecal injection of agents affecting glutamatergic transmission. A single intrathecal injection at the lumbar enlargement of the NMDA receptor blockers MK-801 and 5-APV. just prior to neurectomy. significantly suppressed autotomy. Blocking glycinergic inhibition just prior to neurectomy with a single strychnine injection strikingly enhanced autotomy. Strychnine enhancement of autotomy was prevented by prior injection of MK-801 or 5-APV. These results suggest that the expression of autotomy in rats. and by inference neuropathic pain in humans. is affected by injury discharge. possibly mediated by long-lasting. NMDA receptor-related. spinal disinhibition.
Chronic fatigue in adolescents, Nine female and 6 male adolescents (mean age 14.5 +/- 1.7 [SD] years) were evaluated for chronic fatigue associated with at least three additional symptoms present for 18.4 +/- 8.4 months. Eleven subjects experienced the onset of symptoms with an acute illness (seven Monospot-positive). Medical history. physical examination. and laboratory testing yielded little helpful information. Serologic testing for Coxsackie B viruses 1 through 6. cytomegalovirus. Epstein-Barr virus. human herpesvirus 6. and Toxoplasma gondii in subjects and healthy controls provided little evidence for an infectious cause of persistent fatigue. Children's Depression Inventory scores and psychiatric interviews with the Schedule for Affective Disorders and Schizophrenia-Children's Version (K-SADS) identified five subjects with major depression. On the K-SADS. the 10 fatigued subjects without major depression endorsed many secondary symptoms of depression but were less likely than depressed psychiatric clinic patients to endorse primary symptoms such as depressed mood. guilt. and suicidality. At telephone follow-up 13 to 32 months after intake. 4 subjects were completely well. 4 markedly improved. and 7 unimproved or worse. Further research is necessary to determine whether chronic fatigue in adolescents is prodromal depression. a discrete psychosomatic condition. or an infectious or immunologic disorder that mimics depression.
Preparedness of practicing pediatricians to manage emergencies, To determine pediatrician preparedness to manage emergencies. a nationally representative random sample of 1000 non-hospital-based pediatricians was surveyed about (1) types of emergencies encountered and methods of transport to an emergency facility. (2) availability and use of equipment and medications in the office. and (3) determinants of pediatrician confidence in managing emergencies. The proportion of pediatricians who had encountered specific emergencies ranged from 86% for meningitis to 22% for cardiopulmonary arrest. The majority transported acutely ill children to an emergency department by ambulance. Availability of individual pieces of equipment and medications in offices ranged from 97% for epinephrine 1:1000 to 11% for bone marrow needles for intraosseous access. Combination of equipment available to manage particular emergencies ranged from 61% for severe dehydration to 11% for cardiopulmonary arrest. The equipment available in a pediatrician's office was significantly related to the type of primary work setting. Pediatrician confidence in managing the initial stabilization of emergencies ranged from 58% for seizures to 25% for epiglottitis. Confidence was related significantly to year residency was completed. Advanced Cardiac or Advanced Pediatric Life Support training. work setting. and the availability of equipment in the office. Continuing education regarding initial office management of and equipment for common emergencies should improve the pediatrician's confidence and competence in this area.
Emergency medical services and the pediatric patient. III: Resources of ambulatory care centers, Ambulatory care centers have emerged as a new health care resource in many communities. Little information is available about the services that these centers offer to pediatric patients. A national survey of 254 ambulatory care centers was undertaken to determine their characteristics. including the number of pediatric patients seen. staffing patterns. and pediatric equipment and supplies available. Most clinics were located in urban areas and were within 5 miles of a hospital. They were staffed primarily by physicians who were board certified in emergency medicine. internal medicine. or family medicine. Not all centers had registered nurses on duty and few used extended-role nurses or physicians's assistants. The centers saw an average of 18 patients younger than 18 years of age per day. Some ambulatory care centers received emergency medical service and private ambulance calls and encountered serious illness such as chest pain. seizures. and anaphylaxis; the majority. however. handled mainly minor injuries and illnesses. Although most had pediatric equipment and supplies. some did not have a complete set of pediatric resuscitation equipment even though they were part of the emergency system offering care to the pediatric population.
Tuberculosis in children 10 years of age and younger: three decades of experience during the chemotherapeutic era, The 863 patients. aged 10 years and younger. treated at the Children's Chest Clinic of Bellevue Hospital during three decades (1953 through 1981) clearly indicated the success of antituberculosis therapy. There were no deaths from tuberculosis. Early treatment is associated with a reduction in the serious forms of disease. eg. meningitis. miliary disease. and bone infections. and with preventing death. Medication was well tolerated: only 1.1% of the patients had adverse reactions. all of which were reversible. Consistent compliance with medication of only 62% of patients is a challenge to the medical profession. Only 22.5% of mycobacterial cultures were positive. Long-term follow-up of patients was rewarding: seven pregnancies with healthy mothers and babies. and no reactivation of tuberculosis by later infections. even those such as measles or pneumonia. The severity of disease was related largely to patient's age (3 years and younger) and intimacy of contact. the highest rate being when the mother was the contact. The long-term experiences emphasizes the value of early identification. therapeutic compliance. and comprehensive contact. tracing in the future elimination of tuberculosis. Prophylactic therapy and close observation should be considered for contacts. especially those exposed to human immunodeficiency virus infections and addicted to drugs.
Cholesterol screening in pediatric practice, Four pediatricians introduced a portable cholesterol analyzer into their group practice. Their experience is described on the basis of 12 months of screening in 1665 children and adolescents. The overall 50th and 90th percentile values for a subgroup of 1406 routinely screened children were 156 and 197 mg/dL. respectively. but there was marked variation in these values among specific age and sex groups. Cholesterol levels decreased by age group during the early teenage years and increased thereafter. these changes occurring at ages approximately 2 years younger for girls than for boys. Further analysis of screening results for 398 sibling pairs demonstrated significant concordance between paired cholesterol levels when classified by the respective age- and sex-specific 90th percentile values for each member of the pair. Sibling pairs in which both members' cholesterol values exceeded their 90th percentile value were identified 2.4 times as frequently as expected (confidence interval 1.1 to 4.5. P = .029). The observations reported here indicate that office-based cholesterol screening in a pediatric practice may be both practical and useful. although further consideration of screening criteria is needed. Age- and sex-specific reference values for cholesterol levels during childhood could improve screening results. Special emphasis should be directed toward screening siblings of children in whom high cholesterol levels have been detected.
Family and peer issues among adolescents with spina bifida and cerebral palsy, Increasingly. children with disabling conditions are surviving through childhood into adolescence and beyond. This places increased importance on understanding adolescent. family. and peer relationships. which are critical to healthy development among adolescents in general and to transitions to successful adulthood among youths with physical disabilities in particular. The purpose of this study was to identify the patterns of family and peer interactions. One hundred two youths with spina bifida and 60 adolescents with cerebral palsy between the ages of 12 and 22 completed written psychological measures as well as an in-depth structured interview. Approximately 90% of youths with spina bifida and cerebral palsy resided at home. of whom 80.4% and 72% lived with both parents. Almost without exception. parental relationships were defined as positive. with no difference of attitude noted toward the mother and father. Relationships with parents for teenagers with spina bifida were marked by high levels of dependence on parents for personal care such as bowel programs and. for both groups. low levels of responsibility at home and lack of discussion with parents about sexuality or menstruation. Although friends were viewed as very important by most respondents (approximately 83%). relationships were characterized by extremely limited out-of-school contacts. negligible participation with organized social activities. and a primary orientation toward sedentary activities. Finally. regarding heterosexual relationships. whereas 44.1% of respondents with spina bifida and 54.2% of respondents with cerebral palsy said their friends dated. only 14.7% and 28.3% of study participants indicated that they had ever been on a date and. even for those teenagers. heterosexual social contacts were infrequent.
Toward reducing pediatric injuries from firearms: charting a legislative and regulatory course, Each year in the United States. approximately 3000 children and adolescents younger than age 20 die as a result of homicides. suicides. and unintentional injuries from firearms. The young children. relatives. neighbors. and friends of the 30.000 adults killed by firearms each year in the United States are also affected by this uniquely American epidemic. It is estimated that half of all American homes contain 200 million firearms. including 60 million handguns. Increasingly. pediatricians are becoming involved in efforts to reduce the prevalence of injuries from firearms. as parent educators. experts on children and adolescents. and advocates in the political process. This commentary is intended to aid in the last of these roles. The advocacy goal is identified as reducing the accessibility of guns in the environments of children and adolescents. The pros and cons of 17 possible approaches--ranging from mandatory safety courses in schools to handgun bans--are presented. It is concluded that. while there is no perfect approach. many available approaches will help; there is every reason to be both bold and optimistic.
Informing schools about children's chronic illnesses: parents' opinions, Parents of 217 chronically ill children and adolescents were surveyed concerning their opinions about disclosing medical information to schools. The sample consisted of parents of more than one third of the children and adolescents meeting inclusion criteria who were seen at a university-based pediatric clinic during a 10-week period. Parents were asked (1) whether schools need information about 16 health items. (2) who in the school should know. and (3) who should provide this information. Parents' willingness to disclose information was compared with family and child demographic data. Parents strongly believed that (1) teachers need to be informed and (2) parents should be the primary informers. The consensus that schools need information did not vary with family and child demographics. However. parents of children with poor illness prognosis. greater likelihood of emergencies. and visible illnesses were more supportive of disclosure. Most parents indicated that physicians should provide information on 10 of the 16 items. Physicians were viewed as particularly appropriate informers about recognizing emergencies and medication effects. Only 21% of the parents were aware of any prior contact between the medical care giver and the school concerning their child's illness. Thus. parents want schools informed and believe physicians should be involved in providing information.
Comparison of albuterol and metaproterenol syrup in the treatment of childhood asthma, This study compared the acute and chronic effects of albuterol syrup (2 mg) and metaproterenol syrup (10 mg) three times a day over 28 days in 65 children. aged 6 to 9 years. with mild to moderate asthma. Wright peak flow. symptom scores. and rescue medication use were recorded twice daily during the 28 days; the acute cardiopulmonary effects of these syrups were compared over 8 hours on treatment days 1 and 28. Albuterol syrup produced a significantly greater peak magnitude of bronchodilation than metaproterenol. 29% vs 20% above baseline. respectively. on treatment day 1. Albuterol syrup had a duration of action of at least 8 hours and produced greater bronchodilation than metaproterenol syrup from 2 to 8 hours on both treatment days 1 and 28. The chronotropic effect of metaproterenol was greater than that of albuterol at 1 to 1 1/2 hours postdose on treatment days 1 and 28. There was a trend toward higher morning and evening Wright peak flow measurements during 28 days of treatment in the albuterol group. Side effects of both drugs were comparable. These findings imply therapeutic advantages of albuterol syrup over metaproterenol syrup in currently recommended doses with respect to improvement in pulmonary function. chronotropic effects. and frequency of dosing required to maintain optimum bronchodilation over a 24-hour period.
Randomized, placebo-controlled trial of iron supplementation in infants with low hemoglobin levels fed iron-fortified formula, In spite of the declining prevalence of iron-deficiency anemia. a large proportion of low-income infants have "low-normal" (11-11.5 g/dL) and "low" (less than 11 g/dL) hemoglobin (Hgb) values. Because most of these infants are fed iron-fortified formulas. it was of interest whether additional iron supplementation would enhance Hgb values. A cohort of 334 healthy. inner-city. minority. 6-month-old infants. fed iron-fortified formulas. with Hgb values ranging from 9 to 11.5 g/dL. participated in a double-blind. randomized. placebo-controlled trial of supplemental iron at 0. 3. and 6 mg/kg per day for 3 months. Hemoglobin values increased significantly with age. regardless of assignment to placebo or supplemental iron (means for the entire cohort: 6 months 10.9 g/dL. 8 months 11.2. 10 months 11.3. and 12 months 11.4). The proportion of "responders" (Hgb level increased greater than or equal to 1 g/dL) was 34% and did not differ significantly by placebo or iron dose. There were no significant differences in mean corpuscular volume or levels of erythrocyte porphyrins or serum ferritin between treatment groups. The implications of this clinical trial are twofold: (1) screening healthy infants fed iron-fortified formula at the age of 6 months is not justified. regardless of socioeconomic status; (2) the clinical practice of routinely treating low-income. "low-Hgb" infants with iron supplementation. without regard to dietary considerations. is unwarranted.
Verbal dyspraxia in treated galactosemia, Galactosemia is an inborn error of metabolism that causes life-threatening illness a few days after galactose-containing milk is fed to a newborn. Early treatment with a strict lactose-free diet results in rapid improvement. and. until recently. it was thought that the long-term prognosis in such infants was usually good. The speech characteristics of 24 patients treated for galactosemia were examined. Fifty-four percent had the specific speech disorder. verbal dyspraxia. This finding was not related to age at diagnosis. severity of symptoms in the newborn period. or to biochemical control. There may be. however. a relation between dyspraxia and diminished IQ scores observed in the group of patients with dyspraxia judged as "severe." The findings indicate the association of a specific and unusual speech defect with a specific and rare metabolic disorder.
Bell's palsy. A diagnosis of exclusion, In cases of acute unilateral facial weakness. a careful and systematic evaluation is necessary to identify the cause. Idiopathic facial paralysis (Bell's palsy) is a diagnosis of exclusion. It is also the most common cause of unilateral facial weakness seen by primary care physicians. The most important aspect of initial treatment is eye protection. Administration of systemic oral corticosteroids may lessen severity and duration of symptoms.
Cardiac transplantation. How recipients are selected, Your patients with heart disease may ask about transplantation. Those who are potential candidates need a physician who knows enough about the selection system to get them into it. For other patients. an explanation of why the procedure is contraindicated in their case can help them refocus on compliance with recommended therapy. The authors discuss the principles of recipient selection.
Farm injuries. How can the family farm be made a safer place, Farming is a dangerous life-style and occupation for children and adults. Dangerous situations are taken in stride and considered part of life on a family farm. Regulatory and educational programs and funding have been minimal in the United States. Physicians have been a major force in accident-prevention efforts in other segments of society and can be instrumental in preventing farm injuries as well by extending these educational efforts to rural communities.
Diabetes care in minority groups. Overcoming barriers to meet these patients' special needs, Physicians play a critical role in reaching diabetic patients in minority groups. These patients need professional help to modify their diets and exercise patterns. to follow drug regimens and blood-testing programs. to comply with treatment over the long term. and to pay for treatment. Closing the gap between the treatment levels afforded different groups of Americans is an enormous challenge. but it is one that is critical to the health of our population.
Burning pain in an extremity. Breaking the destructive cycle of reflex sympathetic dystrophy, The pathogenesis of reflex sympathetic dystrophy is controversial. but the condition can result from a major or seemingly minor injury to a limb. or even an insult to an organ. such as stroke or myocardial infarction. Onset can be sudden or insidious. The syndrome is characterized primarily by localized. deep. burning pain in a limb--pain that may not follow any logical distribution. Nonpitting edema. skin hyperesthesia. and guarding of the limb usually accompany the pain. If treatment is not instituted. deformity. contracture. and wasting of the limb can eventually occur. With appropriate therapy. the process can be stopped and often reversed. The keys are a high index of suspicion. early diagnosis. and aggressive treatment.
Febrile seizure. Caring for patients--and their parents, Management of febrile seizure involves diagnosis and treatment of the underlying cause and assessment of risk factors for recurrence. What should physicians tell anxious parents about this frightening occurrence? Is prophylaxis with anticonvulsant agents appropriate? The authors address these questions and discuss the changing approach to management of febrile seizure.
Drug-induced renal toxicity. Help in recognizing offending agents, Drug-induced kidney disease is common. especially in hospitalized patients. and prompt recognition of the various nephrotoxic syndromes is important because many are reversible. Risk factors should be assessed before patients are given an agent that may cause acute renal failure (eg. nonsteroidal anti-inflammatory drug. aminoglycoside antibiotic. angiotensin-converting enzyme inhibitor. radiocontrast agent). Discontinuation of the responsible drug is often the only necessary therapy.
Ventricular arrhythmias. When should they be suppressed, Patients with asymptomatic ventricular premature complexes who do not have evidence of heart disease should not be treated with either class I or class III (Vaughan Williams) antiarrhythmic drugs. Patients who are symptomatic may be given beta blockers. In patients who have heart disease. a number of risk factors may play a part. and the decision regarding therapy is more difficult. However. symptomatic patients with either sustained or nonsustained ventricular tachycardia must be treated with antiarrhythmic agents. In some patients. implantation of an automatic defibrillator may be necessary.
Supraventricular tachycardia. Changes in management, The various forms of supraventricular tachycardia can be differentiated by careful review of a patient's electrocardiogram. If reentrant tachycardia involves the atrioventricular node. intravenous adenosine (Adenocard) provides a rapid means of converting the tachycardia to sinus rhythm. Adverse effects of adenosine. though common. are mild and of brief duration. Wide QRS complex tachycardia of ventricular origin is usually not affected by the drug.
Urinary incontinence. Not a 'normal' part of aging, Urinary incontinence is a common problem that affects millions of elderly men and women and their caregivers. Evaluation of incontinence is easy and inexpensive and does not require hospitalization. A basic evaluation consists of history taking (including a review of drug use). physical examination. and appropriate laboratory testing. Urodynamic evaluation may also be necessary. Treatment may consist of behavior modification techniques (eg. Kegel exercises. biofeedback. bladder retraining). use of a mechanical device or pharmacologic agent. or surgery. Should medical and surgical methods fail. alternatives are available to ensure patients' well-being and comfort.
Formation of the tetraploid intermediate is associated with the development of cells with more than four centrioles in the elastase-simian virus 40 tumor antigen transgenic mouse model of pancreatic cancer [published erratum appears in Proc Natl Acad Sci U S A 1991 Sep 15;88(18):8282, The development of pancreatic cancer in transgenic mice expressing the simian virus 40 tumor antigen placed under controlling regions of the elastase I gene is characterized by the sequential appearance of tetraploid and then multiple aneuploid cell populations. Pancreatic tissues from such transgenic mice were studied between 8 and 32 days of age. Virtually 100% of acinar cell nuclei had immunohistochemically detectable tumor antigen by 18 days. Tetraploid cells were demonstrated by DNA content flow cytometry by 20 days and were associated with the appearance of interphase cells that had 5-11 centrioles per cell in single thin sections of pancreatic tissue examined by electron microscopy. Mitotic cells also were observed that had 5 or more centrioles per cell that were incorporated into the poles of bipolar or at least tripolar spindle apparatuses. These observations indicate that formation of the tetraploid intermediate in the diploid----tetraploid----aneuploid sequence of pancreatic tumor formation in elastase-simian virus 40 tumor antigen transgenic mice is accompanied by the development of cells with 5 or more centrioles that can be incorporated into the poles of abnormal mitotic spindles. We speculate that cells with more than 4 centrioles are predisposed to the formation of multipolar mitoses that may yield daughter cells with chromosomal gains and losses. resulting in the subsequent development of aneuploid tumors.
Colocalization of lymphocytes bearing gamma delta T-cell receptor and heat shock protein hsp65+ oligodendrocytes in multiple sclerosis, The presence of T lymphocytes bearing the gamma delta T-cell receptor (TCR gamma delta) has been studied immunocyto-chemically in central nervous system (CNS) tissue from 13 patients with multiple sclerosis (MS). 4 with inflammatory non-MS CNS disorders. 6 with other neurological diseases. and 3 with nonneurologic conditions. Twenty-eight of 43 MS lesions contained TCR gamma delta cells and these were most frequently found in chronically demyelinated areas. in contrast to the previously studied CD4+. CD8+ (TCR alpha beta) population. which predominated in more active lesions. Some TCR gamma delta lymphocytes had an unusual morphology with long dendritic processes. which were sometimes interconnected forming a network. Because it is generally believed that TCR gamma delta lymphocytes function in a cytotoxic fashion in association with heat shock proteins (hsp). we examined the colocalization of TCR gamma delta cells with 65- and 70-kDa hsp (hsp65 and hsp70) in MS lesions. Hsp65 was expressed on immature oligodendrocytes at the margins of chronic lesions containing TCR gamma delta lymphocytes. The coexpression of these molecules might imply functional relationships perhaps of significance to the chronicity of the MS disease process and the failure of CNS remyelination.
E1A oncogene induction of cytolytic susceptibility eliminates sarcoma cell tumorigenicity, The manner in which oncogenes influence tumorigenicity beyond their ability to immortalize cells is uncertain. We tested the hypothesis that. in addition to subverting cellular growth controls. oncogenes can actively determine tumor-inducing capacity by affecting neoplastic cell susceptibility to destruction by the host cellular immune response. The adenovirus type 5 E1A oncogene. which induces susceptibility to lysis by natural killer cells and encodes epitopes recognized by cytotoxic T lymphocytes. was transfected into highly tumorigenic sarcoma cells. E1A expression in these sarcoma cells eliminated their tumorigenicity in recipients with natural killer cell activity that was competent to lyse these E1A-positive targets. Thymus-dependent responses were not required for tumor rejection. These results indicate that oncogene-regulated cellular pathways that affect neoplastic cell susceptibility to natural killer cell lytic mechanisms may influence tumor development in the immunocompetent host.
v-abl causes hematopoietic disease distinct from that caused by bcr-abl, v-abl. the oncogene transduced by Abelson murine leukemia virus. was first characterized by its ability to transform lymphoid cells. bcr-abl. the oncogene formed by a t(9;22) translocation thought to occur in human hematopoietic stem cells. is detectable in almost all cases of chronic myelogenous leukemia (CML). a malignancy of granulocytic cells. bcr-abl also causes a CML-like syndrome in mice whose bone-marrow cells are infected with a retrovirus transducing the gene. More recent reports have suggested that v-abl can. however. cause a disease similar to CML. We demonstrate here that v-abl. when transduced in a helper virus-containing system. causes disease similar to. but distinct from. the CML-like syndrome induced by bcr-abl. Animals whose bone marrow has been infected by v-abl virus develop modest splenomegaly. marked granulocytosis. and malignant disease of several hematopoietic cell types. Unlike animals with CML-like disease resulting from bcr-abl. the polymorphonuclear leukocytes from animals infected with a v-abl construct do not contain the v-abl provirus at a significant frequency. Histopathologic analysis also shows significant differences between the diseases caused by v-abl and bcr-abl.
Inhibition of promoter activity by methylation: possible involvement of protein mediators, To study the relationship between DNA methylation and promoter activity we have methylated in vitro the promoters of the mouse metallothionein I gene and the herpes simplex virus thymidine kinase gene. We have transiently transfected these promoters fused to the human growth hormone in their methylated or unmethylated state into mouse L or F9 cells. Promoters methylated by methylase (M.) Hpa II and M.Hha I caused inhibition of reporter gene expression in L cells but not in F9 cells. while methylation of all CpGs by M.Sss I caused inhibition in both cell lines. Repression of promoter activity by M.Hpa II and M.Hha I methylation. but not by M.Sss I methylation. could be alleviated by cotransfection with an excess of untranscribable DNA methylated with M.Sss I. The methylated sites in nuclei isolated from the transfected L cells. but not F9 cells. were found to be protected from Msp I digestion. Taken together these results suggest that a factor present in L cells and missing in F9 cells mediates the methylation-directed inhibition of promoter activity. The ability of methylated DNA to overcome the inhibition seems to reflect competition for the mediator factor. Interestingly. treatment with Zn2+ ions brought about activation of the methylated promoter of the metallothionein gene. Similarly. butyrate could override the repression of the thymidine kinase methylated promoter. These activations were not accompanied by demethylation of the promoter or displacement of the mediator factor.
Calcium ion as a cofactor in Na channel gating, Calcium ions in the external medium stabilize the resting state of voltage-dependent channels. including Na channels. This effect of calcium on channel gating is usually explained in terms of the surface charge hypothesis. which proposes that local adsorption of calcium ion to the outside of the membrane alters the intramembranous electric field. thus influencing channel behavior indirectly. Calcium ion has also been shown to block Na channels. most strongly at negative voltage. We have examined these two apparently separate effects of calcium. the gating effect and Ca block. and find the two are closely correlated. We propose that calcium (or a suitable substitute) is an essential cofactor in normal gating and that it produces gating and blocking effects by binding within the channel.
Platelet-derived growth factor (PDGF) and PDGF receptor are induced in mesangial proliferative nephritis in the rat, We investigated whether platelet-derived growth factor (PDGF). or its receptor (PDGF-R). was upregulated in a rat model of mesangial proliferative glomerulonephritis. A marked increase in both PDGF A- and B-chain mRNA could be demonstrated in glomerular RNA by Northern blot analysis 3 and 5 days after disease induction. corresponding to the time of mesangial cell proliferation. PDGF-R beta-subunit mRNA and protein were also increased in glomeruli in mesangial proliferative nephritis. being maximal at day 5. The principal cells expressing PDGF B-chain appeared by immunostaining to be a subpopulation of mesangial cells; in contrast. the majority of the mesangial cells expressed the PDGF-R beta-subunit protein. Both complement depletion and platelet depletion significantly reduced cell proliferation and expression of both PDGF and PDGF-R. Thus. in mesangial proliferative nephritis there is a platelet- and complement-mediated induction of PDGF A and B chain and PDGF-R beta-subunit gene transcription and protein synthesis. The finding that the majority of PDGF is produced by the mesangial cell supports the role of PDGF as an autocrine growth factor in glomerulonephritis.
Expression of the cystic fibrosis transmembrane conductance regulator gene in the respiratory tract of normal individuals and individuals with cystic fibrosis, The most common mutation of the cystic fibrosis transmembrane conductance regulator gene. CFTR. associated with the clinical disorder cystic fibrosis (CF) is called "delta Phe508." a triple-base deletion resulting in loss of phenylalanine at residue 508 of the predicted 1480-amino acid CFTR protein. In the context that the lung is the major site of morbidity and mortality in CF. we evaluated airway epithelial cells for CFTR mRNA transcripts in normal individuals. normal-delta Phe508 heterozygotes. and delta Phe508 homozygotes to determine if the normal and delta Phe508 CFTR alleles are expressed in the respiratory epithelium. to what extent they are expressed. and whether there are relative differences in the expression of the normal and abnormal alleles at the mRNA level. Respiratory tract epithelial cells recovered by fiberoptic bronchoscopy with a cytology brush demonstrated CFTR mRNA transcripts with sequences appropriately reflecting the normal and delta Phe508 CFTR alleles of the various study groups. CFTR gene expression quantified by limited polymerase chain reaction amplification showed that in normal individuals. CFTR mRNA transcripts are expressed in nasal. tracheal. and bronchial epithelial cells at approximately 1-2 copies per cell. more than 100-fold greater than in pharyngeal epithelium. Importantly. allele-specific hybridization studies demonstrated that the normal and delta Phe508 CFTR alleles are expressed in the respiratory epithelium in similar amounts.
Correlation between retinoblastoma gene expression and differentiation in human testicular tumors, Inactivation of the retinoblastoma gene (RB gene) is associated with the development of several human malignancies including retinoblastomas. some osteo- and soft tissue sarcomas. small cell lung cancer. and possibly breast and bladder cancers. To our knowledge. this gene has not been evaluated in human germ-cell malignancies. In this study 67 primary testicular germ-cell tumors and 4 testicular non-germ-cell malignancies were examined to determine the prevalence and nature of RB gene alterations. Decreased expression of RB gene mRNA was found in all testicular germ-cell tumors (both seminomas and nonseminomas) examined. The RB protein could not be detected by immunohistochemical analysis in the undifferentiated cells of any germ-cell tumors whereas the differentiated malignant cells present in 14/15 teratocarcinomas expressed the protein. No gross alterations of the RB gene were found at DNA level in any of the examined specimens. This and the presence of the RB protein in the more differentiated tumor cells of teratocarcinomas suggest that changes in transcript levels rather than mutation(s) of the gene may be responsible for the absent or decreased RB expression in human germ-cell tumors. To date studies on the mechanism of RB regulation have demonstrated that it occurs at the protein level by phosphorylation of the p105 gene product. The findings presented here indicate that additional regulation might occur at the transcript level.
Loss of the endothelin signal pathway in C6 rat glioma cells persistently infected with measles virus, Endothelin 1 causes a strong Ca2+ signal in C6 rat glioma cells as measured by fura-2 fluorescence. This endothelin 1-induced Ca2+ signal was not observed when the cells were persistently infected with a measles virus strain of subacute sclerosing panencephalitis (SSPE. strain Lec). Binding of 125I-labeled endothelin 1 to the C6/SSPE cells was less than 5% of the binding to the C6 control cells. suggesting that the impairment in signal transduction was due to a loss of binding sites for endothelin 1. Treatment of the C6/SSPE cells with measles antiserum resulted in the loss of expression of viral proteins located in the membrane as well as inside the cells (antigenic modulation). but it restored neither the endothelin 1-induced Ca2+ rise nor the 125I-endothelin 1 binding. Cocultivation of uninfected C6 cells with C6/SSPE cells (9:1 ratio) resulting in contact-mediated transmission of measles virus showed that the 125I-endothelin 1 binding activity was gradually lost as a consequence of persistent virus infection.
The C-terminal half of UvrC protein is sufficient to reconstitute (A)BC excinuclease, The UvrC protein is one of three subunits of the Escherichia coli repair enzyme (A)BC excinuclease. This subunit is thought to have at least one of the active sites for nucleophilic attack on the phosphodiester bonds of damaged DNA. To localize the active site. mutant UvrC proteins were constructed by linker-scanning and deletion mutagenesis. In vivo studies revealed that the C-terminal 314 amino acids of the 610-amino acid UvrC protein were sufficient to confer UV resistance to cells lacking the uvrC gene. The portion of the uvrC gene encoding the C-terminal half of the protein was fused to the 3' end of the E. coli malE gene (which encodes maltose binding protein). and the fusion protein MBP-C314C was purified and characterized. The fusion protein. in combination with UvrA and UvrB subunits. reconstituted the excinuclease activity that incised the eighth phosphodiester bond 5' and the fourth phosphodiester bond 3' to a psoralen-thymine adduct. These results suggest that the C-terminal 314 amino acids of UvrC constitute a functional domain capable of interacting with the UvrB-damaged DNA complex and of inducing the two phosphodiester bond incisions characteristic of (A)BC excinuclease.
Clonality in myeloproliferative disorders: analysis by means of the polymerase chain reaction, The myeloproliferative syndromes are acquired disorders of hematopoiesis that provide insights into the transition from somatic cell mutation to neoplasia. The clonal origin of specific blood cells can be assessed in patients with X chromosome-linked polymorphisms. taking advantage of random inactivation of the X chromosome. We have adapted the PCR for determination of clonality on as few as 100 cells. including individual colonies grown in culture. Amplifying a polymorphic portion of the X chromosome-linked phosphoglycerate kinase (PGK) gene after selective digestion of the active X chromosome with a methylation-sensitive restriction enzyme gave results fully concordant with standard Southern blotting of DNA samples from normal (polyclonal) polymorphonuclear cells (PMN) as well as clonal PMN from patients with myelodysplastic syndrome and polycythemia vera (PCV). We have used this technique to demonstrate heterogeneity of lineage involvement in patients with PCV. The same clinical phenotype may arise from clonal proliferation of different hematopoietic progenitors.
Pertussis in developing countries: definition of the problem and prospects for control, Pertussis is a distinct clinical syndrome caused by Bordetella pertussis. The disease has been well characterized and largely controlled in the industrialized countries. Studies of pertussis in developing countries have been much more limited. in large part because of difficulty in culturing the organisms. Conventional whole-cell vaccine is being widely used in developing countries but without clear epidemiologic measures of efficacy. The introduction of new acellular pertussis vaccines has focused attention on the need to define the impact of pertussis in the developing world and to explore the optimal approach to control of this illness.
Pneumococcal vaccine trials in Papua New Guinea: relationships between epidemiology of pneumococcal infection and efficacy of vaccine, Field trials in Papua New Guinea have shown that pneumococcal capsular polysaccharide vaccine protects children less than 2 years of age from death due to acute lower respiratory infections (ALRI). The vaccine appears to reduce mortality by preventing bacteremia. Evidence suggests that highly invasive "adult" pneumococcal serotypes are comparatively more important as a cause of ALRI in developing countries where ALRI-related mortality is higher than in North America. Capsular polysaccharide vaccines are more likely to be immunogenic for these serotypes than for the "pediatric" serotypes. The evaluation of pneumococcal vaccines in areas where mortality is high should have the highest priority. For such trials investigators should. at minimum. define epidemiologic circumstances in terms of (1) the invasive serotypes of pneumococci. (2) the protective levels of antibody. (3) the antibody response to vaccination. and (4) the general immune status of the population.
Pathogenesis and prevention of childhood pneumonia in developing countries: recommendations, Recommendations are presented that emerged from the Conference on the Pathogenesis and Prevention of Pneumonia in Children in Developing Regions held 21-23 August 1989 in Bellagio. Italy. The conference recommendations embrace three major areas: first. the biology. epidemiology. and clinical manifestation of important etiologic agents causing acute lower respiratory infection (ALRI); second. the evaluation of risk factors affecting ALRI in the developing world necessary for planning intervention strategies in diverse ecologic settings; and third. the generation of targeted research questions that will translate into available safe and effective vaccines capable of controlling ALRI-related morbidity and mortality.
Change of disc height, radial disc bulge, and intradiscal pressure from discectomy. An in vitro investigation on human lumbar discs, Partial discectomy was done in vitro on 15 human lumbar discs from donors 20-40 years of age. The change of disc height. radial disc bulge. and intradiscal pressure was measured in relation to the mass of central disc tissue excised. Disc height decreases and radial disc bulge increases approximately in proportion with the mass of the tissue excised. At the same time. intradiscal pressure decreases. On average. removal of 1 g of disc tissue results in a height decrease of 0.8 mm and a radial bulge increase of 0.2 mm. Removal of 3 g of central disc tissue lowers the intradiscal pressure to approximately 40% of its initial value. A mechanical model is presented which explains the observed relation between the volume of material removed and the subsequent change of height. bulge. and pressure. The experimental results and the model provide insight into the rationale of disc pressurization. A high intradiscal pressure is a prerequisite for the mechanical function of the disc under physiologic conditions.
An analysis of normal back shape measured by ISIS scanning, Two hundred seventy-one school children aged 10-16 years and 72 normal adults aged 21-59 years were scanned by ISIS. Subjects with any evidence of scoliosis were excluded from the study. Characteristic ISIS parameters of back shape showed no statistically significant differences related to age or sex for the children. Back shape in both men and women was not significantly different from that of the children. except for kyphosis angles which were greater.
Clinical tests applicable to the study of chronic low-back disability, This symposium has evaluated the possible directions to be taken in designing reliable and valid questionnaires. screening examinations. and paraclinical tests applicable to studies in LBP. The detailed design of such test instruments. field testing. measures of reliability. and validity represent the next step if the current barriers to collaborative clinical research in LBP are to be overcome.
Normal cervical spine morphometry and cervical spinal stenosis in asymptomatic professional football players. Plain film radiography, multiplanar computed tomography, and magnetic resonance imaging, Diagnosis of cervical spinal stenosis or instability rests on the objective findings depicted on static and dynamic radiographs. Before abnormal spinal morphometry can be determined. it is first necessary to establish normal values for the specific patient population being evaluated. Several studies have attempted to establish norms for plain film measurements of the cervical spine in children and adults. but few have applied consistent methods for generating precise measurements. The first part of this study established normal values for cervical spinal morphometry and segmental spinal motion in the elite athlete. The second part of this study determined the most accurate screening method for detecting cervical spinal stenosis. Three sagittal diameters of the cervical spinal canal were compared to determine which represented the smallest midline diameter on static and dynamic radiographs. The Torg ratio was also evaluated as a method to detect significant cervical spinal stenosis and was shown to have a high sensitivity but poor positive predictive value. The study clarified why the ratio yields a large number of false positive cases. From the results of this study. an algorithm has been developed for the evaluation of stenosis of the cervical spine in athletes.
The effect of spinal implant rigidity on vertebral bone density. A canine model, An animal model of anterior and posterior column instability was developed to allow in vivo observation of bone remodeling and arthrodesis following spinal instrumentation. After an initial anterior and posterior destabilizing lesion was created at the L5-L6 vertebral levels in 63 adult beagles. various spinal reconstructive surgical procedures were performed--with or without bilateral posterolateral bone grafting. with or without bilateral oophorectomies. and with or without spinal instrumentation (Harrington distraction. Luque rectangular. Cotrel-Dubousset pedicular. or Steffee pedicular implants). Observation 6 months after surgery revealed a significantly improved probability of achieving a spinal fusion if spinal instrumentation had been used (X2 = 5.84. P = .016). Nondestructive mechanical testing after removal of all metal instrumentation in torsion. axial compression. and flexion revealed that the fusions performed in conjunction with spinal instrumentation were more rigid (P less than .05). Quantitative histomorphometry showed that the volumetric density of bone was significantly lower (ie. device-related osteoporosis occurred) for fused versus unfused spines. In addition. a linear correlation occurred between decreasing volumetric density of bone and increasing rigidity of the spinal implant (r = .778); ie. device-related osteoporosis occurred secondary to Harrington. Cotrel-Dubousset. and Steffee pedicular instrumentation. Oophorectomized dogs became more osteoporotic than their surgically matched controls (posterolateral bone grafting alone. Cotrel-Dubousset pedicular instrumentation. and Steffee pedicular instrumentation); device-related osteoporosis added to the degree of hormonally induced osteoporosis (t = 5.0. P less than .0001). This is the first study to date documenting the occurrence of stress shielding in the spine secondary to spinal instrumentation.
Patients avoiding surgery. Pathology and one-year life status follow-up, Patients were selected for a research study to determine the outcome of patients who had demonstrated enough pathology to have been viewed as surgical candidates and had chosen to avoid surgery. The purpose of the study was to identify the diagnostic categories and to obtain follow-up data on these patients. The patient population consisted of 66 patients with the following pathologies: disc disruption (one and two levels). disc disruption (three levels). stenosis. spondylolisthesis. instability. and herniated nucleus pulposus. The patients were followed for a period of 1 1/2 years and rated on the following lifestyle status categories: Returned to Work. Retired. Retraining. Able to Increase Activity Level. or No Change from Initial Status. Of the nonoperative patients. 18% returned to work. Twelve patients (18%) were retired. Eleven patients (16%) were placed in retraining programs. Twenty patients (29%) were able to increase activity level. Eleven patients (16%) fell under the category of no change.
Clinical correlation between degenerative spine disease and dermatomal somatosensory-evoked potentials in humans, The relationship between clinical status and preoperative and intraoperative dermatomal somatosensory-evoked potentials was investigated as a function of test site. Results indicated that the specificity and sensitivity of dermatomal somatosensory-evoked potentials varied with level of involvement: L5 demonstrated greatest agreement with equal correlation at L3. L4. and S1. Variables that influenced correlation included history of previous surgeries. type of anesthetic used. interpretation criteria. and whether the patient was awake or asleep. It was concluded that dermatomal somatosensory-evoked potentials can provide the surgeon with diagnostic and intraoperative information regarding the functional integrity of single nerve root function.
Differentiation between somatic and cognitive/affective components in commonly used measurements of depression in patients with chronic low-back pain. Let's not mix apples and oranges, Patients with chronic low-back pain are frequently diagnosed as depressed. However. many of the neurovegetative signs of depression may also result from pain. The purpose of the present study was 1) to investigate the relationship between commonly used measurements of depression and pain perception; and 2) to examine the utility of differentiating between somatic signs and cognitive/affective symptoms of depression in patients with chronic low-back pain. The Beck Depression Inventory and the Hamilton Psychiatric Rating Scale for Depression were divided into cognitive/affective and somatic subscales. These measures. as well as the Minnesota Multiphasic Personality Inventory. were administered to 111 patients with chronic low-back pain. Analyses revealed significant correlations between depression scores and self-reported pain intensity. The cognitive/affective subscale of the Beck Depression Inventory resulted in the only nonsignificant correlation with pain intensity. These findings suggest that commonly used measurements of depression are confounded with pain symptomatology and that the cognitive/affective category of the Beck Depression Inventory may prove to be a more accurate measurement of depression in patients with chronic low-back pain.
Awake discography. A comparison study with magnetic resonance imaging, This study was undertaken to determine the correlation between awake discography findings and magnetic resonance imaging in the evaluation of symptomatic lumbar disc disease. The study included 164 consecutive patients who underwent evaluation with discography and magnetic resonance imaging for lumbar disc disease from August 1987 to September 1989. Chronic low-back pain. with or without radicular symptoms. was the presenting complaint in each case. Each patient had previously failed conservative treatment. The average age was 36 (range. 19-66 years). Magnetic resonance images were performed before discography in each case. Discography was performed with patients minimally sedated and under local anesthesia. A lateral approach was used. Magnetic resonance imaging and discography correlated in 90 cases (55%) and differed in 74 (45%). Considering disc levels. discography and magnetic resonance imaging correlated in 371 discs (80%). There were 172 normal discs and 199 abnormal discs. Of the abnormal discs. 151 (76%) reproduced symptoms. In 60 discs (13%). magnetic resonance images showed abnormal findings and the discogram normal findings. Discs levels classified as abnormal on magnetic resonance imaging demonstrated that 108 discs (37%) were asymptomatic. Magnetic resonance imaging showed normal findings and the discogram abnormal findings in 34 discs (7%). of which 21 (5%) recreated exact symptoms and 13 (2%) caused no pain. Magnetic resonance imaging is a static test and discography the only available dynamic test for disc evaluation. Awake discography is a diagnostic study that can determine which abnormal discs are symptomatic via the pain response.
Rotation of load during the prelift period, Lifting is a major source of back injuries because of the mechanical effects on the spinal structures. A number of methods are known by which a lifter can reduce the load on the spine during lifting. This study explores an additional method: rotation of the load before it is actually lifted off the ground. The hypothesis tested is that when a lifter lifts a box. he or she rotates it before it leaves the floor. By the use of an optoelectronic system to study weight box rotation. it was established that rotation occurs in every lift before the actual lift occurs. Rotation time increased with increasing load. indicating that the rotation technique is more important when load reduction is most critical.
Correlation of radiologic assessment of lumbar spine fusions with surgical exploration, Although inspection of posterolateral lumbar fusion is the best method of determining its solidity. routine exploration of the fusion is somewhat impractical because of the morbidity and expense involved. Removal of internal fixation devices or implantable batteries or reoperation for failed back surgery enabled the exploration and assessment of lumbar spine fusions in 214 operations on 175 patients. The preoperative radiologic assessment (plain roentgenographs. polytomography. bending films. and computed tomographic scans) were correlated with surgical findings. This study indicated a significant percentage of inaccuracy of all radiologic modalities used. Noncorrelations were present in 36% of plain roentgenographs. 41% of polytomograms. 38% of bending films. and 43% of computed tomographic scans. Radiologic inaccuracy was manifest on both the positive and negative sides. Computed tomographic scanning presented the lowest percentage of inaccuracy (22%) and bending films the highest percentage (27%). Based on these findings. there exists the need for more accurate noninvasive methods to determine the solidity of spine fusions.
Translaminar facet joint screw fixation for lumbar and lumbosacral fusion. A clinical and biomechanical study, Various systems of supplementing bone grafts with internal fixation in the lumbosacral spine have been used in an effort to improve fusion rates. This study reports biomechanical data of cyclic loading cadaveric spines instrumented with translaminar facet screws as well as early clinical results on this technique. Static loading tests comparing uninstrumented and instrumented spinal motion units show that a ninefold increase in flexion load is necessary for constant displacement after facet screw fixation. Repetitive loading tests show only a small decrease in stiffness of instrumented segments even after 5.000 cycles. To date. 35 patients have undergone fusion by this technique as performed by one surgeon. After excluding Workers' Compensation cases and cases with less than 2 years follow-up. there were 18 cases available for review. Twelve of these 18 cases were two-level fusions. Ten patients underwent concomitant discectomy or nerve root decompression. There were no cases of iatrogenic neurologic injury or pseudoarthrosis. It is concluded that translaminar facet screws have a sound biomechanical basis and are a valuable addition to lumbar fusion procedures.
A carbon fiber implant to aid interbody lumbar fusion. Mechanical testing, A carbon-fiber-reinforced polymer implant has been designed to aid interbody lumbar fusion. The cage-like implant has ridges or teeth to resist pullout or retropulsion. struts to support weight bearing. and a hollow center for packing of autologous bone graft. Because carbon is radiolucent. bony healing can be imaged by standard radiographic techniques. The device has been mechanically tested in cadaver spines and compared with posterior lumbar interbody fusion performed with donor bone. The carbon device required a pullout force of 353 N compared with 126 N for donor bone. In compression testing. posterior lumbar interbody fusion performed with the carbon device bore a load of 5.288 N before failure of the vertebral bone. Posterior lumbar interbody fusion performed with donor bone failed at 4.628 N. and unmodified motion segments failed at 6.043 N. The carbon fiber implant separates the mechanical and biologic functions of posterior lumbar interbody fusion.
Surgical anatomy of the sacrum. A guide for rational screw fixation, Anterior sacral anatomy was studied to allow safe sacral screw placement. The study included 27 bony sacra. Intrapelvic dissections were performed. Cadaveric specimens were dissected and photographed. The position and angulation of the first sacral foramen was extremely variable. After the position of the L5 root. sacral roots. and iliac vessels. was considered. safe posterior sacral screw implantation could be assured through placement above the level of the first sacral foramen directed medially toward the promontory. parallel to the superior sacral end-plate. Complications of indiscriminate screw placement included L5-root damage. iliac vein penetration. and intractable perineal pain due to sacral root injury. Preoperative computed tomography with the scanner gantry tilted to parallel the superior sacral end-plate defined the great vessels. neural foramens. inclination of the superior sacral end-plate. and prominence of the posterior ileum. Surgical accuracy was evaluated after surgery with computed tomography.
Anatomic consideration for sacral screw placement, Instrumentation of the lumbosacral spine increasingly involves screw fixation to the sacrum. Recommended locations and techniques for screw placement vary. particularly when bicortical purchase of the sacrum is performed. The purpose of this study was to describe the critical anatomy and potential injuries to neurovascular and visceral structures anterior to the sacrum. Lack of awareness can lead to life-threatening complications. The study included 22 fresh human cadavers with no prior spinal surgery. Specimens were placed in a prone position. and the lumbosacral spine was exposed. Two 6.5-mm screws were inserted using one of two techniques. respectively: Starting just inferior to the S1 facet one screw was angled 25 degrees caudally and 30 degrees laterally; in the second technique. lateral inclination was increased to 45 degrees. In addition. all specimens had screws placed in the S2 pedicles. An anterior dissection was performed to allow evaluation of the neurovascular and visceral structures at risk for injury by. or adjacent to. the screw tips. All significant neurovascular structures in the area of concern were constant in position. The internal iliac vein and the lumbosacral nerve trunk were most at risk for injury by the 30 and 45 degrees laterally directed screws. The sigmoid colon. though close to the S2 screw. was protected by its mesentery. Screws placed in the S1 pedicle were least likely to injure the neurovascular bundle. A lateral and a midline safe zone were identified.
Unilateral lumbar fusion, Unilateral fusion of the lumbar spine is rarely necessary or indicated. However. in patients with a "far-out syndrome" requiring decompression or in cases where unilateral posterior element resection is necessary for any reason. it may be both necessary and indicated. This unilateral destabilization effectively removes one leg of the tripod. rendering that intervertebral joint potentially unstable. The charts and radiographs of 13 patients (seven men. six women) with an average age of 60 years (range. 25 to 76) who underwent unilateral fusion were retrospectively reviewed. Follow-up time ranged from 12 1/2 to 2 years with a median follow-up of 8 years. Eleven of the fusions were at one level. and two were at two levels. Seven patients had a far-out syndrome secondary to degenerative scoliosis; four were secondary to spondylolisthesis. Two patients had an osteoid osteoma involving a pedicle. A paraspinal approach was used in the majority of patients. Autologous bone graft was used in all patients. Unilateral pedicle screw fixation was used in the last patient in the series. The fusion rate was 85% (11/13). Three patients were smokers. two of whom developed pseudarthrosis. Disc space height did not appear to affect fusion rate. There was no progression of slip noted in any of the patients. One complication was noted in this group: a moderate postoperative infection. which cleared spontaneously.
Two-point fixation of the lumbar spine. Differential stability in rotation, Single vertebral motion segments were tested in torsion. The adjacent vertebrae were transfixed by two 3-mm Steinman pins placed vertically. These were applied in five different positions: between the anterior vertebral bodies. posterior vertebral bodies. pedicles. transverse processes. and lamina. Rotational displacement was limited the most by transfixation between the vertebral bodies (position one or two). Disrupting the anulus fibrosus significantly increased rotation in all positions except those in the vertebral body. These findings may imply that spinal fixation devices that engage the vertebral bodies may offer inherent advantages over purely posterior devices in stabilizing a vertebral motion segment. In addition. an interbody arthrodesis may prevent intervertebral motion better than a posterior or posterolateral fusion.
The transient appearance of small blastoid cells in the marrow after bone marrow transplantation, Of 14 patients who underwent allogeneic or syngeneic bone marrow transplantation. 6 had a transient appearance of small blastoid cells in the bone marrow after transplantation. Most of these patients (11) had leukemia. although 3 had severe aplastic anemia. The cells were 8-18 micron in diameter and had scant cytoplasm and dense nuclei with smooth. homogeneous chromatin. They often had distinct nuclear clefts. These cells constituted 4.0-21.3% of the total number of bone marrow cells. They were not reactive with peroxidase. alpha-naphtyl butylate esterase. naphthol AS-D chloroacetate esterase. or periodic acid-Schiff stains. Immunocytochemical analysis revealed that the small blastoid cells expressed terminal deoxynucleotidyl transferase. Ia-like. CD19. and CD10 antigens and cytoplasmic mu heavy chains. indicating a precursor B-cell phenotype. CD20 antigen was not expressed on these cells. The data suggest that cytoplasmic mu may be expressed earlier than CD20 antigen in the differentiation of B-cell lineage. The morphologic. cytochemical. and immunophenotypic characteristics did not distinguish these nonneoplastic cells distinctly from leukemic lymphoblastic cells. The increase of small blastoid cells was a transient and self-limited phenomenon. in contrast to that of neoplastic blasts. These cells should be recognized as a common component of the bone marrow of marrow transplant recipients. The significance and role of these cells in immune recovery and hematopoiesis remain uncertain.
Congenital atransferrinemia. A case report and review of the literature, A four-year-old Polynesian girl with a two-year history of severe microcytic. hypochromic anemia (which was refractory to iron therapy) had a decreased beta-globulin fraction on serum protein electrophoresis. resulting from the absence of the transferrin (TRF) band. Subsequent assays for TRF showed a level below the detectable range. Liver biopsy revealed significant deposition of hemosiderin within hepatocytes and Kupffer cells. in addition to early fibrosis. Two bone marrow aspirates were hypercellular. with decreased myeloid-erythroid ratios. This case represents the eighth reported example of congenital atransferrinemia. a rare. apparently autosomal recessive disease.
Poorly differentiated adenocarcinoma with lymphoid stroma (lymphoepithelioma-like carcinomas) of the stomach. Report of three cases with Epstein-Barr virus genome demonstrated by the polymerase chain reaction, Lymphoepithelioma of the nasopharynx is an undifferentiated carcinoma with prominent lymphoid infiltration. Histologically similar tumors have been documented in the skin. lung. thymus. salivary gland. tonsil. and uterine cervix. The authors report three cases of gastric carcinoma that were histologically and immunohistochemically similar to lymphoepithelioma. The patients were elderly white persons (61. 76. and 77 years of age); two of them had previous partial gastric resections for benign ulcer disease. The tumors were located on the lesser gastric curvature (two cases) and at a previous anastomotic site (one case) and measured 3. 4. and 7 cm in largest dimension. Grossly. each neoplasm was a raised plaque-like lesion with a central ulcer. Microscopically. all three tumors were similar. with poorly differentiated polygonal tumor cells scattered throughout a dense lymphocytic background. In a few areas. tumor cells formed ill-defined cords. In two cases. the neoplasms invaded the gastric muscle layer but had a well-delineated (pushing) margin. The tumor cells were immunohistochemically positive for AE3-defined keratin. confirming their epithelial nature. The lymphocytes were a mixture of UCHL-1-positive T cells and L-26-positive B cells. Portions of the Epstein-Barr virus genome were present in all cases. as detected by the polymerase chain reaction. The morphologic features of these cases are similar to those of lymphoepithelioma in other anatomic sites. and these tumors represent a unique subtype of gastric carcinoma.
Expression of haptoglobin-related protein in primary and metastatic breast cancers. A longitudinal study of 48 fatal tumors, The ability to establish a prognosis for patients with early breast cancer is an important clinical issue. Recent studies have shown that antibodies to haptoglobin-related protein (Hpr) may be useful in stratifying early patients with breast cancer according to their relative risks of recurrence. Nearly 30% of early breast cancers express proteins bearing Hpr epitopes. Hpr-positive breast cancers are more likely to recur after primary resection and are associated with shorter disease-free intervals. This immunohistochemical study examines temporal changes in Hpr expression during the course of disease in 48 patients with fatal breast carcinoma. Thirty-seven primary tumors (77%) were Hpr positive. Ten of the 11 initially negative tumors (91%) were Hpr positive at the time of recurrence. In contrast. only 10 of the 37 initially positive tumors (27%) were Hpr negative with relapse. Of 18 axillary nodes that were examined. 16 (89%) were Hpr positive; all four lymph nodal metastases in patients with initially negative primary tumors were Hpr positive. The authors conclude that the acquisition of Hpr expression parallels increased malignant potential and that Hpr expression. once acquired. tends to remain a permanent characteristic of any given mammary tumor.
Cell-surface ganglioside GD2 in the immunohistochemical detection and differential diagnosis of neuroblastoma, The expression of the disialoganglioside GD2 was analyzed in 67 solid tumors and normal tissues from children by using the GD2-specific murine monoclonal antibody 3A7 and the indirect immunoperoxidase method. GD2 was expressed in all of 28 neuroblastomas and was most abundant in stroma-poor tumors. In differentiating stroma-rich neuroblastomas. neuroblastic clusters. neurofibrils. and most ganglion-like cells were positive. whereas Schwann's-cell stroma did not express GD2. In ganglioneuromas. only a few ganglion-like cells showed GD2. whereas all other structures were negative. Scattered foci of ganglioside GD2 also were found in some non-neuronal tumors. such as rhabdomyosarcomas and osteosarcomas. but not in lymphomas. Askin tumors. or most Wilms' tumors. The monoclonal antibody 3A7 is a useful aid in the immunohistochemical diagnosis of neuroblastoma. In addition. the intense cell surface staining of neuroblastoma cells by this reagent makes it potentially useful for detecting residual neuroblastoma in bone marrow samples and lymph node biopsies.
An autopsy case of I-cell disease. Ultrastructural and biochemical analyses, An autopsy case of I-cell disease in a 4-year-old Japanese girl is presented. In this report. the authors analyze the relationship between morphologic (including electron microscopic) and biochemical findings. Lymph node. spleen. and kidney. which were stained with Hale's colloidal iron method. contained large amounts of hexosamine. These substances had accumulated in lymphocytes of B-cell lineage.
Detection of clinically suspected deep vein thrombosis using light reflection rheography, Venography is the current standard for the diagnosis of deep vein thrombosis (DVT). Noninvasive tests have differing sensitivity and specificity. are technically demanding. and may be subject to variability in interpretation. Light reflection rheography (LRR) is a noninvasive method utilizing light-emitting diodes and a sensor to measure light reflected from the skin surface. The intensity of reflected light establishes a graphic pattern that indirectly quantifies parameters of venous function by measuring changes in the microcirculation. Seventy-two patients who underwent contrast venography at our institution were also evaluated with LRR. Twenty-four patients were found to have DVT as demonstrated by venography. Of these. 23 also had DVT detected by LRR. No evidence of thrombus was seen in 45 patients studied by venography; in this group. 35 had normal venous emptying indicated by LRR. Using LRR. a sensitivity of 96% was achieved in the evaluation of clinically suspected DVT. This sensitivity is comparable with other noninvasive tests. In addition. LRR is easy to operate. portable. inexpensive. and not technically demanding. Further investigation is needed to confirm these data and further define the role of LRR in the evaluation of clinically suspected DVT.
Use of light reflection rheography for diagnosis of axillary or subclavian venous thrombosis, Noninvasive diagnosis of axillary and subclavian venous thrombosis or documentation of the post-thrombotic syndrome using modalities currently in use is not definitive. Light reflection rheography. which is a reflection of venous pressure changes in the extremity as recorded from the subdermal capillary plexus. was used to correctly diagnose axillary or subclavian venous thrombosis in 11 patients. A positive study was confirmed by phlebography in each instance. There were no instances of false-positive results. The methodology is simple. involving testing of the venous outflow from the upper extremity in response to exercise. application of venous congesting pressure. and measurement of the rate of venous outflow when the congesting pressure is released. Normal respiratory variations of an open venous system are also assessed by this noninvasive modality. The tracing obtained is easy to interpret and provides objective evidence of proximal venous occlusion. The test is not operator-dependent and the instrumentation is relatively inexpensive. We believe that light reflection rheography may be an exciting development in the noninvasive diagnosis of axillary or subclavian venous compromise and merits further trials.
Abnormal esophageal transit in patients with typical reflux symptoms but normal endoscopic and pH profiles, There is a small. well-known cohort of patients who. despite classic reflux symptoms. have a normal esophageal pH profile and endoscopic picture. The treatment of these patients has proved problematic. In an attempt at determining the pathophysiology of this subgroup. we investigated the esophageal transit. using the radiolabeled solid bolus esophageal egg transit technique. in 58 such patients: 25 males. 33 females. mean age 39.5 years (range: 13 to 65 years). The egg transit was normal in 31 (53.4%) patients. In the remaining 27 (46.6%) patients. the condensed image analysis showed the following specific abnormal transit patterns: "step" delay pattern. demonstrating segmental hold-up in mid- or distal esophagus in 16 (59.3%); nonspecific delay in 6 (22.2%); oscillatory pattern in 3 (11.1%); and total nonclearance during the study period (4 minutes) in 2 (7.4%) patients. The patients with abnormal transit patterns had demographic parameters and symptom scores similar to those found in patients with normal transit. This study shows that almost 50% of patients with reflux symptoms and negative pH and endoscopy have abnormal esophageal transit. and almost two thirds of these patients display segmental transit delay in the lower half of the esophagus. The effect on symptomatology by prokinetic agents in the patient subgroup needs evaluation.
A nine-year experience with crossover femoro-femoro-popliteal sequential bypass, Multisegmental arterial occlusive disease may require a combined inflow and outflow procedure for optimal treatment of limb ischemia. Twenty-one patients with unilateral iliac artery stenosis or occlusion and ipsilateral superficial femoral artery occlusion underwent crossover femoro-femoro-popliteal sequential bypass during a 9-year period. Seventeen operations were for limb salvage. Patency rates were determined separately for each segment of the bypass. Primary patency rates for the femoro-femoral segment were 89%. 83%. and 57% at 1. 2. and 5 years. respectively. Primary patency rates for the femoro-popliteal segments were 68%. 62%. and 40% at 1. 2. and 5 years. respectively. Limb salvage rates were 100%. 90%. and 77% at 1. 2. and 5 years. respectively. This experience indicates that femoro-femoro-popliteal bypass is an effective treatment in selected patients with severe ischemia due to combined iliac artery and superficial femoral artery disease.
Laparotomy closure reinforced with buried polyglyconate retention sutures, A method of laparotomy closure using continuous no. 0 polyglycolic acid suture for accurate fascial approximation and buried retention sutures of no. 1 polyglyconate for prolonged wound strength is described. Both security and anatomical precision in fascial closure are achieved without the use of nonabsorbable suture material. This method of laparotomy closure is suitable for patients at high risk for fascial dehiscence.
Outcome of complex vascular and orthopedic injuries of the lower extremity, Thirty-two patients undergoing limb salvage procedures for complex vascular and orthopedic injuries of the lower extremity were studied in order to identify prognostic indicators for delayed amputation in this select group. A high incidence of nerve (38%). soft tissue (66%). and remote injury (47%) was noted. A comprehensive and integrated approach to vascular. orthopedic. and plastic reconstruction was utilized. Of the 32 patients studied. 1 (3.1%) died as a result of remote injury and sepsis. Amputation was required in 9 patients (28%). while 13 (56%) of the patients with limb salvage showed persistent functional or neurologic deficits. Infection was the most significant factor associated with amputation (p less than 0.0005) and was not avoided by the perioperative use of antibiotics. Delayed amputation resulted in a significant extension of total hospitalization (p less than 0.005). The authors favor an aggressive approach to limb salvage with IIIC injury but recommend early amputation in the presence of significant nerve disruption. An attentive use of tissue debridement. intravenous antibiotics. and early wound coverage is needed to limit infection.
Clinical implications of combined hypogastric and profunda femoral artery occlusion, From 1983 to 1990. nine patients with combined hypogastric (HA) and profunda femoral arterial (PFA) occlusive disease presented with five nonhealing hip disarticulations. three nonhealing above-the-knee amputations. perineal necrosis in six patients. buttock necrosis in four patients. visceral ischemia in two patients. and lumbosacral spinal ischemia in one patient. Obviously some patients had more than one regional complication. Five patients died from complications of HA/PFA ischemia. Survivors included two patients who required a hemipelvectomy. one patient who required an axillary-to-hypogastric artery bypass graft for stump salvage. and one patient who survived despite lumbosacral paralysis and complete cystectomy. The 56% mortality and 100% morbidity emphasize the critical significance of combined hypogastric/profunda femoral artery circulatory compromise. Efforts should be made to preserve or re-establish the HA and/or PFA circulation whenever possible. A hemipelvectomy may be required to allow the wounds to finally heal. Furthermore. the certainty of an above-the-knee amputation healing is not present in these patients; therefore. a hemodynamic assessment of the healing potential of an above-the-knee amputation is required.
Unilateral aortofemoral bypass: a safe and effective option for the treatment of unilateral limb-threatening ischemia, To determine whether unilateral aortofemoral (AUF) bypass is a safe and effective option for the treatment of unilateral limb-threatening ischemia in patients with aortic or bilateral iliac occlusive disease. we reviewed the results of 42 AUF bypasses performed using polytetrafluoroethylene grafts in patients operated on for limb salvage; 11 (26%) of the patients also underwent femoropopliteal or femorodistal (FP/D) bypasses. The indications for surgery were tissue necrosis or ulceration in 18 (43%) patients and rest pain in 17 (40%) patients. The 5-year primary graft patency and limb salvage rates for AUF bypass were 74% and 84%. respectively. The perioperative mortality rate was 5%. There were no significant differences in the primary graft patency or limb salvage rates in patients who underwent AUF bypass with or without FP/D bypass. Only 3 of 41 (7%) AUF bypass patients required subsequent femorofemoral bypass. We conclude that: (1) AUF bypass is a safe and effective surgical option in patients with unilateral limb-threatening ischemia and aortic or bilateral iliac occlusive disease; (2) the routine performance of an aortobifemoral or axillobifemoral bypass in patients with unilateral limb-threatening ischemia may be unnecessary; and (3) AUF bypass facilitates the combined inflow and infrainguinal operations that are frequently required for limb salvage in these patients.
Utility of arteriography in penetrating extremity injuries, The role of contrast arteriography in the management of patients with penetrating injuries of the extremities is a subject of active debate. To examine our experience. the charts of patients with penetrating injuries of the extremities were retrospectively reviewed. Data from 82 consecutive patients with 98 wounds over the 5-year period from January 1984 to December 1988 were reviewed. Sixty-five arteriograms were obtained to investigate 98 wounds: 8 to localize a clinically apparent wound and 57 because of proximity of the wound or the trajectory of the injuring agent to a major neurovascular bundle. Of the 57 arteriograms obtained because of proximity. 11 identified a vascular injury (19%). Six of these wounds required vascular repair; five patients were treated expectantly. Six of the eight arteriograms obtained for clinical indications were positive (75%). while two were negative (25%). There were no amputations in the study. and all vascular reconstructions were considered successful by clinical and vascular laboratory criteria. One patient died of thoracic injuries; otherwise. all patients were discharged in good condition. Long-term follow-up was not available. In summary. 19% of arteriograms done because of proximity criteria alone identified a clinically occult vascular injury. While only 11% of all proximity arteriograms revealed injuries requiring surgical repair. this rate of significant injury warrants aggressive use of proximity arteriography in a patient population that is prone to poor follow-up.
Immunological disturbances in anaesthetic personnel chronically exposed to high occupational concentrations of nitrous oxide and halothane, Immunological changes in anaesthetic personnel exposed to occupational concentrations of holothane and nitrous oxide 10-60 times greater than the advised maximum were studied during routine work and after 3-4 weeks holiday. Red cell count. haemoglobin concentration and haematocrit decreased during exposure although not significantly. in comparison with a control group. but all had increased significantly after the holidays. Other changes were altered neutrophils and lymphocyte counts. Basophils disappeared from the blood during the exposure. Monocytes were not affected during the exposure. but increased after its cessation. Percentages of CD2 and CD4 lymphocytes increased significantly. but numbers of cells in T lymphocyte subpopulations (total. helper and cytotoxic/suppressor lymphocytes) were not significantly altered. B lymphocytes were most strongly affected: they decreased during working periods and did not recover after holidays. Natural killer (NK) cells. on the other hand. decreased significantly during exposure. but fully recovered during holidays. After stimulation with mitogens. phytohaemaglutin. concanavalin A. and pokeweed. lymphocytes from exposed personnel incorporated significantly more 3H-thymidine than those from control subjects. but stimulation indices did not differ. The natural killer-cell activity. serum Ig concentrations and phagocytosis by granulocytes were not altered.
Morphine compared with diamorphine. A comparison of dose requirements and side-effects after hip surgery, The dose requirements and side effects of morphine were compared with those of diamorphine administered by patient-controlled analgesia in 40 patients following elective total hip replacement. Patients were allocated randomly to receive in a double-blind manner either morphine or diamorphine for postoperative pain relief. There were no significant differences between the two groups with regard to postoperative sedation. nausea. well-being. pain relief and requirements for antiemetic drugs. The dose requirement for diamorphine was approximately 50% of that for morphine.
A double-blind study of the speed of onset of analgesia following intramuscular administration of ketorolac tromethamine in comparison to intramuscular morphine and placebo, A double-blind. randomised. parallel group. placebo-controlled study was performed in 85 patients to compare the speed of onset of analgesia following the intramuscular administration of a single dose of 30 mg of ketorolac tromethamine. 10 mg of morphine or placebo. A new. sensitive. method was used to measure the latency of analgesia. The onset of analgesia was defined by the time taken for the pain intensity score to reach a specified percentage of the baseline value. Twenty-five percent of patients achieving a 50% reduction in baseline pain intensity score appears to be the most appropriate parameter to assess the speed of onset of analgesia of ketorolac and morphine in the postoperative setting. Paired comparison demonstrated that ketorolac had a significantly faster onset of analgesia (p = 0.03) when compared to placebo. whilst comparison of morphine to placebo analgesic latency (p = 0.06) just failed to reach significance. There was no significant difference between the analgesic onset time of ketorolac and morphine (p = 0.73). Intramuscular ketorolac and intramuscular morphine have comparable analgesic onset times in the postoperative pain context. However. the sensitive method of measuring onset of analgesia described. highlights the slow onset of analgesia when analgesics of known efficacy are given by the intramuscular route in the postoperative period. More attention should be given to the speed of onset of analgesia in future assessments of analgesics.
Epidural analgesia in Eaton-Lambert myasthenic syndrome. Effects on respiratory function, The anaesthetic management of a patient with Eaton-Lambert myasthenic syndrome undergoing thoracotomy is described. Epidural anaesthesia. in combination with a light level of general anaesthesia. provided good operating conditions and postoperative analgesia. Pulmonary function and ventilatory responses to carbon dioxide and hypoxia were measured before operation. These tests were repeated after the epidural administration of 8 ml 2% lignocaine before surgery and after 2 mg morphine sulphate in 10 ml saline postoperatively. Minor reductions in some of the ventilatory parameters were observed. The epidural technique appears to be a useful and safe method by which to manage patients with Eaton-Lambert syndrome undergoing thoracotomy.
Physical training and antiplatelet treatment in stage II peripheral arterial occlusive disease: alone or combined, The efficacy of physical training alone or combined with antiplatelet therapy (dipyridamole and aspirin) was studied in 30 patients with stage II peripheral arterial occlusive disease (PAOD). Patients were randomly allocated to one of the following groups: Group A--dipyridamole 75 mg three times daily and aspirin 330 mg once daily: Group B--physical exercise; Group C--physical exercise and dipyridamole 75 mg three time daily and aspirin 330 mg once daily. After six months' treatment the pain-free walking time (PFWT) and the maximum walking time (MWT) improved significantly (p less than 0.05) in all three groups. In group A the PFWT lengthened by 35% (from 101.00 +/- 34.56 to 137.32 +/- 40.50 s) and the MWT by 38% (from 150.34 +/- 55.60 to 207.26 +/- 60.67 s); in group B the PFWT lengthened by 90% (from 90.65 +/- 40.54 to 171.45 +/- 55.60 s) and the MWT by 86% (from 145.39 +/- 60.50 to 270.63 +/- 63.61 s). When physical exercise was associated with drugs as in group C. the PFWT lengthened by 120% (from 89.51 +/- 43.89 to 196.72 +/- 51.73 s) and the MWT by 105% (from 160.43 +/- 59.84 to 329.05 +/- 63.96 s). No significant variations were observed at any stage of the study in the ankle/arm pressure ratio at rest and after standard treadmill exercise. in the plethysmographic rest and peak flows. or in the transcutaneous oxygen pressure in basal conditions and in its half recovery time after an induced ischemia. The results confirm the benefits of regular exercise in stage II PAOD patients but suggest they may be enhanced by antiplatelet therapy.
Venous thrombosis after long-term transvenous pacing in the Chinese, To determine the incidence of venous thrombosis after long-term transvenous pacing in the Chinese. venograms were performed in 50 consecutive Chinese patients seen at the pacemaker clinic. There were 25 women and 25 men. The mean age was sixty-six years (range thirty-two to eighty-one). The indications for pacing were complete heart block in 16 patients and sick sinus syndrome in the remainder. All pacemakers were of the single-chamber ventricular pacing type and had been implanted for a mean period of four years (range two to seven). In 27 patients the route of entry for the pacing electrode was through the cephalic vein and in the other 23 patients the subclavian veins were used. Of the 50 venograms. 1 showed partial and 1 showed total obstruction at the subclavian vein. Both patients (4%) were asymptomatic. All others (96%) were normal. The incidence of venous thrombosis was not related to the routes of entry of the pacing electrodes. All patients tolerated the procedure well and had no complications. It is concluded that the incidence of venous thrombosis after long-term transvenous pacing is extremely low in the Chinese (4%). and venograms are both safe and useful for identifying venous thrombosis related to transvenous pacing.
Emergency arteriography in the assessment of penetrating trauma to the lower limbs, One hundred emergency arteriographies (EA) were performed in 87 patients with lower limb trauma due to high-velocity missiles. Thirteen patients had bilateral injuries. In 79 cases. EA findings were positive and led to emergency surgery. In 76 cases an arterial injury was found and treated. a positive predictive value of 96% (76/79). In the other 3 cases. no arterial lesion was found (3 false positives). Among the 21 patients with normal findings from angiography. 10 had surgical exploration because of high clinical suspicion of vascular injury. Arterial injury was found in 2 cases (2 false negatives). In 8 patients. arteriography modified the surgical procedure. In the 11 remaining patients. clinical and echo Doppler follow-up results were normal. a negative predictive value of 90% (19/21). Sensitivity was 97%. specificity 86%. and accuracy 95%. These data show that arteriography in stable patients is a safe and accurate procedure. It permits avoidance of unnecessary surgical exploration in selected patients and helps modify the surgical procedure.
Compression therapy of limb edema using hydrostatic pressure of mercury, A new apparatus for the treatment of edema of the extremities is described. The extremity is placed in a cylindrical vertical tank and isolated by a circumferential synthetic rubber membrane. The equipment is programmed to create a mold of the extremity using a slurry of plastic granules from a reservoir. Mercury is then pumped between the mold and the extremity. thereby exerting a pressure gradient on the extremity equal to the hydrostatic pressure of the mercury column. A computerized program forms the mold and runs several compression cycles for each treatment session. Twelve patients were treated (8 upper extremities. 4 lower extremities) on a weekly or semiweekly basis. Progress was followed with computed axial tomography scans. as well as measurements and photographs. Ten patients experienced significant immediate decrease in edema with each treatment. Wrapping or elastic support was required to prevent the return of edema between treatments. No pain. skin injury. or other complication of treatment was noted. The apparatus can safely provide short-term. immediate. significant improvement of extremity edema. Further studies will be necessary to determine long-term benefit.
Effect of blood glucose level in acute cerebral ischemia in spontaneously hypertensive rats--survival and brain pathology, The present study was designed to examine the effect of blood glucose level on survival and pathologic changes of the cortical neuronal cells during and after three-hour incomplete cerebral ischemia. which was induced by bilateral carotid artery ligation in spontaneously hypertensive rats (SHRs). Blood glucose levels were varied by intraperitoneal infusion of 50% glucose (hyperglycemia) or insulin with hypertonic saline (hypoglycemia) or hypertonic saline (normoglycemia). None of the hyperglycemic or normoglycemic animals died during three-hour ischemia. whereas 45% of hypoglycemic animals died (p greater than 0.001). The survival rate for twenty-four hours after recirculation was in the following ascending order: hypoglycemia. normoglycemia. and hyperglycemia. Neither hypoglycemia nor hyperglycemia (38-392 mg/dL) in nonischemic animals developed any morphologic changes in the cerebral cortex. However. both the ischemic and recirculated brains showed various degrees of histologic changes such as shrinkage of the neuronal cells with cytoplasmic vacuoles. perineuronal edema. and swelling of neuropils. Such ischemic damage of the brain was more marked in hypoglycemic animals than in hyperglycemic or normoglycemic ones during ischemia. as well as one hour after recirculation. The results suggest that cerebral ischemia and its outcome become more deleterious in hypoglycemic than in normoglycemic and hyperglycemic states. On the other hand. hyperglycemia is not necessarily a disadvantage in acute cerebral ischemia with or without reperfusion in this model.
Laser-assisted angioplasty in the treatment of prosthetic graft stenosis, Late failure of peripheral bypass grafts has been treated primarily by secondary reconstruction. Laser-assisted angioplasty is an optional therapy that the authors investigated in 28 prosthetic grafts over a two-year period. Twenty-five symptomatic patients with 28 peripheral prosthetic arterial bypass grafts (25 polytetrafluoroethylene [PTFE] grafts and 1 each of knitted Dacron. Teflon. and umbilical vein) demonstrated graft occlusion (25) or high-grade stenoses (3). All patients underwent standard laser-assisted angioplasty using a continuous wave Nd:YAG laser source and hybrid probe. Twenty-one grafts (75%) were successfully recanalized with adequate restoration of flow through the conduit. All 7 failures were in occluded PTFE grafts that presented with either recalcitrant lesions (5) or perforations (2) at the distal anastomoses. There have been 3 long-term failures (14%) to date in the successfully treated group. all in PTFE grafts. Two patients suffered recurrent thrombosis and 1 developed an inexplicable graft infection five months after laser treatment. Laser-assisted angioplasty appears to be a clinically viable alternative treatment for prosthetic graft stenosis and recanalization of grafts occluded at their distal anastomosis.
Splenic vein aneurysm: MR appearance--a case report, A presumed pancreatic head mass by non-contrast CT examination. was proven to be a splenic vein aneurysm by enhanced CT. MRI. sonography and arteriography. Dangerous percutaneous aspiration was avoided.
Timing of breast cancer excision during the menstrual cycle influences duration of disease-free survival, OBJECTIVE: To study disease-free survival at 10 years in relation to timing of breast tumor excision during the menstrual cycle. DESIGN: A prospective study of consecutively treated patients with primary breast cancer. SETTING: Memorial Sloan-Kettering Cancer Center. New York. PATIENTS: Two hundred and eighty-three premenopausal patients treated by mastectomy and axillary dissection. MAIN RESULTS: When the tumor was excised during the follicular phase. approximated by setting the putative day of ovulation on day 14 after the onset of last menses. a higher recurrence risk (43%) was observed compared with excision later in the menstrual cycle (29%. P = 0.02). The rate peaked among patients treated between days 7 and 14 and was lowest between days 20 and 30. Multivariate analysis using the Cox regression model to control for tumor size. nodal status. estrogen receptor status. adjuvant chemotherapy. and family history indicated that the hazard rate of breast cancer recurrence after excision during the follicular phase was 1.53 (95% Cl. 1.02 to 2.29). Stratification by nodal status indicated that the effect of phase was statistically significant only among patients with positive nodes (hazard ratio. 2.10; Cl. 1.19 to 3.70). CONCLUSIONS: Our results support the hypothesis that the risk for recurrence may be affected by the hormonal milieu of the menstrual cycle; these findings must be confirmed. however. by a prospective study in which cycle phase at time of tumor excision is biochemically documented.
Survival in patients with primary pulmonary hypertension. Results from a national prospective registry, OBJECTIVE: To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. DESIGN: Registry with prospective follow-up. SETTING: Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart. Lung. and Blood Institute. PATIENTS: Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. MEASUREMENTS: At diagnosis. measurements of hemodynamic variables. pulmonary function. and gas exchange variables were taken in addition to information on demographic variables. medical history. and life-style. Patients were followed for survival at 6-month intervals. MAIN RESULTS: The estimated median survival of these patients was 2.8 years (95% Cl. 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year. 68% (Cl. 61% to 75%); at 3 years. 48% (Cl. 41% to 55%); and at 5 years. 34% (Cl. 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV. presence of Raynaud phenomenon. elevated mean right atrial pressure. elevated mean pulmonary artery pressure. decreased cardiac index. and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. CONCLUSIONS: Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure. mean right atrial pressure. and cardiac index. Such an equation. once validated prospectively. could be used as an adjunct in planning treatment strategies and allocating medical resources.
Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter study, OBJECTIVE: To evaluate the efficacy and safety of a pH-sensitive. polymer-coated oral preparation of mesalamine in patients with mildly to moderately active ulcerative colitis. DESIGN: A multicenter. double-blind. placebo-controlled randomized trial. SETTING: Five university-based medical centers. one inflammatory bowel disease center. and three private practice sites. PATIENTS: A total of 158 patients with newly or previously diagnosed active ulcerative colitis. INTERVENTION: A pH-sensitive. polymer-coated oral preparation of mesalamine (5-aminosalicylic acid) was used at 1.6 and 2.4 g/d for 6 weeks. MEASUREMENTS: Efficacy was measured by scores for stool frequency. rectal bleeding. patient's functional assessment. sigmoidoscopic findings. and physician's global assessment. Stringent criteria for disease activity were established prospectively. RESULTS: The analysis of protocol-compliant patients showed a significant improvement at 3 weeks in patients taking 2.4 g/d of mesalamine compared with patients taking placebo (32% versus 9%; P = 0.003). At 6 weeks. both the 1.6 g/d (43%) and 2.4 g/d (49%) doses were significantly superior to placebo (23%) (P = 0.03 and P = 0.003. respectively). In addition. more patients worsened in the placebo group compared with the 2.4 g/d group (50% versus 19%; P = 0.003); however. there was no statistically significant difference in worsening between the 1.6 g/d mesalamine group and the placebo group. The oral mesalamine tablet was well tolerated. and no clinically significant changes were observed in hematologic. hepatic. or renal laboratory profiles. CONCLUSION: Colon-targeted oral mesalamine at 2.4 g/d is effective therapy for mildly to moderately active ulcerative colitis. It is well tolerated and should provide a viable therapeutic alternative to sulfasalazine.
Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy, OBJECTIVE: To test the hypothesis that a continuous. low-dose infusion of a loop diuretic is more efficacious and better tolerated than conventional intermittent bolus therapy in patients with severe chronic renal insufficiency (CRI). DESIGN: Randomized. crossover clinical trial with subjects serving as their own controls. SETTING: The General Clinical Research Center of Indiana University Hospital. Indianapolis. Indiana. PATIENTS: Eight adult volunteers with severe stable CRI (mean creatinine clearance. 0.28 mL/s; range. 0.15 to 0.47 mL/s) were recruited from the outpatient nephrology clinics of Indiana University Medical Center. INTERVENTIONS: On admission. diuretic drugs were withdrawn and patients were equilibrated on an 80 mmol/d sodium. 60 mmol/d potassium metabolic diet. Patients were randomized to receive a 12-mg intravenous dose of bumetanide given either as two 6-mg bolus doses separated by 6 hours or as the same total dose administered as a 12-hour continuous infusion. When sodium balance was re-established. each patient was crossed over to the alternative study limb. All patients completed both phases of the study. MEASUREMENTS AND RESULTS: Comparable amounts of bumetanide appeared in the urine during the study period (infusion. 912 +/- 428 micrograms; bolus. 944 +/- 421 micrograms; difference. 32 micrograms; 95% CI. -16 micrograms to 80 micrograms. P = 0.16). The continuous infusion resulted in significantly greater net sodium excretion (infusion. 236 +/- 77 mmol; bolus. 188 +/- 50 mmol; difference. 48 mmol; CI. 16 mmol to 80 mmol. P = 0.01). No patient had episodes of drug-induced myalgias during the continuous infusion compared with 3 of 8 patients with bolus therapy. CONCLUSIONS: In patients with severe CRI. a continuous intravenous infusion of bumetanide is more effective and less toxic than conventional intermittent bolus therapy. Continuous administration will probably be useful in patients with severe CRI who have not achieved an adequate natriuresis or who show evidence of drug toxicity with standard diuretic dosing regimens. A similar benefit may occur in selected diuretic-resistant patients with cardiac or hepatic disease. and studies in these patients seem warranted.
Hemodynamic determinants of exercise capacity in chronic heart failure, PURPOSE: To synthesize information on hemodynamic determinants of exercise capacity in patients with chronic heart failure. DATA IDENTIFICATION: Relevant studies published from the mid-1960s to the present were identified by a manual search of the English-language literature and by bibliographic review of pertinent articles. STUDY SELECTION: Both controlled and observational studies that reported measures of either exercise time or oxygen uptake and hemodynamic variables in patients with heart failure were reviewed for quality and included when relevant to the discussion. DATA EXTRACTION: Key conclusions or data. or both. were extracted from each article and described. DATA SYNTHESIS: Exercise intolerance is a hallmark of chronic congestive heart failure. Studies have emphasized central factors and indices of systolic ventricular function. but poor relations have been consistently found between these measurements and exercise capacity. Recent data suggest that diastolic function (that is. ventricular filling and compliance) is an important factor affecting the ability to increase cardiac output and determining exercise capacity. but this issue needs further study. A clearer picture of histologic and biochemical abnormalities in skeletal muscle has recently emerged; patients with heart failure show greater glycolysis. reduced oxidative phosphorylation. and reduced oxidative enzyme activity. Vasodilatory abnormalities in heart failure were first described more than 20 years ago. and such abnormalities may underlie recently reported reductions in skeletal muscle blood flow during exercise. Relative hyperventilation is commonly observed during exercise in patients with heart failure and is related to ventilation-perfusion mismatching in the lung due to a higher-than-normal fraction of physiologic dead space. Neurohumoral abnormalities include reductions in beta-receptor density and sensitivity and contribute to reduced inotropic and chronotropic responses to exercise. CONCLUSIONS: Systolic function and exercise capacity are unrelated in patients with chronic heart failure. but many hemodynamic abnormalities (including those in the heart. lung. and skeletal muscle) overlap. which leads to exercise intolerance in these patients.
Cyclosporine in psoriasis treatment. Inhibition of keratinocyte cell-cycle progression in G1 independent of effects on transforming growth factor alpha/epidermal growth factor receptor pathways, Cyclosporine. an immunosuppressive drug. is effective in the treatment of recalcitrant psoriasis. Previous work suggested that keratinocyte hyperproliferation and inflammation are linked in psoriasis and that immune mechanisms participate in the pathogenesis of psoriasis. Transforming growth factor (TGF) alpha may be an important regulatory factor of epidermal growth as overproduction of TGF-alpha is associated with epidermal hyperplasia in psoriatic plaques and epidermal growth factor receptors are overexpressed in psoriatic epithelium. In this study. the effects of cyclosporine on cultured human keratinocytes were examined. Cyclosporine specifically inhibited keratinocyte cell-cycle progression in the G1 phase without causing keratinocytes to terminally differentiate. Cyclosporine did not decrease the expression of TGF-alpha or epidermal growth factor receptors. These results suggest that the effects of cyclosporine on psoriatic skin are unrelated to direct effects on autocrine growth regulation of keratinocytes via TGF-alpha production or of epidermal growth factor receptor modulation.
Incidence of psoriasis in Rochester, Minn, 1980-1983, This population-based study was carried out using the medical records linkage data resource for the population of Rochester. Minn. at Mayo Clinic. There were 132 newly diagnosed cases of psoriasis identified during a 4-year period (1980 through 1983); 88% of the cases had been seen and diagnosed by a dermatologist. The overall crude incidence rate was 57.6 per 100.000 population; for men and women. the rates were 54.4 and 60.2. respectively. The overall sex- and age-adjusted (1980 US white population) incidence rate was 60.4 per 100.000 person-years. The highest rate of occurrence (112.6) was in the 60- to 69-year-old age group. Most of the cases of psoriasis diagnosed in this study (58%) were mild. and the patients had psoriatic lesions on less than 10% of their body. There are no other published incidence rates for this condition with which to make comparisons.
Invasive cutaneous melanoma in elderly patients, Clinical and pathologic variables were compared between "older" (greater than or equal to 70 years) and "younger" (30 to 39 years) patients with primary invasive cutaneous melanoma. Older patients had more nodular melanomas and acral lentiginous melanomas (58%); superficial spreading melanomas predominated in younger patients (74%). Mean tumor thickness was greater in the older patients (3.95 vs 2.02 mm). Invasive levels 2 and 3 occurred more often in younger patients (41.1% vs 13%); level 5 occurred more often in older patients (30.4% vs 5.3%). Microscopic ulceration occurred more often in older (46.4%) than in younger patients (19.4%). Older patients classified as clinical stage I at presentation or with primary lesions 1.50- to 3.00-mm thick had poorer survival. Younger women survived longer than younger men; this was not true of older patients. The elderly patients with cutaneous melanoma were more likely to have poor prognostic features and thus more likely to die from melanoma than the younger patients.
Nonmelanoma skin cancer mortality. A population-based study, To estimate the magnitude of nonmelanoma skin cancer mortality and describe its parameters. we reviewed the medical records of all deaths certified as due to this cause among Rhode Island residents from 1979 through 1987. After excluding acquired immunodeficiency syndrome-associated Kaposi's sarcoma. we confirmed that nonmelanoma skin cancer was the cause of death for 51 individuals. a quarter of the number of melanoma deaths reported. The age-adjusted nonmelanoma skin cancer mortality rate was 0.44/10(5) per year. Fifty-nine percent were due to squamous cell carcinoma. and 20% were due to basal cell carcinoma. Most appeared actinically induced. Among deaths from squamous cell carcinoma. the mean age was 73 years. At least 80% of the squamous cell carcinomas metastasized. and 47% arose on the ear. None appeared due to refusal of treatment. Among deaths from basal cell carcinoma. the mean age was 85 years. and refusal of surgical intervention was documented in 40%. Study of nonmelanoma skin cancer mortality provides for estimation of the magnitude of this problem. complements other studies of prognosis. and helps guide prevention. early detection. and treatment.
Costal fringe, Costal fringe consists of a bandlike pattern of venous telangiectases along the anterolateral costal margins. It is a common and easily recognized entity. usually seen in elderly men. Association with underlying disease is not well established. To assess the frequency of costal fringe in a healthy young adult population. we examined 1523 active duty Air Force personnel (1203 men and 320 women) between the ages of 17 and 34 years. All subjects were human immunodeficiency virus seronegative; none had known hyperestrogenic or other disease states. Costal fringe was present in only three individuals. all men. a frequency of 0.2%. Costal fringe is a rare finding in healthy young adults.
Treatment of constitutional growth delay in prepubertal boys with a prolonged course of low dose oxandrolone, Forty six prepubertal boys who had constitutional growth delay were treated with oxandrolone. Mean age at the onset of treatment was 11.9 years (range 9.0-14.0) and bone age delay was 1.9 'years'. The dose of oxandrolone used was a mean of 0.05 mg/kg (range 0.03-0.18) for a mean of 0.9 years (range 0.2-3.6). Height velocity increased from a mean (SD) before treatment of 4.0 (1.0) to 7.5 (1.2) cm/year with oxandrolone. Growth rate was sustained at 7.6 (2.2) cm/year in the period after treatment. Those boys who attained a testicular volume of 4 ml or greater at the end of the treatment period had the most pronounced sustained growth acceleration. Height for bone age SD score did not alter significantly from a mean of -1.0 before treatment to -1.2 after treatment. Oxandrolone is a safe and effective treatment for prepubertal boys with constitutional growth delay.
Screening for familial hypercholesterolaemia by measurement of apolipoproteins in capillary blood, A total of 3025 families with schoolchildren aged 6-8 years were offered pilot screening for familial hypercholesterolaemia by measurement of the concentrations of apolipoproteins A-1 and B in the children's capillary blood and by analysis of their family histories of early ischaemic heart disease. The concentrations of the apolipoproteins were determined by double rocket immunoelectrophoresis of an eluate of blood spotted on filter paper. Results were available from 2085 children. Because their B:A-1 ratio was above the 97.5 centile and their concentration of B was above the 99th centile. 54 children (2.6%) were selected to have their apolipoprotein concentrations reassessed. The 17 children (0.8%) whose values were persistently above the chosen cut off points. and all of their available first and second degree relatives. had fasting determinations of serum lipid concentrations carried out. Raised serum concentrations of low density lipoprotein cholesterol and an autosomal dominant pattern of hypercholesterolaemia were found in 12 children and 10 families. respectively. suggesting a higher incidence of familial hypercholesterolaemia than the reported 1:500. Further investigations among family members disclosed hypercholesterolaemia in 29 relatives. A family history of early ischaemic heart disease was elicited by questionnaire. and was positive in only five of the 12 schoolchildren with hypercholesterolaemia. We conclude that analysis of apolipoproteins from capillary blood spotted on filter paper is suitable for screening for familial hypercholesterolaemia. and that this method is more efficient than screening based on family history.
Vaccine efficacy and control measures in pertussis, An outbreak of pertussis in primary school-children in the St David's area of Pembrokeshire provided the opportunity to estimate pertussis vaccine efficacy. The estimate of efficacy was 88% when notified cases were used. but this fell to 68% when all children with bouts of coughing for two or more weeks were included. Notified cases were significantly less likely to have been vaccinated than other cases with similar symptoms. Therefore vaccine efficacy estimates based upon notified cases are likely to be biased. However. even the lower estimates suggest that pertussis immunisation is highly desirable and efforts to improve coverage should be increased.
Acquired aplastic anaemia: still a serious disease, Over 15 years. 42 children aged 2-14 years were diagnosed as having acquired aplastic anaemia. Adequate clinical details were available for 38 children who were categorised as very severe (n = 13). severe (n = 16). or nonsevere (n = 9) by the modified Camitta criteria. Treatment varied over the study period. Seven children received a bone marrow allograft from a full match family donor and three a matched unrelated donor transplant after failed treatment with antilymphocyte globulin. The remainder were treated with antilymphocyte globulin (n = 11). antilymphocyte globulin and oxymetholone (n = 4). oxymetholone with or without prednisolone (n = 12). or supportive treatment alone (n = 1). With a minimum follow up of one year since treatment. the five year survival was 70% for bone marrow transplantation with a family donor. 30% for antilymphocyte globulin. and 25% for oxymetholone. All three children with a matched unrelated donor transplant died. The prognosis of acquired aplastic anaemia remains poor for most children and new approaches to treatment are urgently required.
Children with pervasive refusal, Four children are described with a potentially life threatening condition manifested by profound and pervasive refusal to eat. drink. walk. talk. or care for themselves in any way over a period of several months. The multiplicity and severity of the symptoms in these children do not fit comfortably into any existing diagnostic category. Long term and highly skilled nursing and psychiatric care is required to help these children to recover. The possible causes of this syndrome are discussed.
Intestinal permeability after single dose gluten challenge in coeliac disease, The changes of intestinal permeability before and after a gluten load were studied. The study group comprised 27 patients with coeliac disease (mean age 12.3 years) and 19 healthy controls matched by sex and age. Intestinal permeability was studied by measuring the urinary excretion of two sugars. lactulose and L-rhamnose. before and six hours after the ingestion of five palatable biscuits made with 50 g of gluten powder. The patients with coeliac disease had been on a gluten free diet during the previous two years. After the gluten load lactulose and L-rhamnose urinary excretion changed significantly in patients. and a significant increase in the lactulose: L-rhamnose ratio was also observed. No significant changes were observed in the controls. In view of the modification of the three biopsies diagnostic protocol made by the European Society for Paediatric Gastroenterology and Nutrition. permeability tests associated with single gluten challenges may be an added contribution to the accuracy of the diagnosis in childhood.
Alteration of urinary carnitine profile induced by benzoate administration, To study the effect of sodium benzoate on carnitine metabolism. the acylcarnitine profile in the urine of five normal volunteers and two patients with urea cycle disorders was examined with fast atom bombardment-mass spectrometry. The volunteer subjects were given 5 g of sodium benzoate orally and the two patients with urea cycle disorders (carbamyl phosphate synthetase deficiency type I and ornithine transcarbamylase deficiency) were already undergoing treatment with sodium benzoate and L-carnitine. The amount of benzoylcarnitine excretion depended on the dose of both sodium benzoate and L-carnitine in a reciprocal relation. Increased excretions of acetylcarnitine and propionylcarnitine were also noted after sodium benzoate administration. The alteration of the urinary aclycarnitine profile was consistent with the change of mitochondrial CoA profile predicted by in vitro studies of an animal model. It is suggested that urinary acylcarnitine analysis is important to assess the effect of benzoate administration on mitochondrial function in vivo. Supplementation with carnitine may be necessary to minimise the adverse effects of sodium benzoate treatment in hyperammonaemia.
Clinical predictors and radiological reliability in atlantoaxial subluxation in Down's syndrome, Clinical signs and symptoms that might predict atlantoaxial subluxation were studied prospectively in 135 of 180 children with Down's syndrome aged 6-14 years who form the Hester Adrian Research Centre cohort. Lateral radiographs of the cervical spine were taken in flexed. extended. and neutral positions. and the percentage of abnormalities in each view was 14. 10. and 10%. respectively. Gait was the only significant clinical predictor. The relative risk of having an abnormal neck radiograph with an abnormal gait was 2.91 (95% confidence interval (CI) 1 to 8). The sensitivity was 50% and the specificity 81%. Nineteen children had repeat radiographs to assess the reliability of radiological diagnosis. Six had abnormalities; five of 19 (26%) had an abnormality on the first radiograph. and four of 19 (21%) had an abnormality on a second radiograph. but only three (15%) had an abnormality on both occasions in any view (95% CI 0 to 25). We conclude that radiographs of the cervical spine are unreliable at identifying atlantoaxial subluxation in children with Down's syndrome. and we failed to identify any reliable clinical predictor.
Subcutaneous or intramuscular insulin injections, To find out whether diabetic children may inject their insulin intramuscularly rather than subcutaneously. a random sample of 32 patients aged 4.3-17.9 (median 11.3) years was studied. Distance from skin to muscle fascia was measured by ultrasonography at standard injection sites on the outer arm. anterior and lateral thigh. abdomen. buttock. and calf. Distances were greater in girls (n = 15) than in boys (n = 17). Whereas in most boys the distances were less than the length of the needle (12.5 mm) at all sites except the buttock. in most girls. the distances were greater than 12.5 mm except over the calf. Over the fascial plane just lateral to the rectus muscle the distance from skin to peritoneum was less than 12.5 mm in 14 of the 17 boys and one of the 15 girls. Twenty five of the 32 children injected at an angle of 90 degrees. and 24 children raised a skinfold before injecting. By raising a skinfold over the anterior thigh. the distance from skin to muscle fascia was increased by 19% (range 0-38%). We conclude that most boys and some girls who use the perpendicular injection technique may often inject insulin into muscle. and perhaps on occasions into the peritoneal cavity.
Cost implications of different approaches to the prevention of respiratory distress syndrome, Because the incidence of both neonatal respiratory distress syndrome and neonatal mortality can be reduced by giving corticosteroids to women expected to deliver preterm and by giving surfactant to babies at high risk of developing hyaline membrane disease. we have considered what effects the adoption of one or both of these preventive policies would have on the costs of neonatal care. We have estimated the effects of treatment from overviews of the relevant controlled trials. and estimated costs from observations of care at one neonatal unit. Our results suggest that if either of these policies is adopted for all babies under 35 weeks' gestation at a drug cost of 150 pounds or less/baby. the overall costs of care would be reduced by between 1 and 10%. The cost per survivor would be reduced by up to 16% even if the drug cost were to be as high as pounds 550/baby. If the policies were to be adopted only for babies under 31 weeks' gestation. both policies would result in a reduction in cost of between 5 and 16%/survivor. although the increased survival resulting from the policies would lead to an increase in overall costs for babies of less then 31 weeks' gestation of between 7 and 32%.
Phosphorus metabolites in the human placenta estimated in vivo by magnetic resonance spectroscopy, Normal human placental metabolism has been studied in vivo by image localised 31P magnetic resonance spectroscopy in 13 women with anterior placentas; five. however. were too fat for useful spectral signals to be obtained. Magnetic resonance spectra of good quality which were considered to have arisen from the placenta were obtained from seven women with uncomplicated pregnancies (median gestational age 35 weeks. range 28-39). One other woman had a twin pregnancy in which one fetus had died a few days before. The phosphodiester signal from the placenta of the dead fetus was outside the 95% confidence intervals for normal placentas. suggesting that this technique may potentially be useful in the assessment of placental function.
Doppler assessment of pulmonary artery pressure during recovery from hyaline membrane disease, The changes in pulmonary artery pressure during recovery from hyaline membrane disease were studied by serial Doppler echocardiography on 37 preterm infants. Pulmonary artery pressure was assessed noninvasively by its inverse relationship with the ratio of pulmonary artery Doppler time to peak velocity and right ventricular ejection time. The pattern of rise in ratio after the acute phase of hyaline membrane disease divided into three types. In 25 infants the ratio returned to the normal range: in 12 (group 1) at the same time as the fractional inspired oxygen fell below 0.5 and in 13 (group 2) after a delay of at least 24 hours. In 12 infants (group 3) the ratio remained below the normal range during their hospital stay. suggesting pulmonary artery pressure remained high. Infants in group 3 were of significantly lower gestation and required oxygen treatment for significantly longer than infants in groups 1 and 2. Persistently raised pulmonary pressures in group 3 may reflect lung damage either directly affecting pulmonary vasculature or exerting a secondary effect on pulmonary vascular resistance through hypoxaemia.
Total cavopulmonary anastomosis versus conventional modified Fontan procedure, The total cavopulmonary anastomosis. lateral tunnel Fontan. has been advocated as a preferred method for Fontan type repair. From 1987 to July 1990. 39 patients underwent total cavopulmonary anastomoses (group 1) and 39 patients underwent modified Fontan procedures (group 2); patients receiving adjustable atrial septal defects were excluded. Diagnoses in group 1 included tricuspid atresia in 5 patients. single ventricle in 32. and pulmonary atresia and intact ventricular septum in 2. Diagnoses in group 2 included tricuspid atresia in 20. single ventricle in 17. hypoplastic left heart syndrome in 1. and pulmonary atresia and intact ventricular septum in 1. There were no significant differences in age. weight. cross-clamp time. duration of inotropic support. postoperative effusions. or hospital stay between the two groups. Early mortality in group 1 was 7.7% (3/39) and in group 2. 2.6% (1/39). There was no difference in the incidence of early dysrhythmias or early pacemaker placement. Late mortality was 2.8% in group 1 and 8% in group 2 with a mean follow-up of 18 and 25 months. respectively. Follow-up in group 1 revealed 33 patients in normal sinus rhythm and 1 patient with episodes of supraventricular tachycardia; no additional patients have required pacemakers. Follow-up in group 2 revealed 27 patients in normal sinus rhythm and supraventricular tachycardia in 4 patients; 5 additional patients have required pacemaker placement. There is no apparent difference in early outcome between the total cavopulmonary anastomosis and the conventional modified Fontan. However. there appears to be an increased incidence of late dysrhythmias and the need for pacemaker placement in the conventional modified Fontan group compared with the lateral tunnel group.
Current indications, risks, and outcome after pericardiectomy, A retrospective analysis of the records of 60 patients who underwent pericardiectomy over a 10-year period (1980 to 1990) at The Johns Hopkins Hospital was performed. Indications for operation were effusive disease in 24 patients and constriction in 36 patients. Six patients (10%) with pericardial effusion had pain as the primary symptom necessitating intervention. The operative approach for pericardiectomy was median sternotomy in 52 patients (4 patients required cardiopulmonary bypass) and left anterior thoracotomy in 8 patients. Nine patients (5 with constriction and 4 with effusion) with a prior limited pericardial procedure required formal pericardiectomy. The operative mortality rate for pericardial effusion and constriction was 4.2% and 5.6%. respectively. Follow-up (median follow-up. 56.9 +/- 38.2 months) was obtained on 56 patients (93.3%). Actuarial survival at 1 year. 5 years. and 10 years for all patients was 82.1% +/- 5.1%. 71.7% +/- 6.7%. and 59.8% +/- 12.2%. respectively. A Cox proportional hazards regression analysis was performed using 20 clinical variables. A history of malignancy. previous pericardial procedure. and preoperative New York Heart Association class IV were found to be predictors of poor survival. All patients who underwent operation primarily for effusion with associated pain are alive and have improved functional capacity without steroid use. We conclude that pericardiectomy can be performed with low mortality and can result in good long-term survival and improved functional capacity. Patients who are seen primarily with pain refractory to steroid therapy can be relieved of symptoms with operation.
Aortic valve replacement with omniscience and omnicarbon valves, Clinical results achieved in 100 cases of aortic valve replacement with the Omniscience (O-S) valve during the period from 1980 to 1985 as well as 100 cases of aortic valve replacement with the Omnicarbon (O-C) valve during the period from 1985 to 1989 were studied. Concomitant surgical procedures including mitral valve replacement were performed in 63 patients in the O-S group and 67 patients in the O-C group. Cumulative follow-up in the two groups was carried out for a total of 559 and 273 patient-years. respectively. The overall 4-year actuarial survival rate was 82% +/- 3.8% in the O-S group and 89.5% +/- 3.2% in the O-C group. the corresponding rates for patients undergoing isolated aortic valve replacement being 82.9% +/- 4.2% in the O-S group and 91.9% +/- 3.5% in the O-C group. The overall 4-year actuarial event-free rate with respect to thromboembolic complications was 88.8% +/- 3.3% in the O-S group and 94.4% +/- 2.8% in the O-C group. as compared with the corresponding rates of 89.2% +/- 3.6% in the O-S group and 95.9% +/- 2.8% in the O-C group for patients undergoing isolated aortic valve replacement. The overall rate of valve-related complications. including thromboembolism. anticoagulant-related hemorrhage. perivalvular leak. infection. and structural failure. was 78.8% +/- 4.2% in the O-S group and 89.3% +/- 3.5% in the O-C group (p less than 0.05). and for isolated aortic valve replacement. 79.7% +/- 4.5% in the O-S group and 89.6% +/- 4.1% in the O-C group.
Preliminary results of left heart bypass in pigs using a heparin-coated centrifugal pump, To assess the feasibility of left ventricular assist without systemic heparinization. we used a commercially available (Sarns 3M) centrifugal pump with tubing set and cannulas. all internally precoated for the purpose of this study with heparin. to bypass the left ventricle in 12 pigs for periods of either 1 or 3 hours. There was no significant activation of clotting and there was no sign of generalized embolization. However. on postmortem studies. 5 kidneys out of 22 examined showed signs of minimal thromboembolism. This experiment shows that artificial left ventricular assist. free of systemic heparinization but using heparin precoating. is feasible and safe. at least for a short period of time.
Preoperative hemostatic activity and excessive bleeding after cardiopulmonary bypass, The rationale for predicting the risk of excessive postoperative bleeding by assessing the hemostatic status of a patient before cardiopulmonary bypass was investigated. A novel. rapid. overall test (hemostatometry) consisting of a physiologically relevant test of platelet function (shear-induced hemostasis) and coagulation was performed using nonanticoagulated blood and compared with the routine coagulation screen. Two hundred five patients undergoing elective coronary revascularization were studied 3 to 4 days before operation. Forty-nine bled excessively for nonsurgical reasons; none were predicted by the routine coagulation tests. Using a stepwise discriminant analysis. hemostatometry correctly predicted 31 of 49 (63%). Thirty of 156 predicted as bleeders by hemostatometry did not bleed. Thus. preoperative hemostatometry predicted 77% of the true outcome. The false predictions suggest. however. that certain bleeding abnormalities probably acquired during cardiopulmonary bypass cannot be predicted. These findings do not justify the routine use of preoperative tests in assessing the bleeding risk in patients undergoing cardiopulmonary bypass.
Current status of coronary artery operation in septuagenarians, Previous reports of elderly patients undergoing coronary artery bypass grafting have not addressed the current era of aggressive percutaneous angioplasty and frequent urgent or emergent operation. To investigate this important subgroup of patients. we analyzed our recent coronary artery bypass grafting experience with patients 70 years of age or older. From January 1984 to January 1989. 121 consecutive patients in this age range underwent surgical revascularization at our institution. Overall in-hospital operative mortality (OM) was 7.4% (9/121). with 77.8% (7/9) of deaths due to cardiac causes. Serious postoperative morbidity occurred in 71.1% (86/121). Surgical priority was significantly correlated with operative mortality: for elective cases. the OM was 2.9% (2/68). but it was 8.6% (3/35) for urgent cases (p less than 0.05) and 22.2% (4/18) for emergency cases (p less than 0.05). Univariate analysis isolated the need for inotropic support. intraaortic balloon pump. reoperation. cardiopulmonary resuscitation. and emergency status as significant risk factors for OM (p less than 0.05). Multivariate stepwise logistic regression analysis identified the need for inotropic support. intravenous nitroglycerin. reoperative coronary artery bypass grafting. and hypertension as independently significant risk factors. A logistic risk equation developed from this population accurately modeled OM at the extremes of operative risk. Three (3.1%) of the 97 patients predicted to have less than 5% OM died. whereas all patients predicted by the model to have greater than 90% OM died. These results indicate that in spite of relatively high morbidity and mortality rates. elderly patients have a very acceptable operative risk in the current era of high-risk coronary artery bypass grafting. This is particularly true if elective revascularization is possible.
Extracardiac valved conduits in the pulmonary circuit, Extracardiac valved conduits represent one of the weakest facets of reconstructive surgery for congenital heart disease in that they invariably need to be replaced because of growth of the patient or because of valve or conduit failure. Between 1979 and 1989. 141 patients had 169 valved conduits placed between the heart and the pulmonary artery circuit. There were 81 male and 60 female patients. aged 2 days to 35 years (mean age. 5.9 years). with 46 patients less than 1 year of age. We performed primary repair in 117 patients; in this group. there have been 28 conduit replacements in 27 patients. In 17 patients initial repair with a conduit was performed elsewhere and we replaced these conduits in 15 and removed them in 2. A further group of 9 patients were seen after repair of tetralogy of Fallot or double-outlet right ventricle. with severe pulmonary incompetence or right ventricular outflow tract aneurysm. All had valved conduits inserted as secondary procedures. The types of valved conduits used were xenograft (n = 126) and homograft (n = 43). There were six hospital deaths (3.6%; 70% confidence limits [CL]. 2% to 6%) and seven late deaths (4.1%; CL. 2.5% to 6.5%) in a total of 169 conduit insertions. Forty-five conduits have been removed and 43 reinserted without early or late mortality (0%; CL. 0% to 4%). Actuarial survival after conduit insertion was 87% at 5 years (CL. 80% to 92%). including operative mortality. Actuarial freedom from conduit replacement was 37% at 5 years (CL. 20% to 56%). Conduit insertion in infants and small children ensures subsequent replacement. but this can be done at low risk.
Mesenchymoma of the chest wall in children, Benign chest wall mesenchymoma in children is an extremely rare disease. Only 20 patients have been reported in the world literature. We report a chest wall mesenchymoma in a 2-year-old boy who was admitted to the hospital after a routine chest roentgenogram showed a mass in the right upper chest wall. The patient was asymptomatic. Clinical examination was negative. but chest roentgenograms and computed tomography showed a mass in the right upper chest wall involving the third rib. A 2 x 2 x 1.5-cm tumor was excised totally with partial resection of the third rib. The histology of the lesion corresponded to a mesenchymoma (hamartoma) of the chest wall. Our patient has been followed up for 8 years without recurrence.
Long-term bridge to transplantation with the Symbion acute ventricular assist device system, A 48-year-old man was supported for 164 days with Symbion biventricular assist devices. During that time. his cytotoxic antibody screen fell from 97% positivity to less than 10%. enabling cardiac transplantation. Complications during the implantation included a 3-minute episode of amaurosis fugax. one positive blood culture. and anemia. which responded to decreased frequency of blood drawing. He is now alive 7 months after transplantation.
Removal of massive right atrial thrombus guided by transesophageal echocardiography, Formation of massive right atrial thrombi around a peritoneovenous shunt is a known complication of these devices. Removal of an obstructive right atrial thrombus requires cardiopulmonary bypass and has been associated with a high morbidity and mortality. Transesophageal echocardiography was used in this case to diagnose and guide the surgical removal of a massive right atrial thrombus.
Videothoracoscopic ligation of bulla and pleurectomy for spontaneous pneumothorax, A thoracoscopic technique to ligate pleural bullae and perform parietal pleurectomy is described. The procedure has been performed on 2 patients. allowing definitive treatment of recurrent spontaneous pneumothoraces. Both patients have been cured of their problem and benefited from the decreased trauma of access by reduced postoperative pain. rapid recovery. and decreased scarring of the skin.
A new balanced operation for complex gastroesophageal reflux disease, Twenty-seven patients with advanced gastroesophageal reflux disease have been treated with combined transthoracic parietal cell vagotomy and Collis-Nissen fundoplication. Gastric acid analyses (n = 20) obtained preoperatively and 6 months postoperatively demonstrated a significant late reduction in gastric acid output. Twenty-six patients (96%) have experienced relief of gastroesophageal reflux disease at a mean of 13.3 months (range. 6 to 25 months) without postvagotomy symptoms. Transthoracic parietal cell vagotomy may be considered as an adjunct to mechanical surgical control of advanced gastroesophageal reflux disease.
Achalasia: current evaluation and therapy, The current evaluation of and therapy for achalasia are reviewed. Esophageal manometry remains the best means for diagnosing achalasia. Initial therapy can include either pneumatic dilation or esophagomyotomy. Symptomatic improvement occurs in 71% of patients after pneumatic dilation. with a risk of perforation of 1.4%. Eight percent of these patients require subsequent esophagomyotomy. Surgical procedures for achalasia can be performed through either an abdominal or a thoracic incision. Nearly all authors favoring an abdominal approach add an antireflux operation to esophagomyotomy. whereas many authors advocating a transthoracic esophagomyotomy believe that an antireflux wrap is unnecessary. Overall results for the various surgical approaches used as initial therapy are excellent. with symptomatic improvement in 89% of patients. a mortality rate of less than 1%. and development of gastroesophageal acid reflux in less than 10%. Factors governing the choice of initial therapy are discussed.
Localized necrotizing arteritis. A report of two cases involving the gallbladder and pancreas, We report two cases of localized necrotizing arteritis. one involving the gallbladder and one involving the pancreas. Both cases were found incidentally in surgically resected specimens. Vascular changes in both cases were similar to those seen in classic polyarteritis nodosa. involving medium-sized muscular arteries characterized by fibrinoid necrosis and panarterial and periarterial inflammations varying from active to resolving stages. Both patients had no constitutional symptoms or underlying serologic abnormalities suggestive of systemic angitis. To our knowledge. pancreas-limited arteritis has not previously been described. Whether these lesions represent an early manifestation of a systemic arteritides syndrome. a variant of polyarteritis nodosa. or a distinct entity should be prudently judged through a long-term follow-up.
Coronary heart disease in rhesus monkeys with diet-induced coronary artery atherosclerosis, Diet-induced coronary artery atherosclerosis develops in rhesus monkeys (Macaca mulatta). The goal of this study was to establish the rhesus monkey as an animal model of coronary heart disease (CHD). From a colony of 160 rhesus monkeys fed an atherogenic diet. we identified 14 monkeys with electrocardiographic and echocardiographic evidence of CHD. When compared with 14 rhesus monkeys matched for age. gender. and dietary history with normal electrocardiograms and echocardiograms. monkeys with CHD had higher arterial blood pressures (mean +/- SEM. 92 +/- 4 mm Hg vs 75 +/- 5 mm Hg. respectively). lower high-density lipoprotein cholesterol concentrations (mean +/- SEM. 1.70 +/- 0.25 mmol/L vs 2.32 +/- 0.28 mmol/L [66 +/- 10 mg/dL vs 90 +/- 11 mg/dl]). and lower A-l apolipoprotein concentrations (mean +/- SEM. 200 +/- 17 mg/dL vs 252 +/- 15 mg/dL). Monkeys with CHD tended to have higher total plasma cholesterol concentrations (mean +/- SEM. 11.6 +/- 1.55 mmol/L vs 9.36 +/- 0.93 mmol/L [450 +/- 60 mg/dL vs 362 +/- 36 mg/dL]) and higher low-density lipoprotein cholesterol concentrations (mean +/- SEM. 8.71 +/- 1.75 mmol/L vs 6.12 +/- 0.90 mmol/L [337 +/- 68 mg/dL vs 237 +/- 35 mg/dl]) than monkeys with normal electrocardiograms and echocardiograms. We conclude that rhesus monkeys. like human beings. develop CHD as a complication of coronary artery atherosclerosis. Furthermore. risk factors for CHD in rhesus monkeys and human beings are similar.
Histologic observations and P-glycoprotein expression in gastric and esophageal adenocarcinomas treated with preoperative chemotherapy, To describe histologic changes associated with chemotherapy response. we reviewed biopsy and resection specimens from 52 patients with locally advanced esophageal or gastric adenocarcinoma who were treated with preoperative chemotherapy. followed by resection. P-Glycoprotein expression in the adenocarcinomas was also determined with the use of antibody C219. Significant changes in morphologic appearance of the tumor between prechemotherapy and postchemotherapy samples was noted in 17 tumors (32.7%). The most frequent changes observed in these 17 tumors were a decrease in tumor cellularity and an increase in dense fibrosis in comparison with the prechemotherapy specimen. In signet-ring cell carcinomas. the intracytoplasmic mucin vacuoles were often smaller after chemotherapy. making tumor cells more difficult to identify. Another finding observed in tumors that showed histologic alteration after chemotherapy was the formation of large mucin pools that contained lymphocytes and macrophages. The remaining 35 tumors showed similar histologic features in prechemotherapy and postchemotherapy specimens. P-Glycoprotein was identified in 15 (29.4%) of 51 specimens after chemotherapy. P-Glycoprotein content of the residual tumors did not correlate with stage. degree of differentiation. or clinically determined chemotherapy response. We concluded that chemotherapy-induced changes in morphology were frequent in patients with upper gastrointestinal tract adenocarcinomas treated with preoperative chemotherapy. These changes should be recognized as they may cause difficulties in both gross and histologic evaluation of the extent of tumor in postchemotherapy resection specimens. The response of adenocarcinomas to this chemotherapy protocol does not appear to be linked to P-glycoprotein expression.
Parainfluenza virus pneumonitis in an adult, Parainfluenza virus uncommonly causes fatal giant cell pneumonia in immunocompromised infants and children. To our knowledge. this is the first adult case of parainfluenza virus pneumonia. A 77-year-old woman who was diagnosed as having small-cell carcinoma of the lung underwent chemotherapy. She died of lung edema. Analysis of her serum showed antibodies to parainfluenza virus types 2 and 3 at titers of 1:64 and 1:128. respectively. The postmortem examination revealed giant cell pneumonia. in which giant cells and detached alveolar lining cells had intracytoplasmic inclusions. On electron microscopic examination. the intracytoplasmic inclusions contained fuzzy-form nucleocapsids.
HMB-45-positive malignant lymphoma. A case report with literature review of aberrant HMB-45 reactivity, The monoclonal antibody HMB-45 is a highly specific and sensitive marker of malignant melanoma. Rarely. however. aberrant reactivity to nonmelanocytic tumors has been observed. We report an immunoblastic lymphoma of B-cell phenotype that reacted with HMB-45 in a 70-year-old white woman. To our knowledge. this is the first report of HMB-45-positive malignant lymphoma (excluding plasmacytoma). Of an additional 13 cases of benign and malignant lymphoid tissue. only benign plasma cells in one case reacted with HMB-45.
Results of surgical therapy for biliary dyskinesia, One hundred eighty-seven patients who presented with symptoms consistent with biliary colic but had no ultrasonic evidence of cholelithiasis were observed in an effort to identify those with a functional gallbladder disorder that might benefit from surgical intervention. All patients underwent quantitative evaluation of gallbladder emptying using cholecystokinin biliary scanning. and ejection fractions less than 35% were considered abnormal. One hundred twenty-nine patients (69%) had abnormal ejection fractions. and 88 (68%) of these subsequently underwent cholecystectomy. Sixty of the surgical specimens revealed pathologic changes. Eighty-four percent of patients successfully contacted for follow-up experienced complete relief. and another 13% had partial relief of preoperative symptoms. Only two patients reported no change in symptom complex. Twenty-nine patients with abnormal ejection fractions elected not to undergo surgery. Fifty-nine percent of these patients continued to experience symptoms of biliary colic at a mean follow-up of 22 months. Of the 44 patients with normal ejection fractions. 35 (80%) reported resolution of symptoms during follow-up of medical treatment. Cholecystokinin biliary scanning can help identify patients with acalculous. functional gallbladder disease who may benefit from cholecystectomy.
Prediction of injury caused by penetrating wounds to the abdomen, flank, and back, Controversy about the appropriate evaluation of penetrating abdominal. flank. and back injuries prompted this retrospective review of 311 patients at an urban level 1 trauma center over 5 years. Seventy-five (24%) patients sustained gunshot wounds to the abdomen. All patients with gunshot wounds underwent exploratory laparotomy; results of 67 laparotomies (89%) were positive. Of 236 patients sustaining stab wounds (140 abdominal wounds. 51 flank wounds. 26 back wounds. and 19 wounds to multiple sites). 147 were treated according to a selective protocol. based on results of physical examination. wound exploration. peritoneal lavage. and ancillary diagnostic studies. No injuries were found at celiotomy in three (2%) of these 147 patients. One false-negative result of evaluation of a flank wound occurred. Significant injuries were found in 13 patients (68%) with stab wounds to multiple sites. 61 patients (44%) with abdominal stab wounds. 15 patients (29%) with flank stab wounds. and four patients (15%) with back stab wounds. Mandatory exploration of gunshot wounds is justified. Physical findings of intra-abdominal injury or positive results of peritoneal lavage identify stab wound victims likely to benefit from surgical exploration. A policy of mandatory observation or routine celiotomy for treatment of stab wounds is not justified.
Modulation of IgM antibody formation by lipid peroxidation products from burn plasma, Lipid peroxides (conjugated dienes) have been shown to increase in the plasma of thermally injured animals and in humans. The purpose of this study was to determine if conjugated diene-rich fractions extracted from the plasma of burned rats 3 hours after injury would alter humoral immune function in unburned animals. Plasma diene extracts from burned or normal rats were dissolved in ethanol and given intraperitoneally to Long-Evans rats. Fifteen minutes after diene injection. the rats were immunized with sheep erythrocytes. Five days later. serum and spleen cells obtained from these immunized rats were tested for IgM immunity against sheep erythrocytes. Both plaque-forming cells from spleen and hemagglutination titers in serum were significantly enhanced in the group treated with dienes obtained from the thermally injured rats. These data suggest that conjugated diene-bearing lipid fractions from burn plasma may modulate immune function and support the concept that humoral immunity is enhanced after thermal injury.
Pyogenic liver abscess. Modern treatment, Historically. open surgical drainage has been the treatment of choice for pyogenic liver abscess. The records of 54 patients with pyogenic liver abscess were reviewed to determine whether earlier diagnosis with current imaging tests and definitive treatment with antibiotics. aspiration. or catheter drainage was an effective alternative to open drainage. Twenty-nine patients were treated with broad-spectrum antibiotics and diagnostic aspiration. Twenty-three (79%) recovered uneventfully. and six required catheter or operative drainage. Twenty-three patients (including five who failed aspiration) underwent drainage with percutaneously placed catheters. Nineteen (83%) recovered; four required open surgical drainage. Of seven patients who required open surgical drainage. six recovered. One (2%) of the 54 patients died following failed aspiration and catheter and surgical drainage. Four patients were successfully treated with antibiotics alone without aspiration. These results confirm that pyogenic liver abscess can be successfully treated with broad-spectrum antibiotics and aspiration or percutaneous catheter drainage. Open surgical drainage is reserved for patients in whom treatment fails or who require celiotomy for concurrent disease.
Fishhook injuries: a prospective evaluation, A prospective study was conducted involving 100 nonrandomized. consecutive patients who suffered fishhook injury during the summer of 1990 in Alaska. Time of injury prior to admission to the emergency department. location of fishhook. method of removal. wound care. systemic antibiotic prophylaxis. anesthetic. tetanus immunization status. fishhook size. and complication rate were evaluated. Results of this study suggest that most fishhook injuries involve the hands or head and that postremoval wound care including oral antibiotic therapy may not be critical. Local anesthetics and simple removal techniques are adequate for nearly all fishhook injuries. Routine systemic antibiotic prophylaxis is not necessary for uncomplicated soft tissue injury due to fishhooks not involving cartilage or tendons.
Evaluation of two rapid screening assays for the detection of human immunodeficiency virus-1 infection in emergency department patients, In order to determine the sensitivity and specificity of two rapid human immunodeficiency virus (HIV-1) assays compared with enzyme immunoassay and Western blot and to assess their potential use for routine screening in an emergency department (ED). we analyzed sera from 492 consecutive ED patients using an identity-unlinked design. Sera were analyzed for HIV-1 by standard enzyme-linked immunosorbent assay and Western blot and two rapid assays: the Abbott Testpack HIV-1 (Abbott Labs. Inc. Abbott Park. IL) and the HIV-1 Genie. (Genetic Systems. Seattle. WA). Seroprevalence of HIV-1 among 492 samples was 5.1%. Both rapid assays were easy to perform and required approximately 10 minutes per test. Sensitivity and specificity of both rapid assays were 100% and 99.8%. with positive and negative predictive values of 96.2% and 100%. respectively. It was concluded that both rapid assays showed high concordance with standard enzyme-linked immunosorbent assay and Western blot. Since the ED is often the primary care setting for many patients at risk for HIV-1. the ED may be an optimal site for routine HIV-1 screening. Rapid assay screening may provide the opportunity for timely identification of HIV-1-infected patients. allowing earlier treatment and counseling. However. ethical and practical questions regarding appropriate application of rapid HIV-1 testing in EDs still needs resolution.
Is the anteroposterior cervical spine radiograph necessary in initial trauma screening, The usefulness of the anteroposterior (AP) radiograph of the cervical spine in contributing to the diagnosis of cervical spine injuries in the acute trauma patient was examined in a retrospective study. All cases of cervical spine fracture or dislocation seen at a level I trauma center over a 3-year period and at a rehabilitation center over a 10-year period were reviewed. The lateral radiograph. open-mouth odontoid radiograph. and AP radiograph of each case were sequentially examined by a neuroradiologist (blinded to the original diagnosis) to determine the contribution of each view in making a diagnosis of cervical spine injury. Results of these reviews showed that there were no cases of cervical spine injury evident on the AP view without an obvious corresponding abnormality on the lateral or open-mouth view. It was concluded that the AP view could be dropped from the initial screening radiographic study of the cervical spine in the trauma patient. Only an adequate lateral view and open-mouth odontoid view would then be necessary to initially evaluate the cervical spine in the trauma patient. and decisions to obtain further studies could be based safely on only the lateral and open-mouth views.
Plasma norepinephrine concentrations during resuscitation in the dog, The objective of this study was to evaluate whether the adrenal glands contribute to the increase in plasma norepinephrine concentrations during cardiopulmonary resuscitation. by releasing norepinephrine and/or by secreting epinephrine that facilitates the release of norepinephrine from sympathetic nerve endings via stimulation of presynaptic beta receptors. The experiments were performed in adrenalectomized and in sham-operated dogs. In adrenalectomized dogs the increase in plasma norepinephrine concentrations during cardiopulmonary arrest and basic life support (BLS) was markedly smaller than in sham-operated dogs. Intravenous infusion of physiologic doses of epinephrine during BLS in adrenalectomized animals did not influence the plasma norepinephrine concentrations. These data indicate that. as suggested by others. the marked increase in plasma norepinephrine concentrations during BLS in dogs is mainly of adrenomedullary origin. They also suggest that presynaptic facilitation of norepinephrine release by epinephrine is not important. but further experiments using higher doses of epinephrine are necessary.
Recurrent pneumoperitoneum following vaginal insufflation, The authors report a case of a 24-year-old nulligravida woman who presented to the hospital with complaints of severe abdominal pain and radiographic evidence of pneumoperitoneum. She had two prior nondiagnostic laparotomies for similar complaints and radiographic findings. After a careful sexual history was taken the patient revealed that she had sexual intercourse preceding every similar episode including this one. during which her partner forcefully blew air into her vagina. Pneumoperitoneum associated with vaginal insufflation has been previously reported in two multigravida patients with and without anatomic abnormalities. When pneumoperitoneum is present in the absence of gastrointestinal symptoms or trauma. a meticulous sexual history should be made to avoid unnecessary laparotomies.
Systemic anaphylaxis after ingestion of a psyllium-containing breakfast cereal, Allergic reactions have been described as an occupational hazard among nurses and pharmaceutical workers who handle psyllium-containing laxatives. This study reports the case of a 38-year-old female nurse who ingested a bowl of psyllium-containing Heartwise Cereal (Kelloggs. Battle Creek. MI) and 25 minutes later developed severe systemic anaphylaxis manifested by hypotension. a feeling of constriction in the throat. hoarseness. dyspnea. wheezing. generalized pruritus. urticaria. and vomiting. She was treated with epinephrine. normal saline. diphenhydramine. and methylprednisolone. and recovered completely. Subsequent IgE immunoblot assay was strongly reactive to psyllium. Ingestion of psyllium-containing breakfast foods by sensitized individuals can be associated with life-threatening systemic anaphylaxis.
Zidovudine therapy is associated with an increased capacity of phytohemagglutinin-stimulated cells to express interleukin-2 receptors.Pittsburgh AIDS Clinical Trial Unit, Zidovudine therapy of AIDS patients has been shown to cause only transient improvements in the numbers of circulating CD4+ cells and the in vitro functional activities of cultured lymphocytes. The present studies were undertaken to determine whether prolonged zidovudine therapy enhanced reactivity in two sensitive assays of T-cell function: the ability of phytohemagglutinin (PHA)-stimulated cells to form T-cell colonies and their capacity to express receptors for the growth factor interleukin-2 (IL-2). Treated patients. studied over periods of 20-60 weeks. showed no improvement in colony formation at any time interval. even in plates supplemented with exogenous IL-2. However. mitogen-stimulated T lymphocytes showed a significant increase in the capacity to express IL-2 receptors (CD25). This enhanced expression resulted primarily from activation of the CD8+ cell subset.
Absence of a clinical correlation for complement-mediated, infection-enhancing antibodies in plasma or sera from HIV-1-infected individuals. Multicenter AIDS Cohort Study Group, Neutralizing and complement-mediated infection-enhancing antibodies to HIV-1 were measured in sera or plasma from 54 HIV-1-positive individuals at various stages of disease. and from an additional 36 HIV-1-positive individuals for whom no clinical data were available. Antibodies were measured in microtiter infection assays utilizing MT-2 cells and the IIIB strain of HIV-1. The frequency of detection of both types of antibodies was identical. being 77 out of 90 cases (86%). Neutralizing and infection-enhancing antibodies were not always found together. and in four cases both were undetectable. No correlation was found between titers of either type of antibody and stage of disease. Furthermore. titers of infection-enhancing antibodies at early stages of disease did not predict rate of disease progression.
Cerebrospinal fluid and serum neopterin and biopterin in D-retrovirus-infected rhesus macaques (Macaca mulatta): relationship to clinical and viral status, Increases in serum and cerebrospinal fluid (CSF) neopterin concentrations accompany many inflammatory diseases. including infection with HIV-1 and may reflect activation of guanosine triphosphate (GTP) cyclohydrolase 1 by gamma-interferon and other cytokines. In the present study. macaques with clinical simian AIDS (SAIDS) infected with the immunosuppressive type-D retrovirus D/1/California had increased concentrations of CSF neopterin but not of biopterin beginning soon after seroconversion. Normal neopterin concentrations in the CSF were found in macaques with SAIDS-related complex as well as asymptomatic. viremic macaques. CSF biopterin. serum neopterin and serum biopterin concentrations of D/1/California-infected macaques were not different from the levels in control animals. The increase in CSF neopterin may reflect local inflammatory responses and paralleled previously documented changes in L-tryptophan metabolism in these macaques. However. the absence of macrophage infiltrates in the brain of the infected macaques suggests a non-macrophage source of both increased CSF neopterin and tryptophan metabolites in the SAIDS macaques.
Biological properties of anti-CD4 autoantibodies purified from HIV-infected patients, We have previously reported the detection of anti-CD4 autoantibodies in the sera of approximately 10% of HIV-1-infected patients. These antibodies recognized epitopes located on the V3V4 domains of the soluble recombinant CD4 molecule but did not recognize CD4 in its native conformation on the cell membrane. To analyse further the biological properties of these antibodies. we have purified them from the sera of six patients using affinity chromatography. We demonstrate that purified and concentrated anti-CD4 antibodies still cannot recognize CD4 either in its native conformation or after the binding of HIV gp120. They also cannot mediate antibody-dependent cellular cytotoxicity on CD4+ or HIV-coated CD4+ cells. In one patient. however. we could detect a minor fraction of anti-CD4 antibodies directed to the V1V2 domains of CD4.
Selection of primers of optimal sensitivity for the detection of HIV-1 from Africa and Europe by polymerase chain reaction, In order to facilitate the detection of integrated HIV-1 proviral DNA from African as well as European patients. four new primer pairs for use in the polymerase chain reaction (PCR). localised in the gag. pol. vif and env genes of HIV-1. were constructed. The primer pairs were compared to all accessible HIV-1 sequences from African and European isolates and to some of the earlier published and most commonly used primer pairs. HIV-1 DNA was detected in blood drawn from 13 out of 13 individuals infected in Africa. in three out of three Tanzanian HIV-1 isolates and in three out of three asymptomatic Swedes infected in Europe. The new selection of primer pairs can be used as an alternative to enhance the detection of HIV-1 of different origins.
Risk factors for HIV among prostitutes in Chiangmai, Thailand, The discovery of a 44% (44 out of 100) prevalence rate of HIV infection among female prostitutes working in brothels in Chiangmai in Thailand in June 1989. prompted this follow-up study in August to confirm the high prevalence rate and to look for risk factors for infection. We studied 238 female prostitutes working in 14 brothels and confirmed this high prevalence rate. Eighty-seven (36.5%) out of 238 prostitutes were found to be HIV-positive by enzyme-linked immunosorbent assay with IFA or Western blot confirmation. Logistic regressions found a significant association between HIV infection and frequency of sexual intercourse greater than 3 times per day [odds ratio (OR) = 2.82. 95% confidence interval (CI) = 1.47-5.41]. sexual service charge less than 150 Baht (OR = 9.1. 95% CI = 2.9-33.3). and post sexual cleansing with water alone (OR = 3.85. 95% CI = 1.90-7.80). Of 56 women found seronegative in the June survey. 35 were re-tested in the August study. Seven (20%) of them were seropositive. giving an HIV seroconversion incidence rate of 10% per month. The findings of this study prompted intensive health education programmes among prostitutes. their customers. and owners of brothels.
Otitis media with effusion in children. Binaural hearing before and after corrective surgery, The masking-level difference (MLD) was investigated in a group of children having no known history of ear disease. and a group of children having a history of otitis media with effusion and hearing loss. The MLD is a psychoacoustic measure of the sensitivity of the auditory system to subtle interaural difference cues of time and amplitude and relates to the ability of the listener to detect and to recognize signals in noisy backgrounds. In the otitis media with effusion group. MLDs were measured both before and 1 and 3 months after the placement of pressure equalization tubes. The MLDs were often abnormally small in the otitis media with effusion group before surgery. when hearing loss was present. Significantly. MLDs sometimes remained abnormally small after surgery (after normal hearing had returned). The postsurgery MLD was particularly likely to be abnormally reduced in subjects who had experienced asymmetric losses of hearing.
Gender influences subsite of origin of laryngeal carcinoma, The relationship of gender to laryngeal cancer is not well understood. We analyzed 688 laryngeal cancers diagnosed in Kansas from 1980 through 1989 for sex differences in subsite distribution (glottis. supraglottis. subglottis. and laryngeal cartilage) as well as survival. histologic grade. and age at diagnosis. The ratio of glottic to supraglottic tumors was 22.12:1 in men and 0.56:1 in women. a highly significant difference. Survival in glottic tumors was significantly better than in supraglottic tumors. but survival was not significantly better for women than it was for men. Glottic tumors were significantly more likely than were supraglottic tumors to be of low-grade malignancy for all subjects and for male subjects alone. but not for female subjects alone. Women were younger at time of diagnosis than were men. but not significantly so. Gender is an important factor in the genesis of laryngeal cancer.
Crack cocaine burns of the larynx, Burn injuries of the larynx are a previously unrecognized complication of cocaine abuse. The clinical presentations and magnetic resonance imaging findings of two patients are presented. Recognition of this entity is important to avoid errors in diagnosis and in management.
Psoriatic arthritis (PA): a clinical, immunological and radiological study of 180 patients, We carried out a prospective study of the clinical. laboratory and radiological features of 180 patients with psoriatic arthritis. We initially classified our patients into five groups as described in the publications of Moll and Wright. Thirty-seven per cent had oligoarthritis. 36% polyarthritis. 23% spondarthritis (sacroiliitis and/or spondylitis) and 4% had the mutilans form. The distal joint arthritis type did not exist as an entity and the distal interphalangeal (DIP) joints were affected in all groups. The spondarthritis form includes patients with exclusively axial manifestations and also those who in addition have peripheral arthritis (oligoarthritis. polyarthritis. DIP arthritis). Only 53% of our patients had nail involvement. We found an increase of IgA levels in patients with axial disease. This suggests a relationship between ankylosing spondylitis and psoriatic spondylitis. The HLA-B17/Cw6 association increased in the oligoarticular form. The increase of antigen B17 correlated with the spondarthritic and oligoarthritis forms whereas Cw6 was more important in the oligoarthritis form. An increase of the HLA-B27/Cw1 association and the spondarthritic form was also found. Moreover. we detected a greater incidence of the HLA-B27 antigen in patients with bilateral sacroiliitis (85%) than in patients with unilateral sacroiliitis (22%). Our work revealed that PA is not a harmless disease; 57% of our patients had erosive arthritis while 19% had ARA class III or IV functional impairment.
Predictors of the long-term outcome of early synovitis: a 5-year follow-up study, One hundred patients who presented to an Early Synovitis Clinic in 1979-81 were called for review after a minimum of 5 years. Sufficient data for analysis were obtained in 88 cases. of whom 36 had a final diagnosis of rheumatoid arthritis (19 seropositive. 17 seronegative) and 16 human parvovirus B19 arthropathy. Outcome was assessed by persistence of symptoms greater than 24 months and functional disability by Health Assessment Questionnaire. Sixty-two patients had persistent disease. with 26 showing some functional impairment (positive HAQ FDI). A number of presenting features were assessed for their ability to predict outcome at 5 years. Polyarticular onset of disease was associated with a poor prognosis but lacked both specificity and sensitivity. Certain laboratory tests at presentation. including positive rheumatoid factor and low serum sulphydryl levels. also indicated a poor outcome. Combining these serological abnormalities gave 100% specificity for detecting persistent. disabling disease but with rather low sensitivity. Thus. other test systems are required to increase further the successful prediction of clinical outcome in patients with early synovitis.
Inorganic pyrophosphate, nucleoside triphosphate pyrophosphatase, and cartilage fragments in normal human synovial fluid, The association between calcium pyrophosphate dihydrate (CPPD) crystal deposition and ageing is unexplained. Levels of inorganic pyrophosphate (PPi) and activity of nucleoside triphosphate pyrophosphatase (NTPP) were estimated in synovial fluid from 91 asymptomatic normal knees. including five with isolated CPPD crystal deposition (70 subjects; median age 47. range 22-83 years). In non-crystal fluids. PPi levels and NTPP activities were low (median. interquartile range: 9.5. 7.6-12.3 microM. and 1. 0.4-2 microM/30 min/mg protein. respectively: n = 50) and a generalized increase with age was not demonstrated. Higher values for PPi and NTPP in all five subjects with isolated CPPD deposition supports involvement of altered PPi metabolism. unrelated to ageing per se. in crystal formation. Presumed cartilage fragments were identified by morphological characteristics in 70% of normal fluids: metachromatic staining and electron microscopy. undertaken in a limited number. supported identification of such particles as cartilage. This finding supports dynamic turnover of healthy matrix. and questions the usefulness of identification. without quantification. cartilage fragments as a measure of cartilage damage.
A limited association of generalized osteoarthritis with alleles at the type II collagen locus: COL2A1, A significant genetic influence in osteoarthritis has been observed in the combination of Heberden's nodes and generalized osteoarthritis. We examined whether mutation in the gene encoding the major cartilage matrix protein type II collagen was responsible by comparing allele frequencies at the locus (COL2A1) in a group of 61 patients with nodal GOA with a control population and by analysing the COL2A1 genotypes of 21 affected sibling pairs. There were no significant allele differences but a slightly increased tendency over chance alone for affected siblings to have inherited the same COL2A1 alleles from their parents.
Surgical collars: a survey of their prescription and use, We report the results of a questionnaire survey of 124 orthopaedic. rheumatology. medical and accident and emergency outpatients prescribed a surgical collar during a 3-month period. Of these. 99 (80%) returned the questionnaire. Instructions received about when to wear the collar differed widely. especially between specialties. Most patients (76%) found benefit in wearing the collar. Pain was the symptom helped most (78%) whilst dizziness was helped least (40%). Problems with the collars were common. many being too hot (69%) and uncomfortable (48%). A third had difficulty putting the collar on. Despite these problems. compliance was good with 19 patients discontinuing collars for reasons other than recovery or medical advice. We believe this study highlights further areas for research and stimulates a re-evaluation of collar usage.
Plasma levels of interleukin-1-alpha in rheumatoid arthritis, Interleukin-1-beta (IL-1 beta) has been implicated as an inflammatory mediator in rheumatoid arthritis (RA) but little is known about the related cytokine. IL-1 alpha. in this disease. IL-1 alpha has biological properties similar to IL-1 beta but. unlike IL-1 beta. remains mostly cell-associated. In this study plasma IL-1 alpha was measured by radioimmunoassay in patients with RA and in healthy controls. Plasma levels were compared with conventional measures of disease activity. The mean levels in the two groups were not significantly different and. within the patient group (n = 53). the only significant cross-sectional correlation was between plasma IL-1 alpha and ESR. In longitudinal studies. some individual patients had plasma IL-1 alpha levels that correlated with different measures of disease activity. We conclude that while IL-1 alpha may be involved in the immunopathogenesis of RA. its measurement in plasma seems to offer little of clinical value.
A comparison of disability measured by the Stanford Health Assessment Questionnaire disability scales (HAQ) in male and female rheumatoid outpatients, Eighty-five consecutive rheumatoid patients (M:F = 22:63) seen during a 10-week period were studied. There were significant differences between the sexes for haemoglobin (means (SD) M = 13.5 (1.2). F = 12.0 (1.6) g/dl. P less than 0.01). presence of nodules (M = 50%. F = 19%. P less than 0.05) and for the HAQ scores (mean (SD) score M = 1.1 (0.9). F = 1.7 (0.9). P = 0.03) but not for age. disease duration. presence of erosions. Larsen score. treatment. pain. early morning stiffness. articular index. ESR. and C-reactive protein. The results suggest that the patients were matched for age. disease activity. severity and duration. The difference in haemoglobin between the sexes is in keeping with a reference population. The data suggest that the impact of RA has a greater effect on the functional status of women.
Guiding catheter-assisted renal artery angioplasty, A guiding catheter was used in seven patients who underwent balloon dilation of nine renal arteries. The advantages of using a guiding catheter for renal angioplasty are analogous to the benefits obtained with a coronary angioplasty guiding catheter used in coronary angioplasty. The guiding catheter provides back-up support to cross lesions and allows selective contrast visualization of the lesion before. during. and after dilation. It is also possible. when using a guiding catheter. to measure pressure gradients across lesions without having to recross the lesion which may help to ensure that adequate dilation of the stenosis has been accomplished.
Balloon diameter of the Inoue balloon catheter during percutaneous transvenous mitral commissurotomy: clinical and experimental study, To determine adequate and effective balloon diameters of the Inoue balloon catheter. we reviewed clinical results and characteristics of the Inoue balloon catheter. especially the relationship between the intra-balloon pressure and the balloon diameter. experimentally and clinically. in 46 patients with mitral stenosis undergoing percutaneous transvenous mitral commissurotomy (PTMC). Mitral valve area increased from 1.1 +/- 0.3 to 2.1 +/- 0.3 cm2 in all patients after PTMC. Based on balloon diameter settings. mitral valve area increased from 1.3 +/- 0.4 to 2.3 +/- 0.5 cm2 in patients treated with a balloon setting greater than 26 mm in diameter. from 1.1 +/- 0.3 to 2.0 +/- 0.5 cm2 in patients with a balloon setting at 26 mm in diameter. and from 1.1 +/- 0.4 to 1.7 +/- 0.4 cm2 in those treated with a balloon setting less than 26 mm in diameter. with an increase in mitral valve area of 1.0 +/- 0.6. 0.9 +/- 0.4. and 0.7 +/- 0.2 cm2. respectively. There was a significant difference between the increase in mitral valve area at a setting of 26 mm in diameter and that observed at a setting less than 26 mm in diameter. We next investigated differences between balloon diameter settings and actual balloon diameters measured from cineangiograms at maximum balloon inflation. The ratio of actual balloon diameter to a setting diameter of less than 26 mm was smaller than that of 26 mm. To evaluate the reason for the difference. we investigated the relationship between intra-balloon pressure and balloon diameter. In the prototype Inoue balloon catheter. intra-balloon pressure increases from 1.0 kg/cm2 at 20 mm in diameter to 2.2 kg/cm2 at 30 mm in diameter at atmospheric pressure. In conclusion. the increase in mitral valve area was inadequate when the balloon was less than 26 mm in diameter because of inadequate intra-balloon pressure. We. therefore. recommend a balloon size set above 26 mm to obtain adequate intra-balloon pressure when using the Inoue balloon catheter.
Crossing failure in PTCA: mind the deflated balloon profile, An attempt to reposition an Integra PTCA balloon-on-a-wire failed although the whole stenosed segment could be crossed before inflation. After careful removal the device showed a grossly altered shape. Deflated balloon profiles. quite different from the initial shape. can determine the outcome both in dissections and in multilesion cases.
Left main coronary artery aneurysm in association with severe atherosclerosis: a case report and review of the literature, Aneurysms of the coronary arteries occur in from 0.3% to 4.9% of angiograms. Only 12 cases of left main artery (LMA) aneurysms have been reported. Of these. seven were associated with atherosclerosis in patients more than 56 years old. This report details the case of a 39-year-old patient with a large LMA aneurysm associated with atherosclerosis.
Coronary angioplasty in octogenarians: comparisons to coronary bypass surgery, Coronary angioplasty was performed in 74 patients 80 years of age and older (mean 83 +/- 3). Single vessel coronary disease was present in 34% and multivessel coronary disease in 66%. Angioplasty of a single vessel was performed in 51 patients (69%). while 23 (31%) had angioplasty of multiple vessels. Angioplasty was successful in 59 of 74 patients (80%). Angioplasty was unsuccessful but uncomplicated in 12 (16%) due to (unyielding) calcified lesions or (impassable) old occlusions. Of these 12. 8 were discharged on medical therapy and 4 underwent elective uncomplicated bypass surgery prior to discharge. Three (4%) patients required emergency coronary bypass surgery due to abrupt vessel closure during the angioplasty procedure. with one hospital death (1.4%). Follow-up (mean 24 +/- 22 months) was obtained in all patients. Of the 59 successful angioplasty patients. late mortality was 10% (cardiac 7% and non-cardiac 3%). Survival and survival without myocardial infarction were both 90%; survival without either infarction or bypass surgery was 86%. Actuarial 3-year survival was 91% and 3-year freedom from death. infarction or bypass surgery was 87% by life-table analysis. Repeat angioplasty for restenosis was performed in 7 patients (12%) without complications.
Proximal rupture and intracoronary entrapment of a rotating device during low-speed rotational coronary angioplasty, While attempting to recanalize a right coronary artery obstruction by using a low-speed rotating catheter (Rotacs). proximal rupture of the catheter body occurred with entrapment of the blunt tip in the obstruction. To retrieve the device. it was necessary to severe the guiding catheter and the flexible tube of the Rotacs. At low-speed rotation the flexible segment of the catheter was then pulled back.
Concurrent double balloon valvotomy for combined rheumatic mitral and tricuspid stenosis, We expanded the application of percutaneous balloon valvotomy (PBV) to 4 adults (age 14 to 30 years. average 22.2 years) with combined rheumatic mitral and tricuspid stenosis. Double balloon dilatation reduced the transmitral gradient from 17.36 +/- 3.54 to 5.52 +/- 0.89 (P less than 0.025) and transtricuspid gradient from 12.65 +/- 2.67 to 3.67 +/- 0.95 (P less than 0.025). Mitral and tricuspid valve area increased from 0.73 +/- 0.20 to 2.57 +/- 0.67 (P less than 0.005) and from 0.77 +/- 0.24 to 2.67 +/- 0.24 cm2 (P less than 0.005). respectively. The procedures were well tolerated. with no significant increase in valvular regurgitation or left to right shunt across the atrial septum. The excellent symptomatic and haemodynamic benefits are sustained at 3-24 months follow-up. It is concluded that combined dilatation of stenotic valves by double balloon technique can emerge as an alternative to surgery in selected patients with polyvalvar rheumatic heart disease.
A new technique for sheathless percutaneous intraaortic balloon catheter insertion, Intraaortic balloon counterpulsation is helpful for controlling myocardial ischemia and providing hemodynamic support. but its applicability is limited by lower extremity ischemic complications in a significant percentage of patients. We developed a new sheathless technique for percutaneous intraaortic balloon catheter insertion which reduces the effective catheter diameter. A pilot study using this new technique resulted in a 10% rate of limb ischemia. without compromise of balloon function. We conclude that this technique may be useful in reducing the incidence of limb ischemia associated with intraaortic balloon counterpulsation.
Postoperative urinary retention associated with total hip and total knee arthroplasties, Urinary retention following total hip and knee arthroplasty is a common problem frequently necessitating either prolonged urethral catheter drainage or intermittent catheterization. The direct relationship of urinary tract instrumentations. procedures. and infections to deep sepsis in total hip replacements is well documented. Pharmacologic therapy to stimulate voiding or augment bladder emptying is thus theoretically preferable to the use of catheterization. Prasozin hydrochloride. an alpha blocker. relaxes the smooth musculature of the posterior urethra and prostrate and has been used to treat urinary obstruction secondary to benign prostatic hypertrophy. A prospective study in 60 male patients showed a statistically significant decrease in postoperative urinary retention with the perioperative administration of prazosin (p less than 0.01). A higher incidence of urinary tract infection was seen in patients who developed urinary retention (3% versus 20%) (p less than 0.01). Uroflowmetry parameters were not predictive of the patient at risk for retention and were unaltered with the administration of prazosin. Prazosin can be an effective adjunct in the prophylaxis of postoperative urinary tract infections and may decrease the potential risk for total joint sepsis.
Investigation of early surface delamination observed in retrieved heat-pressed tibial inserts, The objective was to examine possible reasons for delamination observed in tibial inserts of the porous-coated anatomic (PCA) knee replacement. To date. 33 PCA inserts have been forwarded to the authors' labs. Of these 33. 52% showed severe delamination within four years of implantation. Visual. structural. and mechanical analyses were conducted and data compared on the heat-pressed PCA type and the common machined inserts. Twenty inserts of the two different types were examined. Visual data using polarized light microscopy showed the presence of a surface layer separated from the middle region of the heat-pressed inserts by a line of demarcation 250-580 microns beneath the articulating surface. This anomaly was not observed in machined inserts. Structural analysis showed the new heat-pressed inserts had increased crystallinity in the surface layer when compared to new machined inserts. The retrieved heat-pressed inserts showed increased crystallinity in the surface and middle regions. There was a slight increase in surface crystallinity in the retrieved machined inserts. Microhardness data showed that there was an increased hardness associated with the crystallinity seen on the heat-pressed inserts. Orthopedic surgeons should be aware of early delamination and surface failure in heat-pressed inserts.
Fuller Albright. His concept of postmenopausal osteoporosis and what came of it, Fifty years ago Albright contributed the following to understanding osteoporosis: (1) He recognized it as a deficiency of formation. not of mineralization of bone matrix; (2) he observed that 40 of 42 patients with osteoporosis before age 65 were women past menopause or young women postoophorectomy; (3) he concluded that estrogen stimulates osteoblasts (a conclusion later challenged); (4) he demonstrated by metabolic balance studies that estrogen causes a positive calcium balance in postmenopausal osteoporosis; (5) he introduced periodic progesterone to prevent or treat endometrial hyperplasia from prolonged estrogen therapy; and (6) he showed that long-term therapy arrested vertebral damage and height loss in postmenopausal osteoporosis and prevented them if started early. Since Albright's time. more sensitive methods of assessing bone density have replaced conventional roentgenograms. Some large scale trials of estrogen have indicated increased bone density and fewer fractures. Unopposed estrogen increases risk of endometrial cancer and decreases mortality from other cancers. myocardial infarction. stroke. and osteoporosis. Trials of calcitonin. diphosphonates. fluoride. vitamin D. and high calcium intake have not proved more effective than estrogen.
Chemonucleolysis in the herniated L3-L4 disk, In a continuous series of 770 patients with a herniated disk treated by chemonucleolysis. 16 patients had herniation of the L3-L4 disk (2.1%). There were no complications. and none of these 16 patients had open surgery after the initial treatment. A follow-up study was performed after 39 months (range. six to 80 months) in 15 patients. Three patients were for the most part satisfied and 12 patients were fully satisfied with the result of treatment. Residual pain was minor in most patients. Roentgenographic signs of increased disk degeneration were seen in six patients. and reexpansion of the disk to some degree was noted in four patients. Chemonucleolysis is effective for treatment of the herniated L3-L4 disk.
Scapular fractures. Analysis of 113 cases, Scapular fractures have been the subject of study since Desault's treatise of 1805. but few large-scale studies have been completed with long-term follow-up evaluation of displaced scapular neck and spine fractures. This series of 148 fractures in 116 scapulae (113 patients) appears to be the largest ever reported and the only one with a follow-up study of a significant group (24 patients). Significant disability was found in patients with displaced scapular spine and neck fractures: (1) pain at rest in 50%-100%. (2) weakness with exertion in 40%-60%. and (3) pain with exertion in 20%-66%. Based on these findings. the indications for operative management should be expanded to include displaced scapular neck and spine fractures. Using extensile exposure through a posterior Judet incision. rigid internal fixation. and early motion. results in eight cases were excellent. All patients recovered at least 85 degrees of glenohumeral abduction. normal scapulothoracic motion. and none had resting pain. night pain. or pain with abduction. The minimum follow-up study period was 15 months.
Differences in shoulder muscle activity between patients with generalized joint laxity and normal controls, The aim of the present study was to analyze shoulder muscle activity in patients with generalized joint laxity and shoulder instability and to compare it with muscle activity recorded in healthy subjects from an earlier study. Electromyographic (EMG) activity was recorded from eight shoulder muscles in six patients using surface and intramuscular fine-wire electrodes. Recordings were made from the subscapularis. supraspinatus. infraspinatus. pectoralis major (sternoclavicular part). the anterior. middle. and posterior parts of the deltoid. and the latissimus dorsi. The EMG signal was low-pass filtered. full-wave rectified. and time-average. Normalization of the EMG allowed interindividual and intraindividual comparisons. During abduction and flexion. muscle activity in the anterior and middle parts of the deltoid was significantly decreased in the patients. and during internal rotation activity in the subscapularis was increased. As in healthy subjects. patients showed simultaneous activity in both those muscles producing the movement and in the antagonistic muscles. The altered muscle activity observed in patients with generalized joint laxity provides (1) a basis for understanding the mechanism of their shoulder instability and (2) the rationale for a physical training program for these patients.
Posterior dislocation of the elbow, Posterior dislocation of the elbow is associated with significant morbidity and incomplete recovery. In this series of 32 patients. those with associated fractures. posterolateral dislocations. delayed reduction. and rigid immobilization had the least satisfactory outcome.
In vivo measurements of relative motion between an uncemented femoral total hip component and the femur by roentgen stereophotogrammetric analysis, Roentgen stereophotogrammetric analysis (RSA) was used to study rotation and subsidence of an uncemented polyethylene-coated femoral component for total hip arthroplasty in ten patients younger than 55 years of age. Three years postoperatively. the total subsidence averaged 2.44 mm and the internal rotation was 7.4 degrees. The rate of subsidence decreased between the observation periods. whereas the rate of rotation. after an initial significant decrease. became almost constant. One patient. who was a clinical failure and required revision arthroplasty. had a significantly higher rate of migration after six months. The pattern of subsidence in the absence of pain might be the normal reaction of bone to an uncemented prosthesis. but the continuing rotation suggests the potential for failure of the arthroplasty. The type of analysis made possible in RSA may allow early prediction of the success of arthroplasties and significantly speed the design cycle for arthroplasty components.
Sesamoid disorders and treatment. An update, The anatomy. function. and disorders of the hallucal sesamoids show that the diagnosis and current concept of management are based on the individual patient's problems. The treatment should always be initiated in a conservative fashion. generally using a molded insole with an appropriate excavation to shift weight from a painful sesamoid. The advantages and disadvantages of sesamoidectomy are influenced by surgical technique. Care in handling the medial and lateral hallucal nerves is essential. Removal of both the medial and lateral sesamoids invariably leads to an intractable clawtoe deformity and is absolutely contraindicated.
Anterior cruciate ligament allograft transplantation in dogs, The biomechanical and clinical performance of bone-ligament-bone anterior cruciate ligament (ACL) allografts was studied in eight dogs. Allografts were collected from skeletally mature. healthy dogs using aseptic technique. and stored at -70 degrees for three to five weeks before implantation. The allografts were size-matched to the recipient dogs using ACL length and then rigidly fixed in position with interference screws and Kirschner wires. Three dogs regained a normal gait. and their grafts sustained breaking loads that were 25%. 41%. and 59% of controls. Partial or complete graft failure occurred in the other five dogs at some point in the study. Four had intraligamentous rupture and one had an avulsion fracture of the femoral attachment site. Joint-fluid cytology was normal in all eight dogs. Histologic examination showed persistent lymphoplasmacytic infiltrate. Eventually the allograft cores were incorporated in the host bed. Hyperplasia and fibrosis of the synovial membrane were diffuse and persisted as focal accumulations of mononuclear inflammatory cells.
Total knee arthroplasty at a Veterans Administration Medical Center, Total knee arthroplasty (TKA) was evaluated in 256 consecutive knees in a Veterans Administration hospital. Patient satisfaction and the effect of intercurrent illness were studied in addition to standard clinical and roentgenographic parameters. Evaluation of results show the superiority of condylar knee designs. In general. TKA was successful with a high degree of patient satisfaction.
Results of total knee arthroplasty using the posterior stabilized condylar prosthesis. A report of 137 consecutive cases, One hundred thirty-seven consecutive posterior stabilized total knee arthroplasties (TKAs) were reviewed. Average age of the patient was 61.1 years and length of postoperative follow-up period was 29.2 months. Patients were evaluated using the Hospital for Special Surgery (HSS) knee rating scores. Average preoperative scores improved from 52 to 92. postoperatively. Ninety-eight percent of patients had no pain or mild occasional pain postoperatively compared with 99% of patients experiencing severe to disabling pain preoperatively. Complications included one myocardial infarction. two deep venous thrombosis. one urinary tract infection. one patellar dislocation. and four wound problems. There were two incidences of seroma. one hematoma. and one deep infection requiring revision after joint debridement and systemic antibiotics. Also noted was one incidence of ligamentous laxity and one patella fracture.
Effect of the tibial cut on subsidence following total knee arthroplasty, In 33 total knee arthroplasties (TKAs) using instrumentation designed to cut the tibia with 0 degree posterior slope. ten tibial components demonstrated at least 2 mm of tibial component subsidence. These subsided components were implanted onto tibiae with an average of 8 degrees +/- 2 degrees difference between the preoperative. anatomic posterior slope and their postoperative posterior slope. The remaining 23 components. without subsidence. were implanted onto tibiae cut within 2 degrees +/- 2 degrees of their anatomic slope. To help understand these clinical observations. a laboratory study was performed to compare the load carrying capacity and the stiffness of tibial subchondral bone following two types of tibial cuts: one made perpendicular to the long axis of the tibia and the other made parallel to the articular surface of the tibia. Mock tibial baseplates mounted on paired cadaver tibiae were loaded in compression and force displacement curves were recorded. Tibiae cut parallel to the surface exhibited 40% greater load carrying capacity and 70% greater stiffness than the paired tibiae cut perpendicular to the long axis. The biomechanical data of this study indicated that cutting the tibia perpendicular to the long axis results in weaker bone that may be inadequate to support a tibial component. This may explain the higher incidence of clinical subsidence if the tibial cut is not made approximately parallel to the anatomic slope.
Infections at the site of a hip implant. Successful and unsuccessful management, Thirty-four patients developed the complication of deep infection at the site of a hip implant (n = 35). Multiple factors in existence at the time of implant placement and the time of presentation with infection as well as the therapeutic regimen were retrospectively analyzed. Patients with successful outcomes (n = 15) were relatively younger (mean. 52 years) compared to those that had an unsuccessful outcome (n = 19; mean. 65 years; p less than 0.01). No other factors were predictive of the outcome of treatment. Implant extirpation. expedient wound closure. and. when necessary. muscle transposition favored a successful outcome. Implant retention and open wound packing resulted in prolonged wound healing and. sometimes. hip disarticulation or death.
Blood loss in total knee arthroplasty, Over a two-year period. 112 consecutive primary total knee arthroplasties (TKA) were performed according to a standard protocol and were evaluated to determine the effects of intraoperative tourniquet deflation. suction drainage. and immediate continuous passive motion (CPM) on blood loss and the need for blood transfusions. It has been reported that these measures lead to increased morbidity following TKA. The tourniquet was deflated before closure. hemostasis was obtained. and two suction drains were placed for 24 to 48 hours. CPM was started immediately. and continued for a mean of seven days. Serial hematocrits (Hct) were obtained. Mean age of the 64 males and 48 females was 65 years. The diagnosis was osteoarthritis in 86% and rheumatoid arthritis in 14%. Seventy-three percent of the prostheses were cemented and 27% were uncemented. The mean tourniquet time was 104 minutes and the mean length of surgery was 140 minutes. Blood loss measured at surgery averaged 222 ml. Total calculated blood loss averaged 794 ml. but was higher for patients with a cemented versus uncemented prosthesis (p less than .05). and males versus females (p less than .005). It was not related to diagnosis. tourniquet time. or length of surgery. Of the 38% of patients requiring a transfusion (mean. 2.2 units). there was not a significantly greater drop in Hct (from 36.6 to 26.5; change. 10.1) when compared to patients not receiving a transfusion (from 43.1 to 32.5; change. 10.6). Therefore. the need for transfusion was related to preoperative Hct and not the intraoperative or postoperative blood loss.
Treatment of bronchial asthma with terbutaline inhaled by conespacer combined with positive expiratory pressure mask, The influence of positive expiratory pressure (PEP) applied during inhalation of a beta 2-agonist in treatment of bronchial asthma was investigated in a randomized crossover study with two-week treatment periods. In one period. two puffs (0.5 mg) of terbutaline was given from a metered dose inhaler and inhaled through a device consisting of a conespacer connected to a facemask giving PEP (10 to 15 cm H2O). In a second period. terbutaline 0.5 mg was inhaled similarly but without PEP. and in a third period placebo spray was inhaled with PEP. Treatments were given three times daily. Peak expiratory flow (PEF) was measured before and after each inhalation and symptom scores for dyspnea. cough. and mucus production were noted in a diary. All treatments increased PEF significantly (p less than 0.0001). The mean increase was 32 L/min during treatment with terbutaline and PEP. This was greater than the increase of 25 L/min during terbutaline treatment (p = 0.005). The increase in PEF during terbutaline treatment was significantly higher than the achieved 18 L/min during PEP (p = 0.026). The study showed improved bronchodilation when PEP was combined with inhalation of beta 2-agonist compared with beta 2-agonist alone.
Right ventricular hypertrophy detected by echocardiography in patients with newly diagnosed obstructive sleep apnea, We used polysomnography. echocardiography and ventilatory measurements to study 50 patients suspected of having OSA to determine a link to RVH. Twenty-eight patients (56 percent) had OSA and 20 (71 percent) of those had isolated RVH. We evaluated patients with RVH and divided them into two groups. those with apnea and those without apnea. The patients with sleep apnea were younger. weighed more. had greater BSA and had lower average oxygen saturations during the sleep study period. We divided the group with apnea into those with RVH and those without it. Those patients with RVH had a higher AI. longer average apnea time. a greater duration of longest apnea and a lower average oxygen saturation for the period of the sleep study. In addition. those with RVH had a lower average oxygen saturation during each apneic episode with a p value equaling 0.09.
Phrenic nerve injury. A prospective study, In cardiac surgery. topical iced saline solution slush has become an important adjunct in maintaining myocardial hypothermia during cardioplegic arrest. One complication of this technique is phrenic nerve injury (PNI). In an attempt to reduce the incidence of PNI. a prospective study was undertaken to evaluate the impact of phrenic nerve insulation on PNI during cardiac surgery. Seventy-six consecutive patients who underwent coronary revascularization constituted the control group (CG) and were compared with 76 patients who underwent a similar procedure with the addition of phrenic nerve insulation. In the intervention group (IG). a foam insulation pad was placed between the heart and the pericardium in an effort to reduce exposure of the phrenic nerve to iced saline solution slush. There was no difference in major demographic descriptors or operative variables between the CG and the IG. except that the internal mammary artery was used more frequently in the IG (64 percent vs 36 percent. p = 0.0006). The in-hospital mortality was similar between the groups (CG. 0.0 percent; IG. 1.3 percent; p = 1.0); however. the incidence of roentgenographically diagnosed PNI was much greater in the CG (14/76 patients [18 percent] vs 0/76 patients [0 percent]; p = 0.0006). Patients with and without PNI were similar with regard to age. gender. aortic cross clamp time. cardiopulmonary bypass time. and number of grafts (p greater than 0.05). All unilateral PNI occurred on the left. Three patients with bilateral PNI required tracheostomy and prolonged mechanical ventilation. In-hospital mortality was similar for patients with and without PNI (0 percent vs 0.7 percent). but mean postoperative hospital stay for patients with clinically diagnosed PNI was longer than for those without PNI (32 vs 11 days. p = 0.04). This prospective study demonstrates that the incidence of PNI can be significantly reduced by the routine use of phrenic nerve insulation.
Evaluation of ultrasonically guided biopsies of mediastinal masses, Eighty patients with roentgenographic evidence of mediastinal abnormalities were examined with ultrasonography. Fifty-four lesions were malignant. and 26 lesions were benign. The histologic diagnoses were confirmed by ultrasonically guided fine needle aspiration/cutting needle (Tru-Cut) biopsy. surgical specimens. or transbronchial biopsy. There were no unique ultrasonographic features for diagnosis of specific tumors. Ultrasonically guided aspiration biopsies (UGAB) were performed in 44 of the malignant lesions and in 14 of the benign lesions (nine of the noncystic lesions and five of the cystic lesions). Cytologic diagnosis of malignancies was obtained in 34 (77 percent) of these 44 malignancies; however. accurate histologic classifications of malignancies were achieved in only 24 (55 percent). Accurate diagnoses were achieved in only three (33 percent) of the nine noncystic benign lesions. Ultrasonically guided cutting biopsies (UGCB) were performed in 24 malignant and five benign lesions. All attempts yielded satisfactory specimens for histologic diagnosis. Using UGAB and UGCB together. a positive diagnosis was achieved in 89 percent (39/44) of the malignancies. and accurate histologic diagnosis was achieved in 89 percent and 78 percent (7/9) in malignant and benign noncystic lesions. respectively. Correct histologic diagnosis with UGAB alone is lower in thymoma (55 percent [6/11]) and lymphoma (30 percent [3/10]) but higher in lung cancer (67 percent [8/12]) and metastatic cancer (78 percent [7/9]). There were no complications in this series. We conclude that ultrasonography with UGAB has a high diagnostic yield in diagnosing mediastinal tumors. and UGCB is necessary for thymic tumors. lymphoma. and benign lesions.
Assessment of bronchodilator response to a beta-adrenergic delivered from an ultrasonic nebulizer, We assessed the bronchodilator response to a recently available ultrasonic nebulizer (USN) in a population of 17 stable asthmatic patients. These patients were also evaluated for bronchodilator response to two other aerosol delivery systems routinely used in standard clinical practice. the metered-dose inhaler (MDI) and the jet nebulizer (JN). Albuterol was administered from each of the delivery systems in the following manner: MDI. two actuations (180 micrograms); JN. 0.5 ml of 0.5 percent solution (2.5 mg) in 1.0 ml saline solution diluent; and USN. 0.5 ml of 0.5 percent solution (2.5 mg) in 2.5 ml saline solution diluent. Patients demonstrated significant bronchodilator responses to all three delivery systems (p less than 0.0001). The USN produced a greater percentage of increase in FEV1 15 minutes after treatment with albuterol (35.8 +/- 2.3 percent) than either the MDI (18.2 +/- 3.4 percent) or JN (20.8 +/- 3.1 percent) (p less than 0.005). The mean percentage of increase in FE1 observed over a 4-h period after treatment was also greater for the USN (26.5 +/- 2.5 percent) than either the MDI (18.8 +/- 1.8 percent) or JN (15.0 +/- 1.6 percent) (p less than 0.001). We conclude that the USN yields effective bronchodilation in a population of stable asthmatics.
Response of obstructive sleep apnea to fluoxetine and protriptyline, Protripyline is the pharmacologic agent most commonly used to treat obstructive sleep apnea (OSA); however. its anticholinergic side effects make it intolerable to many patients. Because serotonin may be a central respiratory stimulant and because the serotonin-uptake inhibitor. fluoxetine. is usually well tolerated. we wanted to try fluoxetine in the treatment of OSA. Therefore. we compared the effect of fluoxetine to that of protriptyline in 12 patients with OSA. Both drugs significantly decreased the proportion of REM sleep time and decreased the number of apneas or hypopneas in NREM sleep. The response to fluoxetine was equivalent to that of protriptyline; however. for the group as a whole. there was no significant improvement in the number of arterial oxygen desaturation events. the level of arterial oxygen desaturation. or the number of arousals with either agent. Although there was wide variability in the response to each medication. six of the 12 patients had good responses. including improvement in oxygenation. to either fluoxetine or protriptyline. Three patients could not complete the trial of protriptyline. We conclude that fluoxetine is beneficial to some. but not all. patients with OSA. Fluoxetine was better tolerated than protriptyline.
Intraluminal pulsed Doppler evaluation of the pulmonary artery velocity time curve in a canine model of acute pulmonary hypertension, The velocity pattern of the blood flow in the pulmonary artery was investigated in an animal model of acute pulmonary hypertension. Nine anesthetized. open-chest dogs were embolized with polystyrene microspheres. and the velocity pattern of the blood flow in the pulmonary artery was studied with use of an invasive pulsed Doppler technique. Phasic intraluminal velocity was recorded with use of a miniature piezoelectric crystal activated by 20-MHz Doppler pulses and mounted on the tip of a needle probe introduced into the pulmonary artery. The recorded Doppler quadrature signals were processed by spectral analysis. Significant increases occurred in mean. systolic. and diastolic pulmonary arterial pressures (p less than 0.0002). in pulmonary vascular resistance (p less than 0.005). and in negative velocity time (duration in milliseconds that the mean velocity was directed toward the pulmonic valve) (p less than 0.002). Significant decreases occurred in right ventricular ejection time (p less than 0.006) and in positive velocity time (duration in milliseconds that the mean velocity was directed away from the pulmonic valve) (p less than 0.005). A significant shortening in the time to peak velocity (acceleration time) was found (p less than 0.005). Second-order regression analyses demonstrated an inverse correlation between the ratio of positive velocity time to negative velocity time and the mean pulmonary artery pressure in all animals (r = 0.71). These findings should be compared with the velocity patterns of the blood flow in the pulmonary artery obtained under pulmonary hypertensive conditions due to various causes to facilitate interpretation and understanding of clinical investigations.
Inverse ratio ventilation in ARDS. Rationale and implementation, Conventional ventilatory support of patients with the adult respiratory distress syndrome (ARDS) consists of volume-cycled ventilation with applied positive end-expiratory pressure (PEEP). Unfortunately. recent evidence suggests that this strategy. as currently implemented. may perpetuate lung damage by overinflating and injuring distensible alveolar tissues. An alternative strategy--termed inverse ratio ventilation (IRV)--extends the inspiratory time. and. in concept. maintains or improves gas exchange at lower levels of PEEP and peak distending pressures. There are two methods to administer IRV: (1) volume-cycled ventilation with an end-inspiratory pause. or with a slow or decelerating inspiratory flow rate; or (2) pressure-controlled ventilation applied with a long inspiratory time. There are several real or theoretical problems common to both forms of IRV: excessive gas-trapping; adverse hemodynamic effects; and the need for sedation in most patients. Although there are many anecdotal reports of IRV. there are no controlled studies that compare outcome in ARDS patients treated with IRV as opposed to conventional ventilation. Nonetheless. clinicians are using IRV with increasing frequency. In the absence of well-designed clinical trials. we present interim guidelines for a ventilatory strategy in patients with ARDS based on the literature and our own clinical experience.
Relief of right ventricular angina and increased exercise capacity with long-term oxygen therapy, Long-term low-flow oxygen therapy can lead to improved exercise capacity and improved hemodynamics in selected patients with pulmonary hypertension. We report a patient who presented with severe exercise limitation and anginal chest pain that appeared to result from pulmonary hypertension and predominantly right ventricular ischemia. Acute oxygen therapy led to relief of pain but no change in exercise capacity or of pulmonary hypertension. After eight months of oxygen therapy. the patient's pulmonary hypertension was unchanged. but right ventricular hypertrophy and marked increases in exercise cardiac output and exercise capacity developed. Thus. oxygen can relieve right ventricular angina and facilitate the development of compensatory hypertrophy.
Atypical myxoma, We report the case of a 38-year-old woman with a large thin-walled cystic mass (6 x 5 x 4.5 cm) filled with arterial blood in the right atrium. The cystic mass with blood content was clearly delineated by transesophageal cross-sectional echocardiography and magnetic resonance imaging of the heart. At operation. a silver-whitish. smooth surfaced cystic mass was found attached to the free wall of the right atrium between the superior vena cava and the right atrial appendage with a broad base. Microscopically. the wall of the cyst was composed of stellate mesenchymal cells embedded within a myxoid matrix which was proved by alcian blue stain. To our knowledge. this type of cardiac myxoma has not been previously reported.
Formation and spontaneous closure of an arteriovenous fistula after transvenous pacemaker placement, We report the findings in a patient with the unusual complication of arteriovenous fistula formation of the subclavian vessels seven weeks following placement of a dual-chamber pacemaker. The fistula's subsequent course was equally unusual. closing spontaneously three weeks later. It is postulated that the thrombotic and fibrotic reaction elicited by the leads contributed to the fistula's closure. Two surgical procedures. correction of the fistula and reimplantation of the pacemaker. were thus avoided by careful monitoring of the patient.
Transthoracic and transesophageal echocardiography in the diagnosis and surgical management of right atrial myxoma, An asymptomatic patient was discovered to have a large right atrial myxoma by transthoracic echocardiography. Preoperative considerations included the possibility of satellite lesions. left atrial origin. and a question of tricuspid valve involvement. Subsequent operative transesophageal echocardiography demonstrated single-stalk attachment in the right atrial septal wall and no satellite lesions. Doppler and color flow examination immediately following tumor removal aided in the decision not to perform tricuspid annuloplasty as there was no significant tricuspid regurgitation. The combined use of transthoracic and transesophageal echocardiography with Doppler and color flow imaging aids in the preoperative and intraoperative diagnosis and surgical management of right atrial tumors.
Closure of a tracheoesophageal fistula by bronchoscopic application of fibrin glue and decontamination of the oral cavity, A tracheoesophageal fistula was successfully closed with a fibrin adhesive applied by means of a fiberoptic bronchoscope. instead of by esophagoscopy. To facilitate closure of the fistula. the technique was combined with decontamination of the oral cavity. to avoid bacterial contamination. The procedure is proposed as an alternative to surgery for critically ill patients.
Noninvasive methods in the diagnosis of ruptured aneurysm of Valsalva. Usefulness of magnetic resonance imaging and Doppler echocardiography, A ruptured aneurysm of noncoronary sinus of Valsalva was diagnosed noninvasively by magnetic resonance imaging (MRI). as well as by Doppler echocardiography. Diagnosis of this disease by MRI has not been reported previously.
Balloon dilation of postsurgical subaortic obstruction, Two children aged 10 and 5.5 years underwent balloon dilation for postsurgical subaortic obstruction. The outcome and the role of this procedure are discussed.
Diffuse esophageal spasm. A rare motility disorder not characterized by high-amplitude contractions, Diffuse esophageal spasm (DES) has frequently been described as a motility disorder characterized by simultaneous. high-amplitude contractions. We reviewed the results of esophageal manometry testing on a total of 1480 patients referred to our lab over 36 months. Lower esophageal sphincter (LES) pressure was determined by a mean of four station pull-through. Esophageal body motility was assessed following 10 wet swallows. In our lab a diagnosis of DES is made when greater than 10% but less than 100% of contractions are simultaneous. Manometric findings of DES were rare. with an overall prevalence of 4% (56/1480). Of the 56 patients with a manometric diagnosis of DES. high-amplitude (mean greater than or equal to 180 mm Hg) peristaltic contractions were found in only two (4%). No simultaneous contractions with amplitude greater than or equal to 180 mm Hg were seen. Pressures of simultaneous contractions were consistently lower than peristaltic contractions. A hypertensive LES pressure (greater than or equal to 45 mm Hg) was present in 5/56 DES patients (9%). Poor LES relaxation was found in 7/56 DES patients (13%). We conclude that DES is a rare manometric finding. regardless of the reason for referral. and that the occurrence of high-amplitude contractions in DES is equally rare.
Transcutaneous electrical nerve stimulation decreases lower esophageal sphincter pressure in patients with achalasia, Vasoactive intestinal peptide (VIP) is believed to be an inhibitory neurotransmitter responsible for lower esophageal sphincter (LES) relaxation. In patients with achalasia the concentration of VIP and the number of VIP-containing nerve fibers are reduced or absent. It has been suggested that the response to low-frequency transcutaneous electrical nerve stimulation (TENS) may be mediated by a nonadrenergic noncholinergic pathway in which the release of VIP is responsible for the smooth muscle relaxation. The present study was designed to evaluate the effect of TENS on LES pressure and on VIP plasma concentrations in six patients with achalasia (five female. one male). TENS was performed daily during one week for 45-min sessions with a pocket stimulator that delivered low-frequency pulses (6.5 Hz). at 10 pulses/sec of 0.1-msec duration at intensities of 10-20 mA until rhythmic flexion of the fingers was obtained without producing pain. LES pressure and VIP levels were obtained before TENS. after the first 45-min session. and after a week of daily stimulation. After 45-min. TENS produced a significant reduction (P less than 0.01) in LES resting pressure from the mean value 56 +/- 6.4 mm Hg to 42.3 +/- 6.4 mm Hg; with LES relaxation improvement from 50.6 +/- 3% to 63.1 +/- 3.2% (P less than 0.01). After one week of daily TENS. an additional reduction in LES resting pressure (40.3 +/- 4 mm Hg) was observed (P less than 0.01).
Provocation of transient lower esophageal sphincter relaxations by meals in patients with symptomatic gastroesophageal reflux, The effect of a meal on the rate of transient lower esophageal sphincter (LES) relaxations and patterns of gastroesophageal reflux was investigated in 49 patients referred for evaluation of gastroesophageal reflux. Esophageal motility and pH were recorded concurrently before and after a standard meal. In the patients with symptomatic reflux. the meal induced a four- to sevenfold increase in the gastroesophageal reflux through two mechanisms: a four- to fivefold increase in the rate of transient LES relaxations and an increase in the proportion of transient LES relaxations accompanied by reflux from 47% to 68%. Overall the rate of reflux episodes that occurred by mechanisms other than transient LES relaxation did not increase significantly. An exception to these findings were those in six patients with chronically absent basal LES pressure in whom transient LES relaxations could not be scored. In these patients. reflux increased postprandially through mechanisms other than transient LES relaxation. These findings confirm the pivotal importance of transient LES relaxations in the pathogenesis of gastroesophageal reflux.
A time-dependent study of passive esophageal wall properties and collagen content in rabbits with esophageal varices, The passive biomechanical wall properties of the esophagus were studied in rabbits with esophageal varices and controls using a four-electrode impedance technique. Stepwise pressure inflation and deflation was done for analysis of esophageal cross-sectional area. compliance. and hysteresis monthly during six months. At sacrifice. the esophageal collagen content was determined. A small but statistically insignificant increase in compliance was observed during the six-month observation period in both groups. No differences were observed between the groups (P greater than 0.3). No change in hysteresis was observed in either group. The group with esophageal varices had significantly higher collagen content in the distal esophagus when compared to controls (P less than 0.05). No difference was demonstrated in the proximal part. No correlation was demonstrated between the collagen content and esophageal compliance. The study demonstrated that the method allows measurement of luminal cross-sectional area and tissue elasticity. No relationship was found. however. between the collagen content and compliance of the rabbit esophagus.
Successful shock-wave lithotripsy of bile duct stones using ultrasound guidance, Eighteen patients with 41 gallstones in the common bile duct. common hepatic. cystic. and intrahepatic ducts underwent shock-wave lithotripsy using the electrohydraulic Sonolith 3000 lithotripter. Lithotripsy was performed using ultrasound guidance alone under intravenous analgesia/sedation. All patients previously had failed stone extraction via retrograde endoscopy. T-tube. or cholecystostomy. Lithotripsy was performed according to an FDA-approved protocol allowing a maximum of two 2500 shock-wave treatments at a 48 hr interval. Following the final lithotripsy or cholangiographic evidence of stone fragmentation. residual fragments were removed via endoscopic or percutaneous route within 24-72 hr. Ultrasound localization of gallstones was aided by continuous infusion of the common bile duct with saline solution. In 15 of the 18 patients. complete fragmentation of the stones was accomplished. two had minimal fragmentation. and one with an encysted stone had no fracturing. No serious complications were encountered. Overall nonsurgical stone-free success rate was 17 of 18 patients. indicating biliary duct stones can be successfully treated using an ultrasound-guided lithotripter and intravenous sedation alone.
Gallbladder function and gastric liquid emptying in achalasia, Because of evidence that the abnormalities in achalasia are not restricted to the distal esophagus. we investigated gallbladder function by cholescintigraphy in the steady state and in response to CCK and the scintigraphic gastric emptying of a liquid caloric meal in 10 individuals with achalasia and 10 normal controls. No abnormalities were found during the filling phase of the gallbladder but seven of the 10 patients showed a 50% reduction in the ejection fraction (39.4% +/- 30.4 vs 80.3 +/- 8.3 of controls. mean +/- SD. P = 0.007) and a slower than normal ejection phase (9.1%/min +/- 6.6 vs 18.1 +/- 4.5. P = 0.02. In eight of the 10 patients. gastric liquid emptying was accelerated with a T1/2 of 41.5 min +/- 15.4 vs 74.7 min +/- 11.5 in the controls (P = 0.007). It is concluded that in some achalasia patients extraesophageal functional abnormalities of the gastrointestinal tract may be found. Whether these findings are promoted by degenerative charges of extraesophageal nerve fibers as well as their clinical significance require further investigations.
Collagenous colitis with involvement of terminal ileum, We present a case of collagenous colitis with evidence of terminal ileal involvement. The patient suffered from chronic watery diarrhea of three months' duration. and colonoscopy revealed a normal endoscopic appearance. Histologic examination of biopsies revealed a broad subepithelial band of collagen. with similar histologic findings in the terminal ileum. Additionally. the patient exhibited abnormalities of d-xylose and vitamin B12 absorption. although there were no clinical signs of malabsorption. Biopsy of the proximal small intestine was normal. The significance of these findings for the definition of the clinicopathologic entity of collagenous colitis and its pathogenesis are discussed.
Insulin and cardiovascular disease. Paris Prospective Study, The Paris Prospective Study is a long-term investigation of coronary heart disease (CHD) risk factors in a large population of working men. The baseline cohort included 7028 men. 6093 who had a 75-g oral glucose tolerance test with measurement of plasma insulin and glucose levels (0 and 2 h) and 125 who were known non-insulin-treated diabetic patients. After a mean follow-up of 11 yr. 126 deaths ascribed to CHD were reported. Major independent predictors of CHD death were blood pressure. smoking. plasma cholesterol level. and fasting and 2-h postload plasma insulin level. Impairment of glucose tolerance. including overt diabetes. did not rank as an independent predictor when other baseline variables were accounted for. In the subset of the baseline cohort who presented with impaired glucose tolerance or diabetes (n = 943). 26 died from CHD during the follow-up. The strongest independent predictor of subsequent CHD death in this subsample with abnormal glucose tolerance was plasma triglyceride level. In view of the accumulating evidence that hyperinsulinemia and hypertriglyceridemia generally occur in the same type of subjects. in relation to insulin resistance and central obesity. the epidemiological findings of the Paris Prospective Study and of other investigations support the hypothesis that a constellation of mild metabolic abnormalities may play a deleterious role with regard to cardiovascular disease risk.
The neurology of aging: normal versus pathologic change, Mild changes in neurologic function occur with aging but generally do not substantially interfere with everyday activities unless disease intervenes. Not infrequently. older adults experience minor impairment in memory. speed of cognitive processing. sleep. vision and hearing. vibratory sense in the lower extremities. and gait and posture. In general. these changes correspond with age-associated neuroanatomic changes (eg. diminished brain weight). but there is wide variability in the extent to which these changes occur. Often. "normal" neurologic changes are difficult to distinguish from impairment associated with disease.
Does body posture affect the incidence and mechanism of gastro-oesophageal reflux, We studied eight patients with gastro-oesophageal reflux disease to compare the frequency and mechanism of reflux in the upright and supine positions. Simultaneous oesophageal manometry and pH studies were performed on two separate days in each subject in the fasting and postprandial periods. The frequency of reflux tended to be higher in the upright position. The most prevalent mechanism of reflux in either position was transient relaxation of the lower oesophageal sphincter. The frequency of transient lower oesophageal sphincter relaxation was higher in the upright than in the supine position. There was no difference in the total reflux time. acid clearance time. and number of reflux episodes lasting longer than five minutes in the two positions. We suggest that daytime reflux (upright) may be as important as night time (supine) reflux in the pathogenesis of reflux oesophagitis and needs to be considered when treating patients with reflux disease.
Gastritis due to spiral shaped bacteria other than Helicobacter pylori: clinical, histological, and ultrastructural findings, An intensive histological search for Helicobacter pylori in gastric biopsy specimens has led to the detection of other spiral shaped bacteria in the human gastric mucosa. The clinical and morphological findings of 39 cases (0.25% of all gastric biopsies performed in the observation period) are reported for 34 patients (87.2%) complaining of upper abdominal discomfort. Five patients (12.8%) had chronic gastritis and 34 (87.2%) chronic active gastritis. The organisms were seen by light microscopy deep in the gastric foveolae and intracellularly. The scanning and transmission electron microscopic findings show bacteria which invade and damage gastric mucosal cells. These organisms are similar to the spiral shaped bacteria found in the stomachs of cats and dogs and non-human primates. In eight patients organisms were not detected after four weeks of treatment with bismuth salts. The disappearance of the organisms coincided with resolution of the chronic active gastritis and the symptoms.
Can transcutaneous recordings detect gastric electrical abnormalities, The ability of transcutaneous recordings of gastric electrical activity to detect gastric electrical abnormalities was determined by simultaneous measurements of gastric electrical activity with surgically implanted serosal electrodes and cutaneous electrodes in six patients undergoing abdominal operations. Transient abnormalities in gastric electrical activity were seen in five of the six patients during the postoperative period. Recognition of normal gastric electrical activity by visual analysis was possible 67% of the time and with computer analysis 95% of the time. Ninety four per cent of abnormalities in frequency were detected by visual analysis and 93.7% by computer analysis. Abnormalities involving a loss of coupling. however. were not recognised by transcutaneous recordings. Transcutaneous recordings of gastric electrical activity assessed by computer analysis can usually recognise normal gastric electrical activity and tachygastria. Current techniques. however. are unable to detect abnormalities in electrical coupling.
Serum and tissue autoantibodies to colonic epithelium in ulcerative colitis, Sera and colonic tissue-bound immunoglobulin extracts from patients with ulcerative colitis and disease controls were examined immunohistochemically and by killer cell cytotoxicity assay for the presence of anticolonic epithelial autoantibodies. IgG yields in the tissue extracts from patients with colitis and control subjects were similar. and the extracts were uniformly autoantibody negative. Of 41 sera from patients with inflammatory bowel disease. 'classical' anticolon antibody was present in 41% and was commoner in patients with sclerosing cholangitis. Cytotoxic anticolon antibody was present in 20% overall and was strongly associated with disease activity; it did not correlate with the presence of 'classical' anticolon antibody. The heterogeneous and non-universal antiepithelial autoantibody response and the failure to detect tissue bound autoantibody in vivo argue against the hypothesis that humoral autoimmunity is of major importance in the pathogenesis of ulcerative colitis.
Cell recovery during segmental intestinal perfusion in healthy subjects and patients with Crohn's disease, The recovery of cells arising from small intestinal mucosa alone was studied during continuous perfusion of a closed segment of jejunum. The perfusion technique minimised the contamination of the perfused segment with. for example. proteolytic enzymes from pancreas. allowing recovery of viable cells. The use of hyaluronidase in the perfusion fluid increased the recovery of cells fivefold. the median recovery being 8 x 10(6) cells. The cells were analysed with monoclonal antibodies and flow cytometry. Nearly all cells (98-99%) recovered during perfusion of healthy control subjects and patients with Crohn's disease were epithelial cells. The jejunal cells expressed HLA-DR in similar proportions--around 30%--in patients and control subjects. The ratio between CD4+ and CD8+ lymphocytes was similar (0.2) in control subjects and patients with inactive Crohn's disease but decreased (0.03) in patients with active Crohn's disease in the ileum.
Morphometric studies in rectal biopsy specimens from patients with ulcerative colitis: effect of oral 5 amino salicylic acid and rectal prednisolone treatment, Morphometric measurements were performed on rectal biopsy specimens from 10 normal control subjects and 33 patients with a relapse of distal ulcerative colitis before and after treatment for four weeks in a double blind controlled trial with oral eudragit S coated 5 amino salicylic acid (n = 12) or rectal prednisolone enemas (n = 15). Measurements were assessed using a computer aided measuring system and a counting technique. When untreated patients were compared with the control group there were significant decreases in the area and height of the surface epithelium. in the area of crypt epithelium. and in the ratios of goblet cells to epithelial cells and of surface epithelium to lamina propria. The vascular and lamina propria areas and the number of intraepithelial polymorphs were increased. Treatment with 5 amino salicylic acid and corticosteroids resulted in similar morphological improvements: there was an increase in the area and height of the surface epithelium and the ratios of surface epithelium to lamina propria and of surface to crypt cell height. The ratio of goblet cells to epithelial cells also increased after treatment. while the numbers of polymorphs in the surface and crypt epithelium and lumen decreased. In conclusion. computerised morphometry is valuable for the assessment of the treatment of patients with ulcerative colitis and that in the doses used both treatments were of similar efficacy.
Binding of kidney bean (Phaseolus vulgaris) isolectins to differentiated human colon carcinoma Caco-2 cells and their effect on cellular metabolism, The binding of Phaseolus vulgaris (PHA) isolectins L4 and E4 to the brush border membrane of differentiated Caco-2 cells was studied and the impact on cellular metabolism and microvilli was assessed. Computer analysis of the data based on binding experiments with peroxidase conjugated isolectins gave mean (SD) values for maximal binding of 2540 (151).10(-9) M for PHA-L4 and 2104 (140).10(-9) M for PHA-E4 per mg of brush border membrane protein. The dissociation constants for L4 and E4 binding were 4.3 (1.4).10(-6) M and 1.1 (0.8).10(-6) M. respectively. Incubation of differentiated Caco-2 cells for 30 minutes with ferritin conjugated PHA isolectins showed that. as indicated by the number of ferritin particles. PHA-E4 bound to the microvilli to a greater extent than PHA-L4. Ferritin particles were also localised intracellularly over endocytotic invaginations and vesicles. After incubation for 48 hours with PHA-L4 or PHA-E4. the relative incorporation of precursors for DNA. RNA. and (glyco)protein synthesis into the trichloroacetic acid insoluble fraction of the Caco-2 cells was determined. Both isolectins stimulated the incorporation of thymidine and glucosamine. but neither PHA-L4 nor PHA-E4 were able to influence the incorporation of uridine. With respect to fucose. methionine. and N-acetyl mannosamine. the stimulatory effect remained confined to PHA-E4. Since PHA-L4 and PHA-E4 were tested at the same concentrations. PHA-E4 is more effective than PHA-L4. The changes in the uptake of radioactive precursors were lost after heat inactivation of PHA-E4. Compared with control and PHA-L4 incubated Caco-2 cells. the microvilli of PHA-E4 incubated cells were shortened significantly (p less than 0.01).
In vitro comparison of different gall stone dissolution solvents, Extracorporeal shockwave lithotripsy (ESWL) of gall bladder stones leaves residual fragments that need to be dissolved by chemical solvents. In this study we compared the in vitro dissolving capacity of methyl tert-butyl ether (MTBE). mono-octanoin. limonene. and limonene/mono-octanoin (70%/30%). From nine sets of five human gall stones obtained at cholecystectomy. four stones were used for dissolution and the fifth was used for chemical analysis of cholesterol. calcium. and bilirubin contents. Eight sets were cholesterol stones with a mean (SD) cholesterol content of 89.9 (5.6)%. These stones dissolved completely in either solvent. often leaving sand-like debris. with the exception of one stone. MTBE dissolved cholesterol gall stones 100 times faster than mono-octanoin and 10 times faster than limonene or the limonene/mono-octanoin mixture (p less than 0.001). The combination of limonene and mono-octanoin was as effective as limonene alone. Of the four solvents. MTBE is the best one to evaluate for dissolution of residual fragments after ESWL treatment of gall bladder stones.
Timing for implantation and transplantation in mechanical bridge to transplantation, The implantation of a mechanical blood pump in a deteriorating candidate for heart transplantation is indicated in general if the cardiac index is less than 1.9 L/min/m2 despite maximal inotropic support. Deterioration of end organ function may be taken as a second factor indicating the need for mechanical support as patients with acute onset of shock may react differently from patients with chronic deterioration. Preoperative need for dialysis largely reduces the chances of long-term survival. The time on support should be long enough to normalize or at least improve secondarily damaged organ systems. but with time infectious and thromboembolic complications will increase. So optimal periods for artificial heart support range between two days and four weeks. Age less than 40 years is a positive predictor for outcome in TAH bridging. The general guidelines. however. do not preclude a favourable outcome in complicated cases. as we show in our own series.
Patient selection for mechanical circulatory support as a bridge to cardiac transplantation, Between 7/87 and 9/90 thirty-four patients underwent total artificial heart (Berlin Heart) (n = 2) or biventricular assist device (Berlin Heart) (n = 32) implantation as a bridge to cardiac transplantation. The time of mechanical support ranged from 2 to 60 days. for a mean of 19.2 days. Twenty-three patients received heart transplants. with 74% 30-day survival and 52% long-term survival. Implantation of a mechanical support system became indicated in those patients whose hemodynamic and clinical condition deteriorated despite treatment with enoximone in addition to maximal sympathomimetic medication. The strategy to administer enoximone routinely was the result of a prospective study on 24 pretransplant patients in whom enoximone therapy reduced the need for mechanical assistance by 62%. At the time of device implantation shock-related organ impairment such as cerebral. renal. hepatic. and respiratory dysfunction was present in 62% of patients. In addition. 7 patients had pneumonia. During mechanical support complete recovery of end-organ failure and resolution of pneumonia was observed in the majority of patients. The results indicate that end-organ dysfunction per se should not be considered a contraindication to mechanical circulatory support as a bridge to cardiac transplantation. However. further clinical investigations are needed to identify predictive indicators of irreversible organ damage.
Prognostic indices of survival in patients supported with temporary devices (TAH, VAD), In an attempt to identify current indications and patient selection criteria for the use of mechanical circulatory support. we reviewed our experience in 83 patients who received a total artificial heart (TAH; n = 43). ventricular assist device (VAD) (n = 13). centrifugal pump (n = 17) or extracorporeal membrane oxigenation (ECMO) (n = 8) as a bridge to transplantation (Group I. n = 50) or for recovery from heart failure (Group II. n = 33). Comparing patients successfully transplanted (n = 20) or weaned (n = 9) who survived initial hospitalization. and those who died on mechanical support. there were no differences in preoperative renal. hepatic or pulmonary functions. Postoperative urinary output and bilirubin levels were the earliest variables affecting survival. and urinary output 24 hours after implant was discriminative in patients who survived (p less than 0.01). Age (above or below 40 years) and modality of terminal heart failure (acute versus chronic) were the most important factors affecting survival in the bridge to transplant group: 82% of young patients with acute decompensation were transplanted and 63% are long-term survivors while all patients over 40 years with chronic heart failure died on mechanical support (MS). In postcardiotomy patients. duration of cardiopulmonary by-pass (CPB) was significantly different comparing survivors with those who died in either bridge or recovery groups and all patients who had a CPB greater than 4 hours died on MS or after transplantation or weaning. In conclusion. preoperative indices indicating reversibility of multiple organ dysfunction remain to be identified.
Irreversible drop of systemic vascular resistances in patients implanted with a Jarvik total artificial heart, Maintenance of the body's perfusion by a total artificial heart (TAH) may result in physiological alterations to the circulatory system. Little has been said about modifications to systemic vascular resistances (SVR) during TAH assistance. This paper reports on two patients implanted with a Jarvik - 70 cc TAH. who died after 1 and 3 days. both with an irreversible drop of SVR related to a complete loss of vascular tone but not related to sepsis. Activation of multiple cascades of inflammation. triggered by the extracorporeal circulation (ECC). is maintained during TAH support. Desperately sick patients might not be able to face the vaso-active situations created by the inflammatory response.
Cinematics and sticking of heart valves in pulsatile flow test, The aim of the project was to develop laboratory test devices for studies of the cinematics and sticking behaviour of technical valve protheses. The second step includes testing technical valves of different types and sizes under static and dynamic conditions. A force-deflection balance was developed in order to load valve rims by static radial forces until sticking or loss of a disc (sticking- and clamping-mould point) with computer-controlled force deflection curves. A second deflection device was developed and used for prosthetic valves in the aortic position of a pulsatile mock circulation loop with simultaneous video-cinematography. The stiffness of technical valve rims varied between 0.20 (St. Jude) and about 1.0 N/micron (metal rim valves). The stiffness decreased significantly with increasing valve size. Sticking under pulsatile flow conditions was in good agreement with the static deflection measurements. Hence. valve sticking with increasing danger of thrombus formation is more likely with a less stiff valve rim. In the case of forces acting perpendicularly to the pendulum axis. the clamping mould-point of the valve can be reached. followed by disc dislodgement.
Apheresis-elutriation program for adoptive immunotherapy with autologous activated monocytes in cancer patients, Human blood monocytes (Mo) and monocyte-derived macrophages (M phi) are known to be potent antitumor cytotoxic effector cells through activation with recombinant human interferon gamma (rIFN-gamma). bacterial muramyldipeptide or the synthetic derivative muramyltripeptide phosphatidylethanolamine entrapped in liposomes (L-MTP-PE). Large-scale generation of ex vivo activated Mo from the blood of cancer patients proved feasible. We report our experience with a fixed rotor speed counterflow centrifugation elutration (CEE) procedure using the newly available Beckman high capacity JE-5.0 rotor system that reproducibly isolates up to 1.0-1.5 x 10(9) Mo with greater than 90% purity. in suspension and functionally intact derived from peripheral blood mononuclear cell-enriched suspensions obtained by leukapheresis (LP) from healthy volunteers and cancer patients. The semiclosed. easy to handle CCE system. was adapted to a sterile technique that permitted clinical trials in adoptive monocyte immunotherapy. Freshly isolated Mo did not lose morphological or functional integrity and had no spontaneous activation. Their abilities to become activated to the cytotoxic state after 18-h stimulation with 500 U/ml rIFN-gamma or 1 microgram/ml L-MTP-PE and to differentiate into matured M phi in vitro were not altered. The system was therefore used to isolate large numbers of Mo for a phase I clinical trial of intraperitoneal immunotherapy with L-MTP-PE activated autologous Mo in nine patients with peritoneal carcinomatosis. Each patient received weekly Mo infusions (n = 5) with an intrapatient dose escalation schedule (from 10(7) to 10(9) Mo). Toxicities were mild including fever. chills and abdominal pain. There was no treatment-induced thromboembolic event or capillary leak syndrome.
Muscle hypertrophy response to resistance training in older women, We conducted a 12-wk resistance training program in elderly women [mean age 69 +/- 1.0 (SE) yr] to determine whether increases in muscle strength are associated with changes in cross-sectional fiber area of the vastus lateralis muscle. Twenty-seven healthy women were randomly assigned to either a control or exercise group. The program was satisfactorily completed and adequate biopsy material obtained from 6 controls and 13 exercisers. After initial testing of baseline maximal strength. exercisers began a training regimen consisting of seven exercises that stressed primary muscle groups of the lower extremities. No active intervention was prescribed for the controls. Increases in muscle strength of the exercising subjects were significant compared with baseline values (28-115%) in all muscle groups. No significant strength changes were observed in the controls. Cross-sectional area of type II muscle fibers significantly increased in the exercisers (20.1 +/- 6.8%. P = 0.02) compared with baseline. In contrast. no significant change in type II fiber area was observed in the controls. No significant changes in type I fiber area were found in either group. We conclude that a program of resistance exercise can be safely carried out by elderly women. such a program significantly increases muscle strength. and such gains are due. at least in part. to muscle hypertrophy.
Muscle structure and performance capacity of Himalayan Sherpas, The ultrastructure of the vastus lateralis muscle of Sherpas from Nepal [5 males; age 28 +/- 2.8 (SD) yr. indirect maximal O2 consumption 48.5 +/- 5.4 ml.kg(-1).min(-1)] was assessed and compared with those of sedentary lowlanders and of Caucasian climbers before and after high-altitude exposure. The mean cross-sectional area of the fibers was 3.186 +/- 521 microns2. i.e.. similar to those of Caucasian elite high-altitude climbers (3.108 +/- 303 microns2) and a group of climbers after a 6- to 8-wk sojourn at 5.000-8.600 m (3.360 +/- 580 microns2) but significantly (P less than 0.05) smaller than that of unacclimatized climbers (4.170 +/- 710 microns2) and slightly. although not significantly. lower than that of sedentary lowlanders (3.640 +/- 260 microns2). The number of capillaries per square millimeter of muscle cross section was 467 +/- 22. not significantly smaller than those of climbers on return from a Himalayan expedition (538 +/- 89) and elite high-altitude climbers (542 +/- 127) but significantly (P less than 0.05) greater than that of sedentary lowlanders (387 +/- 25). The volume density of mitochondria was 3.96 +/- 0.54%. significantly (P less than 0.05) less than the values found for any other investigated group. including sedentary subjects at sea level (4.74 +/- 0.30%). It is concluded that Sherpas. like acclimatized Caucasian climbers. are characterized by 1) facilitated convective and diffusive muscle O2 flow conditions and 2) a higher maximal O2 consumption-to-mitochondrial volume ratio than lowlanders despite a reduced mitochondrial volume density.
Renal O2 consumption during progressive hemorrhage, Most mammalian tissues regulate O2 utilization such that O2 consumption (VO2) is relatively constant at O2 delivery (DO2) higher than a critical value (DO2c). We studied the relationship between VO2 and DO2 of kidney and whole body during graded progressive exsanguination. The relationship between whole body VO2 and DO2 was biphasic. and whole body VO2 decreased by 5.6 +/- 14.4% (P = NS) from the initial value to the value nearest whole body DO2c. Kidney DO2 decreased in direct proportion to whole body DO2 such that the average R2 value describing the linear regression of kidney DO2 vs. whole body DO2 was 0.94 +/- 0.02. The relationship between kidney. like whole body. VO2 and DO2 appeared biphasic; however. kidney VO2 decreased by 63.3 +/- 10.4% (P less than 0.0001) from the initial value to the value nearest kidney DO2c. Renal O2 extraction ratio was relatively constant over a wide range of kidney DO2. whereas whole body O2 extraction ratio increased progressively at all whole body DO2 values as whole body DO2 decreased. However. final values of O2 extraction ratio were indistinguishable for whole body (0.86 +/- 0.1) and kidney (0.86 +/- 0.06) (P = NS). We conclude that the pattern of kidney and whole body VO2 response to decreasing DO2 differs during hemorrhage. particularly in the range of DO2 normally associated with tissue wellness.
Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders, Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To assess underlying mechanisms. we studied six Andean Quechua Indians in La Raya. Peru (4.200 m) and at low altitude (less than 700 m) immediately upon arrival in Canada. The experimental strategy compared whole-body performance tests and single (calf) muscle work capacities in the Andeans with those in groups of sedentary. power-trained. and endurance-trained lowlanders. We used 31P nuclear magnetic resonance spectroscopy to monitor noninvasively changes in concentrations of phosphocreatine [( PCr]). [Pi]. [ATP]. [PCr]/[PCr] + creatine ([Cr]). [Pi]/[PCr] + [Cr]. and pH in the gastrocnemius muscle of subjects exercising to fatigue. Our results indicate that the Andeans 1) are phenotypically unique with respect to measures of anaerobic and aerobic work capacity. 2) despite significantly lower anaerobic capacities. are capable of calf muscle work rates equal to those of highly trained power- and endurance-trained athletes. and 3) compared with endurance-trained athletes with significantly higher VO2max values and power-trained athletes with similar VO2max values. display. respectively. similar and reduced perturbation of all parameters related to the phosphorylation potential and to measurements of [Pi]. [PCr]. [ATP]. and muscle pH derivable from nuclear magnetic resonance. Because the lactate paradox may be explained on the basis of tighter ATP demand-supplying coupling. we postulate that a similar mechanism may explain 1) the high calf muscle work capacities in the Andeans relative to measures of whole-body work capacity. 2) the VO2max paradox. and 3) anecdotal reports of exceptional work capacities in indigenous altitude natives.
Respiratory compliance during sedation, anesthesia, and paralysis in infants and young children, Although total respiratory compliance (Crs) has been shown to fall in adults on induction of halothane anesthesia. no successful paired studies have been reported in children. The multiple occlusion technique was used to measure Crs in 17 infants and young children during sedated sleep (CrsS) and shortly after. following induction of halothane anesthesia (CrsA). Crs fell in all but one infant after induction of anesthesia. with a mean fall of 34.7% (range 0-58%). This was accompanied by a reduction in tidal volume and increase in frequency in every case. In 7 of the 17 children. who were to be paralyzed for surgical purposes. Crs was also measured in this anesthetized-paralyzed state. When tidal volume administered during manual ventilation was similar to that observed during measurement of CrsA. Crs during this low-volume ventilation was similar to CrsA. When tidal volume was increased and Crs remeasured. there was a significant increase in every case. with the high-volume Crs within 10% of CrsS in all but one child. in whom there was a 31.4% increase with respect to CrsS. Changes in tidal volume accounted for approximately 50% of the variability in each state. These results demonstrate a highly significant fall in Crs in infants and young children after induction of halothane anesthesia. In addition it appears that this reduction in Crs can be reversed by paralyzing the child and manually ventilating with tidal volumes approximating those seen during sedation.
Effects of left atrial pressure on the pulmonary vascular response to hypoxic ventilation, We investigated the effects of hypoxic ventilation on the pulmonary arterial pressure- (P) flow (Q) relationship in an intact canine preparation. Mean pulmonary P-Q coordinates were obtained during hypoxic ventilation and during ventilation with 100% O2 at normal and at increased left atrial pressure. Specifically. we tested the hypothesis that. over a wide range. changes in left atrial pressure would alter the effects of hypoxic ventilation on pulmonary P-Q characteristics. Seven dogs were studied. When left atrial pressure was normal (5 mmHg). the mean value of the extrapolated intercept (PI) of the linear P-Q relationship was 10.9 mmHg and the slope (incremental vascular resistance. IR) of the P-Q relationship was 2.2 mmHg.l-1.min. Hypoxic ventilation increased PI to 18 mmHg (P less than 0.01) but did not affect IR. Subsequently. during ventilation with 100% O2. when left atrial pressure was increased to 14 mmHg by inflation of left atrial balloon. PI increased to 18 mmHg. IR was 1.6 mmHg.l-1.min. Again. hypoxic ventilation caused an isolated change in PI. Hypoxia increased PI from 18 to 28 mmHg (P less than 0.01). As in the condition of normal left atrial pressure. hypoxic ventilation did not affect IR. We conclude that. in an anesthetized intact canine preparation. hypoxic ventilation causes an isolated increase in the extrapolated pressure intercept of the pulmonary P-Q relationship. Furthermore the effects of hypoxic ventilation on pulmonary P-Q characteristics are not affected by the resting left atrial pressure.
Phrenic neural output during hypoxia in dogs: constant-flow ventilation vs. spontaneous breathing, We studied the effects of removing cyclic pulmonary afferent neural information on respiratory pattern generation in anesthetized dogs. Phrenic neural output during spontaneous breathing (SB) was compared with that occurring during constant-flow ventilation (CFV) at several levels of eucapnic hypoxemia. Hypoxia caused an increase in both the frequency and the amplitude of the moving time average (MTA) phrenic neurogram during both SB and CFV. The change in frequency as arterial saturation was reduced from 90 to 60% during SB was significantly higher than that during CFV [SB. 32.3 +/- 10.9 (SD) breaths/min; CFV. 10.3 +/- 5.8 breaths/min; P = 0.001]. By contrast. the increase in the amplitude of the MTA phrenic neurogram was smaller (SB. 0.62 +/- 0.68 units; CFV. 1.35 +/- 0.81 units; P = 0.01). The changes in frequency with hypoxia during both modes of ventilation resulted primarily from a shortening of expiratory time. Both inspiratory time and expiratory time were greater during CFV than during SB. but their change in response to hypoxia was not significantly different. We conclude that the amplitude response of the MTA phrenic neurogram to hypoxia is similar to that seen during hypercapnia; in the presence of phasic afferent feedback the MTA amplitude response is decreased and the frequency response is increased relative to the response observed in the absence of phasic afferents.
Effect of respiratory muscle fatigue on subsequent exercise performance, The purpose of this study was to determine whether induction of inspiratory muscle fatigue might impair subsequent exercise performance. Ten healthy subjects cycled to volitional exhaustion at 90% of their maximal capacity. Oxygen consumption. breathing pattern. and a visual analogue scale for respiratory effort were measured. Exercise was performed on three separate occasions. once immediately after induction of fatigue. whereas the other two episodes served as controls. Fatigue was achieved by having the subjects breathe against an inspiratory threshold load while generating 80% of their predetermined maximal mouth pressure until they could no longer reach the target pressure. After induction of fatigue. exercise time was reduced compared with control. 238 +/- 69 vs. 311 +/- 96 (SD) s (P less than 0.001). During the last minute of exercise. oxygen consumption and heart rate were lower after induction of fatigue than during control. 2.234 +/- 472 vs. 2.533 +/- 548 ml/min (P less than 0.002) and 167 +/- 15 vs. 177 +/- 12 beats/min (P less than 0.002). At exercise isotime. minutes ventilation and the visual analogue scale for respiratory effort were larger after induction of fatigue than during control. In addition. at exercise isotime. relative tachypnea was observed after induction of fatigue. We conclude that induction of inspiratory muscle fatigue can impair subsequent performance of high-intensity exercise and alter the pattern of breathing during such exercise.
Direct injury to the bronchial vasculature in anesthetized sheep, Injury to the bronchial vasculature may contribute to liquid and solute leakage into the lung during noncardiac pulmonary edema. The purpose of this study was to measure changes in hemodynamics. pulmonary mechanics. extravascular lung water. and lung morphometry after selectively injuring the bronchial vasculature in anesthetized sheep. In two groups of seven sheep. we injected oleic acid (0.1 ml/kg) or normal saline directly into the bronchoesophageal artery. We measured systemic and pulmonary arterial pressures. cardiac output. oxygen saturation. pulmonary resistance and compliance. and lung volumes before and 1 and 4 h after injection. The lungs were removed for measurement of extravascular water. histology. and morphometry. Four hours after injection of oleic acid. cardiac output decreased but pulmonary arterial pressure did not change. In addition. pulmonary resistance increased and dynamic compliance and vital capacity decreased. Extravascular lung water was slightly but significantly greater in the oleic acid group. Histological examination showed interstitial edema and leukocytes in airway walls and sloughing of bronchial epithelium but little or no alveolar edema. Morphometric analysis showed significant thickening of airway walls. We conclude that direct injury to the bronchial vasculature increases lung resistance. decreases dynamic compliance. and increases extravascular lung water by the accumulation of an inflammatory infiltrate in airway walls.
Is fiber mitochondrial volume density a good indicator of muscle fatigability to isometric exercise, The relationship between the ratio of interfibrillar mitochondrial volume density (Vvmit) to myofibrillar volume density (Vvmyo) and isometric fatigue characteristics of the human triceps surae was determined in six bodybuilders. six endurance athletes. and six active controls before and after 16 wk of isometric training at 30 or 100% maximal voluntary contraction (MVC) in six sedentary subjects in a unilateral exercise model. Time to fatigue at 30% MVC was significantly less in sedentary subjects before training than in the other subject groups. but it was similar to the other groups posttraining. Stereological analyses of type I fibers indicated that Vvmit/Vvmyo was less in bodybuilders than in other subjects. Training at 30% MVC increased type I fiber Vvmit/Vvmyo of the soleus by 11% but did not affect the gastrocnemii. Training at 100% MVC did not alter Vvmit/Vvmyo in any muscle. nor was this ratio changed in type II fibers by either training program. Despite the morphological differences. both training protocols increased relative endurance. although greater fatigue resistance was seen after training at 30% MVC. Correlation analyses indicated that isometric endurance and improvements in muscle endurance by isometric exercise were not dependent on increasing interfibrillar Vvmit or Vvmit/Vvmyo in either fiber type.
Effect of preexisting brain ischemia on sympathetic nerve response to intracranial hypertension, The performance of the sympathetic nervous system during sustained moderate cerebral ischemia (CI) was examined in the present study. For this purpose. a Cushing response was elicited repeatedly during incomplete global CI in anesthetized artificially ventilated cats after vagotomy and baroreceptor denervation. In control animals without CI. sympathetic activity in response to brief elevation of intracranial pressure (ICP) showed a well-repeatable two-phase reaction. During CI there was a progressive deterioration of background sympathetic nerve discharge (SND) over a period of 30 min. SND response to repeated elevation of ICP was initially similar to control response but later with progression of CI was seriously changed. 1) Instead of the usual hyperactivation. sympathetic nerve activity was depressed during intracranial hypertension. 2) The characteristic desynchronized activity either appeared later during the reperfusion period or remained absent. The progressive loss of SND response to raised ICP in developed CI was compared with the changes seen in experiments in which repeated ICP elevations were superimposed on asphyxia. These findings suggest that the sympathetic component of the Cushing reaction strongly depends on the actual state of brain stem autonomic circuits and may be seriously altered in pathological situations involving ischemic brain injury.
Cricothyroid muscle responses to increased chemical drive in awake normal humans, To examine the response of the cricothyroid muscle (CT) to increased chemical drive. we measured its electromyogram simultaneously with that of the alae nasi (AN) in seven normal awake subjects. During both progressive hyperoxic hypercapnia and hypoxia. peak integrated inspiratory activity (moving time average. MTA) of the CT and AN increased as a power function of mean inspiratory flow (ratio of tidal volume to inspiratory time. VT/TI). given by MTA = a(VT/TI)b + c (where a. b. and c are constants). The exponent b varied from 0.009 to 3.4 among subjects but was correlated between CT and AN both during hypercapnia (r = 0.86) and hypoxia (r = 0.81). The onset of inspiratory activity of the CT and AN preceded that of inspiratory flow. Expressed as a percentage of expiratory time. the CT lead time rose from 7% at rest to 20% during hyperpnea. The corresponding values for the AN were from 22 to 52% (both P less than 0.03). Thus the pattern of response of the CT and AN is similar and related to that of the inspiratory muscles in a curvilinear manner. The findings suggest that during chemical stimulation the electrical activity of the CT is analogous to that of the AN. an upper airway dilator.
Exercise training elevates RMR during moderate but not severe dietary restriction in obese male rats, This study examined the effects of 11 wk of exercise training (E) on resting O2 uptake (RMR) and the composition of diet-induced weight loss in obese male Sprague-Dawley rats (n = 48). The rats underwent one of three levels of dietary treatment: ad libitum (AL). moderate restriction (MR). and severe restriction (SR). Compared with AL-CC (cage confined; 647 +/- 13 g). the AL-E (84% of AL-CC). MR-CC (77%). MR-E (77%). SR-CC (63%). and SR-E (63%) groups were all reduced in body mass. At the MR level. E significantly reduced fat mass (FM; MR-CC 73 +/- 5. MR-E 45 +/- 5 g) and increased water mass (WM; MR-CC 307 +/- 5. MR-E 329 +/- 5 g) compared with CC. In contrast. no significant differences existed between the SR-CC and SR-E groups. Exercise training did not result in conservation of protein mass at any level of dietary intake. Exercise training significantly elevated RMR (on a kg0.75 basis) by approximately 7% for the AL-E and MR-E groups compared with their respective dietary counterparts. These findings may help reconcile the conflicting results present in the literature with respect to the effects of exercise training during diet-induced weight loss. That is. studies using relatively severe dietary restrictions are less likely to demonstrate exercise-induced changes in RMR. FM. and WM than those employing moderate dietary restrictions.
Effect of denervation or unweighting on GLUT-4 protein in rat soleus muscle, The purpose of this study was to test the hypothesis that the decreased capacity for glucose transport in the denervated rat soleus and the increased capacity for glucose transport in the unweighted rat soleus are related to changes in the expression of the regulatable glucose transporter protein in skeletal muscle (GLUT-4). One day after sciatic nerve sectioning. when decreases in the stimulation of soleus 2-deoxyglucose (2-DG) uptake by insulin (-51%. P less than 0.001). contractions (-29%. P less than 0.05). or insulin and contractions in combination (-40%. P less than 0.001) were observed. there was a slight (-18%. NS) decrease in GLUT-4 protein. By day 3 of denervation. stimulation of 2-DG uptake by insulin (-74%. P less than 0.001). contractions (-31%. P less than 0.001). or the two stimuli in combination (-59%. P less than 0.001). as well as GLUT-4 protein (-52%. P less than 0.001). was further reduced. Soleus muscle from hindlimb-suspended rats. which develops an enhanced capacity for insulin-stimulated glucose transport. showed muscle atrophy similar to denervated soleus but. in contrast. displayed substantial increases in GLUT-4 protein after 3 (+35%. P less than 0.05) and 7 days (+107%. P less than 0.001). These results indicate that altered GLUT-4 expression may be a major contributor to the changes in insulin-stimulated glucose transport that are observed with denervation and unweighting. We conclude that muscle activity is an important factor in the regulation of GLUT-4 expression in skeletal muscle.
Molecular and cell biology of cystic fibrosis, The questions emerged in better focus: we need to know. definitively. what CFTR is and what it does. We need to know how mutant CFTR expression leads to the relentless lung disease that takes the lives of the patients. We need to know how the different mutations in CFTR behave functionally. Much more information is needed on the pathways for ion transport in the airways in order for us to consider therapeutic alternatives. Better information on CFTR expression. particularly in the lung. would greatly facilitate consideration of pathophysiology as well as gene therapy. Many of these questions can be attacked by imaginative use of the tools already in hand. The need is urgent. The wondrous scientific advancements of the last five years and the additional money being spent on CF research have bought no dramatic increase in life expectancy for the patients. Every day. three more succumb.
Arterial injuries. Review of 12 years experience with 32 patients, Thirty-two patients with 41 injured arteries were operated upon during a period of 12 years. Three quarters were men. and the median age was 33 years. Accompanying lesions were seen in 87.5% of the patients. Nearly half the lesions were related to blunt trauma. Occupational accidents constituted the largest group. The diagnosis was made on clinical grounds in most cases. The median time lapse from trauma to operation was 5 hours. The principles of treatment were those that are generally accepted. No patients died. the amputation rate was 12.5%. Median follow-up was 8 months. A successful arterial reconstruction contributed to a good functional result. Postreconstruction thrombosis of arteries were found to occur within the first hours or days after reconstruction. Late thrombosis was rare and the overall long-time patency was 61.4%. Patency of repair of upper limb small vessels was 54.5%.
Paraprosthetic leak: a complication of cardiac valve replacement, Paraprosthetic leak (PPL) is a rare but potentially serious complication of cardiac valve replacement. Between 1974 and 1988. 1175 prosthetic valves were implanted in 1026 patients by one cardiac surgeon at St. Thomas' Hospital. London. Of these 539 (52.5%) were aortic (AVR). 334 (32.6%) mitral (MVR). 7 (0.7%) tricuspid. and 144 (14%) AV and MV double valve replacements (DVR). There were only 2 triple valve replacements. The prosthetic valves implanted were the Starr-Edwards (7%). Bjork Shiley (11.8%). Lillehei-Kaster (23%). Carpentier-Edwards bioprosthesis (35.2%). Duromedics bileaflet (16.4%) and a variety of other mechanical and bioprosthetic valves (6.6%). Over the 15 year period there were a total of 82 (7%) valve failures of which PPL was diagnosed in 29 (2.5%) valves in 24 patients. Presenting features included cardiac decompensation in 72%. bacterial endocarditis in 12% and haemolytic anaemia in 12%. One patient (4%) had no symptoms. Nineteen patients underwent re-operation. Median time to re-operation was 15 months (range 1-65 months) with a re-operative mortality of 22%. Clinical evidence of prosthetic valve infection was found in 79% of MVR and 67% of AVR. A heavily calcified aortic annulus. found in 47% of patients. may also have contributed to PPL after AVR.
Clinical results of mitral valve replacement with and without preservation of the posterior mitral valve leaflet and subvalvular apparatus, In this study we attempted to investigate the importance of posterior leaflet preservation during mitral valve replacement (MVR). One hundred and forty randomly selected patients with isolated mitral insufficiency were studied. half of whom had MVR with preservation of the posterior leaflet (Group I). whereas in the other half conventional MVR was performed. without preservation of the posterior leaflet (Group II). Within these two groups there were no in hospital deaths. but 5 patients in Group II were admitted to the hospital with congestive heart failure and 3 of them died after approximately 6 months. Long term mortality rate was 4.2% in Group II. Ejection fraction (EF) decreased postoperatively from 56% to 50% in Group I (p less than 0.05). and from 59% to 49% in Group II (p less than 0.05). Fifteen patients in each group and aged below 30 with sinus rhythm and in the first functional capacity according to the New York Heart Association classification (NYHA) were subjected to exercise study. 18 months after the operation. After exercise EF increased from 47% to 64% in Group I and decreased from 51% to 47% in Group II. These findings suggested that MVR with the preservation of the chordae tendineae can be done with a low morbidity and mortality rate in the early and late postoperative period.
Three-dimensional characterization of human ventricular myofiber architecture by ultrasonic backscatter, Normal human left ventricular architecture comprises a highly aligned array of cardiac myofibers whose orientation depends on transmural location. This study was designed to determine whether measurement of integrated backscatter could be used detect the progressive transmural shift of myofiber alignment that occurs from epicardium to endocardium in human ventricular wall segments. Integrated backscatter was measured at 32 transmural levels in seven cylindrical biopsy specimens (1.4 cm diam) sampled from normal regions of six explanted fixed human hearts by insonification of samples at 180 independent angles in 2 degrees steps around their entire circumference with a 5-MHz broadband piezoelectric transducer. Histologic analysis was performed to determine fiber orientation. Integrated backscatter varied approximately as a sinusoidal function of the angle of insonification at each transmural level. Greater integrated backscatter was observed for insonification perpendicular as compared with parallel to fibers (difference = 14.5 +/- 0.6 dB). Ultrasonic analysis revealed a progressive transmural shift in fiber orientation of approximately 9.2 +/- 0.7 degrees/mm of tissue. Histologic analysis revealed a concordant shift in fiber orientation of 7.9 +/- 0.8 degrees/mm of tissue. Thus. human myocardium manifests anisotropy of ultrasonic scattering that may be useful for characterization of the intramural fiber alignment and overall three-dimensional organization of cardiac myofibers.
Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene, In a large kindred of 66 individuals. 22 were identified as heterozygous and 3 as homozygous for a mutation (pro664----leu) in the LDL-receptor gene that gives rise to familial hypercholesterolaemia (FH). All the heterozygotes had a raised level of plasma total cholesterol and low density lipoprotein cholesterol. but were remarkably free from premature coronary disease. Determination of apolipoprotein(a) (apo(a)) phenotype and lipoprotein(a) (Lp(a)) concentration in plasma revealed that in many instances. involving individuals with various apo(a) phenotypes. there was no difference in plasma Lp(a) concentration between an FH heterozygote and an unaffected sibling with the same apo(a) phenotype. No significant difference in Lp(a) concentration was observed between groups of FH and non-FH of the same apo(a) phenotype. although in each case the mean value for the FH group was greater than that for the non-FH group. There was also evidence for an inherited trait that markedly increased Lp(a) concentration. which did not segregate with apo(a) phenotype or the defective LDL-receptor allele. The data provide no evidence for a strong multiplicative interaction between the gene loci for apo(a) and the LDL receptor.
Mutations of P450c21 (steroid 21-hydroxylase) at Cys428, Val281, and Ser268 result in complete, partial, or no loss of enzymatic activity, respectively, Steroid 21-hydroxylase deficiency is the major cause of congenital adrenal hyperplasia (CAH). a common genetic disease. To define the relationship between gene mutations and enzyme deficiency. we generated missense mutations of the 21-hydroxylase cDNA at three different sites and characterized the mutant proteins after expressing them in cultured mammalian and yeast cells. Among them. Ser268 and Val281 have been found to be mutated in CAH patients. whereas Cys428 has been implicated as the heme ligand. Our results show mutations at these sites result in complete. partial. or no loss of the enzymatic activity. All the Cys428 mutants had neither enzymatic activity nor P450 absorption. thus supporting the notion that Cys428 is the heme ligand. All the 268-mutants exhibited the same activity as normal 21-hydroxylase. demonstrating that the clinically observed Ser268----Thr change represents a polymorphism rather than the cause of the enzyme deficiency. The 281-mutants had normal Km but greatly reduced Vmax values that also paralleled the reduction in the heme content. in the order Val281 (normal. 100%) greater than Ile281 (50%) greater than Leu281 (20%) greater than Thr281 (10%). Our findings suggest that the methyl group at the beta-carbon of Val281 is required for heme incorporation and consequently enzymatic activity.
Upregulated expression and function of VLA-4 fibronectin receptors on human activated T cells in rheumatoid arthritis, The VLA-4 (CD49d/CD29) integrin is a cell surface receptor involved in the interaction of lymphoid cells with both extracellular matrix (ECM) and endothelial cells. We have investigated the expression and function of VLA-4 fibronectin (FN) receptors on T cells localized in the inflammed synovium of patients with rheumatoid arthritis (RA). A high proportion of T cells in both synovial membrane (SM) and synovial fluid (SF) expressed the activation antigens AIM (CD69) and gp95/85 (Ea2) as well as an increased number of VLA-4 alpha and beta 1 adhesion molecules. as compared with peripheral blood (PB) T cells from the same patients. Furthermore. the majority of these activated SF T cells were able to adhere to a 38-kD FN proteolytic fragment containing the connecting segment-1 (CS-1) specifically through VLA-4 receptors. whereas a significantly lower proportion of PB T cells displayed this capacity. Therefore. our results show that activated T cells selectively localize at sites of tissue injury in RA disease and provide evidence for the in vivo regulation of the expression and function of the VLA-4 integrin. This regulatory mechanism may enable T cells either to facilitate migration or to persist at sites of inflammation.
Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis, Insulin secretion and insulin sensitivity were evaluated in eight clinically stable cirrhotic patients and in 12 controls. OGTT was normal in cirrhotics but plasma insulin response was increased approximately twofold compared with controls. Subjects received a three-step (0.1. 0.5. 1.0 mU/kg.min) euglycemic insulin clamp with indirect calorimetry. [6-3H]-glucose. and [1-14C]-palmitate. During the two highest insulin infusion steps glucose uptake was impaired (3.33 +/- 0.31 vs. 5.06 +/- 0.40 mg/kg.min. P less than 0.01. and 6.09 +/- 0.50 vs. 7.95 +/- 0.52 mg/kg.min. P less than 0.01). Stimulation of glucose oxidation by insulin was normal; in contrast. nonoxidative glucose disposal (i.e.. glycogen synthesis) was markedly reduced. Fasting (r = -0.553. P less than 0.01) and glucose-stimulated (r = -0.592. P less than 0.01) plasma insulin concentration correlated inversely with the severity of insulin resistance. Basal hepatic glucose production was normal in cirrhotics and suppressed normally with insulin. In postabsorptive state. plasma FFA conc (933 +/- 42 vs. 711 +/- 44 mumol/liter. P less than 0.01) and FFA turnover (9.08 +/- 1.20 vs. 6.03 +/- 0.53 mumol/kg.min. P less than 0.01) were elevated in cirrhotics despite basal hyperinsulinemia; basal FFA oxidation was similar in cirrhotic and control subjects. With low-dose insulin infusion. plasma FFA oxidation and turnover failed to suppress normally in cirrhotics. During the two higher insulin infusion steps. all parameters of FFA metabolism suppressed normally. In summary. stable cirrhotic patients with normal glucose tolerance exhibit marked insulin resistance secondary to the impaired nonoxidative glucose disposal. Our results suggest that chronic hyperinsulinism may be responsible for the insulin resistance observed in cirrhosis.
Expression of the early growth response 1 and 2 zinc finger genes during induction of monocytic differentiation, Members of the early growth response (EGR) gene family are rapidly induced after mitogenic stimulation of diverse cell types. The present work has examined EGR gene expression during differentiation of myeloid leukemia cells along the monocytic lineage and in activated monocytes. Low levels of EGR-1 transcripts were detectable in untreated U-937 and HL-60 leukemia cells. In contrast. treatment of these cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) was associated with increases (within 1 h) in EGR-1 mRNA levels. The induction of monocytic differentiation by TPA and other agents was further associated with increases in EGR-2. but not EGR-3 or EGR-4. mRNA levels in these cells. Treatment of resting peripheral blood monocytes with the macrophage colony-stimulating factor (M-CSF) was also associated with rapid (within 15 min) increases in expression of the EGR-1 and EGR-2 genes. The results of nuclear run-on assays demonstrate that EGR-1 mRNA levels are increased in part by transcriptional activation of this gene in M-CSF-stimulated monocytes. The results also demonstrate that both EGR-1 and EGR-2 mRNA levels are regulated at the posttranscriptional level by a labile protein that destabilizes these transcripts. Finally. we demonstrate that dexamethasone. an inhibitor of monocytic differentiation. blocks the associated increases in EGR-1 and EGR-2 expression. Taken together. the results indicate that the EGR-1 and EGR-2 early response genes are involved in the induction of myeloid leukemia cell differentiation along the monocytic lineage and in the activation of human monocytes.
Leukocyte adhesion-deficient neutrophils fail to amplify phagocytic function in response to stimulation. Evidence for CD11b/CD18-dependent and -independent mechanisms of phagocytosis, Stimulation of PMN with inflammatory mediators markedly augments Fc and CR1 receptor-mediated ingestion. However. CD11/CD18-deficient PMN from three patients with complete leukocyte adhesion deficiency (LAD) failed to recruit phagocytic function in response to phorbol esters. cytokine. or Arg-Gly-Asp-containing ligand stimulation. Because stimulated ingestion is protein kinase C (PKC)-dependent. our data indicate that LAD PMN exhibit only PKC-independent phagocytosis. The defect in PKC-dependent ingestion is specific for CD11b/CD18 and not secondary to the chronic or recurrent infections which occur in this disease. The LAD phenotype for phagocytic function can be reproduced in normal PMN by the anti-CD11b MAbs OKM1 and OKM10. In contrast. MAb Mo1 (anti-CD11b) and MAb IB4 (anti-CD18) inhibit both CD11b/CD18-dependent and -independent mechanisms of ingestion by normal PMN. Their ability to inhibit CD11b/CD18-independent ingestion may be mediated by cAMP. as shown by experiments with a protein kinase A inhibitor HA1004 and by direct measurement of cAMP levels in immune complex- and FMLP-stimulated PMN. These data indicate that CD11b/CD18-independent and -dependent mechanisms of phagocytosis exist and that some effects of anti-CD11b/CD18 MAbs may be mediated by alterations in cAMP levels.
Differences in the expression of the cardiopulmonary alterations associated with anti-immunoglobulin E-induced or active anaphylaxis in mast cell-deficient and normal mice. Mast cells are not required for the cardiopulmonary changes associated with certain fatal anaphylactic responses, We compared the changes in heart rate (HR). pulmonary dynamic compliance (Cdyn). and pulmonary conductance (GL) associated with three different models of anaphylaxis in genetically mast cell-deficient WBB6F1-W/Wv and congenic normal (+/+) mice. Intravenous infusion of a monoclonal rat anti-mouse IgE produced a marked tachycardia. diminutions in Cdyn and GL. and death in +/+ but not W/Wv mice. and +/+ mice sensitized to develop high circulating levels of IgE exhibited HR. Cdyn. and GL responses to rat anti-IgE challenge which were significantly less intense than those in nonimmunized +/+ mice. By contrast. virtually identical cardiopulmonary responses were observed in either +/+ or W/Wv mice challenged to elicit pure active anaphylactic responses or simultaneous active and anti-IgE-dependent anaphylaxis. These findings show that anaphylactic responses associated with significant tachycardia. reductions in Cdyn and GL. and death can occur in the virtual absence of tissue mast cells. This is true even though. in normal mice. such responses are associated with extensive degranulation of tissue mast cells. By contrast. certain models of anaphylaxis. such as that induced in nonsensitized mice by anti-mouse IgE. can not be elicited in the absence of mast cells.
Effects of body fat distribution on regional lipolysis in obesity, To determine the contribution of the major body fat depots to systemic free fatty acid (FFA) availability. palmitate ([1-14C]-palmitate) release was measured from leg (lower body) and non-leg (upper body) fat in eight upper body obese (UB Ob). six lower body obese (LB Ob). and six nonobese (Non Ob) age-matched premenopausal women in the overnight postabsorptive state. Splanchnic palmitate release was determined in 16 of these subjects. Results: total palmitate release was greater in UB Ob (P less than 0.005) than LB Ob or Non Ob women (161 +/- 16 vs. 111 +/- 9 vs. 92 +/- 9 mumol/min. respectively). Despite increased leg fat mass in obese women. leg palmitate release was similar in each group. Therefore. leg fat palmitate release was greater in Non Ob women than LB Ob (P less than 0.01) or UB Ob (P = 0.06) women (3.7 +/- 0.3 vs. 2.4 +/- 0.2 vs. 2.7 +/- 0.2 mumol.kg fat-1.min-1. respectively). Upper body fat palmitate release was less (P less than 0.01) in LB Ob than Non Ob or UB Ob women (3.0 +/- 0.4 vs. 5.0 +/- 0.3 vs. 4.9 +/- 0.4 mumol.kg fat-1.min-1. respectively). Splanchnic palmitate release accounted for 20-32% of upper body fat palmitate release in each group (P = NS between groups). Leg fat palmitate release was significantly less than upper body fat palmitate release. We conclude that the major difference in resting FFA metabolism between UB Ob and LB Ob women is the ability of the later to down-regulate upper body fat lipolysis to maintain normal FFA availability.
Familial dysbetalipoproteinemia associated with apolipoprotein E3-Leiden in an extended multigeneration pedigree, By the careful screening of familial dysbetalipoproteinemic (FD) patients. five probands showing heterozygosity for the APOE*3-Leiden allele were found. Genealogical studies revealed that these probands share common ancestry in the 17th century. In a group of 128 family members. spanning three generations. 37 additional heterozygous APOE*3-Leiden gene carriers were detected. Although with a variable degree of severity. all carriers exhibited characteristics of FD such as (a) elevated levels of cholesterol in the very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) fractions. (b) elevated ratios of cholesterol levels in these density fractions over total plasma levels of triglycerides. and (c) strongly increased plasma levels of apolipoprotein E (apoE). Multiple linear regression analysis revealed that most of the variability in expression of FD in APOE*3-Leiden allele carriers can be explained by age. Body mass index showed a less significant influence on the expression of FD. Gender had no effect on the expression in E*3-Leiden allele carriers. nor did it influence the age of onset of FD. In the group of APOE*3-Leiden allele carriers. we found that the E*2 allele enhances the expression of FD. whereas the E*4 allele had the opposite effect. Isoelectric focusing of plasma and of isolated VLDL. IDL. and high density lipoprotein density fractions showed that in E*3-Leiden allele carriers the apoE3-Leiden variant largely predominates over its normal apoE counterpart. especially in the VLDL and IDL density fractions. We conclude that in APOE*3-Leiden allele carriers FD is dominantly inherited with a high rate of penetrance. i.e.. the presence of normally functioning apoE molecules in the plasma does not prevent the age-related expression of this disease.
Acute lung injury. Pathogenesis of intraalveolar fibrosis, In patients dying with acute lung injury. interstitial mesenchymal cells migrate into the airspace where they replicate and deposit connective tissue. We therefore hypothesized that peptides capable of promoting mesenchymal cell migration and replication would be present in the alveolar airspace. To examine this hypothesis. patients with severe acute diffuse lung injury (n = 26) underwent bronchoalveolar lavage. Acutely ill patients without lung injury served as controls (n = 12). Recovered effluent was examined for mesenchymal cell growth-promoting and migration-promoting activity. Lavage cell supernates from both patients and controls were devoid of bioactivity. However. substantial growth-promoting and migration-promoting activity was present in lavage fluid from nearly every patient. whereas little or none was present in fluid from controls. Characterization of the bioactivity indicated a significant proportion consisted of three peptides related to PDGF: (a) a 14-kD peptide that shared with PDGF several biophysical. biochemical. receptor-binding. and antigenic properties; (b) a 29-kD peptide that appeared identical to PDGF of platelet origin; and (c) a 38-kD peptide that was biophysically and antigenically similar to PDGF. These data indicate that peptide moieties are present in the airspace of patients after acute lung injury that can signal mesenchymal cell migration and replication.
Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin, Increasing evidence suggests that autoantibodies in the rheumatic diseases are a consequence of immune selection by self-material. but the nature of the in vivo immunogen is unknown. Insight into this problem may be obtained by measuring autoantibody binding to various forms of a target antigen. Antihistone antibodies arising as a side effect of therapy with various drugs offer an opportunity to explore this premise because many forms of histone have been characterized and adapted to ELISA formats. Two patterns of antibody reactivity were observed. All 21 patients with symptomatic procainamide-induced lupus and 7 of 12 patients with quinidine-induced lupus had IgG antibodies reacting predominantly with the (H2A-H2B)-DNA complex and with chromatin. In contrast. antibodies in 19 of 24 patients taking procainamide without accompanying lupus-like symptoms did not show any pattern. The second pattern was observed in 18/19 chlorpromazine-treated patients and 14/17 patients with hydralazine-induced lupus in which IgM antibodies displayed more reactivity with DNA-free histones than with the corresponding histone-DNA complexes and almost no binding to H1-stripped chromatin. Absorption studies were entirely consistent with these results. Thus. the two patterns of reactivity with nucleosomal components reflect the molecular substructure of chromatin. suggesting that two processes underlie antihistone antibody induction by drugs. In one. IgG autoantibodies appear to be elicited by chromatin. whereas in the other. autoimmune tolerance to native chromatin appears largely intact. and IgM antibodies may be driven by DNA-free histone.
Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines, IL-6 has been shown to be a plasmacytoma growth factor in mice and is believed to play a key role in the development of human multiple myeloma. We investigated the IL-6 requirements for the growth of two human myeloma cell lines. U 266 and RPMI 8226. These cell lines secreted minute amounts of IL-6 (20 U/ml) and featured IL-6 mRNA. IL-6 receptors were detectable at the surface of malignant cells by immunofluorescence. Antibodies to IL-6 did not alter the proliferation of these myeloma cells. There was a dose-dependent decrease. however. in [3H]-thymidine uptake in the presence of IL-6 antisense (and not sense) oligodeoxynucleotides; in the presence of 20 microM IL-6 antisense. an 80 and 95% inhibition of the proliferation of U 266 and RPMI 8226 cells was observed. respectively. These results provide strong evidence for an IL-6 autocrine proliferation of myeloma cells which may occur via internal interaction between IL-6 and the IL-6 receptor.
Truncated forms of DNA-binding estrogen receptors in human breast cancer, The likelihood a breast cancer will respond to antiestrogen therapy depends on the tumor content of immunoreactive or ligand-binding estrogen receptor (ER). To investigate the failure of many ER-positive breast cancers to respond to antiestrogen therapy. we examined by gel-shift assay the ability of tumor ER to bind its cognate estrogen response element (ERE). Analysis of 38 primary breast cancers showed that some tumors containing abundant immunoreactive ER failed to demonstrate DNA binding ER. In many other ER-positive tumors. the fraction of DNA binding ER was low and consisted primarily of truncated receptor forms. which on Western analysis were revealed to be 50 kD homodimers and 67-50 kD ER heterodimers. The use of protease inhibitors during tumor extraction and the demonstration of nuclear-localizing ER and ERE-binding COUP (chicken ovalbumin upstream promoter) protein in these tumors indicated that the truncated forms of ER were likely present in vivo. The presence of intact DNA binding ER correlated with higher tumor content of immunoreactive sex steroid receptors (ER and/or PR). standard predictors of tumor responsiveness to antiestrogen. suggesting that loss or truncation of DNA binding ER may be an important prognostic parameter accounting for some forms of clinical resistance to antiestrogen therapy.
Localization of the cystic fibrosis transmembrane conductance regulator in pancreas, Cystic fibrosis (CF) is characterized by an abnormality in cAMP-regulated chloride transport that results from a primary defect in the protein product of the CF gene. the CF transmembrane conductance regulator (CFTR). In this report. antibodies against CFTR peptides were used to localize the CFTR protein in human pancreas. An affinity purified antibody (alpha-1468) raised against a synthetic CFTR peptide identified a 155-170-kD protein on immunoblot. Cytochemical studies with alpha-1468 localized CFTR to small branching. tubular structures. The same structures were recognized by two other antibodies raised against different regions of the CFTR molecule. To identify the cells being stained. double-label immunofluorescence studies were performed using alpha-1468 and a monoclonal antibody which stains pancreatic centroacinar and intralobular duct cells. Both antibodies localized to the same population of cells. with alpha-1468 being confined to the apical domain of these cells. No conclusive staining of acinar cells was evident. These findings suggest that proximal duct epithelial cells play a key role in the early events leading to pancreatic insufficiency in CF. and imply that apical chloride transport by these cells is essential for normal pancreatic secretory function.
Recapitulation of normal and abnormal BB rat immune system development in scid mouse/rat lymphohemopoietic chimeras, Mice homozygous for the mutation "severe combined immune deficiency" (C.B17-scid/scid) lack functional T and B lymphocytes and readily accept tumor xenografts. Partial lymphohemopoietic scid/human and mouse/rat chimeras have been described. but complete chimerization with thymic engraftment and generation of donor-origin thymocytes has not been achieved. We now report that low-dose irradiation permits the engraftment of BB rat fetal liver stem cells in scid recipients. We observed that BB rat fetal liver cells injected into irradiated scid mice establish a rat hemopoietic system in the scid mouse bone marrow and populate the scid mouse thymus. These stem cells generated rat-origin thymocytes that migrated to the scid mouse spleen. a peripheral lymphoid organ. Finally. we found that xenogeneic chimeras created using fetal liver cells from the abnormal (lymphopenic. diabetes prone) subline of BB rats recapitulated both the quantitative and phenotypic abnormalities of the donor rat. Xenogeneic lymphohemopoietic chimeras established in scid mice may provide a powerful new tool in the study of immune system development and autoimmunity.
Macrophages, microglial cells, and HLA-DR antigens in fetal and infant brain, Immunohistochemical reactions for macrophages. microglia. and HLA-DR antigens were tested on frozen sections of necropsy brain tissue from 20 fetuses and infants ranging in age from 18 weeks' gestation to 8 months post term. No primary central nervous system disease was present but there were four cases of sudden infant death syndrome (SIDS). Macrophages were detected in all the samples studied and were located in the germinal matrix zone. in perivascular spaces throughout the brain. and in the leptomeninges and subependymal layer. Well differentiated microglia were present in all cases examined after 35 weeks' gestation and less well ramified forms were seen at earlier stages of gestation. HLA-DR antigens were detected on a small number of macrophages. chiefly in a perivascular location. in all but three cases. The fewest reactive cells and the weakest reactions occurred in the youngest fetuses. One case of SIDS showed increased foci of microglia in perivascular white matter: this case and one other case of SIDS were the only cases with well ramified microglia that expressed HLA-DR antigens. These findings may be relevant to an understanding of local immune responses in fetal brain infections. including human immunodeficiency virus infection.
Class I and class II major histocompatibility complex antigens on hepatocytes: importance of the method of detection and expression in histologically normal and diseased livers, Methodological differences in major histocompatibility complex (MHC) antigen detection were investigated on isolated. viable hepatocytes and cryostat hepatic sections from 27 children with liver disorders. six of whom had normal histology. Class I antigens were constantly found on sections using a three step immunoperoxidase technique after acetone/chloroform fixation. other techniques being less sensitive. or on isolated hepatocytes by indirect immunofluorescence alone. With mechanical isolation the percentage of positivity ranged from 85 to 100%. while with collagenase isolation it ranged from 22 to 49% on immediate testing. and from 53 to 80% after 24 hour incubation. Class II antigens were only detected in one patient with autoimmune chronic active hepatitis and two with primary sclerosing cholangitis. Flow cytofluorimetric analysis in 11 cases confirmed class II or class I positivity. or both. on isolated hepatocytes. allowing MHC antigen expression on hepatocytes to be measured. Class I and II antigen detection on hepatocytes is influenced by the technique used. Although class I antigens are invariably expressed on hepatocytes. class II antigens are only found on hepatocytes from patients with immune mediated liver disorders.
Simplified procedures for applying the polymerase chain reaction to routinely fixed paraffin wax sections, The polymerase chain reaction was applied to the analysis of DNA contained in archival paraffin wax embedded material. DNA suitable for the reaction was obtained from these tissues by simple extraction methods. without previous dewaxing of tissue sections. When compared with unfixed material. the reaction efficiency was compromised. so that an increased number of amplification cycles were required to produce equivalent amounts of amplified product. This in turn led to an increase in amplification artefacts. which can be minimised by a simple modification of the standard reaction. Amplification of relatively large DNA fragments was not always successful. and it seems prudent to bear this in mind when designing oligonucleotide primers which are to be used for the amplification of archival material. The efficiency of the procedure can be improved by dividing the amplification cycles into two parts: this reduces the amount of reagent needed. is relatively simple and inexpensive. and can be performed in one working day.
Increased central immunoreactive beta-endorphin content in patients with Wernicke-Korsakoff syndrome and in alcoholics, beta-endorphin. adrenocorticotrophin. and alpha-melanocyte stimulating hormone were measured by radioimmunoassay in three areas of human brain at necropsy in seven subjects with Wernicke-Korsakoff syndrome and in 52 controls. Thiamin concentration in six brain areas was also measured. Mamillary body beta-endorphin concentrations were significantly increased in those with the syndrome compared with controls. and those controls with high alcohol intake showed increased mamillary body beta-endorphin compared with controls with low alcohol intake. Brain thiamin concentration was similar in both groups. with the exception of the brainstem. where it was reduced in subjects with Wernicke-Korsakoff syndrome. Thalamic beta-endorphin in controls was inversely correlated with thiamin in frontal white matter. frontal cortex. parietal white matter and parietal cortex. while beta-endorphin in the hypothalamus of patients was inversely correlated with thiamin in frontal cortex. parietal white matter. thalamus and brainstem. These results suggest that there is a disturbance of the endorphinergic system in Wernicke-Korsakoff syndrome which may be related to alcohol intake.
Globin chain synthesis in myelodysplastic syndromes, Globin chain synthesis was studied in the reticulocytes of 30 patients with various myelodysplastic syndromes (MDS) to determine the alpha:beta globin chain synthetic ratio and its probable prognostic value. The mean (SD) value of the total alpha:beta ratio was 0.82 (0.45) ranging from 0.05 to 1.73. The same ratio in 10 normal controls was 1.01 (0.04). This difference was significant. Furthermore. the alpha:beta ratios were lower than normal in 14 patients (alpha-thalassaemia-like) (group I). almost within normal limits in 11 (group II). and higher than normal in five (beta-thalassaemia-like) (group III). In each group almost all the FAB subtypes were represented. The addition of exogenous haem in several of the test samples resulted in a slight to pronounced increase in the alpha:beta ratios. particularly in group I. In 92% of the high risk cases (refractory anaemia with excess blasts (RAEB). chronic myelomonocytic leukaemia (CMML] or 87.5% of patients who finally developed acute non-lyphoid leukaemia (ANLL) low or normal alpha:beta ratios were found. No significant correlation was noticed between alpha:beta ratios and various haematological variables or survival. It is concluded that in MDS the alpha:beta ratio varied enormously across the entire population of patients. as well as within each FAB subtype. thereby restricting its prognostic value. Although haem deficiency may be implicated in some cases of MDS. why this should be remains unclear.
Immunohistochemical analysis of amylase isoenzymes in thyroid cancer, The expression of amylase in various histological types of thyroid cancer was studied by an immunohistochemical technique. using a polyclonal antiamylase antiserum and two monoclonal antibodies specific for salivary and pancreatic-type amylases. respectively. Amylase was expressed in 21 of 24 (88%) thyroid cancers by polyclonal antiserum analysis. Analysis by monoclonal antibodies. however. showed that only 13 (54%) cases and three (13%) cases contained salivary-type and pancreatic-type amylases. respectively. Moreover. immunoreactivity for pancreatic-type amylase was detected only in medullary carcinoma; other histological types were positive for salivary-type amylase. These results show that thyroid cancer frequently expresses amylase. and suggest that the differences between amylase isoenzymes in thyroid cancer may correlate with those found between cellular origin of tumour.
Comparison of image analysis and flow cytometric determination of cellular DNA content, A good correlation (r = 0.94) was obtained between the DNA indices (DI) using flow cytometry and image analysis of nuclei cytospins extracted from paraffin wax embedded tumour sections. Some of the limitations and problems associated with image analysis which came to light included an unacceptably high coefficient of variation (CV) and a "left-shift" in the DI in most DNA histograms obtained when using image analysis of 5 microns sections. In contrast. the DNA histograms generated using image analysis of cytospun nuclei from paraffin wax blocks were of good quality and similar to those obtained using flow cytometry. Variability in Feulgen staining was common and an important source of error despite rigorous control of the staining technique. This could be overcome by using internal controls such as fibroblasts rather than external controls (rat hepatocytes) to determine the diploid DI with image analysis. A thorough understanding and appreciation of the methodological problems associated with image analysis and flow cytometric determination of DNA content is required before these methods find widespread clinical application.
Sinemet (CR4): an open-label study in moderately severe Parkinson's disease, Almost all patients with idiopathic Parkinson's disease respond to levodopa and progress steadily. requiring an increased overall dosage with time. Sinemet CR4 offers a theoretically attractive method of achieving gradual sustained release of levodopa over time which may be more physiological to striatal dopamine receptors in the early stages of the disease. This study evaluated 20 patients with moderate to severe Parkinson's disease who were treated with Sinemet CR4 over a 1-year period. Eleven patients completed the full year on therapy. and nine subjects withdrew. Of the withdrawals. two subjects died from non-Parkinson's disease-related illness. three showed no therapeutic benefit. and four responded well for a minimal 6-month period. but then lost therapeutic benefit and developed more severe dystonias. A higher overall levodopa dosage was required by all patients. and side-effects of levodopa were still present in most patients. However. the nocturnal benefit of this long-acting preparation was observed by all the patients in the study. Slow onset of action of Sinemet CR4 resulted in early-morning immobility. Sinemet CR4 cannot replace standard Sinemet. but appears to be a useful form of adjunct therapy in selected patients.
Long-term effects of simvastatin in familial dysbetalipoproteinaemia, The long-term effects (66 weeks) of simvastatin (40 mg in one or two doses per day). an inhibitor of HMG CoA-reductase. were evaluated in 12 patients with familial dysbetalipoproteinaemia (type III hyperlipoproteinaemia). Simvastatin had a persistent hypolipidaemic effect; the mean reduction in serum cholesterol was 36-51%. and the mean reduction in serum triglycerides was 32-55%. The decrease in serum lipids was caused by a decline in VLDL-cholesterol and LDL-cholesterol levels; the mean ratio between VLDL-cholesterol and serum triglycerides decreased significantly from 1.06 to 0.73. There was no significant difference between the once-a-day and twice-a-day regimens. Simvastatin was well tolerated; no serious side-effects were observed. These data demonstrate the usefulness of simvastatin in the therapy of familial dysbetalipoproteinaemia.
Comparison of the clinical pharmacology of (-)NPA and levodopa in Parkinson's disease, Direct acting dopamine agonists are generally less effective than levodopa in relieving symptoms of Parkinson's disease. In an attempt to quantitate and explain this situation. the acute motor responses to intravenous injections of the dopamine agonist. (-)-N-n-propyl-norapomorphine hydrochloride (NPA). were compared with those of the dopamine precursor. levodopa. At optimum dose levels. the acute anti-Parkinsonian efficacy of NPA averaged only about 50% of maximum. while essentially total symptom suppression was obtained with levodopa in patients previously treated with the amine precursor. Dyskinesia severity. however. was similar with the two drugs. These differences in anti-Parkinsonian efficacy may reflect the fact that while NPA acts mainly on D-2 dopamine receptors. levodopa results in stimulation of both the D-1 and D-2 subsets of receptors at a more physiological ratio. Future efforts to develop dopamine agonists for the treatment of Parkinsonian symptoms may thus have to consider focusing on drugs having pharmacological profile more similar to that of dopamine.
Immunoglobulin producing cells in bone marrow and blood of patients with multiple sclerosis and controls, Multiple sclerosis (MS) is characterised by intrathecal synthesis of IgG. less frequently of IgA and IgM. Local production of antibodies to myelin basic protein (MBP) and other myelin components has also been reported. and autoimmune pathogenesis has been postulated. Whether MS is accompanied by a systemic B cell response is less clear. To elucidate this question. we examined bone marrow and peripheral blood from patients with MS and controls for cells secreting IgG. IgA and IgM. as well as anti-MBP antibodies of these three isotypes. Patients with MS without any signs of concurrent infections had higher numbers of IgG + IgA + IgM secreting cells both in bone marrow and peripheral blood compared with healthy controls. The same abnormalities were observed in patients with other inflammatory neurological diseases (OIND). When analysing individual isotypes. patients with MS and OIND had higher numbers of IgA secreting cells both in bone marrow and blood compared with healthy controls. Only one of 13 MS patients examined had anti-MBP antibody secreting cells in bone marrow and blood. The systemic B cell response registered in MS is also present in other inflammatory neurological diseases and its specificity and possible role in the pathogenesis of MS remains unknown.
Benign vascular sexual headache and exertional headache: interrelationships and long term prognosis, There is a definite relationship between the vascular type of benign sexual headache and benign exertional headache. Forty five patients with benign vascular sexual headache were reviewed. Twenty seven (60%) experienced benign vascular sexual headache alone and eighteen (40%) had experienced both benign vascular sexual headache and benign exertional headache on at least one occasion. The mean age was 34.3 years with a male:female ratio of 5.4:1. Thirty patients with a history of benign vascular sexual headache were followed for an average of 74 months. A personal history of migraine was found in 47% of cases and a family history of migraine in 30%. Forty one per cent of patients with benign vascular sexual headache alone had recurrences after diagnosis. and stress and fatigue were considered major contributing factors to the initial and recurrent headache. Nine patients had experienced benign vascular sexual headache and benign exertional headache within 72 hours of each other on at least one occasion. often with a residual headache between the two. Four patients experienced their benign vascular sexual headache and benign exertional headache separated by months to years. The prognosis of benign vascular sexual headache and the clinical and possible pathophysiological relationships between benign vascular sexual headache and benign exertional headache are discussed. Knowledge of the interrelationships of these varieties of headache is valuable in the counselling of patients.
Maternal reporting of behaviour following very severe blunt head injury, Mothers of 40 very severely head injured male subjects rated their son's behaviour on the Current Behaviour Scale and their ratings were compared with mothers' ratings of 40 control male subjects. The scale was able to discriminate the two groups. by utilising two factors--loss of emotional control and loss of motivation. The mothers' level of emotional distress was closely related to their reporting of loss of emotional control in their sons. but reporting of loss of motivation. or lowered arousal. was strongly predicted by the functional disability of the son. The utility of refining the measurement of post-trauma behaviour is discussed.
Glial swelling following human cerebral contusion: an ultrastructural study, The ultrastructural features of cerebral contusion seen three hours to 11 days after head injury were studied in 18 patients undergoing surgery. Massive astrocytic swelling ("cytotoxic" oedema) was seen three hours to three days after injury. maximal in perivascular foot processes. and compressing some of the underlying capillaries. The tight junctions were not disrupted. Neuronal damage was most marked three to 11 days after injury. The pathophysiological mechanisms leading to oedema formation and neuronal degeneration are discussed.
Changes in intracranial CSF volume after lumbar puncture and their relationship to post-LP headache, Post-lumbar puncture (LP) headache may be due to "low CSF pressure". leading to stretching of pain sensitive intracranial structures. The low intracranial pressure is secondary to net loss of intracranial CSF. It has. however. not been possible to measure intracranial CSF volume accurately during life until recently. Intracranial CSF volume can now be measured non-invasively by a MRI technique. The changes in intracranial CSF volume were studied in 20 patients who had LP. Total intracranial CSF volume was reduced in 19 of the 20 patients 24 hours after LP (range -1.8 mls to -158.6 mls). Most of the CSF was lost from the cortical sulci. Very large reductions in intracranial CSF volume were frequently related to post-LP headache but some patients developed headache with relatively little alteration in the intracranial CSF volume. There was not a measurable change in position of the intracranial structures following LP.
Deficiencies in anti-acetylcholine receptor antibody measurement in myasthenia gravis, In a retrospective case note study of 86 patients with myasthenia gravis. 60 had an anti-acetylcholine receptor antibody assay performed by the regional immunology laboratory. Antibody was detected in 38% which compares with 66-93% in other series. Whilst the use of staphylococcal protein A to precipitate the antibody-receptor complex. rather than anti-human immunoglobulin. may be partly responsible for this low sensitivity. other methodological problems are likely to exist. It is suggested that this potentially critical assay becomes a subject for regular audit.
Contractile properties of lower leg muscles are normal in Parkinson's disease, Contraction parameters (time-to-peak and half relaxation time). responses to short tetani and resistance to stretch were studied in the lower leg muscles of Parkinsonian patients and in age-matched controls. It was possible to distinguish between muscle groups of different fibre type composition in normal subjects on the basis of their contraction and relaxation velocities. These parameters. however. failed to show any abnormalities in the patient group. The only abnormal finding in Parkinsonian subjects was an increased resistance to passive stretch under static conditions. presumably elastic in origin. The results are evidence against a contribution of altered contractile properties to muscular rigidity in Parkinsonism.
Neurosurgical complications after intranasal ethmoidectomy, Intranasal ethmoidectomy is a common otolaryngological procedure. Despite the potential for serious intracranial complications. there is a paucity of reports describing the neurosurgical complications of the procedure. Two patients with intracranial complications of intranasal ethmoidectomy. and the relevant medical literature. are reviewed. The anatomy of the ethmoid air cells and their relation to the intracranial cavity are described. The importance of definitive. emergent repair with attention to the potential for vascular injury is discussed.
Correlation of the amnestic effects of nicotinic antagonists with inhibition of regional brain acetylcholine synthesis in rats, Acetylcholine (ACh) is considered to play a primary role in normal mnemonic functioning. Although most research has centered on the central muscarinic cholinergic system. of recent interest in normal and pathologic cognitive processing is the role of the nicotinic cholinergic system. The purpose of this research was to further characterize the role of the nicotinic system in learning and memory processing in a classical passive avoidance task by rats. The centrally acting nicotinic antagonist mecamylamine produced a dose-dependent impairment of performance in the passive avoidance task. however. the peripherally acting nicotinic antagonist hexamethonium was ineffective in this test. To elucidate the potential neurochemical mechanisms underlying mecamylamine's amnestic effect. we examined the ability of the drug to alter specific dynamic components of rat brain cholinergic systems in five brain regions. Mecamylamine produced a dose-dependent inhibition of the synthesis of [3H]ACh from pulse-injected [3H]choline in all regions examined. but was without effect on endogenous. steady-state levels of ACh. As with the behavioral study. administration of hexamethonium was without effect on [3H]ACh synthesis. Calculation of the turnover rates of ACh allowed a correlation between the inhibition of the behavioral task and the inhibition of central cholinergic function. The high degree of correlation obtained (as well as earlier studies in nonhuman primates) underlined the possibility that presynaptically located nicotinic receptors on brain cholinergic neurons are tonically active and mediate a positive feedback mechanism for controlling cholinergic neuronal activity. These receptors may be the neurochemical substrate which underlie the behavioral changes after administration of nicotinic agonists and antagonists.
The antifibrillatory actions of UK-68,798, a class III antiarrhythmic agent, The electrophysiologic and antifibrillatory properties of UK-68.798 were studied in vivo in a conscious canine model of sudden coronary death. Electrophysiologic testing was performed on conscious male mongrel dogs (14.5-21.5 kg) 3 to 5 days after surgical induction of an anterior myocardial infarction by occlusion (2 h)-reperfusion of the left anterior descending coronary artery. Compared to saline-treated control animals. UK-68.798 at a dose of 0.9 mg/kg i.v. did not (P = .083) suppress the induction of ventricular tachycardia by programmed electrical stimulation. Six of 12 UK-68.798-treated dogs remained inducible. whereas 10 of 12 vehicle-treated dogs responded to electrical induction of arrhythmia. When compared to predrug inducibility. UK-68.798 significantly (P = .007) reduced the incidence of programmed electrical stimulation-induced ventricular tachycardia. In five of the six dogs inducible after UK-68.798 administration. the cycle length of the induced ventricular tachycardia was prolonged (P = .007) compared to the predrug cycle length. Heart rate. PR interval and QRS duration were not affected by UK-68.798 administration. The rate-corrected QT interval was prolonged (P less than .05) by UK-68.798. The ventricular effective refractory period was increased by UK-68.798 (158 +/- 7 msec. predrug vs. 185 +/- 7 msec. postdrug). Subsequent to programmed electrical stimulation. a 150 microA anodal current was applied to the luminal surface of the left circumflex coronary artery to induce transient episodes of posterolateral ischemia in response to electrolytic injury of the vessel wall.
Kindling as a model of drug-resistant partial epilepsy: selection of phenytoin-resistant and nonresistant rats, Complex partial seizures comprise the major uncontrolled seizure type in adult patients with epilepsy. Any improvement of our understanding of the mechanisms through which these seizures are often refractory to antiepileptic drugs is therefore of considerable importance. By examining the effects of the anti-epileptic drug phenytoin in a large group of kindled rats. a widely used model of complex partial seizures. animals with different sensitivity to this drug were selected. Using determination of the focal seizure threshold for evaluation of phenytoin's anticonvulsant effect. most animals (about 60%) showed variable effects in response to phenytoin. However. about 20% of the animals ("phenytoin nonresponders") showed no increase in their focal seizure threshold at repeated test trials with phenytoin. and 20% ("phenytoin responders") exhibited reproducible increases in focal seizure threshold after injection of phenytoin. Phenytoin responders and nonresponders thus selected were used for subsequent experiments. The different response of focal seizures to phenytoin was not related to differences in pharmacokinetics or location of the stimulating electrode. Although phenytoin reproducibly increased the threshold for induction of afterdischarges in responders. it did not alter severity or duration of the elicited seizure response. In contrast to phenytoin. carbamazepine induced increases in focal seizure threshold in all kindled rats. Duration of seizures and afterdischarges were significantly reduced by carbamazepine in phenytoin responders. but not in nonresponders. although plasma levels of carbamazepine were the same in both groups. The difference in response of kindled rats to phenytoin was restricted to kindled seizures. because phenytoin induced the same anticonvulsant effect on the threshold for generalized tonic electroconvulsions (determined via transauricular electrodes) in both groups of kindled rats.
Endothelin and calcium signaling in NG108-15 neuroblastoma x glioma cells, Endothelin (ET)-mediated Ca++ signaling in NG108-15 neuroblastoma x glioma cells was studied by measuring free intracellular Ca++ (Ca++i) levels with the fluorescent Ca++ indicator. fura-2. ET-1 produced biphasic increases in Ca++i consisting of a transient peak elevation followed by a sustained plateau phase. Both peak and plateau Ca++i responses to 5 nM ET-1 were reduced by depletion of extracellular Ca++. Peak responses were also attenuated by inhibitors of inositol phosphate metabolism. whereas plateau responses were affected by dihydropyridine Ca++ channel agonists and antagonists and by differentiation. These results suggest that peak Ca++i responses to ET-1 involve mobilization of Ca++ from inositol phosphate-sensitive intracellular stores and influx of extracellular Ca++ through nonclassical Ca++ channels. whereas plateau responses are mediated by Ca++ influx through dihydropyridine-sensitive. voltage-gated channels.
Interaction between methotrexate, "rescue" agents and cell proliferation as modulators of homocysteine export from cells in culture, Clinical studies on cancer and psoriasis patients have shown that plasma and urinary homocysteine (Hcy) responds to methotrexate (MTX) therapy. indicating that Hcy in extracellular fluids may be an indicator of the antifolate effect. However. the clinical data indicate that the burden of proliferating cells. cytotoxicity and the folate status are also determinants of extracellular Hcy. To evaluate this further. we investigated the modulation of cellular Hcy egress by MTX. rescue agents. cell proliferation and cytotoxicity. Nontransformed and chemically transformed fibroblasts and murine lymphoma cells. which are characterized by different growth behavior and MTX response. were used. The Hcy export rate was correlated positively with the proliferation rate in all cell types. 5-Formyltetrahydrofolate or 5-methyltetrahydrofolate added to fibroblasts not exposed to MTX reduced the Hcy export rate. whereas the export from the lymphoma cells was not affected. All cells types exposed to MTX were rescued by thymidine + hypoxanthine. and this allowed the assessment of Hcy export during MTX exposure without interference from cytotoxicity. In the fibroblasts. MTX with thymidine + hypoxanthine rescue induced a marked increase in Hcy export. and the dose-response paralleled the cytotoxicity curves obtained for MTX without rescue. Nontoxic concentrations of MTX without rescue enhanced the Hcy export. When MTX concentration was increased further. Hcy export was stimulated initially. and then declined rapidly as cell death ensued. MTX did not enhance the Hcy export from the lymphoma cells and. in the absence of rescue. the Hcy export from these cells declined in proportion to inhibition of cell growth.
Evidence for central alpha-2 adrenoceptors, not imidazoline binding sites, mediating the ethanol-attenuating properties of alpha-2 adrenoceptor antagonists, The role of central adrenoceptors in the ethanol-attenuating effects of alpha-2 adrenoceptor blockers was investigated in mice; the centrally active antagonist atipamezole was compared with L 659.066. which penetrates the brain poorly. L 659.066 (1-10 mg/kg) had no effect on the hypothermia induced by ethanol (2 g/kg) or ethanol ataxia (2.4 g/kg). whereas atipamezole (1 mg/kg) significantly attenuated both ethanol-induced hypothermia and ataxia. Atipamezole (1-3 mg/kg) significantly attenuated the ethanol-induced reduction in exploratory head-dipping in a holeboard test whereas L 659.066 was only effective at a dose of 1 mg/kg. higher doses (3 and 10 mg/kg) and a lower dose (0.3 mg/kg) were ineffective. Atipamezole was without effect on ethanol's locomotor stimulant effect in the holeboard but L 659.066 attenuated this effect at doses less than 3 mg/kg Many alpha-2 adrenoceptor ligands also have affinity for nonadrenergic imidazoline-binding sites. The role these sites may play in attenuating ethanol's effects was investigated by comparing RX 821002 (methoxy idazoxan). which has little or no affinity for imidazoline-binding sites with atipamezole. Both atipamezo 1 e (1 mg/kg) and RX 821002 (0.06-0.2 mg/kg) significantly attenuated ethanol-induced hypothermia. ataxia and reduction in head-dipping. but were without effect on ethanol-induced locomotor stimulation. These results suggest that nonadrenergic imidazoline-binding sites are not implicated in the ethanol-attenuating properties of alpha-2 adrenoceptor antagonists.
Caffeine and theophylline as adenosine receptor antagonists in humans, Substantial in vitro and animal data suggest that methylxanthines. such as caffeine and theophylline. act as adenosine receptor antagonists. To test this hypothesis in humans. we first determined if theophylline would antagonize the effects of adenosine. Intravenous administration of adenosine. 80 micrograms/kg/min. increased heart rate 28 +/- 6 bpm. systolic blood pressure 19 +/- 5 mm Hg and minute ventilation 6.1 +/- 2.2 liters/min. All these changes were significantly attenuated during theophylline administration (17 +/- 3 bpm and 1 +/- 2 mm Hg and 1.6 +/- 0.6 liters/min. respectively. P less than .05). at a dose (10 mg/kg over 1 hr. followed by 1.8 micrograms/kg/min i.v.) that produced plasma theophylline levels of 17 +/- 2 micrograms/ml (94 microM). We then determined if chronic caffeine consumption resulted in upregulation of platelet adenosine receptors in eight normal volunteers. After 7 days of caffeine abstinence. the adenosine analog 5'-N-ethylcarboxamidoadenosine produced a dose-dependent inhibition of thrombin-induced aggregation (EC50 = 69 nM). Subjects then were given caffeine. 250 mg p.o. 3 times a day for 7 days. Actual caffeine withdrawal. that is. virtual disappearance of caffeine in plasma. was apparent 60 hr after the last dose of caffeine. Caffeine withdrawal produced a significant shift to the left of 5'-N-ethylcarboxamidoadenosine inhibition of aggregation (EC50 = 49 nM. P less than .01). implying sensitization and/or upregulation of adenosine receptors as seen after chronic exposure to an antagonist. These results suggest that methylxanthines act as adenosine receptor antagonists in humans.
U-78517F: a potent inhibitor of lipid peroxidation with activity in experimental brain injury and ischemia, U-78517F (2-[4-[2.6-di-(1-pyrrolidinyl)-4-pyridinyl)-1-piperazinyl] methyl]-3.4-dihydro-2.5.7.8-tetramethyl-2H-1-benzopyran-6-ol. dihydrochloride). which combines the antioxidant ring portion of alpha-tocopherol together with the amine of the previously described 21-aminosteroids (e.g.. U-74006F). is a novel inhibitor of iron-catalyzed lipid peroxidation. U-78517F was found to have a 50% inhibitory concentration (IC50) of 0.6 microM against 200 microM ferrous chloride-initiated lipid peroxidation in rat brain homogenates. compared to 8 microM for U-74006F. 28 microM for alpha-tocopherol and 43 microM for the ring portion of alpha-tocopherol (i.e.. trolox). Both stereoisomers of the racemic U-78517F proved to be equally active antioxidants. Against lipid peroxidation initiated by xanthine/xanthine oxidase. U-78517F was even more potent. with an IC50 of 0.01 microM. U-78517F was also observed to protect cultured mouse spinal neurons against iron-induced damage. with an IC50 of approximately 0.5 microM. When administered to male CF-1 mice i.v. at 5 min after a severe concussive head injury. U-78517F produced a dose-related improvement in the 1-hr neurological recovery. The minimum effective i.v. dose was 1.0 micrograms/kg. Measurement of U-78517 concentrations in the brains of mice after administration of a 10-mg/kg i.v. dose revealed effective antioxidant levels for as long as 2 hr. Evidence of an in vivo antioxidant action was provided by the attenuation of iron-induced blood-brain barrier disruption (i.e.. Evans' blue extravasation) in rats pretreated with U-78517F.
Studies of concanavalin A in nonobese diabetic mice. II. Lymphocyte tracking and phenotype responses, We studied the tracking of 51chromium-labeled (resting) and Con A-induced (activated) tritiated thymidine-labeled syngeneic lymphocytes to adrenal. blood. brain. heart. liver. lymph nodes. pancreas. spleen. testis/ovary. thymus and thyroid in prediabetic. nonobese diabetic (NOD) mice and in age- and sex-matched C57BL/6 mice. 51Chromium-labeled cells showed no significant difference between strains in tracking to any tissue except lymph nodes (decreased in NOD vs. C57. P less than .05). Con A incubation resulted in no difference between strains in lymphocyte tracking to lymph nodes. but NOD mice had increased pancreatic tracking with Con A-incubated cells compared to C57 mice (P less than .05). Female NOD mice had reduced thymic tracking (P = .001) compared to C57 controls. Positive selection experiments showed the Con A-responsive cell to be a T cell. Both Lyt2+ (CD8+) and L3T4+ (CD4+) enriched T cell populations showed a labeling response to Con A. After 48 h of Con A incubation. the L3T4+/Lyt2+ ratio increased in splenocytes from NOD mice (P less than .05). whereas it decreased in C57 controls (P less than .01). Over the course of 6 days in culture. NOD splenocytes exposed to Con A characteristically exhibited a delayed expansion of the Lyt2+ population. We conclude that Con A incubation of NOD splenocytes results in T cells that. when reinfused. avoid the thymus and track preferentially to the pancreas. Con A immunomodulation as potential treatment for autoimmune disease warrants further study in this murine model.
Propafenone disposition and pharmacodynamics in normal and norepinephrine-induced cardiomyopathic rabbit hearts, The myocardial disposition and pharmacodynamics of propafenone were studied in 10 normal and 10 norepinephrine-induced cardiomyopathic rabbit hearts. The left ventricular propafenone concentrations measured after perfusion of propafenone (0.3 microM) for 150 min were similar in the normal group (18 +/- 8 micrograms/g) compared to the cardiomyopathy group (20 +/- 5 micrograms/g. P = NS). However. the concentration of propafenone in cardiomyopathic left ventricular papillary muscle. which was always extensively involved in the inflammatory process. was significantly lower (11 +/- 2 micrograms/g) compared to normal papillary muscle (19 +/- 4 micrograms/g. P less than .05). During propafenone perfusion a significantly greater increment in ventricular conduction time was observed in the cardiomyopathy group (17 +/- 6 msec) compared to the normal group (12 +/- 3 msec. P less than .05). The propafenone myocardial concentration-effect relationships describing changes in QRS duration were shifted to the left in the cardiomyopathy group. Furthermore. the slopes of these linear concentration-effect relationships were greater in the cardiomyopathy group (1.80 +/- 0.60 msec/micrograms/g) compared to the normal group (1.07 +/- 0.25 msec/micrograms/g. P less than .01). The ventricular effective refractory period was shorter at base line in the cardiomyopathy hearts (156 +/- 21 msec) compared to the normal group (176 +/- 23 msec. P less than .08). However. propafenone effects on changes in the ventricular effective refractory period were similar in the two groups. Thus. the myocardial accumulation of propafenone is reduced in areas of extensive necrosis observed in norepinephrine-induced cardiomyopathy. As well. cardiomyopathic tissue is more responsive to propafenone effects on ventricular conduction time.
Efficacy of danazol in the control of hormonal migraine, Of 131 women with hormonally related migraines unresponsive to standard medication. 67 (51.1%) noted profound relief after a 12-month. phased study using danazol for migraine prevention. The first three phases consisted of two-month cycles: dietary control and acetazolamide. the addition of danazol and danazol discontinuation. Eighty-three women (63.36%) reported control of their hormonal migraines while using danazol. In phase IV. 81 women whose headaches were controlled by danazol restarted danazol for an additional six months. Sixty-seven (82.7%) reported continued success with this medication. Danazol proved highly successful in the control of women's cyclic migraine. Its effectiveness remained consistent throughout the treatment course. In the prophylactic treatment of women's hormonal migraine. 400 mg of danazol administered daily for 25 days each month can prove effective when standard medical therapy fails. Furthermore. the response to danazol supported the concept that hormonal migraine should be treated as a distinct clinical entity.
Use of the drop volume of amniotic fluid in predicting fetal lung maturity. Clinical experience, Respiratory distress syndrome (RDS). resulting from inadequate amounts of alveolar surfactant. is a leading cause of neonatal mortality. This study analyzed the drop volume for predicting the risk of neonatal RDS by evaluating the surface tension of amniotic fluid. The drop-volume method quantifies the surface tension of amniotic fluid using the fact that the volume of a falling drop of liquid is proportional to the quantity of surface-active substances (surfactant) in the solution. Distilled water is used as a reference solution. The test is simple to perform and requires only two minutes and 2 mL of amniotic fluid. Amniotic fluid was obtained by amniocentesis from 120 pregnancies. ranging from 24 to 42 weeks of gestation. within four days of delivery. Specimens contaminated with meconium or hemolyzed blood or from patients with clinical chorioamnionitis were not used. The lecithin:sphingomyelin ratio and phosphatidylglycerol tests were also determined for 54 of the study cases. A mature drop-volume test result was associated with a healthy infant with no RDS 95% of the time (negative predictive value). Fifty-two percent of the healthy infants in the study were predicted by an arbitrary unit of time (S) value of less than or equal to 85.0 (specificity). Thirteen of the 16 infants who developed RDS (81%) were predicted by an S value of greater than or equal to 85.1 (sensitivity). Of those infants with an S value of greater than or equal to 85.1. 21% developed RDS (positive predictive value).
Cervical pregnancy. A report of two cases, Cervical pregnancy is a rarely occurring form of ectopic pregnancy. Given its rarity. the identification of risk factors is based on anecdotal case reports and occasional summarizing reviews. We managed two additional cases with a new. conservative approach. The trend is away from radical therapy and toward conservation of reproductive function.
Relation between patients' own health assessment and clinical and laboratory findings in rheumatoid arthritis, Health status encompasses not only physical aspects. but also psychological and social aspects. A multidimensional health status questionnaire was used in 69 Dutch patients with rheumatoid arthritis to assess their physical. psychological and social well being. The same day clinical and laboratory data were recorded. The health status questionnaire provided additional information to clinical and laboratory findings. The various clinical and laboratory measures of disease activity reflect aspects other than the self-reported measure of physical well being. As such they are not interchangeable. Furthermore clinical and laboratory measures of physical well being appeared to be unrelated with psychological and social measures. In contrast. the patients' self-report of physical well being was related only with depressive mood and to some extent with anxiety.
Comparison of four articular indices for use in clinical trials in rheumatoid arthritis: patient, order and observer variation, Using a Latin square design. 4 patients were examined by 4 rheumatologists. Joints were scored for tenderness and inflammation. The Ritchie. the index of the American Rheumatism Association (ARA). the Hart modified Ritchie and a simplified Lansbury index were calculated from the raw data. The results suggest that an articular index consisting of a simple count of tender joints (Hart modified Ritchie) or a simple count of tender or swollen joints (ARA index) are the most reproducible with multiple observers. We suggest that these indices would be most appropriate for multicenter clinical trials.
Analysis of methotrexate treatment effect in a longitudinal observational study: utility of cluster analysis, We studied 235 patients with rheumatoid arthritis (RA) beginning therapy with methotrexate utilizing a k-means clustering algorithm. Four groups were identified: mild RA (Group 3). very severe RA (Group 4). and 2 groups intermediate in severity (Groups 1 and 2). Group 2. the largest of the clusters (n = 89). appeared to have greater tolerability of RA as measured by severity and psychological variables. and took the drug almost twice as long as other groups. although improvement was not greater nor side effects fewer. All groups improved over a mean of 1.9 years. and the degree of improvement was not related to the initial severity classification. Improvement occurred almost equally in all clusters. and the relative ranking of the groups was maintained at study closure.
Glucocorticoid receptors in systemic lupus erythematosus, Glucocorticosteroids remain the major treatment modality for systemic lupus erythematosus (SLE). but their mechanism of action is unclear. Over the past decade it has become clear that glucocorticosteroid receptors play a significant role in the mechanism of glucocorticosteroid action. We studied glucocorticosteroid receptor density and affinity on peripheral blood mononuclear cells by the glucocorticosteroid binding assay in 33 patients with SLE who had taken no glucocorticosteroid for the previous 6 months and in 32 healthy controls. Patients' disease activity was measured by the SLE Disease Activity Index (SLEDAI). Glucocorticosteroid receptors on leukocytes of patients with SLE were significantly higher than in healthy controls (4419 +/- 306 vs 3369 +/- 196. p less than 0.005). The binding affinity was not different between patients and controls. There was no correlation between glucocorticosteroid receptor number and SLE disease activity.
Effect of bucillamine (SA96) on type II collagen induced arthritis in rats, The effects of bucillamine. a new antirheumatic drug. on type II collagen induced arthritis in rats was examined. Bucillamine inhibited hindpaw swelling in a dose dependent manner. The histopathological study indicated that bucillamine inhibited the proliferation of synovial lining cells. The anti-type II collagen antibody level was also decreased by the treatment with bucillamine. D-penicillamine. on the other hand. showed no beneficial effects on arthritis except for inhibiting new bone formation. Our findings suggest that bucillamine has beneficial effects on type II collagen induced arthritis in rats and that its mechanism of action is different from those of D-penicillamine.
Adsorption with a soluble E. coli antigen fraction improves the specificity of ELISA tests for Lyme disease, We reported that preadsorption of patient serum with heat killed E. coli increased the specificity of ELISA for antibodies to Borrelia burgdorferi. That procedure required extra specimen handling and a preincubation. We report the use of a soluble E. coli antigen fraction that is included in serum diluent. eliminating additional steps. Sera from 220 individuals were tested for antibodies to B. burgdorferi. Twenty sera were obtained from patients with Lyme disease and 200 sera were from a population that included healthy controls and patients with different inflammatory conditions (viral infections and various rheumatic disorders). Testing was performed using either a standard serum diluent or one containing soluble E. coli antigen fraction. Results demonstrate that inclusion of soluble E. coli antigen fraction in serum diluent increased assay specificity from 88% for the standard protocol to 98%. with no change in test sensitivity.
Chondrocyte nonresponsiveness of arthritic articular cartilage caused by short term immobilization, We studied the effect of short term immobilization on chondrocyte synthetic function. Arthritis from intraarticular injection of either glucose oxidase or interleukin 1 (IL-1) led to suppression of proteoglycan synthesis. Extension casting of arthritic knees prevented inhibition of proteoglycan synthesis. whereas later casting restored synthesis to normal. During chronic antigen induced arthritis casting protected chondrocyte synthesis for a period of 5 days. The chondrocyte nonresponsiveness was not from altered penetration of suppressing substances. Radiolabelled biologically active IL-1 showed no difference in retention or localization in articular cartilage of either mobile or immobile knees. Flexion casting did not induce unresponsiveness of chondrocytes and suppression of synthesis was similar to that in mobile arthritic knees. indicating the importance of loading. The nonresponsiveness occurred only during immobilization and rapidly disappeared after removal of the cast. provided that suppressing agents were still present. Thus. during short term immobilization chondrocytes are protected from inhibition of proteoglycan synthesis by suppressing agents. This protection may benefit repair of the depleted cartilage matrix with waning inflammation.
The fibromyalgia impact questionnaire: development and validation, An instrument has been developed to assess the current health status of women with the fibromyalgia syndrome. The Fibromyalgia Impact Questionnaire (FIQ) is a brief 10-item. self-administered instrument that measures physical functioning. work status. depression. anxiety. sleep. pain. stiffness. fatigue. and well being. We describe its development and validation. This initial assessment indicates that the FIQ has sufficient evidence of reliability and validity to warrant further testing in both research and clinical situations.
Complete reversal of rheumatoid nodulosis, A woman first seen in 1978 had a history of seropositive rheumatoid arthritis (RA) of 12 years' duration with attacks of palindromic rheumatism for 3 years. She was treated with D-penicillamine. pyridoxine and hydroxychloroquine and serial measurements of her grip strength and proximal interphalangeal joint circumference were taken. By 1987 all her nodules had resorbed completely. Hydroxychloroquine effects probably helped her improvement. Although spontaneous resorption of a rheumatoid nodule is not a rare event. to the best of our knowledge. this is the first instance of complete resolution of all nodules in a patient with RA with the nodulosis variant.
Bone remodelling after growth factor and cyclosporine A therapy for aplastic anemia, We describe a patient with viral induced aplastic anemia who developed severe bone pain after treatment with multiple courses of antithymocyte globulin. cyclosporine A. recombinant human granulocyte macrophage colony stimulating factor and deferoxamine. Radiographs and bone biopsy revealed extensive new trabecular bone formation in long bone diaphyses and adjacent periosteal reaction. The effects of hematopoietic growth factors. cyclosporine A and deferoxamine on bone metabolism are reviewed.
The subsequent risk of internal cancer with Bowen's disease. A population-based study, OBJECTIVE--To address the subsequent risk of internal cancer in a population-based cohort of patients with Bowen's disease. DESIGN--Incident cases of skin cancers other than malignant melanoma occurring in a defined population were classified as basal cell carcinoma. squamous cell carcinoma. or Bowen's disease. Through medical records. all patients were followed up for the development of subsequent internal cancer until they died. moved from Rochester. Minn. or January 1. 1986. whichever came first. Incidence rates of skin cancer and subsequent cancer were computed; the subsequent rate of internal cancer was compared with that prevailing in the community. PATIENTS--Enrolled were all permanent residents in the population base of Rochester. Minn. who developed basal cell carcinoma (n = 657). squamous cell carcinoma (n = 169). or Bowen's disease (n = 71) on the basis of pathologic examination and clinical presentation from 1976 through 1984. MAIN OUTCOME MEASURE--The relative risk of subsequent internal cancer among patients with Bowen's disease compared with that of the population base from which they arose was 1.1 (95% confidence limits. 0.5. 1.6). RESULTS--Annual incidence rates. adjusted to the 1980 US white population. were 14.9 per 100.000 for Bowen's disease. 38.8 for squamous cell carcinoma. and 146 for basal cell carcinoma. The estimated relative risk for subsequent cancer was 0.9 (95% confidence limits. 0.5. 1.6) among patients with squamous cell carcinoma and 1.0 (95% confidence limits. 0.7. 1.3) for patients with basal cell carcinoma. These risks were not significantly different for various durations of follow-up or for sun-exposed vs sun-protected sites. CONCLUSIONS--We find no evidence in these population-based cohort data of and increased risk of subsequent internal cancer associated with Bowen's disease or other forms of nonmelanomatous skin cancer.
Patients who leave a public hospital emergency department without being seen by a physician. Causes and consequences, OBJECTIVE: To determine whether patients who sought care at a public hospital emergency department and left without being seen by a physician needed immediate medical attention and whether they obtained care after leaving. DESIGN: Follow-up study of patients who left without being seen and of patients who waited to be seen by a physician. SETTING: A public hospital's emergency department in Torrance. Calif. PATIENTS: All patients who registered for care and left without being seen (n = 186) and a 20% random sample of patients who waited until they were seen (n = 211) in a 2-week period during spring 1990. MAIN OUTCOME MEASURES: At time of presentation: triage nurse urgency assessment. clinical acuity rating. and self-reported health status. At follow-up: hospitalization rates. RESULTS: Patients who left reported that they had waited 6.4 hours before leaving; those who stayed reported a 6.2-hour wait before being seen. There were no differences between those who left and those who stayed in chief complaint. triage nurse assessment. acuity ratings. or self-reported health status. Forty-six percent of those who left were judged to need immediate medical attention. and 29% needed care within 24 to 48 hours. Eleven percent of those who left were hospitalized within the next week. and three patients required emergency surgery. Nine percent of those who waited to be seen were hospitalized. Forty-nine percent of patients who left did not see a physician during the 1-week follow-up period. CONCLUSION: Overcrowding in this public hospital's emergency department restricts access to needed ambulatory medical care for the poor and uninsured.
Consequences of queuing for care at a public hospital emergency department, OBJECTIVE: To determine whether the length of a queue at a public hospital emergency department was associated with increased likelihood of patients' leaving without being seen by a physician and whether leaving adversely affected patients' health or affected their subsequent use of health care services. DESIGN: Observational cohort. Patients were surveyed during 1 week in July 1990 and received a follow-up survey 7 to 14 days later. The responses of patients who left without being seen by a physician were compared with those who were seen by a physician. SETTING: Emergency department at San Francisco (Calif) General Hospital. PATIENTS: All English-. Spanish-. and Cantonese-speaking adults waiting for emergency care were eligible. Of 882 eligible individuals. 700 agreed to participate; 85% of enrolled subjects saw a physician and 15% left without being seen. Demographic characteristics of patients who were and who were not seen were not significantly different. MAIN OUTCOME MEASURES: Emergency department waiting time and changes in patients' self-reported health. RESULTS: Patients were more likely to leave as waiting times increased. At follow-up. patients who left without being seen were twice as likely as those who were seen to report that their pain or the seriousness of their problem was worse. Only 4% of patients who left required subsequent hospitalization. but 27% returned to an emergency department. CONCLUSION: Many patients can appropriately decide whether their problem is truly urgent and make alternative plans in the face of long waits. but the health of some patients may be jeopardized by long queues for emergency care.
British Columbia sends patients to Seattle for coronary artery surgery. Bypassing the queue in Canada, Concern about waiting lists for elective procedures has become a highly visible challenge to the universal health insurance program in Canada. In response to lengthening queues for patients waiting for cardiac surgery. British Columbia made contracts with four Seattle hospitals to send a total of 200 patients for coronary artery bypass surgery. This article examines the cause of the queue for cardiac surgery in British Columbia and the events that led to outside contracting. Global hospital budgets and restrictions on capital expansion have limited hospital capacity for cardiac surgery. This constrained supply. combined with periodic shortages in critical care nurses and cardiac perfusion technologists. has resulted in a rapid increase in the waiting list. Reducing wide variations in the lengths of queues for individual surgeons may afford an opportunity to reduce long waits. While the patient queue for cardiac surgery has sparked a public debate about budget limits and health care needs. its clinical impact remains uncertain.
Effect of a taurine-supplemented diet on conjugated bile acids in biliary surgical patients, The effect of a taurine-supplemented diet on the level of conjugated bile acids in postoperative patients was investigated during two consecutive 5-day period. Eighteen hepatobiliary patients with choledochostomies and a specific T-tube insertion were collected and divided randomly into two groups. In group 1. an ordinary postoperative soft diet was prescribed for the first 5 postoperative days and then followed with a taurine-supplemented soft diet (40 mumol/kg per day) for 5 consecutive days. In group 2. the taurine-supplemented diet was prescribed in reverse. At the end of the two periods. on days 5 and 10. bile was collected via a T-tube with an inflatable balloon and low-pressure motor suction. Analysis of conjugated bile acids was done by high-performance liquid chromatography. The results showed that a taurine-supplemented diet increased the concentration of taurocholic acid. glycocholic acid. taurochenodeoxycholic acid. glycochenodeoxycholic acid. and total bile acid from 0.5. 1.9. 0.3. 1.4. and 4.7 mg/mL (on day 5) to 1.1. 3.5. 1.0. 2.6. and 8.9 mg/mL. respectively. on day 10 in group 1. Similar findings were noted in group 2. These results indicate that a taurine-supplemented diet may enhance the conjugation and secretion of bile acid in hepatobiliary patients.
Dietary manipulation of methotrexate-induced enterocolitis, Administration of chemotherapy is limited by host toxicity. which is often manifested by severe enterocolitis. This study evaluated the effects of a liquid. elemental. chemically defined diet (ED) supplemented with 2% glutamine (Glu-ED) compared with a polypeptide diet (PPD) on the morbidity and mortality after methotrexate (MTX) administration. Fischer 344 rats (n = 80) were fed either a regular rat chow diet (RD). a 2% glycine supplemented elemental diet (Gly-ED). a 2% glutamine-supplemented elemental diet (GLU-ED). and a glycine-supplemented polypeptide diet(Gly-PPD) for 7 days prior to administration of MTX (20 mg/kg. ip). After 72 hours. eight rats per group were killed; portal vein and vena cava blood. mesenteric lymph nodes (MLN). liver. small intestine. and cecum were sampled for bacterial culture. Remaining animals were followed to calculate survival. One hundred percent of the Gly-PPD and 25% of the Glu-ED animals survived compared with 0% of the Gly-ED animals. Our data showed that ED resulted in an increased quantity of intestinal Gram-negative bacteria and diminished intestinal mucosal height and mucosal DNA/protein content. The polypeptide diet prevented intestinal mucosal atrophy. avoided MTX-induced enterocolitis and significantly improved animal survival compared with an elemental diet with or without glutamine supplementation.
Comparative hypersensitivity in intravenous lipid emulsions, We report a case of hypersensitivity to Intra-lipid but not to Liposyn II lipid emulsion. The patient had mild allergies to soybean protein. egg yolk. and egg whites by radioallergosorbent testing (RAST). Because protein contamination of the phospholipid binder during the emulsion manufacture may rarely occur. such contamination should be considered as a cause for urticarial eruptions associated with lipid emulsions.
Factors which regulate net hepatic glucose uptake in vivo, The regulation of net hepatic glucose uptake in vivo occurs by way of the hormonal milieu (insulin and glucagon). the glucose level. and the route of glucose delivery. Hyperglycemia in the absence of changes in pancreatic hormones (i.e.. increased insulin and/or decreased glucagon) does not elicit significant glucose uptake by the liver. Net hepatic glucose uptake is augmented in a dose-dependent manner by a rise in insulin and is further stimulated by the presence of a "portal signal." The presence of coordinated changes in insulin. glucagon. and the glucose level in combination with the "portal signal" ensures adequate glucose uptake by the liver in response to a meal.
Donor hearts with impaired hemodynamics. Benefit of warm substrate-enriched blood cardioplegic solution for induction of cardioplegia during cardiac harvesting, Brain-dead donors frequently show circulatory deterioration and often require so much inotropic support that the donor heart is of questionable value. This experimental study quantifies the cardiac metabolic consequences of brain death and the role of warm blood cardioplegic solution for induction of cardioplegia to improve the quality of potential donor hearts with impaired hemodynamics. Twelve dogs were subjected to brain death by interrupting cerebral blood flow (ligation of innominate artery. carotid arteries. and superior vena cava) and were followed up for as long as 6 hours. Each showed progressive hemodynamic deterioration. necessitating inotropic support (dopamine. calcium. and epinephrine) and large amounts of volume replacement (hetastarch; Hespan) to support the circulation (maintain mean arterial blood pressure greater than 60 mm Hg). Biopsy specimens were taken after 6 hours. or when irreversible ventricular fibrillation occurred. and were analyzed for adenosine triphosphate. creatine phosphate. glycogen. glutamate. and lactate. In six dogs the aorta was then clamped. and a 10-minute infusion of warm (37 degrees C) substrate-enriched aspartate/glutamate blood cardioplegic solution (with the dog's own blood) was given by roller pump to simulate warm induction during the harvesting process. Biopsies were then repeated. Myocardial metabolism. expressed as percent of control values. during brain death was characterized by the following: (1) moderate energy depletion (adenosine triphosphate fell 25% +/- 8%. creatine phosphate fell 55% +/- 15%; p less than 0.05 versus control: mean +/- standard error of the mean); (2) substrate depletion (tissue glutamate fell 48% +/- 9.5%. glycogen fell 66% +/- 7.5%; p less than 0.05 versus control: mean +/- standard error of the mean); and (3) evidence of anaerobic metabolism (lactate increased 374% +/- 95%; p less than 0.05 versus control: mean +/- standard error of the mean). Warm induction of blood cardioplegia in these energy- and substrate-depleted ischemic hearts showed (1) return of creatine phosphate levels to normal (113% +/- 16.8%). (2) replenishment of glutamate (201% +/- 24% of control; p less than 0.05 versus control: mean +/- standard error of the mean). and (3) 43% +/- 14% reduction in myocardial lactate content; (p less than 0.05 versus brain-dead animals). These data suggest that brain-dead donors requiring inotropic support sustain energy and substrate depletion and ischemic damage that can be reversed by a brief period of induction of cardioplegia with a warm substrate-enriched blood cardioplegic solution before harvesting.(ABSTRACT TRUNCATED AT 400 WORDS).
Long-term preservation of the mammalian myocardium. Effect of storage medium and temperature on the vulnerability to tissue injury, Human heart preservation for transplantation commonly involves infusion of cold cardioplegic solutions and subsequent immersion in the same solution. The objectives of the present study were (1) to establish the temporal relationship between storage time (at 10 degrees C) and the postischemic recovery of function in the isolated rat heart. (2) to assess. by metabolic and functional measurements. whether storing the heart in fluid as opposed to moist air had any effect on the viability of the preparation. and (3) to ascertain the optimal storage temperature. Isolated rat hearts (at least 6 in each group) were infused for 3 minutes with St. Thomas' Hospital cardioplegic solution No. 2 at 10 degrees C. stored at 10 degrees C for 6. 12. 18. or 24 hours. and then reperfused at 37 degrees C. Mechanical function. assessed by construction of pressure-volume curves (balloon volumes: 20. 40. 60. 80. 100. and 120 microliters). was measured before ischemia and storage and after 60 minutes of reperfusion. Function deteriorated in a time-dependent manner; thus at a balloon volume of 60 microliters the recovery of left ventricular developed pressure was 84.2% +/- 5.3% after 6 hours (p = not significant when compared with preischemic control); 69.1 +/- 3.3% after 12 hours (p less than 0.05); 55.6% +/- 4.4% after 18 hours (p less than 0.05). and 53.0% +/- 6.8% (p less than 0.05) after 24 hours of storage. Other indices of cardiac function. together with creatine kinase leakage and high-energy phosphate content. supported these observations. Since the recovery of the left ventricular developed pressure balloon volume curves were essentially flat after 18 and 24 hours of storage. either 6 or 12 hours of storage were therefore used in subsequent studies. Comparison of storage environment (hearts either immersed in St. Thomas Hospital cardioplegic solution No. 2 or suspended in moist air at 10 degrees C for 6 or 12 hours) revealed no significant differences in functional recovery between the groups. Thus hearts recovered 94.9% +/- 3.5% and 113.7% +/- 12.4%. respectively. after 6 hours of storage and 71.6% +/- 2.4% and 54.2% +/- 7.9%. respectively. after 12 hours of storage. Enzyme leakage and tissue water gain were also similar in both groups of hearts. Finally. hearts (n = 6 per group) were subjected to 12 hours' storage at 1.0 degree. 5.0 degrees. 7.5 degrees. 10.0 degrees. 12.5 degrees. 15.0 degrees. and 20.0 degrees C.(ABSTRACT TRUNCATED AT 400 WORDS).
Low-dose enoximone in subjects awaiting cardiac transplantation. Clinical results and effects on beta-adrenergic receptors, During a 3-year period we administered enoximone. a phosphodiesterase inhibitor with positive inotropic and vasodilator properties. to 73 pretransplantation patients with end-stage heart failure who exhibited a clinical requirement for additional inotropic support. The clinical course and myocardial beta-adrenergic receptor status in the explanted hearts of these 73 patients was compared with results in 113 concurrently listed pretransplantation patients not requiring additional inotropic support. Only three patients required cessation of enoximone because of adverse effects. all from exacerbation of ventricular arrhythmias. Sixty-six of 73 (90.4%) enoximone-treated patients ultimately underwent cardiac transplantation a mean of 39.2 +/- 6.6 days (range 1 to 221 days) after starting enoximone. whereas seven patients (9.6%) died awaiting cardiac transplantation. The respective 1-. 3-. and 6-month pretransplantation survival rates of patients treated with enoximone calculated from their time on the waiting list for transplantation were 88.0%. 82.5%. and 82.5% compared with 92.1%. 83.8%. and 76.2% in control patients not receiving enoximone (all p = not significant). In 25 patients who received enoximone. ventricular myocardial beta-adrenergic receptors were measured at the time of transplantation and compared with values in failing ventricles from 52 pretransplantation patients not exposed to enoximone. Compared with ventricular myocardium of patients not given enoximone or intravenous beta-adrenergic agonists. total beta-adrenergic receptor (beta 1 plus beta 2) density was not decreased in patients treated with enoximone or enoximone plus intravenous beta-adrenergic agonists. but was decreased by 31% (p less than 0.05) in patients given intravenous beta-adrenergic agonists alone. Additionally. patients treated with enoximone had higher myocardial beta 2-adrenergic receptor densities than respective subgroups treated without (28% higher. p less than 0.01) or with (65% higher. p less than 0.01) intravenous beta-adrenergic agonists. Finally. isoproterenol- or calcium-mediated contractile responses in isolated right ventricular preparations from 14 patients treated with enoximone were similar to values in control patients not exposed to enoximone or intravenous beta-adrenergic agonists. suggesting that enoximone-related beta-adrenergic subsensitivity or damage to the contractile apparatus does not occur.
Myocardial reperfusion injury. Platelet-activating factor stimulates polymorphonuclear leukocyte hydrogen peroxide production during myocardial reperfusion, To study the roles of platelet-activating factor. polymorphonuclear leukocytes. and oxygen free radicals in myocardial reperfusion injury. we subjected 10 sheep to 90 minutes of mid-left anterior descending coronary artery followed by 6 hours of reperfusion. Stainings with gentian violet and tetratriphenyl ammonium chloride demonstrated 20% +/- 3% of the left ventricular mass at risk for ischemia. of which 75% +/- 10% underwent infarction. Coronary sinus blood was assayed for platelet-activating factor and neutrophil hydrogen peroxide production before and during coronary occlusion and during reperfusion. Platelet-activating factor was isolated by column chromatography and lipid extraction and quantified by radioimmunoassay. Neutrophil hydrogen peroxide production was measured by a 2'.7'-dichlorofluorescein flow-cytometric assay. Platelet-activating factor was elevated to 899 +/- 210 pg/ml at 15 minutes of reperfusion. compared with the preocclusion level of 271 +/- 55 pg/ml and coronary occlusion level of 359 +/- 64 pg/ml (p less than 0.05; analysis of variance). Neutrophil hydrogen peroxide production. measured on a relative fluorescence scale. was also elevated to a level of 141 +/- 27 at 1 hour of reperfusion. compared with the preocclusion level of 103 +/- 6 and the coronary occlusion level of 114 +/- 13 (p less than 0.01; analysis of variance). Both of these parameters returned toward baselines at the end of 6 hours of reperfusion. Histologic examination revealed infiltration of polymorphonuclear leukocytes into the interstitium of the reperfused myocardium. Neutrophils isolated from unoperated and healthy sheep demonstrated a graded dose response in hydrogen peroxide production when stimulated by purified platelet-activating factor in vitro. These findings suggest that platelet-activating factor is released in the coronary circulation and is a mediator of oxygen free radical production in polymorphonuclear leukocytes during myocardial reperfusion.
High breath pentane concentrations during acute myocardial infarction, To investigate whether reperfusion after myocardial ischaemia leads to free-radical-mediated peroxidation of membrane lipids and cell damage. we measured pentane. a product of lipid peroxidation. in the breath of 10 healthy control subjects and in 20 consecutive patients with suspected acute myocardial infarction. 10 of these patients showed no myocardial damage on electrocardiography (patient control group) and 10 satisfied standard diagnostic criteria for acute myocardial infarction. The three groups were well matched for age. sex. underlying disease. and smoking habits. The time from onset of chest pain to breath collection was similar in the patient control and acute myocardial infarction groups. The breath pentane concentration was higher (p less than 0.0001) in the acute myocardial infarction group (4.96 [1.15] nmol/l) than in the patient control (1.96 [1.04] nmol/l) and healthy control groups (1.71 [0.87] nmol/l). Lipid peroxidation during acute myocardial infarction reflects action of oxygen radicals and their potential for contribution to the pathogenesis of tissue damage.
Evidence of brain methyltransferase inhibition and early brain involvement in HIV-positive patients, The myelopathy associated with human immunodeficiency virus (HIV) infection closely resembles that in subacute combined degeneration. a disorder of vitamin B12 metabolism. To investigate whether the disorders share a pathogenetic mechanism. S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were measured in the cerebrospinal fluid (CSF) of 20 HIV-seropositive patients and 30 HIV-negative patients who were undergoing lumbar puncture for other medical reasons. The HIV-seropositive patients had significantly lower CSF concentrations of SAM (mean 77 [SD 25] vs 131 [35] nmol/l; p less than 0.001) and significantly higher concentrations of SAH (30.5 [6.8] vs 19.0 [7.1] nmol/l; p less than 0.001) than the controls. There was therefore a significant difference between the groups in the SAM/SAH (methylation) ratio (HIV 2.7 [1.0] vs control 7.6 [3.4]; p less than 0.001). There were no correlations between SAM or SAH concentrations or methylation ratio and age or sex in both groups. or serum B12 and folate concentrations. CSF folate. serum or CSF methylmalonic acid. risk factors. body mass index. specific drug treatment received. or disease stage in the HIV group. This finding suggests that HIV affects the brain from a very early stage of the infection. We suggest that. as in the pig. the CSF methylation ratio closely reflects that in the brain. In HIV-infected patients a reduced brain methylation ratio would inhibit methyltransferase enzymes. which would lead to hypomethylation in the central nervous system and ultimately to neurological lesions. In a pig model of subacute combined degeneration and in vitamin-B12-deficient human beings. the primary cause of the low methylation ratio is impaired recycling of SAH back to SAM. a process which requires vitamin-B12-dependent methionine synthase. The HIV patients in this study were vitamin B12 and folate replete. which suggests a different cause for the low methylation ratio.
Preliminary evidence for homoeostatic mechanism regulating endothelin production in pre-eclampsia, To find out whether a serum factor in pre-eclamptic women is the cause of the raised serum endothelin concentrations associated with the disorder. the effect of serum from pre-eclamptic women on endothelin production by endothelial cells was compared with that of serum from pregnant and non-pregnant controls. The finding that pre-eclamptic serum suppresses endothelin production suggests that it contains a factor that might be part of a homoeostatic response to raised serum endothelin concentrations in pre-eclampsia.
Hypoplastic left heart syndrome: more potential transplant recipients than suitable donors, Neonatal cardiac transplantation offers the prospect of survival for babies with hypoplastic left heart syndrome--but only if suitable donors are available. In a retrospective survey in the Northern health region of England and Wales. the likely need for neonatal cardiac transplantation far outweighed the potential availability of donors. Over 8 years (1983-90) hypoplastic left heart syndrome was identified in 38 newborn babies and in 9 fetuses in utero. Of 41 live births (including 3 diagnosed prenatally) 31 would have been candidates for a cardiac transplant. but only 4 suitable donors could be identified (3 with anencephaly born alive during the same period and 1 who died between 1979 and 1986 after a head injury). Analysis of all infant deaths in 1987-89 revealed only 3 potential donors from 426 deaths in the 3 years. Although more widespread antenatal diagnosis may lead to fewer liveborn babies with hypoplastic left heart syndrome. these findings indicate that an alternative source of donors needs to be identified before neonatal cardiac transplantation can be widely used in the treatment of this disorder.
Hypoplastic left heart syndrome: effects of fetal echocardiography on birth prevalence, Hypoplastic left heart syndrome was diagnosed prenatally and confirmed in 105 fetuses since 1983 at a regional referral centre. An increased detection rate since 1988 is probably related to increased experience in the use of a four-chamber view of the fetal heart during routine obstetric ultrasound scanning. When the diagnosis was made sufficiently early. most parents chose to terminate the pregnancy after the prognosis and surgical options were explained. By contrast. after an increase in the mid 1980s. since 1988 there has been a striking fall in the number of newborn babies with hypoplastic left heart syndrome treated at a supraregional referral centre. More widespread use of four-chamber cardiac screening during routine fetal ultrasonography may reduce the number of newborn babies with hypoplastic left heart syndrome--a factor which should be taken into account when the likely requirements for neonatal cardiac transplantation facilities are calculated.
Efficacy of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in US children aged 18-59 months. Haemophilus Influenzae Vaccine Efficacy Study Group, Vaccines prepared from the polyribosylribitol phosphate (PRP) capsule of Haemophilus influenzae b (Hib) have not consistently shown good efficacy in protecting children aged over 18 months from invasive Hib disease. To evaluate the efficacy of conjugate-PRP vaccines in this age-group. and to compare their effect with that of PRP vaccines. a post-marketing case-control study was conducted among 10.400.000 persons. Between Oct 1. 1988. and Feb 28. 1990. 75 patients with Hib disease and 161 control children between 18 and 60 months of age were enrolled. To minimise potentially confounding socioeconomic variables. controls were selected either from among patients' classmates at their day-care centre or from among family acquaintances. 9 of the 75 patients had received the diphtheria toxoid conjugate Hib vaccine more than 2 weeks before onset of illness. After adjusting for age and household crowding. the efficacy of PRP Hib vaccine was 64% (95% Cl = -20.89) and efficacy of the diphtheria toxoid conjugate Hib vaccine was 74% (95% Cl = 30.90). The study shows that the protective efficacy of this conjugate vaccine is less than ideal and highlights the need for additional post-licensing studies to confirm and expand understanding of the efficacy of these new products.
Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia, The clinical relevance of cellular drug resistance in children with acute lymphoblastic leukaemia (ALL) is unknown. The relation between in-vitro sensitivity to chemotherapeutic drugs at initial diagnosis and long-term clinical outcome was investigated in 44 children with ALL. The short-term MTT assay was used to assess sensitivity to prednisolone. vincristine. colaspase (asparaginase). daunorubicin. and thioguanine (instead of mercaptopurine which is unstable in vitro). For vincristine and colaspase there was no difference in outcome (probability of continuous complete remission) between sensitive and resistant patients. However. the probability of continuous complete remission was significantly lower in patients with resistant cells than in those with sensitive cells for thioguanine (p less than 0.01). daunorubicin (p less than 0.02). and prednisolone (p less than 0.05). For prednisolone there was a significant worsening of the prognosis (p less than 0.05) from the extremely sensitive patients through an intermediate group to the most resistant group. The prognostic significance of cellular drug resistance was independent of white-blood-cell count. age. sex. and hepatosplenomegaly. Leukaemic cells from boys were more resistant to thioguanine than those from girls. Thus. the short-term highly efficient MTT assay can help to predict long-term response to chemotherapy in childhood ALL.
Correction of erythrocyte abnormalities in idiopathic calcium-oxalate nephrolithiasis and reduction of urinary oxalate by oral glycosaminoglycans, Calcium-oxalate nephrolithiasis is associated with a defect in erythrocyte oxalate self-exchange and an abnormal rate of erythrocyte membrane protein phosphorylation. There is evidence that glycosaminoglycans (GAGs) have a regulatory effect on both of these processes. This study tested the hypothesis that modifications of erythrocyte oxalate self-exchange induced by oral GAGs are paralleled by similar changes in overall oxalate metabolism. 40 patients with idiopathic calcium-oxalate nephrolithiasis were treated for 15 days with 60 mg/day of a mixture of GAGs. By day 15 of treatment there were significant reductions from baseline in erythrocyte oxalate self-exchange (mean [SD] 1.67 [1.18] vs 2.59 [1.63] x 10(2) per min; p less than 0.005) and erythrocyte membrane protein phosphorylation (55.8 [7.3] vs 72.9 [6.8] x 10(-3) cpm/mg protein; p less than 0.005). but also in urinary oxalate excretion (0.24 [0.09] vs 0.31 [0.15] mmol/24 h; p less than 0.005). This finding suggests similar changes in both erythrocytes and other cells more important in oxalate handling. The changes had reversed by 15 days after withdrawal of treatment. Acute intravenous administration of GAGs (60 mg) induced a fall in carbon-14-labelled oxalate renal clearance (143 [13] vs 169 [28] ml/min; p less than 0.005). which strongly suggests the participation of the kidney. However. reduced oxalate absorption from the intestine. and even decreased synthesis of oxalate. cannot be ruled out.
Hypergastrinaemia: a new mechanism, The mechanism by which lack of gastric acid causes hypergastrinaemia was investigated in seven patients with pernicious anaemia. Perfusion of gastric juice from the fasting patients (adjusted to pH 7.0) into the stomachs of conscious rats caused a significant rise in plasma gastrin (median 14 [range 2-20] pmol/l to 27 [12-65] pmol/l; p less than 0.01). whereas perfusion of bicarbonate buffer (18 [13-23] pmol/l to 20 [9-25] pmol/l) or gastric juice from a duodenal ulcer patient (also pH 7.0; 13 [3-30] pmol/l to 17 [9-27] pmol/l) had no significant effect. During gastric lavage at pH 7.0 the median plasma gastrin concentration of the pernicious anaemia patients fell from 320 (63-1760) pmol/l to 125 (46-760) pmol/l (p less than 0.03).
Laser midline glossectomy as a treatment for obstructive sleep apnea, Multiple site specific procedures have been proposed to treat obstructive sleep apnea syndrome (OSAS). Midline glossectomy (MLG) is a procedure that directly enlarges the hypopharyngeal airspace using the carbon dioxide laser. The initial experience of 12 patients is presented. Midline glossectomy as the sole procedure was performed on 11 patients who had failed uvulopalatopharyngoplasty (UPPP) and who were felt to have significant hypopharyngeal collapse on physical examination and Muller's maneuver. One patient with primary hypopharyngeal narrowing underwent MLG. Five (42%) were considered responders with Respiratory Disturbance Index (RDI) decreasing from 60.6 per hour to 14.5 per hour. In seven nonresponders. there was no significant change in the RDI (62.6 events per hour to 48.4 events per hour). Cephalometric analysis showed that responders tended to be more retrognathic (sella-nasion-supramentale (S-N-B = 74.4 degrees)) than nonresponders (S-N-B = 79.3 degrees). Responders were significantly less obese (body mass index (BMI = 30.6)) than nonresponders (BMI = 37.9). There were five minor complications including minor bleeding (n = 3). prolonged odynophagia (n = 1). and minor change in taste (n = 1). There were no major complications. and no persistent difficulties with speech or swallowing. These results demonstrate that direct surgical modification of the tongue base and associated structures can significantly impact obstructive apnea. Midline glossectomy or similar procedures may be useful in a subset of patients with OSAS.
Stapedectomy: long-term hearing results, The initial improvement in hearing following stapedectomy usually deteriorates with the passage of time. We studied the long-term results of stapedectomies performed on 42 patients (49 ears) between 1959 and 1969 who had a minimum follow-up of 18 years. Both air conduction (AC) and bone conduction (BC) thresholds progressively deteriorated over the long term. The degree of BC loss paralleled that expected from presbycusis alone. A greater deterioration was noted in the AC levels. producing a recurrent conductive hearing loss in the speech frequencies. Age at the time of surgery had no effect on the long-term outcome. Comparison of the average preoperative speech discrimination scores (SDS) to the 1-year postoperative SDS and the long-term SDS revealed a 1.1% and 16.7% drop. respectively. The improvement in the average speech reception threshold (SRT) obtained 1 year postoperatively deteriorated by less than 1 dB per year over the long term. Patients with a higher SDS (more than 95%) preoperatively fared better in the maintenance of speech discrimination than those with a lower SDS (less than 95%). The preoperative SRT level was predictive of the timing for the requirement of hearing amplification. The postoperative SRT level was predictive of the timing for the requirement of hearing amplification. The caused by presbycusis. combined with a recurrent conductive loss in the speech frequencies rather than cochlear otosclerosis. Although the decline in hearing following stapedectomy exceeds the rate of hearing loss due to presbycusis. many individuals. after successful stapes surgery. are able to delay the need for hearing amplification for longer periods than had been previously reported.
A new approach to serial monitoring of ultra-high frequency hearing, Early detection of drug-induced hearing loss is best accomplished by monitoring hearing at the ultra-high frequencies. Unfortunately. at these frequencies. sound pressure at the tympanic membrane (TM) critically depends on the placement of the sound source and on the size and shape of each individual external ear. Thus. presentation of the same sound may yield substantially different sound pressures in different ears. Moreover. only a slight change in the position of an earphone may yield large changes in sound pressure at the tympanic membrane. As a consequence of these characteristics. the reliability of ultra-high-frequency audiometry is poorer than at conventional audiometric frequencies. However. for the early detection of ototoxicity. it is necessary only to monitor for increases in thresholds. Accordingly. a sound-delivery system was developed which fixes the relative position of the sound source and the ear. This system ensures that sounds at the same level may be presented during different test sessions. To assess the stability of ultra-high-frequency thresholds. normal hearing subjects were tested in sessions separated by several weeks. Thresholds were obtained between 1 and 16 kHz and were found to be reliable. It is concluded that this type of system can be used for monitoring the ototoxic effects of drug therapy.
Otoplasty: critical review of clinical results, Although it is generally believed that otoplasty provides uniformly gratifying results. thorough patient follow-up reviews are quite rare. Otoplasty surgery performed on 119 ears was retrospectively reviewed to assess the results of our cartilage-sparing technique. This method of otoplasty relies on a conchal set-back and suture transfixation technique to improve the antihelical contour. Auricular medialization averaged 10.3 mm. Over-correction is required. particularly in the superior pole. as loss of correction with healing was approximately 40% of the initial medialization. Revision surgery due to loss of correction was necessary for 6.6% of the ears initially operated on by the senior author. Patients who presented following cartilage-cutting procedures tended to have a higher rate of revision and persistent postoperative stigmata. Complications in general were few; however. mersilene suture extrusion occurred in 8% of ears. Only one of these required revision surgery for associated loss of correction. Despite these drawbacks. over 95% of patients achieved satisfactory results using cartilage-sparing otoplasty techniques.
P300 response to tones and speech sounds after cochlear implant: a case report, P300 potentials evoked by tones and spoken words were recorded from a 20-year-old man with a House-3M single-channel cochlear implant. Three months after cochlear implantation. there was a slight appearance of P300 response to both pure-tone stimuli and spoken-word stimuli; 6 months later. clearly identifiable P300 response to both pure-tone stimuli and spoken-word stimuli were obtained. These results are consistent with an encoding improvement for re-establishment of information processing after auditory rehabilitation.
A method for the treatment of abductor spasmodic dysphonia with botulinum toxin injections: a preliminary report, A preliminary technical report of the effective treatment of abductor spasmodic dysphonia with botulinum toxin is presented. Our technique attempts to place the toxin close to the posterior cricoarytenoid muscle to allow diffusion of the material to the PCA. Our pilot study demonstrates that botulinum toxin is an effective approach for reducing or eliminating the abductor glottal spasms during phonation and. thereby. providing functional speech communication.
Childhood cancers--New Jersey, 1979-1985, In New Jersey. cancers among children aged 0-14 years account for fewer than 1% of all cancers diagnosed annually; however. childhood cancers account for the greatest number of years of potential life lost from cancer. This report summarizes a study by the New Jersey State Department of Health (NJSDH) that determined the incidence and death rates for the most frequent cancers among children aged 0-14 years in New Jersey during 1979-1985; these rates are compared with those for the United States for a comparable period.
Breakdown of self-tolerance in anergic B lymphocytes, Production of autoantibodies. which characterizes most autoimmune diseases. is normally avoided by active elimination or functional inactivation (anergy) of B and T lymphocytes bearing receptors for self antigens. The mechanisms leading to the escape of self-reactive clones from these normal tolerance mechanisms in autoimmune diseases nevertheless remain obscure. Here. we demonstrate that clonal anergy in B lymphocytes is a reversible process. and that silenced self-reactive B cells can be reactivated under particular conditions to give rise to vigorous antibody responses. Reactivation of anergic lymphocytes may explain many examples of transient autoimmune reactions in normal individuals. and may under pathological conditions be important in the development of chronic autoimmune disease.
The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy, Although murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin. the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration. fibrosis and severe functional deficit comparable to that of DMD limb muscle. although adult mice show no overt respiratory impairment. Progressive functional changes include reductions in strength (to 13.5% of control by two years of age). elasticity. twitch speed and fibre length. The collagen density rises to at least seven times that of control diaphragm and ten times that of mdx hind-limb muscle. By 1.5 years of age. similar but less severe histological changes emerge in the accessory muscles of respiration. On the basis of these findings. we propose that dystrophin deficiency alters the threshold for work-induced injury. Our data provide a quantitative framework for studying the pathogenesis of dystrophy and extend the application of the mdx mouse as an animal model.
GLI3 zinc-finger gene interrupted by translocations in Greig syndrome families, The Greig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder affecting limb and craniofacial development in humans. GCPS-affected individuals are characterized by postaxial polysyndactyly of hands. preaxial polysyndactyly of feet. macroephaly. a broad base of the nose with mild hypertelorism and a prominent forehead. The genetic locus has been pinpointed to chromosome 7p13 by three balanced translocations associated with GCPS in different families. This assignment is corroborated by the detection of two sporadic GCPS cases carrying overlapping deletions in 7p13 (ref. 7). as well as by tight linkage of GCPS to the epidermal growth factor receptor gene in 7p12-13 (ref. 8). Of the genes that map to this region. those encoding T cell receptor-gamma. interferon-beta 2. epidermal growth factor receptor. and Hox1.4. a potential candidate gene for GCPS. have been excluded from the region in which the deletions overlap. Here we show that two of the three translocations interup the GLI3 gene. a zinc-finger gene of the GLI-Kruppel family already localized to 7p13 (refs 5. 6). The breakpoints are within the first third of the coding sequence. In the third translocation. chromosome 7 is broken at about 10 kilobases downstream of the 3' end of GLI3. Our results indicate that mutations disturbing normal GLI3 expression may have a causative role in GCPS.
Preferential DNA secondary structure mutagenesis in the lagging strand of replication in E. coli, When present in single-stranded DNA. palindromic or quasi-palindromic sequences have the potential to form complex secondary structures. including hairpins. which may facilitate interstrand misalignment of direct repeats and be responsible for diverse types of replication-based mutations. including deletions. additions. frameshifts and duplications. In regions of palindromic symmetry. specific deletion events may involve the formation of a hairpin or other DNA secondary structures which can stabilize the misalignment of direct repeats. One model suggests that these deletions occur during DNA replication by slippage of the template strand and misalignment with the progeny strand. The concurrent DNA replication model. involving an asymmetric dimeric DNA polymerase III complex which replicates the leading and lagging strands. has significant implications for mutagenesis. The intermittent looping of the lagging strand template. and the fact that the lagging strand template may contain a region of single-stranded DNA the length of an Okazaki fragment. provides an opportunity for DNA secondary-structure formation and misalignment. Here we report our design of a palindromic fragment to create an 'asymmetric palindromic insert' in the chloramphenicol acetyltransferase gene of plasmid pBR325. The frequency with which the insert was deleted in Escherichia coli depends on the orientation of the gene in the plasmid. Our results suggest that replication-dependent deletion between direct repeats may occur preferentially in the lagging strand.
Common west African HLA antigens are associated with protection from severe malaria, A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501). common in West Africans but rare in other racial groups. are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.
Phosphorylation-regulated Cl- channel in CHO cells stably expressing the cystic fibrosis gene, A cyclic AMP-stimulated chloride conductance appears when the cystic fibrosis gene is expressed in non-epithelial cells by infection with recombinant viruses. Cyclic AMP-stimulated conductance in this system is mediated by the same ohmic. low-conductance Cl- channel as in human secretory epithelia. but control of this channel by phosphorylation has not been directly demonstrated. Here we report the appearance of the low-conductance Cl- channel in Chinese hamster ovary cells after stable transfection with the cystic fibrosis gene. The channel is regulated on-cell by membrane-permeant analogues of cAMP and off-cell by protein kinases A and C and by alkaline phosphatase. These results are further evidence that the cystic fibrosis transmembrane regulator is a Cl- channel which can be activated by specific phosphorylation events and inactivated by dephosphorylation; they reveal an unsuspected synergism between converging kinase regulatory pathways.
The European Stroke Prevention Study: results according to sex, The European Stroke Prevention Study was a multicenter trial comparing the effect of a combination of 75 mg dipyridamole and 330 mg acetylsalicylic acid tid with placebo in the prevention of stroke or death after one or more attacks of recent transient ischemic attacks or stroke of atherothrombotic origin. From the 2.500 patients in the intention-to-treat analysis. the proportion of women was 42%. and from the 1.861 patients in the explanatory analysis it was 44%. The endpoint incidence was significantly higher in men than in women. The endpoint reduction was statistically significant only in the intention-to-treat analysis with total endpoints. However. there was a marked percentage reduction of endpoints in both men and women in explanatory analysis. The risk reduction of strokes was 49% for men and 41% for women. and the reduction of total endpoints was 39% in men and 30% in women. Thus. antiplatelet therapy is effective in the prevention of stroke or death in both sexes.
Spatial contrast sensitivity is reduced in bilateral Parkinson's disease, We studied the contrast sensitivity functions of 41 patients with idiopathic Parkinson's disease (PD) with a wide range of parkinsonian symptomatology (Hoehn and Yahr stages 1 to 4) and 22 age-matched control subjects in a parametric design. Results demonstrated reduced contrast sensitivity in PD patients but only in those patients who had progressed beyond Hoehn and Yahr stage 1. Furthermore. there were deficits in contrast sensitivity related to the severity of PD.
Optic chiasmal neuritis, In four of six patients with clinical optic chiasmal neuritis. MRI demonstrated abnormalities of the chiasm. Optic chiasmal neuritis may be the initial manifestation of multiple sclerosis. a reflection of established CNS demyelination. or an isolated clinical finding.
Quantitative MRI changes in gadolinium-DTPA enhancement after high-dose intravenous methylprednisolone in multiple sclerosis, In 12 patients with definite multiple sclerosis who received a total of 21 courses of high-dose (1 gram daily for 10 consecutive days) intravenous methylprednisolone. we performed MRI of the brain with and without gadolinium-DTPA before and after treatment. On the initial MRI. there was a total of 98 enhancing lesions. 93 of which were also represented on the unenhanced images. After treatment. 13 patients improved clinically. and 78 of the lesions lost enhancement but remained visible on the unenhanced images. There were six new enhancing lesions on the second MRI. Thus. the blood-brain-barrier integrity improved after high-dose IV methylprednisolone. which correlated well with the clinical improvement. The lesions remaining visible on the unenhanced images indicate an incomplete histologic recovery at the time of the second scan. and also demonstrate that unenhanced MRI alone is not sufficient to monitor disease activity in the short term in multiple sclerosis.
Multifocal independent epileptiform discharges in children: ictal correlates and surgical therapy, We obtained continuous EEG/video recordings on four children who had the interictal EEG pattern of multifocal independent epileptiform discharges (MIED). The prominent feature of their evaluation was the evidence that their clinical seizures appeared to be of focal origin; 42/44 seizures were manifested by "fencing postures." Three patients subsequently underwent epilepsy surgery: one focal resection of superior frontal-parietal cortex and two hemidecorticectomies. Seizure control improved in all three patients. and one patient is now seizure-free. Our patients differ from those previously reported in that they had a predominance of tonic seizures and had no history of infantile spasms or Lennox-Gastaut syndrome. Some patients. such as ours. with MIED may have clinical seizures of more focal origin than might be expected from their interictal EEG and. therefore. may benefit from resective epilepsy surgery.
Are demented patients with Parkinson's disease accurately reflected in prevalence surveys? A survival analysis, We re-reviewed 257 patient records previously reviewed for an incidence study of dementia in Parkinson's disease (PD) to determine the frequency. date of death. and cause of death. We posited that if disease duration is shortened when dementia occurs. then dementia may be far more common than reflected in prevalence studies. There were 17 deaths among 65 demented patients and 28 deaths among 168 nondemented patients. When we matched a subset of the nondemented patients to the demented patients by age and disease duration distributions. the demented subjects had significantly more deaths (p less than 0.02). and survival among demented subjects was decreased (p less than 0.05). Dementia was a significant predictor of death in this sample. We conclude that dementia reduces survival in patients with PD. Incidence is a much better measure of dementia in PD than prevalence because shortened duration makes it less likely to detect dementia in prevalence surveys.
Progressive supranuclear palsy: altered sensory processing leads to degraded cognition, We studied the latencies. amplitudes. and scalp distributions of the early and late components of the event-related brain potential (ERP) in patients with progressive supranuclear palsy (PSP) and matched normal controls. In separate choice reaction time (RT) tasks. the subjects pressed buttons to visual stimuli presented randomly at probabilities of either 20/80 or 50/50. Compared with normal controls. PSP patients had significantly reduced amplitudes and increased latencies for both the visual P2 and P300 components at all levels of probability. RTs and percent errors were significantly greater in the patients compared with controls. Neither the amplitude nor latency of the visual N1 component was significantly altered in these patients. There were no significant group differences in the distribution of electrical activity over the scalp for any of these ERP components. a finding which suggests that the neural structures responsible for generating these potentials were intact in these patients. The decreased ERP component amplitudes and increased ERP component latencies. combined with intact scalp distributions and increased RTs and error rates. present a pattern of results suggesting that the stimulus identification or categorization processes in these patients are significantly degraded.
The effects of L-dopa on excessive daytime sleepiness in narcolepsy, We examined the effects of L-dopa on the excessive daytime sleepiness of six narcoleptic patients while using a double-blind design and objective measurements of vigilance. The two treatment periods. L-dopa or placebo. lasted for 2 weeks each. separated by a 1-week washout period. In addition to the standard Multiple Sleep Latency Test (MSLT). two different tests assessed the daytime vigilance: the Analogue Vigilance Scale (AVS) and the Four Choice Reaction Time Test (FCRTT). L-dopa improved vigilance and performance as evaluated by the AVS and the FCRTT. while the capacity to fall asleep rapidly remained unchanged as evaluated by the MSLT. Results of the present study suggest that L-dopa is effective in improving the vigilance level of narcoleptic patients and raises the hypothesis that dopamine may play a role in the physiopathology of excessive daytime sleepiness of this condition.
Acetylcholine receptor-reactive T lymphocytes from healthy subjects and myasthenia gravis patients, Peripheral blood lymphocytes from 23 of 114 (20%) myasthenia gravis (MG) patients showed positive T-cell proliferative responses to native acetylcholine receptor (AChR) purified from the electric fish Torpedo. compared with two of 25 (8%) healthy or other neurologic disease controls. Responsiveness appeared to fluctuate seasonally. Long-term T-cell lines and clones could be selected as readily from the two healthy responders as from the MG cases and showed similar culture behavior. CD4+ phenotype. and HLA class II restrictions. One clone from a control cross-reacted with recombinant human AChR alpha chain (r37-429A) and with the synthetic peptide 125-143(S-S) from its sequence. Both these human antigens stimulated primary proliferative responses at substantially higher frequencies (26 to 59%) than native xeno-AChR--in both patients and controls--demonstrating that truly autoreactive T cells are not inevitably deleted during normal T-cell development.
Reorganization of corticospinal pathways following spinal cord injury, To assess changes in the relationship between cortical motor representation areas and their target muscles following spinal cord lesions. we studied motor evoked potentials (MEPs) to transcranial magnetic stimulation in six patients with complete spinal cord injuries at low thoracic levels and eight healthy subjects. Magnetic stimulation at rest activated a larger fraction of the motoneuron pool and evoked MEPs with shorter latencies from a larger number of scalp positions in muscles immediately rostral to the level of a spinal cord injury than in corresponding muscles in controls. The MEPs associated with maximal voluntary activation were not significantly different in the two groups. These results suggest enhanced excitability of motor pathways targeting muscles rostral to the level of a spinal transection. reflecting reorganization of motor pathways either within cortical motor representation areas or at the level of the spinal cord. The data do not allow the determination of the contribution of spinal or cortical mechanisms. However. they support the notion of a limited flexible relationship between primary motor cortex and its target muscles following alterations of normal input-output patterns.
Dystrophin deficiency in young girls with sporadic myopathy and normal karyotype, We studied dystrophin in three young girls with a sporadic myopathy of early onset. manifested by mild to severe limb weakness. calf hypertrophy. high serum creatine kinase. normal karyotype. and morphologic features in muscle consistent with muscular dystrophy. DNA analysis did not reveal a deletion of the dystrophin gene. Immunohistochemical studies of dystrophin in muscle biopsies showed a mosaic of fibers with and without dystrophin. and immunoblot analysis showed partial dystrophin deficiency in all three patients. more severe in the patient with the highest proportion of dystrophin-deficient fibers. These observations suggest that the patients are Duchenne muscular dystrophy carriers. The data also support the concept that uneven lyonization in muscle is responsible for the clinical myopathy in these patients. We suggest that any girl with sporadic proximal limb weakness should be evaluated as a possible Duchenne carrier by dystrophin studies.
Parental sex effect in familial amyotrophic lateral sclerosis, Since a parental sex effect has been reported in Huntington's disease. we looked to see whether a similar effect is apparent in adult (autosomal dominant) familial ALS. We analyzed the data for 145 patients. with an onset age range of 20 to 68 years and a known affected parent (AP). from 52 families described in the literature. There was a significant increase in the percentage of patients inheriting the gene from an affected mother as a function of the age at onset. There was also a significant correlation between AP and offspring age at onset only when the AP was the mother.
A balanced carbohydrate: protein diet in the management of Parkinson's disease, Although restricting dietary protein is a proposed adjunct to treating Parkinson's disease (PD). the effect of carbohydrate consumption is unknown. We measured plasma levodopa and large neutral amino acid (LNAA) levels in nine PD patients treated with carbidopa/levodopa and different isocaloric meals containing high protein-low carbohydrate. low protein-high carbohydrate. and balanced 5:1 carbohydrate:protein mixtures. We found that levodopa levels increased significantly regardless of the type of diet. but that plasma LNAA levels varied less and motor performance was superior after the balanced diet than after the other two meals. We conclude that PD patients can consume nutritionally adequate meals and still maintain a stable plasma levodopa:LNAA ratio.
Clinical correlation with serum-soluble interleukin-2 receptor levels in Guillain-Barre syndrome, In patients with Guillain-Barre syndrome (GBS) soluble interleukin-2 receptor (sIL-2R) levels were elevated compared with those of patients with other neurologic diseases (OND). and of healthy controls. Smaller increases in sIL-2R levels occurred in OND patients compared to healthy subjects. Monitoring of GBS patients clearly demonstrated that decreases in sIL-2R levels correlated with clinical recovery. Thus. T-cell activation may be relevant in the pathogenesis of GBS.
Theophylline-associated seizures with "therapeutic" or low toxic serum concentrations: risk factors for serious outcome in adults, We report 12 adults with seizures associated with serum theophylline levels between 14 and 35 mg/l. The seizures were frequently prolonged. and outcome was generally poor with eight deaths. Although we did not identify comparable control groups. possible risk factors for serious outcome in theophylline-associated seizures were age. previous brain injury or disease. severe pulmonary disease. and possibly low serum albumin level. In patients with these risk factors. serum theophylline levels should be maintained below 10 to 15 mg/l.
Homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency revealed by stroke in adult siblings, Three patients from a single family of six siblings had homocystinemia and homocystinuria due to 5.10-methylenetetrahydrofolate reductase deficiency and had severe recurrent strokes in adult life. Two of the patients died 1 year after clinical onset.
Prevalence of peripheral neuropathy in the Parsi community of Bombay, We carried out a door-to-door survey to screen for neurologic diseases. including peripheral neuropathy. in a community of 14.010 Parsis living in housing colonies in Bombay. India. The most common neurologic disorder was peripheral neuropathy with 334 cases (2.384 cases/100.000 population). The most common neuropathy was compressive. with diabetes the most common noncompressive etiology. There was no leprosy. and nutritional neuropathies were rare.
Implantation of Kelman-style, open-loop anterior chamber lenses during keratoplasty for aphakic and pseudophakic bullous keratopathy. A comparison with iris-sutured posterior chamber lenses, The clinical and specular microscopic results of 40 cases (39 patients) of penetrating keratoplasty during which a Kelman-style anterior chamber intraocular lens was implanted were reviewed retrospectively. Thirty-one pseudophakic eyes received an intraocular lens exchange and nine aphakic eyes received a secondary intraocular lens. Postoperative follow-up averaged 24.5 months (range. 3 to 51 months). At 1. 2. and 3 years after keratoplasty. 39.3%. 63.2%. and 63.6% of eyes. respectively. had visual acuities of 20/40 or better. Ninety-five percent of the grafts remained clear. Causes of poor postoperative visual acuity included cystoid macular edema (32.5%). new glaucoma (22.5%). and age-related macular degeneration (10.0%). Other causes were endothelial rejection leading to graft failure. corneal ulceration. and retinal detachment. Corneal endothelial cell loss by specular microscopy was 11.5% at 1 years. 21.3% at 2 years. and 25.0% at 3 years. These results were compared with cell loss associated with iris-sutured posterior chamber lenses in penetrating keratoplasty. Visual outcomes and complication rates were similar between these two methods; however. the endothelial attrition at 1 and 2 years for the sutured posterior chamber lens was greater than that of the Kelman anterior chamber lens.
Visual and refractive results of multifocal intraocular lenses, One hundred forty-nine selected patients with bilateral multifocal intraocular lenses (IOLs) were evaluated and compared retrospectively with 131 patients with bilateral monofocal IOLs. Seventy-eight percent of multifocal cases and 74.8% of monofocal cases had uncorrected visual acuity of 20/40 or better. Fifty-four percent of multifocal cases had near uncorrected visions of J1 to J3. Eighteen percent had best-corrected near vision of J4 or worse. Sixty-three percent of multifocal cases versus 4% of monofocal cases needed no spectacle correction. Multifocal cases reported significantly more visual side effects (flare. glare. and halos). The 10% of cases with poor satisfaction (rating vision as fair-to-poor) had significantly (P = 0.03) more postoperative astigmatism (1.1 prism diopters [D] versus 0.74 D) compared with satisfied (good-to-excellent) cases. Patients who were dissatisfied reported more need for corrective lenses but not more side effects. A greater decrease in contrast sensitivity at low contrast levels was detected among multifocal cases. Both groups had similar contrast sensitivity at 96% and 50% contrast. but at 11% contrast. multifocal cases averaged a loss of 3.45 Snellen lines (to 20/48.2) compared with 2.65 lines (to 20/36) for monofocal cases.
Management of dislocated posterior chamber intraocular lenses, Management options for posteriorly dislocated posterior chamber intraocular lenses include observation. removal. exchange. and repositioning. Many microsurgical techniques have been developed for repositioning posterior chamber implants. These include repositioning into the ciliary sulcus without suturing if adequate posterior capsule support remains. iris fixation suturing techniques. and scleral fixation suturing techniques. The indications. timing. and techniques for intervention are reviewed in a series of 32 cases with posteriorly dislocated posterior chamber implants. A final visual acuity of 20/40 or better was achieved in 15 (79%) of 19 IOL repositioned cases. in 6 (75%) of 8 IOL exchanged cases. and in 1 (33%) of 3 IOL removed cases. In two patients observed without surgery. final visual acuity was 20/25 and 20/300. respectively.
National outcomes of cataract extraction. I. Retinal detachment after inpatient surgery, Rehospitalization for retinal detachment (RD) was studied in 338.141 Medicare beneficiaries older than 65 years of age who were undergoing inpatient cataract extraction in 1984. Extracapsular cataract extraction (ECCE) was performed in 60% of patients. intracapsular cataract extraction (ICCE) in 31%. and phacoemulsification in 9%. The risk of rehospitalization for RD within 4 years of ICCE was 1.55% over 1.5 times the risk associated with ECCE (0.9%). The risk of RD after phacoemulsification was 1.17%. Cataract surgery accompanied by anterior vitrectomy was associated with a 5.0%. likelihood of RD at 4 years. which is 4.5 times greater than that for cataract surgery alone (1.12%). White patients were 1.7 times more likely to be rehospitalized for RD than were black patients (1.15% versus 0.67%; P less than 0.001). In both races. younger patients were more likely to be rehospitalized for RD than were older patients (P less than 0.001). While the increased rate of RD after ICCE versus ECCE confirms previously held clinical beliefs. the increase in the risk following phacoemulsification (P less than 0.0001) has not been reported previously.
Visual results after early surgical treatment of unilateral congenital cataracts, The authors reviewed the records of 25 consecutive patients who had been operated on for unilateral congenital cataracts at 1 year of age or younger and who had been followed for a period of 5 years or longer. Excluded were patients who demonstrated retinal and optic nerve anomalies. Five eyes achieved 20/40 or better Snellen visual acuity. 5 eyes achieved 20/50 to 20/100 visual acuity. and 15 eyes had 20/200 or less visual acuity. All patients with visual acuity of 20/40 or better had cataract surgery performed before 17 weeks of age. the critical period. and surgery was scattered within this time frame. For surgery performed between 17 weeks and 1 year of age. the best achieved visual acuity in children with surgically significant unilateral congenital cataracts was between 20/50 and 20/100. There was no correlation between the age at the time of surgery and the attainment of these visual levels in this patient subset.
Incomitant dissociated vertical deviation and superior oblique overaction, When superior oblique overaction coexists with dissociated vertical deviation. it may produce a pattern of disparity in the amount of dissociated vertical deviation in different horizontal gaze fields. which the authors have termed incomitance. Seven patients with the constellation of esotropia. bilateral superior oblique overaction. "A"-pattern. and incomitant dissociated vertical deviation are presented. In each case. a distinctive incomitant pattern of dissociated vertical deviation was noted in which dissociated vertical deviation was least in adduction. moderate in primary position. and greatest in abduction. Four patients underwent asymmetric superior rectus recessions and partial tenotomy of the superior oblique tendons at their insertions as the initial treatment for their incomitant dissociated vertical deviation. Recognition of such a pattern of incomitant dissociated vertical deviation is important in choosing appropriate surgical management.
Dracunculiasis of the orbit and eyelid. Light and electron microscopic observations of two cases, Dracunculiasis. an infection caused by the nematode parasite. Dracunculus medinensis. usually affects the skin and subcutaneous tissue. The authors studied two cases of dracunculiasis involving the orbit and eyelid in African children. In the first case. the patient presented with proptosis and the clinical diagnosis was Burkitt's lymphoma. In the second patient. the eyelid lesion was diagnosed as a dermoid cyst. Histopathologically. the orbital lesion showed a degenerated and partially calcified worm within a large intraconal abscess. The eyelid lesion contained a well-preserved gravid female worm filled with larvae. The results of transmission and scanning electron microscopic studies are discussed.
Biofilm and scleral buckle-associated infections. A mechanism for persistence, Scleral buckle infections tend to be persistent as well as resistant to antimicrobial treatment. Often. scleral buckle infections require removal of the buckling elements for resolution. To determine if bacteria are able to persist on scleral buckles by elaborating a glycocalyx matrix or biofilm that offers protection against host defenses and antimicrobial treatment. the authors cultured 28 scleral buckle elements removed for infection and extrusion. Bacteria were isolated from 18 elements (64%). The most frequently isolated bacteria were Staphylococcus epidermidis and other coagulase-negative staphylococci (8). Staphylococcus aureus (3). corynebacteria (3). Mycobacterium chelonei (3). and Proteus mirabilis (3). Eleven (65%) of 17 buckles evaluated with scanning electron microscopy demonstrated the presence of bacteria encased in biofilm. Biofilm was demonstrated on the surfaces and ends of solid silicon elements. In the silicon sponges. biofilm also extended into the matrix of the sponges. The authors believe that bacterial production of biofilm offers an explanation for the persistence of scleral buckle infections and their ability to withstand antimicrobial treatment.
Delayed rod dark adaptation in patients with Stargardt's disease, Twelve patients with Stargardt's dystrophy were each found to have a prolongation in rod dark adaptation. All had a normal rate of recovery during the early portion of rod dark adaptation but a selective prolongation of the later segment of rod recovery. This observation was apparent in patients with limited fundus flecks and those with extensive fundus flecks. whether or not a dark choroid was observed and independent of the presence or absence of an atrophic-appearing macular lesion. A defect within retinal pigment epithelial cells of an enzyme or intracellular transport mechanism involved in the visual pigment regeneration cycle could account for these findings.
Retinal capillary blood flow measurement with a scanning laser ophthalmoscope. Preliminary results, The scanning laser technique in combination with digital image analysis allows direct objective measurement of flow velocities in perimacular capillaries. In addition. the complete macular network of capillaries can be observed. By means of digital frame-to-frame picture analysis of digital recordings. blood flow velocities and morphologic data have been measured. The mean flow velocity in perimacular capillaries observed with the scanning laser ophthalmoscope in healthy subjects (n = 21) amounted to 3.28 +/- 0.45 mm/second. In patients (n = 13) with diabetes mellitus (no or background retinopathy). the mean flow velocity was significantly reduced (2.89 +/- 0.57 mm/seconds) compared with healthy subjects. Morphologic data of the perifoveal capillary bed showed a significant reduction of capillaries in patients with diabetes mellitus when compared with healthy subjects.
Serologic diagnosis of human brucellosis: analysis of 214 cases by agglutination tests and review of the literature, The serum agglutination test (SAT) and 2-mercaptoethanol (2ME) agglutination were used in studies of the sera of 214 patients in whom brucellosis was suspected. On the basis of historical. epidemiologic. clinical. and serologic data. four groups were identified: group I (108 cases) had negative agglutination reactions. and brucellosis was considered unlikely; group II (57 cases) had positive agglutination reactions. and active brucellosis was diagnosed; group III (37 cases) had positive agglutination reactions. but other factors--notably. a history of prior infection--made inactive brucellosis likely; and group IV (12 cases) had positive agglutination reactions. but insufficient data were available for further classification. Most patients with active brucellosis had agglutinin titers of greater than or equal to 160; however. no single titer was always diagnostic. Although more sensitive tests are available. agglutination reactions provide data sufficient to differentiate active from inactive disease when other factors are considered and follow-up sera are tested. This article discusses individual cases and reviews the literature on the diagnosis of brucellosis.
Antibiotic misuse in two clinical situations: positive blood culture and administration of aminoglycosides, Antibiotic use was examined among randomly and prospectively selected cohorts of 79 patients with a positive blood culture and 88 patients given aminoglycosides for a variety of reasons. Appropriateness of antibiotic use was judged daily for each agent according to specific criteria of misuse. For patients with a positive blood culture. 14.3% of antibiotic-days were judged inappropriate in some regard. while for patients given aminoglycosides. 10.2% of antibiotic-days were thought to be inappropriate. The patterns of misuse were similar for the two groups despite disparate selection criteria. The unnecessary use of antibiotics was the single most common type of misuse in both groups. but errors in dosing collectively accounted for nearly one-half of antibiotic misuse. These results suggest that a variety of factors are responsible for misuse of antibiotics. Although the data presented do not allow conclusions about the optimal methods for control of antibiotic misuse. they imply that a multifaceted approach is probably required.
Survival and disinfectant inactivation of the human immunodeficiency virus: a critical review, The possibility of contracting acquired immunodeficiency syndrome (AIDS) through accidental or inapparent parenteral exposure to human immunodeficiency virus (HIV) has raised concerns among recipients of blood products. health-care professionals. and others who have contact either with HIV or with AIDS patients. Along with these concerns has come an increasing interest in the physical and chemical methods that may be used to inactivate HIV in blood products and other contaminated fluids as well as on contaminated objects and surfaces. This review critically examines the available information on the survival of HIV and the methods used for its inactivation. particularly those that rely on chemical disinfection. Although the risk of acquiring HIV from contaminated materials may be slight compared with that of acquiring other blood-borne pathogens. such as hepatitis B virus. the effectiveness of disinfectants used under clinical conditions may have been overestimated.
Impact of temperature elevation on immunologic defenses, Fever is a common response to infection and to other challenges to host defense. Temperature elevation has been associated with effects on the recognition. recruitment. and effector phases of the immune response. Specific immunologic responses are generally enhanced in the setting of temperature elevation within the physiologic range but not the supraphysiologic range. In contrast. natural immune responses may be unchanged or adversely affected. Temperature elevation appears to affect primarily the phase of recognition and sensitization or activation of mononuclear leukocytes. T lymphocyte responses (and/or the interactions of T lymphocytes with monocytes-macrophages) are enhanced for generation of effector cells. The activities of the effector cells. once generated. are usually not enhanced--or may even be depressed--by temperature elevation. but decreases are more than offset by increased T helper function. Overall. the data suggest that temperature elevations of the febrile response constitute a beneficial component of effective host defense.
Hamartomas of the breast, The clinical and pathologic findings of 17 hamartomas of the breast were studied. All neoplasms were evident as clinically and mammographically discrete masses. The pathologic findings were varied and included circumscribed fibrocystic disease. adenolipoma. fibroadenoma with fat and fibroadenoma with lobules. The heterologous elements identified were cartilage and smooth muscle. All lesions were treated by simple excision. In this study. four different microscopic patterns of hamartoma are described and the necessity for a close clinicopathologic correlation is pointed out in the diagnosis of this lesion.
The wound healing curve as a practical teaching device, Fundamental concepts of clinical wound healing are commonly misunderstood. A hypothetical curve that describes the relationship between wound perfusion and risk of infection is constructed as a teaching device. Although many factors influence this curve. the most important are the presence of bacteria. dead space. necrotic tissue and motion. Subjecting the curve to clinical illustrations enhances its value as a tool for medical education.
Entrapment of the popliteal artery, Although entrapment of the popliteal artery is uncommon. it is an important cause of arterial insufficiency in younger patients. Accurate diagnosis depends on a high index of suspicion combined with dynamic noninvasive testing and "stress angiography." Although angiographic demonstration of medial deviation of the artery is diagnostic. absence of this finding does not exclude the diagnosis of entrapment of the popliteal artery. Positional angiography may be necessary in these instances. Surgical exploration should be performed by a posterior approach. since this facilitates identification of the precise anatomic variant while allowing easy arterial repair. if necessary. The condition of the popliteal popliteal artery must dictate the extent of the surgical procedure. If the popliteal artery is normal. then relief of the constricting lesion alone will suffice. If the artery appears diseased or is thrombosed. then myotomy and arterial reconstruction must be performed. This is best accomplished by bypass grafting using autogenous vein or artery. If thromboendarterectomy is used. the clinician can expect a higher percentage of acute postoperative thromboses.
Descending thoracic aorta-splenic artery graft for occlusive disease of the celiac axis, A new procedure is presented for the restoration of normal blood flow to the celiac axis in cases of orifice lesions of the celiac artery. The operation consists of inserting a graft between the descending thoracic aorta end-to-side and the divided splenic artery end-to-end.
Can infected prosthetic grafts be salvaged with rotational muscle flaps, The conventional approach to prosthetic graft infection. including graft removal and extraanatomic reconstruction. conveys a substantial risk of limb loss and death and mandates more innovative solutions. From January 1985 to January 1989 eight rotational muscle flaps were performed on four men and three women with prosthetic graft infection who ranged in age from 42 to 79 years (mean. 67 years). The grafts involved included aortofemoral (three patients). femoropopliteal (two patients). femorofemoral (one patient). and subclavian-carotid-carotid (one patient) and were composed of Dacron (five grafts) or polytetrafluorethylene (two grafts). Infections were in the groin in six patients and in the neck in the other patient; all patients had anastomotic exposure. Clinical presentations included abscess/purulent drainage (four patients). anastomotic hemorrhage (two patients). and anastomotic false aneurysm (one patient) and was associated with fever and/or leukocytosis in all patients. Positive bacterial cultures were obtained from all patients. Rotational muscle flaps performed included rectus abdominis (five grafts). pectoralis major (one graft). gracilis (one graft). tensor fascia lata (one graft); in two patients. rotational muscle flaps were performed after failed local sartorius muscle transfer. No major complications of the RMF procedures were encountered. One patient died 4 months after the operation of complications of ischemic colitis/perforation. The other six patients were discharged with completely healed wounds. One patient developed recurrent infection 12 months after the rotational muscle flap procedure; five (83%) patients have been followed for 12 to 51 months (mean. 27 months) without evidence of recurrent infection. These preliminary results suggest that rotational muscle flaps are a safe and effective treatment for prosthetic graft infection. even when local sartorius muscle coverage has failed.
Superficial thrombophlebitis diagnosed by duplex scanning, Since July 1982. this noninvasive vascular laboratory has performed 12.856 lower extermity venous duplex examinations. All cases of acute venous thrombosis have been categorized and entered into a computer data base. One thousand four hundred twelve examinations were positive for acute venous thrombosis. This report analyzes the laboratory's entire experience with superficial thrombophlebitis (SVT). One hundred eighty-six patients were diagnosed by duplex scanning to have SVT. Women outnumbered men 99 to 87. They were slightly older (average age 58.4 +/- 16.2 years) compared with the men (53.8 +/- 14.2 years). Men were more likely to have a complicated course of SVT (40% vs 22%; p less than 0.01). Complications included either radiographically documented pulmonary embolism or deep venous involvement. Fifty-seven (31%) patients had at least one complication of SVT. A series of predisposing factors was analyzed and six factors were associated with an increased risk of complications. They are bilateral SVT (p less than 0.01). age greater than 60 years (p less than 0.01). male sex (p less than 0.01). history of deep venous thrombosis (p less than 0.01). bed rest (p less than 0.02). and presence of infection (p less than 0.02). Location of thrombus within the greater saphenous vein (35%) was most likely to be associated with complications. Isolated varicosities (8%) were least likely to be associated with complications. Duplex scanning identifies a significant number of complications of patients with SVT and should be obtained in cases of saphenous vein involvement or in the presence of associated risk factors.
Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: effect of dichloroacetate and glucose infusion, In this study we have assessed the hypothesis that there is a postreceptor defect in glucose metabolism that makes the severely burned patient unable to oxidize glucose efficiently as an energy source. The intracellular pyruvate pool was labeled by the infusion of 3-13C-lactate. and expired CO2 production and isotopic enrichment of both pyruvate and CO2 were determined to calculate the rate of pyruvate production and oxidation. 6.6-d2-Glucose and 15N-alanine were infused simultaneously to relate pyruvate kinetics and oxidation to glucose and alanine kinetics. Five normal volunteers and 10 severely burned patients (mean of 80% +/- 5% body surface burned) were studied in the basal state and during continuous (unlabeled) glucose infusion. Also. the effect of dichloroacetate. which normally stimulates pyruvate dehydrogenase activity. was assessed in both volunteers and patients. The burned patients had many of the classic metabolic responses to severe injury. including significant increases in resting energy expenditure. glucose production. and alanine release from protein breakdown. However. rather than being inhibited. the rate of pyruvate oxidation was increased approximately 300% in burned patients. Although the patients had an elevated mean concentration of lactate. stemming from increased lactate production. no deficit in pyruvate dehydrogenase activity was evident. Rather. the high rate of lactate production was apparently a consequence of the high rate of glycolysis. On the other hand. the direct pathway for synthesis of glycogen from infused glucose appeared to be impaired in burned patients. In both volunteers and patients. dichloroacetate stimulated the percent of pyruvate directed to oxidation. thereby reducing the conversion of pyruvate to other fates. including lactate. However. because there was no deficit in pyruvate dehydrogenase activity in the patients compared with normal volunteers before dichloroacetate treatment. no unique effect of dichloroacetate on glucose or protein kinetics was observed in burned patients. From these results we conclude that if there is a postreceptor defect in glucose metabolism in burned patients. it involves the pathway of direct glycogen synthesis and not the pathway of oxidation.
Hemodynamic effects of varied graft diameters in the venous system, Both in vivo and mathematical models of venous hypertension were used to evaluate the hemodynamic effects of 4. 6. 8. and 10 mm diameter cross-femoral venous bypass grafts (CFBs). Eighteen grafts (length 138 +/- 3.4 mm) were tested in paired sequential fashion (four grafts. 4 and 8 mm; five grafts. 6 and 10 mm) in nine greyhounds (femoral vein diameter. 7.7 +/- 0.09 mm). Bilateral hindlimb venous pressures and flows were measured before and after unilateral iliofemoral venous ligation. 30 minutes after CFB insertion. and for 5 minutes after venous flow augmentation induced by stimulated muscle contraction. CFBs of all sizes were equally effective at relieving the occlusive venous hypertension at rest. Muscle contraction elevated venous pressure in all ligated hindlimbs (p less than 0.0001); however. the pressure returned to baseline by 3 minutes in dogs with 6. 8. and 10 mm grafts but remained elevated (p less than 0.05) with the 4 mm grafts even after 5 minutes. Peak graft flow (first 90 seconds after contraction) was significantly greater through the 8 mm grafts than through the 4 mm grafts (p less than 0.01). although no difference was noted in flow rates between 6 and 10 mm grafts. The pressure gradient across the graft as predicted by the mathematic model for 6 to 10 mm conduits was less than 5 mm Hg for flows up to 1000 ml/min. although the pressure gradient of the 4 mm graft exceeded 5 mm Hg at 200 ml/min and approached 30 mm Hg at 1000 ml/min. Therefore. data from both canine and mathematical models agreed that. at rates approximating human resting flow (1000 ml/min). no adverse short-term hemodynamic consequences result from CFB conduits of 6 to 10 mm diameter.
Treatment of bilateral intrahepatic stones with high duct strictures through selective central hepatic resection, Bilateral intrahepatic duct stones with strictures. more common in the Orient than elsewhere. are difficult to access surgically. The results of surgical procedures have not been generally successful and are attended by a high postoperative complication and recurrence rate. We report the treatment of 30 patients with intrahepatic calculi and high duct strictures by means of selective central hepatic resection without dissection of the major vessels at the hilum. Central hepatic resection provided satisfactory access to the primary and secondary confluences of the intrahepatic ducts. allowed removal of residual stones and ascariasis. and permitted correction of multiple strictures. Twenty-nine patients so treated were followed for a mean of 32 months after operation. No patients developed recurrent fever. biliary colic. or jaundice after the operation. The technique is therefore recommended as an effective alternative to extensive hepatic lobectomy in the treatment of the intrahepatic calculi with multiple strictures.
The surgical management of superficial infections caused by atypical mycobacteria, We have recently treated four patients with atypical mycobacterial skin infections. Two patients were infected with Mycobacterium smegmatis after self-injection with a veterinary-grade anabolic steroid. To our knowledge. this complication has not been previously described. The other patients had steroid-dependent asthma and lower extremity infections involving M. kansasii and M. chelonei after minor household trauma developed. Atypical mycobacterial skin infections may be seen as chronic ulcerations with violaceous edges. rolled margins. and significant subcutaneous necrosis. An indolent course and the clinical appearance may aid in diagnosis. In our experience. limited incision and drainage or dressing changes fail to eradicate these infections. even when accompanied by appropriate antibiotic therapy. Successful treatment requires aggressive debridement of all infected subcutaneous tissues and skin. Split-thickness skin grafting was successfully used to cover large wounds. Grafting did not appear to foster recurrent infection.
Microinfarction in classic migraine? A study with magnetic resonance imaging findings, By means of magnetic resonance imaging we investigated a total of 45 patients suffering from classic migraine; 25 patients had been treated in our department for classic migraine over the past 2 years (group A). and 20 other patients investigated between 1976 and 1984 were reexamined for this study (group B). Thirty-two age- and roughly sex-matched healthy volunteers underwent magnetic resonance imaging and served as controls (group C). There was a trend for patients with classic migraine to have more subcortical patchy lesions on T2-weighted magnetic resonance imaging. In a comparison of our control subjects and patients with a history of greater than 20 attacks of classic migraine taken from groups A and B. this difference in number of lesions was significant (p = 0.02). The results suggest that patchy lesions in patients with classic migraine should be interpreted with particular caution before diagnosing a demyelinating disease since the lesions could be ischemic in origin.
Remote cortical dysfunction in aphasic stroke patients, We studied the effect of deep-seated left hemispheric lesions on cortical blood flow in 18 right-handed aphasic stroke patients. Regional cerebral blood flow was measured at rest and during the performance of a functional naming test using the two-dimensional xenon-133 inhalation method. Compared with 10 controls. at rest the patients showed regional cortical hypoperfusion in the left frontoparietal region. In the controls. activation patterns from the rest to the test condition involved mainly the left hemisphere areas. In the patients. a lack of blood flow change was observed in several areas that were usually hypoperfused at rest. However. in patients with slight verbal expression disorders there were obvious blood flow increases in other brain regions in both hemispheres. Such cortical functional reorganization and the presence of a remote cortical dysfunction could play a role in the pathophysiology of language disorders.
Benefit of a stroke unit: a randomized controlled trial, In a randomized controlled trial we compared the clinical outcome of acute stroke patients. 110 of whom were allocated to treatment in a stroke unit and 110 to treatment in general medical wards. No significant difference existed between these groups with regard to sex. age. marital status. medical history. or functional impairment on admission. Outcome was measured at 6 and 52 weeks after the stroke by the proportion of patients at home. the proportion of patients in an institution. the mortality. and the functional state. After 6 weeks 56.4% of the patients randomized to the stroke unit and 32.7% of the patients randomized to the general medical wards were at home (p = 0.0004). and after 52 weeks 62.7% and 44.6%. respectively. were at home (p = 0.002). After 6 weeks 36.3% of the patients from the stroke unit and 50.0% from the general medical wards were in an institution (p = 0.02); after 52 weeks 12.7% and 22.7%. respectively. were institutionalized (p = 0.016). After 6 weeks mortality was 7.3% for the stroke unit group and 17.3% for the general medical wards group (p = 0.027). After 52 weeks mortality was 24.6% for the stroke unit group and 32.7% for the general medical wards group (difference not significant). Functional state was significantly better for patients treated in the stroke unit after both 6 and 52 weeks. We conclude that care of patients with acute stroke in a stroke unit improves clinical outcome compared with treatment in general medical wards.
Platelet emboli in rat brain cross when the contralateral carotid artery is occluded, The pathogenesis of embolic events ipsilateral to an occluded carotid artery is uncertain. To examine this question we combined occlusion of the left common carotid artery with embolism from the right common carotid artery in rats. Following ligation of the left carotid artery in 20 experimental rats. we irradiated the right carotid artery with a laser (632 nm. 200 mW/cm2. 12-15 minutes) following the intravenous injection of 12.5 mg/kg of the photosensitizing agent Photofrin II. Controls had left carotid artery occlusion with (n = 13) or without (n = 6) Photofrin II. Fifteen of the 20 experimental rats survived to be perfused at 24 hours; cerebral infarcts were identified in 12 rats. with bilateral infarcts in 10. There were 112 infarcts (101 small [less than 2.5 mm] and 11 large [greater than 2.5 mm] on the right and 103 (93 small and 10 large) on the left. Emboli were seen in association with some infarcts and were evenly distributed in the two hemispheres (37 emboli on the right and 40 on the left. with the midline azygous artery occluded in four animals). Left carotid artery occlusion did not produce infarcts or emboli in the controls. We conclude that cerebral infarcts in the distribution of an occluded common carotid artery may be caused by emboli from the contralateral carotid artery in rats.
Safety and tolerance of oral dextromethorphan in patients at risk for brain ischemia, Experimental ischemia models have shown the antitussive dextromethorphan to be an N-methyl-D-aspartate antagonist with neuroprotective properties. We treated 10 patients with a history of recent stroke or transient ischemic attack with oral dextromethorphan (60 mg q.i.d.) for 3 weeks in a placebo-controlled. double-blind. crossover tolerance study. We documented no clinical evidence of toxicity attributable to dextromethorphan in this preliminary study.
A review of hemoglobin and the pathogenesis of cerebral vasospasm, We believe that current experimental and clinical evidence can be most satisfactorily interpreted by assuming that oxyhemoglobin is the cause of cerebral vasospasm that follows subarachnoid hemorrhage. We review the pathogenetic mechanisms by which oxyhemoglobin affects cerebral arteries. The relative importance of each of these mechanisms in the genesis of vasospasm. the biochemical pathways of oxyhemoglobin-induced smooth muscle contraction. and the intracellular actions of oxyhemoglobin on smooth muscle and on other cells in arteries are still not definitely established.
Regression of carotid plaques during low density lipoprotein cholesterol elimination, We performed serial prospective ultrasound examinations of four flat and 17 soft carotid plaques during an average of 17 months in seven patients with heterozygous hypercholesterolemia during heparin-induced extracorporeal low density lipoprotein elimination on precipitation from plasma. By means of a specially designed quantitative three-dimensional ultrasound analysis. significant plaque volume reduction could be evaluated in all subjects. along with a marked reduction of total and low density lipoprotein cholesterol and fibrinogen serum levels.
Prostate balloon dilatation monitored by transrectal ultrasound, Transrectal prostate ultrasound is helpful as an adjunct in monitoring prostate balloon dilatation using the ASI system. This is a review of the important features of this technique.
Effects of prostatectomy on sexual function, We evaluated the effects of prostatectomy on sexual function in 210 patients. 49.6 percent of whom underwent transurethral resection of the prostate (TURP). and the remainder had suprapubic transvesical prostatectomy (SPP). Pre- and postoperative interviews with detailed questionnaires were utilized. Postoperative sexual dysfunction was reported by 18 of 152 patients (11.8%) who were functioning normally prior to surgery. The incidence of postoperative impotence was evenly distributed between the TURP and SPP groups and was age-related; it was highest among older patients. We further observed a strong correlation between the presence of a permanent sexual partner and the preservation of potency. We conclude that the risk of postoperative impotence is dependent on both the patient's age and the presence of a partner. and should be discussed with the patient preoperatively.
Mechanical complications associated with mentor inflatable penile prosthesis, The Mentor inflatable penile prosthesis was developed in an attempt to decrease the mechanical failure rate of the various prostheses' components. We herein report on the reliability of the device in 46 men implanted with the Mentor device from December 1982 to June 1987. Prior to manufacturer device modification in 1985. mechanical failure mainly attributable to input tubing cracks occurred in 10 of 30 implantations. Since device improvement in April 1985. the mechanical failure rate has decreased to 4 percent. The Mentor inflatable penile prosthesis has been a mechanically reliable device since design improvement in 1985.
Relationship between use of diuretics and continence status in the elderly, Although diuretics have been implicated as a cause of urinary incontinence. no evidence has been presented prior to this report to confirm such a relationship. Our epidemiologic survey of 1.956 respondents sixty years of age and older in Washtenaw County. Michigan. revealed 24.6 percent of men and 36.9 percent of women were current users of a diuretic medication. Comparisons between users and non-users of diuretics and continence and incontinence status revealed no significant difference in the prevalence of incontinence in either gender. However. when male respondents who had cystometric examinations were analyzed. it was found that diuretic users who have uninhibited detrusor contractions (UDC) had a significantly higher prevalence of urinary incontinence (85.7%) when compared with non-users with UDC (25%) (p = 0.009). Among men who did not have UDC. use or non-use of diuretics showed a similar relationship but did not reach statistical significance (p = 0.085). There were too few female respondents with UDC to make meaningful analysis in this group.
Correlation of radionuclide urodynamometric and clinical data in 20 men with urinary symptoms, Radionuclide uroflowmetry was performed in 20 patients. These data were correlated with other urologic data. the treatment decision. and the patient's clinical status five to twelve months after testing. In 19 patients the follow-up period confirmed the expectations of the therapeutic plan. We conclude that the radionuclide uroflowmetry technique provides the urologist with objective data which can assist in the decision to perform surgery.
ESWL treatment with ventral shock-wave application: therapy of iliac and distal ureteral calculi, Because of the interposition of bony structures. extracorporeal shock-wave lithotripsy (ESWL) of middle or iliac ureteral calculi is not feasible in the conventional supine position. By a slight modification of the patient's couch allowing the prone positioning of the patient. 22 patients with calculi covered by bony structures were thus treated. The success rate of 95 percent without complications is promising and renders ESWL therapy as an alternative to ureteroscopic extraction of mid and iliac ureteral calculi.
Posterior urethral valves presenting as venous obstruction, A patient with posterior urethral valves presented with unilateral lower leg ecchymosis and edema. He initially had significant renal function impairment. The ecchymosis and edema resolved after appropriate therapy. and his renal function returned to normal.
Extravaginal torsion of spermatic cord in adult, A twenty-six-year-old man with no history of testicular trauma presented with both extra- and intravaginal torsion of the spermatic cord. This phenomenon is extremely rare in the adult. having been reported only twice before.
Ciprofloxacin versus gentamicin in prophylaxis against bacteremia in transrectal prostate needle biopsy, Consecutive patients with abnormal rectal examinations underwent transrectal needle prostate biopsy at VA Medical Center. New Orleans. Each patient was randomized to receive either gentamicin 1.5 mg/kg intravenously (IV) or 500 mg ciprofloxacin (Cipro-Miles) p.o.. before and after the biopsy. Serum and prostate tissue levels of ciprofloxacin and gentamicin were measured by high-pressure liquid chromatography and by competitive binding immunoassay. respectively. Blood cultures were obtained. and the patients were observed for twenty-four hours after biopsy. After discharge the patients were followed up by telephone. The incidence of bacteremia and postbiopsy symptoms were less with ciprofloxacin. Prostate tissue levels of this drug were higher than gentamicin. while serum levels were roughly equivalent. Ciprofloxacin is less nephrotoxic. can be given orally. and has a better antimicrobial spectrum. We. therefore. recommend it as prophylaxis against bacteremia in transrectal prostate needle biopsy. Furthermore. it appears that prostatic drug levels are more important than serum levels in preventing bacteremia.
Effect of radiation combined with hyperthermia on human prostatic carcinoma cell lines in culture, The effect of radiation combined with heat on three human prostatic carcinoma cell lines growing in vitro was investigated. Cells were exposed to different radiation doses followed by heat treatment at 43 degrees C for one hour. Heat treatment. given ten minutes after radiation. significantly enhanced the radiation response of all the cell lines studied. The combined effect of radiation and heat produced greater cytotoxicity than predicted from the additive effects of the two individual treatment modalities alone. These results indicate that a combined treatment regimen of radiation plus hyperthermia (43 degrees. 1 hr) might be an important tool in maintaining a better local control of prostatic cancer.
The sports medicine approach to occupational low back pain, Absenteeism caused by low back pain costs industry millions of dollars per year. Innovative approaches for the prevention and treatment of low back pain in workers are mandatory. The sports medicine approach for aggressive rehabilitation offers a possible solution.
Worker rehabilitation programs. Separating fact from fiction, A few worker rehabilitation programs have had outstanding success in improving ability to function for persons with occupational back pain. Local programs must show that they have similar success. Because the definitions of terms such as "back school." "work hardening." and "functional restoration" are blurred at a local level. the choice of a program for an individual patient must depend primarily on the program's demonstrated success rate with similar patients. The chances of returning to work decrease as a function of time after injury. Therefore. referring physicians. insurers. and employers must be provided with information regarding results in terms of acute (0 to 6 weeks). subacute (7 to 12 weeks). and chronic (more than 12 weeks) back pain. Other important variables include selection criteria. program cost. and dropout rate. We advocate standardized reporting of such data for all worker rehabilitation programs. A model "report to consumers." described here. is a minimal obligation. The validity of a number of important internal quality assurance issues is uncertain. Ethical and legal pressures must be recognized.
Pressure sores--a multifaceted approach to prevention and treatment, The incidence and effect of pressure sores on the disabled and elderly population have created a challenge to physicians and health care professionals. from emergency departments to rehabilitation units. and in the community. If not prevented. the morbidity and mortality of patients and the direct and indirect costs to both patients and the health care system are radically increased. In this article we define the impact on our health care system of pressure sores. provide an overview of a multifaceted approach to their prevention and management. and introduce successful behavioral and educational approaches for patients with chronic. recurrent sores. A coordinated approach with patients as informed participants and their care givers enhances the chances for success.
Postpolio syndrome and cardiopulmonary conditioning, Postpolio syndrome is a group of related signs and symptoms occurring in people who had paralytic poliomyelitis years earlier. New weakness. fatigue. poor endurance. pain. reduced mobility. increased breathing difficulty. intolerance to cold. and sleep disturbance in various degrees and expressions make up the syndrome. The reported incidence is between 25% and 80%. The origins are multifactorial and can be associated with underexertion. overexertion. inactivity due to intercurrent illness or injury. hypo-oxygenation. sleep apnea. deconditioning. and the failure of sprouted. compensatory large motor units. The exercise question in postpolio syndrome is related to the experience of new weakness or loss of muscle function due to overuse. which is often associated with injudicious repeated challenges to weakened musculature. Carefully prescribed exercise can be used for increasing strength and endurance and improving cardiopulmonary conditioning.
Sex and disability are not mutally exclusive. Evaluation and management, Managing sexual problems in persons with disabilities is a team effort. Physicians have three special roles; identifying problems that are sexual; assessing these problems; and providing psychological. pharmacologic. or surgical treatment methods in the context of the patients' rehabilitation programs.
Rehabilitation of severely injured children, Injury is the leading cause of death and disability in childhood. Ideal systems of care integrate comprehensive management of acutely injured children with rehabilitation. We review the nature of childhood injury. its disabling consequences. and the best ways to manage the care of children with serious injuries.
Rehabilitation in cerebral palsy, Cerebral palsy is the most frequent physical disability of childhood onset. Over the past four decades. prevalence has remained remarkably constant at 2 to 3 per 1.000 live births in industrialized countries. In this article I concentrate on the rehabilitation and outcome of patients with cerebral palsy. The epidemiologic. pathogenetic. and diagnostic aspects are highlighted briefly as they pertain to the planning and implementation of the rehabilitation process.
Rehabilitating elderly cardiac patients, The aging cardiovascular system undergoes many anatomic and physiologic changes. Increased vascular resistance. myocardial "stiffness." abnormalities of rhythmicity of the sinoatrial node. irregular cardiac rhythms. and alterations in heart rate and blood pressure responses are all seen more frequently in older patients. These changes are likely to impair these patients' ability to make the rapid adjustments necessary to maintain cardiac output during exercise and activity. When cardiovascular disease processes are superimposed on the "normal" concomitants of aging. greater alterations in hemodynamic response to exercise activity are noted than usually occur in younger cardiac patients. Exercise testing of older cardiac patients is safe and is usually needed to prescribe an appropriate intensity of exercise activity. The choice of the exercise protocol. the timing of the exercise test in relation to taking prescribed cardiac medication. the choice of exercise equipment. and special considerations for devices such as pacemakers and automatic implantable cardiodefibrillators must be considered before the exercise test is done. Many of these factors and the presence of either silent or overt cardiac symptoms or untoward hemodynamic events will also affect the exercise prescription. Elderly patients usually show substantial functional improvement when participating in a cardiac rehabilitation program and comply well with prescribed exercise. Early educational intervention may be crucial to reducing disability in these patients.
Stroke rehabilitation: a model predicting return home, We undertook this study to describe the changes in functional status for patients in a rehabilitation program for acute stroke and to identify the variables that best predict discharge home. Of 282 patients. 75% were discharged home. Increases in functional status were found for all 18 activities of the Functional Independence Measure from admission to discharge. Significant predictors of discharge disposition in a logistic regression model were the admission and discharge functional status scores. length of stay. and living arrangement before the stroke. The functional status at discharge was the most important predictor. Knowledge of these predictors can contribute to more appropriate treatment and discharge planning.
Reversing disability of irreversible lung disease, Pulmonary rehabilitation is a comprehensive multifaceted team approach for integrating medical management. coping skills. self-management techniques. and exercise reconditioning. It provides patients with chronic lung disease the ability to adapt and live full and nearly normal lives. These changes are possible because the overall disability includes significant reversible components: Patients have bronchospasm. infection. and cor pulmonale; they respond to progressively impaired lungs by progressive inactivity. leading to physical deconditioning. Both factors contribute to dyspnea. Because patients naturally fear dyspnea. they panic easily. During panic. their work of breathing may increase and respiratory failure may result. Pulmonary rehabilitation provides good medical management; provides exercises to increase strength. endurance. and tolerance to dyspnea; and trains patients in panic control. These programs have not been shown to lengthen life span or improve static lung function. They increase exercise performance and render patients functional. independent. and subject to fewer hospital admissions. Pulmonary rehabilitation is the only approach to chronic lung disease short of lung transplantation that improves the long-term outlook for these patients.
Exercise testing and training in patients with peripheral vascular disease and lower extremity amputation, Patients with peripheral vascular disease have a high risk of coronary artery disease. The risk is even greater when the peripheral vascular disease leads to lower extremity amputation. Exercise testing using lower extremity exercise has been the "gold standard" for screening for coronary artery disease. but many patients with peripheral vascular disease and those with amputations have difficulty doing this type of exercise. Arm exercise ergometry has been shown to be a safe and effective alternative for the detection of coronary artery disease in patients who cannot do leg exercise. This test has also been used to determine safe exercise levels and may be able to predict the ultimate level of prosthetic use in amputees. Exercise training with arm ergometry also improves cardiovascular efficiency and upper body strength in poorly conditioned patients. Studies are needed to appreciate fully the role of exercise testing and training in the recovery of these patients after amputation.
Spinal cord injury. Rehabilitation adds life to years, The National Spinal Cord Injury Statistical Center data base contains information collected prospectively on 13.763 persons injured since 1973 and treated at model systems of care throughout the United States. These data clearly demonstrate improved neurologic status and independent function in activities of daily living following acute care and rehabilitation for most persons with spinal cord injuries. Decreased lengths of initial and subsequent hospital stays and increased survival rates are also documented. Most persons are discharged to a private residence in the community and remain there. Many complete their educations and return to gainful employment after injury. Spinal cord injury has only a short-term effect on marriage and divorce rates. which appears to dissipate within a few years after injury. Overall. these figures demonstrate the dramatic improvements in length and quality of life achieved by most persons with spinal cord injuries during the past two decades.
Walking after spinal cord injury. Goal or wish, Less than a third of patients walk again after a spinal cord injury. whereas every one of them wants to try. Residual function. energy expenditure. the extent of orthotic support needed. and patient motivation will determine the outcome. Functional electrical stimulation and other new orthotic designs have not notably increased the number of persons able to walk after a spinal injury. Rehabilitation professionals can use patient education. illustrating relearning to walk with examples of infants' and toddlers' progress. to assist patients in understanding their abilities and limitations. The final decision on ambulation and orthotic prescriptions can be made in stages after a patient adjusts to a wheelchair-independent level.
Antineutrophil cytoplasmic autoantibodies: the nephrologist's perspective, Serologic tests for antineutrophil cytoplasmic autoantibodies (ANCA) provide diagnostic and prognostic information in patients with nephritis and systemic vasculitis. Four case histories are discussed that illustrate ANCA positivity in patients with renal impairment caused by interstitial. rather than glomerular. nephritis. Renal biopsy should continue to be used to diagnose the cause of renal impairment in ANCA-positive patients.
Antineutrophil cytoplasmic autoantibody-associated diseases: a pulmonologist's perspective, The development of the antineutrophil cytoplasmic autoantibody (ANCA) test has lent support to the concept of Wegener's granulomatosis as a spectrum that may affect one or more of the major anatomic sites: upper respiratory tract (E). lung (L). or kidney (K). It is C-ANCA that has high specificity for Wegener's granulomatosis (WG). The sensitivity is highest in the fully expressed Wegener's triad. or ELK. and less in local regional disease. It is possible that isolated manifestations such as episcleritis. subglottic stricture. or diffuse alveolar hemorrhage associated with C-ANCA may be considered in the Wegener's spectrum. although traditional histopathologic criteria are lacking. Until specific etiologic agents are uncovered for the various ANCA-associated entities. classification schemes should continue to employ previously established clinicopathologic syndromes such as WG using the ANCA test to better define their clinical spectrums.
Anti-DNA idiotypes deposited in renal glomeruli of patients with lupus nephritis, Idiotypes (Id) of human anti-DNA antibodies. designated as O-81 Id. were specifically detected on the immune deposits of renal glomeruli in 46% of patients with lupus nephritis. Id-binding to anti-Id antibodies was blocked by free O-81 Id and to some extent by free DNA. DNase or acid buffer treatment failed to reveal new Id determinants on the deposits. O-81 Id and NE-1 Id activity were also detected on the renal eluate-derived IgG. but not IgM from the autopsy cases with lupus nephritis. The incidences of O-81 Id were not associated with histological features in the glomeruli. but the distribution patterns were similar to those of IgG deposits. Our study also showed that 65% to 70% of patients with IgG deposits either in the subendothelium or in the subepithelial area of the glomerular basement membrane (GBM) showed positive tests for O-81 Id. It was also noted that most patients with massive proteinuria had O-81 Id in their glomeruli. It is concluded that O-81 Id deposits are relatively specific for active lupus nephritis and that immunofluorescence studies using anti-Id antibodies may be clinically useful for specifying the renal lesions of systemic lupus erythematosus (SLE).
Reversible changes in osmoregulation of vasopressin release due to impaired water excretion, Studies of renal water handling and the effects of altered hydration and posture on the osmoregulation of vasopressin release were performed on a chronically hyponatremic patient with complete cervical spinal cord transection at the C-5 level. Acute oral water loading studies showed marked reduction in free water clearance and urine diluting ability. despite appropriate suppression of plasma vasopressin concentrations. Orthostatic reductions in arterial blood pressure during head-up tilting and following the assumption of sitting posture were also demonstrable. and may have contributed to. but could not fully account for. the defect in renal water excretion. which persisted in supine posture. Hypertonic sodium chloride infusion studies performed before fluid restriction showed that low preinfusion plasma osmolality was associated with a reduced osmotic threshold for vasopressin release. which was subsequently corrected by a period of fluid restriction that restored the patient's plasma osmolality to a normal level. This shift in osmotic threshold can be inferred from both linear regression and log-linear regression analysis of the data. These studies show that marked impairment of renal water excretion coupled with unrestricted water intake can result in altered osmoregulation of vasopressin release in association with persistent plasma hypo-osmolality. which can be corrected by fluid restriction.
XY chromosome nondisjunction in man is associated with diminished recombination in the pseudoautosomal region, To assess the possible association between aberrant recombination and XY chromosome nondisjunction. we compared pseudoautosomal region recombination rates in male meiosis resulting in 47.XXY offspring with those resulting in 46.XY and 46.XX offspring. Forty-one paternally derived 47.XXYs and their parents were tested at six polymorphic loci spanning the pseudoautosomal region. We were able to detect crossing-over in only six of 39 cases informative for the telomeric DXYS14/DXYS20 locus. Subsequently. we used the data to generate a genetic linkage map of the pseudoautosomal region and found it to be significantly shorter than the normal male map of the region. From these analyses we conclude that most paternally derived 47.XXYs result from meiosis in which the X and Y chromosomes did not recombine.
Fine structure mapping of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene region of the human X chromosome (Xq26), The Xq26-q27 region of the X chromosome is interesting. as an unusually large number of genes and anonymous RFLP probes have been mapped in this area. A number of studies have used classical linkage analysis in families to map this region. Here. we use mutant human T-lymphocyte clones known to be deleted for all or part of the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene. to order anonymous probes known to map to Xq26. Fifty-seven T-cell clones were studied. including 44 derived from in vivo mutation and 13 from in vitro irradiated T-lymphocyte cultures. Twenty anonymous probes (DXS10. DXS11. DXS19. DXS37. DXS42. DXS51. DXS53. DXS59. DXS79. DXS86. DXS92. DXS99. DXS100d. DXS102. DXS107. DXS144. DXS172. DXS174. DXS177. and DNF1) were tested for codeletion with the hprt gene by Southern blotting methods. Five of these probes (DXS10. DXS53. DXS79. DXS86 and DXS177) showed codeletion with hprt in some mutants. The mutants established the following unambiguous ordering of the probes relative to the hprt gene: DXS53-DXS79-5'hprt3'-DXS86-DXS10-DXS177 . The centromere appears to map proximal to DXS53. These mappings order several closely linked but previously unordered probes. In addition. these studies indicate that rather large deletions of the functionally haploid X chromosome can occur while still retaining T-cell viability.
Neuroanatomy in fragile X females: the posterior fossa, The relative homogeneity of the neuropsychiatric phenotype in individuals with fragile (fra) X syndrome suggests that there are consistent central nervous system (CNS) abnormalities underlying the observed cognitive and behavioral abnormalities. In this study. the neuroanatomy of the posterior fossa and other selected CNS regions in 12 young fra X females were compared with those of a group of 12 age-. sex-. and IQ-matched females without evidence of the fra X syndrome. Fra X females were shown to have decreased size of the posterior cerebellar vermis and increased size of the fourth ventricle. findings that are identical to those previously reported for fra X males. When compared with fra X male and nonfra X control groups. the distribution of the posterior-vermis and fourth-ventricle variables for the fra X female group was intermediate. These results support the hypothesis that the fra X genetic abnormality leads to hypoplasia of the posterior cerebellar vermis. a neuroanatomical variation of potential importance to both developmental and neuropsychiatric syndromes.
Torsion dystonia genes in two populations confined to a small region on chromosome 9q32-34, Idiopathic torsion dystonia (ITD) is characterized by sustained. involuntary muscle contractions. frequently causing twisting and repetitive movements or abnormal postures. Most familial forms of ITD display autosomal dominant inheritance with reduced penetrance. Linkage analysis has been previously used to localize a dystonia gene to the 9q32-34 region in a large non-Jewish family and in a group of Ashkenazi Jewish families. Utilizing GT repeat polymorphisms from this region. here we demonstrate that the gene causing dystonia in Ashkenazi Jews can be localized to the 11-cM interval between AK1 and D9S10. Linkage analysis in the non-Jewish family is also consistent with occurrence of the gene in this region. although positive lod scores extend over a greater than 20-cM interval in that family. These results set the stage for positional cloning of the dystonia gene. Currently there are no known candidate genes in this region.
A genetic study of platelet adenylate cyclase activity: evidence for a single major locus effect in fluoride-stimulated activity, The activity of membrane-bound platelet adenylate cyclase. when stimulated in vitro by several compounds (including fluoride). is significantly reduced in alcoholics compared with control subjects. We have begun a study of the genetics of this enzyme activity. Complex segregation analysis of basal (unstimulated) platelet adenylate cyclase activity in families reveals a mode of inheritance that cannot be accounted for by a simple mixed model of transmission. By contrast. adenylate cyclase activity stimulated by fluoride ion reveals a single major locus effect with a modest multifactorial background. These results suggest that a single factor in the second-messenger pathway may (a) account for the majority of individual differences in stimulation of adenylate cyclase of fluoride and (b) help explain the reduced activities previously observed in alcoholics.
Analysis in a large hyperkalemic periodic paralysis pedigree supports tight linkage to a sodium channel locus, Hyperkalemic periodic paralysis (HYPP) is an autosomal dominant muscle disease with electrophysiological abnormalities suggesting a defect in a voltage-gated sodium channel (NaCh) gene. A human NaCh gene was recently shown to cosegregate with the disease allele in a family with HYPP. Using an independent clone. we have demonstrated close genetic linkage between an NaCh gene and the HYPP locus in another family. With physiological data demonstrating abnormal NaCh function in HYPP patients. the absence of any obligate recombinations in the two families strengthens the argument that this NaCh gene is the site of the defect in this disorder.
Compound heterozygosity in nonphenylketonuria hyperphenylalanemia: the contribution of mutations for classical phenylketonuria, Hyperphenylalaninemia (HPA) results from defective hydroxylation of phenylalanine in the liver. in most cases because of defective phenylalanine hydroxylase. HPA is highly variable. ranging from moderate elevation of plasma phenylalanine with no clinical consequences to a severe disease. classical phenylketonuria (PKU). Non-PKU HPA was found in excess of PKU in Israel. while the opposite is true in Europe. To study the genetic basis of non-PKU HPA. we performed haplotype analysis at the phenylalanine hydroxylase locus in 27 families with non-PKU HPA. All individuals with this condition were compound heterozygotes. In six of these families. in which both PKU and non-PKU HPA were segregating. haplotype analysis showed that non-PKU HPA resulted from compound heterozygosity for a PKU mutation and a second mutation. with milder effect. which is probably expressed only when it interacts with the severe mutation. The involvement of PKU mutations in non-PKU HPA was further demonstrated in Jewish Yemenite families with non-PKU HPA. in which the individuals with this condition were carriers of the single PKU allele which exists in this community. In addition. two previously known PKU point mutations (R261Q and R408W) were found in individuals with non-PKU HPA. These mutations are associated. in our population. with the same haplotypes as those with which it is associated in Europe. Based on the above-mentioned genetic model for non-PKU HPA. successful prenatal diagnosis of this condition was performed in one family.
Characterization of a COL1A1 splicing defect in a case of Ehlers-Danlos syndrome type VII: further evidence of molecular homogeneity, A child affected by the type VII form of Ehlers-Danlos syndrome (EDS VII) was shown to have a heterozygous structural defect in the amino-terminus of pro-alpha 1(I) collagen. As a result. type I procollagen trimers containing defective subunits are not converted to mature collagen molecules. To identify the cause of the protein abnormality. specifically primed cDNAs and genomic DNA were PCR amplified and sequenced. This analysis disclosed that the protein structural defect is caused by a single base substitution (A for G) at position -1 of the splice donor site of intron 6 of the pro-alpha 1(I) collagen gene (COL1A1). The affected allele produces (a) transcripts lacking exon 6 sequences and (b). in lesser amount. normally spliced transcripts. Furthermore. the rate of exon 6 skipping is temperature dependent. for it appears to decrease substantially when the patient's fibroblasts are incubated at 31 degrees C. These findings are similar to those we previously reported for other unrelated EDS VII cases and. therefore. reemphasize the molecular homogeneity of this rare connective tissue disorder.
Mutations in the arylsulfatase A pseudodeficiency allele causing metachromatic leukodystrophy, We identified a patient suffering from late infantile metachromatic leukodystrophy who genetically seemed to be homozygous for the mutations signifying the arylsulfatase A pseudodeficiency allele. Homozygosity for the pseudodeficiency allele is associated with low arylsulfatase A activity but does not cause a disease. Analysis of the arylsulfatase A gene in this patient revealed a C----T transition in exon 2. causing a Ser 96----Phe substitution in addition to the sequence alterations causing arylsulfatase A pseudodeficiency. Although this mutation was found only in 1 of 78 metachromatic leukodystrophy patients tested. five more patients were identified who seemed hetero- or homozygous for the pseudodeficiency allele. The existence of nonfunctional arylsulfatase A alleles derived from the pseudodeficiency allele calls for caution when the diagnosis of arylsulfatase A pseudodeficiency is based solely on the identification of the mutations characterizing the pseudodeficiency allele.
Molecular heterogeneity of acute intermittent porphyria: identification of four additional mutations resulting in the CRIM-negative subtype of the disease, Four mutations of the porphobilinogen (PBG) deaminase gene that result in cross-reacting immunological material (CRIM)-negative forms of acute intermittent porphyria (AIP) have been identified by in vitro amplification of cDNA from patients and by cloning of the amplified products in a bacterial expression vector. One mutation is a single base deletion which causes a frameshift and which is expected to result in the synthesis of a truncated protein. Two other mutations consist of single base substitutions and lead to amino acid changes. The fourth mutation is a single base substitution producing an aberrant splicing and resulting in an mRNA which would encode a protein missing three amino acids. DNAs from 16 unrelated CRIM-negative AIP patients were screened for the presence of these four mutations. by hybridization with oligonucleotides specific for each of the mutations. but none of the four mutations was identified in additional patients. The results indicate that mutations responsible for CRIM-negative AIP are highly heterogenous.
Occurrence of a Tyr393----Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population, Maple syrup urine disease (MSUD) is caused by a deficiency in the mitochondrial branched-chain alpha-keto acid dehydrogenase complex. The incidence of MSUD in the Philadelphia Mennonites is 1/176 births resulting from consanguinity. In this study. we amplified cDNAs for the decarboxylase E1 alpha subunit of the branched-chain alpha-keto acid dehydrogenase complex from a classical MSUD patient and from an obligatory heterozygote of a Mennonite family by the PCR. Sequencing of the amplified cDNAs disclosed at codon 393 of the mature E1 alpha polypeptide a base substitution changing a tyrosine (encoded by TAC) to an asparagine residue (encoded by AAC). which is designated Y393N. A segment of the E1 alpha gene containing the 5' portion of exon 9 was amplified. Probing of the amplified genomic DNA with allele-specific oligonucleotide probes showed that the mutation in the E1 alpha gene was homozygous in six Mennonites affected with classical MSUD and was present in heterozygous carriers. The identification of the MSUD mutation in the Philadelphia Mennonites will facilitate diagnosis and carrier detection for this population.
Therapeutic adherence in the elderly: transdermal clonidine compared to oral verapamil for hypertension, This double-blind. double-dummy. randomized clinical trial. conducted in elderly patients with mild hypertension. compared adherence to treatment. efficacy. side effects. and quality of life during treatment with transdermal clonidine versus oral sustained-release verapamil (verapamil-SR). Blood pressure declined significantly--from 148/95 mm Hg at baseline to 139/84 after titration and 135/86 after maintenance--with transdermal clonidine (n = 29). and from 156/96 to 144/85 and 148/88. respectively. with verapamil-SR (n = 29). Adverse event rates and quality-of-life questionnaire responses were similar in the two treatment groups. Transdermal clonidine was worn as directed during more than 96% of patient-weeks of treatment. Compliance with the oral verapamil regimen was less consistent: Verapamil-SR was taken as directed during approximately 50% of patient-weeks of therapy. and individual compliance. assessed by tablet counts. varied from 50-120%. In all. 86% of subjects were satisfied or highly satisfied with the convenience of transdermal therapy; 87% reported that side effects were slightly or not bothersome; 65% indicated that transdermal patches were more convenient than oral therapy; and almost 60% preferred transdermal to oral therapy. In this study transdermal clonidine and oral verapamil were equally safe and effective. A substantial majority of patients preferred transdermal to oral therapy. and adherence to treatment was greater with transdermal therapy.
Hypertension, cardiac disease, and compliance in minority patients, In minorities. as in the general population. hypertension is taken seriously because it is a risk factor for cardiovascular disease. Until recently. our understanding of the role that hypertension plays in the heart disease seen in minorities has been limited by a paucity of prospective data regarding the prevalence. natural history. and pathophysiology of the disease process in minority populations. In the last few years large-scale epidemiologic studies and well-controlled clinical studies alike have confirmed usually high rates of hypertension-related morbidity and mortality in minorities. particularly blacks and Hispanics. The severity of end-organ damage. both cardiac and renal. that is seen in these patients--especially when coupled with the severe cerebrovascular damage that is also more common in black and Hispanic hypertensives--mandate that more effective public health measures be taken to reduce the incidence of hypertension in these patient populations. Because hypertension is usually without significant clinical symptoms. noncompliance with drug therapy and high dropout rates are common in all patient populations. They are strikingly higher in inner-city populations. however. where illiteracy. poverty. homelessness. and high rates of chemical dependency combine to exacerbate an already serious problem in treating hypertensive patients. Inner-city patients are. increasingly. black and Hispanic patients. and these patients are more likely to be underinsured or uninsured. to be functionally illiterate in English. to be disinclined to seek health care. and to be less capable of following a prescribed regimen than the populace as a whole. The nature of the therapeutic regimen itself is probably the most important determinant of compliance. and compliance with drug therapy will be improved if the clinic chooses a simplified drug regimen and avoids drugs that produce intolerable side effects. Once-a-day--or. with transdermal clonidine. one-a-week--single-drug therapy may not be possible in all patients. but multiple drug therapy and multiple daily dosing schedules should be avoided wherever possible.
Improving compliance in an inner-city hypertensive patient population, Because hypertension is a "silent" disease process. compliance with therapy is always a problem. In the inner city. where socioeconomic factors such as poverty. illiteracy. and substance abuse raise additional barriers to effective health care. poor compliance with antihypertensive regimens can reach epidemic proportions--as it did in our clinic in the early 1970s. After identifying the major causes of poor compliance in our patients. we instituted measures that led directly to greatly improved compliance and control. among them the expansion of clinic hours. the expediting of laboratory services. and the training of nurse-therapists to assume many of the responsibilities of running the clinic. In recent years a number of new antihypertensive agents have been introduced. and these new drugs have afforded patients better blood pressure control through less complex drug regimens with fewer serious side effects. Indeed. we observed a strong correlation between patient compliance and the administration of agents with longer dosing intervals and improved side effects profiles. This observation led us to consider whether transdermal clonidine--which requires weekly. rather than daily. administration--might not be an especially effective means of controlling blood pressure in inner-city patients. To test this hypothesis. we enrolled 20 patients. all of them blacks. in a pilot study of this unique delivery system. Blood pressure was adequately controlled in all 18 patients who completed the study. and patients were uniformly enthusiastic about this alternative to daily dosing. As a result. compliance with this mode of therapy was excellent.
Skin pretreatment and the use of transdermal clonidine, Although therapy with transdermal clonidine is effective in bringing elevated blood pressure under control. this mode of delivery has been associated with localized dermal reactions in a small percentage of patients. Because anecdotal information suggests that a number of physicians have resorted to various dermal pretreatment strategies in an effort to alleviate or eliminate these dermal reactions. we decided to investigate the two most commonly used pretreatment strategies. to determine if they affected the pharmacokinetics and pharmacodynamics of transdermally administered clonidine. Specifically. we examined the effect of dermal pretreatment with 0.5% hydrocortisone cream and with an over-the-counter antacid. magnesium-aluminum hydroxide suspension. on the pharmacokinetics of transdermal clonidine in 10 adult hypertensive males. Patients were randomized to receive one of the two pretreatment regimens or therapy with the patch alone. and after 7 days of treatment and a 14-day washout period. patients were crossed over to receive one of the other therapies. All patients ultimately received all three therapies. We present here the results from the 10 patients enrolled in our study. Our study found a statistical difference detected in maximum plasma concentration (Cmax). steady-state plasma concentration (Css). and apparent clonidine dose delivered (Doseapp) following dermal pretreatment with hydrocortisone compared with the transdermal patch alone. The mean +/- SD relative extents of absorption (Frel) of clonidine following dermal pretreatment with hydrocortisone and magnesium-aluminum hydroxide in respect to the transdermal patch alone were 94.84 +/- 45.69% and 97.65 +/- 59.65%. respectively. No significant difference was detected in this parameter. Supine and sitting blood pressures and pulse rates were similar during treatment with clonidine alone. following dermal pretreatment with hydrocortisone cream. and following pretreatment with magnesium-aluminum hydroxide suspension. In addition. systemic side effects were evenly distributed among treatments. However. dermal side effects were less frequent following pretreatment with hydrocortisone compared with magnesium-aluminum hydroxide and the patch alone. The results of this study suggest that dermal pretreatment with 0.5 percent hydrocortisone cream may significantly alter the plasma concentrations of transdermally administered clonidine without adversely altering the pharmacodynamics.
Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia, In the multicenter. double-blind EXCEL (Expanded Clinical Evaluation of Lovastatin) study the efficacy of lovastatin in modifying plasma lipids and lipoproteins in 8.245 participants with moderate primary hypercholesterolemia was evaluated. Patients were randomly assigned to 48 weeks of treatment with diet and placebo or diet and lovastatin 20 or 40 mg once a day. or 20 or 40 mg twice a day. At all of these dosages. lovastatin produced substantial dose-dependent reductions in low-density-lipoprotein (LDL)-cholesterol levels. averaging 24% (20 mg/day) to 40% (80 mg/day). The magnitude of the effect of this lipoprotein was further reflected by the percentage of patients who achieved National Cholesterol Education Program (NCEP) goals. In the absence of coronary artery disease (CAD) or two other CAD risk factors. the LDL-cholesterol goal of 4.14 mmol/L (160 mg/dL) was attained by 22% of patients in the placebo group and between 81% (20 mg/day) and 96% (80 mg/day) of those treated with lovastatin. For those with CAD or at least two other CAD risk factors. the LDL-cholesterol goal of 3.36 mmol/L (130 mg/dL) was attained by 4% of placebo patients and between 38% (20 mg/day) and 83% (80 mg/day) of those treated with lovastatin. Lovastatin also increased high-density-lipoprotein cholesterol (7-10%) and decreased triglycerides (10-19%) in a dose-dependent manner. Thus. when used as an adjunct to a prudent diet. lovastatin produces favorable changes in the entire lipoprotein profile and is a highly effective agent for managing patients with primary hypercholesterolemia.
Update on the pathogenesis of atherosclerosis, The major components of atherosclerotic plaque. ultimately responsible for clinical effects. are deposited lipids--mostly cholesteryl esters and cholesterol. derived largely from the lower-density lipoproteins of the blood--and proliferated. modified arterial smooth muscle cells with their synthesized connective tissue products. Advanced plaques vary widely in the proportion of the two components. but evidence indicates that lipid deposition--especially of lipoprotein elements--often occurs in the lesion-prone intimal areas of the artery prior to the buildup of smooth muscle cells. The 1980s were remarkably productive for investigators who study the pathogenesis of atherosclerosis. We now know of the many forms of lower-density lipoproteins. i.e.. low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). some of which are more likely to be associated with accelerated atherosclerosis and some of which are more likely to be influenced by diet. Among these forms of LDL and VLDL are LDL-1. beta-VLDL. and Lp(a). Work has been reported implicating various alterations of endothelial function in the permeability of the arterial endothelial barrier in the transport of these low-density. cholesterol-rich macromolecules. Of possibly greater interest is the developing evidence that such proliferation-stimulating molecules as platelet-derived growth factor (PDGF) can be produced by a number of cells likely to be involved in the progression of atherosclerotic plaque. In addition to platelets. these include activated monocytes and monocyte-derived macrophages. injured endothelial cells. and smooth muscle cells. which can undergo an autocrine conversion to PDGF synthesis--possibly stimulated by LDL from hyperlipidemic serum. Leukotrienes and other endothelium-associated regulatory molecules may also take part in the paracrine and autocrine mechanisms of stimulating smooth-muscle-cell proliferation. Additional recent developments that have led to a better understanding of atherosclerotic pathogenesis have occurred. The first is evidence of the involvement of oxidized LDL and its apolipoprotein B in atherogenesis. Research indicates that antioxidants have a suppressive effect on atherogenesis when oxidized LDL has been involved in lesion development. The data linking the development of autoimmune reactions to these oxidatively altered lipoproteins are also impressive. Further. there is increasing evidence that atherogenesis in nonhuman primates and in people in whom chronic sustained circulating immune complexes are involved is likely to be accelerated. even when few or no classic risk factors are present. These lesions appear to represent a distinct microarchitectural form of concentric and transmural atherosclerosis that is better classified as "atheroarteritis.".
Alcohol abuse: comparison of two methods for assessing its prevalence and associated morbidity in hospitalized patients, PURPOSE: To evaluate two methods for assessing the prevalence of alcohol abuse in hospitalized patients based upon scores on standardized alcoholism screening instruments compared with diagnostic discharge data. and to determine the risk for comorbid conditions in patients who abuse alcohol. PATIENTS AND METHODS: Of 2.534 consecutive patients admitted to five adult inpatient services of an academic center. 1.964 were screened for alcohol abuse using the CAGE and the SMAST. Their discharge diagnoses were obtained and analyzed for the presence of alcohol-related diagnoses and other comorbid conditions. RESULTS: A total of 1.4% of patients had a principal alcohol-related diagnosis (ARD). 6% had a secondary but no principal ARD. and 15% screened positive for alcohol abuse but had no ARD. The overall prevalence of alcohol abuse was 22.4%. Patients with a principal ARD had a higher risk for dementia. chronic obstructive pulmonary disease (COPD). pancreatitis. sequelae of liver disease. and illegal drug abuse. Patients with a secondary ARD were at risk for 19 comorbid conditions. including pancreatitis. injury. pneumonia. COPD. and poly-drug abuse. Patients who screened positive for alcohol abuse but had no ARD were significantly more likely to have a diagnosis of hypertension. arrhythmia. breast cancer. or pelvic inflammatory disease. CONCLUSION: Discharge diagnoses alone markedly underestimate the prevalence of alcohol abuse in hospitalized patients. Patients from the three groups are at higher risk for comorbid conditions. and secondary prevention of alcohol abuse can be achieved by routinely screening every patient using recognized alcoholism screening instruments.
Treatment of dermatomyositis with intravenous gammaglobulin, PURPOSE: The mainstay of pharmacologic therapy in patients with dermatomyositis is corticosteroids. However. because patients sometimes become refractory to these drugs and because these drugs have potential short- and long-term toxicities. alternate therapy is highly desirable. Therefore. a pilot study was initiated using high-dose intravenous gammaglobulin (IVGG) in the treatment of dermatomyositis. PATIENTS AND METHODS: IVGG was administered to five patients with juvenile dermatomyositis. Prior to IVGG treatment. all patients had persistent muscle weakness despite daily corticosteroids and three patients had developed unacceptable steroid toxicity. Two of the patients had previously developed toxicity while receiving immunosuppressive therapy. RESULTS: IVGG therapy resulted in improved muscle strength and ameliorated skin rash in all patients. The percentage increase in muscle strength as measured by sphygmomanometry following the 9-month course of IVGG ranged from 56% to 606% in the proximal lower extremities and from 30% to 186% in the proximal upper extremities. Following IVGG therapy. prednisone could be discontinued or the dose reduced in all patients. CONCLUSION: This study suggests that IVGG may allow steroid sparing in dermatomyositis and may provide a safe alternative to cytotoxic therapy.
Analysis of local antibody production in the vitreous humor of patients with severe uveitis, We analyzed the local antibody production in vitreous humor samples collected during vitrectomy in patients with severe vision-threatening uveitis. In 24 patients. paired serum and undiluted vitreous humor samples were collected and tested for antibodies against Toxoplasma gondii. herpes simplex virus. varicella-zoster virus. cytomegalovirus. Epstein-Barr virus. and Toxocara canis. Total IgG and the Goldmann-Witmer coefficient were determined. The initial diagnosis of ocular toxoplasmosis could be confirmed in six of the seven patients. The seventh patient showed a local antibody production against herpes simplex virus. One of the three patients with chronic panuveitis at initial diagnosis showed a local antibody production against T. gondii. These last two findings resulted in a change in medical treatment. Analysis of local antibody production in vitreous humor samples is a valuable diagnostic tool.
An updated classification of retinal detachment with proliferative vitreoretinopathy, The Retinal Society classification on proliferative vitreoretinopathy of 1983 has been updated to accommodate major progress in understanding of this disease. There are three grades describing increasing severity of the disease. Posterior and anterior location of the proliferations have been emphasized. A more detailed description of posterior and anterior contractions has been made possible by adding contraction types such as focal. diffuse. subretinal. circumferential contraction. and anterior displacement. The extent of the abnormality has been detailed by using clock hours instead of quadrants.
Regional and long-term variability of fundus measurements made with computer-image analysis, We studied the variability of optic disk and peripapillary nerve fiber layer surface contour measurements made by use of computer-image analysis. Six hundred twenty-five measurements of surface contour were made on each eye by use of simultaneous stereoscopic videography. Regional differences in short-term measurement variability were studied in 12 eyes (six normal and six glaucomatous). each imaged nine times over several days. The widths of the 95% confidence interval for the measurements averaged 82 microns for the juxta-papillary surface and 132 microns for the disk surface. Measurements of peripapillary surface contour were significantly less variable than were measurements of the disk surface (P = .000). The greatest variability was detected along large blood vessels and at steep contours. Long-term variability was studied in a separate group of 30 clinically stable patients with glaucoma. each imaged three to six times over a period of more than one year. The widths of the 95% confidence intervals were 132 microns for the peripapillary surface and 217 microns for the disk surface. The long-term variability was significantly greater than the short-term variability (P = .000). The peripapillary nerve fiber layer surface. located away from the margins of large vessels. may provide the most dependable measurements of contour. These estimates of long-term variability of optic disk and peripapillary contour measurements provide clinically relevant confidence intervals with which to detect progressive glaucomatous nerve fiber damage.
Low nm23 protein expression in infiltrating ductal breast carcinomas correlates with reduced patient survival, Protein levels corresponding to nm23 were determined in normal and neoplastic breast tissues by immunoperoxidase staining. Nm23 protein levels were highest in normal breast epithelium. and lower in intraductal carcinomas. Based on nm23 staining. 39 infiltrating ductal carcinomas were separated into two groups: tumors with homogeneously high nm23 protein content. and tumors with low staining in either a homogeneous or heterogeneous pattern. Patients with low nm23 staining tumors. determined by three pathologists independently. had reduced survival times (alpha = 0.034. alpha = 0.012. alpha = 0.052 by the log rank test). Nm23 expression approached significance as an independent predictor of survival in Cox's proportional hazards model. The data provide the first correlation of low nm23 protein expression and reduced breast carcinoma patient survival.
Increased macrophage colony-stimulating factor in neonatal and adult autoimmune MRL-lpr mice, Abnormal macrophages in MRL-lpr mice are implicated in the pathogenesis of autoimmune disease. These mice die of lupus nephritis by 5 to 6 months of age. This study reports that MRL-lpr mice have an increased level of circulating macrophage colony-stimulating factor (M-CSF) detectable as early as 1 week of age. Macrophage colony-stimulating factor decreased between 2 and 4 months and then steadily increased beginning at 4 months of age. In contrast. M-CSF was not detected in sera from congenic MRL-++ mice. normal C3H/FeJ mice. two other mouse strains with the lpr gene (B6-lpr and C3H-lpr). or another lupus model. the NZB/W mouse. These observations indicate that the lpr gene alone is not responsible for inducing this growth factor. and elevated M-CSF is not required for all forms of murine lupus. The entire source of serum M-CSF is not clear. The unique T cells regulated by the lpr gene are not responsible for the increased serum M-CSF levels. as no M-CSFs could be detected in supernatants from cultured lymph nodes from MRL-lpr mice. and the steady-state levels of M-CSF mRNA in lymph nodes and spleens in MRL-lpr. C3H-lpr mice and in their respective congenic strains were similar. The steady-state M-CSF mRNA transcripts in liver. lung. and bone marrow in MRL-lpr. MRL-++. and C3H/FeJ mice were also similar. Macrophage colony-stimulating factor transcripts were clearly elevated in the kidneys of MRL-lpr mice. suggesting a renal source of circulating M-CSF. The increase of M-CSF might be responsible for the increased numbers and enhanced functions of macrophages. which in turn cause tissue destruction in MRL-lpr mice.
Immunohistochemical analysis of neural cell adhesion molecules. Differential expression in small round cell tumors of childhood and adolescence, The neural cell adhesion molecule (NCAM) was discovered in a search for cell surface antigens of chicken neurons that contribute to cell adhesion and pattern formation during development. Homologous adhesion molecules have been identified in several species. including humans. In this immunohistochemical study. the authors examine the role of human NCAM in tumor diagnosis. The authors used a monoclonal antibody (MAb). 5.1H11. to examine NCAM immunoreactivity in frozen sections of more than 450 tumors. including more than 80 small round cell tumors (SRCT) of childhood and adolescence (neuroblastomas. Ewing's sarcomas [ES]. peripheral neuroepitheliomas [PN]. primitive neuroectodermal tumors [PNET]. esthesioneuroblastomas. malignant ectomesenchymoma. medulloblastomas. small cell osteosarcomas. mesenchymal chondrosarcomas. embryonal rhabdomyosarcomas. and lymphomas). The authors show that 1) neuroblastomas and primary brain tumors are NCAM+; 2) ES. most PN/PNETs. and melanomas are NCAM-; 3) embryonal rhabdomyosarcomas and various other sarcomas are NCAM+; 4) neuroendocrine tumors are NCAM+; 5) subsets of carcinomas of kidney. ovary. lung and other organs are NCAM+; and 6) lymphoid tumors are NCAM-. Tests with normal fetal and adult tissues indicate that these findings reflect only in part the NCAM phenotypes of corresponding normal tissues. Notably the NCAM- phenotype of ES and PN/PNET is not explained by current histogenetic models for these tumors. which suggest a primitive neuroectodermal origin. Finally the authors show that NCAM expression among SRCT has an inverse relationship with the expression of p30/32MIC2. a cell surface antigen of ES and PN/PNET detected with MAb HBA71. These results suggest that immunohistochemical assays for NCAM and p30/32MIC2 expression may aid in the further characterization of SRCT of childhood and adolescence.
Expression of mdr-1/P-glycoprotein in human neuroblastoma, Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro. and a similar role has been hypothesized in vivo in human malignancy. Because expression of mdr-1 is increased in neuroblastoma cell lines by differentiating agents. the authors hypothesized a similar correlation with differentiation in vivo in neuroblastomas. In 12 tumors from 11 patients. total RNA analysis demonstrated no correlation with differentiation. but a correlation could be detected in the cell-based methods of analysis. The very primitive 'stroma'-poor. poorly differentiated neuroblastomas had low levels of mdr-1/P-glycoprotein. The intermediate grades had higher levels of expression and although heterogeneity of differentiation appeared within these tumors. both primitive and more differentiated cells expressed the gene at comparable levels within the tumor. One very well-differentiated neuroblastoma. a ganglioneuroma. had no detectable expression in the neurofibrillary material. but demonstrated expression in adjacent large ganglionic cells. Thus mdr-1/P-glycoprotein expression increased with increasing differentiation among tumors. and was present in ganglionic cells in the most well-differentiated tumor. The three tumors with the highest levels of expression were obtained from patients who received preoperative chemotherapy.
Immunohistochemical analysis of Ewing's sarcoma cell surface antigen p30/32MIC2, Monoclonal antibody (MAb) HBA71. which was raised against Ewing's sarcoma cells. recognizes a cell-surface glycoprotein. p30/32MIC2. that is encoded by the MIC2 gene in the pseudoautosomal region of human chromosomes X and Y. This immunohistochemical study evaluates the specificity and sensitivity of MAb HBA71 for tumor diagnosis. Frozen and paraffin-embedded tissues of more than 300 tumors of diverse histologic type. including more than 100 small round cell tumors of childhood and adolescence. were tested with this MAb by the avidin-biotin immunoperoxidase procedure. The authors found HBA71 immunoreactivity in 61 of 63 Ewing's sarcomas studied and 9 of 11 primitive neuroectodermal tumors and peripheral neuroepitheliomas. HBA71-negative tumors included neuroblastomas (0 of 24). melanomas (0 of 13). an esthesioneuroblastoma. small cell osteosarcomas (0 of 2). a malignant ectomesenchymoma. desmoplastic SRCT (0 of 5). and medulloblastomas (0 of 5). Heterogeneous expression of HBA71 immunostaining was found in some embryonal rhabdomyosarcomas (3 of 14) and astrocytomas (4 of 7). and in a few neuroendocrine tumors (4 of 26). carcinomas (3 of 94). and lymphomas (6 of 30). Because Ewing's sarcomas are consistently HBA71 positive. the authors searched for antigen-positive normal cells that may represent precursors for these tumors; however. no obvious candidate for the elusive cell of origin for Ewing's sarcoma was identified in the normal fetal tissues tested. Their findings indicate that HBA71 is a highly restricted cell-surface antigen of Ewing's sarcomas and primitive neuroectodermal tumors. and immunohistochemistry employing this antibody may be of value in the differential diagnosis of selected small round cell tumors in childhood and adolescence.
Abnormal expression of histocompatibility and mitochondrial antigens by cardiac tissue from patients with myocarditis and dilated cardiomyopathy, Autoantibodies against the adenine nucleotide translocator (ANT). the branched chain alpha-ketoacid dehydrogenase (BCKD) complex proteins. and myosin have been implicated in the pathogenesis of human dilated cardiomyopathy (DCM). Cardiac tissue from patients with DCM and. for control purposes. cardiac tissue from patients with other forms of cardiomyopathy and from patients with no history of cardiac disease were stained with heterologous and ANT-. BCKD-. and myosin-specific affinity-purified sera from DCM patients. Data demonstrate that although anti-myosin stains tissues from both patients and normal controls. the ANT- and BCKD-specific heterologous and affinity-purified sera from DCM patients stain only cardiac tissues from DCM patients. Intense staining in patchy areas of cardiac tissue suggests that abnormal increased expression of these putative autoantigens occurs in discrete areas of cardiac myocytes. The reactivity of the antisera was organ specific and only seen in tissues from DCM patients. The organ and disease specificity of these findings suggests that such expression may play an important role in the pathogenesis of human DCM.
Detection of Epstein-Barr virus sequences in Hodgkin's disease by the polymerase chain reaction, The authors examined paraffin-embedded lymph node biopsies from 65 cases of Hodgkin's disease for the presence of Epstein-Barr virus (EBV) DNA. using the highly sensitive polymerase chain reaction technique. Overall 40% of the cases were positive for EBV DNA; there were no statistically significant differences in the frequency of EBV positivity among the different subtypes of Hodgkin's disease. These results are in agreement with those of previous studies that employed less sensitive detection techniques and suggest that EBV either is present in pathologic tissues only in some phases of the evolution of Hodgkin's disease or is a pathogenetic factor involved in only a portion of cases.
Cell migration and actin organization in cultured human primary, recurrent cutaneous and metastatic melanoma. Time-lapse and image analysis, Random cell migration and actin organization in seven human primary. recurrent cutaneous. and metastatic melanoma cell lines were studied by time-lapse video recording and image analysis. The migration of over 800 randomly selected cells from the cell lines were recorded using an inverted microscope with an attached incubator housing. The fraction of cells with random migration rates greater than 10 microns/hour was 8% in an established primary melanoma cell line. 2% and 34% in two recurrent cutaneous melanoma cell lines. and 5%. 30%. 31%. and 60% in four metastatic cell lines. The three metastatic cell lines with significantly higher mean migration rates (P less than 0.001) were derived from lymph node metastases. whereas the fourth metastatic cell line was derived from a visceral metastasis. The cellular morphology and presence of cell nests in the original tissue correlated with in vitro cell morphology and the formation of colonies. The ability of cells to organize actin into stress fibers directly correlated with significantly higher random migration rates and lack of colony formation. Characterization of random migration rates and actin organization of human melanoma cells that are isolated from different stages of tumor progression may lend insight into metastasis.
Increased steady-state levels of mRNA coding for extracellular matrix components in kidneys of NZB/W F1 mice, The present study was carried out to determine how mRNA levels of extracellular matrix (ECM) components including alpha 1(IV) chain. laminin A. B1 and B2 chains. heparan sulfate proteoglycan (HSPG). alpha 1(I) chain. and alpha 1(III) chain are regulated in the kidney of NZB/W F1 mice. Messenger RNA levels for ECM genes except for laminin A chain increased significantly with the progression of nephritis in NZB/W F1 mice. In the NZW kidneys. however. the mRNA levels for alpha 1(IV) chain. laminin B1 and B2 chains. and HSPG declined markedly with age. whereas those for alpha 1(I) and alpha 1(III) chains showed little difference throughout the experimental period. Messenger RNA levels of beta-actin remained constant. and those of laminin A chain could not be detected in either control or diseased kidneys. Immunofluorescent microscopy showed that the intensity and distribution of staining of collagen IV. laminin. and HSPG in the glomeruli of NZB/W F1 mice increased markedly with the progression of disease. Types I and III collagen were not detected in the glomeruli of NZB/W F1 mice by immunofluorescence until 24 weeks of age. after which increased amounts of these collagens were found in the glomeruli and interstitium with progression of disease. These results suggest that increased levels of mRNA coding for ECM components and increased accumulation of these proteins may contribute to a cascade of events. leading to chronic renal injury in lupus nephritis.
Tibial meniscal dynamics using three-dimensional reconstruction of magnetic resonance images, The human knee joint represents a complex biomechanical system of which the menisci are an integral component. At present. little data exists describing the meniscal kinematics of the intact knee. Accordingly. a three-dimensional reconstruction magnetic resonance image model was used to explore this issue. Five fresh cadaveric knees were examined by magnetic resonance imaging throughout a full range of motion at 10 degrees intervals. Computer three-dimensional images of the menisci were generated and evaluated for anteroposterior excursion and deformation. During flexion. the posterior excursion of the medial meniscus was 5.1 mm. while that of the lateral meniscus was 11.2 mm. The anterior horn segments were shown to be more mobile than the posterior horn segments bilaterally. Prior limitations of meniscal kinematic assessment may be overcome with advanced imaging techniques such as magnetic resonance imaging and three-dimensional reconstruction. The menisci are highly mobile and easily deformed structures within the intact. cadaveric knee. This imaging technique may prove useful in the elucidation of meniscal dynamics. In the future. similar techniques may be applied clinically to aid in the diagnosis of joint dysfunction.
Tensile properties of the human femur-anterior cruciate ligament-tibia complex. The effects of specimen age and orientation, The structural properties of 27 pairs of human cadaver knees were evaluated. Specimens were equally divided into three groups of nine pairs each based on age: younger (22 to 35 years). middle (40 to 50 years). and older (60 to 97 years). Anterior-posterior displacement tests with the intact knee at 30 degrees and 90 degrees of flexion revealed a significant effect of knee flexion angle. but not of specimen age. Tensile tests of the femur-ACL-tibia complex were performed at 30 degrees of knee flexion with the ACL aligned vertically along the direction of applied tensile load. One knee from each pair was oriented anatomically (anatomical orientation). and the contralateral knee was oriented with the tibia aligned vertically (tibial orientation). Structural properties of the femur-ACL-tibia complex. as represented by the linear stiffness. ultimate load. and energy absorbed. were found to decrease significantly with specimen age and were also found to have higher values in specimens tested in the anatomical orientation. In the younger specimens. linear stiffness (242 +/- 28 N/mm) and ultimate load (2160 +/- 157 N) values found when the femur-ACL-tibia complex was tested in the anatomical orientation were higher than those reported previously in the literature. These values provide new baseline data for the design and selection of grafts for ACL replacement in an attempt to reproduce normal knee kinematics.
The current state of functional knee bracing research. A review of the literature, This paper reviews recent research on functional knee bracing. Research is categorized by subject. approach. or technique. The authors conclude that. while there is a good deal of excellent research available. there is little data to assist the clinician in selecting an orthosis for a specific application. The authors recommend that future investigations address the physiologic aspects of functional knee bracing and that brace manufacturers assume more responsibility in the validation of both existing and future brace designs.
Acute Grade III ulnar collateral ligament ruptures. A new surgical and rehabilitation protocol, A review is presented here of 36 cases. seen since 1980. of acute Grade III (unstable) sports-related sprains of the thumb metacarpophalangeal joint. In all cases. the injury involved the ulnar collateral ligament. A Stener lesion was present in 97% of cases. Followup was from 2.0 to 8.5 years. the average being 3.9 years. All of the patients underwent repeat examination and radiography at followup. The first seven patients were treated by "traditional" pull-out suture and K-wire fixation. put into a cast for 4 weeks. and then gradually mobilized over 4 additional weeks. Thereafter. a "new method" was used. Avulsed ulnar collateral ligament stumps were sutured to the tendinous insertion of the adductor pollicis or to a soft tissue remnant using strong suture material. Large bony avulsions were pinned; small fragments were excised and the ligament was repaired. This latter method of repair was quite strong and allowed rapid mobilization: only 2 weeks in a cast. then a hand-mounted thumb spica orthosis was used while therapy progressed. Of the patients treated with the new method. 84% had excellent results and. overall. were able to return to sports sooner than patients treated with the traditional method. Pain. stability. and strength were corrected equally between groups; however. strength was restored more rapidly in the new method group. Range of motion was reduced equally in both groups.
Results of knee manipulations after anterior cruciate ligament reconstructions, We analyzed the results of knee manipulations in 42 knees that had persistent flexion or extension deficits after intraarticular ACL reconstructions. All manipulations were done under a spinal or general anesthetic and. in 10 cases. arthroscopic debridement of adhesions also was performed. The average time from reconstruction to manipulation was 7 months (range. 3 to 14 months) and the average followup was 26 months (range. 6 to 56 months). At manipulation. average flexion was increased from 95 degrees to 136 degrees and average extension from 11 degrees to 3 degrees. In no case was motion gained at the expense of joint stability and. at final followup. average flexion and extension were 127 degrees and 4 degrees. respectively. The final range of motion achieved was not affected by the time to manipulation. severity of premanipulation flexion deficit. or concomitant arthroscopic debridement of adhesions. However. knees with premanipulation extension deficits of greater than or equal to 15 degrees achieved significantly less final extension than knees with lesser premanipulation deficits. Overall. manipulations were a safe and effective method for improving both flexion and extension in 86% of the knees that had restricted motion after ACL reconstructions.
Biomechanics of the golf swing in players with pathologic conditions of the forearm, wrist, and hand, Golf is an activity generally stressful to the hands and wrists and particularly can produce increasing symptoms in players with underlying problems such as hand and wrist arthritis or tendinitis. The purpose of this study was to quantitate wrist motion and club head/ball impact force in subjects with pathologic conditions of the hand. wrist. or forearm. within a laboratory environment. A regular straight-handled golf club was compared to a new BioCurve handle design that has a 19 degrees ulnar bend. We measured and compared the effect of the two grips on wrist motion. club head velocity. ball impact force. ball impact location. and isometric torsional strength in 20 subjects who had a variety of upper extremity disorders. This data was then compared to data collected in an identical fashion from golfers without such conditions. The results of our study show that there were no differences related to club handle design on impact force or impact location. club head velocity. or club head path and face angle. Wrist kinematic differences were minimal between handle designs. The differences that were significant (P less than 0.05) centered around the decreased ulnar deviation of the left hand that resulted when subjects used the BioCurve handle design. which also allowed greater resistance to torque than the straight grip club. In addition to collecting objective data. we asked subjects for their opinions of the two grips. As a whole. the normal group and the group with pathologic conditions noted more comfort. improved grip. and less shock transmission with the BioCurve handle.
Bilateral simultaneous rupture of the infrapatellar tendon in a recreational athlete. A case report, Bilateral rupture of the infrapatellar tendons is a rare event in an otherwise healthy athletic individual. The event is usually quite severe and diagnosis can be readily made on a clinical examination. In the case presented here. predisposing factors consisted of an underlying patella alta and a long history of repetitive trauma to the knee. Prompt diagnosis and surgical repair will lead to a good functional result.
Comparison of the effects of a single dose and of four six-monthly doses of ivermectin on adult Onchocerca volvulus, Adult Onchocerca volvulus worms. extracted from nodules of Guatemalans by collagenase digestion. were examined whole and by histological techniques. One group of persons received a single 150 micrograms/kg dose of ivermectin; two other groups (one with older and one with younger nodules) received four similar doses of ivermectin at 6-month intervals. For each group. there were comparable untreated controls. All nodules were removed six months after the last dose. After a single dose. the only significant difference from the controls was in the decreased proportion of female worms producing live microfilariae. After four doses. there were significant increases in the proportions of moribund/dead female worms and of live uninseminated females. when compared with the corresponding controls. There were also fewer male worms present. but this difference was not significant. Six months after the conclusion of the 4-dose regimen. the proportion of female worms producing live microfilariae was significantly lower than in the groups that had received a single dose.
Cellular immune response analysis of patients with leptospirosis, Peripheral blood mononuclear cells (PBMC) from acute leptospirosis patients with and without acute renal failure were studied in order to investigate the status of cellular immunity in this disease. We analyzed the lymphocyte subsets of leptospirosis patients by immunofluorescence and their responsiveness to the mitogens phytohemagglutinin (PHA) and pokeweed mitogen (PWM). Additionally. we investigated the effect of the patients' sera on normal PBMC proliferative response. We observed a decrease in the CD3+ and CD4+ cell subsets in patients with and without acute renal failure. or in percentage values alone in those who had recovered from renal failure. An increase in the number of B lymphocytes was observed in all patients. compared with controls. This increase in B lymphocytes was seen even in patients who had recovered from renal failure. when the number of CD3+ and CD4+ lymphocytes had already returned to normal levels. The low PHA response observed only with lymphocytes from patients with acute renal failure suggests a suppressive effect. The proliferative response to PWM was comparable to controls. even in the patients with acute renal failure. This latter result and the expansion of the B cell number could be related to leptospiral-derived factor(s). We also showed that sera from patients with and without acute renal failure exerted some inhibitory activity on normal PBMC responses to PHA and PWM. Although the redistribution of lymphocyte subsets and the serum suppressor activity were related to acute renal failure and leptospiral factor(s). we suggest that the cellular immune system was not irreversibly affected. which is compatible with the good prognosis seen in the patients studied.
Significance of circumsporozoite-specific antibody in the natural transmission of Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae in an aboriginal (Orang Asli) population of central peninsula Malaysia, Two hundred and seventy-five Orang Asli volunteers living in nine villages in the Pos Legap Valley of Perak State. peninsular Malaysia. participated in a prospective study designed to characterize the epidemiological. parasitological. and entomological characteristics of Plasmodium falciparum. P. vivax. and P. malariae malaria transmission. Prevalence rates for the three plasmodial species at initiation of the study ranged from 56% in the 0-4-year-old age group to 0% in individuals over the age of 40. Entomological surveys were conducted. enabling us to determine mosquito salivary gland-positive rates and entomological inoculation rates of 1.2 infectious mosquito bites per person per month for P. falciparum. 2.4 for P. vivax. and 0.3 for P. malariae. Cumulative incidence rates over the 16 weeks of the study. following radical cure of all volunteers. were 22.5% for P. falciparum. 12.7% for P. vivax. and 1.5% for P. malariae. The median baseline antibody titer against the immunodominant repetitive B cell epitope of P. falciparum or P. vivax circumsporozoite protein was significantly higher for volunteers who did not become parasitemic. Volunteers were selected for further study if they had evidence of being challenged with P. falciparum sporozoites during the study. based on a two-fold or greater increase in antibody titer against the immunodominant repetitive B cell epitope of the circumsporozoite protein. Resistance to infection was seen in six of 10 individuals who had high (greater than 25 OD units) baseline ELISA titers. compared with only three of 24 individuals who had low baseline ELISA titers (chi 2 P less than 0.02). A similar analysis for P. vivax did not show a significant correlation.
Isotypic analysis, antigen specificity, and inhibitory function of maternally transmitted Plasmodium falciparum-specific antibodies in Gabonese newborns, An analysis of Plasmodium falciparum-specific antibodies was performed in pairs of maternal and cord sera from Gabon. a region endemic for malaria. All paired sera (n = 59) had P. falciparum-specific antibodies. Immunofluorescence assays detected parasite-specific IgG1. IgG2. and IgG3 in 100% of the tested pairs (n = 26) and IgG4 in 42% of them. The titers of specific IgG2 and IgG3 were significantly lower in cord than in maternal sera. All maternal sera had specific IgM. Of the seven P. falciparum-IgM positive cord sera. six were associated with malaria-related histological placental changes (MRHPC). In addition. higher titers of specific IgG1 in maternal and cord sera and of specific IgG3 in cord sera were associated with MRHPC. Similar P. falciparum antigens were recognized by cord and corresponding maternal sera in radioimmunoprecipitation and Western blot assays (n = 40). Sixteen of 20 cord sera and 15 of 20 paired maternal sera significantly inhibited in vitro parasite growth. The extent of inhibition did not correlate with the titer of specific antibodies. These data confirm the very effective placental transfer of anti-malarial antibodies. The presence of IgM in some cord sera raise the question of intrauterine sensitization to malaria antigens.
Age-dependent acquired protection against Plasmodium falciparum in people having two years exposure to hyperendemic malaria, An epidemiologic study of susceptibility to frequent and high-grade parasitemia by Plasmodium falciparum revealed that age-dependent acquired protection developed within a two-year period of exposure to hyperendemic infection pressure. The study was conducted in a single village in northeastern Irian Jaya. Indonesia. where half the residents were native to the province and the other half were transmigrants from areas of Java. where there is little or no malaria transmission. Five separate measures of susceptibility to the asexual parasitemia of falciparum malaria were derived from results of four months of biweekly surveillance of 240 volunteers. Increasing protection as a function of age among the Javanese was a consistent pattern among the five estimates of susceptibility. These age-dependent functions of protection were quantitatively parallel to those among life-long residents of Irian Jaya. When humoral immune responsiveness to ring-infected erythrocyte surface antigen (RESA) was measured by ELISA. a similar pattern emerged; the relative level of antibody to RESA increased as parallel functions of age among the two subpopulations. Acquired protective immunity against P. falciparum was not the cumulative product of many years of heavy exposure to antigen. Instead. the full benefit of protection appeared to develop quickly. The degree of protection was governed by recent exposure and age. independent of history of chronic heavy exposure.
Clustering of malaria infections within an endemic population: risk of malaria associated with the type of housing construction, The occurrence of malaria infections due to Plasmodium vivax and P. falciparum was monitored in a population of 3.023 people living in six contiguous villages in Kataragama. an area of endemic malaria in southern Sri Lanka. over a period of 17 months. The annual incidence of malaria in this population during the study period was 25.8%. Malaria attacks were clustered. occurring more frequently than expected in certain individuals and housing groups and less frequently than expected in others. In one of these villages. the distribution of cases was examined in relation to locality and to the type of house construction. There was a strong association between the malaria incidence and house construction. independent of location. The risk of getting malaria was greater for inhabitants of the poorest type of house construction (incomplete. mud. or cadjan (palm) walls. and cadjan thatched roofs) compared to houses with complete brick and plaster walls and tiled roofs. Houses that were better constructed had a significantly lower malaria incidence rate (10.5%) than those that were poorly constructed (21.2%; P less than 0.01. by Student's t-test). There was also a significantly higher number of indoor resting mosquitoes collected from the poorly constructed houses than from those better constructed; the average (geometric mean) of mosquito densities found in houses of better versus poor construction were 0.97 and 1.89 per collection in the dry season. and 1.95 and 3.42 per collection in the wet season. respectively (P less than 0.05 in both seasons). This indicated that the higher malaria risk associated with poorly constructed houses was at least partly due to higher human-mosquito contact among their inhabitants.
Placebo controlled treatment of Ecuadorian cutaneous leishmaniasis, Pentavalent antimony has been considered to be the standard treatment for leishmaniasis. but more recently. the orally administrable agent allopurinol ribonucleoside has been the subject of several clinical trials. In this study. these two agents were evaluated in patients with Ecuadorian cutaneous leishmaniasis. Patients were randomly assigned to the two treatment groups. The mean reduction in lesion size for the 28 patients treated with Pentostam (20 mg Sb/kg/day intramuscularly for 20 days) was 61%. 23%. and 11% after one. two. and three weeks. respectively. There was a wide range in the individual values. and some lesions markedly enlarged in the first week of therapy. An initially healed lesion was defined as one that had greater than 80% re-epithelialized by the 1.5-month post-treatment followup. All Pentostam patients demonstrated this degree of lesion resolution (100% initial healing rate). but one patient showed evidence of relapse at the three month followup resulting in a 96% complete healing rate for the 12 month observation period. Patients in the untreated control group demonstrated a strikingly high rate of healing with 9 of 12 patients having re-epithelialized all lesions after 1.5 months observation (75% initial healing rate). The mean reduction in lesion size for the untreated patients was 56%. 29%. and 25% after one. two. and three weeks. respectively. Twenty-one patients received allopurinol ribonucleoside (1.500 mg QID) plus probenecid (500 mg QID) for 28 days. Lesions in nine of these patients were healed at the time of the 1.5 month followup (41% healing rate).
Is premedication with oral glycopyrrolate as effective as oral atropine in attenuating cardiovascular depression in infants receiving halothane for induction of anesthesia, The authors conducted a double-blind study to compare premedication with oral glycopyrrolate and oral atropine in prevention of bradycardia and hypotension during induction of anesthesia with halothane-N2O in 90 outpatient infants and children aged 1-18 mo who were randomized into three groups to receive either an oral placebo. oral atropine (0.02 mg/kg). or oral glycopyrrolate (0.05 mg/kg) approximately 1 h before induction of anesthesia. Heart rate and mean arterial pressure were measured before drug administration. just before induction of anesthesia. and every minute until surgical stimulation occurred. Glycopyrrolate. at the dose used. was significantly less effective than atropine in attenuating bradycardia during induction; neither glycopyrrolate nor atropine altered the incidence or degree of hypotension. Antisialagogic activity and side effects were comparable. except for significantly more flushing with atropine.
Resistance to vecuronium in patients with cerebral palsy, To determine the electromyographic response of patients with cerebral palsy to vecuronium. 10 children (mean age. 6 yr 10 mo) without cerebral palsy and 11 children with cerebral palsy (mean age. 10 yr 3 mo) were studied. All patients were undergoing abdominal or orthopedic surgery and were anesthetized with isoflurane and nitrous oxide. The time from intravenous administration of 0.1 mg/kg of vecuronium to 25% recovery of control twitch height was 43.9 +/- 5.3 and 18.9 +/- 1.7 min (mean +/- SEM) in children without and with cerebral palsy. respectively (P less than 0.01). The authors conclude that patients with cerebral palsy are either resistant to vecuronium or have a rapid clearance as evidenced by the rapid recovery from neuromuscular blockade.
Effects of volatile anesthetics on response to norepinephrine and acetylcholine in guinea pig atria, The in vitro chronotropic and inotropic effects of norepinephrine and acetylcholine in isolated right and left guinea pig atria were examined in the absence and presence of halothane. isoflurane. and enflurane (0.6 and 1.2 MAC). All three anesthetics elicited dose-dependent reductions in contractile force and spontaneous pacemaker activity. The maximal developed tension observed in the presence of norepinephrine was not altered by the anesthetics and corresponding ED50 values increased only in the presence of 1.2 MAC halothane and 1.2 MAC isoflurane. The anesthetics did not affect (a) the maximal positive chronotropic effect of norepinephrine. (b) the ED50 values for its positive chronotropic effect. and (c) acetylcholine-induced negative inotropic and chronotropic actions and did not induce arrhythmic activity even in the presence of the maximally effective neurotransmitter concentrations. These findings indicate that in isolated guinea pig atria volatile anesthetics. in concentrations up to 1.2 MAC. do not alter the inotropic and chronotropic effects of norepinephrine or acetylcholine and do not induce arrhythmogenic action in the presence of the neurotransmitters. These data suggest that altered atrial responsiveness to adrenergic or muscarinic stimulation does not contribute to the development of anesthetic-induced cardiac arrhythmias.
Deliberate hypotension with nicardipine or nitroprusside during total hip arthroplasty, To induce deliberate hypotension during anesthesia. nicardipine was administered to patients undergoing total hip arthroplasty and was randomly compared with nitroprusside. Hemodynamic measurements were performed before and 10. 20. 30. and 60 min after starting to administer either nicardipine (n = 12) or nitroprusside (n = 12) (B. T1. T2. T3. and T4. respectively); at the end of drug infusion (T5); and 10. 20. and 60 min later (T6. T7. and T8. respectively). Plasma renin activity and catecholamine levels were measured at B. T1. T5. T6. and T7. In addition. plasma nicardipine concentration was measured in five patients at T1. T2. T5. T7. and T8. As with nitroprusside. nicardipine administration (1-3 micrograms.kg-1.min-1. after a titration dose of 4.7 +/- 1.5 mg) resulted in hypotension (up to -34% +/- 3%). a decrease in systemic vascular resistances (up to -49% +/- 4%). and increases in heart rate (up to +17% +/- 6%). cardiac index (up to +37% +/- 8%). plasma norepinephrine (up to +63% +/- 17%) and epinephrine (up to +232% +/- 68%) levels. and plasma renin activity (up to +336% +/- 207%). Ten and 20 minutes after discontinuation of the hypotensive drug. nicardipine led to persistent vasodilation and hypotension. which differed significantly from the hypertensive rebound observed after nitroprusside discontinuation. despite a similar increase in plasma renin activity and catecholamine levels. Our results indicate that after the infusion was terminated. the nicardipine-induced vasodilation was opposed to the vasoconstrictive effects of angiotensin II and catecholamines. thus avoiding hypertensive rebound.
C1 esterase inhibitor deficiency: three presentations [clinical conference, We have presented three patients representing three of the four reported forms of C1 esterase inhibitor deficiency. The C1INH deficiencies are in general distinguishable from each other and from other forms of angioedema by their complement patterns. The acquired C1INH deficiency must be part of the differential in patients without a family history of angioedema since it may precede the diagnosis of more serious medical conditions such as lymphoproliferative disorders.
Effect of inhaled corticosteroid on bone density in asthmatic patients: a pilot study, We investigated the effect of long-term inhaled (ICS) and oral corticosteroid (OCS) therapy on bone density by using single and dual photon absorptiometry. We studied a group of five asthmatic patients who inhaled an average of 326 micrograms/day of beclomethasone dipropionate equivalents for 50 months (range 36 to 62 months) and a control group of five asthmatic patients on OCS. who used 12.5 mg of prednisone equivalents daily for an average of 57 months (range 22 to 120 months). The ICS group's average bone densities relative to age and sex-matched controls were 99.7%. 99.2%. and 90.0% for the radius. spine. and hip. respectively. The OCS group's average bone densities relative to age-matched and sex-matched controls were 94.4%. 85.4%. and 84.5% for the identical sites. A dose-response relationship between the cumulative dose of ICS and the relative bone density was absent in the study group but demonstrable in the control group of asthmatics on long-term OCS therapy. These results suggest that ICS therapy. unlike OCS. may not induce bone loss at the doses used by our subjects. Further research is required to determine whether a single user of ICS with unusually low bone density measurements represents a biologic variant. or a subgroup of patients who are especially sensitive to the systemic effects of ICS.
Lack of graft rejection in a renal transplant recipient with AIDS, A renal transplant recipient developed evidence of human immunodeficiency virus (HIV) infection and severe opportunistic infection 44 months after transplantation. A strikingly reduced dosage of pharmacologic immunosuppression was required to maintain renal graft function. This may be the result of impaired helper T-cell function associated with the acquired immunodeficiency syndrome (AIDS).
Late asthma caused by inhalation of Lepidoglyphus destructor, We report the case of a grain worker who had immediate nasal and conjunctival symptoms and late-phase asthmatic reactions after handling stored grain. Allergy to one storage mite. Lepidoglyphus destructor. was demonstrated by skin testing. specific IgE. and bronchial provocation tests. Bronchial challenge with L. destructor provoked only a late phase asthmatic reaction without an immediate reaction despite the fact that immediate skin tests and specific IgE had been positive. Pretreatment with cromolyn sodium prevented any asthmatic reaction after bronchial challenge. An IgE immunologic mechanism could explain the clinical findings.
Cumulative incidence of atopic disorders in high risk infants fed whey hydrolysate, soy, and conventional cow milk formulas, A recent increase in the prevalence of atopic disorders and the enormous costs of management of atopic patients have prompted attempts at prevention. We have examined the effect of exclusive breast feeding and of feeding different infant formulas on incidence of atopic disease in a prospective randomized controlled study. Seventy-two infants were recruited into each of the following groups: cow milk whey hydrolysate formula (NAN/HA) conventional cow milk formula (Similac). soy-based formula (Isomil). and exclusive breast feeding for greater than 4 months. The cumulative incidence of atopic eczema. recurrent wheezing. rhinitis. gastrointestinal symptoms. and colic were noted. Skin prick tests and radioallergosorbent tests for IgE antibodies to milk and soy were performed. At 12 and 18 months of age. the incidence of atopic eczema as also that of all atopic symptoms was significantly lower and similar in the breast-fed and whey hydrolysate groups. compared with the cow milk and soy formula groups. IgE antibodies were detected more often in the cow milk and soy formula groups. especially the former. Among symptomatic infants. fewer skin positive prick tests were seen in the soy group compared with the cow milk group. Our observations show that among infants at high risk of developing atopic disease because of positive family history. exclusive breast feeding or whey hydrolysate formula is associated with a lower incidence and thus a delay in the occurrence of allergic disorders compared with groups fed conventional cow milk or soy formulas.
Skin testing compared with in vitro testing for screening allergic patients, A new FDA-cleared product has been introduced for screening suspected allergic patients using a small blood sample. The QUIDEL Allergen Screens (AS) are simple to use dipstick tests that measure allergen-specific IgE to ten of the most important regional allergens. We compared the results obtained by prick-puncture skin testing (ST) to those obtained with the AS on 103 patients with allergic symptoms. Of the 103 patients studied. there were 67 with positive skin tests. and 57 of those were positive by AS and ten were AS negative. Of the 36 with negative skin tests. 2 were positive by AS and 34 were AS negative. Compared with ST. the AS results gave a sensitivity of 85% and a specificity of 94% for identifying the allergic patient. Of the ten patients positive by ST but negative by AS. five were ST positive at the 1+ level; the other five were repeatedly negative by AS and confirmed negative by RAST. On an allergen basis. the ST and AS methods showed an 85% agreement. A subset of 24 patients from the foregoing group was studied for total IgE and allergen-specific IgE with products from both Pharmacia (P) and QUIDEL (Q). In this group of patients. skin test results gave seven patients negative and 18 patients positive to one or more allergens. While the overall Total IgE results were higher for ST patients. the Total IgE results alone did not effectively discriminate between ST-positive and ST-negative patients. The allergen-specific. however. results by both methods showed excellent agreement with the ST results.
Potentially fatal asthma: the problem of noncompliance, In spite of available pharmacologic therapy that controls even the most severe cases of asthma. the mortality rate from asthma continues to rise. Patients with potentially fatal asthma (PFA) must be identified and then treated in a manner that will prevent potentially fatal episodes of asthma. Such management will not result in control of patients with PFA when the patient is not compliant with the medical regimen. We report and classify ten PFA patients according to the apparent psychologic abnormality that resulted in. or contributed to the noncompliance. Some of these psychologic abnormalities in patients with PFA such as adolescent noncompliance. prednisonephobia or bipolar affective disorders may be responsive to a combination of medical and psychiatric management. Other psychiatric diseases that may occur in patients with PFA. such as antisocial personality disorders or schizophrenia. may have a poor prognosis even with combined medical and psychiatric care. The managing physician should be aware of the grave prognosis in such cases.
Systemic cold urticaria in a five-year-old boy, A 5-year-old white boy had a history of generalized urticaria on total body exposure to a cold environment. Standard ice cube testing was negative. Plasma analysis revealed the presence of cryofibrinogen. Systemic cold challenge with serial plasma assays for complement. histamine. and prostaglandin D2 disclosed an elevation and peak of plasma histamine and prostaglandin D2 levels after the onset of generalized urticaria with no change in serum complement levels.
Dose tolerance study of fluticasone propionate aqueous nasal spray in patients with seasonal allergic rhinitis, A multicenter. double-blind. parallel-group. dose-tolerance study was conducted to evaluate the safety of fluticasone propionate aqueous nasal spray. a potent new corticosteroid preparation. Ninety-seven adult patients with moderate to severe seasonal allergic rhinitis during the fall weed season received either placebo or fluticasone propionate in doses of 50. 200. or 800 micrograms twice daily for 4 weeks. Safety evaluations included adrenal function evaluation by morning plasma cortisol concentration. response to ACTH stimulation. and 24-hour urinary free cortisol excretion. There was no evidence of effects on adrenal function at any dose. The severity. nature. and frequency of adverse events were similar across all treatment groups. including placebo. Drug-related adverse events were consistent with local nasal irritation. The groups receiving fluticasone propionate showed greater improvement in nasal symptoms (obstruction. rhinorrhea. sneezing. and itching) than did the placebo group. The results demonstrate that fluticasone propionate aqueous nasal spray is safe in doses up to 1600 micrograms per day and effective in the treatment of seasonal allergic rhinitis.
Influence of time of administration on allergic skin prick tests response, This study evaluated influences of time of administration on the response to allergy skin prick tests. There was no significant difference between the mean +/- SEM wheal diameter of positive responses obtained in the morning. 2.98 +/- 0.19 nm. or in the evening. 3.14 +/- 0.18 mm (n = 175).
Radiolabeled antibody imaging in the management of colorectal cancer. Results of a multicenter clinical study, Presurgical colorectal cancer patients (n = 116) received single intravenous infusions of 1 mg of CYT-103 (OncoScint CR103). an immunoconjugate of monoclonal antibody B72.3. radiolabeled with 111In. Following gamma camera imaging. 103 patients underwent an operative procedure: 92 had primary or recurrent colorectal carcinoma. 1 patient evaluated for recurrence of colorectal cancer had a second primary malignancy (small cell lung). and 10 patients had no demonstrable evidence of malignancy. 111In-CYT-103 immunoscintigraphic findings were consistent with the pathologic diagnoses for 70% of patients with colorectal cancer and 90% of disease-free patients. Antibody imaging contributed to surgical decision making through the detection of occult disease (12% of patients) and the confirmation of localized. potentially resectable disease without regional or metastatic spread. Seven patients (6%) experienced adverse effects. primarily fevers and itching. and 33% of patients developed antibodies to murine immunoglobulin after administration of 111In-CYT-103. The results of this study suggest that 111In-CYT-103 is a useful diagnostic tool for the presurgical evaluation of colorectal cancer patients.
The prognosis of melanoma patients with metastases to two or more lymph node areas, The prognosis of melanoma patients who present with metastatic involvement of two or more noncontiguous lymph node regions before the detection of extranodal metastases has not been previously reported. We identified 21 patients with metastatic melanoma in at least two nodal basins in a review of 175 patients with melanoma undergoing lymphadenectomy at the National Cancer Institute. The median survival time of these patients was 46 months. with 55%. 27%. and 17% of the patients alive 2. 5. and 10 years. respectively. after the second lymphadenectomy. Because the prognosis of melanoma patients with metastases to two or more regional nodal areas appears equivalent to that of patients with metastatic involvement of only one regional node site. lymphadenectomy of the involved groups should be performed with therapeutically curative intent.
The complex pattern of cytokines in sepsis. Association between prostaglandins, cachectin, and interleukins, Although the cytokines tumor necrosis factor (TNF). interleukin-1 (IL-1). and interleukin-6 (IL-6) are important mediators of hemodynamic. metabolic. and immunologic alterations in the host during sepsis. it is not known whether there is any association between the release of these cytokines and prostanoids during sepsis. Sepsis induced by cecal ligation and puncture in rats led to a persistent elevation (p less than 0.05) of plasma TNF until 10 hours. steadily increasing (p less than 0.05) IL-1 plasma levels. and enhanced (p less than 0.05) IL-6 plasma levels at all time points compared to the sham group. Prostaglandin E2 plasma levels were elevated (p less than 0.05) at 5 hours (153 +/- 29 pg/mL; control: 47 +/- 11 pg/mL) and 10 hours (96 +/- 16 pg/mL; control: 21 +/- 5 pg/mL). Prostaglandin E2 production by splenic macrophages (sM phi) from septic animals was increased (p less than 0.05) at 5 hours (9.1 +/- 2.2 ng/mL) and 10 hours (5.6 +/- 1.5 ng/mL) compared to controls (3.3 +/- 0.3 ng/mL at 5 hours; 1.3 +/- 1.3 ng/mL at 10 hours). Incubation of sM phi from septic animals with ibuprofen enhanced (p less than 0.05) IL-1 and TNF synthesis. while IL-6 production was reduced (p less than 0.05). These results indicate that the alterations in prostanoid release and elevated plasma prostanoids may regulate the release and consequently the circulating levels of cytokines during sepsis.
Lovastatin inhibits gallstone formation in the cholesterol-fed prairie dog, The efficacy of lovastatin. an inhibitor of hepatic cholesterol synthesis in the prevention of cholesterol gallstone formation. was evaluated in the prairie dog model. Two groups of animals were maintained on either nonlithogenic or 1.2% cholesterol-enriched chow for 21 days. Seven of the animals in each group received lovastatin. and the remaining six received only distilled water. All of the cholesterol-fed/water-treated animals had crystals and 83% had gallstones. but none of the cholesterol-fed/lovastatin-treated animals had gallstones and only three had microscopic crystals. These data indicate that lovastatin inhibits cholesterol gallstone formation in a diet-induced model of gallstone disease.
Dose response of fish oil versus safflower oil on graft arteriosclerosis in rabbit heterotopic cardiac allografts, With the advent of cyclosporin A. accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil. the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2. 3. and 4 animals received a daily supplement of low- (0.25 mL/kg/day). medium- (0.75 mL/kg/day). and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL). respectively. Group 5. 6. and 7 animals were supplemented with equivalent dose of safflower oil (i.e.. 0.25. 0.75. and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted. morphometric planimetry. When the animals were killed. cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages. fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals. there was a trend for more graft vessel disease with increasing fish oil dose. as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group. animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%. p less than 0.017) and intimal thickness (7.9 +/- 1.9 microns versus 34.0 +/- 13.0 microns. analysis of variance: p = 0.054). Low-dose safflower oil also had a slight. but nonsignificant. beneficial effect on graft vessel disease when compared to control rabbits. The same trends were observed in the degree of histologic rejection (0 = none to 3 = severe) in fish oil- and safflower oil-treated animals. Rejection score correlated weakly but significantly (p = 0.0001) with mean luminal occlusion (r = 0.52) and intimal thickness (r = 0.46). Therefore allograft coronary disease in this model appeared to exhibit an unfavorable. direct-dose response to fish oil and safflower oil. independent of effects on plasma lipids.(ABSTRACT TRUNCATED AT 400 WORDS).
Acceleration of superoxide production from leukocytes in trauma patients, Superoxide (O2-) and granulocyte elastase (GE) from neutrophils mediate host defense and tissue injury in inflammation. To determine alterations in leukocyte function after trauma. O2- production and GE secretion from neutrophils were studied in trauma patients (n = 20) and healthy controls (n = 15). The priming effect of tumor necrosis factor (TNF). interleukin-1 alpha (IL-1 alpha). and lipopolysaccharide (LPS) on O2- or GE release also was evaluated. Superoxide production (nmole/10 minutes) was elevated significantly in trauma patients at days 0 (9.5 +/- 4.8). 1 (14.2 +/- 7.3). and 3 (12.2 +/- 5.9) and returned to control levels (4.2 +/- 1.6) by day 7. There was no difference in GE secretion between trauma patients and healthy controls. Incubation of neutrophils with TNF induced release of both O2- and GE. Superoxide production was induced by TNF at concentrations at or greater than 10(-11) mol/L. Granulocyte elastase secretion was induced in a time- and dose-dependent manner by TNF at concentrations between 10(-10) and 10(-7) mol/L. In contrast IL-1 alpha and LPS did not potentiate O2- or GE release. These results suggest that neutrophil O2- production increases acutely in trauma. Tumor necrosis factor may mediate this O2- and GE production by neutrophils involved in the inflammatory response.
Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey, A detailed ocular examination. including perimetry. was conducted on 5308 black and white subjects aged 40 years and older in a population-based prevalence survey in east Baltimore. Md. Repeated. detailed examinations were carried out on selected subjects. Roughly half of all subjects with optic nerve damage from primary open angle glaucoma. regardless of race. were unaware that they had the condition. The average intraocular pressure (IOP) among black patients with glaucoma who were receiving treatment was virtually identical to that in those black patients who were not receiving treatment (median IOP. 20 mm Hg); treated eyes of white patients had a lower IOP than those eyes of white patients who were not receiving treatment (mean [+/- SD] IOP. 18.69 +/- 3.23 mm Hg vs 24.15 +/- 5.23 mm Hg; P less than .001). The risk of glaucomatous optic nerve damage increased with the height of the screening IOP. particularly at levels of 22 to 29 and 30 mm Hg and above (relative rate compared with IOP of 15 mm Hg or lower. 12.8 and 40.1 mm Hg. respectively). More than half of all glaucomatous eyes had a screening IOP below 21 mm Hg. whether these eyes were receiving treatment or not. The IOP in glaucomatous eyes tended to rise on follow-up. in contrast with nonglaucomatous eyes in which the IOP was as likely to rise as to fall. Results confirmed that IOP is an important factor in glaucoma. but did not support the traditional distinction between "normal" and "elevated" pressure. nor its corollaries. "low-tension" glaucoma and "high-tension" glaucoma.
Exercise training reduces intraocular pressure among subjects suspected of having glaucoma, The effect of exercise conditioning on elevated intraocular pressure has not been previously described among sedentary individuals. We prospectively observed intraocular pressure for nine sedentary subjects suspected of having glaucoma before and after 3 months of aerobic exercise training. Mean (+/- SEM) aerobic capacity. as assessed by maximal oxygen uptake. increased 6.3 +/- 1.6 mL.kg-1.min-1 (30%) (P less than .02). Mean intraocular pressure decreased 4.6 +/- 0.4 mmHg (20%) (P less than .001) at the end of the conditioning period. With cessation of exercise and subsequent detraining. intraocular pressure returned to elevated preconditioning levels by 3 weeks. Regular aerobic exercise is associated with a reduction in elevated intraocular pressure and may represent an effective nonpharmacologic intervention for patients suspected of having glaucoma.
Mizuo phenomenon in X-linked retinoschisis. Pathogenesis of the Mizuo phenomenon, Four unrelated males with X-linked retinoschisis and a golden fundus reflex had Mizuo-Nakamura phenomenon. which. to our knowledge. has been described only in Oguchi's disease and X-linked cone dystrophy. These findings. together with experimental observations and data from the literature. led us to hypothesize that the Mizuo-Nakamura phenomenon is caused by an excess of extracellular potassium in the retina as a result of a decreased potassium scavenging capacity of retinal Muller cells.
The probability of obtaining compatible blood from related directed donors, Patients with alloantibodies may request directed blood donations from their relatives despite the lack of any scientific data suggesting that blood from these donors is safer. We have derived formulas that are applicable to any ethnic group for calculating the probability that a given class of relatives will have compatible blood for a given patient. These formulas apply to any non-X-linked blood group system (including the ABO and Rh systems) and are simple enough for routine blood bank use in advising patients as to how likely they are to obtain compatible donors. Use of these formulas may be helpful in counseling patients who may have difficulty in obtaining compatible directed donors because of antibodies or an unusual blood type. In general. the presence of an alloantibody should not automatically exclude a patient from utilizing directed donors. Moreover. for patients with antibodies to high-incidence antigens. directed donations from siblings may be the easiest way to obtain compatible blood.
The limited potential of special ambulance services in the management of cardiac arrest, For six months a survey was made of all the patients in the Nottingham District Health Authority who died or who were brought to hospital after a cardiac arrest outside hospital. During this period just under half of the emergency ambulance shifts were covered by specially trained crews with defibrillators. During the study period the ICD coding of death certificates indicated that 894 (25%) of the 3575 deaths were due to ischaemic heart disease. During this period the ambulance service received 17.749 emergency calls. which included 445 patients who had cardiac arrests outside hospital. One hundred and forty seven of these patients were carried by ambulances equipped with defibrillators and resuscitation was attempted in 83. Seven patients survived to leave hospital. The special ambulance service was cost effective--a simple calculation suggests that the cost per life saved was approximately 2600 pounds. but it seems unlikely that special ambulance services will materially affect community fatality rates from ischaemic heart disease.
Differential expression of CD25 (interleukin-2 receptor) on lamina propria T cells and macrophages in the intestinal lesions in Crohn's disease and ulcerative colitis, Many interleukin-2 receptor (CD25) bearing cells can be identified by alkaline phosphatase immunohistochemistry in the diseased intestinal lamina propria of children with Crohn's disease or ulcerative colitis. but rarely in normal intestine. In both diseases. the CD25+ cells are present as aggregates in the lamina propria below the epithelium. and constitute a large proportion of the lamina propria mononuclear cells. In Crohn's disease. but not ulcerative colitis. CD25+ cells are abundant in the submucosa. The CD25+ cells in Crohn's disease are 58-88% CD3+. CD4+. CD8-. indicating that they are T cells. whereas in ulcerative colitis the CD25+ cells are greater than 80% CD3-. CD4+. HLA-DR+. indicating that they are macrophages. Thus. differential expression of CD25 on T cells and macrophages serves to distinguish the immunologic lesions in ulcerative colitis and Crohn's disease.
Early complications of interventional balloon catheterisation in infants and children, Interventional balloon catheterisation is now the recommended procedure for several congenital heart defects. The overall complication rate in the first 160 children (median age 3 years) to undergo balloon intervention (excluding balloon atrial septostomy) at the Brompton Hospital was 24% (14% excluding haemorrhage and including three deaths (1.9%]. Most complications were related to vascular problems at the site of cardiac catheterisation. Complications were more common in the younger patient. especially neonates. and also in procedures that were ultimately unsuccessful. Most complications were transient and usually had no long term effects. Improvements in equipment design and technical expertise may reduce morbidity from these procedures.
Mechanism of shock associated with right ventricular infarction, Various mechanisms have been proposed to explain the shock sometimes associated with right ventricular infarction. but only small numbers of patients with clinical shock have been studied. The haemodynamic profiles of seven patients with clinical cardiogenic shock after right ventricular myocardial infarction were studied prospectively. They were selected because all had a stable cardiac rhythm and none had absolute hypovolaemia during the study period. In all of them the mean right atrial pressure exceeded the pulmonary artery occlusion pressure. After treatment with varying combinations of dopamine. dobutamine. and glyceryl trinitrate (titrated to achieve the optimum haemodynamic response) the mean systemic arterial pressure increased. as did the cardiac index. There was an associated increase in the left ventricular stroke work index but the right ventricular stroke work index was unchanged. There was no significant change in heart rate. mean right atrial pressure. or pulmonary artery occlusion pressure. This suggests that the probable mechanism of the shock associated with right ventricular infarction is concomitant severe left ventricular dysfunction.
Desirability of immediate surgical standby for coronary angioplasty, OBJECTIVE--To assess the value of emergency surgical standby for percutaneous transluminal coronary angioplasty. DESIGN--Retrospective review of the major complications of coronary angioplasty in a regional cardiac centre. SETTING--All angioplasties were performed in the cardiac catheterisation laboratory of Wythenshawe Hospital with surgical standby in an adjoining operating theatre. PATIENTS--1262 vessels were dilated in 1032 patients (mean age 53 years) between 1984 and 1989. MAIN OUTCOME MEASURES--In-hospital mortality from emergency surgical revascularisation after angioplasty; the rate of myocardial infarction and overall morbidity. RESULTS--Coronary angioplasty achieved primary success in 90% of cases. Thirty eight (3.7%) patients (five women (mean age 55.8) and 33 men (mean age 53.0] were referred for urgent surgical revascularisation--36 direct to operation and two within 24 hours. All patients survived surgery. Five of the 38 had had a previous angioplasty to the same vessel and one had had previous coronary artery grafts. Four of the 38 had an angioplasty for unstable angina. Eighteen had single. 13 double. and seven triple vessel coronary artery disease. The target vessel was the left anterior descending in 25. right coronary artery in nine. circumflex in three. and the left anterior descending and circumflex coronary arteries in one. Five required external cardiac massage on the way to the operating theatre; two of them had a left main stem occlusion. Four internal mammary artery and 60 reversed saphenous vein grafts were implanted (1.6 per patient). Complete revascularisation was achieved in 36 (94.7%) patients. Q wave myocardial infarction occurred in six (15.8%). The final outcome was: none dead. three patients with angina. one late death. one cerebrovascular accident. one late operation for a new left anterior descending lesion. two patients on diuretics with or without an angiotensin converting enzyme inhibitor. One orthotopic transplant was performed in a patient in whom cardiogenic shock developed after the left anterior descending coronary artery became occluded 72 hours after angioplasty. CONCLUSION--There was no surgical mortality and low morbidity among patients for whom immediate surgical cover was requested.
Gradation of unstable angina based on a sensitive immunoassay for serum creatine kinase MB, A newly developed. highly sensitive immunoassay for creatine kinase MB isoenzyme was evaluated in 68 patients with or without different types of ischaemic heart disease. Patients were classified on the basis of clinical criteria in four groups: no ischaemic heart disease. stable angina. unstable angina. and acute myocardial infarction. Enzyme concentration in patients with stable angina was the same (even during exercise) as seen in the patients without ischaemic heart disease. Patients with unstable angina. however. could be divided into two groups. One group showed clear evidence of severe myocardial ischaemia by serial changes and higher mean values of creatine kinase MB up to 40 hours after the onset of symptoms. whereas in the remainder values were stable and resembled those seen in the patients without ischaemic heart disease. The changes in concentration correlated with signs of repetitive ischaemic episodes deduced from continuous ST segment monitoring during the first 24 hours after admission. These findings indicate that patients with unstable angina are a heterogenous group. In some. severe and prolonged ischaemia can be detected by a serological assay with high sensitivity.
Retinoic acid-induced granulocytic differentiation of HL60 human promyelocytic leukemia cells is preceded by downregulation of autonomous generation of inositol lipid-derived second messengers, Inositol phosphates (InsPs) and diacyglycerol (DAG) are second messengers derived via the breakdown of inositol phospholipids. and which play important signalling roles in the regulation of proliferation of some cell types. We have studied the operation of this pathway during the early stages of retionic acid (RA)-induced granulocytic differentiation of HL60 myeloid leukemia cells. The autonomous breakdown of inositol lipids that occurred in HL60 cells labeled with [3H] inositol was completely abolished following 48 hours of RA treatment. The rate of influx of 45Ca2+ was also significantly decreased at 48 hours. consistent with the role of inositol lipid-derived second messengers in regulating Ca2+ entry into cells. The downregulation of inositol lipid metabolism clearly preceded the onset of reduced proliferation induced by RA treatment. and was therefore not a consequence of decreased cell growth. The generation of InsPs in RA-treated cells was reactivated by the fluoroaluminate ion. a direct activator of guanine nucleotide-binding protein(s) (G proteins) that regulate the inositol lipid signalling pathway. Subtle alterations to a regulatory mechanism may therefore mediate the RA-induced downregulation of this pathway. The data are consistent with the hypothesis that the autonomous generation of inositol lipid-derived second messengers may contribute to the continuous proliferation of HL60 cells. and that the RA-induced downregulation of this pathway may. in turn. play a role in signalling the cessation of proliferation that preceedes granulocytic differentiation.
Neutrophils express the high affinity receptor for IgG (Fc gamma RI, CD64) after in vivo application of recombinant human granulocyte colony-stimulating factor, Fc receptors are important effector molecules of neutrophilic granulocytes (polymorphonuclear neutrophils [PMN]). connecting phagocytic cells and the specific immune response. Neutrophils from healthy donors express the low-affinity receptors for IgG Fc gamma RII (CD32) and Fc gamma RIII (CD16). but not the high-affinity receptor Fc gamma RI (CD64). The latter has been found on neutrophils from patients with certain bacterial infections and can be induced in vitro after incubation with interferon-gamma. We show here that neutrophils strongly express Fc gamma RI after in vivo application of recombinant human granulocyte colony-stimulating factor (rhG-CSF). PMN from patients receiving rhG-CSF displayed higher cytotoxicity against Daudi lymphoma cells in vitro compared with control patients and with healthy donors. Fab fragments against Fc gamma RII (monoclonal antibody [MoAb] IV.3) inhibited neutrophil-mediated cytotoxicity of healthy donors but not of patients during rhG-CSF therapy. Therefore. expression of Fc receptors by PMN was investigated by flow cytometry and the mean fluorescence intensity (MFI) was compared. After staining with MoAb 32.2 against Fc gamma RL. the median MFI of neutrophils from G-CSF patients (median. 4.78; range. 2.40 to 8.50; n = 5) was significantly higher (P = .002 and P = .001. respectively) than the median MFI of patients not receiving G-CSF (median. 1.23; range. 1.01 to 1.58; n = 6) and the median MFI of healthy donors (median. 1.04; range. 0.67 to 1.12; n = 6). Fc gamma RI disappeared after the discontinuing of the G-CSF injections. but was reinduced during the next treatment cycle with rhG-CSF. The high expression of Fc gamma RI during rhG-CSF therapy correlated with enhanced cytotoxicity. In vitro incubation with rhG-CSF also enhances cytotoxicity. but only minor increments in Fc gamma RI expression were observed. Thus. during in vivo application of rhG-CSF neutrophils acquire an additional potent receptor for mediating tumor cell killing in vitro by induction of the high-affinity receptor for IgG (Fc gamma RI. CD64).
Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha, Chronic exposure of humans to benzene (BZ). a myelotoxin. causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1). a cytokine essential for hematopoiesis. is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ). a toxic bone marrow (BM) metabolite of BZ. causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages. as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre-IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin. a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression. most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.
Rescue from programmed cell death in leukemic and normal myeloid cells, Growth factor-independent clones of myeloid leukemic cells can regain a growth factor-dependent state during differentiation. Loss of viability in these differentiating leukemic cells in the absence of growth factor was associated with DNA fragmentation and morphologic changes typical of programmed cell death (apoptosis). The differentiating leukemic cells could be rescued from apoptosis by a hematopoietic growth factor such as interleukin-3 (IL-3) and by the tumor-promoting phorbol ester 12-O-tetra-decanoyl-phorbol-13-acetate (TPA). but not by the nonpromoting phorbol ester 4-alpha-TPA. IL-3 and TPA rescued differentiating myeloid leukemic cells by different pathways and also rescued normal myeloid precursor cells from apoptosis. The rescue of differentiating leukemic and normal myeloid cells by IL-3 or TPA was blocked by amiloride inhibitors of the Na+/H+ antiporter. We suggest that TPA may act as a tumor promoter by inhibiting programmed cell death.
Induction of hemoglobin synthesis by downregulation of MYB protein with an antisense oligodeoxynucleotide, Reduced expression of the proto-oncogene c-myb appears necessary for erythroid differentiation induced by chemical agents and by the natural regulator. erythropoietin (Epo). Treatment of Epo-responsive Rauscher erythroleukemia cells with an anti-sense oligodeoxynucleotide to c-myb in the absence of other inducers downregulated myb protein markedly and caused hemoglobinization of the cells within 48 hours. Epo treatment. which downregulates c-myb in these cells. induced hemoglobinization to the same degree. Epo also induced the appearance of anion transport protein on the plasma membrane. consistent with terminal differentiation. In contrast. antisense c-myb did not induce this erythroid marker. The results are consistent with a role for myb protein in the regulation of hemoglobin synthesis.
Functional characterization of an abnormal factor XII molecule (F XII Bern), An 18-year-old healthy woman was found to have cross-reacting material (CRM)-positive factor XII (F XII) deficiency. F XII clotting activity was less than 0.01 U/mL. whereas F XII antigen was 0.11 U/mL. An F XII inhibitor was excluded. To partially characterize the molecular defect of the abnormal F XII. immunologic and functional studies were performed on the proposita's plasma. The abnormal F XII was a single chain molecule with the same molecular weight (80 Kd) and the same isoelectric points (pl. 5.9 to 6.8) as normal F XII. Dextran sulfate activation of the proposita's plasma showed no proteolytic cleavage of F XII even after 120 minutes. whereas F XII in pooled normal plasma. diluted 1:10 with CRM-negative F XII-deficient plasma. was completely cleaved after 40 minutes. Adsorption to kaolin was identical for both abnormal and normal F XII. In the presence of dextran sulfate and exogenous plasma kallikrein. the abnormal F XII was cleaved with the same rate as normal F XII. However. kallikrein-cleaved abnormal F XII was not able to cleave factor XI and plasma prekallikrein. in contrast to activated normal F XII. Thus. these studies show that the functional defect of this abnormal F XII. denoted as F XII Bern. is due to the lack of protease activity of the kallikrein-cleaved molecule. Therefore. the structural defect is likely to be located in the light chain region of F XII. containing the enzymatic active site.
Fluoroscopic guidance in transseptal catheterization for percutaneous mitral balloon valvotomy, A percutaneous mitral balloon valvotomy (PMBV) was attempted on 190 patients with fluoroscopic guidance of atrial septal puncture for transseptal catheterization; in 3 cases. the procedure could not be performed. The left atrium was always reached on the first attempt. when the relationship of the Brockenbrough needle to the aortic catheter was previously observed in 3 fluoroscopic views: anteroposterior. 45 degrees right anterior oblique. and lateral. The atrial septal puncture site was located immediately below the aortic valve level. probably in the fossa ovalis. for the first 80 patients. and at mid distance between the aortic valve level and the diaphragm for the last 110. Hemodynamic data were similar in both groups. Fluoroscopic guidance for atrial septal puncture seemed capital for patients with scoliosis or in whom a vascular distortion (e.g.. advanced pregnancy. right inferior vena cava absence) prevented a perfect parallelism between the needle curve and the needle outer index.
Holmium laser angioplasty after failed coronary balloon dilation: use of a new solid-state, infrared laser system, A new solid-state laser system was used in a case of saphenous vein graft occlusion untreatable by standard very low-profile balloon angioplasty. The 2100 nm infrared pulsed thulium/holmium: YAG laser successfully recanalized an obtuse marginal bypass graft without complications. The holmium laser has several advantages over excimer systems and may prove an effective adjunct or alternative to coronary balloon angioplasty.
Total occlusion of the circumflex artery with collateral supply from the conus artery, The conus artery has long been recognized as an important source of collateral blood supply to a significantly diseased left anterior descending artery. This artery which arises 50% of the time from a separate orifice in the right sinus of Valsalva may also provide collateral circulation to a diseased right coronary artery. To date. there have been no reported instances of the conus artery supplying collateral flow to a totally occluded circumflex artery. In this report we describe such a case in a patient with severe three vessel disease. The implications of such a finding in patient management are also discussed.
Angioplasty of an oversized venous bypass graft using two fixed wire systems, Oversized saphenous vein bypass grafts may be inadequately dilated using currently available coronary angioplasty catheters. The hugging balloon technique has been previously described for lesions in large saphenous vein grafts. We report the initial use of the hugging balloon technique using two fixed wire angioplasty catheters in an oversized saphenous vein graft.
Interpretation of cardiac pathophysiology from pressure waveform analysis: the left-sided V wave [clinical conference, The left-sided V wave is dependent on both left atrial and ventricular pressure/volume filling relationship. The cardiac rhythm and timing of atrial systole also influences the V wave. The morphology of the V wave can reflect the severity of mitral regurgitation with stenosis. but valve areas in this setting may be better assessed by a pressure half-time method. Finally. as queried in our first patient example. V wave alternans is a reflection of left ventricular pressure alternans in a failing heart. Other signs of poor left ventricular function in Figure 1 also included an elevated minimal diastolic pressure and markedly elevated left ventricular end diastolic pressure. Hemodynamic findings of poor left ventricular function will be addressed in detail in a later "Rounds.".
A technique for arthroscopic anterior cruciate ligament repair, Treatment options for anterior cruciate ligament (ACL) tears include rehabilitation therapy. derotation therapy. and surgical repair or reconstruction. This article presents an arthroscopic technique for reattaching the ACL that offers some advantages over other procedures. Advantages include avoiding exposure of the knee joint. improved cosmetic results. and reduced recuperation time.
Posterior cruciate ligament injuries, PCL reconstruction is not often necessary. Arthroscopic techniques using autograft or allograft substitution for the PCL probably bear more physiologic and anatomic likeness to the normal ligament than to tissue transfers posteriorly. The arthroscopic procedure is exacting and technically demanding. It is advisable to supplement the PCL reconstruction with an appropriate capsulorrhaphy when the posterior capsule. arcuate complex. or oblique popliteal ligament are also injured. In combined cruciate injuries. PCL reconstruction is notably easier when staged before reconstruction of the ACL.
Osteochondritis dissecans, Osteochondritis dissecans is a rare orthopaedic disorder of unknown etiology. Advances in CT and MRI scanning have increased our knowledge of the disorder. but arthroscopy remains the principle means of monitoring its progress. Arthroscopic surgery has displaced traditional arthrotomy in many instances and is useful in retrieval of loose bodies. drilling of osteochondral fragments. retrograde bone grafting. and abrasion arthroplasty. Arthrotomy continues to be the best method of pinning and bone grafting of detached lesions. Advances in transplant surgery now permit large craters to be patched with osteochondral allografts.
Weight lifting. Risks and injuries to the shoulder, The weight lifter's desire to achieve higher limits of performance coupled with the rotator cuff's unfavorable position during lifting often leads to shoulder injury. Proper lifting techniques and training habits could reduce the risk of injury. When chronic symptoms occur. however. arthroscopy can help diagnose the injury. and arthroscopic procedures for injuries such as rotator cuff chronic tendinitis and incomplete tears. and biceps tenosynovitis can be performed.
Arthroscopic treatment of Panner's disease, Panner's disease. or osteochondrosis of the capitellum. may actually be a continuum of disorders. In the past. such lesions were treated conservatively with surgery as a final option. With the advent of arthroscopy. a diagnosis can be made. and treatment with limited invasiveness instituted. This article reviews the diagnostic and therapeutic advantages of arthroscopic techniques in the treatment of Panner's disease.
Fetal drug therapy: principles and issues, The 1990s may revolutionize the care of the fetus and create new options in gene control. immunotherapy. and drug therapy not only to identify susceptible populations but to treat selectively that population without increasing the risk to the mother. Fetal therapy is a notable goal. even now somewhat within our grasp. No longer is the womb an isolated. forbidding environment. but it is accessible with such tools as magnetic resonance imaging. ultrasonography. CVS. Doppler. and sound clinical judgement. Current limitations in our understanding of the pharmacokinetics associated with these chemical temper our enthusiasm. The development of biomarkers for appropriate fetal drug therapy is to be encouraged. but also the development of fetal and maternal biomarkers that will assist the physician in actively avoiding inappropriate fetal drug therapy is necessary. whether dose or chemical dependent.
Maternal insulin to lower the risk of fetal macrosomia in diabetic pregnancy, Fetal macrosomia is a well-recognized adverse outcome associated with gestational diabetes. Weekly measurement of fasting and postprandial glucose should identify those with fasting (greater than or equal to 100 or 105 mg/dl) or postprandial (greater than or equal to 120 mg/dl 2 hours after a meal) hyperglycemia who are at increased risk for perinatal mortality. If the prevention of macrosomia is desired. the use of prophylactic insulin. initiated as early as possible. but at the latest before 36 weeks' gestation. without regard to glycemia is effective. Alternatively. glucose self-monitoring (four to six times daily with institution of insulin treatment when fasting glucose exceeds some arbitrary threshold such as 90 mg/dl or postprandial values exceed a threshold such as 100 mg/dl) is likely to be equally effective with fewer patients requiring insulin injections.
Indomethacin therapy in the treatment of symptomatic polyhydramnios, It appears that maternal indomethacin therapy may be a useful adjunct in selected cases of polyhydramnios. Initial evaluation should include glucose tolerance testing and a thorough search for fetal abnormalities by ultrasonography. In the patient with symptoms such as premature labor or respiratory compromise. an initial amniocentesis should be considered for decompression and fetal karotype. Oral indomethacin therapy can then be started. Although the optimal dose is unknown. a 25-mg oral dose every 6 hours appears adequate. Ultrasound assessment of amniotic fluid volume should be done once or twice weekly. If oligohydramnios develops. the indomethacin should be discontinued. and the amniotic fluid volume serially monitored. Fetal echocardiography should be considered in the first 24 hours after therapy has been initiated and weekly thereafter. Evidence of severe constriction of the ductus arteriosus or tricuspid regurgitation warrants discontinuation of the indomethacin; lesser degrees of ductal constriction can be treated by decreasing the dose of the medication.
Pharmacologic induction of fetal lung maturity, The consequences of a preterm birth are usually not secondary to a developmental abnormality but rather due to the immaturity of one or more organ systems. Because neonatal RDS is the most common and the most severe complication of a preterm delivery. a major emphasis has been placed on its prevention and/or treatment. Despite intensive research efforts directed at preventing or inhibiting preterm labor. to date there is no universally effective method that can be used in most patients. As a result. preterm birth will continue to occur and continue to challenge the health care provider. Several medications and hormones have been shown to stimulate endogenous surfactant production in the fetus. Their administration to women at risk of delivering preterm can decrease both the incidence and severity of neonatal RDS. The primary limiting factor with most agents is the need to delay birth for 48 to 72 hours to achieve maximum therapeutic effect. This mandates the obstetric health care provider not only identify parturients who will deliver preterm but also manage their intrapartum course to achieve maximum value from these pharmacologic agents. Lastly. in those patients in whom labor can be neither inhibited nor safely delayed. exogenous surfactant therapy offers real hope particularly to the very low birth weight baby. To obtain maximum benefit in the very premature infant. i.e.. less than 30 weeks' gestation. therapy ideally should begin immediately after birth and before the first breath. However. to offer such therapy. patients need to be identified during the intrapartum period.
Antenatal therapy to minimize neonatal intraventricular hemorrhage, Periventricular-intraventricular hemorrhage is an important problem. resulting in significant mortality and morbidity. Attempts to reduce this complication require an understanding of its pathogenesis. In this chapter a model was proposed. consisting of a series of events resulting in rapid changes of cerebral blood flow and intracranial pressure and leading to rupture of the unique fragile vessels of the germinal matrix and intraventricular regions. Understanding the beneficial physiologic changes induced by such agents such as phenobarbital and vitamin K and that such pharmacologic therapy must be started during the antenatal period has resulted in significant reductions of severe grades of IVH. Further prospective studies are needed to confirm these results using these two drugs alone and in combination. Other potentially beneficial drugs such as indomethacin should be investigated. Although the benefits of such therapy may improve perinatal outcome. the emphasis in our discipline should be the continued attempt to prevent the delivery of these VLBW infants.
Research involving fetal drug therapy: ethical, legal, and practical considerations, Fetal drug therapies have emerged as a promising avenue for the prevention or correction of disease during fetal or immediate postnatal life. Despite slow progress. several medications have been developed for in utero therapy of disorders which relate to fetal and neonatal pulmonary. cardiac. neurologic. and growth disorders. However. ethical and regulatory constraints require protection of the mother and fetus while causing no more than necessary additional risk. Appreciating these constraints will lead to the identification of pragmatic questions which should be answered before evaluating the efficacy and safety of a particular treatment or research proposal.
Ectopic pregnancy, The diagnosis and management of ectopic pregnancy is changing rapidly. More sensitive pregnancy tests and high-resolution transvaginal sonography are making the diagnosis of ectopic pregnancy easier and earlier. In the future. we may become more confident with the ultrasound diagnosis of some ectopic pregnancies such that laparoscopic confirmation will not be required. These patients may be treated with systemic methotrexate. However. at the present time laparoscopy is essential for diagnostic confirmation of most ectopic pregnancies. It is senseless for a skilled laparoscopist to perform a diagnostic laparoscopy. remove the laparoscope. and then proceed with laparotomy or some nonsurgical treatment. There is sufficient evidence in the literature to demonstrate that laparoscopic management of ectopic pregnancies is equally safe. equally effective. and less traumatic than laparotomy. It should replace laparotomy as treatment for most ectopic pregnancies. Unfortunately. there are not enough trained laparoscopists to manage the 88.000 ectopic pregnancies per year in the United States. Operative laparoscopy deserves more emphasis in postgraduate and residency training programs.
Transabdominal and transvaginal sonography of ovarian masses, This chapter outlined the sonographic appearances of most ovarian tumors using both transabdominal and transvaginal sonography. The use of transabdominal and transvaginal sonography for the early detection of ovarian carcinoma seems promising and should be pursued in several institutions as clinical trials.
Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine, The disposition of intravenous antipyrine and lorazepam. administered as model substrates for hepatic oxidative metabolism and conjugation. was evaluated in 50 children (mean age. 7.8 years; range. 2.3 to 17.8 years) with acute lymphocytic leukemia in complete remission and compared with a group of ten healthy adults. Antipyrine clearance normalized to body weight was significantly greater in children than in adults (0.91 versus 0.59 ml/min/kg; p = 0.012). but was not different when normalized to body surface area. In contrast. lorazepam total clearance (CL) and unbound clearance (CLu) normalized to body weight were not significantly different between children and adults but were smaller in children when normalized to body surface area (CL = 31.9 versus 40.6 ml/min/m2. p = 0.036; CLu = 352 versus 485 ml/min/m2. p = 0.010). The mean lorazepam fraction unbound in children was 0.087. which was not different from adult volunteers (0.084). This study has identified significant differences between children and adults in the disposition of these two compounds. with higher milliliter per minute per kilogram clearance for antipyrine but not lorazepam.
Responsiveness of peripheral veins to vasodilators and the effect of nifedipine on alpha-adrenergic responsiveness in hypertension, Vasodilators have varying hemodynamic properties that may be important in determining their efficacy for different disorders. We used the dorsal hand vein technique to measure the effects of several vasodilators infused locally and to measure the action of systemically administered nifedipine. The venodilatory effects of hydralazine. verapamil. diazoxide. and nitroglycerin were determined in peripheral veins of healthy subjects. The potency (ED50. the dose producing half-maximal response) was as follows: nitroglycerin (0.0007 micrograms/min) greater than verapamil (6.5 micrograms/min) greater than diazoxide (75 micrograms/min) greater than hydralazine (660 micrograms/min). The effect of oral nifedipine on alpha-adrenergic responsiveness of hand veins was determined. Nifedipine given in therapeutic doses for the treatment of hypertension was associated with a threefold increase in the ED50 for phenylephrine (92 to 277 ng/min; p less than 0.05) and norepinephrine (2.9 to 11.5 ng/min; p less than 0.05). Therapeutic doses of nifedipine are associated with measurable shifts in the dose-response curves to these two alpha-adrenergic agonists in the hand vein. The hand vein technique can be used not only to compare the potency of locally infused drugs but also to measure venous effects of vasoactive drugs at therapeutic concentrations achieved after systemic administration.
Antibiotic use after cefuroxime prophylaxis in hip and knee joint replacement, The amount of additional antibiotics measured by defined daily dose (DDD) methods after 2651 hip and 362 knee replacements was assessed after prophylaxis with one or three doses (1502/1511 patients) of cefuroxime. No differences were observed between the two regimens with respect to total amount. type. indication. and duration of additional antibiotics. The incidence of joint sepsis did not differ significantly between the two trial arms. but the sample was too small for definite conclusions. There were 11.4 DDD/100 bed days of additional antibiotics used in 21% of patients after hip replacement and 15.7 DDD/100 bed days in 31% after knee replacement. For wound problems. 3.8 and 6.9 DDD/100 bed days were given in the hip- and knee-replacement groups. For distant infection. 6.5 DDD/100 bed days was administered in both groups. Duration of therapy varied only in relation to indication. Prescribed were penicillins (43% to 50%). sulfonamides (18%). cephalosporins (10% to 16%). and nitrofurantoin (8% to 13%); drug use was related to the type of infection.
Submaximal endurance exercise performance during enalapril treatment in patients with essential hypertension, In a double-blind randomized crossover study of 10 patients with mild essential hypertension. the influence of antihypertensive treatment with the angiotensin-I converting enzyme inhibitor enalapril (a single dose of 10 mg.day-1) on submaximal endurance exercise performance at a work rate eliciting a heart rate of 150 beats/min was studied. Resting and exercise blood pressure were significantly reduced during enalapril therapy. Heart rate was unaffected. Submaximal endurance exercise performance was reduced by 12% (p = 0.06). Plasma lactate concentrations were significantly increased and serum nonesterified fatty acid concentrations were decreased during exercise in patients receiving enalapril treatment. Plasma glucose and potassium levels and serum glycerol concentrations were not influenced by enalapril treatment. Because the impairment of endurance performance during enalapril treatment is relatively small compared with the reductions caused by other antihypertensive agents. such as beta-adrenoceptor blocking agents or diuretics. it is of minor clinical importance for most physically active patients with hypertension.
Lymphocyte transformation and thiuram sensitization, The use of a lymphocyte transformation test (LTT) to confirm allergic contact dermatitis from thiurams has been investigated. The responses of peripheral blood mononuclear cells (PBMC) from thiuram-sensitive and non-sensitive individuals following culture with dimethylcarbamoyl-protein (human serum albumin; HSA) and dimethylthiocarbamoyl-HSA conjugates has been compared. Only PBMC from those patients who were patch-test-positive with thiuram-mix and sensitized to tetramethylthiuram monosulphide (TMTM) or TMTM and tetramethylthiuram disulphide (TMTD) exhibited significant proliferative responses to these conjugates. Thiuram-patch-test-negative patients and control donors with no history of allergic contact dermatitis failed to mount a significant response to any concentration of either conjugate. Two of the thiuram-sensitive patients were also nickel-patch-test-positive. and PBMC isolated from these donors. but not from nickel-patch-test-negative patients. proved positive in a nickel LTT. The data reveal that relevant hapten-protein conjugates are capable of provoking specific human lymphocyte proliferative responses in vitro. and that. using this technique. the LTT can. in principle. be used for the investigation and/or diagnosis of skin sensitization to lipophilic contact allergens.
A probable role for vaccines containing thimerosal in thimerosal hypersensitivity, We patch tested 141 patients with 0.05% aq. thimerosal and 222 patients with 0.05% aq. mercuric chloride. including 63 children. The frequency of positive patch test reactions to thimerosal was 16.3%. There was a marked preponderance in the young age groups after vaccination. while none of 36 infants (aged 3-48 months) reacted to thimerosal. Positive reactions to mercuric chloride were found in 23 (10.4%) of 222 patients. We also sensitized guinea pigs with diphtheria-pertussis-tetanus (DPT) vaccine containing 0.01% thimerosal and succeeded in inducing hypersensitivity to thimerosal. From patch testing in humans and animal experiments. it is suggested that 0.01% thimerosal in vaccines can sensitize children. and that hypersensitivity to thimerosal is due to the thiosalicylic part of the molecule and correlates with photosensitivity to piroxicam.
The loss of contact sensitization in man, Little is yet known about the duration of contact sensitivity. but frequent exposure of a target to allergen seems to reduce skin reactivity. The aim of this study was to study the persistence of a specific contact sensitivity in 66 patients with alopecia areata. previously sensitized to DNCB (31 patients) and SADBE (35 patients) between 1978-1985. Patch tests were performed with 0.020 ml of different concentrations of DNCB or SADBE in acetone (0.05%. 0.10%. 0.20%. 1%). The results were read in a standardized manner. Of 66 patients. 47 (71%) had positive reactions and 19 (29%) negative. 8 of the 19 negative patients had been treated with DNCB. 11 with SADBE. Approximately 1/3 of the patients previously sensitized had lost their original sensitivity. and this did not seem to be time-dependent. This phenomenon seemed to be clinically correlated because the majority of the patients were from the "low responders" group. We think that acquired unresponsiveness to topical antigen in man is a possible phenomenon. but that it occurs more rarely than in mice and guinea pigs.
Contact dermatitis due to topical treatment with garlic in Hong Kong, Contact dermatitis due to garlic is usually due to handling of garlic for cooking. Among the Chinese. garlic is also used as a form of topical medicament. 8 patients developed contact dermatitis after rubbing the cut end of a fresh garlic bulb onto the skin to treat fungal and other infections at the groin. neck. lower limb. hand or face. The distribution and morphology of the lesions were different from the classical form as described in the literature. Repeated open application tests with fresh garlic were all positive and patch tests with garlic extract were all negative. 5 controls tested by repeated open application with fresh garlic juice were also positive and patch tests in 10 controls with garlic extract were also negative. The results confirmed that the contact dermatitis was due to irritation. The patients were treated successfully with topical fluorinated steroid. For prevention. the practice of direct application of fresh garlic onto the skin for treating infections should be discouraged.
Tussockosis: an outbreak of dermatitis caused by tussock moths in Singapore, An outbreak of acute pruritic rash occurred in March 1990 among 141 residents of a high-rise public housing estate in Bukit Panjang. Singapore. The typical rash consisted of urticarial lesions distributed over the limbs and trunk. The outbreak was associated with a transient increase in tussock moths in the residential estate following an unusual. short dry spell. The aetiology was established when patch tests with crude moth material produced similar eruptions in 5 out of 7 adult volunteers between 40 min and 12 h. Pharmacological experiments with an aqueous extract of moth hairs in isolated guinea pig ileum elicited a response similar to that induced by histamine.
Contact sensitivity (allergic contact dermatitis) to bis(tri-n-butyltin) oxide in mice, Contact sensitivity (allergic contact dermatitis) to bis(tri-n-butyltin) oxide (TBTO) was demonstrated in the mouse. TBTO (in an acetone:olive olive oil vehicle) or acetone:olive oil alone (as a control) were applied to the shaved flank under an occlusive patch and animals were challenged on the dorsum of the ear 6 days later. Ear swelling was then measured using an engineer's micrometer. 2. 24. 48 or 72 h thereafter. Significant differences in ear swelling between control and TBTO-sensitized animals were found 24 h after challenge: thereafter the elicitation reaction declined rapidly whilst irritant swelling in control animals increased. Maximal elicitation of TBTO sensitivity could only be elicited by concentrations of TBTO that caused irritation. In a separate experiment. a single application of TBTO to the ears of naive animals provoked increase in auricular lymph node weight. cell yield and proliferation of lymph node cells during overnight culture. These data support the conclusion that TBTO is a contact sensitizer and illustrate the potential usefulness of the quantitative methods of contact sensitivity assessment which have been developed in the mouse.
A follow-up study of occupational skin disease in Western Australia, From a total of 993 previously reported cases of occupational skin disease (OSD). 954 (96%) were contacted and 711 (75%) examined. The review time (i.e.. period from original diagnosis of OSD until review) varied from a minimum of 6 months to a maximum of over 8 years. Over 60% of cases were reviewed more than 2 years after the original diagnosis was made. More than 50% were still suffering from OSD or consequences related thereto. Clearance was less likely in those who remained in their original. or similar. occupational environment. However. of those who changed their job due to OSD. many suffered aggravation of the dermatitis from factors in the new work environment. Over 10% of cases had evolved into a persistent postoccupational dermatitis without obvious cause. This condition is responsible for considerable impairment and is of medicolegal importance due to confusion as to its relationship to the original occupational factors.
Contact sensitization to textile dyes: description of 100 subjects, We have described 100 subjects sensitized to textile dyes. Of these. 16 had clinically been suspected of having a textile dermatitis from among 1145 patients referred for patch testing. 41 patients were identified from among 861 consecutive subjects tested with the GIRDCA (Italian Research Group on Contact and Environmental Dermatitis) standard series supplemented with 4 disperse dyes (Disperse Blue 124. Disperse Red 1. Disperse Yellow 3. Disperse Orange 3). The remaining 43 patients were identified from among 746 subjects tested with the GIRDCA standard series. supplemented with the 4 disperse dyes mentioned above and a further series of 12 other textile dyes. The clinical picture was extremely variable: most patients had a typical eczematous dermatitis. but we also observed persistent erythematous-wheal-type reactions. a transient urticarial dermatitis and an erythema-multiforme-like eruption. Among these textile dyes. Disperse Blue 124 caused most reactions. With the addition of the 4 disperse dyes to the GIRDCA standard series. we identified 4.8% sensitized to textile dyes. a much higher figure than the 1.4% observed among patients being patch tested on the basis of their history and the clinical findings; the addition of a further 12 textile dyes to the series further increased the detection rate to 5.8%. We stress the importance of routinely patch testing with textile dyes. which can help to elucidate the cause of certain kinds of atypical dermatitis.
Patch testing with amalgam at various concentrations, 27 patients with positive D3 reactions on patch testing to 3 mercury screening allergens were patch tested with 13 mercury patch test preparations. 6 inorganic and 7 organic. and amalgam 20% pet. The 13 patients (all women) showing positive reactions to 20% amalgam were then patch tested to reducing concentrations. 2 patients reacted down to 1%. 4 down to 2%. 4 down to 5%. 2 down to 10% and 1 only to 20%. a total of 10 of the 13 patients therefore reacting to the 5% concentration of amalgam. The appropriate patch test concentration of amalgam is discussed and the clinical significance and female preponderance of amalgam reactivity suggested as being worthy of further investigation.
Patch test responses to rockwool of different diameters evaluated by cutaneous blood flow measurement, Rockwool is a man-made mineral fiber used mainly for insulation. which can cause mechanical skin irritation. This study was performed to evaluate the irritant potential of rockwools of different diameters and to compare the change of blood flow. measured by laser Doppler flowmetry. at different patch test occlusion times with rockwools. Rockwool A (mean diameter 4.20 +/- 1.96 mu) was more irritating than rockwool B (mean diameter 3.20 +/- 1.5 mu). The difference was more clearly observed in a 48-h patch test than in an 8-h or 24-h test. We concluded that laser Doppler blood flow measurement was a useful experimental tool for the evaluation of irritant patch test responses to mechanical irritants like rockwool. and that 48 h or more of occlusion time was necessary to produce irritant patch test responses to certain types of rockwool.
alpha-Peroxyachifolid and other new sensitizing sesquiterpene lactones from yarrow (Achillea millefolium L., Compositae), Yarrow. Achillea millefolium L.. is one of the commonest weeds of the Compositae family. Cases of allergic contact dermatitis have been described since 1899. Although 10 sesquiterpene lactones (SL) and 3 polyines have previously been identified. the sensitizers of yarrow have escaped detection. A reinvestigation of short ether extracts of yarrow revealed the presence of 5 unsaturated hitherto unknown guaianolides of peroxide character. The main SL. identified as a strong sensitizer in guinea pig sensitization experiments. was named alpha-peroxyachifolid. The minor SL also contribute marginally to the sensitizing capacity. while other known yarrow constituents like dehydromatricaria ester and pontica epoxide appear to play no role. A 5-year follow-up (1985-1990) of Compositae-sensitive patients showed that more than 50% reacted when tested with a short ether extract of yarrow. Exacerbation of the patch test sites by irradiation with UV light was never observed.
Allergic contact dermatitis from para-tertiary-butylphenol-formaldehyde resin (PTBP-FR) in athletic tape and leather adhesive, 4 girls with severe allergic contact dermatitis from a brand of athletic tape and a cobbler with allergic contact dermatitis from leather adhesive are presented. Alkylphenol resin with unknown chemical structure had been compounded in both products. One of the girls developed foot dermatitis later from the adhesive used on the inside of new sneakers. By patch testing and chemical analysis of alkylphenol resin and the products. the 5 patients were given a specific diagnosis of allergic contact dermatitis from PTBP-FR.
Evaluation of calcium magnesium acetate and road salt for contact hypersensitivity potential and dermal irritancy in humans, Calcium magnesium acetate (CMA) and road salt are both de-icing agents to which workers may be dermally exposed. A commercial formulation of CMA (Chevron Ice-B-Gon Deicer) and road salt were tested in a human repeat insult patch test to evaluate the contact hypersensitivity potential of these materials and to evaluate irritation following single or multiple applications. 72 of the initial 82 panelists completed the study. CMA and road salt (each at 10% and 30% w/w in distilled water; 0.3 ml) were administered under occlusive patches on the forearm for 14 h 3 x per week for 3 weeks. The panelists were challenged 2 weeks later; 2 panelists who had mild reactions were subsequently rechallenged 6 weeks later. Neither CMA nor road salt produced contact hypersensitivity in any panelists. Following the first application. moderate acute irritation was observed only at 1 skin site exposed to 30% road salt. Repeated exposure to CMA or road salt produced mild to moderate irritation. The highest incidence of moderate irritation was observed with 30% road salt. Thus. neither material is expected to cause significant dermal effects in exposed workers. CMA is expected to cause dermal irritation equivalent to or less than that caused by road salt.
Prevalence of epilepsy in Rochester, Minnesota: 1940-1980, The prevalence of epilepsy in Rochester. Minnesota has been determined for a specific date in each of 5 decennial census years. Individuals with a diagnosis of epilepsy (recurrent unprovoked seizures) who were known to have experienced a seizure or who had received antiepileptic medication in the preceding 5 years were considered active prevalence cases. By this definition. the age-adjusted prevalence per 1.000 population. increased steadily from 2.7 in 1940 to 6.8 in 1980. At each of five prevalence dates. for all prevalence cases. 60% had epilepsy manifest by partial seizures. and 75% had no known etiology. Prevalence was higher for males than females for all except the last prevalence day. After 1950. prevalence tended to increase with advancing age and was highest in the oldest age groups. On the average. the 1980 prevalence cases had epilepsy less than 10 years and greater than 50% had their first diagnosis in the first 20 years of life.
Magnetic resonance imaging of intractable complex partial seizures: pathologic and electroencephalographic correlation, Prior studies indicate variable usefulness of magnetic resonance imaging (MRI) in the evaluation of patients with complex partial seizures (CPS). but sensitivities as low as 12% have been reported. We analyzed the MRI examinations of 20 patients with medically refractory CPS who later underwent resection of the seizure focus proven by electroencephalography (EEG). MRI studies were correlated with surgical pathology in all patients. Eleven of the 20 CPS patients had mesial temporal sclerosis (MTS). Seven of the 11 (64%) exhibited an MRI abnormality at the site of the EEG-demonstrated histopathologic focus. MRI abnormalities included temporal lobe hypoplasia or atrophy (four patients). and increased signal intensity on long repetition time (TR) sequences (three patients). Four patients had no MRI abnormalities corresponding to the histopathologic focus. Nine of the 20 CPS patients had other abnormalities responsible for the seizures. including astrocytoma. cryptic vascular malformation. hamartoma. polymicrogyria. tuberous sclerosis (forme fruste). arachnoid cyst. and congenital hemiatrophy. No patient had normal MRI studies. Our single most useful MRI sequence was the coronal long TR/dual echo sequence. using cardiac gating and first-order gradient moment nulling to diminish flow-related artifacts that could hinder evaluation of medial temporal lobe structures.
Seizures of fronto-orbital origin: a proven case, Distinguishing characteristics of seizures of frontal origin have not been clearly delineated. We describe a case of seizures of proven fronto-orbital origin to provide further definition of characteristics of seizures arising in that lobe. A 36-year-old man had medically intractable seizures since age 8 years. Clinically the seizures were stereotyped. with cessation of activity followed by turning of head and body to the right and then by struggling. kicking. and vocalizations indicating fear. Total seizure duration was approximately 30 s. with an apparent abrupt return of consciousness. The interictal scalp EEGs were similar to those of primary generalized epilepsy. with bisynchronous though asymmetric epileptiform activity anteriorly. Ictal scalp recordings were not localizing. Recordings from bilateral frontal and temporal subdural electrodes showed an electrical focus in the right fronto-orbital region which was confirmed by electrocorticography (ECoG) at the time of craniotomy. The right fronto-orbital cortex was resected and on pathologic examination showed gliotic tissue and intracytoplasmic neuronal inclusions of periodic acid-Schiff (PAS)-positive granules consistent with lipofuscinosis. The patient has remained seizure-free for 6 years after operation.
Paroxysmal kinesigenic choreoathetosis with abnormal electroencephalogram during attacks, An 18-year-old man with paroxysmal kinesigenic choreoathetosis (PKC) showed rhythmic electroencephalographic (EEG) discharges of 5-Hz spikes over the entire scalp during episodes. The EEG findings in this case suggest that PKC may have an epileptogenic basis.
Seizures in series: similarities between seizures of the west and Lennox-Gastaut syndromes, We observed seizures resembling infantile spasms in patients with Lennox-Gastaut syndrome (LGS). Infantile spasms. the type of seizures that occurs in patients who have West syndrome. have been well characterized by video-EEG studies and typically occur as a series of sudden generalized flexor or extensor jerks. The seizure types that occur in LGS have not been as clearly delineated. Some patients with West syndrome (WS) in early infancy later develop LGS. Using intensive video-EEG monitoring. we evaluated 14 LGS patients who had seizures that occurred in series. Clinically. the seizures greatly resembled infantile spasms. and the ictal EEG changes were identical to those that occur with infantile spasms. These findings expand the number of features known to be shared by these two syndromes and strengthen the hypothesis that the two syndromes represent age-related manifestations of similar epileptogenic processes.
Familial aggregation and severity of epilepsy, Genetic models for complex diseases frequently assume that genetic factors play a greater role in severe forms than in mild forms of disease. This study examined familial aggregation of epilepsy in relation to two measures of severity: duration and remission. The study population comprised 358 offspring born in Rochester. MN. U.S.A.. to parents with epilepsy who were diagnosed in Rochester between 1935 and 1979 and followed for greater than or equal to 5 years after the first seizure. Cox proportional hazards analysis was used to examine the effects of duration of the parent's epilepsy (less than 5 vs. greater than or equal to 5 years) and remission of the parent's epilepsy (greater than or equal to 5 years seizure-free) on risk of unprovoked seizures in offspring. The univariate rate ratio (RR) for parent's duration (long vs. short) was 1.1 (95% confidence interval 0.32-3.57). The RR for parent's remission was 2.5 (0.55-11.41). reflecting a higher risk for offspring of remitting parents. which was not statistically significant. Multivariate analysis was used to control for three other parental attributes associated with offspring seizure risk: sex. age at onset of seizures (less than 20 vs. greater than or equal to 20 years). and seizure type (absence vs. other). The RR for duration was not substantially changed in this analysis (1.2; 0.37-4.16). However. the RR for remission dropped to 1.2 (0.25-5.97). suggesting that the higher risk in offspring of remitting parents was largely explained by confounding with other factors that influence offspring seizure risk.
Ralitoline: a reevaluation of anticonvulsant profile and determination of "active" plasma concentrations in comparison with prototype antiepileptic drugs in mice, Ralitoline (RLT) is a new thiazolidinone derivative with potent anticonvulsant activity in different seizure models. During Phase I studies. RLT was well tolerated in human volunteers and showed linear pharmacokinetics in the dose range tested (up to 150 mg). Since RLT will soon be entering clinical Phase II studies. we were interested in obtaining predictive data for effective plasma concentrations in patients. For this purpose. the anticonvulsant potency of RLT was determined in four seizure models in mice. and plasma levels were measured at time of peak drug effect. The four models were the threshold for maximal (tonic extension) electroshock seizures (MES). the threshold for clonic seizures determined by i.v. infusion of pentylenetetrazol (PTZ). the traditional MES test with supramaximal (50 mA) stimulation. and generalized clonic seizures induced by s.c. administration of PTZ. Furthermore. median minimal "neurotoxic" doses (TD50s) were determined by the rotorod and chimney test for calculation of protective indices. All data obtained for RLT were compared with data obtained with standard antiepileptic drugs: phenobarbital. phenytoin. valproate. and diazepam. The onset of anticonvulsant action after i.p. injection of RLT was very rapid. and the peak drug effect was already obtained after 2 min. In the MES models. RLT was the most potent compound. "Active" plasma levels ranged from approximately 300 ng/ml in the MES threshold test to approximately 1.300 ng/ml in the MES test. RLT was also capable of increasing the PTZ threshold. whereas. possibly because of its short duration of action in mice. it was not very active in the s.c. PTZ seizure test.
Anticonvulsant profiles of the potent and orally active GABA uptake inhibitors SK&F 89976-A and SK&F 100330-A and four prototype antiepileptic drugs in mice and rats, The anticonvulsant profiles of two potent and orally active gamma-aminobutyric acid (GABA) uptake inhibitors. 1-(4.4-diphenyl-3-butenyl)-3-piperidine-carboxylic acid hydrochloride (SK&F 89976-A) and 1-(4.4-diphenyl-3-butenyl)-1.2.5.6-tetrahydro-3-pyridine-carboxylic acid hydrochloride (SK&F 100330-A). were determined with a battery of well-standardized tests in mice and rats and compared with the profiles of phenytoin (PHT). carbamazepine (CBZ). valproate (VPA) and clonazepam (CZP) when subjected to the same tests. ED50 values were calculated and compared with TD50 values for minimal motor impairment to provide protective indexes (PI = TD50/ED50). The anticonvulsant profiles of SK&F 89976-A and SK&F 100330-A were similar and suggest that these compounds raise the threshold for seizure initiation rather than inhibit seizure spread. Like intraperitoneal (i.p.) PHT. CBZ. VPA. and CZP. SK&F 89976-A and SK&F 100330-A inhibited seizures in corneally kindled rats. The profiles of SK&F 89976-A and SK&F 100330-A were most similar to that of CZP and virtually opposite to that of PHT. Intraperitoneal SK&F 100330-A provided complete protection against pentylenetetrazol-induced seizures [subcutaneous (s.c.) PTZ] in mice but was ineffective against seizures induced by maximal electroshock (MES) at doses slightly greater than its TD50. SK&F 100330-A provided complete protection against picrotoxin-induced seizures (s.c. Pic) and against both clonus and forelimb tonic extension induced by NMDA N-methyl-D-aspartate [intracerebral ventricular (i.c.v.)-NMDA] in mice; however. SK&F 100330-A was ineffective against seizures induced by bicuculline (s.c. Bic) and strychnine (s.c. Strych) at doses slightly greater than its TD50. SK&F 89976-A was similar but provided partial protection against NMDA-induced clonus.
Metastatic basal cell carcinoma: report of twelve cases with a review of the literature, Metastatic basal cell carcinoma was found in 12 patients at the University of Wisconsin Mohs Surgery Clinic during the period 1936 to 1989. All patients were white men. The time of onset of the primary tumor ranged from childhood to 71 years. Eleven patients had previous treatment for basal cell carcinoma; two patients had received x-ray radiation to the face for teenage acne. The locations of the primary basal cell carcinomas were the face (n = 10). back (n = 1). and arm (n = 1). The primary tumors ranged from 3.6 x 3.0 to 20.0 x 7.0 cm. The interval from onset to the first sign of metastases ranged from 7 to 34 years. In all cases. the primary tumor was histologically identical to the metastatic lesion. Perineural extension of the basal cell carcinoma in the primary lesion was found in five cases. Regional lymph nodes were the most frequent site of metastasis. Treatment consisted of a combination of surgery. radiation. and chemotherapy. Only two patients survived more than 5 years after surgical treatment. One patient has survived 25 years and is still alive.
Intralesional interferon alfa-2b in the treatment of basal cell carcinoma. Immunohistochemical study on cellular immune reaction leading to tumor regression, Four patients with basal cell carcinomas were treated with intralesional injections of interferon alfa-2b (1.5 million IU per injection) three times a week for 2 weeks. Histopathologic examination of biopsy specimens of the lesions confirmed the absence of basal cell carcinoma in all cases 4 weeks after completion of therapy. A dense mononuclear cell infiltrate and numerous ectatic blood vessels were present in the dermis at the sites of previous basal cell carcinoma. Immunohistologic analysis of the dermal infiltrate revealed a marked increase of Leu-4+ T cells with a slight predominance of Leu-3+ helper/inducer T cells over Leu-2+ suppressor/cytotoxic T cells. Most of the dermal infiltrate expressed HLA-DR antigen. In addition. Leu-11+ natural killer cells were observed in the dermal infiltrate. Immunohistologic changes in the skin lesions at the sites of previous basal cell carcinoma suggest that intralesional interferon alfa-2b acts on tumor cells by enhancement of local T-cell-mediated immune responses.
A double-blind, vehicle-controlled study evaluating masoprocol cream in the treatment of actinic keratoses on the head and neck, This double-blind. vehicle-controlled. multicenter study evaluated the efficacy and safety of a new topical antineoplastic agent. masoprocol. in the treatment of actinic keratoses of the head and neck. Of the 113 patients who applied topical masoprocol twice a day for 14 to 28 days. there was a mean decrease in actinic keratoses from 15.0 to 5.4 and a median percent reduction from baseline actinic keratosis count of 71.4% at the 1-month follow-up visit. Comparable numbers for the vehicle-treated group were 13.4 to 11.1 actinic keratoses and 4.3% median percent reduction. Irritation. as manifested by erythema or flaking. occurred in 61.5% of topical masoprocol-treated patients versus 26.7% of those treated with vehicle and did not correlate with clinical response. Topical masoprocol appears to be useful in the treatment of actinic keratoses.
Topical photoprotection for hereditary polymorphic light eruption of American Indians, We evaluated the photoprotective efficacy of a broad-spectrum sunscreen containing a UVA screen (butyl methoxydibenzoylmethane) and a UVB screen (octyl dimethyl p-aminobenzoic acid) in patients with hereditary polymorphic light eruption. At least 18 of the 30 patients who enrolled in the study were sensitive to sunlight through window glass. an indication of UVA sensitivity. Of the 21 patients who completed the clinical trial. the physician's evaluation was that 18 (86%) obtained good to excellent results. Self-evaluation by the patients revealed that 16 (76%) noted more photoprotection than from previous treatments.
Ultrastructural observations on 'foam cells' and the source of their lipid in verruciform xanthoma, Verruciform xanthomas occur on mucocutaneous surfaces and are characterized by hyperkeratosis. acanthosis. and the occurrence of "foam cells" stuffed with lipid surrounding capillaries in the dermis between rete pegs. Ultrastructural examination of a lesion on the penis revealed the presence of melanocytes with many lipid droplets in the basal layer of the epidermis. We suggest that they are a major source of the lipid of the "foam cells." However. this study provides no information as to the nature or lineage of the "foam cells.".
The five-year cure rate achieved by cryosurgery for skin cancer, Cryosurgery was used to treat 3540 new basal cell and squamous cell carcinomas of the skin from 1971 to 1989; a cure rate of 98.4% was achieved. To determine the 5-year cure rate in more recent years. the results of treatment of 684 nonmelanotic skin cancers from 1980 to 1984 were reviewed. In the group of 628 basal cell carcinomas. the 5-year cure rate was 99.0%. In the group of 52 squamous cell carcinomas. the 5-year cure rate was 96.1%. In the series were also four patients with basosquamous cell carcinomas. all of whom were recurrence free for 5 years or more. The overall 5-year cure rate in the 684 cases was 98.8%. On the basis of these data and our cosmetic results. we conclude that cryosurgery is an effective treatment that compares favorably with other established methods of therapy.
Therapeutic use of cytokines in dermatology, Cytokines are glycoproteins produced by many different cells. Via binding to specific receptors on target cells they regulate the activation. differentiation. and proliferation of immune and nonimmune cells. After injury keratinocytes synthesize and release cytokines such as interleukins. colony stimulating factors. and growth factors. In addition. a network of interacting cytokines appears to be crucial to maintain proper balance. Dysregulation may contribute to certain diseases. particularly those of infectious and autoimmune origin. Therefore many of these mediators appear to be promising candidates to treat infectious and malignant diseases. This article briefly discusses the most important cytokines. Newly developed regimens with cytokines to treat cutaneous disorders will be reviewed.
Classic Kaposi's sarcoma: T-lymphocyte subsets, T4/T8 ratio, and NK cell activity, Lymphocyte function as expressed by T-lymphocyte subsets and natural killer cell activity was evaluated in a group of Israeli patients with classic Kaposi's sarcoma. T-cell subsets were examined in 28 patients. 14 with lesions limited to the lower extremities and 14 with diffuse cutaneous or systemic involvement. CD4 and CD8 lymphocytes and CD4/CD8 ratio were in the normal range in all patients. and mean values of the entire group were similar to a control group. However. CD8 was in the upper limits of the normal range in some patients with diffuse cutaneous or systemic involvement. This factor led to a significantly decreased CD4/CD8 ratio in that group as compared with the group of patients with the disease limited to the lower extremities. Mean values of natural killer cell activity in three effector/target cell ratios were significantly decreased in 13 of the patients with Kaposi's sarcoma with lesions limited to the lower extremities and in all of the patients with normal T-cell subsets and CD4/CD8 ratios.
Salt-split human skin substrate for the immunofluorescent screening of serum from patients with cicatricial pemphigoid and a new method of immunoprecipitation with IgA antibodies, In patients with cicatricial pemphigoid. immunoglobulins (usually IgG) and complement are deposited within the dermoepidermal junction and are detected by direct immunofluorescent staining of perilesional mucous membrane and/or skin with fluorescein-labeled antibodies to human immunoglobulins. Although rare. some patients also have circulating low-titer. anti-basement membrane zone autoantibodies. In this study. we report 11 patients with the clinical. histologic. and immunologic criteria for cicatricial pemphigoid who had circulating anti-BMZ autoantibodies as demonstrated by positive indirect staining of a normal human skin that had been fractured through the dermoepidermal junction by prolonged incubation in a cold. 1 mol/L sodium chloride solution. On this salt-split human skin substrate. 9 of the 11 patients (82%) had autoantibodies that bound to the epidermal roof. one serum stained only the dermal floor. and one serum stained both sides of the separation. The predominant class of immunoglobulin in the patients' sera that bound to the substrate was IgA; IgA was the single immunoglobulin in 55% and was associated with IgG in 18%. IgG was the only immunoglobulin detected in 27% of the cases. No specific protein was detected by either Western immunoblot or a new IgA immunoprecipitation procedure.
Low-dose weekly methotrexate for unusual neutrophilic vascular reactions: cutaneous polyarteritis nodosa and Behcet's disease, Low-dose weekly methotrexate therapy has been used to treat patients with psoriasis for more than 20 years. This regimen has also been used to treat rheumatoid arthritis. inflammatory bowel disease. primary sclerosing cholangitis. and corticosteroid-dependent asthma. We report two patients with Behcet's disease with cutaneous neutrophilic vascular reactions and three with cutaneous polyarteritis nodosa who responded dramatically to low-dose weekly methotrexate therapy.
Gypsy moth caterpillar dermatitis--revisited, Gypsy moth caterpillar dermatitis is a pruritic. papular. urticarial eruption on exposed skin that occurs most commonly after direct contact with the first instar larva of the gypsy moth (Lymantria dispar). We present two case reports to illustrate its clinical and histopathologic features. Both cases occurred during the spring of 1990 and coincided with the greatest infestation of L. dispar in the Northeast to date. The pathogenesis of this distinctive gypsy moth dermatitis most likely involves histamine release by the caterpillar and a delayed hypersensitivity reaction in its host.
Cicatricial pemphigoid, Cicatricial pemphigoid is a subepidermal blistering disease that involves the mucous membranes and the skin. The oral cavity and the eye are most frequently involved. The clinical course is of long duration. and often there is significant scarring that can have devastating sequelae. The majority of the patients are elderly. The disease is characterized by the in vivo deposition of an anti-basement membrane zone antibody. The anti-basement membrane zone antibody cannot be detected in the circulation by routine laboratory techniques. The pathogenesis is poorly understood. and the cause is not known. Cicatricial pemphigoid may remain localized to the oral cavity or the eye or the skin (Brunsting-Perry variety). or it may be generalized. It rarely occurs in children. and it may be drug induced. Efforts must be made to differentiate cicatricial pemphigoid from bullous pemphigoid. epidermolysis bullosa acquisita. linear IgA bullous disease. and other vesiculobullous disease. Early recognition and treatment can improve the prognosis and avoid surgical intervention. Topical therapy is beneficial and expedites healing. Intralesional corticosteroids are effective and can help reduce the dose of systemic steroids. Most patients require systemic corticosteroid therapy. Dapsone is also useful in treating cicatricial pemphigoid. especially in patients in whom systemic steroids are ineffective or in whom they have to be discontinued because of side effects. Immunosuppressive agents (azathioprine or cyclosphosphamide) are indicated in patients with progressive disease. Occasionally both drugs may be needed.
Angioedema: manifestations and management, Angioedema is characterized by localized swelling of sudden onset affecting the skin and/or mucous membranes. It can be classified into hereditary and acquired forms. Hereditary angioedema is a rare disease inherited as an autosomal dominant trait and caused by a deficiency of C1-esterase inhibitor. Acute attacks are life threatening and cannot be managed by antihistamines. corticosteroids. or adrenergic drugs. Prophylactic therapy is possible with danazol or stanozolol. Acquired angioedema includes nonhereditary C1-esterase inhibitor deficiency; idiopathic. allergic. and drug-induced forms; angioedema associated with lupus erythematosus and hypereosinophilia; and angioedema caused by physical stimuli. Treatment of these forms of angioedema depends on identifying and avoiding the cause. induction of tolerance. or symptomatic treatment with systemic antihistamines.
Pharmacologic therapy for urticaria, Treatment of chronic urticaria presents a challenge to both practitioner and patient. Traditional H1 antagonists with good efficacy but substantial side effects are being supplanted in many cases by nonsedating H1 antagonists such as terfenadine and astemizole. Antidepressant medications and combinations of H1 and H2 antagonists offer improved results for selected patients. Further development and investigation of mast cell stabilizers and inhibitors of urticaria mediators other than histamine hold promise. A better understanding of the underlying pathogenesis remains the greatest hope of formulating rational and effective therapy.
Mast cells and their role in urticaria, Mast cells are the primary effector cell type in urticaria and angioedema. Recognition of different types of mast cells has increased the understanding of their cell biology and may help refine the therapy of human allergic diseases. Mast cells containing chymase and tryptase (MCTC) and tryptase alone (MCT) are two distinct types distinguished on the basis of the neutral protease composition of their granules. MCT cells are distributed primarily in the lung and gastrointestinal mucosa. whereas MCTC cells lie primarily in skin and gastrointestinal submucosa. The appearance of MCT cells in intestinal tissue is T-lymphocyte dependent. whereas MCTC cells is not. The granules in unstimulated mature MCT cells typically contain complete scrolls. whereas those of MCTC cells often contain grating or lattice substructures. Major categories for the mediators of mast cells include performed mediators present in the secretory granule. newly generated lipid-derived mediators. and cytokines.
Irregular coronary lesion morphology after thrombolysis predicts early clinical instability, After successful thrombolytic treatment for acute myocardial infarction. recurrent ischemia and infarction may occur with little warning. Coronary lesion morphology was analyzed from angiograms performed in 72 consecutive patients at 1 to 8 days after streptokinase treatment for acute myocardial infarction and the data were evaluated in relation to the subsequent clinical course. All patients were clinically stable at the time of angiography and continued to receive heparin infusion for greater than or equal to 4 days after thrombolysis. The infarct-related artery was patent in 55 patients (76%). In the 10 days after angiography. 15 patients developed prolonged episodes of angina at rest; the condition of 4 stabilized with medical treatment. but 11 required urgent medical intervention (coronary angioplasty in 8 and bypass surgery in 3). There were no differences in age. gender. left ventricular function or extent of coronary artery disease between those patients who developed unstable angina and those who had a stable in-hospital course. However. the median plaque ulceration index of the infarct-related lesion was 6.7 (95% confidence limits 6.3. 10) in the 15 patients with an unstable course versus 3.3 (2. 4.4) in those with a stable course (p less than 0.001). There were no differences between the two patient groups in the severity of stenosis. length of diseased segment. symmetry/eccentricity. presence of a shoulder. location at branch point or bend. presence of globular or linear filling defects. contrast staining or collateral supply. These data show that after thrombolysis. the degree of irregularity of the infarct-related artery is a critical determinant of early clinical instability.
Did prognosis after acute myocardial infarction change during the past 30 years? A meta-analysis, Much effort has been spent to improve survival after acute myocardial infarction. To investigate how effective this effort has been. a meta-analysis was performed of studies published between 1960 and 1987 concerning mortality after acute myocardial infarction. Thirty-six studies were analyzed. They were classified with respect to deaths in the hospital and at 1 month and the 5-year mortality rate starting at hospital discharge. Mortality was assessed from all studies by comparing studies from different institutions with use of identical inclusion criteria (externally controlled studies) and by analyzing studies reporting on changes in mortality in two or more comparable patient cohorts admitted to the same institution at different time periods (internally controlled studies). Reports on clinical trials (for example. thrombolytic therapy. beta-adrenergic blockade) in acute myocardial infarction were excluded. Average overall in-hospital mortality decreased from 29% during the 1960s to 21% during the 1970s and to 16% during the 1980s. The externally controlled studies also showed a declining trend: from 1960 to 1969. 32%. from 1970 to 1979. 19% and from 1980 to 1987. 15%. The 1-month overall mortality rate decreased from 31% during the 1960s to 25% during the 1970s and 18% during the 1980s externally controlled studies. Most internally controlled studies also showed significant improvement in in-hospital and 1-month survival. In contrast. 5-year mortality after hospital discharge did not significantly decrease (33% from 1960 to 1969 and 33% from 1970 to 1979). It is concluded that in the prethrombolytic era. short-term prognosis after acute myocardial infarction has improved since 1960.
Intravenous adenosine: continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease, To assess the use of adenosine as an alternative agent for determination of coronary vasodilator reserve. hemodynamics and coronary blood flow velocity were measured at rest and during peak hyperemic responses to continuous intravenous adenosine infusion (50. 100 and 150 micrograms/kg per min for 3 min) and intracoronary papaverine (10 mg) in 34 patients (17 without [group 1] and 17 with [group 2] significant left coronary artery disease). and in 17 patients (11 without and 6 with left coronary artery disease) after low dose (2.5 mg) intravenous bolus injection of adenosine. The maximal adenosine dose did not change mean arterial pressure (-10 +/- 14% and -6 +/- 12% for groups 1 and 2. respectively) but increased the heart rate (15 +/- 18% and 13 +/- 16. respectively). For continuous adenosine infusions. mean coronary flow velocity increased 64 +/- 104%. 122 +/- 94% and 198 +/- 59% and 15 +/- 51%. 110 +/- 95% and 109 +/- 86% in groups 1 and 2. respectively for each of the three doses. Mean coronary flow velocity increased significantly after 100 and 150 micrograms/kg of adenosine and 10 mg of intracoronary papaverine (48 +/- 25. 52 +/- 19 and 54 +/- 21 cm/s. respectively; all p less than 0.05 vs. baseline) and was significantly higher than in group 2 (37 +/- 24. 32 +/- 16. 41 +/- 23 cm/s; all p less than 0.05 vs. group 1). The coronary vasodilator reserve ratio (calculated as the ratio of hyperemic to basal mean flow velocity) for adenosine and papaverine was 2.94 +/- 1.50 and 2.94 +/- 1.00. respectively. in group 1 and was significantly and similarly reduced in group 2 (2.16 +/- 0.81 and 2.38 +/- 0.78. respectively; both p less than 0.05 vs. group 1). Low dose bolus injection of adenosine increased mean velocity equivalently to that after continuous infusion of 100 micrograms/kg. but less than after papaverine. There was a strong correlation between adenosine infusion and papaverine for both mean coronary flow velocity and coronary vasodilator reserve ratio (r2 = 0.871 and 0.325; SEE = 0.068 and 0.189. respectively; both p less than 0.0005). No patient had significant arrhythmias or prolongation of the corrected QT (QTc) interval with adenosine. but papaverine increased the QT (QTc) interval from 445 +/- 44 to 501 +/- 43 ms (p less than 0.001 vs. both maximal adenosine and baseline) and produced nonsustained ventricular tachycardia in one patient.(ABSTRACT TRUNCATED AT 400 WORDS).
Quantitative thallium-201 single-photon emission computed tomography during maximal pharmacologic coronary vasodilation with adenosine for assessing coronary artery disease, The diagnostic value of maximal pharmacologic coronary vasodilation with intravenously administered adenosine in conjunction with thallium-201 single-photon emission computed tomography (SPECT) for detection of coronary artery disease was investigated in 101 consecutive patients who had concomitant coronary arteriography. Tomographic images were assessed visually and from computer-quantified polar maps of the thallium-201 distribution. Significant coronary artery disease. defined as greater than 50% luminal diameter stenosis. was present in 70 patients. The sensitivity for detecting patients with coronary artery disease using quantitative analysis was 87% in the total group. 82% in patients without myocardial infarction and 96% in those with prior myocardial infarction; the specificity was 90%. The sensitivity for diagnosing coronary artery disease in patients without infarction with single-. double-and triple-vessel disease was 76%. 86% and 90%. respectively. All individual stenoses were identified in 68% of patients with double-vessel disease and in 65% of those with triple-vessel disease. The extent of the perfusion defects. as quantified by polar maps. was directly related to the extent of coronary artery disease. In conclusion. quantitative thallium-201 SPECT during adenosine infusion has high sensitivity and specificity for diagnosing the presence of coronary artery disease. localizing the anatomic site of coronary stenosis and identifying the majority of affected vascular regions in patients with multivessel involvement.
Echocardiographic demonstration of decreased left ventricular dimensions and vigorous myocardial contraction during syncope induced by head-up tilt, Two-dimensional echocardiography was performed during a head-up tilt test in 11 control subjects (group I) and 18 patients with recurrent unexplained syncope. In four patients (group II). the head-up tilt test was negative at baseline and after isoproterenol infusion. Syncope was induced during baseline head-up tilt in nine patients (group III) and after isoproterenol challenge in five (group IV). The echocardiographic variables assessed were left ventricular end-systolic and end-diastolic areas and percent fractional shortening. At the end of head-up tilt. end-systolic area decreased by 4.5 +/- 1.3 and 3.0 +/- 1.2 cm2 in groups III and IV. respectively. compared with 0.5 +/- 0.7 and 0.2 +/- 0.1 cm2 in groups I and II. respectively (p less than 0.04). Similarly. end-diastolic area decreased by 5.5 +/- 2.6 cm2 in group III compared with 2.7 +/- 1.9 and 1.75 +/- 0.4 cm2 in group I and II. respectively (p less than 0.04). Additionally. at the end of the baseline study. fractional shortening was significantly greater in group III and group IV (43 +/- 5%) than in groups I and II (p less than 0.01). In conclusion. syncope induced by head-up tilt is associated with vigorous myocardial contraction and a significant decrease in left ventricular end-systolic dimensions. This left ventricular hypercontractility may play an important role in the pathogenesis of syncope induced by head-up tilt.
Importance of left ventricular systolic function in the assessment of left ventricular diastolic function with Doppler transmitral flow velocity recording, To study the effect of left ventricular systolic function on the Doppler transmitral flow velocity pattern. Doppler echocardiographic variables were correlated with hemodynamic indexes in 11 control subjects and 58 patients with heart disease. All underwent cardiac catheterization performed with use of a Millar micromanometer. The time constant of left ventricular isovolumetric pressure decrease and left ventricular end-diastolic myocardial stiffness was calculated. The 58 patients were classified into two groups according to ejection fraction: group I (n = 30; ejection fraction greater than 55%) and group II (n = 28; ejection fraction less than 50%). Compared with the control subjects. patients in group I had impairment only of left ventricular relaxation (time constant 47 +/- 9 vs. 38 +/- 3 ms; p less than 0.01). whereas patients in group II had. in addition to impaired left ventricular relaxation (time constant 52 +/- 11 vs. 38 +/- 3 ms; p less than 0.01). increased preload. increased pulmonary capillary pressure (12 +/- 8 vs. 5 +/- 3 mm Hg; p less than 0.01) and increased myocardial stiffness (2.018 +/- 980 vs. 1.050 +/- 218 g/cm2; p less than 0.01). In group I. there was a significant partial correlation coefficient between the time constant and deceleration half-time (r = 0.54). In group II. a strong correlation existed between myocardial stiffness and peak atrial filling velocity (r = -0.71) and between myocardial stiffness and the ratio of peak atrial to peak rapid filling velocity (r = -0.71).
Effective aortic regurgitant orifice area: description of a method based on the conservation of mass, The natural history of aortic regurgitation is incompletely understood in part because of the lack of a simple method to estimate the defect size. A method of determining the effective regurgitant orifice area that combines Doppler catheter and Doppler echocardiographic techniques and is based on the principle of conservation of mass (the continuity equation) is described. To validate the application of the Doppler catheter system for measuring regurgitant supravalvular diastolic flow. an in vitro model of retrograde aortic flow was used. These studies indicated that measurements of supravalvular retrograde velocity with the Doppler catheter accurately reflect retrograde diastolic velocity when the aorta is less than 4.8 cm in diameter. Twenty-three patients undergoing cardiac catheterization were studied; 20 of these patients had aortic regurgitation. Retrograde supravalvular diastolic velocity was determined from a Doppler catheter positioned above the aortic valve. The effective regurgitant orifice area was calculated with use of the Doppler catheter-derived regurgitant volume and mean transvalvular diastolic velocity as determined by either catheterization or continuous wave Doppler echocardiography. The catheterization-derived regurgitant orifice area increased with the angiographic grade of as follows: 1+ (0.04 to 0.10 cm2). 2+ (0.15 to 0.49 cm2). 3+ (0.29 to 1.11 cm2) and 4+ (1.24 to 1.33 cm2). By combining Doppler catheter. echocardiographic and cardiac catheterization techniques. the effective aortic regurgitant orifice area may be estimated; this hydrodynamic area correlates with grading by supravalvular aortography. Calculation of this area provides a quantitative alternative to aortography for estimating the severity of aortic regurgitation but should be used with caution in patients with a markedly dilated aorta.
Nuclear magnetic resonance imaging of the palliative operation for hypoplastic left heart syndrome, Electrocardiographic-gated nuclear magnetic resonance (NMR) imaging has been shown to be effective for the evaluation of congenital heart disease. particularly in supracardiac regions. This study evaluated the postoperative status after a stage I palliative operation (Norwood procedure) for hypoplastic left heart syndrome. The NMR images from three patients were compared with those of angiography and depicted all components of the reconstructed supracardiac and intracardiac anatomy after this operation. Nonobstructive anastomosis of the main pulmonary artery to the proximal aorta was clearly demonstrated in each patient. The caliber of the central or branch pulmonary artery. patency and caliber of the systemic to pulmonary artery shunt and the size of the atrial communication were also depicted in each patient and these findings corresponded with angiographic results. The results suggest that NMR imaging is effective for assessing the results of initial palliative surgery for hypoplastic left heart syndrome. which seems to be important for managing patients before subsequent definitive surgery.
A new method for noninvasive estimation of ventricular septal defect shunt flow by Doppler color flow mapping: imaging of the laminar flow convergence region on the left septal surface, An accurate but simple and noninvasive method for quantifying flow across a ventricular septal defect has yet to be implemented for routine clinical use. A region of flow convergence is commonly imaged by Doppler color flow mapping on the left septal surface of the ventricular septal defect. appearing as a narrowed region of laminar flow with aliased flow velocities entering the orifice. If the first aliasing region represents a hemispheric isovelocity boundary of a surface of flow convergence and all flow at this surface crosses the ventricular septal defect. the flow through the defect can be estimated by using the radius (R). measured from the first alias to the orifice. and the Nyquist limit (NL) velocity (the flow velocity at the first alias). Doppler color flow imaging was performed in 18 children with a single membranous ventricular septal defect undergoing cardiac catheterization at a mean age of 29.8 months (Group I). Indexes of maximal flow rate across the defect were developed from either the radius or the area. obtained by planimetry. of the first alias. based on Doppler color flow images. All indexes were corrected for body surface area and compared with shunt flow (Qp-Qs) and pulmonary to systemic flow ratio (Qp/Qs) determined at cardiac catheterization. Doppler color flow indexes derived from images of flow convergence in both the long-axis (n = 15) and oblique four-chamber (n = 10) views correlated closely with Qp/Qs (r = 0.71 to 0.92) and Qp - Qs (r = 0.69 to 0.97).
A novel method to maintain ductus arteriosus patency, Survival of patients with certain ductal-dependent congenital heart diseases depends on continued patency of the ductus arteriosus or the surgical creation of an aortopulmonary shunt. The latter may be difficult in the presence of hypoplastic pulmonary arteries. Long-term prostaglandin therapy may be used to maintain ductal patency but is not without limitation and side effects. This experimental study describes a novel approach to maintain ductal patency with a stainless steel stent. Six newborn lambs less than or equal to 48-h old had a ductal stent placed during right heart catheterization. Two lambs less than 36-h old had a stent delivered by the arterial route. The stent was delivered and released at the target with relative ease and no incidence of embolization. Continued ductal patency up to 3 months was demonstrated by repeat cardiac catheterization and angiography. two-dimensional color Doppler echocardiography and postmortem examination. The experimental model provides a left to right shunt model in which the size may be increased as the animal grows. More important. a ductal stent could be used to maintain ductal blood flow in neonates and infants with ductal-dependent cardiac malformations. thereby avoiding a thoracotomy.
Diastolic mitral regurgitation with atrioventricular conduction abnormalities: relation of mitral flow velocity to transmitral pressure gradients in conscious dogs, Diastolic mitral regurgitation is a common finding that can be detected with use of Doppler echocardiographic techniques in patients with atrioventricular (AV) conduction abnormalities. With use of simultaneous hemodynamic and Doppler techniques. mitral flow velocity. mitral valve motion and transmitral pressure gradient were studied during 50 cardiac cycles each of spontaneous or atrial paced first- and second-degree AV block in five lightly sedated dogs. Diastolic mitral regurgitation was detected during atrial relaxation on all beats in which ventricular contraction was delayed greater than 190 ms. In all dogs the diastolic regurgitation was associated with a reverse transmitral pressure gradient (3.7 +/- 1.1 mm Hg in first-degree AV block and 3.2 +/- 1.5 mm Hg in second-degree AV block) that occurred primarily as the result of a decrease in atrial pressure with atrial relaxation. These reverse pressure gradients were as large as the maximal forward transmitral gradients in early diastole (2.9 +/- 0.9 mm Hg in first-degree AV block and 3.1 +/- 0.7 mm Hg in second-degree AV block) and larger than the maximal forward pressure gradients at atrial contraction (1.7 +/- 0.5 and 1.4 +/- 0.6 mm Hg. respectively. p less than 0.05). The maximal reverse pressure gradient during atrial relaxation was also as large as the reverse pressure gradient in mid-diastole (2.7 +/- 0.9 and 2.8 +/- 1.0 mm Hg. respectively). associated with deceleration of early diastolic mitral flow. Peak diastolic mitral regurgitation velocity coincided with the maximal reverse transmitral gradient and was usually larger than anterograde mitral flow velocity.
Effect of transient coronary occlusion on coronary blood flow autoregulation, vasodilator reserve and response to adenosine in the dog, Myocardial ischemia of short duration (15 to 20 min) produces myocardial "stunning" during reperfusion. The vasoregulatory and contractile status of reperfused myocardium during normal and reduced perfusion pressures is of interest in the treatment of patients with unstable angina. In the present study the effects of 15 min of reversible ischemic injury on several aspects of coronary vasoregulation were assessed with use of pressure-flow curves in anesthetized open chest dogs. The left anterior descending coronary artery was cannulated and perfused with arterial blood with use of a servo-controlled roller pump. The autoregulatory gain and an adenosine dose-response curve for coronary flow before and after ischemia and reperfusion were obtained. The maximal autoregulatory gain values in the pressure range of 140 to 60 mm Hg were not significantly different before and after ischemia and reperfusion (0.41 +/- 0.08 vs. 0.5 +/- 0.06. p greater than 0.1). The adenosine dose-response curve was significantly shifted to the right after reperfusion; however. coronary blood flows during maximal adenosine vasodilation over a large range of perfusion pressures (140 to 60 mm Hg) were significantly greater after ischemia and reperfusion. The pressure-dependent decrease in segment shortening (sonomicrometry) over the coronary pressure range of 160 to 30 mm Hg was similar in myocardium before and after stunning. Contractile function in the stunned myocardium at normal (100 mm Hg) and low (40 mm Hg) coronary perfusion pressures was similarly and significantly enhanced by the administration of adenosine. It is concluded that 1) coronary autoregulation is unchanged after brief ischemia and reperfusion; 2) although maximal coronary vascular conductance assessed with adenosine is greater after ischemia. the coronary circulation shows a decreased coronary sensitivity to exogenous adenosine; 3) the relation of contractile function to coronary pressure before and after stunning is unchanged; and 4) enhancement of function in stunned myocardium by vasodilation with adenosine occurs at low and normal perfusion pressures.
Effect of intracoronary diltiazem on infarct size and regional myocardial function in the ischemic reperfused canine heart, This study was designed to investigate whether intracoronary diltiazem given before reperfusion could enhance myocardial salvage in the canine heart. Twenty-five dogs were subjected to 90 min of coronary occlusion followed by 4 h of reperfusion. The dogs were assigned to one of three experimental groups. The early diltiazem group received intracoronary diltiazem into the distal coronary bed at the onset of coronary occlusion and for 60 min after reperfusion. The late diltiazem group received the same amount of drug beginning 15 min before reperfusion and the control group received saline solution for 90 min of occlusion and 60 min of reperfusion. Infarct size expressed as a percent of the area at risk was significantly smaller in the early and late diltiazem groups (15.6 +/- 3.6% and 21.2 +/- 5.1%. respectively) than in the control group (49 +/- 4.6%) (p less than 0.05). Intracoronary diltiazem restored systolic function of the stunned. previously ischemic tissue to essentially normal preocclusion values. Segmental shortening after reperfusion averaged 21.6% in the early diltiazem group versus 0 +/- 1.7% and 7.3 +/- 4% for the control and late diltiazem groups. respectively (p less than 0.05). Low dose intracoronary diltiazem did not alter hemodynamic variables or myocardial blood flow but did improve segmental shortening 2 and 6 h after reperfusion. These data indicate that intracoronary diltiazem given during occlusion or just before reperfusion increases the salvage of myocardium compared with the salvage achieved by reperfusion alone. These results also suggest that intracoronary diltiazem given during the ischemic period enhances systolic contractile function of postischemic stunned myocardium.
Pica practices of pregnant women, This report summarizes current knowledge about pica practices during pregnancy through a systematic review of the literature for the period 1950 through 1990. Pica behavior was considered in terms of its prevalence. risk factors. clinical profile. and effect on pregnancy outcome. Data on pica practices by pregnant women are limited and inconclusive but reveal several interesting relationships. The prevalence of pica among pregnant women in high-risk groups declined between the 1950s and the 1970s but now remains steady. affecting about one fifth of high-risk women. Women at high risk of pica are more likely to be black. to live in rural areas. and to have a positive childhood and family history of pica. The clinical picture of the disorder during pregnancy is not well described. The evidence suggests that pica during pregnancy results in anemia. but it is not definitive. Pica also has been associated with maternal and perinatal mortality. We conclude that the behavior is more prevalent than commonly believed. shows no sign of further decline. and may have serious effects. particularly anemia. on mother and infant. Dietetic practitioners who counsel pregnant women should ask questions about pica when they conduct nutrition assessments of their clients.
Family-oriented nutrition intervention for a lipid clinic population, We have developed a unique. family-oriented approach to lowering plasma cholesterol concentrations in persons with familial hyperlipidemias. The approach includes individual clinic visits and group nutrition classes and uses dietary goals outlined in The New American Diet. A series of 13 nutrition classes is presented to small groups. usually composed of relatives from pedigrees with familial hypercholesterolemia or other familial hyperlipidemias. Dietary action goals. cooking demonstrations. food tasting. and finger-stick plasma cholesterol determinations are important components of the classes. Problem-solving discussion is encouraged in the group. Over the past 4 years. 143 hyperlipidemic individuals. along with at least 94 unaffected family members. have participated in 31 groups. which have met for at least six classes. Many clinic participants lower plasma cholesterol by 20% or more. Keys to the success of this program include emphasizing dietary therapy. using the family setting for nutrition intervention. providing hands-on experience with food and recipes. promoting problem solving for dietary action goals. measuring blood cholesterol during classes. and encouraging long-term follow-up for participants with physicians and dietitians.
Applications and transfer of technology to the nations of the South. Biotechnology and the control of childhood enteric infections, The optimal use of biotechnology to address the health care needs of developing countries entails the formation of interdisciplinary working groups linking basic biomedical scientists with public health workers. epidemiologists. physicians. and social scientists. Their mission should be congruent with and guided by the public health goals and primary care program of the country or region. Moreover. their research and development activities should lead to products that address a specific need and which are evaluable. cost-effective. and readily transferred to the public health sector. With respect to the enteric infections of childhood. the essential components of an integrated control effort are a field site where infections of this kind are common and readily studied; a local public health laboratory where the performance of new products can be tested and where technology transfer can occur; a basic science laboratory where molecular pathogenicity studies lead to new diagnostic tests. vaccines. and drugs; and a production laboratory where these products can be refined and prepared in sufficient amounts for field testing. This strategy is now being evaluated for the control of infantile diarrhea through the combined use of epidemiologic investigations. DNA probe and amplification techniques. and molecular fingerprinting. Together. these methods are yielding new information about microbial reservoirs and transmission systems; in turn. this information should lead to highly focused public health interventions.
Development of diabetogenic T cells from NOD/Lt marrow is blocked when an allo-H-2 haplotype is expressed on cells of hemopoietic origin, but not on thymic epithelium, Diabetes is a T cell-mediated process in NOD/Lt mice. with a major genetically recessive component of susceptibility linked to homozygous expression of the unique H-2g7 MHC haplotype. Heterozygous expression of the H-2nb1 haplotype derived from the NON/Lt strain confers diabetes resistance both in (NOD x NON)F1 hybrids and in NOD mice congenic for the H-2nb1 haplotype. However. diabetes resistance is abrogated in F1 hybrids by NOD/Lt bone marrow reconstitution. To establish whether the generation of beta cell autoreactive T cells from NOD/Lt bone marrow-derived precursors required at least heterozygous expression of the H-2g7 haplotype on thymic epithelium. adolescent thymectomized (NOD x NON)F1 mice were implanted with neonatal NON/Lt thymus grafts before lethal radiation and reconstitution with NOD/Lt bone marrow. Peripheral T cells maturing through this ectopic thymic implant exclusively expressed the NOD H-2g7 haplotype and were tolerant to H-2nb1 skin grafts. Nevertheless. diabetes developed in 32% of the NON/Lt thymus-grafted chimeras vs 38% of the sham-thymectomized NOD bone marrow chimeras. Thus. homozygous expression of the diabetes-resistant H-2nb1 haplotype on thymic epithelium failed to block development of a diabetogenic T cell repertoire. To examine if expression of H-2nb1 on hemopoietically derived APC could alter the diabetogenic potential of NOD/Lt marrow. diabetes-resistant NOD.NON-H-2nb1 congenic mice were mated with NOD/Lt mice to produce NOD-H-2g7/H-2nb1 heterozygous recipients. These were lethally irradiated and reconstituted with either NOD/Lt marrow alone. NOD.H-2nb1 homozygous congenic marrow alone. or a 1:1 mixture of the two marrow populations. By 25 wk of age. all of the MHC heterozygous recipients of NOD.NON-H-2nb1 marrow remained diabetes-free whereas 75% of the MHC heterozygous recipients of NOD/Lt marrow developed diabetes. A striking decrease in diabetes was observed when T cell precursors derived from NOD/Lt marrow interacted with H-2nb1 gene products on hemopoietically derived APC. inasmuch as only 7% of the MHC heterozygous recipients reconstituted with a 1:1 mixture of NOD/Lt and NOD.NON-H-2nb1 marrow developed diabetes. Peripheral leukocytes in all reconstitution classes expressed the MHC phenotype(s) of the marrow donor(s). Skin grafting confirmed that all reconstitution classes of MHC heterozygous recipients were tolerant to the H-2nb1 haplotype.(ABSTRACT TRUNCATED AT 400 WORDS).
Human articular cartilage and chondrocytes produce hemopoietic colony-stimulating factors in culture in response to IL-1, The hemopoietic CSF. granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF). are cytokines that mediate the clonal proliferation and differentiation of progenitor cells into mature macrophages and/or granulocytes. We have employed an all-human cell culture system. specific ELISA for GM-CSF and G-CSF. and Northern analysis to investigate whether chondrocytes are a potential source of CSF in rheumatoid disease. We report that human rIL-1 stimulated in a dose-dependent manner the production of GM-CSF and G-CSF by human articular cartilage and chondrocyte monolayers in organ and cell culture. respectively. Increased levels of the CSF Ag were detected after 2 to 8 h stimulation with IL-1. and the optimum dose of IL-1 was 10 to 100 U/ml (0.06 to 0.6 nM IL-1 alpha; 0.02 to 0.2 nM IL-1 beta); neither CSF was detectable in nonstimulated cultures nor in IL-1-stimulated cultures treated with actinomycin D or cycloheximide. indicating the requirement for de novo RNA and protein synthesis. The IL-1-mediated increase in GM-CSF could also be inhibited by the corticosteroid. dexamethasone. but not by the cyclo-oxygenase inhibitor. indomethacin. Although having little effect when tested alone. TNF-alpha and lymphotoxin (TNF-beta) could synergize with IL-1 for the production of GM-CSF. Basic fibroblast growth factor. platelet-derived growth factor. and IFN-alpha and IFN-gamma each had no effect on GM-CSF levels. Results obtained by Northern analysis of chondrocyte total RNA reflected those found for the CSF Ag. namely that CSF mRNA levels were elevated in response to IL-1. but not TNF. and that there was synergy between these two cytokines. We propose that chondrocyte CSF production in response to IL-1. and the concurrent destruction of cartilage by IL-1. could provide a mechanism for the chronic nature of rheumatoid disease.
Effect of combinations of cytokines and hormones on synthesis of serum amyloid A and C-reactive protein in Hep 3B cells, We have previously shown that induction of synthesis of the two major human acute phase proteins. serum amyloid A (SAA) and C-reactive protein (CRP). can be accomplished in the human hepatoma cell line Hep 3B. in the presence of dexamethasone. either by conditioned medium from LPS-stimulated monocytes or by the combination of IL-6 and IL-1. Neither of these cytokines alone caused significant induction of either SAA or CRP. In the present study we extended our earlier observations by evaluating the role of dexamethasone. the effect of different concentrations of IL-6 and IL-1 alpha in combination. and the possible role of TNF-alpha in regulating synthesis of SAA and CRP. Dexamethasone alone had no effect on induction of SAA or CRP. Incubation of Hep 3B cells with conditioned medium from LPS-stimulated monocytes. in the absence of dexamethasone. led to modest induction of SAA or CRP. but addition of dexamethasone potentiated this response in a dose-dependent manner. Similar results were obtained for the effect of dexamethasone on the induction of SAA by IL-6 plus IL-1 alpha. Checkerboard titration of IL-6 and IL-1 alpha revealed that increases in concentration of either cytokine led to dose-related increases in synthesis of both SAA and CRP as long as a minimal amount of the other cytokine was present. TNF-alpha alone had no significant effect on synthesis of either SAA or CRP. but the combination of IL-6 plus TNF-alpha led to substantial induction of SAA. This combination was less effective than the combination of IL-6 plus IL-1 alpha. No detectable effect of IL-6 plus TNF-alpha was observed on CRP synthesis. Both combinations of cytokines. IL-6 plus IL-1 alpha. and IL-6 plus TNF-alpha. caused increased SAA mRNA accumulation that roughly paralleled increase in synthesis. These data indicate that IL-6. IL-1 alpha. TNF-alpha. and dexamethasone in various combinations are all capable of influencing synthesis of SAA in Hep 3B cells. whereas only IL-6. IL-1 alpha. and dexamethasone can influence CRP synthesis.
Intracellular interaction of EBV/C3d receptor (CR2) with p68, a calcium-binding protein present in normal but not in transformed B lymphocytes, To analyze direct intracellular interactions of CR2 in normal human B lymphocytes. we used polyclonal anti-Id anti-CR2 antibodies (Ab2) prepared against the highly purified CR2 molecule (gp140) as original immunogen. We previously demonstrated that this Ab2 contained specificities that mimicked extracellular and intracellular domains of CR2 and was helpful for identifying CR2-specific ligands. Indeed. some Ab2 specificities recognized human C3d and EBV. two extracellular CR2 ligands. In addition. other Ab2 specificities interacted directly. as CR2. with the intracellular p53 antioncoprotein that is expressed in transformed cells and not in normal cells. We demonstrate herein that Ab2 detected in normal B lymphocytes a 68-kDa protein. p68. that was not expressed in transformed B cells. p68 was localized in purified plasma membranes and cytosol fractions. Direct interaction of purified CR2 with purified p68 was demonstrated. Competitive studies supported that CR2 and Ab2 interacted with identical sites on p68. These interactions were calcium dependent. p68 was identified as a calcium-binding protein by its ability to be solubilized from B lymphocyte membranes by EGTA. a calcium-chelating agent. to bind specifically on phenothiazine-Sepharose in a calcium-dependent interaction. and to be recognized by specific antibodies directed against human p68. a calcium-binding protein of the annexin VI family. Thus. demonstration of different intracellular interactions of CR2 with distinct regulatory proteins. such as p53. the antioncoprotein. and p68. a calcium-binding protein. supports involvement of two regulatory pathways of signal transduction through CR2. depending on the normal or transformed state of human B lymphocytes.
IgG subclass distribution of primary and secondary immune responses concomitant with viral infection, Infection with mouse hepatitis virus was found to selectively increase the proportion of IgG2a in antibodies elicited by a concomitant administration of unrelated T cell-dependent protein Ag. In contrast. T cell-independent responses were only marginally affected. This isotypic bias. which occurred when the virus was inoculated shortly before or after a primary immunization. persisted in subsequent secondary responses. However. infection concomitant to secondary antibody responses did not affect their isotypic distribution. These observations suggest that the virus can durably modify unrelated T cell responses that are initiated at the time of infection. which could have implications in the pathogenesis of autoimmune reactions.
Lymphokine-activated killer cells are rejected in vivo by activated natural killer cells, A 4-h in vivo cytotoxicity assay was used to study the fate of implanted IL-2-generated. lymphokine-activated killer (LAK) cells in mice undergoing an activated NK cell response. 125Iododeoxyuridine-labeled LAK cells were rejected from selected organs of C57BL/6 mice infected with lymphocytic choriomeningitis virus or treated with IL-2 or the IFN inducer poly I:C. This rejection was abrogated by the selective depletion of NK cells with antibodies to asialo-GM1 and NK1.1 Ag. Similar results were noted when LAK cells were generated from the spleens of B and T cell-deficient severe combined immunodeficiency mice and when LAK cells were implanted into severe combined immunodeficiency mice. These data indicate that NK cells activated by virus infections or by IL-2 infusions directly or indirectly eliminate implanted LAK cells. Because LAK cells are used in the treatment of certain human cancers. the strategy of accompanying this therapy with IL-2 infusions should be reassessed in light of these results.
Comparison between strains of human T lymphotropic virus type I isolated from inhabitants of the Solomon Islands and Papua New Guinea, Strains of human T lymphotropic virus type I (HTLV-I) isolated from T cell lines (SI-1. SI-3. and SI-5) from three individuals in separate regions of the Solomon Islands were compared with a variant (PNG-1) isolated from a healthy person in Papua New Guinea and a prototype strain from Japan (MT-2). The SI-1. SI-3. and SI-5 cell lines were predominantly CD8+. Expression of gag- and env-encoded virus-specific proteins was detected in SI-1. SI-3. and SI-5 and in MT-2 cells by immunofluorescence and Western immunoblot; gag proteins p19 and p24 were absent in PNG-1 cells. HTLV-1 gag and pol gene sequences were detected in DNA extracted from SI-1. SI-3. and SI-5 cells by polymerase chain reaction; env sequences were not found in SI-5 cells. Genomic Southern analysis of PstI digests of SI-1. SI-3. and SI-5 DNA exhibited the three moderate-sized fragments typical of prototype HTLV-I. By contrast. PstI digests of PNG-1 DNA yielded two larger fragments.
Cytomegalovirus (CMV)-specific intravenous immunoglobulin for the prevention of primary CMV infection and disease after marrow transplant, Cytomegalovirus (CMV)-specific immunoglobulin (IVIG) was evaluated in a randomized controlled trial in CMV-seronegative marrow transplant patients with seropositive marrow donors for the prevention of primary CMV infection during the first 100 days after transplant. Patients received 200 mg/kg CMV IVIG on days 8 and 6 before transplant. the day after transplant. weekly for the first month. and then every 2 weeks to complete 10 doses. Patients were followed with weekly CMV cultures and serologic studies and for clinical and histologic evidence of CMV disease. Sixty patients were evaluable in each group. There was significantly less CMV excretion (P = .04) and viremia (P = .01) in the treatment group. However. the incidence of CMV disease including CMV pneumonia. CMV enteritis. and CMV syndrome (fever. leukopenia. hepatitis) was not statistically different. There was also no difference in median time of onset of CMV infection or disease. median number of hospital days. or survival between the two groups.
Monitoring of human cytomegalovirus infections and ganciclovir treatment in heart transplant recipients by determination of viremia, antigenemia, and DNAemia, Fourteen heart transplant recipients were monitored for human cytomegalovirus (HCMV) infection based on determination of antigenemia. viremia. and DNAemia (by polymerase chain reaction [PCR]) in peripheral blood polymorphonuclear leukocytes (PMNL). Three patients had symptomatic primary. 10 had recurrent (3 asymptomatic). and 1 (seronegative) had no HCMV infection. Severe clinical symptoms appeared when levels of viremia/antigenemia were greater than 50 infected PMNL/2 x 10(5) cells examined. Of 200 blood samples examined. 93 (46.5%) were positive for viremia/antigenemia and DNAemia. whereas 48 (24.0%) were positive for DNAemia only; 59 (29.5%) were negative in all assays. Follow-up of HCMV infections in heart transplant recipients showed that PCR can detect viral appearance in blood 7-10 days earlier than assays for antigenemia/viremia. On the other hand. viral disappearance from blood. as assessed by PCR. occurred weeks or months later than revealed by other assays. Detection of virus by PCR only was never associated with overt HCMV-related clinical symptoms. Of the 8 symptomatic patients treated with ganiclovir. 2 became PCR-negative at the end of treatment and 1 cleared virus from blood in the following weeks. whereas 5 showed persistent or recurrent infection.
Streptokinases produced by pathogenic group C streptococci demonstrate species-specific plasminogen activation, The species specificities of plasminogen activation and binding of plasmin by pathogenic group C streptococci isolated from humans. horses. and pigs were examined. Of 56 streptococcal isolates. 52 elaborated plasminogen activator activity and 49 of these had specificity for plasminogen of the homologous host. Analysis of supernatants from 13 isolates indicated that the plasminogen activator activity resulted from secreted streptokinases. These 13 streptokinases were antigenically related and bound all three plasminogens. indicating that the binding recognition sites were conserved despite the observed species-specific activation. In addition. all group C isolates tested demonstrated surface receptors that bound human. equine. and porcine plasmin. Species-specific plasminogen activation may be an early step in events resulting in infection and may account for the species preference of certain streptococci.
Effect of prior infection with virulent Shigella flexneri 2a on the resistance of monkeys to subsequent infection with Shigella sonnei, All virulent shigellae have large plasmids. Plasmid-associated genes encode the expression of membrane-associated proteins (MAP). some of which correlate with the ability to invade susceptible epithelial cells. These MAP are serologically related in all of the shigella serotypes and evoke an antibody response after infection. To determine whether the MAP have a significant role in protection. 24 monkeys were infected with virulent Shigella flexneri 2a. After recovery. one group (with controls) was rechallenged with S. flexneri 2a; another group (with controls) was fed Shigella sonnei. The animals that were rechallenged with S. flexneri 2a were protected. while those that were fed S. sonnei experienced the same incidence of disease as controls. No differences in serum immune response to MAP after primary infection with S. flexneri were detected in immunoblots using lysates of S. flexneri or S. sonnei or in ELISA using water extracts of these strains.
Attaching and effacing enteropathogenic Escherichia coli as a cause of infantile diarrhea in Bangkok, To identify Escherichia coli that cause infantile diarrhea in Bangkok. Thailand. E. coli isolated in a year-long study of infantile diarrhea were examined for O and H serotypes and virulence determinants. Classic enteropathogenic E. coli (EPEC) were isolated from 28 of 509 infants with diarrhea (cases) and 11 of 509 age-matched controls (P = .009; odds ratio [OR]. 2.64). Most of this difference was attributable to EPEC adherence factor (EAF)-positive EPEC that produced an attachment and effacement lesion. as identified in the fluorescence actin staining assay. isolated from 13 cases and 1 control (P = .003; OR. 13.3). EAF-EPEC was isolated from 15 cases and 10 controls (P = .418; OR. 1.52) and EAF+ non-EPEC from 17 cases and 10 controls (P = .242; OR. 1.72). EAF+EPEC that caused an attachment and effacement lesion was found in 3% of children less than 6 months old with diarrhea who were studied in an outpatient clinic in Bangkok in 1988.
In vivo and in vitro expression of Haemophilus influenzae type b lipooligosaccharide epitopes, An indirect immunofluorescence system involving monoclonal antibodies (MAbs) directed against surface epitopes of Haemophilus influenzae type b (Hib) lipooligosaccharide (LOS) was used to examine individual Hib cells in cerebrospinal fluid (CSF) from infants with Hib meningitis. In four of five CSF samples studied. 100% of the bacteria bound at least one LOS-directed MAb. When the bacteria from these CSF samples were grown in broth. most of these cells lost some or all of their ability to bind the MAb(s) that were bound by the same organisms present in human CSF. When in vitro-grown cells were used for intracisternal injection of rabbits. the populations of Hib cells observed in rabbit CSF after the development of meningitis generally resembled those of the respective broth-grown inocula in terms of their LOS antigenic characteristics. Hib cell populations recovered in infant rat CSF after intranasal challenge again had LOS antigenic characteristics similar to those of the in vitro-grown challenge inocula. These results indicate that a population of Hib cells growing in the infected human host may be quite different. with regard to its LOS antigenic characteristics. from the same Hib strain growing in vitro or in vivo in animal models.
Immunologic responses to repeated ivermectin treatment in patients with onchocerciasis, To assess the effect of ivermectin treatment on the immunologic status of individuals with onchocerciasis. 27 patients from Guatemala were studied before and at 6-month intervals during 2 years of repeated semiannual treatment with ivermectin. T cell proliferative responses to onchocercal antigen increased transiently by 6 months (mean stimulation index [SI] rising from 4.17 to 12.81) but returned to preivermectin levels thereafter. Changes in SI to nonparasite antigen paralleled those induced by parasite antigen. There were also significant decreases in levels of blood eosinophils. polyclonal IgG and IgE. parasite-specific IgG antibody. and IgG subclass antibodies by the end of the study. This study emphasizes the apparent long-term safety of ivermectin by demonstrating the absence of immunopathogenic responses induced by repeated ivermectin treatments.
Respiratory viruses induce production of histamine-releasing factor by mononuclear leukocytes: a possible role in the mechanism of virus-induced asthma, Histamine-releasing factor (HRF) is a cytokine produced by mononuclear leukocytes when stimulated with antigens or mitogens. HRF is capable of inducing degranulation of basophils and release of histamine. To determine if respiratory viruses can induce HRF production. mononuclear leukocytes from healthy adult donors were exposed to influenza or respiratory syncytial virus in vitro. HRF activity was tested by culturing the supernatants with fresh peripheral blood leukocytes and measuring the percentage of histamine released. Significant enhancement in histamine release was found in both virus groups compared with that of media controls. Thus. mononuclear leukocytes from normal individuals produce HRF in response to exposure to respiratory viruses. suggesting that this cytokine. which causes basophil degranulation. may play a role in the mechanism of virus-induced bronchospasm.
Outbreak of group A streptococcal bacteremia in Sweden: an epidemiologic and clinical study, The nationwide incidence of group A streptococcal bacteremia in Sweden was 1.8 per 100.000 population in 1987. During the winter season 1988-1989. the reported cases rate doubled and then declined to the previous level. The peak was due to a type T1/M1 Streptococcus pyogenes strain associated with an increased case fatality rate (33% vs. 15% for other T types). The highest incidence rates were found in the age groups less than 12 months and greater than 70 years. Among a sample of 79 patients hospitalized in November or December 1988. a portal of entry. mainly cutaneous. was recognized in 89% of the patients and concomitant conditions in 67%. Among the clinical findings were signs of skin or soft tissue infection (41%). local or generalized pain (41%). vomiting or diarrhea (24%). cough (18%). and upper respiratory tract symptoms (12%). A fatal outcome was associated with high age. lower respiratory tract or unknown focus. leukopenia on admission. start of antibiotic therapy greater than 6 h after the patient's initial contact with a physician. and a rapid clinical course including multiple organ failure. Renewed awareness of the many facets of fulminant streptococcal infection represents one approach to minimize the case fatality rate.
Comparison of the early dynamics of systemic prostacyclin release after administration of tumor necrosis factor and endotoxin to healthy humans, Excessive production of prostaglandins may be of importance for the development of organ damage in generalized infection. To investigate the role of tumor necrosis factor (TNF) in systemic prostacyclin release in gram-negative septicemia. the plasma concentrations of its stable metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were sequentially measured after intravenous bolus injections of recombinant human TNF (50 micrograms/m2; n = 6) and Escherichia coli endotoxin (2 ng/kg; n = 3) in healthy men. TNF induced a rapid increase in plasma 6-keto-PGF1 alpha from 0.11 +/- 0.01 to 0.44 +/- 0.15 ng/ml after 30 min (P less than .001). Endotoxin also elicited a rise in plasma 6-keto-PGF1 alpha. but peak values were reached only after 90 min (from 0.07 +/- 0.01 to 0.19 +/- 0.04 ng/ml; P less than .002). These results indicate that TNF may serve as an intermediate factor in systemic elaboration of prostacyclin in endotoxemia and gram-negative septicemia.
Ciprofloxacin treatment of drug-resistant falciparum malaria, A randomized. open study of high-dose ciprofloxacin (750 mg every 12 h) in uncomplicated falciparum malaria was conducted in Thailand. No patient completed the planned 1-week treatment course. Because of rising parasitemia (threefold higher at 36 h than on admission) and deterioration of clinical status. three individuals required quinine treatment 36 h after commencing ciprofloxacin; a fourth was given quinine at 54 h. The study was terminated early for safety reasons after only four ciprofloxacin and four control patients had been enrolled. Ciprofloxacin was well absorbed and efficiently entered erythrocytes; median plasma and red cell concentrations 90 min after the first dose were 4.0 (range. 3.7-6.8) and 5.1 (3.8-6.0) micrograms/ml. respectively. However. 50% inhibition of parasite growth in vitro required 6.6 micrograms/ml. (5.6-9.6). Ciprofloxacin should not be used alone to treat chloroquine-resistant falciparum malaria.
Pentoxifylline prevents murine cerebral malaria, Pentoxifylline. a widely used methylxanthine. was tested for its capacity to prevent cerebral malaria (CM) in Plasmodium berghei ANKA-infected CBA/Ca mice. Nine of 12 control mice developed neurologic signs and died from CM approximately 2 weeks after infection. All 12 mice treated with daily intraperitoneal pentoxifylline (1 mg) for 10 days after infection did not develop CM. All surviving mice developed high parasitemia and severe anemia and died 2 weeks later without neurologic signs. In pentoxifylline-treated mice. serum tumor necrosis factor (TNF) bioactivity was nondetectable. whereas control mice had high TNF levels on day 6 after infection. These findings were supported by in vitro investigations of malaria antigen-induced TNF synthesis. Northern blot analysis of TNF mRNA from stimulated macrophages showed that pentoxifylline inhibited TNF expression at the transcription level. and TNF bioactivity in supernatants was strongly depressed. These findings make pentoxifylline a potential candidate for study as a supportive agent in human CM.
The present status of akathisia, Akathisia is a common and distressing side effect of antipsychotic and some other psychotropic medications. This paper reviews the current state of knowledge of its clinical features. pathophysiology. and treatment. Restless legs syndrome and akathisia associated with Parkinson's disease are discussed in so far as they help understand drug-induced akathisia. The complexity of the disorder. and the difficulty in characterizing and quantifying it. may explain why researchers have relatively neglected akathisia for so long. The recent upsurge of research interest promises the hope of a better understanding of its pathophysiology so that effective therapy may result.
Gender differences in the specificity of alcoholism transmission among the relatives of opioid addicts, Gender differences in the specificity of drug versus alcohol transmission were examined among 201 opioid addicts and their 877 first-degree relatives using direct interviews and a structured family history method based on the Schedule for Affective Disorders and Schizophrenia Research Diagnostic Criteria. A strong association of parental alcoholism with alcoholism among the proband addicts was found. suggesting some specificity for drug versus alcohol abuse. We also found that among the 477 siblings. those with alcoholism alone did not have parents with drug abuse and those parents with drug abuse did not have children with alcoholism alone. Rates of parental alcoholism were higher in alcoholic female than in alcoholic male probands. suggesting greater female "loading" was needed in order to become alcoholic. This increased loading in women was also found among the siblings. but alcoholic parents appeared to transmit a nonspecific tendency for either drug or alcohol abuse to their female children. Thus. it may take a greater "dose" of parental transmission for a woman to become a substance abuser. and transmission of alcoholism may be specific in men. but not in women.
The antisocial personality disorder diagnosis in substance abusers: problems and issues, This paper examines the question of whether antisocial personality disorder (APD) can be considered a viable substance abuse typology. The data for APD substance abusers are first reviewed with respect to six properties that apply to establishing the validity of a clinical typology. This is followed by a brief description of the historical context and development of current conceptualizations of antisocial personality. Some possible sources of diagnostic unreliability and instability that could serve to limit the validity of the APD diagnosis are then discussed. Finally. evidence indicating considerable psychiatric heterogeneity within APD substance abusers is described. The findings indicate that although APD substance abusers satisfy many of the criteria for a clinical subtype. the fit is sufficiently imprecise to suggest the need for further refinement. We attempt to point out some of the critical questions. issues. and lines of research that could help to guide future efforts to clarify. refine. and revise the APD formulation. particularly as it applies to substance abusers.
Subjective experiences related to alcohol use among schizophrenics, Comorbid alcohol use disorders are common in schizophrenia. Although a variety of explanatory hypotheses involving self-medication have been proposed. few data available regarding schizophrenic patients' subjective experiences while using alcohol. We report interview data from 75 DSM-III-R schizophrenic outpatients regarding their subjective responses to alcohol. Over half of our sample reported that alcohol improved social anxiety. tension. dysphoria. apathy. anhedonia. and sleep difficulties. Other nonpsychotic experiences were frequently improved as well. In contrast. no more than 15% of subjects reported that alcohol relieved any specific psychotic symptom; similar proportions of subjects reported that alcohol aggravated psychotic symptoms. Reporting that alcohol had a positive effect on nonpsychotic experiences was associated with having lifetime alcohol use disorders. Reporting that alcohol relieved psychotic symptoms was associated both with having lifetime alcohol use disorders and with the number of psychotic symptoms reported. We discuss the implications of these findings for understanding alcohol abuse and dependence among schizophrenics.
Trends in the pathophysiology and pharmacotherapy of spasticity [editorial, Spasticity develops after supraspinal or spinal lesions of descending motor systems. with obligate involvement of the corticospinal tract. Spasticity is characterized by an increase in muscle tone. which. in contrast to many other types of enhanced muscle tone. shows a marked velocity-dependent increase when the muscle is passively stretched. The pathophysiological mechanisms underlying this spastic muscle tone remain obscure. Three major causes are currently considered possible: (1) changes in the excitability of spinal interneurones; (2) receptor hypersensitivity; (3) formation of new synapses by sprouting. The latter mechanism could account for the long time course over which spastic muscle tone develops in hemiplegic or paraplegic patients. but there is no experimental evidence for this hypothesis. The electromyographic (EMG) gait analysis of patients with spasticity has thrown doubt on the common belief that the velocity-dependent increase in spastic muscle tone is evoked by stretch reflex activity and has led to the idea that spastic muscle tone resides in the muscle fibres themselves. While such a mechanism may contribute to the slowness of active movements in spastic patients. recent experiments on patients with spastic arm paresis have confirmed the classical view that the spastic muscle tone is related to the EMG activity evoked in the passively stretched muscle. This pathological EMG activity is seen during the entire range of the dynamic phase of the stretch. during which a normal muscle exhibits only an early. phasic burst at the highest stretch velocities employed. For the pharmacological treatment of spasticity. substances with different central or peripheral actions are available. Their assumed receptor actions are described. together with their main indications and side-effects.
Striatopallidonigral degeneration in Pick's disease: a clinicopathological study of 41 cases, The frequency and degree of stiatopallidonigral (SPN) degeneration were examined in 41 autopsy cases of Pick's disease. Based on the degree of SPN degeneration. these cases were arranged into four groups: 1) group I (severely degenerate; 19.5%). 2) group II (moderately degenerate; 22.0%). 3) group III (mildly degenerate; 36.5%). and 4) group IV (non-degenerate; 22.0%). 17 of the 41 cases had a definite (moderate to severe) SPN degeneration. The striatum. especially the caudate nucleus. was most frequently and most severely affected. while the internal segment of the globus pallidus was least frequently and least severely affected. In general. the oral portions of the SPN nuclei were more severely involved. In addition. in the putamen and globus pallidus the dorsomedial portions adjacent to the internal capsule were apt to be affected more markedly than the other portions. In the substantia nigra the degeneration tended to be more predominant in the pars reticulata than in the pars compacta. although both were usually involved. In addition. the medial to central portions of the substantia nigra were more vulnerable. In comparing the severely and moderately degenerate groups (groups I and II) with the mildly and non degenerate groups (groups III and IV). the former had more female cases. longer duration of illness. and more third-stage cases. In addition. the former contained more cases with lower brain weight and (predominant) frontal atrophy type. and more atypical cases without Pick bodies. or with symmetrical pyramidal tract degeneration or with combined traumatic lesions. It is notable that in all cases with definite SPN degeneration no extrapyramidal involuntary movements had been detected.
Somatosensory evoked potentials to median nerve stimulation after partial section of the corpus callosum, Cortical somatosensory evoked potentials (SEPs) to electrical stimulation of the median nerve were studied in four patients with intractable epilepsy who had undergone callosotomy and in a patient with infarction in the corpus callosum in order to determine whether the corpus callosum was involved in the generation of ipsilateral frontal components. Both pre- and postoperative SEPs were recorded in three of four epileptic patients. There were no significant differences in the latencies and amplitudes of the bilateral frontal components (P20. N26) between pre- and postoperative recordings. Furthermore. irrespective of the extent of the section or lesion in the corpus callosum. the nature of the impairment and the existence of the disconnection syndrome. the SEP findings showed no significant differences compared with those of normal subjects. It thus appears unlikely that the ipsilateral SEP responses are transmitted from the contralateral hemisphere through at least the anterior portion of the corpus callosum.
Somatostatin cerebrospinal fluid levels in dementia, Somatostatin levels were measured in cerebrospinal fluid of patients with Alzheimer's disease. multi-infarct dementia and normal pressure hydrocephalus and compared with levels from a normal control group. All pathological groups showed a statistically significant decrease of somatostatin with respect to the control group. but no significant differences were found amongst them. A negative correlation was found between the Mini Mental State Test and the somatostatin levels in Alzheimer's disease patients but not in the other groups. Our results confirm that the lower levels of somatostatin in cerebrospinal fluid are not specific to Alzheimer's disease and indicate that the decrease found in all the groups is probably the result of neuronal destruction or damage in the diseases examined.
Efficacy of dorsal longitudinal myelotomy in treating spinal spasticity: a review of 20 cases, The authors report their experience using dorsal longitudinal myelotomy in treating spasticity in 20 patients with complete spinal cord injuries. These patients suffered from severe painful flexor/extensor spasms that prevented them from wheelchair ambulation and/or their decubitus ulcers healing. All were receiving large doses of various oral drugs. including baclofen. which had failed to control their spasticity. and all underwent a modification of a posterior T-myelotomy as first described by Bischof. All 20 patients enjoyed immediate complete relief of their painful spasms. although two (10%) eventually experienced return of their spasms and are thus classified as long-term failures. Seventeen patients succeeded in markedly reducing. or being completely weaned from. their antispasmodic medications. In 11 of 14 patients. nonhealing decubitus ulcers subsequently healed with treatment. Bladder function was unchanged from the preoperative status in all patients. Chronic intrathecal baclofen infusion has recently been reported as an effective treatment of the spasticity of paraplegia. The results of this study. along with previous reports advocating dorsal longitudinal myelotomy. suggest that this approach is an efficacious alternative to chronic baclofen infusion in reducing spasticity for complete paraplegics. Considering the cost of the infusion pump. along with the fact that chronic intrathecal baclofen therapy necessitates long-term medical supervision. it appears that myelotomy is superior for this select group of patients who have no hope of regaining voluntary motor function.
Etiology of cerebral vasospasm in primates, A primate model was used to determine whether oxyhemoglobin (OxyHb). methemoglobin (MetHb). or bilirubin is likely to be responsible for cerebral vasospasm following subarachnoid hemorrhage (SAH). Forty cynomolgus monkeys were randomly assigned to one of five groups. On Day 0. each animal underwent angiography followed by right craniectomy and placement of an Ommaya reservoir with its catheter adjacent to the right middle cerebral artery (MCA). The animals received intrathecal injections twice a day for 6 days of one of the following solutions: mock cerebrospinal fluid (CSF); OxyHb; MetHb; bilirubin; or supernatant fluid from an incubated mixture of autologous blood and mock CSF. On Day 7. angiography was repeated and the animals were killed. Comparison of angiograms obtained on Day 0 and Day 7 of the experiment showed significant vasospasm of the right MCA and the right anterior cerebral and internal carotid arteries in the animal groups that had received OxyHb or supernatant fluid. There was a smaller reduction in diameter of the same vessels in the bilirubin group (not statistically significant). while no effects were observed in the groups receiving MetHb or mock CSF. Electron microscopy of the right MCA's gave results consistent with the angiographic findings. One monkey in the OxyHb group developed a delayed-onset right MCA infarction. These data suggest that OxyHb is the cause of cerebral vasospasm following SAH.
Effects of hypothermia and hyperthermia on the reactivity of rat intracerebral arterioles in vitro, The effects of hypothermia and hyperthermia on the cerebral microcirculation were studied using isolated perfused intracerebral (parenchymal) arterioles obtained from rats. In a temperature-dependent manner. hypothermia (20.0 degrees to 35.0 degrees C) dilated the spontaneous tone developed by the arterioles and also diminished their contractile response to potassium and prostaglandin F2 alpha. In contrast. hyperthermia (40.0 degrees to 45.0 degrees C) induced a biphasic response consisting of initial vasoconstriction and secondary vasodilation. Exposure of the vessels to 45.0 degrees C for 30 minutes irreversibly abolished the spontaneous tone and responsiveness of the arterioles when the temperature of the preparation was returned to 37.5 degrees C. In calcium-free solutions. however. the arteriolar diameter was not affected within a temperature range of 20.0 degrees to 45 degrees C. Furthermore. arterioles that had been in a calcium-free solution during exposure to 45 degrees C temperature recovered their viability at 37.5 degrees C. These results suggest that changes in ambient temperature alter calcium-induced contraction in arteriolar smooth muscle. and that the irreversible effects of hyperthermia on the arterioles are dependent upon extracellular calcium. These studies indicate that alterations in brain temperature may affect the pathogenesis of cerebral ischemia by mechanisms that are in part independent of parenchymal metabolism.
Expression of platelet-derived growth factor and transforming growth factor and their correlation with cellular morphology in glial tumors, This study was undertaken to evaluate the role of two sets of growth factors. platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). in the induction and maintenance of glial tumors and their phenotypic expression. Explants from eight malignant tumors. five benign tumors. and two nontumor glial cells were analyzed for levels of messenger ribonucleic acid (mRNA) expression of PDGFA. PDGFB. TGF-beta 1. and TGF-beta 2. Results were normalized to the mRNA expression of tubulin. a "housekeeping" gene present in glial cells. Of the 15 explants tested. PDGFB was seen in six. all of which were malignant tumors; PDGFA was seen in all 15 with much higher levels expressed in malignant tumors; and TGF-beta 1 and TGF-beta 2 were seen in all 15 without a clear difference between cell types. although expression tended to be higher in malignant tumors. This project supports the theory that the induction and maintenance of glial tumors is likely to be a multifactorial phenomenon.
Induction of cytosolic free calcium elevation in rat vascular smooth-muscle cells by cerebrospinal fluid from patients after subarachnoid hemorrhage, The purpose of this study was to determine the effects of cerebrospinal fluid (CSF) from patients with subarachnoid hemorrhage (SAH) on cytosolic free calcium in cultured rat vascular smooth-muscle cells using the fluorescent intracellular calcium indicator fura-2/AM. Samples of CSF were collected from 12 patients (seven with and five without vasospasm) on Days 2. 6. 11. and 16 after SAH. Control CSF samples were obtained from five patients 6 to 9 months after they had undergone successful aneurysm surgery following an SAH. All CSF samples in both the non-vasospasm and vasospasm groups. regardless of the day of sampling after the SAH. induced significantly higher transient intracellular calcium elevations when compared to levels induced by control CSF. Furthermore. the addition of 2 mM ethyleneglycol-bis (beta-aminoethylether)-N.N'-tetra-acetic acid (EGTA) caused a slight reduction in the peak height in the CSF-induced intracellular calcium rise which declined more rapidly to basal levels than those studied without EGTA. In the non-vasospasm group. the intracellular calcium concentration remained stable after SAH throughout the study period. In contrast. in the vasospasm group. this concentration was highest on Day 2 post-SAH. but sharply decreased on Day 6 and rose again on Day 11. This result correlated with the clinical signs of vasospasm in these patients. These findings indicated that the intracellular calcium elevations induced by CSF obtained after SAH were due to the combination of the influx of extracellular calcium and the mobilization of intracellular calcium from storage sites. The changes in intracellular calcium concentrations in vascular smooth-muscle cells induced by CSF obtained from patients on successive days following SAH suggest that the substances that induce this repeat calcium elevation on Day 11 post-SAH may be the key spasmogens for vasospasm after SAH.
Primary embryonal-cell carcinoma of the parietal lobe. Case report, A case of primary embryonal-cell carcinoma of the parietal lobe is reported. The unusually chronic presentation of such a malignant tumor is described. The atypical computerized tomography and magnetic resonance imaging characteristics of this lesion are presented. Review of the literature yielded no previous reports of a lobar embryonal-cell carcinoma. The rarity of intracranial germ-cell tumors presenting off the midline is discussed.
Traumatic pericallosal aneurysm in a patient with no major trauma. Case report, The case of a young woman who developed a traumatic distal anterior cerebral artery ("pericallosal") aneurysm from a roller-coaster ride is described. She presented with a subarachnoid hemorrhage (SAH) restricted to the interhemispheric fissure. The initial angiogram was normal but repeat angiography at 8 days revealed the aneurysm. After craniotomy and clipping the patient made a satisfactory recovery. This is the only reported case of a traumatic aneurysm arising under circumstances not usually considered as trauma. It raises questions about the pathophysiology of the formation of such aneurysms and suggests that traumatic pericallosal aneurysms should be considered in SAH of unknown etiology. This case provides further evidence that repeat angiography occasionally helps reveal an aneurysm when the initial study fails to do so.
Stabilization of traumatic atlanto-occipital dislocation. Case report, Traumatic atlanto-occipital dislocation is most often fatal. Consequently. there are only scattered case reports of patients surviving this injury. and treatment modalities are anecdotal and varied. The case of an 18-year-old woman who suffered an anterior atlanto-occipital dislocation as the result of a motor-vehicle accident is presented. Rigid posterior fixation and complete reduction of the dislocation were achieved using an anatomically contoured steel loop secured to the occiput and cervical vertebrae. The addition of cancellous bone to the graft afforded long-term stability. This operative treatment provided anatomical realignment of the dislocation and allowed early mobilization of the patient with the use of aggressive rehabilitation. Previously reported cases of patients surviving anterior atlanto-occipital dislocation are reviewed. The use of cervical traction. halo bracing. and operative stabilization is discussed.
Single-photon emission computed tomography in human immunodeficiency virus encephalopathy: a preliminary report, Depression or psychosis in a previously asymptomatic individual infected with the human immunodeficiency virus (HIV) may be psychogenic. related to brain involvement by the HIV or both. Although prognosis and treatment differ depending on etiology. computed tomography (CT) and magnetic resonance imaging (MRI) are usually unrevealing in early HIV encephalopathy and therefore cannot differentiate it from psychogenic conditions. Thirty of 32 patients (94%) with HIV encephalopathy had single-photon emission computed tomography (SPECT) findings that differed from the findings in 15 patients with non-HIV psychoses and 6 controls. SPECT showed multifocal cortical and subcortical areas of hypoperfusion. In 4 cases. cognitive improvement after 6-8 weeks of zidovudine (AZT) therapy was reflected in amelioration of SPECT findings. CT remained unchanged. SPECT may be a useful technique for the evaluation of HIV encephalopathy.
Assessment of systolic thickening with thallium-201 ECG-gated single-photon emission computed tomography: a parameter for local left ventricular function, We measured left ventricular (LV) systolic thickening expressed as a systolic thickening ratio in 28 patients. using 201Tl ECG-gated SPECT. Five normals. 15 patients with prior myocardial infarction. 5 with hypertrophic cardiomyopathy. and 3 with dilated cardiomyopathy were studied. The systolic thickening ratio was calculated as [(end-systolic--end-diastolic pixel counts) divided by end-diastolic pixel counts]. using the circumferential profile technique of both end-diastolic and end-systolic short axial images. Functional images of the systolic thickening ratio were also displayed with the "bull's-eye" method. The mean systolic thickening ratio thus calculated were as follows: normals. 0.53 +/- 0.05 (mean +/- 1 s.d.); non-transmural prior myocardial infarction. 0.33 +/- 0.09; transmural prior myocardial infarction. 0.14 +/- 0.05; hypertrophic cardiomyopathy in relatively nonhypertrophied areas. 0.56 +/- 0.11; hypertrophic cardiomyopathy in hypertrophied areas. 0.23 +/- 0.07; and dilated cardiomyopathy. 0.19 +/- 0.02. The systolic thickening ratio analysis by gated thallium SPECT offers a unique approach for assessing LV function.
Assessment of 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone as a positron-emitting radiopharmaceutical for the detection of progestin receptors in human breast carcinomas, We have used 21-[18F]fluoro-16 alpha-ethyl-19-norprogesterone (FENP) for imaging progestin receptors by PET in patients with primary carcinoma of the breast. In vitro binding and in vivo tissue distribution studies in rats have shown that FENP has high specific activity. high affinity for progestin receptors. and receptor-mediated uptake in target tissues. Eight patients with primary breast carcinoma were studied. Breast carcinoma was identified correctly in 50% of the patients with progestin-receptor-positive tumors; however. the FENP uptake was not correlated with progestin-receptor levels. We noted a low target-to-background ratio in humans. with high relative activity in the spine. blood pool. and normal breast tissue. Our findings indicate that FENP is not a suitable agent for imaging progestin receptors in humans.
False-negative dipyridamole-thallium-201 myocardial imaging after caffeine infusion, The vasodilator effect of intravenously administered dipyridamole may be caused by an increase in endogenous plasma adenosine levels. We evaluated the effect of caffeine. an adenosine receptor antagonist. on the diagnostic results of dipyridamole-201Tl myocardial imaging in eight patients with coronary artery disease. Caffeine infusion significantly attenuated the dipyridamole-induced fall in blood pressure and the accompanied increase in heart rate. The infusion of dipyridamole alone resulted in chest pain and ST-segment depressions on the electrocardiogram in four patients. whereas none of these problems occurred when the tests were repeated after caffeine. In six of eight patients. caffeine was responsible for false-negative dipyridamole-201Tl tests. Semiquantitive scores of the dipyridamole-induced 201Tl perfusion defects were decreased by caffeine from 9.0 +/- 0.9 to 2.0 +/- 1.1 points (p less than 0.05). Computerized analysis revealed a caffeine-mediated reduction in the percent reversibility of the images from 46% +/- 16% to 6% +/- 10% (p less than 0.05). We conclude that the use of caffeinated products prior to dipyridamole-201Tl testing may be responsible for false-negative findings.
Correlation of technetium-99m-DISIDA hepatobiliary studies with biopsies in liver transplant patients, We compared 76 99mTc-DISIDA hepatobiliary studies with corresponding liver biopsies in 36 liver transplant patients to determine the histopathologic abnormalities that corresponded to scintigraphic abnormalities in uptake and excretion. Uptake was judged normal if the cardiac blood pool was barely visible or invisible on the ten minute image. Excretion was judged normal if images subsequent to the 15-min image showed a subjectively normal rate of decreasing parenchymal intensity. Biopsies were graded subjectively for hepatocyte damage and for findings of cholestasis. Uptake criteria were successful in differentiating high from low hepatocyte damage scores (p less than 0.0001). and excretion criteria were successful in differentiating high from low cholestasis scores (p = 0.002). while uptake criteria were not capable of differentiating high from low cholestasis scores. nor were excretion criteria capable of differentiating high from low hepatocyte damage scores (p's greater than 0.05). These results suggest that scintigraphy can distinguish intrahepatic cholestasis from pure hepatocyte damage.
Glucose uptake, perfusion, and cell proliferation in head and neck tumors: relation of positron emission tomography to flow cytometry, The uptake of 18F-Deoxyglucose (FDG) was studied in vivo in relation to the proliferation rate of human head and neck tumors. Forty-two patients with histologically proven squamous-cell carcinoma of the head and neck and four patients with metastases of head and neck tumors were examined with PET and FDG prior to surgery. In 35 of these patients. a flow cytometric analysis of the DNA content and the proliferation rate was done using one-dimensional flow cytometry rate was done using one-dimensional flow cytometry (DAPI staining). In 17 cases. perfusion studies with 15O-labeled water were performed. Twenty-seven specimens were evaluable by flow cytometry. The analysis of the distribution of the FDG uptake revealed two groups. showing a high and a lower uptake pattern. In both groups the FDG uptake and the proliferation rate were correlated with an r-value of 0.64 and 0.8 respectively. However. the slope of the regression function was flat. No correlation was found between the perfusion and the proliferation rate. It is suggested that these differences in uptake in histologically identical tumor populations may correspond to differences at the molecular level. e.g.. differences in the amount of the glucose carrier. perhaps caused by oncogenic transformation.
Effect of exercise supplementation on dipyridamole thallium-201 image quality, To determine the effect of different types of exercise supplementation on dipyridamole thallium image quality. 78 patients were prospectively randomized to one of three protocols: dipyridamole infusion alone. dipyridamole supplemented with isometric handgrip. and dipyridamole with low-level treadmill exercise. Heart-to-lung. heart-to-liver. and heart-to-adjacent infradiaphragmatic activity ratios were generated from anterior images acquired immediately following the test. Additionally. heart-to-total infradiaphragmatic activity was graded semiquantitatively. Results showed a significantly higher ratio of heart to subdiaphragmatic activity in the treadmill group as compared with dipyridamole alone (p less than 0.001) and dipyridamole supplemented with isometric handgrip exercise (p less than 0.001). No significant difference was observed between patients receiving the dipyridamole infusion. and dipyridamole supplemented with isometric handgrip exercise. We conclude that low-level treadmill exercise supplementation of dipyridamole infusion is an effective means of improving image quality. Supplementation with isometric handgrip does not improve image quality over dipyridamole alone.
Exercise supplementation of dipyridamole for myocardial perfusion imaging [editorial; comment, The substitution of intravenous dipyridamole for symptom-limited treadmill exercise has provided a non-invasive means to diagnose coronary artery disease with 201Tl scintigraphy in patients unable to adequately exercise. Limitations of dipyridamole/thallium imaging are primarily due to suboptimal image quality secondary to hepatic tracer concentration and decreased test sensitivity in patients who are dipyridamole "non-responders." Low-level treadmill exercise supplementation improves image quality. whereas handgrip has little. if any. benefit. The effect of low-level exercise in augmenting coronary blood flow is unknown and reports regarding the effect of handgrip are conflicting. The diagnostic benefit of these maneuvers in improving test sensitivity and decreasing the number of "non-responders" has not been documented. The combination of maximal. symptom-limited treadmill exercise and intravenous dipyridamole is a theoretically attractive option to improve overall test sensitivity. but the physiologic consequences and potential side effects should be more thoroughly investigated.
Imaging of cocaine-induced global and regional myocardial ischemia, Severe and often fatal cardiac complications have been reported in cocaine users with narrowed coronary arteries caused by atherosclerosis as well as in young adults with normal coronaries. We have found that in normal dogs cocaine induces severe temporary hypoperfusion of the left ventricle as indicated by a significantly lower 201Tl concentration compared to the baseline state. The most significant decrease in uptake occurred 5 min after injection and was more pronounced in the septal and apical segments. Following intravenous administration of cocaine. instead of gradual disappearance of 201Tl from the left ventricle. there was continuous increase in 201Tl concentration in the left ventricle. These imaging experiments indicate that the deleterious effects of cocaine on the heart are probably due to spasm of the coronaries and decreased myocardial perfusion. Since spasm of the large subpericardial vessels does not seem to explain the magnitude of the increased coronary resistance and decreased coronary flow after cocaine as described in the literature. it is suggested that microvascular spasm of smaller vessels plays a major role in the temporary decrease in perfusion. The data may also suggest that severe temporary myocardial ischemia is probably the initiating factor for the cardiac complications induced by cocaine.
Synthesis and evaluation of new iodine-125 radiopharmaceuticals as potential tracers for malignant melanoma, The synthesis. labeling. and biodistribution of four 125I radiopharmaceuticals designed to localize in melanoma were tested. Uptake in tumors was demonstrated by autoradiography of whole-body sections and quantitated by measurement of radioactivity of selected tissues and tumors using melanoma-bearing mice. N-(2-diethylaminoethyl)-4-iodobenzamide was selected for its highest melanoma uptake: 60 min after IV injection of 6.5% and 4% ID/g. respectively for murine B16 and human melanotic melanoma. Tumor uptake showed the highest values of all analyzed tissues from 6 to 24 hr after injection. High uptake in melanotic tumor tissue with relatively low uptake in blood. muscle. brain. lung. and liver tissue resulted in high tumor/nontumor ratios (at 24 hr for B16. tumor/blood = 37. tumor/brain = 147. tumor/muscle = 95). This agent was compared with iodoamphetamine. Scintigraphic images of the tumor confirmed that external detection of melanoma is possible with this new radiopharmaceutical.
Quantitation of the critically ischemic zone at risk during acute coronary occlusion using PET, Critical myocardial ischemia has been defined experimentally during acute coronary occlusion as flow reduction of 50% or more since cellular ATP depletion begins to occur beyond this flow reduction threshold. placing tissue at risk of cellular injury. To test the hypothesis that critically ischemic fractional left ventricular mass can be measured noninvasively with PET. nine dogs were imaged in a multi-slice positron camera using the perfusion tracer 13N-ammonia. while radiolabeled microspheres were injected into the left atrium during acute coronary occlusion. Images were processed using a 50% threshold and the size of the resulting perfusion defect was expressed as a fraction of total left ventricular image volume. The critically ischemic left ventricular fraction determined in vitro from the microsphere perfusion data. ranged from 5% to 30% of the total left ventricular weight and correlated closely with that determined noninvasively by PET with r = 0.94 (y = 1.05X - 2.0%). We conclude that the fraction of left ventricular myocardium rendered critically ischemic during acute coronary occlusion can be measured accurately and noninvasively in vivo using perfusion imaging with positron emission tomography.
PET measurements of hyperthermia-induced suppression of protein synthesis in tumors in relation to effects on tumor growth, Hyperthermia-induced metabolic changes in tumor tissue have been monitored by PET. Uptake of L-[1-11C]tyrosine in rhabdomyosarcoma tissue of Wag/Rij rats was dose-dependently reduced after local hyperthermia treatment at 42. 45. or 47 degrees C. Tumor blood flow. as measured by PET with 13NH3. appeared to be unchanged. The L-[1-11C]tyrosine uptake data were compared to uptake data of L-[1-14C]tyrosine and with data on the incorporation of L-[1-14C]tyrosine into tumor proteins. After intravenous injection. the 14C data were obtained from dissected tumor tissue. Heat-induced inhibition of the incorporation of L-[1-14C]tyrosine into tumor proteins tallied with the L-[1-11C]tyrosine uptake data. Heat-induced inhibition of amino acid uptake in the tumor correlated well with regression of tumor growth. It is concluded that PET using L-[1-11C]tyrosine is eligible for monitoring the effect of hyperthermia on tumor growth.
Acute gastrointestinal hemorrhage detected by selective scintigraphic angiography, Intra-arterial 99mTc colloid scintigraphy may have greater sensitivity than either standard intravenous scintigraphy or selective arteriography in detecting gastrointestinal bleeding. Ten millicuries of 99mTc colloid were administered directly into the superior and inferior mesenteric arteries (SMA and IMA) of patients who had undergone selective arterial catheterization for the evaluation of gastrointestinal bleeding. In one patient. 99mTc-albumin colloid was administered directly into the IMA and identified diverticular bleeding. The bleeding had been occult to prior contrast arteriography and refractory to selective intra-arterial Pitressin therapy. In a second patient who had undergone three negative provocative angiograms. selective SMA injection of 99mTc-sulfur colloid identified occult mesenteric varices secondary to portal hypertension. Selective intra-arterial scintigraphy should be valuable in detecting intestinal bleeding occult to conventional studies. This will help in directing further therapy and diagnostic evaluation.
Diagnosis of segmental necrosis in a pancreas transplant by thallium-201 perfusion scintigraphy, Thallium-201 was used to image a patient with a pancreatic transplant. Incomplete visualization of the graft on the 201Tl scan. compared to CT. led to the diagnosis of segmental necrosis of the tail of the graft. Due to the low background and favorable target-to-non-target ratio. 201Tl pancreas scintigraphy may be useful in the follow-up of pancreatic transplants.
PET study of carbon-11-PK 11195 binding to peripheral type benzodiazepine sites in glioblastoma: a case report, The utility of the peripheral type benzodiazepine site ligand 11C-PK 11195. for imaging human glioma in conjunction with Positron Emission Tomography. relies on a high specific binding of the tracer to tumoral peripheral type benzodiazepines sites. In a patient with glioblastoma. we found that 11C-PK 11195 binding was two-fold higher in the tumor than in normal gray matter and that 30% of tumoral binding could be displaced by a large excess of unlabeled drug. These findings suggest that tumoral retention of the ligand is due. in part. to specific binding.
Thallium myocardial scintigraphy in congenitally-corrected transposition of the great arteries, A case of congenitally-corrected transposition of the great arteries is presented with the correlation of thallium scintigraphic results with catheterization data. The essential features of the thallium scintigrams were marked counterclockwise rotation of the heart with perfusion abnormalities of the inferior wall and apex. Since patients with congenitally-corrected transposition of the great arteries may present with the symptom of chest pain. the diagnosis of transposition of the great arteries should be considered in patients with marked counterclockwise rotation of the heart and segmental perfusion abnormalities on thallium scintigraphy.
Evolution of technetium-99m-HMPAO SPECT and brain mapping in a patient presenting with echolalia and palilalia, A 78-yr-old woman presented with transient echolalia and palilalia. She had suffered from Parkinson's disease for 2 yr. Routine laboratory examination showed hypotonic hyponatremia. but was otherwise unremarkable. Brain mapping revealed a bifrontal delta focus. more pronounced on the right. Single photon emission computed tomography (SPECT) of the brain with technetium-99m labeled d.l hexamethylpropylene-amine oxime (99mTc-HMPAO). performed during the acute episode showed relative frontoparietal hypoactivity. Brain mapping performed after disappearance of the echolalia and palilalia. which persisted only for 1 day. was normal. By contrast. SPECT findings persisted for more than 3 wk. Features of particular interest in the presented patient are the extensive defects seen on brain SPECT despite the absence of morphologic lesions. the congruent electrophysiologic changes and their temporal relationship with the clinical evolution.
A nurse-managed special care unit, The authors describe the first year of operation of a nurse-managed intensive care unit (ICU). Concerned with the problems. costs. and inadequacies of caring for long-term patients in traditional ICUs. nurse administrators designed a special care unit that incorporates a physical design facilitating family involvement and rehabilitative care. registered nurse case management. and a shared governance management philosophy. Compared with traditional ICUs. the effectiveness of the special care unit is tested in terms of patient and nurse outcomes. Implications of this innovation for health-care delivery systems and the nursing profession are discussed.
Photodynamic killing of human squamous cell carcinoma cells using a monoclonal antibody-photosensitizer conjugate, We have developed procedures in which the photosensitizer benzoporphyrin derivative monoacid ring A (BPD) can be covalently linked to carrier molecules of modified polyvinyl alcohol (PVA) to produce water-soluble PVA-BPD conjugates with a molecular mass in the range of 30 kd. These carriers can subsequently be covalently linked to monoclonal antibodies (MoAbs) using heterobifunctional linking agents. We describe here such a conjugate in which the MoAb (5E8) has specificity for a glycoprotein detected on human squamous cell carcinomas of the lung. We provide evidence that the conjugates produced were covalently linked and retained both their photosensitizing and antigen-binding activities. We show further that the MoAb-PVA-BPD conjugate. in the presence of 10% fetal calf serum. exhibited highly enhanced phototoxic killing of the target cell line (A549) over that exhibited by free BPD or a control MoAb-PVA-BPD conjugate. These results demonstrate. therefore. both the selectivity and specificity of this MoAb conjugate.
Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine riboside: optimization of 6-methylmercaptopurine riboside dose and schedule through biochemical analysis of sequential tumor biopsy specimens, Preclinical and clinical studies demonstrate that the selective antitumor activity of fluorouracil (5-FU) is enhanced by agents which perturb certain intracellular nucleotide pools. We previously demonstrated that the combination of N-phosphonacetyl-L-aspartate (PALA). which depletes pyrimidine nucleotide pools. and 5-FU yielded a 43% response rate among 37 assessable patients with colorectal carcinoma. In preclinical tumor models. 6-methylmercaptopurine riboside (MMPR). an inhibitor of purine synthesis. elevates phosphoribosylpyrophosphate (PRPP) pools and promotes the anabolism of 5-FU to fluorinated nucleotides. In vivo. the addition of MMPR enhances the therapeutic efficacy of PALA-5-FU. In a phase I trial. we sought to determine the optimal dose and schedule of MMPR in combination with PALA (250 mg/m2 on day 1) and 5-FU (1300 mg/m2 by 24-hour infusion on day 2). MMPR (75-225 mg/m2) was given intravenously on day 1 to 27 patients with solid tumors (15 colorectal. seven breast. five other). Toxic effects were mild to moderate and included leukopenia. mucositis. nausea. or rash. Two of seven patients given MMPR at 225 mg/m2 had grade 3 diarrhea. PRPP was measured using a [14C]orotic acid 14CO2 release assay in tumor biopsy specimens obtained before and 12 hours and 24 hours after MMPR doses were given to 20 patients. The addition of MMPR elevated PRPP pools in human solid tumors. At 12 hours after treatment. two (50%) of four patients showed a twofold or greater elevation of PRPP at the MMPR dose level of 75 mg/m2; a similar elevation was observed in five (71%) of seven patients given 150 mg/m2 MMPR and in three (43%) of seven patients given 225 mg/m2 MMPR. At 24 hours after treatment. results for the respective dose levels of MMPR were two (33%) of six patients. one (20%) of five patients. and four (57%) of seven patients. Administration of the two highest MMPR dose levels appeared to result in a greater increase in tumor PRPP levels. However. toxicity was greater at the 225 mg/m2 dose level; therefore. the 150 mg/m2 dose level was favored. Tumor levels of PRPP decreased between 12 hours and 24 hours in nine (56%) of 16 patients. This time course indicates that MMPR should be administered at the beginning of the 24-hour infusion of 5-FU.
Long-term mortality after 5-year multifactorial primary prevention of cardiovascular diseases in middle-aged men, OBJECTIVE. To investigate the long-term effects of multifactorial primary prevention of cardiovascular diseases (CVD). DESIGN. The 5-year randomized. controlled trial was performed between 1974 and 1980. The subjects and their risk factors were reevaluated in 1985. Posttrial mortality follow-up was continued up to December 31. 1989. SETTING. Institute of Occupational Health. Helsinki. Finland. and Second Department of Medicine. University of Helsinki. PARTICIPANTS. In all. 3490 business executives born during 1919 through 1934 participated in health checkups in the late 1960s. In 1974. 1222 of these men who were clinically healthy. but with CVD risk factors. were entered into the primary prevention trial; 612 were randomized to an intervention and 610 to a control group. INTERVENTIONS. During the 5-year trial. the subjects of the intervention group visited the investigators every fourth month. They were treated with intensive dietetic-hygienic measures and frequently with hypolipidemic (mainly clofibrate and/or probucol) and antihypertensive (mainly beta-blockers and/or diuretics) drugs. The control group was not treated by the investigators. MAIN OUTCOME MEASURES. Total mortality. cardiac mortality. mortality due to other causes. RESULTS. Total coronary heart disease risk was reduced by 46% in the intervention group as compared with the control group at end-trial. During 5 posttrial years. the risk factor and medication differences were largely leveled off between the groups. Between 1974 and 1989 the total number of deaths was 67 in the intervention group and 46 in the control group (relative risk [RR]. 1.45; 95% confidence interval [CI]. 1.01 to 2.08; P = .048); there were 34 and 14 cardiac deaths (RR. 2.42; 95% CI. 1.31 to 4.46; P = .001). two and four deaths due to other CVD (not significant). 13 and 21 deaths due to cancer (RR. 0.62; 95% CI. 0.31 to 1.22; P = .15). and 13 and one deaths due to violence (RR. 13.0; 95% CI. 1.70 to 98.7; P = .002). respectively. Multiple logistic regression analysis of treatments in the intervention group did not explain the 15-year excess cardiac mortality. CONCLUSION. These unexpected results may not question multifactorial prevention as such but do support the need for research on the selection and interaction(s) of methods used in the primary prevention of cardiovascular diseases.
The geographic spread and temporal increase of the Lyme disease epidemic, OBJECTIVE. To describe the temporal and geographic progression of the Lyme disease epidemic in New York State from 1977 through 1989. DESIGN. Communicable disease surveillance system. SETTING. Statewide. MAIN OUTCOME MEASURES. The progression of the epidemic was examined by analyzing trends in Lyme disease cases reported to the state surveillance system. town and county Lyme disease incidence rates. Lyme disease hospital discharge rates. and the distribution of Ixodes dammini ticks obtained from surveillance efforts and submitted for identification. MAIN RESULTS. The number of confirmed Lyme disease cases in New York has increased with concurrent increases in the number of hospital discharges. The number of counties endemic for Lyme disease increased from four to eight between 1985 and 1989. The number of counties with documented I dammini ticks increased from four in 1985 to 22 in 1989. Incidence of the disease also increased within known endemic counties. CONCLUSIONS. Tick surveillance indicated that the range of I dammini has expanded annually into areas up to 384 km from the original known endemic areas of Long Island. NY. and Connecticut. Cumulative data from human surveillance resources document both temporal increases and geographic expansion of the Lyme disease epidemic in New York.
Survival of DNA HLA-DR typed and matched cadaver kidney transplants. The Collaborative Transplant Study, The clinical value of serological HLA matching for cadaver kidney transplantation remains uncertain because the success rate for HLA-matched cadaver transplants is lower than that of HLA-matched sibling grafts. Up to 25% of serological HLA-DR typings may be incorrect when compared with a more accurate DNA-RFLP method. and we have now examined whether incorrect HLA-DR typings account for the lower than expected success rates of HLA-matched cadaver transplants. 58 transplant centres took part in this study and DNA was extracted from over 4000 samples of frozen tissue at the study centre. 8 laboratories then completed blind RFLP typing for HLA-DR. Serological typing data were reported by individual transplant laboratories. 29 of 107 transplants (27%) that were reported as HLA A. B. DR compatible and 76 of 273 (28%) transplants that were reported as HLA B. DR compatible according to serological typing were found to be HLA-DR mismatched by DNA typing. The one-year transplant success rate for DNA-matched HLA. A. B. DR grafts was 87% compared with 69% for mismatched grafts (p less than 0.02); the corresponding success rate for DNA-matched HLA B. DR grafts was 85% compared with 72% for mismatched grafts (p less than 0.01). Many transplants that were previously thought to be HLA matched are mismatched. and this finding may account for previously unexplained graft failures.
Prospective study of alcohol consumption and risk of coronary disease in men, Although an inverse association between alcohol consumption and risk of coronary artery disease has been consistently found in several types of studies. some have argued that the association is due at least partly to the inclusion in the non-drinking reference group of men who abstain because of pre-existing disease. The association between self-reported alcohol intake and coronary disease was studied prospectively among 51.529 male health professionals. In 1986 the participants completed questionnaires about food and alcohol intake and medical history. heart disease risk factors. and dietary changes in the previous 10 years. Follow-up questionnaires in 1988 sought information about newly diagnosed coronary disease. 350 confirmed cases of coronary disease occurred. After adjustment for coronary risk factors. including dietary intake of cholesterol. fat. and dietary fibre. increasing alcohol intake was inversely related to coronary disease incidence (p for trend less than 0.001). Exclusion of 10.302 current non-drinkers or 16.342 men with disorders potentially related to coronary disease (eg. hypertension. diabetes. and gout) which might have led men to reduce their alcohol intake. did not substantially affect the relative risks. These findings support the hypothesis that the inverse relation between alcohol consumption and risk of coronary disease is causal.
Opportunistic non-Hodgkin's lymphomas among severely immunocompromised HIV-infected patients surviving for prolonged periods on antiretroviral therapy--United States, Since 1982. high-grade B-cell non-Hodgkin's lymphomas (NHLs) have been reported among persons with human immunodeficiency virus (HIV) infection (1); in 1985. CDC revised the surveillance case definition for acquired immunodeficiency syndrome (AIDS) to include certain high-grade NHLs. Recent surveillance findings indicate that NHLs occur among approximately 3% of all adults with AIDS reported to CDC. This report characterizes the occurrence of NHLs in a cohort of persons with AIDS or severe HIV infection who have received long-term zidovudine (AZT)-based therapy.
Child passenger restraint use and motor-vehicle--related fatalities among children--United States, 1982-1990, Although in recent years the increase in child safety seat use in the United States has saved lives of and prevented injuries to infants (children aged less than or equal to 1 year) and toddlers (children aged 1-4 years). the leading cause of death among U.S. children aged 1-4 years continues to be injuries to motor-vehicle occupants (1). These injuries account for the largest number of years of potential life lost before age 65 and the highest costs associated with pediatric injury (2). This report. based on data from the Fatal Accident Reporting System (FARS) (maintained by the National Highway Traffic Safety Administration). summarizes overall trends from 1982 through 1990 for motor-vehicle-related fatalities among children and lives saved by child passenger restraint use.
AAEM case report #3: myasthenia gravis, Reported here are the electrodiagnostic findings in a patient with myasthenia gravis who had dysarthria. dysphagia. and dyspnea. The use of repetitive nerve stimulation and single fiber electromyography studies for the evaluation of patients suspected of myasthenia gravis is reviewed.
Electrophysiological improvement following decompression surgery in tarsal tunnel syndrome, Plantar nerve conduction studies 14 months to 3.5 years after decompression surgery in 3 cases of tarsal tunnel syndrome showed an improvement in motor conduction as well as in sensory nerve conduction. This electrophysiological improvement was associated with clinical improvement. However. minor abnormalities still existed in sensory nerve conduction in all 3 cases.
The natural history of minicore-multicore myopathy, To determine the natural history of minicore-multicore myopathy (MMM) we studied 5 patients who were found to have this disorder from 6 to 16 years ago. Four of these patients had improved muscle strength since their original assessment and one patient had deteriorated. There were no clinical electrophysiological or pathological features that distinguished this last patient from the others. We conclude. therefore. that most patients with MMM may be expected to improve as time passes but. for unknown reasons. a minority may deteriorate. This information should be helpful to clinicians in their prognostic advice to new patients.
The extent and time course of motoneuron involvement in amyotrophic lateral sclerosis, The numbers and relative sizes of motor units have been estimated in 373 muscles of 123 patients with ALS: 74 of the muscles were examined on more than one occasion. The median duration between the onset of symptoms and the initial examination was 12 months; by this time. approximately 90% of the tested muscles showed losses of motor units. The evoked motor unit potentials continued to enlarge in most. but not all. muscles as the disease progressed. Once a muscle became affected by the disease process. the average time-course was such that the motor unit population halved in each 6-month period of the first year and diminished more slowly thereafter. A small proportion of patients was encountered in whom the disease progressed much more slowly and there were occasional large fluctuations in the motor unit estimates suggestive of reversible motoneuron dysfunction.
CO2 laser-induced pain-related somatosensory evoked potentials in peripheral neuropathies: correlation between electrophysiological and histopathological findings, Pain-related somatosensory evoked potentials (pain SEPs) following CO2 laser stimulation as well as conventional electrically stimulated SEPs (electric SEPs) were examined in 10 patients with peripheral neuropathies in whom the histopathological examination of the sural nerve was done. Results of pain SEPs showed a positive relationship with clinical impairment of pain sensation and densities of small myelinated fibers of the sural nerve. In contrast. results of electric SEPs showed a positive relationship with clinical impairment of deep and tactile sensations and with densities of large myelinated fibers of the sural nerve. Therefore. pain SEPs are considered to be generated by ascending signals mediated through nociceptive receptors and A delta fibers. The pain SEP is only one noninvasive and objective method currently available to investigate a physiological condition of the sensory pathway responsible for pain sense. and is especially useful when combined with the conventional electric SEPs.
Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery, BACKGROUND. Preterm delivery is the leading cause of neonatal mortality in the United States. but efforts to address the problem are hampered by the inability to predict accurately which pregnancies are at risk. We postulated that damage to the fetal membranes may release fetal fibronectin into the cervix and vagina. giving rise to a biochemical marker for preterm delivery. METHODS. We measured fetal-fibronectin concentrations in cervical and vaginal secretions. amniotic fluid. and maternal plasma with a sensitive immunoassay using the monoclonal antibody FDC-6. Immunohistochemical studies were used to determine the distribution of fetal fibronectin in the placenta and amniochorionic membranes and to ascertain its cell of origin. RESULTS. Women with uncomplicated pregnancies (n = 163) who delivered at term rarely had cervicovaginal fetal-fibronectin concentrations above 0.05 micrograms per milliliter between 21 and 37 weeks of gestation (11 of 267 cervical samples [4 percent] and 9 of 267 vaginal samples [3 percent]. High levels of fetal fibronectin were detected in amniotic fluid and in the cervical or vaginal secretions of 93.8 percent of the women with preterm rupture of membranes (n = 65). Cervical or vaginal fetal fibronectin was also present in 50.4 percent of the women with preterm uterine contractions and intact membranes (n = 117). and its presence identified the women who delivered before term (n = 60) with a sensitivity of 81.7 percent and a specificity of 82.5 percent. In the placenta and membranes. fetal fibronectin was found at points of contact with the uterine wall. CONCLUSIONS. The presence of cervicovaginal fetal fibronectin in the second and third trimesters of pregnancy identifies a subgroup of women who are at high risk for preterm delivery. This phenomenon may reflect the separation of the chorion from the decidual layer of the uterus. with the release of intact or degraded chorionic components of the extracellular matrix into the cervical and vaginal secretions.
Long-term developmental outcome of infants with iron deficiency, BACKGROUND. Iron-deficiency anemia has been associated with lowered scores on tests of mental and motor development in infancy. However. the long-term developmental outcome of infants with iron deficiency is unknown. because developmental tests in infancy do not predict later intellectual functioning. METHODS. This study is a follow-up evaluation of a group of Costa Rican children whose iron status and treatment were documented in infancy. Eighty-five percent (163) of the 191 children in the original group underwent comprehensive clinical. nutritional. and psychoeducational assessments at five years of age. The developmental test battery consisted of the Wechsler Preschool and Primary Scale of Intelligence. the Spanish version of the Woodcock-Johnson Psycho-Educational Battery. the Beery Developmental Test of Visual-Motor Integration. the Goodenough-Harris Draw-a-Man Test. and the Bruininks-Oseretsky Test of Motor Proficiency. RESULTS. All the children had excellent hematologic status and growth at five years of age. However. children who had moderately severe iron-deficiency anemia as infants. with hemoglobin levels less than or equal to 100 g per liter. had lower scores on tests of mental and motor functioning at school entry than the rest of the children. Although these children also came from less socioeconomically advantaged homes. their test scores remained significantly lower than those of the other children after we controlled for a comprehensive set of background factors. For example. the mean (+/- SD) adjusted Woodcock-Johnson preschool cluster score for the children who had moderate anemia in infancy (n = 30) was 448.6 +/- 9.7. as compared with 452.9 +/- 9.2 for the rest of the children (n = 133) (P less than 0.01); the adjusted visual-motor integration score was 5.9 +/- 2.1. as compared with 6.7 +/- 2.3 (P less than 0.05). CONCLUSIONS. Children who have iron-deficiency anemia in infancy are at risk for long-lasting developmental disadvantage as compared with their peers with better iron status.
Intrathecal immune response in patients with the post-polio syndrome, BACKGROUND. The syndrome of progressive muscular atrophy decades after acute paralytic poliomyelitis (post-polio syndrome) is not well understood. The theory that physiologic changes and aging cause the new weakness does not explain the immunologic abnormalities reported in some patients. An alternative explanation is persistent or recurrent poliovirus infection. METHODS. We assessed the intrathecal antibody response to poliovirus and intrathecal production of interleukin-2 and soluble interleukin-2 receptors in 36 patients with the post-polio syndrome and 67 controls (including 13 who had had poliomyelitis but had no new symptoms and 18 with amyotrophic lateral sclerosis). Intrathecal antibody responses to measles. mumps. herpes simplex. and varicella zoster viruses were also determined. RESULTS. Oligoclonal IgM bands specific to poliovirus were detected in the cerebrospinal fluid of 21 of the 36 patients with the post-polio syndrome (58 percent) but in none of the control group (P less than 0.0001). In quantitative studies there was evidence of increased intrathecal synthesis of IgM antibodies to poliovirus only among the patients with the post-polio syndrome; there was no increased synthesis of IgM to measles. mumps. herpes simplex. or varicella zoster viruses. The patients with post-polio syndrome had significantly higher mean (+/- SD) (cerebrospinal fluid levels of interleukin-2 and soluble interleukin-2 receptors than the controls (8.1 +/- 5.3 vs. 1.4 +/- 0.8 U per milliliter and 159.6 +/- 102.9 vs. 10.7 +/- 6.2 U per milliliter. respectively). The intrathecal synthesis of IgM antibodies to poliovirus correlated with the cerebrospinal fluid concentrations of interleukin-2 (P less than 0.0005) and soluble interleukin-2 receptors (P less than 0.001). CONCLUSIONS. An intrathecal immune response against poliovirus is present in many patients with the post-polio syndrome. In some of these patients the recrudescence of muscle weakness may be caused by persistent or recurrent infection of neural cells with the poliovirus.
Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations, BACKGROUND. To evaluate the feasibility and efficacy of measuring immunoreactive trypsinogen in blood to screen for cystic fibrosis. we performed this test in 279.399 newborns in Colorado from 1982 to 1987. METHODS. Immunoreactive trypsinogen was measured in dried blood spots when the infants were 1 to 4 days old; if the level was elevated (greater than or equal to 140 micrograms per liter). the measurement was repeated (mean age. 38 days); if the level was again elevated. sweat testing was performed (mean age. 49 days). For the second test. two cutoff levels (120 and 80 micrograms per liter) were evaluated. RESULTS. We found an incidence of cystic fibrosis of 1 in 3827 (0.26 per 1000). with 3.2 newborns per 1000 requiring repeat measurement. When adjusted for race and compliance with testing. the incidence among the white infants (1 in 2521) was close to the expected incidence. The false positive rate with the initial cutoff level (92.2 percent) was similar to the rate found in neonatal screening programs for other diseases. False negative results occurred because of laboratory error or changes in procedure (three infants) and trypsinogen concentrations lower than the initial cutoff level (three infants) or lower than the remeasurement cutoff level of 120 micrograms per liter (one infant). Sweat tests were negative in 168 infants with an elevated initial trypsinogen level but a level below 80 micrograms per liter on remeasurement. confirming the value of 80 micrograms per liter as an appropriate cutoff for repeat-test results. Overall. 95.2 percent of the infants with cystic fibrosis (95 percent confidence interval. 85 to 99 percent) who did not have meconium ileus could be identified with the use of a trypsinogen cutoff level of 140 micrograms per liter on initial testing and 80 micrograms per liter on repeat testing. CONCLUSIONS. Statewide screening for cystic fibrosis based on measurements of immunoreactive trypsinogen in dried blood spots is feasible and can be implemented with acceptable rates of repeat testing and false positive and false negative results.
A randomized trial of treatment options for alcohol-abusing workers, BACKGROUND. Employee-assistance programs sponsored by companies or labor unions identify workers who abuse alcohol and refer them for care. often to inpatient rehabilitation programs. Yet the effectiveness of inpatient treatment. as compared with a variety of less intensive alternatives. has repeatedly been called into question. In this study. anchored in the work site. we compared the effectiveness of mandatory in-hospital treatment with that of required attendance at the meetings of a self-help group and a choice of treatment options. METHODS. We randomly assigned a series of 227 workers newly identified as abusing alcohol to one of three rehabilitation regimens: compulsory inpatient treatment. compulsory attendance at Alcoholics Anonymous (AA) meetings. and a choice of options. Inpatient backup was provided if needed. The groups were compared in terms of 12 job-performance variables and 12 measures of drinking and drug use during a two-year follow-up period. RESULTS. All three groups improved. and no significant differences were found among the groups in job-related outcome variables. On seven measures of drinking and drug use. however. we found significant differences at several follow-up assessments. The hospital group fared best and that assigned to AA the least well; those allowed to choose a program had intermediate outcomes. Additional inpatient treatment was required significantly more often (P less than 0.0001) by the AA group (63 percent) and the choice group (38 percent) than by subjects assigned to initial treatment in the hospital (23 percent). The differences among the groups were especially pronounced for workers who had used cocaine within six months before study entry. The estimated costs of inpatient treatment for the AA and choice groups averaged only 10 percent less than the costs for the hospital group because of their higher rates of additional treatment. CONCLUSIONS. Even for employed problem drinkers who are not abusing drugs and who have no serious medical problems. an initial referral to AA alone or a choice of programs. although less costly than inpatient care. involves more risk than compulsory inpatient treatment and should be accompanied by close monitoring for signs of incipient relapse.
Large cysts of the pineal gland: report of two cases, Two cases of large. nontumorous cysts of the pineal gland are reported. the histopathology of which was confirmed using surgically resected specimens. Both patients were middle-aged. and the pineal cysts were found incidentally. The histopathological findings in the two cases were strikingly similar to each other and were characterized by the following points: 1) the cyst wall typically consisted of three layers. namely. collagenous fibers. glia-like cells. and normal pineal cells; 2) the cyst wall was relatively thin. approximately 100 to 300 microns in thickness; and 3) deposits of calcification almost always existed on the side of the layer of collagenous fiber. Because these findings are clearly different from those previously reported. large benign cysts of the pineal gland. or at least some of them. may constitute a new pathological entity. It is important to consider this possible pathological diagnosis when dealing with pineal cysts.
Deafness after bilateral midbrain contusion: a correlation of magnetic resonance imaging with auditory brain stem evoked responses, A 46-year-old woman became deaf after a closed head injury. When a computed tomographic scan failed to disclose the cause. conversion disorder was suspected. Magnetic resonance imaging. however. showed bilateral contusions of the inferior colliculi. providing objective evidence for an organic cause of hearing loss. Auditory brain stem evoked responses and stapedial reflexes also provided objective evidence of brain stem injury. This case illustrates the phenomenon of dorsal midbrain injury after head trauma. It indicates the sensitivity of magnetic resonance imaging for small focal lesions after head trauma. and it demonstrates some difficulties in the diagnosis of "hysterical" deafness.
Ossifying fibroma in the sylvian fissure: case report, A rare case of an ossifying fibroma that developed in the sylvian fissure is reported here. During surgery. branches of the middle cerebral artery were encased in osseous tumor. The encased branches were divided and reanastomosed after the mass was removed. Postoperative angiograms demonstrated patency of the anastomosed arteries and a postoperative magnetic resonance imaging scan revealed no infarction distal to the arterial anastomoses. The authors recommend division and anastomosis of the encased arteries rather than partial removal of tumor from around the encased arteries. resulting in residual tumor being left behind.
Intracranial fibromatosis, Fibromatoses are uncommon infiltrative lesions affecting musculoaponeurotic structures. most often of the limbs and trunk. Lesions involving the cranial cavity are rare and require the same aggressive surgical management as elsewhere in the body. This case illustrates their clinical and neuroradiological features and underscores the necessity for aggressive resection to avoid recurrence. The literature is reviewed.
Acoustic schwannomas in children, The clinical presentation and treatment of three cases of acoustic schwannoma occurring in children are described. All the tumors were detected late. when they had attained a large size and were extremely vascular. The use of preoperative tumor embolization as an adjunct to surgical excision is discussed.
Transfalcine approach to a callosomarginal artery aneurysm, We describe a transfalcine approach to clipping and subsequently excising an expanding mycotic callosomarginal aneurysm. The patient had a devastating dominant (left) hemispheric spontaneous intracranial hemorrhage and was neurologically improving at the time of surgery nearly 2 months later. To avoid retracting the left hemisphere. we approached this left callosomarginal aneurysm from the nondominant side through the falx. The approach was straight-forward. and the result was satisfactory.
Neurotoxicity after intracarotid 1,3-bis(2-chloroethyl)-1-nitrosourea administration in the rat: hemodynamic changes studied by double-tracer autoradiography, Changes in blood-brain (BBB) permeability and local cerebral blood flow after intracarotid administration of 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU) were examined quantitatively in rats with double-tracer autoradiography using [14C]alpha-amino-isobutyric acid and [18F]fluoroantipyrine. Forty-eight female Wistar rats were divided into four groups. The control group (Group 1) received 1 ml of 5% dextrose. The other three groups received three different doses of BCNU dissolved in 5% dextrose: Group II rats received 1 mg. Group III 3 mg. and Group IV 10 mg. The tracer study was performed on Day 1 or Days 4 to 12 after intracarotid administration of BCNU. In 11 rats in Group II. there were no changes of BBB permeability. Transient BBB permeability changes were seen in the striatum or hippocampus in 3 of the 5 rats (60%) in Group III within 24 hours. In 8 of 9 rats (89%) in the same group. late BBB permeability changes were observed in the hypothalamus with or without histological changes. BBB permeability changes were seen in all rats of Group IV. Focal increase of local cerebral blood flow on the infused side compared with the non-infused side of the brain was observed. although not at a significant level. in 5 of 25 rats examined with [18F]fluoroantipyrine. The results of BBB permeability and histological examinations and study of heterogenous distribution by [18F]fluorodeoxyglucose indicated that the ipsilateral subcortical structures such as the hypothalamus. amygdala. internal capsule. and caudate putamen have the highest incidence of neurotoxicity. which are closely related to histopathological damage seen in human BCNU leucoencephalopathy.
Extramedullary hematopoiesis in cerebellar hemangioblastoma, Extramedullary hematopoiesis and paraneoplastic erythrocytosis are uncommon in cerebellar hemangioblastoma. and their concomitant occurrence has not been reported. In a study of 26 cases of hemangioblastoma. we found extramedullary hematopoiesis in 4 tumors; one was associated with erythrocytosis. The significance of this association and the possible histogenetic origin of extramedullary hematopoiesis in cerebellar hemangioblastoma are discussed.
Extent of mesiobasal resection determines outcome after temporal lobectomy for intractable complex partial seizures, The extent of resection was assessed in 94 patients who underwent temporal lobectomy for medically intractable complex partial seizures originating from a unilateral seizure focus in the anteromesial temporal lobe. Postoperative magnetic resonance imaging in the coronal plane was used to quantify the extent of resection of lateral and mesiobasal structures according to a 20-compartment model of the temporal lobe. Successful seizure outcome (greater than or equal to 90% reduction in seizure frequency) was accomplished in 83% of the patients (all followed up for more than 1 year; mean duration of follow-up. 25.2 months) and correlated significantly (P less than 0.05) with the extent of mesiobasal resection. regardless of the extent of resection of lateral structures. Successful seizure outcome was accomplished in 81% of the patients with no structural lesions. and also correlated significantly (P less than 0.05) with the extent of mesiobasal resection regardless of the extent of lateral resection. A successful seizure outcome was accomplished in 90% of the 21 patients with structural lesions documented by neuroimaging studies. Two patients who underwent extensive lobectomy without resection of the structural lesion had no reduction in seizure frequency postoperatively. We conclude that the most important factor in determining the outcome of temporal lobectomy in patients with unilateral anteromesial temporal lobe epileptogenicity is the extent of resection of structures in the mesiobasal temporal lobe. In patients with structural lesions. lesion resection may be an added contributor to successful seizure outcome.
Complete temporal lobectomy for surgical resuscitation of patients with transtentorial herniation secondary to unilateral hemispheric swelling, Transtentorial herniation is an ominous finding in the patient with head injuries. We report our experience with 10 patients suffering from acute transtentorial herniation secondary to posttraumatic unilateral hemispheric swelling who were treated aggressively with temporal lobectomy. Eight patients were men and 2 were women. Their ages ranged from 22 to 61 years. with a mean of 37 years. Their preoperative Glasgow Coma Scale scores ranged from 3 to 6. with a mean of 4. All patients had both computed tomographic and clinical evidence of unilateral hemispheric shift and acute herniation without a significant subdural or epidural hematoma. Seven patients had unilateral nonreactive pupils and 3 had bilateral nonreactive pupils. All were taken to the operating room within 2 hours of clinical signs of herniation. Complete unilateral temporal lobectomies including the mesial structures. amygdala. and uncus were performed. In this series. the mortality rate was 30%. including a single patient who was neurologically stable but died from nonneurological injuries. Of the 7 survivors. 4 were functionally independent and 3 required minimal assistance with the activities of daily living. Aggressive. early decompression via complete temporal lobectomy may thus significantly improve the outcome in patients with transtentorial herniation accompanying posttraumatic hemispheric swelling and midline shift.
Sufentanil citrate and morphine/bupivacaine as alternative agents in chronic epidural infusions for intractable non-cancer pain, Intraspinal narcotic (usually intrathecal morphine) infusions with implanted pumps are increasingly used in patients with intractable chronic pain not caused by cancer. In some patients. pain control is difficult with infusions of morphine. Seven patients with diagnoses of arachnoiditis. epidural scarring. and/or vertebral body compression fracture were treated with alternative solutions in an epidural route. For maximal flexibility. Medtronic implanted programmable infusion pumps with catheters to T6-T10 were used. and pain was monitored by verbal pain scales. In three patients. epidural infusions of morphine in 0.5% bupivacaine (MS-MARC) resulted in little or no pain relief without significant side effects (e.g.. headache. nausea. or vomiting). In these same patients. epidural infusions of sufentanil citrate resulted in pain scale reductions of 92%. 82%. and 40%. respectively. with no side effects. Four other patients found more effective pain relief when switched from initial sufentanil citrate infusions to MS-MARC. Pain scale reductions (with no side effects) were 92%. 76%. 59%. and 47% in these patients. Pain relief and minimal side effects with sufentanil citrate is theorized to result from its higher lipophilicity promoting local transdural diffusion to spinal cord and limiting upward diffusion to the brain stem. Sufentanil citrate is also advantageous for programmable pumps because it is 100 times more potent than morphine and therefore allows longer pump refill times and higher infusion doses. Although this study was done on a limited number of patients. sufentanil citrate and MS-MARC in epidural infusions using programmable infusion pumps for non-cancer patients provide significant alternative drug combinations and routes.
Monitoring of somatosensory evoked potentials during surgery for middle cerebral artery aneurysms, Somatosensory evoked potentials (SEPs) were monitored during 53 procedures for aneurysms of the middle cerebral artery (MCA). "Significant" changes were reported to the surgeon. who took corrective action when possible. Changes in the SEPs were categorized as follows: Type I. no change; Type II. significant change with complete return to baseline; Type III. significant change with incomplete return to baseline; Type IV. complete loss with no return; and Type V. no response at baseline. Only 1 of 37 patients with a Type I SEP had a new neurological deficit. and this was a patient who could not be examined for several days after surgery because he was in a pentobarbital coma. All 4 patients with Type III and IV changes had new postoperative neurological deficits. Perhaps of greater importance. 4 of 5 patients with Type II changes had no new deficit. These patients all had changes in SEPs that were completely reversible by clip adjustment (2). prompt removal of temporary clips (1). and inducing hypertension after aneurysm trapping (1). These cases may. therefore. represent instances in which SEP monitoring allowed the clinicians to prevent a neurological deficit. The MCA supplies the area of the somatosensory cortex that controls the hand. Median nerve SEPs are. therefore. a theoretically ideal monitor during surgery for MCA aneurysms. This study suggests that the results of MCA aneurysm surgery may be accurately predicted and improved with SEP monitoring.
Cervicocranial arterial dissection, Dissection of the cervicocranial arteries is becoming more frequently recognized as a cause of neurological disorders. Typical clinical features seen with dissection include unilateral headache. oculosympathetic palsy. amaurosis fugax. and symptoms of focal brain ischemia. The diagnosis of carotid or intracranial dissection is usually best confirmed by angiography. although magnetic resonance imaging and computed tomography have been shown to visualize intimal dissection. The prognosis in cases of spontaneous dissection is generally benign unless the initial manifestation involves infarction with substantial deficit. The best approach to treatment appears to be the administration of the anticoagulant. heparin. followed by warfarin or antiplatelet therapy. Surgical intervention is reserved for cases of progressive or recurrent ischemic complication that occurs despite the administration of adequate doses of anticoagulants.
Landry Guillain-Barre Strohl syndrome in pregnancy: report of three cases treated with plasmapheresis, Landry Guillain-Barre Strohl syndrome complicating pregnancy is a rare occurrence. with only 31 cases previously reported in the obstetric literature. Cytomegalovirus as a potential etiologic agent has been documented in only two of these cases. In the past. symptomatic treatment of pregnant patients with severe and progressive symptoms has been associated with an unacceptably high rate of maternal morbidity and mortality. Recent studies have shown convincingly that plasmapheresis is the treatment of choice for nonpregnant patients acutely ill with Guillain-Barre syndrome. but data regarding its use in pregnancy are limited. We report three patients. two of whom had positive cytomegalovirus titers. in whom aggressive plasmapheresis prevented the need for ventilatory support and its inherent increase in maternal morbidity and mortality.
Placenta membranacea with placenta increta: a case report and literature review, The pregnancy of a patient with placenta membranacea associated with placenta increta and a live-born infant is described. and the literature covering placenta membranacea is reviewed. A total of 26 cases of placenta membranacea in the second and third trimesters have been reported. The condition appears to have an incidence of 1:20.000-40.000. and there have been 14 reported live births associated with this rare placental anomaly. Antepartum and postpartum hemorrhage were reported to complicate 83 and 50% of the cases. respectively. Approximately 30% of the cases involved some form of abnormal placental adherence.
The sonographic diagnosis of circumvallate placenta, Circumvallate placenta. a form of placenta extrachorialis. should be included in the differential diagnosis of vaginal bleeding in the second trimester with a normally implanted placenta. Heretofore. the diagnosis was made after delivery. This report presents a case of circumvallate placenta diagnosed prenatally by ultrasound. Key features included an infolding of the fetal membrane upon the fetal surface of the placenta during the middle of the second trimester. By the third trimester. only a bright border at the periphery of the placenta was noted. Antenatal diagnosis can be made and pregnancy outcome potentially altered.
Massive fetomaternal hemorrhage treated by fetal intravascular transfusion, Two cases of massive fetomaternal hemorrhage are presented. Both women noted a decrease in fetal movement and were advised to come to the hospital for fetal heart rate monitoring. Sinusoidal fetal heart rate patterns were observed and Kleihauer-Betke testing was positive for fetomaternal hemorrhage. The fetuses were preterm and therefore funipuncture was done. which confirmed profound anemia in both. Fetal intravascular transfusion was performed. Shortly after conclusion of the transfusion. prolonged bradycardia occurred in both fetuses and delivery was accomplished by cesarean. Both infants survived.
Ectopic ureter: a rare cause of purulent vaginal discharge, We report two cases in which urologic anomalies presented with vaginal discharge and fever in young women. aged 9 and 18 years. Both patients were ultimately diagnosed as having duplicated collecting systems with ectopic upper-pole ureters opening into the introitus. Although congenital urologic anomalies are a rare cause of vaginal discharge in young women. they should be included in the differential diagnosis of patients presenting with these symptoms.
Clinical usefulness of serum squamous cell carcinoma antigen for early detection of squamous cell carcinoma arising in mature cystic teratoma of the ovary, Squamous cell carcinoma arising in mature cystic teratoma of the ovary is rarely diagnosed preoperatively. We measured the pre-treatment serum levels of squamous cell carcinoma antigen in three stage I patients in order to evaluate its usefulness as a tumor marker for early detection of the disease. The serum levels were elevated in each case. to 26.9. 5.1. and 3.2 ng/mL. respectively. and rapidly dropped to within the normal range after treatment. All patients are recovered and show no evidence of recurrence. and the levels of serum squamous cell carcinoma antigen have remained within normal limits. These results suggest that measurement of the serum squamous cell carcinoma antigen level may be useful in diagnosing an early-stage primary squamous cell carcinoma arising in a mature cystic teratoma of the ovary. An elevated preoperative serum level of squamous cell carcinoma antigen may indicate the need for a rapid pathologic examination of the tumor to look for malignant elements and may influence the surgical regimen.
The concept of uterine preservation with ovarian malignancies, A 30-year-old woman with bilateral. recurrent. borderline papillary serous cystadenocarcinoma of the ovary was treated with bilateral oophorocystectomy and omentectomy with uterine preservation. Ten years later. through induction of an artificial endometrial cycle and ovum donation. she conceived twins and delivered two healthy infants. Staging exploratory laparotomy at the time of cesarean delivery was negative for malignancy. This case illustrates the value of uterine preservation for cases in which classical teaching has indicated hysterectomy with bilateral salpingoophorectomy.
Epidemiology of otitis media, Although otitis media (OM) incidence and prevalence estimates from around the world vary widely. it is clear that OM is a very common childhood disease. It is especially prevalent in children younger than 2 years of age. Furthermore. the earlier the first episode of OM. the greater the risk of subsequent recurrent OM and chronic otitis media with effusion. In addition. a number of other host. agent. and environmental factors have been associated with increased risk of otitis media. Environmental factors that favor the transmission of upper respiratory pathogens increase the risk of OM. recurrent OM. and chronic OME with effusion. Several factors suggest a genetic role in OM susceptibility. which needs further exploration.
Audiologic evaluation of the otitis media patient, Because of the complexity and variability in the expression of otitis media. its effects on auditory function are diverse. The various influences of otitis media on auditory function are described within this article. including acoustic reflex. audiometry. and tympanometry.
Clinical approach to treatment of otitis media, The author presents his experience of 10 years of practice with the treatment of otitis media. He expresses concern for the inconsistencies between articles written recommending treatment protocols for otitis media and actual clinical results from using those treatment protocols. Otitis media varies in its appearance from patient to patient. with its association to other continuous structures and other organ systems making it a challenging disease to correct and cure. Treatment must be tailor-made to fit the patient. and the physician needs to consider other professional opinions and emphasize follow-up care.
Otitis media: the pathogenesis approach. General surgical approach based on pathogenesis. An overall approach, The authors present an overall approach and fundamental concepts based on pathogenesis. They advocate an open-minded approach. tailoring the treatment to each individual patient rather than fitting patients into preestablished classifications.
Atopic dermatitis in infants and children, Atopic dermatitis is a common. chronic inflammatory skin disease triggered by a variety of irritative emotional and allergic factors. Education and simple prevention and maintenance measures such as proper moisturizing greatly reduce disease. Antibiotics and topical corticosteroids are therapeutic mainstays.
Diagnosis and treatment of childhood scabies and pediculosis, Human scabies infestations are still a widespread occurrence. This article discusses the clinical features. infections. lesions. and sites of involvement of different types of scabies as well as pediculosis.
Molecular cloning and expression of a human heat shock factor, HSF1, Human cells respond to heat stress by inducing the binding of a preexisting transcriptional activator (heat shock factor. HSF) to DNA. We have isolated recombinant DNA clones for a human HSF (HSF1) by screening cDNA libraries with a human cDNA fragment. The human HSF1 probe was produced by the PCR with primers deduced from conserved amino acids in the Drosophila and yeast HSF sequences. The human HSF1 mRNA is constitutively expressed in HeLa cells under nonshock conditions and encodes a protein with four conserved leucine zipper motifs. Like its counterpart in Drosophila. human HSF1 produced in Escherichia coli in the absence of heat shock is active as a DNA binding transcription factor. suggesting that the intrinsic activity of HSF is under negative control in human cells. Surprisingly. an independently isolated human HSF clone. HSF2. is related to but significantly different from HSF1 [Schuetz. T. J.. Gallo. G. J.. Sheldon. L.. Tempst. P. & Kingston. R. E. (1991) Proc. Natl. Acad. Sci. USA 88. 6911-6915].
Human type VII collagen: cDNA cloning and chromosomal mapping of the gene, A human keratinocyte cDNA expression library in bacteriophage lambda gt11 was screened with the purified IgG fraction of serum from a patient with epidermolysis bullosa acquisita. which had a high titer of anti-type VII collagen antibodies. Screening of approximately 3 x 10(5) plaques identified 8 positive clones. the largest one (K-131) being approximately 1.9 kilobases in size. Dideoxynucleotide sequencing of K-131 indicated that it consisted of 1875 base pairs and contained an open reading frame coding for a putative N-terminal noncollagenous domain of 439 amino acids and a collagenous C-terminal segment of 186 amino acids. The collagenous domain was characterized by repeating Gly-Xaa-Yaa sequences that were interrupted in several positions by insertions or deletions of 1-3 amino acids. The deduced amino acid sequence also revealed a peptide segment that had a high degree of identity with a published type VII collagen protein sequence. Northern hybridization of the K-131 cDNA with human epidermal keratinocyte and skin fibroblast RNA revealed an mRNA of approximately 8.5 kilobases. The fusion protein produced by the K-131 cDNA. when incubated with epidermolysis bullosa acquisita serum. bound to antibodies that reacted in Western blots with type VII collagen. The genomic location of the type VII collagen gene (COL7A1) was determined by chromosomal in situ hybridization with the K-131 cDNA. The results mapped the COL7A1 to the locus 3p21. The cDNA clones characterized in this study will be valuable for understanding the protein structure and gene expression of type VII collagen present in anchoring fibrils and its aberrations in the dystrophic forms of heritable epidermolysis bullosa.
Change in the expression of a nuclear matrix-associated protein is correlated with cellular transformation, We have identified a monoclonal antibody that recognizes a nuclear matrix-associated protein in NIH 3T3 cells. The immunofluorescence pattern consists predominantly of bright nuclear granule clusters distributed throughout the nucleoplasm. with the exclusion of nucleoli. It recognizes a protein of 190 kDa that is down-regulated to various degrees in a panel of single-oncogene-transformed NIH 3T3 cells. Its localization is similar. but not identical. to the spliceosomal speckles. p190 shows a coordinate expression during the growth cycle of nontransformed NIH 3T3 cells; it is synthesized at the highest level under growth arrest conditions. It is expressed in adult mouse brain and is also present in human IMR-90 fibroblasts.
Transfer of genetic epilepsy by embryonic brain grafts in the chicken, In the Fayoumi chicken. a spontaneous recessive autosomal mutation (F.Epi) is responsible for high susceptibility to seizures that are especially inducible by intermittent light stimulation. Substitution of defined areas of the encephalic neuroepithelium in normal chicken embryos at 2 days of incubation by their counterparts from homozygous F.Epi embryos generates the epileptic phenotype in the chimeras. It was found that grafting primordia of both prosencephalon and mesencephalon of homozygous F.Epi birds is necessary and sufficient for transfer of the full disease. When grafted alone. the homozygous F.Epi prosencephalon. although showing the typical epileptic interictal electroencephalogram. does not allow the complete epileptic seizures to occur in the hosts. Grafts of mesencephalon and/or rhombencephalon modify neither the behavior nor the electroencephalographic pattern of the recipient chickens. Cooperation of forebrain and midbrain activities is therefore required to yield epileptic seizures in this model.
Resistance of primary isolates of human immunodeficiency virus type 1 to soluble CD4 is independent of CD4-rgp120 binding affinity, The infection of human cells by laboratory strains of human immunodeficiency virus type 1 (HIV-1) can be blocked readily in vitro by recombinant soluble CD4 and CD4-immunoglobulin hybrid molecules. In contrast. infection by primary isolates of HIV-1 is much less sensitive to blocking in vitro by soluble CD4-based molecules. To investigate the molecular basis for this difference between HIV-1 strains. we isolated the gp120-encoding genes from several CD4-resistant and CD4-sensitive HIV-1 strains and characterized the CD4-binding properties of their recombinant gp120 (rgp120) products. Extensive amino acid sequence variation was found between the gp120 genes of CD4-resistant and CD4-sensitive HIV-1 isolates. However. the CD4-binding affinities of rgp120 from strains with markedly different CD4 sensitivities were essentially the same. and only small differences were observed in the kinetics of CD4 binding. These results suggest that the lower sensitivity of primary HIV-1 isolates to neutralization by CD4-based molecules is not due to lower binding affinity between soluble CD4 and free gp120.
Repressor to activator switch by mutations in the first Zn finger of the glucocorticoid receptor: is direct DNA binding necessary, Transfection of HeLa cells with cDNA vectors expressing the wild-type human glucocorticoid receptor (GR) enabled dexamethasone to strongly repress cytokine- and second messenger-induced expression of cotransfected chimeric reporter genes containing transcription regulatory DNA elements from the human interleukin 6 (IL-6) promoter. Deletion of the DNA-binding domain or of the second Zn finger or a point mutation in the Zn catenation site in the second finger blocked the ability of GR to mediate repression of the IL-6 promoter. Unexpectedly. deletion of the first Zn finger. a point mutation in the Zn-catenation site in the first finger. or one in the steroid-specificity domain at the base of the first finger converted GR into a dexamethasone-responsive activator that enhanced basal and interleukin 1-induced IL-6 promoter function. These first-finger mutants of GR also mediated dexamethasone-responsive enhancement of expression of the herpesvirus thymidine kinase-chloramphenicol acetyltransferase (TK-105-CAT and TK-80-CAT) reporter genes but not of the murine mammary tumor virus long terminal repeat-CAT or the c-fos-CAT (pFC700) reporter genes. Wild-type GR was able to specifically bind to DNA fragments containing glucocorticoid response element sequences in both the murine mammary tumor virus and IL-6 promoters. albeit weakly to the latter. in a sequential DNA-binding immunoprecipitation assay. The first-finger mutants of GR. however. were inactive in this assay. Thus. mutations in the first Zn finger unmask unusual promoter-specific activation properties of GR that may not require direct high-affinity binding of the mutant GR to target DNA.
Immunocytochemical localization of phospholipase C-gamma in rat embryo fibroblasts, Rat embryo fibroblasts (REF52) exhibit a distinctive. transformation-sensitive distribution of alpha-protein kinase C (alpha-PKC). Receptor-mediated activation of phospholipase C (PLC)-gamma generates diacylglycerol. the major cellular activator of PKC. Immunofluorescence techniques were used to investigate the subcellular localization of two PLC isozymes (PLC-gamma and PLC-delta) in normal and simian virus 40-transformed REF52 cells to determine (i) if PLC colocalizes with alpha-PKC and (ii) if PLC isozyme distribution is sensitive to transformation. PLC-delta was not detected in either cell type. In REF52 cells. PLC-gamma was associated with the actin cytoskeleton and was evenly distributed along the length of the actin microfilaments. PLC-gamma was coincident with alpha-PKC at the points where the filaments are anchored to the membrane (i.e.. the focal contacts). Cytoskeletal association of PLC-gamma was not transformation sensitive. although the actin cytoskeleton was more disordered in simian virus 40-transformed cells. In REF52 cells. platelet-derived growth factor induced tyrosine phosphorylation of both soluble and cytoskeletal PLC-gamma. Tyrosine phosphorylation of PLC-gamma did not seem to be a determinant of its subcellular localization. but there was a detectable increase in cytoskeleton-associated PLC-gamma in response to platelet-derived growth factor treatment.
Protection of macaques with a simian immunodeficiency virus envelope peptide vaccine based on conserved human immunodeficiency virus type 1 sequences, This report describes the vaccination of rhesus macaques with peptides selected from regions of the simian immunodeficiency virus (SIV) envelope that are hydrophilic. immunoreactive. and highly homologous with corresponding conserved envelope sequences of the human immunodeficiency virus (HIV). The peptides. produced as beta-galactosidase fusion proteins. induced virus-neutralizing and peptide-specific antibodies. After challenge with virulent virus. controls became virus positive and developed gradually rising antibody titers to SIV over 63 weeks. Immunized macaques developed a postchallenge anamnestic response to SIVenv antigens within 3-6 weeks followed by a gradual. fluctuating decline in SIV antibody titers and partial or total suppression of detectable SIV. Virus suppression correlated with prechallenge neutralizing antibody titers. Although the average CD4+ cell count in the blood of immunized macaques remained constant. the control macaques exhibited a progressive decrease developing about week 55 after challenge. The conserved nature of the HIV and SIV peptides and the similar humoral immunoreactivity in the respective hosts suggest that homologous HIV peptides may be important components of a successful immunization strategy.
Binding of the adenovirus VAI RNA to the interferon-induced 68-kDa protein kinase correlates with function, In human cells infected with adenovirus. the virus-associated RNA VAI blocks the activation of the interferon-induced double-stranded-RNA-dependent 68-kDa protein kinase (p68) and maintains normal levels of protein synthesis at late times after infection. VAI antagonizes the kinase activity by binding to p68. The structure of VAI consists of two long. base-paired stems connected by a complex short stem-loop structure. Previous work using a series of adenovirus mutants showed that the structural determinants of the VAI RNA that are essential for function reside in the central complex short stem-loop structure and adjacent base-paired regions (functional domain); the long duplex regions were found to be dispensable for function. To determine whether binding of VAI to p68 correlates with function and whether the structural determinants that are essential for function are also essential for binding. we studied the interaction of wild-type and several mutant VAI RNAs with p68 in whole cells. The p68-VAI complexes from mutant- and wild-type-infected cells were immunoprecipitated by an anti-p68 monoclonal antibody. The mutant RNAs that functioned efficiently in the cells bound to p68 efficiently in the cells. whereas functionally impaired mutants failed to bind to p68. indicating that the binding of the VAI RNA to p68 correlates well with function. In vitro binding assays with immunopurified p68 confirmed these observations. Secondary-structure analysis of several mutant VAI RNAs suggests that the binding does not depend on the long duplex regions but requires all the elements of the functional domain. We propose that the functional domain and the p68-binding domain of the VAI RNA are identical.
The Rex regulatory protein of human T-cell lymphotropic virus type I binds specifically to its target site within the viral RNA, The Rex protein of human T-cell leukemia virus type I (HTLV-I) was expressed in bacteria and partially purified. Rex was shown to bind in vitro specifically to an RNA sequence located in the 3' long terminal repeat of HTLV-I. named Rex-responsive element (RXRE). Rex also bound in vitro to the human immunodeficiency virus type 1 (HIV-1) Rev-responsive element (RRE). while purified HIV-1 Rev protein did not bind to the RXRE. The binding results obtained in vitro are therefore in agreement with the nonreciprocal function of Rev and Rex in vivo. Rex binds specifically to both RRE and RXRE and activates expression in both HIV-1 and HTLV-I. while Rev binds to RRE and activates only HIV-1. Binding of Rex to RRE deletion mutants previously shown to lack either the Rev-responsive or the Rex-responsive portion suggested preferential binding of Rex to a distinct target within the RRE. These results demonstrated that Rex. like Rev. acts by binding to a specific RNA target.
Identification of a monocyte receptor on herpesvirus-infected endothelial cells, The adhesion of circulating blood cells to vascular endothelium may be an initial step in atherosclerosis. inflammation. and wound healing. One mechanism for promoting cell-cell adhesion involves the expression of adhesion molecules on the surface of the target cell. Herpes simplex virus infection of endothelium induces arterial injury and has been implicated in the development of human atherosclerosis. We now demonstrate that HSV-infected endothelial cells express the adhesion molecule GMP140 and that this requires cell surface expression of HSV glycoprotein C and local thrombin generation. Monocyte adhesion to HSV-infected endothelial cells was completely inhibited by anti-GMP140 antibodies but not by antibodies to other adhesion molecules such as VCAM and ELAM-1. The induction of GMP140 expression on HSV-infected endothelium may be an important pathophysiological mechanism in virus-induced cell injury and inflammation.
Insulin regulation of the glucagon gene is mediated by an insulin-responsive DNA element, Diabetes mellitus is characterized by insulin deficiency and high plasma glucagon levels. which can be normalized by insulin replacement. It has previously been reported that glucagon gene expression is negatively regulated by insulin at the transcriptional level. By transfection studies. I have now localized a DNA control element that mediates insulin effects on glucagon gene transcription. This element also confers insulin responsiveness to a heterologous promoter. DNA-binding proteins that specifically interact with this insulin-responsive element are found in both glucagon- and non-glucagon-producing cells; and the pattern of binding. as assessed by the gel retardation assay. is not modified by prior insulin treatment.
Inhibition of proteolysis protects hippocampal neurons from ischemia, Intense proteolysis of cytoskeletal proteins occurs in brain within minutes of transient ischemia. possibly because of the activation of calcium-sensitive proteases (calpains). This proteolytic event precedes overt signs of neuronal degeneration. is most pronounced in regions of selective neuronal vulnerability. and could have significant consequences for the integrity of cellular function. The present studies demonstrate that (i) the early phase of enhanced proteolysis is a direct response to hypoxia rather than other actions of ischemia. (ii) it is possible to pharmacologically inhibit the in vivo proteolytic response to ischemia. (iii) inhibition of proteolysis is associated with a marked reduction in the extent of neuronal death. and (iv) protected neurons exhibit normal-appearing electrophysiological responses and retain their capacity for expressing long-term potentiation. a form of physiological plasticity thought to be involved in memory function. These observations indicate that calcium-activated proteolysis is an important component of the post-ischemic neurodegenerative response and that targeting this response may be a viable therapeutic strategy for preserving both the structure and function of vulnerable neurons.
An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P, Deposition of the beta-amyloid protein in senile plaques is a pathologic hallmark of Alzheimer disease (AD). Focal deposition of beta amyloid in the adult rat cerebral cortex caused profound neurodegenerative changes. including neuronal loss and degenerating neurons and neurites. Chronic induction of the Alz-50 antigen appeared in neurons around focal cortical deposits of beta amyloid. Immunoblot analysis showed that beta amyloid induced Alz-50-immunoreactive proteins in rat cerebral cortex that were very similar to the proteins induced in human cerebral cortex from patients with AD. The neuropeptide substance P prevented beta-amyloid-induced neuronal loss and expression of Alz-50 proteins when coadministered into the cerebral cortex. Systemic administration of substance P also provided protection against the effects of intracerebral beta amyloid. Thus. beta amyloid is a potent neurotoxin in the adult brain in vivo. and its effects can be blocked by substance P.
Organization and stability of a polytopic membrane protein: deletion analysis of the lactose permease of Escherichia coli, The overall topology of polytopic membrane proteins is thought to result from either the oriented insertion of the N-terminal alpha-helical domain followed by passive insertion of subsequent helices or from the function of independent topogenic determinants dispersed throughout the molecules. By using the lactose permease of Escherichia coli. a well-characterized membrane protein with 12 transmembrane domains and the N and C termini on the cytoplasmic surface of the membrane. we have studied the insertion and stability of in-frame deletion mutants. So long as the first N-terminal and the last four C-terminal putative alpha-helical domains are retained. stable polypeptides are inserted into the membrane. even when an odd number of helical domains is deleted. Moreover. even when an odd number of helices is deleted. the C terminus remains on the cytoplasmic surface of the membrane. as judged by lacY-phoA fusion analysis. In addition. permease molecules devoid of even or odd numbers of putative transmembrane helices retain a specific pathway for downhill lactose translocation. The findings imply that relatively short C-terminal domains of the permease contain topological information sufficient for insertion in the native orientation regardless of the orientation of the N terminus.
Glandular excision in total glandular mastectomy and modified radical mastectomy: a comparison, Total glandular mastectomy and modified radical mastectomy were compared for the amount of breast tissue remaining after surgery. Multiple biopsies were taken from the anterior chest walls of women following total glandular mastectomy (N = 27) and modified radical mastectomy (N = 28) to try to detect any residual glandular tissue. Regardless of procedure performed. breast tissue was identified histologically in 5 percent of all biopsy specimens (159 and 161. respectively). One of every five operative fields was shown to have glandular elements in at least one of the biopsy sites; the positive biopsies did not form a discernible pattern. The residual breast tissue in each of these patients averaged less than 1 gm. On the basis of this study. modified radical mastectomy and total glandular mastectomy appear to be equally effective in removing most of the breast.
Growth status of children treated for unilateral cleft lip and palate, Cephalometric distances. angles. and proportions were evaluated for 32 children 5 to 8 years of age treated for unilateral cleft lip and palate. The children were age and sex matched with untreated controls with normal skeletal relationships. The unilateral cleft lip and palate sample was treated by the same surgeon and orthodontist using the same techniques and appliances. Measures of overall facial proportions. facial convexity. and prognathism were not significantly different between the two groups. The primary group differences pertain to the posterior aspect of the maxilla. which is vertically short in the unilateral cleft lip and palate sample. Horizontally. the maxilla of the unilateral cleft lip and palate children was significantly longer. producing a steeper palatal plane. In addition. the zygoma and orbits of unilateral cleft lip and palate children were somewhat retruded; the posterior cranial base and total mandibular length also were longer in the unilateral cleft lip and palate children.
The biomechanical effects of deep tissue support as related to brow and facelift procedures, The adverse effects of increased tension across a healing wound are well known. However. the effect of closing a wound in layers in order to decrease tension on the epidermis has been a source of controversy. It is hypothesized that deep tissue support decreases skin tension upon wound closure. In order to clarify this issue. a two-part study was designed to address the immediate effects of deep tissue support in vitro using fresh-frozen cadavers and in vivo on patients undergoing scheduled surgery. Closing skin tension was measured at standard reference points in coronal brow lift and rhytidectomy procedures performed with and without galeal closure and superficial musculoaponeurotic system (SMAS) procedures. respectively. Deep tissue support was found to significantly (p less than 0.05) decrease skin tension at the time of skin closure at standard reference points in coronal brow lift and rhytidectomy procedures performed on fresh-frozen cadavers. Similar significant (p less than 0.05) decreases in closing skin tension also were found in vivo in patients undergoing similar surgical procedures. Stress relaxation was not found to play a significant role in contributing to this immediate decrease in closing skin tension. It would appear. therefore. that deep tissue support. in the form of galeal closure and an SMAS procedure in coronal brow lift and rhytidectomy procedures. respectively. provides increased viscoelastic support. producing immediate significant decreases in closing skin tension in these procedures. The beneficial effects on wound healing. scar formation. tension-related trophic skin changes. and possible improved long-term results are discussed.
Late bleeding after rhytidectomy from injury to the superficial temporal vessels, Five healthy. normotensive women. whose mean age was 49.8 years. developed expanding hematomas between 8 and 10 days (average 9 days) after rhytidectomy. In each patient. the bleeding vessel could be identified: In two. it was the parietal branch of the superficial temporal artery; in two. it was the parietal branch of the superficial temporal vein; and in one. it was the superficial temporal artery immediately before its branching. Contributing factors may have been sudden physical exertion in four of the five patients and in another salicylate ingestion. Several measures can help avoid late bleeding from the superficial temporal vessels or their branches; not using a too potent vasoconstrictive agent (epinephrine) in the local anesthetic so that the vessels will be easier to visualize; not injecting the local anesthetic too deeply or incising to deeply; dividing and ligating the superficial temporal vessel and its major branches if injured; using bipolar coagulation on small branches; and instructing patients repeatedly not to engage in strenuous activity or to ingest salicylates for at least 2 weeks after operation.
Biocompatibility of radiolucent breast implants, Current implants for breast augmentation containing silicone gel. saline. or both are radiopaque on mammographic examination and can totally obscure microcalcifications and soft-tissue masses. The effect of these implants on the detection of early breast cancers in patients who have undergone augmentation mammaplasty remains unproven and controversial. Implants filled with medium-chain triglycerides (peanut oil) are radiolucent on mammographic examination and allow visualization of both soft-tissue masses and microcalcifications. To investigate the biocompatibility of radiolucent implants. 10 cc of sterile. nonpyrogenic peanut oil was injected subcutaneously into rats using silicone gel as a control. Twenty-one rabbits had two 125-cc silicone shell implants inserted on either side of the chest wall. The right-sided shell was filled with 125 cc of sterile saline. and the left-sided shell was filled with 125 cc of sterile. nonpyrogenic peanut oil. Results were determined by both histologic and radiographic examination. Rats injected with peanut oil equivalent to 7 percent of their body weight rapidly absorbed the freely injected oil without detriment. Histologic examination of the lungs. liver. kidneys. and tissues adjacent to the injection sites demonstrated no abnormalities. There was no evidence of allergic. toxic. inflammatory. or neoplastic response. Eighteen of 21 rabbits survived more than 3 months. Radiographs showed the oil-filled implants to be radiolucent. whereas the saline-filled controls obscured the surrounding soft and bony tissues. Histologic examination demonstrated a fibrous capsule surrounding both types of implants. Histologic examination of the lungs. liver. and kidneys showed no significant abnormalities. These and previous studies have shown peanut oil to be biocompatible when freely injected either intramuscularly or subcutaneously. This study demonstrates that a radiolucent. peanut oil-filled implant is biocompatible in animals and that further long-term studies for its use in humans are merited.
Strawberry hemangioma of infancy: early definitive treatment with an argon laser, This report documents the successful treatment of a hemangioma (strawberry hemangioma) at 5 weeks of age with the argon laser. The natural course of strawberry hemangioma of infancy is well known. It begins as a very small spot and develops very rapidly within the first few weeks of life. Many grow to a very large size and produce significant morbidity. It is logical to assume that if these were ablated early. the life cycle could be aborted. The patient of this case study developed two spots that appeared to be typical evolving hemangiomas. One was treated and disappeared. The other was not treated and evolved into a typical strawberry hemangioma that eventually involuted. This would indicate that early treatment holds some promise.
A combined rectus abdominis musculocutaneous flap and vascularized iliac bone graft with double vascular pedicles, Although a free vascularized iliac bone graft has been successfully used for the reconstruction of large bone defects. there is a serious problem of how to repair in one stage patients having a large bone defect with a very wide skin defect. A free combined rectus abdominis musculocutaneous flap and vascularized iliac bone graft with double vascular pedicles seems to be one of the most suitable methods for patients having large defects of both bone and skin. Based on our patient. the main advantage of this flap is the extreme width of the skin territory. The pedicle vessels are large and long. and the donor scar can be made in an unexposed area. This flap should be considered for use in one-stage reconstructions of large defects of both bone and skin in the leg region.
Thumb replantation after cardiac transplantation, Generally. severe medical illnesses. including chronic immunosuppression and heavy steroid use. have been deemed relative contraindications for replantation surgery. We report the successful replantation of an amputated thumb in a patient who had previously undergone heart transplantation and was on therapeutic immunosuppression. Despite extensive soft-tissue damage and joint involvement. thumb function and sensibility returned to acceptable levels. This case demonstrates that digital bony union. tendon repair healing. and nerve regeneration are not significantly altered by the standard immunosuppressive regimen following major organ transplant. The implications raised by this case for possible transplantation of allograft digits or limbs are discussed in detail.
Bilateral latissimus dorsi V-Y musculocutaneous flap for closure of a large meningomyelocele, Reconstruction of a large meningomyelocele defect with bilateral latissimus dorsi V-Y musculocutaneous flaps is reported. This procedure provides a reliable. well-vascularized soft-tissue coverage over the neural repair with minimum donor-site morbidity.
Avianca flight No. 052 accident: a plastic surgical perspective, The crash of Avianca Airlines flight no. 052 en route to JFK Airport on January 25. 1990. in Cove Neck. New York. resulted in the death of 72 passengers. Eighty-nine victims were admitted to 13 regional hospitals. Despite difficult access to the wooded crash site. early warning and prompt response by 37 volunteer fire and rescue units resulted in organized EMS triage and rapid hospital transport. This report reviews the specific injuries incurred. highlights the team management approach to a major aviation accident in a suburban area. and studies the likelihood of accidents of this magnitude. Thirty-eight patients triaged to two level I trauma centers. North Shore University Hospital-Cornell University Medical Center and Nassau County Medical Center. form the basis of this report. Seventeen patients were male; 21 were female. The average patient age was 33 years. Eight patients were children. The average length of stay was 30.9 days (range 2 to greater than 90 days). Twenty-six patients (including nonsurvivors) (68 percent) sustained significant multiple orthopedic injuries. The majority of fractures were open grade II to III tibia-fibula fractures. Bilaterality was commonly seen. Soft-tissue coverage of open long bone fractures was required in 10 patients (11 extremities) and included 3 microvascular muscle transfers. 7 muscle transposition flaps. and 3 skin grafts. Seven patients required open reduction and fixation of complex facial fractures (two of Le Fort II to III type. four of complex naso-orbital-ethmoid type). Plastic surgical repair of complex lacerations was common. Peripheral nerve exploration was required in three patients.
The radiographic diagnosis of emphysema, There are many findings of emphysema by conventional radiography. but the most reliable and reproducible is that of overinflation. which is best judged by the height and contour of the hemidiaphragm. Even in expert hands. the diagnosis of emphysema by conventional radiography is 65% to 80% accurate. depending to a large degree on the clinical population studied. Although most patients with severe emphysema are diagnosed correctly. only half of those patients with mild-to-moderate levels of parenchymal destruction are detected. Emphysema is identified by CT as focal. unmarginated. hypodense areas unassociated with fibrosis. Emphysema also may be detected by computer programs selecting pixels with abnormally low attenuation values. By either method. CT is superior to chest radiography in detection of mild and moderate degrees of emphysema and has detection rates of more than 90% and correlation with extent and severity of disease in more than 80% of patients. CT may be more sensitive to the presence of mild emphysema than pulmonary function tests. which are global indications of lung function. HRCT appears to offer a small. but real. advantage over 10-mm collimation in identification of small areas of emphysema. but areas of emphysema smaller than 0.5 cm in diameter are commonly missed. even with HRCT. Wider use of CT for investigation of relatively asymptomatic smokers may allow early diagnosis of emphysema and provide more information of the natural history of this disease. information that is sorely lacking at this time. Assessment of potential therapy such as smoking cessation or antioxidants will only be possible with widespread use of a method that is of relatively low risk. easy to duplicate. and accurate.
Bronchiectasis, Bronchiectasis is important because (1) it predisposes the patient to infection; (2) it may be accompanied by increased bronchial blood flow and hemoptysis; (3) when widespread. it may be associated with significant airway obstruction; and (4) when focal. it may simulate neoplasms and other diseases. The widespread use of computed tomography (CT) for evaluation of lung diseases has revealed that bronchiectasis is common--even in patients who do not have clinical or plain radiographic suspicion of bronchiectasis. The pathology. pathogenesis. and radiographic findings are presented herein.
High resolution lung computed tomography. Normal anatomic and pathologic findings, The use of high resolution computed tomography (HRCT) for evaluating the lung parenchyma requires an understanding of normal lung anatomy and the pathologic alterations in anatomy that occur in the presence of disease. Most important is an understanding of the secondary pulmonary lobule; HRCT can show many features of the secondary lobule in both normal and abnormal lungs. and many lung diseases. particularly interstitial diseases. produce characteristic alterations in lobular anatomy. HRCT is capable of diagnosing interstitial abnormalities. air-space consolidation airway diseases. and emphysema.
Computed tomography of air-space disease, Although computed tomography (CT) has not been used as often in air-space diseases as in interstitial ones. it often provides useful information. Diseases such as early opportunistic pneumonia may be detected by CT before becoming visible on plain radiographs. Also. extent and location are often better defined by CT than by plain radiographs. Accompanying abnormalities such as abscess. lymphadenopathy. and pleural effusion are often clearly demonstrated by CT. This article reviews the CT findings in a variety of air-space diseases. including pneumonia and other infections. radiation pneumonitis and fibrosis. embolism. eosinophilic pneumonia. alveolar proteinosis. bronchioloalveolar carcinoma. lipoid pneumonitis. sarcoidosis. and trauma.
Imaging of diffuse lung diseases. Past, present, and future, For many years the plain chest radiograph was the only imaging modality used in the assessment of patients who had diffuse lung disease. Presently. high resolution computed tomography (CT) and lung scintigraphy play a major role in the assessment of these patients. Use of magnetic resonance (MR) imaging in the assessment of the lung parenchyma has been limited by poor signal-to-noise ratio and physiologic motion. Recent improvements in technique. however. have allowed assessment of patients with diffuse lung disease. It is likely that MR imaging will play an increasing role in the assessment of these patients in the near future.
A radiographic approach to diffuse lung disease, The chest radiograph remains the first and foremost imaging modality used in the assessment of patients who have diffuse lung disease. An optimal approach to the radiograph requires an understanding of pulmonary anatomy and pathophysiology of disease. The assessment of the radiograph can be based on an anatomic or a descriptive approach. Associated abnormalities. including pleural effusion. pneumothorax. lymphadenopathy. and so forth. also influence the differential diagnosis. This article presents a basic radiologic approach to diffuse lung diseases.
Pulmonary edema and adult respiratory distress syndrome, The pathophysiology and radiographic appearances of hydrostatic and increased permeability pulmonary edema are presented. Both typical and atypical appearances are discussed. The ability of the plain chest radiograph to differentiate between different types of edema is examined.
Diffuse lung disease in the current spectrum of immunocompromised hosts (non-AIDS), Diffuse lung disease occurring in an immunocompromised patient is a nonspecific finding that may result from one or more of a variety of infectious and noninfectious causes. Patient history and clinical information are essential in narrowing the differential diagnosis. but in most patients. diagnostic procedures must be performed to determine appropriate therapy. Diagnostic possibilities include infection. spread of malignancy. reactions to chemotherapy or radiation. nonspecific interstitial pneumonitis. hemorrhage. and unrelated medical conditions. An understanding of the specific nature of the patient's immunologic defect and underlying disease allows one to predict the most likely organisms in cases of infection.
MR imaging of small hepatocellular carcinoma: effect of intratumoral copper content on signal intensity, Small (less than 5 cm) hepatocellular carcinomas (HCCs) in 45 of 112 patients (40.2%) had a high-signal-intensity pattern (relative to that of liver) on T1-weighted magnetic resonance (MR) images. To identify the cause of this pattern. specimens of histologically defined HCC with high- (n = 21). iso- (n = 6). and low- (n = 22) intensity patterns were histologically evaluated for paramagnetic ionic forms of metals. The incidence of steatosis. clear cell formation. and copper accumulation was statistically (P less than .01) higher in tumors with the high-intensity pattern than in those with other patterns. Of 17 HCCs that stained positive for copper. 16 (94%) had a high-intensity pattern; the pattern of one tumor (6%) was isointense. All 21 tumors with the high-intensity pattern had at least one of the findings of steatosis. clear cell formation. or copper accumulation. These features were evident in only four of 28 tumors (14%) with an iso- or low-intensity pattern. Thus. copper accumulation might be a cause of the high-intensity pattern on T1-weighted images of small HCCs.
Hepatocellular carcinomas with excessive copper accumulation: CT and MR findings, Results of orcein staining and findings obtained with non-contrast-medium-enhanced computed tomography (CT) and magnetic resonance (MR) imaging (T1- and T2-weighted images) were compared for 53 histologically confirmed hepatocellular carcinomas (HCCs). HCCs were 5 cm in the largest diameter. Three lesions with diffuse and strong orcein staining were highly attenuating on nonenhanced CT images. Electron x-ray microanalysis of one of them revealed copper. The high attenuation value at nonenhanced CT may have been due to the abundant copper-binding protein in the cancer cells. The difference between orcein staining results and attenuation patterns at CT was statistically significant (chi 2. P less than .001). It could not be concluded that the paramagnetic effects of copper in HCC had an influence on signal intensity on MR images. The difference between orcein staining results and signal-intensity patterns on T1- and T2-weighted images was not statistically significant.
Preoperative segmental localization of hepatic metastases: utility of three-dimensional CT during arterial portography, To evaluate the accuracy of a fast three-dimensional (3D) reconstruction technique in determining the segmental location of hepatic metastases. 14 patients (40 metastases) were prospectively investigated before surgery with dynamic two-dimensional (2D) computed tomography during sequential arterial portography (CTAP). All patients underwent subsequent hepatic tumor resection within 4 days. After computer-generated mapping of hepatic venous structures with high attenuation and metastases with low attenuation. 3D reconstruction was performed. Thirty-six of the 40 lesions (90%) were detected with 2D and 3D CTAP. The accuracy in determining the segmental location of hepatic metastases was 78% (28 of the 36 metastases) for 2D CTAP and 94% (34 of the 36 metastases) for 3D CTAP. The difference in localization rates between 2D CTAP and 3D CTAP was statistically significant. The 3D CTAP technique provides vital data unattainable with other imaging modalities that improve the preoperative assessment of the resectability of hepatic metastases and allows planning a safer surgical approach.
Hepatofugal arterial signal in the main portal vein: an indicator of intravascular tumor spread, Five patients with thrombosis of the main portal vein underwent Doppler ultrasound (US). Three of these patients had confirmed hepatocellular carcinoma. Doppler US allowed differentiation between bland thrombus and tumor thrombus in two of the three patients. Tumor thrombus of the main portal vein was characterized at US by an intraportal arterial waveform in a hepatofugal direction.
Extravasation of iopamidol and iohexol during contrast-enhanced CT: report of 28 cases, Extravasation of intravenously injected contrast medium is a well-known complication of radiologic procedures. Records from a 27-month period were reviewed of 28 patients in whom extravasation of nonionic contrast medium occurred during computed tomographic (CT) scanning. Extravasated amounts ranged from 3 mL in an infant to 100 mL in an adult. There were seven documented major (50-100-mL) events and nine documented moderate (10-49-mL) events. Follow-up showed that none of these patients required medical or surgical intervention as a result of extravasation. The rate of extravasation during neurologic CT scanning (head. orbits. and spine) was 0.09%. while the rate for the rest of the body (chest. abdomen. pelvis. neck) was 0.17%; the overall rate was 0.14%. The higher rate for non-neurologic studies was related to the use of a power injector. Nonionic contrast medium seemed to cause fewer systemic reactions.
Invasive cervical carcinoma: MR imaging after preoperative chemotherapy, To evaluate assessment of tumor regression with magnetic resonance (MR) imaging. the authors studied 21 consecutive patients with cervical carcinoma tumors that were more than 3 cm in diameter. Thirteen of the 21 also demonstrated parametrial invasion. In all cases. MR imaging was performed both before and after chemotherapy. Pathologic specimens were obtained at hysterectomy in all patients. Comparison of pathologic and MR imaging findings after chemotherapy showed that all tumors decreased in size. Size of tumor was correctly determined at MR in 17 cases and was slightly overestimated in four cases. Five patients had residual parametrial invasion that was histologically confirmed. In detecting parametrial spread after treatment. MR imaging had an accuracy of 90.4%. Tumors had high signal intensity on T2-weighted images. whereas intratumoral necrosis was characterized by low signal intensity on the same images. Peritumoral inflammatory tissue found at pathologic examination in four of 21 cases was not specifically identified on MR images. In patients with invasive cervical carcinoma. MR imaging may be useful in evaluating tumor response to preoperative chemotherapy.
Water intoxication: a complication of pelvic US in a patient with syndrome of inappropriate antidiuretic hormone secretion, A woman was first seen with water intoxication caused by the voluntary ingestion of water in an attempt to fill her bladder before undergoing pelvic ultrasound (US). As in two other reported cases. this woman was receiving medication that causes the syndrome of inappropriate antidiuretic hormone secretion. A patient undergoing transabdominal pelvic US who is receiving these medications and whose bladder is not full should undergo examination by means of a transvaginal or endorectal route.
Lateral tibial rim (Segond) fractures: MR imaging characteristics, The magnetic resonance (MR) imaging characteristics of lateral tibial rim (Segond) fractures and their associated injuries were reviewed in 12 patients with radiographic evidence of this fracture. Bone marrow adjacent to the fracture emitted a focally abnormal MR signal. which indicated an injury of the lateral capsular junction. The Segond fragment. however. was seen on MR images in only four of 12 patients. Associated ligamentous and meniscal injuries identified with MR imaging and arthroscopy involved the anterior (n = 11) and medial (n = 7) cruciate ligaments and the lateral (n = 4) and medial (n = 1) menisci. Focal bone marrow edema was due to injury of the lateral capsular junction. MR imaging evidence of such edema should indicate the presence of a lateral capsular injury and fracture. if one has not already been demonstrated with conventional radiography. A high association of Segond fractures with tears of the anterior cruciate ligament was confirmed. and MR imaging signs of a Segond fracture may therefore be used as indirect evidence for tears of that ligament.
Epiphyseal involvement in osteosarcoma, Plain radiography and magnetic resonance (MR) imaging were used to assess the extent of transphyseal involvement in 15 consecutive patients with long bone osteosarcoma and nonfused epiphyses. The findings were correlated with those from surgical and microscopic pathologic examinations. There were no cases of false-positive findings with either MR imaging or plain radiography. Conventional radiography accurately helped predict transphyseal spread in only nine of 15 cases (60%). Spread to the epiphysis was present in 12 of the 15 cases (80%) and was accurately predicted with MR imaging in all 12 cases. This finding contradicts the common misconception that the physis acts as a "barrier" to tumor spread.
Usefulness of mammography and sonography in women less than 35 years of age, Indications. clinical history. mammographic findings. and clinical outcome were reviewed in 1.016 women younger than 35 years who underwent mammography during an 8-year period. The indications for mammography were a palpable mass in 454 (44.7%). findings at routine screening in 237 (23.3%). lumpiness in 29 (14.9%). unilateral nipple discharge in seven (3.5%). localized breast tenderness in six (5.1%). adenopathy in three (1.9%). diffuse tenderness in two (2.9%). bilateral nipple discharge in two (1.5%). and miscellaneous in four (2.2%). In 405 women (39.9%). at least two-thirds of the breast tissue was radiodense; however. in 299 (29.4%) women the breast was predominantly fatty. allowing for excellent mammograms. Six women had carcinomas: Mammographic findings prompted biopsy in one patient. indicated a benign-appearing mass (found to be solid at sonography or aspiration) in three patients with a palpable mass (contributing to delay in biopsy in two). and were negative in two. Sonography was performed in 389 women and was useful in preventing unnecessary biopsy of cysts but was not useful in differentiating benign from malignant solid masses. Younger women with persistent localized breast symptoms should undergo a tailored mammographic examination. but negative findings or findings of a benign lesion should not preclude biopsy of a palpable solid mass.
Medulloblastoma: long-term follow-up of patients treated with electron irradiation of the spinal field, Thirty-two patients with posterior fossa medulloblastoma underwent treatment with electron irradiation to the spinal field. The 5- and 10-year actuarial survival rates were 57% and 50%. respectively. Late complications observed in the 15 patients followed up for more than 5 years were short stature (six patients). decreased sitting-standing height ratio (four patients). scoliosis (two patients). poor school performance (seven patients). xerostomia (one patient). esophageal stricture (one patient). pituitary dysfunction (four patients). primary hypothyroidism (one patient). bilateral eighth-nerve deafness (one patient). and carcinoma of the thyroid (one patient). Complications following treatment with electrons to a spinal field are compared with reported complications following treatment with photons to the spinal field. Although short-term reactions were minimal. the authors found no difference in late complications. More sophisticated treatment planning may show such a long-term benefit in the future.
Selective spinal panangiography: use of a 4-F braided catheter with a soft-tip configuration, A 4-F braided catheter with a soft radiopaque tip was used in selective spinal panangiographic procedures. Results obtained with the catheter were compared with those obtained in procedures with conventional catheters. The catheter was used in the intercostal. lumbar. and sacral arteries. Advantages of using this catheter include excellent maneuverability. reduced patient exposure to contrast medium. and reduced fluoroscopy duration.
Identification of FAP locus genes from chromosome 5q21, Recent studies suggest that one or more genes on chromosome 5q21 are important for the development of colorectal cancers. particularly those associated with familial adenomatous polyposis (FAP). To facilitate the identification of genes from this locus. a portion of the region that is tightly linked to FAP was cloned. Six contiguous stretches of sequence (contigs) containing approximately 5.5 Mb of DNA were isolated. Subclones from these contigs were used to identify and position six genes. all of which were expressed in normal colonic mucosa. Two of these genes (APC and MCC) are likely to contribute to colorectal tumorigenesis. The MCC gene had previously been identified by virtue of its mutation in human colorectal tumors. The APC gene was identified in a contig initiated from the MCC gene and was found to encode an unusually large protein. These two closely spaced genes encode proteins predicted to contain coiled-coil regions. Both genes were also expressed in a wide variety of tissues. Further studies of MCC and APC and their potential interaction should prove useful for understanding colorectal neoplasia.
Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients, Previous studies suggested that one or more genes on chromosome 5q21 are responsible for the inheritance of familial adenomatous polyposis (FAP) and Gardner's syndrome (GS). and contribute to tumor development in patients with noninherited forms of colorectal cancer. Two genes on 5q21 that are tightly linked to FAP (MCC and APC) were found to be somatically altered in tumors from sporadic colorectal cancer patients. One of the genes (APC) was also found to be altered by point mutation in the germ line of FAP and GS patients. These data suggest that more than one gene on chromosome 5q21 may contribute to colorectal neoplasia. and that mutations of the APC gene can cause both FAP and GS. The identification of these genes should aid in understanding the pathogenesis of colorectal neoplasia and in the diagnosis and counseling of patients with inherited predispositions to colorectal cancer.
Risk of tuberculosis in immigrant Asians: culturally acquired immunodeficiency, Study of the 620 Asian immigrants with tuberculosis notified in the Wandsworth area of south London between 1973 and 1988 showed a bimodal pattern of tuberculosis notifications: in 1977 there was a peak among Asians from East Africa. and in 1981 a peak among those from the Indian subcontinent. There was a mean lag time of five years between clinical presentation and immigration. Logit analysis showed that. although overall more men had tuberculosis than women. glandular tuberculosis was more common among women of all groups. and pulmonary tuberculosis was more common among Hindu women than Hindu men. Both subgroups of Asians had a substantially higher incidence of tuberculosis than white people. particularly at extrapulmonary sites. Hindus were also at a significantly greater risk of tuberculosis at all sites than Muslims (Hindu:Muslim risk ratio 5.5 for women and 3.7 for men). The increased susceptibility to tuberculosis of Hindus. particularly Hindu women. may be related to a culturally acquired immunodeficiency caused by vegetarianism and associated vitamin deficiency.
Measures of reversibility in response to bronchodilators in chronic airflow obstruction: relation to airway calibre, A study was carried out to examine the independence from starting prebronchodilator FEV1 of four indices commonly used to express airflow (FEV1) reversibility in response to bronchodilators. In 121 patients with chronic airflow obstruction with a mean prebronchodilator FEV1 of 1.81 (43.9% of predicted values) the change in FEV1 expressed as a percentage of the patient's predicted FEV1 was the least dependent on starting FEV1. Reversibility. expressed as a percentage of the prebronchodilator value or as a percentage of the maximal possible increase (predicted minus starting FEV1) was correlated with starting FEV1.
Urinary symptom and quality of life questions indicative of obstructive benign prostatic hyperplasia. Results of a pilot study, In a pilot study of a urinary symptom and health-related quality-of-life questionnaire for benign prostatic hyperplasia (BPH). responses from 64 Mayo Clinic patients with cystoscopic evidence of obstructive BPH were compared with those of 14 men with no cystoscopic evidence of BPH and a community sample of 64 comparably aged men with no medical history of prostate enlargement. Questions which best discriminated between the groups were those dealing with urinary symptom frequency. bother due to urinary symptoms. and worry and concern about urinary problems. The results suggest that urinary-symptom-bother and worry due to urinary symptoms may be important additions to the more usual questions asked about urinary frequency in the identification of men with BPH. These findings are preliminary. however. and will be verified in an ongoing natural history study of BPH.
Comorbidities and perioperative complications among patients with surgically treated benign prostatic hyperplasia, We address the question of whether or not age and comorbidity are related to intra- and postoperative complications after a transurethral resection. The data are derived from a retrospective. population-based study conducted in Hagen. Germany. which included all patients with an initial prostatectomy for benign prostatic hyperplasia (N = 621) during the five-year period 1984-1988. Seventy-seven percent of the patients had at least one of the following preoperative risk factors: heart disease. hypertension. smoking. chronic obstructive lung disease. and diabetes. There was no intraoperative death. The risk of intraoperative circulatory complications was found to be related to age only for patients without a history of heart diseases or hypertension. The incidence of major complications was 3.1 percent and was significantly higher in the oldest age group. Three patients (0.54%) died postoperatively in the hospital. Infections were the most frequent postoperative complications. The relationship of age and overall postoperative complications was not statistically significant either for patients with (p = 0.121) or without any comorbidity (p = 0.651). Based on this study it seems reasonable to conclude that age is not a clinically relevant risk factor for perioperative complications in patients who have a transurethral resection for benign prostatic hyperplasia.
Imaging of vascular complications associated with renal transplants, Vascular complications associated with renal transplants are a significant cause of graft dysfunction. The most common complications are arterial and venous stenoses and thromboses and intrarenal and extrarenal arteriovenous fistulas and pseudoaneurysms. Although angiography is the imaging gold standard for the diagnosis of these disorders. Doppler sonography. scintigraphy. and occasionally CT are capable of detecting them. An awareness of the different imaging appearances of each complication will aid in their early detection and treatment. In this review. we present this information and provide a perspective on the relative roles of these techniques in the detection of vascular complications from renal transplants.
Motion artifact simulating aortic dissection on CT, We recently imaged two patients clinically suspected of having aortic dissection whose contrast-enhanced CT examinations. obtained on a new scanner with a 1-sec scanning time. showed findings suggesting an ascending aortic dissection. The subsequent clinical course and evaluation implied that the CT findings were predominantly artifactual. We identified identical artifacts in 18% of 50 consecutive contrast-enhanced CT examinations performed for a variety of indications on the same scanner. The double-lumen artifact. simulating an intimal flap. occurs in the proximal ascending aorta and is limited to one or two contiguous transaxial images. The artifact was not detected on two other CT units. We believe the artifact arises from motion of the aortic wall and the surrounding pericardial recesses during image acquisition.
Self-referred mammography patients: analysis of patients' characteristics, Among mammography patients. a small but growing group of highly motivated women refer themselves directly for screening without the suggestion of their physicians. We surveyed 485 patients during a 3-month period to study how self-referred mammography patients differ from physician-referred patients. Self-referred patients were more likely than physician-referred patients to have a family income of more than $30.000 per year. to be college graduates. and to consider their health as good or excellent. A large percentage of self-referred patients performed other health-promoting practices. but were not significantly more likely to do these than were physician-referred patients. Women who referred themselves were more likely to have a friend with breast cancer and to believe that cancer could be cured. They expressed much less worry about radiation exposure and were more likely to consider $50.00 an appropriate charge for a screening mammogram. By far. the greatest motivator for self-referred patients was health promotion and disease prevention. Self-referred mammography patients tend to be wealthier. more education. and less concerned about the cost and radiation dose of mammography when compared with physician-referred mammography patients.
Altered gallbladder contractility after extracorporeal shock-wave cholecystolithotripsy, Change in gallbladder contractility after biliary extracorporeal shock-wave lithotripsy (ESWL) may significantly influence the clearance of fragments after successful gallstone fragmentation. We assessed changes in gallbladder contractility in response to an oral fatty meal in 50 patients 1 month after biliary ESWL (all fragments were smaller than 3 mm) and also in a separate group of 10 patients 3 months after complete clearance of fragments. The prevalence of persistent lumen-obliterating contraction of the gallbladder after biliary ESWL also was analyzed in 325 patients. Gallbladder contractility remained unchanged in 30. increased in nine. and decreased in 11 of the 50 patients. The average reduction in the fasting gallbladder volume after lithotripsy was 28% (p less than .001). Gallbladder contractility remained unchanged 3 months after complete clearance of fragments in six of 10 patients studied separately. A decrease (n = 2) or increase (n = 2) in contractility was seen in the remaining patients. No significant difference occurred in the average ejection fraction of the gallbladder before lithotripsy and after complete clearance of the fragments. Thirty-four of the 325 patients who have so far undergone biliary ESWL had a completely contracted gallbladder with no lumen visible on sonography. The gallbladder returned to a relaxed state in half of these patients within 1-9 months. Thus. biliary ESWL did not significantly alter gallbladder contractility in 60% of patients. A significant reduction in the volume of the fasting gallbladder occurred after lithotripsy. Successful clearance of fragments did not improve the contractility of stonebearing gallbladders in the majority of patients.
Non-Q- and Q-wave infarction after thrombolytic therapy with intravenous streptokinase for chest pain and anterior ST-segment elevation, The clinical features of patients treated with streptokinase for chest pain and anterior ST-segment elevation who subsequently develop non-Q-wave infarction are unknown. Of the 75 consecutive patients who initially presented with chest pain and ST-segment elevation in the anterior leads (V1-V6. I. aVL) and were treated with intravenous streptokinase (time from symptoms to treatment averaged less than 3 hours). 32 (43%) developed a non-Q-wave and 43 (57%) a Q-wave myocardial infarction. Twenty seven of 32 patients (84%) from the non-Q-wave group and 39 of 43 (91%) from the Q-wave group were studied by angiography at 5.16 +/- 2.88 days after the onset of myocardial infarction. Left ventricular end-diastolic pressure was 13 +/- 6 vs 20 +/- 7 mm Hg (p less than 0.001). left ventricular ejection fraction was 60 +/- 8 vs 49 +/- 14% (p less than 0.001) and the infarct vessel patency rate was 85 vs 72% (p = 0.44) in patients with a non-Q versus a Q-wave infarction. respectively. In summary. when patients presenting with chest pain and ST-segment elevation are treated with streptokinase. a significant portion of these symptoms will evolve into a non-Q-wave infarction. Patients with a non-Q-wave infarction will have a better preserved left ventricular function than patients who develop a Q-wave infarction. This suggests the need for equal distribution of such patients in randomized trials of thrombolytic therapy for acute myocardial infarction to avoid misinterpreting data between groups.
Effects of urokinase and heparin on minimal cross-sectional area of the culprit narrowing in unstable angina pectoris, The immediate and delayed effects of urokinase and heparin on minimal cross-sectional area of a patent ischemia-producing coronary artery were prospectively investigated in 43 patients with unstable angina. After baseline angiography. patients were randomized to 3 different treatment groups: group I--urokinase (1.000.000 U intravenous bolus dose). followed by heparin infusion 3 hours later; group II--heparin (10.000 U intravenous bolus. followed by continuous infusion); and group III--conventional therapy only (intravenous nitroglycerin. beta blockers and calcium antagonists). Angiography was repeated at 1 hour and at 8 days of treatment and minimal cross-sectional area was determined in the 35 patients who completed the study. In group I. minimal cross-sectional area increased from 0.84 +/- 0.48 mm2 at baseline to 0.94 +/- 0.49 mm2 at 1 hour (p less than 0.05). and to 1.00 +/- 0.51 mm2 at 8 days (p less than 0.01 vs baseline). In group II. a significant increase in minimal cross-sectional area was observed only at the 8-day angiography (0.64 +/- 0.39 mm2 at baseline; 0.67 +/- 0.37 mm2 at 1 hour [p = not significant]; and 0.79 +/- 0.48 mm2 at 8 days [p less than 0.01] vs baseline). In group III. no significant changes in minimal cross-sectional area occurred either at 1 hour or at 8 days. Thus. both urokinase and heparin improved lesion geometry in patients with unstable angina. although a large individual variation was noticed. The effect occurred earlier with urokinase than with heparin.
Use of a morphologic classification to predict clinical outcome after dissection from coronary angioplasty, To determine if morphology of procedure-associated dissections could help predict clinical outcome. angiograms of 691 coronary artery dissections resulting from percutaneous transluminal coronary angioplasty were categorized according to the National Heart. Lung. and Blood Institute classification system. Classes of dissection were then correlated with clinical outcome: 543 patients with type B dissections had no increase in morbidity and mortality when compared with patients without dissection. with a similar success rate of 93.7%. Complications in this group were low and compared favorably with complication rates in procedures not associated with dissection. One hundred forty-eight procedures associated with dissections of types C to F had a significant increase in in-hospital complications. including acute closure (31%). need for emergency coronary bypass surgery (37%). myocardial infarction (13%) and repeat angioplasty (24%). The overall clinical success rate for those with types C to F dissection was 38%. The differences in clinical success and acute complications between type B and types C to F dissections were statistically significant at p less than 0.0005 for all variables studied. The angiographic morphology of a dissection during coronary angioplasty can predict clinical outcome. aiding in selection of effective therapy.
Noninvasive identification of significant narrowing of the left main coronary artery by dipyridamole thallium scintigraphy, To evaluate the usefulness of dipyridamole thallium scintigraphy with low-level exercise for the identification of left main (LM) coronary artery disease (CAD). 466 consecutive patients with CAD were studied. Thirty-eight patients (8%) had LM stenosis (diameter narrowing greater than or equal to 50%). The LM scintigraphic pattern was present in 9 of 38 patients with LMCAD and 38 of 428 CAD patients without LMCAD (24 vs 9%; p less than 0.005). This pattern was present in 6 of 9 patients with LMCAD without right CAD and in only 3 of 29 patients with LM and right CAD (67 vs 10%; p = 0.0005). Patients with LMCAD had a higher incidence of premature cessation of low-level exercise (53 vs 21%; p less than 0.0001). chest pain (68 vs 48%; p less than 0.02). blood pressure decrease of greater than or equal to 20 mm Hg (44 vs 16%; p less than 0.002) and greater ST depression (0.17 +/- 0.13 vs 0.06 +/- 0.10 mV; p less than 0.001) during dipyridamole loading than patients without LMCAD. Stepwise discriminant analysis revealed that the LM scintigraphic pattern and markers of ischemia during dipyridamole loading best identified (p less than 0.0001) patients with LMCAD without right CAD (sensitivity 67%. specificity 91%). but this predictability is no better than the LM scintigraphic pattern alone. The combination of clinical markers of ischemia during dipyridamole loading and scintigraphic findings of diffuse slow washout. extensive fixed defects and the LM pattern best identified (p less than 0.0001) patients with LM and right CAD (sensitivity 72%. specificity 80%).
Evaluation of dipyridamole-Doppler echocardiography for detection of myocardial ischemia and coronary artery disease, Doppler assessment of left ventricular filling and ejection during dipyridamole stress may supplement wall motion analysis for detection of myocardial ischemia and coronary artery disease (CAD). Thirty-four patients taking no cardioactive therapy were studied using intravenous dipyridamole (0.6 mg/kg) during 2-dimensional and pulsed Doppler echocardiography. Twelve patients had normal coronary arteries (group 1) and the remainder. who had significant CAD. were divided into groups 2 (n = 11) and 3 (n = 11). Only subjects in group 2 developed myocardial ischemia manifest as reversible regional asynergy and ST-segment depression. Heart rate increased (16 +/- 9 beats/min. p less than 0.01) and mean blood pressure decreased (-5 +/- 8 mm Hg. p = not significant) uniformly across groups. Exaggerated hyperkinesia of normally contracting wall segments was the common response to dipyridamole infusion in patients with CAD. The respective mean percent changes in peak early diastolic velocity. peak atrial velocity. their ratio and ejection peak velocity. and mean acceleration for groups 1 (20. 42. -13. 20 and 23%). 2 (22. 32. -2. 10 and 14%) and 3 (23. 33. -6. 16 and 18%) were similar. Comparisons between normal patients and those with CAD and between groups 2 and 3 revealed no significant differences in the effect of dipyridamole on any variable. However. a decrease in both peak velocity and mean acceleration of left ventricular ejection was seen in 3 of 4 group 2 patients who developed severe ischemia. Dipyridamole-Doppler echocardiography is insensitive for detection of CAD and appears unable to identify myocardial ischemia unless this is severe. Hemodynamic changes and compensatory wall motion induced by dipyridamole may explain these findings.
Pronounced reduction of aortic flow velocity and acceleration during heavy isometric exercise in coronary artery disease, Doppler-derived parameters of aortic flow were examined during heavy isometric exercise in 48 men with coronary artery disease (CAD) and in 48 gender- and age-matched healthy controls. The aim was to determine which parameters best separated the groups and to look for a possible relation between exercise-induced Doppler patterns and the extent of CAD. Isometric exercise was performed with a 2-hand bar dynamometer. and the subjects were required to perform 50% of maximal voluntary contraction for 2 minutes. Examination was performed with a pulsed Doppler transducer positioned at the suprasternal notch. Resting peak flow velocity. acceleration time. stroke volume index and cardiac index did not show significant differences between the groups. However. mean acceleration and stroke work were significantly lower in patients with CAD. In this group. exercise peak flow velocity decreased from 98 +/- 13 to 55 +/- 12 cm/s. flow velocity integral from 14 +/- 3 to 7 +/- 3 cm. mean acceleration from 11 +/- 0.9 to 4.7 +/- 1 m/s/s. and stroke volume index from 41 +/- 6 to 23 +/- 4 ml/m2 (p less than 0.001 for all). Cardiac index decreased from 2.7 +/- 0.4 to 2 +/- 0.2 liters/min/m2 (p less than 0.05). Acceleration time increased from 82 +/- 6 to 116 +/- 7 ms. In most of the indexes. the directional changes induced by isometric exercise were similar in patients with CAD and in normal control subjects. The differences compared with the rest values were significantly greater in the CAD group. and especially in patients presenting with 3-vessel disease.
Usefulness of excitable gap and pattern of resetting in atrial flutter for determining reentry circuit location, Clinical and experimental data show that type I atrial flutter is due to a reentry mechanism with an excitable gap. To define the location of the reentry circuit of atrial flutter. width of excitable gap. poststimulation cycle and pattern of reset after premature stimulus were analyzed in 18 patients during atrial flutter at multiple atrial sites (high. lateral. posterior and septal right atrium. and coronary sinus). The pattern of reset was defined as flat or increasing whether the return cycle remained unchanged or prolonged with increasing prematurity. Shorter values of the excitable gap were found at the coronary sinus (33 +/- 8 ms) and high right atrium (30 +/- 10 ms) than at the posterior (43 +/- 9 ms) or septal right atrium (45 +/- 11 ms). Intermediate values (36 +/- 8 ms) were measured at the lateral right atrium. Poststimulation cycle. corrected for atrial flutter cycle length. was shorter in the posterior (6 +/- 7 ms) and septal right atrium (5 +/- 7 ms) than in the coronary sinus (35 +/- 9 ms). and the high (23 +/- 10 ms) and lateral right atrium (15 +/- 9 ms). A flat pattern of resetting occurred more frequently at the septal (18 of 18 patients) and posterior right atrium (15 of 18) than at the lateral (8 of 18) and high right atrium (2 of 17). and was never observed at the coronary sinus. Atrial flutter was successfully terminated by overdrive atrial pacing in 15 of 18 patients. and termination was more easily obtained from the septal and posterior right atrium.
Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome, Patients with the Romano-Ward inherited long QT syndrome have an incompletely defined cardiac sympathetic system abnormality. and exhibit ventricular arrhythmias during exercise. fear and anxiety. Treadmill and bicycle exercise were used to modulate cardiac autonomic activity in 27 Romano-Ward subjects and 27 normal controls. The heart rate. and the QT. QTc and QT/QS2 (ratio of electrical to mechanical systole) intervals were compared. Subjects with long QT were compared with normals. Those with a long QT interval had the following results: similar resting heart rates; lower rates during moderate (151.6 vs 169.6 beats/min. p = 0.04) and maximal (155.9 vs 182.1 beats/min. p = less than 0.001) exercise; an abnormal QT cycle-length relationship. with failure of the QT to shorten normally with increasing heart rate; an increase in QTc versus a decrease in normals; supine rest QT/QS2 ratio of 1.12 vs 0.93. p = 0.001; and an exercise QT/QS2 that increased by 30%. from 1.12 at rest to 1.45. versus 15%. in normals. from 0.93 to 1.07. p = 0.001. The lower heart rates and excessively prolonged QT/QS2 ratios during exercise further support an abnormality of. or abnormal cardiac response to. sympathetic activity. A QT/QS2 greater than 1.0 at rest. an exercise QT/QS2 ratio greater than 1.17. and an increase in QTc during moderate exercise may be helpful diagnostic findings in patients with borderline long QTc intervals at rest.
Hemodynamic effects of celiprolol in essential hypertension, The immediate and short-term (2 week) hemodynamic and humoral effects of the beta-1 antagonist. beta-2 agonist. celiprolol. were compared with those of more prolonged atenolol therapy in 12 patients with essential hypertension. Celiprolol produced an immediate dose-dependent decrease in mean arterial pressure (113 +/- 3 to 102 +/- 2 mm Hg; p less than 0.001) and total peripheral resistance (49 +/- 3 to 38 +/- 1 U/m2; p less than 0.005) that was associated with an increased heart rate (67 +/- 1 to 73 +/- 2 beats/min; p less than 0.01) and cardiac index (2.347 +/- 129 to 2.708 +/- 111 ml/min/m2; p less than 0.01). Both celiprolol and atenolol reduced mean arterial pressure with short-term treatment (p less than 0.01); this was associated with a reduced total peripheral resistance with celiprolol (from 24 +/- 1 to 21 +/- 1 U/m2; p less than 0.02) and was not observed with atenolol. Moreover. in contrast with atenolol. celiprolol did not change heart rate or stroke and cardiac indexes. Splanchnic and forearm vascular resistances decreased with celiprolol (p less than 0.05) but not with atenolol; neither beta-blocking drug altered renal blood flow. These results demonstrate that the hemodynamic effects of celiprolol were strikingly different from atenolol; celiprolol reduced arterial pressure and total peripheral and certain vascular resistances without altering heart rate. cardiac index or regional blood flows. These effects may be explained by celiprolol's cardiac beta-1 receptor inhibitory and peripheral beta-2 receptor agonistic effects.
Use of Valsalva maneuver to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension, It has been suggested that changes in left atrial pressure may mask or mimic left ventricular diastolic function abnormalities detected by Doppler echocardiography. The effect of the Valsalva maneuver on the transmitral flow velocity profile was therefore studied in 28 patients without evidence of coronary artery disease (group 1. mean age +/- standard deviation 50 +/- 8 years) and in 94 patients with evidence of coronary artery disease or systemic hypertension (group 2. mean age 54 +/- 10 years). At baseline. group 2 patients had higher peak late diastolic filling velocity (A). lower peak early (E) to late diastolic filling velocity (E/A) ratio and longer isovolumic relaxation time than group 1. whereas heart rate. E velocity and E deceleration time were similar in both groups. During Valsalva. both groups had similar increases in heart rate and similar decreases in E velocity but E/A ratio decreased significantly only in group 2 because of a lesser decrease in A velocity. The E/A ratio was greater than or equal to 1.0 both before and during Valsalva in all but 1 patient in group 1. whereas in group 2. 32 patients had E/A greater than or equal to 1.0 at rest and during Valsalva. 33 patients had E/A greater than or equal to 1.0 at rest but less than 1.0 both at rest and during Valsalva. Using group 1 as controls. prevalence. specificity and positive predictive value of E/A less than 1.0 in group 2 were 31. 100 and 100% at rest and 66. 96 and 98% during Valsalva.
The molecular basis for Duchenne versus Becker muscular dystrophy: correlation of severity with type of deletion, About 60% of both Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is due to deletions of the dystrophin gene. For cases with a deletion mutation. the "reading frame" hypothesis predicts that BMD patients produce a semifunctional. internally deleted dystrophin protein. whereas DMD patients produce a severely truncated protein that would be unstable. To test the validity of this theory. we analyzed 258 independent deletions at the DMD/BMD locus. The correlation between phenotype and type of deletion mutation is in agreement with the "reading frame" theory in 92% of cases and is of diagnostic and prognostic significance. The distribution and frequency of deletions spanning the entire locus suggests that many "in-frame" deletions of the dystrophin gene are not detected because the individuals bearing them are either asymptomatic or exhibit non-DMD/non-BMD clinical features.
Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene, Eighty unrelated individuals with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7. all exons detected by cDNA8. and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene. detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes. p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD. BMD. or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these. eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact. while 21 DMD patients. 7 intermediate patients. and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus. with two exceptions. frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings. by Malhotra et al.. at the 5' end of the gene.
Etiologic heterogeneity in the familial aggregation of congenital cardiovascular malformations, Recent data indicate that there is increased risk of congenital cardiovascular malformations (CCVM) within families of probands diagnosed with congenital cardiovascular malformations that are due to altered embryonic blood flow (flow lesions). In the present study. regressive models recently developed by Bonney were used to compare specific models of inheritance and to test for etiologic heterogeneity among three subgroups of 375 flow-lesion families identified by the Baltimore-Washington Infant Study. When all families were analyzed as a single group. the best-fitting model was a simple recessive model with Mendelian transmission; race did not have a significant effect on estimated risk. Separate analyses of families of probands with left heart defects. right heart defects. and ventricular septal defects (VSD) confirmed this simple Mendelian recessive model as the model of choice. However. when race was included as a covariate in these genetic models. there was evidence for significant heterogeneity among the three subgroups. There was an increased risk to relatives of white probands with right heart defects and to relatives of black probands with VSD. while there was no effect of race among relatives of probands with left heart defects. These results strongly suggest that there is etiologic heterogeneity in the control of CCVM among flow-lesion families and that the patterns of familial aggregation differ among the races.
Localization of HeLa cell tumor-suppressor gene to the long arm of chromosome II, Cytogenetic and molecular genetic analyses of human intraspecific HeLa x fibroblast hybrids have provided evidence for the presence of a tumor-suppressor gene(s) on chromosome 11 of normal cells. In the present study. we have carried out extensive RFLP analysis of various nontumorigenic and tumorigenic hybrids with at least 50 different chromosome 11-specific probes to determine the precise location of this tumor-suppressor gene(s). Two different hybrid systems. (1) microcell hybrids derived by the transfer of a normal chromosome 11 into a tumorigenic HeLa-derived hybrid cell and (2) somatic cell hybrids derived by the fusion of the HeLa (D98OR) cells to a retinoblastoma (Y79) cell line. were particularly informative. The analysis showed that all but one of the nontumorigenic hybrid cell lines contained a complete copy of the normal chromosome 11. This variant hybrid contained a segment of the long arm but had lost the entire short arm of the chromosome. The tumorigenic microcell and somatic cell hybrids had retained the short arm of the chromosome but had lost at least the q13-23 region of the chromosome. Thus. these results showed a perfect correlation between the presence of the long arm of chromosome 11 and the suppression of the tumorigenic phenotype. We conclude therefore that the gene(s) involved in the suppression of the HeLa cell tumors is localized to the long arm (q arm) of chromosome 11.
Detection of marker associations with a dominant disease gene in genetically complex and heterogeneous diseases, Linkage disequilibrium of a marker allele with disease may characterize a chromosomal region containing the disease gene. In several diseases. only a limited number of pedigrees are linked to a particular region. because of linkage heterogeneity. Disequilibrium in this situation is more easily detected when the association is positive (an infrequent marker allele associated with disease mutation). and sampling is conditional on presence or absence of illness in individuals or gametes. Defining H as the marker frequency in illness-transmitting gametes. and Q the marker frequency in normal chromosomes. we compute the power of a given sample (of ill persons/gametes) to detect association in a disease that is genetically heterogeneous. with a dominantly transmitted form linked to a marker. The estimation of Q and the effects of linkage heterogeneity (when unrelated individuals are examined) are also analyzed. Two linked pedigrees give acceptable power to detect association when the allele is frequent enough in illness gametes (H greater than or equal to .6) and infrequent enough in normals (Q less than or equal to .01). If H greater than or equal to .2. 14 pedigrees are needed to give the same power. From the analysis of different values of Q and H. it appears that even in the presence of considerable genetic heterogeneity and complex inheritance (where some normals carry the disease mutation). association may be detected with clinically feasible sample sizes.
Parental origin of the extra chromosome in trisomy 18, The parental origin of the supernumerary chromosome 18 was investigated by RFLP analysis in 23 individuals with Edwards syndrome. All families were studied with the DNA probe pERT-25. which recognizes a locus of highly polymorphic tandemly repeated DNA sequences on chromosome 18. The extra chromosome was found to be of maternal origin in 19 patients (95%). of paternal origin in one patient (5%). and indeterminate in three patients. In one of the three indeterminate cases. a mosaic. an apparent recombination event had taken place within the pERT-25 locus. The overall high degree of informativeness of pERT-25 illustrates the power of a chromosome-specific variable-number tandem repeat probe (VNTR) in parental origin studies of aneuploidy.
Genetic support groups in the delivery of comprehensive genetic services, This research sought information about the services provided by genetic support groups. their members' experiences in obtaining genetic and related services. and members' recommendations for improving services. Results from a survey of 43 directors of genetic support groups showed that these organizations not only provide their members with a wide range of informational and supportive services but also address the need for education of both the public and health professionals about genetic disorders. A second survey of 931 members of genetic support groups found that. although they obtained genetic information from a variety of professional and informal sources. many of them experienced barriers to obtaining sufficient genetic information. Respondents called for professionals to improve their interpersonal skills in working with clients and to assist families in obtaining a wider variety of services. On the basis of these findings. a service model and priorities are proposed to bring together genetic specialists. community professionals. and genetic support groups for the delivery of comprehensive services to individuals and families with genetic disorders.
Improvement in glucose-induced insulin secretion in diabetic rats after long-term gliclazide treatment: a comparative study using different models of non-insulin-dependent diabetes mellitus induced by neonatal streptozotocin, Understanding of the long-term action of sulfonylureas in humans with non-insulin-dependent diabetes mellitus (NIDDM) may be facilitated by studying the effect of long-term sulfonylurea administration to animal models of the disease. In this study two different versions of the neonatal streptozotocin-induced diabetes (STZ) rat model of NIDDM were used. The n5-STZ model (STZ on day 5 after birth). which is characterized by basal hyperglycemia. a marked reduction of pancreatic insulin stores. and insulin resistance. and the n0-STZ model (STZ on day of birth). which develops mild hyperglycemia. have an approximately 50% reduction in pancreatic insulin content. and no insulin resistance. The diabetic rats were given oral gliclazide (10 mg/kg/day) and compared with untreated diabetic rats and nondiabetic rats. Insulin secretion was studied the day after the last gliclazide dose using the isolated perfused pancreas preparation. In severely hyperglycemic n5-STZ rats (plasma glucose levels greater than 16 mmol/L) the long-term gliclazide treatment did not lower the plasma glucose values. did not affect pancreatic insulin stores. and did not significantly modify in vitro insulin release in response to glucose or arginine. In moderately hyperglycemic n5-STZ rats (plasma glucose levels less than 16 mmol/L) the plasma glucose levels declined progressively and reached a mean of 8 mmol/L at the end of gliclazide therapy. The increase in pancreatic insulin stores in n5-STZ rats remained marginal. In the n0-STZ rats gliclazide treatment did not significantly modify the plasma glucose levels or the pancreatic insulin stores. After gliclazide therapy in both the n5-STZ gliclazide responder group and the n0-STZ group: (a) in vitro glucose-induced insulin secretion was increased three- to fivefold; (b) the response to arginine. which is increased in diabetic rats. was amplified by two- to threefold; (c) insulin release in response to gliclazide was unchanged. In conclusion. long-term gliclazide therapy augments stimulated insulin secretion in these two rat models of NIDDM and does not induce any refractoriness to short-term sulfonylurea administration. The improvement of beta-cell function observed here was not related to the concomitant variations of hyperglycemia and/or pancreatic insulin content.
Hepatic sensitivity to insulin: effects of sulfonylurea drugs, Insulin regulation of hepatic glucose production (HGP) is altered in non-insulin-dependent diabetes mellitus (NIDDM). resulting in increased glucose output by the liver; this contributes to the elevation in plasma glucose concentration observed both in the basal state and postprandially. Therefore. restoration of normal insulin action in the liver must be a goal of hypoglycemic therapy. Sulfonylureas have been widely used for treatment of NIDDM over the past 30 years. In addition to their stimulatory effect on insulin secretion. these compounds seem to possess extrapancreatic effects. Early in vitro studies showed that addition of sulfonylureas to the perfusion medium of liver preparations could exert a significant suppressive effect on HGP. Subsequent experience suggested that these compounds could act at the level of the insulin receptor as well as at various postreceptor sites. These studies showed that sulfonylureas may inhibit glycogenolysis and gluconeogenesis while stimulating glycogen synthesis. Results obtained in vivo in NIDDM patients are in agreement with the in vitro studies. Long-term treatment with sulfonylureas is associated with a decline in fasting plasma glucose concentration and a parallel reduction in HGP. Nevertheless. the direct effect of sulfonylurea administration on the liver remains unclear. since the reduction in HGP that occurs during sulfonylurea treatment may be secondary to an overall improvement in insulin secretion. It is also of interest that in insulin-dependent diabetic patients. sulfonylurea administration in combination with insulin injections is not followed by a significant change in HGP. Possible effects of sulfonylureas on glucagon secretion and on the metabolism of free fatty acids (FFAs) may also contribute to improved sensitivity of the liver to the suppressive action of insulin. since these agents appear to reduce plasma glucagon and FFA concentrations. Thus. present data support an extrapancreatic action of sulfonylureas on the liver. However. it does appear that a certain degree of residual insulin secretion is required for sulfonylurea agents to elicit their hepatic effect.
Current status of non-insulin-dependent diabetes mellitus (type II): management with gliclazide, Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of morbidity and mortality worldwide. with a prevalence of 3-7% in most Western countries. Decreased insulin secretion and diminished tissue insulin sensitivity are both implicated in the pathogenesis of the disease; both may be exacerbated by persistent hyperglycemia and improved by normalization of blood sugar levels. Measures to control hyperglycemia. hypertension. and hyperlipidemia are important in the management of NIDDM and prevention of its long-term complications. The effects of dietary modification. exercise. and antihypertensive and antiplatelet therapy. as well as of pharmacologic control of blood sugar. on the vascular and renal complications of NIDDM have been investigated. Gliclazide is a second-generation sulfonylurea drug whose efficacy in the treatment of NIDDM. alone or in combination with insulin. has been widely demonstrated. Studies of the use of gliclazide. reported at recent symposia. are summarized in this review.
Effect of 6-month gliclazide treatment on insulin release and sensitivity to endogenous insulin in NIDDM: role of initial continuous subcutaneous insulin infusion-induced normoglycemia, In 10 obese. new-onset non-insulin-dependent diabetes mellitus (NIDDM) patients (group A). continuous subcutaneous insulin infusion (CSII) was used to induce normoglycemia during 14 days. Fasting blood glucose was 4.6 +/- 0.2 mmol/L and mean daily blood glucose 5.8 +/- 0.2 mmol/L at the end of the CSII period. This excellent glycemic control was obtained with 35 +/- 4.8 U of insulin per day. corresponding to 0.47 +/- 0.06 U/kg/24 hours. Endogenous insulin production was markedly suppressed. since urinary C-peptide was reduced from 18.5 +/- 0.12 to 7.9 +/- 0.25 nmol/24 hours. Gliclazide was given to group A following CSII. and to five obese NIDDM patients (group B) in their habitual hyperglycemic state. Gliclazide maintained in group A. and induced in group B. excellent metabolic control. This was accompanied by the appearance of a small first-phase insulin response to intravenous glucose. and significant increases in the mean-daily-insulin to mean-daily-blood-glucose ratio. as well as in the 24-hour urinary C-peptide-to-glucose ratio. The gliclazide effects tended to be more pronounced in group A. No significant effect was seen on efficacy of endogenous insulin (slope of disappearance of blood glucose divided by insulin levels). During 6 months of gliclazide treatment. excellent glycemic control was maintained in all patients. This was paralleled by unchanged stimulation by gliclazide of first-phase insulin response to glucose. and augmented mean 48-hour insulin-to-glucose and urinary C-peptide-to-glucose ratios. No change in the ratio of glucose disposal to endogenous insulin was noted. We conclude that physiologic insulin replacement may induce normoglycemia in NIDDM. indicating that insulin resistance is not of clinical significance; gliclazide has a beta-cell-stimulating action that is maintained quantitatively unchanged for at least 6 months; the therapeutic effect of gliclazide in NIDDM seems to be mainly. if not exclusively. the result of its beta-cytotrophic action. Initial normoglycemia. induced here by CSII. may have a lasting enhancing effect on the gliclazide action.
An evaluation of long-term glycemic control in non-insulin-dependent diabetes mellitus: the relevance of glycated hemoglobin, Thirty-six patients were admitted to an open study designed to evaluate the long-term efficacy of gliclazide in the treatment of type II diabetes mellitus. Results from 27 of these patients were analyzed at 36 months. 21 at 48 months. and 16 at 60 months of follow-up. An overall reduction in fasting and postprandial blood sugar was observed (p less than 0.001). Total glycated hemoglobin (HbA1) fell significantly (p less than 0.001). to revert to values within the reference range in over 80% of cases. Body weight remained stable over a period of observation ranging from 36 to 60 months. The incidence of subsequent failure of oral treatment was 2% per annum. These results show that long-term treatment of type II diabetes with gliclazide leads to satisfactory results. with practically no side effects.
Pathophysiology of vascular disease in diabetes: effects of gliclazide, Diabetes mellitus is a major risk factor for coronary heart disease. peripheral vascular disease. and cardiovascular disease. The prevalence of these complications is increased about two- to four-fold in people with diabetes in the United States. and they contribute substantially to morbidity. mortality. and healthcare costs. The pathogenesis of macrovascular disease in diabetes is multifactorial. Endothelial injury is an early event. followed by macrophage adherence and uptake of lipids to produce a fatty streak. Platelet adherence. aggregation. and release of thromboxane and platelet-derived growth factors may then occur. Quantitative and qualitative alterations of lipoproteins are seen. particularly in uncontrolled insulin-dependent and non-insulin-dependent diabetes. Hyperinsulinemia may be contributory. as may elevated plasma proinsulin levels. Glycation of plasma proteins and of components of the vascular wall occurs. and altered coagulation and/or fibrinolysis may lead to thrombosis. The process is accelerated by hypertension. smoking. and hypercholesterolemia. Gliclazide is an oral sulfonylurea agent that has been reported to have actions on platelet function and fibrinolysis in addition to its effects on glycemia. The evidence for this is reviewed. and recommendations for future studies are made.
Pathogenesis of diabetic microangiopathy: an overview, Major susceptibility factors for diabetic microangiopathy include duration of disease and probably quality of metabolic control. The mechanism of development of microangiopathy is incompletely understood but appears to involve functional abnormalities within the microcirculation. enhanced glucose metabolism. hemostatic abnormality. and genetic susceptibility. This article reviews the factors believed to be involved in pathogenesis and attempts to draw these together by suggesting a sequence of pathogenic interactions that could result in the microvascular changes seen in susceptible target organs. Possibilities for therapeutic intervention based on these pathogenic mechanisms are discussed. A small pilot trial of an oral hypoglycemic agent. gliclazide. is reported. providing evidence for a specific action of this drug on thromboxane synthesis and platelet aggregation. This is independent of glycemic control and may in part be mediated by a fall in lipid peroxides.
Diabetic retinopathy in non-insulin-dependent diabetes mellitus patients: the role of gliclazide, Diabetic retinopathy is the most common cause of human blindness between the ages of 30 and 67 in the industrialized world. Retinopathy has a multifactorial etiology. Standard treatment has aimed at correcting only disturbed glucose metabolism. but this may lead only to the partial amelioration of certain hemobiologic factors. In addition to its metabolic action. gliclazide has been shown to have specific hemobiologic properties; studies with gliclazide in animals and humans have shown significant improvements of platelet abnormalities. stimulation of prostaglandin I2 synthesis. and enhancement of fibrinolytic activity. In humans. open-label studies have shown that gliclazide treatment leads to stabilization of background retinopathy in non-insulin-dependent diabetics and. more recently. these beneficial effects have been confirmed in controlled studies lasting up to 37 months in which other sulfonylureas were used. The Japanese Diabetic Retinopathy Program studied the progression of retinopathy over a 5-year period. comparing gliclazide with other sulfonylureas and with placebo. This study showed that. with equivalent metabolic control. there was a trend toward a lower rate of deterioration and a significantly lower incidence of preproliferative retinopathy in the group receiving gliclazide compared with those receiving other sulfonylureas. Overall. the specific hemobiologic actions of gliclazide appear to offset or retard the progression of diabetic retinopathy and may have the advantage of lowering the incidence of preproliferative retinopathy.
Rationale for the association of sulfonylurea and insulin, Approximately 20-30% of patients with non-insulin-dependent diabetes mellitus (NIDDM) started on sulfonylureas fail to respond to treatment (primary failure); in the remaining patients. secondary failure to sulfonylurea therapy occurs at a rate of 5-10% per year. On the other hand. in insulin-treated NIDDM patients a progressive increase in insulin requirement can occur without significant improvement in glucose control. In these patients the combination of oral agents with insulin therapy may be useful. The rationale behind this therapeutic approach resides in the synergistic action of the two agents on specific mechanisms responsible for glucose intolerance and hyperglycemia. Long-acting insulin. administered as a single dose at supper or bedtime. should restrain excessive overnight hepatic glucose production. thus allowing a significant reduction in fasting glucose concentrations. A lower ambient glucose level should favor the stimulatory effect of sulfonylureas on insulin secretion. Sulfonylurea treatment should increase the portal inflow of secreted insulin with a resultant increase in insulin levels draining into liver. thus reducing postprandial hepatic glucose output. Moreover. sulfonylureas might improve insulin action on its target tissue (i.e.. muscle). thus increasing overall insulin-mediated glucose metabolism. The reduction in prevailing plasma glucose levels will reduce the toxic effect of hyperglycemia on the beta-cell and on insulin-sensitive tissues. On this basis. NIDDM patients with secondary failure of monotherapy may benefit from combined therapy. Nevertheless. the effects of combined therapy should be strictly monitored and intensive insulin therapy promptly started if poor control persists.
Mechanisms for hyperglycemia in type II diabetes mellitus: therapeutic implications for sulfonylurea treatment--an update, Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting hyperglycemia associated with defects in the pancreatic islet. the liver. and the peripheral tissues. which together comprise a feedback loop responsible for maintenance of glucose homeostasis. This review focuses on the key role of the endocrine pancreas alpha and beta cells to coordinate glucose output from the liver with glucose utilization. The basal rate of hepatic glucose utilization. The basal rate of hepatic glucose production is elevated in subjects with NIDDM. and this is positively correlated with the degree of fasting hyperglycemia. This increased rate of glucose release by the liver results from impaired hepatic sensitivity to insulin. reduced insulin secretion. and increased glucagon secretion. Though basal immunoreactive insulin levels in patients with NIDDM may appear normal when compared with healthy individuals. islet function testing at matched glucose levels reveals impairments of basal. steady-state. and stimulated insulin secretion due to a reduction in beta-cell secretory capacity and a reduced ability of glucose to suppress glucagon. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia but in a curvilinear fashion. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action. This impairment becomes more important to the hyperglycemia as the islet alpha- and beta-cell function declines. Therapeutic interventions. to be effective. must reduce hepatic glucose production either by improving islet dysfunction and raising plasma insulin levels. or improving the effectiveness of insulin on the liver. Both result in a decline in the fasting glucose levels regardless of the cause of hyperglycemia. We conclude that NIDDM is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a necessary role. Treatment should be based on this physiologic understanding.
Characterization of in vitro chemosensitivity of perioperative human ovarian malignancies by adenosine triphosphate chemosensitivity assay, We report the in vitro chemosensitivity of primary and recurrent human ovarian tumor samples analyzed by adenosine triphosphate chemosensitivity assay. We defined sensitivity as a greater than or equal to 70% decrease in intracellular adenosine triphosphate versus control at 20% of the reported peak plasma concentration per agent tested. Twenty of 21 assays (95.24%) were completed successfully. Single-agent and combined dose-response patterns consisting of decreasing viability with increasing drug concentration were observed consistently. Thirteen primary tumors were assayed. with 15.4% sensitive to cisplatin. 7.7% sensitive to 4-hydroxycyclophosphamide and 53.8% sensitive to their combination. Seven recurrent tumors were assayed. with 14.3% sensitive to cisplatin. 28.6% sensitive to 5-fluorouracil. and 42.9% sensitive to their combination. Dose-response characteristics and in vitro sensitivity rates reported in this article are consistent with reports of patient response in the literature. We conclude that adenosine triphosphate chemosensitivity assay is an efficient and reliable instrument for the in vitro chemosensitivity assessment of human tumors and warrants further clinical investigation.
Appropriateness of intrapartum fetal heart rate management and risk of cerebral palsy, Cerebral palsy affects 2 in 1000 infants in the United States. and the intrapartum period is frequently scrutinized as the etiologic source. In a matched group of 49 infants with cerebral palsy at 1 year of age and 49 controls. no difference in the incidence of inappropriate intrapartum fetal heart rate pattern management was detected. This supports the conclusions of others that the intrapartum period is an infrequent source of cerebral palsy.
Primary invasive vaginal carcinoma, A review of primary vaginal carcinoma treated at the Medical University of South Carolina from January 1970 through December 1989 included 76 squamous carcinomas. 12 adenocarcinomas. and 3 undifferentiated carcinomas. Staging was done according to the system of the International Federal of Gynecology and Obstetrics as modified by Perez et al. Stages I. II. III. and IV included 25. 39. 15. and 12 patients. respectively. Corrected 5-year survival rates were 73% for stage I. 39% for stage II. 38% for stage III. and 25% for stage IV. Sixteen percent of patients had received prior pelvic radiation. Invasive cervical cancer preceded vaginal cancer in 21% of patients. Detection of cancer was accomplished by routine cytologic testing in 17% of patients. palpation of an asymptomatic mass in 10% of patients. or palpation of a symptomatic mass in 72% of patients. Eighty-seven percent of patients were treated with radiation therapy. Survival curves of patients grouped by stage and other potential prognostic factors were compared. Lower stage (p less than 0.01). younger age (p less than 0.02). and no symptoms at detection (p less than 0.01) were statistically significant favorable prognostic factors. Histologic type. extent of vaginal involvement. vaginal location. prior radiation therapy. prior cervical cancer. and prior hysterectomy are factors that did not significantly affect survival.
Endometrial morphology in asymptomatic postmenopausal women, Few data are available regarding endometrial histologic features in asymptomatic perimenopausal and postmenopausal women. This study encompasses endometrial biopsy specimens obtained from 801 such women before enrollment in a multicenter study of estrogen-progestin replacement. One endometrial cancer was found (0.13%); four additional biopsy specimens showed atypia (total 0.63%). The endometrium was atrophic in 373 (46.9%). proliferative in 133 (16.7%). secretory in 54 (6.8%). and hyperplastic in 41 (5.2%). Insufficient tissue for diagnosis was obtained in 195 (24.5%). We conclude that the yield for neoplasia is so low that screening endometrial biopsy is not justified in asymptomatic perimenopausal and postmenopausal women.
Assessment of Kegel pelvic muscle exercise performance after brief verbal instruction, Forty-seven women had urethral pressure profile determinations performed at rest and during a Kegel pelvic muscle contraction. after brief standardized verbal instruction. Twenty-three (49%) had an ideal Kegel effort--a significant increase in the force of urethral closure without an appreciable Valsalva effort. Twelve subjects (25%) displayed a Kegel technique that could potentially promote incontinence. Age. parity. weight. estrogen deprivation. prior continence surgery or hysterectomy. and passive urethral function did not predict a successful effort. We concluded that simple verbal or written instruction does not represent adequate preparation for a patient who is about to start a Kegel exercise program.
Polycystic ovary syndrome and the androgen-insulin connection, The association of hyperandrogenism. insulin resistance. and polycystic ovarian disease is well established. The accompanying hyperinsulinemia results in acanthosis nigricans. an epiphenomenon of this syndrome. The knowledge that states of insulin resistance of diverse causes are associated with ovarian hyperandrogenism makes the argument for insulin-driven ovarian androgen secretion compelling. However. equally compelling evidence suggests that hyperandrogenism may contribute to insulin resistance and hyperinsulinemia. The irreconcilable differences between these two hypotheses have resulted in an array of contradictory studies. In this article a unified concept of polycystic ovary syndrome and its androgen-insulin connection is proposed. The hypothesis incorporates the role of hyperinsulinemia in the androgen excess observed (and vice versa); the key to this connection is the androgen-dependent change in regional body fat distribution and its metabolic consequence. The pathophysiologic features of polycystic ovary syndrome. which has important clinical sequelae. deserve further consideration.
Ultrasonographic screening for the Down syndrome fetus, The usefulness of ultrasonography in detecting fetuses with Down syndrome in the second trimester has been the subject of considerable debate during the past 3 years. Conflicting reports have led to increasing confusion about the subject in the medical community and among the public. A review of the existing literature indicates that structural malformations that are chiefly cardiac are present in half of Down syndrome fetuses but are not consistently found during routine second-trimester ultrasonography. Although excess posterior nuchal skin-fold thickness is frequently present in infants with Down syndrome. it is also not consistently identified during second-trimester ultrasonographic examinations. Studies evaluating the efficacy of screening programs that are based on femur length shortening associated with Down syndrome have revealed markedly discrepant intercenter results. Although variations in methods may account for some of the observed variability. the magnitude of femoral shortening in Down syndrome suggests that this measurement may be only marginally useful. In summary. antenatal ultrasonography will allow for the detection of only those fetuses with Down syndrome who have multiple characteristic phenotypic features or anomalies. Moreover. current second-trimester ultrasonography does not appear to be either sensitive enough specific enough to be used as a unique Down syndrome screening modality; however. it may be a useful adjunct to maternal age and serum biochemical markers in the assignment of risk for Down syndrome.
Acute myocardial infarction associated with prostaglandin E2, Prostaglandin E2 is rarely associated with serious maternal side effects when used for second-trimester pregnancy termination. Acute myocardial infarction complicating therapeutic pregnancy termination with prostaglandin E2 in a patient with chronic glomerulosclerosis and severe hypertension is reported.
CA 125 regression: a model for epithelial ovarian cancer response, The rate of decline of CA 125 in effectively treated epithelial ovarian cancer is described by the exponential regression curve CA 125 = EXP [i - s (days after surgery)]. In this equation i. the y-axis intercept. measures initial tumor burden whereas s. the slope of the regression curve. is determined by the extent of cytoreductive surgery and the subsequent response to chemotherapy. Departure from the regression curve uniformly results in progressive disease. In patients whose cancers had been completely removed. we calculated the mean half-life of CA 125 to be 10.4 days (range 4 to 21). In this case s = 0.0835 and characterizes the ideal regression rate. The model predicts that high-dose cisplatin chemotherapy (s = 0.0671) is more effective than low-dose cisplatin (s = 0.0380) (p less than 0.03) in eliminating residual cancer. Because s can be calculated within 2 to 3 months of treatment and then compared with s for the ideal regression curve and with the values of s reported for standard chemotherapy. evaluation of any new treatment protocol can be facilitated with this method.
Uterine rupture at term pregnancy with the use of intracervical prostaglandin E2 gel for induction of labor, Prostaglandin E2 is a powerful oxytocic agent that reliably initiates labor. even in the presence of an unripe cervix. The low incidence of fetomaternal complication contributes to its universal use. We report a rare case of uterine rupture after intracervical application of prostaglandin E2 gel. Thus far no prostaglandin compound or method of administration seems to be exempt from such a complication.
One-blade rotation of a persistent posterior vertex, Fifteen women in labor at term with no evidence of protraction or arrest disorder successfully underwent a single-blade rotation of the fetus from occipitoposterior to occipitoanterior position. There were no failures. no fetal injuries. and no significant maternal trauma. This method of forceps rotation appears to be a safe alternative to current methods of managing occipitoposterior positions.
Congenital hydronephrosis: correlation of fetal ultrasonographic findings with infant outcome, Although congenital hydronephrosis is a common fetal disorder. ultrasonographic criteria for prenatal diagnosis remain poorly defined. In this study prenatal ultrasonographic findings were correlated with postnatal outcome in 63 fetuses with suspected hydronephrosis. Prenatal ultrasonographic measurements included length. anteroposterior diameter. and transverse diameter of the kidney and renal pelvis. as well as dorsal renal parenchymal thickness. In 45 of the 63 fetuses. hydronephrosis was confirmed postnatally. These infants were divided into two groups on the basis of renal status: (1) abnormal renal function and/or surgery required (n = 31) and (2) normal renal function with no surgery required (n = 14). The anteroposterior diameter of the renal pelvis was the simplest and most sensitive technique for prenatal diagnosis of congenital hydronephrosis. allowing identification of 100% of cases. Postnatal follow-up studies are warranted if an anteroposterior pelvic diameter is greater than or equal to 4 mm before 33 weeks or greater than or equal to 7 mm after 33 weeks.
Endomyocardial ultrastructural findings in preeclampsia, Ultrastructural findings in endomyocardial biopsy specimens obtained during cardiac catheterization in a patient with severe preeclampsia are described. Intramyocardial vessels revealed prominent swelling of the endothelial cell cytoplasm. In addition. cardiac myocyte mitochondria showed swelling and clearing within the matrix. Endomyocardial ultrastructural injury occurs in severe preeclampsia.
Psychosocial support for maternal stress during pregnancy: effect on birth weight, In a previous study we showed that moderate to severe stress during pregnancy was inversely related to infant birth weight. Using the same criteria for stress (according to the Social Readjustment Rating Scale of Holmes and Rahe). we studied 86 white mothers with singleton pregnancies and with no known medical or obstetric risk factors for reduced birth weight. After strict randomization. data were analyzed for 43 mothers who received psychosocial support between enrollment at +/- 20 weeks and delivery at +/- 38 weeks and for 43 control mothers who received standard care at the antenatal clinic. In the supported group seven infants weighed less than 3000 gm at birth versus 18 control infants (p = 0.008). and analysis revealed that this effect was more the result of improved intrauterine growth than of prolongation of pregnancy. These findings are of little clinical relevance as far as the neonate is concerned. but they do indicate that psychosocial support has a significant effect on birth weight. It is possible that previous studies that have looked only for an effect on low- or very-low-birth-weight rates might have missed this clinically measurable benefit of counseling.
Uterine activity after preterm premature rupture of the membranes, Preterm premature rupture of the membranes complicates few pregnancies but is a major contributor to overall perinatal morbidity and mortality. Although a reduced incidence of preterm premature rupture of fetal membranes has been reported in women who had antepartum uterine activity monitoring. there are few data regarding uterine activity after preterm premature rupture of fetal membranes. Therefore daily uterine activity monitoring was performed in 101 consecutive women with preterm premature rupture of fetal membranes between 26 and 34 weeks' gestation. The mean gestational ages at rupture and delivery were 31.4 +/- 2.3 and 33.7 +/- 4.5 weeks. respectively. A significant increase in contraction frequency was identified within 24 hours of onset of preterm labor (p less than 0.005). A contraction frequency of four or more per hour predicted the onset of labor within 24 hours with a sensitivity of 72%. a specificity of 90%. a positive predictive value of 54%. and a negative predictive value of 95%. These results indicate that most women with preterm premature rupture of fetal membranes exhibit a baseline contraction frequency that is similar to that of women with intact membranes and premature labor. An abrupt increase in contraction frequency is a warning of impending labor.
The anaesthetic management of congenital tracheal stenosis, Congenital tracheal stenosis is a rare and potentially lethal condition. Two case reports are presented which demonstrate the problems encountered in the anaesthetic management of this condition.
Acute mercury poisoning, A case of deliberate self poisoning with approximately 7 g mercuric chloride (the lethal dose is about 1 g) is described. The patient died after 6 days despite the use of chelating agents. plasma exchange and intensive supportive therapy. The management of acute mercury toxicity is discussed.
Epidural blood patch for treatment of subarachnoid fistula in children, A subarachnoid-cutaneous fistula developed in two children after the placement of a catheter in the subarachnoid space for drainage of cerebrospinal fluid. The management of this iatrogenic complication with epidural blood patch is described.
Ketamine, midazolam and vecuronium infusion. Anaesthesia for Down's syndrome and congenital heart disease, A ketamine. midazolam and vecuronium infusion was used for total intravenous anesthesia in a patient with Down's syndrome. a ventricular septal defect and pulmonary hypertension. A mixture of ketamine 200 mg. midazolam 5 mg and vecuronium 12 mg in 50 ml of normal saline was infused at 0.5 ml/kg/hour. This simple technique and ventilation with 100% oxygen maintained tissue oxygenation and cardiovascular stability.
Rhabdomyolysis and operating position, Rhabdomyolysis during routine surgery was studied in three groups of patients who had surgery. with limited trauma to muscle. in the lateral and supine positions. and prone on the spinal frame. A range of blood tests was performed (before surgery. and on the first. third and seventh day after operation). These showed that a creatine kinase increase in the 24 hours and the early appearance of myoglobin in the serum were the best indicators. Rhabdomyolysis was associated with the lateral position and long lasting surgery. No blood test before surgery was of any predictive value.
Incremental spinal anaesthesia using a 32-gauge catheter, Incremental spinal anaesthesia using a 32-gauge intrathecal catheter was studied in 13 males scheduled for transurethral resection of the prostate or repair of inguinal hernia. The spinal technique failed in four patients. Dose-response curves were obtained in the remaining nine patients using increments of 0.5% plain bupivacaine. The spinal block was extended safely and reliably without cardiovascular instability. No patient had any postoperative headache and all catheters were removed intact.
Protruding atheromas in the thoracic aorta and systemic embolization, OBJECTIVE: To determine whether protruding atheromas in the thoracic aorta are a risk factor for systemic embolization. DESIGN: Case-control study. SETTING: A referral hospital. PATIENTS: A total of 122 patients with a history of stroke. transient ischemic attack. or peripheral emboli and an equal number of age- and sex-matched control patients. MEASUREMENTS: Evaluation using transesophageal echocardiography was done in case patients to detect protruding atheromas in the thoracic aorta and in control patients for cardiac indications other than emboli. MAIN RESULTS: Matched logistic regression showed that the presence of protruding atheromas was strongly related to the occurrence of embolic symptoms (odds ratio. 3.2; 95% Cl. 1.6 to 6.5; P less than 0.001). Furthermore. atheromas with mobile components were present only in case patients. When known risk factors for stroke (hypertension and diabetes) were added to the model. the presence of protruding atheromas remained an independent risk factor for embolic symptoms (odds ratio. 3.8). Hypertension was also independently associated with embolic symptoms (odds ratio. 2.7). but diabetes was not (odds ratio. 1.0). CONCLUSION: Protruding atheromas in the thoracic aorta can be detected by transesophageal echocardiography and should be considered as a cause of strokes. transient ischemic attacks. and peripheral emboli.
Predicting death in patients hospitalized for community-acquired pneumonia, OBJECTIVE: To validate a previously reported discriminant rule for predicting mortality in adult patients with primary community-acquired pneumonia and to determine which factors available at hospital admission predict a fatal outcome among such patients. DESIGN: Historical cohort study. SETTING: University hospital. PATIENTS: Adults admitted to the hospital for community-acquired pneumonia. MEASUREMENTS: Using stepwise logistic regression. we analyzed prognostic factors (data available at admission and recorded in the medical record) that showed a univariate association with mortality. The predictive values of three discriminant rules were measured to validate the results of a previous study. MAIN RESULTS: Of 245 patients. 20 (8.2%) died. Of 42 prognostic factors identified in previous studies. 8 were associated with mortality. but only a respiratory rate of 30/min or more. a diastolic blood pressure of 60 mm Hg or less. and a blood urea nitrogen of more than 7 mmol/L remained predictive in the multivariate analysis. A discriminant rule composed of these three variables was 70% sensitive and 84% specific in predicting mortality. yielding an overall accuracy of 82%. CONCLUSION: Tachypnea. diastolic hypotension. and an elevated blood urea nitrogen were independently associated with death from pneumonia in our study. confirming the value of a previously reported discriminant rule from the British Thoracic Society. This rule may be useful in triage decisions because it identifies high-risk patients who may benefit from special medical attention.
Pulse oximetry monitoring outside the intensive care unit: progress or problem, OBJECTIVE: To evaluate the use of continuous pulse oximetry monitoring in general care units. DESIGN: Hemoglobin oxygen saturation data collected prospectively by use of pulse oximetry with concurrent review of the medical record. SETTING: General medical-surgical nursing units in a large. tertiary care university hospital. PATIENTS: Forty patients on two nursing units monitored with continuous. bedside pulse oximetry at the request of their primary physicians. MEASUREMENTS: All patients had continuous pulse oximetry monitoring. A research associate visited the bedside two or three times daily and recorded saturation compared with time data from the previous 8.75 hours. Patients were studied for 36 hours or until pulse oximetry monitoring was discontinued. Episodes of desaturation were counted. Patient charts were reviewed for documentation of desaturation in either nursing or physician notes. Orders adjusting oxygen therapy or other respiratory therapy within 12 hours of any desaturation episode were also recorded. MAIN RESULTS: Thirty of the 40 patients (75%) had at least one episode of desaturation to less than 90%; 23 (58%) had at least one episode to less than 85%. Desaturation episodes were documented in nursing notes for only 33% of those patients who desaturated to less than 90% and in physician notes in only 7% of cases. Changes in respiratory therapy were ordered in 20% of patients who desaturated to less than 90% and in only 26% who desaturated to less than 85%. CONCLUSIONS: Despite their repeated occurrence. episodes of hypoxemia were rarely documented in either nursing or physician notes. Further. even in patients who had episodic desaturation. pulse oximetry monitoring had little effect on changes in physician-directed respiratory care.
The pathogenesis of sepsis, Sepsis and its sequelae (sepsis syndrome and septic shock) are increasingly common and are still potentially lethal diagnoses. Many mediators of the pathogenesis of sepsis have recently been described. These include tumor necrosis factor alpha (TNF alpha). interleukins. platelet activating factor. leukotrienes. thromboxane A2. and activators of the complement cascade. Neutrophil and platelet activation may also play a role. Other agents that may participate in the sepsis cascade include adhesion molecules. kinins. thrombin. myocardial depressant substance. beta-endorphin. and heat shock proteins. Endothelium-derived relaxing factor and endothelin-1 are released from the endothelium and seem to exert a regulatory effect. counterbalancing each other. A central mediator of sepsis does not seem to exist. although TNF alpha has been commonly proposed for this role. Animal studies are difficult to extrapolate to the clinical setting because of cross-species differences and variations in experimental design. Rather than being caused by any single pathogenic mechanism. it is more likely that sepsis is related to the state of activation of the target cell. the nearby presence of other mediators. and the ability of the target cell to release other mediators. Also important is the downregulation or negative feedback of these mediators or the generation of natural inflammation inhibitors. such as interleukin-4 and interleukin-8. Endothelial damage in sepsis probably results from persistent and repetitive inflammatory insults. Eventually. these insults produce sufficient damage that downregulation can no longer occur; this leads to a state of metabolic anarchy in which the body can no longer control its own inflammatory response.
Familial sensorineural hearing loss: a correlative study of audiologic, radiographic, and vestibular findings, A multidisciplinary approach to the study of a family with autosomal dominant sensorineural hearing loss is presented. The affected family members underwent extensive clinical and laboratory evaluation. They were found to have various degrees of bilateral congenital inner ear anomalies as imaged by computed tomography. The degree of structural abnormalities in the inner ears correlated with the severity of hearing impairment. Vestibular testing revealed nonspecific abnormalities generally correlating with audiologic and radiographic findings. This report presents a unique form of sensorineural hearing loss not previously described and is the first in-depth clinical study of nonsyndromal "Mondini dysplasia" occurring in a family.
Tetanic response of the cricothyroid muscle, Tetanic response of canine cricothyroid muscle tissue was investigated through a series of experiments conducted in vitro. Two separate portions of the cricothyroid muscle. namely the pars recta and pars oblique. were studied. Samples of the muscle were dissected from dog larynges excised a few minutes before death and kept in Krebs-Ringer solution at a temperature of 37 degrees +/- 1 degrees C and a pH of 7.4 +/- 0.05. Tetanic contraction of the muscle samples was obtained by field stimulation to the muscle through a pair of parallel-plate platinum electrodes and with a train of square pulses of 0.1-millisecond duration and 85-V amplitude. Isometric force responses of the pars recta and pars oblique muscles were obtained electronically with a dual servo system (ergometer). The effect of tissue elongation on the active and passive responses was quantified by stimulation of the sample during cyclic elongation. Both active and passive responses as a function of elongation were obtained on the same sample.
Apron tracheostome, Stenosis of the tracheostome following total laryngectomy is not an infrequent complication. either immediately postoperatively or years later. and it poses a common problem for head and neck surgeons. The opening becomes inadequate and the patient is uncomfortable and panicky. A secondary plastic operation is necessary in order to improve the airway. or a laryngectomy tube must be worn constantly. I have developed a satisfactory technique for tailoring the tracheostome during total laryngectomy so as to minimize postoperative stenosis even in irradiated cases and allow the patient to dispense with the laryngectomy tube. It may render the posterosuperior wall of the tracheostome more suitable for a tracheoesophageal puncture tract for voice restoration after total laryngectomy. These goals are achieved by interdigitating a small skin-thick superiorly based apron flap. raised from the lower midline of the front of the neck. into a similar recipient area at the upper posterior tracheal wall after removal of an equal mucosal apron.
Zinc in the management of tinnitus. Placebo-controlled trial, To assess any possible beneficial effect from zinc on tinnitus we performed a placebo-controlled. randomized. double-blind investigation. Forty-eight patients with tinnitus were randomized to either placebo or the administration of zinc sulfate as sustained-release tablets of 22 mg Zn++ (Zinklet). The tablets were administered three times daily for 8 weeks. Every week the patients stated the severity of tinnitus on a number scale from 0 to 10. The levels of zinc and albumin in serum were determined both before and after treatment. Of 48 patients with tinnitus. hypozincemia was found in only one patient. The zinc level increased significantly in the patients treated with zinc. We could not demonstrate any beneficial effect from zinc on tinnitus. One of the essential reasons for this finding could be that the zinc levels in serum were in the normal range previous to treatment.
Pressure chamber tympanometry in diving candidates, The currently recommended examination for diving fitness ascertains middle ear autoinflation ability only under surface pressure conditions. The purpose of our study was to document and quantify middle ear pressure equalization failure during simulated dives among diving candidates who had otherwise met the otologic criteria for diving fitness. Forty-two candidates for regular naval diving activity were included in the study. Tympanograms of both ears at 1 and 1.1 absolute atmospheres (ATA) were taken inside a pressure chamber with the subjects in two positions: seated and supine. At a pressure of 1 ATA. type A tympanograms were found in all 84 ears examined. At a pressure of 1.1 ATA. with subjects in the upright position. 19 (22.9%) of the ears had type C and 2 (2.4%) type B tympanograms. while with subjects recumbent during descent. 6 of the ears (7.2%) had type C and 7 (8.4%) type B. Our results suggest that successful autoinflation at surface ambient pressure does not necessarily reflect middle ear pressure equalization ability during descent in a dive.
Pertussis in adults. What physicians need to know, Although there is increased awareness among physicians regarding their role in protecting adults against vaccine-preventable diseases. many physicians are unaware that adults develop pertussis. Studies of adults with prolonged cough have found that 20% to 25% have serologic evidence of recent pertussis infection. Investigations of outbreaks have documented that adults develop infection with Bordetella pertussis and transmit the organism to susceptible children. Adults are the major reservoir of infection for children who may develop severe illness. Pediatric health care workers and patients infected with the human immunodeficiency virus might be at higher risk than the general population. Because most adults are susceptible to pertussis. physicians must consider pertussis in the differential diagnosis of patients with prolonged cough. Physicians who care for adults should be active in the diagnosis and treatment of pertussis. supportive of studies of the epidemiology of pertussis in adults. and interested in the development and testing of new diagnostic and preventive measures.
Major infectious diseases causing excess morbidity in the Hispanic population, Current data indicate that there are a number of infectious diseases. ie. acquired immunodeficiency syndrome/human immunodeficiency virus infections. cysticercosis. hepatitis A. syphilis. tuberculosis. and typhoid fever. among others that cause disproportionately increased morbidity in Hispanics. The greater rate of poverty with its associated socioenvironmental problems. increased barriers to health care. and importation of infectious diseases endemic in the mother country are some of the major reasons that probably account for this disparity in disease burden in Hispanics. This formidable health problem can be addressed by targeting efforts at improving health education of family units and communities. environmental improvements. elimination or reduction of barriers to health care management and disease prevention. and appropriate screening programs. A comprehensive and uniform assessment of the impact of infectious diseases on Hispanics (and other minorities) in this country remains elusive. but is of paramount importance in establishing priorities and effective/efficient strategies to address this issue.
Long-term treatment of 189 acromegalic patients with the somatostatin analog octreotide. Results of the International Multicenter Acromegaly Study Group, BACKGROUND: We wanted to determine the clinical and biochemical effects of long-term therapy with the somatostatin analog octreotide in 189 acromegalic patients. METHODS: Patients were treated at 23 medical centers for 6 days to 231 weeks (median. 24.2 weeks) with varying octreotide dosages (100 to 1500 micrograms/d; median. 300 micrograms/d). Serum growth hormone and insulin-like growth factor I (IGF-I) concentrations before and at the end of the study were compared. and correlations between the response to treatment with total daily dosage and duration of treatment were sought. RESULTS: The clinical response rate was 88%. irrespective of dosage or treatment duration. Serum growth hormone levels decreased in 172 (94%) of 182 patients and IGF-I levels decreased in 91 (92%) of 99. The mean pretreatment growth hormone level was 39.4 +/- 4.4 micrograms/L and decreased to 12.2 +/- 1.5 micrograms/L. Growth hormone levels decreased to less than 5 micrograms/L in 82 (45%) of 182 patients. The pretreatment IGF-I level was 5.62 +/- 0.41 U/mL and decreased to 2.64 +/- 0.19 U/mL; suppression to 2 U/mL or lower occurred in 46 (46%) of 99 patients. The degree of growth hormone suppression was associated with longer treatment duration but not with the total octreotide dosage per day. In 34 patients studied prospectively. pituitary tumor size decreased by greater than 20% in 15 (44%). Side effects occurred in 37% of patients and were most commonly transient loose alcoholic stools. pain at the injection site. and abdominal discomfort; severity was mild to moderate. Glucose tolerance was unchanged or improved in 52% and declined in 48% of 25 patients evaluated. CONCLUSIONS: Octreotide is an effective treatment for acromegaly that may be used as primary therapy or after surgery and/or pituitary irradiation.
The value of roentgenographic and fiberbronchoscopic findings in predicting outcome of adults with lower lung field tuberculosis, Proper antituberculosis chemotherapy may not prevent occurrence or progression of endobronchial involvement in patients with pulmonary tuberculosis. We previously reported a higher incidence of endobronchial involvement in adults with lower lung field tuberculosis (LLFTB). We evaluated the value of roentgenographic and fiberbronchoscopic findings in predicting the outcome of adults with LLFTB after 9 months of antituberculosis chemotherapy. The most common change on chest roentgenograms among 101 patients with LLFTB was consolidation. followed by cavitary lesion. lung collapse. and solitary mass. Intrathoracic lymphadenopathy (hilar and/or mediastinal lymphadenopathy) was found in 12 cases. Sputum smear for acid-fast bacilli was positive in 64 patients. and sputum culture for tuberculous bacilli was positive in 37 of 50 patients. Endobronchial involvement was found in 45 of 63 patients who underwent fiberbronchoscopic examination. Of these 45. 18 had ulcerative granuloma. 12 had fibrostenosis. eight had submucosal infiltration. and seven had mucosal redness and swelling. A higher incidence of endobronchial involvement was found in the patients with LLFTB when they presented with roentgenographic findings of pulmonary consolidation. lung collapse. or associated intrathoracic lymphadenopathy. The outcome seemed unfavorable in the patients with LLFTB who presented with roentgenographic findings of lung collapse or pulmonary consolidation. or in those who presented with fiberbronchoscopic findings of fibrostenosis or ulcerative granuloma. Our results show that roentgenographic and fiberbronchoscopic findings are of value in predicting outcome of patients with LLFTB. With proper antituberculosis chemotherapy and close follow-up. fiberbronchoscopy may be clinically indicated in patients with LLFTB to assess the presence and severity of endobronchial involvement. Early surgical intervention can be considered in those with severe endobronchial involvement before serious sequelae occur.
Use of random urine samples to estimate total urinary calcium and phosphate excretion, Calcium-to-creatinine and phosphate-to-creatinine ratios in random single-voided urine specimens were compared with 24-hour calcium and phosphate excretions. respectively. in 67 subjects who were selected prospectively to represent a wide range of renal and parathyroid function as well as urinary calcium and phosphate loss. Simple linear regression analysis revealed significant correlation between the spot urine calcium-to-creatinine ratio and 24-hour total calcium excretion and between the spot urine phosphate-to-creatinine ratio and 24-hour phosphate excretion. Calculating these simple ratios permits easy. rapid. correct. and inexpensive estimation of the daily urinary calcium and phosphate excretion.
Hypocholesterolemic effects of different bulk-forming hydrophilic fibers as adjuncts to dietary therapy in mild to moderate hypercholesterolemia, Hypercholesterolemia is a significant risk factor for coronary heart disease. and the hypocholesterolemic effects of psyllium are well established. This placebo-controlled. parallel study compared psyllium with methylcellulose. calcium polycarbophil. and placebo as dietary adjuncts in treating mild to moderate hypercholesterolemia. Of 163 men and women recruited with serum cholesterol levels above 5.17 mmol/L (200 mg/dL). 105 completed 8 weeks of an American Heart Association step I diet and then augmented the diet with one of the fiber supplements for 8 additional weeks. Incremental differences from placebo for low-density lipoprotein cholesterol were -8.8% for psyllium. -3.2% for methylcellulose (not significant). and +8.7% for calcium polycarbophil; and for total cholesterol the differences were -4.3% for psyllium (not significant). -1.4% for methylcellulose (not significant). and +5.9% for calcium polycarbophil. Compliance was 94% to 96%. and only mild gastrointestinal side effects were observed. In managing mild to moderate hypercholesterolemia. methylcellulose and calcium polycarbophil provide little or no additional benefit. while psyllium significantly enhances the American Heart Association diet effects.
Clinical significance of a dizziness history in medical patients with syncope, To determine the implications of dizziness as a symptom in patients with syncope. we analyzed responses to a standardized battery of questions about dizziness in 121 consecutive patients referred for evaluation of syncope. Associations were sought between final diagnosis (dependent variable) and clinical predictor variables. Dizziness was found in 70% of the patients with syncope. Dizzy patients were younger (mean ages. 47 vs 56 years. respectively). more often female (75% vs 42%). and more likely to be assigned a psychiatric diagnosis. Multivariable logistic regression analysis identified young age and rotatory dizziness (vertigo) to be associated with a psychiatric diagnosis. Dizziness and syncope frequently coexist and in many cases may represent the same pathophysiologic process. A careful dizziness history may guide the initial evaluation of syncope patients in clinical practice.
Protection provided by hepatitis B vaccine in a Yupik Eskimo population. Seven-year results, The long-term immunogenicity and protection provided by a plasma-derived hepatitis B vaccine (Heptavax B) was determined in a cohort of susceptible persons immunized in 1981. In this study 1581 susceptible persons were immunized with the recommended three-dose regimen of hepatitis B vaccine. After 7 years. 74% of vaccinees retained antibody to hepatitis B surface antigen (anti-HBs) levels of 10 mIU/mL or more. Anti-HBs levels at 7 years varied inversely with age and directly with the level of anti-HBs attained 1 year after the first dose. During the 7 years after the first dose of vaccine. five vaccine responders and three other persons developed antibody to hepatitis B core antigen and their level of anti-HBs increased. None developed detectable hepatitis B surface antigen or clinical hepatitis. This update of an ongoing study continues to suggest that the risk of hepatitis B virus infection to most persons with an initial anti-HBs response to hepatitis B virus vaccine of 10 mIU/mL or greater is low. regardless of the initial antibody level.
Use of centrally acting sympatholytic agents in the management of hypertension, Considerable evidence suggests that hyperactivity of the sympathetic nervous system is implicated not only in the pathogenesis of essential hypertension but also in several blood pressure-independent complications of essential hypertension. Even with the advent of newer antihypertensive agents. including angiotensin-converting enzyme inhibitors and calcium antagonists. the centrally acting sympatholytics (alpha 2-adrenoceptor agonists) remain a valuable group of medications for the management of hypertension of all grades of severity. Their advantages include efficacy; rarity of contraindication; absence of most metabolic and serious side effects; favorable effects on systemic hemodynamics; lack of true tolerance and infrequency of volume expansion-related pseudotolerance; suitability in the elderly. in isolated systolic hypertension. and in patients with various concomitant conditions. such as diabetes mellitus; ability to reverse left ventricular hypertrophy; and relative low cost. The long duration of action of guanfacine hydrochloride. the most recently marketed agent. and of the transdermal formulation of clonidine is an especially commendable feature. The principal disadvantages of this class of medications are an overlap between the therapeutic dosage and that producing sedation and dry mouth and the potential to cause the discontinuation syndrome and sexual dysfunction.
Treatment of Wegener's granulomatosis with sulfamethoxazole-trimethoprim, Sulfamethoxazole-trimethoprim may be an alternative or adjunctive treatment for Wegener's granulomatosis. as suggested by our experience with six patients. Two had limited Wegener's granulomatosis; one of these achieved remission with sulfamethoxazole-trimethoprim alone. and the second achieved remission with sulfamethoxazole-trimethoprim and prednisone. Four patients presented with sinus. pulmonary. and renal involvement. One patient initially treated with sulfamethoxazole-trimethoprim developed worsening renal function requiring cytotoxic therapy. Two patients initially treated with cytotoxic agents achieved remission coincident with the addition of sulfamethoxazole-trimethoprim for persistent sinus symptoms. One patient had relapse of pulmonary symptoms after achieving and maintaining a remission during treatment with sulfamethoxazole-trimethoprim alone. This experience suggests that sulfamethoxazole-trimethoprim may be an effective treatment for some patients with Wegener's granulomatosis and may be the only agent required. Patients require careful follow-up and still may need cytotoxic therapy.
Angle closure glaucoma precipitated by aerosolized atropine, Angle closure glaucoma is an infrequent form of glaucoma occurring when the filtration mechanism for the aqueous humor is obstructed by apposition of the peripheral iris to the trabecular meshwork. Anatomic features associated with acute-angle closure include congenitally small anterior segments. increased lens thickness. and shallow anterior chamber depth. We present two patients who developed signs and symptoms of angle closure glaucoma after receiving aerosolized atropine for treatment of chronic obstructive pulmonary disease. We recommend that before instituting therapy with an inhaled anticholinergic agent. the patient should be questioned concerning prior history of angle closure glaucoma symptoms and signs and the anterior chamber depth should be examined using iris illumination. Patients having shallow anterior chambers. or possible prior angle closure glaucoma attacks. should be examined by an ophthalmologist before inhalant anticholinergic therapy.
Lovastatin-induced lupus erythematosus, Two patients. a 64-year-old woman and a 40-year-old man. developed a lupuslike syndrome due to lovastatin therapy. confirmed by signs. symptoms. and positive fluorescent antinuclear antibodies are herein published. The lovastatin-induced lupus was completely reversible on withdrawal of the agent.
Effects of a sodium-potassium ion-exchanging seaweed preparation in mild hypertension, A nonpharmacological approach in the treatment of mild hypertension is often advocated. In an attempt to decrease sodium and increase potassium intake. sixty-two middle-aged patients with mild hypertension were given a potassium loaded ion-exchanging sodium-adsorbing potassium-releasing seaweed preparation (seaweed fiber. SF). The mean blood pressure (MBP). evaluated in a double-blind crossover manner with four weeks familiarization and wash-out periods. showed a significant decrease after four weeks on 12 and 24 g/day SF but not on 6 g/day or placebo treatment. Systolic blood pressure during submaximal exercise decreased on all three SF doses. The decrease in MBP appeared to be significantly higher in sodium-sensitive (11.2 mm Hg. P less than .001) than in sodium-insensitive (5.7 mm Hg. P less than .05) patients and was in salt-sensitive patients significantly correlated to the increase in plasma renin activity (PRA). The urinary sodium excretion decreased. the urinary potassium increased and the sodium/potassium urinary excretion ratio decreased. indicating that the decrease of MBP was dependent on the decreased intestinal absorption of sodium and increased absorption of potassium released from the seaweed preparation. A sodium-potassium ion-exchanging seaweed preparation is an effective means of decreasing sodium and increasing potassium intake. and may be used for antihypertensive treatment in mild hypertension.
Increased dopamine-induced nephrogenous cAMP formation in hypertension, Low doses of exogenous dopamine (3 micrograms/kg/min) were administered intravenously to nine patients with essential hypertension and to six age-matched healthy volunteers. During infusion with dopamine. mean arterial blood pressure decreased in hypertensive patients whereas it did not change in normotensive subjects. Basal levels of sodium excretion were comparable in hypertensive and normotensive subjects. The natriuretic response to dopamine was significantly greater in hypertensive patients. Urinary and nephrogenous cAMP significantly increased in both normotensive and hypertensive subjects. The increase of nephrogenous cAMP was more pronounced in hypertensive patients than in normotensive controls. A significant correlation was found between nephrogenous cAMP and sodium excretion. The enhanced natriuretic response to dopamine in hypertensive patients may be due to increased cAMP formation in response to tubular dopamine receptor stimulation. This is in agreement with the hypothesis of either up-regulation or affinity changes of renal dopamine receptors in patients with essential hypertension. secondary to a decreased endogenous production of intrarenal dopamine.
Double-blind comparison of perindopril and captopril in hypertension. Effects on left ventricular morphology and function, Using digitized M-mode echocardiograms. we compared. in a double-blind study. the effects of 4 to 8 mg perindopril given once daily and 25 to 50 mg captopril given twice daily on the left ventricle (LV) in 20 hypertensive patients. Both treatments significantly (P less than .001) lowered blood pressure. reducing systemic vascular resistances. After 3 months both drugs induced a comparable percentage of reduction in LV mass. with an increase in the peak rate of LV relaxation and no changes in the peak rate of LV contraction. Our results demonstrate that perindopril once daily is an effective antihypertensive agent; it is also able. like captopril. to induce regression of LV hypertrophy. with improvement in diastolic performance and no deterioration in ventricular systolic function.
Role of neurohumoral systems for pressure induced left ventricular hypertrophy in experimental supravalvular aortic stenosis in rats, We studied the role of the sympathetic nervous system and the renin angiotensin system for pressure induced left ventricular hypertrophy (LVH) in 135 rats with experimental supravalvular aortic stenosis (AS). We induced this condition by a silver clip on the ascending aorta. when body weight (BW) was 90 to 100 g. Sympathectomy by 6-OH-dopamine reduced LV norepinephrine content to less than 5%. The renin-angiotensin system was blocked by quinapril. which reduced serum angiotensin converting enzyme (ACE) activity to less than 5%. Aortic stenosis (LV peak systolic pressure 212 +/- 10 mm Hg) induced significant LVH with an increase of LV weight from 198 +/- 3 (sham) to 266 +/- 6 after 6 weeks and to 303 +/- 13 mg/100 g body weight after 12 weeks. Sympathectomy did not reduce LVH 6 weeks after induction of AS (260 +/- 6 mg/100 g body weight). Angiotensin converting enzyme inhibition initiated immediately after induction of AS did not alter the increase of LV mass after 6 weeks (250 +/- 7 mg/100 g body weight). Removing the silver clip 6 weeks after induction of AS resulted in a 90% regression of LVH after 6 more weeks. When ACE-inhibition was started after 6 weeks--ie. once LVH had developed--and maintained for another 6 weeks. an 80% regression of LVH was observed despite the persistent afterload elevation. Our findings of an afterload independent regression of LVH by ACE-inhibition emphasize an important role of the renin angiotensin system for the maintenance of pressure induced LVH.
Ambulatory blood pressure variation is related to plasma renin activity in borderline hypertensive men, The purpose of this study was to examine the relationship between the variability of awake ambulatory blood pressure and the level of plasma renin activity (PRA) in age-matched samples of untreated hypertensive white men. The ambulatory pressures of 376 men (145 under 45 years of age. 231 over 45) were compared across three levels of PRA: less than 1.0 ng/mL/h. 1.0 to 4.0 ng/mL/h and 4.0 ng/mL/h or greater. The results showed that the average diastolic pressure declined with PRA. particularly in men under 45 (95 to 89; P less than .05). but that among the men 45 and older there was a strong. positive relationship between awake diastolic pressure variability and the level of PRA (p less than .001). These results may have important clinical implications since both higher PRA and greater blood pressure variability have been associated with a greater cardiovascular disease risk.
Association between plasma viscosity and blood pressure. Results from the MONICA-project Augsburg, The relationship between determinants of blood viscosity and blood pressure (BP) variables was studied in a large sample of a population aged 25 to 64 years. Plasma viscosity. hemoglobin. and total serum protein were examined. Systolic and diastolic BP and the prevalence of hypertension showed a crude positive association with plasma viscosity levels in both sexes. Age. body mass index. and total serum protein appeared to have a confounding effect on this relationship. whereas hemoglobin. smoking behavior. and alcohol consumption did not. A crude positive association was also found between total serum protein levels and the prevalence of hypertension in men and women; however. since total serum protein was treated as a covariable. no further analyses were carried out. In contrast to findings reported in the literature. hemoglobin levels were not correlated with BP variables in either sex. After adjusting for all confounders. a significant main effect of plasma viscosity still was found. However. the magnitude of the effect was not as large as for body mass index. a well-established risk variable for hypertension. These results indicate that BP is positively associated with plasma viscosity. Whether increased plasma viscosity in hypertension constitutes a primary or a secondary phenomenon remains to be answered. Since plasma viscosity is significantly associated with hypertension but any BP variable. increased levels of plasma proteins (particularly fibrinogen as the main determinant of plasma viscosity) may represent the cause for elevated plasma viscosity. This might contribute to persistently increased resistance to blood flow on the microcirculatory level in arterial hypertension.
Duplex ultrasound in the assessment of vascular disease in clinical hypertension, Duplex ultrasound combines B-mode imaging and pulsed Doppler flow analysis and is rapidly becoming the most useful and widely applied method for the evaluation of atherosclerotic arterial disease. Recent technical improvements including color flow Doppler allow its application to practically all vascular beds in the body. Duplex is noninvasive and in many areas its accuracy in the detection of arterial stenosis and occlusion rivals angiography. Duplex ultrasound has become the preferred method of evaluation of patients with cerebrovascular disease. It provides information about the degree of stenosis. location of disease. and plaque characterization. and in many cases replaces standard cerebral arteriography. Duplex ultrasound has been used to detect renal artery stenosis in patients suspected of having renovascular hypertension with an accuracy of 93% in the diagnosis of hemodynamically significant stenosis. It also has important applications in the assessment of mesenteric artery stenosis. peripheral vascular disease. and venous disease. Because it is accurate. reasonably inexpensive. and noninvasive. duplex ultrasound can be used to follow the progression of untreated atherosclerotic lesions throughout the body. Used in this fashion. it provides important information about the natural history of atherosclerotic lesions. their clinical prognosis. and the effect of interventions. either medical or surgical. on lesions.
Calcium metabolism and dietary calcium in salt sensitive hypertension, Evidence has accumulated over the past decade that suggests a relationship between low calcium intake. abnormalities in cation metabolism and hypertension in certain segments of the essential hypertension population. This evidence has been developed from epidemiological data. calcium intervention trials and observations related to biochemical alterations suggestive of a calcium deficiency in certain patients with hypertension and in animal models of essential hypertension. It is becoming increasingly evident that salt sensitive individuals are especially likely to be characterized by abnormalities of calcium metabolism and blood pressure responses to dietary calcium. In this review the role of calcium in the regulation of blood pressure is examined with an emphasis on epidemiological. biochemical. hemodynamic and dietary intervention data in the salt sensitive hypertensive patient.
Normal serum levels of calcitonin gene-related peptide (CGRP) in mild to moderate essential hypertension, Calcitonin gene-related peptide (CGRP). a highly potent vasodilator. is expressed from the calcitonin-gene and has been localized to nerve fibers of the cardiovascular system. suggesting involvement in the physiologic regulation of vascular tone. In this investigation serum concentrations of CGRP were measured in patients with untreated mild to moderate essential hypertension (WHO I-II) and compared with concentrations in sex- and age-matched normal controls to assess a possible relationship between changes in concentrations of CGRP and this condition. The study showed no significant difference in concentrations of CGRP between patients and the normotensive controls. However. a weak but significant positive correlation was found between systolic (SBP). diastolic (DBP). mean blood pressures (MBP). and circulating concentrations of CGRP when calculated for all individuals included in the study. No correlation was found between heart rates (HR) and concentrations of CGRP. In the normotensive control group. but not in patients with hypertension. a significant positive correlation was present between body weights and concentrations of CGRP. These findings do not support the hypothesis that low expression of CGRP plays a causal role in essential hypertension. but the results do not exclude a potential receptor defect for CGRP to be involved in the disease.
Blunted renal sodium excretion during acute saline loading in normotensive men with positive family histories of hypertension, The natriuretic and intra-arterial blood pressure response to an acute saline load (1000 mL 0.9% NaCl). was studied in normotensive young men with positive (n = 11) and negative (n = 21) family histories of hypertension. The age-matched (36 +/- 5 years) control group with negative family histories of hypertension was subdivided into two groups. one matched for body mass index (BMI) to the subjects with positive family histories of hypertension (n = 10). and another lean control group (n = 11). Baseline blood pressure was significantly higher in subjects with positive family histories of hypertension and in controls matched for BMI as compared with lean controls. Sodium excretion increased in all three groups during the saline infusion. while subjects with positive family histories of hypertension disclosed a diminished natriuretic response as compared with the two control groups. Systolic blood pressure increased significantly during the saline load in subjects with positive family histories of hypertension. while in subjects with negative family histories of hypertension. no significant change in blood pressure was observed. Plasma renin activity. angiotensin II. serum aldosterone. plasma noradrenaline. blood volume. and ouabain-sensitive erythrocyte sodium efflux rate constant did not differ between the three groups at baseline. A significant negative correlation was found between baseline sodium excretion and sodium efflux rate constant in subjects with positive family histories of hypertension. We conclude that the subjects with positive family histories of hypertension exhibit a blunted natriuretic and an exaggerated blood pressure response to an acute saline load as compared with the two control groups with negative family histories of hypertension. This could be of neuronal and/or hormonal origin.
Left ventricular mass index and diastolic filling. Relation to blood pressure and demographic variables in a healthy biracial sample, The relationships of left ventricular (LV) structure and diastolic filling to ambulatory blood pressure. race. age. and gender were studied in 104 young. generally healthy. untreated subjects with normal or marginally elevated blood pressure. Average daytime systolic blood pressure (r = 0.41. P less than .001). diastolic blood pressure (r = 0.38. P less than .001). male gender (r = 0.49. P less than .001). and age (r = 0.32. P less than .001) were univariate correlates of LV mass index as measured by M-mode echocardiography. In a stepwise multiple regression model. male gender. age. and systolic blood pressure were independent predictors of LV mass index. LV filling rate normalized to mitral stroke volume. a Doppler-derived index of diastolic filling. was inversely related to age (r = -0.47. P less than .001). heart rate (r = -0.27. P less than .01). LV mass index (r = -0.32. P less than .001). and diastolic blood pressure (r = -0.20. P less than .05). Age. heart rate. and LV mass index were predictors of normalized peak filling in a stepwise regression model. Race was not significantly related to either LV mass index or diastolic filling. Our results confirm the importance of demographic variables as well as blood pressure in determining LV mass and filling characteristics in humans prior to the development of sustained essential hypertension. These variables contribute to ventricular mass and diastolic function in varying degrees. Gender is strongly correlated with LV mass. but not with filling indices.
Hypertensives' pressor response to norepinephrine. Analysis by infusion rate and plasma levels, After 5 days of a 10 mEq sodium diet or 4 days of a 200 mEq sodium diet. 15 hypertensives and 11 normotensive control subjects received pressor doses of intravenous norepinephrine (NE). Analysis of pressor responses to the rate of NE infusion showed that the high salt diet sensitized subjects so that they needed less NE to raise systolic blood pressure (SBP) 20 mm Hg (P = .005). There was a complex interaction of salt intake. black race. and hypertension on NE pressor sensitivity (P = .03). Hypertensives attained lower plasma NE levels during the stepwise NE infusion. so we reanalyzed NE sensitivity in terms of the changes in plasma NE levels. This analysis also showed that during the high salt diet. subjects initiated a pressor response at lower plasma NE levels (P = .017) and raised SBP 20 mm Hg at lower NE levels (P = .007). The reanalysis showed that hypertensives initiated a pressor response at lower plasma NE levels (P = .03) and raised SBP 20 mm Hg at lower NE levels (P = .002). Plasma NE levels should provide a better guide to the concentration of NE at cardiovascular receptors than the rate of NE infusion. Analysis of pressor responses to plasma NE levels demonstrated that the hypertensives had an exaggerated pressor response to NE.
Nonparallel effects of renin inhibitor treatment on plasma renin activity and angiotensins I and II in hypertensive subjects. An assay-related artifact, Nonparallel effects of renin inhibitor treatment on plasma renin activity (PRA) and the plasma levels of angiotensins (ANG). as well as on blood pressure. have been observed in subjects with hypertension. This study addresses the possibility that renin inhibitors may show a high degree of plasma protein binding in vivo and that displacement of protein-bound inhibitor during the assay of PRA in vitro may lead to overestimation of renin inhibition. Indeed. with the ultrafiltration technique it was found that 96% of the novel renin inhibitor Ro 42-5892. when added to EDTA plasma. was bound to protein. The angiotensinase inhibitors phenylmethylsulfonyl fluoride (PMSF) and 8-hydroxy-quinoline sulfate (8-OHQ). which are currently used in PRA assays. caused a displacement of protein-bound inhibitor. thereby increasing its free concentration. This displacement was sufficient to explain the reduction in IC 50 of Ro 42-5892. which was seen in the PRA assay when PMSF and 8-OHQ were added to plasma. Such reductions in IC 50 were also seen with the renin inhibitors CGP 29-287. CGP 38-560A. and SR 43-845. When Ro 42-5892 was given. 1 mg/kg intravenously in 10 min. to subjects with hypertension. it appeared that plasma ANG I and II returned to baseline after 6-8 h. whereas PRA measured in the presence of PMSF and 8-OHQ was still suppressed. However. when PRA was measured without these angiotensinase inhibitors. the inhibition of PRA was parallel to the suppression of ANG I and II.
Sugar-induced hypertension in Sprague-Dawley rats, Male Sprague-Dawley rats were fed either conventional rat chow. or a diet in which vegetable starch was replaced with either glucose or sucrose for two weeks. At the end of this period. measurements were made of weight. blood pressure. and plasma glucose. insulin. and triglyceride concentrations. The average weight gain over the dietary period was approximately 75 g. and did not vary between the three groups. Mean (+/- SEM) blood pressure remained stable in the rats fed conventional chow (124 +/- 2 to 127 +/- 3 mm Hg). but increased significantly in rats fed the glucose-enriched diet (122 +/- 1 to 134 +/- 2 mm Hg. P less than .02. compared to chow-fed rats). The increase in blood pressure was even greater in rats fed the sucrose-enriched diet (122 +/- 2 to 144 +/- 2). and was significantly greater (P less than .005) than in rats fed either conventional chow or the glucose-enriched diet. Plasma glucose concentrations did not change in any of the groups. but plasma insulin concentration approximately doubled in rats fed either the glucose-enriched or sucrose-enriched diets. Finally. plasma triglyceride concentrations also were significantly higher (P less than .002) in both glucose-fed and sucrose-fed rats than in the control group. However. the increase was greatest in the sucrose-fed rats. and was significantly higher than in rats fed the glucose-enriched diet (P less than .002).
Importance of chloride in the development of salt-induced angiotensin II hypertension in rats, This study attempted to evaluate the effect of anion associated with sodium loading on the development of angiotensin II (AII)-induced hypertension in rats. Hypertension was induced by intraperitoneal infusion of AII(125 ng/min) for 12 days via miniosmotic pump (systolic blood pressure on day 12. 143 +/- 3 mm Hg). High dietary intake of sodium chloride significantly augmented the AII-induced hypertension (systolic blood pressure on day 12. 166 +/- 4 mm Hg). but equimolar sodium loading provided as sodium citrate failed to enhance AII hypertension (systolic blood pressure on day 12. 136 +/- 8 mm Hg). Thus. the data suggest that the full expression of salt (NaCl) sensitivity in AII hypertension depends on high dietary intake of both sodium and chloride.
Response to the cold pressor test in normotensive and hypertensive patients, The response to the cold pressor test (CPT) was studied in 49 normotensive (NT) and 73 patients with essential sustained hypertension (HT). Patients were classified as responders when they increased their systolic pressure (SBP) by at least 16 mm Hg or their diastolic blood pressure (DBP) by at least 12 mm Hg. Forty-seven out of seventy-three (64%) increased their mean blood pressure (MBP) by 18.6 +/- 1.4 mm Hg (mean +/- SEM) in response to CPT. In NT subjects 23 out of 49 (47%) were responders (MBP = 16.3 +/- 1.3 mm Hg). In NT. but not in HT. patients. a negative relationship was observed between MBP changes during CPT and age (P less than .001) or basal DBP (P less than .01). There was no relationship between blood pressure response and the presence of a family history of hypertension. A positive correlation was found in HT patients between basal levels of active renin (AR) in the upright position and MBP changes during CPT (P less than .001). Mean plasma AR was 24.2 +/- 3.5 pg/mL in nonresponders v 37.5 +/- 2.9 pg/mL in responders (P less than .001). In HT. but not in NT. patients. blood pressure changes were associated with a simultaneous increase in HR (P less than .01 between delta MBP and delta HR). These results suggest that blood pressure elevation during CPT is a very common reaction in young normotensive subjects especially in those that have the lowest mean blood pressure. Therefore it is unlikely that CPT may be used as a predictor test of future hypertension in this population.
Stability of ethnic differences in children's pressor responses during three annual examinations, In this study. 395 healthy children had blood pressure and heart rate measured both at rest and during a stressful video game. Identical measurement procedures were used for three annual examinations. Consistently. black children demonstrated significantly greater pressor responses than white children. In view of the greater prevalence of hypertension among black adults than white adults. these data suggest that blacks exhibit hemodynamic irregularities well before the onset or diagnosis of hypertension.
The quest for an AIDS vaccine: the state of the art and current challenges, Despite intense efforts worldwide. using state-of-the-art methods and techniques and despite ever-increasing knowledge about the molecular and structural make-up of HIV. a practical vaccine against acquired immunodeficiency syndrome (AIDS) has yet to be developed. The increasing use of recombinant DNA techniques and synthetic peptide technology has allowed many groups to identify at the epitope level the regions of HIV proteins which act as targets for (and stimulate) the immune response. Epitopes which stimulate and bind neutralizing antibodies have been examined in detail and an ever-increasing number of antibody-dependent cellular cytotoxicity (ADCC) and cytotoxic T lymphocytes (CTL) epitopes are being defined. as are potentially harmful (immunosuppressive or enhancing) domains. It still is not clear which of the different immune responses (or combinations thereof) it will be necessary to stimulate in order to protect from infection. Infected humans develop neutralizing antibodies. ADCC-inducing antibodies and CTL responses against a variety of viral proteins but it is not known which of these can control or prevent infection in vivo. The extensive knowledge of HIV and the immune response it elicits is being used to design and produce a wide variety of putative vaccines. ranging from whole inactivated virus. through recombinant organisms/proteins. to synthetic peptides although each has its inherent advantages and disadvantages. The very nature of HIV makes vaccine development difficult at best. However. recent successes using whole inactivated virus or virus-infected cells in the macaque simian immunodeficiency virus (SIVmac) model system at least show that protection against lethal lentivirus infection can be achieved.
Identification of a recombinant HTLV-II envelope protein for serological detection of HTLV-II carriers, To understand the pathogenic potential and the true extent of human T-cell leukemia virus type II (HTLV-II) infection. it is important to develop a specific HTLV-II antigen-based serological test. Plasmid pIIB was constructed and induced in Escherichia coli to express a recombinant protein (RP) containing 140 amino acids (amino acid residues 96 to 235) from the middle region of the HTLV-II exterior envelope glycoprotein gp52. Serum samples from polymerase chain reaction-confirmed HTLV-II-infected people. HTLV-I carriers. and adult T-cell leukemia (ATL) patients were tested for antibody reactivity to RP-IIB by Western blot assay. The results showed all 27 HTLV-II carriers. 10 of 20 HTLV-I carriers. and 4 of 17 (23.5%) ATL patients had antibody reactivities to RP-IIB. The difference in rates of seropositivity to RP-IIB between HTLV-II carriers (100%) and HTLV-I-infected people (carriers plus ATL patients) (37.8%) is statistically significant (Fisher's exact test. p = 4.30E-08).
Shaking HIV-1 infected cells indicates novel behavior of MN strain, The shaking method of harvesting human immunodeficiency virus type 1 (HIV-1) is a powerful method of obtaining high titer. highly infective virus solutions. In this method infected cells are suspended in a small volume of liquid and the mixture is shaken. Viral infectivity. measured by tissue culture infective dose (TCID50) studies. rises faster than virus titer. as measured by reverse transcriptase levels. It is postulated that this disproportionate increase in infectivity results from improved infectivity for the virus particles obtained from shaking the infected cells. Of the five strains of HIV-1 studied (IIIB. AL1212. 906. RJ4029. and MN). one strain. MN. behaved differently than the others. Upon shaking. its virus titer increased 18-fold. as opposed to the 5-10 fold increase demonstrated by the other strains. These results may indicate that MN virions are retained more on the surface of the infected cells. rather than budding off into the surrounding medium. than other HIV-1 strains. In support of this theory it was found that ratios of immunofluorescence assay scores to reverse transcriptase levels were higher for MN than for other strains.
Infection of human monocytes with HIV-1Ba-L. Effect on accessory cell function for T-cell proliferation in vitro, Major laboratory manifestations of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) include altered levels of circulating CD4+ lymphocytes and decreased in vitro T-cell mitogenic responses. Since T-cell proliferation is regulated by monocytes (M phi). studies were undertaken to determine whether defective M phi function contributes to these poor mitogenic responses. M phi were isolated from peripheral blood mononuclear cells (PBMC) of normal donors by adherence to plastic. After 5 days in culture. the adherent cells were inoculated with the HIV-1 M phi-tropic strain. Ba-L. Under these conditions HIV infection in M phi can be detected 5-7 days after inoculation. Ten to fourteen days postinoculation. the adherent cells were harvested with lidocaine and cocultured with fresh autologous T cells and T-cell mitogens in a 3-day assay. We found decreased proliferative anti-CD3 responses to Leu4 and OKT3 and variable responses to concanavalin A (Con A) by T cells cultured with HIV-infected monocytes compared with T cells cultured with uninfected M phi. Supernatants from HIV-infected M phi cultures decreased proliferative responses of normal PBMC to anti-CD3 monoclonal antibodies. Heat-activated supernatants had the same effect. Inhibitors of HIV binding did not restore proliferative responses of HIV-infected cultures to normal levels. These results indicate that HIV infection of M phi causes the release of soluble factor(s) that suppress anti-CD3-induced T-cell proliferative responses.
Maturation of human immunodeficiency virus particles assembled from the gag precursor protein requires in situ processing by gag-pol protease, The vaccinia virus expression system was used to determine the role of human immunodeficiency virus type 1 (HIV-1) protease in viral morphogenesis and maturation. The unprocessed p55 gag precursor polyprotein alone was assembled to form HIV-1 particles which budded from cells. The particles were spherical and immature. containing an electron-dense shell in the particle submembrane; there was no evidence of core formation. Expression of both gag and pol proteins from a recombinant containing the complete gag-pol coding sequences resulted in intracellular processing of gag-pol proteins and the production of mature particles with electron-dense cores characteristic of wild-type HIV virions. To ascertain the role of protein processing in particle maturation. the pol ORF in the gag-pol recombinant was truncated to limit expression of the pol gene to the protease domain. With this recombinant expressing p55 gag and protease. intracellular processing was observed. Some of the resultant particles were partially mature and contained processed gag protein subunits. In contrast. particle maturation was not observed when the HIV-1 protease and p55 gag were coexpressed from separate recombinants. despite evidence of intracellular gag processing. These findings suggest that HIV-1 protease must be an integral component of the full-length gag-pol precursor for optimal processing and virion maturation.
The epidermal basement membrane in basal cell carcinoma: an immunohistochemical study, An immunohistochemical study of basal cell carcinomas of varying histological type. using a panel of antibodies to constituents of the epidermal basement membrane. showed marked deficiencies in the expression of the antigens identified by the antibodies LH7.2. GB3 and G71. There was no correlation between loss of immunoreactivity to these antibodies and the histological features of the tumour.
Measurement of cutaneous inflammatory reactions using a scanning laser-Doppler velocimeter, The performance of a new scanning laser-Doppler velocimeter (LDV). which can rapidly measure blood flux over a large area of skin without contact with the skin surface. was compared with that of a conventional laser-Doppler instrument. The vascular response was measured to a range of doses of UVB. and dilutions of contact allergens and sodium lauryl sulphate. The detection threshold of the scanning LDV was equal to. or lower than. that of the conventional instrument. For allergic contact hypersensitivity reactions (ACH). the coefficient of variation was significantly less using the scanning LDV. The scanning LDV allowed accurate measurement of the change in area that occurs with increasing intensity of inflammatory reaction. For ACH reactions the area of inflammation continued to increase at dilutions where blood flux had reached a plateau. The flare area was found to increase linearly with log dose of histamine with no change in blood flux.
Plasma levels of 8-methoxypsoralen following oral or bath-water treatment, The plasma levels of 8-methoxypsoralen (8-MOP) were determined in 18 patients on PUVA treatment for their psoriasis and in two control volunteers. Seven of the patients were on oral therapy and 13 having bath treatment. The plasma levels of 8-MOP were determined up to 6 h after treatment and varied between less than 10 ng/ml and 360 ng/ml for the orally treated group. and in the bath-treatment group were all less than 10 ng/ml.
Lupus erythematosus profundus with partial C4 deficiency responding to thalidomide, A female patient with disfiguring lupus erythematosus profundus (LEP) from the age of 13 years was found to have an isolated partial C4 deficiency. with reduced levels of both allotypes. C4A and C4B. A genetic basis for the hypocomplementaemia was confirmed by a family study of complement and HLA types which revealed heterozygous null alleles for C4A and C4B in the proband. Marked improvement in her cutaneous lesions occurred with thalidomide.
Localized pemphigoid shares the same target antigen as bullous pemphigoid, A case of localized pemphigoid is described in which the lesions were only on the lower legs. Immunoblotting of the patients' serum reacted with a 240-kDa polypeptide identical to one of the bullous pemphigoid antigens. IgG1 was detected in the lesional skin and IgG1 and IgG4 in the patient's serum. These observations suggest that the immunopathological mechanisms in the blister formation in localized pemphigoid are similar to those found in more widespread bullous pemphigoid.
Head circumference/abdominal circumference ratio, ponderal index and fetal malnutrition. Should head circumference/abdominal circumference ratio be abandoned, Head circumference/abdominal circumference (HC/AC) ratios of the fetus are accepted as a means of distinguishing different patterns of growth retardation with a high ratio implying malnutrition of the fetus. Ponderal index (birthweight/length3) is used by paediatricians as a measure of neonatal wasting and would therefore be expected to correlate with HC/AC ratios at delivery. Anthropometric data on 999 newborn infants have been collected and analyzed by multiple regression. The results show a poor correlation between ponderal index and HC/AC ratio. worse than that between ponderal index and AC alone. The use of HC/AC ratios antenatally to identify subgroups of intrauterine malnutrition should be abandoned. The prediction of intrauterine malnutrition by weight/length ratios should be investigated further.
A randomized comparison of oxytocin, sulprostone and placebo in the management of the third stage of labour, OBJECTIVE--To compare the effect on post partum bloodloss of the postpartum prophylactic administration of oxytocin or sulprostone in low risk women having an expectant management of the third stage. DESIGN--Randomized. placebo controlled. double-blind trial. SETTING--Radboud University Hospital. Nijmegen (67 women) and Lievensberg Hospital. Bergen op Zoom (10 women). PARTICIPANTS--77 women entered the trial (three were excluded). INTERVENTIONS--The intramuscular injection. immediately after the birth of the baby. of either oxytocin 5 IU. sulprostone 500 micrograms or 0.9% saline. MAIN OUTCOME MEASURES--Quantitative postpartum blood loss and length of third stage. RESULTS--Postpartum blood loss was reduced almost equally. by about 35%. by oxytocin (P = 0.02). or sulprostone (P = 0.05). The mean length of the third stage was shorter in both groups receiving the active treatment. this effect was significant in the sulprostone group (P = 0.01). CONCLUSION--Prophylactic administration of oxytocin or sulprostone directly after delivery followed by expectant management of the third stage reduces post partum blood loss and shortens the third stage.
How obstetricians manage the problem of preterm delivery with special reference to the preterm breech, A questionnaire regarding the route of birth for the preterm fetus with particular reference to the management of the preterm breech was sent to 180 consultants in England and Wales. Only 23% of respondents use electronic fetal monitoring below 26 weeks gestation and only 12% use caesarean section routinely for fetal indications at less than 26 weeks. Only 12% will use caesarean section for the preterm fetus presenting by the vertex in uncomplicated labour. Only 35% of all respondents consider that there is sufficient evidence to support the use of caesarean section for the uncomplicated preterm breech. but 76% will actually use caesarean section for this indication. Overall 71% reported that they are affected by medicolegal considerations in their management of the preterm breech. Overall. 83% said that they might change their practice regarding the mode of delivery of the preterm breech in the light of the findings of a randomized prospective controlled trial.
Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989, OBJECTIVE--To assess the efficacy. toxicity and survival in patients with high risk GTT treated with the EMA/CO regimen (etoposide. methotrexate. actinomycin D. cyclophosphamide. vincristine/oncovine). DESIGN--Open non-randomized study of 148 consecutive patients referred to the Charing Cross Hospital between 1979 and 1989. SETTING--Trophoblastic disease centre in a London teaching hospital. SUBJECTS--148 consecutive patients with high risk GTT were treated with the EMA/CO regimen. 76 patients had received no prior chemotherapy and 72 had received prior chemotherapy. MAIN OUTCOME MEASURES--Survival. causes of treatment failure and toxicity were analysed. RESULTS--Of 76 patients who had received no prior chemotherapy. 62 (82%) are in remission; an overall survival of 85% for the 148 patients. Ten of the 76 patients without prior chemotherapy died from extensive disease within 3 weeks of starting chemotherapy. The complete and partial response rates to EMA/CO chemotherapy were 80% and 18% respectively. The addition of cisplatin salvaged 9 of 11 (82%) who developed drug resistance and did not require surgery. Salvage surgery alone resulted in 7 of 8 (87%) having complete remissions. Relapse after EMA/CO chemotherapy is uncommon (5.4%) but survival is still relatively good with further chemotherapy and/or surgery with 6 (75%) of 8 patients obtaining a further sustained remission. Complications from EMA/CO chemotherapy are acceptable with myelosuppression being dose-limiting. Late sequelae are uncommon: menstruation usually returns with a few months. and no fetal abnormalities have been recorded in subsequent pregnancies. One patient developed what we presume to be a therapy-induced acute myeloid leukaemia. CONCLUSION--At present EMA/CO chemotherapy is our treatment of choice for patients with high risk GTT. Its toxicity is predictable and reversible. In patients developing drug resistance. salvage surgery is important. Future developments may include further dose intensification with the addition of haemopoietic growth factors. earlier diagnosis and the separation of gestational from non-gestational trophoblastic tumours.
Oocyte and follicular fluid characteristics in women with mild endometriosis, The follicular development. fertilization and cleavage rates and follicular fluid endocrinology were assessed in 20 women with mild endometriosis during a spontaneous menstrual cycle. Diagnostic laparoscopy was performed 32 h after the onset of the endogenous luteinizing hormone (LH) surge in the 20 women with laparoscopically confirmed mild endometriosis and in a control group of ten women with tubal infertility. There was no significant difference in oocyte maturity or fertilization and cleavage rates between the women with mild endometriosis and those in the control group. The endocrine milieu of the pre-ovulatory oocyte at the time of aspiration was similar in the two groups.
Neovascular response in ischaemic central retinal vein occlusion after panretinal photocoagulation, Twenty seven eyes treated for ischaemic central retinal vein occlusion with panretinal photocoagulation were reviewed. Prior to laser therapy anterior segment neovascularisation predominated (17 eyes) over posterior segment involvement (6 eyes). After photocoagulation anterior segment new vessels regressed or did not develop in the majority of cases. However. in five eyes previously absent posterior segment neovascularisation occurred. These results suggest that photocoagulation alters but does not eliminate retinal ischemia. thus modulating the neovascular response.
Retinal circulation times in diabetes mellitus type 1, Video fluorescein angiography was performed in 124 patients between 18 and 65 years of age (mean 35.0. SD 12.3 years) with juvenile-onset. insulin-dependent diabetes mellitus (type 1). The arm-retina time (ART) and the retinal arteriovenous passage time (AVP) were measured by means of a picture analysis system to quantify the retinal microcirculation. Glucose metabolism was assessed by the blood level of haemoglobin A1c. The ART 11.5. SD 3.4 s) was similar to that in normal persons (11.2. SD 3.3 s). while the AVP was significantly longer in the diabetics (AVP = 2.35. SD 0.87 s) than in normal persons (AVP = 1.45. SD 0.40 s). The patients with severe diabetic retinopathy showed the most impressive change in AVP. The diabetics with good glycaemic control. that is. with glycosylated haemoglobin (HbA1c) less than or equal to 8.0 g/dl. had a shorter AVP than patients with bad glycaemic control (HbA1c greater than or equal to 9.5 g/dl). The group with a history of diabetes for less than five years showed circulation parameters similar to those of normal persons. The AVP in this group was significantly shorter than in groups with a history of diabetes for five or more years.
Pulsatile ocular blood flow in patients with low tension glaucoma, Measurements of the intraocular pressure (IOP) pulse and pulsatile ocular blood flow (POBF) have been made in 22 patients with bilateral low tension glaucoma (LTG) and 29 healthy subjects matched as closely as possible for age. refractive error. IOP. systemic pulse pressure. and heart rate. Recordings were made in both the standing and supine positions. The amplitude of the intraocular pressure pulse was significantly lower in patients with LTG (1.2. SEM 0.1 mmHg standing. and 1.3. SEM 0.1 mmHg lying) than in healthy subjects (1.9. SEM 0.1 mmHg standing. and 2.0 SEM 0.1 mmHg lying): p less than 0.001 standing and p less than 0.002 lying. Measurement of POBF also showed a significant reduction between the healthy subjects (428 (31) SEM microliters/min standing and 345 (28) SEM microliters/min lying) and subjects with LTG (301 (27) SEM microliters/min standing and 249 (24) SEM microliters/min lying). p less than 0.005 standing and p less than 0.02 lying. This represents a difference of approximately 30% between the two groups in either posture. A close non-parametric correlation existed between the level of IOP and the POBF (r = 0.75. p less than 0.001 standing. and r = -0.55. p less than 0.02 lying). Such a correlation was not present in the healthy subjects. A reduction in POBF occurred in both groups on assuming the supine posture (healthy subjects 83 (16) SEM microliters/min. LTG subjects 52 (17) SEM microliters/min). These figures represent reductions of 19% and 17% respectively in comparison with the standing value. The results lend further confirmation to the hypothesis that vascular factors are associated with low tension glaucoma.
Comparison of the effects of intraocular irrigating solutions on the corneal endothelium in intraocular lens implantation, We conducted a randomised prospective controlled study to determine the effects of a glucose glutathione bicarbonate solution (BSS Plus) and a citrate acetate bicarbonate solution (S-MA2) on the corneal endothelium in patients undergoing extracapsular cataract extraction with posterior chamber lens implantation. One eye of each patient was randomly assigned to receive BSS Plus. and the other eye to receive S-MA2. BSS Plus caused significantly less corneal swelling on the first postoperative day than did S-MA2. There was no difference between the two solutions in their effect on corneal thickness one week and one month postoperatively. Computer assisted morphometric analysis of wide-field specular microscopic photographs demonstrated minimal changes in endothelial morphological characteristics in the eyes irrigated with BSS Plus. By comparison S-MA2. caused a significant loss of endothelial cells and a marked reduction in the figure coefficient. These results indicated that BSS Plus has a clinical advantage over S-MA2 with respect to the corneal endothelium.
Fine needle aspiration biopsy in orbital tumours, Fine needle aspiration biopsy (FNAB) was performed in 46 patients with an orbital mass. Positive cytological identification was made in 43 biopsy specimens. In 26 cases with histopathological control the accuracy was 81%. In experienced hands FNAB is safe and appears to be a valuable tool in establishing a diagnosis of malignancy in orbital tumours.
Regression analysis of visual field progression in low tension glaucoma, Eighty four patients (168 eyes) with low tension glaucoma were retrospectively reviewed (mean follow-up was 28 months). The mean age was 66 years. and 69% were females. Regression analysis of their automated Humphrey fields (a mean of eight fields per eye) showed progression in 50% of patients and in 37% of eyes. There was no statistically significant difference between patients with progression and non-progression with respect to age (p less than 0.05) or intraocular pressure (p less than 0.5). Visual field defects were located most frequently in the superior hemifield in both groups of patients. A considerable proportion of patients had advanced field loss at the time of diagnosis.
Fibrous dysplasia of the skull: disease activity in relation to age, Eighteen of 19 patients with histologically confirmed fibrous dysplasia of the skull seen at the Institute of Neurological Sciences. Glasgow. in the past 20 years have been reviewed and recent radiographs obtained. Sex. age at presentation and at follow-up were recorded. in addition to the site. type and extent of cranial involvement. The findings have been related to disease activity and progression. In comparison with other reports we found the proportion of patients with activity in adulthood to be relatively high (37%). Overall. there was an equal sex distribution. but of seven patients presenting as adults. six were female as were six of seven patients with evidence of disease activity in adulthood.
Extracorporeal shockwave lithotripsy or extracorporeal piezoelectric lithotripsy? Comparison of costs and results, One thousand patients with renal stones up to 3 cm in diameter were divided equally into 2 groups matched for age. sex and stone size. One group was treated on the Dornier HM3 lithotriptor and the other on the EDAP LT01. The results showed that for stones less than 1 cm both lithotriptors were equally effective. with a stone-free rate of 87.5% for the Dornier and 90.4% for the EDAP at 3 months. The success rate fell more steeply for the EDAP machine. however. to become 77.2 and 42.5% respectively as the stone size increased to 3 cm. Treatment time was longer on the EDAP lithotriptor and more sessions were required but patients preferred it to the Dornier. Running costs per patient were higher on the EDAP.
Long-term effect of pelvic floor exercises on female urinary incontinence, In order to assess the permanent effect of pelvic floor exercises on female stress incontinence. 76 incontinent women. referred for incontinence surgery. underwent a 3-month exercise programme conducted by an experienced physiotherapist. The patients were followed up for 1 year. At the last assessment 30% were cured and 17% improved. Altogether 47% avoided surgery. No relapses were seen during the follow-up period. Patients with mild incontinence benefited from intensified training. since 72% could expect to be cured. while patients with severe incontinence and no immediate effect did not benefit from further exercises. Patients with a positive hormone status and those with normal weight had a significantly higher cure rate. The subjective results were confirmed by the 24-h pad test. Anal pressure profilometry was a valid method for instruction and objective control of pelvic floor function. It was concluded that pelvic floor exercises should precede surgery. since exercises had a permanent effect in half of the patients.
The significance of an open bladder neck in women, The significance of an open bladder neck at rest has been investigated in 147 women presenting to a urodynamic clinic. The prevalence of this condition was 21%; there was an association with urethral sphincter incompetence but an open bladder neck was not diagnostic of it. It is suggested that the finding of an open bladder neck at rest during urodynamic investigation is of little consequence.
Forced hydration prior to renography in children with hydronephrosis. An evaluation, We have developed a method of diuretic renography for the assessment of upper urinary tract obstruction in children. A maximal diuresis under standardised conditions is obtained by forced intravenous hydration over a 2-h period prior to renography. We evaluated the predictive value of this method for the clinical and functional outcome in 73 children with apparent unilateral pelviureteric junction obstruction. The predictive value of a non-obstructive pattern was 94%. while the predictive value of an obstructive pattern could not be assessed accurately because the patients concerned subsequently underwent operation. The method is safe and reliable and offers advantages over conventional diuretic renography.
Accuracy of endosonography in the staging of rectal cancer treated by radiotherapy, Endosonography is the best available method for the pretherapeutic staging of rectal cancer. The present prospective study was to determine the influence of previous radiotherapy. widely used in the management of this tumour. on the accuracy of endosonography. A complete endosonographic examination was performed just before surgery in 40 patients with rectal cancer. Endosonographic and pathological staging were compared in group A. 21 patients without previous radiotherapy. and group B. 19 patients with preoperative radiotherapy. While the endosonographic accuracy for lymph node involvement was similar in the two groups (85 per cent compared with 84 per cent). wall invasion was correctly ascertained in 86 per cent in group A but in only 47 per cent in group B (P less than 0.05). After irradiation. the thickening of the rectal wall and the poor visualization of the hyperechoic layers hampered interpretation. Post-radiotherapy inflammation and/or fibrosis probably explained the echographic changes. Radiotherapy therefore altered endosonographic staging of rectal cancer. New interpretation criteria are needed for evaluation and follow-up of rectal cancer treated by radiotherapy.
Use of the ultrathin choledochoscope in cholecystectomy, Use of the ultrathin choledochoscope (2mm) was evaluated in 80 patients undergoing routine cholecystectomy. It was used successfully in 67 (84 per cent) patients. There were eight (12 per cent) explorations of the common bile duct and no negative explorations. The instrument was helpful in determining the nature of an equivocal on-table cholangiogram. The ultrathin choledochoscope may be useful in reducing the rate of negative common bile duct exploration.
Rebound tenderness test, The usefulness of the rebound tenderness test in indicating peritonitis was prospectively assessed in 142 unselected patients admitted as emergencies with abdominal pain and tenderness. It was found to be of no predictive value.
One hundred patients with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinants, One hundred patients with hepatic metastases from colorectal cancer underwent 'radical' liver resection from 1980 to 1989. At least 1 cm of normal parenchyma surrounded the tumour and no microscopic invasion of resection margins was evident. The disease was staged according to our own staging system. Lobectomy was performed in 50 patients and non-anatomical resection in the remainder. The postoperative mortality rate was 5 per cent and the major morbidity rate was 11 per cent. The actuarial 5-year survival rate for patients in stages I. II and III was 42 per cent. 34 per cent and 15 per cent respectively (P less than 0.001). The overall actuarial 5-year survival rate was 30 per cent. The prognostic importance of various patient and tumour variables was evaluated by univariate analysis and then by multivariate analysis. Age of patient. site of primary. disease-free interval between treatment of primary and of hepatic metastases. preoperative carcinoembryonic antigen levels. and number of metastases. did not relate to prognosis. while sex (P = 0.024). stage of primary (P = 0.026). extent of liver involvement (P less than 0.001). distribution of metastases (P = 0.01) and type of surgery (P = 0.028) significantly affected prognosis as single factors. Multivariate analysis revealed that only the extent of liver involvement and stage of the primary tumour were independent predictors of survival. We conclude that liver resection is effective in selected patients with hepatic metastases from colorectal cancer. In resectable patients it is not yet possible to formulate a clear prognosis based on clinical factors. The extent of liver involvement and the staging system used may be significant. although not absolute. indicators of outcome.
Extracorporeal shock wave treatment of common bile duct stones: experience with two different lithotriptors at a single institution, Extracorporeal shock wave lithotripsy (ESWL) is a new treatment modality for retained common bile duct stones. Sixty-two patients (mean age 75 years. range 27-95 years) with retained common bile duct stones were treated with two different lithotriptors. One of the lithotriptors operated on the electrohydraulic principle (Dornier HM-3) (n = 13). the other on the electromagnetic principle (Siemens Lithostar) (n = 49). All HM-3 patients were treated under general anaesthesia. whereas with the Lithostar one patients was treated under general anaesthesia. 43 received analgesia and sedation and five had no analgesia at all. Patients treated with the Lithostar had more sessions (mean 1.9 versus 1.3. P less than 0.05) and needed more stock waves (mean 8611 versus 2534. P less than 0.001) than patients treated with the HM-3. Fragmentation was achieved in all patients treated with the HM-3 and in 42 (86 per cent) patients treated with the Lithostar. In this latter group ten patients underwent common bile duct exploration without complications. Eleven patients had transient haematuria after treatment with the HM-3 and two patients (one in each group) had a subcapsular haematoma of the right kidney. all without clinical sequelae. At follow-up (median: HM-3 43 months. Lithostar 18 months). none of the patients had biliary complaints. We conclude that ESWL of retained common bile duct stones in safe and effective with both lithotriptors and should be considered before surgery in the elderly or high-risk patient.
Problems in the definition and treatment of early gastric cancer, Radical operation with extensive dissection of lymph nodes (R1. 48 patients; R2. 196 patients; R3. one patient) was performed in 245 out of 247 patients with early gastric cancer. The 5-year survival rate was only 73.2 per cent in the 34 patients with lymph node metastases (31.8 per cent). Analysis of factors influencing recurrence revealed that not only lymph node metastases but also the depth of cancer invasion could affect prognosis in early gastric cancer. This study suggests that radical operation with complete dissection of the first and second group of lymph nodes (R2 resection) is a safe and appropriate treatment even for early gastric cancer. We propose that the definition of early gastric cancer be modified to 'carcinoma with invasion confined to the mucosa or submucosa and without evidence of lymph node metastases'.
Lymph node counts in the upper abdomen: anatomical basis for lymphadenectomy in gastric cancer, The number of regional lymph nodes was determined in sites relevant to lymphadenectomy in gastric cancer in 30 cadavers. Tissue was cleared by dissolving fatty tissue. thus making lymph nodes with a diameter of at least 1 mm visible. All lymph node stations indicated by the Japanese Research Society for Gastric Cancer were studied. In stations 1-11 (corresponding with R2 resection) an average of 27 nodes (range 17-44 nodes) was found. whereas stations 1-16 (corresponding with R3 resection) showed an average of 43 nodes (range 25-64 nodes). These values are higher than those usually obtained from lymphadenectomy for gastric cancer. Striking individual differences in the total number of lymph nodes and the number of single stations was observed. The number of lymph nodes in these investigations are the normal anatomical values and serve as quality control of lymph node dissection in gastric carcinoma.
Clinical significance of the large adrenal mass, Current clinical teaching indicates that large (greater than 5 cm in diameter) adrenal masses are often malignant. In a retrospective analysis of patients studied between 1977 and 1988 with computed tomography (CT). adrenal scintigraphy. and when available. magnetic resonance imaging (MRI) 45 were found to have adrenal masses greater than 5 cm (range 5-19 cm) in diameter. Thirty were benign (16 phaeochromocytomas. six adrenocortical adenomas. four adrenal cysts. two myelolipomas. an adrenal hematoma and a ganglioneuroma). Of 15 malignant masses. there were seven adrenocortical carcinomas. five adrenal metastases and three adrenal lymphomas. With the exception of the adrenal myelolipomas. cysts. and the ganglioneuroma neither CT nor MRI demonstrated sufficient diagnostic specificity to distinguish benign from malignant lesions. Functional scintigraphy with 131I-6-beta-iodomethyl-19-norcholesterol for suspected adrenocortical lesions and 131I-metaiodobenzylguanidine for suspected phaeochromocytomas frequently provided useful information.
Node negative breast cancer: the prognostic value of DNA ploidy for long-term survival, The DNA content of breast tumours from 170 patients who presented between 1978 and 1980 was measured by flow cytometry. The relationship between tumour ploidy and disease outcome was assessed and its association with other prognostic factors evaluated. Compared with those with diploid tumours. patients with aneuploid tumours had significantly earlier relapse and shorter survival (P less than 0.0001). Tumour ploidy was strongly related to grade (P less than 0.001). but there was no significant association between DNA ploidy and c-erb-B-2 expression. lymph node status or tumour size. In lymph node negative and c-erb-B-2 negative patients. aneuploid tumours were associated with a poorer prognosis (P less than 0.001) than diploid tumours. Multivariate analysis showed that tumour ploidy gave independent information on disease free and overall survival. Tumour ploidy may be used as an independent prognostic variable in patients with breast cancer and it may be helpful in defining patients within the node negative or c-erb-B-2 negative groups likely to have a poor outcome who might benefit from adjuvant treatment.
Fibrinolytic activity of the arms and legs of patients with lower limb venous disease, Clearance of subcutaneous 125I-labelled fibrin was prolonged from the legs but not from the arms of patients with uncomplicated varicose veins and patients with healed ulcers. compared with controls. The euglobulin clot lysis time (ECLT) of blood from the arms and legs of those with healed ulcers was prolonged; venous congestion significantly shortened the ECLT of blood from all limbs except legs with healed ulcers. The clearance of interstitial fibrin of both legs and arms correlated with the response of the ECLT to venous congestion (P less than 0.05). The clearance of interstitial 125I-labelled albumin in five patients with healed ulcers was faster from the legs than from the arms. whereas the clearance of interstitial 125I-labelled fibrin was faster from the arms in all cases. These results suggest that there is a defect in interstitial fibrinolytic activity as well as vein wall production of plasminogen activator in legs with chronic venous insufficiency.
Time trends in incidence rates of acute, non-traumatic extremity ischaemia: a population-based study during a 19-year period, Time trends in the occurrence of acute limb ischaemia were studied from 1965 to 1983 in a defined geographical area in Sweden. Data were obtained from a computerized register which covers all instances of inpatient care for a population of 1.3 million. Analysis based on 5394 first admissions for acute arterial occlusion revealed that the annual number increased by 2.7 per cent yearly in women and 3.9 per cent in men whereas the age-adjusted incidence remained stable for women and increased by 2.6 per cent yearly for men. A study of 1189 patients who underwent surgical procedures showed that the annual number of embolectomy procedures increased 7.6 per cent for females and 8.6 per cent for males. The corresponding age-adjusted incidence rose annually by 3.0 per cent for women and by 7.5 per cent for men. The introduction of the Fogarty catheter and an increasing interest in vascular surgery may have contributed to the increasing rates of operations during the period of study.
Early computed colour echo Doppler imaging following renal transplantation, Thirty patients with renal allografts were monitored for 15 postoperative days by colour-coded Doppler imaging and categorized as stable. rejection. acute tubular necrosis and cyclosporine toxicity. All forms of graft dysfunction showed significantly raised resistance (P less than 0.01) and pulsatility (P less than 0.01) indices (RI and PI. respectively). It was not possible to use Doppler imaging to differentiate the cause of graft dysfunction. but stable grafts in patients with high cyclosporin levels had significantly higher RI (P less than 0.04) and PI (P less than 0.04) than similar grafts in patients with cyclosporine levels in the therapeutic range.
A review of californium-252 neutron brachytherapy for cervical cancer, Since 1976 a clinical trial has been conducted to test the feasibility. the potential. and to develop methods for using the neutron-emitting radioactive isotope. californium-252 (Cf-252). for the treatment of cervical cancer. A total of 218 patients were treated in the initial study period from 1976 until 1983. The trials initially treated advanced (Stages III and IV) cervical cancer patients using different doses and schedules; they were extended to include unfavorable presentations of Stages I and II because of favorable results in the initial trials. The authors began to treat patients with Stage IB bulky or barrel-shaped tumors and the majority were treated with both radiation and hysterectomy. Actuarial survival was determined for Stage IB disease and was 87% at 5 years and 82% at 10 years. For those tested with preoperative radiation it was 92% at 5 and 87% at 10 years. For Stage II. it was 62% 5 years and 61% at 10. Survival 5 years after combined radiation and surgical therapy for Stage II disease was 68%. For Stage III. it was 33% at 5 years and 25% at 10. However. 5-year survival using the early neutron implant was 46% versus approximately 19% for delayed Cf-252 or cesium 137. Different schedules and sequences of neutrons and photons greatly altered outcome. Neutron treatment before external photon therapy was better for all stages of disease. Only about 5% of all patients developed complications after neutron therapy. No hematologic or mesenchymal second tumors were observed. Neutron brachytherapy was found to be very effective for producing rapid response and greatly improved local control of bulky. barrel. or advanced cervical cancers. The clinical trial identified and evolved schedules. doses. doses per session. and developed methods different from standard photon therapy but highly effective for local control and cure of cervical cancers of all stages. Clinical and radiobiologic understanding for the use of neutron therapy was greatly advanced by this trial. Future trials will focus on patients with advanced disease and will require evaluation of adjuvant chemotherapy studies and neutron-enhancing chemicals.
Inhibitory effects of the gastrin receptor antagonist (L-365,260) on gastrointestinal tumor cells, A selective gastrin receptor (GR) antagonist. L-365.260 is bound to the GR on AR42J cells with a potency 7.5-fold less than G17 (50% inhibitory concentration [IC50] G17. 6 x 10(-9) mol/l; IC50 L365-260. 4.5 x 10(-8) mol/l). G17 is mitogenic for AR42J cells. as assessed by 75Se-selenomethionine uptake and L-365.260 at concentrations of 2.5 x 10(-6) mol/l and 2.5 x 10(-7) mol/l. (55X and 5.5 X the dose required to displace 50% 125I G17. respectively). and reduced optimal G17 stimulated mitogenesis in 75% of experiments. The basal growth of two human colon cancer cell lines. LoVo and C146 was reduced by L-365.260 (2.5 x 10(-7) mol/l) after 5 days of treatment to 44% and 64% of the control. respectively. However. inhibition was followed by a rebound of growth to control levels. The growth of AR42J xenografts in nude mice was increased by administration of G17 (10 micrograms/mouse/d. P less than 0.027). This increase was blocked by coadministration of oral L-365.260 (5 mg/kg/d. P less than 0.034). L-365.260 could be an important therapeutic agent in slowing the growth of GR-positive. G17-sensitive gastrointestinal tumors.
Preoperative radiation therapy followed by extrafascial hysterectomy in patients with stage II endometrial carcinoma, Seventy-four patients with Stage II endometrial cancer were treated by a combination of preoperative radiation therapy followed by extrafascial hysterectomy. bilateral salpingo-oophorectomy. and paraaortic lymph node sampling at the University of Kentucky Medical Center from 1967 to 1988. All patients had histologically confirmed endometrial cancer with involvement of the endocervix. The cell types and numbers of the tumors treated were as follows: adenocarcinoma. 58; adenoacanthoma. six; adenosquamous carcinoma. nine; and clear cell carcinoma. one. Preoperative radiation consisted of 4500 cGy external therapy followed by one intracavitary implant providing an additional 2000 cGy to point A. Surgery was done 4 to 6 weeks after completion of radiation therapy. Five patients (7.1%) had paraaortic lymph node metastases. Four were treated with extended-field radiation therapy and one with platinum-based combination chemotherapy. After treatment. the patients were followed at regular intervals from 2 to 22 years (mean. 5.4 years). Eleven patients (15%) had recurrent cancer. with the vagina and upper abdomen being the most common sites of spread. The estimated 5-year and 10-year disease-free survival rates of these patients are 88% and 76%. respectively. Cell type. depth of myometrial invasion. and lymph node status were the most important prognostic variables in the patients evaluated. These data confirm that the combination of preoperative radiation therapy and surgery produces excellent long-term survival in patients with Stage II endometrial cancer.
Elimination of clonogenic breast cancer cells from human bone marrow. A comparison of immunotoxin treatment with chemoimmunoseparation using 4-hydroperoxycyclophosphamide, monoclonal antibodies, and magnetic microspheres, Autologous bone marrow transplantation (ABMT) may aid in the management of breast cancer. but is currently limited to patients without bone marrow metastases. In earlier studies. 5 logs of malignant clonogenic breast cancer cells could be eliminated from human bone marrow using a combination of chemoseparation with 4-hydroperoxycyclophosphamide (4-HC) and immunoseparation with monoclonal antibodies and magnetic microspheres. In this report the authors compare chemoimmunoseparation to treatment with immunotoxins for elimination of tumor cells from human bone marrow and for the preservation of normal precursors. Breast cancer cells from each of five cell lines were mixed with a tenfold excess of irradiated human bone marrow cells. Treatment with a combination of five immunotoxins reduced clonogenic tumor cell growth by 1.8 to 5.5 logs depending upon the cell line. With two of the five cell lines. clonogenic tumor cells were eliminated quantitatively. Using the CAMA-1 breast cancer cell line. treatment with multiple immunotoxins was compared with chemoimmunoseparation with 4-HC. a panel of five unconjugated monoclonal antibodies and magnetic microspheres. Chemoimmunoseparation eliminated 3.5 to 5.4 logs of malignant cells. while preserving 21% of Colony-forming unit-granulocyte-macrophage (CFU-GM) and 37% of burst-forming unit-erythrocyte (BFU-E). No clonogenic breast cancer cells could be detected. Immunotoxin treatment eliminated 2.2 to 5.4 logs of clonogenic breast cancer cells. but had no effect on the bone marrow precursors. In seven of ten experiments. however. clonogenic breast cancer cells remained after immunotoxin treatment. Consequently. treatment with 4-HC. multiple murine monoclonal antibodies and magnetic microspheres provided more consistent elimination of tumor cells than separation with immunotoxins. but was significantly more toxic for marrow precursors.
B-cell lymphoproliferative disorders after bone marrow transplant. An analysis of ten cases with emphasis on Epstein-Barr virus detection by in situ hybridization, Ten patients with B-cell lymphoproliferative disorders (BLPD) after bone marrow transplant were studied in a retrospective analysis of 81 specimens available from biopsy and autopsy material. Histologic review. immunophenotyping. and in situ hybridization (ISH) for Epstein-Barr virus (EBV) sequences were done. Sixty-four specimens showed morphologic evidence of BLPD. demonstrating a heterogeneous spectrum with various degrees of plasmacytoid differentiation. Immunophenotypic evidence of clonality was found in six patients. The ISH detected EBV sequences in all ten patients. including 60 of the 64 specimens with morphologic evidence of BLPD. In addition. ISH identified EBV-infected lymphoid cells in two of 17 sites without morphologic evidence of BLPD. These data demonstrate the utility of ISH for detecting EBV genome in this setting and provide further evidence for the etiologic role of EBV in the pathogenesis of BLPD.
A significant association of Ha-ras p21 in neuroblastoma cells with patient prognosis. A retrospective study of 103 cases, To evaluate biologic characteristics of neuroblastoma. the authors examined the expression of Ha-ras gene (Ha-ras p21) in 103 primary tumors obtained at the time of diagnosis. Higher expression of the Ha-ras p21 in tumor cells showed a significant association with lower clinical stage of the tumor at diagnosis (chi-square = 35.418. degrees of freedom [df] = 9. P less than 0.001) and survival of the patients (chi-square = 37.111. df = 3. P less than 0.001). Thirty-six (84%) of 43 patients with decreased Ha-ras p21 expression died of aggressive disease. The Ha-ras DNA was examined in the 32 tumors by Southern blot analysis. Neither augmentation nor deletion of the Ha-ras DNA was observed. Amplification of the N-myc DNA was also examined in 43 cases in comparison with Ha-ras p21 expression. N-myc amplification was detected in 12 (55%) of 22 patients who died. and 19 (86%) of the 22 patients showed a low expression of the Ha-ras p21 in tumor cells. Eighteen (86%) of 21 survivors showed a high expression of the Ha-ras p21. The expression of Ha-ras p21 was thought to be a clinically important marker for prognosis in children with neuroblastoma.
Lewis blood group antigens (a and b) in human breast tissues. Loss of Lewis-b in breast cancer cells and correlation with tumor grade, The Lewis blood group antigens (Lewis-a [Lea] and Lewis-b [Leb]) and their precursors are present on various normal human epithelial cell surfaces. The authors examined 35 benign and malignant human breast lesions using mouse monoclonal antibodies to synthetic Lea and Leb carbohydrate antigens. Normal breast lobular and ductal epithelium and benign breast lesions showed Leb staining but only occasional Lea staining. In invasive ductal carcinomas of breast. of all grades. a loss of Leb antigen staining was found in 80% of the breast cancer cases. This reduced Leb antigen expression increased with the grade of malignancy. Therefore. the loss of Leb blood group antigens on breast cancer cell surfaces may suggest altered fucosylation patterns in malignant cells and reflect the degree of malignancy and/or invasiveness.
Pathologic correlates of survival in 378 lymph node-negative infiltrating ductal breast carcinomas. Mitotic count is the best single predictor, Pathologic features of 378 breast carcinomas without axillary lymph node metastases were correlated with long-term prognosis. Mitotic count. the feature best predicting prognosis. was most useful at lower mitotic count levels than usually studied. Cases with less than 4.5 mitotic figures per ten high-power fields had a 20-year tumor-related survival of 73% versus 48% for those with higher mitotic counts. Low and high mitotic count groups had significantly different prognoses for T1c. T2. and T3 tumors. Multivariate analysis showed that the best combination of features predicting tumor-related death were high mitotic count (relative risk. x 2.8). large tumor size (relative risk. x 1.7). lymphatic invasion (relative risk. x 1.7). and skin or subjacent muscle or chest wall invasion (relative risk. x 2.5). Nuclear grade. Bloom-Richardson grade. modified Scarff-Bloom-Richardson grade. Fisher's grade. and necrosis correlated well with survival but had no significant additional predictive value when adjusted for the mitotic count.
Surgical pathology of gastrinoma. Site, size, multicentricity, association with multiple endocrine neoplasia type 1, and malignancy, Specimens from the pancreas and duodenum of 26 patients with sporadic Zollinger-Ellison syndrome (ZES) and 18 patients with multiple endocrine neoplasia type 1 (MEN-1) and hypergastrinemia (17 with ZES) were screened immunocytochemically for gastrinomas. Location. size. multicentricity. and malignancy of the gastrinomas were evaluated. The MEN-1 patients had gastrinomas in the duodenum (nine of 18). pancreas (one of 18). and periduodenal lymph nodes (two of 18). No gastrinoma was identified in six patients. Most duodenal gastrinomas were multiple (five of nine) and smaller than 0.6 cm (six of nine). Lymph node metastases were present in eight of 12 patients. All 26 patients with sporadic ZES had a solitary gastrinoma; 14 were found in the pancreas and had a diameter greater than 2 cm. Ten patients had a duodenal gastrinoma. two with a diameter less than 0.6 cm. In two patients. only periduodenal "lymph node gastrinomas" were detected. Eighteen of the sporadic gastrinomas were malignant. These results suggest that duodenal location and multicentricity of gastrinomas are associated with the MEN-1 syndrome. and solitary gastrinomas. either in the pancreas or the duodenum. are predominantly seen in sporadic ZES.
Lymphomas in University College Hospital, Ibadan, Nigeria, The authors reviewed 508 cases of lymphoma seen during a 16-year period in University College Hospital. Ibadan. Nigeria. Hodgkin's disease was diagnosed in 95 (18.6%) patients. of which 45% had mixed cellularity type; 19%. lymphocyte predominance; 18%. nodular sclerosis; and 18%. lymphocyte depletion. The age distribution showed a single mode in the 11 to 25-year-old group. Male preponderance was more marked in children who made up 32% of the Hodgkin's disease patients. Non-Hodgkin's lymphoma occurred in 413 cases. of which 296 (71.7%) were high-grade malignancies. Burkitt's tumor occurred in 211 (41.5%) patients. 95% of whom were children. and showed a male to female ratio of 1.7:1. Compared with previous findings in this hospital. Hodgkin's disease showed increased proportions of the lymphocyte predominant and nodular sclerosing types. However. the characteristics of Burkitt's lymphoma did not change appreciably in the last three decades.
Kaposi's sarcoma in a child after autologous bone marrow transplantation for non-Hodgkin's lymphoma, A case of Kaposi's sarcoma in a child with no serologic evidence of human immunodeficiency virus (HIV) infection is reported. A 7-year-old boy with Stage IV non-Hodgkin's lymphoma. after conventional chemotherapy. underwent autologous bone marrow transplantation (ABMT). Five months later he presented with supraclavicular mass and mediastinal enlargement. A bone marrow biopsy showed hypoplasia with no signs of the underlying disease. whereas the excised mass revealed a typical histologic pattern of Kaposi's sarcoma. The child is currently being treated with recombinant alpha-interferon (alpha-IFN) and regression of the disease has been achieved.
Angiofollicular lymph node hyperplasia (Castleman's disease) in an adolescent female. Clinical and immunologic findings, Angiofollicular lymph node hyperplasia is a heterogeneous disorder of unclear etiology and has a wide spectrum of systemic symptoms. This report describes a case of this disorder in a 15-year-old girl and examines the response of the primary mass. systemic symptoms. and alterations of selected immune parameters at diagnosis. as a result of steroid therapy and radiation therapy (RT). The patient had a 1-year history of growth failure. delayed puberty. and refractory iron deficiency anemia. Computed tomography scan showed a posterior mediastinal mass. Biopsy revealed angiofollicular lymph node hyperplasia of mixed hyaline-vascular and plasma cell type histologic type. Immunoperoxidase studies showed polyclonal B-cells. predominance of T-helper cells (CD4) over cytotoxic/suppressor T-cells (CD8). and the presence of natural killer (NK) cells. Southern blot analysis demonstrated germ line gene configuration for the T-cell antigen receptor and Ig heavy chain. The patient clinically improved with RT after failing to respond to steroids. Immunophenotyping of peripheral blood lymphocytes before therapy revealed a CD4:CD8 ratio of 0.8 with decreased numbers of circulating T-cells; this increased to 1.4 after steroid therapy. The patient's T-lymphocytes had no proliferative response to phytohemagglutinin (PHA) or concanavalin A (Con A) before RT. After RT. a small but significant mitogenic response to these reagents was noticed. The proliferative response to recombinant interleukin-2 (rIL-2) remained similar to that of control lymphocytes. Induction of second messenger signals by activation of protein kinase C (PKC) and elevation of free cytosolic calcium through the use of the phorbol ester. phorbol 12. 13-dibutyrate (PDBu). and ionomycin (Io) resulted in a strong proliferative response at diagnosis and after RT. In vitro cytotoxicity assays revealed diminished NK activity before and after therapy. Lymphokine-activated killer (LAK) activity remained comparable with that of control cells and was not affected by therapy. Before RT patient lymphocytes maintained cytotoxic capabilities after coincubation with rIL-2 and PDBu plus Io. whereas coincubation with these reagents abrogated cytotoxic function of normal cells. This case demonstrates a clinical response to RT as well as improvement in immune parameters. Intact signal transduction mechanisms through PKC activation and elevation of cytosolic calcium were also demonstrated in the circulating lymphocytes.
A population-based study on the incidence and survival rates of 3857 glioma patients diagnosed from 1953 to 1984, Intracranial glioma was diagnosed during the patient's life and histologically verified in 3857 patients between 1953 and 1984 in Finland. Their survival up to the end of 1987 was analyzed. the follow-up being complete. The treatment was by operation in 1193 cases. radiation in 459 cases. both operation and radiation in 1486 cases. and neither operation nor radiation in 719 cases. The 1-year. 5-year. 10-year. and 15-year cumulative relative survival rates were 0.53. 0.29. 0.20. and 0.18. respectively. The newborn to 14-year-olds lost 56% of their life expectancy; the 15-year-olds to 44-year-olds. 71%; the 45-year-olds to 64-year-olds. 88%; and the 65-year-olds to 99-year-olds. 91%. According to the model with the best fit in regression analysis the prognosis was significantly better among young. recently diagnosed patients who had undergone both operation and radiation.
Prolactin and growth hormone levels in premenopausal women with breast cancer and healthy women with a strong family history of breast cancer, Although both prolactin and growth hormone are believed to play roles in the development and growth of rodent mammary cancer. the role of these hormones in human breast cancer is uncertain. Under carefully specified conditions. serum levels of these hormones were determined by radioimmunoassay (RIA) and prolactin was determined by bioassay in 18 premenopausal women with breast cancer. 23 healthy women with a strong family history of breast cancer. and 39 healthy women with no significant family history of breast cancer. Parity was associated strongly with decreased prolactin levels. and increasing age was associated strongly with decreased growth hormone levels. After controlling for these variables. no differences in prolactin or growth hormone levels were found among the three groups of women. These data do not support roles for these RIA-measured hormones or bioassay-measured prolactin in premenopausal or familial breast cancer in omnivorous white women.
CAncer Rehabilitation Evaluation System--short form (CARES-SF). A cancer specific rehabilitation and quality of life instrument, The CAncer Rehabilitation Evaluation System (CARES) (CARES Consultants. Santa Monica. CA) a rehabilitation and quality of life instrument with well-documented reliability and validity. has been shortened. This report describes the development and psychometric properties of the new instrument. the CAncer Rehabilitation Evaluation System--Short Form (CARES-SF). The data from four existing samples of cancer patients demonstrate that the CARES-SF is highly related to the CARES (r = 0.98). has excellent test-retest reliability (86% agreement). concurrent validity with related measures. and acceptable internal consistency of summary scales (alpha = 0.85 to 0.61). In a new sample of breast cancer patients evaluated at three points in time (1 month. 7 months. and 13 months after diagnosis) the instrument appears to be sensitive to change and is highly related to the Functional Living Index--Cancer (FLIC). an existing quality of life instrument. The authors conclude that the CARES-SF has excellent potential as a quality of life instrument for use in clinical trials.
Alterations in myocyte shape and basement membrane attachment with tachycardia-induced heart failure, Chronic supraventricular tachycardia (SVT) results in left ventricular (LV) dilatation and dysfunction. However. the underlying mechanisms responsible for LV failure in this setting are not known. LV force production is dependent on the coupling of myocytes to the extracellular matrix. which is mediated through the basement membrane. This study was designed to determine whether alterations in myocyte geometry and basement membrane attachment are associated with LV failure in a pacing-induced model of cardiomyopathy. Echocardiographic measurement of LV function was performed in six pigs after 3 weeks of pacing-induced SVT (240 beats/min) and in eight sham-operated controls. Myocytes from these hearts were isolated. and attachment studies to specific components of the basement membrane were performed using laminin. fibronectin. and collagen IV. The SVT group when compared with the control group showed a significant reduction of LV fractional shortening (14 +/- 2% versus 31 +/- 2%. respectively; p less than 0.05). increased end-diastolic dimension (50 +/- 1 versus 35 +/- 1 mm. respectively; p less than 0.05). and lengthening of isolated myocytes (196 +/- 18 versus 142 +/- 9 microns. respectively; p less than 0.05). Myocyte attachment to laminin (50 micrograms/ml) was significantly decreased at 60 minutes in the SVT group compared with the control group (18.2 +/- 4.5 versus 60.9 +/- 4.5 cells/mm2. respectively; p less than 0.05). Similar reductions in myocyte attachment to fibronectin and collagen IV were observed. Ultrastructural examination of LV sections revealed focal disruptions of the basement membrane-sarcolemmal interface and a reduced number of sarcolemmal festoons in SVT hearts compared with control hearts (0.8 +/- 0.6 versus 2.8 +/- 0.8/4 microns. respectively; p less than 0.05). These alterations in myocyte morphology and basement membrane attachment may contribute to the LV failure associated with chronic SVT. Further. these structural changes may play a significant role in the progression of ventricular dysfunction as well as recovery from chronic SVT.
Effect of angiotensin converting enzyme inhibition on pressure-induced left ventricular hypertrophy in rats, The influence of angiotensin converting enzyme inhibition on the development of left ventricular (LV) hypertrophy due to stenosis of the aortic arch was studied in female Sprague-Dawley rats. The aortic arch was banded to an outer diameter of 1.0 mm. After 14 days. LV and right ventricular functional parameters and transstenotic pressure gradient were measured in anesthetized rats. In addition. regional heart weights were determined. and myocytes of three different heart regions were isolated and subjected to morphometric analysis. To inhibit the angiotensin converting enzyme. ramipril was administered orally by gavage in a single daily dose of 1 mg/kg. Rats with aortic stenosis showed a marked increase in LV systolic pressure. mean prestenotic aortic pressure. and LV stroke work compared with sham-operated rats and demonstrated a systolic transstenotic pressure gradient of 82 mm Hg. This increase in LV hemodynamic load was paralleled by the development of LV hypertrophy as determined by a 37% increase in LV weight and by a 20% increase in cell volume of isolated LV myocytes. Concomitant ramipril treatment did not significantly affect LV functional parameters. The transstenotic pressure gradient was the same as in untreated rats with aortic stenosis. Likewise. the weight gain of the LV as well as the development of cellular hypertrophy of the LV were not influenced. Thus. in this model. angiotensin converting enzyme inhibition did not reduce the development of LV hypertrophy independent of the hemodynamic load.
Vasoconstriction of canine coronary collateral vessels with vasopressin limits blood flow to collateral-dependent myocardium during exercise, This study was performed to test the hypothesis that active constriction of coronary collateral vessels can worsen hypoperfusion of collateral-dependent myocardium during exercise. Studies were performed in seven adult mongrel dogs in which intermittent followed by permanent occlusion of the left circumflex coronary artery produced an area of collateral-dependent myocardium without gross evidence of infarct. Myocardial blood flow was determined with microspheres while measurement of aortic and distal coronary pressures allowed calculation of collateral and small vessel resistance at rest and during treadmill exercise. The ability of collateral vessel constriction to limit blood flow was assessed by infusion of vasopressin during exercise. During control conditions. blood flow in the collateral zone underwent a subnormal increase during exercise in comparison with the normal zone (1.74 +/- 0.27 versus 2.50 +/- 0.40 ml/min/g. respectively. p less than 0.05). Infusion of vasopressin in a dose that caused no change in normal zone flow (0.01 microgram/kg/min i.v.) produced a 30 +/- 5% further decrease in flow to the collateral zone (p less than 0.01). This decrease in collateral zone flow resulted from a 48 +/- 14% increase in transcollateral resistance in response to vasopressin infusion (p less than 0.01). as well as a 40 +/- 9% increase in small vessel resistance in the collateral zone (p less than 0.01). These data demonstrate that active constriction of both collateral vessels and coronary resistance vessels can contribute to hypoperfusion of collateral-dependent myocardium during exercise.
Flow-mediated dilatation of the basilar artery in vivo, Flow-mediated dilatation has been described mainly in peripheral conduit arteries. The goal of this study was to examine mechanisms and functional implications of flow-mediated dilatation in large cerebral arteries in vivo. Vessel diameter and velocity of blood flow through the basilar artery were measured using a cranial window in 45 anesthetized rats. Mean blood flow velocity through the basilar artery increased by 94 +/- 8% during unilateral common carotid artery occlusion and 203 +/- 13% during bilateral occlusion. Diameter of the basilar artery increased by 10 +/- 1% during unilateral common carotid artery occlusion and 29 +/- 2% during bilateral occlusion from control diameter of 275 +/- 8 microns. Vasodilatation appeared with a delay of 13 +/- 1 seconds after the onset of the increase in flow velocity. With systemic arterial pressure maintained at baseline levels. pressure in the basilar artery (servonull) decreased initially during carotid occlusion. and during dilatation of the basilar artery. pressure was restored partially toward normal. Indomethacin (10 mg/kg i.v.). topical application of tetrodotoxin (10(-6) M). NG-monomethyl L-arginine (5 x 10(-6) M). tetraethylammonium chloride (10(-2) M). glibenclamide (10(-5) M). SKF 525A (3 x 10(-5) M). and ouabain (10(-5) M) had no effect on flow-mediated dilatation.
Combined effect of neonatal sympathectomy and adrenal demedullation on blood pressure and vascular changes in spontaneously hypertensive rats, Neonatal sympathectomy using a combined treatment with antiserum to nerve growth factor and guanethidine during the first 4 weeks after birth was carried out in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Bilateral adrenal demedullation was performed in 4-week-old sympathectomized SHR and WKY rats. The development of hypertension in SHR was prevented by sympathectomy. but the blood pressure (BP) was still higher than in age-matched WKY rats. Demedullation reduced the BP of sympathectomized SHR to the same level as that of WKY rats. Heart rates of SHR and WKY rats were not affected by the treatments. Morphometric measurements of the mesenteric arteries showed that sympathectomy significantly reduced the medial mass in the mesenteric arteries of SHR. mainly through a reduction in the number of smooth muscle cell layers. In sympathectomized SHR. demedullation increased the lumen size of muscular arteries under maximally relaxed conditions. which might explain the further reduction in BP in these animals. Demedullation in sympathectomized SHR and WKY rats caused a decrease in smooth muscle cell layers in the superior mesenteric artery. but the same treatment resulted in a slight increase in the number of smooth muscle cell layers in the large and small mesenteric arteries of SHR and WKY rats. Adventitial area was increased in some mesenteric arteries of SHR and WKY rats by sympathectomy. and demedullation caused a further increase in the size of adventitia in WKY rats. Heart weight in SHR was normalized to the level found in WKY rats by sympathectomy and demedullation. We conclude that in sympathectomized SHR. the elevated BP was maintained by the adrenal medulla.
Postischemic myocardial "stunning". Identification of major differences between the open-chest and the conscious dog and evaluation of the oxygen radical hypothesis in the conscious dog, Recent studies suggest that oxygen-derived free radicals contribute to the pathogenesis of postischemic myocardial dysfunction (myocardial "stunning"). This concept. however. is predicated exclusively on results obtained in open-chest preparations. which are subject to the confounding influence of many unphysiological conditions. The lack of supporting evidence in more physiological animal models represents a major persisting limitation of the oxy-radical hypothesis of myocardial stunning. The goal of this study was to address two fundamental (and related) questions: 1) Does the open-chest animal model alter the phenomenon of myocardial stunning? 2) If so. how valid are the concepts. derived from such a model. regarding the pathogenetic role of oxy-radicals? In part 1 of the study. myocardial stunning after a 15-minute coronary occlusion was compared in 30 pentobarbital-anesthetized open-chest dogs and in 19 conscious dogs. For any given level of collateral flow during occlusion. the recovery of systolic wall thickening after reperfusion was markedly less in open-chest animals. In an additional group of five open-chest dogs. a close inverse relation was noted between body temperature and postischemic wall thickening. indicating that the recovery of the stunned myocardium in acute experiments may vary markedly depending on how temperature is controlled. Because of these major differences between open-chest and conscious dogs. the oxy-radical hypothesis needs to be tested in the latter model. Thus. in part 2 of the study. conscious unsedated dogs undergoing a 15-minute coronary occlusion were randomized to an intravenous infusion of either saline (19 coronary occlusions) or superoxide dismutase (SOD) plus catalase (CAT) (21 coronary occlusions). Despite the fact that the plasma levels of SOD and CAT declined rapidly after reperfusion. postischemic wall thickening was significantly greater in treated compared with control dogs throughout the first 6 hours of reflow. Thus. a brief (60-minute) infusion of SOD and CAT produced a sustained improvement of recovery of contractility. The magnitude of this beneficial effect was a function of the severity of ischemia: the lower the collateral perfusion. the greater the improvement effected by the enzymes. The accelerated recovery produced by SOD and CAT was not followed by any deterioration of contractility. suggesting that postischemic dysfunction is not a teleologically "protective" phenomenon. In conclusion. the severity of myocardial stunning is greatly exaggerated by the unphysiological conditions present in the barbiturate-anesthetized open-chest dog.(ABSTRACT TRUNCATED AT 400 WORDS).
Rabbit ear model of injury-induced arterial smooth muscle cell proliferation. Kinetics, reproducibility, and implications, Recently. considerable interest has focused on the vascular smooth muscle cell (SMC) response to injury. particularly as it relates to restenosis after angioplasty. In an effort to find an optimal experimental model of arterial SMC proliferation after injury. we examined the effects of external injury to the central artery of the rabbit ear and assessed the reproducibility. morphological changes. and time course of cellular proliferation after such an injury. With rabbits under general anesthesia. direct pressure was applied at two sites along the central artery of the ears of 19 New Zealand White rabbits. Rabbits were maintained on a diet of 2.4% fat and 0.001% cholesterol throughout the experiment. In seven rabbits examined after 21 days. marked SMC proliferation with neointimal formation was observed at all 28 sites (100%). Mean neointimal area. expressed as a percentage of the area of the tunica media. was 82 +/- 40% (range. 21-203%). Compared with the uninvolved artery displaced 2 mm from the injury site. mechanical crush caused a 38% increase in total vessel area (p less than 0.001). a 40% decrease in luminal area (p less than 0.002). and no change in the area of the media. Serial histological studies were performed 1-42 days after injury. using light and electron microscopy and bromodeoxyuridine immunohistochemistry. Beginning at day 3. activated medial SMCs were noted to migrate through defects in the internal elastic membrane. with a gradual increase in neointimal area between days 5 and 12. Peak DNA synthesis was identified in the media 5 days after injury. with proliferative activity shifting almost exclusively to the neointima thereafter.
Mechanism of the enhanced epidermal growth factor-induced growth response of genetically hypertensive vascular myocytes, Although enhanced growth of the vascular myocyte is believed to play a role in hypertensive cardiovascular disease. the cellular basis of altered growth regulation is not completely understood. The present study demonstrates that in the presence of 10% fetal calf serum. the logarithmic growth rate of cultured mesenteric artery myocytes of the spontaneously hypertensive rat (SHR) is similar to that of the normotensive Wistar-Kyoto (WKY) control rat. However. in the presence of low levels of fetal calf serum. SHR myocytes respond to epidermal growth factor (EGF) with increased growth. whereas WKY cells do not. This difference does not result from different numbers or affinities of EGF receptors in these cell lines. Examination of EGF-induced growth responses of SHR and WKY myocytes in the presence of varying levels of insulin or fetal calf serum indicates that. compared with WKY myocytes. SHR myocytes have a lower requirement for factors that confer competence to respond to EGF. Another property of the SHR myocytes is an elevation of free intracellular Ca2+. To determine whether a difference in cellular Ca2+ metabolism might play a role in the differential growth response. growth of myocytes in medium containing 0.25. 0.75. or 1.25 mM extracellular Ca2+ and 5% fetal calf serum was examined. Myocytes of SHR showed enhanced growth in the presence of 5% fetal calf serum at all levels of extracellular Ca2+. It is concluded that. although vascular myocytes of SHR and WKY rats have the capacity to grow at similar rates. under limiting conditions. the SHR myocyte growth response is enhanced.
Distribution of carbon flux within fatty acid utilization during myocardial ischemia and reperfusion, Twenty-nine intact. working pig hearts were extracorporeally perfused and divided into two study groups (16 Aerobic and 13 Ischemic/Reflow hearts). Step function. equilibrium labeling with [14C]palmitate was used to develop uptake and washout curves of radioactive fatty acid products contained in coronary effluent during either aerobic perfusion or reperfusion after ischemia (60% reduction in left anterior descending coronary flow for 30 minutes). Left anterior descending control flows were slightly overperfused in Aerobic hearts (18% higher than in Ischemic/Reflow hearts); otherwise. circumflex and right coronary flows. left ventricular pressure. and serum fatty acids and blood sugar levels were comparable between groups. As expected in Ischemic/Reflow hearts. recovery of regional systolic shortening and myocardial oxygen consumption in reperfusion was only modestly impaired (-20% and -19%. respectively. not significant and p less than 0.011 compared with preischemic values. not significant from Aerobic hearts). The only significant metabolized product to be released from labeled fatty acid utilization in either group was 14CO2. A smaller fatty acid pool also was measured and accounted for by that contained in the coronary intravascular volume. We could determine no significant back diffusion of fatty acids from myocardium in either perfusion condition. Uptake time constants of the early phase of 14CO2 production also were virtually identical in both groups (19.9 +/- 3.2 versus 16.7 +/- 3.2 minutes in Aerobic and Ischemic/Reflow hearts. respectively) and strongly correlated with hemodynamics as described by heart rate. In washout studies. tissue radioactivity in the aqueous soluble and fatty acid pools declined in both study groups. and counts in complex lipids and cholesterol/cholesteryl esters remained steady. whereas those in triacylglycerols varied. Washout of 14CO2 in both groups never reached background radioactivity over a 40-minute sampling after cessation of isotope infusion into the perfusate. suggesting slow release of trapped substrate from intracellular pools. which then proceeded to fatty acid oxidation. In conclusion. these experiments have demonstrated very similar findings with respect to fatty acid uptake. storage. and release characteristics between aerobic and reperfused myocardium. We found no differences in preferred substrate utilization and oxidation as a result of reversible ischemia followed by reflow.
Intracellular calcium transients and arrhythmia in isolated heart cells, Intracellular calcium ([Ca2+]i) elevation may mediate cardiac arrhythmias. However. direct measurement of the rapid alterations of [Ca2+]i on a beat-to-beat basis using fast temporal resolution and without signal averaging in the spontaneously beating in vivo heart is lacking. Furthermore. data from an isolated spontaneously beating myocyte preparation that develops arrhythmia similar to that in the in vivo heart are unavailable. We measured rapid changes of [Ca2+]i with fast temporal resolution in isolated spontaneously beating neonatal rat ventricular myocytes with cell-to-cell communication and characterized the interrelation between [Ca2+]i and arrhythmia. An elevated extracellular calcium ([Ca2+]o) concentration of 10.8 mM induced premature beats. a rapid beating rate (tachyarrhythmia). and chaotic or fibrillatory beating activity in a small group of myocytes. [Ca2+]i levels during systole increased from the nanomolar to micromolar concentration range before arrhythmia development. Spontaneous oscillations of [Ca2+]i during diastole could evoke a spontaneous tachyarrhythmia. In the presence of [Ca2+]i elevation. a spontaneous tachyarrhythmia could induce severe [Ca2+]i overload. Reduction of [Ca2+]i with 1.2-bis(2-aminophenoxy)ethane-N.N.N'.N'-tetraacetic acid AM (5 microM) in the presence of 10.8 mM [Ca2+]o reversed the arrhythmia. In single ventricular myocytes superfused with 10.8 mM [Ca2+]o. oscillations of membrane potential characteristic of transient inward current occurred that were prevented by ryanodine (0.1 microM). an inhibitor of Ca2+ flux across the sarcoplasmic reticulum. This study characterizes 1) an isolated multicellular myocyte model of arrhythmia similar to that evident in in vivo hearts. 2) elevation of [Ca2+]i with systolic [Ca2+]i levels of 1-3 microM and diastolic [Ca2+]i oscillations before the initiation of arrhythmia. 3) tachyarrhythmia as a cause of severe [Ca2+]i overload. which may be important in the perpetuation and degeneration of arrhythmias. and 4) reversal of arrhythmia with reduction of [Ca2+]i. The results in the isolated myocyte model may have relevance to the generation and perpetuation of certain cardiac arrhythmias associated with calcium overload.
Dose-dependent inhibition of stretch-induced arrhythmias by gadolinium in isolated canine ventricles. Evidence for a unique mode of antiarrhythmic action, Transient diastolic dilatation of the isolated canine left ventricle predictably elicits arrhythmias. To test the hypothesis that such arrhythmias may be mediated by sarcolemmal stretch-activated channels. we attempted to inhibit stretch-induced arrhythmias with gadolinium (Gd3+). a potent stretch-activated channel blocker. In experiments with six isolated canine hearts. left ventricular volume was increased for 50 msec during early diastole and then returned to initial volume by a computerized servopump. The stretch volume was adjusted to yield a probability of eliciting a stretch-induced arrhythmia of 95 +/- 2% before treatment with Gd3+. When Gd3+ (1-10 microM) was administered. dose-dependent suppression of stretch-induced arrhythmias was observed. The probability of a stretch-induced arrhythmia was reduced to 13 +/- 10% (p less than 0.05) with 10 microM Gd3+. Washout of Gd3+ completely reversed this effect. Since Gd3+ is known to be a calcium channel antagonist. we compared the effect of Gd3+ on stretch-induced arrhythmias with that of verapamil and nifedipine. These calcium channel blockers produced no demonstrable inhibition of stretch-induced arrhythmias when administered at concentrations (1 microM) that substantially depressed left ventricular pressure development. Thus. our results indirectly implicate stretch-activated channels in the genesis of stretch-induced arrhythmias and provide preliminary evidence for a potential new mode of antiarrhythmic drug action--blockade of stretch-activated channels.
Copper loading of hearts increases postischemic reperfusion injury, We studied the role of copper as a potential mediator of postischemic reperfusion injury in the isolated. perfused rat heart. Hearts were equilibrated with Krebs-Henseleit buffer for 10 minutes and then loaded with copper by way of perfusion with buffer containing 20 microM copper(II)-bis-histidial for 30 minutes. Control hearts were perfused with Krebs-Henseleit buffer alone during the loading period. Hearts than were washed with buffer for 10 minutes and subjected to 20 minutes of normothermic global ischemia followed by 30 minutes of reperfusion. Atomic absorption spectroscopy revealed a 67% increase in total copper content in loaded hearts by the end of the wash. By the end of the 30-minute period of reperfusion. control hearts demonstrated a 50-60% recovery of myocardial function as determined by peak systolic pressure. contractility. and heart rate. In contrast. copper-loaded hearts exhibited virtually no functional recovery within the 30-minute time period. Using salicylate as a probe. we determined that peak and duration of .OH formation appears to be increased in copper-loaded hearts during reperfusion. Furthermore. efflux of lactic dehydrogenase was significantly increased in copper-loaded hearts. Our results clearly demonstrate that increasing cardiac content of copper results in enhanced postischemic reperfusion injury associated with increased formation of .OH. thus suggesting an important catalytic role for this transition metal.
Glomerular proteinuria as an early sign of renal-transplant rejection, The introduction of cyclosporin gave rise to an additional problem in the surveillance of renal transplant patients. namely the differentiation between cyclosporin toxicity and acute transplant rejection. The development of assays for specific proteins in urine has produced a non-invasive solution to this problem. In 55 renal transplant patients the following proteins were determined daily in 24 h-urine samples: IgG. transferrin (TF). albumin. beta 2-microglobulin (beta 2-MG). retinol binding protein (RBP). alpha 1-microglobulin (alpha 1-MG) and alpha 1-antitrypsin (alpha 1-AT). All proteins were determined quantitatively using immunoluminometric assays and 10 microliters urine in dilutions from 1:1-1:100. The urinary protein excretion was related to the actual creatinine clearance as this index gave the best differentiation between normal and abnormal status. In 24 h-urine. intraindividual peaks of IgG. TF and albumin were seen regularly in acute rejection episodes. However. a peak in the "tubular" proteins (RBP. beta 2-MG. alpha 1-MG) could not be detected. After effective treatment of the rejection episode. the renal function improved and the protein excretion returned to prerejection episode levels. In bacterial infection of the urogenital tract. urinary alpha1-AT levels rose. They returned to normal after successful antibiotic treatment. In two cases of cyclosporin toxicity neither glomerular nor tubular proteins were excreted in abnormal amounts when compared with transplant patients without complications. the only changes being an increase in serum creatinine as a result of reduced renal function.
Pulmonary cytology, Cytomorphologic criteria for the diagnosis and classification of primary pulmonary carcinomas are described and illustrated. Helpful hints for the differential diagnosis from benign entities and tumors and the cytologic limitations are stated. The fact that pulmonary cytologic interpretations must be made in the light of accurate clinical presentation is emphasized.
Tetanus: pathophysiology, management, and prophylaxis, As tetanus has become a rare disease in the developed world. physicians have become less comfortable with its diagnosis and management. The extent of adequate antitetanus immunity in the adult population. especially the elderly. is waning. in great measure because primary care physicians have not made prophylaxis a priority in their routine encounters with patients. Furthermore. as the population of immunocompromised hosts grows. an increasing percentage of our patients may not respond to standard active immunization routines. Unless these trends are reversed. we face a substantial increase in the incidence of this dread disorder. Tetanus is also of interest as a relatively simple model of disordered motor control that can instruct us in the management of the many more common causes of neurogenic muscular rigidity. The toxin produced by Clostridium tetani finds increasing use in laboratories investigating brain function as well. Clinical tetanus is divided into four symptomatic types: generalized tetanus. local tetanus. cephalic tetanus. and neonatal tetanus. This monograph discusses the diagnostic aspects of each type of tetanus. its pathophysiology. diagnosis. differential diagnosis. and treatment. Preventing tetanus should be a high priority for all primary care physicians. Active immunization with tetanus toxoid is remarkably effective and safe. Passive immunization with human tetanus immune globulin is indicated in certain circumstances. which are discussed below.
Direct and sex-specific enhancement of bone formation and calcification by sex steroids in fetal mice long bone in vitro (biochemical and morphometric study, The study was carried out to examine the direct effect of the sex hormones 17 beta-estradiol (E2) and testosterone on the modeling of cultured fetal mouse long bones separated according to their sex. The culture system used allowed for the simultaneous assessment of bone growth. mineralization. and resorption on each bone. Bones from 16-day-old male and female mouse fetuses were cultured in BGJ medium. supplemented with either 10% fetal calf serum or 4 mg/ml BSA (serum-free medium) for 48 h. The bones were harvested. and their length; the length of their diaphyses; their hydroxyproline. calcium. and phosphorus contents; and their 45Ca release were measured. Histomorphometric analyses on midlongitudinal sections of bones from parallel experiments were also performed. The results indicate that in medium supplemented with 10% fetal calf serum. E2 had a dose-dependent stimulatory effect on bone formation and mineralization at 10(-7) and 10(-9) M. with no effect on bone resorption. This effect was specific to bones from female mice and to E2. since 17-alpha-estradiol had no effect. Testosterone had similar effects specific to bones from male mice. resulting in the stimulation of bone formation and mineralization at 10(-7)- and 10(-9)-M concentrations. These effects were absent when serum-free medium was used. E2 and testosterone had an anabolic effect on endochondral and periosteal bone formation and mineralization. but no effect on bone resorption. This effect is dependent on the presence of a serum factor(s).
Influence of castration, alone or combined with thymectomy, on the development of diabetes in the nonobese diabetic mouse, The nonobese diabetic (NOD) mouse is a recognized model for studying immunologically-mediated insulin-dependent diabetes mellitus. The disease appears with a greater preponderance in females than in males. Castration at weaning led to a significant increase in the prevalence of diabetes in NOD males. whereas a tendency to a decreased prevalence was observed in NOD females. Castration combined with thymectomy was found to further increase the prevalence of diabetes in NOD males. whereas in females castration reversed the effect of thymectomy. These results on changes in diabetes prevalence were corroborated by the degree of lymphocytic infiltration directed toward the pancreatic islets of Langerhans. Taken together these results indicate a direct relationship between the endocrine and immune systems. whereby orchidectomy has a deleterious effect on the immunopathogenesis of diabetes. In addition. we examined whether the distribution of lymphocyte subpopulations. mitogen reactivity. lymphokine production. and in vivo response to a thymus-dependent antigen. such as sheer red blood cell. were dependent or independent of the sex steroid environment.
Thyroid adenocarcinomas secondary to tissue-specific expression of simian virus-40 large T-antigen in transgenic mice, A hybrid gene comprising the bovine thyroglobulin gene promoter and the coding region for the simian virus-40 large T- and small t-antigens was used to generate 30 transgenic mice by microinjection into the pronuclei of single cell embryos. All animals except three developed. as single primitive pathology. a dramatic enlargement of the thyroid gland. Compression of trachea and esophagus. accompanied by dyspnea. inspiratory stridor. and dysphagia. led to a progressive cachexia and premature death attributed to respiratory failure. Despite the large thyroid volume. T4 levels were abnormally low. and the progression of the syndrome could be delayed by a substitutive treatment with thyroid hormones. The rapid evolution of the disease. leading to the death of most founder transgenic animals before the breeding age. prevented transmission of the transgene to their offspring. Only two transgenic lines are presently surviving. Immunohistochemical analysis of the tissues revealed a specific expression of the simian virus-40 antigens in the thyroid cells. Hyperplasia was already obvious at birth. Older animals displayed moderately to poorly differentiated thyroid adenocarcinomas. Electron microscopy revealed. however. the persistence of cell polarity and the presence of microfollicles between the densely packed cells. Cell lines derived from these large T-expressing thyroids were shown to have lost expression of both thyroglobulin and thyroperoxidase. while expressing low levels of TSH receptors. These transgenic mice could constitute an interesting model of aggressive adenocarcinoma. sharing phenotypical similarities with the anaplastic type of human thyroid tumors.
Functional antagonism between endogenous mouse growth hormone (GH) and a GH analog results in dwarf transgenic mice, A dwarf transgenic mouse (DTM) line has been established in which mice express relatively high levels of a mutated bovine (b) GH gene. This bGH analog binds to mouse liver membrane preparations with an affinity similar to that of wild-type bGH. The mean growth ratio of these mice is approximately 0.7 relative to that of their nontransgenic littermates. Serum insulin-like growth factor-I (IGF-I) levels of DTM were found to be approximately half those in nontransgenic littermates. Liver GH receptor levels were up-regulated in DTM or wild-type bGH transgenic mice. Pituitary GH levels were negatively correlated with serum IGF-I concentrations. Wild-type bGH transgenic mice contain relatively high serum IGF-I and low pituitary GH levels. whereas DTM possess low serum IGF-I and high pituitary GH levels. The decrease in serum IGF-I resulting from the interaction between the bGH analog. the endogenous mouse GH. and GH receptor(s) apparently leads to a dwarf phenotype. These data suggest that this bGH analog has uncoupled GH ligand-receptor binding from IGF-I production and acts as a functional antagonist to the action of endogenous mGH.
Thrombin and parathyroid hormone mobilize intracellular calcium in rat osteosarcoma cells by distinct pathways, The mechanisms by which PTH and thrombin mobilize intracellular Ca2+ (Cai2+) were examined in UMR 106-H5 rat osteosarcoma cells. Bovine PTH-(1-34) (24 pM to 240 nM) produced a dose-dependent increase in Cai2+ (EC50. 3 nM). which returned to baseline within 75 sec. Human alpha-thrombin produced an increase in Cai2+ (ECmax. 10 U/ml) which was similar to that of PTH with respect to both magnitude and time course. Chelation of extracellular calcium with 5.0 mM EGTA did not alter the Cai2+ response to either PTH or thrombin. When added together at maximally effective concentrations. PTH and thrombin produced additive effects on Cai2+ in the presence and absence of EGTA. The additive effects of PTH and thrombin on Cai2+ were confirmed at the single cell level. using laser-based image analysis. Bradykinin (1 microM) produced a significant increase in Cai2+ in UMR 106-H5 cells which was of lesser magnitude than the peak 2- to 3-fold increase elicited by PTH or thrombin. Preexposure of cells to 10 U/ml thrombin for 2 min abolished the Cai2+ response to bradykinin. whereas preexposure to 240 nM PTH had no effect on the Cai2+ response to bradykinin. Thrombin elicited a rapid increase in the accumulation of 3H-labeled inositol phosphates (IP2 and IP3) in UMR 106-H5 cells. with increases in [3H]1.4.5-IP3 detectable as early as 15 sec after the addition of thrombin. Bradykinin increased [3H]IP production to a lesser extent than thrombin. whereas PTH neither increased [3H]IP accumulation nor potentiated the [3H]IP response to thrombin. The results suggest that thrombin and bradykinin mobilize Cai2+ from a shared IP3-responsive calcium pool. whereas PTH may use signals in addition to 1.4.5-IP3 to mobilize calcium from a distinct cellular calcium pool. Alternatively. specific calcium compartmentalization exists. and there is differential coupling of these agonists to the 1.4.5-IP3/Cai2+ pathway.
Diazepam binding inhibitor and its processing products stimulate mitochondrial steroid biosynthesis via an interaction with mitochondrial benzodiazepine receptors, A recognition site for benzodiazepines structurally different from that linked to various gamma-aminobutyric acid A (GABAA) receptor subtypes is located on the outer mitochondrial membranes of steroidogenic cells. This protein has been signified to be important in the regulation of steroid biosynthesis. Because of its location it is designated herein as the mitochondrial benzodiazepine receptor (MBR). A putative endogenous ligand for MBR is the peptide diazepam binding inhibitor (DBI). previously shown to displace drugs from MBR and to be expressed and stored in steroidogenic cells rich in MBR. The two model systems used to study steroidogenic regulation by DBI were the Y-1 adrenocortical and MA-10 Leydig cell lines previously shown to be applicable in studies of mitochondrial steroidogenesis. Both cell lines contain DBI as well as DBI processing products. including the DBI fragments that on reverse phase HPLC coelute with the naturally occurring triakontatetraneuropeptide [TTN; DBI-(17-50)] and octadecaneuropeptide [DBI-(33-50)]. When DBI purified from rat brain was added to mitochondria prepared from Y-1 and MA-10 cell lines. it increased the rates of pregnenolone formation in a dose-related manner. In both cell lines. maximal stimulation (3-fold) of mitochondrial steroidogenesis was obtained with 0.33 microM DBI. with an EC50 of approximately 0.1 microM. However. DBI concentrations higher than 1 microM caused a smaller increase in pregnenolone formation. Flunitrazepam. a benzodiazepine that binds with high nanomolar affinity to MBR. was recently shown to act as an antagonist of ACTH and LH/hCG-induced steroidogenesis and was found in the present studies to inhibit DBI-stimulated mitochondrial steroidogenesis. During the incubation with mitochondria. DBI was partially processed to different peptide fragments. including octadecaneuropeptide and TTN. To determine whether DBI processing products influence mitochondrial steroid biosynthesis. several DBI fragments and other peptides structurally unrelated to DBI were tested. Among these. only TTN stimulated mitochondrial steroid synthesis in a dose-dependent manner similar to DBI.
Activation of the pituitary-adrenocortical axis in day-old rats by insulin-induced hypoglycemia, Most newborn mammals. including humans. are susceptible to neonatal hypoglycemia shortly after birth. especially if fasted. Glycogenolysis provides short term benefit. but gluconeogenesis is required for glucose homeostasis at this stage of development. A functional hypothalamic-pituitary-adrenocortical (HPA) axis is essential for glucose homeostasis in adults. but little is known of the importance of this endocrine axis in this regard during the neonatal period. The neonatal rat is an excellent model for study of both glucose metabolism and the HPA. and shares many similarities with other mammals. For the first 2 weeks of postnatal life. the rat HPA appears to be relatively unresponsive to stress. however. which would seem maladaptive during the critical first 24 h. The present study examined the ability of day-old rats to respond to hypoglycemia with activation of the HPA system. Each of three doses of insulin resulted in hypoglycemia (glucose. less than 40 mg/dl). with the greatest decrease in glucose 120 min after an insulin dose of 2.5 U/kg BW. At this dose. plasma corticosterone was increased to levels comparable to those observed in adults. The steroid response was associated with a small but significant increase in ACTH. and both endocrine responses were delayed compared to those in adults. There was no difference in adrenal response time to ACTH in incubations of adrenal cells isolated from day-old or adult rats. however. The stimulatory effect of insulin was progressively diminished in older animals (2-6 days postnatal). Insulin had no direct effect on adrenal steroidogenesis either alone or in combination with ACTH when tested on dispersed cells in vitro. We conclude that 1) the adrenal gland is very sensitive to the stress of hypoglycemia for 1 day after birth. but rapidly declines in activity over the first 6 days of life; 2) the response time of the HPA axis to hypoglycemia stress is delayed in day-old rats. and this delay occurs above the level of the adrenal; and 3) there may be factors in addition to ACTH that promote steroidogenesis on the first postnatal day. or there may be bioactive or immunoreactive differences in the ACTH molecule during this time.
Two distinct effects of recombinant human tumor necrosis factor-alpha on osteoclast development and subsequent resorption of mineralized matrix, The multifunctional cytokine tumor necrosis factor-alpha (TNF alpha) stimulates osteoclastic resorption. It is not known which steps in osteoclast formation are affected by TNF alpha. We have investigated the effects of recombinant human TNF alpha (rhTNF alpha) on osteoclast development and osteoclastic resorption in two different in vitro resorption systems which are each characterized by a different stage of development of the osteoclast. The effects were further compared to those of bovine PTH-(1-84). rhTNF alpha at concentrations between 0.01-50 ng/ml (3 x 10(-13) to 1.5 x 10(-9) M) did not alter the activity of mature osteoclasts. measured as 45Ca release in fetal mouse radii. In the osteoclast precursor-dependent system (fetal mouse metacarpals) rhTNF alpha had a biphasic effect. It stimulated resorption dose-dependently from 0.01 ng/ml onward. with a maximal response at 0.5 ng/ml. At concentrations above 10 ng/ml rhTNF alpha. resorption was inhibited. In experiments in which irradiation was used to block replication. it was found that TNF alpha stimulates the proliferation of osteoclast progenitors at both low and high concentrations. As a result. at relatively low concentrations. more osteoclasts were formed in the calcified matrix. coinciding with an increased release of 45Ca. However. at relatively high concentrations. the increase in osteoclast progenitors did not lead to increased resorption. since the putative osteoclast progenitors were arrested in the periosteum. In comparison. bovine PTH-(1-84) stimulated resorption independent of proliferation by enhancing the differentiation of postmitotic osteoclast precursors and activating mature osteoclasts. In conclusion. the effects of TNF alpha on osteoclastic resorption are dependent on the stage of osteoclast development and the concentrations applied.
Population density alters the responsiveness of GH4C1 pituitary tumor cells to 17 beta-estradiol, In this study we have examined the effect of population density on the ability of 17 beta-estradiol (E2) to induce PRL mRNA. DNA synthesis. and progesterone receptor in GH4C1 pituitary tumor cells. These parameters were examined at three subconfluent population densities that varied over a 4-fold range. The culture medium was changed daily in these experiments to reduce the possibility of nutrient depletion. medium toxification. or E2 metabolism. At the low population density. a 5-day treatment with E2 at a concentration of 1.0 nM resulted in an 8.1-fold increase in the level of PRL mRNA. as measured by the cytosolic dot blot procedure. At the intermediate density. E2 induced PRL mRNA 2.4-fold. At the high density. the level of PRL mRNA was reduced by 50% in response to 5 days of treatment with E2. The cytosolic dot blot procedure would reflect changes in the level of PRL mRNA per cell as well as changes in the number of cells per culture. Therefore. the level of beta-actin mRNA was also measured. assuming that it would remain constant on a per cell basis. When the level of PRL mRNA was normalized to the level of beta-actin mRNA in the same cytosols. E2 increased PRL mRNA 2.6-fold in the low density cultures and 1.9-fold in the intermediate density cultures. and had no effect on the level of PRL mRNA in the high density cultures. The effect of population density on the induction of GH4C1 cell proliferation by E2 was examined directly by measuring cellular DNA. thymidine incorporation by whole cells. and deoxythymidine triphosphate (dTTP) incorporation by isolated nuclei. At the low density. E2 initially stimulated GH4C1 cell proliferation. as evidenced by an increased rate of dTTP incorporation. However. this stimulatory effect was lost by day 5 of treatment. as the population density of the E2-treated low density cultures increased. At the high density. the inhibitory effect of E2 on dTTP incorporation was observed by day 2 of treatment and thereafter become more pronounced. These stimulatory and inhibitory effects of E2 were also revealed when the level of cellular DNA was measured. In contrast to the effects of population density on the induction of PRL mRNA and cell proliferation. an increase in density had no observable effect on the induction of progesterone receptor by E2. These data illustrate the critical importance of the culture environment in studies examining estrogen action in vitro.
Antibodies to cytoplasmic sequences of cloned liver growth hormone (GH) receptors recognize GH receptors associated with tyrosine kinase activity, GH stimulates tyrosyl phosphorylation of GH receptors in 3T3-F442A fibroblasts. and highly purified GH receptor preparations exhibit tyrosine kinase activity. Paradoxically. however. the GH receptor cloned from liver exhibits no sequence similarity to receptors with known signal transduction mechanisms. including those exhibiting ligand-activated tyrosine kinase activity. These observations raise the possibility that there are two kinds of receptors for GH: the first represented by the cloned liver GH receptor. and the second by a tyrosine kinase-containing GH receptor. To inquire into the possibility of two distinct GH receptors. we determined whether the cloned liver GH receptor shares structural similarities with the tyrosine kinase-associated GH receptor. When the cloned rabbit liver GH receptor is expressed in human kidney 293 cells. it migrates with a mol wt appropriate for the tyrosine kinase-associated GH receptor. despite the calculated mol wt of the cloned GH receptor being 60.000 smaller than that of the tyrosine kinase-associated GH receptor. The recognition of tyrosine kinase-associated GH receptor by antipeptide antibodies to three different epitopes on the cytoplasmic domain of the cloned liver GH receptor was also tested. Tyrosyl phosphorylated [125I]human GH-receptor complexes were prepared by immunoprecipitation with phosphotyrosyl-binding antibody; this subpopulation of GH-receptor complexes was recognized by all three antipeptide antibodies. The antibodies also recognized similarly isolated tyrosyl phosphorylated GH-receptor complexes. which had been further phosphorylated in solution on tyrosyl residues upon addition of [gamma 32P] ATP. Furthermore. highly purified GH receptors prepared by sequential immunoprecipitation using phosphotyrosyl-binding antibody and any one of the three antipeptide antibodies incorporated 32P into tyrosyl residues upon the addition of [gamma 32P] ATP. These results provide evidence that tyrosine kinase-associated GH receptors share sequence similarity in the cytoplasmic domain with the cloned liver GH receptor. The cloned GH receptor and the tyrosine kinase-associated GH receptor. therefore. are likely to be the same receptor or related receptor isoforms.
Human galanin: molecular cloning reveals a unique structure, Galanin. a novel neuropeptide/hypothalamic hormone originally identified and isolated by virtue of its carboxy-terminal amide group. has recently been shown to have a diverse range of biological activities. including potent effects on the secretion of insulin and growth hormone. The physiological role of galanin remains unclear. with different effects being observed when porcine and rat galanin have been used in various animal model systems and in human studies. Molecular cloning of cDNA encoding human galanin and galanin mRNA associated peptide (GMAP) from both pituitary and neuroblastoma sources has revealed a unique and unexpected structure. In contrast to porcine. bovine and rodent galanin. human galanin lacks a carboxy-terminal amide. By analogy to other neurohormones. the absence of carboxy-terminal amidation would be expected to have significant effects on functional properties such as affinity for different receptor subtypes and physiological half life. and may be responsible for the species specificity observed in the action of galanin.
Dutch general practice care for patients with epilepsy: results from the Dutch National Survey of Morbidity and Interventions, This study aimed to assess the share which Dutch general practice has in the care of patients with epilepsy. During a 3-month period 400.000 patient contacts in 103 general practices with a total list of 335.000 patients were registered. 1536 of these. concerning 1059 patients. concerned epilepsy. Contacts with patients with known epilepsy in Dutch General Practice were handled mainly by the practice nurse and most involved repeat prescriptions. Patients suspected of having epilepsy had more attention from the General Practitioner. The involvement of General Practitioners in the care of epilepsy was found to be small. but not unimportant. GPs are in a crucial position as regards the detection of epilepsy. They can enlarge their role in respect of patients with known epilepsy and improve continuity of care.
Fever: management and self-medication. Results from a Norwegian population study, A representative sample of the Norwegian population was interviewed in 1988 as part of a monthly national opinion poll to investigate lay management and self-medication of fever. Six hundred and nineteen women and 592 men over the age of 15 were interviewed in their homes. Approximately one-fifth reported inappropriate measuring of body temperature. A variety of management and self-medication was found. In cases of common cold or influenza with fever. 35% would use antipyretics. Forty per cent would start to use antipyretics at a temperature below 39.0 degrees C. Forty-four per cent did not know any antipyretic brand names at all. The results indicate a need for more definite and consistent information to make fever management and self-medication more rational. Such information should be discussed and given by general practitioners. nurses at child welfare centers and pharmacists.
Increased expression of intercellular adhesion molecule 1 on bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis, It has been suggested that immunological mechanisms involving lymphocyte-mediated damage are important in the characteristic bile-duct damage that occurs in primary biliary cirrhosis and primary sclerosing cholangitis. Because adhesion is necessary for the interaction of lymphocytes with their target structures. we have studied the expression of intercellular adhesion molecule 1. a ligand for the leukocyte adhesion receptor lymphocyte function-associated antigen 1 in the liver of patients with primary biliary cirrhosis and primary sclerosing cholangitis. Strong expression of intercellular adhesion molecule 1 was seen on interlobular bile ducts and proliferating bile ductules in both conditions. In primary biliary cirrhosis. medium-sized ducts. which are spared by the disease. were negative. Minimal bile-duct staining was seen in conditions in which bile-duct damage is not a major feature. such as nonbiliary cirrhosis and acute liver diseases. In patients with cirrhosis from any cause. strong expression of intercellular adhesion molecule 1 was detected on the periseptal hepatocytes adjacent to new connective tissue. The intensity of immunohistochemical staining was recorded using a semiquantitative visual scoring system that was subsequently validated quantitatively by confocal laser scanning microscopy. The expression/induction of intercellular adhesion molecule 1 on bile ducts may be important in the pathogenesis of bile-duct damage in primary biliary cirrhosis and primary sclerosing cholangitis and is further evidence to support an immune pathogenesis in these two conditions. Furthermore. the induction of intercellular adhesion molecule 1 on hepatocytes may be an important factor in the liver-cell damage and fibrosis that occur during the development of cirrhosis.
Effect of insulin and plasma amino acid concentration on leucine metabolism in cirrhosis, Clinically stable patients with cirrhosis demonstrate insulin resistance with regard to glucose metabolism. However. much less is known about the two major factors. insulin and plasma amino acid concentration. that regulate protein metabolism in cirrhotic patients. To examine this question. we performed paired euglycemic insulin clamp studies in combination with 14C-leucine and indirect calorimetry. In the first study insulin alone was infused. and the plasma amino acid concentration was allowed to decline. During the second study a balanced amino acid solution was infused with insulin to increase the total plasma amino acid concentration approximately twofold. Insulin-mediated glucose disposal (4.68 vs. 6.45 mg/kg-min. p less than 0.01) was significantly impaired by 30% in cirrhotic patients during both insulin clamp studies. In the postabsorptive state. cirrhotic patients manifested low plasma leucine (76 vs. 102 mumol/L) and alpha-ketoisocaproate (19 vs. 30 mumol/L) concentrations. but all parameters of leucine turnover were normal. When insulin alone was infused. the endogenous leucine flux (an index of protein degradation) declined similarly in cirrhotic patients (30.8 mumol/m2-min) and control (26.9) subjects. and this was accompanied by a similar decrease in plasma leucine concentration (31% vs. 33%). The decline in circulating leucine concentration was accompanied by a parallel decline in leucine oxidation (5.1 vs. 4.6 mumol/m2-min) and nonoxidative (28.9 vs. 26.0 mumol/m2-min) leucine disposal. which were of similar magnitude in cirrhotic patients and control subjects. respectively. In both cirrhotic patients and control subjects. combined hyperinsulinemia/hyperaminoacidemia elicited a similar stimulation of nonoxidative leucine disposal (an index of protein synthesis) and leucine oxidation while causing a greater suppression of endogenous leucine flux than observed with insulin alone. Thus the suppressive effect of insulin on protein degradation and the stimulatory effect of insulin/amino acid infusion on protein synthesis are not impaired in cirrhotic patients. demonstrating a clear-cut dissociation between the effects of insulin on protein and glucose metabolism.
Distribution of dihydrolipoamide acetyltransferase (E2) in the liver and portal lymph nodes of patients with primary biliary cirrhosis: an immunohistochemical study, The reason for the close association between primary biliary cirrhosis and the appearance of antibodies that recognize the E2 component of pyruvate dehydrogenase complex is not understood. The distribution of the three pyruvate dehydrogenase complex subunits was examined in the liver and lymph nodes of patients with primary biliary cirrhosis. patients with other liver diseases and normal subjects by immunohistochemistry using affinity-purified antibodies. Intensity of staining was assessed semiquantitatively and validated by scanning laser confocal microscopy. In primary biliary cirrhosis tissue. the E2 staining pattern did not parallel the reported distribution of mitochondria. E2 staining in biliary epithelial cells was consistently stronger than in hepatocytes. In primary biliary cirrhotic liver. staining of biliary epithelium was significantly stronger than in normal or other liver disease controls; many bile ducts in primary biliary cirrhotic liver demonstrated very high intensity. diffuse distribution of stain. No differences in staining intensity were seen between perivenular hepatocytes in primary biliary cirrhotic liver and those in controls; periportal hepatocytes in primary biliary cirrhotic liver were. however. more intensely stained than perivenular cells. In primary biliary cirrhotic portal lymph nodes. a subset of macrophages showed high-intensity. diffuse distribution of stain. By contrast. staining with antibodies to E1 and E3 (other components of pyruvate dehydrogenase complex) produced uniform-intensity. mitochondrial distribution both in primary biliary cirrhosis and control tissue. The increased intensity of E2 in primary biliary cirrhotic tissue could be explained in terms of abnormal metabolism of E2 by biliary epithelial cells.
Quantitative evaluation of parenchymal liver cell volume and total hepatocyte number in cirrhotic patients, A simple morphometrical method was developed using a color image analyzing system. which allowed quantitative evaluation of parenchymal liver cell volume and total hepatocyte number in cirrhotic patients. With this method. we estimated these values in 29 cirrhotic patients who underwent hepatic resection (nine cases) or nonshunting operation (20 cases). Liver volume. calculated from computed tomographic images. was 976 +/- 196 cm3 (range = 602 to 1.376 cm3); the parenchymal cell volume ratio. obtained based on liver histological appearance with silver stain. was 0.665 +/- 0.092 (range = 0.510 to 0.881); and the parenchymal cell volume. calculated by multiplying the liver volume with the parenchymal cell volume ratio. was 645 +/- 140 cm3 (range = 403 to 936 cm3). The total hepatocyte number obtained in a similar manner using hematoxylin-stained specimens was 1.72 +/- 0.56 x 10(11) (range = 0.74 to 2.94 x 10(11)). The validity and applicability of the method is discussed. and the data are compared with those reported in other studies.
The lack of relationship between hepatotoxicity and lithocholic-acid sulfation in biliary bile acids during chenodiol therapy in the National Cooperative Gallstone Study, To test whether hepatotoxicity occurring in National Cooperative Gallstone Study patients was caused by a toxic effect of chenodiol per se or of lithocholate caused by defective sulfation. bile samples were analyzed using a new high-performance liquid chromatography method that measures the proportions of the four individual lithocholate amidates (sulfated and unsulfated lithocholylglycine and lithocholyltaurine) and all common bile acid amidates. Samples were obtained from National Cooperative Gallstone Study patients (n = 17) with abnormal light microscopic liver biopsy results or major aminotransferase elevations and from a matched control group of patients (n = 14) who received similar chenodiol doses but had no evidence of liver injury. Bile samples from 45 healthy subjects were also analyzed. The analytical method was validated by showing that the percentage of chenodiol and cholic and deoxycholic acid obtained by high-performance liquid chromatography correlated highly (r greater than 0.94) with previous gas-liquid chromatography analyses of these samples by the National Cooperative Gallstone Study Reference Laboratory. No significant differences were seen between gallstone patients with and without evidence of liver injury for percent total lithocholate amidates. percent sulfated or unsulfated lithocholate amidates or percent chenodiol amidates. Lithocholate was partially sulfated in all bile samples (52% +/- 17% [mean +/- S.D.. n = 50]). but the extent of sulfation varied widely between and within patients during the course of therapy. Mean values of healthy subjects were similar and also showed a wide range in the extent of lithocholate sulfation. It is concluded that (a) liver injury caused by these doses of chenodiol could not be attributed to the accumulation of unsulfated lithocholate per se in circulating bile acids; (b) liver injury appeared to be. directly or indirectly. caused by enrichment in circulating bile acids with chenodiol or chenodiol together with lithocholate. suggesting that the hepatocytes of those patients with hepatotoxicity were injured by the change induced in bile-acid metabolism by the feeding of chenodiol; and (c) about half of lithocholate amidates in bile samples were sulfated. but the extent of sulfation was highly variable both in gallstone patients and healthy subjects.
Are patients with primary biliary cirrhosis hypermetabolic? A comparison between patients before and after liver transplantation and controls, Wasting is common in end-stage primary biliary cirrhosis and causes concern in patients facing liver transplantation. We have quantified resting metabolic rate and diet-induced thermogenesis in seven patients with primary biliary cirrhosis. in seven patients after liver transplantation who had previously been diagnosed as having primary biliary cirrhosis and in seven controls. Resting metabolic rate was elevated in the primary biliary cirrhosis group (4.44 +/- 0.81 kJ/hr/kg body wt; mean +/- S.D.) compared with the post-liver-transplantation group (3.39 +/- 0.40 kJ/hr/kg body wt) (p less than 0.005) and compared with control subjects (3.65 +/- 0.23 kJ/hr/kg body wt) (p less than 0.01). A highly significant relationship was found between the severity of liver disease in the primary biliary cirrhosis group. as assessed by Child-Pugh score. and the resting metabolic rate group (r = 0.93; p less than 0.005). After a liquid meal (41 kJ/kg body wt). the metabolic rate increased. with similar peak changes from baseline occurring in all three groups. However. the rise persisted significantly longer in the primary biliary cirrhosis patients. and thus the integrated mean postprandial energy expenditure over the 4-hr postprandial observation period was greater in the primary biliary cirrhosis group than in the other two groups (p less than 0.001).
Histological and morphometrical indicators for a biopsy diagnosis of well-differentiated hepatocellular carcinoma, Among 597 patients with nodular hepatic lesions who underwent ultrasonically guided needle biopsy. 305 were histologically confirmed as having hepatocellular carcinoma. and 37 patients had borderline lesions. Histological reexamination was correlated with morphometrical analysis on selected cases of well-differentiated. microtrabecular hepatocellular carcinomas (n = 29). borderline lesion (n = 10). typical (mid-sized and macrotrabecular) hepatocellular carcinomas (n = 15) and cirrhotic liver tissue obtained from extranodular hepatic parenchyma of hepatocellular carcinoma patients (n = 47). Morphometrical analyses revealed that the mean cell size and nucleocytoplasmic ratio were most useful for distinguishing well-differentiated. microtrabecular hepatocellular carcinoma from cirrhosis. These two parameters were well correlated with nuclear density. The grade of nuclear density. therefore. seemed to be a convenient semiquantitative indicator for diagnosing well-differentiated hepatocellular carcinoma. A comparison between intranodular and extranodular hepatic tissues was particularly important for its assessment. It is concluded from the results that hepatic nodules presenting a nuclear density larger than two times that of controls could be classified into the overt hepatocellular carcinoma group. From the statistical aspect. the possibility of microtrabecular hepatocellular carcinoma should be considered when a nodule has a nuclear density exceeding 1.3 times that of the extranodular tissue.
Systemic, splanchnic and renal hemodynamic effects of a dopaminergic dose of dopamine in patients with cirrhosis, The effects of dopamine on kidney function have not been elucidated in patients with cirrhosis. Moreover. although increased portal pressure has been observed with supradopaminergic doses of dopamine in these patients. the splanchnic hemodynamic effects of low doses of dopamine have not been previously studied. Thus we studied the acute systemic. splanchnic and renal hemodynamic effects of a dopaminergic dose of dopamine (1.5 micrograms/kg body wt min) in nine cirrhotic patients. Plasma dopamine levels increased markedly from 35 +/- 20 pg/ml to 31.400 +/- 4.900 pg/ml during dopamine administration. A significant diastolic pressure decrease of 10% was associated with a 15% increase in heart rate. Cardiac output was not altered. Although dopamine significantly increased azygos blood flow by 16%. wedged and free hepatic venous pressures were not altered. Dopamine significantly increased renal blood flow by 31%. but did not change the glomerular filtration rate. We conclude that a dopaminergic dose of dopamine increases azygos blood flow but not the hepatic venous pressure gradient. Finally. although it increases renal blood flow. dopamine does not seem to have any beneficial effects on glomerular filtration rate in cirrhotic patients.
Natural killer activity of human liver-derived lymphocytes in various liver diseases, Liver-derived lymphocytes were isolated from 40 human livers with end-stage liver disease that were removed at the time of orthotopic liver transplantation. In addition. 10 resection specimens or whole livers removed from patients with liver cancer and seven normal livers (unused donor organs) were studied as controls. Liver-derived lymphocytes were isolated from enzymatically digested tissue by gradient centrifugation and adherence to plastic. Their phenotypical characteristics were studied by two-color flow cytometry. and effector cell function was determined in 4-hr 51Cr-release assays against a natural killer-sensitive target. K562 (natural killer activity). natural killer-resistant Daudi line (lymphokine-activated killer activity) and by P815 line with or without phytohemagglutinin to assess lectin-dependent cellular cytotoxicity. Liver-derived lymphocytes isolated from normal liver contained equal proportions of T and natural killer lymphocytes (mean natural killer/T ratio = 0.7). CD3-CD56+CD16- natural killer cells were the main natural killer subset present in liver-derived lymphocytes. in contrast to the predominant natural killer phenotype in the circulation (CD56+CD16+). Control liver-derived lymphocytes had levels of cytotoxicity significantly greater than those of the normal peripheral-blood lymphocytes against all three targets. In contrast. liver-derived lymphocytes isolated from organs with advanced liver disease differed markedly in the natural killer/T cell ratio and levels of liver-derived lymphocyte cytotoxicity. Liver-derived lymphocytes obtained from hepatocellular carcinoma or rejecting allografts treated by immunosuppressive therapy had virtually no cytotoxicity.
Accurate prediction of death by serial determination of galactose elimination capacity in primary biliary cirrhosis: a comparison with the Mayo model, We retrospectively analyzed the predictive accuracy of serial determinations of galactose elimination capacity in 61 patients with primary biliary cirrhosis. Death was predicted from the time that the regression line describing the decline in galactose elimination capacity vs. time intersected a value of 4 mg.min-1.kg-1. Thirty-one patients exhibited decreasing galactose elimination capacity; in 11 patients it remained stable and in 19 patients only one value was available. Among those patients with decreasing galactose elimination capacity. 10 died and three underwent liver transplantation; prediction of death was accurate to 7 +/- 19 mo. This criterion incorrectly predicted death in two patients with portal-vein thrombosis; otherwise. it did better than or as well as the Mayo clinic score. The latter was also tested on our patients and was found to adequately describe risk in yet another independent population of patients with primary biliary cirrhosis. Cox regression analysis selected only bilirubin and galactose elimination capacity. however. as independent predictors of death. We submit that serial determination of galactose elimination capacity in patients with primary biliary cirrhosis may be a useful adjunct to optimize the timing of liver transplantation and to evaluate new pharmacological treatment modalities of this disease.
Effect of cyclosporine and steroids on canine bile flow, Cyclosporine and hydrocortisone are the main immunosuppressants used in transplant surgery. The purpose of this study was to determine the effect of intravenous administration of cyclosporine and hydrocortisone on bile flow in dogs. Cyclosporine in doses of 0.5. 1.0 and 1.5 mg.kg-1.hr-1 were administered along with 18 mumol/min intravenous sodium taurocholate to dogs with chronic biliary and gastric fistulas. Bile volume and bile chloride concentration and output were increased by cyclosporine in a dose-related manner. whereas bile salt concentration decreased and bile salt output was unchanged. Hydrocortisone produced small but significant increases in bile flow only at the highest dose of hydrocortisone administered. Subsequently. experiments were performed when sodium taurocholate was administered in progressively increasing doses (9. 18 and 36 mumol/min). with the dose changed every hour. Bile volume. [14C]erythritol clearance in bile and bile salt concentrations were measured with and without cyclosporine and hydrocortisone administration. Cyclosporine increased the bile salt-independent fraction of canalicular bile flow and ductular bile flow. Experiments evaluating the role of the cyclosporine carrier polyoxyethylated castor oil (Cremophor EL) demonstrated that this substance had no independent choleretic activity. whereas cyclosporine dissolved in ethanol and administered without Cremophor EL significantly increased bile flow. The results of this study indicate that cyclosporine stimulates chloride-rich choleresis independent of bile salt secretion.
Protection by 16,16-dimethyl prostaglandin E2 and dibutyryl cyclic AMP against complement-mediated hepatic necrosis in rats, 16.16-Dimethyl prostaglandin E2. a known cytoprotective agent. was examined for its ability to protect the liver against complement-mediated necrosis induced by an intravenous injection of a monoclonal antibody against a rat liver-specific antigen in rats. The hepatic injury induced by the antibody was characterized by (a) rapid development of numerous massive hemorrhagic foci of necrotic liver cells. (b) marked increases in serum liver enzyme activities and (c) pronounced reduction in the CH50 level. presumably as a result of complement consumption in the liver. Pretreatment with 16.16-dimethyl prostaglandin E2 at intraperitoneal doses of 20 and 100 micrograms/kg suppressed the hepatic injury. as evidenced by markedly mitigated liver-cell necrosis and much smaller increases in the serum-enzyme activities compared with the values in diseased control animals. The prostaglandin analogue failed to prevent serum complement consumption in response to the antibody injection or affect the CH50 level at the preinjury stage. indicating that neither complement inactivation nor interference with the antigen-antibody reaction was involved in the hepatic protection. The hepatoprotective doses of 16.16-dimethyl prostaglandin E2 produced a significant increase in liver cyclic AMP content in a dose-related manner. In addition. intravenous dibutyryl cyclic AMP at 3 and 10 mg/kg dose-dependently prevented histological and biochemical changes in the hepatic damage without altering the rate of reduction in serum complement activity. Like 16.16-dimethyl prostaglandin E2. dibutyryl cyclic AMP did not affect the preinjury CH50 level.
AIDS: debate on infection control guidelines shifts to Congress, When Congress reconvenes this month. it will consider several bills aimed at protecting patients from AIDS. The American Hospital Association is supporting one requiring states to adopt the recommendations of the Centers for Disease Control by regulation or legislation. But the Senate has also passed a punitive amendment. which many AIDS experts and providers oppose.
Radiographic detection of metal-induced synovitis as a complication of arthroplasty of the knee, Radiographs of eighteen patients who had had a diagnosis of metal-induced synovitis subsequent to a knee-replacement arthroplasty were retrospectively reviewed. The presence of a dense line outlining a portion of the capsule or articular surface of the knee joint (the so-called metal-line sign) was noted in association with wear in eleven patients. In the nine patients who had a positive sign and also had specimens available for histological examination. there was dense deposition of metal particles. whereas in the six patients who did not have a metal-line sign and had specimens available for histological examination. five had only a slight amount of metal in the synovial tissue and one. a moderate amount. The presence of the metal-line sign was associated with metal-induced synovitis in eleven of the eighteen patients. The sign should be useful in helping to make this diagnosis preoperatively in many patients.
Peripheral nerve lesions in hemophilia, Between 1962 and 1986. eighty-one of the 1351 admissions of patients who had hemophilia to the Nuffield Orthopaedic Centre were for peripheral nerve lesions. Eighty-eight such lesions were identified in fifty-four patients. and thirty-nine of these patients (sixty-one lesions) had adequate follow-up (mean. 8.4 years; range. four months to eighteen years). The femoral nerve was most commonly involved. but involvement of other peripheral nerves also occurred. In thirty (49 per cent) of the sixty-one lesions. the nerve had full motor and sensory recovery; in twenty-one (34 per cent). a residual sensory deficit; and in ten (16 per cent). both a persistent motor and sensory deficit. Patients who had antibodies to factor VIII were significantly less likely to recover full motor or sensory function than were those who did not have such antibodies. and the time to full motor recovery in these patients was significantly longer.
Blood loss after total knee replacement. Effects of tourniquet release and continuous passive motion, We prospectively studied the cases of 121 patients who were being operated on for insertion of a unilateral total knee prosthesis with cement. and we placed them randomly in four groups. In Group I. the tourniquet was inflated throughout the operative procedure. and we released it postoperatively after a compressive dressing had been applied; a splint was used postoperatively for three days. In Group II. the tourniquet remained inflated throughout the operation. but no splint was applied postoperatively. and continuous passive motion was started immediately in the recovery room. In Group III. the tourniquet was released intraoperatively. and hemostasis was achieved by cauterization; postoperatively. a compressive dressing was applied. and a splint was used for three days. In Group IV. the tourniquet was released intraoperatively. hemostasis was established. and then the tourniquet was reinflated; a compressive dressing was applied. and continuous passive motion was started immediately in the recovery room. Hemoglobin and hematocrit values were monitored in all patients. Blood loss in suction drainage was recorded. and the total blood loss was calculated. The results show that total knee arthroplasty is associated with major loss of blood (mean. 1518 milliliters). The calculated blood loss for Groups I. II. and III averaged 1443 milliliters. while that for Group IV averaged 1793 milliliters. Loss in suction drainage correlated with total estimated blood loss and averaged 511 milliliters. The magnitude of blood loss after total knee arthroplasty should be appreciated. and special attention should be paid to the availability of adequate fluid and blood products. preferably blood donated by the patient preoperatively.
Patellofemoral pain caused by overactivity. A prospective study of risk factors in infantry recruits, A prospective study of 390 infantry recruits revealed that the medial tibial intercondylar distance and that the isometric strength of the quadriceps. tested at 85 degrees of flexion of the knee. had a statistically significant correlation with the incidence of patellofemoral pain caused by overactivity. Increased medial tibial intercondylar distance and increased strength of the quadriceps were therefore deemed to be risk factors for this syndrome.
Prophylaxis against infection. Single-dose cefonicid compared with multiple-dose cefamandole, A total of 1489 patients were included in a prospective. randomized study that compared the efficacy of a single dose of cefonicid in 474 patients (Group I) with that of three doses of cefamandole in 510 patients (Group II) and five doses of cefamandole in 505 patients (Group III). for prophylaxis against infection after an operation on bone. The operations involved the insertion of a Moore prosthesis. an Ender and Kuntscher nail. a bone-plate. or another device for internal fixation. Patients who had an open fracture or a total joint replacement were not included in the study. The three groups were similar with regard to mean age. sex ratio. duration of preoperative hospitalization. underlying risk factors. and type of operation. The rates of wound infection were not significantly different in the three groups (p = 0.8) or when the rates were stratified according to the type of operation (p greater than 0.3). Staphylococcus aureus and gram-negative bacilli were the most common infecting microorganisms. The rate of mortality related to infection was similar in all three groups (p = 0.2). No adverse side-effects of drugs were encountered. A single preoperative dose of cefonicid. three doses of cefamandole. and five doses of cefamandole were equally effective prophylaxis against infection of the wound in these patients.
Lateral distraction injuries to the thoracic and lumbar spine. A report of three cases, Three patients sustained a lateral distraction injury to the thoracic or lumbar spine. These injuries were associated with multiple fractures of the ribs and extremities as well as with thoracic and abdominal visceral injuries. No patient had an injury to the spinal cord or cauda equina. The injuries to the spine were successfully treated with open reduction of the unilateral subluxation of the facet joint and with internal fixation with Harrington instrumentation. Fusion was achieved with the spine in anatomical alignment. without any complications. in all three patients.
Nerve palsy associated with total hip replacement. Risk factors and prognosis, We reviewed the results of 3126 consecutive total hip replacements and identified postoperative neuropathy in the ipsilateral lower extremity after fifty-three (1.7 per cent) over-all and after 1.3 per cent of the primary arthroplasties. The prevalence was 5.2 per cent after the primary arthroplasties that had been done for congenital dislocation or dysplasia of the hip and 3.2 per cent after the revisions (all diagnoses). Thus. these two types of operations were risk factors (p less than 0.01). Limb-lengthening only partially accounted for the increased prevalence of neuropathy after these procedures. The sciatic nerve was involved in all but five extremities. The cause of the palsy was unclear or unknown in thirty (57 per cent) of the extremities. When the patients were last seen. at a minimum of one year and a maximum of sixteen and one-half years after the operation. seven extremities were normal neurologically. thirty-three had a mild neurological deficit. and thirteen had a major deficit. All patients who had complete recovery of neurological function had it by twenty-one months. Of thirty-six extremities that were evaluated at a minimum of twenty-four months after the operation. seven were neurologically normal. twenty-three had a mild persistent deficit. and six had a major persistent deficit. The ability to walk decreased for all patients who had a nerve palsy. The greatest disability was in the patients who had been forty-eight years old or less and had had a primary total hip replacement (p = 0.037). The prognosis for neurological recovery was related to the degree to which the nerve was damaged.
Complications of a failed Bristow procedure and their management, The management of patients who have a failed Bristow reconstruction of the shoulder is very complex. In order to determine the complications that occur when a Bristow procedure fails. and how they should be managed. we retrospectively evaluated forty shoulders in thirty-nine patients who had been treated by the senior one of us for a failed Bristow procedure from 1977 to 1987. The complications of the index Bristow procedures included recurrent painful anterior instability. injury to the articular cartilage. failure of the coracoid bone-block to unite with the glenoid. loosening of the screw. neurovascular injury. and posterior instability. The primary etiology of failure of the index Bristow procedure was excessive laxity of the capsule in thirty-two shoulders (80 per cent) that were affected by chronic. painful anterior or posterior instability. An untreated Perthes-Bankart lesion was present in the remaining eight shoulders (20 per cent). The use of anterior reconstruction for the revision of a failed Bristow procedure is a difficult operation that necessitates meticulous technique. As our over-all plan of treatment resulted in a good or excellent outcome in only 50 per cent of the patients. we do not recommend the Bristow procedure for primary treatment of symptomatic anterior instability of the shoulder.
Repairs of the rotator cuff. Correlation of functional results with integrity of the cuff, We evaluated the results of 105 operative repairs of tears of the rotator cuff of the shoulder in eighty-nine patients at an average of five years postoperatively. We correlated the functional result with the integrity of the cuff. as determined by ultrasonography. Eighty per cent of the repairs of a tear involving only the supraspinatus tendon were intact at the time of the most recent follow-up. while more than 50 per cent of the repairs of a tear involving more than the supraspinatus tendon had a recurrent defect. Older patients and patients in whom a larger tear had been repaired had a greater prevalence of recurrent defects. At the time of the most recent follow-up. most of the patients were more comfortable and were satisfied with the result of the repair. even when they had sonographic evidence of a recurrent defect. The shoulders in which the repaired cuff was intact at the time of follow-up had better function during activities of daily living and a better range of active flexion (129 +/- 20 degrees compared with 71 +/- 41 degrees) compared with the shoulders that had a large recurrent defect. Similar correlations were noted for the range of active external and internal rotation and for strength of flexion. abduction. and internal rotation. In the shoulders in which the cuff was not intact. the degree of functional loss was related to the size of the recurrent defect.
Effect of gemfibrozil treatment in sulfonylurea-treated patients with noninsulin-dependent diabetes mellitus, This study was initiated to 1) assess gemfibrozil's ability to lower plasma triglyceride (TG) concentration in patients with NIDDM. and 2) determine whether this effect was associated with any changes in glycemic control. Measurements were made of mean hourly plasma glucose. insulin. TG. and FFA concentrations from 1200-1600 h in response to a test meal; hepatic glucose production (HGP); insulin-stimulated glucose uptake during a hyperinsulinemic glucose clamp study (MCR); and fasting plasma lipoprotein TG and cholesterol concentrations in 12 patients with NIDDM before and 3 months after gemfibrozil treatment. Although ambient plasma TG and FFA concentrations fell significantly. plasma glucose. insulin. HGP. concentrations fell significantly. plasma glucose. insulin. HGP. and glucose MCR did not change. However. when patients were divided into two groups. those with fasting plasma glucose levels above 9 mmol/L (fair control) and those with levels below 9 mmol/L (good control). a different phenomenon was observed. Patients in fair control had significant decreases in mean hourly plasma concentrations of glucose (15.1 +/- 1.7 to 12.6 +/- 0.9 mmol/L; P less than 0.001). insulin (523 +/- 59 to 471 +/- 75 pmol/L; P less than 0.001). FFA (652 +/- 150 to 504 +/- 76 mumol/L). and HGP (9.5 0.4 to 8.1 +/- 0.4 mumol/kg.min; P less than 0.005). and an increase in glucose MCR (2.63 +/- 0.49 to 3.72 +/- 0.54 mL/kg.min; P less than 0.07) in association with a fall in TG from 6.9 +/- 1.3 to 3.5 +/- 0.9 mmol/L (P less than 0.001). Although fasting low density lipoprotein cholesterol increased (1.8 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.05). the ratio of total to high density lipoprotein cholesterol decreased (6.84 +/- 0.88 to 5.80 +/- 1.05; P less than 0.02). Despite a significant fall in mean hourly TG concentration (4.6 +/- 0.7 to 3.8 +/- 0.7 mmol/L; P less than 0.001). neither insulin. FFA. HGP. nor glucose MCR changed in patients in good control. Furthermore. the mean hourly plasma glucose concentration increased from 9.2 +/- 0.7 to 11.7 +/- 1.4 mmol/L (P less than 0.001). Low density lipoprotein cholesterol also increased in this group (1.9 +/- 0.2 to 2.7 +/- 0.2 mmol/L; P less than 0.02). but. as before. the ratio of total to high density lipoprotein cholesterol decreased (8.15 +/- 1.93 to 6.36 +/- 1.03; P less than 0.02).
Calcium supplementation reduces vertebral bone loss in perimenopausal women: a controlled trial in 248 women between 46 and 55 years of age, To study the effect of calcium supplementation on perimenopausal bone loss. 295 women were randomized into a control group and 2 supplementation groups receiving. respectively. 1000 and 2000 mg elemental calcium/day for a period of 2 yr. We observed a significant decrease in lumbar bone loss in relation to the calcium supplementation (mean loss after 2 yr of 3.5% in the control group vs. 1.3% and 0.7% in the 1000 and 2000 mg groups. respectively). a significant increase in urinary calcium excretion. and a significant decrease in the urinary hydroxyproline/creatine ratio. serum alkaline phosphatase. osteocalcin. and 1.25-dihydroxyvitamin D. The effect of calcium supplementation on lumbar bone loss was significant in the first year of supplementation. but not in the second. However. the urinary hydroxyproline/creatinine ratio and the serum alkaline phosphatase level remained significantly decreased in the treatment groups at the end of the study; this was not the case for serum osteocalcin. Calcium supplementation did not have a significant effect on metacarpal cortical bone loss. The difference in biochemical parameters between the 2 supplementation groups was small. No significant interaction was observed between the menopausal status of the subjects and the effect of calcium supplementation. We conclude that calcium supplementation retards lumbar bone loss in the first year of calcium supplementation by reducing bone turnover. However. the effect on lumbar bone loss over a longer time span is still uncertain.
Hormonal responses during insulin-induced hypoglycemia in manic-depressed, unipolar depressed, and healthy control subjects, Early studies using the insulin tolerance test (ITT) in affective disorders reported a blunted GH response in some depressed patients. However. results from subsequent studies were less consistent. These discrepancies resulted in part from limited sample sizes causing diagnostic heterogeneity. In the present study we examined hormonal response patterns during the ITT in 25 bipolar patients (19 depressed and 6 hypomanic). 91 unipolar depressives. and 51 healthy volunteers to determine whether distinct neuroendocrine response patterns characterized specific diagnostic subgroups. We measured the glucose. GH. PRL. and cortisol responses during a 75-min ITT and observed a diminished cumulative GH response in bipolar hypomanic patients compared to bipolar depressives (P = 0.004) and healthy volunteers (P less than 0.001). and a larger cumulative GH response in bipolar depressives compared to unipolar patients (P = 0.02). No differences were observed in either PRL or cortisol responses among subject groups. The present findings suggest that GH responses during the ITT may be more complex than initially described and partially dependent upon affective disorder subtype. Thus. bipolar patients may have distinctive GH response patterns compared to those of unipolar depressives and healthy controls. Moreover. some of the difference observed in the GH response to the ITT may result from the phase of the manic-depressive illness. These data indicate differences in neuroendocrine substrates between affective disorder subtypes.
Acanthosis Nigricans, insulin action, and hyperandrogenism: clinical, histological, and biochemical findings, Acanthosis nigricans (AN) is a frequent clinical finding in hyperandrogenic women. Its presence has been used to subgroup such women. We performed this study in order to determine the actual histological prevalence of AN and its relationship to sex hormone levels and insulin action. Insulin-mediated glucose disposal was determined by the euglycemic clamp technique. and neck or axillary skin biopsies were graded blind for the presence and severity of AN in lean and obese women with the polycystic ovary syndrome (PCO) and in age- and weight-matched normal ovulatory controls. AN was present on clinical examination in 11 of 13 obese PCO. 3 of 6 lean PCO. 4 of 14 obese normal. and 0 of 4 lean normal women. AN was present on histological examination in 13 of 13 obese PCO. 5 of 6 lean PCO. 13 of 14 obese normal. and 1 of 4 lean normal women. The severity of histological AN was most highly correlated with insulin-mediated glucose disposal (r = -0.61; P less than 0.001) rather than fasting (r = 0.46; P less than 0.05) or glucose-stimulated insulin levels (r = 0.48; P less than 0.01). The only sex steroid correlated with histological AN was dehydroepiandrosterone sulfate (r = 0.46; P less than 0.01). We conclude that 1) clinical skin examination was very insensitive for detecting AN; 2) the best biochemical correlate of histological AN was decreased insulin action. rather than insulin or androgen levels per se; and 3) AN is a very common epiphenomenon of insulin resistance. and its clinical presence should not be used as a criterion for stratifying hyperandrogenic women.
The lack of nocturnal serum thyrotropin surge in patients with nontoxic nodular goiter may predict the subsequent occurrence of hyperthyroidism, TSH secretion. with particular regard to the nocturnal TSH surge. was evaluated in 115 subjects with non-toxic nodular goiter. All patients were clinically and biochemically euthyroid. After 18-36 months of follow-up (mean. 24 months). hyperthyroidism occurred in 21 (18%; group 1). while the remaining 94 remained euthyroid (82%; group II). The analysis of hormonal data at the time of first observation showed that the 2 groups had similar total and free T4 and T3 serum concentrations. Morning serum TSH values in group I were lower than those in group II patients (0.6 +/- 0.1 vs. 1.1 +/- 0.1 mU/L; P less than 0.001); this difference was even more striking for the nocturnal values (0.6 +/- 0.1 vs. 2.2 +/- 0.2 mU/L; P less than 0.0001); nocturnal values were significantly lower than morning values in group II. but not in group I. The mean peak TSH value after TRH was also significantly reduced in group I (5.5 +/- 0.4 vs. 9.2 +/- 0.7 mU/L; P less than 0.001). Morning TSH values in group II did not differ from those in controls (1.3 +/- 0.1 mU/L). whereas nocturnal and TRH stimulated peak TSH values were slightly but significantly lower. The nocturnal serum TSH values in control subjects were 62-390% higher than morning values. The nocturnal TSH surge was abolished in 18 of 21 (86%) group I patients and in 7 of 94 (8%) group II patients. TRH testing resulted in an absent or blunted TSH responses in 5 subjects in group I and 6 in group II. Analysis by the Galen and Gambino predictive model; comparing the abolition of the nocturnal TSH surge and the abnormal TRH test as predictors of the subsequent occurrence of hyperthyroidism. showed that the former had higher sensitivity (86% vs. 24%) and predictivity (72% vs. 45%). In conclusion. the results of the present study demonstrate that the evaluation of the nocturnal TSH surge may be useful in identifying patients with nontoxic nodular goiter in whom hyperthyroidism may eventually occur. Patients who lack the nocturnal serum TSH surge are more prone to develop thyroid hyperfunction; their thyroid status should. therefore. be more carefully and frequently monitored.
Preservation of pulsatile luteinizing hormone release during postpartum lactational amenorrhea, To evaluate the pulsatile mode of immunoactive LH release during physiological lactational amenorrhea. we withdrew blood samples at 10-min intervals for 24 h from breastfeeding women (n = 9) at both 3 weeks and 3 months postpartum. Nonlactating women (n = 7) were sampled similarly in the early follicular phase of the normal menstrual cycle. Objective LH pulse analysis revealed that the mean frequencies of pulsatile LH release were similar at both times postpartum and in menstruating young women. By 3 months postpartum. mean serum PRL concentrations had declined 50%. and serum LH peak areas doubled. In contrast. LH interpulse interval. peak duration. and maximal. incremental. and fractional LH pulse amplitude did not change significantly. When deconvolution analysis was used to assess pituitary responses to two pulses of exogenous GnRH at 3 months (vs. 3 weeks) postpartum. we found significant increases in maximal LH secretory rates and the total mass of LH secreted. There was no change in the duration or timing of the evoked LH secretory burst and/or the estimated half-life of endogenous LH. In summary. during lactational amenorrhea. pulsatile LH release occurs at a mean frequency no different from that in the normal early follicular phase. As hyperprolactinemia wanes. there is increased pituitary responsiveness to exogenously administered GnRH and a doubling of spontaneous serum LH concentration peak areas. Such amplitude changes are consistent with the hypothesis of increased endogenous GnRH drive (e.g. augmented GnRH secretion per burst and/or increased pituitary responsiveness to available GnRH) during recovery of the postpartum hypothalamopituitary-ovarian axis.
Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow, To define the kinetic mechanisms of insulin resistance (IR) in insulin-dependent diabetes (IDDM). we studied seven control (C) and five IDDM (glycohemoglobin. 14 +/- 2+) men matched for age (36 +/- 2 vs. 37 +/- 3 yr). lean body mass (59 +/- 2 vs. 58 +/- 3 kg). and leg volume (mean +/- SEM. 10.4 +/- 0.3 vs. 9.8 +/- 0.5 L). Maximal capacity (Vmax) and affinity (Km) for glucose uptake in whole body (WBGU) and leg skeletal muscle (LGU) were measured during a 120 mU/m2.min insulin infusion. and blood glucose was clamped at about 4. 7. 12. and 21 mmol/L. LGU = femoral arterio-venous glucose difference (FAVGD) X leg blood flow (LBF). Compared to C. IDDMs had about 35% lower rates of WBGU at all glucose levels (P less than 0.01). The FAVGD (millimoles per L) in C vs. IDDM was 1.23 +/- 0.05 vs. 1.06 +/- 0.09. 2.44 +/- 0.11 vs. 2.24 +/- 0.16. 2.91 +/- 0.18 vs. 2.91 +/- 0.30. and 3.27 +/- 0.12 vs. 3.35 +/- 0.4 (P = NS at each glucose). LBF (decaliters per min) was reduced in IDDM vs. C [2.8 +/- 0.5 vs. 4.3 +/- 0.4 (P less than 0.05). 3.1 +/- 0.4 vs. 5.1 +/- 0.7 (P less than 0.05). 2.7 +/- 0.2 vs. 6.3 +/- 0.8 (P less than 0.01). and 3.1 +/- 0.7 vs. 6.5 +/- 0.8 (P less than 0.01) at each glucose level]. Kinetic analysis revealed that 1) the Vmax for WBGU and LGU were reduced in IDDM vs. C (P less than 0.05). and 2) the Vmax for skeletal muscle glucose extraction (FAVGD) was identical in C and IDDM (3.6 mmol/L). The Km values for WBGU. LGU. and glucose extraction were not different in C and IDDM (approximately 6 mmol/L). Thus. in IDDM 1) decreased glucose uptake is due to reduced skeletal muscle glucose uptake; 2) muscle glucose extraction is normal. but blood flow is reduced; and thus. 3) in IDDM. IR is due to reduced glucose and insulin delivery (blood flow) to skeletal muscle. This represents a novel mechanism for in vivo IR.
Structural aberration of the rough endoplasmic reticulum and melanosome compartmentalization in long-term cultures of melanocytes from vitiligo patients, Long-term cultures of melanocytes were established from 14 subjects with vitiligo and from five normal controls and analyzed ultrastructurally. Cultured melanocytes from 78.6% of the vitiligo patients demonstrated abnormalities that consisted of 1) dilation of the rough endoplasmic reticulum (RER). 2) circular RER profiles. and/or 3) membrane bound compartments of melanosomes. Cultured melanocytes from control subjects were predominantly normal with only one of the normal cultures demonstrating minimal circular RER profiles. The three unique abnormal structures in cultured vitiligo melanocytes were not always concomitantly expressed and could not be associated with any specific clinical feature of vitiligo. Quantitative analysis of the RER demonstrated that the profiles of dilated RER in cultured vitiligo melanocytes expressed a significant 1.5-2.8-times increase in mean cisternal area over cultured control melanocytes (i.e.. 5.41-9.92 microns 2 versus 3.53 microns 2. respectively). The cisterna of the dilated RER profiles frequently contained floccular material that appeared to originate from the ribosomes. an indication that the floccular material may be translation products. The dilation of RER in melanocytes from the same patient persisted through repeated subculturing for up to 14.75 months. Epidermal melanocytes in biopsied skin from a patient whose cultured melanocytes were aberrant also demonstrated dilated and circular RER profiles. These results demonstrate that melanocytes from most vitiligo patients express an innate defect when cultured. Although this defect does not appear to be cytotoxic in vitro. this abnormality may be the primary defect that elicits melanocyte destruction in vivo.
Detection of Epstein-Barr virus-DNA in tongue epithelium of human immunodeficiency virus-infected patients, Oral hairy leukoplakia is a lesion on the lateral part of the tongue that contains replicating Epstein-Barr virus (EBV) and presages progression from human immunodeficiency virus (HIV) infection to AIDS. To clarify the role of EBV in the development of the lesions. we used filter in situ DNA hybridization to determine the prevalence of EBV and of human papillomavirus (HPV) in epithelial cells obtained on swabs from the tongue of HIV-infected patients who had hairy leukoplakia. HIV-infected patients who did not have hairy leukoplakia. and healthy uninfected control persons. In samples collected from the 35 uninfected control persons. EBV DNA could not be detected except at low concentrations in three people. In contrast. all but one of the samples from 11 HIV-infected patients who had hairy leukoplakia contained EBV DNA. Of greatest interest. in 19 of 32 HIV-infected patients who had no signs of hairy leukoplakia. EBV DNA was also detected on the epithelium of the tongue. DNA filter in situ hybridization for the detection of HPV serotypes 6. 11. 16. and 18 in all cases yielded negative results. Statistical analysis showed that the presence of EBV DNA was significantly correlated with the clinical status of the HIV-infected persons. as determined by Walter Reed staging classification. whereas hairy leukoplakia was not. It is concluded that detection of EBV DNA in oral epithelium may be an earlier and more powerful predictor of progression to AIDS than is hairy leukoplakia.
Tumor-infiltrating CD3- NK cells are more effective than CD3+ T cells in killing autologous melanoma cells, We have studied the phenotype and functional activity of tumor-infiltrating lymphocytes (TIL) derived from eight human melanomas cultured for up to 60 d in the presence of recombinant IL-2. In the early period of the cultures. TIL were predominantly T cells of CD8+ phenotype and contained 10-30% of CD3- cells. Four of the five early TIL cultures tested in a cytotoxicity assay displayed a degree of MHC-unrestricted lysis on a series of autologous and allogenic melanoma cell lines as well as the K562 natural killer-sensitive target. With longer periods of time in culture. all TIL lines showed a decrease in lytic activity that was associated with the loss of CD3- cells. Thus. most of the killing of short-term TIL cultures appeared to be mediated by CD3- natural killer cells. whereas CD3+ T cells were found to be weak anti-tumor effectors. Even though the CD3+ T cells were not cytotoxic on K562 targets. their lytic activity (even weak) against melanoma cells appeared to be non-MHC restricted. and was blocked by anti-CD3 antibodies. In addition. cytotoxicity of the CD3+ TIL cultures was compared to that of a CD3-/NKH1+ cell line purified from peripheral blood. It was found that natural killer cells were much more potent than CD3+ TIL on the melanoma cell lines tested.
Squamous carcinoma cell lines produce 1,25 dihydroxyvitamin D, but fail to respond to its prodifferentiating effect, The active metabolite of vitamin D3. 1.25 dihydroxyvitamin D3 [1.25(OH)2D]. is produced by normal human keratinocytes (NKC) and regulates their differentiation. Squamous carcinoma cell (SCC) lines lack the ability to differentiate in vitro. which might involve defective 1.25(OH)2D synthesis or response. To address this possibility we obtained four SCC lines (12F2. 12B2. 25. and A431) and first determined whether they could produce 1.25(OH)2D from its substrate 25 hydroxyvitamin D3 (250HD). All could (12F2 greater than NKC greater than 25 greater than 12B2 greater than A431). Furthermore. exogenously added 1.25(OH)2D inhibited 1.25(OH)2D production and stimulated 24.25 dihydroxyvitamin D3 [24.25(OH)2D] production in all cell lines but with different potency (25 = A431 greater than NKC greater than 12B2 greater than 12F2). Cellular binding studies suggested that the high-affinity binding site for 1.25(OH)2D in NKC is not found in 12F2 and 12B2. When the effect of 1.25(OH)2D on differentiation was determined. only NKC responded with an increase in cornified envelope formation. although some of the cell lines responded to the proliferative [at low 1.25(OH)2D concentration] or antiproliferative [at high 1.25(OH)2D concentration] effect of 1.25(OH)2D. Thus. although SCC lines synthesize 1.25(OH)2D and respond to exogenous 1.25(OH)2D with respect to appropriate regulation of endogenous 250HD metabolism. these cell lines fail to respond to the differentiating influence of this vitamin D metabolite.
T-lymphocyte-activating properties of epidermal antigen-presenting cells from normal and psoriatic skin: evidence that psoriatic epidermal antigen-presenting cells resemble cultured normal Langerhans cells, Fresh and cultured human Langerhans cells display disparate functional programs. based on their capacities to activate autologous and allogeneic T cells. and with respect to their susceptibility to inhibition by transforming growth factor-beta (TGF beta). We have compared the functional properties of epidermal antigen-presenting cells (APC) procured from uninvolved and involved skin of patients with psoriasis with fresh and cultured normal epidermal cells. Freshly obtained psoriatic epidermal APC resembled cultured normal epidermal cells in their superior capacity to activate syngeneic and allogeneic T cells; fresh normal epidermal cells failed to activate syngeneic T cells. and induced only modest proliferation among allogeneic T cells. The modest T-cell--activating properties of fresh. normal epidermal cells were not suppressed by TGF beta. whereas the T-cell--activating potential of psoriatic epidermal cells. cultured normal epidermal cells. and blood APC was inhibited approximately 50% by TGF beta. Thus. fresh psoriatic epidermal APC resemble cultured normal epidermal cells functionally. Because these properties are already evident in cells obtained from uninvolved psoriatic skin. the "cultured" functional phenotype of epidermal APC in this disease may precede the appearance of active psoriatic skin lesions. Surface marker analysis of normal and psoriatic epidermal cell suspensions revealed that virtually all of the bone marrow--derived cells in normal epidermal cell suspensions were conventional (CD1+) Langerhans cells. whereas CD1+ cells comprised only a minority of bone marrow--derived (CD45+) cells in psoriatic epidermis. It is speculated that some of the CD1-. CD45+ cells in psoriatic epidermis may be Langerhans cells that have lost their "fresh" phenotype. These data indicate that an abnormality in epidermal APC function exists in psoriatic skin--even before clinical lesions develop. and we speculate that the abnormal capacity of psoriatic epidermal APC to activate syngeneic T cells may be important in the expression of keratinocyte pathology. Because psoriatic epidermal APC functions were profoundly inhibited in vitro by treatment with cyclosporin A. the effectiveness of this drug in psoriasis may be due in part to its ability to inhibit epidermal antigen-presenting cell function in vivo.
Collagen metabolism in cutis laxa fibroblasts: increased collagenase gene expression associated with unaltered expression of type I and type III collagen, Collagen metabolism was studied in cutis laxa by analyzing collagen and collagenase gene expression in three dermal fibroblast strains from patients with congenital cutis laxa and comparing them with fibroblasts obtained from age-matched healthy subjects. Normal collagen synthetic activity was observed in the cutis laxa fibroblasts. An increased level of collagenase mRNA and unaltered levels of alpha 1(I) and alpha 1(III) collagen mRNA were found in all cutis laxa cell strains by dot blot hybridization. Reduced levels of elastin mRNA were also detected in these strains. However. no qualitative differences in these mRNA transcripts were detected between the control and cutis laxa fibroblasts by Northern blot analysis. Collagenase activity in fibroblast culture supernatants was then measured using fluorescein isothiocyanate (FITC)-labeled type I collagen. Increased collagenolytic activity in cutis laxa fibroblast culture supernatants was also found. These data suggest that increased collagenase expression of fibroblasts is related to the structural abnormality of dermal connective tissue in cutis laxa.
Irradiation of protoporphyric mice induces down-regulation of epidermal eicosanoid metabolism, This study investigated the effect of radiation on clinical and histologic changes. and on cutaneous eicosanoid metabolism. in Skh:HR-1 hairless albino mice rendered protoporphyric by the administration of collidine. At 0.1-18 h after exposure to 12 kJ/m2 of 396-406 nm irradiation. thicknesses of back skin and ears were measured. and histologic changes were evaluated by using hematoxylin and eosin (H-E) and Giemsa's stains. Activities of eicosanoid-metabolizing enzymes in epidermal and dermal homogenates were assessed by incubating the tissue homogenates with 3H-AA. followed by quantitation of the eicosanoids generated by radio-TLC. In irradiated protoporphyric mice. an increase of back-skin thickness was noted at 0.1 h. reaching a peak at 18 h. whereas maximal increase in ear thickness was observed at 12 h. Histologic changes included dermal edema. increased mast cell degranulation. and mononuclear cells in the dermis. In these irradiated protoporphyric animals. generations of 6 keto-PGF1a. PGF2a. PGE2. PGD2. and HETE by epidermal eicosanoid-metabolizing enzymes were markedly suppressed at all the timepoints studied. Dermal eicosanoid-metabolizing enzymes of irradiated protoporphyric mice generated increased amounts of PGE2 and HETE at 18 h. probably reflecting the presence of dermal cellular infiltrates. The suppression of the activities of epidermal eicosanoid-metabolizing enzymes was prevented by intraperitoneal injection of WR-2721. a sulfhydryl group generator. prior to irradiation. suggesting that the suppression was secondary to photo-oxidative damage of the enzymes during the in vivo phototoxic response. These results suggest that the effect of protoporphyrin and radiation on cutaneous eicosanoid metabolism in this animal model in vivo is that of a down regulation of the activities of epidermal eicosanoid-metabolizing enzymes.
Blood mononuclear cells from patients with psoriasis exhibit an enhanced adherence to cultured vascular endothelium, Blood mononuclear cells (MNC) from patients with psoriasis were more adherent to monolayers of endothelial cells prepared from human umbilical cord vein than otherwise similar cells from control subjects. This increase in adherence occurred in the presence (mean 37% increase; p less than 0.01) and absence (mean 47% increase; p less than 0.05) of 10% autologous serum and was not related to the disease severity of the patients. The augmented adhesiveness of the patients' cells was also apparent when using monolayers of endothelial cells isolated from human skin. The levels of immune complexes. complement. alpha 2-macroglobulin. acute phase proteins (alpha 1-acid glycoprotein. C-reactive protein and alpha 1-antitrypsin). and tumor necrosis factor alpha (TNF alpha). interleukin-1 alpha (IL-1 alpha). and interleukin-1 beta (IL-1 beta) in the patients' sera were within normal limits. When MNC were added to endothelial monolayers that had been incubated with either TNF alpha or the highest concentration of rIL-1 beta used in the study. both the patients' and control's cells exhibited a similar increase in attachment (p less than 0.01). Pretreatment of endothelium with interferon-gamma did not enhance the attachment of MNC from either group of subjects. The augmented adherence of the patient's MNC appears to be due to an abnormal adhesiveness of the lymphocytes rather than the monocytes and is not related to an enhanced expression of the cell-surface adhesion molecules CD11a/CD18. It is likely that the circulating MNC of psoriatic patients may be predisposed for extravasation into skin.
CD36(OKM5)+ dendritic cells in the oral mucosa of HIV- and HIV+ subjects, In this study. we have investigated by light and electron microscopy the presence. distribution. and inner structure of CD36(OKM5)+ dendritic cells (DC) in the lamina propria and epithelium of the oral mucosa of HIV- and HIV+ subjects; in the latter. both clinically healthy areas and areas of hairy leukoplakia (HL) were studied. Perivascular CD36+ DC were present in the lamina propria of all the specimens studied. They were also found in small numbers in the epithelium of clinically healthy mucosa of HIV- and HIV+ subjects. but were practically absent from the epithelium of HL. CD36+ DC seemed to be regularly HLA-DR+ in HIV-subjects; this positivity was recognized only in some cells in the clinically healthy mucosa of HIV+ subjects. and practically never in HL. Because the only perivascular cells observed in the clinically healthy areas of HIV+ subjects were CD36+. we investigated the ultrastructure of perivascular DC in these same areas. These cells were characterized by the presence of a prominent Golgi apparatus. many lysosomes. and focal adhesions to the extracellular matrix. It may be concluded that 1) CD36+ DC are physiologic components of the oral mucosa. 2) they share some ultrastructural features with macrophages. 3) no differences in numbers were found between HIV+ and HIV- subjects. and 4) these cells are affected in their expression of HLA-DR antigens during HIV infection. particularly in areas of HL. This may be a hint that the antigen-presenting function of these cells in the oral mucosa is negatively affected during HIV infection.
Detection of human papillomaviruses in paraffin-embedded condylomata acuminata--comparison of immunohistochemistry, in situ hybridization, and polymerase chain reaction, The polymerase chain reaction (PCR) is used for detection of human papillomavirus (HPV) DNA in paraffin-embedded tissue sections of condylomata acuminata. Incorporation of biotinylated nucleotides during the amplification process allows a highly sensitive. fast. and non-isotopic detection of viral DNA in a subsequent Southern dot blot. In 100% (13 of 13) of histologically confirmed condylomata. HPV-6 or -11 could be detected by polymerase chain reaction. By in situ hybridization 77% (10 of 13) and by immunohistochemistry (IHC) 69% (nine of 13) positive results were obtained. Because HPV genital infection is linked to penile and cervical dysplasia. polymerase chain reaction provides a powerful and highly sensitive tool for epidemiologic studies on sexual transmission of HPV.
Soluble interleukin-2 receptor levels in patients with dermatitis herpetiformis, To determine the role of T-cell activation in dermatitis herpetiformis (DH). soluble IL-2R levels were measured by enzyme-linked immunosorbent assay (ELISA) in the sera of 30 patients with DH. Levels of this shed receptor are considered to be a measure of in vivo T-lymphocyte activation. and are elevated in the sera of many patients with inflammatory and immune-mediated diseases. Fifteen of the thirty (50%) patients with DH had elevated levels of soluble IL-2R compared to one of 31 (3%) healthy HLA-B8 or HLA-DR3 control subjects (p less than 0.00001) and one of 10 (10%) healthy non-HLA-B8/-DR3 subjects (p less than 0.0018). In addition. the mean soluble IL-2R level in the patients with DH (744 +/- 381 U/ml) was also significantly higher than that seen in 31 healthy HLA B8 or HLA DR3 individuals (388 +/- 160 U/ml. p = 0.0001) and 10 healthy non-HLA-B8/DR3 individuals (397 +/- 201 U/ml. p = 0.002). Only two of the 30 patients with DH had active skin lesions at the time of serum sampling. one of whom had elevated levels of IL-2R. Measurement of soluble IL-2R levels in sequential serum samples. available in four patients with DH at times of active and inactive skin disease. demonstrated a temporal association between soluble IL-2R level elevations and active skin disease in two patients and no association in two patients. In one patient a marked elevation in soluble IL-2R levels occurred with the onset of gastrointestinal symptoms. which decreased by 14% with institution of a gluten-free diet. In order to determine if soluble IL-2R levels are related to the mucosal immune response. the IL-2R levels were compared to the level of IgA antibodies directed against the dietary antigen beta-lactoglobulin. Ten of eleven (91%) patients with circulating IgA anti-beta lactoglobulin antibodies were also found to have elevated levels of IL-2R. In contrast. in the patients with no detectable IgA anti-beta lactoglobulin antibodies. only four of 16 (25%) had elevated levels of IL-2R (p = 0.001). Because IL-2R levels are not related to activity of the skin disease in patients with DH but are associated with the presence of IgA antibodies against the dietary antigen beta-lactoglobulin. these results suggest that some of the T-cell activation commonly present in DH reflects an ongoing immune response in the gastrointestinal tract.
Expression and secretion of leukocyte chemotactic cytokines by normal human melanocytes and melanoma cells, The capacity of human melanocytes and melanoma cells to produce IL-8 and monocyte chemotactic and activating factor (MCAF) was investigated. Melanocytes expressed mRNA for IL-8 and MCAF. when stimulated with either IL-1 alpha or TNF alpha. but not when stimulated with IL-6. IFN gamma. or LPS alone. IL-8 and MCAF could be induced in a dose-dependent fashion with doses as low as 0.1 ng/ml TNF alpha and 0.5 ng/ml IL-1 alpha. IL-8 and MCAF mRNA were rapidly expressed and peaked between 2 and 4 h for IL-8 and between 4 and 8 h for MCAF. This correlated well with the accumulation of IL-8 antigen as measured by a radioimmunoassay. Supernatants from melanocyte cultures stimulated with either IL-1 alpha or TNF alpha and separated on a heparin-Sepharose column became positive for neutrophil and monocyte chemotactic activity in a dose- and time-dependent fashion. When IFN gamma was added to melanocyte cultures stimulated with suboptimal doses of TNF alpha there was a synergistic increase in secreted IL-8 protein and monocyte chemotactic activity. These data provide further evidence for the possible role of melanocytes in the initiation of an inflammatory reaction. Three different malignant melanoma cell lines stimulated with either TNF alpha or IL-1 alpha expressed IL-8 mRNA. but not mRNA for MCAF. The IL-8 mRNA signal corresponded well with the amount of secreted IL-8 protein. These data suggest that IL-8 and MCAF may play a role in growth regulation and spreading of melanomas.
Management of retraction pockets of the pars tensa, A study of 73 patients with retraction pockets of the pars tensa (93 affected ears) has been carried out. Of these 32 per cent had otalgia and 31 per cent reported episodes of aural discharge. Adequate audiometric data was available on 75 ears. Mean air-bone gaps were calculated using 500 Hz. 1000 Hz. 2000 Hz and 4000 Hz. Thirty per cent of ears had air-bone gaps of less than 10 dB and in 93 per cent the air-bone gap was less than 30 dB. Air-bone gaps of more than 40 dB were found in seven per cent. Of this group. seven patients were selected for surgical treatment. In all cases the retraction pockets were elevated and averted. In six cases. the thinned tympanic membrane was reinforced with a composite graft of cartilage and perichondrium. This technique has also been used in three patients not included in this study group. An ossiculoplasty was performed in four cases. In the early months. the retraction pockets remained completely everted. However. by 12 months some degree of retraction had recurred in four of the six patients who have been followed for more than 12 months.
Interpretation of maxillary sinus radiographs in children, Nasal symptoms are a frequent cause of referral to paediatric ENT clinics. It is the policy of our unit to view sinus radiographs without a report at the initial clinic attendance. This study demonstrates there is no statistically significant difference in the interpretation of the radiographs between two ENT surgeons and a radiologist although there was a tendency for the radiologist to have a greater specificity. This finding may have financial implications. In addition a clear sinus radiograph is shown to be a significant negative finding.
Submucous resection of the nasal septum as an outpatient procedure, We report our experience of submucous resection of the nasal septum under local anaesthesia as an outpatient procedure. We have audited 50 consecutive cases and compared the results with a similar group of patients in whom the operation was carried out in the usual way under general anaesthesia. We have found the procedure to be safe. effective and economically advantageous.
Total avulsion of an osseointegrated screw, The close union achieved between pure grade titanium and healthy bone makes dislocation a rare event. We report the case of the total avulsion of an apparently well-integrated implant from a healthy mastoid bone.
Unusually placed oesophageal foreign body, Oesophageal foreign bodies are common occurrences. A variety of cases have been reported in the past. We present here a unique case of an unusually placed foreign body.
A randomized trial of amsacrine and rubidazone in 39 patients with acute promyelocytic leukemia, Thirty-nine patients with untreated acute promyelocytic leukemia (APL) were randomly allocated to receive rubidazone (zorubicin) 200 mg/m2/d. days 1 to 4 plus cytarabine (Ara C) 200 mg/m2/d. days 1 to 7 (arm A. 21 patients). or amsacrine (Amsa) 150 mg/m2/d. days 1 to 4 plus Ara C 200 mg/m2/d. days 1 to 7 (arm B. 18 patients). Prophylaxis of disseminated intravascular coagulation was made by platelet transfusions and heparin. In case of leukemic resistance. patients received a second course with 2 days of rubidazone (arm A) or Amsa (arm B) and 3 days of Ara C. Patients who achieved complete remission (CR) received three consolidation courses with the two drugs used for induction and maintenance therapy for 3 years. Two patients in arm A and one in arm B were allografted in first CR. Initial characteristics were similar in both arms. In arm A. 18 patients (86%) reached CR. two had hypoplastic death. and one had leukemic resistance after two courses. In arm B. 12 patients (66%) achieved CR. two had early death (CNS bleeding. one case; ventricular fibrillation. one case). and four had resistant leukemia after two courses. The difference in CR rate between the two arms was not significant. In arm A. disease-free survival (DFS) showed a plateau at 54.3% after 34 months (95% confidence interval [CI]. 32.1% to 74.9%). with eight CRs longer than 34 months. In arm B. DFS was significantly shorter (P less than .03). showing a plateau at 16.7% after 38 months (95% confidence interval. 4.7% to 44.6%). and only two prolonged CRs were seen. The difference in DFS remained significant after censoring allografted patients and patients who died in CR (one in arm A. two in arm B). Our results suggest that Amsa-Ara C combinations may be inferior to anthracycline-Ara C combinations in the treatment of APL. because they seem to provide shorter DFS and. possibly. a higher incidence of initial leukemic resistance. However. studies with larger numbers of patients are required.
A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia, Using a loading dose/continuous infusion schedule. fludarabine phosphate was administered to 51 patients with previously treated chronic lymphocytic leukemia (CLL). All patients had evidence of active disease. and the majority had advanced Rai stages. Of the 42 patients assessable for response. 22 (52%) achieved a partial response. five (12%) had stable disease. and 15 (36%) progressed. Thirteen of the 22 responders improved their Rai stages with fludarabine therapy. including six patients who achieved stage 0. Response rates for pretreatment stages III and IV were 60% and 53%. respectively. Patients with final Rai stages 0 to II had better survival than those with stages III and IV. Patients who had undergone splenectomy before starting therapy were more likely to respond. Myelosuppression was the primary toxicity and did not appear to be cumulative. Severe leukopenia and thrombocytopenia. although infrequent. were associated with several deaths in the early cycles of treatment. Nonhematologic toxicity was mild with no serious neurotoxicity noted. Infections were common with 22 minor. 18 major. and 10 fatal episodes. Fludarabine phosphate by this alternative dosing schedule is effective in refractory advanced CLL and is well tolerated by the majority of patients.
Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia, The survival of patients with acute leukemia who do not achieve a remission with primary therapy is very poor. High-dose chemoradiotherapy followed by allogeneic bone marrow transplantation (BMT) has been shown to be effective therapy for patients with acute and chronic leukemia. Therefore. we determined the long-term disease-free survival of patients who did not achieve a remission and were then treated with high-dose therapy and bone marrow allografting from matched sibling donors. Twenty-one patients (median age. 28 years) who did not achieve a remission with induction chemotherapy were subsequently treated with allogeneic BMT. After BMT. 90% achieved a complete remission. Six died of complications of the therapy. and six patients relapsed between 27 and 448 days after BMT. Nine patients (43%; median age. 25 years) are alive between 556 and 4.174 days after BMT. The cumulative probability of disease-free survival at 10 years is 43%. This study suggests that allogeneic BMT can be an effective therapy to achieve long-term control of acute leukemia. even in those patients who do not achieve a remission with primary therapy.
Importance of bone marrow cytogenetic evaluation before autologous bone marrow transplantation for Hodgkin's disease, Alkylating agents used either with or without radiation therapy have been associated with the development of myelodysplastic syndrome (MDS) and acute nonlymphoblastic leukemia (ANLL) after treatment of both malignant and nonmalignant disorders. This report describes seven patients with recurrent Hodgkin's disease (HD) evaluated for bone marrow transplantation (BMT) who developed chromosomal abnormalities. and emphasizes the importance of bone marrow cytogenetic studies before bone marrow harvest. Three patients with histologically normal bone marrow underwent autologous BMT and subsequently developed an MDS or ANLL. Four patients had the clonal abnormality detected before bone marrow harvest and did not proceed to BMT.
Impact of intensified therapy on clinical outcome in infants and children with neuroblastoma: the St Jude Children's Research Hospital experience, 1962 to 1988, To gauge the impact of intensified therapy on the survival of infants (younger than 1 year. n = 129) and children (greater than or equal to 1 year of age. n = 275) with neuroblastoma. we analyzed the results of eight successive clinical trials comparing various combinations of antineoplastic drugs. surgery. and radiotherapy. Changes in treatment did not affect the survival of children with involved noncontiguous lymph nodes or distant metastatic disease until the combination of cisplatin and teniposide (CDDP/VM26) was added to a basic regimen of cyclophosphamide and doxorubicin (CTX/DOX). The resulting 4-year survival was 28% +/- 5% (SE) compared with 7% +/- 2% for previous treatments (P less than .001 by the log-rank test). The 4-year survival of infants with metastatic disease was improved by administering CTX/DOX to all patients. reserving CDDP/VM26 for those whose disease was resistant to the former combination: 82% +/- 6% versus 45% +/- 8% in earlier studies; P less than .001. In the subset of infants whose tumors had disseminated to bone or bone marrow at diagnosis. this therapeutic approach increased the probability of long-term survival from 48% +/- 10% to 85% +/- 9% (P = .01). The small group of children over 1 year of age with localized unresectable tumors also fared significantly better with the switch to CTX/DOX chemotherapy (4-year survival. 93% +/- 7% v 42% +/- 13%; P = .02). Multivariate analysis indicated that young age. limited-disease stage. nonadrenal primary site. and intensified treatment were independent predictors of a more favorable outcome. We conclude that substantial advances in the treatment of neuroblastoma have occurred over the past 25 years at this institution. The current overall 4-year survival probability of 57% +/- 4% compares favorably with estimates for most other common solid tumors of childhood.
Impact of autologous bone marrow infusion on hematopoietic recovery after high-dose cyclophosphamide, etoposide, and cisplatin, Because of potential tumor contamination and inadequacy of current purging technique of bone marrow in patients with solid tumors. we investigated an alternative approach to high-dose therapy without autologous bone marrow (ABM) infusion. Three levels of nonmyeloablative doses of cyclophosphamide 4.5 to 5.25 g/m2. etoposide 750 to 1.200 mg/m2. and cisplatin 120 to 165 mg/m2 (CVP) were administered to patients with metastatic solid tumors. Patients were randomized to ABM (n = 46) or no-ABM (NABM) (n = 46) infusion after CVP to study the impact of ABM on hematopoietic recovery. morbidity. and mortality. All patients had ABM harvested. underwent conventional chemotherapy. and then received CVP. Seventy-three patients received two courses of similar doses. The following were the median days to absolute neutrophil count (ANC) of 0.1 x 10(9)/L: for the ABM arm. 19. 21. and 19 and for the NABM arm. 23. 20. and 21 at levels 1. 2. and 3. respectively. during course 1 (P = .01. .80. and .01. respectively). During course 2. ANCs to 0.1 x 10(9)/L and 0.5 x 10(9)/L were attained significantly faster at levels 1 and 3 in the ABM arm. ANC to 1.0 x 10(9)/L was comparable in both arms. Incidence of infection and duration of fever were similar in both arms. Although mortality and the incidence of delayed hematopoietic recovery were more frequent in the NABM arm. this was not statistically significant. Platelet recovery was consistently prolonged in course 2 in both arms. with demonstrable benefit of ABM in course 2 when dose levels were collectively considered. We conclude that (1) ABM enhanced recovery of ANC to 0.1 x 10(9)/L; (2) ABM did not decrease the incidence of infections and the duration of fever; and (3) CVP can be safely given without ABM to carefully selected patients.
Teniposide and etoposide in previously untreated small-cell lung cancer: a randomized study, A randomized study comparing teniposide (VM-26) and etoposide (VP-16) was performed to investigate whether there are any differences in the activity and toxicity of these two analogs in small-cell lung cancer (SCLC). Only previously untreated patients with SCLC were included; 46 and 48 patients receiving VP-16 and VM-26. respectively. are assessable for response. There were no differences between the two groups with respect to extent of disease. median age. and performance status (PS). The initial doses were for both compounds 70 mg/m2 intravenously (IV) daily for 5 days every 3 weeks. After inclusion of 25 patients in the study. the doses were increased to 80 mg/m2 for VM-26 and 90 mg/m2 for VP-16 because of differences in toxicity. VM-26 caused more hematologic toxicity than VP-16 throughout the study. The overall responses (complete response [CR] plus partial response [PR]) were 65% for VP-16 and 71% for VM-26. with CR occurring in 24% and 23%. respectively. for the two compounds. Median survival was 8.5 months for VP-16-treated patients versus 11.3 months for VM-26-treated patients (P = .58). It is concluded that both VP-16 and VM-26 are highly active single agents in SCLC.
Intensive weekly chemotherapy for the treatment of extensive-stage small-cell lung cancer, The regimen of cisplatin. vincristine. doxorubicin. and etoposide (CODE) was designed to double the dose intensity of these drugs in comparison with a standard regimen (alternating cyclophosphamide. doxorubicin. and vincristine [CAV] and etoposide-cisplatin [EP]) for extensive-stage small-cell lung cancer (SCLC). The dose intensity was increased by more frequent treatments rather than by increasing the dose size. The structure of this outpatient protocol includes weekly administration of chemotherapy. alternation of myelosuppressive and nonmyelosuppressive treatments. supportive corticosteroids. gastroprotective agents. and prophylactic antibiotics. Although the duration of chemotherapy was brief (9 to 12 weeks). the total cumulative doses of drugs delivered were similar to the standard regimen. Patients with no residual disease outside the chest after chemotherapy received thoracic irradiation. and patients with complete responses (CRs) received prophylactic cranial irradiation. Eligible extensive-stage SCLC patients were ambulatory. younger than 66 years of age. and free of brain metastasis. Forty-eight extensive-stage SCLC patients were treated. Forty-five (94%) responded to chemotherapy. with 19 (40%) attaining CR. After consolidative thoracic irradiation. the CR rate was 56%. The median time to progression was 43 weeks. and the median survival was 61 weeks. The 2-year survival rate was 30%. The most common site of first relapse was brain (38%). Although two patients (4%) died of toxicity. overall toxicity was acceptable for an outpatient regimen. We conclude that the CODE regimen reliably produces palliative remissions for selected extensive-stage SCLC patients. and it may be associated with durable remissions for some patients. The results of this pilot study are sufficiently promising to justify a phase III trial of CODE versus standard (alternating CAV and EP) chemotherapy.
Small-cell carcinoma of the lung: derivation of a prognostic staging system, Retrospective data on 22 pretreatment attributes were evaluated in 614 patients with small-cell carcinoma of the lung (SCCL). The series included 284 patients with limited disease (LD) and 328 patients with extensive disease (ED) managed between 1974 and 1986. Prognostic factors were evaluated by univariate analysis and by the Cox multivariate regression model. Recursive partition and amalgamation algorithm (RECPAM). two clustering methods well suited for obtaining strata and adapted for censoring survival data. were developed and used in the formulation of a new prognostic staging system. In univariate analysis. prognosis was significantly influenced by extent of disease (DE). the number of metastatic sites. and the detection of mediastinal spread in LD. Poor performance status (PS). male sex. and advanced age were negatively correlated with survival. as were increased serum levels of alkaline phosphates (AP). lactate dehydrogenase (LDH). carcinoembryonic antigen (CEA). total WBC count (WBCC). and low platelet count and low serum sodium. The Cox model identified plasma LDH and mediastinal spread as the only significant factors in LD; the influence of PS. number of metastatic sites. bone metastasis. brain metastasis. and platelet count were identified as significant in ED. The RECPAM model identified four distinct risk groups defined in a classification tree by the following eight attributes: DE. PS. serum AP. serum LDH. mediastinal spread. sex. WBCC. and liver metastasis. The four groups were distinguished by median survival times of 59. 49. 35. and 24 weeks. respectively (P = .0001). Interactions among prognostic factors are emphasized in the RECPAM classification model as evidenced by reassignment of patients across conventional staging barriers into alternate prognostic groups. The advantages of using RECPAM over the more conventional Cox regression techniques for a new staging system are discussed.
Prognosis in T2N0M0 stage I breast carcinoma: a 20-year follow-up study, In a study of prognosis in node-negative breast carcinoma. we investigated 293 T2N0M0 patients treated by mastectomy and axillary dissection with a median follow-up of 19.8 years. The probability of surviving 20 years considering all causes of death was 41.3% +/- 3.0%. Recurrence-free survival (Kaplan-Meier estimate) was 68.6% +/- 3% at 10 years and 63.2% +/- 3.1% at 20 years. The estimated probability of cure determined by the method of Brinkley and Haybittle was 63% (95% confidence interval [Cl]. 55% to 72%). Prognosis was related to primary tumor size with the best separation (P = .06) when tumors from 2.1 to 3.0 cm (33% chance of recurrence at 20 years) and from 3.1 to 5.0 cm (44% chance of recurrence at 20 years) were compared. The histologic tumor type was prognostically important. Recurrence at 20 years was not significantly different for patients with invasive duct (34%) and lobular (42%) carcinoma. Women with special types (medullary. mucinous. papillary. etc) of carcinoma had a 25% chance of recurrence. Subsequent contralateral breast carcinoma was diagnosed in 29 patients. and four of these were fatal. accounting for only 4.6% of breast carcinoma deaths. Thirty-two patients (10.9%) developed a nonmammary malignant neoplasm (NMMN) after the ipsilateral breast carcinoma. and 69% of these lesions were fatal. Although the chances of recurrence at 20 years related to tumor size and type did not differ statistically in the series. there were trends that suggest that T2N0M0 patients can be stratified into recurrence risk groups based on tumor size and histologic type. These factors should be taken into consideration in the design and analysis of clinical adjuvant therapy trials. Measures for the early detection of common NMMNs should be included in the routine follow-up of T2N0M0 breast carcinoma patients.
Integration of conservative surgery, radiotherapy, and chemotherapy for the treatment of early-stage, node-positive breast cancer: sequencing, timing, and outcome, The optimal means of combining breast-conserving surgery. radiation therapy. and chemotherapy for the treatment of patients with early-stage. node-positive breast cancer is not known. We reviewed the results in 295 patients treated at the Joint Center for Radiation Therapy and affiliated institutions from 1976 to 1985. All patients had positive axillary nodes on dissection. had no gross residual disease in the breast or axilla after surgery. and received breast irradiation (with or without nodal irradiation) and three or more cycles of a cyclophosphamide. methotrexate. and fluorouracil (CMF)-based or doxorubicin-containing regimen. Median follow-up in patients without any failure was 78 months. Breast failure rates were assessed in relation to the sequencing of radiotherapy and chemotherapy. The different sequences were not randomly assigned. and the characteristics of the sequence groups differed. The actuarial 5-year breast failure rate was 4% in 99 patients receiving radiotherapy before chemotherapy; 8% in 54 patients sequentially receiving some chemotherapy. then radiotherapy without concurrent chemotherapy. then further chemotherapy; and 6% in 116 patients receiving concurrent chemotherapy and radiotherapy. However. the failure rate was 41% in 26 patients who received all chemotherapy before radiotherapy. The crude incidences of local failure within 4 years of treatment in these groups were 3%. 2%. 4%. and 15%. respectively (P = .065 for all four groups not being the same). The actuarial 5-year local failure rate was 5% for 252 patients irradiated within 16 weeks after surgery compared with 35% for 34 patients irradiated more than 16 weeks after surgery. The 4-year crude incidences were 4% and 12% for the two groups. respectively (P = .06). These results suggest that delaying the initiation of radiotherapy may result in an increased likelihood of local failure. Formal randomized controlled trials will be needed to confirm these results and to improve the integration of these treatment modalities.
Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin, and cisplatin chemotherapy of ovarian carcinoma: a meta-analysis. The Ovarian Cancer Meta-Analysis Project, Four randomized clinical trials comparing cyclophosphamide plus cisplatin (CP) versus cyclophosphamide. doxorubicin. and cisplatin (CAP) individually failed to show a significant survival difference in the treatment of ovarian carcinoma. However. by pooling 1.194 patients from these trials in a meta-analysis. there is a statistically significant survival benefit for CAP (P = .02); in addition. there is a significant advantage for CAP in frequency of negative second-look laparotomy (CAP. 30%; CP. 23%; P = .01). Because the dose intensity of CAP was greater than CP in three of the trials. it remains unresolved to what extent the benefit of CAP is from greater dose intensity and to what extent it is from the doxorubicin itself. Either interpretation suggests directions for improving the chemotherapy of ovarian carcinoma.
Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma, Leucovorin potentiates the cytotoxicity of fluorouracil (5-FU) in experimental tumor systems and appears to enhance the effectiveness of 5-FU in patients with colon cancer. Twenty-two eligible patients (18 previously untreated) with advanced pancreatic adenocarcinoma were treated in a phase II trial of leucovorin 500 mg/m2/d for 6 days by continuous intravenous infusion with 5-FU 370 mg/m2/d by rapid intravenous injection on 5 consecutive days. beginning 24 hours after initiation of leucovorin infusion. Among the 20 assessable patients. there were no complete or partial regressions. although there was one minor response lasting 4 months. Three patients had stable disease for 5. 20. and 21 months. respectively. Median survival was 10 weeks. Toxicity was predominantly mucosal; stomatitis grade 2 or worse was seen in five patients. and diarrhea grade 2 or worse was seen in four. Hospitalization for toxicity was necessary in four previously untreated patients and three previously treated patients. The median WBC nadir was 4.6 (range. 1.4 to 9.6) x 10(3)/microL. and the median platelet nadir was 147.0 (range. 69.0 to 240.0) x 10(3)/microL. This combination of leucovorin and 5-FU did not demonstrate meaningful therapeutic activity in patients with adenocarcinoma of the pancreas and was associated with moderate to severe toxicity. It should not be considered a standard treatment for patients with this disease.
Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study, Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2(IL2). 18 x 10(6) IU/m2/d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC). 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment. consisting of IL2. 18 x 10(6) IU/m2/d for 5 days alternating with DTIC. 850 mg/m2 IV every 3 weeks. for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free periods of 6 months and longer were seen in the two complete responders (8 and 17+ months). in two of the four partial responders (7 and 12+ months). and in three of the five patients with stable disease (9+. 15. and 17+ months). Toxicity included fever. skin rash. fatigue. anorexia. and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient). ventricular tachycardia (one). hypotension and oliguria (four). and sepsis (two). Sequential treatment with IL2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone.
Randomized dose-searching phase ILE/II trials of fractionation in radiation therapy for cancer, This article describes a new design. phase ILE/II dose searching. used in four prospective. randomized. multicenter clinical trials of escalating total doses of hyperfractionated radiation. This design combines an experimental protocol with a statistical application of ranking and selection theory. Its purpose was to identify (within a certain margin of error) a dose that achieved the highest rate of clinical response from a set of doses that were tolerable in terms of both acute (within 90 days) and late (more than 90 days) toxic effects (LE). We calculated the number of patients required to reliably test toxicity under various assumptions. To determine the maximum tolerated total dose for hyperfractionated radiation. we randomly assigned patients with tumors that responded to radiation therapy in a dose-dependent manner from four body sites (lung. upper respiratory and digestive tract. bladder. and brain) to one of three regimens receiving total doses (D1. D2. or D3) differing by increments of 4.8 Gy. All patients received two fractions of 1.2 Gy each (separated by 4-6 hours) daily 5 days a week. The lowest total dose was set at the level considered tolerable with standard once-a-day radiation therapy. We tested tumor responses and late toxic effects of higher doses by assigning patients to these three regimens until acute effects and early estimates of late effects were found to be acceptable for the highest dose D3; thereafter. regimen D1 was closed. and additional patients were assigned to D2. D3. and D4 (an escalated total dose greater than D3 by an increment of 4.8 Gy). The assignment of patients was performed in a weighted manner (1:1:2). so that greater numbers were assigned to the highest dose regimen (whether D3 or D4) to allow rapid evaluation of the feasibility of the highest dose.
Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study, Four hundred eleven women with metastatic breast cancer were randomly assigned to receive either 60 mg/m2 doxorubicin (130 patients). 320 mg/m2 bisantrene (146 patients). or 14 mg/m2 mitoxantrone (135 patients). The doses were given intravenously every 3 weeks with a cross-over design to determine their relative efficacy and toxicity. To be eligible. patients must have had one previous chemotherapy regimen. and patients who were estrogen receptor positive must have failed endocrine therapy. There were 365 patients assessable for response and 399 assessable for toxic effects. The median age was 57 years; 18% were premenopausal or perimenopausal. Visceral dominant disease was present in 66% of the patients. Ninety-seven percent of the patients had a disease-free interval from diagnosis to first recurrence of less than 1 year. The response rate was 28% with doxorubicin. 13% with bisantrene. and 14% with mitoxantrone (P = .004). Median time to treatment failure was 133 days with doxorubicin. 66 days with bisantrene. and 68 days with mitoxantrone (logrank P = .06). The median survival was 315 days for doxorubicin. 290 days for bisantrene. and 177 days for mitoxantrone (logrank P = .04). although survival at 2 years was similar for all three agents. There were five responses in the 66 patients crossed over to doxorubicin and one response each for patients crossed over to bisantrene (39 patients) or mitoxantrone (63 patients). Toxicity leading to discontinuance of therapy was more common with doxorubicin. and discontinuance of therapy was due primarily to patient's request or cardiotoxicity. The major dose-limiting toxic effect for all three agents was leukopenia. Nausea and vomiting. mucositis. and alopecia were more severe with doxorubicin. Congestive heart failure developed in nine patients treated with doxorubicin. zero patients treated with bisantrene. and two patients treated with mitoxantrone. A decrease in the left ventricular ejection fraction. as defined by moderate to severe Alexander grade changes. was more common in patients treated with doxorubicin (doxorubicin-treated patients = 20%. bisantrene-treated patients = 5%. and mitoxantrone-treated patients = 10%). This study demonstrates that bisantrene and mitoxantrone have only modest activity in metastatic breast carcinoma. The activity of doxorubicin is greater than that of the other two agents. but at a cost of increased toxicity.
Nonrandom distribution of N-myc oncogene genotypes in neuroblastoma, The distributions of Pvu II and Sph I alleles of the N-myc oncogene (also known as MYCN) were studied in a series of normal individuals and pediatric patients with solid tumors. In the case of Pvu II. where the polymorphic site is located 3' of the gene. the frequencies of the allele were 0.27 (11-kilobase fragment) and 0.73 (8-kilobase fragment) in 43 unrelated normal Caucasians. The frequencies of the allele were similar in 40 non-N-myc-amplified neuroblastomas. 47 Wilms' tumors. and 31 other pediatric tumors. In these cases. the genotypes were in Hardy-Weinberg equilibrium. In 18 N-myc-amplified neuroblastomas. however. the observed genotype frequencies deviated from Hardy-Weinberg equilibrium (P less than .005). Similar observations were made with an Sph I restriction fragment length polymorphism where the polymorphic site is located in intron 2. The differences between amplified and nonamplified neuroblastomas suggest a possible involvement of sequences at or near N-myc in the progression of tumors where the N-myc gene is amplified.
"Directed" emergency room thoracotomy: a prognostic prerequisite for survival, The results of 163 patients (49 SWs. 85 GSWs. 29 blunt trauma) who had resuscitative thoracotomy in the emergency room (ERT) were reviewed to reassess the indications for the procedure. The Revised Trauma Score (RTS) of the patients ranged from 0 to 3 in 138. 4 to 8 in 21. and greater than 8 in four. No patient with blunt trauma survived. Sixteen patients [12 (24.5%) with stab wounds and 4 (4.7%) with gunshot wounds] were eventually discharged. an overall survival of 9.8%. Eight of the survivors were without vital signs on arrival at the emergency center and one of them had only signs of life at the scene. Survival was best when the site of penetration was thoracic (n = 84) and the ERT was "directed" at potential cardiac injury. Fifty-six of these patients (66.6%) did have cardiac wounds with tamponade and 12 of them survived (21.4%). Two of the remaining 28 patients. both with pulmonary injury. were salvaged. This was significantly (p less than 0.001) higher than in patients with head and neck (n = 4). abdominal (n = 19). or multiple site (n = 40) injury when the ERT was nondirected. Two of the five patients (40%) with extremity vascular injuries survived after ERT was successful in restoring a cardiac rhythm. These data suggest that in patients without vital signs. ERT "directed" at potential cardiac injury based on thoracic penetration is an important prognostic prerequisite for survival. Emergency room thoracotomy is not beneficial in blunt trauma and its role in penetrating abdominal injuries remains unproven.
Defining the major trauma patient and trauma severity, Criteria for defining the major trauma patient have been specified by physicians using Injury Patient Management Categories (PMCs). a computerized classification that can be used effectively with routinely collected discharge abstract data from non-trauma center hospitals as well as trauma centers. These criteria for major trauma not only include the more severe and complex single injuries. but also include criteria for identifying combinations of injuries that require tertiary level care. Major trauma patients identified as tertiary using PMCs are compared with existing and frequently used measures of injury severity such as AIS and ISS. Analyses suggest that the Injury PMCs identify major trauma patients accurately and more specifically than other indicators of severity that are commonly used. In addition. unlike other measures that are generally limited to registries. PMC tertiary patient criteria differentiate major trauma patients at both trauma centers and non-trauma centers without additional data collection. Using this method thus facilitates trauma systems evaluation and patient outcome assessment.
A randomized trial of replacement antioxidant vitamin therapy for neutrophil locomotory dysfunction in blunt trauma, Studies in patients with serious trauma indicate that the observed neutrophil (PMN) locomotory dysfunction is partly the result of auto-oxidation as shown by evidence of preactivation. diminished reducing capacity. and low serum and cellular ascorbic acid and alpha-tocopherol. To investigate whether replacement of the antioxidant vitamins ascorbic acid and alpha-tocopherol can improve the PMN locomotory defect. ascorbic acid. alpha-tocopherol. ascorbic acid and alpha-tocopherol. or placebo was administered to a total of 46 victims of blunt trauma. PMN locomotion was quantitated using a micropore filter assay. Locomotion data were analyzed by repeated measures analysis with a split plot design and data for days 2-6 after injury were compared. Compared with placebo. the antioxidants improved PMN locomotion. The mean differences in distance migrated (treated minus placebo) were ascorbic acid and alpha-tocopherol = 11.3 +/- 3.0 microns (one-tailed p = 0.001) (mean +/- SE); ascorbic acid = 4.7 +/- 3.4 microns (p = 0.19); and alpha-tocopherol = 3.3 +/- 2.9 microns (p = 0.27). Although both antioxidants given together produced the best results. a plot of the 95% confidence intervals indicates that ascorbic acid and alpha-tocopherol. either given alone. were also better than placebo. We conclude that antioxidant replacement therapy significantly improves the PMN locomotory abnormality in blunt trauma.
Continuous arteriovenous rewarming: report of a new technique for treating hypothermia, Survival is rare after major trauma if core temperature falls below 32 degrees C. Available rewarming methods are often ineffective. We utilized arterial and venous catheters to create a circulatory fistula through the heating mechanism of a modified commercially available counter-current fluid warmer to achieve simple. rapid extracorporeal rewarming.
Aminoglycoside combinations versus beta-lactams alone for penetrating abdominal trauma: a meta-analysis, Despite several small comparative clinical trials. controversy persists over the best choice of antimicrobial therapy for penetrating abdominal trauma. Some still question whether single drug regimens are as effective as the traditional combinations containing an aminoglycoside. A meta-analysis was performed to address this issue. Meta-analysis is a relatively new statistical tool whereby data from a number of clinical trials is analyzed and pooled to produce useful and more reliable data. In this study. a meta-analysis of 17 published randomized trials was performed to assess the effectiveness of single beta-lactam antimicrobials versus combinations containing aminoglycoside when used for penetrating abdominal trauma. The overall summary odds ratio of the pooled results of these trials was 0.96 (p = 0.833) with a 95% confidence interval of 0.30-3.05. Since not significantly different from unity (1.0). we conclude that single beta-lactam antimicrobials are as effective as traditional combinations containing aminoglycoside in this setting.
Peritoneal lavage enzyme determinations following blunt and penetrating abdominal trauma, Diagnostic peritoneal lavage (DPL) provides a rapid and sensitive means of investigating the peritoneal cavity following blunt and penetrating trauma. However. its shortcomings include insensitivity in the early identification of isolated hollow viscus injuries. We have routinely assayed lavage amylase (LAM) and alkaline phosphatase (LAP) in acutely injured patients for more than 4 years to assess the contribution of lavage enzyme analysis to the overall accuracy of DPL. From 1.969 DPLs. LAM was analyzed in 1.881 (96%) and LAP in 1.734 (88%) of 1.536 blunt and 433 penetrating trauma cases. Of 28 patients with negative lavage by LRBC but LAM greater than or equal to 20 IU/L. 13 (46%) had clinically significant injury requiring laparotomy. Seventy-seven percent of these cases involved the small bowel. In this group. LAM greater than or equal to 20 IU/L had a sensitivity of 87%. specificity of 75%. and positive predictive value of 46% for significant intra-abdominal injury. Seven patients had LAM greater than or equal to 20 IU/L and LAP greater than or equal to 3 IU/L. These values had a sensitivity of 54%. specificity of 98%. and positive predictive value of 88% for significant abdominal injury. Elevations of LAM (greater than or equal to 20 IU/L) and LAP (greater than or equal to 3 IU/L) mandate laparotomy where the history is consistent with possible small bowel injury. Elevation of either enzyme alone should raise the suspicion of hollow visceral organ injury and warrant close observation.
The autotransfusion effect of external leg counterpressure in simulated mild hypovolemia, We examined the cardiovascular response of external leg counterpressure in healthy volunteers at 100 mm Hg compression pressure. To stimulate mild hypovolemia. measurements were made with the subjects in a 60 degrees head-up tilt position. Left ventricular end-diastolic volume (LVEDV) and cardiac output (CO) were calculated from two-dimensional echocardiography. Flow through the inferior vena cava (IVC) below the origin of the hepatic veins was determined by the Doppler ultrasound technique. The application of counterpressure significantly increased LVEDV. CO. and arterial blood pressure over that seen with tilting without the device. These responses were accompanied by a small but significant increase in IVC flow. We therefore concluded that external leg counterpressure transferred blood to the central circulation by compression of the venous capacitance vessels (an autotransfusion effect) in mild hypovolemia. but such an effect may not benefit patients in a hypovolemic shock state because of the small amount of translocated blood.
Predictors of abdominal injury in children with pelvic fracture, During a 48-month period. 2.248 children (aged less than 15 years) were consecutively admitted to a regional pediatric trauma center with blunt trauma (ICD-9-CM code greater than or equal to 800). Fifty-four children (2.4%) had injury to the pelvic circle. as diagnosed by radiographic examination; 13 of these children had concomitant abdominal or genitourinary (GU) injury. Contingency table analysis and stepwise logistic regression were used to determine the best predictors of abdominal injury. The mean age of the children was 8.6 years. Eighty-nine percent of the injuries were motor-vehicle related (59% pedestrian; 30% crash occupant). Nine children (17%) required transfusions of packed red blood cells; 9 children (17%) required surgery. There were 6 deaths in this group. a mortality rate of 11.1%. The most common fracture sites in the pelvis were the pubic rami (59%). ilium or pelvic rim (17%). and the sacrum (6%). Ten children (19%) had multiple pelvic fractures. Location of fracture was strongly associated with the probability of abdominal injury: 80% of children with multiple pelvic fractures had concomitant abdominal or GU injury. compared with 33% with fracture of the ilium or pelvic rim. and 6% with isolated pubic fractures (p less than 0.001). The variables that best predicted abdominal or GU injury using a backward-elimination. stepwise logistic model were the presence of multiple pelvic fractures (p less than 0.002) and unweighted Revised Trauma Score (p less than 0.05); age of child. systolic blood pressure. respiration rate. Glasgow Coma Scale score. and mechanism of injury were not predictive.
Superselective embolization of superior gluteal artery pseudoaneurysms following intramuscular injection: case report, Two bleeding superior gluteal artery pseudoaneurysms occurred in a patient with advanced malignant disease following an intramuscular injection. This was diagnosed by angiography and successfully managed by superselective embolization. This avoided further surgery and no additional complication from the pseudoaneurysm occurred up to the time of the patient's demise.
Fine needle cytodiagnosis of renal tuberculosis, A total of 8 patients in whom renal tuberculosis was suspected on clinical or radiological grounds but in whom confirmation could not be achieved by urine culture underwent renal fine needle aspiration. Immediate cytodiagnosis was accomplished in 7 of 8 patients by the finding of Langhans' giant histiocytes. epithelioid histiocytes and necrotic debris. Later confirmation was obtained in all 8 cases by radiometric culture of aspiration material or saline rinses of the fine needles. This experience introduces fine needle aspiration cytology as a diagnostic modality in renal tuberculosis.
Extracorporeal shock wave lithotripsy: an outpatient procedure, At many centers circumstances have dictated that extracorporeal shock wave lithotripsy (ESWL*) be performed on an outpatient (that is same-day surgery or 1-day stay) basis. At our center. Louisiana Lithotripter. Inc.. which is a privately owned ESWL unit located at Tulane University Hospital. we have had the opportunity to treat patients in the inpatient and outpatient setting since inception. Since our first ESWL treatment on December 18. 1985 we have treated more than 2.500 patients. Additionally. our unit was named an American Urological Association Training Center in October 1986. resulting in more than 200 urologist. nurse and technician trainee visits. The first 1.779 cases through December 31. 1988 have been thoroughly reviewed. The rate of outpatient ESWL has increased from 22% of the first 100 cases to more than 90% of the last 100. The cumulative over-all rate reached 70%. Currently. more than 95% of our cases are planned as same-day procedures. Safe and effective outpatient ESWL is able to be performed with first generation technology. paving the way for appropriate clinical application to newer technological modalities.
Analgesia in anesthesia-free extracorporeal shock wave lithotripsy: a standardized protocol, We treated 101 patients at our stone facility with the Dornier HM3 lithotriptor modified with the anesthesia-free design upgrade. A protocol designed by our anesthesiologists consisting of intravenous and intramuscular injections for sedation was used without any general or regional anesthesia required. Pre-medication with intramuscular meperidine and promethazine. and oral diazepam was sufficient sedation in 43 patients. while 37 required additional intravenous meperidine and/or midazolam during the procedure. 16 were treated with intraprocedural medication alone and 5 required no medication at all. Care before. during and after the procedure was rendered by the urology staff for patients in American Society of Anesthesiologists risk category I or II. Treatment was successfully completed in all patients without complications. We compared this group to the 99 patients treated consecutively before the modification. Voltage used. number of shocks and stone burden were comparable in the 2 groups but average treatment time was prolonged with the upgraded equipment (39.2 versus 27.1 minutes) to a significant degree (p less than 0.001).
Treatment of ureteral calculi with extracorporeal shock wave lithotripsy using the Lithostar device, Shock wave requirements for fragmentation and the ultimate outcome after extracorporeal shock wave lithotripsy (ESWL) with the Lithostar device were analyzed in 107 renal units with solitary ureteral calculi. In situ treatment was done in 54 stones without prior manipulation and in 15 after failure of endoscopic manipulation. A total of 25 ureteral calculi was treated after bypass with a ureteral catheter or stent and 13 after push back to the pelvicaliceal system. Shock wave requirement for fragmentation was significantly higher for calculi of 101 to 400 mm. X mm. when compared with the requirement for smaller calculi. Shock wave requirement was also significantly higher for patients with similar sized stones treated in the prone compared to the supine position. The average number of shock waves required for disintegration was not significantly different among in situ or any of the manipulation categories of similar sized stone populations. Over-all satisfactory clearance was achieved in 77.5% of the treated ureteral calculi. Clearance status was unaffected by size up to 400 mm. X mm. and the position of the patient during treatment (prone or supine). Clearance of ureteral stones treated in situ without prior manipulation (76.5%) was numerically inferior. although statistically insignificant. to that for successfully manipulated calculi (bypassed 88% and pushed back 92.3%) but it was significantly better than the outcome obtained after failed manipulation (46.2%). ESWL with the Lithostar device is a successful mode of treatment within the entire ureteral length. and a vigorous attempt at push back before lithotripsy is unnecessary.
Balloon dilation of the distal ureter to 24F: an effective method for ureteroscopic stone retrieval, Early in our ureteroscopic experience. in an effort to facilitate retrieval of ureteral calculi with the 11.5F and 12.5F rigid ureteroscopes. the distal ureter was routinely balloon dilated to 24F. Among 131 ureteroscopic procedures all consecutive 108 distal ureteral calculi were successfully removed. However. only 65% of 23 upper ureteral calculi were extracted. A followup excretory urogram (6 weeks or later) in 86 patients revealed no distal ureteral strictures. A followup cystogram in 30 patients showed low grade vesicoureteral reflux in 20% of the patients and none of these individuals was symptomatic. As such. balloon dilation of the distal ureter to 24F appears to be well tolerated. Presently. given the advent of smaller ureteroscopes and lithotriptor probes. such extensive ureteral dilation is necessary only in a minority of patients with distal ureteral calculi. In these few patients with calculi resistant to lithotripsy balloon dilation of the ureter to 24F may allow for successful. safe stone extraction. thereby precluding open ureterolithotomy.
Conversion of the electrohydraulic electrode to an electromechanical stone impactor: basic studies and a case report, A 3.3F electrohydraulic electrode (Wolf 2137.23) has been confined within a spring with a metal end cap. irrigated with water and covered with a 0.003-inch metal sheath (outside diameter 5F). The electrohydraulic lithotripsy discharge (Wolf Generator 2137.50) at E1 causes the metal cap to extend 3 mm. at 1.500 cm. per second and creates an impact pressure of 600 to 800 bar. Stone fragmentation efficiency of the electromechanical impactor was equivalent to unshielded electrohydraulic lithotripsy (gallstone 2.83 mg. per pulse. struvite/apatite 1.41 mg. per pulse. cystine 0.41 mg. per pulse. uric acid 1.48 mg. per pulse and 100% calcium oxalate monohydrate 0.10 mg. per pulse). Studies of the discharge of the electromechanical impactor within the pig ureter showed that minimal ureteral submucosal edema and hemorrhage occurred at 300 shocks discharged at a single point. and disruption of the mucosa and partial injury to the muscle layer occurred after 600 shocks given at the site of a pinched pig ureter. Pushing the electromechanical impactor perpendicular to the wall of the pig bladder will create a mechanical perforation within 35 shocks (electrohydraulic lithotripsy within 2 shocks). One patient had excellent fragmentation of a lower ureteral mixed monohydrate and dihydrate stone under direct vision performed with the electromechanical impactor passed via a 9.5F ureteroscope. There was no evidence of mucosal injury with 500 shocks. The electromechanical impactor has been developed to provide a safe and inexpensive method of ureteral stone fragmentation or disimpaction. These studies were performed to establish limits of safety that may allow use of the electromechanical impactor for stone fragmentation in the ureter without the need for ureteroscopy.
Early clinical experience with the transverse colon-gastric tube continent urinary reservoir, The clinical results of the first 4 patients undergoing reconstruction with the transverse colon-gastric tube urinary reservoir are presented. All patients had a minimum 1-year follow-up. All 4 patients are continent with stable or improved renal function. Two patients required reoperation. Indications as well as possible modifications of this procedure are discussed.
Lower urinary tract reconstruction following cystectomy: experience and results in 126 patients using the Kock ileal reservoir with bilateral ureteroileal urethrostomy, Between May 1986 and February 1990. 126 consecutive men underwent lower urinary tract reconstruction by means of bilateral ureteroileal urethrostomy using a Kock ileal reservoir. The early complication rate was 11.1%. Late complications requiring rehospitalization or reoperation have been surprisingly few: 1 for prolapse of the afferent antirefluxing nipple valve. 1 for calculi and 4 for artificial urinary sphincter placement due to unsatisfactory continence. Good continence has been achieved in 94% of the patients during the day and in 84% at night. Tumor recurred in the pelvis in 5 patients. with 4 requiring cutaneous urinary diversion. All patients had progression or died of metastatic disease. Our experience has yielded extraordinary results in terms of patient acceptance with few late complications or need for reoperation.
Penile sensory disorders in erectile dysfunction: results of a comprehensive neuro-urophysiological diagnostic evaluation in 123 patients, A total of 123 patients with complaints of erectile dysfunction and no clinically overt neurological disease underwent a comprehensive neuro-urophysiological diagnostic evaluation. The results were compared with those obtained in 50 healthy volunteers. Data gathered consisted of somatosensory evoked potentials from the posterior tibial nerve (tibial evoked potential) and from the dorsal penile nerve (pudendal evoked potential). Also. 2 sacral reflex latencies were measured (bulbocavernosus reflex and urethro-anal reflex). A total of 58 patients (47%) had at least 1 abnormal neuro-urophysiological measurement. Neuro-urophysiological abnormalities were found more frequently in older patients. The tibial evoked potential was abnormal in 30 patients (24%). pudendal evoked potential in 21 (17%). bulbocavernosus reflex in 26 (21%) and urethro-anal reflex in 32 (26%). It was concluded that somatosensory disturbances constitute an important part of neuro-urophysiological abnormalities. Our results suggest a relationship between erectile dysfunction and subclinical. age-related (penile) sensory disorders. Our study corroborates the importance of penile sensibility for erectile (patho)physiology as suggested by others and supports the concept of sensory deficit impotence as an important cause of erectile dysfunction.
Controlled trial of infusion cavernosometry in impotent and potent men, Infusion cavernosometry often is performed to diagnose venous leak impotence. However. normal values have seldom been established in proved potent men. We performed a prospective study of infusion cavernosometry on nocturnal penile tumescence confirmed potent male volunteers and impotent men. Of 20 potent male controls 19 had resistance values of greater than 5 (mm. Hg.minute)/ml. Of 38 impotent men 20 (53%) had resistance values of less than 5 (mm.Hg. minute)/ml. There was considerable overlap between resistance values and infusion rates in potent and impotent men. Impotent men with resistances of greater than 5 (mm.Hg.minute)/ml. more often had normal nocturnal penile tumescence results than men with lower resistance values. Venous leakage is a significant cause of impotence.
Pharmacological erection program using prostaglandin E1, A total of 72 impotent patients entered into a pharmacological erection program using prostaglandin E1. Of the men 35 (49%) used prostaglandin E1 on a regular basis. while 37 (51%) failed to continue in the program beyond the in-office dose titration period. In patients who continue to use prostaglandin E1 the median duration of drug use is 7 months. with a range of 2 to 28 months. There have been no instances of cavernous fibrosis. systemic reaction or chemical priapism (erection present longer than 4 hours) in any patient. Only 8 men (11%) were unable to achieve an adequate erection with prostaglandin E1 injections. The most common adverse effect of prostaglandin E1 was penile pain after injection. The incidence of severe pain leading to drug discontinuation was 17% (12 of 72 patients) while mild to moderate pain occurred in 22% (16 of 72). Over-all. intracavernous prostaglandin E1 injections appear to be a safe. effective treatment for impotence in most men.
Urinary excretion of Tamm-Horsfall protein in elderly women, The incidence of urinary tract infection is higher in the geriatric population than in younger adults despite the exclusion of patients with known risk factors. Tamm-Horsfall protein. a renal glycoprotein excreted in urine. may constitute a natural defense mechanism against ascending urinary tract infection by binding mannose-sensitive fimbriated microorganisms. We hypothesized that the quantity of Tamm-Horsfall protein excreted is decreased in the elderly. Native aggregated Tamm-Horsfall protein was measured in urine samples from 24 young women (group 1. mean age 33 years) and 47 female nursing home patients (group 2. mean age 84 years) using enzyme-linked immunosorbent assay techniques. Another 16 elderly women (group 3. mean age 85 years) had active urinary tract infection. The aggregated Tamm-Horsfall protein was then disaggregated by dilution and quantified. Significant differences in mean urinary disaggregated Tamm-Horsfall protein concentrations were found between groups 1 (64.22 mg./l.) and 2 (35.07 mg./l.). and between groups 1 and 3 (34.71 mg./l.). respectively. In contrast. mean aggregated Tamm-Horsfall protein levels were significantly higher in group 2 (1.56 mg./l.) than in group 1 (0.92 mg./l.) or group 3 (0.97 mg./l.). Our studies show that urinary disaggregated Tamm-Horsfall protein concentration is decreased in the elderly. and that aggregated Tamm-Horsfall protein is increased compared to younger adults. The aggregated Tamm-Horsfall protein concentration is decreased in the elderly during episodes of urinary tract infection.
Clinical application of video image flexible ureteronephroscope for diagnosis of upper urinary tract disorders, Ureteroscopy has become the diagnostic and therapeutic procedure of choice for many conditions of the upper urinary tract. Technology is progressing rapidly in endourology. facilitating both goals. As reported previously. we developed a 2F video image flexible ureteronephroscope. This instrument is the smallest caliber of all ureteronephroscopes available to date. Because of the small diameter the device can be inserted into the ureter cystoscopically in a manner similar to catheter insertion. The procedure is done with the patient under local anesthesia. We performed ureteronephroscopic procedures on 79 patients using mainly a 6F passively deflecting flexible ureteronephroscope. which consists of the aforementioned 2F video image flexible ureteronephroscope and a 3F working channel. The area to be viewed was accessed successfully in 41 of 43 patients (95%). Over-all. diagnostic maneuvers were successful in 64 of 79 patients (87%). We suggest that the 2F and 6F flexible ureteronephroscopes would be indicated when conclusive diagnosis for upper urinary disease is not obtained by other means.
Filling and voiding pressures measured by ambulatory monitoring and conventional studies during natural and artificial bladder filling, A total of 20 men awaiting elective prostatectomy for bladder outflow obstruction underwent conventional medium filling cystometry and ambulatory monitoring of bladder pressures during natural bladder filling. Total bladder capacity was similar during both tests (medium filling cystometry 256 +/- 138 ml. and ambulatory monitoring 248 +/- 120 ml.. p not significant) as was the voided volume (medium filling cystometry 180 +/- 100 ml. and ambulatory monitoring 179 +/- 88 ml.. p not significant). However. the peak urinary flow rate at the end of medium filling cystometry (4 +/- 6 ml. per second) was significantly lower than during ambulatory monitoring (9 +/- 4 ml. per second. p less than 0.05). The bladder contraction pressure during medium filling cystometry (79 +/- 44 cm. water) was significantly lower than during ambulatory monitoring (107 +/- 39 cm. water. p less than 0.005). Bladder pressures during voiding recorded after natural filling were significantly greater than after artificial filling. This finding may have significant implications for the use of conventional cystometry to study conditions such as outflow obstruction.
Transperineal ultrasonic voiding cystourethrography using a newly devised chair, Using a newly devised chair for transperineal sonography we performed ultrasonic voiding cystourethrography in a total of 219 male patients and volunteers. The study produced adequate images in more than 80% of the people examined. Valsalva's maneuver during urination elicited an intermittent depression of the bladder dome toward the bladder base. In patients with benign prostatic hyperplasia or bladder neck contracture the bladder neck did not open well. Urethral stricture was associated with a marked opening of the bladder neck and posterior urethra. In patients with detrusor-sphincter dyssynergia an involuntary contraction of the external sphincter was observed. These results indicate that this method is useful for screening male patients for diseases causing voiding disturbance and for making differential diagnosis of such diseases.
Segmental renal hypoplasia of vascular origin causing renal hypertension in a 3-year-old girl, A rare case of renal hypertension in a 3-year-old girl caused by segmental renal hypoplasia of vascular origin is presented. Resection of the hypoplastic segment of the kidney permitted successful treatment of the high blood pressure with preservation of renal function. Elevated plasma renin activity in the renal vein of the affected side and biochemical investigations demonstrated that the resected segment of the renal cortex was the source of the renin leading to hypertension by activation of the renin-angiotensin-aldosterone system.
Chromosomal anomaly and malformation syndrome with abdominal polyorchidism, We describe a neonate who presented with multiple severe malformations including polyorchidism. To our knowledge this is the second case reported with ipsilateral testes located intra-abdominally. Chromosomal studies in cases of polyorchidism have been reported previously only once and the patient exhibited a normal karyotype. Our patient had a chromosome 21 long arm deletion. Interestingly. a trisomy 21 patient has been reported with agonadism. We suggest that genes on chromosome 21 may have some role in gonadal development.
Epilation of hair-bearing urethral grafts using the neodymium:YAG surgical laser, Nonhair-bearing skin should be used when grafting is necessary during urethroplasty for stricture or hypospadias repair. Occasionally. this is not possible or hair-bearing skin is used inadvertently. Traditionally. electrocoagulation has been the method used for epilation when intraluminal hair has become a problem. such as interfering with flow. as a focus for recurrent urinary tract infection or acting as a nidus for calculus formation. Electrocautery also is performed during grafting in an attempt to prevent the growth of hair when hair-bearing skin is used. Unfortunately. due to lack of penetration the hair follicles are not destroyed and the epilating procedure fails or is only partially successful. The neodymium:YAG surgical laser can photocoagulate tissue to a depth up to 5.0 mm. and thus. has the ability to destroy hair follicles. We report 4 cases presenting with clinical problems directly related to hair-bearing urethral grafts successfully treated by neodymium:YAG laser epilation.
Primary seminoma of the seminal vesicle: report of a case, We report on the clinical and histological findings of a primary extragonadal germ cell tumor that was proved to be a seminoma of the seminal vesicle. The patient had left ureteral obstruction at diagnosis. The testes were normal on physical and ultrasound examination. and the retroperitoneum was free of tumor. There was no recurrence 8 months postoperatively.
Three-D muscular arrangement at the ureteropelvic junction and its changes in congenital hydronephrosis: a stereo-morphometric study, Ureteral walls were obtained from twelve autopsies without urological diseases and from surgical material of twelve patients operated for congenital hydronephrosis. The specimens were submitted to computer-assisted analysis of 3-D muscular architecture at the ureteropelvic junction (UPJ). Serial histologic sections in parallel with the wall were prepared. A geometric model was introduced to simplify the muscular layer. replacing bundles with vectors of corresponding size and direction. The vector distribution visualized that normally. the ureteral muscles change their arrangement with age. from a circular pattern in neonates to an oblique mesh in adults. In addition. longitudinal muscles emerged at the age of two years in the subepithelial layer. In patients with congenital hydronephrosis. not only were such growth-related changes ambiguous or lacking. but there also were various abnormalities; segmental muscular hypoplasia. disarrangement of bundles or lack of longitudinal fibers. These were considered to closely correlate with the urinary obstruction in patients with this disease.
Changes in the incidence of alcohol-impaired driving in the United States, 1973-1986, Studies of motor vehicle fatality data have indicated that alcohol involvement in fatal crashes has declined substantially in the United States since 1980. To determine the actual incidence of alcohol-impaired drivers on U.S. roads. a national roadside survey using portable breath-testing devices was carried out in 32 localities in the spring of 1986. The same sampling design and survey procedures used in a 1973 national roadside survey were followed as much as possible. The 1986 survey found 3.1% of the late-night weekend drivers to have a blood alcohol concentration (BAC) of 0.10% or more. compared to 4.9% of drivers in 1973. Similarly. 8.3% of the 1986 drivers were at or above 0.05% BAC. compared to 13.5% in 1973. The data indicate that the incidence of alcohol-impaired driving on weekend nights has fallen by one-third or more in the United States since 1973 and that the decline affected most population subgroups.
Alcohol-related relative risk of fatal driver injuries in relation to driver age and sex, The relative risks of fatal crash involvement at various blood alcohol concentrations (BACs) were examined using data on fatal driver injuries from the Fatal Accident Reporting System in conjunction with driver exposure data from the second national road-side breath-testing survey. Based on driver fatalities in single-vehicle crashes. it was estimated that each 0.02 percentage increase in the BAC of a driver with non-zero BAC nearly doubles the risk of being in a fatal crash. Crash risk was found to increase with increasing BAC among all of the six age and sex groups studied. At BACs in the 0.05-0.09 percent range. the likelihood of a crash was at least nine times greater than at zero BAC for all age groups. Younger drivers with BACs in the 0.05-0.09 range had higher relative risks than older drivers. and females had higher relative risks than males. At very high BACs (at or above 0.15 percent). the risk of crashing was 300 to 600 times the risk at zero or near-zero BACs. These relative risk estimates are considerably higher than estimated in other studies. but other studies have based their estimates on all crashes rather than single-vehicle crashes only. In this study. relative risks were also lower when based on driver fatalities in all crashes. However. when plausible assumptions were made about the BAC distributions of other participants in multiple-vehicle crashes (whose actual BAC is often unknown). the relative risks based on the maximum BAC of the crash participants were nearly as high as those estimated in single-vehicle crashes.
Differences between roadside and subsequent evidential breath alcohol results and their forensic significance, Breath alcohol measurements for forensic purposes are typically not made at the time of a driving incident but at some later time. Therefore. the magnitude of variation in breath alcohol concentration (BrAC) following the time of arrest is of concern. The use of roadside preliminary breath test (PBT) instruments can provide data on BrAC closer to the time of a driving incident and allow for comparison with later evidential analysis. This retrospective study evaluates two distributions (N = 968): differences between PBT results and the first evidential breath test (PBT-BrAC1) and differences between two (duplicate) evidential breath alcohol tests (BrAC1-BrAC2). The two distributions were shown to vary from each other and from the normal with statistical significance (p less than .05). The PBT-BrAC1 distribution had greater variability (SD = .025) than the BrAC1-BrAC2 distribution (SD = .010). An important result was that the PBT was equal to (within duplicate sampling variability) or greater than BrAC1 in approximately 85.5% of the cases. The remaining 14.5% could not be explained by sampling variability within the duplicate test distribution. The variability in both distributions typically exceeds the normally accepted alcohol elimination rates. The conclusion is that differences between roadside and subsequent evidential breath results cannot be attributed solely to absorption or elimination kinetics. Intra-individual breath sample differences can be large and thus obscure the accurate evaluation of absorption and elimination rates. Breath tests conducted within approximately 2 hours of driving will reflect. within experimental uncertainty. the BrAC at the time of driving.
The prevalence of antisocial behavior among U.S. Army DWI offenders, This study compares arrest records for three groups of male soldiers. The first group of 76 had been arrested for DWI. completed a 5-day. in-patient evaluation/education program and were subsequently re-arrested. all within the period from January 1985 through December 1987. The second group of 76 was composed of a random sample. matched by age and ethnicity who had completed the 5-day program following a DWI but had not been re-arrested. The third group was a control group of 76. matched by age and ethnicity. but with no record of DWI. who were randomly selected from the same military units as the initial two groups. Soldiers with one DWI had significantly more arrests than did soldiers in the control group; soldiers with two DWI arrests had significantly more arrests than either of the other groups. The data indicate that soldiers apprehended for DWI are more likely than non-arrestees to be arrested for a wide variety of antisocial behaviors.
Attitudes toward alcoholism among psychologists and marriage, family and child counselors, This study examines the attitudes of 589 randomly chosen licensed California psychologists and marriage. family and child counselors toward alcoholism. Their anonymous replies revealed that the two professional groups were relatively homogeneous in nature. The majority of each subscribed to the disease concept of alcoholism. recognized the importance of abstinence in problem resolution and as a treatment goal. rejected insight as a prerequisite of sobriety. believed in a positive prognosis and were extremely willing to be involved in the treatment of alcoholics. Negative attitudes toward alcoholics were expressed with respect to attribution of responsibility and a persistence of stigmatization of the alcoholic.
Gender-specific drinking styles in alcoholics and nonalcoholics, This study examined sex differences in drinking style when considering both alcoholics and nonalcoholics (controls). The Alcohol Use Inventory was employed as a descriptive instrument. Of the 16 primary scales two results of significant interaction were obtained indicating sex differences in problem drinking practices corrected. as it were. for sex differences in normal drinking practices. Female alcoholics used alcohol to alter their mood more than did the alcoholic men. whereas women in the control group used it less for this purpose than did the male controls. The second interaction effect indicated that female alcoholics drank in response to marital difficulties much more than did male alcoholics. The control women. by contrast. demonstrated less of a likelihood to drink for this reason than did male controls.
Personality characteristics of alcoholic fathers and their sons, Recovering alcoholic fathers with a positive family history of alcoholism and their 10-15 year-old sons were assessed on a variety of personality measures and compared to a matched group of nonalcoholic fathers with a negative family history of alcoholism. and their sons. Assessment instruments for the sons included the Personality Inventory for Children. High School Personality Questionnaire. Junior Eysenck Personality Inventory and the Tridimensional Personality Questionnaire. Comparable questionnaires were administered to the fathers: the MMPI. 16 Personality Factor Questionnaire. Eysenck Personality Inventory and the Tridimensional Personality Questionnaire. No psychopathology or extreme personality variants were observed in either fathers' or sons' groups. However. MANOVAS and linear discriminant functions revealed significant differences on several personality measures between fathers' and sons' groups. Compared to sons of nonalcoholics. sons of alcoholics were relatively more compulsive. insecure and fearful while being more subdued and detached. The recovering alcoholics were more impulsive and regimented than the nonalcoholics. An index resulting from the combination of the best personality discriminators was significantly correlated in father-son pairs. In addition. this index was significantly correlated with key neurocognitive variables from our previous study which assessed the same father-son pairs. This atypical CNS profile. encompassing altered electrophysiology. neuropsychological performance and personality traits. may be useful in identifying those at increased risk for developing alcoholism.
Drinking among subgroups in the adult population of New York State: a classification analysis using CART, Using data from a representative sample of 5.952 adults in New York State. CART (Classification and Regression Trees) methodology was used to classify abstainers and drinkers according to interactions among 10 sociodemographic characteristics. A CART analysis classifying abstainers versus drinkers selected income at $25.000 for the initial split with high rates of drinking among higher income individuals. Low rates of drinking were shown for low income women with less than a high school education. A second CART analysis was performed for drinkers only. revealing a number of subgroups of heavier drinkers. including non-Jewish. non-Oriental men under 35 years old and never-married or divorced minority women over the age of 24.
The prevalence and extent of vibration sensitivity impairment in men with chronic ethanol abuse, We have studied vibration sensitivity impairment in 100 male alcoholic veterans and 52 control subjects who had no etiologic factors for peripheral neuropathy. Vibration sensitivity was quantitated at the hallux with the Vibration Sensitivity Tester. Alcoholic subjects had impairment of vibration sensitivity when compared with control subjects (p less than .001). This difference persisted when a covariance analysis was performed which included age (coefficient +/- SE: 1.40 +/- 0.35 units. p less than .001). Asymptomatic subjects also had vibration sensitivity impairment (p less than .01). In subjects whose ages were greater than or equal to 45 years. 47% of the alcoholics had poorer vibration sensitivity than did any of the controls. Among the alcoholic subjects there were significant correlations of the vibration perception threshold with both age (r = 0.39. p less than .001) and drinking duration (r = 0.35. p less than .001). In multiple regression analyses these associations remained significant (p less than .05). These data indicate that vibration sensitivity impairment is highly prevalent in alcoholic subjects and that impairment may even occur in those who are asymptomatic.
Randomised trial of laxatives in treatment of childhood encopresis, Primary faecal incontinence (encopresis) in children is usually treated with laxative medication and a behaviour modification programme aimed at promoting regular toileting. but the effectiveness of laxatives has never been adequately investigated. 169 children with encopresis and evidence of stool on plain abdominal radiograph were randomly allocated to receive multimodal (MM) therapy (laxatives plus behaviour modification; n = 83) or behaviour modification alone (BM; n = 86). Mean (SD) follow-up was 55.1 (27.0) weeks and 56.7 (32.0) weeks. respectively. By 12 months' follow-up 42 (51%) of the MM group and 31 (36%) of the BM group (p = 0.079) had achieved remission (at least one 4 week period with no soiling episodes) and 52 (63%) vs 37 (43%) (p = 0.016) had achieved at least partial remission (soiling no more than once a week). MM subjects achieved remission significantly sooner than BM subjects. and the difference in the Kaplan-Meier remission curves was most striking in the first 30 weeks of follow-up (p = 0.012). The patterns of compliance with toileting in the treatment groups were almost identical. although about 1 in 8 children overall did not comply with the sitting programme. After exclusion of the 24 poor compliers. there was no significant difference between BM and MM groups. This study shows a clear advantage overall for the use of laxative medication. although the benefit may not be as great for children who are able to maintain regular toileting.
Platelet aggregates in small lung vessels and death during liver transplantation, 10 children who died suddenly during liver transplantation were found at necropsy to have extensive obstruction of small lung vessels by platelet aggregates. In 7 of these patients pulmonary artery pressure changes before death were consistent with acute obstruction of the pulmonary vascular bed. Platelet aggregates were not strikingly increased in blood vessels in other tissues. No single obvious cause for these unusual histological findings could be identified. although the presence of intravascular catheters. perioperative blood and platelet concentrate transfusions. and cellular debris from the liver forced into the circulation during surgery might predispose to platelet aggregation.
Adjuvant chemotherapy in early breast cancer and incidence of new primary malignancies, Adjuvant chemotherapy is increasingly being given to patients with early breast cancer. Long-term follow-up studies suggest a higher frequency of secondary tumours. especially leukaemias. among women receiving such cytotoxic drugs. We studied the frequency of new primary malignancies in 1113 patients with early breast cancer who had been included in a randomised trial to compare chemotherapy as an adjunct to primary surgery with adjuvant locoregional radiotherapy. The estimated rate of new primary malignancies at ten years was significantly lower (p less than 0.0003) in the chemotherapy group (1%) than in the radiotherapy group (6%). The corresponding rate among 1986 patients treated with surgery alone was 5%. Our findings suggest that adjuvant chemotherapy in early breast cancer may protect against the development of new primary tumours in the first ten years of follow-up.
Prognostic value of a treadmill exercise score in outpatients with suspected coronary artery disease, BACKGROUND. The treadmill exercise test identifies patients with different degrees of risk of death from cardiovascular events. We devised a prognostic score. based on the results of treadmill exercise testing. that accurately predicts outcome among inpatients referred for cardiac catheterization. This study was designed to determine whether this score could also accurately predict prognosis in unselected outpatients. METHODS. We prospectively studied 613 consecutive outpatients with suspected coronary disease who were referred for exercise testing between 1983 and 1985. Follow-up was 98 percent complete at four years. The treadmill score was calculated as follows: duration of exercise in minutes--(5 x the maximal ST-segment deviation during or after exercise. in millimeters)--(4 x the treadmill angina index). The numerical treadmill angina index was 0 for no angina. 1 for nonlimiting angina. and 2 for exercise-limiting angina. Treadmill scores ranged from -25 (indicating the highest risk) to +15 (indicating the lowest risk). RESULTS. Predicted outcomes for the outpatients. based on their treadmill scores. agreed closely with the observed outcomes. The score accurately separated patients who subsequently died from those who lived for four years (area under the receiver-operating-characteristic curve = 0.849). The treadmill score was a better discriminator than the clinical data and was even more useful for outpatients than it had been for inpatients. Approximately two thirds of the outpatients had treadmill scores indicating low risk (greater than or equal to +5). reflecting longer exercise times and little or no ST-segment deviation. and their four-year survival rate was 99 percent (average annual mortality rate. 0.25 percent). Four percent of the outpatients had scores indicating high risk (less than -10). reflecting shorter exercise times and more severe ST-segment deviation; their four-year survival rate was 79 percent (average annual mortality rate. 5 percent). CONCLUSIONS. The treadmill score is a useful and valid tool that can help clinicians determine prognosis and decide whether to refer outpatients with suspected coronary disease for cardiac catheterization. In this study. it was a better predictor of outcome than the clinical assessment.
Symptomatic Chiari malformation in adults: a new classification based on magnetic resonance imaging with clinical and prognostic significance, Thirty-five consecutive adults with Chiari malformation and progressive symptoms underwent surgical treatment at a single institution over a 3-year period. All patients underwent magnetic resonance imaging scan before and after surgery. Images of the craniovertebral junction confirmed tonsillar herniation in all cases and allowed the definition of two anatomically distinct categories of the Chiari malformation in this age group. Twenty of the 35 patients had concomitant syringomyelia and were classified as Type A. The remaining 15 patients had evidence of frank herniation of the brain stem below the foramen magnum without evidence of syringomyelia and were labeled Type B. Type A patients had a predominant central cord symptomatology; Type B patients exhibited signs and symptoms of brain stem or cerebellar compression. The principal surgical procedure consisted of decompression of the foramen magnum. opening of the fourth ventricular outlet. and plugging of the obex. Significant improvement in preoperative symptoms and signs was observed in 9 of the 20 patients (45%) with syringomyelia (Type A). as compared to 13 of the 15 patients (87%) without syringomyelia (Type B). Postoperative reduction in syrinx volume was observed in 11 of the 20 patients with syringomyelia. including all 9 patients with excellent results. Magnetic resonance imaging has allowed a classification of the adult Chiari malformation in adults based on objective anatomic criteria. with clinical and prognostic relevance. The presence of syringomyelia implies a less favorable response to surgical intervention.
Conservative treatment of patients with acoustic tumors, Seventy of 178 patients with acoustic tumors initially were treated conservatively and have been followed up for an average of 26 +/- 2 months. The tumor size was determined by the mean maximum anteroposterior and mediolateral diameters. using computed tomographic or magnetic resonance imaging scans obtained sequentially throughout the follow-up period. The average tumor growth was 1.6 +/- 0.4 mm the 1st year. and 1.9 +/- 1.0 mm the 2nd year (range. -2 to 17 mm/y): 4 tumors showed apparent regression. 28 (40%) had no detectable growth. and 37 (53%) exhibited growth (average. 3.8 +/- 1.2 mm/y). Within individual patients. the tumor growth rate determined during the 1st year of follow-up was predictive of tumor growth rate determined during the following year. Rapid tumor growth or clinical deterioration in 9 of the 70 patients (13%) who initially were treated conservatively necessitated subsequent surgery an average of 14 +/- 5 months after the patient was initially seen. This group had a larger initial tumor size (27.0 +/- 3.4 mm vs. 21.3 +/- 0.9 mm. P less than 0.05). and a faster 1-year growth rate (7.9 +/- 2.3 mm/y vs. 1.3 +/- 0.3 mm/y. P less than 0.05) than the 61 patients who did not require surgery. Two patients. however. experienced neurological deterioration that required surgery. even though there was no tumor growth. The high incidence of acoustic tumors with no detectable growth or apparent spontaneous regression must be taken into account when evaluating the indications for surgery and the efficacy of radiotherapy.
C6 glioma-astrocytoma cell and fetal astrocyte migration into artificial basement membrane: a permissive substrate for neural tumors but not fetal astrocytes, Cortically homografted C6 glioma-astrocytoma cells both invade the rat host brain as a mass and migrate as individual cells. In contrast. fetal astrocytes derived from homografted whole pieces of fetal cortex migrate only as individual cells throughout the brain of the rat but are not capable of invasion. Our experiment explored the migratory capacity (over 7 days) of cultured purified fetal astrocytes and C6 cells after seeding 10(6) cells on a hydrated artificial basement membrane wafer (Matrigel). The artificial basement membrane wafer was not a suitable substrate for the growth of cultured fetal astrocytes. In contrast. C6 cells migrated as individual cells from the surface of the wafer into the substrate. Individual C6 cells migrated 1.8 mm in the first 4 days and then ceased migration. The C6 cells were observed at the base of a digestion tube that extended from and was open to the surface of the wafer. At 3 days. micropockets were observed to form around each C6 cell at the base of each tube. By 7 days. the majority of pockets observed were large and contained several C6 cells. These multiple cell groups appeared to be progenitors of tumor masses. These data indicate that C6 glioma-astrocytoma cells. which in vivo appear to be a model for glioblastoma multiforme. primarily migrate as individual cells through artificial basement membrane and secondarily form tumor masses. Progenitor tumor masses form by coalescence of individual C6 cell micropockets or the division of a single cell in an individual micropocket.
Failed back surgery syndrome: 5-year follow-up in 102 patients undergoing repeated operation, The indications for repeated operation in patients with persistent or recurrent pain after lumbosacral spine surgery are not well established. Long-term results have been reported infrequently. and in no case has mean follow-up exceeded 3 years. We report 5-year mean follow-up for a series of repeated operations performed between 1979 and 1983. Patient characteristics and modes of treatment have been assessed as predictors of long-term outcome. One hundred two patients with "failed back surgery syndrome" (averaging 2.4 previous operations). who underwent a repeated operation for lumbosacral decompression and/or stabilization. were interviewed by a disinterested third party a mean of 5.05 years postoperatively. Successful outcome (at least 50% sustained relief of pain for 2 years or at last follow-up. and patient satisfaction with the result) was recorded in 34% of patients. Twenty-one patients who were disabled preoperatively returned to work postoperatively; 15 who were working preoperatively became disabled or retired postoperatively. Improvements in activities of daily living were recorded. overall. as often as decrements. Loss of neurological function (strength. sensation. bowel and bladder control) was reported by patients more often than improvement. Most patients reduced or eliminated analgesic intake. Statistical analysis (including univariate and multivariate logistic regression) of patient characteristics as prognostic factors showed significant advantages for young patients and for female patients. Favorable outcome also was associated with a history of good results from previous operations. with the absence of epidural scar requiring surgical lysis. with employment before surgery. and with predominance of radicular (as opposed to axial) pain.
Failed back surgery syndrome: 5-year follow-up after spinal cord stimulator implantation, Spinal cord stimulation. in use for more than 20 years. has evolved into an easily implemented technique. with percutaneous methods for electrode placement. We have reviewed our experience with this technique in treating "failed back surgery syndrome." and have assessed patient and treatment characteristics as predictors of long-term outcome. A series of 50 patients with failed back surgery syndrome (averaging 3.1 previous operations). who underwent spinal cord stimulator implantation. was interviewed by impartial third parties. at mean follow-up intervals of 2.2 years and 5.0 years. Successful outcome (at least 50% sustained relief of pain and patient satisfaction with the result) was recorded in 53% of patients at 2.2 years and in 47% of patients at 5.0 years postoperatively. Ten of 40 patients who were disabled preoperatively returned to work. Improvements in activities of daily living were recorded in most patients for most activities; loss of function was rare. Most patients reduced or eliminated analgesic intake. Statistical analysis (including univariate and multivariate logistic regression) of patient characteristics as prognostic factors showed significant advantages for female patients and for those with programmable multi-contact implanted devices. These results. in patients with postsurgical lumbar arachnoid and epidural fibrosis and without surgically remediable lesions. compare favorably with the results in two separate series of patients with failed back surgery syndrome. in whom 1) surgical lesions were diagnosed and repeated operation performed; and 2) monoradicular pain syndromes were diagnosed and dorsal root ganglionectomies performed at our institution. This suggests the need for further assessment of selection criteria. critical analysis of treatment outcome. and prospective study of spinal cord stimulation and alternative approaches to failed back surgery syndrome.
Use of intrathecally administered morphine in the treatment of postoperative pain after lumbar spinal surgery: a prospective, double-blind, placebo-controlled study, Improved control of postoperative pain is now known to reduce the incidence of morbidity. Although spinally administered narcotics have found a clear role in chest and abdominal surgery. their role in lumbar spinal surgery is debated. We conducted a prospective. double-blind. randomized. placebo-controlled trial of intrathecally administered morphine sulfate after lumbar spinal surgery in 56 patients. Patients received 0. 0.125. 0.25. or 0.5 mg of intrathecally administered morphine during extradural lumbar spinal operations. and the effects on postoperative analog pain scores. narcotic consumption. complications. and length of hospitalization were assessed. As compared with systemic narcotic administration. intrathecally administered morphine provided superior analgesia in a dose-dependent fashion without an increase in narcotic side effects. Consumption of parenteral narcotics on the first postoperative day and over the total hospitalization period decreased in correlation with increasing doses of intrathecally administered morphine. Mean length of hospitalization was significantly decreased. as compared with the control group. in patients receiving 0.25 or 0.5 mg of intrathecally administered morphine. When proper precautions are observed. intrathecally administered morphine can improve the postoperative care of patients undergoing lumbar spinal surgery.
A familial coincidence of pseudotumor cerebri and communicating hydrocephalus, A family in which the mother and two of four daughters had a diagnosis of pseudotumor cerebri and one son developed communicating hydrocephalus is described. The other two daughters both have a long history of headaches but no signs of intracranial hypertension. The argument is advanced that there exists a defect of cerebrospinal fluid absorption common to pseudotumor cerebri and communicating hydrocephalus.
Giant pseudoaneurysm of the extracranial vertebral artery successfully treated using intraoperative balloon catheters, Traumatic pseudoaneurysms of the extracranial vertebral artery rarely occur. because of its deeply protected anatomical location. Because the direct surgical approach has resulted in high morbidity and mortality rates. ligation of the vertebral artery has been adopted. but this can cause an ischemia in the vertebrobasilar system. We report the case of a 73-year-old woman with a huge pseudoaneurysm of the right vertebral artery that occurred after attempted placement of a cardiac pacemaker. The aneurysm was 7 x 7 x 5 cm in size and its neck was situated just distal to the right subclavian artery. Direct surgical repair of the injured vessel and removal of the aneurysm were successfully performed using balloon catheters placed intraoperatively in both the innominate artery and the right vertebral artery.
Brain stem abscess treated successfully by medical therapy, A case of a solitary brain stem abscess in a 55-year-old man is presented. The computed tomographic scan and clinical picture allowed the presumptive diagnosis to be made. The abscess resolved completely after treatment with chloramphenicol. vancomycin. and ceftazidime administered intravenously. Medical therapy should be considered as an effective treatment of a brain stem abscess. provided the antibiotic therapy is administered under close clinical and computed tomographic monitoring.
Double compartment hydrocephalus in an adult, A case of double-compartment hydrocephalus in an adult is presented. Although this entity is infrequently noted in children. it is diagnosed even more rarely in the adult population. A discussion of the spectrum of abnormal cerebrospinal fluid dynamics of the 4th ventricle and treatment options are presented.
Continuous intratumoral infusion of methotrexate for recurrent glioblastoma: a pilot study, Five patients with documented recurrences of glioblastoma multiforme were given continuous infusions of methotrexate delivered intratumorally using implantable catheters and subcutaneous refillable pumps. A continuous infusion of methotrexate (1 mg/d) was begun with concomitant oral administration of folinic acid. The methotrexate dose was increased every 2 weeks to 3. 10. 30. and. ultimately. 75 mg/d in two patients. Samples of serum and ventricular cerebrospinal fluid (CSF) were obtained to determine the levels of methotrexate and total bioactive folates. and brain tissue was obtained from two patients for determination of methotrexate concentration. The patients survived from 7 to 49 weeks after the implantation of the infusion device. Neither the clinical examination nor sequential radiological studies gave clear evidence of reduction in tumor size. Pneumonia developed in one patient. and mild hepatitis and increased seizure frequency in another. Methotrexate was stable in the delivery system over 12 days. and ventricular CSF reached steady-state levels by 5 days. Steady-state ventricular CSF levels of methotrexate were higher than serum levels in some patients. while the reverse was true in others. Levels of total bioactive folates in the CSF did not increase above the normal range. Methotrexate concentrations were highest at the center of the tumor. but measurable amounts of methotrexate were detectable in all areas of the brain. At autopsy in four patients. variable liquefactive necrosis of the brain tumors was seen. and viable tumor was found at the periphery of the tumor bed. These preliminary results suggest that it is technically feasible to infuse methotrexate into brain tumor cavities. and show that little central nervous system or systemic toxicity was encountered in five patients. Better delineation of the safety and efficacy of this therapeutic approach will require further clinical trials.
Subependymoma with rhabdomyosarcomatous differentiation: report of a case and literature review, A unique gliomesenchymal neoplasm. consisting of a subependymoma. a form of low-grade glioma. and a rhabdomyosarcoma. is described. It arose and recurred in the brain stem of a 52-year-old man. Immunohistochemical studies demonstrated the presence of a neuroectodermal marker S-100 protein within some sarcoma cells. The occurrence of this rare tumor supports the concept that striated muscle may derive from a neuroectodermal precursor lesion.
The relationship between recent cocaine use and pregnancy outcome, We conducted urine screening for cocaine metabolite in 500 consecutive women admitted to a labor and delivery unit. The pregnancy outcome of 411 of the women was determined at that admission. The prevalence of cocaine-positive urines was 15.3% (95% confidence interval 11.8-18.8%). A subset of this population that had not received prenatal care had a prevalence of 62% (95% confidence interval 47.2-76.6%). Women with positive urines were almost four times more likely to have preterm labor and over twice as likely to deliver a premature infant or one with a 1-minute Apgar score of 6 or lower. Our findings support the concept that urine drug screening for cocaine and/or other drugs of abuse should be considered in patients who present with no prenatal care. premature labor. premature delivery. and delivery of an infant with a 1-minute Apgar score of 6 or less. This strategy may enable us to identify and bring to therapy a population of women that could potentially go unrecognized.
Uterine contraction pressures achieved in parturients with active phase arrest, An adequate trial of labor preceding cesarean delivery for arrest of cervical dilatation in the active phase of labor has not been defined precisely. We reviewed the records of 85 consecutive women at term who received oxytocin for induction or augmentation of labor and who subsequently delivered by cesarean for arrest of labor in the active phase. The mean duration of oxytocin infusion was 15 hours for induction of labor and 8.9 hours for augmentation. Thirty-four (92%) of the 37 women who received oxytocin induction and 44 (92%) of the 48 who had oxytocin for augmentation achieved at least 200 Montevideo units of uterine pressure. All 85 newborns were vigorous at birth and had no complications during their stay in the hospital nursery. Evaluation of uterine contraction pressure can provide a quantifiable end point for the management of oxytocin induction or augmentation of labor.
Umbilical artery resistance index as a screening test for fetal well-being. I: Prospective revealed evaluation, Abnormalities of the human fetoplacental circulation. a common association with fetal morbidity and mortality. can be detected by Doppler ultrasound examination of the umbilical arterial blood flow. The value of this procedure as a screening test was assessed in 369 women whose fetuses were evaluated on 1354 occasions using both computerized antenatal fetal heart rate (FHR) analysis and continuous-wave Doppler ultrasound. The FHR analyses were used to guide management. but the results of the Doppler measurements were not made available to the clinical staff. The mean duration of each nonstress test (NST) was 27 minutes. compared with 6 minutes for the Doppler examination. Increased resistance indices in the umbilical artery identified those fetuses with an abnormal NST or a clinical diagnosis of antenatal distress with a high sensitivity and negative predictive value. The high rate of false-positive results with respect to these two end points was reduced when fetal distress in labor was included as a third end point. The value of the Doppler examination in predicting fetal distress was applicable to appropriately grown as well as small for gestational age fetuses.
Umbilical artery resistance index as a screening test for fetal well-being. II: Randomized feasibility study, To determine whether the time taken for fetal assessment could safely be reduced by preliminary screening with Doppler ultrasound. 897 women having fetal assessment in the high-risk unit of the John Radcliffe Hospital. Oxford. were randomly allocated to two groups. In the Doppler group. preliminary assessment was by umbilical artery resistance estimation. and in the fetal heart rate (FHR) group by computerized FHR analysis. To minimize the risk of failing to recognize fetal distress. the criteria for using the nonallocated method as well were deliberately conservative. Thus. 66% of the 1869 Doppler studies done in the Doppler group and 39% of the 2069 FHR tests done in the FHR group needed to be followed by the nonallocated tests. Trained nursing staff performed the Doppler studies as part of their routine duties. Doppler studies were unsuccessful in obtaining a result on 26% of the occasions. Under the above clinical circumstances. preliminary Doppler screening did not reduce the time taken for fetal assessment. There were no significant differences in perinatal outcome between the groups. except that emergency as opposed to elective cesareans were less frequent in the Doppler group. As this finding was not predicted by previous hypothesis. it needs to be confirmed.
Doppler evaluation of umbilical and uterine-arcuate arteries in the postdates pregnancy, To assess the correlation between Doppler velocimetry and perinatal outcome in the postdates pregnancy. 75 women who were at least 41 weeks' gestation were evaluated twice weekly until delivery. Evaluation included Doppler velocimetry of the umbilical and uterine-arcuate arteries. as well as nonstress testing and amniotic fluid volume estimation. The mean umbilical artery systolic-diastolic ratio (S/D) was significantly higher in the pregnancies with subsequent abnormal perinatal outcomes than in those with normal outcomes (2.42 versus 2.19; P = .03). Using a receiver operating characteristic curve. an abnormal umbilical artery S/D was defined as 2.40 or greater. Using this value. sensitivity was 57.1% and specificity was 77.8%. Our study suggests that an umbilical artery S/D of 2.40. rather than the more traditionally accepted cutoff of 3.0. may be a useful threshold to identify those postdates pregnancies at high risk for abnormal perinatal outcome.
The impact of National Health Service Corps physicians in the lowering perinatal mortality rate in Dade County, Florida, In some parts of Dade County. Florida. perinatal mortality rates have revealed serious problems in the delivery of health care to poor pregnant women. From 1982-1985. the reported perinatal mortality rates varied from 32-36 per 1000 live births. more than double the national average. Under the leadership of the Primary Health Care Consortium of Dade County (a federation of community health centers and other primary care providers). National Health Service Corps obstetricians and pediatricians served inner-city. medically needy patients as part of a coordinated perinatal plan from 1987-1989. Data on fetal and neonatal deaths. collected from census tracts adjacent to the community health centers. were used to study the impact of Corps obstetrician and pediatrician placement. The respective perinatal mortality rates were compared with those of 1986 as historic controls. Within a year. the overall perinatal mortality rate was reduced by 45%. As a result. an estimated 320 lives were saved between 1987-1989. This public health achievement represents a measurable impact due to assignment of National Health Service Corps physicians and can be used as a working model to reduce perinatal mortality in medically underserved communities in the United States.
Problems encountered with the Bethesda System: the University of Iowa experience, This paper provides a descriptive summary of 1 year's experience with the Bethesda Cytologic Classification System at the University of Iowa Hospitals and Clinics. Cytotechnologists and pathologists criticized the failure of the new classification system to provide microscopic criteria for the following categories: adequacy of the smear (satisfactory. less than optimal. unsatisfactory). atypical squamous cells of undetermined significance. atypical glandular cells of undetermined significance. and inflammation-associated changes. Clinicians criticized the "less than optimal" category and the reporting of koilocytosis. moderate dysplasia. and endometrial cells. Suggestions for modifying the Bethesda System include: eliminating the less than optimal response. defining what constitutes an unsatisfactory smear. eliminating the terms low-grade and high-grade squamous intraepithelial lesion. and changing the reporting of endometrial cells.
A computer method for visual presentation and programmed evaluation of labor, Manual graphing of the progress of labor is considered useful but is not often done. The early detection of some deviations requires special graphics aids. Our objective was to develop an easy-to-use computer program for the integrated visual presentation of information characterizing the progress of labor. Through the use of inexpensive personal computers equipped with graphics monitors. the program provides a combined graphics display of timed progressive cervical dilatation. fetal station. and stimulation of uterine activity (oxytocin infusion). For the early detection of abnormalities. phase-specific normal ranges (reference areas) are displayed. In addition. protraction/arrest as well as precipitate labor disorders are highlighted and computer messages are displayed. The program was evaluated through the assessment of 405 labors entered into a local area network of computers. On average. the program identified 1.5 abnormalities per recorded labor (2.0 for labors resulting in vaginal delivery). The graphic presentation of the labor curve. produced within 3 seconds. displayed 27% more information than the tabular format on the same screen area and provided a single-screen display of the labor curve even for patients with excessive data. The computer-generated display of labor curves facilitates visual presentation and interpretation of labor progress and can also help to translate quality assurance criteria into clinical practice.
Clinical use of immunoperoxidase markers in excluding ectopic gestation, Ectopic pregnancy is suspected when a pregnancy test is positive and an Arias-Stella phenomenon with decidua is seen on endometrial curettings in the absence of chorionic villi and trophoblast. We performed immunoperoxidase stains for beta-hCG. hPL. placental alkaline phosphatase. and keratin (AE1/AE3) on endometrial curettings of 72 patients with first-trimester bleeding in whom ectopic pregnancy was suspected based on routine hematoxylin and eosin (H&E) stain. Negative immunoperoxidase stains correlated with a retrospective patient chart review identified only ten patients with extrauterine pregnancy. a prevalence of 14%. The sensitivity of hCG. hPL. placental alkaline phosphatase. and keratin markers in detecting trophoblastic cells in the curettings was 42. 48. 24. and 69%. respectively. Each marker had a specificity of 100%. When both keratin and hPL were used. the sensitivity improved to 73%; however. there was no advantage in using three or more markers. We conclude that 73% of patients suspected to have ectopic pregnancy would be spared additional diagnostic techniques when immunoperoxidase markers for keratin and hPL are used on endometrial curettings without trophoblast on routine H&E stain. The procedure requires only 3 hours of laboratory time.
Laparoscopic tubal sterilization under local anesthesia in women with cyanotic heart disease, Laparoscopic tubal sterilization under local anesthesia with intravenous sedation has been shown to be a safe procedure. However. the use of laparoscopy in patients with cyanotic cardiovascular disease is controversial and is generally contraindicated. Five women were referred with uncorrectable cyanotic heart disease and pulmonary hypertension. The mean preoperative arterial oxygen pressure was 56.2 +/- 5 mmHg (N = 5). After cardiology and cardiovascular anesthesia consultation and clearance. the patients underwent laparoscopic sterilization with Silastic rings under local anesthesia using direct trocar entry. Continuous hemodynamic monitoring and pulse oximetry were employed. The patients were kept in the intensive care unit or the hospital for 24 hours for monitoring. and all did well. This hospital for 24 hours for monitoring. and all did well. This small retrospective series demonstrates that laparoscopic sterilization under local anesthesia is a sterilization technique that may be suitable and safe for such patients when appropriate monitoring is performed. Tubal sterilization may be the contraceptive method of choice in women with heart disease when pregnancy is contraindicated.
Improving the Cytobrush as an aid in the evaluation of the abnormal Papanicolaou test, In a series of 39 patients undergoing cervical conization. the Cytobrush was used to determine whether dysplasia involved the endocervical canal. To improve the specificity of the Cytobrush for this purpose. a sleeve was designed to guide the brush into the endocervical canal in order to minimize contamination from ectocervical lesions. Both the unsleeved and sleeved Cytobrush demonstrated good sensitivity for detecting dysplasia within the endocervical canal (89 and 95%. respectively). The sleeved Cytobrush demonstrated greater specificity than the unsleeved Cytobrush (90 versus 60%; P less than .05). Compared with endocervical curettage. the Cytobrush used in conjunction with the described "cytosleeve" offers an inexpensive. less painful. and accurate method of determining endocervical involvement of dysplasia.
The intussusception salpingostomy technique for the therapy of distal oviductal occlusion at laparoscopy, A new technique of salpingostomy by laparoscopy for treatment of distal oviductal occlusion is described. This technique uses sharp dissection and can be performed rapidly. The intussusception salpingostomy is undertaken by making a relatively short incision in the hydrosalpinx and then prolapsing the tubal mucosa through this neostium. The borders of the incision thus act as a restrictive collar to maintain the mucosa in this newly everted configuration. In a series of 40 women subjected to this procedure. 22 were followed for more than 12 months postoperatively; the term pregnancy rate was 22.7%. This fertility is similar to that after salpingostomy by microsurgical laparotomy.
Counseling the infertile couple: when enough is enough, Therapy of infertility rarely offers a clear end point for cessation after repeated failure. Yet fertility treatment. especially if repeatedly unsuccessful. is associated with economic as well as emotional cost. Stopping treatment becomes an increasingly important option for couples whose therapy does not produce the desired result. It is the clinician's obligation to make infertile couples aware of this option early in the treatment plan and to give specific suggestions that allow these couples to stop treatment at a medically arbitrary. yet temporally well-defined point. To this end. we suggest the following for infertile couples undergoing treatment: 1) an ongoing relationship with a qualified counselor; 2) the best estimates for pregnancy rates. including the background (treatment-independent) rate. for all forms of treatment available at any point in time; 3) the option of stopping treatment from the start; 4) encouragement to seek second opinions throughout treatment; 5) time off from treatment; and 6) the opportunity to set arbitrary but relatively firm time limits. Incorporation of these suggestions into the therapeutic plan for infertile couples underscores the imperfect nature of infertility treatment and acknowledges that sometimes the most we can do for our patients is to help them stop.
Relationship between perceived self-control of pain, pain description and functioning, Recent research has shown an association between preferred coping style and pain report. The present study explores in a sample of 51 patients with chronic pain of myofascial origin the relationship between a dispositional measure of coping. the internality dimension of the Pain Locus of Control Scale (PLOC). and ratings of pain intensity. frequency. and pain-related behavioral functioning. Patients above the median on the internality dimension of the PLOC reported their pain as less intense and frequent than those below the median. No differences were noted on the behavioral functioning measures. Results are consistent with previous studies and indicate an association between ability to control pain and variations in magnitude and periodicity of pain. The clinical implication of the data is that strategies which provide reduction in pain intensity and frequency might be expected to result in increased perception of personal control of pain.
Mechanism of analgesia induced by hypnosis and acupuncture: is there a difference, Hypnosis and acupuncture can alleviate experimentally induced pain but the mechanism of analgesia remains unclear for both techniques. Experimental pain was induced by cold pressor test (CPT) in 8 male volunteers. Analgesic effect of hypnosis (HA) and acupuncture (AA) was assessed before and after double-blind administration of placebo or naloxone. in a prospective. cross-over study. We found that pain intensity was significantly lower with HA as compared with AA. both with naloxone (P less than 0.001) and placebo (P less than 0.001). Within HA or AA groups. pain scores did not differ significantly when naloxone or placebo was administered. During AA. however. pain scores were similar to control values when naloxone was given (P = 0.05) but decreased significantly with placebo (P less than 0.002). Analog scales for pain intensity and pain relief showed a good correlation (r = 0.94). Plasma levels of beta-endorphins did not change significantly in any combination. Heart rate. peripheral arterial blood pressure and skin conductance were very insensitive indices to assess pain intensity or relief. as well as intensity of acupuncture stimulation or depth of hypnotic trance. We conclude: (1) HA and AA can significantly reduce pain from CPT. and HA is more effective than AA: (2) HA and AA are not primarily mediated by the opiate endorphin system; and (3) plasmatic levels of beta-endorphins are not significantly affected by either HA or AA nor by naloxone or placebo administration.
Long-term results of peridural morphine in 225 patients, The long-term results of peridural morphine in 225 cancer patients have been evaluated. Two methods were employed: percutaneously implanted catheter (175 patients) and subcutaneous reservoirs (50 patients). In the 225 patients. the mean duration of implantation of the peridural catheter was 47.3 days (7-420 days). the mean daily dose of morphine was 13.4 +/- 6.9 (5-80 mg) delivered by 2.6 +/- 0.7 (1-8) injections. The mean duration of action was calculated to be 9.3 +/- 3.8 h (3-32 h). Satisfactory analgesia was achieved in 133 patients (59.1%) in whom peridural morphine was the sole analgesic treatment. Peridural morphine appeared to be especially effective in patients with pain arising in the abdominal region. Complications due to morphine and the catheter were evaluated.
Ischaemic spinal cord lesion following percutaneous radiofrequency spinal rhizotomy, Two patients are presented in whom percutaneous radiofrequency spinal rhizotomy was complicated by contralateral paresis. Both patients were elderly and suffered from cardiac failure. chronic obstructive respiratory disease. and generalized vascular disease. Investigation of the paresis indicated a contralateral ischaemic cord lesion. It is suggested that local haemodynamic changes induced by heat-mediated rhizotomy may compromise oxygen delivery to the adjacent cord. especially in the presence of pre-existent cardiovascular disease.
The effect of 'detailing' on physicians' prescribing behavior for postsurgical narcotic analgesia, Physicians have been frequently reported to prescribe inadequately pain medication in the hospitalized patient. A number of methods and techniques have been attempted to alter this phenomenon including audit. standard setting. drug utilization evaluation and sanctioning. The purpose of the following study was to demonstrate the behavioral efficacy of the technique of detailing. We reviewed the postsurgical records of 320 patients for pre-established criteria on the administration of meperidine before and after detailing of the proper prescribing with regard to timing and dose. The data show 30% of the sample meeting the criteria before detailing and 43% after detailing had been given. We conclude the method of detailing can be effective in altering physician's prescribing behavior for meperidine in postoperative surgical patients.
The effects of dorsal column stimulation on measures of clinical and experimental pain in man, Despite the extensive use of dorsal column stimulation (DCS) for the control of various chronic pain conditions. most clinicians report only modest success rates. Surprisingly. there has been little placebo-controlled investigation of its efficacy for altering either clinical or experimental pain perception. The current study compared the effects of DCS to placebo stimulation on clinical pain perception. perceived intensity of painful heat stimuli and visual stimuli. and the discrimination of small changes in noxious heat intensity and in light intensity. We found that DCS. but not placebo stimulation. significantly altered ratings of spontaneous clinical pain as well as those of painful cutaneous heat. In addition. heat discrimination thresholds were increased by DCS. but not placebo. On the other hand. DCS had no effect on ratings of visual stimulus intensity nor on visual discrimination. suggesting that the DCS modulation of pain perception was not due to a general change in attention. These data indicate that DCS significantly alters pain transmission in humans. Nevertheless. the relatively small reduction in clinical pain (less than 30%) must be weighed against the invasive nature of electrode implantation.
Comparison of human pain sensation and flexion withdrawal evoked by noxious radiant heat, The purpose of this study was to determine the reliability of flexion withdrawal magnitude as an indicator of pain sensation. In 10 healthy human volunteers. we compared the magnitude and latency of integrated biceps EMG with the subjects' rating of pain. using a visual analog scale. elicited by noxious radiant heat stimuli applied to the dorsal forearm. The magnitude and inverse latency of withdrawal. although variable. increased exponentially as a functions of stimulus temperature. The stimulus response functions for mean withdrawal magnitude and mean pain intensity were similar for lower stimulus temperatures. but at higher temperatures the withdrawal continued to increase exponentially whereas pain intensity reached a plateau. The pain intensity and withdrawal magnitude for each stimulus were poorly correlated. Under the conditions of this experiment. mean pain intensity and mean withdrawal magnitude were both well correlated with stimulus temperature. but the magnitude of withdrawal did not reliably reflect the intensity of pain sensation.
Spinal and supraspinal correlates of nociception in man, The objective of this work was to simultaneously measure pain-related spinal and supraspinal physiological responses in humans. The sural nerve compound action potential (CAP). the spinal withdrawal reflex (RIII). the somatosensory evoked potential (SEP) and subjective magnitude ratings were elicited by electrical stimulation of the sural nerve in 10 healthy subjects. The sural nerve CAP was used to normalize the evoking stimulus current and to help identify the peripheral nerve afferent types contributing to the physiological and psychophysical responses. Normalizing stimulus current to a proportion of that which elicited a just maximal sural nerve CAP significantly reduced individual variability in magnitude ratings. the RIII and the SEP. Pain and RIII responses only occurred at stimulus levels that were greater than or equal to 1.5 x that which produced a just maximal sural nerve CAP and both responses were positively related to stimulus intensity above that level. Activity in the large diameter A beta fibers will be saturated at stimulus levels near that which produced a just maximal CAP. which implies that both the pain and RIII responses can be attributed to recruitment of the smaller diameter A delta fibers. Although the amplitudes of the P200 and P300 peaks of the SEP were significantly related to stimulation at noxious levels. both were also affected by stimulation at innocuous levels. This result implies that these peaks receive contributions from both noxious and innocuous somatosensory processes. Clearly. the non-pain-related components of these SEP peaks must be identified and isolated before their potential in measuring supraspinal nociceptive processes can be fully realized.
Efficacy of ICS 205-930, a novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist, in the prevention of migraine attacks. A complex answer to a simple question. ICS 205-930 Migraine Study Group, To investigate whether the novel. potent and highly selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist ICS 205-930 can prevent migraine attacks. we conducted simultaneously two randomized. double-blind. placebo-controlled. multicentre. international trials. involving a total of 204 patients. suffering from classic or common migraine. Both trials had the same parallel-group design (1 month baseline observation. followed by 3 months treatment) and both produced remarkably similar results. The primary efficacy parameter was the proportional reduction in attack frequency recorded after 3 months of treatment. Twenty-two patients withdrew prematurely from the trials and could not be assessed for efficacy. Mild to severe constipation was reported by about 50% of the patients on active treatment. None of the doses of ICS 205-930 tested (50 mg. 25 mg and 15 mg daily) produced a statistically significantly better result to reduce attack frequency than did placebo. However. confidence intervals for the difference in effect with placebo were wide. indicating that 15 mg ICS 205-930 may produce a 57% reduction in attack frequency as compared to placebo. The most unusual finding was that. for all efficacy parameters. the best results were obtained with the lowest dose (15 mg). the worst results with the highest dose (50 mg) and an intermediate effect with 25 mg. Such an inverse relation between dose and efficacy suggests a bell-shaped dose-response curve. implying that doses lower than 15 mg might well prove to be more effective. Thus. the present study has produced inconclusive. but intriguing results. Lower doses should be further investigated before drawing any definite conclusion on the efficacy of ICS 205-930 in the prophylactic treatment of migraine.
Prediction of postoperative pain and duration of hospitalization using two anxiety measures, This study examined the extent to which measures of anxiety could predict pain and the length of hospitalization following surgery in 111 patients with gallstones over and above what could be predicted on the basis of biographical and medical status variables. Self-reported pain on the third day postoperative could hardly be explained by the variables measured. Preoperative anxiety did not increase the value of the prediction. Age. type of surgery. cystitis and wound infection explained a significant proportion of the variance in postoperative hospital stay. Over and above these variables. A-state on the third postoperative day and also A-state and specific anxiety measured 1 day before surgery exerted a significant increase on the values of prediction of the length of postoperative hospitalization.
Central pruritus. Case report, An 82-year-old woman experienced generalized pruritus not due to skin or systemic disease. Scratching the skin with a needle induced a crisis of intense pruritus. insensitive to any drug. The pruritus had the characteristics of a central sensation.
Effects of sympathectomy in a model of causalgiform pain produced by partial sciatic nerve injury in rats, In a previous report we presented a novel behavioral model of neuropathic pain disorders. produced in rat by a unilateral ligation of about half of the sciatic nerve. The model is characterized by rapid onset of behaviors suggesting spontaneous pain and disordered responses to non-noxious and noxious stimuli. These include reduced withdrawal thresholds to repetitive touch in the partially deafferented skin ('touched-evoked hyperesthesia'). touch-evoked allodynia. reduced withdrawal thresholds to noxious thermal stimuli and exaggerated responses to noxious heat and mechanical stimuli ('thermal hyperalgesia'). Some of these disorders are seen at mirror image sites on the hind limb opposite the lesion. These disorder start within hours after partial nerve injury. last many months and are very similar to causalgia in humans following partial nerve injury. Since sympathetic efferent activity is known to aggravate causalgia in humans and sympathectomy is known to relieve it. we studied the effect of changing sympathetic outflow in the rat model. Reversible sympathectomy was carried out using guanethidine injected intraperitoneally in 3 experiments. each at a different time in relation to the partial nerve injury. We found that: (1) sympathectomy performed several months postoperatively alleviated the sensory disorders bilaterally; (2) sympathectomy prior to nerve injury partially prevented the appearance of thermal hyperalgesia but did not affect hyperesthesia to repetitive touch; and (3) sympathectomy at the time of nerve injury aggravated the sensory disorders during the first few days. As maintenance and production of the sensory disorders in this animal model depended on sympathetic nervous outflow. we conclude that the rats were suffering from a syndrome analogous to sympathetically maintained causalgia in man.
Resolution of otitis media with effusion with the use of a stepped treatment regimen of trimethoprim-sulfamethoxazole and prednisone, This double blind. placebo-controlled trial was designed to determine whether intervention with a stepped regimen of trimethoprim-sulfamethoxazole (TMP-SMX) and prednisone would prevent high risk children from developing chronic otitis media with effusion (OME) and recurrent acute otitis media. Forty-two children were enrolled. assigned to treatment with active drug or placebo and then examined at 2-week intervals. They received TMP-SMX (or placebo) during the first 2 weeks. TMP-SMX and prednisone (or placebo) during Weeks 3 and 4 for persistent OME and TMP-SMX (or placebo) for Weeks 5 and 6 if OME was still unresolved. After treatment 48% of active drug and 14% of placebo subjects resolved OME bilaterally (P less than 0.05). Active drug subjects also had fewer acute otitis media episodes than placebo subjects while receiving study treatment (P less than 0.01). Although this treatment regimen produced short term OME resolution. long term benefits were not demonstrated.
Toxic exposures and ingestions in Honolulu: I. A prospective pediatric ED cohort; II. A prospective poison center cohort, Poisonings and toxic exposures are a frequent cause of preventable morbidity in children requiring emergency care. Ingestions and toxic substance exposures were studied in two prospective cohorts in Hawaii to examine the epidemiology of these events in this community in order to assess the effectiveness of current poison prevention practices and to identify additional measures to further prevent and reduce morbidity and mortality. During a 12-month period ending on 11/30/88. data were collected on 286 pediatric patients visiting a pediatric ED with an ingestion or a toxic substance exposure. Most of the younger children were males with unintentional incidents. Most of the adolescents were females with intentional ingestions. Syrup of ipecac was given in 16% of the patients. When given at home. ipecac was given an average of 1.3 hours after an ingestion. Activated charcoal was given to 32% of the patients. During a 13-month period ending 1/31/90. 14.408 phone calls to the Hawaii Poison Center were analyzed. Twenty-six percent of the callers had ipecac at home. Sixty-eight percent of callers with acute ingestions claimed to have called within 30 minutes of the ingestion. and 77% claimed to have called within 60 minutes of the ingestion. Of those calling within 60 minutes. 36% had ipecac at home. Although ipecac is widely recommended as a pre-hospital intervention. it use is limited owing to unavailability in the home and the short period of time during which it must be given. Since the dispensing of pharmaceuticals in limited quantities and in childproof containers began. it appears that other measures to further reduce morbidity and mortality owing to poisonings have had less additional effect. It appears that serious morbidity and mortality from poisonings in this cohort were uncommon.
Effects of albumin on ionized calcium in vitro, Human serum albumin is used to treat hypoproteinemia in neonates or used as a volume expander. We tested the hypothesis that the addition of human serum albumin to neonatal serum decreases the serum ionized calcium (iCa) concentration. Concentrated human serum albumin was added to 12 placental and cord serum samples to reach seven incremental concentrations from 0 to 20.0 g/L. Serum iCa concentration decreased significantly with the addition of serum albumin. From multiple regression analysis. the effect of albumin addition on serum iCa concentration had more marked effects at high baseline albumin or low baseline Ca concentrations. From this in vitro study. we speculate that fast infusion of albumin in human neonates has the potential for acutely lowering serum iCa concentration.
Pediatric chin injury: occult condylar fractures of the mandible, The diagnosis of occult mandibular condylar fractures in children is often missed or delayed on initial examination when children present with a laceration to the chin. A clue to the diagnosis of this type of skeletal injury to the mandible is the knowledge of a commonly occurring pattern of injury associated with chin trauma. Chin laceration. fracture of the parasymphyseal region near the chin. and fracture of the condyles are often concomitant injuries of the mandible. This article reviews three case reports of children who sustained a chin laceration. fracture in the region near the chin. and fracture to the mandibular condyles secondary to chin trauma that were not initially diagnosed on clinical examination.
Lung injury resulting from a nonaccidental crush injury to the chest, A six-week-old infant presented with rib trauma and a lung contusion from a nonaccidental compressive chest injury. He developed an illness consistent with diffuse alveolar damage. which worsened over 26 hours. This was complicated by a pneumomediastinum. and the patient recovered with conservative management. The value of isotope bone scanning in addition to x-rays is discussed. Nonaccidental injury should be considered in the differential diagnosis of a pulmonary contusion.
Congenital syphilis: an emerging emergency, Is a condition such as congenital syphilis within the purview of pediatric emergency medicine? The following case histories would suggest that it is.
Depression and chronic fatigue in children. A masquerade ball, Major depression disease is uncommon in children; it occurs mostly in children with a depressed parent or in children under major psychosocial stress such as physical or sexual abuse. Most depression in children is masked. i.e.. the child presents with signs or symptoms such as headaches. abdominal pain. muscle weakness. vomiting. dizziness. hyperactivity. or school avoidance. Careful evaluation of the history is required to assist in the diagnosis. Some basic laboratory tests should be done to rule out organic disease. Psychiatric referral should be carried out after an appropriate evaluation.
Depression, chronic fatigue syndrome, and the adolescent, To summarize. CFS and depression present very real problems for adolescent patients. their families. and their physicians. The wealth of symptoms presented may signal the presence of any number of psychiatric or physiologic disorders. As part of the evaluation to rule out other maladies. the physician must identify the developmental issues and life stress events with which patients or their families are struggling. Helping patients to accept psychiatric referral to address these issues is indicated if it is thought that they may be contributing to the onset or maintenance of the symptoms. Referral is also indicated if a protracted clinical course evolves and the patient's normal course of growth and development appears to be in jeopardy.
Exercise. Practical treatment for the patient with depression and chronic fatigue, Exercise should be part of everyone's lifestyle. but may be a particularly important part of the treatment of patients with depression and chronic fatigue. It will reliably and consistently decrease feelings of tiredness and despondency. although it is seldom sufficient as a sole treatment intervention for such patients. When initiating an exercise program. a baseline assessment should be followed by an exercise prescription and an appropriate degree of patient education about exercise physiology. This should be followed. in addition to other treatment interventions. by regular follow-up visits to make appropriate adjustments; provide encouragement and motivation to continue; monitor weight. body fat. and nutrition; and assess the effectiveness of the program on the underlying problem.
Depression and chronic fatigue in the high school student and athlete, By presenting the salient aspects of a case study of a high school student athlete. we have attempted to show how participation in sports can negatively impact on self-concept. self-esteem. physical acceptance. and self-efficacy. thereby contributing to an overall feeling of inadequacy. helplessness. hopelessness. and ultimately leading to depression and chronic fatigue. An early maturer. this student experienced early success in several sports without a great deal of effort and investment. and derived much of his sense of being from the recognition and reinforcement accorded him by significant others. most notably from a father who placed a higher premium on success in athletics than on other equally worthwhile pursuits. When continued success was not forthcoming. and as later-maturing peers caught up to and surpassed his athletic accomplishments. the student sought to protect his sense of self-esteem by rationalizing that his lack of success was due to a physical problem. He became obsessed with the thought that he was gradually losing his athletic identity and he lapsed deeper and deeper into a depressed state. His compulsive overtraining and starvation diet failed to produce his image of the "ideal body" that. of course. was unachievable because of his distorted view of reality. Ultimately. this behavior resulted in hospitalization for treatment of an eating disorder and clinical depression. Even a successful senior football season after his psychiatric care could not filter through his distorted perceptions and he could not cope with the thought of participating in another track and field season and having his performance bested by others whom he had once handily beaten. Thus. once again. he engaged in self-protective behavior and sought verification from sportsmedicine professionals. Diagnosis of Tom's condition was possible only through the collaborative efforts of the athletic trainer. physical therapist. sport psychologist. and family physician. Professionals involved in sportsmedicine must be aware of the critical role that highly valued activities like sports play in the psychosocial development of adolescents. To the adult. these activities may seem trivial. frivolous. and removed from the "real world." but to the adolescent. they are an important source of self-esteem during a critical and volatile period of self-concept edification. During a period of awakening sexuality and heightened awareness of their physical being. activities that emphasize the physical aspect of self gain prominence. Those who derive positive experiences benefit from enhanced feelings of physical self-efficacy and self-esteem.(ABSTRACT TRUNCATED AT 400 WORDS).
Depression and chronic fatigue in the college student-athlete, For the most part. the intercollegiate athlete is a well-adjusted individual who demonstrates considerable vigor and well-being and less depression. anxiety. and fatigue when compared with nonathletic counterparts. The well trained athlete also demonstrates a personality that may be somewhat rigid. is strongly goal oriented. and strives for excellence. It is not unrealistic to expect that when confronted with diminished performance or success. athletes may be compelled to drive themselves harder to succeed. Such behavior typically leads to the phenomenon of overtraining. which can express itself in the form of chronic fatigue and depression. A number of other organic causes of chronic fatigue and depression must be excluded by careful evaluation and appropriate diagnostic testing. Although the evaluation of the athlete who presents with chronic fatigue and depression can be somewhat complex. a diagnostic framework has been outlined that may assist the clinician in the assessment of the athlete who presents with such complaints.
Fatigue and depression in the patient in the intensive care unit, The recognition. management. and treatment of fatigue and depression in the patient in the intensive care unit has been presented in a framework to allow consideration of intrapsychic. interpersonal. environmental. and disease factors that can be altered by various means. It is rare that fatigue so seriously complicates the primary illness as to be life threatening itself. Depression and delirium are associated with increased morbidity and mortality on their own; therefore. prompt attention to major depressive disorders and organic effective disorders is necessary. Through it all. attention to the person who has the disease with fatigue. depression. or both is essential.
Depression, chronic fatigue, and the premenstrual syndrome, Depression. chronic fatigue. and premenstrual syndrome often coexist in women seeking treatment for premenstrual distress. A reliable diagnosis can be made by prospectively rating symptoms for two cycles. taking a careful history. performing physical and gynecologic examinations. and obtaining basic laboratory test results and a psychosocial evaluation. Appropriate dietary. hormonal. or antidepressant treatment provided in a caring and competent manner can benefit many women suffering from this otherwise disabling/condition.
Chronic fatigue and depression in the ambulatory patient, Fatigue. pain. and emotional upset remain the most common problems affecting humanity and for which we still know so very little. Chronic fatigue syndrome is most likely a number of as yet unproven various undifferentiated illnesses that are exceedingly difficult to distinguish from depression. There probably is a subset of patients with CFS who do have true immune dysfunction and persistent viral infection. and this particular group of patients should be further investigated. This group is the minority of patients who present with chronic fatigue. Although chronic fatigue syndrome may be the result of an organic illness in psychologically susceptible individuals. it remains most important to assess underlying psychologic factors that then need to be addressed. These factors may very likely have a profound effect on immune function. but more research is needed in this area. The diagnostic evaluation of patients with chronic fatigue syndrome should initially focus on causes for fatigue other than Epstein-Barr viral infection. Significant underlying medical conditions should be ruled out. and extensive inquiry into symptoms suggestive of depression and anxiety should be aggressively pursued. Treatment should include psychiatric support and counseling. good nutrition. adequate rest. and a gradual increase in activity. Anti-inflammatory agents and serotonin-replenishing antidepressants are helpful when muscle pain and tenderness are a major part of the patient's symptoms. Psychoactive drugs are useful when indicated. Low doses of antidepressants such as doxepin (10-25 mg at night) are generally well tolerated and have shown efficacy in numerous patients. although there are no reports of controlled trials.
Depression and chronic fatigue. Indications for psychiatric consultation, Symptoms of fatigue and the fatigue syndrome itself are familiar complaints heard by nonpsychiatric physicians in the general hospital. The nature of these complaints is often diffuse and frequently conceals atypical psychiatric disorders. In the general hospital setting. consultation psychiatry. which functions as the interface between psychiatry and these medical practitioners. is ideally situated to assist in the assessment and management of these patients. This article reviews the methods of approach that psychiatric consultants can use to assist their nonpsychiatric colleagues in identification and referral for problems involving fatigue. In addition. a brief review of diagnosis. management. and treatment of such patients is given.
Proliferative assessment of GFAP-positive and GFAP-negative glioma cells by nucleolar organizer region staining, The proliferative potential of two types of tumor cells that did or did not express glial fibrillary acidic protein (GFAP) in 19 cases of high-grade gliomas. including nine anaplastic astrocytomas (WHO criteria. grade 3) and 10 glioblastoma multiforme (grade 4). was investigated by a combined staining technique. one-step silver colloid method for nucleolar organizer region-associated argyrophilic protein (Ag-NOR) and immunocytochemistry for GFAP. The mean numbers of Ag-NORs in GFAP-positive cells and GFAP-negative cells of high-grade gliomas were 2.68 and 3.74. respectively. The value of GFAP-negative cells was significantly greater than that of GFAP-positive cells (p less than 0.01). Our results show that. by means of the immunocytochemistry for GFAP. tumor cells in human high-grade gliomas can be divided into two groups expressing GFAP or not. and that the mean number of Ag-NORs of GFAP-negative cells is more representative of the degree of histological malignancy than that of positive cells. It is considered that the proliferative assessment of GFAP-negative tumor cells in high-grade gliomas by combined staining of Ag-NOR silver staining and GFAP immunocytochemistry is useful for understanding the histological malignancy of high-grade gliomas.
Cerebral granular cell tumor occurring with glioblastoma multiforme: case report, A 65-year-old man presented with 4 weeks of partial right visual field loss. A left occipital granular cell tumor was diagnosed via open biopsy. No specific tumoricidal therapy was given. and the patient returned 2 weeks later with fluent dysphasia and mild right hemiparesis. and formed visual hallucinations. A large left parietotemporal mass. separate from the granular cell tumor. was diagnosed as a glioblastoma multiforme by stereotactic biopsy. The histogenesis of cerebral granular cell tumors is controversial; this case supports recent speculation of their possible glial origin.
Ruptured saccular aneurysm associated with duplication of the vertebral artery, A case of a ruptured aneurysm arising from a duplicated segment of the intracranial portion of the vertebral artery is reported. This particular association. which can be explained by the embryological development of the vertebral artery. has not been described previously.
Budesonide and terbutaline or terbutaline alone in children with mild asthma: effects on bronchial hyperresponsiveness and diurnal variation in peak flow, The effects of treatment with budesonide (200 micrograms twice daily) and terbutaline (500 micrograms four times daily) has been compared with the effects of placebo and terbutaline in 27 children with mild asthma. aged 7-14 years. in a double blind. randomised placebo controlled study over eight weeks. Bronchial responsiveness (PC20 histamine). lung function. the amplitude of diurnal variation in peak expiratory flow (PEF). and symptom scores were measured. Baseline FEV1 was over 70% predicted and PC20 histamine less than 8 mg/ml. Twelve children were treated with budesonide and terbutaline and 15 with placebo and terbutaline. After four and eight weeks of treatment the change in PC20 was significantly greater after budesonide and terbutaline than after terbutaline alone by 2.1 (95% CI 0.5-3.8) and 1.3 (95% CI 0.1-2.5) doubling doses respectively. Mean FEV1 did not change in either group. The change in afternoon and nocturnal PEF was significantly greater after budesonide and terbutaline than after terbutaline alone. The amplitude of diurnal variation in PEF did not change significantly in either group. Peak flow reversibility decreased in the budesonide group. There were no differences between treatments for cough and dyspnoea. but wheeze improved in the budesonide group. The children with mild asthma treated with budesonide and terbutaline showed improvement in bronchial responsiveness. afternoon and nocturnal PEF. and symptoms of wheeze and a fall in peak flow reversibility by comparison with those who received terbutaline alone.
The incidental renal mass. Management alternatives, The problem of the incidental renal mass will confront all urologists with increasing regularity. and no universal strategy can be employed. Complete excision of the mass. including a margin of normal tissue. may be adequate therapy if a cancer is present and will preserve renal parenchyma if the lesion is benign. Care must be taken not to stretch the limits of this approach. Larger lesions (greater than 3-4 cm) are likely to be cancer and are better treated with a nephrectomy. While this management philosophy is logical and appealing. it has not been validated by clinical experience. and caution must still be exercised.
Accuracy of imaging modalities in staging the local extent of prostate cancer, In this study. none of the evaluated clinical staging methods was found to predict reliably the presence or absence of extracapsular growth of histologically proved carcinoma of the prostate. In this respect. digital rectal examination. transrectal ultrasound. CT. and MR imaging cannot contribute to treatment decisions in localized prostate cancer. Further studies are under way to determine the value of 7.5-MHz scanners in transrectal ultrasound and high-resolution surface coils in MR imaging.
Long-term follow-up after radical prostatectomy. Identification of prognostic variables, We report one of the largest series of patients treated by radical prostatectomy followed for a minimum of 10 years. The tumor-free survival rate at 10 years seems superior to that achieved with alternative methods of treatment. Pathologic stage. DNA histograms. and tumor grade all correlate with prognosis but none is sufficiently powerful as an independent factor to allow selection of patients for surgery. Although a survival benefit has not been demonstrated. adjuvant treatment such as postoperative irradiation or early hormonal therapy may be indicated in patients with established poor prognostic factors.
Environmental and nutritional factors significantly associated with cancer of the urinary tract among different ethnic groups, A high incidence rate of urinary tract cancer in the Acre District among the Jewish population compared with the non-Jewish population has been studied. The dietary and environmental factors identified and the possible mechanisms of the protective effect that may be conferred by fluid intake. olives and olive oil. cumin. and pepper (chili pepper and pepper) are discussed.
Evaluation of a new bladder tumor marker, Two monoclonal antibodies have been developed that bind to a shed bladder tumor-associated antigen. Preliminary data have demonstrated that antigen-positive tumors shed detectable amounts of antigen in the urine while antigen-negative tumors do not. This antigen may be differentially metabolized by normal and malignant urothelial cells. Further characterization of this antigen and its evaluation as a urinary marker for antigen positive bladder cancers is continuing.
Molecular and immunologic approaches in the management of bladder cancer, Because of the heterogeneous nature of bladder cancer and the various therapeutic options available. the management of the disease is a constant challenge to clinicians. A variety of new biologic approaches are beginning to unravel some of the pathophysiology underlying the behavior of these tumors and provide means to assess it at the clinical level. Monoclonal antibodies are particularly well suited for more immediate application as diagnostic and prognostic tools and may also have an impact on the treatment of patients with bladder cancer.
Transurethral resection and intravesical therapy of superficial bladder tumors, The treatment of superficial bladder cancer is aimed at eradicating existing disease. inhibiting tumor recurrence. and preventing progression to invasion or metastasis. Transurethral resection is the primary modality. with intravesical therapy used in some cases to kill residual overt or occult carcinoma and premalignant lesions. Among the agents tested extensively. BCG appears to be more effective than mitomycin C. doxorubicin. or thiotepa. especially against carcinoma in situ. A number of questions remain to be answered about the management of this disease.
Neoadjuvant therapy in invasive bladder cancer. Problems and pitfalls, It is clear that some transitional-cell tumors of the bladder will respond to combined therapy. However. in the absence of randomized controlled trials. the impact of repeated transurethral resections versus the effect of chemotherapy cannot be assessed adequately. and such trials are urgently needed before neoadjuvant therapy can be considered standard. In addition. newer chemotherapy agents or the combination of currently available drugs with the addition of hematopoietic growth factors such as granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor to reduce toxicity and permit dose intensification in an attempt to increase overall response rates offer fruitful avenues for clinical research. Although cisplatin-based chemotherapy obviously does not have the same impact on bladder cancer that it does on testicular cancer. the initial results are encouraging. The "wall" has been breached. and the demonstration that urothelial tumors can be added to the list of chemotherapeutically responsive tumors should encourage urologic. radiologic. and medical oncologists to combine efforts in randomized. controlled studies of integrated approaches to therapy.
The ileal neobladder, The ileal neobladder in many respects approximates the theoretically ideal continent urinary diversion. The technique. while more technically demanding than the performance of the standard ileal loop diversion. is not difficult. particularly for surgeons used to performing radical retropubic prostatectomies. The ileal neobladder appears to approximate most closely the optimal bladder substitution. Although currently feasible only in males. future considerations could conceivably involve urologists working with their colleagues in gynecology and colorectal surgery to extend the benefits of bladder substitution using the ileal neobladder to selected patients having cystectomy for associated gynecologic or colorectal malignancies.
Evolution of the management of stage I nonseminomatous germ-cell tumors of the testis, The sequence of treatment modalities for stage I nonseminomatous germ-cell cancer presented herein represents the evolution of treatment over the past three decades: from retroperitoneal lymphadenectomy or radiation therapy to surveillance to modified retroperitoneal lymphadenectomy or nerve-sparing retroperitoneal lymphadenectomy. Each new concept has prompted investigators to critically assess patient eligibility criteria and predictors of response and relapse. Primary predictors of treatment success have been local tumor stage (T status). the presence of vascular or lymphatic invasion. and primary tumor histology. These studies have also allowed critical review of the accuracy of radiologic staging. which. although markedly improved over the past decade. remains imperfect. With the advent of effective chemotherapy and improved patient salvage at relapse. these studies have allowed quality of life issues to become incorporated into management decisions. If there can be one conclusion concerning the management of stage I nonseminomatous germ-cell cancer. it must be that there is no one best treatment for all patients. Each treatment is associated with advantages and disadvantages. The treatment therefore should be individualized for each patient. As patients are evaluated. emphasis must be placed on the identification of relapse risk factors through meticulous pathologic review and accurate radiologic staging. Thus. the patients with clinical stage I disease and unfavorable prognostic factors (such as the presence of vascular invasion in the primary tumor. embryonal carcinoma. T2-T4 tumor) should be advised to undergo retroperitoneal lymphadenectomy; if the nodes are negative on frozen section. then modified retroperitoneal lymphadenectomy or nerve-sparing retroperitoneal lymphadenectomy should be performed; otherwise. bilateral retroperitoneal lymphadenectomy would provide the best chance of cure. Patients with stage I disease and favorable prognostic factors (such as T1 tumor. teratocarcinoma. absence of vascular invasion in the primary tumor) are suitable for either surveillance or modified or nerve-sparing retroperitoneal lymphadenectomy; these options should be thoroughly explained to the patient before any decision is made. Future efforts in this field may take a number of directions. As fertility remains a paramount issue to most patients. long-term studies will be necessary to investigate changes in semen characteristics and eventual paternity in patients followed on surveillance protocols or after either nerve-sparing or modified retroperitoneal lymphadenectomy. With continuing improvements in chemotherapy--improved efficacy with reduced toxicity--pathologic. radiographic. or serologic predictors of the site of eventual relapse will become of increasing importance. Indeed. if patients can be identified who are at a significant risk of distant relapse. an initial chemotherapy protocol may be warranted.(ABSTRACT TRUNCATED AT 400 WORDS).
Wilms' tumor 1991. Clinical evaluation and treatment, Wilms' tumor is the most common malignant tumor of the kidney in children. Although only 500 cases per year are diagnosed in the US. the tumor has been studied extensively in the National Wilms' Tumor Committee Cooperative Studies. These prospective studies have led to improved survival and at the same time reduced treatment and complications in the more favorable cases. Similar results have been shown by the European cooperative study group SIOP using different treatment protocols. These studies have identified a group of tumors with unfavorable histology that are more resistant to treatment and will require more intensive protocols. Diagnosis of Wilms' tumor by the finding of a large flank mass in an otherwise healthy-appearing child is usually easy. Imaging techniques of CT or IVU will give accurate confirmation of Wilms' tumor in 95% of children. Modern treatment in the US by radical nephrectomy followed by chemotherapy with or without radiotherapy depends on tumor stage and histology. Early-stage tumors with favorable histology can be controlled by shorter courses of two-drug treatment (dactinomycin and vincristine) without radiation. Advanced tumors respond to treatment but require more intensive chemotherapy combined with radiation. The final challenge is the child with a tumor of unfavorable histology. particularly if there is advanced-stage disease. Whereas Wilms' tumor showing favorable histology now has a survival rate exceeding 90%. survival of those with tumors of unfavorable histology remains poor. The European (SIOP) studies have shown similar survival figures using preoperative chemotherapy. This technique produces shrinkage of tumors. making them less hemorrhagic and producing a lower incidence of rupture at subsequent surgery. Preoperative chemotherapy does not change the histologic diagnosis of Wilms' tumor and is a useful alternative approach for the large hemorrhagic or infiltrating tumors.
Transurethral resection of prostate under sedation and local anesthesia (sedoanalgesia). Experience in 100 patients, One hundred male patients (average age 68.2 yrs) with acute retention (n = 20) or with symptoms of outflow obstruction (n = 80) underwent transurethral resection of the prostate (TURP) under sedation (midazolam) and local anesthesia (lidocaine)--referred to as sedoanalgesia technique. Procedures lasted twenty-four minutes on average (range 15-35 min). and the weight of prostatic tissue resected ranged from 2-35 g (average 11.1 g). There were no complications related to the use of midazolam or lidocaine. The technique of sedoanalgesia proved safe and acceptable to all patients regardless of their pre-existing medical condition. Where the weight of prostate to be resected is estimated to be less than 40 g. TURP under sedoanalgesia proves an effective alternative to general or regional anesthesia.
Urinary incontinence volume patterns in elderly inpatient men, Urinary incontinence is a costly and debilitating disease of the aged. Although the most common clinical finding is detrusor hyperreflexia on filling cystometry. the role of this urodynamic abnormality in the etiology of incontinence is uncertain. The purpose of this study was to evaluate elderly patients who have cystometric detrusor hyperreflexia and to determine the incontinence volume characteristics of these patients during regular daily activities. Ten patients with detrusor hyperreflexia during filling cystometry and an incontinence volume level above 1 L per day were evaluated according to the volume of urine loss per incontinence episode during a ten-day measurement period. All patients studied were found to have an irregular urinary incontinence volume distribution with a wide range of involuntary urine loss per incontinence episode. An irregular pattern of incontinence volume was found in each patient which suggests that detrusor hyperreflexia is manifest as an irregular involuntary loss of urine during daily activities of elderly inpatients. This unstable bladder activity relative to the volume of urine loss appears to be an important factor in the pathophysiology of urinary incontinence in aged inpatients.
Macroscopic vasovasostomy re-examined, Results of 273 consecutive macroscopic vasovasostomy procedures performed at a single institution over a nine-year period between 1978 and 1987 were reviewed. When patients operated on less than five years after vasectomy were compared with those in whom more than five years had elapsed since vasectomy. significant declines in technical success rates as measured by return of sperm to the ejaculate (93% vs. 74%. p less than 0.004). biologic recovery as measured by mean sperm counts (55 million vs. 35 million) and mean progressive sperm motility (30% vs. 13%). and clinical success as measured by pregnancy rates (52% vs. 30%. p less than 0.02). were observed. Examination of complications of vasovasostomy showed a 7.7 percent overall complication rate and a 1.5 percent incidence of major complications.
Enuresis and the voiding cystourethrogram: a re-evaluation, Eighty-three children with a chief complaint of nocturnal enuresis and no history of urinary tract infection (UTI) were prospectively evaluated with a contrast voiding cystourethrogram (VCUG). The following four historical details of presentation were noted: primary vs. secondary enuresis. daytime wetting. urgency. and frequency. Each of these four symptoms were treated as a dichotomous variable. and the prognostic value with respect to vesicoureteral (VUR) reflux was assessed using a linear logistic regression model. Nineteen ureters in 13 patients (16%) demonstrated VUR: grade I. 7 ureters; grade II. 5 ureters; grade III. 3 ureters; grade IV. 4 ureters; and grade V. 0 ureters. Three patients demonstrated renal scarring (16%) and 2 patients underwent surgery. The linear regression analysis revealed that no one symptom. group of symptoms. or absence of all four symptoms segregated those patients likely to have reflux with statistical validity. One of 6 children. therefore. who present with nocturnal enuresis and sterile urine will have reflux. Screening these children with a VCUG should be considered.
Treatment of staghorn calculi with extracorporeal shock-wave lithotripsy and percutaneous nephrolithotomy, Between August 1983 and August 1987. 72 staghorn calculi were treated in 66 patients. Treatment was with percutaneous nephrolithotomy (PCNL) in 30. extracorporeal shock-wave lithotripsy (ESWL) in 18. combination PCNL-ESWL in 23. and nephrectomy in 1. Complications occurred in 59 percent of patients and were twice as common after PCNL as after ESWL. Radiologic follow-up on 69 kidneys (97%) showed 58 percent were stone-free. 15 percent had residual sand or matchheads less than 5 mm. 17 percent had residual fragments of 5-15 mm. and 10 percent had greater than 15 mm residual stone burden. With a mean follow-up of thirty months. 2 of 40 stone-free patients had persistent asymptomatic Proteus urinary tract infections. and 4 of 22 patients with residual calculi less than or equal to 15 mm required additional operative treatment.
Effect of occluding the urethra while recording urethral stress profile, The correlation between clinical and tonometric incontinence is frequently poor. with urethral profile results that do not correspond to clinical reality. Among potential causal factors. we have attempted to determine the importance of the absorption of kinetic energy from the mass of urine driven against the urethral captor (the hydraulic ram effect). Twenty patients (average age 50 +/- 10 years. para 2) suffering from genuine stress urinary incontinence. underwent urodynamic investigation with a constant air-flow pneumatic catheter equipped with two captors separated by an inflatable cuff located just above the urethral captor to block the inrush of urine into the urethra. After cystometric examination had excluded an unstable bladder. two urethral profiles were registered successively. first with cuff deflated. and then with cuff inflated. The values for urethral functional length (FL) and transmission factor (TF) show no significant changes. The values for the maximal urethral closing pressure (MUCP) were significantly lower in the second profile (cuff inflated) in 18 of 20 cases (average decrease 7 cm H2O). which corresponds to 14 percent of the average MUCP measured during the first profile (cuff deflated). The depression quotient increased from an average 0.80 to 1.05 from first to second profile. This study allows quantification of the urethral "hydraulic ram effect" which modifies determination of the MUCP during registration of urinary stress profile.
Diagnostic usefulness of post-void film in intravenous urogram, A survey was sent to urologists to assess their subjective evaluation of the post-void film in the intravenous urogram (IVU). Most of the urologists believed that the post-void film should be a routine part of all IVUs. particularly in men over forty years of age. and estimated that the film contributed useful information in 30 percent of cases. One hundred fifty IVUs were reviewed to assess the actual value of the post-void film in 119 different patients. In these patients. the postvoid film was seen to give unique information not available by history or films of the filled bladder in only 3 percent of the cases. Therefore. we conclude the post-void film should not be a routine part of every IVU. and should be obtained on an as-needed basis only.
Adrenal cortical carcinoma with vena cava tumor thrombus requiring cardiopulmonary bypass for resection, We believe this is the fifteenth case report of adrenal cortical carcinoma with tumor thrombus to the vena cava. and the fourth reported case of a left-side tumor propagating thrombus to the vena cava. The patient underwent successful resection which required cardiopulmonary bypass. The caval tumor thrombus was very friable and gelatinous. unlike many renal cell thrombi. and required special surgical considerations.
Diagnosis and antibiotic treatment of community-acquired pneumonia, Only a few pathogens cause most community-acquired pneumonias. In outpatients. treatment is empiric. based on the results of chest films. leukocyte counts. and Gram's stains (if available). Antibiotics must always cover pneumococci and should cover Mycoplasma pneumoniae in young adults and during epidemic periods. A follow-up chest film in smokers and those older than 40 years is strongly recommended. In inpatients. the evaluation and treatment are tailored to individual cases. A search for a wider range of causes. using invasive tests if necessary. is undertaken. and all likely pathogens should be covered with the initial antibiotic therapy.
Hypoglycemias, Low plasma glucose concentrations that may or may not be sufficiently low to result in symptoms can be observed as a concomitant of several diverse diseases. Treatment of the primary underlying disorder usually alleviates the hypoglycemia. For patients whose primary symptom is that of hypoglycemia. it is essential to confirm that the plasma glucose concentration is low during the occurrence of symptoms. Symptoms that occur after meals usually are mild and rarely signify serious disease. With rare exceptions. hypoglycemia resulting in major symptoms occurs in the food-deprived state. Lower concentrations of plasma insulin and C-peptide and a concomitant low plasma glucose are major clues to a correct diagnosis.
The health status of minority populations in the United States, There is increasing national recognition that while our nation's health care system is the most expensive in the world. the health care status of Americans overall ranks poorly compared with other Western. industrialized nations. In the United States we tend to look at minority-majority variations of health status. as well as the variations of many other indicators by race or ethnicity. because race and ethnicity are particularly important components of our society. In general. health status indicators of minority Americans are worse than those of whites. In some locales. death rates of minority Americans are comparable to those of Third World nations. At the same time. minority Americans make up a rapidly increasing proportion of the nation's population and work force. Our baseline national data on some minority groups. however. currently are inadequate to detect shifts in health status. Finally. the rapidly expanding problem of the acquired immunodeficiency syndrome among some minority populations provides both an imperative and an opportunity to learn how model prevention programs should be designed and executed.
Fine needle aspiration biopsy of superficial masses in children, Fine needle aspiration biopsy (FNAB) is an underused diagnostic procedure in children. particularly in the evaluation of superficial masses. A total of 54 FNABs of superficial masses were performed in children aged 1 month to 15 years. Adequate material for diagnosis was obtained in 50 attempts. The cytologic diagnosis increased clinical understanding and provided a guide for treatment in 46 of the 50 cases. The cytologic diagnosis was confirmed in 15 of 19 patients who underwent an operation. Surgical intervention was obviated in 31 patients. There was one false-positive diagnosis of cancer. We describe the role of FNAB in children and its technique. accuracy. and diagnostic problems.
Nonsteroidal anti-inflammatory drugs. Proposed guidelines for monitoring toxicity, The most common toxicities of nonsteroidal anti-inflammatory drugs (NSAIDs) are gastropathy. renal dysfunction. and liver function abnormalities. We outline an approach to monitoring patients on long-term NSAID therapy. focusing on the early detection of complications. Gastropathy caused by NSAID use is more common in elderly patients or those with a history of dyspepsia. peptic ulcer disease. or alcohol abuse. Fecal occult blood testing and hemograms are less accurate in detecting gastropathy than direct visualization but are convenient and relatively inexpensive. We recommend the periodic use of these tests to detect NSAID-induced acute or chronic blood loss. Renal toxicity is seen in patients with preexisting renal disease or functional volume depletion and in the elderly. Complications include renal insufficiency. hyponatremia. hyperkalemia. and protein-uria. Renal function should be monitored during the first few weeks of NSAID therapy. especially in high-risk patients. with periodic testing thereafter. Hepatic toxicity is less common but warrants occasional determinations of alanine aminotransferase levels. Elderly patients and those with renal insufficiency or alcohol abuse have a higher risk of complications. Nonsteroidal anti-inflammatory drugs should be used cautiously in those patients at high risk for complications. Strategies can be used to limit toxicity. Patients taking these drugs long term should be monitored periodically for signs of blood loss. renal dysfunction. and hepatic dysfunction.
The clinical diagnosis of splenomegaly, Assessing for the presence of splenomegaly is an important component of the physical examination. Although several methods of palpation and percussion of the spleen have been described. until recently they have not been validated by noninvasive imaging techniques such as ultrasonography. radionuclide scanning. and computed tomography that offer objective means to assess splenomegaly. We review the literature comparing various physical examination techniques with noninvasive imaging modalities and conclude that palpation and percussion of the spleen are complementary but frequently insensitive and that further studies are needed to evaluate the efficacy of specific diagnostic methods.
Understanding osteoporosis, Considerable progress has been achieved recently in our understanding of the normal process by which bone mass is regulated. Age-related trabecular bone loss is characterized not simply by a global loss of bone but also by cortical porosity and loss of trabecular connections. Because bone strength depends on architectural as well as material properties. bone quantity alone cannot define fracture risk with precision. Traditional therapies for osteoporosis increase bone mass. and estrogen therapy. in particular. profoundly decreases fracture risk. The pharmacologic restoration of bone quantity and quality. however. remains elusive. Modern biotechnology offers the hope that progress may come about through the development of growth factors and other osteotropic compounds for clinical use.
Painful subacute thyroiditis in Hawaii, Between 1960 and 1982 we prospectively studied 269 patients with painful subacute thyroiditis to determine the demographic characteristics. seasonality. and natural course of the disease. The mean age for all patients was 37.1 years. The female:male ratio was 6.7:1. At the first visit. disease was bilateral in 69%. No epidemic or seasonal pattern was identified. The mean duration of thyroid tenderness was 2.2 months and that of palpable thyroid lumps was 2.8 months. This time difference. sometimes lasting many months. left a painfree "window" during which the palpable hard residual mass of subacute thyroiditis may be confused with other thyroid problems. especially cancer.
Comparative study of fluconazole and clotrimazole in the treatment of vulvovaginal candidiasis, Fluconazole is a new oral triazole antifungal with good activity against Candida spp. In this study. we investigated the effectiveness and tolerability of a three-day course of treatment with fluconazole compared with clotrimazole vaginal tablets in nonpregnant women with acute Candida vaginitis. Of the 90 evaluable patients who received fluconazole. 76 (84 percent) were asymptomatic seven to ten days after treatment compared with 84 of 95 (88 percent) treated with clotrimazole. An additional ten patients in the fluconazole group (11 percent) and seven in the clotrimazole group (7 percent) had improvement in their signs and symptoms. Only four patients in each group (4 percent) were considered treatment failures. Mycological cures were obtained in 89 and 93 percent of patients treated with fluconazole and clotrimazole. respectively. seven to ten days posttreatment. Clinical cure rates remained high one month posttreatment: 79 percent in the fluconazole group and 83 percent in the clotrimazole group. Both therapies were well tolerated. One patient discontinued treatment after she developed diarrhea while receiving fluconazole. The most common adverse effects associated with fluconazole use were nausea (six percent) and diarrhea (three percent). No clinically significant laboratory abnormalities were observed. In this investigation. oral fluconazole therapy was found to be as safe and effective as clotrimazole vaginal tablets in women with acute vulvovaginal candidiasis.
Patient acceptance of Nordiject: a new drug delivery system for growth hormone, Twenty-seven children. aged 5-20 years. with growth retardation were enrolled in an open study to evaluate the acceptability of a new injection pen (Nordiject 24. Novo Nordisk A/S) for administration of recombinant human growth hormone (r-hGH). Prior to this study. 17 of the patients had been receiving treatment with r-hGH administered via syringes and vials; their experiences with this conventional technique have been used for comparison with Nordiject. The injection pen is provided with a replaceable 27-gauge needle and a cartridge containing 24 IU of reconstituted r-hGH (12 IU/mL). A benzyl alcohol 0.9% solution is used as the solvent for the reconstitution. The pen can be regulated for doses from 0.5 to 8 IU per injection; regulation is accomplished by a turning movement. The patients had no problems with the dissolving procedure or handling the pen. Nearly two-thirds of the patients experienced less injection pain with the pen as compared with the syringe. Special attention was paid to local tolerability. which was reported to be good. The thigh was the preferred injection site. The residual contents from 68 cartridges returned by the patients were analyzed for microbial contamination. Contamination was detected in only one cartridge. which could not be confirmed in a repeated test. Because of the simplification of the injection procedure afforded by the injection pen. 20 of 27 patients were able to perform the injections themselves and hence assume a more active role in their treatment. The patients who previously had been using conventional syringes strongly preferred the pen. and all patients wished to continue using the device.
Decreased hypoprothrombinemic response to warfarin secondary to the warfarin-nafcillin interaction, Patients who are receiving multiple medications must be screened for significant drug interactions. The specific mechanism of a drug interaction determines whether the patient may experience a subtherapeutic effect or a potentially toxic reaction. Three cases of relative warfarin resistance. possibly related to high-dose nafcillin. are described in this report. Several reports have suggested that penicillinase-resistant penicillins. such as nafcillin and dicloxacillin. exert an important enzyme-inducing effect in patients receiving warfarin. This potential interaction must be appropriately recognized and managed in order to maintain adequate anticoagulation in this patient population.
Chemical peritonitis associated with intraperitoneal vancomycin, A case of chemical peritonitis associated with intraperitoneal vancomycin is reported. A 23-year-old woman presented with signs and symptoms consistent with a chronic ambulatory peritoneal dialysis catheter exit-site infection. Intraperitoneal vancomycin (Vancoled) 1 g was given. followed by 25 mg/L into each subsequent exchange. On day 4 the patient developed abdominal pain and cloudy dialysis effluent. The vancomycin was discontinued. and the dialysate cleared by day 8. Fluid cultures were negative. and Staphylococcus aureus was isolated from the exit site. Subsequent intravenous vancomycin. and smaller intraperitoneal doses. failed to repeat the event. Fluid and serum white blood cell count. serum immunoglobulins and complement. culture results. and the temporal relationship are strongly suggestive of a vancomycin-induced chemical peritonitis.
The controversy of heparin therapy as an adjunct to thrombolysis in acute myocardial infarction, Heparin is used routinely in the US as adjunct therapy for prevention of reocclusion after thrombolysis during acute myocardial infarction. A review of the literature shows controversy over the efficacy of heparin following thrombolysis. Both beneficial and a lack of beneficial effects have been reported with heparin. From a pathophysiologic viewpoint. there appears to be a need for full heparinization in the postlytic period because the residual stenosis is highly thrombogenic. However. optimal dose. time. and mode of heparin therapy has not been defined. Despite a lack of definitive data. it seems reasonable to administer intravenous heparin immediately after thrombolytic therapy to achieve a partial thromboplastin time 1.5-2.0 times control that is concurrent with an antiplatelet agent such as aspirin. These recommendations are consistent with the consensus opinion of the American College of Cardiology and the American Heart Association.
Therapeutic advances in the prevention of hepatitis B: yeast-derived recombinant hepatitis B vaccines, Viral hepatitis is second to gonorrhea as the most commonly reported infectious disease in the US. Hepatitis B accounts for the majority of viral hepatitis cases. Fortunately. the disease is self-limiting and frequently resolves completely with minimal complications; however. a significant number of individuals may experience long-term sequelae. Research utilizing genetic engineering has led to the development of yeast-derived recombinant DNA (YDR) hepatitis vaccines--a significant advancement in the control and prevention of hepatitis B. The recombinant process allows production of unlimited quantities of vaccine at considerably lower cost and without the potential threat of blood-borne illness. Clinical trials in various high-risk populations have demonstrated the effectiveness and safety of YDR vaccines. However. questions regarding optimal regimen and the need for periodic revaccination remain unanswered. Persons at risk should be adequately vaccinated against hepatitis B.
Intradermal hepatitis B vaccination, The availability of vaccine since 1982 for immunization against hepatitis B virus (HBV) has had minimal impact on the disease; mass immunization has been suggested. Intradermal vaccination. which has precedent in prophylaxis of other infectious diseases. has been investigated as a low-cost alternative to traditional intramuscular HBV vaccination. Results of open and comparative trials indicate similar seroconversion rates for intradermal and intramuscular HBV vaccination routes in healthy adults. However. antibody titers and. presumably. duration of antibody protection appear to be decreased with intradermal HBV vaccination. Limited data suggest that demographic factors such as age and gender may affect vaccine responsiveness to intradermal HBV vaccine. Adverse skin reactions are common but do not represent a deterrent to continued intradermal HBV vaccination. There is a need for large-scale prospective comparative trials to substantiate the value of intradermal HBV vaccination. Nevertheless. the potential economic and epidemiologic benefit of intradermal vaccination justifies continued investigation for prevention of HBV infection.
Optimizing drug delivery from metered-dose inhalers, Metered-dose inhalers (MDIs) are being used with increasing frequency to administer medication used in the treatment of respiratory tract disorders. Inhaled medication is delivered directly to the tracheobronchial tree. allowing for a rapid and predictable onset of action. Studies show that only about ten percent of the dose from an MDI actually reaches the lung. The site of deposition within the lung is influenced by the aerosol characteristics. interpatient variability. and the technique by which the patient uses the inhaler. Spacer devices have been designed to overcome some of the problems encountered with MDIs and may be beneficial in certain groups of patients. The studies reviewed in this article suggest ways to alter the variables affecting inhalation in order to optimize drug delivery so that the patient will obtain the most benefit from the inhaled medication.
Pharmacokinetic simulation of the effect of multiple-dose activated charcoal in phenytoin poisoning--report of two pediatric cases, Activated charcoal is commonly used to inhibit the absorption of phenytoin after acute overdose. There are also reports of multiple-dose activated charcoal (MDAC) increasing the clearance of phenytoin in adults. We describe our experience modeling phenytoin pharmacokinetics during therapy with MDAC in the treatment of two cases of acute phenytoin poisoning in children. After extensive attempts at modeling the serum phenytoin concentrations. simulations were performed to identify the possible consequences of MDAC administration. Phenytoin elimination was more rapid than was expected. based on previously reported phenytoin pharmacokinetic parameters. Moreover. the time to peak phenytoin concentration and time course of phenytoin intoxication appeared to be shorter than available reports of phenytoin intoxication treated with a single dose of activated charcoal. MDAC may prevent continued phenytoin absorption and increase phenytoin elimination rate via gastrointestinal dialysis. The effect of MDAC on the clearance of phenytoin can be described by a first-order elimination rate constant of approximately 0.02-0.04/h.
Tuberculosis in the elderly: incidence, manifestations, PPD skin tests, and preventive therapy, Tuberculosis is a chronic infection caused by Mycobacterium tuberculosis. The incidence of tuberculosis has declined dramatically over the past decades. but it is still highly prevalent in the geriatric population. This report describes the etiology. clinical manifestations. and immunologic changes of tuberculosis in the elderly. The basis for tuberculin skin testing and its interpretation in patients over 65 years of age are discussed. as well as the controversies regarding preventive therapy with isoniazid in the elderly. Guidelines for tuberculosis screening in long-term care facilities are proposed.
Use of restricted antibiotics in primary care, The objective of this study was to detect and evaluate the use of restricted antibiotics (RAs) in our ambulatory care site. We retrospectively analyzed 1084 treatments of a selected group of intramuscularly administered antibiotics that are usually considered restricted for use in hospitals. Five cephalosporins. four aminoglycosides. and one acylureidopenicillin were analyzed. The study was conducted in 47 primary health centers over six months. We reported the information on a special order form for parenteral prescriptions and evaluated the selection and the dosing interval of each antibiotic. Of the 1084 treatments. cefonicid was the antibiotic most frequently prescribed (61.3 percent). followed by tobramycin (15.3 percent). cefotaxime sodium (6.7 percent). amikacin (3.8 percent). cefuroxime (3.8 percent). mezlocillin (3.7 percent). netilmicin sulfate (3.7 percent). ceftizoxime sodium (0.8 percent). cefoxitin (0.5 percent). and streptomycin sulfate (0.4 percent). Based on our survey criteria. 59 percent of the 710 orders that indicated diagnosis had a correct or possibly correct indication; the remaining percentage was considered unnecessary therapy or poor drug choice. Of the 1050 orders that indicated a dosing interval. 75.4 percent showed an appropriate dosing interval. We assume that most of the infections treated in our ambulatory care site could be resolved with or without common antibiotics. In this study we obtained objective data of the use of ten RAs in order to determine if their use in ambulatory patients was justified. We observed that a small number of prescriptions agreed with the recommended criteria stated in this survey for use of these antibiotics in outpatient infections.
Esophageal foreign bodies, An impacted esophageal foreign body is most often an urgent. rather than a life-threatening. medical situation. Pharmacologic or mechanical methods can be used to relieve the impaction. depending on the patient. as well as the location and physical properties of the foreign body. Flexible fiberoptic esophagoscopy is the accepted standard of care for removal of an object that is not smooth. radiopaque. inert or recently impacted. Although controversial. balloon catheter extraction may be an acceptable alternative in selected cases of esophageal impaction. Intravenous glucagon is useful in relieving distal impaction.
Syphilis--an STD on the increase, The number of reported cases of syphilis. including primary. secondary and congenital syphilis. has been rapidly rising since 1987. The greatest increases have occurred in urban areas. An association between human immunodeficiency virus infection and syphilis has been established. Primary syphilis is manifested by a clean. painless ulcer called a chancre. Secondary disease often presents with constitutional symptoms and a maculopapular rash. Most infants with congenital syphilis are born without signs of infection. Serologic testing for both nontreponemal and treponemal antibodies is essential for diagnosis. Penicillin is the treatment of choice for all stages of syphilis. Case reporting and treatment of sexual contacts are two aspects of this disease that warrant greater attention from physicians.
Office dermatologic testing: the Tzanck preparation, Whether a vesicobullous disease is intraepidermal or subepidermal is often difficult to determine from the clinical examination. The Tzanck preparation can provide clues that aid in the diagnosis of a number of diseases. It is particularly helpful in confirming the diagnosis of herpes infection. This article outlines the materials and steps for performing this valuable test.
Diagnosing rheumatoid arthritis: current criteria, Rheumatoid arthritis is a chronic. systemic inflammatory connective tissue disorder with major effects on the articular system. Causative mechanisms remain unknown. and no specific diagnostic tests are available. Descriptive criteria form the basis of disease classification and diagnosis. Either the 1987 American College of Rheumatology criteria for classification of rheumatoid arthritis or the new rheumatoid arthritis classification tree may be used to diagnose and classify this disease.
Idiopathic hemochromatosis, Hemochromatosis is a rare disorder in which about four times the normal amount of iron is absorbed in the intestine. resulting in the accumulation of iron in the skin. liver. pancreas and heart. Radiographic features may include a small liver on plain abdominal films. increased hepatic density on computed tomographic imaging. and loss of liver signal on magnetic resonance imaging as a result of the strong paramagnetic effect of iron. Management includes phlebotomy and supportive treatment of damaged organs.
Treatment of diabetes in the elderly, Diabetes mellitus is one of the most common medical problems in elderly patients. There is a strong rationale for therapy in most patients with diabetes. even those who are asymptomatic. Family physicians should be aware of several age-associated differences in the management and treatment of diabetes in older patients. For elderly patients. dietary modifications may include an increase in the percentage of carbohydrates and a decrease in the percentage of fat. For obese patients. dietary therapy should also emphasize a decrease in overall calories. Oral hypoglycemic agents are generally used as the initial drug therapy. Insulin therapy should be instituted when oral agents fail to reduce the blood glucose level. when the blood glucose level is very high and in other special circumstances. A careful choice of medications for other common problems associated with diabetes. such as hypertension. hyperlipidemia and peripheral neuropathy. is also essential.
Adenosine for paroxysmal supraventricular tachycardia, Adenosine is the most recent drug approved for the treatment of paroxysmal supraventricular tachycardia. Its advantage is that it is just as effective as verapamil and is far less toxic. The lack of toxicity is due to the extremely short half-life (one to seven seconds). The mechanism of action of adenosine is different from that of other antiarrhythmic agents. For the specific purpose of ameliorating paroxysmal supraventricular tachycardia. adenosine appears to be an ideal antiarrhythmic drug.
Frequency of late reversibility in stress-redistribution thallium-201 SPECT using an early reinjection protocol, To assess the efficacy of an early thallium-201 reinjection protocol for reducing the need for late redistribution imaging. the frequency of thallium-201 late reversibility was prospectively assessed in 62 patients who had stress-redistribution thallium-201 studies by single-photon emission computerized tomography (SPECT). and who received 1 mCi of thallium-201 reinjection immediately following stress tomographic acquisition. These patients also demonstrated greater than or equal to 2 segments with nonreversible defects at 4-hour imaging and underwent late (18-to 72-hour) redistribution imaging. When the criterion of late reversibility was defined as greater than or equal to 1 segment with a 4-hour nonreversible defect demonstrating late reversibility. late reversibility was present in 36 (58%) of the 62 patients and in 88 (24%) of 368 SPECT segments. When the criterion of greater than or equal to 2 segments was used. late reversibility was found in 21 (34%) of the 62 patients and in 73 (20%) of the 368 segments. Of the 21 patients who had greater than or equal to 2 late reversible segments. 12 (57%) exhibited late reversibility in greater than or equal to 3 segments. The frequency of detected reversible defects increased from 32% by 4-hour imaging to 48% by combined 4-hour and late imaging (p less than 0.0001). The patients who demonstrated late reversibility could not be distinguished from those who had only late nonreversible defects by analysis of the clinical. exercise. and electrocardiographic (ECG) variables.
Long-term angiographic follow-up after angioplasty of venous coronary bypass grafts, From April 1981 to June 1987. 57 patients underwent venous coronary bypass graft percutaneous angioplasty and had a minimal follow-up of 18 months. The procedure was elective for 28 patients. urgent for 19. and was considered as an emergency for 10. A total of 64 grafts were dilated that had been bypassed 58 +/- 48 months previously (range 2 to 184 months); lesions were located on the aortic anastomosis in 12 grafts. on the body in 38. and on the coronary anastomosis in 14. Technical success was 95.3% (61 of 64) per lesion; clinical success was 84.4% (54 of 64) per lesion and 82.5% (47 of 57) per patient. Thrombotic complications with images of a lacunar defect occurred in 11 grafts (17.2%). Predictive factors for these complications were: age of grafts 38.5% for greater than 60 month grafts versus 2.6% for less than 60 month grafts (p less than 0.01); site of lesion. body lesion 28.9% versus anastomosis none (p less than 0.01); type of lesion. concentric and short 6% versus other 29% (p less than 0.05); and recent fibrinolysis in 66% versus 10.6% (p less than 0.05). Long-term follow-up is available in the 47 successful patients and the three limited non-Q wave myocardial infarction patients. Two patients died at 13 and 17 months. Long-term angiographic follow-up is available in 45 of 48 patients or 94%. At the end of the study. 35 of 57 (61.4%) venous bypass grafts in 32 patients (64%) were patent after one or more percutaneous transluminal angioplasties.
A comparison of multilesion percutaneous transluminal coronary angioplasty in elderly patients (greater than 70 years) and younger subjects, Results of multilesion percutaneous transluminal coronary angioplasty (PTCA) were compared in 210 elderly patients (70 to 92 years. [group I] and 210 younger patients (40 to 69 years. [group II]. The elderly patients included more women (43% versus 24%) and patients with unstable angina (73% versus 55%). PTCA was successful in 87% of lesions in group I and in 94% in group II (p less than 0.001). Only circumflex artery dilatation was less successful in group I (78% versus 91%. p less than 0.002). PTCA was successful in all lesions of at least one vessel in 89% of group I patients and in 94% of group II patients (p less than 0.06). Successful dilatation of all lesions was achieved in 77% of group I and in 85% of group II patients (p less than 0.05). Complication rates were similar for both groups. These data demonstrate a high rate of success and safety in elderly patients undergoing multilesion PTCA despite the presence of several risk factors (advanced age. female sex. unstable angina). The lower PTCA success rate in these patients compared with younger subjects is almost entirely attributable to reduced success for circumflex artery lesions.
Inability of coronary blood flow reserve measurements to assess the efficacy of coronary angioplasty in the first 24 hours in unselected patients, To determine functional and anatomic changes in the first 24 hours after coronary angioplasty. we studied at random 15 patients (9 men. mean age 60 years) who underwent coronary angioplasty of 16 coronary arteries. Quantitative coronary angiography and coronary flow reserve measurements from digitized coronary angiograms were performed before. immediately after. and 24 hours after coronary angioplasty. Calculated were the minimal luminal diameter. obstruction area. and percentage diameter stenosis from two preferably orthogonal projections. Prior myocardial infarction in the myocardial region of interest was present in four patients. Seven patients had multivessel disease. Collateral vessels supplying the compromised flow region were observed in three patients. Six patients had refractory unstable angina pectoris. After coronary angioplasty. angiographically visible dissection was noted in six patients. whereas side branch occlusion was observed in one. Minimal luminal diameter before. immediately after. and 24 hours after was 0.93 +/- 0.18 mm. 1.53 +/- 28 mm. and 1.53 +/- 0.21 mm. respectively; obstruction area was 0.70 +/- 0.26 mm2. 1.92 +/- 0.69 mm2. and 1.87 +/- 0.51 mm2. respectively; diameter stenosis was 60.4 +/- 8.0%. 36.8 +/- 11.4%. and 37.6 +/- 5.3%. respectively. The coronary flow reserve (lower limit of normal with this technique 3.4) was essentially the same before and immediately after coronary angioplasty (1.26 +/- 0.59 vs 1.30 +/- 0.42. p = NS) with a slight improvement to 1.78 +/- 0.90 (p less than 0.05) 1 day later. Coronary artery dimensions correlated poorly with coronary blood flow reserve before and after angioplasty.
The coronary artery response to implantation of a balloon-expandable flexible stent in the aspirin- and non-aspirin-treated swine model, Intracoronary stents may potentially alleviate some of the problems associated with coronary angioplasty. Since the anatomy and physiology of swine coronary arteries closely resemble those of humans. the response to implantation of the Glanturco-Roubin. balloon-expandable. flexible stent was studied in this model. Additionally. the effect of aspirin. 1 mg/kg/day orally. on this response was evaluated. Eighteen Hanford minature swine underwent stenting of the left anterior descending coronary artery. Two died within 24 hours of stent implantation. The 16 survivors were put to death at 4 (n = 4). 11 (n = 4). 28 (n = 4). 56 (n = 3). and 180 (n = 1) days. Angiographically. reduction of stent lumen diameter of 0.1 to 1.3 mm was observed and was maximum at 11 days. with gradual improvement at subsequent time periods. Scanning electron microscopy. transmission electron microscopy. and light microscopy showed early disruption of subjacent endothelium. and adherence of platelets to exposed subendothelium and stent wires. Microthrombi were readily apparent. At 11 days. intimal thickening. made up predominantly of smooth muscle cells with abundant extracellular matrix. was observed and covered the stent wires. At 28 days. regression of intimal thickening was apparent and a confluent endothelium with flow-directed orientation was seen. At 56 and 180 days. the luminal surface was smooth; intimal thickening averaged 525 microns over the stent wires and 55 microns away from the wires. Findings in aspirin-treated animals were similar to results in those that did not receive aspirin. Thus in this swine model. stent implantation results in a time-dependent and self-limited vascular response.
Attenuation of circadian variation by combined antianginal therapy with suppression of morning and evening increases in transient myocardial ischemia, The circadian variation of total ischemic activity was examined during 3289 hours of ambulatory ECG monitoring in 101 patients with stable angina pectoris and proved coronary artery disease. who were not receiving any prophylactic antianginal therapy. The 101 patients displayed 411 episodes of ischemia. 312 (76%) of which were silent; a circadian rhythm was noted for the occurrence of total and silent ischemia. Thirty-eight percent of the ischemic episodes occurred between 6 AM and 12 noon. and total and silent ischemia were significantly more frequent during this period compared with the other three 6-hour periods (p less than 0.01); a lesser peak was noted in the evening. The effects of metoprolol and combined therapy with metoprolol and nifedipine on the circadian variation of ischemic activity were studied in two subgroups of patients in a random. double-blind study design (31 patients receiving metoprolol and 42 receiving combined therapy). During therapy with metoprolol the morning increase in ischemic activity was attenuated. and the highest frequency of ischemia was then noted in the evening (6 AM to 12 noon compared with 6 PM to 12 midnight; p less than 0.05). Combined therapy abolished the morning peak as did metoprolol monotherapy. but even the evening increase in ischemic activity was attenuated (p less than 0.05). The diurnal distribution of the mean heart rate at the onset of ischemia. when patients were off therapy. showed a morning increase similar to the increase in ischemic activity but no second peak in the evening.
Functional recovery of hibernating myocardium after coronary bypass surgery: does it coincide with improvement in perfusion, To determine the relationship between functional recovery and improvement in perfusion after coronary artery bypass graft surgery (CABG). 49 patients were studied. Radionuclide angiography was performed before. 1 month after. and 6 to 12 months after CABG to evaluate regional wall motion. Exercise thallium-201 myocardial perfusion imaging was done before and 1 month after CABG to assess regional perfusion. Preoperative asynergy was observed in 108 segments. and 74 of them showed an improvement in wall motion 1 month after CABG (segment A). Sixty-six of these segments (89%) were associated with an improvement in perfusion. Eight segments that had not improved 1 month after CABG demonstrated a delayed recovery of wall motion 6 to 12 months after CABG (segment B). However. seven of eight segments (88%) already showed an improvement in perfusion 1 month after CABG. A total of 82 segments exhibited functional recovery after CABG and were considered hibernating segments. In the preoperative study segment B more frequently had areas of akinesis or dyskinesis than segment A (75% vs 34%. p less than 0.05). The mean percent thallium-201 uptake in segment B was lower than that in segment A (74% +/- 9% vs 83% +/- 8%. p less than 0.05). Functional recovery of hibernating myocardium usually coincided with an improvement in perfusion. However. delayed functional recovery after reperfusion was observed in some instances. Severe asynergy and severe thallium-201 defects were more frequently observed in these segments with delayed recovery. Hibernating myocardium might remain stunned during those recovery periods.
U74006F, a novel 21-aminosteroid, inhibits in vivo lipid peroxidation but fails to limit infarct size in a canine model of myocardial ischemia reperfusion, Peroxidation of membrane lipids has been suggested to play a role in the pathogenesis of myocardial ischemia/reperfusion injury. We therefore assessed the efficacy of U74006F. a potent in vitro vitamin E-like inhibitor of lipid peroxidation. in limiting infarct size in a canine model of transient coronary artery occlusion. Twenty dogs underwent 2 hours of occlusion of the left anterior descending coronary artery and 6 hours of reperfusion. U74006F or saline solution was administered continuously from 1 hour of occlusion to the end of the experiment. U74006F blunted any increase in production of conjugated dienes (an index of lipid peroxidation) at both 30 minutes (1.73 +/- 0.16 mol/L x 10(-4) vs 2.62 +/- 0.22 in control dogs. p less than 0.05) and 6 hours (1.39 +/- 0.22 vs 2.06 +/- 0.18 in control dogs. p less than 0.05) after reperfusion. Furthermore. 6 hours after reflow vitamin E levels tended to be lower than baseline values in control dogs and higher than baseline values in dogs treated with U74006F. However. analysis of infarct size indicated no statistically significant difference between the two groups when expressed either as a percentage of the left ventricle (10.4 +/- 1.8% in U74006F vs 15.2 +/- 2.4% in control dogs) or as a percentage of the area at risk (33.0 +/- 5.5% in U74006F vs 37.8 +/- 4.5% in control dogs). Although U74006F appeared to be a potent in vivo inhibitor of lipid peroxidation. it failed to limit infarct size after 2 hours of occlusion and 6 hours of reperfusion in this canine model.
Effect of atenolol on myocardial infarct expansion in a nonreperfused rat model, Acute myocardial infarct expansion is associated with a poor prognosis. This study was performed to assess potential beneficial effects of beta-blockers on inhibiting expansion. A pilot study showed that atenolol (10 mg/kg) achieved sustained beta-blockade in rats. In the main study. following left coronary ligation. 36 rats received atenolol and 18 rats received placebo daily for 7 days. Infarct size was similar in treated and control rats (25 +/- 13% versus 28 +/- 11%). Expansion grades and a quantitative index of expansion were similar for both groups. Infarct size and expansion index were significantly related. but linear regression lines were similar for treated and control rats. We conclude that atenolol has no significant effect on infarct expansion in this nonreperfused rat model.
Single- versus dual-chamber sensor-driven pacing: comparison of cardiac outputs, Previous studies have shown that single-chamber sensor-driven pacing improves exercise tolerance for patients with chronotropic incompetence. However. long-term single-chamber pacing has a number of inherent problems that limit its usefulness. Although sensor-driven dual-chamber pacing largely obviates the problems inherent with single-chamber sensor-driven pacing. the physiologic benefit of dual-chamber sensor-driven pacing has not yet been demonstrated. Accordingly. the purpose of this study was to compare exercise-induced cardiac output for patients with chronotropic incompetence. after programming their pacemakers to either a simulated sensor-driven single or simulated dual-chamber mode. Cardiac output was measured noninvasively at rest and peak exercise using standard Doppler-derived measurements. obtained in a blinded fashion. At rest the Doppler-derived resting VVI and DDD cardiac outputs were 4.49 +/- 0.3 L/min and 4.68 +/- 0.3 L/min. respectively. At peak exercise. the DDD cardiac output was 5.07 +/- 0.5 L/min. whereas the simulated activity VVI and DDD cardiac outputs were 6.33 +/- 0.6 L/min and 7.41 +/- 0.70 L/min. respectively. Analysis of variance showed that there was an overall significant difference in cardiac output from rest to peak exercise (p less than 0.001). However. only the simulated activity DDD cardiac output was significantly different from its respective control value (p less than 0.05). Thus this study shows for the first time that the addition of rate responsiveness to dual-chamber pacing results in a significant improvement in cardiac output for patients with chronotropic incompetence.
Mixed venous oxygen saturation for differentiating stable from unstable tachycardias, Current antitachycardia systems are incapable of adequately distinguishing stable from unstable tachycardias. Previously. integration of a pressure sensor or an impedance sensor. together with electrogram analysis. has been investigated as an improved method of identifying unstable arrhythmias. A mixed venous oxygen saturation sensor was investigated for differentiating stable from unstable paced and induced tachycardias in 10 patients. During rapid pacing at 600. 500. 400. 350. 300. and 250 msec cycle lengths. mixed venous oxygen saturation decreased as cycle length decreased. For any given cycle length. rapid ventricular pacing tended to result in greater mixed venous oxygen desaturation compared with atrial pacing. Mixed venous oxygen saturation decreased similarly during induced ventricular tachycardias at cycle lengths greater than 230 msec. However. ventricular tachycardias at cycle lengths less than or equal to 230 msec and ventricular fibrillation had no effect on mixed venous oxygen saturation until after termination. Subsequently. a mixed venous oxygen saturation-tiered therapy algorithm (cycle length less than or equal to 230 msec = unstable; cycle length greater than 230 msec and MVO2 greater than or equal to 6% over 30 seconds = unstable) was developed and was tested retrospectively in 113 paced and induced tachyarrhythmias in these 10 patients for detecting unstable tachycardias (defined as a decrease from baseline systolic arterial pressure of greater than or equal to 50 mm Hg at 15 seconds). The mixed venous oxygen algorithm had 93% sensitivity and 96% specificity compared with rate-only (rate greater than or equal to 170 beats/min) detection with 93% sensitivity and 71% specificity.
Age-related changes in the clinical and electrophysiologic characteristics of patients with Wolff-Parkinson-White syndrome: comparative study between young and elderly patients, The natural history of patients with Wolff-Parkinson-White (WPW) syndrome remains an intriguing question with respect to clinical decision-making. since serial electrophysiologic data spread over several decades in the same patient are not available in the literature. To study the age-related changes in WPW syndrome. we compared two separate groups of patients referred to this Medical Center for electrophysiologic studies because of a clinical presentation with significant arrhythmias. An elderly group of 42 patients aged 50 years or more were compared with a younger group of 51 patients aged 15 to 30 years. The groups were comparable in terms of clinical presentation. including the number of patients who had reported syncopal episodes and those requiring cardioversion of their tachyarrhythmias. Baseline electrophysiologic variables such as sinus rate; sinoatrial conduction time; corrected sinus node recovery time; AH interval; and effective refractory periods of the right atrium. atrioventricular (AV) node. and right ventricular muscle. were significantly greater in the elderly group. Similarly. the anterograde effective refractory period of the bypass tract. the shortest atrial pacing cycle length with 1:1 anterograde conduction via the bypass tract. retrograde effective refractory period of the bypass tract. the shortest ventricular pacing cycle length with 1:1 retrograde conduction via the bypass tract. the shortest consecutive preexcited R-R interval during atrial fibrillation. and the cycle length of orthodromic atrial ventricular reciprocating tachycardia were significantly greater in the elderly group.
Clinical pharmacology of intravenous enoximone: pharmacodynamics and pharmacokinetics in patients with heart failure, Twenty-one patients with heart failure (New York Heart Association [NYHA] class II to IV) received a 24-hour infusion of enoximone followed by a 12-hour washout period. Patients were randomly assigned to one of four treatment groups. Groups I to III received an 0.5 mg/kg bolus. followed by a maintenance infusion of 2.5. 5.0. or 10.0 micrograms/kg/min. Group IV patients received a maintenance infusion of 5.0 micrograms/kg/min without a loading dose. Serial assessment of hemodynamics. plasma levels of enoximone and enoximone sulfoxide. and ventricular ectopy were performed. Enoximone produced a clinically significant increase in cardiac index. and a decrease in mean pulmonary artery wedge pressure and systemic vascular resistance in all groups. Enoximone mildly increased heart rate. and had a minimal effect on mean arterial pressure. There was no statistically significant change in ventricular ectopy during the infusion. Significant hemodynamic improvement was noted at even the lowest infusion rate. and did not increase in linear fashion at higher infusion rates. In patients who did not receive an initial loading bolus of 0.5 mg/kg. the increase in cardiac index was delayed by approximately 1 hour. Plasma concentrations of both enoximone and its major metabolite continued to rise throughout the 24-hour infusion in group III (10.0 micrograms/kg/min). rather than reaching steady state as predicted by the terminal exponential half-lives of these compounds. This is suggestive of nonlinear pharmacokinetics and indicates a potential for excessive accumulation of enoximone and its metabolite during prolonged infusion. These findings may have important implications in guiding the intravenous administration of enoximone.
Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus, Ninety-one patients with dilated cardiomyopathy were studied by two-dimensional. pulsed. and color Doppler echocardiography (1) to detect and quantify mitral regurgitation (MR). (2) to record apical flow velocities in systole and diastole. and (3) to detect the presence of left ventricular thrombi. MR was detected in 57% of the patients and thrombi were present in 40%. but the occurrence of both MR and thrombus was rare (8%). Apical flow velocity was significantly higher throughout the cardiac cycle in the group with MR (diastole 15 +/- 7 vs 9 +/- 7 cm/sec; systole 29 +/- 12 vs 16 +/- 13 cm/sec; p less than 0.001 for both). accounting for the rarity of thrombi in this group. Follow-up data on 89% of the patients showed markedly decreased survival in the group with MR (22% vs 60% at 32 +/- 6 months. p less than 0.005). and this was evident even in patients with mild MR. Thus although MR is a noninvasively obtainable marker of a large subgroup of patients with dilated cardiomyopathy "protected" from left ventricular thrombus formation. it is a sensitive marker of decreased survival.
Characteristics of serial electrocardiograms in heart transplant recipients, To characterize "normal electrocardiogram patterns" after transplantation. serial surface 12-lead electrocardiograms (ECGs) taken 2 weeks. 1 month. and 1 year postoperatively in a group of 50 heart transplant recipients were analyzed and were correlated with clinical parameters. Some recipient atrial activity was evident in 40% of patients at 2 weeks. but in only 16% at 1 year; donor atrial activity was normal in 90% to 94% of patients at all times. ECG intervals generally were normal and did not change over time. The most prevalent abnormality was the presence of incomplete (IRBBB) or complete right bundle branch block (RBBB) patterns (14% at 2 weeks. 16% at 1 month. and 22% at 1 year). In patients with hemodynamic measurements available approximately at the time of the ECG recording 1 year following transplantation. there was a significant correlation between the presence of IRBBB and RBBB patterns and somewhat higher levels of right atrial mean pressure (6.8 versus 3.9 mm Hg. p = 0.01). pulmonary artery systolic pressure (32.5 versus 24.5 mm Hg. p = 0.001) and diastolic pressure (16.2 versus 11.2 mm Hg. p = 0.004). and right ventricular systolic pressure (31.4 versus 26.9 mm Hg. p = 0.019) and pulmonary artery wedge mean pressure (11.3 versus 7.9 mm Hg. p = 0.010). Repolarization changes were also common but decreased in frequency over time (78% at 2 weeks to 34% at 1 year) and did not correlate with the presence or absence of rejection. We conclude that ECG abnormalities in heart transplant recipients are generally mild and that IRBBB and RBBB patterns correlate with increased right heart pressures.
Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy, Myocardial high-energy phosphate metabolism in patients with dilated cardiomyopathy (DCM) of ischemic or idiopathic etiology was assessed at rest by one-dimensional phase-encoded 31P-nuclear magnetic resonance (NMR) spectroscopy studies performed in conjunction with 1H imaging in 20 patients with DCM and in 12 normal volunteers. The measured values of anterior myocardial phosphocreatine/beta-adenosine triphosphate (PCr/beta-ATP). corrected for partial saturation and contamination of the spectra by blood metabolites. averaged 1.80 +/- 0.06 (mean +/- SE) in normal volunteers and 1.46 +/- 0.07 in the patients overall. a highly significant (p less than 0.001) decrease. In patients with DCM accompanied by coronary artery disease (n = 9). the PCr/beta-ATP ratio averaged 1.53 +/- 0.07. while in those with DCM alone it was 1.41 +/- 0.12 (n = 11). a value that was not significantly different. There was no significant correlation (r = 0.34) between myocardial PCr/ATP ratio and left ventricular ejection fraction in patients. These studies demonstrate that myocardial PCr/ATP ratios are reduced at rest in human ischemic and idiopathic dilated cardiomyopathy.
Effects of laser-generated tissue debris on aggregation of human platelets, This study examined the effects of laser-generated tissue debris from thrombus. atheroma. and normal aorta on platelet aggregation. Debris supernatant and suspension from lased thrombus induced dose-related aggregation. maximal at 48 +/- 12% and 65 +/- 2%. respectively. Debris suspension from normal aorta induced maximal aggregation of 35 +/- 12%. but the debris from atheromatous aorta surprisingly had no effect on platelet aggregation. The debris particle count was in the range of 10(10) to 10(12) per liter. Aspirin. 0.2 and 2.0 mmol/L. only weakly inhibited the debris-induced aggregation. and heparin up to 10 U/ml was ineffective. However. iloprost reduced aggregation to 40 +/- 11% of control at 0.3 ng/ml. and totally abolished it at 3 ng/ml. Soluble and particulate laser-generated debris from vascular tissue and thrombus may cause platelet aggregation in vitro. This may have implications for laser coronary angioplasty.
Electrocardiographic diagnosis of left ventricular hypertrophy in the presence of bundle branch block, Autopsy and echocardiographic studies indicate that ECG criteria for LVH tend to maintain their sensitivity in the presence of LBBB. with the exception of left precordial lead criteria alone. With RBBB. ECG criteria for LVH using right precordial S waves and combination criteria of right precordial S waves and left precordial R waves have a marked reduction in sensitivity. whereas left precordial R wave criteria have modestly reduced sensitivity. Limb lead criteria for LVH have increased sensitivity in the presence of RBBB and. to a lesser extent. in the presence of LBBB. Acceptable sensitivity for the diagnosis of LVH in patients with bundle branch block requires a combination of limb and precordial lead voltage criteria and/or other nonvoltage ECG criteria. since the prevalence of LVH in the presence of RBBB or LBBB appears higher than the sensitivity of individual criteria.
Tricuspid atresia: association with persistent truncus arteriosus, Clinical. echo-Doppler. and pathologic data of a rare case of tricuspid atresia in association with truncus arteriosus are presented. There are only six patients (including the patient reported here) with this anomaly in whom detailed pathologic and/or clinical descriptions are available in the literature. An additional six cases were mentioned in the literature but without any details. A prevalence rate of 1.4% among tricuspid atresia cases is estimated. All infants presented with symptoms of cyanosis and/or congestive heart failure within a few days to 2 months after birth and died shortly thereafter. Cardiomegaly and increased pulmonary vascular markings on the chest x-ray film and left axis deviation with left ventricular hypertrophy on the ECG are usually present. Echocardiographic. catheterization. and angiocardiographic studies are helpful in documenting anatomic and physiologic features of this anomaly. Pathologically. the muscular type of tricuspid atresia. type I or II truncus arteriosus. a large subtruncal VSD. and a hypoplastic right ventricle are present. It is concluded that coexistence of tricuspid atresia and truncus arteriosus is rare; clinical. laboratory. and pathologic features are distinctive; the clinical presentation early in life with rapid demise is common; and prompt palliative surgery immediately after recognition of this anomaly should be undertaken.
Comparative angiographic quantitative analysis of the immediate efficacy of coronary atherectomy with balloon angioplasty, stenting, and rotational ablation, Interventional cardiology has branched in two directions: devices that primarily dilate coronary stenoses and those that debulk coronary tissue. Presently the optimum coronary intervention has not been found. While patients are awaiting randomized trials. a comparison based on matched quantitative coronary analysis may be useful to evaluate results of new interventional techniques. Therefore we compared 51 patients undergoing atherectomy with individually matched patients who were undergoing balloon angioplasty and stenting. The lesions were matched according to location of stenosis and reference diameter. Atherectomy and stenting resulted in larger gains in minimal luminal diameter compared with conventional balloon angioplasty. The minimal luminal diameter was increased from 1.2 +/- 0.4 mm to 2.6 +/- 0.4 mm in the atherectomy group and from 1.2 +/- 0.3 mm to 1.9 +/- 0.4 mm in the angioplasty group (p less than 0.00001). Atherectomy and stenting resulted in similar gains in minimum luminal diameter (1.4 mm vs 1.3 mm. p = NS). In addition. atherectomy and stenting appear to be more effective in resisting elastic recoil because of tissue removal and an intrinsic dilating effect. respectively. In matched populations directional atherectomy and stenting appear to be more effective intracoronary interventional devices than balloon angioplasty based on the immediate results. However. atherectomy is limited in smaller coronary vessels because of its larger size.
Clinical implications of pathophysiologic changes in the midlife hypertensive patient, Both aging and hypertension decrease cardiac output through a lower stroke volume and a diminished beta-adrenergic responsiveness. In parallel. the vascular resistance increases because of vascular hypertrophy. In addition. in hypertension the alpha-adrenergic responsiveness is enhanced. Aging and hypertension are also associated with an increase in plasma cholesterol and insulin values. These alterations in cholesterol and insulin levels become particularly pronounced in middle-aged patients with hypertension. alpha-Adrenergic-blocking agents have a positive effect on lipids and insulin resistance. The shift toward enhanced alpha-adrenergic responsiveness. and the fact that vasodilators do not diminish exercise performance favor the use of alpha-blockers as a first drug in middle-aged patients with hypertension. Blood pressure lowering still remains the paramount goal. and these compounds should be used only if proved to be efficacious in a given individual patient.
Acute hemodynamic effects of terazosin in hypertensive and normotensive patients, Terazosin. a selective alpha 1-adrenergic antagonist. was administered intravenously to 10 patients undergoing cardiac catheterization to determine its short-term hemodynamic effects. Hemodynamic measurements were performed before and 30 minutes after three doses of the drug: 1. 1. and 3 mg. One milligram of terazosin reduced the blood pressure (systolic/diastolic. mean) from a mean of 152.0/86.3. 110.7 mm Hg by -24.3/-9.4. -15.3 mm Hg (p less than 0.05). In the five patients who received 5 mg of the drug. blood pressure declined in a dose-dependent manner by -21.8/-3.8. -11.6 mm Hg after 1 mg. and by -35.8/-14.8. -22.8 mm Hg (p less than 0.05) after all 5 mg of the drug. The changes in blood pressure paralleled the terazosin-induced decrease in systemic resistance. Similar changes were recorded for pulmonary artery and capillary wedge pressures and pulmonary vascular resistance. The greatest hemodynamic response was noted with the first drug dose; succeeding doses had a progressively diminished incremental effect. Cardiac output. heart rate. and maximum left ventricular dp/dt demonstrated little change. whereas left ventricular end-diastolic pressure decreased after all three doses. reaching significance after 2 mg (-3.4 +/- 0.9 mm Hg. p less than 0.05). and left ventricular ejection fraction tended to increase (+5.6% +/- 2.4%. p less than 0.05 after 1 mg) and showed a dose dependence analogous to that of systemic resistance. Although not generally reaching statistical significance. indexes of aortic stiffness and compliance displayed a favorable effect. These data are consistent with terazosin's specific alpha 1-antagonism. Left ventricular performance is improved by afterload reduction. since terazosin demonstrated no direct effect on cardiac contractility.
Antihypertensive dose-response relationships: studies with the selective alpha 1-blocking agent terazosin, Terazosin is a selective alpha 1-adrenergic-blocking agent indicated for the treatment of hypertension. The aim of this multicenter study. performed in 256 patients with mild to moderate essential hypertension. was to define the dosing characteristics of terazosin (in the range of 1 to 80 mg) administered once daily. Patients were randomly assigned to placebo or active treatment groups; each group received 3 months of treatment. which comprised three ascending doses of terazosin. each administered for a 1-month period. As determined by conventional office measurements of supine diastolic blood pressure and by automated ambulatory blood pressure monitoring. there was a clear antihypertensive dose-response relationship for terazosin in the range of 1 to 5 mg daily. Except for the 80 mg dose. none of the doses above 5 mg (10 to 40 mg) appeared to provide additional efficacy. Both the office measurements and the monitoring data indicated that the ratio of trough (effect at the end of the dosing interval) to peak (maximum effect during the dosing interval) was at least 50% or greater during treatment with the 5 mg dose. Thus the 5 mg dose appeared to provide meaningful clinical antihypertensive efficacy and to sustain its effects throughout the full 24-hour period.
Antihypertensive therapy: taking lipids into consideration, Several antihypertensive agents have been found to influence serum lipid profiles. Thiazide diuretics increase total cholesterol. low-density lipoprotein cholesterol. and triglyceride levels and slightly reduce high-density lipoprotein (HDL) cholesterol. Most beta-blockers substantially increase triglycerides and lower HDL cholesterol. Angiotensin-converting enzyme inhibitors. calcium channel antagonists. alpha- and beta-blockers. and beta-blockers with intrinsic sympathomimetic activity are lipid neutral. alpha 1-Antagonists (e.g.. terazosin and prazosin) lower total cholesterol. low-density lipoprotein cholesterol. and triglyceride levels and improve total cholesterol/HDL ratios. Observational epidemiologic studies indicate that the lipid effects of antihypertensive agents are large enough to account for substantial differences in the predicted incidence of coronary heart disease. Combination therapy with the alpha 1-antagonist terazosin plus either thiazides or beta-blockers also ameliorates the adverse lipid effects of these agents used alone. A reasonable approach to managing the lipid problems often associated with hypertension is to advise a cholesterol-lowering. low-sodium diet and weight reduction and to select drugs that alone or in combination do not adversely affect lipid profiles.
Long-term efficacy and safety of terazosin alone and in combination with other antihypertensive agents, This open. multicenter phase III study was designed to assess the efficacy and long-term safety of terazosin (1 to 40 mg/day). alone or in combination with other antihypertensive drugs. in 364 patients with mild to moderate essential hypertension. Compared with baseline values. long-term terazosin monotherapy or combination therapy resulted in consistent decreases in both systolic and diastolic blood pressures. with a mean reduction in supine diastolic pressure of 12 to 14 mm Hg. The numbers of patients with controlled blood pressure at the last evaluable visit of each therapy period were as follows: terazosin alone. 106 of 245 (43%); terazosin with added diuretic. 70 of 112 (63%); diuretic with added terazosin. 47 of 88 (53%); and terazosin plus diuretic with added beta-blocker. 22 of 32 (69%). Most adverse events were mild or moderate in severity. Only pain in extremities had a higher incidence during long-term treatment (6%. 181 to 360-day period) than during initial short-term treatment (5%. 1 to 90-day period). Three of six syncopal events occurred during the initial 180 days of treatment; this 0.8% (3/364) incidence was comparable with that reported previously for short-term studies. Only one case of syncope occurred during terazosin monotherapy. Terazosin was judged to be a safe and effective long-term medication for the treatment of hypertension.
Combination antihypertensive therapy with terazosin and other antihypertensive agents: results of clinical trials, Clinical trials in which the selective alpha 1-adrenergic receptor blocker terazosin was given in combination with other antihypertensive agents are reviewed. Results of a recent study examining the effects of combination terazosin and verapamil therapy on blood pressure and heart rate are also presented. In several studies of the combination of terazosin plus a diuretic (hydrochlorothiazide. methyclothiazide. chlorthalidone. furosemide. amiloride. triamterene. metolazone. or spironolactone). significant decreases in one or more of the blood pressure variables studied were demonstrated (compared with diuretic plus placebo). In a placebo-controlled. double-blind study of terazosin plus atenolol. supine and standing blood pressures decreased significantly from baseline (atenolol monotherapy) after the addition of terazosin but not placebo. In a study of terazosin added to background therapy (including beta-blockers. diuretics. methyldopa. clonidine. captopril. guanethidine. hydralazine. and nifedipine). the addition of terazosin resulted in significant decreases in supine and standing diastolic blood pressures compared with baseline values (background therapy alone). Combination antihypertensive therapy with terazosin and verapamil reduced blood pressure to a significantly greater extent than either agent alone. Preliminary pharmacokinetic results indicate that terazosin did not alter the metabolism of verapamil. No significant abnormal laboratory test results have been reported for patients taking terazosin in combination with other antihypertensive agents; in fact some evidence suggests that terazosin may attenuate adverse lipid. glucose. and potassium changes associated with thiazide diuretics. Adverse experiences associated with terazosin combination therapy are usually mild to moderate. Results from all these studies suggest that terazosin effectively controls mild-to-moderate hypertension when it is used in combination with other antihypertensive agents without cumulative adverse effects.
The safety and efficacy of terazosin in the treatment of essential hypertension in blacks, Terazosin. a new selective alpha 1-adrenergic receptor antagonist. has been found to be an effective antihypertensive agent. In a series of studies. the safety and efficacy of terazosin. alone and in combination with other antihypertensive agents. were evaluated in 1180 black patients with mild to moderate essential hypertension. Terazosin was effective in lowering blood pressure when administered alone (in dosages of 1 to 80 mg/day) and when prescribed (in dosages of 1 to 20 mg/day) in combination with other antihypertensive agents. In elderly black patients. terazosin. 1 to 10 mg daily. was as effective in lowering blood pressure as propranolol (40 to 120 mg twice daily). Changes (mean +/- SE) in sitting diastolic blood pressure from baseline were -8.1 +/- 1.4 mm Hg for terazosin and -5.0 +/- 1.5 mm Hg for propranolol. Terazosin (5 mg) combined with methyclothiazide (2.5 to 5 mg) produced a significantly greater (p less than 0.01) antihypertensive effect than that of terazosin alone. Changes (mean +/- SE) in standing diastolic blood pressure from baseline were -7.9 +/- 2.0 mm Hg for terazosin alone. -15.1 +/- 2.1 mm Hg for terazosin plus 2.5 mg of methyclothiazide. and -15.0 +/- 2.0 mm Hg for terazosin plus 5 mg of methyclothiazide. Terazosin had a favorable effect on serum lipid levels and appeared to compensate for the negative lipid effects associated with diuretics and beta-blockers when used in combination with these agents. Terazosin. alone and combined with other antihypertensive agents. was well tolerated with minimal side effects in black hypertensive patients.
Comparison of chest pain, electrocardiographic changes and thallium-201 scintigraphy during varying exercise intensities in men with stable angina pectoris, This study was performed to evaluate the presence of angina pectoris. electrocardiographic changes and reversible thallium-201 defects resulting from 2 different levels of exercise in 19 patients with known coronary artery disease and evidence of exercise-induced ischemia. The exercise protocols consisted of a symptom-limited incremental exercise test (Bruce protocol) followed within 3 to 14 days by a submaximal. steady-state exercise test performed at 70% of the maximal heart rate achieved during the Bruce protocol. The presence and time of onset of angina and electrocardiographic changes (greater than or equal to 0.1 mV ST-segment depression) as well as oxygen uptake. exercise duration and pressure-rate product were recorded. Thallium-201 (2.5 to 3.0 mCi) was injected during the last minute of exercise during both protocols. and the images were analyzed using both computer-assisted quantitation and visual interpretations. Incremental exercise resulted in anginal symptoms in 84% of patients. and electrocardiographic changes and reversible thallium-201 defects in all patients. In contrast. submaximal exercise produced anginal symptoms in only 26% (p less than 0.01) and electrocardiographic changes in only 47% (p less than 0.05). but resulted in thallium-201 defects in 89% of patients (p = not significant). The locations of the thallium-201 defects. when present. were not different between the 2 exercise protocols. These findings confirm the sequence of the ischemic cascade using 2 levels of exercise and demonstrate that the cascade theory is applicable during varying ischemic intensities in the same patient.
Usefulness of technetium-99m-MIBI and thallium-201 in tomographic imaging combined with high-dose dipyridamole and handgrip exercise for detecting coronary artery disease, Forty-two patients with known stable coronary artery disease. referred for coronary angiography. were examined with technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile (MIBI) tomography combined with a high-dose dipyridamole infusion (0.7 mg/kg) and handgrip stress. MIBI tomography was unable to show coronary artery disease only in 2 patients. thus yielding a sensitivity figure of 95%. MIBI tomography correctly identified 27 (82%) of 33 stenotic lesions (greater than or equal to 50% diameter stenosis) of the left anterior descending artery. 17 (61%) of 28 of those of the left circumflex artery. and 28 (90%) of 31 of those of the right coronary artery. The overall vessel sensitivity was 78%. The computed lumen diameter stenoses were more advanced in cases detected than in those not detected with MIBI tomography: 87 +/- 14 vs 76 +/- 14% (p less than 0.01). The 50 to 69% stenoses did not show any tendency to produce less positive findings than those with greater than or equal to 70% stenoses. In the subgroup of 21 patients who also presented for thallium scintigraphy. the overall diseased vessel identification rate was 76% for thallium tomography and 83% for MIBI tomography (p = not significant). Minor noncardiac side effects related to the dipyridamole-handgrip test occurred only in 5% of 63 study sessions. A high-dose dipyridamole combined with isometric exercise is a safe stress method. and when used during scintigraphy. MIBI tomography is at least as efficient a tool as thallium tomography in detecting diseased vessel territories in patients in coronary artery disease.
Impairment of left ventricular function during coronary angioplastic occlusion evaluated with a nonimaging scintillation probe, Impairment of left ventricular function during controlled myocardial ischemia induced by coronary angioplasty has been reported from angiographic and echocardiographic studies. Ejection fraction. peak ejection. peak filling rates. and end-systolic and end-diastolic volumes were investigated before. during and after coronary occlusion on-line with a nonimaging scintillation probe. The study consisted of 18 patients (mean age 59 +/- 10 years) with coronary artery stenosis of greater than 70%. During balloon inflation of 60 seconds' duration. coronary occlusion pressure was 31.6 +/- 12 mm Hg. There was no significant change in heart rate. Delay between first and second dilatation was 109 +/- 63 seconds. Ejection fraction decreased from 53 +/- 16 to 40 +/- 12% (first dilatation. p less than 0.01) and to 39 +/- 14% (second dilatation. p less than 0.01) and recovered to 51 +/- 16% 5 minutes after the second dilatation. Peak ejection rate was significantly reduced during the first and second balloon inflations. Peak filling rate decreased from 2.5 +/- 0.8 to 2.0 +/- 0.7 end-diastolic volume.s-1 (first dilatation. p less than 0.01) and to 1.8 +/- 0.7 end-diastolic volume.s-1 (second dilatation. p less than 0.01) and remained reduced at 2.2 +/- 0.7 end-diastolic volume.s-1 (p = not significant) at 5 minutes after the second dilatation. End-systolic and end-diastolic volumes increased significantly during the first and second dilatations and returned to normal after dilatation. It is concluded that short. controlled myocardial ischemia during coronary angioplasty leads to a decrease in systolic and diastolic left ventricular function. Sequential dilatations do not further decrease function if a sufficient interval is kept.
Dispersion of ventricular repolarization in the long QT syndrome, To identify markers of dispersion of the ventricular repolarization in the idiopathic long QT syndrome. body surface potential maps were analyzed in 40 such patients (mean age +/- standard deviation 21 +/- 11 years) and in 30 healthy control subjects (mean age 24 +/- 7 years). In each subject. 117 chest leads were recorded and maps of the integral values of the QRST interval were calculated. A multipolar distribution of the values. a marker of gross electrical inequalities of repolarization. was found only in 4 patients. To detect minor regional disparities of ventricular recovery. all the ST-T waveforms were analyzed in each subject. The ST-T waves were represented by a discrete series of potential values. The "similarity index" was computed by applying a principal component analysis. which represents (in percent) to what extent 1 fundamental pattern of ST-T reproduces all the recorded waveforms. The mean value of the similarity index was significantly lower in patients with long QT syndrome than in control subjects (49 +/- 10 vs 77 +/- 8%. p less than 0.0001). A value less than 61% (corresponding to 2 standard deviations below the mean value for controls) was found in 35 of 40 patients and in only 1 control subject (sensitivity 87%. specificity 96%). Thus. the similarity index is a more sensitive marker than the multipolar distribution of QRST integral maps in revealing electrical disparities of the ventricular recovery times.
Electrocardiographic correlates with left ventricular morphology in idiopathic dilated cardiomyopathy, The purpose of the present study was to verify whether the electrocardiographic pattern of patients with idiopathic dilated cardiomyopathy (IDC) might be useful in predicting measurements of left ventricular (LV) morphology. A total of 12 electrocardiographic criteria for LV enlargement were evaluated in 67 patients with IDC. aged 14 to 68 years (mean 48). and were correlated to LV wall thickness. volume and mass. as assessed at angiography (all patients) and echocardiography (50 patients). Linear regression analysis showed weak correlations between multiple electrocardiographic criteria and LV wall thickness. volume and mass. Multiple logistic regression analysis showed that total 12-lead QRS amplitude. voltage criteria of Sokolow and Lyon. overshoot and U-wave inversion were the variables significantly related to LV wall thickness. as assessed by angiography (r = 0.55. p less than 0.005) and echocardiography (r = 0.43. p less than 0.025). The sum of T/R-wave ratios. the RV6/RV5 ratio and the Romhilt-Estes score were predictors of LV end-diastolic volume. as determined by angiography (r = 0.83. p less than 0.001) and echocardiography (r = 0.77. p less than 0.005). Total 12-lead QRS amplitude and the sum of T/R-wave ratios were the only independent predictors of LV mass. either angiographically (r = 0.81. p less than 0.001) or echocardiographically measured (r = 0.71. p less than 0.025). It is concluded that a single electrocardiographic criterion for prediction of LV morphology in patients with IDC is barely effective. Multiple electrocardiographic criteria should be utilized to better predict LV mass and distinguish reliably between LV wall thickening and dilatation.
Long-term assessment of right ventricular diastolic filling in patients with pulmonic valve stenosis successfully treated in childhood, Patients with severe pulmonic stenosis (PS) have right ventricular (RV) diastolic filling abnormalities detectable by tricuspid valve pulsed Doppler examination. To determine if these abnormalities persist long term after successful therapy of PS. 19 patients were examined 8 +/- 3 years after PS therapy. At the time of follow-up Doppler examination. the PS gradient was 15 +/- 8 mm Hg. From the tricuspid valve inflow Doppler study. the following measurements were obtained at peak inspiration: peak velocities at rapid filling (peak E) and during atrial contraction (peak A). ratio of peak E to peak A velocities. RV peak filling rate normalized for stroke volume. deceleration time. the fraction of filling in the first 0.33 of diastole as well as under the E and A waves. and the ratio of E to A area. Data from PS follow-up patients were compared with our previously reported data from 12 age-related control subjects and 14 untreated patients with PS. Patients with PS who were followed up had higher peak E velocity (0.75 +/- 0.14 vs 0.59 +/- 0.21 m/s). lower peak A velocity (0.47 +/- 0.09 vs 0.64 +/- 0.28 m/s). higher E/A velocity ratio (1.65 +/- 0.33 vs 1.11 +/- 0.52). higher 0.33 area fraction (0.52 +/- 0.08 vs 0.34 +/- 0.14). lower A area fraction (0.29 +/- 0.06 vs 0.45 +/- 0.21) and higher E/A area ratio (2.48 +/- 0.82 vs 1.73 +/- 1.05) than PS patients without treatment (p less than 0.03). All Doppler indexes of the patients with PS who were followed up were the same as those of the control subjects except for the peak E velocity that was slightly higher (0.75 +/- 0.14 vs 0.63 +/- 0.11 m/s). the peak A velocity that was slightly higher (0.47 +/- 0.09 vs 0.38 +/- 0.09 m/s) and the E/A area ratio that was slightly lower (2.48 +/- 0.82 vs 3.50 +/- 1.25) (p less than 0.03). Thus. at long-term follow-up. all RV diastolic filling indexes in successfully treated patients with PS improved compared with the untreated patients and approached values found in normal subjects.
Intracellular potassium and membrane potential in rat muscles during malnutrition and subsequent refeeding, Nutrition alters total body potassium (TBK) and muscle potassium but little is known about in vivo intracellular K+. We measured free intracellular potassium-ion activity (aKi+). membrane potential (Em). and total potassium (Kt) and calculated intracellular potassium concentration [K+]i in predominantly slow- (soleus) and fast- (extensor digitorum longus) twitch muscles in rats undergoing underfeeding and subsequent refeeding. After underfeeding. aKi+ and Em decreased (P less than 0.025 and P less than 0.006. respectively) only in soleus muscle with restoration after refeeding. whereas [K+]i decreased in both muscles (P less than 0.005) and remained low after refeeding. K+ supplementation did not significantly change these indices or the ratio of free to total intracellular potassium (gamma Ki+). The data show that aKi+ behaves differently from [K+]i during malnutrition and that changes in aKi+ occur especially in slow-twitch fibers. suggesting that previously observed changes in TBK and muscle function are the result of fundamental alterations in muscle-cell energetics and membrane functions. not just mass.
Energy requirements of a postobese man reporting a low energy intake at weight maintenance, Three experiments were performed to test the validity of the low reported energy intake of weight maintenance in a postobese man. In the first experiment the subject reported a mean energy intake of 8008 kJ/d during 16 d and he maintained a stable body weight. This finding was not reproduced in the second experiment. which consisted of a 6-d inpatient study during which the subject was confined to a whole-body calorimeter for 5 d. Indeed. he lost weight when fed a controlled energy intake of 7950 kJ/d. Moreover. this experiment showed that direct and indirect calorimetry provided comparable energy-expenditure measurements during this period. Finally. when the subject was refed a controlled energy intake of 7950 kJ/d for 21 d. body weight and fat losses were observed. Therefore. these observations do not support the validity of the low energy intake that may be reported by people predisposed to obesity.
Digestion of bovine milk proteins in patients with a high jejunostomy, Digestion of milk proteins was studied in short-bowel patients. After ingestion of water. purified beta-lactoglobulin (beta-Ig). or skim milk. effluents were collected at the stoma. The flow rate of the effluent peaked in the first 30-min period after ingestion and returned to the basal value within the first 60 min. After milk ingestion 1) the nitrogen concentration of effluents peaked in the first 30 min. 2) SDS-polyacrylamide gel electrophoresis and Western blot indicated the presence of beta-Ig and alpha-lactalbumin (alpha-lac) in jejunal effluents but only during the first 30 min whereas caseins were detected during the initial 1-2 h effluents. and 3) immunoenzymo metric assay indicated that 64% and 44% of the beta-Ig and alpha-lac. respectively. were recovered in an intact antigenic form. Results indicate that the digestion of milk proteins in humans differs quantitatively. Digestion appeared partially incomplete in the upper jejunum. suggesting the importance of the ileum for completion of digestion.
Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in patients with both Crohn's disease and intestinal resection, We compared the intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in patients with Crohn's disease and resections of the small bowel. Patients were subgrouped into those with small (less than 100 cm). intermediate (100-300 cm). and large (greater than 300 cm) resections. [3H]cholecalciferol or [3H]25-hydroxycholecalciferol were given orally and serial blood samples were taken for measurement of plasma radiolabeled vitamin. Absorption of both forms of the vitamin decreased with extent of resection but 25-hydroxycholecalciferol absorption was always greater than that of cholecalciferol. When compared with normal control subjects. 25-hydroxycholecalciferol absorption in these patients was better maintained than that of cholecalciferol. These data indicate that vitamin D malabsorption reflects the extent of distal small-bowel resection in Crohn's disease. Treatment with oral cholecalciferol is sufficient in those with small or moderate resections but oral 25-hydroxycholecalciferol supplementation may be preferred in those with a severe short-bowel syndrome.
Nutritional status of infants with cystic fibrosis associated with early diagnosis and intervention, The purpose of this study was to characterize the nutritional status of infants diagnosed with cystic fibrosis (CF) through neonatal screening and to determine if they would achieve normal nutrition when managed with early intervention. In addition. nutrient intake was assessed to determine energy and macronutrient-consumption patterns. Evaluation of growth revealed that normal patterns could be achieved with mean energy intake values at ages 6 and 12 mo of 481 and 426 kJ/kg body wt (115 and 102 kcal/kg body wt). respectively. Biochemical assessment demonstrated low alpha-tocopherol and linoleic acid values at diagnosis in the majority of infants whereas one-third had abnormal indices of protein nutriture. Essential fatty acid deficiency was also demonstrated at diagnosis by abnormal triene-tetraene ratio values in 27% of screened infants. With predigested formula and dietary supplementation. there was improvement in all indices of nutritional status and only a low percentage of patients showed mild biochemical abnormalities at age 12 mo.
Carbohydrate and lipid metabolism in patients with non-insulin-dependent diabetes mellitus: effects of a low-fat, high-carbohydrate diet vs a diet high in monounsaturated fatty acids, Nineteen patients affected by non-insulin dependent diabetes mellitus (NIDDM). in good glycemic control (fasting plasma glucose 7.2 +/- 0.3 mmol/L. glycosylated hemoglobin 6.3 +/- 0.2%). underwent three isocaloric dietary phases. In phases 1 and 3 the diet was rich in complex carbohydrates (Carbo) whereas in phase 2 it was rich in monounsaturated fatty acids (Mono). Plasma glucose concentrations were 7.1 +/- 0.3 and 7.2 +/- 0.3 mmol/L for the two Carbo phases and 7.5 +/- 0.4 mmol/L for the Mono phase (NS). Plasma total cholesterol values for the Carbo phases were 6.2 +/- 0.2 and 6.4 +/- 0.2 mmol/L. respectively. and 6.5 +/- 0.2 mmol/L on the Mono phase (NS). Similarly. no significant changes were noticed for plasma triglycerides and high-density-lipoprotein (HDL) cholesterol. Thus. both diets were well-tolerated and did not alter glucose homeostasis or worsen plasma lipid concentrations. Consequently. these results suggest that a wider dietary choice can be made available to NIDDM patients without producing unwanted side effects.
Coronary-heart-disease risk-factor status of the Cretan urban population in the 1980s, The traditional Cretan diet has been associated with low coronary-heart-disease (CHD) mortality rates. This study reports on the prevalence of CHD risk factors among 387 Cretan bank employees. Mean cholesterol concentration has risen by 36% over 26-y; dietary intake has changed: consumption of meat. fish. and cheese has increased and consumption of bread. fruit. and potatoes has decreased. Although the percentage contribution of fat to total energy intake has decreased from 40% to 36%. there has been a reduction in monounsaturated fatty acid consumption and an increase in the consumption of saturated fatty acids whereas the consumption of polyunsaturates has not been altered. Exception for diminished physical activity. the prevalence of other risk factors (smoking. blood pressure. and body mass index) remained relatively stable over this period. These changes in the CHD risk-factor status of the Cretan urban population occurred over a period in which CHD mortality rates are reported to have increased.
Distribution of BCA-225 in adenocarcinomas. An immunohistochemical study of 446 cases, BCA-225 is a glycoprotein identified in human breast carcinoma cells that has been reported to show a restricted distribution in other human tissues. To further define the presence of BCA-225 in human carcinomas. the authors performed an immunohistochemical study. applying a commercially available monoclonal antibody to BCA-225 to formalin-fixed. paraffin-embedded sections of 446 adenocarcinomas from a variety of sites. BCA-225 expression was found to be common in adenocarcinomas of the breast (98%). kidney (94%). ovary (80%). and lung (74%) but was infrequent in adenocarcinomas of the gastrointestinal tract (10-16%). Adenocarcinomas of the prostate. bile ducts. thyroid. endometrium. endocervix. and pancreas showed an intermediate frequency of BCA-225 expression (36-68%). Although rare tumor cells in three hepatocellular carcinomas showed reactivity for BCA-225. staining of more than 10% of the tumor cells was not seen in any of the 23 hepatocellular carcinomas that were studied. The authors conclude that BCA-225 is expressed commonly in human adenocarcinomas and that it is not a breast-specific antigen. Antibodies to BCA-225 may have utility in helping one to exclude hepatocellular carcinoma in certain clinical settings.
Primary carcinoid of the common bile duct. Immunohistochemical characterization of a case and review of the literature, A 39-year-old woman with a primary carcinoid of the common bile duct is presented. The tumor showed argyrophilia; and. by immunohistochemical studies. chromogranin. serotonin. and somatostatin were demonstrated. The patient has no symptoms 42 months after surgical treatment. To the authors' knowledge. this is the first report of a carcinoid of the common bile duct as studied by immunohistochemistry. When six choledochal carcinoids were reviewed. the following characteristics were observed: in none of the cases were endocrine symptoms present; women were affected more frequently than men; the carcinoids occurred in younger patients than did adenocarcinomas; metastases were present in half of the patients; and. as a group. carcinoids seemed to have a better prognosis than adenocarcinomas in this location.
Frozen sections of cellular lymphoid proliferations provide adequate DNA for routine gene rearrangement analysis, Optimal use of frozen tissue procured as part of a thorough diagnostic workup of suspected lymphoma is important. and conservation of similar samples is a prerequisite for maintaining a large and varied frozen archive repository. The authors have evaluated a simple tissue-conserving method for the preparation of cellular lymphoid specimens for immunoglobulin and T-cell receptor gene rearrangement analysis. Initially. 16-microns-thick frozen tonsil sections were examined to determine adequacy for DNA extraction. Specimens containing three. six. and nine sections each were evaluated separately. DNA quantitation disclosed yields ranging from 84 to 204 micrograms (mean. 156 micrograms). The authors have used this technique on 24 cellular lymphoid proliferations from their frozen archives. Six to ten 16-microns sections were used. depending on tissue size. DNA quantitation ranged from 0 to 520 micrograms (mean. 135 micrograms). Twenty-one of 24 cases yielded adequate DNA for analysis; each showed appropriate germline or rear-ranged bands with respect to the particular morphologic diagnosis. Attempts to obtain adequate DNA with the use of this technique on skin biopsy specimens with lymphoid infiltrates resulted in overall poor yields; this may be because of dermal collagen or small sample size. This method of sample preparation provides adequate DNA for routine Southern blot hybridization analysis of cellular lymphoid tissues and offers the additional advantage of allowing preservation of frozen tissue for future study.
The impact of a clinic for adults with HIV infection on the microbiology laboratory, The Infectious Diseases Clinic (IDC) discussed serves adults who are seropositive for human immunodeficiency virus. The authors reviewed the outpatient and inpatient microbiology tests of a three-month period during 1989 for a systematic sample of IDC patients. The 249 patients in the sample had 682 microbiology tests performed during the period (mean 2.7 tests per patient). Tests most frequently requested were mycobacterial culture. routine blood culture. and cryptococcal antigen determination. Patients with acquired immunodeficiency syndrome (43% of IDC patients) accounted for 63% of the requested IDC tests. IDC patients comprised about 2.4% of patients served but accounted for 3.9% of the requested microbiology tests and 6.6% of the microbiology work load for reported tests. Using Centers for Disease Control case projections. the authors estimated that services to IDC patients in 1993 would comprise 6.6% of all microbiology tests and 10.6% of the microbiology work load. The implications of these data for microbiology probably also apply to other laboratory testing and emphasize the need for more efficient ways to use and perform diagnostic studies required by patients with HIV infection.
Optimal positioning of endotracheal tubes for ventilation of preterm infants, Accurate knowledge of upper-airway dimensions is required to prevent malpositioning of endotracheal tubes in preterm infants. We measured vocal cord-carina. oral-carina. and nasal-carina distances in situ at autopsy of two groups of infants (less than 1000 and greater than or equal to 1000 g). In all 24 infants. crown-heel length. crown-rump length. and occipitofrontal circumference were better than weight in predicting upper-airway dimensions. Flexion of the neck decreased and extension increased both nasal-carina and oral-carina distances. Lateral rotation produced no significant changes. The postmortem data were not different from nasal-carina distances measured radiologically in 40 living. nasally intubated and ventilated infants. confirming the clinical validity of our findings. Regression equations were derived to predict optimal endotracheal tube lengths based on the external measurements of crown-rump length and crown-heel length.
Ductal patency in neonates with respiratory distress syndrome. A randomized surfactant trial, The purpose of this study was to evaluate in a controlled study the effect of exogenous surfactant on various manifestations of ductal patency. Premature infants with respiratory distress syndrome were randomized to receive surfactant (Survanta) (n = 22) or air (n = 14). In neonates receiving surfactant. there was a greater tendency for an audible murmur to develop (13 of 22 vs four of 14). In spite of this. the clinical use of indomethacin was similar for the two groups. 10 (45%) of 22 vs six (43%) of 14. Excluding neonates given indomethacin early. a comparable number of surfactant-treated neonates (9/17 [53%]) vs control neonates (6/12 [50%]) demonstrated spontaneous closure of the ductus within a physiologic time frame (on or before day 4). For the gestational ages studied. the beneficial effects of exogenous surfactant were not associated with either an increased risk for delayed closure of the ductus arteriosus or a greater incidence of indomethacin usage. Utilization of exogenous surfactant does not appear to have an adverse impact on ductal patency.
Safety of a preadolescent basketball program, A preadolescent youth basketball program was prospectively studied to determine injury rates and the kinds of injuries sustained. The overall injury rate was 7.6% (39 injuries among the 510 children aged 5 to 12 years). Girls had a higher injury rate than boys (P less than .02). Only 12 children (2.4%) suffered significant injuries as defined by the inability to play for at least one session. Most injuries were contusions (35.9%). followed by strains or sprains (28.2%). epistaxis (12.8%). lacerations (5.1%). and one finger fracture (2.6%). the most significant injury. Games were more likely to produce injuries than practice sessions; most injuries occurred in the second half of game play. This study documents a low injury rate in an organized preadolescent basketball program.
Family history of myocardial infarction and hemodynamic responses to exercise in young black boys, The influence of family history of coronary artery disease on children's hemodynamic responses to exercise was examined with 25 black boys aged 7 to 10 years. Blood pressure. heart rate. cardiac output. stroke volume. and total peripheral resistance were evaluated during preexercise. peak exercise. and recovery stages. Children with a family history of CAD exhibited greater systolic blood pressure and total peripheral resistance during preexercise and peak exercise stages than did those without a family history of coronary artery disease. After controlling for preexercise differences. the group with a family history of coronary artery disease exhibited greater increases in systolic blood pressure and less attenuation of total peripheral resistance to peak exercise than the group without a family history of coronary artery disease. Cardiac output indexed by body surface area and stroke volumes were higher at all times in the group without a family history compared with the group with a family history of coronary artery disease. Findings are compared with those of adult studies in terms of influence of family history of coronary artery disease on cardiovascular reactivity to stress.
Arterial catheter-related infections in children. A 1-year cohort analysis, To determine the incidence of infection secondary to arterial catheterization in children as well as the risk markers. we prospectively evaluated. during a 1-year period. all arterial catheters installed in children admitted to the pediatric intensive care unit. A total of 340 cannulas were placed in 310 children aged 80 +/- 4 months (mean +/- SEM) for a period of 64 +/- 4 hours. Most catheters were inserted percutaneously (99%) in the radial artery (86.5%). Ninety-two percent (313/340) of the catheters were sterile (group 1). 5% (17/340) were contaminated (less than 10 colony-forming units on semiquantitative culture) (group 2). and 3% (10/340) were considered either locally infected (ie. greater than or equal to 10 colony-forming units) (eight of 10) or associated with a possible catheter-related sepsis (two of 10) (group 3. or infected group). The incidence of local inflammation at the insertion site was higher in group 2 than in group 1 (18% vs 2.9%) but not statistically different between groups 3 and 1 (10% vs 2.9%). The duration of arterial catheterization was longer in group 3 than in group 1 (125 +/- 31 vs 61 +/- 4 hours). The risk of infection was nonexistent in the first 48 hours of catheterization. Thereafter it was calculated as being 6.2% (10/161). but it correlated poorly with the duration of arterial catheterization. These results confirm the very low incidence of infection related to arterial catheterization in children. Thus. routine catheter reinsertion is. in our opinion. unjustified.
The effect of valproic acid on plasma carnitine levels, Plasma total. free. and acyl carnitine levels were determined in four groups of children: (1) those treated with valproic acid as monotherapy (n = 43). (2) those treated with valproic acid plus other antiepileptics as polytherapy (n = 91). (3) those treated with other antiepileptic drugs alone (n = 43). and (4) normal patients (n = 89). The mean free carnitine level was significantly lower in both the valproic acid monotherapy (29.9 mumol/L) and polytherapy (21.4 mumol/L) groups compared with normal subjects (36.8 mumol/L); it was also significantly lower than that in patients treated with other antiepileptic drugs (36.7 mumol/L). Comparison of valproic acid polytherapy and monotherapy yielded significantly lower free carnitine levels in the polytherapy group. The ratios of acyl to free carnitine for monotherapy (0.41) and polytherapy (0.45) were significantly higher than that in the normal group (0.25). This study indicates that a general decrease in the carnitine pool should be anticipated in patients taking valproic acid polytherapy and. to a lesser degree. monotherapy. Carnitine levels in the group taking other drugs did not differ from normal.
Dengue-1 virus envelope glycoprotein gene expressed in recombinant baculovirus elicits virus-neutralizing antibody in mice and protects them from virus challenge, In order to test the feasibility of baculovirus (Autographa californica nuclear polyhedrosis virus. AcNPV) expression vectors for making immunogens against dengue-1 (DEN-1) virus. a portion of the envelope (E) glycoprotein gene of DEN-1 virus was cloned and expressed. The recombinant baculovirus contains 107 nucleotides from the 3' terminus of the DEN-1 matrix (M) gene. which encodes a hydrophobic signal peptide and extends through the first 1. 245 nucleotides of E. terminating 243 nucleotides before the 3' terminus of E. When the recombinant virus was grown in Spodoptera frugiperda cells. about 1 mg of E antigen was made per 10(9) cells. Recombinant E antigen reacted with E protein-specific monoclonal antibodies and stimulated production of DEN-1 virus neutralizing antibody in BALB/c mice. Mice immunized with recombinant E antigen or with heat-inactivated DEN-1 virus were protected significantly against lethal DEN-1 virus challenge. A dose/response effect was observed. with increasing amounts of recombinant antigen leading to increased survival. These results demonstrate the utility of baculovirus for producing immunogens against DEN-1 virus.
Alveolar hydatid disease of the liver: a report on thirty-nine surgical cases in eastern Anatolia, Turkey, The charts of 39 consecutive patients who underwent surgery between 1979 and 1989 with a diagnosis of alveolar hydatid disease (AHD) of the liver were reviewed. The analysis of these cases from eastern Anatolia. which is the endemic region in Turkey. was undertaken to determine the current experience for AHD lesions. Of these patients. 33 (84.6%) had unresectable disease and the remaining six patients (15.4%) were treated by hepatic resection of the primary lesion. In the unresectable cases. laparotomy with biopsy was the most commonly used surgical procedure (56.4%). followed by tube drainage of the necrotic cavity (18.0%). marsupialization (5.1%). and cystojejunostomy (5.1%). Diagnostic studies and operative findings were useful in detecting the AHD lesions. Differential diagnosis was established mainly by histopathologic examination of a biopsy specimen or resected tissue. Pulmonary metastases were seen in two cases. and mortality occurred due to brain metastases in two other cases. Mebendazole was administered postoperatively to 19 patients with indications for 1) advanced AHD. 2) adjuvant therapy to radical and palliative surgical procedures. and 3) recurrences of disease after hepatic resection. The patients were treated with daily doses of approximately 50 mg/kg for periods of one and six years (median 3.2 years). Encouraging results were obtained in 11 of nineteen patients. Five-year survival was seen in 8 of the patients with AHD in this series. There were 18 deaths (46.2%) in our 39 patients. Long-term follow-up was not possible in four cases. and 17 patients (43.6%) were still living. The causes of mortality were advanced AHD in 14 cases. brain metastases in two. and acute myocardial infarction in another two.
Infection of Aedes albopictus and Aedes aegypti mosquitoes with dengue parent and progeny candidate vaccine viruses: a possible marker of human attenuation, Dengue (DEN-1) and DEN-4 parent (P) and progeny candidate vaccine (CV) viruses were compared in their abilities to infect and to replicate in Aedes aegypti and Aedes albopictus mosquitoes. The DEN CV clones were temperature sensitive (ts) and had small plaque morphology. The DEN-1 and DEN-4 CV viruses differed in their ability to infect. to replicate in. and to be transmitted by mosquitoes. The DEN-1 CV virus was not attenuated for the vector mosquitoes; oral infection rates with the CV virus were as high as or higher than the P virus. and the CV virus replicated efficiently in mosquitoes after oral infection. The DEN-4 CV virus was attenuated; it was less efficient than its P virus in infection and replication in mosquitoes. Thus. the ts phenotype and small plaque morphology are not reliable biological markers for prediction of vector attenuation. Similar results were reported by others for attenuation in man and monkeys. These studies with DEN-1 and DEN-4 viruses. and previously reported studies with DEN-2 virus and with DEN-3 virus suggest that vector and vertebrate host attenuation are genetically linked. Thus. vector attenuation may be a biological marker for human attenuation.
Hypnozoites of Plasmodium simiovale, Hypnozoites of Plasmodium simiovale were detected in liver biopsies from a rhesus monkey (Macaca mulatta) inoculated eight days previously with sporozoites from heavily infected anopheline mosquitoes. The tissue forms. 6 mu in diameter. were found within the cytoplasm of hepatic parenchymal cells by immunofluorescence and restained with Giemsa. This is the first report of latent. pre-erythrocytic stages from an ovale-type relapsing malaria.
Anopheline ecology and malaria infection during the irrigation development of an area of the Mahaweli Project, Sri Lanka, A study on adult anopheline ecology and malaria vector incrimination was carried out from 1986 to 1989 during irrigation development in an area of the Mahaweli Project in eastern Sri Lanka. Eleven potential vector species were collected resting indoors or by using human or bovid bait. and from light trap catches. Overall. Anopheles vagus (Donitz). An. annularis (van der Wulp). and An. subpictus (Grassi) were the most prevalent. and An. culicifacies (Giles) and An. barbirostris (van der Wulp) were the least prevalent species. The abundance of An. aconitus (Donitz). An. jamesii (Theobald). An. pallidus (Theobald). and An. subpictus increased after irrigation development. while An. annularis. An. barbirostris. An. culicifacies and An. varuna (Iyengar) decreased. Populations of An. nigerrimus (Giles). An. tessellatus (Theobald). and An. vagus did not change substantially. Seven species were infected with malaria parasites. as determined by enzyme-linked immunosorbent assays (ELISA) done on mosquito head-thorax triturates. The main species involved were An. annularis. at peak abundance during the 1986-1987 period of development leading to the onset of irrigation. and An. subpictus. during times of seasonal abundance in the post-irrigation period of 1988 to 1989. Although occurring at low abundance. An. culicifacies was involved in malaria transmission irregularly throughout the study period. While there was strong ELISA-based evidence implicating An. subpictus as a major post-irrigation vector. confirmation of its vector status must await dissection and ELISA-based evidence of P. vivax and P. falciparum sporozoite infection rates in salivary glands.
Standard and reduced doses of mefloquine for treatment of Plasmodium falciparum in Tanzania: whole blood concentrations in relation to adverse reactions, in vivo response, and in vitro susceptibility, Fifty-three asymptomatic Tanzanian school children with 400-31.000 asexual Plasmodium falciparum parasites/microliter of blood were given standard. one-half. one-quarter. or one-eighth of the recommended mefloquine treatment dose of 25 mg base/kg body weight. Mefloquine and main metabolite concentrations were determined in 100 microliters of capillary blood using a high performance liquid chromatographic method. In the standard. one-half. and one-quarter dose groups. all children cleared the parasites within three days after treatment. Reappearance was noted in one of the children in the one-quarter dose group during 49-56 days of followup. Among the children given one-eighth of a dose. two had an RII response and four had an RI response with early recrudescence. All 24-hour in vitro micro-tests (n = 30) showed full susceptibility for mefloquine. Adverse gastrointestinal reactions were reported by eight children on the first day after treatment. four of whom had been given a standard dose. These children had higher mefloquine concentrations one day after treatment than the other children in this group (P less than 0.05). In the standard dose group (n = 13). the area under the curve of capillary whole blood concentrations of mefloquine versus time was 52.4-112.1 mumol/liter x days. The highest concentration on day 1 was 2.75-7.20 mumol/liter and the median terminal half-life was 17.4 days. The highest concentrations of the main metabolite were observed 1-2 weeks after treatment and the median half-life was 18.9 days. The concentrations in the other groups were approximately proportional to those in the standard dose group both for mefloquine and the metabolite.
Pre-travel health, immunization status, and demographics of travel to the developing world for individuals visiting a travel medicine service, It is estimated that five million Americans will travel to the developing world over the next year. This study examines the demographic profile. past medical and immunization history. itinerary. and reason for travel of 2. 445 travelers to the developing world seen at a travel medicine service from 1984 through 1989. The travelers age ranged from three months to 85 years (mean age 43). A chronic medical condition was reported by 654 (27%). Four percent of all travelers were intolerant of sulfonamides. and 9% had contraindications to mefloquine for malaria prophylaxis. Many travelers were due to receive the primary series or updatings of routinely recommended immunizations: 43% for tetanus/diphtheria. 55% of those born after 1956 for measles. and 70% for polio if their travel itinerary included a polio risk. Most travel (71%) was for vacations. 13% was for teaching or study. 11% for business. and 5% for missionary activities. The median duration of travel was 21 days; 5% traveled for more than one year. While over 150 countries were visited. 52% of all travel was to 10 countries in East Africa. the Indian subcontinent. the Far East. and South America. Information about the epidemiology of travel to the developing world can help physicians and travel medicine services develop more effective preventive measures for travelers.
Ethanol consumption inhibits fetal DNA methylation in mice: implications for the fetal alcohol syndrome, Acute ethanol administration (3 g/kg twice a day) to pregnant mice. from the 9th thru the 11th day of gestation. resulted in hypomethylation of fetal deoxyribonucleic acid (DNA). Nuclei isolated from the fetuses of the ethanol-treated mice had lower levels of methylase activity relative to controls even in the presence of excess S-adenosylmethionine. which serves as the methyl donor for the enzyme DNA methyltransferase. Acetaldehyde. at concentrations as low as 3 to 10 microM. inhibited DNA methyltransferase activity in vitro. Since DNA methylation is thought to play an important role in the regulation of gene expression during embryogenesis. ethanol-associated alterations in fetal DNA methylation may contribute to the developmental abnormalities seen in the fetal alcohol syndrome.
Chronic tolerance and sensitization to alcohol in sons of alcoholics, In view of conflicting results concerning differences between sons of alcoholics and sons of nonalcoholics in response to a single alcohol challenge (with a given dose). we exposed these high and low risk groups to several sessions in which they drank alcohol at the same dose in order to measure the development of chronic tolerance or sensitization with repeated doses. Sons of alcoholics and sons of nonalcoholics received a moderate dose of alcohol (0.5 g/kg) in three sessions with alcohol. followed by a placebo session. Sons of alcoholics developed reverse tolerance or chronic sensitization to repeated dosings of alcohol in finger pulse amplitude. while sons of nonalcoholics did not. Sons of alcoholics failed to show chronic tolerance in skin conductance and finger temperature. while sons of alcoholics did show the development of tolerance. Sons of alcoholics demonstrated greater motor activity throughout the sessions. both before and after alcohol. These results indicate that high and low risk groups differ in terms of their developmental adaptation to alcohol. as well as in the temperamental trait of behavioral activity.
Changes with age in the proliferative response of splenic T cells from rats exposed to ethanol in utero, The fetal alcohol syndrome is associated with altered immunity. Several laboratories have confirmed that rodents exposed to ethanol in utero demonstrate both diminished proliferative responses of T cells to mitogens and diminished proliferative responses of T-blast cells to human recombinant interleukin 2 (rIL2). We examined the developmental time course of these altered immune responses by testing the immune function of in utero ethanol-exposed rats at various ages. We found that while diminished splenic T cell proliferative responses could not be detected at 2 weeks. they were present at 6 weeks after birth and suppression was maximal at 6 weeks and 3 months. Thereafter. at 5 and 7 months. the altered immune responses gradually declined and normalized at 8 months of age. Thus. both altered T cell mitogenesis and the blunted IL2-induced proliferative response of T-blast cells could serve as biomarkers of fetal exposure to ethanol.
Trauma in cirrhosis: an indicator of the pattern of alcohol abuse in different societies, While some morbidities associated with the excessive use of alcohol are related to the total amount of alcohol consumed--cirrhosis being an example--other pathologies. such as trauma and those of psycho-social origin. are mainly related to the frequency of acute alcoholic intoxication rather than to the total amount consumed. The balance between these two types of alcohol-associated morbidities can provide an indication of the relative frequency of intoxication. and thus of the pattern of alcohol abuse in a population. Since trauma is highly associated with acute alcoholic intoxication. the prevalence of bone fractures was determined in cirrhotics in nine countries. The prevalence of rib and vertebral fractures on routine chest x-rays showed a 17-fold variation in the different countries. from 2% and 6% in Spain and Italy to 30% and 34% in Canada and the USA. suggesting marked differences in the pattern of alcohol abuse to intoxication. Conversely. the prevalence of cirrhosis is twice as high in Spain and Italy than in Canada and the USA. A strong positive correlation between per capita consumption and cirrhosis mortality (r = 0.86; p less than 0.01) exists among the nine countries studied. while the correlation between per capita alcohol consumption and the prevalence of trauma is not statistically significant (r = 0.40). Supporting a strong association between trauma and alcoholic intoxication. the prevalence of trauma was found to be highly correlated: r = 0.88. p less than 0.002. with the degree of concern for the psycho-social consequences of alcohol abuse in the different countries. Data indicate that trauma can be used as an objective indicator to assess the pattern of alcohol abuse in a population.
Neuroadaptive responses to chronic ethanol, Cellular responses of neuronal tissue to chronic ethanol exposure are reviewed. Evidence for adaptive responses to the acute actions of ethanol is available for five systems: GABA-activated chloride channels. voltage-sensitive calcium channels. NMDA-activated cation channels. receptors coupled through stimulatory guanine nucleotide binding proteins. and membrane lipid order. We suggest that at least some of these adaptive responses occur because of ethanol actions at the level of gene expression.
Personality stability and adolescent substance use behaviors, Several personality needs have consistently been identified as placing adolescents at heightened risk for the relatively intensive use of alcohol and other drugs. At the same time. little is known about the natural history of personality change during adolescence as it relates to substance use behaviors. Yet. this question is of clear importance to our understanding of personality risk factors for substance use because personality needs appear less temporally stable during adolescence than later in the life span. In this study. we use prospective longitudinal data to investigate the relation of high-risk personality needs to substance use in two groups of adolescents: those who maintained a temporally stable personality need structure across 3 years and those who showed considerable changes in personality needs during the same time interval. Subjects were 12. 15. or 18 years old at the first test time and 15. 18. or 21 years old. respectively. at the second test time. For subjects of both sexes. only those who maintained a temporally stable. low-risk personality profile showed quite conservative substance use patterns across time compared with all others. Generalized personality changes were linked to more intensive substance use behaviors in males. especially among those who had high levels of risky personality needs at the first test time. In contrast. personality change. per se. did not appear as relevant to females' alcohol and other drug use behaviors until combined with information regarding their level of high-risk personality needs. The results are discussed in terms of their implications for prevention and future research.
Ethanol inhalation and dietary n-6, n-3, and n-9 fatty acids in the rat: effect on platelet and aortic fatty acid composition, The effects of 18-carbon n-6. n-3. and n-9 fatty acid diets and ethanol exposure on the fatty acyl composition of platelets and vascular tissue were examined. An experimental design was devised to control the dietary content of 18-carbon fatty acids. The levels of 18:3n6. 18:3n3 and 18:1n9 were varied by a formulation of dietary oils which contained similar proportions of 18:2n6. Male Sprague-Dawley rats were fed a purified diet containing 11% by weight of either borage oil (BOR) rich in 18:3n6. linseed/safflower oil (LSO) rich in 18:3n3. or sesame oil (SES) rich in 18:1n9 for 7 weeks and exposed to ethanol vapors by means of inhalation for the final 6 days of the dietary regimen. Moderate blood ethanol levels of 118 +/- 6.6 mg/dl were obtained. Total lipids were extracted from platelets and aortae. and the fatty acid distributions were analyzed by gas chromatography. BOR feeding resulted in increases in the proportion of n-6 fatty acids (18:3n6. 20:3n6. 20:4n6) in platelets and aorta. Animals fed the LSO diet had increased levels of n-3 fatty acids (18:3n3. 20:5n3. 22:6n3). The SES-based diet resulted in an increase in 18:1n9 in both aorta and platelets. Following ethanol exposure alone. the most marked change in the fatty acid profile was a decrease in 20:4n6 in the platelet. This effect was not observed in rats supplemented with BOR. No significant changes were observed in the aortic fatty acid content at this level of ethanol exposure. The results suggested that. in the rat. a diet enriched with BOR effectively prevented ethanol-induced alterations in platelet fatty acid composition.
Estimation of blood alcohol concentrations in young male drinkers, This research examined individual differences in the ability to self-monitor the effects of alcohol. Thirty-nine male subjects consumed 0.75 ml/kg alcohol and estimated their blood alcohol concentrations (BACs) at peak BAC and on the ascending and descending limbs of the blood alcohol curve. Family history of alcohol dependence did not affect the accuracy of estimation of BACs. Subjects who reported lower levels of subjective intoxication underestimated their BACs more than did subjects who reported higher levels of subjective intoxication. Subjects with less behavioral impairment underestimated their BACs more than subjects with greater behavioral impairment on the ascending limb of the blood alcohol curve. Accuracy was better on the ascending limb compared with peak BAC and the descending limb. and accuracy became worse over time on the descending limb. It appears that cues to the effects of alcohol rapidly become unavailable on the descending limb. which may contribute to decisions concerning further alcohol consumption and driving after drinking.
In vivo microdialysis study of brain ethanol concentrations in rats following oral self-administration, Using intracerebral microdialysis. the time-course of ethanol absorption was determined in the striatum of rats after oral self-administration of an ethanol solution. Microdialysis samples were collected every 10 min for 1 hr before and 1 hr after consumption of ethanol over a 5-min period. Substantial levels of ethanol were detected in the brain in the first sample taken after self-administration although these levels did not correlate with the amount of ethanol consumed. Striatal ethanol levels reached maximum or near maximum by the second sample and remained constant for the time points between 20 and 60 min; at these times. brain ethanol levels correlated significantly with the amount consumed. This study demonstrates that oral consumption of ethanol leads to measurable brain levels within a relatively short time. Results suggest that experimental animals may experience the central effects of ethanol during the course of drinking and this could play a role in alcohol preference or avoidance behavior.
Individual mood profiles in alcohol withdrawal, Daily self-reports of moods. using a Swedish Mood Adjective Check List with six bipolar dimensions. were performed in patients with alcohol dependence. One group (n = 13). consisting of inpatients in late withdrawal at a home for addicts. was studied for 6 weeks; another group (n = 12). consisting of outpatients in full remission. was studied for 1 week. The results of the ratings on the check-list were used to test a statistical model for its capacity to describe the individual courses of mood states during the recovery process. Time Series Analysis revealed that the individual courses of moods fitted an autoregressive statistical model and could thereby be summarized in numerical measures for individual baselines. amplitudes. and lengths of recovery. Such individual profiles of the alcohol recovery process. may be useful for both clinical and research purposes. making it possible. for instance. to predict points in time for an individual's recovery with respect to his total well-being. as well as the various dimensions of his mood states.
A revised conservative estimate of the incidence of FAS and its economic impact, We have conducted a new analysis of the incidence of fetal alcohol syndrome (FAS) and its economic impact based on prospectively gathered data of consecutive pregnancies. This more conservative analysis reflects our concern over possible inclusion of "false positives" in our previous estimate and now puts the overall rate in the western world at 0.33 cases per 1000. The estimate among whites is 0.29 per 1000 compared with 0.48 per 1000 for blacks. We did not include estimates for native Americans owing to the absence of prospectively gathered data on FAS for this group. Retrospective studies suggest larger disparities. Both prospective and retrospective studies may be influenced by examiner bias especially for minorities since minorities are often evaluated against standards derived from whites. Based on our estimates and the number of black and white children born each year. we estimate that about 1200 children are born with FAS each year in the United States. This is a probable lower limit based on considerations of ascertainment and absence of relevant information for other minorities such as native Americans. In calculating economic costs. we have now adjusted our estimates to take into account costs that would be incurred whether cases were FAS or not. and also have now included estimated costs for anomalies in FAS cases not considered in previous estimates. Based on these considerations. we now estimate the incremented annual cost of treating this disorder at $74.6 million. About three-quarters of this economic burden is associated with care of FAS cases with mental retardation.
Suppression of immune responsiveness: sex differences in prenatal ethanol effects, Exposure to ethanol in utero results in changes in the offspring's developing immune system. including thymus lymphocyte subpopulation shifts and functional lymphocyte changes that persist in adult animals. The present study was designed to define further the extent of changes in the immune system that result from fetal ethanol exposure and to compare effects in male and female offspring. In adulthood. male and female offspring from Sprague-Dawley dams fed an ethanol-containing liquid diet (alcohol. A). an isocaloric liquid control diet (pair-fed. PF). or laboratory chow and water (control. C) during pregnancy were tested for several measures of immune competency. Prenatal ethanol exposure differentially affected male and female offspring. Fetal ethanol-exposed males exhibited a decrease in thymocyte number as well as a decreased splenic lymphocyte proliferative response to the T-cell mitogen. concanavalin A (Con A). with a concomitant decrease in recoverable blast cells. when compared with PF and C males. Further. the defect in T-cell proliferation of A males was not due to an inability to produce the critical growth factor. interleukin-2 (IL-2). but to an inability of lymphoblasts to utilize exogenous IL-2. Fetal ethanol-exposed females showed some suggestion of lower thymocyte counts and decreased splenic T-cell proliferative responses to Con A compared to PF and C females. For most of the immune measures. however. no significant differences occurred among A. PF. and C females. In utero ethanol exposure did not significantly alter spleen cell counts or IL-2 production. splenic B-cell proliferation to bacterial lipopolysaccharide (LPS). or thymocyte response to IL-2 in animals of either sex.
Response of three hormones to diazepam challenge in sons of alcoholics and controls, This study evaluates the hypothesis that the decreased reaction to ethanol reported for sons of alcoholics will also be observed following infusions of a benzodiazepine. The investigation compared 37 men who were family history positive for alcoholism with 37 family history negative controls on postinfusion levels of cortisol. prolactin. and growth hormone following 0.12 and 0.20 mg/kg of diazepam given IV over 7 minutes. The results demonstrated no evidence of a decreased response for the sons of alcoholics on the levels of these three hormones.
Vitamin B12 and folate status in rats after chronic administration of ethanol and acute exposure to nitrous oxide, The chronic administration of ethanol or brief exposure to nitrous oxide (N2O) decreases the activity of hepatic methionine synthase and disrupts normal metabolic processes that require folate and vitamin B12. This combination of drugs has clinical relevance since alcoholic patients often require surgery and receive N2O as a component of their anesthetic. To assess this clinical problem using a rodent model. rats were given a liquid ethanol diet (35% of calories as ethanol) and control rats were pair-fed a liquid diet with carbohydrate substituting for the caloric content of ethanol. After receiving liquid diets for 6 weeks. rats were exposed to 60% N2O/40% O2 for 6 hr. Urinary excretions of formic acid and formiminoglutamic acid (FIGLU) were used as indirect markers of folate status. In both the ethanol-fed and control groups. excretion of formic acid and FIGLU markedly increased the first day after N2O and returned towards background values by the second day after N2O exposure. Ethanol treatment alone decreased methionine synthase activities in liver. but not kidney or brain. Exposure to N2O further decreased methionine synthase activities. and recovery of methionine synthase activity after N2O occurred over a period of 4 days at the same rate in both the ethanol-fed and control groups. Ethanol treatment for 6 weeks combined with acute exposure to N2O did not deplete the rats of vitamin B12 in blood. liver. kidney. or brain. We conclude that in this animal model. chronic treatment with ethanol does not markedly exacerbate the disturbances in folate/vitamin B12 metabolism caused by brief exposure to N2O.
Serum beta-hexosaminidase isoenzyme: a sensitive marker for alcohol abuse, Serum beta-hexosaminidase (Hex) isoenzymes analyzed by enzyme immunoassay were investigated in a group of alcoholics (n = 38) hospitalized for detoxication. in another group of alcoholics (n = 22) abstinent between 6 days and 10 years and in a reference group (n = 20). Hex "B" isoenzyme was elevated in all 38 patients hospitalized for detoxication but only 35 of these had total Hex values above the upper limit of the reference group. The Hex A isoenzyme. gamma-glutamyltransferase. and aspartate aminotransferase showed considerable overlap between these patients and the reference group. In the group of 22 abstinent patients only one had an increased level of Hex A. Hex "B." and total Hex. whereas 10 had gamma-glutamyltransferase values above the upper limit of the reference group. It is concluded that Hex "B" is a useful marker for alcohol abuse.
Plasma norharman (beta-carboline) levels are elevated in chronic alcoholics, Based on the hypothesis that condensation products of neurotransmitters with aldehydes are involved in the pathogenesis of alcoholism. aromatic beta-carbolines (norharman and harman) were measured in the blood plasma of alcoholics and nonalcoholics. The identity of the extracted compounds was confirmed by various elution conditions of the high performance liquid chromatography (HPLC). newly developed radioreceptor assays. and the mass spectrum of norharman. The levels of norharman and harman in nonalcoholics were unchanged after a load with ethanol (1 g/kg body weight). The norharman levels of the alcoholics were significantly higher than that of the nonalcoholic controls (99.5 +/- 26.6 pg/ml vs. 26.9 +/- 10.7 pg/ml; p less than 0.001) and did not change significantly during a 3-week detoxication period. In the subgroup of alcoholics with delirium or hallucinosis. a slight increase of norharman during detoxication could be detected while in alcoholics with vegetative withdrawal symptoms norharman levels dropped slightly over time (p = 0.07). No difference was found with respect to harman between nonalcoholics and alcoholics. These results suggest disturbed regulatory processes in the formation and/or metabolism of norharman in alcoholics. Further investigations are needed to reveal a possible marker function of norharman in alcoholic patients.
Hypothesis: prenatal ethanol-induced birth defects and retinoic acid, A hypothesis is presented to explain the biochemical basis of ethanol-induced birth defects. Prenatal ethanol exposure causes central nervous system and limb abnormalities in humans and in animals. Retinoic acid and didehydroretinoic acid are known to play an important role in the central nervous system and limb developments. Ethanol is known to inhibit the formation of retinoic acid from retinol and deplete hepatic retinoid levels. It is hypothesized that ethanol reduces the levels of retinoic acid in the developing embryo either by inhibiting conversion of retinol to retinoic acid and/or by depleting the level of retinol. thereby causing central nervous system and limb abnormalities.
A hypothetical mechanism for fetal alcohol syndrome involving ethanol inhibition of retinoic acid synthesis at the alcohol dehydrogenase step, Ethanol acts as a teratogen causing brain. craniofacial. and limb abnormalities in those suffering from fetal alcohol syndrome. Normal embryonic development of the vertebrate nervous system and limbs has recently been shown to be governed by retinoic acid. the active form of vitamin A. Retinol dehydrogenase is an enzyme needed to convert vitamin A (retinol) to retinoic acid. a molecule that specifies embryonic pattern formation by controlling gene expression. Ethanol acts as a competitive inhibitor of the retinol dehydrogenase activity attributed to mammalian alcohol dehydrogenase (ADH). an enzyme that uses both retinol and ethanol as substrates. An hypothesis is presented in which many of the abnormalities observed in fetal alcohol syndrome may be caused by high levels of ethanol acting as a competitive inhibitor of ADH-catalyzed retinol oxidation in the embryo or fetus. This would presumably result in a reduction of retinoic acid synthesis in embryonic tissues such as the nervous system and limbs that require critical levels of this molecule to specify spatial patterns.
Diazepam and intubation in emergency treatment of seizures in children, STUDY OBJECTIVES: This study was undertaken to determine the incidence of endotracheal intubation after the use of diazepam compared with phenobarbital or phenytoin in emergency treatment of seizures in children. DESIGN: The records of all children (98) were reviewed in a case-control fashion. A logistic regression model was used to determine whether there was an association between diazepam administration and intubation. adjusting for all other covariates (age. weight. convulsion time before first anticonvulsant was given. response latency. diagnosis. and therapy). SETTING: All children were treated in an emergency department and then transported to a tertiary pediatric center by a pediatric transport team. TYPE OF PARTICIPANTS: All patients were children. with a median age of 2.7 years (range 0.17 to 15.3 years). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Only the use of diazepam was found to be significantly associated with intubation after adjusting for all other covariates (adjusted odds ratio. 49.4; P less than .001). In the comparison of diazepam versus phenobarbital or phenytoin used as the first anticonvulsant. median response latency did not differ (27.0 vs 32.5 minutes. P greater than .83). CONCLUSION: A significant association was found between diazepam use and intubation. Response latency was not shorter when diazepam was used as the initial anticonvulsant compared with phenobarbital or phenytoin.
Respiratory effects of spinal immobilization in children, STUDY OBJECTIVE: To assess the restrictive effects of two spinal immobilization strapping techniques on the respiratory capacity of normal. healthy children. DESIGN: Prospective study with each subject serving as his own control. PARTICIPANTS: Fifty-one healthy children 6 to 15 years old. INTERVENTIONS: Participants' forced vital capacity (FVC) measurements were first obtained with children standing and lying supine and then in full spinal immobilization using two different strapping configurations. cross straps and lateral straps. Straps were tightened to allow one hand to fit snugly between the strap and child. MEASUREMENTS AND MAIN RESULTS: Supine FVC was less than upright FVC (P less than .001). FVC in spinal immobilization ranged from 41% to 96% of supine FVC (80 +/- 9%). There was no difference in FVCs between strapping techniques (P = .83). CONCLUSION: Spinal immobilization significantly reduced respiratory capacity as measured by FVC in healthy patients 6 to 15 years old. There is no significant benefit of one strapping technique over the other.
Permanently imbedded subcutaneous acupuncture needles: radiographic appearance, During the evaluation of a victim of a motor vehicle accident. routine radiographs of the patient's cervical spine. chest. and pelvis revealed multiple radiopaque foreign bodies along his posterior neck. chest. abdomen. and pelvis. Repeat examination of the patient disclosed no evidence of foreign bodies. Further questioning revealed that the patient had received acupuncture therapy five years earlier in Korea. We discuss the radiographic findings of permanently imbedded subcutaneous acupuncture needles and their differential diagnosis. The medical complications of acupuncture are reviewed.
Dissections of the cervicocerebral arteries, We present four cases of cerebral ischemia secondary to dissections of cervicocerebal arteries. The majority of patients presented with transient ischemic attacks and strokes. although one patient presented with headache and focal seizure. In addition to history and physical examination. the diagnostic evaluation of these patients included computed tomography scan. carotid duplex studies. angiogram. and. in some cases. magnetic resonance imaging studies. Initially. the patients were anticoagulated with heparin and then with warfarin for a period of six to eight weeks. The emergency physician must consider such dissections in younger patients with sudden neurologic deficits and no or few risk factors for cerebrovascular disease. In our experience. these are not rare syndromes; with proper workup. prompt diagnosis. and therapy. the prognosis is usually excellent.
The potential utility of a rapid CK-MB assay in evaluating emergency department patients with possible myocardial infarction, STUDY OBJECTIVES: To determine the sensitivity. specificity. and predictive values of a new rapid creatine kinase-MB (R-CK-MB) assay compared with a standard CK-MB (S-CK-MB) assay and to determine its potential use in the evaluation of emergency department patients with possible myocardial infarction. DESIGN: Retrospective patient identification with subsequent testing of excess sera for CK-MB and total CK using an identity-unlinked procedure. SETTING: Large. urban. teaching hospital ED. PARTICIPANTS: All adult patients with excess sera and one of several defined presentations chosen to identify those with possible myocardial ischemia or infarction. Patients with clearly documented noncardiac etiologies of their symptoms or signs were excluded. MAIN RESULTS: The sensitivity. specificity. and positive and negative predictive values of 271 patient specimens for the R-CK-MB assay compared with the S-CK-MB assay were 100%. 96.8%. 75.0%. and 100%. respectively. The R-CK-MB assay was positive for 32 patients (11.8%). Of these. eight (25.0%) were admitted to unmonitored beds. and five (15.6%) were discharged home. All of these 13 patients had initial ECGs without evidence of ischemia or infarction. On follow-up. at least eight of the 13 had evidence of infarction. CONCLUSION: The R-CK-MB assay demonstrated high sensitivity and specificity compared with the S-CK-MB assay. When used for patients in whom a cardiac care unit admission is not considered. the rapid assay may identify some patients with unsuspected myocardial infarction and prevent inadvertent discharge or admission to unmonitored beds.
Transesophageal electrocardiography using a temporary pacing balloon-tipped electrode in acute cardiac care, STUDY OBJECTIVE: The study was undertaken to determine the feasibility of obtaining esophageal ECGs using resterilized 3F temporary pacing balloon-inflated electrodes in place of the more expensive pill-electrode and its associated expensive preamplifier. SETTING: Tests were conducted in the emergency department and ICU. TYPE OF PARTICIPANTS: Subjects were 12 acutely ill patients for whom standard 12-lead surface ECGs were insufficient to afford accurate. immediate arrhythmia diagnosis. INTERVENTIONS: Reasonable quality esophageal ECGs were obtained by use of the electrodes. generally with minimal patient discomfort. The test never required more than ten minutes. Of the 12 patients who participated in this preliminary study. esophageal ECGs enabled definitive diagnoses to be made in ten cases. CONCLUSION: The use of resterilized temporary pacing balloon-inflated electrodes enables esophageal ECGs to be obtained in an acute care setting.
Prediction of electrolyte abnormalities in elderly emergency patients, STUDY OBJECTIVES: To evaluate the operating characteristics of a previously published decision rule (Lowe's criteria) for the ordering of the stat serum electrolyte panel (SEP) and to identify features from the history and physical examination that are predictive for clinically significant electrolyte abnormalities (CSEA) in older emergency patients. DESIGN: A cross-sectional study using a physician questionnaire. record review. and telephone follow-up. SETTING: An urban. university hospital emergency department with approximately 70.000 patient visits a year. TYPE OF PARTICIPANTS: A convenience sample of patients 55 years of age or older who presented for care for any reason were identified by a research associate stationed in the ED. INTERVENTIONS: Physicians managing 1.766 patients were interviewed to determine the presence or absence of 20 dichotomous clinical variables. ten of which constitute Lowe's criteria set. All patients were followed by chart review and/or telephone interview. MEASUREMENTS AND MAIN RESULTS: The determination of clinical significance was made on record review using pre-established guidelines. The SEP was ordered on 800 of the patients on the index visit. The yield of CSEA in this group was 16%. Lowe's criteria operated with a sensitivity of 0.95 (95% confidence intervals. 0.89-0.98) and a specificity of 0.10 (95% confidence intervals. 0.07-0.12) for predicting CSEAs in this population. Logistic regression analysis showed that impaired ability to communicate. acute seizures. vomiting. and prior abnormal electrolytes were independent predictors for CSEA. CONCLUSION: Lowe's criteria showed useful sensitivity but poor specificity in this population. The criteria may be used to encourage selective test ordering by physicians when a low pretest probability for CSEA exists and as part of an algorithm for emergency nurses who order tests to expedite patient care.
A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies, Mitochondrial encephalomyopathies are usually divided into three distinct clinical subgroups: (1) mitochondrial myopathy. encephalopathy. lactic acidosis and stroke-like episodes (MELAS); (2) myoclonus epilepsy associated with ragged-red fibres (MERRF); and (3) chronic progressive external ophthalmoplegia (CPEO) including Kearns-Sayre syndrome. Large deletions of human mitochondrial DNA and a transition mutation at the mitochondrial transfer RNALys gene give rise to CPEO including Kearns-Sayre syndrome and MERRF. respectively. Here we report an A-to-G transition mutation at nucleotide pair 3.243 in the dihydrouridine loop of mitochondrial tRNA(Leu)(UUR) that is specific to patients with MELAS. Because this mutation creates an ApaI restriction site. we could perform a simple molecular diagnostic test for the disease. The mutation was present in 26 out of 31 independent MELAS patients and 1 out of 29 CPEO patients. but absent in the 5 MERRF and 50 controls tested. Southern blot analysis confirmed that the mutant DNA always coexists with the wild-type DNA (heteroplasmy).
Radionuclide esophageal transit study in detection of esophageal motor dysfunction: comparison with motility studies (manometry), Radionuclide esophageal transit study (RETS) has been developed to assess motor function of the esophagus. The purpose of this study was to compare RETS to esophageal motility studies (EMS) in detection of motility disorders. A total of 109 consecutive patients without previous history of surgery on the esophagus underwent both RETS and EMS within one month of each other. Final diagnosis was divided into three categories: I--primary esophageal motor disorders (n = 39); II--reflux disease (n = 48); and III--non-cardiac chest pain and/or dysphagia (n = 22). Using EMS as the standard. the results of RETS were as follows: sensitivity for detection of motor dysfunction was 97%. 92%. and 77% for Groups I. II. and III. respectively. while specificity was 91% for Group II and 100% for Group III. Global sensitivity was 92% and specificity was 88%. No clinically significant motor disorders were missed by RETS. In conclusion. RETS is a useful noninvasive test for the screening of patients with symptoms thought to be of esophageal origin.
Regional anaesthesia and cough effectiveness. A study in patients undergoing caesarean section, We report the results of a study of the effects of spinal and epidural anaesthesia for Caesarean section on commonly used indicators of a patient's ability to cough effectively. Both spinal and epidural anaesthesia. after the achievement of a block adequate for surgery. were associated with statistically significant decreases (p less than 0.05) in all the respiratory variables recorded: forced vital capacity. forced expiratory volume in one second. peak expiratory flow rate and maximum expiratory pressure. We conclude that although the observed changes are unlikely to impair the normal patient's ability to cough effectively in these circumstances. there may be clinically significant impairment in the presence of an inadvertently high block or in a patient with pre-existing pulmonary disease.
Community obstetric care in West Berkshire, OBJECTIVE--To assess the effects of a revised obstetric booking policy whereby all low risk pregnant women received their antenatal care entirely in the community. DESIGN--Comparison of the distribution of antenatal clinic attendances. transfers. and perinatal mortality rates for 1987 and 1989. before and after introduction of the revised policy. SETTING--West Berkshire Health District. SUBJECTS--All women who delivered with a registrable birth in the district in 1987 (5817 women) and 1989 (5372). MAIN OUTCOME MEASURES--Attendances at community and consultant antenatal clinics; bookings transferred from community care to consultant care; perinatal mortality rates. RESULTS--Of 5372 women delivering in West Berkshire in 1989. 3185 (58.3%) were originally booked for general practitioner-midwife care. of whom 1567 (49.2% of general practitioner-midwife bookings) were transferred to consultant care. 1618 women (30.1% of all women delivered) received their entire obstetric care from general practitioners and midwives. Attendance at hospital antenatal clinics was reduced by 16%. In 1989 the perinatal mortality rates (1987 values) for the district were 6.3 (7.6) per 1000 births overall; 8.2 (8.3) per 1000 consultant bookings; 5.0 (4.7) per 1000 for community bookings; and 10.2 (14.4) per 1000 for women transferred to consultant care. CONCLUSION--Antenatal care of low risk pregnant women may safely be provided by their general practitioner and midwife.
The value of brainstem auditory evoked potentials in early diagnosis of Wernicke's encephalopathy, Statistical analysis of the interpeak latencies of brainstem auditory evoked potentials (BAEP) shows that a delayed IPL I-V is a very sensitive indicator for an early diagnosis of Wernicke's encephalopathy. In cases of uncomplicated delirium tremens no significant deviations of BAEP were found.
Hepatic transmethylation and blood alcohol levels, Golden Syrian hamsters that have elevated hepatic alcohol dehydrogenase activity were divided into four groups and group-fed on four different liquid diets for five weeks. Group I was fed a control diet formulated for hamsters. Group II was fed the control diet containing 20 micrograms of 4 methylpyrazole per litre. Group III was fed the hamster ethanol liquid diet (ethanol amounting to 36% of total calories). Group IV was fed the ethanol diet to which 4-methylpyrazole (20 micrograms/litre) was added. Groups I. II and III were group-fed the amount consumed by Group IV on a daily basis. Upon killing the animals. blood alcohol levels were found to be elevated in Group IV but not in Group III. Hepatic methionine synthetase (MS) was inhibited in Group IV. Betaine-homocysteine methyltransferase was induced in this group to compensate for the MS inhibition and liver betaine was lowered reflecting this induction. None of these changes were seen in Group III. Since none of the animals showed an aversion to their respective diets and gained weight normally. these data indicate that it was the elevated blood levels of ethanol rather than nutritional factors that were related to the changes in methionine metabolism.
Acamprosate and diazepam differentially modulate alcohol-induced behavioural and cortical alterations in rats following chronic inhalation of ethanol vapour, The effects of Acamprosate (the calcium salt of an acetylated form of homotaurine) and the benzodiazepine-receptor agonist Diazepam. were investigated on the alcohol-induced behavioural preference towards alcohol following chronic alcoholization by inhalation. We also examined the effects of Acamprosate and Diazepam on the blood alcohol level (BAL) and on the cortical microvascular network. Acamprosate (50. 100. 200 and 400 mg/kg daily per os during the alcoholization period) did not significantly reduce either BAL or alcohol-induced cortical hypervascularization. Increasing dosages of Acamprosate (i.e. 50. 100. and 200 mg/kg/day). however. progressively reduced preference for alcohol as expressed in a free choice beverage procedure. whereas 400 mg/kg/day of Acamprosate immediately stopped this behaviour. Acamprosate (50 mg/kg/day) also reduced the spontaneous activity of rats during the withdrawal syndrome. By contrast. Diazepam (5 mg/kg) induced inversion in the animals' choice (i.e. increased water consumption versus decreased alcohol intake) during the same experimental procedure. and potentiated the alcohol-induced hypermotility of the animals during the withdrawal syndrome without altering cortical hypervascularization. Taken together. our data provide evidence that both substances exert dose-dependent effects on preference towards alcohol. but display opposite profiles on spontaneous motor activity during the withdrawal phase without any modification of brain microvascularization or blood alcohol levels.
Comparison of the generation of albumin-associated cytotoxic activity in supernatants from ethanol-containing cultures of human blood monocyte-derived macrophages and of two human hepatoma cell lines, The rates of oxidation of ethanol to acetate by human blood monocyte-derived macrophages and the two human hepatoma cell lines PLC/PRF/5 and Hep G2 were studied. The average rates obtained were. respectively. 621. 447 and 596 nmol/h/mg cellular protein. Cultures of these three cell types. containing known quantities of cellular protein per flask. were incubated with 0 or 2 mg ethanol/ml for 72 h and the culture supernatants subjected to affinity chromatography on blue sepharose CL-6B. Pure albumin fractions obtained in this way were adjusted to the same optical density and tested for cytotoxicity against A9 cells. The data showed that the albumin fractions obtained from ethanol-containing macrophage cultures were considerably more cytotoxic than those obtained from ethanol-containing cultures of PLC/PRF/5 and Hep G2 cells. It appeared that. for a given quantity of ethanol metabolised. considerably more acetaldehyde was released extracellularly by macrophages than by the two hepatoma cell lines and that this acetaldehyde bound to albumin to form cytotoxic acetaldehyde-albumin complexes. The data raise the possibility that macrophages are an important source of extracellular acetaldehyde and circulating acetaldehyde-albumin complexes in vivo.
Effect of calcium-channel blockers on alcohol consumption in alcohol-drinking monkeys, Experiments were performed to determine the effect of the calcium-channel blockers verapamil and diltiazem on ethanol preference in monkeys. Two days of administration of 10 mg/kg verapamil but not diltiazem or saline significantly decreased ethanol intake in all monkeys tested. Chronic treatment with verapamil. but not saline. dose-dependently attenuated alcohol intake. without significantly influencing water intake. These findings suggest that verapamil exerts an inhibitory action on ethanol preference in chronically alcohol-drinking monkeys. possibly by interfering with Ca(2+)-channels and/or by interacting with the activity of certain central neurotransmitters.
Maternal alcohol exposure before and during pregnancy: effect on development of neurons and glial cells in culture, The effect of maternal alcohol exposure on nerve cell development was investigated in neurons and glial cells cultured from foetal rat brain. Neurons were grown for one week from two-week-old cortical brain cells and glial cells were cultured for four weeks from newborn cortical brain cells. Two types of maternal alcohol treatment were performed; either before and during pregnancy or only until the beginning of pregnancy. In both situations. we found a delayed nerve cell maturation assessed by microscopic observations and determination of enzymatic markers of nerve cell development (non-neuronal and neuron-specific enolase for the neuronal cells. non-neuronal enolase and glutamine synthetase for the glial cells). The results confirmed our previous in vivo experiments pointing out long-lasting effects of maternal alcohol exposure in the offspring.
The relationship between social skills and adolescent drinking, Studies of the drinking patterns of Australian youth have revealed the widespread use of alcohol. with substantial numbers of high school students drinking on a daily basis and regularly becoming intoxicated. The present research investigated the relationship between social skills and drinking behaviour in teenagers. The Adolescent Alcohol Involvement Scale was administered to 82 males and females aged between 13 and 16 to distinguish among drinkers. problem drinkers and non-drinkers. To measure social skills. the Adolescent Problem Inventory was administered to boys and the Problem Inventory for Adolescent Girls to girls. There were significant group differences on the social skills measures with non-drinkers receiving the highest scores. indicating the most social skills. followed by drinkers and problem drinkers. An analysis of results showed that 11% of drinkers and 50% of problem drinkers were in the incompetent range of social skills performance while no non-drinkers scored in this range. None of the problem drinkers scored in the highly competent range of performance whereas 22% of drinkers and 40% of non-drinkers did. Results are discussed in terms of linking a number of problem behaviours in adolescence. such as drinking. smoking and delinquent behaviour. to deficits in social skills.
Alcohol consumption patterns in a primary care population, Over a one-year period the authors administered the Diagnostic Interview Schedule to 459 randomly selected patients attending an urban general medicine practice. Alcohol abuse and alcohol dependence disorders were diagnosed as current in 12% of the patients. while 19% of the patients met criteria for a past disorder. In addition. 11% and 3%. respectively. reported a history of previous or current heavy consumption. The lifetime prevalence of alcohol consumption disorders is significantly higher in males than females. while current disorders are significantly more common in younger than older individuals. Based upon the number of reported symptoms. patients reporting current disorders appear to have a more serious form of disease than patients reporting a past disorder. We conclude that disorders of alcohol consumption are common in our medical practice. Moreover. our findings suggest that many patients do recover from alcohol consumption disorders (i.e. are currently symptom-free by self-report) and disease severity may be an important factor in this process.
Long-term consequences of CNS treatment for childhood cancer, Part I: Pathologic consequences and potential for oncogenesis, The pathologic changes associated with the treatment of cancer of the nervous system are reviewed. Computed tomographic. magnetic resonance imaging. and positron emission tomographic findings of these abnormalities are described. followed by discussion of the known histopathologic features. For the most part. pathologic effects are primary vascular and/or demyelinating. We review each of these effects at all levels of the neural axis. This review concludes with a discussion of the risk of developing second malignancies. Although this complication is infrequent. the likelihood that survivors of childhood cancer will develop a second malignancy is 10 times that of age-matched controls. This phenomenon in part relates to genetic predisposition. environmental factors. and host susceptibility. These qualifications not withstanding. most studies implicate central nervous system radiation with and without chemotherapy as the primary etiology for second malignancies.
Phasic sleep components in infants with cyanosis during feeding, Although brainstem immaturity has been postulated as one of the pathogenesis underlying cyanosis during feeding (CDF). there has been no widely accepted physiologic parameter that reflects brainstem function. We recently proposed that the dissociation index (DI). one of the phasic sleep parameters. is a reliable and quantitative sleep parameter for assessing brainstem maturation during early infancy. In the present study. we evaluated brainstem impairment in infants with CDF using phasic sleep components. Polysomnographies were obtained for 12 infants with CDF who were equally divided into 2 groups: one had or subsequently experienced apparent life-threatening events or sudden infant death syndrome (ALTE-SIDS group) and the other did not (CDF group). Rapid eye movement density and the number of gross movements (body movements. including the trunk. lasting greater than or equal to 2 sec) in the patients were identical to those in the controls. In the CDF group. the decrease of the average DI value from the controls was significantly less than the decrease in the ALTE-SIDS group. CDF may be a mild expression of brainstem immaturity. DI appears to be useful when evaluating infants with cyanosis during feeding.
Monomelic amyotrophy in siblings, Monomelic amyotrophy is a rare. benign motor neuron disorder. Electrophysiologic studies are suggestive of localized chronic anterior horn cell disease. Two young siblings are reported with monomelic amyotrophy who had proximal muscle weakness confined to one arm. We propose that monomelic amyotrophy. at least in this family. is inherited as an autosomal recessive trait.
A comparison of changes in the transcutaneous oxygen tension and capillary blood flow in the skin with increasing compressive weights, Two measures are being advocated to evaluate physiologic changes associated with compression of skin: transcutaneous oxygen tension (tcO2) and laser-Doppler blood flow. This study asked: 1) What changes occur in tcO2 and laser-Doppler blood flow with increasing compressive weight; and 2) do these measures respond differently to increasing weight? An indenter was used to apply incremental weight to the trochanter of healthy volunteers. During the first session. tcO2 was measured. and laser-Doppler blood flow was measured during the second session. The mean values of tcO2 and laser-Doppler blood flow were analyzed for significant changes over the range of applied weight. If significant change occurred. the polynomial that best described the data was determined. Mean values for tcO2 showed a significant decrease with increasing compressive weight. Its decrease was described by a second degree polynomial (quadratic). The weight that resulted in the tcO2 reaching zero for individual subjects ranged from 400-1000. Mean values for laser-Doppler blood flow showed a significant decrease with increased weight. The decrease was best described by a first degree polynomial (line). which is a different pattern from the tcO2. Laser-Doppler blood flow continued to decline with increasing weight beyond the point where tcO2 reached zero. During low-flow states. tissue oxygen utilization may exceed oxygen delivery and lead to ischemia even though capillary closure has not occurred.
Tethered cord syndrome complicating spina bifida occulta. A case report, The insidious onset of back and/or leg pain. weakness and spasticity of the lower limb. sensory deficits and neurogenic bladder and bowel in a child with spina bifida might represent a tethered cord syndrome. A case report of a child with sudden neurologic deterioration describes this condition. The successful management in children and adults with tethered cord syndrome is improved with early recognition and careful monitoring.
Phase I trial of H65-RTA immunoconjugate in patients with cutaneous T-cell lymphoma, H65-RTA is an immunoconjugate that consists of the A chain of ricin (RTA). a ribosomal-inhibiting protein. coupled to a murine monoclonal antibody (H65) directed against the pan-T-cell antigen CD5. The CD5 antigen is heterogeneously expressed on cutaneous T-cell lymphoma tumor cells. but is not expressed on normal cells except lymphocytes. A phase I trial was therefore conducted in which 14 patients with cutaneous T-cell lymphoma progressive on other therapies were treated with up to three cycles of H65-RTA. The maximal tolerated dose (MTD) of H65-RTA was 0.33 mg/kg/d administered intravenously for 10 days as defined by dyspnea at rest at higher doses. Other reversible side effects included myalgia. mild hypoalbuminemia with weight gain. pedal edema. fatigue. fevers. and chills. Six patients received more than one cycle of H65-RTA without increased side effects compared with the first cycle. Pharmacokinetic analysis showed that peak serum drug levels were dose-dependent. and ranged from 1.13 to 5.56 micrograms/mL. with a terminal half-life ranging from 1.0 to 2.9 hours. The development of antibodies against the immunoconjugate was associated with a lower peak drug level. but not with enhanced side effects. Partial responses lasting from 3 to 8 months were documented in four patients. Three of the responding patients received more than one cycle of H65-RTA in the presence of anti-immunoconjugate antibodies. The results from this phase I trial suggest that H65-RTA is an active drug in the treatment of cutaneous T-cell lymphoma. The immunoconjugate may be safely administered repeatedly. even in the presence of anti-immunoconjugate antibodies. with responses noted. Additional studies at the MTD are needed to define the response rate in this disease.
Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia, A patient with primary plasma cell leukemia resistant to chemotherapy was treated for 2 months with daily intravenous injections of anti-interleukin-6 (IL-6) monoclonal antibodies (MoAbs). The patient's clinical status improved throughout the treatment and no major side effects were observed. Serial monitoring showed blockage of the myeloma cell proliferation in the bone marrow (from 4.5% to 0% myeloma cells in the S-phase in vivo) as well as reduction in the serum calcium. serum monoclonal IgG. and the serum C-reactive protein levels. The serum calcium and serum monoclonal IgG corrected by approximately 30%. whereas the C-reactive protein corrected to undetectable levels during treatment. No major side effects developed. although both platelet and circulating neutrophil counts decreased during anti-IL-6 therapy. A transient immunization was detected 15 days after the initiation of the treatment. which could explain the recovery of myeloma cell proliferation after 2 months of treatment (2% myeloma cells in the S phase). In conclusion. this first anti-IL-6 clinical trial demonstrated the feasibility of injecting anti-IL-6 MoAbs. and also a transient tumor cytostasis and a reduction in IL-6-related toxicities. It gave insight into the major biologic activities of IL-6 in vivo and may serve as a basis for further development of anti-IL-6 therapy in myeloma and other IL-6-related diseases.
Demonstration of osteonectin mRNA in megakaryocytes: the use of the polymerase chain reaction, Platelets have been shown to release osteonectin on thrombin stimulation. The origin of platelet osteonectin was unclear as it may have been synthesized by megakaryocytes or it may have been endocytosed from plasma as other platelet alpha-granule constituents are. Platelet osteonectin has a larger apparent molecular size than the bone species. although the molecular basis for this difference has not been elucidated. These two issues have been addressed here by (1) examining the potential for osteonectin biosynthesis in human megakaryocytes by demonstrating the presence of osteonectin mRNA in purified megakaryocytes. and (2) comparing the coding portion of osteonectin transcript in megakaryocytes to the size of its bone counterpart. Because of the limitations of cell population purity and in obtaining sufficient numbers of megakaryocyte cells for Northern analysis. we have used the polymerase chain reaction (PCR) to detect the presence of human osteonectin mRNA in megakaryocyte and megakaryocyte-depleted bone marrow cells. Isolation of RNA. cDNA synthesis. and PCR were performed on human osteosarcoma SaOS-2 cells. enriched megakaryocytes. and megakaryocyte-depleted cells. Restriction enzyme analysis of PCR DNA products confirmed the identity of the products as those encoding osteonectin for all three cell populations studied. In addition. the sizes of DNA indicate that osteonectin genomic DNA. nuclear RNA. or altered transcript were not amplified. and that the transcript from megakaryocytes is the same size as that from bone cells. These data suggest that the difference in protein size between platelet and bone osteonectin is due to posttranslational modification. To overcome the possibility that megakaryocyte signal originated from contaminating cells (less than 5% by cell count). all three cell populations were diluted to less than one cell per tube and PCR amplification was performed. Limiting dilution analyses demonstrated the presence of osteonectin mRNA in single megakaryocytes as well as in single cells from the cell population depleted of megakaryocytes. suggesting the capacity for osteonectin biosynthesis in all cells studied. The procedure we describe in this report can be used to examine specific characteristics of mRNA molecules in heterogeneous cell populations and in situations where only small quantities of cells can be obtained.
Endothelial cells express the interleukin-1 receptor type I, Interleukin-1 (IL-1) profoundly affects a number of functions of vascular cells. Two distinct IL-1 receptors (IL-1R) are expressed on different cell types: the 80 Kd IL-1RI on T cells and fibroblasts. and the 68 Kd IL-1RII on B cells and myelomonocytic cells. The presence and functionality of IL-1R on vascular cells has been investigated by using polyomatransformed mouse endothelial cell (EC) lines (sEnd.1 and tEnd.1). These cells expressed specific and saturable binding sites for IL-1 (1.273 sites per cell with kd 9.5 x 10(-11) mol/L for sEnd.1. and 771 sites per cell with kd 8.5 x 10(-11) mol/L for tEnd.1. with radioiodinated IL-1 alpha as ligand). Binding of IL-1 was also evident at single cell level by autoradiography. By cross-linking studies. the molecular weight of the IL-1 binding protein on EC was approximately 80 Kd. This was confirmed by the presence in EC of mRNA for the 80 Kd IL-1RI. The IL-1RI on EC was apparently functional. since EC responded to IL-1 with IL-6 mRNA expression and IL-6 bioactivity production. These results were extended to human EC and vascular smooth muscle cells. which were also found to express mRNA for IL-1RI.
Activation signals leading to proliferation of normal and leukemic CD3+ large granular lymphocytes, The activation signals leading to proliferation of normal and leukemic CD3+ large granular lymphocytes (LGL) were studied in vitro. Anti-CD3 monoclonal antibody (MoAb) alone (P less than .01) and recombinant interleukin-2 (IL-2) alone (P less than .01) caused significant stimulation of peripheral blood mononuclear cells (PBMC) from four CD3+ LGL leukemia patients. as measured in a 3H-thymidine incorporation assay. Recombinant interleukin-4 (IL-4) alone had no effect (P = .11). The combination signals of anti-CD3 MoAb and either IL-2 or IL-4 produced a proliferative response greater than anti-CD3 MoAb alone (P less than .01) or lymphokine alone (P less than .01). Leukemic LGL. purified by two-color sorting. were subsequently activated by anti-CD3 MoAb and IL-2 and assessed for DNA content by viable Hoechst No. 33342 (HO) staining. Results of these studies demonstrated that leukemic LGL were stimulated directly by anti-CD3 MoAb and IL-2. with the percentage of cells in cell cycle (S + G2/M) ranging from 16% to 72%. Normal CD3+ LGL were also stimulated to enter the cell cycle by anti-CD3 and IL-2. These results show that leukemic LGL proliferate in vitro after activation through the T-cell receptor and/or lymphokine.
The role of interleukin-1 and granulocyte-macrophage colony-stimulating factor in the paracrine stimulation of an in vivo-derived murine myeloid leukemia, WEHI-274.3 is a cell line isolated from an in vivo-derived. murine myelomonocytic leukemia. Although the survival and growth of WEHI-274.3 cells in vitro is absolutely dependent on the addition of exogenous growth factors such as interleukin-3 (IL-3). granulocyte-macrophage colony-stimulating factor (GM-CSF). or colony-stimulating factor-1. when injected into syngeneic mice the cell line is tumorigenic. Sera from normal mice contain low levels of an activity that sustains survival of WEHI-274.3 but does not stimulate growth. In contrast. sera from mice bearing the WEHI-274.3 leukemia contained levels of CSF-1 and GM-CSF that stimulated the growth of WEHI-274.3 cells. Supernatants of cultures of WEHI-274.3 cells contained an activity that stimulated 3T3 fibroblasts to release an activity that stimulated the growth of the WEHI-274.3 cells. The 3T3-stimulatory activity released by the WEHI-274.3 cells was neutralized completely with an antiserum specific for murine IL-1 alpha. but not with antiserum specific for IL-1 beta. Moreover. WEHI-274.3 cells both in vitro and in vivo contained high levels of IL-1 alpha and IL-1 beta mRNAs. The leukemia-stimulatory activity released by the 3T3 cells was neutralized by an antiserum specific for GM-CSF. We postulate that the IL-1 alpha constitutively released by the WEHI-274.3 cells stimulates the production of GM-CSF from host cells such as fibroblasts or endothelial cells. A similar paracrine mechanism of growth stimulation may occur in acute myeloid leukemias in humans.
Regulation of human fetal and adult globin genes in mouse erythroleukemia cells, We have examined whether transfected mouse erythroleukaemia (MEL) cells can be used to examine differential expression of human gamma- and beta-globin genes. These cells. which express only their adult globin genes. will transcribe the human adult beta gene but not the fetal gamma genes when they are introduced on an intact human chromosome 11 by cell fusion. However. MEL cells stably transfected with the human A gamma gene attached to one of the active elements (HS2) of the beta-globin locus control region (LCR) readily produce gamma-globin mRNA in amounts equivalent to those seen with a comparable beta gene insert. When both beta and gamma genes are attached to HS2. equal amounts of beta A gamma mRNAs are produced. irrespective of the gene order. Furthermore. when HS2 is inserted into the 5' end of a 40-kb cosmid containing the G gamma A gamma-117 delta beta genes in their normal chromosomal organization (but with the Greek HPFH -117 A gamma gene mutation). it directs expression of readily detectable amounts of G gamma A gamma and beta-globin mRNAs in MEL cells. Therefore. under these circumstances we have observed no competition between beta and gamma genes for expression in MEL cells. These findings suggest that MEL cells are capable of perpetuating regulatory information involved in developmental control when it is provided by an intact chromosome. but are incapable of reconstructing such information on transfected DNA.
Heterogeneity of the molecular basis of hereditary pyropoikilocytosis and hereditary elliptocytosis associated with increased levels of the spectrin alpha I/74-kilodalton tryptic peptide, Hereditary pyropoikilocytosis (HPP) and hereditary elliptocytosis are closely related. congenital disorders of the red blood cell usually associated with defective spectrin self-association and abnormal limited tryptic digestion of the N-terminal of domain of spectrin. Enhanced cleavage by trypsin of spectrin from affected individuals at arginyl residue 45* and lysyl residue 48* frequently yields increased amounts of an alpha 1/74-Kd fragment at the expense of the normal alpha 1/80-Kd parent fragment. Limited tryptic digestion of three unrelated individuals with HPP showed the alpha 1/74 defect. To ascertain the molecular defect responsible for the abnormality. the structure of exon 2 of the alpha-spectrin gene was examined. Genomic DNA from the subjects was amplified by the polymerase chain reaction using primers flanking exon 2. Restriction endonuclease digestion of amplified products showed the loss of the HindIII site at codons 47 and 48 in one allele of subject 1 and abolished the AhaII site at codons 27 and 28 in one allele of subjects 2 and 3. Nucleotide sequence analysis of subcloned amplified DNA from the HPP subjects showed three novel amino acid substitutions. In subject 1 (a black individual). a single base substitution (AAG----AGG) at codon position 48 changes amino acid residue lysine to arginine. In subject 2 (a white individual). a single base substitution (CGT----AGT) at codon 28 changes arginine to serine. In subject 3 (a black individual). a different base substitution at position 28 (CGT----CTT) changes arginine to leucine. These mutations occur at positions of the alpha l domain where other mutations have also been described. indicating that the normal residues at these positions play an important role in spectrin dimer self-association and thus. in membrane stability.
Cytotoxic T-lymphocyte response to cytomegalovirus after human allogeneic bone marrow transplantation: pattern of recovery and correlation with cytomegalovirus infection and disease, The high rate of severe cytomegalovirus (CMV) disease after bone marrow transplantation (BMT) is related to the profound immunodeficiency posttransplant. Because cytotoxic T lymphocytes (CTL) have been implicated in resistance to viral infections. we examined the restoration of the CMV-specific CTL response in 20 patients who received bone marrow from HLA-matched. CMV-seropositive donors. Blood specimens were obtained from patients at 1. 2. and 3 months after BMT and from the donors on a single occasion. Peripheral blood mononuclear cells were cocultured with CMV-infected donor-derived fibroblasts for 2 weeks and then tested for cytotoxicity against CMV-infected and uninfected autologous or HLA-mismatched fibroblasts. Cytolytic activity was detected in all 20 donors. with specificity for autologous CMV-infected targets demonstrable in 17 (median CMV-specific lysis at an effector:target ratio of 15:1 was 32%. range 18% to 83%). Specific lysis was mediated by CD8+. class I-restricted T cells. as shown by inhibition with anti-class I monoclonal antibody and by selective depletion of effector cells. By contrast. CMV-specific CTL were detected in only 10 of 20 patients after BMT (median lysis 29% at 3 months post-BMT). None of these 10 patients developed CMV pneumonia. whereas 6 of the 10 patients with an undetectable CMV-specific CTL response after BMT died with CMV pneumonia. These results demonstrate that restoration of CMV-specific CTL responses may require an extended time period after BMT in some patients. and that such patients are at increased risk of developing severe CMV disease. Approaches to reconstitute CMV immunity in BMT patients by adoptive transfer of CMV-specific CD8+ CTL clones derived from the bone marrow donor are now being pursued.
Comparison of breast carcinomas diagnosed in the 1980s with those diagnosed in the 1940s to 1960s, OBJECTIVE--To find out if breast carcinomas diagnosed in the 1980s differ from those diagnosed a few decades ago. DESIGN--Retrospective comparative cohort study. SETTING--City of Turku. south western Finland. PATIENTS--439 patients with breast carcinoma diagnosed in 1945-65 with a median follow up of 27 years (95% of all those histologically diagnosed in Turku); and 370 patients with breast carcinoma diagnosed in 1980-4 with a median follow up of 6 years (94% of all those histologically diagnosed in Turku). MAIN OUTCOME MEASURES--Breast cancer incidence. mortality from breast cancer. age at diagnosis. stage of cancer. seven histological factors. DNA ploidy. RESULTS--Age adjusted incidence of breast cancer increased from 30.8/100.000 person years in 1953-7 to 62.2/100.000 in 1983-7; mortality in breast cancer increased from 16.7 to 17.2/100.000 person years. Survival of patients with stages II to IV (but not with stage I) improved. The mean age at diagnosis increased from 55.5 years in 1945-55 to 62.5 years in 1980-4 (p less than 0.0001); the proportion of patients with T0-1 carcinomas increased from 13% to 41% (p less than 0.0001) and with pN0 carcinomas from 43% to 55% (p = 0.003) from 1945-65 to 1980-4. There was no change in histological type or DNA ploidy of breast cancer. but in the 1980-4 cohort carcinomas were more often well differentiated. had lower mitotic counts and less nuclear pleomorphism. more often had a well defined tumour margin. and had less tumour necrosis. There was. however. no difference between the two cohorts in these histological characteristics except for tumour necrosis when they were compared in a multivariate log linear model at a given size of primary tumour. CONCLUSION--Improved survival with breast cancer can at least partially be explained by detection of increased numbers of small carcinomas with favourable histological characteristics.
Insulin dependent diabetes in childhood and material deprivation in northern England, 1977-86, OBJECTIVE--To determine the incidence of insulin dependent diabetes in the Northern region of England in children less than 16 years old in the period 1977 to 1986 and to relate the incidence data to an index of deprivation. DESIGN--Retrospective analysis of hospital case records identified from the regional health authority's computer; validation of the primary source with hospital clinic registers and community paediatric registers. SETTING--Northern region. excluding South Cumbria District Health Authority (659.300 children under 16 in 1981). PATIENTS--All children diagnosed with insulin dependent diabetes before the age of 16 and resident in the region at time of diagnosis. MAIN OUTCOME MEASURES--Incidence rates for the 10 year period and analysis of incidence rates within categories of deprivation. RESULTS--919 incident cases were identified. The validation procedure covered 54% of all cases identified and gave 95% completeness of ascertainment. The average annual incidence over the 10 year period was 14.8/100.000 for girls and 13.4/100.000 for boys. The annual incidence for the most and least deprived areas of the region was 18.7/100.000 (95% confidence interval 16.2 to 21.5) for boys and 7/100.000 (5.6 to 8.8) for girls. There was a highly significant trend (p less than 0.001) of decreasing incidence with decreasing level of deprivation. CONCLUSIONS--In the north of England the incidence of childhood diabetes is related to material deprivation.
Growth of asthmatic children during treatment with budesonide: a double blind trial, OBJECTIVE--To determine whether the inhaled glucocorticosteroid budesonide has any adverse effect on short term linear growth in children with mild asthma. SETTING--Outpatient clinic in secondary referral centre. PATIENTS--15 children aged 6-13 years with normal statural growth velocity during the previous year. no signs of puberty. and no use of systemic or topical steroids in the two months before the study. DESIGN OF INTERVENTIONS--Double blind. randomised crossover trial with two active periods in which budesonide was given in divided daily doses of 200 micrograms and 800 micrograms. During run in and two washout periods placebo was given. After the second washout period the children received open treatment with 400 micrograms budesonide daily. All periods were of 18 days' duration. MAIN OUTCOME MEASURE--Growth of the lower leg as measured twice a week by knemometry. RESULTS--Mean growth velocity of the lower leg was 0.63 mm/week during run in and during washout 0.64 mm/week. Budesonide treatment was associated with a significant dose related reduction of growth velocity: the mean reduction in growth velocity during treatment was 0.11 (95% confidence interval -0.15 0.36 (0.13 to 0.59) mm/week with 800 micrograms budesonide (p less than 0.05; Page's test). During treatment with 400 micrograms budesonide a reduction of 0.17 (-0.10 to 0.45) mm/week was found. CONCLUSIONS--Treatment with inhaled budesonide is associated with a dose related suppression of short term linear growth in children with mild asthma.
Questionable cancer practices in Tijuana and other Mexican border clinics, Tijuana. Mexico. has become a refuge for cancer patients who have been convinced that they may be cured of their terminal illness by unconventional. unproved. and disproved methods offered in the border clinics. About a dozen United States promoters have joined with Mexican colleagues to offer a variety of treatments. Some patients are diagnosed using standard methods prior to arrival at the clinics. but many healthy individuals are misdiagnosed as having cancer or "precancer" and are then treated there. Others are told they have been cured or are improving even though they still have active disease. The modalities and regimens used are often referred to as "metabolic therapy" and. for the most part. are either not based on sound scientific principles or have been shown in controlled clinical trials to be useless or even dangerous. A basic metabolic regimen consists of three phases: detoxification with fasting and bowel cleansing. strengthening the immune system with numerous "supplements." and attacking cancer with "natural and non-toxic" chemicals. Popular treatments include injections of hydrogen peroxide. large quantities of pressed liver and carrot juice. coffee enemas. infusions of Laetrile mixed with massive doses of vitamins and dimethylsulfoxide (DMSO). special diets. and a host of other pseudoscientific regimens. Unfortunately. no evidence exists that any of these modalities is more effective than no treatment at all. Patients traveling to the Mexican border clinics for metabolic therapy are subjecting themselves to costly and hazardous regimens. especially if they forgo responsible medical care in the process. The American Cancer Society. therefore. strongly urges individuals with cancer not to seek treatment with metabolic therapies in the Mexican border clinics.
Mechanisms and management of stroke in the elderly, OBJECTIVE: To highlight the mechanisms. common causes and management of stroke in the elderly. DATA SOURCES: MEDLINE was searched for articles published from 1967 to 1990. The following key words were used: "stroke." "cerebrovascular disease." "elderly." "aging." "hypertension." "drug interactions." "etiology." "evaluation." "management" and "recovery of function." Original articles with large series of patients were reviewed in detail. STUDY SELECTION: Of about 750 original articles reviewed 116 were finally selected for detailed analysis. Those that dealt with cause. pathophysiologic features and management of stroke with emphasis on the elderly were chosen. DATA SYNTHESIS: With increasing age the incidence of stroke increases. cardiovascular reserve decreases. catecholamine responsiveness diminishes and cardiac arrhythmias become more common. Blood pressure. especially systolic. rises. and the benefits of its treatment become both more difficult to assess and less certain. In the elderly population embolic stroke. particularly that due to nonvalvular atrial fibrillation. is seen with increasing frequency. Because of postural hypotension. cardiac arrhythmias and overmedication. watershed infarction occurs more frequently with increasing age. Amyloid angiopathy now represents the most common cause of spontaneous intracerebral hemorrhage. CONCLUSIONS: Because of the altered drug metabolism and pharmacodynamics in the elderly the therapeutic armamentarium is growing. and so are the risks of such treatments. Stroke in the elderly poses unique problems that deserve distinctive solutions. Further research is needed to study the effect of cerebral ischemia to understand better how the older brain handles the stress of the ischemic insult.
Historic aspects of intravenous immunoglobulin therapy, The earliest preparations of immunoglobulins (Ig) decreased the susceptibility of agammaglobulinemic patients to infections caused by pneumococci. Haemophilus influenzae. meningococci. streptococci. and Pseudomonas aeruginosa. Intramuscular administration of such preparations was painful and traumatic. especially for children. Ethanol-fractionated Ig could not be administered intravenously (IV) because the IgG molecules tended to aggregate and thus were more likely to produce anaphylactoid reactions. New Ig preparations. isolated at low pH (e.g.. pH 4) in the presence of traces of pepsin to inhibit reaggregation. were well tolerated when administered IV. Thus a new era of treatment and prophylaxis of disease using IV Ig (IVIG) was launched. The IVIG preparations revolutionized the management of virtually all immunodeficiency syndromes characterized by failure of antibody responses. Amelioration of antibody deficiency secondary to certain chronic diseases or surgical trauma can be achieved with these preparations. Newer uses of IVIG include treatment of some autoimmune diseases; in some conditions. the beneficial influences may be attributable to antiidiotype antibodies present in the IVIG. Another likely explanation is that IVIG inhibits damage to cells and tissues by antibody-mediated cellular cytotoxicity or blocks phagocytosis that is facilitated by Fc receptor mechanisms. The value of IVIG in preventing infection in patients undergoing bone marrow or organ transplantation and in the treatment and prophylaxis of life-threatening infections in neonates and premature infants also is reviewed.
Use of intravenous immunoglobulin in chronic lymphocytic leukemia. A brief review, Chronic lymphocytic leukemia (CLL) is a disorder with multiple defects leading to an increased susceptibility to infection. Hypogammaglobulinemia is present in about 20% to 70% of patients with CLL. Intravenous immunoglobulin (IVIG) supplementation (400 mg/kg body weight every 3 weeks) prevented bacterial infections in these patients. An ongoing study is being conducted to compare doses of 250 mg/kg/mo with those of 500 mg/kg/mo in 36 patients included so far. As of this writing. the rate of infection in the two treatment groups was not significantly different. and no substantial loss of protection against bacterial infection was found in the lower-dose group. It seems likely that the lower dose is almost as effective as the standard therapy. If this is so. cost savings would be substantial.
The management of peritonsillar sepsis by needle aspiration, 172 consecutive patients admitted with suspected unilateral peritonsillar sepsis were studied. Needle aspiration of the peritonsillar space was performed. and they were all then treated with intravenous antibiotics (usually benzylpenicillin). Any pus obtained was cultured. The aspiration was repeated if the patient was not improving after 24 h. A quantity of pus was aspirated at the first attempt from 91 patients (53%); 82 of these required no further aspiration but 7 required a further single aspiration and 2 required a further 2 aspirations before resolution of the sepsis. 71 of the 81 patients (88%) from whom pus had not been aspirated. and who were therefore initially considered to have peritonsillar cellulitis. required no further aspirations. However. 6 subsequently drained pus spontaneously and 4 produced a positive aspirate on a second occasion. Four patients required a change in their antibiotic therapy. We have found the combination of needle aspiration and parenteral antibiotics to be an effective treatment of peritonsillar sepsis. All patients were spared the unpleasant and painful experience of an incision and drainage procedure.
Is laterality important in neck node metastases in head and neck cancer, We present a series of 2219 previously untreated squamous carcinomas of the head and neck. 141 (6.5%) of whom had bilateral nodes at presentation. Bilateral nodes became progressively less common with increasing age but were not related to other host factors. They were also strongly related to the site of the primary tumour. its T-stage and its histological grade. being more common in tumours of the oro or naso-pharynx. in poorly or moderately differentiated tumours. and in tumour stages T3 or T4 at presentation. There were also interactions between these tumour factors. and patients with all three factors had a 25% incidence of bilateral nodes. 126 of these patients could be matched for the main prognostic factors with 126 patients with unilateral neck node disease. The survival rate of the latter group was 9% better than that of the unilateral group. Further breakdown showed that the survival of patients with nodes smaller than 6 cm is not affected by laterality. whereas it is for patients with massive nodes.
Secretory otitis media: a review of management by consultant otolaryngologists, A questionnaire concerning various aspects of secretory otitis media was completed by a random sample of Consultant Otolaryngologists in the United Kingdom. The replies to questions associated with the management of this condition are presented. The results suggest only a moderate degree of agreement between Consultants in many areas of management and these findings are discussed in the light of current research.
The role of bupivacaine in post-tonsillectomy pain, The peritonsillar tissues on one side of 45 consecutive patients undergoing tonsillectomy were infiltrated with bupivacaine and adrenaline. the opposite side serving as a control. Although a significant difference was noted between the two sides this was not a substantial difference in terms of pain relief.
An analysis of the aetiology of early childhood deafness, It is generally believed that one in every thousand children is profoundly deaf. An understanding of the aetiology of early childhood deafness and timely detection is crucial in rehabilitation of these children. This study analyses the aetiology of early childhood deafness and shows that deafness is more often acquired than inherited. Non-syndromic deafness. especially occurring on its own. usually produces profoundly deaf children and thus there is the need for genetic studies--in the child. laterally. and longitudinally into generations. Meningitis appears to be the commonest cause of acquired deafness. especially if due to pneumococcus. Only 40 of the 80 cases presented before the age of 2 years. It was therefore interesting to note what factors invoked awareness of deafness to facilitate early presentation.
Ultrasonography as a method of examination of the frontal sinus, This prospective study was performed to evaluate the reliability of ultrasonography for the detection of fluid and mucosal swelling in the frontal sinus. The evaluation was based on a comparison of the preoperative ultrasonographic results with the surgical findings in 27 frontal sinuses. Ultrasonography was found to be a reliable method for the demonstration or exclusion of mucosal swelling and accumulated fluid (sensitivity 92%; specificity 93%).
Clinical investigation of hearing loss in the elderly, The prevalence of hearing loss increases with age. Epidemiological and histopathological studies relating hearing loss to age are reviewed and clinical evidence presented suggesting that hearing loss is due not only to age but also to disease processes known to be associated with hearing threshold deterioration. 80 elderly patients presenting with a hearing problem at hospital have been studied and compared with 287 'non-complainers'. 83% of the study group were found to have factors. additional to age. contributing to their hearing loss; 50% had a medical condition previously unrecognized; 30% were taking potentially ototoxic drugs. Audiometric measurements indicate that hearing thresholds of the elderly are influenced by numerous disease processes. Patients attending hospital with hearing impairment are at greater risk of having a vascular or biochemical abnormality than a group of elderly 'non-complainers'. Elderly patients presenting with hearing loss should therefore be adequately investigated before being labelled as having presbyacusis.
Sun protection in childhood, There is compelling evidence that childhood is a particularly vulnerable time for the photocarcinogenic effects of sun exposure on the skin. Studies indicate that excessive sun exposure during the first 10-20 years of life greatly increases the risk of skin cancer. Nonmelanoma skin cancer (basal cell and squamous cell carcinoma) has been associated with cumulative sun exposure. whereas melanoma has been associated with short. intense sun exposure or blistering sunburn. Under normal circumstances. children receive three times the annual sun exposure of adults; most of one's lifetime sun exposure occurs in childhood. Depletion of the earth's protective ozone layer adds to the photodamage problem. It is clear that sun protection is most vital in the early years. Those with fair skin are at highest risk. Photoprotective measures including sunscreen. clothing. and sun avoidance in childhood may significantly reduce the occurrence of melanoma and other skin cancer in later life. Regular use of sunscreen with a sun protection factor of 15 during the first 18 years of life could reduce the lifetime incidence of nonmelanoma skin cancer by 78%. Pediatricians can play a major role in educating parents and children.
Gastroesophageal reflux in the older child: presentation, response to treatment and long-term follow-up, Much attention has been focused on the natural history of gastroesophageal reflux (GER) in neurologically normal infants which generally resolves by two years of age. In contrast. little is known of the outcome of GER diagnosed in normal older children. The charts of 32 children (21 males) without neurologic or esophageal anatomic abnormalities. age 3.5 to 16 years (mean = 9.8) at the time of diagnosis. were reviewed. Diagnosis was based on suggestive presenting symptoms and evaluation of prolonged intraesophageal pH monitoring. Esophagitis was diagnosed by histologic criteria in 16 of the 32 patients. Medical treatment consisted of prokinetic agents (metoclopramide. bethanechol) and H2-receptor antagonists. After a one to eight year follow-up period (mean +/- SD - 3.4 +/- 2.1). the symptoms in 13 children had resolved or were sufficiently improved to discontinue medication. In 13 patients. symptoms were improved but medication was required for adequate control. Four children were symptomatic without improvement in spite of medical therapy and two others required fundoplication for continued severe symptoms and refractory esophagitis. In summary. less than 50% of otherwise normal older children with GER undergo spontaneous resolution of marked improvement in symptoms and the remainder require continued long-term medical and/or surgical management.
The value of the autopsy in congenital heart disease, We reviewed autopsies in 50 consecutive cases of congenital heart disease between 1980 and 1988. Autopsy results were compared to premortem clinical diagnosis. The patients ranged in age from two days to 66.5 years with a mean age of 6.42 years; 68% were less than one year of age. The most common diagnoses were hypoplastic left heart syndrome in 16 (32%) and ventricular septal defect in five (10%). Other common diagnoses included coarctation of the aorta. hypoplastic right heart syndrome. tetralogy of Fallot. transposition of the great vessels and tricuspid atresia. No patient had a missed diagnosis that would have changed survival (Class 1). Four (8%) of the patients had one missed major diagnosis that did not change their survival because they were already being symptomatically treated or because no clinical treatment was available (Class 2). The majority of autopsy derived data were missed minor diagnoses that were related [14 (28%)-Class 3] or unrelated [12 (24%) - Class 4] to the terminal disease process. However. despite the small percentage of autopsy findings that would have directly affected survival. the autopsy provided important additional clinical information in 30 (60%) patients. This information could be used to correct management errors and to develop protocols for prophylaxis against known complications. The pediatric autopsy can provide useful clinical data that may be a guide to altering clinical therapy and is essential in providing genetic counseling.
Current issues in neonatal herpes simplex virus infection, Significant progress has been made in the recognition and treatment of herpes simplex disease in the newborn. This review discusses four current issues surrounding this severe and important infection. First. the reasons underlying the failure of antenatal screening programs to identify high-risk pregnancies for herpes simplex are analyzed. Second. typical and atypical clinical manifestations of neonatal herpetic infection are reviewed. Third. determinants of disease. particularly the immune status of the mother and child. and their therapeutic implications are discussed. Finally. controversies surrounding antiviral therapy are examined.
Perinatal human immunodeficiency virus infection, Infection with HIV is rarely clinically apparent in the newborn period. At present. there is no satisfactorily sensitive and specific test to diagnose infection in the newborn nursery. Identification of women at risk for transmission of HIV to their infants and of infants at risk for vertically transmitted HIV infection. so that early diagnosis and treatment can be instituted. is the currently recommended approach.
Neonatal candidiasis: the current challenge, The current challenge of neonatal candidiasis arises from the increased survival of very low birthweight infants. It is important to understand those factors affecting normal colonization of the neonate. concomitant with those factors that predispose to fungal invasiveness. Disseminated candidiasis may present with subtle signs and symptoms. but has the potential for a wide variety of organ system involvement. Early initiation of aggressive therapy. with careful monitoring. can lead to a successful outcome.
Coagulase-negative staphylococcal infection in the neonate, During the last decade. improved neonatal care has permitted the survival of extremely low birthweight infants who are at increased risk for the development of nosocomial infection. The coagulase-negative staphylococci currently represent the most frequent nosocomial pathogen isolated from infants in the newborn intensive care unit. This article details pathogenesis. clinical manifestations. diagnosis. treatment. and prevention of neonatal infection with this organism.
Clinicopathologic approach to the diagnosis of neonatal sepsis, Perinatally acquired bacterial neonatal sepsis is a low-incidence. high-risk disease with a relatively benign treatment. Accurate diagnosis is difficult because there is no definitive diagnostic test; even blood cultures have an unacceptably low sensitivity. Therefore. the clinician must accept that a number of neonates will have treatment initiated for sepsis who do not have the disease. In order to treat rapidly all infants with sepsis and to minimize therapy for those without infection. historical. clinical. and laboratory data can be used together in a management approach to achieve optimal results.
Crohn's disease of the small bowel, Crohn's disease is a perplexing panintestinal disease whose etiology is unknown. Symptoms and complications vary greatly from patient to patient. Despite the fact that no cure exists. thoughtful. well-planned therapy and appropriate timely intervention. where needed. can result in maintenance of a high quality of life for affected patients.
Immediate and follow-up management of hepatic trauma, There has been a considerable evolution in the management of patients with hepatic injuries in the past 5-10 years. CT is now the mainstay of diagnosis for stable patients with blunt hepatic injuries. This allows for nonoperative therapy in many patients with lacerations. intrahepatic hematomas. or subcapsular hematomas. Simple operative techniques are used in 60% of patients with blunt injuries. and any deaths in this group are usually due to associated injuries. In patients requiring advanced techniques of repair. postoperative management emphasizes basic techniques including correction of hypothermia and coagulopathies and early use of enteral feeding. Postoperative complications are not rare when Class III. IV. or V hepatic injuries have been treated. but can be managed with the assistance of the interventional radiologist. blood bank. or by use of early reoperation. Mortality depends on mechanism of injury and magnitude of hepatic injury. and ranges from 14-31% for patients with blunt trauma.
Effort thrombosis of the axillosubclavian vein: a disabling vascular disorder, In the natural history of this disorder. resumption of normal activity after a period of recuperation (following an episode of thrombosis) frequently leads to symptoms of upper extremity venous hypertension exacerbated by using the arms in the overhead position. This position can be demonstrated venographically to further occlude collateral vessels in thoracic outlet. A number of patients develop more extensive symptoms of neurogenic thoracic outlet syndrome. Anticoagulation may protect the collateral vessels and interrupt the period of active clot propagation resulting in a better functional result than would be expected from the natural history of the thrombotic event. In our experience. local Urokinase was the most effective means for reestablishing venous patency. With clot dissolution the underlying compression of the vein at the thoracic outlet can be demonstrated. Balloon angioplasty should not be undertaken in the acute setting nor prior to relieving the tendinous compression. The acute phlebitic process should resolve under the protection of Coumadin for three months. At that time it can be determined more effectively which patients require additional therapy. Removal of the first rib will decompress the axillosubclavian vein and the thoracic outlet collaterals permitting the vein to regain its normal configuration particularly in younger patients with more acute onset of compression. In those patients with more chronic compression the vein becomes stenotic. Improvement of the luminal configuration has been accomplished with transvenous balloon angioplasty without the necessity for venous reconstructive procedures in this series. Patients with Paget-Schroetter syndrome have a symptom complex which often reflects more extensive neurovascular compression at the thoracic outlet than that which might result from venous hypertension alone. Although thrombolytic therapy can restore patency of the axillosubclavian vein. first rib resection is necessary to relieve the external compression. This procedure was very effective in patients who had restoration of subclavian vein patency. and to a lesser degree in those with residual occlusion.
Update: drug therapy for acute myocardial infarction, Acute myocardial infarction is potentially a highly treatable disease. Immediate interventions are directed to decreasing tissue hypoxia with oxygen and improving bloodflow to ischemic myocardium using nitrates and thrombolytic agents. Cardiac workload should be reduced by eliminating endogenous catecholamine release with analgesia and sedation. and beta blockade in patients without CHF to decrease heart rate and myocardial oxygen demand. Treatment of the complications of AMI include dysrhythmia prophylaxis. monitoring and specific therapy. Treatment of pump failure includes using vasodilators. vasopressors and positive inotropic agents. Early recognition and timely initiation of appropriate therapy should be every physician's goal.
The renin-angiotensin system: renal actions and blood pressure regulation, The RAS is part of an extremely powerful feedback system for long-term control of blood pressure and volume homeostasis. Disturbances that tend to lower blood pressure. such as heart failure. cirrhosis. and peripheral vasodilation. cause sodium and water retention until blood pressure returns to normal due. in large part. to the combined actions of ANGII and reduced arterial pressure. In response to increased sodium intake. decreased ANGII formation greatly amplifies the effectiveness of pressure natriuresis. thereby preventing large increases in body fluid volumes and blood pressure. In circumstances in which the RAS is inappropriately activated. the sodium retaining effects of ANGII necessitate increased blood pressure to maintain sodium balance via pressure natriuresis. Because the RAS is so powerful in regulating blood pressure. blockade of the system with ACE inhibitors offers a powerful therapeutic tool in diseases such as hypertension and congestive heart failure. The control of sodium excretion and blood pressure by ANGII is exerted through multiple intrarenal as well as extrarenal effects. including stimulation of aldosterone secretion. which can influence renal excretion. Current evidence suggests that the intrarenal effects of ANGII are quantitatively more important than those mediated by aldosterone in controlling blood pressure and renal excretion. The most important intrarenal effects of ANGII include efferent arteriolar constriction as well as direct effects on sodium transport. The constrictor effect on efferent arterioles also is important in preventing reductions in GFR in circumstances associated with impaired renal perfusion. Therefore blockade of ANGII formation in circumstances such as renal artery stenosis may caused marked reductions in GFR. However. in many patients efferent arteriolar vasodilation caused by ANGII blockade may not lower GFR markedly because of other autoregulatory mechanisms that compensate by causing parallel reductions in afferent arteriolar resistance. In these individuals. chronic ACE inhibition may prove to be beneficial in slowing the progression of renal disease because a reduction in glomerular hydrostatic pressure may help to prevent glomerular damage.
Factors affecting decisions to institutionalize demented elderly, This study followed 321 community-based patients with documented dementias. 22% of whom were institutionalized after 1 year. Multivariate analyses indicated that none of the patient characteristics. such as level of cognitive. psychiatric. or neurological impairment. predicted institutionalization. Social psychological characteristics. type and number of caregivers. and subjective caregiver distress did predict which patients were ultimately institutionalized. Implications for treatment planning are discussed.
Time spent caregiving and help received by spouses and adult children of brain-impaired adults, Caregivers for brain-impaired adults differ in living arrangements. amount of time spent giving care. and assistance received from family and friends and from paid help depending on their kin relationship and employment status. Spousal caregivers devote large amounts of time to caregiving. and husbands spend no less time than wives. Most caregivers receive little assistance from other family members and friends. but husbands receive more than others. Employed spouses receive more paid help than those without jobs. but employment does not affect the amount of paid help received by adult daughters.
Information and referral service usage among caregivers for dementia patients, Questionnaires were mailed to 257 callers of a toll-free telephone "helpline" specializing in Alzheimer's disease and related dementing illnesses; 125 (48.6%) were completed and returned. On the average. 3.94 requests for information were made per call. The most common requests concerned services delivered to the home. general information about dementia. information about adult day care. and support group information. Results indicated that a telephone-based information and referral helpline is useful in disseminating knowledge about resources to caregivers of older community-residing adults with cognitive impairment.
Hair anatomy for the clinician, The rational evaluation of hair disorders requires familiarity with follicular anatomy. Hair structure can be easily examined by studying clipped hair shafts. entire hairs gently pulled or forcibly plucked from the scalp. and scalp biopsies (sectioned vertically or transversely). Anatomic features will be different depending on whether a given hair is in the anagen. catagen. or telogen phase. Follicle size will also vary. from the minute vellus hair to the long. thick terminal hair. Each follicle can be divided into distinct regions--bulb. suprabulbar zone. isthmus. and infundibulum. Activity growing (anagen) hairs are characterized by a hair matrix surrounding a dermal papilla; inner and outer root sheaths are present and well developed. A catagen hair can be identified by its markedly thickened vitreous layer and fibrous root sheath. which surrounds an epithelial column; above this column. the presumptive club forms. A telogen hair is distinguished by its fully keratinized club. which is surrounded by an epithelial sac. Below this lies the secondary hair germ and condensed dermal papilla. waiting for the mysterious signal that initiates a new life cycle.
Studies of laminin and type IV collagen in blisters of porphyria cutanea tarda and drug-induced pseudoporphyria, Blisters from five patients with porphyria cutanea tarda and two patients with drug-induced pseudoporphyria were examined by direct immunofluorescence and by immunofluorescence mapping with antibodies against laminin and type IV collagen to determine the level of subepidermal separation. Primary screening by direct immunofluorescence revealed the characteristic immune deposits in the vessel walls of the upper dermal plexus in all cases and at the dermoepidermal junction in five of seven cases. Type IV collagen and laminin were reactive in six and five cases. respectively. and appeared in the floor of the bulla. The findings were identical in porphyria and pseudoporphyria. In one case in which the bullous pemphigoid antigen could be detected. it appeared in the epidermal roof of the bulla. These findings indicate that the split in porphyria and pseudoporphyria occurs in the lamina lucida. We propose that a multistep mechanism involved in the induction of blisters may be similar in porphyria and pseudoporphyria.
Photopatch testing: the 5-year experience of the German, Austrian, and Swiss Photopatch Test Group, A cooperative photopatch test study was conducted by 45 dermatologic centers in Austria. Germany. and Switzerland. Results obtained from 1985 to 1990 are presented. A standard photopatch test tray of 32 substances was applied to the back of patients with suspected photosensivity. After applications for 24 hours. test sites were irradiated with 10 joules/cm2UVA. Unirradiated controls were included. Readings were performed immediately and 24. 48. and 72 hours after irradiation; responses were qualitatively graded on a 4-point scale. All data were stored and processed by a computer. With computer-assisted analysis of reaction patterns photoallergic reactions were identified and distinguished from phototoxic reactions. Data of 1129 patients were evaluated. Among a total of 2859 positive test reactions in 870 patients. 2041 in 778 patients were found to be photoinduced and 818 in 413 patients were contact reactions; 108 reactions in 83 patients were classified as photoallergic. Nonsteroidal anti-inflammatory drugs. disinfectants. sunscreens. phenothiazines. and fragrances caused most often photoallergic reactions. Many unspecific phototoxic reactions were induced by tiaprofenic acid. promethazine. carprofen. chlorpromazine. fenticolar. wood balsam of Peru. and perfumes. Despite the distinction between photoallergic and phototoxic responses. many test reactions lacked relevance for the patients' dermatoses.
Toxic epidermal necrolysis: a review, This article reviews the many facets of toxic epidermal necrolysis. Emphasis is placed on the importance of early diagnosis. burn unit placement. supportive care. and avoidance of systemic steroids. Discussion also includes other therapeutic options and the pathophysiology of the disease.
Studies on the cellular origin of neurothekeoma: clinical, light microscopic, immunohistochemical, and ultrastructural observations, The clinical. histopathologic. and immunohistochemical features of 11 cases of neurothekeoma are reported. One case was examined by electron microscopy. The mean age of the patients was 27.1 years; the study comprised eight female and three male patients. Most lesions were nondescript papules and located on the upper part of the body. seven cases of neurothekeoma on the head. Eight cases were classified as cellular neurothekeoma on the basis of a striking fascicular pattern and three cases as myxomatous neurothekeoma because of prominent myxoid stromal change. All cellular neurothekeomas failed to express S-100 protein. whereas the three myxomatous types were strongly positive for this marker. Other than vimentin. there was no significant immunoreactivity with other immunohistochemical markers. Ultrastructural study of one case of cellular neurothekeoma was inconclusive for cell type although a perineurial origin could not be excluded. On the basis of these results. we conclude that cellular neurothekeoma differs from myxomatous neurothekeoma not only by clinical and histologic findings but also by immunoreactivity with S-100 protein. These findings also suggest the existence of two distinct subtypes of neurothekeoma and possible origin of the two variants of neurothekeoma from different cell types or at least variation in phenotypic expression of a common cell type. On the other hand. it cannot be excluded that these two variants are different stages in the natural history of neurothekeoma.
What dermatologists should know about digital imaging, The digital imaging revolution that swept other medical specialties in the late 1970s and early 1980s is beginning to find new and important roles in dermatology. This technology has a wide range of educational. clinical. and research applications. Dermatologists should understand certain basic concepts about images and imaging techniques to take advantage of progress in this field and eventually apply it to their own research and/or clinical practice.
Comparison of platelet-activating factor-induced chemotaxis of normodense and hypodense eosinophils, Platelet-activating factor (PAF)-induced eosinophil (EOS) migration is an important event in the development of tissue eosinophilia and allergic inflammation. EOSs are heterogeneous cells in that different states of activation have been ascribed to EOSs of varying densities. We therefore studied the ability of PAF to induce hypodense and normodense EOS chemotaxis. Both hypodense and normodense EOSs were isolated in pure form from seven subjects and studied concurrently. Dose-response and time-course experiments indicated no significant differences in PAF-induced hypodense versus normodense EOS chemotactic responses. Hypodense and normodense cells achieved maximal chemotaxis in response to 1 mumol/L of PAF. and maximal chemotaxis was achieved at 2 hours. However. marked differences in PAF-induced EOS chemotactic responses existed between patients. We conclude that PAF is a potent EOS chemoattractant. and despite reported differences in metabolic activity. normodense and hypodense EOSs exhibit similar chemotactic responsiveness to PAF.
The effect of inhalation of the leukotriene receptor antagonist, SK&F 104353, on leukotriene C4- and leukotriene E4-induced bronchoconstriction in subjects with asthma, The effect of prior inhalation of the sulfidopeptide leukotriene receptor antagonist. SK&F 104353 (963 +/- 43.7 micrograms; mean +/- SEM). on (LTC4)- and leukotriene E4 (LTE4)-induced bronchoconstriction has been studied in six subjects with asthma (six male subjects. aged 24 to 36 years). Inhalation challenges with either synthetic LTC4 or LTE4 were performed after prior inhalation of aerosolized SK&F 104353 or placebo in a double-blind. randomized fashion. Airway responsiveness to each agonist was determined by the cumulative dose of agonist required to induce a 35% fall in specific airway conductance (PD35) as determined by linear interpolation of the log dose-response curve. There was no change in baseline specific airway conductance after inhalation of either placebo or SK&F 104353. LTC4- and LTE4-induced bronchoconstrictions were significantly inhibited by aerosolized inhalation of SK&F 104353 30 minutes before challenge. The geometric mean (GM) PD35 of LTC4 on the open-therapy and placebo-therapy days was 0.043 nmol (range. 0.01 to 0.1 nmol) and 0.036 nmol (range. 0.01 to 0.1 nmol). respectively. On the treatment day with SK&F 104353. it was not possible to obtain a GM PD35 LTC4 up to a maximum concentration of 0.52 nmol LTC4 (p less than 0.01). The GM PD35 of LTE4 on the open-therapy and placebo-therapy days was 0.30 nmol (range. 0.13 to 0.76 nmol) and 0.39 nmol (range. 0.14 to 0.9 nmol). respectively. On the treatment day with SK&F 104353. it was not possible to obtain a GM PD35 LTE4 up to a maximum concentration of 5 nmol LTE4 (p less than 0.005). Thus. LTC4- and LTE4-induced bronchoconstrictions are both inhibited by SK&F 104353.
Methotrexate in the treatment of steroid-dependent asthma, A double-blind. placebo-controlled. crossover study was designed to compare steroid requirements between placebo and methotrexate (MTX) treatment in subjects with corticosteroid-requiring asthma. Subjects began with a steroid taper and then were randomized to a 3-month trial of drug or placebo therapy. Subjects received 15 mg of MTX a week or identical placebo. A 1-month washout period was completed before the crossover trial. Symptom scores. peak flow rates. spirometry. and beta-agonist frequency were closely monitored. Ten subjects completed the study. The average dose of prednisone during the placebo-treatment period was 11.97 mg/day compared to 8.37 mg/day while subjects were taking MTX. This was a 30% reduction in daily steroid requirement (p less than 0.01). Symptom scores and spirometry did not differ between the crossover trials. and overall clinical status was not altered. Complications from MTX were mild and included anorexia. alopecia. and stomatitis. All complications resolved with dose reduction or when MTX was stopped at the end of the study. No subjects withdrew from the study because of MTX complications. Low-dose MTX significantly reduced the steroid requirement in this group of subjects with steroid-dependent asthma. This reduction in steroid requirement was obtained without altering clinical status and without significant complication.
Penicillin resensitization among hospitalized patients, The purpose of this study was to determine the frequency of resensitization to penicillin after oral or intravenous treatment with beta-lactam antibiotics in hospitalized patients with histories of penicillin allergy. Seventeen adults (aged 24 to 76 years) and one child (aged 10 years) were treated intravenously and/or orally with beta-lactam antibiotics after negative skin tests were obtained with benzylpenicilloyl polylysine. potassium penicillin G. and alkaline hydrolysis products of penicillin G as minor determinant mixture. Repeat skin testing was performed 1 to 12 months after the therapy. Three patients (16%) became skin test positive after the treatment. Two patients reacted to potassium penicillin G alone. and the other patient reacted to benzylpenicilloyl polylysine and minor determinant mixture. These three patients were among the 15 patients who were treated with intravenous antibiotics. This study reveals a high percentage of skin test conversion after intravenously administered penicillin therapy and confirms the present practice of advising patients with a history of penicillin allergy who have successfully completed penicillin treatment to have a repeat skin test before future exposure to beta-lactam antibiotics.
Inhibition of different dosages of oxatomide or placebo on skin prick test and nasal allergen provocation, In this two-stage. double-blind study. we evaluated the effects of different dosages of oxatomide (1 and 2 mg/kg/day) on nasal provocation and skin reaction wheal induced by grass-pollen challenge. Children with a positive history of allergic rhinoconjunctivitis and positive responses to skin prick test and nasal provocation test to grass pollen were studied out of season. The results obtained with 1 mg/kg/day of oxatomide demonstrated no significant difference in wheal areas and nasal secretion induced by allergen challenge between treated and untreated patients. The administration of 2 mg/kg/day demonstrated a significant suppression in wheal reaction and nasal secretion induced by specific challenge.
Identification of the major activity derived from cultured human peripheral blood mononuclear cells, which enhances eosinophil viability, as granulocyte macrophage colony-stimulating factor (GM-CSF), Eosinophils (EOSs) cultured in the presence of 50% peripheral blood mononuclear cell (PBMC)-derived culture supernatants remained 67% +/- 7% (mean +/- SEM; n = 5) viable for 7 days. In the absence of PBMC supernatant. only 15% +/- 7% of cells remained viable for 7 days. PBMC supernatants from six atopic individuals. with eosinophilia. and six normal subjects. with no eosinophilia. were compared for EOS viability-enhancing activity with the same target EOSs. Optimal conditions for the production of viability-enhancing activity by mononuclear cells were established as a 24-hour culture period. with a concentration of 2 x 10(6) cells per milliliter. Comparison of monocyte-enriched and lymphocyte-enriched culture supernatants for the production of the EOS viability-enhancing activity indicated that both cell types released the factor. C-18 Sep-Pak separation of the PBMC culture supernatant yielded a major EOS viability-enhancing activity in the aqueous eluent. suggesting a hydrophilic molecule. This major activity was neutralized by a specific antibody to granulocyte/macrophage colony-stimulating factor but was unaffected by specific antibodies to interleukin-3 and interleukin-5. A second. minor viability-enhancing activity was observed in the 100% methanol fraction. indicating the presence of a more hydrophobic molecule. The supernatants from the PBMCs of the atopic individuals consistently enhanced EOS survival to a greater extent than supernatants from the PBMCs of the normal. nonatopic individuals.
Intranasal fluocortin butyl in patients with perennial rhinitis: a 12-month efficacy and safety study including nasal biopsy, Fluocortin butyl (FCB) is a recently developed topical intranasal corticosteroid that is inhaled as a powder and has been demonstrated to be well tolerated and to improve symptoms and signs of perennial rhinitis in previous short-term studies. This multicenter. open-label study evaluated the efficacy and safety of FCB during a 12-month treatment period in patients with perennial rhinitis. Treatment was initiated with one inhalation of FCB in each nostril three times a day (total dosage. 3 mg/day). In subsequent months. one third of the patients was maintained at the dosage of 3 mg/day. one third at a lower dosage of 2 mg/day. and the remaining one third of the patients at a larger dosage of 4 to 8 mg/day. Of 109 patients enrolled in the study. 90 patients (82.6%) completed all 12 months of treatment. Symptom and sign scores decreased significantly (p less than 0.001) at the 2-month evaluation compared to scores at baseline. and the improvement was maintained throughout the 12-month study period. After 12 months. greater than 80% of the patients had substantial control of symptoms. Specimens of nasal biopsies. performed at the beginning and end of treatment. revealed a decrease in eosinophils and other cellular infiltrates. a slight tendency of an increase in mast cell counts. and a trend toward normalization of the nasal mucosa. There were few adverse effects. Mean plasma cortisol levels were normal before and after corticotropin stimulation at baseline and after 12 months of FCB therapy.
The I-Abm12 mutation, which confers resistance to experimental myasthenia gravis, drastically affects the epitope repertoire of murine CD4+ cells sensitized to nicotinic acetylcholine receptor, Susceptibility to experimental autoimmune myasthenia gravis (EAMG). which is induced in mice by injection of purified Torpedo nicotinic acetylcholine receptor (TAChR). is influenced by the I-A locus products. which restrict presentation of AChR Th epitopes. The bm12 mutation of the I-Ab molecule in the C57BL/6 strain. which is highly susceptible to EAMG. yields the EAMG resistant mutant B6.C-H-2bm12 (bm12). We investigated here the consequences of the bm 12 mutation on the CD4+ response to the TAChR alpha subunit. Upon immunization with TAChR. CD4+ cells became sensitized to TAChR and anti-AChR antibodies were produced in both bm12 and C57BL/6 strains. Overlapping synthetic peptides. corresponding to the complete sequence of TAChR alpha subunit. were used to identify Th epitopes. CD4+ cells from C57BL/6 mice recognized peptides T alpha 150-169. T alpha 181-200. and T alpha 360-378. CD4+ cells from bm12 mice did not respond to any synthetic sequence. Upon injection of the three C57BL/6 Th epitope peptides. either individually or as a pool. CD4+ cells from C57BL/6 mice recognized each peptide and TAChR. Therefore they recognized epitopes similar or identical to those originated from TAChR processing. CD4+ cells from bm12 mice injected with the same peptides responded to T alpha 360-378 strongly. to a lesser extent to T alpha 181-200. never to peptide T alpha 150-169. Only CD4+ cells sensitized against the T epitope peptide T alpha 181-200 responded to TAChR. We tested if lack of response to T alpha 150-169. and the low response to T alpha 181-200. was due to inability of the I-Abm12 molecule to present the T epitope peptides. bm12 and C57BL/6 APC were used to present the T epitope peptides to specifically sensitized CD4+ cells from C57BL/6 mice. All T epitope peptides were presented by bm12 APC. although T alpha 150-169 was presented less efficiently than by C57BL/6 APC. Resistance to EAMG induced by the bm12 mutation may be due to the change in the epitope repertoire of AChR-specific Th cells. and lack of recognition of otherwise immunodominant Th epitopes. For at least one epitope this might be due to absence of potentially reactive. specific CD4+ clones.
Type I transforming growth factor-beta receptors on neutrophils mediate chemotaxis to transforming growth factor-beta, Participation of human polymorphonuclear neutrophils in the inflammatory response is mediated. in part. by soluble factors such as chemotactic peptides and cytokines. Although the cytokine. transforming growth factor beta (TGF-beta). has been shown to recruit monocytes and promote the inflammatory process. its effects on neutrophils are unknown. In this investigation. [125I]TGF-beta 1 affinity binding studies were employed to show that neutrophils express TGF-beta receptors (350 +/- 20 receptors/cell). which exhibit high affinity for the ligand (dissociation constant. 50 pM). Affinity cross-linking studies identified the receptors to be primarily of the type I class. In contrast to the receptors on monocytes. neutrophil TGF-beta receptors were not down-regulated by exposure to specific inflammatory mediators. Additional studies examined whether exposure of neutrophils to TGF-beta could enhance specific functions. as occurs with monocytes. TGF-beta was shown to cause directed migration of neutrophils at femtomolar concentrations. thus it is the most potent neutrophil chemotactic factor yet identified. Neutrophil production of reactive oxygen intermediates was not stimulated by TGF-beta. nor did TGF-beta enhance or depress subsequent PMA- or FMLP-stimulated superoxide production. However. the stable expression of neutrophil TGF-beta receptors. and the capacity of this cytokine to stimulate neutrophil chemotaxis. suggest that the pro-inflammatory effects of TGF-beta are mediated by neutrophils in addition to monocytes.
Effect of dietary alpha-linolenate on platelet-activating factor production in rat peritoneal polymorphonuclear leukocytes, The effects of dietary alpha-linolenate (18:3. n-3) and linoleate (18:2. n-6) on platelet-activating factor (PAF) production were examined. Rats were fed an alpha-linolenic acid-rich (perilla oil) diet or a linoleic acid-rich (safflower oil) diet for 6 wk. and polymorphonuclear leukocytes (PMN) were elicited by peritoneal injection of casein. The overall phospholipid content and composition as well as the subclass distribution of choline and ethanolamine glycerophospholipids in PMN were not altered by these diets. However. with the perilla oil diet their content of a putative precursor of PAF. 1-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine was approximately 50% of that with safflower oil diet. On exposure to various concentrations of FMLP. PAF formation by PMN in the perilla oil group was less than 50% of that by PMN in the safflower oil group. A larger difference in PAF productions by PMN in the two dietary groups was observed on their stimulation with calcium ionophore A23187. These results demonstrate that PAF production is modulated in some as yet unknown way by changing the alpha-linolenate/linoleate balance of the diet.
Mast cells are critical for the production of leukotrienes responsible for neutrophil recruitment in immune complex-induced peritonitis in mice, Mast cells are secretory cells strategically located in the vicinity of blood vessels where they can readily initiate and modulate various inflammatory processes. including plasma exudation and leukocyte infiltration. We have previously shown that 50% of the neutrophil influx during immune complex peritonitis in mice is due to mast cells. Eicosanoids are important mediators of various inflammatory processes including neutrophil infiltration. The possibility that mast cells are essential for the production of leukotrienes (LT) involved in the elicitation of neutrophils in immune complex peritonitis was investigated in mast cell-deficient. WBB6F1-W/WV. and normal. WBB6F(1-)+/+. mice. The time course and amounts of immunoreactive PGE2. 6-keto-PGF1 alpha. and TX3B2 released into the peritoneal exudates were similar in both sets of mice. LTB4 and LTC4 levels. however. were twofold higher in +/+ than in W/WV mice 2 h after stimulation. HPLC analysis of the peritoneal exudate confirmed the presence of leukotrienes. The 5-lipoxygenase inhibitor A-63162 blocked leukotriene production in a dose-dependent manner in both sets of mice. However. this compound caused a significant reduction (60%) of neutrophil infiltration only in WBB6F(1-)+/+ but not in the mast cell-deficient mice. Mast cell reconstitution of WBB6F1-W/WV mice restored the effect of A-63162 on PMN recruitment. These data suggest that mast cells in the vicinity of blood vessels are important for the synthesis of leukotrienes responsible for PMN recruitment.
A clinical trial of the American Heart Association step one diet for treatment of hypercholesterolemia, BACKGROUND. Although diet therapy is the primary treatment for hypercholesterolemia. a trial to determine the effectiveness of the new American Heart Association Step One Diet (AHA diet) in lowering cholesterol has to our knowledge never been carried out. METHODS. A clinical trial was conducted to assess the plasma lipids response and adherence to the AHA diet in 120 men and women with hypercholesterolemia. All subjects were advised to follow the AHA diet for 18 weeks. RESULTS. After 6 weeks of the AHA diet intervention. there were modest but significant reductions in plasma total cholesterol (-2.6%) and low-density lipoprotein (LDL) cholesterol (-3.5%). but no further significant reductions were observed thereafter. Rather. there was a tendency to return to and even exceed baseline levels of total cholesterol and LDL cholesterol over the subsequent 12 weeks. in spite of the subjects' reported continued adherence to the AHA diet and maintenance of weight loss throughout the entire study period. Nevertheless. 51% of the subjects had experienced improvement (-0.2% to -26.3%) in their plasma LDL cholesterol levels by the end of the study. CONCLUSIONS. A probable reason for the limited response of the diet was low baseline levels in intake of saturated fat and cholesterol by participants. The subjects who were older and had higher levels of plasma LDL cholesterol and total fat intake at baseline experienced better plasma LDL cholesterol response to the AHA diet. Thus. practicing physicians should consider assessing the baseline dietary fat and cholesterol intake of patients with hypercholesterolemia before starting the AHA diet. since patients may already be following a relatively prudent self-selected diet. Additional dietary gains in lipid management might well require a more severe restriction of dietary fats and cholesterol. Long-term efficacy of the AHA diet should also be evaluated clinically with periodic lipid profiles.
Central motor pathways in patients with mirror movements, Central motor pathways were investigated in three patients with congenital mirror movements using magnetic motor cortex stimulation. Response thresholds. amplitudes and latencies were normal. The projection of the corticomotoneuronal pathways was assessed by placing the coil over the vertex and comparing the size of responses in the first dorsal interosseous (FDI) muscles evoked by clockwise and anticlockwise coil currents. In normal subjects. right FDI responses are larger with clockwise currents than with anticlockwise currents at the same stimulation strength and vice versa. In two out of three patients with congenital mirror movements. this sensitivity of response amplitude to coil current direction was reversed. The third patient with congenital mirror movements and a fourth patient with acquired mirror movements had responses which were normally sensitive to current direction. These findings support the hypothesis that some cases of congenital mirror movements may be due to abnormal projection of corticomotoneuronal pathways.
Diurnal variation of essential and physiological tremor, Evaluations were made of the diurnal variations of tremor power at rest. after fatigue and after mass loading. and plasma norepinephrine in patients with familial essential tremor and normal subjects. Diurnal tremor power rhythms for both essential and physiological tremor pursued identical temporal profiles. Plasma norepinephrine levels followed a congruent diurnal pattern with later peak values than the peak values of tremor power. Sympathetic nervous system activity is unlikely to be the cause of diurnal tremor power variation. The consistent diurnal rhythm of tremor power may affect dosage schemes of tremorolytic drugs.
Assessment of autonomic function in myotonic dystrophy, Published reports suggested autonomic nervous system dysfunction in myotonic dystrophy but were inconclusive partly due to small patient numbers and because only a limited number of tests was used. Autonomic nervous system function with noninvasive tests was assessed in ten myotonic dystrophy patients and age and sex matched healthy controls. Statistically significant differences included reduction in the heart rate response to standing and in the blood pressure response to sustained handgrip. Latency of the pupillary light reflex was not different from controls but the time to reach peak velocity of contraction was significantly longer in the myotonic dystrophy group. It is argued that these results reflect dysfunction of voluntary and iris smooth muscle rather than autonomic nervous system dysfunction.
Immunohistochemical quantification of substance P in spinal dorsal horns of patients with multiple system atrophy, Using a computer-assisted image analyser. an immunohistochemical quantification method of substance P-like immunoreactivity (SPLI) in laminae I + II of spinal dorsal horn was established and applied to 13 patients with multiple system atrophy (MSA) with no disturbance of pain sensation. including olivo-ponto-cerebellar atrophy and striatonigral degeneration. and 13 neurologically normal controls. To investigate whether alteration of SPLI is related to an autonomic disorder. myelinated fibre counts of the fourth thoracic ventral roots were performed. Eleven of 13 MSA patients showed a significant decrease in small and large myelinated fibres. and were diagnosed with definite Shy-Drager syndrome (SDS). with the exception of two who had no apparent history of autonomic dysfunction. SPLIs in laminae I + II in 10 of these 11 patients. when adjusted for age. were significantly decreased at both levels of the fourth thoracic and third lumbar spinal segments. The results suggest the disorder of SP-containing synapses of primary afferent neurons and/or those of interneurons in SDS.
Allele frequencies of the third component of complement (C3) in MS patients, No difference was found in the allele frequency of C3 (third component of complement) in 129 multiple sclerosis (MS) patients compared with both 69 controls or with similar reported controls from the published literature. An association cannot be confirmed between C3 and MS.
Antenatal diagnosis of pelvic hydronephrosis: assessment of renal function and drainage as a guide to management, The optimal management of children with antenatally diagnosed unilateral hydronephrotic kidneys is unclear. We have monitored renal function and drainage using 99mTc-DTPA renography in 77 children with such kidneys presenting at 1-14 mo of age with the aims of throwing light on the natural history of the condition and evaluating the response of the kidney to pyeloplasty. Since management was independent of the drainage criteria on renography. the opportunity also was presented to evaluate the efficacy of diuretic renography for diagnosing obstruction in these children. Follow-up ranged between 1 and 6 yr. during which renography was performed between 2 and 6 times in each patient. Thirty-nine patients were treated conservatively. while 30 patients underwent pyeloplasty at varying times after presentation. No overall significant change in function was observed either in the nonoperated children or as a result of surgery. This also applied to sub-groups of children with poor drainage. Function improved significantly. however. in a sub-group of nonoperated children who presented with impaired function in the hydronephrotic kidney. Surgery. although having no overall effect on function. significantly improved drainage. As a means of identifying obstruction. 99mTc-DTPA diuretic renography was unreliable. erroneously indicating obstruction in 24 nonoperated children in whom function of the hydronephrotic kidney never became abnormal and who could not. therefore. have been considered to have obstruction. This retrospective study underlines the importance of performing a randomized prospective study on the value of pyeloplasty in this group of children.
Comparison of oral iodine-131-cellulose and indium-111-DTPA as tracers for colon transit scintigraphy: analysis by colon activity profiles, In 11 normal subjects and 11 patients with a clinical diagnosis of constipation. oral 131I-cellulose and 111In-DTPA were compared simultaneously as tracers for radionuclide colon transit scintigraphy. Visual assessment of the images revealed no differences between tracers. Quantitation was performed using total and segmental percent retention and the derived value of clearance half-time. In addition. profiles of the activity distribution along the length of the colon were generated and the mean position of the activity in the colon calculated. For all indices. the results were similar in both normal subjects and constipated patients when comparing tracers. although marked differences were present between normal subjects and constipated patients for each tracer. Indium-111-DTPA was easy to administer and dosimetry was more acceptable than for 131I-cellulose. especially in constipated patients. It is concluded that 111In-DTPA is the preferred tracer for oral colon transit scintigraphy.
Visual and quantitative analysis of interictal SPECT with technetium-99m-HMPAO in temporal lobe epilepsy, Interictal 99mTc-HMPAO SPECT images were compared to ictal EEG localization in 51 patients with intractable temporal lobe epilepsy to determine their usefulness for preoperative seizure focus localization. Both quantified temporal lobe asymmetry and blinded visual detection of temporal lobe hypoperfusion were employed. Visual analysis detected ipsilateral hypoperfusion in 18 (39%) of the 46 patients with a unilateral focus and contralateral hypoperfusion in 3. None of the five patients with bitemporal foci had unilateral hypoperfusion. The positive predictive value of unilateral temporal lobe hypoperfusion was 86% (18/21). Quantified anterior temporal lobe asymmetry. greater than a previously derived normal range. correctly identified the focus in 22 (48%) but gave the wrong side in 5. resulting in a predictive value of 81%. The degree of asymmetry correlated inversely with age of seizure onset. but not with other clinical parameters. histology. or verbal and nonverbal memory. The usefulness of interictal 99mTc-HMPAO SPECT for pre-operative seizure focus localization is limited by low sensitivity when performed with a conventional rotating gamma camera. This suggests that ictal or immediate postictal imaging may be necessary for this purpose.
Muscle perfusion with technetium-MIBI in lower extremity peripheral arterial diseases, There have been several methods utilized in the diagnosis or assessment of medical or surgical treatments of peripheral arterial diseases. In this study. the diagnostic value of a new tracer: 99mTc-methoxy-isobutyl-isonitrile (MIBI) has been demonstrated in patients with leg claudication. We successively performed muscle perfusion scans in 6 normals and 18 patients with claudication pain during rest and after exercise on the same day. Muscle perfusion abnormalities in all patients were consistent with the defects in the arteries of the affected limbs. The results show that this is a simple and accurate diagnostic procedure and superior to those that have been previously used.
Technetium-99m-MAG3 clearance as a parameter of effective renal plasma flow in patients with proteinuria and lowered serum albumin levels, Although the renal clearance of 99mTc-MAG3 is about 60% of the 131I-hippurate clearance. 99mTc-MAG3 clearance may be useful to estimate ERPF. In one study. however. proteinuria seemed to influence the MAG3/hippurate clearance ratio. In order to establish whether proteinuria or serum albumin level has influence on this ratio. a comparison was made between 99mTc-MAG3 clearance and 131I-hippurate clearance in 14 patients. There was a good linear correlation between MAG3 and hippurate clearance. although the standard error of estimate of ERPF from MAG3 was relatively large. which remained unexplained. No correlation was found between proteinuria and MAG3/hippurate clearance ratio nor between serum albumin level. GFR. FF. ERPF and the MAG3/hippurate clearance ratio. We therefore conclude that there is no correlation between proteinuria and albumin level and the MAG3/hippurate ratio. A reasonable estimation of ERPF with MAG3 can be made in patients with proteinuria and lowered serum albumin levels although the estimation may be less accurate.
Rest-injected thallium-201 imaging for assessing viability of severe asynergic regions, To evaluate the utility of rest-injected 201Tl initial and delayed images for assessing the viability of severe asynergic regions. we studied 17 patients with apparently prior infarcted myocardium in combination with 99mTc ventriculography before and after revascularization. In 51 regions with severe asynergy. the percent 201Tl uptake was calculated as the ratio of counts on the segment with asynergy to the maximum counts on the normal segment. Eleven of 14 regions with resting 201Tl redistribution (Group 1) had improved wall motion after revascularization. However. 14 of 37 regions without redistribution also improved (Group 2). Twenty-three regions without redistribution or improved wall motion after revascularization (Group 3) had lower regional 201Tl uptake on their delayed images than those in Groups 1 and 2. Moreover. the initial regional uptake of Group 2 was higher than that of Group 3. These results suggest that redistribution on rest-injected 201Tl scans indicates reversibility of severely asynergic myocardium and that high 201Tl uptake in regions without redistribution may predict improvement in wall motion after revascularization. We conclude that 201Tl uptake may be useful as a marker of viability of severe asynergic regions before revascularization.
Gamma imaging with negatively charge-modified monoclonal antibody: modification with synthetic polymers, Antimyosin Fab has been modified to carry highly negatively charged synthetic polymers containing DTPAs (DTPA-PL) as chelating agents. of starting molecular weights 3.3 and 17 kD. The immunoreactivities of the modified antibodies were unaffected by the modification procedure. The isoelectric points (PI) of unmodified antimyosin (AM) Fab (PI range 7-9. Mr = 52kD) were changed to PIs predominantly between 4 and 5 (Mr = 59 kD for DTPA-PL3.3kD-AM-Fab and 67kD for DTPA-PL17kD-AM-Fab). These AM-Fab preparations were tested for specific target localization and visualization in vivo in an experimental canine model of acute myocardial infarction. The charge-modified 111In-labeled AM-Fab preparations showed enhanced target (necrotic myocardium) visualization within 30 min of intravenous infusion and decreased background activity in normal myocardium (mean %ID/g +/- s.e.m.. 0.0076 +/- 0.0006. n = 164. and 0.0056 +/- 0.0004. n = 92. for 111In-DTPA-PL3.3kD- and DTPA-PL17kD-AM-Fab respectively) relative to conventional 111In-DTPA-AM-Fab (0.0263 +/- 0.0037. n = 135) (p less than 0.001) or radioiodinated AM-Fab (0.0098 +/- 0.0006. n = 256) (p less than or equal to 0.001). Furthermore. the concentration of negatively charged 111In-labeled antimyosin Fab decreased in non-target organs such as the liver and kidneys. In diagnostic and therapeutic applications. charge-modified macromolecules may improve target localization and reduce non-target organ activity.
Radioiodinated 1-(5-iodo-5-deoxy-beta-D-arabinofuranosyl)-2-nitroimidazole (iodoazomycin arabinoside: IAZA): a novel marker of tissue hypoxia, 1-(5-Iodo-5-deoxy-beta-D-arabinofuranosyl)-2-nitroimidazole (IAZA) has been synthesised and labeled with 125I. Radioiodinated IAZA was shown to undergo hypoxia-dependent binding in EMT-6 cells in vitro and to have an initial binding rate of 284 pmole/10(6) cells/hr at a substrate concentration of 30 microM. This binding rate is more than three times that of the reference compound. misonidazole (89 pmole/10(6) cells/hr). The elevated binding rate was accompanied by in vitro cytotoxicity 30-40 times greater than that observed for misonidazole. Whole-body elimination and biodistribution studies in BALB/c mice bearing implanted. subcutaneous EMT-6 tumors showed a rapid excretion (greater than 98% in 24 hr) with moderate tissue levels which. in general. declined as a function of blood clearance. Tumor-to-blood ratios of 4.6 (4 hr) and 8.7 (8 hr). with respective tumor uptake values of 2.08% and 1.22% ID/g of tissue. form a rational basis for evaluation of this and related 2-nitroimidazole analogs as radiopharmaceuticals suitable for scintigraphic evaluation of tissue (tumor) hypoxia.
Pentavalent technetium-99m-DMSA uptake in a patient having multiple myeloma without amyloidosis, A pentavalent 99mTc-dimercaptosuccinic acid (DMSA) scan was performed on a patient with multiple myeloma without amyloidosis. A high accumulation of the tracer was found in numerous tumors. We believe that the accumulation of DMSA is unrelated to amyloidosis and that the DMSA scan may have potential for the staging of tumors in patients presenting with multiple myeloma.
Reorientation of the left ventricular long-axis on myocardial transaxial tomograms by a linear fitting method, A method is described for reorientating the left ventricular (LV) long-axis from myocardial transaxial tomographic data. On a midventricular transverse slice and on a midventricular sagittal slice. the apical and basal limits are selected successively by the operator. The linear activity profiles between these two limits are plotted line by line. In each profile. the two points with the maximum counts in the septal and lateral walls on the transverse slice. or in the anterior and inferior walls on the sagittal slice. are detected. The intermediate point with the minimum counts is then determined. The set of points with minimum counts are fitted by a straight line using the least squares method. This line is taken as the LV long-axis. In a series of 15 cases with stress-delayed 201Tl SPECT. the reproducibility of the reorientation with this semi-automatic method was compared with manual selection of the LV long-axis. In all patients. a successful reorientation was obtained with the present method. The reproducibility was significantly better with the semi-automatic method than with the manual selection of the LV long-axis.
An improved method for the quantification of left-to-right cardiac shunts, We have investigated a technique for quantifying QP/QS in left-to-right cardiac shunts. In this method. the gamma variate. which is fitted to the first-pass portion of the lung curve. is used to generate a curve. which simulates the response of a normal lung curve with systemic recirculation. The difference between this curve and the observed lung curve is then used to calculate QP/QS. This method was evaluated on a set of simulated lung time-activity curves with precisely known QP/QS values on a group of 11 patients with no clinical suspicion of cardiac shunt and on a group of 30 patients referred for cardiac shunt studies. The QP/QS in each of these studies was determined by three individuals using both the Maltz-Treves method and the new method. This method yielded QP/QS values that were more accurate on the simulated lung data and had less interobserver variation on all the studies than those obtained from the Maltz-Treves method.
Glutathione levels and related enzyme activities in vitamin B-6-deficient rats fed a high methionine and low cystine diet, We examined the change in glutathione metabolism in vitamin B-6-deficient rats. Vitamin B-6-deficient rats were fed a vitamin B-6-deficient diet containing 0.56% methionine and 0.075% cystine for 8 wk. Controls were fed an identical diet supplemented with 10 mg pyridoxine hydrochloride/kg diet. Glutathione concentrations in each organ examined were similar in control and vitamin B-6-deficient rats. and the values were comparably lower after intraperitoneal injection of diethylmaleate. However. buthionine sulfoximine caused a significantly greater decrease in glutathione levels in the liver and lungs of vitamin B-6-deficient rats relative to controls. Glutathione peroxidase activity in the liver of vitamin B-6-deficient rats was higher than in control animals; however. glutathione transferase activity in tissues other than liver of vitamin B-6-deficient rats was higher than in the controls. The activities of gamma-glutamyl-transferase in the liver and spleen of vitamin B-6-deficient rats were significantly lower than control values. The holoenzyme activities of cystathionine beta-synthase and cystathionine gamma-lyase in the liver of vitamin B-6-deficient rats were markedly reduced. These findings indicate that although the activities of enzymes that synthesize cysteine from methionine were decreased by vitamin B-6 deficiency. the level of synthesis and supply of cysteine in vitamin B-6-deficient rats were sufficient to maintain the same glutathione level as in controls. and that glutathione utilization in the liver was accelerated by vitamin B-6 deficiency.
Lymphocyte subpopulations in the thymus, lymph nodes and spleen of iron-deficient and rehabilitated mice, Three groups of weanling female mice were fed one of two iron-deficient diets (5 and 12 mg Fe/kg diet) or a normal diet (30 mg Fe/kg diet) for 6 wk. A control pair-fed group was included. Seven mice received the 5 mg Fe/kg diet for 6 wk. then were rehabilitated using the 30 mg Fe/kg diet for 10 d. Mice fed the 5 mg Fe/kg diet were moderately iron-deficient. as shown by indices of iron status. No significant differences were observed in thymus weight or in the proportion and number of thymocyte subsets in thymuses of anemic. moderately iron-deficient and control mice. Thymus weight was decreased in pair-fed mice. No significant difference was found in lymph node subsets. In the spleen of anemic mice. the proportions and total number of Thy-1+ splenocytes. CD4-8+ and CD4+8- cells were very low compared with control (P less than 0.01) and iron-deficient (P less than 0.02) mice. The decrease was not only observed for the percentage of subsets but also for the absolute number of cell subtypes per spleen. Thy-1+ splenocyte subpopulations were normalized after rehabilitation. These quantitative modifications could explain alterations in the blastogenic response of splenic lymphocytes described by other authors.
Increased dietary branched-chain amino acids do not improve growth in developing rats with chronic biliary obstruction, We studied dietary branched-chain amino acid enrichment in cholestatic weanling rats. Growth was assessed with body weight. muscle weight and nitrogen balance. Systemic metabolic measurements that reflect liver function were evaluated. including plasma ammonia. albumin. amino acids. glucose. triglyceride and branched-chain ketoacids. as well as urinary carnitine excretion. Twenty-two rats underwent bile-duct ligation at 14 d of age. At weaning. 11 rats were fed a control diet and 11 an isoenergetic. isonitrogenous branched-chain amino acid-enriched diet for 3 wk. each with a sham-operated. pair-fed control. Body weights were similar in all four groups. Changes due to bile-duct ligation and not affected by the diet manipulation included lower plasma glucose. nitrogen balance and muscle weight. and higher triglyceride concentration. carnitine excretion and liver weight. Changes due to ligation that were normalized by dietary manipulation included plasma albumin. ammonia and total amino acid concentrations. The ratio of branched-chain to aromatic amino acids was decreased in ligated animals fed both diets; however. branched-chain amino acids were lower in the two groups fed more branched-chain amino acids.
High protein intake promotes the growth of hepatic preneoplastic foci in Fischer #344 rats: evidence that early remodeled foci retain the potential for future growth, The effects of successive administration. withdrawal and readministration of high protein diets (20% casein) on the promotional growth. remodeling and regrowth of aflatoxin B1-induced preneoplastic liver lesions (foci) were examined. Weanling male Fischer 344 rats were given 10 intragastric doses of aflatoxin B1 at a level of 250 micrograms/kg body weight over a 2-wk dosing period (initiation). The subsequent 12-wk period was subdivided into four feeding periods. each lasting 3 wk (promotion). Two groups of rats were fed either a 20 or 5% casein diet during all four periods; additional groups were alternately fed these diets in different sequences. Switching from the high protein diet to a low protein diet (5% casein) resulted in marked remodeling (regression) of the growing lesions to a response level similar to that in animals that did not receive the initial promotional stimulus of high protein feeding. However. refeeding the high protein diet caused significant reappearance of these lesions. The restimulated development of these remodeled lesions far exceeded lesion growth in animals receiving only the late promotional stimulus of high dietary protein. Thus. these data suggest that a second occurrence of high protein feeding promotes the growth of remodeled foci. thus demonstrating their potential for future promotional growth.
Value of degenerative change in neutrophils as a diagnostic test for Kawasaki syndrome, STUDY OBJECTIVE: To determine whether the presence of vacuoles and toxic granulation in neutrophils can be used as a diagnostic test to help differentiate children with Kawasaki syndrome from those with clinically similar illnesses. DESIGN: Peripheral blood smears of 23 patients with Kawasaki syndrome. 23 disease control patients. and 23 hematology laboratory control subjects were examined in random order by technicians unaware of either the diagnosis or the previously recorded laboratory results. SETTING: Tertiary care children's hospital in Ottawa. Canada. PATIENTS: All 23 consecutive patients with Kawasaki syndrome satisfied established criteria for the diagnosis. Disease control patients were selected from the hospital registry of patients with other illnesses frequently considered as part of the differential diagnosis for Kawasaki syndrome. MEASUREMENTS AND MAIN RESULTS: Compared with disease control patients. patients with Kawasaki syndrome had a higher percentage of neutrophils with vacuoles (mean +/- SEM. 31% +/- 5% vs 14% +/- 3%; p = 0.006) and toxic granulation (mean +/- SEM. 43% +/- 7% vs 14% +/- 4%; p less than 0.001). If the sum of the number of neutrophils with vacuoles and the number with toxic granulation (per 100 mature neutrophils examined) was at least 70. this "toxic neutrophil" test had a specificity of 0.96 and a likelihood ratio of a positive test result of 12. CONCLUSIONS: Degenerative change in neutrophils is common in the early stages of Kawasaki syndrome. The toxic neutrophil test is potentially a helpful adjunct to the clinical examination. particularly in the case of infants and other patients with subtle manifestations who might otherwise be at risk for delayed diagnosis.
High incidence of serum antibodies to Escherichia coli O157 lipopolysaccharide in children with hemolytic-uremic syndrome, Because the classic hemolytic-uremic syndrome has been etiologically linked to intestinal infections by Escherichia coli 0157 and other verotoxin-producing E. coli (VTEC). we examined 22 consecutive children with acute hemolytic-uremic syndrome for the presence of VTEC. using microbiologic methods. and for a specific immune response to 0157 lipopolysaccharide in acute-phase and follow-up sera. using the indirect hemagglutination assay and the immunoblot procedure. Of 22 children with enteropathic hemolytic-uremic syndrome. 15 (68%) had evidence of VTEC infection by culture of the pathogen or detection of free verotoxin in the feces. or both. Significantly elevated titers of short-lived agglutinins and IgM class antibodies against the 0157 lipopolysaccharide were found in 20 (91%) of 22 patients. but not in two of three patients with non-0157 E. coli isolates or in healthy children or children with diarrhea caused by other enteric pathogens (p less than 0.01). The combined microbiologic and serologic procedures provided evidence for VTEC infection in all 22 patients. The high incidence of anti-0157 lipopolysaccharide antibodies in these patients indicates the predominance and the pathogenic potential of this serogroup. Both serologic techniques proved to be valuable tools to further characterize this form of hemolytic-uremic syndrome. Future studies on the induction of protective immunity seem warranted.
Natural history of isolated atrial flutter in infancy, To clarify the natural history of isolated (i.e.. without associated congenital cardiac anomalies) atrial flutter in infancy. we reviewed the clinical course in nine patients who were seen with this arrhythmia in the first year of life (range 1 day to 4 months). Atrial flutter was identified by the typical sawtooth pattern in leads II. III. and aVF of the surface electrocardiogram or the pattern of atrial flutter on an atrial electrogram recorded through the esophagus. The mean cycle length of the atrial flutter was 151 msec (atrial rate 397 beats/min). Six of the nine patients had other perinatal problems. such as immune and nonimmune hydrops fetalis (two patients). pneumonia (one patient). anemia (five patients). or low birth weight (one patient). In all patients the rhythm reverted to normal. either spontaneously (two patients). with overdrive pacing (four patients). or after oral digoxin therapy (three patients). No consistent temporal relationship between digoxin administration and conversion was observed; conversion was instantaneous in the four patients who received atrial overdrive pacing. Four patients were discharged receiving digoxin therapy (6 months to 1 year). One patient had supraventricular tachycardia after discharge that was controlled with digoxin. No recurrence of atrial flutter was observed among the nine patients during a mean follow-up of 6.8 years (range 0.2 to 20 years). We conclude that isolated atrial flutter in infancy is rare. has a good prognosis. may be related to transient perinatal events. and often spontaneously converts to normal sinus rhythm; however. when it does not. it will respond to transesophageal pacing. Acute and chronic digoxin therapy is probably unnecessary.
Hyperlipidemia and fatty acid composition in patients treated for type IA glycogen storage disease, Because glycogen storage disease type IA (GSD-IA) is characterized by recurrent episodes of hypoglycemia that promote a marked elevation in blood triglyceride levels. we evaluated plasma lipid levels in 12 patients with GSD-IA on a regular basis. Six of the 12 patients had plasma fatty acid composition measured; because of possible essential fatty acid deficiency. urinary prostaglandin excretion was also measured. All patients had triglyceride levels between 1440 and 6120 mg/dl (16.25 to 69.09 mmol/L) before treatment. After treatment to promote blood glucose levels of 75 to 85 mg/dl (4.2 to 4.7 mmol/L). triglyceride levels in each of 11 patients were between 189 +/- 31 (2.13 +/- 0.35 mmol/L) and 510 +/- 60 mg/dl (5.76 +/- 0.68 mmol/L). The lipoprotein fatty acid composition in six patients showed a substantial elevation in C16:0. C16:1 omega 7. and C18:1 omega 9. but no increase in C20:3 omega 9 (the fatty acid that characteristically increases in essential fatty acid deficiency). In addition. each of the six patients had normal 24-hour urinary excretion of prostaglandin. One patient. whose triglyceride levels remained elevated despite dietary treatment. was given either clofibrate. lovastatin. niacin. or fish oil. With the exception of lovastatin. these agents produced a decrease in triglyceride values for 1 to 2 months; however. by 3 months triglycerides reached pretreatment levels. Combined treatment with clofibrate and niacin resulted in a sustained decrease in plasma triglyceride levels for 4 months. The findings indicate that dietary management of GSD-IA is usually associated with improvements in triglyceride levels; however. patients maintain triglyceride values between 300 and 500 mg/dl (3.38 to 5.65 mmol/L). No patient had biochemical evidence of essential fatty acid deficiency.
Immediate improvement in lung volume after exogenous surfactant: alveolar recruitment versus increased distention, To determine whether changes in lung volume may be responsible for the clinical improvement in preterm infants given exogenous surfactant. we measured functional residual capacity (FRC). lung mechanics. and partial pressure of oxygen in seven ventilated neonates (birth weight 1080 +/- 361 gm (mean +/- SD); gestational age 28.3 +/- 2.6 weeks) less than 9 hours of age who had findings typical of hyaline membrane disease. All patients received 100 mg/kg calf lung surfactant extract. FRC was measured by a closed-circuit helium-dilution technique. and lung mechanics were determined by least mean squares analysis. FRC increased in all patients (range 56% to 330%; p less than 0.03). Dynamic lung compliance and total airway conductance did not change. Mean +/- SEM specific lung compliance (dynamic lung compliance/FRC) decreased 55.93% +/- 4.27% (p less than 0.02) and mean specific conductance (total airway conductance/FRC) decreased 45.91% +/- 9.74% (p less than 0.009). Mean alveolar/arterial partial pressure of oxygen ratio decreased 51.0% +/- 8.67% (p less than 0.01). These data indicate that the immediate improvement in oxygenation after surfactant administration is related to increased lung volumes. The decrease in specific lung compliance and specific airway conductance is suggestive of increased distention rather than recruitment of functional alveoli.
Results of a multicenter study of the modified hook-titanium Greenfield filter, Initial efforts to modify the stainless steel Greenfield filter for percutaneous insertion led to development of a titanium Greenfield filter. which could be inserted by use of a 12F carrier. This device functioned well as a filter but had an unacceptable 30% rate of migration. tilting. and penetration. Therefore a titanium Greenfield filter with modified hooks was developed and has been tested in 186 patients at 10 institutions. Successful placement occurred in 181 (97%); placement of the remainder was precluded by unfavorable anatomy. A contraindication to anticoagulation was the most frequent indication for insertion (75%). All but two were inserted percutaneously. predominantly via the right femoral vein (70%). Initial incomplete opening was seen in four patients (2%). which was corrected by guide wire manipulation and asymmetry of the legs in 10 (5.4%). Insertion site hematoma occurred in one patient. and apical penetration of the cava during insertion occurred in a second patient. Both events were without sequelae. Follow-up examinations were performed at 30 days at which time 35 deaths had occurred. Recurrent embolism was suspected in six patients (3%) and two of three deaths were confirmed by autopsy. Filter movement greater than 9 mm was seen in 13 patients. (11%) and increase in base diameter greater than or equal to 5 mm was seen in 17 patients (14%). CT scanning showed evidence of caval penetration in only one patient (0.8%). Insertion site venous thrombosis was seen in 4/46 (8.7%) patients screened. The modified hook titanium Greenfield filter is inserted percutaneously or operatively through a sheath. eliminating concern for misplacement from premature discharge.
Spontaneous carotid dissection: duplex scanning in diagnosis and management, The clinical. duplex. and angiographic findings in six patients with seven spontaneous extracranial carotid artery dissections are reported. Four dissections resulted in internal carotid artery occlusion. These patients complained of ipsilateral headache followed by contralateral hemiplegia. The other three dissections involved the common carotid artery and resulted in dual (one true and one false) lumens. Two of these dissections were asymptomatic. All dissections were treated nonoperatively with anticoagulant therapy. Neurologic deficits improved or disappeared in all symptomatic patients. On follow-up studies. one of the four internal carotid occlusions completely resolved with normalization of the duplex examination. All three dual lumen dissections remained patent on serial studies. Diagnostic duplex characteristics. both conclusive and supportive. of carotid dissections are described. Duplex scanning is shown to be accurate in diagnosing and ideally suited for serially following spontaneous carotid dissections.
Clinical and laboratory features of murine typhus in south Texas, 1980 through 1987, OBJECTIVE.--The clinical and laboratory features of patients with murine typhus have not been extensively reviewed since 1946. We have updated these findings in patients from south Texas who were examined by modern clinical and laboratory methods from 1980 through 1987. DESIGN.--Patients were identified by serological methods in this case series. and clinical. epidemiologic. laboratory. and therapeutic data were compiled and analyzed. SETTING.--The majority of patients (77 of 80) were identified in a primary care community hospital setting; the remainder (3 of 80) were ambulatory hospital outpatients. PATIENTS.--From 1980 through 1987. a total of 345 patients were diagnosed with murine typhus; 90 of these patients were seen at four hospitals in south Texas; of these. 80 had clinical and laboratory data available for review. MAIN OUTCOME MEASURES.--The frequency of common clinical manifestations (eg. headache. fever. and rash) and laboratory findings (eg. leukocyte and platelet counts and serum chemistry abnormalities) of patients with infectious diseases was tabulated. Clinical severity was semiquantitatively assessed and was correlated with clinical. laboratory. and therapeutic results. RESULTS.--Most cases (69%) occurred from April through August. Rash occurred in 54%; the triad of fever. headache. and rash was observed in only 12.5% of patients when first examined by a physician; respiratory and gastrointestinal symptoms were also frequent. Multiple organ involvement was documented by frequent abnormal laboratory findings of the hematologic. respiratory. hepatic. and renal systems. Disease severity was related to older patient age. the presence of renal dysfunction. leukocytosis. and hypoalbuminemia. and previous therapy with sulfa antibiotics. CONCLUSIONS.--Infection by Rickettsia typhi causes a systemic illness with clinical and laboratory abnormalities not previously recognized or described. Early clinical diagnosis and treatment are needed to avoid undue morbidity and mortality.
The neonatal costs of maternal cocaine use, OBJECTIVE.--To examine the added neonatal cost and length of hospital stay associated with fetal cocaine exposure. DESIGN.--All cocaine-exposed infants in the study population (n = 355) were compared with a random sample of unexposed infants (n = 199). Regression analysis was used to control for the independent effects of maternal age. smoking. alcohol consumption. prenatal care. race. gravidity. and sex of the infant. SETTING.--A large. public. inner-city hospital studied from 1985 to 1986. PATIENTS.--All infants were routinely tested for illicit substances. records were reviewed for maternal histories of substance abuse. and all known cocaine-exposed singleton infants were included. MAIN OUTCOME MEASURES.--Cost and length of stay until each infant was medically cleared for hospital discharge and cost and length of stay until each infant was actually discharged from the hospital. RESULTS.--Neonatal hospital costs until medically cleared for discharge were $5200 more for cocaine-exposed infants than for unexposed infants (a difference of $7957 vs $2757 [P = .003]). The costs of infants remaining in the nursery while awaiting home and social evaluation or foster care placement increased this difference by more than $3500 (P less than .0001). Compared with other forms of cocaine. fetal exposure to crack was associated with much larger cost increases ($6735 vs $1226). Exposure to other illicit substances in addition to cocaine was also associated with much larger cost increases ($8450 vs $1283). CONCLUSIONS.--At the national level. we estimate that these individual medical costs add up to about $500 million. The large magnitude of these costs indicates that effective treatment programs for maternal cocaine abusers could yield savings within their first year of operation.
Evidence for major gene transmission of developmental dyslexia, OBJECTIVE.--There is strong evidence that developmental dyslexia is both familial and heritable. but the mode of genetic transmission has remained unclear. In this article. we examine specific genetic hypotheses about the mode of transmission of developmental dyslexia by performing complex segregation analyses. DESIGN.--A family study method was applied. whereby the relatives of dyslexic probands were examined for dyslexia. The families studied represent four independently ascertained samples. SETTING.--The four samples of families were primarily from rural and suburban communities of Colorado. Washington State. and Iowa. PARTICIPANTS.--A total of 204 families and 1698 individuals in the four samples combined. MAIN OUTCOME MEASURES.--The complex segregation program. POINTER. was used to test competing genetic hypotheses of how a categorical trait (dyslexia) is transmitted in families. RESULTS.--The results were consistent with major locus transmission in three of four samples and with polygenic transmission in the fourth. In these three samples. the estimates of penetrance for the AA. Aa. and aa genotypes (where A is the abnormal allele) were. respectively. 1.000. 1.000. and 0.001 to 0.039 in males. and 0.560 to 1.000. 0.550 to 0.897. and 0.000 in females. The estimated gene frequency of the major locus was between 3% and 5%. CONCLUSIONS.--Sex-influenced. additive. or dominant transmission occurs in a significant proportion of dyslexic families. Other evidence indicates. however. that dyslexia is etiologically heterogeneous and that there is genetic heterogeneity even among families selected for apparent dominant transmission. Thus. while no single major locus may account for all of dyslexia. it is important to pursue potential major loci for dyslexia using linkage techniques.
Group- vs home-based exercise training in healthy older men and women. A community-based clinical trial, OBJECTIVE.--To determine the effectiveness of group- vs home-based exercise training of higher and lower intensities among healthy. sedentary older adults. DESIGN.--Year-long randomized. controlled trial comparing (1) higher-intensity group-based exercise training; (2) higher-intensity home-based exercise training; (3) lower-intensity home-based exercise training; or (4) assessment-only control. SETTING.--General community located in northern California. PARTICIPANTS.--One hundred sixty women and 197 men 50 to 65 years of age who were sedentary and free of cardiovascular disease. One out of nine persons contacted through a community random-digit-dial telephone survey and citywide promotion were randomized. INTERVENTIONS.--For higher-intensity exercise training. three 40-minute endurance training sessions per week were prescribed at 73% to 88% of peak treadmill heart rate. For lower-intensity exercise training. five 30-minute endurance training sessions per week were prescribed at 60% to 73% of peak treadmill heart rate. MAIN OUTCOME MEASURES.--Treadmill exercise test performance. exercise participation rates. and heart disease risk factors. RESULTS.--Compared with controls. subjects in all three exercise training conditions showed significant improvements in treadmill exercise test performance at 6 and 12 months (P less than .03). Lower-intensity exercise training achieved changes comparable with those of higher-intensity exercise training. Twelve-month exercise adherence rates were better for the two home-based exercise training conditions relative to the group-based exercise training condition (P less than .0005). There were no significant training-induced changes in lipid levels. weight. or blood pressure. CONCLUSIONS.--We conclude that (1) this community-based exercise training program improved fitness but not heart disease risk factors among sedentary. healthy older adults; (2) home-based exercise was as effective as group exercise in producing these changes; (3) lower-intensity exercise training was as effective as higher-intensity exercise training in the home setting; and (4) the exercise programs were relatively safe.
The measles epidemic. The problems, barriers, and recommendations. The National Vaccine Advisory Committee, The nation has experienced a marked increase in measles cases during 1989 and 1990. Almost one half of all cases have occurred in unvaccinated preschool children. mostly minorities. The principal cause for the epidemic is failure to provide vaccine to vulnerable children on schedule. Major reasons for the low vaccine coverage exist within the health care system itself. which creates barriers to obtaining immunization and fails to take advantage of many opportunities to provide vaccines to children. Ideally. immunizations should be given as part of a comprehensive child health care program. However. immunization cannot await the development of such an ideal system. Essential changes can and should be made now. Specific recommendations include improved availability of immunization; improved management of immunization services; improved capacity to measure childhood immunization status; implementation of the two-dose measles vaccine strategy; and laboratory. epidemiologic. and operational studies to further define the determinants of decreased vaccine coverage and to develop new combinations of vaccines that can be administered earlier in life. The measles epidemic may be a warning flag of problems with our system of primary health care.
Tubuloglomerular feedback in obstructive uropathy, The tubuloglomerular feedback (TGF) mechanism was studied in rats with chronic partial ureteral occlusion (hydronephrosis) with the use of the stop-flow pressure techniques and measurements of single nephron glomerular filtration rate. In hydropenic conditions. TGF was normal in hydronephrotic kidneys. but TGF sensitivity and activity increased in response to extracellular volume expansion. which is the opposite of normal resetting. The increased sensitivity may be due to an increased production of thromboxane A2 in the hydronephrotic kidney. since both inhibition of thromboxane synthetase and blockade of thromboxane/prostaglandin endoperoxide receptors normalized the resetting during volume expansion. Pelvic pressure in hydronephrotic kidneys was low in hydropenia and increased moderately during volume expansion. Thromboxane synthesis inhibition before volume expansion allowed pelvic pressure to increase by more than 100% as compared with untreated hydronephrotics. Also. when pelvic pressure increases were prevented during volume expansion. TGF resetting was normalized. An increased thromboxane synthesis during volume expansion may be protective in hydronephrotic kidneys. in that TGF resets to a higher sensitivity to prevent increases in glomerular filtration rate and urine formation which otherwise would increase pelvic pressure. A resetting to a higher sensitivity was also elicited by intraarterial or intratubular administration of bradykinin. This suggests that thromboxane release may be mediated through an increased bradykinin production during volume expansion in hydronephrotics. In contrast. bradykinin resets TGF to a lower sensitivity in control kidneys.
Tubuloglomerular feedback in one-kidney, one-clip hypertensive rats, Previous studies have shown that hydropenic one-kidney. one-clip (1-K. 1-C) hypertensive HT rats exhibit impaired autoregulation of glomerular filtration rate (GFR) in response to reduced arterial perfusion pressure. We investigated the possible role of altered tubuloglomerular feedback (TGF) activity in this phenomenon. Uninephrectomized Wistar rats were studied acutely 3 weeks after placing silver clips (0.2 mm) on the renal artery. Experiments were performed in 1-K.1-C HT rats and in uninephrectomized control animals. TGF activity was assessed as changes in proximal tubule stop-flow pressure (SFP) in response to orthograde microperfusion from 0 to 80 nl/min into late proximal tubule segments. Only the highest perfusion rates (approximately 40 nl/min) into late proximal tubule segments resulted in maximal decreases in SFP. indicating a marked rightward shift of overall TGF activity in 1-K.1-C HT rats. Similar responses were observed in the uninephrectomized animals. In contrast. changes of SFP were observed at lower perfusion rates in normal animals and maximal responses were observed at perfusion rates of approximately 20 nl/min. These observations are consistent with the possibility that altered TGF activity contributes to impaired autoregulation of GFR in 1-K.1-C HT rats in response to reduced renal perfusion pressure. In response to treatment with i.v. captopril. the 1-K.1-C HT rats exhibited marked decreases in systemic arterial pressure associated with decreases in SFP and virtually complete inhibition of TGF activity. It is attractive to hypothesize that these alterations in TGF characteristics in the 1-K.1-C HT rats play a significant pathophysiologic role in the acute renal dysfunction observed in response to acute decreases of blood pressure during conditions of augmented angiotensin activity. Additional future studies will allow us to address the precise role for intrarenal angiotensin in these phenomena.
Endothelin effects on renal function and tubuloglomerular feedback, Analysis of our data in conjunction with other recent literature allows the following conclusions regarding the role of endothelin in the tubuloglomerular feedback control mechanism and in the pathogenesis of acute ischemic renal failure: (1) Endothelin reduces nephron filtration rate in the nephrons with interrupted signal perception at the macula densa. in accord with preglomerular arteriolar constriction. Yet. the increase in filtration fraction in the whole kidney clearance study suggests a preferential postglomerular arteriolar constriction. Taken together. endothelin. which is a very potent renal vasoconstrictor. seems to constrict both preglomerular and postglomerular arterioles with a predominant constriction of the latter at the doses employed. (2) The endothelin-induced natriuresis is due to a fall in tubular reabsorption. reflecting a direct tubular action. possibly related to an elevation in blood pressure. (3) At the doses of endothelin used and under the present experimental conditions. changes in the magnitude of tubuloglomerular feedback (TGF) response or the feedback characteristic could not be detected. (4) No evidence was found for a participation of endothelin in the pathogenesis of acute postischemic renal failure. as evidenced by the absence of an improvement in glomerular filtration after treatment with endothelin antiserum.
Hyperreactivity of tubuloglomerular feedback in chronically salt-loaded spontaneous hypertensive rats, In order to investigate the mechanisms of the hyperreactivity of the tubuloglomerular feedback (TGF) mechanism in spontaneous hypertensive rats (SHR) the resetting of TGF by chronic dietary NaCl loading was studied in SHR and normotensive Wistar Kyoto rats (WKY). This treatment is known to reset the TGF by an inhibitory factor in tubular fluid and not by alterations of the intrinsic characteristics of the juxtaglomerular apparatus (JGA). TGF reactivity. and its resetting. were determined by loop of Henle perfusion with artificial late proximal tubular fluid and with harvested endogenous tubular fluid respectively. Dietary effects of the high sodium intake were measured by means of the systolic blood pressure (SBP). plasma volume (PV). and renal sodium excretion. The 4-week dietary treatment had no significant influence on SBP in WKY. whereas it accelerated the rise of SBP in SHR significantly. After 1 week of treatment. PV was increased in both WKY and SHR as compared with the control groups kept on the normal diet. Whereas PV in WKY declined to control values over the next 3 weeks. SHR remained expanded. GFR was similar in all groups. whereas urinary sodium excretion was significantly increased in salt-loaded SHR and WKY. Dietary salt loading was paralleled by the appearance of a TGF-inhibiting substance in the tubular fluid in SHR and WKY. However. when assayed with artificial late proximal tubular fluid. hyperreactivity was similar in normal and salt-loaded SHR as compared with WKY. Thus. in SHR TGF hyperreactivity is maintained in spite of volume expansion and TGF resetting by a humoral factor in tubular fluid.
The evolution of single lung transplantation for emphysema. The Washington University Lung Transplant Group, Classic transplantation dogma mandated bilateral lung replacement for lung transplant candidates with end-stage emphysema to avoid air trapping in the native lung and subsequent crowding of the newly transplanted lung. During a recent 12-month period 11 patients with emphysema received a single lung transplant. There was no hospital mortality and only one patient had any notable degree of air trapping in the native lung. Substantial improvement in pulmonary function was seen as early as 2 weeks after transplantation. with significant functional improvement seen by 6 weeks. despite some residual ventilation-perfusion mismatch. We have demonstrated the utility and safety of single lung transplantation for patients with end-stage emphysema. and it is our operation of choice in recipients more than 50 years of age.
The influence of preoperative shock on outcome in sequential endocardial resection for ventricular tachycardia, Sequential endocardial resection was used in 92 consecutive patients to treat ventricular tachycardia. All patients had coronary artery disease with previous myocardial infarction. All patients had repeated cycles of mapping and resection of arrhythmogenic foci in the normothermic beating heart until ventricular tachycardia was no longer inducible. Eighty-six patients (93%) survived to hospital discharge. The survival rate in patients normotensive at the time of operation was 98% and in patients in shock at the time of operation. 43%. By Cox regression analysis. preoperative shock was the significant predictor (p less than 0.001) of operative mortality. Seventy-four of the 86 operative survivors (86%) had no sustained ventricular tachycardia at initial postoperative electrophysiologic study when receiving no antiarrhythmic drugs. Eighty-three of the 86 operative survivors (97%) had no sustained ventricular tachycardia at final postoperative electrophysiologic study when using antiarrhythmic drugs as needed. After a median follow-up of 21 months (range 1 to 79 months) there were 4 sudden cardiac deaths. 12 other cardiac deaths. and 3 noncardiac deaths. There were no documented nonfatal episodes of sustained monomorphic ventricular tachycardia after hospital discharge. Use of the sequential endocardial resection technique is effective in curing ventricular tachycardia with low operative morbidity and mortality.
Pediatric heart transplantation after operations involving the pulmonary arteries, A prohibitive perioperative mortality has been previously ascribed to pediatric heart transplantation after palliative operations for congenital heart disease involving the pulmonary arteries. Of 46 children who have undergone heart transplantation at our institution between June 1984 and February 1990. 7 (15%; mean age 8 +/- 3 years; range 1 to 18 years) have previously undergone such operations: right ventricle to pulmonary artery conduit/homograft for levo-transposition of the great arteries (2). Waterston shunt for tricuspid and pulmonary atresia (1). pulmonary artery banding for single ventricle (1). Fontan procedure for single ventricle (1). first-stage Norwood procedure for hypoplastic left heart syndrome (1). and classic right Blalock-Taussig shunt for atrioventricular canal with pulmonic stenosis (1). Three categories of pulmonary artery anatomy that require different approaches to reconstruction at the time of transplantation are recognized: abnormalities of position. pulmonary outflow obstruction. and previous systemic- or atrial-pulmonary connections. At operation. individualized pulmonary arterial reconstruction was employed. including use of previously created right ventricular-pulmonary artery conduits/homografts and angioplasty (with and without pericardial patches). Transplantation was successful in all patients. Posttransplant right ventricular-pulmonary artery pressure gradients and pulmonary vascular resistance indices were acceptable. with a tendency to decrease with time. Two patients had critical right ventricular failure postoperatively; one of them required support with extracorporeal membrane oxygenation. There was no perioperative mortality. with three deaths occurring from 5 to 39 months after transplantation. All surviving patients are in New York Heart Association functional class I. Techniques borrowed from the repair of congenital cardiac lesions can be applied to subgroups of children undergoing heart transplantation. Additional length of donor aorta and pulmonary artery should be harvested for possible use in designing pulmonary artery connections. Previous palliative operations involving the pulmonary arteries with associated complex pulmonary artery anatomy are not of themselves an insurmountable obstacle to successful heart transplantation.
St. Thomas' Hospital cardioplegic solution. Beneficial effect of glucose and multidose reinfusions of cardioplegic solution, The intention of this study was to determine whether glucose is beneficial in a cardioplegic solution when the end products of metabolism produced during the ischemic period are intermittently removed. The experimental model used was the isolated working rat heart. with a 3-hour hypothermic 10 degrees C cardioplegic arrest period. Cardioplegic solutions tested were the St. Thomas' Hospital No. 2 and a modified Krebs-Henseleit cardioplegic solution. Glucose (11 mmol/L) was beneficial when multidose cardioplegia was administered every 30 minutes. Including glucose in Krebs-Henseleit cardioplegic solution improved postischemic recovery of aortic output from 57.0% +/- 1.8% to 65.8% +/- 2.2%; p less than 0.025. The addition of glucose to St. Thomas' Hospital No. 2 cardioplegic solution improved aortic output from 74.6% +/- 1.9% to 87.4% +/- 1.9%; p less than 0.005. Furthermore. a dose-response curve showed that a glucose concentration of 20 mmol/L gave no better recovery than 0 mmol/L. and glucose in St. Thomas Hospital No. 2 cardioplegic solution was beneficial only in the range of 7 to 11 mmol/L. In addition. we showed that multidose cardioplegia was beneficial independent of glucose. Multidose St. Thomas' Hospital No. 2 cardioplegia. as opposed to single-dose cardioplegia. improved aortic output recovery from 57.4% +/- 5.2% to 74.6% +/- 1.9%; p less than 0.025. and with St. Thomas' Hospital No. 2 cardioplegic solution plus glucose (11 mmol/L) aortic output recovery improved from 65.9% +/- 2.9% to 87.4% +/- 1.9%; p less than 0.005. Hence. at least in this screening model. the St. Thomas' Hospital cardioplegic solution should contain glucose in the range of 7 mmol/L to 11 mmol/L. provided multidose cardioplegia is given. We cautiously suggest extrapolation to the human heart. on the basis of supporting clinical arguments that appear general enough to apply to both rat and human metabolisms.
Resection of residual mediastinal germ cell masses with the Cavitron ultrasonic surgical aspirator, Residual mediastinal masses after chemotherapy for germ cell tumors should be resected. Complete excision of bulky residual masses may sometimes be difficult because of problems with exposure in the region of the great vessels and important nerves. Two cases are presented in which the Cavitron ultrasonic surgical aspirator (Valleylab Inc.. Surgical Systems Division. Stamford. Conn.) facilitated excision of large masses after intensive chemotherapy. We found that the collapsed pseudocapsule remaining after aspiration of tumor mass allowed early improved exposure and safer dissection from neighboring vessels and neural structures. Complete excisions were accomplished and no viable tumor was found. so that the patients were spared the immediate need for further therapy. Both had uneventful recoveries.
Atherogenic effect of barotrauma on in situ saphenous veins in monkeys, The objectives of this study were to determine whether veins subjected to barotrauma in situ undergo lipid uptake and morphologic changes to the same extent as veins grafted into the arterial circulation. Saphenous veins in seven stump-tailed macaque monkeys were exposed bilaterally and were circumferentially dissected free from surrounding tissue only at isolated sites. Segments of the veins were distended for 1 minute at hydrostatic pressures of 125 or 350 mm Hg. An undistended segment served as control. A cephalic vein graft was interposed in the femoral artery for comparison with in situ veins. The animals were fed a diet that sustains plasma cholesterol levels of approximately 225 mg/dl. Saphenous veins and the cephalic vein grafts were explanted at 3 months for biochemical and histologic analyses. Cholesterol content in undistended saphenous veins was similar to that in veins distended at 125 or 350 mm Hg--105 +/- 15. 122 +/- 14. and 109 +/- 30 micrograms/100 mg wet tissue weight. respectively. Cholesterol content in cephalic vein grafts. 473 +/- 122 micrograms/100 mg. was greater (p less than 0.001) than in saphenous veins at all distention pressures studied. There was no difference among the distention pressures in the intimal fraction of saphenous vein wall. with the pooled value being 20% +/- 12%. This contrasted with the value of 59% +/- 11% in cephalic vein grafts (p less than 0.01). Endothelial coverage of the luminal surface in saphenous veins was similar among the levels of barotrauma. with the pooled value being 83% +/- 15%. Less of the lumen was covered with endothelium in cephalic vein grafts. 46% +/- 18% (p less than 0.01). Slightly more medial fibrosis was observed in cephalic vein grafts as compared with saphenous veins (p less than 0.05). These data demonstrate that barotrauma alone does not cause veins that remain in the venous system to undergo the lipid uptake or morphologic changes that occur in veins grafted into the arterial circulation in nonhuman primates.
Clinical and electrophysiological aspects of acute paralytic disease of children and young adults in northern China, Acute peripheral nervous system diseases leading to paralysis in children are rare in Europe and the USA. whereas epidemics of a Guillain-Barre-like syndrome occur annually among children in rural parts of northern China. To clarify the features of this disorder 36 patients. aged 15 months to 37 years (median 7) with this syndrome were investigated; 91% were from rural areas. In 47%. a prodromal illness was reported in the preceding 4 weeks. Leg weakness and resistance to neck flexion were the earliest symptoms. The weakness ascended rapidly and symmetrically to affect the arms and respiratory muscles. with maximum weakness occurring a mean of 6 days after onset of weakness. Bulbar weakness occurred in 61% of patients. but only 1 had extraocular paresis. Respiratory assistance was needed by 31% of patients. Tendon reflexes were lost as weakness developed. 42% of patients had raised concentrations of protein in the cerebrospinal fluid. and the mean cell count was 3 cells/microliters (range 0-12/microliters). Electrodiagnostic studies in 22 patients showed severe reductions in motor evoked amplitudes from distal stimulation. Sensory action potentials were normal. Electromyography revealed denervation potentials in limb muscles. The distinctive epidemiological. clinical. and neurophysiological characteristics of this illness suggest that the disorder is different from both Guillain-Barre syndrome and poliomyelitis. The neurophysiological findings support the hypothesis that the disorder is a reversible distal motor nerve terminal or anterior horn cell lesion.
Heparin treatment in sinus venous thrombosis, Treatment of sinus venous thrombosis (SVT) is controversial. Although heparin has been used for this condition. many investigators have opposed its use because of the frequent occurrence of intracranial haemorrhage (ICH) and SVT. Therefore we have evaluated anticoagulation with adjusted-dose intravenous heparin for treatment of aseptic SVT in a randomised. blinded (patient and observer). placebo-controlled study in 20 patients (10 heparin. 10 placebo). The clinical course of the two groups. as judged by a newly designed SVT-severity scale. started to differ in favour of the heparin group after 3 days of treatment (p less than 0.05. Mann-Whitney U-test) and the difference remained significant (p less than 0.01) after 8 days of treatment. After 3 months. 8 of the heparin-treated patients had a complete clinical recovery and 2 had slight residual neurological deficits. In the placebo group. only 1 patient had a complete recovery. 6 patients had neurological deficits. and 3 patients died (p less than 0.01. modified Fisher's exact test). An additional retrospective study on the relation between heparin treatment and ICH in SVT patients was based on 102 patients. 43 of whom had an ICH. 27 of these patients were treated with dose-adjusted. intravenous heparin after the ICH. Of these 27 patients. 4 died (mortality 15%). and 14 patients completely recovered. Of the 13 patients that did not receive heparin after ICH. 9 died (mortality 69%) and only 3 patients completely recovered. We conclude that anticoagulation with dose-adjusted intravenous heparin is an effective treatment in patients with SVT and that ICH is not a contraindication to heparin treatment in these patients.
Pilot study of screening for prostate cancer in general practice, The success of a screening programme for cancer depends on the sensitivity of the tests used and on the proportion of the target population that comes forward for screening. To assess the value of digital rectal screening and prostate-specific antigen (PSA) measurement as screening measures. the 814 men in a city general practice aged between 55 and 70 were recruited in one of five different ways. Men with a palpably suspicious prostate or a serum PSA greater than 4 ng/ml were referred for transrectal ultrasonography and. if indicated. biopsy. 472 men (58%) were screened; of these 68 underwent transrectal ultrasonography and 29 biopsy. In 7 the biopsy specimen showed carcinoma. Serum PSA was better than digital examination as a screening test--all men with prostate cancer had raised concentrations of serum PSA. whereas only 1 had a palpably abnormal prostate. All 7 had localised disease. and 5 underwent radical prostatectomy. The best methods of patient recruitment were to send an appointment for screening and to "tag" the patient's notes.
Contractile properties of the human diaphragm during chronic hyperinflation, BACKGROUND. In patients with chronic obstructive pulmonary disease (COPD) and hyperinflation of the lungs. dysfunction of the diaphragm may contribute to respiratory decompensation. We evaluated the contractile function of the diaphragm in well-nourished patients with stable COPD. using supramaximal. bilateral phrenic-nerve stimulation. which provides information about the strength and inspiratory action of the diaphragm. METHODS. In eight patients with COPD and five control subjects of similar age. the transdiaphragmatic pressure generated by the twitch response to phrenic-nerve stimulation was recorded at various base-line lung volumes. from functional residual capacity to total lung capacity. and during relaxation and graded voluntary efforts at functional residual capacity (twitch occlusion). RESULTS. At functional residual capacity. the twitch transdiaphragmatic pressure ranged from 10.9 to 26.6 cm of water (1.07 to 2.60 kPa) in the patients and from 19.8 to 37.1 cm of water (1.94 to 3.64 kPa) in the controls. indicating considerable overlap between the two groups. The ratio of esophageal pressure to twitch transdiaphragmatic pressure. an index of the inspiratory action of the diaphragm. was -0.50 +/- 0.05 in the patients. as compared with -0.43 +/- 0.02 in the controls (indicating more efficient inspiratory action in the patients than in the controls). At comparable volumes. the twitch transdiaphragmatic pressure and esophageal-to-transdiaphragmatic pressure ratio were higher in the patients than in normal subjects. indicating that the strength and inspiratory action of the diaphragm in the patients were actually better than in the controls. Twitch occlusion (a measure of the maximal activation of the diaphragm) indicated near-maximal activation in the patients with COPD. and the maximal transdiaphragmatic pressure was 106.9 +/- 13.8 cm of water (10.48 +/- 1.35 kPa). CONCLUSIONS. The functioning of the diaphragms of the patients with stable COPD is as good as in normal subjects at the same lung volume. Compensatory phenomena appear to counterbalance the deleterious effects of hyperinflation on the contractility and inspiratory action of the diaphragm in patients with COPD. Our findings cast doubt on the existence of chronic fatigue of the diaphragm in such patients and therefore on the need for therapeutic interventions aimed at improving diaphragm function.
The B-cell antigen receptor of the five immunoglobulin classes, Several proteins associate with surface IgM to form the antigen receptor. We show that just two. the alpha and beta associated chains. are sufficient to reconstitute an IgM surface receptor in fibroblasts. Contrary to expectation. a common alpha chain associates with all five immunoglobulin classes. We propose that B-cell antigen receptors consist of a common alpha/beta heterodimer associated with each immunoglobulin class. But the classes differ both in the glycosylation of their associated alpha chain and in their dependence on alpha/beta for surface transport.
Is colour vision possible with only rods and blue-sensitive cones, At night all cats are grey. but with the approach of dawn they take on colour. By starlight. a single class of photoreceptors. the rods. function. whereas by daylight. three classes. the blue-. green- and red-sensitive cones. are active and provide colour vision. Only by comparing the rates of quantal absorption in more than one photoreceptor class is colour vision possible. Although the comparisons generally take place between the cones. they can involve the rods as well. Here we investigate the wavelength discrimination of an extremely rare group of individuals. blue-cone monochromats. who have only rods and one class of cones. We find that these individuals can distinguish wavelengths (440 to 500 nm) in the twilight region where the rods and blue-sensitive cones are simultaneously active.
Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs, Duchenne's muscular dystrophy (DMD). which affects one in 3.500 males. causes progressive myopathy of skeletal and cardiac muscles and premature death. One approach to treatment would be to introduce the normal dystrophin gene into diseased muscle cells. When pure plasmid DNA is injected into rodent skeletal or cardiac muscle. the cells express reporter genes. We now show that a 12-kilobase full-length human dystrophin complementary DNA gene and a 6.3-kilobase Becker-like gene can be expressed in cultured cells and in vivo. When the human dystrophin expression plasmids are injected intramuscularly into dystrophin-deficient mdx mice. the human dystrophin proteins are present in the cytoplasm and sarcolemma of approximately 1% of the myofibres. Myofibres expressing human dystrophin contain an increased proportion of peripheral nuclei. The results indicate that transfer of the dystrophin gene into the myofibres of DMD patients could be beneficial. but a larger number of genetically modified myofibres will be necessary for clinical efficacy.
Randomized, double-blind trial of deflazacort versus prednisone in juvenile chronic (or rheumatoid) arthritis: a relatively bone-sparing effect of deflazacort, Thirty-four children with juvenile chronic (rheumatoid) arthritis were recruited to a randomized. double-blind study of deflazacort (an oxazolone derivative of prednisone) vs prednisone. All had been receiving glucocorticoid therapy for at least 1 year and required at least 5 mg/d of prednisolone (usually as 10 mg every 2 days). Thirty-one children completed the study. Bone density trends were measured in the spine by dual photon absorptiometry and in the forearm by single photon quantitative computed tomography at 3-monthly intervals. Trends (velocities) in bone and soft tissue growth were calculated. In the spine. bone growth correlated well with indices of soft tissue growth. but covariance analysis showed a significant advantage (P less than .007) of deflazacort when spinal bone mineral growth was compared to body surface area and weight. In part this was due to a temporary interruption in weight by children receiving deflazacort. whose gain in height was comparable with that of the prednisone group. Some children in both groups improved clinically and showed catch-up growth; in these children relative spinal bone mineral growth velocities were about twice those observed for height and weight. It is concluded that during the first year of deflazacort. their spinal bone mineral content at a level that was appropriate for their height and weight. Further observations are required to establish whether this advantage can be maintained subsequently. The anti-inflammatory effects of the two glucocorticoids appeared similar.
The infant with acute, unexplained, excessive crying, This study describes 56 infants who presented to the Emergency Department of The Children's Hospital of Denver during a 1-year period with an episode of excessive. prolonged crying. without fever and without a cause that was apparent to the parents. The final diagnoses included a broad array of conditions. of which 61% were considered serious. The history provided clues to the final diagnosis in 20% of cases. Physical examination revealed the final diagnosis in 41% and provided clues to the diagnosis in another 13%. Accurate diagnosis requires a thorough physical examination. which should include careful skin inspection underneath all clothing. palpation of all large bones. fluorescein staining of the cornea. eversion of eyelids. rectal examination. retinal examination. and thorough neurologic examination. "Screening" laboratory tests. except for urinalysis and urine culture. were of little help. This study indicates that for those patients in whom the physical examination is not diagnostic. the persistence of excessive crying after the initial examination predicts the presence of a serious cause. Those infants who cease crying before or during the initial assessment are unlikely to have a serious cause. Recommendations for a stepwise assessment are offered.
Use of western blot and enzyme-linked immunosorbent assays to assist in the diagnosis of Lyme disease, Without evidence of erythema chronicum migrans. diagnostic confirmation of Lyme disease may be difficult. particularly if there are conflicting laboratory results. Often. for families and physicians. the clinical dilemma is whether fatigue. arthritis/arthralgias. a positive enzyme-linked immunosorbent assay (ELISA). and tick exposure. but no evidence of erythema chronicum migrans. are sufficient to diagnose and treat Lyme disease. Patients with discordant ELISA and Western blot (WB) assay results for Borrelia burgdorferi were studied to determine whether there was sufficient clinical evidence to support a diagnosis of Lyme disease. Of 650 consecutive sera analyzed by ELISA in a laboratory within a 1-year period. 77 were subsequently tested by WB. The clinical data from these patients were then analyzed. The study population was divided into three groups: group 1 (positive ELISA. positive WB). group 2 (positive ELISA. negative WB). and group 3 (negative ELISA. negative WB). Findings included the following: (1) Patients with a strong clinical history of Lyme disease were usually positive by both WB and ELISA (group 1). (2) All patients with erythema chronicum migrans had both positive WB and ELISA tests. (3) Ninety-one percent of group 2 had a rheumatic or inflammatory condition other than Lyme disease. (4) A definite response to antibiotics occurred in 75% of patients wherein both ELISA and WB were positive but in only 11% of cases with a positive ELISA but a negative WB. (5) History of tick exposure and degree of fever were not significantly different among the three serologic groups. and thus they were not diagnostically helpful.
Long-bone fractures in young children: distinguishing accidental injuries from child abuse, While testifying in child abuse cases. physicians have been frustrated by the lawyer who asks. "Doctor. how did this injury happen?" The medical records and radiographs of 215 children younger than the age of 3 with fractures evaluated by a pediatric service during a 5-year period were retrospectively reviewed in an attempt to elucidate the mechanism of childhood fractures. Based on these reviews. two clinicians and two pediatric radiologists rated the likelihood that the fracture was either accidental or due to child abuse. Long-bone fractures were strongly associated with abuse. This report focuses on the 39 children with either humeral or femoral fractures. Fourteen children had humerus fractures. Eleven were considered to be the result of child abuse. and 3 the result of accidents. The latter 3 were supracondylar elbow fractures in children who fell from a tricycle. a rocking horse. or downstairs. Humerus fractures other than supracondylar fractures were all found to be due to abuse. There were 25 femur fractures. Nine were found to be from abuse. 14 were found to be from accidents. and 2 could not be rated. Sixty percent of femur fractions in infants younger than 1 year of age were due to abuse. Although it is taught that femur fractures in young children are inflicted unless proven otherwise. in this study it was found that femur fractures often are accidental and that the femur can be fractured when the running child trips and falls.
Perinatal cocaine effects on neonatal stress behavior and performance on the Brazelton Scale, Fifty-two newborns were assessed for the effects of maternal cocaine use on their performance on the Brazelton Neonatal Behavior Assessment Scale and on their stress behaviors during the Brazelton as tapped by the Neonatal Stress Scale. The cocaine-exposed newborns experienced more obstetric complications. had smaller head circumferences. showed more limited habituation abilities on the Brazelton Scale. and exhibited more stress behaviors than control newborns.
Long-term mental health effects of a pediatric home care program, The increased survival of youngsters with chronic physical disorders has led to concern about their long-term psychological adjustment. Few data are available on how to reduce the psychological morbidity that occurs in the presence of chronic childhood illness. An earlier report of a randomized controlled trial of a pediatric home care program demonstrated that this program. combining comprehensive biomedical and psychosocial care. reduced the short-term psychological morbidity of those receiving home care. However. data have not previously been available on whether the short-term improvement in adjustment is associated with any long-term benefits. This report presents long-term follow-up data collected 4 1/2 to 5 years after enrollment on 68% of the original sample. After this interval there were even larger differences between the experimental and control groups than those previously observed at 6 months and 1 year. This finding provides strong evidence that a comprehensive family-oriented outreach program for youngsters with chronic physical disorders can have long-term mental health benefits. It should encourage clinicians to develop similar programs and investigators to look for long-term effects of other interventions.
Who benefits from a pediatric home care program?, Earlier reports of a randomized controlled trial of the Pediatric Home Care (PHC) program for children with chronic physical illness demonstrated overall benefits for the group enrolled in the PHC program. This paper examines which subgroups benefited most (relative to control subjects) and which benefited least from the PHC intervention. Prior to the randomized controlled trial. PHC served those with the most burdensome medical conditions from the families with the fewest coping resources. However. data from the randomized controlled trial (N = 219) show that these were not the subjects who benefited most. Maximal benefit was evident when illness burden was small. but coping resources were low (social. educational. financial. and personal). Analyses of covariance show that subjects in PHC with both low burden and low resources had consistently better outcomes than similar subjects in Standard Care. When the illness burden was similarly low. but resources were more abundant. those in Standard Care appear to have had better outcomes than those in PHC. For those whose illness burden was more severe. the results were mixed. These findings suggest that the conventional priority of allocating existing intervention resources to the medically most burdensome cases may not always be maximally beneficial. Those with less burdensome conditions may derive greater benefit relative to control subjects from an intervention than those with extreme needs. Both medical and social factors should enter into the decision regarding the allocation of scarce resources.
Informational needs of parents of sick neonates, Sixty-one parents of 43 neonates in a neonatal intensive care unit were interviewed within 3 days of their first conference with the neonatologist to assess their needs for medical information. The conference with the physician and the interview with the investigator were audiotaped. Information given by the physician and information recalled by the parents was categorized and rated by the investigator. The physicians gave very detailed information about diagnosis in 77% of cases whereas 39% of the parents recalled diagnostic information in great detail. Respective percentages for prognosis were 16 and 33; for current management (eg. investigation. therapy). 28 and 66; and for cause of illness. 16 and 18. The statistical significance of the differences between the very detailed information int he physician-parent conferences and in the parent-investigator interviews was. by category. less than .002. less than .041. less than .004. and not significant. respectively. Information in the respective categories was described as "most helpful" by 20%. 67%. 90%. and 8% of parents. All but one of the parents stated that they wanted the whole truth. Physician uncertainty in providing information was significantly associated with severity of illness. It is concluded that while parents wanted information in all categories. they paid most attention to that relating to management. Physician-parent discordances with respect to information about management. diagnosis. and prognosis suggest directions for future investigation of the optimal content of information for parents in this context.
Six-year follow-up of early physiotherapy intervention in very low birth weight infants, Eighty very low birth weight infants assigned to neurologically normal or at-risk groups on the basis of a neurodevelopmental score were previously described. Infants were assigned to physiotherapy or control groups. and the effect of physiotherapy was assessed at 1 year. At-risk infants had a significantly lower developmental quotient than the normal group and no beneficial effect of physiotherapy was shown. Of the original 80 subjects. 49 were reassessed at a mean age of 74.7 months. As observed previously. physiotherapy until 1 year did not influence subsequent outcome in either normal or at-risk children. At-risk and normal children had similar mean developmental quotients at 6 years. but the locomotor score of at-risk children was significantly below that of normal children. Cerebral palsy occurred in 6 of 24 at-risk vs 0 of 25 normal subjects (P less than .01) and remedial therapy was recommended in 17 of 24 at-risk subjects vs 6 of 25 normal subjects (P less than .001). These results confirm that the neurodevelopmental score predicts a risk for either cerebral palsy or soft neurological problems. and early physiotherapy is of questionable benefit in preventing such problems.
Morbidity estimates of conditions originating in the perinatal period: United States, 1986 through 1987, Morbidity estimates of conditions originating in the perinatal period have not been reported in the United States. Conditions originating in the perinatal period were identified according to the International Classification of Diseases. The National Hospital Discharge Survey provided a weighted. nationally representative sample of newborns discharged each year from short-stay. nonfederal hospitals. From 1986 through 1987. 33.7% of all newborns had at least one nonteratologic perinatal condition. However. 6.8% of all newborns had physiologic jaundice as their only discharge diagnosis. Nonphysiologic jaundice was diagnosed in 4.4%. maternal causes of perinatal morbidity in 3.1%. birth trauma in 2.5%. fetal distress in 2.3%. birth asphyxia in 2.1%. and infections specific to the perinatal period in 2.0% of all newborn discharges. The average hospital stay for all newborns was 3.5 days. but it was 5.3 days for newborns with at least one nonteratologic perinatal condition and 2.6 for newborns discharged without a morbid condition. This study provides nationally representative estimates of perinatal morbidity useful for comparisons with smaller hospital-based samples. In addition. the study provides estimates of the public health impact of these conditions in terms of hospital stay days.
Tap water burn prevention: the effect of legislation, Five years after a 1983 Washington State law required new water heaters to be preset at 49 degrees C (120 degrees F). 77% of homes (84% of homes with postlaw and 70% of homes with prelaw water heaters) had tap water temperatures of less than 54 degrees C. In 1977. 80% of homes had tap water temperatures greater than 54 degrees C. Mean temperature in 1988 was 50 degrees C compared with 61 degrees C in 1977. Both changes were significant compared with 1977 temperatures. Few people increased their heater temperature after installation. Eighteen burn victims were identified from July 1979 through May 1988. for an average admission rate of 2.4 per year. compared with 5.5 per year in the 1970s. Compared with the 1970s. total body surface area burned. mortality. grafting. scarring. and length of hospital stay were all reduced. while the likelihood that scald burns were the result of child abuse increased to 50%. Both education campaigns and legislation have resulted in significantly safer water temperatures. Further. this change seems to have resulted in a reduction in frequency. morbidity. and mortality of tap water burn injuries in children. Lower water heater settings proved acceptable to the consumer.
Factors influencing the epidemiology of Helicobacter pylori infection in children, The epidemiology of Helicobacter pylori infection was studied in 245 healthy children (between 3 and 20 years of age) who presented for day surgery at Arkansas Children's Hospital. H pylori infection was identified serologically using an enzyme-linked immunosorbent assay to detect the presence of IgG against the high molecular weight. cell-associated antigens of H pylori. Demographic information collected included age. gender. race. family income. type of housing. location of housing. water supply. health status. upper gastrointestinal symptoms. and keeping pets. One hundred eighty-nine white children and 56 black children were studied; 139 were boys and 106 were girls. The data were analyzed by logistic regression analysis. H pylori infection increased significantly with age (P less than .05). The frequency of H pylori infection was higher in blacks than whites (P less than .01). and this difference remained after adjusting for age. gender. and family income. Family income was used as a measure of socioeconomic class and was an important factor related to infection; the rate of acquisition of H pylori in those children with family income less than +5000/year was twice that of those with incomes greater than +75.000/year (P less than .001). There were no significant differences in H pylori infection related to gender. type of housing. location of housing. or source of water supply. It is concluded that the rate of acquisition of H pylori infection increases with age. is higher in blacks than whites. and is inversely related to socioeconomic class.
Immunogenicity of subcutaneous versus intramuscular Oka/Merck varicella vaccination in healthy children, To compare the immunogenicity and safety of varicella vaccine by either subcutaneous or intramuscular injection. 166 healthy children aged 12 months to 10 years old who had no prior history of varicella were enrolled from two pediatric practices and randomly assigned to receive 0.5 mL of a single lot of varicella vaccine. Sera from the day of and 6 weeks postvaccination were tested for varicella antibody by gpELISA. Parents recorded clinical events occurring in the 6 weeks following vaccination. In the 132 evaluable children. the mean prevaccination titer was 0.3 gpELISA units for both groups. Sixty-three (97%) of the 65 receiving varicella vaccine by the subcutaneous route seroconverted compared with 67 (100%) of 67 immunized intramuscularly. Postvaccination geometric mean titer in the subcutaneous group was 6.9 +/- 7.0 gpELISA units and did not differ significantly from the geometric mean titer of 10.5 +/- 4.4 in the intramuscular group. Varicella vaccine was generally well tolerated by either route; 21% of both groups complained of reactions at the injection site and 7% had a varicella-like rash. Although varicella vaccine is recommended to be given subcutaneously. the results of this study indicate that inadvertent intramuscular administration of varicella vaccine is not reason for revaccination.
Myocardial rupture. Your patient's survival may depend on you, Myocardial rupture is the second leading cause of in-hospital death from acute myocardial infarction. It is most likely to occur in the elderly. women. and patients with transmural infarction and no previous history of angina. A high index of suspicion is critical to the diagnosis. Myocardial rupture should be suspected when recurrent chest pain or hemodynamic instability develops after myocardial infarction. Rapid intervention and appropriate infarct-limiting therapy may reduce the mortality rate of this catastrophic complication.
How to diagnose bleeding disorders, Patients with problems of hemostasis are not uncommon in the primary care setting. The bleeding history provides critical information that helps in guiding evaluation of these patients. Results of frequently used screening tests of coagulation can be abnormal in patients who have no significant hemostatic defect and can be normal in patients who do have one.
Carotid and coronary atherosclerosis. What are the connections, In recent years research has revealed an association between carotid atherosclerosis and coronary atherosclerosis that parallels the long-recognized association between clinically manifest cerebrovascular disease and clinically manifest coronary artery disease (CAD). Validation of B-mode ultrasonography as a method for quantitative imaging of the extracranial carotid arteries has made it possible to identify risk factors for extracranial carotid atherosclerosis and its progression and to test pharmacologic agents for their ability to retard that progression. Extent of atherosclerosis in the extracranial carotid arteries has been shown to be a risk factor or "marker" for symptomatic CAD. In addition. CAD has been identified as an important predictor of progression of extracranial carotid atherosclerosis.
Fecal occult blood testing. Guidelines for follow-up after positive findings, Fecal occult blood testing should be performed under optimal conditions to minimize false-positive test results. Obvious bleeding from the rectum or other sources during the test period should be investigated and testing should be postponed. When a fecal occult blood test is positive. colonoscopy is recommended as the definitive method of diagnosis and often of treatment. When a complete colonoscopy cannot be performed. sigmoidoscopy with air-contrast barium enema is the next best alternative for direct visualization of the distal bowel and indirect investigation of the proximal colon.
Hypertension in young patients, Hypertension is often unrecognized in infants and children. Primary care physicians need the equipment necessary to measure blood pressure in young patients and tables or graphs showing normal values for age and sex. Children should have a blood pressure measurement and preventive counseling at each yearly checkup. Significant hypertension should never be dismissed as a temporary problem but rather should be carefully investigated. treated. and followed up.
Septic shock. When patients fail to respond to conventional therapy, Patients in septic shock require rapid evaluation and prompt initiation of therapy with appropriate antibiotics and fluids. When fluids do not restore perfusion. dopamine (Dopastat. Inotropin) therapy is begun. Some patients who fail to respond to these measures will respond to a combination of low-dose dopamine and regulation of blood pressure with norepinephrine (Levophed).
Common triggers of asthma, Control of asthma is enhanced when careful consideration is given to underlying mechanisms. Patients can be advised of ways to avoid or minimize contact with offending allergens. and. in some cases. pharmacologic management may not be necessary. Care must be taken when treating patients with concomitant disorders. such as hyperthyroidism. Also. psychological factors may have a role in exacerbating symptoms in suggestible patients. Noncompliance. in some cases due to inability to pay for medication. may be an unrecognized cause of treatment failure.
Acute life-threatening asthma, Although adrenergic therapy may be lifesaving in patients with severe acute asthma. attention must also be directed toward reversing underlying inflammation with corticosteroids. Other therapy for acute severe bronchospasm is controversial. although inhalant anticholinergic therapy may have adjunctive benefit. Aminophylline or magnesium sulfate may be indicated in those patients with life-threatening asthma who do not respond to conventional therapy. Chest radiographs are needed in patients who (1) present in extreme distress. (2) need to be hospitalized. or (3) have clinical manifestations of pneumonia or pneumothorax. Antibiotics are not used for acute asthma in the absence of pneumonia.
Rehabilitation of asthmatic patients. Motivating your patients to improve their life-style, Complete rehabilitation of asthmatic patients requires consideration of their medication use. psychological adjustment. and quality of life and their family's adaptation to chronic disease. Physicians can significantly improve their patients' well-being by encouraging them to achieve and maintain a maximal level of fitness and to stop smoking. Motivation and support for smoking cessation should be available through office-based programs and follow-up. With pretreatment for vigorous sports. asthmatic patients should be able to participate in nearly any activity.
Inhibition of interferon-inducible gene expression by adenovirus E1A proteins: block in transcriptional complex formation, Infection with wild-type adenovirus 5. but not with a mutant lacking the E1A gene. prevented the induction by interferon (IFN) alpha of chloramphenicol acetyltransferase (CAT) activity in HeLaM cell lines that had been permanently transfected with chimeric CAT reporter genes driven by the transcriptional regulatory regions of the IFN-responsive genes 561 and 6-16. Similar inhibition of IFN-inducible CAT activity was observed in cells that were cotransfected with the same reporter genes and plasmids expressing either the E1A 289- or 243-amino acid protein. These proteins also prevented the induction of CAT activity by IFN-gamma from a cotransfected HLA-DR alpha-CAT gene. Experiments with E1A mutants mapped the inhibitory activity to amino acid residues 38-65 of these proteins. In a HeLa cell line permanently expressing the E1A 289-amino acid protein. the replication of vesicular stomatitis virus and encephalomyocarditis virus was not inhibited by IFN-alpha. suggesting a global blockade of IFN responses. In accord with this theory. induction of 561. 1-8. and (2'-5')oligoadenylate synthetase mRNAs by IFN was blocked in these cells at the transcriptional level. The observed transcriptional inhibition could be attributed to the lack of formation of the crucial IFN-stimulated gene factor 3 (ISGF3) transcriptional complex. As shown by mobility shift assays. this complex was not formed in the nuclear extracts of IFN-treated adenovirus-infected cells or IFN-treated E1A-producing cells. These nuclear extracts were deficient in both ISGF3 alpha and ISGF3 gamma subunits. However. they did not block the formation of ISGF3 complex from exogenously added components.
cAMP-inducible chloride conductance in mouse fibroblast lines stably expressing the human cystic fibrosis transmembrane conductance regulator, A cAMP-inducible chloride permeability has been detected in mouse fibroblast (L cell) lines upon stable integration of a full-length cDNA encoding the human cystic fibrosis transmembrane conductance regulator (CFTR). As indicated by a Cl(-)-indicator dye. the Cl- permeability of the plasma membrane increases by 10- to 30-fold within 2 min after treatment of the cells with forskolin. an activator of adenylyl cyclase. The properties of the conductance are similar to those described in secretory epithelial cells; the whole-cell current-voltage relationship is linear and there is no evidence of voltage-dependent inactivation or activation. In contrast. this cAMP-dependent Cl- flux is undetectable in the untransfected cells or cells harboring defective cDNA constructs. including one with a phenylalanine deletion at amino acid position 508 (delta F508). the most common mutation causing cystic fibrosis. These observations are consistent with the hypothesis that the CFTR is a cAMP-dependent Cl- channel. The availability of a heterologous (nonepithelial) cell type expressing the CFTR offers an excellent system to understand the basic mechanisms underlying this CFTR-associated ion permeability and to study the structure and function of the CFTR.
Functional significance of an overlapping consensus binding motif for Sp1 and Zif268 in the murine adenosine deaminase gene promoter, The murine adenosine deaminase (ADA) gene has a (G + C)-rich promoter that can support diverse tissue-specific gene expression. By using deletion and mutation analyses. we have identified a cis-acting "repressor" element located immediately upstream of the proximal Sp1 binding site in the ADA gene promoter. This repressor element was localized to a binding site for the immediate-early. serum-responsive. DNA binding factor Zif268. This Zif268 binding site partially overlaps a binding site for the general transcription activator Sp1. Disruption of the Zif268 binding site without disturbing the Sp1 binding motif abolished Zif268 binding and resulted in significantly elevated promoter function. Conversely. disruption of the proximal consensus Sp1 binding motif without disturbing the Zif268 binding site resulted in a loss of Sp1 binding at that region and greatly reduced promoter activity. Our results suggest that one function of Zif268 may be to down-regulate this type of mammalian gene promoter by competing with Sp1 for binding to the overlapping binding motif.
Deletional switch recombination occurs in interleukin-4-induced isotype switching to IgE expression by human B cells, There is controversy as to whether deletional rearrangement occurs between the IgM and IgE switch regions (S mu and S epsilon. respectively) during switching to the IgE isotype. We have addressed the issue by stimulating normal human B cells. sorted for lack of expression of surface IgE. to produce IgE by infection with Epstein-Barr virus (EBV) in the presence of interleukin 4 (IL-4). Genomic DNA was amplified for S mu/S epsilon switch junction fragments by utilizing the nested-primer polymerase chain reaction. Switch junction fragments were amplified from B cells infected with EBV in the presence of IL-4 but not from B cells infected with EBV alone. The DNA sequence of these "switch fragments" revealed direct joining of S mu to S epsilon in each case. The recombination sites within S mu were clustered within 900 base pairs at the 5' end of the switch region. suggesting that there are "hot spots" for recombination within S mu. The S epsilon recombination sites were scattered throughout the S epsilon region. These findings indicate that IL-4-induced isotype switching to IgE production in human B cells is accompanied by DNA rearrangements with joining of S mu to S epsilon.
Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo, The lectin homing receptor LECAM-1 (LAM-1. Leu8) and the beta 2 integrins. particularly Mac-1 (CD11b/CD18). participate in leukocyte-endothelial cell interactions in inflammation. LECAM-1 is rapidly shed while Mac-1 expression is dramatically increased upon neutrophil activation. suggesting functionally distinct roles for these molecules. Using intravital video microscopy. we have compared the effect of antibodies against LECAM-1 and CD18 on leukocyte interactions with rabbit mesenteric venules. Anti-LECAM-1 monoclonal antibody and its Fab fragments inhibited initial reversible leukocyte rolling along the vascular wall. Anti-CD18 monoclonal antibody had no effect on rolling but prevented subsequent firm attachment of leukocytes to venular endothelium. These results support a two-step model of leukocyte-endothelial cell interactions: reversible rolling mediated in part by LECAM-1 facilitates leukocyte recruitment by the local microenvironment and precedes activation-dependent firm attachment involving beta 2 integrins.
Mouse macrophage clones immortalized by retroviruses are functionally heterogeneous, Murine macrophage clones were generated from thymus. spleen. brain. and bone marrow by in vitro immortalization with recombinant retroviruses carrying an avian v-myc oncogene. The cloned cell lines express F4/80 molecules. exert phagocytosis. have nonspecific esterase activity. and express class II molecules after interferon gamma activation. The macrophage clones are diploid and their karyotypes have remained stable for greater than 3 years in culture. After the macrophage clones were activated. their pattern of cytokine production was investigated. Functional heterogeneity in cytokine transcription was demonstrated: one of six liposaccharide-activated macrophages was unable to transcribe interleukin 1 alpha. whereas all of the liposaccharide-activated clones were able to transcribe tumor necrosis factor alpha. Interleukin 6 production was detected in three of six clones. The production of nitrite and tumor necrosis factor alpha as effector molecules of cytotoxicity was detected in all clones. thus showing that a single macrophage can exert more than one cytotoxic mechanism. The results indicate that immortalized and cloned macrophages have a differentially regulated expression of cytokine genes. adding further evidence for the existence of functional heterogeneity among cloned macrophages. This heterogeneity seems to derive from differentiation-related mechanisms rather than from external constraints.
Transformed mammalian cells are deficient in kinase-mediated control of progression through the G1 phase of the cell cycle, To investigate the role of kinase-mediated mechanisms in regulating mammalian cell proliferation. we determined the effects of the general protein kinase inhibitor staurosporine on the proliferation of a series of nontransformed and transformed cultured rodent and human cells. Levels of staurosporine as low as 1 ng/ml prevented nontransformed cells from entering S phase (i.e.. induced G1 arrest). indicating that kinase-mediated processes are essential for commitment to DNA replication in normal cells. At higher concentrations of staurosporine (50-75 ng/ml). nontransformed mammalian cells were arrested in both G1 and G2. The period of sensitivity of nontransformed human diploid fibroblasts to low levels of the drug commenced 3 hr later than the G0/G1 boundary and extended through the G1/S boundary. Interference with activity of the G1-essential kinase(s) caused nontransformed human cells traversing mid-to-late G1 at the time of staurosporine addition to be "set back" to the initial staurosporine block point. suggesting the existence of a kinase-dependent "G1 clock" mechanism that must function continuously throughout the early cycle in normal cells. The initial staurosporine block point at 3 hr into G1 corresponds to neither the serum nor the amino acid restriction point. In marked contrast to the behavior of nontransformed cells. neither low nor high concentrations of staurosporine affected G1 progression in transformed cultures; high drug concentrations caused transformed cells to be arrested solely in G2. These results indicate that kinase-mediated regulation of DNA replication is lost as the result of neoplastic transformation. but the G2-arrest mechanism remains intact.
A wild-type DNA ligase I gene is expressed in Bloom's syndrome cells, Alteration of DNA ligase I activity is a consistent biochemical feature of Bloom's syndrome (BS) cells. DNA ligase I activity in BS cells either is reduced and abnormally thermolabile or is present in an anomalously dimeric form. To assess the role of DNA ligase function in the etiology of BS. we have cloned the DNA ligase I cDNA from normal human cells by a PCR strategy using degenerate oligonucleotide primers based on conserved regions of the Saccharomyces cerevisiae and Schizosaccharomyces pombe DNA ligase genes. Human DNA ligase I cDNAs from normal and BS cells complemented a S. cerevisiae DNA ligase mutation. and protein extracts prepared from S. cerevisiae transformants expressing normal and BS cDNA contained comparable levels of DNA ligase I activity. DNA sequencing and Northern blot analysis of DNA ligase I expression in two BS human fibroblast lines representing each of the two aberrant DNA ligase I molecular phenotypes demonstrated that this gene was unchanged in BS cells. Thus. another factor may be responsible for the observed reduction in DNA ligase I activity associated with this chromosomal breakage syndrome.
Detection of human T-lymphotropic virus-like particles in cultures of peripheral blood lymphocytes from patients with mycosis fungoides, Because of seronegativity and absence of a leukemic phase in most patients with mycosis fungoides. a role for the human T-lymphotropic virus type I (HTLV-I) in this disease has remained tenuous. Virus particles are not seen in fresh isolates of skin or blood lymphocytes and the malignant cells (Sezary cells) have been difficult to culture. The availability of growth factors and biomolecular techniques have prompted a renewed attempt to find evidence of virus infection in these patients. We report here the successful culture of blood lymphocytes of 17 patients with mycosis fungoides and 1 patient with the Sezary syndrome. The cells of 2 additional patients failed to grow after 4-6 weeks in vitro. Ultrastructural analysis of the cultures showed an abundance of HTLV-like particles in the specimens of 18 of the 20 patients. Preliminary immunohistochemical studies carried out with various antisera directed against HTLV-I and the polymerase chain reaction utilizing a probe for a conserved region of the pol gene of HTLV-I were positive on only a portion of the specimens. Although definitive characterization of this organism awaits further analysis. it seems likely that circulating lymphocytes of all patients with mycosis fungoides harbor a virus that morphologically resembles HTLV-I.
Human immunodeficiency virus induction of malignant transformation in human B lymphocytes, Aggressive B-cell lymphomas are occurring with increasing incidence among individuals infected with human immunodeficiency virus (HIV). Several lines of evidence implicate both Epstein-Barr virus (EBV) and c-myc activation in the pathogenesis of a major subset of these tumors. These observations prompted our investigation of interactions among EBV. c-myc. and HIV in primary B cells. We show that nonimmortalized peripheral B lymphocytes from EBV-seropositive. HIV-seronegative donors can be infected by HIV and that a subset of these lymphocytes become transformed. Malignant transformation was documented by several criteria. These cells displayed altered growth properties. propagating in 1% serum and cloning in soft agar. and formed invasive tumors of Burkitt lymphoma phenotype after subcutaneous injection into severe combined immunodeficiency mice. Such cells revealed marked enhancement of EBV DNA and RNA and of endogenous c-myc transcripts and protein. HIV-1 infection of already immortalized B-cell lines led to a similar upregulation of EBV and c-myc transcripts. These data indicate that HIV has properties of a transforming retrovirus. as it mediates two events linked to B-cell neoplasia: deregulation of c-myc and activation of EBV. They also raise the possibility of a role for HIV. apart from induction of immune suppression. in the pathogenesis of B-cell lymphoma in the acquired immune deficiency syndrome.
Two closely linked Drosophila POU domain genes are expressed in neuroblasts and sensory elements, We have characterized two Drosophila POU genes designated dPOU-19 and dPOU-28. These genes are transcribed as 3.1- and 2.2-kilobase mRNAs. respectively. which accumulate maximally during the first 12 hr of embryogenesis. The mRNAs encode 601- and 475-amino acid deduced proteins; their POU domains are most related to those of the human OCT1 and OCT2. Both genes give similar nervous system expression patterns and map to an indistinguishable site at 33F on the cytological map. Transcription of the genes is first observed in the cellular blastoderm. In the course of embryonic development. expression is observed in the neuroectoderm. with subsets of neuroblasts in the procephalic and germband central nervous system as well as a subset of peripheral nervous system elements. The expression patterns of the two POU genes suggest a possible functional role for these putative transcription factors in neurogenesis and neurospecification.
Enhanced GABAergic inhibition preserves hippocampal structure and function in a model of epilepsy, Extensive electrical stimulation of the perforant pathway input to the hippocampus results in a characteristic pattern of neuronal death. which is accompanied by an impairment of cognitive functions similar to that seen in human temporal lobe epilepsy. The excitotoxic hypothesis of epileptic cell death [Olney. J. W. (1978) in Kainic Acid as a Tool in Neurobiology. eds. McGeer. E.. Olney. J. W. & McGeer. P. (Raven. New York). pp. 95-121; Olney. J. W. (1983) in Excitotoxins. eds. Fuxe. K.. Roberts. P. J. & Schwartch. R. (Wenner-Gren International Symposium Series. Macmillan. London). Vol. 39. pp. 82-96; and Rothman. S. M. & Olney. J. W. (1986) Ann. Neurol. 19. 105-111] predicts an imbalance between excitation and inhibition. which occurs probably as a result of hyperactivity in afferent pathways or impaired inhibition. In the present study. we investigated whether the enhancement of gamma-aminobutyric acid (GABA)-mediated (GABAergic) inhibition of neurotransmission by blocking the GABA-metabolizing enzyme. GABA transaminase. could influence the histopathological and/or the behavioral outcome in this epilepsy model. We demonstrate that the loss of pyramidal cells and hilar somatostatin-containing neurons can be abolished by enhancing the level of synaptically released GABA. and that the preservation of hippocampal structure is accompanied by a significant sparing of spatial memory as compared with placebo-treated controls. These results suggest that enhanced GABAergic inhibition can effectively block the pathophysiological processes that lead to excitotoxic cell death and. as a result. protect the brain from seizure-induced cognitive impairment.
Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide, Nuclear extracts from teniposide (VM-26)-resistant sublines of the human leukemic cell line CCRF-CEM have decreased levels of DNA topoisomerase II catalytic activity and decreased capacity to form drug-stabilized covalent protein-DNA complexes. The ATP concentration required for equivalent activity in a DNA-unknotting assay is 2- to 8-fold higher in nuclear extracts from drug-resistant cell lines as compared with the parental line. When adenosine 5'-[beta.gamma-imido]triphosphate is substituted for ATP in complex-formation assays. no significant change is seen with drug-sensitive cells. but a 50-65% reduction is seen with VM-26-resistant cells. Collectively. these results indicate that an alteration in ATP binding may be involved in the resistance phenotype. Therefore. we identified regions of the topoisomerase II sequence that conform to previously identified nucleotide-binding sites. Starting with cDNA as the template we determined the sequence of the topoisomerase II mRNA surrounding these sites by sequencing DNA fragments produced by the polymerase chain reaction. In the region corresponding to the consensus B ATP-binding sequence described by Walker et al. [Walker. J. E.. Saraste. M.. Runswick. M. J. & Gay. N. J. (1982) EMBO J. 1. 945-951]. the cDNA from the two VM-26-resistant sublines contained an altered sequence having a G----A base change. This base substitution results in the replacement of the conserved arginine at position 449 with a glutamine. Hybridization with allele-specific oligonucleotides confirmed the presence of both the normal and the altered sequence in the resistant cell lines. whereas only the normal sequence was found in the sensitive CEM cells. A chemical mismatch cleavage procedure for the detection of mispaired bases in DNA duplexes identified no other alterations in the 5' third of the mRNA coding sequence. which contains the complete ATP-binding domain of topoisomerase II. The presence of mRNA encoding topoisomerase II with Gln449 correlates both with the presence of a topoisomerase II protein whose interaction with ATP is altered and with increased resistance to the cytotoxicity of VM-26.
I-TevI, the endonuclease encoded by the mobile td intron, recognizes binding and cleavage domains on its DNA target, Mobility of the phage T4 td intron depends on activity of an intron-encoded endonuclease (I-TevI). which cleaves a homologous intronless (delta In) target gene. The double-strand break initiates a recombination event that leads to intron transfer. We found previously that I-TevI cleaves td delta In target DNA 23-26 nucleotides upstream of the intron insertion site. DNase I-footprinting experiments and gel-shift assays indicate that I-TevI makes primary contacts around the intron insertion site. A synthetic DNA duplex spanning the insertion site but lacking the cleavage site was shown to bind I-TevI specifically. and when cloned. to direct cleavage into vector sequences. The behavior of the cloned duplex and that of deletion and insertion mutants support a primary role for sequences surrounding the insertion site in directing I-TevI binding. conferring cleavage ability. and determining cleavage polarity. On the other hand. sequences around the cleavage site were shown to influence cleavage efficiency and cut-site selection. The role of cleavage-site sequences in determining cleavage distance argues against a strict "ruler" mechanism for cleavage by I-TevI. The complex nature of the homing site recognized by this unusual type of endonuclease is considered in the context of intron spread.
Antisense oligodeoxynucleotide to the cystic fibrosis gene inhibits anion transport in normal cultured sweat duct cells, We have tested the hypothesis that the cystic fibrosis (CF) gene product. called the CF transmembrane conductance regulator (CFTR). mediates anion transport in normal human sweat duct cells. Sweat duct cells in primary culture were treated with oligodeoxynucleotides that were antisense to the CFTR gene transcript in order to block the expression of the wild-type CFTR. Anion transport in CFTR transcript antisense-treated cells was then assessed with a halide-specific dye. 6-methoxy-N-(3-sulfopropyl)quinolinium. and fluorescent digital imaging microscopy to monitor halide influx and efflux from single sweat duct cells. Antisense oligodeoxynucleotide treatment (3.9 or 1.3 microM) for 24 hr virtually abolished Cl- transport in sweat duct cells compared with untreated cells or control cells treated with sense oligodeoxynucleotides. Br- uptake into sweat duct cells was also blocked after a 24-hr CFTR transcript antisense treatment. but not after treatment for only 4 hr. Lower concentrations of antisense oligodeoxynucleotides were less effective at inhibiting Cl- transport. These results indicate that oligodeoxynucleotides that are antisense to CFTR transcript inhibit sweat duct Cl- permeability in both a time-dependent and dose-dependent manner. This approach provides evidence that inhibition of the expression of the wild-type CFTR gene in a normal. untransfected epithelial cell results in an inhibition of Cl- permeability.
Differential expression of epidermal growth factor-related proteins in human colorectal tumors, Amphiregulin (AR) and cripto are proteins that are structurally related to epidermal growth factor (EGF) and transforming growth factor alpha (TGF-alpha). AR is also functionally related to this family of growth regulatory molecules and is able to bind and activate the 170-kDa EGF receptor (EGFR). Human EGFR-3 (HER3)/ERBB3 is a recently identified protein related to the EGFR that is widely expressed in breast carcinomas and is a candidate receptor for EGF-like growth factors. Differential expression of these putative ligands and receptors in transformed cells suggests that they may function in an autocrine manner to regulate tumor cell growth. Specific mRNA transcripts for TGF-alpha [4.8 kilobases (kb)]. AR (1.4 kb). cripto (2.2 kb). and HER3 (6.2 kb) were expressed in a majority of human colon cancer cell lines. HER3 mRNA was detected in 55% of primary or metastatic human colorectal carcinomas but in only 22% of normal colon mucosa and 32% of normal liver samples. In contrast. cripto and AR mRNA were expressed in 60-70% of primary or metastatic human colorectal cancers but in only 2-7% of normal human colonic mucosa. Immunostaining also detected AR protein in primary and metastatic colorectal tumors but not in normal colon or uninvolved liver. These findings suggest that cripto and AR may be useful markers to discriminate between normal and malignant colonic epithelium and may provide a selective growth advantage for colorectal carcinomas.
Rat obesity gene fatty (fa) maps to chromosome 5: evidence for homology with the mouse gene diabetes (db), The autosomal recessive mutations fa (rat) and db (mouse) cause obesity syndromes that develop early and ultimately become severe. Although both fa/fa rats and db/db mice have been studied extensively as models of human obesity and diabetes. the molecular bases of these phenotypes remain unknown. We have mapped fa in 50 fa/fa (obese) offspring of a (13M x Brown Norway) F1 fa/+ intercross relative to two molecular markers. Ifa and Glut-1. which flank db on mouse chromosome 4 and which are located on rat chromosome 5. Ifa and Glut-1 are linked to fa. with a gene order. Ifa-fa-Glut-1. that is identical to that for the region around db in the mouse genome. These results place fa on rat chromosome 5 and suggest that db and fa are mutations in homologous genes.
Xeroderma pigmentosum variant cells are less likely than normal cells to incorporate dAMP opposite photoproducts during replication of UV-irradiated plasmids, Xeroderma pigmentosum (XP) variant patients show the clinical characteristics of the disease. with increased frequencies of skin cancer. but their cells have a normal. or nearly normal. rate of nucleotide excision repair of UV-induced DNA damage and are only slightly more sensitive than normal cells to the cytotoxic effect of UV radiation. However. they are significantly more sensitive to its mutagenic effect. To examine the mechanisms responsible for this hypermutability. we transfected an XP variant cell line with a UV-irradiated (at 254 nm) shuttle vector carrying the supF gene as a target for mutations. allowed replication of the plasmid. determined the frequency and spectrum of mutations induced. and compared the results with those obtained previously when irradiated plasmids carrying the same target gene replicated in a normal cell line [Bredberg. A.. Kraemer. K. H. & Seidman. M. M. (1986) Proc. Natl. Acad. Sci. USA 83. 8273-8277]. The frequency of mutants increased linearly with dose. but with a slope 5 times steeper than that seen with normal cells. Sequence analysis of the supF gene showed that 52 of 53 independent mutants generated in the XP variant cells contained base substitutions. with 62 of 64 of the substitutions involving a dipyrimidine. Twenty-eight percent of the mutations involved A.T base pairs. with the majority found at position 136. the middle of a run of three A.T base pairs. (In the normal cells. this value was only 11%.) If the rate of excision of lesions from supF in the two cell lines is equal. our data suggest that XP variant cells are less likely than normal cells to incorporate dAMP opposite bases involved in photo-products. If such incorporation also occurs during replication of chromosomal DNA. this could account for the hypermutability of XP variant cells with UV irradiation.
Identification of a germ-line mutation in the p53 gene in a patient with an intracranial ependymoma, We detected a germ-line mutation of the p53 gene in a patient with a malignant ependymoma of the posterior fossa. This mutation. which was found at codon 242. resulted in an amino acid substitution in a highly conserved site of exon 7 of the p53 gene; the same mutation was found in both the germ-line and the tumor tissue. This is the most common region of previously described somatic p53 mutations in tumor specimens and of the germ-line p53 mutations in patients with the Li-Fraumeni cancer syndrome. Evaluation of the patient's family revealed several direct maternal and paternal relatives who had died at a young age from different types of cancer. The association of a germ-line p53 mutation with an intracranial malignancy and a strong family history of cancer suggests that p53 gene mutations predispose a person to malignancy and. like retinoblastoma mutations. may be inherited.
Amino acid substitutions in the coat protein result in loss of insect transmissibility of a plant virus, Amino acids near the N terminus of the coat protein of tobacco vein mottling virus were deleted or altered by site-directed mutagenesis to determine the effect on aphid transmissibility of the virus. Deletion of a three amino acid sequence Asp-Ala-Gly. which is conserved in aphid-transmissible potyvirus isolates. abolished transmission. The mutation Ala----Thr in this triplet drastically reduced transmission. whereas the mutation Asp----Asn had no effect. and the mutation Asp----Lys consistently reverted to the wild-type residue. The mutation Lys----Glu. in the residue adjacent to the glycine of the triplet. drastically reduced transmission. whereas the mutation Gln----Pro. seven residues downstream from the glycine had no effect. Comparison of the sequences of other potyviruses suggests that the presence of a glycine residue at the third position of the Asp-Ala-Gly triplet is critical for aphid transmissibility and that certain changes in the residues adjacent to this position abolish or greatly reduce aphid transmissibility.
Magnetic resonance imaging of pulmonary artery aneurysm, Pulmonary artery aneurysm is a rare condition. We have presented what we believe to be the first case in the English literature to be diagnosed by magnetic resonance imaging.
Massive bone allografts for traumatic skeletal defects, Large bone allograft transplants have been successfully used to reconstruct skeletal defects created by tumor resections and failed arthroplasties. but little has been reported on their use in traumatic defects. Of approximately 500 allograft procedures done at the Massachusetts General Hospital from 1979 to 1988. 11 were done for restoration of traumatic bone loss. The average age of the patients was 30 (range 11 to 71 years). and the location of the defect was the tibia or femur in 10 of the 11 patients studied. Eight osteoarticular grafts (six hemicondylar and two total condylar) and three intercalary grafts were used for six open and five closed fractures. The time from injury to reconstruction averaged 17 months (3 to 96 months). Primary reconstruction was done in three cases and a salvage procedure in eight. Patients were assessed by the operating surgeon and a physical therapist using an evaluation system that considers function. life-style. and emotional acceptance. According to the system. nine patients had excellent or good results (six hemicondylar grafts. three intercalary grafts). one patient had a fair result (total elbow graft). and one patient had failure of a total condylar graft and subsequently required an amputation. This study suggests that large bone allografts are of value in reconstructing traumatic skeletal defects. especially those involving an articular surface in a young patient.
Dupuytren's contracture, Dupuytren's contracture is a disease of the palmar and digital fascia that results in a flexion deformity of the fingers. Although the first case was reported more than 350 years ago. many questions remain unanswered. With our present state of knowledge. treatment remains empiric and operative intervention is the only successful mode of treatment. Controversies continue over the type of procedure used. as well as its timing. In light of the high rate of recurrence of flexion contractures after apparently successful operations. current research is being directed toward identifying a biochemical or histologic marker to indicate the probability of recurrence.
Scleral implants: an historical perspective, Scleral implants are made of absorbable or nonabsorbable materials. One category of absorbable materials consists of donor tissue. either autogenous (fascia lata. plantaris gracilis tendon) or from cadavers (dura mater. sclera. fascia lata). A second category includes gelatin. reconstituted collagen. absorbable gut. fibrin. blood plasma. air. and sodium hyaluronate; of these. specially prepared gelatin seems to be the most useful. Nonabsorbable implant materials have proven more practical than absorbable implants. Solid silicone rubber is currently the most popular scleral implant material. It is soft. easy to handle. and well tolerated. Expandable implants. either temporary or permanent. are used in the form of a silicone balloon filled with liquid. Silicone sponge. also widely used. has the advantage of great softness. However. hydrogels seem to be the ideal scleral implants. The only one commercially available is Refojo's MAI implant. It is very soft and is not damaged by sutures. has a smooth surface. is molded in several sizes and shapes. and has small pores that microorganisms cannot penetrate. When saturated with a water-soluble antibiotic before implantation. this implant releases the antibiotic postoperatively for a longer time than any other implant material. Finally. surgical adhesives are useful when the sclera is too thin or weak to tolerate sutures. The best adhesive available seems to be isobutyl cyanoacrylate.
Intimal tears of the right atrium of the heart due to blunt force injuries to the abdomen. Its mechanism and implications, We present six cases involving intimal tears of the right atrium of the heart. A proposed mechanism for this injury is discussed. along with implications of the lesion in fatally abused children and traumatized older patients who survive until hospitalization.
Firearms and adult, domestic homicides. The role of alcohol and the victim, An epidemiological study was conducted to characterize adult. domestic homicides committed with firearms and to determine the role of alcohol intoxication in the likelihood of becoming a homicide victim. Data on 129 homicides in Ohio occurring between 1982 and 1985 were collected from police departments of major cities. the Ohio Department of Rehabilitation and Corrections. and county medical examiners. Forty-eight offenders were interviewed. Temporal and geographical patterns are discussed. as well as offender-victim relationships and the characteristics of the firearms used. High levels of blood alcohol in the victims suggest that alcohol is a risk factor for becoming a homicide victim. although data on alcohol consumption patterns in the population are necessary to advance this association.
The moving, projected, annual total. A kinetic prognostic entity, A simple. inexpensive method of prognostically calculating and graphically recording annual case loads of the various deaths investigated by today's medicolegal offices is presented. Graphic depiction of the numerical data provides a convenient way to compare current prognostications with the records of preceding years.
Mass deaths by gas or chemical poisoning. A historical perspective, This review chronicles the characteristics of deliberate and accidental mass poisonings that occurred in World Wars I and II. in Bhopal. and in other historical cases up to and including modern wars. It also considers approaches to the investigation of such cases from the medicolegal as well as general standpoints.
Unusual blunt force wound patterns due to a hexagonal steel bar, Pathologists routinely examine victims with blunt force traumatic injuries. Many of these victims exhibit injury patterns that can help identify the weapon used in the assault. Proper documentation that accurately portrays the injury pattern and allows for comparison with recovered weapons is therefore essential. Our office investigated a homicide with unusual blunt force injuries. This article presents the procedure that we followed to identify the weapon.
A forensic application of DNA typing. Paternity determination in a putrefied fetus, Using minisatellite DNA probes that hybridize to a variable number of tandemly repeated loci. an individual-specific DNA fingerprint can be determined. In the case reported here. we succeeded in extracting high-molecular-weight DNA from a 3-month-old fetus discovered during the autopsy of a murdered 28-year-old pregnant woman reported missing 10 days earlier. The results of analysis of restriction-fragment-length polymorphisms showed that all bands present in the fetus's pattern. but absent in the mother's. matched only those of the putative father. Thus. the paternity of the victim's husband was ruled out.
Identification of human remains lacking skull and teeth. A case report with some methodological considerations, This report deals with a case in Denmark in which close cooperation among the local police. the Central Missing and Wanted Persons Search Squad. and the Institute of Forensic Medicine resulted in the positive identification of human remains (part of a skeleton). although the deceased's skull was missing. he had no teeth (but a dental prostheses). and an attempt at blood typing produced a false result. When the remains were found. there was no idea who the deceased might be. The initial forensic examination provided a general description (age. height. and sex). and reconstruction of the vertebral column showed extensive changes caused by arthrosis and changes typical for Scheurmann's disease. The description made on this basis was sent to police stations throughout the country and. far from where the remains were found. a police officer had received the report of a missing person who could have been the deceased. Further investigation was based mainly on the medical history of this missing person and the tracing of the effects found with the remains. and emphasized radiographic comparison.
"Beaten to death". An autopsy series of homicidal blunt force injuries, Although gunshot is by far the most common means of homicide in the United States. significant numbers of homicides are also perpetrated by other means. Blunt-force injuries are produced by a variety of objects. including hands and feet and many different weapons. Some of these objects produce distinctive patterns of injury of potential evidentiary value. This paper presents a series of 20 consecutive blunt-force homicides in adults. Seventy percent (14 cases) of the victims were men. Thirty percent (six cases) followed an argument or altercation. A number of the weapons used were "weapons of opportunity" seized in the course of the incidents. Sixty-nine percent (nine cases) of known assailants were acquainted with their victims. Few characteristic patterned injuries were seen. Not surprisingly. craniocerebral trauma was the most common cause of death. One half (10 cases) the victims survived their assaults for varying periods of time. Homicides due to blunt-force injury still pose a significant challenge for the forensic pathologist. who must obtain a complete and accurate history of the fatal incident. interpret patterns of injury and other findings at autopsy. and correlate all of the findings to make an accurate ruling of the cause and manner of death.
Drug-induced esophagitis, Drug-induced esophagitis is being recognized increasingly in the past few years. We have reviewed 175 cases with a view to classifying this disease based on pathology. Drug-induced esophageal injury tends to occur at the anatomical site of narrowing. with the middle third behind the left atrium predominating. The disease is classified broadly into two groups. The first group is transient and self-limiting. as exemplified by tetracycline- and emepronium-induced injury (57.3%). The second is the persistent esophagitis group. often with stricture with two distinct entities: 1) patients on nonsteroidal antiinflammatory agents whose injury is aggravated by gastroesophageal reflux (26.2%) (reflux aggravated). and 2) patients with potassium chloride and quinidine sulfate-induced injury (16.2%) (persisting drug injury). We report a case that highlights the pathophysiology (delayed transit. persisting potassium within the stricture) of this type of injury which is not reflux aggravated.
Which pH threshold is best in esophageal pH monitoring, Two questions were examined. namely. 1) whether pH 4 is really the optimal threshold for the definition of acid gastroesophageal reflux. and 2) to what extent shifting of the upper limits of normal affects sensitivity and specificity of 24-h pH monitoring. To answer these questions. we studied 74 patients with proven reflux disease and 37 asymptomatic volunteers. using ambulatory 24-h esophageal pH monitoring. Gastroesophageal reflux was defined as episodes with esophageal pH of less than the threshold values 3.0. 3.5. 4.0. 4.5. or 5.0. respectively. For each of these pH thresholds. the percentage time with esophageal pH below the threshold was calculated separately for periods of upright and supine body position. Two-dimensional receiver-operating-characteristic (ROC) analysis was used to define upper limits of normal. A maximum of sensitivity. specificity. and rate of correct decisions (all 89%) was obtained using pH 4 for the definition of gastroesophageal reflux. although other pH thresholds were not much worse. On the basis of pH 4. the upper limits of normal could be shifted around the "optimal upper limit of normal" within a certain limit without considerable loss of accuracy of pH monitoring. This may explain the divergences between upper limits of normal obtained by different laboratories. In conclusion. 1) the threshold pH 4 should further be used for the definition of acid gastroesophageal reflux. and. 2) within certain limits. shifting of the upper limits of normal has little effect on the accuracy of pH monitoring in gastroesophageal reflux disease.
Failure of initial 24-hour esophageal pH monitoring to predict refractoriness and intractability in reflux esophagitis, Prolonged esophageal pH monitoring is considered to be the most sensitive and specific test for the diagnosis of gastroesophageal reflux disease (GERD). However. the role of pH monitoring in predicting the clinical and endoscopic response of reflux esophagitis is not well defined. In this study. 106 patients with moderate to severe symptoms of GERD and esophagitis (grades 0-IV) by endoscopy were initially studied by ambulatory esophageal pH monitoring. and their clinical response to standard H2 antagonist therapy was monitored at 8 wk. Refractory patients were defined as those who failed to heal and/or had intractable reflux symptoms after 8 wk of H2 antagonist therapy. and who required continuous therapy with higher doses of H2 antagonists. addition of prokinetic agents. or omeprazole. There was a positive correlation (r = 0.89) between endoscopic severity of esophagitis upon entry into the study and refractoriness to standard medical therapy. However. there were no differences in the various pH parameters analyzed between the 58 patients who responded and the 48 patients who were refractory to medical therapy. regardless of the endoscopic grading of their esophagitis. We conclude that 24-h ambulatory esophageal pH monitoring does not predict refractoriness of reflux esophagitis to standard therapy. The decision for more aggressive methods of treatment probably requires assessment of symptomatic and endoscopic response after 8 week standard H2 antagonist therapy.
Basal and maximum acid output after continuous overnight gastric aspiration, Basal and maximum acid outputs were measured on two occasions in a group of 15 duodenal ulcer (DU) patients in remission. The initial study was carried out after a nocturnal acid collection. whereas the second was carried out in the conventional manner without preceding nocturnal aspiration. No difference in the basal acid output. concentration. or volume of secretion was found between the two study days. Maximum acid output on the other hand. was significantly (p less than 0.02) reduced from 30.9 (14.2-41.2) mmol/h. median (+range). to 23.7 (8.1-33.7) mmol/h after overnight aspiration. The reduction in maximum acid output was attributable to a fall in the volume of gastric secretion from 280 (170-371) ml to 230 (142-280) ml. No fall in acid concentration was seen. We conclude that overnight gastric aspiration does not affect basal gastric secretion. but reduces the maximum acid output as a result of a reduced secretory volume.
The role of epidermal growth factor in the pathogenesis of peptic ulcer disease, Duodenal biopsies obtained from seven normal subjects and six ulcerous patients were cultured in vitro for 30 min at 37 degrees C under various experimental conditions. Epidermal growth factor (EGF) and somatostatin released in the culture medium were determined by radioimmunoassay. Under basal conditions. EGF and somatostatin levels were significantly higher in normal subjects (11.49 +/- 3.07 ng/mg protein and 3.06 +/- 0.8 ng/mg protein. respectively) than in ulcerous patients (6.9 +/- 1.98 ng/mg protein and 1.75 +/- 1.23 ng/mg protein. respectively). However. when antibodies to somatostatin and vasoactive intestinal polypeptide (VIP) were added together to the culture media. in ulcerous patients. EGF levels also were lower as absolute values. but were higher as a percentage of variation than controls (p less than 0.05). The fall of EGF secretion from tissue cultures of ulcerous patients could be the consequence of endocrine cellular loss or damage. rather than the cause of ulceration. Moreover. the EGF-producing cells around the lesion in ulcerous patients seems to be hyperactive. and this hyperfunction of EGF-producing cells might contribute to the in vivo repair of tissue damage.
Immunohistochemical expression of carbohydrate antigen 19-9 in gastric carcinoma, Immunohistochemical localization for carbohydrate antigen 19-9 (CA19-9) was studied in the gastric tissues from 115 patients with advanced gastric carcinoma. We compared two groups: 57 patients who died of recurrence or metastases within 2 yr (group I) and 58 patients who survived 5 yr or more after resection (group II). The staining patterns were classified into negative. apical. and/or cytoplasmic type and stromal type. Thirty-three cases (58%) of group I showed a stromal type. whereas only 17 cases (30%) of group II showed the same type. In undifferentiated type carcinoma. the stromal type was seen in 20 cases (65%) of group I and seven cases (23%) of group II. However. in differentiated type carcinoma. there was only a small difference in the appearance of stromal type between group I (50%) and group II (37%). The immunohistochemical localization for CA19-9 in the tumor tissues. particularly in undifferentiated carcinoma. will be useful in predicting the prognosis of the patients with advanced gastric carcinoma.
Small cell carcinoma of the stomach: a clinicopathologic study of 17 cases, Of 17 cases of small cell carcinoma of the stomach. three were early and 14 were advanced. Grossly. the tumors were mostly polypoid at the early stage. and as they advanced. deep ulcerations developed. Histologically. only one tumor was "oat cell type." and the other 16 were "intermediate cell type." With regard to tumor components. five were "pure" tumor. and 12 were "composite" admixing glandular and/or squamous differentiation. Argyrophil cells were seen in eight tumors. Immunohistochemically positive cells for chromogranin. neuron-specific enolase. and keratin were seen in 12. 10. and 7 tumors. respectively. Carcinoembryonic antigen was negative in the small cell component of most tumors as opposed to strong positivity in the glandular component. Electron-dense core granules were evident in seven of nine tumors examined. These findings suggest that histologic variety is quite characteristic of the small cell carcinomas of the stomach. and this type of carcinoma takes an aggressive clinical course like its counterparts in other organs.
Laparoscopic cholecystectomy: 111 consecutive cases, Laparoscopic cholecystectomy removes the gallbladder through three or four puncture wounds in the abdominal wall. The technique reduces the recuperative time to full activity. from as long as 4 wk to as little as 3 days. compared with conventional cholecystectomy. We herein present our initial experience with this procedure. In this series of 111 laparoscopic cholecystectomies. there were no mortalities and only one morbidity. Thirty-nine patients (35%) had a history of prior abdominal surgery. Fourteen underwent laparoscopic lysis of adhesions. Intraoperative cholangiograms were performed in 24 patients (21%). demonstrating choledocholithiasis in three. Two of the three patients underwent postoperative endoscopic retrograde cholangiopancreatography (ERCP); in the other. laparoscopic common bile duct exploration was performed. In each case. the common bile duct (CBD) was completely cleared of stones. Incidental laparoscopic appendectomy was also performed in three patients. The average time for completion of laparoscopic cholecystectomy in cases of chronic cholecystitis was 40 min. If the gallbladder was acutely inflamed. the procedure took a mean of 126 min. This series had a higher percentage of patients (19%) with acute cholecystitis then previously reported; therefore. the 2% conversion rate in this series emphasizes the broad applicability of the technique. The average length of stay in the hospital was 1.4 days. and patients returned to work in about 7 days.
Hepatocellular and biliary expression of HLA antigens in primary biliary cirrhosis before and after ursodeoxycholic acid therapy, Recently. there have been reports that ursodeoxycholic acid (UDCA) therapy has a beneficial effect on liver function in patients with primary biliary cirrhosis. However. information regarding the effects of UDCA therapy on hepatic histology remains insufficient. Aberrant expression of HLA antigens on hepatocytes is regarded important in the progression of hepatocellular damages mediated by cytotoxic T-cells in primary biliary cirrhosis. In this study. we examined immunohistochemically hepatocellular expression of HLA antigens on hepatocytes before and after UDCA therapy in four patients with asymptomatic primary biliary cirrhosis. Piecemeal necrosis. intralobular focal necrosis. and portal inflammation. as well as infiltration of activated T-lymphocytes and expression of HLA class I antigens on hepatocytes. disappeared. or diminished in parallel after the therapy. In two of four patients. expression of HLA-DR on some periportal hepatocytes before the therapy also disappeared after the therapy. These observations imply that UDCA therapy decreases the hepatocellular expression of HLA antigens and thereby reduces or abolishes T-cell-mediated hepatocellular necrosis in primary biliary cirrhosis.
Antibody to hepatitis C is common among patients with alcoholic liver disease with and without risk factors, Thirty-seven patients with clinically suspected alcoholic liver disease were retrospectively studied for the prevalence of antibody to hepatitis C virus (HCV) by enzyme-linked immunosorbent assay (ELISA) and immunoblot assay. Twenty-four had biopsy-proven cirrhosis. Nineteen had identifiable risk factors for non-A. non-B viral hepatitis. and 18 did not. Five of 19 high-risk (26%) and 6 of 18 low-risk (33%) patients had positive antibody. compared with two of 179 healthy blood donors (p less than 0.01 for either group of alcoholics compared with blood donors). Nine of 11 ELISA-positive patients were also either positive or indeterminable by immunoblot testing. Histologic scores for parameters commonly associated with chronic viral hepatitis were numerically worse among anti-HCV-positive patients. but none reached statistical significance. Clinically. seven of 11 (64%) of anti-HCV-positive patients versus 14 of 26 (54%) anti-HCV-negative patients were Child's class C. Among the 21 Child's class C patients. seven (33%) were anti-HCV-positive versus four of 16 (25%) of Child's class A/B patients. A weak correlation between IgG and ELISA optical density was observed (r = 0.52). We conclude that antibody to hepatitis C by ELISA and immunoblot is common among alcoholics with liver disease even in the absence of known or suspected risk factors for viral hepatitis. Although hepatitis C-positive patients tended to have more severe histologic disease. neither histologic parameters nor clinical findings were adequate to predict antibody seropositivity.
Acute delta hepatitis: serological diagnosis with particular reference to hepatitis delta virus RNA, To evaluate serologic diagnosis of hepatitis delta virus. we tested HDV RNA in stored sera from 48 patients with acute delta hepatitis who were identified with anti-HD antibodies. Initial sera were positive for HDV RNA in 27 of 48 (56%) patients. In comparison. isolated IgM anti-HD was present in 18 (38%) patients. although IgM and IgG anti-HD were present concurrently in 16 (33%) additional patients. Overall. either HDV RNA or IgM anti-HD was present in 69% of the initial sera. The HDV infection was self-limiting in all except two patients who died of fulminant hepatitis and nine others in whom chronic delta hepatitis ensued. Patterns of HDV seropositivity during progression to chronicity induced variable persistence. disappearance or recrudescence of either HDV RNA or IgM and IgG anti-HD. Results of HDV RNA and IgM anti-HD tests were concordant in only 40-50% of instances. Our results indicate that serological testing for HDV RNA is direct and will demonstrate HDV replication in a large number of cases with acute delta hepatitis. Testing for IgM anti-HD could provide supplemental evidence for HDV infection. Sequential testing for these markers will facilitate assessment of the outcome of acute HDV infection.
Selective elevation of monomeric IgA1 in IgA nephropathy patients with normal renal function, The molecular form of the pathognomonic IgA in IgA nephropathy (IgAN) remains controversial. Because characterization of the molecular form of IgA molecules can lend insight into their origin (systemic v mucosal). we developed immunoassays to measure both total and J chain-containing (polymeric) IgA1 and IgA2. These assays were used to measure IgA in sera from two groups of IgAN patients (with normal or decreased renal function). as well as from a group of normal individuals. IgA1 levels were higher in both groups of patients with IgAN when compared with the controls. The elevation appeared to be restricted to non-J chain-containing (monomeric) IgA1 in patients with normal renal function. whereas polymeric IgA1 was also slightly elevated in patients whose renal function was diminished. While there were no significant differences between the groups in terms of the levels of total IgA2. the patient group with normal kidney function appeared to have lower levels of polymeric IgA2. The observation that the elevation in serum IgA appears to be restricted to the monomeric form of IgA1. at least when renal function is normal. implies a systemic origin of the pathognomonic IgA in IgAN and further suggests an abnormality in the regulation of IgA secretion by immunoglobulin-producing cells in bone marrow. the site of systemic IgA synthesis.
Parathyroid hormone and myocardial performance in dialysis patients, Whether parathyroid hormone (PTH) has a clinically important effect on myocardial performance is unclear. Previous investigations of cardiac function before and after parathyroidectomy have failed to control for ionized calcium. other biochemical parameters. or heart rate and cardiovascular loading conditions. We performed load- and rate-independent measurements of myocardial contractility in seven stable hemodialysis patients before and after surgical parathyroidectomy under identical conditions of blood ionized calcium (Ca2+). electrolytes. pH. PO2. and hematocrit. Mid-molecule PTH decreased from 44 +/- 8 to 2 +/- 1 ng/mL. Aortic systolic and diastolic pressures. left ventricular chamber dimensions. end systolic wall stress. left ventricular contractility at a common level of afterload. and contractile reserve evaluated with dobutamine were similar before and after parathyroidectomy. Thus. PTH appears not to have a direct effect on myocardial contractile state in dialysis patients.
Mortality in dialysis patients: analysis of the causes of death, The objective of this study was to identify the causes of death in maintenance dialysis patients who survived at least 90 days and were monitored during a 16-year period. Of 532 patients starting dialysis. 222 died. The causes of death were grouped into six categories: cardiac. infectious. withdrawal from dialysis. sudden. vascular. and "other." The greatest number of deaths were due to infections. followed by withdrawal from dialysis. cardiac. sudden death. vascular. and other. The risk of dying increased for the first 4 years of dialysis. decreased in years 5 through 10. and had a second increase at 11 years. The mortality during the first 4 years consisted largely of infectious and cardiac deaths. The late peak of deaths was mainly due to infections and withdrawal from dialysis. Overall. infections accounted for more than 36% of all deaths. Withdrawal occurred in 21.2% of the patients and was most common in patients over age 61. Notably. cardiac deaths accounted for only 14.4% of all deaths and no patient died from a cardiac cause after surviving on dialysis more than 8.5 years. We conclude that infection is the leading cause of death in our dialysis patient population. Withdrawal from dialysis was a common cause of death. especially in older patients. Cardiac mortality was not as frequent as anticipated and occurred mainly in patients on dialysis less than 4 years. suggesting that it is the result of preexisting disease.
Changing patterns of end-stage renal disease due to hypertension, We analyzed the records of all residents of Jefferson County. Alabama. accepted for renal replacement therapy between 1982 and 1987 and compared them with those accepted between 1974 and 1978 to determine any changes in the distribution and frequency of end-stage renal disease (ESRD) due to hypertension (H-ESRD). H-ESRD increased from 6.4 to 9.6 per 100.000 in blacks and from 0.36 to 0.62 per 100.000 in whites. Smoothed age- and race-specific yearly H-ESRD rates decreased in blacks under age 50. Peak incidence of H-ESRD shifted from age 40 to 49 in 1974 through 1978 to age 50 to 59 in 1982 through 1987 (P less than 0.0001). Blacks were referred for care with significantly higher blood pressure levels and serum creatinine concentrations than whites. and had more severe retinal vascular disease. Factors significantly associated with a shorter time from referral to renal replacement therapy were black race. female gender. blood urea nitrogen and serum creatinine concentrations. carbohydrate intolerance. and the use of alpha-agonist and/or angiotensin-converting enzyme (ACE) inhibitor. We conclude that racial distribution and risk for H-ESRD have not changed. Peak rates of H-ESRD have been delayed nearly a decade. suggesting a possible effect of better awareness and treatment of hypertension.
Independent effects of cyclosporine and prednisone on posttransplant hypercholesterolemia, To clarify the relative influences of cyclosporine (CsA) therapy. corticosteroid therapy. and other clinical variables on posttransplant hypercholesterolemia. total serum cholesterol levels were measured in 107 renal transplant recipients receiving one of three immunosuppression regimens: CsA and azathioprine (AZA) (group I); CsA. AZA. and prednisone (group II); or AZA and prednisone (group III). Multivariate analysis demonstrated that prednisone therapy. CsA therapy. patient age. and pretransplant cholesterol levels correlated independently with posttransplant cholesterol levels at last follow-up (ranging from 13 to 84 months after transplantation). In 32 patients successfully withdrawn from corticosteroid therapy and maintained on AZA and stable doses of CsA. serum cholesterol decreased from 6.55 +/- 1.1 mmol/L (253.5 +/- 43.1 mg/dL) to 5.27 +/- 1.2 mmol/L (203.9 +/- 45.6 mg/dL). Results of this analysis indicate that prednisone and CsA are independent factors in the pathogenesis of posttransplant hypercholesterolemia. Complete withdrawal of corticosteroids partially corrects hypercholesterolemia in CsA-treated renal transplant recipients.
Reduction of remnant nephron hypermetabolism by protein restriction, To study the metabolic mechanisms involved in the protective effect of dietary protein restriction on the progression of chronic renal failure. experiments were performed in Sprague-Dawley rats subjected to five-sixths nephrectomy and pair-fed on isocaloric low (4%) protein (LP) or high (50%) protein (HP) diets. Protein restriction reduced the severity of uremia. with lower blood urea nitrogen (BUN) concentrations (8.9 +/- 1.1 v 30.0 +/- 2.9 mmol/L [25 +/- 3 v 84 +/- 8 mg/dL] both n = 12. P less than 0.01). and resulted in lower mortality at 2 weeks (0% v 33%. P less than 0.05). 4 weeks (16% v 58%. P less than 0.05). and 10 weeks (16 v 83%. P less than 0.01). Isolated perfusion of the remnant kidney at 3 weeks demonstrated reduced O2 consumption (QO2) (0.77 +/- 0.2 v 2.56 +/- 0.5 mumol/min/g. both n = 7. P less than 0.05) in the absence of significant differences in inulin clearance (239 +/- 53 v 341 +/- 39 microL/min/g. NS) and net sodium reabsorption (34 +/- 8 v 49 +/- 6 mumol/min/g. NS) in rats fed the LP diet. A lower renal QO2 in protein-restricted animals was also demonstrated in vivo (4.1 +/- 0.9 v 13.8 +/- 2.7 mumol/min/g. P less than 0.01). In vivo P-31 nuclear magnetic resonance (NMR) studies of remnant kidneys did not demonstrate any difference in the steady-state tissue concentrations of adenosine triphosphate (ATP) or inorganic phosphate between rats fed LP and HP diets. Dietary protein restriction decreases the severity of uremia and diminishes renal QO2 in the remnant kidney model.
Reflex sympathetic dystrophy syndrome of the hand after placement of an arteriovenous graft for hemodialysis, Reflex sympathetic dystrophy syndrome (RSDS). a complex clinical syndrome characterized by pain and swelling of an affected extremity. is most commonly seen after trauma. We report the case of a woman with diabetes mellitus and chronic renal failure who presented with RSDS 5 months after placement of an arteriovenous (AV) graft for hemodialysis. The temporal relationship between RSDS and the vascular surgery suggests AV graft placement as the precipitating event for the development of RSDS. Treatment with systemic corticosteroids successfully relieved the patient's symptoms. We believe that RSDS should be included in the differential diagnosis of unexplained limb pain and swelling after AV graft placement.
Finnish type of familial amyloidosis: cosegregation of Asp187----Asn mutation of gelsolin with the disease in three large families, Familial amyloidosis of Finnish type (FAF) is one of the familial amyloidotic polyneuropathy (FAP) syndromes. a group of inherited disorders characterized by extracellular accumulation of amyloid and by clinical symptoms and signs of polyneuropathy. FAF. an autosomal dominant trait. belongs to those rare monogenic disorders which occur with increased frequency in the Finnish population: only single FAF cases have been reported from other populations. In most types of FAP syndromes the accumulating protein is a transthyretin variant. However. recent evidence has suggested that the amyloid peptides in FAF are related to gelsolin. an actin modulating protein. The gelsolin fragments isolated from at least one patient with amyloidosis have been reported to have an amino acid substitution. with asparagine replacing aspartic acid at position 187 of the plasma gelsolin. In this study allele-specific oligonucleotides were used to analyze three large FAF families with multiple affected individuals as well as healthy family members. We found the corresponding G-A mutation in nucleotide 654 of the plasma gelsolin gene to cosegregate with the disease. The result was confirmed by sequencing and strongly suggests that the mutation has caused all the FAF cases of these families. Since the disease is clustered in restricted areas on the southern coast of Finland. this mutation most probably causes the majority. if not all. of FAF cases in Finland.
Down syndrome due to de novo Robertsonian translocation t(14q;21q): DNA polymorphism analysis suggests that the origin of the extra 21q is maternal, Down syndrome is rarely due to a de novo Robertsonian translocation t(14q;21q). DNA polymorphisms in eight families with Down syndrome due to de novo t(14q;21q) demonstrated maternal origin of the extra chromosome 21q in all cases. In seven nonmosaic cases the DNA markers showed crossing-over between two maternal chromosomes 21. and in one mosaic case no crossing-over was observed (this case was probably due to an early postzygotic nondisjunction). In the majority of cases (five of six informative families) the proximal marker D21S120 was reduced to homozygosity in the offspring with trisomy 21. The data can be best explained by chromatid translocation in meiosis I and by normal crossover and segregation in meiosis I and meiosis II.
Sequence and localization of a partial cDNA encoding the human alpha 3 chain of type IV collagen, A novel type IV collagen. alpha 3(IV). has recently been identified in human and bovine basement membranes. Here we describe the cloning and sequencing of a cDNA encoding 218 residues of the NC1 domain of the human alpha 3(IV) chain. Of interest is the possible role of abnormalities of the alpha 3(IV) chain in Alport syndrome. as suggested by the failure to detect the NC1 domain of alpha 3(IV) in the basement membranes of some Alport syndrome patients. To determine whether the alpha 3(IV) gene (COL4A3) may be mutated in Alport syndrome. we localized it. by somatic cell hybrid analysis and in situ hybridization of metaphase chromosomes. to chromosome 2q35-2q37. Mutations in alpha 3(IV) cannot therefore be responsible for the vast majority of cases of Alport syndrome. which have been shown to be X linked. One explanation for the immunochemical data implicating alpha 3(IV) in Alport syndrome pathogenesis is that mutations of the alpha 5(IV) chain. which has been localized to Xq22 and found to be mutated in at least three kindreds with Alport syndrome. lead to failure to incorporate the alpha 3(IV) chains into the multimeric structure of glomerular basement membrane in a stable fashion.
Molecular characterization of variant alpha-subunit of electron transfer flavoprotein in three patients with glutaric acidemia type II--and identification of glycine substitution for valine-157 in the sequence of the precursor, producing an unstable mature protein in a patient, In our previous study of eight glutaric acidemia type II (GAII) fibroblast lines by using [35S]methionine labeling and immunoprecipitation. three of them had a defect in the synthesis of the alpha-subunit of electron transfer flavoprotein (alpha-ETF) (Ikeda et al. 1986). In one of them (YH1313) the labeling of the mature alpha-ETF was barely detectable. while that of the precursor (p) was stronger. In another (YH605) no synthesis of immunoreactive p alpha-ETF was detectable. In the third cell line (YH1391) the rate of variant p alpha-ETF synthesis was comparable to normal. but its electrophoretic mobility was slightly faster than normal. In the present study. the northern blot analysis revealed that all three mutant cell lines contained p alpha-ETF mRNA and that their size and amount were comparable to normal. In immunoblot analysis. both alpha- and beta-ETF bands were barely detectable in YH1313 and YH605 but were detectable in YH1391 in amounts comparable to normal. Sequencing of YH1313 p alpha-ETF cDNA via PCR identified a transversion of T-470 to G. We then devised a simple PCR method for the 119-bp section (T-443/G-561) for detecting this mutation. In the upstream primer. A-466 was artificially replaced with C. to introduce a BstNI site into the amplified copies in the presence of G-470 from the variant sequence. The genomic DNA analysis using this method demonstrated that YH1313 was homozygous for T----G-470 transversion. It was not detected either in two other alpha-ETF-deficient GAII or in seven control cell lines. The alpha-ETF cDNA sequence in YH605 was identical to normal.
The neurofibroma in von Recklinghausen neurofibromatosis has a unicellular origin, von Recklinghausen neurofibromatosis (NF1) is the most common hereditary syndrome predisposing to neoplasia. NF1 is an autosomal dominant disease caused by a single gene which maps to chromosome 17q11.2. The most common symptomatic manifestation of NF1 is the benign neurofibroma. Our previous studies of tumors in NF1. studies which detected a loss of heterozygosity for DNA markers from the NF1 region of chromosome 17 in malignant tumors. did not detect a loss in neurofibromas. We report here that a more extensive study. including the analysis of neurofibromas from 19 unrelated NF1 patients by using seven probes. failed to detect a single instance of loss of heterozygosity. This finding suggests that neurofibromas are either polyclonal or monoclonal in origin but arise by a mechanism different from that of NF1 malignancies. In order to investigate the first possibility. we analyzed neurofibromas from female NF1 patients by using an X chromosome-specific probe. from the phosphoglycerokinase (PGK) gene. which detects an RFLP. The detected alleles carry additional recognition sites for the methylation-sensitive enzyme HpaII. so that the allele derived from the active X chromosome is digested by HpaII while the one from the hypermethylated. inactive X chromosome is not. We analyzed neurofibromas from 30 unrelated females with NF1. Eight patients were heterozygous for the PGK RFLP. By this assay. neurofibromas from all eight appeared monoclonal in origin. These results suggest that benign neurofibromas in NF1 arise by a mechanism that is different from that of malignant tumors.
Trisomy 21: association between reduced recombination and nondisjunction, To assess the association between recombination and nondisjunction of chromosome 21. we analyzed cytogenetic and DNA markers in 104 trisomy 21 individuals and their parents. Our DNA marker studies of parental origin were informative in 100 cases. with the overwhelming majority (94) being maternal in origin. This value is significantly higher than the 75%-80% maternal nondisjunction rate typically observed in cytogenetic studies of trisomy 21 and illustrates the increased accuracy of the molecular approach. Using the maternally derived cases and probing at 19 polymorphic sites on chromosome 21. we created a genetic map that spans most of the long arm of chromosome 21. The map was significantly shorter than the normal female linkage map. indicating that absence of pairing and/or recombination contributes to nondisjunction in a substantial proportion of cases of trisomy 21.
Isolation of a human DNA sequence which spans the fragile X, To identify the sequences involved in the expression of the fragile X and to characterize the molecular basis of the genetic lesion. we have constructed yeast artificial chromosomes (YACs) containing human DNA and have screened them with cloned DNA probes which map close to the fragile site at Xq27.3. We have isolated and partly characterized a YAC containing approximately 270 kb of human DNA from an X chromosome which expresses the fragile X. This sequence in a yeast artificial ring chromosome. XTY26. hybridizes to the two closest DNA markers. VK16 and Do33. which flank the fragile site. The human DNA sequence in XTY26 also spans the fragile site on chromosome in situ hybridization. When a restriction map of XTY26. derived by using infrequently cutting restriction enzymes. is compared with similar YAC maps derived from non-fragile-X patients. no large-scale differences are observed. This YAC. XTY26. may enable (a) the fragile site to be fully characterized at the molecular level and (b) the pathogenetic basis of the fragile-X syndrome to be determined.
Marfan syndrome: no evidence for heterogeneity in different populations, and more precise mapping of the gene, Marfan syndrome is a dominantly inherited connective tissue disorder with manifestations in the cardiovascular. ocular. and skeletal systems. The diagnosis is hampered by both high variability in the phenotypic expression and late manifestation of symptoms. The cause of Marfan syndrome remains unknown. but our group has recently reported the genetic linkage of Marfan syndrome to a polymorphic marker on chromosome 15. To analyze the possible heterogeneity behind Marfan syndrome. we have performed linkage analyses for four chromosome 15 markers in 17 families from five different populations: Scottish. English. Swiss. American. and Finnish. By combining the linkage data of all the studied families into a LINKMAP analysis we obtained a maximal LOD score of 11.2. which maps the Marfan syndrome locus between D15S25 and D15S45 on the long arm of chromosome 15. The data reveal no evidence for genetic heterogeneity behind Marfan syndrome and provide us with a more precise location of both the Marfan syndrome locus and flanking markers. This information will provide the basis for the DNA diagnostics of Marfan syndrome in the future.
Complex segregation analysis of nonsyndromic cleft lip and palate, This study was undertaken to examine the inheritance pattern of nonsyndromic cleft lip with or without cleft palate (CL/P). Complex segregation analysis using the unified model as in POINTER and the regressive model as in REGD programs were applied to analyze a midwestern U.S. Caucasian population of 79 families ascertained through a proband with CL/F. In REGD. the dominant or codominant Mendelian major locus models of inheritance were the most parsimonious fit. In POINTER. besides the Mendelian major locus model. the multifactorial threshold (MF/T) model and the mixed model were also consistent with the observed data. However. the high heritability parameter of .93 (SD .063) in the MF/T model suggests that any random exogenous factors are unlikely to be the underlying mechanisms. and the mixed model indicates that this high heritability is accounted for by a major dominant locus component. These findings indicate that the best explanation for the etiology of CL/P in this study population is a putative major locus associated with markedly decreased penetrance. Molecular studies may provide further insight into the genetic mechanism underlying CL/P.
Cleft lip and palate: no evidence of linkage to transforming growth factor alpha, Recently. an association of a specific transforming growth factor alpha (TGFA) haplotype has been reported to occur in patients with nonsyndromic cleft lip and palate (CLP) who had a positive family history of the disorder. We tested linkage of CLP to TGFA in 12 multiplex families with clefting. TGFA haplotypes were constructed on the basis of three polymorphic restriction sites. No haplotype was associated with CLP. and discordant inheritance of TGFA haplotypes was observed in a single informative family. The log odds (LOD) score was -2.1 at theta = .05. These findings indicate that CLP and TGFA are not tightly linked in these families.
Healing of erosive esophagitis with sucralfate and cimetidine: influence of pretreatment lower esophageal sphincter pressure and serum pepsinogen I levels, Forty-eight patients with erosive reflux esophagitis were allocated to either sucralfate tablets. 4 g/day. or cimetidine. 1.6 g/day. for 8 weeks in a randomized. prospective. single-blind. cross-over therapeutic trial. Pretreatment lower esophageal sphincter (LES) pressure and serum pepsinogen I (PG-I) levels were investigated as possible predictors of healing with either drug. The trial was completed by 41 patients (21 in the sucralfate group and 20 in the cimetidine group); one patient in each group was removed because of side effects. Symptom improvement occurred to a similar extent in both groups. Endoscopic results after 8 weeks of treatment with sucralfate revealed complete healing of esophageal erosions in 48% (cimetidine. 55%) and improvement in an additional 19% (cimetidine. 20%). Neither of these differences was statistically significant. Some patients refractory to one drug had endoscopic healing of esophagitis when treated with the other drug after crossover. LES pressure did not influence outcome in patients treated with sucralfate. whereas significantly (p = 0.024) more patients refractory to cimetidine had an LES pressure less than 7 mm Hg than did those with a good response to the histamine-2 (H2)-receptor blockade. Patients whose esophagitis healed or improved after sucralfate tended to have lower serum PG-I levels than those with treatment failure (104 +/- 35 ng/mL vs 125 +/- 45 ng/mL). whereas the opposite occurred in patients treated with cimetidine (132 +/- 58 ng/mL in responders vs 78 +/- 27 ng/mL in nonresponders. p = 0.048). The results confirm that sucralfate is a valuable alternative to H2-receptor inhibitors for the treatment of reflux esophagitis. They also provide preliminary evidence that LES pressures and serum PG-I levels may have predictive value of the response to one or the other of these two drugs.
Sucralfate versus cimetidine in the treatment of reflux esophagitis, with special reference to the esophageal motor function, Sixty patients entered a double-blind clinical trial comparing the effect of 1 g of sucralfate granulate given four times daily and cimetidine. 400 mg twice daily. Twenty-six patients treated with sucralfate and 26 treated with cimetidine were examined with short-term pH monitoring before and after 12 weeks of treatment. Thirty patients. 19 treated with cimetidine and 11 treated with sucralfate. had esophageal motility studied by a radionuclide test before and after 12 weeks of treatment. The efficacy of the treatments was judged by symptoms and endoscopic response after 4. 8. and 12 weeks of treatment. The endpoint healing rate was approximately 60% in both groups and symptoms were relieved in half of the patients in both groups (difference not significant). The effect of the treatments on pH and number of spikes reflected the different pharmacodynamic profiles of the drugs. whereas the mean transit time (MTT) was not changed by the treatments. The residual activity after radionuclide transit in the sitting position was significantly increased after treatment with cimetidine. The data support the hypothesis that primary dysmotility might be involved in the pathogenesis of reflux esophagitis in about 33% of the patients. Possibilities for a combination therapy with sucralfate and cimetidine are stressed.
Reflux esophagitis therapy: sucralfate versus ranitidine in a double blind multicenter trial, Sucralfate (Sc) suspension 6 g/day and ranitidine (Rn) tablets. 150 mg. were compared in 125 patients in a double-blind. multicenter. endoscopically controlled trial in the treatment of reflux esophagitis. Inclusion criteria were symptomatic reflux (number and severity of attacks) and endoscopic evidence of esophagitis (grades 1 to 4). Clinical assessments were performed on entry. and at 4 and at 8 weeks. and endoscopy was repeated at 8 weeks. Sc suspension and Rn placebo or Sc placebo and Rn tablets were taken on waking and immediately before retiring at night. Of the 125 patients. 27 were withdrawn because of default (Rn = 4; Sc = 14). noncompliance (Rn = 1; Sc = 2). or the development of congestive cardiac failure (Rn = 1). diarrhea (Rn = 1; Sc = 1). nausea (Sc = 1). constipation (Sc = 1). and hematemesis (Sc = 1). Analysis was performed on the remaining 98 patients. 43 of whom had been treated with Sc and 55 with Rn. Heartburn. acid regurgitation. epigastric pain. dysphagia. and chest pain were relieved in 34% vs 40%. 67% vs 72%. 71% vs 57%. and 86% vs 63% for Sc and Rn. respectively. There was no significant difference between the two groups. Endoscopic healing occurred in 47% of the Sc- and in 31% of the Rn-treated patients (chi 2 = 2.50). and healing or improvement was noted in 81% of the Sc- and 64% of the Rn-treated patients. This difference approached statistical significance (chi 2 = 3.73). There was no obvious endoscopic benefit in 8 of the 43 and 20 of the 55 patients in the groups treated with Sc and Rn. respectively. Although the findings with sucralfate and ranitidine in patients with reflux esophagitis completing the trial suggest a benefit of these agents. the absence of a placebo control group and the high default rates. particularly for those receiving sucralfate. preclude any firm conclusions as to relative or specific efficacy of these agents in this condition.
Enhancement of the protective qualities of gastric mucus by sucralfate: role of phosphoinositides, The effects of intragastric administration of sucralfate on the physicochemical properties of gastric mucus. and the mechanism of its protective action against alcohol-induced mucosal injury were investigated using in vivo and in vitro models. The experiments in vivo were conducted with groups of rats receiving a dose of 100 mg sucralfate twice daily for 5 consecutive days. The animals were sacrificed 16 hours after the last dose. their stomachs dissected. and the mucosa subjected to physicochemical measurements. In the in vitro studies. gastric mucosa was cultured in the presence of sucralfate. ethanol. or both. The in vivo results revealed that sucralfate elicited an 8% increase in mucus gel dimension. while its sulfo- and sialomucin content increased by 63% and 81%. respectively. The changes in mucus gel mucin content with sucralfate were accompanied by a 9.5% increase in mucus hydrogen ion (H+) retardation capacity. 1.9-fold increase in viscosity. and a 60% increase in the gel hydrophobicity. The mucus elaborated in the presence of sucralfate exhibited 14% lower protein content and 62% higher content of carbohydrate than that of control. and contained more neutral lipids. Furthermore. the gastric mucus of the sucralfate group showed a marked increase in mucus glycoprotein polymeric form. The data obtained with gastric mucosal culture demonstrated that sucralfate elicited a significant increase in mucin synthesis. which was reflected in the enhanced metabolism of mucosal phosphoinositides. In contrast. ethanol. which exhibited detrimental effects on mucin synthesis. also caused alterations in the phosphoinositide signal pathway. The changes in mucin and phosphoinositide distribution patterns evoked by ethanol were prevented by sucralfate. Our results suggest that the mucosal strengthening action of sucralfate occurs through the stimulation of the metabolism of phosphoinositide-derived messenger molecules.
Mechanisms of gastroduodenal protection by sucralfate, Over the past 5-10 years. a number of studies have shown that topical sucralfate enhances a number of gastric and duodenal mechanisms. e.g.. the "mucus-bicarbonate barrier." mucosal hydrophobicity. mucosal blood flow. cell viability. and local production of prostaglandins. as well as endogenous mediators of tissue injury and repair. It seems likely that the complex actions of sucralfate are in part related to direct interaction between the drug or its components (aluminum. sucrose. and sulfate) and gastric mucosal tissues. and in part related to effects of the drug on the various mucosal mediators of tissue injury and repair. Local actions may play a role in accelerating healing of ulcer-damaged mucosa. but this does not explain the protective actions of sucralfate on normal mucosa. Thus sucralfate appears to enhance the protective function of the "mucus-bicarbonate" barrier by actions on both components. This may depend in part on an interaction with the unstirred layer overlying gastric epithelium. Sucralfate has also been shown to increase the hydrophobicity of mucus gel. There is little doubt that sucralfate increases local production and release of protective prostaglandins (PGs). but the precise role played by these agents in mediating mucosal protection and in chronic ulcer healing remains uncertain. Currently. the mechanism of action of sucralfate on vascular integrity remains unknown and the role of PGs in this protective function is unclear. There is little evidence that epidermal growth factor plays any role in mediating mucosal protection by sucralfate. but it may be important in its ulcer-healing action. Sucralfate has been shown to be truly "cytoprotective" in that it protects isolated epithelial cells from damage by noxious agents. In animals treated with sucralfate. the surface epithelial cells were disrupted. but necrotic lesions in the deep proliferative zone were virtually absent. It seems likely that investigations of the actions of sucralfate and its components will move ever closer to defining the target cells. the intracellular events. and the mediators that bring about its protective and ulcer-healing activity.
Comparative study of sucralfate 2 grams twice daily versus sucralfate 1 gram four times daily in the treatment of benign gastric ulcers in outpatients, In a double-blind. randomized study. we compared the healing of gastric ulcer during a twice-daily regimen of 2 g sucralfate or sucralfate 1 g q.i.d. Patients receiving the former therapy received the tablets one-half hour before breakfast and at bedtime. Patients receiving sucralfate 1 g q.i.d. received their therapy 30 minutes before breakfast. lunch. and supper. and at bedtime. The study included 52 patients with endoscopically proven gastric ulcer; 41 patients completed the study. Healing was endoscopically assessed at 8 weeks and 12 weeks. After 8 and 12 weeks the healing rate for sucralfate 2 g b.i.d. was 67% and 92%. respectively; the healing rate of sucralfate 1 g q.i.d. was 59% and 71%. respectively. No statistically significant difference was found between the two regimens. The results suggest that 2 g sucralfate twice daily is as effective in the healing of gastric ulcer as 1 g sucralfate q.i.d.
Clinical efficacy of sucralfate in the treatment of gastric ulcer, We performed a randomized. single-blind study in Japan to investigate the efficacy and safety of two dosage regimens of sucralfate granules. 2 g. twice daily (b.i.d. group. n = 30) and 1 g. 4 times daily (q.i.d. group. n = 27). on ulcer healing in 57 patients with endoscopically proven gastric ulcer. Endoscopy was performed after 4 weeks and. if complete healing was not achieved. again after an additional 4 weeks. Of 57 patients. 11 were excluded from the statistical analysis because of protocol violation (six in b.i.d. group. five in q.i.d. group). Of 46 patients eligible for the analysis of healing rates. four patients in the b.i.d. group (all at 8 weeks) and five patients in the q.i.d. group (two at 4 weeks and three at 8 weeks) were withdrawn due to patients' inconvenience. As the possibility that the withdrawals were due to the treatment failures could not be denied. we used the Kaplan-Meier method and generalized Wilcoxon test/logrank test for the calculation and evaluation of healing rates in this study. respectively. Healing rates at 4 and 8 weeks were 50% and 94% in the b.i.d. group and 35% and 68% in the q.i.d. group. There was no significant difference in healing rates between the groups. No serious adverse effect was observed in either group. These results suggest that the 2 g b.i.d. dose of sucralfate in granule form is at least as effective as the conventional dose of 1 g q.i.d. in the treatment of active gastric ulcers and could lead to better patient compliance.
Fenestrated sheen macular dystrophy, We examined a family with fenestrated sheen macular dystrophy. The red macular lesions were strikingly apparent in the propositus and more subtle in one affected cousin. Pronounced macular retinal pigment epithelial disruption or mottling was present in the father of the propositus. who also had markedly reduced electroretinogram rod and cone responses. The extent of electroretinogram amplitude reduction indicates abnormal function of the peripheral retina in addition to the clinically evident macular changes. Affected family members showed peripheral retinal pigment epithelial granularity. Central visual acuity remained normal despite the presence of macular lesions.
Identifying progression of subclinical keratoconus by serial topography analysis, We performed serial slit-lamp examinations and topography analysis on a patient whose initial topographic map suggested a diagnosis of keratoconus to us but which others interpreted as normal topography. Topography analysis documented cone progression during a two-year period. The initial map showed a cone apex power of 44.5 diopters located 2.1 mm inferior to the vertex normal. An oblong-shaped area of maximum power was surrounded by concentric bands of lower power. Corneal surface power ranged from 41.5 to 44.5 diopters. Two years later cone apex power increased to 51.0 diopters. and the patient developed a Fleischer's ring. Vogt's striae. and mild visual aberration. Our findings suggest the use of topography analysis systems in documenting subclinical cone progression. Topography systems may be a useful tool in the study of the true incidence and natural progression of subclinical keratoconus.
Diode laser compared with argon laser for trabeculoplasty, A randomized prospective study on two groups of ten patients compared the efficacy of diode laser and argon laser trabeculoplasty. In the diode laser group the intraocular pressure was 23.0 +/- 3.97 mm Hg before the treatment. 20.2 +/- 4.49 mm Hg at two hours. 16.3 +/- 3.13 at six months. and 16.9 +/- 2.80 mm Hg at one year. The differences from baseline were statistically significant at six months (P = .0001) and at one year (P = .0001) but not at two hours. In the argon laser group the intraocular pressure was 23.4 +/- 3.6 mm Hg before the treatment. 22.7 +/- 4.35 mm Hg at two hours. and 17.6 +/- 4.53 mm Hg at six months. One patient had uncontrolled mean high intraocular pressure and underwent surgery. In the nine patients who completed the study the intraocular pressure at one year was 16.7 +/- 3.00 mm Hg. The differences from baseline were significant at six months (N = 10; P = .0001) and 12 months (N = 9; P = .0001) but not at two hours. Differences between the two groups were not significant at two hours. six months. and one year. Laser trabeculoplasty may be effectively with a diode laser.
Evaluation of once-daily levobunolol 0.25% and timolol 0.25% therapy for increased intraocular pressure, In a three-month. double-masked. randomized clinical trial. we evaluated the once-daily ocular hypotensive efficacy of 0.25% levobunolol and 0.25% timolol in 80 patients with open-angle glaucoma or ocular hypertension. Thirty-seven of the 39 patients (95%) in the 0.25% levobunolol group and 35 of the 41 patients (85%) in the 0.25% timolol group successfully completed the three-month study period. The overall mean decrease in intraocular pressure was 5.3 mm Hg (22%) in the 0.25% levobunolol group and 5.4 mm Hg (22%) in the 0.25% timolol group. This difference was not statistically significant. In both treatment groups. effects on mean heart rate and blood pressure were minimal. The data suggest that levobunolol 0.25% and timolol 0.25%. administered once daily. are equally effective in the treatment of open-angle glaucoma and ocular hypertension.
Diurnal intraocular pressure after successful primary laser trabeculoplasty, In 20 patients who were successfully treated with laser trabeculoplasty as the primary therapy for glaucoma. we measured the intraocular pressure every two hours between 8:00 A.M. and 8:00 P.M. Success was defined as intraocular pressure of 22 mm Hg or less without medication. Of 20 patients. three had open-angle glaucoma and 17 had exfoliative glaucoma. Intraocular pressure was stable with small fluctuations during the daytime.
Intrathecal antibody production against viruses of the herpesvirus family in acute retinal necrosis syndrome, Viruses of the herpesvirus family cause acute retinal necrosis syndrome. a devastating necrotic retinitis in immunocompetent individuals. Direct proof of the viral origin of this disease may be obtained by demonstration of the virus. viral antigens. or viral DNA in biopsy specimens of retinas. In search of alternative diagnostic methods. we analyzed cerebrospinal fluid and serum with enzyme-linked immunosorbent assays for virus-specific antibody activity. Intrathecally produced viral antibodies were found in three consecutive patients with acute retinal necrosis syndrome: herpes simplex type 2 in a 30-year-old woman with a history of suspected neonatal herpes encephalitis. herpes simplex type 1 in a 35-year-old man. and varicella-zoster virus activity in a 62-year-old woman. None of the patients had clinical signs indicating an acute disorder in the central nervous system. This serologic approach seems to be of value for the diagnosis of an associated intracerebral viral infection in cases of acute retinal necrosis syndrome.
Decrease in the risk of bilateral acute retinal necrosis by acyclovir therapy, We reviewed the course of 54 patients who had unilateral acute retinal necrosis at initial examination. Thirty-one patients were treated with acyclovir. whereas 23 were not. Of the 31 patients treated with acyclovir. 27 (87.1%) had fellow eyes that remained disease-free throughout a median follow-up of 12 months. Of the 23 patients not treated with acyclovir. seven (30.4%) had fellow eyes that remained disease-free throughout a median follow-up of 11 months. Survival analysis indicated that the fellow eyes of the group of patients treated with acyclovir were more likely to remain disease-free than the fellow eyes of the group not treated with acyclovir (P = .0013). Two years after initial onset. the proportion of fellow eyes that remained disease-free was 75.3% for the group treated with acyclovir and 35.1% for the group not treated with acyclovir. These results suggest that acyclovir treatment reduces the risk of involvement of the fellow eye in patients with acute retinal necrosis.
Retinal function and rhodopsin levels in autosomal dominant retinitis pigmentosa with rhodopsin mutations, We studied rod and cone function in 20 patients from six families with autosomal dominant retinitis pigmentosa. who represented five different point mutations in the gene encoding rhodopsin. In a family with a stop codon mutation at the carboxyl end of the molecule (glutamine-344). young members with the mutation were asymptomatic and clinically unaffected but showed about 1 log unit of rod sensitivity loss across the visual field and decreased rhodopsin levels; at this stage. cone function was essentially normal. In three families with mutations at the border of a transmembrane segment (arginine-135-leucine and arginine-135-tryptophan). there was neither detectable rod function nor measurable rhodopsin; cone function was variably impaired. Two families carrying different mutations (threonine-17-methionine and threonine-58-arginine) had altitudinal visual field defects with less impaired rod and cone function in the inferior than in the superior field. Rod adaptation was abnormal in both families. but the time course of adaptation differed between patients with the two mutations. Differences in the pattern of retinal dysfunction were therefore discernible in patients with different rhodopsin mutations.
B-scan ultrasonography of eyes containing intravitreal gas, Contact B-scan ultrasonography was performed on postoperative eyes containing intravitreal gas. Correlation of the ultrasonograms with the ophthalmoscopic findings disclosed that intraocular gas had a characteristic appearance on B-scan ultrasonography. Gas-fluid and gas-tissue interfaces were so highly reflective that no structures within or behind a bubble could be visualized. Shadowing. reverberation. and reflection artifacts were prominent. and dominated ultrasonographic findings. If the ultrasonographic characteristics of gas are understood. it is possible to use B-scan ultrasonography to determine if intraocular gas is present. whether there are one or several bubbles. and what percentage of the vitreous cavity is filled by gas. Specular reflection from a gas-fluid interface may be used to examine portions of the eye that might not otherwise be easily seen with ultrasonography.
Lens capsule and epithelium in age-related cataract, On the basis of preoperative assessment of patient characteristics. intraoperative obtainment of a lens-capsule and epithelium specimen. histopathologic investigation of lens capsule and epithelium. and biochemical analysis of glutathione reductase in lens epithelium. age-related cataract was studied in 50 adult patients who underwent consecutive extracapsular cataract-posterior chamber lens implant surgery. Patients (25 men and 25 women; age range. 41 to 91 years; mean age. 75 years) had a wide range of systemic and ocular disease; 17 of 50 (34%) patients had a history of severe vision-impairing cataract in a first-degree relative. Anterior lens-capsule thickness ranged from 10 to 22 microns. with a mean of 17 microns. Statistical analysis of lens-epithelium ultrastructure in 41 of 50 specimens documented mixing of normal and abnormal cells. verified a gradation in the degree of abnormal ultrastructural features. and demonstrated a statistically significant decrease in epithelial cytologic activity with advancing age (P = .038). Biochemical analysis documented a severe glutathione reductase deficiency in nine of 39 (23%) lens-epithelium specimens. possibly reflecting a dietary deficiency of riboflavin.
Conjunctival impression cytology in patients with glaucoma using long-term topical medication, Increasing evidence indicates that long-term use of topically administered medications can induce changes in the conjunctiva and ocular surface. We used the technique of conjunctival impression cytology to evaluate the conjunctival changes that develop with long-term use of topically administered antiglaucoma medications. Patients with glaucoma who were on a stable regimen of one. two. or three topically administered medications were recruited for study; glaucoma suspects who were not using topically administered medications served as controls. Eyes with clinical or historical evidence of external eye disease or conjunctival surgery were excluded. Impression cytology specimens. collected from the bulbar and palpebral conjunctiva. were coded and subsequently graded by a masked observer. We examined specimens from 72 eyes by using this technique. Aggregate scores for the bulbar conjunctiva were compiled. using a previously described grading system with a range of 0 (normal) to 3 (diffuse. severe metaplasia). The results show statistically significant degrees of conjunctival metaplasia associated with the number of glaucoma medications used. These results suggest that the long-term use of antiglaucoma medications induces changes in the conjunctival surface. These changes may be related to the medications themselves. the preservatives in the commercial preparations. or the duration of topical treatment. The clinical relevance of these changes remains unknown.
A clinical trial of metipranolol, a noncardioselective beta-adrenergic antagonist, in ocular hypertension, In randomized. double-masked fashion. 24 volunteers with ocular hypertension received 0.3% or 0.6% metipranolol. a noncardioselective beta blocker; or placebo twice daily to both eyes for six weeks. Intraocular pressure (mean +/- SEM) was reduced (P = .01) in the metipranolol-treated patients (baseline measurement. 25.9 +/- 0.5 mm Hg to 18.1 +/- 1.2 mm Hg at six weeks. 0.6% concentration; baseline measurement. 27.1 +/- 0.4 mm Hg to 21.6 +/- 1.5 mm Hg at six weeks. 0.3% concentration). Intraocular pressure was not markedly changed in placebo-treated patients. Outflow facility was unaltered two hours after instillation of metipranolol at study week 2 compared to baseline measurement. Aqueous humor flow rates were reduced (P = .02) 20% after 0.6% or 0.3% metipranolol instillation and were unchanged after placebo administration compared to baseline measurement. Mean systolic blood pressure. diastolic blood pressure. and pulse rate were not markedly altered. Metipranolol reduces intraocular pressure by suppressing aqueous humor flow rates.
Isolating the effects of primary open-angle glaucoma on the contrast sensitivity function, We evaluated spatial contrast sensitivity functions in age-matched and lens density-matched healthy eyes. eyes with primary open-angle glaucoma. and eyes with ocular hypertension. We also controlled for refraction. visual acuity. pupil size. and previous ocular history. We found an overall reduction in contrast sensitivity for the glaucomatous eyes with a significant difference at 12 cycles per degree (P less than .012). Eyes with ocular hypertension were not significantly different from normal eyes. Significant differences were noted at several spatial frequencies with less careful controls for age and lens effects. We concluded that spatial contrast sensitivity may be a useful adjunctive diagnostic test for glaucoma. but interpreting the results without other clinical data may lead to errors in diagnosis.
Psychosis and physical aggression in probable Alzheimer's disease, OBJECTIVE: The purpose of this study was to determine the frequency and type of psychotic symptoms in patients with probable Alzheimer's disease and to test whether there is a relationship between specific psychotic symptoms and episodes of physical aggression. METHOD: From 209 patients with possible or probable Alzheimer's disease who had been assessed in a research clinic every 6 months for up to 4.5 years. 181 subjects with probable Alzheimer's disease were selected for study. On the basis of the summary note for each visit in the patients' charts. the presence of delusions. hallucinations. misidentifications. and episodes of physical aggression was determined. Data regarding psychotic symptoms and aggression were available for 170 and 169 subjects. respectively. RESULTS: Delusions had been reported for 74 (43.5%) of the patients and were the most frequent psychotic symptom; persecutory delusions were the most common type. Physical aggression had been noted for 50 (29.6%) of the patients. Delusions and misidentifications frequently preceded and were significantly associated with episodes of physical aggression. The presence of delusions was a significant predictor of physical aggression but accounted for only 3.5% of the variance. CONCLUSIONS: This study suggests that delusions are a risk factor for physical aggression in patients with probable Alzheimer's disease who have moderate to severe cognitive impairment. As delusions accounted for only a small percentage of the variance. further research is needed to identify other variables that may be significant predictors of physical aggression in this population.
Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test, OBJECTIVE: This study characterized objectively the hypersomnia frequently seen in the depressed phase of bipolar affective disorder. On the basis of previous work in sleep and affective disorders. it has been hypothesized that the hypersomnia is related to greater REM sleep. This hypothesis was tested by using a multiple sleep latency test to compare bipolar affective disorder with narcolepsy. a well-defined primary sleep disorder associated with known REM sleep dysfunction. METHOD: Twenty-five bipolar depressed patients were selected on the basis of complaints of hypersomnia. They underwent 2 nights of polysomnography followed by a multiple sleep latency test. Data on their nocturnal sleep and daytime naps were compared with similar data on 23 nondepressed narcoleptic patients referred for sleep evaluation. RESULTS: Despite their complaints of hypersomnia. no abnormalities were noted for the bipolar group in the results from the multiple sleep latency test. Contrary to the working hypothesis. REM sleep was notably absent during daytime naps in the depressed patients. in marked contrast to the findings for the narcoleptic group. CONCLUSIONS: The complaint of sleepiness in the hypersomnic bipolar depressed patient appears to be related to the lack of interest. withdrawal. decreased energy. or psychomotor retardation inherent in the anergic depressed condition. rather than an increase in true sleep propensity or REM sleep propensity.
Long-term outcome of antidepressant treatment for bulimia nervosa, OBJECTIVE: The purpose of this study was 1) to replicate previous work indicating that antidepressant medication is superior to placebo in the treatment of bulimia nervosa and 2) to assess the long-term efficacy of this form of treatment. METHOD: Eighty patients entered a three-phase treatment protocol. An 8-week double-blind initiation phase was used to compare the effects of desipramine and placebo. Patients who responded satisfactorily to desipramine entered a 16-week maintenance phase. Patients who remained well were then randomly assigned to either desipramine or placebo for 6 additional months (discontinuation phase). The primary outcome measure was binge frequency. which was assessed weekly by self-report diaries. RESULTS: In the initiation phase the superiority of desipramine over placebo in reducing binge frequency was demonstrated. Patients treated with desipramine had a mean reduction in binge frequency of 47% at termination. whereas patients taking placebo experienced a mean increase of 7%. Less than half of the patients treated with desipramine met the criteria for entering the maintenance phase. and 29% of the patients entering that phase relapsed in the following 4 months. There were not enough patients in the discontinuation phase to permit clear conclusions about the need for continued antidepressant medication after 6 months of treatment. CONCLUSIONS: The study documents a beneficial effect of desipramine in the treatment of bulimia nervosa when compared to placebo. However. limited improvement and considerable relapse with continued treatment suggest serious limitations to the long-term efficacy of a single antidepressant trial in treating bulimia nervosa.
Serum nortriptyline levels in nursing mothers and their infants, The nortriptyline levels of seven depressed mothers and their breast-fed infants were obtained. Nortriptyline was not detected in the infants' sera. However. two of four infants evaluated developed low concentrations of 10-hydroxynortriptyline. No adverse effects were observed.
Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women, OBJECTIVES: To determine whether relative vitamin D deficiency during the winter months contributes to age-related bone loss and whether rates of change in hard- and soft-tissue mass vary during the year. DESIGN: Double-blind. placebo-controlled. 1-year trial in 249 women in which equal numbers of women were randomized to either placebo or 400 IU of vitamin D daily. All women received 377 mg/d of supplemental calcium largely as calcium citrate malate. PATIENTS: Healthy. ambulatory postmenopausal women with usual intakes of vitamin D of 100 IU/d. MEASUREMENTS: Duplicate spine and whole-body scans were done by dual energy x-ray absorptiometry at 6-month intervals that were timed to periods when 25-hydroxyvitamin D levels were highest and lowest. Period 1 was June-July to December-January and period 2 was December-January to the next June-July. Serum parathyroid hormone and plasma 25-hydroxyvitamin D levels were measured during periods 1 and 2. MAIN RESULTS: In the placebo group. spinal bone mineral density increased in period 1. decreased in period 2. and sustained no net change. Women treated with vitamin D had a similar spinal increase in period 1 (1.46% compared with 1.40% in placebo). less loss in period 2 (-0.54% compared with -1.22%. CI for the difference. 0.05% to 1.31%. P = 0.032) and a significant overall benefit (0.85% compared with 0.15%. CI for the difference. 0.03% to 1.37%. P = 0.04). In period 2. 25-hydroxyvitamin D levels were lower and parathyroid hormone levels were higher in the placebo than in the vitamin D group. Whole-body lean and fat tissue and bone mineral density varied during the year but did not change overall. CONCLUSIONS: At latitude 42 degrees. healthy postmenopausal women with vitamin D intakes of 100 IU daily can significantly reduce late wintertime bone loss and improve net bone density of the spine over one year by increasing their intake of vitamin D to 500 IU daily. A long-term benefit of preventing vitamin D insufficiency in the winter seems likely although it remains to be shown. Observed changes in bone as well as in fat and lean tissue appear to be related to season.
The T-cell proliferative assay in the diagnosis of Lyme disease, OBJECTIVE: To determine the sensitivity and specificity of the T-cell proliferative assay as a diagnostic test in Lyme disease. DESIGN: Cross-sectional study of patients with Lyme arthritis or chronic neuroborreliosis who had a history of erythema migrans. positive antibody responses to Borrelia burgdorferi by enzyme-linked immunosorbent assay (ELISA). or both; patients with other diseases; and healthy subjects. SETTING: Diagnostic Lyme disease clinic in a university hospital. PATIENTS: Forty-two of the 67 patients with active Lyme arthritis or chronic neuroborreliosis who were seen during the study period; 16 patients with inactive late Lyme disease; 77 patients with other rheumatologic or neurologic diseases; 9 workers from the Borrelia laboratory; and 9 healthy subjects. MEASUREMENTS AND MAIN RESULTS: Nineteen of 42 patients with Lyme arthritis or chronic neuroborreliosis and 4 of 77 patients with other diseases had positive T-cell proliferative responses to B. burgdorferi antigens. The sensitivity of the proliferative assay was 45% (95% Cl. 30% to 60%) and the specificity was 95% (95% Cl. 87% to 99%). Twelve of 27 patients with active Lyme arthritis. 7 of 15 patients with chronic neuroborreliosis. 4 of 16 patients with inactive Lyme disease. 4 of 9 healthy Borrelia laboratory workers. and 0 of 9 healthy subjects had positive responses. Three of five patients with Lyme disease who had negative or indeterminant antibody responses by ELISA had positive T-cell proliferative responses. CONCLUSION: The T-cell proliferative assay may be a helpful diagnostic test in the small subset of patients with late Lyme disease who have negative or indeterminant antibody responses by ELISA.
NIH conference. Systemic lupus erythematosus, Although the cause of systemic lupus erythematosus remains unknown. pathogenic mechanisms are becoming clearer. Both genetic and environmental factors have been implicated in the induction and in the perpetuation of lupus. Implicated environmental triggers include ultraviolet light. chemicals (hydrazines. hair dyes. drugs). some foods. and possibly infectious agents. Lupus is mediated by the immune system. Patients have excess numbers of antibody-forming cells. including those that produce antibodies reactive with self-antigens. Patients also have an increased number of activated T cells. some of which help B cells to produce autoantibodies. A loss of tolerance is a critical immune abnormality in lupus; many of the activated helper T cells may result from a failure in normal tolerance mechanisms. A hematopoietic stem-cell defect could give rise to both B- and T-cell abnormalities. Such a stem-cell abnormality might lead to both a loss of self-tolerance and polyclonal B-cell activation. Antigen-driven. T-cell-dependent expansion of B-cell clones would then give rise to pathogenic autoantibodies. including anti-DNA. We believe that lupus is a syndrome: Patients differ regarding specific inciting factors and immune defects. Some patients have genetically conditioned abnormalities. similar to those found in mice with lupus; others have a combination of genetic and acquired defects. We hope that insights into pathogenesis lead to improved and more individualized therapy.
When should patients with lethal ventricular arrhythmia resume driving? An analysis of state regulations and physician practices, Most states have specific laws governing whether patients with seizure disorders can drive. To learn whether similar laws exist for patients with lethal ventricular arrhythmias. we surveyed the Departments of Motor Vehicles in all 50 states. In addition. either an arrhythmia specialist (n = 25) or a general cardiologist (n = 25) was chosen randomly from each state and interviewed to study physician awareness of such laws and physician attitudes toward driving by patients with arrhythmias. Forty-two states (84%) have laws restricting driving by patients who have seizures; only 8 states (16%) have specific laws for patients with arrhythmias. No state makes a distinction between driving by patients with arrhythmias who are managed with an implantable cardioverter-defibrillator (ICD) compared with patients who are managed medically. Seventy-four percent of physicians did not know their own state's laws about driving by patients who have ventricular arrhythmias. Cardiologists were more likely to advise no driving restriction for medically treated patients than for ICD-treated patients. Cardiologists were also more likely to advise permanent restriction for patients with ICDs than for patients treated medically. We conclude that greater legal and medical consensus is needed to guide physicians in advising patients with lethal ventricular arrhythmias about driving restrictions.
Comorbidity of psychiatric diagnoses in anorexia nervosa, The comorbidity of psychiatric diagnoses was examined with the Diagnostic Interview Schedule in 62 women who participated in a 10-year follow-up study of anorexia nervosa. Sixty-two age- and sex-matched controls. their parents. and parents of the anorectic probands were also interviewed with the Diagnostic Interview Schedule. There was a statistically significant comorbidity of the affective and anxiety disorders with anorexia nervosa. The first-degree relatives of the anorectic probands had significantly more alcoholism and total number of psychiatric diagnoses compared with the first-degree relatives of controls. There were two mothers with bulimia nervosa. two cases of anorexia nervosa and two of bulimia nervosa in other first-degree relatives of anorectic probands. and no cases of eating disorders in the first-degree relatives of controls.
Characterizing organic delusional syndrome, We present a first comprehensive description of the clinical features of patients with organic delusional syndrome. This description is based on information from 39 patients with organic delusional syndrome among 14.889 patients who presented for initial evaluation over a 5-year period at our institution. This description includes an enumeration of the common clinical symptoms of this syndrome and the respective prevalence and mean severity of each symptom. The severity of the symptoms of organic delusional syndrome are compared with those of schizophrenia to determine which symptoms distinguish between these two diagnostic categories. Patients with organic delusional syndrome demonstrated significantly more symptoms of "acquired intellectual impairment." "impaired sensorium." and "hallucinations of smell. taste. or touch." while schizophrenic patients demonstrated more "flat affect." "emotional coldness." and "thought disorganization." In addition. associated factors are presented concerning demographics. modes of treatment. level of functioning. and current physical problems associated with organic delusional syndrome.
Nicotine potentiation of haloperidol in reducing tic frequency in Tourette's disorder [published erratum appears in Am J Psychiatry 1991 Sep;148(9):1282, In an open. nonblind study. 10 patients with Tourette's disorder who were being treated with haloperidol were videotaped before. while. and after chewing nicotine gum. The frequency of tics was reduced significantly during the 30-minute gum-chewing period and during the 1 hour after gum chewing. Nicotine appears to potentiate haloperidol effects in patients with Tourette's disorder.
Efficacy of SIV/deltaB670 glycoprotein-enriched and glycoprotein-depleted subunit vaccines in protecting against infection and disease in rhesus monkeys, Immunization with an inactivated whole-virus vaccine is highly effective in preventing lentivirus infection. The viral protein(s) essential to the induction of protective responses. however. have not been identified. To define the role of virion components in the induction of protective immunity. we evaluated the efficacy of glycoprotein-enriched and glycoprotein-depleted simian immunodeficiency virus (SIV) subunit vaccines prepared by lentil-lectin affinity chromatography of gradient-purified virions using the immunization and challenge regimen previously found successful with an inactivated whole-virus vaccine. Infection was determined by successful recovery of virus. the induction of SIV-specific antibody responses. and infection of naive recipients by inoculation with lymph-node-derived lymphocytes from the vaccinates. Immunization with the glycoprotein-enriched preparation prevented infection in two out of four monkeys. whereas the glycoprotein-depleted vaccine failed to prevent infection in all four vaccinates tested. However. the glycoprotein-depleted vaccine appeared to moderate the progression of SIV-induced disease compared with non-immunized infected control monkeys inoculated with the same challenge dose. These data suggest that subunit vaccines containing sufficient quantities of viral glycoproteins can protect against SIV infection. whereas subunit vaccines composed predominantly of viral core proteins cannot. The development of effective vaccines against HIV infection should include studies on the optimum presentation of the viral envelope glycoproteins to produce long-term broadly protective immune responses.
Evidence for molecular subtypes of HIV-associated lymphoma: division into peripheral monoclonal, polyclonal and central nervous system lymphoma, The pathogenesis of the HIV-associated lymphomas is not well understood. In order to begin characterizing this class of lymphoma. we initiated a molecular genetic study of DNA extracted from 31 diagnostic biopsy specimens from patients diagnosed with AIDS-associated non-Hodgkin's lymphoma. Analysis of 25 peripheral lymphomas showed that 14 were monoclonal B-cell processes. while 11 appeared to be of polyclonal origin. Five of the 14 monoclonal lymphomas were found to have rearrangements of the c-myc gene. Epstein-Barr virus (EBV) genomes were found in seven out of 14 monoclonal samples. but only two out of nine polyclonal samples. The six primary central nervous system (CNS) lymphoma samples were more homogeneous than the peripheral samples and all were monoclonal. positive for EBV and lacked detectable c-myc gene rearrangements. This study allows us to subdivide the HIV-associated lymphomas into three major molecular subtypes: (1) monoclonal B-cell process frequently associated with c-myc rearrangement or detectable EBV genomes. (2) polyclonal B-cell process typically without evidence of EBV. and (3) monoclonal primary CNS process associated with EBV genomes and lacking detectable c-myc rearrangement.
Sexual partners, penetrative sexual partners and HIV risk, This paper argues that the notion of sexual partners per se is insufficient for estimating levels of HIV risk behaviour or changes in HIV risk over time. even though it is a crucial element of most epidemiological models of HIV. The concept of a penetrative sexual partner (PSP) is introduced as a considerably more accurate measure of HIV risk. Using data from a longitudinal study of 930 homosexually active men in England and Wales. this paper demonstrates that variation in numbers of PSPs (and thus HIV risk) is not related to variation in the gross numbers of sexual partners.
Development of language in 18-30-month-old HIV-1-infected but not ill children, Thirty-six children (age range. 18-30 months) born to HIV-1-infected mothers were studied for speech development by matching 18 infected with 18 non-infected subjects for age. sex and socioeconomic status. All the children were in good health. Each child was given three comprehension and three production tasks. In addition. each child's mean length of utterance (MLU) was obtained by observation of natural child-parent interactions. The development quotients (DQ) were assessed by Brunet-Lezine's tests. Infection significantly affected children's MLU. the infected children being less advanced than those non-infected. Both infected and non-infected children progressed in language acquisition from the second to the third year of age. but infected children had significantly greater production difficulty than non-infected children in the second year of life. The matched subjects design adopted gives some strength to the conclusion that HIV-1 infection impairs the genesis rather than the later development of language in infected but not ill children.
Relapse in sexual behavior among homosexual men: a 2-year follow-up from the Chicago MACS/CCS, Serial biannual cross-sectional assessments of HIV sexual risk indicated a consistent increase in safer sexual practices among homosexual men participating in the Chicago-Multicenter AIDS Cohort Study (MACS)/Coping and Change Study (CCS) in 1986-1988. Safer sexual practices were achieved by avoidance of anal sex and less often by consistent use of condoms. Longitudinal patterns of variability in individual behavior were also assessed. After 1 year of follow-up. 53% of the participants maintained safer practices in receptive anal sex. 6% maintained unsafe practices. while 31% relapsed at least once. After 2 years. 45% maintained safer practices. 3% maintained unsafe practices and 47% relapsed at least once. Similar trends were observed in insertive anal sex.
Quantitative angiography after directional coronary atherectomy, OBJECTIVE--To assess by quantitative analysis the immediate angiographic results of directional coronary atherectomy. To compare the effects of successful atherectomy with those of successful balloon dilatation in a series of patients with matched lesions. DESIGN--Case series. SETTING--Tertiary referral centre. PATIENTS--62 patients in whom directional coronary atherectomy was attempted between 7 September 1989 and 31 December 1990. INTERVENTIONS--Directional coronary atherectomy. MAIN OUTCOME MEASURES--Increase in minimal luminal diameter of coronary artery segment. RESULTS--Angiographic success on the basis of intention to treat was obtained in 54 patients (87%). In four patients the lesion could not be crossed by the atherectomy device; all four had an uneventful conventional balloon angioplasty. Four of the 58 patients who underwent atherectomy were subsequently referred for coronary bypass surgery because of failure or complications; three of them sustained a transmural infarction. In the successful cases. coronary atherectomy resulted in an increase in the minimal luminal diameter from 1.1 mm to 2.5 mm with a concomitant decrease of the diameter stenosis from 62% to 22%. In the subset of 37 patients in which the changes induced were compared with conventional balloon angioplasty atherectomy increased the minimal luminal diameter more than balloon angioplasty (1.6 v 0.8 mm; p less than 0.0001). Conventional histology showed media or adventitia in 26% of the atherectomy specimens. In hospital complications occurred in six patients who had undergone a successful procedure: two transmural infarctions. two subendocardial infarctions. one transient ischaemia attack. and one death due to delayed rupture of the atherectomised vessel. All patients were clinically evaluated at one and six months. One patient had persisting angina (New York Heart Association class II). one patient sustained a myocardial infarction. one patient underwent a percutaneous transluminal coronary angioplasty for early restenosis. and one patient underwent coronary bypass surgery because of a coronary aneurysm formation. At six months 80% (36/47) of the patients were symptom free. CONCLUSIONS--Coronary atherectomy achieved a better immediate angiographic result than balloon angioplasty; however. in view of the complication rate in this preliminary series. which may be related to a learning curve. a randomised study is needed to show whether this procedure is as safe as a conventional balloon angioplasty.
Post-prandial worsening of angina: all due to changes in cardiac output, BACKGROUND--The precise mechanism leading to the post-prandial worsening of angina has yet to be adequately defined. It has been attributed to an increase in double product but is perhaps more likely to be related to an increase in cardiac output after food. This study was designed to evaluate the effects of food on patients' exercise tolerance and compare these with changes in haemodynamic variables. METHODS--23 patients with chronic stable angina who had post-prandial worsening of their angina were studied. The patients were evaluated on two occasions and at each visit they underwent two symptom limited treadmill exercise tests. They remained fasting on the first visit and were given a 1400 kcal meal 60 minutes before the second exercise test on the second visit. Time to onset of 1 mm ST segment depression. heart rate. systemic arterial blood pressure. and cardiac output were measured at rest and during exercise. RESULTS--There were no differences in any of the variables during the two exercise tests on the day the patients remained fasting. After the meal exercise tolerance fell significantly by 136 seconds and the stage at which 1 mm ST segment depression was first seen was also significantly reduced. Resting cardiac output increased significantly by 0.86 1/min with the patients sitting and by 0.89 1/min standing. The exercise times after food were significantly related to cardiac output even when fasting times were taken into account. Resting heart rate increased significantly by 8.3 beats per minute sitting and 10.4 beats per minute standing. There was little change in blood pressure and no evidence that the double product predicted the post-prandial exercise time. CONCLUSIONS--Worsening of angina was related to the increase in cardiac output after a meal and successful treatment will depend upon the prevention of this increase.
Mitral valve repair: a valuable procedure with good long term results even when performed infrequently, OBJECTIVE--To assess the results of mitral valve repair in a series with a low frequency of repair despite a policy to conserve the valve whenever possible. DESIGN--Retrospective review of case notes with clinical and echocardiographic examination of survivors. SETTING--Cardiac surgery unit in a university teaching hospital. PATIENTS--62 consecutive patients undergoing mitral valve repair by one surgeon between 1979 and 1989. INTERVENTIONS--Mitral valve repair according to the criteria and techniques of Carpentier. MAIN OUTCOME MEASURES--Frequency of repair. operative mortality. actuarial survival. freedom from reoperation and thromboembolism. clinical state. and echocardiographic state. RESULTS--The 62 patients. median age 58 years (interquartile range 51 to 64 years). represent 14% (70% confidence interval 12% to 15%) of the 454 mitral valve operations performed in the study period. Operative mortality was 8% (70% CI 5% to 13%). Actuarial survival was 62% (70% CI 43% to 81%) at nine years. At nine years actuarial freedom from reoperation was 91% (70% CI 79% to 102%) and freedom from thromboembolism 91% (70% CI 80% to 102%). At a median follow up of 33 months (interquartile range 21 to 74 months). 38 of 46 survivors had improved functional state. Of 21 patients who underwent echocardiography one had severe mitral regurgitation and one mitral stenosis. CONCLUSION--Although compared with other reports of mitral valve repair the prevalence of repair was low in this series the results are comparable and justify a positive approach to repair in all patients undergoing mitral valve surgery even if this can only be achieved in a small proportion of patients.
Multivariate analysis to simplify the differential diagnosis of broad complex tachycardia, Univariate analysis has identified several criteria that aid the differential diagnosis of broad complex tachycardia. In this study of 102 consecutive patients multivariate analysis was performed to identify which of 15 clinical and 11 electrocardiographic variables were independent predictors of ventricular tachycardia. These were shown to be a history of myocardial infarction. the QRS waveforms in leads aVF and V1. and a change in axis from sinus rhythm to tachycardia of more than 40 degrees. If none of the criteria was met. the diagnosis was almost certainly supraventricular tachycardia. If one criterion was met the diagnosis was probably supraventricular tachycardia. If two criteria were met then the diagnosis was probably ventricular tachycardia. If three or four criteria were met. the diagnosis was almost certainly ventricular tachycardia. The predictive accuracy was 93%. This was increased to 95% by including two other criteria--definite independent P wave activity and ventricular extrasystoles with the same QRS configuration as that in tachycardia. These criteria were not included in the multivariate analysis because though they were 100% specific they were seldom seen. These four criteria can be used as simple rules in determining the origin of a broad complex tachycardia.
Comparison between prostaglandin E1 and epoprostenol (prostacyclin) in infants after heart surgery, OBJECTIVE--To study the dose response characteristics of prostaglandin E1 and epoprostenol (prostacyclin) and directly to compare their effectiveness as pulmonary vasodilators in infants with pulmonary hypertension. DESIGN--A crossover design with each patient receiving both drugs in random order. SETTING--Infants were studied in the intensive care unit while they were sedated. paralysed. and ventilated. PATIENTS--Twenty infants who had undergone corrective cardiac surgery and who were in sinus rhythm. had stable haemodynamic function. and had a pulmonary artery catheter in place. All infants were receiving dopamine and phenoxybenzamine. INTERVENTIONS--Baseline haemodynamic measurements were taken and an infusion of the first drug was started at the lowest dose: after 20 minutes the measurements were repeated and the dose increased. This protocol was repeated for all doses of both drugs: 10. 30. and 100 ng/kg/min of prostaglandin E1 and 5. 10. and 25 ng/kg/min of epoprostenol. Cardiac output was measured by the pulsed Doppler ultrasound method. MAIN OUTCOME MEASURES--Pulmonary and systemic vascular resistances were calculated from the cardiac output and compared by the Wilcoxon signed ranks test. RESULTS--Both prostaglandin E1 and epoprostenol were effective vasodilators: 5 ng/kg/min of epoprostenol was equivalent to 30 ng/kg/min of prostaglandin E1. CONCLUSIONS--Neither drug showed pulmonary specificity.
Thrombus within a submitral left ventricular aneurysm: diagnosis on cross sectional echocardiography, Subvalvar left ventricular aneurysms are rare and occur predominantly in black Africans. A submitral left ventricular aneurysm was diagnosed on cross sectional echocardiography in a black woman born in the United Kingdom. The left parasternal long axis view showed a highly echogenic mass apparently attached to the wall of a dilated left atrium. but the apical two-chamber view showed that this was thrombus in the apex of a left ventricular aneurysm. The patient subsequently underwent surgical correction.
Intrapulmonary agenesis of venous system and bronchopulmonary arterial anastomosis, Agenesis of the intrapulmonary and extrapulmonary veins of the right lung was found by angiography and histological examination in a three year old boy. Blood supplied by the intersegmental arteries drained via the pulmonary arteries of the right lung into main and left pulmonary arteries. This caused a shunt between the aorta and pulmonary artery. Agenesis of the pulmonary venous system as a cause of left to right shunt has not been reported before.
An analysis of factors influencing the outcome of 232 consecutive tubal microsurgery cases, A consecutive series of 232 tubal microsurgical operations performed at the Jessop Hospital for Women. Sheffield. between 1983 and 1989. was analysed. The various contributory factors to tuboperitoneal damage were reviewed. Eighty patients (35%) conceived. resulting in 66 (29%) live births and 14 (6%) miscarriages. A further 12 (5%) had ectopic pregnancies. The overall cumulative conception rate (CCR) was 40% at the end of 50 months. Microsurgery has been most successful in the adhesiolysis group (n = 78) with a CCR of 46% at the end of 50 months. The terminal salpingostomy group (n = 97) had a CCR of 40% at the end of 36 months. There was a significant reduction in the live birth rate for the group with hydrosalpinx greater than 20 mm in diameter compared with the group with less than 20 mm (P = 0.05). The proximal anastomosis group (n = 27) had a CCR of 33%. No pregnancy was reported following reconstructive surgery for multiple occlusion sites. Overall. the extent of pelvic adhesions had a significant influence on the outcome (P = 0.02). The likelihood of conception was significantly influenced by the duration of infertility (P = 0.02) but not affected by the aetiology of tuboperitoneal damage. parity or age of the patient. In our hands. tubomicrosurgery is more cost-effective than in-vitro-fertilization as a primary treatment of infertility due to tubal diseases.
Microsurgical salpingostomy is not an obsolete procedure, OBJECTIVE--A review of the results of microsurgery for bilateral distal tubal blockage. DESIGN--A retrospective review. SETTING--Hammersmith Hospital London and local private hospitals. SUBJECTS--388 patients with bilateral ampullary occlusion treated between 1971 and 1988 by microsurgery. INTERVENTIONS--Full investigation for other causes of infertility followed by abdominal microsurgical salpingostomy. Repeated meticulous follow-up was essential with check laparoscopy one year after surgery. MAIN OUTCOME MEASURE--Successful pregnancy in relation to tubal damage. RESULTS--In 65 women microsurgery followed tubal reocclusion after failed conventionally performed salpingostomy. 74 women (23%) had one term pregnancy after primary salpingostomy and 12 women (18%) after repeat salpingostomy. Over half the women having a term pregnancy subsequently had a second infant. The tubal damage was classified in four stages according to the degree of mucosal damage and tubal fibrosis. the presence of isthmic disease and the quality of tubal and ovarian adhesions. Approximately one quarter of patients had stage I disease and amongst these 39% had babies after primary salpingostomy and 25% after repeat salpingostomy. CONCLUSION--Microsurgical salpingostomy is a specialized procedure. Proper selection of patients. competent microsurgical technique and adequate follow-up appear crucial to success. In selected patients treatment by salpingostomy gives better results than multiple cycles of in vitro fertilization.
The variation of endometrial response to a standard hormone replacement therapy in women with premature ovarian failure. An ultrasonographic and histological study, The endometrial response to a standard hormone replacement therapy in 18 women with premature ovarian failure was examined by serial ultrasonographic measurement of endometrial thickness and histological study of endometrial biopsy taken on day 19 of the cycle. Women with idiopathic ovarian failure (n = 10) had significantly better response than women with Turner's syndrome (n = 4). whereas women with premature ovarian failure associated with previous chemotherapy (n = 4) had an intermediate response. These observations suggest that the endometria of women with Turner's syndrome responded suboptimally to steroid hormones. However. all endometrial biopsies studied revealed secretory changes. Overall. the results of histological dating of endometrial biopsy were found to be positively correlated with endometrial thickness on day 19 of the cycle (r = 0.72. P less than 0.01). The plasma concentration of oestradiol on days 15. 19 and 29 of the artificial cycle were found to be significantly higher than those on the corresponding days of the natural cycle.
Delivery in an obstetric birth chair: a randomized controlled trial, OBJECTIVE--To determine whether nulliparae whose second stage of labour is conducted in an obstetric birth chair have a lower incidence of instrumental delivery than those using a conventional delivery bed. DESIGN--Randomized controlled trial using sealed. opaque envelopes for allocation. SETTING--Delivery ward in a busy teaching hospital. PATIENTS--1250 nulliparae with a singleton live fetus with cephalic presentation. without epidural anaesthesia. who had achieved full dilatation. INTERVENTION--Intention to conduct second and third stages of labour in either the Birth-EZ chair or the conventional delivery bed. as randomly allocated. MAIN OUTCOME MEASURES--Primary measure: vaginal operative delivery; principal secondary measures: duration of second stage. perineal trauma. blood loss. women's views. and neonatal status. RESULTS--Delivery in the birth chair did not result in a reduction in operative delivery. overall. However. there was a reduction in vaginal operative delivery for fetal heart rate abnormality. There was no beneficial effect on perineal trauma or puerperal perineal pain. Post-partum haemorrhage was more frequent in the birth chair group. CONCLUSIONS--Delivery in the birth chair does not offer any obvious advantage to women over delivery on a bed.
Partial placenta membranacea, Seven pregnancies complicated by partial placenta membranacea occurring over a 2-year period are described. The condition is encountered more frequently than the total or near-total form. but is similarly associated with recurrent antepartum haemorrhage. miscarriage or preterm delivery. Diagnosis by ultrasound scan may prove difficult. Five pregnancies had histological evidence of chorioamnionitis. which may have helped to precipitate labour; three fetuses showed pulmonary inflammatory changes of at least 2 days' duration. No maternal predisposing factors could be elicited.
Autoreactivity in women with endometriosis, Serum samples from 71 patients with laparoscopically staged endometriosis and from 109 age-matched non-pregnant control women were tested for antibodies to nuclear. phospholipid. smooth muscle and sperm antigens. Immunoglobulin G. M and A and complement components C3 and C4 were measured. Prevalence of the following autoantibodies was statistically significantly greater in women with endometriosis than in the control group: antinuclear antibodies. antibodies to ribonucleoproteins. smooth muscle antibodies. lupus anticoagulant and anticardiolipin antibody. Forty-one women with endometriosis (58%) had some type of autoantibody compared with 13 controls (12%). More women in the endometriosis group had IgG and IgM levels above the normal range. This was statistically significant for IgG in women with grade 3 and for IgM in those with grade 4 endometriosis. IgG levels were significantly higher in antibody-positive women with endometriosis than in the control group. Immunoglobulin and complement component levels tended to have a positive correlation with stage of disease.
Maternal plasma corticotrophin-releasing hormone--elevated in preterm labour but unaffected by indomethacin or nylidrin, The role of corticotrophin-releasing hormone (CRH) in preterm labour was studied in 23 women in preterm labour at between 26 and 33 weeks gestation who were randomly allocated to receive treatment with indomethacin (n = 11) or with nylidrin a beta-sympathomimetic agent (n = 12). Maternal plasma CRH in the preterm group (median 70. range 9-597 pmol/l) before therapy was higher (P less than 0.05) than that in 23 control pregnancies. without uterine contractions. matched for gestational age (median 51. range 4-127 pmol/l). CHR levels determined after 3 and 24 h of treatment showed a 10% decrease in the indomethacin group and 10-20% decrease in the nylidrin group. but these changes were not statistically significant. After cessation of uterine contractions during tocolysis. 12 women proceeded to give birth preterm (less than 37 weeks) and their pretreatment CRH levels (median 195. range 9-597 pmol/l) were higher (P less than 0.05) than those in women whose pregnancy proceeded to term (median 52. range 16-207 pmol/l). In another group of women. full-term labour was not accompanied by any changes in maternal CRH levels. Umbilical plasma CRH levels were 1.1-9.8% of the paired maternal levels and did not rise with advancing gestational age. Nor had the type of delivery (elective caesarean section before labour. or preterm or term vaginal delivery) any effect on fetal CRH levels.
Prediction of lethal pulmonary hypoplasia and chorioamnionitis by assessment of fetal breathing, Twenty-three pregnancies with fetuses at risk for pulmonary hypoplasia were studied weekly until delivery. The amount of time spent in fetal breathing activity was recorded under controlled conditions during 1 h using real-time ultrasound. An amniotic fluid index was determined. The clinicians and the pathologist were unaware of the ultrasound findings. Eight of 23 fetuses did not breathe at the last ultrasound examination. Three babies died of pulmonary hypoplasia and two of these showed fetal breathing before birth. The three deaths were associated with rupture of the membranes at less than or equal to 20 weeks gestation and of greater than or equal to 44 days duration. One infant developed bronchopulmonary dysplasia. The amniotic fluid index in these four pregnancies was low and the newborn infants had limb contractures. Chorioamnionitis/funisitis was noted in 13 placentas. Eight fetuses were assessed for fetal breathing within 2 days of birth. The lack of fetal breathing had sensitivity. specificity. positive and negative predictive values of 0.75 for chorioamnionitis/funisitis. In this pilot study the absence of fetal breathing was of no value in predicting lethal pulmonary hypoplasia. but was related to chorioamnionitis/funisitis. We recommend further studies of fetal breathing in relation to fetal/neonatal infections.
A comparative study of ethamsylate and mefenamic acid in dysfunctional uterine bleeding, The effects of ethamsylate and mefenamic acid on menstrual blood loss were compared in a double-blind trial in 34 women with menorrhagia. Both drugs produced statistically significant reductions in blood loss during the 3 months of treatment; the overall reduction was 20% in the ethamsylate group and 24% in the mefenamic acid group. Compared with pretreatment values. blood loss was significantly less in each of the 3 treatment months in the mefenamic acid group. but only in the second and third months of treatment in the ethamsylate group. However. more women had a clinically useful reduction in blood loss (greater than 40%) in the ethamsylate group. The onset of effect of mefenamic acid was rapid but ethamsylate showed a comparatively greater effect as the trial progressed. Cessation of treatment was followed by an increase in blood loss. more pronounced in mefenamic acid group who reverted to pre-treatment levels. A greater number of side-effects were reported with mefenamic acid.
Metabolic aspects of protection by glycine against hypoxic injury to isolated proximal tubules, To clarify the roles of butyrate and acylglycine formation in hypoxic proximal tubule cell injury and protection by glycine and to test the contribution of iodoacetate-suppressible metabolism to protection. (1) it was determined whether protection by glycine is fully expressed when glucose. lactate. alanine. and butyrate are replaced by alpha-ketoglutarate as the sole substrate for the tubules. (2) butyrate metabolism and acylglycine formation were directly measured in control and hypoxic preparations. and (3) it was assessed whether injury produced by iodoacetate. a potent inhibitor of glycolytic metabolism. is subject to protection by glycine. Susceptibility to hypoxic injury in medium with alpha-ketoglutarate as the sole substrate was similar to that seen in medium containing glucose. lactate. alanine. and butyrate. Tubules in alpha-ketoglutarate medium showed high degrees of protection by glycine against injury produced by 30-min of hypoxia. by iodoacetate alone. and by iodoacetate combined with hypoxia. Protection did not require preservation of cell ATP or glutathione. In glucose-lactate-alanine-butyrate medium. butyrate. measured by gas chromatography. was rapidly metabolized by oxygenated tubules and fully accounted for basal rates of oxygen consumption. Butyrate utilization stopped during hypoxia. Neither aspect of butyrate metabolism was altered by glycine. Formation of acylglycines was assessed by gas chromatography/mass spectroscopy. In preparations treated with glycine. butyrylglycine was detected under both oxygenated and hypoxic conditions; the quantities. however. were small and no other acylglycines were found. These observations indicate that protective effects of glycine are independent of short-chain acylglycine formation and glycolytic metabolism.
Minimal role of xanthine oxidase and oxygen free radicals in rat renal tubular reoxygenation injury, The role of xanthine oxidase and oxygen free radicals in postischemic reperfusion injury in the rat kidney remains controversial. Proximal tubules. the focal segment affected by ischemic renal injury. were isolated in bulk. assayed for xanthine oxidase activity. and subjected to 60 min of anoxia or hypoxia and 60 min of reoxygenation to evaluate the participation of xanthine oxidase and oxygen radicals in proximal tubule reoxygenation injury. The total xanthine oxidase in isolated rat proximal tubules was 1.1 mU/mg of protein. approximately 30% to 40% of the activity found in rat intestine and liver. Lactate dehydrogenase release. an indicator of irreversible cell damage. increased substantially during anoxia (39.8 +/- 2.3 versus 9.8 +/- 1.8% in controls) with an additional 8 to 12% release during reoxygenation. Addition of 0.2 mM allopurinol. a potent xanthine oxidase inhibitor. and dimethylthiourea. a hydroxyl radical scavenger. failed to protect against the reoxygenation lactate dehydrogenase release. Analysis of xanthine oxidase substrate levels after anoxia and flux rates during reoxygenation indicates that hypoxanthine and xanthine concentrations are in a 15-fold excess over the enzyme Km and 0.3 mU/mg of protein of xanthine oxidase activity exists during reoxygenation. Hypoxic tubule suspensions had a minimal lactate dehydrogenase release during hypoxia and failed to demonstrate accelerated injury upon reoxygenation. In conclusion. although xanthine oxidase is present and active during reoxygenation in isolated rat proximal tubules. oxygen radicals did not mediate reoxygenation injury.
A hereditary model of slowly progressive polycystic kidney disease in the mouse, There are two known forms of hereditary polycystic kidney disease (PKD) in humans. Although both forms initiate early in life. autosomal recessive PKD is rapidly progressive to kidney failure shortly after birth whereas autosomal dominant PKD is slowly progressive. taking many years to end stage. Research in this field has been limited by the availability of suitable animal models of PKD. Recently the C57BL/6J-cpk mouse has been used to study the pathogenesis of rapidly progressive hereditary PKD. The study presented here describes a slowly progressive PKD in the DBA/2-pcy mouse. The disease trait is transmitted in an autosomal recessive pattern and was localized to chromosome 9 through linkage to the dilute coat color and transferrin genes. Whereas some cystic changes were seen in fetal and newborn affected mice. renal enlargement did not develop until after 8 weeks of age and azotemia did not develop until after 18 weeks of age. Renal cysts were identified in all segments of the nephron and collecting duct and progressively enlarged with age. Individual cysts were found to be lined by a single layer of epithelial cells in most areas. with focal polyps and mounds of cells principally in collecting duct cysts. Early stages of cyst formation were associated with some abnormalities of tubular and glomerular basement membranes and accelerated eruption of incisors. Late stages of the disease were characterized by azotemia and chronic renal interstitial inflammatory infiltrates in all affected animals and cerebral vascular aneurysms in a few. We conclude that the DBA/2-pcy mouse has a form of renal cystic disease that appears similar in many respects to that seen in the dominant form of human PKD.
Bubble cells: renal tubular cells in the urinary sediment with characteristics of viability, The urinary sediment was examined by light microscopy in 65 consecutive inpatients with renal insufficiency (not due to pre- or postrenal factors) referred to a nephrology consult service for evaluation. In the 60 patients in whom a single diagnosis was reached. the sediments of 34 (57%) contained an easily recognized cell. which we have called the "bubble cell". These cells were bizarre. large cells with a single nucleus. which appeared to contain one or more fluid-filled vesicles. Bubble cells were most prevalent in the sediment of patients with acute tubular necrosis but were also seen a variety of other renal diseases. In most patients with acute tubular necrosis. the sediment also contained "normal"-appearing renal tubular cells. muddy brown casts. and oval fat bodies which were indistinguishable from those seen in the nephrotic syndrome. By electron microscopy. the bubble cells appeared to be vacuolated renal tubular epithelial cells. which had characteristics of viable cells. Most bubble cells excluded the vital dye Trypan blue. whereas the normal-appearing renal tubular cells were typically strongly positive. It was concluded that bubble cells. often accompanied by oval fat bodies. are commonly present in the sediment of patients with acute tubular necrosis as well as many other types of renal disease. Most cells which would be classified as "normal" renal tubular cells in these sediments are dead. In contrast. the findings suggest that the bubble cell represents an injured but viable renal tubular cell. The frequent finding of oval fat bodies in the same sediments suggests that the oval fat body is also produced by tubular cell injury.
Identification of the c-kit ligand: end of the road for understanding aplastic anemia in steel mutant mice, We here report the initiation of hematopoietic recovery in congenitally hypoplastic S1/S1d mice by the cytotoxic ablation of cells bearing the natural killer (NK) phenotype (NK 1.1+). The most striking finding was the early several-fold increase in the cycling fraction of stem and progenitor cells (with the exception of progenitors committed to megakaryocytopoiesis) in the anti-NK 1.1+ antibody-treated group. This increase resulted in an early. complete restoration of total marrow cellularity to the normal (+/+) littermate level. Our data suggest that NK 1.1+ cells exert functions critical to the negative control of hematopoietic cell proliferation in S1/S1d mice.
Temporal replacement of donor erythrocytes and leukocytes in nonanemic W44J/W44J and severely anemic W/Wv mice, The dominant white spotting. W. locus in the mouse encodes Kit. a receptor molecule with cytosolic tyrosine kinase activity. Mutations in Kit deplete hematopoietic cells by an as yet unknown mechanism. but one that presumably affects the early progenitors of all cell lineages. To examine cell lineage-specific changes caused by different W mutations. we injected genetically marked normal marrow cells into mutant mice and monitored repopulation kinetics. In the present report. we compare repopulation of the various peripheral blood cells in nonanemic W44J/W44J and severely anemic W/Wv mice administered increasing increments of donor cells. At all doses of cells tested. donor erythrocyte repopulation precedes leukocyte repopulation regardless of the recipient phenotype. There is. in fact. little difference in the rate or extent of nonerythroid repopulation in W44J/W44J mice injected with between 6 x 10(6) and 2 x 10(7) donor cells. The fact that donor cells rapidly replace erythrocytes. even in the nonanemic W44J/W44J host. while other cell lineages become donor type more slowly provides further evidence that mutations at the W locus are especially damaging to erythrocyte progenitors. We suggest that host nonerythroid hematopoietic cells compete with normal cells. probably at the level of early progenitors rather than at the level of the totipotent hematopoietic stem cell. The fact that successively higher doses of donor cells do not markedly alter nonerythroid repopulation kinetics implies that it may be possible to maximize autologous therapeutic marrow transplantation.
Suppression of chronic myelogenous leukemia colony growth by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors: a novel application for inhibitors of IL-1 activity, In this study. we investigated the role of interleukin-1 beta (IL-1 beta) in the malignant evolution of chronic myelogenous leukemia (CML) and the functional activity of IL-1 inhibitors. Bone marrow (BM) and peripheral blood (PB) low-density cells from 38 CML patients were studied in the colony-forming unit-granulocyte. erythrocyte. monocyte. megakaryocyte colony culture assay. Samples from patients with early stage. interferon-alpha (IFN)-sensitive disease formed hematopoietic colonies in the presence of fetal calf serum (FCS). erythropoietin (Epo). and one of the following: granulocyte-macrophage colony-stimulating factor (10 ng/mL). IL-3 (15 ng/mL). both. or phytohemagglutinin-conditioned medium. The addition of IL-1 beta augmented IFN-sensitive CML colony growth in a dose-dependent manner at concentrations of 10 to 100 U/mL. In sharp contrast. addition of the above growth factors did not augment the colony growth-promoting effect of FCS and Epo in samples from IFN-resistant patients; further. adherent cell fractionation or T-lymphocyte depletion attenuated the "autonomous" colony growth. Lysates of 2.5 x 10(7) low-density cells from each of six IFN-resistant and six IFN-sensitive CML patients and three normal volunteers were tested for intrinsic IL-1 beta content in an enzyme-linked immunosorbent assay and yielded a mean of 610 pg. 54.6 pg. and 49.4 pg of IL-1 beta. respectively (P less than .045). Interestingly. both soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) at concentrations of 5 to 100 ng/mL (sIL-1R) and 10 to 500 ng/mL (IL-1RA) inhibited CML colony growth in a dose-dependent fashion. with maximal inhibition of 64% and 65%. respectively. A similar effect was noted with the use of anti-IL-1 beta neutralizing antibodies. These data implicate IL-1 beta in CML disease progression and suggest that the inhibitory effects of molecules such as sIL-1R and IL-1RA could conceivably be the basis of a novel therapeutic strategy against this disorder.
Lambda-like and V pre-B genes expression: an early B-lineage marker of human leukemias, V pre-B and lambda-like genes are selectively expressed in human pre-B cells and encode polypeptide chains that associate in a mu-pseudolight chain complex that may regulate some crucial steps of early B-cell differentiation. We have followed by polymerase chain reaction and Northern blot analysis the expression of these "pre-B-specific" genes in correlation with the status (rearranged v germline) of Ig gene loci (H. kappa. lambda) in a panel of 32 leukemias pertaining mostly to the B lineage and including a number of ambiguously characterized samples. All cells that had rearranged the H locus only expressed V pre-B and lambda-like transcripts. in agreement with a pre-B status. In this group. some biphenotypic leukemias (mostly My/B) might. in fact. be already engaged in the B lineage. Rearrangement of V kappa or V lambda loci correlated with the disappearance of the pre-B gene products. In a pre-B acute lymphoblastic leukemia cell line that was induced to mature to the B-cell stage in culture upon kappa gene rearrangement. the mu-pseudolight chain complex was actually replaced by the classical mu-kappa molecule. Finally. V pre-B and lambda-like genes were found expressed in two leukemic cells that had retained all Ig loci in germline configuration. This finding raises the possibility of having an early pro-B progenitor in which V pre-B and lambda-like products associate with a H chain surrogate in a complex that would trigger an early event of B-cell differentiation such as the H locus rearrangements.
Presenting features and prognosis of chronic lymphocytic leukemia in younger adults, We have analyzed 117 younger patients with chronic lymphocytic leukemia (CLL) (mean age. 44.5 years; SD. 4.8; range. 19 to 49; male/female ratio. 2.08) with three main objectives: (1) to see whether these patients have distinctive presenting clinical features; (2) to investigate the impact of the disease on survival; and (3) to analyze whether already well-known prognostic factors are also useful when applied to these patients. As compared with an older age population (greater than or equal to 50 years). there were no major differences in presenting features except for an increased proportion of males (2.08 v 1.21; P less than .025) and a higher hemoglobin level (13.47 +/- 2.70 g/dL v 12.84 +/- 2.77 g/dL; P less than .05) in the younger group. Median survival is 12.3 years (expected median from a control group. 31.2 years). Clinical stages. bone marrow patterns. blood lymphocyte counts. and its doubling time are all useful to separate different risk groups of patients. Whereas patients with favorable prognostic factors have a survival probability of about 80% 14 years after diagnosis. those with poor prognostic features have a median survival of less than 3 years. It is concluded that CLL in younger adults has no major distinctive presenting features and that known prognostic factors are useful to separate different risk groups of patients. These results should be of help in planning therapy for younger persons with CLL.
Enhanced detection of the t(14;18) translocation in malignant lymphoma using pulsed-field gel electrophoresis, The t(14;18) chromosomal translocation that results in the juxtaposition of the bcl-2 proto-oncogene with the heavy chain JH locus is a common cytogenetic abnormality in human lymphoma. In particular. it is seen in about 85% of follicular lymphoma (FL) and up to one-third of diffuse lymphomas (DL). The chromosome 18 breakpoints have been shown to cluster into two regions. The major breakpoint region (mbr) within the 3' untranslated region of the bcl-2 proto-oncogene accounts for approximately 60% of the cases and the minor cluster region (mcr) 30 kb 3' of bcl-2 accounts for approximately 25% of the breakpoints. Because of variability in the position of the breakpoint. detection of the t(14;18) by Southern blot analysis provides an important clonal marker for the tumor. However. conventional electrophoresis (CE) fails to detect the translocation in 15% to 25% of cases. We have applied pulsed-field gel electrophoresis (PFGE) to the detection of the t(14;18) in a series of lymphoma prospectively analyzed by CE. polymerase chain reaction (PCR). and cytogenetic analysis. PFGE readily detected t(14;18) rearrangements as indicated by comigration of bands detected with probes for the mbr region (chromosome 18) and the JH locus (chromosome 14). In a series of 40 patients with FL. this method proved to be the most comprehensive for detection of the translocation compared with standard methods; in fact. in one case only PFGE was able to detect the chromosomal rearrangement. Ten percent of the FL cases were negative by all methods tested. In a separate analysis of matched tissue specimens from cases of tumor progression of FL to diffuse lymphoma. PFGE detected a common t(14;18) rearrangement confirming a clonal origin in seven of seven cases. whereas CE detected a rearrangement in only three of seven cases. Overall. PFGE was able to detect a translocation in 8 of 12 cases that were negative by CE and four of eight negative by cytogenetic analysis. In conclusion. PFGE analysis is more comprehensive than CE. PCR. and cytogenetic analysis for the detection of the t(14;18) breakpoint in tissue biopsies of malignant lymphoma.
VpreB gene expression in hematopoietic malignancies: a lineage- and stage-restricted marker for B-cell precursor leukemias, We show here that analysis of VpreB gene transcription can be a specific way to identify acute leukemias of cells at very early stages of B-cell development. Northern blot analysis of RNAs from 63 leukemia samples showed that VpreB RNA was present in malignancies of precursor B cells. the expression being a feature of both common acute lymphoblastic leukemia (ALL) (CD10+) and null ALL (CD10-). It was absent from malignancies of mature B cells (surface Ig positive). from acute leukemias of the T-cell lineage and granulocyte-macrophage lineages. and from normal tonsil B and T lymphocytes. Chronic myeloid leukemia blast crises of the B-precursor-cell type expressed the VpreB gene while myeloid blast crises did not. VpreB RNA was also expressed in the neoplastic cells of one of three patients with acute undifferentiated leukemias. These data show that VpreB RNA expression is a marker of the malignant forms of precursor B cells. and that it appears at least as early as cytoplasmic CD22 and CD19 in tumors of the B-cell lineage.
Improvement of mouse beta-thalassemia by recombinant human erythropoietin, Homozygous beta thalassemic mice received 50 U (1.660 U/kg) of recombinant human erythropoietin (rhEpo) 5 days a week for 2 weeks. Hemoglobin increased from 9.2 +/- 0.6 g/dL to 10.5 +/- 0.4 g/dL (P = .002) and hematocrit increased from 29.2% +/- 0.9% to 34.1% +/- 1.9% (P = .0014). The beta minor/alpha globin chain synthesis ratio increased slightly but significantly between day -4 (0.75 +/- 0.07) and day 4 (0.81 +/- 0.04) (P = .01) and reached a minimum ratio (0.67 +/- 0.03) on day 15 (P = .001). being parallel to reticulocyte counts and to the incorporated trichloracetic acid (TCA)-insoluble radioactivity. therefore parallel to the erythropoietic output in thalassemic mice. as in normal mice. Erythrocyte defects were improved in beta thalassemic mice treated by rhEpo: membrane-associated alpha globin was significantly decreased (P less than .01). thiol group reactivity of ankyrin was significantly improved (P less than .05). spectrin alterations were reduced. and deformability of mouse thalassemic red blood cells was normalized. These results provide experimental criteria for modulating globin chain imbalance necessary for the therapy of human beta thalassemia intermedia. and suggest that rhEpo might be of interest to improve the red blood cell mass and reduce erythrocyte alterations in this disease.
Myeloablative chemoradiotherapy and autologous bone marrow infusions for treatment of neuroblastoma: factors influencing engraftment, Bone marrow harvested from cancer patients for autologous bone marrow reinfusion (ABMR) after myeloablative treatment may be injured. in both its proliferating and stromal cell pools. by either previous treatment or manipulation at the time of harvest. We have examined the relative effects of seven covariates on hematologic recovery after ABMR in children with neuroblastoma (NBL) using univariate and step-up analysis. We measured recovery by times to achieve (1) white blood cell counts greater than 1.000/microL; (2) absolute neutrophil counts greater than 500/microL; and (3) platelet counts greater than 20.000/microL without transfusion. In univariate analysis. recovery was significantly associated with the amount of prior chemotherapy and the interval between last chemotherapy and marrow harvest. Patient sex. the number of granulocyte-macrophage colonies infused. harvest-to-freeze interval. and use of purging were marginally associated. After adjusting for potential confounders in a multivariate model. the amounts of chemotherapy and granulocyte-macrophage colonies infused were independently significant predictors of time to total white blood cell count recovery; chemotherapy courses and chemo-to-harvest interval were predictors of neutrophil count recovery; and sex. use of purging. and harvest-to-freeze interval were marginal predictors of platelet recovery. The speed of hematologic recovery after ABMR seems to depend mainly on pre-existing factors and marginally on manipulation of the marrow after harvest. These factors may affect both proliferating and stromal cell pools.
Impaired erythropoietin production in mice treated with cyclosporin A, Because recent data indicate that erythropoietin (Epo) production is defective in allogeneic bone marrow transplant (BMT) patients. we investigated the role of the immunosuppressant. nephrotoxic. agent cyclosporin A (CsA) on renal Epo production using an animal model. Mice were injected with 1.0 to 40.0 mg/kg/d CsA for 15 days. Thereafter. circulating Epo levels were evaluated in both intact animals and in mice made anemic with phenylhydrazine (PHZ). Serum Epo levels measured in CsA-treated animals were then compared with the predicted levels. which had been calculated in a reference population of normal. either intact or anemic. mice. In CsA-treated. intact animals both hematocrit and serum Epo levels were not significantly different from controls. However. serum Epo levels in CsA-treated. anemic mice were significantly lower than those expected in a control population of untreated. anemic mice with similar degrees of anemia. No significant increase in serum creatinine was recorded even at the highest doses of CsA used. nor were we able to document signs of renal toxicity by histologic examination of the kidneys. Therefore. therapeutical doses of CsA appear to affect the production of Epo under conditions in which the demand of the hormone is increased. as in response to anemia. We suggest that a subclinical kidney toxicity produced by CsA might have a role in the pathogenesis of the impaired Epo production observed in BMT patients. and may contribute to a delayed erythroid engraftment in at least some BMT patients.
Treatment type and amount influenced human immunodeficiency virus seroprevalence of patients with congenital bleeding disorders, Two hundred and eighty-two patients with congenital bleeding disorders received blood component replacement therapy between January 1979 and April 1985. were followed-up by the Puget Sound Blood Center's Hemophilia Care Program. and were tested for antibody to human immunodeficiency virus (HIV). Serologic results were obtained at least 1 year after the last exposure to volunteer donor products that were prepared before donor HIV screening or after the last exposure to concentrates produced before the manufacturer's use of treatment methods for inactivation of HIV. In all. 106 patients were anti-HIV positive. The risk of HIV infection was greater in patients with more severe bleeding tendencies. greater exposure to components. and exposure to lyophilized concentrates from large pools of donors. Of 100 patients with hemophilia A who only received cryoprecipitate from volunteer donors from Washington State (during the 6.3-year period). 14% had become anti-HIV positive. Of 27 patients receiving mostly cryoprecipitate but also being exposed to a single lot of concentrate during the same period. 13 (48%) were positive. Of 49 patients treated predominantly or solely with factor VIII concentrates during this period. 43 (88%) were anti-HIV positive. Of 29 patients with von Willebrand disease. four were anti-HIV positive. including 2 of 26 receiving only cryoprecipitate and two of three who had received a single dose of factor VIII concentrate. Of 19 patients who were treated solely with volunteer donor plasma. all remained anti-HIV negative. Of 47 patients exposed to factor IX concentrate. 28 (60%) were positive. Data relevant to the risk of HIV transmission subsequent to screening of the volunteer donor population were also obtained. Treatment records of 55 hemophilia A patients who have remained anti-HIV negative through at least June 1990 showed exposure to 71.173 screened donors from May 1985 through December 1989. and all 55 patients have remained anti-HIV negative.
Alcohol consumption and risk of coronary heart disease, OBJECTIVE--To investigate the hypothesis that the apparent protective effect of habitual alcohol consumption on coronary heart disease is due to drinkers at high risk of coronary heart disease becoming non-drinkers. DESIGN--Case-control population based study. Data were obtained from interviews with patients with non-fatal myocardial infarction and their controls and with the next of kin of those who had died of coronary heart disease and their controls. SETTING--Auckland. New Zealand. SUBJECTS--Two groups of cases were studied. The first comprised 227 men and 72 women with non-fatal myocardial infarction identified from a population based surveillance programme for coronary heart disease; controls were 525 men and 341 women randomly selected from the same population group and matched for age and sex. The second group comprised 128 men and 30 women who had died of coronary heart disease and had been identified from the surveillance programme; controls were a sample of the previous control group and comprised 330 men and 214 women matched for age and sex. All participants were aged 25-64 years and without diagnosed coronary heart disease. MAIN OUTCOME MEASURES--Regular alcohol consumption; high density lipoprotein cholesterol and low density lipoprotein concentrations. RESULTS--Men with myocardial infarction and men who had died of coronary heart disease were more likely to have been never drinkers (had never drunk more than once a month) than controls (18% v 12% and 23% v 13% respectively). After possible confounding factors had been controlled for. people in all categories of drinking (up to more than 56 drinks per week) had at least a 40% reduction in risk of fatal and non-fatal coronary heart disease compared with never drinkers. Former drinkers also had a lower risk of non-fatal myocardial infarction than never drinkers (relative risks 0.41 and 0.10 in men and women respectively) but a similar risk of death from coronary heart disease. The reduction in risk was consistently greater in women than in men in all drinking categories but there was no clear dose-response effect in either sex. CONCLUSIONS--The results support the hypothesis that light and moderate alcohol consumption reduces the risk of coronary heart disease. This protective effect in this population was not due to the misclassification of former drinkers with a high risk of coronary heart disease as non-drinkers.
Prevalence of primary fibromyalgia in the Finnish population, OBJECTIVE--To obtain descriptive epidemiological data on fibromyalgia and its components in a representative sample of the Finnish population. DESIGN--Cross sectional study of 8000 Finns aged 30 or more invited for screening and a main examination for musculoskeletal disorders and other major disorders. SETTING--A mobile clinic. POPULATION--7217 subjects who attended the screening phase; 3434 subjects positive on screening who attended the main examination for musculoskeletal disorders. MAIN OUTCOME MEASURES--Musculoskeletal. mental. and other symptoms detected by interview and questionnaire; results of standardised clinical examination of the musculoskeletal system; operational definition of fibromyalgia; mortality at 10 years. RESULTS--The prevalence of fibromyalgia was low (54 cases; 0.75%) and related to age (peak prevalence at 55-64 years). female sex (twice as prevalent in women). occupation (no cases among 1596 white collar professionals). level of education (strong inverse gradient). and high levels of physical stress at work. No significant associations were found with body mass index. smoking. or mental stress at work. The prevalence of fibromyalgia was sensitive to even minor modifications of the definition. Fibromyalgia was strongly coincident with many other disorders. especially musculoskeletal conditions. Fibromyalgia did not predict mortality. CONCLUSION--Descriptive epidemiological data offer little support for the concept of fibromyalgia.
Non-specific aorto-arteritis (Takayasu's disease) in children, Digital subtraction panaorto-arteriography was performed in 32 consecutive children (21 females. mean age 10.8 years) with non-specific aorto-arteritis to assess digital subtraction angiography (DSA) in imaging these children and to study the patterns of involvement in the Indian sub-continent. Diagnostic quality DSA images were obtained in 21 out of 27 intravenous and nine out of 11 intra-arterial studies. Obstructive lesions were present in all the patients and commonly involved the abdominal aorta (24 patients) and renal arteries (20 patients). Aneurysms were seen in five patients and predominantly involved the descending thoracic aorta. Pulmonary artery involvement was uncommon (five out of 20 patients) and clinically silent. Based on clinical and angiographic features. percutaneous transluminal angioplasty was performed for the management of uncontrolled hypertension in eight patients (10 lesions). Initial success was obtained in eight procedures (80%). Re-stenosis occurred after 5.5 months in one patient. but was successfully re-dilated. The follow-up period ranged between 5 and 16 months (mean 9 months). Long-term efficacy of transluminal angioplasty in the management of these children is awaited.
A new coaxial needle for pre-operative localization of breast abnormalities, A new coaxial needle. containing a retractable anchoring wire with a helical tip. has been developed for purposes of mammographic and sonographic localization of non-palpable suspicious breast abnormalities before surgical excision. The helically shaped tip provides the needle with a number of potential advantages over other currently available localization needles. During in vitro comparisons with other needles quantitative and qualitative evidence was obtained to suggest that the new needle can be expected to have improved anchoring capability. be deflected less by tough fibrous tissue interfaces and be more visible sonographically. The anchoring wire can also be retracted and repositioned. Preliminary clinical experience with the needle was consistent with these expectations.
Embolization with steel coils using a saline flush technique, A method using saline flush to push Gianturco steel coils through catheters is described. and has been successfully used in 45 patients. The saline flush technique requires no precise matching of coils and catheters. solves problems associated with the conventional method and simplifies the coil embolization procedure.
Evaluation of 99Tcm Technegas ventilation scintigraphy in the diagnosis of pulmonary embolism, In the diagnosis of pulmonary embolism. perfusion lung scintigraphy offers high sensitivity but low specificity. The specificity can be significantly increased by the use of combined ventilation and perfusion studies. Most aspects of perfusion lung scintigraphy are uniformly accepted but the technique of ventilation imaging varies from centre to centre. This study describes a new technique for the performance of ventilation scintigraphy using a suspension of ultrafine carbon particles labelled with 99Tcm ("Technegas"). The technique combines the ready availability of 99Tcm and its optimal imaging properties with an easily administered radiopharmaceutical of particle size sufficiently small to deposit in the alveoli. Of 63 patients studied by conventional perfusion scintigraphy plus Technegas ventilation scintigraphy. images of diagnostic quality were obtained in all. 31 of these patients also had a ventilation study using 81Krm gas and in only one instance did the two methods of ventilation imaging lead to differing interpretations. We conclude that high quality diagnostic images may be obtained using this new technique. which can be made available on both a routine and an emergency basis. thus improving the service provided for patients suspected of having pulmonary embolism.
Organ doses to atomic bomb survivors during photofluorography, fluoroscopy and computed tomography, Doses to the salivary glands. thyroid gland. breast. lung. stomach and colon during mass radiological gastric screening. mass radiographic chest screening. upper gastrointestinal series and computed tomography were determined by exposing a female human phantom to simulated radiological X-ray examinations as performed in community hospitals. The doses were measured using thermoluminescent dosimeters. and the results will be used to document organ doses received by participants in the Atomic Bomb Casualty Commission/Radiation Effects Research Foundation Adult Health Study.
Response of the mouse mediastinum to single and fractionated X-rays, The acute oesophageal response. after localized mediastinal irradiation in unanaesthetized mice. was assessed with a sequential. non-invasive and clinically orientated assay. Changes in body weight. after single and fractionated X-ray doses (8 fractions in 8 or 15 days and 4 fractions in 4 or 13 days). were recorded and the nadir of weight loss for each regime was used as the end-point. In our studies. quantal and non-quantal analyses of the weight loss data gave good dose-response relationships. The shapes of the dose-effect curves for single doses. 4F/4 days and 8F/8 days showed a remarkable degree of radioresistance. which became less apparent when the overall time was increased to 13 and 15 days for 4 and 8 fractions. respectively. The alpha/beta values (7-17 Gy) are within the range found for other acutely responding normal tissues. Histopathological changes were also assessed and the structural changes observed in the oesophageal epithelium. after a single dose of 34 Gy or after 46 Gy given as 3F/6 days. correlated with the gross changes observed in body weight.
Ambulatory monitoring and electronic measurement of urinary leakage in the diagnosis of detrusor instability and incontinence, The ability of conventional artificial filling urodynamic studies (CMG) and ambulatory monitoring during natural bladder filling (AM) to detect phasic detrusor activity (detrusor instability) and incontinence was studied in 52 patients suspected on clinical grounds of having bladder dysfunction. but in whom a CMG had not provided an adequate explanation of their symptoms. Detrusor instability (DI) was found on AM in 31 patients who were not unstable on conventional CMG using the criteria of the International Continence Society: DI was diagnosed on filling in 20 patients and on provocation in a further 11. Incontinence was demonstrated by electronic nappy testing in 23 patients: 13 had urge incontinence due to DI. 7 had genuine stress incontinence alone and 3 had both genuine stress incontinence and detrusor instability. Thus DI was diagnosed significantly more frequently by AM than by CMG. Ambulatory monitoring was more sensitive in the diagnosis of instability and incontinence and it may prove to be a valuable aid in the diagnosis of bladder dysfunction not detected during conventional cystometry.
The value of ultrasound scanning of the upper urinary tract in patients with bladder outlet obstruction, Ultrasound scanning of the upper urinary tract enables a urologist to allocate a degree of urgency for surgery when upper tract dilatation is present. We have studied whether other assessments of bladder outlet obstruction could eliminate this investigation. The study group comprised 223 consecutive patients who had ultrasound scans for bladder outlet obstruction. Estimation of urea. creatinine. residual urine and flow rate could not predict the presence of upper tract dilatation and it was concluded that ultrasound scanning of the upper tracts should continue to be used as a means of deciding how urgently a patient requires prostatic surgery.
The sonographic appearance of irradiated prostate cancer, Transrectal ultrasonography of the prostate was performed before radical prostatectomy in 22 patients with persistent or recurrent cancer after definitive radiotherapy. Serial transverse sonograms were compared with whole-mount step-sections of the prostatectomy specimens to evaluate the sonographic features of irradiated prostate cancer. To define more clearly the effects of radiation on malignant prostatic tissue. we assessed the degree of histological change induced by the irradiation (radiation effects) as none. mild. moderate or severe. A total of 121 areas of cancer greater than 4 mm in maximum diameter were identified on the histological sections. Of these. 105 (87%) showed no radiation effects or mild effects. and 72% (76/105) of these appeared hypoechoic on the corresponding sonogram. There were 16 foci with moderate or severe radiation effects and only 25% (4/16) appeared hypoechoic. The remaining 12 foci were isoechoic. Areas of cancer which show moderate or severe radiation effects tend to become isoechoic while large (greater than 4 mm) foci of cancer in the irradiated prostate usually show little radiation effect. and these foci typically appear hypoechoic.
Colour duplex sonography in the assessment of impotence, We present our experience with colour duplex sonography (Acuson 128) in the assessment of 83 impotent men. Cavernosal artery measurements were taken before and after the intracorporeal injection of papaverine. The peak velocities following papaverine injection correlated well with the degree of clinical response. Percentage diameter change corresponded with some groups of clinical erection grade. although it was not as good a discriminator as peak velocity. Twelve patients with 24 cavernosal arteries were also examined using pharmacological selective arteriography. Correlation between duplex sonography and arteriography showed an accuracy of 87.5%. specificity of 100.0% and sensitivity of 82.4%. All patients with a clinically good response following papaverine injection had peak bilateral cavernosal artery velocities greater than or equal to 25 cm/s. Amongst the remaining suboptimal responders. 18 also had this finding. Fifteen of these underwent pharmacological cavernosography and 14 exhibited venous leakage. Duplex sonography is a valuable and non-invasive tool in the assessment of impotence and can provide valuable information in deciding the course of further evaluation and treatment. The procedure was always completed more quickly with the guidance of colour Doppler.
Experience with the Fowler Stephens and microvascular procedures in the management of intraabdominal testes, The Fowler Stephens operation and microvascular procedures were compared for the management of 23 intra-abdominal testes in 15 boys. 7 of whom had the prune belly syndrome. The Fowler Stephens operation was used for 15 testes (4 single-stage and 11 two-stage) and microvascular transfer was used for 8 testes. Eleven testes treated by the Fowler Stephens procedure (73%) and 7 treated by microvascular procedures (88%) were viable and intrascrotal after an average follow-up of 3.0 years. giving an overall success rate of 78%. Eight of 9 post-pubertal testes were biopsied. Severe maturational arrest was evident in all and carcinoma in situ was present in one.
Simultanagnosia. To see but not two see, Simultanagnosia is a disorder of visual perception characterized by the inability to interpret complex visual arrays despite preserved recognition of single objects. We report a series of investigations on a simultanagnosic patient which attempt to establish the nature of this visual processing disturbance. The patient performed normally on a feature detection task but was impaired on a test of attention-requiring visual search in which she was asked to distinguish between stimuli containing different numbers of targets. She was not impaired on a visual-spatial orienting task. She identified single briefly presented words and objects as rapidly and reliably as controls suggesting that access to stored structural descriptions was not impaired. With brief. simultaneous presentation of 2 words or drawings. she identified both stimuli significantly more frequently when the stimuli were semantically related than when they were unrelated. On the basis of these and other data. we suggest that the patient's simultanagnosia is attributable to an impairment in the process by which activated structural descriptions are linked to information coding the location of the object.
Early onset cerebellar ataxia with retained tendon reflexes. Clinical, electrophysiological and MRI observations in comparison with Friedreich's ataxia, Fourteen patients with the clinical diagnosis of early onset cerebellar ataxia with retained tendon reflexes (EOCA) were examined and compared with 11 patients with Friedreich's ataxia (FA). The mean age of onset in EOCA was 15.9 +/- 6.0 yrs (FA: 14.0 +/- 5.7 yrs). Annual progression rate and the percentage of patients who were wheelchair-bound was lower in EOCA as compared with FA. although the difference did not reach statistical significance. The latency until becoming wheelchair-bound. however. was significantly longer in EOCA than in FA. The segregation ratio in EOCA was significantly lower than 0.25. Clinically. EOCA and FA patients presented with a progressive cerebellar syndrome. Associated symptoms. such as muscle wasting. sensory disturbances. foot deformity. scoliosis and electrocardiographic abnormalities were encountered less frequently in EOCA than in FA patients. The electrophysiological findings in EOCA were variable and pointed to axonal degeneration in peripheral nerves and central pathways. Posturographic measurements revealed a higher incidence of anteroposterior sway direction in EOCA as compared with FA. suggesting a cerebellar type of ataxia in EOCA. Eleven out of the 14 EOCA patients had cerebellar atrophy in MRI. The characteristic MRI finding in FA was upper cervical cord shrinkage and only minor atrophy of the cerebellum. The demonstration of cerebellar atrophy in the majority of EOCA patients supports the view that EOCA is distinct from FA. It is uncertain. however. whether EOCA is a homogenous disease entity or a group of phenotypically similar syndromes.
Mechanisms of visual spatial neglect. Absence of directional hypokinesia in spatial exploration, This study examines whether visuospatial neglect derives from failure in directing hand movements to the left (directional hypokinesia). or from loss of mental representation of the left side of space. Forty right brain-lesioned patients. 28 of whom revealed mild. moderate. or severe neglect in clock drawing and cancellation tasks. were asked to search for concealed targets on a stimulus display board. by either (1) moving a covering panel with a small window until the target appeared. or (2) moving the stimulus display board beneath a stationary covering panel until the target became visible through the window. In the second procedure. the direction of physical space exploration and hand movement is reversed. so that in order to bring a target from the right side of the stimulus into view (under the window) the entire display board had to be moved to the left. This pair of procedures was supplemented by an analogous pair of visual tasks in which the entire display board was visible during the search. As expected. response times were generally longer for targets located on the left side of the display board; however. the direction of required hand movement (left vs right) did not have a significant effect on response times. irrespective of the degree of clinically assessed neglect.
Cerebral potentials evoked by painful, laser stimuli in patients with syringomyelia, Brief cutaneous heat stimuli generated by a CO2 laser were used to elicit late somatosensory evoked cerebral potentials (SEPc) in 10 patients with syringomyelia. For comparison. early and late cerebral potentials in response to electrical nerve stimuli (SEPn) were recorded in the same session. In 8 patients with localized impairment of pain and temperature sensitivity we found complete absence of SEPc after stimulation of the affected area; in another patient with similar sensory deficits. the SEPc was grossly attenuated and delayed. In 1 patient with intact pain sensitivity but absent temperature sensitivity. a well defined SEPc could be recorded. Both early cortical SEPn and late SEPn in response to conventional nerve stimuli were normal in all patients and thus did not differentiate control and affected areas. These data indicate that alteration of SEPc correlates with altered pain sensitivity in patients with a circumscribed spinal lesion. SEPc may thus be used as a neurophysiological test in the assessment of hypalgesic dermatomes.
A history of boron neutron capture therapy of brain tumours. Postulation of a brain radiation dose tolerance limit, Boron neutron capture therapy (BNCT) is a form of radiation therapy mediated by the short-range (less than 10 microns) energetic alpha (4He) and lithium-7 (7Li) ionizing particles that result from the prompt disintegration by slow neutrons of the stable (nonradioactive) nucleus boron-10 (10B). Recent advances in radiobiological and toxicological evaluation of tumour-affinitive boron-containing drugs and in optimization of the energies of neutrons in the incident beam have spurred interest in BNCT. This article presents a history of BNCT that emphasizes studies in the USA. A new dosimetric analysis of the 1959-1961 clinical trials of BNCT at Brookhaven National Laboratory is also presented. This analysis yields an acute radiation dose tolerance limit estimate of approximately 10 Gy-Eq to the capillary endothelium of human basal ganglia from BNCT. (Gy-Eq: Gray-equivalent. or relative biological effectiveness of a radiation component multiplied by the physical dose of the component (Gy). summed over the component kinds of radiation.).
Visual recognition memory. Neurophysiological evidence for the role of temporal white matter in man, A novel event-related potential (ERP) elicited by a visuospatial recognition memory task was recorded in 20 patients with temporal lobe epilepsy using depth electrodes sited in the temporal lobes. The ERPs comprised two components. an N400 and a P600. and were similar in morphology to the previously reported ERP to verbal recognition memory tasks. The two ERP components in both verbal and visuospatial tasks were dependent on stimulus type and our data suggest that they do not simply represent delayed P300 ERP responses. In 17/20 patients robust. reliable bilaterally present ERPs were elicited by both verbal and visuospatial memory tasks. N400 amplitude was larger in response to novel stimuli. whereas P600 amplitude was larger to repeated stimuli. P600 amplitude was larger in the right temporal lobe to both visuospatial and verbal stimulus material. N400 and P600 latencies did not vary with task. stimulus type or side of recording. In 3/20 patients. no ERPs were elicited by either memory task. In all 3 cases. unilateral temporal white matter abnormalities were demonstrated by magnetic resonance imaging. Behavioural measures. expressed in the form of standardized accuracy scores. did not differ from those of a normal control group. and hence are unlikely to account for the abnormalities in ERPs. These results are discussed with reference to the primate visual recognition memory pathway and suggest that ERPs to recognition memory tasks are generated by an interaction between the two homologous inferotemporal recognition memory pathways.
The aphasic isolate. A clinical-CT scan study of a particularly severe subgroup of global aphasics, This paper outlines the clinical and CT scan features of a subtype of global aphasia. characterized by an extreme loss of communicative abilities. verbal as well as nonverbal. Three to four weeks after a left hemisphere stroke. 17 patients were completely unable to communicate with people addressing them. Though there were differences in their willingness to interact with the environment. they were characterized by complete loss of speech output and by inaccessibility to any kind of message. whether given verbally or through gestures. Patients who survived were reassessed 6 and 12 mos later and half of them were still found in a state of complete communicative isolation. The remainder had somewhat improved. but remained globally aphasic. The attempt to find a CT scan basis for this picture was disappointing. Only 35% of patients had a lesional pattern in agreement with the traditional view that ascribes global aphasia to the involvement of Broca's and Wernicke's areas. The location of lesion in the other cases spanned from anterior cortical damage. to posterior cortical damage. to deep nuclei damage and none of the lesions that have been proposed to account for subcortical global aphasia was consistently observed.
An analysis of lymphocyte 3H-N-methyl-scopolamine binding in neurological patients. Evidence of altered binding in Alzheimer's disease, Muscarinic cholinergic receptors were analysed in lymphocyte membranes from 35 patients with early (n = 20) and late onset (n = 15) Alzheimer's disease (AD). 86 patients with other neurological disorders and 60 normal controls by the specific binding of 3H-N-methyl-scopolamine (3H-NMS). The number of binding sites of 3H-NMS (Bmax) was significantly decreased both in early and late onset AD groups as compared with age-matched controls. by 54% and 40%. respectively. whereas the apparent binding affinity (Kd) was the same in all disease and control groups. In addition. the average Bmax in early AD was significantly lower than in late AD. The density of the binding of 3H-NMS was also significantly lower in a subgroup of old subjects with Down's syndrome (DS). whereas no changes were found in younger individuals with DS or in patients with Parkinson's disease. whether they were demented or not. multi-infarct dementia. myasthenia gravis or epilepsy. In the AD group. the difference in binding sites was unrelated either to the severity of dementia or disease duration. Treatment of the patients with cholinergic agents did not alter the binding values in any of the examined group. We conclude that the alteration of lymphocyte muscarinic receptors is highly associated with AD. but whether this reflects the central cholinergic deficit in these patients is uncertain.
The pathophysiology of chronic relapsing experimental allergic encephalomyelitis in the Lewis rat, Electrophysiological studies were performed in Lewis rats with chronic relapsing experimental allergic encephalomyelitis (EAE) induced by inoculation with guinea-pig spinal cord and adjuvants and treatment with low dose cyclosporin A. During clinical episodes there was conduction failure in the central nervous system (CNS). namely the spinal cord dorsal columns. and in the afferent fibres in the peripheral nervous system (PNS). The following observations indicated that the conduction failure was mainly due to demyelination-induced conduction block: (1) rate-dependent conduction block in the CNS and PNS; (2) temporal dispersion due to slowing of PNS conduction; (3) restoration of PNS conduction by cooling; (4) restoration of CNS conduction by ouabain; (5) previously demonstrated histological evidence of primary demyelination in the dorsal columns. dorsal root ganglia and dorsal roots; and (6) the temporal association of restoration of conduction with remyelination. However. it is likely that CNS and PNS axonal degeneration. which occurs in this disease. also contributed to the conduction failure. In clinical remissions there was restoration of conduction in the CNS and PNS which can be explained by ensheathment/remyelination by oligodendrocytes and Schwann cells. respectively. In most rats during clinical episodes the cerebral somatosensory evoked potential was reduced in amplitude and prolonged in latency. which can be accounted for by demyelination and axonal degeneration in the CNS and PNS components of the afferent pathway. In 2 rats with episodes of EAE. however. this potential was markedly increased in amplitude. which might have been due to demyelination-induced conduction block of descending pathways that normally inhibit synaptic transmission in the afferent pathway. In well-established remission there was residual conduction failure in the CNS and PNS which can be mainly accounted for by axonal degeneration.
Pain-related somatosensory evoked potentials in syringomyelia, Pain-related somatosensory evoked potentials following CO2 laser stimulation (pain SEPs) and conventional electrically-stimulated SEPs (electric SEPs) were examined in 8 patients with syringomyelia who showed various forms of dissociated sensory loss. Unlike clinical examination using a pin or needle. pain SEP is considered to be an objective and quantitative test to investigate functions of peripheral and central sensory pathways responsible for pain-temperature sensation (A delta fibres and the spinothalamic tract). Pain SEPs were abnormal in all patients. The results were generally compatible with the degree of a clinical impairment of pain-temperature sensation. Subclinical abnormality was detected in 3 patients. Electric median nerve SEPs using the scalp reference (Fz) were normal in 6 out of 8 patients. However. anterior and posterior cervical responses using a noncephalic reference were absent or small in 7 patients. Electric SEPs following tibial nerve stimulation were normal in 7 patients. These findings suggest that the function of the ascending fibres through the dorsal columns is intact in most patients. whereas the dorsal horn. where a fixed cervical potential is generated. is impaired. Pain SEPs combined with electric SEPs therefore appear to be extremely useful for investigating physiological function in the sensory pathways in patients who show 'dissociated sensory loss' such as in syringomyelia.
Through a looking glass. A new technique to demonstrate directional hypokinesia in unilateral neglect, A line cancellation task was performed by right brain-damaged patients with neglect in two response conditions. The task was presented either in normal view or through a 90 degree angle mirror with direct view prevented. The latter decouples the direction of visual attention and of arm movement. In the mirror condition. 4 of 18 patients cancelled lines only in right hemispace which means that they directed their visual attention to the left but failed to execute movements towards contralateral hemispace--what has been termed directional hypokinesia. In contrast. 10 patients cancelled lines only in left hemispace in the mirror condition. which accords better with attention-representation deficit hypotheses. Our results support a division of the neglect syndrome according to whether perceptual or premotor deficits are predominant.
Phonolexical agraphia. Superimposition of acquired lexical agraphia on developmental phonological dysgraphia, Study of neuropsychological sequelae of a focal acquired brain lesion may bring out and help delineate the features of a compensated developmental language disorder and its anatomical substrate. A left-handed man with a history of phonological developmental dyslexia and dysgraphia learned in early adulthood to read and write using a lexical system. Following a small posterior right parietal infarct when aged 56 yrs he developed a severe agraphia displaying features of phonological dysgraphia with impaired segmentation and features of lexical agraphia. Writing was severely impaired for all classes of word and nonword stimuli but his errors did not resemble those attributable to a deficit in the system responsible for the short-term storage of the graphemic representation of a word (graphemic output buffer). These observations imply that an acquired lexical agraphia has been superimposed on his developmental phonological dysgraphia. resulting in a combined or 'phonolexical' agraphia.
Pharmacokinetics of drugs in cystic fibrosis, Considerable work has been conducted on patients with CF to clearly demonstrate enhanced clearances of many. but not all drugs. The precise mechanisms for enhanced drug clearance in CF remain to be elucidated. and it will be important to examine the two major organs of drug elimination. the kidney and liver. for answers to these questions. Although it has not been studied to date. the role of the lung as a contributor to enhanced drug clearance in CF needs to be considered as well. In the liver it appears that both hepatic biotransformation as well as biliary excretion may be enhanced. In the kidney. there is enhanced CL of acidic drugs. but variable findings for cationic and zwitterionic drugs. The latter finding can be explained on the basis of the pKa of the drugs and the urine pH. It would be most appealing if enhanced renal and nonrenal clearance of drugs in CF could be attributed to a common single defect. At this time. there is no obvious candidate. although altered transmembrane transport would represent a place to start.
Heart-lung and lung transplantation for cystic fibrosis, End-stage lung disease in Cystic Fibrosis (CF) now is considered to be one of the indications for heart-lung or double lung transplantation. Results of this surgery for 50 or so CF patients in the US and Europe are about the same as for other diseases. although there are some postoperative problems specific for this diagnosis. These include: need for higher oral dosages of cyclosporine. likelihood of precipitation of diabetes mellitus with high dosage corticosteroid therapy for acute lung rejection. constant threat of pathogens remaining in the sinuses. increased likelihood of drug toxicity to the liver and kidneys. and need to make a psychological transition from a patient with a fatal disease to one with optimism about the future. Although improved postoperative management likely will improve postoperative mortality and morbidity. scarcity of donor organs and the high cost of the procedure will limit the impact of this procedure on the general CF population.
Trends in use of coronary angiography in subacute phase of myocardial infarction, BACKGROUND. Most patients do not undergo acute reperfusion after myocardial infarction. and which of these patients should undergo coronary angiography is still debated. METHODS AND RESULTS. We analyzed the 1-year clinical outcomes and rates of coronary angiography performed as late as 60 days after myocardial infarction in 3.804 patients admitted between 1979 and 1988 and followed in six different centers. Patients less than 75 years old were classified into low-. medium-. and high-risk groups using a multivariate analysis of historical and clinical variables gathered during the first 8 hospital days. Patients who underwent early reperfusion (17%. all after 1984) were analyzed separately. To analyze time trends. patients were compared before and after mid-1984. Mortalities from day 9 through 1 year were similar for the two time periods in the low- (3.3% versus 2.5%) and medium-risk (7.4% versus 5.6%) groups. but mortality was lower for the high-risk group after 1984 (31.6% versus 20.0%). The proportion of patients undergoing coronary angiography increased dramatically in each group after 1984 (low risk. 18% versus 48%; medium risk. 23% versus 49%; high risk. 10% versus 32%. before and after 1984. respectively). Furthermore. a large percentage of patients (more than 40%) in the low-risk group did not have at least one of the indications for coronary angiography recently recommended by a joint task force. Among patients undergoing coronary angiography. the proportion of patients with three-vessel coronary artery disease decreased after 1984. whereas the proportion undergoing mechanical revascularization in the year after infarction increased in all risk groups. CONCLUSIONS. Despite the recent development of noninvasive techniques with high sensitivity for detecting high-risk patients after myocardial infarction. coronary angiography is being performed increasingly in all patients. including those determined to be at low risk for complications based on clinical data. The economic consequences of such a trend could be considerable. and its impact requires careful analysis.
Left ventricular pressure-volume and Frank-Starling relations in endurance athletes. Implications for orthostatic tolerance and exercise performance, BACKGROUND. Endurance athletes have a high incidence of orthostatic intolerance. We hypothesized that this is related to an abnormally large decrease in left ventricular end-diastolic volume (LVEDV) and stroke volume (SV) for any given decrease in filling pressure. METHODS AND RESULTS. We measured pulmonary capillary wedge (PCW) pressure (Swan-Ganz catheter). LVEDV (two-dimensional echocardiography). and cardiac output (C2H2 rebreathing) during lower body negative pressure (LBNP. -15 and -30 mm Hg) and rapid saline infusion (15 and 30 ml/kg) in seven athletes and six controls (VO2max. 68 +/- 7 and 41 +/- 4 ml/kg/min). Orthostatic tolerance was determined by progressive LBNP to presyncope. Athletes had steeper slopes of their SV/PCW pressure curves than nonathletes (5.5 +/- 2.7 versus 2.7 +/- 1.5 ml/mm Hg. p less than 0.05). The slope of the steep. linear portion of this curve correlated significantly with the duration of LBNP tolerance (r = 0.58. p = 0.04). The athletes also had reduced chamber stiffness (increased chamber compliance) expressed as the slope (k) of the dP/dV versus P relation (chamber stiffness. k = 0.008 +/- 0.004 versus 0.031 +/- 0.004. p less than 0.005; chamber compliance. 1/k = 449.8 +/- 283.8 versus 35.3 +/- 4.3). This resulted in larger absolute and relative changes in end-diastolic volume over an equivalent range of filling pressures. CONCLUSIONS. Endurance athletes have greater ventricular diastolic chamber compliance and distensibility than nonathletes and thus operate on the steep portion of their Starling curve. This may be a mechanical. nonautonomic cause of orthostatic intolerance.
Effects of beta-adrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle, BACKGROUND. We tested the hypothesis that beta-adrenergic receptor-stimulated acceleration of left ventricular (LV) isovolumic relaxation (i.e.. positive lusitropic response) is attenuated in patients with severe congestive heart failure (CHF) compared with patients without LV dysfunction or CHF. METHODS AND RESULTS. The beta-adrenergic agonist dobutamine was infused by the intracoronary route in 14 subjects (normal group. six; CHF patients. eight) and by the intravenous route in a second group of 14 subjects (normal group. four; CHF patients. 10). The positive inotropic response to intracoronary or intravenous dobutamine was substantially and significantly reduced in the patients with CHF. LV isovolumic relaxation rate was determined by the methods of Weiss (TL). Mirsky (T1/2). and by a nonlinear regression technique (TNL). LV isovolumic relaxation assessed by all three methods was significantly prolonged in CHF patients compared with normal subjects. Intracoronary and intravenous infusions of dobutamine caused significant acceleration of LV isovolumic relaxation in both normal subjects and patients with CHF. The magnitude of the dobutamine-stimulated acceleration of isovolumic relaxation in patients with CHF was comparable with that in normal subjects. CONCLUSIONS. These data demonstrate that beta-adrenergic receptor stimulation causes significant acceleration of LV isovolumic relaxation in both normal subjects and patients with severe CHF. Coronary to our hypothesis. the lusitropic response to beta-adrenergic stimulation is well preserved in patients with severe CHF despite substantial attenuation of the beta-adrenergic positive inotropic response. These findings have potentially important implications regarding the physiology and pharmacology of adrenergically mediated LV relaxation in humans.
Arterial hemodynamics in human hypertension. Effects of adrenergic blockade, BACKGROUND. Resistance. pulse wave velocity. and wave reflections have been shown to be increased in patients with essential hypertension compared with normotensive controls. These alterations are completely normalized by nitroprusside infusion but exacerbated during beta-adrenergic blockade. suggesting an enhanced smooth muscle tone that is in part modulated by adrenergically mediated vasodilation. The present study was performed to examine the extent to which this apparently enhanced smooth muscle tone is a result of alpha-adrenergically mediated vasoconstriction. METHODS AND RESULTS. Age-matched normotensive and hypertensive Chinese subjects were instrumented with catheter-tipped micromanometers and an electromagnetic flow velocity sensor positioned in the ascending aorta. Aortic impedance and wave reflection properties were obtained from Fourier analysis of the pressure and flow signals during baseline conditions. after beta-blockade with propranolol (0.15 mg/kg i.v.). and after alpha-blockade with intravenous phentolamine (range. 15-80 mg) that was sufficient to either normalize blood pressure or produce a pressure that could not be further lowered. Compared with normotensives. in the baseline state. hypertensives had elevated resistance (1.962 versus 1.268 dyne.sec/cm5. p less than 0.001). total power (1.893 versus 1.568 mW. p less than 0.08). reflected pressure wave component (25.6 versus 13.5 mm Hg. p less than 0.001). ratio of reflected to forward wave (0.65 versus 0.42. p less than 0.001). and pulse wave velocity as determined from the frequency of the first zero-crossing of impedance phase angle (4.6 versus 3.5 Hz. p less than 0.03). During combined alpha- and beta-adrenergic blockade. blood pressure decreased into the normal range (from 162/103 to 131/87 mm Hg) but was still somewhat higher than that in the normotensive subjects. Resistance (1.914 dyne.sec/cm5. p less than 0.03). reflected wave (19.5 mm Hg. p less than 0.01). and ratio of reflected to forward wave (0.61. p less than 0.001) were. however. persistently elevated above normal values. CONCLUSIONS. alpha-Adrenergically mediated vasoconstriction cannot account for all of the hemodynamic alterations seen in essential hypertension.
Epicardial and endocardial mapping of ventricular tachycardia in patients with myocardial infarction. Is the origin of the tachycardia always subendocardially localized, BACKGROUND. Left ventricular endocardial reentry is the conventional concept underlying surgery for ventricular tachycardia (VT). We assessed the incidences of patterns showing complete reentry circuits at either the subendocardial or subepicardial level and of patterns in which left ventricular endocardial mapping could only in part account for a reentrant mechanism. METHODS AND RESULTS. We retrospectively analyzed epicardial and left ventricular endocardial isochronal maps of 47 VTs induced in 28 patients with chronic myocardial infarction (inferior. 14 patients; anteroseptal. 14 patients). Electrograms were recorded intraoperatively from 128 sites with epicardial sock and transatrial left ventricular endocardial balloon electrode arrays. Given the methodology used in this study. the mapping characteristics of the tachycardias suggested five types of activation patterns: 1) complete (90% or more of VT cycle length) subendocardial reentry circuits in seven VTs (15%) and seven patients (25%). 2) complete subepicardial reentry circuits in four VTs (9%) and four patients (14%). 3) incompletely mapped circuits with a left ventricular endocardial breakthrough preceding the epicardial breakthrough in 25 VTs (53%) and 21 patients (75%). 4) incompletely mapped circuits with a left ventricular epicardial breakthrough preceding the endocardial breakthrough in three VTs (6%) and three patients (11%). and 5) a right ventricular epicardial breakthrough preceding the left ventricular endocardial breakthrough in eight VTs (17%) and seven patients (25%). After surgery. one type 3 VT and three type 5 VTs were reinducible. Thus. left ventricular endocardial reentry substrates (types 1 and 3) accounted for 68% of VTs. but substrates involving subepicardial (types 2 and 4) and deep septal layers (type 5) accounted for 32% of VTs. CONCLUSIONS: In a substantial number of VTs. a substrate localization that is at variance with the conventional concept can be detected by simultaneous epicardial and endocardial mapping and may require modification of the surgical approach conventionally aimed at endocardial layers.
Regional three-dimensional geometry and function of left ventricles with fibrous aneurysms. A cine-computed tomography study, BACKGROUND. To assess the extent and nature of the dysfunction surrounding aneurysms of the left ventricle (LV). we examined the parameters of local and global three-dimensional shape. size. and function of LVs of eight patients with histologically confirmed anterior fibrous aneurysms. METHODS AND RESULTS. Three-dimensional reconstructions of each LV were made from 10-12 short-axis fast cine-angiographic computed tomography (cine-CT) slices encompassing the entire heart at end diastole and end systole. Regional three-dimensional wall thickness. thickening. motion. curvature. and stress index were calculated for 84 elements encompassing the entire LV. The aneurysmal border was defined by a sharp decrease in end-diastolic wall thickness and separated the LV into an aneurysmal zone and a normal zone that was further divided into adjacent normal (AN) and remote normal (RN) zones. As expected. thickening was negligible in both the aneurysmal and the border zones. Although both the AN and the RN zones had normal wall thickness (1.05 +/- 0.20 and 1.09 +/- 0.20 cm. respectively). thickening was depressed in the AN (0.22 +/- 0.08 cm) but not the RN (0.44 +/- 0.19 cm) zones. The size of the dysfunction zone (defined as less than 2 mm thickening) was found to be considerably greater than the anatomic size of the aneurysm (60.9 +/- 13.7% versus 33.6 +/- 7.6% of the left ventricular endocardial area. respectively; p less than 0.001). In addition. the AN zone had a smaller curvature and a higher stress index than the RN zone. CONCLUSIONS. LVs with fibrous aneurysms are characterized by a relatively large region of nonfunction that encompasses the thin aneurysmal area and its transitional border zone. a normally functioning remote zone. and an intermediate region of normal wall thickness but with reduced function. which may be attributed to its low curvature and high stress index.
Intravascular ultrasound assessment of lumen size and wall morphology in normal subjects and patients with coronary artery disease, BACKGROUND. Necropsy studies demonstrate that coronary artery disease (CAD) is frequently complex and eccentric. However. angiography provides only a silhouette of the vessel lumen. Intravascular ultrasound is a new tomographic imaging method for evaluation of coronary dimensions and wall morphology. Few data exist regarding intravascular ultrasound in patients with CAD. and no data exist for subjects with normal coronaries. METHODS AND RESULTS. We used a multielement 5.5F. 20-MHz ultrasound catheter to examine eight normal subjects and 43 patients with CAD. We assessed the safety of coronary ultrasound and the effect of vessel eccentricity on comparison of minimum luminal diameter by angiography and ultrasound. Normal and atherosclerotic wall morphology and stenosis severity were also evaluated by intravascular ultrasound. The only untoward effect was transient coronary spasm in five patients. At 33 sites in normal subjects. the lumen was nearly circular. yielding a close correlation between angiographic and ultrasonic minimum diameter (r = 0.92). At 90 sites in patients with CAD. ultrasound demonstrated a concentric cross section; correlation was also close (r = 0.93). However. at 72 eccentric sites. correlation was not as close (r = 0.77). For 41 stenoses. correlation between angiography and ultrasound for area reduction was moderate (r = 0.63). In normal subjects. wall morphology revealed a thin (0.30 mm or less) intimal leading edge and subadjacent sonolucent zone (0.20 mm or less). Patients with CAD exhibited increased thickness and echogenicity of the leading edge. thickened sonolucent zones. and/or attenuation of ultrasound transmission. CONCLUSIONS. These data establish that intravascular ultrasound is feasible and safe and yields luminal measurements that correlate generally with angiography. Differences between angiographic and ultrasound measures of lumen size in eccentric vessels probably reflect the dissimilar perspectives of tomographic and silhouette imaging techniques. Intravascular ultrasound provides detailed images of normal and abnormal wall morphology not previously possible in vivo.
Dipyridamole echocardiography test. A new tool for detecting jeopardized myocardium after thrombolytic therapy, BACKGROUND. We wished to assess whether dipyridamole echocardiography test (DET) can detect jeopardized myocardium after thrombolytic therapy. METHODS AND RESULTS. Seventy-six consecutive patients with a first acute myocardial infarction (AMI) were treated with 2 million IU urokinase i.v. within 4 hours of the onset of AMI and underwent high-dose (as much as 0.84 mg/kg over 10 minutes) DET 8-10 days after AMI. The results were correlated to the anatomy of the infarct-related vessel (IRV). In patients with positive DET. we evaluated the wall motion score index (WMSI; a semiquantitative integrated estimation of extent and severity of the stress-induced dyssynergy). WMSI was derived by summation of individual segment scores divided by the number of interpreted segments. In a 13-segment model. each segment was assigned a score ranging from 1 (normal) to 4 (dyskinetic). Fifty-three patients had positive results on DET. Of these. 42 had dipyridamole-induced new wall motion abnormalities (WMAs) confined to the infarct zone or adjacent segments. In these patients. mean WMSI increased from 1.46 +/- 0.26 (at resting conditions) to 1.73 +/- 0.35 (at peak dipyridamole) (p less than 0.01). whereas no significant change was detected in negative patients (1.6 +/- 0.34 versus 1.57 +/- 0.34. p = NS). Coronary angiography showed a patent IRV (TIMI grade 2 or 3) in 53 patients and no or minimal reperfusion (TIMI grade 0 or 1) in 23 patients. A patent IRV with critical residual stenosis was found in 35 of 42 patients with dipyridamole-induced WMAs in the infarct zone and in 18 of 34 patients without WMAs (p less than 0.05). Among the 23 patients with occluded IRVs. nine had collateral flow to the distal vessel; six of these had a positive DET. Thus. the sensitivity and specificity for identifying a critically stenotic but patent IRV or the presence of a collateral-dependent zone were 66% and 93%. respectively. In a subset of nine patients with a positive DET in the infarct zone or adjacent segments. DET and a control coronary angiography were repeated 1-3 months after an angiographically successful (residual stenosis. 50% or less) coronary angioplasty in the IRV. The repeat DET was negative in eight patients (all with patent IRV at control angiography) and again positive in one patient. who showed restenosis at angiography. The WMSI. at resting conditions was similar before and after angioplasty. whereas it differed significantly at peak dipyridamole (1.7 +/- 0.2 versus 1.4 +/- 0.2. p less than 0.01). CONCLUSIONS. DET can identify the anatomy of the IRV. and dipyridamole-induced WMAs within the infarct zone detect regions with jeopardized myocardium that may benefit from intervention.
The long QT syndrome. Prospective longitudinal study of 328 families, BACKGROUND. The Long QT Syndrome (LQTS) is an infrequently occurring familial disorder in which affected individuals have electrocardiographic QT interval prolongation and a propensity to ventricular tachyarrhythmic syncope and sudden death. We prospectively investigated the clinical characteristics and the long-term course of 3.343 individuals from 328 families in which one or more members were identified as affected with LQTS (QTc greater than 0.44 sec1/2). METHODS AND RESULTS. The first member of a family to be identified with LQTS. the proband. was usually brought to medical attention because of a syncopal episode during childhood or teenage years. Probands (n = 328) were younger at first contact (age 21 +/- 15 years). more likely to be female (69%). and had a higher frequency of preenrollment syncope or cardiac arrest with resuscitation (80%). congenital deafness (7%). a resting heart rate less than 60 beats/min (31%). QTc greater than or equal to 0.50 sec1/2 (52%). and a history of ventricular tachyarrhythmia (47%) than other affected (n = 688) and unaffected (n = 1.004) family members. Arrhythmogenic syncope often occurred in association with acute physical. emotional. or auditory arousal. The syncopal episodes were frequently misinterpreted as a seizure disorder. By age 12 years. 50% of the probands had experienced at least one syncopal episode or death. The rates of postenrollment syncope (one or more episodes) and probable LQTS-related death (before age 50 years) for probands (n = 235; average follow-up 54 months per patient) were 5.0% per year and 0.9% per year. respectively; these event rates were considerably higher than those observed among affected and unaffected family members. CONCLUSIONS. Among 232 probands and 1.264 family members with prospective follow-up. three factors made significant independent contributions to the risk of subsequent syncope or probable LQTS-related death before age 50 years. whichever occurred first (Cox hazard ratio; 95% confidence limits): 1) QTc (1.052; 1.017. 1.088). 2) history of cardiac event (3.1; 1.3. 7.2). and 3) heart rate (1.017; 1.004. 1.031). The findings from this prospective longitudinal study highlight the clinical features. risk factors. and course of LQTS.
Adenosine as a vasodilator in primary pulmonary hypertension, BACKGROUND. The acute administration of vasodilator drugs to patients with primary pulmonary hypertension has been advocated to identify those with reversible pulmonary vasoconstriction. Unfortunately. the usefulness of the drugs currently available is limited by accompanying systemic hypotension. A vasodilator with effects confined to the pulmonary circulation would therefore be advantageous in such patients. METHODS AND RESULTS. The purine nucleoside adenosine was infused into the pulmonary artery in seven patients with primary pulmonary hypertension (baseline pulmonary vascular resistance [PVR]. 442-1.295 dyne/cm/sec-5) to determine its effect on PVR. In all patients. there was a dose-dependent and significant reduction (mean maximal percent decrease from baseline. 38.9%; p less than 0.001) in PVR mediated through a decrease in pulmonary artery pressure and an increase in cardiac output. Systemic vascular resistance (SVR) also decreased. but the ratio of PVR to SVR decreased (maximal mean percent decrease from baseline) by 10.5% (p less than 0.025). indicating that adenosine has a preferential vasodilator effect on the pulmonary circulation when administered in this manner. CONCLUSIONS. Because of its pharmacokinetic and vasodilator properties. adenosine may have a specific role in the investigation of primary pulmonary hypertension.
Anomalous insertion of papillary muscle directly into anterior mitral leaflet in hypertrophic cardiomyopathy. Significance in producing left ventricular outflow obstruction, BACKGROUND. Obstruction to left ventricular outflow in hypertrophic cardiomyopathy (HCM) is usually due to systolic anterior motion of the mitral valve. Occurrence of structural mitral valve abnormalities in HCM and their significance in producing outflow obstruction (even in the absence of typical systolic anterior motion) has not been fully appreciated. METHODS AND RESULTS. Analysis of 78 mitral valves excised from patients with obstructive HCM showed that 10 (13%) had anomalous insertion of one or both left ventricular papillary muscles directly into the anterior mitral leaflet. This malformation was identified by echocardiography. which demonstrated direct continuity between the hypertrophied papillary muscle and mitral leaflet. resulting in a long rigid area of midcavity narrowing that appeared to be solely or largely responsible for outflow obstruction. Basal subaortic pressure gradients were large (70-150 mm Hg). Mitral valve replacement reduced the outflow gradient substantially to 0-15 mm Hg in four patients with postoperative cardiac catheterization. However. two other patients who underwent septal myotomy/myectomy had persistent symptoms and incomplete relief of obstruction (gradients 60 and 70 mm Hg) because of continued midcavity apposition of papillary muscle and ventricular septum. CONCLUSIONS. Anomalous papillary muscle insertion into anterior mitral leaflet represents a mechanism of obstruction to left ventricular outflow in patients with HCM and differs considerably from typical dynamic obstruction caused by mitral valve systolic anterior motion that occurs in many other patients with HCM. Recognition of this malformation emphasizes the diverse morphological expression of HCM and also has important clinical implications for patients requiring operation because the gradient is likely to persist even after adequate myotomy/myectomy; consequently. mitral valve replacement would appear to be the operation of choice in most such patients.
Transmural distribution of myocardial tissue growth induced by volume-overload hypertrophy in the dog, BACKGROUND. Although chronic volume overload is thought to induce uniform cardiac enlargement. the stimulus for tissue growth has not been defined. Changes in diastolic and systolic stress or strain have been proposed as mechanical factors that may stimulate hypertrophy. Since there are thought to be transmural variations in these stresses and strains. three-dimensional patterns of myocardial tissue growth may provide insight into the role of these factors. METHODS AND RESULTS. To assess the transmural variation in tissue growth after volume overload. the configurations of three columns of four to six gold beads (1-mm diameter) implanted in the left ventricular anterior free wall were recorded in five dogs before and after cardiac enlargement induced by creating a systemic arteriovenous fistula. Data were obtained with end-diastolic pressures adjusted to the same level in the control and hypertrophic states. End-diastolic wall thickness remained constant. whereas left ventricular diameter increased. Small increases in transmural systolic strain were seen. The volumes defined by four beads (a tetrahedron) at end diastole showed increases in myocardial mass of 20-27% after 3.6 (mean) weeks of hypertrophy and were uniform across the wall of the left ventricle. The edges of single bilinear-quadratic finite elements were fitted to the three columns of the bead set at end diastole in control and at end diastole after hypertrophy at equal end-diastolic pressures. Thus. continuous transmural strain distribution were obtained at the hypertrophic state with respect to the control state. The transmural distributions of these end-diastolic growth strains were uniform and positive for both the circumferential and longitudinal components measured in a cardiac coordinate system. with small radial growth strain indicating that growth was predominantly parallel to the epicardial tangent plane. Moreover. when strains were transformed (rotated) to fiber coordinates. in-plane fiber and cross-fiber growth strains were both positive at all locations across the wall and approximately equal in magnitude. indicating considerable growth in the cross-fiber direction. CONCLUSIONS. These results indicate that the stimulus for volume-overload hypertrophy may be constant across the wall and that substantial cross-fiber growth occurs during volume-overload hypertrophy.
Roles of thrombin and platelet membrane glycoprotein IIb/IIIa in platelet-subendothelial deposition after angioplasty in an ex vivo whole artery model, BACKGROUND. Platelet deposition at the site of injury caused by balloon angioplasty is associated with acute closure and restenosis. METHODS AND RESULTS. In a new ex vivo whole artery angioplasty model. we examined the roles of thrombin inhibition with D-Phe-Pro-ArgCH2Cl (PPACK) and inhibition of the platelet membrane fibrinogen receptor glycoprotein IIb/IIIa (GPIIb/IIIa) with monoclonal antibody 7E3 on platelet deposition at the site of balloon injury. Fresh rabbit aortas were mounted in a perfusion chamber. One half of the mounted arterial segment was dilated with a standard angioplasty balloon catheter and the uninjured half served as the control segment. The vessels were perfused with human blood at physiological pressure and shear rates of 180-250 second-1 for 30 minutes. Platelet deposition was measured using 111In-labeled platelets and scanning electron microscopy. With heparin (2 units/ml) anticoagulation. 8.2 +/- 2.2 x 10(6) platelets/cm2 were deposited at the site of balloon injury compared with 0.7 +/- 0.2 x 10(6) platelets/cm2 on uninjured segments (p less than 0.02. n = 7). PPACK was tested at a concentration (10 microM) that totally inhibited platelet aggregation in response to thrombin. 7E3 was tested at a concentration (10 micrograms/ml) that totally inhibited platelet aggregation. Platelet deposition at the site of balloon injury was reduced 47% by PPACK and 70% by 7E3 compared with heparin. CONCLUSIONS. At shear rates seen in nonstenotic coronary arteries. PPACK and 7E3 are more effective than heparin in reducing platelet deposition at the site of balloon injury. The significant inhibition of platelet deposition by PPACK demonstrates the importance of heparin-resistant thrombin in platelet thrombus formation. The 7E3 results suggest that approximately 70% of platelet deposition at the site of balloon injury is GPIIb/IIIa dependent and that the remaining 30% results from non-GPIIb/IIIa-mediated platelet-subendothelial adhesion. Finally. the ex vivo whole artery system is a useful model for studying platelet-vessel wall interactions under physiologically defined parameters.
Relation of early hemodynamic changes to final cardiac phenotype and survival after neural crest ablation in chick embryos, BACKGROUND. Microcinephotography was used to study a model of persistent truncus arteriosus created in chick embryos by ablation of premigratory neural crest destined for the third and fourth aortic arch arteries as well as the septum of the cardiac outflow tract. METHODS AND RESULTS. Twenty-five control embryos and 105 of 202 experimental embryos were filmed on day 3 of incubation and then reincubated. The remaining 97 experimental embryos were not filmed because of twisting of the embryos. but they were reincubated. There was no difference in either the survival rate (p greater than 0.23) from day 3 to day 11 of incubation or the incidence of persistent truncus arteriosus (p greater than 0.08) between the filmed and the nonfilmed embryos. Incomplete looping of the cardiac tube observed in experimental embryos during early cardiogenesis correlated with a right ventricular origin of the outflow vessels in the definitive heart. Hemodynamic measurements indicated that there was no difference in heart rate. ejection fraction. systolic and diastolic areas. stroke volume. and cardiac output between controls and the experimental group as a whole. However. embryos that did not survive to day 11 had decreased stroke volume (p less than 0.001) and cardiac output (p less than 0.001). whereas embryos that survived to day 11 with cardiac malformations had increased stroke volume and cardiac output in early embryogenesis. CONCLUSIONS. Increased stroke volume and cardiac output may be necessary factors for survival in embryos with cardiac dysmorphogenesis and probably are associated with dilation of the ventricular portion of the cardiac tube. which leads to malalignment of the outflow vessel or vessels.
Reentrant excitation around a fixed obstacle in uniform anisotropic ventricular myocardium, BACKGROUND. The purpose of this study was to investigate the role of tissue anisotropy and dispersion of refractoriness on initiation of reentrant ventricular tachycardia (VT). METHODS AND RESULTS. A ring of perfused uniform anisotropic ventricular epicardium in Langendorff-perfused rabbit hearts was created by an endocardial freezing technique. High-resolution mapping (248 channels) was used to analyze epicardial activation of the left ventricle. One to three premature beats were induced at a total of 272 points in 17 experiments (16 different points around the ring in each experiment). Reentrant VT could be initiated at 43 of the 272 points tested. The cycle length of VT was stable and ranged from 128 to 198 msec (mean. 161 +/- 19 msec). Correlation between conduction velocity and the angle between the circulating activation wave and epicardial fiber orientation showed that in segments of the ring where conduction was perpendicular to the fiber axis. mean conduction velocity was 25 +/- 5 cm/sec compared with 60 +/- 7 cm/sec when conduction was parallel to the fiber orientation. Analysis of the site of unidirectional conduction block showed that in 41 of 43 cases. block occurred while the impulse was propagating parallel to the fiber orientation. Measurement of the refractory periods at either side of the line of unidirectional block showed that only in 12 of 43 cases did block occur while the impulse was propagating into an area with a longer (more than 10 msec) refractory period. CONCLUSIONS. In uniform anisotropic ventricular myocardium. reentrant VT is initiated because lowering the stimulating efficacy of the depolarization wave by premature beats leads to preferential conduction block parallel to the fiber orientation.
Differential effects of heptanol, potassium, and tetrodotoxin on reentrant ventricular tachycardia around a fixed obstacle in anisotropic myocardium, BACKGROUND. The aim of this study was to test the hypothesis that electrical uncoupling and depression of the fast sodium channels have differential effects on propagation of the electrical impulse relative to the fiber orientation. METHODS AND RESULTS. In a model of reentrant ventricular tachycardia (VT) (mean cycle length. 144 +/- 13 msec) around a ring of anisotropic myocardium in 10 Langendorff-perfused rabbit hearts. the effects of extracellular K+ concentration [( K+]o) and heptanol were studied. [K+]o and heptanol each had a dose-dependent effect on VT cycle length. However. high [K+]o slowed the VT mainly by depressing longitudinal conduction. whereas heptanol preferentially depressed transverse conduction. The ratio between longitudinal and transverse conduction velocities progressively decreased with high [K+]o and progressively increased with heptanol. Heptanol terminated VT at a mean concentration of 3.5 +/- 0.5 mM. The cycle length before termination was 446 +/- 120 msec (p less than 0.001). In eight of 10 experiments. termination occurred by failure of conduction during transverse propagation. VT terminated at a mean [K+]o of 11.6 +/- 1.8 mM. The cycle length before termination was 493 +/- 341 msec (p less than 0.01). In seven of 10 cases. termination occurred by failure of conduction during longitudinal propagation. In the remaining five episodes (two with heptanol and three with high [K+]o). termination occurred by collision of the reentrant beat with an antidromic impulse being reflected within the ring. In a separate series of six hearts. tetrodotoxin was administered during VT. Like high [K+]o. tetrodotoxin prolonged the cycle length of the VT by preferentially slowing longitudinal conduction. and VT was terminated by longitudinal block. CONCLUSIONS. During reentrant VT. electrical uncoupling of cells by heptanol or modification of active membrane properties by high [K+]o or tetrodotoxin has a differential depressing effect on propagation of the impulse relative to the fiber orientation.
Localization of breakthrough site of canine monomorphic ventricular tachycardia by pacemapping. A vectorial approach, BACKGROUND. The precision and limitations of ventricular pacemapping as a method to localize the site of earliest breakthrough of ventricular tachycardia (VT) were investigated in a canine model of experimental myocardial infarction. METHODS AND RESULTS. Forty-one episodes of VT induced in 10 animals were mapped using a standard grid of 64 endocardial and epicardial bipolar electrodes to determine the site of earliest endocardial or epicardial breakthrough of activation during VT. Each of these 64 recording sites was also used for ventricular pacing during sinus rhythm at cycle lengths comparable to those of the VTs. Orthogonal X. Y. and Z Frank electrocardiographic (ECG) leads were recorded during all episodes of VT and ventricular pacing from all sites after the chest was closed in all animals. Surface ECG waveforms corresponding to each VT and each ventricular pacing were compared pairwise by measuring the Euclidean metric difference between the VT and ventricular pacing vectors with the orthogonal ECG leads as their X. Y. and Z components. The pacing site that generated the vector most similar to VT vector (smallest vectorial difference) was defined as the predicted breakthrough site. This predicted site of breakthrough was identical to the actual site of breakthrough determined by activation sequence mapping during VT for only nine VTs (22%). However. for an additional 27 VTs (66%). the observed and predicted breakthrough locations were at adjacent (1 cm or less apart) recording sites. For five VTs (12%). the two sites were remote. the distance between them exceeding 1 cm. CONCLUSIONS. In this model. locating the breakthrough site by pacemapping is exact in only a small minority of VTs. However. when orthogonal surface ECG leads are used for comparison. pacemapping can predict the site of earliest breakthrough during VT with a 1-cm resolution in the majority of VTs.
Repolarization inhomogeneities in ventricular myocardium change dynamically with abrupt cycle length shortening, BACKGROUND. In single heart cells. abrupt changes in stimulation rate elicit complex alterations in repolarization. The effects of rate change on dispersion of repolarization. however. have not been well characterized. METHODS AND RESULTS. To determine the effects of abrupt cycle length (CL) shortening on spatial inhomogeneity of repolarization in a syncytium of ventricular cells. 124 action potentials were simultaneously recorded from Langendorff-perfused guinea pig hearts using high-resolution optical mapping with voltage-sensitive dye. The distribution of ventricular action potential durations (APDs) mapped during each cardiac cycle was used to calculate mean APD and repolarization dispersion index (DI). defined as the variance of the distribution. After abruptly shortening CL from 500 to 300 msec. mean APD declined exponentially in normoxic controls (by 23 +/- 3 msec. p less than 0.0001). This response was characterized by beat-to-beat oscillations of APD that were synchronized at all ventricular sites. After 30 minutes of hypoxia. mean APD decreased from 175.0 +/- 13.3 to 76 +/- 25.7 msec. However. during hypoxia. abrupt CL shortening lowered mean APD by only an additional 6 +/- 6 msec. and APD oscillations were no longer synchronized throughout the ventricle. In controls. beat-to-beat DI decreased significantly (-51.0 +/- 6.8%. p less than 0.01) by the sixth post-CL shortening beat and then recovered (by 15-20 beats). In contrast. DI failed to decrease during hypoxia (+7.1 +/- 23%). Two mechanisms for the transient decline of DI in controls were identified: synchronous APD oscillations and transient diminution of the apical-to-basal ventricular APD gradient. CONCLUSIONS. These data demonstrate that inhomogeneity of ventricular repolarization. as measured by DI. changes dynamically with CL shortening. Furthermore. the hypoxic ventricle does not attenuate DI after abrupt CL shortening and thereby lacks a physiological response expected to diminish vulnerability to arrhythmias.
Effect of altered activation sequence on epicardial QRST area and refractory period in dogs, BACKGROUND. We investigated the effects of activation sequence on cardiac surface QRST areas and refractory periods in experiments on dogs. METHODS AND RESULTS. Right and left ventricular pacings were performed. and the pacing site was altered every 6 minutes. After 4 minutes of a given pacing. 54 unipolar electrograms distributed over the entire cardiac surface were recorded. Next. refractory periods at electrode sites near pacing electrodes were measured. Paired right ventricular/left ventricular (RV/LV) pacing data were obtained six or seven times in each sample. Although the QRST isoarea maps during the two activation orders were qualitatively similar. it was recognized consistently from the right ventricle-left ventricle difference map that leads around the RV free wall had positive values and that leads around the LV free wall and apex had negative values. Compared with the same leads at RV and LV pacing. QRST areas were larger when pacing sites were near the leads. The local QRST areas of individual leads at which we measured local refractory period were consistently larger during drive from proximal pacing sites than during drive from distant pacing sites. Refractory periods were consistently longer during proximal pacing than during distal pacing. and there was a positive correlation between change in local QRST area and change in refractory period (r = 0.64) during altered activation sequence. whereas there was an inverse correlation between change in QRST area and change in refractory period (r = -0.91) during localized myocardial warming. CONCLUSIONS. Both local QRST areas and local refractory periods were dependent on the activation sequence. and there was a positive correlation between QRST areas and refractory periods during various activation sequences compared with localized myocardial warming.
Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments, BACKGROUND. The use of flecainide and encainide was terminated in the Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac deaths in the active treatment group. Such events might arise from reentrant rhythms initiated by premature stimulation in the presence of anisotropic sodium channel availability. Drugs that bind to sodium channels increase the functional dispersion of refractoriness by slowing (a result of the drug-unbinding process) the transition from an inexcitable state to an excitable state. It is interesting that encainide and flecainide unbind slowly (15-20 seconds). whereas lidocaine and moricizine unbind rapidly (0.2-1.3 seconds). METHODS AND RESULTS. With a computer representation of a cable with Beeler-Reuter membrane properties. we found a small (6 msec) vulnerable window that occurred 338 msec after the last drive stimulus. Premature stimuli falling within the vulnerable window resulted in unidirectional block and reentrant activation. In the presence of a slowly unbinding drug. the window was delayed an additional 341 msec. and its duration was extended to 38 msec. The delay (antiarrhythmic effect) before the onset of the vulnerable window and its duration (proarrhythmic effect) were both dependent on the sodium channel availability and the recovery process. Both effects were also prolonged when sodium channel availability was reduced by membrane depolarization. Defining the proarrhythmic potential as the duration of the vulnerable window. we found that hypothetical use-dependent class I drugs have a greater proarrhythmic potential than non-use-dependent drugs. CONCLUSIONS. The antiarrhythmic and proarrhythmic properties of pure sodium channel antagonists are both dependent on sodium channel availability. Consequently. the price for increased antiarrhythmic efficacy (suppressed premature ventricular contractions) is an increased proarrhythmic vulnerability to unsuppressed premature ventricular contractions.
Effects of an increase in intracellular free [Mg2+] after myocardial stunning on sarcoplasmic reticulum Ca2+ transport, BACKGROUND. Myocardial stunning has been associated with a greater than twofold increase in intracellular free [Mg2+] from 0.6 to 1.5 mM. The effect of this increase in free [Mg2+] on the function of the sarcoplasmic reticulum (SR) Ca2+ pump was assessed in SR isolated from Langendorff perfused. isovolumic rabbit hearts after 15 minutes of global ischemia. METHODS AND RESULTS. Our results indicate that myocardial stunning results in a shift in the Ca2+ sensitivity of oxalate-supported. Ca2+ transport over the entire range of free [Ca2+] associated with the cardiac cycle. Using 0.6 mM free Mg2+ as control. maximal rates of Ca2+ transport occurred at 1 microM free Ca2+ (control. 519 +/- 32; stunned. 337 +/- 37 nmol Ca2+.min-1.mg-1). At 0.56 microM free Ca2+. SR Ca2+ transport was reduced from a control of 351 +/- 49 to 263 +/- 12 nmol Ca2+.min-1.mg-1 at 0.6 mM free [Mg2+]. Moreover. an increase in the free [Mg2+] from 0.6 to 1.5 mM results in a greater shift in the Ca2+ activation curve with no change in the level of maximal activation. Ca2+ transport at 0.56 microM free Ca2+ was shifted in the stunned SR from 263 +/- 12 to 138 +/- 29 nmol Ca2+.min-1.mg-1 at 0.6 and 1.5 mM free Mg2+. respectively. CONCLUSIONS. These results indicate that an increase in free [Mg2+] after stunning in combination with the inherent defect in the SR Ca2+ ATPase may reduce the ability of the cell to regulate Ca2+ to a greater extent than previously observed. This impairment in Ca2+ regulatory function may contribute directly to the increase in diastolic tone and indirectly to the reduced systolic function characteristic of the stunned myocardium.
A lesson from the controversy about heart rate adjustment of ST segment depression, To summarize the literature review. the heart rate adjustment appears to be able to perfectly discriminate patients with different numbers of diseased coronary vessels in one center. to increase the diagnostic accuracy of three-vessel or left main disease in eight centers. and unable to improve accuracy in seven centers. To explain those differences. several methodological and statistical biases have been considered. However. a recent report regarding the application of the method in eight centers and a meticulous literature review could not explain the superior performance in some laboratories.
Radionuclide assessment of infarct size and left ventricular function in clinical trials of thrombolysis, Mortality. left ventricular ejection fraction. and infarct size are important end points in evaluating the efficiency of thrombolytic treatment in clinical trials. Radionuclide assessment of ejection fraction and infarct size is safe. accurate. reproducible. and readily available. Its use in clinical trials supplements mortality data and allows meaningful results in trials with smaller patient numbers. Single photon emission computed tomography improves the detection and quantification of infarct size. and its use with new radiopharmaceuticals will assume an important role in future trials. For an 8-year period. these radionuclide techniques have been used in the Western Washington Thrombolysis Trials and have generally shown smaller infarct size and higher ejection fractions in patients receiving streptokinase and tissue-type plasminogen activator. However. in the most recent trial there was no direct relation between these end points and the time between symptom onset and initiation of treatment. Future trials that direct efforts to treatment in the first hour after symptom onset should further clarify this observation.
The role of echocardiography in the evaluation of mechanical complications of acute myocardial infarction, With the introduction of the coronary care unit and more effective therapy for primary life-threatening arrhythmias. cardiogenic shock and the mechanical complications of acute myocardial infarction are now responsible for the majority of in-hospital deaths. These mechanical complications. which include myocardial rupture of the left ventricular free wall. rupture of the ventricular septum. and rupture of the papillary muscle. are estimated to account for 25.000 fatalities yearly in the United States. Although the mechanism of myocardial rupture has not been clearly defined. there is increasing evidence that infarct expansion. which can be readily detected by two-dimensional echocardiography. may be an important pathophysiologic factor. The ready availability of echocardiography in the coronary care unit has made a major impact on the immediate diagnosis of mechanical complications in the hemodynamically compromised patient with acute myocardial infarction. In particular. two-dimensional and Doppler echocardiographic techniques have been extremely useful in the identification and localization of ventricular septal rupture. In addition. papillary muscle rupture can be readily diagnosed by Doppler approaches and is easily distinguished from ventricular septal rupture. In view of increasing evidence that early surgical intervention is indicated in these patients. these echocardiographic approaches offer the surgeon prompt diagnostic and anatomic information. Unfortunately. rupture of the free wall of the left ventricle often results in sudden death within minutes before echocardiographic evaluation can be attempted. Nevertheless. rapid echocardiographic diagnosis provides the patient with the possibility of potential life-saving resuscitative interventions before immediate surgery. Thus. over the past decade. echocardiography has become a vital tool in the diagnosis and evaluation of patients with mechanical complications of acute myocardial infarction. The development of Doppler techniques. color flow Doppler. and esophageal approaches should further enhance our diagnostic abilities and allow careful monitoring of patients before. during. and after surgical repair. It is hoped that with the improvements in echocardiographic evaluation of mechanical rupture and more rapid surgical intervention. future studies will demonstrate better surgical results with good long-term survival in patients with myocardial rupture.
Positron emission tomography for the assessment of myocardial viability, The detection of viable myocardium or ischemically injured myocardium with a reversible impairment of contractile function remains clinically important but challenging. Detection of reversible dysfunction and distinction from irreversible tissue injury by positron emission tomography is based on identification of preserved or even enhanced glucose metabolism with F-18 2-fluoro 2-deoxyglucose. Regional patterns of myocardial glucose utilization and blood flow. defined as perfusion-metabolism mismatches or matches. on positron emission tomography in patients with chronic or even acute ischemic heart disease are highly accurate in predicting the functional outcome after interventional revascularization. Compared with thallium-201 redistribution scintigraphy. positron emission tomography appears to be diagnostically more accurate. especially in patients with severely impaired left ventricular function. While larger clinical trials are needed for further confirmation. positron emission tomography has already proved clinically useful for stratifying patients with poor left ventricular function to the most appropriate therapeutic approach.
Dipyridamole 201Tl scintigraphy in the evaluation of prognosis after myocardial infarction, Dipyridamole 201Tl imaging has been proposed as an alternative to exercise ECG testing for the prehospital discharge evaluation of patients recovering from myocardial infarction. The rationale is that many postinfarction patients with exercise-induced ischemia experience later cardiac events. and the sensitivity of predischarge exercise ECG testing in patients with multivessel disease ranges from only 45% to 62%. In addition. several groups of investigators have shown the sensitivity of submaximum exercise 201Tl imaging to be less than ideal. This report summarizes the current status of dipyridamole 201Tl imaging in the period of 1-13 days after myocardial infarction. Although the number of studies performed to date is limited. the following conclusions can be drawn: dipyridamole 201Tl imaging after myocardial infarction was associated with no serious side effects. and those present could be quickly reversed with aminophylline; redistribution with dipyridamole 201Tl images definitely correlates with prognosis after uncomplicated myocardial infarction; dipyridamole 201Tl imaging is definitely useful in patients unable to exercise for a variety of reasons; and future studies are definitely indicated to further define the role of dipyridamole 201Tl imaging for assessing prognosis. especially in those patients undergoing interventional therapy after acute myocardial infarction.
Noninvasive imaging in acute coronary disease. A clinical perspective, Numerous highly complex and sensitive noninvasive imaging techniques have enhanced the care of patients with acute myocardial infarction. Optimum use requires specific objectives to be defined in advance. including a review of the potential impact of the test on subsequent decisions. An additional issue that is subject to scrutiny in the current climate of cost containment relates to the incremental value of a specific examination. The imaging modality to be used will partially depend on other issues. including accessibility. cost. and interindividual or institutional expertise with a particular technique. Major applications in noninvasive imaging in the acute coronary syndromes include the following: 1) diagnosis. including identification of associated diseases and contraindications for acute reperfusion; 2) evaluation and management of complications (mechanical and nonmechanical); 3) determination of prognosis (both early and late); 4) estimation of myocardial viability; 5) assessment of therapeutic efficacy; 6) investigational approaches. including 99mTc-sestamibi tomographic imaging. ultrafast cine computed tomographic scanning. and nuclear magnetic resonance imaging. Previous studies in the prethrombolytic era have documented the powerful impact of radionuclide stress testing on prognosis. but this needs to be reevaluated in the light of the changing current population undergoing stress testing. Preliminary data imply that the prognostic accuracy of stress testing after thrombolytic therapy is diminished. Moreover. the role of the open infarct-related artery in traditional estimates of prognosis (e.g.. ejection fraction) requires further study. Noninvasive imaging has multiple applications in the diagnosis and management of patients with acute coronary disease. but the decision to use a specific technology in a particular circumstance mandates good clinical judgment and selectivity.
Value of planar 201Tl imaging in risk stratification of patients recovering from acute myocardial infarction, Although exercise ECG testing has been shown to have important prognostic value after acute myocardial infarction. exercise 201Tl scintigraphy offers several potential advantages. including: 1) increased sensitivity for detecting residual myocardial ischemia; 2) the ability to localize ischemia to a specific area or areas subtended by a specific coronary artery; 3) the ability to identify exercise-induced left ventricular dysfunction. which is manifested by increased lung uptake or transient left ventricular dilation; and 4) more reliable risk stratification of individual patients. The more optimal prognostic efficiency of 201Tl scintigraphy partially results from the fact that the error rate in falsely classifying patients as low risk is significantly smaller with 201Tl scintigraphy than with stress ECG. Because of these substantial advantages. there seems to be adequate rationale for recommending exercise perfusion imaging rather than exercise ECG alone as the preferred method for evaluating mortality and morbidity risks after acute myocardial infarction.
Risk stratification after myocardial infarction with exercise and Doppler echocardiography, Exercise testing early after myocardial infarction has been shown to be of further risk stratification value among otherwise low-risk patients on the basis of an uncomplicated clinical course. The addition of cardiac imaging modalities to exercise testing has augmented this capacity. Exercise echocardiographic imaging before and immediately after treadmill exercise can be accomplished in 85-95% of patients. New or worsening wall motion abnormalities identify 63-80% of patients who will suffer cardiac events and correctly predict 78-95% of those who will not. In addition. exercise echocardiography can detect multivessel coronary artery disease with a sensitivity of 80% and a specificity of 90%. These results are superior to those obtained by analyzing global left ventricular function during exercise. exercise aortic Doppler velocity profiles. or exercise electrocardiography. How exercise echocardiography compares with 201Tl perfusion imaging after myocardial infarction awaits a systematic study. Therefore. the choice between exercise echocardiography and perfusion imaging depends on physician preference. availability. cost. and service.
Radionuclide assessment of ventricular function and risk stratification after myocardial infarction, Prognosis after acute myocardial infarction is determined primarily by left ventricular function and by the extent to which additional coronary obstructions jeopardize viable myocardium. Radionuclide ventriculography is well suited for noninvasive assessments of resting and exercise ventricular function after acute myocardial infarction. The prognostic importance of resting left ventricular function after acute myocardial infarction is well established. Several studies have reported the prognostic utility of submaximal exercise radionuclide ventriculography at the time of hospital discharge. Patients with globally depressed left ventricular function after acute myocardial infarction are at increased risk for cardiac death. while patients with normal resting ventricular function but abnormal function during exercise appear to be at risk for nonfatal ischemic events. The development of gated tomographic techniques and new radiopharmaceuticals will make available more accurate and detailed assessments of ventricular function and combined assessments of function and perfusion. These new developments require further investigation but appear to be promising new techniques with the potential for providing improved assessments of prognosis after acute myocardial infarction.
Assessment of aortic and pulmonic stenosis by echocardiography, Doppler and imaging echocardiography are highly useful methods of identifying and quantifying both aortic and pulmonic stenosis. The presence of valve stenosis and associated regurgitation is based on detecting abnormal intracardiac velocity patterns near the affected valve. Defining the specific valve involved and the type of lesion present is based on determining the location and timing of the abnormal velocities. Both color flow imaging and duplex pulsed Doppler with two-dimensional echocardiographic imaging are highly accurate in identifying the lesions present. Quantification of the severity of stenotic lesions requires calculation of the pressure gradient across the valve and estimation of valve area; quantification of volume flow rate is frequently helpful. The pressure gradient is calculated from high velocity data acquired in the stenotic valve orifice by using the Bernoulli equation. Volume flow rate through the valve can be estimated by using Doppler velocity data and two-dimensional echocardiographic imaging data acquired at sites upstream from the stenotic valve. The continuity equation allows calculation of valve area that is based on this noninvasive stroke volume and pressure gradient data. This review characterizes flow patterns present near stenotic valves. discusses the equations required to quantify aortic and pulmonic stenosis. and then describes the clinical approach to the noninvasive quantification of both stenotic lesions.
Quantification of valvular regurgitation by Doppler echocardiography, One of the widest uses of color Doppler echocardiography is for the quantification of valvular regurgitation. In this article we review the physics and instrumentation factors related to the most commonly applied method. that of planimetering areas of regurgitant jet spray within the receiving chamber. and relate features such as instrument gain. pulse repetition frequency. and important physical parameters such as receiving chamber compliance and driving pressure to the application of this method for precordial as well as transesophageal echocardiography. New approaches to the quantification of valvular insufficiency. such as measurement of the momentum of the jet and study of the acceleration flow in the proximal flow convergence region within the chamber of origin of an insufficiency jet and proximal to the orifice. are described and preliminary results given for a new method of quantification of volume flow across regurgitant orifices.
Role of echocardiography in the diagnosis and evaluation of severity of mitral and tricuspid stenosis, The presence. severity. and hemodynamic consequences of mitral and tricuspid stenosis can be determined by echocardiographic techniques. In mitral stenosis two-dimensional echocardiographic imaging allows definition of leaflet anatomy and dynamics. subvalvular disease. ventricular function. and involvement of other valves. Spectral and color Doppler echocardiographic techniques permit accurate measurement of transvalvular gradient. determination of functional orifice area. evaluation of associated valvular regurgitation. and assessment of pulmonary artery pressures. These approaches are of recognized clinical value. and they provide additional diagnostic information that is unavailable from clinical assessment alone in a significant number of patients. Compared with available invasive diagnostic standards of reference. echocardiographic data have been found to be comparable in accuracy. In tricuspid stenosis echocardiographic imaging and Doppler techniques provide an assessment of valve morphology and function that should be similarly useful in clinical management decisions. although rigorous comparative studies have not been performed. Currently. carefully done echocardiographic studies are a definitive means of establishing the presence and significance of mitral stenosis and tricuspid stenosis. thereby obviating the need for invasive evaluation in many patients. reducing risk. and potentially decreasing the cost of diagnostic assessment.
Evaluation of valvular heart disease with cine gradient echo magnetic resonance imaging, Electrocardiographic referenced repetitive gradient echo magnetic resonance imaging (cine GRE) has been used to detect and quantify valvular regurgitation. Regurgitation is recognized as a signal void in the high intensity blood pool on these images. Mitral regurgitation causes a signal void in the left atrium in systole. and aortic regurgitation produces one in the left ventricle in diastole. The specificity. sensitivity. and diagnostic accuracy of cine GRE for the detection of mitral and aortic regurgitation was greater than 0.93. 0.89. and 0.92. respectively. The severity of regurgitation has been quantified as the difference in the stroke volume between the two ventricles by measuring the volume of the blood pool. as shown in the stack of magnetic resonance tomograms. Severity has also been assessed by measuring the volume of the signal void. Finally. measurements of the volume of aortic regurgitation have recently been achieved by using velocity-encoded cine GRE. This technique provides a direct measurement of retrograde flow in the aorta during diastole. New cine GRE imaging techniques provide a noninvasive means for quantification of valvular as well as ventricular function.
Radionuclide angiographic evaluation of left ventricular diastolic function, Left ventricular diastolic function is altered in the majority of patients with cardiac diseases. especially those characterized by myocardial ischemia or hypertrophy. In many circumstances. such abnormalities related to impaired relaxation or reduced distensibility may precede evidence of left ventricular systolic dysfunction. Radionuclide angiography may be adapted to study the rapid filling phase of diastole. the duration of the isovolumic relaxation phase. the relative contributions of rapid filling and atrial systole to left ventricular stroke volume. and the relation between regional nonuniformity of left ventricular function and global filling properties. Technical aspects of data acquisition that must be considered for such studies include the effects of cardiac cycle length fluctuations. temporal resolution. temporal smoothing. and normalization parameters. As noninvasive radionuclide methods (and any other analyses using purely noninvasive techniques) do not permit assessment of the left atrial-left ventricular pressure gradient or the simultaneous evaluation of changes in left ventricular pressure and volume during relaxation and filling. complete clinical interpretation of "abnormal" left ventricular filling indexes. or changes in these indexes after interventions. is not possible. Despite the inherent limitations of noninvasive assessment of left ventricular diastolic function. radionuclide evaluation of left ventricular filling may provide clinically useful insights. especially in patients with congestive heart failure symptoms and normal left ventricular systolic function.
Nuclear magnetic resonance imaging for assessment and follow-up of patients with valve disease, Nuclear magnetic resonance (NMR) imaging now offers a powerful means of assessing a variety of clinically important parameters in patients with valvular heart disease. NMR approaches will probably be most useful in patients with chronic valvular regurgitation. in which there continues to be uncertainty regarding the optimum timing for surgical intervention. In these patients it is possible to simultaneously assess both the valvular regurgitation and the resulting changes in myocardial structure and function. In patients with aortic stenosis. NMR can be applied to the assessment of left ventricular mass. both before and after valvuloplasty or valve replacement. In mitral stenosis. NMR may be applied to the assessment of right ventricular volumes and function. NMR may be used for the detection of prosthetic valve regurgitation when Doppler studies are equivocal. Finally. NMR imaging may be applied in patients with congenital or aortic root disease to evaluate valvular function in addition to diagnostic assessment of such patients. The future development of isotropic three-dimensional acquisition approaches. ultrafast imaging strategies. automated surface detection techniques. and more rapid function and flow analysis could considerably enhance the use of the current NMR approaches. The application of spectroscopic techniques could provide a means of monitoring myocardial metabolic abnormalities in ventricles exposed to chronic overload. Meanwhile. in patients with valvular regurgitation and stenosis. it would seem timely to initiate long-term serial NMR studies to further define natural history and the effects of various medical regimens and to ultimately help determine optimum medical and interventional regimens.
Clinical cardiac positron emission tomography: state of the art, Cardiac positron emission tomography (PET) has evolved rapidly from a relatively esoteric research tool into clinical applications providing unique. quantitative information on myocardial perfusion. metabolism. and cell membrane function and having a potentially significant impact on cardiovascular medicine. Although there are many different positron radionuclides for imaging diverse myocardial behavior. three radionuclides have reached accepted clinical utility. Cardiac PET using nitrogen-13-ammonia. rubidium-82. and fluoro-18-deoxyglucose has proved accurate and definitive in multiple university and private-practice sites for diagnosing and assessing severity and location of coronary artery disease in symptomatic or asymptomatic patients. for identifying injured but viable myocardium potentially salvageable by revascularization. and for ruling out clinically significant coronary artery stenosis with a high specificity in patients who might otherwise undergo coronary arteriography to document the absence of significant disease.
The role of echocardiography/Doppler in catheter balloon treatment of adults with aortic and mitral stenosis, Doppler and two-dimensional echocardiography (2DE) have played a major role in the evaluation of patients undergoing catheter balloon treatment of aortic and mitral stenosis. Doppler/2DE has made possible an understanding of the mechanism of increase in valve area. Before the procedure. Doppler/2DE provides a reasonable estimate of the severity of the valvular stenosis and associated cardiac abnormalities. The evaluation of mitral valve morphology by 2DE before catheter balloon treatment has shown that patients with excellent leaflet motion and minimal increase in valve thickness have the greatest increase in mitral valve area. During the procedure. Doppler/2DE can aid in the transseptal puncture. in positioning the balloons across the stenotic orifice. and in the immediate assessment of changes in valve function and complications. The estimate of the aortic and mitral valve gradients and areas by Doppler/2DE before catheter balloon treatment shows a reasonable correlation with hemodynamic measurements. Immediately after the procedure. the Doppler/2DE estimates of aortic valve gradient and area show a fair correlation with data from cardiac catheterization. provided care is taken to avoid technical problems. Doppler/2DE assessment of mitral valve area immediately after catheter balloon commissurotomy (CBC) shows a poor correlation with catheterization data. which has been attributed to rapid changes in left atrial compliance and gradient. However. the correlation of Doppler estimates of mitral valve area with catheterization data improves at 3 months after CBC. Serial evaluations of patients after aortic or mitral catheter balloon dilatation should permit detection of restenosis and valve regurgitation and assessment of ventricular function and may provide valuable insights into the mechanisms of restenosis and changing clinical status.
The use of color flow mapping for intraoperative assessment of valve repair, Repair procedures that preserve a patient's native valve are associated with a lower perioperative and late mortality. a lower incidence of thromboembolic events. and better preservation of left ventricular function than prosthetic replacement. Traditionally employed procedures for intraoperative assessment of the adequacy of repair. such as fluid injection into the arrested ventricle for assessment of valve leakage. measurement of atrial pressure and height of V-waves. and palpation of the atria for the presence of systolic thrills. have not proved to be reliable approaches in the intraoperative evaluation of mitral and tricuspid regurgitation and in the assessment of the adequacy of repair procedures. Intraoperative color Doppler. using either the epicardial or the transesophageal approach. offers rapid and accurate information about the presence and severity of mitral regurgitation at the time of surgery. This technique provides instantaneous evaluation of the adequacy of mitral and tricuspid valvuloplasty and appears capable of predicting postoperative outcome. Intraoperative color Doppler is useful for evaluation of the adequacy of repair before chest closure and may thus help to avoid the need for reoperation. This approach may ultimately allow valve repair procedures to be performed in greater numbers of patients with better control over outcome and with lower reoperation rates.
Valvular heart disease: management and intervention. Clinical overview and discussion, The diagnosis and estimation of severity of valvular disease can usually be made by a well done history and physical examination. We now have a wealth of noninvasive techniques capable of imaging the heart and the great vessels. With Doppler echocardiography and magnetic resonance imaging we are beginning to develop methods that can measure pressures and flow. All of these advances have duplicated to a large extent the information obtainable in the past only from cardiac catheterization and angiography. In some instances. in aortic and mitral stenosis. for example. echo-Doppler evaluation is so good that catheterization is rendered unnecessary. The decision to send patients to surgery without catheterization is especially secure when the valvular obstruction is very severe. When the gradient is only moderately increased. then estimation of severity depends on flow. and in many cases these patients are sent to catheterization before surgery is recommended. With regurgitant lesions there is less confidence with noninvasive techniques that the severity is always correctly estimated. and therefore catheterization and angiography are more often necessary before sending the patient to surgery. At the present time cardiac catheterization and angiography are required 1) whenever there is an inconsistency between the clinical picture and noninvasive information. for example. the symptomatic patient with aortic stenosis who has mild-to-moderate aortic stenosis by echo-Doppler techniques. and 2) whenever additional information not obtainable by noninvasive techniques is necessary. for example. the need to know the status of the coronary arterial circulation. Noninvasive techniques have not in any way replaced a good history and physical examination.
Metabolic imaging of patients with cardiomyopathy, The cardiomyopathies comprise a diverse group of illnesses that can be characterized functionally by several techniques. However. the delineation of derangements of regional perfusion and metabolism have been accomplished only relatively recently with positron emission tomography (PET). Regional myocardial accumulation and clearance of 11C-palmitate. the primary myocardial substrate under most conditions. demonstrate marked spatial heterogeneity when studied under fasting conditions or with glucose loading. PET with 11C-palmitate permits the noninvasive differentiation of patients with nonischemic from ischemic dilated cardiomyopathy. since patients with ischemic cardiomyopathy demonstrate large zones of intensely depressed accumulation of 11C-palmitate. probably reflecting prior infarction. Patients with hypertrophic cardiomyopathy and Duchenne's muscular dystrophy demonstrate relatively unique patterns of myocardial abnormalities of perfusion and metabolism. The availability of new tracers and techniques for the evaluation of myocardial metabolism (11C-acetate). perfusion (H2(15)O). and autonomic tone (11-C-hydroxyephedrine) should facilitate further understanding of the pathogenesis of the cardiomyopathies.
Radionuclide angiography in the management of asymptomatic aortic regurgitation, Left ventricular systolic function is an important determinant of long-term prognosis in patients with chronic aortic regurgitation. In patients undergoing aortic valve replacement. those with preoperative left ventricular dysfunction have a greater risk of postoperative congestive heart failure and death than do those in whom preoperative left ventricular systolic function is normal. However. patients with preoperative left ventricular dysfunction are not a homogeneous group but may be further stratified according to risk on the basis of the severity of symptoms. exercise intolerance. and temporal duration of left ventricular dysfunction. Therefore. asymptomatic patients with reproducible and definite evidence of impaired left ventricular function should undergo operation without waiting for the development of symptoms or more severe left ventricular dysfunction. In addition. among asymptomatic patients with normal systolic function. indexes of left ventricular function are also helpful. especially when measured serially. in predicting the development of symptoms and the need for valve replacement surgery over the course of the next 5 to 10 years. Noninvasive imaging techniques should play a major role in this evaluation. and radionuclide angiography is ideally suited for the quantitative evaluation of systolic function in the volume-overloaded left ventricle. Although the prognostic value of left ventricular ejection fraction at rest is well established. ejection fraction during exercise has little value once age and left ventricular function at rest are accounted for and is of minor importance in formulating patient management decisions.
Echocardiography and Doppler ultrasound in the evaluation of pericardial disease, Echocardiography and Doppler ultrasound are useful in evaluating a variety of pathological conditions affecting the pericardium. Cardiac tamponade results in right atrial collapse and right ventricular diastolic collapse detectable by echocardiography. These echocardiographic signs have a high degree of sensitivity and specificity. False-negative echocardiographic studies may be seen in patients with pulmonary hypertension. and false-positive studies for cardiac tamponade may occur in severe hypovolemia. Although cardiac tamponade is usually caused by pericardial effusion. less commonly intrapericardial clot may result in hemodynamic compromise. Pericardial clot may be echogenic. and hence the diagnosis potentially can be missed. If the intrapericardial clot is localized. the classic echocardiographic signs of pericardial effusion may be absent. and a localized mass may be seen on the echocardiogram. Increased respiratory variation in transvalvular blood flow velocities detectable by Doppler ultrasound is found in cardiac tamponade. Doppler ultrasound studies may be particularly useful in those patients in whom the characteristic echocardiographic abnormalities are absent. Both M-mode and two-dimensional echocardiography may be useful in diagnosing pericardial thickening. Constrictive pericarditis results in a variety of echocardiographic abnormalities including pericardial thickening; biatrial enlargement with good left ventricular function; a diastolic septal bounce; and a dilated inferior vena cava without significant respiratory variation. Doppler echocardiographic abnormalities are commonly found in constrictive pericarditis. Echocardiography is also useful as a guide to performing pericardiocentesis and in the detection of pericardial adhesions and pericardial metastases.
Magnetic resonance imaging of great vessel, myocardial, and pericardial disease, The outstanding ability of magnetic resonance imaging to provide anatomic information over a large field of view in any plane in patients of all sizes and body habitus has made it the current modality of choice for evaluating the thoracic aorta and for differentiating constrictive pericarditis from restrictive cardiomyopathy. The lack of radiation exposure makes it particularly advantageous for patients requiring serial studies. It serves as an important clinical adjunct to ultrasound in evaluating diseases of the abdominal aorta. other great vessels. the myocardium. and the pericardium. Myocardial function. thickness. and mass can be assessed without geometric assumptions. Myocardial tagging offers a unique way to study cardiac biomechanics. The combination of anatomic and quantitative functional information becoming available in clinically reasonable acquisition times makes magnetic resonance imaging an increasingly attractive noninvasive tool. The contribution of tissue characterization has been disappointing. but may improve with utilization of contrast agents; that of in vivo spectroscopy remains investigational.
Echocardiographic assessment of atherosclerotic coronary lesions, Echocardiographic techniques to visualize normal and atherosclerotic coronary arteries include transthoracic. transesophageal. epicardial (intraoperative). and intravascular approaches. All are capable of visualizing portions of the coronary arteries. especially proximal. and demonstrating atherosclerotic lesions. However. none of these methods are able. at present. to completely examine the coronary tree. and therefore none are ready to be used as a standard clinical technique for the diagnosis and management of coronary artery disease. Technological advances will enhance the future clinical value and applicability of these techniques.
Perfusion imaging with 99mTc-sestamibi for the assessment of myocardial area at risk and the efficacy of acute treatment in myocardial infarction, There is a clear need to develop better measurement tools for assessment of the effect of acute therapy in myocardial infarction. Such tools must permit accurate measurement of the amount of myocardium that is initially at risk. 99mTc-sestamibi is a new radiopharmaceutical with unique properties that are well suited to the measurement of myocardium at risk without any delay in acute therapy. Tomographic imaging with this agent has been shown to provide accurate quantitative estimates of the myocardium at risk. which varies widely. even for patients with a similar coronary occlusion. For example. there is more than a threefold range in myocardium at risk for patients with a nonproximal occlusion of the left anterior descending coronary artery. The determination of the myocardium at risk before intervention and the change in this region after intervention constitute a promising measurement tool for the assessment of the effect of acute therapy. Initial studies with tomographic imaging have shown a significant improvement in a group of patients treated with thrombolysis. although the magnitude of improvement is highly variable in individual patients. Qualitatively similar results have been reported with planar imaging. Although it has a number of technical limitations. sequential imaging with 99mTc-sestamibi seems to have a clear advantage over those end points that have previously been used to assess acute therapy. This new measurement tool should facilitate future clinical trials of different treatments in acute myocardial infarction.
Stress echocardiography for detection of coronary artery disease, Stress echocardiography is a relatively new technique that combines cardiovascular stress with echocardiographic imaging for the diagnosis of coronary artery disease. It is based on the hypothesis that stress-induced ischemia will result in regional wall motion abnormalities that can be detected by two-dimensional echocardiography or abnormalities of global function that can be detected with Doppler ultrasound. Its accuracy for detecting coronary artery disease is high enough to allow for clinical use. In such a role it has added value to the analysis of the routine electrocardiogram and symptoms during exercise. In the patient unable to exercise. pharmacological stress with the use of dobutamine or dipyridamole are realistic alternatives. In addition to the diagnosis of coronary disease. stress echocardiography can be used to demonstrate recovery of function after interventions and to assess prognosis after myocardial infarction.
Overview: diagnosis of ischemic heart disease by noninvasive techniques, Noninvasive tests have greatly improved in their ability to diagnose coronary artery disease. In addition. new testing modalities have been added to our armamentarium. However. no test is clearly superior to all others in every clinical circumstance. Moreover. none have been shown to provide sensitivities and specificities consistently above 90%. Therefore. their use for diagnostic purposes in populations with a lower prevalence of disease is only of moderate value. Conversely. for the assessment of the functional significance of coronary artery disease or prognosis in patients with ischemic heart disease. the addition of noninvasive imaging modalities to exercise testing is of high value.
Exercise radionuclide angiocardiography predicts cardiac death in patients with coronary artery disease, The purpose of this investigation was to document the relative importance of three clinical and three radionuclide variables for prediction of cardiac death in a consecutive group of patients evaluated for coronary artery disease. During a 6 1/2-year period. beginning in January 1978. 2.042 consecutive patients underwent radionuclide angiocardiography. with a clinical diagnosis of coronary artery disease. at Duke University Medical Center. A subgroup of 318 patients who underwent surgical myocardial revascularization near the time of initial study were excluded from later analysis. Clinical follow-up information was complete in a group of 1.663 patients who did not undergo interventional therapy. The 141 cardiac deaths in these 1.663 patients were the study end point. Cox proportional hazards models analyzed the prognostic information contained in three clinical variables (pain type. age. and sex) and three radionuclide angiocardiogram variables (exercise ejection fraction. resting end-diastolic volume. and change in heart rate with exercise). One-variable models confirmed the prognostic importance of each of these six variables. A multivariable model in which all six variables were used showed clinical variables to contain only 5% and the radionuclide variables 95% of the prognostic information. The exercise ejection fraction was the single most important variable. which alone contained 85% of the total information in the model. Curves relating probability of no cardiac death to the exercise ejection fraction identified a value of 0.50 as an inflection point. Patients with exercise ejection fractions below 0.50 demonstrate a probability of cardiac death that increases as the ejection fraction decreases.
The new 99mTc myocardial perfusion imaging agents: 99mTc-sestamibi and 99mTc-teboroxime, The two new 99m (99mTc) labeled myocardial perfusion agents. 99mTc-Sestamibi and 99mTc-Teboroxime. are now available for routine clinical application. Both agents allow assessment of ejection fraction by the first-pass technique at rest or during exercise. thus providing additional information not available with thallium-201. 99mTc-Sestamibi has long myocardial residence time. as well as adequate myocardial extraction. providing images of higher count density and superior quality compared with thallium-201. 99mTc-Teboroxime has excellent myocardial uptake characteristics but is cleared very rapidly from the myocardium. Both tracers have shown results similar to those obtained with thallium-201 for detection of coronary artery disease and the assessment of defect reversibility. 99mTc-Sestamibi studies using the rest/stress imaging sequence can be accomplished in approximately 5 hours; studies using dual-isotope imaging (rest thallium-201 and stress 99mTc-Sestamibi injection) can be completed in 1 to 2 hours. Gated stress images can be performed with 99mTc-Sestamibi. providing simultaneous information of myocardial perfusion at stress and resting wall motion or thickening and allowing rapid differentiation of ischemic from infarcted tissue. Because of its slow myocardial clearance and absence of redistribution. 99mTc-Sestamibi allows uncoupling of the time of injection from the time of imaging and thus can be valuable in the evaluation of acute myocardial infarction and outcome of thrombolytic therapy. With 99mTc-Teboroxime. rapid serial studies are feasible. Pharmacologic stress and rest studies with 99mTc-Teboroxime single photon emission computed tomography potentially can be completed in under 30 minutes.
Value of regional wall motion abnormality in the emergency room diagnosis of acute myocardial infarction. A prospective study using two-dimensional echocardiography, Because regional wall motion abnormality (RWMA) is usually noted during ischemia. we hypothesized that the presence of this finding with two-dimensional echocardiography would be superior to conventional methods of diagnosing acute myocardial infarction (AMI) in the emergency room. We also hypothesized that because the absence of RWMA would probably not be associated with AMI. the use of two-dimensional echocardiography would significantly limit unnecessary hospital admissions. To test these hypotheses. we undertook a prospective study that used two-dimensional echocardiography in 180 patients presenting to the emergency room with symptoms suggestive of AMI. The emergency room physicians were not informed of the two-dimensional echocardiography findings. and their decision to admit or not admit to the hospital was based on conventional clinical and electrocardiographic criteria. Forty patients were not admitted to the hospital and 140 were admitted. Of the 30 patients with enzyme-confirmed AMI. nine had typical ST elevation on the ECG that was consistent with acute injury. three had normal ECGs. and eight had ECGs in the presence of which AMI could not have been diagnosed (left bundle branch block. paced rhythm. or repolarization changes); the rest had nonspecific ECG findings. Of the 29 AMI patients with technically adequate two-dimensional echocardiography studies. two did not demonstrate RWMA and 27 had RWMA. compared with nine with diagnostic ECG changes (p less than 0.001). Of the 13 patients with in-hospital complications only four had an initial ECG showing ST elevation. and all 13 had RWMA (p less than 0.001).(ABSTRACT TRUNCATED AT 400 WORDS).
IIB osteosarcoma. Current management and survival statistics in the USSR, Three hundred and ninety-three patients with IIB osteosarcoma were treated at the author's institution between 1955 and 1986. In the first stage of the study. 88 patients were treated with surgery only. The five-year disease-free survival rate was 7%. In the second stage of the study. the efficacy of preventive chemotherapy after radical surgery was studied in 55 patients. The five-year disease-free survival rate was 34.4%. In the third stage of the study. the efficacy of combination therapy consisting of preoperative treatment. limb-saving surgery. and preventive chemotherapy was studied in 66 patients. The five-year disease-free survival rate was 35.5%. The authors examined results in 21 patients with Grade IV responses to evaluate the relationship between prognosis and morphogenic changes after preoperative radiotherapy and chemotherapy. The five-year disease-free survival rate was 57.9%. In the fourth stage of the study (conducted in 1986). two regimens of preoperative chemotherapy were initiated. The first regimen consists of intraarterial platinum infusions to patients with lower extremity bone damage. The second regimen consists of high-dose methotrexate infusions. The preliminary conclusion is that primary tumor damage is significantly more marked after intraarterial cisplatin infusion.
Surface osteosarcoma, Osteosarcoma arising on the periosteal aspect of bone comprises a biologically heterogeneous group of neoplasms. The group as a whole may be referred to by a single descriptive term that emphasizes their common site of origin and underscores their malignant osteogenic potential: surface osteosarcoma. Its biologic heterogeneity may be approached via a number of avenues. Detailed description of individual tumors and grading are frequently employed. However. implementation of a classification system based upon reproducible clinical. roentgenographic. macroscopic. and histologic parameters is advantageous. The suggested classification system serves to clearly define parosteal and periosteal osteosarcoma. as well as recognize unusual variants. Most important. it defines therapeutic strategy. The classification system identifies low-grade. biologically indolent forms (i.e.. parosteal osteosarcoma and periosteal osteosarcoma) that are best treated by surgery alone. At the same time. it recognizes high-grade forms with significant potential for life-threatening behavior (i.e.. 'dedifferentiated' parosteal osteosarcoma and high-grade surface osteosarcoma) that are best managed by multimodality therapy incorporating chemotherapy and surgery.
Intraarterial cisplatin in the management of stage IIB osteosarcoma in the pediatric and adolescent age group, Sixty patients with extremity osteosarcoma were treated with intraarterial cisplatin. This was followed by surgical resection (amputation or limb salvage) and postoperative adjuvant chemotherapy utilizing two different protocols. Seventy-five percent of patients achieved an initial response. Overall disease-free survival was 58%. The number of patients treated with limb-salvage surgery gradually increased to the extent that 80% of newly-registered patients achieved a response and were subjected to limb salvage. Disease-free survival was 48% in amputation and 68% in limb salvage. The only factors found to have prognostic significance in determining disease-free survival were extent of tumor destruction induced by preoperative chemotherapy and tumor size.
Allograft prosthetic composite arthroplasty for osteosarcoma and other aggressive bone tumors, Allograft prosthetic composite arthroplasty is a reconstruction alternative after limb salvage for aggressive bone tumors. It combines an off-the-shelf implant with a fresh-frozen allograft and has several potential advantages over conventional techniques. Good clinical results can be achieved with acceptable morbidity. The procedure can be performed successfully even in patients receiving chemotherapy. Nonunion was the most common complication encountered but was amenable to autogenous iliac bone graft. The procedure can be customized to meet the needs of the patient. making custom implant manufacturing delay and expense unnecessary.
Impact of two cycles of preoperative chemotherapy with intraarterial cisplatin and intravenous doxorubicin on the choice of surgical procedure for high-grade bone sarcomas of the extremities, The authors assessed the impact of two cycles of preoperative chemotherapy (POCT) with intraarterial cisplatin (120 mg/m2) and continuous intravenous doxorubicin hydrochloride (Adriamycin; 20 mg/m2/day x 3 days) on the decision to perform a limb-sparing procedure (LSP) or amputation in 22 patients with high-grade bone sarcomas of the extremities. The tumor types were osteosarcoma (17). malignant fibrous histiocytoma (three). leiomyosarcoma (one). and malignant schwannoma (one). Surgical stages were IIA (three). IIB (17). and IIIB (two). The prechemotherapy surgical options chosen were 12 amputations (55% of patients) and ten LSPs (45%). The initial decisions to amputate were based on a combination of the following: improper biopsy (five cases). large tumors (ten) and those with neurovascular encroachment (six). and pathological fracture (one). Following chemotherapy. 18 LSPs (81%) and four amputations (19%) were performed. Nine of 12 patients (75%) initially deemed unresectable were converted to LSP. The median tumor response (necrosis; range. 0%-100%) was 70%; ten of 22 specimens had necrosis greater than 95%. Median tumor necrosis for the patients treated by amputation and LSPs was 45% and 88%. respectively. Following surgery. all patients received four additional cycles of cisplatin and doxorubicin. The median follow-up period is 30 months; six patients have developed metastatic disease. with a median disease-free interval of 16.6 months. The rate of local tumor control is 95% (21 of 22 patients).
Experience with multiagent chemotherapy for osteosarcoma. Improved outcome, Clinical researches at the authors' institution have been treating patients with osteosarcoma with effective adjuvant chemotherapy for 18 years. including 14-years experience with limb-salvage surgery. The outlook for patients with nonmetastatic high-grade osteosarcoma has improved dramatically since 1972. Updated results of the single-agent adjuvant (postoperative) chemotherapy trial project a five-year disease-free survival (DFS) of 42% (95% confidence interval [CI]. 14% to 70%) with follow-up periods of 5.7 to 13.8 years compared to a two-year DFS of 78% (60% to 95%) and follow-up periods of 0.6 to 6.8 years with six-agent. alternating. adjuvant postoperative chemotherapy. Additionally. since limb-salvage surgery began to be offered in 1976 to selected patients. 36 of 74 patients (49%) have had limb-salvage operations performed. The two-year DFS is 69% (52% to 85%) for patients having limb-salvage operations with follow-up periods of 0.6 to 10.3 years compared to 72% (57% to 87%) for amputees with follow-up periods of 0.3 to 10.3 years. It is concluded that patients receiving limb-salvage operations appear to be at no greater risk for relapse than patients receiving cross-bone amputation and that the administration of alternating. multiagent. adjuvant chemotherapy has significantly improved the DFS for patients who present with nonmetastatic high-grade osteosarcoma.
Rotationplasty as a reconstructive operation after tumor resection, Reconstruction in the skeletally immature patient following resection of osteosarcoma about the knee is a challenging problem. Salvaging of the limb with allogeneic or prosthetic replacement results in a shortened limb with functional limitations. Arthrodesis yields a stiff and shortened limb. The so-called growing prosthesis has a high complication rate and is still unproven. However. rotationplasty has been successfully used as a reconstructive technique following resection of these types of tumors in the skeletally immature patient. A limb with normal sensation and proprioceptions. adequate range of motion. and without leg-length discrepancies. functional limitations. or painful neuroma is to be expected. Although a prosthesis must be worn. these patients are active and participate in unrestricted physical activity. Cosmetic acceptance has not been a problem and complications are minimal. Thus. rotationplasty requires only a single operation and results in a highly functional limb.
Diagnostic imaging of osteosarcoma, The diagnosis. treatment planning. and follow-up evaluation of osteosarcoma rely heavily on a variety of imaging techniques. Plain roentgenography. radionuclide bone scanning. computed tomography. and magnetic resonance imaging play important roles in defining local tumor extent. detecting metastatic disease. and monitoring for recurrent tumor. Invasive studies such as angiography are now rarely necessary. In the future. newer imaging modalities. including positron emission tomography. can be expected to become important tools for evaluation of these tumors.
A longitudinal study of growth velocity and development of secondary gender characteristics versus onset of idiopathic scoliosis, This study focused on evaluating the impact of the adolescent growth spurt on the onset of idiopathic scoliosis. A total of 698 students (362 girls and 336 boys aged nine to 12 years) were followed for three years to study their growth in the pubertal period and changes in spinal status. Every six months measurements were taken of body height and the development of secondary gender characteristics was recorded. The onset of the adolescent growth spurt could thus be detected in each child. When children with and without scoliosis were compared. it became evident that scoliotic children grew faster. Girls whose scoliosis developed from a previously normal body posture showed a peak height velocity (PHV) of 8.1 cm per year. whereas girls with a normal body posture throughout the pubertal stage had a PHV of 7.1 cm per year. The most rapid growth spurt was observed in Stages 2 and 3 of breast and pubic hair development. Simultaneously. the most frequent spinal status changes occurred in Stages 2 and 3 of sexual maturity; they were twice as frequent as in Stage 1 and four times as frequent as in Stages 4 and 5. Students in whom scoliosis developed in puberty during the adolescent growth spurt grew faster than their peers who did not develop scoliosis. which need not imply that they will eventually be taller after growth is completed.
The use of methylmethacrylate in primary total knee replacements with large tibial defects, Bone defects in the tibial plateau present technical problems in primary knee replacement surgery. A variety of techniques is available to solve these problems. Of 59 patients treated with a cement fill and followed an average of 7.1 years (range. five to 11 years). there was only one failure requiring revision. Overall. knee scores averaged 78 points and roentgenogram scores averaged 85 points. Radiolucent lines were noted in 43 of the 59 patients. but none were progressive except in the one failure. There was no clinical correlation between the presence of radiolucent lines and clinical symptoms. Good long-term results might be expected from the cement fill when the bone defects are smaller than 20 mm and affect less than 50% of either plateau.
Stage IIB osteogenic sarcoma, Two hundred seventy-one consecutive patients treated from 1976 through 1986 were reviewed to estimate long-term survival. Disease-free survival for the entire cohort was 77% at five years and 74% at ten years. Humeral lesions had the best probability of survival (84% at ten years). followed by tibial lesions (81%) and femoral lesions (67%). Histologic response to preoperative chemotherapy was the strongest predictor of outcome. Those with little response had a survival estimate of 54% at ten years as compared to 68% for partial responders and approximately 90% for complete responders. Local recurrence was seen in 6.6% and was associated with an adverse effect on survival. Only two of the 18 patients with local recurrence have been rendered long-term disease-free survivors.
A pneumatic leg brace for the treatment of tibial stress fractures, Forty-two competitive athletes with posterior medial pain in the lower one-half of the tibia were evaluated by plain roentgenograms and bone scans. Twenty stress fractures were diagnosed in 17 patients by plain roentgenograms or bone scans or both. The remaining 25 patients were diagnosed as having shin splints. All 42 patients subsequently had a pneumatic leg brace applied to the affected limb or limbs. The 17 patients with stress fractures were able to ambulate without pain and were allowed to resume light training in an average of one week. Their injuries were nontender to palpation. The patients were allowed to resume intensive training at an average of 3.7 weeks postinjury. Patients returned to competition at the preinjury level in an average of 5.3 weeks after application of the brace. The pneumatic leg brace allowed the athletes with tibial stress fractures to begin pain-free ambulation and rehabilitation. thus facilitating the maintenance of their cardiovascular fitness and permitting an early return to competition.
A review of 13-years experience of osteosarcoma, Since the inception of the authors' facility. 365 patients with osteogenic sarcoma have been treated. While other facilities were surgically treating patients with primary amputation. this facility attempted limb-salvage surgery. The majority of patients being treated with limb-salvage surgery had the resected bone replaced by a metallic endoprosthetic replacement. The emphasis on conservative surgery led to the development of growing endoprosthetic replacements with the first being used in 1975. The cumulative survival of those patients with Stage 2 osteosarcoma treated at this facility between 1977 and 1984 is 48% at five years.
Management of osteogenic sarcoma in children and adolescents, The management of osteogenic sarcoma in children has made a fantastic step on the survival rate. but there still remains unexpected late metastatic recurrence even in initially good responders to chemotherapy and lower survival rate in the bad responder group. Therefore. the research on etiology and on the understanding and rating of oncologic power of the tumoral cells as well as other kinds of treatment (vaccine. immunotherapy. and other types of chemotherapy) must be increased. The initial function after replacement is good and is often excellent but increasing deterioration is noticed during each follow-up evaluation. A considerable effort is still to be done for bone and joint replacement. Biocompatible material with mechanical strength and resistance to wear will be used for a long time because of the young age of the patients. There must be better use and understanding of the allograft revascularization. as well as a better biologic connection between the bone host and replacement device. This will probably be used in the future with less cement and more of a modular system. The final prognosis will remain for a long time in the perfect cooperation between the various members of the teams (oncologist. surgeon. imager. pathologist. and research team) who treat the patients.
IIB osteosarcoma. Current management, local control, and survival statistics--Sao Paulo, Brazil, Ninety-two patients with IIB osteosarcoma of the extremities were treated with intraarterial (IA) cisplatinum (CDDP) followed by surgery [amputation (61.6%) or resection with endoprosthesis (38.4%)]. Postoperative chemotherapy alternating adriamycin and CDDP was used. The total three-year survival was 62.1%. and the disease-free survival was 41.1%. The pathologic evaluation of the degree of tumor necrosis in response to the IA CDDP showed that in 53.2%. the necrosis was over 90%. The multivariate analysis of prognostic factors has shown that the highest survival was among females with tumors smaller than 15 cm. Patients with lesions equal to or larger than 15 cm were three times as likely to die of the disease. A second. more aggressive study is now underway. in which high dose methotrexate (HDMTX) is preoperatively combined with adriamycin and CDDP. Following operation. ifosfamide is added to the cases with a smaller degree of tumor necrosis. while the other group of patients will continue with HDMTX. in addition to CDDP and adriamycin (these last two drugs are used in both arms). Until now. complete remission has been achieved in 82% and 86%. respectively. with a follow-up examination varying from four to 26 months (average. 14 months). This is of extreme importance. because the majority of the authors' patients have tumors at initial evaluation larger than 10 cm in diameter.
IIB osteosarcoma. Current management, local control, and survival statistics--The Netherlands, Guarded optimism is justified in light of the results of treatment of IIB osteosarcoma in the Netherlands. This is due to improvements in diagnostic imaging techniques. staging. adjuvant chemotherapy. and surgical treatment. Five-year survival rates have increased from 25% to 80%. En bloc resection is currently possible. This makes reconstructive procedure justified. both from an oncologic and orthopedic view. Many questions are still unanswered. concerning evaluation of tumor necrosis because of chemotherapy. optimal adjuvant therapy. functional evaluation of different types of reconstruction. and psychological development of the patient. An international gathering of data on the overall treatment of IIB osteosarcoma is advocated to find answers on the above-mentioned questions. A noninvasive adjustable-lengthening prosthesis is mentioned as a Dutch solution to leg-length discrepancy. This prosthesis can be used after limb-saving surgery in young children.
Local control and survival from the Cooperative Osteosarcoma Study Group studies of the German Society of Pediatric Oncology and the Vienna Bone Tumor Registry, The use of aggressive chemotherapy undoubtedly has brought about a dramatic increase in the cure rate of osteosarcoma. The authors' investigations have increased the authors' knowledge of chemotherapy for osteosarcoma. the differential efficacy of currently used agents. and the pronounced schedule dependency and relative route independency of their efficiency. The authors were able to confirm the prognostic significance of tumor response after preoperative chemotherapy. Preoperative chemotherapy in itself has facilitated and promoted limb-salvage surgery. Also. more patients can be cured today by use of aggressive thoracic surgery in case of primary or secondary pulmonary metastases. The authors' efforts to steadily increase metastasis-free survival rates by intensifying chemotherapy in this series of studies. however. have been only moderately successful. Still. chemotherapy-related acute toxicity is considerable and increases with aggressiveness of treatment. and the manifestations of late toxicity may continue to increase with follow-up time. Future trials should be targeted toward exploration of the minimum indispensable amount of toxic treatment yielding comparable or even better results than those currently attainable.
Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study, The Multi-Institutional Osteosarcoma Study (MIOS) was designed to determine whether intensive multiagent adjuvant chemotherapy improves the outcome of patients with nonmetastatic high-grade osteosarcoma of the extremity as compared with concurrent controls. After definitive surgery of the primary tumor. patients were randomly assigned to immediate adjuvant chemotherapy or to observation without adjuvant treatment. Updated results of this trial indicate that the projected six-year event-free survival for the control group is 11% compared to 61% for the chemotherapy group (p less than 0.001). Similar results were observed in patients who declined randomization but who were followed according to the treatment arms of the protocol. When randomized and nonrandomized patients are pooled according to assigned treatment. a survival advantage favoring those patients treated with immediate adjuvant chemotherapy is apparent. An analysis of prognostic factors among patients receiving immediate adjuvant chemotherapy reveals that elevation of the serum lactic dehydrogenase at diagnosis is the factor most predictive of adverse outcome. Location of the primary site in the tibia confers a favorable prognosis. The authors conclude that the natural history of high-grade osteosarcoma of the extremity has not changed over the past two decades. The administration of immediate adjuvant chemotherapy has a significant favorable impact on event-free survival and should be recommended for all such patients.
Neoadjuvant chemotherapy for nonmetastatic osteosarcoma of the extremities, Between September 1986 and December 1988. 125 patients with osteosarcoma of the extremities entered the second neoadjuvant study at the authors' institution. Patients received preoperatively two cycles of methotrexate (MTX) intravenously. followed by cisplatinum (CDP) intraarterially. plus adriamycin (ADM) intravenously. After surgery. the patients classified as "good responders" (more than 90% tumor necrosis) received ADM. MTX. and CDP. while the "poor responders" (less than 90% tumor necrosis) had a longer chemotherapy that included ifosfamide and etoposide (VP-16) in addition to MTX. ADM. and CDP. Limb salvage was possible in 85% of patients. 8% had an amputation. and 7% had a rotationplasty. The surgical margins were adequate (radical or wide) in 88% of cases and inadequate (marginal or intralesional) in 12%. At an average follow-up period of 28 months (range. 13 to 41). 109 patients (87%) remained continuously disease free. 15 (12%) relapsed with pulmonary metastases. and one patient (0.8%) had a local recurrence. Compared with the first neoadjuvant study at the authors' institution that used only MTX and CDP preoperatively. the percentage of limb salvages. "good responders." and continuously disease-free survival at two years was significantly higher in the second Rizzoli neoadjuvant study (85%. 74%. and 87% versus 77%. 52%. and 59%). Systemic toxicity because of chemotherapy was superimposable. A retrospective analysis of the real dose intensity for each patient demonstrated a correlation between the intensity of chemotherapy and prognosis.
Treatment of gram-negative septic shock with an immunoglobulin preparation: a prospective, randomized clinical trial, OBJECTIVE: To evaluate the effectiveness of a polyclonal immunoglobulin (Ig) preparation containing IgG. IgM. and IgA as an adjunctive therapy for septic shock. DESIGN: Prospective. randomized clinical trial. SETTING: A clinical immunology ward at the center for internal medicine in a university hospital. PATIENTS: Fifty-five patients with septic shock were randomly allocated to two groups according to criteria of septic shock. INTERVENTION: One group of patients (n = 27) received a commercially available immunoglobulin preparation (containing high titers of antibodies specific for determinants to bacterial endotoxin) during the first 3 days after inclusion in the study. The other randomized group (n = 28) did not receive any immunoglobulin preparation. MEASUREMENTS AND MAIN RESULTS: During the period of less than or equal to 6 wks after the beginning of clinically apparent septic shock. death related to the septic process occurred in one (4%) of 27 patients who received immunoglobulin. By comparison. nine (32%) of 28 control group patients died during this period (p less than .01). Within the first 48 hrs after onset of the clinically apparent septic process. significantly increased activity of circulating endotoxin and simultaneously decreased specific IgG serum titers to lipid A were detected in the group of nonsurvivors. CONCLUSION: Administration of a polyclonal immunoglobulin preparation in the early phase of septic shock was associated with significantly improved survival.
Lactic acid kinetics in respiratory alkalosis, OBJECTIVE: To evaluate the impact of respiratory alkalosis on the elimination of intravenously infused lactate. DESIGN: Prospective. randomized. crossover study. SETTING: Medical ICU of a university hospital. PATIENTS: Eight patients treated by ventilatory support for neurologic or neuromuscular diseases. INTERVENTIONS: Patients were investigated on two occasions: during normoventilation (pH 7.42 +/- 0.1. PCO2 41 +/- 2 torr [5.5 +/- 0.2 kPa]) and during respiratory alkalosis (pH 7.59 +/- 0.1. PCO2 27 +/- 2 torr [3.6 +/- 0.2 kPa]) induced by controlled hyperventilation. To evaluate lactate elimination kinetics. 1 mmol/kg body weight of L-lactic acid was infused over 5 mins. MEASUREMENTS AND MAIN RESULTS: Arterial lactate concentrations and blood gas values were determined before and repeatedly after the infusion. Lactate elimination variables were calculated from the plasma curve by using a two-compartment model. Respiratory alkalosis increased plasma lactate from 1.56 +/- 0.1 to 2.49 +/- 0.2 mmol/L (p less than .001). The lactate elimination half-life increased from 4.57 +/- 0.2 mins at pH 7.42. to 9.96 +/- 1.1 mins during pH 7.59 (p less than .01). and beta half-life increased from 12.2 +/- 1.9 to 44.1 +/- 1 mins (p less than .01). Whole-body clearance decreased 40% from 24.2 +/- 2.9 to 14.3 +/- 2.0 mL/kg body weight-min (p less than .01). CONCLUSIONS: Respiratory alkalosis increases the basal concentration of plasma lactate and decreases clearance of infused lactic acid. These findings provide further evidence of the adverse effects of alkalosis.
Heparin treatment in thrombin-induced disseminated intravascular coagulation in the baboon, BACKGROUND AND METHODS: We postulated that low-dose heparin (10 IU/kg.hr) administered as a continuous iv infusion may prevent or ameliorate the induction of thrombin-induced disseminated intravascular coagulation in baboons under general anesthesia. In a nonrandomized experiment lasting 8 hrs. animals were divided into three groups: 11 received thrombin only (group A); ten were pretreated with heparin before thrombin administration (group B); and 15 received heparin 2 hrs after disseminated intravascular coagulation was induced with thrombin (group C). All animals were monitored hemodynamically and coagulation tests were performed hourly. Tests included the following: one-stage prothrombin ratio; activated partial thromboplastin time; fibrinogen and fibrin degradation products; thrombin time; plasma fibrinogen level; antithrombin III and activated clotting time. After the acute phase of the experiment. the animals were observed for 6 days and a postmortem examination was performed on a survivor of each group. RESULTS: Six (55%) group A animals died within 6 days. while there were no deaths in group B and one animal (7%) died in group C. In group C. the administration of heparin could not normalize the clotting profile. but the mortality rate was significantly less than in group A. The prophylactic administration of heparin in group B prevented the induction of disseminated intravascular coagulation. The postmortem findings were of interest. but no statistically valid conclusions could be made. as only one autopsy was done for each group. However. the results suggest that heparin pretreatment may protect against lung edema and liver necrosis. CONCLUSIONS: The results suggest that heparin. in a dose of 10 IU/kg.hr iv. could possibly be safely used in patients at high risk of developing disseminated intravascular coagulation and in those patients with established disseminated intravascular coagulation.
Image processing in swallowing and speech research, An image processing system for application to studies of the temporal and spatial parameters of movement during swallowing and speech is described. Image sequences from videotape are digitized for computerized manipulation and analysis in an attempt to improve on conventional visual inspection. The system is "interactive" or "event-driven": after executing a function. the computer waits for guidance from the user who controls the program through keyboard and mouse input. selecting options from menus and responding to prompts. The analyst alters image clarity by the application of filters and heightens contrast through video enhancement. A technique called "remapping" reduces head motion and provides uniform spatial scaling. Animated sequences of images are used. as opposed to frame-by-frame analysis. to preserve temporal context and increase efficiency of measurement. Low cost off-the-shelf personal computer hardware is used along with original software tailored to the application.
Natural history of gastro-oesophageal reflux disease without oesophagitis, This retrospective study was undertaken to characterise the clinical course and reflux pattern of patients with gastro-oesophageal reflux without evidence of oesophagitis. We investigated 33 patients (12 women. 21 men; mean age 36 years) with typical symptoms. a negative oesophagoscopy. and a 24 hour oesophageal pH-metry indicative of pathological gastro-oesophageal reflux. All patients received antacids or prokinetic drugs or both for three to six months. Nineteen of 33 patients still had symptoms at the end of treatment. of whom five had developed erosive changes of the oesophageal mucosa. The other 14 discontinued treatment and remained asymptomatic during a six month follow up period. Comparison of the pretreatment pH-metry data of the 19 symptomatic patients and the 14 asymptomatic patients showed no differences in the pattern of gastro-oesophageal reflux in the two groups. We conclude that in a substantial proportion of patients with pathological reflux without oesophagitis symptoms may persist and mucosal lesions may develop during conventional treatment without any apparent change in the reflux. Patients who developed endoscopic oesophagitis did not have a more severe pretreatment pattern of gastro-oesophageal reflux when compared with those who did not develop oesophageal mucosal damage.
Serum pepsinogen I concentrations in peptic ulcer patients in relation to ulcer location and stage, To investigate the relation of the serum group I pepsinogen (PG I) concentration to the location of gastric ulcers and chronicity of peptic ulcers. ulcer patients (n = 322) were compared with endoscopically normal subjects (n = 174). The mean PG I concentration was significantly higher in male control subjects (n = 90) than in female control subjects (n = 84). In male patients with ulcers in the duodenum (n = 69). antrum (n = 34). or angulus portion (the lower third of the body; n = 83). the mean serum PG I concentration was significantly higher than in the control subjects but in patients with an ulcer in the upper body (n = 49) it was similar to control values. Men with active or healing ulcers (n = 149) showed a significantly higher serum PG I concentration than those with scarred lesions (n = 86) when the abnormality was located in either the upper body or in the angulus portion. For female patients (n = 87). the results were similar. These results suggest that serum PG I concentrations reflect the stages of activity of peptic ulcer.
Effect of inhibition of Helicobacter pylori urease activity by acetohydroxamic acid on serum gastrin in duodenal ulcer subjects, The mechanism of the hypergastrinaemia associated with Helicobacter pylori infection is unknown. It may be an effect of the ammonia produced by the bacterium near the antral epithelial surface. We have examined the effect on serum gastrin of inhibiting H pylori urease activity with acetohydroxamic acid in six duodenal ulcer patients. On day 1 the fasted patients received placebo tablets at 8 am. a peptide meal at 10 am. and a 14C urea breath test at 11.30 am. The next day 750 mg acetohydroxamic acid was administered orally in place of the placebo. The median (range) 30 minute breath test value (dose/mmol CO2 X kg body wt X 100) was 152 (111-335) on day 1. but only 22 (14-95) the next day (p less than 0.03). Further studies performed in one subject confirmed that acetohydroxamic acid lowered the ammonium concentration and raised the urea concentration in gastric juice. The inhibition of urease activity and ammonia production did not result in a fall in the basal gastrin concentration or in the median integrated gastrin response to the peptide meal. which was 78 ng/1.h (range 21-222) on day 1 and 79 ng/1.h (33-207) the next day. Ten days after acetohydroxamic acid. the urea breath test values were similar to those before treatment. This study shows that the raised gastrin concentration in patients with H pylori infection is not directly related to the organism's urease activity. It also shows that temporary suppression of H pylori urease activity does not clear the infection.
Compliance of adolescents with coeliac disease with a gluten free diet, A cohort of 123 patients with coeliac disease. diagnosed in the first three years of life and followed up for at least 10 years. was reevaluated during the teenage period in terms of compliance with the diet and clinical state. Mucosal structure and lymphocytes were assessed in small intestinal biopsy specimens obtained from 36 subjects. by computerised image analysis. Of these adolescents with coeliac disease. 65% were adhering to a strict gluten free diet. 11.4% were on a gluten free diet but with occasional gluten intake. and 23.6% were on a gluten containing diet. Clinical symptoms occurred more frequently in patients on a gluten containing diet. but not in patients on a semi-strict diet. Occasional intake of small amounts (0.06-2 g/day) of gluten did not produce increased concentrations of antigliadin antibodies but resulted in an appreciably increased crypt epithelial volume and expanded crypt intraepithelial lymphocyte population.
Measurement of intracellular mediators in enterocytes isolated from jejunal biopsy specimens of control and cystic fibrosis patients, A method that maximises the yield of viable enterocytes has been developed for the isolation of enterocytes from human jejunal biopsy specimens. These enterocytes have been used to study the values of intracellular free calcium and the rises in adenosine 3'5'-cyclic monophosphate (cAMP) induced by secretagogues in normal and cystic fibrosis cells. Basal intracellular free calcium of cystic fibrosis enterocytes. measured fluorimetrically with fura-2. was within the range of the basal intracellular free calcium of non-cystic fibrosis enterocytes (cystic fibrosis 263 nmol/l; non-cystic fibrosis 287 nmol/l). Changes in intracellular free calcium were observed after exposure to ionomycin: a 100 nmol/l solution induced a 2.5 fold increase in intracellular free calcium in the cystic fibrosis enterocytes and a 2.2 fold increase in the intracellular free calcium concentration of the non-cystic fibrosis enterocytes. Basal cAMP values were not significantly different between cystic fibrosis and non-cystic fibrosis enterocytes (cystic fibrosis 575 fmol/100.000 cells; non-cystic fibrosis 716 fmol/100.000 cells. p greater than 0.05) and the enterocyte cAMP value increased in response to stimulation with prostaglandin E2 (7 mumol/l) (cystic fibrosis 2.2 fold increase over basal. p less than 0.05; non-cystic fibrosis 1.9 fold stimulation over basal. p less than 0.05) and vasoactive intestinal polypeptide (100 nmol/l) (cystic fibrosis 7.1 fold increase over basal. p less than 0.05; non-cystic fibrosis 5.8 fold increase over basal. p less than 0.05). There was no significant difference in the magnitude of the response between cystic fibrosis and non-cystic fibrosis enterocytes (p greater than 0.05).
Coexpression of CD4 and CD8 on peripheral blood T cells and lamina propria T cells in inflammatory bowel disease by two colour immunofluorescence and flow cytometric analysis, Using two colour immunofluorescence with fluorescein isothiocyanate and phycoerythrin labelled monoclonal antibodies and multiparameter flow cytometry. we investigated the coexpression of CD4 and CD8 antigens on peripheral blood lymphocytes and lamina propria lymphocytes of patients with ulcerative colitis and Crohn's disease and normal control subjects. Both the absolute number and the proportion of peripheral blood CD4+. CD8+ cells in inflammatory bowel disease were small but significantly increased compared with those in normal control subjects. Peripheral blood lymphocytes activated with phytohaemagglutinin showed appreciably increased coexpression of CD4+. CD8+. These CD4. CD8 positive cells were large and granular. Thus the increased number of peripheral blood CD4+. CD8+ cells in inflammatory bowel disease suggests that chronic immune activation occurs not only in the active state of the disease but also in remission. The proportion of CD4+. CD8+ cells in the lamina propria was greater than in peripheral blood in normal subjects. suggesting chronic immune stimulation of the local immune system. This was also seen in patients with Crohn's disease or inactive ulcerative colitis. The proportion of CD4+. CD8+ cells was. however. significantly less in the lamina propria of patients with active ulcerative colitis. Whether this implies a possible defect in mucosal immunoregulation in active ulcerative colitis cannot be determined from these results.
Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis, 5-Aminosalicylic acid (5-ASA). the active moiety of sulphasalazine (SASP). was given as a rectal enema to patients with mild to moderate distal ulcerative colitis to determine the minimum effective dosage. A double blind study was carried out using enemas containing 1. 2. or 4 g or 5-ASA or placebo for a one month treatment period. One hundred and thirteen patients with ulcerative colitis attending our outpatient clinic volunteered to participate. Clinical. sigmoidoscopic. and histological assessments were carried out at the beginning of the study and after 15 and 30 days of treatment. All patients who received 5-ASA enemas showed significantly better results than those who received a placebo enema (p less than 0.001) but no difference was detected among the patients receiving differing concentrations of 5-ASA. This study suggests that 1 g 5-ASA (in a 100 ml enema) is a sufficient dosage for patients with a mild to moderate attack of ulcerative colitis.
Proliferative activity of neuroendocrine tumours of the gastroenteropancreatic endocrine system: DNA flow cytometric and immunohistological investigations, The proliferative activity of 16 tumour specimens from 13 patients with neuroendocrine tumours of the gastroenteropancreatic endocrine system was studied by DNA flow cytometry and immunohistology for the nuclear Ki67 proliferation antigen. Equivalent results were obtained with both methods. which showed the proliferative activity of gastroenteropancreatic neuroendocrine tumours to be heterogeneous. In four malignant small intestinal carcinoids and one extravisceral carcinoid localised in the retroperitoneum the percentage (index) of proliferating tumour cells as measured by DNA flow cytometry ranged from 2.9 to 36.2% corresponding to low. moderate. or high proliferative activity. In four malignant pancreatic endocrine tumours and their metastases indices ranged from 8.7 to 18.3%. corresponding to low. moderate. or high proliferative activity. In four benign pancreatic endocrine tumours indices ranged from 4.3 to 7.7%. all corresponding to low proliferative activity. This heterogeneity of proliferative activity may in part explain the heterogeneous results reported of chemotherapy treatment. As chemotherapy of tumours is largely affected by favourable cell cycling kinetics. individual diagnostic investigations of the proliferative activity of these neuroendocrine tumours may be of value for identifying patients suitable for this treatment.
Hodgkin's disease presenting as liver abscesses, A patient is reported who presented with sterile hepatic abscesses which proved to be the first manifestation of Hodgkin's disease. He failed to improve with antibiotic treatment but responded to combined chemotherapy. Liver involvement as the first sign of Hodgkin's disease is rare. Liver abscesses due to Hodgkin's disease seem to be previously unreported.
Endothelial dysfunction and subendothelial monocyte macrophages in hypertension. Effect of angiotensin converting enzyme inhibition, Hypertension is associated with an impairment of endothelium-dependent relaxation. The angiotensin converting enzyme inhibitors captopril and cilazapril can prevent this endothelial dysfunction. We recently observed that long-term treatment with cilazapril could also prevent subendothelial infiltration by mononuclear cells in spontaneously hypertensive rats. This prompted us to examine whether. in spontaneously hypertensive rats. endothelial dysfunction and subendothelial infiltration by mononuclear cells are associated. These cells were characterized as monocyte macrophages. Infiltration by monocyte macrophages was quantified by morphometry. Endothelial function was estimated by calculating serotonin ratio (maximal contraction to serotonin on isolated arterial rings with endothelium over maximal contraction on paired rings without endothelium). The regional distribution of endothelial dysfunction and subendothelial monocyte macrophages was similar. Both were maximal in the carotid artery. less in the aorta. and nonexistent in the renal artery. A 2-week treatment with cilazapril decreased both endothelial dysfunction (serotonin ratio decreased by 32%) and the number of subendothelial monocyte macrophages in the aorta. which decreased by 38%. We conclude that in spontaneously hypertensive rats. endothelial dysfunction and subendothelial monocyte macrophage infiltration are associated and that cilazapril can decrease both. The observation that angiotensin converting enzyme inhibitors affect subendothelial accumulation of monocyte macrophage may lead to a better understanding of the mechanism of action of this class of drugs.
Role of endothelium-derived prostanoid in angiotensin-induced vasoconstriction, To test the hypothesis that prostanoids contribute to angiotensin II-induced vascular contraction. we compared the effect of angiotensin II on isometric tension development by rings of descending thoracic aorta bathed in Krebs' bicarbonate buffer with and without indomethacin (10 microM) to inhibit cyclooxygenase. CGS13080 (10 microM) to inhibit thromboxane A2 synthesis. or SQ29548 (1 microM) to block thromboxane A2/prostaglandin endoperoxide receptors. The comparisons were made in rings of aorta taken from normotensive rats and from rats with aortic coarctation-induced hypertension at 12 days and 90-113 days after coarctation. These rings released thromboxane B2. which was found to be endothelium dependent. increased in hypertensive rats. and stimulated by angiotensin II (10(-6) M) in normotensive rats and in hypertensive rats at 12 days after coarctation. The angiotensin II (10(-6) to 10(-5)M)-induced contraction of aortic rings was increased by about 30% at 12 days after coarctation and decreased at 90-113 days after coarctation. Removal of the endothelium increased the contractile effect of angiotensin II (10(-6) M) in aortic rings of normotensive rats and hypertensive rats at 90-113 days after coarctation but decreased the effect in aortic rings of hypertensive rats at 12 days after coarctation. In rats at 12 days after coarctation. the angiotensin II (10(-6) M)-induced contraction of aortic rings with endothelium was attenuated by indomethacin and SQ29548 but not by CGS13080. These data suggest that a prostanoid-mediated and endothelium-dependent mechanism of vasoconstriction contributes to the constrictor effect of angiotensin II in aortic rings of rats in the early phase of aortic coarctation-induced hypertension.
Interleukin-2 and spontaneous hypertension, There are conflicting reports with regard to the antihypertensive of interleukin-2 in the spontaneously hypertensive rat. Recently. the original claim of a normalization of arterial pressure in the spontaneously hypertensive rat after a single administration of interleukin-2 has been disputed. Therefore. the present study was performed to determine whether the administration of interleukin-2 was effective in attenuating both the development and maintenance of hypertension in the spontaneously hypertensive rat. Both young prehypertensive spontaneously hypertensive rats and adult spontaneously hypertensive rats with established hypertension received a single subcutaneous dose of 5.000 units/kg human recombinant interleukin-2. Arterial pressure was monitored at weekly intervals in both control and treated animals by the tail-cuff technique. Interleukin-2 administered as a one time single injection had no effect on the development of hypertension in the young animals or on the maintenance of hypertension in the adult animals. Interleukin-2 also was administered as a continuous infusion via osmotic minipumps at dose levels of 5.000 and 50.000 units/kg/wk to both young and adult spontaneously hypertensive rats. Continuous administration of interleukin-2 also had no effect on the development or maintenance of spontaneous hypertension. Therefore. this study firmly demonstrates that interleukin-2 has no effect on the onset or maintenance of hypertension in the spontaneously hypertensive rat.
Sodium-lithium countertransport and hypertension in Rochester, Minnesota, The objectives of the present study were to determine whether increased sodium-lithium countertransport is associated with essential hypertension in the general Caucasian population and to determine whether this association is independent of the effects of gender. age. body size. and plasma lipids. We studied 543 men and 589 women from the population of Rochester. Minnesota. Mean sodium-lithium countertransport was higher in hypertensive than in normotensive subjects in men (370 +/- 147 [mean +/- SD] versus 315 +/- 110 mumol/l red blood cells [RBC]/hr. p less than 0.001) and in women (339 +/- 114 versus 269 +/- 92 mumol/l RBC/hr. p less than 0.001). Interindividual differences in plasma triglycerides. body mass index (wt/[ht]2). and plasma total cholesterol explained 13.0% of sodium-lithium countertransport variation in men (p less than 0.001) and 20.2% in women (p less than 0.001). Age did not predict additional sodium-lithium countertransport variation in either gender. Slopes of the regressions of sodium-lithium countertransport on plasma triglycerides. body mass index. and plasma total cholesterol did not differ between diagnostic groups in men (p = 0.31) or in women (p = 0.29). After adjustment to remove sodium-lithium countertransport variation attributable to these covariates. mean sodium-lithium countertransport remained significantly higher in hypertensive than in normotensive subjects in men (354 +/- 139 versus 319 +/- 104 mumol/l RBC/hr. p less than 0.01) and in women (311 +/- 103 versus 278 +/- 83 mumol/l RBC/hr. p less than 0.01).
Sodium-lithium countertransport and cardiorenal abnormalities in essential hypertension, The rate of red blood cell sodium-lithium countertransport is elevated only in a subgroup of patients with essential hypertension. We have therefore compared renal and cardiac function and morphology in two groups of hypertensive patients with high (n = 23) or normal (n = 22) sodium-lithium countertransport (mean +/- SEM: 0.61 +/- 0.10 versus 0.29 +/- 0.07 mmol/l red blood cells.hr). The two groups were similar in age. sex distribution. body mass index. smoking habit. duration of hypertension. and actual levels of untreated blood pressure. Hypertensive patients with elevated sodium-lithium countertransport activity showed elevated glomerular filtration rate (118 +/- 2 versus 109 +/- 2 ml/min.1.73 m2; p less than 0.001). albumin excretion rate (23 +/- 3 versus 14 +/- 2 micrograms/min; p less than 0.001). larger kidney volume (250 +/- 15 versus 203 +/- 13 ml.1.73 m2; p less than 0.01). lower lithium clearance rate (26.7 +/- 0.3 versus 28.9 +/- 0.3 ml/min.1.73 m2; p less than 0.01). and higher total body exchangeable sodium (2.716 +/- 33 versus 2.485 +/- 41 mmol.1.73 m2; p less than 0.01). Left ventricular mass index (139 +/- 6 versus 119 +/- 6 g/m2; p less than 0.05). relative wall thickness (0.39 +/- 0.05 versus 0.29 +/- 0.04 cm; p less than 0.001). and left posterior wall plus intraventricular septum thickness (2.02 +/- 0.04 versus 1.76 +/- 0.03 cm; p less than 0.05) were also higher in patients with high sodium-lithium countertransport. Hypertensive patients with normal sodium-lithium countertransport had renal and cardiac parameters similar to those of a normotensive control group (n = 21) except for a higher glomerular filtration rate and left ventricular mass index.
Postexercise hypotension is not sustained in normal and hypertensive humans, Blood pressure falls after a single session of exercise. The duration for which this fall in blood pressure persists is not known. Sustained hypotension after a single session of exercise may have important implications in the treatment of patients with mild hypertension. We studied 24 subjects (12 normotensive subjects and 12 patients with mild or borderline hypertension). Blood pressure was measured in the laboratory for 30 minutes before and for an hour after graded bicycle exercise to maximal voluntary capacity. Subjects then left the hospital and measured their blood pressures at home (three measurements every 2 hours) following a strict measurement protocol for the rest of the day (usually between 8 and 12 hours). These home blood pressure measurements were compared with home blood pressure measurements recorded at the same times on a nonexercise control day. At 30 minutes after the graded maximal exercise test. the hypertensive patients experienced a fall in blood pressure from 142 +/- 3.5/93 +/- 6.5 mm Hg (mean +/- SEM) to 124 +/- 4.5/79 +/- 2.8 mm Hg (p less than 0.01). For the normotensive subjects. blood pressure after exercise fell from 117 +/- 3.1/70 +/- 2.1 mm Hg to 109 +/- 3.1/62 +/- 2.8 mm Hg (p less than 0.01). Despite these striking blood pressure reductions for the second half hour after exercise. blood pressure measurements recorded at home were not significantly different on the exercise and control days in either group. We conclude that although a single bout of exercise lowers blood pressure for a short (1-hour) period. this hypotension is not sustained.
Intrahypothalamic clonidine infusion prevents NaCl-sensitive hypertension, We have previously shown that dietary NaCl supplementation increases blood pressure and sympathetic nervous system activity in association with decreased norepinephrine release and increased alpha 2-adrenergic receptor number in the anterior hypothalamic area of salt-sensitive spontaneously hypertensive rats (SHR-S) but not in salt-resistant spontaneously hypertensive rats (SHR-R) or Wistar-Kyoto (WKY) rats. Further. acute microinjection of clonidine into the anterior hypothalamic area produced depressor responses that were augmented by high salt feeding in SHR-S but not in SHR-R or WKY rats. The current study tested the hypothesis that chronic infusion of clonidine into the anterior hypothalamic area prevents salt-sensitive hypertension in SHR-S. Beginning at age 7 weeks. immediately before initiation of 1% or 8% salt diets. clonidine (2 ng/min) or saline vehicle was infused into the anterior hypothalamic area or femoral vein of male SHR-S via osmotic minipump for 20 days. In SHR-S fed an 8% salt diet. chronic microinfusion of clonidine into the anterior hypothalamic area offset the hypertensive effect of the dietary salt supplementation and reduced the enhancing effects of dietary salt on left ventricular weight and plasma norepinephrine levels. In contrast. chronic microinfusion of clonidine into the anterior hypothalamic area did not significantly affect any of these measures in 1% salt-fed SHR-S. Intravenous infusion of clonidine at the rate used for the anterior hypothalamic area infusion did not alter any of these measures in 8% salt-fed SHR-S.
Time delay compensation for closed-loop insulin delivery systems: a simulation study, Closed loop insulin therapy certainly represents the best possible approach to insulin replacement. However. present limitations preclude wider application of the so-called artificial pancreas. Therefore. a thorough understanding of these limitations is needed to design better systems for future long-term use. The present simulation study was design: to obtain better information on the impact of the measurement delay of currently available closed-loop devices both during closed-loop insulin delivery and blood glucose clamp studies. and to design and test a time delay compensator based on the method originally described by O.J. Smith. Simulations were performed on a Compaq Deskpro 486/25 personal computer under MS-DOS operating system using Simnon rel. 3.00 software. There was a direct relationship between measurement delay and amount of insulin delivered. i.e.. the longer the delay the higher the insulin dose needed to control a rise in blood glucose; the closed-loop response in presence of a time delay was qualitatively impaired both during insulin delivery and blood glucose clamp studies; time delay compensation was effective in reducing the insulin dose and improving controller stability during the early phase of clamp studies. However. the robustness of a Smith's predictor-based controller should be carefully evaluated before implementation in closed-loop systems can be considered.
Adrenal activation and the prolactin response to exercise in eumenorrheic and amenorrheic runners, Adrenocorticotropic hormone (ACTH). cortisol. and prolactin responses following maximal and submaximal (40 min at 80% maximal O2 consumption) running were studied in eumenorrheic (ER; n = 8. 29.0 +/- 1.5 yr) and amenorrheic (AR; n = 8. 24.5 +/- 2.0 yr) runners. ER were studied in the early follicular and midluteal phases of the menstrual cycle. Physical. training. and gynecological characteristics were similar. and cardiorespiratory and metabolic responses to the exercises were indistinguishable in the groups. ACTH. cortisol. and prolactin data from the follicular luteal phases in ER were combined for comparison to AR. because no differences were noted between the menstrual phases at rest. Similar preexercise ACTH levels and responses following exercise occurred in both groups. but preexercise cortisol levels were elevated (ER = 293.1 +/- 46.3. AR = 479.6 +/- 42.4 nmol/l) and cortisol responses blunted in AR. Adrenal sensitivity was blunted in AR compared with ER after submaximal (ER = 121.9 +/- 17.4. AR = 51.7 +/- 13.6) and maximal exercise (ER = 27.9 +/- 9.2. AR = 12.1 +/- 3.8). Preexercise prolactin levels were reduced (ER = 16.4 +/- 2.7. AR = 10 +/- 2.3 micrograms/l). and prolactin responses to maximal exercises were blunted in AR. despite high lactate levels (11.4 +/- 0.4 mmol/l). We conclude that 1) control for menstrual phase in ER is important in studies of prolactin responses following exercise but not in studies of ACTH and cortisol responses following exercise. 2) cortisol responses following submaximal and maximal exercise in AR are blunted at the adrenal level. 3) prolactin responses following submaximal and maximal exercise are also blunted in AR. and 4) prolactin responses following exercise may be mediated by adrenal activation.
Hypoxia-mediated in vivo release of dopamine in nucleus tractus solitarii of rabbits, A wide variety of neuroactive substances have been suggested to be involved in the respiratory depression observed in response to severe hypoxia. By use of the technique of microdialysis. the release of dopamine (DA) was measured in the nucleus tractus solitarii during severe hypoxic provocations (6% O2 in N2) in the adult pentobarbital-anesthetized rabbit. DA release was analyzed by high-performance liquid chromatography with electrochemical detection. Such hypoxic provocations caused pronounced phase of depression in the phrenic nerve activity and enhanced release of DA. After bilateral carotid sinus nerve denervation. acute severe hypoxia did not give rise to enhanced release of DA or to phrenic nerve depression. Mild hypoxic (9% or 12% O2 in N2) or hypercapnic (6% CO2) stimuli resulted in an increased phrenic nerve activity without any concomitant changes in DA release. Decerebration at the midcollicular level in rabbits prevented an enhanced release of DA in the nucleus tractus solitarii during severe hypoxia. The results suggest that 1) DA is involved in the central ventilatory response to severe hypoxia. 2) not only the initial excitatory but also the second depressive phase in response to severe hypoxia is mediated partially by the peripheral chemoreceptors. and 3) the depressive phase is dependent on intact connections from suprapontine structures.
Effect of atelectasis and surface tension on pulmonary vascular compliance, The effects of atelectasis and surface tension on the vascular volume and compliance in an isolated perfused dog lung lobe were studied using vascular occlusion and indicator-dilution methods. Measurements were made during atelectasis and again after the lobes were inflated with either a gas mixture (air) or 0.9% saline. Inflation with air resulted in a 20% increase in vascular volume (P less than 0.02). whereas saline inflation had no effect on vascular volume. Inflation with either air or saline increased static vascular compliance by approximately 58% (P less than 0.001) and dynamic vascular compliance by approximately 85% (P less than 0.001). The larger dynamic compliance in the inflated lobes appears to have been mainly due to a larger microvascular compliance. The results suggest that atelectasis can result in a stiffer pulmonary capillary bed. This effect appears to be due primarily to the reconfiguration of the lung tissue structure. because replacing the air with an incompressible fluid did not have the same effect.
Air interface and elastic recoil affect vascular resistance in three zones of rabbit lungs, We examined the effect of the air interface on pulmonary vascular resistance (PVR) in zones 1. 2. and 3 by comparing pressure-flow data of air- and liquid-filled isolated rabbit lungs. Lungs were perfused with Tyrode's solution osmotically balanced with 1% albumin and 4% dextran and containing the vasodilator papaverine (0.05 mg/ml). Lung volume was varied by negative pleural pressure form 0 to -25 cmH2O. Pulmonary artery (Ppa) and venous (Ppv) pressures were fixed at various levels relative to the lung base. Alveolar pressure (PA) was always zero. and perfusate flow was measured continuously. In zone 1 Ppa was -2.5 cmH2O and Ppv was -15 cmH2O. In zone 2 Ppa was 10 cmH2O and Ppv was -5 cmH2O. In zone 3 Ppa was 15 cmH2O and Ppv was 8 cmH2O. We found that in zone 1 the interface was essential for perfusion. but in zones 2 and 3 it had much lesser effects. In general. PVR depended almost uniquely (i.e.. with small hysteresis) on transpulmonary pressure. whereas a large hysteresis existed between PVR and lung volume. PVR was high in collapsed and especially in atelectatic lungs. fell sharply with moderate inflation. and within the ranges of vascular pressure studied did not rise again toward total lung capacity. These results suggest that in zone 1 the interface maintains the patency of some alveolar vessels. probably in corners. The majority of alveolar septal vessels appears to be exposed directly to PA in zones 2 and 3. because at equal transpulmonary pressure the PVR is similar in the presence or absence of an interface.
Restriction of regional blood flow and diaphragmatic contractility, We have tested the hypothesis that the diaphragmatic head-to-head arterial anastomosis system should maintain adequate diaphragmatic function even during occlusion of some of its arteries. In six anesthetized open-chest dogs. left phrenic vein blood flow (Qphv) was measured by pulsed Doppler flowmetry. Contractility was measured by sonomicrometry in the left costal and crural diaphragm. The diaphragm was paced for 15 min by continuous bilateral supramaximal phrenic nerve stimulation. In five separate runs the following arteries were occluded at minute 5: 1) left phrenic artery. 2) internal mammary artery (IMA). 3) left phrenic artery and IMA. 4) descending aorta. and 5) descending aorta and IMA. Occlusion was then released at minute 10 of the run. In runs 1-3 there were no changes in contractility in costal or crural diaphragm and no changes in Qphv. However. in runs 4 and 5. Qphv decreased to 55.2 +/- 7.4 and 24.0 +/- 6.5% of control values. respectively. In run 4. percent maximum shortening from functional residual capacity (%LFRC) of the crural diaphragm decreased by 39.1%. while %LFRC of the costal diaphragm increased by 41.4% and abdominal pressure decreased by 47.0%. In run 5. abdominal pressure decreased by 53.5% and %LFRC of the crural and costal diaphragm decreased by 45.5 and 5.8%. respectively. Also relative postocclusion hyperemia was greater in run 5 (64.8%) than in run 4 (40.2%).
Neutrophil-associated lung injury after the infusion of activated plasma, Previous studies from our laboratory have shown that the infusion of zymosan-activated plasma (ZAP) caused large numbers of neutrophils (PMN) to accumulate in the lung. Although PMN are known to be activated by ZAP. it is unclear whether PMN delayed in the lung by ZAP infusion actually cause lung injury. The present study was designed to examine this question by measuring airway epithelial and endothelial injury. Airway epithelial injury was determined by depositing a known dose of fluorescein isothiocyanate-labeled dextran in the lung and measuring its appearance in the blood. and endothelial injury was measured by injecting colloidal carbon and measuring its accumulation in the microvasculature of the lung. The data show that ZAP infusion caused a mild epithelial and endothelial injury that did not increase either extravascular water or protein. This injury could be prevented either by depleting the animals of PMN or by pretreating them with indomethacin. In addition. the effect of ZAP infusion could be partially restored by transfusing donor PMN into the PMN-depleted animals. We conclude that ZAP infusion produces a mild lung injury that is dependent on PMN and the products of the cyclooxygenase pathway of arachidonic acid metabolism.
Effect of exogenous cAMP and aminophylline on alveolar and lung liquid clearance in anesthetized sheep, A substantial body of evidence indicates that active transport of ions is important in modulating the resolution process of pulmonary edema. The biochemical regulation of this ion transport mechanism is still under investigation. In this study we evaluated the effect of an adenosine 3'.5'-cyclic monophosphate (cAMP) analogue [dibutyryl cAMP (DBcAMP)] and a phosphodiesterase inhibitor (aminophylline) given alone or together on lung liquid and protein clearance. To study lung liquid and protein clearance. we measured the removal of 100 ml of autologous serum from the air spaces of anesthetized and ventilated adult sheep. Either serum alone or serum mixed with 10(-3) M DBcAMP. 10(-3) M or 10(-5) M aminophylline. or 10(-3) M aminophylline plus 10(-3) M DBcAMP was instilled. After 4 h. the residual lung water was 73.5 +/- 8.7 ml when serum alone was instilled and 56.8 +/- 13.6 ml when aminophylline and DBcAMP were given together. Neither aminophylline nor DBcAMP alone increased lung liquid clearance. However. the increase in clearance cannot be explained by an increase in protein clearance or changes in the pulmonary hemodynamics. These data suggest that the cAMP second messenger system can stimulate lung liquid clearance in vivo.
Muscle damage induced by eccentric contractions of 25% strain, Contractile and morphological properties were measured in the rabbit tibialis anterior muscle 1 h after isometric contraction (IC). passive stretch (PS). or eccentric contraction (EC). Maximal tetanic tension (Po) was reduced after 30 min of PS (P less than 0.001). IC (P less than 0.001). or EC (P less than 0.0001). However. the magnitude of the force deficit was a function of the treatment method. After 30 min of cyclic PS. Po decreased by 13%. whereas after IC or EC. Po decreased by 31 and 69%. respectively. The time course of tension decline in the various groups suggested that the EC-induced injury occurred during the first few minutes of treatment. Although the morphology of samples from the PS and IC groups appeared normal. eccentrically exercised muscles exhibited portions of abnormally large fibers (diam greater than or equal to 110 microns) when viewed in cross section. Examination of 231 such fibers from 6 muscles revealed that all enlarged fibers were exclusively of the fast-twitch glycolytic fiber type. Although no ultrastructural abnormalities were observed in any of the muscles from the IC or PS groups. a significant portion of the fibers in the EC group displayed various degrees of disorganization of the sarcomeric band pattern. Taken together. these studies highlight the importance of fiber oxidative capacity in EC-induced injury. which may be related to the damage mechanism.
Respiratory-related recruitment of the masseter: response to hypercapnia and loading, To test the hypothesis that a muscle that closes the jaw. the masseter. can be recruited by ventilatory stimuli. we studied the electromyographic activation of the masseter and genioglossus in seven normal awake males who were exposed in random order to progressive hyperoxic hypercapnia. inspiratory threshold loading (-40 cmH2O). and combined hypercapnia and loading. With hypercapnia. the masseter was generally recruited after the genioglossus had been activated. Once recruited. activation of both muscles increased linearly with increasing CO2. Combined hypercapnia and loading produced more activation than either stimulus alone. These data indicate that the masseter is activated by ventilatory stimuli that activate the genioglossus. Earlier recruitment of the genioglossus suggests that activation of the masseter serves to stabilize the mandible and allow the genioglossus to function as a more efficient dilator of the upper airway.
Mitogenic response of T-lymphocytes to exercise training and stress, The impact of exercise training and stress on the immune response was examined by measuring the mitogenic response of spleen lymphocytes to the T-cell mitogen concanavalin A (Con-A). Male Sprague-Dawley rats were divided into four groups: sedentary controls (n = 11). handled controls (n = 12). treadmill runners (n = 10). and voluntary runners (n = 11) housed in running wheels. The treadmill group ran at 22 m/min (0.8 mph) for 45 min. 5 days/wk for 8 wk. After the training period. spleen lymphocytes isolated from each rat were incubated with Con-A for 54 h. pulsed with radiolabeled thymidine for 18 h. and counted for tritium activity. Counts per minute per group (means +/- SE) were as follows: sedentary. 6.839 +/- 1.461; handled. 8.959 +/- 1.576; voluntary runners. 13.126 +/- 2.069; and treadmill runners. 18.950 +/- 5.975. One-way analysis of variance and Tukey's highly significant difference test found the counts per minute of the treadmill runners to be significantly different from the counts per minute of the sedentary animals. These results indicate that the responsiveness of spleen lymphocytes to Con-A increases as the level of stress and exercise increases.
Presynaptic regulation of cardiac sympathetic function in hypoxic guinea pigs, In the normal heart. presynaptic cholinergic muscarinic and alpha 2-adrenergic mechanisms modify the fractional rate constant for norepinephrine (NE) synthesis (kNE). an index of sympathetic neural function. To evaluate presynaptic regulation of kNE. conscious guinea pigs subjected to normoxia and then hypoxia (n = 7-8 in each group) were pretreated with 1) vehicle; 2) a cholinergic muscarinic antagonist. methyl atropine; 3) an alpha 2-antagonist. yohimbine; or 4) a combination of the two. An increase of kNE was determined from incorporation of radiolabeled tyrosine into NE in a control period (arterial PO2 130 +/- 1.7 Torr. PCO2 36 +/- 0.5 Torr) and during a hypoxic state (PO2 49.6 +/- 1.0 Torr. PCO2 36 +/- 0.5 Torr). Hypoxia activated kNE in the atrioventricular node and right ventricular moderator band in vehicle-treated animals (P less than 0.05). Sympathetic activation was more general. however. because alpha 2-presynaptic influence acted to limit kNE in all tissues tested (P less than 0.05) except muscle. spleen. and posterior left ventricle. Cholinergic muscarinic presynaptic restraint on kNE was detected during hypoxia only in the left atrial appendage and lung (P less than 0.05). These data indicate that hypoxia increases kNE in the heart. but restraint by cholinergic muscarinic and alpha 2-adrenergic presynaptic mechanisms limits increases in neurotransmitter synthesis and noradrenergic activation regionally.
Pulmonary and chest wall mechanics in anesthetized paralyzed humans, Pulmonary and chest wall mechanics were studied in 18 anesthetized paralyzed supine humans by use of the technique of rapid airway occlusion during constant-flow inflation. Analysis of the changes in transpulmonary pressure after flow interruption allowed partitioning of the overall resistance of the lung (RL) into two compartments. one (Rint.L) reflecting airway resistance and the other (delta RL) representing the viscoelastic properties of the pulmonary tissues. Similar analysis of the changes in esophageal pressure indicates that chest wall resistance (RW) was due entirely to the viscoelastic properties of the chest wall tissues (delta RW = RW). In line with previous measurements of airway resistance. Rint.L increased with increasing flow and decreased with increasing volume. The opposite was true for both delta RL and delta RW. This behavior was interpreted in terms of a viscoelastic model that allowed computation of the viscoelastic constants of the lung and chest wall. This model also accounts for frequency. volume. and flow dependence of elastance of the lung and chest wall. Static and dynamic elastances. as well as delta R. were higher for the lung than for the chest wall.
Expiratory muscle fatigue in normal subjects, We examined expiratory muscle fatigue during expiratory resistive loading in 11 normal subjects. Subjects breathed against expiratory resistances at their own breathing frequency and tidal volume until exhaustion or for 60 min. Respiratory muscle strength was assessed from both the maximum static expiratory and inspiratory mouth pressures (PEmax and PImax). At the lowest resistance. PEmax and PImax measured after completion of the expiratory loaded breathing were not different from control values. With higher resistance. both PEmax and PImax were decreased (P less than 0.05). and the decrease lasted for greater than or equal to 60 min. The electromyogram high-to-low frequency power ratio for the rectus abdominis muscle decreased progressively during loading (P less than 0.01). but the integrated EMG activity did not change during recovery. Transdiaphragmatic pressure during loading was increased 3.6-fold compared with control (P less than 0.05). These findings suggest that expiratory resistive loaded breathing induces muscle fatigue in both expiratory and inspiratory muscles. Fatigue of the expiratory muscles can be attributed directly to the high work load and that of the inspiratory muscles may be related to increased work due to shortened inspiratory time.
Role for tumor necrosis factor as mediator of lung injury following lower torso ischemia, Ischemia and reperfusion of the ischemic lower torso lead to a neutrophil- (PMN) dependent lung injury characterized by PMN sequestration and permeability edema. This mimics the injury seen after infusion of tumor necrosis factor alpha (TNF). a potent activator of PMN and endothelium. This study tests whether TNF is a mediator of the lung injury after lower torso ischemia. Anesthetized rats underwent 4 h of bilateral hindlimb tourniquet ischemia. followed by reperfusion for 10 min. 30 min. 1. 2. 3. and 4 h (n = 6 for each time point). Quantitative lung histology indicated progressive sequestration of PMN in the lungs. 25 +/- 3 (SE) PMN/10 high-power fields (HPF) 10 min after reperfusion vs. 20 +/- 2 PMN/10 HPF in sham animals (NS). increasing to 53 +/- 5 PMN/10 HPF after 4 h vs. 23 +/- 3 PMN/10 HPF in sham animals (P less than 0.01). There was lung permeability. shown by increasing protein accumulation in bronchoalveolar lavage (BAL) fluid. which 4 h after reperfusion was 599 +/- 91 vs. 214 +/- 35 micrograms/ml in sham animals (P less than 0.01). Similarly. there was edema. shown by the lung wet-to-dry weight ratio. which increased by 4 h to 4.70 +/- 0.12 vs. 4.02 +/- 0.17 in sham animals (P less than 0.01). There was generation of leukotriene B4 in BAL fluid (720 +/- 140 vs. 240 +/- 40 pg/ml. P less than 0.01). and in three of six rats tested at this time TNF was detected in plasma. with a mean value of 167 pg/ml. TNF was not detectable in any sham animal.
Exposure of neonatal rats to carbon monoxide alters cardiac adaptation to aortic constriction, We tested the hypothesis that a 32-day exposure of newborn rats to 500 ppm carbon monoxide (CO) would alter the adaptive response of the heart to aortic constriction in adulthood. At 110 days of age aortic constriction or sham operations were performed. and hearts were studied 28 days later. Aortic constriction increased left ventricular (LV) mass by 40% over the control value of 611 +/- 27 mg; this adaptive response was not altered by CO exposure. Aortic constriction and CO exposure increased right ventricular (RV) mass by 10 and 11%. respectively. over the control value of 185 +/- 10 mg. The effects of both experimental procedures on RV mass were additive (23%). Peak LV pressure development (dP/dtmax) in vitro increased 29% after aortic constriction in the nonexposed rats. CO exposure blunted the increase in peak LV systolic pressure due to aortic constriction. Maximum positive and negative dP/dtmax decreased by 19% after aortic constriction and were unaffected by CO exposure. The percentage of alpha-myosin heavy chain (MHC) in the ventricles was 94 +/- 2% in the control group and was decreased to 81 +/- 3% by aortic constriction. In contrast. the percentage of alpha-MHC was 87 +/- 2% for CO-exposed rats and was not significantly altered after aortic constriction. In vitro coronary flow was increased 18% in hearts of adult rats exposed to CO as neonates. Exposure of neonatal rats to CO induced chronic adaptations in the myocardium. some of which became evident in adulthood only when hearts were challenged by aortic constriction.
Analysis of behavior of the respiratory system in ARDS patients: effects of flow, volume, and time, The effects of inspiratory flow (V) and inflation volume (delta V) on the mechanical properties of the respiratory system in eight ARDS patients were investigated using the technique of rapid airway occlusion during constant-flow inflation. We measured interrupter resistance (Rint.rs). which in humans represents airway resistance. the additional resistance (delta Rrs) due to viscoelastic pressure dissipations and time constant inequalities. and static (Est.rs) and dynamic (Edyn.rs) elastance. The results were compared with a previous study on 16 normal anesthetized paralyzed humans (D'Angelo et al. J. Appl. Physiol. 67: 2556-2564. 1989). We observed that 1) resistance and elastance were higher in ARDS patients; 2) with increasing V. Rint.rs and Est.rs did not change. delta Rrs decreased progressively. and Edyn.rs increased progressively; 3) with increasing delta V. Rint.rs decreased slightly. delta Rrs increased progressively. and Est.rs and Edyn.rs showed an initial decrease followed by a secondary increase noted only in the ARDS patients. The above findings could be explained in terms of a model incorporating a standard resistance in parallel with a standard elastance and a series spring-and-dashpot body that represents the stress adaptation units within the tissues of the respiratory system.
Respiratory neuronal activity during apnea and other breathing patterns induced by laryngeal stimulation, Respiration cycles through three distinct phases (inspiration. postinspiration. and expiration) each having corresponding medullary cells that are excited during one phase and inhibited during the other two. Laryngeal stimulation is known to induce apnea in newborn animals. but the cellular mechanisms underlying this effect are not known. Intracellular recording of ventral respiratory group neurons was accomplished in intact anesthetized. paralyzed. and mechanically ventilated piglets. Apnea was induced by insufflation of the larynx with ammonia-saturated air. smoke. or water. Laryngeal insufflation induced phrenic nerve apnea. stimulation of postinspiratory neurons. and stable membrane potentials in inspiratory and expiratory cells consistent with postinspiratory inhibition. Usually the membrane potential of each neuronal type cycled through an expiratory level before onset of the first recovery breath. Variants of the apnea response. probably reflecting the aspiration reflex or sniffing. sneezing. coughing. and swallowing. were also observed. These latter patterns showed oscillation between inspiration and postinspiration without an apparent intervening stage II expiratory phase. However. stage II expiratory activity always preceded onset of the first ramp inspiration after such a pattern. These findings suggest that activation of postinspiratory mechanisms causes profound alterations in the respiratory pattern and that stage II expiration importantly modulates recovery of ramp inspiratory activity. The mechanism of this latter effect may be inhibition of early inspiratory neurons with consequent postinhibitory rebound.
Perialveolar interstitial resistance and compliance in isolated rat lung, We have developed a method to characterize fluid transport through the perialveolar interstitium using micropuncture techniques. In 10 experiments we established isolated perfused rat lung preparations. The lungs were initially isogravimetric at 10 cmH2O arterial pressure. 2 cmH2O venous pressure. and 5 cmH2O alveolar pressure. Perialveolar interstitial pressure was determined by micropuncture at alveolar junctions by use of the servo-null technique. Simultaneously a second micropipette was placed in an alveolar junction 20-40 microns away. and a bolus of albumin solution (3.5 g/100 ml) was injected. The resulting pressure transient was recorded for injection durations of 1 and 4 s in nonedematous lungs. The measurements were repeated after gross edema formation induced by elevated perfusion pressure. We model the interstitium as a homogeneous linearly poroelastic material and assume the initial pressure distribution due to the injection to be Gaussian. The pressure decay is inversely proportional to time. with time constant T. where T is a measure of the ratio of interstitial tissue stiffness to interstitial resistance to fluid flow. A linear regression was performed on the reciprocal of the pressure for the decaying portion of the transients to determine T. Comparing pressure transients in nonedematous and edematous lungs. we found that T was 4.0 +/- 1.4 and 1.4 +/- 0.6 s. respectively. We have shown that fluid transport through the pulmonary interstitium on a local level is sensitive to changes in interstitial stiffness and resistance. These results are consistent with the decreased stiffness and resistance in the perialveolar interstitium that accompany increased hydration.
Water and electrolyte balance in the vascular space during graded exercise in humans, We analyzed the changes in water content and electrolyte concentrations in the vascular space during graded exercise of short duration. Six male volunteers exercised on a cycle ergometer at 20 degrees C (relative humidity = 30%) as exercise intensity was increased stepwise until voluntary exhaustion. Blood samples were collected at exercise intensities of 29. 56. 70. and 95% of maximum aerobic power (VO2max). A curvilinear relationship between exercise intensity and Na+ concentration in plasma ([Na+]p) was observed. [Na+]p significantly increased at 70% VO2max and at 95% VO2max was approximately 8 meq/kgH2O higher than control. The change in lactate concentration in plasma ([Lac-]p) was closely correlated with the change in [Na+]p (delta[Na+]p = 0.687 delta[Lac-]p + 1.79. r = 0.99). The change in [Lac-]p was also inversely correlated with the change in HCO3- concentration in plasma (delta[HCO3-]p = -0.761 delta[Lac-]p + 0.22. r = -1.00). At an exercise intensity of 95% VO2max. 60% of the increase in plasma osmolality (Posmol) was accounted for by an increase in [Na+]p. These results suggest that lactic acid released into the vascular space from active skeletal muscles reacts with [HCO3-]p to produce CO2 gas and Lac-. The data raise the intriguing notion that increase in [Na+]p during exercise may be caused by elevated Lac-.
Current thoughts on the assessment of protein metabolism in humans, An understanding of protein metabolism is crucial in increasing knowledge about wound healing and functional recovery after burns. Recent advances in the clinical study of protein metabolism were addressed at a conference sponsored by the Shriners Burns Institute that took place March 7 to 8. 1990. New methods of clinical study of protein metabolism involving various isotopic labeling techniques were discussed. Conference participants concluded that advances in quantitation techniques and modeling approaches promise a better understanding of human protein metabolism. but also thought that current techniques still have limitations.
Analysis of burns caused by long-term exposure to a heating pad, The potential for creating a second-degree burn by extended exposure to an electric heating pad was evaluated in a simple model. Extrapolation of empirical results from experiments in thermal burns and in hyperthermia indicated that a heating pad at the low power setting can produce a burn within a threshold time of approximately 12 to 20 hours.
Early upper-extremity prosthetic fit in patients with burns, Patients with upper-extremity amputations necessitated by burn injury have frequently faced delays in prosthetic fit. At the Regional Medical Center. Memphis. Tennessee. seven patients required amputations because of burns. These injuries were electrical in four cases. thermal and crush in one case. thermal in one case. and steam and crush in one case. Five patients had below-elbow amputations. one had a bilateral below-elbow amputation. and one had a bilateral above-elbow amputation. All patients were fitted with prostheses within 30 days of the last definitive surgery on the amputated extremity. All patients continued to wear a prosthesis and no patient exhibited skin breakdown. Patients returned to independence with self care within 2 weeks and to preamputation activities within an average of 2.5 months.
A survey of pediatric discharge educational programs in North American burn units, In this study we contacted all of the 149 major North American burn facilities that treat children. The survey determined topics covered in discharge teaching. personnel administering the programs. methods used. and obstacles encountered. The subjects addressed and the personnel involved have changed little from a decade ago. Unfortunately. one fourth of the centers still do not deal with emotional aspects of burns in their discharge programs. For program delivery. videotape is becoming an increasingly accepted teaching method. Eighty-five percent of burn facilities experienced barriers to patient education at discharge. with more than half reporting three or more difficulties. The most common difficulty was time constraints (50%). followed by language and sociocultural barriers (41%). lack of receptivity by clientele (39%). lack of educational materials and planning (26%). and inadequate funding (25%). Some of these problems might be alleviated by the establishment of a clearinghouse for burn educational materials.
Analysis of materials for splinting of the thermally injured patient, Good results have been achieved in the treatment of patients with burns with new splinting materials and proper splinting techniques. This article focuses on the thermoplastic splinting materials Clinic and Spectrum (Northcoast Medical Inc.. San Jose. Calif.) and the comparable thermoplastic products Polyform (Smith & Nephew Rolyan. Inc.. Menomonee Falls. Wis.) and Orthoplast (Johnson & Johnson Orthopedics. New Brunswick. N.J.). Qualities such as self-bonding. recyclability. and rigidity were tested for these materials. Splint rigidity was measured by a calibrated hook scale and determined by the force per pound needed to bend the material 20 degrees. Spectrum and Clinic products were judged more economical and. we contend. they are therefore better choices for splinting the thermally injured patient.
Research priorities for burn nursing. Report of the Wound Care and Infection Control Group, This study was designed to identify research priorities in burn nursing. The Delphi technique of sequential questionnaires was used for data collection. Ninety-four participants completed four rounds of questionnaires. One hundred one research questions were identified and prioritized according to impact on the welfare of patients with burns and impact on the profession of burn nursing. Twenty-three of these research questions concerned issues of wound care or infection control. This group of questions was further analyzed to determine priority research issues. The five most highly ranked questions in the category of wound care/infection control with regard to impact on patient welfare concerned healing of donor sites and skin grafts. wound cleansing. and the effect of pressure garments on wound healing. Similarly. the five most highly ranked questions with regard to impact on the profession of burn nursing concerned the impact of combining patients with burns and patients without burns in the same unit. healing of donor sites and skin grafts. care of the patient with burns who also has acquired immune deficiency syndrome. infection control. and dressing of the burn wound.
Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts, Free radicals have been implicated in the pathogenesis of reperfusion injury. but it is unclear how they exert their deleterious effects on cellular metabolism. Several lines of indirect evidence suggest that free radicals elevate intracellular Ca2+ concentration ([Ca2+]i) and inhibit glycolysis as part of their mechanism of injury. We tested these ideas directly in hearts subjected to hydroxyl radicals produced by the Fenton and Haber-Weiss reactions. Nuclear magnetic resonance spectra were obtained from Langendorff-perfused rabbit hearts before. during. and after 4 min of perfusion with H2O2 (0.75 mM) and Fe(3+)-chelate (0.1 mM). Isovolumic left ventricular pressure exhibited progressive functional deterioration and contracture after exposure to H2O2 + Fe3+. Phosphorus nuclear magnetic resonance (NMR) spectra revealed partial ATP depletion and sugar phosphate accumulation indicative of glycolytic inhibition. To measure [Ca2+]i. fluorine NMR spectra were acquired in a separate group of hearts loaded with the Ca2+ indicator 5F-BAPTA [5.5'-difluoro derivative of 1.2-bis-(o-aminophenoxy)ethane- N.N.N'.N'-tetraacetic acid]. Mean time-averaged [Ca2+]i increased from 347 +/- 14 nM in control to 1.026 +/- 295 nM 4 min after free radical generation (means +/- SEM. n = 7). and remained elevated thereafter. We conclude that free radicals induce clear-cut. specific derangements of cellular metabolism in the form of glycolytic inhibition and calcium overload. The observed increase in [Ca2+]i suggests that the deleterious effects of free radicals are at least partially mediated by secondary changes in cellular calcium homeostasis.
Maple syrup urine disease in Mennonites. Evidence that the Y393N mutation in E1 alpha impedes assembly of the E1 component of branched-chain alpha-keto acid dehydrogenase complex, Maple Syrup Urine Disease (MSUD) in Mennonites is associated with homozygosity for a T to A transversion in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex. This causes a tyrosine to asparagine substitution at position 393 (Y393N). To assess the functional significance of this missense mutation. we have carried out transfection studies using E1 alpha-deficient MSUD lymphoblasts (Lo) as a host. The level of E1 beta subunit is also greatly reduced in Lo cells. Efficient episomal expression in lymphoblasts was achieved using the EBO vector. The inserts employed were chimeric bovine-human cDNAs which encode mitochondrial import competent E1 alpha subunit precursors. Transfection with normal E1 alpha cDNA into Lo cells restored decarboxylation activity of intact cells. Western blotting showed that both E1 alpha and E1 beta subunits were markedly increased. Introduction of Y393N mutant E1 alpha cDNA failed to produce any measurable decarboxylation activity. Mutant E1 alpha subunit was expressed at a normal level. however. the E1 beta subunit was undetectable. These results provide the first evidence that Y393N mutation is the cause of MSUD. Moreover. this mutation impedes the assembly of E1 alpha with E1 beta into a stable alpha 2 beta 2 structure. resulting in the degradation of the free E1 beta subunit.
Endobronchial allergen challenge in asthma. Demonstration of cellular source of granulocyte macrophage colony-stimulating factor by in situ hybridization, Airway inflammation is thought to play an important role in the pathogenesis of asthma. We have used in situ hybridization and an immunoassay to determine whether granulocyte macrophage colony-stimulating factor (GM-CSF) (a cytokine capable of eosinophil activation) is present in the airway of asthmatics (n = 6) who have 37.0 +/- 15.1% airway eosinophilia after endobronchial allergen challenge. Levels of immunoreactive GM-CSF (less than 4 pg/ml pre-allergen versus 180.5 +/- 46.9 pg/ml post-allergen) increased significantly 24 h after endobronchial allergen stimulation. The cellular source of bronchoalveolar lavage (BAL) GM-CSF. as determined by in situ hybridization and immunoperoxidase staining. was derived predominantly from UCHL-1 positive BAL lymphocytes. as well as from a smaller population of alveolar macrophages. Before local endobronchial allergen challenge. less than 1% of lymphocytes and alveolar macrophages recovered by BAL expressed GM-CSF mRNA. whereas after allergen stimulation 92.6 +/- 3.4% of lymphocytes and 17.5 +/- 22.7% of alveolar macrophages expressed GM-CSF mRNA. This study provides evidence that in an experimental model of allergen-induced asthma. activation of the immune and inflammatory response (BAL lymphocyte and alveolar macrophage production of GM-CSF) is temporally associated with an inflammatory cell influx of eosinophils into the airway.
Four different mutations in codon 28 of alpha spectrin are associated with structurally and functionally abnormal spectrin alpha I/74 in hereditary elliptocytosis, Hereditary elliptocytosis (HE) Sp alpha I/74 is a disorder associated with defective spectrin (Sp) heterodimer self-association and an abnormal tryptic cleavage of the 80-kD alpha I domain of Sp resulting in increased amounts of a 74-kD peptide. The molecular basis of this disorder is heterogeneous and mutations in codons 28. 46. 48. and 49 (codons 22. 40. 42. and 43 in the previous nomenclature which did not include the six NH2-terminal amino acids) have been reported. In this study we present data on seven unrelated HE Sp alpha I/74 kindred from diverse racial backgrounds in whom we identified four different mutations all occurring in exon 2 of alpha Sp at codon 28. Utilizing the polymerase chain reaction we established a CGT----CTT; Arg----Leu 28 mutation in one kindred of Arab/Druze origin. In two unrelated white kindred of English/European origin the substitution is CGT----AGT; Arg----Ser 28 and in two apparently unrelated white kindred from New Zealand. the mutation is CGT----TGT; Arg----Cys 28. Finally. in one American black kindred and in a black kindred from Ghana the mutation involves CGT----CAT; Arg----His 28. Allele specific oligonucleotide hybridization confirmed that the probands are heterozygous for the respective mutant alleles. All four point mutations abolished an Aha II restriction enzyme site which allowed verification of linkage of the mutation with HE Sp alpha I/74. Our results imply that codon 28 of alpha Sp is a "hot spot" for mutations and also indicate that Arg 28 is critical for the conformational stability and functional self association of Sp heterodimers.
Nonsense mutations affect C1 inhibitor messenger RNA levels in patients with type I hereditary angioneurotic edema, Members of two unrelated families with type I hereditary angioneurotic edema (HANE) were found to have elevated levels of C1 inhibitor (C1INH) mRNA. DNA sequence analysis of PCR-amplified monocyte C1INH mRNA revealed normal and mutant transcripts. as expected in this disorder that occurs in heterozygous individuals. Single base mutations near the 3' end of the coding sequence were identified in affected members of each family. One mutation consisted of insertion of an adenosine at position 1304 which created a premature termination codon (TAA). whereas the second consisted of deletion of the thymidine at position 1298 which created a premature termination codon (TGA) 23 nucleotides downstream. These mutations are approximately 250 nucleotides upstream of the natural termination codon. Nuclear run-off experiments in one kindred revealed no difference in transcription rates of the C1INH gene between the patients and normals. C1INH mRNA half-life experiments were not technically feasible because of the prolonged half-life of the normal transcript. Dideoxynucleotide primer extension experiments allowed the differentiation of the normal and mutant transcripts. These studies showed that the mutant transcript was not decreased relative to the normal. and this therefore was at least partially responsible for the C1INH mRNA elevation. This elevation may be due to the decreased catabolism of the mutant transcript.
Intra-islet insulin permits glucose to directly suppress pancreatic A cell function, Inhibition of pancreatic glucagon secretion during hyperglycemia could be mediated by (a) glucose. (b) insulin. (c) somatostatin. or (d) glucose in conjunction with insulin. To determine the role of these factors in the mediation of glucagon suppression. we injected alloxan while clamping the arterial supply of the pancreatic splenic lobe of dogs. thus inducing insulin deficiency localized to the ventral lobe and avoiding hyperglycemia. Ventral lobe insulin. glucagon. and somatostatin outputs were then measured in response to a stepped IV glucose infusion. In control dogs glucagon suppression occurred at a glucose level of 150 mg/dl and somatostatin output increased at glucose greater than 250 mg/dl. In alloxan-treated dogs glucagon output was not suppressed nor did somatostatin output increase. We concluded that insulin was required in the mediation of glucagon suppression and somatostatin stimulation. Subsequently. we infused insulin at high rates directly into the artery that supplied the beta cell-deficient lobe in six alloxan-treated dogs. Insulin infusion alone did not cause suppression of glucagon or stimulation of somatostatin; however. insulin repletion during glucose infusions did restore the ability of hyperglycemia to suppress glucagon and stimulate somatostatin. We conclude that intra-islet insulin permits glucose to suppress glucagon secretion and stimulate somatostatin during hyperglycemia.
Autocrine stimulation by erythropoietin and autonomous growth of human erythroid leukemic cells in vitro, Autonomous colony formation is a frequent event in erythroleukemia. In 13 cases of early erythroid leukemias. we investigated whether erythropoietin (Epo) autocrine stimulation was responsible for the growth factor autonomy. Epo transcripts were detected by Northern blotting in cells from one patient. These cells also expressed an Epo receptor (1.000 receptors per cell) with a 420-pM affinity and Epo was detected in the supernatant of cultured cells. In 8 of the 13 cases. Epo transcripts were revealed by the polymerase chain reaction ranging from 0.5 to 500 copies per cell. In situ hybridization proved that these Epo transcripts were present in the blast cells. No Epo gene abnormalities were detected by Southern blotting. In two cases. leukemic cells were grown in the presence of Epo-neutralizing antibodies or Epo antisense oligomers. In one case. the antibody significantly reduced autonomous growth. In contrast. the antibody had no effect in the second case in which blast cells transcribed the Epo gene at a low level. However. Epo antisense oligomers partially inhibited autonomous growth. This inhibition was reversed by addition of exogenous Epo. Overall. these results suggest that an extracellular or intracellular autocrine Epo stimulation occurs in some cases of erythroid malignancies.
Acidic polyamino acids inhibit human eosinophil granule major basic protein toxicity. Evidence of a functional role for ProMBP, Eosinophil granule major basic protein (MBP). a potent toxin for helminths and mammalian cells in vitro. is a single polypeptide chain rich in arginine. MBP has been localized on damaged helminths and tissues in hypersensitivity diseases including bronchial asthma. The MBP cDNA indicates that MBP is translated as a slightly acidic preproprotein with an acidic propart. To test the hypothesis that the acidic pro-part of proMBP inhibits the toxicity of mature MBP. acidic polyamino acids (aa) were used as antagonists of MBP toxicity to K562 cells and guinea pig tracheal epithelium and used as antagonists of MBP airway hyperresponsiveness in primates. The acidic poly aa inhibited MBP toxicity and MBP airway hyperresposiveness. The acidic poly aa inhibited MBP toxicity in a charge-dependent manner similar to that proposed for proMBP. suggesting that the acidic pro-part of proMBP functions to mask mature MBP toxicity. This inhibition was not limited to MBP. but also applied to polyarginine and eosinophil cationic protein. These acidic poly aa may be useful to inhibit the actions of a number of cationic toxins released by the eosinophil in numerous hypersensitivity diseases.
Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients, Types A and B Niemann-Pick disease both result from the deficient activity of the lysosomal hydrolase. acid sphingomyelinase (E.C. 3.1.4.12). Type A Niemann-Pick disease is a severe neurodegenerative disorder of infancy which leads to death by three years of age. whereas Type B disease has a later age at onset. little or no neurologic involvement. and most patients survive into adulthood. To investigate the molecular basis for the remarkable phenotypic heterogeneity. the nature of the mutations causing Type B Niemann-Pick disease in Ashkenazi Jewish patients was determined. The entire acid sphingomyelinase coding region from an Ashkenazi Jewish Type B patient was polymerase chain reaction-amplified. subcloned. and completely sequenced. A three-base deletion was identified of nucleotides 1821-1823 in the cDNA which predicted the removal of an arginine residue from position 608 of the acid sphingomyelinase polypeptide (delta R608). The other cDNA clones from this patient had the R496L mutation previously identified in Type A Niemann-Pick disease patients. Both Ashkenazi Jewish Type B patients were heteroallelic for the delta R608 mutation. whereas this allele was not present in 15 unrelated non-Jewish Type B patients. with the notable exception of one mildly affected patient of Arabic descent who was homoallelic for the delta R608 mutation. These results indicate that the delta R608 mutation predicts the Type B Niemann-Pick disease phenotype. even in the presence of the R496L Type A allele. thereby providing the first genotype/phenotype correlation for this lysosomal storage disease. Although only two patients have been studied. it appears that the delta R608 mutation occurs frequently in Type B Niemann-Pick disease patients of Ashkenazi Jewish descent.
Altered transcriptional regulation of phosphoenolpyruvate carboxykinase in rats following endotoxin treatment, The molecular mechanism involved in altered regulation of the rate-limiting enzyme in hepatic gluconeogenesis. phosphoenolpyruvate carboxykinase (PEPCK). during endotoxemia is not completely understood. We examined. therefore. the effect of a nonlethal dose of Escherichia coli endotoxin on PEPCK gene expression in fasted rats. 5 h after endotoxin treatment. the PEPCK transcription rate and the amount of mRNA(PEPCK) were significantly decreased at a time when the insulin/glucagon (I/G) molar ratio and plasma corticosterone levels were significantly increased. Similar results were observed in a time course study. in which altered cAMP induction of PEPCK gene expression paralleled changes in the I/G molar ratio. In diabetic rats treated with endotoxin. PEPCK gene expression was decreased in the absence. however. of an increased I/G molar ratio. This finding indicates that other factors. such as inflammatory mediators or cytokines. alter PEPCK gene transcription during endotoxemia. IL-6. a putative mediator of endotoxin action in the liver. had no effect on PEPCK gene expression in fasted rats. but did decrease cAMP induction of PEPCK gene expression. These results indicate that. during endotoxemia. regulation of PEPCK gene expression is influenced by inflammatory mediators in addition to the classical endocrine hormones. IL-6. however. does not appear to be involved directly in the altered regulation of the PEPCK gene during endotoxemia.
Augmentation of reverse arthus reaction by mast cells in mice, Immune complex-induced injury is an important pathogenic factor in antibody-mediated nephritis. systemic lupus erythematosus. rheumatoid arthritis. and other diseases. In this study we investigated the role mast cells in immune complex-mediated injury in mouse skin. Reverse Arthus reaction was induced in mast cell-deficient WBB6F1-W/Wv mice and their congenic controls (WBB6F1(-)+/+). Serial skin sections were evaluated for neutrophil infiltration. edema. and hemorrhage. In WBB6F1-W/Wv mice the neutrophil influx was only 40% and edema 60% of that in congenic controls. Hemorrhage was also significantly reduced in the mast cell-deficient mice. After mast cell reconstitution. the magnitude of the reaction in WBB6F1-W/Wv was equivalent to that in WBB6F1(-)+/+ mice. Mast cell release in reverse Arthus reaction was evaluated by measuring fluorescence intensity after avidin-FITC staining of mast cell granules. There was a 70% decrease in fluorescence intensity. The 5-lipoxygenase inhibitor A-63162 significantly decreased neutrophil accumulation (40%). edema (60%). and hemorrhage in WBB6F1(-)+/+. but not in mast cell-deficient mice. Mast cell reconstitution of WBB6F1-W/Wv mice restored the effect of A-63162. The results indicate that mast cells and their mediators. including leukotrienes. make an important contribution to reverse Arthus reaction.
Localization of human platelet autoantigens to the cysteine-rich region of glycoprotein IIIa, The object of this study was to further localize autoantigenic structures on IIb-IIIa and. if possible. to precisely identify the epitopes recognized by human autoantibodies. In this paper. we identify a 50-kD chymotryptic fragment of IIIa that is recognized by a high percentage of human autoantibodies. typified by the prototype IgG autoantibody RA. which binds to IIIa on intact platelets as well as in an immunoblot assay under nonreduced conditions. Using an immunoblot assay. a carboxy-terminal region of this fragment (33 kD) that contains the cysteine-rich domains of IIIa was found to carry the epitope(s) recognized by the prototype autoantibody RA. The amino-terminal amino acid sequence of the reduced 33-kD fragment. the smallest fragment that retains the RA epitope. is XPSQQDEXSP. and that of the reduced 50-kD fragment is IVQVTFD. This indicates that the 33-kD fragment consists of approximately 175 amino acids beginning at residue 479 and extending at least through residues 636-654. while the 50-kD fragment spans the same region but begins at residue 427. It is apparent that the 33-kD fragment is generated from the 50-kD fragment by additional chymotryptic hydrolysis but remains associated because of the multiple disulfide bonds that are characteristic of this cysteine-rich domain. Sera from 48% of patients with chronic ITP and 2 of 8 patients with acute ITP contain antibodies that bind to the 50-kD fragment in an ELISA. Antibodies of the same specificity are also found in one-third of patients with either secondary immune thrombocytopenia or apparent non-immune thrombocytopenia. We conclude that the 50-kD cysteine-rich region of IIIa is a frequent target of autoantibodies in ITP. but that such antibodies may also be present in cases of thrombocytopenia that cannot be linked to an apparent autoimmune process.
Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin, Although intravenous Escherichia coli endotoxin has been used extensively in experimental studies to increase lung endothelial permeability. the effect of E. coli endotoxin on lung epithelial permeability has not been well studied. To examine this issue in sheep. bidirectional movement of protein across the lung epithelial barrier was studied by labeling the vascular space with 131I-albumin and by instilling 3 ml/kg of an isosmolar protein solution with 125I-albumin into the alveoli. E. coli endotoxin was administered according to one of three protocols: intravenous alone (5-500 micrograms/kg). intravenous (5 micrograms/kg) plus low-dose alveolar endotoxin (10 micrograms/kg). and high-dose alveolar endotoxin alone (50-100 micrograms/kg). Alveolar liquid clearance was estimated based on the concentration of the instilled native protein. Sheep were studied for either 4 or 24 h. Although intravenous E. coli endotoxin produced a marked increase in transvascular protein flux and interstitial pulmonary edema. there was no effect on the clearance of either the vascular (131I-albumin) or the alveolar (125I-albumin) protein tracer across the epithelial barrier. High-dose alveolar E. coli endotoxin caused a 10-fold increase in the number of leukocytes. particularly neutrophils. that accumulated in the air spaces. In spite of the marked chemotactic effect of alveolar endotoxin. there was no change in the permeability of the epithelial barrier to the vascular or alveolar protein tracers. Also. alveolar epithelial liquid clearance was normal. Morphologic studies confirmed that the alveolar epithelial barrier was not injured by either intravenous or alveolar E. coli endotoxin. Thus. the alveolar epithelium in sheep is significantly more resistant than the lung endothelium to the injurious effects of E. coli endotoxin.
Construction of peptides encompassing multideterminant clusters of human immunodeficiency virus envelope to induce in vitro T cell responses in mice and humans of multiple MHC types, To make synthetic peptide vaccines effective in a broad population of outbred humans. one would have to incorporate enough antigenic determinants to elicit recognition by T cells of most HLA types. We have previously defined multideterminant regions of the human immunodeficiency virus (HIV) envelope that include overlapping determinants seen by proliferating T cells of three or four haplotypes of mice. We have now tested the hypothesis that synthetic peptides encompassing such multideterminant regions will be recognized by T cells of multiple murine MHC types as well as by human T cells representing multiple HLA types. Six such peptides of 20-33 residues in length were prepared. and tested for their ability to stimulate T cells from mice of four distinct MHC types immunized with recombinant envelope protein rgp 160. as well as from 42 HIV-infected humans of different HLA types. Results identify several such peptides that are broadly recognized by mice of four H-2 types and by 52-73% of infected humans who still retain IL-2 productive responses to control recall antigens such as influenza A virus or tetanus toxoid. 86% of such infected donors tested against at least three peptides respond to at least one of the six peptides. and 77% of an additional group of seropositives respond to a mixture of the peptides. Moreover. the peptides can be used to immunize mice to elicit T cells reactive with the intact HIV envelope protein. These peptides therefore may be useful for both vaccine development in the broad human population. and diagnostic or prognostic use.
Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans, We have recently shown in vitro that the peroxisomal fraction of a rat liver homogenate has the highest capacity to beta-oxidize prostaglandins. In order to evaluate the relative importance of peroxisomes for this conversion also in vivo. we administered [3H]prostaglandin F2 alpha to an infant suffering from Zellweger syndrome. a congenital disorder characterized by the absence of intact peroxisomes. As a control. labeled compound was administered to two healthy volunteers. Urine was collected. fractionated on a SEP-PAK C18 cartridge. and subjected to reversed-phase high-performance liquid chromatography. The Zellweger patient was found to excrete prostaglandin metabolites considerably less polar than those of the control subjects. The major urinary metabolite in the control subjects was practically absent in the urine from the Zellweger patient. The major urinary prostaglandin F2 alpha metabolite from the Zellweger patient was identified as an omega-oxidized C20-prostaglandin. 9.11-dihydroxy-15-oxoprost-5-ene-1.20-dioic acid. The major urinary prostaglandin F2 alpha metabolite from the control subjects had chromatographic properties of a tetranor (C16) prostaglandin. in accordance with earlier published data. The present results. in combination with our previous in vitro data. indicate that peroxisomal beta-oxidation is of major importance for in vivo chain shortening of prostaglandins.
Chylomicron-retinyl palmitate clearance in type I hyperlipidemic families, Our primary aim was to determine the extent to which intraplasmic retinyl palmitate (RP) transfers to other lipoprotein particles when chylomicron remnants are not produced and/or the plasma RP residence time is increased. The study was conducted on three familial type I hyperlipoproteinemic patients. four lipoprotein lipase (LpL)-deficient heterozygotes. and three controls on a metabolic research unit. To each subject. a fat load was administered containing 16% of total daily calories in type I patients. 40% in heterozygotes and controls. plus 60.000 U/m2 vitamin A. Triglyceride (TG) and RP levels were evaluated in chylomicron and nonchylomicron fractions. Delay in the clearance of chylomicron fraction RP and the marked deficiency in nonchylomicron-RP (presumed lack of remnant production) in all three type I patients suggests that RP does not demonstrate significant intraplasmic transfer from chylomicrons to existent apolipoprotein B100 particles. In contrast to noncoincident TG and RP peaking in the normal subject. heterozygotes were found to demonstrate coincident plasma TG and RP curves. which is consistent with a common catabolic pathway for both TG and RP and inconsistent with intraplasmic RP transfer. This corroborates reports on compromised chylomicron clearance in heterozygotes. We conclude that RP is an appropriate representative marker for intestinally derived particles in LpL-deficient or partially deficient individuals.
Newer variants and simulants of basal cell carcinoma, Basal cell carcinoma (BCC) has characteristic clinical and histopathologic findings that facilitate accurate diagnosis. There are. however. many variants and simulants of BCC that may cause clinical and/or histopathologic confusion. These entities often have features in common with BCC. with nodular or sclerosing basaloid islands. peripheral palisading. stromal retraction. (pseudo)-glandular formation. and/or prominent mucin. Recently described BCC variants. including signet-ring BCC and granular cell BCC. are discussed. Less commonly appreciated basaloid simulants. including ameloblastoma. cloacogenic carcinoma. and mucinous carcinoma. are described. Distinguishing among these variants and simulants of BCC is important because treatment and prognosis of each may vary.
Growth of human basal cell carcinomas transplanted to C57/Balb/C bgJ/bgJ nu/nu (beige-nude) mice, The purpose of this study was to measure growth parameters of transplanted basal cell carcinoma (BCC) to beige-nude mice during a 4-month observation time. Forty male beige-nude mice were transplanted with human BCC with our reported subcutaneous implantation technique. Initial volume and wet weight were determined for each tumor. The tumors were measured every 2 weeks by calipers with a final volume determined at 120 days. at which time the tumors were harvested. weighed. and processed for routine histology. Thirty-two tumor sites were positive for persistent tumor at harvest. Tumor volumes declined by an average of 51% and average tumor weight by 33%. There were increased numbers of mast cells surrounding the BCC tumor lobules. These results indicate that BCC can survive for 120 days in the beige-nude mouse.
Adjuncts to scalp reduction surgery. Intraoperative tissue expanders and hyaluronidase, Scalp reduction has become an important part of the cosmetic surgeon's armamentarium in the treatment of male pattern alopecia. Recently. the use of two-stage tissue expansion has been advocated for scalp reduction. Intraoperative tissue expansion obviates many of the disadvantages of delayed expansion and increases the yield of excised scalp by 20-30% over standard reduction techniques in the 20 patients studied. The addition of hyaluronidase to the local anesthetic facilitates its diffusion. enhancing anesthesia and the ease of dissection. Therefore. the use of intraoperative tissue expansion and the addition of hyaluronidase to the local anesthetic are two separate adjuncts to scalp reduction surgery.
Diagnostic and therapeutic nail surgery, The function of the nail unit is as a protective covering over the dorsal distal end of the digit. Some basic disease processes affecting the nail unit and the surgical techniques used for diagnosis and treatment are reviewed.
Current issues in the performance of Mohs micrographic surgery, Recently. a survey was sent to all members of the American College of Mohs Micrographic Surgery and Cutaneous Oncology concerning their performance of Mohs micrographic surgery. Responses to numerous questions regarding the daily practice of this technique revealed that many useful modifications have evolved over the years that serve to enhance the efficacy and the efficiency of the original Mohs surgical procedure. The results of this survey are presented and discussed.
The relation of dizziness to functional decline, OBJECTIVE: to assess the effect of dizziness on the probability that an older person will die or become functionally disabled within 2 years. Dizziness is a common symptom for which the prognosis is uncertain. This report compares the prognoses for dizzy and not-dizzy older people in order to assist clinicians who diagnose and treat these patients. DESIGN: a prospective study of a representative sample of elderly (70+) non-institutionalized Americans. Elderly subjects (n = 3.798) in the Longitudinal Study of Aging (LSOA) were asked questions about the presence of dizziness. medical conditions. and functional disability in 1984. The cohort was reinterviewed about functional disability in 1986. OUTCOME MEASURE: transition from functional ability to disability after 2 years. RESULTS: Bivariate analyses showed that dizziness predicts functional decline but not mortality. Multivariate models revealed that age. race. sensory impairment. vascular disease. and other morbidity are independent predictors of becoming disabled. Controlling for these potential confounders. dizziness does not predict an increased probability of becoming disabled. CONCLUSION: Elderly people who are dizzy should be evaluated for the presence of these related conditions.
The ethics of pressure sore prevention and treatment in the elderly: a practical approach, The management of pressure sores in elderly patients raises a number of ethical dilemmas for health care professionals. Aggressive treatment of advanced pressure sores is often inconsistent with the overall goals of therapy. Private and public funding for effective prevention and early treatment are restricted and constrained. Little information is available that proves treatment efficacy. Health care professionals and their institutions are often stigmatized by the occurrence of a pressure sore even though accountabilities may lie in the natural history of the disease. We use case analysis to identify ethical dilemmas in pressure sore prevention and management and suggest a framework for ethical decisionmaking so that health care professionals and public policy analysts can make informed judgments about patients and standards of quality care.
Oral cancer screening in the elderly, Oral cancers represent approximately 3% of all cancers diagnosed in the United States. Oral cancer is one-fifth as common as cancer of the breast. colon. and lung but more than twice as common as cervical cancer. Incidence rates for oral cancer are highest among older men. Epidemiologic data identify alcohol and tobacco as major risk factors associated with the disease. Screening for oral cancer is a simple. non-invasive procedure which can be easily incorporated into the comprehensive assessment of older patients. Oral cancer screening can detect early. localized lesions which are associated with an improved prognosis. Five-year survival rates are more than four times greater in individuals with localized lesions than those with distant metastases. Since older Americans visit their physician more often than their dentist. the physician's medical examination provides an excellent opportunity to screen for oral cancers.
Clinical studies of sucralfate in reflux esophagitis. The European experience, Reflux esophagitis is encountered quite frequently in clinical practice. Symptoms can be mild. moderate. or severe and complications can occur. particularly if the disorder is untreated or undertreated. Treatment is aimed at relieving symptoms. healing lesions. and preventing complications. Various pharmacologic options are available for treatment. including antacids. alginate/antacid compounds. acid-reducing agents. prokinetic drugs. and agents that protect the mucosa. This article reviews a number of clinical studies evaluating sucralfate in the treatment of reflux esophagitis. Almost all of the investigations were conducted in Europe and encompassed open-label studies. placebo-controlled trials. and comparative studies. From the studies discussed. it can be concluded that sucralfate not only has a place in the treatment of peptic ulcer disease. but is also effective in treating reflux esophagitis. Sucralfate is comparable to H2-receptor antagonists in symptom improvement and healing rates. In addition. the studies reviewed have shown sucralfate to be safe and well tolerated.
Non-acid mechanisms of gastric and duodenal ulcer formation, The pathophysiology of gastric and duodenal ulcer disease has two sides: the aggressive attack. principally by the highly corrosive gastric acid; and the defending forces of mucus. mucosal resistance. and other protective substances and functions. This report reviews the roles of both the attacking and defending forces in the pathophysiology of ulcer disease. It also discusses how an early notion of ulcer formation (e.g.. the Schwarz dictum of "no acid. no ulcer." first published in 1910) became the slogan by which ulcer disease was understood and from which therapy took its cue. Subsequent work has since found that the Schwarz dictum holds for duodenal ulcer. but not for gastric ulcer. Non-acid mechanisms of ulcer formation--i.e.. impairment of at least one of the defending or protective forces--are also described. as are treatment approaches to ulcer disease. Although suppression of acid secretion is a mainstay of treatment. agents that safely and effectively strengthen the defense are being used more frequently. There are signs that the safe limits for acid-suppressing therapy have been reached or passed. On the other hand. the search for therapy that strengthens the defensive factors has only begun.
Pathogenesis and management of gastroesophageal reflux disease, Several pathophysiologic abnormalities known to be associated with the development of gastroesophageal reflux disease (GERD) are reviewed. Among them are the contributions of lower esophageal sphincter pressure. length. and relaxation. the role of hiatal hernia. delayed esophageal acid clearance. and impaired esophageal mucosal resistance. Gastric factors--volume. secretion. the character of the refluxant. and the rate of gastric emptying--also play a role in the pathogenesis of GERD. Treatment requires an individualized approach based on the extent of the symptoms. esophagitis. and other reflux complications. Three phases of treatment--lifestyle modifications. pharmacologic manipulation. and surgery--are discussed. as is maintenance therapy and prevention of recurrent disease.
Special diagnostic and therapeutic considerations in elderly patients with upper gastrointestinal disease, Special diagnostic and therapeutic considerations apply to older patients with upper gastrointestinal disease. Age-related anatomical and physiologic changes occur in the major organ systems. affecting functions as diverse as swallowing and hepatic and renal clearance of therapeutic drugs. Because of these factors. and because older patients are more likely to be receiving multiple drugs for concomitant illness. they are more prone to drug-drug interactions and to medication-induced injury of the esophagus and stomach. In addition. several gastrointestinal disorders. notably gastroesophageal reflux and peptic ulcer disease. are commonly seen in the elderly. This report reviews those age-related system changes that affect the gastrointestinal tract. and also reviews the esophageal and gastric disorders that are common and/or particularly problematic in the elderly. Diagnostic techniques to evaluate gastrointestinal disease in older patients and approaches to therapy for this population are described as well.
Stereotactic radiosurgery for arteriovenous malformations of the brain, Stereotactic radiosurgery successfully obliterates carefully selected arteriovenous malformations (AVM's) of the brain. In an initial 3-year experience using the 201-source cobalt-60 gamma knife at the University of Pittsburgh. 227 patients with AVM's were treated. Symptoms at presentation included prior hemorrhage in 143 patients (63%). headache in 104 (46%). and seizures in 70 (31%). Neurological deficits were present in 102 patients (45%). Prior surgical resection (resulting in subtotal removal) had been performed in 36 patients (16%). In 47 selected patients (21%). embolization procedures were performed in an attempt to reduce the AVM size prior to radiosurgery. The lesions were classified according to the Spetzler grading system: 64 (28%) were Grade VI (inoperable). 22 (10%) were Grade IV. 90 (40%) were Grade III. 43 (19%) were Grade II. and eight (4%) were Grade I. With the aid of computer imaging-integrated isodose plans for single-treatment irradiation. total coverage of the AVM nidus was possible in 216 patients (95%). The location and volume of the AVM were the most important factors for the selection of radiation dose. Magnetic resonance (MR) imaging was performed at 6-month intervals in 161 patients. Seventeen patients who had MR evidence of complete obliteration underwent angiography within 3 months of imaging: in 14 (82%) complete obliteration was confirmation being 4 months (mean 17 months) after radiosurgery. The 2-year obliteration rates according to volume were: all eight (100%) AVM's less than 1 cu cm; 22 (85%) of 26 AVM's of 1 to 4 cu cm; and seven (58%) of 12 AVM's greater than 4 cu cm. Magnetic resonance imaging revealed postirradiation changes in 38 (24%) of 161 patients at a mean interval of 10.2 months after radiosurgery; only 10 (26%) of those 38 patients were symptomatic. In the entire series. two patients developed permanent new neurological deficits believed to be treatment-related. Two patients died of repeat hemorrhage at 6 and 23 months after treatment during the latency interval prior to obliteration. Stereotactic radiosurgery is an important method to obliterate AVM's. especially those previously considered inoperable. Success and complication risks are related to the AVM location and the volume treated.
Determination of cerebrospinal fluid shunt obstruction with magnetic resonance phase imaging, The cerebrospinal fluid (CSF) flow rates in 12 patients with symptoms suggestive of CSF shunt obstruction were measured with magnetic resonance (MR) phase imaging. The shunts were imaged over the skull. just distal to any reservoir. using a curved surface coil. Images perpendicular to the direction of flow were made on a 1.5-tesla clinical unit with a flow-sensitive pulse sequence. The patients' ages ranged from 2 months to 28 years. All patients had ancillary investigations to determine the functional status of the shunt. No flow was detected in seven patients with blocked shunts. Flow rates between 3 and 40 cc/hr were found in three patients with functioning shunts. Two patients. one with a blocked shunt and one with a functioning shunt. could not be imaged due to motion artifact. Magnetic resonance phase imaging is a promising technique in the determination of CSF shunt obstruction.
Malignant astrocytomas: focal tumor recurrence after focal external beam radiation therapy, Hochberg and Pruitt have reported glioblastomas recurring within 2 cm of the primary site in 90% of patients after whole-brain radiation therapy. They suggested that computerized tomography (CT) scan accuracy would permit smaller radiation fields. A treatment protocol with smaller-field focal brain irradiation following surgical resection is reported. The first 4500 cGy of radiation is focused to within a 3-cm margin around the tumor. with a 1500-cGy boost within a 1.5-cm margin. Forty-two patients with grade III or IV astrocytoma. treated with focal brain radiation therapy were reviewed retrospectively to assess patterns of tumor recurrence. Thirty patients received intra-arterial bromodeoxyuridine (BUdR) radiosensitization with focal brain radiation therapy. and 12 patients underwent conventional focal brain radiation therapy. Tumor margin was defined on preoperative and recurrence CT scans as the contrast-enhanced area; these were traced on acetate templates and compared with each other and with the actual scans. In all 42 patients. the lesion recurred within a 2-cm margin of the original tumor. Four patients had two recurrent areas: the second area was within the 2-cm margin in two. and outside this margin in two. These results are similar to those of Hochberg and Pruitt. It is suggested that focal irradiation is now the optimal treatment for malignant astrocytoma. Since recurrences continue to be within the irradiated volumes. it appears that higher focal doses of radiation are appropriate for clinical treatment trials of malignant astrocytomas.
Medulloblastoma: freedom from relapse longer than 8 years--a therapeutic cure, Seventy-seven patients presenting with medulloblastoma between 1958 and 1986 were treated at Stanford University Medical Center and studied retrospectively. Multimodality therapy utilized surgical extirpation followed by megavoltage irradiation. In 15 cases chemotherapy was used as adjunctive treatment. The 10- and 15-year actuarial survival rates were both 41% with an 18-year maximum follow-up period (median 4.75 years). There were no treatment failures after 8 years of tumor-free survival. Gross total removal of tumor was achieved in 22 patients (32%); the surgical mortality rate was 3.9%. No significant difference was noted in the incidence of metastatic disease between shunted and nonshunted patients. The classical form of medulloblastoma was present in 67% of cases while the desmoplastic subtype was found in 16%. Survival rates were best for patients presenting after 1970. for those with desmoplastic tumors. and for patients receiving high-dose irradiation (greater than or equal to 5000 cGy) to the posterior fossa. Although early data on freedom from relapse suggested a possible beneficial effect from chemotherapy. long-term follow-up results showed no advantage from this modality of treatment. The patterns of relapse and survival were examined; 64% of relapses occurred within the central nervous system. and Collins' rule was applicable in 83% of cases beyond the period of risk. Although patients treated for recurrent disease could be palliated. none were long-term survivors. The study data indicate that freedom from relapse beyond 8 years from diagnosis can be considered as a cure in this disease. Long-term follow-up monitoring is essential to determine efficacy of treatment and to assess survival patterns accurately.
Symptomatic subependymoma: a clinicopathological and flow cytometric study, Twenty-one intracranial subependymomas were reviewed with regard to presentation. diagnosis. operative findings. and long-term follow-up data. The histopathological features were critically reviewed. and deoxyribunucleic acid analysis was performed by flow cytometry. The patients' mean age was 48.5 years (range 32 to 72 years). In 14 cases the tumor was located in the fourth ventricle. in six within a lateral ventricle. and in one in the third ventricle with extension into the lateral ventricle. Radiographic characteristics included isodensity with minimal enhancement on computerized tomography. frequent dystrophic calcification. and isointensity on T1-weighted or slight hyperintensity on T2-weighted magnetic resonance images. The predominant histological features in all cases were those of classic subependymoma. Nonetheless. pathological examination showed a minor (less than 20%) ependymoma component in five cases. significant cytological atypia in seven. mitoses in 11. endothelial prominence in four. and focal hemorrhage-associated necrosis in two. Flow cytometry revealed a diploid pattern in 12 patients. tetraploidy in two. and aneuploidy in one. Two patients died in the perioperative period. Of the remaining 19. 12 underwent gross total resection (two of whom received postoperative irradiation) and seven underwent subtotal resection (five of whom received irradiation). None of the 12 non-irradiated patients developed tumor progression or died of direct tumor-related causes. Of the seven irradiated patients. follow-up imaging studies demonstrated their tumors to be radioresponsive. particularly with doses of 5000 cGy or greater. Despite the presence of cytological atypia and mitotic activity in the majority of cases. the prognostic effects of such factors as tumor location and the extent of surgical resection outweighed those of the standard histopathological parameters. Routine postoperative irradiation is not recommended. but should be reserved for cases with a symptomatic residual or recurrent subependymomas following surgery.
"Angioglioma" and the arteriovenous malformation-glioma association, The term "angioglioma" denotes a highly vascular glioma. most of which are low-grade lesions associated with a favorable prognosis. The authors encountered an example of this pathology. a cystic oligodendroglioma associated with prominent vasculature which both clinically and histologically mimicked an occult arteriovenous malformation (AVM). This case and reports of the association of AVM and glioma prompted a histological review of 1034 surgically resected AVM's. both angiographically occult and visible. among which no oligodendroglial or astrocytic forms of "angioglioma" were found. Eight cases were observed. however. wherein oligodendroglial cells were increased in number within or about the malformation. Two basic histological patterns of oligodendroglial cell excess were seen; one appeared to be malformative in nature with abnormal disposition of oligodendroglial cells being an integral part of the AVM. whereas in the other an apparent increase in cellularity seemed the result of chronic ischemia with condensation of white matter. It appeared that the areas of increased oligodendrocyte content seen in association with AVM are non-neoplastic lesions that exhibit two rather distinct histological patterns of differing origin. In an effort to determine the frequency of "angioglioma." the authors examined Tissue Registry data for several glioma groups in which highly vascular examples are prone to occur. Tumors selected for study included 104 cerebellar-type (pilocytic) astrocytomas. 82 oligodendrogliomas. and 51 supratentorial pilocytic astrocytomas. Histological hypervascularity mimicking a vascular malformation (that is. an "angioglioma") was encountered in 5%. 4%. and 12% of the cases. respectively. Based upon clinical. radiological. and pathological reviews of these cases. as well as a careful review of the literature. it was concluded that 1) "angiogliomas" are neither rare nor represent a distinct clinicopathological entity; 2) in histological but not necessarily angiographic surgical terms. they represent simply highly vascular gliomas. usually of low grade; and 3) the clinicopathological and angiographic features as well as the prognosis of such lesions do not differ from those of similar gliomas without angioma-like vasculature. Finally. "angiogliomas" must not be confused with gliomas of high-grade malignancy which. due to neovascularity. may be highly vascular at angiography and at surgery.
Effects of recombinant human tumor necrosis factor on rodent gliomas and normal brain, In a study examining the possible therapeutic effects of recombinant human tumor necrosis factor-alpha (rHuTNF-alpha) on malignant gliomas without expression of tumor necrosis factor (TNF)-receptors. RG-2 glioma cells were tested in vitro as well as in a rat experimental glioma model. A growth inhibition assay revealed no inhibiting effect in vitro up to a concentration of 20 micrograms/ml rHuTNF-alpha. Receptor-binding studies showed that RG-2 cells did not present specific receptors for rHuTNF-alpha. The pharmacokinetics of rHuTNF-alpha after intravenous injection were studied with respect to serum. tissue. and brain tumor concentrations and showed increased glioma concentrations of (mean +/- standard error of the mean) 0.47 +/- 0.18 ng TNF/mg brain compared to 0.15 +/- 0.05 ng TNF/mg brain in the normal contralateral hemisphere. No therapeutic effect on solid RG-2 gliomas could be observed after stereotactic injection of 7.3 micrograms rHuTNF/10 microliter buffer solution into the tumor in 10 animals. Immunohistochemical studies after stereotactic injection of rHuTNF-alpha showed total disappearance of the substance after 24 hours without internalization into tumor cells. Stereotactic injection of 7.3 micrograms rHuTNF 10 microliters into normal brain resulted in marked inflammatory response around the injection track. including microvascular thrombosis. These results demonstrate that rHuTNF has neither direct nor indirect cytotoxic activity on RG-2 glioma cells. Furthermore. before clinical use of rHuTNF-alpha in malignant gliomas. the authors suggest that receptor studies be done in each patient. In receptor-positive patients undergoing treatment with rHuTNF-alpha. precautions should be taken to prevent local encephalitic reactions.
Reduction of central nervous system ischemic injury by monoclonal antibody to intercellular adhesion molecule, Activated leukocytes appear to be directly involved in potentiating ischemic central nervous system (CNS) injury. Adhesion of leukocytes to endothelium is essential for their migration and requires the binding of adhesion receptors of the leukocyte (CD 18) to an intercellular adhesion molecule (ICAM) on endothelium. Monoclonal antibodies to an ICAM can block leukocyte adhesion and transendothelial migration. To determine the efficacy of anti-ICAM antibody treatment in preserving neurological function after CNS ischemia. two animal models were used. A 1-mg/kg dose of anti-ICAM was given to rabbits 30 minutes before induction of ischemia either in the spinal cord using temporary aortic occlusion or in the brain using intra-arterial microspheres. In this study. treatment with anti-ICAM produced a significant reduction in neurological deficits in the reversible spinal cord ischemia model but not in the irreversible brain ischemia model. This protective effect supports the active role of leukocytes in CNS reperfusion ischemic injury and offers potential for future therapy.
Spontaneous dissecting aneurysms of the basilar artery presenting with a subarachnoid hemorrhage. Report of two cases, A spontaneous dissecting aneurysm of the basilar artery is a rare disorder. usually presenting with ischemia rather than a subarachnoid hemorrhage (SAH). Two cases are described of a dissecting aneurysm of the basilar artery presenting with an SAH. Vertebral angiography revealed a double lumen to the basilar artery. Magnetic resonance (MR) imaging detected the intramural hematoma. One patient was treated conservatively. and the other underwent operative intervention with wrapping of the aneurysm. The usefulness of MR imaging in the diagnosis and the treatment options are discussed.
Curative treatment of scalp arteriovenous fistulas by direct puncture and embolization with absolute alcohol. Report of three cases, Three cases of direct arteriovenous fistulas of the scalp (two involving cirsoid aneurysms) are presented. All three patients were treated with direct puncture of the venous pouch and injection of absolute ethyl alcohol during compression of the venous outflow of the fistula. Two of the three patients were cured with this treatment alone. The third patient. with a very high-flow giant fistula. required injection of glue to close the fistula and subsequent surgical extirpation of the resulting hard mass lesion.
Successful excision of a juvenile-type spinal arteriovenous malformation following intraoperative embolization. Case report, The case of a 57-year-old woman with a 14-year history of progressive paraparesis is presented. Selective spinal angiography revealed a juvenile-type spinal arteriovenous malformation (AVM) with a typical large size and rapid flow. The AVM was located primarily in the retromedullary space at the cervicothoracic junction. The AVM was successfully obliterated by intraoperative embolization using isobutyl-2-cyanoacrylate and surgical excision.
Embolization of arteriovenous malformations with peripheral aneurysms using ethylene vinyl alcohol copolymer. Report of three cases, The authors report three cases of arteriovenous malformations (AVM's) with aneurysms arising from the feeding artery; all were successfully treated with a new nonadhesive liquid embolic material. ethylene vinyl alcohol copolymer (EVAL). In two patients the AVM's were totally removed without difficulty. and in one the AVM was managed conservatively after embolization. No new neurological deficits appeared during or after embolization. After road-mapping techniques. EVAL was injected slowly until the feeding artery and aneurysm were completely obliterated. This embolic agent is easy to handle and is considered safe compared with other adhesive liquid embolic agents. such as isobutyl-2-cyanoacrylate or n-butyl cyanoacrylate. It is concluded that EVAL is an excellent agent for embolizing an AVM with a peripheral aneurysm on the feeding artery.
The effect of a chlorhexidine rinse on the incidence of alveolar osteitis following the surgical removal of impacted mandibular third molars, A prospective randomized double-blind placebo-controlled study was conducted with 139 patients (278 bilaterally impacted mandibular third molars) to determine the effect of a perioperative 0.12% chlorhexidine gluconate rinse on the incidence of alveolar osteitis following surgical removal of impacted mandibular third molars. A statistically significant 60% reduction in the incidence of alveolar osteitis was obtained in the chlorhexidine group compared with the placebo group. In most subgroups analyzed. chlorhexidine was associated with at least a 50% reduction in alveolar osteitis compared with control groups.
Cardiohemodynamic and serum catecholamine response to surgical removal of impacted mandibular third molars under local anesthesia: a randomized double-blind parallel group and crossover study, The aim of this study was to differentiate between the extent to which surgical stress and the epinephrine in local anesthetic solutions influence serum catecholamine. cAMP. and potassium levels. and contribute to changes in cardiohemodynamic parameters. One hundred sixty mg of articaine hydrochloride (4.0 mL of a 4% articaine hydrochloride solution) with two different epinephrine doses was injected into outpatients prior to removal of an impacted mandibular third molar in a randomized. double-blind parallel group and crossover design. The results showed that the amount of epinephrine absorbed from the intraoral injection site predominantly determined the serum epinephrine concentration. The anesthetic-induced increase in the serum epinephrine level did not correlate with changes in the cardiohemodynamic parameters under study at any time during the operative procedure. The serum cAMP changes correlated with those of epinephrine. whereas the serum potassium levels remained unchanged. The procedure of tooth extraction was a stressful event when the 1:200.000 epinephrine-containing anesthetic solution was used. showing that the risk of inducing a cardiovascular incident during oral surgery seems to be higher the greater the extent of operation and the lower the epinephrine dose in the anesthetic solution.
An epidemiologic and anatomic survey of odontogenic infections, An 81-month review of patients with infections of odontogenic origin admitted to the oral and maxillofacial surgery service at a county hospital and teaching facility in northeast Ohio is presented. Age. sex. race. etiology. pathogens isolated. admission temperature. and admission white blood cell count were identified and related to the anatomic space(s) encountered. Multispace and single-space infections occurred with equal distribution. In both the multispace and single-space infections. the submandibular and buccal spaces were most frequently involved. Males were affected with single-space infections twice as often as females. An equal distribution among sexes was found in multispace infections. The most common age range for all infections was 25 to 30 years. alpha-Hemolytic streptococci. Bacteroides melaninogenicus. and beta-hemolytic streptococci were the most frequently isolated pathogens. Third molars were the prevalent cause in both multispace and single-space infections that required hospital admission.
Histomorphometric study of trabecular bone remodeling during condylar process fracture healing in the growing period: experimental study, Trabecular bone remodeling during condylar fracture healing in the growing period was analyzed by histomorphometry with a synchronous system. Data from the study showed displacement of the fractured condyle was compensated by the changes in remodeling ascribed to the pubertal spurt of growth. and that such remodeling still continued even after clinical healing. The regional acceleratory phenomenon. evolved to potentiate tissue healing. was observed 1 week after induction of the fracture. Mesenchymal cells were presumably modulated into chondroblasts that promoted endochondral ossification. It was concluded that trabecular bone remodeling plays an important role in healing of condylar fractures during the growth period.
Progesterone receptor gene restriction fragment length polymorphisms in human breast tumors, We examined the progesterone receptor (PgR) gene in tissue from both primary human breast tumors and normal placentas. detecting restriction fragment length polymorphisms (RFLPs) with the restriction endonucleases Pst I/Sst I and HindIII. There was a general agreement of the Pst I and Sst I polymorphisms in any individual tumor. suggesting that they define two alleles in the human PgR locus. one being characterized by a deletion of about 300 base pairs with respect to the other. Both primary human breast tumor specimens (n = 36) and human term placentas (n = 48) displayed similar allele frequencies and typical mendelian distribution of these Pst I/Sst I alleles. The previously reported HindIII PgR RFLP was also investigated in 132 breast tumors. The HindIII PgR gene RFLP did not display typical mendelian distribution in the breast tumors; the factors affecting the HindIII allele frequencies are presently unknown. Neither the HindIII RFLP nor the deletion defined by Pst I and Sst I correlated with PgR expression as determined by a ligand-binding assay. suggesting that neither is related to the heterogeneity of PgR expression seen in breast tumors.
Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy, Prophylactic treatment with the anti-estrogen tamoxifen may reduce the risk of breast cancer because estrogens are thought to act as promoters in the pathogenesis of the disease. This article presents results on the incidence of contralateral new primary tumors among 1846 postmenopausal breast cancer patients included in a randomized trial of adjuvant tamoxifen therapy for 2 or 5 years after surgery versus no adjuvant endocrine therapy. The median follow-up was 7 years (range. 3-13 years). There was a significant reduction of contralateral breast cancer in the 931 patients in the tamoxifen group versus that in the 915 control patients (29 versus 47 cases. respectively; P = .03). The cumulative incidence at 10 years in the tamoxifen group and the control group was 5% and 8%. respectively. Analysis of the relative hazard of contralateral tumor over time showed that the benefit with tamoxifen therapy was greatest during the first 1-2 years. but there was a continued risk reduction during the entire follow-up period. i.e.. more than 10 years after cessation of treatment. There was no significant difference in the number of contralateral cancers in the patients randomly assigned to 2 or 5 years of treatment. but the 95% confidence interval of the relative hazard was wide. The proportion of estrogen receptor-negative contralateral breast cancers was higher in the tamoxifen group than in the control group. There was no difference. however. between the two groups in recurrence-free survival time from the diagnosis of the contralateral cancer.
Tumor cell adhesion to endothelial cells: endothelial leukocyte adhesion molecule-1 as an inducible adhesive receptor specific for colon carcinoma cells, Activation of endothelial cells by the two inflammatory mediators interleukin-1 (IL-1) and tumor necrosis factor strongly increases tumor cell adhesion. We describe antibody inhibition studies showing that the endothelial leukocyte adhesion molecule-1 (ELAM-1). a cell-surface glycoprotein selectively expressed by cytokine-activated endothelial cells and responsible for neutrophil adhesion. is the major. if not the only. mediator of colon carcinoma cell adhesion to activated endothelial cells. Among the different tumor cell lines tested. seven colon carcinoma cell lines were sensitive to ELAM-1 antibodies. Adhesion of melanoma. osteosarcoma. and lung. cervix. or kidney carcinoma cell lines to IL-1-treated endothelial cells was not affected by the ELAM-1 antibody. This result suggests that ELAM-1 is selectively recognized by colon carcinoma cells and that adhesion of tumor cells to activated endothelial cells could be mediated by different and specific mechanisms.
Physical activity and risk of developing colorectal cancer among college alumni, The assessment of physical activity at a single time to evaluate its association with cancer may be limited. since such a measure may not adequately reflect activity over the long term. To overcome this limitation. we studied 17.148 Harvard alumni aged 30-79 years who were followed prospectively for the occurrence of colon cancer (n = 225) and rectal cancer (n = 44) from 1965 through 1988. Physical activity. based on self-reported stair climbing. walking. and sports play. was assessed in either 1962 or 1966 (1962/1966) and again in 1977. The increased activity evaluated using either assessment (1962/1966 or 1977) taken alone was not associated with risk of colon cancer. However. alumni who were highly active (energy expenditure of greater than 2500 kilocalories/wk) at both assessments had half the risk of developing colon cancer relative to those who were inactive (less than 1000 kilocalories/wk) at both assessments (age-adjusted rate ratio = 0.50; 90% confidence interval = 0.27-0.93). whereas those who were moderately active (1000-2500 kilocalories/wk) at both assessments had an age-adjusted rate ratio of 0.52 (90% confidence interval = 0.28-0.94). We conclude that either consistently higher levels of activity are necessary to protect against colon cancer or combining two assessments increased the precision of physical activity measurement. We found no evidence that increased physical activity protected against rectal cancer.
Increased therapeutic index of antineoplastic drugs in combination with intracellular histamine antagonists, L-Histidinol. a protein synthesis inhibitor and structural analogue of L-histidine. has been demonstrated in chemotherapy-treated mice to be cytoprotective to normal stem cells but to enhance cytotoxicity to tumor cells. N.N-Diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine.HCl (DPPE) is an antagonist of recently described microsomal and nuclear intracellular histamine receptors implicated in the mediation of proliferation and modulation of prostaglandin synthesis. DPPE is cytotoxic to tumor cells in vitro and cytoprotective to the gut in vivo. Noting the similar pharmacologic profiles for histidinol and DPPE and the structural resemblance between histidinol and histamine. we tested 1) whether binding to intracellular histamine receptors may be important to the action of histidinol. 2) whether there exists a differential effect of DPPE and histidinol on proliferating normal and transformed or malignant cells. and 3) whether DPPE. like histidinol. protects host cells from the effects of chemotherapy while augmenting tumor cell kill in vivo. It was observed that histidinol does compete at intracellular histamine receptors in isolated microsomes and nuclei. but with significantly lower affinity than DPPE. Nevertheless. for each agent. potency at intracellular histamine receptors correlates with potency to inhibit DNA and protein synthesis. without cytotoxicity. in normal mitogen-stimulated murine lymphocytes and to kill transformed mouse lymphocytes or MCF-7 human breast cancer cells. As demonstrated previously for histidinol (1-2 g/kg). DPPE (4 mg/kg) protected murine bone marrow progenitors from doxorubicin or fluorouracil. while doses of 4-50 mg/kg significantly enhanced the antitumor activity of doxorubicin and daunorubicin in murine models of early cancer. One postulate to explain the effects of intracellular histamine receptor ligands is that intracellular histamine mediates DNA and protein synthesis. possibly through a downward modulation of growth-inhibitory prostaglandin levels. Antagonism of the intracellular action of histamine at intracellular histamine receptors by DPPE or histidinol may result in differential perturbations of growth/eicosanoid metabolism in normal and malignant cells. thus forming the basis of a new approach to chemotherapy.
Mechanisms of glove tears and sharp injuries among surgical personnel, OBJECTIVE.--The development of strategies to prevent exposure to blood for operating room personnel has been hampered by a lack of knowledge about the specific mechanisms of exposure. The purpose of this study was to classify the mechanisms of glove tears and sharp injuries in the operating room. DESIGN.--During a 3-month period. a nurse interviewed operating room personnel immediately after a glove tear or sharp injury had occurred. SETTING.--Yale-New Haven (Conn) Hospital is a tertiary care teaching hospital. RESULTS.--There were 249 glove tears and 70 sharp injuries. Visible skin contact with the patient's blood occurred in 156 glove tears (63%). The mechanism causing the tear could be identified in only 81 (33%). For 230 glove tears (92%). personnel were wearing single gloves. Of 70 sharp injuries. 47 (67%) were caused by needles and usually occurred during suturing. The following three mechanisms accounted for 40 sharp injuries (57%): (1) hands injured while stationary and holding an instrument. 11 (16%)-a position of risk not previously identified; (2) hands injured while retracting tissue. 12 (17%); and (3) injuries caused by sharp instruments not being used. 17 (24%). Instrument passage caused only four sharp injuries (6%). CONCLUSIONS.--The majority of glove tears have an unknown mechanism. and alteration in the manufacture or number of gloves worn may be helpful in reducing cutaneous blood exposures. The identification of specific mechanisms of sharp injuries should lead to effective strategies to prevent exposure to the human immunodeficiency virus and other blood-borne pathogens in the operating room.
Estimating an individual's true cholesterol level and response to intervention, An individual's blood cholesterol measurement may differ from the true level because of short-term biological and technical measurement variability. Using data on the within-individual and population variance of serum cholesterol. we addressed the following clinical concerns: Given a cholesterol measurement. what is the individual's likely true level? The confidence interval for the true level is wide and asymmetrical around extreme measurements because of regression to the mean. Of particular concern is the misclassification of people with a screening measurement below 5.2 mmol/L who may be advised that their cholesterol level is "desirable" when their true level warrants further action To what extent does blood cholesterol change in response to an intervention? In general. confidence intervals are too wide to allow decision making and patient feedback about an individual's cholesterol response to a dietary intervention. even with multiple measurements. If no change is observed in an individual's cholesterol value based on three measurements before and three after dietary intervention. the 80% confidence interval ranges from a true increase of 4% to a true decrease of 9%.
Urine collection from disposable nappies, Urine was collected for microscopy and culture by standard use of sterile adhesive bags and by extraction from wet disposable nappies from 45 patients aged 1 to 23 months. Urine can readily be obtained by compression of wet nappy fibres within a 20 ml syringe if highly absorbent brands that contain gel beads are avoided. Red and white cell numbers were reduced on light microscopy of specimens obtained from nappies. but bacterial counts were unchanged. On culture. 6 children were shown to have urinary tract infections by both methods; of the children who did not have a urine infection. the contamination rate was lower from nappy collections (10/39 vs 17/39 from urine bags). Biochemical analysis of urine collected from 11 older children showed very close correlation for sodium. potassium. urea. and creatinine concentrations and osmolality between freshly voided urine and samples obtained after they were soaked into disposable nappies for 3 h and reclaimed. although there was greater variation for measurements of calcium and phosphate. Extraction of urine from disposable nappies put on within 4 h and which are not soiled by faeces is an inexpensive. rapid. and simple method to collect urine from young children for culture. microscopy for bacteria. and biochemical analysis.
Functional evaluation following microvascular oromandibular reconstruction of the oral cancer patient: a comparative study of reconstructed and nonreconstructed patients, Over the past decade. the use of free flap transfers in head and neck surgery has led to remarkable advances in the reliability and the ultimate results of oromandibular reconstruction. Stable and retentive dental restorations have been achieved using enosseous implants placed directly into the vascularized bone flaps. However. the functional assessment of patients who underwent primary mandibular reconstruction with these techniques has not been previously reported. A group of 10 reconstructed and 10 nonreconstructed segmental hemimandibulectomy patients were compared using a battery of tests to assess their overall well-being. cosmesis. deglutition. oral competence. speech. length of hospitalization. and dental rehabilitation. In addition. objective measures of the masticatory apparatus (interincisal opening. bite force. chewing performance. and chewing stroke) were used to compare these two groups as well as normal healthy subjects and edentulous patients restored with conventional and implant-borne dentures. The results show a clear advantage for the reconstructed patients in almost all categories. Persistent problems and future directions in oromandibular reconstruction are discussed.
Quantifying the spread of botulinum toxin through muscle fascia, Botulinum toxin was recently approved for treating several head and neck dystonias. Paralysis of neighboring muscles is the major complication of its use. Spread of toxin from the injected muscle has been suggested as an etiology. This study examines how botulinum toxin crosses muscle fascia by a novel method of quantifying muscular paralysis. Botulinum toxin (0.2 to 10 U) was placed onto the fascia of rat tibialis anterior (TA) muscles (n = 6). Toxin was also placed on dose-matched muscles that had their fascia surgically removed (n = 6). Twenty-four hours later. the nerve to the tibialis anterior was electrically stimulated to deplete the muscle fibers of glycogen. Toxin-paralyzed fibers retained their glycogen and appeared purple on periodic acid-Schiff (PAS) stain. Botulinum toxin easily passed through muscle fascia even at subclinical doses. The presence of fascia reduced the spread of botulinum toxin by 23%. These results suggest that spread of botulinum toxin can be prevented only by delivering small doses to the center of a target muscle.
Otoacoustic emissions in normal and hearing-impaired children and normal adults, Although distortion-product otoacoustic emissions (DPOEs) have been studied in adults recently. there is little information regarding them in young children. DPOEs and click-evoked otoacoustic emissions (CEOEs) were measured from a same group of normal and hearing-impaired children (age 4 through 10 years) and normal adults (age 22 through 29 years). Measurements of DPOEs in 13 children's ears with normal hearing showed higher levels of emissions in the 700- to 1400-Hz and 5.7-kHz regions relative to the data obtained in 10 normal adult ears. The 22 ears of children with sensorineural hearing loss demonstrated agreement between pure-tone audiograms and "DPOE audiograms." Measurements of CEOEs revealed that the average level of emission in 15 normal-hearing children's ears was slightly lower than that previously obtained in newborns. but slightly higher than that of adults. In children. the CEOE spectral components in the 4- to 6-kHz region were lower than in newborns. but higher than in adults. These results support the view that the DPOEs and CEOEs comprise a valuable tool in assessment of cochlear function in subjects of all ages.
Introduction: physiologic adaptations to exercise training in cardiac patients: contemporary issues and concerns, This symposium dealt with contemporary issues and concerns in cardiac rehabilitation. Selected topics included: the potential of exercise training to enhance coronary collateral circulation; safety and efficacy of high intensity training; influence of beta-blocking agents on exercise prescription and trainability; value of physical conditioning in patients with left ventricular dysfunction or cardiac transplantation; and the effect of exercise on serum lipids and lipoproteins. Each article attempted to assimilate the physiologically germane literature in an area and provide the reader with associated clinical and practical implications.
Exercise training and coronary collateral circulation, This review examines the potential for an exercise-induced increase in coronary collateral circulation. with specific reference to the role and functional significance of collateral vessels. highlighting animal and human studies in particular. and their inherent methodological limitations. Exercise training may enhance myocardial oxygen supply by promoting transient periods of myocardial ischemia. a potent trigger of collateral growth. Some human studies have shown that moderate-to-high intensity training can result in a higher double product at the onset of angina and/or ischemic ST-segment depression. suggesting that myocardial oxygen supply has increased. Attempts to use thallium-201 exercise scintigraphy to assess myocardial perfusion before and after a physical training program have produced conflicting data. whereas angiographic studies in group trials have. without exception. yielded disappointing results. Thus. direct evidence that exercise stimulates collateralization in humans is lacking.
Exercise training in patients with impaired left ventricular function, Advances in the understanding of the pathophysiology of congestive heart failure have guided efforts in formulating effective treatment strategies. The epidemiology. etiology. and medical management of congestive failure are reviewed. The changing approaches to exercise and exercise training in patients with heart failure are discussed. Recent studies of the impact of exercise training in this important patient group are presented.
Physiologic adaptations to prolonged high-intensity exercise training in patients with coronary artery disease, Exercise training elicits numerous beneficial adaptations in patients with coronary artery disease (CAD). but until 10 yr ago these adaptations were generally believed to be peripheral adaptations rather than improvements in myocardial blood supply. However. animal models of CAD have been shown to elicit improvements in myocardial blood flow and left ventricular performance with prolonged. intense exercise training. More recently we have provided electrocardiographic. echocardiographic hemodynamic. and radionuclide evidence of central cardiovascular adaptations in patients with CAD after a year-long program of 1 h of exercise at 70-90% of VO2max 5 d.wk(-1). These training-induced adaptations are consistent with an improvement in myocardial oxygenation and concomitantly an enhanced left ventricular function in these patients. This program also resulted in improvements in glucose tolerance. insulin sensitivity. and plasma lipoprotein-lipid profile. We have also shown that these beneficial cardiovascular and metabolic adaptations are maintained during six additional years of training in patients with CAD. These results do not imply that all patients with CAD should initiate such an intense training program. but rather that. in selected patients undergoing a training stimulus well in excess of that conventionally prescribed for coronary patients. the training-induced adaptations may be substantially greater than previously believed.
Effect of beta-blockers on exercise physiology: implications for exercise training, We conducted a series of studies aimed at investigating the effect of beta-blockers on exercise physiology. On the basis of these and other existing studies. it is possible to draw the following conclusions and to make the following tentative recommendations for patients engaged in exercise training who receive beta-blocker therapy: i) CAD patients treated with beta-blockers are capable of deriving the expected enhancement of cardiorespiratory fitness during training. irrespective of the type of drug used; ii) beta1-selective blockers are preferable to nonselective agents for hypertensive patients engaged in exercise training; iii) because beta1-selective blockers impair exercise tolerance in some hypertensive patients. physicians should look out for this adverse reaction and. if present. consider alternative antihypertensive therapy; iv) intrinsic sympathomimetic activity confers no advantage during exercise training; v) exercise intensity prescription for patients receiving beta-blockers should be in accordance with traditional guidelines and based on results of individualized exercise testing performed on medication; vi) exercise training is desirable during beta-blocker therapy in that it appears to offset adverse alterations in lipoprotein metabolism; and vii) nonselective beta-blockers may increase predisposition to exertional hyperthermia. and patients must therefore be encouraged to adhere strictly to accepted guidelines for heat injury prevention.
Exercise training after cardiac transplantation, During the last decade. cardiac transplantation has become the accepted form of treatment for selected patients with end-stage heart disease. which usually results from dilated cardiomyopathy or coronary artery disease. Although 5-yr survival is currently 85%. patients have complicated courses after surgery. with an ever present risk of infection and graft rejection. Because of physical inactivity and severe limitation of cardiac output preoperatively. these deconditioned patients are excellent candidates for medically supervised rehabilitative exercise training programs. Denervation of the myocardium. which occurs with cardiac transplantation. results in a loss of autonomic nervous system modulation of cardiac output. with reliance on circulating catecholamines and with a delayed heart rate and cardiac output response to the onset of exercise. Oxygen uptake kinetics are prolonged. and maximal oxygen uptake is reduced. Additional abnormalities in cardiac and pulmonary artery pressures and in ventilation during exercise have been described. The literature contains seven studies concerning the effects of exercise training in cardiac transplant recipients. Benefits resulting from training include increases in maximal oxygen uptake. peak exercise power output. anaerobic threshold. and lean body mass. reduced perceived exertion. heart rate. and blood pressure during submaximal exercise. and a lowered resting heart rate and blood pressure. There are no data to suggest that exercise training alters the incidence of infection or rejection or improves longevity or return to pre-illness lifestyle.
Effects of exercise training on glucose control, lipid metabolism, and insulin sensitivity in hypertriglyceridemia and non-insulin dependent diabetes mellitus, Exercise training has potential benefits for patients with hyperlipidemia and/or non-insulin dependent diabetes mellitus. In nondiabetic. nonobese subjects with hypertriglyceridemia. exercise training alone increased insulin sensitivity. improved glucose tolerance. and lowered serum triglyceride and cholesterol levels. These improvements did not occur when exercise training alone was given to similar patients with impaired glucose tolerance. In severely obese (X = 125 kg) subjects without diabetes melitus. a 600 calorie diet alone decreased glucose and insulin concentrations and improved glucose tolerance but did not increase insulin sensitivity. The addition of exercise training improved insulin sensitivity. Obese. non-insulin dependent diabetes mellitus subjects on sulfonylurea therapy alone increased insulin levels but failed to improve insulin sensitivity or glucose levels. In contrast. the addition of exercise training to this medication resulted in improved insulin sensitivity and lowered glucose levels. We conclude that exercise training has major effects on lowering triglyceride levels in hyperlipidemic subjects and can potentiate the effect of diet or drug therapy on glucose metabolism in patients with non-insulin dependent diabetes mellitus.
Ventilatory response to sustained hypoxia during exercise, The ventilatory stimulating effects of hypoxia occurring at carotid bodies are potentiated by exercise. However. hypoxia also has central ventilatory depressive effects; the potential interactions between this hypoxic depression and exercise have not been studied. We examined the ventilatory response to a 20 min period of isocapnic hypoxia (end-tidal O2. PETO2. of 50 mm Hg). preceded and followed by a 5 min period of isocapnic hyperoxia in seven normal adult males at rest and during moderate exercise (45-75 W). When hypoxia was introduced at rest (PETO2 = 42 mmHg). ventilation initially increased from 13.73 +/- 3.04 (mean +/- SD) to 23.69 +/- 5.48 1.min-1 and then slowly declined to 19.01 +/- 4.68 1 min-1. The increase was caused by increases in tidal volume and respiratory frequency. but the decline was solely in tidal volume. During a background of moderate exercise (PETCO2 = 46 mmHg). introduction of hypoxia caused ventilation to increase from 30.84 +/- 6.31 to 56.44 +/- 10.58 1.min-1. Ventilation subsequently did not decline; at the end of the hypoxic period. ventilation was 57.06 +/- 12.59 1.min-1. The increase was also associated with an increase in tidal volume and respiratory frequency. as seen as rest. but with much larger magnitudes. Despite the absence of ventilatory decline. there was still a decline in tidal volume. but it was compensated by an increase in respiratory frequency. We conclude that exercise potentiated the acute ventilatory response to hypoxia by modifying both tidal volume and respiratory frequency but that exercise abolished or greatly reduced hypoxic decline by increasing respiratory rate.
Development of human neural transplantation, The possibility of altering the course of Parkinson's disease by brain grafting is slowly becoming a reality through the efforts of many research groups worldwide. It has been shown that this procedure. as performed in high-level medical research centers. usually produces no permanent adverse effects and can effectively ameliorate parkinsonian signs in certain patients. This progress has served to reinforce our commitment to develop neural transplantation into an effective therapy to treat such a devastating neurodegenerative disease. We have summarized the most important events that have shaped the initial phase of this research. In the course of the last 4 years. considerable knowledge has been gained in the clinical neurosciences regarding the real potential of various brain grafting procedures in treating Parkinson's disease. their shortcomings. and their usefulness in carefully selected patients. There is still no consensus regarding the various fundamental aspects of human brain grafting in Parkinson's disease. Questions concerning surgical technique. candidate selection. the optimal brain regions for implantation. the optimal tissue for implantation. and the real usefulness of brain grafting must be addressed. The importance of the quality of adrenal medulla fragments for grafting. the requirement for immunosuppressors in fetal brain grafting. and the optimal fetal age and the amount of donor tissue for effective grafting are additional areas of concern. The potential of xenografting. preserved tissues. and genetically engineered cells for human brain grafting remain unanswered. The development of human neural transplantation is the responsibility and privilege of neurosurgery.
The effect of nicardipine on vasospasm in rabbit basilar artery after subarachnoid hemorrhage, This study was performed to examine the effect of the dihydropyridine calcium antagonist. nicardipine. on vasospasm after experimental subarachnoid hemorrhage (SAH) in the rabbit. The study was carried out in two parts: 1) effect of intravenous nicardipine (n = 45) and 2) effect of intracisternal nicardipine (n = 21). SAH was induced by injecting 5 ml of autologous arterial blood into the cisterna magna. In the intravenous study. there were five groups: 1) SAH without treatment; 2) SAH with vehicle (saline); 3) SAH and intravenous infusion of low-dose nicardipine (0.01 mg/kg/h); 4) SAH and intravenous infusion of high-dose nicardipine (0.15 mg/kg/h); and 5) controls without SAH. The intravenous infusions were started immediately after SAH and continued for 48 hours until death. In the intracisternal study. there were three groups: 1) SAH without treatment; 2) SAH with intracisternal administration of nicardipine (0.37 mg/h); and 3) controls without SAH. Intracisternal infusions were begun 70 hours after SAH and continued for 2 hours until death. After perfusion-fixation. the basilar artery was removed and processed for morphometric analysis. In the intravenous study. vessels from animals subjected to SAH were significantly narrowed when compared with controls. although after high-dose nicardipine vessel caliber was slightly larger than in the other SAH groups. Animals given intracisternal nicardipine showed a nonsignificant reduction of caliber as compared with controls: only 12% decrease in diameter and 22% decrease in luminal area. In the rabbit SAH model. nicardipine had a very modest effect on vasospasm at the doses tested.
Nucleolar organizer regions in vascular and neoplastic cells of human gliomas, The number of nucleolar organizer regions in vascular cells and neoplastic cells of human gliomas was counted by a combined staining technique: one-step silver colloid method for nucleolar organizer region-associated argyrophilic protein (AgNOR) and periodic acid-Schiff staining for basement membrane of vascular components. The number of AgNORs (mean +/- SD) in the vascular and neoplastic cells of various tumors tested was as follows: benign astrocytoma (Grade 2. n = 4). 1.52 +/- 0.07 and 1.80 +/- 0.13. respectively; anaplastic astrocytoma (Grade 3. n = 7). 1.98 +/- 0.23 and 2.87 +/- 0.50; and glioblastoma multiforme (Grade 4. n = 11). 2.05 +/- 0.29 and 3.13 +/- 1.13. AgNOR scores in vascular cells of benign astrocytomas. anaplastic astrocytomas. and glioblastomas were significantly higher than those of vascular cells in normal brain tissue without neoplastic alteration (1.26 +/- 0.05; n = 3; P less than 0.01. P less than 0.001. and P less than 0.001. respectively). Moreover. the AgNOR scores of vascular cells in high-grade gliomas (Grades 3 and 4) were significantly higher than those in low-grade gliomas (Grade 2) (P less than 0.01). These results indicate that the proliferative activity of both vascular and neoplastic cells in gliomas increased as histological malignancy advanced. and that the quantification of AgNORs was useful in evaluating proliferative activity in vascular cells as well as in assessing the malignancy of neoplastic tissues.
Elevated cortical venous pressure in hydrocephalus, To gain a better understanding of cerebrospinal fluid (CSF) hydrodynamics and their relationship to the cerebrovascular system. normal and naturally hydrocephalic dogs were studied to determine transmantle [lateral ventricle (LV) to subarachnoid space] and transparenchymal [LV to cortical vein (CV)] pressures. Pressure was also measured in the sagittal sinus. cisterna magna. and femoral artery. CV pressure has not previously been measured in hydrocephalus. Ventricular volume was determined by computed tomography. Four groups of animals were studied. In Group 1 (n = 5) transmantle pressure was measured; in Group 2 (n = 5). transparenchymal pressure in normal animals was measured. In Group 3 (n = 5) was measured all the pressures in spontaneously normal animals. and in Group 4 (n = 6) was measured the pressures in hydrocephalic animals. The pressure-volume index and CSF outflow resistance were also measured. LV volume in the normal dogs was 1.3 +/- 0.7 ml and in the hydrocephalic dogs was 5.1 +/- 2.7 ml (P less than 0.005). Although LV. subarachnoid space. and sagittal sinus pressures were elevated in the hydrocephalic dogs (15.1 versus 10.2. 16.4 versus 10.5. and 8.4 versus 5.2 mm Hg. respectively). the transmantle pressure and subarachnoid space to sagittal sinus gradients were not significantly altered. CV pressure was markedly elevated in the hydrocephalic animals (21.5 versus 11.7 mm Hg. P less than 0.005). The pressure-volume index and outflow resistance were not significantly different. These results suggest that an elevated CV pressure plays a role in the development and/or maintenance of hydrocephalus. and that the pathway for CSF absorption includes transcapillary or transvenular absorption of CSF from the interstitial space.
The effect of apnea on brain compliance and intracranial pressure, The effect of 2 minutes of apnea during endotracheal intubation on intracranial pressure (ICP). compliance. and cerebral blood volume (CBV) was studied in 19 adult dogs during normo-. hypo-. and hypercapnia. The compliance was measured from the cisterna magna in response to an intrathecal bolus injection (pressure-volume index). CBV was monitored by radiolabeled red blood cell activity. These measurements were made before and after 2 minutes of apnea. At normocapnia (pCO2 of 35-40 mm Hg). a period of apnea resulted in an increase in ICP from 9.6 to 26.3 mm Hg. a decrease in compliance from 0.051 to 0.020 ml/mm Hg (60%). and an increase in CBV of 0.26 ml (9.6%). When the animals were hypocapnic (pCO2 of 24-28 mm Hg). ICP increased from 12.8 to 19.6 mm Hg. compliance fell from 0.041 to 0.029 ml/mm Hg(29%). and CBV increased 0.07 ml (3.1%). Hypercapnia (pCO2 of 50-58 mm Hg) before apnea resulted in an increase in ICP from 21.5 to 47.1 mm Hg. a decrease in compliance from 0.032 to 0.015 ml/mm Hg (52%). and an increase in CBV of 0.41 ml (13.4%). These results suggest that hyperventilation (hypocapnia) before intubation limits the adverse decrease in brain compliance and increase in ICP by reducing changes in cerebral blood volume.
Dissecting aneurysm of the posterior cerebral artery: spontaneous resolution, Dissecting aneurysms of the intracranial arteries display vascular pathological features that appear sporadically. generally affecting young adults. The clinical features of this condition may involve both ischemic episodes and hemorrhages. Posterior circulation is affected less than the rest of the intracranial arteries. and it is extremely rare to find the posterior cerebral arteries only affected. Mortality is high in patients where the lesion is located in the posterior intracranial circulation. although dissecting aneurysms limited to the posterior cerebral arteries may. to a certain extent. be benign. We report the case of a young woman with ischemia in the territory of the posterior cerebral artery that occurred subsequent to a dissecting aneurysm that resolved spontaneously to a complete remission. both clinically and as demonstrated by angiography. A review of the literature is made. analyzing the pathogenic. clinical. angiographic. and therapeutic characteristics of such lesions.
Managing the cleft lip and palate patient, We have attempted to elucidate. first through an examination of the basic science of clefting and then through a description of the roles of the various members of the cleft palate team. an understanding of the multiplicity of problems faced by this heterogeneous group of children with cleft lip or palate. With an incidence of cleft of 1 in 700 births. all practicing pediatricians will at some time be faced with a patient with a cleft. Pediatric management begins in the hospital nursery by ruling out possible associated anomalies (e.g.. congenital heart disease or urinary tract) or syndromes. At the same time. cleft palate nursers may be needed to overcome feeding problems. Simultaneously. counseling for the family begins with a positive attitude toward outcome and an initial explanation of the schedule of corrective procedures. i.e.. lip repair at 3 months of age and palate repair at about 1 year. The counseling should incorporate an understanding of the cause of clefting. both its genetics and teratogenetics. and then proceed to noting the actual recurrence risks of 1% for a new cleft and 16% if there is a positive family history in a first-degree relative. The recurrence risks in recognized syndromes may follow mendelian patterns. Later. the pediatrician can help the family deal with multiple ear infections and the likely need for tympanostomy tubes. anticipating the need for tubes in a way that might facilitate placement at the time of anesthesia for the lip or the palate repairs. An understanding of the speech and language difficulties that may be encountered in later infancy may relieve parental anxiety. Later. after palate repair. knowledge of velopharyngeal incompetence may avert premature hypernasal speech problems caused by adenoidectomy. which should be avoided if at all possible. The pediatrician needs to be aware of the tooth malformations that accompany clefting of the alveolus as well as the increased susceptibility to caries. so that the family may be directed to early intervention by the pediatric dentist. With support by pediatrics of the efforts of pediatric dentistry. the child is then in optimal condition for orthodontics. Continually keeping the child's emotional adjustment in mind. the pediatrician can encourage the child and family. knowing that with palatal expansion techniques plus possible bone graft surgery to the cleft alveolus at about 9 years of age. the child may be orthodontically corrected to very near normal.(ABSTRACT TRUNCATED AT 400 WORDS).
Identifying normal and abnormal development of dental occlusion, Abnormalities of occlusal development manifest themselves clinically as a need for orthodontic treatment. There are many circumstances in which there is an interaction between traditional pediatric concerns and occlusal abnormalities. In some cases medical treatment impacts on the development of occlusion. In other cases. occlusal abnormalities contribute to clinical conditions seemingly far removed from the dentition.
The role of the pediatrician in identifying and treating dental caries, Although dental caries has been reduced greatly in the last two generations. this infectious disease persists. The pediatrician can play a direct and indirect role in preventing dental caries. The pediatrician can provide counseling on feeding practices to prevent baby bottle tooth decay as well as identify children at risk. Dental caries of the grooves of molar teeth now accounts for dental caries in more children than any other form of caries. Dental sealants are recommended to coat the grooves and prevent dental caries. Restoration of decayed teeth is the most direct means of treating dental caries.
Periodontal health and disease in children and adolescents, The prevention and treatment of periodontal diseases in children and adolescents are most desirable and the physician should be involved in the achievement of these goals. Furthermore. cooperation between the physician and the dentist may be imperative for the comprehensive treatment of some patients. One should be aware of the influence of the general growth and development of the periodontium in order to be able to differentiate between health and disease. Periodontal diseases in children and adolescents include chronic gingivitis. gingival recession. chronic periodontitis. prepubertal periodontitis. juvenile periodontitis. and cases with peculiar causes. The main cause for periodontal diseases is the microorganisms in the dental plaque. In addition. the systemic status of the individual may affect the response of the periodontal tissues and vice versa. The physician and dentist should cooperate with the purpose of providing comprehensive prevention. diagnosis. and treatment of periodontal diseases and systemic diseases.
Preventive oral health care for the infant, child, and adolescent, Although we have the knowledge and technology necessary to prevent it. most children experience dental disease. and a few children continue to experience high rates of decay. The appropriateness and effectiveness of preventive measures vary throughout the life of a child. and recommendations should be tailored to the needs of the individual. Water fluoridation continues to be the most cost-effective preventive measure available. For patients who do not have access to fluoridated water. dietary supplementation offers similar benefits. A wide variety of professionally applied and home use topical fluoride products such as dentrifrices. gels. and rinses can also reduce the risk of dental caries. particularly on the smooth surfaces of the teeth. The most common site of decay in children is the fissures of the molar teeth. These areas can be protected by the professional application of plastic sealants. Dietary practices influence caries rates. and patients should be advised to limit the frequency of carbohydrate exposures rather than the total amount of carbohydrates consumed. Parents of infants should be advised to discontinue bottle feeding around the age of 12 months to avoid nursing caries. Although oral hygiene practices are not as effective in reducing caries rates as is generally believed. daily toothbrushing and flossing are unquestionably effective in preventing periodontal disease. In order to be maximally effective. preventive efforts should be initiated early in the life of the child. Although most children experience dental disease. a mouth free of caries and periodontal disease is a potentially attainable goal for all children when they use currently available techniques.
Oral habits. A behavioral approach, Thumb-sucking. pacifier use. and other oral habits are not so harmful or beneficial to the child to justify ill-timed aggressive discontinuance. Indeed there is ample time to guide the child to forming desired behaviors. In nearly every case success in habit management depends on the child making a personal commitment to discontinue the habit. Control can be placed in the child's hands after that decision is made.
Invasion of the neurovascular bundle by prostate cancer: evaluation with MR imaging, Preservation of the neurovascular bundle (NVB) and potency without compromising tumor control are current objectives of radical retropubic prostatectomy as treatment for prostate cancer. but preoperative determination of whether cancer has invaded the NVB can be difficult. The use of conventional body-coil magnetic resonance (MR) imaging to make this preoperative determination was evaluated in 50 patients with biopsy-proved cancer. All patients underwent radical retropubic prostatectomy after MR imaging. MR imaging. surgical. and pathologic data were correlated relative to tumor location and volume. Gleason grade. presence of capsular penetration. and depth of NVB invasion. The sensitivity of MR imaging for invasion was 68%. specificity was 59%. and overall accuracy was 64%. Results of this study indicate that MR imaging can help identify the NVB and predict invasion of the NVB by tumor. but the usefulness of the technique is limited by the lack of spatial resolution associated with use of the whole-body coil.
Idiopathic intractable epistaxis: endovascular therapy, Thirty patients with intractable idiopathic epistaxis were treated with endovascular therapy. Embolization of the internal maxillary artery controlled the epistaxis in 87% of the patients. and the success rate was increased to 97% after supplemental embolization of the facial artery. The only complication observed was transient postembolization hemiparesis. which occurred in one of the 30 patients. Intractable idiopathic epistaxis is defined as epistaxis of unknown cause that is refractory to nasal packing. Such epistaxis is commonly treated with surgical intervention. including ligation of the terminal segments of the internal maxillary artery and the ethmoid arteries. An alternative approach is performance of endovascular therapy. In our opinion. embolization is a safe and effective procedure when it is carried out by appropriately trained personnel. In most patients. its performance requires use of only neuroleptanalgesia; surgery can be avoided. and the duration of hospitalization is significantly shortened. We recommend that embolization be adopted as the primary modality for the treatment of idiopathic intractable epistaxis.
Comparison of CT, low-field-strength MR imaging, and high-field-strength MR imaging. Work in progress, To assess objectively the sensitivity and specificity of low-field-strength (0.064 T) magnetic resonance (MR) imaging. a prospective blind study of 280 examinations was performed to compare low-field-strength MR imaging with computed tomography (CT) and with high-field-strength (1.5-T) MR imaging of the cranium. The sensitivity (defined as the true-positive rate) with high-field MR imaging was superior to that with low-field MR imaging and CT in helping detect overall abnormalities. Sensitivities were generally similar over a broad range of specific cranial central nervous system diseases. Low-field and high-field MR imaging were equivalent in the blind diagnoses of neoplasms and white matter disease. whereas low-field MR and CT were equivalent in the blind diagnoses of contusion. subdural and epidural hematoma. sinus disease. normality. and abnormality. The specificities with low-field MR imaging and CT were substantially better than those with high-field MR imaging.
In utero analysis of fetal growth: a sonographic weight standard, Regression analysis was used to develop an in utero fetal weight model from a population of 392 predominantly middle-class white patients with certain menstrual histories. There was a gradual increase in fetal weight from 35 g at 10 weeks to 3.619 g at 40 weeks. with uniform variance of +/- 12.7% (1 standard deviation) throughout gestation. When tested against the estimated weights of 1.771 chromosomally normal fetuses between 14 and 21 weeks. the mean percent difference was 0.8% and the average absolute percent error was 3.3%. When compared with actual delivery data for 163 fetuses in the group. the mean percent difference was 0.8% and the average absolute percent error was 1.1%. These data are compared with other prenatal weight curves obtained at ultrasound and with data from several large postnatal weight studies.
Occult breast masses: use of a mammographic localizing grid for US evaluation, To determine if there was a problem of misidentification of mammographically detected masses with freehand ultrasound (US). the authors examined 50 mammographically distinct masses in 47 patients who were scheduled to undergo needle localization. In only six cases were the masses to be localized in an area of the breast that contained other mammographic opacities that could have led to problems of identification. The patients were first studied with freehand US. Results were then compared with those subsequently obtained with a fenestrated mammographic compression grid to guide the US evaluation. Needle localization was then performed. In five of 50 cases. masses detected with freehand US and initially believed to correspond to the mammographically detected mass were subsequently found to represent different areas of the breast when US was used with the compression grid. These results suggest that the potential for misidentification of masses with freehand US is real and that a mammographic grid localization device can be used to overcome this problem.
Air enema for diagnosis and reduction of intussusception: clinical experience and pressure correlates, Air enema was used for exclusion. diagnosis. initial movement. and complete reduction of intussusception in 186 pediatric patients. Average pressure needed for initial movement of intussusception was 56.5 mm Hg; average maximum pressure of 97.8 mm Hg was required for complete reduction. Average fluoroscopy time required for intussusception reduction was 94.8 seconds; an average of 41.8 seconds was required to exclude intussusception. Intussusception was diagnosed in 75 patients. and reduction was accomplished in 65 (87%). Of 100 consecutive patients that underwent hydrostatic reduction of intussusception at the authors' institution. reduction was successful in 55. Compared with hydrostatic enema. air enema involves shorter fluoroscopy time and lower radiation dose to the patient. Air enema is safe and effective for diagnosis and treatment of intussusception in infants and children and has replaced hydrostatic enema for such procedures at the authors' institution.
Metabolic and destructive brain disorders in children: findings with localized proton MR spectroscopy, The diagnostic potential of volume-selective proton magnetic resonance (MR) spectroscopy in vivo was evaluated in 20 children and young adults with various neurodegenerative brain disorders. All patients were examined with MR spectroscopy in conjunction with MR imaging of the brain on a whole-body imager at 1.5 T. Comparison of spectra in our patients with those of children with normal myelination (prominent signals from N-acetylaspartate [NAA]. creatine/phosphocreatine. and choline) revealed a marked decrease of NAA in 12 of 17 patients with focal or generalized demyelination. In patients with Canavan disease. NAA signal intensity was markedly increased. but no choline signal was found. Increased signal intensity from lactate occurred in patients with Leigh disease. neuroaxonal dystrophy. Schilder disease. and Cockayne disease. which indicated a disturbed energy metabolism in the examined region. These results demonstrate that proton MR spectroscopy can be applied in a clinical environment to facilitate diagnosis of hereditary and acquired brain disorders in children.
Blunt splenic injuries: nonsurgical treatment with CT, arteriography, and transcatheter arterial embolization of the splenic artery, The management and outcome of blunt splenic injury diagnosed with computed tomography (CT) were studied in 44 consecutive patients who were hemodynamically stable or whose condition stabilized rapidly with resuscitation. Celiac and splenic arteriography was used in the triage of patients for nonsurgical treatment or for hemostasis. Patients without arterial extravasation of contrast material at arteriography were treated with bed rest only (group 1. n = 19); patients who had such extravasation were treated with bed rest after percutaneous transcatheter coil occlusion of the proximal splenic artery (group 2. n = 17). Abdominal exploration without angiography or embolotherapy was begun if the patient or attending surgeon did not agree with the treatment protocol (group 3. n = 8). Treatment with bed rest alone was successful in 18 patients. Clinical control of hemorrhage was accomplished in all patients in group 2 and one patient in group 1. Thus. exploratory laparotomy was avoided in 34 of 36 patients (94%) in whom nonoperative management was attempted; splenic salvage was achieved in 35 of 36 patients (97%).
Early hepatocellular carcinoma: MR imaging, All areas in hepatic lesions designated as adenomatous hyperplasia (AH) with malignant foci have recently been recognized as cancer. AH with malignant foci can be classified into two types. depending on the presence of overt cancerous nodules. Lesions without macroscopic nodules are defined as early hepatocellular carcinoma (HCC). while those with a macroscopic component are defined as HCC with early components. A comparative study of early HCC and HCC with early components was performed with magnetic resonance imaging. Early HCC lesions (n = 20) were isointense (n = 11) and hyperintense (n = 9) on T1-weighted spin-echo images and isointense (n = 17). partially hyperintense (n = 2). or hypointense (n = 1) on T2-weighted spin-echo images relative to the surrounding liver. Lesions classified as HCC with early components (n = 8) were hyperintense (n = 5). isointense (n = 2). and of mixed signal intensity (n = 1) on T2-weighted images. T1-weighted imaging was superior to T2-weighted imaging in depicting early HCC. but the latter could be useful in evaluating the progression of HCC in the histopathologically early stages.
Volvulus of the splenic flexure: radiographic features, Six cases of splenic flexure volvulus were studied over a 14-year period. The patients were aged 15-62 years. Five of the six patients were mentally retarded. lifelong residents of a long-term-care institution. Two patients had congenital absence of normal colonic attachments; the other four patients had elongated mesocolons. presumably from chronic constipation. All patients underwent abdominal radiography. followed by a barium enema study. In the appropriate clinical setting. radiographic diagnosis of a splenic flexure volvulus is suggested when the following are seen: (a) a markedly dilated. air-filled colon wtih an abrupt termination at the anatomic splenic flexure; (b) two widely separated air-fluid levels. one in the transverse colon and the other in the cecum; (c) an empty descending and sigmoid colon; and (d) a characteristic beak at the anatomic splenic flexure at a barium enema examination.
Clean and dirty shadowing at US: a reappraisal, Clean and dirty shadowing are common phenomena in ultrasound (US) imaging. Clean shadowing is thought to be produced by sound-absorbing materials (ie. stones). and dirty shadowing is thought to be produced by sound-reflecting materials (ie. abdominal gas). but these properties are not consistent. To evaluate the characteristics of shadows behind different objects at US. the authors scanned two renal stones and a bovine femur (each of which had part of its surface artificially smoothed or roughened) and a tissue-mimicking phantom comprising air-containing cylinders of different radii of curvature. The rougher and/or smaller the radius of curvature of the surface insonified by the sound beam. the cleaner was the shadow. independent of the composition of the underlying reflecting medium. Clean and dirty shadowing were primarily related to the properties of the surface of the shadowing object and provided little information about the structural nature of the object.
Tumor vascularization: assessment with duplex sonography, In this prospective study. the authors examined 123 patients with benign or malignant neoplasms (breast cancer. n = 44; liver neoplasms. n = 43; and tumors affecting other organs. n = 36) to establish general criteria for evaluation of neoplastic lesions by means of duplex sonography. The frequency shifts determined by means of different Doppler frequencies (2.31 or 3.75 MHz) were converted into flow velocities. Only the highest systolic peak flow velocity obtained from a lesion was used for statistical evaluation. Receiver operating characteristic curves showed that a flow velocity of 0.4 m/sec is the optimal threshold value with which to differentiate benign from malignant tumors. The data obtained in all lesions indicated that only positive findings are potentially reliable. It is concluded that negative results of sonography should not be used to diagnose the presence of a benign lesion. The resistive index of the tumors was of negligible importance.
Polyclonal human immunoglobulin G labeled with polymeric iron oxide: antibody MR imaging, Human polyclonal immunoglobulin (Ig) G was attached to a monocrystalline iron oxide nanocompound (MION). a small superparamagnetic probe developed for receptor and antibody magnetic resonance (MR) imaging. The resulting complex. MION-IgG. had a slightly negative surface charge. a molecular weight of 150-180 kDa. and 0.36 microgram of IgG attached per milligram of iron. After intravenous administration of MION-IgG to normal rats. most of the compound localized in liver. spleen. and bone marrow. In an animal model of myositis. MION-IgG caused reduced signal intensity (most apparent on T2-weighted spin-echo and gradient-echo images) at the site of inflammation. No change in signal intensity existed after an injection of unlabeled MION. Site-specific localization of MION-IgG was corroborated with scintigraphic imaging with indium-111 IgG and MION-In-111-IgG and was confirmed histologically with iron staining. These results indicate that antibody MR imaging is feasible in vivo. Target-specific and antibody MR imaging could be easily extended to other applications. including detection of cancer. infarction. and degenerative diseases.
T1-weighted snapshot gradient-echo MR imaging of the abdomen, Magnetization-prepared ultrashort-repetition-time (snapshot) gradient-echo imaging is a technique of magnetic resonance (MR) imaging with many potential applications. In the application of this technique to abdominal imaging. the effects on contrast of phase-encoding order. resolution. preparation-phase inversion time. and data-acquisition flip angle were predicted and then demonstrated with images obtained in examinations of 22 patients. In the analysis of 36 liver lesions. snapshot images were compared with corresponding T1-weighted spin-echo images on the basis of signal-to-noise ratio (S/N) of liver and contrast-to-noise ratio (C/N) between liver and lesion. Snapshot MR imaging produced abdominal images with 192 (or 256) x 256 resolution. negligible motion artifact. and C/N 1.29 times (+/- 0.48) higher than that in T1-weighted spin-echo imaging. Acquisition times were 13 seconds or less. short enough for imaging during suspended respiration. Also. use of a phased-array multicoil further improves the S/N in snapshot images without acquisition-time penalty.
Acute and chronic tears of the anterior cruciate ligament: differential features at MR imaging, To evaluate the differential features of acute and chronic tears of the anterior cruciate ligament at magnetic resonance (MR) imaging. the authors performed a retrospective evaluation of findings in 81 MR examinations correlated with results at arthroscopy. Intact anterior cruciate ligaments (ACLs) were present in 29 patients; acute complete ACL tears. in 22; and chronic complete ACL tears. in 30. Acute tears were accurately distinguished from intact ligaments and were characterized by the presence of edema. Chronic tears had a more variable appearance: Nine (30%) were depicted at MR as intact bands with low signal intensity that bridged the expected origin and insertion of the ACL. This appearance is likely due to the presence of bridging fibrous scars within the intercondylar notch. Five of these nine cases were correctly characterized as chronically torn because of the presence of focal angulation. In four of these nine cases the scarred fragments produced a relatively straight band that mimicked an intact ligament. Although chronic and acute ACL tears usually have distinct findings at MR. a chronic tear will occasionally be difficult to distinguish from an intact ligament.
Progression of meniscal degenerative changes in college football players: evaluation with MR imaging, Intrameniscal degenerative changes. presumably due to mild repetitive trauma. have been shown in many college and professional athletes. but it is uncertain over what period of time they can develop or significantly progress. To ascertain this period. the authors used magnetic resonance (MR) imaging to examine one knee in each of 20 players in the starting lineup of a major college football team before and after the season. Only asymptomatic knees (right. n = 10; left. n = 10) were examined; the images were reviewed blindly by one experienced observer without reference to the other examination. A significant progression existed in the grade of signal intensity shown in the menisci over the course of the season (P less than .001). Although this is a small study covering only 1 year. these preliminary results suggest that significant degeneration can occur in the menisci of asymptomatic players over a single season.
Exercise-induced muscle modifications: study of healthy subjects and patients with metabolic myopathies with MR imaging and P-31 spectroscopy, Exercise-induced variations in proton signal intensity at magnetic resonance (MR) imaging and in intracellular pH were studied in the forearm muscles of healthy subjects and patients with muscular glycogenoses. The relative increase in T2 was measured from MR images obtained at 0.5 T. and end-exercise pH was measured with surface coil phosphorus-31 spectroscopy at 2 T. Eight healthy subjects showed a relative increase in T2 ranging from 20% to 44% in the flexor digitorum superficialis muscle and a drop in pH ranging from 0.35 to 1.1. Seven patients with muscular glycogenosis (six with McArdle disease and one with phosphofructokinase deficiency) showed only a slight variation in T2 (0%-17%) and no decrease in pH. Variations in T2 and in end-exercise pH were found to be correlated. perhaps reflecting the stimulation of muscular perfusion caused by acidosis.
Effect of arm rotation on MR imaging of the rotator cuff, The effect of humeral rotation on the appearance of the rotator cuff tendon in oblique coronal magnetic resonance images was evaluated in 70 such images. Internal rotation produced overlap of the supraspinatus and infraspinatus tendons with soft-tissue interposition or apparent discontinuity of the tendon in 22 cases. including 14 of 15 shoulders positioned in the first 30 degrees between extreme internal and external rotation. Imaging in internal rotation makes assessment of the tendon difficult and should be avoided.
Osteoid osteoma: CT-guided percutaneous treatment, Seven patients with presumed osteoid osteoma were treated with percutaneous destruction or drill resection with computed tomographic (CT) guidance. The diagnosis of osteoid osteoma was made on the basis of findings in the clinical history and results at plain radiography. bone scintigraphy. and CT. In four patients. histologic confirmation was obtained. Hospital stay lasted from 1 to 3 days. After 11-38 months of follow-up examinations. all patients were asymptomatic. The authors report this simple procedure as an alternative to the more traditional open surgery technique.
Standards for evaluating and reporting the results of surgical and percutaneous therapy for peripheral arterial disease, By adopting precise definitions of essential terms. developing objective criteria by which the various measures of success or failure can be judged. and establishing a standardized scheme by which severity of disease. degrees of improvement or deterioration. and risk factors that affect outcome can be graded. the quality of published reports of revascularization procedures for lower extremity ischemia can be greatly improved. allowing comparative evaluation of treatment modalities.
Small, deep pelvic abscesses: definition and drainage guided with an endovaginal probe, Four small. deep pelvic abscesses were easily drained transvaginally by using an endovaginal transducer for guidance. support. and continuous monitoring of catheter placement. Collections that could not be drained percutaneously or at surgery were effectively managed with this technique. An inexpensive guide (estimated cost. $1.65) facilitated control of the catheter. All four abscesses resolved without further intervention.
Pelvic abscesses: CT-guided transrectal drainage, Percutaneous drainage of pelvic abscesses has been performed by using a number of approaches. including transabdominal. transgluteal. and transrectal. The authors present a technique for the drainage of pelvic abscesses by a transrectal route with use of computed tomographic (CT) guidance. Equipment for the technique included a plastic introducer tube. standard needle. angiographic guide wire. and pigtail catheters. The pelvic abscesses of 10 patients (six after appendectomy. three after colon resection. one secondary to diverticulitis) were successfully drained by using the new technique. No complications or recurrences were experienced. After initial catheter placement. patients were treated with use of gravity drainage and appropriate antibiotics. Success of drainage was determined with sequential CT scans. Compared with the transgluteal approach. the transrectal approach offered increased patient comfort and minimal risk of potential complications such as injury to the sciatic nerve or tracking of the abscess. Use of the plastic introducer tube promoted operator safety by protecting the guiding finger. On the basis of this initial series. CT-guided transrectal drainage appears to be an effective and well-tolerated method for the drainage of pelvic abscesses.
Total peripheral artery occlusions: conventional versus laser thermal recanalization with a hybrid probe in percutaneous angioplasty--results of a randomized trial, Increasing the primary success rate in recanalization of peripheral vascular occlusions is one aim of using laser techniques in the treatment of peripheral vascular disease. Although reports of lasers enabling recanalization after failure of guide wires have been numerous. direct comparisons of the success of the two techniques in a randomized trial have been few. The results of a randomized trial showed no statistical difference in recanalization of femoropopliteal occlusions between the conventional guide wire and hybrid laser probe. The number of patients with iliac occlusions was small and comparisons are difficult to make. but the findings suggest that the hybrid laser probe has little to offer. Immediate crossover to the alternative method allowed investigation of the relationship between the two methods in practice. Combining the two methods improved the primary success rate from 82% to 91% for femoropopliteal occlusions randomized to laser thermal recanalization and from 74% to 91% for those randomized to conventional recanalization.
Femoropopliteal arterial occlusions: laser-assisted versus conventional percutaneous transluminal angioplasty, Recanalization of 75 femoropopliteal arterial occlusions was attempted with either conventional percutaneous transluminal angioplasty (n = 28; mean occlusion length. 5.5 cm) or percutaneous laser-assisted angioplasty (PLA) (n = 47; mean occlusion length. 11.6 cm). Conventional recanalization was technically successful in 21 patients (mean occlusion length. 4.4 cm +/- 3.9) and was a technical failure in seven (mean occlusion length. 8.7 cm +/- 6.2). The technical outcome was a function of the length of the occlusion (P = .04). The PLA procedure. performed with a laser with a sapphire probe. was a technical success in 32 patients (mean length. 10.7 cm +/- 6.5) and a technical failure in 15 (mean length. 13.6 cm +/- 8.2). With PLA. the length of the occlusion did not determine the technical (P = .20) or clinical (P = .12) outcome. In patients with gangrene. PLA of occlusions longer than 5 cm failed clinically (P = .02). This PLA method appeared to be safe and allowed passage through occlusions longer than 10 cm.
Occlusive and reperfused myocardial infarcts: MR imaging differentiation with nonionic Gd-DTPA-BMA, To increase the time during which effective contrast exists between normal and infarcted myocardium. a high dose (0.6 mmol/kg) of the nonionic contrast medium gadolinium diethylenetriaminepentaacetic acid bismethylamide (Gd-DTPA-BMA) was used to distinguish between occlusive and reperfused myocardial infarctions in rats. After administration of Gd-DTPA-BMA. there was clear and persistent demarcation of both occlusive and reperfused infarcts on T1-weighted MR images. In occlusive infarcts. normal. infarcted. and periinfarcted myocardium could be identified. High signal intensity was evident for 60 minutes in a band straddling the border between infarcted and normal myocardium. namely. the periinfarction zone. In the reperfused infarct. normal and infarcted myocardium could be identified. The reperfused zone was immediately enhanced after injection of Gd-DTPA-BMA. A differential pattern of enhancement between occlusive and reperfused myocardial infarcts was evident for 1 hour. Thus. Gd-DTPA-BMA has the potential to allow (a) depiction of occlusive and reperfused acute myocardial infarcts. (b) documentation of reperfusion of myocardial infarction. and (c) distinction between occlusive and reperfused infarction.
Hemodialysis grafts: color Doppler flow imaging correlated with digital subtraction angiography and functional status, Twenty-two patients with hemodialysis grafts were prospectively evaluated with color Doppler flow imaging and digital subtraction angiography (DSA). Eighteen patients had normal functional parameters during hemodialysis. and four had increased venous pressure during hemodialysis. Color Doppler flow imaging allowed identification of nine macroaneurysms related to wall degeneration. two cases of spontaneous fistula formation between the graft and peripheral veins. and 20 stenoses. Use of color Doppler flow imaging led to overestimation of the degree of stenosis at the venous anastomosis when compared with use of angiography. Three cases of subclavian venous stenosis were identified only at angiography. Color Doppler flow imaging appears accurate in the detection of stenoses and seems sufficient for follow-up of normally functioning grafts. However. because of its low sensitivity for identification of proximal stenoses and the necessity of obtaining an angiogram to plan surgical or percutaneous correction. DSA remains the technique of choice.
Approaches to immunotherapy of cancer: characterization of lymphokines as second signals for cytotoxic T-cell generation, Lymphokines. the soluble molecules produced by cells of the immune system. regulate cell-cell interactions and. consequently. the functional status of the immune system. Altering immunoregulatory pathways with lymphokines in vivo may provide a mechanism for controlling a variety of immunologic disorders. Although normally produced in vivo in very small quantities. the widespread availability of recombinant lymphokines has made it possible to study the molecular signals involved in production of lymphocyte effectors with activity against tumor. For example. interleukin-2-based cancer immunotherapy programs have. in certain clinical situations. suggested that immunologic intervention can influence the regression of metastatic cancer. Ultimately the successful application of these biologic agents requires an understanding of the interaction between the immune system and tumor on a molecular level. To induce a given biologic effect. it is necessary both to classify the required lymphokines and to identify the relevant effector cell populations. This review will examine the progress made in identifying the requirements for lymphokine-induced cytotoxic T-lymphocyte function.
Iliofemoral venous thrombectomy followed by percutaneous closure of the temporary arteriovenous fistula, Iliofemoral venous thrombosis treated by anticoagulants alone almost invariably results in postthrombotic sequelae with deep venous reflux alone or combined with an outflow obstruction. This study evaluates the result of iliofemoral venous thrombectomy with temporary proximal arteriovenous fistula (AVF) performed on 48 consecutive patients. In 10 patients the thrombus extended in the inferior vena cava. and the thrombectomy was combined with inferior vena cava interruption. The AVF closed spontaneously in 8 of 48 patients (patency rate. 84%). An attempt to close the AVF by placing a detachable balloon percutaneously under radiographic control was made 6 to 12 weeks later (success rate. 87%; complications. rare). A preclosure arteriovenography of the femoro-iliaco-caval segment revealed 34 of 38 segments open (patency rate. 89%). Four patients had severe stenosis of the iliac segment. and a transvenous percutaneous dilatation was successfully performed in three of the four patients. keeping the fistula. At AVF closure 4 weeks later the arteriovenography showed sustained dilatation in only two patients. Thirty-seven patients were followed for 3 to 48 months (median. 24 months) and 30 of 37 patients (81%) who had no symptoms were not using compression stockings. Doppler investigation revealed patent and competent femoral and popliteal veins and normal photoplethysmography in 56% of the patients. Four iliac veins were occluded (patency rate. 88%). No recurrence of fistula had occurred. Venous iliofemoral thrombectomy seems to better preserve valve function. The percutaneous balloon closure of the AVF has decreased the complication rate. facilitated venographic evaluation of the result. and made possible the performance of percutaneous interventions under the protection of the AVF.
Cerebral hemodynamic effects of fluid resuscitation in the presence of an experimental intracranial mass, We addressed the impact on intracranial pressure (ICP) of posthemorrhage fluid resuscitation with a protocol in which additional fluid was infused to maintain a stable cardiac output after an initial bolus of fluid was infused. Anesthetized. mechanically ventilated mongrel dogs (n = 27) underwent a 30-minute interval of hemorrhagic shock (mean arterial pressure = 55 mm Hg) during which inflation of a subdural balloon maintained ICP at 15 mm Hg. After shock. animals were resuscitated with one of four randomly assigned fluids: (1) slightly hypotonic crystalloid (Na+. 125 mEq.L-1; designated Na-125); (2) hypertonic crystalloid (Na+. 250 mEq.L-1; designated Na-250); (3) slightly hypotonic crystalloid plus 10% pentastarch (Na-125P); or (4) hypertonic crystalloid plus 10% pentastarch (Na-250P). Supplemental fluid was administered as needed to maintain cardiac output comparable to baseline values. ICP increased progressively in all fluid groups during resuscitation. Cerebral blood flow. measured by the cerebral venous outflow method. increased immediately after resuscitation and then declined steadily over time in all groups. Fluids containing pentastarch maintained hemodynamic stability with minimal supplementation throughout most of the postresuscitation period. compared with crystalloid alone. which required substantial additional volume. If decreased intracranial compliance and hemorrhage are combined. ongoing resuscitation is associated with significantly increased ICP and significantly decreased cerebral blood flow. independent of the tonicity and oncotic pressure of the infused fluid.
The detrimental effects of intravenous crystalloid after aortotomy in swine, We tested the hypothesis that. after aortotomy. rapidly replacing three times the blood volume deficit with intravenous crystalloid will increase hemorrhage and decrease survival. Sixteen anesthetized Yorkshire swine underwent splenectomy and stainless steel wire placement in the infrarenal aorta and were instrumented with pulmonary artery and carotid artery catheters. The wire was pulled. producing a 5 mm aortotomy and spontaneous intraperitoneal hemorrhage. The animals had been alternately assigned to either an untreated control group (n = 8) or a treatment group (n = 8). which received 80 ml/kg lactated Ringer's solution intravenously. The volume of hemorrhage and the mortality rate were significantly increased (p less than 0.05) in the treatment group receiving lactated Ringer's solution relative to the control animals (2142 +/- 178 ml versus 783 +/- 85 ml. and eight of eight animals versus zero of eight animals. respectively). From these data we conclude that. in this model of uncontrolled arterial hemorrhage resulting from abdominal aortotomy. rapidly administering lactated Ringer's solution intravenously significantly increases hemorrhage and death.
Role of conversion of xanthine dehydrogenase to oxidase in ischemic rat liver cell injury, This study was undertaken to determine whether hepatic ischemia and the subsequent reflow of blood have any effect on the conversion of xanthine dehydrogenase to xanthine oxidase (XO). Ischemia of the liver for 90 or 120 minutes did not permit survival of the animals. XO represented 15% of the total xanthine dehydrogenase plus XO activity in the control liver. XO activity remained unchanged even after 90 minutes of hepatic ischemia. although a marked increase in lipid peroxide in the liver tissue was observed during the reperfusion. When hepatic ischemia was prolonged for 6 hours (animals were dead). XO activity rose to 35% of the total activity. Incubation of the liver at 37 degrees C resulted in a definite change in XO activity dependent on the length of incubation period. Although no significant changes occurred in XO activity during the first 2 hours of incubation. a marked XO conversion was observed between 2 and 4 hours. and a maximal conversion was achieved after 6 hours of incubation. These results suggest that XO newly generated during ischemia has a very limited role in oxygen free radical production after resuming perfusion.
Ovarian carcinoma metastatic to the breast and axillary node, Breast cancer is a common primary malignancy in women. On rare occasion the breast is also the site of metastatic disease. This report describes the evaluation of breast and axillary masses in a patient with known ovarian cancer. including the radiographic evaluation and special immunohistochemical stains with CA-125. Flow cytometric determinations and hormonal receptor analysis on both the primary and metastatic tumors demonstrate similar biologic characteristics. Both tumor sites demonstrated positive CA-125 staining. aneuploid DNA populations. moderately positive estrogen receptor content. and negative progesterone receptors. The mammogram demonstrated a well-circumscribed lesion with several areas of microcalcifications. Blood-borne metastasis from the ovary to the breast can show a varied clinical picture that can be differentiated from that of a primary breast carcinoma.
Placement of an ileal loop urinary diversion back in continuity with the intestinal tract, The use of ileum from a previously constructed urinary conduit for lengthening the small bowel has not been previously reported. We describe a patient with the short-bowel syndrome from previous small-bowel resections. radiation enteritis. and an ileal urinary diversion. The ileal conduit was revised because of recurrent hyperammonemic encephalopathy and apparent stricture of the ureteroenteric anastomosis. In an attempt to increase intestinal length. the ileal conduit was replaced by a colon conduit and the ileum was placed back in continuity with the intestinal tract. The patient had an uneventful recovery. and her chronic diarrhea. nutritional deficiencies. and metabolic derangements resolved. The ileal loop segment regained a normal intestinal appearance on radiographic studies. We suggest that when revision of an ileal urinary diversion is required restoration of the ileum into the intestinal tract may be of particular benefit to patients with the short-bowel syndrome.
Annular colon lipoma: a case report and review of the literature, Colonic lipomas are generally mildly symptomatic or asymptomatic pedunculated or sessile polyps. although they have been reported to cause intussusception or significant bleeding. The difficulty in differentiation is primarily with adenomatous polyps. We describe the unique case of a symptomatic annular colon lipoma simulating an annular colon carcinoma.
Percutaneous nephrolithotomy in transplanted kidney, Renal transplant patients with urologic complications can be managed safely with percutaneous techniques. The development of renal calculi in transplanted kidneys is uncommon. but in these cases complications such as infection and urinary tract obstruction with impairment of graft function can occur. We report 2 cases managed successfully with percutaneous nephrolithotomy.
Renal dynamics after pyeloplasty, Dismembered pyeloplasty was done on 12 renal units for ureteropelvic junction obstruction. Postoperatively. response of repaired kidney to standard diuretic dose of furosemide (0.3 mg/kg) was evaluated. Also renal pelvic pressures at rest and during diuresis were measured. All renal units responded to the diuretic by increasing their urine output an average of three times over baseline value. Renal pelvic pressure registration revealed no significant change after diuresis over baseline values. Diuretic technetium-99 DTPA renal scans were obtained two to six months postoperatively and compared with preoperative scans; the best results were obtained in renal units whose intrapelvic pressures did not exceed 10 cm of water in the immediate postoperative period.
Leiomyosarcoma of renal vein, Leiomyosarcomas arising from the renal vein are rare tumors: only 13 cases are found in the literature. We report a case in a sixty-one-year-old woman who presented with back pain and hematuria. She underwent resection of the tumor and an ipsilateral nephrectomy. The tumor recurred locally. and the patient died thirty months after diagnosis. Review of the cases reported in the literature reveals the aggressive nature of these tumors and the need for a combined therapeutic approach.
Association of Epstein-Barr virus with undifferentiated gastric carcinomas with intense lymphoid infiltration. Lymphoepithelioma-like carcinoma, Some undifferentiated gastric carcinomas with intense lymphoid infiltration have a striking resemblance to nasopharyngeal lymphoepithelioma. The authors identified eight such cases (seven patients from Japan and one from the United States) of undifferentiated gastric carcinoma (lymphoepithelioma-like carcinoma [LELC]) and examined them for Epstein-Barr (EBV) viral sequences using polymerase chain reaction (PCR) and in situ hybridization (ISH) techniques. EBV was detected in seven of the eight cases by PCR. including a lymph-node metastasis. ISH that was performed in six of these cases showed EBV genomes to be uniformly present in the carcinoma cells and not present in the reactive lymphoid infiltrate or normal gastric mucosa. PCR of a polymorphic EBV locus (lymphocyte-determined membrane antigen) showed that a single genotype was present in each gastric LELC. consistent with a clonal process. These findings suggest that some undifferentiated gastric carcinomas are EBV-related and that focal EBV infection occurs before transformation.
Transgenic oncogene mice. Tumor phenotype predicts genotype, The hypothesis that oncogenes influence tumor phenotype was tested by examining slides from 607 mammary tumors from 407 transgenic mice bearing the ras. myc. and/or neu oncogenes. Most tumors (91%) had patterns (phenotypes) that could not be classified by Dunn's standard nomenclature. The nonstandard tumors were described as eosinophilic small cell (SC). basophilic large cell (LC). or pale intermediate cell (IC). The SC tumor was associated with ras. the LC was associated with myc. and the IC was associated with neu. with specificities more than .90 and sensitivities ranging from .99 to .48. Thus. the tumor phenotype could be used to predict which oncogene was present in the animal. The presence of myc in combination with either ras or neu resulted in the predominance of LC tumors and accelerated tumorigenesis. The combination of ras and neu resulted in a decreased tumor incidence. Thus. knowledge of the oncogenes that were present could be used to predict the natural history of the disease.
Activated T-cell subsets in benign lymphoid hyperplasias and B-cell non-Hodgkin's lymphomas, Activated tumor-infiltrating T lymphocytes (TIL-T) were quantitated prospectively in excisional biopsy specimens of 49 B-cell non-Hodgkin's lymphomas (NHL) of various grades and compared with eight benign lymphoid hyperplasias (BLH) to identify any potential difference in host T-cell response. Immunotyping of tissue-cell suspensions was done by three-color flow cytometry. which was complemented by immunocytology by using cytocentrifuged preparations. Two activated T-cell subsets were studied: acutely activated TIL-T (CD3+ CD25+ HLADr-) and chronically activated TIL-T (CD3+ CD25- HLADr+). Results showed an association of the more aggressive intermediate/high-grade B-cell NHL with a higher percentage of late-phase activated TIL-T and a progressive increase with the grade of malignancy: 10.29%. 23.25%. 33.87%. and 47.78% (means) for BLH and for low-. intermediate- and high-grade B-cell NHL. respectively. Differences for this subset were significant (P less than 0.050) for the following comparisons: hyperplasia versus intermediate-grade NHL (P less than 0.0012). hyperplasia versus high-grade NHL (P less than 0.0002). and low versus high-grade NHL (P less than 0.0080). The percentage of acutely activated TIL-T cells did not show a statistically significant difference between the groups. The results suggest a host T-cell response to proliferating neoplastic cells in B-cell NHL. Paradoxically. the response does not appear to be protective for the host since the intensity is directly proportional to the grade of malignancy. However. the recognition of this response may have clinical applications since its amplification with biological response modifiers may result in effective adoptive immunotherapy of B-cell NHL. Further clarification of the specificity and biologic significance of host T-cell activation in B-cell NHL will require functional studies of isolated lymphocytic subpopulations from neoplastic tissue.
Oval cell proliferation and the origin of small hepatocytes in liver injury induced by D-galactosamine, Oval cells may function as facultative liver stem cells and tumor progenitors in liver carcinogenesis. The authors determined whether oval cells proliferate and if small hepatocytes might be generated from epithelial cell progenitors in noncarcinogenic liver injury. The authors found that oval cells similar to those detected in early carcinogenesis proliferate in response to D-galactosamine (GaIN). Oval cells expressed gamma-glutamyl transpeptidase activity. bile duct-type cytokeratins and peanut agglutinin binding. Two unusual types of hepatocytes also appeared after injury: small hepatocytes (less than or equal to 16 microns in diameter) and hepatocytes lining atypical ductlike structures. In situ hybridization studies showed that the fetal form of alphafetoprotein mRNA was expressed by many oval cells. some bile duct cells. and occasional hepatocytes. By following the fate of epithelial cells labeled early after GaIN administration. the authors conclude that duct cells can generate both oval cells and small hepatocytes in response to GaIN.
Abnormal differentiation of tissue macrophage populations in 'osteopetrosis' (op) mice defective in the production of macrophage colony-stimulating factor, Examination of the op/op mouse disclosed marked reduction and abnormal differentiation of osteoclasts in the bones and of tissue-specific macrophages in various visceral organs and tissues. Most of these macrophages were immature as judged by ultrastructural criteria. In co-cultures of normal mouse bone marrow cells with fibroblast cell lines prepared from the lungs of the op/op mice. a defective differentiation of monocytes into macrophages was confirmed. supporting previous evidence that the fibroblast cell lines of the mutant mouse failed to produce functional macrophage colony-stimulating factor (M-CSF/CSF-1). In such co-cultures. however. a small number of macrophages apparently mature under the influence of granulocyte/macrophage colony-stimulating factor (GM-CSF) produced by the op/op fibroblast cell lines. In the mutant mice. the numbers of macrophages in the uterine wall and ovaries were severely reduced. Compared with the tissues of normal littermates. those of the mutants contained about 60% fewer macrophages in many tissues. This suggests that an M-CSF-independent population of macrophages is derived from granulocyte/macrophage-colony-forming cells (GM-CFC) or earlier hematopoietic progenitors.
Comparative morphologic and immunohistochemical studies of estrogen plus alpha-naphthoflavone-induced liver tumors in Syrian hamsters and rats, Syrian hamsters were treated with ethinylestradiol and maintained on a diet containing alpha-naphthoflavone (alpha NF). a regimen that produces a high incidence of liver tumors. Morphologic analyses (light microscopy. immunoperoxidase studies. and electron microscopy) were performed on livers of these animals. After 4 months of hormone plus alpha NF treatment. marked hepatocyte cell changes were already present. as demonstrated by loss of eosinophilic staining of hepatocyte cytoplasm. Large multinucleated hepatocytes exhibiting frequent mitoses were observed around central veins. After 5 months of treatment. there was proliferation of bile ducts. and small cells with eosinophilic cytoplasm resembling hepatocytes appeared surrounding these bile ducts. At 7 to 8 months. the first tumor nodules (foci) were seen. Tumor foci in the portal area consisted of small clusters of large cells resembling hepatocytes with irregular nuclei. At the same time. dysplastic glands were identified among proliferating bile ducts. By 8 to 10 months. large tumors were present. These were trabecular hepatocellular carcinomas with widely varying individual cell morphology. Compared with adjacent liver. dysplastic glands in the portal areas. microcarcinomas. and large tumors all showed intense immunostaining for cytokeratin. Rats treated with the same regimen also developed hepatic tumors. but the light and electron microscopy results and immunohistochemical profiles were very different. Altered hepatic foci composed of small hepatocytes were typically prominent; however. malignant tumors did not arise from the portal area. Neither altered foci nor tumors stained significantly for cytokeratin. These data suggest that the biochemical events giving rise to these liver tumors differ between the species studied. despite the animals being exposed to the same treatment regimens.
Oral ketamine. Its use for mentally retarded adults requiring day care dental treatment, Four cases of severely mentally handicapped young adults requiring day care dental treatment are reported. All had required varying degrees of restraint during previous dental treatments. which had been distressing for the patient. the relatives and the ward staff. In all cases. administration of oral ketamine 10 mg/kg. 30-60 minutes before the procedure. facilitated subsequent induction of anaesthesia.
The laryngeal mask airway. An unusual complication, The laryngeal mask airway is an important addition to the anaesthetist's armamentarium. but its use is not without the possibility for misfortune. We encountered an unusual and potentially serious complication. A patient's epiglottis became trapped between the pliable grates in the mask portion of the laryngeal mask and partially obstructed his airway. Should this problem occur and remain unnoticed. in addition to the problem of airway obstruction during the anaesthetic. the oedematous epiglottis could be severely injured upon removal of the laryngeal mask. This. in turn. could result in airway obstruction requiring emergency treatment.
Inaccuracy of pulse oximetry in patients with severe tricuspid regurgitation, The accuracy of pulse oximetry was studied in a group of patients with severe tricuspid regurgitation. Measurements of arterial oxygen saturation from a finger and an ear probe were compared with those from a radial arterial blood sample analysed in vitro. Lower values were obtained using the pulse oximeter; the difference ranged from +2% to -11%. The discrepancies between pulse oximeter and laboratory oximeter readings were greater in this group of patients than in a control group who did not have tricuspid regurgitation. There was. however. no correlation between the magnitude of this discrepancy and either the peak central venous pressure or the venous pulse pressure.
Pain on intradermal injection with lignocaine. The effect of concentration, Twenty ASA 1 volunteers were each injected intradermally with four solutions containing 0.2 ml of 0.5%. 1%. and 2% lignocaine and 0.9% saline to determine whether the pain experienced on injection was related to the concentration of local anaesthetic. A 10 cm linear analogue pain scoring system was used. and the solutions were ranked from most painful to least painful. There were no differences between the different concentrations of lignocaine and 0.9% saline in the severity of pain experienced. We conclude that any concentration of lignocaine may be used intradermally before inserting intravenous catheters without affecting the degree of pain experienced by that injection.
The effect of intrathecal morphine on somatosensory evoked potentials in awake humans, Although the effect of systemic opioids on somatosensory evoked potentials has been well described. little is known about the interaction between intrathecally administered opioid analgesics and somatosensory evoked potentials. Accordingly. the influence of intrathecally administered morphine on posterior tibial nerve somatosensory cortical evoked potentials (PTSCEPs) was investigated in 22 unpremedicated. awake. neurologically normal patients scheduled to undergo elective abdominal or pelvic procedures. Patients were randomly assigned to receive either preservation-free intrathecal morphine sulfate (ITMS) or placebo. After baseline PTSCEP. heart rate and. mean blood pressure were recorded. ITMS (15 micrograms.kg-1) was injected via standard dural puncture with the patient in the lateral position. PTSCEPs. heart rate. and mean blood pressure were recorded again at 5. 10. 20. 30. 60. 90. and 120 min. Control patients were treated identically (including position. sterile preparation. and subcutaneous tissue infiltration with local anesthetic). except for lumbar puncture. and were unaware of their randomization. Before administration of ITMS. PTSCEP P1. N1. P2. N2. and P3 latencies were 39.4 +/- 3.2. 47.6 +/- 3.9. 59.2 +/- 3.2. 70.4 +/- 3.7. and 84.6 +/- 5.5 ms. (mean +/- standard deviation). respectively. The corresponding P1-N1. N1-P2. and P2-N2 amplitudes were 2.4 +/- 1.1. 2.4 +/- 1.1. and 2.3 +/- 0.9 microV. respectively. There were no significant changes over time between the control and ITMS groups. PTSCEPs resulting from left-sided stimulation were not different from those elicited by right-sided stimulation. All ITMS patients had intense postoperative analgesia for at least 24 h. It is concluded that ITMS does not affect PTSCEP waveforms in the 35-90 ms latency range during the awake state.
Effects of calcium-free solution, calcium antagonists, and the calcium agonist BAY K 8644 on mechanical responses of skeletal muscle from patients susceptible to malignant hyperthermia, The purpose of this investigation was to determine if alteration in the function of the dihydropyridine receptor may in turn modify halothane-induced contractures in muscle bundles from patients susceptible to malignant hyperthermia (MH). The effects of Ca(2+)-free Krebs Ringer (KR) solution. 5 microM verapamil. 5 microM nifedipine. and 10 microM of the Ca2+ agonist BAY K 8644 on halothane-induced contracture were therefore investigated. The halothane-induced contracture was prevented in the absence of extracellular Ca2+ and significantly reduced in the presence of verapamil or nifedipine. BAY K 8644 significantly enhanced the 0.5-. 1.0-. and 1.5-vol % halothane-induced contracture in MH-susceptible muscle bundles. When BAY K 8644 was dissolved in Ca(2+)-free KR solution. no contracture was observed in MH-susceptible muscle bundles. These results on cut MH-susceptible human muscle bundles support the hypothesis that halothane-induced contracture in MH can be modified by the binding of Ca2+ agonists or antagonists to the dihydropyridine receptor. The role of Ca2+ entry phenomena remains unclear. but the results suggest that extracellular Ca2+ is required to reprime or to bind to some sites of the dihydropyridine receptors.
Effect of epidural clonidine on analgesia and pharmacokinetics of epidural fentanyl in postoperative patients, Epidural clonidine produces postoperative analgesia in patients and potentiates opioid analgesia in animals. The aim of the current study was to assess the effect of epidural clonidine on the plasma concentrations and analgesic effect of fentanyl after epidural administration. Twenty ASA physical status 2 or 3 patients recovering from abdominal surgery were allocated randomly to receive either epidural fentanyl (100 micrograms in 10 ml isotonic saline; EF group) or epidural fentanyl (same dose) plus epidural clonidine (150 micrograms; EF + C group) in isotonic saline solution. Analgesia was assessed over a period of 12 h after epidural injection. Venous samples were obtained until 360 min after epidural injection for radioimmunoassay determination of plasma fentanyl concentration. Onset of analgesia was similar in the two groups of patients (13 +/- 6 and 13 +/- 3 min. respectively. after injection). but duration was more than doubled in the patients receiving clonidine (543 +/- 183 vs. 250 +/- 64 min). Peak plasma fentanyl concentrations (Fmax) and the time to reach Cmax (Tmax) were comparable in the two groups (0.29 +/- 0.15 ng.ml-1 at 16.2 +/- 14.8 min in the EF group and 0.27 +/- 0.11 ng.ml-1 at 8.3 +/- 5.5 min in the EF + C group). as were plasma concentrations at each definite time of measurement. Drowsiness and hypotension were noticed in the EF + C group. Thus. epidural clonidine appears to prolong epidural fentanyl analgesia without affecting its plasma concentration.
Blood conservation techniques and platelet function in cardiac surgery, Postoperative alterations in platelet function induced by cardiopulmonary bypass (CPB) are of importance. The effect on platelet aggregation of three different techniques for reducing blood consumption was studied in 30 patients undergoing elective aortocoronary bypass grafting from the beginning of anesthesia until the 1st postoperative day. The patients were randomly divided into three groups. in which 1) a cell separator was used during and after CPB; 2) a hemofiltration device was used; and 3) high-dose aprotinin was used in order to reduce the need of homologous blood. A fourth group undergoing neurosurgery procedures served as a control. Platelet aggregation induced by adenosine diphosphate (concentration 0.25. 0.50. 1.0. and 2.0 microM). collagen (4 microliters/ml). and epinephrine (25 microM) was determined by the turbidimetric method. Platelet aggregation was not significantly changed in the control group. indicating that the operation itself did not impair platelet function. At the end of the operation (after retransfusion of the salvaged pump blood). the maximum aggregation and maximum gradient of aggregation induced by all three inductors were most reduced (significantly) in the cell-separator patients. On the 1st postoperative day. platelet aggregation in the hemofiltration patients and the patients treated with aprotinin had normalized. Aggregation of patients pretreated with high-dose aprotinin was not different from that of the hemofiltration patients throughout the investigation. Blood loss was significantly highest in the cell-separator group (770 +/- 400 ml on the 1st postoperative day) but was not different between the hemofiltration (390 +/- 230 ml) and the aprotinin-treated patients (260 +/- 160 ml).
Postoperative epidural morphine is safe on surgical wards, The use of epidural morphine for postoperative analgesia outside of intensive care units remains controversial. In this report our anesthesiology-based acute pain service documents experience with 1.106 consecutive postoperative patients treated with epidural morphine on regular surgical wards. This experience involved 4.343 total patient days of care and 11.089 individual epidural morphine injections. On a 0-10 verbal analog scale. patient-reported median pain scores at rest and with coughing or ambulation were 1 (inter-quartile range 3) and 4 (interquartile range 4). respectively. The incidence of side effects requiring medication were as follows: pruritus 24%. nausea 29%. and respiratory depression 0.2%. There were no deaths. neurologic injuries. or infections associated with the technique. Migration of epidural catheters into the subarachnoid space and into epidural veins each occurred twice. Overall. 1.051 of the 1.106 patients (95%) experienced none of the following problems: catheter obstruction. premature dislodgement. painful injections. catheter migration. infection. or respiratory depression. We conclude that postoperative pain can be safely and effectively treated with epidural morphine on surgical wards.
Right- and left-arm blood pressure discrepancies in vascular surgery patients, To identify a relationship between atherosclerotic vascular disease and differences in blood pressure between the right and left arms. blood pressure differences between arms were measured in patients with peripheral vascular disease (PVD. n = 58). in patients with coronary artery disease (CAD. n = 38). and in patients with no evidence of atherosclerotic disease. who served as a control group (n = 38). The incidence and magnitude of right and left arm pressure difference determined by the oscillometric technique were compared between the patient groups. The incidence of systolic pressure difference greater than or equal to 20 mmHg between arms in patients with PVD (21%) was greater than that in either those with CAD (3%) (P less than or equal to 0.05) or control subjects (0%) (P less than 0.01). The incidence of systolic pressure difference greater than or equal to 45 mmHg between arms in patients with PVD (10%) was greater than that in either those with CAD (0%) (P less than 0.05) or control subjects (0%) (P less than 0.05). Patients with PVD also had a greater incidence of right and left arm difference than did those with CAD or controls for mean and diastolic blood pressures. Of all patients with a systolic difference greater than 10 mmHg. neither the right nor the left arm blood pressure was consistently higher: 21 of 35 (60%) had a higher pressure in the right arm. and 14 of 35 (40%) had a higher pressure in the left arm (P = 0.33). Gender. diabetes. hypertension. smoking. and age were not associated with a difference in blood pressure between the right and left arms.
Altered load dependence of postischemic myocardium, Intermittent myocardial ischemia can produce areas of postischemic ("stunned") myocardium in the heart of the human with coronary artery disease. These areas are no longer ischemic. but have diminished contractile performance. Although the effects of loading conditions on systolic contraction of normal. ischemic. and failing myocardium have been investigated in great detail. the way in which load affects contraction of postischemic myocardium is not known. The aim of this study was to determine in anesthetized dogs how loading conditions affect the systolic function of a region of myocardium after 10 min of ischemia and 1 h of reperfusion. Sets of piezoelectric crystals were implanted in a test zone and in a remote zone of myocardium. Measurements of systolic wall thickening were made during nine combinations of left atrial pressure (3. 6. and 9 cmH2O) and mean arterial pressure (70. 90. and 110 mmHg). One set of measurements was made under baseline conditions. and a second set was made after 10 min of coronary occlusion and 1 h of reperfusion. Ischemia and reperfusion reduced wall thickening in the test zone 36 +/- 3% and diminished the response to increases in preload. In contrast. the response of the test zone to changes in afterload was unchanged. An interaction between the test zone (in which depressed contraction was observed) and the surrounding myocardium (in which enhanced function was observed) produced the appearance of a regional wall motion abnormality as afterload increased. These results emphasize that the load dependence of postischemic myocardium differs from that of normal myocardium and must be taken into account in clinical studies in which regional contraction is used to monitor the heart for ischemia.
A thromboxane analog increases pulmonary capillary pressure but not permeability in the perfused rabbit lung, Thromboxane has been implicated as a mediator of pulmonary hypertension and pulmonary edema in acute respiratory failure. Pulmonary edema may result from increased pulmonary capillary hydrostatic pressure or from increased pulmonary vascular permeability. We therefore studied the effects of a stable thromboxane analog. U46619. on these two parameters in the perfused rabbit lung. Pulmonary capillary pressure was measured by the double vascular occlusion method. and pulmonary vascular permeability was estimated by measurement of the pulmonary fluid filtration coefficient (Kf). U46619 infusion produced pulmonary hypertension and lung weight gain; increased both the arterial (precapillary) and venous (postcapillary) components of pulmonary vascular resistance; and increased pulmonary capillary pressure from 4.7 +/- 0.5 to 9.0 +/- 0.7 mmHg (P less than 0.01). The isogravimetric pressure (equivalent to the capillary pressure corresponding to no lung weight gain) was 4.0 +/- 0.4 mmHg before U46619 and 4.6 +/- 0.4 mmHg during U46619. Therefore. U46619 significantly increased capillary pressure above isogravimetric pressure and resulted in the development of pulmonary edema. U46619 did not affect vascular permeability as measured by Kf. We conclude that pulmonary venoconstriction resulting in increased pulmonary capillary hydrostatic pressure is the major mechanism by which thromboxane produces pulmonary edema in isolated lungs.
The prevention of tetanus in the elderly, Tetanus is a rare disease in the United States. which predominantly affects the elderly and who have a lower prevalence of tetanus immunity compared with younger age groups. A large proportion of the elderly have not received primary immunization for tetanus and do not receive recommended tetanus booster immunizations. Although expert panels support immunization of all persons. without an upper age limit. physicians either are unaware of or do not act on recommendations to immunize the elderly. Improved education of physicians and patients. emphasizing a case-finding approach. may reduce the number of tetanus cases in the elderly. Studies are needed to find ways to improve tetanus immunity in the elderly.
Marine oil capsule therapy for the treatment of hyperlipidemia, Because marine oil capsules may vary widely in their content of omega-3 fatty acids. saturated fat. and cholesterol composition and. therefore. their biologic potency. we compared the lipid-lowering effects of three representative preparations in patients with different forms of hyperlipidemia. The ester and triglyceride forms of marine oil both effectively lowered triglyceride. but the response of low-density lipoprotein cholesterol was variable; it declined modestly in patients with hypercholesterolemia and was either unchanged or increased in those with hypertriglyceridemia. The saturated fat and cholesterol content of the marine oil preparation appeared to influence the low-density lipoprotein cholesterol response. Therefore. marine oil capsules are useful for lowering levels of very-low-density lipoprotein cholesterol. but the large dose required to achieve and sustain this effect (4.5 g of omega-3 fatty acids. or nine to 18 capsules daily) may limit long-term compliance.
Influenza vaccination. Are we doing better than we think, Patients who were candidates for influenza vaccination seen in the primary care center of a community teaching hospital were studied to determine whether there is a differential immunization rate depending on risk level. The immunization rate was as follows: moderate risk group. 44%; high risk group. 59%; and very high risk group. 81%. The immunization rate was also closely associated with the frequency of clinic visits. ranging from 34% for those with low visit frequency to 73% for those with high visit frequency. The highest vaccination rates were thus found in the groups at highest risk for influenza-associated morbidity and mortality. Although influenza complication rates are lower in the healthy elderly. this group is so large that the public health impact of a low vaccination rate will be significant. The healthy elderly should be the special targets of future influenza vaccination campaigns.
Beta-adrenergic blocker therapy does not worsen intermittent claudication in subjects with peripheral arterial disease. A meta-analysis of randomized controlled trials, Beta-Adrenergic blockers have been considered relatively contraindicated in peripheral arterial disease because of the perceived risk that these drugs could worsen intermittent claudication. Therefore. we conducted a meta-analysis of available randomized controlled trials from the English-language literature to determine whether or not beta-blockers exacerbate intermittent claudication. The primary focus of this analysis was the effect of beta-blockers on exercise duration. measured as walking capacity or endurance time. Outcomes were pooled where appropriate. Of 11 eligible reports. six included 11 individual controlled treatment comparisons that provided data for an analysis of pain-free exercise capacity; no effect size was statistically significant. The pooled effect size for pain-free walking distance was -0.24 (95% confidence interval. -0.62 to 0.14). indicating no significant impairment of walking capacity compared with placebo. Only one study reported that certain beta-blockers were associated with worsening of intermittent claudication. These results strongly suggest that beta-blockers do not adversely affect walking capacity or symptoms of intermittent claudication in patients with mild to moderate peripheral arterial disease. In the absence of other contraindications. beta-blockers can probably be used safely in such patients.
Resistant hypertension in a tertiary care clinic, STUDY OBJECTIVE.--To determine the prevalence of resistant hypertension in a tertiary care facility. the frequency of its various causes. and the results of treatment. DESIGN.--Review of clinic records of all patients seen for the first time between January 1. 1986. and December 31. 1988. METHODS.--Patients meeting criteria for resistant hypertension were examined for appropriateness of their medical regimen. presence of secondary causes of hypertension. noncompliance. interfering substances. drug interactions. office resistance (elevated blood pressure in the office only while receiving treatment). and other potential causes of resistance. RESULTS.--Of the 436 charts reviewed. 91 were those of patients who met criteria for resistant hypertension and were seen more than once. The most common cause was a suboptimal medical regimen (39 patients). followed by medication intolerance (13 patients). previously undiagnosed secondary hypertension (10 patients). noncompliance (nine patients). psychiatric causes (seven patients). office resistance (two patients). an interfering substance (two patients). and drug interaction (one patient). Blood pressure control. defined as diastolic blood pressure of 90 mm Hg or less and systolic blood pressure of 140 mm Hg or less for patients aged 50 years or less (less than or equal to 150 mm Hg for those aged 51 to 60 years and less than or equal to 160 mm Hg for those aged greater than 60 years). was achieved in 48 (53%) of those 91 patients. Another 10 had significant improvement in their blood pressure (greater than or equal to 15% decrease in diastolic blood pressure). Of patients whose blood pressure was controlled after they had been on a suboptimal regimen. the two most frequently used therapeutic strategies were to add (50%) or modify (24%) diuretic therapy or to add (50%) or increase the dose of (12%) a newer drug. either a calcium entry blocker or angiotensin-converting enzyme inhibitor. CONCLUSION.--We conclude that resistant hypertension is common in a tertiary care facility and that a suboptimal regimen is the most common reason. Furthermore. in the majority of these patients. the elevated blood pressures can be controlled or significantly improved.
A randomized controlled trial of the effects of three antihypertensive agents on blood pressure control and quality of life in older women, We conducted a multicenter. randomized. double-blind. parallel group trial to compare the impact of titrated doses of atenolol (50 to 100 mg once a day). enalapril (5 to 20 mg once a day). and diltiazem (sustained release) (60 to 180 mg twice a day) on blood pressure and quality of life in older hypertensive women. Two hundred forty-two patients were randomized. Dose titration was completed by week 4 after randomization. and the maintenance phase was completed at week 16. Diltiazem (sustained release) demonstrated greater diastolic blood pressure lowering at both weeks 8 and 16 by an intent-to-treat analysis. At week 16. diltiazem changed diastolic blood pressure -13.7 +/- 0.7 mm Hg compared with -10.8 +/- 1.1 mm Hg for atenolol. and -10.5 +/- 0.9 mm Hg for enalapril. Diltiazem also demonstrated greater lowering of systolic blood pressure at week 3. but these differences in systolic blood pressure had decreased by week 16. More patients were classified as treatment failures during the 16 weeks of the trial for atenolol (15%) than for diltiazem (2.5%). while the treatment failure rate was intermediate with enalapril (8%). Total rates of adverse events were equivalent across the three treatment arms. There were few significant differences in the impact of the three treatments on mean scores of quality-of-life measures at week 16. There was a trend for atenolol to have somewhat worse quality-of-life scores. but none of these differences were statistically significant. In conclusion. all three treatment regimens were effective in lowering diastolic blood pressure without significant differences in rates of adverse events or deleterious effects on quality of life.
Problems in the use of serologic tests for the diagnosis of Lyme disease, Lyme disease can be reliably diagnosed in the presence of erythema migrans. When erythema migrans is absent. serologic tests are often used to confirm the diagnosis. To choose a test for our Lyme disease diagnostic center. serum samples were obtained from 34 patients and tested for antibodies to Borrelia burgdorferi. We evaluated five enzyme-linked immunosorbent assays from Stony Brook (NY) University Hospital. Cambridge Bioscience (Worcester. Mass). Hillcrest Biologicals (Cypress. Calif). Sigma Diagnostics (St Louis. Mo). and Zeus-Wampole Scientific Inc (Raritan. NJ) and two fluorescent antibody tests (3M [Diagnostic Systems Inc. Santa Clara. Calif] and FIAX [Whittaker M.A. Bioproducts Inc. Walkersville. Md]). A positive sample by any test was further analyzed by Western blot. Using the Centers for Disease Control (Atlanta. Ga) epidemiologic case definitions. patients were classified into those with clinical Lyme disease. patients not meeting the Centers for Disease Control definitions. and asymptomatic patients. Sensitivities of Lyme serologies varied from 13% to 73%. with Hillcrest showing the highest value and Sigma the lowest value. False-positive test results were found in 0% to 27% of patients. Western blot analysis was positive in six of 15 patients with clinical Lyme disease. These results emphasize the need for better serologic testing for Lyme disease and underline their usefulness only as adjuncts in the clinical diagnosis of Lyme disease.
Feasibility of universal screening mammography. Lessons from a community intervention, It is estimated that 44.500 American women will die of breast cancer in 1991. The breast cancer screening guidelines of the American Cancer Society and the National Cancer Institute calling for annual mammography for all women older than 50 years have been endorsed by numerous professional groups. Third-party reimbursement for screening mammography is becoming more prevalent. and payment for screening mammography is now a Medicare benefit. Our studies. conducted as part of a National Cancer Institute grant to increase the routine use of screening mammography and clinical breast examination in women 50 to 75 years of age. have uncovered a number of significant barriers to the implementation of screening guidelines among women. primary care physicians. and providers of mammography services. These barriers. as well as methods to assure the quality of mammography. need to be addressed before universal screening is feasible.
Nifedipine GITS (gastrointestinal therapeutic system) bezoar, In a patient with a gastroplasty. gastric outlet obstruction developed after the dosage of nifedipine GITS (gastrointestinal therapeutic system) was increased from 30 to 60 mg/d. The hard. insoluble shell for this extended-release tablet appears causative.
Psychiatric illness and irritable bowel syndrome: a comparison with inflammatory bowel disease, Structured psychiatric interviews and psychological self-report measures were administered to 28 patients with irritable bowel syndrome and 19 patients with inflammatory bowel disease. Significantly more of the patients with irritable bowel syndrome had lifetime diagnoses of major depression. somatization disorder. generalized anxiety disorder. panic disorder. and phobic disorder. They had significantly more medically unexplained somatic symptoms. and most had suffered from psychiatric disorders. particularly anxiety disorders. before the onset of their irritable bowel symptoms.
Access to information about AIDS, Medical information related to human immunodeficiency virus (HIV) infection is highly diverse. and the practicing physician or researcher may find specific information difficult to locate. To provide timely access to medical information on topics related to the acquired immunodeficiency syndrome (AIDS). several computer-based products have recently been developed. Some are available from vendors of online information systems. whereas others are available only on CD-ROM or floppy disk. We review several computer-based products. AIDSLINE is the most comprehensive bibliographic index. AIDSTRIALS contains specific information about ongoing unpublished investigational studies. and AIDS Knowledge Base from San Francisco General Hospital is an up-to-date electronic textbook covering all aspects of AIDS. COMPACT LIBRARY: AIDS operates on a microcomputer and combines several databases. including full-text AIDS-related articles from nine major medical journals. AIDS References from the Bureau of Hygiene and Tropical Diseases provides critical analysis of publications worldwide. Although smaller in size than AIDSLINE. about one third of the publications covered by this resource are not covered by AIDSLINE.
Physiotherapy for stress urinary incontinence: a national survey, OBJECTIVE--To study the physiotherapeutic treatment of urinary stress incontinence in England. DESIGN--Postal questionnaire survey. SETTING--All 192 English district health authorities. SUBJECTS--One physiotherapist from each district who was primarily concerned with urinary incontinence. A consensus view was requested. MAIN OUTCOME MEASURES--Responses to questionnaire and analysis of a visual analogue scale to indicate effectiveness. RESULTS--There was a 98% response rate. Treatment was often by senior physiotherapists (108 senior I grade or above) who. in 117 districts. claimed to have made a specialty of treating the condition. Gynaecologists and obstetricians were far more likely to refer patients than any other agency (147 respondents said that they were the commonest source of referral). One hundred and fifty four respondents stated that physiotherapy was usually used as the first line of treatment. Pelvic floor exercises and interferential treatment were most commonly used (by 178 and 144 respondents respectively) and thought to be the most effective. especially in combination. though various techniques were used in applying them. Positive motivation (108). recent onset of symptoms (55). and youth (40) were viewed optimistically. and obesity (60). previous surgery (59). prolapse (42). and a chronic cough (36) were considered to be bad prognostic features. The number of patients treated varied greatly (range 10-360) between districts and was poorly correlated with catchment size (correlation coefficient 0.3). CONCLUSIONS--As physiotherapists are treating considerable numbers of patients with stress incontinence research is urgently needed to produce efficacy data to enable rationalisation of resources to cater for the whole population.
Sequential and simultaneous "in series" hemodialysis and hemoperfusion in the management of theophylline intoxication, Hemodialysis and hemoperfusion have been evaluated. and both are effective in removing theophylline. We report two consecutive cases of theophylline intoxication in which the sequential treatment of charcoal hemoperfusion and hemodialysis is contrasted to the simultaneous "in series" treatment of hemodialysis and charcoal hemoperfusion. Analysis of the two methodologies shows that the combined in series technique offers several advantages. including increased extraction efficiency. decreased time of hemoperfusion cartridge saturation. and rapid correction of electrolyte and acid-base abnormalities. and that it is well tolerated clinically. Simultaneous hemodialysis and charcoal hemoperfusion should be considered in cases of extreme theophylline intoxication.
Ocular pharmacokinetics of subconjunctivally administered cyclosporine in the rabbit, The authors assessed the ocular toxicity and pharmacokinetics of subconjunctivally and intravenously administered cyclosporine in New Zealand white rabbits. Fifteen rabbits received a subconjunctival injection of 5 (five animals). 10 (five animals) or 25 (five animals) mg of cyclosporine in 0.1 mL (intravenous solution of Sandimmune [50 mg/mL]); 5 mg was found to be the maximum tolerable dose. This dose was given as a bolus to 36 other rabbits either subconjunctivally (18 animals) or intravenously (18 animals). In both groups the cyclosporine concentrations in the ocular compartments. blood and urine were measured by means of high-pressure liquid chromatography at 0.5. 1. 2. 4. 8 and 12 hours. three animals being assessed at each interval. Subconjunctival administration resulted in peak cyclosporine concentrations of 718 ng/mL in the aqueous humour and 1078 ng/mL in the vitreous humour. compared with no detectable levels in the aqueous humour and a peak concentration of 292 ng/mL in the vitreous following intravenous administration. The peak blood cyclosporine levels were 10 times lower after subconjunctival injection than after intravenous injection. The results indicate that subconjunctival administration is superior to intravenous administration in enhancing the ocular absorption of cyclosporine while minimizing systemic exposure in the rabbit.
Contact thermal burns of the cornea, The records of 59 patients (66 eyes) with contact thermal burns of the cornea (unilateral in 52 cases and bilateral in 7) were reviewed to determine the causes. clinical presentation. management and complications of such injuries. Most of the injuries (90%) occurred at home. The commonest cause was splashing of boiling fluids (42% of cases). followed by contact with red-hot firecracker particles (18%) and lit match heads (17%). In 59 eyes (89%) the burn was limited to the corneal epithelium. in 5 (8%) the superficial stroma was also involved. and in 2 (3%) there was associated corneal perforation caused by mechanical impact of foreign bodies. Debridement of the coagulated epithelium with patching was the most successful treatment. healing 48 (73%) of the eyes. Postburn complications were rare. the most common being development of inferior symblepharon. in three eyes (4%).
A femoral vein-femoral artery loop technique for aortic dilatation in children, Balloon aortic dilatation is now a recognized therapy for aortic stenosis in children. Using retrograde approaches with either single or double balloons. successful dilatation can be readily achieved. but with little control of balloon position across the valve. We describe a femoral vein-femoral artery loop technique via a transseptal approach which facilitates antegrade crossing of the stenotic aortic valve and allows optimal balloon control and simultaneous pressure gradient recording during the procedure.
The NACI Registry: an instrument for the evaluation of new approaches to coronary intervention. The NACI Investigators, The New Approaches to Coronary Intervention (NACI) Registry was developed to collect in-depth data about patients whose coronary artery lesions are being treated with new interventional techniques such as atherectomy. stents. and laser devices. The NACI Registry database distinguishes among several possible "modes" for device use. such as preparatory. planned definitive. and bailout use. Common definitions are used for data collection across all devices. and device-specific forms are used to record procedural details. NACI's unique modular form design facilitates thorough data collection. even for the most complex treatment scenarios. The database structure allows for data analysis at the patient. procedure. lesion. and device levels. as required to perform in-depth analyses of the immediate and long-term success of new devices. Once adequate knowledge of basic device performance has been collected. the Registry structure can also allow expeditious planning and performance of randomized trials comparing a new device to conventional PTCA.
Relationship between coronary blood flow and perfusion pressure during reactive hyperemia: a case report in an awake unanesthetized woman with normal coronary arteries, The linear relationship between coronary blood flow and mean arterial pressure during reactive hyperemia is presented for the first time in an awake unanesthetized woman with normal coronary arteries during systemic hypotension induced by pharmacologic vasodilation. This case demonstrates the critical dependence of coronary flow reserve on simultaneous perfusion pressure.
Brachial approach to management of an abdominal aortic occlusion with prolonged lysis and subsequent angioplasty, The brachial approach for recanalizing an abdominal aortic occlusion utilizing a combination of thrombolysis and balloon angioplasty is described. The patient was deemed too ill to permit any surgical intervention. The unique aspects of the procedure are described including angioplasty of the unmasked (by lytic therapy) aortoiliac bifurcation stenoses utilizing double wires and double balloons through a single arteriotomy site. The advantages of the brachial approach in managing this unusual entity are outlined.
Autoreactive lymphocytotoxic IgM antibodies in highly sensitized dialysis patients waiting for a kidney transplant: identification and clinical relevance, The contribution of different families of lymphocytotoxic antibodies in the serologic reactivity of 45 highly sensitized dialysis patients (HSDP) (panel reactivity antibody value-PRA greater than 80%) was assessed by analyzing patients' sera for the presence of auto- and alloreactive IgM and alloreactive IgG antibodies. A total of 220 sera was screened at different incubation temperatures. before and after treatment with the reducing agent dithiothreitol. against a large variety of cell targets by means of complement dependent cytotoxicity (CDC) and antiglobulin augmented (AHG) CDC assays. The results allowed to subdivide the HSDP under study into four groups: Group 1 consisted of 13 untransplanted patients and 14 patients with a prior failed graft whose PRA values did not change following DTT treatment. Alloreactive IgG antibodies alone. with anti-HLA specificity. were present in the sera of this patient group. Group 2 consisted of 3 untransplanted patients whose sera did not contain any autolymphocytotoxic antibody but appeared completely unreactive to panel lymphocytes following DTT treatment. thus confirming the presence of alloreactive IgM only endowed with antiHLA reactivity. Group 3 consisted of 4 untransplanted and 4 patients with a prior failed graft whose sera were found to contain in addition to autoreactive IgM also alloreactive IgG antibodies. Their PRA values declined after DTT treatment on average from 96.2% to 45% and from 95% to 52.5%. respectively. Group 4 consisted of 6 untransplanted patients whose PRA reactivity to both autologous and panel lymphocytes completely disappeared following DTT treatment. thus indicating that their sera contained exclusively autolymphocytotoxic IgM antibodies.
Pharmacokinetics of vancomycin in patients undergoing hemodialysis with polyacrylonitrile, The pharmacokinetics of vancomycin in patients undergoing dialysis with cuprophane membranes are well known. however little has been reported of the use of polyacrylonitrile membranes in dialysis. We studied. in a crossover design. eight dialysis patients (7 men. 1 woman) aged 30 to 66 years who prospectively received 1 gram of vancomycin i.v. before first dialysis and were subsequently hemodialyzed with cuprophane every second day for a total of three times. A month later trial was repeated using polyacrylonitrile. A mono-compartment model was used to calculated pharmacokinetic parameters. Mean +/- standard deviation of vancomycin clearance varied from 5.2 +/- 2.1 ml/min in the interdialysis period to 9.7 +/- 2.7 ml/min during dialysis with cuprophane and to 58.4 +/- 15.6 ml/min during dialysis with polyacrylonitrile (p less than 0.001). Vancomycin half-life varied from 71.5 +/- 23.0 to 35.9 +/- 9.8 and to 6.1 +/- 1.4 hours. respectively (p less than 0.001). Fractional removal of vancomycin increased from 4% using the cuprophane dialyzer to 34% using the polyacrylonitrile dialyzer (p less than 0.001). Serum vancomycin levels at 100 and 168 hours were higher with cuprophane than with polyacrylonitrile (7.0 +/- 2.2 vs 3.9 +/- 1.2 micrograms/ml) (p less than 0.001). Moreover. the mean levels at 100 hours were suboptimal on polyacrylonitrile. Approximately 208 +/- 53 mg of vancomycin were removed during one polyacrylonitrile dialysis. Thus. those patients who undergo dialysis with polyacrylonitrile and are treated with vancomycin may need supplementary doses post dialysis or to lessen dosage intervals than those traditionally used for dialysis patients since clearance of the drug is significantly higher than with cuprophane dialyzers. Continuous monitoring of vancomycin levels is also recommended.
Pattern of proteinuria in IgA nephritis by SDS-PAGE: clinical significance, Of sixty patients with IgA nephritis. none had CRF at first examination. 13 developed CRF with creatinine above 1.6 mg/dl within 6 years. Among these patients who had analysis of proteinuria by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). 31 patients had middle molecular weight (MMW) proteinuria alone (pattern 1). 10 had MMW and Low MW (LMW) or tubular proteinuria (pattern 2). 10 had high MW (HMW) and MMW proteinuria (Pattern 3) and 9 had HMW. MMW and LMW proteinuria (Pattern 4). At the end of a follow up period of 6 years (1983-1989) patients with mixed proteinuria had a higher incidence of chronic renal failure (CRF). 11/29 (38%) compared to those with pattern 1 proteinuria. 2/31 (6%) (chi 2 = 8.7. p less than 0.005). Based on the glomerular selectivity index (GSI). 19 patients had nonselective proteinuria but they did not have a higher incidence of CRF. By the selectivity index (SI). 18 patients had nonselective proteinuria and they showed a significantly higher incidence of CRF. Compared to the 41 patients who did not have LMW proteinuria. 19 patients with LMW proteinuria had more severe proteinuria. After a follow-up period of 6 years. patients with LMW proteinuria had a higher incidence of CRF (10% versus 47%. p less than 0.001). The presence of LMW proteinuria indicates a less favourable outcome and the pattern of proteinuria as assessed by the SDS-PAGE appears to be a better prognostic index in IgA nephritis than the SI and the GSI.
Haemolytic effects of exercise, 1. Exercise-induced haemolysis has been implicated in the sub-optimal iron status of endurance-trained athletes. Accordingly. erythrocyte survival studies using 51Cr were performed on male and female distance runners (n = 20) and sedentary control subjects (n = 10) in order to determine whether the rate of erythrocyte destruction was altered as a consequence of repetitive exercise training. 2. The chromium half-disappearance time of the male (25.4 +/- 3.6 days. mean +/- SD) but not the female (28.3 +/- 4.6 days) athletes was significantly lower than that of the male (33.1 +/- 4.5 days) and female (32.3 +/- 2.6 days) control subjects (P less than 0.01). The mean erythrocyte lifespan of the male and female distance runners (67.2 +/- 22.2 and 72.4 +/- 26.0 days. respectively) was significantly shorter than that of the non-exercising male and female subjects (113.4 +/- 31.0 and 114.1 +/- 29.0 days. respectively) (P less than 0.01). 3. There was no correlation between the mean erythrocyte lifespan and the haemoglobin concentration. serum ferritin levels. body mass. weekly training distance. number of years running or daily protein intake. The mean cell volume and reticulocyte count measured in the same athletes before and after completing a standard 42 km marathon race were within the normal range. whereas the plasma haemoglobin levels were elevated (77.0 +/- 50.5 mg/l) and the serum haptoglobin levels were decreased (0.89 +/- 0.4 g/l) at rest. with a further significant decrease after running (0.69 +/- 0.4 g/l) in the latter measurement (P less than 0.05). 4. It is concluded that the demonstrated increase in erythrocyte turnover may be sufficient to precipitate an iron deficiency in endurance athletes when dietary intake or absorption does not meet the accelerated erythropoietic demands.
A defect in insulin release in women at risk of future non-insulin-dependent diabetes, 1. A study on seven Caucasian glucose-tolerant women with previous gestational diabetes and seven matched control subjects is presented. The insulin response to oral glucose. insulin sensitivity and fasting glucose production rates were measured by using a 75 g oral glucose tolerance test. an insulin tolerance test and a non-radioactive tracer. [6.6-2H]glucose. respectively. 2. Fasting plasma glucose levels were similar between the women with previous gestational diabetes and the control subjects (4.8 +/- 0.3 versus 4.7 +/- 0.2 mmol/l). as were fasting plasma insulin levels (median 4 m-units/l. range 1-13 m-units/l versus median 4 m-units/l. range 1-24 m-units/l). After oral glucose the 60 min plasma glucose levels in the women with previous gestational diabetes were significantly higher (8.5 +/- 0.6 versus 6.7 +/- 0.8 mmol/l. P less than 0.05). whereas the plasma insulin level was significantly lower at both 30 min (median 23 m-units/l. range 4-47 m-units/l versus median 55 m-units/l. range 23-100 m-units/l. P less than 0.02) and at 60 min (median 23 m-units/l. range 4-43 m-units/l versus median 60 m-units/l. range 16-126 m-units/l. P less than 0.02). 3. Insulin sensitivity. expressed as the slope of the regression line of plasma glucose level against time after intravenous infusion of insulin (0.05 unit/kg). was similar in the women with previous gestational diabetes and the control subjects (mean slope. -0.17 +/- 0.01 versus -0.17 +/- 0.01). 4. Fasting glucose production rates were similar in the women with previous gestational diabetes and the control subjects (2.2 +/- 0.3 versus 1.9 +/- 0.1 mg min-1 kg-1).
Evidence for two distinct and functionally important sites of enhanced thromboxane production after bilateral ureteral obstruction in the rat, 1. After bilateral ureteral obstruction there is an enhanced production of thromboxane A2 by the kidney which contributes to a decline in renal function. An acute interstitial macrophage infiltrate also occurs. 2. The relative contribution of infiltrating cells and intrinsic renal cells to the enhanced production of thromboxane A2 by the hydronephrotic kidney were determined. The effects of both irradiation and subsequent administration of the thromboxane synthesis inhibitor OKY-046 on both thromboxane B2 excretion and renal function were examined in rats with 24 h bilateral ureteral obstruction. 3. Irradiation effectively prevented the leucocyte infiltrate after bilateral ureteral obstruction (1.2 +/- 0.8 x 10(5) versus 27.1 +/- 0.1 x 10(5) cells/g of cortex. n = 4 in each group). resulted in a significantly higher inulin clearance (2.78 +/- 0.27 versus 1.49 +/- 0.17 ml min-1 kg-1 body weight. n = 7 and n = 8. respectively. P less than 0.001) and reduced thromboxane B2 excretion to 39% of non-irradiated values. Subsequent administration of OKY-046 to previously irradiated animals further reduced thromboxane B2 excretion to 20% of the value in non-irradiated rats with bilateral obstruction and further increased inulin clearance to 3.34 +/- 0.26 ml min-1 kg-1 body weight. 4. Glomerular macrophage numbers were decreased after bilateral ureteral obstruction (in contrast to the interstitium). However. glomeruli isolated from rats with 24 h bilateral ureteral obstruction exhibited enhanced production of thromboxane B2 compared with sham-operated control rats (855.6 +/- 31.1 versus 392.2 +/- 25.5 pg 60 min-1 mg-1 of protein. P less than 0.001).
Vascular responsiveness and cation exchange in insulin-dependent diabetes, 1. We measured forearm blood flow during brachial artery infusions of vasoconstrictors (angiotensin II and noradrenaline) and vasodilators (sodium nitroprusside and carbachol) in 16 healthy control subjects and in 18 patients with uncomplicated insulin-dependent diabetes mellitus. Erythrocyte Na+/Li+ countertransport and platelet Na+/H+ antiport activities were also measured. 2. The mean basal forearm vascular resistance was 22% lower in diabetic patients than in control subjects. The effects of each infusion on forearm vascular resistance were similar in diabetic patients and control subjects. 3. Erythrocyte Na+/Li+ countertransport activities were similar in diabetic patients and control subjects. Platelet Na+/H+ exchange (Vmax) was approximately 40% greater in diabetic patients than in control subjects. whereas the Km for Na+ was similar. 4. In diabetic patients. but not in control subjects. the responses to sodium nitroprusside and carbachol correlated inversely with Na+/Li+ countertransport in erythrocytes (rs = -0.76. P less than 0.001. and rs = -0.66. P less than 0.005. respectively). but not with Na+/H+ exchange in platelets.
Metalloproteinases in degenerative aortic disease, 1. Atherosclerosis and aneurysm of the abdominal aorta are associated with thinning of the medial connective tissue. We have investigated the presence of the connective-tissue-degrading metalloproteinases in homogenates prepared from atherosclerotic. aneurysmal and control aortic media. 2. Gelatinase activity was much increased in homogenates from atherosclerotic and aneurysmal aorta [10.9 +/- 1.8 and 13.3 +/- 3.3 micrograms of gelatin hydrolysed h-1 (mg of protein)-1 respectively]. This gelatinase activity was highest at the luminal aspect of the aortic media. where the activity increased three- to five-fold after the destruction of alpha 2-macroglobulin. Zymograms demonstrated the principal gelatinase in atherosclerotic aorta to have a molecular mass of about 92 kDa. whereas in aneurysmal aorta there was a spectrum of gelatinase activity from 92 to 55 kDa. 3. Collagenase and stromelysin (proteoglycanase) could be detected by immunoblotting in homogenates of aneurysmal aorta. but rarely in atherosclerotic aorta and never in control aorta. Collagenase and stromelysin activities were low. but increased two- to three-fold after the destruction of tissue inhibitor of metalloproteinases. Collagenase and stromelysin activities were highest at the adventitial aspect of aneurysmal media. 4. The secretion of gelatinase by inflammatory cells at the intima of diseased aorta could have a pathological role in establishing atherosclerotic plaques and medial thinning. Secretion of collagenase. gelatinase and stromelysin from the adventitia could accelerate connective tissue degradation in the media of aneurysmal aorta.
Spectrum of orthostatic disorders: classification based on an analysis of the short-term circulatory response upon standing, 1. In 31 consecutively referred patients (20 females. 11 males) with overt or suspected orthostatic disorders. the changes in blood pressure and heart rate that occur in the first 2 min of standing were analysed. 2. Blood pressure was measured continuously by Finapres. The blood pressure and heart rate responses after 1-2 min of standing (early steady-state response) were used to classify the patients as follows: group I (n = 17. age 42 +/- 17 years). normal early steady-state blood pressure and heart rate responses; group II (n = 5. age 40 +/- 14 years). combination of normal early steady-state blood pressure and postural tachycardia; group III (n = 9. age 51 +/- 14 years). hypotensive orthostatic response with (4/9) or without (5/9) postural tachycardia. We examined whether additional information could be obtained by beat-to-beat analysis of the initial circulatory response (first 30 s). It was quantified by identifying the blood pressure trough and overshoot and the maximum heart rate and relative bradycardia. 3. The initial drop in systolic and diastolic blood pressures did not differ between the three groups. A recovery of blood pressure with a systolic and/or diastolic blood pressure overshoot was present in all group I and II patients. but was absent in all except two patients in group III. The initial maximum heart rate increase did not differ between the three groups. The relative bradycardia was less in groups II and III than in group I. 4. We conclude that analysis of the beat-to-beat blood pressure changes in the first 30 s after the onset of standing provides almost all the information that is necessary to determine abnormalities in orthostatic circulatory control.
Influence of nifedipine on cyclosporin A nephrotoxicity after unilateral nephrectomy in the spontaneously hypertensive rat, 1. Nifedipine ameliorates cyclosporin A-induced renal impairment in surgically intact (two-kidney) rats. This study investigates the effect of nifedipine on cyclosporin A nephrotoxicity in spontaneously hypertensive rats after either uninephrectomy or uninephrectomy with contralateral renal denervation. 2. Fourteen days after uninephrectomy pair-fed rats were injected for 14 days with cyclosporin A (25 mg/kg body weight) via the subcutaneous route and with nifedipine (0.1 mg/kg body weight) via the intraperitoneal route. Renal and systemic haemodynamics were measured in conscious unrestrained rats. 3. Whole-blood levels of cyclosporin A did not differ between groups (overall 352 +/- 22 ng/ml. means +/- SEM). After uninephrectomy. cyclosporin A decreased the glomerular filtration rate (olive oil versus cyclosporin A: 0.96 +/- 0.04 versus 0.70 +/- 0.06 ml min-1 100 g body weight. P less than 0.02) and effective renal plasma flow (1.94 +/- 0.10 versus 1.38 +/- 0.13. P less than 0.01). and increased renal vascular resistance [(20.2 +/- 1.8) x 10(4) versus (31.6 +/- 3.3) x 10(4) kPa l-1 s [(20.2 +/- 1.8) x 10(3) versus (31.6 +/- 3.3) x 10(3) dyn s cm-5]. P less than 0.02] and mean arterial pressure (146.7 +/- 6.7 versus 167.3 +/- 2.9 mmHg. P less than 0.05). Neither renal denervation nor nifedipine prevented the reduction in glomerular filtration rate or effective renal plasma flow induced by cyclosporin A. 4. This study infers that the sympathetic nervous system does not play an active role in cyclosporin A nephrotoxicity and demonstrates that the concomitant administration of nifedipine to rats with reduced renal mass does not ameliorate cyclosporin A-induced renal impairment.
Respi-Care. An innovative home care program for the patient with chronic obstructive pulmonary disease, The purpose of the present study was to evaluate the effectiveness of a hospital-based home care program for a group of patients with severe COPD. Respi-Care was a multidisciplinary home care program administered by Norwalk Hospital in cooperation with the public health nursing departments of the city of Norwalk and the town of Wilton. Conn. The overall goal of Respi-Care was to provide more comprehensive home care services to patients previously requiring frequent hospitalizations by combining the advantages of hospital resources and community agencies through a unique cooperative effort. Preprogram and on-program data were collected on the following variables for the 48 months of Respi-Care operation: hospitalizations; hospital days; emergency room visits; home care services; and the costs of these services. Costs of operating the Respi-Care program were included in on-program data. Seventeen subjects completed 320.5 months on Respi-Care. Each subject was matched to an equal length of time prior to entering the program. for a total of 641 months analyzed. There were 88 preprogram hospitalizations for the group; hospitalizations while participating in Respi-Care dropped to 53 (p = 0.022; paired t statistics). On-program hospital days showed a significant decrease. from 1.181 preprogram days to 667 on-program days (p = 0.024). Emergency room visits decreased from 105 before the program to 64 during the program (p = 0.017). Costs of care also decreased. Costs for hospitalizations. emergency room visits. and home care fell from $908.031 to $802.999. resulting in a $105.032 savings or $328 per patient per month.
Psychological outcomes of a pulmonary rehabilitation program, This study assessed physiologic. psychological. and cognitive functioning in outpatients with COPD. Sixty-four subjects. 53 to 82 years of age. participated in the 30-day exercise rehabilitation program. The program consisted of exercise. education and psychosocial counselling. Participants were assessed prior to beginning the program and at the end of 30 days. Assessments at both times included physiologic functioning (bicycle ergometry testing. pulmonary function tests. 12-min walk). psychological well-being (anxiety. depression. psychiatric symptoms. perceived well-being) and an abbreviated neuropsychological test battery. Results indicate significant improvement in physical endurance and pulmonary function. significant reductions in symptoms of depression and anxiety. and improvement in measures of general well-being and neuropsychological functioning. The study suggests that exercise rehabilitation of older adults with COPD contributes not only to improvements in physical functioning and endurance. but also to enhanced cognitive functioning and psychological well-being.
Maximum intensity exercise training in patients with chronic obstructive pulmonary disease, We studied high intensity. symptom-limited. endurance exercise training in 52 patients with COPD participating in a pulmonary rehabilitation program. The patients had moderate to severe airway obstruction and reduced exercise tolerance with ventilatory limitation. The target workload for endurance exercise testing was 95 percent of the baseline maximum treadmill work load. At training weeks 1. 4 and 8. they were training at 85. 84. and 86 percent respectively. of baseline maximum. After rehabilitation. there was an increase in maximal treadmill work load. VO2max. and endurance exercise time. and a decrease in perceived symptoms. Patients who did not reach anaerobic threshold (group 2) were able to train at a higher percentage of maximum exercise tolerance than patients who reached anaerobic threshold (group 1). The increase in exercise performance of both groups. however. was similar. We conclude that patients with moderate to severe COPD can perform exercise training successfully at intensity targets which represent higher percentages of maximum than typically recommended in normal individuals or other patients.
Screening for sleep apnea using pulse oximetry and a clinical score, Confirmation of the diagnosis of OSA currently requires overnight polysomnography. This study evaluates the usefulness of pulse oximetry together with a clinical score in identifying OSA. Forty patients were assigned a clinical score based on the presence or absence of loud snoring. observations of interrupted breathing during sleep. hypersomnolence. obesity and essential hypertension. Each underwent a night of domiciliary pulse oximetry followed by nocturnal polysomnography. Significant OSA was confirmed in 26. All 15 patients with positive pulse oximetry tracings had significant OSA (apnea index greater than or equal to 10). Five of eight with negative tracings were also shown to have significant OSA along with six of the seven patients with inadequate or indeterminate tracings. Clinical scores were significantly different for those with and without OSA. This study confirms the usefulness of nocturnal pulse oximetry in establishing the diagnosis of OSA and highlights the value of a clinical score in improving its sensitivity as a screening tool.
Priority of peak circadian variation of bronchial responsiveness to the trough of circadian variation of bronchial caliber in asthmatic children, To study the temporal relation between the peak of circadian variation of bronchial responsiveness and the trough of circadian variation of bronchial caliber. we performed seven inhalation challenges with histamine at 4-h intervals in six stable asthmatic children aged eight to ten years. Bronchial responsiveness was expressed as PC20. Coefficient of variation of baseline FEV1 within the study day was less than 7 percent in all. The trough of FEV1 variation by cosinor analysis ranged from 02.50 to 11.99 h (mean. 05.66). All had both significant (p less than 0.05) or marginally significant (0.05 less than p less than 0.1) cosinusoidal rhythm of PC20 and two or more doubling concentration differences between the highest and lowest PC20s. The trough of PC20 variation ranged from 16.32 to 02.87 h (mean. 22.30). There was a significant (p less than 0.05) difference between troughs of FEV1 and PC20 variations. We conclude that the peak of circadian variation of bronchial responsiveness precedes the trough of circadian variation of bronchial caliber in asthmatic children.
Pulmonary function, nutrition, and self-concept in cystic fibrosis summer campers, Children with cystic fibrosis (CF) often attend special summer camps. We postulated that beyond the simple fun of camp. attendance at camp might improve the clinical status and self-image of the campers. We therefore studied lung function. nutrition. and self-image in 45 children between the ages 6 and 12 years after a two-week CF summer camp. Although there was a 10 percent fall in respiratory rate during camp. spirometry did not change significantly. There were. however. significant gains in weight. skin fold thickness. and midarm circumference after two weeks at camp. and these increases were positively correlated with the number of pancreatic enzymes taken daily by the child. The Primary Self-Concept Inventory test was completed by each camper on the first and last days of camp. Although there was a trend toward increasing self-concept during camp. this did not reach statistical significance. Two weeks' attendance at summer camp appears to be associated with improved nutrition in children with CF. This may be due to increased emphasis on weight gain and appropriate use of pancreatic enzymes or to other factors. like avoidance of tobacco smoke exposure. that are unique to the summer camp setting.
Pulmonary embolectomy by catheter device in massive pulmonary embolism, From 1982 to 1989. ECD was performed on 18 patients suffering from poorly-tolerated massive pulmonary embolism. for whom classic treatments (fibrinolytics and surgery) were impossible. Eleven of these 18 patients immediately improved (S group). This procedure was unsuccessful in other seven patients (F group). Thirteen patients survived (72 percent). The time lag between the first episode of pulmonary embolism and ECD was significantly shorter in the S group than in the F group (4.7 +/- 5.4 days vs 18.3 +/- 6.9 days. p = 0.0004). So was the elapsed time between the onset of hemodynamic impairment and ECD (13 +/- 12 hours vs 59 +/- 38 hours. p = 0.003). We conclude that ECD should be considered when other treatments are impossible especially when the first symptoms date back less than 15 days and the hemodynamic impairment less than 48 h.
Comparison of oxygen desaturation during sleep and exercise in patients with cystic fibrosis, Patients with cystic fibrosis (CF) desaturate during sleep and during exercise but by different mechanisms. To determine the need for supplemental oxygen. many centers measure resting and exercise arterial oxygen saturation (SaO2). We examined the associations among resting. sleep. and exercise SaO2 to ascertain the validity of this approach. We studied 21 adult and adolescent CF patients. eight of whom were hypoxemic (SaO2 less than 95 percent; group A) and 13 of whom were nonhypoxemic (SaO2 greater than or equal to 95 percent; group B) by overnight oximetry and treadmill exercise testing. The whole group desaturated more during sleep than during exercise. the change in SaO2 being 10.59 +/- 8.35 vs 6.25 +/- 4.44 (p less than 0.002). Group B desaturated significantly more during sleep than during exercise. with a reduction in SaO2 of 7.9 +/- 3.3 vs 3.3 +/- 1.49 (p less than 0.05). Group A desaturated more during exercise than group B. with a reduction of 11 +/- 3.2 vs 3.3 +/- 1.5 (p less than 0.001). Despite a strong correlation between awake SaO2 and mean sleep SaO2 (r = 0.68; p less than 0.001). minimum sleep SaO2 (r = 0.55; p less than 0.01). and minimum exercise SaO2 (r = 0.92; p less than 0.001). there was no correlation between awake SaO2 and sleep-related desaturation or between exercise- and sleep-related desaturation. In conclusion. clinically significant oxygen desaturation during sleep may be missed unless specifically checked in CF patients. and awake and exercise SaO2 may not give an indication of the degree of sleep-related desaturation.
High prevalence of positive antibodies to Legionella pneumophila among outpatients, A serologic survey of antibodies to Legionella pneumophila serogroups 1 through 6 was performed to assess the prevalence of positive antibody titers among outpatients and to evaluate the association between elevated antibody titers and previously identified risk factors for legionellosis. Subjects were recruited from outpatient clinics at the Minneapolis VA Medical Center. Each participant completed a self-administered questionnaire which asked about their general health and any recent symptoms of illness. Medical records were also audited for all participants to provide additional information on medical history and known risk factors for Legionella infection. Single samples of serum were obtained from each subject. and antibody titers to L pneumophila serogroups 1 through 6 were assayed. Three hundred ninety-six subjects were enrolled in the study. They had a mean age of 67 years. and 98 percent were male subjects. Overall. 36 percent of the subjects had positive antibody titers (greater than or equal to 1:128) to L pneumophila. There were no differences between those with and without elevated titers with respect to recent systemic symptoms or other previously established risk factors for legionellosis. We conclude that positive anti-Legionella antibodies are a frequent occurrence among these outpatients. This has important implications for the interpretation of single or static antibody titers from patients who are acutely ill.
Routine initial computed tomography of the chest in blunt torso trauma, Computer tomography (CT) is an effective technique in the initial evaluation of the abdomen and head following blunt trauma. To evaluate the role of CT of the thorax. a prospective study comparing routine early thoracic CT scanning with initial chest roentgenogram (CXR) was carried out on 73 patients with blunt torso trauma undergoing concomitant abdominal CT examination. Initial CXR and CT scans were interpreted independently by radiologists in a blinded fashion. CXR diagnosed more bony injuries than CT. while the CT identified pulmonary contusions and effusions more accurately. Only those contusions diagnosed by CXR proved clinically significant. Patient treatment was changed in one case based on CT findings. In the absence of CXR findings. chest CT scanning frequently identifies abnormalities with limited clinical significance. Although more sensitive. CT of the thorax has a limited role in the initial emergent evaluation of victims of blunt torso trauma.
Action of budesonide on asthmatic bronchial hyperresponsiveness. Effects on directly and indirectly acting bronchoconstrictors, We have investigated the effects of inhaled budesonide on the bronchial responsiveness to both directly and indirectly acting spasmogens in man. Following treatment with budesonide or placebo for three weeks in a double-blind. crossover trial with a three-week washout. the response to histamine and bradykinin was determined in ten patients with mild asthma. After treatment with budesonide. the response to both inhaled histamine and bradykinin was decreased when compared with placebo. The PD35 histamine was increased by 1.95 doubling doses and PD35 bradykinin by 2.1 doubling doses. Daily (PEF) recordings were significantly increased during budesonide therapy. the morning PEF by 34.8 +/- 14.1 L/min and evening by 50.3 +/- 23.1 L/min. Baseline laboratory lung function on the study days was not altered by budesonide nor were symptom records altered significantly. Inhaled budesonide therefore inhibits to the same extent the exaggerated response to both directly acting histamine and bradykinin which acts through airway nerves.
Antibody levels to whole culture filtrate antigens and to purified P32 during treatment of smear-positive tuberculosis, Antimycobacterial IgG levels were measured repeatedly during treatment in 12 patients with moderate or severe pulmonary tuberculous disease using a dot immunobinding assay. We used reflectance densitometry equipment to quantify the immunoperoxidase staining and a Mycobacterium bovis BCG culture filtrate and the purified P32 protein as antigens. Antibody response against whole culture filtrate and P32 antigen increased after a three-month period of treatment. After this antibiotherapy was completed. the estimated amount of antibodies directed against the P32 decreased while those against the whole culture filtrate remained at the same level. A serologic test using P32 as the antigen seems to allow a better discrimination between active and healed tuberculosis.
Appearance of thrombosis-inducing activity in the plasma of patients undergoing pulmonary resection, Thrombosis-inducing activity (TIA) was detected in the peripheral blood of patients with lung cancer who had undergone pulmonary resection. TIA was examined by intravenously injecting plasma from the patients into BALB/c mice. The plasma containing TIA induced multiple thromboses in the lung and caused the mice to die 3 to 30 minutes after injection. The subjects were 19 patients whose plasma contained no TIA before operation. TIA was detected in 5.3 percent (1/19) on the first postoperative day (POD). 47.4 percent (9/19) on the seventh POD. 47.1 percent (8/17) on the 14th POD. 26.7 percent (4/15) on the 21st POD. and 20 percent (2/10) on the 28th POD. Plasma fibrinogen levels and peripheral platelet counts increased postoperatively and reached a maximum on the seventh and 14th POD. respectively. Peripheral blood with TIA had a significant elevation of plasma fibrinogen levels and platelet counts as compared to that without TIA. These observations suggest that TIA is present in blood in a hypercoagulable state in patients after pulmonary resection. Since tumor necrosis factor and interleukin 1 are known to induce hypercoagulable states both in vitro and in vivo. we tried to determine whether it was possible to detect both cytokines in blood indicated as hypercoagulable state by the presence of TIA. They did not. however. reach detectable levels in the blood.
Effects of air pollution resulting from wire reclamation incineration on pulmonary function in children, This study evaluated the effect of long-term air pollution resulting from wire reclamation incineration on pulmonary function in children. General physical examination and the determination of spirometric parameters. including forced vital capacity (FVC). forced expiratory volume in 1 s (FEV1). and forced mid-expiratory flow (FEF25-75%) were conducted in 400 primary school children between ages 9 and 11 years who reside in one control and three polluted areas. A survey using ATS-DLD-78-C questionnaire indicated that there were no significant differences in their demographic characteristics among children in the four areas under study. Those who had nonrespiratory diseases that might affect pulmonary function and those who failed to perform spirometric measurements were excluded from the study; therefore. 382 children were included in data analysis. The results revealed that (1) the mean values of FVC and FEV1 (expressed as percentage of predicted values calculated from Polgar's equations) in the polluted areas were significantly lower than the nonpolluted area (p less than 0.05). and (2) the incidence of pulmonary function abnormality in the polluted areas was greater than that of the nonpolluted area (p less than 0.05). The results indicated that air pollution produced by wire reclamation incineration can impair children's pulmonary function.
Radionuclide evaluation of cardiac function during sleep in children with bronchopulmonary dysplasia, The influence of sleep on cardiac function in severe bronchopulmonary dysplasia was assessed in five children 1.5 to 5 years of age. Left and right ventricular ejection fractions (LVEF and RVEF) were investigated by equilibrium radionuclide ventriculography in five children undergoing polygraphic monitoring during the different states of alertness: wakefulness. nonrapid eye movement sleep. and rapid eye movement sleep. Intraobserver and interobserver LVEF and RVEF measurement reproducibility was high. During quiet. supine wakefulness. LVEF was normal. but RVEF was low. During sleep. a decrease in both LVEF and RVEF. expressed as a percentage of the awake value. was marked in the two children with the most nocturnal desaturation and longest duration of paradoxic rib cage motion during inspiration. It is concluded that radionuclide ventriculography can be easily performed during sleep in children and can provide useful information regarding right ventricular function during sleep in children with severe bronchopulmonary dysplasia.
Use of Medicare claims data to evaluate outcomes in elderly patients undergoing lung resection for lung cancer, OBJECTIVE: To estimate. using Medicare claims data. the outcomes in elderly Americans undergoing lung resection for lung cancer. DESIGN: We used discharge diagnosis and procedure codes in 1983 to 1985 Medicare hospital (part A) claims records to identify patients who underwent lung resection for lung cancer; we assessed perioperative. one-year. and two-year survival using Medicare enrollment file data. PATIENTS: From a nationally random sample of 1.138.000 Medicare beneficiaries over 65 years of age. we identified 1.290 individuals who fulfilled our definition for lung resection for lung cancer. MEASUREMENTS AND MAIN RESULTS: Overall perioperative (30-day) mortality was 7.4 percent. Postoperative survival at one and two years was 69 percent and 54 percent. respectively. Male sex. older age. and pneumonectomy. as opposed to a lesser procedure. were associated with reduced perioperative and one-year and two-year survival. The adverse effect of advanced age on one-year and two-year survival following lung resection was not explained by the lower life expectancy of older individuals. CONCLUSIONS: Medicare claims data can be used to estimate likely outcomes for elderly patients undergoing surgery for lung cancer. Expected outcomes vary with the patient's age. sex. and the type of surgical procedure performed.
Serial measurement of pulmonary mechanics assists in weaning from extracorporeal membrane oxygenation in neonates with respiratory failure, Extracorporeal membrane oxygenation (ECMO) is a highly invasive therapy for intractable neonatal respiratory failure. and serious complications may occur with increasing duration of bypass. Weaning from bypass is empirical at present. Thus. there is a need to accurately predict when infants can be successfully decannulated. We hypothesized that pulmonary mechanics would reflect lung recovery and. therefore. predict successful weaning from ECMO. We measured pulmonary mechanics daily in 22 neonates. at gestational age of 37.8 +/- 0.6 weeks (SE) requiring ECMO for severe respiratory failure (oxygen index 66 +/- 6). Pulmonary resistance (Rpul). dynamic compliance (Cdyn). and tidal volume (VT) were measured. Rpul did not predict lung recovery. Cdyn within 24 hours of starting ECMO was 0.3 +/- 0.04 ml/cm H2O. Cdyn within 24 hours of weaning from ECMO was 1.2 +/- 0.09 ml/cm H2O (p less than 0.001). All 22 infants had Cdyn greater than 0.6 ml/cm H2O at the time of decannulation. but four infants (20 percent) with Cdyn less than 0.6 ml/cm H2O could not be weaned from ECMO within 20 hours (p less than 0.01). Thus. a minimum Cdyn of 0.6 ml/cm H2O is associated with successful weaning from ECMO. Cdyn of 0.8 ml/cm H2O provided better overall discrimination between those who could be successfully weaned from ECMO. We conclude that serial measurement of dynamic pulmonary compliance predicts successful weaning from ECMO.
Antibiotic prophylaxis of respiratory tract infection in mechanically ventilated patients. A prospective, blinded, randomized trial of the effect of a novel regimen, The objective of this study was to assess the effect of a novel regimen of antibiotic prophylaxis on the incidence of lower respiratory tract infection in patients requiring prolonged (at least five days) mechanical ventilation. The design was a controlled. prospective. randomized trial. with blinded comparison of the groups regarding the incidence of respiratory tract infection in an intensive care unit of a university hospital. After determination of the APACHE II score for severity of disease. 88 patients were randomly divided in three groups. Twenty-four of these patients did not complete five days of mechanical ventilation. and eight were withdrawn for other reasons. Fifty-six patients (18 in group 1. 21 in group 2. 17 in group 3) completed the study. Patients in both control groups 1 and 2 did not receive antibiotic prophylaxis. but the two groups differed in the antibiotic policy in case of infection. Patients in group 3 received antibiotic prophylaxis consisting of norfloxacin. polymyxin E. and amphotericin B. applied topically in oropharynx and stomach from time of ICU admission until extubation. and intravenous cefotaxime 500 mg three times a day during the first five days of admission. In both control groups. about 90 percent of the patients acquired microbial colonization of oropharynx or stomach. In group 3. only 12 percent and 24 percent of the patients acquired colonization of oropharynx and stomach. respectively (p less than 0.001). This resulted in a reduction of the incidence of lower respiratory tract infection (78 percent in group 1. 62 percent in group 2. 6 percent in group 3 [p = 0.0001]). The regimen of antibiotic prophylaxis studied prevented respiratory tract infection in mechanically ventilated patients. Antibiotic prophylaxis should be considered in all patients expected to require prolonged mechanical ventilation.
Effects of high- and low-carbohydrate meals on maximum exercise performance in chronic airflow obstruction, The purpose of this study was to compare the effects of isocaloric liquid meals with high fat (55 percent) and low carbohydrate (28 percent) content (Pulmocare) to meals with low fat (30 percent) and high carbohydrate (53 percent) content (Ensureplus) on exercise performance in subjects with chronic airflow obstruction (CAO). Twelve stable subjects with CAO (FEV1 = 1.30 +/- 0.47 L) underwent incremental symptom-limited exercise tests 90 minutes following the ingestion of 920 calories of EnsurePlus HN (E). 920 calories of Pulmocare (P). or a noncaloric placebo (C). Tests were performed on three days. in a double-blind randomized fashion. Expired gases were collected continuously and analyzed every 30 seconds. The mean maximal work load after E (81 +/- 24 W) was significantly less than that after P (88 +/- 21 W) or C (88 +/- 24 W). The mean ventilation at exhaustion was similar after E (48 +/- 13 L/min). P (51 +/- 11 L/min). and C (49 +/- 10 L/min). In comparison to C. six of the 12 individuals had a decreased work load following E. while only one had a decreased maximal tolerated work load following P. The results of this study suggest that meals with a higher fat and lower carbohydrate content may be less likely to impair work performance of patients with CAO in the absorptive phase than meals with a lower fat and higher carbohydrate content. These findings may have clinical significance to patients with CAO who complain of postprandial exertional dyspnea.
Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism, In a canine model of pulmonary embolism (PE) produced by infusion of autologous blood clots. mean arterial blood pressure (MAP) decreased to 73 +/- 4 mm Hg while cardiac output (CO) decreased to less than 50 percent of baseline. Intravenous infusion of phenylephrine (PHEN) and norepinephrine (NE) restored MAP to somewhat above baseline values. However. only NE restored CO to control levels. The right ventricular myocardial blood flow increased 15 percent in the PE group with PHEN and 229 percent with NE at equipressor concentrations. The right ventricular myocardial oxygen consumption (RVMVo2) was not significantly different between PE and PE + PHEN while PE + NE increased RVMVO2 by 144 percent to 20.2 +/- 1.8 ml/min/100 g. The RV output was not adequately restored with PE. but when RV contractility was augmented with NE. RV output was restored to baseline. Right ventricular minute work increased 100 percent with NE and was maintained with a 100 percent increase in oxygen consumption. Calculated pulmonary vascular resistance (PVR) was decreased during PE by 36 percent with PE + PHEN while PVR in NE-treated dogs decreased by 59 percent. In NE-treated animals. systemic vascular resistance (SVR) was restored to control levels while in PHEN-treated animals SVR increased about 75 percent from baseline. We conclude that the salutary effects of NE on RV output are due to both alpha and beta receptor stimulation. which increased contractility. RVMBF. and RVMVo2. and decreased both PVR and SVR. In the PHEN-treated dogs. our indices of minute-work. RVMBF. and RVMVo2 suggest that coronary autoregulation was intact; however. there was no apparent benefit to RV output. This study suggests that in the clinical setting of acute PE. the judicious use of NE. rather than PHEN. may be more beneficial in restoring RV function and systemic hemodynamics.
Gram-negative sepsis. Background, clinical features, and intervention, Gram-negative sepsis remains an urgent medical problem. with more than 200.000 cases occurring each year in the United States and an associated mortality rate of 20 to 50 percent. Since the onset of shock greatly worsens prognosis and to encourage early intervention. the term sepsis syndrome was developed to describe the features of a preshock septic state. Early clinical and metabolic indicators are discussed. and current therapy is reviewed. Better understanding of the pathophysiology of endotoxin release from Gram-negative bacteria and advances in biotechnology have led to the development of potential new treatments for sepsis. One such development--monoclonal antibodies to endotoxin--has shown great promise in the effort to block the progression to septic shock. reduce mortality. and decrease the overall costs of sepsis to the patient and to the national economy.
Use of TAO without methylprednisolone in the treatment of severe asthma, The antimicrobial agent troleandomycin (TAO) has been shown to be effective in reducing corticosteroid requirements in patients with corticosteroid-dependent asthma. To our knowledge. the efficacy of TAO without concomitant use of corticosteroids has never been documented. We report the case of a 12-year-old patient with corticosteroid-dependent asthma who has remained asymptomatic and without any evidence of pulmonary deterioration during treatment with TAO without concomitant use of corticosteroids.
Check-valve mechanism as a cause of bilateral spontaneous pneumothorax complicating bronchioloalveolar cell carcinoma, We present a rare case of simultaneous bilateral pneumothorax complicating bronchioloalveolar cell carcinoma. Autopsy revealed that numerous subpleural alveolar spaces were distended and most of the small airways were narrowed by cancer cells. We conclude that a check-valve mechanism may be responsible for pneumothorax in patients with bronchioloalveolar cell carcinoma.
J-shaped catheter for endobronchial aspiration of right upper lobe bronchus during rigid bronchoscopy in pediatric patients, A J-shaped suction catheter was tailored to facilitate aspiration of the right upper lobe bronchus during rigid bronchoscopy in pediatric patients. This suction catheter was used successfully in three patients.
Percutaneous balloon valvotomy for the treatment of isolated tricuspid stenosis, A 46-year-old woman with isolated tricuspid stenosis complained of increasing fatigue and dyspnea on exertion. Exercise Doppler echocardiography reproduced her symptoms and revealed a marked increase in trans-tricuspid gradient. Successful percutaneous balloon tricuspid valvotomy was performed. with resolution of her symptoms.
The thoracic vent. Clinical experience with a new device for treating simple pneumothorax, We report recent experience with a new device. the thoracic vent. in the management of simple pneumothorax. There were 16 patients aged 19 to 73 years who suffered pneumothorax due to spontaneous (4). traumatic (3). or iatrogenic (9) causes. Ease of insertion. patient tolerance. and the presence of a unique signal diaphragm all contributed to patient and physician acceptance of the device. Average time to pneumothorax resolution was 2.5 days. and time to thoracic vent removal averaged 3.2 days. There were no immediate recurrences or significant complications. We conclude that the thoracic vent is an effective device for initial and definitive therapy of simple pneumothorax.
In vivo evidence of altered chloride but not potassium secretion in cystic fibrosis rectal mucosa, In cystic fibrosis. cyclic adenosine monophosphate-mediated chloride secretion is abnormal in respiratory. small intestinal. and rectal mucosa. Calcium-mediated chloride secretion is also aberrant in CF small intestinal mucosa in cystic fibrosis. in contrast to the respiratory epithelia. where it appears to be normal. To determine whether this disparity between calcium- and cyclic adenosine monophosphate-mediated chloride secretion exists in cystic fibrosis rectal mucosa in vivo. transrectal potential difference was measured in age-matched adult cystic fibrosis subjects (n = 8) and control subjects (n = 9) in response to 10-minute luminal perfusions of bethanechol (1 mmol/L) or theophylline (5 mmol/L). In response to bethanechol. an initial (1-minute) negative change in potential difference (-1.4 +/- 1.1 mV; mean +/- SEM) was seen in control subjects. in contrast to a positive change in mean potential difference (+2.5 +/- 1.0 mV) in cystic fibrosis subjects (control vs. cystic fibrosis. P less than 0.05). After 1 minute. mean potential differences changes in both control and cystic fibrosis subjects were positive. Theophylline perfusion resulted in a significant (P less than 0.01) difference in potential difference response between groups; at 10 minutes. the potential difference became more negative (-3.6 +/- 1.4 mV) in control subjects and more positive in cystic fibrosis subjects (+3.9 +/- 1.4 mV). To determine whether second messenger-mediated potassium secretion contributed to the observed potential difference changes in response to bethanechol and theophylline. studies were repeated in the presence of barium chloride. a known blocker of potassium conductance. In the control group. barium chloride significantly enhanced the theophylline-induced negative potential difference change (P less than 0.05) and reduced the positive potential difference change seen with bethanechol alone. In subjects with cystic fibrosis. barium chloride completely abolished the previously seen positive potential difference change in response to either bethanechol or theophylline alone. These in vivo studies suggest that there is active potassium secretion in both control and cystic fibrosis rectal mucosa in response to cyclic adenosine monophosphate- and calcium-dependent secretagogues and that the magnitude of the potential difference changes attributable to barium-inhibitable potassium secretion is the same in cystic fibrosis and control subjects. In contrast. it appears that in cystic fibrosis rectal mucosa in vivo. calcium- as well as cyclic adenosine monophosphate-dependent chloride secretion is aberrant.
Increased activation of isolated intestinal lamina propria mononuclear cells in inflammatory bowel disease, Normal human lamina propria lymphocytes are in a heightened state of activation compared with peripheral blood with regard to cell-surface activation antigen expression (transferrin receptor. interleukin-2 receptor. 4F2) and the increased spontaneous secretion of immunoglobulins in vitro. This study evaluates the cell-surface expression of activation-associated antigens in different subpopulations of isolated colonic lamina propria mononuclear cells in inflammatory bowel disease. In pilot studies using three-color flow cytometry. autofluorescence was observed that was emitted by unstained lamina propria mononuclear cells. which interfered with both the sensitivity and the specificity of the analyses. Because a major portion of the intestinal lymphocyte populations of interest were autofluorescent. a method to remove autofluorescence signals was developed by designing a computer program for the subtraction of autofluorescence from the emissions of each individual cell. This technique increases both the sensitivity and specificity of flow-cytometric analyses of intestinal lamina propria mononuclear cells. Using fluorescence-activated cell-sorter analyses with subtraction of autofluorescence on a single-cell basis. increased expression of lymphocyte activation antigens (interleukin-2 receptor. transferrin receptor. 4F2) was found on the cell surface of isolated intestinal B cells. T cells. CD4+ T cells. and CD8+ T cells in both Crohn's disease and ulcerative colitis. Therefore. markedly increased intestinal lymphocyte activation is a major immunological alteration in inflammatory bowel disease and includes all lymphocyte subpopulations investigated in this study. In addition. 5-aminosalicylic acid. which is used for the treatment of intestinal inflammation in inflammatory bowel disease. inhibits the expression of cell-surface activation antigens on mitogen-activated peripheral blood lymphocytes in a dose-dependent manner. These observations suggest that lymphocyte activation may play an important role in underlying immune processes that lead to chronicity and perpetuation of inflammatory bowel disease and may implicate an additional mechanism for the therapeutic action of 5-aminosalicylic acid.
Defective Fc receptor-mediated clearance in patients with primary biliary cirrhosis, Fc receptor-mediated clearance of immunoglobulin G-coated autologous erythrocytes was studied in patients with primary biliary cirrhosis (n = 14). alcoholic liver cirrhosis (n = 5) and healthy reference individuals (n = 14). The mean half-life of the sensitized erythrocytes was significantly prolonged in patients with primary biliary cirrhosis (85 +/- 25 minutes; P less than 0.001) compared with the corresponding value in patients with alcoholic cirrhosis (16 +/- 2 minutes) and healthy reference individuals (20 +/- 5 minutes). respectively. No correlation between clearance rate and age. liver histopathology. or serum levels of bilirubin. aminotransferases. immunoglobulin G. immunoglobulin A. and Clq binding or C3-containing immune complexes was found. The results presented here indicate a profound disturbance of Fc receptor-mediated immune clearance function in patients with primary biliary cirrhosis.
Aspirin does not inhibit cholesterol cholelithiasis in two established animal models, The effect of aspirin on cholesterol cholelithiasis was examined in the hamster and the prairie dog. In the prairie dog. diets were composed of semipurified components of chow. plus cholesterol (1.2%). with and without aspirin. Animals were studied for either 2 weeks or 4 weeks. Cholesterol gallstones were present in all groups at the end of each period; aspirin did not alter the incidence of cholelithiasis. All animals studied had cholesterol crystals in the bile when they were killed. Liver cholesterol levels in prairie dogs with and without aspirin tended to be lower in animals fed chow than in animals fed semipurified diets. There were no significant differences in cholesterol levels in the plasma or bile. The cholesterol saturation index of all biles approached unity when animals were fed chow with aspirin; animals fed the semipurified diets had cholesterol saturation indices of less than 1.0. The prairie dogs fed aspirin plus cholesterol in the semipurified diet showed increased levels of biliary chenodeoxycholic acid amidates and concomitant decreased levels of cholic acid amidates compared with animals fed the same diet without aspirin. Hamsters fed aspirin plus cholesterol in a semipurified diet tended to have a greater incidence of gallstones than animals given no aspirin (80% vs. 55%). Liver and bile cholesterol levels were similar with and without aspirin; plasma cholesterol levels increased significantly with aspirin [14.20 vs. 7.80 mmol/L (549 vs. 301 mg/dL)]. Lithogenic indices in all hamsters were above unity; biliary lipids. total lipid concentration. and biliary bile acid composition were similar. These results show that the addition of aspirin to a lithogenic diet does not reduce the incidence of cholelithiasis.
Electrolyte transport in piglets infected with transmissible gastroenteritis virus. Stimulation by verapamil and clonidine, The effects of clonidine. an alpha 2-adrenergic agonist. and verapamil. a Ca2+ channel blocker. on Na+ and Cl- absorption were studied in stripped jejunal mucosa from control and transmissible-gastroenteritis-virus-infected piglets. All infected piglets developed severe diarrhea 18-24 hours after oral inoculation. Jejunum from infected animals. as compared with control jejunum. had decreased mucosal-to-serosal. serosal-to-mucosal. and net Na+ and Cl- fluxes. Clonidine and verapamil caused a decrease in short-circuit current and stimulation of Na+ and Cl- absorption in control jejunum. In infected piglets. although the jejunum exhibited severe villus atrophy. both drugs stimulated Na+ and Cl- absorption and the magnitude of Na+ and Cl- absorption was similar in control and transmissible-gastroenteritis-infected jejunum. In contrast. D-glucose stimulated Na+ absorption. and the decrease in short-circuit current caused by verapamil and clonidine. were decreased in transmissible-gastroenteritis-infected jejunum. Such pharmacological stimulation of Na+ and Cl- absorption might be useful in the management and treatment of certain viral diarrheal diseases.
Comparative evaluation of acid- and bile-induced damage to pedicled jejunal or colonic segments in the rat, The choice of the esophageal substitute after surgical resection for peptic stricture lies between the colon and jejunum. The current study was designed to compare long-term resistance of the colonic and jejunal mucosa to gastric or mixed duodenogastric secretions. The following preparations were performed in Wistar rats: transposition of a colonic or jejunal patch (a) to the gastric body. with or without truncal vagotomy. or (b) to the gastric antrum and proximal duodenum. with or without truncal vagotomy. Jejunal and colonic patches were removed 4. 8. and 12 months after surgery. The only damage to the transposed mucosae was the alteration of microvilli. The alteration was more severe in colonic than in jejunal patches and was prevented by truncal vagotomy. Long-term resistance of the transposed mucosae to the environmental challenge may depend on their adaptation potentiality. involving both specific and nonspecific mechanisms. Nonspecific mechanisms include the increased production of mucus and the gastric-like transformation of the superficial epithelial layer. Specific mechanisms include the reduction of the mucosal surface size for jejunal segments and the shifting in mucin secretion patterns for colonic segments.
Mechanism of inhibitory action of prostaglandins on the growth of human gastric carcinoma cell line KATO III, Prostaglandins (PGs) play important roles in the regulation of various gastric functions. In this study. the effects of various PGs on the growth of the human gastric carcinoma cell line KATO III were investigated. All the PGs tested inhibited KATO III cell growth with a relative potency order of PGE2 greater than PGE1 greater than 17S.20-dimethyl-6-oxo PGE1-methyl ester (ornoprostil) greater than PGF2 alpha. This inhibition was accompanied by an increase of cyclic adenosine monophosphate production. Furthermore. in the presence of guanosine triphosphate. these PGs stimulated adenylate cyclase activity in the plasma membrane of KATO III cells. followed by enhancement of membrane guanosine triphosphatase activity. The relative potencies of these PGs for increasing cyclic adenosine monophosphate levels. activating adenylate cyclase. and enhancing guanosine triphosphatase activity were all comparable to those for inhibiting cell growth. On the other hand. the proliferation of KATO III cells was also inhibited by forskolin as well as dibutyryl cyclic adenosine monophosphate. whereas none of the agents that did not increase cyclic adenosine monophosphate levels had any effect. These results suggest that PGs inhibit KATO III cell growth by stimulating cyclic adenosine monophosphate production via a guanosine triphosphate-dependent process. suggesting the involvement of guanosine triphosphate-binding stimulatory protein. probably coupled to PGE2 receptors. in the action of PGs.
Reverse-perfused sleeve: an improved device for measurement of sphincteric function of the crural diaphragm, The sphincteric function of the crural diaphragm has been difficult to measure in humans. The authors recently reported the use of a Dent sleeve device to measure esophagogastric junction pressure during contraction of the crural diaphragm. However. the major limitation of the conventional sleeve device is its slow response rate. and sustained diaphragmatic contractions of 6-8 seconds must be induced to measure the true pressure. In this article. the principles of a reverse-perfused sleeve device and the theoretical basis for its fast response rate are reported. The reverse-perfused sleeve is validated in an in vitro model of the lower esophageal sphincter. Furthermore. in vivo studies were performed in seven healthy human subjects. Standardized Muller maneuvers and straight-leg raises were performed to induce diaphragmatic contractions. Pressure increases of 50-150 mm Hg during diaphragmatic contractions were attained in less than 1 second. The delay between the actual contraction of the diaphragm as measured by simultaneously recorded crural diaphragm electromyography and pressure recorded by the sleeve was only 0.25-0.50 seconds. Increasing the rate of infusion of the sleeve from 0.5 to 1.0 mL/min did not further improve the response rate of the reverse perfused sleeve. It was concluded that the reverse-perfused sleeve is a considerable improvement over the conventional sleeve for quantitating the sphincteric function of the crural diaphragm. The role of the crural diaphragm in reflux esophagitis may be easily investigated using a reverse-perfused sleeve device.
Effect of age on gastric acid secretion and serum gastrin concentrations in healthy men and women, The effects of age on basal. meal-stimulated. and human gastrin-17-stimulated gastric acid secretion rates and serum pepsinogen concentrations were evaluated in 41 healthy men and women. Older subjects (ages 44-71 years; mean. 57 years) had higher mean basal. meal-stimulated. and gastrin-17-stimulated acid secretory rates and basal serum pepsinogen I and II concentrations than younger subjects (ages 23-42 years; mean. 33 years). Age-related differences in acid secretion were especially prominent in men. and age-related differences in serum pepsinogen I and II concentrations were more prominent in women. Higher gastric acid secretion rates in older subjects could not be explained by body size (height. weight. body surface area. or fat-free body mass) or by the higher incidence of infection with Helicobacter pylori. Using a multivariate linear regression model. age had an independent positive effect on acid secretion. and H. pylori infection had an independent negative effect. It was concluded that aging is associated with an increase in gastric acid secretion in humans. especially in men. while infection with H. pylori is associated with lower acid secretion rates.
Enterogastric reflux after various types of antiulcer gastric surgery: quantitation by 99mTc-HIDA scintigraphy, In 28 controls and 142 patients subjected to a variety of antiulcer procedures. the enterogastric reflux (EGR) was quantitated by 99mTc-HIDA scintigraphy and expressed as the EGR index on 229 different occasions. The EGR index was calculated according to two different formulas: one based on the maximal radioactivity over the gastric area as a percentage value of the total abdominal activity (EGR-Im) and the other based on the relative maximal radioactivity over the gastric area as a percentage value of the relative hepatobiliary activity (EGR-It). There was a significant positive correlation of values between the two methods (P less than 0.0001). In patients with an EGR-Im greater than 20% or EGR-It greater than 57% and postgastric surgery symptoms some of the symptoms were attributed to EGR. an antireflux procedure is expected to relieve those symptoms. Sixteen of these patients underwent Roux-en-Y gastrectomy and their preoperative symptoms were relieved.
Malignant tumors of the eye in geriatric patients, The ocular tissues can be the site of a number of malignant tumors in adults and geriatric patients. In addition to posing a threat to the patient's life. these tumors can cause severe visual loss or blindness. Therefore. the primary care clinician should be capable of prompt diagnosis of the various malignant ocular tumors and be prepared to refer the patient for appropriate management. This article provides a photographic guide to the most common primary and secondary malignancies that can affect the eyelid. conjunctiva. intraocular structures. and orbit in the geriatric patient.
Obesity: it's time to 'clean house', Inactive older patients are at high risk for overeating. Caring doctors can help them tune out temptation and trim down.
Vascular renin-angiotensin system and neurotransmission in hypertensive persons, The existence of a vascular renin-angiotensin system and its role in modulating sympathetic activity were evaluated in forearm arterioles of hypertensive individuals. Isoproterenol (0.03. 0.01. 0.3 microgram/100 ml/min for 5 minutes each; n = 5) was infused into the brachial artery. and active and inactive renin. angiotensin II. and norepinephrine forearm balance (venous-arterial differences corrected for forearm blood flow by strain-gauge plethysmography) were measured. Isoproterenol caused vasodilation and a dose-dependent active and inactive renin. angiotensin II. and norepinephrine outflow. an effect blunted by propranolol (10 micrograms/100 ml/min). To evaluate the role of local angiotensin II on beta-mediated norepinephrine overflow. the experiment was repeated with captopril (2.5 micrograms/100 ml/min for 10 minutes; n = 5). which abolished angiotensin II release and significantly reduced norepinephrine overflow. To test whether angiotensin II facilitates both prejunctional norepinephrine release and its postjunctional action. we evaluated the effect of exogenous angiotensin II. infused into the brachial artery at low concentrations (0.001 microgram/100 ml/min). on forearm vasoconstriction and norepinephrine release induced by endogenous sympathetic activation (application of a lower body negative pressure: -10 and -20 mm Hg for 5 minutes. n = 10) and on the vasoconstrictor effect of local norepinephrine (0.0015. 0.005. 0.015. 0.05. 0.15 micrograms/100 ml/min for 3 minutes each; n = 6). Although angiotensin II increased the vasoconstricting effect and the norepinephrine release induced by lower body negative pressure. it failed to affect norepinephrine-mediated vasoconstriction. Our data indicate the existence in hypertensive individuals of a vascular renin-angiotensin system that seems to modulate sympathetic activity through the presynaptic facilitation of norepinephrine release.
Simplified captopril renography in diagnosis and treatment of renal artery stenosis, To improve the diagnosis and forecast the response to surgery or renal angioplasty in patients with hypertension and renal artery stenosis. we employed a simplified captopril renography protocol in conjunction with renal arteriography in 94 clinically selected patients. Fifty hypertensive patients (group 1) with a high clinical likelihood of renovascular hypertension were evaluated using a simplified captopril renography protocol and renal angiography on the arterial side. Criteria for normal captopril renal scintigrams were established based on this original cohort and validated in an additional 44 clinically comparable patients (group 2). Renal revascularization or nephrectomy was performed in 39 patients. and success of the procedure was determined in the 34 patients for whom 3-month follow-up was available. In the 94 patients. 44 (47%) had renal artery stenosis. Simplified captopril renography was 91% sensitive and 94% specific in identifying or excluding renal artery stenosis in the combined group. with no difference in the diagnostic utility between groups 1 and 2. or in those with renal insufficiency (n = 38) or those with bilateral disease (n = 17). Scintigraphic abnormalities induced by captopril were strongly associated with cure or improvement in blood pressure control following revascularization or nephrectomy (15 of 18). while the lack of captopril-induced changes was associated with failure of such intervention (13 of 16) (p = 0.0004). We conclude that simplified captopril renography is highly sensitive and specific in the diagnosis of renal artery stenosis in a clinically selected high-risk population and that the test accurately predicts the success or failure of therapeutic intervention.
Glucose tolerance and insulin action in rats with renovascular hypertension, To test whether hypertension can cause hyperinsulinemia or insulin resistance. we performed intravenous glucose tolerance tests at 1 month and euglycemic clamps at 3 months after induction of two-kidney. one clip renovascular hypertension in rats. At 1 month. systolic pressure was higher in 21 clipped than in 12 control animals (161 +/- 5 mm Hg. range 134-187 mm Hg versus 119 +/- 3 mm Hg. range 108-146 mm Hg; p less than 0.001). Glucose tolerance. assessed as the glucose fractional disappearance rate between 3 and 11 minutes after the glucose injection. was similar in the clipped and sham groups (0.059 +/- 0.002 versus 0.056 +/- 0.002 min-1. respectively; p greater than 0.4). The total area under the insulin curve during glucose tolerance tests was also similar in the clipped and sham groups (926 +/- 95 versus 869 +/- 126 microunits/ml x min; p greater than 0.4). There was no significant relation between systolic blood pressure and insulin area during glucose tolerance tests in the clipped group. but there was a positive rectilinear relation in the control group (r = 0.66; p = 0.01). Fourteen animals had euglycemic clamps 2 months after glucose tolerance tests. At that time. systolic pressure (direct femoral measurement) was higher in the seven clipped animals (189 +/- 13 mm Hg versus 122 +/- 5 mm Hg in controls; p less than 0.001). Insulin infusions of 1 and 4 milliunits/min/kg body wt effected similar plasma insulin levels in the two groups.
Nutrition and hypertension prevention, Hypertension has been related to both obesity and a high salt intake. Evidence for the associations of blood pressure with body weight and dietary salt intake is summarized. In both adolescents and adults correlations between blood pressure and weight are highly significant. and in longitudinal studies change in blood pressure over time is correlated with change in weight. Correlations between salt intake and blood pressure are less striking. and the results of trials of modest salt restriction demonstrate a small but significant effect on blood pressure. Individuals vary in their susceptibility to salt. and hypertensive individuals are more responsive than normotensive individuals. Dietary deficiencies of potassium and calcium may amplify the effect of a high salt intake on blood pressure. Animal models provide compelling evidence for a genetic component to salt sensitivity of blood pressure. In two hypertension prevention trials. change in blood pressure was more convincingly related to change in weight than to change in dietary salt. Avoidance of obesity. or weight reduction in overweight individuals. should be key strategies for hypertension prevention. Avoidance of salt excess is also appropriate. although currently available trial data do not justify a recommendation of rigorous salt restriction for the entire population.
Hypertension and coronary artery disease. Can the chain be broken, Hypertension is an established risk factor for all the clinical sequelae of coronary artery disease. Despite this. individual therapeutic trials of antihypertensive therapy have not demonstrated the expected reduction in coronary morbidity and mortality. This apparent failure is perhaps not surprising when one considers the multifactorial nature of coronary artery disease and the different ways in which hypertension may affect the coronary circulation. Much debate has also centered on the antihypertensive therapy used in major trials in that it may in some way prevent the reduction in coronary mortality. However. thus far no clear evidence of a harmful effect has emerged. Reducing coronary mortality in hypertensive patients is a major challenge but one that can be effectively surmounted by approaching these different factors in a concerted manner. The ultimate goal must be to prevent the development of hypertension and left ventricular hypertrophy. but until such time as that can be achieved. the early detection of hypertension is mandatory. The optimal levels of systolic and diastolic blood pressures must be established. Studies on the more recent antihypertensive agents hold promise for a more specific effect on the atherosclerotic process as well as sustained control of arterial blood pressure. In this regard. it would seem essential to develop more precise ways of quantifying atherosclerosis and thus clarifying the nature of its relation to hypertension. Finally. management of hypertension must include precise assessment of the patient's overall cardiovascular risk status and appropriate and aggressive management of all risk factors for coronary artery disease.
Is reversal of left ventricular hypertrophy in hypertension beneficial, The left ventricle increases its mass and wall thickness in hypertension as a result of the progressive increase in hemodynamic overload offered by increasing arterial blood pressure and total peripheral resistance. However. evidence is increasing that nonhemodynamic factors may also be important in the development of left ventricular hypertrophy (LVH). This LVH resulting from hypertensive disease conveys an independent risk of premature cardiovascular morbidity and mortality. The specific mechanisms accounting for this increased risk are not known with assurance. although several mechanisms are under active study; they include more prominently ventricular dysrhythmias and myocardial ischemia. It is possible to diminish the increased left ventricular mass with pharmacological agents. although currently it is not known whether this reversal also diminishes the risk associated with LVH. Therefore. at the present time the best means for preventing the risk of LVH is to prevent its development in the first place. and this seems to be preventable through control of arterial blood pressure at the earliest stages of hypertension. Risk may also be diminished in patients with existing LVH who are receiving digitalis or diuretics or who have chronic fluid- and electrolyte-disturbing diseases. Under these circumstances. the careful use and selection of antihypertensive therapy and control of electrolyte balance no doubt will prevent unnecessary morbidity and mortality.
Are some antihypertensive therapies more efficacious than others in preventing complications and prolonging life, Antihypertensive therapy has been used for almost 35 years to reduce blood pressure and prevent morbidity and mortality related to the hypertensive state. Malignant. severe. and moderate hypertension have all been shown to be worthy of drug treatment. but controversy remains as to the degree of benefit that is achievable by treating milder hypertension. A variety of clinical trials have demonstrated that antihypertensive therapy reduces the incidence of stroke. congestive heart failure. and left ventricular hypertrophy and the progression in severity of hypertension. The benefits with respect to prevention of coronary heart disease (CHD) have been much less impressive. Thiazide diuretics have been the base therapy for the bulk of the hypertensive subjects studied to date who have not demonstrated reduced incidence of CHD. Therapy with beta-blockers has the potential for reducing CHD. but an analysis of four studies finds only two with positive results. On the other hand. since that study found reduced total mortality as well as CHD compared with thiazide diuretic. its findings cannot be ignored. Other questions deserving further investigation include how other antihypertensive therapies compare with respect to the risk reduction found with thiazide diuretics and beta-blockers. the optimal posttreatment blood pressure. whether persons with mild hypertension benefit from therapy. whether women should be treated differently. and whether atherosclerosis may be affected by specific antihypertensive therapies.
Long-term effectiveness of nonpharmacological treatment of hypertension, Various nonpharmacological therapies reduce the blood pressure of a significant portion of both patients with established hypertension and people who are considered to be at high risk for the development of hypertension; that is. they are secondary and primary preventions. Of the various therapies. weight reduction. sodium restriction. moderation of alcohol intake. and regular aerobic exercise have been shown to be most effective. whereas the effectiveness of other practices has been less uniform or smaller in degree. Changes in lifestyle. mainly involving diet and physical activity. should be widely used to treat and. hopefully. to prevent hypertension.
Dissecting the primary causes of genetic hypertension in rats, Blood pressure has a genetic component influenced by several to many genetic loci in both humans and animals; that is. blood pressure is a polygenic trait. Ultimately. the primary causes of genetic hypertension can only be established with genetic techniques. The primary tools for this analysis in animals are inbred strains of rodents selectively bred for differences in blood pressure and the genetic analysis of these strains by cosegregation techniques. This analysis determines whether it is possible to separate specific alleles at a candidate genetic locus from a component of blood pressure in genetically segregating populations. If the candidate alleles cosegregate with a component of blood pressure. these alleles must be the cause of the blood pressure differences or be linked on the same chromosome to alleles at other loci that cause blood pressure differences. If. on the other hand. the candidate alleles do not cosegregate with blood pressure. they cannot be the cause of the blood pressure differences. This analysis is straightforward in the case of a single-locus Mendelian candidate trait but is less informative if a candidate trait is itself polygenic. In this case. genetic analysis yields either 1) results that are compatible with. but not definitive proof for. a genetic role of the trait in causing blood pressure differences or 2) results that eliminate the trait as a cause of genetic differences in blood pressure. A complete listing of all the traits that have undergone genetic cosegregation analysis in rodents is given.
Are vascular abnormalities a primary cause or secondary consequence of hypertension, This paper reviews the evidence that the resistance vasculature is altered in hypertension and the role that the vasculature may play in the pathogenesis of the disease. Although functional changes (i.e.. increased vascular smooth muscle sensitivity) have been found to be associated with some models of hypertension (e.g.. spontaneously hypertensive rat). in human essential hypertension it appears that the abnormalities that predominate in the resistance vasculature are structural in nature. These changes result in an increased media/lumen ratio of the more proximal resistance vessels (i.d. 100-300 microns). and the changes are such that they could account for many of the altered hemodynamic characteristics seen in patients with essential hypertension (e.g.. increased minimum vascular resistance. increased pressor response). However. evidence that the abnormal structure of the peripheral vasculature is a prime determinant of blood pressure is still lacking. and much of the available evidence suggests that the altered structure is a secondary adaptation. Nevertheless. the abnormal vascular structure may play an important pathological role concerning the morbid consequences of the hypertensive disease. suggesting that normalization of vascular structure is a desirable aim for antihypertensive treatment. At present it seems that treatment must be continued for long periods. maybe many years. before vascular structure is normalized.
Local hormonal factors (intracrine, autocrine, and paracrine) in hypertension, Vasoactive hormones acting as endocrine. neuroendocrine. or local hormonal systems (intracrine. autocrine. and paracrine) are an important component of the many factors that regulate blood pressure. Hypertension may be the result of an alteration in the balance between vasodepressor and vasopressor hormonal systems. Changes in this balance could be due to genetic factors such as mutations in one of the genes of the vasoactive system or environmental factors that alter the synthesis and release of one or more vasoactive hormones. Endocrine and neuroendocrine vasopressor hormonal systems. such as the renin-angiotensin system and catecholamines. play a well-established and important role in the regulation of blood pressure and the pathogenesis of some secondary forms of hypertension. The blockade of such systems has already resulted in effective antihypertensive treatment. The role of local hormonal systems is less well established; however. recent evidence suggests they also play an important role in the regulation of blood pressure and the pathogenesis of hypertension. Some vasopressor hormonal systems. such as the renin-angiotensin system. can act as both endocrine or local hormonal systems. Work using transgenic rats harboring the mouse Ren-2 gene has conclusively demonstrated that the renin-angiotensin system. acting as a local hormonal system. has the capability to cause severe hypertension. Whether this model of experimental hypertension mimics any type of human hypertension is not known. Vasodepressor hormones such as kinins. prostaglandins. and endothelium-derived relaxing factor (EDRF) act mainly as local hormonal systems. with the notable exception of atrial natriuretic factor. which may act as both an endocrine and a local hormone. The tissue kallikrein-kinin system. acting either directly or via paracrine eicosanoids or EDRF. participates in local regulation of the circulation. renal function. and the acute antihypertensive effect of angiotensin converting enzyme inhibitors. A restriction fragment length polymorphism (RFLP) that distinguishes the kallikrein gene family of a strain of spontaneously hypertensive rats (SHR) from normotensive Brown Norway rats has been identified. In a set of 32 recombinant inbred strains derived from these SHR and Brown Norway strains. the RFLP marking the kallikrein gene family of SHR cosegregated with an increase in blood pressure. Also. in a study of Utah families it was found that a dominant-allele kallikrein gene expressed as high urinary kallikrein excretion was associated with a decreased risk of essential hypertension. In conclusion. vasopressor and vasodepressor hormones. acting not only as endocrine but also as local hormones. play an important role in the regulation of blood pressure and the pathogenesis of hypertension.(ABSTRACT TRUNCATED AT 400 WORDS).
Can essential hypertension be subclassified with respect to mechanism, Hypertension may result from a variety of abnormalities. The rise in blood pressure may trigger other secondary events that further influence cardiovascular homeostasis. The ability to measure some markers associated with hypertension or the responsiveness of blood pressure to nutritional interventions or to specific therapeutic agents may also have pathogenetic implications. The ultimate goal of further knowledge in this area should be to understand the fundamental abnormalities responsible for hypertension. Such insight would permit more effective treatment and. perhaps. primary prevention of this ubiquitous and multifaceted disorder.
Blood pressure and high blood pressure. Aspects of risk, This report deals with three aspects of risk related to blood pressure and high blood pressure. The first aspect of risk concerns distributions of systolic blood pressure (SBP) and diastolic blood pressure (DBP) in the adult population and their relation to long-term risk of morbidity and mortality. By middle age. only a minority (about 20%) of Americans have optimal SBP and DBP levels. less than 120 mm Hg and less than 80 mm Hg. respectively. For the majority with higher levels. risks of major clinical events. including death from cardiovascular diseases and from all causes. are markedly increased. The relations of SBP and DBP with risk are strong. continuous. and graded. Risk is sizable not only for persons with high blood pressure by usual clinical criteria (SBP greater than or equal to 140 mm Hg or DBP greater than or equal to 90 mm Hg). but also for those with "high-normal" blood pressure (e.g.. SBP 130-139 mm Hg or DBP 80-89 mm Hg). Thus. the blood pressure problem is a population-wide one and requires for its control a combined population-wide and high-risk strategy. A major component of this strategy must be nutritional-hygienic measures for the primary prevention of the rise in blood pressure during adulthood and of high blood pressure (i.e.. primary prevention not only of the complications of high blood pressure but also of high blood pressure itself) through improved lifestyles having the potential to shift downward the blood pressure distribution of the whole population. The second aspect of risk concerns the known risk factors (i.e.. aspects of modern lifestyle) leading to the mass occurrence of blood pressure rise during adulthood and of high blood pressure. These risk factors are high salt intake. high dietary sodium/potassium ratio. calorie imbalance and resultant obesity. and high alcohol intake. The extensive data base establishing the role of these common traits in the etiology of the blood pressure/high blood pressure problem is the scientific foundation for efforts to achieve the primary prevention of high blood pressure. The third aspect of risk relates to the combined impact of other risk factors along with blood pressure-high blood pressure in markedly increasing the probabilities of morbidity and mortality (e.g.. "rich" diet. diet-dependent serum cholesterol and uric acid. smoking. diabetes. and target-organ damage). Prevention and control of lifestyle-related traits are essential components of the strategy for dealing with the blood pressure-high blood pressure problem.
In vivo comparative evaluation of hemodialysis tubing plasticized with DEHP and TEHTM, The migration of plasticizers from blood lines was studied in 11 patients with chronic renal failure on hemodialysis for a period of six months. Di-2-ethylhexylphthalate (DEHP). the conventional plasticizer. was compared with tri-2-ethylhexyltrimellitate (TEHTM). A liquid chromatography method for quantitative determination of DEHP and TEHTM in human blood plasma is described. During treatment with tubing containing DEHP. the plasma level of DEHP rose from 0.10 micrograms/ml (less than 0.05-0.17 n = 11) to 0.70 micrograms/ml (0.30-1.6 n = 11). When the patients were changed to tubing containing TEHTM. the concentration of DEHP was below or close to the detection limit and TEHTM could not be detected. No adverse events of either tubing were found as regards acute toxic effects. performance or applicability.
Mesh-constricted varicose and dilated veins used as arterial bypass grafts, To avoid non-autogenous vascular prostheses in coronary and peripheral vascular procedures. otherwise unusable dilated. varicose or thin-walled veins can be implanted as naturally endothelialized grafts after being calibrated by insertion into mesh tubes. In six sheep the 14 mm diameter jugular vein was inserted into a 12 cm long. 6 mm diameter Dacron mesh tube and implanted as a femoropopliteal graft. On the contralateral side the femoral vein with a maximal diameter of 7 to 8 mm was implanted. At control angiography after two months all grafts were patent. none of the wrapped grafts showed wrinkles or signs of anastomotic hyperplasia. Segments of wrapped veins were casted in paraffin under physiological pressure and cut transversely. In all cases the vein wall was pressed against the mesh tubes without forming folds. Mesh-wrapped varicose veins were used for three femorocrural and seven femoropopliteal reconstructions. All grafts showed a smooth flow surface at control angiography. Indentations occurred only at sites where thick-walled side branches had been ligated rather than oversewn. One popliteo-pedal reconstruction occluded after two months and one patient with a crural reconstruction died two months after surgery with a patent graft. The remaining grafts were patent after 11 (2-32) months. Oversized veins can be considerably constricted by tubes without forming wrinkles. By this technique varicose veins can be used as bypass grafts and in general vein grafts can be matched in size to the recipient vessel.
Neural processing of craniovascular pain: a synthesis of the central structures involved in migraine, In order to determine the anatomical distribution of cells concerned with relaying craniovascular nociception. local cerebral glucose utilization was determined by the 2-deoxyglucose method in tissue autoradiographs of the alpha-chloralose anesthetized cat. The superior sagittal sinus was carefully lifted from the brain by sectioning the dura laterally and the falx inferiorly and suspending the sinus across two platinum hook electrodes for stimulation. The sinus was stimulated electrically and its effect on caudal brainstem. upper cervical spinal cord and diencephalic metabolic activity determined. Stimulation of the sinus caused increased metabolic activity in the trigeminal nucleus caudalis. in the cervical dorsal horn and in a discrete area in the dorsolateral spinal cord at the second cervical segment. Metabolic activity was also increased in the ventrobasal thalamus. specifically in the ventroposteromedial (188%) nuclear group. in the medial nucleus of the posterior complex (70%) and the intralaminar complex (49%). There was no change in the surrounding thalamus. lateral geniculate nucleus or overlying cerebral cortex. These increases in 2-deoxyglucose utilisation were blocked by bilateral trigeminal ganglion ablation. The dorsolateral area activated in the spinal cord corresponds to a hitherto unrecognised group of cells in or near the lateral cervical nucleus that may form an important relay for craniovascular nociception. Further electrophysiological studies with glass coated tungsten microelectrodes have characterised the cells in these regions of the thalamus to be responsible for relaying nociceptive information. An understanding of the connections and properties of the neurons that subserve craniovascular pain is an essential prerequisite to understanding the complex pathophysiology of migraine.
Migraine and epilepsy with infantile onset and electroencephalographic findings of occipital spike-wave complexes, An EEG finding of temporo-occipital or temporo-parieto-occipital spike-wave complexes. suppressed by eye opening. coexisting with classical migraine. was observed in 14 children; in 13 of these patients. seizures were present. Classical migraine. visual phenomena and seizures coexisted in different clinical patterns.
Criteria for the diagnosis of migraine in clinical practice, Criteria for the diagnosis of migraine have evolved from generalized descriptions to specific rules designed to ensure the selection of homogenous groups of patients for research studies. For clinical practice. the former are insufficiently specific and the latter are too complex. For care of headache patients by primary care physicians. we propose that the diagnosis of migraine without aura (common migraine) is warranted if any two of the following symptoms are present: unilateral site. throbbing quality. nausea. photophobia or phonophobia. These criteria are derived from a study comparing the features of 100 patients with migraine without aura and 100 patients with chronic daily headache. The proposed criteria for the diagnosis of migraine without aura were highly sensitive and adequately specific in discriminating groups. These simple criteria should facilitate the diagnosis of migraine by primary care physicians.
Flunarizine in migraine: a minireview, Flunarizine is a non-selective calcium antagonist. It distributes preferentially in the adipose tissue and passes the blood brain barrier. Numerous controlled clinical studies have established that flunarizine is efficacious in migraine prophylaxis. including double-blind studies in which the drug was compared with placebo or other antimigraine drugs. To avoid side effects a special schedule or administration is necessary. Flunarizine has no myogenic effect on smooth muscle cells of the vessles. It is said to be the only calcium antagonist able to protect brain cells against hypoxic damage. In addition. the considerable body of information which shows flunarizine capable of directly influencing the central nervous system. suggests that the drug's anti-migraine action may depend on its ability to influence central phenomena.
Visual evoked potentials and background EEG activity in migraine, To investigate whether quantification of the background EEG during a visual evoked potential (VEP) study is of value for the diagnosis of migraine we studied 8 unmedicated migraineurs between attacks. and 10 age-matched controls. Three paradigms were used: the first two concerned pattern-reversal VEPs with different analysis times (500 and 1500 ms). and in the third paradigm the pattern did not reverse. Power spectra were calculated for individual responses. and the delta. theta. alpha and beta areas of the averaged spectra were noted as indicators of background reactivity. Alpha and beta powers were consistently but not significantly higher in the migraine group. The difference was too small to be of value as a diagnostic test. Alpha power was (not significantly) lower in the presence of photic stimulation than in its absence. As this was the case in both groups photic stimulation does not explain the higher alpha powers in the migraine group. We conclude that EEG background activity during the VEP does not distinguish reliably between migraineurs and controls.
An unusual angiographic picture in status migrainosus, Arteriographic findings suggestive of inflammation are described in a 26-year-old woman presenting with headache and syncope. There were no clinical findings of angitis. and a diagnosis of status migrainosus was eventually made. We present her case. as well as a review of previous cases of arterial changes in patients with headache. Most previous cases report arterial narrowing. felt to reflect spasm. whereas our patient demonstrated segmental stenoses and dilatations. perhaps implicating inflammation. The inflammatory process has been postulated as the pathogenesis of migraine pain. As most migraineurs do not undergo arteriography. the incidence of arterial change in these patients is unknown. This finding has therapeutic implications for selecting the optimal anti-migraine agent.
Changes in neutrophil met-enkephalin containing peptides in episodic cluster headache, We have previously demonstrated an increase in plasma met-enkephalin levels during the pain attacks in episodic cluster headache. The present study was undertaken in order to clarify the source of the plasma met-enkephalin increase. Recent evidence has shown that peripheral blood polymorphonuclear cells contain peptides derived from the proenkephalin A system. which can be released by specific stimuli. We studied neutrophil met-enkephalin containing peptides (NMECP) in 27 episodic cluster headache patients: 24 in a cluster period (6 of them during a pain attack). and 3 in the remission period. Neutrophil met-enkephalin containing peptide levels (after sequential enzymatic digestion with trypsin and carboxypeptidase B) were determined by radioimmunoassay with specific antiserum. Neutrophil peptide concentration (pmol/mg prot) was lower (p less than 0.01) in patients during the pain attack (14.4 +/- 0.36) than after their pain had subsided (36.7 +/- 0.31) and lower than in the remission period patients (35.8 +/- 0.4). We conclude that neutrophil met-enkephalin containing peptides decrease during pain in episodic cluster headache. and that they may be involved in the concomitant plasma met-enkephalin increase.
Blood leukotrienes in headache: correlation with platelet activity, Platelet hyperactivity. one of the commonest findings associated with migraine. has been related to increased release of biologically active substances such as catecholamines and arachidonic acid metabolites. which seem to play a role in the pathogenesis of migraine. In this study. in vitro platelet aggregation tests were performed on samples from patients with different types of headache. The presence of platelet hyperactivity was clearly demonstrated in 11 patients with classical migraine between attacks. but not in 4 patients between attacks of common migraine. Nevertheless. the presence of a marked platelet hyporesponsivity was found during the attack phase of both classical and common migraine. No difference in platelet aggregability was found between attack and post-attack phases in 5 patients with cluster headache. Blood leukotrienes were analyzed in 8 patients with classical migraine and in the 5 patients with cluster headache. During the attack phase of classical migraine both LTC4 and LTB4 were present in the peripheral blood. while the post-attack phase was characterized by the disappearance of LTC4 and the presence of LTB4 and its transisomer delta 6-trans-LTB4. Blood leukotrienes were constantly absent during both phases of cluster headache. Incubation of normal platelets with LTC4 or delta 6-trans-LTB4 was followed by inhibition of platelet response to epinephrine. delta 6-trans-LTB4. at higher concentrations. induced the opposite effect. A possible role of blood leukotrienes in the changes occurring in platelet aggregability during the different phases of classical migraine. is discussed.
Unwashed filtered shed blood collected after knee and hip arthroplasties. A source of autologous red blood cells, We evaluated the results of twelve hematological and plasma protein determinations in 450 to 500-milliliter volumes of shed blood that had been collected with or without acid-citrate-dextrose anticoagulant (National Institutes of Health Formula A) from knees and hips during the first twelve hours after arthroplasty. We also evaluated the effects on the recipients when the blood was used for reinfusion. The findings in the units that had been obtained in less than four hours. in between four and six hours. and in more than six hours after the arthroplasty were similar whether or not the acid-citrate-dextrose anticoagulant had been used. The mean values for the collected units were: in the blood. a concentration of hemoglobin of 115 grams per liter. a hematocrit of 0.34. a white blood-cell count of 4.8 x 10(9) per liter. and a red blood-cell count of 3.7 x 10(12) per liter. and. in the plasma. a level of hemoglobin of 160 grams per liter. a level of fibrinogen of less than 0.2 gram per liter. a level of factor-V clotting protein of less than 10 per cent of normal. a level of factor-VIII clotting protein that was 45 per cent of normal. a level of antithrombin III that was 45 per cent of normal. a level of plasminogen that was 55 per cent of normal. a level of protein C that was 100 per cent of normal. and a level of fibrin-degradation products of 1000 micrograms per milliliter of plasma. The clinical response of the patient was assessed after the reinfusion of a total of 205 units of unwashed shed blood into 153 patients. In addition. in 126 of the 153 patients. hematological and plasma-protein measurements were analyzed before the autotransfusion and one and twenty-four hours afterward. Each of these patients had received one to four units of shed blood that had been filtered but not washed. Only two (2 per cent) of the ninety-nine patients who received shed blood that had been collected six hours or less after the operation had a febrile reaction. whereas twelve (22 per cent) of the fifty-four patients who received blood that had been collected six to twelve hours after the operation had such a reaction.(ABSTRACT TRUNCATED AT 400 WORDS).
A new device for the fixation of unstable pertrochanteric fractures of the hip, A new type of fixation device for the treatment of pertrochanteric fractures of the hip is described. The device has an axial-compression screw to allow compression along an axis parallel to the femoral shaft. As the fracture settles postoperatively. dynamic axial compression continues. This axial-compression device was used in twenty-five patients who had an unstable intertrochanteric or proximal subtrochanteric fracture of the proximal part of the femur. The average extent of axial impaction or settling was five millimeters (standard deviation. 1.3 millimeters) at the most recent follow-up examination. and the relationship between the femoral head and shaft was altered less than with the use of a conventional compression screw-plate device. A larger proportion of the patients who had the new device were able to walk fifteen meters (fifty feet) independently by the time of discharge from the hospital. even though they left the hospital earlier. No technical failures were seen in the patients who were treated with the axial-compression screw device. We believe that the axial-compression screw-plate device is appropriate for the treatment of unstable pertrochanteric fractures of the hip.
Vibratory response in adolescents who have idiopathic scoliosis, The PVD Bio-Thesiometer was tested as a tool for measuring vibratory thresholds and for detecting possible differences in these thresholds between adolescents who have idiopathic scoliosis and those who do not. It was found to be limited by low reliability and large errors in measurement. with the metatarsophalangeal joint being the only reliable site for measurement. The vibratory thresholds at this site were significantly higher in the fourteen subjects who had scoliosis than in the twenty-two control subjects. No significant asymmetry in vibratory thresholds was found between the concave and convex or the right and left sides in either the scoliotic or the control group. Because there was no significant difference between the readings from the concave and convex sides. it is unlikely that a lesion of the posterior column is responsible for idiopathic scoliosis. If there is a difference. then the PVD Bio-Thesiometer is not sufficiently reliable to detect it.
Non-union of fractures of the mid-shaft of the clavicle. Treatment with a modified Hagie intramedullary pin and autogenous bone-grafting, We reviewed a series of fifty patients who had a non-union of a fracture of the clavicle. Twenty-one patients (42 per cent) who had a symptomatic non-union of the middle of the shaft of the clavicle were treated with open reduction. internal fixation with a modified Hagie intramedullary pin. and autogenous bone-grafting. and those patients form the basis for the report. The average duration of follow-up was thirty-five months (range. five months to eleven years). Healing occurred in twenty (95 per cent) of the twenty-one patients. Intramedullary fixation has several advantages compared with other treatments. such as fixation with a plate and screws. It can be performed through a cosmetically acceptable incision in the Langer line; less dissection of the soft tissues is needed; and. after healing. the pin can be removed through a small incision under local anesthesia.
Elevated plasma adrenocorticotropin (ACTH) with adrenal hyperplasia: a new factor in ACTH regulation, We report a patient with Cushing's syndrome in whom the etiology of the hypercortisolemia could not be definitely established despite extensive biochemical investigations. Results included raised basal serum cortisol. plasma ACTH. and urinary free cortisol; failure to suppress even a paradoxical rise in serum cortisol after dexamethasone (1 mg overnight. 2. 8. and 16 mg/day); and a definite but not exaggerated rise in 11-deoxycortisol after metyrapone. After iv CRF. plasma ACTH rose from 22 to 30 pmol/L. Abdominal computed tomographic scanning showed adrenal hyperplasia; the presence of an adrenal adenoma. although suspected. was not established. An unusual finding was the presence in the urine of large amounts of 21-deoxycortisol metabolites. including 3 alpha.11 beta.17 alpha-trihydroxy-5 beta-pregnan-20-one and 5 beta-pregnane 3 alpha.11 beta.17 alpha.20 alpha-tetrol. On the basis of preoperative biochemical/radiological findings. a provisional diagnosis of ACTH-dependent Cushing's syndrome associated with autonomous bilateral adrenal hyperplasia was made. Incomplete bilateral adrenalectomy was performed; adrenal hyperplasia was histologically confirmed. but no tumor was found. However. ACTH was measured 1) just before operation when the patient was receiving treatment with metyrapone. and 2) postoperatively when the patient was receiving steroid replacement only. and on these occasions ACTH levels were lower than during the initial investigations. Pituitary scans before and after adrenalectomy were similar. offering no evidence of pituitary infarction. We propose that abnormal production of 21-deoxycortisol contributed to the aberrant regulation of ACTH and cortisol in this case. providing an example of a previously unreported cause of hypercortisolemia.
Contribution of postprandial insulin and glucose to glucose disposal in normal and insulin-resistant obese subjects, We recently found that postprandial hyperinsulinemia does not compensate for the insulin resistance of obese subjects and proposed that postprandial hyperglycemia might be more important in promoting glucose disposal via the mass action effect of glucose. To test this idea we perform oral glucose tolerance tests (OGTT) in six lean and eight obese subjects. measuring glucose and insulin levels. Afterward two insulin infusion studies were performed. During infusion study I. insulin was infused in a dynamic square wave fashion to mimic the individual post-OGTT insulin levels at content euglycemic glucose levels. During study II. glucose and insulin infusions were varied to mimic post-OGTT levels in each subject. Overall glucose turnover was measured isotopically by infusion of [3-3H] glucose. During the OGTT the obese subjects exhibited significantly higher insulin (P less than 0.005) and glucose levels (P less than 0.002). Insulin-stimulated glucose disposal rates and total incremental glucose disposal (IGD) over 4 h during study I at euglycemia were significantly lower in obese compared to lean subjects (area under the curve. 824 +/- 166 vs. 1222 +/- 161 mmol/L.m2; P less than 0.01) despite higher post-OGTT insulin levels in obese subjects. When insulin plus glucose levels were matched to the individual OGTT levels. IGD was not significantly different between obese and control subjects (1712 +/- 253 vs. 1617 +/- 444 mmol/L.m2; P = NS). A significant inverse correlation (r = -0.73; P less than 0.05) existed between the degree of glucose intolerance (OGTT) and the decrease in IGD during the phasic hyperinsulinemic euglycemic study (infusion study I). These data suggest that with increasing insulin resistance. hyperinsulinemia is less effective in compensating for this decrease in insulin action. and hyperglycemia becomes more important in augmenting overall glucose disposal values.
Decreased serum growth hormone-binding protein in patients with liver cirrhosis, The recently characterized GH-binding protein (GH-BP) has an amino acid sequence identical to the extracellular domain of the GH receptor. Serum GH-BP reflects the amount of GH receptors. and the liver seems to be their main source. To evaluate the effect of liver disease on GH-BP. 52 patients with liver cirrhosis were studied. Serum GH-BP was measured by a binding assay with dextran-coated charcoal separation. Levels of GH-BP were correlated against the clinical state. assessed by Pugh's score. The GH-BP of 31 Pugh's class A patients was 9.7 +/- 0.5%/50 microL serum. and that of 21 Pugh's class B and C patients was 7.2 +/- 0.5%/50 microL serum compared to 11.3 +/- 0.5%/50 microL serum in age-matched controls. GH-BP correlated negatively with Pugh's score and serum bilirubin. and positively with serum albumin. It did not correlate with serum liver enzymes or serum insulin-like growth factor-I. Scatchard analysis of GH binding to the GH-BP revealed similar binding affinities in Pugh's A. B. and C patients and controls. The binding capacity in cirrhosis was significantly lower than that in controls. We conclude that serum GH-BP is controlled mainly by the liver and can provide an additional measure of disease severity in liver cirrhosis.
Ras oncogene mutations in benign and malignant thyroid neoplasms, Current models for tumorigenesis propose that a series of genetic alterations occur during the progression from the normal cell to the malignant phenotype. Mutations in each of the three ras genes (K-ras. H-ras. and N-ras) have been identified in many human neoplasms. including thyroid cancer. In this study we examined genomic DNA from benign and malignant thyroid neoplasms for mutations that are known to activate the ras oncogenes (codons 12. 13. and 61). DNA from frozen surgically excised tissue (n = 8) and from formalin-fixed paraffin-embedded tissue (n = 30) was amplified by the polymerase chain reaction and screened for mutations using oligonucleotide-specific hybridization. No mutations were identified in follicular adenomas (n = 9). In follicular carcinomas. 2 of 14 tumors contained mutations (N-ras 61. Gln to Arg). and both of these patients had bone metastases. One of 15 papillary carcinomas had a ras mutation (H-ras 12. Gly to Ser). In contrast to other studies. we found that ras mutations are relatively uncommon in both benign and malignant thyroid neoplasms. Studies of larger numbers of tumors and comparisons of different patient populations will be required to assess a possible association of mutations in N-ras 61 with clinically aggressive follicular cancer.
Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians, Pima Indians have the highest reported prevalence rate of noninsulin-dependent diabetes mellitus (NIDDM) in the world. so that metabolic comparisons with caucasians. who have a much lower rate. should provide insights into the pathogenesis of NIDDM. We have compared 81 caucasians with 211 Pima Indian nondiabetic subjects similar in age. sex. degree of obesity. and glucose tolerance. During a hyperinsulinemic euglycemic clamp at physiological insulin concentrations. Pima Indians were 17% more insulin resistant than caucasians after accounting for any differences in degree of obesity (P less than 0.0001). During oral glucose tolerance testing. mean plasma insulin concentrations were 33% higher in the Pimas (P less than 0.0001). but these differences were largely explained by the greater insulin resistance in the Pimas. Insulin clearance did not differ between the races. However. early insulin responses were exaggerated in the Indians and not explained by insulin resistance. After accounting for differences in insulin action. plasma insulin concentrations in Pima Indians were 50% higher than those in caucasians 3-5 min after iv glucose (P less than 0.0001). 38% higher 10 min after the end of a meal (P less than 0.0001). and 20% higher 30 min after an oral glucose load (P less than 0.006). These data suggest that in addition to insulin resistance. Pima Indians have exaggerated early insulin release and either increased beta-cell mass or enhanced beta-cell sensitivity to glucose. The data argue against low or delayed insulin secretion as primary factors leading to NIDDM in Pima Indians and favor insulin resistance as the underlying and initiating cause of the disease.
A mutation in the tyrosine kinase domain of the insulin receptor associated with insulin resistance in an obese woman, Insulin resistance is frequently associated with acanthosis nigricans and hyperandrogenism. In patients with type A insulin resistance. this has been shown to be due to genetic defects in insulin receptor function. However. other patients with a similar clinical syndrome have been reported to have a variant of this syndrome. in which assays of insulin receptor function were normal. We have sequenced a portion of the insulin receptor gene in one such patient. a 29-yr-old woman with obesity and insulin resistance. The patient is heterozygous for a mutation substituting isoleucine for methionine at position 1153. Met1153 is located in the intracellular domain of the receptor near the cluster of tyrosine phosphorylation sites at positions 1158. 1162. and 1163. Studies of the mutant receptor expressed in NIH-3T3 cells demonstrated that the Ile1153-mutation impairs the ability of insulin to stimulate autophosphorylation of solubilized insulin receptors. In addition. the mutation impairs the ability of insulin to stimulate receptor tyrosine kinase activity to phosphorylate an artificial substrate [poly(Glu-Tyr)]. It seems likely that this defect in receptor tyrosine kinase activity explains the defect in the ability of the patient's insulin receptors to mediate insulin action in vivo. Furthermore. this patient provides a paradigm in which genetic factors act in concert with other risk factors. such as obesity. to cause clinically important insulin resistance.
Determination at the molecular level of a B-cell epitope on thyroid peroxidase likely to be associated with autoimmune thyroid disease, In a panel of 13 mouse monoclonal antibodies generated against native (nondenatured) human thyroid peroxidase (TPO). only 1 (monoclonal antibody 47) recognized TPO protein fragments expressed in a human TPO cDNA sublibrary. Determination of the nucleotide sequences of 18 clones recognized by monoclonal antibody 47 localized its epitope to 9 amino acids (residues 713-721) in the human TPO protein. On Western blot analysis. only TPO monoclonal antibody 47 recognized the 933-amino acid TPO molecule after denaturation and reduction of the latter. supporting the concept that the major part of the epitope is represented by a continuous portion of the TPO sequence. The binding of TPO monoclonal antibody 47 to native TPO is inhibited by immunoglobulin G in the serum of patients with autoimmune thyroid disease. The epitope for monoclonal antibody 47 defined in the present study is. therefore. part of or in the vicinity of an epitope for autoimmune thyroid disease-associated TPO antibodies.
Heterogeneity of T cell lymphoblastic leukaemias, Twenty eight out of 170 consecutive cases of acute lymphoblastic leukaemia (ALL) were examined. They were of T cell origin. with the following distribution: seven (28%) cases had pre-T or prothymic features; nine (36%) cases showed early thymocytic features. six (24%) had cortical features; and three (12%) had a "mature" phenotype. The remaining three cases could not be sub-classified. A striking finding was that pre-T ALL differed from intrathymic ALL not only in the absence of both E rosettes and intrathymic differentiation antigens. but also in the expression of two non-lineage specific antigens HLA-DR and CD10. Both antigens appear in the bone marrow from the very first stages of lymphoid differentiation. implying that the origin for pre-T ALL is bone marrow. A comparison of the clinical features of pre-T and thymic ALL showed that pre-T ALL disease showed a pattern more similar to non-T ALL disease: a lower incidence of mediastinal mass. absence of extrahaematopoietic disease. lower white cell counts and haemoglobin concentrations. and a higher incidence of bone pain. No obvious difference in response to treatment was apparent. The results show that T-ALL is not only a heterogeneous immunological group but also suggest that it may have different origins: bone marrow for pre-T ALL and the thymus for thymic ALL.
Immunohistological diagnosis of "plasmacytoid T cell lymphoma" in paraffin wax sections, An immunohistological study of paraffin wax embedded tissue from three cases of plasmacytoid monocyte neoplasms. using a panel of antibodies which react with fixation resistant leucocyte markers. is reported. This neoplasm was found to have a distinctive antigenic profile. being negative for CD3 and elastase. but positive for CD43 and CD68. This immunological phenotype. coupled with its characteristic morphological features. should facilitate the recognition of this rare neoplasm in routinely processed tissue. Furthermore. the term "plasmacytoid monocyte sarcoma" is proposed to designate it because it is inappropriate to refer to it as a lymphoma. As all cases have been associated with a myeloproliferative disorder (usually an acute or chronic myeloid leukaemia). these tumours probably represent the accumulation in lymphoid tissue of neoplastic cells which have differentiated along the plasmacytoid monocyte pathway.
Ber-ACT8: new monoclonal antibody to the mucosa lymphocyte antigen, Using a newly established HTLV-1 positive T cell line as an immunogen. a new monoclonal antibody. Ber-ACT8. was produced. It reacts with in vitro activated T cells and a small subset of normal resting T cells. but not with resting B cells or any of the 29 established human permanent cell lines tested. Immunohistological analysis of a wide spectrum of human tissues showed that Ber-ACT8 reactivity is restricted to a few T cells in the peripheral blood. the extrafollicular areas of lymph nodes and tonsils. and splenic red pulp. In the gut Ber-ACT8 labelled most intraepithelial T cells and up to 50% of lamina propria T cells. The antibody also immunostained T cells present in the oral and bronchial mucosa. Double labelling on splenic cells. fresh blood lymphocytes. and in vitro activated T cells showed that most Ber-ACT8 positive cells coexpressed CD8. Ber-ACT8 did not react with any of the 14 Hodgkin's lymphomas nor any of the 172 non-Hodgkin's lymphomas tested. with the exception of 10 cases of T cell lymphomas. five of which were located in the jejunum and associated with coeliac disease. and one B cell lymphoma. and most cases of hairy cell leukaemia tested. Parallel immunostainings with Ber-ACT8. anti-TCR-beta (beta F1). and anti-TCR-delta showed that most Ber-ACT8 positive T cells carry the TCR of alpha beta type. Comparison of Ber-ACT8 with HML-1. B-ly7. and LF61 showed essentially the same reactivity and an identical molecular target. The molecular structure recognised seems to be a trimeric molecule with components of 150. 125 and 105 kilodaltons. with the Ber-ACT8 epitope localised on the 150 kilodalton chain. The 150 kilodalton molecule contains an 0-linked carbohydrate moiety of about 10 kilodaltons. Because of its very selective distribution. the trimeric antigen is a powerful reagent for the diagnosis of gut T cell-derived T cell lymphomas and other extranodal T cell lymphomas. as well as hairy cell leukaemia.
Breslow thickness of cutaneous malignant melanoma in paraffin wax and frozen sections, Breslow tumour thickness was measured in frozen and paraffin wax sections from 21 excision biopsies of cutaneous malignant melanomas by two observers. There was no consistent variation between frozen and paraffin wax sections. with recorded differences ranging from +0.3 mm to -0.2 mm. Interobserver differences ranged from +0.4 mm to -0.2 mm. The interobserver variations exceeded the intraobserver variations. but neither were significant. These findings show conclusively that. when using high quality frozen sections. there is no significant difference between Breslow thickness measured in frozen or paraffin wax sections and therefore that frozen sections can be used to microstage melanoma. Interobserver variations seem to be a more likely source of erroneous measurements of tumour thickness.
Prognostic value of proliferating cell nuclear antigen in gastric carcinoma, A new monoclonal antibody to proliferating cell nuclear antigen (PCNA). PC10. which can be used on routinely processed tissue. was applied to 93 cases of gastric carcinoma. Significant intra-tumoural variation in staining occurred. In addition to a PCNA index (percentage of positive cells per 1000 tumour cells). a semiquantitative PCNA grading system was devised. based on estimates of less than or more than 50% of positive tumour cells in whole sections. Neither PCNA index nor PCNA grade showed any correlation with established histological variables. tumour stage. or the presence of lymph node metastases. No significant correlation was observed between PCNA index and S + G2M phase fraction measured by flow cytometric analysis. To analyse survival tumours with PCNA indices above and below the median level (41%) were compared. Those with a higher index tended to have a worse prognosis. but when PCNA grade was considered. it was found to have definite independent prognostic value. tumours of low grade surviving better than those of high grade. The ability of semiquantitative PCNA grading to allow for intra-tumoural variation suggests it may have advantages over absolute counting. which is prone to sampling error when tumour heterogeneity is a major factor. The prognostic value of PC10 staining in gastric carcinoma is therefore promising.
Comparison of commercially available cytokeratin antibodies in normal and neoplastic adult epithelial and non-epithelial tissues, Five commercially available cytokeratin antibodies (lu-5. AE1/AE3. CAM 5.2. MFN116 and anti-cytokeratin 18) were used to stain a wide range of normal and neoplastic epithelial and non-epithelial tissues to assess their potential value in diagnostic histopathology. All five showed good specificity. with some cross-reactivity in smooth muscle cells. The wider reactivity of AE1/AE3. lu-5. and MFN 116. which includes cytokeratins 8.18 (Moll's catalogue) expressed in simple epithelia and their tumours. as well as cytokeratins expressed in complex stratified squamous epithelia. permits identification of a wider range of epithelial derived tumours. This wider spectrum of reactivity may allow these antibodies to be used in a diagnostic panel for the identification of poorly differentiated tumours.
Use of monoclonal antibodies to recognise osteoclasts in routinely processed bone biopsy specimens, In decalcified (5% nitric acid) and undecalcified (glycol-methacrylate or resin embedded) routinely processed bone specimens osteoclasts against resorbing surfaces were identified with monoclonal antibodies directed against leucocyte common antigen (LCA) (PD7/26. 2B11). CD68 (KP1). and gpIIIa (Y2/51) but not against HLA-DR (CR3/43 and Ta11B5). Mononuclear cells on resorbing surfaces and occasional mononuclear cells against or near resting surfaces showed a similar pattern of reactivity. This study shows that immunohistochemistry is a sensitive and useful technique for identifying osteoclasts in routinely processed bone specimens. It also suggests a role for mononuclear cells (possibly pre-osteoclasts) in bone resorption.
Streptococci from primary isolation plates grouped by reverse passive haemagglutination, Reverse passive haemagglutination. a novel microtitre based assay. was compared with the Streptex (Wellcome UK) latex slide agglutination kit for streptococcal grouping in a diagnostic microbiology laboratory. Three hundred and fifty two extracts from 349 consecutive primary isolation plates were assayed by both methods. Reverse passive haemagglutination gave identical grouping results for 98.0% of the 345 streptococci identified by Streptex. and the kappa coefficient of agreement between the methods for all 352 extracts tested was 0.973. Cross reactions with Listeria spp seen with Streptex were not found by reverse passive haemagglutination. In the reverse passive haemagglutination method 11 streptococci could be grouped on each 96-well plate and most reactions were stable for at least 30 minutes. Reverse passive haemagglutination is more rapid to perform than latex slide agglutination when many organisms are to be grouped. and the patterns of haemagglutination are easily recognised. If the method was taken into routine use in a diagnostic laboratory. the persistence of reverse passive haemagglutination reactions would enable grouping results to be checked for quality control purposes.
Detection of Epstein-Barr virus genomes in AIDS related lymphomas: sensitivity and specificity of in situ hybridisation compared with Southern blotting, Eighteen cases of AIDS related. non-Hodgkin's lymphomas were examined for the presence of Epstein-Barr virus (EBV) genomes using in situ hybridisation with a 35S-labelled probe. The results were compared with those obtained independently by Southern blot analysis with a 32P-labelled probe of frozen tissue from the same tumours. Technically satisfactory results were obtained with both methods in 15 lymphomas. EBV DNA was detected in seven of 15 (47%) cases by in situ hybridisation and in eight of 15 (53%) cases by Southern blotting (including all the cases positive by in situ hybridisation). The results of EBV DNA detection by the two techniques were identical in 14 of 15 (93%) cases. In situ hybridisation gave no false positive results. This study shows that the sensitivity and specificity of in situ hybridisation for the detection of EBV genomes in AIDS related lymphomas approaches that of Southern blotting. even when using routinely processed archival. paraffin wax embedded material.
HTLV-1 associated T cell lymphoma in South East Asia: case report and family study, Geographic clustering of human T cell lymphoma/leukaemia virus type 1 (HTLV-1) infection is well recognised. particularly in south western Japan. parts of West and Central Africa. the south eastern United States and the Caribbean islands. Sporadic cases have been reported in many other parts of the world. The first case of HTLV-1 associated leukaemia/lymphoma (ATLL) in South East Asia is reported. Contact tracing showed a high incidence of carriers among the relatives.
Detection of Helicobacter pylori carriers by discriminant analysis of urea and pH levels in gastric juices, An alternative approach to the problems inherent in current methods for detecting Helicobacter pylori carriers--that of being generally time-consuming. expensive. and not sufficiently sensitive--was devised by using the urea concentration and pH levels of gastric juices. A linear discriminant analysis of these variables. measured in 54 patients submitted to digestive endoscopy for gastritis. provided a mathematical formula for assigning the subjects (previously classified by other standard methods) to groups of either positive or negative H pylori carriers. The results obtained showed a correct classification in 52 out of 54 cases with only one false negative and one false positive case.
Acanthamoeba keratitis: experience in a non-specialist microbiology laboratory, Acanthamoeba keratitis is an unusual complication of wearing soft contact lenses: a case was diagnosed by culturing corneal scrapings. Acanthamoeba are tolerant of variations in osmolarity in the culture media. Page's saline. recommended for culture agar plates. can easily be substituted with salines which are suitable for cell culture media. thereby avoiding the cumbersome manufacture of special saline. Early diagnosis as a result of successful isolation may avoid the need for keratoplasty.
Recurrence rates of treated basal cell carcinomas. Part 1: Overview, This is the first article in a series reviewing the extensive experience of the Oncology Section of the Skin and Cancer Unit. from 1955 through 1982. with 5755 basal cell carcinomas (BCCs) treated by curettage-electrodesiccation. surgical excision. or x-ray therapy. Recurrence rates were calculated by three methods for each of the treatment modalities: 1) by the raw recurrence rate method; 2) by the "strict" 5-year recurrence rate method; and 3) by modification of the life-table method. Our analyses show that the last method best approximates the true recurrence rate. Primary (previously untreated) BCCs had a 5-year recurrence rate of 10.6% (standard error 0.6%). and previously treated BCCs had a rate of 15.4% (standard error 1.3%) (P = .0002). The greatest risk for recurrence of treated primary BCCs occurred 1 to 4 years after therapy. It is concluded that recurrence rates of primary BCCs should be reported separately from those of previously treated BCCs and that the modified life-table method is best suited to calculate 5-year recurrence rates.
Recurrence rates of treated basal cell carcinomas. Part 2: Curettage-electrodesiccation, This is the second article in a series that reviews the experience in the Skin and Cancer Unit. from 1955 through 1982. with the treatment of basal cell carcinomas (BCCs). This report deals with 2314 previously untreated (primary) BCCs removed by curettage-electrodesiccation. Multivariate analysis showed that increasing lesion diameter (P less than .001). high-risk anatomic sites (nose. paranasal. nasal-labial groove. ear. chin. mandibular. peri-oral. and peri-ocular areas) (P less than .001). middle-risk anatomical sites (scalp. forehead. pre- and post-auricular. and malar areas) (P less than .001). and time-span treated (1955 to 1963) (P = .012) were independent risk factors for high recurrence rates. The patient's age. sex. and lesion duration before treatment did not affect the recurrence rates. In order to best illustrate our current experience with BCCs. the last time-span (1973 to 1982) was examined in detail. For the low-risk sites (neck. trunk. and four extremities). BCCs of all diameters responded well to curettage-electrodesiccation with an overall 5-year recurrence rate of 3.3% (SE = 1.5%) determined by the modified life-table method. In the middle-risk sites BCCs less than 10 mm in diameter had a recurrence rate of 5.3% (SE = 2.7%). Finally. in the high-risk sites. lesions less than 6 mm in diameter had a recurrence rate of 4.5% (SE = 2.6%). Thus. BCCs less than 6 mm in diameter. regardless of anatomic site. as well as selected larger BCCs depending on their anatomic site. are effectively treated by currettage-electrodesiccation.
Multiple pilomatricomas and myotonic dystrophy, Multiple pilomatricomas are rare. However. among patients with myotonic dystrophy. the occurrence is higher. The authors report a patient. to their knowledge the 11th case of multiple pilomatricomas associated with myotonic dystrophy. to emphasize that these tumors may be associated with the disease.
Use of the argon-pumped tunable dye laser for port-wine stains in children, The authors reported previously a new technique using a low power argon-pumped tunable dye laser at a wave-length of 577nm (yellow light) to treat port-wine stains in adults. The authors report their results using this same technique as a form of treatment for 92 children with facial port-wine stains.
Liposculpture. 2: Evaluation of the patient for liposculpture, The author discusses cannula development and patient evaluation and selection for liposculpture. The author recommends that surgeons new to liposculpture should choose their patients carefully to avoid poor cosmetic outcomes.
Excision of exposed cartilage for management of Mohs surgery defects of the ear, Cartilage of the ear is often exposed during Mohs surgical procedures. Fenestration of the cartilage with a skin punch has been recommended to stimulate granulation tissue where the perichondrium has been destroyed. This article describes an alternative method--the excision of a window through the exposed cartilage. fully exposing the perichondrium on the other side of the cartilage. This promotes the rapid healing by second intention or provides a vascular bed for immediate skin grafting. Also. aggressive excision of nonviable cartilage helps prevent chondritis or perichondritis.
Reduced responsiveness of adenylate cyclase in alveolar macrophages from patients with asthma, Alveolar macrophages from patients with asthma accumulated less cyclic adenosine monophosphate when these macrophages were exposed to isobutyl methylxanthine. salbutamol. or prostaglandin E2. compared to cells from control subjects without asthma. and the degree of the hyporesponsiveness was related to the severity of asthma. In addition. a significantly lower adenylate cyclase activity was observed in crude membrane fractions of macrophages from the group with asthma in the presence of salbutamol and prostaglandin E2. The refractoriness observed in patients with asthma is thus not accounted for by a specific beta-adrenergic desensitization at the adenylate cyclase receptor level but should rather be explained by a cyclic adenosine monophosphate-dependent postreceptor mechanism.
Clinical and immunologic follow-up of patients who stop venom immunotherapy, We prospectively studied 51 self-selected Hymenoptera sting-sensitive patients to determine (1) whether a minimal or optimal duration for venom immunotherapy (VIT) exists and (2) whether clinical or immunologic parameters exist that are predictive of clinical immunity after VIT was stopped. After 2 to 10 years of VIT. all patients had deliberate sting challenges (DSCs) from live insects. If DSCs were tolerated. patients voluntarily stopped VIT and returned annually for repeat venom skin tests (VSTs) and DSCs. In most patients. it was possible to monitor VST and venom-specific antibody (Ab) levels before and after VIT was stopped. One-year after VIT. VST and venom-specific IgE and IgG Ab level results were variable; 49 patients tolerated DSC. whereas two patients exhibited generalized reactions. These two patients had pre-VIT histories of grade IV field-sting reactions and had received VIT for 2 years and 4 years. respectively. The short-term (1 year) risk of recurrence of clinical allergy to stings after VIT was higher in patients who had experienced grade IV field-sting reactions before VIT versus patients experiencing grade I to III reactions before VIT (2/15. 13% versus 0/36. 0%) and higher in patients who had received VIT for less than 5 years versus patients who received VIT for 5 or more years (2/20. 10% versus 0/31. 0%). We suggest that VIT should be continued for 5 years in patients with pre-VIT field-sting reactions of grade IV severity. VST and venom-specific Ab results do not reliably predict the outcome of DSC or the subsequent clinical course in individual patients stopping VIT.
Identification of anti-idiotypic antibodies in the sera of ryegrass-allergic and nonallergic individuals, Anti-idiotypic (Id) antibodies (Abs) are generated in the humoral response to antigen (Ag). Some of these anti-Id Abs are capable of binding to the combining site or paratope of Abs that bind Ag. These Ab2 can competitively inhibit the binding of Ab1 to Ag may trigger an Ab1 response similar to the response induced by Ag. To determine if specific Ab2 that inhibit the binding of IgE Abs to ryegrass (RG)-pollen allergens are present in the sera of RG-allergic (RGA) individuals before the initiation of allergen-specific hyposensitization with RG-pollen extract. we studied sera from five RGA and four nonallergic (NA) subjects in an IgE anti-RG RAST-inhibition assay. Ab2-enriched serum fractions were prepared from these study subjects by exhaustive mixed grass-pollen affinity chromatography to remove IgE and IgG anti-RG Ab1 from whole serum aliquots containing Ab1. Unabsorbed. twice-concentrated sera were diluted to one-time concentrated sera with equal volumes of either Ab2-enriched sera without Ab1 or borate-buffered saline absorbed by mixed grass-pollen affinity chromatography. IgE anti-RG Ab1 was determined by a standard RG RAST assay. We have detected Ab2 in the sera of the RGA patients. which inhibit the binding of autologous and allogeneic IgE anti-RG to RG Ags in solid phase. Parallel RG RAST assays with sera from NA subjects demonstrated no significant inhibition. Ab2-enriched sera from some grass-allergic and some NA subjects inhibited IgE anti-RG binding found in some RGA patients' sera. We conclude that anti-Id Abs. Ab2. specific for IgE anti-RG. Ab1. are present in some RGA patients and NA individuals.
The usefulness of routine screening for salivary secretory component, Secretory IgA is a dimeric immunoglobulin found in association with the J chain and secretory component (SC). It is secreted into saliva and other mucosal fluids and is involved in mucosal immunity. The absence of either SC or secretory IgA may be associated with recurrent sinopulmonary infections. diarrhea. and failure to thrive. We present a retrospective study of 1262 samples from 877 patients who were screened for salivary IgA. SC. and serum immunoglobulin levels. Forty-six patients (5.2%) of those tested were found to have absent salivary SC. Although only 19 of these patients (41.3%) could be retested. all were found to have SC on repeated testing. Of the patients whose initial samples of saliva exhibited no SC. 15% (6/46) had low or absent serum IGA (less than 10 mg/dl) in contrast to 8.6% (66/769) of patients whose saliva contained detectable SC. but this was not statistically significant (chi 2 = 1.93; p greater than 0.1). There was also no correlation between serum immunoglobulin levels and the absence of SC. Because of the rarity of salivary SC deficiency. routine screening is not valuable.
An examination of food hypersensitivity as a cause of increased bronchial responsiveness to inhaled methacholine, To determine if food challenges could alter bronchial hyperresponsiveness. methacholine challenges were performed before and 24 hours after double-blind. placebo-controlled food challenges on 11 subjects with asthma with a history of food-induced asthma and positive skin prick tests to the suspect food. An equal number of patients demonstrated increased methacholine sensitivity after food and placebo challenges. Thus. we could not find evidence that allergic reactions to food induced bronchial hyperresponsiveness.
Changes in carbohydrate and lipid metabolism in children with asthma inhaling budesonide, In a longitudinal study. antiasthmatic and metabolic effects of budesonide inhalations in initially high (800 micrograms/m2/day for 1 month) and subsequently lower (400 micrograms/m2/day for 4 months) dosage were evaluated in nine children with asthma. aged 5 to 10 years. The FEV1 increased significantly after high dosage (median. 96.5% versus 105.5%; p = 0.0339). After lower dosage. FEV1 was still higher than at the baseline (106% versus 96.5%; p = 0.0339). Clinically. no additional beta2-agonist was needed after 2 weeks of treatment. Serum high-density lipoprotein cholesterol increased significantly by 22% after high dosage (medians. 1.18 versus 1.44 mmol/L). A significant decline to 1.31 mmol/L was observed when the dose was reduced (overall. p = 0.0319). The treatment had no significant effect on serum total cholesterol. on serum triglycerides. on the ratio of high-density lipoprotein to total cholesterol. on the body mass index. or on glucose tolerance. The high dosage increased significantly the ratio of serum insulin to blood glucose. calculated from the areas under the incremental 2-hour curves in the glucose tolerance test (medians. 17.3 versus 23.2 mU/mmol). After lower dosage. the ratio declined significantly to 13.5 mU/mmol (overall. p = 0.0164). No significant changes were observed in plasma cortisol in the 2-hour adrenocorticotropic hormone test. The antiasthmatic effect of budesonide inhalations in a dose of 800 micrograms/m2/day for 1 month was accompanied by detectable changes in lipid and carbohydrate metabolism. These metabolic changes were reversible. and the antiasthmatic effect could be maintained by a dose of 400 micrograms/m2 for 4 months without significant systemic effects. This dose is safe and efficient in the maintenance treatment of childhood asthma.
Anaphylactic reactions to a psyllium-containing cereal, Historical data were obtained by questionnaire and telephone survey on 20 of 24 women with reported allergic reactions to a psyllium-containing cereal. Heartwise. Protein fractions from this new cereal. as well as from psyllium mucilloid and a psyllium-containing laxative. Metamucil. were extracted. quantitated. and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Patients' sera were collected. and specific IgE and IgG antibodies to these psyllium antigens were detected by immunoblotting techniques. Of the 20 women evaluated. all but six were nurses. Eighteen (90%) of the women had historical and/or laboratory evidence of atopy. Exposures included ingestion or dispensing of psyllium-containing products. Only three women denied prior exposure to psyllium. Symptoms developed shortly after small amounts of the cereal were ingested and most commonly included moderate to severe wheezing. throat and chest tightness. and urticaria. All the women required medical therapy. 11 (55%) in an emergency room. Specific IgE and IgG antibodies to various psyllium protein fractions were documented in all the subjects. It was concluded that individuals sensitized by occupational exposure to psyllium dust are at high risk for allergic reactions to ingested psyllium-containing products.
Myocardial fibrosis in aging germ-free and conventional Lobund-Wistar rats: the protective effect of diet restriction, The influences of diet restriction and germ-free environment on aging were studied in 127 male Lobund-Wistar rats ranging in age from 7 to 48 months. There was an age-related increase in collagen deposition of the heart. particularly involving the left ventricle. The degree of fibrosis was significantly less extensive in middle and old age rats (18 mo. 30 mo. 32+ mo) maintained on a restricted diet. No clear-cut influence of germ-free environment was apparent. No amyloid was detected in 175 tissue sections examined from hearts. lungs. and livers.
Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction, The Glucocorticoid Cascade Hypothesis of Aging and the hypothesis that food restriction retards the aging processes by preventing the development with age of hyperadrenocorticism were investigated. A longitudinal life span study of the daily concentration pattern of plasma corticosterone was conducted in male Fischer 344 rats fed ad libitum or restricted to 60% of the mean food intake of ad libitum fed rats. In another group of ad libitum fed and food-restricted rats. the influence of age on the response of plasma corticosterone levels to restraint stress was measured as was the time course of the return of plasma corticosterone to basal levels following the stress. The findings do not support the hypothesis that food restriction retards the aging processes by preventing the development of hyperadrenocorticism with advancing age. They also indicate that the Glucocorticoid Cascade Hypothesis does not describe a major aspect of the aging processes. Rather. the results suggest the possibility that a lifetime of daily periods of mild hyperadrenocorticism may. if anything. retard the aging processes.
Postural change in blood pressure associated with age and systolic blood pressure. The National Health and Nutrition Examination Survey II, The prevalence of postural change in blood pressure and its association with age and systolic blood pressure were examined in data from 8.574 White nondiabetic persons aged 25-74 who participated in the second National Health and Nutrition Examination Survey (1976-1980). Postural change in blood pressure was defined as a drop of 20 mm Hg or more on change from supine to seated position. In subjects on no antihypertensive medications (n = 7.316). the prevalence of postural change in blood pressure increased with older age and with higher blood pressure levels. regardless of age. However. systolic blood pressure levels also increased with age. In logistic regression models. level of supine systolic blood pressure was strongly related to postural change in blood pressure (Relative odds (RO) = 1.59. 95% confidence interval (CI) = 1.49. 1.70 for a 10 mm Hg increase in systolic blood pressure) whereas age was not related to postural change in blood pressure (RO for age = 1.07. Cl = .89. 1.19 for a 10-year increase in age). Results were similar for those medicated for hypertension. All results were unchanged by addition of health status indicators. including reports of hospitalization and number of medical conditions. to the model. These data suggest that the age-related increase in the prevalence of postural hypotension previously reported may be partially explained by age-associated increases in systolic blood pressure.
Effect of age on fever response to recombinant tumor necrosis factor alpha in a murine model, Certain elderly humans show a blunted fever response to infection. A study was designed using a murine model to assess the influence of age on the febrile response to the endogenous pyrogen. tumor necrosis factor alpha (TNF alpha). Twenty (10 young: 4-6 months; 10 old: 24-28 months) BALB/c mice were injected with 50 ng of TNF alpha into the intraperitoneal space; the experiments were repeated one week later with 100 ng TNF alpha. Control animals received intraperitoneal injections of pyrogen-free phosphate buffered saline. Temperatures were measured rectally at baseline and at 10-minute intervals for 90 minutes post-injection using a thermistor probe and temperature gauge. In the majority of the time intervals following injection. the mean temperature changes of young mice were significantly higher than old mice for both 50 ng and 100 ng doses of TNF alpha. Similarly. peak temperature changes from baseline were consistently higher in young animals following injection of TNF alpha. Moreover. the peak temperature changes in young mice after 50 ng TNF alpha injection were significantly higher than those in old mice following a 100 ng injection of TNF alpha. These findings confirm that (a) TNF alpha has a role in the pathogenesis of fever; (b) aging alters significantly the febrile response; and (c) a mechanism of this age-related blunted febrile response may involve TNF alpha.
Recognizing and naming tunes: memory impairment in the elderly, Subjects over the age of 50 listened to theme tunes of remote. recent. and frequent television programs. If they recognized the tune. they were asked for the name of the program and for as much information about the program as possible. From the responses to a subsequent questionnaire. it was possible to divide the data according to whether or not the subjects watched the programs. There was no effect of age on the recognition and naming of programs subjects never watched. For programs they watched (a true test of memory). older subjects recognized fewer tunes as familiar and were less able than younger subjects to name the programs with familiar tunes. Neither the amount of exposure nor the delay since exposure had a significant influence on the recognition and naming impairments with age. Older subjects reported less information about programs they watched than younger subjects. In multiple regression analyses. age was a better predictor of performance than measures of current cognitive ability. The results are compared with the effects of age on the recognition and naming of famous faces (Maylor. 1990a). It is argued that the studies together support the view that the information processing rate decreases with age; therefore the elderly are poor at speeded tasks. the most dramatic effects appearing for later components of sequential processes.
Choice enhances performance in non-insulin dependent diabetics and controls, Cognitive performance on a number of tasks is poorer in individuals with non-insulin dependent diabetes mellitus (NIDDM) than in age-matched nondiabetics. In this study. diabetic and nondiabetic individuals. 55-74 years of age. learned target words. half of which were self-chosen and the remainder assigned. To evaluate susceptibility to background interference. each target was accompanied by one or more unrelated background words. On a recognition test. susceptibility to background interference appeared to be greater in diabetic individuals. The allocation of processing resources to target and background stimuli was more uniform in diabetic than in nondiabetic individuals. While choice improved recognition of target and background words for both groups. its effectiveness was attenuated in NIDDM. Choice facilitates the differentiation of target from background stimuli--a process that may reduce interference from background stimuli.
Age differences in depressive symptom experiences, Age differences in depressive symptom experiences were investigated in a community sample of 368 women between the ages of 51 and 92 who were administered the SCL-90 Depression and Additional Symptoms Scales. Confirmatory factor analysis was used to assess and compare depressive symptom experiences in a younger (age 51-65) and older (age 66-92) age cohort. Findings show that two somewhat different depressive syndromes underlie symptom reporting patterns. one having higher levels in the older age cohort. the other having higher levels in the younger age cohort. In addition. three more delimited forms of distress -- feelings of enervation. dysphoria. and sleep disturbances -- show higher levels among the older cohort. Implications of these findings for future research on the relation between aging and depression are discussed.
Social density, stressors, and depression: gender differences among the black elderly, This research examined gender differences with regard to the effects of social density and stressors upon depressive symptomatology among 600 Black elderly community residents (aged 55-85 years) of Nashville. Tennessee. The sample had more females than males and fewer married individuals. Approximately half of the males and females lived alone. Regression analyses show that poor ego and chronic medical problems were the common predictors of depression among both the males and females. Gender differences were found with regard to life events in that females tended to become more depressed as the number of events increased and as level of contact with relatives and friends decreased. Further. females with lower levels of social attachment. guidance. and reliability were more depressed. None of these social support dimensions related to depression among the males. These relationships tended to be stronger for those living alone than for those living with others.
A longitudinal investigation of the factor structure of subjective well-being: the case of the Philadelphia Geriatric Center Morale Scale, The purpose of this research was twofold: (a) to replicate the hierarchical factor structure of well-being with rural data; and (b) to investigate the longitudinal invariance of this factor structure. Subjective well-being was hypothesized to have a hierarchical factor structure with a second order factor. well-being. explaining variance in first order dimensions labeled agitation. lonely dissatisfaction. and attitude toward one's aging. The latent constructs were measured by items composing the PGC Scale (Lawton. 1975). Maximum likelihood confirmatory factor analysis techniques were used to test the fit of the model. Subjective well-being was investigated using a panel of older rural adults surviving a ten-year. two-wave investigation. Results of the study provided support for the hierarchical factor structure of well-being in cross-sectional analyses. This factor structure was varied across time. however.
Race and the self-reported health of elderly persons, This research examined race differences in the structure and measurement of six self-reports of health that are widely used in studies of elderly persons. Second-order confirmatory factor analyses (LISREL) revealed race differences only in the validity of subjective interpretations of health state and in the measurement error of a chronic conditions indicator. No race differences were found in the form of the four-factor model of self-reported health. Results. interpreted within a cognitive illness-labeling framework. have implications for future race-comparative health research.
Protein kinase C plays a role in the induction of tyrosine phosphorylation of lymphoid microtubule-associated protein-2 kinase. Evidence for a CD3-associated cascade that includes pp56lck and that is defective in HPB-ALL, Ligation of the CD3 receptor induces multiple signal transduction events that modify the activation state of the T cell. We have compared two lines that express biologically active CD3 receptors but differ in their biochemical activation pathways during ligation of this receptor. Jurkat cells respond to anti-CD3 with Ca2+ mobilization. PKC activation. induction of protein tyrosine phosphorylation. and activation of newly characterized lymphoid microtubule associated protein-2 kinase (MAP-2K). MAP-2K itself is a 43-kDa phosphoprotein that requires tyrosine phosphorylation for activation. Although ligation of the CD3 receptor in HPB-ALL could stimulate tyrosine phosphorylation of a 59- kDa substrate. there was no associated induction of [Ca2+]i flux. PKC. or MAP-2K activation. A specific PKC agonist. PMA. which bypasses the CD3 receptor. could. however. activate MAP-2K in HPB-ALL cells. This implies that defective stimulation of PKC by the CD3 receptor is responsible for its failure to activate MAP-2K in HPB-ALL. The defect in PKC activation is likely distal to the CD3 receptor as A1F14- failed to activate MAP-2K in HPB-ALL but was effective in Jurkat cells. The stimulatory effect of PMA on MAP-2K activity in HPB-ALL was accompanied by tyrosine phosphorylation of this kinase which implies that PKC may. in some way. regulate tyrosine phosphorylation of MAP-2K. A candidate for this role is pp56lck which underwent posttranslational modification (seen as mobility change on SDS-PAGE) during anti-CD3 and PMA stimulation in Jurkat or PMA treatment in HPB-ALL. There was. in fact. exact coincidence between induction of PKC activity. posttranslational modification of lck and tyrosine phosphorylation/activation of MAP-2K. Lck kinase activity in an immune complex kinase assay was unchanged during PMA treatment. An alternative explanation is that modification of lck may alter its substrate profile. We therefore looked at the previously documented ability of PKC to dissociate lck from the CD4 receptor and found that PMA could reduce the stoichiometry of the lck interaction with CD4 in HPB-ALL and to a lesser extent in Jurkat cells. These results imply the existence of a kinase cascade that is initiated by PKC and. in the course of which. lck and MAP-2K may interact.
Molecular mapping of Osp-A mediated immunity against Borrelia burgdorferi, the agent of Lyme disease, It is paradoxical that although antibodies to the outer surface protein (Osp) A of Borrelia burgdorferi protect mice against infection and that immunization of uninfected mice with Osp-A is protective. antibodies to Osp-A induced early in natural infection of mice are not curative. A region recognized by a neutralizing mAb is also recognized by sera from chronically infected or immunized mice but is not bound by sera from mice infected for 15 days. Infection in mice. despite the presence of early Osp-A antibody. may therefore be explained in part by the lack of response to this epitope. Sera from infected humans recognizes this region. although in this case the immune response to Osp-A occurs only late in infection. Nonetheless. the fact that both human sera and sera from mice immunized with Osp-A bind a conformationally dependent epitope that localizes to the same region tentatively suggests that humans are able to respond to a protective epitope and that an Osp-A-based vaccine may elicit protective immunity in humans.
Molecular characterization of a supratypic cross-reactive idiotype associated with IgM autoantibodies, Neoplastic B cells from patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphomas (SLL) frequently express surface Ig reactive with the mouse mAb. Lc1. Raised against a human monoclonal IgM with rheumatoid factor activity. Lc1 detects a major cross-reactive Id (CRI) present on the H chain of many monoclonal IgM autoantibodies. In contrast to other major autoantibody-CRI investigated to date. we note that the Lc1-CRI is expressed by subpopulation of cells in the germinal centers. as well as in the mantle zones. of secondary human B cell follicles. To examine the molecular basis for Lc1 expression. we used the polymerase chain reaction to isolate the functionally rearranged Ig VH genes of monoclonal Lc1-reactive B cell populations from six unrelated patients with CLL or SLL. Although the neoplastic B cells from most patients with CLL or SLL express the CD5 surface differentiation Ag. the lymphoma cells from one patient with SLL were CD5-negative. We find that the Lc1-reactive cells from each cell population have Ig rearrangements involving a VH gene of the VH4 subgroup. However. the VH4 genes rearranged in different Lc1-reactive tumor populations may originate from at least two disparate germ-line VH4 genes. Also. in contrast to the CD5-positive tumor populations. we find evidence for intraclonal diversity in the functionally rearranged VH4 genes of the CD5-negative SLL. Collectively. this study discerns a degeneracy in the VH4 genes that can encode the Lc1 CRI. indicating the term "supratypic cross-reactive idiotype" may best describe the specificity of the Lc1 mAb. Also. this study suggests that expression of CD5 may delineate categories of B cell SLL that differ in their relative rates of constitutive Ig V gene somatic mutation.
The immunogenicity and safety of intradermal hepatitis B vaccine, BACKGROUND. One of the chief barriers to a greater use of hepatitis B vaccine is the high cost of the vaccine itself. A number of small research trials have shown that an adequate immune response can be induced at a much lower cost by administering one tenth of the vaccine using an intradermal technique. The purpose of this study was to ascertain whether these results could be replicated in a larger clinical trial. METHODS. Vaccine recipients included health care providers. police officers. and firefighters. Recipients were given 0.1 mL of plasma-derived hepatitis B vaccine intradermally on days 1. 30. and 180. Antibody response was measured on day 210. with seroconversion defined as a sample-to-negative (S/N) ratio of greater than or equal to 10. Any local and systemic side effects were documented. RESULTS. Six hundred sixteen individuals completed the vaccination series. and seroconversion occurred in 534 (86.7%). The rate of seroconversion in those younger than 40 years was 91.2% and in those 40 years and older was 75.1%. The mean S/N ratio was 154.9 (range 0 to 620) and decreased with increasing age (r = -.25. P = .0001). Side effects were largely limited to local reactions. CONCLUSIONS. The results support the use of the intradermal technique as a cost-effective alternative to the intramuscular route in individuals younger than 40 years. The intradermal technique may be used in older individuals if titers are obtained to assure seroconversion. Because of the restricted availability of the plasma-derived vaccine used in this study. similar trials with recombinant vaccine should be undertaken.
Screening healthy people for diabetes: is it worthwhile, BACKGROUND. The objectives of this study were (1) to estimate the prevalence of previously unknown diabetes mellitus in an apparently healthy population aged 40 years and older. (2) to estimate the ratio of known to unknown diabetics. and (3) from this information. to estimate the true prevalence of diabetes. METHODS. A one in five random sample of healthy patients aged 40 years and older attending six rural family physician offices had their fasting plasma glucose (FPG) level tested with a reflectance glucometer. If the FPG was greater than or equal to 7.8 mmol/L (140.5 mg/dL). a second FPG test was done on a later day. RESULTS. The sample of 1264 patients contained 139 known patients with diabetes. Of the remaining 1125 patients. 936 (83%) were tested. Twenty-three patients had an elevated FPG level on the first test. but only nine of them had an elevated FPG level on the second test. One new patient with diabetes was found for each 15 patients already diagnosed; thus. the prevalence of unknown diabetes in the study population was 0.7%. As a result of this survey. the estimated prevalence of diabetes in the population age 40 years and older rose from 11.0% to 11.7%. and the estimated prevalence for the entire population rose from 4.4% to 4.6%. CONCLUSIONS. Routine screening for diabetes mellitus in otherwise healthy patients aged 40 years and older is not worthwhile. Such screening should be restricted to high-risk groups.
Koilocytotic atypia and underlying dysplasia, BACKGROUND. Several studies have examined the agreement between Papanicolaou smear cytology and subsequent biopsy results in the diagnosis of cervical dysplasia. However. few studies have focused specifically on koilocytotic (KC) atypia. Given the increasing frequency of reporting KC atypia on Papanicolaou smears. we sought to obtain more information on the relationship between Papanicolaou smears and subsequent colposcopically directed cervical biopsies. METHODS. Retrospectively. we compared the Papanicolaou smears and colposcopically guided biopsy results for 132 college women who had abnormal Papanicolaou smears (KC. cervical intraepithelial neoplasia [CIN]. or reactive atypia [RA]). Data were compiled through systematic review of the charts of these women. The cervical biopsies were taken 6 months or less after the Papanicolaou smears. RESULTS. Of 99 women having only KC atypia on cytology. histology revealed concordance in 51 cases and underlying dysplasia in 16 cases. Only one biopsy revealed CIN III. and no biopsies showed invasive carcinoma. We also noted variation in the histologic results between the laboratories that analyzed the biopsy specimens. In comparing the biopsy results after one or two KC atypic Papanicolaou smears 6 months or less apart. we found no statistically significant difference. CONCLUSIONS. These findings suggest that physicians who obtain an initial Papanicolaou smear read as KC atypia could obtain a second smear 3 months later to determine if there is persistent KC atypia before advising a patient to have cervical biopsy. In addition. physicians also should know the limitations of the laboratories providing them with information.
The negative association in women between cigarette smoking and uncomplicated angina pectoris in the Framingham Heart Study data, As a result of a more complete analysis of available Framingham Heart Study data on the association of cigarette smoking to incidence of uncomplicated angina pectoris than has previously been published in Framingham papers. it was determined that there is a consistently negative risk factor association for women at every follow-up period from 12 to 30 years. with Framingham women cigarette smokers experiencing 30-40% lower rates of uncomplicated angina pectoris than non-smokers. the rates also declining with increasing amounts of cigarettes smoked. Our analysis confirms the absence of a predictive risk factor association in the case of men previously indicated by Framingham investigators. The published declarations by Framingham investigators of an absence of association between cigarette smoking and angina pectoris in Framingham women. is a failure to publicly recognize the distinctive negative association present in the Framingham female data. The Framingham data on the relationship of smoking to angina incidence is clearly at variance with the Surgeon General's sketchy finding of an inconsistent positive association for men and an uncertain relationship for women. It is suggested that special attention should be directed to these results of the Framingham data because of the preeminence of Framingham material world wide. because angina pectoris is the most common manifestation of coronary heart disease. because it will improve the "conventional wisdom" on this subject. and because the negative relationship found for Framingham women does not lend support to the belief held by some that smoking enhances the degree of coronary atherosclerosis.
The epidemiology of exposure to electromagnetic fields: an overview of the recent literature, Epidemiologic studies of exposure to electromagnetic fields (EMF) have been reviewed. Possible links to incidences of cancer and abnormal fetal development have been suggested by some investigators. In general. the results have been inconsistent. There are many deficiencies in the studies. and many questions have been raised about the validity of some of the conclusions proposed. There is currently no definitive evidence of an association between exposure to EMF and the alleged risks. Due to problems and limitations inherent in future studies (misconceptions about exposure levels. uncertainty about field variability. criticisms of surrogate measures). this question is unlikely to ever be answered with certainty. Unfortunately. many highly-publicized accounts of speculative and unsubstantiated claims have caused undue concern among the general public.
The hospital costs of diagnostic procedures for colorectal cancer, Diagnosis for colorectal cancer is commonly made using either colonoscopy or double contrast barium enema techniques. To data. little attention has been paid to the comparative costs of these two procedures and the paper presents estimates of hospital costs for each. using data from the colorectal study being undertaken in Nottingham. U.K. Consideration is also given to procedure sensitivity and the frequency of referral to the alternative technique in cases of incomplete diagnosis. The paper presents the conditions under which a given technique may be considered cost-superior to its alternative but concludes that the absence of conclusive clinical trial data and other considerations precludes the identification of a definitively optimum technique from the economic point of view.
Latency and time-dependent exposure in a case-control study, Detailed historical data are elicited often from subjects in retrospective studies. yielding time-dependent measures of exposures. Investigation of a hypothesized period of latency can be made by examining disease/exposure relationships in multiple time windows. either along the age or time-before diagnosis axes. We suggest splitting the data into many time intervals and separately fitting regression models to the available data in each interval. Covariances between estimated coefficients from different intervals are empirically estimated. and used for assessing variability of specified functions of the time-specific coefficients. Alternative methods of interval formation and their consequences are discussed. We apply these methods to a French case-control study of oral contraceptive use and cervical cancer incidence. and compare the results to those of standard analyses.
Risk factors for subarachnoid hemorrhage in a longitudinal population study, The known risk factors of atherosclerotic diseases may be involved in the development of a subarachnoid hemorrhage. We studied the morbidity and mortality due to subarachnoid hemorrhage among 42.862 men and women aged 20-69 years who had participated in a large health survey in Finland. During a mean follow-up of 12 years. 102 non-fatal and 85 fatal cases of subarachnoid hemorrhage were observed. The total incidence was 37 per 100.000 person-years. Smoking and hypertension were positively associated and body mass index was inversely associated with the risk of subarachnoid hemorrhage. These associations were not confounded by age or each other. No statistically significant association with risk was detected for serum cholesterol level. hematocrit content. known heart disease. or diabetes. The risk was especially elevated among lean hypertensive subjects and lean smoking subjects. The age-adjusted relative risks of subarachnoid hemorrhage for lean. hypertensive smokers were 18.3 (95% confidence interval (CI). 7.8-42.7) among women and 6.7 (95% CI. 2.3-19.7) among men as compared to the risk among subjects without these risk factors. We conclude that modifiable risk factors are predictive of subarachnoid hemorrhage. for which reason subarachnoid hemorrhage may in part be preventable. Leanness combined with arterial hypertension and/or smoking. in particular. poses a substantially elevated risk.
Does alcohol protect against the formation of gallstones? A demonstration of protopathic bias, Previous studies have found an inverse relation between alcohol use and clinical gallstone disease. suggestive of a protective effect of alcohol use. However. such an inverse relation may (at least partly) be explained by a reduction of alcohol use because of symptoms related to clinical gallstone disease (protopathic bias). We empirically evaluated the consequences of different designs for the avoidance of such bias in a series of case-control studies. A first study deliberately used a design that is commonly seen in the literature. Cases of clinical gallstone disease. referred to hospital because of symptoms. were contrasted with general population controls. The results suggested an inverse relation between alcohol use and gallstones. Next. three alternative case-control studies were performed using designs that safeguard against protopathic bias. In none of these studies was an association between alcohol use and gallstones found. This demonstrates the probable existence of protopathic bias in case-control studies on alcohol use and gallstones. It is argued that earlier non-experimental studies on this topic were susceptible to such bias. This has most likely led to an overestimation of the protective effect.
Intra- and interindividual variability of glucose tolerance in an elderly population, The intra- and interindividual variability of the oral glucose tolerance test (OGTT) and other risk factors was investigated in 237 subjects. aged 64-87. examined annually in the period 1971-1975. Coefficients of intraindividual variation (CVa) were calculated from individual regressions on time. The lowest CVa was found for the summary index including fasting glucose (area under the curve. AUC): 10.0 +/- 4.9%. For fasting and 30. 60. and 120 min glucose the values ranged from 12 to 18%. The CVa's were not associated with age. gender. drug use. and disease prevalence. and may also be applied to other populations. The reliability coefficient depended on the prevalence of diabetes in the population and was higher than observed in younger populations. The highest reliability coefficient was observed for AUC: 0.81. For the combined information of OGTT. reflected by AUC or by classification according to WHO criteria. the variability was comparable to that of other cardiovascular risk factors such as serum total cholesterol.
Measurement of tissue oxygen tension: comparison between two subcutaneous oxygen tonometers, We compared the 95% response time (95% RT) of two tissue oxygen tonometers under two sets of circumstances. We first evaluated the devices during normoxia. hyperoxia. and anoxia in vitro. using a transcutaneous PO2 electrode (PtcO2) as the reference. The responses to normoxia and to different grades of hyperoxia were examined in vivo in 8 healthy volunteers to assess the relationship between changes in subcutaneous PO2 and PtcO2. an estimate of arterial PO2 (PaO2). One subcutaneous method (ScA) used a technique based on a polarographic needle electrode in situ connected to an ammeter; the second method (ScB) was based on a blood gas analyzer system first described by Hunt (Lancet 164;2:1370). ScA and PtcO2 both responded to stepwise changes in ambient oxygen concentration (21-100%) in vitro within 10 seconds; the 95% RT of ScA was 1.39 +/- 0.5 to 2.39 +/- 0.8 minutes and that of PtcO2 was 0.32 +/- 0.1 to 0.49 +/- 0.1 minutes. ScB had a lag of 3 minutes. and the 95% RT was 6.75 +/- 0.5 to 8.2 +/- 0.8 minutes. In contrast to the results in vitro. the response of ScA to changes in FiO2 in vivo was delayed compared with the rapid response of PtcO2. reflecting the physiologic delay of tissue PO2 in response to increased PaO2. The time lag and the long 95% RT of ScB were even more evident in vivo. ScA reacted three to four times faster than ScB. both in vitro and in vivo. to changes in the oxygen environment. The in vitro 95% RT of ScA to changes in ambient oxygen varied from 2 to 3.5 minutes.
A survey of alcohol use in an inner-city ambulatory care setting, OBJECTIVE: To measure the prevalence of current drinking and potential problem drinking in an inner-city ambulatory care setting. using the CAGE questionnaire. DESIGN: Survey of patients attending ambulatory care clinics. using structured personal interviews. SETTING: Three ambulatory care clinics serving an indigent. predominantly black population of metropolitan Atlanta: a general medical appointment clinic. a walk-in clinic. and a neighborhood primary care clinic. PATIENTS/PARTICIPANTS: Patients over the age of 18 who attended one of the above clinics on a day when interviewers were available and who were estimated to have more than a 45-minute wait prior to seeing their health provider. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: 15.3% of subjects had CAGE scores greater than or equal to 2 (95% CI 12.2. 19.0). A CAGE score of greater than or equal to 2 was almost three times more common in men than in women. 26.7% vs. 9.5%. Only 8.6% (95% CI 6.3. 11.7) of subjects reported drinking greater than or equal to 2 drinks per day. These findings suggest that problem drinking may affect as many as one in six people seeking care in inner-city ambulatory care clinics and provide support for the use of screening instruments such as the CAGE questionnaire for improved sensitivity in detecting alcoholism in these practice settings.
A prospective study of the effects of cigarette smoking and alcohol abuse on mortality, OBJECTIVE: To compare the relative risks of alcohol abuse and cigarette smoking. DESIGN: Cohort studies utilizing a 12-to-16-year follow-up of 47-to-52-year old men. PARTICIPANTS AND SETTING: 237 Caucasian college sophomores (COLLEGE sample) and 366 socially disadvantaged junior high school students (CORE-CITY sample) selected in 1940-43 for relative mental health and for interdisciplinary study. MAIN RESULTS: The presence of many risk factors for death. including alcohol abuse and smoking. had been assessed prior to age 47 (CORE-CITY sample) and age 52 (COLLEGE sample). Over the next 12 years (CORE-CITY sample) and the next 16 years (COLLEGE sample). the men's mortality was monitored. Heavy use of cigarettes and alcohol abuse were highly correlated. When the effect of alcohol abuse was controlled. heavy smoking was associated with elevated mortality risks in both samples. although this was not statistically significant in the CORE-CITY sample. When smoking was controlled. the odds ratios for mortality from alcohol abuse were substantial in both samples. CONCLUSIONS: These results and a literature review suggest that insufficient alcohol abuse histories may lead clinicians to underestimate the mortality risk of alcohol abuse.
Smoking cessation following admission to a coronary care unit, OBJECTIVE: To determine the impact of an episode of serious cardiovascular disease on smoking behavior and to identify factors associated with smoking cessation in this setting. DESIGN: Prospective observational study in which smokers admitted to a coronary care unit (CCU) were followed for one year after hospital discharge to determine subsequent smoking behavior. SETTING: Coronary care unit of a teaching hospital. PATIENTS: Preadmission smoking status was assessed in all 828 patients admitted to the CCU during one year. The 310 smokers surviving to hospital discharge were followed and their smoking behaviors assessed by self-report at six and 12 months. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Six months after discharge. 32% of survivors were not smoking; the rate of sustained cessation at one year was 25%. Smokers with a new diagnosis of coronary heart disease (CHD) made during hospitalization had the highest cessation rate (53% vs. 31%. p = 0.01). On multivariate analysis. smoking cessation was more likely if patients were discharged with a diagnosis of CHD. had no prior history of CHD. were lighter smokers (less than 1 pack/day). and had congestive heart failure during hospitalization. Among smokers admitted because of suspected myocardial infarction (MI). cessation was more likely if the diagnosis was CHD than if it was noncoronary (37% vs. 19%. p less than 0.05). but a diagnosis of MI led to no more smoking cessation than did coronary insufficiency. CONCLUSION: Hospitalization in a CCU is a stimulus to long-term smoking cessation. especially for lighter smokers and those with a new diagnosis of CHD. Admission to a CCU may represent a time when smoking habits are particularly susceptible to intervention. Smoking cessation in this setting should improve patient outcomes because cessation reduces cardiovascular mortality. even when quitting occurs after the onset of CHD.
Social and clinical features as predictors of outcome in outpatient alcohol withdrawal, OBJECTIVE: To identify patient features--both social and clinical--that may be associated with treatment failure in outpatient alcohol withdrawal. DESIGN: A prospective observational cohort study of patients who underwent outpatient management of the alcohol withdrawal syndrome. SETTING: Community hospital-based outpatient alcohol treatment program. PATIENTS: The 179 patients who were eligible for and participated in a clinical trial of drug therapy for outpatient management of the alcohol withdrawal syndrome. MAIN RESULTS: Treatment failure occurred for 45% (80/179) of the patients. Failure rating did not vary according to diverse sociodemographic features such as age. level of education. income. medical insurance status. and marital status. Persons who were homeless did as well as those who were not. In contrast. two clinical features of withdrawal were associated with significantly higher rates of treatment failure: craving and withdrawal symptom severity. High cravers had a treatment failure rate of 56% (22/39). compared with 36% (41/115) for those with lower scores (p less than 0.03). Among those with moderate-to-high withdrawal symptom severity. 49% (74/151) represented treatment failures. compared with 22% (6/27) of those in the low-symptom group (p less than 0.01). CONCLUSIONS: While these data do not confirm that socially disadvantaged persons are at increased risk for withdrawal treatment failure. two clinical features--craving and withdrawal symptom severity--may help identify high-risk patients.
Computerized digital enhancement in craniofacial cephalometric radiography, Application of digital radiologic imaging techniques to cephalometric assessment of the craniofacial skeleton is presented. Digital-enhanced and standard cephalometric radiographs were compared by osseous and soft tissue landmark analysis. Although both radiographic methods exhibited comparable accuracy at identifying bony landmarks. digital enhancement was consistently superior at delineating soft tissue relationships.
Postoperative computed tomography study of pterygomaxillary separation during the Le Fort I osteotomy, Computed tomography (CT) was used postoperatively to assess the pterygomaxillary region in 12 orthognathic surgery patients who had had a Le Fort I osteotomy. Although pterygomaxillary separation was successful in all cases. in only 41.6% of the sides did fractures of the plate not occur. The incidence of low pterygoid plate fracture was 37.5% and that of high pterygoid plate fracture was 25%; 4.2% of sides showed a maxillary tuberosity fracture. Multiple fractures were observed in 8.3% of separated plates. Of 17 pterygoid plates judged clinically to be intact. only 10 were intact as assessed by CT. The significance of these findings and application of CT to evaluation of modifications to the Le Fort I osteotomy is discussed.
Modified Le Fort I (maxillary-zygomatic) osteotomy: rationale, basis, and surgical technique, A modified version of the Le Fort I maxillary osteotomy is described. The esthetic and anatomic basis. the surgical technique. and possible complications are discussed and two representative cases are shown. This technique has been used to treat 38 patients with various degrees of combined maxillary-zygomatic deficiency in the last 3 years. Based on this experience. it is concluded that this procedure provides a predictable esthetic result and excellent skeletal stability with few intraoperative and postoperative complications. Furthermore. the need for simultaneous bone grafting or alloplastic implants. as in the conventional Le Fort I. is virtually eliminated using this osteotomy.
Bridging of mandibular defects with two different reconstruction systems: an experimental study, To compare two different mandibular reconstruction systems. a 5-cm angular resection was performed in nine adult sheep. The defect was reconstructed using either a classic AO plate or the AO-THORP reconstruction system. The animals were killed 5. 9. and 14 weeks after operation. Serial sections with the plates and screws in place were prepared and studied histologically and with microradiography and fluorescence microscopy. Twenty-six percent of the 2.7-mm AO cortical screws were adequately fixed. The corresponding percentage for AO-THORP hollow screws was 73%. The main advantage of the latter system is the screw-plate locking principle. which allows plate stability to be maintained even if bone is resorbed under the plate. Whether the existence of a screw lumen is an advantage has not yet been established.
A methodology for building an AIDS research file using Medicaid claims and administrative data bases, There is a current and continuing need for health services research on the epidemiology of AIDS and its impact on health care systems. However. large data bases designed for other purposes. such as hospital discharge abstract systems and medical claims systems. are the primary source of data for AIDS research. Thus. methodologies must be developed that enable researchers to investigate AIDS using data bases designed for other purposes. In this report. we describe a methodology for utilizing Medicaid Management Information Systems (MMIS) data to conduct health services research on AIDS. We developed an ICD-9-CM diagnosis-based algorithm that accurately identified the majority of AIDS cases. both before and after AIDS-specific ICD-9-CM codes became available in October 1986. Using diagnostic categories that we had developed previously to identify AIDS cases among disabled young men in California on Medicaid. we expanded the methodology to include children. men. and women of all ages in California and New York. The algorithm worked best with young disabled males. older males. and females between 18 and 50 years of age. The algorithm worked least well with nondisabled males. females over age 50 years. and children. We also developed methodologies for defining Medicaid AIDS onset. risk group. and date of death. Our research resulted in the identification of a study population representing the majority of Medicaid AIDS cases between 1983 and 1986 in California and New York. The AIDS study population data base was used in further research on eligibility patterns. the epidemiology of the AIDS epidemic. lifetime Medicaid utilization and expenditures. and the development of a survival-based severity index for Medicaid recipients with AIDS.
The epidemiology of AIDS in the New York and California Medicaid programs, An epidemiological analysis of the impact of AIDS on the New York and California Medicaid programs was conducted for 1983-1986. The epidemic affected the New York and California Medicaid programs in several similar ways. The total number of cases grew rapidly over the study time period. In both states. the epidemic was mostly confined to the young adult (21-44 years) age group. Cases were geographically concentrated and highly localized even within counties. but evidence of geographic dispersion to counties outside of the urban centers was also evident. Some dramatic differences were also found between California and New York. Patients with claims histories of drug use were far more likely to be found in the New York population and the proportion of other adult males (our proxy for the homosexual risk group) was higher in California. A much higher proportion of New York's population was female (30 vs. 5%). New York also had many more pediatric cases. Most importantly. New York's raw number of cases was substantially higher than California. with approximately three times as many cases during the time period (1983-1986). There is also substantial evidence that transmission of the disease to heterosexual partners of drug users places heterosexual urban minorities at grave risk of contracting the disease through interaction with infected persons.
Medicaid eligibility patterns for persons with AIDS in California and New York, 1982-1987, An analysis of Medicaid eligibility patterns for persons with AIDS (PWAs) was conducted. based on the longitudinal Medicaid eligibility histories of 1.314 AIDS decedents in California and 6.273 AIDS decedents in New York between 1982 and 1987. The study analyzed what eligibility groups or categories and which financial standards PWAs were using to qualify for Medicaid. States have many options with regard to the categories of people they cover under Medicaid and where they set their financial thresholds. The study findings are useful in showing how these policy decisions affect PWAs. A major conclusion of the study is the importance of medically needy coverage for PWAs. Medically needy coverage. which is optional to states. opens up Medicaid to persons of any income level. assuming their medical expenses are high enough. The study also found that PWAs who qualify only through the medically needy provisions have much shorter enrollment and lower lifetime Medicaid expenditures than other PWAs on Medicaid. Presumably. most medically needy only enrollees have other sources of health care coverage in the early stages of the illness. Study data also suggested significant administrative obstacles for PWAs in dealing with the Medicaid eligibility process. Finally. an unexpected study result was that all states may not be aggressively utilizing federal Medicaid financing options for covering the medical assistance expenditures for a significant proportion of the low-income AIDS population.
Lifetime Medicaid service utilization and expenditures for AIDS in New York and California, Several important gaps exists in information on the health care resources used by people with AIDS. including patterns of outpatient care. differences between populations at risk of the disease. and services paid for by Medicaid. To address the shortage of information in these areas. this study examined average Medicaid expenditures and service use for the time period a person has AIDS. The study population was Medicaid enrollees with AIDS in New York and California who died between October 1985 and September 1986. The study focused on the differences between the two states and between four groups that were proxies for at-risk populations: children. women. drug-using men. and non-drug-using men. Mean lifetime Medicaid expenditures were about $30.000 in New York and $20.000 in California. Inpatient use was higher and outpatient service use was lower in New York than in California after controlling for risk group. diagnosis. and Medicaid eligibility group (a proxy for income level). In California. women had higher expenditures and inpatient use than men. In New York. women and drug-using men had higher expenditures and use of inpatient and outpatient services (except home health care) than the non-drug-using men. Children in New York had higher expenditures and hospital use than adults but similar outpatient service use. Multivariate analyses suggest that differences between risk groups were largely attributable to differences in diagnosis and income level (as measured by Medicaid eligibility group).
The AIDS-defining diagnosis and subsequent complications: a survival-based severity index, To define a survival-based severity measure for AIDS. we convened a panel of AIDS experts who identified factors influencing AIDS prognosis and estimated the impact of prognostic factors on survival time. The resulting conceptual model included 19 AIDS-defining conditions and 80 subsequent AIDS-related complications. This model was tested on longitudinal disease histories of 3.937 AIDS patients in the New York State Medicaid Program diagnosed between 1983 and 1986 and followed through 1988. The initial AIDS diagnosis and complications within 3 months of AIDS onset were identified from coded diagnoses recorded on inpatient and outpatient claims. Three AIDS-defining diagnosis groups were created; survival times from least to most severe group were 25. 10. and 7 months. To determine the influence of subsequent complications on risk of death. the survival times associated with combinations of defining diagnosis groups and four severity levels of subsequent complications were determined. Median survival ranged from 43 months for the least severe defining diagnosis group without early complications to 12 months for the group with severe defining diagnoses and serious complications. The matrix of AIDS-defining diagnoses and complications was divided into four severity categories with significantly different survival curves. This severity measure uses longitudinal data commonly available to clinicians and researchers to create distinct AIDS prognostic categories.
An open-label, dose-ranging trial of AL 721 in patients with persistent generalized lymphadenopathy and AIDS-related complex, AL 721. a lipid mixture with reported in vitro activity against human immunodeficiency virus (HIV) via cell membrane or virion cholesterol depletion. was evaluated in a multicenter. open-label. dose-ranging trial. Forty men with persistent generalized lymphadenopathy or AIDS-related complex were treated with doses of 20. 30. 40. or 50 g orally twice daily for 8 weeks. and monitored for toxicity. disease progression. and with immunologic. virologic. and serum lipid profiles. The compound was found to be well tolerated over the broad range of doses examined; adverse reactions were confined to the gastrointestinal tract. of mild to moderate severity. and self-limited in duration. Modest weight gains observed on treatment were reversed within 4 weeks following cessation of therapy. While disease progression was not observed in this short-term study. we could find no indication of an immunorestorative or antiviral effect of AL 721. as determined by T-lymphocyte subset quantitation or HIV culture. All three patients who were HIV p24 antigenemic at entry retained positive antigen levels throughout treatment. As a consequence of therapy. however. significant increases in serum lipids were observed. including elevations in both triglyceride and total cholesterol levels. In conclusion. our experience on the largest group of HIV-infected patients treated with the highest doses of AL 721 provides no support for the use of this compound as an antiretroviral agent.
Specific synthetic peptides for detection of and discrimination between HIV-1 and HIV-2 infection, A panel of highly purified synthetic oligopeptides representing defined parts of the gag and env proteins of HIV-1 and HIV-2 were used as antigens in ELISA for serodiagnosis of HIV-1 and HIV-2 infection. The analysis included sera from 321 HIV-infected patients and 201 healthy controls from the Ivory Coast. where the prevalence is high for both HIV-1 and HIV-2. and sera from European HIV-1-infected individuals. All sera from HIV-1-infected individuals reacted with a 20 amino acid (a.a.) peptide JB-4c (a.a. 594-613) derived from a highly immunogenic conserved region of the external part of gp41. An equally good response was seen in the HIV-2-infected individuals to a 20 a.a. peptide. JB-16c. from the corresponding part of HIV-2 gp36. Both HIV-1- and HIV-2-seropositive individuals responded well to a peptide. JB-8pc (a.a. 427-448). representing the C-terminal end of the putative CD4-binding site of gp120 of HIV-1. The frequency of reactivity to three selected HIV-1 gag peptides derived from p17 and p15 was 60-70% in both HIV-1 and HIV-2-positive sera. To distinguish between HIV-1 and HIV-2 infection. the sera were titrated against the peptides. Although there was a high degree of cross-reactivity at lower serum dilutions. it was possible to discriminate the infections at higher dilutions to the HIV-1 and HIV-2 gp41/gp36 peptides JB-4c and JB-16c. Analysis of serum reactivity to several selected peptides thus allowed the identification of HIV infection. and the discrimination between HIV-1 and HIV-2.
Liposomal encapsulation of 3'-azido-3'-deoxythymidine (AZT) results in decreased bone marrow toxicity and enhanced activity against murine AIDS-induced immunosuppression, The effect of liposome encapsulation on the bone marrow toxicity and antiviral activity of AZT in C57BL/6 mice was determined. Liposomal encapsulation of AZT enhanced localization in the liver. spleen. and lung. and reduced localization in bone marrow. AZT administered i.v. (0.08-50 mg/kg/day) had significant bone marrow toxicity (30-50% reduction in cellularity) after five injections. maximum toxicity occurring at greater than or equal to 2 mg/kg/day. Parallel reductions in the number of erythrocytes and leukocytes were observed. AZT encapsulated in liposomes had no bone marrow toxicity at doses of 0.08-10 mg/kg/day. and erythrocyte and leukocyte numbers remained normal. Infection of C57BL/6 mice with LP-BM5 murine leukemia virus suppressed T- and B-cell mitogenic responses. Treatment of LP-BM5 retrovirus-infected mice with 2 mg/kg AZT three times weekly partially protected the mitogenic response at 4 but not at 7 weeks postinfection. Treatment with liposomal AZT resulted in normal T- and B-cell mitogenic responses at both 4 and 7 weeks postinfection.
More rapid progression to AIDS in older HIV-infected people: the role of CD4+ T-cell counts, The tendency for older people with HIV infection to progress more rapidly to AIDS than younger people was studied in a group of 111 anti-HIV-positive haemophiliacs followed for up to 10 years from seroconversion. After 7 years of seropositivity. those aged over 30 years at the time of the first positive anti-HIV test had a cumulative progression rate to AIDS of 50%. compared with only 12% for those aged 10-19 years (Kaplan-Meier estimates). Overall. the relative risk of developing AIDS by any given time after seroconversion was 1.45 for each 10 year increase in age (p = 0.002; 95% confidence limits of 1.15. 1.85; Cox proportional hazards model). After adjustment for the CD4+ T-cell count (median of 10 count measurements per patient. fitted as a time-dependent covariate). the relative risk fell to 1.31 but remained statistically significant (p less than 0.05; 95% confidence limits of 1.03. 1.67). This implies that older people may be at higher risk of progression than their younger counterparts. even if their CD4+ T-cell counts are the same. Hence. prophylaxis against opportunistic infections may be indicated at higher CD4+ T-cell counts in older people than in younger people.
Alcohol consumption and unsafe sex: a comparison of heterosexuals and homosexual men, Recent studies have suggested that drinking in conjunction with sexual activity is related to unsafe sexual activities known to increase the risk of AIDS transmission. However. these studies have used general measures of frequency of both drinking and sexual behavior. giving insufficient information to establish that drinking and risky sex occur in the same sexual encounters. This article presents data from a mail survey of the adult population of San Francisco in which respondents were queried about the circumstances of specific sexual encounters that took place in conjunction with alcohol consumption. The results showed that subjective intoxication was related to practice of unsafe sex among homosexual men and heterosexual women but not among heterosexual men. In addition. respondents whose sexual partners were met in locations construed as "pickup" environments were more likely to practice safe sex. A focus on specific sexual events can contribute to a better understanding of the dynamics of sexual encounters and of the predictors of risky sex in these encounters.
The supply and demand dynamics of sexual behavior: implications for heterosexual HIV epidemics, This article investigates the supply and demand dynamics of sexual behavior in a simple epidemiological model of heterosexual transmission of human immunodeficiency virus (HIV). The supply and demand dynamics of sexual behavior are modeled by specifying implicit sexual behavior change (ISBC) mechanisms. These mechanisms specify how males and females modify their rates of sex partner change in response to changes in the availability of the opposite sex. During an epidemic. the availability of both sexes will change owing to recruitment and mortality; consequently. implicit sexual behavior changes will be induced. These behavior changes will be independent of any explicit sexual behavioral changes that may occur as a result of intervention strategies. We investigate four different ISBC mechanisms: the two extremes of the continuum of possible mechanisms (where only one sex changes behavior). as well as two intermediate possibilities (where both sexes change behavior). The results show that the epidemiological effects of these ISBC mechanisms depend upon the transmission speed of the virus. If HIV transmission is slow. the epidemiological effects of the four ISBC mechanisms cannot be differentiated. If HIV transmission is fast. the four ISBC mechanisms differ considerably in the degree to which they modify the gender-specific rates of sex partner change. but the sexual behavioral changes occur too late to significantly decrease the cumulative number of infected persons. However. if HIV transmission is moderately fast. the four different ISBC mechanisms produce significantly different epidemics. The differences between the epidemics. produced by the four ISBC mechanisms. are magnified as the degree of asymmetry between the heterosexual transmission efficiencies increases. We discuss the implications of our results for both the future number of AIDS cases that will be observed in the "real world" and the number of AIDS cases that will be predicted from mathematical models. We also discuss the implications for studies that evaluate the causation of sexual behavior changes.
Influence of perfusate pH on the postischemic recovery of cardiac contractile function: involvement of sodium-hydrogen exchange, During reperfusion with pH 7.2 media after 55 min of ischemia. the recovery of developed tension (DT) and the maximal resting tension (RT) of the isolated right ventricular wall of rats were 58.8 +/- 6.5 and 201 +/- 20%. respectively. of the preischemic values. DT and RT in the ventricular wall perfused with pH 7.9 media for 6 min during reperfusion were 40 +/- 5.9 and 285 +/- 13%. respectively. of the preischemic values (P less than .05 vs. pH 7.2 group). The Na(+)-H+ exchange inhibitor. 5-(N.N-dimethyl)amiloride (DMA). effectively antagonized the detrimental effect of pH 7.9 media. A pH 6.5 media inhibited DT recovery and the rise in RT in the first 6 min of reperfusion. Subsequent reperfusion with pH 7.2 media resulted in cardiac dysfunction similar to that observed when reperfused at pH 7.2 only. Cellular Na+ and Ca++ were significantly elevated after 6 min of reperfusion at pH 7.2. Na+ and Ca++ levels were increased further if reperfusion was carried out at pH 7.9. Inclusion of 20 microM DMA during reperfusion at 7.9 significantly reduced cellular Na+ and Ca++. Creatine phosphokinase activity in the coronary effluent rose significantly during reperfusion at pH 7.2 and this was exacerbated if the reperfusion pH was 7.9. DMA treatment during reperfusion could significantly inhibit this elevation. The data lend further support for an important role of Na(+)-H+ exchange in the development of ischemia-reperfusion injury.
Phencyclidine increased release of beta-endorphin from anterior lobe of the pituitary, Phencyclidine (PCP) has been found to affect neuroendocrine function by altering the release of the anterior pituitary hormones. adrenocorticotrophin. luteinizing hormone and prolactin. The purpose of this study was to examine the effect of PCP on release of the two pituitary hormones also derived from the adrenocorticotropin precursor. namely. alpha-melanocyte-stimulating hormone and beta-endorphin (beta-E). synthesized in the neurointermediate and anterior lobes of the pituitary. At behaviorally active doses. PCP administered i.c.v. increased plasma levels of immunoreactive beta-E (i beta-E) without affecting the concentration of immunoreactive alpha-melanocyte-stimulating hormone. suggesting that PCP increased the release of beta-E from only the anterior lobe of the pituitary. Dexamethasone pretreatment blocked the PCP-induced increase in i beta-E which indicated further the anterior lobe effects of PCP. MK-801 [(+)-5-methyl-10.11-dihydro-5H-dibenzo [a.d]cyclohepten-5.10-imine maleate). a selective PCP ligand. at behaviorally active doses also increased the plasma concentration of i beta-E. The dose-response curves for induction of behavior was very different from that for increasing the concentration of i beta-E in plasma. The increase in release of i beta-E was stereoselective as (+)-(1-(1-phenylcyclohexyl)-3 methylpiperidine but not (-)-(1-(1-phenylcyclohexyl)-3 methylpiperidine increased release of i beta-E. The increase in plasma levels of beta-E was not due to an interaction with opioid receptors because naloxone did not block PCP-induced release of beta-E. In vitro. PCP also significantly increased release of i beta-E from anterior lobe of the pituitary.
No association between an allele at the D2 dopamine receptor gene (DRD2) and alcoholism, OBJECTIVE.--We attempted to replicate a positive allelic association between the A1 allele of DRD2 (the D2 dopamine receptor locus) and alcoholism that has been reported. DESIGN.--We compared allele frequencies at the previously described Taq I restriction fragment length polymorphism system of DRD2 in alcoholics and random population controls. SUBJECTS.--The alcoholic subjects were 44 unrelated white individuals. diagnosed by direct structured interview to have alcohol dependence (by the Diagnostic and Statistical Manual of Mental Disorders. Revised Third Edition. criteria). The subjects in our random population control group (N = 68) were also white. RESULTS.--For the control group. allele frequencies at DRD2 were 0.20 (A1) and 0.80 (A2). For the alcoholic group overall. allele frequencies were 0.23 (A1) and 0.77 (A2). There were no significant differences in allele frequencies at the DRD2 locus between alcoholics and controls. The allele frequencies in both groups agreed closely with those observed in most previously described control populations. Subtyping the alcoholic group according to presence or absence of family history of alcoholism. presence or absence of antisocial personality disorder. age of onset. presence or absence of physical withdrawal symptoms. or recent alcohol consumption (as a measure of severity) did not in any case reveal significant differences in allele frequencies. CONCLUSION.--We were not able to replicate the results previously reported. We conclude that our data do not support an allelic association between the A1 allele at DRD2 and alcoholism.
Characterization and control of proton-ATPase along the nephron, Since it is now well established that the Na-H exchanger accounts for only part of tubular proton secretion. we attempted to characterize the molecular processes responsible for the remaining moiety. In particular. we evaluated the possible roles of proton pumps in urinary acidification. For this purpose. we characterized ATPase activities associated with the electrogenic H pump. on the one hand. and with H-K-ATPase. on the other. In order to circumvent the axial heterogeneity of nephron. this study was carried out on microdissected segments of nephron. The present report summarized experiments which aimed: (1) at characterizing H-ATPase and H-K-ATPase on kinetic and pharmacologic bases in the successive segments of mammalian nephrons; (2) at evaluating the ionic transport mediated by these two ATPases; and (3) at determining the factors which control the activity of these pumps.
Molecular biology of renal Na(+)-H+ exchangers, Na(+)-H+ exchangers are plasma membrane proteins that are responsible for Cl- and HCO3- reabsorption and regulation of intracellular pH in several nephron segments. Recently. a cDNA encoding a human Na(+)-H+ exchanger of unknown tissue origin was cloned. and Northern blot analysis revealed that structurally similar transcripts were expressed in rabbit kidney and porcine renal epithelial cells (LLC-PK1). To clone these renal transcripts we employed cDNA library screening and the polymerase chain reaction (PCR). We obtained 2.5 kb and 1.4 kb cDNAs corresponding to the 5' untranslated region and the membrane-associated domain of a rabbit renal Na(+)-H+ exchanger. From LLC-PK1 cells we obtained 1.5 kb and 1.3 kb cDNAs encoding the membrane-associated and cytoplasmic domains. The sequences of cDNAs from these three species were very similar and suggested a high degree of evolutionary conservation. Immunolocalization of synthetic oligopeptides derived from the deduced amino acid sequences indicated that the cloned cDNAs encoded the amiloride-sensitive form of the Na(+)-H+ exchanger present in basolateral membranes of epithelia. cDNAs were also used to study regulation of Na(+)-H+ exchanger gene expression in the kidney. and we found that metabolic acidosis stimulated both the transport rate and steady-state transcript levels of the basolateral Na(+)-H+ exchanger in LLC-PK1 cells.
Proliferation index in various stages of breast cancer determined by Ki-67 immunostaining, To investigate factors involved in progression of breast cancer. we estimated the growth fraction of malignant cell populations in various stages of mammary cancer growth. Frozen sections were immunostained with the Ki-67 monoclonal antibody and the proliferation index determined using static image analysis. Pure intraductal carcinoma. intraductal carcinoma coexisting with invasive disease. and metastatic sites coexisting with primary tumors were studied. The proliferation index of pure intraductal carcinomas (mean 4.5%. median 1.8%) was not significantly different from invasive mammary cancers (mean 5.1%. median 2.2%). The proliferation index determined for the in situ component of primary cancers (mean 3.8%. median 1.5%) was not significantly different from values obtained from the invasive component of growth (mean 4.2%. median 2.1%). Variability between in situ and invasive components for individual cases was minimal in tumors whose proliferation index was less than 3.0%; for tumors with higher proliferation indices. the differences were greater. However. there was no trend toward a decrease or increase in growth fraction for the two components of primary tumor growth. The mean proliferative index for primary tumors (mean 4.9%. median 4.0%) was not significantly different from the mean proliferative score from a matched group of metastatic sites in the same patients (mean 5.7%. median 5.5%). Comparison of individual cases uncovered differences in some tumors; again no consistent trends in either direction were noted. An increase (or decrease) in growth activity does not accompany the transition from intraductal (in situ) disease to invasive mammary cancer. nor does a change in growth fraction necessarily accompany progression of mammary cancer from the primary to regional metastatic site.
Metastatic pattern of infiltrating lobular carcinoma of the breast: an autopsy study, We analyzed the autopsy records and autopsy histological slides of 261 patients with breast carcinoma who died at the Institute of Oncology. Ljubljana. from January 1972 to October 1989. with particular attention to the metastatic pattern of infiltrating lobular carcinoma (ILC) which we compared with infiltrating ductal carcinoma (IDC). In 226 of 261 patients who died with metastatic disease there were 25 cases of ILC. 195 cases of IDC. 4 cases of mixed IDC-ILC. and 2 cases of mucinous carcinoma. There was no statistically significant difference in frequency of metastases to common metastatic sites. such as the liver. bone. and pleura. with the exception of the lungs. in which IDC metastases prevailed (P less than 0.006). By contrast. a statistically highly significant prevalence of ILC metastases to the peritoneum/retroperitoneum. hollow viscera. internal genital organs. leptomeninges. and myocardium was found (P values of less than 0.006- less than 10(-6). The metastases to these sites were characterized by diffuse growth of neoplastic cells that infiltrated in a lymphoma or leukemia-like fashion. Such metastases may remain clinically silent for a long time. in spite of their extensiveness. The difference of metastatic pattern between ILC and IDC is insufficiently appreciated in most of the published studies on ILC.
Five-year survival for cisplatin-based chemotherapy versus single-agent melphalan in patients with advanced ovarian cancer and optimal debulking surgery, The purpose of this study was to evaluate 5-year survival and 5-year progression-free survival in previously untreated patients with advanced ovarian cancer treated with single-agent melphalan in which very few patients underwent optimal debulking surgery (less than 2 cm residual) as compared with the patients treated with Cisplatin-based chemotherapy in which most patients underwent optimal debulking surgery. Significant increases in 5-year survival and 5-year progression-free survival were noted as we changed from the melphalan trial. in which only 14% underwent optimal debulking surgery. to PAC-H. in which 57% and the PAC trial in which 90%. respectively. underwent optimal debulking surgery. However. for those patients whose tumors were optimally debulked in the three trials. there were no statistically significant differences in median survival. median progression-free survival. 5-year survival. or 5-year progression-free survival in those patients treated with melphalan. PAC-H. or PAC. Without optimal debulking surgery. Cisplatin-based multiagent chemotherapy offered a small survival advantage. These results are similar to that reported by Gruppo Interregionale Cooperativo Oncologico Ginecologia. in which survival curves were identical for all the subgroups of chemotherapy regimens for those patients with residual disease less than 2 cm at the onset of chemotherapy whether they received (1) cyclophosphamide; (2) cyclophosphamide and Adriamycin; (3) cyclophosphamide. Adriamycin. and Cisplatin; (4) cyclophosphamide. Adriamycin. and hexamethylmelamine; (5) Cisplatin and cyclophosphamide; (6) low-dose Cisplatin; (7) high-dose Cisplatin; or (8) carboplatin.
Patterns of DNA-ploidy in operable colorectal carcinoma: a prospective study of 100 cases, A prospective study of cellular DNA content was made by means of flow cytometry in a nonconsecutive series of 100 patients undergoing surgery for primary colorectal adenocarcinoma. DNA-aneuploidy was present in 80% of cases (80/100); 39% of these were multiclonal (31/80). There was no significant correlation between DNA-ploidy and the clinical and pathological features examined. except for the primary tumor site (right colon vs. left colon vs. rectum: P less than 0.001). After a minimum follow-up of 30 months. out of 40 patients with no local invasion and/or distant metastases. 100% (9/9) of those with DNA-diploid neoplasias showed no signs of disease relapse. vs. 55% (17/31) of the DNA-aneuploid cases (P less than 0.05). Furthermore. in 45 cases with a minimum follow-up of 30 months. overall survival was 90% in patients with DNA-diploid carcinomas and 43% in the DNA-aneuploid cases (P less than 0.05).
Effects of antiplatelet agents alone or in combinations on platelet aggregation and on liver metastases from a human pancreatic adenocarcinoma in the nude mouse, There is ample evidence to suggest that hematogenous metastasis may be related to the ability of tumor cells to promote aggregation of host platelets. Arachidonic acid metabolism in platelets and vessel walls may also contribute to the metastatic process. Several preliminary trials of platelet inhibitory agents have been performed. Ketoconazole (inhibitor of lipoxygenase and thromboxane synthetase). verapamil (calcium antagonist). forskolin (stimulator of platelet adenylate cyclase). and indomethacin (inhibitor of cyclooxygenase) were examined. alone and in combination. to investigate their effects on platelet aggregation and on hepatic metastases from human pancreatic tumor cells (RWP-2) in nude mice. The tumor cells were injected intrasplenically. and the animals were divided into control. single-drug and combination treatment groups. The agents were administered intraperitoneally 1 hr before and every 24 hr after the tumor cell injections for 6 days. Statistically significant differences were observed between the control and single-treatment groups on the reduction of liver tumor nodules (range P less than 0.001-0.032) and in the liver surface areas occupied by tumor (range P less than 0.001-0.013). Furthermore. when these agents were combined. similar reductions in liver tumor nodules were noted (range P less than 0.001-0.008). while even greater inhibitory effects were seen in the liver surface areas occupied by tumor (P less than 0.001) compared with the single-treatment groups. Also. the combination studies strongly inhibited RWP-2-induced platelet aggregation in human platelet-rich plasma.
Results of multimodal therapy in Ewing's sarcoma: a retrospective analysis of 20 patients, A retrospective analysis was performed of 20 patients with Ewing's sarcoma treated by combined modality therapy. consisting of surgery. radiotherapy. and chemotherapy. Fourteen patients (70%) achieved complete remission and 5 patients (25%) were in partial remission at the end of treatment. One patient (5%) failed to respond to combined modality therapy. The overall 5 year actuarial survival was 64% and the disease free survival. 55%. Persistent or recurrent disease occurred in 8 patients (40%); one of them was salvaged by surgery and chemotherapy. Site and extent of primary lesion were prognosticators of patients' outcome. One patient developed radiation-related-sequelae. The efficacy of aggressive management consisting of wide surgery. radiotherapy and intermittent high dose chemotherapy is discussed.
Adenocarcinoma of the pancreas: a multimodality approach--a single surgeon's experience (1979-1988), A retrospective review of a single surgeon's experience with adenocarcinoma of the pancreas was performed. One hundred-one patients were treated over a 10-year period from 1979 to 1988. Seven patients underwent potentially curative resections and 28 patients presented with metastatic (stage IV) disease. Sixty-four patients had locally advanced and unresectable primary lesions. A total of 51 patients received I-125 seed implantation. There was no statistically significant difference in morbidity (33% vs. 30%) or mortality (6% vs. 8%) between patients receiving I-125 implantation and those undergoing palliative surgical procedures without implantation. Operative mortality was highest in patients presenting with stage IV lesions (11%). In those patients with locally advanced and unresectable carcinomas. there was a nonsignificant increase in survival (12.8 mo vs. 10.7 mo) in those receiving intraoperative I-125 implants when compared to those who did not when both groups received postoperative adjuvant chemotherapy and external beam radiotherapy. Based on these encouraging results. it is concluded that I-125 implantation can be performed safely and shows a trend toward improving long-term survivorship in patients with locally advanced pancreatic carcinoma when used in conjunction with chemotherapy and external beam radiation.
Chronic fatigue syndrome: clinical condition associated with immune activation, There is much conflicting immunological and viral data about the causes of chronic fatigue syndrome (CFS); some findings support the notion that CFS may be due to one or more immune disorders that have resulted from exposure to an infectious agent. In the present study. flow cytometry and several different monoclonal antibodies recognising T. B. and natural killer (NK) cell populations as well as activation and cell adhesion antigens were used to study 147 individuals with CFS. Compared with healthy controls. a reduced CD8 suppressor cell population and increased activation markers (CD38. HLA-DR) on CD8 cells were found. The differences were significant (p = 0.01) in patient with major symptoms of the disease. These immunological indices were not observed in 80 healthy individuals. in 22 contacts of CFS patients. or in 43 patients with other diseases. No correlation of these findings in CFS patients with any known human viruses could be detected by serology. The findings suggest that immune activation is associated with many cases of CFS.
Role of psychosocial stress in recovery from common whiplash [see comment, It is widely accepted that psychosocial factors are related to illness behaviour and there is some evidence that they may influence the rate of recovery from post-traumatic disorders. The abilities of psychosocial stress. somatic symptoms. and subjectively assessed cognitive impairment to predict delayed recovery from common whiplash were investigated in a follow-up study. 78 consecutive patients referred 7.2 (SD 4.5) days after they had sustained common whiplash in car accidents were assessed for psychosocial stress. negative affectivity. personality traits. somatic complaints. and cognitive impairment by semistructured interview and by several standardised tests. On examination 6 months later 57 patients were fully recovered and 21 had persisting symptoms. The groups' scores for the independent variables assessed at the baseline examination were compared. Stepwise regression analysis showed that psychosocial factors. negative affectivity. and personality traits were not significant in predicting the outcome. However. initial neck pain intensity. injury-related cognitive impairment. and age were significant factors predicting illness behaviour. This study. which was based on a random sample and which considered many other possible predictive factors as well as psychosocial status. does not support previous findings that psychosocial factors predict illness behaviour in post-trauma patients.
Outbreak of paralytic poliomyelitis in Oman: evidence for widespread transmission among fully vaccinated children, From January. 1988. to March. 1989. a widespread outbreak (118 cases) of poliomyelitis type 1 occurred in Oman. Incidence of paralytic disease was highest in children younger than 2 years (87/100.000) despite an immunisation programme that recently had raised coverage with 3 doses of oral poliovirus vaccine (OPV) among 12-month-old children from 67% to 87%. We did a case-control study (70 case-patients. 692 age-matched controls) to estimate the clinical efficacy of OPV. assessed the immunogenicity of OPV and extent of poliovirus spread by serology. retrospectively evaluated the cold chain and vaccine potency. and sought the origin of the outbreak strain by genomic sequencing. 3 doses of OPV reduced the risk of paralysis by 91%; vaccine failures could not be explained by failures in the cold chain nor on suboptimum vaccine potency. Cases and controls had virtually identical type 1 neutralising antibody profiles. suggesting that poliovirus type 1 circulation was widespread. Genomic sequencing indicated that the outbreak strain had been recently imported from South Asia and was distinguishable from isolates indigenous to the Middle East. Accumulation of enough children to sustain the outbreak seems to have been due to previous success of the immunisation programme in reducing spread of endemic strains. suboptimum efficacy of OPV. and delay in completing the primary immunisation series until 7 months of age. Additionally. the estimated attack rate of infection among children aged 9-23 months exceeded 25% in some regions. suggesting that a substantial proportion of fully vaccinated children had been involved in the chain of transmission.
Reaction of human non-collagenous polypeptides with coeliac disease autoantibodies, We identified and purified six human noncollagenous protein molecules that specifically bind to serum IgA from patients with coeliac disease. and which as a combination can act as true antigen to reticulin antibodies. In affinity chromatography. the purified human protein molecules removed antibodies against reticulin and endomysium from serum samples of coeliac disease patients. We postulate that an autoimmune mechanism operates in generating the jejunal damage in gluten-sensitive enteropathy and that the human protein molecules described here act as self-antigens in the disease.
Possible transmission of Mycobacterium leprae in a group of UK leprosy contacts, A case of infectious leprosy in residential accommodation in the UK prompted a study of the cellular and humoral response to Mycobacterium leprae in two groups of individuals who were in contact with the index case for almost a year. In the younger staff group (mean age 44 years) 23 of 30 individuals had positive Mitsuda skin tests. 25 showed lymphocyte transformation to a soluble sonciate of M leprae and 2 had slightly raised IgM antibody concentrations to the terminal disaccharide of M leprae phenolic glycolipid-1. In the older group of residents (mean age 83 years) 7 of 36 individuals were skin-test positive. 25 of 33 were positive by lymphocyte transformation. but none had raised antibody levels. When retested on two further occasions. the same 2 individuals in the younger group still had raised antibody concentrations. 1 of whom had a persistent lepromin skin-test response for over 8 months and showed a pronounced increase in lymphocyte transformation to mycobacterial antigens. The findings suggest that transmission of M leprae may have occurred in these 2 contacts. who were therefore given 6 months' chemoprophylaxis with rifampicin.
AAEM minimonograph #11: Needle examination in clinical electromyography, The physiologic and histologic principles underlying clinical electromyographic studies are briefly reviewed as an introduction to the normal and abnormal findings in human subjects. Technical aspects of recordings as well as the specific types of discharges and their significance are discussed.
An endogenous inhibitor of calcium-activated neutral protease in UMX 7.1 hamster dystrophy, An endogenous inhibitor for calcium-activated neutral protease (CANP) from skeletal and cardiac muscles of muscular dystrophic hamsters (UMX 7.1) was compared with that from normal control animals at 4 and 10 weeks of age by Western blotting using antibody raised against CANP inhibitor. Fragmented CANP inhibitor was found in dystrophic skeletal muscles in all cases at both ages. while only intact inhibitor was detected in the skeletal muscle of the normal hamsters. A total absence of intact inhibitor was shown in one 10-week-old dystrophic hamster. In contrast. there was little difference in CANP inhibitor from heart between dystrophic and control hamsters at 4 weeks. However. fragmentation similar to that in skeletal muscle was seen in the heart inhibitor in a few of the 10-week-old dystrophic hamsters.
Large amplitude sensory action potentials in myelopathy: an observation, Subjects with at least one sensory action potential (SAP) amplitude greater than 2 SD above the age-matched mean during standard nerve conduction tests were evaluated for evidence of spinal cord disease. From a total of 153 subjects. 16 had at least one large amplitude SAP and 12 of 16 (75%) had a documented myelopathy. While a mechanism has yet to be determined. this observation suggests that SAP amplitudes greater than 2 SD above normal may be correlated with clinical evidence of injury to the central nervous system.
Magnetic resonance imaging of the muscles in patients with polymyositis and dermatomyositis, Magnetic resonance imaging (MRI) of the muscles was performed in patients with polymyositis and dermatomyositis. Lesions with high intensity on T2-weighted image. but normal intensity on T1-weighted image. were observed in 7 of 8 patients in the active stage of the disease. Following clinical improvement with corticosteroid therapy in 4 patients. the high intensity lesions reverted to normal. The high intensity lesions seen on T2-weighted image in the active stage may represent edema and inflammation of the muscle. MRI of the muscle may serve as a diagnostic tool and be useful for follow-up of the patients with polymyositis or dermatomyositis.
Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children, BACKGROUND. Although asthma diagnosed by a physician is known to be related to serum IgE levels. it is not known whether there is a relation between the level of IgE and airway hyperresponsiveness to a methacholine challenge. The characteristics of asymptomatic persons that predispose them to airway hyperresponsiveness are also unknown. METHODS. We studied the relation between the serum total IgE level and airway hyperresponsiveness in the presence or absence of asthma and other atopic diseases in a birth cohort of children. Data from a questionnaire regarding respiratory symptoms. plus measurements of the serum total IgE level and airway responsiveness to inhaled methacholine. were obtained for 562 11-year-olds in New Zealand. RESULTS. The boys had a higher prevalence than the girls of current diagnosed asthma (13 percent vs. 6 percent). current symptoms of wheezing (22 percent vs. 15 percent). and airflow obstruction at base line (6 percent vs. 1 percent) and had a wider distribution of IgE levels. although mean IgE levels (120.8 IU per milliliter in the boys and 98.1 IU per milliliter in the girls) did not differ significantly between the sexes. The prevalence of diagnosed asthma was strongly related to the serum IgE level (P for trend less than 0.0001). No asthma was reported in children with IgE levels less than 32 IU per milliliter. whereas 36 percent of those with IgE levels greater than or equal to 1000 IU per milliliter were reported to have asthma. This relation with the serum IgE level was not explained by a concomitant diagnosis of allergic rhinitis or eczema. Airway hyperresponsiveness to a methacholine challenge also correlated very highly (P less than 0.0001) with the serum IgE level. This relation remained significant even after the exclusion of children with diagnosed asthma (P less than 0.0001) and of all children with a history of wheezing. allergic rhinitis. or eczema (P less than 0.0001). CONCLUSIONS. Even in children who have been asymptomatic throughout their lives and have no history of atopic disease. airway hyperresponsiveness appears to be closely linked to an allergic diathesis. as reflected by the serum total IgE level.
Cardiogenic shock after acute myocardial infarction. Incidence and mortality from a community-wide perspective, 1975 to 1988, BACKGROUND. Cardiogenic shock resulting from acute myocardial infarction is a serious complication with a high mortality rate. but little is known about whether its incidence or outcome has changed over time. As part of an ongoing population-based study of acute myocardial infarction. we examined trends over time in the incidence and mortality rate of cardiogenic shock after acute myocardial infarction. METHODS. We studied 4762 patients with acute myocardial infarction who were admitted to 16 hospitals in the Worcester. Massachusetts. metropolitan area between 1975 and 1988. We determined the incidence of and short-term and long-term mortality due to cardiogenic shock in each of six years during this study period. RESULTS. The incidence of cardiogenic shock complicating acute myocardial infarction remained relatively constant. averaging 7.5 percent. Multivariate regression analysis that controlled for variables affecting incidence revealed significant though inconsistent temporal trends in the incidence of cardiogenic shock. As compared with the risk in 1975. the adjusted relative risk (with 95 percent confidence interval) was 0.83 (0.54 to 1.28) in 1978. 0.96 (0.63 to 1.48) in 1981. 0.68 (0.42 to 1.12) in 1984. 1.16 (0.70 to 1.92) in 1986. and 1.65 (0.99 to 2.77) in 1988. The overall in-hospital mortality rate among patients with cardiogenic shock was significantly higher than that among patients without this complication (77.7 percent vs. 13.5 percent. P less than 0.001). The in-hospital mortality among the patients with shock did not improve between 1975 (73.7 percent) and 1988 (81.7 percent). Long-term survival during the 14-year follow-up period was significantly worse among patients who survived cardiogenic shock during hospitalization than among patients who did not have shock (P less than 0.001). CONCLUSIONS. The results of this observational. community-wide study suggest that neither the incidence nor the prognosis of cardiogenic shock resulting from acute myocardial infarction has improved over time. Both in-hospital and long-term survival remain poor for patients with this complication.
Analgesic effect of intraarticular morphine after arthroscopic knee surgery, BACKGROUND. Opioids can produce potent antinociceptive effects by interacting with local opioid receptors in inflamed peripheral tissue. In this study we examined the analgesic effects of the intraarticular. as compared with intravenous. administration of morphine after arthroscopic knee surgery. METHODS. In a double-blind. randomized trial. we studied 52 patients who had received one of four injections at the end of surgery. The patients in group 1 (n = 18) received 1 mg of morphine intraarticularly and saline intravenously; those in group 2 (n = 15). saline intraarticularly and 1 mg of morphine intravenously; those in group 3 (n = 10). 0.5 mg of morphine intraarticularly and saline intravenously; and those in group 4 (n = 9). 1 mg of morphine and 0.1 mg of naloxone intraarticularly and saline intravenously. The volume of the intraarticular injections was 40 ml. and that of the intravenous injections was 1 ml. After 1. 2. 3. 4. 6. and 24 hours. postoperative pain was assessed with a visual-analogue scale. a numerical-rating scale. and the McGill pain questionnaire. The need for supplemental analgesic agents. the patients' vital signs. and the occurrence of side effects were monitored. RESULTS. All pain scores were lower in group 1 than in group 2 at all times. The differences were significant (P less than 0.05) at three. four. and six hours (mean [+/- SD] visual-analogue score at six hours. 9 +/- 13 mm vs. 37 +/- 31 mm). The mean (+/- SD) consumption of supplemental analgesic medication per 24 hours was significantly lower in group 1 (36 +/- 51 mg of diclofenac and 1.2 +/- 3.4 mg of meperidine) than in group 2 (75 +/- 42 mg of diclofenac and 14 +/- 18 mg of meperidine. P less than 0.05). The visual-analogue scores in group 3 were slightly but not significantly higher than those in group 1 at all times except 6 and 24 hours after injection. The visual-analogue scores were significantly higher in group 4 than in group 1 one to four hours after injection (P less than 0.05). indicating that the analgesic effect of intraarticular morphine was reversible by naloxone. CONCLUSIONS. Low doses of intraarticular morphine can significantly reduce pain after knee surgery through an action specific to local opioid receptors that reaches its maximal effect three to six hours after injection.
4-Aminopyridine in multiple sclerosis: prolonged administration, In an earlier study. we demonstrated efficacy of single oral doses of 4-aminopyridine (4-AP) in improving motor and visual signs in multiple sclerosis (MS) patients for a mean of 4.97 hours. We attempted to determine whether efficacy could safely be prolonged using multiple daily doses over several days by administering 7.5 to 52.5 mg 4-AP to 17 temperature-sensitive MS patients in one to three daily doses at 3- to 4-hour intervals over 1 to 5 days in a double-blind study. Nine of these patients were also tested with identically appearing placebo. Thirteen of the 17 patients (76%) given 4-AP showed clinically important motor and visual improvements compared with three of nine in the placebo group. Average peak improvement scores were 0.40 for 4-AP and 0.12 for placebo. Seventy percent of the daily 4-AP improvements lasted 7 to 10 hours. The improvements for two consecutive doses of 4-AP lasted a mean of 7.07 hours (83% of the average 8.53-hour treatment-observation period) compared with 2.36 hours for placebo (26% of the average 9.06-hour treatment-observation period). No serious side effects occurred. 4-AP is a promising drug for the symptomatic treatment of MS.
HTLV-I-associated myelopathy/tropical spastic paraparesis in the United States, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is endemic in the Caribbean basin and Japan. Because of the close proximity of the United States to the Caribbean and the presence of HTLV-I-seropositive persons in the United States. we sought reports of patients who were HTLV-I seropositive and had a slowly progressive myelopathy. Over a 2-year period. there were 25 patients reported. 19 of whom were black and 12 of whom had been born in the United States. All patients except two had become symptomatic while living in the United States. Six patients had no apparent risk factor for acquiring HTLV-I. These data demonstrate that HAM/TSP is occurring in the United States and that the diagnosis of HAM/TSP should be considered in patients with a slowly progressive myelopathy regardless of risk factors for acquiring HTLV-I.
Autosomal recessive distal dystrophy, We describe five new cases of autosomal recessive distal dystrophy (Miyoshi myopathy) and emphasize the distinctive clinical and laboratory features of this unusual muscular dystrophy. Symptoms began at age 15 to 25. the gastrocnemius muscles were selectively involved. and creatine kinase was elevated more than 10 times normal. The EMG showed abundant brief motor units with numerous fibrillations. Dystrophic features without vacuoles were best seen in the biceps femoris muscle. Asymptomatic creatine kinase elevation was present years prior to the development of weakness. The disorder appears to be inherited in an autosomal recessive pattern. Miyoshi myopathy can be distinguished from other distal muscular dystrophies. We propose a new classification for the distal muscular dystrophies.
Frontal lobe degeneration: clinical, neuropsychological, and SPECT characteristics, The clinical. neuropsychological. and cerebral blood flow characteristics of eight patients with frontal lobe degeneration (FLD) were studied. Social withdrawal and behavioral disinhibition were the earliest and most common clinical presentations. and psychiatric symptoms typically preceded the onset of dementia by several years. Neuropsychological testing showed selective impairment of frontal and memory tasks with relative sparing of attention. language. and visuospatial skills. Single-photon emission computerized tomography demonstrated frontal and temporal hypoperfusion with relative sparing of parietal and occipital blood flow. Previous studies suggest that the neuropathologic findings in patients with FLD are varied; some demonstrate frontal gliosis. neuronal loss. and Pick bodies while others show only gliosis and neuronal loss.
Globoid cell leukodystrophy: a family with both late-infantile and adult type, We present a patient with adult-onset globoid cell leukodystrophy (GBL) who had almost complete deficiency of galactosylceramide beta-galactosidase. A brother of the index patient deteriorated neurologically and died at the age of 4. probably from the late-infantile form of the disease. In this family. two clinical types of GBL are probably different expressions of an identical genotype.
The Libyan Creutzfeldt-Jakob disease focus in Israel: an epidemiologic evaluation, In a country-wide study of Creutzfeldt-Jakob disease (CJD) in Israel. we diagnosed 114 cases. among them 49 Libyan-born. with onset of their disease during the years 1963-1987. After age adjustment. the mean annual incidence rate per million population was 43 among Libyan-born and 0.9 in the rest of the population. Among Jews born in Egypt and Tunisia. neighboring countries of Libya. the adjusted rates were higher than in the other Israelis (3.5 and 2.3 per million. respectively). Among Libyan Jews. there was no association between incidence rate of CJD and age at immigration. ie. duration of exposure to hypothetical infectious factor in Libya. The percent of familial cases among Libyan Jews (41 to 47%) is one of the highest ever published. Genetic factors seem to be important for the high incidence of CJD among Libyan Jews.
Do Creutzfeldt-Jakob disease patients of Jewish Libyan origin have unique clinical features, A focus of Creutzfeldt-Jakob disease is present in Israel among Jews born in Libya. The present study examines the clinical features in this particular group of patients. In a country-wide study of Creutzfeldt-Jakob disease. we identified 114 patients; 49 were Libyan immigrants. and 65 (three of whom had Libyan ancestors) were born in other countries. The clinical presentation and evolution of the disease is very similar in patients born in Libya and others without Libyan ancestors. but it tends to be more classical in the Libyan patients. with higher frequency of myoclonic jerks and periodic EEG and a progressive course of shorter duration. The Libyan patients tend to complain more often of headache. which is most probably an ethnic expression for depression and loss of concentration. There was no difference between the familial and nonfamilial cases.
Clinical risk factors for Alzheimer's disease: a population-based case-control study, Using information on clinical risk factors provided through the medical record linkage system of the Rochester Epidemiology Project. we conducted a population-based case-control study of Alzheimer's disease (AD). During the period 1960 to 1974. we identified 415 newly diagnosed cases of AD among residents of Rochester. Minnesota. and matched one community control to each case based on age. sex. and duration of community medical record. We estimated odds ratios using conditional logistic regression for several potential clinical risk factors of AD. Among more than 20 clinical risk factors that were evaluated. the only statistically significant findings were for episodic depression. personality disorder. and hypertension.
Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD, Immunocytochemistry with antibodies to ubiquitin is currently the most sensitive method for detecting cortical Lewy bodies. which are a sine qua non for the diagnosis of diffuse Lewy body disease (DLBD). an increasingly recognized form of primary degenerative dementia. In the systematic application of ubiquitin immunocytochemistry to sections of hippocampus from control subjects and patients with a wide spectrum of neurodegenerative diseases. we noted the frequent occurrence of ubiquitin-immunoreactive neurites in the CA2-3 region in DLBD. The nature of these neurites was investigated with immunocytochemistry in DLBD. Alzheimer's disease (AD). normal elderly subjects. and Parkinson's disease (PD). Although the number of neurites varied from case to case. they were virtually always detected in DLBD but not in normal. AD. or PD brains. Double immunolabeling studies with anti-ubiquitin demonstrated a small fraction of double-stained neurites with antibodies to neurofilament or Alz-50. but no double staining with an antibody to Alzheimer neurofibrillary tangles. These results are different from those for neurites in AD. which are rarely seen in CA2-3 and which are immunoreactive with all these antibodies. Neuritic degeneration in the CA2-3 region of the hippocampus appears to be a specific histopathologic feature of DLBD.
Clinical characteristics of transient ischemic attacks in black patients, We analyzed the clinical. CT. and angiographic findings in 50 black patients with carotid transient ischemic attacks (TIAs). Thirty-two percent had TIAs lasting less than 1 hour. 26% had TIAs lasting 1 to 6 hours. and 42% had TIAs lasting 6 to 24 hours. Fifty-two percent of TIA patients had CT evidence of cerebral infarction despite complete clinical recovery. CT was abnormal in two of 16 (13%) patients with TIAs lasting less than 1 hour; however. CT was abnormal in 24 of 34 (70%) patients with TIAs lasting longer than 1 hour. Angiographic findings of extracranial carotid disease appropriate to TIA symptoms were present in 12 (24%) patients. Two patients in whom the TIA episode lasted less than 1 hour later had clinical cerebral infarction. whereas 20 patients with longer-duration TIAs developed ischemic stroke within 4 months. Of these black TIA patients. 22 (44%) developed clinical cerebral infarction.
Spinal muscular atrophy is not the result of mutations at the beta-hexosaminidase or GM2-activator locus, The disease locus for the clinically heterogeneous childhood spinal muscular atrophies (SMA) maps to the chromosome 5 subregion. 5q11.2-13.3. The beta-subunit of beta-D-N-acetylhexosaminidase (hexosaminidase) (EC 3.2.1.52) (Hex B) maps to the same region. and the protein required for substrate recognition by this enzyme. GM2-activator protein. likewise maps to chromosome 5. We have investigated the possibility of allelic variation among some forms of SMA and hexosaminidase deficiency. Recombination between the Hex B and SMA loci eliminates this enzyme as a candidate site for defects causing the illness. Furthermore. we show that. despite previous evidence to the contrary. the GM2-activator locus does not map to chromosome 5. thereby eliminating it as a candidate gene for SMA.
Clinicopathologic observations in essential tremor: report of six cases, Essential tremor (ET) is the most common pathologic tremor. but only eight cases have been studied pathologically. We report detailed clinical and neuropathologic studies of six additional patients. We did not find any neuropathologic lesions that might be specific for ET. Moreover. there were no abnormalities of the substantia nigra consistent with Parkinson's disease. The neuropathologic substrate of ET remains unknown.
Spike voltage topography identifies two types of frontotemporal epileptic foci, We characterized voltage topography of frontotemporal EEG spikes in 24 patients with complex partial seizures and identified two distinct patterns. "Type 1" spikes possessed a "dipolar" field with a negative region over the inferolateral temporal scalp and a positive region over the contralateral. centroparietal scalp. "Type 2" spikes showed only a broad. frontotemporal negative field. One or the other spike type predominated in all but two patients. Correlations with clinical data and intracranial EEG suggest that type 2 spikes arise from temporal or frontal neocortex. while type 1 spikes involve mesial temporal structures as well as lateral cortex.
Parkinson's disease rigidity: magnetic motor evoked potentials in a small hand muscle, We studied the EMG potentials evoked in the bilateral first dorsal interosseus muscle by electromagnetic stimulation of the corticomotoneuronal descending system in 10 Parkinson's disease patients and in 10 age- and sex-matched normal controls. We selected patients who did not have tremor but had predominant rigidity with asymmetric body involvement. On the rigid side of the PD patients. the threshold to cortical stimulation was lower than on the contralateral side or than normal values. On average. patients had normal central conduction times. but their motor evoked potentials (MEPs) on the rigid side were larger than those of controls when the cortical stimulus was at rest or during slight tonic contraction of the target muscle. In the latter condition. a silent period shorter than that of controls followed MEPs. whereas the peripheral silent period following ulnar nerve stimulation at the wrist was prolonged. Alpha motor neuron excitability. tested by the F-wave method. was enhanced on the rigid side at rest. In rigidity. spinal motor nuclei may be more responsive than normal to descending inputs from motor cortex. or the entire corticomotoneuron system may prove hyperexcitable under given conditions.
Baroreflexes in patients with diabetes mellitus, We evaluated baroreflexes in 58 diabetic and 15 control subjects by determining the latency of response between the end of a Valsalva maneuver (VM) and points on the resultant blood pressure and heart rate (HR) response curves. Prolonged latencies indicative of sympathetic dysfunction were demonstrated in 44% to 88% of diabetic subjects. The results challenge the view that sympathetic dysfunction cannot be detected before parasympathetic abnormalities are manifest. Baroreflex latencies reflected sympathetic dysfunction early in the course of diabetes. sometimes in patients with normal HR responses to deep breathing and to a VM.
Motor initiation versus execution in normal and Parkinson's disease subjects, We studied motor initiation and execution using wrist extension movements to changing target locations in eight normal subjects and nine Parkinson's disease (PD) patients before and after medications. Late changes resulted in double trajectories. indicating commitment to the initial target acquisition program followed by a correcting movement. There was compensation for earlier changes. even after onset of agonist muscle activity. resulting in a single trajectory. implying that the original trajectory had not yet been specified. However. movements were slowed in PD patients implying an abnormality in the content of the target acquisition program but not in the timing of its specification. In PD patients. the timing of the second movement onset correlated best with the timing of target location change and did not depend on initial movement completion. Thus. PD patients were able to program the second movement while the first movement was under way.
Reaction time and movement velocity abnormalities in Parkinson's disease under different task conditions, We examined reaction times. movement velocities. and the associated agonist and antagonist muscle behaviors in nine Parkinson's disease (PD) patients and eight normal subjects before and after medications. using a wrist extension task to changing locations of a visual target. Targets changing 500 msec before an auditory "go" signal act as a preparatory cue. while targets changing at the time of the go signal provide a combined auditory and visual stimulus. Late target changes allowed examination of (1) reaction times during an ongoing movement. and (2) movement in the presence and absence of visual targets. PD prolonged the time from the onset agonist electromyographic activity and reduction of antagonist activity to movement onset. Both were shortened by preparatory cues and combined visual and auditory go signals. PD slowed movement only in a subset of trials in which there was movement to a displayed target.
Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity, Multiple lines of evidence indicate that PrPSc. found only in scrapie. is a necessary component of the infectious scrapie agent. Equally compelling is the evidence that its accumulation in the brain causes the neuropathology characteristic of scrapie. We measured the regional concentration of PrPSc in nine brain regions throughout the course of scrapie in the Syrian hamster following intrathalamic inoculation of prions. PrPSc was compared to the regional concentration of glial fibrillary acidic protein. a measure of reactive astrocytic gliosis. PrPSc was detected first in the thalamus 14 to 21 days postinoculation and next in the septum at 28 days. Initiation of PrPSc synthesis and accumulation in the thalamus was attributable to the inoculum and in the septum to ventricular spread of de novo synthesized PrPSc. The timing and pattern of PrPSc accumulation in all other brain regions suggested transmission along neuroanatomic pathways. Reactive astrocytic gliosis followed PrPSc accumulation in each region by 1 to 2 weeks. Brain PrPSc. determined by summing the concentrations in each brain region. correlated well with scrapie infectivity titers throughout the course of infection (correlation coefficient = 0.975; slope of linear regression line = 1.136). Our results support the hypothesis that PrPSc participates in both the etiology and pathogenesis of prion diseases.
The prognostic value of postoperative seizures following epilepsy surgery, Among 55 patients undergoing temporal lobectomy for refractory epilepsy. patients with seizures in the week following surgery had a poor long-term. seizure-free outcome compared with patients without seizures. Outcome for patients with single seizures or seizures restricted to the first postoperative day seemed favorable compared with patients with multiple or later seizures. Seizure type and similarity to preoperative events did not predict outcome.
Presence of human T lymphotropic virus type I in two patients with progressive myelopathy in Puerto Rico, Two patients from Puerto Rico with progressive paraparesis had serum positive for human T lymphotropic virus type I (HTLV-I) antibodies by ELISA and Western blot. and one patient had HTLV-I antibodies in CSF by the ELISA method. Although the Caribbean basin is considered to be an endemic area for tropical spastic paraparesis. this is the first report of the isolation of HTLV-I antibodies in the serum and CSF of patients with chronic myelopathies in Puerto Rico.
Mononeuropathy multiplex complicating idiopathic thrombocytopenic purpura, Peripheral nerve hemorrhage has rarely been reported with idiopathic thrombocytopenic purpura (ITP). We describe a patient with severe ITP who developed mononeuropathy multiplex. At autopsy. multisystem hemorrhages were found. including intraneural hemorrhage. without evidence of extraneural hematoma. ITP represents an unusual cause for clinical mononeuropathy multiplex.
Corneal topography as a predictor of refractive change in the prospective evaluation of radial keratotomy (PERK) study, The first operated eyes of 435 patients undergoing radial keratotomy in the Prospective Evaluation of Radial Keratotomy (PERK) study were evaluated by photokeratography to document the preoperative and postoperative corneal shape. We determined by regression analysis and analysis of variance that the corneal shape preoperatively improved the prediction of the corneal shape 6 months postoperatively in the 3-mm-clear-zone population. The reduction of myopia in all 435 eyes ranged from 1.25 to 9.75 diopters. We studied the effect of the preoperative corneal shape on this variability in the outcome of the surgery using rings 2 and 7 on photokeratography and corneal diameter. In the 3-mm-clear-zone group. eyes with flat prolate corneas had a greater reduction in myopia (4.65 D); those with steeper. more spherical corneas had less reduction in myopia (3.48 D). In addition. eyes with a 3-mm clear zone and flat central corneas alone (8.0 mm = 42.19 D) flattened approximately 0.75 D more than those with steep central corneas (7.0 mm = 48.21 D). In the 3.5-mm and 4.0-mm clear zone groups. the change in corneal curvature was not related to the preoperative curvature. A stepwise regression analysis of the 151 eyes in the 3.0-mm-clear-zone population demonstrated the following predictive equation for radial keratotomy; change in cycloplegic refraction = -14.55 + [-2.097 x average ring-2 radius] + [3.605 x average ring-7 radius] + [0.69 x horizontal corneal diameter] + [0.079 x age] + [-0.379 x spherical equivalent cycloplegic refraction]. There was a 1.17-D observed difference in the effect of radial keratotomy between those eyes with a steep/steep corneal topography (7.2% of the 3.0-mm-clear-zone population) and the flat/flat topography (29% of the 3.0-mm-clear-zone PERK population). A knowledge of corneal topography provides an additional tool for understanding the operative variability of radial keratotomy.
Extracapsular cataract extraction and posterior chamber lens implantation in controlled open-angle glaucoma, A consecutive series of 103 eyes. 37 with controlled simple glaucoma (SG) and 66 with capsular glaucoma (CG). underwent extracapsular cataract extraction (ECCE) and posterior chamber lens (PC-IOL) implantation. Two to 6 weeks after surgery. 48% of the SG eyes and 62% of the CG eyes had visual acuities better than 0.4. as compared with 8% and 3%. respectively. preoperatively. The corresponding figures after 12 to 43 months in the SG eyes were 62%. and after 14 to 38 months in the CG eyes. 55%. A slight increase of mean intraocular pressure (IOP). from 19.0 +/- 4.8 mm Hg to 25.3 +/- 13.3 mm Hg in the SG eyes. and from 19.0 +/- 3.9 mm Hg to 24.5 +/- 9.6 mm Hg in the CG eyes occurred 1 to 2 weeks after surgery; at 2 to 6 weeks the mean IOPs had returned to preoperative levels: 18.1 +/- 6.4 mm Hg in the SG eyes and 18.4 +/- 5.9 mm Hg in the CG eyes. After a mean of 26.5 months (range. 12 to 43 months). IOP had decreased to 17.3 +/- 2.9 mm Hg in the SG eyes; and after 24.2 months (range. 14 to 38 months) to 17.6 +/- 5.7 mm Hg in the CG eyes. The need for glaucoma medication was diminished at 2 to 6 weeks after surgery: IOP was controlled (less than 21 mm Hg) without glaucoma medication in 43% of the SG. and in 50% of the CG eyes (preoperatively. all of the SG and 89% of the CG eyes required medication).
Multilevel full-thickness eyelid resection for the correction of severe acquired ptosis in the poorly functioning eyelid, Six eyelids (4 patients) with severe myogenic (4 eyelids). neurogenic (1 eyelid). or mechanical (1 eyelid) ptosis underwent surgical correction with a multilevel full-thickness resection of eyelid tissue combined with a plication of the levator aponeurosis-Muller's muscle complex. All eyelids had poor levator function. fair to poor orbicularis function. and a poor Bell's phenomenon. In all cases. the upper eyelids were elevated to an acceptable functional level without exposure keratopathy. This resection procedure preserves orbicularis function while allowing correction of severely ptotic eyelids with poor levator function. providing an acceptable alternative to other techniques for correcting this problem.
Total pupillary capture with a foldable silicone intraocular lens, We report a case of total pupillary capture on the 1st postoperative day in a patient who had undergone phacoemulsification and placement of a silicone foldable posterior chamber intraocular lens. Anterior displacement of the lens optic resulted in 2.25 diopters of induced myopia. Dilation of the pupil corrected the lens capture and reversed the induced myopia. yielding a refraction of plano. Higher rates of pupillary capture have been associated with sulcus fixation and nonangulated flexible (polypropylene) haptics. Contraction of the capsular bag on the flexible polypropylene haptics of this silicone lens is thought to force the optic anteriorly. increasing the probability of lens capture by the iris.
Optimal astigmatism to enhance depth of focus after cataract surgery, A small amount of myopic astigmatism can enhance the depth of focus of the pseudophakic eye. optimally providing at least 20/30 visual acuity for both near and distance fixation. For given spherocylindrical refractive errors and fixation distances. the cross-sectional area of Sturm's conoid at the retina was calculated for a schematic eye. These data were used to determine the optimal astigmatic error needed to obtain maximum depth of focus and least theoretical blur for any given spherical equivalent refractive error. Optimal depth of focus was obtained when the plus cylindrical component equaled negative sphere - 0.25 diopters. The near and distance visual acuities of ten pseudophakic patients with induced refractive errors were highly correlated with this model. Low myopic astigmatism after cataract surgery may represent an alternative to multifocal intraocular lenses by providing spectacle independence.
Effect of cataract on automated perimetry, Humphrey visual fields (30-2 program) were performed on 24 otherwise healthy patients before and after cataract extraction to examine the effect of cataract on automated visual fields. All patients met reliability index criteria and recovered visual acuity of 20/25 or better. The effect of learning associated with repeated testing was controlled with visual fields of the fellow eye. Although a greater absolute threshold recovery occurred in the central region of the visual field after cataract extraction. the percent of threshold recovery did not vary across the visual field except for the most peripheral testing points. which demonstrated less recovery. Thus. cataracts depress an automated visual field fairly uniformly. Clinical grading of cataracts by a single experienced clinician was generally a poor predictor of visual field loss. Only the presence of posterior subcapsular plaque in the visual axis and the preoperative visual acuity correlated significantly with postoperative central threshold recovery. Pattern standard deviation remained unchanged after cataract removal. confirming it as a useful way of estimating visual loss from cataracts.
The nonapproved use of medications, The need for new treatments for both established and recently described disorders has heightened awareness of the drug approval process. In particular. many ophthalmologists have questioned the ramifications of using approved drugs in nonapproved settings (such as apraclonidine) and the means of obtaining investigational drugs for patient use. The authors review the legal structures established to address these concerns and recommended approaches ophthalmologists can take to minimize their exposure to legal complications.
Additive effect of 1% apraclonidine hydrochloride to nonselective beta-blockers, The short-term additive effect and side effects of adding 1% apraclonidine hydrochloride to nonselective beta-blockers were investigated in 21 patients with ocular hypertension or early primary open-angle glaucoma. After a unilateral single dose application of topical 1% apraclonidine hydrochloride. intraocular pressure (IOP). heart rate. and interpalpebral distance were measured. The mean IOP of treated eyes showed a decline from a baseline of 20.0 +/- 3.0 mmHg to 18.1 +/- 3.2 mmHg at 1 hour (P less than 0.005). 16.5 +/- 2.6 mmHg at 2 hours (P less than 0.001). 15.2 +/- 2.5 mmHg at 3 hours (P less than 0.001). 18.5 +/- 3.0 mmHg at 12 hours (P = 0.02). and 19.2 +/- 2.9 mmHg at 24 hours (P = 0.2). No statistically significant change in the heart rate was seen. The interpalpebral distance of the treated eyes showed a significant increase (P less than 0.05) at all time intervals except 24 hours (P = 0.17). The authors conclude that 1% apraclonidine hydrochloride provides an additive pressure-lowering effect to nonselective beta-blockers for at least 12 hours after a single application. and shows promise as a useful adjunctive agent for short-term use in glaucoma therapy.
Additivity of prostaglandin F2 alpha-1-isopropyl ester to timolol in glaucoma patients, The effect on intraocular pressure (IOP) of adding prostaglandin F2 alpha-1-isopropyl ester (PGF2 alpha-IE) to timolol was studied in 21 eyes of 13 patients with newly diagnosed primary open-angle glaucoma that was inadequately controlled with timolol alone. After at least 2 weeks of twice daily timolol 0.5% therapy. PGF2 alpha-IE. 0.5 microgram in 30 microliters. was topically applied twice daily at 8 AM and 8 PM. 5 minutes before each timolol dose. for 7 days. Intraocular pressures were measured before timolol treatment. and at 8 AM. 8:30 AM. 12 PM. 2 PM. and 4 PM on the day before the addition of PGF2 alpha-IE. and on day 1 and on day 7 of combined therapy. Mean IOP was 39 +/- 2 mmHg (+/- standard error) before timolol therapy and 31 +/- 2 mmHg after at least 2 weeks of treatment with timolol alone. A significant (P = 0.004) further reduction of IOP was first observed 4 hours after the first dose of PGF2 alpha-IE. which was maintained throughout the duration of combined therapy. During the last day of combined treatment and at 12 hours after the final dose. IOP was reduced a mean of 6 to 9 mmHg (mean. 9.0 +/- 1.5 mmHg at 12 hours) below baseline values obtained with timolol alone. These results indicate that adding PGF2 alpha-IE in patients treated with timolol causes a further reduction of IOP that may prove to be clinically useful in glaucoma therapy.
Apraclonidine prophylaxis for postcycloplegic intraocular pressure spikes, A randomized. prospective. double-masked study was undertaken to determine the risk of postcycloplegic intraocular pressure spikes in patients with open-angle glaucoma and to evaluate apraclonidine prophylaxis in minimizing these spikes. Patients were stratified as miotic treated or untreated and each group was randomized to receive either placebo (artificial tears) or apraclonidine in both eyes before instillation of tropicamide. In both the miotic treated and untreated groups that received placebo. there was a high incidence. (37% and 38%. respectively) of clinically significant (greater than or equal to 6 mmHg) intraocular pressure spikes after instillation of tropicamide. In both the miotic treated and untreated groups. there was a statistically significant difference in postcycloplegic intraocular pressure between the subgroup that received placebo and the group that received apraclonidine prophylaxis (P = 0.003 and P = 0.006. respectively). Additionally. four eyes that received placebo had a spike of over 10 mmHg (range. 12 to 27 mmHg). while only one eye had an increase of greater than 10 mmHg (12 mmHg) in the apraclonidine group. Thus. apraclonidine appears to be a useful agent for minimizing precipitous increases in intraocular pressure after cycloplegia in eyes of open-angle glaucoma patients prone to this complication of cycloplegia.
Management of late-onset angle-closure glaucoma associated with retinopathy of prematurity, Late-onset angle-closure glaucoma secondary to retinopathy of prematurity (ROP) occurred in ten eyes of ten patients. The age at presentation ranged from 12 to 45 years (mean. 32 years). Eight eyes had nonneovascular mechanisms for the angle closure while two had neovascular angle closure. Treatment of eyes with this form of secondary angle closure included medical management alone. peripheral iridectomy. trabeculectomy. lensectomy. alloplastic tube shunt implantation. and cilioablative procedures. Three eyes required more than one of these treatments. The choice of therapy was based on the initial intraocular pressure and vision. degree of lens opacity and intumescence. presence of anterior segment neovascularization. and the gonioscopic appearance of the anterior chamber angle. The clinical features of this condition are described and a proposed mechanism and therapeutic approach are presented.
Evaluation of eyes with advanced stages of retinopathy of prematurity using standardized echography, The authors evaluated 36 patients (72 eyes) who had either Stage 4 or Stage 5 retinopathy of prematurity (ROP) with standardized A-scan and B-scan echography. The eyes were evaluated for vitreous opacities. retrolental membranes. and retinal detachments. Stage 5 retinal detachments were present in 94% (68 of 72) of the eyes with 65% (47 of 72) having a wide anterior and narrow posterior configuration. Anterior retinal loops were noted in 36% of the eyes. Subretinal opacities were present in 47% of the eyes. Choroidal thickening and intraocular calcium were noted in 22% and 14% of eyes. respectively. The axial eye length was measured and adjusted for the differences in chronological and gestational age and compared with data from normal eyes. This showed that eyes with ROP were much smaller. The standardized A-scan was helpful in confirming the diagnosis of retinal detachment. evaluating the peripheral retina. and examining the subretinal space. The combination of A-scan and B-scan echography is helpful in predicting anatomic findings in patients with ROP undergoing surgery.
Vitreoretinal traction and perimacular retinal folds in the eyes of deliberately traumatized children, The pathophysiology of perimacular folds in eyes of deliberately traumatized children is disputed. The authors reviewed the clinical and forensic records and systemic and ocular findings at autopsy of three children with perimacular retinal folds who died after being violently shaken. Two of the children suffered direct head trauma in addition to being shaken; one patient was violently shaken without any physical or forensic evidence of direct head trauma. No direct ocular trauma was detected. In each case. the vitreous had partially separated from the retina but remained attached to the internal limiting membrane at the apices of the folds and the vitreous base. implicating traction in the pathogenesis of these folds. Although some intraocular findings in deliberately traumatized children may be explained by direct head injury. the possibility of both direct head trauma and shaking must be considered. Perimacular folds may develop without direct ocular or head trauma and may constitute evidence supporting violent shaking.
The Wisconsin age-related maculopathy grading system, A new system for grading age-related maculopathy is described and measures of reliability are reported. A number of characteristics of age-related maculopathy are graded in a semiquantitative fashion from stereoscopic 30 degrees color fundus photographs. using a grid to define subfields. standard circles printed on plastic to assess size and area. and a specially designed lightbox to allow better discrimination of subtle drusen. The degree of exact agreement achieved between two trained graders across a variety of lesions ranged from 67.1% for drusen size to 99.6% for geographic atrophy. Kappa scores ranged from 0.55 (for drusen confluence) to 0.95 for geographic atrophy. This system will be useful in epidemiologic studies and clinical trials.
Kinetic ultrasound evaluation of the posterior vitreoretinal interface, The evaluation of the posterior vitreoretinal interface is important in the study of the natural course and preoperative evaluation of numerous disorders of the retina. The exact status of the posterior vitreous cannot always be reliably determined by ophthalmoscopic examination. The diagnostic value of kinetic contact ultrasonography was investigated to evaluate the status of the posterior vitreous in 70 eyes with clear ocular media. Contact B-scan ultrasound provided an extremely accurate method for evaluating the posterior vitreoretinal interface in 69 of the 70 eyes in this study. when compared with all conventional clinical means of examination including slit-lamp biomicroscopy with the Goldmann contact lens and fundus photography with the El Bayadi-Kajiura lens. Contact B-scan ultrasonography is an important diagnostic adjunct in determining the status of the vitreoretinal interface.
Histologic evaluation of the pulpal response to temperature probe placement in the Macaca fascicularis monkey, A method to measure intrapulpal temperatures during cavity preparation and restorative procedures has been developed. It involves placement of temperature probes to the dentinoenamel and dentinopulpal junctions. After placement of the probes. the pulps of the test teeth were examined histologically to determine whether their placement caused a pulpal response. The test teeth displayed no adverse response in the areas of the pulp opposite or adjacent to the position of the probes. Therefore the developed method of temperature probe placement to measure intrapulpal temperatures does not interfere with those measurements by adversely affecting the pulp tissues.
Dentin dysplasia: review of the literature and a proposed subclassification based on radiographic findings, The literature is reviewed to determine the radiographic appearance of the reported cases of dentin dysplasia. The sometimes confusing nomenclature is rationalized. Four distinct forms of dentin dysplasia type I and one form of dentin dysplasia type II are identified. There seems to be no need to identify more than two distinct types of this relatively rare inherited defect of human dentin. but a proposed subclassification of type I dentin dysplasia could make identification of the two types easier.
Desmoplastic fibroma of the maxillary sinus. Report of a case and review of the literature, A desmoplastic fibroma of the maxillary sinus is reported in a 15-year-old boy. Desmoplastic fibroma is a rare benign tumor in the maxillofacial region. The features of this case and of 49 previously described lesions are analyzed and discussed.
Differences in salivary flow rates in elderly subjects using xerostomatic medications, Stimulated whole salivary flow rate (SWSFR) was measured in a group of elderly subjects who were examined for the use of xerostomia-inducing medications. SWSFR was significantly reduced in elderly subjects using one of these medications when compared with control subjects (0.94 vs 1.52 ml/min). Increasing use of up to four different xerostomia-inducing medications did not result in additional significant reduction of stimulated salivary flow rate. Psychotropic and diuretic agents were the most commonly used xerostomatic medications. and these were almost equally potent in reducing mean flow rate (0.79 vs 0.84 ml/min). The use of potentially xerostomatic medications did not affect decayed. missing. or filled surface scores or unstimulated whole saliva pH values. A weak. statistically significant. positive correlation (r = 0.39. p less than 0.01) was found between subject age and salivary flow rate in this population of elderly subjects. and this suggests that SWSRF is influenced more by factors such as medication than by aging.
Central granular cell tumor of the jaw. An electron microscopic and immunohistochemical study, Central granular cell tumor of the jaw was formerly known as granular cell ameloblastic fibroma; recently. the term central granular cell odontogenic fibroma has been proposed. This study attempts to determine the ultrastructural features and selected immunohistochemical properties of the tumor cells. Four formalin-fixed specimens were processed for electron microscopy. and for immunohistochemical staining with antiactin. anti-glial fibrillary acidic protein. and OKT6 (CD1) with the avidin-biotin-peroxidase complex method. Tumor cells contained many primary lysosomes. autophagic vacuoles. and phagocytic vacuoles. The phagocytic vacuoles appeared to contain collagen fibrils. Tumor cells stained positive with antiactin and OKT6 (CD1). and negative with anti-glial fibrillary acidic protein. The results indicate that tumor cells are actively phagocytic and suggest that tumor cells might arise from Langerhans' cells.
The influence of preschool pertussis immunization on an epidemic of pertussis, Between 1988 and 1989 there were 896 reported cases of pertussis in Arizona. Of the 781 investigated cases 55 were identified in children younger than 5 years of age. Thirty-five percent of children between 6 months and 5 years of age were not fully immunized; 3 infants died. Approximately 50% of infected children between 5 and 14 years of age had not received 5 doses of pertussis vaccine. Of the 413 physician respondents to a questionnaire. fully 10% do not administer pertussis vaccine to preschool children because of parental. personal or other reasons. We hypothesize that the reservoir of pertussis-susceptible older children and young adults is augmented by this omission of the fifth diphtheria-tetanus toxoids-pertussis vaccine. Newer educational and vaccine strategies are necessary to prevent epidemics of pertussis.
Practical psychopharmacologic considerations in depression, Of the antidepressants on the US market. only alprazolam and trazodone have questionable antidepressant efficacy. Because all other antidepressants are equally effective in major depressive illness. drugs are used based on particular patient characteristics matched with individual antidepressant drug profiles. In general. antidepressant plasma concentration monitoring is only clinically useful with some of the TCAs. Nortriptyline. imipramine. and desipramine have demonstrated the highest correlation between clinical response and plasma concentration. MAO inhibitors are useful but require a reliable patient who can comply with dietary restrictions. Maprotiline and amoxapine are not first- or second-line antidepressants. Clomipramine and fluoxetine offer unique properties that make them first- or second-line antidepressants for particular patients. There are significant drug interactions with antidepressants that should be avoided.
The conspiracy of culture. Women's issues in body size, This article challenges nurses to rethink cultural values and ideals regarding beauty and body weight. respond appropriately to persons suffering from any of the eating disorders. and work together to change self-deprecation into a celebration of womanhood.
Compulsive overeating, Compulsive overeating is a behavior used in an attempt to numb or nurture feelings that are threatening to the person. Emotional states are soothed by use of food. Treatment is designed to respond to internal. biologic causes of hunger and satiety while simultaneously allowing feelings to surface and be dealt with. Work on the inner child enables the person to identify and deal with unmet needs and correct distortions from childhood. The secondary gain realized from the extra weight is examined. and direct means of dealing with these needs explored. The focus of recovery is on learning to nurture the self. physically and emotionally.
Eating disorders as a special problem for persons with insulin-dependent diabetes mellitus, Diabetes and eating disorders can be a deadly combination. Patients may omit or reduce their insulin dosages. which will induce glycosuria. Counseling and behavior modification are essential to prevent the development of complications such as DKA. frequent hypoglycemia. and the early onset of chronic complications. Diabetes education and insulin regulation must be combined with an interdisciplinary team approach to correct maladaptive coping mechanisms.
Unlocking sexual issues. Counseling strategies for nurses, Providing truly holistic care means that nurses must recognize that their clients are sexual beings and that they often suffer from sexual concerns and problems related to their past history and their current medical problems. In addition to helping clients move toward physical wellness. nurses should intervene with intrapersonal and interpersonal problems affecting client's sexual feelings and behaviors.
Managing the care of patients with dementia. How to maximize level of functioning and minimize behavior problems, Effective treatment of patients with dementia involves supporting and educating the primary caregiver. uncovering and correcting the underlying cause of any decompensation that may occur. and deciding when drug therapy is appropriate. Caregivers must be taught how to cope with the patient's denial and how to modify the patient's environment so that it is safe and easy to understand. Pharmacologic therapy for depression accompanying dementia can improve a patient's quality of life and independence considerably; drugs may also be of help in dealing with patients who resist care. Psychotic symptoms usually do not require pharmacologic treatment. and hypnotics should. if possible. be avoided as a solution to sleep problems.
Cocaine-induced myocardial infarction. A growing threat to men in their 30s, A clear association has been established between cocaine use and acute myocardial infarction. Because of the continuing rise in cocaine use in the United States. many more young patients have or will have this disorder. Such patients are usually managed conservatively with calcium channel blockade and have an excellent in-hospital prognosis. If chest pain recurs or stress testing reveals evidence of ischemia. cardiac catheterization should be done. If cocaine use is discontinued. the long-term prognosis of a typical patient with cocaine-induced acute myocardial infarction is excellent in the absence of other chronic illnesses.
Jaundice and cholestasis. Some common and uncommon causes, Jaundiced patients may not always be as sick as they look. and cholestatic patients may be quite ill but not yet jaundiced. There is variability in presentation of cholestasis. and jaundice may be intrahepatic or extrahepatic and acute or chronic. Even though the diagnosis of jaundice can be elusive. an unnecessarily exhaustive search for a cause should be avoided. because some tests are not without dangers. Dr Gordon describes many possible causes. some of which are rare but are still worth consideration.
Cell cycle regulation of histone H1 kinase activity associated with the adenoviral protein E1A, Several cellular proteins form stable complexes with the proteins encoded by the adenovirus early region 1A (E1A) gene in extracts derived from adenovirus infected or transformed cells. Two of the cellular proteins that bind to E1A have been identified; one. a 105-kilodalton protein (pRb). is the product of the retinoblastoma gene. and the other. a 60-kilodalton protein. is a human cyclin A. Two other proteins that bind E1A have now been shown to be related to p34cdc2. This E1A complex displayed histone H1-specific kinase activity; the kinase activity was modulated during the cell division cycle. and association of pRb with E1A apparently was not required for this activity.
Proton-pump inhibition for acid-related disease, Omeprazole and lansoprazole are the forerunners of a group of substituted benzimidazole compounds that block the gastric proton pump. These drugs exert a potent antisecretory effect by blocking the final common pathway of acid secretion. Prolonged. potent reduction of acid secretion using omeprazole has resulted in significant therapeutic advantage over existing antisecretory medication. such as H2 receptor antagonists (H2RAs). Research experience with lansoprazole indicates that it has treatment properties for acid-related disease that are similar to those of omeprazole. Omeprazole has been used successfully in the treatment of reflux esophagitis and the Zollinger-Ellison syndrome in the United States over the past year and has received approval recently as first-line therapy for duodenal ulcer disease. Research involving more than 20.000 individuals. postmarketing surveillance studies. and thorough safety studies in man and animals have shown omeprazole to be well tolerated. with an incidence and spectrum of adverse events in clinical trials similar to those observed with H2RAs.
HIV-related characteristics of migrant workers in rural South Carolina, After finding human immunodeficiency virus (HIV) infection in a migrant worker named as a syphilis contact. the South Carolina Department of Health and Environmental Control offered HIV counseling and testing and syphilis screening to migrant workers in the surrounding two-county area. In addition. a brief questionnaire was administered to document demographics and risk behavior. Of the 265 workers aged 16 and older in 15 migrant camps. 198 (75%) consented to the survey and testing. Of the 198 tested. 85% were male and 75% single. The median age was 39. with a range of 16 to 69 years. Twenty-five (13%) were HIV antibody positive. and 32 (16%) had reactive serologic tests for syphilis. Of the 166 workers who reported the frequency of condom use. 77 (46%) indicated they never use condoms. We conclude that there is a relatively high rate of HIV infection in these rural South Carolina migrant workers. whose behavior puts them at risk for HIV infection and other sexually transmitted diseases.
Epidemiology and clinical characteristics of tularemia in Oklahoma, 1979 to 1985, We studied the clinical and epidemiologic characteristics of tularemia in 165 Oklahomans from 1979 to 1985. The ulceroglandular form of the disease was most common (60%). followed by typhoidal (18%). glandular (15%). oropharyngeal (7%). and oculoglandular (1%) forms. The male-female ratio was 3.7:1. and the highest rates of disease were found in the age groups 5 to 14. 35 to 44. and 55 to 74. Ticks were most frequently implicated as the source of infection (84/154 [55%]). followed by rabbits. (58/154 [38%]). Seventy percent of the patients were hospitalized. and four (2.5%) died. The annual number of patients who reported that rabbits were their probable source of exposure to Francisella tularensis and the estimated number of rabbits harvested (ie. killed by hunters) for the year correlated closely with the total number of cases reported from year to year.
Train versus pedestrian accidents, Railroad-related trauma has been associated with injuries causing considerable morbidity. This is a retrospective study of 15 consecutive patients who were run over by trains. The initial injury produced a traumatic amputation of 10 extremities in eight patients. Limb salvage in two other patients with severe fractures failed. and subsequent lower extremity amputation was required. Despite efforts to salvage the most distal tissue possible. 8 of 12 extremities amputated in the acute traumatic period required revision to a more proximal level. Alcohol ingestion was involved in 13 of the 15 incidents in the study. No patient received posthospitalization alcohol rehabilitation. In addition. despite the young age of the patients in this series. only one patient was rehabilitated to a prosthetic ambulator.
Accelerated fractionation radiation therapy for advanced squamous cell carcinoma of the head and neck, We treated 14 patients who had advanced head and neck cancer with an accelerated fractionation schedule of irradiation consisting of two fractions given 6 hours apart. In the morning a volume of 1.7 Gy was given to an area that encompassed the entire tumor. enlarged lymph nodes. and all areas at risk for microscopic disease. Six hours later. 1.1 Gy was given to an area that included only the tumor and any enlarged lymph nodes. with a 2-cm margin. The treatment was well tolerated; of the 13 patients who completed therapy. six did not require a break in therapy. and seven patients did. The median rest period was 2 days. There was no grade 4 toxicity. Grade 3 toxicity included skin changes (one case). mucositis (two). dysphagia (two). weight loss (three). and a decrease in the hemoglobin level (one case). The response rate in the 13 who completed therapy was 13/13 (100%); 11 of the 13 (83%) had a complete response. Only one of the 11 who achieved a complete response had failure at the primary site. At a median follow-up of 24 months. the absolute survival was 7/13 (54%) and the corrected survival was 7/10 (70%). This technique permits radiation therapy to be given on an accelerated schedule without a planned break in treatment. The overall response rate and survival at 2 years was excellent.
Hand function in patients with diabetes mellitus, Using validated clinical tests and standardized controls. we measured hand function in diabetic subjects. Fifteen diabetic patients (median age 48 years). all having used insulin for a minimum of 5 years. were randomly selected from inpatient and outpatient services of an academic medical center. Testing was done on an outpatient basis. The three hand function tests used were the Purdue Pegboard. O'Connor Tweezer Dexterity. and Smith Hand Function. A symptom questionnaire was also included in the study. Function was significantly decreased in the diabetic group. and the decrease was out of proportion to their own subjective pretest assessments. These findings may have implications for occupational performance as well as activities of daily living.
Curative potential of primary whole-abdomen irradiation in ovarian carcinoma, Ovarian carcinoma remains a leading cause of cancer mortality in American women. The identification of active chemotherapy drugs and regimens has resulted in much less frequent use of radiation therapy at a time when technical and conceptual advances have been made. Unfortunately. the shift from radiotherapy to chemotherapy has not produced a discernible improvement in patient survival. Retrospective and prospective data suggest that whole-abdomen irradiation offers curative potential in patients with nonbulky residual disease after surgical cytoreduction. Its use should therefore be reconsidered as a primary adjuvant therapy in properly selected patients.
Magnetic resonance imaging in the evaluation of knee injuries, To better define the role of magnetic resonance imaging (MRI) in the evaluation of knee injuries. we analyzed 10 recently published articles comparing MRI and arthroscopy in the detection of meniscal and anterior cruciate ligament tears. Sensitivity (SN). specificity (SP). positive predictive value (PPV). and negative predictive value (NPV) for medial meniscus (MM) tears. lateral meniscus (LM) tears. and anterior cruciate ligament (ACL) tears were either obtained or calculated from data contained in each article. The medians of measurements for MM tears were 97% SN. 89% SP. 88% PPV. and 96% NPV. Measurement medians for LM tears were 85% SN. 94% SP. 86% PPV. and 95% NPV. ACL tear measurement medians were 100% SN. 96% SP. 80% PPV. and 98% NPV. High NPVs were found in several studies. many of which were 100%. The high NPV of MR imaging suggests that diagnostic arthroscopic surgery is not necessary in the evaluation of patients with negative MRI studies. The superior sensitivity of MRI in detecting frank posterior horn tears. intrasubstance meniscal tears. and significant incidental findings also suggests that screening MRI scans can facilitate preoperative planning.
Aortoiliac dissection after percutaneous insertion of an intra-aortic balloon pump, Aortic or aortoiliac dissection may complicate percutaneous intra-aortic balloon pump insertion in various ways. Thrombosis can escape clinical recognition if no major obstruction develops. Death due to perforation after dissection is not uncommon. In this case study. aortoiliac dissection led to bilateral iliac artery stenosis. an unusual complication of percutaneous femoral cannulation for insertion of a balloon pump.
External iliac artery rupture during angioplasty: control by balloon tamponade, Transluminal angioplasty. particularly of stenoses of the iliofemoral arteries. is an excellent technique with a success rate greater than 90%. an overall complication rate of less than 5%. and a low incidence of major complications. Of these major complications. arterial rupture is one of the most urgent. We have presented a case of external iliac artery rupture during angioplasty that graphically demonstrates the value of balloon tamponade in managing this potentially catastrophic event. The angiographer's sensitivity to the possibility of arterial rupture and prompt management. combined with close collaboration with the vascular surgeon. can lead to a good clinical outcome.
Spontaneous internal carotid artery dissection shown by magnetic resonance imaging, We have reported a case of spontaneous dissection of the internal carotid artery. with MRI and angiographic findings. We conclude that MRI is a beneficial noninvasive test for the detection and study of carotid artery dissection.
Severe frostbite caused by Freon gas, We have reported a case of severe frostbite due to direct exposure to liquid Freon gas (monochlorodifluoromethane). a fluorinated hydrocarbon widely used as refrigerants. propellants. and industrial solvents. The patient was treated for severe third- and fourth-degree frostbite to the hand. The severity of the injury was apparently the result of direct through-and-through injury from exposure to the liquid (boiling point -40.5 degrees C) and a possible systemic vasoconstrictive effect on arterial smooth muscle due to inhalation of Freon gas.
Management of patients aged over 60 years with supratentorial glioma: lessons from an audit, This audit of clinical management confirmed the poor prognosis for patients (n = 80) aged over 60 years with a diagnosis of supratentorial glioma. The median survival time after diagnosis was 9 weeks following steroids and 7 weeks after biopsy and steroids. Cytoreductive surgery and radiotherapy improved median survival time by a maximum of 16 weeks. but there was significant morbidity in some patients undergoing craniotomy. Although 92% of the biopsied lesions were either glioblastoma or anaplastic astrocytoma. the median survival of these patients was similar to the 8% of patients confirmed as having intermediate grade astrocytoma. Patients presenting with minimal functional deficit (WHO grade I or II) had longer median survival times than those presenting in poor condition (WHO grade III or IV). In this series there was no relationship between management undertaken and clinical status of the patient. The 9% of the cohort that survived 1 year were treated in a variety of ways. This audit. together with results from other studies. suggests that a prospective clinical trial of different management regimes in elderly patients with supratentorial gliomas is needed. Since median survival time in the most intensively treated patients will be around 6 months. treatment evaluation must consider the quality of life provided.
Characterization of the mononuclear cell infiltrate and HLA-Dr expression in 19 oligodendrogliomas, We have studied frozen tissue from 19 oligodendrogliomas with a panel of antibodies to lymphocytes and their subsets. macrophages. natural killer cells. and HLA-Dr antigens. Macrophages were detected in moderate numbers in 60%-100% of tumors depending on the antibody used. T lymphocytes were fewer in number than macrophages and were present in 62% of cases. Most of the T lymphocytes were of the CD8 phenotype. CD4 lymphocytes were very few in number and present in only 18%. B cells and natural killer cells were absent from all cases. HLA-Dr antigens were expressed by macrophages in all cases but never on tumor cells. The implications of these findings are that macrophages and. to a lesser extent. CD8 lymphocytes are the predominant cells infiltrating oligodendrogliomas and that they may exert cellular immune functions.
Magnetic resonance images of brain stem infarct in periarteritis nodosa, A 35-year-old woman displayed unusual symptoms of progressive bulbar dysfunction. At necropsy. systemic necrotizing vasculitis and small pontine infarcts were demonstrated. The angiographic and magnetic resonance imaging findings are described. The latter investigation is a sensitive method for detecting such pontine lesions. To our knowledge. this case is the first report of magnetic resonance imaging findings of brain stem infarct in a patient with periarteritis nodosa.
Hysterosalpingography in the 1990s, All physicians involved in the evaluation and treatment of infertility rely heavily on the information provided by hysterosalpingography. For many years this study has provided images of the lumina of the fallopian tubes that are not available by other diagnostic means. and it also gives the most accurate outline of the uterine cavity. Hysterosalpingography will therefore continue to be a valuable study in the upcoming decade. and it is important now to take account of the many advances in technology that impinge on the execution and interpretation of this study. In this article we first update the continuing debate about elements of the study itself. involving techniques and the choice of contrast material. We also consider surgical advances. such as the widespread use of microsurgical reconstruction of the fallopian tube. that increase the demand for hysterosalpingography. Since radiologists are asked to evaluate the results of surgery. it is essential for them to be familiar with the postoperative appearances of the fallopian tube. Finally. we consider what must be by far the most important development of the 1990s. the continuing integration of hysterosalpingography with new interventional and imaging techniques. Fallopian tube catheterization expands the examination of the fallopian tube and offers new therapeutic applications. Transvaginal sonography and MR imaging have allowed noninvasive exploration of the female pelvis. Correlation of hysterosalpingography and MR imaging is particularly useful in the diagnosis of uterine myomas and congenital uterine duplication anomalies when surgery to preserve or enhance the reproductive capacity of the uterus is indicated. Sonography and MR imaging should be correlated with hysterosalpingography to provide a more efficient diagnostic and therapeutic approach to the common mechanical causes of infertility.
Percutaneous procedures for the diagnosis and treatment of lower back pain: diskography, facet-joint injection, and epidural injection, This review discusses the indications. techniques. complications. and results of three percutaneous procedures used to evaluate and treat lower back pain: diskography. facet-joint injection. and epidural injection. Diskography. performed by injection of contrast medium into the nucleus pulposus. is a technique used to determine the cause of lower back pain in patients in whom findings on other imaging studies are normal or conflicting. Injection of steroids and anesthetic into the facet joints of the lumbar spine is useful to diagnose or treat patients with facet syndrome (back pain caused by abnormalities of the facet joints). Injection of steroids and anesthetic agents into the epidural space provides short-term relief. and can sometimes provide permanent relief. of lower back pain.
Phylloides tumor: findings on mammography, sonography, and aspiration cytology in 10 cases, Phylloides tumor is a rare fibroepithelial breast tumor that occasionally has unpredictable clinical behavior. In nine cases of histologically benign tumors and one case of malignant phylloides tumor. the findings on physical examination. mammography. sonography. and aspiration biopsy were correlated retrospectively with the histologic diagnosis of resected specimens. Mammograms showed a round or lobulated benign-appearing opacity in nine cases; one small tumor was missed mammographically. Sonography depicted all tumors as mostly solid masses. Sonographic features included low-level internal echoes. either uniform or scattered; smooth contours; and no significant posterior shadowing. Intramural cysts were shown in six cases. Neither mammography nor sonography allowed reliable differentiation between benign and malignant phylloides tumors. Aspiration biopsy permitted accurate diagnosis of seven benign tumors. The malignant phylloides tumor was classified as a malignant tumor. but the definite differentiation from a carcinoma could not be made. Two histologically benign phylloides tumors were misdiagnosed as carcinomas. Although uncommon. phylloides tumor should be considered in the differential diagnosis of mammographically benign-appearing breast masses. especially if sonography shows intramural cysts within a well-defined solid lesion. Aspiration cytology is unreliable because of the inhomogeneity of the tumor; both intraoperative frozen section and permanent sections are needed for correct histologic diagnosis.
Detection of hepatic masses in patients with carcinoma: comparative sensitivities of sonography, CT, and MR imaging, To evaluate the sensitivity of sonography. CT. and MR imaging in the detection of hepatic masses in carcinoma patients. we conducted a prospective study of 75 consecutive patients with gastrointestinal tumors who were admitted for surgical resection of the primary tumor. Sonography was performed with convex transducers of 3.5 and 5.0 MHz. Three noninvasive CT techniques were used: unenhanced CT scans. the incremental bolus dynamic scanning technique. and delayed scanning 4-6 hr after bolus injection of 60 g of iodine. MR images (1.5 T) were acquired as presaturated T1- and T2-weighted spin-echo sequences and as breath-holding fast low-angle shot (FLASH) 60 degrees and FLASH 15 degrees sequences. As it is difficult to distinguish benign from malignant masses solely on the basis of morphologic criteria. the techniques for each imaging method were designed to detect and not to characterize hepatic lesions. Each examination was interpreted blindly. and the results were compared with surgical findings. intraoperative sonography. and biopsy of the liver as the gold standard. All focal hepatic masses verified at surgery. malignant or benign. were included in the analysis. Sixty-five (68%) of 95 focal hepatic masses were detected by CT. 60 lesions (63%) by MR. and 50 lesions (53%) by sonography. Although lesions 1-2 cm were shown almost equally well by CT and MR (74% and 77%. respectively). the detection rate of smaller lesions (less than 1.0 cm) decreased more drastically with MR (31%) than with CT (49%). Sonography had a sensitivity of only 20% with the smaller lesions. All imaging techniques had a sensitivity of 100% for focal hepatic masses larger than 2.0 cm. Our results show that CT has a higher overall sensitivity (68%) than MR and sonography for the detection of focal hepatic masses. When the results of the three procedures are combined. the overall sensitivity is 77%. This is unsatisfactorily low. as CT and MR have a size threshold of about 1.0 cm and are relatively unreliable for the detection of smaller lesions.
Gallstone lithotripsy: results when number of stones is excluded as a criterion for treatment, The Siemens Lithostar Plus protocol (Siemens Medical Systems. Iselin. NJ) allows investigators to perform gallstone lithotripsy on patients regardless of the number of stones they have. provided the stones occupy less than 50% of the gallbladder lumen. The purpose of this study was to determine the interrelationships between stone burden. fragmentation response. and stone-free rates when treatment is not limited to three stones or fewer. Of 200 patients initially examined. 80 (40%) underwent lithotripsy. The mean number of treatments per patient was 2.1. and the mean number of shock waves per patient was 7386. In 60 patients in whom 6-month follow-up was available. the overall stone-free rate. based on actual results. was 32% (19/60). The stone-free rates for solitary stones. two or three stones. and four or more stones were 50%. 12%. and 26%. respectively. Regardless of number of stones. patients who ultimately became stone free had significantly smaller mean fragment size (0.25 cm) 2 weeks after lithotripsy than did those who did not become stone free (0.51 cm). Retrospective volume analysis showed that seven (47%) of 15 patients with multiple stones occupying less than 2000 mm3 were stone free; none became stone free when this volume was exceeded. Lithotripsy remains a practical option for patients with solitary stones. Comparable stone-free rates to those achieved for solitary stones can be obtained in patients with multiple stones. regardless of their number. provided treatment is aggressive and the stone aggregate is less than 2000 mm3.
Osteoarthritis of the knee: comparison of radiography, CT, and MR imaging to assess extent and severity, Although conventional radiography is the method most frequently used for monitoring progression of osteoarthritis. it may not show osteoarthritic changes of the knee until late in the disease. and it may show involvement of only one or two compartments in patients who have tricompartmental disease. We compared radiography. CT. and MR imaging for assessing the extent and severity of osteoarthritis of the knee in 20 patients. Radiography included posteroanterior weight-bearing. true lateral. and sunrise patellar projections. Axial CT scans were reformatted in sagittal and coronal planes. MR imaging consisted of spin-echo (600-800/20; 2000/60. 120 [TR/TE]). and gradient-echo (600/30. theta = 30 degrees) sequences. The severity of osteoarthritic changes was graded from 0 to 3. MR frequently showed tricompartmental cartilage loss when radiography and CT showed only bicompartmental involvement in the medial and patellofemoral compartments. In the lateral compartment. MR showed a higher prevalence of cartilage loss (60%) than radiography (35%) and CT (25%) did. In the medial compartment. CT and MR showed osteophytes in 100% of the knees. whereas radiography showed osteophytes in only 60%. Notably. radiography often failed to show osteophytes in the posterior medial femoral condyle. On MR images. meniscal degeneration or tears were found in all 20 knees studied. Partial and complete tears of the anterior cruciate ligament were found in three and seven patients. respectively. MR is more sensitive than radiography and CT for assessing the extent and severity of osteoarthritic changes and frequently shows tricompartmental disease in patients in whom radiography and CT show only bicompartmental involvement. MR imaging is unique for evaluating meniscal and ligamentous disease related to osteoarthritis.
Response of osteosarcoma and Ewing sarcoma to chemotherapy: imaging evaluation, The importance of diagnostic imaging in evaluating therapeutic response of bone sarcomas has increased with the use of chemotherapy administered before radiation therapy or surgery. The information provided by imaging studies is used to estimate prognosis; modify preoperative chemotherapy; and plan radiation therapy. surgery. and postoperative chemotherapy. This review examines the value and illustrates some pitfalls of traditional imaging methods. including conventional radiography. angiography. CT. and radionuclide scintigraphy. and discusses recent efforts to monitor therapy by using MR imaging and MR spectroscopy.
Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists, Thromboxane (Tx) A2 is a product of cyclooxygenase catalyzed metabolism of arachidonic acid. It is formed via prostaglandin (PG) endoperoxide intermediates (PGG2 and PGH2) by a specific synthase. PGH2 appears to exert the same biologic effects as TxA2. The cDNA for a TxA2 receptor has been cloned from a human placental library. Although pharmacologic and biochemical studies suggest the presence of multiple isoforms. this remains to be confirmed at the molecular level. A hydropathy plot of the deduced amino acid sequence of the available clone suggests that it has 7 transmembrane spanning domains. typical of a G protein linked receptor. Pharmacologic studies imply that Tx receptors in platelets are linked to phospholipase C activation via pertussis toxin insensitive G proteins. Candidates include the 42 kD Gq and the 60 kD Ge. TxA2 acts as an amplifying signal for platelet agonists and the response to this eicosanoid is tightly regulated. Mechanisms include rapid hydrolysis of the agonist to the inactive TxB2. autoinactivation of Tx synthase. rapid homologous TxA2 receptor desensitization due to receptor-G protein uncoupling. coincidental sensitization to counterregulatory Gs linked receptor systems and stimulation of prostacyclin formation by TxA2. Due to its role as an amplification signal in platelet activation. inhibition of Tx synthesis and action is an effective mechanism for preventing platelet-dependent vascular occlusion. Aspirin is of proven efficacy in this regard. Tx synthase inhibitors and antagonists are under clinical investigation.
Thrombolysis in refractory unstable angina, Multiple drug therapy. including nitrates. beta blockers. calcium antagonists. aspirin. and heparin. has been advocated as effective in the treatment of unstable angina. a syndrome with a multifactorial pathogenesis. Recently. plaque rupture and thrombosis have been demonstrated as the most important pathogenetic mechanisms. Nevertheless. clear-cut results on the effects of thrombolytic treatment in unstable angina are still lacking. Some possible explanations why the medical treatment of unstable angina has still not yet been standardized. whereas that of myocardial infarction has. are suggested. A review of randomized and nonrandomized studies published on this topic evaluating the role of different thrombolytic agents in unstable angina is presented. In addition the role of coronary angiography is discussed. In view of the disappointing results of coronary artery bypass surgery performed in the acute phase of the disease. one of the goals of clinical research is to identify subsets of patients at high and low risk and who undergo different types of therapeutic interventions. To support published data suggesting that total myocardial ischemia has a significant impact on prognosis. we present our results of a study carried out on patients with refractory unstable angina treated with thrombolytic therapy and evaluated with continuous electrocardiographic monitoring in the attempt to correlate total myocardial ischemia with short-term prognosis. Data in favor of the prognostic role of continuous electrocardiographic monitoring in unstable angina are also reviewed. Finally. we propose some suggestions that might be useful for future studies.
Thrombolysis in postinfarction angina, Postinfarction angina carries a poor prognosis. with a 20-70% incidence of recurrent myocardial infarction (MI) or death within the subsequent 3-6 months. The pathophysiologic mechanisms causing postinfarction angina may include thrombus. complex coronary arterial lesions that form a nidus for thrombus formation. inadequate collateral supply following acute MI. or intimal endothelial dysfunction. The role of thrombus has been established in the pathophysiology of Q-wave MI. and thrombolytic treatment of patients presenting with acute transmural MI has been shown to salvage left ventricular function and to reduce mortality. However. thrombolytic therapy for the acute MI does not reduce the incidence of recurrent ischemia or infarction. as is evident from the 18-26% incidence of recurrent ischemia reported in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) and Thrombolysis in Myocardial Infarction (TIMI) trials. In the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) study the incidence of reinfarction was documented as 4% in the streptokinase group. which was actually significantly greater than in the placebo group (2%). In a randomized placebo-controlled study of thrombolysis for postinfarction angina. 29 patients were randomized to placebo (P group. n = 17) or to thrombolytic therapy (T group. n = 12). Patient groups were similar with respect to age. location of MI. ejection fraction. severity of coronary artery disease. and antianginal therapy. Patients underwent coronary angiography 6 +/- 1 days postinfarction. Filling defects consistent with intracoronary thrombus was seen in 11 of 12 T group patients and in 11 of 17 P group patients prior to treatment. Lysis occurred in 7 of 11 T patients and 1 of 11 P (p less than 0.02). Holter-detected silent ischemia was compared pre- and posttherapy.
Percutaneous transluminal coronary angioplasty for unstable angina, Coronary angioplasty is an effective treatment for patients with angina at rest. either refractory or initially stabilized but returning despite pharmacologic treatment. and with early postinfarction angina. The procedure has a high initial success rate. but there is an increased risk of major complications resulting from a higher incidence of acute closure. which may be related to preexisting thrombus. Resolution of this problem may be achieved by the use of more potent antiplatelet treatment. pretreatment with thrombolytic agents. or treatment that can be applied locally (e.g.. laser energy. atherectomy) at the site of the unstable plaque. Results in this study have been obtained from selected groups of patients: those with predominantly single-vessel disease and well-preserved left ventricular function. It remains to be determined whether the same benefits can be achieved in patients with multivessel disease or in those who have severely reduced left ventricular function.
Integration of anticoagulation, thrombolysis and coronary angioplasty for unstable angina pectoris, Unstable angina pectoris remains a challenging acute ischemic syndrome to treat despite recent randomized trials that confirm the benefit of intravenous heparin. Coronary angioplasty. which is often required to treat the underlying arterial lesion. is adversely affected by the presence of thrombus with at least a 2-fold increase in abrupt closure. Four studies with heparin treatment prior to angioplasty indicate a reduction of abrupt vessel closure from 8-33% to 0-6% with apparent reduction of morbidity; no controlled trials are thus far available for heparin pretreatment. Another therapeutic alternative. thrombolytic therapy. has had quite equivocal results with several negative small studies. When angioplasty has been performed with thrombolytic therapy. a nonfibrin-specific plasminogen activator appears to be preferable. Newer studies that focus on thrombin inhibitors that bind to clot-bound thrombin and potent antiplatelet agents are in the early phase of clinical investigation. This review offers current recommendations for the integration of heparin. thrombolysis. and coronary angioplasty for unstable angina pectoris.
The elusive cause of instability in unstable angina, The causes of unstable angina are still largely unknown. However. some facts deriving from angiographic. postmortem. and pathophysiologic studies are well established. Angiographic findings: coronary thrombi and complicated stenoses are more frequent in unstable than in stable angina. Conversely. the severity of coronary atherosclerosis and the development of collateral circulation is similar in both coronary syndromes. Postmortem findings: the following features are more frequent in unstable than in stable angina: (1) mural thrombi. which often represent out-growth from the inside of a fissured plaque; (2) inflammatory cells at the site of plaques and in perivascular nerves; and (3) contraction bands in smooth muscle cells of the media surrounding plaques. However. fissured plaques can be found in 10% of individuals dying of noncardiac causes. and fissured plaque may occasionally be missing under the coronary thrombus in unstable angina. Pathophysiologic findings: patients with unstable angina compared with those with stable angina exhibit: (1) higher levels of serotonin in the coronary sinus; (2) higher systemic levels of fibrino-peptide A; (3) higher urinary levels of thromboxane A2 metabolites; and (4) a greater coronary reactivity to constrictor stimuli. A critical analysis of these established facts is required to set the stage for a better comprehension of the causes which can cause a coronary segment to progress in a stuttering way toward acute persistent coronary occlusion and myocardial infarction. Plaque fissure is likely to be an important background thrombogenic stimulus in many cases.
Pathogenesis of thrombosis in unstable angina, Plaque rupture of the thinned. weak fibrous cap infiltrated by macrophages and overlying a pool of lipid in the arterial wall initiates the acute thrombotic event of unstable angina. Thrombosis may be advanced within minutes. Most lesions that precede plaque rupture are minor (less than 50% stenosis); thus. thrombus greatly contributes to sudden flow limitation and onset of symptoms. If thrombosis can be totally blocked (not possible with current antithrombotic agents). clinical events should be preventable. and endogenous thrombolysis may be possible within days. Local and systemic factors contribute to arterial thrombosis. With type III injury (fissure into plaque or media) platelet-rich thrombus anchors in the fissure. tracks along the site of deep injury. extends into the lumen. and requires the highest blood level of specific thrombin inhibition (a molar concentration that inhibits the total concentration of prothrombin in circulating blood). Thus. the thrombin content requiring inhibition in type III injury is highest. Local factors for thrombosis associated with type III injury include the rheology of blood flow (increased shear rate forces platelets to the periphery) and substrates in the arterial wall. Plaque substrates include the more thrombogenic collagens (types I and III and diabetic or glycosylated collagen). tissue thromboplastin. lipid gruel. thrombin bound to arterial wall matrix. and decreased prostacyclin. There is a direct relation between platelet deposition (thrombus) and local vasoconstriction. which may perpetuate each other. Thrombus as a substrate is more thrombogenic than type III arterial injury.
The heart in fatal unstable angina pectoris, Compared to patients with sudden coronary death and acute myocardial infarction. relatively little morphologic data has been reported in patients with unstable angina pectoris. This article reviews necropsy data collected from one laboratory on unstable angina pectoris. From these data. several observations are appropriate: (1) Patients with unstable angina as a group have more coronary narrowing by atherosclerotic plaque than do patients with sudden coronary death or acute or healed myocardial infarction. (2) Patients with unstable angina have a much higher frequency of severe narrowing of the left main coronary artery than do patients in other coronary subsets. (3) The coronary atherosclerotic plaques in unstable angina consist primarily of fibrous tissue. and they are more similar to those found in patients with sudden coronary death than in patients with acute myocardial infarction. (4) The frequency of acute coronary lesions (thrombi. plaque rupture. and plaque hemorrhage) is similar to that observed in patients with sudden coronary death and significantly less than that observed in acute myocardial infarction. (5) The frequency of multiluminal channels throughout the major coronary arteries is significantly higher in unstable angina compared to sudden coronary death or acute myocardial infarction. (6) The major epicardial arteries and the heart are smaller in patients with unstable angina than in patients with sudden coronary death or acute myocardial infarction. (7) The left ventricular cavity is usually of normal size in patients with unstable angina and therefore left ventricular function is usually normal.
Coronary thrombosis: pathogenesis and clinical manifestations, The majority (greater than 75%) of major coronary thrombi are precipitated by a sudden rupture of the surface of an atherosclerotic plaque (plaque fissuring) causing platelet aggregation where thrombogenic subendothelial tissue has been exposed. Whether the thrombus remains mural and limited. just sealing the rupture. or evolves into an occlusive thrombus seems to depend on: (1) the amount and character of exposed thrombogenic material; (2) the actual thrombotic-thrombolytic equilibrium; and (3) local flow disturbances due to preexisting atherosclerotic stenosis. Thrombus formation may take place within the stenosis. where blood velocity and shear forces are highest. or it may take place or extend poststenotically. where flow separation. recirculation. and turbulence prevail. Platelet aggregation within the stenosis is responsible for the primary flow obstruction. but fibrin subsequently enmeshes the platelets and thus stabilizes the thrombus. Most thrombi have a layered structure. indicating an episodic growth that may alternate with thrombus fragmentation and peripheral embolization: thrombosis and thrombolysis are dynamic processes occurring simultaneously. If the platelet-rich thrombus at the rupture site evolves into an occlusive thrombus. the blood proximal and distal to the occlusion may stagnate and coagulate. giving rise to a secondarily formed red stagnation thrombosis consisting predominantly of erythrocytes held together by fibrin membranes. A ruptured plaque with a dynamic thrombosis superimposed (with or without spasm) seems to underlie the great majority of acute ischemic syndromes: unstable angina. acute infarction. and sudden death. The clinical presentation and the outcome depend on the severity and duration of ischemia: whether the obstruction is occlusive or nonocclusive. transient or persistent--modified by the magnitude of collateral flow.
Platelet activation in the pathogenesis of unstable angina: importance in determining the response to plasminogen activators, Unstable angina is a clinical syndrome of recurrent myocardial ischemia. In some cases. this reflects episodic platelet activation and coronary thrombosis. Thus. the biosynthesis of thromboxane A2. which is largely derived from activated platelets. is increased. often coincident with chest pain. The major role of platelets in unstable angina may influence the response to plasminogen activators. Platelets increase the resistance of thrombi to lysis. by inducing clot retraction and cross-linking and by releasing inhibitors. Thus. coronary thrombi in unstable angina may be resistant to lysis. Furthermore. both t-PA and streptokinase cause platelet activation and thrombin formation in vivo. possibly via plasmin. Plasmin can activate platelets and factor V directly. These prothrombotic effects of plasminogen activators may limit their activity in unstable angina. At the very least. their therapeutic efficacy may be highly dependent on the coadministration of potent antiplatelet agents and anticoagulants.
Fibrinopeptide A excretion in urine: a marker of the cumulative thrombin activity in stable versus unstable angina patients, Plasma levels and 24-hour urine excretion of fibrinopeptide A were measured in a consecutive series of 179 patients with angina pectoris. Sixty-four patients had stable angina and 115 patients had unstable angina. Urine was collected over 24 hours the day before coronary arteriography. and blood samples were taken at the end of urine collection. When the values of fibrinopeptide A in plasma and in the 24-hour urine specimens were compared. no significant correlation was found in patients with either stable (rs = 0.16. difference not significant) and unstable (rs = 0.07. difference not significant) angina. The concentrations of fibrinopeptide A in the plasma did not differ significantly when patients with stable angina (range 0.1 to 82.6. median 7.4 ng/mL) were compared with patients with unstable angina (range 0.2 to 61.7. median 14 ng/mL. p = 0.055). whereas fibrinopeptide A 24-hour urinary excretion was significantly higher in patients with unstable angina (range 0.3 to 38.1. median 11.8 micrograms/24 hr) than in patients with stable angina (range 0.4 to 38.1. median 3.8 micrograms/24 hr. p less than 0.001). Twenty-four-hour urine excretion of fibrinopeptide A in patients with unstable angina and angiographically documented intracoronary thrombi were higher than the corresponding values in patients with unstable angina without such angiographic characteristic (p less than 0.001). The largest increase in plasma and urine concentration of fibrinopeptide A was observed in patients whose first episode of angina at rest occurred within the previous 48 hours. We conclude that the cumulative thrombin activity. assessed by 24-hour urinary excretion of fibrinopeptide A. is a more useful index. compared with single fibrinopeptide A measurement in plasma. for discriminating between patients with stable and with unstable angina pectoris.
Granulocyte function in coronary artery disease, Granulocytes defend the body against invading microbes by producing a complex armamentarium of toxic substances. such as proteolytic enzymes. oxygen radicals and arachidonic acid metabolites. Under certain circumstances. however. such compounds may be released in the absence of phagocytosable particles. resulting in injury to normal cell and connective tissue degradation. Recent experimental studies have emphasized the potential role of granulocytes in the pathogenesis of myocardial ischemia. Clinical investigations have also shown alterations in neutrophil function in stable and unstable clinical manifestations of ischemic heart disease. "Priming" of granulocytes in stable forms of coronary disease may predispose to the subsequent development of acute coronary events. whereas activation of neutrophils may lead to alterations in vascular permeability and coronary flow regulation. leading to further myocardial and endothelial injury in acute myocardial infarction. unstable angina and coronary angioplasty.
Angiography in unstable angina, Within the last decade. it has been appreciated that the acute coronary syndromes of unstable angina. non-Q-wave. and Q-wave myocardial infarction often share a common pathogenesis based on plaque disruption and thrombosis. Such "acute" lesions frequently have a characteristic angiographic appearance with sharp overhanging edges. irregular borders. and intraluminal lucency. This review focuses on the benefits and limitations of qualitative assessment of coronary lesion morphology. with respect to the sensitivity. specificity. and prognostic significance of complex lesions and intracoronary thrombi. Angiographic findings following thrombolysis for unstable angina are discussed. as well as the possible role for thrombolytic therapy as an adjunct to angioplasty in unstable angina.
Antiplatelet and antithrombotic therapy in unstable angina, In 4 well-controlled clinical trials. aspirin reduced the incidence of coronary events in unstable angina. The benefits were present during the acute. subacute and more chronic phases of the disease and were independent of the doses and of other protocol differences. This benefit of aspirin can be extended to some. but not all. other antiplatelet drugs. In 4 clinical trials. heparin used acutely added substantial benefit to the management of unstable angina. reducing the event rate and also the incidence of refractory angina more than aspirin. The long-term benefit of antithrombin therapy remains to be more thoroughly investigated. Despite these successes. the failure rate of aspirin and of heparin remains high. justifying a continuing search for more potent and safe antiplatelet and antithrombotic drugs.
Thrombolysis in unstable angina: results of clinical studies, Ample evidence exists to support the major role of intracoronary thrombosis superimposed on a disrupted plaque in unstable angina. Consequently. thrombolytic treatment. already established to be highly beneficial in patients with acute myocardial infarction. might also be indicated in patients with unstable angina. The clinical response to thrombolytic treatment has been evaluated in several small-sized studies with inconsistent and somewhat deceiving results. Thus. the role of thrombolysis in the treatment of unstable angina is still controversial. Two ongoing large-scale. randomized. controlled trials. the Third Thrombolysis in Myocardial Infarction (TIMI III) in the United States testing recombinant tissue-type plasminogen activator and UNASEM in Europe testing anisoylated plasminogen-streptokinase activator complex will. it is hoped. solve the debate. At present. early thrombolysis might be considered for the treatment of the subset of patients with severe rest angina associated with transient ST-T ischemic changes.
Incremental prognostic accuracy of clinical, radionuclide and hemodynamic data in acute myocardial infarction, A logical sequence of testing in evaluating prognosis early in acute myocardial infarction (AMI) would be to use clinical data first. then add noninvasive data and finally add invasive data. The incremental prognostic information concerning 1-year survival obtained from such a sequence in 107 patients with AMI was studied using logistic regression and receiver-operating characteristic curves. Cardiac mortality was 24% at 1 year. Clinical data obtained soon after admission (prior myocardial infarction. heart rate. blood pressure. age) were 78 +/- 5% accurate in the prediction of 1-year survival. The addition of radionuclide-estimated left ventricular ejection fraction or invasive hemodynamic data to the clinical model at this time improved prognostic accuracy to 84 +/- 5% (p = 0.05) and 87 +/- 4% (p = 0.007). respectively. The further addition of invasive data to the model containing clinical and left ventricular ejection fraction data provided a further increment in prognostic accuracy to 89 +/- 4%. whereas no significant increase in accuracy was seen on addition of left ventricular ejection fraction to the model containing clinical and invasive data. It is concluded that clinical data provide important prognostic information concerning late survival early in the course of AMI. This may be improved by the logical application of noninvasive and invasive studies at this time.
Beat-to-beat electrocardiographic morphology variation in healed myocardial infarction, Using high-fidelity electrocardiographic (ECG) amplifiers. we measured subtle beat-to-beat ECG morphologic variations at different phases of the ECG complex. The electrocardiograms were recorded from 49 men with a documented Q-wave myocardial infarction and from 30 age-matched normal men. Forty consecutive beats were averaged to achieve an average ECG signal from which variance could be calculated. The relative variance. defined as the ratio between the integrated variance of the examined window and the integrated variance of the ECG signal that was close to full cycle length. was calculated at QRS onset and at offset in 2 frequency bands (4 to 40 and 60 to 120 Hz). Patients with healed infarction had a relative variance of 2.1 +/- 0.5 (mean +/- standard deviation [SD]) at QRS offset (a window of 40 ms). which was significantly lower than that of the healthy volunteers: 2.5 +/- 0.33 (mean +/- SD; p less than 0.02) at the low-frequency band. At the high-frequency band. patients with healed infarction had a significantly higher relative variance than the control subjects at QRS onset: 1.95 +/- 0.58 vs 1.55 +/- 0.35 (mean +/- SD; p less than 0.005). A model based on the numerous minor conduction abnormalities that exist in the chronically ischemic myocardium is presented to explain the changes in variance at the onset and offset of the QRS. The variance changes described can eventually serve as quantitative indexes of myocardial injury and electrical stability in patients with ischemic heart disease.
Quantitative analysis of signal-averaged P waves in idiopathic paroxysmal atrial fibrillation, Detailed analysis of the QRS complex can identify patients at risk from ventricular arrhythmias. but similar techniques applied to the atria have been disappointing. This study attempts to quantitate differences in the fine morphology of P waves in a group of 9 patients with paroxysmal atrial fibrillation (AF) versus 15 control subjects. Atrial triggered signal-averaging was combined with a detailed investigation of P-wave duration. high-frequency spatial voltage and spatial velocity. Signal-averaged P-wave duration was significantly increased in patients with paroxysmal AF (135 +/- 8 vs 126 +/- 4 ms. p less than 0.05). The root-mean-square voltage at frequencies greater than 35 Hz in these patients was also significantly greater (16 +/- 3 vs 12 +/- 1 microV. p less than 0.05). Similar observations were made at frequencies greater than 40 Hz (10 +/- 3 vs 7 +/- 1 microV. p less than 0.05). These differences appeared to be confined to the third quarter of the P wave (third quarter root-mean-square voltage at greater than 40 Hz expressed as a ratio of total P-wave root-mean-square voltage. 1.4 +/- 0.1 vs 1.2 +/- 0.1. p = 0.005). Spatial velocity was also increased in the paroxysmal AF group (peak spatial velocity 6.4 +/- 1.8 vs 4.6 +/- 0.5 mV/s. p less than 0.05). These observations support previous intracardiac data that implicate delay and fragmentation of intraatrial conduction in the pathogenesis of paroxysmal AF.
Diagnostic accuracy of exercise thallium-201 single-photon emission computed tomography in patients with left bundle branch block, Recent reports have proposed that abnormal apical or anterior wall perfusion with exercise thallium-201 imaging may increase diagnostic accuracy for disease of the left anterior descending artery in patients with left bundle branch block (LBBB). To evaluate these suggestions. 83 patients with LBBB who underwent thallium-201 single-photon emission computed tomography and coronary angiography within an interval of 3 months were retrospectively reviewed. There were 59 men and 24 women aged 33 to 84 years (mean 65). Myocardial perfusion to the apex. anterior wall and anterior septum were scored qualitatively by consensus of 2 experienced observers and by quantitative analysis in comparison with a normal data base. The sensitivity. specificity and accuracy of perfusion defects in these segments were then expressed according to angiographic findings. Significant stenosis of vessels within the left anterior descending artery territory was present in 38 patients. By receiver-operator characteristic analysis. a fixed or reversible defect within the apex by the qualitative method was the best criterion for coronary artery disease. However. although highly sensitive (79 and 85% by the qualitative and quantitative methods. respectively). an apical defect was neither specific (38 and 16%. respectively). nor accurate (57 and 46%. respectively). Perfusion abnormalities in the anterior wall and septum were also of limited diagnostic accuracy. Thus. modified interpretative criteria in patients with LBBB are not clinically useful in the assessment of left anterior descending artery disease.
Rapid detection of Epstein-Barr viral DNA by nonisotopic in situ hybridization. Correlation with the polymerase chain reaction, A nonisotopic. in situ hybridization procedure is described for detecting Epstein-Barr viral (EBV) DNA in cytopreparations of pepsin-digested. unfixed cells in less than 3 hours. The procedure. which uses an EBV Bam HI W DNA probe conjugated directly to horseradish peroxidase. first was optimized using an EBV-infected cell line (ARH-77) and then validated on four positive control specimens and six negative control specimens. Optimization studies demonstrated distinct nuclear hybridization signal in less than 10% of formaldehyde-fixed. pepsin-digested ARH-77 cells. When formaldehyde fixation was omitted. more than 50% of the pepsin-digested ARH-77 cells had strong nuclear staining. Unfixed cells from the four positive controls had detectable hybridization signal; the presence of EBV-DNA in these specimens also was confirmed by a polymerase chain reaction. There was no hybridization signal in the six negative control specimens. The results indicate that this nonisotopic. in situ hybridization procedure rapidly detects the presence of EBV-DNA in cytopreparations of unfixed. pepsin-digested cells from clinical specimens. There is a tradeoff. however. between assay sensitivity and preservation of cytologic details.
The slide centrifuge gram stain as a urine screening method, A slide centrifuge Gram stain procedure was performed to screen for bacteriuria 4161 urine specimens submitted in urine preservative tubes for routine culture. For slide centrifuge Gram staining. each urine sample was mixed well. Thereafter. 0.2 mL of each sample was placed. using a pipette. into a slide centrifuge chamber and centrifuged at 2.000 rpm for 5 minutes. The slides were heat fixed. Gram stained. and read by laboratory personnel who scanned 12 consecutive oil-immersion fields using a set pattern. The presence of the same organism in six or more fields was defined as a positive urine screen. Urine samples were cultured using a 0.001-mL loop and a comparison of culture growth with slide centrifuge screening was made. When growth of 100.000 or more colony-forming units per milliliter (CFU/mL) was the reference for comparison. the screen had a sensitivity rate of 98%. a specificity rate of 90%. a negative predictive value of 99%. and a positive predictive value of 65%. When a lower colony count of 10.000 or more CFU/mL was the reference for comparison. the screen had a sensitivity rate of 88%. a specificity rate of 95%. a negative predictive value of 96%. and a positive predictive value of 84%. The slide centrifuge Gram stain is a very sensitive screening method to detect bacteriuria in an adult male population.
Serum lactate dehydrogenase-3 isoenzyme in chronic granulocytic leukemia, Abnormal levels of serum lactate dehydrogenase-3 (LD-3) activity were observed in 92% of patients (35 of 38) with active chronic granulocytic leukemia (CGL). in 40% of patients (4 of 10) in partial remission. and in 13% of patients (1 of 8) in complete remission. In evaluating the electrophoretic LD isoenzyme patterns of these patients. three criteria were used. In criterion-1 elevations. the LD-3/total LD ratio. expressed as a fraction of serum total LD. and LD-3 value. expressed in absolute units. were greater than the upper limit of the reference range. In criterion-2 elevations. only the LD-3/total LD ratio was greater than the upper limit of the reference range. In criterion-3 elevations. only the absolute LD-3 activity exceeded the upper limit of the reference range. and these specimens showed isomorphic elevation of all five LD isoenzymes. Use of the last of these criteria increased the clinical sensitivity of serum LD-3 elevations in active CGL from 82% to 92%. The mean serum LD-3 absolute value and serum total LD activity usually showed statistically significant differences (P less than 0.05) among patients with active CGL. those in partial remission. and those in complete remission. but did not distinguish between subgroups of individuals with active CGL. Elevation of the serum LD-5/total LD ratio in 16 of 58 patients was due to hepatic injury or methodologic imprecision. showing analytically insignificant. borderline abnormalities in all cases of active CGL. In 10 of 62 patients in complete remission or partial remission. however. such elevation was unexplained. Our results indicate that the evaluation of serum LD-3 values in both absolute and relative terms slightly increases the clinical sensitivity of LD-3. and. therefore. suggest that LD-3 might be a useful marker for CGL.
High-molecular-weight alkaline phosphatase in serum has properties similar to the enzyme in plasma membranes of the liver, Partially purified high-molecular-weight alkaline phosphatase from serum was compared with two other forms of the enzyme from the human liver. enzyme in native plasma membranes and purified alkaline phosphatase as a hydrophilic dimer. In a high-molecular-weight form from serum and plasma membranes. and when treated with 1% (v/v) Triton X-100. alkaline phosphatase showed a major band on gradient gel electrophoresis with a mobility equivalent to 400 kD. Nondetergent-treated material from both sources did not enter the gel and was in the voided volume of a gel permeation column. Stimulation of catalytic activity by four different phospholipids and by albumin yielded similar results for high-molecular-weight alkaline phosphatase and for the enzyme in plasma membranes. but these were different from the hydrophilic form. Inhibitors of alkaline phosphatase had similar effects on all forms. Of the three forms of the enzyme. only the hydrophilic dimer did not become incorporated into liposomes or adsorb to octyl-Sepharose after solubilization with Triton X-100 and removal of the detergent. Km (substrate concentration to give half maximal velocity) values with p-nitrophenylphosphate and heat and sodium dodecyl sulfate stabilities were similar for all forms. In the high-molecular-weight form from serum and in plasma membranes. alkaline phosphatase and 5'-nucleotidase showed similar rates of release by phosphatidylinositol phospholipase C. Three preparations of phospholipase D failed to release alkaline phosphatase from either the high-molecular-weight form or from plasma membranes. Based on these similarities. it is probable that the complex of high-molecular-weight alkaline phosphatase in serum most often originates from fragments of hepatic plasma membranes.
The role of gene rearrangements for antigen receptors in the diagnosis of lymphoma obtained by fine-needle aspiration. A study of 63 cases with concomitant immunophenotyping, To assess the efficacy of performing genotyping in addition to immunophenotyping as an adjunct to cytologic diagnosis. 63 consecutive patients with fine-needle aspirates of lymphoproliferative lesions who had concurrent immunophenotyping and genotyping performed on fine-needle aspirate cell suspensions were studied. Thirty-nine of 63 specimens (62%) that appeared to contain non-Hodgkin's lymphoma and that proved to be of B-cell lineage by genotyping were accurately phenotyped and shown to be monotypic for immunoglobulin light chains by cell suspension immunocytochemistry. Genotyping facilitated lineage assignment and/or confirmed clonality in 17 of 63 specimens (27%) that were difficult to determine based on morphologic data. These include cases of atypical lymphoid proliferations with polyclonal or inconclusive markers (n = 6). peripheral T-cell lymphoma (n = 3). extracutaneous mycosis fungoides (n = 1). lymphoblastic lymphoma (n = 4). null cell lymphoma (n = 1). and specimens with equivocal or technically unsatisfactory markers (n = 2). Based on these results. it is proposed that genotyping for lineage assignment and/or clonality be performed to include cases of atypical lymphoid proliferations. T-cell malignant neoplasms. lymphoid malignant neoplasms with equivocal markers. and differentiation of lymphoid from nonlymphoid neoplasms. Genotyping by antigen-receptor gene rearrangement appears to be redundant in cases with mature B-cell phenotypes that demonstrate monoclonality by immunophenotyping.
Intraplatelet serotonin, beta-thromboglobulin, and histamine concentrations and thromboxane A2 synthesis in renal disease, Intraplatelet serotonin (5-HT). beta-thromboglobulin (beta-TG). and histamine content as well as platelet total thromboxane A2 (TXA2) synthesizing capacity were measured in 53 patients with chronic renal disease: nephrotic syndrome (n = 18); end-stage renal failure (ESRF; n = 13); continuous ambulatory peritoneal dialysis (CAPD; n = 9); hemodialysis (HD; n = 13). These indices of platelet function were correlated with plasma total cholesterol (TC). low-density lipoprotein cholesterol (LDL-C). high-density lipoprotein cholesterol (HDL-C). and triglyceride (TG) concentrations. When compared with controls. intraplatelet 5-HT was significantly reduced in all patient groups studied and beta-TG was diminished in all patient groups except CAPD. Total platelet TXA2 synthesizing capacity was increased in ESRF and HD groups. Intraplatelet histamine content was not altered in any of the patient groups studied. There was a significant inverse correlation between intraplatelet 5-HT content on the one hand and plasma TC. LDL-C. and TG on the other. The depletion of intraplatelet 5-HT and beta-TG and the increase in total TXA2 synthesizing capacity are consistent with platelet activation in chronic renal disease. The correlation between these indices of platelet activation and TC. LDL-C. HDL-C. and TG suggests that changes in the concentrations of these lipids may contribute to the activation of platelets in these conditions.
Tumor proliferative fraction in solid malignant neoplasms. A comparative study of Ki-67 immunostaining and flow cytometric determinations, Tumor proliferative fraction (TPF) has been shown to correlate with prognosis in some malignancies. A method for its determination that is practical. accurate. and reproducible is still being sought. In this comparative study of techniques. TPF values were determined in mirror-image samples of 126 consecutive solid malignant neoplasms using flow cytometry and immunostaining with Ki-67. a monoclonal antibody that recognizes an unknown nuclear antigen expressed during the entire cell proliferation cycle but not in resting cells. The mean TPF values for all cases were 19.5 +/- 15.6% (percentage of tumor cells stained) by Ki-67 (range. 1-86%) and 15.7 +/- 9.6% (S + G2M) by flow cytometry (range. 3-60%). which correlated significantly at r = 0.53 and P = 0.005. The correlation was less strong in tumors with low S-phase values (less than or equal to 10%. r = 0.28) than in tumors with intermediate and high S-phase values (r = 0.66). Ki-67 staining percentages did not correlate with patient age. sex. or tissue origin of the tumor. Ki-67 staining appears comparable to flow cytometry determination of TPF in solid malignancies with intermediate and high S-phase values. In tumors with low S-phase values. Ki-67 immunostaining shows higher TPF values. which perhaps reflect an increase in the proportion of G1-phase cells or dilutional effect of nonneoplastic cells in the tumors with low proliferative fraction.
Glassy cell features in adenosquamous carcinoma of the uterine cervix. Histologic, ultrastructural, immunohistochemical, and clinical findings, Glassy cell features (GCF) were identified as composing a predominant pattern (more than 85% of histology) in six cases and a focal pattern (33-85% of histology) in 10 cases of a series of 53 adenocarcinomas (AC) and adenosquamous carcinomas (ADSQ) of the uterine cervix. In three cases examined ultrastructurally. GCFs correlated with many cytoplasmic polyribosomes and abundant rough endoplasmic reticulum. but Golgi complexes and tonofilaments were scant and intracytoplasmic lumina were absent. Intracellular mucin was present in the areas showing GCFs of four ADSQs with predominant GCFs and six ADSQs with focal GCFs. Two of three cases examined ultrastructurally showed intracellular electron-dense material that corresponded to mucin secretory material. Immunohistochemical studies of the six ADSQs with predominant GCF cases showed the following pattern of reactivity: monoclonal carcinoembryonic antigen (CEA). 2 of 6 cases; polyclonal CEA. 3 of 6; CA 125. 0 of 6; CA 19-9. 0 of 6; placental alkaline phosphatase. 0 of 6; and vimentin. 1 of 6. Focal GCF areas showed monoclonal CEA. 4 of 9 cases; polyclonal CEA. 3 of 9; vimentin. 4 of 9; while CA 125. CA 19-9. and placental alkaline phosphatase were negative in areas of GCFs. One of three patients with ADSQ with predominant GCFs and five of nine patients with ADSQ with focal GCFs with at least 1 year of follow-up were disease free. No association between GCFs (combined focal and predominant) and recurrent disease was present when compared to the other 29 AC and ADSQ patients with follow-up. Recurrent disease in our series of AC and ADSQ was only associated with stage III or IV disease at presentation (P less than 0.001). There was no association with adenosquamous histology. histologic grade. lymphatic invasion. or age. There were insufficient cases of ADSQ with predominant GCFs with follow-up to evaluate fully prognostic significance of this subgroup. Our study suggests that GCFs are part of the spectrum of differentiation in ADSQ of the cervix rather than a distinct histologic type of carcinoma with unique clinical significance.
Ovarian cancer screening: potential effect on mortality, Serum tumor markers and ultrasonography are being investigated as possible ovarian cancer screening tests. Data from the United States on ovarian cancer incidence and survival were used to estimate the potential benefit on ovarian cancer mortality from screening tests of various sensitivities. A test with 80% sensitivity could reduce ovarian cancer mortality by 50% if all screening-detected cases were to experience current stage I survival rates; the benefit would be greatest among women aged 45 or older. For each cancer detected there would be at least 50 false-positive screening tests unless test specificity is greater than 98%. If our most optimistic assumptions about screening could be met. then universal periodic screening of women aged 45 to 74 would result in about 5000 additional 5-year survivors of ovarian cancer annually. Uptake of existing screening tests is far less than universal; thus we would expect the impact of any ovarian cancer screening program to fall short of these projections.
Short-term variation in abnormal antenatal fetal heart rate records, In a retrospective study the relation of reduced fetal heart rate variation to fetal acidemia was analyzed with a computerized system for numeric analysis. Between 1983 and 1987. 78 pregnancies were identified in which at least one record of the fetal heart rate had very low long-term variation. The outcome was analyzed to determine the numeric criteria of fetal heart rate variation that most efficiently detect a fetus that will die (preterminal) or is dying (terminal). Because fetal compromise was found on occasion to be associated with a slow sinusoidal fetal heart rate rhythm that increased measures of long-term variation. It was necessary to define a new index of short-term fetal heart rate variation (the 1/16 minute epoch-epoch variation). This was closely related to long-term variation (r = 0.9) but provided better detection of preterminal records as judged by metabolic acidemia at delivery or intrauterine death.
Hypoplastic left heart syndrome: prenatal diagnosis, clinical profile, and management, We diagnosed hypoplastic left heart syndrome. generally regarded as a lethal congenital heart defect. by fetal echocardiography in 20 pregnancies in the last 5 years. The clinical profile. management. and outcome of these pregnancies were reviewed. We found a 40% association of karyotype and extracardiac malformations. Elective abortion was performed in nine pregnancies. Two of seven live-born babies had early neonatal assessment and intervention as a result of in utero diagnosis and counseling. Prolonged survival was achieved in both infants. We conclude that prenatal diagnosis of the hypoplastic left heart syndrome necessitates complete evaluation of the fetus for associated genetic and extracardiac malformations. Prenatal diagnosis of this defect provides opportunities for in depth counseling of parents and obtaining informed consent for either postnatal intervention or nonintervention before the medical and emotional complexities associated with the neonatal intensive care setting are encountered.
Use of hydroxyurea in chronic myeloid leukemia during pregnancy: a case report, The concomitant occurrence of pregnancy and chronic myeloid leukemia is uncommon. The use of hydroxyurea in chronic myeloid leukemia during pregnancy is unknown. We report on a patient with chronic myeloid leukemia in whom hydroxyurea was used during pregnancy with a successful outcome for both mother and fetus.
Oral tocolysis with magnesium chloride: a randomized controlled prospective clinical trial, A prospective randomized clinical trial was conducted to assess the efficacy and safety of enteric-coated magnesium chloride (SLOW MAG) as an oral tocolytic agent. Seventy-five patients between 24 and 34 weeks' gestation who were treated with intravenous magnesium sulfate for a first episode of preterm labor were enrolled. After a 12-hour contraction-free period on intravenous therapy. patients were randomized by sealed envelope to one of three groups: group 1. SLOW MAG (535 mg every 4 hours); group 2. oral ritodrine (20 mg every 4 hours); or group 3. no therapy (control). Patients receiving oral therapy were treated until delivery or completion of 36 weeks' gestation. No difference was found between groups with respect to time gained with the use of oral therapy or number completing 36 weeks' gestation. Therapy with enteric-coated magnesium chloride was associated with significantly fewer side effects (20%) as compared with ritodrine (48%) (p less than 0.01). Our results suggest that compared with ritodrine. enteric-coated magnesium chloride is as effective in prolonging pregnancy and preventing recurrent preterm labor. However. neither enteric-coated magnesium chloride nor ritodrine appeared to be any more effective in the prevention of preterm delivery than observation alone.
Vasopressin and operative hysteroscopy in the management of delayed postabortion and postpartum bleeding, Two women. one with refractory postabortion hemorrhage and the other with refractory postpartum hemorrhage. were managed with vasopressin. operative hysteroscopy. and a dilute vasopressin pack. Both patients had been treated by standard methods (i.e.. dilation and curettage) and both were being prepared for a surgical intervention procedure. It was decided in both cases to try to slow the bleeding by injection of vasopressin paracervically and then performance of operative hysteroscopy. In both cases. the injection of dilute vasopressin paracervically when coupled with operative hysteroscopy was quite effective in determining the cause of the bleeding and was instrumental in avoiding major operative procedures.
Expression and amplification of the HER-2/neu (c-erbB-2) protooncogene in epithelial ovarian tumors and cell lines, Amplification of the c-erbB-2 protooncogene has been associated with a poor prognosis in human breast and ovarian cancers. Our study was undertaken to examine whether amplification. rearrangement. or overexpression of c-erbB-2 and other protooncogenes was frequently observed in epithelial ovarian cancers. c-erbB-2 was expressed in 87% of 22 ovarian cancers analyzed. but expression was significantly increased in only one of the 22 tumor specimens. In this case elevated c-erbB-2 expression was associated with dramatic amplification of the gene. In another tumor a 3.8 kb EcoRI fragment was found. in addition to the usual 4.4 and 6.0 kb fragments; this is consistent with a possible gene rearrangement or a restriction fragment length polymorphism. To place these results in perspective. expression of several other protooncogenes has been examined in ovarian carcinomas. The c-fos. c-myc. n-myc. c-fms. and c-Ha-ras protooncogenes were expressed in different fractions of tumors. but expression of l-myc. c-erbB. c-myb. c-sis. and c-mos was not detectable. Aside from c-erbB-2. neither amplification nor rearrangement was observed among the other protooncogenes studied. Expression of c-erbB-2. c-fms. c-myc. n-myc. c-fos. and c-Ha-ras deserves further evaluation as a prognostic factor in ovarian cancer.
Adverse psychologic consequences of positive cytologic cervical screening, Cervical cancer is still widely prevalent in the female population. This study explores the relationship of cervical cancer screening. positive versus negative Papanicolaou's test results. and psychologic status among lower-income minority women. All patients were interviewed 3 months after they had received initial test results. One hundred six women with normal Papanicolaou's test results were compared with 118 women who were referred for colposcopic examination for follow-up of positive test results. Women with positive Papanicolaou's-test results showed statistically significant elevations in worries about cancer and impairments in mood. daily activities. sexual interest. and sleep patterns. More fine-grained analyses revealed that the effects of positive results were most pronounced among those women who did not comply with colposcopy (n = 53). These findings suggest that lack of compliance with follow-up may maintain high levels of uncertainty about disease and may interfere with successful psychologic adaptation. Health education targeted to psychologically vulnerable individuals may reduce psychologic distress and enhance compliance.
Prospective evaluation of maternal serum human chorionic gonadotropin levels in 3428 pregnancies, As part of a multicenter prospective study. second-trimester human chorionic gonadotropin and alpha-fetoprotein concentrations were evaluated. Data included maternal age. human chorionic gonadotropin level. alpha-fetoprotein level. weight. race. and pregnancy outcome of 3428 pregnancies at between 15 and 20 weeks' gestation. The results of the study indicate that human chorionic gonadotropin levels decrease as maternal weight increases. that weight-adjusted human chorionic gonadotropin levels for Oriental and black women are higher than for white or Hispanic women. and that twin pregnancies have higher human chorionic gonadotropin levels than singleton pregnancies. Of 255 pregnancies that did not have normal outcomes. 54 (21.2%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median and 26 (10.2%) had alpha-fetoprotein levels greater than 2.5 multiples of the median. Of 11 pregnancies with fetal aneuploidy. 6 (54.5%) had human chorionic gonadotropin levels greater than 2.0 multiples of the median. It is concluded that in human chorionic gonadotropin screening programs for fetal Down syndrome. weight and race adjustments are necessary for accurate risk assessment.
Effectiveness of antibiotic prophylaxis in preventing bacteriuria after multichannel urodynamic investigations: a blind, randomized study in 124 female patients, One hundred twenty-four women with chronic. persistent lower urinary tract symptoms who had been scheduled for elective urodynamic investigations at Mount Sinai's Urodynamic Investigative Unit were divided into two blind. randomized groups. receiving either a placebo or prophylactic antibiotic. At the time of urodynamic testing. the rate of unsuspected urinary tract infection was 8.1%. There was no statistically significant decrease in postinstrumentation infection rate in the group who received prophylactic antibiotics. We conclude that. given in the fashion described in the study. prophylactic antibiotics are not effective in preventing urinary tract infections caused by urodynamic testing.
Expression of cytokine receptors and markers of differentiation in human papillomavirus-infected cervical tissues, Human papillomavirus infection of the uterine cervix is associated with a spectrum of benign. premalignant. and malignant epithelial lesions. a process that appears to require the coordinated effects of secondary cellular and environmental events. We have used flow cytometry and immunohistochemistry to examine the expression of the cellular markers for proliferation (interleukin-1. epidermal growth factor receptor. and transferrin receptor) and the markers of cellular differentiation (filaggrin and low-molecular-weight cytokeratin) in normal and human papillomavirus--infected human cervical tissues representing the natural range of human papillomavirus--induced disease. The results were correlated with the histologic grade of disease. human papillomavirus type. cellular deoxyribonucleic acid content. and cell cycle status. Interleukin-1 and transferrin receptor were slightly increased in high-grade dysplasias and in squamous cell carcinomas. Filaggrin expression was found to be inversely related and cytokeratin and epidermal growth factor receptor expression directly related to the degree of neoplasia. These findings indicate that cytokeratin and epidermal growth factor receptor are useful markers of cell proliferation in human papillomavirus--infected tissues and that their expression may directly increase as a result of infection.
Prenatal diagnosis of fetal cytomegalovirus infection, Twelve fetuses were evaluated with a combination of ultrasonography. amniocentesis. and blood sampling for possible cytomegalovirus infection. In seven the mother had a documented primary cytomegalovirus infection. All seven women had normal ultrasonographic findings and one fetus was found to be infected. In the other five cases fetal cytomegalovirus infection was diagnosed in association with abnormal ultrasonographic findings. There was no history of maternal infection in the latter group. All positive and negative diagnoses were confirmed and none of the six infected fetuses survived. In this series. the most reliable parameters of infection were the isolation of the virus from amniotic fluid and elevations of total immunoglobulin M and gamma-glutamyl transpeptidase in fetal blood. In the majority of infected fetuses cytomegalovirus-specific immunoglobulin M was not detected in blood. Prenatal diagnosis of fetal cytomegalovirus infection is possible with a combination of amniocentesis and fetal blood sampling.
Increased inducibility of inflammatory mediators from peripheral blood mononuclear cells of women with salpingitis, To investigate whether immune system activation may contribute to the tissue damage observed in salpingitis. we isolated peripheral blood mononuclear cells and quantitated production of the monocyte activation products tumor necrosis factor-alpha. interleukin-1. and interleukin-6. Unstimulated cells from 7 of 20 women with salpingitis spontaneously released tumor necrosis factor at a concentration greater than 2 SD above the mean value produced by cells from 29 healthy donors. Interferon gamma (200 U/ml) further induced production of tumor necrosis factor from mononuclear cells of 11 women with salpingitis. In contrast. production of tumor necrosis factor by each of 23 other patients who lacked laparoscopic or clinical evidence of salpingitis was similar to that of the controls. In a subset of women whose cells were tested for production of other monokines. three of nine women with salpingitis spontaneously released interleukin-1 but none of the others did so. Four of nine patients with salpingitis also produced interleukin-6. but none of the others did so. None of the monokines were detected in serum from any subject. The results suggest that monocytes from women with salpingitis are primed in vivo and produce inflammatory mediators under conditions where monocytes from other women are poorly responsive. This increased monokine inducibility may contribute to the tubal damage that is the hallmark of salpingitis.
In utero fetal muscle biopsy for the diagnosis of Duchenne muscular dystrophy, Deoxyribonucleic acid techniques can be used to diagnose Duchenne muscular dystrophy prenatally in male fetuses that are at risk. Deoxyribonucleic acid-based prenatal diagnosis can be impossible when there is only one prior affected male and there is no identifiable deletion or alteration. We performed fetal muscle biopsy in utero in such a case and documented the presence of dystrophin. thereby confirming normality in a male fetus at risk. This first in utero experience adds fetal muscle biopsy to the available procedures for fetal tissue diagnosis.
Pemphigus gestationis (herpes gestationis): a case report, Pemphigus gestationis is a rare disease. probably of immunologic origin. that causes the placenta to absorb immunoglobulins and deposit them in its basement membrane. The resulting placental insufficiency leads to increased morbidity and mortality among the offspring of such patients. A case of pemphigus gestationis is presented. and the importance of early diagnosis is discussed.
The effect of interleukin-1 on adhesion formation in the rat, The potential role of interleukin-1 in postoperative adhesion formation was examined. Cecal abrasion gave a consistently higher adhesion score when compared with sham laparotomy. on the basis of adhesion number. density. and vascularity. and so was chosen for use in further studies. The extent of serosal bleeding during cecal abrasion did not affect adhesion scores. Intraperitoneal injection of 10 micrograms murine recombinant interleukin-1 alpha in cecally abraded animals on the day of surgery and on the following 4 days resulted in a significant increase in adhesion scores when compared with those of cecally abraded animals injected with vehicle alone. Adhesions enhanced with murine recombinant interleukin-1 alpha. which were thicker and more vascular. were equivalently enhanced at doses from 10 to 10.000 ng. implying maximal response over that range. Rats not operated on and receiving recombinant interleukin-1 alpha 2 weeks after injury had increased adhesion formation. These results demonstrate that interleukin-1 alpha may be an important short-term mediator of postsurgical adhesion formation.
Thermal effects and histologic changes from Nd:YAG laser irradiation on normal and diseased aortic tissue using a novel angioplasty catheter with a mobile optical fiber: an in vitro assessment, Although various laser angioplasty devices are currently being examined. thermal damage and perforation of the vessel wall remains the major acute complication of vascular laser recanalization. Consequently. the aim of this study was to investigate the thermal effects and histologic changes from laser irradiation (Nd:YAG. 1064 nm) on normal and diseased aortic tissue using a novel angioplasty device. During laser emission the coaxially guided optical fiber tip was positioned in reference to the end hole of the metallic capped probe as follows: (1) at the end hole (metal-cap position). (2) protruding 10 mm from that end hole (bare-fiber position). (3) withdrawn 5 mm into the metal cap's lumen (hot-tip position). In total. 96 laser impacts (25 joule: 5 W. 5 s. each) were produced on normal and atherosclerotic aorta in air through a 0.2-mm-core-diameter silica quartz fiber. with direct contact on the intimal surface of the target tissue by both the fiber and the metal cap and by either the fiber or the metal cap (n = 32 each). Tissue temperature was measured by means of special sensors positioned opposite the irradiated intimal spot in direct contact with the adventitial surface. Morphohistologic evaluation of lesions was performed and injury indexes were determined.
Same-day angioplasty and diagnostic catheterization: safe and effective but riskier in unstable angina, Percutaneous transluminal coronary angioplasty was performed at the time of the diagnostic catheterization in 188 patients (215 lesions) at a University Hospital in order to assess the efficacy of this approach and the potential role it should play in the evaluation and treatment of patients. Patients either presented for diagnostic catheterization for evaluation of stable coronary disease (79 patients) or for unstable or new onset anginal symptoms (109 patients). Lesions were graded as to whether they were simple or complex; and post angioplasty films were reviewed for success rate. and degree of revascularization. Patients who were referred for stable anginal symptoms had a slightly higher success rate (91%) compared to those who were referred for new onset or more unstable symptomatology (85%. p = ns). Additionally. lesions morphology was judged to be more complex in unstable patients. as 67% had complex lesions with the presence of thrombus or ulcerated plaque in 56% of these stenoses. Angioplasty success was high for simple lesions in all patients. but was most unfavorable for complex stenoses in patients who presented with unstable symptoms (81% success rate). In patients who presented with new onset or unstable symptoms multivessel disease was present in 69% and angioplasty was more often geared at dilating a culprit stenosis leaving only 49% of these patients with complete revascularization. On the other hand. in 76% of those patients who presented with stable angina complete revascularization was a common outcome. Length of hospital stay was considerably shorter at 2.9 +/- 0.8 days in those patients who presented with stable symptoms.
Quantitation of early myocardial ischemia using acridine orange fluorescence--an experimental study, It has been observed in the present investigation that ischemic myocardium consistently produces bright green fluorescence after Acridine Orange (AO) staining. The area of ischemia in the left ventricular myocardium at different time intervals after onset of experimental ischemia has been calculated by use of this AO fluorescence technique. Zonal distribution of ischemia in the epicardial. middle. and endocardial zones has also been evaluated quantitatively from ten minutes to six hours after ligation of the anterior descending branch of the left coronary artery in the Wistar strain of albino rats. No similar study was available for comparison from the literature reviewed. The total area of left ventricular ischemia showed an increase with the prolongation of duration of coronary ligation from 13.39 +/- 2.69 mm2 at ten to twenty-five minutes to 32.99 +/- 5.69 mm2 at six hours after ligation. Statistical analysis of the zonal area of ischemia has shown that ischemia in the middle and endocardial zones was greater than that in the epicardial zone at all time intervals recorded. Middle zone ischemia extended over a larger area than that over the endocardial zone at all intervals except at intervals II (30-45 min). IV (2-2 1/2 hrs) and V (3-4 hrs). The results of this experimental investigation are significant for these point to the value of Acridine Orange fluorescence in detecting early myocardial ischemia and in demarcating zonal differences in ischemia. The authors have successfully utilized the method in a few human cases of clinically suspected myocardial infarction and recommend the technique for routine use to detect early human myocardial ischemia.
Silent ischemia and severity of pain in acute myocardial infarction, An overall low tendency to complain of pain. due to a low perception of pain. has been suggested in the pathogenesis of silent ischemia. independent of the extent of the diseased coronaries and a history of previous acute myocardial infarction. This hypothesis has been tested indirectly in this retrospective study by comparison of the use of analgesics during admission for a first acute myocardial infarction with the occurrence of silent ischemia at exertion tests four weeks after discharge from hospital. The study did not show a lower use of analgesics in patients with silent ischemia. but this may be due to methodologic problems. Suggestions are given for another study design to overcome these problems.
The influence of CLS 2210 on the course of myocardial infarction: a pilot study in man, To assess the effect of CLS 2210 (a new formulation of calcium dobesilate) on the evolution of acute myocardial infarction. 100 patients presenting their first infarct were distributed. according to their sequential admissions to the hospital. into CLS 2210-treated group (50 patients) or a comparison group (50 patients not receiving CLS 2210). The two groups were similar in age. sex. predisposing factors. and site of infarction. Intravenous infusion of CLS 2210 was begun within six hours of onset of chest pain and continued for seventy-two hours. Thereafter. it was given. as oral capsules. in a dose of 1.000 mg every eight hours throughout the hospitalization. Before and during the trial. blood samples were drawn for the measurements of serum concentrations of creatine kinase (CK). and twelve-lead electrocardiograms (ECGs) were obtained serially in each patient. All objective data were analyzed on a coded basis without reference to the treatment. In the comparison group. thirty-six to forty-eight hours was required for CK to fall to 50% of the baseline value. whereas in the CLS 2210-treated group it reached 50% of the baseline in eighteen to twenty-four hours. For each infarction site. a statistically significant fall was reached earlier in the CLS 2210 group. CK. the ECG index. and the sum of the ST segments showed earlier and more rapid improvement in the CLS 2210 group than in the comparison group. The consumption of narcotic analgesic agents and nitroglycerin was substantially less in the CLS 2210 group than in the comparison group.
Impedance cardiography for repeated determination of stroke volume in elderly hypertensives: correlation with pulsed Doppler echocardiography, In this double-blind. crossover study the authors have validated stroke volume determination by impedance cardiography against the pulsed Doppler echocardiographic method in elderly hypertensives. They found a good correlation between the stroke volume values obtained by the two methods over a range of values from 30 to 130 mL. The coefficient of linear regression was about .95 at each visit. The mean of the differences was -0.73 mL with a standard deviation of 8.46. Given that individual differences are normally distributed. the values corresponding to 2 standard deviations of the mean define a range covering 95% of the observed differences. From the distribution of the data around the mean plot it appears that. in comparison with pulsed Doppler. impedance cardiography tends to slightly underestimate stroke volumes of greater than 90 mL and to overestimate values of less than 50 mL. The results of this study indicate that impedance cardiography may represent a reliable alternative to pulsed Doppler echocardiography for the noninvasive estimation of cardiac output at rest in elderly patients.
Serum lipoprotein (a) levels in men with peripheral vascular disease, The authors quantified serum lipoprotein (a) (Lp) (a) by enzymo-immuno-analysis in 86 outpatient men suffering peripheral vascular disease (PVD) and in 53 age-matched healthy men. They further measured serum cholesterol. serum triglycerides. low density lipoproteins-cholesterol. high density lipoproteins (HDL)-cholesterol and serum apolipoprotein B. Serum triglycerides were significantly increased in patients with PVD versus controls (148 +/- 8 and 114 +/- 7 mg/dL. mean +/- SEM). HDL-cholesterol levels were significantly lower in patients versus controls (36 +/- 1 and 43 +/- 2 mg/dL. respectively). Serum Lp(a) levels in patients with PVD were 20 +/- 2 mg/dL. whereas in controls they were 16 +/- 3 (p: NS). Serum Lp(a) concentrations were identical in smoker and nonsmoker patients. There was no correlation between Lp(a) concentration and the other lipid parameters. Conversely. as occurs in coronary heart disease and in cerebrovascular disease. Lp(a) does not seem to be a marker for PVD. although a trend toward a higher mean levels was found.
Striking CT scan findings in a case of unilateral moyamoya disease--a case report, The authors report striking CT scan findings in a young woman with unilateral Moyamoya disease. Serial CT scans showed features that paralleled the clinical and pathophysiologic evolution of the disorder. in much the same way as has been reported in studies using serial angiograms.
Effect of weight loss on upper airway collapsibility in obstructive sleep apnea, Previous investigators have demonstrated in patients with obstructive sleep apnea that weight reduction results in a decrease in apnea severity. Although the mechanism for this decrease is not clear. we hypothesize that decreases in upper airway collapsibility account for decreases in apnea severity with weight loss. To determine whether weight loss causes decreases in collapsibility. we measured the upper airway critical pressure (Pcrit) before and after a 17.4 +/- 3.4% (mean +/- SD) reduction in body mass index in 13 patients with obstructive sleep apnea. Thirteen weight-stable control subjects matched for age. body mass index. gender (all men). and non-REM disordered breathing rate (DBR) also were studied before and after usual care intervention. During non-REM sleep. maximal inspiratory airflow was measured by varying the level of nasal pressure and Pcrit was determined by the level of nasal pressure below which maximal inspiratory airflow ceased. In the weight loss group. a significant decrease in DBR from 83.3 +/- 31.0 to 32.5 +/- 35.9 episodes/h and in Pcrit from 3.1 +/- 4.2 to -2.4 +/- 4.4 cm H2O (p less than 0.00001) was demonstrated. Moreover. decreases in Pcrit were associated with nearly complete elimination of apnea in each patient whose Pcrit fell below -4 cm H2O. In contrast. no significant change in DBR and a minimal reduction in Pcrit from 5.2 +/- 2.3 to 4.2 +/- 1.8 cm H2O (p = 0.031) was observed in the "usual care" group. We conclude that (1) weight loss is associated with decreases in upper airway collapsibility in obstructive sleep apnea. and that (2) the resolution of sleep apnea depends on the absolute level to which Pcrit falls.
Influence of posture and sustained loss of lung volume on pulmonary function in awake asthmatic subjects, Nocturnal worsening occurs commonly in the asthmatic patient population and contributes substantially to the morbidity and even mortality of asthma. However. no physiologic process has yet been identified as the major contributor to this pattern. Sleep is typically associated with both the supine posture and substantial decrements in lung volume. and both have been proposed to have a role in the pattern of nocturnal worsening. To assess the effects of posture and sleep-associated reductions in functional residual capacity on pulmonary function. eight asthmatic patients were first monitored overnight in a horizontal volume-displacement body plethysmograph to determine mean FRC during sleep for each subject. We then compared. during wakefulness. the effects on FEV1 and methacholine responsiveness from chest wall and abdomen strapping (to maintain FRC at mean sleep levels) for 6 h in the supine and upright postures. FEV1 was significantly decreased after strapping in the supine posture (2.54 +/- 0.36 versus 3.38 +/- 0.29 L on control day. p = 0.0001) but was not affected by strapping in the upright posture (3.07 +/- 0.30 versus 3.34 +/- 0.31 L on control day. not significant. NS). Bronchial responsiveness to methacholine was not altered after strapping in either posture. These observations suggest that the supine posture. in conjunction with the reduction in lung volume associated with sleep. may contribute to the nocturnal worsening of asthma.
The influence of cigarette smoking on lung function in patients with idiopathic pulmonary fibrosis, The purpose of this investigation was to quantify the effect of cigarette smoking on standard measures of lung function in patients with idiopathic pulmonary fibrosis (IPF). Our study population consisted of 73 patients in whom IPF had been clinically diagnosed; in 67% the diagnosis was confirmed by open lung biopsy. The average age was 63 yr; 62% were men. and 70% were either former or current cigarette smokers. Current cigarette smokers were found to have a greater percent predicted residual volume. Interestingly. in a univariate analysis. pack-years of cigarette smoking was found to be directly associated with increased measures of lung volumes (TLC. FRC. and RV) and diminished gas exchange (DLCO). Linear multivariate regression models demonstrated that current cigarette smokers have greater measures of RV and FRC and that increasing pack-years of cigarette smoking is associated with diminished gas exchange. Importantly. the FEV/FVC ratio was not significantly related to either smoking status or pack-years of cigarette smoking. Results from our study indicated that among patients with IPF. current cigarette smokers will tend to trap air (higher RV and FRC). and that cigarette smoking appears to adversely alter gas exchange. Moreover. IPF appears to reduce the likelihood of developing physiologic correlates of airflow obstruction among cigarette smokers. However. this does not imply that IPF prevents the development of cigarette-induced lung disease. In fact. the association between cigarette smoking and both increased lung volumes and diminished gas exchange suggests the presence of both emphysema and interstitial fibrosis.
Changes in end-expiratory lung volume during exercise in cystic fibrosis relate to severity of lung disease, Changes in end-expiratory lung volume (EELV) during exercise in normal subjects and in patients with severe chronic obstructive lung disease have previously been examined. To date there are no studies that have examined the changes in EELV in patients with mild to moderate lung disease. We studied the changes in EELV during exercise in patients with cystic fibrosis (CF) with a wide range of pulmonary impairment to determine if changes in EELV were related to the severity of lung disease. Twenty-two patients with CF were studied (FEV1 17 to 112% of predicted) during progressive bicycle exercise. and changes in EELV were determined by repeat measures of inspiratory capacity. Changes in EELV at end exercise ranged from an increase of 0.67 L to a decrease of 0.61 L. and significant relationships were found between the changes in EELV and resting lung function (FEV1 percent predicted r = 0.79 and VR/TLC r = 0.58). indices of maximal expiratory flow (FEF50 r = -0.72 and FEF25-75 r = -0.71). and maximal work capacity (W-Max r = -0.76 and W-Max percent predicted r = -0.69). For subsequent analysis. patients were divided into two subgroups. Patients who were able to decrease EELV during exercise (Subgroup A) had significantly better resting lung function and SaO2 and significantly higher W-Max. peak oxygen consumption. and SaO2 at W-Max. Patients in Subgroup A also had a near normal ventilatory pattern during exercise. In contrast. the patients who increased EELV during exercise (Subgroup B) had severe lung disease (mean FEV1 29 +/- 4 percent predicted). limited work capacity. and desaturated during exercise.
Gas exchange during exercise in mild chronic obstructive pulmonary disease. Correlation with lung structure, To investigate whether or not the pathologic features in the lungs of patients with chronic obstructive pulmonary disease (COPD) are related to the gas exchange response during exercise. we studied 17 patients (15 men. two women) with mild-to-moderate airflow obstruction (FEV1/FVC ratio. 59 +/- 3%). undergoing resective lung surgery. at rest and during submaximal exercise (71 +/- 5% predicted VO2max). During exercise. arterial PO2 increased (from 81 +/- 3 to 86 +/- 3 mm Hg. p less than 0.05) as a result of an overall improvement in VA/Q relationships. This improvement included an increase in the mean VA/Q ratios of both ventilation and blood flow distributions. and a more homogeneous ventilation distribution (logSD V. from 0.66 +/- 0.06 to 0.50 +/- 0.03; p less than 0.01; normal value. less than or equal to 0.6). The morphologic evaluation of the resected specimens disclosed a moderate degree of emphysema (emphysema score. 16 +/- 4) and mild abnormalities in membranous bronchioles (total pathology score. 107 +/- 8). At rest. significant correlations were found between the severity of the pathologic findings and both the degree of hypoxemia and the extent of VA/Q mismatching. During exercise. no relationship between bronchiolar abnormalities and gas exchange measurements was observed. whereas the severity of emphysema was correlated with PaO2 (r = -0.54. p less than 0.05). Both the overall increase in and the more efficient distribution of ventilation accounted for the improvement in VA/Q distributions during exercise. These changes were more pronounced in patients with a greater degree of bronchiolar abnormalities.
Effects of positive end-expiratory pressure, lung volume, and inspiratory flow on interrupter resistance in patients with adult respiratory distress syndrome, Although it has been shown in normal subjects that airway resistance changes significantly with changes in lung volume and inspiratory flow. no studies have as yet examined these phenomena in patients with adult respiratory distress syndrome (ARDS). The effect of positive end-expiratory pressure (PEEP) on airway resistance in ARDS also is unknown. We have used the technique of rapid airway occlusion during constant-flow inflation to measure the interrupter resistance (Rint.rs). which in humans is thought to correspond to airway resistance. in nine patients with ARDS under different inflation flows and volumes. This procedure was carried out at four levels of PEEP (0. 5. 10. and 15 cm H2O). We found that (1) at constant inflation volume. Rint.rs did not change significantly with increasing flow; (2) at constant inflation flow. Rint.rs showed an initial decrease followed by a distinct rise with increasing lung volume; (3) on average. PEEP did not significantly change Rint.rs measured during baseline ventilation; and (4) this latter finding occurred because patients behaved differently with application of PEEP. depending on their degree of lung inflation: Rint.rs measured close to full inflation almost invariably exhibited a rise. but values obtained at lower volumes exhibited the characteristic decrease of Rint.rs with increasing inflation volume.
Effects of positive end-expiratory pressure on alveolar recruitment and gas exchange in patients with the adult respiratory distress syndrome, The effects of different levels of positive end-expiratory pressure (PEEP) (zero to 15 cm H2O) on the static inflation volume-pressure (V-P) curve of the respiratory system and on gas exchange were studied in eight patients with the adult respiratory distress syndrome (ARDS). Alveolar recruitment with PEEP was quantified in terms of recruited volume. i.e.. as difference in lung volume between PEEP and zero end-expiratory pressure (ZEEP) for the same static inflation pressure (20 cm H2O) from the V-P curves obtained at the different PEEP levels. In addition. static compliance of the respiratory system at fixed tidal volume (0.7 L) was determined at the different PEEP levels. The results suggest that: (1) in some patients with ARDS the V-P curves determined on ZEEP exhibit an upward concavity reflecting progressive alveolar recruitment with increasing inflation volume. and PEEP results in alveolar recruitment (range of recruited volume at 15 cm H2O of PEEP: 0.11 to 0.36 L); (2) in other patients with ARDS the V-P curves on ZEEP are characterized by an upward convexity. and PEEP results in a volume displacement along this curve without alveolar recruitment and with enhanced risk of barotrauma; (3) the PEEP-induced increase in arterial oxygenation is significantly correlated to the recruited volume but not to the changes in static compliance. The shape of the static inflation V-P curves on ZEEP allows the prediction of alveolar recruitment with PEEP.
Stability of positive tuberculin tests: are boosted reactions valid, To determine the stability and presumed significance of tuberculin skin tests. we followed a cohort of 380 tuberculin-positive patients living in chronic care facilities. Each patient had a positive reaction (greater than or equal to 10 mm induration to 5 tuberculin units of purified protein derivative) to one of three sequential baseline tuberculin tests. One year after the initial series. each patient had a single repeat skin test. Reversion to a negative test occurred in 98 (26%) of the 380 patients. Decreases in induration of 6 mm or more occurred in 88 (90%) of the reverters. Initially positive tests were more likely (p less than 0.001) to remain stable than tests that were "boosted" to positive reactions on the second or third initial administration. Stable responses were found in 96% of those whose tests had greater than or equal to 15 mm induration compared with 61% of those with reactions of 10 to 14 mm induration. Increasing age also was associated with a high rate of reversion. The instability of boosted tuberculin reactions brings into question the clinical significance of these tests. We propose limiting tuberculin testing to two sequential tests.
Therapeutic efficacy of liposome-encapsulated kanamycin against Mycobacterium intracellulare infection induced in mice, Liposome-encapsulated kanamycin (KM) was examined for therapeutic efficacy against experimental infection induced with Mycobacterium intracellulare in mice. Liposomal KM injections (once weekly for up to 8 wk) led to a greater reduction in the degree of gross pulmonary lesions and in the growth of the organisms in the visceral organs (lungs. liver. spleen. and kidneys) of infected mice than did either free KM alone or free KM mixed with empty liposomal vesicles. The therapeutic effect of the liposome-encapsulated KM was dose dependent for doses from 50 to 200 micrograms KM/mouse/injection. Liposome encapsulation markedly changed the tissue distribution of KM. in particular in the reticuloendothelial organs. such as liver and spleen. In these organs. accumulation and retention of liposome-entrapped KM was remarkably higher than that of free KM. Moreover. considerably prolonged retention was seen for liposome-encapsulated KM in serum and lungs. Encapsulation of KM into liposomal vesicles increased incorporation of the drug into the host peritoneal macrophages and enhanced the antimicrobial activity of the agent against M. intracellulare phagocytosed into macrophages.
Simultaneous exposure of sheep to endotoxin and 100% oxygen, The purpose of this study was to determine the effect of endotoxin on the development of vascular and airway dysfunction during O2 toxicity. Sheep were prepared for chronic measurement of vascular pressures. cardiac output. gas exchange. and collection of lung lymph. Tracheostomies were made for accurate delivery of gas mixtures. Sheep were placed in one of three experimental groups: those receiving endotoxin (n = 9). those breathing 100% O2 and receiving endotoxin (n = 7). and those exposed to 100% O2 alone (n = 6). Sheep had daily measurements of hypoxic vasoconstriction (FIO2 = 0.12). gas exchange. circulating white blood cell counts. lymph flow. and lymph and plasma protein concentrations. Lung neutrophils were counted. and copper-zinc superoxide dismutase and manganous superoxide dismutase were measured in lung samples from some sheep biopsies taken at baseline surgery and postmortem. Endotoxin markedly prolonged survival time and partially protected against the increased lung vascular permeability in sheep breathing 100% oxygen. but impairment of gas exchange. loss of hypoxic pulmonary vasoconstriction. and ultimate progression of respiratory failure were not prevented. Induction of MnSOD occurred in sheep breathing 100% O2. in sheep receiving endotoxin alone. and in those exposed to 100% O2 plus endotoxin. We conclude that endotoxin markedly increases tolerance to O2 toxicity but that some of the pathophysiology of O2 toxicity is unaltered. The role of superoxide dismutase in the observed protection is unclear.
MK-571, a potent antagonist of leukotriene D4-induced bronchoconstriction in the human, MK-571 is a novel leukotriene D4/E4 (LTD4/E4) receptor antagonist. The ability of MK-571 to inhibit LTD4-induced bronchoconstriction was examined both in six healthy volunteers and in six asthmatic subjects in a double-blind. placebo-controlled. randomized crossover study design. LTD4 challenges were performed during a constant infusion with placebo or the active compound. The provocative concentration of LTD4 causing a 35% decrease in SGaw (PC35 SGaw) was 4.8 +/- 0.6 x 10(-5) M (mean +/- SEM) in healthy volunteers and 1.8 +/- 0.7 x 10(-6) M in asthmatic subjects during placebo treatment. Intravenous MK-571 (1.500. 86. or 28 mg) inhibited the LTD4-induced bronchoconstriction completely in healthy volunteers. up to an inhaled concentration of 10(-4) M LTD4. In asthmatic subjects. 28 mg MK-571 caused a significant. at least 44-fold. rightward shift of the dose-response curve to LTD4. whereas 277 mg shifted the dose-response curve at least 84-fold to the right. MK-571 is therefore a potent antagonist of LTD4-induced bronchoconstriction in both normal volunteers and asthmatic patients. MK-571 also caused a small but significant increase in baseline airway caliber in asthmatic patients. suggesting the presence of LTD4 in asthmatic airways and thus providing further support to a role for sulfidopeptide leukotrienes in the pathogenesis of asthma.
A three-month comparison of twice daily inhaled formoterol versus four times daily inhaled albuterol in the management of stable asthma, We compared the efficacy of inhaled formoterol. a long-acting beta 2-agonist. with inhaled albuterol in 145 stable adult asthmatics in a 12-wk multicenter trial. Patients were allocated in randomized double-blind fashion to maintenance therapy with either formoterol 12 micrograms twice a day or albuterol 200 micrograms four times a day in addition to their other asthma medications. Patients were allowed to use "rescue" 100-micrograms albuterol puffs on an as-needed basis. Mean baseline FEV. in the morning before bronchodilator was 2.14 +/- 0.76 L and 1.98 +/- 0.71 L for the formoterol and albuterol groups. respectively. these values being used as baseline covariates in subsequent analysis of predrug and postdrug FEV1. Measured at each clinic visit. morning predrug FEV1 rose significantly with formoterol treatment and was significantly greater at all visits than in the albuterol group. the greatest difference being in Week 8 (2.40 +/- 0.77 versus 1.92 +/- 0.66 L. p less than 0.001). Morning FEV1 30 min postdrug was significantly higher in the formoterol group at Weeks 2 and 8. the trend not reaching statistical significance at other times. Diurnal variation in prebronchodilator peak flow rates was significantly reduced in the formoterol group throughout the trial (17 versus 42 L/min at Week 12. p less than 0.0001). The number of asthma episodes per week was significantly less in the formoterol group during Weeks 4. 8. and 12 as were the number of sleep disruptions during Weeks 2. 4. 6. 8. and 12. Significantly more rescue albuterol was required in the albuterol group by Week 2 and throughout the remainder of the study.
A single-dose comparison of inhaled albuterol and two formulations of salmeterol on airway reactivity in asthmatic subjects, Salmeterol is a new beta 2-selective agonist with a long duration of action. We compared the effect of 50 micrograms salmeterol administered by metered dose inhaler (MDI) and dry powder inhaler (DPI). with 200 micrograms albuterol (by MDI) on FEV1 and histamine-induced bronchoconstriction in 12 asthmatic subjects in a double-blind. placebo-controlled crossover study. Subjects were studied for 12 h on four occasions with a histamine challenge test at 1. 4. 8. and 12 h. the response being measured as the dose of histamine causing a 20% fall in FEV1 (PD20). There was no difference in the mean +/- standard error of the mean maximum increase in FEV1 between salmeterol MDI. salmeterol DPI. or albuterol (0.57 +/- 0.078. 0.54 +/- 0.089. and 0.49 +/- 0.081 L. respectively); the increase following placebo was 0.25 +/- 0.082 L. The area under the 12-h time-response curve for FEV1 was greater for both formulations of salmeterol (MDI and DPI) than for albuterol. The three active drugs protected against histamine-induced bronchoconstriction. The increase in PD20 at 1 and 12 h and the area under the 12-h time-response curve for PD20 were greater following both formulations of salmeterol than after albuterol. The greater change in geometric mean PD20 values at 1 h after both formulations of salmeterol (2.21 and 1.88 mumol) relative to albuterol (0.98 mumol) suggests that despite similar effects on FEV1 the doses used do not have an equivalent effect on the airways.
Relation of dose-response slope to respiratory symptoms in a population of Australian schoolchildren, To describe bronchial responsiveness in populations. the dose-response slope (DRS). which is the linear slope of the dose-response curve. may be a more useful measure of severity than the provoking dose that causes a 20% fall in FEV1 (PD20 FEV1). To examine the distribution of DRS measurements and their relation to respiratory symptoms in children. we have analyzed data collected during a population study designed to measure the prevalence of bronchial hyper-responsiveness and respiratory symptoms. In this study. respiratory symptom history was measured by a self-administered questionnaire to parents and bronchial responsiveness was measured using the rapid inhalation method. Of 1.217 children studied. DRS values were obtained for 1.203 children who had technically satisfactory bronchial challenge data. In asymptomatic children. DRS values were distributed symmetrically on a logarithmic scale. The geometric mean DRS was reliable measure of the central position of the curve. and 1.96 standard deviations only slightly underestimated the 95% interval. In children with recent wheeze. the distribution was skewed toward larger DRS values. Mean DRS values were significantly different between groups determined according to symptom frequency. It appears that DRS values are more useful than PD20 FEV1 values in epidemiologic studies of respiratory illness in children because a value that relates well to symptom history can be calculated for the entire sample. The major advantages are that the measurement more clearly discriminates between symptom severity groups and that a value that represents abnormal responsiveness can be calculated.
The clinical utility and reliability of asbestos bodies in bronchoalveolar fluid, Although asbestos bodies are easily identified in bronchoalveolar lavage (BAL) fluid and are thought to be strongly associated with the asbestos body burden in the lung parenchyma. the clinical utility and reliability of this biologic measure of exposure has not been sufficiently studied. To assess the clinical relevance of BAL asbestos bodies we compared this bioassay of exposure to other measures of exposure and also indices of lung disease in asbestos-exposed workers (n = 71). The median concentration of asbestos bodies was 0.8 bodies per ml of BAL fluid (range 0 to 34.3). Seven workers or 9.9% had zero asbestos bodies identified in the BAL fluid. The concentration of BAL asbestos bodies was not associated with the duration of exposure (r = -0.02). the time from first exposure to asbestos (r = 0.12). or the time since last exposure to asbestos (r = 0.05). Moreover. radiographic and physiologic measures of asbestos-induced lung disease were not found to be associated with the concentration of BAL asbestos bodies. In fact. of the seven study subjects with zero BAL asbestos bodies. the mean duration of exposure was 32 yr. and six of these subjects had radiographic evidence of asbestos-induced lung disease. To assess the reliability of measuring BAL asbestos bodies. we performed a second bronchoscopy on 54 subjects and directly compared the concentration of BAL asbestos bodies from both the first and second BAL samples. Within these 54 subjects. the concentration of BAL asbestos bodies was found to be a very reliable measure (r = 0.76; p = 0.0001).
Computed tomography scan in the early detection of silicosis, We evaluated the ability of both the conventional and high resolution computed tomography (CCT and HRCT. respectively) scans of the thorax to detect early silicosis in subjects exposed to silica dust in the mines and foundries of Quebec for an average of 29 +/- 2 yr. The study was limited to subjects with chest radiograph (CR) of the International Labor Organization (ILO) Categories 0 or 1 as determined independently a priori. All subjects had a standard high-kilovoltage posteroanterior and lateral CR. a set of 10 to 15 1 cm collimation CCT scans. and a set of three to five 2 mm collimation HRCT scans in the upper. middle. and lower lung fields. For each CR and sets of CT scans. readings were done independently by four experienced readers. For small opacities of the lung parenchyma on CR. 32 of the 51 subjects were normal (Group A). six were indeterminate (Group B). and 13 were abnormal (Group C). By the combined readings of HRCT and CCT. 13 of the subjects (40%) in Group A were abnormal (p less than 0.001); four of the subjects in Group B were abnormal. and in Group C. one subject was normal. one indeterminate. and 11 (84%) abnormal. For confluence of small opacities. 48 of the 51 subjects were negative (Group 0). and three were positive (Group 1) on the CR. By the CT scan. 42 of the 48 subjects in Group 0 were negative. and the three subjects in Group 1 were positive; thus the CT scan added six positive cases with confluence of small opacities (six of 48. 12.5%).
Mucin in disease. Modification of mucin gene expression in airway disease, Mucus hypersecretion is a characteristic feature of several human airway diseases. including chronic bronchitis. cystic fibrosis. and asthma. Although its pathogenesis is poorly understood. hypersecretion apparently results from the abnormally large number of mucous cells found in hypersecretory airways. The factors giving rise to these mucous cells are unknown. but experimental evidence supports possible roles for both mitosis (mucous cell hyperplasia) and differentiation (mucous cell metaplasia). On the basis of the hypothesis that differentiation would require activation of mucin mRNA transcription. we have used mucin cDNA to monitor mucin mRNA levels in an animal model of chronic bronchitis. We first showed that a mucin gene (SMUC or MUC-2) cloned from the human intestine is also expressed in the human airways and is the same or homologous to genes expressed in other human mucin-producing organs. We next showed that a homologue of the SMUC gene is expressed in several animal species. including the rat. Finally. we showed that the induction of experimental chronic bronchitis by SO2 in rats is accompanied by the induction (from near zero baseline) of airway mucin mRNA. The induction by irritants of high steady-state levels of mucin mRNA may represent one of the early events in mucous cell differentiation and hypersecretion.
Enterobacter bacteremia: clinical features and emergence of antibiotic resistance during therapy, OBJECTIVES: To study the effect of previously administered antibiotics on the antibiotic susceptibility profile of Enterobacter. the factors affecting mortality. and the emergence of antibiotic resistance during therapy for Enterobacter bacteremia. DESIGN: Prospective. observational study of consecutive patients with Enterobacter bacteremia. SETTING: Three university tertiary care centers. one major university-affiliated hospital. and two university-affiliated Veterans Affairs medical centers. PATIENTS: A total of 129 adult patients were studied. MEASUREMENTS: The two main end points were emergence of resistance during antibiotic therapy and death. MAIN RESULTS: Previous administration of third-generation cephalosporins was more likely to be associated with multiresistant Enterobacter isolates in an initial. positive blood culture (22 of 32. 69%) than was administration of antibiotics that did not include a third-generation cephalosporin (14 of 71. 20%; P less than 0.001). Isolation of multiresistant Enterobacter sp. in the initial blood culture was associated with a higher mortality rate (12 of 37. 32%) than was isolation of a more sensitive Enterobacter sp. (14 of 92. 15%; P = 0.03). Emergence of resistance to third-generation cephalosporin therapy (6 of 31. 19%) occurred more often than did emergence of resistance to aminoglycoside (1 of 89. 0.01%; P = 0.001) or other beta-lactam (0 of 50; P = 0.002) therapy. CONCLUSIONS: More judicious use of third-generation cephalosporins may decrease the incidence of nosocomial multiresistant Enterobacter spp.. which in turn may result in a lower mortality for Enterobacter bacteremia. When Enterobacter organisms are isolated from blood. it may be prudent to avoid third-generation cephalosporin therapy regardless of in-vitro susceptibility.
Clinical genetics and genetic counseling in Alzheimer disease, Because of growing evidence for genetic causes of Alzheimer disease. clinicians are often asked about risks for this disorder among relatives of patients. This paper briefly reviews the evidence for genetic and other causes of Alzheimer disease. including specifically its typical late-onset variant. Several recent developments in the molecular genetics of early-onset Alzheimer disease are described briefly. These findings. however. may not apply to more typical. late-onset Alzheimer disease. Genetic studies of the latter disorder are complicated by the censorship of any inherited predisposition to disease by death from other causes. Hence. heritable disease may be apparent only in families with large numbers of elderly relatives at risk. Relying on empiric observations of risk among relatives from several recent studies of pooled Alzheimer families. curves are presented describing theoretic age-specific risks in relatives of patients and unaffected controls. Real (current) lifetime risks of Alzheimer disease are then estimated by modification of the theoretic figures with corresponding current age-specific mortality characteristics of the U.S. population. The lifetime incidence among relatives of patients with Alzheimer disease is estimated to be 19%. or three to four times the risk among control relatives. Because both mortality of and risk for Alzheimer disease change rapidly with advancing age. it may be possible to reduce the current morbidity from Alzheimer disease by 50% if onset can be postponed by only 5 years.
Benefits of monitoring plasma levodopa in Parkinson's disease patients with drug-induced chorea, We studied the temporal patterns of chorea and plasma levodopa profiles in 30 patients with Parkinson's disease whose motor fluctuations were difficult to characterize and treat on the basis of observation alone. We were able to determine whether chorea was associated with high levodopa concentrations or low levodopa concentrations or both. We found the following patterns of levodopa-associated chorea: chorea due to inadequate levodopa levels. chorea due to biphasic levodopa absorption. chorea associated with either rapid or slow levodopa absorption. and chorea due to long-duration levodopa absorption mimicking a sustained-release preparation. Seven patients benefited after their dosing schedules were rearranged as a result of information gained from monitoring. We conclude that any patient with levodopa-associated chorea who cannot be regulated on the basis of observation alone should be studied with simultaneous plasma levodopa measurements and clinical monitoring to detect an unusual plasma levodopa pattern that may be improved by adjustment of dosing schedule.
Intracerebral hemorrhage: external validation and extension of a model for prediction of 30-day survival, We report validation of a previously reported logistic regression model for predicting 30-day survival after supratentorial intracerebral hemorrhage using independent. prospectively collected data. The original model. using initial Glasgow Coma Scale score. hemorrhage size. and pulse pressure. accounted for mortality or survival at 30 days in 92% of patients in the Pilot Stroke Data Bank with a sensitivity of 0.84 and a specificity of 0.96. For external validation. the model was used to predict 30-day status for each patient in the Main Phase Stroke Data Bank for whom complete risk factor information was available. Overall. 90% of patients' outcomes were correctly predicted with a sensitivity of 0.85 and a specificity of 0.92. Two factors not collected in the Pilot Stroke Data Bank. hyperglycemia and intraventricular hemorrhage extension. were assessed to determine if they provided additional predictive information on 30-day mortality. Intraventricular hemorrhage extension contributed significant predictive information in a logistic regression. whereas hyperglycemia did not. The resulting four-factor model with an interaction term (intraventricular hemorrhage extension and Glasgow Coma Scale score) correctly classified the survival status of 94% of patients at 30 days. A more general outcome. death or failure to achieve a "good" Activities of Daily Living Score by one year. was analyzed with respect to the same four factors. The resulting model correctly classified 95% of the patients in the cohort.
Positron emission tomography suggests that the rate of progression of idiopathic parkinsonism is slow, We performed sequential positron emission tomography scans with 6-[18F]fluoro-L-dopa in 9 patients with idiopathic parkinsonism and 7 age-matched normal control subjects to compare changes in the nigrostriatal dopaminergic pathway over time. The mean interval between the scans was 3.3 years for the group with idiopathic parkinsonism and 3.9 years for the control subjects. The scans were analyzed by calculating the ratio of striatal to background radioactivity. Both groups showed statistically significant reductions of striatal uptake over the interval. The rate of decrease was almost identical in each group (p = 0.6). We infer that the usual rate of loss of integrity of the dopaminergic nigrostriatal pathway in patients with idiopathic parkinsonism is slow and the rate of change between the two groups was comparable.
The time course and magnitude of spontaneous recovery of parkinsonism produced by intracarotid administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to monkeys, We studied rhesus monkeys with hemiparkinsonism or bilateral parkinsonism produced by unilateral or bilateral intracarotid administration of 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine. Using a standardized clinical rating scale. 4 hemiparkinsonian monkeys showed a 13 to 56% (mean. 36%) spontaneous improvement during an observation period of up to 25 weeks. Generally. recovery leveled off after 14 weeks. Four bilaterally parkinsonian monkeys showed a 5 to 42% (mean. 22%) improvement over a period of up to 30 weeks. Our findings emphasize that spontaneous recovery is a potentially confounding characteristic of this monkey model when used for assessing novel antiparkinsonian therapies.
Linear focal elastosis. An ultrastructural study, We studied an 86-year-old Japanese man with linear focal elastosis. The lesions were asymptomatic yellow striae in the lumbar region. histologically composed of massive. well-demarcated basophilic fibers that stained positively with elastic tissue stains. Electron microscopy revealed fine. reticular or granular electron-dense materials. and elastic fiber microfibril-like materials in the matrix. in addition to numerous mature and immature elastic fibers. These findings suggest that active elastogenesis was occurring in the lesions. The four cases reported so far have the three common features of age. sex. and lesion location.
The invisible dermatoses, The central tenet of invisible dermatology is that visible lesions represent a late stage of development. The eye is an unreliable instrument for judging the normalcy of skin. In chronic widespread dermatoses. the uninvolved skin is at least physiologically abnormal. Recently healed skin is always abnormal. Recognition of occult changes will have a substantial impact on the prevention and treatment of diseases of the skin.
HIV prevalence and risk behaviours for HIV transmission in South Australian prisons, During the latter half of 1989. HIV prevalence in South Australian prisoners was 1.4%. The prevalence of HIV infection across the prison system did not change significantly during 1989 but there was clustering of HIV-infected prisoners in some prisons. Almost half the prisoners from all of the South Australian prisons agreed to participate in our studies. from which we estimate that about 42% of prisoners engage in risk behaviours at least once while incarcerated. Prisoners estimated that 36% of all prisoners inject drugs intravenously at some stage during their stay and that 12% engage in anal intercourse at least once. Interviews with former prisoners who had a history of intravenous drug use revealed that about half had injected themselves while in prison. 60% shared needles and most did not clean shared needles adequately. Most of these prisoners injected themselves once a month or less frequently. The conditions for spread of HIV within the prison system exist but at the current prevalence of infection. transmission can be expected to be infrequent. The opportunity exists now to improve and expand preventive measures.
Evaluation of saliva as a specimen for monitoring zidovudine therapy in HIV-infected patients, To facilitate studies of the pharmacokinetic properties of zidovudine. the relationship between plasma and salivary concentrations of the drug was studied. after oral dosage. in 10 HIV-infected patients. Zidovudine concentrations were determined in plasma. unstimulated mixed saliva and citric-acid-stimulated mixed saliva over a period of 3 1/2 hours by high-performance liquid chromatography. Correlation coefficients were r = 0.97 (P less than 0.0001) for stimulated saliva compared with plasma and r = 0.89 (P less than 0.0001) for unstimulated saliva. with average values in unstimulated saliva being 113.8 +/- 44.6% in plasma and 67.8 +/- 25.4% in stimulated saliva. Stimulated saliva values found to be 70% of the total reflected the concentration of the unbound drug in plasma. Except for a shorter half-life time (t1/2) in saliva. pharmacokinetic parameters showed a good correlation in the three types of specimen. These findings and the convenience of sample collection suggest that citric-acid-stimulated saliva might be an appropriate specimen for monitoring zidovudine therapy.
An inhibition enzyme immunoassay using a human monoclonal antibody (K14) reactive with gp41 of HIV-1 for the serology of HIV-1 infections, An inhibition enzyme immunoassay (IEIA). using a human monoclonal antibody (K14) reactive with gp41 of HIV-1. was evaluated for its applicability to the serology of HIV-1 infections. Using panels of serum samples from seronegative and confirmed HIV-1-seropositive individuals. it was shown that all the HIV-1-positive samples in a panel from The Netherlands and 97% of the HIV-1-positive samples from Tanzania were identified by this IEIA. Six per cent of the IEIA-positive samples from Tanzania could not be confirmed in other assays. Testing of serial dilutions of serum samples from African individuals with confirmed HIV-1. HIV-2 or HIV(ANI70) infections in the K14 IEIA. indicated that a HIV-1-specific assay based on this principle may be developed.
Laryngeal airway resistance. The relationships of airflow, pressure, and aperture, In the surgical treatment of the paralyzed larynx. a compromise often needs to be made between an orifice size needed to preserve voice and that needed for adequate inspiratory airflow rates. To assess the negative pressures needed to generate normal airflows across a narrowed vocal cord aperture. we measured pressure and flow changes across cadaveric larynges while altering aperture size. Best-fit quadratic equations for each aperture area selected were derived and showed that if the aperture were 0.5 cm2 or less. the resistance to normal breathing would be significantly increased. Aperture sizes of 0.67 cm2 or greater are not associated with such an increase in resistance.
A new technique for quantitative measurement of laryngeal videostroboscopic images, The objective measurement of laryngeal function and pathophysiology is one of the goals of current laryngeal research. We describe a new computerized tool for voice analysis systems that allows the quantitative analysis of individual videostroboscopic images. We describe this new technique compared with previous methods of videostroboscopic image analysis and discuss its clinical and research applications.
Use of tap water and disinfection practices in outpatient settings. A survey of otolaryngologists, A survey of otolaryngologists belonging to the American Academy of Otolaryngology-Head and Neck Surgery was conducted to estimate the frequency of tap water use during otologic examinations and to assess methods used for disinfection of otologic instruments in outpatient settings. Questionnaires were returned by 516 persons residing in 49 states. Tap water was used commonly for rinsing suction tips while suctioning patients even with tympanic membrane perforations (45%). Most respondents (87%) reported that their otologic instruments undergo either high-level disinfection or sterilization between patient examinations; however. only 63% to 67% of respondents reported adequate duration of treatment times (high-level disinfection. greater than or equal to 30 minutes; boiling. greater than or equal to 5 minutes; or autoclaving. greater than or equal to 20 minutes). The risk posed by the use of tap water during otologic examinations and the need for adequate disinfection of otologic instruments between patient examinations are presented.
Functional and phenotypic analysis of lymphocytes in head and neck cancer, We compared the phenotype and antitumor effector function of lymphocytes obtained from tumor tissues. lymph nodes. and the peripheral blood of patients with head and neck cancer. Freshly isolated tumor-infiltrating lymphocytes were deficient in CD4+ T cells in comparison with lymph node lymphocytes (LNL) and peripheral blood lymphocytes. A significantly higher CD4/CD8 ratio observed in LNL vs tumor-infiltrating lymphocytes and peripheral blood lymphocytes was attributable to both a significant enrichment in CD4+ T cells as well as a decrease in CD8+ T cells. The percentage of natural killer cells (CD3-CD56+) was uniformly low in both tumor-infiltrating lymphocytes and LNL. In patients with cervical metastases. LNL contained an increased proportion of CD16+ cells. Tumor-involved lymph nodes were not enriched in the CD8+C11b+ subset of T "suppressor" lymphocytes compared with uninvolved lymph nodes. Also. tumor-involved lymph nodes had significantly fewer CD4+ T cells than did uninvolved lymph nodes. In comparison with peripheral blood lymphocytes. freshly isolated tumor-infiltrating lymphocytes and LNL were depleted of cytotoxic effector cells. as indicated by low or absent cytotoxic activity against tumor cell targets. The ability to generate lymphokine-activated killer cells was significantly reduced in LNL in comparison with peripheral blood lymphocytes. In patients with head and neck cancer. depressed local and regional antitumor responses are associated with a deficiency of functional cytotoxic effector cells rather than an increase in suppressor T lymphocytes.
Facial weakness. A comparison of clinical and photographic methods of observation, The search for an internationally acceptable facial grading system has resulted in an assessment of existing methods by several investigators. These studies were based on observations of video film taken of patients with varying degrees of facial malfunction. Although the grading systems were evaluated. the use of videotape has never been compared with clinical examination and its suitability for this type of work is. therefore. unknown. We used nine facial grading systems to compare the results of clinical observation with those of photographic methods of presentation. The latter included videotape. photographic slides. and a combination of the two. The correlation between clinical examination findings and findings of any of the photographic methods was poor. suggesting the need for a standard form of presentation when grading patients. The most consistent results were found with either clinical examination or photographic slides; videotape was the least reliable.
Mediation of immune glomerular injury, This paper reviews current concepts of glomerular immune injury of both inflammatory and noninflammatory types. In noninflammatory lesions induced by antibody alone or C5b-9. the glomerular epithelial cell appears to be the principal target of injury. Similar mechanisms are probably operative in human diseases such as minimal change nephrotic syndrome and membranous nephropathy. In inflammatory lesions. circulating effector cells including neutrophils. macrophages. platelets. and probably lymphocytes as well as resident glomerular mesangial cells may mediate tissue injury. Human equivalents of these inflammatory lesions include most diseases associated with mesangial and/or subendothelial immune deposits and/or mesangial cell proliferation. Neutrophil-mediated injury appears to be consequent to both proteinases and oxidants. particularly the myeloperoxidase-H2O2-halide system. Platelets may be critically involved in neutrophil mediated injury as well. Platelets also mediate mesangial cell proliferation. probably by a release of platelet growth factors and stimulation of mesangial cell platelet-derived growth factor and platelet-derived growth factor receptor expression. Immunologically induced mesangial cell proliferation is associated with increased production of nephritogenic proteinase in vivo.
Cerebral circulation: humoral regulation and effects of chronic hypertension, New concepts have emerged in recent years concerning regulation of cerebral circulation. The purpose of this review is to summarize briefly several of these concepts. First. humoral mechanisms may have important effects on cerebral blood vessels and blood flow to choroid plexus. Recent evidence suggests that several vasoactive peptides may have major effects on fluid and ion balance in the brain by altering blood flow to the choroid plexus and possibly the production of cerebrospinal fluid. Second. chronic hypertension produces structural remodeling and hypertrophy of cerebral blood vessels and a shift in the relationship of cerebral blood flow to systemic blood pressure. Third. endothelium-dependent responses of cerebral arterioles to receptor and nonreceptor mediated agonists are impaired during chronic hypertension. Alterations in endothelium-dependent responses of cerebral arterioles during chronic hypertension appears to be due to release of an endothelium-derived contracting factor.
Adaptation to low-protein diets in renal failure: leucine turnover and nitrogen balance, In normal subjects. short to intermediate responses to dietary protein restriction include decreased amino acid oxidation and protein degradation plus increased utilization of amino acids for protein synthesis; these responses are activated to improve amino acid utilization and nitrogen balance. To assess whether chronic renal failure (CRF) impairs the adaptive responses to a low-protein diet. we measured nitrogen balance and the kinetics of infused L-(15N.1-13C)leucine during fasting and feeding. In six adult CRF and four control (C) subjects. 0.6 (LP) and 1.0 (HP) g protein kg-1 day-1 diets were compared. LP reduced feeding stimulated oxidation of leucine by 26% in CRF and 33% in C (P = NS). During fasting. oxidation was unaffected by diet or CRF. For both groups. feeding suppressed protein degradation to the same extent; leucine incorporation into protein did not change. Nitrogen balance during the two diets was the same with C and CRF. as was protein balance estimated from results of measured leucine kinetics. Thus. patients with CRF can activate appropriate adaptive responses to LP inasmuch as reduced amino acid oxidation occurring with feeding and estimates of protein balance did not differ from control.
Endothelin mediates the renal vasoconstriction induced by cyclosporine in the rat, The effect of cyclosporine on renal function was first investigated in the isolated perfused rat kidney. Kidneys from normal male Sprague-Dawley rats were perfused at constant pressure. After control clearance periods. cyclosporine (0.6. 1.2. or 3 mg/min) or vehicle was infused over 5 min period in the renal artery and then four 10-min experimental periods followed. Cyclosporine. but not vehicle caused a dose dependent fall in renal perfusate flow associated with a concomitant increase in renal vascular resistance. Glomerular filtration rate was also decreased in parallel. We also examined whether endogenous endothelin mediates cyclosporine-induced acute renal vasoconstriction. In isolated kidneys pre-exposed to specific anti-endothelin antibody and then challenged with cyclosporine (1.2 mg/min) the renal perfusate flow. renal resistance. and glomerular filtration rate were 22.3 +/- 1.8 ml/min. 4.50 +/- 0.36 mmHg/ml.min-1. 1.06 +/- 0.05 ml/min. respectively. as compared with 12.9 +/- 1.2 ml/min. 7.8 +/- 1.2 mmHg/ml.min-1. 0.55 +/- 0.06 ml/min (P less than 0.01) measured in isolated kidneys pre-exposed to a non-immunized rabbit serum. The effectiveness and specificity of anti-endothelin antibody were confirmed by its capability of preventing the renal function deterioration caused by a single bolus dose (150 pmol) of synthetic endothelin. but not by infusion of angiotensin II. norepinephrine. or thromboxane A2 mimetic U-46619 in isolated kidneys. To test further the relationship between endogenous endothelin and cyclosporine-induced renal vasoconstriction. a second series of in vivo studies was performed in normal rats.
Cranial computed tomography and magnetic resonance imaging in autosomal dominant polycystic kidney disease, High resolution computed tomography or magnetic resonance imaging of the head with 3-mm sections through the circle of Willis was obtained in 96 patients with autosomal dominant polycystic kidney disease. These scans are well suited for the noninvasive. presymptomatic diagnosis of intracranial aneurysms at high risk of rupture. since the risk of rupture of unruptured aneurysms is heavily dependent on their size. and aneurysms equal to or larger than 6 mm in diameter are not likely to escape detection by these techniques. No definite aneurysm was observed in any of the 96 patients. Small areas (2-4 mm) of contrast enhancement or signal void were detected in 11 patients. These areas are possibly due to vascular tortuosity. but the studies were considered to be indeterminate because a small aneurysm could not be ruled out. Cerebral angiography in two of these 11 patients was normal. Arachnoid cysts were observed more frequently in the patients with polycystic kidney disease than in a control group of patients matched by gender. age. and type and date of examination.
Greater loop chloride uptake contributes to blunted pressure natriuresis in Dahl salt sensitive rats, A blunted pressure natriuretic response is present in Dahl salt sensitive rats. To determine whether this results from tubular or glomerular mechanisms. late proximal. early distal. and late distal micropuncture were performed in salt resistant (R). salt sensitive (S). or salt sensitive rats with renal perfusion reduced to that of R rats (S-AC). Differences in neuro-endocrine background between groups were eliminated by renal denervation and by fixing plasma aldosterone. norepinephrine. and vasopressin levels by infusion. Renal perfusion pressure was greater (P less than 0.05) and inulin clearance less (P less than 0.05) in S than R rats. Urinary sodium excretion. however. was not different. S-AC had renal perfusion pressures that were similar to R rats and inulin clearance similar to S rats. Urinary NaCl excretion was less (P less than 0.05) than either group. Single nephron inulin clearance. fluid. and chloride delivery to late proximal sites were not different between groups. Absolute and fractional chloride delivery to early distal sites was less (P less than 0.05) in S-AC than R or S but not different between R and S. Late distal chloride delivery was not different between any group. Calculated loop chloride reabsorption was greater in S-AC than R or S. Thus. the lower urinary NaCl excretion in S-AC rats is in part due to increased loop chloride reabsorption. This effect is probably intrinsic to the S kidney as it occurs despite renal denervation when plasma levels of vasopressin. norepinephrine. and aldosterone are fixed. The increased loop chloride uptake is abolished when perfusion pressure increases.
Uric acid crystal binding to renal inner medullary collecting duct cells in primary culture, Attachment of microcrystals to cellular membranes may be an important component in the pathophysiology of urolithiasis. This study characterizes the concentration-dependent binding of uric acid crystals to rat renal inner medullary collecting duct cells in primary culture. Collecting duct cell cultures grew as monolayers with interspersed aggregates of rounded cells. Cultures were incubated with 14C-uric acid crystals. and the crystals that bound were quantitated by adherent radioactivity. Uric acid crystal adherence demonstrated concentration dependent saturation with a 1/alpha value (maximum micrograms of crystals adhering to 1 cm2 of binding area) of 645 micrograms/cm2. The beta values (fraction of cross-sectional area which bound crystals) of uric acid (mean = 0.15) and calcium oxalate monohydrate (mean = 0.13) crystals did not differ significantly. Uric acid crystal binding was inhibited by pre-bound calcium oxalate monohydrate crystals in a concentration dependent manner. These data suggest that uric acid and calcium oxalate crystals exhibit similar binding patterns to rat renal inner medullary collecting duct cells in primary culture.
Transepithelial water permeability in an in vitro model of renal cysts, Renal cysts develop from microscopic tubules and may enlarge progressively several thousandfold. Sustained epithelial proliferation. intracavitary fluid accumulation. and extracellular matrix remodeling are central elements in a multistep process that leads to the formation and enlargement of cysts. MDCK cells suspended within medium-hydrated collagen gels grow to form spherical. monolayered. fluid-filled cysts that enlarge steadily. Vasopressin and other agents that increase intracellular levels of cAMP stimulate the rate of MDCK cyst growth and net fluid/solute secretion when added to defined medium in vitro. In this model. net fluid secretion is the only means by which fluid can accumulate within the cyst cavity. We used this cyst-forming line of epithelial cells to evaluate several membrane transport properties that are important in the coupled movements of solute and water in the process of secretory fluid transport. Individual cysts were microdissected from collagen gels. held by a micropipet in a thermostated chamber. and examined at a high magnification by video microscopy. Transepithelial water flow was initiated by rapidly exchanging the bath medium with hyperosmotic solutions. Net water flux. Jv. determined from the initial rate of decrease in cyst diameter. was proportionate to the transmembrane osmotic gradient of NaCl or raffinose; the reflection coefficient for NaCl was indistinguishable from 1.0. Osmotic water permeability (cm3/cm2/osm/min x 10(-6)) was 739 +/- 99 (N = 11) in medium augmented by an NaCl concentration of 100 mosmol/kg. Hydraulic conductivity (Pt). estimated in control cysts. was 6.8 +/- 0.9 microns/s. a value similar to that of medullary and cortical thick ascending limbs of Henle.
Adverse reactions to the preschool (fifth) dose of adsorbed diphtheria-pertussis-tetanus vaccine in Canadian children, OBJECTIVE: To quantify accurately the rate of adverse reactions after the preschool (fifth) dose of adsorbed diphtheria toxoid-pertussis vaccine-tetanus toxoid (DPT) vaccine and to test the hypothesis that large local reactions are attributable to the diphtheria toxoid. DESIGN: Double-blind randomized controlled trial. SETTING: Suburban community public health unit. PARTICIPANTS: Healthy children 4 to 5 years of age with a history of having received four doses of adsorbed DPT vaccine. INTERVENTIONS: Subjects were given either the standard DPT vaccine (with 25 Lf units of diphtheria toxoid) or a modified DPT vaccine (with 10 Lf units of diphtheria toxoid). They were assessed 24 hours later by a nurse. Serum samples obtained before vaccination were tested for diphtheria and tetanus antitoxin levels by means of neutralization assay and enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Rates of large local reactions (an area of redness or swelling or both of 5 cm or greater) 24 hours after vaccination in the two groups. Relation between serum antitoxin levels before vaccination and the rate of large local reactions in each group. RESULTS: Of the 250 subjects enrolled 124 received the standard vaccine and 126 the modified one. Large local reactions occurred in 71% of the subjects receiving the standard vaccine and 52% of those receiving the modified one (p less than 0.01). In the former group large erythematous reactions occurred significantly more often in those with an elevated prevaccination diphtheria antitoxin level than in those without an elevated level; no relation was found between such reactions and the prevaccination tetanus antitoxin level. Reduced arm movement was evident in 45% of the children in the two groups. Few had systemic adverse reactions. CONCLUSIONS: Large local reactions occur frequently after the preschool administration of the DPT vaccine. These reactions are uncomfortable but not serious. They result in part from the large amount of diphtheria toxoid in the standard DPT vaccine.
DNA flow cytometric analysis of primary operable breast cancer. Relation of ploidy and S-phase fraction to outcome of patients in NSABP B-04, Between 1971 and 1974. 1665 women with primary operable breast cancer were randomized into a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial (B-04) conducted to evaluate the effectiveness of several different regimens of surgical and radiation therapy. No systemic therapy was given. Cells from archival paraffin-embedded tumor tissue taken from 398 patients were analyzed for ploidy and S-phase fraction (SPF) using flow cytometry. Characteristics and outcome of patients with satisfactory DNA histograms were comparable to those from whom no satisfactory cytometric studies were available. In patients with diploid tumors (43%). the mean SPF was 3.4% +/- 2.3%; in the aneuploid population (57%). the SPF was 7.9% +/- 6.3%. Only 29.9% +/- 17.3% of cells in aneuploid tumors were aneuploid. Diploid tumors were more likely than aneuploid tumors to be of good nuclear grade (P less than 0.001) and smaller size (P equals 0.03). More tumors with high SPF were of poor nuclear grade than were tumors with low SPF (P equals 0.002). No significant difference in 10-year disease-free survival (P equals 0.3) or survival (P equals 0.1) was found between women with diploid or aneuploid tumors. Patients with low SPF tumors had a 13% better disease-free survival (P equals 0.0006) than those with a high SPF and a 14% better survival (P equals 0.007) at 10 years than patients with high SPF tumors. After adjustment for clinical tumor size. the difference in both disease-free survival and survival between patients with high and low SPF tumors was only 10% (P equals 0.04 and 0.08. respectively). Although SPF was found to be of independent prognostic significance for disease-free survival and marginal significance for survival. it did not detect patients with such a good prognosis as to preclude their receiving chemotherapy. The overall survival of patients with low SPF was only 53% at 10 years. These findings and those of others indicate that additional studies are necessary before tumor ploidy and SPF can be used to select patients who should or should not receive systemic therapy.
Stage I and II subdiaphragmatic Hodgkin's disease, From January 1971 to December 1986. 521 patients with Hodgkin's disease were evaluated and treated at the Yale University School of Medicine or one of its close affiliates. A total of 258 patients had pathologic stage (PS) I or II disease. with 239 patients having Hodgkin's disease above the diaphragm (ADHD) and 19 patients having Hodgkin's disease below the diaphragm (BDHD). A comparison of patients with BDHD versus patients with ADHD showed that patients with BDHD were older (mean age. 42 versus 28 years of age. P = 0.005). were initially seen less often with nodular sclerosis subtype (32% versus 77%. P = 0.00001). and had a higher male: female ratio (2.8 versus 1.2. P = 0.12). Ten patients with BDHD (53%) had positive findings at staging laparotomy (0 of 4 clinical stage [CS] IA patients and 10 of 15 (67%) CS II patients). Radiation therapy alone was the initial treatment of choice for 74% of patients with BDHD versus 94% of the patients with ADHD. There was no statistical difference in the overall survival or relapse-free survival rates for patients with BDHD versus ADHD (10-year survival rates. BDHD = 73% and ADHD = 81%). However. patients with BDHD who initially had intra-abdominal disease had a statistically significant increase in death rate (60%) due to Hodgkin's disease compared with patients with BDHD who initially had only peripheral nodal disease (0%). Treatment recommendations for patients with BDHD should be tailored to the specific clinical presentation of each patient. For most PS IA/IIA patients initially seen with peripheral nodal disease. radiation therapy alone is a successful treatment program. However. combined modality therapy should be the treatment of choice for patients with BDHD initially seen with intra-abdominal disease.
Should all patients with node-negative breast cancer receive adjuvant therapy? Identifying additional subsets of low-risk patients who are highly curable by surgery alone, This study. which used combined first-generation prognostic factors (tumor size. histologic differentiation. and age) on 408 patients with axillary node-negative (ANN) breast cancer treated by surgery alone without systemic adjuvant therapy between 1976 and 1987 at the Roswell Park Cancer Institute. discerned four subsets of low-risk patients with a 7-year relapse rate of 6% or better. The first subset consisted of 48 patients (12% of the population) with tumors 1 cm or less in diameter that were well or moderately differentiated. These patients had a disease-free rate (DFR) of 100% (95% confidence interval [CI]. 94% to 100%). The second subset consisted of 35 patients (9% of the population) with tumors less than or equal to 1 cm that were poorly differentiated or anaplastic. These patients older than 50 years of age had a DFR of 97% (95% CI. 91% to 100%). The third subset consisted of 36 patients (9% of the population) with tumors 1.1 to 2 cm that were well or moderately differentiated. These patients were older than 50 years of age and had a DFR of 94% (95% CI. 85% to 100%). The fourth subset consisted of 36 patients with ductal carcinoma in situ with microscopic invasion. These patients had a DFR of 100% (95% CI. 87% to 100%). Twenty-two of these patients. not in the other subsets mentioned. comprised 5% of the total population. These patients at low risk of recurrence. who comprise one third of the entire node-negative population. are highly curable by local therapy alone and may be spared the risks and costs of routine adjuvant systemic therapy (AST). Patients with tumors larger than 2 cm (152 patients; 37% of the population) are at high risk of recurrence (26% with a DFR of 74% [95% CI. 64% to 84%]) and should routinely receive systemic adjuvant therapy. Patients with tumors up to 2 cm who are not in the low-risk groups fall in a gray area (recurrence. 15% to 21%; DFR. 79% to 85%). For these groups. combining second-generation prognostic factors such as DNA ploidy. S-phase fraction. or cathepsin D should give the physician additional information to aid in making decisions regarding adjuvant therapy.
Resectable gastric carcinoma. An evaluation of preoperative and postoperative chemotherapy, Patients with locoregional gastric carcinoma often die because of the low rates of curative resection and frequent appearance of distant metastases (mainly peritoneal and hepatic). To evaluate the feasibility of preoperative and postoperative chemotherapy. 25 consecutive previously untreated patients with potentially resectable locoregional gastric carcinoma received two preoperative and three postoperative courses of etoposide. 5-fluorouracil. and cisplatin (EFP). Ninety-eight courses (median. five courses; range. two to five courses) were administered. Six patients had major responses to EFP. Eighteen patients (72%) had curative resections. and three specimens (12%) contained only microscopic carcinoma. At a median follow-up of 25 months. the median survival of 25 patients was 15 months (range. 4 to 32+ months). Peritoneal carcinomatosis was the most common indication of failure. One patient died of postoperative complications. but there were no deaths due to chemotherapy. EFP-induced toxic reactions were moderate. Preoperative and postoperative chemotherapy for locoregional gastric carcinoma is feasible. and additional studies to develop regimens that could result in 5% to 10% complete pathologic responses may be warranted.
A randomized controlled trial of adjuvant immunotherapy (murine monoclonal antibody 494/32) in resectable pancreatic cancer, In a prospective randomized multicentric trial. 61 patients from six hospitals with resectable pancreatic cancer were recruited between 1987 and 1989. All patients underwent a Whipple resection. Two weeks after surgery. the patients were randomized to be given either intravenous (IV) treatment with 370 mg (100 mg loading dose. 9 x 30 mg continuing within 10 days) of monoclonal antibody (MoAb) 494/32 (Behringwerke AG. Marsburg. Germany) or no additional anti-cancer treatment. This murine immunoglobulin (Ig) G1 antibody has been shown to strongly bind to human pancreatic cancer cells and to induce an antibody-dependent cellular cytotoxicity (ADCC). Both study groups were well matched with respect to age. sex. tumor staging. and grading. Six patients suffered from minor toxicity (vomiting and abdominal pain) after immunotherapy. Ten months after the end of the recruitment period. 65% and 53% of the patients in the treatment and control groups. respectively. had died. Of the living patients. 60% and 53% are alive with recurrent or progressive cancer disease. Median survival time was 428 days (range. 248 to 510 days) and 386 days (range. 296 to 509 days) in the treatment and control groups. respectively. The authors concluded that repeated IV treatment with the antibody 494/32 is not helpful in resectable pancreatic cancer. This study provides the first controlled data on passive immunotherapy in solid cancer.
Salvage therapy with high-dose chemotherapy and autologous bone marrow support in the treatment of primary nonseminomatous mediastinal germ cell tumors, The authors reported their experience with the use of high-dose chemotherapy and autologous bone marrow rescue (ABMR) as salvage therapy in the treatment of patients with recurrent and refractory primary nonseminomatous mediastinal germ cell tumors (PMGCT). Since 1987. the authors have treated 12 patients with PMGCT with high-dose carboplatin (1500 mg/m2 to 1800 mg/m2) and etoposide (1200 mg/m2 to 1350 mg/m2) (in two patients ifosfamide [10 g/m2] was added) with ABMR. Patients were either in second relapse or cisplatin refractory (progression within 4 weeks of last cisplatin dosing). They had received a median of two prior chemotherapy regimens (range. one to three). all had had prior cisplatin therapy. and most had failed ifosfamide-based therapy. Six patients were cisplatin refractory and of these only one achieved a partial response (PR) that was of short duration. It was planned that all patients would undergo two rounds of therapy; however. only 5 of 12 patients received two courses. The remainder had only one round of therapy either because of inadequate response (three patients) or excessive toxicity (four patients). There were four patients who died in the peritransplant period due to sepsis (two patients) or bleeding (two patients). The median survival of the group was 107 days (range. 14 days to 347 days). No patient achieved a complete remission. but there were six partial remissions. four with stable disease. and two with progressive disease. The use of high-dose carboplatin and etoposide with or without ifosfamide and ABMR was not effective in the treatment of this group of patients with PMGCT who were in second relapse or cisplatin refractory.
Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study, Histopathologic examination was done on 18 cases after percutaneous ethanol injection therapy (PEIT) for hepatocellular carcinoma. In eight cases. the lesion was treated by PEIT alone; in the other ten cases. PEIT was combined with transcatheter arterial embolization. The lesion was completely necrotic in 13 cases. 90% necrotic in four cases. and 70% necrotic in the rest. In addition. PEIT seemed to be effective against intercapsular. extracapsular. and vascular invasions. In the four cases of incomplete necrosis. the viable cancer tissue remained in small tumor nodules around the main tumor. in portions isolated by septa. or along the edge of the lesion. Therefore. ethanol should be injected not only into the center of the lesion. but also into sites close to its edge. Ethanol did not damage noncancerous liver parenchyma distant from injected sites. Local dissemination of the cancer cells was not found in any case. Therefore. PEIT seems to be a valuable therapy and may be an alternative to surgery in some cases.
Coexpression of adult T-cell leukemia-derived factor, a human thioredoxin homologue, and human papillomavirus DNA in neoplastic cervical squamous epithelium, Adult T-cell leukemia-derived factor (ADF) is an autocrine interleukin-2 receptor-inducing factor produced by human T-lymphotropic virus-1 (HTLV-1)-transformed lymphocytes. which has a high structural homology with an endogenous dithiol reducing coenzyme. thioredoxin. Its localization was investigated immunohistochemically in the cervix. using normal tissue (27 samples) and squamous neoplastic tissue (three condylomas. 42 cervical intraepithelial neoplasia [CIN] samples. 34 invasive squamous cell carcinoma samples). The expression of human papillomavirus (HPV) DNA was also studied in serial sections of the same subjects. Normal squamous cells and glandular cells of the cervix were negative for ADF. However. intracytoplasmic and/or intranuclear ADF-positive cells were usually found in the intermediate and superficial layers of the neoplastic squamous epithelium of condylomas (three of three cases) and CIN (35/42 cases). HPV DNA was detected in all condylomas and in 27 of 42 CIN specimens. HPV DNA-positive cells were usually localized in the intermediate and superficial layers of the neoplastic squamous epithelium. These HPV DNA-positive cells were also positive for ADF. Invasive squamous cell carcinoma was also positive for ADF (24/34 cases) and HPV DNA (11/34 cases). The coexpression of HPV DNA and ADF was observed in all HPV DNA-positive cases. Coexistence of HPV DNA and ADF immunopositivity in neoplastic squamous cells of the cervix suggests that ADF expression closely reflects the intracellular event on HPV DNA replication.
Prostate-specific antigen levels from completely sectioned, clinically benign, whole prostates, Clinically benign whole. untrimmed prostates and pelvic lymph nodes were obtained from 105 patients at autopsy. All 105 patients had premortem serum from which prostate-specific antigen (PSA) levels were obtained. Sixty-eight did not have carcinoma of the prostate (CAP). 28 had CAP less than 1 ml and 9 had CAP larger than 1 ml. Eleven untrimmed prostates weighed 80 g or more and eight had elevated PSA levels (more than 4.0 ng/ml): five of eight without CAP. two of two with CAP less than 1 ml. and one of one with CAP larger than 1 ml. Ninety-four whole untrimmed prostates weighed less than 80 g and 20 had elevated PSA levels: ten of 60 without CAP. two of 26 with CAP less than 1 ml. and eight of eight with CAP larger than 1 ml. This study suggests that PSA levels from patients with untrimmed prostates weighing 80 g or more (equivalent to a 60-g trimmed prostate) are usually elevated regardless whether CAP is present. However. CAP less than 1 ml. in untrimmed prostates less than 80 g. usually does not elevate PSA levels whereas CAP larger than 1 ml usually does (P less than 0.0001). The likelihood that elevated PSA levels. from patients with untrimmed prostates less than 80 g. are due to CAP larger than 1 ml increases as the PSA level increases.
The change in patterns of relapse in medulloblastoma, The authors reviewed 89 patients treated for cerebellar medulloblastoma between 1970 and 1989 to determine the impact of changing treatment (high-dose posterior fossa radiation therapy and chemotherapy) on the pattern of failure in medulloblastoma. Between 1970 and 1983. 50 patients (median follow-up. 110 months) were treated with surgery and postoperative craniospinal irradiation (CSI). Nineteen of the 50 (38%) recurred in the central nervous system (CNS). Isolated systemic (bone) metastases occurred in six. The median time to the development of bone metastases was 12 months. Since 1984. 39 patients (median follow-up. 27 months) were treated with preradiation chemotherapy consisting of cisplatin and vincristine for 9 weeks before initiation of CSI. Nine of the 39 (23%) patients recurred in the CNS. There were no systemic failures in this cohort. The actuarial 5-year disease-free survival was 55 +/- 7% for the earlier cohort and 72 +/- 8% for the later cohort (P equals 0.3). Posterior fossa recurrence was associated with radiation therapy to this area. The cumulative incidence of posterior fossa relapse was 50 +/- 13% in patients who received less than 5300 cGy and 18 +/- 7% in those who received 5300 cGy or more (P equals 0.005). All six bone relapses were in patients treated with CSI alone and 5300 cGy or more to the posterior fossa for a 5-year cumulative incidence of bone metastases of 18 +/- 7% compared with 0% for patients treated with 5300 cGy or more and chemotherapy (P equals 0.03). The authors concluded that high-dose radiation therapy has altered the pattern of relapse with an increase in systemic recurrence after radiation therapy alone that is now equivalent to the risk of recurrence in the posterior fossa. Chemotherapy may be indicated in an attempt to decrease this high risk of systemic metastases.
Detection of field change in oral cancer using oral exfoliative cytologic study, Four smears were taken from the normal buccal mucosa of 55 oral cancer patients and 76 cancer-free patients. In each case. two were stained by the Papanicolaou method and two underwent Feulgen hydrolysis. Quantitative assessment of nuclear area (NA) and cytoplasmic area (CA) of the Papanicolaou smears was undertaken using a semiautomatic image analysis system. DNA profiles were assessed from the Feulgen smears using a Vickers M85 microdensitometer (Vickers Instruments. York. England) and were found to be diploid for all patients. Results were then analyzed with respect to those patients who took alcohol. tobacco. combination of alcohol and tobacco. and those who took neither. A significant reduction in CA for the oral cancer group (P equals 0.001) but no change in NA (P equals 0.74) was observed. A detailed analysis of alcohol and tobacco habits could identify no significant role for these two factors. in the reduction in cytoplasmic area. Such field change may prove to be of value in predicting the development of second malignant tumors.
Turcot's syndrome. Flow cytometric analysis, Turcot's syndrome is a rare. genetically transmittable disease in which patients with colonic polyposis (possibly complicated by the progression to adenocarcinoma) have malignant central nervous system neoplasms. Dominant. recessive. and sporadic cases have been described. A 26-year-old man is reported with no relevant family history who had intermittent abdominal discomfort in 1986. Sigmoidoscopy revealed numerous polyps. several of which showed carcinomatous change. Dukes' Stage C colorectal carcinoma was diagnosed. Treatment consisted of total colectomy with construction of a Koch's pouch. He remained well for 3 years until onset of headache. nausea. and vomiting. Computed tomographic scan disclosed a large. circumscribed. enhancing. right frontoparietal mass. After craniotomy and partial resection. histologic review disclosed anaplastic astrocytoma. He received cranial radiation therapy. 6000 cGy. by parallel opposed ports to the tumor bed. and carmustine 200 mg/m2 intravenously every 8 weeks. Flow cytometric DNA analysis was done on the paraffin-embedded archival material from the patient's normal colon. colonic adenocarcinoma. and anaplastic astrocytoma. DNA histograms revealed diploid distributions in all three samples. The G2/M fraction of the astrocytoma was elevated at 16%. and the S-phase fraction of the colonic adenocarcinoma was 19.4%.
Conservative management of anal leiomyosarcoma, Leiomyosarcomas of the large intestine are unusual neoplasms. comprising less than 0.1% of all malignancies of the colon and rectum. Six cases of leiomyosarcoma of the anus have been reported. The optimal treatment for this neoplasm is not known. The standard surgical approach is abdominoperineal resection. The authors report the seventh case of this rare neoplasm and outline its treatment using local excision and iridium 192 brachytherapy in an attempt to preserve the anal sphincter. In selected patients. conservative surgery followed by radiation therapy may be an alternative to radical surgery. with the goals of local control of the disease and anal sphincter preservation. However. more experience is needed before this approach could be recommended routinely.
Knowledge and beliefs about cancer in a socioeconomically disadvantaged population, Americans living in poverty experience a higher incidence of and greater mortality from cancer than the nonpoor. At least 50% of the difference in mortality is believed to be due to delay in diagnosis. although risk-promoting lifestyles and behaviors also contribute to decreased survival. A potential exacerbating factor among the poor is inadequate information and knowledge about cancer and its treatment. Interviews were conducted with 128 cancer patients from a socioeconomically disadvantaged population to assess knowledge of cancer and its treatment and to evaluate care-seeking behaviors. Results indicated that although patients relied primarily on their physicians for information about their disease and treatment. a number of misconceptions regarding cancer existed in this population. Notably. nearly 50% of the patients surveyed either denied or did not know that smoking was related to the development of cancer. Additionally. patients frequently reported inappropriate care-seeking behaviors when asked to respond to a series of common disease-related signs or symptoms. These findings suggest that misinformation and misconceptions regarding cancer and its treatment among patients in this sample may contribute to inappropriate care-seeking behaviors.
Health aspects of carbonless copy paper, In the past 20 years. there have been numerous reports of skin and mucous membrane disorders allegedly caused by the use of carbonless copy paper. to such an extent that some people in Europe were refusing to work with it and concern was expressed in the European Parliament. In view of its undoubted convenience and superiority over carbon paper. the author was asked by the Commission of the European Communities for a report. Based on visits to manufacturers and users and the investigation of complaints. the conclusion is that. as exposure to the constituents of the paper during its manufacture is considerably greater than in its use and no cases have arisen in his experience in the industry. the complaints are more likely to be attributable to "sick building syndrome" than to the specific effect of any component of the paper.
Contact sensitization to 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (MCI/MI). A European multicentre study, The frequency of positive reactions to 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (MCI/MI) were studied at 22 European contact dermatitis clinics over a period of 1 year. A total of 4713 patients participated. All the patients were patch tested with nickel sulphate. formaldehyde. paraben-mix. and MCI/MI. 19.4% of the patients had positive patch tests to nickel. making this the most common allergen. 3% of the patients reacted to 100 ppm MCI/MI. while 2.6% reacted to formaldehyde and 1.1% to parabens. There was great variation in the frequency of MCI/MI sensitivity among the 22 centres. MCI/MI contact allergy was most common among women and in patients with facial dermatitis. while it was rarely seen in patients with dermatitis on the lower legs. There were no fluctuations in the number of positive patch tests to MCI/MI on a monthly basis when the results from all centres were combined. 117 of the 141 MCI/MI sensitized patients included in the study were retested. 88% had positive patch tests when retested. 101 of the MCI/MI-sensitive patients participated in a double-blind. placebo-controlled product use test. This test showed that 31% of the MCI/MI-sensitive patients had a positive reaction to a MCI/MI-preserved product. Only a few patients reacted to a control product. It is concluded that the preservative MCI/MI is an important new contact allergen.
Pre-employment screening for contact dermatitis among the pupils of a metal industry school, 79 male pupils of a metal industry school were investigated. none of whom had yet been occupationally exposed to metals or to cutting oils. In 1 or 2 years. depending on their grade and age. they would all be employees in the metal industry. Each was patch tested with nickel sulfate 5% pet.. cobalt chloride 1% pet.. and potassium dichromate 0.5% pet.. and 28 had a positive reaction to 1 or more of the metals tested. This finding indicates the necessity not only for pre-employment patch testing in industries where contact dermatitis is likely to occur. but that patch testing should be done even earlier in school children. before they decide to enter certain occupations.
Contact sensitivity to captafol in BALB/c mice, The fungicide captafol has been reported as causing irritant and allergic contact dermatitis in humans and in guinea pigs. This study investigated the ability of purified captafol to cause contact sensitization in BALB/c mice. Female mice were pretreated with an intraperitoneal injection of cyclophosphamide or saline. Applications of captafol (18.7 or 37.4 mg/ml). dinitrofluorobenzene (DNFB; 5 mg/ml) or solvent (4:1 acetone:ethanol mixture) were administered to the shaved abdomen on 2 consecutive days. or on days 1. 2. 8. 15. 22 and 29. Following challenge with captafol (37.4 mg/ml) or DNFB (2 mg/ml) on the right ear 6 days after the last induction. ear thickness ratios (right ear/left ear) were significantly larger after challenge in captafol-induced and DNFB-induced mice compared to control mice. A slightly larger response was observed with the smaller induction dose level of captafol and with multiple inductions over the course of a month. The overall maximum response to captafol was not increased by pretreatment with cyclophosphamide. Histologically. ears from captafol-induced and DNFB-induced mice showed edema and cellular infiltration. This study demonstrated the ability of captafol to produce contact hypersensitivity in the BALB/c mouse.
Combined evaluation of total and functional liver plasma flows and intrahepatic shunting, A diagnostic protocol was studied. designed to evaluate the main parameters of liver circulation in man. A water solution of D-sorbitol (S) and indocyanine green (ICG) was infused intravenously in six controls and nine cirrhotics. Steady-state renal and hepatic S clearances as well as hepatic ICG clearance were calculated. In controls the values (mean +/- SD) of the independent measurements of S and ICG hepatic clearance were 978 +/- 107 and 519 +/- 142 ml/min. respectively. while in cirrhotic patients they were 554 +/- 238 and 231 +/- 90 ml/min. Owing to the kinetic properties of S. its hepatic clearance may be regarded as a measure of functional liver plasma flow (FLPF). The total liver plasma flow (TLPF) values (mean +/- SD). calculated according to Fick's principle. were 1091 +/- 157 ml/min (S method) and 1033 +/- 153 ml/min (ICG method) in controls. and 1251 +/- 554 and 1284 +/- 677 ml/min in cirrhotics. In controls. FLPF was found to be very close to TLPF. In cirrhotic patients the difference between TLPF and FLPF (ranging from 169 to 2093 ml/min when measured by S method) was considered as an approximate estimate of intrahepatic shunting. The procedure is safe and simple and may add a new dimension to the investigation of hepatic circulation.
Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in patients with cirrhosis. Comparison with the Pugh score, Seventy-eight patients with cirrhosis were prospectively followed for up to 20 months. on the average. At entry into the study. galactose elimination capacity. aminopyrine breath test. and ICG clearance were measured. At the end of the study. 27 patients had died. Univariate analysis using the Kaplan-Meier method showed that both quantitative liver function tests (galactose elimination capacity: P less than 0.025; aminopyrine breath test: P less than 0.001; ICG clearance: P less than 0.005) and common clinical and biochemical data (encephalopathy: P less than 0.001; ascites: P less than 0.001; serum bilirubin: P less than 0.005; serum albumin: P less than 0.001; prothrombin index: P less than 0.05) were significant predictors of survival. To investigate whether quantitative liver function tests could contribute to a better definition of the prognosis. once Pugh score had already been taken into account. a multiple regression analysis according to the Cox model was performed. Pugh score and galactose elimination capacity resulted in the only independent prognostic covariates. From them a prognostic index was calculated. and the model was validated in an additional sample of 70 patients investigated according to the same protocol. The contribution GEC gave to the assessment of overall prognosis over that obtained using the Pugh score was slight. as estimated by the statistical parameters of the Cox's model. but was significant as assessed by a ROC curve analysis (P = 0.05). These data show that all quantitative liver function tests were predictors of survival in cirrhosis. and that the galactose elimination capacity added some new prognostic information to those already available using the Child-Turcotte-Pugh classification.
Suppressor T-cell deficiency in primary sclerosing cholangitis. Case and family study, Primary sclerosing cholangitis is considered to be an autoimmune disease of the liver in which there is an association with the HLA phenotypes B8 and DR3 and in which circulating autoantibodies occur. Abnormalities of immune regulation may be present but whether or not they are primary or acquired is not known. This report is of a patient with primary sclerosing cholangitis who was homozygous for HLA B8 DR3. had a circulating antinuclear antibody. and a defect in nonspecific suppressor T-cell activity despite glucocorticosteroid treatment. Nevertheless. family studies revealed no evidence of an immunoregulatory defect in first-degree relatives despite the presence of Raynaud's phenomenon and malignancy in two sisters.
A double-blinded, randomized trial of hydrocortisone in acute hepatic failure. The Acute Hepatic Failure Study Group, The Acute Hepatic Failure Study Group (AHFSG) has conducted a double-blinded. randomized evaluation of hydrocortisone in patients with acute hepatic failure. From July 1975 through August 1978. a 38-month period. 18 medical centers in the United States and one in Canada participated in this trial. A total of 64 patients were accessed and found eligible to participate in the study; two of them were subsequently eliminated from our analysis. Eighteen patients received placebo; 23 received 400 mg hydrocortisone per day. and 21 patients were administered 800 mg hydrocortisone per day. We did not observe any therapeutic effect of hydrocortisone. and the survival rates for placebo versus 400 mg and versus 800 mg hydrocortisone per day were 22%. 9%. and 24%. respectively. Fulminant hepatitis associated with drug hepatotoxicity or non-A. non-B hepatitis seemed to have a worse prognosis than fulminant B. although these differences were not significant. Serum alpha-fetoprotein had a modest prognostic value of survival and seemed to be limited to fulminant B. The AHFSG recommends. therefore. that corticosteroid use in acute hepatic failure with hepatic encephalopathy be discontinued.
Hepatic lesions in alcoholic HBV carriers, Liver biopsies were taken from 54 alcoholic HBV carriers with liver dysfunction to assess whether HBV infection or habitual drinking was the main cause of their illness. In 28 cases. ultrastructural studies were done. Results showed that 50% of the cases predominantly displayed virus-related histological changes. whereas 13% of them mainly had alcohol-related ones. Both pathological changes were evenly distributed in four cases. The remaining 15 cases showed nonspecific or other histological changes. Electron microscopy revealed that HBV core and Dane particles were seen with Mallory bodies in the same hepatocytes. Thus. we postulate that HBV-related changes are more often encountered than alcoholic ones in alcoholic HBV carriers and that HBV replication can occur even in hepatocytes bearing Mallory bodies.
Chronic mitoinhibition during promotion of hepatocarcinogenesis, We have reported previously that orotic acid (OA). a precursor for pyrimidine nucleotide biosynthesis. is able to promote carcinogenic process in both liver and duodenum of rats. The present study investigates the possible role of mitoinhibitory effects of OA as being responsible for its promotional effects. Male Fischer 344 rats were given a semisynthetic basal diet (BD) or a diet containing 1% OA for four weeks coupled with 2/3 partial hepatectomy (PH). and all animals were then continued on BD for an additional four weeks. This protocol is known to exert a promoting effect on the initiated rat liver. Livers were perfused. and the labeling index (LI) of isolated cultured hepatocytes was monitored. Hepatocytes isolated from livers of rats fed a BD or 1% OA exhibited in vitro an LI of 39 +/- 2 and 24 +/- 1%. respectively. The lowered in vitro LI was seen even upon exposure to epidermal growth factor (EGF) (67 +/- 2% in OA-treated livers compared to 91 +/- 2% in hepatocytes from control rat liver). A similar four-week exposure to OA coupled with PH decreased hepatic DNA synthesis induced by a choline-deficient diet in vivo by about 50%. These results indicate that OA is able to decrease the response of normal hepatocytes to growth factors and suggest a possible mechanism of chronic differential mitoinhibition as a basis for promotion induced by OA.
Role of estrogens and epidermal growth factor in hepatocellular carcinoma (HCC), Estrogen (E) and epidermal growth factors (EGF) receptors were assayed in the liver of nine patients with hepatocellular carcinoma (HCC). Total E and nuclear E receptors were decreased significantly in neoplastic tissue as compared to the levels found in surrounding nonneoplastic tissue. The EGF receptor was decreased also in neoplastic tissue. On the basis of binding data. a decrease in the number but not in affinity of both the E and EGF receptors was found.
Quantitation of estrogen and androgen receptors in hepatocellular carcinoma and adjacent normal human liver, Sex hormones have been shown to influence the development and course of several liver diseases. The worldwide predominance of hepatocellular carcinoma (HCC) in males has led to the suggestion that this disease might be hormone-responsive. Therefore. the hepatic estrogen (ER) and androgen receptor (AR) status of liver specimens from such patients was investigated. Samples were obtained from three female and six males patients undergoing liver resection; in each case. a small sample of both the tumor and adjacent normal tissue was collected. All patients had primary hepatocellular carcinoma without cirrhosis. In most cases. the tumor and the normal specimen had an equivalent content of cytosolic ER; however. three of the tumor samples (one female and two male) displayed considerably elevated cytosolic ER levels as compared to that of the normal tissue. In every sample. the tumor contained less nuclear ER than did the normal liver. When AR was measured. tumors of three patients (one female and two male) demonstrated a twofold elevation in cytosolic AR as compared to adjacent normal tissue. In the two male patients. an approximately twofold greater nuclear AR was found. Two other samples from male patients showed a modest elevation of cytosolic AR in the tumors. The patients whose tumors showed elevations in ER were not the same patients as those in whom the AR was elevated. Thus. these studies indicate that certain. but not all. specimens of HCC demonstrate either elevated ER or AR and suggest that a determination of receptor content might be useful prior to initiation of certain antihormone therapies.
Artificial liver. State of the art, If an effective hepatic assist system existed. it could serve as a bridge to transplantation. Most of the patients waiting for liver transplantation have chronic liver insufficiency but are not in hepatic coma. Various hepatic assist systems have been used to salvage patients with acute liver insufficiency. Most attempts have been disappointing. The methods used have included plasma exchange. plasma adsorption. double filtration. cryofiltration. thermofiltration. the combination of plasma exchange and amino acid hemodialysis. and others. For patients with chronic liver disease with moderate liver function impairment and limited to one or only a few areas of metabolic abnormality. a hepatic assist might allow the life of the patient to be maintained temporarily. The application of hepatic assist methods for chronic liver disease patients treated at the Cleveland Clinic has been encouraging. One of the patients who suffered from sclerosing cholangitis has maintained a near-normal life for almost five years by 170 plasma treatments. This is in spite of the fact that. at the onset of treatment. the patient was nearly comatose. Unfortunately. this patient did not wish to receive a liver transplantation. Based upon this experience. the concept of a bridge to transplantation approach to hepatic assist devices appears feasible. In addition. it is speculated that hepatic assistance during the early recovery stage of liver transplantation and during mild episodes of rejection may be useful.
Use of the infectious disease laboratory in emergency medicine, Until relatively recent advances in the identification of infectious agents. the emergency physician found only limited usefulness of the infectious disease laboratory. There are some tests that can provide information rapidly enough for the Emergency Department setting and new technologies that hold even greater promise for the future. The tests described in this article are currently available in most moderately sized Emergency Departments.
Cat-scratch disease, Cat-scratch disease is a relatively common disorder that is the result of infection with a recently identified gram-negative bacillus. Although it is overwhelmingly a benign. self-limited illness requiring only supportive care. serious complications can occur and the disease may be life-threatening on occasion. Although randomized clinical trials of antibiotic therapy for CSD do not exist. CSD has demonstrated in vitro susceptibility to several antibiotics. and gentamicin has been reported beneficial in a few patients with systemic manifestations of the illness. Therefore. pending clinical trials. gentamicin may be worthy of consideration in CSD patients with serious manifestations of this illness. CSD is one of the most common causes of adenopathy and should be considered in all patients who present with unilateral or regional lymphadenopathy.
The appropriate upper age limit for semen donors: a review of the genetic effects of paternal age, There is little evidence to support a correlation between increased paternal age and the incidence of chromosome anomalies. Though a few early studies demonstrated an increased risk of Down syndrome with advanced paternal age. especially after the age of 55. numerous later studies failed to confirm any paternal age effect. Among structural chromosome anomalies. only the inherited reciprocal translocations were found to be more common among children of older fathers. Chromosome analysis of semen donors would rule out this problem. There is evidence. however. that the incidence of serious nonchromosomal birth defects. especially those arising from new autosomal mutations. increases with paternal age. Risk estimates have been established for increased paternal age and contribution to new dominant mutations. The established association between increased paternal age and new autosomal mutations and the fact that most of the disorders associated with such mutations cannot be prenatally diagnosed may be important in establishing the upper age limit for semen donors. Recommendations from the literature are interpreted to advise men to have their children before age 40. This suggestion would obviously benefit immediate offspring and perhaps successive generations as well. The limit of 35 years set by AATB standards. therefore. is in harmony with such benefit. but may be too stringent in eliminating potential donors. Accordingly. the Reproductive Council of the AATB has initiated steps to modify its standards to the age limit of 40.
Effect of obesity on the response to acute adrenocorticotropin stimulation in eumenorrheic women, OBJECTIVE: Alterations in adrenocortical biosynthesis. as measured by the steroid response to acute adrenocorticotropic hormone (ACTH) stimulation. have frequently been reported in female hyperandrogenism. These patients are also commonly obese. which may account for some of these abnormalities. The object of this study was to test the hypothesis that obesity alters the adrenal response to acute adrenal stimulation. DESIGN: A prospective study of healthy premenopausal women of varying weights. SETTING: University-based clinical research center. PATIENTS: Fifty-seven healthy. eumenorrheic. nonhirsute female volunteers were studied. 30 weighing between 90% and 110% (normal-weight) and 27 weighing greater than 120% (obese) their ideal body weight. INTERVENTIONS: All subjects underwent a 60-minute acute intravenous ACTH-(1-24) stimulation test in the follicular phase (days 3 to 8) of the menstrual cycle. MAIN OUTCOME MEASURES: The basal levels of dehydroepiandrosterone sulfate (DHEAS). total and free testosterone (T). sex hormone-binding globulin (SHBG). estrone. estradiol. prolactin. and the luteinizing and follicle-stimulating hormone ratio were measured. Basal and poststimulation levels of androstenedione (A). dehydroepiandrosterone (DHEA). 17 alpha-hydroxyprogesterone (17 alpha-OHP). 17-hydroxypregnenolone (17-PREG). 11-deoxycortisol (S). and cortisol (F) were also obtained. and the net increments after stimulation were calculated. RESULTS: Normal-weight and obese women did not differ in age. height. or waist-hip ratio. Obese volunteers demonstrated lower circulating SHBG. 17-PREG. and S levels. and S/F ratio. but a higher free T and DHEAS/DHEA levels. No other differences were observed in either basal or adrenal response measures. with the exception of the net increment in A. which was almost twofold higher in obese volunteers (P less than 0.001). CONCLUSIONS: Obesity in eumenorrheic nonhirsute women is associated with lower circulating SHBG activity and higher free T and DHEAS/DHEA levels. No significant difference in adrenocortical response to acute ACTH-(1-24) stimulation was observed between obese and normal-weight women. with the exception of a higher net adrenal output of A. It does not appear that the abnormal adrenal stimulation results frequently observed in hyperandrogenic women are a consequence of their obesity.
Gamete intrafallopian transfer by hysteroscopy as an alternative treatment for infertility, OBJECTIVE: To evaluate efficacy and safety of the hysteroscopic cannulation by flexible catheter of the fallopian tubes for gamete intrafallopian transfer (GIFT). DESIGN: We studied the pregnancy rate (PR) and the safety of this new technique. SETTING: All patients were enlisted for GIFT at our Reproductive Medicine Unit. PATIENTS: We treated 26 patients whose infertility causes were terminal tubal damage. male factors. unexplained factors. and endometriosis. Patients with uterine tubal ostia unsuitable for gamete transfer or cervical incontinence were not included in the group. INTERVENTIONS: The patients underwent ovulation induction and oocyte retrieval by transvaginal ultrasonically guided puncture. The gamete transfers were carried out by hysteroscopic procedure using a flexible catheter put through the operating channel. MAIN OUTCOME MEASURE: The efficacy was evaluated by the PR (25.9%). RESULTS: Seven clinical pregnancies were obtained. but two patients aborted during the first weeks of pregnancy. No ectopic pregnancies were observed. CONCLUSIONS: Our results indicate that hysteroscopic GIFT is an alternative. safe. effective. and not invasive technique for fertility problems.
Occurrence of serum antisperm antibodies in patients with cystic fibrosis, OBJECTIVE: To determine if acquired obstruction of the vas deferens in men with cystic fibrosis (CF) induced the development of antisperm antibodies with genital tract obstruction similar to other men. DESIGN: Serum antisperm antibodies were assayed by an indirect immunobead test and an indirect immunofluorescence assay. Both homologous (human sperm/human zona) and heterologous (human sperm/zona-free hamster ova) sperm/egg interactions were evaluated in the presence of serum antisperm antibodies from patients with CF. SETTING: Cystic Fibrosis Clinic at the University of Oklahoma Health Sciences Center. a tertiary care referral center. PATIENTS: Fifteen CF patients (10 male and 5 female). 3 non-CF antisperm antibody-positive infertile patients (2 male and 1 female). 20 fertile controls (7 males and 13 females). and 9 fertile sperm donors were used. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Serum antisperm antibody levels in patients with CF. In those patients with antisperm antibodies. determine effect of these sperm antibodies on sperm/egg interactions and complement-mediated events. RESULTS: Sera from 3 (30%) of 10 men with CF demonstrated immunoglobulin (Ig)G. IgA. and/or IgM antisperm antibodies. whereas sera from all 5 CF women and the 20 control sera were negative for antisperm antibodies. The maximal titers for IgG. IgA. and IgM antisperm antibody were 1:8. 192. 1:256. and 1:64. respectively. The immunobead binding. which was restricted to the sperm head and tail-tip or the midpiece and tail-tip. correlated with the indirect immunofluorescence pattern. Antisperm antibody-positive sera from men with CF impaired both the binding and penetration of human zonae and the penetration of hamster ova by human sperm. CONCLUSIONS: Similar to other men with congenital or acquired obstruction of their genital tract. antisperm antibodies may occur in some men with CF. Antisperm antibodies may contribute to immune sperm dysfunction in some men with CF by activated complement-mediated events and interfering with sperm/egg interactions.
The microsperm penetration assay: development of a sperm penetration assay suitable for oligospermic males, OBJECTIVE: To develop a specialized sperm penetration assay (SPA) for the evaluation of sperm from oligospermic patients. DESIGN: The development of the assay is in four parts: determine optimal sperm number; demonstrate quality control; establish statistical limits for fertile population; compare results to in vitro fertilization (IVF) outcome. SETTING AND PATIENTS: A group of 63 patients with oligospermia and/or poor motility and a group of 17 fertile donors were compared using the optimized SPA and the micro-SPA. Sperm from a third group of 35 patients were simultaneously incubated with human ova (IVF) and hamster ova (micro-SPA). MAIN OUTCOME MEASURES: Both types of SPA scores are expressed as a sperm capacitation index (penetrations per ovum). Outcome of IVF is expressed as a percent of ova fertilized. RESULTS: Using 25.000 sperm was found to be optimal. The normal fertile range was statistically determined to have a lower limit (-2 SD) of 2.0 penetrations per ovum. When scores from 63 male factor patients were compared using the optimized SPA. only 43% had sufficient swim-up sperm. However. the micro-SPA could accurately test 100% of the samples because it requires only one tenth the number of sperm. CONCLUSION: The micro-SPA provides a valuable diagnostic test for the evaluation of the male factor patient.
Changes in body composition with danazol therapy, Whole body lean and fat mass measurements by dual energy x-ray absorptiometry were performed in 14 premenopausal women undergoing danazol treatment for endometriosis. After 6 months. there was a significant increase in lean tissue mass. Body fat decreased but this was significantly less in the android (upper body segment) region than in the gynoid (lower body segment) region. Danazol thus has both anabolic and androgenic effects on body composition. Dual energy x-ray absorptiometry provides a new. noninvasive. and rapid means of studying body composition.
Preclinical markers in studies of Parkinson's disease, The development of reliable preclinical detection procedures for idiopathic Parkinson's disease may be the fundamental advance required for the establishment of the cause. the natural history. and ultimately. the prevention of this neurodegenerative disorder. The usefulness of these preclinical markers in efforts to better understand the etiology and development of this disorder will relate to whether they are direct measures of dopamine production or indirect measures such as metabolic changes or comorbidity. whether they can be used in the first or later decades of life. whether they are invasive. and whether they are expensive and sophisticated or simple and cheap. An overview of the criteria for evaluation of the utility of specific markers. as well as an assessment of the importance of early markers in future research. is presented.
Preclinical detection of motor and nonmotor manifestations, The advent of possible protective therapies for Parkinson's disease has created a need for methods of diagnosing the disease before the clinical features become fully evident. As a number of motor and nonmotor manifestations of the disease emerge months to years before a diagnosis can be made. a battery of clinical tests might be sufficient to identify individuals at an earlier stage than is currently possible using the standard history and physical examination. A list of questions regarding possible risk factors. specific symptoms. and observations of family members could be combined in a self-administered questionnaire that might identify individuals with a high probability of early. but otherwise undiagnosable. Parkinson's disease. Identification of subtle motor features is another possible screening method. For example. handwriting and speech are commonly affected prior to diagnosis; thus. automated analysis of these motor actions might also provide detection of incipient disease.
Olfactory dysfunction in three neurodegenerative diseases, Olfactory dysfunction is among the first signs of Alzheimer's disease (AD). idiopathic Parkinson's disease (PD). and the parkinsonism-dementia complex (PDC) of Guam. We have recently demonstrated that the odor identification and detection deficits of patients with PD are equivalent to those of patients with mild AD when subtle differences in cognitive function are statistically controlled for by analysis of covariance. In contrast. patients with progressive supranuclear palsy (PSP) and patients with 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP)-induced parkinsonism evidence olfactory function much more similar to that of normal controls. In the present study. we administered the University of Pennsylvania Smell Identification Test and the Picture Identification Test to 24 patients with early signs of the PDC of Guam and statistically compared their test scores to those of 24 early-stage AD and 24 early-stage PD patients of similar age and gender from the United States mainland. Although the PDC group evidenced slightly more difficulty in identifying pictures than did the other 2 groups. the odor identification deficit associated with this disorder was of the same magnitude as that observed in AD and PD. suggesting that olfactory testing cannot be used to distinguish among these 3 diseases and that the olfactory dysfunction of these disorders may reflect a common neurologic substrate.
Liver enzyme abnormalities in Parkinson's disease, If toxicant exposure contributes to the cause of Parkinson's disease. poor function of detoxifying enzymes could increase vulnerability for Parkinson's disease. Although no hepatic enzyme system has been shown universally to be dysfunctional in Parkinson's disease patients. several have been suggested to be dysfunctional in subgroups. such as those with young age at disease onset. Specific enzymes implicated include several P450 enzymes. most notably P450 IID6. and cysteine dioxygenase. If hepatic enzyme abnormalities contribute to the development of Parkinson's disease. molecular genetic techniques may allow the development of screening tests to identify at-risk subjects in order to intervene with protective therapies.
Cerebral balloon angioplasty for treatment of vasospasm after subarachnoid hemorrhage, Percutaneous transluminal balloon angioplasty can offer marked improvement to selected patients with ischemic deficits caused by cerebral vasospasm. Vasospasm resulting from subarachnoid hemorrhage related to aneurysmal rupture or occurring during detachable balloon embolization therapy for treatment of an aneurysm has responded to angioplasty when conventional methods have failed. Indications. appropriate timing. patient selection. and nursing implications for cerebral angioplasty are discussed in this article.
Review of neurobehavioral assessment tools, Behavioral. cognitive. and memory deficits are frequently observed sequelae of brain injury. Yet in most critical care settings. neurologic assessment is limited to evaluation of arousal. pupillary response. orientation. and motor capability. Behavior. cognition. and memory are not routinely evaluated. Several brief. bedside assessment tools are reviewed. All may be used in the critical care setting to evaluate the type and extent of residual deficits in the neurologically impaired patient. Nursing implications. based on the evaluation of deficits. are also discussed.
Effect of lung hyperinflation and endotracheal suctioning on heart rate and rhythm in patients after coronary artery bypass graft surgery, We examined the effect of lung hyperinflation and suction on PaO2. heart rate. and rhythm in patients after coronary artery bypass graft surgery (N = 26). Three lung hyperinflation breaths. at one of five randomly ordered volumes (tidal volume. 12 cc/kg. 14 cc/kg. 16 cc/kg. or 18 cc/kg of lean body weight) were delivered. by a ventilator (fraction of inspired oxygen 1.0). followed by 10 seconds of continuous suction. Lung hyperinflation and suctioning were repeated three times. Repeated-measures analysis of variance revealed a statistically significant increase (p = 0.000) in PaO2 immediately after the third suction pass. which was volume dependent (p = 0.009). A statistically significant (p less than 0.001) increase in heart rate from baseline occurred over the three lung hyperinflation-suctioning sequences that was not volume dependent. The mean increase in heart rate was 6.8 beats/min. The majority of rhythm changes for lung hyperinflation and suctioning were from normal sinus rhythm to sinus tachycardia. Suction was associated with a greater incidence of rhythm (53.9%) and arrhythmia (80.8%) changes. The most frequent arrhythmia was premature atrial contraction.
Pulmonary embolism associated with the act of defecation, Pulmonary embolism associated with the act of defecation has not been well described in the medical literature. We report our experience with deep vein thrombosis in patients who had a pulmonary embolism triggered by the act of defecation. In these individuals the embolization of peripheral thrombus appeared to have resulted from the performance of the Valsalva maneuver and its effects on peripheral blood flow and intrathoracic pressures. In addition. the important role of nursing personnel in recognizing and diagnosing this disorder as well as in initiating prophylactic measures directed against the development of thromboembolic disease is discussed.
Acetazolamide in the treatment of metabolic alkalosis in critically ill patients, Metabolic alkalosis is a common acid-base disturbance in critically ill patients. In many patients correction of fluid and electrolyte status does not fully correct the metabolic derangement. In this study we examined the effect of 500 mg of intravenous acetazolamide. after correcting for fluid and electrolyte abnormalities. on the acid-base status of 30 ventilated patients. In all patients studied there was a fall of total serum bicarbonate; the mean reduction at 24 hours was 6.4 mmol/L. with a normalization of the base excess and pH. The onset of action was rapid (within 2 hours). and the maximal effect occurred at a mean of 15.5 hours. although there was wide variation. The effect of acetazolamide was still apparent at 48 hours. No adverse effects were noted. We conclude that in patients with metabolic alkalosis. once fluid and electrolyte abnormalities have been corrected. acetazolamide is an effective and safe form of therapy with a quick onset and long duration of action.
Overview of work-related hazards in nursing: health and safety issues, Nurses working in hospital environments are exposed to a number of occupational health hazards. For five categories of hazards we present research-based documentation of potential and actual health-related problems. and avenues for health promotion and prevention of exposures. Both personal and organizational responsibilities for self-health protection are addressed.
Crisis and ethical dilemmas: who will care for the rural nurse, The critical care nurse who works in the small rural community faces the unique experience of indistinct personal and professional roles. Established relationships in the rural community place the critical care nurse at risk of becoming a victim when ethical and crisis events arise.
Update on thrombolytic therapy in acute myocardial infarction, There is a continuum of clinical research in thrombolytic therapy that will eventually evolve into the most effective regimen to chemically open a thrombosed artery. Numerous previous clinical trials. a number of ongoing trials. and planned future trials are shown in a list of acronyms and their translations as a convenience for identifying the trials.
Overview: rationale of thrombolysis in treating acute myocardial infarction, Treatment of coronary thrombosis with thrombolytic agents was first introduced in the 1950s. Clinical trials. primarily with streptokinase during the 1960s and 1970s. addressed the effects of thrombolysis on mortality rates after acute myocardial infarction. but were inconclusive and largely ignored. In 1976. Chazov et al. from the Soviet Union demonstrated that intracoronary streptokinase could produce prompt recanalization of a totally occluded infarct-related artery. In 1980. DeWood et al. demonstrated that 87% of patients with classic Q-wave myocardial infarction had total occlusion from coronary thrombosis of the infarct-related artery when studied during the first 4 hours of their infarction and that 65% of these arteries were still occluded when patients were studied between 12 and 24 hours after infarction. These observations stimulated renewed interest in thrombolytic therapy for acute myocardial infarction. Mortality trials have subsequently demonstrated that agents such as recombinant tissue plasminogen activator. streptokinase. and anisoylated plasminogen streptokinase activator complex remarkably reduce early mortality rates among patients with acute myocardial infarction when treatment is instituted within the first 6 hours of infarction. Benefit has yet to be demonstrated. however. in patients with acute myocardial infarction characterized by ST-segment depression. This whole area is currently under study by the TIMI investigators. TIMI-3B is a mortality study in which patients with either non-Q-wave myocardial infarction or unstable angina with rest pain are randomly assigned to receive either tissue plasminogen activator or placebo. Results of this trial will help us in the future to determine the appropriate role of thrombolytic therapy in treating acute ischemic syndromes other than transmural myocardial infarction.
Clinical management of patients receiving thrombolytic therapy, Rapid delivery of thrombolytic therapy to suitable patients with acute myocardial infarction can limit myocardial damage and reduce the risk of death. This requires an emergency department team approach following a written protocol to initiate thrombolytic therapy within 45 minutes of the patient's arrival at the emergency department. Nurses and physicians caring for patients with acute myocardial infarction must be aware of inclusion and exclusion criteria. drug preparation. dosage and administration. recommended adjunctive therapies. and potential complications associated with pharmacologic thrombolysis. All patients with acute myocardial infarction should be carefully screened for their potential for receiving thrombolytic therapy with a favorable benefit/risk ratio.
Delays in the treatment of acute myocardial infarction: an overview, Delays in treatment of acute myocardial infarction prevent a substantial portion of patients from receiving maximal benefit from reperfusion therapy. Median delay between onset of symptoms and arrival at the hospital is 2 to 4 hours. Average time between arrival at the hospital and initiation of thrombolytic therapy is 84 minutes. Approximately 50% of patients hospitalized for suspected acute myocardial infarction do not use the emergency medical service system. Delay before treatment can be divided into several components: patient delay. emergency medical service delay. and hospital delay. Factors contributing to delay in each component and possible approaches to decreasing these delays are discussed. The effects of treatment delay on prognosis and future care-seeking behavior of patients hospitalized with suspected acute myocardial infarction are also discussed.
Treatment-seeking behavior among those with signs and symptoms of acute myocardial infarction, Significant delays in seeking definitive treatment for the signs and symptoms of acute myocardial infarction increase morbidity and mortality. In most studies. delay times average more than 4 hours. The following variables are associated with increased delay: a medical history of angina. diabetes mellitus. or hypertension; older age; black race; seeking advice from a family member or a physician; symptom onset on a weekday; and attempts at self-treatment. Variables associated with reduced delay times are the following: pain recognized as cardiac in origin. hemodynamic instability. severe chest pain. younger age. and consultation with a coworker. Surprisingly. patients who have already experienced a myocardial infarction are just as likely to delay as patients who have not had this experience. These findings provide direction for developing and testing patient and family interventions. establishing community education programs. and reducing patient delay in response to the signs and symptoms of acute myocardial infarction.
Role of emergency medical services, For thrombolytic therapy to be effective in the treatment of acute myocardial infarction. the patient must enter the health care center delivery system in an efficient manner. Some entry delays are due to patient decisions and interactions with others. In the United States. prehospital care is delivered by a variety of different systems. varying from public service types such as fire-department based to private types of service. These personnel vary in level of training from paramedics with a high level of training to Emergency Medical Technicians-Ambulance with basic training (first aid). even less in some areas. The training should be upgraded so that training as an emergency medical technician with the ability to defibrillate would be the minimum level for emergency ambulance personnel; wherever economically and logistically feasible. ambulance personnel should be paramedics. Although the 911 emergency telephone system exists in some areas. there is no centralized. universal system for access. causing confusion and delays in obtaining care in critical situations such as cardiac arrest. There is a need for a national emergency number--911--with the ability to identify the calling number and address. Since dispatchers have little medical dispatch training. needed instructions are not given to the caller. which can reduce the patient's chance of survival. Trained dispatchers are needed to dispatch resources efficiently and to offer assistance until trained rescuers arrive. Ambulances are inefficiently located in some areas of the United States. slowing response to the patient.
The role of hospital delivery systems in the treatment of patients with acute myocardial infarction: rural hospital setting, Discussions on the use of thrombolytic therapy include when is the best time for administration. where is the best place for administration. and who is the most appropriate to begin the administration. Rapid triage and intervention for patients with suspected acute myocardial infarction are special challenges in rural communities. To evaluate the possibility of instituting rapid. "golden hour" treatment for the patient with acute myocardial infarction. rural health care resources must be reviewed. Changes in the health care environment and access to emergent care for the patient with acute myocardial infarction directly affect any treatment. Timely interventions depend on available personnel. appropriate clinical protocols. and regional network systems.
Problems faced by the urban emergency department in providing rapid triage and intervention for the patient with suspected acute myocardial infarction, Widespread application of thrombolytic therapy has increased the importance of rapid triage and intervention for the patient who seeks treatment in the emergency department (ED) for suspected acute myocardial infarction. It has been suggested that all patients with acute myocardial infarction who might benefit from thrombolytic therapy should receive treatment within the first "golden hour" of arrival at the hospital ED. Busy urban medical centers. particularly public hospitals serving a large proportion of indigent patients. face special challenges in attempting to meet this goal. ED overcrowding. in part caused by patient "dumping." and diminishing governmental financial support have created an environment in which rapid triage and treatment are difficult. Because only 4% to 5% of all patients who are seen in the ED with chest pain actually require thrombolytic therapy. there is negative reinforcement for the triage nursing staff. The busy urban ED environment also creates greater litigation potential for the physician and nurse. Problems created by the busy ED environment can be minimized by providing adequate nursing staff. standing orders and protocols for evaluation of the patient with chest pain. equipment for an immediate electrocardiogram. and a thrombolytic drug stock in the ED. Hospital administrators must recognize the unique problems created in the ED when inpatient beds are unavailable. The hospital must also have efficient bed turnover and a community-wide plan for dealing with patients when the ED "closes" to incoming ambulance traffic. Governmental entities must recognize the consequences of their actions in curtailing health care benefits for those who cannot afford care in private hospitals.
Coronal alignment after total knee replacement, Maquet's line passes from the centre of the femoral head to the centre of the body of the talus. The distance of this line from the centre of the knee on a long-leg radiograph provides the most accurate measure of coronal alignment. Malalignment causes abnormal forces which may lead to loosening after knee replacement. We report a series of 115 Denham knee replacements performed between 1976 and 1981 using the earliest design of components. inserted with intramedullary guide rods. Patients were assessed clinically and long-leg standing radiographs were taken before operation. soon after surgery and up to 12 years later. In two-thirds of the knees (68%) Maquet's line passed through the middle third of the prosthesis on postoperative films and the incidence of subsequent loosening was 3%. When Maquet's line was medial or lateral to this. an error of approximately +/- 3 degrees. the incidence of loosening at a median period of eight years was 24%. This difference is highly significant (p = 0.001). Accurate coronal alignment appears to be an important factor in prevention of loosening. Means of improving the accuracy of alignment and of measuring it on long-leg radiographs are discussed.
Measurement of hip prostheses using image analysis. The maxima hip technique, A computer-based image analysis system has been developed as a research tool in total hip replacement. The system has been programmed to take multiple measurements from coronal plane radiographs. Poor quality radiographic images can be enhanced and standardised. The measurements which can be obtained include stem subsidence. cup migration. cup wear. and stem loosening. Reproducibility and accuracy were +/- 0.01 mm and +/- 0.5 mm respectively. The present application is in retrospective research. but prospective monitoring of radiographs is planned.
Survivorship analysis and confidence intervals. An assessment with reference to the Stanmore total knee replacement, Survivorship analysis is a useful way of expressing the long-term results of joint replacement: it provides a means of comparing the life span of one type of prosthesis with another. However. such studies should include a full life-table and the confidence intervals for the survival rates at given times. At least 40 surviving prostheses are required to provide reliable results.
Bonding of hydroxyapatite-coated femoral prostheses. Histopathology of specimens from four cases, We examined specimens of hydroxyapatite-coated femoral prostheses from four patients who had died within nine months of implantation for fractured neck of femur. Histology showed newly formed immature bone overlying the hydroxyapatite coating with new trabeculae bridging to the endosteal bone layer. In the diaphysis. where there had been contact between the hydroxyapatite and the cortex. there was dense. firmly anchored bone with an haversian architecture. In other places the newly formed bone had a trabecular structure. containing bone marrow tissue with normal cellularity. It appeared that biological osseointegration had taken place.
Revision of failed knee replacements using fixed-axis hinges, Forty failed hinged arthroplasties of the knee were revised by the insertion of another hinged implant. In 14 cases the prosthesis used at the revision operation was similar to the primary implant; in 26. a hinge with an elongated femoral stem was used. usually replacing part of the femoral shaft. In seven of these knees an elongated tibial stem was also required. though the tibial shaft was replaced in only two of them. There were many complications. Fracture of the femur at the tip of the femoral stem was the most frequent. Sixteen first revisions failed and were revised a second time; 12 required replacement of the distal femoral shaft and three required replacement of the proximal tibia. The incidence of complications in knees requiring a second revision was even higher. Four required a third revision after an average interval of three years. Failure of a hinged prosthesis results in bone loss mainly in the femur. Revision of a failed hinged prosthesis with another of the same design is unlikely to be successful and may cause fracture of the femur.
Quantifying bone loss from the proximal femur after total hip arthroplasty, To define the natural history of bone loss around a femoral prosthesis. the bone mineral content and bone mineral density were measured for each femur in 28 patients with unilateral total hip arthroplasty. 18 age-matched controls. and seven patients with unilateral osteoarthritis. The areas measured were inside the lesser trochanter and 4.8 cm distal to it. The contralateral hip served as the control. Three years after arthroplasty there was 40% loss in average bone mineral content inside the lesser trochanter. and 28% loss in average bone mineral content 4.8 cm distally in the medial cortex. At seven to 14 years after operation. patients had lost 40% of bone proximally and 49% distally. The data suggest that this may progress in a proximal-to-distal fashion. and could account for a 50% decrease in bone mass seven to 14 years after surgery.
Effect of hypotensive epidural anaesthesia on acetabular cement-bone fixation in total hip arthroplasty, We selected 20 matched pairs of patients who had had total hip arthroplasty by the same surgeon using the same cemented technique. Matching was by age. sex. height. weight and diagnosis. One of each pair had received hypotensive epidural anaesthesia. with less than 300 ml blood loss: the other had normotensive general anaesthesia with more than 500 ml of blood loss. Early postoperative radiographs were evaluated independently by three blinded observers. using a scoring criteria which assessed the quality of the cement-bone interface. The results showed that patients who had received epidural anaesthesia had significantly better radiographic scores (p less than 0.02). Our findings suggest that hypotensive anaesthesia facilitates penetration of cement into bone.
Polyethylene wear from retrieved acetabular cups, Laboratory wear testing of ultra high molecular weight polyethylene from 12 Charnley acetabular cups. removed after periods of up to 17.5 years showed that the large patient-to-patient variations in clinical penetration rate cannot be explained by batch-to-batch variation in the wear resistance of the material. Nor was there any evidence of a time-dependent degradation in wear resistance of the material.
Ultraviolet radiation compared to an ultra-clean air enclosure. Comparison of air bacteria counts in operating rooms, Clean air in the operating room is important during joint replacement surgery. We compared monochromatic ultraviolet radiation of 254 nm with the use of a Charnley-Howorth air enclosure by bacterial air-sampling during 113 total hip arthroplasties. Air samples were taken continuously at the edge of the wound and every 15 minutes at a site 130 cm from the operating table. We also tested the effect of occlusive clothing for all personnel. Ultraviolet light was more efficient than the ultra-clean air enclosure. and occlusive clothing on its own or in combination also produced improvement. The implications of these findings are discussed.
Prediction of amputation after severe lower limb trauma, The Mangled Extremity Severity Score was applied to 152 patients with severely injured lower limbs. All cases with a score of seven or more required amputation; some with scores of less than seven eventually came to amputation. These observations are discussed.
The effect of devascularisation upon early bone healing in dynamic external fixation, We examined the effect of periosteal devascularisation upon the early healing of osteotomies of sheep tibiae held in an instrumented external fixation system with an axial stiffness of 240 N/mm. At 14 days. cortical blood flow measured by the microsphere technique was 19.3 ml/min/100g in the well-vascularised osteotomies. but only 1.7 ml/min/100g in the devascularised osteotomies. despite an increase in medullary flow (p less than 0.0005). Delay in healing of the devascularised osteotomies was suggested by an in vivo monitoring system and confirmed by post-mortem mechanical testing. We suggest that the osteogenic stimulus of dynamic external fixation is dependent on the early restoration of cortical blood flow in devascularised fractures.
Need the thumb be immobilised in scaphoid fractures? A randomised prospective trial, Immobilisation of the thumb is widely believed to be important in the management of fractures of the carpal scaphoid. To assess the need for this. we randomly allocated 392 fresh fractures for treatment by either a forearm gauntlet (Colles') cast. leaving the thumb free. or by a conventional 'scaphoid' plaster incorporating the thumb as far as its interphalangeal joint. In the 292 fractures which were followed for six months. the incidence of nonunion was independent of the type of cast used.
Proprioception and function after anterior cruciate reconstruction, We have assessed 45 patients who had undergone anterior cruciate reconstruction by a modified MacIntosh-Jones method. The results. using standard knee scores and clinical ligament testing. correlated poorly with the patient's own opinion and with the functional result. However. measurement of proprioception in the knee correlated well with both function (r = 0.84) and with patient satisfaction (r = 0.9). This study indicates that proprioception. rather than the clinical excellence of the repair. is a major factor in the outcome of anterior cruciate ligament reconstruction.
Pachydysostosis of the fibula, We report four patients with unilateral bowing of the lower leg. affecting only the fibula. The bone is too long with anterolateral curvature of the distal third. Because of its regressive course and the absence of cutaneous involvement. this newly described entity can be distinguished from other forms of bowing of the leg.
Progressive noninfectious anterior vertebral fusion, We reviewed 26 patients with progressive spinal kyphosis due to anterior fusion between the vertebrae. No patient had back pain or any neurological defect. The kyphosis appeared to be progressive until the fusion had included all of the disc. Progression was faster during the adolescent growth-spurt. Kyphosis increased with the number of discs involved. from one to six. and the extent of fusion within each disc. In six of the nine cases treated by spinal bracing. progression of the kyphosis was arrested.
Cutaneous multilobated T-cell lymphoma with aggressive course, Cutaneous multilobated T-cell lymphoma is an uncommon variant of skin-based peripheral T-cell lymphoma typically characterized by cutaneous nodules in elderly patients and a chronic clinical course. We report a case of the disease that led to the patient's death within 2 years after onset. This disease may be associated with a more aggressive clinical course than generally recognized.
Imipramine hyperpigmentation: a slate-gray discoloration caused by long-term imipramine administration, A 48-year-old white woman. skin type III. had a slate-gray discoloration of the face and dorsa of both hands after ingesting imipramine. 150 mg/day for 5 years. Her iris color was also darkened. One year after cessation of the therapy. the discoloration became lighter. Sun-protected skin showed no discoloration. Light microscopy revealed an accumulation of doubly refractile golden yellow granules in the papillary dermis. mostly scattered. with some concentration around the blood vessels but not in the endothelial cells. Electron micrographs showed numerous amorphous electron-dense inclusion bodies in histiocytes. phagocytes. fibroblasts. and dermal dendrocytes. Melanosomes were phagocytosed in the same cells but in separated locations. Imipramine is structurally related to chlorpromazine and can cause slate-gray discoloration. However. the color of the granules deposited in the papillary dermis is golden-yellow and they are not deposited in endothelial cells.
Allergy to coined money: nickel contact dermatitis in cashiers, We report a 48-year-old cashier with nickel allergy and hand eczema and discuss the relevance of nickel-induced occupational hand dermatitis in cashiers. A literature review revealed that hand eczema together with nickel contact allergy is not rare in cashiers. The problems of various test results in nickel allergy and its importance in atopic eczema and in occupational dermatoses are considered. Provocative use tests are recommended to assess the relevance of patch test findings.
Erythema multiforme after contact dermatitis in response to an epoxy sealant, A case of erythema multiforme associated with an allergic contact dermatitis in response to an epoxy-based compound is presented. Patch tests revealed a positive reaction to both the epoxy resin and the hardener. Chemicals applied directly to the skin should be considered as a potential cause of erythema multiforme.
Cutaneous metastasis from papillary carcinoma of the thyroid gland, Cutaneous metastases from carcinoma of the thyroid gland are rare. We present the clinical. histologic. and immunohistochemical features of a solitary metastasis from papillary carcinoma of the thyroid. Our results indicate that this tumor can produce epithelial mucin and. therefore. must be differentiated from other metastatic carcinomas and from primary apocrine tumors of the skin. Positive staining for thyroglobulin confirmed the diagnosis in this case.
Subcutaneous cysticercosis, A case of subcutaneous cysticercosis is presented. and 35 other cases from the literature are reviewed. Patients usually have multiple subcutaneous nodules that are firm. mobile. and sometimes painful. occurring mainly on the trunk and extremities. Diagnosis is made by biopsy; however. radiologic and immunologic studies can be helpful in the diagnosis and work-up. Treatment options include surgery. praziquantel. and albendazole.
Cutaneous Histoplasma capsulatum in a nonimmunocompromised patient with previously treated cutaneous Mycobacterium kansasii, This report describes a black woman with a history of cutaneous Mycobacterium kansasii responsive to antituberculous drugs. A culture several years later of cutaneous lesions was also positive for Histoplasma capsulatum. Both cutaneous diseases are rare and most often occur in immunocompromised hosts. There is no known association between these two diseases. This patient may have an as-yet unidentified immunodeficiency that predisposes her to these rare infections. Her case emphasizes the importance of repeat biopsy for atypical skin lesions.
Macroreentry in the infarcted human heart: the mechanism of ventricular tachycardias with a "focal" activation pattern, Endocardial mapping of electrical activity was carried out in 150 patients to guide antiarrhythmic surgery for drug-resistant ventricular tachycardia in the chronic phase of myocardial infarction. In 20 of these patients. the activation pattern of 27 distinct tachycardias was focal and diastolic potentials were recorded at three or more sites. In 26 tachycardias. the sequence of diastolic potentials progressed from the area of latest activation of one cycle toward the "origin" of the next cycle. In two patients. the heart was stimulated during tachycardia. resulting in entrainment of the tachycardia in both. Late potentials were recorded during entrainment at sites where diastolic potentials occurred during tachycardia. In 11 of the 20 patients. endocardial mapping was performed during sinus rhythm. In four of these. late potentials were observed during sinus rhythm at sites where diastolic potentials were recorded during tachycardia. In two patients without late potentials during sinus rhythm. late potentials were observed during stimulation and induced ectopic beats. The results support the concept that the mechanism of several of these tachycardias is based on reentry in a macrocircuit comprising a tract of surviving tissue traversing the infarct and the remaining healthy tissue. They also indicate that the absence of late potentials during sinus rhythm does not guarantee the absence of arrhythmogenic pathways.
Sympathetic neural responses to induced ventricular tachycardia, Although sympathetic mechanisms play a major role in buffering abrupt arterial pressure reductions. including those that occur during tachyarrhythmias. human sympathetic nervous system responses to ventricular tachycardia have not been measured. Muscle sympathetic nerve activity was recorded directly from the peroneal nerve in 16 patients during diagnostic induction of 19 episodes of sustained monomorphic ventricular tachycardia (average rate 189 beats/min. range 130 to 250). Average systolic and diastolic pressures decreased from 149/78 to 61/49 mm Hg by 10 s and increased toward baseline levels to 88/64 mm Hg by 1 min of ventricular tachycardia. Average sympathetic nerve activity increased by 92% at 10 s in direct proportion to arterial pressure reductions and in inverse proportion to ventricular rate and remained 83% above baseline levels at 1 min. The late recovery of arterial pressure during ventricular tachycardia was related significantly to the magnitude of early sympathetic responses. Sympathetic activity tended to lose its discrete bursting pattern during ventricular tachycardia. and power spectral analysis showed that the large sympathetic peaks at the heart rate frequency present during sinus rhythm are absent during ventricular tachycardia. This study is the first to delineate human sympathetic nervous system responses to ventricular tachycardia. The results suggest that in the patients studied. large early sympathetic surges differed from those that occur during sinus rhythm and contributed to hemodynamic stability during ventricular tachycardia.
Echocardiographic estimation of critical left ventricular size in infants with isolated aortic valve stenosis, With the current trend to performing surgical valvotomy for infantile aortic stenosis without cardiac catheterization. there is a need to develop echocardiographic criteria for adequacy of left ventricular size. The echocardiograms and catheterization data of all 25 infants less than 3 months of age undergoing aortic valvotomy for isolated aortic valve stenosis from September 1980 through July 1990 were reviewed. Significant differences (p less than 0.05) between the survivors and nonsurvivors were noted for age at operation (30 +/- 28 vs. 3 +/- 1.5 days). mitral valve diameter (10.1 +/- 1.7 vs. 7.7 +/- 1.5 mm). left ventricular end-diastolic dimension (18.4 +/- 6.4 vs. 11.4 +/- 3 mm). left atrial dimensions (15.3 +/- 3.8 vs. 10 +/- 2.4 mm). left ventricular cross-sectional area on the parasternal long-axis echocardiogram (4 +/- 1.9 vs. 2 +/- 1.9 cm2) and angiographically determined left ventricular end-diastolic volume (43 +/- 23 vs. 11 +/- 5 ml/m2). There was no difference with respect to patient weight. body surface area. aortic root dimension or left ventricular ejection fraction. Left ventricular cross-sectional area less than 2 cm2 as measured on the parasternal long-axis echocardiogram was found in 5 of 7 nonsurvivors and 0 of 12 survivors. making this a risk factor for perioperative death (p less than 0.05). Left ventricular end-diastolic dimension less than 13 mm was found in 5 of 6 nonsurvivors and 2 of 17 survivors. making this another risk factor for early mortality (p less than 0.05).
Congenitally corrected transposition and Ebstein's anomaly of the systemic atrioventricular valve: association with aortic arch obstruction, Aortic arch abnormalities are uncommon in patients with congenitally corrected transposition of the great arteries. Over a 20-year period. 10 patients with congenitally corrected transposition and Ebstein's anomaly of the systemic atrioventricular (AV) valve were identified. Five neonates had severe systemic AV valve regurgitation with severe coarctation of the aorta (n = 4) or aortic atresia (n = 1) and presented with heart failure. Four died in the neonatal period and one who had coarctation repair died 7 months postoperatively. The remaining five patients with congenitally corrected transposition and Ebstein's anomaly had mild left AV valve regurgitation; none of these had aortic arch obstruction. In neonates who have coexisting Ebstein's anomaly of the systemic AV valve and congenitally corrected transposition. obstruction to aortic arch flow is common. Severe systemic AV valve regurgitation with a morphologic systemic right ventricle may have contributed to low anterograde flow in the ascending aorta prenatally and thereby to the aortic arch abnormality.
Exercise hemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure, Hemodynamics and myocardial metabolism at rest and during exercise were investigated in 21 patients with heart failure. The patients were evaluated before and after long-term treatment (14 +/- 7 months) with the beta-adrenergic blocking agent metoprolol. Clinical improvement with increased functional capacity occurred during treatment. Maximal work load increased by 25% (104 to 130 W; p less than 0.001). Hemodynamic data showed an increased cardiac index (3.8 to 4.6 liters/min per m2; p less than 0.02) during exercise. Pulmonary capillary wedge pressure decreased at rest (20 to 13 mm Hg; p less than 0.01) and during exercise (32 to 28 mm Hg; p = NS). Stroke volume index (30 to 39 g.m/m2; p less than 0.006) and stroke work index (28 to 46 g.m/m2; p less than 0.006) increased during exercise and long-term metoprolol treatment. The arterial norepinephrine concentration decreased at rest (3.72 to 2.19 nmol/liter; p less than 0.02) but not during exercise (13.2 to 11.1 nmol/liter; p = NS). The arterial-coronary sinus norepinephrine difference suggested a decrease in myocardial spillover during metoprolol treatment (-0.28 to -0.13 nmol/liter; p = NS at rest and -1.13 to -0.27 nmol/liter; p less than 0.05 during exercise). Coronary sinus blood flow was unchanged during treatment. Four patients produced myocardial lactate before the study. but none produced lactate after beta-blockade (p less than 0.05). There was no obvious improvement in a subgroup of patients with ischemic cardiomyopathy. In summary. there were signs of increased myocardial work load without higher metabolic costs after treatment with metoprolol.
Influence of calcium administration on the short-term hemodynamic and anti-ischemic effects of nifedipine, This prospective study investigated whether pretreatment with intravenously administered calcium would influence the effect of nifedipine on rest hemodynamics and treadmill performance in patients with ischemic heart disease. Seventeen patients were studied after undergoing a qualifying treadmill exercise test that revealed ST segment depression indicative of ischemic heart disease. Study subjects performed three additional treadmill tests as part of the protocol. One treadmill test was obtained from each patient to provide baseline measurements without a preceding intravenous infusion and in the absence of all antianginal drugs including nifedipine; two additional exercise tests were preceded by an infusion and 10 mg of bite-and-swallow nifedipine. The infusions. administered in a randomized. double-blind. crossover fashion. consisted of either 10 ml of 10% calcium chloride (13.6 mEq) in 50 ml of 5% dextrose in water or 5% dextrose in water alone. Rest systolic blood pressure (134 +/- 4.6 mm Hg) was unchanged after placebo infusion (135 +/- 4.6 mm Hg) but decreased to 124 +/- 4.1 mm Hg (p less than 0.01) 25 min after nifedipine administration. Rest systolic blood pressure increased after calcium infusion (from 139 +/- 4.3 to 148 +/- 4.8 mm Hg. p less than 0.01) and then decreased significantly 25 min after nifedipine administration to 135 +/- 4.2 mm Hg (p less than 0.01). Despite a decrease at the time of peak nifedipine effect after either infusion. systolic blood pressure was significantly lower after administration of nifedipine alone than after administration of calcium and nifedipine (124 +/- 4.1 vs. 135 +/- 4.2 mm Hg. p less than 0.01).
Load dependence of the effective regurgitant orifice area in a sheep model of aortic regurgitation, Treatment of patients with aortic regurgitation with vasodilators reduces regurgitant volume. ventricular dilation and left ventricular mass. Although these effects are presumably due to afterload reduction. it is also possible that the aortic regurgitant orifice area is not constant. To test the latter hypothesis. aortic regurgitation was created in 10 open chest sheep by partial resection of the noncoronary leaflet under direct visualization. Regurgitant flow was measured with an aortic supravalvular electromagnetic probe; aortic and left ventricular pressures were measured with catheter-tipped micromanometer pressure transducers. The effective regurgitant orifice area was calculated by a modification of the continuity equation in a manner similar to the Gorlin equation. The regurgitant orifice area was measured three times: after aortic regurgitation was created. after mean arterial pressure was increased by 15 to 25 mm Hg with intravenous dopamine and after mean arterial pressure was reduced by 15 to 25 mm Hg with intravenous sodium nitroprusside. Comparison of regurgitant volumes and areas obtained after creation of aortic regurgitation and at the conclusion of the experiment in the absence of dopamine or sodium nitroprusside demonstrated no significant change over time. Dopamine administration was associated with an 86 +/- 81% increase in regurgitant volume (p less than 0.01) and a 38 +/- 44% increase in regurgitant orifice area (p less than 0.01). Sodium nitroprusside administration resulted in a 51 +/- 14% decrease in regurgitant volume (p less than 0.001) and a 28 +/- 21% reduction in regurgitant orifice area (p = 0.007). In this model of acute aortic regurgitation. the effective regurgitant orifice area was altered by increasing or decreasing the aortic transvalvular pressure gradient.
Chronic hypokalemia and the left ventricular responses to epinephrine and preload, The effects of moderate. chronic (5 days) potassium depletion on cardiac function were assessed in 14 normokalemic and 13 hypokalemic open chest. anesthetized dogs. Cardiac responses to intravenous bolus injection of 2.5 micrograms/kg body weight epinephrine (10 normokalemic and 11 hypokalemic dogs) and to rapidly increased preload (8 dogs in each group) were evaluated. Hypokalemic dogs received a low potassium diet plus chlorthalidone. Plasma potassium levels were lower (p less than 0.001) in the hypokalemic dogs (3.2 +/- 0.1 mEq/liter [mean +/- SEM]) than in the normokalemic dogs (4.1 +/- 0.1). The inotropic response to epinephrine was lower in hypokalemic than in normokalemic dogs. the response of the maximal rate of rise of left ventricular pressure was 20% greater (p less than 0.03) and the response of the peak rate of change of ejection power was 60% greater in the normokalemic dogs. The relaxation response to epinephrine (the maximal rate of fall of left ventricular pressure) was 33% lower (p less than 0.02) in hypokalemic dogs. Responses to rapid volume expansion were impaired by hypokalemia; maximal stroke volume index was 31% lower (p less than 0.01). maximal cardiac index was 26% lower (p less than 0.01) and the peak response to the maximal rate of filling was 51% lower (p less than 0.01). There were no differences in basal cardiac function. Therefore. modest potassium depletion within the clinical range impaired the contractile and relaxation responses to epinephrine and preload and impaired rapid filling.
Transesophageal echocardiographic demonstration of distinct mechanisms for right to left shunting across a patent foramen ovale in the absence of pulmonary hypertension, The optimal visualization of the atrial septum and fossa ovalis by transesophageal echocardiography was utilized to demonstrate saline contrast transit across the atrial septum and to relate it to the motion of the flap valve (septum primum) of the fossa ovalis. In three cases. three distinct mechanisms of right to left interatrial shunting in the absence of right ventricular systolic hypertension were identified: 1) transient spontaneous reversal of the left to right atrial pressure differential with each cardiac cycle; 2) sustained elevation of right atrial pressure above left atrial pressure induced by respiratory maneuvers; and 3) aberrant flow redirection across the foramen ovale due to a large right atrial mass. Any of these three mechanisms may be operative during paradoxic embolism in the absence of elevation of right ventricular pressures.
Progression of coronary atherosclerosis: is coronary spasm related to progression, A total of 239 patients undergoing serial coronary angiography with a concomitant ergonovine provocation test were studied between July 1974 and June 1987. The progression of coronary artery disease was evaluated in relation to risk factors. especially coronary artery spasm. Patients were classified into three groups: 1) new myocardial infarction group (39 patients); 2) progression without infarction group (90 patients); and 3) nonprogression group (110 patients). To assess how risk factors and coronary spasm are related to the occurrence of new myocardial infarction and progression without infarction. 11 variables in the three groups were examined: age. gender. the time interval between the studies. fasting blood sugar. systolic blood pressure. diastolic blood pressure. smoking. serum cholesterol. triglyceride. uric acid and a positive response to the ergonovine provocation test. Multiple regression analysis selected three independent predictors of progression without infarction: cholesterol (p less than 0.01). systolic blood pressure (p less than 0.05) and a positive response to the ergonovine provocation test (p less than 0.001). Multiple regression analysis also selected three independent predictors of the occurrence of new myocardial infarction: fasting blood sugar (p less than 0.01). systolic blood pressure (p less than 0.05) and a positive response to the ergonovine provocation test (p less than 0.001). A positive response to the ergonovine provocation test was the strongest factor for occurrence of both new myocardial infarction and progression without infarction. To evaluate segmental arterial changes. 3.275 coronary artery segments were analyzed in the 239 patients.
Lipoprotein(a) and apolipoprotein changes after cardiac transplantation, Although lipoprotein changes after cardiac transplantation have been documented. the effects of transplantation and subsequent immunosuppressive therapy (particularly the combination of prednisone. azathioprine and cyclosporine) on apolipoprotein levels and lipoprotein(a) have not been reported. Fasting cholesterol. triglycerides. high density lipoprotein (HDL) cholesterol. low density lipoprotein (LDL) cholesterol. apolipoprotein A-1 and B-100 and lipoprotein(a) were evaluated in 69 consecutive patients during the waiting period before cardiac transplantation. There were 28 deaths before donor organ identification and 41 patients received a cardiac allograft. The lipoprotein levels of transplant recipients were again assayed 3 months postoperatively. Mean (+/- SEM) values increased for total plasma cholesterol (from 180 +/- 8 to 228 +/- 8 mg/dl. p less than or equal to 0.001). triglycerides (from 126 +/- 11 to 207 +/- 14 mg/dl; p less than or equal to 0.001). HDL cholesterol (from 39 +/- 2 to 49 +/- 3 mg/dl; p less than or equal to 0.002) and LDL cholesterol (from 119 +/- 7 to 138 +/- 7 mg/dl; p less than 0.02). Apolipoprotein A-1 and B-100 also increased. but lipoprotein(a) decreased from 11.7 +/- 1.7 to 6.8 +/- 1.1 mg/dl; p less than or equal to 0.0001) after transplantation. Although total cholesterol. triglycerides. LDL cholesterol. apolipoprotein A-1 and B-100 increased dramatically after cardiac transplantation. so did HDL cholesterol. thereby keeping the LDL/HDL cholesterol ratio constant. The surprising decrease in lipoprotein(a) after cardiac transplantation suggests that metabolism of lipoprotein(a) is independent of LDL cholesterol and that immunosuppressive drugs either decrease the synthesis or increase catabolism of lipoprotein(a).
Cardiac involvement in patients with primary antiphospholipid syndrome, To evaluate cardiac involvement in primary antiphospholipid syndrome. two-dimensional and Doppler echocardiographic studies were performed in 34 consecutive patients with this syndrome. All patients had an increased level of serum anticardiolipin antibodies with no evidence of malignancy or systemic lupus erythematosus. The clinical manifestations of primary antiphospholipid syndrome were arterial thrombosis in 14 patients. venous thrombosis in 6 and recurrent fetal loss in 14. Valvular lesions were observed on two-dimensional echocardiography in 11 patients (32%) (9 women and 2 men). aged 24 to 57 years (mean +/- 1 SD 36 +/- 10). Abnormal echocardiographic findings were observed in 9 (64%) of 14 patients with arterial thrombosis versus 1 (17%) of 6 patients with venous thrombosis and 1 (7%) of 14 patients with recurrent fetal loss. The most common echocardiographic abnormality was mitral leaflet thickening. found in five patients; this was associated with mitral regurgitation in three and with combined mild mitral stenosis and regurgitation in one patient. Localized subvalvular mitral thickening was observed in one patient and calcification of the anulus in another. Aortic valve thickening was observed in two patients. one of whom also had a moderate degree of aortic regurgitation. Vegetation-like lesions on the mitral or aortic valve were found in two patients. It is concluded that valvular lesions are commonly found in primary antiphospholipid syndrome. particularly when the syndrome is manifested by peripheral arterial thrombosis. The location and appearance of valvular lesions in this syndrome are heterogeneous. Most patients have no clinically significant valvular disease. Two-dimensional and Doppler echocardiographic studies are often informative in these patients.
Metabolic and functional recovery of ischemic human myocardium after coronary angioplasty, Although revascularization of hypoperfused but metabolically active human myocardium improves segmental function. the temporal relations among restoration of blood flow. normalization of tissue metabolism and recovery of segmental function have not been determined. To examine the effects of coronary angioplasty on 13 asynergic vascular territories in 12 patients. positron emission tomography and two-dimensional echocardiography were performed before and within 72 h of revascularization. Ten patients underwent late echocardiography (67 +/- 19 days) and eight underwent a late positron emission tomographic study (68 +/- 19 days). The extent and severity of abnormalities of wall motion. perfusion and glucose metabolism were expressed as wall motion scores. perfusion defect scores and perfusion-metabolism mismatch scores. Angioplasty significantly increased mean stenosis cross-sectional area (from 0.95 +/- 0.9 to 2.7 +/- 1.4 mm2) and mean cross-sectional luminal diameter (from 0.9 +/- 0.6 to 1.9 +/- 0.5 mm) (both p less than 0.001). Perfusion defect scores in dependent vascular territories improved early after angioplasty (from 116 +/- 166 to 31 +/- 51. p less than 0.002) with no further improvement on the late follow-up study. The mean perfusion-metabolism mismatch score decreased from 159 +/- 175 to 65 +/- 117 early after angioplasty (p less than 0.01) and to 26 +/- 29 at late follow-up (p less than 0.001 vs. before angioplasty; p = NS vs. early after angioplasty). However. absolute rates of glucose utilization remained elevated early after revascularization. normalizing only at late follow-up.
The double-balloon and Inoue techniques in percutaneous mitral valvuloplasty: comparative results in a series of 232 cases, Immediate hemodynamic results of percutaneous mitral valvuloplasty were compared in two consecutive series of unselected patients from the same institution undergoing valvuloplasty with the double-balloon (161 patients) or the Inoue balloon (71 patients) technique. Before valvuloplasty. the patient series were comparable with regard to average age. gender repartition and most clinical. electrocardiographic. X-ray and hemodynamic variables. Poor anatomic forms of mitral stenosis were equally distributed in both series (41% vs. 45%. p = NS). The magnitude of mitral valve area increase and of mean mitral gradient decrease during percutaneous mitral valvuloplasty did not differ significantly in the Inoue balloon and double-balloon series (mean +/- SEM 1.1 +/- 0.2 to 1.95 +/- 0.5 and 1.0 +/- 0.2 to 1.97 +/- 0.5 cm2. respectively. for mitral valve area and 12 +/- 3 to 5 +/- 2 and 13 +/- 4 to 5 +/- 2 mm Hg. respectively. for mean mitral gradient). Four cases of 3+ mitral regurgitation occurred in the Inoue balloon series and 7 in the double-balloon series (p = NS). A good immediate result--defined as mitral valve area greater than or equal to 1.5 cm2 with greater than or equal to 25% in mitral valve area gain and mitral regurgitation less than 2+ at the end of the procedure--was observed in 78% of patients in both series. Three cases of tamponade due to chamber perforation and 14 cases of transient air embolism in the right coronary system due to balloon rupture were observed in the double-balloon series.
Reproducibility of left ventricular myocardial volume and mass measurements by ultrafast computed tomography, Ultrafast computed tomography has been reported to be an accurate method of measuring left ventricular mass in dogs. To assess the interstudy. intraobserver and interobserver variability of left ventricular myocardial mass measurements in humans. left ventricular myocardial volume was measured three times within 24 h in 16 patients with ischemic heart disease. The mean percent difference of the mean of the three studies performed was -0.01 +/- 1.4% (range -2.9% to 3.6%). The regression analysis for the intraobserver variability at baseline was: Y = -4.33 + 1.03X; r = 0.99. SEE = 3.5 ml. The mean percent difference of the mean of the two sets of measurements performed by two independent observers was 0.28 +/- 2.1% (range -4.35% to 4.35%). The interobserver variability excluding papillary muscles at baseline study was: Y = -4.34 + 1.06X; r = 0.99. SEE = 1.5 ml. The regression analysis with versus without papillary muscles showed: Y = -8.72 + 0.97X; r = 0.96. SEE = 2.6 ml. Regression analysis to assess the variability of 24-h studies at end-systole versus end-diastole revealed: Y = 3.07 + 0.94X; r = 0.97. SEE = 1.8 ml. In conclusion. ultrafast computed tomography is a minimally invasive technique. with very low interstudy. intraobserver and interobserver variability for left ventricular myocardial volume and mass determinations in serial studies.
Indeterminate human immunodeficiency virus type 1 western blots: seroconversion risk, specificity of supplemental tests, and an algorithm for evaluation, The human immunodeficiency virus type 1 (HIV-1) Western blot is indeterminate in 10%-20% of sera reactive by EIA. Eighty-nine individuals with prior repeatedly reactive EIA and indeterminate Western blots were followed prospectively to study the risk of seroconversion and specificity of supplemental tests. Four high-risk cases seroconverted within 10 months after enrollment (seroconversion risk. 4.5%. 95% confidence interval. 1.2%-11.1%). Among cases with p24 bands initially. 4 (18.2%) of 22 high-risk individuals seroconverted compared with 0 of 33 low-risk cases (P = .03). Specificities of HIV-1 culture. serum p24 antigen. polymerase chain reaction. and recombinant ENV 9 EIA were 100%. 100%. 98.6%. and 94.4%. respectively. An expedited evaluation protocol is proposed. Low-risk individuals with nonreactive EIAs upon repeat testing do not need further follow-up; high-risk individuals should be followed serologically for at least 6 months. especially those with p24 bands on Western blot.
Clinical features and analysis of risk factors for invasive candidal infection after marrow transplantation, Of 1506 marrow transplant patients from 1980 through 1986 reviewed for risk factors for invasive candidal infection defined by positive blood cultures. biopsy. or histologic evidence of tissue invasion. 171 (11.4%) had invasive infection. with a significantly higher incidence in the more recent years of review; 40% (69 patients) had evidence of tissue-invasive disease without fungemia. Of 102 patients with fungemia. 45% had candidemia alone with a mortality of 39%. Mortality in patients with tissue involvement was 90% with or without fungemia. Factors that increased infection were age. acute graft-versus-host disease. and donor mismatch. Factors that decreased infection included conditioning with 12 Gy of fractionated irradiation and cyclophosphamide. transplantation for aplastic anemia. and more rapid engraftment. Among fungemic patients. the number of days of fungemia was a risk factor for tissue invasion while more rapid engraftment was protective.
Differences in release of tumor necrosis factor from THP-1 cells stimulated by filtrates of antibiotic-killed Escherichia coli, Bacterial products. such as endotoxin. activate mononuclear cells to produce tumor necrosis factor (TNF) and other monokines capable of producing host cell injury. THP-1 cell TNF release in response to bacterial products generated during antibiotic killing of Escherichia coli (ATCC 12014) was evaluated. THP-1 is a mature monocytic leukemia cell line that produces TNF in a dose-dependent fashion in response to purified endotoxin. E. coli were incubated in the presence of amikacin. ciprofloxacin. ceftazidime. cefotaxime. aztreonam. or imipenem at concentrations that killed greater than 99.9% of the organisms. Aliquots of these antibiotic-bacterial cultures were added to THP-1 cells. and TNF concentrations were determined by specific immunoassay. Amikacin and imipenem produced rapid bacterial killing and were associated with low TNF levels. Ceftazidime. aztreonam. and cefotaxime killed E. coli at a slower rate and were associated with significant increases in mononuclear cell TNF responses. Ciprofloxacin produced intermediate TNF levels. Differences exist among bactericidal antibodies in their ability to generate products capable of stimulating mononuclear cell TNF release.
Antifilarial cellular responses detected in a Haitian pediatric population by use of a microblastogenesis assay, Previous reports have demonstrated age-related shifts in antifilarial humoral immune responses in 6- to 10-year-old Haitian children; the responses consisted of elevated parasite-specific IgG2 and IgG3 in amicrofilaremic children and elevated IgG4 in microfilaremic children. In this study. the cell-mediated immune responses to soluble adult and microfilarial extracts of Brugia pahangi. determined by use of a microblastogenesis assay. were examined. Capillary blood samples were collected by finger prick from 176 Haitian children in an area with endemic Wuchereria bancrofti. Antigen-specific cellular responsiveness varied as a function of infection status but not age or sex; amicrofilaremic children had significantly greater responses to adult antigens than did microfilaremic children. Significant responses were detected in children less than 2 years of age; thus. correlations observed between filarial antigen-specific responses and infection status are established early in life.
Changes in circulating parasite antigen levels after treatment of bancroftian filariasis with diethylcarbamazine and ivermectin, This study assessed changes in circulating parasite antigen levels after diethylcarbamazine (DEC) and ivermectin treatment of bancroftian filariasis to determine effects of these drugs on adult Wuchereria bancrofti in vivo. Thirty adult Haitians with microfilaremia were treated with 1 mg of ivermectin to reduce counts of microfilariae. Later. subjects were treated with either one or two 200 micrograms/kg doses of ivermectin or with 12 daily 6 mg/kg doses of DEC. Macrofilaricidal activity of these drugs was indirectly monitored by measuring circulating W. bancrofti antigen by EIA. Antigen levels fell by 75% after DEC and by 34% after ivermectin. These results suggest that low-dose ivermectin treatment followed by a standard course of DEC is a more effective macrofilaricidal regimen for W. bancrofti than either of the multidose ivermectin regimens used in this study.
Visceral fat accumulation: the missing link between psychosocial factors and cardiovascular disease, Neuroendocrine responses to psychosocial pressures have been well characterized. The defence reaction is followed by increased activity of the sympathetic nervous system. Essential hypertension might be induced by such mechanisms. The defeat reaction is characterized by increased activity along the corticotropin releasing factor-adrenocorticotropin hormone-cortisol axis. resulting in the inhibition of gonadotropin secretion. Such endocrine disturbances are followed by metabolic aberrations. and probably also by the accumulation of visceral fat. Subjects with abdominal fat accumulation (high waist/hip circumference ratio. WHR) have recently been found to exhibit a number of psychosocial handicaps. together with endocrine aberrations characteristic of the defence and. in particular. the defeat reaction. as well as the associated circulatory and metabolic aberrations. Such abnormalities. including the WHR itself. are established risk factors for cardiovascular disease and diabetes. It is postulated that increased WHR is a symptom of chronic hypothalamic arousal as a result of a defeat reaction to psychosocial pressures. This might lead to the development of disease via circulatory and metabolic derangements.
Non-invasive evaluation of long-term cardiac effects of captopril in systemic sclerosis, Impairment of left ventricular (LV) function has previously been reported in patients with systemic sclerosis (SScl). An intermittent vasospastic process in the myocardium may contribute to the development of myocardial dysfunction. Vasodilators may therefore be potentially useful in the treatment of cardiac dysfunction in patients with SScl. This study was designed to evaluate the long-term effects of captopril on the myocardial function of patients with SScl. Twenty-two patients with SScl (15 patients with diffuse scleroderma and 7 patients with CREST syndrome. i.e. calcinosis. Raynaud's phenomenon. oesophageal hypomotility. sclerodactyly. telangiectasia) were investigated by means of Doppler and echophonocardiography before and after treatment with captopril (1.3 mg kg-1 body weight d-1) for 11-15 months. There were no significant differences in heart rate. systolic and diastolic blood pressure. end-systolic blood pressure. total peripheral resistance or LV diameters before or after treatment. However. captopril treatment exerted significant effects on LV function: the pre-ejection period (PEP) and the ratio of pre-ejection period to LV ejection time decreased significantly (P less than 0.05). Mitral E-point septal separation decreased significantly (P less than 0.01). even after adjustment for LV end-diastolic diameter (P less than 0.01). The ejection fraction increased significantly (P less than 0.05). and the isovolumic relaxation time decreased (P less than 0.01). The left atrial emptying index increased (P less than 0.01). The Doppler peak late to early ventricular filling velocity decreased (P less than 0.05). and the isovolumic index was also reduced (P less than 0.05). We conclude that both systolic and diastolic LV function indices improved in patients with SScl after captopril treatment for a mean period of 1 year. The effects of captopril might be due to vasodilation of the myocardial vessels and/or a direct effect on the renin-angiotensin system of the heart.
Antihypertensive efficacy and tolerability of enalapril and slow-release verapamil in essential hypertension: a double-blind, cross-over study, The antihypertensive efficacy and tolerability of enalapril (E) and slow-release verapamil (V) were compared in a 2-month double-blind cross-over study in 22 patients with mild to moderate essential hypertension. After 1 month. significantly lower systolic (P less than 0.01) and diastolic (P less than 0.02) blood pressures (BP) were achieved with E. 20 mg d-1. compared with V. 240 mg d-1. After 2 months of treatment. BP reductions were similar after E. 40 mg d-1. and V. 240 mg twice a day. The fall in supine mean BP after 2 months of treatment with V was significantly greater in patients aged greater than or equal to 50 years of age (P = 0.02) (median 18 mmHg) than in patients aged less than 50 years (10 mmHg). E showed similar effectiveness in both age groups. Statistical group analysis of a quality-of-life questionnaire showed no significant differences between the active drugs and the placebo. It is concluded that E and V are equally effective as antihypertensive agents. and that both drugs are well tolerated.
Long-term prognosis after early intervention with metoprolol in suspected acute myocardial infarction: experiences from the MIAMI Trial. The MIAMI Trial Research Group, A total of 5778 patients with suspected acute myocardial infarction were randomized to early intravenous metoprolol followed by oral treatment for 15 d. or to placebo. Thereafter. the two groups were treated similarly. During a 1-year follow-up period the mortality in patients who were randomized to early metoprolol was 10.6% compared to 10.7% for placebo (P greater than 0.2). Among patients with a higher risk of death. the tendency towards a reduced mortality in the metoprolol group that was observed after 15 d remained similar after 1 year. It is concluded that early intervention with metoprolol in suspected acute myocardial infarction did not improve the long-term prognosis compared to placebo treatment.
Sleep difficulties, pain and other correlates, A multiple regression analysis was used with variables relevant to sleeping problems from a large community health survey in South Australia. The variables that were found to be most strongly correlated with sleep problems were. in order of importance. pain. anxiety. age. somatic health and annual household income. all of which accounted for 22% of the variance. Weight problems. depression and sex of the respondent were not so important in this analysis. Arthritis. which often increases with age. appeared to be most strongly associated with pain. explaining in part why sleeping problems increase with age. Anxiety. pain and poor somatic health were most strongly associated with lying awake at night or sleeping badly. and anxiety and pain were most strongly correlated with taking longer to get to sleep. Poor somatic health and anxiety were most strongly associated with waking early. and age and pain were the most important variables in taking tablets to aid sleep.
Screening for haemochromatosis: prevalence among Danish blood donors, Hereditary haemochromatosis is an autosomal recessive disease that is genetically expressed by excessive accumulation of iron in the tissues. resulting in cirrhosis. diabetes mellitus. cardiomyopathy and hypogonadism. As the disease may be diagnosed before the appearance of symptoms. and prevented by repeated phlebotomies. there are strong implications for adoption of a screening procedure. Determinations of transferrin saturation (TS) and serum ferritin concentration (SF) were used to screen 4302 blood donors. who were selected for follow-up studies if they fulfilled any of the following three criteria: (i) TS greater than or equal to 0.7; (ii) TS greater than or equal to 0.5 together with SF greater than or equal to 150 micrograms l-1; (iii) SF greater than or equal to 300 micrograms l-1. A total of 58 subjects who fulfilled at least one of these criteria were reinvestigated. after which 18 individuals still fulfilled at least one criterion. Fifteen subjects having SF greater than or equal to 300 micrograms l-1 were offered liver biopsy and thirteen of these accepted. In one individual. no stainable iron was detected. and two subjects did not fulfil the previously established diagnostic criteria for the diagnosis of hereditary haemochromatosis. Ten subjects who had a high TS and liver iron grade 2-4 according to Bassett were classified accordingly as homozygotes. On the basis of these results. the prevalence of haemochromatosis in Denmark was estimated to be 0.0037-0.0046.
Intravenous prostacyclin in thrombotic thrombocytopenic purpura: case report and review of the literature, The use of prostacyclin infusion in thrombotic thrombocytopenic purpura is consistent with the hypothesis that patients may lack a plasma factor stimulating prostacyclin production. However. prostacyclin therapy. alone or in combination with aspirin. dipyridamole. steroid and plasmapheresis. failed in many cases. We here describe the case of a patient who responded dramatically to a combination of prostacyclin and plasma infusions. after conventional therapy had failed (plasmapheresis. fresh frozen plasma infusions). Prostacyclin was infused intravenously initially for 120 h from 4 to 9 ng kg min-1 and then continuously for 48 h at 9 ng kg min-1. Despite the scarcity of case reports in the literature. we conclude that the failure of prostacyclin in thrombotic thrombocytopenic purpura appears to be related to insufficient doses and/or duration of therapy.
Prospective neuropathological validation of Hachinski's Ischaemic Score in dementias, The sensitivity and specificity of Hachinski's Ischaemic Score (IS) in the diagnosis of the vascular aetiology of dementia was studied in a series of 32 demented patients. dementia of the Alzheimer type (16). multi-infarct dementia (7). mixed dementia (6). Pick's disease (3). with neuropathological diagnosis as the point of reference. The IS distinguished between primary degenerative dementia and multi-infarct or mixed dementia. As single features of the IS "a positive history of stroke" and "a fluctuating course" showed differing prevalences in the latter two diagnostic categories. The IS labelled 21% of patients with primary degenerative dementia as having a vascular aetiology. The uncritical application of the IS to large samples in epidemiological studies may cause incorrect labelling of a significant proportion of patients with primary degenerative dementia as vascular dementia. These results are based on observations of long-term inpatients and depend on neuropathological criteria. While the definite diagnosis of DAT by threshold criteria concerning plaque and tangle counts is well established. neither clinical nor pathological evidence of stroke necessarily means that cerebrovascular disease has anything to do with a patient's dementia.
Dopaminergic induced changes in cognitive and motor processing in Parkinson's disease: an electrophysiological investigation, Event-related potentials and reaction time measures to auditory discrimination tasks of graded difficulty were used to separate cognitive from motor processing time in 27 patients with newly diagnosed. previously untreated Parkinson's disease and later on optimal levodopa treatment. Before treatment event-related potential P3 and task performance were normal but the reaction time was prolonged compared with age matched controls. After treatment P3 latency was significantly prolonged and the reaction time reduced suggesting a dopamine induced dissociation between cognitive and motor processing. In early Parkinson's disease cognitive processing time remains normal but the motor processing time is prolonged. Dopamine replacement is followed by significantly reduced motor processing time despite increased cognitive processing time. Motor processing may reflect the dopamine status of the putamen whereas dopaminergic over-stimulation of other regions may adversely affect cognitive processing in patients treated with levodopa.
Uncompacted inner myelin lamellae in inherited tendency to pressure palsy, Nerves in patients with inherited tendency to pressure palsy (ITPP) are susceptible to degrees of traction or compression which in nonaffected persons do not induce neuropathic symptoms or deficits. conduction block of fibers. or electromyographic changes characteristic of the disorder. Two observations suggest a widespread asymptomatic abnormality of nerves: 1) low conduction velocity of clinically unaffected nerves. and 2) focal thickenings (tomacula) on teased myelinated fibers of clinically unaffected sural nerves. Sural nerves from five patients and five healthy subjects were assessed for morphologic abnormality in ITPP that might account for the susceptibility of nerves to compression. Teased nerve fibers showed a higher frequency of segmental demyelination or remyelination. or both (p less than 0.003). The mean frequency of fibers showing focal myelin thickenings was 57 +/- 10% in ITPP and 0% in controls. In electron micrographs. regions of uncompacted myelin lamellae. usually affecting the innermost lamellae and extending for a variable distance averaging 9 +/- 4 microns were seen in 11 +/- 4% of fibers in ITPP. None were found in the control nerves. The finding of uncompacted myelin lamellae may suggest an abnormality of myelin composition or of interaction of Schwann cells and axons accounting for the increased susceptibility to pressure palsy. tomaculous formation. or demyelination. From electron microscopic evaluation of serial skip sections we infer that myelin of tomaculae is in continuity with internodal myelin and is reduplicated (full-thickness or cleaved layers are longitudinally or circumferentially folded-back on themselves).
Comparative histology of experimental allergic neuritis induced with minimum length neuritogenic peptides by adoptive transfer with sensitized cells or direct sensitization, Using synthetic peptides representing specific regions of the bovine myelin protein P2. the minimum peptide length requirement for the T-cell epitope necessary for successful production of experimental allergic neuritis (EAN) has been shown to involve residues 61-70 of the P2 protein. In this study. morphometric analysis was used to compare the histologic changes in sciatic nerves of Lewis rats after disease was induced by P2 specific neuritogenic T-cell lines (P(2)3) or. alternatively. by direct inoculation of synthetic peptides representing residues 60-70 or 61-70 of the P2 protein sequence. Inoculation with cell line P(2)3 stimulated with residue 61-70 failed to elicit demyelination in sciatic nerves. However. cells stimulated with residue 60-70 produced inflammation. endoneurial edema. mild demyelination and axonal degeneration within seven days. In contrast. disease induced with either peptide by direct sensitization was more severe. Morphometric analysis revealed that inflammation was most severe in animals sensitized to the decapeptide. In the sciatic nerve. axonal degeneration was proportional in frequency to the extent of inflammation. Inflammation was especially intense in spinal roots with extensive destruction of axons including unmyelinated fibers. Spinal root changes were associated with Wallerian degeneration in the posterior white matter tracts of the spinal cord and were apparently secondary to endoneurial inflammation. Disruption of the blood-nerve-barrier (BNB). evident as physical separation of endothelial cells in association with severe perivascular inflammation. was observed.
Brain stem atrophy in Joseph disease: a morphometric study using two-dimensional (area) measurement by computed tomography, Eight Japanese patients with Joseph disease were studied using computed tomography (CT). Morphometric analysis using the two-dimensional (area) measurement by CT was performed in the infratentorial region. The brain-stem index. an index of brain-stem atrophy or pontine atrophy. revealed a significant decrease (P less than 0.01). with a mean of 66.7% when compared with 16 control subjects. The patients showed a significant increase (P less than 0.01). with a mean of three times that of the controls in the fourth ventricular index. an index of fourth ventricular dilatation. There were no differences in the cerebellar index. an index of cerebellar atrophy. between these patients and the controls. although the patients had an increased number of visible cerebellar vermian (2.0. SD 0.7) and hemispheric sulci (2.6 SD 0.6) as compared with the controls (vermian sulci: 0.4. SD 0.7: hemispheric sulci: 0). These data indicate severe pontine atrophy. fourth ventricular dilatation with mild involvement of the cerebellum and correlate well with the common pathological features of Joseph disease. The present morphometric evaluation by CT may be useful in the clinical diagnosis of Joseph disease.
Nocturnal sleep in Huntington's disease, Nocturnal sleep was studied in 16 inpatients with Huntington's disease. In comparison with healthy controls. patients exhibited a disturbed sleep pattern with increased sleep onset latency. reduced sleep efficiency. frequent nocturnal awakenings. more time spent awake and less slow wave sleep. These abnormalities correlated in part with duration of illness. severity of clinical symptoms. and degree of atrophy of the caudate nucleus. Patients showed an increased density of sleep spindles.
Amplification of the c-erbB oncogene is associated with malignancy in primary tumours of neuroepithelial tissue, In various primary brain tumours of neuroepithelial tissue recombinant DNA techniques were used to demonstrate changes of the epidermal growth factor receptor gene. which is homologous to the c-erbB oncogene. Twenty-one of 40 grade III/IV tumours. but only 1 of 16 grade I/II tumours were found to contain amplified and/or rearranged c-erbB sequences. This highly significant difference suggest that c-erbB amplification. rearrangement. or both. are important steps in malignant transformation in a subset of patients with neuroepithelial tumours.
Determination of erythrocyte-bound acetylcholinesterase activity for monitoring pyridostigmine therapy in myasthenia gravis, Monitoring of pyridostigmine therapy in patients with myasthenia gravis is not routinely performed. since the daily pyridostigmine doses are adjusted to the patient's actual clinical status rather than to pyridostigmine plasma concentrations (PPC). Moreover. PPC determination is time-consuming and needs much technical equipment. Since pyridostigmine reversible blocks acetylcholinesterase (AChE) at the neuromuscular junction. we studied the correlation between the enzyme's blood activity (erythrocyte-bound AChE) and PPC. on the one hand. and between blood AChE activity and the clinical status of the individual patient. on the other. In five previously untreated patients with myasthenia gravis blood AChE activity decreased in accordance with the actual PPC after a single oral dose of 60 mg pyridostigmine (group A). Amelioration of the clinical status corresponded to the decrease of AChE activity in the same way. In another five patients. who were on stable pyridostigmine medication for at least 1 week. AChE activity and PPC were constant during the day (group B). Since it is easier to perform than PPC. our results suggest that the determination of AChE activity may be superior to measuring PPC for monitoring cholinesterase inhibitor therapy in selected cases.
Isolated angiitis of the central nervous system: involvement of penetrating vessels at the base of the brain, Isolated angiitis of the central nervous system (IAC) was diagnosed in a 40-year-old Caucasian male by histological examination of a leptomeningeal biopsy specimen. and the exclusion of systemic inflammatory or infective disease. Therapy with prednisone 30 mg/day and cyclophosphamide 100 mg/day resulted in clinical and radiological improvement. which have been maintained for an 8-month follow-up period. Magnetic resonance imaging (MRI) showed lesions implicating involvement of specific penetrating vessels at the base of the brain. an unusual complication of IAC. and allowed an accurate MRI-clinical correlation.
Peripheral nerve function in persons with asymptomatic or minimally symptomatic HIV disease: absence of zidovudine neurotoxicity, Nucleoside-induced neuropathy characteristically appears as a painful. symmetric. distal polyneuropathy. To evaluate the neurotoxic potential of zidovudine (ZDV. or azidothymidine). in persons with little confounding human immunodeficiency virus (HIV) neuropathy. we evaluated peripheral nerve function in persons completing placebo-controlled studies of ZDV in early HIV disease. Participants had been receiving placebo or ZDV at doses of 800-1.200 mg daily for a median 52 weeks at the time of evaluation. Neuropathic symptoms and abnormalities of motor and sensory function were present in fewer than 10% of both treatment groups. Depressed reflexes were found in 19% of the ZDV group and 18% of the placebo group. Quantitative sensory testing for vibration was abnormal in fewer than 10% of participants and the absolute scores favored the ZDV group. We thus found a low prevalence of peripheral nerve abnormalities and no evidence of ZDV neurotoxicity in this population.
Intensity of in-hospital care for persons with AIDS, We evaluated the intensity of medical care for 30 consecutive AIDS patients at one hospital. using methodology based on the Delay Tool of Selker et al. Of 25 AIDS patients who survived hospitalization. 15 had at least one delay day in the hospital. Major factors associated with care that could have been provided at an alternative site included difficulty with skilled nursing facility placement in 20% of the patients. difficulty coordinating out-of-hospital care in 28%. and scheduling of outpatient surgical procedures in 12%. For the 15 patients who could have received some of their care at a lower intensity setting. a median of 7 hospital days could have been potentially saved with better coordination of outpatient care and increased availability of skilled nursing facilities. The five patients who died in hospital also used large amounts of resources and had long lengths of stay. Prior studies of non-AIDS patients revealed similar results. suggesting that. for reasons of quality of care. quality of life. and economics. policy-makers must develop managed care programs. skilled nursing facilities that accept AIDS patients. inpatient psychiatry facilities. and increased hospice availability.
Canadian multicenter azidothymidine trial: AZT pharmacokinetics, The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early. asymptomatic human immunodeficiency virus (HIV)-infected individuals. The study design was a multicenter. prospective. descriptive single-dose pharmacokinetic study. Each of 66 fasting. male. HIV-infected homosexuals older than 18 years of age and in CDC classifications II. III. and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite. glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers. 29 nonsmokers). of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function. the following parameters were described: AZT. area under the curve (AUC) +/- SD. 9.9 +/- 5.7 microM.h. maximum concentration (Cmax) +/- SD. 7.3 +/- 4.7 microM; time to maximum concentration (Tmax) +/- SD. 0.93 +/- 0.42 h. and half-life (t1/2) +/- SD. 1.0 +/- 0.8 h. Corresponding values for GAZT were: AUC +/- SD 35.7 +/- 10.3 microM.h. Cmax +/- SD 21.3 +/- 7.3 microM. Tmax +/- SD 1.2 +/- 0.50 h. t1/2 +/- SD 0.98 +/- 0.62 h. No significant differences were found in comparisons of study site. CDC classification of disease. smokers versus nonsmokers. and in patients with hepatic dysfunction. although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomatic HIV disease when compared with previous reports in patients with later disease.
Populations at increased risk of HIV infection: current knowledge and limitations, Research data describing the prevalence and patterns of behaviors that place persons at increased risk of HIV infection are extremely limited. The scarcity of data has constrained potential applications of surveillance data. research on specific high-risk behaviors. and epidemiological studies. This article critically reviews available research for four population groups: intravenous drug users. homosexual males. and sexually active adolescents and adults. The fallacies inherent in estimating risk group size underscore the need for population-based research that can provide detailed data on sexual and drug use behaviors.
HIV prevention among injecting drug users: three years of experience from a syringe exchange program in Sweden, Exchange of syringes and needles has for the last 3 years been offered to injecting drug users as part of an HIV prevention project in a small university town in south Sweden. The program at the local hospital has been visited by 979 drug users. of which 182 have participated on a more regular basis. The typical participant is a 30-year-old male who has injected amphetamine or heroin for at least 10 years. The seroprevalence for HIV among drug users in south Sweden has been maintained at approximately 1% in contrast to up to 60% in subpopulations from other Scandinavian regions with a comparable drug problem. No project participant has become HIV infected during the study period and a reduction in risk behavior has been noted among local drug injectors. The HIV prevention project has attracted many individuals with no previous contact with drug rehabilitation programs; for a number of drug users. the syringe exchange has served as an introduction to such treatment efforts.
Changes in sexual practices over 5 years of follow-up among heterosexual men in San Francisco, This report describes changes in sexual behavior of 209 heterosexual men enrolled in a prospective study since 1984. Data were analyzed separately for men who married during the 60 months of follow-up. Study subjects reported fewer total sexual partners and an increase in condom use in the more recent time periods compared to the first period. The proportion of never married men reporting two or more partners in the previous 6 months decreased from 53.2 to 40.7%. All of these men were human immunodeficiency virus seronegative on entry and only one documented seroconversion occurred during the follow-up.
Factors that could influence the spread of AIDS in Ghana, West Africa: knowledge of AIDS, sexual behavior, prostitution, and traditional medical practices, Ghana is a West African nation in the early stages of the human immunodeficiency virus (HIV) epidemic. In a series of surveys done between 1987 and 1989. we examined factors related to the spread of HIV infection. including knowledge about the acquired immune deficiency syndrome (AIDS). sexual habits. use of prostitutes. traditional healer practices. and skin-piercing customs. Although a polygamous society. three-fourths of married men had only one wife. The number of sexual partners at any one time was generally low. However. the divorce rate was more than 29% and 55% of married men had current sexual partners in addition to their wives. Knowledge about AIDS was widespread. yet 4% of men interviewed had had a sexual encounter with a prostitute within the last month. Use of condoms was very limited and 66% of customers of high-class prostitutes refused to use a condom even after a request to do so by the prostitute. Skin piercing. including scarification. was done by an unsterile instrument by 39% of 74 rural traditional healers. many of whom had more than one patient per day. To combat the spread of AIDS. Ghanaians will have to apply their knowledge of AIDS risk factors to their actual behavior. Many of the social customs are products of poverty and its ensuing social consequences. Funds are needed for specific AIDS prevention programs as well as improved education and health care throughout the country.
Comparison of cyclosporine and D-penicillamine for rheumatoid arthritis: a randomized, double blind, multicenter study, Ninety-two patients with active rheumatoid arthritis (RA) were entered in a randomized double blind study of 24 weeks comparing cyclosporine (initial daily dose 5 mg/kg) with D-penicillamine (initial daily dose 250 mg). The groups were well balanced in baseline characteristics. In the cyclosporine group. 10 patients stopped prematurely. one because of inefficacy. In the D-penicillamine group. 9 patients stopped prematurely. 3 because of inefficacy. The 2 antirheumatic drugs were equally effective in reducing disease activity. except for a significant (p = 0.005) decrease in erythrocyte sedimentation rate with D-penicillamine treatment. We conclude that under the conditions of this trial. cyclosporine can serve as an alternative to D-penicillamine for the treatment of patients with RA.
Response to glucocorticoid treatment in rheumatoid arthritis: in vitro cell mediated immune assay predicts in vivo responses, Variable treatment responses to glucocorticoids occur in patients with rheumatoid arthritis (RA). In renal transplantation and asthma treatment responses correlate with in vitro tests of glucocorticoid immunosuppression. We compared in vitro methylprednisolone suppression of concanavalin A stimulated cellular proliferation with clinical responses to methylprednisolone in patients with RA. Patients found to be glucocorticoid sensitive by in vitro testing had significantly greater improvements in joint score and soluble interleukin 2 receptor (sIL-2R) levels compared to control patients. indicating that individual responsiveness to glucocorticoid exists in RA. Similar in vitro and in vivo changes of sIL-2R levels suggests that they reflect cell mediated immune events in vivo.
The impact of increased contact on psychosocial outcomes in patients with osteoarthritis: a randomized, controlled trial, After baseline in home interviews. 439 patients with osteoarthritis (OA) were randomly assigned to the control or one of 3 intervention groups which differed only in method of delivery (i.e.. phone. clinic. both). Trained nonclinical interviewers reviewed medications. problems with joint pain. gastrointestinal symptoms. early warning signs for common chronic diseases. scheduled outpatient visits. an evening/weekend clinic telephone number. barriers to care. and suggestions to encourage participation during clinic visits. We hypothesized that the intervention would enhance social support. satisfaction with care. morale. and medication compliance. We found that none of the interventions had any effect upon these outcomes.
Hydroxyapatite crystals are a frequent finding in osteoarthritic synovial fluid, but are not related to increased concentrations of keratan sulfate or interleukin 1 beta, Synovial fluid (SF) was obtained from 40 patients with varying grades of osteoarthritis (OA) of the knee and examined by transmission electron microscopy to ascertain how frequently hydroxyapatite crystals (HA) were present and whether they were related to disease severity or putative markers or promoters of cartilage resorption. HA crystals were conspicuous and abundant in specimens from 21 of the 40 patients studied. Patients in whom HA was present had significantly larger effusions (13.0 +/- 8.9 vs 8.7 +/- 6.1 ml. p less than 0.05). They also tended to have radiologically more severe disease (radiological grade: 2.91 +/- 0.92 vs 2.39 +/- 0.85. p = 0.056). No difference in keratan sulfate (KS) concentrations was observed. Moreover. despite the presence in some specimens of numerous free histiocytes which were actively phagocytosing HA aggregates. the concentrations of interleukin 1 beta (IL-1 beta). a monocyte product with cartilage and bone resorbing activity. were below the limit of detection (20 pg/ml). Our results confirm that HA crystals are a common finding in patients with OA of the knee and show that HA is associated with larger effusions. but not increased SF concentrations of cartilage proteoglycan substituents (KS) or IL-1 beta.
HLA-DQA1*0101 haplotypes and disease outcome in early onset pauciarticular juvenile rheumatoid arthritis, To further investigate a clinical impression that patients with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) who carry HLA-DQw1 have more severe arthritis. we subtyped HLA-DQw1 in American midwestern patients with EOPA-JRA. The HLA-DQA1*0101 subtype was present in 10 of 19 patients who developed persistent polyarticular erosive disease compared with 18 of 92 healthy controls (chi 2 = 9.13. p = 0.003. RR = 4.6). and occurred more frequently in this polyarticular group than in patients without polyarticular erosive disease (chi 2 = 4.11. p = 0.040. RR = 3.0). The presence of HLA-DQA1*0101 was significantly lower in patients with chronic iridocyclitis than in patients without chronic iridocyclitis (chi 2 = 7.07. p = 0.008. RR = 0.21). In HLA-DQA1*0101 positive patients. DNA sequences of the beta-1 domain of the HLA-DQ alpha and HLA-DQ beta genes (HLA-DQA1*0101. HLA-DQB1*0501 and HLA-DQB1*0503) were identical to those in controls. In this midwestern EOPA-JRA population. HLA-DQA1*0101 or genes in linkage disequilibrium with it. are associated with a cohort of patients with EOPA-JRA with distinct clinical characteristics.
The incidence of Peyronie's disease in Rochester, Minnesota, 1950 through 1984, Peyronie's disease was diagnosed in 101 male residents of Rochester. Minnesota between 1950 and 1984. Mean patient age at diagnosis was 53 years. The average age-adjusted annual incidence rate of 25.7 and a prevalence rate of 388.6 per 100.000 male population were noted. The steady increase in incidence with time may reflect an increasing tendency to obtain medical help. However. the possibility of a true increase in the incidence rate cannot be ruled out. An effort was made to identify possible risk factors and other disease associations. Rheumatoid arthritis and hypertension were more common among the patients compared to the Rochester population. In contrast. no excess of diabetes mellitus was observed among patients with Peyronie's disease.
Calcitonin-gene-related peptide: a possible role in human penile erection and its therapeutic application in impotent patients, A functional study was done to examine a possible role of calcitonin-gene-related peptide in human penile erection and its possible therapeutic applications for patients with erectile dysfunction. In the determination of an effective dosage. 5 ng. (2 patients). 50 ng. (2 patients). 500 ng. (4 patients). 5 micrograms (4 patients) and 25 micrograms (7 patients) were injected intracavernously. and pulse and blood pressure were monitored. Arterial inflow was measured by Doppler sonography. smooth muscle relaxation was determined by the analysis of cavernous electrical activity and cavernous outflow occlusion was recorded by cavernosometry. In 12 patients the erectile response of prostaglandin E1 was compared to the response of an equal (6 patients) or decreased dose of prostaglandin E1 combined with an equal weight of calcitonin-gene-related peptide. In 14 patients the erectile response to the combination of calcitonin-gene-related peptide and prostaglandin E1 was compared to the response of prostaglandin E1 alone. and with a combination of 15 mg./ml. papaverine and 0.5 mg./ml. phentolamine. Calcitonin-gene-related peptide induced an increase in the penile arterial inflow. cavernous smooth muscle relaxation and cavernous outflow occlusion. Histochemical results indicated nerve fibers positive for calcitonin-gene-related peptide within the cavernous bodies. A dose-dependent erectile response to calcitonin-gene-related peptide was observed at doses of 500 ng. to 25 micrograms. Systemic side effects were first observed at a dose of 25 micrograms in 2 of 7 patients. The combination of calcitonin-gene-related peptide and prostaglandin E1 was more effective in inducing a full erection than either prostaglandin E1 alone or the combination of papaverine and phentolamine. Pain was reported in 4% of the patients who received the combination of calcitonin-gene-related peptide and prostaglandin E1. whereas 42% of those who received prostaglandin E1 alone reported pain. Our results suggest that calcitonin-gene-related peptide may be a possible neurotransmitter for penile erection. A combination of calcitonin-gene-related peptide and prostaglandin E1 seems to be an effective alternative combination in the treatment of impotence.
Computerized analysis of smooth muscle fibers in potent and impotent patients, Reduction or dysfunction of the intracavernous smooth muscle fibers can provoke impotence. Computerized digital image analysis of corpus cavernosum biopsies was performed in potent and impotent patients to quantify the percentage of smooth muscle fibers. In 5 normal patients the smooth muscle area represented 40 to 52% of the specimen. in 20 patients with cavernous dysfunction it was 10 to 36% and in 10 patients with arterial disease it was 13 to 25%. This method appears to be important to understand better certain mechanisms of impotence and to approach the potential treatment.
Changes in penile sensitivity following papaverine-induced erection in sexually functional and dysfunctional men, To understand more clearly the role of penile sensitivity in sexual functioning. changes in penile thresholds resulting from papaverine-induced tumescence were studied in men who were either sexually functional or suffering from erectile dysfunction. Variable vibratory tactile stimulation was applied to 2 different sites. the base and tip of the underside of the penis. With standard psychophysical methodology. subjective thresholds were determined from a minimum of 5 threshold crossings. Results indicated a significant elevation in threshold after intracavernous papaverine injection. even though only partial erection was induced in most subjects. Men with erectile dysfunction had higher thresholds than control subjects but no difference in sensitivity was found between the base and tip of the penis. These findings indicate that low penile sensitivity is characteristic of some. although not all. men experiencing erectile problems and that this sensitivity is even lower during tumescence.
Pharmacologically induced erections among geriatric men, Intracavernous injection of vasoactive drugs for the treatment of erectile impotence has become a standard therapeutic technique. Previous reports detailing experience with this treatment are based on patient populations significantly younger than most patients who suffer from impotence. The geriatric population. which comprises the majority of patients with importance. is unique due to the physical. psychological and social changes associated with the aging process. To characterize better elderly men with impotence. and determine whether intracavernous injection therapy is safe and effective in this age group. a retrospective analysis was performed upon patients attending the male sexual dysfunction clinic at our university medical center who received a standard papaverine and phentolamine mixture (30 mg. papaverine and 1.0 mg. phentolamine per ml.). The etiology of impotence. degree of patient satisfaction and complication rate of 65 patients 65 years or older (mean age 70 years) undergoing papaverine plus phentolamine self-injection therapy were compared to a similar size group of impotent men approximately 20 years younger (mean age 47 years). Significant differences in etiology of impotence were evident between the 2 groups. Treatment response rates were equal for the 2 age groups although elderly patients required a higher dose of papaverine and phentolamine to obtain an erection. and used the medication less frequently. Complications were few. of minimal consequence and occurred with equal frequency between the 2 age groups.
Can stage A1 tumor extent be predicted by transurethral resection tumor volume, per cent or grade? A study of 64 stage A1 radical prostatectomies with comparison to prostates removed for stages A2 and B disease, We studied 64 totally embedded radical prostatectomy specimens of stage A1 prostate cancer. The transurethral resection specimens were studied and compared to previously studied stages A2 and B cancer in which tumor volumes also were calculated. At radical prostatectomy 6% of the specimens had no residual cancer. 74% had minimal cancer and 20% had substantial cancer. Although most stages A2 and B tumors were larger. there was overlap among all stages. Transurethral resection tumor volume. per cent and grade were not statistically correlated with either radical prostatectomy residual tumor volume. or whether tumor was classified as minimal or substantial. Gleason sum 2 to 4 versus 5 to 7 tumor on transurethral resection showed no difference in predicting radical prostatectomy residual tumor or minimal versus substantial tumor status. Because 20% of all stage A1 cancers have substantial tumor at radical prostatectomy unpredictable by transurethral resection. radical prostatectomy remains an option for young men with stage A1 prostate cancer.
Prostate specific antigen and prostatic acid phosphatase for monitoring therapy of carcinoma of the prostate, Serial serum prostatic acid phosphatase (PAP) and prostate specific antigen (PSA) measurements were performed in 871 patients treated with hormonal combination therapy for stage C (95 patients) or stage D2 (776) prostate cancer for an average followup of 26 months. The relative efficacy of serum PAP and PSA for predicting recurrence of the disease was evaluated by 2 statistical methods at the time of progression as well as 6 and 12 months before clinical relapse of disease using optimized cut-off values of 2.0 and 4.0 micrograms/l. for serum PAP and PSA. respectively. At the time of progression the sensitivity (plus or minus standard deviation) of the 2 tests was estimated at 61.1 +/- 3.2% and 86.7 +/- 3.1% for PAP and PSA. respectively. while the specificity (plus or minus standard deviation) was calculated at respective values of 79.6 +/- 1.3% and 92.4 +/- 4.1%. Receiver operating characteristic analysis disclosed a greater accuracy for PSA at 89.2 +/- 1.7% versus 78.7 +/- 1.6% (plus or minus standard deviation) for PAP. The somewhat lower positive predictive value of the PSA test (81.4% versus 89.6%) is more than compensated by its superior negative predictive value (92.4% versus 79.6%). The present data also show that serum PSA measurements are superior to those of serum PAP for predicting disease recurrence in stages C and D prostate cancer patients treated by combination endocrine therapy and they indicate that measurement of serum PAP does not add significantly to single measurement of serum PSA alone.
A comparison of the morphological features of cancer arising in the transition zone and in the peripheral zone of the prostate, To determine the characteristics of transition zone and peripheral zone prostate cancer. we examined a series of 42 stage A and 54 stage B radical prostatectomy specimens with particular attention to the number of separate foci of cancer. zone of origin. volume and grade of each focus. and presence of severe intraductal dysplasia (high grade prostatic intraepithelial neoplasia). extra-capsular extension and seminal vesicle invasion associated with cancer in each zone. We found that there were fundamental differences between transition zone and peripheral zone cancers. and that the features that characterize these tumors were apparent in stages A and B disease. Although the total tumor burden was similar in stages A (3.98 cc) and B (4.56 cc) disease. stage A cancer tended to be multifocal (3.1 tumors per prostate) and more diffuse. While 81% of stage A prostate specimens contained a tumor of transition zone origin and 93% had cancer of peripheral zone origin. transurethral resection of the prostate sampled a transition zone cancer in 77% and a peripheral zone cancer in 31% (8% had both types). Stage B cancer tended to be more focal (2.3 cancers per prostate). All stage B prostate specimens contained a peripheral zone cancer and 43% had a transition zone cancer as well. In only 1 stage B cancer patient was the transition zone tumor the palpable or index cancer. In stages A and B disease. peripheral zone tumors were less well differentiated (median Gleason sum 6 and 7) than transition zone tumors (5 and 5. respectively) and more likely to extend through the capsule (44% versus 11%). Seminal vesicle invasion arose from 19% of the peripheral zone but none of the transition zone cancers. Peripheral zone tumors were almost always (93%) associated with high grade prostatic intraepithelial neoplasia. while none of the transition zone cancers was so associated. For peripheral zone disease there was a moderate correlation between volume and grade (tau = 0.46. p less than 0.001) so that the larger the tumor the higher the Gleason sum but within transition zone disease this correlation was poor (tau = 0.23) and not statistically significant (p greater than 0.05). Extracapsular extension occurred at a smaller volume with peripheral zone cancer (mean 3.86. minimum 0.06 cc) than transition zone cancer (mean 4.98. minimum 0.39 cc). Cancer that arises in the transition zone appears to have a different histogenesis. is associated with more favorable pathological features and may have less malignant potential than tumors that arise in the peripheral zone.
Preperitoneal approach for hernia repair: clinical application in pediatric urology, The preperitoneal approach for inguinal hernia repair rarely is indicated in children. However. we report on its clinical usefulness for children in whom the perivesical space must be exposed. such as during surgical repair of bladder exstrophy. ureterocele and ureteral reimplantation. This approach allows for a true high ligation of the hernia sac. and the repair is safe. fast and effective.
Primary angiosarcoma of adrenal gland presenting as paraneoplastic syndrome: case report, Angiosarcoma is an uncommon neoplasm that rarely involves the adrenal gland. We report on a patient with primary angiosarcoma of the adrenal gland who presented with symptoms best characterized as a paraneoplastic syndrome.
Mast cell infiltration in intestine used for bladder augmentation in interstitial cystitis, Two patients with histologically confirmed interstitial cystitis underwent bladder augmentation procedures (clam cystoplasty and Mainz pouch cystoplasty) because of therapy resistant low abdominal pain and decreased functional bladder capacity. However. symptoms of low abdominal pain and urinary retention (1 patient) persisted. and cystectomy was performed in both patients after 14 and 20 months. respectively. Histological examination of the specimens showed changes in the intestinal areas of the augmented bladder. resembling interstitial cystitis. The etiology of this phenomenon and the possible role of intestinal interstitial cystitis in augmentation failures are discussed.
Proteus mirabilis biofilm protection against struvite crystal dissolution and its implications in struvite urolithiasis, Proteus mirabilis biofilm formation. struvite (MgNH4PO4.6H2O) crystal formation and dissolution in an artificial urine mixture were monitored using computer-enhanced microscopy (CEM) and a 1 x 3 mm. glass flow cell. Image analysis showed that P. mirabilis biofilm formation did not occur to any extent at macroenvironment flow rates greater than two mL/h (equivalent to a microenvironment flow rate of less than 5 microns./sec). Essentially. cells attached to glass surfaces. grew slowly and divided. Daughter cells were generally released directly into the medium where they could then presumably colonize other regions. Microcolonies formed by the adhesion of aggregates of cells from the medium. and over time grew into biofilms. Struvite crystallization due to urease activity and pH elevation above neutrality. was preceded by the deposition of organic matter on the glass surface. followed by the appearance of a number of tiny (one to two microns.) crystals. Crystals forming within a biofilm at low dilution rates took on a characteristic twinned or "X-shaped" appearance (crystal habit) indicative of a rapid growth rate. Those forming outside the biofilm took on a more tabular appearance reflecting their slower growth. When the macroenvironment flow rate of artificial urine (initial pH 5.8) in the glass flow cell was increased from two mL/h to four mL/h. struvite crystals not associated with biofilms dissolved within five to 10 min. Crystals entrapped within the P. mirabilis biofilm withstood flow rates up to 200 mL/h presumably due to the maintenance of an alkaline Mg-saturated microenvironment within the biofilm. These observations may suggest a mechanism by which struvite calculi can grow in spite of neutral or acidic urine pH and resist mild acidification therapy.
Treatment of the Dunning prostate rat tumor R3327-AT1 with pulsed high energy ultrasound shock waves (PHEUS): growth delay and histomorphologic changes, We are interested in the interaction of pulsed high energy shock waves (PHEUS) on soft tissues treated in situ to evaluate its potential for therapeutic use. The experimental apparatus built by us was adapted from a lithotripter designed for clinical use. For the present studies we used the R3327-AT1 Dunning prostate tumor growing s.c. in the thigh of Copenhagen rats. The treatments consisted of four groups of eight animals each who received 500 or 2000 pulses at 1 or 5 Hz. Sham-treated tumor bearing animals served as controls (n = 11). During each PHEUS treatment. petechial bleeding of the skin at the point of entry and exit of sound appeared. Sonication at a repetition rate of five Hz seemed to induce more macroscopic damage in terms of hematomas and skin effects. The cytotoxic effects of PHEUS to tumor tissue were sufficient to induce a significant delay (p less than 0.05) in tumor growth but no clear-cut dose relationship was established. Histological studies revealed widespread early rupture of the fine vasculature with extravasation of erythrocytes. By 72 hr.. in PHEUS treated tumors. a large necrosis was seen within the central zone which was never observed in sham-treated tumors. Our results clearly indicate that PHEUS has a cytotoxic potential. The observation of a rapid onset of hemostasis. stark hemorrhage and necrosis in the treatment field would suggest that vascular damage is an important contributing factor.
Acquired cystic disease of the kidney analyzed by microdissection, Four cases of acquired cystic disease of the kidney (ACDK) were studied by the microdissection technique (MD) of Darmady and Baert to analyze the cystic transformation. No patient had a history or clinical evidence of the adult polycystic disease of the kidney (APDK). Hypothetical models related the pathogenesis of cystic transformation to either obstructive or degenerative factors. Microdissection was performed in four nephrectomy specimens of hemodialyzed patients and a total of 155 nephrons were isolated. The atrophy of the glomeruli has already been described histopathologically but MD demonstrated the existence of nephrons consisting of sclerotic glomeruli and enlarged segments between the atrophic convoluted proximal and distal tubules. Diverticula and cysts were located. above all along the proximal (mainly dilated) convoluted tubules: they were always in continuity with the tubules. Phase contrast microscopy showed a patent lumen in 80% of the proximal and distal convoluted tubules. and a regular lining of the cysts. These data support the hypothesis that ACDK is the result of hyperplasia and dilation of remaining nephrons. rather than a result of obstruction and/or fibrosis.
Effects of interferon beta ser and transforming growth factor beta on prostatic cell lines, The effect of interferon beta ser (IFN beta ser) on the growth of three prostatic cancer cell lines DU-145. PC-3 and LNCaP was studied. IFN beta ser inhibited growth of anchorage dependent semiconfluent monolayers and anchorage dependent colony formation of both DU-145 and PC-3 in a dose dependent manner but had no effect on LNCaP. Transforming growth factor beta (TGF beta 1) inhibited proliferation of DU-145 and PC-3 cells in 1% but not 8% fetal calf serum. The combination of TGF beta 1 and IFN beta ser was additive in its effects on growth. Neither epidermal growth factor (EGF) nor transforming growth factor alpha (TGF alpha) reduced the antiproliferative effect of IFN beta ser on these cells. These antiproliferative effects were reproduced in studies on primary epithelial cell cultures derived from prostate specimens with various pathologies. The potential use of IFN beta ser in combination with hormonal therapy to delay the development of hormone refractory tumors is discussed.
Transplantation of kidneys from pediatric cadaver donors to adult recipients, Pediatric donors (less than 12 years old) are a potentially important source of kidneys for adult recipients. Previous reports of decreased graft survival and increased complication rates have made surgeons wary of using such kidneys. In 64 kidneys from younger donors transplanted to adult recipients the delayed graft function rate (41 versus 42%). and 2 and 3-year graft survival rates (67 versus 72% and 61 versus 65%. respectively) were similar to those seen with kidneys from adult donors. Kidneys from donors 24 months old or less experienced an 80% rate of graft loss at 1 year. When these kidneys are excluded the 1-year graft survival rate was similar to kidneys from older and younger donors (70 versus 77%). Mean serum creatinine at 1 year was similar in both groups (155 +/- 21 versus 151 +/- 10). Pediatric kidneys except those obtained from donors 2 years old or less are suitable for adult recipients. However. kidneys from very young donors may be more appropriate to pediatric recipients.
Adjunct controlled inversion therapy following extracorporeal shock wave lithotripsy for lower pole caliceal stones, The lower calix is responsible for a significant number of kidneys with residual stone fragments after extracorporeal shock wave lithotripsy (ESWL*). To compare the effectiveness of controlled inversion therapy as an adjunctive method to the elimination of calculous fragments. 42 patients who had undergone treatment for lower caliceal stones with a Siemens Lithostar lithotriptor were reviewed. Of the patients 25 had no adjunctive therapy and 17 underwent controlled inversion therapy. The success rate. effectiveness quotient and complication rate were analyzed. Followup consisted of ultrasound and a nephrotomogram 1 day and 1 to 3 months postoperatively. Complete removal of all stone fragments was achieved in 84% of the patients without an adjunctive maneuver and in 64.7% of those treated with controlled inversion therapy. The effectiveness quotient was 72.4% and 35.5%. respectively. The group treated without adjunctive therapy had fewer retreatment sessions and a lower complication rate. There were no complications related to the controlled inversion therapy and patient acceptance was generally enthusiastic. We conclude that controlled inversion therapy did not improve the results of ESWL for lower pole caliceal calculi.
Vesicoureteral reflux in patients with double pigtail stents, A prospective study of 30 renal units in 27 patients with double pigtail ureteral stents seen at our hospital was done. The aim of the study was to confirm or rule out the occurrence of vesicoureteral reflux radiologically. and to define its degree in stented patients. During the filling phase of the cystourethrogram. reflux occurred in 19 of the 30 renal units (63%). Of those 19 renal units the reflux was grade 1/4 in 15 (79%). while in 4 (21%) it was of higher grades (2 to 3/4). During the voiding phase of the cystourethrogram reflux was observed in 24 of 30 renal units (80%). Of those 24 renal units reflux was of high grade (2 to 4/4) in 20 (83%). while it was low grade (1/4) in 4 (17%). In the presence of a double pigtail stent the ureteral peristaltic waves were sluggish and averaged 1 to 2 waves per minute in the 15 patients observed fluoroscopically for 1 minute after voiding. We conclude that in the majority of patients with double pigtail ureteral stents vesicoureteral reflux occurs at a low grade during vesical filling and at a high grade during voiding. Also. the stents adversely affect the ureteral peristaltic activities.
Urethral controlled bladder substitution: a comparison between Parks S pouch and hemi-Kock pouch, To study the effect of the configuration of ileal reservoirs on the urodynamic features. 12 S bladders and 12 Kock pouches were compared. Volume capacity and pressure characteristics were studied 6 months postoperatively. The mean capacity of the reservoirs was 500 +/- 83 ml. for the S bladder and 536 +/- 56 ml. for the Kock pouch. The amplitudes of phasic contractions at 50%. 80% and 100% capacity were similar in both groups. However. the frequency of these contractions was higher in the S bladder. The intraluminal pressure at full capacity was 31 +/- 15 cm. water for the S bladder and 39 +/- 20 cm. water for the Kock pouch. The similar urodynamic features of the S and Kock pouches indicate their ultimate expansion into reservoirs of close physical characteristics and urodynamic behavior.
Spongiosography: a valuable adjunct to the diagnosis of urethral strictures, To obtain better information on fibrotic tissue damage in urethral strictures we performed spongiosography. that is opacification of the spongy body by injection of contrast medium. in 32 patients in whom the diagnosis had already been established by uroflowmetry. urethrography and urethroscopy. Another 18 patients with erectile dysfunction served as the control group. The investigation was well tolerated by all patients and no side effects or complications were encountered. Attenuation or even interruption of the contrast medium within the corpus spongiosum on spongiosography clearly revealed the fibrosis in urethral strictures. The extent of scarring was completely independent of the clinical symptoms and urethrographic findings. Accordingly. our decision on the appropriate surgical treatment was based mainly on the results of spongiosography. If used as an additional routine investigation in cases of urethral stricture spongiosography may help to decrease the recurrence rate in the future.
Patient-controlled analgesia. Does a concurrent opioid infusion improve pain management after surgery, OBJECTIVE.--To assess the influence of a continuous (basal) morphine infusion as part of a patient-controlled analgesia (PCA) system on the postoperative analgesic requirement and on recovery parameters following abdominal hysterectomy. DESIGN.--Single-center. randomized. controlled protocol. SETTING.--University medical center. PARTICIPANTS.--A total of 230 adult women were randomly assigned to receive no morphine infusion (control group) or a continuous 0.5-. 1.0-. or 2.0-mg/h morphine infusion. Each patient was able to self-administer supplemental intravenous bolus doses of morphine (1 to 2 mg) using a PCA infuser. MAIN OUTCOME MEASURES.--Use of the PCA device. opioid-related side effects. recovery times. and the patients' assessment of pain and sedation on linear visual analog scales were recorded during the 72-hour study period. Follow-up questionnaires were completed by the patients and their health care professionals to assess the overall adequacy of PCA therapy. RESULTS.--Patients who received the 2-mg/h morphine infusions received significantly more opioid medication 9 to 72 hours after their operation than those who received no infusion (control group). The presence of a continuous morphine infusion of 0.5 to 2 mg/h did not significantly decrease the number of patient demands or supplemental bolus doses administered compared with the control group. Overall. 168 (84%) of the 199 patients who completed the 72-hour study were able to achieve adequate analgesia without requiring changes in the PCA regimen or experiencing major side effects. Recovery times and outcome variables were similar in all four groups. CONCLUSION.--The routine use of a continuous opioid infusion in combination with a standard PCA regimen does not improve pain management compared with PCA alone after abdominal hysterectomy.
Immunoglobulin deficiency and idiotype expression in children developing Haemophilus influenzae type b disease after vaccination with conjugate vaccine. The Collaborative Study Group, OBJECTIVE.--Haemophilus influenzae type b (Hib) conjugate vaccines are effective in preventing Haemophilus disease in most children. The reasons why the vaccination fails in some children are unknown. This study investigated host factors in children who developed the disease despite conjugate vaccination. DESIGN. PATIENTS. OUTCOME MEASURES.--A convenience sample of 23 patients in whom Hib disease developed 14 days or more after conjugate vaccination was investigated for the presence of subnormal serum immunoglobulin concentrations and anticapsular antibody responses to Hib disease. We also investigated expression of the Hib idiotype 1 (Hibld-1). a serological marker of a VKII chain that comprises a major portion of the normal variable region repertoire of the antibody response to Hib polysaccharide. The results were compared with those of 149 patients in whom the unconjugated Hib polysaccharide vaccine failed and of 90 unvaccinated patients who developed the disease. RESULTS.--Compared with children in whom the unconjugated polysaccharide vaccination failed. the relative risk of a subnormal serum concentration of IgM. IgA. IgG. and/or IgG2 in the children in whom the conjugate vaccination failed was 4.9 (95% confidence interval [CI]. 1.8 to 14; P less than .003) and of IgG2 was 22 (95% CI. 3.5 to 146; P less than .001). With the exception of the children with subnormal serum immunoglobulin concentrations. most of the children with conjugate vaccination failure showed normal or high anticapsular antibody responses to the disease. whereas the children with polysaccharide vaccination failure showed impaired responses. The Hibld-1 was expressed by the majority of the children in both vaccination failure groups and of the unvaccinated patients. CONCLUSIONS.--In most patients. vaccination failure is not attributable to lack of expression of the variable region gene encoding Hibld-1. However. children in whom conjugate vaccination has failed frequently have subnormal serum immunoglobulin concentrations and should be evaluated for immunodeficiency.
Successful surgical treatment of atrial fibrillation. Review and clinical update, Atrial fibrillation is the most common of all sustained cardiac arrhythmias. yet it has no effective medical or surgical therapy. During the past decade. multipoint computerized electrophysiological mapping systems were used to map both experimental and human atrial fibrillation. On the basis of these studies. a new surgical procedure was developed for atrial fibrillation. Between September 25. 1987. and July 1. 1991. this procedure was applied in 22 patients with paroxysmal atrial flutter (n = 2). paroxysmal atrial fibrillation (n = 11). or chronic atrial fibrillation (n = 9) of 2 to 21 years' duration. All patients were refractory to all antiarrhythmic medications. and each patient failed to receive the desired therapeutic benefits of an average of five drugs administered preoperatively. There were no operative deaths and all perioperative morbidity resolved. All 22 patients have been successfully treated for atrial fibrillation with surgery alone. Three patients developed one late isolated episode of atrial flutter at 5. 6. and 15 months postoperatively. and each of these patient's symptoms is now controlled by a single antiarrhythmic drug. Preservation of atrial transport function has been documented in all patients postoperatively. and all have experienced marked clinical improvement.
Ultrasonography of acute abdominal pain in children, OBJECTIVE.--To determine the ability of ultrasonography to detect appendicitis and to identify other conditions responsible for symptoms in children with acute abdominal pain. DESIGN.--Cohort study. The accuracy of ultrasonographic results was assessed in relation to final diagnoses established by surgery or by composite clinical data and follow-up. SETTING.--Metropolitan. pediatric hospital; ambulatory and hospitalized patients. PATIENTS.--Consecutive sample of 178 pediatric patients who were referred for ultrasonography because of suspected acute appendicitis. but in whom the diagnosis could not be definitively established by clinical criteria. RESULTS.--Appendicitis was proven at surgery in 38 patients. Ultrasonography demonstrated the findings of appendicitis (noncompressible appendix with or without concomitant periappendiceal fluid collection or appendicolith) in 31 (82%) of these patients. Among the 140 children without appendicitis. other specific diagnoses were established by clinical. laboratory. and radiologic findings in 58 patients (including gynecologic diseases in 25. gastrointestinal tract abnormalities in 17. renal diseases in six. and extra-abdominal disease in 10). Ultrasonography aided in the diagnosis of other conditions in 34 (59%) of these 58 patients. No definitive clinical diagnosis was established in the remaining 82 patients. There were no false-positive results of ultrasonography. CONCLUSION.--Approximately half of children referred for suspected appendicitis will have a final diagnosis of abdominal pain of unknown origin. In the remainder. ultrasonography is useful. both to establish the diagnosis of appendicitis and to aid in diagnosing other causes of acute abdominal pain.
A new approach to the diagnosis of central venous catheter sepsis, One hundred forty-four cancer patients harboring a central venous catheter (CVC) were prospectively investigated to assess the relationship between hub culture. clinical assessment of sepsis before removal. and CVC sepsis. In 22 patients. the CVC was removed because of clinical assessment of catheter sepsis expressed by the staff prior to the removal. For each CVC removal. peripheral blood (qualitative method). hub. and CVC tip (quantitative method) cultures were performed. Clinical sepsis (disappearance of fever after CVC removal) was observed in 13 patients. microbiologic "sepsis" (identification of the same microorganisms on the CVC tip and in the peripheral blood) in seven patients. and clinical and/or microbiologic sepsis in 16 patients. Staphylococcus epidermidis was the microorganism most frequently identified. Hub culture was negative in 48% and positive for a low number and a high number of colonies in 35% and 17%. respectively. The predictive value of hub culture was 96% when testing negative and 8% and 37% (p = 3 x 10(-3)) when testing positive for a low and a high number of colonies. respectively. Predictive values of clinical assessment were 55% if positive and 97% if negative. Combining hub cultures and clinical assessment. the risk of sepsis varied from 2% with both evaluations negative to 89% in the case of positive clinical assessment associated with positive high-count hub. Inasmuch as the CVCs used have a disposable hub. it is possible to have an accurate diagnosis of CVC sepsis without removing the CVC.
Assessment of energy expenditure by indirect calorimetry in healthy subjects and patients with liver cirrhosis, The reliability of resting energy expenditure (REE) measurements by indirect calorimetry with a ventilated hood was investigated in 50 healthy controls and 10 patients with liver cirrhosis. In each subject basal energy expenditure (BEE) was determined once and REE three times (morning REE1. noon REE2. afternoon REE3). In controls and patients the first 5-minute BEE and first 5-minute REE (controls also second 5-minute REE) were higher than in the remainder of the 30-minute recording. Only the last 20 minutes of recordings were used to calculate BEE (1645 +/- 315. mean +/- SD. in kilocalories per day). REE1 (1880 +/- 365). REE2 (1782 +/- 384). and REE3 (1775 +/- 316) in controls. and in cirrhotics: BEE (1530 +/- 235). REE1 (1714 +/- 267). REE2 (1715 +/- 238). and REE3 (1779 +/- 275). REE was higher than BEE in controls and cirrhotics (p less than 0.05). The REE variation coefficient was 5 +/- 3% in controls and 5 +/- 2% in cirrhotics. No systematic difference between REE1. REE2. and REE3 was found. Energy expenditure predicted by the Harris-Benedict equation differed up to 21% from measured BEE in individual controls; group mean BEE. however. was correctly predicted. In cirrhotics differences between measured and predicted BEE up to 26% occurred. while measured BEE was higher than predicted BEE (p = 0.06). It is concluded that REE can be reliably assessed by indirect calorimetry with a ventilated hood system in controls and patients at any time of the day. when values obtained in the first 10 minutes are deleted.
Evaluation of serum visceral protein levels as indicators of nitrogen balance in thermally injured patients, The use of serum visceral protein concentrations as predictors of nitrogen balance was assessed during the first 4 weeks following thermal injury. The correlation between nitrogen balance and serum albumin was not significant. Statistically significant correlations were found between nitrogen balance and serum prealbumin. retinol-binding protein. and transferrin. However. even the best correlation (retinol-binding protein. r = 0.388) was too weak to permit prediction of nitrogen balance on the basis of the visceral protein concentration. The correlation between change in direction of nitrogen balance and change in direction of protein concentration over time showed all four visceral proteins to be poor predictors of change in nitrogen balance. The efficiency was less than 50% for each visceral protein. Stepwise multiple regression analysis performed to determine which indices were most closely correlated with nitrogen balance showed that a calculation using readily available information (nitrogen intake. postburn day. percent total body surface burned. and age) provided better prediction of nitrogen balance (r = 0.765) than any of the visceral protein concentrations. In view of these findings. measurement of serum visceral protein concentrations to monitor adequacy of nutritional support seems an unwarranted expense in patients with thermal injury.
Use of albumin as a volume expander, In some hospitals. albumin products account for 10% of the pharmaceutical budget. As much as 60% of these prescriptions are empiric. and from 40 to 70% of albumin that is administered is given for inappropriate reasons. Although the reasons for albumin administration vary. prevention or reversal of hypovolemia is part of the reason in the majority of cases.
SGP-2 expression as a genetic marker of progressive cellular pathology in experimental hydronephrosis, The onset of hydronephrosis following unilateral ureteral obstruction is associated with the induced expression of RNA and proteins encoded by the SGP-2 gene. SGP-2 expression has been shown to demarcate mammalian cells undergoing apoptosis. Using in situ hybridization. the cellular localization of SGP-2 expression in the obstructed kidney was determined as a means to study the various phases involved in the progression of hydronephrosis. Within 30 minutes of obstruction. SGP-2 mRNA expression was localized to the adventitial layers of the hilar arteries and intrarenal arterioles. Increasing time of obstruction resulted in the notable absence or depletion of this layer. In addition. the pattern of SGP-2 expression changed with time to the collecting ducts and distal tubules. This study identifies the vascular support tissue of the kidney as the initial site of reaction and potential cell death following ureteral obstruction. We believe that this observation may be of importance in explaining the early alterations in blood flow associated with hydronephrosis.
Effects of nifedipine and enalapril on glomerular structure and function in uninephrectomized SHR, Spontaneously hypertensive rats (SHR) that underwent uninephrectomy (UNX) at six weeks of age were randomly assigned to receive no treatment. the calcium channel blocker. nifedipine. or the angiotensin converting enzyme inhibitor. enalapril. Both drugs reduced systemic blood pressure. however. blood pressure tended to be greater in rats given nifedipine than in those on enalapril. After six months. proteinuria and the relevance of glomerula sclerosis were significantly reduced in the two treated groups compared to values observed in untreated SHR. Kidney weight was also reduced by therapy. suggesting that both enalapril and nifedipine inhibited compensatory kidney growth. Micropuncture studies performed in similarly treated groups of rats. but at 11 weeks of age. revealed that PGC was elevated in untreated UNX SHR and reduced by both nifedipine and enalapril. These findings support the hypothesis that glomerular hypertension and renal hypertrophy are important risk factors for glomerular injury. They suggest that calcium blockers are as effective as angiotensin converting enzyme inhibitors in preventing progressive kidney damage.
Impact of dietary fatty acid supplementation on renal injury in obese Zucker rats, We previously reported that renal injury in hyperlipidemic. obese Zucker rats was associated with a relative deficiency of tissue polyunsaturated fatty acids (PUFA). In the present study 10-week-old obese Zucker rats were pair fed regular chow or chow containing either 20% sunflower oil rich in n-6 PUFA. fish oil rich in n-3 PUFA. coconut oil medium-chain saturated fatty acid. or beef tallow long-chain saturated fatty acid. At 34 weeks of age there were comparable reductions in albuminuria. mesangial matrix expansion. and glomerulosclerosis in the fish oil and sunflower oil groups. While both fish oil and sunflower oil reduced serum triglycerides. and improved the composition of triglyceride-enriched lipoproteins. only fish oil decreased serum cholesterol. The effect of the dietary fatty acid supplementation on fatty acid profiles were similar in isolated glomeruli and cortical tissue. In general. the amelioration in injury in the fish oil and sunflower oil fed rats was most closely linked to glomerular levels of PUFA. either n-6 or n-3. These data suggest that hyperlipidemia and abnormalities in tissue FA are closely linked. and that dietary supplementation with PUFA may ameliorate chronic. progressive renal injury.
Disassociation between glomerular hyperfiltration and extracellular volume in diabetic rats, The relationship of the development of glomerular hyperfiltration in diabetes to changes in extracellular fluid volume has not been previously examined. To accomplish this task. male Wistar rats were chronically cannulated in the bladder. femoral artery and vein. Control measurements of glomerular filtration rate (GFR). renal plasma flow (RPF). extracellular fluid volume (ECF). and urinary sodium excretion were performed on two separate days prior to infusion of streptozotocin (65 mg/kg body wt i.v.). After infusion of streptozotocin. the IDDM rats were separated into two groups: untreated IDDM group of rats and IDDM rats treated with insulin at doses sufficient to normalize blood glucose (Ultralente. 2 to 8 IU/day). A third group of normal non-diabetic rats served as time controls. Measurements of renal function occurred at 1. 4. 7. 11. and 15 days after infusion of streptozotocin. Blood glucose in the non-diabetic measurement period averaged 137 +/- 30 mg/dl and increased from 412 +/- 55 after 24 hours in the untreated diabetic rats to 533 +/- 33 mg/dl after 15 days of IDDM. The time controls and the insulin-treated diabetic rats did not differ in blood glucose values at the time measurements were performed. Glomerular filtration rate increased from 1.0 +/- 0.1 to 1.7 +/- 0.1 ml/min/100 g body wt by day 15 in the untreated diabetic rats with significant increases in GFR within 24 hours. GFR of both time controls and the insulin-treated IDDM rats did not significantly vary during the time of the study. The increase in GFR in the untreated IDDM group was associated with a concomitant increase in RPF.
Diet, vitamin D and vertebral mineral density in hypercalciuric calcium stone formers, To elucidate the pathophysiology of dietary calcium independent hypercalciuria. 42 calcium stone formers (Ca SF) were selected because they had on free diet a calciuria greater than 0.1 mmol/kg/day. For four days they were put on a diet restricted in calcium (Ca RD) by exclusion of the dairy products. They collected 24 hour urines on free diet and on day 4 of Ca RD as well as the two-hour fasting urines on the morning of the day 5 and the four-hour urines passed after an oral calcium load of 1 g. for measurement of creatinine. Ca. PO4. urea and total hydroxyprolinuria (THP). On day 5 fasting plasma concentrations of Ca. PO4. intact PTH. Gla protein. calcidiol and calcitriol were measured. The patients were firstly classified into dietary hypercalciuria (DH. 18 patients) and dietary calcium-independent hypercalciuria (IH. 24 patients) on the basis of the disappearance or not of hypercalciuria on Ca RD. Then the patients with IH were subclassified into absorptive hypercalciuria (AH) because of normal fasting calciuria (8 patients) and into fasting hypercalciuria (16 patients). Fasting hypercalciuric patients were subsequently divided according to the PTH levels into renal hypercalciuria (RH. 1 patient) with elevated fasting PTH becoming normal after the Ca load and undetermined hypercalciuria (UH. 15 patients) with normal PTH levels. Furthermore. their vertebral mineral density (VMD) was measured by quantitative computerized tomography which was normal in DH (91 +/- 6% of the normal mean for age and sex) but was decreased in IH to 69 +/- 4%. No difference in VMD was observed between AH and UH. Urinary excretions of urea. phosphate and THP was higher in IH than in DH and comparable in AH and UH. Sodium excretion Ca RD was the same in all groups and subgroups as well as the plasma parameters. Plasma calcitriol was increased in IH and DH comparatively to normal in spite of normal plasma calcidiol. Calciuria increase after oral calcium load. an index of Ca absorption. was higher in IH than in controls and comparable in IH and DH as well as in the three subgroups of IH. From these data and correlation studies in IH it is concluded: (1.) VMD is decreased in Ca stone formers with IH but not in those with DH. making the distinction of these two groups of hypercalciuria patients clinically relevant.(ABSTRACT TRUNCATED AT 400 WORDS).
Role of duplex scanning for the detection of atherosclerotic renal artery disease, To assess the accuracy of renal artery duplex scanning for the purpose of diagnosing atherosclerotic renal artery stenosis. we compared the findings of renal arteriograms to the results of duplex scanning in 41 patients. Using an increase of renal artery peak systolic flow velocity of greater than 180 cm/sec. duplex scanning was able to discriminate normal from diseased renal arteries with a sensitivity of 95% and a specificity of 90%. Using the principle that blood flow velocity across a stenosis is roughly proportional to the degree of stenosis. it appeared that a ratio of the peak velocity in the renal artery to the aorta (RAR) of greater 3.5 predicted a greater than 60% diameter reduction of that renal artery. which is felt to be a significant stenosis. Forty-eight vessels were classified as having a greater than 60% diameter reduction by arteriography. Using the RAR of greater than 3.5. duplex scanning agreed in 44 renal arteries (sensitivity 92%). In the 26 renal arteries where arteriography showed a less than 60% diameter reduction. duplex scanning agreed in 16 vessels and correctly detected a focal narrowing in nine of the remaining ten vessels. Ten of 11 occluded renal arteries were correctly identified by duplex scanning. Duplex scanning determined the location of the renal artery lesion with an accuracy of 95% (kappa 0.74). Since duplex scanning can accurately demonstrate and locate focal renal artery stenosis. we believe it may become an accurate screening test for renovascular hypertension.
Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy, Clearances of uncharged dextrans of broad size distribution were used to evaluate the effects of a 30 day course of enalapril on glomerular barrier function in 10 patients with IgA nephropathy and proteinuria (from 1.4 to 5.6 g/day). Dextran clearance experiments were repeated three times: before enalapril therapy. after 30 days of enalapril and again 30 days after enalapril withdrawal. GFR. but not RPF. was significantly reduced by enalapril (basal 38.3 +/- 11.9. enalapril 30.2 +/- 12.6 ml/min/1.73 m2) and returned to basal values after enalapril withdrawal. Urinary protein excretion and fractional clearance of albumin were both significantly reduced by enalapril (basal 2.3 +/- 1.1 g/day and 102 +/- 90 x 10(-5). enalapril 1.2 +/- 0.6 g/day and 51 +/- 23 x 10(-5). respectively) and returned to basal values after enalapril withdrawal. Transglomerular passage of large dextrans (radii 54 to 62 A). but not of lower size (26 to 42 A) were significantly lowered by enalapril. When enalapril was withdrawn the dextran-sieving profile returned comparable to the baseline levels. A theoretical analysis of dextran-sieving profiles indicated that enalapril lowered the radius of largest membrane pores. This effect was independent from glomerular hemodynamic changes. We conclude that angiotensin converting enzyme inhibitors (CEI) in humans with IgA nephropathy reduces urinary protein excretion by a primary action on the intrinsic glomerular membrane properties enhancing barrier size-selective function. The hypofiltration associated with enalapril therapy in these patients. which was eliminated by its withdrawal. has to be taken into account as a possible undesired effect of CEI in long-term treatment.
Psychiatric disorders in patients with esophageal disease, Psychiatric disorders have potentially important roles in the manifestations of esophageal disease. A primary causative role for psychiatric factors in the common motility disorders associated with chest pain (esophageal spasm and the nonspecific motor disorders) remains unproven. but psychiatric disorders appear particularly prevalent in this group. In most other esophageal diseases. psychiatric factors interact through recognized psychophysiologic or behavioral mechanisms to affect the clinical presentation. Recognizing the possible levels of interaction has significant therapeutic implications.
Mitral valve prolapse, panic disorder, and chest pain, Mitral valve prolapse is a common cardiac disorder that can readily be diagnosed by characteristic auscultatory and echocardiographic criteria. Although many diseases have been associated with mitral valve prolapse. most affected individuals have the primary form of the disorder. Mitral valve prolapse is an inherited condition commonly associated with myxomatous degeneration of the mitral valve and its support structures. Complications of mitral valve prolapse. including cardiac arrhythmias. sudden death. infective endocarditis. severe mitral regurgitation (with or without chordae tendineae rupture). and cerebral ischemic events. occur infrequently considering the wide prevalence of the disorder. Panic disorder is a specific type of anxiety disorder characterized by at least three panic attacks within a 3-week period or one panic attack followed by fear of subsequent panic attacks for at least 1 month. It too is a common condition with a prevalence and age and gender distribution similar to that of mitral valve prolapse. Panic disorder and mitral valve prolapse share many nonspecific symptoms. including chest pain or discomfort. palpitations. dyspnea. effort intolerance. and pre-syncope. Chest pain is the symptom in both conditions that most commonly brings the patient to medical attention. The clinical description of chest pain in patients with mitral valve prolapse is highly variable. possibly reflecting multiple etiologies. Chest pain in panic disorder is usually characterized as atypical angina pectoris and as such bears resemblance to the chest pain commonly described by patients with mitral valve prolapse. Multiple investigative attempts to elucidate the mechanism of chest pain in both conditions have failed to identify a unifying cause. Review of the literature leaves little doubt that mitral valve prolapse and panic disorder frequently co-occur. Given the similarities in their symptomatology. a high rate of co-occurrence is. in fact. entirely predictable. There is. however. no convincing evidence of a cause-effect relationship between the two disorders. nor has a single pathophysiologic or biochemical mechanism been identified that unites these two common conditions. Until specific biologic markers for these disorders are identified. it may be impossible to do so. The lack of a proven cause-and-effect relationship between mitral valve prolapse and panic disorder and the absence of a unifying mechanism do not diminish the clinical significance of the high rate of co-occurrence between the two conditions. Primary care physicians and cardiologists frequently encounter patients with mitral valve prolapse and nonspecific symptoms with no discernible objective cause who fail to respond to beta-blockade. Panic disorder should be considered as a possible explanation for symptoms in such patients.(ABSTRACT TRUNCATED AT 400 WORDS).
Validating studies for panic disorder in patients with angiographically normal coronary arteries, This article describes validating studies for diagnosing panic disorder in some patients with angiographically normal coronary arteries (NCA) and chest pain. Psychiatric interviews of 94 such patients showed that 34% met the diagnostic criteria for panic disorder. Further studies showed that NCA patients with panic disorder were more disabled at 3.5-year follow-up. had more relatives with panic disorder. were more likely to suffer from major depression. and were more likely to respond to 35% CO2 challenge with panic symptoms. Because panic disorder is highly disabling but responds well to psychological and pharmacologic treatments. screening NCA patients in the cardiology population for this disorder is recommended.
Practical approach to the diagnosis of unexplained chest pain, Chest pain is a frequent medical problem causing concern for both patients and physicians. A multidisciplinary meeting recently developed algorithms for evaluating these patients in the two most common scenarios for the presentation of chest pain: (1) new onset of chest pain in the primary care setting. and (2) recurrent chest pain in the the referral setting. In both situations. the primary care physician. rather than specialists. should direct the evaluation and treatment of patients with chest pain and normal coronary angiograms.
Fatal and other major complications of endoscopic sinus surgery, Endoscopic sinus surgery has become an acceptable technique for the treatment of chronic sinus disease. This report analyzes five complications which came to my attention. Two cases were orbital:1 bilateral blindness due to damage of the optic nerves. and 1 damage of medial rectus muscle. The other 3 cases were intracranial:two cribriform plate damage with frontal lobe injury and hematoma. and 1 damage of the anterior cerebral artery. resulting in death. This rather novel technique. especially when used by less-experienced surgeons. has major complications similar to what has been reported with the traditional intranasal sphenoethmoidectomy. Knowledge of anatomy. good training. and meticulous surgical technique are very important. Endoscopic sinus surgery in patients with extensive pathology should be used with caution. especially if general anesthesia is selected or if excessive bleeding occurs. It would be beneficial to otolaryngologists to have previous experience in the traditional technique before adopting endoscopic sinus surgery to their armamentarium. Even then. major complications may occur in the hands of very experienced surgeons. Early recognition and proper management of these complications are of utmost importance in order to minimize disability or prevent death.
Electromagnetic semi-implantable hearing device: phase I. Clinical trials, Conventional hearing aids have improved significantly in recent years; however. amplification of sound within the external auditory canal creates a number of intrinsic problems. including acoustic feedback and the need for a tight ear mold to increase usable gain. Nonacoustic alternatives which could obviate these encumbrances have not become practical due to inefficient coupling (piezoelectric techniques) or unfeasible power requirements (electromagnetic techniques). Recent technical advances. however. prompted a major clinical investigation of a new electromagnetic. semi-implantable hearing device. This study presents the details of clinical phase I. in which an electromagnetic driver was coupled with a target magnet temporarily affixed onto the lateral surface of the malleus of six hearing aid users with sensorineural losses. The results indicate that the electromagnetic hearing device provides sufficient gain and output characteristics to benefit individuals with sensorineural hearing loss. Significant improvements compared to conventional hearing aids were noted in pure-tone testing and. to a lesser degree. in speech discrimination. Subjective responses were quite favorable. indicating that the electromagnetic hearing device 1. produces no acoustic feedback; 2. works well in noisy environments; and 3. provides a more quiet. natural sound than patients' conventional hearing aids. These favorable results led to phase II of the project. in which patients with surgically amendable mixed hearing losses were implanted with the target magnet incorporated within a hydroxyapatite ossicular prosthesis. The results of this second-stage investigation were also encouraging and will be reported separately.
Studying whole-mounted sections of the paranasal sinuses to understand the complications of endoscopic sinus surgery, Endoscopic techniques for paranasal sinus surgery have allowed detailed and complete removal of sinus disease while promising minimum distress to the patient. The telescopic view of the operative field shows detail of the sinus anatomy and its disease. not possible in earlier transnasal techniques. Several articles document the serious complications seen with the endoscopic surgery. To understand the paranasal sinuses and their relationships to the orbit and cribriform plate. blocks of cadaver heads that included the orbit and paranasal sinuses were whole sectioned. It has been possible to see areas of the cribriform and orbital wall that are at risk to produce cerebrospinal fluid rhinorrhea and orbital complications. At the same time. landmarks for avoiding these complications can be defined to guide the surgeon during this dissection as seen through the endoscope.
Auditory performance with simultaneous intracochlear multichannel stimulation, Different sound processing strategies are used in the various cochlear implant designs. This report presents auditory data on 35 patients implanted at the University of Utah from April 1984 to April 1989. A multichannel monopolar electrode system is inserted intracochlearly. During daily use and auditory performance testing. four electrodes receive simultaneous input. The incoming acoustic signal is amplified and routed to the different electrodes through a band-pass filter system. Mean pure-tone performances were: 500 Hz-29.6 +/- 9.4 dB; 1000 Hz-23.5 +/- 13.2 dB; 2000 Hz-25.4 +/- 9.6 dB; 4000 Hz-32.1 +/- 11.5 dB; and 6000 Hz-42.2 +/- 7.7 dB. Audio-only CID sentence testing showed 51.4% of patients scoring better than 60% and 40% scoring better than 80%. The percutaneous pedestal is well tolerated; patients have had the systems in place for 13 and 15 years.
Update: ansa cervicalis to recurrent laryngeal nerve anastomosis for unilateral laryngeal paralysis, Twenty cases of unilateral laryngeal paralysis are reported. Satisfactory follow-up intervals and data (videostroboscopy and glottographic analysis) were available on 12 patients. The excellent to normal phonatory quality achieved in many of these patients indicates that the ansa cervicalis to recurrent laryngeal nerve anastomosis is the procedure of choice in selected patients with unilateral vocal cord paralysis. Excellent medialization of the paralyzed cord. as well as correction of arytenoid malposition and thyroarytenoid muscle atrophy appear to explain the technique's success. since the reinnervated cord neither abducts nor adducts. We feel that this technique is the procedure of choice in younger patients. or those who use their voices professionally. since the phonatory quality achieved is superior to Teflon injection or Isshiki thyroplasty. and the technique is reversible.
Squamous cell carcinoma of the upper aerodigestive tract associated with well-differentiated carcinoma of the thyroid gland, The association of squamous cell carcinoma of the upper aerodigestive tract with well-differentiated thyroid carcinomas has rarely been reported in the literature. We report 10 cases illustrating this occurrence. In eight cases. the thyroid carcinoma was discovered accidentally on histological examination of a single neck node. a neck node dissection specimen. an unexpectedly found thyroid nodule. or a systematically resected thyroid lobe. all during surgical treatment of an upper aerodigestive tract carcinoma. In the other two cases. metastatic thyroid neck nodes appeared during the follow-up of a patient with an upper aerodigestive tract carcinoma. No case of upper aerodigestive tract carcinomas was found during the follow-up of thyroid cancer patients. In most cases. adequate thyroid cancer surgery was performed simultaneously or later. Prognosis was essentially determined by the upper aerodigestive tract cancer.
Argon laser therapy for perianal Bowen's disease: a case report, Bowen's disease (intraepithelial squamous cell carcinoma) may occasionally occur in anal canal or perianal region. Surgical excision in this area may result in significant complications and a recurrence rate of 9-19%. A case of successful treatment of anal and perianal Bowen's disease using argon laser therapy is presented. No acute or chronic complications resulted from laser therapy. Twenty-eight months after the initial diagnosis the patient is disease free. Laser therapy also provides the potential for repeated treatment of recurrent lesions without significant patient discomfort or inconvenience. Argon laser therapy should be considered as a therapeutic option in the treatment of Bowen's disease.
Publicly funded HIV counseling and testing--United States, 1990, A critical component of CDC's national human immunodeficiency virus (HIV)-prevention program is support for HIV counseling and testing (CT) services. Sixty-five HIV-prevention programs are in health departments in 50 states. the District of Columbia. six cities. and eight territories. Each calendar quarter. the programs report to CDC aggregate or client record data about the number of 1) pretest counseling sessions. HIV-antibody tests. positive tests. and posttest counseling sessions. by CT site; 2) HIV-antibody tests and positive tests. by self-reported risk category; and 3) HIV-antibody tests and positive tests. by age group. sex. and race/ethnicity. This report summarizes data reported for 1990.
Type 1 diabetes in mice is linked to the interleukin-1 receptor and Lsh/Ity/Bcg genes on chromosome 1, Human type 1 (insulin-dependent) diabetes is a common auto-immune disease of the insulin-producing beta cells of the pancreas which is caused by both genetic and environmental factors. Several features of the genetics and immunopathology of diabetes in nonobese diabetic (NOD) mice are shared with the human disease. Of the three diabetes-susceptibility genes. Idd-1 -3 and -4 that have been mapped in mice to date. only in the case of Idd-1 is there any evidence for the identity of the gene product: allelic variation within the murine immune response I-A beta gene and its human homologue HLA-DQB1 correlates with susceptibility. implying that I-A beta is a component of Idd-1. We report here the mapping of Idd-5 to the proximal region of mouse chromosome 1. This region contains at least two candidate susceptibility genes. the interleukin-1 receptor gene and Lsh/Ity/Bcg. which encodes resistance to bacterial and parasitic infections and affects the function of macrophages.
Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3' untranslated region, Selenocysteine is incorporated cotranslationally at UGA codons. normally read as stop codons. in several bacterial proteins and in the mammalian proteins glutathione peroxidase (GPX). selenoprotein P and Type I iodothyronine 5' deiodinase (5'DI). Previous analyses in bacteria have suggested that a stem-loop structure involving the UGA codon and adjacent sequences is necessary and sufficient for selenocysteine incorporation into formate dehydrogenase and glycine reductase. We used the recently cloned 5'DI to investigate selenoprotein synthesis in eukaryotes. We show that successful incorporation of selenocysteine into this enzyme requires a specific 3' untranslated (3'ut) segment of about 200 nucleotides. which is found in both rat and human 5'DI messenger RNAs. These sequences are not required for expression of a cysteine-mutant deiodinase. Although there is little primary sequence similarity between the 3'ut regions of these mRNAs and those encoding GPX. the 3'ut sequences of rat GPX can substitute for the 5'DI sequences in directing selenocysteine insertion. Computer analyses predict similar stem-loop structures in the 3'ut regions of the 5'DI and GPX mRNAs. Limited mutations in these structures reduce or eliminate their capacity to permit 5'DI translation. These results identify a 'selenocysteine-insertion sequence' motif in the 3'ut region of these mRNAs that is essential for successful translation of 5'DI. presumably GPX. and possibly other eukaryotic selenocysteine-containing proteins.
In vivo cell-specific expression of the cystic fibrosis transmembrane conductance regulator, Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The principal manifestations of CF include increased concentration of Cl- in exocrine gland secretions. pancreatic insufficiency. chronic lung disease. intestinal blockage and malabsorption of fat. and male and female infertility. Insight into the function of CFTR can be gained by correlating its cell-specific expression with the physiology of those cells and with CF pathology. Determination of CFTR messenger RNA in rat tissues by in situ hybridization shows that it is specifically expressed in the ductal cells of the pancreas and the salivary glands. In the intestine. decreasing gradients of expression of the CFTR gene are observed on both the crypt-villus and the proximal-distal axes. This expression is consistent with CFTR being responsible for bidirectional Cl- transport. secretion in the intestinal crypts and reabsorption in the silivary gland ducts. and suggests that in these tissues CFTR functions as a regulated Cl- channel. In the lung. a broad band of hybridization includes the mucosa and submucosa of the bronchi and bronchioles. In the testis. CFTR expression is regulated during the cycle of the seminiferous epithelium. Postmeiotic expression is maximal in the round spermatids of stages VII and VIII. suggesting that CFTR plays a critical role in spermatogenesis and that deficiency of this function contributes to CF male infertility.
Recognition of a chromosome truncation site associated with alpha-thalassaemia by human telomerase, Telomeres define the ends of chromosomes; they consist of short tandemly repeated DNA sequences loosely conserved in eukaryotes (G1-8(T/A)1-4). Telomerase is a ribonucleoprotein which. in vitro. recognizes a single-stranded G-rich telomere primer and adds multiple telomeric repeats to its 3' end by using a template in the RNA moiety. In conjunction with other components. telomerase may balance the loss of telomeric repeats due to DNA replication. Another role of telomerase may be the de novo formation of telomeres. In eukaryotes like Tetrahymena. this process is an integral part of the formation of macronuclear chromosomes. In other eukaryotes this process stabilizes broken chromosomes. A case of human alpha-thalassaemia is caused by a truncation of chromosome 16 that has been healed by the addition of telomeric repeats (TTAGGG)n. Using an in vitro assay. I show here that human telomerase correctly recognizes the chromosome 16 breakpoint sequence and adds (TTAGGG)n repeats. The DNA sequence requirements are minimal and seem to define two modes of DNA recognition by telomerase.
Modified levator aponeurosis recession for upper eyelid retraction in Graves' disease, Recession of the levator aponeurosis has proved to be an excellent operation to correct upper eyelid retraction in Graves' disease. Harvey and Anderson's original description included recession of the levator aponeurosis along its entire width and complete extirpation of Muller's muscle. In a modification of the technique. we recess only the lateral two thirds of the levator/Muller's complex. Also. rather than excising Muller's muscle. we simply recess it en bloc with the levator aponeurosis. The lateral horn of the levator is cut. as previously advocated. to relieve the marked temporal elevation of the eyelid characteristic of Graves' lid retraction. This modified procedure provides good upper lid lengthening. with less surgical manipulation. less bleeding. and avoids medial over-corrections. Of 22 upper lids (12 patients) treated with this procedure. 19 (86.3%) were considered "good" after the operation.
The Glaucoma Laser Trial: 4. Contralateral effects of timolol on the intraocular pressure of eyes treated with ALT. GLT Research Group, Several reports have documented a contralateral intraocular pressure (IOP) lowering effect after unilateral instillation of timolol. Data derived from the Glaucoma Laser Trial (GLT). a randomized trial of the efficacy and safety of argon laser trabeculoplasty (ALT) as compared with the efficacy and safety of topical medications as initial therapy for primary open-angle glaucoma (POAG). demonstrated an estimated mean pressure reduction of 0.5 mm Hg in the contralateral eye that had received ALT. This contralateral effect is smaller than that observed in other studies of POAG patients. Lower initial IOP. longer duration of treatment with timolol. and/or improved outflow facility modulation in the ALT-treated eyes may be responsible for the smaller contralateral effect of timolol observed in the GLT patients.
Anterior capsule adherence to iris leading to pseudophakic pupillary block, We present a rare case of anterior capsule adherence to the iris following extracapsular cataract extraction with posterior chamber intraocular lens implantation and leading to pseudophakic pupillary block. There were no synechiae at the pupillary margins associated with the capsule/iris adherence. but aqueous was entrapped behind the iris and intraocular pressure rose. Laser iridotomy was temporarily beneficial. but it had to be repeated several times.
Repair of inferior iridodialysis using a partial-thickness scleral flap, We present a technique of inferior iridodialysis repair using a partial-thickness scleral flap. which. in turn. employs a modification of the technique currently used to suture posterior chamber intraocular lenses under scleral flaps.
The effects of induced mood on laboratory pain, Sixty-five subjects experienced 2 cold pressor immersions. Following the initial immersion. subjects participated in the Velten mood induction procedure by reading either depressive. neutral or elative statements. The sensory discriminative response to pain was measured by ratings of pain. and the affective-reactive response to pain was measured by pain tolerance. Pain tolerance. but not pain ratings. were affected by mood inductions with subjects in the depression condition shortening their tolerance times more than the subjects in the neutral condition and the subjects in the elative condition increasing their tolerance times.
Glycerol injection into the trigeminal ganglion provokes a selective increase in human cerebral blood flow, Fourteen patients suffering from idiopathic trigeminal neuralgia (refractory to medication) were treated by injection of glycerol into the trigeminal ganglion. The changes in cerebral blood flow (CBF) after glycerol injection were quantified by intravenous 133Xe emission tomography. There was a significant 11% (P less than 0.01) increase in ipsilateral CBF and an 8% (P less than 0.05) increase in contralateral CBF 1 h after glycerol injection. The interhemispheric difference was significant (P less than 0.05). The increase was significantly greater in the ipsilateral internal carotid territory. in the anterior cerebral artery and middle cerebral artery territories (superficial (P less than 0.05). deep territories (P less than 0.001]. We suggest that these changes are due to the release of substance P and/or calcitonin gene-related peptide. from terminals of the trigeminal-vascular system during glycerol injection.
Intravenous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy, In some patients. ongoing and evoked neurogenic pain is relieved by pharmacological or destructive block of the sympathetic innervation of the affected part. In others. sympatholysis is ineffective. The present report shows that these two groups of patients can be distinguished by a safe and simple diagnostic test. Individuals in whom the pain was transiently relieved by intravenous phentolamine (Regitine) were very likely to respond favourably to subsequent sympatholytic treatment with i.v. regional guanethidine. Individuals in whom the phentolamine test was negative did not enjoy pain relief from this type of sympatholysis.
Quantitative sensory testing before and after regional guanethidine block in patients with neuralgia in the hand, Using reference values from healthy volunteers. thermal and vibration-induced pain thresholds and the sensibility for warm and cold were studied in 18 patients with neuralgia in one hand following a traumatic injury or surgery. All patients had spontaneous pain and allodynia to vibration. They were treated with intravenous regional guanethidine block (RGB). Quantitative sensory testing was performed on both hands before and 1-3 days after treatment. Eleven patients benefitted considerably from the block. with pain relief for 2 weeks or more. Ten of these 11 patients had mild nerve injuries caused by compressive trauma to the nerve. Before RGB they showed a moderate loss in temperature discrimination capacity; their heat pain thresholds were reduced and they exhibited allodynia to cold and vibration on the injured side. After RGB. the pain thresholds were normalised both to thermal and vibratory stimuli. These patients were classified as having sympathetically maintained pain (SMP). Seven patients reported no or only minor pain-relieving effect of RGB lasting 1-5 days. Severe nerve injuries were most frequent in this group of patients. On the injured side. before RGB. their ability to discriminate between warm and cold was markedly impaired. thermal pain thresholds were normal. and they showed allodynia to vibration. After RGB. there was no change in thermal pain thresholds and the allodynia to vibration persisted. These patients were classified as having sympathetically independent pain (SIP). The results indicate that quantitative thermal sensory tests. together with clinical evaluation of the nerve trauma. can help to predict which patients will have long-lasting pain alleviation after RGB treatment.
Can anxiety help us tolerate pain, It was hypothesized that anxiety which is relevant to the source of pain exacerbates pain. whereas anxiety which is irrelevant to the source of pain reduces the experience of pain. Female subjects were given either high or low anxiety provoking information about a cold pressor task (relevant anxiety) or high or low anxiety provoking information about a potential shock (irrelevant anxiety). Subjects were then exposed to the cold pressor. The results demonstrated that subjects who were highly anxious about the cold pressor reported experiencing the most pain. Subjects who were highly anxious about the shock reported the least pain and reported significantly less pain than subjects who were highly anxious about the cold pressor. These findings clearly demonstrate that the relationship between anxiety and pain is not always positive or unidirectional.
A novel technique for the evaluation of mechanical pain and hyperalgesia, We describe a new technique which is useful for the evaluation of mechanically induced pain and hyperalgesia. Light metal cylinders are guided and accelerated in a barrel. On impact against the skin they elicit a brief sensation of pain. This method allows the application of a wide range of controllable innocuous and noxious impact velocities of the cylinder at variable stimulus repetition rates. The system is sufficiently flexible to stimulate perpendicularly any skin area and to move rapidly to adjacent target regions if desired. Psychophysical testing using magnitude estimation techniques revealed that pain thresholds were normally distributed. Over a wide range of stimulation intensities monotonically increasing stimulus response functions were obtained. Repeated testing showed a good intra-individual reproducibility of both threshold and supramaximal pain ratings. The method was also useful in determining the time course of pain and mechanical hyperalgesia following a brief painful stimulus. We conclude that the new technique is useful for evaluating psychophysical stimulus response functions of mechanically induced pain and its changes following tissue injury. This technique may also hold some promise in quantifying altered pain sensitivity in patients.
Stress analgesia: the opioid analgesia of long swims suppresses the non-opioid analgesia induced by short swims in mice, In mice. room temperature swimming for as short a period as 15 sec has been found to induce a non-opioid analgesia with a time course of 10-12 min. As the duration of the swim is increased. an opioid analgesia develops with a longer persistence (25-30 min); the development of the opioid analgesia appears to suppress the expression of the non-opioid analgesia so that none of the latter is evident after 3 min swims. The characteristics of the tail-flick nociceptive test are also described.
Pediatric prehospital care in urban and rural areas, There are limited data concerning pediatric prehospital care. although pediatric prehospital calls constitute 10% of emergency medical services activity. Data from 10.493 prehospital care reports in 11 counties of California (four emergency medical services systems in rural and urban areas) were collected and analyzed. Comparison of urban and rural data found few significant differences in parameters analyzed. Use of the emergency medical services system by pediatric patients increased with age. but 12.5% of all calls were for children younger than 2 years. Calls for medical problems were most common for patients younger than 5 years of age; trauma was a more common complaint in rural areas (64%. P = .0001). Frequency of vital sign assessment differed by region. as did hospital contact (P less than .0001). Complete assessment of young pediatric patients. with a full set of vital signs and neurologic assessment. was rarely performed. Advanced life support providers were often on the scene. but advanced life support treatments and procedures were infrequently used. This study suggests the need for additional data on which to base emergency medical services system design and some directions for education of prehospital care providers.
Pediatric emergency transport and the private practitioner, A mail survey of 182 pediatricians and 92 family practitioners in Pennsylvania was conducted to determine their methods of transport of seriously ill children from their offices to referral centers and their involvement with professional transport services. Although most physicians (93.1%) stated that they had professional services available to them (at their office location). more than half (53.8%) indicated that the patient's family automobile was their most commonly used method of transport of ill children to tertiary care centers. This was true regardless of the disease entity involved. including suspected epiglottitis. Practice setting had little influence on transport method. However. in general. younger children were judged to need ambulance transport more often than older children. Reasons cited for not using professional transport from the office included a perceived better efficiency of the family car (61.8%). the prohibitively high expense of professional transport (9.8%). and failure to consider professional transport (6.5%). Further study of this component of office preparedness is suggested.
Child care options for ill children, Care of ill children who normally attend out-of-home child care programs poses a problem for many working parents. employers. and child care workers. Children cared for in child care centers have an increased incidence of illness and consequently their parents miss work more often compared with children cared for in other child care arrangements. Programs for the care of ill children are discussed to provide the practicing pediatrician with an understanding of the various programs currently or potentially available in the community. The paper ends with a discussion of the various solutions to enhance the economic gains of working parents while serving the need of children for nurturant care.
Perceptions of vulnerability 3 1/2 years after problems of feeding and crying behavior in early infancy, The long-term consequences for infants with problems of feeding and crying behavior remain unknown. The purpose of this research was to determine whether such children are later perceived by their parents as vulnerable and more often have behavior problems and have different personalities than children without problems in infancy. The implications of managing such problems by changing milk formulas is explored. Mothers of 379 infants were enrolled in the postpartum period. Information about problems of feeding and crying behavior was obtained at 4 months. Thirty-six percent of the infants had problems and the formula had been changed for 17%. At 3 1/2 years. 320 (84%) mothers completed a questionnaire. Children who had had problems were more often perceived as vulnerable (relative risk [RR] 1.86; 95% confidence interval [CI] 1.09. 3.19) and more often had behavior problems (RR 1.78; 95% CI 1.03. 3.07). There were no differences in personality. Children whose problems had been managed by changing milk formulas were more often perceived as vulnerable (RR 2.18; 95% CI 1.05. 4.53). Although allergies were reported significantly more often for those children who had had problems. there were no differences in the prevalence of asthma or eczema. Problems of feeding and crying behavior in early infancy and the way they are managed may have long-term implications for the child.
Prevention of pedestrian injuries to children: effectiveness of a school training program, Pedestrian injuries are a complex problem for which no single intervention will be completely effective. One component of a community-wide program. training of schoolchildren in street-crossing skills. is evaluated. The program targeted public school students in grades K through 4 with an eight-session training program by a single teacher. cross-age teaching. videotape feedback. and in 1990 parent-child activity workbooks. Children's street crossing was observed pretraining and posttraining and graded on four behaviors: WALKING on sidewalk/shoulder vs in the street; STOPPING at the curb; LOOKING L-R-L before crossing; KEEP LOOKING while crossing. Analysis was conducted on matched pairs in which observations pretraining were compared with those posttraining on same child. Observations were completed on 137 children in 1989 and 92 in 1990. Nearly all children walked on the side of the road; however. fewer than 50% of children STOPPED. 25% LOOKED. and fewer than 20% KEPT LOOKING before training. Training did not improve the performance on the first two behaviors in either year. significantly increased LOOKING in 1990. and increased KEEP LOOKING by twofold in 1989 and threefold in 1990. It is concluded that pedestrian skills of children can be improved but that such a program must be part of a broader effort if pedestrian injuries are to decrease.
Pedestrian injuries to children younger than 5 years of age, Historically. research on pediatric pedestrian injuries has analyzed children younger than 5 years of age as a single group. However. in this study. these children were divided into two age groups which were reflective of differences in behavior and development. The data demonstrate differences in the circumstances of the pedestrian injury events between toddlers (0 through 2 years and ambulatory) and preschoolers (3- and 4-year-olds). Toddlers were more likely to be injured in nontraffic events whereas preschoolers were more frequently injured in traffic situations. A high proportion of toddler injuries occurred in residential driveways and were caused by vehicles backing up. The majority of preschoolers. often without supervision. were injured while crossing/darting midblock on residential streets near their homes. Reflecting these differences in circumstances and also developmental differences between toddlers and preschool children. there is a need for age-specific interventions to reduce pedestrian injuries in children younger than 5 years of age.
Injuries to children and adolescents: impact on physical health, Disability resulting from injuries was examined in a health maintenance organization population of children and adolescents 0 through 19 years of age. The physical health status instrument from the Rand Health Insurance Study was used to evaluate functional outcome of patients seen in the emergency room and outpatient clinic. Overall. 55.1% of individuals had limitations in their usual activities during the week following injury; 16.4% and 3.8% were not yet back to full activities after 1 week and 1 month. respectively. Individuals 10 years of age and older had more functional impairment than did younger children. Restrictions were greatest for fractures/dislocations and sprains and for injuries due to sports. play/recreational activities. and falls.
Incidence of intrauterine cocaine exposure in a suburban setting, This study endeavored to determine the incidence of intrauterine cocaine exposure in a socioeconomically mixed suburban setting. It also assessed the effectiveness of an anonymous questionnaire in eliciting information on maternal use of illicit drugs during pregnancy. Meconium was collected from 500 consecutively born infants and analyzed for the presence of cocaine and its metabolites. An anonymous two-page questionnaire also was distributed to all postpartum mothers. Of the infants' mothers. (73.2%) were covered by some form of insurance (private). whereas 26.8% either had no insurance or were covered by Medicaid (clinic). Fifty-nine (11.8%) babies tested positive for cocaine. The meconium of 6.3% of the babies whose mothers had private insurance tested positive. while the meconium of 26.9% of the babies whose mothers had Medicaid or no insurance tested positive. 316 (63.2%) of the mothers returned a questionnaire. 73% had private insurance and 27% were covered by Medicaid (clinic). Only five mothers with no insurance or covered by Medicaid admitted using cocaine. It appears that neonatal exposure to cocaine may be an even greater problem than previously imagined. particularly in the private population. In addition. anonymous maternal self-reporting forms probably will not be helpful in identifying infants at risk for illicit exposure to drugs.
Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years of age, To estimate the effect of neonatal hyperbilirubinemia on long-term cognitive ability in full-term newborns with a negative Coombs test. we performed a 17-year historical prospective study of 1948 subjects. Intelligence tests and medical examinations performed at the military draft board were stratified according to serum bilirubin concentration. A logistic regression analysis was used to adjust for the confounding effects of gestational age. birth weight. Apgar score. ethnic origin. socioeconomic class. paternal education. birth order. and the administration of phototherapy and exchange transfusion. No direct linear association was shown between neonatal bilirubin levels and intelligence test scores or school achievement at 17 years of age. However. the risk for low intelligence test scores (IQ score less than 85) was found to be significantly higher (P = .014) among full-term male subjects with serum bilirubin levels above 342 mumol/L (20 mg/dL) (odds ratio. 2.96; 95% confidence interval. 1.29-6.79). This association was not observed among female subjects. We conclude that severe neonatal hyperbilirubinemia. among full-term male newborns with a negative Coombs test. could be associated with lower IQ scores at 17 years of age.
Focal encephalitis with enterovirus infections, We report on four pediatric patients with Enterovirus infections who were admitted to the hospital with signs or symptoms of acute. focal encephalitis. All four experienced focal seizures. Each had a cerebrospinal fluid pleocytosis at the initial lumbar puncture. In all four patients the diagnosis of herpes simplex encephalitis was entertained. Each child improved spontaneously within a few days of admission to the hospital. and only one had residual neurologic abnormalities at the time of discharge. A brief review of these cases. and three additional cases from the literature. indicate that the enteroviruses. particularly the group A Coxsackieviruses. are rare causes of acute focal encephalitis in children and adolescents.
Psychosocial influences on acquired immunodeficiency syndrome-risk behaviors among high school students, A survey measuring acquired immunodeficiency syndrome (AIDS)-related behaviors and selected psychosocial factors was administered to 1091 tenth grade students residing in or near an AIDS epicenter. The purpose of the survey was to identify salient risk factors that could be targeted in AIDS prevention programs. By 15 years of age. one quarter of students reported engaging in behaviors that placed them at higher risk for acquiring infection with human immunodeficiency virus. and 3% of students reported engaging in very high-risk behaviors. Students exposed to certain psychosocial stressors (ie. adverse life circumstances and poor parental support). who engaged in other problem behaviors (ie. substance use and academic problems) and who had higher self-esteem. were more likely to engage in higher risk behaviors. Pediatricians and other clinicians. particularly those working in or near AIDS epicenters. who encounter adolescents with multiple psychosocial problems. should be alert to the possibility that these youths also are engaging in behaviors that place them at risk for AIDS. Comprehensive care for these teenagers must include an assessment of involvement in AIDS-risk behaviors and appropriate behavioral counseling.
Standards for selected anthropometric measurements in Prader-Willi syndrome, We report standards (95th. 50th. and 5th centiles) in Prader-Willi syndrome for weight. height. sitting height. head circumference. head length. head breadth. hand length. middle finger length. palm length. hand breadth. foot length. foot breadth. triceps skinfold. and subscapular skinfold. For comparison with Prader-Willi syndrome standardized curves. normal control data from the literature were plotted similarly and standard curves were produced. We encourage the use of these standards with the examination of patients who have Prader-Willi syndrome and in the comparison of the patient who has Prader-Willi syndrome with other similarly affected individuals. The standards may also be useful for assisting in the diagnosis of Prader-Willi syndrome. particularly in younger individuals.
Beliefs about AIDS, health, and illness in low-income white women, A sample of 42 low-income white women were interviewed to describe their beliefs about AIDS and its treatment and to determine whether these beliefs were related to the subjects' general framework of beliefs about illness and its treatment. Content analysis was used to classify data. The causes and treatment of AIDS were categorized as professional sector. popular sector. and traditional sector health care beliefs. Professional sector beliefs included the cause and major modes of transmission and prevention identified by the biomedical system and the public health service. Popular sector misconceptions included beliefs about casual transmission and immunizations. Traditional sector beliefs concerned causes such as contamination and impurities and remedies such as herbs and diet. The respondents' explanations for the causes and treatment of AIDS in these three areas were integrated into a lay explanatory model of illness involving germs. resistance. and the immune system.
Empowering potential: a theory of wellness motivation, Data were collected from 29 individuals who were attempting to initiate and sustain programs of cardiac risk factor modification. Data were analyzed through the technique of constant comparative analysis. Empowering potential. the basic social process identified from the data. explained individual motivation to initiate and sustain cardiovascular health behavior. Empowering potential was a continuous process of individual growth and development which facilitated the emergence of new and positive health patterns. Within the process of empowering potential. individuals use a variety of strategies which guide the initiation and maintenance of health-related change. The process of empowering potential consists of three stages: appraising readiness. changing. and integrating change. Two categories occurred throughout the process of empowering potential: imaging and social support systems. These findings provide a better understanding of how motivated action is initiated and reinitiated over time.
Newborn behavioral performance in colic and noncolic infants, The specific purpose of this investigation was to examine the newborn performance of colic and noncolic infants on the Brazelton Neonatal Behavior Assessment Scale (BNBAS). The sample was composed of 119 firstborn infants from healthy. married. white couples. Data were collected prenatally. during the perinatal period. and postnatally from birth through four months of infant age. A total of 38 infants (32%) were believed to have colic. Colicky infants differed significantly from noncolicky infants on one of the seven item clusters. labeled the BNBAS Orientation cluster (p less than .05).
Repression of the interferon signal transduction pathway by the adenovirus E1A oncogene, The signal transduction pathway initiated by type I interferon (alpha and beta interferons) is inhibited by expression of the adenovirus type 5 E1A oncogene. Cotransfection analyses with the E1A oncogene and an interferon-stimulated reporter gene show that mutations within an amino-terminal domain of the E1A oncoprotein are defective in transcriptional repression. Cotransfection experiments also revealed that the transcriptional repression is mediated through the interferon-stimulated response element (ISRE) found within the promoter of interferon-stimulated genes. Since interferon treatment activates a latent cytoplasmic DNA-binding factor that can recognize the ISRE and subsequently stimulate transcription. the appearance of this factor was analyzed in a cell line that constitutively expresses the E1A oncogene. The DNA binding activity of this transcriptional activator was found to be inhibited in the E1A-expressing cell line. In vitro cytoplasmic mixing experiments with extracts from control and E1A-expressing cells identified a specific component of this multimeric transcription factor to be defective.
A cluster of related zinc finger protein genes is deleted in the mouse embryonic lethal mutation tw18, We report that a number of related zinc finger protein genes are closely linked on mouse chromosome 17. At least four of these genes are transcribed in the 8.5-day postcoitum embryo and are deleted in the t complex early acting embryonic lethal mutation tw18. We have evidence that additional finger protein genes are located in this region. These findings demonstrate that related finger protein genes can be clustered in the murine genome and identify genes that may be considered as candidates for the tw18 mutation.
Physiological and anatomical evidence for a magnocellular defect in developmental dyslexia, Several behavioral studies have shown that developmental dyslexics do poorly in tests requiring rapid visual processing. In primates fast. low-contrast visual information is carried by the magnocellular subdivision of the visual pathway. and slow. high-contrast information is carried by the parvocellular division. In this study. we found that dyslexic subjects showed diminished visually evoked potentials to rapid. low-contrast stimuli but normal responses to slow or high-contrast stimuli. The abnormalities in the dyslexic subjects' evoked potentials were consistent with a defect in the magnocellular pathway at the level of visual area 1 or earlier. We then compared the lateral geniculate nuclei from five dyslexic brains to five control brains and found abnormalities in the magnocellular. but not the parvocellular. layers. Studies using auditory and somatosensory tests have shown that dyslexics do poorly in these modalities only when the tests require rapid discriminations. We therefore hypothesize that many cortical systems are similarly divided into a fast and a slow subdivision and that dyslexia specifically affects the fast subdivisions.
Retroviral-mediated gene therapy for the treatment of hepatocellular carcinoma: an innovative approach for cancer therapy, An approach involving retroviral-mediated gene therapy for the treatment of neoplastic disease is described. This therapeutic approach is called "virus-directed enzyme/prodrug therapy" (VDEPT). The VDEPT approach exploits the transcriptional differences between normal and neoplastic cells to achieve selective killing of neoplastic cells. We now describe development of the VDEPT approach for the treatment of hepatocellular carcinoma. Replication-defective. amphotrophic retroviruses were constructed containing a chimeric varicella-zoster virus thymidine kinase (VZV TK) gene that is transcriptionally regulated by either the hepatoma-associated alpha-fetoprotein or liver-associated albumin transcriptional regulatory sequences. Subsequent to retroviral infection. expression of VZV TK was limited to either alpha-fetoprotein- or albumin-positive cells. respectively. VZV TK metabolically activated the nontoxic prodrug 6-methoxypurine arabinonucleoside (araM). ultimately leading to the formation of the cytotoxic anabolite adenine arabinonucleoside triphosphate (araATP). Cells that selectively expressed VZV TK became selectively sensitive to araM due to the VZV TK-dependent anabolism of araM to araATP. Hence. these retroviral-delivered chimeric genes generated tissue-specific expression of VZV TK. tissue-specific anabolism of araM to araATP. and tissue-specific cytotoxicity due to araM exposure. By utilizing such retroviral vectors. araM was anabolized to araATP in hepatoma cells. producing a selective cytotoxic effect.
Molecular characterization of a region of DNA associated with mutations at the agouti locus in the mouse, Molecular characterization of a radiation-induced agouti (a)-locus mutation has resulted in the isolation of a segment of DNA that maps at or near the a locus on chromosome 2 in the mouse. This region of DNA is deleted in several radiation- or chemical-induced homozygous-lethal a-locus mutations and is associated with specific DNA structural alterations in two viable a-locus mutations. We propose that DNA probes from this region of chromosome 2 will be useful for ultimately characterizing the individual gene or genes associated with a-locus function.
Two integrin-binding peptides abrogate T cell-mediated immune responses in vivo, Two VLA proteins (or beta 1 integrins; originally called very late activation antigens) that bind to distinct determinants on fibronectin (FN) are increased on activated immune or memory T cells. VLA-4 binds to the peptide sequence Gly-Pro-Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr (GPEILDVPST in single-letter code) on the alternatively spliced CS-1 form of FN. whereas VLA-5 binds to an Arg-Gly-Asp sequence found on all forms of FN. It has been proposed that the migration of immune T cells out of blood vessels and through connective tissue to a site of antigenic challenge is facilitated by the interaction of such integrins with matrix protein molecules. We have examined directly the role of T-cell integrins in vivo by using the well-characterized. T-cell-mediated contact hypersensitivity (CHS) response to the hapten trinitrochlorobenzene (TNCB). We demonstrate that the cells that transfer CHS to TNCB adhere to FN in the presence of Ca2+/Mg2+. and T-cell populations depleted of FN-adherent cells do not transfer immunity. We further show that TNCB-immune T cells treated with the synthetic peptides GPEILDVPST or Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP in single-letter code). ligands for VLA-4 and VLA-5. respectively. lose their ability to mediate this immune response in a murine model. whereas the control peptides Val-Ile-Pro-Asp-Leu-Thr-Glu-Ser-Pro-Gly and Gly-Arg-Gly-Glu-Ser-Pro have no effect. Neither GPEILDVPST nor GRGDSP significantly inhibited the proliferative response of TNCB-immune T cells in vitro. These data suggest that FN-binding integrins on T cells play a role in the localization of T cells to sites of antigenic challenge in tissue.
Development of vivo of genetic variability of simian immunodeficiency virus, Rapid development of genetic variability may contribute to the pathogenicity of lentiviruses as it may allow escape from immune surveillance and/or from suppression of virus replication. Although apathogenic in African green monkeys. simian immunodeficiency virus isolated from African green monkeys is shown to display extensive genetic variability and defectiveness in the V1- and V2-like variable domains of the external envelope protein comparable to that known for human immunodeficiency virus. However. in contrast to the situation in human immunodeficiency virus-infected individuals. a predominant major virus variant was detected neither in a monkey naturally infected for more than 10 years nor in two monkeys infected with a molecular virus clone for 15-20 months. Extensive variability evolves from a single genotype with a maximal rate of 7.7 mutations per 1000 nucleotides per year. A remarkable selection for nonsynonymous mutations that accounts for 92% of all changes indicates continuous selection of variants.
cDNA cloning of human R-type pyruvate kinase and identification of a single amino acid substitution (Thr384----Met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic anemia, cDNA clones for human R-type pyruvate kinase (PK) were isolated from a human reticulocyte cDNA library. constructed by PCR with a single gene-specific primer. The full-length cDNA was 2060 base pairs long. and the cDNA encoded 574 amino acids. the same number as that by rat R-type PK. Compared with human L-type PK. R-type PK was 31 amino acids longer at the amino terminus. We also cloned and characterized R-type PK cDNA clones from patients with hereditary hemolytic anemia from a PK deficiency. PK Tokyo. A single nucleotide substitution (ACG to ATG) was found at nucleotide 1151 of the coding sequence of the R-type PK. which caused an amino acid substitution. Thr384----Met. Dot blot hybridization of PCR-amplified genomic DNA from patients and their parents by allele-specific oligonucleotide probes showed that the parents. who were second cousins. were heterozygous. To confirm that the nucleotide change was responsible for the variant phenotype. we expressed the L-type PK with the single amino acid change in Escherichia coli and characterized the enzyme. The variant PK was thermolabile and moved slowly in the polyacrylamide gel buffered in 10 mM Tris.HCl. pH 8.3; these characteristics were fully compatible with data obtained from the patient's PK. From these results. we concluded that enzymatic stability of the variant was affected by the point mutation of the PK-encoding gene.
Enhanced malignant transformation induced by expression of a distinct protein domain of ribonucleotide reductase large subunit from herpes simplex virus type 2, The 1.3-kilobase (kb) Pst I DNA fragment C (Pst I-C) of herpes simplex virus type 2 (HSV-2) morphological transforming region III (mtrIII; map unit 0.562-0.570) encodes part of the N-terminal half of the large subunit of ribonucleotide reductase (RR1; amino acid residues 71-502) and induces the neoplastic transformation of immortalized cell lines. To assess directly the role of these RR1 protein sequences in cell transformation. the Pst I-C fragment was cloned in an expression vector (p91023) containing an adenovirus-simian virus 40 promoter-enhancer to generate recombinant plasmid p9-C. Expression of a protein domain (approximately 65 kDa) was observed in p9-C-transfected COS-7 and Rat2 cells but not in those transfected with plasmid pHC-14 (Pst I-C in a promoterless vector). In Rat2 cells. p9-C induced highly transformed foci at an elevated frequency compared with that of pHC-14. Introduction of translation termination (TAG) condons within the RR1 coding sequence and within all three reading frames inactivated RR1 protein expression from p9-C and reduced its transforming activity to the level seen with the standard pHC-14 construct. Wild-type p9-C specified a protein kinase capable of autophosphorylation. Computer-assisted analysis further revealed significant similarity between regions of mtrIII-specific RR1 and amino acid patterns conserved within the proinsulin precursor family and DNA transposition proteins. These results identify a distinct domain of the HSV-2 RR1 protein involved in the induction of enhanced malignant transformation. In addition. the data indicate that the mtrIII DNA itself can induce basal-level transformation in the absence of protein expression.
Retinoic acid affects the expression of nuclear retinoic acid receptors in tissues of retinol-deficient rats, The multitude of biological effects of the vitamin A metabolite. retinoic acid. are mediated by nuclear retinoic acid receptors (RARs). which are members of the steroid/thyroid hormone receptor superfamily. RAR-alpha. -beta. and -gamma are encoded by three genes from which multiple isoforms can be generated. Recent studies suggest that the expression of at least some RAR isoforms can be regulated by retinoic acid in certain cell lines. Here we examined regulation of RAR expression in the adult animal. RARs were analyzed by Northern blots from lung. liver. and testes of retinol-deficient rats. Retinol deficiency caused a 65-70% decrease in the mRNA levels of lung and liver RAR-beta. whereas no change was observed in RAR-alpha and -gamma mRNA levels in these organs. In the testes of retinol-deficient animals. two transcripts. RAR-alpha 1 (3.7 kb) and RAR-alpha 2 (2.8 kb). were detected as compared with one RAR-alpha 1 (3.7 kb) transcript in retinol-sufficient testes. When retinol-deficient rats were orally administered 1 dose of retinoic acid (100 micrograms per rat). lung RAR-beta mRNA levels started to increase after 1 hr and reached a 16-fold higher level after 4 hr; after 4 hr these retinoic acid-fed rats also showed a 7-fold increase in liver RAR-beta mRNA levels as compared with levels in the retinol-deficient rats. In contrast. liver. lung. and testes RAR-alpha transcripts remained either unchanged or showed only a slight increase in response to retinoic acid. RAR-gamma was constitutively expressed in lung. and its mRNA levels were induced 2-fold by retinoic acid. These results show tissue diversity in the rapid induction of RAR-beta and RAR-gamma by retinoic acid in the adult animal and suggest distinct roles for the various receptor isoforms in the control of the retinoid response.
Craniofacial suture stenosis: morphologic effects, Craniofacial anomalies. such as Apert's and Crouzon's syndromes. are presumed to be related to premature growth arrest of cranial base growth sites. However. premature growth arrest at cranial vault sutures in animals appears to play a causative role in the development of cranial deformities characteristic of single-suture. or simple. craniosynostosis in humans. To study the possible causative role of cranial vault and other (interface) suture stenoses on the development of craniofacial deformity. a vault suture and an interface suture between the cranial vault and facial skeleton were simultaneously immobilized. Thirty-one New Zealand White rabbits at 9 days of age underwent implantation of dental amalgam growth markers adjacent to cranial vault and facial sutures. In the experimental group (n = 15). methylcyanoacrylate adhesive was applied over the coronal (vault) and frontonasal (interface suture between vault and facial skeleton) sutures to immobilize them. The remaining 16 animals served as sham-treated controls. All animals underwent serial radiographic cephalometry to document growth effects in the cranial vault. cranial base. and facial skeleton. Application of adhesive resulted in statistically significant (p less than 0.05) reduction in growth at the coronal and frontonasal sutures. This was accompanied by an overall significant reduction in neurocranial vault length during the first 30 days of development.
Aesthetic improvements in free-flap mandible reconstruction, Mandible reconstruction with free flaps has become a well-established technique. Efforts are now focused on obtaining superior functional and aesthetic results. Improvements in the quality of the latter are possible with a systematic approach to shaping the bone graft. Important elements in this approach have been defined based on experience in 50 consecutive cases. Preoperative studies include the lateral cephalogram and a transverse plane CT scan from which mandible templates are constructed. These templates are models of the mandible in two planes and are used to shape the bone with a high degree of precision. They allow the bone to be completely shaped while still attached by the pedicle at the donor site. The surgical specimen serves as an additional key visual reference and as a source of measurements to determine overall bone-graft length. Miniplates alone provide sufficient fixation to stabilize the bone as it is shaped segment by segment. Intermaxillary fixation is used only to prevent errors in total bone-graft length. Hemimandible and anterior defects represent two completely different bone-shaping problems. Although the bone-shaping methods described have been developed primarily with the fibula. they have been successfully applied to the scapula and radius donor sites as well.
Use of the AO plate for immediate mandibular reconstruction in cancer patients, Free vascularized bone grafts have revolutionized mandibular reconstruction. yet their use in all mandibulectomy patients is not always necessary. A recently developed alternative to bony reconstruction has been the use of the AO reconstruction plate. We compared the use of the AO reconstruction plate with immediate free bone graft mandibular reconstruction in 31 patients. Reconstruction plates were used in 20 and immediate free bone grafts were used in 11 patients. The overall success rate for use of the plate was 15 of 20 (75 percent). There were 6 anterior reconstructions. of which only 2 (33 percent) were successful. This is opposed to 13 of 14 (93 percent) lateral reconstructions that were successful in lateral plate placements. There were 11 immediate composite free flaps: 4 iliac crest. 4 scapula. 2 fibula. and 1 composite radial forearm flaps. Six repairs were for anterior defects. and there were 5 full-thickness defects. 3 of which were in the anterior position. All 11 flaps were successful. In conclusion. we believe the reconstruction plates are a useful adjunct for mandibular replacement in the head and neck cancer patient but should be reserved for lateral defects. For anterior reconstructions. even in patients with locally advanced disease. free-tissue transfer of composite osteocutaneous flaps is the reconstructive method of choice.
The free tongue graft for correction of secondary deformities of the vermilion in patients with cleft lip, From January of 1985 to January of 1990. 31 patients with repaired cleft lip and secondary vermilion defects underwent 45 revisional procedures. A free tongue graft was utilized seven times in six patients (19 percent). Indications for its use were a V-shaped vermilion deficit or a "whistling" deformity associated with a sagittal vermilion deficiency and normal or insufficient lateral vermilion bulk. Of the seven free tongue grafts. none was lost. Three patients have required revisions. including repeat free tongue graft in one. Proper positioning of the graft along the free vermilion border has made color and texture match satisfactory. The free tongue graft is a simple and reliable means of transferring both vermilion bulk and surface mucosa. Introduction of the free tongue graft has eliminated the need for more cumbersome procedures. such as the Abbe flap or the tongue flap. in properly selected patients.
Staged sequential flap reconstruction for large lower lip defects, A method for the reconstruction of total or nearly total defects of the lower lip is described that utilizes a staged sequence of flaps that are familiar to most plastic surgeons. The recommended sequence is an extended Karapandzic flap to reestablish the oral sphincter. then two sequential Abbe flaps from the upper lip to restore balance and augment the central lower lip. and finally a commissureplasty using a sliding myomucosal flap in conjunction with final revision of the scars. Intervals of 3 weeks separate the surgical procedures. Using this strategy. essentially normal lip function and a relatively normal appearance have been obtained in four patients with large lip defects.
Breast reconstruction utilizing subcutaneous tissue expansion followed by polyurethane-covered silicone implants: a 6-year experience, Reconstruction of the breast after modified radical mastectomy can be safely and adequately performed in the subcutaneous plane. Placement of a subcutaneous tissue expander (as either an immediate or a delayed procedure). rapid expansion over a 3- to 4-month period. capsulotomy. and placement of a polyurethane-coated implant have led to satisfactory results over a 6-year period. Breast reconstruction methods are well documented; however. the utilization of expanded subcutaneous chest wall skin has not been reported heretofore.
Bilateral gluteal thigh flaps for closure of large defects in the lumbosacral region and perineal region, Large defects in the lumbosacral and perineal regions were reconstructed with bilateral gluteal thigh flaps. These two patients demonstrate the versatility of the flap. which also was used as a sensory flap in one patient.
Double-layered free temporal fascia flap as a two-layered tendon-gliding surface, We report the use of a two-layered free fascial flap consisting of temporoparietal and deep temporal fascia based on a single vascular pedicle. the superficial temporal artery and vein. The flap was used to reconstruct an extensive degloving injury of the dorsum of the hand. in which multiple intact extensor tendons lay fully exposed on all sides. with exposed bone beneath them. By sandwiching the tendons between the layers of vascularized fascia. gliding surfaces were provided. both superficial and deep to the exposed tendons. The single-stage reconstruction was completed with a split-thickness skin graft. The patient returned to heavy manual work within 12 weeks of injury. He obtained an excellent range of movement without the need for tenolysis.
Transplantation of an osteoarthrotendinous allograft with autogenous soft-tissue coverage for thumb reconstruction, A fresh-frozen thumb osteoarthrotendinous allograft and autogenous coverage were used to reconstruct a thumb. Immunosuppressants were not used. The components of the composite allograft are present and functioning 1 year post-operatively. Host cells have replaced and are replacing bone and tendinous structures. The "survival" of this osteoarthrotendinous allograft may have important implications in the treatment of patients with previous digital amputations. congenital absence of digits. and amputated digits that have failed replantation or are not replantable because of severely damaged vessels.
Reconstruction of the medial half of the lower eyelid using a "switch" split-lid procedure, Reconstruction of the medial half of the lower eyelid has one major disadvantage: It produces a scar at right angles to the eyelid rim. In contrast. use of a "switch" split-lid procedure avoids this inconvenience. The lateral half of the lower eyelid is split in two lamellae. The inner layer is transferred medially. and the resulting defect is closed with a buccal graft. The outer layer is drawn laterally to cover the raw surface of the mucosal pedicle and graft. The surplus of skin over the lateral canthal area is removed. This procedure. which so far has been used in three patients. promises to be a useful alternative for reconstruction of the medial half. but not more. of the lower eyelid.
Selective photothermolysis and removal of cutaneous vasculopathies and tattoos by pulsed laser, The evolution of the laser as a medical device has been a process of continued improvement. Research into increasing our understanding of the optical characteristics of skin has made it possible to concentrate not on the effects of any particular laser system. but on basic biologic and physical principles of laser-tissue interaction. The lasers available in the 1960s and 1970s offered few possibilities for modification. However. modern technology allows us to manipulate the physical characteristics of lasers and design them for specific therapeutic purposes. Selective photothermolysis relies on chromophore-specific absorption of a brief pulse of light to generate and confine heat to certain targets within the skin without nonspecific thermal damage to adjacent structures. Thermally mediated target alterations can be confined from the level of large multicellular tissue structures (e.g.. blood vessels) to individual microscopic pigmented structures (e.g.. tattoo pigment granules). The purpose of this report is to describe the current progress being made and to summarize the present theories for achieving increasing selective removal. without scarring or other skin textural changes. of cutaneous vasculopathies and tattoo pigment by pulsed laser.
The medial temporal lobe memory system, Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent. anatomically related cortex. including entorhinal. perirhinal. and parahippocampal cortices. These structures. presumably by virtue of their widespread and reciprocal connections with neocortex. are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However. the role of this system is only temporary. As time passes after learning. memory stored in neocortex gradually becomes independent of medial temporal lobe structures.
Transcriptional repression mediated by the WT1 Wilms tumor gene product, The wt1 gene. a putative tumor suppressor gene located at the Wilms tumor (WT) locus on chromosome 11p13. encodes a zinc finger-containing protein that binds to the same DNA sequence as EGR-1. a mitogen-inducible immediate-early gene product that activates transcription. The transcriptional regulatory potential of WT1 has not been demonstrated. In transient transfection assays. the WT1 protein functioned as a repressor of transcription when bound to the EGR-1 site. The repression function was mapped to the glutamine- and proline-rich NH2-terminus of WT1; fusion of this domain to the zinc finger region of EGR-1 converted EGR-1 into a transcriptional repressor.
Magnetic-resonance imaging used for determining fat distribution in obesity and diabetes, Computed-tomography scanning and magnetic-resonance imaging (MRI) have been used to quantify intraabdominal and subcutaneous fat depots. In this study MRI was used to define fat-distribution patterns in 24 obese females with non-insulin-dependent diabetes (NIDDM) and 12 females with simple obesity. Subjects had anthropometric measurements and single-slice abdominal scans performed at the umbilicus. In addition. in 10 of the nondiabetic females. measurements were repeated after 10 wk of a very-low-calorie diet. Nondiabetic females had significantly less intraabdominal fat (P less than 0.01) than did the diabetics but had equivalent subcutaneous fat. There was no significant relationship between waist-to-hip ratio and intraabdominal fat. subcutaneous fat. or their ratio. After a weight loss of 10.6 +/- 3.8 kg there were significant decreases in both intraabdominal and subcutaneous fat (P less than 0.01). Weight loss is associated with decreases in fat in both depots.
Taste preferences in human obesity: environmental and familial factors, Taste-response profiles influence food selection and may help distinguish among potential subgroups of obese individuals. A representative community-based sample of 61 obese and 31 lean adults tasted five sucrose solutions and nine fat-containing solid stimuli resembling cake icings. Solid stimuli contained 15-35% fat and 20-70% sucrose (by weight). No significant differences in taste responsiveness were observed between obese and lean groups. Obese subjects were then divided into subgroups based on age at onset of obesity and past fluctuations in body weight. Obese subjects characterized by large weight fluctuations showed elevated preferences for sugar and fat mixtures compared with the stable subgroup. In contrast. early age at onset of obesity (less than 10 y). thought to be a measure of familial risk. had no significant effects on taste preferences. Environmental as opposed to familial factors may be more immediate determinants of taste preferences and food choice.
Nutritional supplementation, psychosocial stimulation, and growth of stunted children: the Jamaican study, The benefits of nutritional supplementation. with or without psychosocial stimulation. on the growth of stunted children were evaluated. Children aged 9-24 mo with lengths less than -2 SD of the National Center for Health Statistics references (n = 129) were randomly assigned to four groups: control. nutritional supplementation. stimulation. and both interventions. A fifth group with lengths greater than -1 SD was also enrolled. Length. weight. head and arm circumferences. and triceps and subscapular skinfold thicknesses were measured on enrollment and 6 and 12 mo later. Multiple-regression analysis was used to determine the effects of the interventions in which age. sex. initial status. initial dietary intake. and several socioeconomic variables were controlled for. Stimulation had no effect on growth and there was no interaction between the interventions. After 12 mo supplemented children had significantly increased length. weight. and head circumference (all P less than 0.01). The effects of supplementation were not cumulative but occurred in the first 6 mo.
Lipid responses of hypercholesterolemic men to oat-bran and wheat-bran intake, The hypocholesterolemic effects of oat bran (OB) have been recently challenged. To carefully document the hypocholesterolemic effects of OB. 20 hypercholesterolemic men admitted to a metabolic ward were randomly allocated to either OB or wheat bran (WB) for 21 d after a 7-d control-diet period. Control and treatment diets were designed to be identical in energy content and nutrients. differing only in the amount of soluble fiber. After 21 d. OB significantly decreased total cholesterol by 12.8% (P less than 0.001). low-density-lipoprotein cholesterol by 12.1% (P less than 0.004). and apolipoprotein B-100 by 13.7% (P less than 0.001) whereas WB had no significant effect. High-density-lipoprotein cholesterol and apolipoprotein A-I did not change significantly in either group. Serum triglycerides decreased by 10% in both groups but the decrease was only significant (P less than 0.04) in WB subjects. OB but not WB significantly reduced total cholesterol and other atherogenic lipoprotein fractions independent of other dietary changes.
Supplementation of patients with homozygous sickle cell disease with zinc, alpha-tocopherol, vitamin C, soybean oil, and fish oil, Thirteen patients (aged 0.7-17.9 y) with homozygous sickle cell disease were supplemented with alpha-tocopherol. vitamin C. zinc. and soybean oil (suppl 1; for 8 mo) and alpha-tocopherol. vitamin C. and fish oil (suppl 2; for 7 mo). Urinary zinc (suppl 1). plasma vitamin C. plasma cholesterol ester and erythrocyte (RBC) omega 3 fatty acids (suppl 2). and plasma and RBC alpha-tocopherol (suppl 1 and 2) increased. Suppl 1 decreased irreversibly sickled cells by 37.5%. decreased RBC protoporphyrin and urinary porphyrins. and increased the RBC total fatty acid-cholesterol ratio. Suppl 2 decreased plasma triglycerides. further increased the RBC alpha-tocopherol. moderately increased the RBC double-bond index. but decreased the RBC total fatty acid-cholesterol ratio. Zinc. copper. and porphyrins showed prolonged changes. The supplements did not change hemoglobin concentrations. RBC age (reticulocytes. polyamines). or number of aplastic and vasoocclusive crises. Zinc reduces irreversibly sickled cells. Augmentation of RBC antioxidant status by alpha-tocopherol and vitamin C and incorporation of omega 3 fatty acids into RBCs do not affect hemolytic component. Effects on vasoocclusive component are unclear.
Identification of novel rhodopsin mutations associated with retinitis pigmentosa by GC-clamped denaturing gradient gel electrophoresis, Retinitis pigmentosa (RP) is a group of disorders characterized by progressive degeneration of the outer retina. resulting in night blindness. visual field loss. an abnormal electroretinogram. and characteristic retinal pigmentary changes. An important step in the understanding of RP has been the recognition that some cases of autosomal dominant RP (ADRP) are caused by mutations in the rhodopsin gene. Multiple different point mutations within the coding sequence of the rhodopsin gene have been associated with ADRP. We have developed a GC-clamped denaturing-gradient-gel electrophoresis (DGGE) assay for the coding region of the rhodopsin gene and have used this assay to screen ADRP patients for mutations. The assay consists of amplifying with PCR the five exons of the rhodopsin gene and then analyzing each PCR product by DGGE. We have used this assay to detect three previously unreported rhodopsin base substitutions associated with ADRP. The use of this assay to identify ADRP patients who have various rhodopsin mutations has allowed us to begin studies seeking to correlate molecular genotype with clinical phenotype. Furthermore. GC-clamped DGGE has allowed us to identify families with ADRP not caused by a rhodopsin mutation. Such families will be important in the search for other genes involved in ADRP.
Molecular characterization of the human delta-aminolevulinate dehydratase 2 (ALAD2) allele: implications for molecular screening of individuals for genetic susceptibility to lead poisoning, The second enzyme in the heme biosynthetic pathway. delta-aminolevulinate dehydratase (ALAD). is a homooctameric protein encoded by a gene localized to human chromosome 9q34. Expression of the two common alleles. ALAD1 (p = .9) and ALAD2 (q = .1). results in a polymorphic enzyme system with three distinct charge isozymes. designated 1-1. 1-2. and 2-2. Individuals heterozygous (2pq = .18) or homozygous (q2 = .01) for the ALAD2 allele have significantly higher blood lead levels than do ALAD1 homozygotes. when exposed to low or high levels of lead in the environment. To investigate the molecular nature of this common polymorphism. total RNA from an ALAD2 homozygote was oligo-dT primed and reverse transcribed. and then the ALAD2 cDNA was amplified. subcloned. and sequenced. Compared with the ALAD1 sequence. the only difference in the ALAD2 cDNA was a G-to-C transversion of nucleotide 177 in the coding region. which created an MspI restriction site. This base substitution predicted the replacement of a positively charged lysine by a neutral asparagine (K59N). an amino acid change consistent with the more electronegative charge of the ALAD-2 subunit. The ALAD1 and ALAD2 alleles were easily detected by amplification of a 916-bp region of genomic DNA and MspI digestion which results in 582- and 511-bp products. respectively. Molecular analysis of 85 ALAD1/ALAD2 heterozygotes and of eight ALAD2 homozygotes revealed no discrepancy between the predicted genotype and the erythrocyte isozyme phenotype. indicating that all the ALAD2 alleles analyzed had the G-to-C transversion.
Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity, Tuberous sclerosis (TSC) is an autosomal dominant disorder with both neurological and cutaneous manifestations often resulting in significant disability. Although it has been studied clinically and biochemically for many years. the underlying pathophysiology remains unknown. Genetic linkage analysis provides an alternative strategy for understanding the genetic etiology of this disease. Genetic linkage of a gene for TSC to loci in 9q32-9q34 has been reported but has not been a universal finding. since absence of linkage to 9q loci. as well as linkage to loci on 11q. have also been reported. We present here data on 22 families (21 previously unreported) segregating TSC. Our results strongly support a TSC locus in the 9q32-34 region for approximately one-third of families and provide significant evidence for genetic heterogeneity. Application of newly described highly polymorphic dinucleotide repeat marker loci in TSC greatly enhanced the informativeness of our pedigrees and was vital for detecting the heterogeneity. No clear evidence of linkage to chromosome 11q22 markers was found. suggesting that a still unidentified TSC locus elsewhere in the genome may account for the majority of TSC families.
Regressive logistic models for familial diseases: a formulation assuming an underlying liability model, Statistical models have been developed to delineate the major-gene and non-major-gene factors accounting for the familial aggregation of complex diseases. The mixed model assumes an underlying liability to the disease. to which a major gene. a multifactorial component. and random environment contribute independently. Affection is defined by a threshold on the liability scale. The regressive logistic models assume that the logarithm of the odds of being affected is a linear function of major genotype. phenotypes of antecedents and other covariates. An equivalence between these two approaches cannot be derived analytically. I propose a formulation of the regressive logistic models on the supposition of an underlying liability model of disease. Relatives are assumed to have correlated liabilities to the disease; affected persons have liabilities exceeding an estimable threshold. Under the assumption that the correlation structure of the relatives' liabilities follows a regressive model. the regression coefficients on antecedents are expressed in terms of the relevant familial correlations. A parsimonious parameterization is a consequence of the assumed liability model. and a one-to-one correspondence with the parameters of the mixed model can be established. The logits. derived under the class A regressive model and under the class D regressive model. can be extended to include a large variety of patterns of family dependence. as well as gene-environment interactions.
Human type VII collagen: genetic linkage of the gene (COL7A1) on chromosome 3 to dominant dystrophic epidermolysis bullosa, Epidermolysis bullosa (EB) is a heterogeneous group of heritable blistering disorders affecting the skin and the mucous membranes. Previous ultrastructural studies on the dystrophic (scarring) forms of EB have demonstrated abnormalities in the anchoring fibrils. morphologically distinct structures below the basal lamina at the dermal/epidermal basement membrane zone. Type VII collagen is the major collagenous component of the anchoring fibrils. and it is therefore a candidate gene for mutations in some families with dystrophic forms of EB. In this study. we performed genetic linkage analyses in a large kindred with dominant dystrophic EB. A 1.9-kb type VII collagen cDNA clone was used to identify a PvuII RFLP to follow the inheritance of the gene. This RFLP cosegregated with the EB phenotype in this family. strongly supporting genetic linkage (Z = 5.37; theta = .0). In addition. we assigned the type VII collagen gene (COL7A1) to chromosome 3 by hybridization to a panel of human x rodent somatic cell hybrids. These data demonstrate very close genetic linkage between the clinical phenotype in this family and the polymorphism in the type VII collagen gene mapped to chromosome 3. The absence of recombination between EB and the type VII collagen gene locus. as well as the observed abnormalities in the anchoring fibrils. strongly suggest that this collagen gene is the mutant locus in this kindred.
High frequency of the Gaucher disease mutation at nucleotide 1226 among Ashkenazi Jews, Reliable estimates of the frequency of Gaucher disease-producing mutations are not available. The high frequency of Gaucher disease in the Ashkenazi Jewish population is due to the occurrence of a mutation at nucleotide (nt) 1226. We have screened 593 DNA samples from normal Ashkenazi Jews. as well as 62 DNA samples from all our Ashkenazi Jewish patients with Gaucher disease. for the presence of the 1226 mutation. In the 593 presumed normal Ashkenazi Jewish individuals the 1226 mutation was identified in the heterozygous state in 37 and in the homozygous state in two. giving a gene frequency of .035 for the mutation. This 1226 mutation represented 73% of the 124 Gaucher disease alleles in Jewish Gaucher disease patients. Accordingly we estimate that the gene frequency for Gaucher disease among the Ashkenazi Jewish population is .047. which is equivalent to a carrier frequency of 8.9% and a birth incidence of 1:450.
GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene mutations in 11 patients from a defined region in Portugal, The GM2-gangliosidosis B1 variant occurs at an exceptionally high frequency in the northern part of Portugal. In most patients. the disease manifests itself as a juvenile form. as opposed to the late-infantile form described for many patients from other parts of the world. We have analyzed the beta-hexosaminidase alpha gene in 11 patients. as well as in some relatives. in order to characterize the underlying abnormalities. They were screened for the two previously identified mutations responsible for the B1 variant phenotype (G533----A. also designated as the "DN allele." and C532---T) by PCR amplification of an 800-bp DNA fragment and subsequent dot-blot hybridization with allele-specific oligonucleotides. The fragment amplified from one patient was also subcloned and sequenced. Ten patients. constituting a clinically and biochemically homogeneous group. were found to be homozygous for the DN allele. The other. whose clinical profile more resembled the late-infantile phenotype often described in the literature. was a compound heterozygote carrying the DN allele and another. as yet unidentified. abnormal allele. Our results. corroborated by previously published data. suggest that homozygotes and compound heterozygotes for the DN allele may be distinguishable at the phenotypic level. depending on the nature of the abnormality in the other allele. A common ancestral origin for the DN allele can also be postulated.
Case report: Crouzon syndrome with short stature, A five-year-old boy with Crouzon Syndrome. short stature. and delayed bone age was found to have partial growth hormone deficiency. Accelerated growth was observed after human growth hormone replacement. Children with Crouzon Syndrome should be followed closely for all growth parameters. not just head circumference.
Effects of bicarbonate supplementation on urinary mineral excretion during very low energy diets, Metabolic acidosis is associated with increased calciuria and ammoniagenesis. This study evaluated the effects of oral sodium bicarbonate (NaHCO3) or combined potassium bicarbonate-calcium carbonate supplementation on urinary mineral excretion during the ketoacidosis of a very-low-energy protein diet. Seventeen healthy obese subjects (BMI: 37.5 +/- 3.2 kg/m2. weight: 100 +/- 3 kg) were given a 1.72 MJ all protein (93 g) liquid formula and a multivitamin-mineral supplement daily for 3 weeks. Subjects in groups 1 (n = 6) and 2 (n = 5) received 16 mmol KCl. In addition. subjects in group 1 received 60 mmol Na+ daily as sodium chloride. subjects in group 2. 60 mmol Na+ as NaHCO3. The subjects in group 3 (n = 6) were given 32 mmol K+ as bicarbonate and 16 mmol Ca++ as carbonate daily. Metabolic acidosis was prevented in groups 2 and 3 with bicarbonate and bicarbonate-carbonate administration. This was reflected in significant curtailment of the augmented ammonium nitrogen excretion found in group 1. The additional oral K+ in group 3 improved K+ balance and probably also inhibited ammoniagenesis. Urine calcium was greater (p less than 0.04) in group 1 subjects. but similar in groups 2 and 3. despite higher calcium intake in group 3. Urinary phosphorus decreased with time in all groups. but more so in the group 2 subjects who received NaHCO3. Acidosis was associated with the reverse effect on urinary magnesium. which decreased in group 1 subjects.
Altered beta adrenergic receptor function in subjects with symptomatic mitral valve prolapse, Individuals with mitral valve prolapse (MVP) frequently show symptoms of a hyperadrenergic state. beta adrenergic receptor characteristics were compared in the lymphocytes of subjects with symptomatic MVP and control subjects during rest and exercise. At rest. the proportion of receptors binding agonist with high affinity. as determined from isoproterenol competition for (-)[125I]-iodopindolol binding sites. was greater in MVP subjects than in controls. With exercise. the proportion of high-affinity receptors in MVP subjects decreased to control levels. Isoproterenol stimulation of lymphocyte 3'.5'-cyclic adenosine monophosphate (cyclic AMP) also was greater in MVP subjects than in controls at rest. but not during exercise. Plasma catecholamine concentrations in MVP subjects were normal during both rest and exercise. Unlike exercise. isoproterenol infusion elicited clinical manifestations of increased adrenergic responsiveness in MVP subjects. The beta receptor in exercised MVP subjects exhibited unusually high affinity agonist binding (i.e. a lower dissociation constant KH than in either the same subjects at rest or exercised controls) and also abnormal coupling to the stimulatory guanine nucleotide-binding regulatory protein (GS) of adenylate cyclase. as reflected by the inability of guanine nucleotide to convert the receptor to a low-affinity state. These findings suggest that functional alteration of the beta adrenergic receptor. in the absence of abnormal plasma catecholamine levels. might contribute to the hyperadrenergic state of MVP subjects at rest. However. desensitization of high affinity beta receptors or altered receptor-GS coupling might preserve normal adrenergic responsiveness during exercise.
Substance abuse disorders: a psychiatric priority. Group for the Advancement of Psychiatry Committee on Alcoholism and the Addictions, The renewed public. governmental. and professional interest in addictive disorders should serve to encourage the interest of psychiatrists in this important and rapidly changing field. It is the view of the Group for the Advancement of Psychiatry (GAP) Committee on Alcoholism and the Addictions that all psychiatrists should possess expertise in the recognition. assessment. and treatment of substance use disorders. This position paper by the GAP committee reviews the role of the psychiatrist in the evaluation and treatment of patients with substance use disorders. It also notes some of the obstacles to full involvement in this field by medical practitioners in general and psychiatrists in particular. The psychiatrist has a critical role to play in the diagnosis and treatment of patients with substance use disorders. As biopsychosocial phenomena. substance abuse problems constitute a special and direct challenge to the psychiatrist. whose training. perspective. and competence should span all three domains. Psychiatrists must be willing to accept this challenge and fully participate in the development and application of treatment strategies adequate to cope with the enormous human suffering resulting from the abuse of alcohol and other psychoactive drugs.
Recent advances in the phencyclidine model of schizophrenia, OBJECTIVE: Phencyclidine (PCP. "angel dust") induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis. PCP-induced psychosis incorporates both positive (e.g.. hallucinations. paranoia) and negative (e.g.. emotional withdrawal. motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding of schizophrenic pathophysiology. METHOD: Twenty-five papers were identified that described the clinical dose and serum and CSF levels at which PCP induces its psychotomimetic effects. The dose range of PCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. RESULTS: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation of its receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. CONCLUSIONS: These findings suggest that endogenous dysfunction of NMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models of schizophrenia are discussed in relationship to the diagnosis and etiology of schizophrenia.
The pharmacology of stuttering: a critical review, OBJECTIVE: The author critically examines the limited world literature on pharmacologic treatments of stuttering. METHOD: The literature on stuttering and drugs was identified by means of two computer-assisted searches. FINDINGS: A great variety of pharmacologic agents have been used to treat stuttering. reflecting the many theories about the origin and nature of the disorder. In some instances new hypotheses about the nature of stuttering have followed the chance discovery of agents having some efficacy. CONCLUSIONS: Few studies have used adequate experimental designs. Promising avenues of research. both for the treatment of stuttering and for exploring its nature. include the use of calcium channel blocking agents and cholinergic drugs.
High nocturnal body temperature in premenstrual syndrome and late luteal phase dysphoric disorder, OBJECTIVE: Because women with late luteal phase dysphoric disorder (LLPDD) experience symptomatic affective states predictably. they can be studied to determine whether there are biological findings related solely to the clinically symptomatic state. The authors sought to answer the question. Does body temperature change with affective state? METHOD: The core body temperature and motor activity patterns of 10 women with premenstrual syndrome (PMS). six of whom also met criteria for LLPDD. and no other psychological or medical illness were compared to those of six women with chronic. noncyclic dysphoria and six asymptomatic comparison women at four phases of the menstrual cycle. RESULTS: The nocturnal temperatures of the women with PMS/LLPDD were significantly higher than those of the comparison subjects across the entire menstrual cycle. but there were no differences in nocturnal activity levels. The women with noncyclic dysphoria had a mean nocturnal temperature in the follicular phase as high as that of the women with PMS/LLPDD. The temperatures of all women were higher in the luteal phase than in the follicular phase. CONCLUSIONS: These findings suggest that in the future investigators should document menstrual cycle phase in all female subjects and. when studying body temperature. should carefully monitor symptomatic state in comparison subjects.
Cognitive outcome following tricyclic and electroconvulsive treatment of major depression in the elderly, OBJECTIVE: This study sought to ascertain the affective and cognitive outcome after tricyclic and electroconvulsive treatment of elderly medical-psychiatric patients meeting diagnostic criteria for major depression. some of whom had normal cognitive functioning and some of whom were cognitively impaired before treatment. METHOD: Patients who met criteria for major depression on the basis of a structured diagnostic interview and who scored 17 or more on the Hamilton Rating Scale for Depression were evaluated with the Mattis Dementia Rating Scale. The patients were then treated in a nonrandom manner with either tricyclic antidepressants or ECT (followed by tricyclic maintenance therapy). The majority of the patients treated with ECT had not responded previously to tricyclics. Follow-up psychometric testing was repeated in 6 months. RESULTS: Among the patients with normal pretreatment cognitive functioning. cognition was generally stable. Among the patients with pretreatment cognitive impairment. a substantial number--including those receiving ECT--demonstrated improvement in cognition. While the majority of patients improved with respect to both their affective and cognitive states. certain treatment-refractory subgroups were nevertheless identified. CONCLUSIONS: The data suggest that cognitive dysfunction associated with depression may improve after treatment in a substantial number of elderly patients. including those receiving ECT. Relapse rates. however. may be relatively high. and residual symptoms may persist. which emphasizes the need for optimal initial and long-term antidepressant strategies for this population.
Predictors of relapse into major depressive disorder in a nonclinical population, OBJECTIVE: This study sought to describe. the natural history of major depressive disorder in a large group of nonclinical subjects. In particular. the analysis determined demographic and clinical risk factors for the recurrence of major depressive disorder. METHOD: Relatives. comparison subjects (matched to relatives for age and sex). and spouses of affectively ill probands underwent structured clinical assessments before and after a 6-year interval. RESULTS: Of 396 individuals who had had only major depressive disorder that ended before the initial evaluation. 33.8% (N = 134) developed a new episode during the 6-year follow-up period. Youth. but not sex. was an important demographic risk factor. The presence of minor depression at the time of initial evaluation and the number of symptoms recalled from the worst previous episode were additional clinical risk factors. At the initial evaluation. 200 other subjects had described a previous history of both major depressive disorder and a nonaffective mental disorder. When compared to the subjects who recalled only a history of major depressive disorder. these subjects were more likely to have been in an episode of chronic intermittent depression at the initial evaluation and to recall a greater number of episodes as well as a greater number of symptoms in the worst episode. A history of a nonaffective mental disorder significantly increased the risk of relapse into major depressive disorder. CONCLUSIONS: These findings agree well with a recent review of clinically based follow-up studies. Thus. youth and a history of nonaffective illness are important risk factors for the recurrence of major affective disorder in a broad variety of settings.
Impact biomechanics of lateral knee bracing. The anterior cruciate ligament, We evaluated the effects of six different prophylactic braces on ACL ligament strain under dynamic valgus loads using a mechanical surrogate limb validated against human cadaveric specimens. Medical collateral ligament and anterior cruciate ligament peak forces. medial collateral ligament and anterior cruciate ligament tension initiation times. and impact safety factors were calculated for both braced and unbraced conditions. These tests were conducted to determine whether or not application of a prophylactic brace might provide protection to the anterior cruciate ligament under valgus loading conditions. The results of this study indicate that those braces that increased impact duration appear to differentially protect the anterior cruciate ligament more than the medial collateral ligament. and that most of the braces tested appear to provide some degree of protection to the anterior cruciate ligament under direct lateral impacts. These findings should be confirmed clinically.
Soccer injuries among elite female players, Injuries occurring in two female elite soccer teams were recorded during 1 year. Of 41 players. 33 (80%) sustained 78 injuries. The incidence of injury during games was 24/1000 hours. while the incidence during training was 7/1000 hours. The majority (88%) of injuries were localized to the lower extremities. with equal occurrence in the left and right legs. Forty-nine percent of the injuries occurred in the knee or ankle. Most of the injuries were minor (49%). while 36% were moderate and 15% were major. Of the major injuries (N = 12). 10 were due to trauma and 7 (58%) were knee ligament or meniscal tears. Overuse injuries constituted 28% of all injuries and occurred mainly during preseason training and at the beginning and end of the competitive season. Traumatic injuries (72%) occurred mainly during games with a predominance at the beginning of the competitive season. Almost 80% of the traumatic injuries occurred during physical contact with an opponent. Extrinsic factors such as weather. playing surface. temperature. or the position of the player within the team did not influence the injury rate. We conclude that female elite soccer players sustain a high incidence of injury. Few injuries were major. but 17% of the players sustained a major knee injury during the year.
Stress avulsion fracture of the tarsal navicular. An uncommon sports-related overuse injury, We report nine cases of stress-related avulsion fracture of the tarsal navicular in athletes. This uncommon over-use injury is thought to occur following repetitive cyclic compressive loading secondary to an impingement of the tarsal navicular. The small dorsal triangular fragment is best seen in weightbearing lateral view radiographs and isotope scan and/or tomography help confirm the diagnosis. We feel that operative treatment is the method of choice in highly symptomatic cases and among top athletes because of the shorter recovery time.
Magnetic resonance imaging of traumatic knee articular cartilage injuries, The purpose of this study was to assess the sensitivity of magnetic resonance imaging in determining the presence of articular cartilage injuries of the knee with arthroscopy as the standard for comparison. Forty-nine articular cartilage lesions were documented in 28 knees (27 patients) by arthroscopy. There were 22 men and 5 women with an average age of 29 years. Multiplanar magnetic resonance imaging was performed with spin echo and gradient-refocused acquisition in a steady state pulse technique. All of the knees had magnetic resonance imaging done within 4 weeks prior to arthroscopy. The magnetic resonance images were interpreted before arthroscopy and interpreted again after the results of arthroscopy were known to better define the potential learning curve for evaluating chondral lesions and to identify the technical limits of the existing imaging protocol/software. For full-thickness articular cartilage lesions. the prearthroscopy sensitivity of magnetic resonance imaging was 41% (12/29) and the postarthroscopy sensitivity was 83% (24/29). For partial-thickness chondral injury. the prearthroscopy sensitivity of magnetic resonance imaging was 15% (3/20) and the postarthroscopy sensitivity was 55% (11/20). The presence of an intraarticular effusion assisted the detection of chondral lesions because of an "arthrogram" effect. As a noninvasive method of evaluating articular cartilage and despite experienced interpretation and the benefit of retrospective analysis. both the prearthroscopy and the postarthroscopy sensitivity of magnetic resonance imaging was low using the imaging parameters described. Injury to articular cartilage is a frequent cause of knee pain and knee surgery; it is important to note at this time that magnetic resonance imaging cannot reliably exclude the presence of an articular cartilage injury.
Partial rupture of the patellar ligament. Results after operative treatment, Partial rupture of the patellar ligament. also known as jumper's knee. is defined as a repetitive overload lesion at the bone-ligament junction at the lower patellar pole. It is found mainly in athletes and is caused either by microruptures or partial macroruptures of the proximal part of the ligament. The abnormal anatomical lesion is focal degeneration. microruptures and macroruptures. and devitalized tissue at the insertion of the patellar ligament. Proliferation and neovascularization are often found. as well as degeneration and incomplete tissue healing. Surgical treatment is indicated only if a prolonged and well-supervised conservative treatment program fails. We operated on 78 patients with jumper's knee. by carefully removing the abnormal tissue from the ligament. At follow-up examination. 71 of 78 patients had excellent or good functional results and complete resumption of sports activities. Objective measurements of thigh muscle strength using a Cybex II dynamometer correlated with the functional results at a low angular velocity.
Effectiveness of orthotic shoe inserts in the long-distance runner, Five hundred questionnaires were distributed to long-distance runners who had used. or who were using orthotic shoe inserts for symptomatic relief of lower extremity complaints. Three hundred forty-seven (69.4%) responded (males. 71%; females. 29%). The mean age of the respondents was 36 years (range. 15 to 61). The average distance run per week was 39.6 miles (range. 5 to 98). The mean duration for use of the orthotic inserts was 23 months (range. 1 to 96). The predominant (63%) type of orthotic device used was flexible. The presumed diagnoses in the population studied were excessive pronation (31.1%). leg length discrepancy (13.5%). patellofemoral disorders (12.6%). plantar fasciitis (20.7%). Achilles tendinitis (18.5%). shin splints (7.2%). and miscellaneous (4.9%). Of the runners responding. 262 (75.5%) reported complete resolution or great improvement of their symptoms. Results of treatment with orthotic shoe inserts were independent of the diagnosis or the runner's level of participation. A high degree of overall satisfaction was demonstrated by the finding that 90% of the runners continued to use the orthotic devices even after resolution of their symptoms. Orthotic shoe inserts were most effective in the treatment of symptoms arising from biomechanical abnormalities. such as excessive pronation or leg length discrepancy. Along with other conservative measures. orthotic shoe inserts may allow the athlete to continue participation in running and avoid other treatment modalities that are more costly and time consuming. and therefore less acceptable to them.
Neurapraxia of the femoral nerve in a modern dancer, We have presented a case of an acute onset femoral nerve neurapraxia in a pure modern dancer. Repeated mild stretching of the femoral nerve during an established dance routine over a period of several months is implicated as the etiology. The thigh muscles quickly weakened. but regained strength within 3 months. Electromyographic evidence of specific femoral nerve injury initially was negative. but was evident 6 weeks following injury. Overuse syndrome in dancers can cause rapid loss of strength. Other conditions such as herniated intervertebral disc. acute hemorrhage. trauma. iliopsoas rupture. and acute stretching must be ruled out. Complete recovery was the natural outcome.
Isolated avulsion of the popliteus tendon. A case report, We have reported a rare case of an isolated avulsion of the popliteus tendon. In this case the avulsed tendon was associated with a large osteochondral fragment that was easily relocated and fixed anatomically. We believe that the popliteus tendon is important to the mechanics of the knee. We would recommend the treatment as presented in this case should one of these rare cases be encountered.
Comparison of 40 milliliters of 0.25% intrapleural bupivacaine with epinephrine with 20 milliliters of 0.5% intrapleural bupivacaine with epinephrine after cholecystectomy, To determine the influence of the volume of local anesthetic injected for intrapleural analgesia. 40 patients undergoing cholecystectomy were randomly allocated to two groups of 20 patients each. One group received 40 mL of 0.25% bupivacaine with epinephrine injected intrapleurally postoperatively. The other group received 20 mL of 0.5% bupivacaine with epinephrine. The onset time of analgesia was nearly the same in both groups and within 25 min all patients were nearly pain free. Our data demonstrate that 100 mg of bupivacaine with epinephrine elicits effective analgesia after cholecystectomy. There are only minor differences between 20 and 40 mL with regard to pain relief. The authors conclude that the volume of local anesthetic within the range of 20-40 mL in an adult has little influence on the extent or duration of intrapleural analgesia.
Epidural sufentanil for postoperative analgesia: dose-response in patients recovering from major gynecologic surgery, To determine the lowest effective dose of epidural sufentanil given for analgesia. 41 patients undergoing elective abdominal gynecologic surgery during continuous epidural anesthesia (lidocaine 2%) were randomly assigned to one of four postoperative treatment groups. Patients received an epidural bolus of either 25 (group A). 40 (group B). 55 (group C). or 70 micrograms (group D) sufentanil in 10 mL of saline. They were evaluated for the next 8 h using a 10-cm visual analogue scale. Except for two individuals in group A. all patients achieved a visual analogue scale score of 1 cm or less during the study interval. The onset of analgesia was most rapid in the two higher dose groups (A vs C and D; P less than 0.05). Pairwise comparison between groups showed a significant difference in the time needed to achieve maximum pain relief between the lowest and highest treatment groups (A vs D; P less than 0.05). Duration of analgesia was also significantly longer in groups C and D than in group A (208.0 +/- 21.1 and 224.0 +/- 14.7 vs 140.0 +/- 10.7 min; P less than 0.05). There were no differences among groups with regard to mean respiratory rate. level of sedation. 24-h narcotic requirements. or incidence of nausea. vomiting. and pruritus (P = NS). A single patient in group D suffered profound respiratory depression within seconds of administration. We conclude that. in patients recovering from lower abdominal surgery. a single 40-55-micrograms epidural bolus of sufentanil provides 3-3.5 h of effective analgesia. and that larger doses are not warranted.
Enhanced potency of receptor-selective opioids after acute burn injury, Dose-response curves of three receptor-selective opioids were established in a group of nonburned and a group of burned rats. Morphine (mu-agonist). biphalin (mu- and delta-agonist). and U50488H (kappa-agonist) were administered to each group. and analgesia was measured by tail flick latency testing. Each opioid had a significant increase in potency (i.e.. a decrease in ED50 values) in the burned (15% body surface area) compared with the nonburned groups. Moderate doses of each drug (i.e.. ED50 doses estimated from nonburned group data) in each case augmented stress-induced analgesia in the burned group. Analgesic doses failed to prevent a significant increase in plasma beta-endorphin and corticosterone after larger surface area (25%) burns. Regardless of receptor specificity. opioid analgesic potency is increased acutely after burn injuries.
Cardiovascular effects of volatile anesthesia in rabbits: influence of chronic heart failure and enalaprilat treatment, Circulatory responses to isoflurane and halothane anesthesia were studied in eight rabbits with biventricular cardiomyopathy induced by doxorubicin (Adriamycin. 14 mg/kg IV over 7 wk) and in eight controls (saline injections). In preliminary operations pulsed-Doppler flow probes were placed on the ascending aorta. left renal artery. and lower abdominal aorta. Each group was studied after 4. 6. and 7 wk of treatment. The development of congestive heart failure (CHF) was associated with decreases in mean arterial pressure and cardiac output (CO) of 14% and 16%. respectively. (P less than 0.05) and an increase in heart rate. In controls. each anesthetic agent produced dose-related decreases in mean arterial pressure and increases in heart rate. but not significant changes in CO. Renal blood flow was reduced to a similar degree by 1.3 MAC halothane (24% decrease) and 1.3 MAC isoflurane (21% decrease); hindlimb blood flow was reduced only by halothane. As CHF developed there was an attenuation of the heart rate response to anesthesia. Halothane. but not isoflurane. significantly reduced CO in more advanced stages of CHF. The changes in renal blood flow and hindlimb blood flow with each anesthetic in the CHF group were similar to those observed in controls and did not vary with week of treatment. Administration of the angiotensin-converting enzyme inhibitor enalaprilat (0.2 mg/kg IV) reversed the CO and renal blood flow effects of halothane except after 7 wk of treatment in the CHF group. when the combination of halothane and enalaprilat resulted in severe circulatory depression.
Comparison between Bricanyl Turbuhaler and Ventolin metered dose inhaler in the treatment of exercise-induced asthma in adults, The aim of the present study was to compare the effect of Bricanyl Turbuhaler (0.5 mg x 1 terbutaline) with the effect of albuterol metered dose inhaler (0.1 mg x 2 albuterol) in patients with reproducible bronchoconstriction. The study was performed as a double-blind placebo-controlled trial in sixteen asthmatic adults. Bronchoconstriction was induced by steady state running on a treadmill. Both 0.5 mg terbutaline and 0.2 mg albuterol have good bronchodilating effects in patients with exercise-induced asthma. There was. however. a faster onset of action after albuterol. The clinical value of this observed difference is uncertain.
Once daily fluticasone propionate aqueous nasal spray is an effective treatment for seasonal allergic rhinitis, A multicenter double-blind. randomized. parallel group study was conducted to evaluate the once daily administration of fluticasone propionate. a potent. new corticosteroid preparation. for the treatment of seasonal allergic rhinitis. Adult patients (n = 227) were treated for 2 weeks with fluticasone propionate aqueous nasal spray 200 micrograms QD or 100 micrograms BID or matching placebo during the autumn pollen season. Overall. the administration of fluticasone propionate once daily in the morning was as effective as the twice daily dosage regimen. and either regimen was more effective than placebo. Improvement in clinician-rated and patient-rated nasal symptom scores. including morning nasal obstruction. was evident within three days of fluticasone propionate therapy and continued throughout the treatment period. Fewer patients receiving fluticasone propionate used rescue medication and had nasal eosinophilia compared with patients receiving placebo. Adverse events were similar in frequency and nature in all three treatment groups. Morning plasma cortisol concentrations and response to cosyntropin stimulation were similar across groups and offered no evidence of HPA axis suppression. We conclude that fluticasone propionate aqueous nasal spray administered once daily is a safe and effective treatment for seasonal allergic rhinitis. The convenience of a once daily regimen may encourage better compliance.
Use of methotrexate in the treatment of steroid-dependent adolescent asthmatics, Five children 10 to 16 years of age with steroid-dependent asthma were treated with methotrexate. All were able to reduce their doses of prednisone and all had improvement in their clinical status. No significant side effects were noted in patients treated 1 to 3 years. This open study suggests that methotrexate should be considered in the treatment of older children with severe asthma and morbidity from their steroid therapy.
Relationships of total IgE level, skin prick test response, and smoking habits, Epidemiologic observations on 331 men showed that increased serum IgE concentration was associated with a wheal response to skin prick testing. but also to an erythema response in the absence of any wheal. and to heavy smoking. The association between IgE and the various skin prick test responses remained after taking into account smoking and asthma.
Efficacy of ketotifen in corticosteroid-dependent idiopathic anaphylaxis, To assess the potential benefit of ketotifen in the treatment of patients with corticosteroid-dependent idiopathic anaphylaxis. ketotifen was administered in an open trial to nine patients with idiopathic anaphylaxis who required maintenance prednisone for control of their disease. A double-blind trial was not done for reasons of patient safety. After a period of management with prednisone and establishment of the minimal dose of prednisone that controlled idiopathic anaphylaxis. ketotifen was initiated and cautious reduction of prednisone was attempted. The prednisone requirement was not altered in two patients. but prednisone was either substantially reduced or terminated in seven patients. Of these seven. three patients developed recurrent symptoms of idiopathic anaphylaxis after tapering and discontinuation of ketotifen. and ketotifen had to be resumed. The statistical analysis of prednisone reduction was highly significant (P less than .004) and we conclude ketotifen was of significant benefit in seven of nine patients with corticosteroid-dependent idiopathic anaphylaxis.
Peak nasal inspiratory flow and Wright peak flow: a comparison of their reproducibility, The measurement of peak nasal inspiratory flow (PNIF) is a rapid. convenient. and objective way to assess nasal patency. It is used much less commonly. however. than Wright Peak Flow (WPF). in part. because of concerns about its reproducibility. In order to compare the reproducibility of PNIF with WPF. we obtained multiple measurements of both flows in each of ten healthy. nonsmoking. trained subjects five times throughout the same day and daily throughout the same week. Mean PNIFs (L/min) were 140 immediately after arising. 170 at breakfast time. 183 at lunch time. 170 at dinner time. and 161 at bedtime. Corresponding mean WPFs were 528. 528. 535. 535 and 531 L/min. Peak nasal inspiratory flow coefficients of variation representing minute to minute. hour to hour. and day to day variation were 9.8. 13.5. and 9.7. respectively. Corresponding coefficients of variation with WPF. 2.4. 1.9. and 2.3. were significantly lower. Variability of PNIF and WPF did not increase with increased time spans. suggesting that variation in airway size is less important than variation in technique. Responses to intranasal oxymetazoline. as determined by changes in PNIF and changes in subjective assessments of nasal patency. were then evaluated in ten patients with nasal obstruction. These persons noted a mean subjective improvement of 68% (P = .0002) and demonstrated a mean objective improvement of 21% (P = .05). Posttreatment PNIFs of many individuals who reported substantial subjective improvement failed to exceed the expected variability of the test. This experience fails to demonstrate the utility of PNIF determinations for routine clinical use.
Platelet-activating factor in stroke and brain injury, Platelet-activating factor. an endogenous phospholipid of proinflammatory. hemostatic. and vasoactive properties. is synthesized by neurons and in injured brain. Platelet-activating factor is released together with eicosanoids such as thromboxane A2. prostacyclin. and leukotrienes. Its effects in neurons are mediated through a specific receptor coupled to phospholipase C and phosphoinositol metabolism. The cerebrovascular effects of platelet-activating factor include disruption of the blood-brain barrier. edema formation. and vasospasm. It has also been described to possess direct toxicity to neuronal cells in culture. Discovery and development of several highly potent and selective antagonists to platelet-activating factor receptors facilitated experimental studies underscoring the role of this factor as an endogenous mediator in cerebral disorders. particularly cerebral ischemia and trauma. Significant biochemical. microvascular. functional. and behavioral recovery has been demonstrated using these antagonists in an array of experimental models of focal and global ischemia in the central nervous system (CNS). Clearly. studies of platelet-activating factor in experimental models of CNS ischemia and reperfusion injury open a new perspective on phospholipid metabolism in stroke and offer an exceptionally promising therapeutic prospect. Data supporting this factor as a mediator of specific pathological sequelae in stroke and neuroinjury are surveyed in this review. We discuss the mechanisms and significance of platelet-activating factor-mediated effects and propose directions for future studies.
The spectrum of lissencephaly: report of ten patients analyzed by magnetic resonance imaging, Clinical data and magnetic resonance imaging scans from 10 patients with lissencephaly were reviewed. Although 6 of the 10 patients were less than 1 year old at the time of their most recent examination. those who were old enough for developmental assessment were. with a single exception. severely developmentally delayed. All patients had anatomical features compatible with impaired neuronal migration but normal myelination and. consequently. adequate glial migration. The severity of the lissencephaly did not seem to correlate with the severity of the clinical manifestations. One patient showed less delayed development than anticipated. perhaps because the most severely involved region of the brain was the prefrontal area.
Presynaptic and postsynaptic striatal dopaminergic function in neuroacanthocytosis: a positron emission tomographic study, Using [18F]dopa. [11C]raclopride. C15O2. and positron emission tomography. we have assessed striatal dopamine storage capacity. dopamine D2-receptor integrity. and regional cerebral blood flow. respectively. of 6 patients with neuroacanthocytosis. The patients with neurocanthocytosis all had chorea and variable combinations of seizures. dementia. axonal neuropathy. and orolingual self-multiation. [18F]dopa positron emmission tomographic findings were compared with 30 normal controls and 16 patients with sporadic. L-dopa-responsive. Parkinson's disease. Caudate and anterior putamen [18F]dopa uptake were normal in patients with neuroacanthocytosis. but mean posterior putamen [18F]dopa uptake was reduced to 42% of normal. similar to that in patients with Parkinson's disease. In patients with neuroacanthocytosis. mean equilibrium caudate: cerebellum and putamen: cerebellum [11C]raclopride uptake ratios were reduced to 54% and 62% of normal. compatible with a 65% and 53% loss of caudate and putamen D2-receptor-binding sites. respectively. Striatal and frontal blood flow was also depressed. The severe loss of D2-receptor-bearing striatal neuron. with concomitant loss of dopaminergic projections from the nigra to the posterior putamen. is consistent with both chorea and extrapyramidal rigidity being features of patients with neuroacanthocytosis.
Reduced D2 dopamine and muscarinic cholinergic receptor densities in caudate specimens from fluctuating parkinsonian patients, Binding of spiperone and 3-quinuclidinyl benzilate (QNB). both labeled with hydrogen 3 (3H). were measured in caudate tissue obtained from 8 living parkinsonian patients at the time of cerebral transplantation. This was clinically homogeneous group of patients. All remained predominantly responsive to levodopa. although with marked disability secondary to clinical fluctuations (short-duration responses) and medication-induced dyskinesias; all were receiving substantial doses of levodopa and 6 of the 8 patients were additionally receiving bromocriptine or pergolide. Binding densities of dopamine D2 receptors. as measured by [3H]spiperone binding. were reduced in this group of patients. compared to caudate specimens from autopsy control subjects. This findings may reflect medication-induced receptor downregulation. Parallel changes occurred with muscarinic cholinergic receptors; [3H]QNB binding was significantly reduced. compared to autopsy control values. This reduction of muscarinic receptors might be due to loss of nigrostriatal terminals that are known to contain muscarinic receptors. Alternatively. muscarinic receptors may have been downregulated by increased corticostriatal glutamatergic input to cholinergic cells. inferred to be present based on the prominent levodopa-induced dyskinesias. Finally. receptor deficits could have been a reflection of more widespread degenerative cerebral disease. although levodopa-refractory symptoms were generally not pronounced in these patients.
Catecholaminergic neurons in the parabrachial nucleus of normal individuals and patients with idiopathic Parkinson's disease, The parabrachial nucleus is believed to play a role in autonomic regulation. We have used the Fontana-Masson ammoniacal silver nitrate method and a tyrosine hydroxylase-immunostaining technique to demonstrate the presence of neuromelanin-containing catecholaminergic neurons in the parabrachial nucleus of normal individuals. In addition. we also show that there is a significant reduction of these catecholaminergic neurons and presence of Lewy bodies in the parabrachial nucleus of patients with idiopathic Parkinson's disease. These findings may be related to the several autonomic disturbances that may occur in idiopathic Parkinson's disease.
Asymmetrical ocular pursuit with posterior fossa tumors, We report two patients with posterior fossa neoplasms who demonstrated asymmetrically impaired horizontal ocular pursuit documented with electrooculography. One patient had impaired pursuit contralateral to a pontomedullary lesion. whereas the second patient had impaired pursuit ipsilateral to a pontocerebellar lesion. These patients demonstrate that posterior fossa lesions may impair ocular pursuit either contralaterally or ipsilaterally unlike cerebral hemispheric lesions. which impair ocular pursuit ipsilaterally or bilaterally.
Paravermal infarct and isolated cerebellar dysarthria, A patient with isolated cerebellar dysarthria is reported. Computed tomography showed a small infarct in the left paravermal zone of the rostal cerebellum (lobulus simplex and semilunaris superior) in the territory of the medial branch of the superior cerebellar artery. This patient demonstrates the important role of this area of cerebellum in the control of voice.
Impaired critical flicker frequency in recovered optic neuritis, Thirteen patients with optic neuritis who recovered normal visual acuity and kinetic perimetry all showed impairment of foveal critical flicker frequency. a psychophysical test of visual temporal resolution. Because the magnocellular visual system demonstrates higher temporal resolution than the parvocellular system. this finding implicates involvement of axonal projections of magnocellular retinal ganglion cells in recovered optic neuritis.
Bilateral sequential lung transplantation: the procedure of choice for double-lung replacement, We recently described a technique for bilateral sequential lung transplantation that replaces the en bloc double-lung operation. a procedure that was accompanied by frequent problems with airway healing. Twenty-seven patients have undergone 28 bilateral sequential lung transplantations over the past 14 months. Eighteen patients had transplantation because of end-stage emphysema; 6. cystic fibrosis; and 1 each. obliterative bronchiolitis. usual interstitial pneumonitis with pulmonary fibrosis. and bronchiectasis. Cardiopulmonary bypass was used electively in the first 5 patients until it was recognized that the procedure could be done safely without it. and in only 3 additional recipients has it been employed. Mean ischemic time for the first lung was 276 +/- 43 minutes and for the second lung. 410 +/- 64 minutes. There have been five deaths. three in the postoperative period (11% operative mortality) and two late. The other patients are alive and well and do not require oxygen 2 to 15 months after transplantation. Mean forced expiratory volume in 1 second rose from 16% +/- 8% of predicted to 84% +/- 17% at 12 weeks. Six-minute walk values increased from a mean of 251 +/- 91 m to 666 +/- 42 m at 24 weeks. The excellent exposure afforded to both hemithoraces by the thoracosternotomy incision and the rare need of cardiopulmonary bypass have allowed us to offer the option of transplantation to patients who formerly would have been turned down because of previous pulmonary resection or pleurectomy. On four occasions. ventilator-dependent patients underwent successful transplantation.
Indications and limitations of aortic valve reconstruction, To elucidate the value of conservative operation for aortic regurgitation. all consecutive patients operated on between July 1988 and July 1990 were reviewed. Of 251 patients with aortic regurgitation. 107 (42.6%) had nonprosthetic operation. The mean age was 23 years. and 90 patients (84.1%) were rheumatic. Two techniques were used: repair (annular and leaflet plasties. 69 cases) and cusp extension with glutaraldehyde-treated pericardium (25 bovine. 13 autologous). There were two hospital deaths (1.8%). both in the repair group. and no late deaths or embolic events. Only 5 patients (4.7%) were anticoagulated. In the repair group there were 12 reoperations. four (5.9%) due to aortic and eight to mitral dysfunction. In the cusp extension group there were two reoperations due to mitral dysfunction. Echocardiographic follow-up showed better results with cusp extension. In conclusion. conservative operation for aortic regurgitation is possible in a high percentage of young rheumatic patients and does not require anticoagulation. Cusp extension is more reliable than repair in terms of early results. although its long-term durability is not yet known.
Warm heart surgery and results of operation for recent myocardial infarction, Revascularization procedures after recent myocardial infarction are associated with higher mortality and morbidity compared with elective coronary artery bypass grafting. Traditional methods of myocardial protection impose a further ischemic insult on already compromised myocardium. Continuous cold blood cardioplegia may eliminate ischemia but may still leave the heart anaerobic. Theoretically. warm aerobic arrest addresses both of these issues and may become an attractive alternative to standard hypothermic ischemic arrest in this setting. In 115 nonrandomized patients undergoing coronary artery bypass grafting within 6 hours to 7 days of an acute myocardial infarction. myocardial protection was provided with continuous cold (4 degrees C) or continuous warm (37 degrees C) blood cardioplegia. Fifty-one patients (after 1988) protected with warm blood cardioplegia were compared with a historical cohort of 64 patients (before 1988) protected with cold blood cardioplegia. Results indicate that the warm cardioplegia group had no mortality versus 10.9% for the cold group (p less than 0.05). a myocardial infarction rate of 2.0% in the warm versus 9.3% in the cold group. and use of intraaortic balloon pump of 0% versus 12.5%. respectively (p less than 0.05). It is concluded that continuous warm aerobic arrest may minimize ischemia and anaerobic metabolism during the operative procedure. and may be of benefit to patients who have a limited tolerance to ischemic insult.
Effect of a cyclic adenosine monophosphate phosphodiesterase inhibitor, DN-9693, on myocardial reperfusion injury, A new cyclic adenosine monophosphate phosphodiesterase inhibitor. DN-9693. was examined to see whether myocardial reperfusion injury could be reduced in a setting of cardioplegic arrest through its antiaggregation effect on leukocytes. Isolated rabbit heart models with whole blood perfusion were used. and 18 hearts were divided into three groups according to the reperfusion method: control (G-1. n = 5). DN-9693 (G-2. n = 7). and leukocyte depletion (G-3. n = 6). The hearts were subjected to 120 minutes of cold global ischemia under crystalloid cardioplegia followed by 30 minutes of reperfusion. A dose of 20 micrograms.kg-1.min-1 of DN-9693 was administered in G-2. and a leukocyte removal filter was used in G-3 during reperfusion. Ultrastructural changes in mitochondrial injuries. intracellular edema. and capillary injuries of the myocardium showed worse changes in G-1 than in G-2 and G-3. Under microscopic study. the intracapillary leukocyte count was significantly higher in G-1 than in G-2 and G-3. Recovery of rate-pressure product. left ventricular developed pressure. and coronary flow were significantly better in G-2 and G-3 than in G-1. There were no significant differences between G-2 and G-3 for all these indices. These results indicate that reperfusion with leukocyte-depleted blood attenuates reperfusion myocardial injury and DN-9693 has a comparable myocardial protective effect with possible inhibition of leukocyte aggregation.
Conventional blood conservation techniques in 500 consecutive coronary artery bypass operations, With use of a nonpharmacological. simple. and inexpensive program for blood conservation. 500 consecutive patients underwent elective coronary artery bypass grafting without need of homologous red cell transfusions in 493 (98.6%). At least one internal mammary artery was grafted in all but 1 patient. with supplemental saphenous vein grafts. Intraoperatively. autologous heparinized blood was removed before bypass and retransfused at the conclusion of extracorporeal circulation. The volume remaining in the oxygenator and tubing set was returned without cell processing or hemofiltration. Using the hard-shell cardiotomy reservoir from the heart-lung machine. autotransfusion of the shed mediastinal blood was continued hourly up to 18 hours after operation. The mean postoperative mediastinal blood loss was 643 +/- 354 mL. whereas 624 +/- 296 mL was autotransfused. Thirteen patients (2.6%) needed reexploration for bleeding. of whom 7 (7/500. 1.4%) received homologous blood. No other patients required red cell transfusions. In addition. 9 patients were given a mean of 2.6 units of fresh frozen plasma because of suspected coagulopathy. No platelets were transfused. and no cryoprecipitate therapy was undertaken. Thus. in total. 484 patients (96.8%) were not exposed to any homologous blood products during the hospital stay. At discharge. the mean hemoglobin concentration was 121 +/- 14 g/L (12.1 +/- 1.4 g/dL) and the hematocrit. 0.36 +/- 0.04. Postoperative complications were few. There was one in-hospital death (0.2%).
Treatment of cardiogenic shock with the Hemopump left ventricular assist device, A multiinstitutional study is in progress to evaluate the Hemopump in the treatment of cardiogenic shock. Fifty-three patients with refractory cardiogenic shock were selected for Hemopump assistance. The hemodynamic definition of cardiogenic shock included (1) a cardiac index of less than 2.0 L.min-1.m-2. (2) pulmonary capillary wedge pressure of greater than 18 mm Hg. and (3) a systolic blood pressure of less than 90 mm Hg or a left ventricular work index of less than 1.500 g-m.m-2.min-1. The Hemopump was successfully inserted in 41 of 53 patients (77.3%). A significant improvement in the hemodynamic status was seen during Hemopump assistance. A minimal level of hemolysis was observed. No leg ischemia was observed. The 30-day overall survival of the Hemopump group was 31.7%. Criteria establishing indications for use and clinical utility are proposed. We conclude that the Hemopump provides significant hemodynamic support of the patient in cardiogenic shock allowing for recovery from ventricular stunning in marginal ventricles. and that in select patients the Hemopump may offer a major improvement in survival over conventional therapy.
Early postoperative sternal approximation after ITA harvesting: computed tomographic evaluation, Between November 1989 and February 1990. 66 randomized sternotomized patients underwent aortocoronary bypass and were subjected to a sternal scanner in the early postoperative period. Each examination included a manubrial and a sternal body print. At each level. we studied the occurrence of spacing or misalignment of the sternal layers. The 66 patients were subdivided into four groups according to the type of conduit harvested (single left internal thoracic artery or saphenous vein) and the type of material used for the sternal closure (steel wires or nylon yarns). In all cases. adequate early sternal approximation. which is represented by a good alignment as well as by an excellent contact of the sternal layers. was infrequently demonstrated. Moreover. the two abnormalities most often observed were manubrial spacing and sternal body misalignment. The sternal closure technique and internal thoracic artery harvesting had no significant effect on the sternal approximation. To minimize manubrial spacing and sternal body misalignment. we propose that the surgeon should apply three threads through the manubrium. withdraw the shoulder roll beforehand. elevate both of the patient's shoulders. and maintain the two xyphoid layers in the same plane and in fairly close contact during the tightening of the wires.
Prophylaxis of atrial fibrillation with magnesium sulfate after coronary artery bypass grafting, Ninety-nine consecutive consenting patients were prospectively entered into a randomized. double-blind. placebo-controlled trial to determine the efficacy of postoperative magnesium therapy on the incidence of cardiac arrhythmias after elective coronary artery bypass grafting. No patient had documented or suspected arrhythmias preoperatively. Forty-nine patients received 178 mEq of magnesium given over the first 4 postoperative days. and 50 patients received only placebo. The clinical characteristics of both groups were similar. The preoperative mean serum magnesium concentration was similar in both study (1.90 mEq/L) and placebo (1.90 mEq/L) groups. The mean postoperative serum magnesium concentration in study patients was significantly elevated over postoperative days 1 through 4 when compared with preoperative levels (p less than 0.001). The postoperative mean serum magnesium concentration in control patients declined and remained significantly depressed through postoperative day 3 (p less than 0.001). but increased to preoperative levels by postoperative day 4. The mean serum magnesium concentration was significantly greater in the study patients as compared with the control patients over postoperative days 1 through 4 (p less than 0.001). Although there was no significant difference between groups with respect to episodes of ventricular arrhythmias. there was a significant decrease in the number of episodes of atrial fibrillation in the group receiving magnesium therapy (p less than 0.02). There were no recognized adverse effects of magnesium therapy. Prophylactic magnesium administration seems to lessen the incidence and severity of atrial fibrillation after coronary artery bypass grafting.
Complement activation during bypass in acquired C1 esterase inhibitor deficiency, Serial complement estimations during cardiopulmonary bypass are reported in a patient with acquired C1 esterase inhibitor deficiency. Although the extent of classic and alternative pathway activation appeared appropriate. exaggerated common pathway activation with massive increase in the C3d:C3 ratio occurred. A fatal hemostatic disorder. pulmonary edema. and circulatory collapse ensued despite prophylaxis and therapy.
Bidirectional cavopulmonary anastomosis using vertical vein for right isomerism, pulmonary atresia, and TAPVR, An 8-year-old girl who was diagnosed as having right atrial isomerism. pulmonary atresia. butterfly-shaped juxtaductal pulmonary arterial stenosis. total anomalous pulmonary venous return of the supracardiac type. regurgitant common atrioventricular valve. and univentricular heart of the right ventricular type underwent bilateral. bidirectional cavopulmonary anastomosis using a vertical vein and anastomosis between the common pulmonary venous trunk and atrium. The surgical procedure in this patient is described.
Large mediastinal mass secondary to an aortocoronary saphenous vein bypass graft aneurysm, A case of a 62-year-old man with a large mediastinal mass who had undergone aortocoronary bypass grafting 17 years earlier is presented. Computed tomography showed a 13-cm extrinsic cystic mass believed to represent a pericardial cyst or teratoma. Intraoperatively. the patient was noted to have an aneurysm of his right coronary artery bypass graft. We were able to find 4 other cases seen in this manner.
Long-term function in University of Cape Town prostheses in the tricuspid position, A 55-year-old woman undergoing triple-valve replacement was found at operation to have a well preserved and functioning University of Cape Town prosthesis that had been inserted 18 years earlier for tricuspid stenosis. Case reporting. valve reappraisal. and factual updating on another case. the world's first documented tricuspid valve replacement for Ebstein's anomaly. are presented. These two remarkable in vivo successes speak well for this historic collar stud valve.
Perfusion without systemic heparinization for rewarming in accidental hypothermia, We report on a patient with accidental deep hypothermia (23.3 degrees C) and cardiorespiratory arrest resulting from severe craniocerebral injury. Systemic anticoagulation was contraindicated. and the decision was reached to rewarm the patient with cardiopulmonary bypass without systemic heparinization using heparin-coated perfusion equipment. The patient was successfully rewarmed. was weaned from cardiopulmonary bypass. and recovered.
Resternotomy in patients with valved conduits adherent to the sternum, Twenty-two patients with valved conduits adherent to the sternum underwent resternotomy. Mean age was 10 +/- 6 years. and mean conduit age was 4 +/- 4 years. Diagnoses were D-transposition (7). truncus arteriosus (7). univentricular heart (6). Taussig-Bing anomaly (1). and corrected transposition (1). The majority of patients (68%) had reoperation for outgrown or degenerated conduits. In 17 patients. the sternum was opened with a chisel. Two of these patients sustained conduit neointimal collapse from manipulation. and 3 had conduit tear requiring immediate cardiopulmonary bypass through the femoral vessels. In the last 5 patients. the sternum was opened above and below the conduit. and the inner table was chiseled and left attached to the conduit avoiding injury and undue conduit manipulation. Cardiopulmonary bypass and operation were carried out uneventfully. We believe that the recent technique described provides a safe alternative approach to valved conduits adherent to the sternum.
Cystic and bullous lung disease, One of the most difficult problems facing clinicians is the evaluation and management of patients with dyspnea whose chest roentgenogram shows single or multiple large cystic spaces. This is made more difficult when underlying lung disease is present. The dilemma focuses on whether the obliteration or removal of the cystic areas will benefit or cause further deterioration of the patient's condition. The pathophysiology of the problem is not completely understood. but accumulated clinical experience has shown that surgical therapy can be beneficial but requires proper patient selection.
The myth of the aortic annulus: the anatomy of the subaortic outflow tract, Surgical repair of the small aortic root is limited in part by the very structure of the outflow tract from the left ventricle. The root is not constructed on the basis of a ringlike annulus supporting the leaflets of the aortic valve. The only truly circular structure within the outflow tract is the junction of the aortic wall with the underlying ventricular structures. themselves partly muscular and partly fibrous. This circular ventriculoarterial junction is crossed by the semilunar attachments of the leaflets of the aortic valve. producing an interlinking arrangement between the expanded aortic sinuses and three triangles of fibrous tissue placed beneath the apexes of the commissures between the valve leaflets. The triangles form extensions of the left ventricle that are related. in part. to the pericardial cavity surrounding the heart. The arrangements of the attachment of the leaflets in malformed valves with two (or only one) effective leaflets are highly abnormal. although these valves are usually produced on the template of three aortic sinuses. The valve with two leaflets rarely gives problems during childhood. In valves producing "critical stenosis". there is usually only one effective leaflet. a condition due to incomplete liberation of two of the anticipated three commissures. Detailed study shows that. in these malformed hearts. the attachment of the leaflets is much more annular than in normal valves. with inadequate formation of the fibrous triangles.
Extended aortic valvuloplasty: a new approach for the management of congenital valvar aortic stenosis, A new technique for the treatment of congenital valvar aortic stenosis is described. It consists of augmenting the aortic cusp by extending the commissurotomy incision into the aortic wall around the leaflet insertion. mobilizing the valve cusp attachment at the commissures. and freeing the aortic insertion of the rudimentary commissure. The results of standard valvotomy performed on 48 patients (group 1) were compared with those of the new extended valvuloplasty carried out on 16 patients (group 2). The two groups were comparable in age at operation (2.7 +/- 2.1 years for group 1 versus 2.1 +/- 1.7 years for group 2; p = not significant) and in preoperative pressure gradient (58 +/- 25 mm Hg for group 1 versus 61 +/- 36 mm Hg for group 2; p = not significant). There was no operative mortality in either group. Follow-up is available on all patients. with a mean of 4.3 +/- 2.6 years for group 1 versus 1.7 +/- 0.5 years for group 2 (p = 0.05). There was one late death in group 1. Postoperative gradient was 47 +/- 13 mm Hg in group 1 versus 19 +/- 13 mm Hg in group 2 (p = 0.05). Moderate or severe regurgitation was present in 18 patients (38%) in group 1 and 2 patients (13%) in group 2 (p = not significant). Reoperation was needed in 8 patients (17%) in group 1 versus 2 patients (13%) in group 2 (p = not significant). The described valvuloplasty procedure addresses the unique pathological features of valvar aortic stenosis and provides better relief of the obstruction than the presently available techniques. Longer follow-up is needed to determine the late results of this approach.
Pediatric cardiac transplantation despite atrial and venous return anomalies, Congenital anomalies of the atrium. pulmonary venous return. and systemic venous return are often regarded as anatomical contraindications to orthotopic cardiac transplantation. Among our pediatric transplant patients. 10 children aged 3 to 15 years. weighing 9 to 45 kg. and all previously operated on for a total of 18 interventions had 32 anomalies needing correction at the time of transplantation. Besides the 18 instances of great vessel abnormalities. 14 anomalies of the atrium and of the venous return were encountered either alone or in combination: single atrium or previous septectomy (4). hypoplastic left atrium (2). previous Mustard procedure (1). cor triatriatum (1). anomalous pulmonary venous return (3). and anomalous systemic venous return (3). The preparation of the donor heart was modified in four ways: right atrial paraseptal incision. left atrial flap technique. full-length mobilization of the pulmonary arteries. and aortic arch incision. Correction of the atrial and venous return anomalies was carried out at the time of orthotopic transplantation with the following techniques: atrial septation. atrial enlargement. superior systemic venous return reroofing. inferior systemic venous return reroofing. double venous rerouting (pulmonary and systemic). and septal realignment. One child died of pulmonary hypertension in the early postoperative period. After a follow-up ranging from 1 month to 52 months. all survivors are asymptomatic. Based on echocardiography. heart catheterization. and angiography. there are no stenoses and no shunts. and the atrial dimensions are good. Based on the results achieved with these surgical techniques. we conclude that most atrial lesions. anomalous pulmonary venous returns. and anomalous systemic venous returns are correctable at the time of orthotopic transplantation and do not preclude a successful outcome in children.
Expanding applicability of transplantation after multiple prior palliative procedures. The Paediatric Heart Transplant Group, The number of heart transplantations performed over the past 3 years has plateaued. However. the number of pediatric transplantations continues to slowly increase. Unlike adult heart transplantation. for which cardiomyopathy remains the most frequent indication. structural congenital heart disease is the primary indication in children. This report reviews our experience with orthotopic heart transplantation in the presence of structural congenital heart disease with and without prior palliative repair. The diagnoses included transposition of the great arteries. common atrium. left superior vena cava with and without a bridging innominate vein. dextrocardia. and univentricular configurations. The palliative repairs included Blalock-Taussig shunt. bilateral Glenn shunt. Fontan repair. and Mustard and Rastelli procedure. There were no early deaths. Two rejection-related late deaths have occurred at 8 months and at 3 years postoperatively. Extended use of donor tissue and modifications to surgical technique allowed for successful orthotopic heart transplantation in these patients who had structural congenital heart disease with and without prior surgical palliation.
How to build a computer-assisted, diagnosis-finding system. An example in dermatopathology, We present a computer-assisted. diagnosis-finding system based on the simple stochastic approach of Bayes; this system was realized in a standard database architecture and run on DOS personal computers. The expert knowledge in the form of specified morphologic criteria was keyed in by means of pull-down menus or downloaded if the system was linked with a reporting system according to the dBASE (Ashton-Tate. Inc. Torrance. Calif) database standard. We present a simple example in dermatopathology but the system shell can also be used for applications in other fields of pathology. This article is not restricted to general remarks about computer-assisted diagnosis finding. The compiled program and the easily comprehensible and well-documented program listings in the CLIPPER (Nantucket Corp. Los Angeles. Calif) or DOS language is available on request.
Colorectal smooth-muscle tumors. A pathobiologic study with immunohistochemistry and histomorphometry, Smooth-muscle tumors are an interesting group of tumors that show considerable site specificity in their pathobiology. Recent work has also shown that some previously so-called smooth-muscle tumors were not. in fact. truly leiomyogenic. hence the origin of the more embracing term stromal tumors. The purpose of this retrospective study was to delineate the tumor subsets constituting colorectal stromal tumors. and to determine the histopathologic correlates for biologic aggressiveness for these tumors. The cohort was constituted of 12 patients; the mean follow-up was 6.6 years with a median of 5.0 years. Immunohistochemical evaluations showed tumoral positivity for muscle-specific actin (12 of 12). vimentin (11 of 12). desmin (two of 12). and S100 protein (zero of 12). Electron microscopic examinations corroborated this leiomyogenicity profile (five of five). Semiquantitative histomorphometric analysis showed that tumor size. cellularity. mitoses. and necrosis. in that order. correlated with biologic aggressiveness. The immunohistochemistry results for this cohort of colorectal stromal tumors vindicated the traditional histochemical evaluations in that all tumors showed features of leiomyogenicity. For colorectal smooth-muscle tumors. tumor size appears to be the best predictor for biologic aggressiveness. This study reinforces the concept of site-specificity for smooth-muscle tumors.
Mucinous carcinomas of the colon and rectum. An analysis of 62 stage B and C lesions, The significance of a large extracellular mucinous component in colorectal adenocarcinomas continues to be controversial. We studied 62 stage B and C mucinous carcinomas defined by 60% or greater mucinous component. Sixty of these patients had matched nonmucinous adenocarcinoma controls. Patients with mucinous carcinomas with a residual adenoma had a significantly greater survival than those who did not. Overall. no difference was noted in 5-year survival between patients with mucinous carcinoma and nonmucinous adenocarcinoma (64% each). However. when the stages were considered separately. patients with stage B mucinous carcinoma fared significantly worse and had more local sites of treatment failure. We speculate that patients with stage B mucinous carcinoma may have a worse prognosis owing to the extra-cellular mucin. which may make a complete surgical extirpation more difficult.
Origin of so-called mesothelioma of the atrioventricular node. An immunohistochemical study, To determine the origin of a mesothelioma of the atrioventricular node. immunohistochemical studies that used various antibodies. including the antibody against mesothelial cells. were performed on a mesothelioma of the atrioventricular node in a case. The lining cells of the tubules that composed the tumor were negative when tested with anti-mesothelial cell antibodies. Carcinoembryonic antigen was negative. but the secretory component was positive. Serotonin and calcitonin were positive in a few cells. We concluded that a mesothelial origin was unlikely. and it was suggested that the tumor was of an entodermal origin.
Glial fibrillary acidic protein expression in pleomorphic adenoma, chordoma, and astrocytoma. A comparison of three antibodies, Glial fibrillary acidic protein (GFAP) is a major constituent of glial cytoplasmic intermediate filaments. Glial fibrillary acidic protein expression has been accepted as a marker of astroglial differentiation or origin. However. GFAP expression has been demonstrated in a variety of normal and neoplastic tissues outside the central nervous system. including pleomorphic adenomas. chordomas. bone. and cartilage. It has been postulated that coexpression of GFAP and vimentin in neoplastic myoepithelial cells in pleomorphic adenomas reflects early chondroid differentiation. Glial fibrillary acidic protein expression in chondromyxoid and chordoid tumors was studied in formaldehyde solution-fixed. paraffin-embedded sections of 20 pleomorphic adenomas and 10 chordomas by the immunoperoxidase method with the use of commercially available monoclonal (n = 2) and polyclonal (n = 1) antibodies. All pleomorphic adenomas and chordomas demonstrated expression of GFAP with the use of the polyclonal antibody (Biomeda Corp [Foster City. Calif]). Variable expression of GFAP was present in 90% (18/20) and 70% (14/20) of pleomorphic adenomas. and in 20% (2/10) and 0% of chordomas. with the use of the two monoclonal preparations (Dakopatts [Glostrup. Denmark] and BioGenex Laboratories [San Ramon. Calif]). respectively. Normal brain tissue and eight astrocytomas were used as "controls" to compare staining intensity and quality between the polyclonal and monoclonal anti-GFAP antibodies. Glial fibrillary acidic protein positivity with the polyclonal antibody was more intense than that with either monoclonal antibody despite similar (congruent) distributions of tumor cell types that were stained in control brain and astrocytoma tissues. The GFAP polyclonal antibody was more frequently immunoreactive than the monoclonal antibodies. particularly in cells that exhibited chondroid differentiation. These findings may have practical application in surgical pathology.
An immunohistochemical study of benign clear cell ('sugar') tumor of the lung, Benign clear cell ("sugar") tumor is a rare and most unusual pulmonary neoplasm. Although several reports in the literature have focused on the ultrastructural features of benign clear cell tumor. only a few cases have been formally studied by immunochemistry. Using a broad panel of polyclonal and monoclonal antibodies. five cases were evaluated. In all five cases. there was diffuse immunoreactivity for cathepsin B. Four cases showed immunoreactivity for HMB-45 and for alpha 1-antitrypsin. By two different sources for antivimentin. there was immunoreactivity in four cases (Biogenex. Dublin. Calif) and in two cases (DAKO. Santa Barbara. Calif). respectively. Additional immunoreactivity was present for S100 protein (three cases). HAM-56 (two cases). factor XIIIA (two cases). and neuron-specific enolase (one case). No case expressed immunoreactivity for keratin (AE 1. AE 3. or CAM 5.2). carcinoembryonic antigen. chromogranin. synaptophysin. glial fibrillary acidic protein. or alpha 1-antichymotrypsin. This immunochemical profile suggests that HMB-45. in combination with a variety of immunostains. may serve to distinguish benign clear cell tumor from other clear cell neoplasms.
Kaposi's sarcoma of spleen with unusual clinical and histologic features, We report a case of Kaposi's sarcoma in a young woman who presented with unusual clinical and histologic features. The unusual clinical features were the absence of cutaneous lesions; the presence of a splenic mass; and extensive involvement of the peritoneum. resulting in massive ascites and intestinal and ureteral obstruction. We postulate that the spleen was the primary site of the tumor. The unusual histologic features were the presence of both sclerotic and cavernous hemangioma variants in the same tumor and extensive areas of calcium deposits in the tumor. Such atypical clinical and histologic features can pose diagnostic difficulties for both clinicians and pathologists.
Pleomorphic fibroma of skin. A case report and immunohistochemical study, An immunohistochemical study of a clinically benin but cytologically atypical mesenchymal lesion of the skin is presented. This lesion has been previously reported as pleomorphic fibroma and was shown to follow a benign course with a potential for local recurrence. These lesions contain occasional markedly atypical enlarged spindle cells with anaplastic-appearing nuclei. Nonmirror image mitotic figures may be present. Histogenesis of this neoplasm remains controversial with a fibroblastic origin being favored by previous authors. Our immunohistochemical findings would support this conclusion.
Massive cardiac involvement of adult T-cell leukemia/lymphoma. An autopsy case, We describe an unusual autopsy case of adult T-cell leukemia/lymphoma with massive cardiac involvement. The patient was admitted to the hospital with symptoms of fever and cervical lymph node enlargement. which improved following treatment with vincristine sulfate. cyclophosphamide (Endoxan). prednisolone sodium succinate. and doxorubicin hydrochloride (Adriamycin). He was then followed up in the outpatient clinic. but was readmitted to the hospital with palpitations and dyspnea. Cardiomegaly developed rapidly. and the patient died of congestive heart failure 3 months after readmission. The heart was massively enlarged at autopsy. The heart. including adhered surrounding tissue. weighed 1600 g. The myocardium was found to be replaced by massive infiltration of atypical lymphoid cells. Cardiac involvement by adult T-cell leukemia/lymphoma may result from extension or retrograde flow through cardiac lymphatics from the destroyed mediastinal lymphatic system.
Danazol-induced hepatocellular adenomas. A case report and review of the literature, We report a case of hepatocellular adenomas in a 39-year-old woman who had been taking danazol for uterine fibroids. To our knowledge. this is the first case in which multiple hepatocellular adenomas were discovered after only 6 months of danazol intake.
HLA-DR expression on the microvasculature of portal tracts in idiopathic portal hypertension. Immunohistochemical characteristics and relation to portal phlebosclerosis, We recently reported that HLA-DR antigen was expressed on the microvasculature of portal tracts more frequently in idiopathic portal hypertension (IPH) than in normal livers or in other hepatic diseases. and that this HLA-DR expression may be involved in the development of the portal venopathy characteristic of IPH. The present study was performed to evaluate the relationship between the HLA-DR expression and portal tract lesions. as well as to investigate the immunohistochemical characteristics of the HLA-DR-positive microvasculature using liver wedge biopsy specimens obtained from 32 patients with IPH. According to the degree of phlebosclerosis of the portal veins. the portal tracts were divided into three groups: mild. moderate. and severe. The microvasculature in portal tracts was positive for HLA-DR in 21 (66%) of the 32 specimens and in 133 (44%) of 302 portal tracts. In the 21 specimens. there was no significant difference in the prevalence of HLA-DR-positive microvasculature among the three groups: it occurred in 57 (66%) of 86 portal tracts in the mild group. 53 (61%) of 87 portal tracts in the moderate group. and 23 (49%) of 47 portal tracts in the severe group. The HLA-DR-positive microvasculature was positive for type IV collagen and receptors of Ulex europaeus lectin I. suggesting that HLA-DR-positive microvessels are blood vessels. These findings suggest that HLA-DR antigen is already expressed on portal microvessels in the incipient stage of IPH. and that HLA-DR expression persists during the progression of portal phlebosclerosis. The HLA-DR expression may be an initiating factor leading to immunologic assault on portal microvessels in IPH.
Diagnostic criteria for multiple sclerosis research involving multiply affected families, Existing diagnostic criteria for multiple sclerosis present significant limitations when assessing multiplex families for three reasons: (1) restricting age of onset to 10 to 50 years is likely to exclude 10% of patients known to have a later onset. (2) diagnoses based on subjective information can potentially result in a false-positive diagnosis. and (3) including progressive myelopathies occurring within families. particularly when highly symmetrical. may result in the improper inclusion of genetically determined neurological diseases such as familial spastic paraparesis. The validity of any molecular genetic approach for determining disease susceptibility critically depends on diagnostic accuracy. We present adapted diagnostic criteria that address each of these diagnostic pitfalls unique to multiplex multiple sclerosis family research.
Stereotaxic implantation of autologous adrenal medulla into caudate nucleus in four patients with parkinsonism. One-year follow-up, Four patients with levodopa-responsive parkinsonism (aged 26. 35. 45. and 49 years) received autologous adrenal medullary implants into or near the left caudate nucleus by stereotaxic implantation after flank adrenalectomy. All patients had an immediate response to implantation lasting several days. during which parkinsonian signs and symptoms decreased. This period was followed by a gradual reappearance of symptoms in all but one patient. This patient had had a dramatic increase in "on" time without dyskinesias and a decrease in the severity and duration of "off" time. He died of multifocal glioblastoma 1 year after transplantation. Autopsy revealed no surviving adrenal cells. In one case. the stereotaxic implantation missed the basal ganglia. resulting in the placement of the adrenal medullary tissue into the medial thalamus and near the third ventricle; the patient did not improve. In the other two cases. a modest but definite increase in "on" time without dyskinesia and a reduction in the severity and duration of "off" time has been observed. The role of autologous adrenal medullary transplantation in patients with parkinsonism remains to be determined. Patients with a family history of cerebral malignancy may be at increased risk for the development of transplant-induced malignancy.
Implantation of human fetal ventral mesencephalon to the right caudate nucleus in advanced Parkinson's disease, Disaggregated ventral mesencephalic tissue from single aborted human fetuses of 11 to 18 weeks' gestation was implanted stereotaxically into a consistent striatal site in 12 patients with advanced Parkinson's disease. All were receiving optimum levodopa therapy and were examined preoperatively and at 3.6.9. and 12 months postoperatively. Immunosuppression was not used. There were significant sustained improvements at 12 months in three patients; motor fluctuations were absent in two. There were modest group improvements up to 6 months. with increased quality of "on" and "off" phases. quantity of on times. and specific improvements in contralateral upper limb bradykinesia. Preoperative levodopa requirements were reduced to a mean of 64% at 6 months and 61% at 12 months. Deterioration below baseline ratings occurred in three of nine patients who had consistent follow-up to 12 months. Grafting of midgestational human fetal tissue can lead to improvement in Parkinson's disease. Individual disease severity may be critical. and further trials are needed to identify host factors influencing outcome.
Myasthenia gravis in childhood and infancy. Usefulness of electrophysiologic studies, The diagnostic yield of electrodiagnostic tests was evaluated in 21 children with myasthenia gravis (MG). Twelve children had juvenile autoimmune MG. four had neonatal MG. four had congenital MG. and one had MG with arthrogryposis. Repetitive stimulation (RS) of the ulnar nerve was performed in every patient. sometimes with sensitization by ischemia. When the RS test was negative. the spinal or facial nerve was tested. In the group with neonatal MG. the RS test disclosed a significant decrement in 75% of the patients. Among the 17 other children. the overall percentage of positive RS tests was 88%. An ulnar nerve RS test was positive in 41% of them. Sensitization of ulnar nerve RS by ischemia improved the diagnostic yield to 66%. A spinal or facial nerve RS test was positive in seven of 10 patients. These results confirmed the diagnostic value of RS. with sensitization by ischemia. when necessary. in childhood MG whenever a careful technique is provided.
Generalized cortical dysplasia. Clinical and pathologic aspects, Three children with profound mental retardation and intractable seizures died at ages 10 months. 3 years. and 7 years. respectively. Complete examination of their brains showed generalized cortical dysplasia. without any major malformation of the external gyral pattern. The neuropathologic features of cortical dysplasia include abnormally thickened cortex with indistinct demarcation of the gray-white matter junction. In many areas. the cortex contained increased numbers of large neurons with disordered cortical lamination. Heterotopic neurons were scattered throughout the white matter with decreased myelination of the underlying white matter. To our knowledge. these cases represent the first fully detailed neuropathologic study of diffuse cortical dysplasia--a newly recognized entity of abnormal neuronal migration.
Parkinson's disease in Ferrara, Italy, 1967 through 1987, Epidemiological surveys on Parkinson's disease that have been carried out in different parts of the world have suggested that the disease is uniformly distributed in white populations. The position with regard to the Mediterranean peoples is still controversial. because of the large variation of the frequencies observed in the different areas that have been investigated. We therefore studied the frequency of Parkinson's disease in the Local Health Service of Ferrara. northeastern Italy (mean population. 187.000). Based on 394 patients. the mean incidence per year for the period from 1967 through 1987 was 10.01/100.000. The incidence rate of Parkinson's disease among cases with early onset was found to be statistically higher in rural areas as compared with urban ones (6.32/100.000 vs 3.11/100.000). Moreover. the study revealed a significantly higher incidence rate among agricultural workers (20.6/100.000). These results would seem to give further support to the hypothesis of a possible causal role of environmental factors that are mainly linked to agriculture. most likely due to the continual exposure to toxic agents in this area. However. further studies. which are not exclusively epidemiological. are necessary before any conclusions may be drawn. because many confounding variables may account for the results from surveys of this type.
Local thrombin synthesis and fibrin formation in an in vitro thrombosis model result in platelet recruitment and thrombus stabilization on collagen in heparinized blood, The role of the local synthesis of thrombin in platelet recruitment and thrombus stabilization in heparinized blood was examined in vitro. Mural thrombosis was visualized and measured in a thin. rectangular. collagen-coated capillary under controlled rheological conditions by using fluorescence digital videomicroscopy and fluorescence microphotometry. Thrombin activity was inhibited in heparinized blood by the synthetic competitive inhibitor. D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone (FPRCH2Cl). resulting in a marked reduction in the rate of platelet accumulation on collagen surfaces. indicating a role for thrombin in platelet recruitment. Similar although lesser effects were observed by reducing thrombin synthesis with antibodies to factors II and X. To decouple the role of thrombin in platelet recruitment by direct stimulation of platelet activity from its role in thrombus stabilization via fibrin formation. thrombosis was measured in heparinized blood treated with the tetrapeptide glycyl-prolyl-arginyl-proline. which inhibits fibrin monomer assembly into fibrin. The ultimate level but not the initial rate of platelet accumulation was reduced markedly. indicating a role for fibrin in thrombus stabilization against hemodynamic forces. Scanning electron micrographs demonstrated fibrin stands in the heparinized control samples but not in the heparinized samples with glycyl-prolyl-arginyl-proline. These results demonstrate a role for the local action of thrombin synthesized on the surfaces of thrombi even under conditions when the thrombin exerts no bulk effect. such as under heparin anticoagulation. Furthermore. this role appears to be a result of both platelet recruitment and thrombus stabilization.
The effect of caffeine on postprandial hypotension in the elderly, In a double-blind. randomized trial the effects of caffeinated and decaffeinated drinks on postprandial hemodynamic and neurohumoral changes were studied in seven fit. elderly subjects after a standard 2.4MJ meal. There was a significant difference in supine postprandial systolic blood pressure between the placebo and caffeine phases (P less than 0.01); at 60 minutes. supine systolic blood pressure had fallen 14 mmHg [95% confidence interval (CI)-7 to-21 mmHg. p less than 0.01) after placebo. but was unchanged after caffeine (+9 mmHg. CI 0 to 18 mmHg. NS]. Similar differences between placebo and caffeine were seen in erect systolic and diastolic blood pressure (P less than 0.01). although orthostatic tolerance was maintained throughout each study period. Postprandial plasma noradrenaline levels were higher (P less than 0.02) and the increase greater (P less than 0.02) after caffeine than after placebo. Caffeine administered at the end of a standard test meal prevents the postprandial fall in blood pressure in fit. elderly subjects. The clinical relevance of this finding has yet to be determined. but it may offer a simple remedy for patients with symptomatic postprandial hypotension.
Differential enhancement of interferon-gamma-induced MHC class II expression of HEp-2 cells by 1,25-dihydroxyvitamin D3, Interferon-gamma (IFN-gamma) induces the expression of MHC class II antigens on non-lymphoid cells. In this study we investigated the effect of 1.25-dihydroxyvitamin D3 (1.25(OH)2D3). the most active metabolite of vitamin D3. on the IFN-gamma-induced expression of MHC class II antigens on HEp-2 cells. We found that 1.25(OH)2D3 enhanced the IFN-gamma-induced expression of HLA-DR on these cells. Differential effects on the MHC class II antigens HLA-DR. -DQ and -DP were also observed.
Fibrin fragment D-dimer and fibrinogen B beta peptides in plasma as markers of clot lysis during thrombolytic therapy in acute myocardial infarction, The validity of markers in plasma of in vitro thrombolysis was investigated in 12 patients with extensive fibrinogen breakdown (greater than 80%. group 1) and in 12 patients with minimal breakdown (less than 20%. group 2). The patients were treated with 100 mg of recombinant tissue-type plasminogen activator (rt-PA) in the "Thrombolysis in Myocardial Infarction II" (TIMI II) trial. Cross-linked fibrin degradation product levels were measured with two variant enzyme-linked immunosorbent assays (ELISAs). both using a fibrin fragment D-dimer specific capture antibody. In one instance. a tag antibody was used that cross-reacts with fibrinogen (pan-specific tag ELISA); in the other. the tag antibody was specific for fibrin fragment D (fibrin-specific tag ELISA). Apparent concentrations of cross-linked fibrin degradation products at baseline were within normal limits with both assays in most patients. At 8 hours after rt-PA infusion. the measured cross-linked fibrin degradation products were increased about twofold to fourfold in group 2 with both assays. However. in group 1. levels were significantly higher with the pan-specific tag ELISA (5.8 +/- 4.2 micrograms/mL) compared with the fibrin-specific tag ELISA (1.5 +/- 1.3 micrograms/mL). This observation was most likely a result of detection of fibrinogen degradation products in the pan-specific ELISA. Apparent levels of fibrinopeptide B beta 1-42. a marker of fragment X formation. increased during thrombolysis from 4.2 +/- 2.8 pmol/mL to 2.000 +/- 230 pmol/mL in group 1 and from 4.1 +/- 2.1 pmol/mL to 300 +/- 43 pmol/mL in group 2. and were correlated significantly with the extent of fibrinogen breakdown (r = -0.8). Fibrinopeptide beta 15-42 levels increased from 4.3 +/- 3 pmol/mL to 70 +/- 19 pmol/mL in group 1. but did not increase in group 2. The apparent increase in group 1 could be explained by cross-reactivity of fibrinopeptide B beta 1-42 in the fibrinopeptide beta 15-42 assay. We conclude that cross-linked fibrin degradation product levels as measured with a pan-specific tag ELISA and fibrinopeptide beta 15-42 levels as measured with certain monoclonal antibody-based ELISA are influenced by the extent of fibrinogen degradation. Fibrinopeptide B beta 1-42 is a marker specific for fibrinogen breakdown. Cross-linked fibrin degradation product levels. measured with a fibrin-specific tag ELISA. appear to be markers specific for thrombolysis. Consequently. assays similar to the fibrin-specific tag ELISA may provide more accurate information when correlated with clinical endpoints.
Multiple myeloma: increased circulating lymphocytes carrying plasma cell-associated antigens as an indicator of poor survival, In multiple myeloma (MM) an increase in circulating lymphocytes expressing plasma cell-associated antigens (PCAA) has been described. Its prognostic significance was evaluated in this study. The immunologic phenotype of peripheral blood lymphocytes was analyzed with a panel of monoclonal antibodies specific for B. T. natural killer lymphocytes. and PCAA (CD38. PCA1) in 52 MM patients at diagnosis. remission. and during relapse. 18 monoclonal gammopathy of undetermined significance (MGUS). and 25 normal controls. No significant phenotypic alteration was observed in MGUS. In MM. the number of B lymphocytes was in the normal range at diagnosis and during the subsequent phases. A CD4/CD8 ratio decrease. during relapse. was due to both a CD4+ reduction and to an expansion of a subset of CD8+ activated suppressor lymphocytes. CD38+ and PCA1+ lymphocytes at diagnosis were significantly higher than in MGUS. and a further increase was observed during relapse. suggesting a correlation between PCAA expression and disease activity. The prognostic significance of increased PCAA was confirmed by a survival analysis of 32 patients evaluated at diagnosis using a CD38 cutoff of 0.45 x 10(9)/L positive lymphocytes. Median survival for patients with high values was only 14 months. whereas it was not reached at 32 months by those with low values (P less than .0007).
Characterization of recombinant factor VIII and a recombinant factor VIII deletion mutant using a rabbit immunogenicity model system, The use of factor VIII prepared genetically engineered cell lines (rFVIII) may avoid some of the problems inherently associated with administering plasma-derived factor VIII (pdFVIII) concentrates to hemophilia A patients. Although rFVIII may represent an improvement over traditional therapeutics. the chance exists that protein production in cell culture may result in the presence of novel epitopes that may enhance the formation of inhibitor antibodies capable of neutralizing either rFVIII or pdFVIII. To assess the differences between rFVIII and its plasma-derived homologue. a rabbit immunogenicity model system was developed. Antibodies raised to rFVIII in rabbits were tested for the presence of antibodies capable of binding rFVIII but not pdFVIII. the presence of which would suggest that novel epitope(s) were present. This analysis was performed using a competitive enzyme-linked immunosorbent assay. as well as immunoadsorption. For either technique. rFVIII-specific antibodies were not detected. indicating that differences between rFVIII and pdFVIII were not found. When a rFVIII B-region deletion mutant was similarly tested. antibodies specific for this protein were found. These specific antibodies appeared to bind in the vicinity of the deletion site and their binding was not affected by carbohydrate removal. These results indicate that the rabbit immunogenicity model system is sensitive to alterations in the factor VIII molecule and suggest that full-length rFVIII will not be any more immunogenic in human patients than pdFVIII.
Differential response of malignant human B-cells to anti-IgM immunoglobulin (anti-mu) and B-cell growth factor: unique direct cytotoxicity of anti-mu on prolymphocytic leukemia cells, We examined in vitro tritiated thymidine uptake by B cells from seven prolymphocytic leukemia (PLL). seven chronic lymphocytic leukemia (CLL). and four plasma cell leukemia (PCL) patients in response to culture with anti-human IgM antibody (anti-mu) and B-cell growth factor (BCGF). In contrast to the stimulatory effect observed in normal B-cell cultures. the divalent F(ab')2 anti-mu antibody uniquely inhibited the autonomous proliferation and induced marked cytotoxicity in six of seven PLL cell cultures independent of complement or Fc-receptor-mediated mechanisms. There was neither stimulation or inhibition of the slgM+ CLL or the slgM- PCL cells. The inhibitory effect on the PLL cells was observed at an anti-mu concentration below the stimulatory threshold for normal B cells. Significant impairment of trypan blue exclusion was delayed until 48 hours. with morphological cellular changes suggestive of a programmed cell death mechanism or apoptosis. The cytotoxicity was independent of the slgM-staining intensity or the autonomous and BCGF-augmented DNA synthetic activity of the PLL cells and was similar in patients with de novo PLL or with prolymphocytic transformation of CLL. Cells from a PLL patient were separated by elutriation into two fractions. a BCGF-unresponsive large "transformed" cell fraction with marked autonomous DNA synthesis and a smaller lymphoid cell subset with low 3H-thymidine uptake that could be augmented by BCGF. Both fractions were equally susceptible to the cytotoxic effect of anti-mu. These data suggest that certain slgM-bearing malignant B cells are susceptible to anti-mu-triggered cytotoxicity. They may represent the malignant counterpart of a "tolerogenic" normal B-cell subset. and the unique direct cytotoxicity of anti-mu may provide a therapeutic strategy specifically for PLL.
Receptors for tumor necrosis factor on neoplastic B cells from chronic lymphocytic leukemia are expressed in vitro but not in vivo, Recombinant tumor necrosis factor-alpha (TNF-alpha) is a cytokine that induces proliferation of neoplastic B cells from patients with chronic lymphocytic leukemia (CLL). To gain insight into the mechanisms involved in regulating TNF responsiveness. we have examined TNF receptor expression on neoplastic B-CLL cells. We have demonstrated that freshly isolated neoplastic B cells from patients with CLL did not express TNF receptors. After 1 day of incubation in culture medium. TNF receptors were detectable in the range of 540 to 1.500/cell. Kinetic experiments revealed that receptor expression was half-maximal after 3 hours of culturing and required de novo protein synthesis. The Scatchard plots of TNF-alpha binding indicated a single set of high-affinity TNF receptors with a dissociation constant of 70 pmol/L. TNF receptor expression in vitro was found in all examined cases. All cytokines tested. with the exception of IL-2. did not influence the expression of TNF receptors. The TNF receptor expression is enhanced in B-CLL cells cultured in the presence of interleukin-2 when compared with the receptor expression of cells cultured in medium alone. Our data suggest that neoplastic B-CLL cells in patients with stable disease do not express TNF receptors in vivo and that an unknown mechanism suppressing TNF receptor expression in vivo may play a role in growth regulation of neoplastic B cells.
Serum follicle stimulating hormone--predictor of cancer in the remaining testis in patients with unilateral testicular cancer, In 10 of 13 patients with unilateral testicular cancer and subsequent invasive cancer or carcinoma in situ in the remaining testis. the follicle stimulating hormone (FSH) level was elevated after the first orchiectomy and before further treatment. In only 4 of 26 comparable control patients was the FSH level raised. This may be because elevated serum FSH often reflects disturbances in spermatogenesis and fertility. the latter being a known risk factor for testicular cancer. An elevated FSH level that occurs after orchiectomy for unilateral testicular cancer and before further treatment identifies patients at high risk of developing a tumour in the remaining testis.
A model for breast cancer screening, A model for breast cancer screening has been developed. When the appropriate screening policy is specified. the model reproduces the detection rates and the incidence of interval cancers as observed in the recent screening projects in Utrecht and Nijmegen. the Netherlands. The model-predicted mortality rate reduction is in accordance with the results of the Kopparberg/Ostergotland randomized trial in Sweden. Key parameters of the model are the duration of the preclinical stages and the sensitivity of mammography. The average duration is approximately 2 years at age 40 and increases to approximately 5 years at age 70. The sensitivity is high (approximately 95%) for tumors larger than 1 cm. The model is used in the prospective evaluation of effects and costs of various screening policies.
The benefit of the Hemonetics cell saver apparatus during cardiac surgery, This retrospective chart review of 155 patients having coronary artery bypass graft surgery (CABG) over a two-month period determined whether the use of a cell saver apparatus (CSA) (1) reduced or increased the requirements for homologous blood; (2) increased the incidence of post-surgical bleeding; (3) was cost-effective. Two groups of patients were identified. Group 1 (n = 99) received both CSA processed red blood cells and homologous blood components. Requirement for homologous blood products was reduced in the first 24 hr after surgery (0.5 +/- 1.0 vs 1.3 +/- 1.8 units; P less than 0.05) when compared with Group 2 (n = 56) in whom only homologous blood products were utilized. More patients in Group 1 had no transfusion requirements (45 vs 8; P less than 0.05) and there was no increased risk of major haemorrhage. When the capital costs are included. utilization of the CSA was not cost-effective. We conclude that utilisation of a CSA was safe. with no increased risk of bleeding. reduced requirements for homologous blood transfusions. but added to the cost of the procedure.
Impaired potassium-induced dilation in hypertensive rat cerebral arteries does not reflect altered Na+,K(+)-ATPase dilation, We have recently demonstrated that K(+)-induced dilation of cerebral resistance-sized vessels has two independent components. only one of which seemed sodium pump dependent. In our current investigation. potassium-induced dilation of spontaneous tone was compared in cerebral arteries from normotensive Wistar-Kyoto rats and age-matched stroke-prone spontaneously hypertensive rats. Branches of the posterior cerebral artery were cannulated and pressurized. and these vessels developed spontaneous tone. After a 5-minute period in K(+)-free physiological saline solution. K+ was increased in 1-mM increments to a final concentration of 15 mM. In the normotensive arteries. K+ concentrations between 0 and 5 mM K+ resulted in dilations that had a transient (sodium pump-dependent) component. and K+ concentrations in excess of 7 mM produced dilations that lacked a transient (sodium pump-independent) component. Similar branches from the hypertensive rat also responded with transient dilations to K+ (less than 5 mM). and these were significantly greater at 3 mM K+. However. the maintained dilations to K+ (greater than 7 mM). noted in preparations from Wistar-Kyoto rats. were absent in seven of eight preparations. Thus. the impaired dilations. in the hypertensive vessels. to K+ described here is a consequence of altered function of some sodium pump-independent component rather than altered Na+.K(+)-ATPase activity.
The dorsal antiglide plate in the treatment of Danis-Weber type-B fractures of the distal fibula, The results of 93 of 107 consecutive antiglide plate internal fixations of Danis-Weber Type-B fractures of the distal fibula are reported with a follow-up period of just over one year. Using the ankle evaluation scale of Weber. 66.7% excellent. 27.9% good. and only 5.4% poor results were found. The method of dorsal antiglide plate fixation is possible in most of the frequent Type-B ankle fractures. Stabilization is better with the antiglide plate. especially in older patients with osteoporotic bone. Because of these advantages and the biomechanically sound technique. the antiglide plate is recommended for stabilization of the Danis-Weber Type-B fracture of the distal fibula.
Serum immunoglobulin G subclasses in patients during acute hepatitis A, IgG subclasses were measured in sera of 47 patients with acute hepatitis A during the course of the disease. IgG1 and IgG3 serum levels were found to be elevated. whereas IgG2 and IgG4 subclass concentrations did not differ from that found in healthy control individuals. These findings indicate that. similar to the specific antiviral antibody. the polyclonal increase of serum concentrations of IgG in acute hepatitis A is not equally distributed to all IgG subclasses but is restricted to IgG1 and IgG3.
Comparison of modified amino acids and standard amino acids in parenteral nutrition support of thermally injured patients, Twenty thermally injured patients who could not tolerate enteral nutrition support were randomized to receive parenteral nutrition (PN) with either modified amino acids (MAA) or standard amino acids (SAA). There was no significant difference between groups for age. sex. weight. percent BSA area burn. percent third-degree burn. or operative procedures. N balance (NB) was measured and serum was harvested for circulating fibronectin (Fn). somatomedin-C/insulin-like growth Factor I (Sm-C). prealbumin (PA). and retinol-binding protein (RBP) analysis on days 1. 4. 7. 14. 21. and 28 of PN. The patient groups received similar doses of PN for a similar number of days. Fn did not change significantly from baseline in either group and there was no significant difference between groups. Sm-C increased significantly from baseline at day 7 in the SAA group and in both groups on day 14. but there was no significant difference between groups. PA and RBP increased significantly from baseline on day 7 in the MAA group and in both groups on days 14. 21. and 28. RBP was significantly higher in the MAA group only on day 21. and there was no significant difference between groups for PA. NB increased significantly from baseline for all study days; however. there was no significant difference between groups. PN in thermally injured patients significantly improves NB and increases visceral protein concentrations. However. there appears to be no difference between PN with MAA or SAA.
Factors affecting ability to resume oral nutrition in the oropharyngeal dysphagic individual, Successful oral intake of nutrition depends not only on the patient's ability to swallow efficiently and safely but also a number of cognitive. neurolinguistic. and behavioral variables. This paper reviews these competencies as they are integrated into the act of oral feeding and describes the types of disorders that affect these abilities. Methods of evaluating and treating the abilities needed for successful oral intake are described.
Dietary adjustments and nutritional therapy during treatment for oral-pharyngeal dysphagia, Dietary adjustments are an important part of the therapy for dysphagia. Once dysphagia is diagnosed. the patient must be nourished safely while being taught therapeutic and compensatory strategies for dealing with the swallowing disorder. The patient's nutritional status must be maintained despite any limitations on oral intake. Liquids may be thickened and the consistency of solid foods may be adjusted to ensure an adequate diet that is safe for the patient. When the patient cannot eat safely or take adequate amounts of food orally. an alternative feeding method should be instituted.
Feeding strategies for the dysphagic patient: a nursing perspective, The goal of treatment for the dysphagic patient is to maintain safe oral feeding. Achieving this goal requires an individualized care plan using selected feeding strategies. This care plan will need to be altered as changes in the patient's condition occur.
Volunteer participation in feeding residents: training and supervision in a long-term care facility, The increasing number of residents in long-term care facilities who require full and partial assistance during meals has created a need for volunteer support to enhance the quality of life for residents. The correlation between dependence in eating and the existence of swallowing disorders and the risk of aspiration in persons with swallowing disorders suggests that training must be given to volunteers who feed residents. A formalized program for volunteer training and supervision was implemented at Coler Memorial Hospital. a long-term care facility. The program's development and benefits are outlined. Implementation of this program resulted in better training of volunteers. increased socialization. communication. and safety for patients during meals.
Efficacy of positive vs negative pressure ventilation in unloading the respiratory muscles, We compared the efficacy of positive pressure ventilation (PPV) vs negative pressure ventilation (NPV) in providing ventilatory muscle rest for five normal subjects and six patients with chronic obstructive pulmonary disease (COPD). All participants underwent measurement of transdiaphragmatic pressure (Pdi). pressure time integral of the diaphragm (PTI). integrated diaphragmatic electromyogram (iEMG). minute ventilation (Ve). tidal volume (Vt). and end-tidal CO2 (etCO2) during 15 minutes of PPV and NPV. For each subject. ventilator adjustments were made to obtain Ve similar to levels measured during quiet breathing (QB). We found that the iEMG. Pdi. PTI. and average coefficient of variation of the tidal volume (CV-Vt) were consistently lower during PPV as compared with NPV (p = 0.01). The iEMG normalized for Ve and Vt was also significantly lower during PPV (p = 0.01). During PPV. subjects were mildly hyperventilated (lower etCO2 and higher Ve) compared with QB and NPV. but no significant correlation was noted between the change in etCO2 and the change in iEMG. The change in PTI was significantly correlated with the change in iEMG (p less than 0.01). We conclude that in the short term. PPV is more effective than NPV in reducing diaphragmatic activity. Positive pressure ventilation may be the preferred method of assisted ventilation in future studies of ventilatory muscle rest therapy.
Diaphragmatic rest during negative pressure ventilation by pneumowrap. Assessment in normal and COPD patients, In the present study. we assessed the occurrence of respiratory muscle rest during long lasting INPV runs using a pneumowrap ventilator at different pressure levels. We measured two indices of diaphragmatic activity: transdiaphragmatic pressure and the electrical activity of the diaphragm. Five healthy volunteers and six COPD patients were studied during spontaneous breathing and during 30-minute runs of INPV at a pressure of -2. -15 and -30 cmH2O. Ventilation. rib cage and abdomen motion were measured by inductive plethysmography; Pdi was obtained as the difference between gastric and esophageal pressures; Edi was recorded with surface electrodes. About 10 minutes of INPV (adaptation phase) were needed to obtain stable values in all the variables recorded. Ventilation increased in both groups up to threefold by increasing the negative pressure applied. this being due to changes in tidal volume. Changes in Pga swings mainly accounted for the reduction in Pdi that became negative during the run at -30 cmH2O. In both groups. Edi. after adaptation. showed no change during INPV at -2 cmH2O but a progressive reduction from control. during INPV at -15 and -30 cmH2O. We conclude that INPV by a pneumowrap ventilator can induce partial respiratory muscle rest in normal subjects and COPD patients.
Antigen-presenting capacity in patients with sarcoidosis, Antigen-presenting capacity by monocytes and AMs was determined in 13 patients with sarcoidosis and nine healthy control subjects. using PPD as the antigen. The patients and healthy control subjects all had positive PPD skin tests. Monocytes from both the control subjects and the patients with sarcoidosis exhibited antigen-presenting capacity to autologous peripheral T-lymphocytes. without any significant difference between the two groups. The AMs from patients. but not control subjects. demonstrated antigen-presenting capacity to autologous peripheral T-lymphocytes. Antigen-presenting capacity by monocytes and AMs to lung T-lymphocytes was lower than to peripheral T-lymphocytes. but not significantly. Antigen-presenting capacity was not significantly different between patients with sarcoidosis who had positive and negative PPD skin tests. The mechanism of enhanced antigen-presenting capacity by AMs in sarcoidosis is uncertain at present. but no significant difference was observed in DR antigen expression on AMs between controls and patients with sarcoidosis. and the addition of exogenous IL-1 or IFN-gamma did not induce antigen-presenting capacity by AMs in controls. suggesting that neither increased DR antigen expression on AMs nor increased release of IL-1 or IFN-gamma from AMs is responsible. Thus. these results suggest that T-lymphocyte activation in sarcoidosis may in part be attributable to an enhanced antigen-presenting capacity by AMs.
Identical orocecal transit time and serum motilin in hyperthermia and normothermia, Fever. exercise. and exposure to a hot environment can all cause symptoms of gastrointestinal dysfunction as they elevate body temperature. Nonetheless. the link between hyperthermia per se and these symptoms is unknown. To test the functional significance of increased body temperature. we investigated the influence of substantial passive hyperthermia on orocecal transit in 12 young. healthy men. Transit time was determined by a consistent rise in H2 concentration in a rebreathing apparatus after oral ingestion of 0.7 g lactulose/kg body weight. Lactulose was given in combination with a 350-ml liquid meal (360 kcal). After raising core temperature in warm water to 38.3 degrees C. orocecal transit time was identical to control (90 +/- 13 min at 38.3 degrees C. 92 +/- 13 min at 37.1 degrees C). While hyperthermia did elevate heart rate and minute ventilation. serum motilin. gastrin. and cortisol were similar in the two conditions. The failure of a passive core temperature rise to alter mouth-to-cecum transit suggests that this aspect of alimentary function is independent of body temperature.
Acute actions of sulfonylurea drugs during long-term treatment of NIDDM, The acute effect of sulfonylurea drugs during long-term treatment was evaluated in two separate studies. In the first study. the levels of plasma glucose. insulin. and C-peptide were measured after intake of 10 mg glyburide alone or together with a standardized mixed meal in 10 non-insulin-dependent diabetes mellitus (NIDDM) patients treated with 10-20 mg glyburide/day for greater than 2 yr. There was no acute effect of glyburide on the insulin and C-peptide responses to the meal or during continued fasting. indicating the absence of an acute insulinotropic action of glyburide during chronic treatment. The glucose increase after the meal was also unchanged. but a significant glucose reduction was found after glyburide intake during continued fasting. suggesting a sustained acute extrapancreatic (hepatic) effect. In the second study. the diurnal glycemic excursions in 8 NIDDM patients chronically and continuously (24 h/day) exposed to glipizide (2.5-7.5 mg 3 times/day) were similar when the drug was taken 30 min before each of the three main meals and when taken immediately before the meals. It is concluded that there is no acute insulinotropic action of sulfonylurea drugs during chronic continuous exposure. whereas an acute extrapancreatic action may prevail. During such exposure. there seems to be no clinical benefit in taking a sulfonylurea 30 min before rather than at the start of a meal.
Vitamin A levels in premenstrual syndrome, To determine whether changes in peripheral vitamin A levels are associated with symptoms of premenstrual syndrome (PMS). 10 PMS patients and 10 controls were studied. They gave blood at 2- or 3-day intervals through three menstrual cycles. The vitamin A was measured by fluorometry after cyclohexane extraction. In the controls. vitamin A values were 68.0 +/- 3.2 micrograms/dL (mean +/- SE) during the luteal phase and 69.8 +/- 4.2 micrograms/dL during the follicular phase. No significant changes were noted between the two values. In the patients. the values were 73.9 +/- 4.2 micrograms/dL during the luteal phase. which was not significantly different from 72.7 +/- 1.8 micrograms/dL during the follicular phase. No significant changes were noted between the controls and the patients in either the luteal or the follicular phase. Vitamin A deficiency in PMS patients was not demonstrated in our study.
Ovarian cyst aspiration and the outcome of in vitro fertilization, This study was designed to ascertain whether any benefit would be derived from aspirating ovarian cysts identified before ovarian stimulation in patients undergoing in vitro fertilization. Thirty-seven patients who had ovarian cysts were categorized into two groups: group A (n = 14) with baseline ovarian cysts and group B (n = 23) with ovarian cysts that developed during pituitary suppression with the gonadotropin-releasing hormone analog. Each group was prospectively randomized into two subgroups depending on whether the ovarian cysts were aspirated or not. In group A. there was a significantly greater number of follicles and oocytes in the ovaries in which cysts were aspirated. However. there was no significant difference in the total number of follicles. oocytes retrieved and fertilized. or in the final outcome. In group B. there was no significant difference in folliculogenesis between the aspirated and nonaspirated subgroups. These observations suggest that the presence of a baseline ovarian cyst may reduce folliculogenesis but do not support routine cyst aspiration if the patient has two functional ovaries.
Treatment with pulsatile luteinizing hormone-releasing hormone modulates folliculogenesis in response to ovarian stimulation with exogenous gonadotropins in patients with polycystic ovaries, Combined treatment with pulsatile LH-RH and hMG. given to eight patients who had anovulation associated with PCO and resistant to CC. significantly reduced the number of large follicles induced by hMG alone. A direct effect of pulsatile LH-RH on the ovary is postulated. This combined treatment eased the problems of multifollicular development. thereby increasing efficiency and reducing complications in patients with PCO stimulated by gonadotropins.
Glomerular filtration rate in streptozocin-induced diabetic rats. Role of exchangeable sodium, vasoactive hormones, and insulin therapy, The interrelationships of sodium and volume status. atrial natriuretic peptide (ANP). plasma renin activity (PRA). insulinlike growth factor I (IGF-I). and kidney weight and their influence on glomerular filtration rate (GFR) were investigated in rats during the first 4 wk of streptozocin-induced diabetes (STZ-D). In each of three experiments. untreated diabetic rats were compared with nondiabetic control rats and rats with varying degrees of glycemic control during insulin therapy. The first experiment evaluated exchangeable sodium. plasma volume. and GFR. In untreated diabetic rats. exchangeable sodium and plasma volume. but not GFR. were increased by approximately 25% compared with control rats. Insulin-treated diabetic rats with plasma glucose levels ranging from 12 to 30 mM had increased GFR. whereas exchangeable sodium and plasma volume were reduced toward control values. Daily insulin therapy. titrated to maintain euglycemia. further reduced exchangeable sodium and plasma volume and decreased but did not normalize GFR. The second experiment evaluated the relationship between vasoactive hormones and GFR. In untreated diabetic rats. plasma ANP levels increased 89% and urinary cyclic GMP (cGMP) excretion increased 94%. with an 85% decrease in PRA. whereas GFR was unchanged. Moderate hyperglycemia (plasma glucose 12-30 mM) was associated with normalized plasma ANP levels and urinary cGMP excretion. a 52% decrease in PRA. and a 13% increase in GFR. The third experiment studied serial changes in food and water intake and vasoactive hormones and end-point measurement of kidney weight. GFR. and plasma IGF-I. In the untreated diabetic group. urinary cGMP excretion was significantly elevated after 3 wk. whereas the reduction in PRA levels was apparent after 1 wk.
Endogenous prostaglandin endoperoxides and prostacyclin modulate the thrombolytic activity of tissue plasminogen activator. Effects of simultaneous inhibition of thromboxane A2 synthase and blockade of thromboxane A2/prostaglandin H2 receptors in a canine model of coronary thrombosis, We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation. the animals received saline (controls. n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion). a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion). a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion). a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then. all dogs received heparin (200 U/kg) and a bolus of t-PA (80 micrograms/kg) followed by a continuous infusion (8 micrograms/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 +/- 5 vs. 56 +/- 7 min. respectively. P = NS). but it was significantly shortened by R 68070 and dazoxiben (11 +/- 2 and 25 +/- 6 min. respectively. P less than 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P less than 0.01). Reocclusion was observed in eight of eight control dogs. five of seven SQ 29548-treated dogs. seven of nine dazoxiben-treated dogs. and zero of eight R 68070-treated animals (P less than 0.001). TxB2 and 6-keto-PGF1 alpha. measured in blood samples obtained from the coronary artery distal to the thrombus. were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels. whereas 6-keto-PGF1 alpha levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus. simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either intervention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.
Apolipoprotein A-I and its amphipathic helix peptide analogues inhibit human immunodeficiency virus-induced syncytium formation, The envelope (membrane) glycoprotein of HIV is essential for virus attachment and entry into host cells. Additionally. when expressed on the plasma membrane of infected cells. the envelope protein is responsible for mediating cell-cell fusion which leads to the formation of multinucleated giant cells. one of the major cytopathic effects of HIV infections. The envelope glycoproteins of HIV contain regions that can fold into amphipathic alpha-helixes. and these regions have been suggested to play a role in subunit associations and in virus-induced cell fusion and cytopathic effects of HIV. We therefore tested the possibility that amphipathic helix-containing peptides and proteins may interfere with the HIV amphipathic peptides and inhibit those steps of HIV infection involving membrane fusion. Apolipoprotein A-I. the major protein component of high density lipoprotein. and its amphipathic peptide analogue were found to inhibit cell fusion. both in HIV-1-infected T cells and in recombinant vaccinia-virus-infected CD4+ HeLa cells expressing HIV envelope protein on their surfaces. The amphipathic peptides inhibited the infectivity of HIV-1. The inhibitory effects were manifest when the virus. but not cells. was pretreated with the peptides. Also. a reduction in HIV-induced cell killing was observed when virus-infected cell cultures were maintained in presence of amphipathic peptides. These results have potential implications for HIV biology and therapy.
Lack of induction of suppressor T cells by intestinal epithelial cells from patients with inflammatory bowel disease, The mechanisms underlying the chronic unrelenting inflammatory response seen in inflammatory bowel disease (IBD) are poorly understood. We have recently proposed a novel role for the normal intestinal enterocyte. that of antigen presenting cell. However. in contrast to conventional antigen presenting cells. normal enterocytes appear to selectively activate CD8+ antigen nonspecific suppressor T cells. To determine whether failure of this process may be occurring in inflammatory bowel disease. freshly isolated enterocytes from small and large bowel from normal patients. patients with Crohn's disease. ulcerative colitis. and inflammatory (diverticulitis. ischemic colitis. and gold induced colitis) controls were co-cultured with allogeneic T cells in a modified mixed lymphocyte reaction. In contrast to normal enterocytes. 42/42 Crohn's and 35/38 ulcerative colitis-derived epithelial cells stimulated CD4+ T cells. whereas 65/66 and 9/9 normal and inflammatory control enterocytes. respectively. stimulated CD8+ T cells (as previously described). suggesting that the results seen were not just a reflection of underlying inflammation. Furthermore. IBD enterocytes from both histologically involved and uninvolved tissue were similar in their ability to selectively activate CD4+ T cells. speaking for a more global defect in epithelial cells in IBD. Finally. activated T cells from IBD epithelial cell-stimulated mixed lymphocyte cultures displayed potent T helper activity in an antigen nonspecific fashion. Taken together. these data suggest that there may be an intrinsic defect in epithelial cells from patients with IBD. resulting in the inability to normally stimulate suppressor T cells in an antigen overloaded environment.
The complete nucleotide sequences of the heavy chain variable regions of six monospecific rheumatoid factors derived from Epstein-Barr virus-transformed B cells isolated from the synovial tissue of patients with rheumatoid arthritis. Further evidence that some autoantibodies are unmutated copies of germ line genes, Structural studies of human monoclonal rheumatoid factors (RF) derived from patients with monoclonal gammapathies have revealed a restriction in the usage of heavy and light chain variable regions. These studies have suggested that germline genes with little if any somatic mutation can generate RF specificity. However. there is no information presently available regarding the primary structure and genetic origin of RF in rheumatoid arthritis. In this study. we have isolated and sequenced the VH regions of six monoclonal RF derived from the synovial membranes of two patients with rheumatoid arthritis and one with the juvenile polyarticular form of the disease. We found the same VH families as previously reported among monoclonal paraproteins with RF activity. However. our sample was diverse regarding the VH. DH. and JH gene segments used. Among VHI RF there was conservation in the length of CDRIII as well as restriction in the amino acid generated at the V-D junction. as opposed to VHIII RF and non-RF VHI molecules that are highly heterogeneous in these two aspects. We also found that different JH gene segments may contribute to RF specificity. The VH. DH. and JH elements of one RF in our study all had clearly identifiable germline counterparts. This RF displays a nearly germline configuration throughout its entire heavy chain and represents another example of an autoantibody encoded by one of the VH gene segments from the preimmune fetal repertoire.
Biogenesis of intestinal lactase-phlorizin hydrolase in adults with lactose intolerance. Evidence for reduced biosynthesis and slowed-down maturation in enterocytes, Enzymatic activity. biosynthesis. and maturation of lactasephlorizin hydrolase (LPH) were investigated in adult volunteers with suspected lactose intolerance. Mean LPH activity in jejunal biopsy homogenates of these individuals was 31% compared to LPH-persistent individuals. and was accompanied by a reduced level of LPH-protein. Mean sucrase activity in individuals with low LPH was increased to 162% and was accompanied by an increase in sucrase-isomaltase (SI)-protein. Biosynthesis of LPH. SI. and aminopeptidase N (APN) was studied in organ culture of small intestinal biopsy specimens. In individuals with LPH restriction. the rate of synthesis of LPH was drastically decreased. reaching just 6% of the LPH-persistent group after 20 h of culture. while the rate of synthesis of SI appeared to be increased. In addition. maturation of pro-LPH to mature LPH occurred at a slower rate in LPH-restricted tissue. Immunoelectron microscopy revealed an accumulation of immunoreactive LPH in the Golgi region of enterocytes from LPH-restricted individuals and reduced labeling of microvillus membranes. Therefore. lactose intolerance in adults is mainly due to a decreased biosynthesis of LPH. either at the transcriptional or translational level. In addition. intracellular transport and maturation is retarded in some of the LPH-restricted individuals. and this leads to an accumulation of newly synthesized LPH in the Golgi and a failure of LPH to reach the microvillus membrane.
Assessment of fetal-maternal haemorrhage in mothers with hereditary persistence of fetal haemoglobin, Kleihauer examination of peripheral blood cannot be used reliably to detect transplacental fetal-maternal haemorrhage in mothers with hereditary persistence of fetal haemoglobin (HPFH). In Rh(D) negative pregnancies diagnostic confusion with a large fetal-maternal haemorrhage could result in the administration of inappropriately excessive amounts of anti-D immunoglobulin. and the inability to diagnose and quantify transplacental haemorrhage in maternal HPFH by current methods could result in insufficient anti-D administration and subsequent Rh(D) sensitisation. Accordingly. a method to detect and quantify fetal-Rh(D) positive maternal haemorrhage using erythrocyte fluorescent immunocytometry was developed. An indirect immunofluorescence method with IgG anti-D immunoglobulin as the primary antibody was used. combined with quantitative analysis on a fluorescence activated cell sorter. The method was accurate. specific. and sensitive and could detect a contaminating population of 0.1% Rh(D) positive cells in Rh(D) negative blood--a level of fetal-maternal haemorrhage well covered by a single dose of 500 IU of anti-D immunoglobulin.
Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with N-acetylcysteine, To better understand the mechanism of nitrate tolerance in patients with congestive heart failure. 13 patients received a 24 h infusion of nitroglycerin (1.5 micrograms/kg body weight per min) with or without N-acetylcysteine (225 mg/kg per 24 h). The infusions were separated by a 24 h nitrate-free interval. By the end of the nitroglycerin infusion. mean arterial pressure had returned to baseline values and there was a significant increase in ventricular filling pressures and systemic vascular resistance compared with values after 1 h of treatment. The simultaneous infusion of N-acetylcysteine had no effect on these changes. Although a strict fluid restriction of 1.5 liters/day was maintained for 1 week before and throughout the study. after 24 h of nitroglycerin infusion there was a significant and similar degree of hemodilution whether nitroglycerin was infused alone (9.1 +/- 4.3%) or with N-acetylcysteine (8.7 +/- 4.1%). This hemodilution corresponded to an increase in intravascular volume of 745 +/- 382 ml. most of which occurred during the 1st h. Plasma renin activity increased and plasma atrial natriuretic peptide decreased during the infusion. The results of this study suggest that nitrate tolerance is multifactorial. In addition to the previously described pharmacologic tolerance to the effect of nitroglycerin on vascular smooth muscle. a capillary fluid shift from the extravascular to intravascular space appears to be involved. especially during the 1st h of the infusion. A third mechanism. reflex neurohumoral activation. also seems to contribute to the genesis of nitroglycerin tolerance.
Atrial natriuretic factor (ANF) is a potent bronchodilator in asthma, The bronchodilating effects of atrial natriuretic factor (ANF) were compared to effects of salbutamol in a double-blind. placebo-controlled. crossover study in eight subjects with asthma and with airflow limitation. ANF was infused intravenously (0.1 microgram/kg/min during 30 minutes) and caused a short-lasting significant (p less than 0.012) bronchodilation in all patients similar in intensity to intravenous salbutamol (0.13 microgram/kg/min). The duration of the effect of the beta 2-agonist. however. was longer. No severe side effects were noted with ANF infusion. ANF may play a role in the modulation of the bronchial tone in humans. but its usefulness in the treatment of asthma remains to be determined.
Roles of muscularis mucosae and myofibroblasts in the healing process of acetic acid-induced ulcer, The changes in the localization of FITC-phalloidin-positive smooth muscle cells and interstitial cells were studied in control and acetic acid-treated rat fundic mucosa. In the control rats. the FITC-phalloidin-positive cells mostly corresponded to the smooth muscle cells of the muscularis mucosae. and the arteriolar and venular smooth muscle cells. On the other hand. 1 week after the acetic acid treatment. the fluorescence of the smooth muscle cells of the muscularis mucosae disappeared and a large number of fluorescent interstitial cells. probably corresponding to myofibroblasts. appeared in the regenerated mucosal layer. Three weeks after the application. severely thickened fluorescent muscularis mucosae were formed and the fluorescence of the interstitial cells was rather decreased.
Intracranial hemorrhage and hemophilia: case report and management guidelines, Hemophiliacs. as a result of low coagulation factor levels. may suffer spontaneous intracranial hemorrhage. A case of intracranial hemorrhage in a hemophiliac patient with a history of intravenous drug abuse and HIV infection is reported. Factor replacement. airway management. and risks of HIV exposure to emergency department personnel are discussed.
Molecular analysis of a germ line-encoded idiotypic marker of pathogenic human lupus autoantibodies, Id-16/6 is an idiotypic marker found in both IgM and IgG antibodies. as well as in the tissue lesions of patients with SLE. The prototypic Id-16/6+ mAb is 18/2. whose VH3-derived H chain is encoded by an unmutated germ-line gene. We found that the H chains of VH3-derived Id-16/6+ antibodies contain the major determinants of Id-16/6. Moreover. B cell clones from which those antibodies were harvested produce RNA that hybridized under conditions of high stringency to oligonucleotide probes corresponding to the CDR of the VH segment of 18/2. Western blots of Id-16/6+ mAbs with anti-Id confirmed the association of the Id with H chains. Id-16/6 can identify a subgroup of VH3-derived antibodies we have termed the 18/2 CDR family. However. Id-16/6 can also be expressed in some antibodies unrelated to the 18/2 CDR family. No characteristic Ag-binding specificity was found among the members of the 18/2 CDR family. The principal phenotypic feature shared by all known members of the family is Id-16/6.
A soluble factor produced by inoculation of human monocytes with Leishmania donovani promastigotes suppresses IFN-gamma-dependent monocyte activation, Whereas human cultured monocytes preactivated with IFN-gamma increase their antileishmanial capacity. monocytes inoculated with Leishmania donovani before IFN-gamma treatment fail to respond with an increase of antileishmanial capacity. Cell surface expression of class II MHC products also fails to be increased by IFN-gamma in the infected monocytes. although the accumulation of HLA-DR alpha-chain mRNA is increased to the same extent in infected and noninfected activated monocytes. This inhibition of monocyte activation is caused in a dose-dependent manner by a soluble substance elaborated into the cell supernatant after inoculation of monocytes with L. donovani and is referred to as activation suppressing factor (ASF). ASF activity can be abrogated by dialysis and by treatment with a proteinase. indicating that ASF is a small peptide.
Activation of human monocyte-derived macrophages to kill schistosomula of Schistosoma mansoni in vitro, Human peripheral blood monocytes from normal donors were isolated by elutriation and differentiated by culture in the presence or absence of various immunomodulators. Cells were harvested between 0 and 24 days and tested for their ability to kill schistosomula of Schistosoma mansoni in vitro as a measure of activation. Freshly isolated monocytes showed no significant cytotoxic activity in the presence or absence of IFN-gamma or LPS. As the cells matured in vitro. there was a slight increase in their inherent toxicity against the parasite. which was greatly enhanced by pretreatment with either IFN-gamma or CSF-1. Optimal antibody-independent larvicidal activity occurred after stimulation with both IFN-gamma and CSF-1. using cells that had matured for at least 7 days in vitro. Under these conditions. killing of up to 70% of the larvae was observed. Although enhanced larvicidal activity was not found to strictly correlate with production of any of several proposed effector molecules examined. activated monocyte-derived macrophages were capable of producing significant amounts of H2O2 and TNF-alpha. These observations indicate that cytokine-activated human monocyte-derived macrophages are able to kill schistosome larvae by an antibody-independent mechanism. as has been observed using murine peritoneal macrophages. Stimulation with multiple differentiation and activation signals. as would occur in vivo. may be required for development of optimal larvicidal activity.
The role of IFN-gamma in the pathology of experimental endotoxemia, Proinflammatory cytokines provoked by circulating bacterial LPS mediate many of the destructive host responses characteristic of septic shock. To determine if the lymphokine IFN-gamma has a similar pathogenic role during endotoxic shock. mice were pretreated with murine rIFN-gamma (rMuIFN-gamma) at various times relative to challenge with Salmonella enteritidis LPS. Subsequent mortality was increased when rMuIFN-gamma was administered before or up to 4 h after endotoxin challenge. Pretreatment with rMuIFN-gamma resulted in nearly fivefold increases in serum TNF during endotoxemia. but TNF levels were unaffected by IFN administered after endotoxin. The increased levels of serum TNF probably reflected enhanced translation of this factor. as tissue expression of TNF mRNA did not increase correspondingly in IFN-pretreated mice. To examine the role of IFN-gamma produced endogenously during endotoxemia. mice were pretreated with 0.5 mg of anti-IFN-gamma mAb before endotoxin injection. This treatment significantly reduced mortality from endotoxic shock but caused only minor decreases in serum TNF. Anti-IFN-gamma administered 2 h after endotoxin was similarly protective. These results demonstrate a significant role for IFN-gamma in the pathology of septic shock. both indirectly as an activator of monokines known to promote lethality and possibly by other. late-acting mechanisms.
Immune responses during human Schistosoma mansoni. XVII. Recognition by monoclonal anti-idiotypic antibodies of several idiotopes on a monoclonal anti-soluble schistosomal egg antigen antibody and anti-soluble schistosomal egg antigen antibodies from patients with different clinical forms of infection, A monoclonal human anti-soluble schistosomal egg Ag(SEA) antibody (E5) that stimulates anti-Id T cells and is idiotypically represented in pools of immunoaffinity-purified human anti-SEA antibodies from chronic. generally asymptomatic. intestinal (INT) patients (AM1 and AM5) was used to raise several monoclonal anti-Id: 1C2. 1C6. 4A8. 4F9. and 2A7. Cross-inhibition between these anti-Id identified distinct idiotopes on E5. Anti-SEA preparations from schistosomiasis patients (AM1. AM5. and others) were tested for their inhibition of the E5/monoclonal anti-Id reactions. in competitive ELISA. In either the E5/4A8 or E5/1C6 ELISA system. anti-SEA from INT (AM1 or AM5) or hepatointestinal (HI) (AM7) patients were able to inhibit these reactions. However. anti-SEA antibodies from acute (AM9) or hepatosplenic (HS) (AM3 or AM8) patients did not express Id that were inhibitory in these systems. These results suggest that a relatively high proportion of INT and HI anti-SEA antibodies express a dominant cross-reactive idiotope (CRI) recognized by 1C6/4A8. This CRI is also easily detected in plasmas from individual INT patients. Anti-Id 1C2 reacted strongly with an Id in AM1. AM5. or AM7. but one which also occurred. to a lesser extent. in AM3. AM8. and AM9. Monoclonal anti-Id 4F9 and 2A7 reacted weakly with idiotopes expressed by antibodies from all patients. regardless of the clinical form of their infection. These observations indicate that anti-SEA antibodies from INT and HI. but not acute or HS patients express dominant. CRI that are identified by 1C6. 4A8. or 1C2 and are also expressed on the INT-derived anti-SEA mAb E5.
Intrathecal synthesis of anti-mycobacterial antibodies in patients with tuberculous meningitis. An immunoblotting study, Cerebrospinal fluid (CSF) and serum samples from eight patients with bacteriologically proven (6) or clinically suspected (2) tuberculous meningitis were tested for the presence of anti-mycobacterial IgG antibodies by an affinity-mediated immunoblot technique. This technique is based on agarose gel isoelectric focusing of paired CSF and serum samples diluted to the same IgG concentration. and transfer of the specific IgG antibodies onto mycobacterial antigen-loaded nitrocellulose sheets. An intrathecal synthesis of anti-mycobacterial oligoclonal IgG antibodies. often superimposed on diffuse polyclonal production was shown in all patients but not in patients with tension headache or other neurological disorders. Similar results were obtained when a purified mycobacterial antigen. A60. was used for coating the nitrocellulose sheets in place of a whole mycobacterial homogenate. indicating that A60 was a major immunogen. The number of anti-mycobacterial oligoclonal IgG bands increased with time. and persisted for years even in clinically cured patients. Some IgG bands had no detectable anti-mycobacterial activity. at least with the antigens preparations used in this study. The demonstration of such anti-mycobacterial IgG bands in the CSF could be a useful adjunct for the diagnosis of tuberculous meningitis. especially in the case of negative cultures.
Delays in the discharge of elderly patients, This paper reports a prospective study of the incidence and magnitude of delays in the discharge of 80 elderly (65+ years old) patients admitted to two general medical services in teaching hospitals in Edmonton. Alberta. The average length of stay was 16.6 days. Discharges were delayed in 14% (11/80) patients. accounting for 21% of the total days stay. Patients whose discharge was delayed tended to be older. to have delirium and/or dementia. to more often come from or require transfer to long term care (LTC) institutions. and/or to be dependent in essential activities of daily living. The 4-Score. an index for predicting non-medical days. was useful in identifying patients at risk for delays in discharge. and had a sensitivity of 0.82. and a specificity of 0.90. Interventions to reduce delays in discharge must address the frail nature of the patients. their lack of support and existing administrative relationships with LTC institutions. Acute care hospitals will likely need to undertake formal programs for the long term care of many of these patients.
Long-term fertility and Leydig cell function in patients treated for germ cell cancer with cisplatin, vinblastine, and bleomycin versus surveillance, Fertility and Leydig cell function were investigated in 31 patients previously treated for nonseminomatous testicular cancer. Twenty-two patients with metastatic cancer had received cisplatin-based chemotherapy. and the median follow-up was 64 months (range. 42 to 100 months). Nine patients without metastases were treated with orchiectomy alone. and follow-up in this group was a median of 61 months (range. 40 to 77 months). None of the patients have relapsed and retroperitoneal lymph node dissection was not performed in any patient. Both the concentration of spermatozoa and the volume of the remaining testis are significantly reduced in patients who had previously received chemotherapy when compared with patients treated with orchiectomy alone (P less than .05). There were no significant differences between groups when comparing morphology. motility. and penetration of the spermatozoa. Subclinical Leydig cell dysfunction with normal testosterone and elevated luteinizing hormone (LH) was observed in one patient (11%) treated with orchiectomy alone. while 59% of the patients who had received chemotherapy had elevated LH (P less than .05). We conclude that cisplatin-based chemotherapy leads to a persistent impairment of fertility and Leydig cell function in the majority of patients with testicular cancer.
Cholesterol uptake by human glioma cells via receptor-mediated endocytosis of low-density lipoprotein, Low-density lipoprotein (LDL) is a carrier of the cholesterol found in human plasma. Cells utilize cholesterol for membrane synthesis by taking up LDL via receptor-mediated endocytosis. In the present study. interactions of LDL with human malignant glioma cell lines (U-251 MG and KMG-5) were investigated biochemically and morphologically. The LDL. labeled with the fluorescent dyes 1.1'-dioctadecyl-3.3.3'.3'-tetramethylindocarbocyanine (DiI) and fluorescein isothiocyanate (FITC). was internalized by both cell processes and cell bodies. Reductive methylation of DiI-labeled LDL. which abolishes the ability of the cell to bind to the LDL receptor. prevented the internalization of the cholesterol moiety of LDL. Cellular binding of 125I-LDL to U-251 MG cells at 4 degrees C revealed the presence of a specific saturable-associated receptor (dissociation constant (Kd) approximately 38 micrograms/ml). Endocytic uptake of 125I-LDL or 3H-cholesterol oleate-labeled LDL (3H-LDL) at 37 degrees C demonstrated the cell-associated 125I-LDL and 3H-LDL increase. The intracellular degradation of protein moiety increased linearly with time. Reductive methylation of 3H-LDL led to a remarkable decrease in the cell-associated cholesterol moiety of LDL. The difference in uptake of the cholesterol moiety of LDL between U-251MG cells and KMG-5 cells showed that the U-251MG cells. which proliferate more actively than KMG-5 cells. take up more of the cholesterol moiety of LDL than do the KMG-5 cells. Thus. LDL cholesterol seems to be endocytosed predominantly via the LDL receptor present on the plasma membrane of malignant glioma cells. In addition. for growth. these cells may require large amounts of the cholesterol moiety of LDL.
Regional cerebral blood flow imaging: a quantitative comparison of technetium-99m-HMPAO SPECT with C15O2 PET, The aim of this study was to compare technetium-99m-hexamethylpropyleneamineoxime (99mTc-HMPAO) single-photon emission computed tomography (SPECT) with regional cerebral blood flow (rCBF) imaging using positron emission tomography (PET). As investigation of dementia is likely to be one of the main uses of routine rCBF imaging. 18 demented patients were imaged with both techniques. The PET data were compared quantitatively with three versions of the SPECT data. These were. first. data normalized to the SPECT cerebellar uptake. second. data linearly corrected using the PET cerebellar value and. finally. data Lassen corrected for washout from the high flow areas. Both the linearly-corrected (r = 0.81) and the Lassen-corrected (r = 0.79) HMPAO SPECT data showed good correlation with the PET rCBF data. The relationship between the normalized HMPAO SPECT data and the PET data was nonlinear. It is not yet possible to obtain rCBF values in absolute units from HMPAO SPECT without knowledge of the true rCBF in one reference region for each patient.
Detection of HIV-1 DNA in crude cell lysates of peripheral blood mononuclear cells by the polymerase chain reaction and nonradioactive oligonucleotide probes, The aim of this study was to detect HIV-1 proviral DNA in lysates of peripheral blood mononuclear cells (PBMCs) by the polymerase chain reaction (PCR) and hybridization with a nonradioactive probe. PBMCs were lysed in 1% Triton X-100. PCR was then carried out using primers complementary to a conserved region of the HIV-1 pol gene. Bracket and nested amplification protocols were used. Products were identified by dot-blot hybridization or agarose gel electrophoresis and Southern hybridization. using an alkaline phosphatase-linked oligonucleotide probe specific for amplified sequences. Colorimetric and chemiluminescent substrates were used. HIV-1 DNA was detected in PBMCs of 57/59 HIV-1-seropositive individuals. 8 of which were positive only following the use of nested primers. Of 12 seropositive samples that were negative by other HIV-1 diagnostic tests (PBMC coculture and serum p24 antigen detection). 11 were positive by PCR. PCR using PBMC lysates is a very sensitive method of detecting HIV-1 proviral sequences. The use of nested primers appears to increase the sensitivity of the procedure.
Anticardiolipin and antineutrophil antibodies in giant cell arteritis, IgG anticardiolipin antibodies (aCL) were found in a patient with Takayasu's arteritis and then in 11 of 22 patients with temporal arteritis (TA) studied prospectively. In comparison IgG aCL were found in only one of 18 elderly controls with rheumatoid arthritis and one of 47 healthy elderly controls. In TA IgG aCL were more frequent in those with acute disease (8/12). in those with an accompanying history of polymyalgia rheumatica (9/13). p less than 0.05); and levels normalized with corticosteroid treatment. Antineutrophil cytoplasmic antibodies (c-ANCA) were present in one patient with TA who had no systemic disease.
Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts, During a continuous 14-year observation period we prospectively recorded clinical data on all patients with rheumatoid arthritis (RA) attending an outpatient clinic. Six hundred seventy-one patients received 1017 new administrations of slow acting antirheumatic drugs during more than 2000 patient years of observation. The median time to discontinuation for intramuscular gold. auranofin. hydroxychloroquine or penicillamine was 2 years or less. but was 4.25 years for methotrexate (p = 0.008 vs all other drugs combined). Adverse reactions were a more common reason for discontinuation than efficacy. and both were less common in patients taking methotrexate (p less than 0.01). Neither disease duration. disease severity. or demographic factors were useful predictors of discontinuation. Since controlled clinical trials do not provide long-term outcome assessments. measurement of time to termination is a practical tool to estimate drug inefficacy.
Enhancement of mammary carcinogenesis by high levels of dietary fat: a phenomenon dependent on ad libitum feeding, Female 55-day-old Sprague-Dawley rats were treated with a single intravenous dose of 7.12-dimethylbenzanthracene (DMBA). 2 mg/100 g of body weight each. At 60 days of age. the rats were divided into four dietary groups (41-42 rats/group):I. 5% corn oil diet fed ad libitum; II. 20% corn oil diet fed ad libitum; III. 5% corn oil diet fed 12% less than group I; and IV. 20% corn oil diet fed 12% less than group II. The 5% and 20% corn oil diets were purified semisynthetic diets that were isonutrient on a caloric basis. All animals were housed individually in single cages; food consumption of each animal was computed daily throughout the study. Sixteen weeks after carcinogen treatment. mean numbers of mammary carcinomas per rat (+/- SE) in groups I. II. III. and IV were 4.1 +/- 0.6. 6.8 +/- 0.7. 3.0 +/- 0.3. and 4.1 +/- 0.5. respectively. Mean weight of mammary carcinomas per rat (g +/- SE) in groups I. II. III. and IV were 3.5 +/- 0.7. 8.0 +/- 1.3. 3.0 +/- 1.1. and 4.6 +/- 1.3. respectively. Mammary carcinoma number and weight were significantly (P less than .01) increased in the animals fed the 20% corn oil diet ad libitum when compared with those fed the 5% corn oil diet ad libitum; however. no significant differences in mammary tumor number or weight were observed between the animals fed a restricted. 20% corn oil diet and those fed a restricted. 5% corn oil diet. The study involving the animals fed the 12%-restricted diets was repeated (38-42 rats/group). with virtually identical results. i.e.. the mean number of mammary carcinomas per rat in the groups fed the restricted 5% fat and 20% fat diets at termination of the study was 3.1 +/- 0.4 and 3.7 +/- 0.3. respectively. and the mean weight (g) of mammary carcinomas per rat was 4.3 +/- 1.2 and 4.0 +/- 1.1. respectively (no significant differences). Thus. high levels of dietary fat can significantly enhance mammary carcinogenesis in female rats. but only in animals on an ad libitum feeding protocol. A slight restriction in amount consumed (12% less than ad libitum) abolished the mammary carcinogenic differential between a high-fat and a low-fat diet.
Identifying injuries and trauma severity in large databases, In order to assess the cost and effectiveness of inpatient trauma care. trauma patients and their levels of severity must first be identified accurately using data from all hospitals. not just trauma centers. The present study provides the methodology to identify injuries and trauma severity using discharge abstract data collected routinely by all hospitals. In this study. the validity of defining trauma patients using routinely collected abstract data and two computerized patient classifications--Diagnosis Related Groups (DRGs) and Patient Management Categories (PMCs)--was tested using the trauma registry data of one major trauma center as the gold standard. Medical records were reviewed to assess whether patients were accurately classified as having injuries by each of the two systems and whether patients were incorrectly omitted from the registry. Results indicated that trauma patients are more accurately identified by PMCs (95.1% accuracy) than by either DRGs (44.4% accuracy) or the registry standard itself (91.8% accuracy). Because patients identified by DRGs as trauma were not likely to be injured (21.2% specificity). and many true injuries were not identified as such by DRGs (47.9% sensitivity). per case payments to hospitals are unpredictable. and management based on DRG data is misleading. By contrast. PMCs (97.8% sensitivity; 77.7% specificity) can be used to improve injury surveillance methods. to monitor outcomes in terms of morbidity and mortality. and to make hospital payment systems more equitable.
Life-sustaining therapy. A model for appropriate use, New strategies are needed to curb the proliferation of life-sustaining therapies that rarely benefit patients. We propose a model for appropriate use of such therapies that incorporates effectiveness. utility. and marginal costs. If a therapy is rarely effective and rarely desirable. it is considered medically inappropriate. If the marginal cost-effectiveness ratio is inordinately high. it is considered economically inappropriate. If a therapy is either medically or economically inappropriate. it should not be automatically offered. The model provides an operational definition of futility and is illustrated with an analysis of out-of-hospital cardiopulmonary resuscitation for chronically ill older people. Advance directives. explicit health care rationing. and defining futile therapy based on survival predictions are alternatives to the appropriate care model. but are insufficient strategies to solve the problem of inappropriate life-sustaining care.
Neonatal detection of generalized resistance to thyroid hormone [published erratum appears in JAMA 1991 Feb 20;265(7):869, Generalized resistance to thyroid hormone (GRTH) is an inherited disease that is usually suspected when elevated serum thyroid hormone levels are associated with nonsuppressed thyrotropin. Often these test results are obtained because of short stature. decreased intelligence. and/or hyperactivity with learning disability noted in childhood and adolescence. or because of goiter in adulthood. We detected GRTH at birth by analysis of blood obtained during routine neonatal screening. The proposita. born to a mother with GRTH. had a thyrotropin level of 26 mU/L and a corresponding thyroxine concentration of 656 nmol/L (normal. 84 to 232 nmol/L). Administration of thyroid hormone in doses eightfold to 10-fold above replacement levels (liothyronine sodium. 21 micrograms/kg per day. and levothyroxine sodium. 44 micrograms/kg per day) were required to reduce serum thyrotropin to normal levels without induction of hypermetabolism. This case. and the retrospective finding of high thyroxine levels in five newborns subsequently diagnosed as having GRTH. suggest that measurement of thyroxine at birth. in conjunction with thyrotropin. could allow the early detection of GRTH.
Surgical treatment of carcinoid heart disease, Right heart failure in patients with carcinoid heart disease is a serious prognostic sign. Consideration and adequate timing of valvular operations seem essential for the postoperative outcome. Without any relation to duration or progression of the metastasizing tumor disease. right heart failure developed and increased rapidly for a period of 12 to 17 months in four patients with classic carcinoid syndrome. Invasive hemodynamic and cardiac ultrasound investigations revealed severe carcinoid heart disease. and medical decompensation treatment gradually failed. Tricuspid and pulmonic valve replacement operations resulted in dramatic improvement in three of the patients. and these patients were still free of cardiac symptoms 10. 12. and 38 months postoperatively. One patient died 5 days postoperatively probably of septicemia. The preoperative and postoperative development of the cardiac disease is evaluated clinically. by cardiac ultrasound and plasma atrial natriuretic peptide concentrations. and related to the tumor disease. Surgical anatomy and operative technique are reported. and the beneficial value of prophylactic treatment of the effects of tumor-released vasoactive substances by a somatostatin analog is emphasized.
Inhibitory effect of non-steroidal anti-inflammatory drugs on mucosal cell proliferation associated with gastric ulcer healing, To find out whether non-steroidial anti-inflammatory drugs (NSAIDs) inhibit the proliferation of mucosal cells that normally leads to healing of gastric ulcers a microdissection technique was used to quantify mitosis in gastric glands at the ulcer edge in relation to that in the adjacent mucosa. The regeneration index thus obtained of the ulcer edge was greater in the 9 subjects with gastric ulcers not taking NSAIDs (mean index 3.1 [SEM 0.61]) than that in the 8 patients taking NSAIDs (index 1.49 [0.16]). In rats in which gastric ulcers were produced with a cryoprobe. the ulcers were larger and slower to heal in those receiving indomethacin than in controls; also. immunohistochemical staining indicated significantly fewer mitotic cells in glands adjacent to the ulcer in indomethacin-treated rats (8 mitoses [SEM 3]) than in control animals (25 [5]). The prostaglandin E1 analogue misoprostol reversed the inhibition of healing and substantially restored the proliferative rate in the animals. Inhibition of epithelial cell division normally involved in gastric ulcer healing would contribute to the high prevalence of gastric ulcer during NSAID therapy.
Inhibitory effect of sandostatin on secretion of luteinising hormone and ovarian steroids in polycystic ovary syndrome, Hyperinsulinism accompanies the raised luteinising hormone (LH) concentrations in women with the polycystic ovary syndrome (PCOS). Somatostatin inhibits insulin and LH secretion in healthy adults. so the effect of treatment with a long-acting somatostatin analogue ('Sandostatin') on gonadotropin and androgen secretion in PCOS was investigated. LH pulsatility. androgen concentrations. and hormonal responses to an oral glucose load and to administration of a GnRH agonist (buserelin) were measured before and after 7 days' treatment with sandostatin 100 micrograms subcutaneously twice a day in 10 amenorrhoeic women with classic features of PCOS. Sandostatin significantly reduced integrated LH concentrations and LH pulse amplitudes. oestradiol. testosterone. and androstenedione concentrations. and LH responses to buserelin; it also suppressed insulin and C-peptide responses to an oral glucose load. Thus sandostatin inhibits pituitary and ovarian hormonal responses in part by a direct influence on pituitary activity. and the possibility of an indirect effect mediated by changes in insulin concentrations requires investigation. These findings have implications for the treatment of infertility in women with PCOS.
Preliminary report: activation of the cerebellum in essential tremor [published erratum appears in Lancet 1990 Nov 24;336(8726):1330, Several images of cerebral blood flow were recorded during inhalation of carbon-15-labelled carbon dioxide by positron emission tomography in four patients with essential tremor and four normal controls. Unilateral involuntary postural tremor in essential tremor patients was associated with blood flow significantly greater than that at rest in the contralateral sensorimotor cortex. both lateral premotor regions. and both cerebellar hemispheres. Of these regions. only the cerebellum was not activated in normal controls holding a posture without tremor or in essential tremor patients undergoing passive wrist movement. The increased flow in the cerebellum therefore seems to represent neural activity involved in tremor generation. It is proposed that essential tremor is due to oscillation within cerebello-olivary pathways. relayed by way of the thalamus and motor cortex to the spinal cord.
A pilot study of low-dose zidovudine in human immunodeficiency virus infection, BACKGROUND. Zidovudine delays the progression of human immunodeficiency virus (HIV) infection but is associated with hematologic toxicity at high doses. Regimens are needed that preserve or enhance efficacy and reduce toxicity. Acyclovir has been reported to potentiate the effect of zidovudine on HIV in vitro. METHODS. We conducted a Phase II open-label. dose-escalating trial to evaluate the clinical and antiviral effects of zidovudine at low (300 mg daily. 28 subjects). medium (600 mg. 24 subjects). and high (1500 mg. 15 subjects) doses. either with or without acyclovir (4.8 g) by random assignment. The subjects had the acquired immunodeficiency syndrome (AIDS)-related complex. but not AIDS. All of them had either HIV p24 antigenemia or plasma viremia and CD4-lymphocyte counts of 200 to 500 per cubic millimeter when they began treatment. RESULTS. Performance scores and fatigue improved the most in the low- and medium-dose zidovudine groups (both P less than or equal to 0.025). Those assigned to low-dose zidovudine gained the most weight and had the greatest improvement in the mean CD4-lymphocyte count (from 321 per cubic millimeter at base line to 412 per cubic millimeter after 12 weeks. P = 0.01). The proportion of subjects in whom HIV antigenemia resolved. the decrease in the level of antigenemia. and the reduction in the plasma virus titers were similar at all three doses. Subjects assigned to receive the low or medium dose who subsequently crossed over to the 1500-mg dose (n = 19) did not have an increase in CD4-cell counts or a decline in levels of HIV antigen. but they did have dose-related toxicity. The addition of acyclovir to zidovudine was well tolerated. but it did not enhance any of zidovudine's antiretroviral effects. CONCLUSIONS. In this pilot study a very low dose of zidovudine (300 mg) had clinical and virologic effects similar to those of higher daily doses (600 and 1500 mg). The minimal effective dose of zidovudine for the treatment of HIV infection has yet to be determined. and further studies of very low daily doses are warranted.
Evaluation of antibodies to hepatitis C virus in a study of transfusion-associated hepatitis, BACKGROUND. The hepatitis C virus (HCV) is now known to be the chief cause of transfusion-associated non-A. non-B hepatitis. but the prevalence of HCV among blood donors and the frequency of transmission by blood transfusion are unknown. METHODS. To assess the sensitivity and specificity of a test for antibody to HCV. we tested serum samples from participants in a large study of transfusion-associated hepatitis. Samples were obtained prospectively from consecutive adults undergoing open-heart surgery in Spain. but were tested retrospectively. after the antibody enzyme immunoassay for anti-HCV became available. RESULTS. Of 280 transfusion recipients given a total of 1109 units of blood. 27 (9.6 percent) had transfusion-associated non-A. non-B hepatitis (mean follow-up. 52 weeks) and 24 of the 27 seroconverted to anti-HCV-positive. whereas only 2 (0.8 percent) of the remaining transfusion recipients seroconverted. Among the 1044 donor specimens available for testing. 16 (1.5 percent) had anti-HCV antibody. Only 1 additional seropositive donor was found when 44 implicated donors who had been seronegative were retested 9 to 12 months later. Of the 16 recipients of anti-HCV-positive blood. 14 (88 percent) had transfusion-associated hepatitis and seroconverted to anti-HCV-positive. The remaining two recipients had neither hepatitis nor anti-HCV antibody. Among 25 patients with non-A. non-B hepatitis for whom all transfused blood was tested. 14 had received blood positive for anti-HCV. CONCLUSIONS. About 90 percent of blood donors with antibody to HCV have infectious virus in their blood. The screening of blood donors for anti-HCV antibody should prevent about half the cases of transfusion-associated hepatitis. but the donors with infectious virus who are anti-HCV-negative may remain seronegative for prolonged periods.
Screening of selected male blood donors for p24 antigen of human immunodeficiency virus type 1. The Transfusion Safety Study Group, BACKGROUND. The p24 antigen of human immunodeficiency virus type 1 (HIV-1) is sometimes detected before antibody (anti-HIV-1) is detectable in the serum of recently infected persons. This has led to the consideration of p24-antigen testing for routine screening of blood donors. METHODS. To estimate how many HIV-infected seronegative donors would be identified if p24-antigen screening was introduced. we tested selected donations from a repository of 200.000 serum samples from voluntary donors that was established in late 1984 and early 1985. The 8597 serum samples selected for p24-antigen screening were chosen because their donors had demographic characteristics known to be associated with a high prevalence of seropositivity. RESULTS. The prevalence of anti-HIV-1 antibodies in the 1984-1985 serum samples selected for p24-antigen screening was 1.54 percent--more than 100 times the 0.012 percent prevalence in present-day donations in the United States. The antigen was detected in 15 of 132 serum samples (11.4 percent) from donors who had already been confirmed as seropositive. No instance of confirmed positivity for p24 antigen was found among the 8465 seronegative serum samples. CONCLUSIONS. These data indicate that the yield of screening for p24 antigen in volunteer donors to identify HIV-1 carriers would be negligible. We therefore recommend against routine screening with currently available p24-antigen assays.
Rapid diagnosis of tuberculous meningitis by polymerase chain reaction (PCR), Using a rapid and highly sensitive method for the diagnosis of tuberculous meningitis by polymerase chain reaction (PCR). we detected the Mycobacterium tuberculosis genome in CSF of 5 of 6 patients with clinically diagnosed tuberculous meningitis. The genome was not present in CSF from 10 patients with other types of meningitis and 10 normal controls.
Prophylactic ankle bracing, Many choices are available to athletes seeking an ankle support. The time-honored tradition of ankle taping with adhesive tape does offer protection against ankle sprains during activity. Laced stabilizers offer an equal or possibly greater amount of support. are less costly and easier to apply. and can be retightened frequently during activity. The physician should become familiar with one of these two methods and choose one based on availability and feasibility in the community. The air stirrup may be indicated for patients with a history of ankle injury who are undergoing a graduated rehabilitation program. Nevertheless. the air stirrup has not been shown to provide significantly greater inversion restriction than taping or lace-on braces and is not recommended as a first-line method of support for individuals with no history of recent ankle sprain. High-top shoes are better when the ankle is taped. although low-top shoes are better when a laced stabilizer is worn. Elastic guards help reduce ankle edema but do not provide ankle stability.
Asthma in primary care patients. Challenges and controversies, Asthma varies in intensity. and patients must be treated as individuals to whom formulas do not apply. Often. the most difficult person to treat is the first-time patient whose clinical course is unknown and whose response to medications is totally untested. Although exacerbating substances should be avoided whenever possible. medication unfortunately is still needed by most asthmatic patients. At present. the choice of initial medication is subject to individual physician preference; beta 2-adrenergic agonists. cromolyn sodium (Intal). theophylline. and aerosol corticosteroids are all acceptable as first-line treatment. Addition of a second. third. or fourth medication again depends on individual response and physician choice. Patients with asthma need to be educated regarding the nature of the disease and its almost total unpredictability. Equally important is a frequent review of medications and a willingness to alter regimens as situations require.
Patterns of rates of mortality from narcotics and cocaine overdose in Texas, 1976-87, Drug overdose mortality data for narcotics and cocaine for Texas for 1976-87 reveal a cyclic pattern of narcotics mortality falling from 0.92 per 100.000 population in 1976 to a low of 0.13 in 1979. and rising to 0.62 in 1986. The data also show a sharp increase in cocaine mortality from 0.07 per 100.000 in 1983 to 0.38 in 1987. The data indicate that men consistently are at higher risk than women for overdose from both categories of drugs. Hispanics in the El Paso and San Antonio areas were found to have much higher risk of mortality from narcotics than expected. while blacks in the Houston and Dallas areas were at higher risk of cocaine mortality. The evidence suggests that narcotics and cocaine mortality is highest among the blue collar categories of the work force. The cyclical pattern of drug overdose mortality suggests the need for more examination of the historical interplay of public policies and social factors against the magnitude of the drug problems. The differences in mortality patterns by sex. ethnicity. and location indicate the need to develop policies and programs that address the unique characteristics of different at-risk populations.
Providing cost efficient detoxification services to alcoholic patients, The literature was reviewed to determine whether social model detoxification programs are safe and adequate for treating persons with alcohol withdrawal symptoms. The alcohol withdrawal syndrome has three stages. Each stage. more severe than the last. is reached by a smaller percentage of those withdrawing from alcohol. The literature showed that the majority of alcoholics can be detoxified safely in social model programs. These programs presented two main benefits. program cost efficiency and the patients' increased commitment to treatment compared with those treated at medical model programs. Medically operated detoxification programs appeared necessary for patients with a severe withdrawal condition at intake (abnormal blood pressure and pulse) and those with a history of severe withdrawal symptomatology. The results of the review reiterated the importance of screening clients at intake to ensure the safety of the patient and the appropriateness of the detoxification program.
Health practice correlates in three adult age groups: results from two community surveys, Independently done surveys of a target population can make an important contribution to knowledge about the determinants of personal health behavior by highlighting variables that consistently emerge as significant predictors. This investigation examined the correlates of four health practice and knowledge indices related to cardiovascular disease (CVD) in two baseline community surveys of the Pawtucket Heart Health Program (N = 2.413; N = 2.808). An additional dimension was the use of three adult age groups (18-29. 30-49. 50-64) in conducting the analyses. Results of both surveys showed that sex was the strongest correlate of the four indices--knowledge of CVD. encouraging health practice changes in others. dietary intake. and exercise. The four indices related to CVD were also associated with years of education. primary language. and whether or not a recent cholesterol measurement had been obtained. although these relationships were not as consistent as the results for sex. Overall. about half of each survey's significant associations were also found in the other survey (survey 1. 30 of 62; survey 2. 30 of 56). Consistency of significant results between surveys was best for the group ages 30-49. In either survey. it was rare for an association between a predictor and behavioral index to appear in each of the three age groups. This study supports the importance of the subjects' sex in research on personal health practices. suggests the potential for independence even among health-related indices pertinent to a single type of illness. and emphasizes the usefulness of utilizing independent samples to identify important correlates of health behavior.
Sanitary product use by white, black, and Mexican American women, In 1988-89. the use of menstrual sanitary products was surveyed among 699 white. 477 black. and 425 Mexican American women to detect age and racial or ethnic differences in product use that might explain the differences in the incidence of toxic shock syndrome (TSS) in these demographic categories. Forty percent of the women had never used tampons. Significantly more whites used tampons alone (26 percent) or with pads (36 percent) than did blacks. Proportionately more blacks used tampons alone (16 percent) or with pads (27 percent) compared with Mexican Americans. 11 percent of whom used tampons alone and 21 percent of whom used tampons and pads. Since a substantial proportion of black women used tampons. racial-ethnic variations in use patterns alone cannot completely explain the low incidence of TSS among black women. Tampon use started in the early teen years. but women in the age group 20-29 had the highest frequency of use of tampons either alone (26 percent) or with pads (33 percent). These percentages suggest that age-related differences in product use may not explain the age-related differences in the incidence of TSS. Fear was the most common specific reason for not using tampons in response to information about TSS. Decreased use of tampons in response to information about TSS was reported by 39 percent of whites. 50 percent of blacks. 46 percent of Mexican Americans. and by 36 percent of women less than 19 years. 41 percent of 20-29-year-olds. and 47 percent of women 30 years and older.
AIDS-related knowledge, attitudes, and precautionary behaviors among emergency medical professionals, AIDS-related knowledge. attitudes. and precautionary behaviors were assessed among a random sample of Michigan-licensed emergency medical service (EMS) professionals between June and August 1988. Of 2.000 mailed questionnaires. 1.020 were returned (51 percent response). and 997 of the returned questionnaires were used in the final analysis. Survey results indicated that most respondents were able to correctly identify the transmission routes of the human immunodeficiency virus (HIV). but many respondents had misconceptions about nonviable routes. the incidence of HIV infection among health care workers. and some aspects of the natural history of HIV. More than half of the respondents (56.6 percent) believed that their chances of becoming infected with HIV were "somewhat high" or "very high." although the number of documented HIV seroconversions due to occupational HIV exposures in health care settings is low. Although only six respondents (0.6 percent) reported that they had refused treatment to patients known or suspected to be infected with HIV. 25 percent felt that EMS professionals should be allowed to refuse treatment under such circumstances. Potential exposures to HIV were assessed through respondents' reports of three activities in the 6 months prior to the survey. For each activity. use of universal precautions recommended by the Centers for Disease Control was also assessed. In general. few respondents reported the consistent use of precautions. While the majority of those attempting resuscitations (86.9 percent) reported that they always use a protective device. only 36.7 percent of those treating bleeding patients reported that they always wear gloves. and only 21.9 percent of those using needles reported that they do not recap them after use.
Drug users' AIDS-related knowledge, attitudes, and behaviors before and after AIDS education sessions, The investigators interviewed 100 drug users in a detoxification facility before and after they received information about acquired immunodeficiency syndrome (AIDS) and human immunodeficiency virus (HIV). The drug users already had a considerable amount of information about AIDS and HIV transmission modes before they received the information. However. 79 percent of them reported never having used condoms. Fifty percent of intravenous drug users acknowledged having shared needles during the previous year. Subjects exhibited psychological denial in appraising the riskiness of their personal sexual and needle-sharing behaviors. which they rated as less risky than those activities in general. Following their participation in an AIDS and HIV education program. their knowledge concerning modes of transmission and disease progression increased. Subjects became more aware of their personal risk for HIV infection. and their faith in condom effectiveness and their intent to use them increased. Intravenous drug users reported increased determination to stop their drug use. The results suggest that AIDS education efforts can be useful in programs to help prevent HIV transmission among drug users.
Cognitive laboratory approach to designing questionnaires for surveys of the elderly, Data from surveys of the elderly are used by policy analysts to design health services programs. Consequently. the quality of survey data on elderly respondents has important implications for this growing segment of society: improving the quality of data should result in more cost effective programs for the elderly. However. studies suggest that the quality of responses from the elderly may be less than that for other respondents. Moreover. the increasing needs of policy analysts and health researchers for data have resulted in more complex survey questions that place a high cognitive burden on respondents. New methods for improving the design of these questionnaires are needed. This project investigated whether new techniques of questionnaire design. adapted from the theories and methods of cognitive psychology. could be effectively used in interviewing older respondents. The techniques used in this study. concurrent think-aloud interviews with followup probe questions. have been shown recently to be effective with younger respondents. Problems that elderly respondents have in comprehending survey questions. retrieving relevant information from memory. and using decision processes to estimate and provide answers were investigated. Questions on functional ability and social support were taken from the 1984 Supplement on Aging to the National Health Interview Survey. Analysis of respondents' think-aloud protocols and responses to probes suggest that the cognitive interview procedures were effective in identifying problems with the survey questions that would result in data of poorer quality and in suggesting the wording of questions that would be likely to result in answers of greater validity and reliability. Implications of these results for survey design and validation studies are discussed.
Dental decay rates among children of migrant workers in Yakima, WA, The literature documents a significant decline in the prevalence of dental caries among children. Unfortunately. dental decay rates of children of migrant workers remain high. This study collected data from 885 migrant children in central Washington. This community is in the west coast migrant stream. The area is served by a health center funded through the community and migrant health center program. There is an active dental program provided through the health center. The children were found to have a high rate of dental decay. However. there was a high rate of treatment of this decay and a rate of sealants (a preventive measure) nearly three times the rate in the general population. Although dental decay remains a serious problem in the migrant community. the migrant health centers appear to be making a positive impact on the dental health of the children.
Prenatal care comparisons among privately insured, uninsured, and Medicaid-enrolled women, Women without health insurance and those covered by Medicaid have been shown to obtain prenatal care later in pregnancy and make fewer visits for care than do women with private insurance. Factors that keep women from obtaining care include inadequate maternity care resources. difficulty in securing financial coverage. and the psychosocial issues of pregnancy. This study identified and compared prenatal care use patterns. insurance coverage changes. and psychosocial factors among 149 women in Minneapolis. MN. with private health insurance. Medicaid. and no health insurance. Little information has been available on the insurance status of women at the start of pregnancy and the paths subsequently taken to obtain financial coverage for prenatal care.
Renal cancer and cigarette smoking in a 26-year followup of U.S. veterans, The cigarette smoking habits of a cohort of almost 250.000 U. S. veterans were analyzed for their relationship to renal cancer. Information on smoking habits was collected in 1954 and in 1957 for nonrespondents to the first effort. Of the veterans. 84 percent returned their questionnaires. The cohort was followed for mortality until 1980. or 26 years. The followup of these military veterans. mostly of World War I. revealed 719 deaths from renal cancer. making this the largest study of renal cancer and cigarette smoking to date. Current smokers had a 47 percent increase in risk relative to nonsmokers. The relative risk for renal cancer increased significantly with the number of cigarettes smoked per day. from 1.31 for 1-9. 1.37 for 10-20. 1.60 for 21-39. and 2.06 for 40 or more. This analysis was unable to separate the risks of cigarette smoking for tumors of the renal parenchyma from those for tumors of the renal pelvis and ureter. However. the results suggest that almost one-fifth of all renal cancer deaths are attributable to cigarette smoking.
Lipid results of partial ileal bypass in patients with heterozygous, type II-A hyperlipoproteinemia. Program on the Surgical Control of the Hyperlipidemias, Although reduction in total plasma cholesterol has yet to be shown to have a beneficial effect on overall mortality. the weight of experimental and epidemiologic evidence supports efforts to lower total plasma cholesterol levels to reduce the risk of death from coronary heart disease (CHD). This is especially true in patients with heterozygous. type II-A hyperlipoproteinemia. whose total plasma cholesterol levels above the 90th percentile for age and sex place them at markedly increased risk of death from CHD. The lipid results of partial ileal bypass (PIB) were assessed in 110 patients with heterozygous. type II-A hyperlipoproteinemia in the Program on the Surgical Control of the Hyperlipidemias. a randomized. prospective clinical trial assessing the effects of cholesterol reduction on overall mortality and the course of CHD. Compared with dietary control (n = 52). PIB (n = 58) reduced total plasma cholesterol levels 24% +/- 2% (mean +/- SEM). reduced low-density lipoprotein (LDL) cholesterol levels 34% +/- 3%. and increased high-density lipoprotein (HDL) cholesterol levels 5% +/- 5% 5 years after surgery. Very low-density lipoprotein cholesterol levels were 28% +/- 21% higher and plasma triglyceride levels were 24% +/- 11% higher in the surgical group. The HDL cholesterol/total plasma cholesterol and HDL cholesterol/LDL cholesterol ratios were significantly higher after PIB. Apolipoprotein A-I and HDL subfraction 2 levels were significantly higher and apolipoprotein B-100 levels were significantly lower in the surgical group. PIB successfully lowered mean total plasma cholesterol and LDL cholesterol levels below the limits recommended by the National Cholesterol Education Program to minimize the risk of death from CHD. These results confirm the efficacy and support the role of PIB in the management of patients with marked hypercholesterolemia.
Comparison of almitrine bismesylate and medroxyprogesterone acetate on oxygenation during wakefulness and sleep in patients with chronic obstructive lung disease, The effects of almitrine bismesylate and medroxyprogesterone acetate on oxygenation during wakefulness and sleep were compared in six patients with chronic obstructive lung disease and carbon dioxide retention. Patients received 1.5 mg/kg almitrine (a peripheral chemoreceptor stimulant). 100 mg of medroxyprogesterone (a central respiratory stimulant). or matched placebo daily for 15 days in random order in a crossover trial. When subjects were awake almitrine increased the ventilatory response to hypoxia and increased arterial oxygen tension (PaO2) to a greater extent than medroxyprogesterone. whereas medroxyprogesterone augmented the ventilatory response to hypercapnia and decreased arterial carbon dioxide tension (PaCO2) to a greater extent than almitrine. Neither drug influenced sleep architecture significantly. except that medroxyprogesterone increased the number of arousals. Almitrine had a more favourable effect than placebo on oxygenation as estimated from arterial oxygen saturation (SaO2) during the different stages of sleep. the number of episodes of hypoxaemia. and the amount of time that SaO2 was below 80%. The only change with medroxyprogesterone by comparison with placebo was a decrease in the number of hypoxaemic episodes. It is concluded that both active drugs improved blood gases during wakefulness. but that 1.5 mg/kg of almitrine is superior to 100 mg of medroxyprogesterone in improving SaO2 during sleep.
Failure to detect evidence of human immunodeficiency virus type 1 (HIV-1) infection by polymerase chain reaction assay in blood donors with isolated core antibodies (anti-p24 or -p17) to HIV-1, Individuals with isolated and persistent core antibodies (anti-p24 or -p17) to HIV-1 are sometimes diagnosed through the systematic screening of blood donations. The significance of such serum reactivities remains unknown. Polymerase chain reaction (PCR) is a new technique allowing the direct detection of HIV-1 DNA in blood samples. In this study. PCR was used to detect HIV-1 DNA in 20 individuals with isolated and persistent core antibodies (14 anti-p24 and 6 -p17). in seven sexual partners of these individuals. in 55 HIV-1-seropositive individuals (positive controls). and in 105 HIV-1-seronegative blood donors at low risk of HIV-1 infection (negative controls). No HIV-1 DNA was detected in individuals with isolated and persistent core antibodies. in their sexual partners. or in negative control individuals. although PCR was positive in 54 of 55 seropositive control individuals. These results strongly suggest that individuals with isolated and persistent core antibodies are not infected with HIV-1.
Experience with a transfusion recipient education program about hepatitis C, Shortly after test kits for antibodies to the hepatitis C virus (HCV) were licensed in May of 1990. our medical community undertook a public education program encouraging previous transfusion recipients to see their physicians about the wisdom of being tested for anti-HCV. In response. 1034 samples were received for testing. All samples repeatably reactive (RR) with anti-HCV enzyme-linked immunoassay (EIA) were tested further with a research recombinant immunoblot assay (RIBA). Overall. 76 of the 1034 (7.4%) recipient samples were RR and 64 of these (84.2%) were reactive with RIBA. Recipients transfused prior to surrogate testing (alanine aminotransferase [ALT] and anti-hepatitis B core [anti-HBc]) in 1986 showed a 8.6 percent reactivity with RIBA and those transfused after surrogate testing showed a 4.8 percent reactivity. a 44 percent reduction. Of the 57 recipient samples reactive with RIBA and suitable for assay. 11 (19.3%) had an elevated ALT. Among 76 randomly selected blood donors with RR EIAs studied for comparison with recipients. 20 (26.3%) were reactive with RIBA. 9 of which had an abnormal surrogate test that would have disqualified them. ALT concentrations were abnormal in 6 (30%) of the donors who were reactive on RIBA. We conclude that an education program that encourages previous transfusion recipients to seek medical advice about anti-HCV testing is practical from the standpoint of the blood center. We believe more widespread implementation of similar programs should be considered.
Statistical considerations in cancer screening programs, The goal of cancer screening is the early detection and treatment of disease. with a consequent reduction in the mortality rate. Evaluation of whether a particular screening program can achieve this goal is a difficult task. Two components of the screening process must be assessed. The first is the ability of the screening test to detect cancer early while minimizing the number of false-positive results. In this regard. the specificity of the test ordinarily must be very high. approaching 99%. No screening test for prostate cancer has yet been reported to have a specificity this high. indicating that any prostate cancer screening program using currently available tests will have to deal with the problem of a large number of false-positive findings. To evaluate the overall impact of a screening program. the best procedure is the randomized controlled trial with cancer-specific mortality as the endpoint. This endpoint is used because it avoids the lead time and length biases inherent in other outcome variables such as stage shift and case survival. The screening randomized controlled trial must be carefully planned and implemented. because it is lengthier and more costly than the usual therapy trial because of differences in study populations. trial design relative to the planned population intervention. and the extent of knowledge of disease natural history. A further important component of screening evaluation is cost. The decision to implement or continue a screening program can be aided by using cost-effectiveness analysis. which bases a decision on the ranking of cost-to-benefit ratios for the various programs contending for limited funds. Screening cost includes the cost of the test. the cost of side effects of the test. and the costs of biopsy and treatment. while screening benefit can be measured in terms of lives saved. life years saved. or quality-adjusted life years.
Detection of malignant bone tumors: MR imaging vs scintigraphy, One hundred six patients with a known or suspected diagnosis of bone cancer (11 patients with biopsy-proved primary tumors. 95 patients with metastatic disease) were evaluated with scintigraphy and MR imaging to determine the relative sensitivity of each technique in the detection of bone disease. MR imaging was performed at 0.5 T as part of the entry evaluation into Intramural Research Board protocols (30%). for evaluation of cord compression. or because of an equivocal scintigram. MR was performed with T1-weighted (e.g.. 300-500/10-20 [TR/TE]). T2-weighted (e.g.. 2000/80) spin-echo (SE). and a short-TI inversion recovery (STIR) pulse sequence. Scintigrams were performed with 99mTc-methylene diphosphonate. A retrospective analysis showed that in 30 (28%) of 106 patients. MR imaging performed over a limited region of interest revealed a focal abnormality consistent with tumor that was not observed on scintigraphy. Only one patient had an abnormality on scintigraphy. caused by a metastasis. that was not found on MR images. In 73 (69%) of the 106 patients. the results of MR imaging and scintigraphy were equivalent; in 41 cases results of both techniques were normal. A McNemar analysis of the discordant cases showed MR imaging to be more sensitive than scintigraphy was (p less than .001). Our results suggest that although MR imaging has a greater sensitivity in detecting focal disease. scintigraphy is still the most useful screening test for evaluating the entire skeleton. MR imaging should be reserved for clarification of scintigraphic findings when suspicion is high for tumor.
Osteochondral impaction of the femoral head associated with hip dislocation: CT study in 35 patients, Chondral and osteochondral impactions are insults to articular cartilage and subchondral bone of the femoral head during hip dislocation. To evaluate the frequency and sites of femoral head impaction. we reviewed CT scans of 35 patients with hip dislocation (32 posterior and three anterior). Osteochondral impaction fractures were present in 20 (63%) of the 32 patients with posterior hip dislocation and in all three patients with anterior dislocation. In patients with posterior dislocation. the impaction occurred anteriorly in an arc between the 11-o'clock and 1-o'clock positions in all seven cases (100%) of right-sided dislocation and in eight (61%) of 13 cases of left-sided dislocation. Twelve (60%) of the 20 patients with femoral head impaction fracture underwent surgery; osteochondral impaction was substantiated in all 12. In those with anterior dislocation. osteochondral impaction occurred at the posterolateral aspect of the femoral head in an arc between the 4-o'clock and 5-o'clock positions. A high rate of osteochondral impaction after hip dislocation was detected in this series. Observing the site of femoral head impaction allows determination of the type of original dislocation. Alternatively. when the type of original dislocation is known. the site of femoral head impaction can be predicted.
Determination of the extent of lower-extremity peripheral arterial disease with color-assisted duplex sonography: comparison with angiography, Color-assisted duplex sonography combines color Doppler flow imaging with duplex sonography to rapidly survey the vasculature. Color Doppler sonography displays the motion of flowing blood on a sonogram and is used to visualize directly arterial lumen narrowing of greater than 50%. Absence of Doppler signals signifies arterial occlusion. Preangiographic triage of patients for surgical or interventional therapy requires that a rapid and accurate survey be performed of the extent of arterial disease. Color-assisted duplex sonography was applied prospectively in 17 consecutive patients with the clinical diagnosis of peripheral arterial disease who had not previously undergone angiography. Results of angiography of the femoropopliteal arteries were graded and localized in one of seven approximately equal arterial segments. These were compared with similar segmental maps made with sonography. For the detection of stenosis or occlusion in any of the 238 segments. the sensitivity was 0.88 (49/56). specificity 0.95 (173/182). and accuracy 0.93 (222/238). The average time taken to survey both limbs was 29 min. We conclude that color-assisted duplex sonography is an accurate and rapid tool for the noninvasive mapping of the extent of femoropopliteal arterial disease.
Fat-saturation MR imaging of the upper abdomen, The fat-saturation (fatsat) MR technique decreases the signal intensity of fat. thereby enhancing the definition of upper abdominal organs and reducing artifacts while maintaining the T1 and T2 information available on spin-echo sequences. To evaluate the potential of fatsat in examining the abdomen. we conducted a prospective study involving 30 subjects. including four normal volunteers. 18 patients investigated for liver disease. and eight patients studied for miscellaneous abdominal disease. Short TR. 300-600/15-20 (TR/TE). and long TR. 2000-2500/20-30. 70-80. spin-echo images with and without fatsat were compared. The images were evaluated both qualitatively and quantitatively. Qualitative assessment was made with receiver-operating-characteristic (ROC) curve analysis of the confidence level of observers to detect the presence of disease. comparing fatsat with standard spin-echo sequences. ROC analysis showed greater interpreter confidence and accuracy for fatsat sequences than for standard spin-echo sequences. The measured signal-difference-to-noise (SD/N) ratio comparing upper abdominal organs with surrounding tissue revealed the highest values for short TR/TE regular spin echo. followed by short TR/TE fatsat. The highest SD/N ratio for hepatic masses was with long TR/TE fatsat followed by short TR/TE fatsat. The results of this study suggest that the fatsat technique may improve abdominal MR imaging.
Spatial misregistration of vascular flow during MR imaging of the CNS: cause and clinical significance, Spatial misregistration of signal recovered from flowing spins within vascular structures is a common phenomenon seen in MR imaging of the CNS. The condition is displayed as a bright line or dot offset from the true anatomic location of the lumen of the imaged vessel. Its origin is the time delay between application of the phase- and frequency-encoding gradients used to locate spins within the plane of section. The principal condition necessary for the production of spatial misregistration is flow oblique to the axis of the phase-encoding gradient. Flow-related enhancement (entry slice phenomenon). even-echo rephasing. and gradient-moment nulling contribute to the production of the bright signal of spatial misregistration. Familiarity with the typical appearance of flow-dependent spatial misregistration permits confirmation of a vessel's patency; identification of the direction of flow; estimation of the velocity of flow; and differentiation of this flow artifact from atheromas. dissection. intraluminal clot. and artifacts such as chemical shift.
Malignant pleural mesothelioma: CT manifestations in 50 cases, Malignant pleural mesothelioma. a rare and usually fatal neoplasm that is associated with asbestos exposure. is being encountered with increasing frequency. Pretreatment CT findings from 50 patients with malignant pleural mesothelioma are illustrated. Pleural thickening was found in 46 (92%) of the 50 patients. thickening of the pleural surfaces of the interlobar fissures in 43 (86%). pleural calcifications in 10 (20%). and pleural effusions in 37 (74%). The volume of the involved hemithorax varied appreciably. Contractions of the involved hemithorax was noted in 21 (42%) of 50 patients and contralateral mediastinal shift in seven (14%). Disease beyond the parietal pleura was found in the chest wall (nine patients). mediastinum. lymph nodes. and diaphragm.
Mammography-guided stereotactic fine-needle aspiration cytology of nonpalpable breast lesions: prospective comparison with surgical biopsy results, We assessed the usefulness of fine-needle aspiration cytology (FNAC) in evaluating nonpalpable breast abnormalities by prospectively performing stereotactic mammography-guided FNAC on 100 women undergoing surgical excisional biopsy. Mammographic and cytologic diagnoses. on a scale of 1 (benign) to 4 (malignant). were assigned for each case and compared with the surgical pathologic diagnosis. Sensitivity and specificity were examined at different diagnostic cutoff points for regarding a mammographic or cytologic diagnosis as positive or negative. Of the 100 breast biopsy specimens. 70 were benign and 30 were malignant. For both mammography and FNAC. the optimal diagnostic cutoff point was between diagnosis 2 (mammography. probably benign; cytology. atypical) and 3 (mammography and cytology both suspicious for malignancy). At this cutoff point. FNAC had a sensitivity of 0.77 and specificity of 1.00. vs 0.73 sensitivity and 0.79 specificity for mammography. Pearson coefficient analysis revealed significant correlations between both mammographic and FNAC diagnoses and surgical pathology (p less than .001 for both). Our results suggest that use of mammography-guided FNAC may reduce the number of breast biopsies performed for benign lesions.
Obliteration of the fat surrounding the celiac axis and superior mesenteric artery is not a specific CT finding of carcinoma of the pancreas, Partial or complete obliteration of the fat surrounding the celiac axis and superior mesenteric artery on CT is considered so characteristic of pancreatic carcinoma that many consider it diagnostic. However. this finding may be present on CT scans of some treatable tumors. During a 2-year period. we retrospectively collected 10 cases of nonpancreatic tumors that obliterated the fat surrounding the celiac axis and/or superior mesenteric artery. Four patients had metastatic disease. three had lymphoma. two had primary small-bowel adenocarcinoma. and one had a diffuse retroperitoneal endocrine tumor. The scans were analyzed for presence. location. and morphology of the mass and biliary and/or pancreatic ductal dilatation. Of the patients with metastatic disease. three had focal. retropancreatic. periceliac masses without ductal dilatation. One had an infiltrative retroperitoneal process enveloping the pancreas and causing biliary dilatation. Of the patients with lymphoma. two had focal masses in the mesenteric root without ductal dilatation. and one had an infiltrative retroperitoneal process. Of the two patients with primary carcinoma of the small bowel. one had a mesenteric mass without ductal dilatation and the other had an infiltrative retroperitoneal process enveloping the pancreatic head and obstructing the ducts. The patient with the neuroendocrine tumor had an infiltrative retroperitoneal process enveloping the pancreas without ductal dilatation. Obliteration of the fat surrounding the celiac axis and superior mesenteric artery is not a specific CT finding of carcinoma of the pancreas. One cannot rely solely on its presence for the diagnosis of pancreatic carcinoma but should use other important findings such as a focal pancreatic mass and ductal dilatation.
Detection of pancreatic fluid and urine leakage after pancreas transplantation: value of CT and cystography, Leakage from the urinary bladder or duodenal stump after pancreas transplantation with urinary bladder drainage of the graft is difficult to diagnose clinically. We retrospectively reviewed our experience with fluoroscopic cystography and CT to determine their relative merit in the diagnosis of pancreatic fluid and urine leakage as documented by surgical exploration in pancreas transplant recipients. Thirteen leaks were diagnosed by fluoroscopic cystography or by CT in 11 patients after pancreas transplantation with urinary bladder drainage of pancreatic fluid. Conventional retrograde fluoroscopic cystography showed 11 leaks; CT with retrograde bladder opacification showed three leaks. Of the five CT studies that did not show a leak and that also were done within 7 days of a cystogram with abnormal findings. failure to use retrograde bladder opacification accounted for the majority (three cases) of missed diagnoses. Focal or free peritoneal abdominal fluid was seen in all CT examinations. with extravasation of contrast material seen into both walled-off collections and free ascites. Our experience suggests that retrograde bladder and duodenal stump opacification should be a routine part of the CT evaluation performed to detect leakage from the urinary bladder or duodenal stump after pancreas transplantation.
Myocardial infarct size reduction by the synergistic effect of hyperbaric oxygen and recombinant tissue plasminogen activator, Fasting mongrel dogs underwent hyperbaric oxygen treatment (HBOT). recombinant tissue plasminogen activator (rt-PA) treatment. and simultaneous HBOT and rt-PA treatment following prior experimental left anterior descending coronary artery occlusion for 2 hours. Thrombosis in and around a copper coil was recorded angiographically at regular intervals. and immediately prior to treatment conclusion. Controls (n = 10) were untreated. Group two animals (n = 10) were treated additionally with 90 minutes of HBOT at 2 atm absolute. Group three animals (n = 8) were treated additionally with 50 mg rt-PA over 90 minutes. Group four animals (n = 10) were treated additionally with simultaneous HBOT and rt-PA over 90 minutes. Myocardial injury was determined by a combination of triphenyltetrazolium chloride histochemical staining and by formazan dye extraction. Damage was measured as a percent of left ventricular cross-sectional area studied. HBOT alone restored 35.9% of oxidative enzyme activity (p greater than 0.001). Treatment with rt-PA alone restored 48.9% of enzyme activity (p greater than 0.001). The combination of HBOT and simultaneous rt-PA resulted in 96.9% restoration of oxidative enzyme activity versus the control group (p greater than 0.001).
Delayed decline in plasma atrial natriuretic peptide levels after an abrupt reduction in atrial pressures: observation in patients with dual-chamber pacing, The effect of an abrupt reduction in atrial pressures on atrial natriuretic peptide (ANP) secretion was studied in four patients with complete atrioventricular block with a dual-chamber pacemaker when the pacing mode was changed from the VVI to the DVI mode at an equal rate of 70/min. Simultaneous continuous hemodynamic monitoring was performed using a balloon-tipped thermodilution catheter. With DVI pacing. there was an immediate decrease of right atrial pressure from 4.5 +/- 0.9 to 1.8 +/- 1.1 mm Hg. and a reduction of pulmonary arterial wedge pressure from 7 +/- 0.8 to 4.5 +/- 0.9 mm Hg. together with a rise in cardiac output from 3.1 +/- 0.2 to 3.7 +/- 0.2 L/min. However. despite a constant hemodynamic status after dual-chamber pacing. the arterial ANP level steadily decreased from 151 +/- 26 pg/ml to a steady low level of 78 +/- 15 pg/ml after 20 minutes of dual-chamber pacing (percentage reduction- 48 +/- 8%. p less than 0.05). This persisted until the end of the study at 60 minutes. The time-dependent decay in ANP secretion after an abrupt and constant change in hemodynamic status should be considered when interpreting ANP levels.
Expression of natriuretic peptide in ventricular myocardium of failing human hearts and its correlation with the severity of clinical and hemodynamic impairment, Atrial natriuretic peptide (ANP) was immunohistochemically investigated in (1) right ventricular endomyocardial biopsy specimens from 87 apparently healthy donor hearts taken from victims of cerebral accidents; (2) 1 normal heart not suitable for transplantation (HBsAg carrier); (3) right ventricular endomyocardial biopsy specimens from 151 patients with dilated cardiomyopathy (DC); and (4) 57 explanted hearts. 26 with DC and 31 with ischemic heart disease. No ANP immunoreactivity was found in normal ventricles. Failing hearts showed ventricular positivity in 31% of the DC biopsy series. in 61% of the left ventricles. and in 30% of the right ventricles of the explanted heart series. An endoepicardial gradient was observed. because ANP positivity was greater and more extensive in the subendocardial layers. Ultrastructural studies were performed on biopsy specimens from 10 normal hearts and 132 DC biopsy samples. No ANP-storing granules were found in biopsy samples of normal ventricles. whereas ANP granules were seen in 15 of 132 (11.4%) DC cases. In parallel immunoblotting. investigation showed the same 13 kDa band protein in 1 normal atrium as well as in 8 failing atria and ventricles. ANP immunoreactivity was positively correlated with higher New York Heart Association functional classes as well as with higher left ventricular end-diastolic pressure (p less than 0.005). end-diastolic volume (p less than 0.005) and end-diastolic volume index (p less than 0.005). In conclusion. apparently healthy ventricles do not show ANP immunoreactivity. whereas failing ventricles do. ANP expression seems to be independent of the underlying disease. but positively related to the clinical status and the degree of left ventricular impairment and dilatation.
Thrombolytic therapy for myocardial infarction: assessment of efficacy by myocardial perfusion imaging with technetium-99m sestamibi, Technetium-99m (Tc-99m) sestamibi has been used to evaluate the efficacy of thrombolytic therapy. Improved image quality due to the higher photon energy of Tc-99m and the increased allowable doses of this radiopharmaceutical along with its lack of redistribution makes Tc-99m sestamibi an acceptable imaging agent for such studies. This imaging agent was used for serial quantitative planar and tomographic imaging to assess the initial risk area of infarction. its change over time and the relation to infarct-related artery patency in patients with a first acute myocardial infarction. Twenty-three of 30 patients were treated with recombinant tissue-type plasminogen activator (rt-PA) within 4 hours after onset of acute chest pain. Seven patients were treated in the conventional manner and did not receive thrombolytic therapy. The initial area at risk varied greatly both in patients treated with rt-PA and in those who received conventional therapy. Patients with successful thrombolysis and patient infarct arteries had a significantly greater reduction of Tc-99m sestamibi defect size than patients who had persistent coronary occlusion. Serial imaging with Tc-99m sestamibi could find important application in future clinical research evaluating the efficacy of new thrombolytic agents. Direct measurements of the amount of hypoperfused myocardium before and after thrombolysis could provide rapid and unequivocal results using fewer patients and avoiding the use of "mortality" as an end point. This approach has not yet been widely tested in the clinical arena.
Genotypic and immunophenotypic characterization of two human light chain-only B-cell non-Hodgkin's lymphomas, Two atypical human non-Hodgkin's lymphomas (NHLs) that exhibited unusual genotypic and in situ immunophenotypic abnormalities are described. Immunophenotypically. both NHLs lacked surface Ig heavy chains. With the exception of the MB2 B-cell-associated antigen. no B- and T-cell differentiation antigen was detected in case 1. NHL 2 failed to show evidence of clonality by immunohistochemical analysis but revealed the presence of many B-lymphocytes with an abnormal phenotypic profile: CD19+. CD20+. CD22+. kappa-. lambda-. CD9-. CD10-. CD21-. and CD24-. Genotypic analysis indicated that both lymphomas derived from anomalously matured pre-B-cells that had rearranged the lambda or kappa light chain genes but not the Ig heavy chain gene. The neoplastic cells of the two NHLs resemble the light chain-only B-cells recently discovered. following Epstein-Barr virus immortalization. in the human bone marrow. The authors' data confirm. therefore. the existence of the light chain-only B-cells in the human hematopoietic compartment. Moreover. their results emphasize the conclusive role of the immunogenotypic analysis in defining clonality. lineage. and maturation abnormalities of such atypical NHLs.
Health care policies/economics of the geriatric renal population, The end-stage renal disease (ESRD) program is the only Medicare program for which entitlement is based on the presence of a medical diagnosis. In addition. entitlement is nearly universal. Over 90% of persons with ESRD receive Medicare benefits. Because of these unique characteristics. the ESRD program has been the subject of continuing debates about the role of the Federal government in the categorical funding of high-cost illnesses. reimbursement policies. and the ethical issues of treatment of terminal. or near terminal. patients. This report presents descriptive data from the Medicare ESRD Program Management and Medical Information System (PMMIS) concerning trends in program expenditures. incidence and prevalence of ESRD. and mortality. The purpose is to provide background material for informed discussions of these issues. Expenditures for the ESRD program have grown from $240 million in 1974 to $3.3 billion in 1987. During that same time. total Medicare expenditures increased at a comparable rate so that ESRD costs have remained a relatively constant proportion of Medicare costs for the last decade. The ESRD population is rapidly changing. Between 1978 and 1987. enrollment nearly tripled. from 44.000 to 124.000. Much of this change has occurred in the elderly population. Persons over 65 accounted for 20% of total enrollment in 1978 and 29% of total enrollment in 1987. Census projections show that the "graying" of the ESRD population will continue into the foreseeable future. Transplantation has had a marked effect on the ESRD population. Persons with a functioning kidney graft have increased from 11% of the total population in 1978 to 22% in 1987.
Compound heterozygote for lipoprotein lipase deficiency: Ser----Thr244 and transition in 3' splice site of intron 2 (AG----AA) in the lipoprotein lipase gene, Cloning and sequencing of translated exons and intron-exon boundaries of the lipoprotein lipase gene in a patient of French descent who has the chylomicronemia syndrome revealed that he was a compound heterozygote for two nucleotide substitutions. One (TCC----ACC) leads to an amino acid substitution (Ser----Thr244). while the other alters the 3' splice site of intron 2 (AG----AA). The functional significance of the Thr244 amino acid substitution was established by in vitro expression in cultured mammalian cells.
Role of vasopressin in mediation of fetal cardiovascular responses to acute hypoxia, The present study was designed to test the hypothesis that arginine vasopressin mediates the fetal cardiovascular response to acute hypoxia. Chronically catheterized sheep fetuses at 126 to 138 days' gestation were infused with either an arginine vasopressin pressor antagonist (n = 8) or saline solution as control (n = 8). A 30-minute hypoxia was induced by infusion of nitrogen containing 5% carbon dioxide into the maternal trachea. Fetal arterial PO2 decreased 13.1 +/- 1.3 (SE) mm Hg from a basal value of 23.8 +/- 1.5 mm Hg and there was no significant difference in the degree of hypoxia between the two groups. Fetal arterial and venous pressures increased significantly. whereas the blood volume decreased. but these changes were similar between the control and arginine vasopressin-blocked fetuses. Heart rate fell similarly in both groups during hypoxia by an average of 35 beats/min. At the termination of hypoxia. heart rate in the blocked group rebounded to levels significantly above baseline and remained elevated for 30 minutes. whereas heart rate in the control group returned slowly to basal values. Recovery of arterial pressure. venous pressure. and blood volume were similar in the two groups. Thus it appears that arginine vasopressin may mediate in part the fetal heart rate response to acute hypoxia. However. the blood volume. arterial pressure. and venous pressure responses to hypoxia appear to be induced by factors other than arginine vasopressin.
Effects of magnesium and isradipine on contractile activation induced by the thromboxane A2 analog U46619 in human uteroplacental arteries in term pregnancy, The effects of Mg++ and the dihydropyridine calcium channel blocker isradipine on contractions induced by the thromboxane A2 mimetic U46619 were studied in isolated human uteroplacental arteries. In all preparations investigated U46619 10(-10) to 10(-6) mol/L induced concentration-related contractile responses. In maternal vessels U46619 produced a biphasic concentration-response curve. whereas the compound in fetal vessels produced a sigmoid concentration-response curve parallel to that of prostaglandin F2 alpha. Mg++ (1.0 to 6.0 mmol/L) and isradipine (10(-10) to 10(-5) mol/L) both relaxed U46619-induced contractions by up to about 40%. In preparations precontracted by U46619 and exposed to isradipine 10(-6) mol/L. addition of Mg++ 6.0 mmol/L consistently produced a further small relaxation. Removal of the endothelium or pretreatment with indomethacin 10(-6) mol/L or digoxin 10(-6) mol/L did not influence the inhibition produced by Mg++ or isradipine. In vessels pretreated in Ca(++)-free medium Mg++ 6.0 mmol/L depressed and isradipine abolished responses to Ca++ (0.01 to 4.0 mmol/L) after depolarization with K+ 124 mmol/L. In maternal and fetal arteries stimulated with U46619. however. Mg++ 6.0 mmol/L and isradipine 10(-6) mol/L produced a similar. partial inhibition of responses to Ca++ (0.01 to 4.0 mmol/L). Mg++ seems to inhibit transmembrane Ca++ influx. although less efficiently than the dihydropyridine calcium antagonist isradipine. In addition. Mg++ may interfere with Ca++ at intracellular binding sites. Provided that preeclampsia comprises enhanced vascular actions of thromboxane A2. the present results support the established use of Mg++ in the treatment of this condition and suggest that calcium antagonists are of potential benefit.
Immunohistologic assessment of cytokine production of infiltrating cells in various forms of leprosy, The aim of this study was to determine cytokines in human leprosy lesions by means of immunohistologic examination. Cryostat sections of skin biopsies from 57 patients with various forms of leprosy were immunostained according to the APAAP method. using monoclonal antibodies against interleukin-1 beta (IL-1 beta). tumor necrosis factor-alpha (TNF-alpha). interferon-gamma (IFN-gamma). and. in addition. against CD 1 antigen. Granulomas in biopsies of untreated patients with tuberculoid leprosy showed large amounts of cells positive for IL-1 beta. TNF-alpha. IFN-gamma. and CD 1. whereas no positive signals could be detected in untreated patients with lepromatous leprosy. However. in those biopsies obtained from lepromatous leprosy patients undergoing chemotherapy. positive staining for cytokines as well as subepidermal Langerhans cells increased to a detectable amount. Remarkably. in tuberculoid leprosy patients. the number of IL-1 beta--positive cells did not vary under therapy. while the number of TNF-alpha and IFN-gamma reactive cells decreased. These results suggest that immunohistologic determination of cytokines in combination with the assessment of subepidermal Langerhans cells in human leprosy lesions may be used as a parameter for the patient's status of cell-mediated immunity under chemotherapeutic treatment.
T-lymphocyte effects on murine cytomegalovirus pulmonary infection, Cytomegalovirus (CMV) infections were induced in male BALB/c mice treated with rat monoclonal antibodies (MAb) to deplete selectively CD8 and CD4 cell populations in vivo. The animals were then inoculated intraperitoneally with murine CMV and the infection was monitored virologically and histologically. High concentrations of virus were found in the lungs of mice depleted of CD4 or both CD4 and CD8 cells. These animals developed pulmonary infections that persisted for at least 49 days after inoculation. In contrast. immunologically intact mice and those administered anti-CD8 MAb experienced only a transient infection of the lungs. Focal interstitial infiltrates of mononuclear cells were demonstrated in pulmonary tissues of CD4 MAb-treated animals. but not in normal mice and those receiving the CD8 MAb. Adoptive transfer of CD4 cells to animals (rendered immune-incompetent by thymectomy and irradiation) protected against pulmonary infection and the development of interstitial pneumonia. Mice treated with CD4 MAb failed to produce specific CMV antibody. whereas the depletion of CD8 cells had no effect on antibody elaboration. Administration of anti-CD4 and CD8 MAb did not affect virus replication in the salivary glands. the preferential site for CMV infection in the mouse. Induction of pulmonary infection and interstitial pneumonia by CMV in BALB/c mice is mediated by CD4 T cells.
Detection of immunoglobulin light-chain mRNA in lymphoid tissues using a practical in situ hybridization method, The identification of immunoglobulin protein in routinely fixed and paraffin-embedded sections using antibodies combined with immunoperoxidase or similar techniques of detection is often problematic. We developed an in situ hybridization methodology for the identification of light-chain mRNA that is applicable to formalin-fixed. paraffin-embedded tissues. using either radiolabeled or biotinylated oligonucleotide probes based on the kappa and lambda light-chain gene-constant regions. Reactive plasma cells can be consistently identified in reactive lymphoid tissues. and a monotypic pattern of light-chain mRNA restriction was seen in each of eight cases of multiple myeloma/plasmacytoma. Immunoblasts and germinal center cells also are labeled in reactive lymphoid tissues. Using 355-labeled probes. 29 of 93 cases (30%) of non-Hodgkin's lymphomas had detectable light-chain mRNA. while 19% of non-Hodgkin's lymphomas were positive using biotinylated probes.
Relation of psychopathology in general medical inpatients to use and cost of services, The authors investigated the relation between psychopathology in medically ill inpatients and use and cost of medical care services. Of 455 medical inpatients. the Medical Inpatient Screening Test identified 27.9% as very depressed. 27.5% as very anxious. 20.2% as having cognitive dysfunction. and 8.6% as having high pain levels. Overall. the test identified 51% of the patients as having high levels of psychopathology or pain. These subjects had a 40% longer median length of hospital stay and 35% greater mean hospital costs than those with low levels of psychopathology or pain. Patients with greater psychopathology also had higher hospital charges. more procedures during hospitalization. and more discharge diagnoses but did not differ from the other patients in sex. race. age. diagnosis-related group (DRG) major diagnostic category. or DRG weight.
Enhanced platelet adherence and aggregation in Chagas' disease: a potential pathogenic mechanism for cardiomyopathy, Spasm and thrombosis of the coronary microcirculation has been implicated in the pathogenesis of the cardiomyopathy of Chagas' disease. We demonstrate that increases in platelet adherence and aggregation accompany Trypanosoma cruzi infection and may contribute to the observed microvascular pathology. Scanning electron microscopy and radiolabeled platelets studies revealed that platelet adherence to T. cruzi-infected human endothelial cells was significantly increased when compared to controls (P = 0.024). In in vitro experiments. we determined the influence of infection on prostacyclin production. a marker of endothelial cell perturbation. The basal levels of 6-keto-prostaglandin F1 alpha was significantly greater in the supernatant of infected endothelial cells than in those of uninfected endothelial cells (P less than 0.05). The influence of infection was assessed on platelet aggregation at days 5 and 12 post-infection in A/J mice. Platelets from T. cruzi-infected mice were 2-6-fold more sensitive to aggregation induced by adenosine diphosphate and sodium arachidonate than controls. Thromboxane B2 levels in the plasma of infected mice were greater than controls. These data support the hypothesis that heightened platelet reactivity and endothelial cell dysfunction are associated with acute Chagas' disease and may cause coronary microvascular spasm and/or occlusion.
Multi-laboratory evaluation of a scrub typhus diagnostic kit, Scrub typhus is a major cause of febrile illness throughout the Asia-Pacific region. It is commonly undiagnosed. partly because of the lack of a simple. reliable diagnostic test which can be used in clinical laboratories. The indirect immunoperoxidase technique. configured into a test kit. was provided to technicians who were trained in its use. They used the kit during a 2 year field trial in their respective clinical hospital laboratories throughout Malaysia. In an evaluation using 1.722 consecutive sera tested in those laboratories. the kit was found to have a median sensitivity for IgG detection of 0.85 (range 0.33-0.95). a median specificity of 0.94 (range 0.88-1.00). reproducibility of 0.86. and efficiency of 0.92 when compared to the reference laboratory. In a proficiency survey in which 10 laboratories received 3 coded test samples. all but 2 laboratories had results within 1 dilution of the reference laboratory in quantitating specific IgG. whereas 7 laboratories were within 1 dilution in quantitating IgM. The shelf life of the kit was at least 1 year at 4 degrees C.
Simultaneous measurement of all thrombosis parameters from native human blood: usefulness in monitoring efficacy and complications of thrombolytic therapy, The sequelae of thrombus formation. both by shear forces and by collagen fiber. the subsequent coagulation. and the dislodgement of thrombi (thrombolysis) were measured from a small volume of nonanticoagulated blood sample. by a new instrument. Addition of streptokinase (SK) or tissue-type plasminogen activator (rt-PA) to the blood sample eliminated the need for anticoagulation for thrombolysis measurement: clot lysis preceded and allowed thrombolysis to occur. The test revealed activation of platelets and coagulation by SK and rt-PA. Apart from this general trend. platelet reactivity in response to plasminogen activator showed great individual variation. Whether the greatly enhanced (42%) or prolonged hemostasis (13%). observed in different blood samples with rt-PA. could be used as a predictor of reocclusion or bleeding complications remains to be established. Thrombolysis did not occur in 12% of the samples tested. These thrombolysis models may be useful for developing new agents for the dissolution of platelet-rich thrombi. It is suggested that this technique be used for monitoring thrombolytic therapy.
Use of i.v. radionuclide total body arteriography to evaluate arterial bypass shunts--a new method--a review of several cases, Currently. Doppler ultrasound and contrast angiography are the main imaging procedures being used to evaluate arterial bypass shunts. IV radionuclide total body arteriography (TBA) is another useful imaging procedure for evaluation of bypass shunts. The authors reviewed 33 patients. 19 women and 14 men. ranging in age from forty-three to eighty-five. who had TBA done after arterial bypass surgery. Ten patients had multiple shunts and 5 had multiple follow-up studies. In total there were 80 shunts. including 43 femoropopliteal. 16 axillofemoral. 1 axillopopliteal. 13 crossover femorofemoral. and 7 aortofemoral shunts. Sixty-two of the 80 shunts were patent. 14 were occluded. and 4 had partial occlusion. The results were confirmed by Doppler studies. contrast angiograms. and/or surgical exploration without false positives or false negatives. Since the radiotracer used was 99mTc-labeled red blood cells. a MUGA study can also be performed immediately following TBA in the same injection. Twenty-eight patients had gated cardiac blood pool studies (MUGA) done; 16 had abnormal wall motion and diminished ventricular function. TBA requires only a single IV injection of radiotracer (less than 1 cc) in the upper limb. The imaging times for total body arterial and perfusion images are seventy seconds and five minutes respectively. Both total body arterial and perfusion images clearly demonstrated the entire course of shunts (single or multiple); underlying and coexisting arterial abnormalities. e g. occlusive disease (27 patients). or aneurysm (3 patients); and related perfusion changes in the extremities. TBA has unique features. It permits a complete. excellent visualization of the bypass graft without the hazard of contrast media injection. It is a simple and a virtually noninvasive procedure. particularly useful for preoperative workups and postoperative follow-ups.
Restored hypoxic pulmonary vasoconstriction by peripheral chemoreceptor agonists in dogs, Hypoxic stimulation of the peripheral chemoreceptors inhibits hypoxic pulmonary vasoconstriction (HPV). On the other hand. almitrine. a peripheral chemoreceptor agonist. has been reported in some studies to enhance HPV. To further explore this apparent contradiction. we investigated the effects of two different low intravenous doses of almitrine on pulmonary arterial pressure (Ppa) versus cardiac index (Q) plots in 32 pentobarbital-anesthetized dogs ventilated alternatively in hyperoxia (FIO2. 0.4) and in hypoxia (FIO2 0.1). HPV. defined as a hypoxia-induced increase in Ppa over the entire range of Q studied. from 2 to 5 L/min/m2. was elicited in 16 dogs. In the first eight of these "responders." almitrine 2 micrograms/kg/min had no vascular effect. and in the other eight. almitrine 4 micrograms/kg/min inhibited HPV. In 16 other dogs. hypoxia did not affect Ppa over the entire range of Q. In these "nonresponders." almitrine 2 micrograms/kg/min (n = 8) as well as 4 micrograms/kg/min (n = 8) restored HPV. To answer the question whether the ability to restore HPV would be specific to almitrine. we administered intravenously the structurally unrelated chemoreceptor agonist doxapram at the dose of 20 micrograms/kg/min to an additional group of eight "nonresponders." and this treatment also restored HPV. Intravenous infusion of the malic acid solution solvent of almitrine had no effect on Ppa/Q plots in a final group of eight "nonresponders". We conclude that low dose almitrine and doxapram restore HPV in dogs with a naturally absent hypoxic pulmonary pressor response. probably by a direct effect at the pulmonary vessels.
Oxygen supplementation during exercise in cystic fibrosis, Fourteen female and 22 male patients with cystic fibrosis (CF). 8 to 29 yr of age. performed two progressive exercise tests to exhaustion on a cycle ergometer. breathing normoxic air (21% O2) for one test. and hyperoxic air (30% O2) for the other test. The order of gas administration was randomized. Minute ventilation (VE). oxygen uptake (VO2). end-tidal CO2 tension (PETCO2). work rate. oxyhemoglobin saturation (SAO2). and heart rate (HR) were measured throughout the tests. The SaO2 of 11 patients at peak exercise was 90% or less ("Low Sat" group). The SaO2 of 23 patients remained above 90% throughout the exercise ("High Sat" group). Hyperoxic air minimized desaturation during exercise in the Low Sat group to 2 +/- 2% compared to a decrease of 10 +/- 5% with normoxic air. The decrease in saturation was not significant for the High Sat group (1 +/- 1% for both 21% and 30% O2). Peak work rate and VO2 did not differ significantly between normoxic and hyperoxic conditions. However. VE and HR at peak exercise tended to be lower. and PETCO2 was higher during peak exercise with 30% O2 than 21% O2 for both groups. During submaximal exercise. O2 desaturation was diminished and HR was significantly lower with supplemental O2. specifically in the Low Sat group. VE was significantly lower for both groups during submaximal exercise with hyperoxic air. The results suggest that O2 supplementation minimizes O2 desaturation and enables patients with CF to exercise with reduced ventilatory and cardiovascular work.
A cost-effectiveness analysis of the routine use of isoniazid prophylaxis in patients with a positive Mantoux skin test, The role of isoniazid prophylaxis in low-risk patients with positive Mantoux skin tests has recently been questioned. In general. recent research has focused on the risk/benefit ratio. We. therefore. decided to extend these data and apply a cost-effectiveness analysis of the routine use of isoniazid prophylaxis from a societal perspective. Costs per case prevented were calculated for a 20-. 50-. and 70-yr-old low-risk patient who had a positive Mantoux test with base. high. and low costings. Rates were also calculated based on the use of direct costs alone and direct and indirect costs combined. Costs varied from Canadian $8.586.00 in a 20-yr-old patient to $40.102.00 in a 70-yr-old patient per case prevented based on direct costs with costs ranging from $3.236.00 to $11.320.00 with both direct and indirect costs included. These costs could be considered reasonable from a societal perspective but do not address the issue of any increased life expectancy resulting from chemoprophylaxis.
In vitro activities of fleroxacin, cefetamet, ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, and amoxicillin-clavulanic acid against rare members of the family Enterobacteriaceae primarily of human (clinical) origin, Fleroxacin and cefetamet were evaluated in vitro against 38 infrequently encountered species (250 strains) of the family Enterobacteriaceae and compared with four established compounds. For all the strains tested. the fleroxacin MIC was less than or equal to 0.5 mg/liter. and for 98% of strains the cefetamet MIC was less than or equal to 8 mg/liter; even though the two new compounds did not quite reach the activities (on a weight-by-weight basis) of ciprofloxacin and ceftriaxone. respectively. they nonetheless clearly surpassed trimethoprim-sulfamethaxazole and amoxicillin-clavulanic acid. The very potent new oral compounds tested in this study appear to be promising for the treatment of clinically relevant infections due to uncommon species of Enterobacteriaceae.
A controlled trial of intralesional recombinant interferon-gamma in the treatment of keloidal scarring. Clinical and histologic findings, Interferon-gamma (IFN-gamma) suppresses the synthesis of collagen by fibroblasts in vitro and the synthesis of collagen in vivo in animal models. Therefore. recombinant human IFN-gamma was examined for its ability to clinically modify keloids. Subjects were treated by injection of either 0.01 or 0.1 mg of recombinant human IFN-gamma into one lesional site and diluent alone into another lesional site three times per week for 3 weeks. Keloids were measured and photographed before beginning therapy and weekly thereafter. Three days after the final injection. biopsies were performed on treated and control sites. Six of eight subjects who finished the course of treatment demonstrated reduction in size at the treated site with an average reduction in height of 30.4% vs 1.1% for control sites. Lesions treated with recombinant human IFN-gamma demonstrated alterations in both the epidermis and dermis. The epidermis showed thinning of the suprapapillary plates. compact hyperkeratosis. focal or diffuse parakeratosis. exocytosis of lymphocytes. and an increased quantity of mucin. The dermis contained a diminished quantity of thickened collagen bundles and active fibroblasts and an increased number of inflammatory cells and quantity of mucin. These results suggest the feasibility of using IFN-gamma in the treatment of abnormal fibrosis. Dose-ranging studies are required to establish whether IFN-gamma can fulfill a true clinical need in the treatment of keloidal scarring.
Effects of recombinant human growth hormone on donor-site healing in severely burned children, The beneficial effects of growth hormone on wound healing in severely burned children were studied. Forty patients who were 2 to 18 years old. with 40% or more total body surface area (TBSA) and 20% or more TBSA full-thickness flame or scald burns. were randomized in a double-blind study to receive placebo or 0.1 mg/kg/day recombinant human growth hormone (rHGH) until the first donor site healed or to receive 0.2 mg/kg/day rHGH or placebo from admission throughout hospitalization. Patients receiving 0.2 mg/kg/day rHGH demonstrated significantly higher serum IGF-1 levels at 4.8 +/- 1.7 U/mL compared to placebos at 1.6 +/- 0.4 U/mL (p less than 0.05) and a significant decrease in donor-site healing times compared to placebo (p less than 0.05). Length of hospital stay (LOS/%TBSA) was decreased from 0.80 +/- 0.10 days/%TBSA burned in the placebo group to 0.54 +/- 0.04 days/%TBSA burned in the 0.2 mg/kg/day treatment group (p less than 0.05). This translates. for the average 60% TBSA burned patient. to a decrease in LOS from 46 to 32 days.
Clinical spectrum of endobronchial tuberculosis in elderly patients, We describe 11 elderly patients with bacteriologically proved endobronchial tuberculosis. representing 15% of our 73 geriatric patients with pulmonary tuberculosis in the period 1980 to 1987. In seven (64%) of the 11 patients. an incorrect diagnosis was initially made. Cough. mostly nonproductive. was invariably present. and general symptoms (fever. anorexia. weight loss) predominated over specific pulmonary symptoms. The radiographic features were rather "unusual": in only two (18%) of the 11 cases. apicoposterior consolidations with or without cavitation were found. Fiberoptic bronchoscopy showed a range of endobronchial abnormalities that included ulcerations. mass lesions. and fibrostenoses. Antituberculous treatment generally led to satisfactory results. Still. residual bronchostenosis was observed in four (57%) of seven patients in whom a control bronchoscopy was done. In one of these four patients. a pneumonectomy had to be performed for uncontrollable retro-obstructive infections. and in another. repeated endoscopic dilatations were effective. In elderly patients. endobronchial tuberculosis should be considered in the differential diagnosis. especially in the presence of chronic cough. In these patients. the chest roentgenogram may be clear or suggestive of bronchial carcinoma or pneumonitis.
The validity of acid-fast smears in the diagnosis of pulmonary tuberculosis, The acid-fast smear remains an important tool in the diagnosis of tuberculosis. Some reports have questioned the validity of this stain in situations of low prevalence. We examined the relationship between prevalence and predictive value of sputum smears in one laboratory during periods of both low and high laboratory prevalence of Mycobacterium tuberculosis. Smears were examined by fluorescence and confirmed by Kinyoun stain. The number of samples positive for mycobacteria increased from 128 (4.3%) of 2956 during the 1975 through 1978 study period to 197 (8.4%) of 2347 during the 1979 through 1982 study period. Of 47 positive smears during the first study period. only one was a false-positive. None of 96 positive smears during the second period was a false-positive. The positive predictive value of acid-fast microscopy was 97.9% and 100% for the two periods examined. We have demonstrated in practice the small effect of a shift in prevalence on the positive predictive value of an acid-fast smear when specificity is maintained.
Comprehensive management of renal failure in infants, From 1986 through 1989. 23 infants (18 of whom were less than 30 days old) required peritoneal dialysis within their first 6 months of life. Modifications to conventional peritoneal dialysis included modified Silastic Tenckhoff catheters. peel-away sheaths for percutaneous insertion. automated peritoneal dialysis "cyclers." and generous omentectomy. With these modifications. there were no bowel perforations. and the infants were successfully dialyzed for prolonged periods. Eight of the 23 infants developed end-stage renal failure and were prepared for transplantation. All had gastrostomy tubes placed to supplement oral nutrition. Living. related transplantation was performed when the child weighted 10 kg. Four of the eight completed this protocol. One child with congenital nephrotic syndrome died before transplantation. One transplant was complicated by a technical problem (venous thrombosis). which resulted in allograft loss and return to peritoneal dialysis. Kidney function. growth. and development in the survivors were excellent.
Progressive myoclonic ataxia (the Ramsay Hunt syndrome), It has been suggested from studies of patients with progressive myoclonus epilepsy that the term Ramsay Hunt syndrome should be abandoned. as its use has led to nosologic confusion. and because. in the light of modern diagnostic techniques. the majority of cases can be allocated to specific disease categories. chiefly. Unverricht-Lundborg disease (Baltic myoclonus) and mitochondrial encephalomyopathy. Review of 30 cases of this syndrome. defined as progressive ataxia and myoclonus and infrequent seizures in the absence of dementia. showed that a clinical or biochemically supported diagnosis could not be made in 43%. This low diagnostic yield probably reflects differences in ascertainment of patients; those described here were referred with a syndrome of progressive myoclonic ataxia (the Ramsay Hunt syndrome) rather than progressive myoclonus epilepsy. These two syndromes share common causes. but a smaller proportion of patients with progressive myoclonic ataxia can currently be diagnosed precisely during life.
Effects of a moderate dose of alcohol on blood lipids and lipoproteins postprandially and in the fasting state, Effects of a moderate dose of alcohol on blood lipids and lipoproteins were studied in volunteers of two age groups (20-30 and 45-55 years). each consisting of eight healthy men. The alcohol (30 g in red port and wine) was consumed during a standard dinner. Two blood samples were drawn: one in the postprandial phase. and one the next morning after fasting overnight. In the postprandial phase. one hour after intake. alcohol increased high-density lipoprotein cholesterol (HDL-C) by 11.5%. triglycerides (TG) by 15.3% and apolipoprotein A2 (Apo-A2) by 7.3% (P = 0.002. P = 0.044 and P = 0.024. respectively). The increase in HDL-C appeared to be mainly attributed to the HDL2-C subfraction which increased by 15.3% (P = 0.066). Furthermore. the increases in HDL-C. HDL2-C and TG were more pronounced in the middle-aged men then in the young men. After fasting overnight the effects of alcohol had disappeared.
Effect of prazosin treatment on HDL kinetics in patients with hypertension, The effect of prazosin treatment on blood pressure. plasma HDL-cholesterol concentration. and apoprotein-AI/HDL (apoAI/HDL) kinetics was studied in 11 patients with mild hypertension. Blood pressure (mean +/- SEM) fell from 143 +/- 1/96 +/- 1 to 134 +/- 1/86 +/- 1 mm Hg after 4 to 5 months of prazosin treatment (P less than .001). associated with an increase in plasma HDL-cholesterol concentration from 38 +/- 2 to 46 +/- 2 mg/dL (P less than .001). Both the fractional catabolic rate (FCR) and total synthetic rate of apoAI/HDL. which were higher than previous reported values for normal individuals. decreased from 0.36 +/- 0.02 to 0.30 +/- 0.02 L/day and 17.4 +/- 1.1 to 13.8 +/- 1.1 mg/kg/min. respectively. These changes were statistically significant. and the post-treatment values for both variables were now within the normal range. When the decay curve was further analyzed by nonlinear curve fitting. it was shown that the return to normal of the FCR of apoAI/HDL in patients treated with prazosin was accounted for by the decrease of the decay constants of the second [p(2)] and third [p(3)] components of the 125I-AI/HDL disappearance curve. In conclusion. abnormalities in HDL concentration and HDL kinetics exist in patients with very mild hypertension. These defects were significantly improved with prazosin treatment. and this may render the compound of particular clinical benefit in the treatment of patients with mild hypertension.
Plasma atrial natriuretic peptide in young normotensive subjects with a family history of hypertension and in young hypertensive patients, Plasma atrial natriuretic peptide (ANP) behavior was evaluated in 26 untreated essential hypertensives. 21 normotensives. and 20 normotensives with hypertensive heredity under normal sodium intake (120 mEq of Na+/day). All subjects were men. mean age 22.1 +/- 1.9 years. Plasma ANP was evaluated by radioimmunoassay on samples collected in supine position upon waking and again after 1 h of orthostatism. Resulting data showed that ANP in hypertensives (supine = 44.5 +/- 19.4 pg/mL. orthostatism = 24.1 +/- 11.6 pg/mL) was at higher levels than in controls (supine = 38.3 +/- 19.4 pg/mL. orthostatism = 19.9 +/- 10.6 pg/mL) or in normotensives with hypertensive heredity (supine = 42.1 +/- 16.8 pg/mL. orthostatism = 23.2 +/- 10.8 pg/mL). Mean ANP level was higher in the latter group than in the control group (supine = +9%; orthostatism = +14.2%). In conclusion. plasma ANP is raised in young essential hypertensives. resulting in slightly elevated levels in normotensives with hypertensive heredity.
Atrial natriuretic peptide infusion in primary aldosteronism. Renal, hemodynamic and hormonal effects, We have previously shown that a bolus injection of alpha-human atrial natriuretic peptide (alpha-h-ANP) (100 micrograms) in patients with primary aldosteronism induces a transient decrease of blood pressure and a marked natriuresis. but no changes in plasma aldosterone levels. Eight additional cases were studied with a different protocol. Alpha-h-ANP was infused at the dose of 50 ng/kg/min over 1 h. after a bolus of 50 micrograms; saline alone was infused as control. Blood pressure. heart rate. plasma aldosterone. plasma renin activity. cortisol. serum and urinary Na and K and urinary volume were measured. A slight fall in blood pressure. without heart rate changes. was obtained within the first 5 min; this lasted throughout the infusion and for 1 h afterwards. Urinary volume and urinary sodium were significantly higher than controls during the first 2 h. while urinary potassium slightly increased only during the first hour. Plasma renin activity remained suppressed. Plasma aldosterone levels were similar throughout the infusion. Cortisol was not significantly different than placebo except that there was a significant rise after stopping ANP. These data confirm the potent natriuretic effect of ANP infusion and the lack of correlation between ANP induced natriuresis and the effect of ANP on aldosterone in patients with primary aldosteronism.
Atrial natriuretic peptide in patients with diabetes mellitus type I. Effects on systemic and renal hemodynamics and renal excretory function, In the present study the effects of 1 h intravenous infusion of alpha-human atrial natriuretic peptide (24 ng/min/kg) on systemic and renal hemodynamics and on renal excretory function were studied in six insulin-treated and metabolically well-controlled patients with diabetes mellitus (DM) type I and in six healthy control subjects (C). Basal plasma atrial natriuretic peptide (ANP) concentration was 14.6 +/- 2.0 in DM patients and 14.9 +/- 1.3 pmol/L in C and rose similarly in both groups to 87.1 +/- 22.1 and to 86.9 +/- 11.1 pmol/L. respectively. during alpha-hANP infusion (P less than .05). Maximal effects of alpha-hANP occurred between 30 and 60 min after the start of the infusion. Mean arterial pressure (MAP) (83 +/- 5 v 81 +/- 3 mm Hg). heart rate (HR) (63 +/- 2 v 64 +/- 4/min) and total peripheral resistance (TPR) (11 +/- 1 v 10 +/- 1 mm Hg.min/L) remained unaltered in patients with DM. In contrast. in C MAP and TPR decreased from 83 +/- 3 to 77 +/- 2 mm Hg and from 12 +/- 1 to 10 +/- 1 1 mm Hg.min/L. respectively (P less than .05). whereas HR increased from 53 +/- 2 to 59 +/- 3 beats/min (P less than .05). Cardiac output (CO) rose initially by 11% and by 9% in DM and C. respectively. Urine flow increased from 4.1 +/- 0.9 to 11.3 +/- 1.5 mL/min in DM patients and from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min in C (P less than .05).
The role of the left ventricle in atrial natriuretic peptide secretion in acute mitral regurgitation, To examine the role of the ventricle in ANP secretion. the atrial natriuretic peptide (ANP) concentration in the plasma. left atrial tissue and left ventricular tissue were observed in a canine during the course of experimental reversible mitral regurgitation (MR). For reversible MR. a basket catheter was inserted into the left atrium via the pulmonary vein and fixed at the mitral valve. The regurgitation arose when the tip basket wire was extended and disappeared immediately when it was closed. Left atrial pressure (LAP). right atrial pressure (RAP) and pulmonary artery pressure (PAP) increased significantly during MR. and decreased to the normal level after recovery from MR. Plasma ANP concentration showed a reversible change in correlation with LAP and RAP in each canine studied. The ANP level in the atrial and ventricular tissue decreased during MR. and the low levels were maintained after recovery from MR. Both the left arterial and left ventricular tissue ANP levels showed the same changes in acute MR. Therefore. it was suggested that normal ventricles might play a role in ANP secretion in acute MR.
Restriction of HIV replication in infected T cells and monocytes by interferon-alpha, Human recombinant interferon-alpha (IFN alpha) restricted viral replication in human immunodeficiency virus- (HIV) infected T cells and monocytes. With T cells. reverse transcriptase (RT) activity in culture fluids was reduced threefold from that of control infected cells by IFN treatment. but HIV p24 antigen levels were unchanged. In contrast. levels of p24 antigen and RT activity in lysates of IFN-treated infected cells were threefold greater than those of controls. These differences suggest that the mechanism for IFN-induced antiviral effects in HIV-infected T cells resides in the terminal events (assembly and release) of the virus replication cycle. Monocytes treated with IFN at the time of virus challenge showed no p24 antigen or RT activity. no HIV-specific mRNA. and no proviral DNA in cells for up to 3 weeks after infection. IFN treatment of chronically infected monocytes also decreased virus replication. as assessed by p24 antigen. mRNA and RT detection assays. However. levels of proviral DNA in the IFN-treated and control HIV-infected cells were indistinguishable. The presence of large quantities of proviral DNA in cells with little or no evidence for active transcription documents a situation approaching true microbiological latency.
Rapid resolution of ST elevation and prediction of clinical outcome in patients undergoing thrombolysis with alteplase (recombinant tissue-type plasminogen activator): results of the Israeli Study of Early Intervention in Myocardial Infarction, Alteplase (recombinant tissue-type plasminogen activator (rt-PA)) was infused within four hours of onset of symptoms in 286 patients with acute myocardial infarction. Delayed coronary angiography was performed 72 hours after admission with coronary angioplasty if indicated. Electrocardiographic monitoring was continuous during the first hour of treatment. The sum of the ST segment elevations (sigma ST) was calculated on electrocardiograms recorded at entry and an hour later. ST elevations resolved rapidly within one hour of treatment in 189 patients and persisted in 97 patients. Rapid resolution of ST elevation correlated with angiographic coronary patency as determined by coronary angiography 72 hours after admission. The patients with rapid resolution of sigma ST had significantly smaller infarcts and a better clinical outcome than the patients with persistent ST elevation. sigma ST values at entry and one hour after treatment had no additional independent predictive value. Rapid resolution of ST elevations in patients undergoing thrombolysis with alteplase was associated with a significantly smaller release of creatine kinase. better preservation of left ventricular function. lower morbidity. and less short and long term mortality. Rapid resolution of sigma ST elevation is an efficient indicator of clinical outcome in groups of patients with acute myocardial infarction undergoing thrombolysis with alteplase.
Estimation of serum V kappa IIIb light chains in rheumatoid arthritis and correlation with CD5-positive B-cells, The presence of V kappa IIIb light chains in the sera of rheumatoid arthritis (RA) patients has been evaluated by an enzyme-linked immunosorbent assay (ELISA). V kappa IIIb light chains have been confirmed to be largely restricted to IgM. and were rarely detected in the IgG fraction of sera. The concentration of total serum V kappa IIIb did not significantly vary with age. nor did it correlate with IgM-rheumatoid factor (RF) titre. Although total serum V kappa IIIb was not significantly increased in RA patients compared with matched controls. IgM-RFs frequently contained V kappa IIIb. Using flow cytometry. CD5-positive B-cells were not increased in these RA patients compared with healthy laboratory control personnel. Furthermore. there was no direct correlation between total serum IgM V kappa IIIb content and CD5-positive B-cell numbers in peripheral blood.
Immunogenetics of polymyalgia rheumatica, Evidence suggests that polymyalgia rheumatica (PMR) may be an immune-mediated disease. Therefore. the role of HLA class II genes. the switch region of immunoglobin mu and alpha 1 heavy chain as the T-cell receptor (TcR) genes were investigated by Southern blot analysis. The frequency of DR4 specificity was increased in PMR (67.4% versus 30.3%; P = 0.00017). No association was found with the DQA and DQB genes. the switch region of immunoglobulin mu and alpha 1 heavy chain genes. and the TcR alpha. beta and gamma genes. This study suggests that HLA-DR4 is an important susceptibility factor for PMR. Further studies are needed to elucidate the role of Ig and TcR genes.
Reduced bladder capacity in patients receiving intravesical chemoprophylaxis with mitomycin C, After complete resection of superficial bladder carcinoma (Tis-2. G1-3). 75 patients were treated prophylactically with either 20 or 30 mg mitomycin C. Six patients developed a substantial reduction in bladder capacity (less than 200 ml). In 2 patients radical cystectomy of an otherwise tumour-free fibrotic bladder was necessary. The results of long-term treatment (2 years) suggest that reduced bladder capacity correlates with the cumulative dosage of mitomycin C.
Targeting cancer chemotherapeutic agents by use of lipiodol contrast medium, Arterially administered Lipiodol Ultrafluid contrast medium selectively remained in various malignant solid tumors because of the difference in time required for the removal of Lipiodol contrast medium from normal capillaries and tumor neovasculature. Although blood flow was maintained in the tumor. even immediately after injection Lipiodol contrast medium remained in the neovasculature of the tumor. To target anti-cancer agents to tumors by using Lipiodol contrast medium as a carrier. the characteristics of the agents were examined. Anti-cancer agents had to be soluble in Lipiodol. be stable in it. and separate gradually from it so that the anti-cancer agents would selectively remain in the tumor. These conditions were found to be necessary on the basis of the measurement of radioactivity in VX2 tumors implanted in the liver of 16 rabbits that received arterial injections of 14C-labeled doxorubicin. Antitumor activities and side effects of arterial injections of two types of anti-cancer agents were compared in 76 rabbits with VX2 tumors. Oily anti-cancer agents that had characteristics essential for targeting were compared with simple mixtures of anti-cancer agents with Lipiodol contrast medium that did not have these essential characteristics. Groups of rabbits that received oily anti-cancer agents responded significantly better than groups that received simple mixtures. and side effects were observed more frequently in the groups that received the simple mixtures. These results suggest that targeting of the anti-cancer agent to the tumor is important for treatment of solid malignant tumors.
Effects of tissue-type plasminogen activator and anisoylated plasminogen streptokinase activator complex on mortality in acute myocardial infarction, An overview of eight randomized controlled trials of tissue-type plasminogen activator (Alteplase or Duteplase) and 10 of anisoylated plasminogen streptokinase activator complex (Anistreplase) showed that the odds of early death were reduced by 29% by tissue-type plasminogen activator and 46% by anisoylated plasminogen streptokinase activator complex. with overlapping 95% confidence intervals. Although the beneficial effects of both agents are consistent and are strengthened when all the trials are considered together. the available data do not permit comparisons of the relative efficacy of these two agents with each other or with streptokinase.
Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD), Neuroendocrine activation is known to occur in patients with congestive heart failure. but there is uncertainty as to whether this occurs before or after the presence of overt symptoms. In the Studies of Left Ventricular Dysfunction (SOLVD). a multicenter study of patients with ejection fractions of 35% or less. we compared baseline plasma norepinephrine. plasma renin activity. plasma atrial natriuretic factor. and plasma arginine vasopressin in 56 control subjects. 151 patients with left ventricular dysfunction (no overt heart failure). and 81 patients with overt heart failure before randomization. Median values for plasma norepinephrine (p = 0.0001). plasma atrial natriuretic factor (p less than 0.0001). plasma arginine vasopressin (p = 0.006). and plasma renin activity (p = 0.03) were significantly higher in patients with left ventricular dysfunction than in normal control subjects. Neuroendocrine values were highest in patients with overt heart failure. Plasma renin activity was normal in patients with left ventricular dysfunction without heart failure who were not receiving diuretics and was significantly increased (p less than 0.05) in patients on diuretic therapy. We conclude that neuroendocrine activation occurs in patients with left ventricular dysfunction and no heart failure. Neuroendocrine activation is further increased as overt heart failure ensues and diuretics are added to therapy.
Thrombolytic and pharmacokinetic properties of a conjugate of recombinant single-chain urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin in a baboon venous thrombosis model, Chemical conjugates between recombinant single-chain urokinase-type plasminogen activator (rscu-PA) and a murine monoclonal antibody directed against fragment D-dimer of cross-linked human fibrin (MA-15C5). rscu-PA/MA-15C5. and between rscu-PA and a control monoclonal antibody (MA-1C8). rscu-PA/MA-1C8. were produced by cross-linking with N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). In an in vitro system composed of a [125 I]fibrin-labeled baboon plasma clot immersed in autologous citrated plasma. dose- and time-dependent lysis was obtained with a ratio of the potencies of free and conjugated rscu-PA similar to that in human plasma: 50% lysis in 2 hours required 4.3 micrograms/ml rscu-PA. 1.0 microgram/ml urokinase-type plasminogen activator (u-PA) equivalent rscu-PA/MA-15C5. or 15 micrograms/ml u-PA equivalent rscu-PA/MA-1C8. The thrombolytic and pharmacokinetic properties of rscu-PA and of rscu-PA/MA-15C5 were compared in baboons with a 0.8-1.0 ml [125 I]fibrin-labeled autologous blood clot produced in a femoral vein. Continuous intravenous infusion of these compounds during a 2-hour period resulted in dose- and time-dependent lysis. The thrombolytic potency of rscu-PA/MA-15C5 was 3.0 +/- 0.5 times higher (50% lysis with 0.3 +/- 0.02 mg u-PA equivalent/kg body wt) than that of rscu-PA measured by ex vivo isotope recovery from the femoral vein segment (p less than 0.001) and was 2.7 +/- 0.5 times higher (50% lysis with 0.35 +/- 0.02 mg/kg rscu-PA/MA-15C5) by external radioisotope counting (p less than 0.001). A dose of 0.5 mg/kg of rscu-PA/MA-1C8 was much less active than rscu-PA. After the end of the infusion. u-PA-related antigen disappeared from plasma in a biphasic manner with an initial half-time of 2.7 +/- 0.5 for rscu-PA. 24 +/- 1.2 for rscu-PA/MA-15C5. and 21 +/- 0.5 minutes for rscu-PA/MA-1C8 with corresponding plasma clearances of 340 +/- 40. 20 +/- 3. and 24 +/- 2 ml/min. respectively. In conclusion. the increased thrombolytic potency of rscu-PA/MA-15C5 is the result of a reduction of the thrombolytic potency due to coupling of rscu-PA to the antibody molecule. which is counter-balanced by an enhancement of the thrombolytic potency due to fibrin targeting by the specific idiotype.
Neutralization of low molecular weight heparin by polybrene prevents thromboxane release and severe pulmonary hypertension in awake sheep, Protamine reversal of heparin anticoagulation in patients is occasionally associated with life-threatening acute pulmonary hypertension. In a sheep model. we evaluated the effect on this adverse cardiopulmonary reaction of modifying the type of heparin (low molecular weight heparin compared with unfractionated heparin) and the type of heparin antagonist (polybrene compared with protamine). Protamine reversal of low molecular weight heparin (LMWH) and polybrene reversal of unfractionated heparin induced more than a 10-fold increase of plasma thromboxane B2 levels. a threefold increase of pulmonary vascular resistance and pulmonary artery pressure. and a 25% decrease of PaO2. A similar adverse reaction followed protamine reversal of conventional unfractionated heparin. However. with polybrene (1 mg/kg) reversal of LMWH (1 mg/kg). we measured neither pulmonary hypertension (pulmonary artery pressure was 22.6 +/- 3.6 mm Hg at 1 minute after polybrene reversal of LMWH compared with 47.9 +/- 4.2 mm Hg after protamine reversal of unfractionated heparin. p less than 0.005 groups differ). hypoxemia (PaO2 was unchanged 2 minutes after polybrene compared with a decrease of 26 mm Hg 2 minutes after protamine. p less than 0.05). nor acute release of thromboxane into arterial plasma (thromboxane B2 was 0.2 +/- 0.1 at 1 minute after polybrene compared with 3.7 +/- 1.7 ng/ml at 1 minute after protamine. p less than 0.005). The hemodynamic effects and mediator release were also benign after neutralization of larger doses of LMWH (3 mg/kg) by polybrene (3 mg/kg). The increases of activated clotting time and activated partial thromboplastin time due to both types of heparin were completely reversed with polybrene. Anti-Xa activity increased to more than 3 IU/ml 4 minutes after LMWH anticoagulation (p less than 0.01) but was only partially neutralized by polybrene. Various polyanion-polycation complexes that are formed when heparin anticoagulation is reversed induce thromboxane release and acute pulmonary vasoconstriction in awake sheep. Reversal of LMWH anticoagulation with polybrene does not elicit this adverse reaction.
Vascular reactivity after balloon angioplasty in an atherosclerotic rabbit, Alterations in vessel wall reactivity (VR) at or adjacent to the dilation site after balloon angioplasty (BA) may vary according to the inflation protocol and the time after angioplasty and may influence outcome. In 64 atherosclerotic rabbit femoral arteries. we evaluated VR after BA with intravenous ergonovine (ERGO) (40 micrograms/min for 5 minutes) and intra-arterial nitroglycerin (NTG) (2.500 micrograms single bolus) 24-72 hours and 28 days after BA. Comparisons were made with atherosclerotic. nonangioplastied. age-matched controls. BA was standardized to three 1-minute inflations. each 1 minute apart. For each balloon size. 2.5- (appropriate size) or 3.0-mm (oversized) vessels were allocated to either 5 or 10 atm inflation pressure. For the analysis. four groups were compared: Group 1. 3.0/5; group 2. 3.0/10; group 3. 2.5/5. and group 4. 2.5 mm/10 atm. Angiographic diameters were measured at. proximal. and distal to the lesion at baseline. 10 minutes after ERGO. and 5 minutes after NTG. Angiograms were measured with electronic calipers by two blinded observers. All segments of control vessels vasoconstricted to ERGO and vasodilated to NTG (p less than 0.05 versus baseline). indicating a normal response. At 24-72 hours after dilatation. the angioplasty sites for all inflation pressure/balloon size combinations were not responsive to either ERGO or NTG. All segments distal to the dilatation sites vasoconstricted to ERGO and dilated to NTG (p less than 0.05 versus baseline). indicating a normal response. Proximal segments of vessels dilated with a 2.5-mm balloon (appropriate size) responded positively to both stimuli (p less than 0.05). Those vessels dilated with a large balloon (3.0 mm) were nonreactive in the segment proximal to the angioplasty site. Twenty-eight days later angioplasty sites dilated with a 2.5-mm balloon (appropriately sized) regained reactivity; however. segments dilated with a large balloon (3.0 mm) remained unresponsive. All proximal segments. including those from vessels dilated with a large balloon. reacted positively. All distal segments reacted appropriately. Restenosis rates were not different between the over- and appropriately sized balloon groups. These data demonstrate that immediately after angioplasty. vessels lose reactivity at the dilatation site. Those vessels dilated with the smaller-size balloon (2.5 mm) regained reactivity. For large balloons. reactivity is not regained at 28 days. For segments proximal to the site of dilatation. transient loss of reactivity is seen only when a large balloon is used. Thus. acute closure originating at the site of dilatation is not a result of spasm.(ABSTRACT TRUNCATED AT 400 WORDS).
Cardiac allograft function with corticosteroid-free maintenance immunosuppression, Potent prophylactic immunosuppressive protocols promote the safe withdrawal of corticosteroid maintenance. The benefits of corticosteroid-free maintenance immunosuppression include the absence of the cushingoid habitus. fewer infections. less obesity. and lower serum cholesterol. The incidence of allograft coronary artery disease is not increased by corticosteroid-free maintenance. To assess the long-term effects of corticosteroid-free immunosuppression on allograft function. we compared results of hemodynamic study and noninvasive evaluation over the 2-year follow-up of 57 patients on corticosteroid-free maintenance to 40 patients who required corticosteroid. Age and pretransplantation diagnoses were similar. but a greater percentage of those who required corticosteroid maintenance were female (28% versus 2%. p less than 0.001). Indexes of allograft function were similar in both groups and these indexes included ejection fraction. right atrial pressure. pulmonary artery pressure. pulmonary capillary wedge pressure. cardiac index. left ventricular end-diastolic dimension. and posterior wall thickness. Patient survival was identical in the two groups (98%). These data indicate that corticosteroids can be safely withdrawn with the subsequent early benefits and without compromising long-term allograft function.
Absorbable rings for pediatric valvuloplasty. Preliminary study, Secondary valvular stenosis is a significant risk of annular ring implantation during valvular repair in children. To avoid this problem. we have developed an absorbable prosthetic ring (APR). which induces the generation of a biologic fibroelastic ring with mitotic capability and thereby allows atrioventricular annulus growth with age. Twelve polydioxanone (PDS) biodegradable APRs were surgically implanted in immature goats. To avoid possible embolic complications from ring fragments during the absorption period. APRs were covered with an extensible sewing sheath of high-porosity polyester. allowing contact between the PDS. blood. and endocardium. Four APRs were implanted into the right atrial cavity. four in the tricuspid position. and four in the mitral position. Histological studies at 6 months showed a considerable amount of remaining PDS. At 1 year. only small residual fragments of PDS were present. surrounded by collagen and elastic fibers as well as fibroblasts with mitotic activity. This histological structure represents a new biologic fibroelastic ring. which has originated from PDS rings. Echocardiography at 12 months showed that the elasticity of APRs and fibrotic tissue allows normal systolic and diastolic valve motions. These findings. which demonstrate histological changes in native valve annuli as well as stable and elastic annuloplasty without secondary stenosis in growing animals. call for new studies involving hearts with valvular disease.
Plasma conjugated androgens in a dialysis-dependent male as immunoreactive digitalis-like factors, Endogenous digitalis-like factors (DLF) including those which were immunoreactive with digoxin antibody and those which displaced ouabain from Na.K-ATPase. were isolated from the plasma of a dialysis-dependent male patient not taking digoxin. Plasma was passed through a C18 disposable column. the DLF eluted with methanol and separated by HPLC on a C8 column. Immunoreactive DLF were measured in each 1 ml HPLC fraction using radioimmunoassay (RIA) for digoxin. The immunoreactive peaks were determined and aliquots from each peak analyzed by fast atom bombardment mass spectroscopy (FAB-ms). The compounds in the five major HPLC immunoreactive peaks were identified as: 1) dehydroepiandrosterone glucuronide and tetrahydrocortisone glucuronide; 2) epiandrosterone glucuronide; 3) dehydroepiandrosterone sulfate and androsterone glucuronide; 4) epiandrosterone sulfate and 5) androsterone sulfate and androstanediol glucuronide. These immunoreactive DLF represent 70% of the total plasma immunoreactive DLF of 0.124 micrograms digoxin equivalents/l. Aliquots of the HPLC fractions were also assayed for ability to displace ouabain from Na.K-ATPase. The ouabain displacing DLF gave a very different elution pattern from that obtained by RIA with the major Na.K-ATPase ouabain displacing DLF eluting in the more polar fractions. They remain unidentified.
Multicenter comparison of once- and twice-daily isradipine to hydrochlorothiazide for the treatment of hypertension in elderly patients, After 8 weeks of isradipine. a twice-a-day dihydropyridine calcium channel blocker. 49% of elderly patients showed a complete response (sitting diastolic blood pressure less than or equal to 85 mm Hg) and 36% showed a partial response (sitting diastolic blood pressure decrease greater than or equal to 10 mm Hg) for an 85% total response rate. Hydrochlorothiazide gave a complete response in 36% of the patients and a partial response in 33%. for a 69% total response rate (p less than 0.0046). Because elderly subjects have reduced clearance for many drugs. we determined how those who responded to twice-a-day administration would respond to once-a-day administration. After 4 weeks of isradipine administered once a day. 54% of the patients showed a complete or partial response. whereas 38% of the patients who were changed to placebo showed a response. In contrast. 82% of patients receiving hydrochlorothiazide once a day showed a response. whereas 60% of patients who were changed to placebo showed a response. These data indicate that the standard formulation of isradipine was not effective when administered once a day.
Effect of sodium-transport inhibitors on bronchial reactivity in vivo, 1. We have recently shown that ouabain. an inhibitor of Na+/K(+)-adenosine triphosphatase. causes contraction of bovine and human airways in vitro. and that amiloride causes relaxation and inhibits receptor-operated contraction in bovine trachealis. 2. To determine whether such drugs alter bronchial reactivity in vivo. we have studied the effect of oral digoxin (an inhibitor of Na+/K(+)-adenosine triphosphatase) and oral and inhaled amiloride on bronchial reactivity to histamine in three double-blind. placebo-controlled studies. 3. Histamine reactivity was measured as the provocative dose causing a 20% reduction in the forced expiratory volume in 1 s (PD20FEV1) or. when normal subjects were included. the provocative dose causing a 35% reduction in the specific airways conductance (PD35sGaw); the results are given as geometric mean values. 4. In study 1. 13 atopic asthmatic subjects were given 20 mg of oral amiloride or placebo on separate days. Two hours after the drug. the geometric mean PD20FEV1 for histamine was 0.43 mumol after amiloride and 0.54 mumol after placebo (95% confidence intervals for the difference: 0.9 to -0.2 doubling doses of histamine; P = 0.2). 5. In study 2. six normal and 24 atopic asthmatic men inhaled 10 ml of 10(-2) mol/l amiloride or diluent control in a crossover study. The mean values of PD35sGaw for histamine immediately after inhalation of amiloride and placebo were 3.0 mumol and 4.3 mumol. respectively. in the normal subjects (95% confidence intervals for the difference: -0.53 to 1.52 doubling doses. P = 0.2). and 0.33 mumol and 0.29 mumol in the asthmatic subjects (95% confidence intervals for the difference: -0.95 to 0.57 doubling doses; P = 0.6).
Effect of cardiac tamponade on atrial natriuretic peptide concentrations: influence of stretch and pressure, 1. In order to study the role of atrial pressure and atrial stretch on the release of atrial natriuretic peptide we have measured plasma atrial natriuretic peptide concentration. urine output and haemodynamic variables in eight patients during and 30 min after the relief of cardiac tamponade. This condition is characterized by high atrial pressure with little or no atrial stretch. 2. Relief of tamponade was associated with a rise in urine output (53 +/- 27.9 to 101 +/- 24.5 ml/h. mean +/- SEM; P = 0.09). systolic blood pressure (95 +/- 9.6 to 126 +/- 7.0 mmHg. P less than 0.0001). and plasma atrial natriuretic peptide concentration (369.5 +/- 70.9 to 490.3 +/- 94.7 pg/ml. P less than 0.05) despite a large fall in right atrial pressure (18.6 +/- 1.6 to 9.5 +/- 1.3 mmHg. P less than 0.001). 3. These results suggest. therefore. that an increase in atrial stretch. rather than in atrial pressure. stimulates the release of atrial natriuretic peptide.
Gene mapping in the idiopathic generalized epilepsies: juvenile myoclonic epilepsy, childhood absence epilepsy, epilepsy with grand mal seizures, and early childhood myoclonic epilepsy, Idiopathic generalized epilepsies. i.e.. juvenile myoclonic epilepsy (JME). childhood absence epilepsy. and epilepsy with grand mal [generalized tonic-clonic seizures (GTCS)]. are the most common genetic epilepsies. Linkage studies using Bf. HLA serologic. and DNA markers by three independent investigators. one from Los Angeles and two from Berlin. have localized the JME locus to the short arm of chromosome 6 (6p). Because members of the same JME family have the same JME phenotype of childhood absence epilepsy. epilepsy with grand mal (GTCS) seizures. or early childhood myoclonic epilepsy (ECME). our observations give evidence for a single-locus etiology in 6p for JME and for at least some of the childhood absence seizures. epilepsy with grand mal (GTCS) seizures. and ECME. Studies should now address whether locus heterogeneity exists within childhood absence epilepsy. epilepsy with grand mal (GTCS) seizures. or ECME. Markers linked to JME (Bf. HLA serologic. and DNA markers in the DQ region) can be used to resolve etiologic heterogeneity. Using such markers. both linked and unlinked forms of phenotypes that are clinically indistinguishable may be detected and provide evidence for etiologic heterogeneity. Studies should also concentrate on narrowing the JME locus to 2 to 3 cm by screening families with recombinant events using RFLPs. candidate genes. and new expressed sequences on chromosome 6.
Luteinizing hormone bioactivity and variable responses to clomiphene citrate in chronic anovulation, In 18 women with infertility and chronic anovulation with normal gonadotropins. three different responses were observed to increasing doses (250 to 750 mg) of clomiphene citrate (CC). Follicle development and ovulation in 8. follicle development but no ovulation without human chorionic gonadotropin (hCG) in 6. and no response to CC in 4. Serum concentrations of bioactive luteinizing hormone (bioactive-LH). immunoactive (immunoactive-LH). follicle-stimulating hormone. and estradiol (E2) were measured and follicle growth was assessed by daily ultrasound. Findings were compared with 8 normal ovulatory controls. Folliculogenesis on CC therapy. based on our data. was 78%; however. only 44% ovulated spontaneously. 34% required hCG for follicle rupture. There were no apparent hormonal indicators to predict responders from nonresponders. The absence of an LH surge in the presence of follicles and sustained high E2 concentrations in 34% of patients may be associated with a decreased E2 sensitivity at the hypothalamic-pituitary level. Ultrasound easily identified patients who responded to CC with folliculogenesis but did not initiate an LH surge. Follicle rupture was achieved promptly by hCG administration.
Randomized, prospective trial of leuprolide acetate and conventional superovulation in first cycles of in vitro fertilization and gamete intrafallopian transfer, Ovarian stimulation after pituitary suppression with gonadotropin-releasing hormone agonists (GnRH-a) has been effective in women who have exhibited a poor response to conventional superovulation strategies. Their effectiveness in unselected women undergoing their first cycle of in vitro fertilization or gamete intrafallopian transfer. however. remains to be established. To address this question. we randomized 114 women to one of two treatment protocols. Protocol 1 consisted of 100 mg of clomiphene citrate on days 5 to 9. followed by 150 IU human menopausal gonadotropin (hMG) beginning on day 9. Protocol 2 consisted of daily GnRH-a beginning in the midluteal phase. Stimulation with 150 IU hMG commenced after pituitary down regulation and ovarian suppression were achieved. Human menopausal gonadotropin was continued in both protocols until adequate follicular development and serum estradiol concentrations were obtained. Protocol 2 patients reached egg retrieval significantly more often (87%) than Protocol 1 patients (61%). but the mean number of mature eggs retrieved and the pregnancy rate per retrieval were not significantly different between the two groups.
Management of severe fibrocystic disease of the breast with leuprolide acetate, Symptoms of severe fibrocystic disease of the breast were successfully ameliorated in two patients as a result of treatment with daily subcutaneous LA without adverse effects. A state of drug-induced hypogonadotropic hypogonadism appears to be responsible for the clinical effect and is further suggestive of the hormonal dependence of this common disorder.
Effect of insulin on oxidation of intracellularly and extracellularly derived glucose in patients with NIDDM. Evidence for primary defect in glucose transport and/or phosphorylation but not oxidation, Insulin-stimulated glucose oxidation is decreased in patients with non-insulin-dependent diabetes mellitus (NIDDM). It is not known whether this decrease is due to a primary defect in the oxidative pathway or is secondary to impaired glucose transport and/or phosphorylation. To address this issue. glucose oxidation was measured under steady-state conditions at low (approximately 270 pmol) and high (approximately 17 mumol) insulin concentrations in seven patients with NIDDM and seven healthy nondiabetic subjects matched for sex. age. and obesity. Glucose oxidation was measured simultaneously by indirect calorimetry and the isotopedilution technique. Although glucose oxidation and nonoxidative storage were lower (P less than 0.05) in diabetic than nondiabetic subjects during the low- and high-dose insulin infusions. oxidation of intracellularly derived glucose. estimated by subtracting the rate of oxidation measured isotopically (i.e.. glucose oxidation derived from the extracellular space) from that measured by indirect calorimetry (i.e.. total glucose oxidation). did not differ in diabetic and nondiabetic subjects during the low-dose insulin infusion (3.3 +/- 0.1 vs. 3.0 +/- 0.1 mumol.kg-1.min-1). Both techniques provided identical estimates of glucose oxidation during the high-dose insulin infusion. Impaired oxidation of extracellularly but not intracellularly derived glucose strongly suggests that the cause of decreased glucose oxidation in patients with NIDDM is secondary to impaired glucose transport and/or phosphorylation rather than a primary abnormality in the oxidative pathway.
Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM, To assess the role of muscle and liver in the pathogenesis of postprandial hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM). we administered an oral glucose load enriched with [14C]glucose to 10 NIDDM subjects and 10 age- and weight-matched nondiabetic volunteers and compared muscle glucose disposal by measuring forearm balance of glucose. lactate. alanine. O2. and CO2 (with forearm calorimetry). In addition. we used the dual-lable isotope method to compare overall rates of glucose appearance (Ra) and disappearance (Rd). suppression of endogenous glucose output. and splanchnic glucose sequestration. During the initial 1-1.5 h after glucose ingestion. plasma glucose increased by approximately 8 mM in NIDDM vs. approximately 3 mM in nondiabetic subjects (P less than 0.01); overall glucose Ra was nearly 11 g greater in NIDDM than nondiabetic subjects (45.1 +/- 2.3 vs. 34.4 +/- 1.5 g. P less than 0.01). but glucose Rd was not significantly different in NIDDM (35.1 +/- 2.4 g) and nondiabetic (33.3 +/- 2.7 g) subjects. The greater overall glucose Ra of NIDDM subjects was due to 6.8 g greater endogenous glucose output (13.7 +/- 1.1 vs. 6.8 +/- 1.0 g. P less than 0.01) and 3.8 g less oral glucose splanchnic sequestration of the oral load (31.4 +/- 1.5 vs. 27.5 +/- 0.9 g. P less than 0.05). Although glucose taken up by muscle was not significantly different in NIDDM and nondiabetic subjects (39.3 +/- 3.5 vs. 41.0 +/- 2.5 g/5 h). a greater amount of the glucose taken up by muscle in NIDDM was released as lactate and alanine (11.7 +/- 1.0 vs. 5.2 +/- 0.3 g in nondiabetic subjects. P less than 0.01). and less was stored (11.7 +/- 1.3 vs. 16.9 +/- 1.5 g. P less than 0.05). We conclude that increased systemic glucose delivery. due primarily to reduced suppression of endogenous hepatic glucose output and. to a lesser extent. reduced splanchnic glucose sequestration. is the predominant factor responsible for postprandial hyperglycemia in NIDDM.
Wisconsin Epidemiologic Study of Diabetic Retinopathy. XII. Relationship of C-peptide and diabetic retinopathy, The relationship between plasma C-peptide and the frequency and severity of diabetic retinopathy was examined in a population-based study in Wisconsin in 1984-1986. Individuals with younger- (n = 835) and older- (n = 940) onset diabetes were included. C-peptide was measured by radioimmunoassay with Heding's M1230 antiserum. Retinopathy was determined from stereoscopic fundus photographs. The highest frequencies and most severe retinopathy were found in insulin-using individuals with undetectable or low plasma C-peptide (less than 0.3 nM). whereas the lowest frequencies of retinopathy were found in older-onset overweight individuals not using insulin. In older-onset individuals using insulin. having no detectable C-peptide was significantly associated with the presence of proliferative retinopathy. Otherwise. within each group (younger onset using insulin. older onset using insulin. and older onset not using insulin). after controlling for other characteristics associated with retinopathy. there was no relationship between higher levels of C-peptide and lower frequency of or less severe retinopathy.
Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients, We searched for metabolic crossover points in muscle glucose metabolite profiles during maintenance of matched glucose fluxes across forearm muscle in insulin-resistant type I (insulin-dependent) diabetic patients and nondiabetic subjects. To classify subjects as insulin sensitive or insulin resistant. whole-body and forearm glucose disposal. oxidative and nonoxidative glucose disposal (indirect calorimetry). and glycogen synthesis (muscle glycogen content in needle biopsies) were measured under euglycemic conditions at two insulin concentrations. Whole-body and forearm muscle glucose disposal were significantly reduced in diabetic patients compared with control subjects. The reduction in total glucose disposal was due to similar relative reductions in oxidative and nonoxidative glucose disposal. pointing toward rate limitation early in glucose metabolism. The defect in nonoxidative glucose disposal was at least partly due to a defect in muscle glycogen synthesis. because muscle glycogen content failed to increase in response to an increase in the plasma insulin concentration in the diabetic patients. The most-insulin-resistant type 1 diabetic patients were restudied under conditions where. by glucose mass action. whole-body glucose disposal was forced to be similar to that in the control subjects. Matching glucose fluxes in the two groups resulted in similar rates of forearm and whole-body oxidative and nonoxidative glucose disposal and muscle glycogen synthesis. but it did not result in accumulation of free intracellular glucose. glucose-6-phosphate. glucose-1-phosphate. fructose-6-phosphate. or lactate in muscle. These data imply that the rate-limiting defect for glucose disposal in skeletal muscle of type I diabetic patients is at the level of glucose transport.
Favorable response to parenteral nutrition and medical therapy in Crohn's colitis. A report of 38 patients comparing severe Crohn's and ulcerative colitis, The courses of 38 patients with severe. uncomplicated acute colitis (16 with Crohn's colitis and 22 with ulcerative colitis) were analyzed retrospectively. The patients were placed on total parenteral nutrition and treated concomitantly with corticosteroids. antibiotics (often metronidazole). sulfasalazine. and/or azathioprine. Fifteen of the 16 Crohn's colitis patients were initially managed without surgery. Four patients subsequently relapsed. two responded to reinstituted medical therapy. and two underwent colon resection 2 and 4 years later. Of 22 ulcerative colitis patients. 16 required surgery during the initial hospitalization. one patient subsequently had surgery. and one died after refusing surgery. Three of the other four continue in remission on medical therapy. Thus. there were significant differences in this series between the clinical courses of severe ulcerative colitis and severe Crohn's colitis. While most of the ulcerative colitis patients with severe disease underwent colectomy. most of the patients with severe but uncomplicated Crohn's colitis responded to aggressive medical therapy. of which total parenteral nutrition and perhaps bowel rest seemed to be an important part. Afterwards. the majority remained in remission on long-term medical therapy.
Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6, Human hepatocytes in primary culture were used as a model system to investigate the mechanism(s) involved in the induction of the acute-phase response in human liver. Hepatocytes were incubated with increasing amounts of recombinant human interleukin-1 beta. recombinant interleukin-6 and tumor necrosis factor-alpha. Synthesis of C-reactive protein was studied at the mRNA and protein levels. Only recombinant interleukin-6 was capable of inducing C-reactive protein-mRNA and C-reactive protein-protein synthesis. Also. fibrinogen and alpha-1-antitrypsin synthesis measured by immunoprecipitation with specific antisera increased in a dose-dependent. time-dependent manner. whereas albumin synthesis decreased to about 50% of controls. Maximal effects were observed at 100 to 300 units of recombinant interleukin-6/ml culture medium after 20 hr of incubation. Although the synthetic glucocorticoid dexamethasone slightly modulated the effect of recombinant interleukin-6. it was not an absolute requirement for the induction of acute-phase protein synthesis in human hepatocytes. In pulse-chase experiments it was shown that the time course of the disappearance of the acute-phase proteins from the cells and their appearance in the medium is not influenced by recombinant interleukin-6. This finding suggests that recombinant interleukin-6 exerts its regulatory effect on acute-phase protein synthesis at the pretranslational level.
Effect of artificial surfactant on pulmonary function in preterm and full-term lambs, We hypothesized that agents very different from surfactant may still support lung function. To test this hypothesis. we instilled FC-100. a fluorocarbon. and Tween 20. a detergent. which have higher minimum surface tensions and less hysteresis than surfactant. into 15 full-term and 14 preterm lambs. FC-100 and Tween 20 were as efficient as natural surfactant in improving gas exchange and compliance in preterm lambs with respiratory failure. Dynamic compliance correlated with the equilibrium surface tension of the alveolar wash in both full-term (P less than 0.02) and preterm (P less than 0.008) lambs. Functional residual capacity in full-term and preterm lambs was lower after treatment with the two test agents than with surfactant. findings consistent with qualitative histology. Oxygenation in full-term lambs correlated with mean lung volumes (P less than 0.003). suggesting that the hysteresis and/or low minimum surface tension of surfactant may improve mean lung volume. and hence oxygenation. by maintaining functional residual capacity. The effects of the test agents suggest that agents with biophysical properties different from surfactant may still aid lung expansion.
Effects of sleep-induced increases in upper airway resistance on ventilation, To determine the effects of the sleep-induced increases in upper airway resistance on ventilatory output. we studied five subjects who were habitual snorers but otherwise normal while awake (AW) and during non-rapid-eye-movement (NREM) sleep under the following conditions: 1) stage 2. low-resistance sleep (LRS); 2) stage 3-4. high-resistance sleep (HRS) (snoring); 3) with continuous positive airway pressure (CPAP); 4) CPAP + end-tidal CO2 partial pressure (PETCO2) mode isocapnic to LRS; and 5) CPAP + PETCO2 isocapnic to HRS. We measured ventilatory output via pneumotachograph in the nasal mask. PETCO2. esophageal pressure. inspiratory and expiratory resistance (RL.I and RL.E). Changes in PETCO2 were confirmed with PCO2 measurements in arterialized venous blood in all conditions in one subject. During wakefulness. pulmonary resistance (RL) remained constant throughout inspiration. whereas in stage 2 and especially in stage 3-4 NREM sleep. RL rose markedly throughout inspiration. Expired minute ventilation (VE) decreased by 12% in HRS. and PETCO2 increased in LRS (3.3 Torr) and HRS (4.9 Torr). CPAP decreased RL.I to AW levels and increased end-expiratory lung volume 0.25-0.93 liter. Tidal volume (VT) and mean inspiratory flow rate (VT/TI) increased significantly with CPAP. Inspiratory time (TI) shortened. and PETCO2 decreased 3.6 Torr but remained 1.3 Torr above AW. During CPAP (RL.I equal to AW). with PETCO2 returned to the level of LRS. VT/TI and VE were 83 and 52% higher than during LRS alone. Also on CPAP. with PETCO2 made equal to HRS. VT. VT/TI. and VE were 67. 112. and 67% higher than during HRS alone.
Arterial chemoreceptor input to respiratory hypoglossal motoneurons, To better understand the role of the arterial chemoreceptors in the regulation of upper airway patency at the level of the oropharynx. intracellular recordings were obtained from inspiratory hypoglossal motoneurons (IHMs). and the responses to selective activation of the carotid body chemoreceptors were examined. In pentobarbital-anesthetized. vagotomized. paralyzed. and artificially ventilated cats. chemoreceptor activation enhanced the inspiratory depolarization of membrane potential in 32 of 36 IHMs. This was manifested as an increase in either the amplitude (n = 13) or duration (n = 3) or an increase in both amplitude and duration (n = 16) of the inspiratory membrane potential depolarization. The amplitude and duration of the inspiratory membrane potential depolarization increased 98 +/- 15% (n = 29) and 78 +/- 13% (n = 19). respectively. Similar patterns of enhanced activity (increased duration and/or amplitude of membrane depolarization) were observed in five expiratory hypoglossal motoneurons (EHMs) after chemoreceptor activation. In 16 of the 32 IHMs. chemoreceptor activation also evoked changes in IHM membrane potential during expiration: enhanced post-inspiratory discharge (n = 6). expiratory depolarization/discharge (n = 6). and tonic depolarization/discharge. which persisted for several respiratory cycles (n = 4). The arterial chemoreceptors provide a powerful excitatory input to IHMs during both inspiration and expiration. This excitatory drive to IHMs and EHMs will aid in the maintenance of upper airway patency throughout the respiratory cycle during increases in end-tidal CO2.
Prostacyclin production by blood-contacting surfaces of endothelialized vascular prostheses, This study examines prostacyclin production by blood-contacting surfaces within woven vascular prostheses of polydioxanone (PDS). polyglactin 910 (PG910). or Dacron interposed into rabbit infrarenal aortas. Grafts and normal aortic segments were explanted after 1. 3. and 6 months for pulsatile perfusion with Medium-199 for 60 minutes. Aliquots were removed serially for 6-keto-PGF1 alpha assay. After 30 minutes sodium arachidonate (10 micrograms/ml) was added. Specimens were studied by light microscopy. SEM and TEM. Patency in all three groups exceeded 90%. All three showed re-endothelialization at one month. Normal aorta produced low basal 6-keto-PGF1 alpha with a marked evanescent post arachidonate increase. Dacron did not differ from normal aorta. PG910 and PDS both produced significantly less 6-keto-PGF1 alpha post arachidonate at one month but both increased to normal by three months.
Coexistence of autoantibody to human thyrotropin (TSH) and autoanti-idiotypic antibody to antihuman TSH antibody in a case with simple goiter, A 70-yr-old woman with simple goiter showed normal serum levels of T4. T3. free T4. TSH receptor antibody (TRAb) and increased TBG. Discrepancy in serum hTSH level was observed by different assay methods. Coexistence of both autoantibodies for hTSH and for anti-hTSH antibody were demonstrated by the reaction of the patient's antibody with both 125I-hTSH and 125I-anti-hTSH (monoclonal antibody; mAb). These two autoantibodies belong to the polyclonal immunoglobulin G (IgG). The autoantibody for hTSH recognized only beta-subunit of hTSH. Neither stimulating type of TRAb in Graves' disease nor blocking type of TRAb in primary hypothyroidism interfered with the binding of the patient's antibody to 125I-hTSH or 125I-anti-hTSH. Anti-idiotypic antibody (anti-ID antibody) for anti-hTSH antibody was purified by anti-hTSH antibody affinity chromatography. The binding reaction of 125I-anti-hTSH (mAb) with this anti-ID antibody could be inhibited by the unlabeled hTSH. This anti-ID antibody might represent the internal image of the nonbiological active site of TSH molecule. because of absence of thyroid stimulating activity. Goiter in this patient may have occurred by the unbound TSH with IgG (free TSH) and the bound TSH with IgG. because TSH levels in both the whole serum and the IgG free serum (the unbound TSH with IgG) were decreased significantly by T4 treatment. Coexistence of these antibodies may participate in the autoimmune mechanism of an idiotype-anti-idiotype network.
Immunochemical analysis of the alpha-subunit of the stimulatory G-protein of adenylyl cyclase in patients with Albright's hereditary osteodystrophy, Albright's hereditary osteodystrophy (AHO) is an autosomal dominant disorder characterized by an unusual phenotypic appearance and reduced biological activity of the alpha-subunit of the stimulatory G-protein of adenylyl cyclase (Gs alpha). In most AHO patients deficient Gs alpha activity is associated with generalized target organ resistance to hormones that act via stimulation of adenylyl cyclase. This form of the disorder is termed pseudohypoparathyroidism type Ia (PHP Ia). By contrast. other patients with Gs alpha deficiency fail to demonstrate clinical evidence of hormone resistance and are considered to have the related disorder pseudopseudohypoparathyroidism (pseudoPHP). Previous studies demonstrating deficient Gs alpha bioactivity in cell membranes from patients with AHO used functional assays that were unable to distinguish between reduced amounts of normal Gs alpha protein and normal amounts of defective Gs alpha protein. In the present study we used specific Gs alpha antisera to analyze immunoactive Gs alpha protein in erythrocyte and fibroblast membranes from 20 patients with AHO who had either normal or reduced levels of Gs alpha mRNA. Cell membranes were subjected to immunoblot analysis using Gs alpha antisera developed against synthetic peptides corresponding to amino acid sequences in the amino- or carboxyl-terminus of the Gs alpha molecule. Fibroblast membranes from patients with AHO who had reduced or normal levels of Gs alpha mRNA contained both the 45- and 52-kDa forms of the Gs alpha protein in quantities that were significantly less [mean +/- SE. 52 +/- 6%; (n = 8) for reduced mRNA and 35 +/- 19% (n = 2) for normal mRNA. percentage of control values] than those present in membranes from normal subjects. Similar reductions were found in the level of the 45-kDa form of Gs alpha in erythrocyte membranes from all AHO patients studied [40 +/- 4% (mean +/- SE) of control values]. No abnormal forms of Gs alpha protein were detected. Cell membranes from patients with PHP type Ia and from patients with pseudoPHP contained levels of immunoactive Gs alpha that were equivalently reduced (43 +/- 4% vs. 42 +/- 5%. respectively). By contrast. erythrocyte membranes from patients with PHP type Ib. who have normal Gs alpha activity. had normal levels of Gs alpha immunoactivity (101 +/- 7%). These results indicate that most patients with AHO have reduced levels of Gs alpha protein as the basis for deficient Gs alpha bioactivity.
Effect of age on response to human menopausal gonadotropin stimulation, Conception rates decline in the latter part of the reproductive years. To examine which ovarian parameters are altered with aging. 486 cycles from 225 ovulatory infertile women undergoing human menopausal gonadotropin (hMG) superovulation and washed intrauterine insemination were analyzed. Infertility factors included endometriosis (68%). unexplained infertility (8.4%). male factor (12.9%). and ovulatory dysfunction (10.7%). Parameters that demonstrated a linear relationship with increasing age included numbers of ampules of hMG required per cycle (r = 0.79; P less than 0.05). days of stimulation (r = 0.73; P less than 0.01). estradiol level at the time of hCG (r = -0.92; P less than 0.0001). number of follicles larger than 15 mm (r = -0.61; P less than 0.05). and rate of rise of estradiol (r = -0.92; P less than 0.0001). These same age-dependent changes were observed in women receiving a standard stimulation protocol (3 ampules hMG beginning on cycle day 2). When standard cycles were limited to the first cycle only. the preovulatory estradiol (r = -0.92; P less than 0.005). slope of estradiol rise (r = -0.92; P less than 0.005). and number of preovulatory follicles (r = -0.92; P less than 0.005) still showed a significant decrease with age. Although the mean estradiol level per preovulatory follicle showed a slight decrease with maternal age. no statistically significant trend was noted. In addition. the cycle day of hCG administration was unaffected by age. With advancing age. there appears to be a decreased ovarian response to an increased amount of stimulation. as measured by steroidogenesis and follicular recruitment; yet the estradiol/follicle remains unaltered. indicating continued health of the follicle. These observations may explain in part the observed decrease in fecundity in older women.
Fasting hyperglycemia normalizes oxidative and nonoxidative pathways of insulin-stimulated glucose metabolism in noninsulin-dependent diabetes mellitus, The present studies were undertaken to determine whether fasting hyperglycemia can compensate for decreased insulin-stimulated glucose disposal. oxidation. and storage in noninsulin-dependent diabetes mellitus (NIDDM) as well as to determine whether hyperglycemia normalizes insulin-stimulated skeletal muscle glycogen synthase and pyruvate dehydrogenase (PDH) activities. To accomplish this. we used the glucose clamp technique with isotopic determination of glucose disposal and indirect calorimetry for measuring the pathways of glucose metabolism. and vastus lateralis muscle biopsies to determine the effects of insulin on glycogen synthase and PDH activities. Nine patients with NIDDM and eight matched non-diabetic subjects were infused with insulin (40 mU/m2.min) while plasma glucose was maintained at the prevailing fasting concentration. During insulin infusion. rates of glucose disposal. storage. and oxidation were the same in the two groups. Insulin infusion significantly activated glycogen synthase fractional velocity to the same extent in NIDDM (0.210 +/- 0.056 vs. 0.332 +/- 0.079) and controls (0.192 +/- 0.036 vs. 0.294 +/- 0.050). Insulin infusion increased PDH fractional velocity in controls (from 0.281 +/- 0.022 to 0.404 +/- 0.038). but not in NIDDM (from 0.356 +/- 0.043 to 0.436 +/- 0.060). although the activity of PDH during insulin infusion did not differ between the groups. We conclude that prevailing fasting hyperglycemia normalizes the nonoxidative and oxidative pathways of insulin-stimulated glucose in metabolism in NIDDM and may act as a homeostatic mechanism to normalize muscle glucose metabolism.
Simultaneous occurrence of cutaneous T cell lymphoma and low-grade B cell lymphoproliferative diseases. A report of two cases, Two previously unreported patients with cutaneous T cell lymphoma associated with systemic low-grade B cell proliferations are presented. The first patient had Waldenstrom's macroglobulinemia and the second had simultaneous chronic lymphocytic leukemia. The use of immunosuppressive drugs or a genetic predisposition may have contributed to the second malignancy. However. the possibility that malignant helper/inducer T lymphocytes were a factor in the promotion of the proliferation of B cells cannot be excluded.
Cutaneous type of adult T cell leukemia/lymphoma in a French West Indian woman. Clonal rearrangement of T-cell receptor beta and gamma genes and monoclonal integration of HTLV-I proviral DNA in the skin infiltrate, A 45-year-old woman. a native of the French West Indies who had lived in France since 1973. developed multiple cutaneous plaques and nodules in 1987. Histopathologic studies revealed dermal infiltration with mature activated T cells (CD4+. CD25+. DR+) with nuclear convolutions and epidermatotropisim. High titers of specific human T lymphotropic virus (HTLV)-I antibodies were detected in the serum. Molecular analysis of DNA extracted from the skin tumor biopsy specimen showed a clonal integration of an HTLV-I provirus and a T-cell clonal population as demonstrated by T-cell receptor beta and gamma gene rearrangement studies. Neither HTLV-I provirus nor T-cell receptor rearrangements were detected in peripheral blood mononuclear cells DNA despite the presence of rare adult T cell leukemia cells (less than 1%) and a small excess of DR-expressing cells. and detection of HTLV-I Pol and Px sequences by in vitro gene amplification. In this case only gene analysis of the skin lesions made possible an early diagnosis of a cutaneous adult T cell leukemia. This illustrates the need for such molecular studies to differentiate. in HTLV-I seropositive patients from endemic areas. a HTLV-I-induced T cell lymphoma from HTLV-I-nonrelated cutaneous T cell lymphomas.
Coronary hemodynamic effects of atrial natriuretic peptide in humans, Studies of the effects of atrial natriuretic peptide on the coronary circulation have yielded conflicting results in animals and have not been fully investigated in human subjects. To further characterize the direct coronary hemodynamic actions of atrial natriuretic peptide in humans and to assess the safety of its administration in patients with coronary artery disease. incremental doses of synthetic atrial natriuretic peptide and nitroglycerin were infused into the left coronary artery in 14 patients. 11 of whom had coronary artery disease. Both agents caused dose-related increases in total coronary sinus blood flow. The largest dose of atrial natriuretic peptide given to all patients (100 micrograms) increased mean coronary sinus blood flow from 127 +/- 7 to 149 +/- 9 ml/min (p less than 0.05) and decreased coronary vascular resistance from 0.93 +/- 0.07 to 0.81 +/- 0.05 mm Hg/ml per min (p less than 0.05); mean arterial blood pressure and heart rate were not affected by this dose of atrial natriuretic peptide. The greatest changes in coronary sinus blood flow (+25%) and coronary vascular resistance (-18%) after atrial natriuretic peptide administration occurred in the patients with coronary artery disease and no other associated cardiovascular disease. The maximal effects of atrial natriuretic peptide were similar to those of nitroglycerin. and no untoward effects were observed. Thus. atrial natriuretic peptide is a direct coronary vasodilator in humans. Its maximal dose effects are similar to those of nitroglycerin and were well tolerated in this small group of patients. The physiologic importance and therapeutic potential of atrial natriuretic peptide in patients with coronary artery disease merit further investigation.
Tocainide and mortality after myocardial infarction: a prospective study in conscious dogs, The production of an anterior myocardial infarction as part of an experimental animal model for sudden death was burdened by a persistently elevated mortality rate (30%) despite the use of traditional antiarrhythmic drugs. Mortality was reduced when tocainide (600 mg three times daily) was empirically administered for 4 days before and 4 days after myocardial infarction. Retrospective analysis showed that mortality at 4 days after infarction was significantly lower in the tocainide-treated dogs than in the preceding large group of dogs that had not been so treated (5 [9%] of 55. versus 64 [32%] of 199. p less than 0.01). This difference was still evident 30 days after myocardial infarction (13 [24%] of 55 versus 83 [42%] of 199; p less than 0.05). This observation led to the present prospective study in 106 dogs with a similar protocol but with a randomized sequence. At 4 days after myocardial infarction. the mortality rate was 55% lower in the tocainide group than in the control group (7 [12.5%] of 56 versus 14 [28%] of 50; p less than 0.05). During the 10 days after treatment withdrawal 9 (18%) of 49 dogs in the tocainide group died compared with only 2 (5%) of 36 in the control group. This rebound in mortality produced similar survival figures in the two groups at 14 and at 30 days after infarction when mortality was 30% (17 of 56) in the tocainide group and 34% (17 of 50) in the control group. The tocainide plasma levels were 7.4 +/- 4 micrograms/ml the day before infarction and 7.2 +/- 3 micrograms/ml 3 days after infarction.
In vitro tests for the diagnosis of aspirin-sensitive asthma, In patients with aspirin-sensitive asthma. no significant changes in plasma beta-thromboglobulin or bicyclic prostaglandin (PG) E2 were observed during aspirin challenge. The addition of aspirin to platelet suspensions from patients with aspirin-sensitive asthma produced no detectable chemiluminescence. Small concentrations of aspirin generated PGF2 alpha but not PGE2 or PGD2 from plasma in vitro. PGF2 alpha levels were significantly higher in plasma from aspirin-sensitive patients and distinguished aspirin-sensitive from aspirin-tolerant patients with asthma. The results of this study suggest that the displacement of protein-bound PGF2 alpha may be of importance in the pathogenesis of aspirin-induced asthma.
Allergen-induced increase in nonspecific nasal reactivity is blocked by antihistamines without a clear-cut relationship to eosinophil influx, Antihistaminic compounds have been suggested to possess other properties besides H1-receptor antagonism. To evaluate whether two different antihistamines could inhibit local eosinophil infiltration and allergen-induced nonspecific nasal hyperreactivity. 15 subjects with seasonal allergic rhinitis participated in a double-blind. randomized. placebo-controlled study outside the pollen season. At steady-state levels of either 60 mg of terfenadine. twice daily. cetirizine. 10 mg once daily. or placebo. a nasal methacholine challenge was performed before and 24 hours after a nasal allergen challenge. The volume of the methacholine-induced nasal secretions was measured. The response to allergen was determined with a scoring technique. Cells from the nasal mucosal surface were harvested with the aid of a rhinobrush. Both antihistamines induced a similar (p less than 0.01) reduction in nasal symptoms after the allergen challenge compared with placebo. Both antihistamines inhibited the increased nonspecific nasal reactivity induced by methacholine 24 hours later (p less than 0.05). The allergen challenge induced an increase in surface eosinophils. which. however. appeared unaffected by any of the active treatments. Since histamine per se does not induce changes in nonspecific reactivity. we suggest that the antihistamines possess other properties besides being H1-receptor antagonists.
A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares during 24 hours in normal subjects, We objectively tested the relative antihistaminic effects of cetirizine. 10 mg; terfenadine. 120 mg; terfenadine. 60 mg; loratadine. 10 mg; astemizole. 10 mg; chlorpheniramine. 4 mg; and placebo in healthy. male volunteers. mean age 25 +/- 4 years. and mean weight. 73 +/- 9 kg. The wheal areas and flare areas produced by epicutaneous tests with histamine phosphate. 1 mg/ml. before ingestion of the H1-receptor antagonist or placebo. and afterward. at 0.3 and 0.7 hours. then hourly from 1 to 12 hours and at 24 hours. were traced at 10 minutes and measured with an IBM-PC digitizer and stereometric software. In this experimental model. the H1-receptor antagonists differed significantly with regard to time of onset of action. amount of suppression of the histamine-induced wheal and flare. and duration of action. The rank order was. from most effective to least effective. cetirizine. 10 mg; terfenadine. 120 mg; terfenadine. 60 mg; loratadine. 10 mg; astemizole. 10 mg; chlorpheniramine. 4 mg; and placebo.
A multicenter trial of nedocromil sodium, 1% nasal solution, compared with cromolyn sodium and placebo in ragweed seasonal allergic rhinitis, This study was a double-blind. parallel-group study to evaluate a new medication. nedocromil sodium. 1%. in comparison with placebo and cromolyn sodium. 4%. for treatment of ragweed seasonal allergic rhinitis. Two hundred thirty-three patients (aged 12 to 65 years) from eight centers were randomized to treatment. one spray per nostril. four times daily. with nedocromil sodium. cromolyn sodium. or matched placebo (80. 76. and 77 patients. respectively). All patients had at least a 2-year history of ragweed seasonal allergic rhinitis. Treatment was for 8 weeks during the ragweed season. and daily pollen counts were used to identify the peak 3-week period. Clinic examinations were made before and after the 1-week baseline and after 1. 3. 5. and 8 weeks of treatment. Rhinitis symptoms were recorded each day by the patients. Nedocromil sodium was more effective than placebo (p less than 0.05) in relieving symptoms as recorded by the patients. Cromolyn sodium was also more effective than placebo. but the difference was not usually significant. Similarly. the active treatments were both better than placebo for clinical parameters measured at visits and for global opinions of treatment. and more rescue therapy was used by the placebo-treated group. There was no significant difference between the two active treatments. but the trend throughout was in favor of nedocromil sodium. Our findings demonstrated nedocromil sodium to be at least as effective as an established therapy (cromolyn sodium) in reducing symptoms of rhinitis during the peak ragweed pollen season.
Antihistamines in the treatment of clinical asthma, Because the older antihistamines possessed relatively weak antihistaminic action. as well as sedative and anticholinergic effects. they could not be administered in doses high enough to confer relief to atopic patients with asthma. In contrast. the newer nonsedating. more potent H1-receptor antagonists appear to achieve effective histamine blockade in patients with asthma. Terfenadine and astemizole inhibit bronchoconstriction induced by inhaled allergens by 50% in the early asthmatic reaction. High-potency antihistamines also significantly reduce cough and wheeze as compared with placebo in grass pollen-sensitive asthma patients. Significant reductions in symptom severity and bronchodilator use were found with terfenadine. 120 mg twice daily. although these improvements may be confined to younger patients. Some of the newer antihistamines have demonstrated interesting effects on the late-phase allergic response. Azelastine partially inhibits bronchoconstriction in the allergen-induced late reaction of atopic persons with asthma. possibly by suppressing the release of additional inflammatory mediators. In the skin. cetirizine has been found to reduce eosinophil and neutrophil late-phase infiltration and prostaglandin D2 release. These interesting properties now warrant further investigation in clinical studies.
Factors associated with short- versus long-term skilled nursing facility placement among community-living hip fracture patients, Characteristics associated with long-term placement among community-living patients admitted to a skilled nursing facility (SNF) after a hip fracture were identified. Subjects were 151 consecutive. elderly. community-living persons discharged from two acute hospitals to SNFs after surgery for a hip fracture. Medical. functional. psychological. social. and outcome data were collected from hospital and nursing home charts. Ninety-seven subjects (64%) were discharged home within 6 months; 50 (33%) became permanent SNF residents; and four died. Multiple logistic regression identified orientation. younger age. ability to bathe independently. family involvement. ability to ambulate or transfer independently. and greater number of available physical therapy hours as factors contributing independently to returning home. Likelihood of returning home increased from 7% among subjects with fewer than two of the patient characteristics to 82% among subjects with four or more characteristics (P less than .0005). These results suggest that hip fracture patients at high risk of permanent SNF placement can be identified at time of hospital discharge. Investigations are needed to determine whether more intensive rehabilitation and discharge planning may improve the chance of returning home for a large percent of hip fracture patients.
Depletion of CD8+ cells exacerbates organ-specific autoimmune diseases induced by CD4+ T cells in semiallogeneic hosts with MHC class II disparity, Autoimmune diseases are known to be induced in some donor-recipient combinations of mice undergoing the graft-vs-host reaction (GVHR). In this paper. we report on the development of primary biliary cirrhosis (PBC)-like hepatic lesions and also on pancreatic insulitis in (B6 x bm12)F1 mice injected with B6 CD4+ T cells. At the sites of these lesions. cellular infiltration around ductal structure was observed. Immunohistochemical studies revealed that both CD4+ and CD8+ T cells were present in the lesions of the liver and pancreas. To clarify the role of the CD8+ T cells. which were probably of host origin. we used a mAb against the Lyt-2 molecule. Both the PBC-like hepatic lesions and pancreatic insulitis were exacerbated by eliminating CD8+ T cells from mice with MHC class II GVHR. Also. autoantibodies against the pyruvate dehydrogenase-E2 component. which has been recently found to contain an immunodominant site (autoepitope) for B cell reactivity in patients with PBC. were detected in the sera of these mice by ELISA and their presence was confirmed by immunoblotting procedures. Our findings suggest that similar mechanisms as in GVHR caused by MHC class II disparity are active in the development of PBC. It should also be noted that. in addition to the hepatic lesions. insulitis closely resembling that seen in the nonobese diabetic mouse was induced in our experimental system. The results suggest that our model provides a unique opportunity to study organ-specific autoimmune diseases. Because the effector in our experimental system was defined to be CD4+ T cells responding to Iabm12 Ag. our findings support the hypothesis that an excessive immune response directed against Ia Ag can produce autoimmune disease.
IL-6 is produced by osteoblasts and induces bone resorption, To examine the possible involvement of IL-6 in bone metabolism. a mouse osteoblastic cell line (MC3T3-E1) and primary osteoblast-like cells from fetal mouse calvaria were cultured with several systemic and local bone-resorbing agents and their expression of IL-6 mRNA was determined. Local bone-resorbing agents such as IL-1 alpha. IL-1 beta. TNF-alpha. and LPS greatly induced IL-6 mRNA expression in both MC3T3-E1 cells and primary osteoblast-like cells. Parathyroid hormone slightly increased expression of IL-6 mRNA in primary osteoblast-like cells but not in MC3T3-E1 cells. Neither IL-6 nor 1 alpha.25-dihydroxyvitamin D3 increased expression of IL-6 mRNA in either of the osteoblast-like cells. In agreement with the expression of IL-6 mRNA. biologically active IL-6 was produced in response to the treatment with IL-1 alpha. TNF-alpha. and LPS in MC3T3-E1 cells. Adding IL-6 dose dependently stimulated the release of 45Ca from prelabeled fetal mouse calvaria. Simultaneously adding suboptimal concentrations of IL-6 and IL-1 alpha induced bone resorption cooperatively. In accord with the increase in the release of 45Ca by IL-6. there were three times as many osteoclasts in the bone sections of calvaria cultured with IL-6 for 5 days as in the controls. IL-6 slightly suppressed alkaline phosphatase activity and collagen synthesis in MC3T3-E1 cells. These results indicate that IL-6 is also produced by osteoblasts. preferentially in response to local bone-resorbing agents. and it induces bone resorption both alone and in concert with other bone-resorbing agents.
Class I MHC genes and CD8+ T cells determine cyst number in Toxoplasma gondii infection, To determine roles of MHC class I and II genes in protection against Toxoplasma gondii. H-2 congenic and mutant mice were infected perorally with bradyzoites of T. gondii and brain cysts were enumerated 30 days later. As B10 mice (H-2b) are cyst susceptible and B10.A mice (H-2a) are cyst resistant. B10 congenic mice having the same alleles but different H-2 haplotypes were used to locate the controlling gene. Genes located at H-2L (i.e.. class I genes) were found to regulate the number of brain cysts which form following peroral infection with T. gondii (p less than 0.001) with Ld being resistant and Lb being susceptible. The regulatory function of the H-2L gene product was confirmed through the study of D mutant (dm) mice. B10.D2-H-2dm1 (dm1) mice have a gain-loss mutation in Dd and Ld (i.e.. recombination of Ld and Dd) and BALB/c-H-2dm2 (dm2) mice have a deletion of the Ld gene. Both these dm strains were cyst susceptible (p less than 0.001). These results provide the first direct evidence that class I genes regulate numbers of T. gondii cysts that form. In vivo ablation of CD8+ T cells with mAb YTS 169.4 converted cyst resistant B10.BAR12 mice to cyst susceptible. This result is consistent with a role for MHC restricted CD8+ cytotoxic (or suppressor) T cell regulation of cyst formation. A mutation in Ia in B6.C-H-2bm12 (bm12) mice amplified cyst numbers in susceptible mice. which is consistent with the importance of helper/inducer T cells in the induction of cytotoxic T cells. These findings are relevant to understanding the complex immunologic mechanisms that protect against T. gondii infection. development of protective preparations. and provide a conceptual basis for determining whether similar immunogenetic regulation of susceptibility is also operative in humans.
Tissue plasminogen activator in psoriasis, Elevated levels of the serine proteinase plasminogen activator are observed in psoriatic lesions. In contrast to normal epidermis. lesional psoriatic epidermis contains primarily tissue type plasminogen activator (tPA) activity and much lower levels of urokinase type plasminogen activator (uPA) activity. Tissue plasminogen activator is also detectable immunocytochemically in lesional psoriatic but not normal epidermis. Similarly. mRNA for tPA is observed in lesional epidermis only. These results suggest that lesional psoriatic epidermis synthesizes enhanced levels of tPA compared to normal. Additional data support the hypothesis that enhanced tPA may be another marker common to psoriatic epidermis. epidermis during wound repair. and keratinocytes in culture. The significance of elevated tPA in psoriatic lesions is presently unclear. but its possible relationship to epidermal proliferation and cutaneous inflammation is under study.
mRNA for tissue-type plasminogen activator is present in lesional epidermis from patients with psoriasis, pemphigus, or bullous pemphigoid, but is not detected in normal epidermis, Plasminogen activator (PA). which catalyzes the conversion of plasminogen to the proteinase plasmin. has been implicated in a variety of cutaneous disorders. Lesional epidermis from patients with psoriasis. pemphigus. bullous pemphigoid. and Hailey-Hailey disease contains elevated levels of tissue-type PA (tPA) activity compared to non-lesional epidermis or to epidermis from normal individuals. In the present study. we have used Northern blot analysis to demonstrate that mRNA for tPA is detectable in lesions from patients with psoriasis. pemphigus. and bullous pemphigoid. but is not detectable in normal epidermis. These data strongly suggest that the tPA enzymatic activity present in lesional epidermis results from enhanced synthesis of the enzyme in situ. secondary to elevated steady-state levels of tPA mRNA. Cultured keratinocytes likewise are shown to contain tPA mRNA. Previous investigators have suggested that the phenotypes of keratinocytes in culture. psoriatic epidermis. and epidermis in the process of wound reepithelialization are comparable. Our findings. combined with those of other investigators. suggest that elevated tPA expression may be another common feature of epidermis under these circumstances.
Human nidogen gene: identification of multiple RFLP and exclusion as candidate gene in a family with epidermolysis bullosa (EBS2) with evidence for linkage to chromosome 1, Epidermolysis bullosa (EB) is a group of heritable blistering diseases affecting the dermal-epidermal basement membrane zone. We have recently provided evidence for genetic linkage of the molecular defect in a large family with dominant simplex. generalized (Koebner) type of EB (EBS2) to the long arm of chromosome 1. Because human nidogen gene has been mapped to chromosomal locus 1q43 in the human genome. we examined the possibility that nidogen. an integral component of all basement membranes. would be the candidate gene in this family of EBS2. Restriction fragment-length polymorphism. which was shown with several restriction endonucleases to be present within the nidogen gene. was utilized for linkage analyses. The results using an informative PvuII polymorphism as a marker of allelic inheritance supported exclusion of the EBS2 locus from approximately 10 cM in either side of the nidogen locus. when Lod score of -2.0 was taken as the limit of exclusion. This study demonstrates the feasibility of examining other families with EB for possible linkage to the nidogen locus.
Fc epsilon receptor II/CD23 positive lymphocytes in atopic dermatitis: II. Infiltration of Fc epsilon R II(+) T cells in the skin lesion, Cells expressing Fc receptors for IgE (Fc epsilon R II) were identified in skin from patients with atopic dermatitis (AD). eczematous dermatitis (ED). and in skin from normal nonatopic subjects. with the use of monoclonal antibodies to human lymphocyte Fc epsilon R II. H107. and to lymphoid cell-surface antigens by double immunofluorescence staining. Two to four percent of infiltrating mononuclear cells expressed Fc epsilon R II. and more than half of these cells were T epsilon cells in both acute and chronic AD lesions. Fc epsilon R II(+) T cells (T epsilon cells) bearing CD8 infiltrated preferentially acute lesions. whereas chronic lesions contained either CD8(+) or CD4(+) T epsilon cells. or both. Fc epsilon R II(+) cells rarely were present in ED lesions. There was no significant correlation between % Fc epsilon R II(+) peripheral blood mononuclear cells and the proportion of lesional Fc epsilon R II(+) cells. extent of skin lesions. or serum IgE levels. implying the selective accumulation of Fc epsilon R II(+) cells in the inflammatory infiltrate of AD. These observations suggest that the increased generation of Fc epsilon R II(+) cells in skin lesions. including CD8 (+) T epsilon cells. is involved in the pathogenesis of AD.
Circulating human immunodeficiency virus (HIV) p24 antigen-positive lymphocytes: a flow cytometric measure of HIV infection, Asymptomatic individuals seropositive for human immunodeficiency virus (HIV) progress in a heterogeneous fashion toward AIDS. To facilitate monitoring of disease progression and response to therapy. a rapid. new flow cytometric assay (FCA) lymphocyte p24-FCA. has been devised to quantify peripheral blood lymphocytes expressing cell-associated HIV-1 p24 antigen. Results from 55 asymptomatic. HIV-1-seropositive. serum p24 antigen-negative individuals ranged from undetectable (less than 0.1%) to 13.6% p24+ lymphocytes (mean. 2.0%). Mean values for three other groups studied were 0.1% for seronegative. viral culture-negative laboratory workers (n = 24); 4.2% for untreated patients with AIDS (n = 16); and 0.3% for AIDS patients receiving zidovudine (n = 11). Lymphocyte p24-FCA values were inversely related to the number of days to positive viral cultures and to levels of CD4+ lymphocytes. The ratio of p24+ lymphocytes to CD4+ lymphocytes may reflect the fraction of infected CD4+ lymphocytes. Lymphocyte p24-FCA determination may provide a method for monitoring response to antiretroviral therapy regardless of serum p24 antigen status.
Branhamella catarrhalis: antigenic determinants and the development of the IgG subclass response in childhood, A recently developed whole cell ELISA was used to investigate the development of IgG subclass antibodies to Branhamella catarrhalis in childhood. In addition. SDS-PAGE and immunoblotting were used to study the interaction between the outer membrane proteins (OMPs) of B. catarrhalis and IgG subclass antibodies. Specific IgG3 antibodies were undetectable or present only in low amounts in children less than 4 years old but were an important constituent of the response of older children. OMPs prepared from different isolates had similar molecular masses and bound IgG with identical immunoblotting patterns. Binding appeared subclass-specific. with IgG3 binding to the broadest range of OMPs. These findings should provide a better understanding of the pathogenic role of this organism and suggest possible strategies for the development of a vaccine.
Pulmonary clearance and phagocytic cell response in a murine model of Branhamella catarrhalis infection, C5-sufficient Swiss-Webster mice (C5+) and C5-deficient DBA/2J mice (C5-) when challenged endotracheally with 2 x 10(7) cfu of Branhamella catarrhalis rapidly clear the lungs of viable bacteria in 48 h. This rapid clearance correlates with a striking influx of polymorphonuclear neutrophils that is of equal magnitude in both C5+ and C5- animals. Supernatant from Todd-Hewitt broth culture of B. catarrhalis exhibits in vivo chemotactic activity in the murine lung and in vitro chemotactic activity in Boyden chambers. The ability of B. catarrhalis to recruit granulocytes. independent of complement. may suggest a role for this organism in promoting protease-mediated lung destruction.
Phenotypes and functions of lymphocytes in congenital toxoplasmosis, Comparisons of lymphocyte surface phenotypes and functions were made among 25 pediatric patients with congenital toxoplasmosis (ages 1 month to 5 years) and 24 uninfected babies. a baby with postnatally acquired infection. and 6 uninfected. 7 recently infected. and 6 chronically infected adults. Percentages of lymphocytes with B1. T11. T3. T4. T8. T6. B4. Ia. NKH phenotypes and T4 to T8 ratios of infected and uninfected babies were the same (p greater than 0.05). Lymphocytes from congenitally infected babies had lower blastogenic responses (mean stimulation index [SI] = 5) to Toxoplasma lysate antigens (TLA) than lymphocytes from adult control groups with recent and chronic infection (Mean SIs = 32. 72; p less than 0.001). Compared to infected adults. congenitally infected children had similar or greater responses to concanavalin A (mean SIs = 94; 118. 76. p greater than 0.05) and in mixed leukocyte culture (mean SIs = 63; 22. 26. p greater than 0.05). For symptomatic babies. low blastogenic response to TLA correlated with more severe disease at presentation (p = 0.002). Lymphocyte blastogenic responses to TLA were increased for most children when they were older than 15 months. but responses remained less than adult levels for 9 of the 17 older children studied. There was no correlation between concomitant serum pyrimethamine levels and lymphocyte blastogenic responses to TLA. Pyrimethamine and sulfonamide treatment in vitro and in vivo did not alter lymphocyte response to TLA. Lymphocytes from congenitally infected babies failed to produce either gamma interferon or Interleukin 2 when cultured with TLA. In contrast. they produced these lymphokines when cultured with concanavalin A or phytohemagglutinin. Specific deficits in cell-mediated immune responses to TLA may account for the significant organ damage that occurs in infants and children with congenital toxoplasmosis.
Role of radiation therapy for 'juvenile' angiofibroma, Juvenile nasopharyngeal angiofibroma (JNA) is a rare benign neoplasm which occurs primarily in male adolescents and is characterized by aggressive local growth. The controversy concerning appropriate treatment for patients with juvenile angiofibroma persists. Radiation therapy and surgical resection have both been reported to be effective to control a high proportion of these tumours. The case reported here demonstrates a locally advanced JNA controlled by radiation therapy.
Ifosfamide plus etoposide combined with regional hyperthermia in patients with locally advanced sarcomas: a phase II study, From July 1986 to July 1989. 40 patients (92% pretreated) with deep-seated. advanced soft tissue sarcomas (STS. 25 patients). Ewing's sarcomas (ES. eight patients). osteosarcomas (OS. three patients) and chondrosarcomas (ChS. four patients) were treated at the University of Munich in a protocol involving regional hyperthermia (RHT) combined with ifosfamide plus etoposide. A total of 265 RHT treatments (mean. 6.6 RHT per patient) were applied including 33 pelvic. four extremity. and three abdominal sites. The mean tumor volume was 537 cc (range. 50 to 2.980 cc). For systemic chemotherapy. all patients received ifosfamide (1.5 g/m2. days 1 to 5). etoposide (100 mg/m2. days 1. 3. and 5). and mesna (300 mg/m2 x 4. days 1 to 5) with RHT given only on days 1 and 5 in repeated cycles every 4 weeks. Acute toxicity consisted primarily of pain (57%) combined with local discomfort within the annular phased array applicator (AA) of the BSD hyperthermia system (BSD Medical Corp. Salt Lake City. UT). The average maximum systemic temperature was 37.4 +/- 0.5 degrees C. and there was no indication of enhanced bone marrow toxicity due to the addition of RHT to the systemic chemotherapy. Detailed thermal mapping by invasive thermometry was performed in all patients. In 38 assessable patients. the overall objective response rate was 37%: six complete responses (CRs). four partial responses (PRs). and four favorable histologic responses (FHRs) (95% confidence limits. 22% to 54%). Complete responders are alive and disease-free at 40. 35. 23. 19. 19. and 8 months. Of patients with PR and FHR. two died from metastatic disease after 4 and 17 months and one died from other disease after 27 months. The remaining five patients are stable at 37. 25. 21. 13. and 8 months. Eleven patients showed no change (NC). and 13 patients showed local tumor progression (PD). The mean observation time for all patients was 11.6 months. The time-averaged temperatures (Ts) of all RHT treatments calculated as 20% (T20). 50% (T50). or 90% (T90) of measured tumor sites differed significantly between responders and nonresponders (T20. P = .003; T50. P = .006; and T90. P = .004; respectively). These data support activity for ifosfamide-etoposide combined with RHT in pretreated patients with advanced sarcomas.
Trimetrexate in prostatic cancer: preliminary observations on the use of prostate-specific antigen and acid phosphatase as a marker in measurable hormone-refractory disease, Thirty-one patients with bidimensionally measurable hormone-refractory prostatic cancer received trimetrexate (TMTX). Serial values of prostate-specific antigen (PSA) and acid phosphatase (SAP) were correlated with response. Five patients (17%; 95% confidence interval. 3% to 30%) achieved a partial remission for a median of 3 months (range. 3 to 7.5 months). Marker levels showed large variations with no discernible patterns. Serial PSA and SAP in 19 patients with abnormal baseline values showed a correlation with measurable disease response in only 68% (13 of 19) and 47% (nine of 19) of patients. respectively. Values were then smoothed using an exploratory data analysis technique of running medians and averages. Trends in marker changes were much more apparent. Several "decision rules" were evaluated for use of markers as indices of disease progression. A 50% increase from the patient's minimum value in either PSA or SAP on two successive determinations correlated with progression in 90% of cases in this trial. TMTX has modest activity in prostatic cancer. and further trials are not warranted. Biochemical markers do not uniformly reflect disease activity in hormone-refractory disease. and changes in biochemical markers must be interpreted cautiously when used as the sole end point to assess efficacy in clinical trials.
Effects of radiation on testicular function in long-term survivors of childhood acute lymphoblastic leukemia: a report from the Children Cancer Study Group, Testicular function was evaluated in 60 long-term survivors of childhood acute lymphoblastic leukemia (ALL). All the patients were treated on two consecutive Children Cancer Study Group protocols and received identical chemotherapy and either 18 or 24 Gy radiation therapy (RT) to one of the following fields: craniospinal plus 12 Gy abdominal RT including the gonads (group 1); craniospinal (group 2); or cranial (group 3). The median age at the time of their last evaluation was 14.5 years (range. 10.5 to 25.7). which took place a median of 5.0 years (range. 1 to 10.3) after discontinuing therapy. The incidence of primary germ cell dysfunction as judged by raised levels of follicle-stimulating hormone (FSH) and/or reduced testicular volume was significantly associated with field of RT; 55% of group 1. 17% of group 2. and 0% of group 3 were abnormal (P = .002). Leydig cell function. as assessed by plasma concentrations of luteinizing hormone (LH) and testosterone. and pubertal development. was unaffected in the majority of subjects regardless of RT field. These data indicate that in boys undergoing therapy for ALL. germ cell dysfunction is common following testicular irradiation and can occur following exposure to scattered irradiation from craniospinal RT. In contrast. Leydig cell function appears resistant to direct irradiation with doses as high as 12 Gy.
Phase II trial of interferon gamma and monoclonal antibody 17-1A in pancreatic cancer: biologic and clinical effects, Thirty patients with advanced measurable pancreatic adenocarcinoma were entered onto a phase II trial with recombinant interferon gamma (Biogen. Cambridge. MA; 10(6) U/m2 daily for 4 days) and monoclonal antibody (Mab) 17-1A (Centocor. Malvern. PA; 150 mg in autologous leukocytes on days 2. 3. and 4 following interferon infusion). The effect of a single interferon gamma treatment on natural and antibody-dependent cellular cytotoxicity (ADCC). Fc receptor occupancy by antibody. and human leukocyte antigen-DR (HLA-DR) expression on monocytes and lymphocytes was also studied. Toxicity was modest and generally limited to grade I to II fever. nausea and vomiting. and hepatotoxicity. Five patients were considered to be nonassessable for response. Of the 25 assessable patients. one objective response (complete remission for a duration of 4 months) was observed. Stable disease for 2 months or greater was noted in nine patients. The median survival for the group was 5 months. Analysis of cytotoxicity data obtained prior to treatment showed reduced natural cytotoxic activity in these patients compared with normal volunteers. A significant improvement in natural cytotoxic activity to normal levels occurred within 24 hours following the interferon gamma infusion. This was also associated with augmented antibody-dependent cellular cytotoxicity. Although HLA-DR expression was not increased on either monocytes or lymphocytes. an increased capacity of both lymphocytes and monocytes to bind Mab 17-1A was observed. In all in vitro assays of ADCC. the presence of antibody excess was associated with improved cytolytic activity. In spite of the favorable modulation of cytolytic activity and improved ability of effector cells to bind Mab. we failed to demonstrated adequate clinical efficacy in the treatment of patients with pancreatic adenocarcinoma using this dose and schedule of interferon gamma and Mab 17-1A. Future trials will focus on alternate schedules of Mab 17-1A with the hope of improving tumor antigen saturation and circulating levels of infused antibody.
Can iodine-131 whole-body scan be replaced by thyroglobulin measurement in the post-surgical follow-up of differentiated thyroid carcinoma, This study compared serum thyroglobulin measurement and whole-body scans in the post-surgical follow-up of patients with differentiated thyroid carcinoma. Thyroglobulin levels were measured in 61 patients receiving L-thyroxine therapy after thyroidectomy. and again after suspension of therapy. before performing a whole-body scan with iodine-131. The sensitivity. specificity. and accuracy of thyroglobulin levels. measured during L-thyroxine therapy. for diagnosis of tumor residue or metastases were then calculated and compared with results obtained by diagnostic whole-body scanning. Our data show that neither thyroglobulin levels nor whole-body scans alone can discriminate between patients with or without metastases. Sensitivity reached 95.7%. specificity 100%. and accuracy 96.7% if results of both procedures were also taken into consideration. We conclude that in the management and follow-up of patients with differentiated thyroid carcinoma both parameters need to be evaluated.
Detection of talocalcaneal coalitions by magnification bone scintigraphy, Fibrocartilaginous talocalcaneal coalitions are very difficult to identify on plain radiography in symptomatic children and adolescents before gross ossification occurs. Computed tomography (CT) has been successful in identifying osseous and some fibro-osseous coalitions. In this series. magnification imaging of the tarsus on bone scintigraphy in the medial-lateral projection correctly identified talocalcaneal coalitions. seven of the nine bars were fibrous or fibro-osseous. Three of the fibrous lesions were equivocal or normal on conventional radiography and CT. Physiologic accumulations of activity in the growing hind foot are also presented from a control pediatric population. Magnification scintigraphy of the hind foot is offered as an adjunct to plain radiography and CT in the diagnosis of elusive nonosseous subtalar bars.
Transcutaneous carbon dioxide pressure for monitoring patients with severe croup, In a prospective investigation of 17 children with severe croup. we analyzed the effect of epinephrine inhalations and mild sedation with chloral hydrate on transcutaneous carbon dioxide pressure (tcPCO2). pulse oximetry measurements. and croup scores. There was a highly significant reduction (p less than 0.001) in the tcPCO2 values and croup scores after inhalation of epinephrine. The changes in the tcPCO2 values correlated with the clinical findings. Mild sedation also significantly improved the croup scores but failed to influence the tcPCO2 values. There was not statistically significant difference in pulse oximetry saturation. fraction of administered oxygen. heart rate. or respiratory rate before and after inhalation of epinephrine or chloral hydrate administration. Monitoring tcPCO2 appears to be a reliable and objective tool for managing patients with upper airway obstruction. whereas croup scores may be misleading.
Early randomized intervention with high-frequency jet ventilation in respiratory distress syndrome, To determine whether early use of high-frequency jet ventilation reduces neonatal mortality or pulmonary morbidity rates. we randomly selected 42 infants with clinical and radiographic evidence of severe respiratory distress syndrome to receive either high-frequency jet ventilation or conventional ventilation. Separate sequential analyses (two-sided. alpha = 0.05. power = 0.95 to detect 85:15 advantage) were performed for mortality rates. air leaks. bronchopulmonary dysplasia. intraventricular hemorrhage. and assignment crossover. and a combined analysis was performed. with death overriding other outcome variables. Enrollment was completed when the combined analysis reached the sequential design boundary indicating no treatment difference. Mortality rates (19% among infants receiving high-frequency jet ventilation vs 24% among infants receiving conventional ventilation). the incidence of air leaks (48% vs 52%). bronchopulmonary dysplasia (39% vs 41%). and intraventricular hemorrhage (33% vs 43%). and assignment crossovers (14% vs 24%) did not differs significantly between the treatment groups. We conclude that early use of high-frequency jet ventilation does not prevent or substantially reduce mortality or morbidity rates associated with assisted ventilation.
Influence of chondroitin sulfate, heparin sulfate, and citrate on Proteus mirabilis-induced struvite crystallization in vitro, Struvite crystals were produced by Proteus mirabilis growth in artificial urine. in the presence of a number of naturally occurring crystallization inhibitors. The use of phase contrast light microscopy enabled the effects of added chondroitin sulfate A. chondroitin sulfate C. heparin sulfate. or sodium citrate. on struvite crystal growth rates to be rapidly monitored as changes in crystal habit. Struvite crystals formed as a consequence of the urease activity of P. mirabilis under all chemical conditions. In the absence of inhibitor. early crystal development was marked by large quantities of amorphous precipitate. followed immediately by the appearance of rapidly growing X-shaped or planar crystals. Addition of the glycosaminoglycans. chondroitin sulfate A. chondroitin sulfate C. or heparin sulfate to the artificial urine mixture had no effect on the rate of crystal growth or appearance. When sodium citrate was present in elevated concentrations. crystal appearance was generally slowed. and the crystals assumed an octahedral. slow growing appearance. None of the added compounds had any influence on bacterial viability. pH. or urease activity. It is therefore likely that the inhibitory activity displayed by sodium citrate might be related to its ability to complex magnesium or to interfere with the crystal structure during struvite formation. From these experiments it would appear that citrate may be a factor in the natural resistance of whole urine to struvite crystallization.
Prognostic significance of prostate specific antigen in endocrine treatment for prostatic cancer, The prognostic value of prostate specific antigen was evaluated to predict disease progression after endocrine therapy in patients with prostatic cancer. A total of 73 patients was studied (6 with stage B2. 16 with stage C. 9 with stage D1 and 42 with stage D2 disease). Endocrine therapy included bilateral orchiectomy. diethylstilbestrol diphosphate and luteinizing hormone-releasing hormone analogue. Pre-treatment serum prostate specific antigen levels were determined in all patients with an enzyme immunoassay kit. During a followup of 4 to 68 months (average 24 months) clinical disease progression occurred in 24 of the 73 patients. The pre-treatment prostate specific antigen level by itself did not predict disease progression. Changes in prostate specific antigen level with treatment were correlated with the interval to disease progression in the 44 patients who had prostate specific antigen determinations at regular intervals after endocrine therapy and whose initial level was greater than 10 ng./ml. Patients who had a decrease in the prostate specific antigen levels of 80% or more within 1 month after the beginning of therapy survived significantly longer free of disease progression (p less than 0.001). Patients whose prostate specific antigen level remained elevated for more than 3 months had a high risk of disease progression within 2 years. Our study suggests that patients with the more favorable prognosis can be identified early. after 1 to 3 months of endocrine therapy. by the rapid decrease in the prostate specific antigen levels.
Paratesticular rhabdomyosarcoma: results of therapy in 18 cases, The management of paratesticular rhabdomyosarcoma has evolved more slowly than that for testicular germ cell tumors. mainly due to its lower incidence and the lack of standardized treatment protocols. With gradual refinements in staging and therapy the prognosis has improved. Between 1960 and 1988. 18 patients 2 to 18 years old were treated at the Children's Hospital. Management consisted of inguinal orchiectomy. staging evaluation and retroperitoneal lymph node dissection. followed by chemotherapy and radiotherapy according to the stage of the disease. In 11 patients (61%) the disease was confined to the scrotum. while 7 presented with spread to the retroperitoneal lymph nodes. including 3 children with more distant metastases. Histological study revealed predominantly embryonal characteristics except for 1 alveolar cell type. Chemotherapy consisted of actinomycin D in 2 patients. vincristine. actinomycin D and cyclophosphamide in 2. pulse vincristine. actinomycin D and cyclophosphamide in 10. and doxorubicin plus vincristine. actinomycin D and cyclophosphamide in 4. A total of 17 patients remain free of disease (median followup 4 years) with 1 death. The actuarial survival without relapse and over-all survival rate are 89 and 94%. respectively. We conclude that paratesticular rhabdomyosarcoma represents a favorable subgroup of rhabdomyosarcoma.
Malignant mesothelioma of the tunica vaginalis testis, Malignant mesothelioma of the tunica vaginalis is an extremely rare tumor. Appropriate treatment consists of inquinal orchiectomy with close followup. Treatment of locally recurrent malignant mesothelioma of the tunica vaginalis has not been standardized. We recommend radical resection for the initial presentation of locally recurrent disease rather than saving surgical resection as salvage therapy after other treatment modalities have failed. We report case 37 of malignant mesothelioma of the tunica vaginalis and review the literature.
Risk factors for measles in a previously vaccinated population and cost-effectiveness of revaccination strategies, Using data from a large measles outbreak that occurred in Dane County (Wisconsin) in 1986. we conducted a case-control study to evaluate risk factors for vaccine failure and assessed the cost-effectiveness of school-based revaccination strategies. Vaccination before a change in the measles vaccine stabilizer in 1979 (odds ratio. 5.5; 95% confidence interval. 1.05 to 28.9) and vaccination before age 15 months (odds ratio. 13.9; 95% confidence interval. 5.9 to 32.6) were identified as risk factors. Revaccination strategies for all students ($3444 per case prevented). students vaccinated before 1980 ($3166 per case prevented). and students vaccinated before age 15 months ($2546 per case prevented) were evaluated. assuming use of measles-mumps-rubella vaccine after the initial case was detected in a school. However. a large proportion of cases (43% to 53%) may not have been preventable using these strategies. Therefore. revaccination in all schools assessed to be at risk for measles may be necessary to prevent large outbreaks until a two-dose vaccination schedule is fully implemented.
Torsades de pointes occurring in association with terfenadine use, Torsades de pointes is a form of polymorphic ventricular tachycardia that is associated with prolongation of the QT interval. Although found in many clinical settings. torsades de pointes is most often drug induced. This report describes the first association (exclusive of drug overdose) of symptomatic torsades de pointes occurring with the use of terfenadine in a patient who was taking the recommended prescribed dose of this drug in addition to cefaclor. ketoconazole. and medroxyprogesterone. Measured serum concentrations of terfenadine and its main metabolite showed excessive levels of parent terfenadine and proportionately reduced concentrations of metabolite. suggesting inhibition of terfenadine metabolism. We believe that a drug interaction between terfenadine and ketoconazole resulted in the elevated terfenadine levels in plasma and in the cardiotoxicity previously seen only in cases of terfenadine overdose.
Nucleic acid labeling with [3H]orotic acid and nucleotide profile in rats in protein deprivation, enteral and parenteral essential amino acid administration, and 5-fluorouracil treatment, Rats were fed a 0% casein diet for 1 week. with or without enteral or parenteral administration of essential amino acids. or a 25% casein diet. in one group supplemented with 5-fluorouracil treatment. Ninety minutes before sacrifice the rats were given a tracer of [3H]orotic acid. Incorporation into the acid soluble fraction. RNA. and DNA was determined in liver. small intestine. bone marrow. and kidney. Nucleotide profile was examined in liver and intestine. Protein deficiency caused inter alia a decrease in body weight; a decrease in RNA/DNA ratio and an increase in the specific RNA labeling in liver and kidney; an altered nucleotide profile in the liver; an increase in the nucleotide/DNA and RNA/DNA ratios and a decrease in the specific labeling of the acid soluble fraction. RNA. and DNA in the bone marrow. These changes were prevented to the same extent by giving essential amino acids. either orally or intravenously. The minor changes in intestinal nucleotide profile in protein deprivation were prevented to a slightly larger extent by amino acids orally than parenterally. 5-Fluorouracil treatment gave a decrease in the RNA/DNA ratio in the liver and kidney but an increase in the nucleotide/DNA and RNA/DNA ratios in the bone marrow. Nucleotide profiles were unaltered. The amount of DNA per gram of tissue decreased in bone marrow and increased in kidney. Parenteral administration per se resulted in almost no changes.
A clinical application of exercise physiology and nutritional support for the mechanically ventilated patient, A challenging problem facing the clinician is the management of critically ill patients in whom repeated attempts at weaning from mechanical ventilation are unsuccessful. The difficulty weaning these patients from the ventilator can be augmented in the presence of detraining of respiratory muscles. malnutrition. stress and the metabolic response to injury. and/or immobilization. An understanding of basic concepts of established tenets of exercise physiology and of nutritional support will allow their application to respiratory muscle function with the goal of facilitating the endurance and strength of respiratory muscles needed to sustain spontaneous ventilation.
Nutrition and translocation, It is now clear that atrophy of the intestinal mucosa can occur rapidly after injury and that the degree of atrophy is quantitatively related to the severity of injury. Such atrophy can be associated with translocation of bacteria and endotoxin. which can trigger the hypermetabolic response and induce a septic state. which may ultimately lead to multiple system organ failure. Early enteral feeding following trauma can prevent atrophy of the intestinal mucosa and is associated with a decrease in the hypermetabolic response and the incidence of septic complications and diarrhea. Enteral feeding of complete diets can also improve outcome with other forms of intestinal injury such as gamma irradiation or cytotoxic drugs. In contrast. total parenteral nutrition and elemental enteral diets are associated with atrophy of the intestinal mucosa and increased translocation. The addition of glutamine and/or fiber to elemental diets may decrease translocation in some but not all circumstances. It is now clear that enteral nutrition can influence the incidence and severity of translocation. which in turn can potentially reverse or prevent the adverse effects of injury and inflammation in traumatic injury and serious illness.
Adrenergic regulation of (Na+, K+)-ATPase activity in proximal tubules of spontaneously hypertensive rats, Increased renal nerve activity and sodium retention have been implicated in the development of hypertension in genetically transmitted forms of this disease. The present studies were designed to investigate the relationship between renal nerve integrity and renal proximal tubule (Na+. K+)-ATPase activity in spontaneously hypertensive rats (SHR). (Na+. K+)-ATPase activity of basolateral membranes (BLMs) enriched from proximal tubules of five-week-old SHR was greater. 328.6 +/- 18.9 nmol Pi/mg protein.min. than in age-matched genetic controls rats (Wistar-Kyoto. WKY. rats). 262.3 +/- 34.6 nmol Pi/mg protein.min (P less than 0.02). There was no detectable difference in (Na+. K+)-ATPase activity of 13-week-old SHR and WKY rats. Prior renal denervation was associated with a reduction in proximal tubule basolateral membrane (BLM) (Na+. K+)-ATPase activity. 316.8 +/- 23.8 to 223.1 +/- 23.9 nmol Pi/mg protein/min (P less than 0.02). in five-week SHR. However. denervation had no effect on renal (Na+. K+)-ATPase activity in either WKY rats. nor did sham-denervation in SHR. In addition. exogenous norepinephrine. 1 microM. produced a more pronounced stimulation of (Na+. K+)-ATPase activity in basolateral membranes from SHR as opposed to WKY controls (40.2% vs. 28.7%). Therefore. renal nerve integrity and exogenous catecholamines have a greater stimulatory influence on proximal tubule (Na+. K+)-ATPase activity in the early stages (prior to 5 weeks) of the development of hypertension in SHR than in age-matched WKY rats.
Small cell lung carcinoma: clinicopathological, immunohistochemical, and ultrastructural study, Sixty-seven cases of small cell lung carcinoma (SCLA) in Tri-Service General Hospital (TSGH) during the past 16 years were studied. For patients with extensive stage of disease. the mean survival time and 2-year survival rate were 7.2 months and 3.1% versus 13.4 months and 16.7% for patients with limited stage. A better prognosis was obtained by treatment with a combination of intensive chemotherapy and radiotherapy. Immunohistochemical studies were performed by the peroxidase-antiperoxidase method. The positive rates in descending order were bombesin (80%). synaptophysin (74.3%). neurofilament (68.6%). neuron-specific enolase (60%). low molecular weight cytokeratin (54.3%). high molecular weight cytokeratin (25.7%). chromogranin-A (22.9%). adrenocorticotrophic hormone (0). Seven cases were examined and found to be ultrastructure; only 3 cases were found to contain neurosecretory granules. We emphasize that electron microscopy is not necessary as a routine diagnostic procedure. while light microscopy should be employed whenever possible; the immunohistochemical study should be considered within this context.
Adjuvant chemotherapy enhances long-term survival of patients with advanced gastric cancer following curative resection, We examined the effectiveness of postoperative adjuvant chemotherapy with mitomycin C (MMC). 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur). plus PSK. an immunomodulator. for patients with advanced gastric cancer who underwent histological curative resection. The effect of chemotherapy on prognostic serosal (ps) invasion [ps(-) or ps(+)] and lymph node metastasis [n(-) or N(+)] was examined. One hundred eighteen patients were in the no-chemotherapy group and 137 were on the drugs. The median follow-up time for the 86 survivors at the time of analysis was 13.8 years. With regard to prognostic factors. there were no differences between the two groups. Generalized Wilcoxon test of the two survival patterns revealed a P value of .0351. and the survival rate for 15 years was 45.7% for patients in the no-chemotherapy group and 56.9% for those of the chemotherapy group. In particular. adjuvant chemotherapy was effective for patients with ps(-)n(+) (P less than .05) and ps(+)n(-) (P less than .05). but not for those with ps(-)n(-) and ps(+)n(+). Our findings show that the concomitant prescription of MMC. tegafur. and PSK improves the 15-year survival rate for patients with advanced gastric cancer. following curative resection. As the survival rate is low for the patients with ps(+)n(+). an even more aggressive postoperative chemotherapy is recommended.
Nutrition and immune function, Despite provision of adequate calories and nitrogen. patients receiving current nutrition support formulations often have suppression of immune function. Certain nutrients may act pharmacologically on the immune system. The choice of nutrients appropriate for a given disease state must take into consideration the nutritional status of the subject. presence of infection. injury or hypermetabolism. and the specific immune defect. Nutritional therapy specific for certain disease states is complex and in its infancy but may hold promise for improved patient outcome. Randomized prospective trials to evaluate efficacy are mandatory. Continued research into individual nutrients to elucidate mechanisms of immunomodulation must follow. In the meantime. broad application of products shown to be effective for a specific indication is inappropriate.
Recommendations for collection of laboratory specimens associated with outbreaks of gastroenteritis, Recent discoveries have implicated a number of "new" (i.e.. previously unrecognized) infectious agents as important causes of outbreaks of gastroenteritis. Unfortunately. the ability to detect these agents in an outbreak can be limited by two factors: 1) the lack of appropriate assays-many of which are still in developmental stages and are not readily available to clinical laboratories. and 2) inadequately or improperly collected specimens. At CDC. many newly developed assays are being used for research and for outbreak investigations. The information in this report is especially intended for public health agencies that collaborate with CDC in investigating outbreaks of gastroenteritis. The report provides an update on guidelines and recommendations for the proper collection of specimens to be sent to CDC. gives general background information concerning some recently discovered pathogens. lists some of the tests available at CDC. and provides a list of CDC contacts. The guidelines and the general information provided on causes of outbreaks of gastroenteritis can be also used by public health workers for investigations when specific testing is available and appropriate.
The GTPase superfamily: a conserved switch for diverse cell functions, Proteins that bind and hydrolyse GTP are being discovered at a rapidly increasing rate. Each of these many GTPases acts as a molecular switch whose 'on' and 'off' states are triggered by binding and hydrolysis of GTP. Conserved structure and mechanism in myriad versions of the switch--in bacteria. yeast. flies and vertebrates--suggest that all derive from a single primordial protein. repeatedly modified in the course of evolution to perform a dazzling variety of functions.
Chronic acetazolamide monotherapy in the treatment of juvenile myoclonic epilepsy, We reviewed the charts of 84 patients with juvenile myoclonic epilepsy (JME) whom we had followed over the past 12 years. and identified 51 treated with acetazolamide (AZM) either because of a poor response to conventional antiepileptic drugs or to avoid valproate-associated adverse effects. Among the 51 we could isolate the effect of AZM on the generalized tonic-clonic seizures (GTCS) of JME in thirty-one. Chronic AZM monotherapy controlled GTCS in 14 of 31 patients. Most tolerated AZM very well; 5. however. developed renal calculi. Chronic AZM monotherapy controls GTCS in some patients with JME. but the development of renal calculi may limit its usefulness.
Clinical chorioamnionitis is not predicted by an ultrasonic biophysical profile in patients with premature rupture of membranes, A modified biophysical profile was assessed serially in 47 patients with premature rupture of membranes who were not in labor. This profile included fetal movement. fetal tone. fetal breathing. amniotic fluid volume. and placental grade. The most recent study. obtained within 2 days of delivery. was compared with pregnancy outcome as reflected by the development of chorioamnionitis and/or neonatal sepsis. No study patient received antibiotics. steroids. or tocolytics before labor. Neither the composite biophysical profile nor any of its components were found to be different between patients with and without clinical chorioamnionitis. Neonatal sepsis was not observed. These data do not support the use of the biophysical profile as a predictor of maternal infection.
Use of a carbon dioxide laser for lesions extending into the lashes, Thirty-six patients with benign lesions extending into the lashes treated with the carbon dioxide laser are reported. Histopathologically adequate specimens and cosmetically acceptable results were obtained in all cases.
Bacterial adherence and contamination during radiographic processing, Oral fluids are potential contaminants of radiographic processors. This investigation measured bacterial contamination in a radiographic processing room during times of high and low clinical activity and processing effects on five types of microorganisms. Cultures in the clinical setting. during high and low activity. were taken by brain-heart infusion agar plates placed near automatic processors. Site samples were taken of entrance. developer. fixer. water. and exit surfaces. Measurements of processing effects were accomplished by intentional contamination of films run in series through an automatic processor. Site samples were again taken of the processor. In the clinical setting colony-forming units increased with activity. Radiographic processing after intentional contamination decreased colony-forming units on films. but they increased for all processing solutions. Bacteria on radiographic film survived processing. Although processing procedures significantly reduce the number of bacteria on films. the potential for contamination and cross-contamination remains.
Acoustic neuroma: a cost-effective approach, A cost-effective approach to the diagnosis and treatment of acoustic neuromas continues to evolve as diagnostic methods improve. In the past 7 months. since gadolinium-enhanced magnetic resonance imaging (MRI) has become available in our practice. our screening and presurgical workup has changed. The purpose of this article is to outline the current philosophy of the senior authors in relation to acoustic neuroma management on the basis of 72 patients diagnosed from July 1988 to February 1989. With more sensitive diagnostic means. older less sensitive studies may be eliminated from the routine workup. thus maintaining cost-effectiveness while preserving the highest standard of patient care. The body of this article will review our current use of the many available diagnostic options and emphasize a cost-effective approach.
Estrogen and progesterone binding by acoustic neuroma tissue, Tissue samples from 37 acoustic neuromas were assayed for estrogen and progesterone hormone receptor binding by radioimmunoassay using a dextran-coated charcoal method and Scatchard plot analysis. Twenty-one of the samples were from men. and 16 of the samples were from women. Seven of 37 samples (19%) were positive for estrogen receptor and six of 36 samples (17%) were positive for progesterone receptor. Three of 37 samples (8%) were positive for both receptors. There was no correlation of estrogen receptor positivity with the sex of the patient. These results indicate that estrogen or progesterone receptor binding activity or both are present in a small subset of acoustic tumors. Evidence is lacking. however. that binding of estrogen to the receptor results in growth changes in the tumor. The empirical use of antiestrogen treatment in acoustic neuroma does not appear to be justified at the present time.
The use of masseter electromyography with electroneurography in the evaluation of facial paralysis, In the evaluation of facial paralysis. electroneurography provides a quantitative assessment of the degree of degeneration. Near the endpoint of degeneration. the facial musculature compound action potential may be contaminated by masseter artifact resulting from supramaximal stimulation. We propose the use of both masseter electromyography and electroneurography in the evaluation of advanced degeneration to better define the current level for supramaximal stimulation. to eliminate masseter artifact. and to more accurately assess the degree of facial nerve degeneration.
Facial translocation: a new approach to the cranial base, Nasopharynx. clivus. and cavernous sinus are difficult regions of the cranial base in which to perform oncologic surgery. We have developed an approach to this area by using facial soft tissue translocation and craniofacial osteotomies. Surgical field obtained at the skull base can extend from the contralateral eustachian tube to ipsilateral geniculate ganglion. It includes the nasopharynx. clivus. sphenoid. and cavernous sinus. as well as the entire infratemporal fossa and superior orbital fissure. Our experience with this technique in 12 patients is reported. All patients healed primarily.
Physiologic status of regenerated hair cells in the avian inner ear following aminoglycoside ototoxicity, Regeneration of avian inner ear hair cells has been demonstrated after administration of aminoglycoside and after acoustic trauma. However. no published study to date has documented functional recovery of these regenerated sensory receptor cells. Newborn chicks were treated with gentamicin sulfate (50 mg/kg/day) for a total of either 5 (n = 10) or 10 (n = 76) days. Evoked potential thresholds were obtained one day after the 5-day treatment. or at intervals between one day and 20 weeks after the 10-day treatment course. and compared to thresholds of age-matched control animals. A significant hearing loss. predominantly in the high frequencies. was present after as few as 5 days of drug administration. The magnitude of hearing loss continued to increase. especially at lower frequencies. as survival increased from 1 day to 5 weeks after gentamicin treatment. Sixteen-to-20 weeks after treatment. partial recovery of thresholds was evident. These findings demonstrate that functional recovery does occur in the avian inner ear following aminoglycoside administration. Recovery occurs at all frequencies. but predominantly at low and middle frequencies. leaving significant residual high-frequency threshold elevation. Recovery lags 14 to 18 weeks behind anatomic evidence of hair cell regeneration. which was demonstrated in one study by 2 weeks after comparable administration of gentamicin.
Rhinolift operation in the treatment of the aging nose, Disturbance of the normal relationship between the caudal border of the upper lateral cartilage and the cephalic margin of the lobular cartilage--the so-called "cul-de-sac" area--can result in alar collapse and nasal airway obstruction. This may be caused by either the aging process or trauma. both surgical and nonsurgical. Rhinolift is a surgical procedure that was developed for the treatment of the aging ptotic nasal tip. We have applied this technique to patients with nasal airway obstruction resulting from alar collapse. Elevation of the cephalic margin of the lobular cartilage to a position superficial to the upper lateral cartilage restores the normal relationship between these two structures. The upper lateral cartilage then assists in stenting the vestibule open. and thereby improves nasal breathing. Over the past 10 years. 20 patients have had rhinolifts at our institution for the relief of nasal airway obstruction. Concomitant surgery included nasal septal reconstruction in 12 patients. polypectomy in one patient. and placement of a silicone rubber septal prosthesis for closure of a large septal perforation in three patients. Rhinolift was the sole procedure used for the correction of valvular pathology in 10 patients. The other 10 patients had modifications made in their upper lateral cartilage along with the rhinolift. Five patients described restoration of normal nasal breathing. while 14 patients showed partial symptomatic improvement. One patient reported no improvement in nasal breathing. Rhinolift is a safe effective surgical technique for functional improvement of nasal breathing in patients with alar collapse resulting from inadequate cartilaginous support.
Birth interval among breast-feeding women not using contraceptives, One hundred twelve Orthodox Jewish mothers were surveyed by means of questionnaire about birth interval in relationship to formula-feeding (n = 30) and breast-feeding (n = 236) experiences in the absence of birth control. Analyses indicate that mothers who breast-fed have longer birth intervals than those who did not. Moreover. data obtained from the same mothers show that birth intervals preceded by breast-feeding were longer than those preceded by formula-feeding of the previous infant. For those mothers who breast-fed. there was significant positive correlation between duration of breast-feeding and the length of lactational amenorrhea and total birth interval. The age at which night feeding was terminated had corresponding but less strong associations with lactational amenorrhea and total birth interval.
Immunoglobulin switch circular DNA in the mouse infected with Nippostrongylus brasiliensis: evidence for successive class switching from mu to epsilon via gamma 1, We have characterized immunoglobulin switch circular DNA in mice infected with the nematode parasite Nippostrongylus brasiliensis. Two kinds of circular DNA were identified in the lymph nodes as excision products of switch recombination of immunoglobulin heavy-chain constant region (CH) genes. One is a recombinant between C mu and C gamma 1 (gamma 1 circle). and the other is a recombinant between C gamma 1 and C epsilon (epsilon circle). In the epsilon circle. a short piece of switch mu (S mu) sequence was inserted between S epsilon and S gamma 1 sequences. The inserted S mu sequence could be a trace of the preceding switch from C mu to C gamma 1. These findings indicate that parasitic infection can induce class switch recombinations in a successive manner. first from C mu to C gamma 1. and then from C gamma 1 to C epsilon.
Structural requirements for recognition of the HLA-Dw14 class II epitope: a key HLA determinant associated with rheumatoid arthritis, Although HLA genes have been shown to be associated with certain diseases. the basis for this association is unknown. Recent studies. however. have documented patterns of nucleotide sequence variation among some HLA genes associated with a particular disease. For rheumatoid arthritis. HLA genes in most patients have a shared nucleotide sequence encoding a key structural element of an HLA class II polypeptide; this sequence element is critical for the interaction of the HLA molecule with antigenic peptides and with responding T cells. suggestive of a direct role for this sequence element in disease susceptibility. We describe the serological and cellular immunologic characteristics encoded by this rheumatoid arthritis-associated sequence element. Site-directed mutagenesis of the DRB1 gene was used to define amino acids critical for antibody and T-cell recognition of this structural element. focusing on residues that distinguish the rheumatoid arthritis-associated alleles Dw4 and Dw14 from a closely related allele. Dw10. not associated with disease. Both the gain and loss of rheumatoid arthritis-associated epitopes were highly dependent on three residues within a discrete domain of the HLA-DR molecule. Recognition was most strongly influenced by the following amino acids (in order): 70 greater than 71 greater than 67. Some alloreactive T-cell clones were also influenced by amino acid variation in portions of the DR molecule lying outside the shared sequence element.
A single amino acid substitution in the variable region of the light chain specifically blocks immunoglobulin secretion, Although immunoglobulin light chains are usually secreted in association with heavy chains. free light chains can be secreted by lymphocytes. To identify the structural features of light chains that are essential for their secretion. we mutated a conserved sequence in the variable domain of a lambda I light chain. The effects of the mutations on secretion were assayed by transient expression in COS-1 cells. One mutant (AV60). which replaced Ala-60 with Val. was secreted as efficiently as wild-type lambda I by transfected COS-1 cells. This result was not surprising because secreted lambda II chains contain valine in this position. However. a second lambda I mutant (AV60FS62). which replaced Phe-62 with Ser as well as Ala-60 with Val. was not secreted. This mutant was arrested in the endoplasmic reticulum. as judged by immunofluorescence and by its association with a lumenal endoplasmic reticulum protein. immunoglobulin heavy chain binding protein (BiP). The defect in secretion was not due to gross misfolding of the lambda I chain. since cells cotransfected with AV60FS62 and an immunoglobulin heavy chain gene produced functional antigen-binding antibodies. These assembled IgM molecules were still not secreted. Hence. the replacement of Phe-62 with Ser specifically affects a determinant on the lambda I light chain that is necessary for the intracellular transport of this molecule.
Acquisition of protease resistance by prion proteins in scrapie-infected cells does not require asparagine-linked glycosylation, The scrapie and cellular isoforms of the prion protein (PrPSc and PrPC) differ strikingly in a number of their biochemical and metabolic properties. The structural features underlying these differences are unknown. but they are thought to result from a posttranslational process. Both PrP isoforms contain complex type oligosaccharides. raising the possibility that differences in the asparagine-linked glycosylation account for the properties that distinguish PrPC and PrPSc. ScN2a and ScHaB cells in culture produce several PrP molecules with relative molecular masses of 26-35 kDa and proteinase K-resistant cores of 19-29 kDa. When the cells were treated with tunicamycin. this heterogeneity was eliminated and a single PrP species of 26 kDa was observed. Several hours after its synthesis. a fraction of this protein became insoluble in detergents and acquired a proteinase K-resistant core. thus displaying two of the biochemical hallmarks of PrPSc. Synthesis in the presence of tunicamycin restricted the proteinase K-resistant cores of PrP to a single species of 19 kDa. No proteinase K-resistant PrP was found in uninfected cells. Expression of a mutated PrP gene lacking both asparagine-linked glycosylation sites in ScN2a cells resulted in the synthesis of 19-kDa proteinase K-resistant PrP molecules. We conclude that asparagine-linked glycosylation is not essential for the synthesis of proteinase K-resistant PrP and that structural differences unrelated to asparagine-linked oligosaccharides must exist between PrPC and PrPSc. Whether unglycosylated PrPSc molecules are associated with scrapie prion infectivity remains to be established.
Mutations of the Gs alpha-subunit gene in Albright hereditary osteodystrophy detected by denaturing gradient gel electrophoresis, Affected members of most kindreds with Albright hereditary osteodystrophy have a partial deficiency of functional Gs. the guanine nucleotide-binding protein that stimulates adenylyl cyclase. By use of the polymerase chain reaction to amplify genomic fragments with the attachment of a high-melting G + C-rich region (GC clamp) and analysis of these fragments by denaturing gradient gel electrophoresis. heterozygous mutations in the Gs alpha-subunit gene were found in two kindreds. These included a G----C substitution at the donor splice junction of intron 10 and a coding frameshift created by a single base deletion within exon 10. The findings illustrate the heterogeneity of genetic defects in Albright hereditary osteodystrophy and the usefulness of the polymerase chain reaction-denaturing gradient gel electrophoresis method to search rapidly for mutations in a large candidate gene.
Identification of nuclear tau isoforms in human neuroblastoma cells, The tau proteins have been reported only in association with microtubules and with ribosomes in situ. in the normal central nervous system. In addition. tau has been shown to be an integral component of paired helical filaments. the principal constituent of the neurofibrillary tangles found in brains of patients with Alzheimer disease and of most aged individuals with Down syndrome (trisomy 21). We report here the localization of the well-characterized Tau-1 monoclonal antibody to the nucleolar organizer regions of the acrocentric chromosomes and to their interphase counterpart. the fibrillar component of the nucleolus. in human neuroblastoma cells. Similar localization to the nucleolar organizer regions was also observed in other human cell lines and in one monkey kidney cell line but was not seen in non-primate species. Immunochemically. we further demonstrate the existence of the entire tau molecule in the isolated nuclei of neuroblastoma cells. Nuclear tau proteins. like the tau proteins of the paired helical filaments. cannot be extracted in standard SDS-containing electrophoresis sample buffer but require pretreatment with formic acid prior to immunoblot analysis. This work indicates that tau may function in processes not directly associated with microtubules and that highly insoluble complexes of tau may also play a role in normal cellular physiology.
Hunter syndrome: isolation of an iduronate-2-sulfatase cDNA clone and analysis of patient DNA, Iduronate 2-sulfatase (IDS. EC 3.1.6.13) is required for the lysosomal degradation of heparan sulfate and dermatan sulfate. Mutations causing IDS deficiency in humans result in the lysosomal storage of these glycosaminoglycans and Hunter syndrome. an X chromosome-linked disease. We have isolated and sequenced a 2.3-kilobase cDNA clone coding for the entire sequence of human IDS. Analysis of the deduced 550-amino acid IDS precursor sequence indicates that IDS has a 25-amino acid amino-terminal signal sequence. followed by 8 amino acids that are removed from the proprotein. An internal proteolytic cleavage occurs to produce the mature IDS present in human liver shown to contain a 42-kDa polypeptide N-terminal to a 14-kDa polypeptide. The IDS sequence has strong sequence homology with other sulfatases (such as sea urchin arylsulfatase. human arylsulfatases A. B. and C. and human glucosamine 6-sulfatase). suggesting that the sulfatases comprise an evolutionarily related family of genes that arose by gene duplication and divergent evolution. The arylsulfatases have a greater homology with each other than with the non-arylsulfatases (IDS and glucosamine 6-sulfatase). The IDS cDNA detected RNA species of 5.7. 5.4. 2.1. and 1.4 kilobases in human placental RNA and revealed structural alterations and gross deletions of the IDS gene in many of the clinically severe Hunter syndrome patients studied.
Differentiation of F9 embryonal carcinoma cells induced by the c-jun and activated c-Ha-ras oncogenes, The activated c-Ha-ras oncogene induced AP1-site DNA-binding activity in F9 cells. This induction appeared to be due. at least in part. to the induction of c-jun transcription. Both activated c-Ha-ras and c-jun induced the differentiation of F9 cells to endoderm-like cells. Thus. AP1 appears to play a key role in the initial stage of F9 cell differentiation.
Collodion as a safe, cost-effective dressing for central venous catheters, Catheter-related sepsis continues to be a major problem with the use of central venous catheters. Controversy exists with respect to dressing material and frequency of dressing changes. Collodion is a solution of pyroxylin in a solution of 75% ether and 25% alcohol. Camphor and castor oil are added to create a flexible noncontracting dressing when applied to the skin. We retrospectively reviewed the charts of 34 patients requiring central venous catheters between 1986 and 1988. All catheters were placed via the subclavian approach. Collodion was used as a dressing on all patients. Dressings were not routinely changed. The catheters remained in position an average of 16.5 days. No insertion site became infected; one episode of catheter-related sepsis occurred. and two catheters were inadvertently dislodged. The overall incidence of catheter-related sepsis was 2.9%.
Adenosine triphosphate-sensitive potassium channels in anoxia, Potassium channels that are activated by decreasing adenosine trisphosphate levels are blocked by sulfonylurea drugs such as glibenclamide but are opened by diazoxide and some endogenous peptides. Judging from the effects of such drugs. it seems that in the hippocampus. these channels are present not on cell bodies but rather on glutamate-releasing nerve terminals (especially those of mossy fibers in the CA3 region). Because activation of these presynaptic potassium channels reduces anoxic glutamate release. they may be a useful target for specific drug therapy that might prevent the excitoxic effects of excessive glutamate release during anoxia/ischemia.
Acid-base changes during complete brain ischemia, We examined the proposal that preischemic hyperglycemia causes exaggerated brain damage by decreasing intracellular or extracellular pH to below a specified threshold value. We also provide a critical appraisal of two related hypotheses. The first is that hyperglycemia enhances brain damage by causing excessive intraglial acidosis; the second. that the critical degree of acidosis is reached not during the ischemia but when recirculation is instituted. The following conclusions are drawn. First. the evidence is inconclusive in favor of marked compartmentation of H+ during ischemia. based on a discontinuous delta lactate/delta PCO2 relation and on direct intracellular pH measurements. In fact. results obtained with identical techniques in normoglycemic animals suggest that the acid compartment assumed to be glia is very small and may be of another origin. Second. although recirculation may give rise to a further increase in either extracellular or intracellular acidosis under certain conditions. this acidosis is not a prerequisite for increased tissue damage or infarction. Third. a critical appraisal of reports supports the contention that enhanced damage is triggered below a specified threshold pH value. In complete or near-complete ischemia. this value corresponds to a tissue lactate content of 17-20 mM.kg-1 wet wt. No correlation exists between subthreshold values for delta lactate and the severity of tissue damage. Furthermore. hyperglycemia cannot be expected to enhance damage if conditions prevent lactate from reaching threshold values or if they uncouple changes in lactate and pH.
Prevalence of anti-HCV in Norwegian blood donors with anti-HBc or increased ALT levels, Testing for hepatitis B core antibodies (anti-HBc) was performed in 12.104 consecutive blood donors. 139 (1.15%) of whom were found to be positive. The first 6036 donors were also screened for ALT; 91 (1.51%) had repeatedly elevated values. ALT screening was of no help in detecting anti-HBc-positive donors. Those with anti-HBc or repeatedly raised ALT levels were further tested for hepatitis C virus antibodies (anti-HCV). and 3 (2.16%) and 1 (1.10%) anti-HCV-positive donors were detected. respectively. This prevalence of anti-HCV (0.5%) is not significantly different from that found in 1000 unselected donors at our blood bank. Testing for ALT and anti-HBc as surrogate markers for hepatitis C is therefore not recommended in Norwegian blood donors and should be replaced by anti-HCV screening.
Fracture of the pelvis: current concepts of classification, Historically. pelvic fractures have been classified according to whether there is pelvic stability or instability. although confusion has been caused by the inclusion of many eponyms that mainly reflect the observation of a single author on a particular fracture pattern. Pennal and Tile were the first authors to attempt to classify pelvic fractures according to the force vector causing them. This concept was refined by Young and Burgess. who provided a more detailed classification system. again relating to force vectors. This article focuses on this classification and its significance with regard to pelvic stability. type of pelvic disruption. and hence the type of corrective forces that should be applied in the surgical management. Use of a classification system of pelvic fractures based on force vectors allows the orthopedic surgeon to apply external fixation in the most appropriate manner to correct pelvic deformity and to maximize patients' survival.
Gastrointestinal lipomas: a radiologic and pathologic review, Lipomas of the gastrointestinal tract are an infrequent finding on radiologic examination; however. they occur often enough to warrant consideration in the differential diagnosis of mass lesions of the gut. In many instances. their morphologic characteristics allow the specific diagnosis of a lipoma. In this report. we review gastrointestinal lipomas with an emphasis on their radiologic and pathologic correlation.
Piezoelectric biliary lithotripsy: an in vitro study of factors affecting gallstone fragmentation, Factors affecting the fragmentation of gallstones with piezoelectric lithotripsy were studied in vitro. with a goal of providing data that will help direct treatment with piezoelectric lithotriptors. Two hundred fifty-seven stones from 50 patients were treated with the EDAP LT.O1 lithotriptor until all fragments measured 2 mm or less in diameter. The fragmentation process was observed. and two patterns were evident: central fragmentation and peripheral chipping. The majority of stones fragmented centrally. Fragmentation characteristics in different stones from the same patient were compared with those from different patients. Stone diameter. shock-wave frequency and power. and CT appearance were examined and correlated with fragmentation. Gallstones from the same patient showed uniform fragmentation patterns and consistent relationships between fragmentation time and gallstone size. shock-wave frequency. and power. In stones from the same patient. gallstone size had a marked effect on fragmentation time. which correlated with the cube of the stone diameter. and shock-wave frequency and power had a proportional inverse linear relationship with fragmentation time. When controlling for stone size and treatment parameters. stones from multiple patients showed marked differences in fragmentation time. and because of this. poor correlation between stone size and fragmentation time. Stones grouped according to CT pattern and attenuation showed wide variation and no correlation between CT characteristics and fragmentation pattern or fragmentation time. Our results show that a great variability exists in fragmentation time of gallstones. making it impossible to accurately predict fragmentation time at a given stone size. Only rough estimates of longer fragmentation times with increasing stone size can be made. The linear relationships between shock-wave frequency or power and fragmentation time allow one to easily predict the effect of manipulating these variables and to tailor treatment to each patient's tolerance. Finally. CT appearance does not appear to be predictive of fragmentation outcome.
Nonaspiration fine-needle cytology of the liver: a new technique for obtaining diagnostic samples, We studied a new method of obtaining diagnostic cytology samples from the liver that differs from fine-needle aspiration cytology in that no suction is used to obtain the sample. This method is simpler to perform than traditional aspiration biopsy and yields concentrated cell smears that are easier to interpret. The sample enters the needle because of capillary action. a physical property of fluid that causes it to flow into the lumen of a narrow channel. This nonaspiration technique was used in 40 consecutive patients undergoing fine-needle biopsy of mass lesions of the liver. A 22-gauge spinal needle was used in all procedures. The cytology smears obtained were prepared. stained. and interpreted by the same methods used for conventional fine-needle cytology specimens. Specific diagnoses were rendered in 36 patients (90%) and in 32 (94%) of those patients with malignant tumors. An average of 1.7 needle passes (range. 1-4) was needed per patient. We conclude that the results from nonaspiration fine-needle cytology of the liver are as good as those from conventional aspiration technique. and the nonaspiration technique is easier to perform and results in smears that are easier to interpret.
Percutaneous ethanol injection therapy of hepatocellular carcinoma: analysis of 77 patients, Although sonographically guided percutaneous ethanol injection therapy has been attracting a great deal of attention in the treatment of liver neoplasms. few reports regarding long-term results of this therapy have been published. We report here our 4-year experience. in which ethanol injection was performed 419 times on 108 lesions in 77 patients with hepatocellular carcinoma. Histopathologic examination performed in 14 cases after the therapy revealed that the lesion was completely necrotic in 10 cases. 90% necrotic in three cases. and 70% necrotic in the remaining case. Angiography performed after the therapy showed complete disappearance of tumor stain in 37 of 42 cases treated with ethanol injection. CT after the therapy showed no enhancement of the treated lesion in 55 of 56 cases. Elevated serum levels of alpha-fetoprotein decreased in 21 of 24 cases. Ethanol injection improved the long-term prognosis of the patients. Among the 50 patients in whom there were three or fewer lesions and all lesions were treated by ethanol injection. the 1-. 2-. 3-. and 4-year survival rates were 89%. 74%. 68%. and 60%. respectively. Factors that significantly affected the prognosis were the goal of the treatment. liver function. and size of the largest lesion. Serious complications rarely occurred even in patients with severe liver dysfunction. Percutaneous ethanol injection therapy appears to be valuable for treatment of hepatocellular carcinoma.
Regenerating nodules in hepatic cirrhosis: MR findings with pathologic correlation, To establish clearly the pathologic basis for small low-intensity nodules seen on MR images of the cirrhotic liver. we obtained MR images in 26 patients with cirrhosis in whom partial hepatectomy for hepatoma (15 patients). laparoscopy for cirrhosis (10 patients). or autopsy (one patient) was subsequently performed. Small low-intensity nodules were seen on gradient-echo images with short TEs (10-13 msec) in 13 of the 26 patients. In 12 of these 13 patients. small low-intensity nodules appeared larger and clearer as the TE was prolonged (14-25 msec). On T2-weighted spin-echo images. small low-intensity nodules were seen in 12 of the 13 patients. but not seen as well as on gradient-echo images. Pathologic correlation in these 13 patients revealed that the nodules on the MR images corresponded to iron deposits in regenerating nodules. Small low-intensity nodules were observed only on T2-weighted spin-echo images in two of the remaining 13 patients. in whom microscopic examination of the liver revealed marked inflammatory cell infiltration in the fibrous septa and no iron deposition. We conclude that small low-intensity nodules observed on MR images are caused by iron deposits in regenerating nodules. and that gradient-echo images with short and prolonged TEs are useful to confirm the presence of iron deposits in regenerating nodules.
Extraadrenal retroperitoneal paraganglioma: clinical, pathologic, and CT findings, Paragangliomas of the retroperitoneum arise from specialized neural crest cells distributed along the aorta in association with the sympathetic chain. In order to ascertain characteristic CT features of extraadrenal retroperitoneal paragangliomas to differentiate them from other retroperitoneal tumors. 31 discrete tumors and two cases of paragangliomatosis in 28 patients were reviewed retrospectively. and the CT features were correlated with clinical and pathologic findings. There were 16 men and 12 women. Average age was 37 years (range. 11-70 years). Twenty-four patients (86%) had hypertension. Of these. catecholamine levels were elevated in all 18 patients who had biochemical studies. Four patients (14%) had malignant paragangliomas. The discrete tumors were classified by location as suprarenal (26%). renal hilar (32%). or infrarenal (42%). Suprarenal paragangliomas could not be distinguished from the ipsilateral adrenal gland on CT. The average size of functional tumors was smaller (7.0 cm) than that of nonfunctional tumors (12.0 cm). but the sizes of the two groups overlapped. Smaller tumors were more likely to be homogeneous and have well-defined margins than were larger tumors. Our findings indicate that extraadrenal retroperitoneal paragangliomas are functionally active more often than previously reported and that they are readily detected by CT as soft-tissue masses closely associated with the entire length of the abdominal aorta. However. no CT feature was found that was unique for paraganglioma.
Value of MR imaging in differentiating benign from malignant soft-tissue masses: study of 95 lesions, MR imaging has largely replaced CT as the technique of choice for preoperative staging of patients with soft-tissue masses. Whether MR imaging can be used to differentiate benign from malignant masses is controversial. Our experience suggests that MR imaging often can characterize soft-tissue masses accurately. To evaluate this question further. we studied 95 consecutive lesions (50 benign and 45 malignant). Consecutive cases were selected to simulate our clinical practice. Surgical proof was available for all masses except hematomas. for which clinical follow-up confirmed the diagnosis. MR images were interpreted twice by three radiologists. The first review was accomplished without any clinical history and the second review with clinical history. Reviewers were asked to classify the lesion as benign or malignant on the basis of their clinical knowledge and analysis of MR image features (size. lesion margin. signal homogeneity. and neurovascular or bone involvement). Although interpretation varied somewhat because of the experience of the reviewers. the specificity and accuracy of diagnosis averaged 90% for both benign and malignant lesions. Negative predictive value for malignancy averaged 94% among the three reviewers. MR imaging is the technique of choice for identification and characterization of soft-tissue masses. The nature of the lesion (benign vs malignant) can be determined in the majority of cases.
MR imaging findings in patients with bone-chip allografts, Increasing use of MR to evaluate primary bone neoplasms has stimulated numerous articles on the initial assessment of these lesions. However. scant MR literature has been written about the postoperative MR appearance. We studied the MR appearance of lesions treated by curettage followed by packing with cancellous bone-chip allograft. We retrospectively reviewed the MR scans of 18 consecutive patients treated in this way. Pathologic diagnoses of these lesions were confirmed according to commonly accepted criteria. The allograft sites showed a distinctive pattern of speckled bright signal on T1-weighted images in eight cases. Thirteen of 18 grafts showed a whorled or speckled pattern of increased signal on the T2-weighted images. Only four allograft regions had predominantly low signal on both T1- and T2-weighted images. Two of 18 patients had recurrent tumor proved by open biopsy. MR images in these cases showed areas of homogeneous signal that replaced areas of speckled hyperintensity on both T1- and T2-weighted images. In both these recurrences the tumor had signal intensity similar to that seen on the preoperative MR study. We conclude that knowledge of the MR appearance of cancellous bone chip allografts is important to avoid misinterpreting areas of high signal on T1- or T2-weighted images as areas of recurrence of tumor and/or hemorrhage.
Cloacal exstrophy: radiologic findings in 13 patients, Cloacal exstrophy is a complex. multisystem malformation that has not received much attention in the radiologic literature. The clinical histories and imaging studies of 13 cases of cloacal exstrophy proved surgically or at autopsy were reviewed. Radiologic observations were based on skeletal plain films (13). contrast-enhanced examinations of the genitourinary system (12). abdominopelvic sonograms (nine). gastrointestinal studies (seven). CT scans of the pelvis and CNS (seven). MR images of the pelvis and CNS (six). renal nuclear medicine scans (three). myelography (three). and three-dimensional scans of the pelvis (two). Genitourinary and gastrointestinal abnormalities identified in our 13 patients included bladder malformations (13). hindgut anomalies (13). undescended testes (five). malrotation (five). duplicated mullerian structures (four). and renal ectopia (four). Skeletal abnormalities included symphysis pubis diastasis (13). posterior element dysraphism (12). vertebral segmentation anomalies (12). clubfeet (six). and hip dislocations (five). CNS anomalies included meningocele (nine) and Chiari malformation (one). Immediate surgical closure of the defect with maximal bowel preservation and diverting colostomy offers optimal chances for survival. Appropriate preoperative gastrointestinal and genitourinary evaluation is essential.
Localization and guided removal of soft-tissue foreign bodies with sonography, Sonography was used to detect. localize. and guide removal of foreign bodies in the soft tissues of the extremities and neck. Twenty localization procedures were performed in 19 patients (12 children and seven adults) with 21 foreign bodies including wood. glass. stone. metal. and lead pencil. Localization was accomplished by using anatomic landmarks. ink marks on the skin. and needle and hemostat markers. Localization was facilitated by the use of small standoff pads that were cut for use on small surfaces. The foreign bodies were visualized as hyperechoic foci with acoustic shadows that were partial or complete depending on the angle of insonation and foreign body composition. Hyperechoic comet-tail artifacts (reverberation artifacts) were seen with six metallic foreign bodies and one glass fragment. Nine foreign bodies were surrounded by hypoechoic halos caused by edema. abscess. or granulation tissue. A slow meticulous scanning technique and high-frequency transducer helped in detection of small foreign bodies. Sonographically guided removal of the foreign body was successful in all four patients in whom it was attempted. Scanning with the ultrasound beam parallel to the long axis of the hemostat and the foreign body was the fastest way to guide the hemostat to the tip of a foreign body. The procedure was accomplished most easily and quickly when one physician performed sonography and hemostat removal of the foreign body simultaneously. Our experience with these cases indicates that sonography is a useful tool in the localization and removal of soft-tissue foreign bodies.
MR imaging of the normal and abnormal clivus, We retrospectively reviewed 330 T1-weighted sagittal images. 80 T2-weighted sagittal images. and 83 gadopentetate-dimeglumine-enhanced scans of normal adults to determine the MR appearance of the normal adult clivus. MR images of 21 patients with an abnormal clivus (19 with tumor invasion and two with marrow reconversion) were also evaluated retrospectively and compared with those of the control group to assess MR features distinguishing the two groups. Our study revealed that a normal adult clivus consisted of low- and high-intensity portions mixed in various proportions on T1-weighted images. The low-intensity portion was isointense or hyperintense relative to the pons and always contained foci of bright signal intensity. The low-intensity tumor of a pathologic clivus tended to be hypointense relative to the pons (17/19). and was completely devoid of foci of bright signal intensity. The normal adult clivus was approximately isointense relative to the pons on T2-weighted images. Clival tumors were grossly hyperintense relative to the pons on T2-weighted images in 11 of 17 patients. In the remaining six patients. either a portion of or the entire lesion was isointense relative to the pons and. therefore. was not detectable on T2-weighted images. A normal adult clivus can enhance to some degree (19/83). Clival tumors were found to enhance intensely. A clivus of very low signal intensity (signal void) on T1- or T2-weighted images was always abnormal. The clivus with marrow reconversion was uniformly hypointense relative to the pons on T1-weighted images and isointense relative to normal marrow on T2-weighted images. The intensity patterns of the normal clivus on T1- and T2-weighted MR images change predictably with advancing age. Intensity patterns of abnormal clivi differ from those of normal clivi. When contrast material is used. normal and abnormal clivi generally show different patterns of enhancement.
Critically ischemic myocardium in clinically stable patients following thrombolytic therapy for acute myocardial infarction: potential implications for early coronary angioplasty in selected patients, The utility of post-thrombolysis. rest-redistribution thallium (TI)-201 scintigraphy was studied in 32 patients with a first myocardial infarction who were clinically stable following reperfusion. Day 1 scintigraphy obtained 5 +/- 4 hours (range 1 to 16) after thrombolysis revealed an average perfusion defect of 6.5 +/- 2.6 segments (range 1 to 11). There was a total of 208 abnormal segments. 137 of which were nonreversible at 4 hours. 50 of which were fully or partially reversible. and 21 of which had a reverse redistribution pattern. Repeat TI-201 scintigraphy on day 10 revealed significantly smaller perfusion defects of 4.9 +/- 2.4 segments (range 0 to 9) with improvement predominantly of the day 1 reversible segments. and the improvement in segmental perfusion correlated with better regional left ventricular function. Twenty-nine (58%) of the 50 reversible segments normalized by day 10. and 11 (22%) improved. whereas only 16 (12%) of 137 nonreversible segments had normalized by day 10. only 9 had (6%) improved and 112 (82%) were unchanged (p less than 0.001 reversible versus nonreversible). There was no significant change in segments with a pattern of reverse redistribution. The improvement of reversible segments was greater in the 16 patients who underwent coronary angioplasty (PTCA) during the interval between the two scintigrams than in the 16 who did not. All 24 reversible segments in the PTCA group improved or normalized by day 10 compared with 16 (62%) of 26 reversible segments in the No PTCA group (p less than 0.001). Furthermore. 8 of the 10 reversible segments in the No PTCA group that did not improve actually deteriorated and became nonreversible by day 10. The minor improvement of nonreversible segments was not related to PTCA. Consistent with the findings in individual segments. the 19 patients with a reversible component on the day 1 TI-201 scintigram had significantly greater improvement in perfusion defect by day 10 than the 13 patients without a reversible component (37 +/- 33% versus 7 +/- 22% decrease in perfusion defect severity. p less than 0.05). and this improvement was greatest in the 10 patients with a reversible component who underwent PTCA. In contrast. PTCA had no impact on the perfusion defect in the 13 patients without a reversible component. Our data suggest that following thrombolytic therapy for acute myocardial infarction. viable myocardium in the reperfused zone may remain ischemic. as manifested by a reversible pattern of TI-201 redistribution at rest. and thus may be in jeopardy of gradual progression to necrosis.(ABSTRACT TRUNCATED AT 400 WORDS).
Renal, hormonal, and hemodynamic effects of low-dose infusion of atrial natriuretic factor in acute myocardial infarction, The effects of low-dose infusion of atrial natriuretic factor (ANF; 3 pmol/kg/min; i.e.. 10 ng/kg/min) were investigated in a single-blind. random-order. placebo-controlled study of 12 patients with uncomplicated acute myocardial infarction (MI). Compared with the placebo. ANF induced an increase in urine volume (p less than 0.05). sodium excretion (p less than 0.05). and chloride excretion (p less than 0.05). Urinary potassium and creatinine clearance were unchanged. The maximal response of urinary sodium excretion rate after ANF infusion was positively correlated with the basal sodium excretion rate (r = 0.579; p less than 0.05) and inversely correlated with basal plasma renin activity (r = -0.623; p less than 0.05). Furthermore. the plasma aldosterone concentration (PAC) after infusion of ANF was significantly decreased compared with the basal level. The maximal change in PAC was closely correlated with the basal PAC (r = -0.857; p less than 0.01). However. no significant effect on hemodynamic variables was detected with infusion of ANF. Although additional studies are needed to assess the clinical efficacy of ANF infusion in acute MI. our observations suggest that low-dose infusion of the peptide is potentially valuable. as either sole or adjunctive therapy. for the management of water-sodium retention in acute MI.
Visual function in patients undergoing long-term total parenteral nutrition, To evaluate the effects of long-term total parenteral nutrition (TPN) on eye function. 27 adults and 12 children in the UCLA Home TPN Clinic underwent ophthalmoscopic examination and visual-function testing. Direct inspection of the fundus showed a marked granularity of the retinal pigmented epithelium in some patients. About one-half of the children and one-third of the adults tested had at least one and usually two abnormalities in their electroretinogram. Determination of blood nutrients thought to affect vision revealed that zinc and vitamin E were within normal range. Vitamin A concentrations were above normal in 10 of 19 adults and selenium concentrations were below normal in 10 of 10 children and 17 of 21 adults tested. Linoleic and linolenic acid concentrations were low; plasma. platelet. and urine taurine concentrations were significantly lower than normal. Despite these diffuse nutrient abnormalities. only zinc and vitamin E concentrations correlated significantly with any index of visual function.
Olfactory neuroblastoma. Additional immunohistochemical characterization, A panel of 12 antibodies was used to further characterize the immunohistochemical staining profile of olfactory neuroblastoma. The following results were obtained for the 11 neoplasms that were immunostained: neuron-specific enolase 11/11(+). S-100 protein 8/11(+). microtubule-associated protein-2 8/11(+). class III beta-tubulin isotype 9/11(+). neurofilament 200 kD 8/11(+). synaptophysin 7/11(+). glial fibrillary acidic protein 1/11(+). chromogranin A 1/11(+). vimentin 1/11(+). keratin (CAM 5.2) 4/11(+). keratin (AEI/AE3) 0/11(+). and epithelial membrane antigen 0/11(+). Expression of two intermediate filaments was found in 4 of the 11 tumors. The authors' data showing that 72% of olfactory neuroblastomas were S-100 protein positive and only one was immunoreactive for glial fibrillary acidic protein agree with other published immunohistochemical studies. With only a single exception. each of the 11 neoplasms was labeled with one or more antibodies that detect neuronal cytoskeletal proteins (class III beta-tubulin isotype. microtubule-associated protein-2. neurofilament 200 kD). These immunohistochemical results are complementary to the reported electron microscopic findings of intermediate filaments and microtubules in olfactory neuroblastomas.
Temporal profiles of urinary excretion of NH2-terminal big gastrin immunoreactivity in humans, We studied the temporal profile of urinary NH2-terminal big gastrin immunoreactivity (NT G-34-IR) excretion in order to evaluate the dynamics of gastrin secretion. The temporal profile of urinary NT G-34-IR excretion in normal subjects represented three peaks corresponding to each meal. In contrast. the profile in antrectomized patients and patients under total parenteral nutrition (TPN) represented a flat pattern. Urinary NT G-34-IR excretions during fasting 2-h periods in antrectomized patients and TPN patients were about one-sixth and one-third. respectively. of basal NT G-34-IR excretion in normal subjects (53.1 +/- 13.9 pmol/h). Total urinary NT G-34-IR excretion during 24 h both in antrectomized patients (220 +/- 35 pmol/24 h) and TPN patients (390 +/- 68 pmol/24 h) was also significantly lower than in normal subjects (1985 +/- 403 pmol/24 h). The present study showed that the main source of urinary NT G-34-IR is the gastric antrum. that the main factor fluctuating its excretion is food intake. and that long-term TPN reduces basal gastrin secretion. Urinary NT G-34-IR would be a useful indicator for total gastrin secretion.
Prostaglandin-stimulated recovery of the human duodenal epithelium: effects of misoprostol on ethanol damage, This study was designed to determine whether prostaglandins can stimulate the repair of human duodenal epithelium. Ten healthy volunteers were given 50 ml 40% ethanol through an endoscope onto the duodenal mucosa 1-7 cm from the pyloric sphincter; 3 min later. misoprostol (200 micrograms) or inert vehicle (5 ml) was given locally in the same way. One and 5 h later. endoscopy was repeated to evaluate the damage. The conditions of the mucosa were evaluated by endoscopy and by scanning and transmission electron microscopy in biopsies taken at time 0 and 3 min. 1 and 5 h after ethanol. The study was double-blind with a cross-over balanced design. Three minutes after ethanol administration. the duodenal mucosa showed hyperemia with hemorrhagic lesions. Under the electron microscope. the lesions were caused by vascular engorgement or red blood cell extravasation into the submucosa; the epithelium underlining lesions showed loss of superficial cells and damage to the upper layer of the mucosa. One hour after ethanol. there was a striking difference between the two treatment groups. with a substantial recovery of the duodenal epithelium in the misoprostol-treated volunteers. Although spontaneous recovery was evident in the control group. there was also a significant difference at 5 h. Our results suggest that prostaglandins are able to stimulate the recovery of the duodenal epithelium after acute damage.
Malignant fibrous histiocytoma of the gastrointestinal tract in a patient with neurofibromatosis, Malignant fibrous histiocytoma (MFH) of the gastrointestinal tract is extremely rare. A case of MFH of the colon associated with neurofibromatosis is presented. MFH is a high-grade soft-tissue sarcoma of fibroblast cell origin with a strong propensity for metastasis and recurrence. Immunochemical markers help to differentiate MFH from other sarcomas. The most successful treatment of MFH is surgical extirpation. Adjuvant chemotherapy and radiotherapy have not been definitively shown to be of value.
Cost-effective treatment of constipation in the elderly: a randomized double-blind comparison of sorbitol and lactulose, PURPOSE: The purpose of this study was to evaluate the use of sorbitol as an inexpensive alternative to lactulose for treating constipation in the elderly. PATIENTS AND METHODS: Thirty men aged 65 to 86 with chronic constipation were studied in a randomized. double-blind. cross-over trial in which lactulose and 70% sorbitol (0 to 60 mL daily) were each given for 4 weeks preceded by a 2-week washout period. RESULTS: The average number of bowel movements per week was 6.71 with sorbitol and 7.02 with lactulose (95% confidence interval of the difference: -0.43 to 1.06). and the average number of days per week with bowel movements was 5.23 with sorbitol and 5.31 with lactulose (95% confidence interval of the difference: -0.32 to 0.48). Eleven patients stated a preference for sorbitol. 12 for lactulose. and seven had no preference. On a visual analogue scale measuring severity of constipation (0 to 100 mm). the average score for sorbitol was 35.6 mm versus 37.1 mm for lactulose (95% confidence interval of the difference: -6.4 to 9.3). The sorbitol and lactulose treatment periods were also similar in percent of bowel movements recorded as "normal." frequency and severity of symptoms such as bloating. cramping. and excessive flatulence. and overall health status as assessed by a previously validated five-category questionnaire. There were no significant differences between sorbitol and lactulose in any outcome measured except nausea. which was increased with lactulose (p less than 0.05). CONCLUSION: These results support the hypothesis that sorbitol and lactulose have no clinically significant differences in laxative effect. Sorbitol can be recommended as a cost-effective alternative to lactulose for the treatment of constipation in the elderly.
Vitamin E levels in premenstrual syndrome, To determine whether changes in peripheral vitamin E levels are associated with symptoms of premenstrual syndrome. 10 patients with premenstrual syndrome and 10 control subjects were studied. They gave blood at 2- or 3-day intervals throughout three menstrual cycles. The vitamin E was measured by fluorometry after hexane extraction and luteinizing hormone was measured by radioimmunoassay. In the control group. vitamin E values were 854 +/- 45 micrograms/dl (mean +/- SE) during the luteal phase and 925 +/- 55 micrograms/dl during the follicular phase. No significant changes were noted between the two values. In the patients with premenstrual syndrome. the values were 849 +/- 53 micrograms/dl during the luteal phase. which was not significantly different from 858 +/- 48 micrograms/dl during the follicular phase. No significant changes were noted between the control group and the patients with premenstrual syndrome in either the luteal or the follicular phase. Vitamin E deficiency in patients with premenstrual syndrome was not shown by peripheral vitamin E levels in our study.
Gonadotropin-releasing hormone deficiency in men: diagnosis and treatment with exogenous gonadotropin-releasing hormone, Idiopathic hypogonadotropic hypogonadism in men is the result of absent or abnormal secretion of gonadotropin-releasing hormone. which prevents pubertal development. Isolated gonadotropin-releasing hormone deficiency is clinically and neuroendocrinologically heterogeneous. largely because of variation in the degree of gonadotropin-releasing hormone deficiency. Treatment with pulsatile gonadotropin-releasing hormone results in normal pubertal changes and virilization. Such treatment has been uniformly successful in normalizing release of gonadotropins and secretion of testosterone. Improvement in secondary sex characteristics and induction of spermatogenesis have been achieved in most patients. Eight of nine patients desiring induction of fertility were able to father a child. Use of pulsatile gonadotropin-releasing hormone presents a powerful model in which to examine regulation of gonadotropin secretion and the role of hypothalamic gonadotropin-releasing hormone in control of the male reproductive axis.
Monocrotaline-induced angiogenesis. Differences in the bronchial and pulmonary vasculature, Vascular corrosion casting was used to search for angiogenesis in the blood vessels of the lungs of rats given monocrotaline. Animals treated with monocrotaline had new well-differentiated arteries and veins on their pleural surfaces. Animals not treated had no large vessel on their pleural surfaces. Animals receiving monocrotaline had capillaries around major arteries that were more dense. widened. and less tubular than normal. These capillaries occasionally occurred in sheets and had blind endings. The control animals had delicate. uniform. tubular capillaries. Alveolar capillaries in both groups showed no evidence of increase in size or number or change in shape. Light microscopy confirmed the finding of new vessels found with the casts. The finding of angiogenesis on the pleural surface and in the bronchovascular bundle. but not in the alveolar capillaries. suggests a basic difference in how these capillary beds respond to angiogenic stimuli. If alveolar capillaries are unable to undergo angiogenesis. concepts of lung development and tumor growth may be significantly altered. The lung may be a unique organ to study angiogenesis because of the different angiogenic potential of its two circulations. Study of these differences may lead to better understanding of inhibition of angiogenesis.
Human abdominal aortic aneurysms. Immunophenotypic analysis suggesting an immune-mediated response, Cellular immunity may play a role in the pathogenesis of atherosclerosis. In this report the potential role of these cells in the formation of abdominal aortic aneurysms by immunohistochemistry was investigated. Aortic tissues from 32 patients were examined: 4 normal aortas. 6 aortas with occlusive atherosclerotic disease. 17 abdominal aortic aneurysms. and 5 inflammatory abdominal aneurysms. Using monoclonal anti-CD3 (T cells). anti-CD19 (B cells). anti-CD11c (macrophages). anti-CD4 (T helper cells). and anti-CD8 (T suppressor cells). several distinctions among these groups were found. The amount of inflammatory cell infiltrate was as follows: inflammatory aneurysms more than abdominal aortic aneurysms more than occlusive aortas more than normal aortas. CD3-positive T lymphocytes rarely were found in the adventitia of normal or occlusive aortas. In contrast. abdominal aortic aneurysms and inflammatory aneurysms exhibited most of the CD3-positive infiltrates in the adventitia. CD19-positive B lymphocytes were present mainly in the adventitia of all pathologic tissues. The CD4-positive:CD8-positive ratio was greater in abdominal aortic aneurysms and inflammatory aneurysms than in the other groups. both in the adventitia and in the media of the aortas. CD11c-positive macrophages were present throughout the diseased tissues. often surrounded by lymphoid aggregates; the greatest numbers of macrophages were found in the inflammatory aneurysm group. Our data suggests that the aneurysmal disease may progress from occlusive disease and is accompanied by an increase in chronic inflammatory cells as well as a redistribution of these cell types. Therefore it is suggested that aneurysmal disease may represent an immune-mediated event.
Epidemiology of high-level gentamicin resistant enterococcal isolates from Zimbabwe, High-level gentamicin resistance (minimum inhibitory concentration of greater than or equal to 2.000 mcg/ml) in Enterococcus faecalis has not previously been reported in Africa to our knowledge. Eight of 28 (29%) rectal swab specimens obtained from hospitalized patients in Zimbabwe had gentamicin resistant enterococci. Previous exposure to penicillins or aminoglycosides were risk factors for colonization with these organisms. This study documents the presence of high-level gentamicin resistant enterococci in Africa and suggests that penicillin or aminoglycoside usage may select for gentamicin resistant enterococcal plasmids in Africa.
Duodenal obstruction by a nondeflating Foley catheter gastrostomy tube, We report the case of a 36-year-old mentally retarded man who presented to our emergency department after one day of vomiting and one episode of coffee-ground emesis. The Foley catheter used as his gastrostomy tube was found to be obstructing the duodenum. and the balloon could not be deflated. Removal was accomplished by rupturing the balloon by endoscopy. Our case illustrates one of many possible complications of feeding gastrostomy tubes.
The lavage fluid from a patient with alveolar proteinosis inhibits the in vitro chemiluminescence response and arachidonic acid metabolism of normal guinea pig alveolar macrophages, Pulmonary alveolar proteinosis is characterized by the accumulation of a lipoproteinaceous material within the alveoli of the lung. It is well established that patients with pulmonary alveolar proteinosis have a high incidence of complicating pulmonary infections possibly resulting from defects of antibacterial functions of alveolar macrophages. Moreover. for unclear reasons. an inflammatory response in the airways is frequently absent. In order to investigate the role of the lipoproteinaceous material in these two patterns. we tested the in vitro effects of a lavage fluid from a human pulmonary alveolar proteinosis on the secretion of reactive oxygen intermediates and arachidonic acid metabolites by normal guinea pig alveolar macrophages. After incubation with the lipoproteinaceous material. the luminol-enhanced chemiluminescence of zymosan-triggered alveolar macrophages was reduced in a dose-dependent fashion. The lipoproteinaceous material similarly reduced the chemiluminescence response in a cell-free xanthine-xanthine oxidase system generating superoxide anions. This latter observation suggests that the lipoproteinaceous material acts as a scavenger for superoxide anions produced by alveolar macrophages. Its purified protein or phospholipid fractions also resulted in a general inhibition of the secretion of arachidonic acid metabolites by alveolar macrophages challenged in vitro with zymosan. Our results suggest that the alveolar filling material of pulmonary alveolar proteinosis may inhibit the action of antibacterial and/or proinflammatory agents produced by alveolar macrophages. We speculate that such effects of the lipoproteinaceous material may play a role in vivo in the high incidence of pulmonary infections and in the absence of discernible interstitial or intraalveolar inflammation seen in pulmonary alveolar proteinosis.
Myocardial revascularization for chronic stable angina. Analysis of the role of percutaneous transluminal coronary angioplasty based on data available in 1989, No prospective. randomized clinical trial comparing coronary artery bypass grafting. percutaneous transluminal coronary angioplasty. and conservative therapy has been reported. To address when revascularization is indicated. we constructed a decision analytic model. Our model incorporates procedure-related mortality and morbidity. coronary artery disease-related mortality. and the benefit of revascularization. We determined the quality-adjusted life expectancy and expected costs for each strategy. Our model suggests that angioplasty is a reasonable alternative to bypass surgery in patients with favorable lesions if angioplasty would provide a comparable degree of revascularization. Our model predicts that patients treated with angioplasty will have more revascularization procedures than will patients treated with bypass surgery but predicts that both treatments will cost the same over the typical patient's lifetime. In many patients with severe angina or documented ischemia. angioplasty is indicated for stenosis of a single artery. In patients with two vessel disease that is amenable to angioplasty. angioplasty may be a reasonable alternative to bypass surgery. Even in patients whose three vessel disease can be completely revascularized by angioplasty. bypass surgery. although relatively expensive. is slightly better than angioplasty. In patients with three vessel disease and comorbidities that increase operative risk. angioplasty may be a reasonable alternative to either bypass surgery or medical therapy.
Sarcoptes scabiei in histopathologic sections of skin in human scabies, The usual methods of diagnosis remove Sarcoptes scabiei from its habitat. Thus. one has no appreciation of the host-endoparasitic interaction. especially the pathologic response of the surrounding tissue and the means by which the mite survives and lives its life cycle in the skin. The biopsy specimen described in this article demonstrates the tissue reaction that can be correlated with clinical symptoms. It also clearly depicts the actual position. morphological features. and developmental cycle of the mite in the skin.
National High Blood Pressure Education Program Working Group report on ambulatory blood pressure monitoring, Blood pressure measurements obtained in a physician's office may not represent a patient's blood pressure during an entire day. Ambulatory blood pressure monitoring (ABPM) provides multiple readings over time. This review of the literature on ABPM addresses the current state of ABPM methods. normal blood pressure profiles. the clinical and research uses of ABPM. cost considerations. and recommendations for use of ABPM in selected circumstances. Current ABPM devices use either auscultatory or oscillometric methods to determine blood pressure. A rigorous comparison of these methods is needed to determine whether one method is more reliable. A nonbiased assessment of all available equipment is necessary. Normative data provided by ABPM research are needed for populations by age. race. gender. body habitus. and conditions. such as pregnancy. While ABPM is not cost-effective for all hypertensive patients. it can assist in the evaluation of such problems as target organ complications. syncopal episodes. episodic hypertension. and autonomic dysfunction.
IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis, The spinal cord and motor cortex of patients with amyotrophic lateral sclerosis (ALS) were examined with immunohistochemical methods for the presence of IgG. In 13 of 15 spinal cords. a population of motoneurons stained positively for IgG in a granular pattern. characteristic of binding to the rough endoplasmic reticulum. In 6 of 11 motor cortices. a proportion of pyramidal cells also stained positively for IgG. No such reactivity was noted in motoneurons of control human tissues. although positive IgG staining was present in astrocytes of ALS and control specimens. Reactive microglia and/or macrophages were detected in the territory of degenerating pyramidal tracts and ventral horns. The surface of most of these cells stained positively for IgG. and 50% stained positively for HLA-DR. The accumulation of IgG in motoneurons and the presence of immunologically active macrophages provide additional evidence for the participation of immunologic factors in the pathogenesis of ALS.
Polymorphism and expression of the galactosyltransferase-associated protein kinase gene in normal individuals and galactosylation-defective rheumatoid arthritis patients, We used restriction endonuclease digestion of leukocyte DNA to assess the structural integrity of an N-acetylglucosamine beta 1----4 galactosyltransferase (GalTase)-associated (GTA) protein kinase gene in rheumatoid arthritis (RA) patients. This analysis provides evidence that the gross structure of the GTA protein kinase gene locus remains intact in patients with defective galactosylation and that this gene locus is polymorphic both in normal individuals and in patients with RA. although no polymorphisms unique to RA patients were observed. Initial data on the expression of this gene indicate that comparable levels of GTA protein kinase messenger RNA are present in the lymphocytes of normal individuals and RA patients. irrespective of whether lymphocytes were obtained from patients with decreased or normal levels of galactosylation.
Phase I-II study of advanced head and neck squamous cell carcinoma patients treated with recombinant human interferon gamma, The association of immunodeficiency with head and neck squamous cell carcinoma has generated the concept of supplying immunologically active agents as a means of treating these cancers. One of the most active immunologic messengers is interferon gamma. which has been observed in our laboratories to also have a direct cytotoxic effect on cultures of squamous cell carcinoma derived from the head and neck. To test the feasibility of treating patients with advanced but resectable head and neck cancer with this agent. we designed a phase I-II trial of recombinant human interferon gamma using a 24-hour infusion repeated weekly for four times. In this study. both tumor and immunologic parameters were studied before and after treatment. Eight patients were entered into the study with the highest recombinant human interferon gamma dose attempted being 0.25 mg/m2 per 24 hours. Minimal side effects were observed. Three patients had clinically measurable responses. four had stabilization of disease. and one had progression while receiving treatment. Histopathologic results of treatment were similar to in vitro observations. Necrosis. as well as differentiation of tumor cells. was observed. In some tumors there was a marked decrease in cellularity without a change in tumor volume due to increased extracellular keratin deposition. Our study indicates that evaluation of adoptive immunotherapy trials in head and neck cancer needs to include parameters other than simple tumor regression as an end point. otherwise therapeutically important lymphokine-induced changes may be missed. Further evaluation of recombinant human interferon gamma and agents that induce human interferon gamma are warranted.
Characterization of common variable immunodeficiency: identification of a subset of patients with distinctive immunophenotypic and clinical features, The peripheral blood lymphocyte surface markers and clinical features of 38 patients with common variable immunodeficiency (CVID) were assessed. These studies identified a subset of CVID consisting of 14 of the 38 patients with a distinctive T-cell immunophenotype and clinical findings. The phenotypic changes were characterized by an abnormally low CD4/CD8 ratio (less than or equal to 0.9) due primarily to a significant increase in CD8 T cells. In addition. there was an expansion in CD8 T cells coexpressing CD57 and increased expression of the activation markers HLA-DR and interleukin-2 receptor (IL-2R) by these cells. This group of immunophenotypically abnormal CVID patients also had characteristic clinical features. including splenomegaly (P less than .02) and in vivo T-cell dysfunction based on the evaluation of delayed-type hypersensitivity (P less than .05). Approximately 71% of these patients had splenomegaly and 42% were anergic in contrast to the remaining group of CVID patients. in which 29% had splenomegaly and 7% were anergic. These findings define a subgroup of CVID patients that have specific immunophenotypic features and functional T-cell abnormalities.
Detection of minimal residual disease in acute lymphoblastic leukemia using immunoglobulin hypervariable region specific oligonucleotide probes, To develop a sensitive and specific assay for minimal residual disease in acute lymphoblastic leukemia (ALL). we exploited the enormous diversity of genomic sequences created by immune receptor gene rearrangements. To isolate clone-specific sequences. we first synthesized oligonucleotides that match conserved variable (VH) and joining (JH) sequences flanking the third hypervariable region (HVR3) in the rearranged immunoglobulin heavy chain (IgH) locus. In polymerase chain reactions (PCR). these primers were then used to amplify the intervening HVR3 segments from leukemic DNA samples. Of 12 B-lineage ALLs studied. ten generated one or more fragments of the size expected for HVR3 gene segments. Thus. this single pair of amplimers was sufficient to isolate HVR3 sequences from a majority of acute lymphoblastic leukemias. To verify that the amplified fragments originated from HVR3 alleles and to assess their diversity. we sequenced 7 PCR products derived from 6 leukemias. In addition to elements of recognized D segments. each of the 7 fragments contained novel VH-D and D-JH junctional sequences. including N nucleotides. not known to be present in the germline. Each sequence was unique. and allele-specific oligonucleotide probes hybridized only to HVR3 segments from which the probes were derived. Therefore. as anticipated. these HVR3 segments appeared to possess the diversity required to serve as clonal markers for leukemic populations. To demonstrate that these amplified HVR3 alleles could serve as the basis for a sensitive and specific assay to detect rare leukemic cells. we analyzed in detail one pre-B leukemia that had rearranged 2 IgH alleles. The HVR3 sequences were shown to be linked to rearranged JH-containing restriction fragments in digests of genomic DNA. establishing their origin in the leukemic cells. We synthesized oligonucleotides corresponding to the unique junctional sequences in the HVR3 segments. Using these novel amplimers in an allele-specific amplification and hybridization procedure. we showed that this assay can detect 10 leukemic cells in a background of 10(6) normal blood mononuclear cells. In contrast. the leukemic HVR3 sequences were not detected in extracts of normal or unrelated remission leukemic leukocytes. We conclude that the assay for specific IgH HVR3 sequences is a realistic strategy for detection of minimal residual disease in B-lineage ALL.
Permeability characteristics of deoxygenated sickle cells, This study investigated the effect of acute deoxygenation on membrane permeability characteristics of sickle cells. Measured fluxes of Na+ and K+ in ouabain-inhibited cells. of chloride and sulfate exchange in 4.4'-diisothiocyanostilbene-2.2'-disulfonate (DIDS)-inhibited and untreated cells. and of erythritol. mannitol. and arabinose in cytochalasin B-inhibited cells indicated that a deoxygenation-induced permeability change occurred in sickle cells only for cations and chloride. Monovalent cation permeabilities increased five-fold. and chloride influx into DIDS treated cells was enhanced nearly threefold on sickle cell deoxygenation. In contrast. no detectable increase in permeability to the other solutes was found. To gain perspective on these findings. similar measurements were performed in normal cells treated with diamide. an agent shown by others to induce a coupled increase in membrane permeability and phospholipid translocation. reminiscent of deoxygenation-induced changes in sickle cells. Although the increase in cation permeability was no greater than that in sickled cells. treatment with 2 mmol/L diamide also produced a twofold increase in the first order rate constants for sulfate exchange and mannitol efflux. indicating a relatively nonselective permeability increase that permitted flux of larger solutes than in the case of deoxygenated sickle cells. These results suggest that the deoxygenation of sickle cells induces a permeability increase that is relatively insensitive to charge. but is restrictive with respect to solute size.
Long term reduction in sodium balance: possible additional mechanism whereby nifedipine lowers blood pressure, OBJECTIVE--To assess the changes in sodium excretion and sodium balance after withdrawal of long term nifedipine. DESIGN--Single blind. placebo controlled study in patients receiving fixed sodium and potassium intakes. SETTING--Blood pressure unit of a teaching hospital in south London. PATIENTS--Eight patients with mild to moderate uncomplicated essential hypertension who had been taking nifedipine 20 mg twice daily for at least six weeks. INTERVENTIONS--Withdrawal of nifedipine and replacement with matching placebo for one week. MAIN OUTCOME MEASURES--Urinary sodium excretion and cumulative sodium balance. body weight. plasma atrial natriuretic peptide concentrations. plasma renin activity and aldosterone concentrations. and blood pressure. RESULTS--During nifedipine withdrawal there was a significant reduction in urinary sodium excretion (day 1: -62.7 mmol/24 h; 95% confidence interval -90.3 to -35.0) and each patient retained a mean of 146 (SEM 26) mmol sodium over the week of replacement with placebo. Body weight and plasma atrial natriuretic peptide concentrations increased during the placebo period and seemed to be associated with the amount of sodium retained. Systolic blood pressure rose from 157 (9) to 165 (9) mmHg (95% confidence interval of difference -7.1 to 22.1) when nifedipine was replaced with matching placebo. and the rise seemed to be related to the amount of sodium that was retained. CONCLUSIONS--Nifedipine causes a long term reduction in sodium balance in patients with essential hypertension. This long term effect may contribute to the mechanism whereby nifedipine lowers blood pressure.
Stereotactic multiple arc radiotherapy, A radiotherapy technique is presented for delivering a concentrated pattern of absorbed dose to intracranial lesions. Treatment takes place on a conventional. isocentrically mounted linear accelerator. rotated in several planes around a single target site. A new. relocatable stereotactic frame is used which enables fractionated radiotherapy to be administered if required. Calculations of the absorbed dose distribution in three orthogonal planes are performed using specially prepared software on a computer used for standard treatment planning. In this way. the need for excessive computing power is avoided.
Comparison of propranolol, diltiazem, and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Differential effects on ambulatory ischemia, exercise performance, and anginal symptoms. The ASIS Study Group, Episodes of transient myocardial ischemia during ambulatory activities are common in patients with stable coronary artery disease and who are often asymptomatic. Selection of therapy for episodes of asymptomatic ischemia is limited by a lack of direct comparative studies. To determine the most effective monotherapy for patients with stable angina and a high frequency of asymptomatic ischemic episodes. propranolol-LA (mean daily dose. 293 mg). diltiazem-SR (mean daily dose. 350 mg). nifedipine (mean daily dose. 79 mg) were each compared with placebo. each for 2 weeks. in a randomized. double-blinded. crossover trial. Entry criteria were a positive exercise treadmill test during placebo therapy characterized by 1.0 mm or more ST segment depression and angina pectoris. and six or more episodes of transient ST segment depression of 1.0 mm or more on a 48-hour ambulatory electrocardiogram. One hundred ninety-four patients were screened. 63 were eligible and received randomized therapy. of which 56 patients completed at least two of the four treatment periods and were included in an intent-to-treat analysis. Fifty patients completed all four treatment phases and were included in the protocol-completed analysis. Anti-ischemia efficacy was assessed by 48-hour ambulatory electrocardiographic monitoring. exercise treadmill tests. and anginal diaries. Ninety-four percent of all episodes of ambulatory ischemia were asymptomatic. Compared with placebo. only propranolol was associated with a marked reduction in all manifestations of asymptomatic ischemia during ambulatory electrocardiographic monitoring (2.3 versus 1.0 episodes/24 hr; mean duration of ischemia per 24 hours. 43.6 versus 5.7 minutes; both p less than 0.0001). Diltiazem's reduction of the frequency of episodes compared with placebo (2.3 versus 1.9 episodes/24 hr) was associated with a trend (p = 0.08) in the protocol-completed analysis and with a significant reduction in the intent-to-treat analysis (p = 0.03). Nifedipine had no significant effect on any measured variable of ambulatory ischemia. The dosages of medication used may have been excessive for some patients. and a more beneficial effect may have been evident at a lower dose. In contrast to the marked effects of the active agents on ambulatory asymptomatic ischemia. the effects on exercise performance and angina pectoris were slight. The active agents modestly improved treadmill exercise duration time until 1 mm ST segment depression (3%). and only propranolol and diltiazem had significant effects. Only diltiazem significantly prolonged the total exercise time. Anginal frequency was significantly decreased by both propranolol and diltiazem.(ABSTRACT TRUNCATED AT 400 WORDS).
Transcriptional regulation of c-jun gene expression by arabinofuranosylcytosine in human myeloid leukemia cells, Previous studies have demonstrated that 1-beta-D-arabinofuranosylcytosine (ara-C) induces terminal differentiation of human myeloid leukemia cells. Other studies have shown that the c-jun protooncogene is expressed during phorbol ester-induced myeloid differentiation. This work examines the effects of ara-C on c-jun gene expression in human KG-1 myeloid leukemia cells. The results demonstrate that c-jun transcripts are undetectable in uninduced KG-1 cells and that ara-C induces expression of this gene in a concentration- and time-dependent manner. Ara-C treatment was also associated with increases in c-jun transcripts in U-937. THP-1. and HL-60 myeloid leukemia cells. Furthermore. transcriptional run-on analysis has demonstrated that exposure to ara-C increases the rate of c-jun gene transcription. The results also demonstrate that while inhibition of protein synthesis superinduces c-jun mRNA levels in phorbol ester-treated KG-1 cells. cycloheximide had no effect on the induction of c-jun transcripts during ara-C treatment. Moreover. the half-life of c-jun transcripts in ara-C-treated KG-1 cells was 42 min. These findings suggest that the increase in c-jun mRNA observed during ara-C treatment is regulated by a transcriptional mechanism. and that c-jun may be involved in the induction of differentiation and regulation of gene expression by ara-C.
Atrial natriuretic polypeptide inhibits hypertrophy of vascular smooth muscle cells, Vascular remodeling is central to the pathophysiology of hypertension and atherosclerosis. Recent evidence suggests that vasoconstrictive substances. such as angiotensin II (AII). may function as a vascular smooth muscle growth promoting substance. To explore the role of the counterregulatory hormone. atrial natriuretic polypeptide (ANP) in this process. we examined the effect of ANP (alpha-rat ANP [1-28]) on the growth characteristics of cultured rat aortic smooth muscle (RASM) cells. ANP (10(-7) M) significantly suppressed the proliferative effect of 1% and 5% serum as measured by 3H-thymidine incorporation and cell number. confirming ANP as an antimitogenic factor. In quiescent RASM cells. ANP (10(-7). 10(-6) M) significantly suppressed the basal incorporations of 3H-uridine and leucine by 50 and 30%. respectively. ANP (10(-7). 10(-6) M) also suppressed AII-induced RNA and protein syntheses (by 30-40%) with the concomitant reduction of the cell size. Furthermore. ANP also significantly attenuated the increase of 3H-uridine and leucine incorporations caused by transforming growth factor-beta (4 x 10(-11). 4 x 10(-10) M). a potent hypertrophic factor. These results indicate that ANP possesses an antihypertrophic action on vascular smooth muscle cells. Down-regulation of protein kinase C by 24-h treatment with phorbol 12.13-dibutyrate did not inhibit ANP-induced suppression on 3H-uridine incorporation. Based on the observation that ANP was more potent than a ring-deleted analogue of ANP on inhibiting 3H-uridine incorporation. we conclude that the ANP's inhibitory effect is primarily mediated via the activation of a guanylate cyclase-linked ANP receptor(s). Indeed 8-bromo cGMP mimicked the antihypertrophic action of ANP. Accordingly. we speculate that in addition to its vasorelaxant and natriuretic effects. the antihypertrophic action of ANP observed in the present study may serve as an additional compensatory mechanism of ANP in hypertension.
Detection of hepatitis C virus ribonucleic acid in the serum by amplification with polymerase chain reaction, Hepatitis C virus (HCV) RNA was detected in the sera of patients with non-A. non-B chronic liver disease by polymerase chain reaction (PCR). RNA was extracted from the serum. reverse transcribed to cDNA. and amplified by PCR. With this method. 30 patients with non-A. non-B chronic liver disease and 10 healthy subjects were tested. HCV RNA was detected in 13 of 16 (81%) anti-HCV-positive patients and also in 7 of 14 (50%) anti-HCV-negative patients. but in none of 10 anti-HCV-negative healthy subjects. Specificity of this method was confirmed by direct sequencing of amplified cDNA segment. The nucleotide sequences (37 nucleotides) obtained from 15 patients showed only 68-78% homology compared with the prototype HCV nucleotide sequence. In addition. of 15 nucleotide sequences. there were 12 different types. But the translated amino acid sequences (12 amino acids) showed 83-100% homology compared with the prototype HCV amino acid sequence. These data suggest the majority of anti-HCV-positive patients are carriers of HCV. But to detect all the viremic patients. the anti-HCV antibody testing may be insufficient. Direct detection of HCV RNA may be useful in the study of virus replication and its association with various liver diseases.
Potentiating effect of ribavirin on the in vitro and in vivo antiretrovirus activities of 2',3'-dideoxyinosine and 2',3'-dideoxy-2,6-diaminopurine riboside, 2'.3'-Dideoxyinosine (DDI) and 2'.3'-dideoxy-2.6-diaminopurine riboside (ddDAPR) are potent and selective inhibitors of human immunodeficiency virus (HIV) replication in MT-4 cells. They are also inhibitory to the transformation of C3H/3T3 cells by Moloney murine sarcoma virus (MSV). In vivo. they are only marginally effective in delaying MSV-induced tumor formation. and mortality associated therewith in newborn NMRI mice. When combined with ribavirin. DDI and ddDAPR become much more effective in inhibiting MSV and HIV replication in vitro and MSV-induced tumor formation in vivo. These observations point to the potential role of ribavirin in potentiating the anti-HIV activity of DDI in AIDS patients.
Interleukin-1 and a 7-kDa T-cell inhibitory monokine reflect disease activity in infection with HIV-1, Previous studies demonstrated that cultured peripheral blood mononuclear cells (PBMC) from patients with AIDS produce high levels of interleukin 1 (IL-1) and a 7-kDa T-cell inhibitory monokine (TCIM). To determine if the increase in the production of these cytokines corresponded with disease activity. we studied the production of IL-1 and TCIM by PBMC from patients with different stages of human immunodeficiency virus (HIV) infection. Eight patients with asymptomatic seropositive infection. three patients with AIDS-related complex (ARC). three patients with persistent generalized lymphadenopathy (PGL). and six patients meeting the full criteria for diagnosis of AIDS were studied. Patients with AIDS produced increased amounts of TCIM (4.1 times control values. p less than 0.003) and IL-1 (2.0 times control values. p less than 0.05). In contrast. asymptomatic seropositive patients produced less TCIM (0.36 times control values. p less than 0.004) and IL-1 (0.61 times control values. p less than 0.05). Different trends in the levels of these factors produced by patients with ARC and PGL were noted. although results were not statistically significant in general. Patients with ARC tended to produce less IL-1 (0.42 times control values. p less than 0.05). whereas patients with PGL tended to produce increased amounts of IL-1 (1.7 times control values. NS). ARC patients produced a wide range of TCIM values (0.05-2.8 times control values. NS). and patients with PGL tended to produce increased TCIM values. (4.0 times control values. p less than 0.02). No correlations between the levels of IL-1 or TCIM and T-cell subpopulation numbers (CD4 or CD8) or CD4/CD8 ratios were found.
Neuromodulatory effects of atrial natriuretic factor are independent of guanylate cyclase in adrenergic neuronal pheochromocytoma cells, This study tests the hypothesis that atrial natriuretic factor (ANF) and C-ANF(4-23)-NH2 (C-ANF) augment cGMP generation and inhibit both cAMP generation and depolarization-induced catecholamine release in nerve growth factor treated pheochromocytoma cells by a pertussis toxin (PTX)-sensitive mechanism. Synthetic rat ANF(99-126) and the clearance receptor antagonist C-ANF (10(-12)-10(-9) M) inhibited basal and 5 microM vasoactive intestinal peptide (VIP)-induced cAMP generation in a concentration-dependent manner. These actions of ANF and C-ANF were blocked by 12-18 h pretreatment with PTX (100 ng/ml). suggesting ANF receptor coupling to adenylate cyclase via an inhibitory guanine nucleotide-binding protein. Both ANF (10(-11)-10(-9) M) and C-ANF (10(-11)-10(-8) M) also inhibited K(+)-induced catecholamine release in a concentration-dependent manner. ANF (10(-11)-10(-8) M) increased cGMP generation in a concentration-dependent manner but C-ANF did not. The accumulation of cGMP in response to ANF was not altered by treatment with PTX. Therefore. PTX dissociated the increased concentrations of cGMP from the ANF-mediated depression of evoked catecholamine release. C-ANF also dissociated elevations in cGMP concentrations from an ANF-mediated attenuation of evoked catecholamine release. The results of this study indicate that ANF inhibits adrenergic neurotransmission independent of guanylate cyclase.
Effects of TRH-analog treatment on tissue cations, phospholipids and energy metabolism after spinal cord injury, Effects of thyrotropin-releasing hormone analog CG3703 on biochemical changes following impact spinal cord trauma were investigated by 31P magnetic resonance spectroscopy. atomic absorption spectrophotometry. high-pressure liquid chromatography and radioimmunoassay using parallel injury models in rabbits and rats. Treatment with CG3703 at 45 min after trauma in rabbits significantly attenuated decreases in intracellular pH and reversed increases in phosphodiester to phosphomonoester ratio. as shown by 31P magnetic resonance spectroscopy. The improved phosphodiester/phosphomonoester ratio was correlated with improved ATP status after treatment. although there was no improvement in aerobic bioenergetic capacity as reflected by phosphocreatine to inorganic phosphate ratios. In rats. treatment with CG3703 significantly reduced changes in tissue cations (Na+. K+. Mg2+) and water content following trauma. but did not significantly alter the accumulation of free fatty acids or thromboxane B2. Thus. the beneficial effects of treatment with thyrotropin-releasing hormone or thyrotropin-releasing hormone analogs on outcome following traumatic spinal cord injury may be due. in part. to actions relating to ion homeostasis.
Genetically determined steady-state interaction between encainide and quinidine in patients with arrhythmias, A genetically determined pharmacokinetic and pharmacodynamic interaction between quinidine and single doses of encainide in healthy volunteers has previously been described. In subjects with the extensive metabolizer phenotype. quinidine blunted encainide-induced QRS prolongation (a marker of sodium channel block) because it impaired encainide biotransformation to the potent active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide. Therefore. the purpose of this study was to test the hypothesis that quinidine would inhibit sodium channel block (and by inference arrhythmia suppression) during encainide therapy in patients with the extensive metabolizer phenotype. Surprisingly. however. in eight extensive metabolizer patients. the extent of QRS prolongation during chronic encainide therapy was unaltered by quinidine (139 +/- 21 vs. 139 +/- 22 msec) whereas arrhythmia suppression was enhanced (64 +/- 22 to 77 +/- 19%; P = .05). Plasma concentration data demonstrated that although encainide metabolism to ODE was partially impaired by quinidine. subsequent 3-methoxy-O-desmethyl encainide formation from ODE was virtually completely inhibited; thus steady-state plasma ODE remained unchanged whereas plasma encainide increased 10-fold (21 +/- 30 to 240 +/- 118 ng/ml; P less than .05). In contrast. no changes in disposition or in pharmacodynamics were observed in two poor metabolizers. It is concluded that the effect of this drug interaction in patients is determined by differential sensitivities to inhibition by quinidine of encainide O-demethylation and subsequent ODE 3-methoxylation. Evaluation of potential drug interactions should include assessment of possible genetic factors as well as of steady-state effects.
Iloprost attenuates the increased permeability in skeletal muscle after ischemia and reperfusion, Increased vascular permeability is an early and sensitive indicator of ischemic muscle injury. occurring before significant histologic or radionuclide changes are evident. We investigated the effect of iloprost. a stable prostacyclin analog. on microvascular permeability in a rat striated muscle model. In six control and six experimental animals the cremaster muscle was dissected. placed in a closed-flow acrylic chamber. and suffused with a bicarbonate buffer solution. Dextran labeled with fluorescein was injected intravenously as a macromolecular tracer. and microvascular permeability was determined on the basis of clearance of the fluorescent tracer. Two hours of ischemia were followed by 2 hours of reperfusion. In the experimental group iloprost (0.5 microgram/kg/min) was given in a continuous intravenous infusion. Microvascular permeability increased significantly during reperfusion in both control and experimental animals (p less than 0.0001). Treatment with iloprost. however. significantly attenuated this response compared to the control group. 4.8 +/- 0.3 versus 7.3 +/- 0.5 microliters/gm/min. respectively (p less than 0.0001). Iloprost decreases the rise in vascular permeability after ischemia and reperfusion. Experimental clinical use of iloprost under controlled conditions in the treatment of patients with acute skeletal muscle ischemia appears justified.
Reducing high blood cholesterol level with drugs. Cost-effectiveness of pharmacologic management, We performed a cost-effectiveness analysis of pharmacologic treatment of high blood cholesterol levels. Agents modeled were cholestyramine. colestipol. gemfibrozil. lovastatin. niacin. and probucol. Pharmacologic effectiveness was estimated from reported studies. Cost estimates reflect societal resource consumption. Annual costs for therapy ranged from $327 (niacin) to $1881 (lovastatin. 80 mg/d). Niacin was the most efficient agent for reducing low-density lipoprotein cholesterol levels. having an average cost over 5 years of $139 per percent reduction in low-density lipoprotein cholesterol level. Lovastatin (20 mg/d) was also efficient ($177 per percent reduction). Cholestyramine was least efficient at $347. For high-density lipoprotein cholesterol. niacin was most efficient. at $116 per percent increase in high-density lipoprotein cholesterol level. followed by gemfibrozil at $271. Analyses combining low-density lipoprotein cholesterol and high-density lipoprotein cholesterol effects suggest that niacin and lovastatin (20 mg/d) were most efficient for reducing cardiovascular risk.
Preventing upper gastrointestinal bleeding in patients receiving nonsteroidal antiinflammatory drugs, Severe upper gastrointestinal (GI) bleeding is a serious adverse effect of nonsteroidal antiinflammatory drugs (NSAIDs) and the elderly are at increased risk of developing this complication. Bleeding episodes can be prevented. Replacing NSAIDs with acetaminophen may be appropriate when a simple analgesic is needed that eliminates the risk of GI bleeding. Using the lowest effective NSAID dose may decrease the incidence and severity of NSAID gastropathy. Histamine H2-receptor antagonists. sucralfate. and misoprostol have been studied for the prevention of NSAID gastropathy. but only misoprostol prevents mucosal injury in both the stomach and duodenum. Patients who have a history of peptic ulcer disease or gastric bleeding from NSAIDs are candidates for prophylactic measures. Although other patients are at risk. no one knows who should receive prophylactic therapy for NSAID gastropathy. Future studies should attempt to define patient populations that warrant prophylactic therapy.
Usefulness of late coronary thrombolysis (recombinant tissue-type plasminogen activator) in preserving left ventricular function in acute myocardial infarction, This study assesses whether administration of recombinant tissue-type plasminogen activator (rt-PA) up to 8 hours after onset of symptoms of acute myocardial infarction (AMI) may result in a significant improvement in left ventricular function. Sixty patients were classified into 3 groups: group A (n = 21) received rt-PA within 4 hours from symptom onset; the remaining 39 patients. admitted between 4 and 8 hours. were randomized into 2 groups--group B (n = 19) received rt-PA. and group C (n = 21) was treated with conventional therapy. Coronary and left ventricular angiograms were recorded 8 to 10 days after rt-PA administration. The patency rate of the infarct-related artery was 76% in group A. and 63 and 35% in group B and C. respectively. The Thrombolysis in Myocardial Infarction trial perfusion grade was higher in group A and B than in group C (A vs C: p less than 0.005; B vs C: p less than 0.01). Left ventricular ejection fraction was significantly higher in group A (60.2 +/- 10%) and B (54.7 +/- 12%) compared with group C (44.2 +/- 12%) (A vs C: p less than 0.01; B vs C: p less than 0.05). Regional wall motion of the entire ischemic zone was better in group A and B than in group C (A vs C: p less than 0.001; B vs C: p less than 0.01). In contrast. the kinesis of the central ischemic zone was significantly better in group A than in both group B and C (A vs B: p less than 0.05; A vs C: p less than 0.001).
Validation of a computerized technique for detection of the gas exchange anaerobic threshold in cardiac disease, Respiratory gas exchange data were collected from 77 men greater than 6 months after acute myocardial infarction. Maximal exercise was performed on an ergometer cycle programmed for a ramp protocol of 15 W/min. The gas exchange anaerobic threshold (ATge) was determined by analysis of the carbon dioxide elimination (VCO2) vs oxygen consumption (VO2) curve below a respiratory exchange ratio of 1.00 using a computerized algorithm. This value was estimated at the inflection of VCO2 from a line with a slope of 1 which intersects the VCO2 vs VO2 curve. The relation of the ATge to the lactate acidosis threshold was studied in 29 patients. The reproducibility of the ATge method was studied in 77 patients. Mean (+/- standard deviation) VO2 for the ATge was 905 +/- 220 vs 866 +/- 299 ml/min for the lactate acidosis threshold (r = 0.86. p less than 0.001). Mean VO2 at the ATge for test 1 was 968 +/- 225 vs 952 +/- 217 ml/min for test 2 (r = 0.71. p less than 0.001). Mean peak VO2 was 1.392 +/- 379 vs 912 +/- 202 ml/min at the ATge (r = 0.76. p less than 0.001). Results demonstrate that this ATge method correlates well with the lactate acidosis threshold. is reproducible. and should be useful as an objective measure of submaximal exercise performance.
Long-term predictors of outcome in abstinent alcoholic men, Twenty-nine alcoholic men who had been abstinent for more than 2 years were evaluated behaviorally and neuroendocrinologically and then followed for 2 years. Mean length of abstinence at intake was shorter in the eight patients with histories of depression (3.3 years) than in the patients without such histories (6.8 years). Six patients relapsed during follow-up. all of whom had been sober less than 5 years. None of the neuroendocrine variables studied was predictive of outcome. In summary. abstinence of less than 5 years and comorbidity with depression were most predictive of poor outcome.
Changes in the cochlear iron enzymes and adenosine triphosphatase in experimental iron deficiency, The influences of iron deficiency on the cochlear iron enzymes and adenosine triphosphatase were studied in 68 iron-deficient rats and 68 control rats (normal and with chronic anemia). A disorderly or topographic distribution and reduction or disappearance of the cochlear succinic dehydrogenase and peroxidase reaction products were found in 37.8% of the rats fed on a basic iron-deficient diet for 14 to 100 days. The activity of cochlear sodium-potassium-dependent adenosine triphosphatase in iron-deficient rats was slightly increased. compared to that in normal controls. These results suggest that iron deficiency would produce significant abnormalities of succinic dehydrogenase and peroxidase activity. which in turn would disturb cell respiration and initiate peroxidative damage to the inner ear cells. result in sensorineural hearing loss. or provide a pathologic basis for cochlear deafness.
Absorptive hyperemia restores intestinal blood flow during Escherichia coli sepsis in the rat, Enteral nutritional support has been found to result in better maintenance of mucosal integrity during stress than parenterally administered nutritional support. In our experiments. we employed in vivo microvascular techniques to examine the effect of mucosally applied glucose on intestinal microvascular blood flow during hyperdynamic live Escherichia coli bacteremia in the rat. We observed a significant decrease in intestinal microvascular blood flow during bacteremia when the mucosa was suffused with a nonglucose solution. Blood flow was rapidly restored to above-baseline values after glucose was added. The restoration of blood flow resulted from dilation of arterioles at all branch orders and was associated with dilation of premucosal arterioles to above-baseline diameters. Our results show that glucose-induced absorptive hyperemia restores intestinal blood flow during live E coli bacteremia. Restoration of intestinal microvascular blood flow may be a contributing factor to the improved maintenance of mucosal integrity associated with enteral feeding.
Plasma concentration of atrial natriuretic peptide in spontaneous atrioventricular re-entrant tachycardias of childhood, Plasma atrial natriuretic peptide was measured in 13 children between the ages of 1 week and 2 years 9 months during atrioventricular re-entrant tachycardia and 15 minutes after the restoration of sinus rhythm. There was a significant decline in atrial natriuretic peptide during sinus rhythm. Plasma concentrations of the peptide were significantly higher during tachycardia in seven infants under 1 year than in the six older children. The heart rates and the duration of tachycardia were not significantly different in the two age groups. Cardiac failure was present in five of seven children under 18 weeks of age during tachycardia but in none of the older children. The plasma concentration of atrial natriuretic peptide did not significantly correlate with duration of tachycardia or heart rate. If tachycardia occurs in young infants the low functional reserve capacity of the developing heart leads to cardiac failure more frequently and it is likely that this was the cause of the significantly higher plasma concentration of atrial natriuretic peptide in the younger children.
Growth-inhibitory effect of combination chemotherapy for human pancreatic cancer cell lines, Sensitivities to anti-tumor drugs. mitomycin C (MMC). aclarubicin hydrochloride (ACR). doxorubicin hydrochloride (ADR). cisplatin. and 5-fluorouracil (5FU). were examined using PK-1. -8. -9. -12. -14. and -16 cell lines derived from human pancreatic cancer. These cell lines showed different sensitivities to each of the above anti-tumor drugs. The concentrations required for 50% growth-inhibition (IC50) after 2 hours of exposure were 0.096 to 0.35 micrograms/ml for MMC. 0.0074 to 0.0076 micrograms/ml for ACR. 0.033 to 0.23 micrograms/ml for ADR. 0.35 to 1.9 micrograms/ml for cisplatin. and 21 to 42 micrograms/ml for 5FU. IC50 of each anti-tumor drug decreased significantly after 48 hours of exposure. The combination of any two out of MMC. ACR. and 5FU showed synergistic inhibition of the growth of PK-1 and PK-8 cell lines. These results show that MMC. ACR. ADR. cisplatin. and 5FU have sufficient anti-tumor effect against six human pancreatic cancer cell lines even at clinically achievable concentrations and exposure times. and chemotherapy for pancreatic cancers requires naturally effective drug delivery into cancer tissues.
In vivo thrombin inhibition enhances and sustains arterial recanalization with recombinant tissue-type plasminogen activator, The effects of heparin and the synthetic competitive thrombin inhibitor (2R.4R)-4-methyl-1-[N2-(3-methyl-1.2.3.4-tetrahydro-8-quinolinesulfon yl)-L-arginyl]-2-piperidinecarboxylic acid monohydrate (Argatroban) on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) was studied in groups of six or seven rabbits with arterial thrombosis. The model consisted of a whole-blood clot produced in a 1-cm isolated femoral arterial segment with superimposed endothelial damage and distal high-grade stenosis. rt-PA was injected as an intravenous bolus of 0.45 mg/kg body wt at 15-minute intervals until recanalization. or up to a maximum of four boluses. In seven rabbits given an intravenous injection of 17 mg/kg aspirin. rt-PA induced transient reflow in only one animal. In seven rabbits that received intravenous heparin (200 units/kg over 60 minutes). rt-PA administration produced reflow in five animals. which was persistent in two rabbits. Combined administration of aspirin and heparin in seven rabbits was associated with similar rt-PA-induced recanalization. rt-PA administration in six rabbits given intravenous Argatroban (100 micrograms/kg/min for 60 minutes) caused recanalization in five. with persistent patency in three. In six rabbits given aspirin and Argatroban. rt-PA caused recanalization in all. with persistent patency in five animals. Reflow occurred significantly more rapidly with Argatroban (14 +/- 7 minutes) than with heparin (35 +/- 11 minutes). reflow was obtained with fewer boluses of rt-PA in combination with Argatroban (median value of one bolus) than with heparin (median value. three boluses). and reocclusion after reflow was less frequent with Argatroban (0 of 11 versus 5 of 10 rabbits). Furthermore. the degree of thrombolysis determined by pathological analysis was significantly more extensive with Argatroban than with heparin. and patency persisted during a 3-hour observation period. despite elimination of Argatroban from the circulation. Thus. Argatroban. relative to heparin. enhances and sustains thrombolysis with rt-PA. It may offer promise as an adjunctive agent for thrombolytic therapy of arterial thrombosis.
The effect of radiation therapy on the fixation strength of an experimental porous-coated implant in dogs, Radiation therapy prevents heterotopic ossification after cemented total hip arthroplasty. but its effect on the fixation of porous-coated devices is not known. The purpose of this study was to determine the effect of irradiation on the pullout strength of a porous implant in the canine model. A custom-designed titanium fiber metal-coated cylinder was implanted into the distal femurs of 12 dogs. One femur of each dog was irradiated with 10 Gy. given in four 2.5-Gy daily fractions beginning one day after surgery. Serial bone scans were performed at one. two. four. and six weeks postoperatively. At six weeks. the femurs were harvested. and eight were randomly selected for mechanical testing. Scintigraphic evaluation showed a significant reduction in uptake at one and two weeks in the irradiated limb. but this had returned to normal at four and six weeks. The failure to pullout was significantly less in the irradiated limb compared with the control limb six weeks postoperatively. In this canine model. the pullout strength of the titanium fiber implant was significantly reduced by a dose of radiation commonly used in the prevention of heterotopic ossification. If irradiation is chosen for prophylaxis. either the porous implant should be adequately shielded or a cemented implant should be utilized.
Clinical application of the metabolic cart to the delivery of total parenteral nutrition, In critically ill patients. the inaccuracy of predictive formulas for nutritional assessment often leads to inappropriate and potentially detrimental feeding regimens. This study evaluates the clinical utility of the metabolic cart in an urban university hospital setting. Twenty-six studies were performed on each of 26 patients (18 surgical. 8 medical) using an MMC Horizon metabolic cart. Although 58% of patients were overweight. 42% were still shown to have a kwashiorkorlike pattern of malnutrition. Three patients demonstrated a marasmic-like pattern. Fifteen percent of studies showed patients to be hypometabolic and 62% hypermetabolic. Harris-Benedict resting energy expenditure. based on actual or ideal body weight. underestimated needs; however. addition of a metabolic activity factor overestimated needs. Only 32% of patients were fed appropriately; 41% were underfed. and 27% were overfed. Urine area nitrogen correlated poorly with energy expenditure. Measured RQ appropriately reflected substrate utilization in 77% of studies; multiple factors may have caused differences between measured and predicted RQ in 23%. Use of the metabolic cart determines precisely the metabolic state. identifies problems with substrate utilization. and enables the physician to design the most efficacious nutritional regimen.
Influence of parenteral nutrition on leg nitrogen exchange in injured patients, Body N balance. 3-methylhistidine (MEH) excretion. amino acid (AA) plasma concentration. and fluxes across the leg were investigated both during fasting and during parenteral nutrition of injured patients in order to better understand protein-sparing mechanisms induced by metabolic support in the whole body and in skeletal muscle. Patients were randomized to receive 15 or 30 kcal/kg.day coupled with 0.30 g of N either with standard or branch-chain (BC)-enriched AA solutions. During fasting. patients were highly catabolic (N balance -14.7 +/- 1.2 g N/m2.day. MEH excretion 422 +/- 25 mumol/m2.day) and showed a high efflux of AA N from the leg (5.08 +/- 2.1 g N/m2.day) without difference between the groups. During treatment. body N balance (-5.55 +/- 0.88. p less than .001) and MEH excretion (284 +/- 20. p less than .001) were significantly reduced without difference among the groups; also. AA N leg efflux (2.64 +/- 0.47. p less than .001) was reduced. Moreover. considering the effect of calorie load. patients receiving 30 kcal/kg.day showed a lower efflux of total AA N and of some AA considered as markers of muscle protein catabolism. such as phe. lys. met. and glu. The main difference between solutions was in the efflux of BCAA; particularly. val and leu efflux was turned into uptake in the BCAA group. No significant difference among the groups was found in N balance and MEH excretion during treatment. In brief. muscle catabolism was reduced in an amount dependent on glucose and insulin load. but it was not influenced by BCAA supply. Whole body net protein catabolism was reduced through different mechanisms. either an increased visceral N retention or a decreased muscle N loss. However. muscle N loss was never abolished even in the high calorie groups.
Nd:YAG laser and photodynamic therapy for esophageal and endobronchial tumors under general and local anesthesia. Effects on arterial blood gas levels, STUDY OBJECTIVE: Our objective was to determine the respiratory and acid-base metabolism response to endoscopic laser surgery for obstructive tumors. as related to the duration and different types of endoscopy. anesthesia. and laser treatment. DESIGN: The design was a case-control. cohort analytic. nonrandomized controlled survey of case series before and after endoscopic procedures. SETTING: A referral-based surgery and oncology practice at one hospital's laser center. PATIENTS: We studied a sequential sample of 82 patients in the age range from 35 to 92 years. with malignant and benign. primary and metastatic. partially and completely obstructing esophageal (15 patients) and endobronchial (67 patients) tumors. INTERVENTIONS: A total of 229 diagnostic. laser treatment. and follow-up endoscopic procedures was performed under general or local anesthesia (46 esophagoscopies and 183 bronchoscopies). The latter group consisted of 29 cases of general and 154 cases of local topical anesthesia. The last group involved 37 diagnostic and toilet bronchoscopies. 86 cases of YAG-laser tumor ablation. and 31 cases of PDT. MEASUREMENTS AND MAIN RESULTS: Direct-reading electrode measurements of arterial blood. sampled before and immediately after the endoscopic procedure. revealed statistically significant (p less than 0.001) increases in PaCO2 (200 of 229 cases) and decreases in pH (195 of 229 cases) and PaO2 (215 of 229 cases). These findings were similar after bronchoscopy and esophagoscopy. general and local anesthesia (only the decrease in pH was less pronounced in the latter case). and explorative endoscopies and different laser treatments and did not correlate with the total duration of the procedure within the wide time range of 7 to 210 minutes. The initial preoperative level of PaCO2 was considerably higher and the level of PaO2 was significantly lower in patients with endobronchial tumors. as compared to patients with esophageal cancer. A strong. inverse linear relationship was found between the perioperative changes in PaO2 and its initial level and between PaCO2 and pH changes. CONCLUSIONS: The PDT for esophageal and endobronchial malignancies is no more harmful for acid-base metabolism and respiratory functions than YAG-laser tumor ablation or any other common. nonlaser endoscopic procedure.
Cardiorespiratory effects of pressure controlled ventilation in severe respiratory failure, Cardiorespiratory values were measured in ten patients with severe respiratory failure on volume controlled and pressure controlled ventilation. Tidal volume. respirator rate. PEEP. auto-PEEP. inspiratory:expiratory ratio (1:2) and FIo2 were maintained at the same value for both ventilatory modalities. Changing from VCV to PCV was associated with significant improvements in PaO2. oxygen delivery. and tissue oxygen consumption. Peak inspiratory pressure fell. There were no significant changes in other cardiorespiratory values. such as arterial blood pressure. nor in ventilatory measurements. such as mean airway pressure. associated with the use of PCV. These results suggest that PCV may be a beneficial ventilatory modality in the treatment of severe respiratory failure since it results in improvement in arterial oxygenation. tissue oxygen delivery and utilization without any concomitant adverse effects on other hemodynamic or ventilatory factors.
Positional changes in gas exchange after unilateral pulmonary embolism, We describe positional changes in oxygenation in two patients with respiratory failure due to massive pulmonary embolism. In both patients. oxygenation improved when the "sick" lung was dependent and deteriorated when the "healthy" lung was in the dependent position. These positional changes are different from previously reported changes in unilateral pulmonary disease. We speculate that a combination of unilateral pulmonary embolism and mechanical ventilation was responsible for the improvement in gas exchange when the "sick" lung was placed in the dependent position. The relative contribution of these two components to the development of this phenomenon is unclear.
Cortical benzodiazepine receptor binding in patients with generalized and partial epilepsy, Impaired cortical inhibition may be involved in epileptogenic mechanisms. In a positron-emission tomography (PET) study. we demonstrated a reduction of the cortical benzodiazepine (BZD) receptor density in the epileptic foci of patients with partial epileptic seizures. In the present study. we used the same method in 10 patients with primary generalized epilepsy to determine whether an altered BZD receptor binding could also be demonstrated in this patient group. The [11C]-labeled BZD receptor antagonist Ro 15-1788 was used as ligand. Receptor affinities and densities were calculated in various cortical regions and then compared with the values from corresponding "nonepileptic" regions in the previously examined partial epilepsy patients. Focal alterations of the BZD receptor density or affinity were not demonstrated in patients with generalized epilepsy. This patient group had a slight tendency toward lower mean cortical BZD receptor density. however. as compared with corresponding values from 10 patients with partial epilepsy. Our results strongly suggest that a focal alteration of cortical inhibition is not a prominent feature of human generalized epilepsy. The observed tendency toward lower mean cortical BZD receptor density may be a consequence of diffusely impaired cortical inhibition. Further investigations of this issue are therefore indicated.
Some genetic aspects of idiopathic and symptomatic absence seizures: waking and sleep EEGs in siblings, Epileptic activity was recorded in the waking and sleep EEG of 62.5% of 80 siblings of 38 patients with absence seizures. Epileptic discharges were noted in waking only in 8.7%. in waking as well as sleep in 28.8%. and in sleep only in 25%. Generalized. partly irregular. and slow spike-wave complexes were found. twice with lateral emphasis. Spike-wave complexes were recorded in 72% of 50 siblings of patients with idiopathic absence and in 46.7% of 30 siblings of patients with symptomatic absence. One epileptic discharge was observed every 108.6 s on the average. without striking differences between siblings of patients with idiopathic (99.7 s) and symptomatic absence (119.3 s). Without any differences between siblings of children with idiopathic and symptomatic absence. the most epileptic discharges were activated in sleep stages C and D. followed by stages A and B. The highest activation rate was observed in the 7-14-year-old group (73.5%) and to a somewhat lesser degree in the group between 15 and 20 years of age (66.7%); fewer epileptic discharges were recorded in younger (25%) and older patients (28.6%). The higher activation rates in the male sex were significant only in siblings of patients with idiopathic absence. Although only five patients (13.2%) were photosensitive. a photosensitivity was found in 24% of siblings of children with idiopathic absence and in 20% of siblings of patients with symptomatic absence. Three siblings of patients with idiopathic absence also had absence seizures; in one of them a febrile seizure occurred at an earlier age. All of them showed generalized spike wave discharges in waking as well as sleep. Occipital theta delta activity with generalization was observed more frequently in siblings of patients with idiopathic absence (82.2%) than in those of patients with symptomatic absence (63.6%). Our waking and sleep EEG recordings prove that concerning etiology-genetic factors play a striking role in idiopathic absence. but are also of considerable significance in the symptomatic types.
Early follicular phase follicle-stimulating hormone treatment of endometrial luteal phase deficiency, Fifteen infertile women with inadequate luteal phase. histologically documented in at least two separate cycles. and normal midluteal plasma levels of progesterone (greater than or equal to 10 ng/mL). estradiol (70 to 300 pg/mL). and prolactin (less than 20 ng/mL) received "pure" follicle-stimulating hormone (pFSH). 150 IU intramuscularly. for 4 days (days 1 to 4 of the cycle). The endometrial defect was corrected in 7 of the 15 (46.7%) patients during the first treated cycle. Hormonal levels were similar in control and treatment cycles. Two of 5 patients with no additional infertility factors except luteal phase deficiency (LPD) became pregnant and carried to term singleton pregnancies. In 5 additional infertile patients with normal luteal function as assessed by endometrial histological study (2 cycles) and hormone measurements (first study cycle). a third biopsy was performed in a consecutive cycle under pFSH administration. In no case was the normal secretory pattern impaired. It is concluded that (1) some forms of LPD may be successfully treated by early follicular pFSH therapy and (2) pFSH does not alter the normal endometrial secretory pattern.
Treatment of endometriosis with goserelin depot, a long-acting gonadotropin-releasing hormone agonist analog: endocrine and clinical results, Thirty-two patients with laparoscopic diagnosis of endometriosis were treated for 6 months with the gonadotropin-releasing hormone agonist goserelin depot. Hormonal and clinical evaluations were conducted during treatment and for a 6-month follow-up period. Serum 17 beta-estradiol levels were sharply suppressed. Luteinizing hormone was also decreased. whereas follicle-stimulating hormone. after an initial fall. gradually rose to pretreatment levels. Ovarian androgenic production was less inhibited. total testosterone being the only significantly suppressed hormone. There was a marked improvement of signs and symptoms of endometriosis and a 47.3% reduction of laparoscopic score. The results of this study suggest that goserelin depot provides a very good suppression of ovarian estrogen production and is highly effective in decreasing the symptoms of endometriosis with an acceptable compliance by the patient.
Na(+)-K(+)-ATPase and changes in ATP hydrolysis, monovalent cation affinity, and K+ occlusion in diabetic and galactosemic rats, This study showed that steady-state kinetics of ATP hydrolysis by Na(+)-K(+)-ATPase are altered in the BB Wistar diabetic rat and experimental galactosemia. Four days after onset. this change was not evident if NaCNBH3 was omitted during enzyme preparations (indicating reversibility). Ninety days after onset. NaCNBH3 reduction was not necessary to see the change in ATP hydrolysis kinetics (indicating nonreversibility). The change in steady-state ATP hydrolysis was similar to that reported earlier for Na(+)-K(+)-ATPase of the lens epithelium and kidney medulla of diabetic individuals and for two in vitro glycosylation models. Our study also showed that the affinities of Na(+)-K(+)-ATPase for K+ are altered. and Na(+)-K(+)-ATPase-dependent K+ occlusion is inhibited in diabetic and galactosemic animals. Because K+ occlusion is required for efficient K+ transport. this finding supports previous in vitro studies that indicated that glycosylation inhibits pump-dependent K+ transport. Furthermore. our study suggested an irreversible impairment of Na(+)-K(+)-ATPase function in the diabetic BB Wistar rat as early as 15 days after onset. even when blood glucose was maintained at 6.7 mM by daily insulin injection.
Effects of diabetes on cholinergic transmission in two rat gut preparations, The gut may be a site of early diabetic neuropathy in humans and rats. The latter may provide appropriate models of these conditions. Therefore. cholinergic function was examined in two gut smooth muscle preparations from control. 30-day. and 6-month streptozotocin-diabetic and similarly diabetic rats that had received continuous treatment with an aldose reductase inhibitor. ponalrestat. Responses of terminal ileum longitudinal muscle to transmural nerve stimulation were depressed in preparations from untreated 30-day diabetic animals. Responses to exogenous acetylcholine were also depressed. by at least the same extent. in preparations from both 30-day and 6-month diabetic groups. Ponalrestat treatment prevented both changes in the 30-day study but did not prevent a depression of responses to acetylcholine in the 6-month study. Neither diabetes nor ponalrestat affected responses of esophageal muscularis mucosa to electrical stimulation or to exogenous acetylcholine. These observations suggest a change in the smooth muscle and/or noncholinergic innervation rather than in the cholinergic nerves of the ileal preparation. Cholinergic function in the ileum did not. therefore. seem to be an appropriate model of diabetic neuropathy.
Hypoxic exposure and activation of the afterdischarge mechanism in conscious humans, After voluntary hyperventilation. normal humans do not develop a significant ventilatory depression despite low arterial CO2 tension. a phenomenon attributed to activation of a brain stem mechanism referred to as the "afterdischarge." Afterdischarge is one of the factors that promote ventilatory stability. It is not known whether physiological stimuli. such as hypoxia. are able to activate the afterdischarge in humans. To test this. breath-by-breath ventilation (VI) was measured in nine young adults during and immediately after a brief period (35-51 s) of acute hypoxia (end-tidal O2 tension 55 Torr). Hypoxia was terminated by switching to 100% O2 (end-tidal O2 tension of first posthypoxic breath greater than 100 Torr). Brief hypoxia increased VI and decreased end-tidal CO2 tension. In all subjects. termination of hypoxia was followed by a gradual ventilatory decay; hyperoxic VI remained higher than the normoxic baseline for several breaths and. despite the negative chemical stimulus of hyperoxia and hypocapnia. reached a new steady state without an apparent undershoot. We conclude that brief hypoxia is able to activate the afterdischarge mechanism in conscious humans. This contrasts sharply with the ventilatory undershoot that follows relief of sustained hypoxia. thereby suggesting that sustained hypoxia inactivates the afterdischarge mechanism. The present findings are of relevance to the pathogenesis of periodic breathing in a hypoxic environment. Furthermore. brief exposure to hypoxia might be useful for evaluation of the role of afterdischarge in other disorders associated with unstable breathing.
Acute lung injury from mechanical ventilation at moderately high airway pressures, We have explored adverse pulmonary effects of mechanical ventilation at a peak inspiratory pressure of 30 cmH2O in paralyzed and anesthetized healthy sheep. A control group of eight sheep (group A) was mechanically ventilated with 40% oxygen at a tidal volume of 10 ml/kg. a frequency of 15 breaths/min. a peak inspiratory pressure less than 18 cmH2O. and a positive end-expiratory pressure of 3-5 cmH2O. During the ensuing 48 h. there were no measurable deleterious changes in lung function or arterial blood gases. Another 19 sheep were ventilated with 40% oxygen at a peak inspiratory pressure of 30 cmH2O under a different set of conditions and were randomly assigned to two groups. In group B. the respiratory rate was kept near 4 breaths/min to keep arterial PCO2 in the normal range; in group C. the frequency was kept near 15 breaths/min by including a variable dead space in the ventilator circuit to keep arterial PCO2 near baseline values. There was a progressive deterioration in total static lung compliance. functional residual capacity. and arterial blood gases. After some hours. there were abnormal chest roentgenographic changes. At time of death we found severe pulmonary atelectasis. increased wet lung weight. and an increase in the minimum surface tension of saline lung lavage fluid.
Current treatment reduces calories required to maintain weight in pediatric patients with burns, A previous study indicated that formulas for determining caloric requirements of severely burned children overestimated their needs. This study was undertaken to determine the caloric intake required to maintain weight in patients under 12 years of age with burns over more than 30% total body surface area. The 102 patients studied were divided into two groups according to weight changes. A comparison of the actual caloric intakes of these groups was conducted. Multivariate regression analysis indicated that body surface area in square meters and burn surface were significant predictors of caloric requirements to maintain weight in these patients. It was determined that 1800 kcal was a plausible value for the calories per body surface area. Therefore the regression was formed with 1800 kcal as the multiplier of body surface area. and the multiplier of burn surface area was estimated. The resulting formula provides 1300 kcal/m2 burned. which is 900 kcal/m2 burned less than our previously suggested formula.
Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma mansoni in the mouse, To investigate the role of anaphylactic immune responses in protective immunity against schistosomiasis. mice vaccinated with irradiated cercariae of Schistosoma mansoni were treated with neutralizing mAb antibodies against either IL-5 or IL-4 before and during challenge infection. Anti-IL-5-treated vaccinated mice showed a complete ablation of circulating as well as tissue eosinophils present in inflammatory reactions to migrating schistosomula in the skin and lungs but nevertheless eliminated challenge infections as effectively as vaccinated animals treated with a control mAb. Similarly. treatment of vaccinated mice with an anti-IL-4 mAb markedly reduced serum IgE although failing to diminish immunity. The effect of anti-IL-5 mediated eosinophil depletion was also assessed in a second model in which resistance is induced by concomitant chronic infection. Again. normal. unaltered protection was observed in the absence of circulating and tissue eosinophils. In contrast to the above findings. treatment with anti-IFN-gamma was found to cause a partial depletion of immunity in vaccinated mice whereas. paradoxically. increasing the numbers of inflammatory reactions against invading schistosomula in the lungs. These observations argue against a requirement for either eosinophils or IgE in the anti-schistosome immunity induced by vaccination with irradiated cercariae or for eosinophils in the resistance resulting from previous infection in mice and support previous data suggesting a role for an IFN-gamma dependent cell-mediated effector mechanism in vaccine-induced resistance.
Sulpiride in tardive dyskinesia, The abnormal involuntary movements in tardive dyskinesia can be reduced by the dopamine antagonist drugs. phenothiazines and butyrophenones. but most cause an increase in Parkinsonian signs. Sulpiride. a benzamide derivative. and selective antagonist of D2 receptors had a significantly beneficial effect on most of 15 patients (p less than 0.01). In 12 patients the improvement was marked. The reduction of abnormal movements was observed even with low doses. and it was not necessary to increase the dose of sulpiride above 600 mg daily. There were no significant side effects during the trial nor during an additional three months of treatment.
Gonorrhea, During a 10-year period from 1976 to 1985. N. gonorrhoeae demonstrated remarkable genetic resiliency in developing clinically important antimicrobial resistance through a variety of chromosomal mutations and by acquiring either entire plasmids or resistance determinants on plasmids from other species. Gonococcal resistance is widespread. and few communities will be spared all types. None of the newer diagnostic technologies has provided any performance or cost advantages over traditional Gram-stained smears and cultures. The two most important components of a control program are (1) the National Gonococcal Isolate Surveillance project and (2) treatment with ceftriaxone. 125 or 250 mg intramuscularly. which is active against all known types of resistance and will cure all forms of uncomplicated gonorrhea. including the more difficult-to-treat infections of the pharynx and anorectum. Fear of AIDS has had a powerful motivating effect on sexual behavior. and in the United States has been associated with an overall reduction in incidence of gonorrhea in homosexual men of over 95%. After peaking in 1985. incidence of gonorrhea in white heterosexual men and women has declined as well. A diagnosis of gonorrhea in 1990 implies recent high-risk behavior for acquiring HIV infection. The gonorrhea epidemic in the United States is rapidly contracting down around poor urban minorities; although this is not good. at least it tells us where to target our resources.
Alcohol-related traffic fatalities--United States, 1982-1989, Traffic crashes are the leading cause of death in the United States for all age groups from 1 through 34 years (1). Almost half of all traffic fatalities are alcohol-related (2.3). and an estimated 40% of all persons in the United States may be involved in an alcohol-related traffic crash sometime during their lives (3). This report summarizes data from the National Highway Traffic Safety Administration's (NHTSA) Fatal Accident Reporting System on trends in alcohol-related traffic fatalities (ARTFs) in the United States during 1982-1989.
Seasonality in sudden infant death syndrome--United States, 1980-1987, Sudden infant death syndrome (SIDS) is the sudden death of an infant less than 1 year of age that remains unexplained after a complete postmortem investigation. including autopsy. examination of the death scene. and review of the case history. SIDS. which usually occurs during sleep. is the leading cause of death in the postneonatal period (i.e.. from 28 days through 364 days) and the eighth leading cause of years of potential life lost in the United States (1). The risk for SIDS is greatest for infants aged 1-4 months and during the cold season of the year (2); however. an independent contribution of the season of birth to the etiology of SIDS has not been consistently demonstrated (3). This report summarizes an assessment of the association between the risk for SIDS and an infant's month of birth. month of death. and age at death.
Update: influenza activity--United States and Worldwide, 1990, Influenza activity in the United States is monitored by CDC through surveillance systems developed in cooperation with state and local health departments; in addition. CDC receives reports of worldwide influenza activity from international World Health Organization (WHO) collaborating laboratories and WHO. Geneva. This report summarizes influenza activity in the United States and worldwide for April through November 1990.
Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A. recombinant Factor VIII Study Group, BACKGROUND. Current treatment of hemophilia A. a hereditary disorder affecting approximately 1 in 10.000 males. relies on plasma-derived factor VIII concentrates. We tested the safety and efficacy of a recombinant factor VIII preparation for the treatment of this disorder. METHODS. We conducted the investigation in three stages: comparing the pharmacokinetics of plasma-derived and recombinant factor VIII. assessing the efficacy of recombinant factor VIII for home therapy. and assessing its efficacy for major surgical procedures and hemorrhage. A total of 107 subjects with hemophilia. 20 of whom had not been treated previously. enrolled in the investigation. RESULTS. The in vivo recovery and elimination half-lives of recombinant factor VIII equaled or exceeded those of plasma-derived factor VIII. Seventy-six subjects participated in a home-treatment program. using recombinant factor VIII for 69 to 807 days (median. 618); home diaries of 56 subjects treated for 5 months were analyzed. Of 540 bleeding episodes. 399 (73.9 percent) required only one treatment with recombinant factor VIII. The projected annual consumption of recombinant factor VIII was similar to that of plasma-derived factor VIII concentrate. Twenty-six subjects received recombinant factor VIII for 22 surgical procedures and 10 serious hemorrhages; hemostasis was excellent in all cases. De novo formation of inhibitors occurred in only 1 of 85 previously treated subjects. Inhibitor antibodies also developed in 6 of 21 children. 20 of whom had not previously been treated; 5 had low levels (less than or equal to 7.5 Bethesda units) despite continued treatment with recombinant factor VIII. There was no evidence of new formation of antibody to foreign proteins. and recombinant factor VIII was well tolerated. CONCLUSIONS. Recombinant factor VIII has biologic activity comparable to that of plasma factor VIII and is safe and efficacious for the treatment of hemophilia A.
Access to health care in the United States: barriers for neurologic patients, challenges for neurologic physicians, Approximately 34 million people in the United States have no health insurance. Up to 80 million people have insurance inadequate to provide care for severe or long-term illness (the underinsured). In 1986. an estimated 1 million persons in the US could not obtain needed health care for financial reasons. and another 18.8 million had difficulty obtaining care. There probably are 3.2 million people with neurologic disorders among the 34 million uninsured. and more among the underinsured. Those patients probably have difficulty obtaining health care. including neurologic consultations. laboratory tests. and radiologic procedures. Congress and many state legislatures are considering various proposals to address the problems of the un- and underinsured. Several national medical professional societies have developed programs to improve access to care for their patients. The American Academy of Neurology Task Force on Access to Health Care is studying access to care for neurologic patients and will recommend a course of action to the Academy. The Task Force welcomes suggestions concerning appropriate steps to improve access to health care for patients with neurologic disorders.
The significance of myoclonic status epilepticus in postanoxic coma, We report 11 adults who exhibited myoclonic status epilepticus (MSE) after cardiac arrest. Based on pathologic. electroencephalographic. and clinical evidence. we conclude that our patients died from the initial anoxic-ischemic insult rather than as a result of MSE. We suggest that the seizures in these nonsurvivors were self-limited events arising from lethal damage to neurons. Thus. in patients with bilaterally synchronous facial myoclonus. bilateral loss of pupillary or oculovestibular reflexes. and suppression and burst-suppression on EEG. it is not warranted to use anesthetic barbiturates to treat MSE.
First place--Resident Clinical Science Award 1990. Suppression of lymphokine-activated killer cell cytotoxicity by a soluble factor produced by squamous tumors of the head and neck, Incubation of human peripheral blood lymphocytes (PBL) in the presence of interleukin-2 results in the generation of lymphokine-activated killer (LAK) cells that are highly cytotoxic to a variety of autologous and allogenic tumor targets. We have identified a noncytotoxic. soluble factor. produced by human squamous cell cancers of the head and neck. that profoundly inhibits the generation of LAK cytotoxicity. Inhibition of the generation of cytotoxicity was demonstrated with coculture of PBL and freshly disaggregated tumor cells in a Transwell two-chamber system. Alternatively. inhibition occurred when LAK cells were generated in the presence of tumor-conditioned supernatants alone. These effects were not observed with conditioned supernatants from autologous or allogenic lymphocytes. human fibroblasts. or the erythroleukemia cell line K562. The presence of this inhibitory factor(s) was not required during the entire period of LAK generation. Suppression of cytotoxicity. measured after 4 days of LAK generation. could also be demonstrated when the conditioned tumor supernatant was present in only the last 24 hours of incubation. Suppression is mediated by a heat-labile factor with a molecular weight of greater than 75 kd. These results suggest that LAK cytotoxicity may be significantly impaired by soluble immunoregulatory factors present within the tumor milieu of squamous cell carcinomas of the head and neck. Further characterization of these factors may lead to the development of more rational and effective forms of immunotherapy.
Predictive value of brainstem evoked response in the diagnosis of acoustic neuroma, Predictive value positive is the probability that a positive test result represents a true positive finding. Twenty-six patients with brainstem evoked response findings characteristic of retrocochlear hearing loss were studied. Four acoustic neuromas were diagnosed in this group after radiologic workup. The predictive value in this population was 15%. Statistical considerations are presented.
Diagnosis and treatment of arachnoid cysts of the posterior fossa, Arachnoid cysts of the posterior fossa are rare. When arachnoid cysts are encountered. the presenting symptoms are frequently otologic. with hearing loss and imbalance occurring commonly. Three cases are presented with a previously unreported otologic symptom. that of bilateral hearing loss. which in one case was fluctuant. None of the patients had the common symptoms of unilateral hearing loss and headache. With the advent of computed tomography and magnetic resonance imaging. these cysts may be readily identified. usually with diagnostic imaging alone. Unfortunately there is often a delay in diagnosis because of the vague and fleeting nature of the symptoms. Because no single diagnostic symptom pattern is able to characterize all cases. it is believed computed tomography or magnetic resonance imaging or both are indicated in patients with long-standing otologic complaints--even in the absence of unilateral symptoms. Treatment of posterior fossa arachnoid cysts primarily consists of surgical procedures designed to decompress the cyst. In this series. treatment with diuretics alone resulted in improvement of symptoms during several years of followup. with no evidence of enlargement of the cysts.
Reduction of salivary flow with transdermal scopolamine: a four-year experience, Scopoderm transdermal therapeutic system (TTS) is applied to prevent nausea and vomiting associated with motion sickness. Dry mouth is the most common side effect. appearing in up to two thirds of the patients treated. We have used this side effect to the benefit of patients with sialorrhea or with difficulties swallowing normally secreted amounts of saliva. More than 100 patients with tumors of the aerodigestive tract before and after surgery. and patients after parotidectomies. after tracheotomies. with peritonsillar abscesses. tonsillitis and pharyngitis. and neurologic disorders were thus treated. Reduced secretion of saliva was seen in 50% to 100% of the treatment groups. Other side effects were minimal and we recommend the use of scopoderm TTS for reduction of salivary flow.
Severity of obstructive sleep apnea, A four-level severity scale for obstructive sleep apnea is offered using four criteria: maximum oxygen desaturation. apnea/hyponea index. symptoms of excessive day-time sleepiness. and symptoms of related cardiac disease. Oxygen desaturation and the apnea/hyponea index for 175 patients. all having had uvulopalatopharyngoplasty surgery. showed 19% mild. 33% moderate. 17% moderately severe. and 31% severe obstructive sleep apnea. There was a very poor correlation between oxygen desaturations and number of obstructive events. which demands that both be used in any estimation of disease severity.
The difficult dilation: a method for dilation of severe esophageal strictures in children, Occasionally severe esophageal strictures will develop in children that will not allow the passage of standard Jackson or bougie dilators. These small strictures can be successfully treated using a standard intubating laryngoscope for visualization and Rush urethral Filiform dilators.
Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors, We have previously described a recombinant protein. designated CD4(178)-PE40. consisting of the human immunodeficiency virus (HIV) envelope glycoprotein-binding region of human CD4 linked to the translocation and ADP-ribosylation domains of Pseudomonas aeruginosa exotoxin A. By virtue of its affinity for gp120 (the external subunit of the HIV envelope glycoprotein). the hybrid toxin selectively binds to and kills HIV-1-infected human T cells expressing surface envelope glycoprotein and also inhibits HIV-1 spread in mixed cultures of infected and uninfected cells. We now report that CD4(178)-PE40 and reverse transcriptase inhibitors exert highly synergistic effects against HIV-1 spread in cultured human primary T cells. Furthermore. combination treatment can completely eliminate infectious HIV-1 from cultures of human T-cell lines. This conclusion is based on protection of a susceptible cell population from HIV-induced killing. complete inhibition of virus protein accumulation. and elimination of HIV DNA (as judged by quantitative polymerase chain reaction analysis). The results highlight the therapeutic potential of treatment regimens involving combination of a virostatic drug that inhibits virus replication plus an agent that selectively kills HIV-infected cells.
A large-scale, office-based study evaluates the use of a new class of non-sedating antihistamines. A report from CEN, The two newest agents in the class of nonsedating antihistamines were studied in a wide variety of family practice patients. In a Phase IV. prospective. alternating sequence. open-label design. patients having allergic rhinitis (AR) were assigned to receive either astemizole (n = 659) or terfenadine (n = 639). The resultant treatment groups. typical of family practices. were comparable for demographics. signs and symptoms of allergic rhinitis. and clinical profile. The groups differed in that astemizole patients had a longer history of AR and a higher frequency of family history of AR. Patients who were treated for 3 to 8 weeks were grouped for analyses. The frequency and severity of the signs and symptoms of AR and patient complaints decreased markedly in both groups. Self-reported improvement in quality of life based on nine measures was the same for each group. No differences were seen between treatments when positive-rated outcomes were combined in the final overall assessment by physicians and patients. In rating the success of therapy. physicians' ratings of "excellent" and patients' ratings of "felt much better" were reported more frequently (P less than 0.05) for astemizole. while physicians' ratings of "good" and patients' ratings of "better" were reported more frequently (P less than 0.05) for terfenadine.
Dynamic exercise-induced elevation in plasma levels of atrial natriuretic peptide in patients with effort angina pectoris, We investigated the relationship between plasma atrial natriuretic polypeptide (ANP) levels and hemodynamic indices during dynamic exercise testing in 15 patients with effort angina pectoris. Patients exercised on an angina-limited. supine. multistage bicycle ergometer. and plasma ANP levels and hemodynamic indices were measured at rest. at peak exercise. and 6 minutes after exercise. Plasma ANP levels increased significantly at peak exercise. Pulmonary artery wedge pressure (PAWP) and coronary sinus blood flow (CSBF) were significantly correlated with plasma ANP levels before and at peak exercise (PAWP: r = 0.69. p less than 0.001; CSBF; r = 0.45. p less than 0.05). In six of eight patients whose PAWP exceeded 20 mm Hg at peak exercise. plasma ANP levels were increased at 6 minutes after exercise. whereas PAWP had decreased relative to the values obtained at peak exercise. Plasma ANP concentrations at 6 minutes after exercise were not correlated with PAWP at the same time. However. PAWP at peak exercise was correlated with the plasma ANP levels at 6 minutes after exercise (r = 0.80. p less than 0.001). These results suggest that in patients with effort angina pectoris left ventricular dysfunction resulting from exercise-induced myocardial ischemia may increase preload excessively and may contribute to the excess secretion of ANP after dynamic exercise.
Stimulation of atrial natriuretic peptide and vasopressin during retrograde mitral valvuloplasty, Acute mitral obstruction may lead to an increase in atrial natriuretic peptide (ANP) due to increased atrial pressure and a large increase in arginine vasopressin (AVP) due to simultaneous arterial and ventricular baroreceptor unloading. We measured ANP and AVP concentration after transseptal puncture and during percutaneous retrograde mitral balloon valvuloplasty (PRMV) in 11 patients (mean age 57 +/- 12 years; nine women) with mitral stenosis and congestive heart failure. Atrial septal puncture per se resulted in a significant increase in ANP and AVP without a significant change in aortic pressure. Subsequent PRMV led to a further increase in ANP. a transient decrease in aortic pressure from 89 +/- 7 to 45 +/- 4 mm Hg. and a large (fivefold) increase in AVP. ANP and AVP were no longer different from baseline values 18 to 24 after the procedure. This study suggests that transseptal puncture and acute mitral obstruction are major stimuli to ANP release and that combined unloading of arterial and left ventricular mechanoreceptors is a very potent vasopressinergic stimulus.
Neurohumoral activation in congestive heart failure, This article reviews the evidence that congestive heart failure is accompanied by an increased plasma norepinephrine concentration and that this is due not only to a reduced tissue clearance of the substance but also to a marked increase in sympathetic nerve activity. It also reports data that indicate that the sympathetic activation is associated with an activation of the renin-angiotensin system and an increased plasma level of vasopressin. At which degree of congestive heart failure these phenomena become manifest is not clear. but some studies suggest that the sympathetic and renin-angiotensin systems may be normal in asymptomatic congestive heart failure but already somewhat activated when this condition reaches New York Heart Association class II. There is also evidence that this activation. though initially compensatory. is eventually responsible for a number of adverse cardiovascular effects that account for the negative relationship between this event and survival. Finally. the article discusses the inability of the increased plasma level of atrial natriuretic peptide that characterizes congestive heart failure to offset the adverse effects of the neurohumoral activation and the variable influence of drug treatment on this phenomenon. This is not impossible to achieve. however. because heart transplantation appears to rapidly normalize a major factor in the increased sympathetic activity observed before surgical intervention. that is. impairment of the arterial baroreflex.
Red cell membrane sodium transport: possible genetic role and use in identifying patients at risk of essential hypertension, To investigate the influence of a family history of essential hypertension on abnormalities of red cell membrane sodium transport. 28 hypertensive children and their families were studied. In 15 families one or both parents had either essential hypertension or a strong family history. In 13 families neither parent had essential hypertension or a positive family history. There were significant differences between the children with a positive family history of essential hypertension compared with those without. Values are expressed as mean (SD): intracellular sodium concentration (mmol/l cells) 8.19 (2.18) compared with 6.41 (0.98); sodium efflux rate constant 0.4873 (0.1379) compared with 0.5831 (0.1104); and numbers of sodium-potassium ATPase pump sites (BMax) (nmol/l cells) 7.96 (1.71) compared with 9.56 (1.7). Significant differences were also found when the index hypertensive children were excluded and the normotensive siblings with and without hypertensive family histories were compared. These data suggest that abnormal red cell membrane sodium transport has a familial component. and although it is not caused by the hypertension it may be the earliest pathophysiological step in its development. perhaps allowing the identification of children at risk of essential hypertension.
Excessive secretion of antidiuretic hormone in infections with respiratory syncytial virus, The association between infections with respiratory syncytial virus and plasma concentrations of antidiuretic hormone was assessed in 48 patients who had been admitted to hospital. The mean (SEM) concentration of antidiuretic hormone was significantly raised in patients with bronchiolitis (9.3 (1.4) ng/l) compared with non-pulmonary respiratory syncytial virus infections that cause apnoea or upper respiratory tract symptoms (6.1 (1.7) ng/l). The highest concentrations of antidiuretic hormone were seen in patients receiving mechanical ventilation (18.0 (6.7) ng/l). There were no differences in mean serum sodium concentrations among the subgroups. Hypertranslucency on chest radiograph or an arterial carbon dioxide tension above 6.67 kPa were associated with a significantly higher concentration of antidiuretic hormone. Increased or normal maintenance fluid intake in children with pulmonary respiratory syncytial virus infections may cause the same symptoms of fluid overload as the syndrome of inappropriate secretion of antidiuretic hormone. Patients with pulmonary respiratory syncytial virus infection. hypertranslucency in chest radiograph. hypercapnia. or mechanical ventilation are at risk for raised concentrations of antidiuretic hormone. Restricted fluid intake and careful monitoring of fluid balance and plasma electrolyte concentrations are therefore necessary in these patients.
Soft tissue Ewing's sarcoma. Characterization in established cultures and xenografts with evidence of a neuroectodermic phenotype, This study characterizes the histogenesis of soft tissue Ewing's sarcoma (StEs) based upon an analysis of three tumors. Long-term cultured cell lines and nude mice xenografts were established from original neoplasms or from their metastases. Histologically they revealed a small round cell pattern without signs of differentiation. Several ultrastructural features of neural type were found; the same were also seen on culture cell lines. Moreover. immunohistochemical study for neural markers revealed the presence of HNK-1. NSE. LIRC-LON 36. S-100 protein. glial fibrillary acidic protein. neurofilaments (70 kilodaltons). and chromogranin; some of these markers were present only in the transplants. Cytokeratin was also seen. The translocation t(11;22)(q24;q12) was found in all three neoplasms together with other chromosomal abnormalities. N-myc RNA gave negative results whereas c-myc RNA was expressed. Therefore it may be postulated that StEs displays neuroectodermal features somewhat similar to those seen in peripheral neuroepithelioma as well as in atypical Ewing's sarcoma of bone.
Improved compliance measures: applications in an ambulatory hypertensive drug trial, To assess the value of improved monitoring of medication-taking behavior in a drug trial. we employed a modified pill vial with microcircuitry to record the precise times when the vials were opened. After a 3-week placebo washout period. 21 ambulatory subjects with mild hypertension (mean age. 57 years; 67% men; 76% white) randomly received isradipine or enalapril twice daily in a double-blind titration during 10 weeks. Both drugs achieved a 13% reduction in sitting diastolic blood pressure (p less than 0.01) with minimal symptomatic or laboratory toxicity. Although pill counts indicated near-perfect compliance (92% to 99% for both groups). the electronic monitor showed that fewer than half of all openings occurred at the prescribed interval of 12 +/- 2 hours. Modest overdispensing was documented in the 3 days before scheduled visits. The monitor confirmed that pill count misclassified compliance sufficiency in 22% of visits and permitted more discrete attribution for drug-associated adverse reactions and secondary resistance to treatment. We conclude that the electronic monitor reduces ambiguity about medication compliance and helps interpret both the biology and pharmacology of the trial.
Insulin resistance after surgery: normalization by insulin treatment, 1. Injury is known to be associated with variable degrees of tissue insensitivity to insulin. We measured insulin resistance in a group of non-obese. glucose-tolerant patients undergoing major elective surgery with an uncomplicated post-operative course. 2. Shortly after surgery. hyperglycaemia (7.3 +/- 0.6 versus 4.2 +/- 0.3 mmol/l glucose pre-surgery. mean +/- SEM. P less than 0.01) with normal insulin concentrations (73 +/- 15 versus 64 +/- 18 pmol/l) suggested the presence of insulin resistance. Counter-regulatory hormones were raised. whole-body protein oxidation was doubled (P less than 0.01) and energy expenditure was up by 18% (P less than 0.01). 3. Insulin sensitivity was quantified by clamping plasma glucose concentrations at 5.6 mmol/l during 24 h of total parenteral nutrition (15% protein. 55% glucose and 30% fat. supplying 1.25 times the measured resting energy expenditure) with a variable infusion of exogenous insulin. After surgery. eight times more insulin was needed than before surgery (14.14 +/- 1.15 versus 1.78 +/- 0.29 pmol min-1 kg-1. P less than 0.001) to maintain euglycemia. 4. After surgery. stimulation of net carbohydrate oxidation (18.8 +/- 1.4 versus 17.2 +/- 1.8 mumol min-1 kg-1 preoperatively. not significant). suppression of lipolysis and lipid oxidation and inhibition of ketogenesis occurred to the same extent as before surgery. Of the infused nutrients. the glucose was all oxidized. amino acids replaced endogenous protein losses (= neutral nitrogen balance) and lipids were stored. Insulin administration caused no further increment in oxygen consumption or energy expenditure.
Receptors for luteinizing hormone-releasing hormone (LHRH) in Dunning R3327 prostate cancers and rat anterior pituitaries after treatment with a sustained delivery system of LHRH antagonist SB-75, Membrane receptors for LHRH were evaluated in Dunning R3327 prostate cancers and rat anterior pituitaries. The receptors were characterized both in untreated animals and after in vivo treatment with microcapsules of the agonist D-Trp6-LHRH and a sustained delivery system releasing different doses (23.8. 47.6. 71.4 micrograms/day) of LHRH antagonist [Ac-D-Nal(2)1-D-Phe(4Cl)2-D-Pal(3)3.D-Cit6. D-Ala10]-LHRH (SB-75). The therapy. which lasted 8 weeks. strongly inhibited tumor growth. A group of normal Sprague-Dawley male rats was also treated for 6 weeks with microcapsules of SB-75 releasing 25 micrograms/day. In the Dunning tumors from the control group. ligand [125I. D-Trp6]-LHRH was bound to two classes of binding sites [dissociation constant. class a (Kda) = 1.01 +/- 0.30 x 10(-9) M; Kdb = 1.71 +/- 0.41 x 10(-6) M; maximal binding capacity of receptors. class a (Bmaxa) = 48.66 +/- 22.13 fmol/mg of protein; Bmaxb = 92.10 +/- 29.40 pmol/mg of protein] in both kinetic and equilibrium studies. Treatment with D-Trp6-LHRH produced down-regulation of membrane receptors for LHRH in Dunning tumors. Microcapsules of SB-75 resulted in dose-dependent up-regulation of binding sites for LHRH in Dunning tumors. Analysis of the binding data showed that interaction of labeled D-Trp6-LHRH with binding sites in anterior pituitaries was consistent with the presence of a single class of noncooperative receptors (Kd = 43.75 x 10(-9) M; Bmax = 5.25 pmol/mg membrane proteins). Prolonged treatment with microcapsules of D-Trp6-LHRH reduced both Bmax and Kd. Lower doses of SB-75 (23.8 and 47.6 micrograms/day) produced up-regulation. whereas the highest dose (71.4 micrograms/day) resulted in down-regulation of binding sites for LHRH in rat pituitaries. In normal Sprague-Dawley rats. treatment with microcapsules of SB-75 (25 micrograms/day) for 6 weeks produced a slight increase in the number of available binding sites (Bmax = 2.35 +/- 0.82 pmol/mg membrane protein) and a moderate decrease in affinity (Kd = 35.10 +/- 15.19 x 10(-9) M) of pituitary membrane receptors for LHRH. The findings provide additional support for the view that LHRH analogs exert direct effects on tumor cells. Our findings indicate that prolonged treatment with high doses of modern LHRH antagonists produces down-regulation of pituitary receptors. Our work in tumors also implies that some differences may exist between LHRH receptors. even in the same tissue. leading to the concept of subclassification of LHRH receptors.
Evidence that ethanol induces prolactin secretion in GH4C1 cells by producing cell swelling with resultant calcium influx, Although acute exposure to ethanol has been reported to affect hormone secretion. the data are sometimes conflicting. and the mechanism of action of ethanol is unclear. We have examined in GH4C1 cells the effect of isotonic ethanol on cell volume measured with a Coulter counter. the cytosolic Ca2+ concentration ([Ca2+]i) monitored with fura-2. and PRL secretion analyzed in a perifusion system. Isotonic ethanol caused prompt cell swelling and an explosive rise in both [Ca2+]i and PRL secretion proportional to the concentration of ethanol between 5-120 mM. The increases in both [Ca2+]i and PRL secretion induced by 80 mM isotonic ethanol were essentially abolished by removal of medium Ca2+ or by nifedipine; the nifedipine IC50 was approximately 20 nM. Cell swelling induced by hyposmolarity or isotonic urea similarly increased both [Ca2+]i and PRL secretion. Hypertonic ethanol did not cause cell swelling and was ineffective in inducing an increase in either [Ca2+]i or PRL secretion. These data suggest that in GH4C1 cells a major mechanism by which ethanol stimulates PRL secretion is to induce cell swelling. thus producing enhanced Ca2+ influx through dihydropyridine-sensitive Ca2+ channels.
Melanocytic differentiation of human neuroblastoma: expression of a human melanosome-associated antigen, Five human neuroblastoma cell lines were examined for expression of a human melanosome-associated antigen (HMSA). Only cell line SK-N-SH reacted with a monoclonal antibody. HMSA-2. shown to recognize melanosomal glycoproteins. To further characterize the melanocytic lineages of SK-N-SH. three morphologically distinct clones designated SK-N-SH-N (neuroblast type). SK-N-SH-F (fibroblast type). and SK-N-SH-EP (epithelial type) were established by colony formation cloning. By fluorescence-activated cell sorter analysis and tyrosinase assay. we found that only SK-N-SH-EP and SK-N-SH-F reacted with HMSA-2 and had tyrosinase activity. These results suggest that epithelial-type and fibroblast-type cells appear to possess the melanocytic potential. but not neuroblast-type cells. Furthermore. SK-N-SH-EP was found to spontaneously convert to neuroblast-type or fibroblast-type cells. whereas SK-N-SH-N and SK-N-SH-F clones have remained morphologically stable. Our results suggest that at least one neuroblastoma cell line. SK-N-SH. may be an excellent model for investigating clonal maturation and the melanocytic differentiation of neuroblastoma.
Influenza surveillance--Wales, 1988-89, Important functions of influenza surveillance include early detection of epidemics-enabling immunization of persons not previously covered by routine immunization programs. notification of health providers to prepare for the possible impact on clinical workloads and hospital admissions. and characterization of prevalent strains to permit the timely production of appropriate vaccines. In 1986. a general-practice-based surveillance system was established in Wales to facilitate reporting of infectious diseases. including influenza and influenza-like illnesses. This report summarizes influenza surveillance findings in Wales for 1988 and 1989.
Decline in Haemophilus influenzae type b meningitis--Seattle-King County, Washington, 1984-1989, The first vaccines licensed in the United States for prevention of Haemophilus influenzae type b (Hib) disease were composed of the capsular polysaccharide of Hib. polyribosylribitol phosphate (PRP). The vaccines. licensed in 1985. were moderately effective in preventing Hib disease in children aged 24-59 months. In December 1987. the first Hib conjugate vaccine was licensed. The vaccine was recommended for use in children aged 18-59 months to prevent meningitis and other forms of invasive disease caused by Hib. This report summarizes surveillance for Hib meningitis and provides data on the use of Hib vaccine in Seattle-King County. Washington. where Hib meningitis surveillance methods have remained the same since 1984.
Treatment of experimental suprachoroidal hemorrhage with subconjunctival injection of tissue plasminogen activator: a negative report, Suprachoroidal hemorrhage was created in 10 albino rabbit eyes. Five eyes were treated with subconjunctival injections of 40.000 IU of tissue plasminogen activator (tPA) daily for 6 days; five eyes served as controls. It took approximately the same amount of time for the suprachoroidal hemorrhages to clear in both the control and treatment eyes. We conclude that subconjunctival injection of tPA does not accelerate the clearance of suprachoroidal hemorrhage.
Microphonic versus end-tidal carbon dioxide nasal airflow detection in neonates with apnea, Impedance pneumography in combination with expired CO2 monitoring are commonly used techniques for detecting central and obstructive apnea in infants. In this investigation an American Telephone and Telegraph StarSet-1 3000-ohm self-actuating microphone connected to the end of an infant cannula was used to monitor neonatal nasal airflow to detect breaths and apnea. The microphone was placed in a soundproof container to eliminate environmental sound artifacts. Analyses of 100 breaths from five patient samples during active and quiet sleep showed that there was no significant difference between microphone and expired CO2 recording of respiration. The techniques were 98% and 96% sensitive. respectively. Microphonic detection of nasal airflow identified 27 of the 32 episodes of upper airway obstruction (84.2%) registered by end-tidal CO2 recording. Inspiratory and expiratory events could also be well documented. Microphonic recording of nasal airflow is a reliable and inexpensive technique to detect apnea.
Human immunoglobulins for intravenous use: comparison of available preparations for group B streptococcal antibody levels, opsonic activity, and efficacy in animal models, Currently available human immunoglobulin preparations for intravenous use (IVIGs) are being used (with antibiotics) by some physicians for therapy of sepsis in newborns. Most neonatal sepsis and/or meningitis in this country is caused by group B Streptococcus (GBS). and most of these cases are due to type III GBS (III-GBS). The killing of III-GBS in vitro is dependent on specific IgG antibody. Adequate serum levels of specific III-GBS antibody protect the exposed newborn from the development of invasive disease. Therefore. III-GBS was used as a model to evaluate the activity of three IVIG preparations available for clinical use. Specific antibody levels. in vitro opsonophagocytic killing. and protective efficacy in animal models revealed differences in activity for III-GBS between the three IVIG preparations as well as between IVIG lots from the same manufacturer. Furthermore. it was found that the effect of IVIG using one of the assay methods may not reliably predict activity obtained using the other assays. These data document the inability to predict functional activity against a specific pathogen such as GBS on the part of a lot of IVIG chosen at random. In view of these findings and of the limited data evaluating clinical efficacy. IVIG cannot be recommended at this time for use in the therapy of infectious diseases such as neonatal sepsis.
Interferon gamma response region in the promoter of the human DPA gene, The interferon gamma (IFN-gamma) response region of the human class II major histocompatibility complex gene. DPA. has been localized to a 52-base-pair (bp) DNA fragment in the proximal promotor at -107 to -55 bp after transfection into HeLa cells of a series of 5'. 3'. and gap deletion mutants linked to a reporter gene. human growth hormone. as well as of synthetic oligonucleotides fused to the heterologous promoter thymidine kinase. The 52-mer sequence contains the X and Y box elements conserved in all class II genes; their presence is indispensable for IFN-gamma inducibility. Furthermore. an additional 5 bp immediately 5' of the X box of the DPA gene are necessary and sufficient for IFN-gamma induction. This region may contain an IFN-gamma response element. A closely related sequence has also been found in the vicinity of the critical deletion sites of three other well-studied class II gene promoters. all of which require a much longer sequence 5' of the X box. A fourth element. the W element. located about 15 bp 5' of the X box in all class II genes. is clearly of little importance in IFN-gamma inducibility of the DPA gene.
Ossification of posterior longitudinal ligament of the cervical spine in non-Japanese Asians, "The Japanese disease." ossification of the posterior longitudinal ligament. is not confined to the Japanese only. A similar incidence of 0.8% was found in this study among non-Japanese Asians. Of 5167 patients who attended the Mount Elizabeth Hospital in Singapore for cervical spine complaints. 43 patients were found to have ossification of the posterior longitudinal ligament. forming the largest non-Japanese series. All but one patient were of Mongolian origin. and males were affected four times more commonly than females. Diabetes mellitus was present in 16%. There was a significant association between ossification of the posterior longitudinal ligament and calcification of other cervical paraspinal ligaments. It is suggested that a generalized tendency to calcification may be an important etiological factor in ossification of the posterior longitudinal ligament. Four of the patients required surgery. and in our experience. anterior spinal fusion with removal of the ossified ligament or multilevel laminoplasty gives satisfactory results.
Changes in standard electrocardiographic ST-segment elevation predictive of successful reperfusion in acute myocardial infarction, The ability of the electrocardiographic ST segment to predict successful reperfusion after thrombolytic therapy remains controversial. To evaluate whether angiographically determined reperfusion could be predicted from changes in ST-segment elevation. the sum of ST-segment elevation in affected leads of the electrocardiogram was compared before and after thrombolytic therapy in 53 patients with acute myocardial infarction (AMI). Reperfusion status of the infarct-related artery was determined angiographically less than 8 hours from onset of symptoms. According to the Thrombolysis in Myocardial Infarction trial (TIMI) criteria. 33 patients had successful reperfusion (TIMI grade 2 to 3 flow) after thrombolytic therapy and 20 patients did not (TIMI grade 0 to 1 flow). Logistic multiple regression analysis showed that the proportional value for the shift in the sum of ST elevation. termed the "% ST change." was more strongly associated with reperfusion than the absolute measured difference in millimeters (chi-square = 11.34 vs 9.22). The entire spectra of sensitivities and specificities were determined to identify a level of the percent ST change with simultaneous high sensitivity and specificity. A 20% decrease in ST elevation provided such a level (88% sensitivity. 80% specificity). The positive and negative predictive values of a 20% decrease in ST elevation were 88 and 80%. respectively. These results suggest that a decrease of only 20% in the sum of ST elevation in the standard electrocardiogram after thrombolytic therapy is a useful noninvasive predictor of reperfusion status in patients with evolving AMI.
Effect of heparin on coronary arterial patency after thrombolysis with tissue plasminogen activator in acute myocardial infarction, Infarct artery patency rates at 90 minutes after coronary thrombolysis using recombinant tissue-type plasminogen activator (rt-PA) with and without concurrent heparin anticoagulation have been shown to be comparable. The contribution of heparin to efficacy and safety after thrombolysis with rt-PA is unknown. In this pilot study. 84 patients were treated within 6 hours of onset of acute myocardial infarction (mean of 2.7 hours) with the standard dose of 100 mg of rt-PA over 3 hours. Forty-two patients were randomized to receive additionally immediate intravenous heparin anticoagulation (5.000 U of intravenous bolus followed by 1.000 U/hour titrated to a partial thromboplastin time of 1.5 to 2.0 times control) while 42 patients received rt-PA alone. Coronary angiography performed on day 3 (48 to 72 hours. mean 57) after rt-PA therapy revealed infarct artery patency rates of 71 and 43% in anticoagulated and control patients. respectively (p = 0.015). Recurrent ischemia or infarction. or both. occurred in 3 (7.1%) anticoagulated patients and 5 (11.9%) control patients (difference not significant). Mild. moderate and severe bleeding occurred in 52. 10 and 2% of the group receiving anticoagulation. respectively. and 34. 2 and 0% of patients in the control group. respectively (p = 0.006). These data indicate that after rt-PA therapy of acute myocardial infarction. heparin therapy is associated with substantially higher coronary patency rates 3 days after thrombolysis but is accompanied by an increased incidence of minor bleeding complications.
Usefulness of a pericardial friction rub after thrombolytic therapy during acute myocardial infarction in predicting amount of myocardial damage. The TAMI Study Group, To evaluate the clinical incidence and outcomes of patients with pericarditis after thrombolytic therapy. 810 patients were prospectively studied during acute myocardial infarction (AMI). Pericarditis was defined as the presence of a pericardial friction rub during the hospital course. Only 5% of patients developed a rub during AMI. a low percent compared with that in the prethrombolytic era. A pericardial friction rub more often occurred in the setting of an anterior wall AMI. Patients with. compared to those without. a pericardial friction rub had lower ejection fractions (45 vs 51%. p = 0.002); worse regional left ventricular function (-3.2 vs 2.7. standard deviation per chord); higher in-hospital mortality (15 vs 6%. p = 0.056); a higher frequency of power failure (83 vs 57%); a higher frequency of anterior wall location of the AMI (53% of cases. p = 0.002); and a higher frequency of 3-vessel disease. Therefore. although the frequency of a pericardial friction rub was low (5%) compared with that in the prethrombolytic era. its occurrence denotes more extensive myocardial damage with a worse clinical outcome. Perhaps with successful reperfusion of the infarct-related vessel. transmural myocardial necrosis is prevented and with it the development of pericarditis. Cardiac tamponade did not occur clinically in any patient who developed a pericardial friction rub.
Serum zinc, copper, and selenium levels in inflammatory bowel disease: effect of total enteral nutrition on trace element status, Serum levels of zinc. copper. and selenium. and alkaline phosphatase activity were prospectively studied in 29 patients with inflammatory bowel disease. Fifteen patients had extensive active colitis (active colitis group). Seven patients had active. and seven cases inactive small bowel or ileocecal Crohn's disease (small bowel disease group). Ninety-three healthy subjects acted as controls. Serum trace element levels were considered in relation to vitamin A and E levels. nutritional parameters. the activity of the disease. and the recent intake of steroids. The effect of total enteral nutrition on serum trace elements was studied in seven cases. Serum zinc levels were lower and serum copper levels higher in the active colitis group than in controls (p = 0.0007. and p = 0.02. respectively). More than 50% of patients with active colonic or small bowel disease showed zinc levels below the 15th percentile of the control group. Serum zinc levels correlated with plasma vitamin A in acute colitis (r = 0.67; p = 0.006). and with both serum albumin concentration (r = 0.76; p = 0.002) and disease activity score (r = -0.67. p = 0.009) in patients with small bowel disease. The copper:zinc ratio was higher in the active colitis group than in controls (p = 0.002). In spite of the increase in serum albumin levels and the decrease in disease activity. serum zinc levels remained low after total enteral nutrition. The implications of the abnormal trace element status in patients with inflammatory bowel disease are discussed.
Long-term patient-controlled analgesia in children, Three children who received patient-controlled analgesia for periods of up to 41 days are described. In each case patient-controlled analgesia allowed pain control to be achieved in difficult situations. No patient developed tolerance or clinical signs of dependence. This use of long-term patient-controlled analgesia warrants further evaluation.
Effect of platelet-activating factor receptor antagonism on endotoxin-induced lung dysfunction in awake sheep, To test the hypothesis that PAF partially mediates endotoxin-induced lung dysfunction. we studied the effects of two structurally dissimilar PAF receptor antagonists (SRI 63-441 and WEB 2086) on endotoxin-induced lung dysfunction in chronically instrumented awake sheep. Each animal was studied three times in varied order: infusion of endotoxin alone (Escherichia coli endotoxin 0.5 micrograms/kg over 20 min [E]). infusion of the competitive platelet-activating factor (PAF) receptor antagonist alone. or with endotoxin given 1 h after beginning the 6-h drug infusion (E + SRI. E + WEB). Neither drug alone had significant effects on any of the measured variables. but both were able to abolish the pulmonary pressor effect of a 0.25-micrograms/kg bolus of PAF. SRI 63-441 (10 to 20 mg/kg/h) attenuated the endotoxin-induced pulmonary hypertension (peak pulmonary arterial pressure. 53 +/- 12 versus 65 +/- 7 cm H2O; p greater than 0.05) and fall in dynamic compliance of the lungs (to 65.1 +/- 9.8% baseline versus 32.6 +/- 5.1% baseline). Lung lymph flow increased 6.1- and 5.8-fold at 2 and 5 h for (E) versus 1.9- and 2.5-fold at identical time points for (E + SRI). SRI 63-441 attenuated the acute leukopenia noted after endotoxemia. WEB 2086 (20 mg/kg/h) similarly attenuated the late alterations in lung mechanics and lymph flow caused by endotoxin. but it had little effect on the early pulmonary hypertension and lung mechanic changes. Both agents significantly attenuated the rise in lymph thromboxane B2 levels after endotoxemia.
Community-based short-course treatment of pulmonary tuberculosis in a developing nation. Initial report of an eight-month, largely intermittent regimen in a population with a high prevalence of drug resistance, A community-based tuberculosis case-finding and short-course chemotherapy program was conducted in a suburb of Manila and featured 1 month of daily isoniazid (INH). rifampin (RIF). ethambutol (EMB). and pyrazinamide (PZA) followed by 7 months of twice-weekly. high dose. directly observed INH + EMB + PZA. Church-affiliated lay workers obtained 1.990 sputum specimens from subjects who complained of chronic cough or wasting symptoms; 207 of the specimens were positive on Ziehl-Neelsen smears. On culture. 176 yielded a significant growth of M. tuberculosis. Of these 176 patients. 144 were selected to enter the study; 10 were lost because of withdrawal or death and four (2.7%) because of drug toxicity. This left 130 patients who were followed long-term. Remarkably. 80% (104) were initially shedding drug-resistant organisms; 26% (34) were resistant to one drug. 30% (40) were resistant to two drugs. and 24% (30) were resistant to three or more drugs. Responses to therapy corresponded closely to the extent of drug resistance: 80% (48 of 60) of patients with drug-susceptible or single resistance had a favorable outcome; 43% (28 of 65) were resistant to two or three drugs. and 0% (0 of 5) of those were resistant to four or more drugs. Notable findings of this study were the success of a community-based program in conducting prolonged. directly observed treatment. the unexpectedly high prevalence of multiple-drug-resistant organisms in this population. and the inadequacy of INH + PZA + EMB during the continuation phase of therapy in this setting.
Differing patterns of striatal 18F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy, Using positron emission tomography (PET). we studied regional striatal 18F-dopa uptake in 16 patients with L-dopa-responsive Parkinson's disease (PD). 18 patients with multiple system atrophy. and 10 patients with progressive supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD showed significantly reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls. but while function in the posterior part of the putamen was severely impaired (45% of normal). function in the anterior part of the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean 18F-dopa uptake in the posterior putamen was depressed to similar levels in all patients. Unlike patients with PD. the patients with progressive supranuclear palsy showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in patients with progressive supranuclear palsy than in patients with PD. being depressed to the same level as that in the putamen. Mean 18F-dopa uptake values in the anterior putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in striatal 18F-dopa uptake. but this was not the case for the patients with progressive supranuclear palsy. We conclude that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic function in the anterior putamen and caudate. whereas there is progressively more extensive nigral involvement in multiple system atrophy and progressive supranuclear palsy.
Glycosaminoglycans in pleomorphic adenoma and adenoid cystic carcinoma of the salivary gland, One of the common histopathologic features of pleomorphic adenoma (PA) and adenoid cystic carcinoma (ACC) of the salivary gland is the abundant accumulation of glycosaminoglycans (GAGs). To study a relationship between the histologic distribution of GAGs and the morphologic pattern of salivary gland tumors. we carried out immunohistochemical and biochemical analyses of GAGs on 16 cases of PA and three cases of ACC. Immunohistochemically. several GAG fractions such as chondroitin-6-sulfate. unsulfated chondroitin sulfate. and keratan sulfate were seen mainly at the plasma membrane of both PA and ACC cells and of myoepithelial cells of normal salivary glands. Most of these GAG-positive cells were distributed in solid and chondromyxoid parts of PA and in the cellular part of ACC. Biochemical GAG analysis of both PA and ACC. separated into nonsulfated and sulfated fractions by two-dimensional electrophoresis. revealed high concentrations of chondroitin sulfate in both neoplasms. but the concentration of hyaluronic acid. was significantly higher in PA than in ACC. The results show that the concentration of hyaluronic acid. a major nonsulfated GAG fraction. was significantly higher in PA than in ACC and. therefore. this difference may be useful in the differentiation of the two neoplasms.
The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease, A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer. 6-L-(18F)-fluorodopa. was used as an analog of levodopa to assess its regional brain uptake. conversion into. and retention as dopamine and further metabolites. The second tracer. (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease. striatal uptake of both tracers was decreased. putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen. but not caudate. correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values. suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful. a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.
A newly developed drug delivery system using fine particles of activated charcoal for targeting chemotherapy, Targeting chemotherapy to the metastatic lesions of the lymph nodes after surgical removal of the main tumor. a drug delivery system using ultrafine particles of activated charcoal was developed and examined for its ability to adsorb mitomycin C (MMC) and to transport MMC to the lymph system. Satisfactory results were obtained. In animal experiments. serial sampling of thoracic duct lymph by cannulation and serial samplings of peripheral vein blood after injection of MMC-charcoal solution into the subserosal space of the intestinal wall were made to study the pharmacodynamics of the lymph-blood system through analysis of MMC regression curves. Clearance (K) and half-life (t1/2) are calculated from the formula; C(t) = C(t0) X e-kt. and compared with that of MMC-saline. Activated charcoal has a proven ability to transport MMC to the lymphatic system. With activated charcoal. MMC is retained for much longer in the lymph nodes than with saline. Congestion of the lymph system was produced by ligation of the thoracic duct in CH-40. with 25% prolongation of t1/2. In conclusion. these drug delivery systems are suitable for targeting chemotherapy at lymph node metastases. and it is proven that 1500 AA Mitsubishi ultrafine charcoal is a good carrier of drug and a slow drug-release material in the lymphatics. Minimal side effects are expected because of the constant low concentrations in the general circulation.
Waterborne Pseudomonas septicemia, A small cluster of waterborne septicemias with Pseudomonas species occurred in a dialysis unit despite regular control of bacterial contents of tap water and dialysate conforming to preset standards. Pseudomonas aeruginosa. P. maltophilia. and/or P. vesicularis were found in the blood cultures of three patients in whom four pyrogenic reactions developed. The cluster occurred only in patients treated with formaldehyde-reused dialyzers. Pseudomonads were also cultured from the effluent of two dialyzers reprocessed with formaldehyde and not yet used; these two dialyzers had extremely low formaldehyde concentrations. The tap water used for dialyzer rinsing in the reuse procedure contained only 220 colony forming units/ml pseudomonads. The problem appeared to be related to the inadequate mixing of the sterilant with the tap water used in the automated reprocessing device--in the absence of an alarm for this failure. After immediate discontinuation of the reuse procedure with this device (that had been in use for 6 years) no further septicemic episodes were registered. It is concluded that septicemias may occur despite a bacteriologic contamination level of water conforming to preset standards. Such episodes can be avoided only by total water decontamination.
Longitudinal survey of apolipoproteins and atherogenic risk in hemodialysis and continuous ambulatory peritoneal dialysis patients, Total cholesterol (TC) and HDL-cholesterol (HDL-C) have been studied in dialysis patients. but a systematic study of apolipoprotein (apo) A-I. apo B. and the anti-atherogenic risk ratio. apo A-I/apo B. over time has not been done. We report lipid and apo values over 12-14 months in 55 hemodialysis (HD) and 40 continuous ambulatory peritoneal dialysis (CAPD) patients. For HD patients. mean TC fell. but not significantly. and HDL-C and TC/HDL-C. an atherogenic risk ratio. did not change over time. Apo A-I/apo B correlated with months on HD (r = 0.30. p less than 0.04) and rose significantly (p less than 0.005) during the study period. Paired t-test analysis by race. gender. and diabetes showed that in nondiabetics. apo A-I rose. apo B fell (p less than 0.05). and apo A-I/apo B improved (p less than 0.002). Similar trends were seen in all subgroups except for diabetics. For CAPD patients. total months of treatment correlated with TC/HDL-C (r = 0.46. p less than 0.05) and with HDL-C (r = -0.53. p less than 0.02). but paired t-test analysis of longitudinal data showed no significant changes in TC. HDL-C. apo A-I. apo B. TC/HDL-C. or apo A-I/apo B. The lipoprotein patterns of all patients who died were not significantly different from those of the surviving patients. Our longitudinal data reveal that lipids. apolipoproteins. and risk ratios remain stable over time on HD and CAPD. In fact. the anti-atherogenic index of apo A-I/apo B improved in HD patients. especially in nondiabetics.
Vasoactive hormones during hemodialysis with intermittent ultrafiltration, The correlations between actual blood volume (BV). blood pressure (BP). heart rate. and plasma levels of renin activity (PRA). serum aldosterone (ALD). antidiuretic hormone (ADH). epinephrine (E). norepinephrine (NE). atrial natriuretic factor (ANF). cGMP. and cAMP were investigated in 10 stable patients during HD. HD consisted of four periods of about 60 min each. One half with an UF rate greater than 1.000 ml/h. followed by a time interval of 30 min without UF resulting in a "saw tooth" profile of BV. Decrease in BV was measured by continuous hemoglobinometry. Average total decrease in BV was 25%. while BP and HR did not change significantly. E. NE. ANF and ADH levels were directly related to actual changes in BV. suggesting that BP regulation in this special mode of HD is mainly supported by endogenous catecholamine and ADH secretion. The second messenger cGMP did not follow actual BV changes. but showed a significant decrease correlated with diminished BV. A significant change in PRA and ALD was missing. It is concluded that vascular stability in these patients is maintained by the response of catecholamins and ADH to decrease in blood volume. and not by the renin-aldosterone system.
Relationship between phagocyte metabolic function and years of maintenance dialysis, An index of the activation of NADPH-oxidase in the production of free radicals is CO2 production by the hexose monophosphate shunt of polymorphonuclear cells (PMN). 14CO2 production from glucose-1-C14 was studied as an indicator of PMN function after addition of latex or zymosan to predialysis whole blood. and correlated with the years spent on hemodialysis. In a series of 49 patients. a nadir in PMN metabolic activity. when compared with healthy controls. was reached in a subgroup treated for less than 24 months (n = 24. latex: 109.5 +/- 10.1 vs. 233.7 +/- 11.8; zymosan: 181.9 +/- 18.9 vs. 407.8 +/- 19.3 DPM/10(3) PMNs; p less than 0.01). In patients treated by dialysis for longer than 24 months. PMN metabolic function was significantly better. resulting in partial correction of the defect for both latex and zymosan. Phagocyte CO2 production in response to latex or zymosan correlated significantly with years of dialysis treatment (r = 0.63 and 0.56. respectively. n = 49; p less than 0.001). These findings may have implications for phagocyte reactivity towards infection. bioincompatible dialyzer membranes. and renal transplantation.
Development of alumina ceramic transcutaneous connector to prevent skin exit site infections around CAPD catheters, It is very important to prevent skin exit site infections in order to continue continuous ambulatory peritoneal dialysis (CAPD) safely over the long-term. The silicon material conventionally used can result in sinus formation between the skin and the catheter. and may trigger exit site infections. To resolve this problem. we employed a bioinert. rigid. and nonporous transcutaneous connector made of alumina ceramic. Earlier long-term animal experiments with alumina ceramic placed in soft tissue demonstrated the outstanding biocompatibility of this material. The transcutaneous connector was designed with a simple cylindrical configuration; in order to make sufficient contact between this connector and the patient. a silicon tube was made into a swan neck catheter with a disk-shaped Dacron cuff at the upper position in order to reinforce adhesion to soft tissue. Ten CAPD patients (maximum time on dialysis of 14 months) have used the new CAPD catheter system with no exit site infections to date. Furthermore. there has been virtually no downgrowth of the skin around the connector. while the connector and tissue have remained in very close contact.
Comparison of low molecular weight heparin and standard heparin in hemodialysis, The anticoagulant and antithrombotic effect of heparin has been known for many decades. Since low molecular weight heparin has been available. several advantages over standard heparin were observed. especially in long-term use during hemodialysis. In 27 patients. we found a lower bleeding risk. a lower need for erythrocyte transfusions. a lesser increase in activity of various coagulation factors. and lower triglyceride levels. Therefore. low molecular weight heparin would appear to be a good alternative to standard heparin in dialysis patients.
Gonadotrophin releasing hormone agonist (buserelin) in the treatment of endometriosis: changes in the extent of the disease and in CA 125 serum levels after 6-month therapy, Twenty-two women with endometriosis were treated with the luteinizing hormone-releasing hormone (LHRH) agonist buserelin for 6 months. At second-look laparoscopy the mean score of endometriosis had decreased from 23.1 (SD 17.0) to 17.2 (SD 20.2) (P less than 0.05). CA 125 serum levels decreased from 38.4 (SD 32.2) U/ml at diagnosis to 15.5 (SD 7.0) at second look (P less than 0.005). CA 125 levels correlated at diagnosis with total score of endometriosis (P less than 0.05) and with active score of endometriosis (P less than 0.05). but not with the adhesion score. CA 125 levels were not correlated with endometriosis scores at second look laparoscopy. thus suggesting that mechanisms other than the change in the extent of the disease may be involved in the CA 125 decrease during therapy. CA 125 levels may therefore not be a reliable indicator for monitoring the efficacy of LHRH agonist treatment of endometriosis.
Meakin adjuvant regimen in premenopausal patients with breast cancer, A 10-year experience using ovarian ablation and prednisolone as adjuvant therapy for premenopausal patients with breast carcinoma. emphasizing tolerability and morbidity is reported. Thirty patients (15 aged less than 45 years. 15 aged greater than or equal to 45 years; range 28-54 years) underwent mastectomy/lumpectomy with axillary clearance (with or without local irradiation) followed by ovarian irradiation and prednisolone therapy (2.5 mg three times daily for 5 years). Patients were reviewed every 3 months for the first 3 years and every 6 months thereafter. Follow-up was between 1.5 and 10 years (median 5 years). Twenty-four patients are still alive. Three patients stopped therapy because of side-effects. There was a mean(s.e.m.) weight gain of 8.46(1.69) per cent on therapy. Nineteen patients have been weaned off prednisolone over a period of 0.5-7.5 months (median 2 months) and the median length of time off steroids is now 3 years (range 0.5-5 years). This regimen appears to be associated with an acceptable level of patient tolerability and a low chronic morbidity rate and should be considered as an alternative to adjuvant systemic cytotoxic therapy.
Kidney stones and lithotripters: critical analysis of the introduction of extracorporeal shock wave lithotripsy into Canada, It is possible for a nonpharmaceutical medical innovation to enter the mainstream of the health care system without its efficacy and effectiveness having first been established by means of a randomized controlled trial (RCT). The result of this omission may be the discreditation and abandonment of the technology or procedure but not before precious resources that could have been better used elsewhere in the health care system are absorbed. A possible example of such a misallocation of resources is the introduction into Canada of extracorporeal shock wave lithotripsy (ESWL) for the treatment of urolithiasis. We review the development and diffusion of ESWL and recommend ways in which the deficiencies in regulating the introduction of new medical technologies can be corrected.
Epidural anaesthesia attenuates the catecholamine response to hypoventilation, The effect of a high epidural block on the catecholamine response to hypoventilation was studied in six unanesthetized dogs given intravenous sufentanil (15 micrograms.kg-1). Sufentanil alone resulted in a increase of norepinephrine (NE) concentration from 108 +/- 73 pg.ml-1 to 843 +/- 399 pg.ml-1 and epinephrine (E) from 279 +/- 80 pg.ml-1 to 2010 +/- 1416 pg.ml-1. At least one week later. an epidural block to T1 was achieved using 8-10 ml. two per cent lidocaine. Plasma NE and E decreased after EA to about 50 per cent of resting baseline measurements. The addition of sufentanil increased NE and E levels to reach approximately the resting base-line levels. In all dogs intravenous sufentanil resulted in bradypnoea. bradycardia. hypoxaemia. and hypercarbia. Intravenous lidocaine infusions had no significant effect on plasma catecholamine levels when plasma lidocaine levels ranged from 1.7 micrograms.ml-1 to 5.3 micrograms.ml-1. We conclude that a high two per cent lidocaine epidural block attenuates the catecholamine response to hypoventilation in dogs. but the persistence of baseline plasma levels of NE and E suggests that the efferent sympathetic block by high EA is incomplete.
The chemoreflex control of breathing and its measurement, The chemoreflex control of breathing is described in terms of a graphical model. The central chemoreflex. the ventilatory response to carbon dioxide mediated by the central chemoreceptors. is modelled as a straight-line relation between the ventilatory response and the arterial level of carbon dioxide. The peripheral chemoreflex. the ventilatory response to carbon dioxide and hypoxia mediated by the peripheral chemoreceptors. is broken into two relations. First. a straight-line relation between the ventilatory response and the arterial level of carbon dioxide whose slope (sensitivity) increases as the oxygen level varies from hyperoxic to hypoxic. Second. a rectangular hyperbolic relation between the ventilatory response and the arterial level of oxygen with ventilation increasing with increasing hypoxia. The three ventilatory response relations (one central and two peripheral) add to produce the total chemoreflex ventilatory response which forms the feedback part of the respiratory regulator. The forward part consists of the relation between the arterial level of carbon dioxide and ventilation when ventilation is controlled (the metabolic hyperbola). The forward and feedback parts of the respiratory regulator can be combined so as to predict resting ventilation and carbon dioxide levels under a number of circumstances. Methods of measurement of these chemoreflex ventilatory responses are also described so as to illustrate the physiological principles involved in the model.
Gastric H+,K(+)-ATPase as a therapeutic target in peptic ulcer disease, The presence of unbuffered acid appears to be an essential contributory factor in the pathogenesis of peptic ulcer disease. Treatment has concentrated therefore on the reduction of acidity. and the last decade has seen the widespread and effective use of H2 antagonists. They are. at low doses. more successful in improving the natural history of duodenal ulcer disease than of gastric or esophageal ulceration. The H2 receptor plays a central role in activation of parietal cell acid secretion. and antagonists at this receptor block most (but not all) of the acid secretion due to even gastrinergic or muscarinic (vagal) stimulation. In hypergastrinemic states such as Zollinger-Ellison syndrome. or where acid secretion has to be inhibited by more than 20% over a 24-hr period. such as for treatment of esophagitis. NSAID damage. or gastric ulcers. the dose and frequency of administration of the currently available antagonists must be increased to achieve reliable therapy. This has led to a search for an alternative target for acid inhibitory drugs. such as the gastric acid pump. the H+.K(+)-ATPase. This article focuses on the function of this ATPase and suggests that inhibition of this pump will provide a more efficacious means of reduction of acid secretion by the stomach. hence improving and simplifying therapy of acid related diseases.
Severe rheumatoid arthritis: current options in drug therapy, Therapeutic advances have been made in rheumatoid arthritis (RA). but patients (and sometimes physicians) may become frustrated at the apparent lack of breakthrough treatments. The latest advances in the treatment of severe RA are discussed. along with what investigators are using experimentally both in combination with other drugs and alone to treat RA now and. possibly. in the future. These agents include methotrexate. cyclosporine. gamma-interferon. and omega-3 fatty acids.
Effects of radiation on fixation of non-cemented porous-coated implants in a canine model, A non-weight-bearing porous-coated rod was implanted bilaterally in the proximal part of the humerus in thirty-five adult male mongrel dogs. In all of the animals. one limb was treated with radiation and the opposite limb served as the control. In twenty-one animals. the dose was 1000 centigrays (rads) and in fourteen. it was 500 centigrays. The strength of fixation and the volume fraction of ingrowth of bone were determined two. four. and eight weeks after the operation in the group that received 1000 centigrays and two and four weeks after the operation in the group that received 500 centigrays. Treatment with 500 centigrays had no significant effect on the strength of fixation or the amount of ingrowth of bone. In contrast. at two weeks. treatment with 1000 centigrays had reduced the strength of fixation to 50 per cent of the control value (p less than 0.01). although. at four and eight weeks. the strength of fixation was not significantly different than that in the control limb. The amount of ingrowth of bone in the irradiated limb was significantly reduced at two weeks (30 per cent of the control value) (p less than 0.01). four weeks (70 per cent of the control value) (p less than 0.05). and eight weeks (56 per cent of the control value) (p less than 0.05).
Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes, The effects of a broad array of cytokines. individually and in combination. were determined on separate functions (proliferation. collagenase production. and granulocyte macrophage colony-stimulating factor [GM-CSF] production) and phenotype (expression of class II MHC antigens) of cultured fibroblast-like RA synoviocytes. The following recombinant cytokines were used: IL-1 beta. IL-2. IL-3. IL-4. IFN-gamma. tumor necrosis factor (TNF)-alpha. GM-CSF. and macrophage colony-stimulating factor (M-CSF). Only IFN-gamma induced HLA-DR (but not HLA-DQ) expression. TNF-alpha inhibited IFN-gamma-mediated HLA-DR expression (46.7 +/- 4.1% inhibition) and HLA-DR mRNA accumulation. This inhibitory effect was also observed in osteoarthritis synoviocytes. Only TNF-alpha and IL-1 increased synoviocyte proliferation (stimulation index 3.60 +/- 1.03 and 2.31 +/- 0.46. respectively). IFN-gamma (but none of the other cytokines) inhibited TNF-alpha-induced proliferation (70 +/- 14% inhibition) without affecting the activity of IL-1. Only IL-1 beta and TNF-alpha induced collagenase production (from less than 0.10 U/ml to 1.10 +/- 0.15 and 0.72 +/- 0.24. respectively). IFN-gamma decreased TNF-alpha-mediated collagenase production (69 +/- 19% inhibition) and GM-CSF production but had no effect on the action of IL-1. These data demonstrate mutual antagonism between IFN-gamma and TNF-alpha on fibroblast-like synoviocytes and suggest a novel homeostatic control mechanism that might be defective in RA where very little IFN-gamma is produced.
Association between a T cell receptor restriction fragment length polymorphism and systemic lupus erythematosus, The present study was designed to test the possibility that T cell receptor genes are associated/linked to those involved in systemic lupus erythematosus (SLE). Genomic DNA was isolated from 31 unrelated Caucasian SLE patients. 34 unrelated Caucasian normals. 5 multiplex American Caucasian SLE families. 9 multiplex Mexican SLE families. and 13 unrelated Mexican normals. The DNA was digested with Pst I. electrophoresed. and transferred to membranes by the Southern blot method. The blots were probed with a cDNA probe for the alpha chain of the T cell receptor. 13 polymorphic RFLP patterns were recognized. 1.3- and 3.0-kb band pairs were observed in 15 of 31 of American Caucasian patients and 4 of 34 American Caucasian controls (chi square. 8.81; P less than 0.002; relative risk. 7); there was no association of any RFLP pattern with Mexican SLE. The cDNA probe was cut with Rsa I. EcoR I. and Ava II into fragments corresponding to the V. J. C. and 3'UT regions. Only the fragment corresponding to the constant region reacted with the 1.3/3.0-kb band pair. These observations suggest that a genetic marker of the constant region of the alpha chain of the T cell receptor is associated with genes involved in SLE.
Blockade of endogenous anterior hypothalamic atrial natriuretic peptide with monoclonal antibody lowers blood pressure in spontaneously hypertensive rats, We have previously shown that the atrial natriuretic peptide (ANP) content of the anterior hypothalamic region of NaCl-sensitive spontaneously hypertensive rats (SHR-S) is higher than that of Wistar-Kyoto (WKY) rats. ANP has been shown to inhibit neuronal norepinephrine release and to reduce the excitability of hypothalamic neurons. This study tested the hypothesis that blockade of endogenous ANP in the anterior hypothalamus by local microinjection of a monoclonal antibody to ANP (MAb KY-ANP-II) lowers blood pressure in SHR-S. Purified MAb KY-ANP-II (0.055 and 0.55 micrograms) or control mouse IgG in 200 nl saline was microinjected into the anterior hypothalamic area (AHA) of conscious SHR-S and control WKY rats. As a further control. Mab KY-ANP-II (0.55 microgram) was microinjected into the posterior hypothalamic area (PHA) of SHR-S. Anterior hypothalamic microinjection of MAb KY-ANP-II caused significant dose-related decreases in mean arterial pressure (MAP) and heart rate (HR) in SHR-S but not in WKY rats. Control injections of equal volumes of IgG had no effect on MAP or HR. Microinjection of Mab KY-ANP-II into PHA produced no significant alteration in MAP or HR in SHR-S. These data provide the first demonstration that endogenous ANP in a region of brain known to influence cardiovascular function mediates BP and HR control in the rat. These findings suggest that the increased endogenous ANP in the anterior hypothalamus of SHR-S may be involved in the central regulation of BP in the model.
Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus, The diminished ability of insulin to promote glucose disposal and storage in muscle has been ascribed to impaired activation of glycogen synthase (GS). It is possible that decreased glucose storage could occur as a consequence of decreased glucose uptake. and that GS is impaired secondarily. Muscle glucose uptake in 15 diabetic subjects was matched to 15 nondiabetic subjects by maintaining fasting hyperglycemia during infusion of insulin. Leg muscle glucose uptake. glucose oxidation (local indirect calorimetry). release of glycolytic products. and muscle glucose storage. as well as muscle GS and pyruvate dehydrogenase (PDH) were determined before and during insulin infusion. Basal leg glucose oxidation and PDH were increased in the diabetics. Insulin-stimulated leg glucose uptake in the diabetics (8.05 +/- 1.41 mumol/[min.100 ml leg tissue]) did not differ from controls (5.64 +/- 0.37). Insulin-stimulated leg glucose oxidation. nonoxidized glycolysis. and glucose storage (2.48 +/- 0.27. 0.68 +/- 0.15. and 5.04 +/- 1.34 mumol/[min.100 ml]. respectively) were not different from controls (2.18 +/- 0.12. 0.62 +/- 0.16. and 2.83 +/- 0.31). PDH and GS in noninsulin-dependent diabetes mellitus (NIDDM) were also normal during insulin infusion. When diabetics were restudied after being rendered euglycemic by overnight insulin infusion. GS and PDH were reduced compared with hyperglycemia. Thus. fasting hyperglycemia is sufficient to normalize insulin-stimulated muscle glucose uptake in NIDDM. and glucose is distributed normally to glycogenesis and glucose oxidation. possibly by normalization of GS and PDH.
Mechanisms of lymphocytotoxicity induced by extracorporeal photochemotherapy for cutaneous T cell lymphoma, Extracorporeal photochemotherapy is an effective treatment for cutaneous T cell lymphoma but its mode of action is uncertain. The reduction in viability of patients' photoirradiated buffy coat lymphocytes was correlated with a 35% increase in DNA single-strand breaks and marked decreases in cellular ATP and NAD levels (to 58 and 34% of control. respectively) immediately after photoirradiation. Complementary in vitro studies were conducted with normal human peripheral blood lymphocytes using a Therakos ultraviolet A (UVA) light box. UVA light was cytotoxic on its own but was potentiated by 8-methoxysporalen. 3-aminobenzamide. a poly (ADP-ribose) synthetase inhibitor. mitigated the cytotoxic effect of ultraviolet A light in the presence of 8-methoxypsoralen in lymphocytes and reduced the amount of nucleotide depletion they caused. 10 J/cm2 of UVA light in the presence of 300 ng/ml 8-methoxypsoralen increased the poly (ADP-ribose) synthetase activity of peripheral blood lymphocytes. Exposing lymphocytes to deoxycoformycin and deoxyadenosine was found to induce biochemical and physical effects similar to those of photochemotherapy. In summary. we have shown that the lymphocytotoxic effect of extracorporeal photochemotherapy for cutaneous T cell lymphoma is apparently mediated by DNA damage. subsequent poly (ADP-ribosyl)ation and adenine nucleotide depletion. It is not known how the DNA damage and resultant biochemical effects relate to the possible immunological mechanism of extracorporeal photochemotherapy; however. it is possible that its effects can be mimicked by other DNA-damaging agents.
Use of oligonucleotide probes directed against T cell antigen receptor gamma delta variable-(diversity)-joining junctional sequences as a general method for detecting minimal residual disease in acute lymphoblastic leukemias, To provide a sensitive and generally applicable method to detect clonal cells in acute lymphoblastic leukemias (ALL). we have designed a new strategy based on the polymerase chain reaction (PCR) amplification of the T cell receptor gamma delta gene rearrangements found in most T and B lineage ALLs. PCR allows rapid sequencing of variable-(diversity)-joining (V-[D]-J) junctions from tumor DNA and construction of anti-junctional oligonucleotides (AJOs) used as probes to detect clonal cells in the same patient. We have defined oligonucleotides suitable for all T cell receptor (TCR) rearrangements involving functional V gamma segments. Oligonucleotides corresponding to preferential TCR delta rearrangements in T and B lineage ALLs were also used. By analysis of the nucleotide sequence of 52 V gamma-V gamma junctions from 30 cases of B and T ALLs. we demonstrate that V-J junctional sequences are clone specific in both lineages and at all stages of differentiation examined despite the frequent presence of the recently described P nucleotides. Experiments performed with TCR gamma delta AJOs on DNA from tumor cells and polyclonal T cells show that AJOs can be used to differentiate clonal cells from polyclonal T cells. distinguish between different T cell clones. and detect residual clonal populations at 10(-4)/10(-5) dilution. AJOs were also used to detect residual disease in samples from patients in clinical and morphological complete remission. Finally. rearrangement patterns were studied by classical Southern analysis in selected cases at both presentation and subsequent relapse showing absence of clonal evolution in most cases. V-(D)-J nucleotide sequences of rearrangements with an identical pattern of rearrangement at presentation and relapse were identical in all cases analyzed. We therefore describe a new. specific. and clinically useful strategy for the detection of minor clonal populations applicable in the majority of cases of ALL.
Segmental neurofibromatosis, Two patients had localized multiple cutaneous neurofibromas; one had bilateral involvement of the scalp and the other had true segmental neurofibromatosis. Other signs of neurofibromatosis were absent. Segmental neurofibromatosis may not be related to the generalized types of neurofibromatosis but may be a cutaneous hamartoma.
Thrombolysis in Myocardial Infarction (TIMI) phase II trial: outcome comparison of a "conservative strategy" in community versus tertiary hospitals. The TIMI Research Group, In the conservative strategy arm of phase II of the Thrombolysis in Myocardial Infarction (TIMI) trial. 1.461 patients were treated with intravenous recombinant tissue-type plasminogen activator (rt-PA). Coronary angiography. with angioplasty if feasible. was to be performed only for recurrent spontaneous or exercise-induced ischemia. In this study results in patients treated by this strategy in community and tertiary hospitals are compared. Despite similar baseline findings in the two groups. coronary angiography was performed within 42 days in more patients (542 [48%] of 1.155) initially admitted to a tertiary hospital (on-site coronary angiography/angioplasty available) than in those (94 [32%] of 306) admitted to a community hospital (transfer to tertiary hospital for coronary angiography/angioplasty) (p less than 0.001). This different approach resulted in a greater use of coronary angioplasty (203 [18%] of 1.155 versus 32 [11%] of 306. p less than 0.01). coronary artery bypass surgery (133 [12%] of 1.155 versus 23 [8%] of 306. p less than 0.05) and blood transfusions (139 [12%] of 1.155 versus 17 [5.5%] of 306. p less than 0.001) in patients admitted to a tertiary than to a community hospital. However. there were no significant differences between the two groups in mortality. recurrent myocardial infarction or left ventricular function. These results demonstrate that a conservative strategy after treatment of acute myocardial infarction with rt-PA is applicable in the community hospital setting.
Precordial ST segment depression predicts a worse prognosis in inferior infarction despite reperfusion therapy. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group, The impact of associated precordial ST segment depression in inferior myocardial infarction on angiographic and clinical outcomes after thrombolytic therapy and selective coronary angioplasty was studied in 583 patients with acute myocardial infarction. Anterior infarction (Group I). inferior infarction with precordial ST segment depression (Group II) and inferior infarction without precordial ST segment depression (Group III) were present in 289. 135 and 159 patients. respectively. Precordial ST segment depression was more frequent in circumflex than right coronary infarct-related arteries (44 [71%] of 62 versus 91 [40%] of 230; p = 0.000). Although acute patency rates were not statistically different. there was a trend toward different patency rates at day 7 (Group I 88%. Group II 84%. Group III 80%; p = 0.089) partly because of insignificantly higher reocclusion rates in inferior infarction without precordial ST segment depression (Group I 11%. Group II 10%. Group III 18%. p = 0.104). Infarct zone regional wall motion (standard deviations/chord) in inferior infarction was lower with precordial ST segment depression. both acutely (Group I -2.8 +/- 0.9. Group II -2.5 +/- 1.2. Group III 2.0 +/- 1.1; p = 0.000) and at day 7 (Group I -2.2 +/- 1.1. Group II -2.3 +/- 1.1. Group III -1.9 +/- 1.3; p = 0.011). Precordial ST segment depression was associated with a lower ejection fraction in inferior infarction both acutely (Group I 47 +/- 11%. Group II 53 +/- 11%. Group III 58 +/- 9%; p = 0.000) and at day 7 (Group I 49 +/- 12%. Group II 53 +/- 10%. Group III 58 +/- 8%; p = 0.000). Complication rates tended to be higher in inferior infarction when precordial ST segment depression was present. Mortality rates for Groups I. II and III were 8%. 6% and 5%. respectively. These results suggest that precordial ST segment depression in inferior infarction predicts a worse ventriculographic and clinical outcome despite reperfusion therapy.
Early coronary reperfusion blunts the procoagulant response of plasminogen activator inhibitor-1 and von Willebrand factor in acute myocardial infarction, The effects of early coronary recanalization on the plasma levels of two procoagulant acute phase proteins. the fastacting plasminogen activator inhibitor and von Willebrand factor. were investigated in 24 patients with myocardial infarction receiving intravenous recombinant tissue-type plasminogen activator (rt-PA) within 6 h of the onset of symptoms. Coronary angiography was performed before and 90 min after the start of rt-PA infusion. Continuous electrocardiographic recordings and 4 h plasma creatine kinase MB isoenzyme (CK MB) were performed over the first 24 h. Plasma plasminogen activator inhibitor activity. von Willebrand factor and C-reactive protein were measured before rt-PA infusion. daily for the first 3 days and after 90 days. In the entire group. plasminogen activator inhibitor activity peaked at 24 h (day 1). representing a significant increase over values at all other times (p = 0.03). von Willebrand factor was higher in the first 2 days of infarction compared with after 90 days (p = 0.001). C-reactive protein peaked on day 2. with an eightfold increase over values on admission (p = 0.001). In the 16 patients with a patent infarct-related artery at 90 min. infarct size estimated by integrated 24 h CK MB. time for ST segment elevation to decrease to half-maximum and peak C-reactive protein were reduced significantly by more than twofold compared with values in the 8 patients with an occluded artery at 90 min. The patients with early recanalization also had lower plasminogen activator inhibitor activity on day 2 (p = 0.05) and day 3 (p = 0.02) and lower 0 to 72 h averaged von Willebrand factor (p = 0.01). Thus. early coronary recanalization curtails the response of plasminogen activator inhibitor activity and von Willebrand factor to myocardial infarction. most likely by reducing the extent of ischemia and necrosis and the consequent acute phase reaction. By blunting the early postinfarction procoagulant state. prompt recanalization may reduce the risk of thromboembolic complications in the first days after myocardial infarction.
Effects of late administration of tissue-type plasminogen activator on left ventricular remodeling and function after myocardial infarction, To evaluate the effects of late thrombolysis on left ventricular volume and function in acute myocardial infarction. two-dimensional echocardiography and radionuclide angiography were performed before discharge and after 1 year of follow-up study in 34 patients with acute anterior myocardial infarction. Of these. 10 admitted to the coronary care unit within 4 h from the onset of symptoms were treated with recombinant tissue-type plasminogen activator (rt-PA) (Group A) and 24 admitted between 4 and 8 h after onset were randomly assigned to receive either rt-PA (Group B. n = 12) or conventional therapy (Group C. n = 12). Seven to 10 days after admission. all patients underwent cardiac catheterization and coronary angiography. Patency of the infarct-related vessel was 70% in Group A. 66% in Group B and 33% in Group C and the average Thrombolysis in Myocardial Infarction (TIMI) coronary perfusion grade was 1.9 +/- 0.8 for Group A. 1.6 +/- 1.0 for Group B and 0.84 +/- 0.95 for Group C (Group A versus Group C p less than 0.01; Group B versus Group C p less than 0.05). At predischarge evaluation. mean left ventricular end-systolic and end-diastolic volumes were higher in Group C than in Group B (p less than 0.001 and 0.05. respectively) and Group A (p less than 0.005 for both); mean left ventricular ejection fraction at rest was lower in Group C than in Group B and Group A (p less than 0.05 for both). At 1 year follow-up study. end-systolic and end-diastolic volumes remained higher in Group C than in Group B (p less than 0.05 for both) and Group A (p less than 0.005 for end-systolic volume and p less than 0.001 for end-diastolic volume); ejection fraction at rest was lower in Group C than in Groups A and B (p less than 0.05 for both); during exercise. it increased more in Group A than in Group C (p less than 0.01). Comparison of data obtained before discharge and at the 1 year follow-up study revealed a significant differences in end-systolic volume (p less than 0.05) in Group C patients and in end-diastolic volume in patients in Groups B (p less than 0.05) and C (p less than 0.001). The beneficial effect of late thrombolysis with rt-PA may be related to a reduction in myocardial expansion and thus to a favorable influence on postinfarction left ventricular remodeling.
Expression of atrial natriuretic factor in the human ventricle is independent of chamber dilation, This study investigated the presence of atrial natriuretic factor in ventricular tissue obtained from humans with dilated or restrictive heart disease. In 17 patients with ventricular dilation and impaired systolic function and in 8 patients with restrictive heart disease and preserved systolic function. the presence of ventricular atrial natriuretic factor was investigated in tissue obtained by ventricular endomyocardial biopsy. The objective of the study was to determine if the ventricular presence of atrial natriuretic factor is dependent on ventricular dilation. Left ventricular end-diastolic volume index was greater in the group with dilated cardiomyopathy than in the group with restrictive cardiomyopathy (134 +/- 13 versus 78 +/- 5 ml/m2. p less than 0.05); end-diastolic pressure was elevated in the two groups (20 +/- 2 versus 25 +/- 4 mm Hg. p = NS). With the use of immunohistochemical techniques. ventricular atrial natriuretic factor was clearly detected in 15 of the 17 patients with dilated cardiomyopathy and in 6 of the 8 patients with restrictive cardiomyopathy. This study demonstrates the high prevalence of ventricular atrial natriuretic factor in living patients with either systolic or diastolic dysfunction. Whereas in the atria. stretch or dilation may be an important stimulus. atrial natriuretic factor in the ventricular chamber occurs independent of dilation.
Mismatch of left ventricular function and infarct size demonstrated by technetium-99m isonitrile imaging after reperfusion therapy for acute myocardial infarction: identification of myocardial stunning and hyperkinesia, Quantitation of perfusion defect size using tomographic imaging with technetium-99m-hexakis-2-methoxy isobutyl isonitrile was performed at the time of hospital discharge in 32 patients with a first myocardial infarction who underwent successful coronary reperfusion within 8 h of the onset of chest pain. Reperfusion was accomplished with thrombolysis or primary coronary angioplasty. Radionuclide angiography was performed at discharge and 6 weeks later. There was a close correlation between perfusion defect size and values for ejection fraction and regional wall motion both at discharge (r = -0.80 and -0.75. respectively) and 6 weeks later (r = -0.81 and -0.81. respectively). There was no overall group difference in ejection fraction between the value at discharge and at 6 weeks; however. five patients had a significant increase (greater than or equal to 0.08) and six had a significant decrease (greater than or equal to 0.08) in ejection fraction. In patients with a significant increase at 6 weeks. ejection fraction was significantly lower at discharge than the value predicted from perfusion defect size (0.37 +/- 0.09 measured versus 0.47 +/- 0.13 predicted. p less than 0.05) and it improved at 6 weeks to near predicted values (0.51 +/- 0.07). In patients with a significant decrease at 6 weeks. ejection fraction was significantly higher at discharge than the value predicted from perfusion defect size (0.60 +/- 0.10 measured versus 0.50 +/- 0.10 predicted. p less than 0.05) and it decreased at 6 weeks to near predicted levels (0.51 +/- 0.09). Left ventricular ejection fraction at the time of hospital discharge is a potentially misleading index of the efficacy of reperfusion therapy for myocardial infarction. In a significant minority (34%) of patients this index does not accurately reflect perfusion defect size. apparently because of the effects of myocardial stunning and compensatory hyperkinesia.
Electrophysiologic effects of isoproterenol in patients with atrioventricular reentrant tachycardia treated with flecainide, The electrophysiologic effects of isoproterenol in patients treated with flecainide for atrioventricular (AV) reentrant tachycardia were studied to evaluate the mechanism of tachycardia inducibility after isoproterenol and the value of isoproterenol challenge as a predictor of spontaneous arrhythmia recurrence. Seventeen patients underwent electrophysiologic study before and after oral flecainide administration and after the addition of isoproterenol to flecainide. No patient had inducible sustained supraventricular tachycardia after flecainide alone. Two patients had inducible sustained and six had inducible nonsustained tachycardia after isoproterenol was added to flecainide. The patients were then followed up on the same flecainide dose they received at the time of the electrophysiologic study. Findings: 1) Flecainide treatment prolonged HV and VA intervals. and the addition of isoproterenol did not affect these variables. 2) Isoproterenol shortened anterograde and retrograde block cycle length and the refractory period of the accessory pathway and the AV node. It also decreased the tachycardia cycle length. an effect that was due solely to shortening of AV node conduction time. 3) Flecainide treatment prevented tachycardia induction by affecting retrograde conduction over the accessory pathway. Isoproterenol allowed for tachycardia induction and for more sustained episodes of tachycardia by reversing the effect of flecainide on retrograde accessory pathway conduction. 4) Tachycardia recurred during follow-up in all three patients in whom tachycardia of greater than or equal to 10 s duration was induced after isoproterenol but in no patient who had no or shorter episodes of induced tachycardia (and who did not have a change in medical regimen). Conclusions: 1) Isoproterenol reverses flecainide-induced prolongation of block cycle length and refractory periods of the accessory pathway and AV node. 2) Isoproterenol reverses flecainide-induced prevention of tachycardia induction through reversal of the effects of flecainide on the retrograde accessory pathway. 3) The addition of isoproterenol during flecainide restudy is valuable in predicting long-term drug efficacy.
Lysis of plasminogen activator-resistant platelet-rich coronary artery thrombus with combined bolus injection of recombinant tissue-type plasminogen activator and antiplatelet GPIIb/IIIa antibody, Resistance of coronary occlusive thrombus to thrombolytic therapy. found in some patients with acute myocardial infarction. may be due to the presence of platelet-rich coronary clot. Reperfusion therapy in such patients may require the development and evaluation of alternative strategies in animal models. Therefore. platelet-rich coronary artery thrombus was developed by excision. eversion (inside out) and reanastomosis of a 1 cm segment of the left circumflex coronary artery in anesthetized dogs maintained on heparin antiocoagulation. Blood flow was restored in 25 of 27 dogs. Thrombotic occlusion of the everted segment graft with primarily platelet-rich thrombus or thrombus containing platelet-rich and erythrocyte-rich zones. persisting for at least 30 min. occurred within 4.5 +/- 3.5 min (mean +/- SD) in 20 of these 25 dogs. In 5 of these 20 dogs (group I. control). stable occlusion. as monitored with an ultrasound flow probe and coronary angiography. was maintained during a 2 h observation period. In group II (n = 5). intravenous bolus injections of recombinant tissue-type plasminogen activator (rt-PA) at a dose of 0.45 mg/kg body weight at four 15 min intervals did not cause reperfusion in four dogs and produced cyclic reperfusion and reocclusion in one dog. In group III (n = 5). a single intravenous bolus injection of 0.8 mg/kg of the F(ab')2 fragment of a murine monoclonal antibody (7E3) against the human platelet GPIIb/IIIa receptor [7E3-F(ab')2] produced stable reperfusion in two of the five dogs. whereas occlusion persisted in the other three. In group IV (n = 5). injection of 7E3-F(ab')2 (0.8 mg/kg) followed by rt-PA (0.45 mg/kg) caused stable reperfusion without reocclusion in all dogs (p less than 0.05 versus rt-PA alone and p less than 0.01 versus control). This study confirms that platelet-rich occlusive coronary thrombus is very resistant to lysis with intravenous rt-PA. However. this resistance may be overcome by the combined use of a reduced dose of rt-PA and the antiplatelet GPIIb/IIIa receptor antibody 7E3. The results indicate that platelet-rich thrombus resistant to thrombolytic agents may be dispersed pharmacologically without resort to mechanical recanalization. The present dog model may be useful in investigating specific strategies for the dispersion of resistant platelet-rich coronary thrombus.
Role of membrane proteins in monosodium urate crystal-membrane interactions. I. Effect of pretreatment of erythrocyte membranes with glutaraldehyde and neuraminidase, Intact human erythrocytes were pretreated with glutaraldehyde. neuraminidase or a combination of both treatments. incubated with monosodium urate monohydrate (MSUM) crystals and the percent hemolysis values determined by measuring hemoglobin release from the cells. The binding of MSUM crystals to pretreated erythrocyte membranes was also quantitated. Neuraminidase treated cells gave higher percent hemolysis values than untreated cells due primarily to the increased binding of MSUM to neuraminidase treated erythrocyte membranes. Pretreatment of red cells with glutaraldehyde up to a maximum concentration of 0.015% inhibited MSUM induced hemolysis but the binding of MSUM to glutaraldehyde treated and untreated cell membranes was the same. We propose a "pore" model for MSUM induced hemolysis.
The route of feeding influences injury responses, The balance of current clinical data suggests that the route by which patients are fed during the postinjury phase may influence immunologic and metabolic responses to subsequent insults. The mechanisms underlying such amplification processes are presumed to be generated by loss of intestinal barrier function. The resulting host exposure to toxins is hypothesized to induce regional production of inflammatory mediators which serve to alter organ-specific and systemic responses. The cytokine class of mediators appears capable of altering splanchnic tissue function in a manner consistent with observed clinical responses. The breadth of tissue activity influenced by the cytokines spans those benefitting tissue homeostasis and repair to an exaggerated response which may induce tissue injury and organ failure. Data are presented from both clinical and experimental studies to suggest that a lack of intestinal nutrient provision. such as that induced by parenteral feeding. appears to predispose to enhanced cytokine mediator production in hepatic tissues. Thus alterations in the route of antecedent feeding may influence immunologic and metabolic function in a manner which will amplify responses to a subsequent inflammatory challenge.
Endoscopic injection of glutaraldehyde cross-linked bovine dermal collagen for correction of vesicoureteral reflux, From November 1986 through May 1989. a Food and Drug Administration approved investigational study was done to assess the safety and efficacy of glutaraldehyde cross-linked bovine dermal collagen in the endoscopic treatment of vesicoureteral reflux. Over-all. 57 patients (92 ureters) were treated. The majority of ureters (68.5%) had grade II to III/V vesicoureteral reflux (international classification). One treatment was given in 61.4% of the patients. while 33.3% required 2 and 5.3% required 3 treatments. Nonduplicated/primarily refluxing ureters comprised 68.5% of the total. while 13% were duplex/primarily refluxing and 18.5% were surgical failures. The procedures were performed on an outpatient basis in all but 3 patients. Patients were evaluated by voiding cystourethrogram and renal/bladder sonography before and after treatment at 1 month and 1 year. Cure at 1 month after the last treatment was achieved in 75% of the ureters. Among the ureters cured at 1 month the cure persisted in 79% at 1 year after treatment. Cure at 1 year was achieved in 65% of all ureters evaluated. regardless of the status at 1 month. Procedure-related morbidity was minimal and there were no adverse reactions to the implant substance. Thus. glutaraldehyde cross-linked bovine dermal collagen appears to be safe and effective in the endoscopic treatment of vesicoureteral reflux.
Intractable partial epilepsy: evaluation and treatment, Partial (focal or localization--related) epilepsy is the most common seizure disorder encountered in patients with epilepsy. These seizures are focal at onset-that is. emanating from a localized region of the brain. Patients with partial epilepsy may have seizures that are refractory to antiepileptic drug medication. The financial burden for these patients includes the cost of medical care and often the loss of employment. Psychosocial deterioration may be progressive as long as the seizures are intractable. Management includes confirmation of the type (or types) of seizures. exclusion of an intracranial epileptogenic lesion. and use of appropriate antiepileptic drug therapy. Referral of affected patients to a comprehensive epilepsy center for possible surgical treatment and investigational drug studies should be considered. In the care of the patient with intractable partial epilepsy. the goals should be to render the patient free of seizures and to allow the patient to become a participating and productive member of society.
Premarital sexual experience among adolescent women--United States, 1970-1988, The initiation of sexual intercourse early in life is associated with an increased number of sex partners and a greater risk for sexually transmitted diseases (STDs). This report describes trends in age at first premarital sexual intercourse for adolescent women (15-19 years of age) in the United States during 1970-1988 and indicates an accelerated increase in the proportion having had premarital sex from 1986 to 1988.
False-positive results with the use of chlamydia tests in the evaluation of suspected sexual abuse--Ohio, 1990, On June 21. 1990. a commercial laboratory reported to a private residential-care facility for profoundly retarded persons in Ohio that rectal cultures from 10 residents tested positive for Chlamydia trachomatis. This report summarizes the epidemiologic and laboratory investigation by public health officials in Ohio and at CDC. which concluded that the C. trachomatis results were false-positive.
HIV prevalence estimates and AIDS case projections for the United States: report based upon a workshop, This document presents conclusions and recommendations from a workshop convened to discuss national estimates of human immunodeficiency virus (HIV) prevalence. acquired immunodeficiency virus (AIDS) case projections. and the proportion of HIV-infected persons with laboratory evidence of immune dysfunction. Appendices describe analyses performed before and after the workshop to estimate HIV prevalence and to predict future AIDS cases. the prevalence of persons with AIDS. and deaths among persons with AIDS. On the basis of these analyses. CDC estimates that approximately 750.000 persons in the United States were infected with AIDS at the beginning of 1986 and that approximately 1.000.000 Americans are currently infected with HIV. At least 40.000 new HIV infections occur each year among adults and adolescents. and an estimated 1.500-2.000 new infections occur each year among newborns as a result of perinatal HIV transmission. Approximately 60% of the estimated 1.000.000 HIV-infected persons in the United States may have T-helper lymphocyte (CD4+ cell) counts of less than 500/mm3 of blood and may benefit from early treatment with zidovudine. The number of AIDS cases will continue to increase over the next 4 years. with a projection of 52.000-57.000 cases to be diagnosed in 1990. Both AIDS case projections and HIV-prevalence estimates are influenced by the slowing of the rapid upward trend in AIDS incidence that occurred in 1987. particularly among homosexual and bisexual men who are not intravenous drug users. Data available during and after the workshop suggest that medical therapy or a decline in the incidence of new HIV infections among homosexual men in the early 1980s could have contributed to this change in trend. but the relative contributions of these and other factors (including changes in the completeness or timeliness of AIDS case reporting) require further study.
Efficacy and cost effectiveness of adjuvant chemotherapy in women with node-negative breast cancer. A decision-analysis model, BACKGROUND. In 1988 the National Cancer Institute issued a Clinical Alert that has been widely interpreted as recommending that all women with node-negative breast cancer receive adjuvant chemotherapy. Acceptance of this recommendation is controversial. since many women who would not have a recurrence would be treated. METHODS. Using a decision-analysis model. we studied the cost effectiveness of chemotherapy in cohorts of 45-year-old and 60-year-old women with node-negative breast cancer by calculating life expectancy as adjusted for quality of life. The analysis evaluated different scenarios of the benefit of therapy: improved disease-free survival for five years. with a lesser effect on overall survival (base line); a lifelong benefit from chemotherapy; and a benefit in disease-free survival with no change in overall survival by year 10. The base-line analysis assumed a 30 percent reduction in the relative risk of recurrence for five years after treatment. RESULTS. For the 45-year-old woman. the base-line analysis found an average lifetime benefit from chemotherapy of 5.1 quality-months at a cost of $15.400 per quality-year. The 60-year-old women gained 4.0 quality-months at a cost of $18.800 per quality-year. Under the more and less optimistic scenarios. the benefit of chemotherapy varied from 1.4 to 14.0 quality-months for both groups. CONCLUSIONS. Chemotherapy substantially increases the quality-adjusted life expectancy of an average woman at a cost comparable to that of other widely accepted therapies. This benefit decreases markedly if the changes in long-term survival are less than in disease-free survival. Given its uncertain duration. the benefit may be too small for many women to choose chemotherapy. Selective use of chemotherapy to maximize the benefit to individual patients may be possible with refinements in risk stratification and explicit assessment of the patients' risk preferences.
Surgical method for treatment of syndactyly with osseous fusion of the distal phalanges, For the interdigital space plasty to correct a syndactyly with fusion of the distal phalanges. we adopted a new operative procedure. covering the exposed distal bone with local rectangular flaps designed transversely on both dorsal and volar surfaces. A full-thickness skin graft from the groin region covers the remaining raw surface. The procedure was performed in six patients. and the flaps measured 6 mm (width) x 12 to 16 mm (length) in four patients. 5 x 15 mm in one patient. and 5 x 18 mm in one patient. Partial necrosis was observed in only one patient. in whom a narrow flap of 5 x 18 mm was used. In the other five patients. however. the results were satisfactory on both external appearance and function during the follow-up period of 3 to 6 years.
The role of beta 2-microglobulin in peptide binding by class I molecules, Efficient transport of class I major histocompatibility complex molecules to the cell surface requires association of the class I heavy chain with endogenous peptide and the class I light chain. beta 2-microglobulin (beta 2M). A mutant cell line deficient in beta 2M transports low amounts of nonpeptide-associated heavy chains to the cell surface that can associate with exogenously provided beta 2M and synthetic peptide antigens. Normal beta 2M-sufficient cells grown in serum-free media devoid of beta 2M also require an exogenous source of beta 2M to efficiently bind synthetic peptide. Thus. class I molecules on normal cells do not spontaneously bind or exchange peptides.
MR imaging of displaced bucket-handle tear of the medial meniscus, A bucket-handle tear of the meniscus is a vertical or oblique tear with longitudinal extension toward the anterior horn in which the inner fragment is frequently displaced toward the intercondylar notch with resultant mechanical locking of the knee joint. A precise MR diagnosis requires identification of the centrally displaced fragment because the peripheral nondisplaced component may have only a subtle truncated or foreshortened appearance that may escape detection. Eighteen consecutive cases of displaced bucket-handle tears of the medial meniscus diagnosed by MR had a characteristic low-signal band extending across the joint and projecting over the medial tibial eminence. The posterior portion was parallel and beneath the posterior cruciate ligament on both sagittal and coronal images. Arthroscopy confirmed the presence and location of the displaced fragment in all 18 cases. Awareness of this characteristic MR finding may increase the sensitivity of MR imaging in the diagnosis of bucket-handle tears of the medial meniscus.
Urethral abnormalities in male neonates with VATER association, In the past 3 years. eight of 20 male neonates with stigmata of the VATER association were found to have significant urethral abnormalities. Three had megalourethra. two had duplication of the urethra. and one each had an anterior urethral valve. congenital stricture. and hypospadias. In only five of eight was the extent of the abnormality clinically apparent. All three infants with megalourethra and imperforate anus died because of the coexistence of other severe congenital anomalies. Prior literature has described but not stressed the increased prevalence of urethral abnormalities in children with the VATER association. Because of the high prevalence (eight of 20) of significant urethral anomalies. we perform voiding cystourethrography on all males with the stigmata of the VATER association. even in the absence of clinical symptoms.
Sonography in neonatal congenital adrenal hyperplasia, Adrenal gland size was evaluated in six infants with congenital adrenal hyperplasia. All of the infants had a severe deficiency of the 21-hydroxylase enzyme resulting in the salt-losing form of congenital adrenal hyperplasia. The adrenal measurements were compared with those of 40 consecutive age-matched. asymptomatic infants. Mean adrenal length was 14.4 mm and width was 1.9 mm in asymptomatic infants. whereas in infants with congenital adrenal hyperplasia mean adrenal length was 23.7 mm and width was 5.3 mm. Although infants with congenital adrenal hyperplasia may have normal-sized adrenal glands. mean length measurements of 20 mm or greater and mean width measurements of 4 mm or greater suggest the diagnosis.
Mediastinal pseudomass caused by compression of the thymus in neonates with anterior pneumothorax, We studied the radiographs of 115 neonates with anterior pneumothoraces to determine how often the pneumothorax created the impression of a mediastinal pseudomass. The pseudomass results from compression of the thymus gland by air under pressure. To the unwary. the resulting configuration can lead to an erroneous diagnosis of a mediastinal mass. In experienced hands. however. it can serve as a strong clue to the presence of an underlying anterior pneumothorax. A pseudomass was present in 27 (33%) of 82 neonates with unilateral pneumothoraces and in 29 (88%) of the 33 patients with bilateral anterior pneumothoraces. A free lung edge was visualized in 26% of the patients with a unilateral pseudomass and in 55% of the neonates with a bilateral pseudomass. The pseudomass was large enough to potentially lead to a misdiagnosis in one third of the cases. In the other neonates the mass was smaller and not particularly problematic. The majority of the neonates with pseudomasses were large. not intubated. and not on positive-pressure assisted ventilation. Over half had no underlying pulmonary disease. The appearance of a mediastinal pseudomass on radiographs of neonates can obscure a pneumothorax. and lead to an erroneous diagnosis. Recognition of the pseudomass as a manifestation of pneumothoraces is important.
The evaluation of coronary bypass graft patency: direct and indirect techniques other than coronary arteriography, Patients having one or more coronary artery bypass graft operations constitute an important part of the practice of cardiac radiology. Bypass graft patency can be determined by indirect and direct methods. The indirect imaging methods include radionuclide ventriculography. thallium-201 scintigraphy. and positron emission tomography. The direct methods include conventional CT. ultrafast CT. MR imaging. digital subtraction angiography. and Doppler sonography. This review discusses the advantages and limitations of these methods and attempts to define the relative importance of each of these techniques in the evaluation of bypass graft patency.
Focal high signal on MR scans of the midbrain caused by enlarged perivascular spaces: MR-pathologic correlation, Punctate and linear foci of abnormal signal were observed near the substantia nigra in the midbrains of 32 (20%) of 157 patients undergoing high-resolution MR imaging of the brainstem. The lesions were most easily seen on long TR/long TE images. where they were of high signal intensity. Their location was consistently in the lower mesencephalon near the junction of the substantia nigra and cerebral peduncle. Unilateral lesions were observed in 18 cases. while bilateral lesions were noted in 14. A review of anatomic specimens revealed the constant presence of penetrating branches of the collicular or accessory collicular arteries in this location. Enlarged perivascular spaces around these vessels were frequently seen in the specimens and probably account for punctate and linear foci observed on high-resolution MR images of the midbrain.
Diaphragmatic rupture due to blunt trauma: sensitivity of plain chest radiographs, Preoperative diagnosis of diaphragmatic rupture caused by blunt injury is often difficult because of serious concurrent injuries. a lack of specific clinical signs. and simultaneous lung disease that may mask or mimic the diagnosis radiologically. Previous reports have suggested that a preoperative diagnosis is established on the basis of chest radiographs in only one third of patients. In order to assess the value of chest radiographs and other imaging techniques in diagnosing traumatic rupture of the diaphragm. we retrospectively reviewed all preoperative diagnostic imaging performed in 50 patients with surgically proved hemidiaphragmatic rupture due to blunt trauma. Chest radiographs were diagnostic in 20 (46%) of 44 patients with left-sided rupture and were considered suspicious enough to warrant further diagnostic studies in an additional eight patients (18%). Five patients with initially normal findings on chest radiographs had diagnostic findings on delayed chest radiographs. Chest radiographs were strongly suggestive in only one (17%) of six patients with right-sided hemidiaphragmatic rupture. CT was diagnostic for diaphragmatic rupture in only one (14%) of seven instances in which it was performed. MR was diagnostic in both patients in whom it was performed. Our experience indicates that chest radiographs obtained at admission and repeated soon after are more valuable in suggesting the diagnosis of traumatic rupture of the diaphragm than previously reported. particularly in the more frequent. left-sided injuries. This increased sensitivity may be due to a greater level of suspicion maintained in a trauma referral center in which this injury is not uncommon.
Thickening at the root of the superior mesenteric artery on sonography: evidence of vascular involvement in patients with cancer of the pancreas, Thickening of the root of the superior mesenteric artery (SMA) was studied by using preoperative sonography in 23 patients with pancreatic cancer and in 10 healthy control subjects. Of the 23 with cancer. 11 had neoplastic involvement of the SMA and 12 did not. Prominent thickening of the area around the SMA with (six patients) or without (five patients) decreased echogenicity compared with the adjacent retropancreatic connective tissue was observed in patients with involvement of the SMA. a finding called the "cuff sign." Mean thickness of the periarterial area in the cancer patients with and without involvement of the SMA and in control subjects were 8.5 mm. 4.0 mm. and 2.9 mm. respectively. With an upper limit of normal of 7.0 mm for the thickness of the SMA. the sensitivity. specificity. and overall accuracy of this sign in the evaluation of involvement of the SMA were 91%. 100%. and 96%. respectively. Decreased echogenicity of the periarterial area was not observed in patients without involvement of the SMA or in control subjects. Our results show that sonographic evidence of periarterial thickening of the root of the SMA (cuff sign). especially with decreased echogenicity. is a reliable finding of tumor infiltration of the SMA in patients with pancreatic carcinoma.
Duplex Doppler sonography of the hepatic vein in tricuspid regurgitation, Patients with tricuspid regurgitation may present initially with vague abdominal symptoms and elevated liver enzymes. In the absence of diagnostic sonographic findings. patients may be subjected to an unnecessary invasive liver biopsy for an accurate diagnosis. We recently described the association of the pulsatile portal venous waveform on duplex Doppler sonography with tricuspid regurgitation in 15 patients. In this study I describe the changes in the hepatic venous waveform in these patients and compare the findings with the final diagnosis as determined by Doppler echocardiography (n = 14) or ultrafast CT (n = 1). All patients had clinical findings consistent with liver dysfunction and were referred for sonography to rule out diseases of the liver. biliary tree. or hepatic or portal veins. All patients had persistently dilated hepatic veins and inferior venae cavae. Twenty-four volunteers. 11 of whom had simultaneous ECG tracings. served as a control group. The main findings on the hepatic duplex sonogram in the disease group were a decrease in the size of the antegrade systolic wave with a systolic/diastolic flow velocity ratio of less than 0.6 (n = 4) or reversal of the systolic wave (n = 10). In all volunteers. systolic flow was antegrade and the ratio was more than 0.6. Two diagnoses were false positive and one was false negative. In some patients with sonographic signs of congestive heart failure. duplex Doppler sonography of the hepatic vein may be helpful in the diagnosis of one of the causes of liver dysfunction. tricuspid regurgitation.
Prevalence of malnutrition and vitamin A deficiency in the Diourbel, Fatick, and Kaolack regions of Senegal: a controlled study, Two hundred and six Senegalese preschool children included in an epidemiological study were selected by their results from impression cytology with transfer (ICT) for assessment of their nutritional state by means of biological variables and for assessment of the diagnostic values of the ICT. A problem of protein-calorie malnutrition existed (transthyretin and retinol-binding protein concentrations were low) associated with vitamin A deficiency (retinol concentrations were low). The sensitivity and specificity of the ICT defined with respect to retinol (threshold fixed at 0.35 mumol/L) varied with the classification criteria of ICT and seemed to be fairly insensitive but specific.
Proliferative and antiproliferative effects of interferon-gamma and tumor necrosis factor-alpha on cell lines derived from cervical and ovarian malignancies, Four human cell lines derived from cervical carcinomas (ME-180. SiHa. HT-3. and MS751) and three human cell lines derived from ovarian carcinomas (SK-OV-3. Caov-3. and NIH:OVCAR-3) were analyzed in vitro to determine the effect of recombinant interferon-gamma and recombinant human tumor necrosis factor-alpha on cell growth and survival. The effects of interferon-gamma. tumor necrosis factor-alpha. and both interferon-gamma and tumor necrosis factor-alpha on cell growth were measured after 24 and 72 hours of incubation by the incorporation of chromium 51. The results of this analysis showed that all seven cell lines were resistant to the antiproliferative action of tumor necrosis factor-alpha. that the growth of most cell lines was inhibited by interferon-gamma by 72 hours of incubation. and that after 72 hours of incubation all cell lines demonstrated a synergistic antiproliferative response to the combination of interferon-gamma and tumor necrosis factor-alpha. However. the effects of these cytokines on cell growth were found to differ among cell lines and varied with the concentration and the duration of incubation. The growth of one cell line (Caov-3) was stimulated by both tumor necrosis factor-alpha and interferon-gamma. These results suggest that the clinical effects of these cytokines on the growth of gynecologic cancers may be more complex than previously supposed.
Elimination of coincident Staphylococcus aureus nasal and hand carriage with intranasal application of mupirocin calcium ointment, OBJECTIVE: To determine the safety and efficacy of mupirocin calcium ointment in the elimination of Staphylococcus aureus nasal and hand carriage in healthy persons. DESIGN: A double-blind. placebo-controlled. randomized trial. SETTING: Clinical research unit of a tertiary medical center. SUBJECTS: Health care workers with stable S. aureus nasal carriage. INTERVENTIONS: Subjects (n = 68) were randomly assigned to receive either mupirocin or placebo intranasally twice daily for 5 days. MEASUREMENTS AND MAIN RESULTS: Cultures of the hands and nares were obtained at baseline and 72 hours after therapy. The nares were also cultured 1. 2. 4. and 12 weeks after therapy. Antimicrobial susceptibility testing and restriction endonuclease analysis of plasmid DNA were used to confirm strain identity. There were no serious side effects. Mupirocin decreased the frequency of S. aureus nasal carriage at each time interval: At 3 months. 71% of subjects receiving mupirocin remained free of nasal S. aureus compared with 18% of controls. This difference (53%; 95% CI; 26% to 80%) was significant (P less than 0.0001). Additionally. analysis of plasmid patterns showed that 79% of subjects in the mupirocin group were free of the initial colonizing strain at 3 months. The proportion of hand cultures positive for S. aureus in the mupirocin group after therapy was lower than in the placebo group (2.9% compared with 57.6%). This difference (53%; 95 CI. 30% to 80%) was significant. after adjustment for the frequency of hand carriage at baseline (P less than 0.0001). CONCLUSIONS: When applied intranasally for 5 days. mupirocin calcium ointment is safe and effective in eliminating S. aureus nasal carriage in healthy persons for up to 3 months and appears to have a corresponding effect on hand carriage at 72 hours after therapy.
Sensitivity of in vivo X-ray fluorescence determination of skeletal lead stores, Eighteen patients with known past occupational lead exposure underwent parenteral diagnostic chelation with ethylenediaminetetraacetic acid and x-ray fluorescent determination of in vivo skeletal lead stores at the distal styloid process of the ulna and at the temporal base bone using a cobalt 57 source and measuring lead Ka x-rays. X-ray fluorescent lead measurements in both locations correlated with results of diagnostic chelation. Using a post-chelation urinary excretion of greater than 600 micrograms lead/24 h as the definition of "high-" lead stores. sensitivity of x-ray fluorescence at the wrist and temple was 56% and 39%. respectively.
The RIIIS/J inbred mouse strain as a model for von Willebrand disease, Mice of the RIIIS/J inbred strain have prolonged bleeding times (greater than 15 minutes) after experimental injury when compared with normal C57BL/6J mice (1.8 minutes) and other strains of mice. The prolonged bleeding time was accompanied by normal platelet counts. Platelet aggregation with collagen and agglutination with ristocetin were not significantly altered in RIIIS/J mice. Also. platelets from RIIIS/J mice had normal serotonin content and normal numbers of dense granules by electron microscopy. Thus. the bleeding abnormality is not due to platelet storage pool deficiency as has been found in several other mouse mutants. The activated partial thromboplastin time (APTT) which plasma from RIIIS/J mice was prolonged compared with normal mice. and factor VIII:C activity and von Willebrand antigen levels were one half to one third that of normal mouse plasma. Factor XI activity was also significantly deficient (levels at 42% to 64% of normal). Plasma of RIIIS/J mice contained the full complement of multimers of von Willebrand factor. although each multimer was lower in concentration compared with that in normal mice. Platelet alpha-granule von Willebrand antigen levels were similar to those of normal mice. The prolonged bleeding time of RIIIS/J mice was corrected by treatment with desmopressin. Heterozygous C57BL/6J x RIIIS/J F1 animals had low plasma von Willebrand antigen levels like the RIIIS/J parent and had variable bleeding times. Inheritance of the bleeding tendency was as an incomplete dominant. autosomal trait. These data indicate the RIIIS/J strain is a suitable animal model for type IA von Willebrand disease.
Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products, Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI-1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion. whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were slightly decreased. 5% on average. suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products. and separately of fibrin degradation products and fibrinogen degradation products. was found. This indicates that fibrinolysis persisted. at least partly. in the presence of high levels of PAI activity. Whereas PAI-1 production increased. t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore. it is possible that thrombin. not TNF. is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients.
Clonal B-cell populations in patients with idiopathic thrombocytopenic purpura, Idiopathic thrombocytopenic purpura (ITP) may be associated with other autoimmune diseases and the development of lymphoproliferative malignancies. In Sjogren's disease. Graves' disease. and essential mixed cryoglobulinemia. which are also associated with the development of B-cell neoplasia. clonal B-cell expansions have been detected. Eleven patients with ITP were investigated for the presence of a clonal excess (CE) using kappa-lambda flow cytometry and DNA analysis for rearrangement of immunoglobulin heavy and light chain genes in blood and/or spleen lymphocytes. In 10 of 11 patients. clonal B-cell populations were found by one or both tests. In three of these patients. oligoclonal B-cell populations were suggested by the combined findings. In all four patients with a small paraproteinemia. the isotype was confirmed by either flow cytometry or DNA rearrangement analysis. Our data suggest that the oligoclonal expansions are not restricted to CD5+ B cells. as in the majority of patients this subset was below the detection level of flow cytometry or DNA rearrangement analysis. None of the patients developed clinical manifestations of malignant lymphoma during a follow-up period of 10 to 44 months after sampling. We conclude that clonal excess populations of B cells are not a unique feature of malignant lymphoma. but may occur in autoimmune diseases. suggesting a benign (oligo)clonal B-cell proliferation.
Biosynthesis and processing of cathepsin G and neutrophil elastase in the leukemic myeloid cell line U-937, The processing of the neutral proteases cathepsin G and neutrophil elastase. normally synthesized in myeloid precursor cells and stored in azurophil granules. were investigated by biosynthetic labeling with 14C-leucine of the monoblastic cell line U-937. The proteases were precipitated with specific antibodies and the immunoprecipitates were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by fluorography. The transfer to lysosomes of newly synthesized proteases was demonstrated in pulse-chase labeling experiments followed by centrifugation of cell homogenates in a Percoll gradient. The presence of a closely spaced polypeptide band-doublet at intermediate gradient density suggested cleavage of the specific aminoterminal pro dipeptide extension before storage in lysosomes. The molecular heterogeneity observed for cathepsin G and neutrophil elastase seemed to be due to modifications occurring after sorting into lysosomes. most likely because of C-terminal processing. Modifications of the secreted enzymes were not detectable by SDS-PAGE. In contrast to other lysosomal enzymes. no phosphorylation was demonstrated. Newly synthesized cathepsin G and neutrophil elastase rapidly became resistant to endoglycosidase H. indicating transport through the medial and trans cisternae of the Golgi complex and conversion to "complex" oligosaccharide side chains. This conversion was inhibited by an agent swainsonine. but translocation from the Golgi complex and secretion were unaffected. The processing described may play a role in activation of the proteases.
Plasma level of atrial natriuretic peptide as an indicator of increased cardiac load in uremic patients, Plasma levels of atrial natriuretic peptide (ANP) were measured by radioimmunoassay in 43 non-dialyzed uremic patients at rest and during maximal exercise to assess the possible relationship between plasma ANP levels and cardiac function. as judged by M-mode echocardiography and exercise tolerance. Patients with poor exercise capacity (exercise time less than 6 min) on dynamic exercise test had decreased left ventricular ejection fraction. increased left atrial diameter. and increased left ventricular mass index (LVMI). compared with patients with better exercise capacity (exercise time greater than 6 min). Plasma ANP was significantly higher in patients with poor exercise capacity and impaired cardiac function (202 pg/ml [95% confidence interval 119 to 284] at rest and 227 pg/ml [149 to 304] during exercise). compared with patients with better exercise capacity (75 pg/ml [50 to 102]. p less than 0.005. and 123 pg/ml [80 to 167]. p less than 0.05. respectively). Plasma ANP increased significantly (p less than 0.005) during exercise only in patients with better cardiac function. The best correlation among the variables studied was found between LVMI and plasma ANP concentration at rest (r = 0.56. p less than 0.001) and during exercise (r = 0.51. p less than 0.005). whereas neither blood pressure nor renal function showed any significant correlation with ANP levels. We conclude that plasma ANP levels are elevated in uremic patients with impaired cardiac function. correlating with increased LVMI. Plasma ANP determinations are useful in identifying increased cardiac load and consequent cardiac hypertrophy and dysfunction with known associations with increased cardiovascular mortality in patients with chronic renal failure.
Site-directed mutagenesis of lysine within the immunodominant autoepitope of PDC-E2, The major autoantigens of PBC have been identified as the four closely related mitochondrial enzymes PDC-E2. BCKD-E2 OGDC-E2 and protein X. A major structural similarity of these enzymes is the presence of one or more lipoyl domains. The immunodominant epitope of each autoantigen has either been postulated or been demonstrated to be located within the lipoate binding region. However. it is not clear whether the binding of lipoic acid to the epitope is necessary for autoantibody recognition. To address this issue we have constructed by oligonucleotide site-directed mutatagenesis three mutants in the lipoyl domain of human PDC-E2. Because lipoic acid is covalently bound to the zeta-amino group of the lysine residue of PDC-E2. the mutants were designed to replace the lysine residue in the lipoyl domain with glutamine. a negatively charged amino acid; histidine. a positively charged amino acid; and tyrosine. an aromatic amino acid. Binding reactivity of sera from patients with PBC were analyzed by enzyme-linked immunosorbent assay. immunoblotting and specific absorption against each of the three mutants and control clones. All data were compared with parallel studies with a control recombinant clone. the liver-specific F alloantigen. We believe the recognition of the lipoyl domain is a reflection of the surface-exposed. hydrophilic and relatively mobile nature of this region of the autoantigen. Further studies on direct assay for the presence of lipoic acid will be needed to clarify these issues.
Leishmania major amastigotes initiate the L-arginine-dependent killing mechanism in IFN-gamma-stimulated macrophages by induction of tumor necrosis factor-alpha, Macrophages exposed to IFN-gamma and infected with amastigotes of Leishmania major develop the capacity to eliminate the intracellular pathogen. This antimicrobial activity of activated macrophages correlates with the initiation of nitrogen oxidation of L-arginine. yet other reports suggest that two signals are required for induction of this biochemical pathway for effector activity. In the present studies. macrophages treated with up to 100 U/ml IFN-gamma. or 100 ng LPS. or 10(7) amastigotes produced minimal quantities (less than 9 microM) of NO2- and failed to develop cytotoxic effector activities. In contrast. the combination of IFN-gamma and either LPS (greater than 0.1 ng) or amastigotes (10(6) induced high concentrations (much greater than 30 microM) of NO2- and macrophage cytotoxicity against intra- and extracellular targets. The induction of nitrogen oxidation by amastigotes could be dissociated from LPS-induced events by 1) performing the assays in the presence of polymyxin B (which blocked LPS effects. but not amastigote effects). 2) determining the threshold of IFN-gamma required to prime cells for subsequent trigger (1 U/ml for LPS trigger effects; 10-fold higher for amastigotes). and 3) determining the heat sensitivity of the two trigger agents (amastigote effects abolished at 100 degrees C; LPS effects unaffected at this temperature). Further. culture fluids from amastigote-infected macrophages did not contain detectable LPS (less than 6 pg/ml). Possible parasite and cell-associated factors that could contribute to the induction of nitrogen oxidation and cytotoxic activity of IFN-gamma treated macrophages were examined: only certain intact microorganisms. LPS from a variety of bacteria. and the cytokine TNF alpha were effective. Both NO2- production and intracellular killing were abolished by the addition of anti-TNF-alpha mAb in the assay. TNF-alpha was produced by amastigote-infected macrophages and IFN-gamma dramatically enhanced secretion of this cytokine; IFN-gamma alone had no effect. Endogenous TNF-alpha produced during infection of macrophages with L. major acted in an autocrine fashion to trigger the production of L-arginine-derived toxic nitrogen intermediates that killed the intracellular parasites.
Tumor necrosis factor-alpha synergizes with IFN-gamma in mediating killing of Leishmania major through the induction of nitric oxide, CBA mice develop cutaneous lesions when infected with Leishmania major. The disease development was significantly reduced by injecting into the lesion a combination of rIFN-gamma and rTNF-alpha. The doses of IFN-gamma and TNF-alpha used were suboptimal in that either cytokine alone did not have any effect. The therapeutic effect of IFN-gamma and TNF-alpha in vivo is reflected in their ability to activate macrophages to kill the intracellular parasites in vitro. The macrophage leishmanicidal activity induced by TNF-alpha and IFN-gamma can be completely inhibited by a specific inhibitor (L-NG monomethyl arginine) of nitric oxide synthesis. There was a direct correlation between the intracellular killing of the parasites and the production of nitric oxide by the macrophages. In contrast. there was no correlation between leishmanicidal activity and superoxide production by macrophages.
Transformation of T lymphocytes by the v-fos oncogene, Activation of T lymphocytes through the T cell antigen receptor has been shown to stimulate a rapid and transient accumulation of c-fos mRNA and protein. Transfection of a normal murine T lymphocyte clone with the FBJ-v-fos oncogene resulted in generation of a cell line that was morphologically transformed. had lost the requirement for IL-2 for proliferation. and was tumorigenic in adult syngeneic mice; however. the transformed cells retained the ability to proliferate in response to IL-2. The transformed cells did not show constitutive expression of IL-2 or c-fos mRNA. although the promoter regions of both IL-2 and c-fos genes contain AP-1 sites that are expected to be targets for binding of Fos/Jun complexes. In contrast. the transformed T cells showed increased constitutive expression of IL-2R alpha and c-myc mRNA; these genes may represent cellular targets for transformation by v-fos and physiologic activation by c-fos. We discuss the possibility that these transformed cells behave as cells partially activated through the TCR. and that transformation occurs through a mechanism independent of IL-2.
Anti-idiotype-induced, lipopolysaccharide-specific antibody response to Pseudomonas aeruginosa. II. Isotype and functional activity of the anti-idiotype-induced antibodies, We recently developed a murine anti-idiotypic mAb that functioned as a molecular mimic of the O-specific polysaccharide side chain (Ps) of Pseudomonas aeruginosa LPS in vitro. and which induced Ps-specific antibodies in syngeneic BALB/c ByJ mice. In the current studies. we demonstrate that these anti-Id-induced. Ps-specific antibodies fix complement to the bacterial cell surface. and protect neutropenic mice from fatal P. aeruginosa sepsis. The isotypic distribution of the anti-Id-induced antibodies. however. resembles the restricted pattern (IgM and IgG3) seen after administration of purified Ps to mice. The immunogenicity and number of isotypes of Ps-specific antibody produced could be enhanced by conjugating the anti-Id to keyhole limpet hemocyanin. Finally. the anti-Id administered before immunization with purified Ps. primed BALB/c ByJ mice for production of other Ps-specific antibody isotypes (IgG1). These studies show that this anti-Id induces functional anti-Ps antibodies in syngeneic mice. and when used in conjugate form or as a priming agent before Ps immunization. yields an antibody response consistent with "T cell dependence." These immunization strategies may be useful for the induction of polysaccharide-specific antibodies in man.
The mast cell-committed progenitor. In vitro generation of committed progenitors from bone marrow, Mast cell-committed progenitors are detected in the unique microenvironment of the mesenteric lymph node (MLN) of Nippostrongylus brasiliensis-infected mice but not in naive bone marrow. We have determined that MLN cells. after infection. produce high levels of IL-3. IL-4. and IgE. presumably in the form of immune complexes with antigens produced by the infecting helminth. After N. brasiliensis infection. peak production of these factors occurs several days before the peak appearance of mast cell-committed progenitors in the MLN. To determine if these factors play a role in mast cell commitment. we recreated these conditions. in vitro. Naive bone marrow cells were cultured with combinations of IL-3. IL-4. and IgE immune complexes. or on IgE-coated plates. and then assayed for acquisition of the ability to form mast cell colonies when supplemented with fibroblast-conditioned medium alone. IL-3 and IgE immune complexes. and. unexpectedly. IgE immune complexes alone were found to be capable of producing mast cell-committed progenitors. i.e.. cells responsive to fibroblast-conditioned medium alone. from bone marrow. whereas IL-4 did not enhance production of mast cell-committed progenitors from bone marrow. Production of IFN-gamma peaked at the same time point as committed progenitor activity and may be responsible for down regulating the response.
Macrophage activation for intracellular killing as induced by calcium ionophore. Correlation with biologic and biochemical events, Changes in the concentration of cytosolic Ca2+ are known to affect various macrophage functions; in particular. exposure in vitro to the Ca2+ ionophore A23187 primes macrophages for tumor cell killing. In the present report. it is shown that treatment with this ionophore similarly mimics IFN-gamma as a priming signal for induction of microbicidal activity. Incubation of mouse bone marrow-derived macrophages with 10(-7) to 10(-6) M A23187 (in the presence of Ca2+) led to intracellular killing of the protozoan parasite Leishmania enriettii within 24 h. provided LPS (1 ng/ml) was also present; no microbicidal activity was observed using either compound alone. A 4-h exposure to the ionophore in the presence of Ca2+ (priming phase) was sufficient to induce leishmanicidal activity upon reincubation with LPS. here acting as a necessary second signal. Addition of EGTA during the priming phase blocked intracellular killing upon subsequent LPS treatment; microbicidal activity could be restored by excess Ca2+. but not Mg2+. suggesting that changes in the concentration of cytosolic Ca2+ are sufficient to mediate the molecular events that lead to acquisition of microbicidal potential. Ionophore-induced leishmanicidal activity was paralleled by a stimulation of the hexosemonophosphate shunt pathway and production of nitrites. which are biochemical correlates of the activated state. In addition. sequential exposure to A23187 and LPS markedly stimulated macrophages to release TNF and PGE2. two agents thought to act as modulators of macrophage activation.
Natural killer cell-dependent mycobacteriostatic and mycobactericidal activity in human macrophages, Host defense mechanisms against Mycobacterium avium complex (MAC) are poorly understood. Recent evidence suggests the role of NK cells in the host defense against some intracellular pathogens. We investigated whether NK cells play a role in MAC infection. IL-2-activated human NK cells were incubated with human monocyte-derived macrophages either before or after infection with MAC. Macrophages were lysed 3 and 5 days after infection for quantitation of viable intracellular organisms. Although no killing was observed by nonstimulated macrophages. exposure to IL-2-treated NK cells for 24 h before infection induced macrophage to kill 70 +/- 8% of intracellular MAC by 3 days. and 81% +/- 4% in 5 days (p less than 0.01 for both compared with control). Killing was not blocked by incubation with anti-TNF antibody (Ab) or anti-IFN-gamma Ab. Similarly. incubation of macrophages for 24 h with supernatant obtained from IL-2 activated NK cells was associated with 74 +/- 4% killing of intracellular MAC in 3 days and 81 +/- 6% in 5 days (p less than 0.01 for both compared with control). However. the supernatant-mediated activation was partially blocked by anti-TNF Ab (46 +/- 6%; p less than 0.05) but not by anti-IFN gamma Ab. When infected macrophages were incubated with NK cells 24 h after infection for 48 h. they killed 54 +/- 3% of intracellular M. avium in 3 days and 73 +/- 5% in 5 days (p less than 0.02 for both compared with control). This effect was also not blocked by either anti-TNF or anti-IFN gamma Ab. These results suggest that activated NK cells may have an important role in the intracellular killing of MAC and that the NK-mediated activation of macrophages is in part mediated by TNF.
Phagocytosis of Leishmania enhances macrophage activation by IFN-gamma and lipopolysaccharide, This investigation describes the ability of Leishmania promastigotes to enhance activation of bone marrow-derived murine macrophages in vitro if added together with rIFN-gamma in the presence or absence of LPS. Activation was defined as the capacity for arginine-derived NO2- production and the killing of intracellular Leishmania. Enhanced NO2- production was observed for either CBA or C3H/HeJ macrophages undergoing phagocytosis at the time of activation. Other phagocytic stimuli including inert polystyrene latex beads were as effective as Leishmania. No correlation could be demonstrated between the enhanced NO2- release and secretion of products of the respiratory burst or PGE2. However. TNF-alpha secretion was elevated in cultures undergoing phagocytosis and a relationship between hexosemonophosphate shunt activity and NO2- levels was evident. These studies confirm and extend previous reports that phagocytosis plays an important role in the regulation of macrophage physiology.
Synergistic role of CD4+ and CD8+ T lymphocytes in IFN-gamma production and protective immunity induced by an attenuated Toxoplasma gondii vaccine, BALB/c mice vaccinated with a temperature-sensitive mutant (TS-4) of Toxoplasma gondii develop complete resistance to lethal challenge with a highly virulent toxoplasma strain (RH). This immunity is known to be dependent on IFN-gamma synthesis. In vitro and in vivo T cell depletions were performed in order to identify the subsets responsible for both protective immunity and IFN-gamma production. When stimulated with crude tachyzoite Ag in vitro. CD4+ cells from vaccinated mice produced high levels of TH1 cytokines (IL-2 and IFN-gamma) but not TH2 cytokines (IL-4 and IL-5). CD8+ cells. in contrast. produced less IFN-gamma and no detectable IL-2. Nevertheless. they could be induced to synthesize IFN-gamma when exposed in culture to exogenous IL-2. In vivo treatment with anti-CD4 plus anti-CD8 or anti-IFN-gamma antibodies during challenge infection completely abrogated resistance to T. gondii. In contrast. treatment with anti-CD4 alone failed to reduce immunity. whereas anti-CD8 treatment partially decreased vaccine-induced resistance. These results suggest that although IFN-gamma and IL-2-producing CD4+ lymphocytes are induced by vaccination. IFN-gamma-producing CD8+ T cells are the major effectors of immunity in vivo. Nevertheless. CD4+ lymphocytes appear to play a synergistic role in vaccine-induced immunity. probably through the augmentation of IFN-gamma synthesis by the CD8+ effector cells. This hypothesis is supported by the observation that when giving during vaccination. as opposed to after challenge. anti-CD4 antibodies are capable of blocking protective immunity.
Entry of antivirally active T lymphocytes into the thymus of virus-infected mice, The thymus has long been regarded as an immunologically "privileged site" by being shielded against the entry of exogenous Ag as well as protective elements of the immune system. After i.p. infection of mice. the lymphocytic choriomeningitis virus multiplied in this organ. Viral Ag was found predominantly in the epithelial-reticular cells of the medulla and to a lesser extent in such cells of the cortex. Beginning on day 7 after infection. the virus disappeared. a process that could be blocked by depleting the mice of peripheral T lymphocytes or of CD8+ cytotoxic T lymphocytes. Viral clearance was accelerated by i.v. injection of splenocytes from mice. which themselves were just eliminating the virus. CD8+ cells from CD8-congenic donor mice. most with blast morphology. were detected immunocytochemically in the thymus. predominantly in the medulla. A few CD8+ T lymphocytes from donors not previously infected were also demonstrated in the thymic tissue of infected mice. Our findings indicate that the lymphocytic choriomeningitis virus has access to the thymus and suggest that it is cleared by the antiviral activity of circulating cytotoxic T lymphocytes. Thus. just as other organs. the thymus appears to be subject to immune surveillance by mature T lymphocytes that have their origin in secondary lymphoid tissues.
The role of cytophilic IgG3 antibody in T cell-mediated resistance to infection with the extracellular bacterium, Pseudomonas aeruginosa, Previous studies have demonstrated that T lymphocytes from mice immunized with a high m.w. polysaccharide Ag from Fisher-Devlin immunotype I Pseudomonas aeruginosa can adoptively transfer protection against challenge with the homologous bacterial strain to susceptible mice. This T cell-mediated resistance has been found to be B cell dependent. although serum from immunized mice is incapable of passively transferring protection to nonimmune mice. The current studies demonstrate that T cells from immunized mice possess receptors that permit them to be adsorbed to IgG3-secreting hybridomas. but not to IgM-secreting hybridomas. Cross-linking of antibody on the surface of immune T cells results in release of a soluble factor that inhibits bacterial growth. Treatment of T cells to remove cytophilic antibody eliminates their ability to adoptively transfer protection to nonimmune mice. and the protective ability can be restored by co-incubating the T cells with monoclonal P. aeruginosa-specific IgG3 antibody before adoptive transfer to nonimmune mice. These observations are consistent with a model in which T lymphocytes from immunized mice are activated by cross-linking of FcR for IgG3 to secrete an antibacterial lymphokine. The ability of IgG3 at low antibody concentrations to act synergistically with T lymphocytes to inhibit bacterial growth could explain the evolutionary selection of this antibody isotype as the predominant subclass of IgG secreted in response to bacterial capsular polysaccharide Ag.
Suppression of human monocyte function against Candida albicans by autologous IL-2-induced lymphokine-activated killer cells, We have previously reported that IL-2-induced lymphokine-activated killer (LAK) cells have the capacity to lyse autologous and allogeneic monocytes. To understand the biologic significance of this interaction. we investigated the function of human monocytes against the opportunistic pathogen. Candida albicans. subsequent to a short exposure to autologous LAK cells. A highly sensitive radiolabel assay. which makes use of the incorporation of [3H]glucose into residual Candida after their incubation with monocytes. was developed to measure antifungal activity. Cultured monocytes. after 2 to 6 h exposure to LAK cells. were found to be substantially suppressed in their ability to control fungal growth. Moreover. monocytes cultured in the presence of granulocyte/macrophage (GM)-CSF or IL-3. were even more suppressed in function after a short incubation with LAK cells. The effect of GM-CSF was both time and dose dependent. with peak susceptibility induced after 4 days of culture with as little as 10 U/ml of the cytokine. These GM-CSF-cultured monocytes. however. were relatively resistant to inhibition by freshly isolated large granular lymphocytic NK cells. Therefore. IL-2 induces in large granular lymphocytic cells the capacity to inhibit monocyte function. In contrast to GM-CSF and IL-3. IFN-gamma was found to have a protective effect on monocytes. because monocytes cultured 4 days in IFN-gamma were not significantly inhibited by LAK cells. These results indicate that LAK cells may be involved in regulation of monocyte function and suggest that the state of differentiation induced by different cytokines may dictate the level of control of the monocytes by LAK cells.
Characterization of a new, potent, immunopathogenic epitope in S-antigen that elicits T cells expressing V beta 8 and V alpha 2-like genes, Experimental autoimmune uveoretinitis (EAU) is a predominantly T cell-mediated autoimmune disease induced in susceptible animals by active immunization with human or bovine retinal S-Ag or by passive transfer of activated S-Ag or peptide-specific CD4+ T cells. During the course of studies aimed at the identification of T cell and B cell recognition sites in bovine and human S-Ag. a new potent uveitogenic region. located near the carboxy terminus of the molecule. was identified and characterized. Analysis of several synthetic peptides from this region showed that a 14 amino acid residue peptide. BSAg339-352. was highly uveitogenic when injected with adjuvants into Lewis rats. A uveitogenic T cell line. R737. was raised by in vitro selection of lymphocytes from animals immunized with peptide BSAg333-352. Northern blot analysis of mRNA from the R737 T cell line was positive for the rat homologs of murine V beta 8 and V alpha 2 T cell receptor gene probes. Whereas peptide BSAg339-352 defined the pathogenic site. nonpathogenic. proliferative sites were found in close physical association. This region is immediately adjacent to previously characterized pathogenic and proliferative sites contained in residues BSAg352-364. These results. as well as our previous observations. show S-Ag to be a complex molecule with several highly conserved amino acid sequences that can elicit pathogenic T cells with restricted T cell receptor V gene usage capable of active and passive elicitation of experimental autoimmune uveoretinitis.
Treatment of psoriasis and psoriatic arthritis with interferon gamma, In a placebo-controlled double-blind randomized study. 24 patients with psoriatic arthritis were given 28 d of treatment. and in an open study. 56 patients were treated for 9 months. We treated patients with 100 micrograms IFN gamma per subcutaneous injections. which were given daily for the first 2 weeks and then 3 times per week. The principal criterion for evaluation of therapeutic success on arthritis was improvement of the Ritchie joint pain index by at least 25% in the double-blind and 30% in the long-term study. In the double-blind study. the interferon arm was superior to the placebo arm with a statistically significant. one-side error probability of less than 5% in the chi-square test. In the long-term study. IFN gamma caused an improvement in a portion of patients in the first 3 months of therapy. No further improvement was observed after the third month. and patients classified as responders in the first months showed a deterioration of the disease by continuing treatment. The humoral inflammatory parameters did not normalize during therapy. Regression of the skin manifestations could not be observed. IFN gamma is evidently capable of inducing a psoriasis on the injection site. Investigations of IFN gamma serum levels. IFN antibodies. 2'-5' A synthetase levels in serum. and mononuclear blood cells and NK cell activity under long-term therapy showed no explanation for the loss of efficacy after 3 months treatment.
Role of interferons in the therapy of melanoma, A range of potent immunoregulatory molecules termed cytokines has become available for the therapy of human melanoma. Among the cytokines. the interferons (IFN) have been examined in great depth for the therapy of melanoma. IFN are able to modulate host effector cell function. including the tumor cytolytic function of lymphocytes and monocytes. IFN also have the capacity to regulate the distribution of circulating immunoregulatory (T) lymphocytes and the expression of tumor cell surface antigens. as well as class I and II products of the major histocompatibility locus. These activities of the IFN have led to their early application for treatment of human melanoma. The empirical evidence that IFN alpha exerts clinically significant anti-tumor effects against melanoma is reviewed. and evolving status of adjuvant trials of IFN alpha and gamma is noted. New indirect host-mediated anti-tumor activities that may potentially be manifest by IFN have yet to be fully harnessed. The opportunity to obtain meaningful anti-tumor activity in advanced disease or adjuvant settings. at dose ranges below those which are toxic (conventional maximal tolerable). are at hand. The U.S. cooperative groups [Eastern Cooperative Oncology Group (ECOG). Cancer and Leukemia Group B (CALGB). and South West Oncology Group (SWOG)] are studying IFN gamma in pursuit of this goal in advanced and adjuvant settings for melanoma and other tumors. The determination of the clinical role of IFN as biologic response modifiers demands equal commitment to the clinical assessment of immunobiologic mechanisms and anti-tumor effects. The immunologic assessment of IFN and a number of other cytokines is a major focus of the Pittsburgh Cancer Institute. Regional delivery of cytokines such as interleukin-2 (IL-2) may be the most appropriate and least toxic approach. given their half-life. Regional therapy by the intralesional route has yielded enhanced activity for a range of biologics. including bacillus Calmette-Guerin (BCG). IL-2. and tumor necrosis factor (TNF). Intralymphatic therapy with methanol extraction residue of BCG (MER-BCG) has been tested. and trials are now in progress with IL-2 to assess the optimal dosage by this route. It is likely that the optimal role of IFN and other cytokines will be found in combination with one another. and with different biologic modalities such as monoclonal antibodies and vaccines. to allow expansion and heightened activity of the desired effector cell populations in the host. Enhanced host toxicities. as well as anti-tumor effects. may require that special attention be devoted to optimal sequence of administration to enhance the therapeutic index.
Disseminated malignant melanoma and recombinant interferon: analysis of seven consecutive phase II investigations, We have performed seven phase II trials with recombinant interferons (IFN) involving 191 patients with biopsy-proved. measurable disseminated malignant melanoma. The regimens and numbers of patients have included IFN-alpha 2A. 50 X 10(6) U/m2 subcutaneous (SQ) TIW (regimen A. 31 patients); IFN-alpha 2A. 12 X 10(6) U/m2 SQ TIW (regimen B. 30 patients); IFN-alpha 2A with cimetidine as an immunorestorative agent (regimen C. 35 patients); IFN-gamma (regimen E. 29 patients); IFN-alpha 2A with IFN gamma (Regimen E. 20 patients); IFN-alpha 2A with bis-chloroethylnitrosourea (BCNU) (regimen F. 30 patients); and IFN-alpha 2A with the biochemical modulator. difluoromethylornithine (DFMO) (regimen G. 16 patients). The objective regression rates were as follows: A. 23%; B. 20%; C. 23%; D. 10%; E. 5%; F. 7%; G. 0%. Despite the higher response rate from regimen A. there appeared to be no survival advantage from any of these programs. The median time to progression was 1 month with a median survival time of 6 months. Most regressions involved soft tissue disease. were partial. and occurred within 2-3 months of treatment. Four patients received IFN for approximately 6 months and have manifested extraordinarily durable regressions of greater than 4+ years. The alpha-regimens produced a flu-type illness and anorexia which were dose-related. Leukopenia was most noteworthy with regimens containing gamma-interferon. Ongoing trials involving alternative and improved immune-related modalities are awaited with keen interest.
Antitumor activities of interferon alpha, beta, and gamma and their combinations on human melanoma cells in vitro: changes of proliferation, melanin synthesis, and immunophenotype, The antitumor activities of human interferon (IFN) alpha. beta. and gamma alone or in combination were studied on four human melanoma cell lines (StML-11. StML-12. StML-14. and SKMel-28) in various concentrations (1-50.000 IU/ml IFN alpha. 0.1-1000 IU/ml IFN beta. 1-10.000 IU/ml IFN gamma) in vitro. In all experiments IFN beta exhibited the most potent antiproliferative effect of all IFN tested. After 3 d of incubation a 50% growth inhibition was achieved with 20-40 IU/ml for natural IFN beta and with 600-1200 U/ml for recombinant IFN gamma. Substantially higher doses (7.000 to more than 50.000 IU/ml) of recombinant IFN alpha 2a were required to achieve a 50% growth inhibition. A strong synergistic antiproliferative activity resulted from the combination of IFN alpha with IFN gamma and IFN beta with IFN gamma. None of the IFN tested induced terminal differentiation of melanoma cells in vitro. The formation of dendrites was inhibited. and the portion of differentiated cells in vitro was reduced after treatment with IFN in comparison to the untreated controls (untreated controls: 100%; portion of differentiated cells after treatment with IFN alpha: 58%-74%. IFN beta: 48%-96%. IFN gamma: 10%-33%). The melanin synthesis was slightly elevated after treatment with IFN alpha (untreated controls: 100%; after treatment with IFN alpha: 103%-157%. ns.) and decreased significantly after treatment with IFN beta (49%-71%. p less than 0.05) as well as with IFN gamma (80%-88%. ns.). Cell surface markers were modulated varyingly by the IFN: HLA-I antigens were enhanced by all IFN. with IFN beta emerging as the most potent inducer. Only IFN gamma. however. induced a de novo expression of HLA-DR and -DQ antigens and increased the expression of the ICAM-1 molecule and of the melanoma progression marker A.1.43. Possibly. these findings indicate a biologically more aggressive phenotype of melanoma cells.
Correlation of the antiproliferative effect and the Mx-homologous protein induction by IFN in patients with malignant melanoma, The human interferon-induced intracellular protein homologous to the murine Mx-protein has recently been identified by means of a specific monoclonal antibody. Three of six melanoma cell lines elicited this intracellular human Mx-homolog upon incubation with IFN-alpha or IFN-gamma. yet all six melanoma cell lines tested were susceptible to the antiproliferative effect of IFN-alpha and IFN-gamma. Compared per antiviral unit. IFN-gamma had weaker Mx-inducing but stronger antiproliferative activity than IFN-alpha. These data suggest that the IFN-induced Mx-homologous protein is not involved in the antiproliferative action of IFN on malignant melanoma cell lines. Furthermore. 51 patients with advanced malignant melanoma were treated thrice weekly with 10 x 10(6) IU rIFN-alpha-2b and 6 x 10(6) nIFN-alpha. respectively. Nine of the 51 patients experienced systemic objective tumor responses (3 complete response. 6 partial response). but had Mx concentrations in their mononuclear cells equal to the Mx levels of non-responders during IFN-alpha therapy. Therefore. the level of Mx-homologous protein induced during IFN therapy is not a predictive marker for an antitumor response in malignant melanoma.
Immunologic effects of interferon, Interferons can be defined as a family of induced proteins sharing the capacity to exert pleiotropic effects on cell functions and to render cells resistant to virus infection. They are activating genes coding for a number of enzymes. most of which have not yet been characterized. and also by enhancing the synthesis of cell surface components. This enables interferons to modulate the immune response at different levels. This article will focus on the effects of interferon on antigen presentation. regulation of the immune response. activation of macrophage functions. and on its role in the pathogenesis of some diseases.
Human immunization with Pgh 3-2 gonococcal pilus results in cross-reactive antibody to the cyanogen bromide fragment-2 of pilin, In 1983. a gonococcal pilus vaccine failed to show protection in a large. placebo-controlled. double-blind field trial. The epitopic response to this vaccine was investigated in a random subgroup of 20 vaccine recipients. Using Western blot analysis of the immunizing pilus and its cyanogen bromide (CNBr) fragments. IgG antibody to pilin was detected before immunization in all individuals. Preexistent antibody to the CNBr-2 and CNBr-3 fragments of pilin was detected in 65% and 5% of individuals. respectively. Pilus immunization resulted in a vigorous response to the CNBr-2 fragment in 100% of the individuals tested; only 33% developed antibody to the CNBr-3 fragment. Absorptions of postimmunization sera with different gonococcal strains resulted in either complete or partial removal of antibody to the CNBr-2 fragment. In the context of an unsuccessful vaccine trial. these results suggest that antibody to the CNBr-2 fragment of pilin may not be protective.
Chemical synthesis and seroreactivity of a neoantigen containing the oligosaccharide hapten of the Mycobacterium tuberculosis-specific phenolic glycolipid, The report of a major triglycosyl phenol phthiocerol (phenolic) glycolipid in some strains of Mycobacterium tuberculosis that resembles the phenolic glycolipid I of Mycobacterium leprae raised the prospects of a specific serodiagnostic tool for human tuberculosis. The terminal diglycosyl unit of the M. tuberculosis product was synthesized and converted to a corresponding neoglycoprotein. the O-(2.3.4-tri-O-methyl-alpha-L-fucopyranosyl)-(1----3)-O-alpha-L- rhamnopyranosyl)-(1----9)-oxynonanoyl-bovine serum albumin. and applied. in ELISA. to sera from individuals with tuberculosis. Although the correlation coefficient between the synthetic product and the native glycolipid was excellent. the seroreactivity rate of tuberculous sera was disappointing; only 24 of 119 sera from tuberculosis patients showed evidence of anti-glycolipid antibodies. In isolates of M. tuberculosis from tuberculosis patients the glycolipid was present in only 1 of 11. A partially deglycosylated version was present in two other isolates; however. most isolates lacked the glycolipid. Accordingly. while the results. unlike those of others. do not portend a future for this form of serodiagnosis in the management of tuberculosis. they offer intriguing hints as to the basis of the variable immunogenicity and pathogenicity of strains of M. tuberculosis.
Rapid development of resistance to antifolates in vitro: possible clinical implication, Within three repeated 7-day incubation periods with either methotrexate (MTX) or trimetrexate (TMTX). human colon adenocarcinoma cells (HCT-8) developed high levels of resistance to these drugs. as evidenced by approximately 20- and 50-fold increases. respectively. in the median effective doses. Similarly. within six short-term exposures (4 hours) to the same drugs. a high degree of resistance developed in the cells. Alternating 4-hour treatment cycles with MTX and TMTX did not delay the onset of resistance to these antimetabolites in the HCT-8 cells. The same strategy produced no better results than giving either MTX or TMTX alone to (C57BL/6 x DBA/2)F1 mice bearing murine leukemia P388 cells. Furthermore. HCT-8 cells resistant to short-term (4-hour) exposure to MTX were cross-resistant to the same drug given for 7 days continuously. and cells resistant to MTX given continuously for 7 days were cross-resistant to the same drug given for 4 hours. Analogous results were obtained with TMTX. indicating that. under these circumstances. changing the schedule of administration of the same agent does not overcome resistance to it. The clinical relevance of these data to prolonged adjuvant chemotherapy. as well as loco-regional and continuous-infusion chemotherapy. is discussed.
Bronchial blood flow and eicosanoid blockade following airway acid aspiration, The systemic circulation to the lung is thought to be an important microvascular exchange region which may contribute to pulmonary edema resulting from airway injury. In a chronic sheep model. we have evaluated the flow through the bronchial artery after airway injury caused by the aspiration of 2.5 ml/kg of 0.1 N hydrochloric acid with and without inhibition of thromboxane synthetase and cyclooxygenase. Cyclooxygenase inhibition with ibuprofen resulted in no rise in bronchial artery blood flow associated with airway acid aspiration (9.8 +/- 1.72 ml/min to 63.7 +/- 8.9 ml/min in the control group versus 11.3 +/- 2.5 ml/min to 10.3 +/- 3.4 ml/min in the ibuprofen group). No difference in bronchial artery blood flow was noted between control acid aspiration and acid aspiration with thromboxane synthetase inhibition. Significant early reduction in lung lymph flow was noted in the cyclooxygenase inhibition group compared to control. These data suggest that inhibition of the cyclooxygenase pathway of eicosanoid production may lessen the injury caused by airway acid aspiration. The decrease in airway blood flow with associated reduction in lymph flow suggests that airway blood flow may be important in the generation of pulmonary edema in this model.
Daily chronic headache, Headache is a disabling condition. and medical science has not. until recently. begun to address it in a fashion consistent with its widespread impact. Despite the limitations in our current understanding. as well as the historical prejudice directed toward patients with this condition. current understanding and treatment approaches can provide hope and relief for most patients who have these disorders.
Pilot study of a household survey to determine HIV seroprevalence, A survey based on a probability sample of U.S. households was suggested as a method to determine the number of persons infected with human immunodeficiency virus (HIV). To test the feasibility of such a survey. CDC's National Center for Health Statistics (NCHS) recently conducted a pilot study in two sites through a contract with the Research Triangle Institute. The first field test. conducted in January 1989. used a random sample of adults from households in Allegheny County (Pittsburgh). Pennsylvania; the response rate of 81% suggested that the majority of the sample population might participate in a carefully planned household HIV survey. This report summarizes the second field test. which was conducted in Dallas County. Texas. from September through December 1989.
Health and nutritional status of Liberian refugee children--Guinea, 1990, Since December 1989. civil strife in Liberia has caused mass displacement of persons to neighboring Guinea and Ivory Coast (Figure 1). Liberian refugees initially settled in the Forest Region of Guinea and shared food and shelter with members of the same ethnic groups (mainly Gio and Mano) already residing in the area. The number of refugees overwhelmed the capacity of affected villages to provide basic needs. and camp-like settlements were established that received substantial external relief. In May 1990. to determine appropriate priorities for relief assistance. the health and nutritional status of Liberian refugees in the Forest Region of Guinea was assessed by CDC for the U.S. Department of State's Bureau for Refugee Programs. In May. an estimated 80.000 refugees were in the area; by December the number had increased to an estimated 400.000. This report summarizes findings of the health and nutritional assessment of Liberian refugee children.
Residential arrangements for adults with cerebral palsy--California, 1988, In the United States. an estimated 274.000 persons have cerebral palsy (CP). a neurologic condition defined as a group of nonprogressive disorders in which an abnormality of the central nervous system can result in motor dysfunction (e.g.. paresis. involuntary movement. and incoordination). CP is the third leading cause of the need for assistance with basic life activities and the fifth leading cause of activity limitation. An adult with CP may require adaptive housing to improve accessibility (e.g.. to entrances and toilet facilities). attendant care to assist with activities of daily living. and/or nursing care to meet specific health-care needs. These needs can be met through a variety of residential accommodations. However. because the residential environment has a considerable impact on well-being and quality of life. the accommodations should be in the least restrictive environment and. when possible. community-based. This report summarizes an assessment of characteristics of adults with CP to determine which factors are associated with placement in a more restrictive environment.
HIV antibody seroprevalence among childbearing women surveyed in Maryland, Because blood specimens from newborns reflect the antibody status of the mother. seroprevalence rates among childbearing women are obtainable from analysis of the specimens. A blinded survey of human immunodeficiency virus (HIV) antibody seroprevalence among childbearing women was conducted in Maryland. The survey used 31.273 dried filter paper blood spot specimens obtained from newborns screened for hereditary disorders. Overall. 99 specimens were positive on two enzyme-linked immunoassays and on Western blot. providing a seroprevalence rate of 0.32 percent. The rate for child-bearing women residing within the City of Baltimore. 0.7 percent. was significantly higher than the rate for those residing elsewhere in Maryland. 0.1 percent. The statewide rate for nonwhite women. 0.8 percent. was higher than for white women. 0.007 percent. No statistically significant associations were found with residence in an inner city area. as opposed to residence in other areas of the city; birth weight group; reported health of the infant; or the infant having received a transfusion.
National Health Interview Survey data on adult knowledge of AIDS in the United States, Information collected with the 1989 National Health Interview Survey of AIDS Knowledge and Attitudes from a nationally representative sample of 40.609 adults was examined to determine how knowledge about AIDS varied within demographic subgroups of the population. Most adults (83 percent) had seen or heard public service announcements about AIDS in the month prior to interview. and 51 percent had read an AIDS brochure in the past. Sixty-seven percent of adults responded correctly to at least 10 of 14 general AIDS knowledge questions. Knowledge levels were higher among those who were more educated and those who had seen or heard public service announcements or had read brochures. White adults responded correctly to these questions more often than their black counterparts; non-Hispanics responded correctly more often than Hispanics (for statistical purposes. the population is divided twice. in the first instance racially and in the second. ethnically--white and black. Hispanic and non-Hispanic). Even with relatively high information levels. misperceptions about casual transmission persisted. with one-third of adults answering more than half of the questions about casual transmission incorrectly. The same population groups that had less general AIDS knowledge had more misperceptions about transmission. More than 80 percent of adults recognized that use of condoms and a monogamous relationship between two uninfected persons were effective means of preventing the spread of the AIDS virus. Seventy-four percent of adults had heard of the HIV antibody test.
Cost estimates for statewide reporting of injuries by E coding hospital discharge abstract data base systems, A key element in the study of trauma problems is the design and development of adequate and affordable surveillance systems. One proposed method is the use of data available from hospital discharge abstract data base systems. However. surveillance systems based on existing data bases usually do not include codes that can identify the external causes of injuries. a critical limitation of the ability to determine the mechanisms of injuries. One obstacle to adding external cause of injury codes. known as E codes under the International Classification of Diseases. to uniform hospital discharge abstract data base systems is the cost of such a change. This study provided an estimate of the type and size of the costs for one State. based upon a survey of hospitals. information system vendors. and medical records experts. Two categories of the costs involved in adding E codes to hospital discharge abstract data base systems were identified. One-time implementation costs. which include modification of the computerized data base and the coding guidelines used by medical record personnel. average $600 per hospital. Annual costs resulting from increased operating expenses to include E codes average about $600 per hospital. because of the increased workload of coding and entry of the additional data. Adding E codes to hospital discharge abstract data base systems appears to be financially feasible for statewide surveillance of serious injury.
A study of the deficiencies in the condom-use skills of gay men, The use of condoms has been advocated as an important method of reducing the risk of AIDS for such people as gay men. prostitutes. IV drug users. adolescents. hemophiliacs. and others who may become infected with the human immunodeficiency virus (HIV) that causes AIDS. Although AIDS risk-reduction programs have provided information on condoms. none has assessed baseline or followup skills in their use. Because most condom failures have been attributed to errors in use. promoters of condom use should determine whether they are used correctly among those persons targeted for education. A total of 219 gay men entering an AIDS risk-reduction program were asked to demonstrate the use of condoms on a model. All errors made during the demonstration were corrected. and participants were trained during the exercise in the proper use of condoms. More than 80 percent required correction in such things as opening the package. determining the outside of the condom. unrolling the condom to the base of the penis. and expressing air from the space at the tip of the penis. Although proper use of condoms may seem obvious. this small study demonstrates that it must be taught. Since instructions found in condom packaging frequently are not easily understood by potential users. explicit instructions for condom use are needed.
An open, multicenter trial of recombinant tissue plasminogen activator in acute stroke. A progress report. The rt-PA Acute Stroke Study Group, Sixteen clinical centers in two countries have undertaken a prospective open angiography- and computed tomography scan-based safety and efficacy dose-rate finding study of recombinant (two-chain) tissue plasminogen activator (rt-PA) in acute thrombotic and thromboembolic stroke. Preliminary experience with 71 rt-PA treated patients in seven dose-rate groups has demonstrated both partial and complete recanalization. documented by angiography. although a dose response has not yet been achieved. Hemorrhagic infarction has been documented at all dose rates. and dose-rate independent cerebral hematomas have been observed. The study continues at higher dose rates while still remaining within the safety guidelines.
Production of transforming growth factor alpha by hamster eosinophils, Previously it was demonstrated that malignant transformation of the Syrian hamster cheek pouch mucosa is associated with the expression of TGF-alpha. Therefore in situ hybridization and immunohistochemistry was used to investigate the cellular sources of TGF-alpha production in this model system. Surprisingly one cell type in the inflammatory infiltrate present in the connective tissue adjacent to the transformed epithelium represented a major source of TGF-alpha mRNA. Detailed analysis of these cells revealed that they were eosinophils. In addition to TGF-alpha mRNA. about 40% of the eosinophils associated with the oral tumors exhibited TGF-alpha product reactive with a monoclonal antibody against the C terminus of the mature TGF-alpha peptide. Normal hamster bone marrow eosinophils also exhibited TGF-alpha mRNA and product by in situ hybridization and immunohistochemistry. These results suggest that the eosinophil represents a biologically significant source of TGF-alpha.
Safety and efficacy of oral flecainide therapy in patients with atrioventricular re-entrant tachycardia, OBJECTIVE: To assess the short- and long-term safety and efficacy of oral flecainide therapy in patients with symptomatic tachycardia and an extranodal accessory pathway. DESIGN: Open-label. uncontrolled trial with a mean follow-up of 24 months. SETTING: Referral-based. teaching medical center. PATIENTS: Sixty-three patients with symptomatic tachycardia and an extranodal accessory pathway. INTERVENTIONS: Patients had electrophysiologic testing before and after the initiation of oral flecainide therapy and were followed long-term for the presence of symptoms. new physical limitations. and adverse effects of therapy. MEASUREMENTS AND MAIN RESULTS: Flecainide therapy prevented or slowed (324 +/- 59 ms to 398 +/- 55 ms; P less than 0.001) inducible sustained atrioventricular reciprocating tachycardia in 44 of 63 patients (70%). Of the 44 patients discharged from the hospital. 33 (75%) have continued to receive flecainide therapy and have shown no adverse effects (mean follow-up. 24 +/- 10 months). Adverse cardiac reactions (proarrhythmia or sinus node suppression) attributable to flecainide occurred in 11 of 63 patients (17%); in 9 (82%) of these 11 patients. events were detected during either in-hospital monitoring or the electrophysiologic study done before discharge. Structural heart disease was detected by two-dimensional echocardiography in 8 of 11 patients who had adverse cardiac events and in 6 of 52 patients who did not have such events (P less than 0.001). Isoproterenol reversed the effects of flecainide therapy in 11 of 21 patients; 7 of the 11 patients had spontaneous clinical recurrences of tachycardia or palpitations during the follow-up period. but these symptoms occurred in only 1 of 10 patients who did not show isoproterenol-induced reversal (P = 0.02). CONCLUSIONS: Oral flecainide therapy was effective in 33 of 63 patients who had tachycardia and an extranodal accessory connection. Hospital monitoring during initial therapy is recommended. and flecainide should be used with caution. if at all. in patients with structural heart disease. An isoproterenol challenge appears to be helpful in predicting late recurrence of tachycardia.
Androgen replacement therapy in male patients with rheumatoid arthritis, A hypogonadic condition characterized by low serum testosterone levels has been identified in male patients with rheumatoid arthritis (RA). Seven men with active RA were treated daily for 6 months with oral testosterone undecanoate plus a nonsteroidal antiinflammatory drug in an attempt to evaluate the immunologic response. the overall clinical response. and the sex hormone response to such replacement therapy. At the end of the 6 months. there was a significant increase in serum testosterone levels (P less than 0.05). an increase in the number of CD8+ T cells. and a decrease in the CD4+:CD8+ T cell ratio. The IgM rheumatoid factor concentration decreased significantly (P less than 0.05). There was a concurrent significant reduction in the number of affected joints (P less than 0.05) and in the daily intake of nonsteroidal antiinflammatory drugs (P less than 0.01). The well-known immunosuppressive action of androgens probably contributed to our findings in these RA patients.
Prognostic significance of anticentromere antibodies and anti-topoisomerase I antibodies in Raynaud's disease. A prospective study, Seventy-seven patients with Raynaud's disease were studied for a mean of 4 years (range 1-11 years) to determine the relationship between autoantibodies and long-term clinical outcome. Anticentromere antibodies (ACA) were assayed by indirect immunofluorescence and by immunoblotting of HeLa cell chromosome extracts. Antibodies to topoisomerase I (anti-topo I) were assayed by immunodiffusion and immunoblotting. Antibodies to the major centromeric protein. CENP-B. and anti-topo I were studied by enzyme-linked immunosorbent assay (ELISA). Eight patients developed telangiectasias. 4 developed skin tightening. and 4 developed a connective tissue disease other than scleroderma. The presence of ACA at the start of the study was associated with the development of telangiectasias (P less than 0.003). An initial 100-kd band on immunoblot in conjunction with a positive anti-topo I ELISA result was associated with the development of tight skin (P less than 0.0025). while a 100-kd band with a negative anti-topo I ELISA result was associated with the subsequent development of a connective tissue disease other than scleroderma (P less than 0.0073). Patients who were initially ACA positive. had the 100-kd band on immunoblot. or had positive ELISA results for anti-topo I or for anti-CENP-B were 63-fold more likely to develop signs of connective tissue disease by the end of the study (P less than 0.000009). The presence of any of these autoantibodies was more sensitive (100%). although less specific (75%). than were findings from nailfold capillaroscopy (sensitivity 67% and specificity 95%) in predicting subsequent clinical progression. We conclude that findings of assays for anti-topo I and ACA complement the findings from nailfold capillaroscopy in providing useful prognostic information in Raynaud's disease.
Performance characteristics of a novel immunoassay based on hybrid Ty virus-like particles (Ty-VLPs): rapid differentiation between HIV-1 and HIV-2 infection, Recombinant antigens containing all or parts of the HIV-1 proteins p24. Nef and gp41 and HIV-2 gp36 have been purified and used to develop a rapid immunoassay to detect and differentiate between HIV-1 and HIV-2 antibodies in a single test. The antigens were produced as particulate fusion proteins by exploiting the ability of a protein encoded by the yeast retrotransposon Ty to assemble into virus-like particles (Ty-VLPs). Hybrid HIV: Ty-VLPs carrying each of the antigens were applied to nitrocellulose strips at specified locations in a slot-blot format and then used to detect antibodies present in human serum and plasma samples of diverse geographical origin. Previously confirmed HIV-1- and HIV-2-positive samples were readily and reliably identified. The assay was used to identify a case of HIV-2 infection in an African woman who had been resident in the Oxford region for the last 3 years and to analyse the prevalence of anti-HIV antibodies in a longitudinal study of seroconverting patients. We also demonstrate that the assay works efficiently with whole blood.
Successful use of pooled sera to determine HIV-1 seroprevalence in Zaire with development of cost-efficiency models, To determine the accuracy and cost efficiency of pooling sera prior to HIV-1 testing. sera from 8.000 Kinshasa factory workers and their spouses were screened individually (2.44% seropositive) and in 800 pools of 10 sera each. There were no false-negative or false-positive pools. resulting in a calculated seroprevalence estimate of 2.42%. Further testing of all sera in positive pools can identify HIV-positive individuals. These applications were modeled to compare the cost-efficiency of pooling with individual testing under different conditions. The results suggest that pooling provides an alternative test format for use in both developing and industrialized countries when the seroprevalence and/or the marginal cost of obtaining a sample are sufficiently low. For our cohort. testing only the pools for seroprevalence estimation resulted in a 78% cost saving compared with individual testing; pooling with subsequent identification of individual seropositives represented a 56% cost reduction.
Syncytium induction by fresh HIV isolates: quantitative analysis using a transactivation beta-gal assay, We used a quantitative bioassay (the beta-gal assay) to visualize and quantify syncytium induction by fresh HIV isolates. This bioassay is based on the transactivation by tat of a chimeric gene comprising an HIV-1 long terminal repeat (LTR) fused to a modified lacZ gene of Escherichia coli. The chimeric gene encodes a beta-galactosidase which is translocated to the nucleus. It allows the enzymatic staining of all nuclei from HIV-induced syncytia. Using this unequivocal assay (the beta-gal assay). we could assess the syncytium-inducing properties of fresh HIV isolates after only 4 days of coculture of patient lymphocytes with activated normal lymphocytes. Syncytium-inducing HIV isolates were detected in 11 out of 40 seropositive patients studied. They were isolated mainly from AIDS patients: eight out of 17 grade IV (according to Centers for Disease Control criteria) patients were infected with syncytium-inducing strains. However. of 23 grade II and III patients tested. syncytium-inducing HIV strains were isolated from three cases. These three patients displayed no detectable p24 antigenaemia and had a CD4+ cell count of greater than 300 cells/microliter. The in vitro replication rate of HIV grown from 36 patient blood samples was then examined by sequential p24 antigen measurements in coculture supernatants. The 10 samples leading to syncytium formation also exhibited the highest replication rate. The possibility of unequivocally detecting syncytium-inducing strains after only a few days of coculture will make this detection routine and rapid. In addition. the limited period of amplification required is a significant advantage as it minimizes the emergence of HIV variants selected during long-term in vitro cultures.
Renal effects of atrial natriuretic peptide during dopamine infusion, To study whether the renal effects of atrial natriuretic peptide (ANP) are different from those of dopamine. we compared the effects of dopamine and dopamine plus ANP on renal circulation. Dopamine was infused at 1 microgram/kg/min for 120 min into 7 patients with essential hypertension (EH) and 5 normotensive subjects (NT). After 40 min of dopamine infusion. ANP infusion at 25 ng/kg/min was added to dopamine for 40 min. Before. during and after the infusion. renal function and nephrogenous cGMP were determined. Dopamine did not influence blood pressure. but increased urinary Na excretion (UNaV) by 100% in EH and NT. Addition of ANP further increased UNaV by 90%. but increases in UNaV were greater in EH than in NT. Renal blood flow was increased only by dopamine. while glomerular filtration rate (GFR) was increased by both dopamine (+8%) and dopamine plus ANP (+7%) as a whole. resulting in a significant increase in filtration fraction by the addition of ANP. Plasma and urinary cGMP and nephrogenous cGMP were elevated only during ANP infusion. These results suggest that the effects of ANP and dopamine on both GFR and UNaV were additive. However. in contrast with dopamine. ANP increased efferent resistance and nephrogenous cGMP. suggesting that the renal effects of ANP are different from those of dopamine.
T-cell receptor delta gene recombination in common acute lymphoblastic leukemia: preferential usage of V delta 2 and frequent involvement of the J alpha cluster, A high frequency (greater than 80%) of acute lymphoblastic leukemias (ALL) exhibit a recombination of the T-cell receptor (TCR) delta chain locus. Interestingly. distinct TCR delta elements are preferentially used in immunologic subtypes. In a recent series of 201 children with common ALL (cALL) we observed a TCR delta rearrangement in 162 patients. 57% of the latter showing a hybridization pattern in Southern blots suggestive of a V delta 2 to D delta 3 recombination. To verify this interpretation and to elucidate in more detail the diversity of this common type of TCR delta recombination we amplified and sequenced the junctional region of nine cALL patients and cell line REH-6 by polymerase chain reaction (PCR). A V delta 2 D delta 3 recombination was confirmed in all cases; convincing evidence for the participation of D delta 1 or D delta 2 elements was not obtained. Eight of nine patients and REH-6 showed complete 5' D delta 3 boundaries within V delta 2 D delta 3 segments. a limitation of junctional diversity also detected in 50% of peripheral blood cell clones derived from two healthy probands. Notably. sequence identity at the V delta 2 D delta 3 junction was demonstrated for a cALL and one of the control clones. Another group of 35 of 162 cALL patients was characterized by V delta 2 rearrangements and biallelic deletion of J delta and C delta sequences. Using a J alpha consensus primer. PCR-directed sequence analysis demonstrated V delta 2 D delta 3 J alpha recombinations in all four cases analyzed by this approach. The J alpha segments of these patients differed. but were identical or homologous to published J alpha elements. Our data suggest a recombination pathway of the TCR delta/alpha locus leading to chimeric TCR alpha molecules. containing V delta and. remarkably. also D delta sequences.
The dyad symmetry element is the molecular target for c-fos induction and inhibition during K 562 differentiation along mutually exclusive lineages, The c-fos proto-oncogene seems to play an important role during differentiation and activation of cells from the hematopoietic lineage. Therefore. it is of interest to investigate the mechanism underlying its transcriptional activation in these cells. To delineate the sequences and factors involved in c-fos transcriptional activation during the course of myeloid cell differentiation. we have used the K 562 chronic leukemic cell line as a model. K 562 cells were transfected with chloramphenicol transacetylase (CAT) reporter constructs. including various regions of the human c-fos promoter. and induced to differentiate by two distinct agents: 12-O-tetradecanoyl phorbol-13-acetate (TPA). which activates a differentiation program along the megakaryoblastic pathway; and hemin. which induces erythroid differentiation. We show here that TPA treatment of K 562 cells induces fos CAT reporter constructs activation. whereas treatment with hemin does not. Furthermore. predifferentiation of the cells with hemin blocks a subsequent induction by TPA. in correlation with the inhibition by hemin of megakaryoblastic differentiation markers appearance. Both the induction by TPA and the inhibition by hemin are mediated by a dyad symmetry element (DSE) located in the upstream regulatory region. between -318 and -296. These results suggest that the protein complex binding to the DSE regulatory element is the target for c-fos activation by TPA and inhibition by hemin in K 562 cells. However. no modulation of protein affinity for the DSE sequence was detected by gel shift assay during the course of induction or inhibition. suggesting that the structural change responsible for the transcriptional modulation is too unstable or too subtle to be detected by this method.
FDP D-dimer induces the secretion of interleukin-1, urokinase-type plasminogen activator, and plasminogen activator inhibitor-2 in a human promonocytic leukemia cell line, We studied the effect of fibrinogen degradation products D. E. and D-dimer on a human promonocytic leukemia cell line. NOMO-1. After exposure to a 10(-5)-mol/L fragment D or D-dimer. the cells displayed macrophage-like characteristics. such as adherence to plastic surfaces. and showed approximately a twofold increase in response to the nitroblue tetrazolium reduction test. The secretion of interleukin-1 alpha (IL-1 alpha) into the medium was markedly stimulated by a 10(-5)-mol/L fragment D. E. and D-dimer. whereas a significant increase in IL-1 beta secretion was observed only in D-dimer-stimulated cells. In addition. D-dimer induced a rapid increase in urokinase-type plasminogen activator on day 1 (0.52 +/- 0.02 ng/mL v 0.07 +/- 0.01 ng/mL in the control culture) and a slow increase in plasminogen activator inhibitor-2 on day 5 (3.9 +/- 1.6 ng/mL v 1.2 +/- 0.2 ng/mL in the control culture). An increase in tissue factor (TF) was also demonstrated on the cell surface of NOMO-1 cells exposed to fragment D or D-dimer by indirect immunofluorescence using an anti-TF monoclonal antibody. Scatchard plot analysis showed that fragment D and D-dimer bound to the NOMO-1 cells with a kd of 3.3 nmol/L and 2.7 nmol/L. respectively. These results suggest that fragment D-dimer specifically stimulates cells of monocyte-macrophage lineage to secrete key substances that regulate blood coagulation. fibrinolysis. and inflammation.
Flecainide acetate prevents recurrence of symptomatic paroxysmal supraventricular tachycardia. The Flecainide Supraventricular Tachycardia Study Group, Oral flecainide acetate was administered to 34 patients with documented symptomatic paroxysmal supraventricular tachycardia (PSVT) with a double-blind. placebo-controlled. 8-week crossover trial design. PSVT was defined as a regular tachycardia of at least 120 beats/min without evidence of atrioventricular dissociation. The study required considerable patient cooperation. Patients first entered a 4-week qualifying phase followed by a 3-week. open label. flecainide dose-ranging phase. They were then randomized in a blind fashion to receive either placebo or tolerated flecainide dose for an 8-week treatment period and then crossed over after four symptomatic documented episodes of PSVT or at the end of the treatment period. By all efficacy parameters analyzed. flecainide was superior to placebo. Flecainide was associated with an actuarial 79% freedom from symptomatic PSVT events compared with only 15% on placebo at 60 days (p less than 0.001). Of the 34 patients. 29 had recurrence of symptomatic PSVT at least once during the placebo phase; only eight patients had a recurrence during the flecainide phase (p less than 0.001). The median time to the first symptomatic PSVT event was 11 days in the placebo group and greater than 55 days in the flecainide group (p less than 0.001). Likewise. the interval between attacks was a median of 12 days on placebo compared with more than 55 days on flecainide (p less than 0.001). Finally. the flecainide slowed symptomatic PSVT heart rates to 143 +/- 12 beats/min from 178 +/- 12 on placebo (p less than 0.02) in the seven patients who had events in the placebo and flecainide treatment phases.
Racial differences in responses to thrombolytic therapy with recombinant tissue-type plasminogen activator. Increased fibrin(ogen)olysis in blacks. The Thrombolysis and Angioplasty in Myocardial Infarction Study Group, To determine whether there are differences in responses to thrombolytic therapy in certain populations. the data for the Thrombolysis and Angioplasty in Myocardial Infarction (phase 1) study were analyzed for black and white patients. Baseline variables including risk factors and extent of coronary artery disease were similar in the 352 white and 24 black patients. The time from onset of chest pain to recombinant tissue-type plasminogen activator (rt-PA) therapy and rt-PA dosing regimens were the same in the two groups. The patency rate of the infarct-related artery at 90 minutes was 91% for blacks and was 72% for whites (p = 0.051). Blacks displayed significantly lower nadir fibrinogen levels (0.57 +/- 0.62 versus 1.3 +/- 0.76 g/l. p less than 0.0001). greater delta fibrinogen (baseline-nadir) (2.7 +/- 1.1 versus 1.7 +/- 1.1 g/l. p less than 0.0001). and increased peak levels of fibrin(ogen) degradation products (837 +/- 865 versus 245 +/- 475 micrograms/ml. p less than 0.0001). rt-PA antigen levels tended to be higher in blacks than in whites (2.8 +/- 2.2 versus 2.2 +/- 3.2 micrograms/ml [p = 0.10] at the peak and 1.6 +/- 1.3 versus 0.99 +/- 1.4 micrograms/ml [p = 0.06] at the end of the maintenance infusion). Major clinical outcomes including survival until time of hospital discharge (92% black versus 93% white. p = 0.68) were not significantly different. However. despite undergoing fewer angioplasty procedures (25% versus 46.3%. p = 0.047). blacks received more transfusions (58.8% versus 19.5% were administered greater than or equal to 2 units packed erythrocytes. p = 0.001).
Expression and distribution of atrial natriuretic peptide in human hypertrophic ventricle of hypertensive hearts and hearts with hypertrophic cardiomyopathy, To investigate the ventricular expression of atrial natriuretic peptide (ANP) in human hypertrophic hearts. we conducted an immunohistochemical study of 130 endomyocardial biopsy specimens obtained from the right side of the ventricular septum (RVB). left ventricular free wall (LVB). or both from a total of 80 patients: 44 patients with hypertrophic cardiomyopathy (HCM). 14 with apical hypertrophic cardiomyopathy (APH). 13 with hypertensive hearts (HHD). and nine without hypertrophy (controls). No patients had apparent congestive heart failure. ANP was not seen in ventricular myocytes in controls but was identified in biopsy specimens of hypertrophic hearts. and its distribution was characteristic in each hypertrophic group: 15 RVB (37%) and two LVB (7%) of the HCM group. one RVB (7%) and two LVB (18%) of the APH group. and zero RVB (0%) and five LVB (46%) of the HHD group. Clinical data (including echocardiographic. hemodynamic. and angiographic data) were not directly related to ventricular ANP expression in HCM. APH. or HHD with one exception. In HHD patients. LVB specimens with ANP showed greater ventricular wall thickness than LVB specimens without ANP. According to histological data. however. the ANP-present RVB specimens of HCM or ANP-present LVB specimens of HHD had greater myocyte size than did the ANP-absent specimens. In addition. in HCM patients. the ANP-present RVB specimens showed more severe fibrosis and myofiber disarray than did the ANP-absent specimens. We conclude that a failing state and hemodynamic overload are not likely to be indispensable for ANP expression in human hypertrophic ventricles and that ventricular ANP expression occurs as a response to disease-specific changes: hemodynamic overload in HHD and histological changes such as myocardial fiber disarray. hypertrophy of myocytes. and fibrosis in HCM. which may reflect the characteristic distribution of intraventricular ANP.
Mechanisms involved in the response to prolonged infusion of atrial natriuretic factor in patients with chronic heart failure, We examined the mechanisms involved in the cardiovascular and renal response to prolonged infusion of atrial natriuretic factor (ANF) in patients with chronic heart failure. ANF infusion was titrated to produce a 30% decrease in pulmonary capillary wedge pressure or a 20% increase in cardiac output. and this dose (average. 75 +/- 4 ng/kg/min) was then administered for 20 hours. The short-term response to ANF included significant reductions in central filling pressures. increases in cardiac output. modest increases in diuresis and glomerular filtration rates. significant reduction in plasma aldosterone levels. and a 3.6-fold increase in plasma cyclic GMP levels. During prolonged infusion. plasma cGMP levels and cardiac output gradually returned to baseline. Similarly. the initially increased diuretic effects were completely abolished during prolonged ANF infusion. although plasma alpha-hANF levels remained consistently elevated above baseline values (control. 198 +/- 38; titration. 2.760 +/- 596; 20 hours. 3.499 +/- 659 pg/ml). Four hours after beginning the ANF infusion. marked increases in hematocrit levels were noted (42.5 +/- 1.0% versus 45.3 +/- 1.4%. control and infusion. respectively. p less than 0.05); during this time. no change in total plasma protein concentration occurred. indicating extravascular shift of fluid and plasma proteins. No evidence was noted for activation of vasoconstrictor hormones during prolonged ANF infusion. although mean arterial pressure was significantly reduced throughout the infusion period. Plasma pro-ANF (31-67) levels. determined as a marker for endogenous ANF secretion. were significantly suppressed as were the reductions of central filling pressures. After ANF discontinuation. heart rate and pulmonary capillary wedge pressure increased significantly above baseline values without evidence for sympathetic stimulation. We conclude that 1) prolonged infusion of ANF causes only transient increases in plasma cGMP levels but a sustained reduction of the cardiac release of ANF and that 2) the beneficial hemodynamic effects of ANF. that is. unloading of the ventricles. may be associated with or. in part. may be secondary to a shift of plasma constituents into the extravascular space. The latter may limit the therapeutic potential of ANF for long-term treatment.
Radiation therapy to prevent heterotopic ossification after cementless total hip arthroplasty, Clinical and roentgenographic observations on a postoperative low-dose radiation of 1000 cGy for prevention of heterotopic ossification in high-risk patients after 48 noncemented total hip arthroplasties demonstrated no overall statistical difference in the Harris hip scores between the treated group (92.2) and the control group (91.0). There was no difference in the incidence of radiolucent lines about the components. and there were no revisions for aseptic loosening in the treated group. The incidence of clinically significant (Brooker Grades III and IV) heterotopic bone formation was lower in the treated group (7%) than in the control group (32%). This difference in the incidence of heterotopic bone formation was statistically significant. Radiation therapy was effective in preventing postoperative heterotopic bone formation in biologically fixed total hip implants.
Drug-resistant tuberculosis after gastrectomy. Double jeopardy, Although an increased incidence of Mycobacterium tuberculosis infection is found in patients after subtotal gastrectomy. to my knowledge. the potential for gastrectomy to alter the course and outcome of typical mycobacterial disease has not been noted. I report the case of a patient who developed tuberculosis after a Billroth II subtotal gastrectomy. malabsorbed his antibiotics. and subsequently manifested infection with a drug-resistant strain of M tuberculosis. Altered drug pharmacokinetics should be considered as an important metabolic consequence of subtotal gastrectomy.
Bronchoscopy with bronchoalveolar lavage in tuberculosis and fungal infections, STUDY OBJECTIVE: To determine the utility of bronchoscopy with bronchoalveolar lavage for diagnosing M tuberculosis and fungal infections. DESIGN: Retrospective review of patients over a six-year period. SETTING: In- and outpatients of one University hospital and affiliated Veterans Administration Medical Center. PATIENTS: Those who were subsequently found to have either M tuberculosis or fungal infections. INTERVENTIONS: Bronchoscopy with bronchoalveolar lavage specimens were compared to prebronchoscopy sputum. when available. Specimens were sent for smear and culture for both acid-fast bacilli and fungi. In the case of lavage. an aliquot also was studied for cellular differential. MEASUREMENTS AND RESULTS: For TB. sputum was smear-positive in 6/47 (34 percent) and culture positive in 24/47 (51 percent). while bronchoscopy was smear positive in 34/50 (68 percent) and culture positive in 46/50 (92 percent). For fungal infections. no sputum was smear-positive and only 1/22 (5 percent) was sputum culture-positive. while bronchoscopy was smear-positive in 14/41 (34 percent) and culture positive in 35/41 (85 percent). Bronchoscopy washings and BAL provided complementary specimens. Eighty-three patients had adequate lavages and the cellularity was significantly different from controls (lymphocytes: TB 18 +/- 11.2 percent [mean +/- SD]; fungal: 13 +/- 11.1 percent; controls 6 +/- 3.1 percent; p less than 0.001; neutrophils: TB 9 +/- 11.5 percent; fungal: 6 +/- 9.1 percent controls: 2 +/- 1.5 percent. p less than 0.01); however. there was overlap and no pattern was characteristic for TB or fungal infections. CONCLUSION: Bronchoscopy with BAL is useful in diagnosing tuberculosis and fungal infections.
Different hepatobiliary effects of oral and transdermal estradiol in postmenopausal women, Estrogen-replacement therapy is important for the prevention of postmenopausal osteoporosis. However. oral synthetic and conjugated estrogens increase biliary cholesterol saturation index and risk of gallstone disease. To examine whether transdermal estrogen administration could avoid these adverse effects. 17 postmenopausal women were treated with transdermal estradiol (Estraderm TTS; Ciba-Geigy. Arnhem. The Netherlands). 100 micrograms/day for 4 weeks. and after 1 month without therapy. with oral estradiol (Progynova; Schering. Weesp. The Netherlands). 2 mg/day for 4 weeks. The increase in the serum estradiol level was much higher during transdermal than oral estradiol administration. On the contrary. the increase in the serum estrone level was much more pronounced during oral treatment. Both modes of treatment led to a similar reduction of urinary calcium excretion. A highly significant decrease in serum phosphate levels was found during transdermal therapy. Biliary cholesterol saturation index did not change during transdermal therapy (mean +/- SEM. 1.25 +/- 0.06 before and 1.22 +/- 0.07 at the end of transdermal therapy; P = NS). A slight increase in cholesterol saturation index that did not reach statistical significance was found during oral therapy (1.28 +/- 0.09 before and 1.36 +/- 0.09 during oral treatment). However. the subgroup of women with strong increases in serum estrone levels during oral estradiol therapy (greater than 0.5 pmol/mL; n = 8) generally had increased biliary cholesterol saturation index. a decrease in relative percentage chenodeoxycholic acid in bile. and increased serum sex hormone-binding globulin levels during oral treatment. Cholesterol monohydrate crystals were never found in duodenal biles during either treatment. This study indicates that transdermal estradiol does not induce lithogenic bile. On the contrary. oral estradiol leads to lithogenic bile in a subgroup of women with strong increases in serum estrone levels during oral treatment.
Ventilatory responses to chemoreceptor stimulation after hypoxic acclimatization in awake goats, Our objective was to test the hypothesis that exposure to prolonged hypoxia results in altered responsiveness to chemoreceptor stimulation. Acclimatization to hypoxia occurs rapidly in the awake goat relative to other species. We tested the sensitivity of the central and peripheral chemoreceptors to chemical stimuli before and after 4 h of either isocapnic or poikilocapnic hypoxia (arterial PO2 40 Torr). We confirmed that arterial PCO2 decreased progressively. reaching a stable value after 4 h of hypoxic exposure (poikilocapnic group). In the isocapnic group. inspired minute ventilation increased over the same time course. Thus. acclimatization occurred in both groups. In goats. isocapnic hypoxia did not result in hyperventilation on return to normoxia. whereas poikilocapnic hypoxia did cause hyperventilation. indicating a different mechanism for acclimatization and the persistent hyperventilation on return to normoxia. Goats exposed to isocapnic hypoxia exhibited an increased slope of the CO2 response curve. Goats exposed to poikilocapnic hypoxia had no increase in slope but did exhibit a parallel leftward shift of the CO2 response curve. Neither group exhibited a significant change in response to bolus NaCN injections or dopamine infusions after prolonged hypoxia. However. both groups demonstrated a similar significant increase in the ventilatory response to subsequent acute exposure to isocapnic hypoxia. The increase in hypoxic ventilatory sensitivity. which was not dependent on the modality of hypoxic exposure (isocapnic vs. poikilocapnic). reinforces the key role of the carotid chemoreceptors in ventilatory acclimatization to hypoxia.
GABA antagonism reverses hypoxic respiratory depression in the cat, We assessed the role of gamma-aminobutyric acid (GABA) as a potential causative agent of hypoxic respiratory depression by monitoring the response of the phrenic neurogram to systemic infusion of the GABA antagonist bicuculline (0.01 mg.kg-1.min-1) under control conditions and during isocapnic brain hypoxia produced by CO inhalation in separate groups of anesthetized. glomectomized. vagotomized. paralyzed. and ventilated cats with blood pressure held constant. The maximum effect of bicuculline in subseizure doses in control cats was to increase minute phrenic activity to 151 +/- 14% of preinfusion values. Infusion was continued until seizure activity was seen in the electroencephalogram. A 53% decrease of arterial O2 content resulted in a marked reduction of both peak phrenic amplitude and phrenic firing frequency to 16 and 64% of control values. respectively. Infusion of bicuculline while the level of hypoxia was maintained constant restored both peak phrenic amplitude and phrenic firing frequency to prehypoxic levels. The maximum effect of bicuculline was to increase minute phrenic activity to 123 +/- 13% of the prehypoxic value. These results suggest that although GABA has only a modest role in determining the output of the control phrenic neurogram. a significant portion of the phrenic depression that occurs during hypoxia can be attributed to inhibition of respiratory neurons by GABA.
Effect of LY171883 on endotoxin-induced lung injury in pigs, We evaluated the role of sulfidopeptide leukotrienes as mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of LY171883. a specific leukotriene D4 (LTD4)/LTE4 receptor antagonist. Endotoxin caused hemoconcentration. granulocytopenia. decreased cardiac index. systemic hypotension. pulmonary hypertension. increased pulmonary vascular resistance. bronchoconstriction. hypoxemia. increased permeability of the alveolar-capillary membrane. pulmonary edema. and increased plasma concentrations of thromboxane B2 (TxB2). prostaglandin F2 alpha (PGF2 alpha). and 6-keto-PGF1 alpha. LY171883 did not modify endotoxin-induced cardiopulmonary and hematologic abnormalities. except for a modest attenuation of pulmonary hypertension (at 1 h) and increased pulmonary vascular resistance (at 1-2 h). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2. PGF2 alpha. and LTB4. These increases were not significantly modified in blood derived from pigs treated with LY171883. indicating no inhibition of cyclooxygenase or 5-lipoxygenase. We conclude that LTD4 and LTE4 are not important mediators of endotoxin-induced lung injury in anesthetized pigs. although they may contribute modestly to pulmonary vasoconstriction.
Ca2(+)-sensitive binding of thrombospondin to U937 cells is due to the formation of calcium precipitate in the binding medium, Thrombospondin (TSP) binds to U937 monocytic cells in a Ca2(+)-enhancible and EDTA-inhibitable manner (Silverstein. R. L.. and R. L. Nachman. 1987. J. Clin. Invest. 79:867-874; Silverstein. R. L.. A. S. Asch. and R. L. Nachman. 1989. J. Clin. Invest. 84:546-552). We reproduced the results when RPMI cell culture medium. but not when HBSS was used as binding medium. Addition of 1 mM Ca2+ to RPMI medium increased the binding of TSP to suspended U937 cells more than eightfold; the increase was blocked by EDTA but not by heparin. Further studies showed that addition of 1 mM Ca2+ to RPMI medium resulted in an insoluble precipitate. which did not form when EDTA was present or when 1 mM extra Ca2+ was added to HBSS. TSP bound to the precipitate in a saturable and specific manner. The precipitate enhanced binding of TSP to MG63 osteosarcoma cells in a monolayer binding assay. Enhancement of binding in the monolayer assay was observed for fibronectin and vitronectin as well. Our data indicate that there is not a specific Ca2(+)-dependent TSP receptor on U937 cell surface. Instead. the extra binding enhanced by Ca2+ is due to the formation of insoluble salts in the medium.
Bone matrix constituents stimulate interleukin-1 release from human blood mononuclear cells, To test the hypothesis that mononuclear cells are stimulated to release interleukin 1 (IL-1) by bone fragments released in the bone microenvironment during the remodeling cycle. we have investigated the effects of bone matrix and some of its constituents on IL-1 secretin from peripheral blood mononuclear cells (PBMC). Increases in IL-1 activity were observed when either PBMC or adherent monocytes. but not lymphocytes depleted of monocytes. were co-cultured with either human or rat bone particles but not with latex particles of similar size. Co-culture of PBMC with bone particles in a transwell system where the cells were physically separated from the bone particles. or with osteoblast- or osteoclast-covered bone particles. did not stimulate IL-1 release. indicating that a physical contact between PBMC and the bone surface is required for eliciting IL-1 release. This was confirmed by the finding of a lower stimulatory effect of bone particles pretreated with etidronate. a bisphosphonate which decreases the bone binding capacity of PBMC. Constituents of bone matrix. such as collagen fragments. hydroxyproline. and. to a lesser extent. transforming growth factor-beta. but not osteocalcin. alpha 2HS glycoprotein. fragments of either bone sialoprotein or osteopontin. and fibronectin. stimulated PBMC IL-1 release in a dose-dependent fashion. Collagen-stimulated IL-1 release was partially and specifically inhibited by a monoclonal antibody directed against the alpha 2 beta 1-integrin cell surface collagen receptor. These data demonstrate that products of bone resorption. known to be chemotactic for mononuclear cells. stimulate PBMC IL-1 activity. These findings may help explain previous documentation of increased IL-1 secretion by circulating monocytes obtained from patients with high turnover osteoporosis.
Lack of HLA class I antigen expression by cultured melanoma cells FO-1 due to a defect in B2m gene expression, The melanoma cell line FO-1 does not express HLA class I antigens and does not acquire them on the cell surface after incubation with IFN-gamma. Immunochemical studies showed that FO-1 cells synthesize HLA class I heavy chain. but do not synthesize beta 2-microglobulin (beta 2-mu). The latter abnormality is associated with lack of beta 2-mu mRNA which remains undetectable in FO-1 cells incubated with IFN-gamma. The defect was identified as a genetic lesion in the B2m gene. since DNA hybridization analysis detected a deletion of the first exon of the 5'-flanking region. and of a segment of the first intron of the B2m gene. HLA class I antigen expression was reconstituted on melanoma cells FO-1 after transfection with the wild-type mouse B2m gene. thereby confirming the abnormality of the endogenous B2m gene. The defect identified in FO-1 cells is distinct from that underlying the lack of HLA class I antigen expression by lymphoblastoid cells Daudi. but is remarkably similar to that causing lack of H-2 class I antigen expression by mouse lymphoblastoid cells R1 (TL-). These results suggest that genetic recombination in the 5' region of the B2m gene is a recurrent mechanism in B2m gene defects. In addition to contributing to our understanding of molecular abnormalities in HLA class I antigen expression by melanoma cells. FO-1 cells represent a useful model for analyzing the role of HLA class I antigens in the biology of melanoma cells and in their interaction with cells of the immune system.
Decreased Gs alpha mRNA levels accompany the fall in Gs and adenylyl cyclase activities in compensated left ventricular hypertrophy. In heart failure, only the impairment in adenylyl cyclase activation progresses, We have previously reported that there is a global reduction in adenylyl cyclase associated with a decrement in Gs functional activity in cardiac sarcolemma from animals with pressure overload-induced hypertrophy and heart failure. This study was performed to determine whether hypertrophy alone in the absence of heart failure is sufficient to promote these changes and whether the superimposition of heart failure intensified these changes. Basal and stimulated adenylyl cyclase and Gs activity. as determined in the S49 cyc- reconstitution assay. were measured in sarcolemma from normal (NL). left ventricular hypertrophy (LVH) and heart failure (HF) animals. Simultaneously. we measured the mRNA level encoding for the Gs alpha subunit. These studies indicate that Gs activity and Gs alpha mRNA are decreased by approximately 30% both in the failing heart and even in the heart with compensated hypertrophy before heart failure develops (Gs activity. pmol cyclic AMP/10 min per microgram. NL 4.2 +/- 0.4. LVH 3.0 +/- 0.2. HF 3.2 +/- 0.3; Gs alpha mRNA. pg/10 micrograms RNA. NL 131 +/- 9.0. LVH 104 +/- 7.4. HF 97.4 +/- 9.1; P less than 0.05 as compared with NL for LVH and HF). Accompanying this decrement in Gs activity is a fall in adenylyl cyclase. both basal and stimulated. However. we also identified a further decrease in adenylyl cyclase without any additional change in Gs or in its alpha subunit mRNA level. This is seen only in the sarcolemma from animals with heart failure as compared with those with compensated LV hypertrophy (e.g.. NaF-stimulated activity. pmol cyclic AMP/min per mg. NL 420.2 +/- 17.5. LVH 347.1 +/- 29.6. HF 244.2 +/- 27.3; P less than 0.05 compared with NL for LVH and HF. P less than 0.05 compared with LVH for HF). In summary. these studies indicate that both Gs and adenylyl cyclase activities fall in parallel with the development of LV hypertrophy followed by a further decrement in adenylyl cyclase. independent of Gs. in the setting of heart failure.
H1-receptor antagonist treatment of seasonal allergic rhinitis, H1-receptor antagonists are usually first-line treatment given for seasonal allergic rhinitis. However. many patients suffer with symptoms of allergic rhinitis rather than tolerate the sedative and anticholinergic side effects of the first-generation H1-receptor antagonists. Researchers have sought to replace these older H1-receptor antagonists with a new generation of H1-receptor antagonists that approach the optimal therapy: clinically effective. safe. free of side effects. and convenient for the patient. Among the new second-generation H1-receptor antagonists are terfenadine and astemizole (already marketed) and loratadine and cetirizine. which are expected to be approved soon. All four demonstrate efficacy. convenience. and minimal side effects on the central nervous system. In this review of the current treatment of seasonal allergic rhinitis. the clinical studies that compare these four new second-generation H1-receptor antagonists are discussed.
Perennial allergic rhinitis: clinical efficacy of a new antihistamine, Nasal itching. sneezing. and rhinorrhea are troublesome symptoms in patients with perennial allergic rhinitis. Most first-generation H1-receptor agonists achieve a 50% reduction in these symptoms. but their benefits are frequently offset by annoying anticholinergic and sedative side effects. Cetirizine is a major metabolite of hydroxyzine that has little anticholinergic activity and causes significantly less sedation. In addition. it can be given once a day. In placebo-controlled comparisons with terfendadine. both active drugs were comparably effective and significantly better than placebo in relieving sneezing. rhinorrhea. and nasal itching. In a multicenter. double-blind comparison with placebo. both cetirizine. 10 and 20 mg given once daily. were similarly effective and superior to placebo in reducing the overall symptoms of rhinitis. In another multicenter. double-blind study. cetirizine was comparable with diphenhydramine and significantly superior to placebo in reducing total symptom severity. sneezing. rhinorrhea. and ocular itching. The safety of cetirizine was demonstrated in all studies. Cetirizine tended to be less sedating than diphenhydramine.
Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice, Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro. the formation of 14C-acid-soluble beta-oxidation products from [U-14C]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate. whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo. exhalation of [14C]CO2 from [U-14C]palmitic acid was decreased by 31. 40. 58 and 78%. respectively. in mice receiving 19. 25. 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of [U-14C]palmitic acid. One hour after 100 mg.kg-1. the exhalation of [14C]CO2 from [1-14C]palmitic acid. [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 78. 72 and 53%. respectively. Exhalation of [14C]CO2 from [1-14C]palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride. but was still inhibited by 71 and 37%. 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone. hepatic triglycerides were increased by 150%. and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.
Ineffectiveness of parenteral fluoxetine or RU-486 to alter long-term food intake, body weight or body composition of genetically obese mice, The effects of 3 weeks of daily subcutaneous injections of a serotonin agonist (fluoxetine. 20 mg/kg) or agent having antiglucocorticoid properties (RU-486. 20 mg/kg) on food intake and body growth were examined in C57BL/6 ob/ob and lean mice. Fluoxetine injections during ad libitum feeding led to depressed food intake and body weight in both obese and lean mice over the initial 10 days of treatment with full recovery of both intake and weight by the end of the study. Fluoxetine treatment of mice restricted to 3.2 g of laboratory diet per day caused small but persistent depressions of body weight in both phenotypes. RU-486 did not affect food intake weight or weight gain in either phenotype or feeding condition and neither drug affected carcass composition. Insulin levels were also unaffected by treatment but final corticosterone concentrations were consistently higher in fluoxetine-treated mice and lower in RU-486-treated mice. Although transient benefits on feeding and weight gain were observed with fluoxetine administration. the present results show that neither fluoxetine nor RU-486 administered parenterally provides significant long-term improvement in the metabolic. growth or behavioral disturbances that characterize ob/ob mice.
Rapid diagnosis of tuberculous meningitis by polymerase chain reaction, The polymerase chain reaction (PCR) in cerebrospinal fluid was compared with conventional bacteriology and an enzyme-linked immunosorbent assay (ELISA) for cerebrospinal fluid antibodies in the diagnosis of tuberculous meningitis (TBM). PCR was the most sensitive technique; it detected 15 (75%) of 20 cases of highly probable TBM (based on clinical features). 4 (57%) of 7 probable cases. and 3 (43%) of 7 possible cases. ELISA detected 11 (55%) of the highly probable cases and 2 each of the probable and possible cases. Culture was positive in only 4 of the highly probable cases. Among the controls (14 pyogenic meningitis. 3 aseptic meningitis. 34 other neurological disorders). 6 subjects tested early in the study (2 pyogenic meningitis. 4 other disorders) were PCR positive. Second DNA preparations from their stored cerebrospinal fluid samples were all PCR negative. suggesting that the false-positive results were due to cross-contamination. 18 PCR-positive TBM samples retested were all still PCR positive. The antibody ELISA was positive in 3 controls despite the use of a high cutoff value.
Automatic end-expiratory air sampling device for breath hydrogen test in infants, An automatic electronically operated end-expiratory air sampler has been developed for use in small infants. Upon expiration. which is detected by a hot-wire sensor. a small portion of the end-expiratory air is automatically collected into a syringe mounted on a syringe driver. The sampler obtained 87% of the end-expiratory air sample. Additionally. highly reproducible and consistent results were obtained for the respiratory gases (O2. N2. CO2). The sampler has been applied for studying breath hydrogen excretion to detect lactose malabsorption. It may also be applicable to study other expiratory gases in infants.
Update--transmission of HIV infection during an invasive dental procedure--Florida, Possible transmission of human immunodeficiency virus (HIV) infection during an invasive dental procedure was previously reported in a young woman (patient A) with acquired immunodeficiency syndrome (AIDS). Patient A had no identified risk factor for HIV infection and was infected with a strain of HIV closely related to that of her dentist as determined by viral DNA sequencing. A follow-up investigation has identified four additional patients of the dentist who are infected with HIV. Laboratory and epidemiologic investigation has been completed on three of these patients; two are infected with strains closely related to those of the dentist and patient A but not to strains from other persons residing in the same geographic area as the dental practice. The follow-up investigation included review of medical records of the dentist and interviews of former staff on the infection-control procedures of the dental practice. This report summarizes the findings of the investigation.
Tornado disaster--Illinois, 1990, On August 28. 1990. from 3:15 to 3:45 p.m.. the strongest tornado in northern Illinois in greater than 20 years struck the towns of Plainfield. Crest Hill. and Joliet in Will County. As a result of the storm's impact phase. 302 persons were injured (28 fatally). This report summarizes an investigation of injuries and deaths that resulted from the tornado's impact.
Measles vaccination levels among selected groups of preschool-aged children--United States, In 1989 and 1990. the incidence of measles increased dramatically among preschool-aged children in inner cities. The largest outbreaks occurred primarily among unvaccinated black and Hispanic children in large cities (e.g.. Chicago [2]. Dallas. Houston. Los Angeles. Milwaukee. and New York). However. measles outbreaks have not occurred in all large U.S. cities; differences in vaccine coverage could account for these variations. This report describes surveys of vaccination levels among nonrandomly selected first- and fifth-grade students in Boston. part of New York City (Bronx). Cleveland. Houston. Jersey City. Philadelphia. Pittsburgh. and Seattle.
A novel testis-stimulating factor in familial male precocious puberty, BACKGROUND. Familial male precocious puberty is a gonadotropin-independent form of precocious puberty that occurs only in males. The cause of the disorder is unknown. To examine the hypothesis that the plasma of boys with familial male precocious puberty contains a novel stimulator of testicular testosterone production. we developed a bioassay using adult male cynomolgus monkeys. METHODS. We collected plasma from 12 boys with familial male precocious puberty. 7 normal prepubertal boys of similar ages and with similar plasma gonadotropin levels. and 1 boy with hypogonadotropic hypogonadism and infused it into the testicular artery of adult male cynomolgus monkeys that had been pretreated with gonadotropin-releasing-hormone antagonist to inhibit the endogenous secretion of gonadotropins. Testicular venous effluent was collected at 15-minute intervals for 3 or 5 hours for the measurement of testosterone. RESULTS. The mean (+/- SE) peak testosterone response. as compared with base line. was significantly greater in the monkeys infused with plasma from the 12 boys with familial male precocious puberty than in the monkeys infused with plasma from the 7 normal prepubertal boys and the boy with hypogonadotropic hypogonadism (385 +/- 51 vs. 184 +/- 25 percent. P less than 0.005) in the three-hour studies. Plasma from 92 percent of the boys with familial male precocious puberty and 12.5 percent of the normal prepubertal boys stimulated a response greater than 195 percent of base-line values. In the animals studied for five hours after receiving a second dose of antagonist. the mean peak testosterone response. as compared with base line. was significantly greater in the monkeys infused with plasma from three boys with familial male precocious puberty than in the monkeys infused with plasma from three normal prepubertal boys (363 +/- 81 vs. 115 +/- 6 percent. P less than 0.01). The mean area under the testosterone-response curve was significantly larger in the monkeys infused with plasma from the boys with familial male precocious puberty in the five-hour studies (154 +/- 34 vs. -58 +/- 10 percent. P less than 0.005). but not in the three-hour studies. CONCLUSIONS. These findings support the presence of a circulating testis-stimulating factor in the plasma of boys with familial male precocious puberty. The production of such a factor would explain the biologic nature of the disorder.
Ankle sprains are always more than 'just a sprain', When your patient sprains an ankle. you know what to do. The diagnosis is not difficult. treatment is minimal. and the prognosis is excellent--right? Not always. Reading Dr Stanley's article will help you diagnose. treat. and rehabilitate with confidence.
Mutational analysis of an archaebacterial promoter: essential role of a TATA box for transcription efficiency and start-site selection in vitro, By using a recently developed in vitro transcription assay. the 16S/23S rRNA-encoding DNA promoter from the archaebacterium Sulfolobus sp. B12 was dissected by deletion and linker substitution mutagenesis. The analysis of 5' and 3' deletion mutants defined a core promoter region between positions -38 and -2 containing all information for efficient and specific transcription. Further characterization of this region by linker substitution mutagenesis indicated two sequence elements important for promoter function--one located between positions -38 and -25 (distal promoter element) and the other one located between positions -11 and -2 (proximal promoter element). The distal promoter element encompassed the TATA-like "box A" element located approximately 26 nucleotides upstream of the majority of transcription start sites in archaebacteria (Archaeobacteria). All mutations within this box A motif virtually abolished promoter function. Complete inactivation of the proximal promoter element was dependent on extensive mutagenesis; this element is not conserved between archaebacterial promoters except for a high A + T content in stable RNA gene promoters from Sulfolobus. Mutants containing insertions or deletions between the distal and proximal promoter elements were only slightly affected in their transcription efficiency but displayed a shift in their major initiation site. retaining an essentially fixed distance between the distal promoter element and the transcription start site. Thus. efficient transcription and start-site selection were dependent on a conserved TATA-like sequence centered approximately 26 nucleotides upstream of the initiation site. a situation unlike that of eubacterial promoters but resembling the core structure of most eukaryotic RNA polymerase II (and some RNA polymerase III) promoters. This finding suggests a common evolutionary origin of these promoters consistent with the known similarities between archaebacterial and eukaryotic RNA polymerases.
Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis, The nucleotide sequence of the Japanese type of hepatitis C virus (HCV-J) genome. consisting of 9413 nucleotides. was determined by analyses of cDNA clones from plasma specimens from Japanese patients with chronic hepatitis. HCV-J genome contains a long open reading frame that can encode a sequence of 3010 amino acid residues. Comparison of HCV-J with the American isolate of HCV showed 22.6% difference in nucleotide sequence and 15.1% difference in amino acid sequence. Thus HCV-J and the American isolate of HCV are probably different subtypes of HCV. The relationship of HCV-J with other animal RNA virus families and the putative organization of the HCV-J genome are discussed.
Development of a stable Leishmania expression vector and application to the study of parasite surface antigen genes, Trypanosomatid protozoan parasites cause several important tropical diseases and have been a fertile ground for the discovery of molecular paradigms such as trans-splicing and RNA editing. Transfection-based methods for the study of these organisms have recently been developed. and we have now designed an expression vector. pX. which contains only 2.3 kilobases of Leishmania DNA and can be stably transfected with high efficiency. Genes encoding Escherichia coli beta-galactosidase or a Leishmania amazonensis protective membrane glycoprotein (GP46A/M-2) were inserted into the pX expression site and transfected into Leishmania major. where they directed the synthesis of high levels of mRNAs formed by 5' and 3' processing events occurring predominantly at the sites used by the normal transcripts. Colony assays and immunoblot analysis showed that both proteins were produced; enzymatically active beta-galactosidase comprised approximately 1% of total protein. Sizes of the GP46A protein synthesized in transfected L. major or L. amazonensis were similar and differed from the predominant L. amazonensis GP46. suggesting that the GP46A gene may encode a variant GP46 family member. Because these vectors function efficiently in pathogenic species of Leishmania. pX will facilitate the genetic analyses of parasite proteins crucial for infectivity as well as the identification of cis-acting elements mediating transcription and replication.
Method for identifying microbial antigens that stimulate specific lymphocyte responses: application to Salmonella, Vaccine development and understanding of cellular immune stimulatory mechanisms have been impeded by the paucity of data on microbial antigens that stimulate protective immunity. We describe here a general method for identifying and isolating peptide antigens that specifically stimulate sensitized lymphocytes. First. Salmonella typhimurium C5 genomic DNA fragments were subcloned into Escherichia coli by use of the lambda gt11 expression vector. Next. antigens expressed by recombinant phage from this genomic library were tested for their capacity to stimulate proliferative responses in pooled lymphocytes obtained from BALB/c mice infected 14 days earlier with S. typhimurium. Of 2000 recombinant phages tested. 5 stimulated a polypeptide-antigen-specific proliferative response. Physical analyses of these 5 recombinant phages revealed cloned inserts of 0.5-2.4 kilobase pairs representing nonoverlapping regions of the C5 chromosome. Four of the five insert DNAs hybridized at high stringency to both S. typhimurium and Salmonella typhi total chromosomal DNA. suggesting that these pathogens of different host specificity share several antigenic determinants. Use of sensitized primary polyclonal lymphocytes provides a rapid and simple method for screening recombinant DNA libraries for clones that stimulate specific immune responses and avoids the use of cloned lymphocyte cell lines. This approach should be generally applicable to similar studies in different hosts of many other microbial pathogens.
Brain magnetic resonance imaging with contrast dependent on blood oxygenation, Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high fields. we demonstrate in vivo images of brain microvasculature with image contrast reflecting the blood oxygen level. This blood oxygenation level-dependent (BOLD) contrast follows blood oxygen changes induced by anesthetics. by insulin-induced hypoglycemia. and by inhaled gas mixtures that alter metabolic demand or blood flow. The results suggest that BOLD contrast can be used to provide in vivo real-time maps of blood oxygenation in the brain under normal physiological conditions. BOLD contrast adds an additional feature to magnetic resonance imaging and complements other techniques that are attempting to provide positron emission tomography-like measurements related to regional neural activity.
Coordinate occupancy of AP-1 sites in the vitamin D-responsive and CCAAT box elements by Fos-Jun in the osteocalcin gene: model for phenotype suppression of transcription, Osteocalcin. a bone-specific protein and marker of the mature osteoblast. is expressed only in nonproliferating osteoblasts in a mineralizing extracellular matrix. while type I collagen is expressed in proliferating cells. The nuclear proteins encoded by the c-fos and c-jun protooncogenes are expressed during the proliferation period of osteoblast phenotype development. We present evidence that AP-1 (HeLa cell-activating protein 1) sites residing within two promoter elements of the osteocalcin gene bind the Fos-Jun protein complex: the osteocalcin box (OC box; nucleotides -99 to -76). which contains a CCAAT motif as a central element and influences tissue-specific basal levels of osteocalcin gene transcription. and the vitamin D-responsive element (VDRE; nucleotides -462 to -440). which mediates enhancement of osteocalcin gene transcription. Gel electrophoretic mobility-shift analysis demonstrated high AP-1 binding activity in proliferating osteoblasts and dramatic changes in this activity after the down-regulation of proliferation and the initiation of extracellular-matrix mineralization in primary cultures of normal diploid osteoblasts. Methylation interference analysis established at single nucleotide resolution that purified recombinant Fos and Jun proteins bind in a sequence-specific manner to the AP-1 sites within the VDRE and OC box. Similarly. an AP-1 motif within a putative VDRE of the alkaline phosphatase gene. which is also expressed after the completion of proliferation. binds the Fos-Jun complex. These results support a model in which coordinate occupancy of the AP-1 sites in the VDRE and OC box in proliferating osteoblasts may suppress both basal level and vitamin D-enhanced osteocalcin gene transcription as well as transcription of other genes associated with osteoblast differentiation--a phenomenon we describe as phenotype suppression. This model is further supported by binding of the Fos-Jun complex at an AP-1 site in the type alpha I collagen promoter that is contiguous with. but not overlapping. the VDRE. Such a sequence organization in the collagen VDRE motif is compatible with vitamin D modulation of collagen but not with osteocalcin and alkaline phosphatase expression in proliferating osteoblasts.
Tissue plasminogen activator reduces brain injury in a rabbit model of thromboembolic stroke, Tissue plasminogen activator is an endogenous fibrin-specific serine protease with potent thrombolytic activity. We investigated the efficacy of tissue plasminogen activator in reducing cerebral infarct size after thromboembolic stroke in a rabbit model. Seventeen rabbits were randomized to receive either tissue plasminogen activator (2.5 mg/kg. n = 6) or vehicle control (n = 11). We controlled mean arterial pressure. hematocrit. and arterial blood gases before and after the intracarotid embolization of an autologous clot. Cerebral blood flow (cm3/100 g/min) (mean +/- SEM) was immediately reduced from 55.2 +/- 7.7 to 8.5 +/- 2.5 in the control group and from 61.8 +/- 14.8 to 10.0 +/- 3.5 in the treated group after embolization. Cerebral blood flow recovered significantly within 60 minutes of thrombolytic therapy and attained a value of 59.6 +/- 10.0 cm3/100 g/min 4 hours after embolization. whereas cerebral blood flow in control animals demonstrated only a minimal recovery to 15.3 +/- 8.9 cm3/100 g/min. Cerebral infarct size (percent of hemisphere) was reduced from 34.4 +/- 5.6% in control animals to 8.8 +/- 5.6% in treated animals (mean +/- SEM. p less than 0.01). These results suggest that tissue plasminogen activator may be efficacious in restoring cerebral blood flow and thus limiting infarct size in acute thromboembolic stroke.
Prehospital diagnosis and treatment of acute myocardial infarction: a north-south perspective. The Cincinnati Heart Project and the Nashville Prehospital TPA Trial, Intravenous thrombolytic therapy improves left ventricular function and reduces mortality in patients with acute myocardial infarction (AMI). In European and Middle Eastern trials. prehospital delivery of thrombolytic agents by physician-directed mobile intensive care units has been successful. This report describes two independently conceived and performed trials that used cellular telephone transmission of 12-lead ECGs to deliver recombinant tissue plasminogen activator (r-tPA) in the field to patients with AMI. In the Nashville Prehospital TPA Trial. 85 patients with chest pain were evaluated in the field for possible administration of r-tPA over a 6-month period. Three of 85 patients (3.5%) were found to be actual candidates for r-tPA treatment in the field. In phase II (dry-run phase) of the Cincinnati Heart Project. 374 patients were evaluated in the field with 14 documented cases of AMI (3.7%) before r-tPA was placed in ambulances for administration by paramedics. In phase III (active with r-TPA in ambulances). over a 1-year period 103 patients were evaluated with six (5.8%) documented cases of AMI. Three of five r-tPA field treatment decisions by emergency physicians using transmitted 12-lead ECGs were accurate (60%). When patients in phases II and III were combined. only 20 of 477 total patients (4.2%) were documented to have AMI. A decline in paramedic skills was noted because of the infrequent administration of the thrombolytic agent. Combining the Nashville and Cincinnati experiences. only 27 of 562 total patients with chest pain (4.8%) were candidates for prehospital thrombolysis. We conclude that few patients evaluated in the prehospital setting are actual candidates for thrombolytic therapy. Substantial allocation of financial and human resources for prehospital delivery of intravenous thrombolytic therapy does not appear warranted.
Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity, We identified two different exonic point mutations causing beta-glucuronidase (beta G1) deficiency in two Japanese patients with mucopolysaccharidosis type VII (MPSVII). Enzyme assay of lysates of the lymphocytes and cultured fibroblasts showed little residual activity. The beta G1-specific mRNA levels were normal. as determined by northern blot analysis. Mutated cDNA clones. including the entire coding sequence. were isolated using the polymerase chain reaction (PCR) products derived from beta G1-deficient fibroblasts. Sequence analysis of the full-length mutated cDNAs showed C----T transitions. which resulted in a single Ala619----Val change (case 1. a 24-year-old male) and a Arg382----Cys change (case 2. a 7-year-old female). The former change was revealed by a loss of the cleavage site for the Fnu4HI in the mutated cDNA. On the basis of the loss of Fnu4HI restriction site. the patient (case 1) was a homozygote with this mutation. The mutational change in patient 2 was confirmed by direct sequencing and by demonstrating heterozygosity for the mutation in her parents. The Ala619----Val and Arg382----Cys mutations each disrupt a different domain which is highly conserved among human. rat. and Escherichia coli beta G1s. Each of these two amino acid changes reduced the beta G1 activity of the corresponding mutant beta G1 expressed following transfection of COS cells with expression vectors harboring the mutated cDNAs.
Pravastatin vs gemfibrozil in the treatment of primary hypercholesterolemia. The Italian Multicenter Pravastatin Study I, This study compared the efficacy and safety of pravastatin and gemfibrozil in the treatment of primary hypercholesterolemia. Three hundred eighty-five outpatients from 13 lipid clinics in Italy participated in this randomized double-blind study. Patients were assigned to receive either 40 mg once daily of pravastatin or 600 mg of gemfibrozil twice daily after an initial diet lead-in period. After 24 weeks. mean reductions from baseline values of plasma total and low-density lipoprotein cholesterol were. respectively. 23% and 30% with pravastatin and 14% and 17% with gemfibrozil. Significant lipid-lowering effects were noted within 4 weeks. Apolipoprotein B decrease was 21% with pravastatin and 13% with gemfibrozil. A statistically significant increase of high-density lipoprotein cholesterol of 5% was achieved with pravastatin compared with a 13% increase for gemfibrozil. Serum triglyceride values decreased 5% with pravastatin and 37% with gemfibrozil. Familial and polygenic hypercholesterolemic patients were also examined separately. Pravastatin effectiveness in reducing low-density lipoprotein cholesterol was greater by 6% in polygenic than in familial hypercholesterolemic patients. Treatment for 25 patients (eight treated with pravastatin and 17 treated with gemfibrozil) was discontinued during the study. The incidence of clinical symptoms and laboratory alterations was low for both treatment groups. Pravastatin and gemfibrozil were well tolerated. but pravastatin was significantly more effective in reducing total and low-density lipoprotein cholesterol levels in primary (either familial or polygenic) hypercholesterolemias than gemfibrozil.
Interferon-gamma reverses bone marrow inhibition following hemorrhagic shock, Hemorrhagic shock has been demonstrated to alter the myelopoietic response to bacterial lipopolysaccharide. Interferon-gamma has been shown to improve the immune response following experimental shock and injury; however. its effect on myelopoiesis is controversial. This study was performed to determine whether treatment with interferon-gamma will improve the bone marrow response to lipopolysaccharide after hemorrhagic shock. Rats subjected to either shock or a sham procedure were allocated into three groups: (1) control rats received no further treatment; (2) lipopolysaccharide-treated rats received saline for 3 days and then were challenged with lipopolysaccharide to stimulate myelopoiesis; and (3) interferon-treated rats received interferon-gamma (7500 U subcutaneously 1 hour after shock and then every day for 3 days) and lipopolysaccharide as in group 2. Serum colony-stimulating factor levels were measured 6 hours and bone marrow white blood cell count and granulocyte-macrophage colony-forming units (CFU-GM) were measured 24 hours following lipopolysaccharide administration. In sham-treated rats. lipopolysaccharide increased CFU-GM 77% compared with controls. In contrast. treatment with lipopolysaccharide decreased CFU-GM 43% following shock. Treatment with interferon-gamma increased CFU-GM in all animals and reversed the decline in CFU-GM seen in shocked lipopolysaccharide-treated animals. Serum colony-stimulating factor levels were unaffected by either shock or interferon-gamma administration. These data demonstrate that interferon-gamma exerts a stimulatory effect on bone marrow following shock and restores the myelopoietic response to lipopolysaccharide.
Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients, The effect of growth hormone on protein kinetics was assessed in burned patients during the hyperdynamic phase using N15 lysine and balance data across the leg. Levels of resting energy expenditure and cardiac index were comparably elevated in all patients. but leg blood flow was greater in the patients receiving growth hormone. Growth hormone therapy (0.2 mg/kg per day) significantly stimulated protein synthesis in the whole body and in the studied leg. A hyperinsulinemic clamp. which raised the insulin concentration to more than 1435 pmol/L of blood. caused comparable stimulation of leg protein synthesis in patients not receiving growth hormone. but did not further increase protein synthesis in the growth hormone-treated patients. These results suggest that administration of exogenous growth hormone may limit the peripheral protein wasting in severely injured patients by a mechanism similar to that of insulin.
Survival following severe overdose with mexiletene, nifedipine, and nitroglycerine, Survival following attempted suicide in a 50-year-old man by ingestion of 12.4 g of mexiletine. 620 mg of nifedipine and 50 to 100 tablets of sublingual nitroglycerine 1:150 is reported. Initial presentation was that of mental obtundation. vomiting. tonic-clonic seizure. high-degree atrioventricular block. profound vasodilation and cardiovascular collapse. Treatment consisted of intravenous calcium gluconate and aggressive fluid management. Maintenance of cardiovascular stability required continuous infusion phenylephrine. dopamine and epinephrine. The patient made a full recovery and was medically discharged on the fourth hospital day. This case represents the largest overdose of mexiletine to date to end in patient survival.
Pseudonormoglycemia in diabetic ketoacidosis with elevated triglycerides, A 24-year-old newly diagnosed male patient with diabetes presented with diabetic ketoacidosis (DKA) (pH 7.16. HCO3 6.0) and extreme hypertriglyceridemia (239.35 mmol/L). The diagnosis of DKA was delayed because of the apparent depression of the true serum glucose (to 11 mmol/L). He was treated with intravenous (IV) insulin and rehydration. which normalized his pH. HCO3. and triglyceride levels. To the authors' knowledge. this is both the highest triglyceride level recorded and the first report of a high triglyceride level as the apparent cause of a factitiously low glucose level.
Retropharyngeal space infections in a community hospital, The emergency physician often has to deal with infectious disease emergencies. The authors have seen four cases of retropharyngeal infection of potentially life-threatening severity in less than 1 year. all were admitted through the emergency department (ED). Reporting these cases is important to increase awareness among emergency physicians of this classic disease entity. The characteristics of the patients are discussed including initial diagnostic approaches and the use of computed tomography (CT) scanning of the neck and mediastinum. One case of retropharyngeal space infection caused by Neisseria meningitidis serotype W-135 is described. This is the first such reported case. The recommendations are that. in the absence of overt focal infection. a non-surgical approach to the treatment of these patients is indicated. This should include suitable neck roentgenograms. CT scanning. and high-dose. intravenous. beta-lactamase-resistant antibiotics.
Carboxyhaemoglobin concentrations, pulse oximetry and arterial blood-gas tensions during jet ventilation for Nd-YAG laser bronchoscopy, Oxygen saturation measured with pulse oximetry (SpO2) is overestimated in the presence of carboxyhaemoglobin (COHb). Smoke produced during laser resection of tracheobronchial malignancies may increase concentrations of COHb. We have measured COHb concentrations in 14 patients undergoing laser resection and compared SpO2 with functional oxygen saturation (SaO2) to ascertain if pulse oximetry is an accurate monitor of oxygen saturation. During the procedure frequent changes occur in ventilatory mechanics. Arterial blood-gas tensions were measured to see if gas exchange was satisfactory. Mean preoperative COHb was 1.4%. There was no significant change in COHb in any patient at any stage during treatment. The highest value was 2.05%. The mean difference between SaO2 and SpO2 was 1.13% (95% confidence interval 0.70-1.56%). Oxygen saturation may therefore safely be monitored by pulse oximetry in patients managed by our technique. Empirical setting of a jet ventilator provided acceptable blood-gas tensions. although sometimes it was necessary to increase the FlO2 to greater than 0.3 to maintain oxygenation.
Expression of extracellular matrix in hair follicle mesenchyme in alopecia areata, Human hair follicle mesenchyme contains a distinctive extracellular matrix which varies in volume and composition in concert with the hair growth cycle. To investigate the possibility that mesenchymal function is disturbed in alopecia areata we have studied the expression of extracellular matrix constituents in scalp biopsies from 14 patients by immunohistochemical staining for basement membrane proteins. proteoglycans and interstitial collagens. The staining patterns in follicles from non-lesional scalp were normal. Miniature anagen follicles from bald patches also showed relatively normal expression of basement membrane proteins and proteoglycans. However. in some large anagen follicles from lesional sites. there was loss of the normal staining pattern for chondroitin-6-sulphate in the dermal papilla. In lesional catagen follicles. the glassy membranes showed marked convolution and thickening. These structures stained strongly for laminin and type IV collagen but only weakly for interstitial collagens.
Restoration of phagocyte function by interferon-gamma in X-linked chronic granulomatous disease occurs at the level of a progenitor cell, Phagocytes from X-linked chronic granulomatous disease (X-CGD) patients are deficient in their ability to generate superoxide because of a defective gene that encodes a heavy chain of cytochrome b. a critical component in the superoxide-generating pathway. Previously we have shown that a single in vivo treatment of selected X-CGD patients with interferon-gamma (INF-gamma) resulted 14 days later in near-normal levels of superoxide generation by phagocytes. The effect persisted for 28 days. This prolonged effect suggested that the lymphokine affected progenitor cells. In this study. we examined progenitor-derived colonies from the peripheral blood from this unusual X-CGD kindred. Progenitor-derived colonies examined before treatment were unable to generate superoxide as visualized by lack of nitro blue tetrazolium (NBT) reduction compared with normal controls. By contrast. colonies derived 7 days after a single INF-gamma injection were able to generate superoxide as shown by increased NBT reduction. Colonies harvested 21 days after treatment contained only rare cells capable of NBT reduction. Our results indicate that INF-gamma can reprogram the myeloid progenitor cells to express a partially corrected phenotype. This corrected phenotype is later expressed in daughter cells.
Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells, Detailed immunophenotypic analyses of immunologically classified leukemias and lymphomas showed that CD40 displays an exquisite B-lineage specificity within the human lymphopoietic system. Notably. 82% of B-lineage chronic lymphocytic leukemias (CLLs). 82% of B-lineage hairy cell leukemias (HCLs). 86% of B-lineage non-Hodgkin's lymphomas (NHLs). and 29% of B-lineage acute lymphoblastic leukemias (ALLs) were CD40+. Quantitative analyses of the correlated expression of CD40 and other B-lineage differentiation antigens on fetal lymphoid precursor cells by multiparameter two-color/three-color flow cytometry. combined with analyses of sequential antigen expression on fluorescence-activated cell fluorescence activated cell sorter (FACS) isolated immunologically distinct fetal B-cell precursor subpopulations during in vitro proliferation and differentiation. provided evidence that the acquisition of CD40 antigen in human B-cell ontogeny occurs subsequent to the expression of CD10 and CD19 antigens but before the surface expression of CD20. CD21. CD22. CD24. and surface immunoglobulin M (sIgM). Some leukemic pro-B cells from ALL patients as well as normal pro-B cell clones from fetal livers displaying germline Ig heavy chain genes were CD40+. indicating that the acquisition of CD40 antigen likely precedes the rearrangement of Ig heavy chain genes. CD40+ FACS-sorted malignant cells from B-lineage ALL as well as B-lineage NHL patients were capable of in vitro clonogenic growth. indicating the CD40 antigen is expressed on clonogenic leukemia and lymphoma cells. This hypothesis was confirmed by the ability of an anti-CD40 immunotoxin that we used as an antigen-specific cytotoxic probe to effectively kill clonogenic B-lineage ALL and NHL cells.
Immunity against Pseudomonas aeruginosa adoptively transferred to bone marrow transplant recipients, Infection is a common problem for bone marrow transplant (BMT) recipients during the period of neutropenia that immediately follows the procedure. Gram-negative infections present a particular hazard in these immunocompromised hosts. To augment host defenses against one such pathogen. Pseudomonas aeruginosa. we immunized bone marrow transplant donors and/or recipients with a polyvalent O-polysaccharide-toxin A conjugate vaccine. When either donor or recipient alone was vaccinated before transplant. no increase in specific antibody titers to any of the vaccine components was observed in the recipient. However. when both donor and recipient were vaccinated before transplant. increases in antibody titers to all polysaccharide components occurred to levels shown to be protective in animal models of gram-negative sepsis. Specific antibodies were primarily of the IgG1 and IgG2 subclass even though IgG2 subclass deficiency is common after BMT. The requirement for both donor and recipient immunization reflects the need for primed donor B lymphocytes in the marrow inoculum to be transferred into an antigen-containing environment so that maximum B-cell proliferation and antibody secretion can occur. Adoptive transfer of antibody responses to Pseudomonas aeruginosa and other common bacterial pathogens has the potential to reduce infection-related morbidity and mortality after allogeneic bone marrow transplantation.
Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways, Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes. and reached a maximal level after 60 to 90 minutes. In each volunteer. the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase. and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases. whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation. as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes. was noted after 120 minutes. in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes. respectively. The release of t-PA coincided with activation of the fibrinolytic pathway. as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor. observed 150 minutes after the endotoxin injection. and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early. rapidly counteracted fibrinolytic response. and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition. our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.
Use of polymerase chain reactions to monitor minimal residual disease in acute lymphoblastic leukemia patients, T-cell receptor (TCR) delta gene rearrangements are observed in more than 80% of acute lymphoblastic leukemia (ALL) patients. Moreover. a preferential usage of specific genetic elements has been shown in different ALL subtypes: V delta 1 DJ delta 1 rearrangements predominate in T-ALL. while most B-precursor ALLs show a recombination of V delta 2 to D delta 3. Recently we have proposed a strategy for the detection of minimal residual disease (MRD) based on the isolation of clonospecific probes following the in vitro amplification of V delta 1 DJ delta 1 junctions by polymerase chain reaction (PCR) and now have adapted this method to the preparation of specific V delta 2 D delta 3 fragments. In the present study. clonospecific probes were generated from 11 T-ALL and 16 cALL patients (21 children. 6 adults). The sensitivity of these 27 probes in detecting residual leukemia cells varied between 10(-4) to 10(-6) as determined by semiquantitative evaluation of dilution experiments. PCR analysis of 55 bone marrow (BM) and peripheral blood (PB) samples obtained from the 27 patients during complete clinical remission showed the following results: (1) Evidence for MRD was obtained in the BM of all patients (eight of eight) investigated 2 to 6 months after remission induction and also in 6 of 11 cases on maintenance therapy 7 to 19 months after diagnosis. (2) In contrast. all patients but one (10 of 11) analyzed 6 to 41 months after the termination of treatment lacked apparent evidence for leukemia DNA; the exception was a girl exhibiting 10(-4) to 10(-5) residual cells in her PB 5.5 years after diagnosis. (3) Longitudinal analysis in nine patients disclosed marked individual differences in the intervals between achievement of clinical remission and complete eradication of the leukemia cell clone. (4) Differences in the duration of MRD were not associated with distinct clinical-hematologic features. (5) Detection of residual disease by PCR proceeded clinical relapse in two cases.
A case report of malignant pleural mesothelioma with long-term disease control after chemotherapy, Long duration of responses to chemotherapy in patients with malignant pleural mesothelioma (MPM) is rare. The authors report a patient with inoperable MPM who achieved complete remission with combination chemotherapy of cyclophosphamide. doxorubicin. and cisplatin. 5-fluorouracil and mitomycin C (FM) induced another remission after recurrence of the tumor. Retreatment with FM after chemotherapy had been stopped for 20 months yielded another continuing response. The overall tumor-control time is more than 4 years. Literature reviews and the authors' results suggest that MPM may be a chemosensitive tumor in some patients. Additional evaluations of CAP. FM. and methotrexate combination regimens in this disease should be considered.
Prolactin and pituitary gonadotropin values and responses to acute luteinizing hormone-releasing hormone (LHRH) challenge in patients having long-term treatment with a depot LHRH analogue, Sixty patients with advanced prostatic carcinoma were treated with monthly subcutaneous injections of a depot formulation of goserelin. a luteinizing hormone-releasing hormone (LHRH) analogue (Zoladex. ICI Pharma. Destelbergen. Belgium). All patients were regularly evaluated with measurements of luteinizing hormone (LH). follicle-stimulating hormone (FSH). testosterone (T). and prolactin (PRL) levels. In 15 patients among them who could be treated for more than 42 months. an LHRH stimulation test was performed at the end of each 28-day period and before the next administration of the depot formulation. A complete and maintained suppression of both T and LH levels was seen. FSH levels also decreased. but to a lesser extent than LH levels. and showed a small escape after reaching a minimum value after 1 month of therapy. The LHRH challenge after 42 months of therapy elicited no significant responses of LH and FSH levels. The PRL values showed a small decrease.
Glial contribution to seizure: carbonic anhydrase activity in epileptic mammalian brain, The activity of carbonic anhydrase (CA). a glial enzyme. was measured in the epileptic cortex of audiogenic DBA/2 mice and of cats with a freeze lesion. In mice. the activity increased with age from birth to 24 days. but were always higher in audiogenic mice than in normal C57/BL mice. reflecting species differences. The difference between the two strains increased sharply from 25 to 40 days of age. after the period of maximal audiogenic susceptibility. Acetazolamide. a CA-specific inhibitor. greatly decreased the seizure severity score of DBA/2 mice after a single intraperitoneal (i.p.) administration (150 mg/kg). After 24 days of age. when CA activities were high. the effect of acetazolamide was less important. suggesting that the increased cortical CA activity might reflect a protective mechanism. In cats with a freeze lesion. no significant changes in CA activities were observed in the actively discharging primary and secondary foci as compared with the nonepileptogenic perifocal cortex and the control cortex of sham-operated animals. The results indicate that the cortex of genetically susceptible audiogenic mice has an increased CA activity. The hypothesis of an adaptive glial mechanism. relating to the age-dependent decrease of seizure susceptibility in DBA/2 mice. is postulated.
Effect of milacemide on audiogenic seizures and cortical (Na+, K+)-ATPase of DBA/2J mice, Milacemide (MLM. CP 1552 S. 2-N-pentylaminoacetamide). a glycinamide derivative. is currently being evaluated clinically for antiepileptic activity. Anticonvulsant properties have been shown in various animal models. but the mechanism of action of MLM is unclear. We studied its activity in audiogenic seizures of DBA/2J mice. MLM was effective in inhibiting the convulsions induced by sound with a biphasic dose-effect relation. The ED50 was 109 mg/kg orally against tonic extension. Higher doses were necessary to abolish clonic convulsion and running response. Because impaired cerebral (Na+. K+)-ATPase activity is supposed to play a role in epileptogenesis. we tested MLM on in vitro cortical enzymatic activity of DBA/2J mice. Basal (Na+. K+)-ATPase activity was unchanged by several concentrations of MLM in normal C57BL/6J and audiogenic DBA/2J mice. K+ activation (from 3 to 18 mM) of (Na+. K+)-ATPase is abolished in DBA/2J mice as compared with C57BL/6J mice. suggesting impaired glial (Na+. K+)-ATPase. In the presence of MLM (from 30 to 1000 mg/L). cortical (Na+. K+)-ATPase of DBA/2J mice is activated by high concentrations of K+. as in C57BL/6J mice. Results suggest that the antiepileptic activity of MLM in audiogenic mice may be secondary to an activation of a deficient glial (Na+. K+)-ATPase.
Effect of DN-1417 on photosensitivity and cortically kindled seizure in Senegalese baboons, Papio papio, The effect of DN-1417. a thyrotropin-releasing hormone (TRH) analogue. on photosensitivity and cortically kindled seizures was examined in seven Senegalese baboons (Papio papio). Intravenous (i.v.) administration of 2 mg/kg had no effect on either photosensitivity or cortically kindled seizures. When this agent was administered intracisternally. both the photomyoclonic response and cortically kindled seizures were suppressed for 4-5 days. A study of the transcallosal response also showed a long-lasting attenuation of the early positive wave (P1) amplitude (peak latency. 5-10 ms) elicited by a single stimulus after cisternal injection of DN-1417. These findings are consistent with the assumption that endogenous TRH is involved in suppression of epileptic seizures.
Partial motor epilepsy with "negative myoclonus", Three children had both nocturnal unilateral motor seizures and daytime ipsilateral "negative myoclonus" which occurred so frequently that it resembled asterixis. Neurophysiologic studies demonstrated lateralized spike discharges that were time-locked to postural lapse in the contralateral outstretched arm. The clinical course was characterized by good seizure control with benzodiazepines.
Gonadotropin, steroid, and inhibin levels in women with incipient ovarian failure during anovulatory and ovulatory rebound cycles, We have identified a group of women with infertility and regular menses who have persistently raised FSH levels and probable incipient ovarian failure (IOF). Thirteen such women (19 cycles) had serum samples taken for RIA of LH. FSH. estradiol. and progesterone (P) 3 times a week over 1 menstrual cycle. Sixty infertile women with normal ovulatory cycles (as determined by hormones and ultrasound scan) served as controls. Overall. the FSH was higher (P less than 0.01) on all days of the cycle in the IOF group. serum LH was raised on days-14 to-5 before and days 5-11 after the LH surge. There was no difference between estradiol and P levels in the two groups. Ultrasound scanning showed failure of normal ovulation in the IOF group. Inhibin. measured by RIA in 9 cycles in the IOF group was lower (P less than 0.01) during the follicular phase than in 43 normal cycles. The highest inhibin level was seen in the luteal phase. as in normal cycles. but levels were still lower (P less than 0.01) in the IOF group. Inhibin was inversely correlated with FSH (P less than 0.05) during the follicular and luteal phases and was correlated with P during the luteal phase (P less than 0.05) in the IOF group. After 3 weeks of suppression (39 cycles) with an estrogen-progestogen preparation in the IOF group. LH and FSH fell to normal values. Ovulation occurred in 22 cycles on withdrawal of suppression in the presence of high FSH levels and low inhibin levels. No pregnancies occurred. These findings are consistent with the suggestion that diminished ovarian inhibin secretion may contribute to the elevated FSH levels of IOF and indicate that ovulation in the rebound cycle after suppression occurs in the presence of high FSH and low inhibin levels. Such cycles. however. still appear to be subfertile.
Early difference in the endocrine profile of long and short lactational amenorrhea, The endocrine profiles associated with long and short lactational amenorrhea were assessed in a longitudinal study in which morning blood samples were drawn in 48 women from the first postpartum month until the recovery of ovulation and in a cross-sectional study in which the samples were drawn throughout 24 h at the end of the third postpartum month in 10 fully nursing and amenorrheic women. PRL. LH. FSH. estradiol (E2). progesterone. cortisol. and dehydroepiandrosterone sulfate were measured. In both studies we detected a smaller PRL increase in response to suckling (P less than 0.001) and higher E2 levels (P less than 0.001) in nursing women who ovulated within 6 months postpartum compared to those in women who did not. Such differences were observed early after delivery when all women were fully nursing and amenorrheic. These results suggest some probable sources of variability in the duration of lactational amenorrhea in our population. The greater PRL response to suckling associated with longer amenorrhea may be due to higher sensitivity of the breast-hypothalamus-pituitary system or a stronger suckling stimulus in this group. Differences in plasma E2 levels between longer and shorter periods of amenorrhea may reflect dissimilar endogenous production. intake. or clearance of estrogens.
Effect of deslorelin dose in the treatment of central precocious puberty, Central precocious puberty is effectively treated with long-acting LHRH analogs (LHRHas). Although at least six LHRHas have now been used in children. there have been no studies to determine the least effective dose of any of these analogs. We sought to determine the effect of decreasing an efficacious dose of deslorelin (D-Trp6-Pro9-NEt-LHRH) on basal and LHRH-stimulated gonadotropins. estradiol levels. and the rates of linear growth and skeletal maturation in subjects with central precocious puberty. Twenty-nine children with central precocious puberty were enrolled in a double blinded study. All subjects were treated for the initial 3 months with deslorelin at a dose (4 micrograms/kg.day. sc) known to suppress gonadotropins. linear growth velocity. and the rate of skeletal maturation. After 3 months. the subjects were randomly assigned to receive one of three daily sc doses of deslorelin: 4 micrograms/kg (n = 9). 2 micrograms/kg (n = 11). or 1 micrograms/kg (n = 9). They were treated at this dose in double blinded fashion for 15 months. after which time they resumed therapy at a dose of 4 micrograms/kg.day for an additional year. The children in the three groups did not differ in terms of chronological age. bone age. pretreatment growth rate. or Tanner stage at the onset of therapy. Similarly. there were no differences in the clinical and hormonal responses to the first 3 months of LHRHa therapy (4 micrograms/kg.day). During the 15-month period at the three different doses. the three dose groups could not be distinguished from each other in terms of pubertal stage. linear growth velocity. rate of skeletal maturation. sex steroid levels. mean LH or FSH levels. or peak FSH response to LHRH stimulation or to a dose of deslorelin. In contrast. the peak LH response to LHRH stimulation was highest in children treated with the lowest dose (1 micrograms/kg.day; P less than 0.025. by multiple analysis of variance). In addition. the peak LH response to a dose of deslorelin (the LHRHa test) was higher in children treated with 1 micrograms/kg.day than in those treated with 4 micrograms/kg.day (P less than 0.04). In summary. the LHRHa test is a sensitive means for detecting activation of the hypothalamic-pituitary-gonadal axis. and deslorelin at a dose of 1 micrograms/kg.day results in less gonadotropin suppression than a dose of 4 micrograms/kg.day.
Interrelationship between coagulant activity and tissue-type plasminogen activator (t-PA) system in acute ischaemic heart disease. Possible role of the endothelium, Patients with unstable angina pectoris (UAP; n = 20) and acute myocardial infarction (AMI; n = 34) were studied in the acute phase of ischaemic heart disease. We found significantly higher levels of thrombin-antithrombin-III (TAT) complexes. lower levels of systemic tissue plasminogen activator (t-PA) activity. and higher levels of plasminogen activator inhibitor (PAI) activity in the AMI patients compared to the UAP patients. In contrast to these specific changes. general acute phase reactants such as C-reactive protein. fibrinogen and von Willebrand factor did not differ significantly between the two groups. Studies of the relationship between coagulation (TAT-complexes) and fibrinolysis data revealed a significant positive correlation between plasma antigen concentrations of TAT-complexes and t-PA (P less than 0.02). and between TAT-complexes and PAI-I (P less than 0.002). These observations indicate a common pathophysiological mechanism underlying the changes in coagulation and fibrinolysis. suggesting that coagulation activity and t-PA-related fibrinolysis are interrelated processes in vivo. and probably take place at the level of the endothelial cell.
The effect of carbonic anhydrase inhibition on calcium and bone homeostasis in healthy postmenopausal women, Carbonic anhydrase localized in bone resorptive cells generates the protons necessary for bone resorption. Inhibition of the enzyme is a potential mechanism for decreasing bone resorption. Eight healthy post-menopausal women received oral acetazolamide 250 mg twice daily for 28 d. Bone resorption. evaluated by serum acid phosphatase activity and the renal excretion of hydroxyproline. was unaltered. as was bone formation estimated by serum levels of alkaline phosphatase and osteocalcin. The fasting renal excretion of calcium was increased. whereas serum ionized calcium was unchanged. The maximal renal reabsorption of phosphate decreased. but it was not an effect of PTH as it decreased significantly during the treatment period. In conclusion. no significant effect on biochemical markers of bone remodelling could be detected during the study period. The observed changes in calcium and phosphate metabolism may be secondary to the renal effect of acetazolamide.
Validation of a simplified carbon-14-urea breath test for routine use for detecting Helicobacter [correction of Heliobacter] pylori noninvasively, A carbon-14 (14C) urea breath test for detecting Helicobacter pylori with multiple breath sampling was developed. Carbon-14-urea (110 kBq) administered orally to 18 normal subjects and to 82 patients with Helicobacter infection. The exhaled 14C-labeled CO2 was trapped at 10-min intervals for 90 min. The total 14C activity exhaled over 90 min was integrated and expressed in %activity of the total dose given. In normals. a mean of 0.59% +/- 0.24% was measured. resulting in an upper limit of normal of 1.07%. In 82 patients. a sensitivity of 90.2%. a specificity of 83.8%. and a positive predictive value of 90.2% was found. The single probes at intervals of 40-60 min correlated best with the integrated result. with r ranging from 0.986 to 0.990. The test's diagnostic accuracy did not change at all when reevaluated with the 40-. 50-. or 60-min sample data alone. Thus. the 14C-urea breath test can be applied routinely as a noninvasive. low-cost and one-sample test with high diagnostic accuracy in detecting Helicobacter pylori colonization.
Scales modified for dose determination in population-based chemotherapy, Integration of schistosomiasis control into primary health care services in The Gambia required semiliterate health workers to administer praziquantel and metrifonate to the community in doses based on weight. Special scales to weigh people with a direct readout in the form of numbers of tablets obviated the need to read figures or make calculations at the scene. The scales were used with a simple record system. Coverage of up to 97% was achieved with single dose praziquantel; for three doses of metrifonate spread over 2 months. coverage reached 82.4%. The tablet scale was easy to devise and fit to commercial scales.
Familial combined hyperlipidaemia linked to the apolipoprotein AI-CII-AIV gene cluster on chromosome 11q23-q24, Familial combined hyperlipidaemia (FCHL) is a common inherited disorder of lipid metabolism with a prevalence of 0.5-2.0% (refs 1. 2). It is estimated to cause 10% of premature coronary heart disease. The underlying metabolic and genetic defects in FCHL have not been identified. but a population study has suggested an association between FCHL and an XmnI restriction fragment length polymorphism (RFLP) within the apolipoprotein AI-CIII-AIV gene cluster. Here we confirm this association and show that it results from linkage disequilibrium between FCHL and the 6.6-kilobase (kb) allele of the XmnI RFLP. Subsequent analysis in seven FCHL families. ascertained through a proband carrying the 6.6 kb XmnI allele. demonstrated linkage to the AI-CIII-AIV cluster on 11q23-q24. zeta = 6.86 with no recombinants. This assignment will facilitate the identification of the mutation that causes hyperlipidaemia in these families.
The sinusitis cycle, Recent discoveries make it necessary to reevaluate many of the traditional assumptions concerning sinusitis. Within the past 10 years. investigators have detailed the pathophysiology of sinusitis. Occlusion of the sinus ostia initiates the sinusitis cycle; untreated. this leads to chronic sinusitis. Anatomic abnormalities also predispose the patient to chronic sinusitis because of ostial blockage. Investigators have identified and detailed the prevalence of both aerobic and anaerobic environments within the sinuses. demonstrating that ostial blockage creates an ideal culture medium within the sinus. Keeping the ostial passageways open is essential to allow reversal of the sinusitis cycle. especially in the presence of predisposing factors.
Paranasal sinus imaging, The inability of plain radiographs to yield conclusive information about the ostiomeatal complex in sinusitis is no longer a significant problem. Computed tomography (CT). magnetic resonance imaging (MRI). and improved endoscopic technology now enable almost complete exploration of the sinus anatomy and the pathophysiology of sinus disease. Nasal endoscopy provides a clear view of the anterior nasal cavity--including the middle meatus--in patients with symptoms of sinusitis. However. the maxillary ostia are still difficult to visualize directly. CT is required for noninvasive evaluation of deep ostiomeatal air passages and posterior ethmoid and sphenoid sinuses. MRI of the nasal cavity and paranasal sinuses. although of limited use for displaying nasal morphology. is even more sensitive than CT in identifying fungal concretions and neoplasms.
The clinician's view of sinusitis, Widespread underdiagnosis and inadequate treatment of acute sinusitis may be inferred from the prevalence of chronic sinusitis in the United States. Thus the otolaryngologist's role in the management of sinusitis goes beyond treatment of referred patients. It also includes the responsibility to educate referring physicians in improved diagnostic methods and earlier. more effective forms of therapy. While antral puncture is the sine qua non for determining specific diagnosis. standard radiographs and sound clinical judgment may offer practical alternatives. Early. aggressive antibiotic therapy (with ampicillin. amoxicillin. amoxicillin-clavulanate potassium. or appropriate cephalosporins). plus oral decongestants for symptomatic relief. provides therapeutic efficacy for acute sinusitis and should be considered the initial step toward prevention of chronic sinusitis.
Adjuncts to medical management of sinusitis, The basic principles of sinusitis therapy are to treat any infection present. facilitate drainage. and promote drainage both during and after treatment to prevent recurrence. Adjunctive measures promoting ciliary function and drainage through the sinus ostia include the following nonpharmacologic measures: steam. astringents. inhalations. saline. and hot. dry air. Pharmacologic measures include decongestants. topical corticosteroids for chronic sinusitis. mucoevacuants. and analgesics. Antihistamines are indicated for acute sinusitis only when a patient with concomitant allergies is symptomatic during the allergy season or after infection has been ruled out as the primary cause of sinusitis. Sinusitis may be associated with asthma. and some patients do not respond optimally to asthma therapy until their sinusitis is diagnosed and treated.
First-line management of sinusitis: a national problem? Surgical update, Radical stripping of diseased sinus mucosa has been considered the correct surgical approach to chronic sinusitis on the basis that severe mucosal thickening was irreversible. Now. nasal endoscopy has disproved this belief by showing that chronic sinusitis is primarily a disease of obstruction. with inflammation as a secondary manifestation. Once obstruction is surgically corrected and ventilation restored. the mucosa may regain near-normal appearance and function. For chronic sinusitis that fails to respond to antibiotic therapy--and for recurrent acute sinusitis associated with abnormalities of the ostiomeatal complex--functional endoscopic sinus surgery offers the patient real hope of permanent relief from symptoms of sinusitis. Careful postoperative follow-up with endoscopic evaluation enhances effectiveness of this more recent approach to sinus surgery. The importance of presurgical evaluation via endoscopy and computed tomography cannot be overemphasized.
Human papillomavirus type 16 nucleoprotein E7 is a tumor rejection antigen, It has been speculated that immunological mechanisms play an important role in the control of carcinomas associated with human papillomavirus (HPV). such as cervical cancers. We have now demonstrated that immunization of C3H/HeN mice by syngeneic nontumorigenic fibroblast-like cells that contain the transfected HPV-16 E7 gene conferred protection against transplanted cells from a HPV-16 E7-positive syngeneic tumor. This protection was HPV-16 E7-specific and was mediated by CD8+ lymphocytes. which presumably were cytotoxic T lymphocytes. These results indicate that tumor cells containing HPV-16 E7. either as a result of transfection. as in our studies. or naturally. as occurs in many human carcinomas. can induce a tumor-specific rejection response and serve as targets for such a response. The system described here provides an animal model to further study immune responses to HPV-associated malignancies and to test the efficacy of anti-HPV vaccines toward the therapy and prevention of such tumors.
Malignant melanoma in transgenic mice, Ocular and cutaneous melanomas arose in new inbred lines of transgenic mice having an integrated recombinant gene comprised of the tyrosinase promoter. expressed in pigment cells. and the simian virus 40 early-region transforming sequences. The tumors were hypomelanotic and were histopathologically similar to corresponding human melanomas. Eye melanomas often originated at a young age. chiefly from the retinal pigment epithelium. also from the choroid. and rarely from the ciliary body. The eye tumors grew aggressively. were highly invasive. and metastasized to local and distant sites. The earliest formation of these tumors was associated with higher copy numbers of the transgene; mice of different single-copy lines varied greatly in age of onset and frequency of eye tumors. Coat pigmentation was reduced in almost all lines. to various extents. Primary skin melanomas arose later and less frequently than eye melanomas. Hence they were at early stages and of unknown long-range incidence in this investigation. in which autopsies covered the first half-year of life. For both ocular and cutaneous melanomas. the transgenic mice offer numerous possibilities for experimental study of mechanisms underlying formation and spread of melanomas.
Purification of a plasma membrane-associated GTPase-activating protein specific for rap1/Krev-1 from HL60 cells, rap1/Krev-1 is a p21ras-related GTP-binding protein that has been implicated in the reversion of the ras-transformed cell phenotype. We have identified a GTPase-activating protein (GAP) specific for rap in plasma membranes isolated from differentiated HL60 cells. The rap GAP activity remained quantitatively associated with the membrane following washes with buffered 1 M LiCl containing 20 mM EDTA but was solubilized with the detergents Nonidet P-40 and deoxycholate. On the basis of size-exclusion chromatography. the membrane-associated rap GAP (rap GAPm) appeared distinct from the rap GAP detected in the cytosolic fraction from HL60 cells. The molecular sizes of the membrane and cytosolic forms were estimated to be 36 and 54 A. respectively. rap GAPm was solubilized and purified to near homogeneity by successive column chromatographies in the presence of detergent. The rap GAPm activity corresponded to a single polypeptide that migrated with a molecular mass of approximately 88 kDa on SDS/polyacrylamide gels. The purified rap GAPm was inactive toward the GTP-bound forms of p21ras. rho. G25K. and rac-1 and did not stimulate dissociation of guanine nucleotide from rap.
Glycosylphosphatidylinositol: a candidate system for interleukin-2 signal transduction, The mechanism of interleukin-2 (IL-2) signal transduction was analyzed by use of an inducible B lymphoma. Like normal antigen-activated B lymphocytes. the lymphoma cells respond to IL-2 by proliferating and differentiating into antibody-secreting cells; both responses are blocked by a second interleukin. IL-4. Analyses of the signaling pathway showed that IL-2 stimulated the rapid hydrolysis of an inositol-containing glycolipid to yield two possible second messengers. a myristylated diacylglycerol and an inositol phosphate-glycan. The myristylated diacylglycerol response exhibited the same IL-2 dose dependence as the growth and differentiative responses. and the generation of both hydrolysis products was inhibited by IL-4. These correlations implicate the glycosyl-phosphatidylinositol system in the intracellular relay of the IL-2 signal.
Storage of saline-adenine-glucose-mannitol-suspended red cells in a new plastic container: polyvinylchloride plasticized with butyryl-n-trihexyl-citrate, Blood collection and component preparation have been performed in integrally connected multiple plastic containers made with a new plastic. This polyvinylchloride (PVC) container plasticized with butyryl-n-trihexyl-citrate (BTHC) is a new material for blood storage; it contains no di(2-ethylhexyl)phthalate (DEHP). After removal of plasma and buffy coat. the red cells were suspended in saline-adenine-glucose-mannitol (SAGM) medium. After 42-day refrigerator storage. the total adenine nucleotide concentration remained the same as the initial concentration in the red cells. whereas ATP levels had decreased to 61 percent of the initial value. The 2.3 DPG concentration was 62 percent of normal on Day 7 and 21 percent on Day 14. Glucose consumption. lactate production. potassium leakage from red cells. and pH levels were similar to those found after storage in DEHP-plasticized containers under the same conditions. After 42 days. hemolysis levels were 0.56 +/- 0.21 percent and 0.42 +/- 0.17 percent in two series of units mixed weekly and 0.70 +/- 0.27 percent in units stored unmixed. Although even higher levels of hemolysis were observed in the units stored unmixed and used for 24-hour posttransfusion survival. the autologous red cell recovery results were excellent (83.2 +/- 5.1%. n = 8). BTHC-plasticized PVC is found to be a suitable material for 42-day storage of red cells in SAGM solution.
Response to orchiectomy following Zoladex therapy for metastatic prostate carcinoma, Serum testosterone and prostate-specific antigen (PSA) levels were measured in 3 patients with Stage D2 prostate cancer before and after discontinuation of the long-acting LHRH agonist. goserelin acetate (Zoladex). The patients had received goserelin acetate for ten. sixteen. and thirty months prior to discontinuing the drug because of progressive metastatic disease. In all 3 patients. PSA and testosterone levels increased after goserelin acetate was discontinued. In 2 patients the testosterone level reached normal levels. A bilateral orchiectomy was performed one hundred sixty. one hundred. and seven days. respectively. after the drug was discontinued. In all 3 cases PSA and testosterone levels were reduced following castration. although PSA levels again began to increase within two weeks of orchiectomy in 2 of the 3 patients. These findings suggest that suppression of testosterone by LHRH agonists is not permanent and if tumor progression occurs. maintaining hormone suppression may still be beneficial.
Benjamin Felson lecture. Chronic interstitial lung disease of unknown cause: a new classification based on pathogenesis, Chronic interstitial lung disease of unknown cause is usually classified on the basis of descriptive histology. In this lecture. a recently published series of 910 cases of chronic interstitial lung disease is used to show that these descriptive terms can be reorganized into a classification that is based on inflammatory and neoplastic processes. The proposed classification includes three major diagnostic categories. two of which are based on the chronic inflammatory response and a third that results from infiltration of the interstitial space by neoplastic cells of either a benign. borderline. or frankly malignant nature. An argument is presented that the steps involved in the development of the endstage of chronic interstitial lung disease are similar in all three groups. The advantage of this new classification is that it shifts the emphasis from descriptive terminology to pathogenesis. which provides a more critical basis for investigation of the causes of these diseases.
Value of sonography in monitoring the therapeutic response of mediastinal lymphoma: comparison with chest radiography and CT, The aim of this retrospective study was to assess the diagnostic value of mediastinal sonography. compared with that of chest radiographs and CT. in the follow-up of patients with mediastinal lymphomas and in the prediction of clinical outcome. The sonograms. chest radiographs. and CT scans of 40 consecutive patients with Hodgkin (n = 29) and non-Hodgkin (n = 11) lymphoma obtained before and after completion of therapy were analyzed blindly and independently by three radiologists and compared with clinical outcome. Nine patients were treated with radiotherapy. 12 with chemotherapy. and 19 with combined therapy. Therapeutic response was assessed from all available clinical and biochemical findings as well as from the combined results of all imaging studies performed on further follow-up. The sonograms showed obvious changes in the size and echogenicity of the mediastinal lymphomas that corresponded closely with the response to therapy. Sonography showed complete regression of the lymphomas in 30 patients who had complete remission. In five patients with incomplete remission. sonographic diagnoses were correct. All lymph nodes. irrespective of size. detected with sonography after a phase of complete remission indicated recurrence (five patients). Sonographic findings corresponded with those of CT in 25 (81%) of 31 cases. Clinical outcome suggested that the sonographic findings were more reliable in the five cases in which CT and sonographic findings conflicted. Chest radiographs were inadequate for monitoring the response of mediastinal lymphomas to therapy; in 17 (43%) of 40 cases. a false impression was obtained of the extent and therapeutic response of mediastinal lymphomas. The results of this study indicate that sonography is clearly superior to chest radiographs and comparable to CT for monitoring patients with mediastinal lymphomas.
Videofluoroscopy in elderly patients with aspiration: importance of evaluating both oral and pharyngeal stages of deglutition, Oropharyngeal functional impairment increases with age so that radiologists frequently are asked to determine the cause of aspiration in elderly patients. Neuromuscular and cognitive impairment often make it difficult to perform and interpret videofluoroscopic deglutition examinations in these patients. We retrospectively reviewed the barium swallow examinations in 50 elderly patients (mean age. 87 years) who were known to aspirate. We looked for specific patterns of oropharyngeal dysfunction that resulted in bolus misdirection. Analysis revealed that aspiration was due to abnormalities of the oral stage in 23. pharyngeal stage in 10. and both stages in 17. Dysfunction in the oral stage was due to ingestion of large volumes or rapid acquisition rates in nine. failure of containment during processing (bolus manipulation) in 18. and dissociation of lingual delivery and swallowing initiation in the transitional phase in 13. Dysfunction in the pharyngeal stage was due to incomplete transport (bolus retention) in 21 and defective closure of the laryngeal vestibule in 11. No significant relationship between conditions known to cause oropharyngeal dysfunction (dementia. stroke. Parkinson disease. disuse deconditioning) and the specific pattern of dysfunction was identified. These results indicate that an accurate and valid assessment of oropharyngeal dysfunction in elderly patients with aspiration is possible if specific patterns of dysfunction are sought. Our study indicates the importance of evaluating the oral and pharyngeal stages of deglutition in elderly patients who aspirate.
Carcinoma of the esophagus: CT vs MR imaging in determining resectability, MR imaging and CT were performed prospectively in 35 patients with esophageal carcinoma to determine the resectability of the primary tumors. because at our institution patients with resectable tumors have surgery regardless of the presence of distant metastases. Tumors with evidence of aortic or tracheobronchial invasion on MR or CT were considered to be unresectable. Tracheobronchial invasion was diagnosed when the tumor extended into the lumen of the airway. and aortic invasion was diagnosed when the triangular fat space between the esophagus. aorta. and spine adjacent to the primary tumor was obliterated. Two patients were excluded because of suboptimal MR images produced by motion artifacts. Pathologic proof was obtained from either surgery or autopsy in 31 patients. Of these. six patients (19%) had proved unresectable tumors (three aortic invasion and three tracheobronchial invasion). In all six cases. these features were correctly detected with both MR and CT. One patient had false-positive findings on MR and CT. An indeterminate diagnosis was obtained with MR in three patients and with CT in four patients. These incorrect or indeterminate results were all related to the diagnosis of aortic invasion. No patient had a false-negative result. When indeterminate diagnoses were considered false-positive. sensitivity. specificity. and accuracy for resectability were 100%. 84%. and 87%. respectively. for MR and 100%. 80%. and 84%. respectively. for CT. We conclude that MR and CT have nearly the same accuracy in predicting resectability of tumors in patients with esophageal carcinoma.
Fatty infiltration of the liver: quantification with phase-contrast MR imaging at 1.5 T vs biopsy, Quantification of hepatic fat content by application of MR phase-contrast imaging (Dixon method) at 1.5 T was compared with results of biopsy in 16 patients with a variety of liver abnormalities. Motion artifact was suppressed by employing six or eight averages of short TR in-phase (echo offset. 0 msec). out-of-phase (echo offset. 1.1 msec). and in-phase (echo offset. 2.2 msec) spin-echo pulse sequences. The 360 degree out-of-phase sequence was used to assess the impact of T2* decay on this method of estimating fat fraction. A standard two-echo long TR sequence also was obtained in all patients. Histologic preparations from the biopsy specimens were examined by a pathologist who had no knowledge of the MR results and were graded according to overall visual assessment as belonging to one of four categories of fat fraction. Results of the MR-calculated apparent fat fraction were compared directly with biopsy category and were also placed in MR fat fraction categories. allowing estimation of the statistical correlation between the biopsy and MR grading systems. Eight of eight patients with biopsy categories indicating a fat fraction of less than 0.25 were computed by MR to have a fat fraction of less than 0.1. Seven of eight patients with biopsy categories indicating a fat fraction of greater than 0.25 were computed by MR to have a fat fraction of at least 0.24. The MR-calculated apparent fat fraction category correlated significantly with the histologic biopsy category (r = .86. p less than .01). When compared with the in-phase image. decreased signal from liver was visually apparent on the 180 degree out-of-phase images in all cases in which the fat fraction was at least 0.24. but there was no indication of fatty liver on the standard T1- or T2-weighted images. Calculated T2 also showed no correlation with degree of fatty deposition. Correction for T2* decay by using the 360 degree out-of-phase acquisition in addition to the standard 0 degree and 180 degree out-of-phase images had little effect on fat fraction computation. Phase-contrast MR is a promising noninvasive method for quantitative assessment of fatty deposition in the liver.
Focal nodular hyperplasia of the liver: MR findings in 35 proved cases, MR images of 28 patients with 35 lesions of hepatic focal nodular hyperplasia were reviewed to determine the frequency of findings considered typical of this condition (isointensity on T1- and T2-weighted pulse sequences. a central hyperintense scar on T2-weighted images. and homogeneous signal intensity). Fifteen lesions were imaged at 0.6 T with T1- and T2-weighted spin-echo (SE) pulse sequences; 20 lesions were imaged at 1.5 T with T1-weighted SE and gradient-echo pulse sequences and T2-weighted SE pulse sequences. Diagnosis of focal nodular hyperplasia was made pathologically in 25 patients. with nuclear scintigraphy in four. and with follow-up imaging in six. Only seven lesions (20%) were isointense relative to normal liver on both T1- and T2-weighted images. On T1-weighted SE images. 21 lesions (60%) were isointense relative to normal liver. 12 (34%) were hypointense. and two (6%) were hyperintense. On T2-weighted SE images. 12 lesions (34%) were isointense and 23 (66%) were hyperintense relative to normal liver. A central scar was present in 17 lesions (49%) and was hypointense relative to the lesion on T1-weighted images and hyperintense on T2-weighted images. Twenty lesions (57%) were of homogeneous signal intensity throughout the lesion. except for the presence of a central scar. All three MR imaging characteristics were present in three cases (9%). We conclude that hepatic focal nodular hyperplasia has a wide range of signal intensity on MR imaging.
Choledochal cysts: classification and cholangiographic appearance, A classification scheme for choledochal cysts is outlined and their appearance on cholangiograms is illustrated. Choledochal cysts are uncommon anomalies of the biliary system and are probably congenital in origin. They are manifested by cystic dilatation of the extra- or intrahepatic biliary tree or both. The classification system described here divides choledochal cysts into one of five main types. The most common. which is manifested by cystic or focal segmental dilatation of the common bile duct or fusiform choledochal dilatation. accounts for 80-90% of cases.
MR of the knee: the significance of high signal in the meniscus that does not clearly extend to the surface, On MR images of the knee it is sometimes impossible to determine with confidence if a focus of high signal in the meniscus is confined to the substance of the meniscus or if it extends to involve the surface. This is a critical differentiation because the latter represents meniscal tears that can be found and treated at arthroscopy. whereas the former represents degeneration. tears. or perhaps normal variants that cannot be detected or treated arthroscopically. We make an equivocal diagnosis of a tear when it is difficult to decide if signal in a meniscus involves the meniscal surface. We studied MR scans of the knee in 142 consecutive patients for the presence of such equivocal tears. Their prevalence was 14% (20/142); 17 were in the posterior horn of the lateral meniscus and three were in the posterior horn of the medial meniscus. In 13 cases with arthroscopy/arthrotomy correlation. no tears were found. In one of the 20 patients in whom the meniscus was removed during arthroplasty. histologic examination of the meniscus showed separation of collagen bundles. which was caused by meniscal degeneration confined to the substance of the meniscus. These results suggest that a meniscal tear is unlikely when MR scans show a focus of high signal in a meniscus that does not unequivocally extend to involve the surface of the meniscus.
MR imaging of synovial sarcoma, The MR imaging findings in 12 cases of synovial sarcoma are illustrated. The MR appearance most indicative of the tumor is an inhomogeneous septated mass with infiltrative margins located close to a joint. a tendon. or bursae. especially if soft-tissue calcification can be seen on CT scans or plain radiographs.
Calcification of the ligamentum arteriosum in children: a normal finding on CT, Calcification of the ligamentum arteriosum is a rare finding on plain radiographs. We commonly have seen the calcification on unenhanced CT scans of the chest. a finding not previously reported. A retrospective review of unenhanced CT scans of the chest was undertaken to determine the frequency of the described finding. Seven (13%) of 53 patients had a well-demarcated focus of calcification in the region of the ligamentum arteriosum. None of these patients had evidence of a patent ductus arteriosum. Calcification within the ligamentum arteriosum was seen in 13% of routine CT examinations of the chest in children and should not be confused with a pathologic process producing mediastinal calcifications.
Unilateral hydrocephalus: prenatal sonographic diagnosis, We studied six cases of unilateral hydrocephalus detected prenatally to analyze the sonographic features of the abnormality and to determine the cause and clinical outcome. In all cases. third-trimester sonograms showed marked unilateral lateral ventriculomegaly (mean atrial width. 4.4 cm) and normal contralateral lateral. third. and fourth ventricles. Five of the six cases had marked thinning of the cortical mantle on the affected side and shift of midline structures to the contralateral side. The causes of unilateral hydrocephalus were agenesis or stenosis of the foramen of Monro in three cases. transient obstruction of the foramen in one fetus with an intraventricular hematoma. underlying brain dysplasia in one fetus with a variant of holoprosencephaly. and undetermined in one case. All six neonates had placement of a ventriculoperitoneal shunt catheter; four of these have had normal cognitive development at follow-up. The remaining two infants have moderate to severe developmental impairment. Unilateral hydrocephalus is a rare anomaly that can be recognized by prenatal sonography. Even though unilateral ventriculomegaly may be marked. early diagnosis and treatment may result in a favorable clinical outcome.
Intracranial vascular abnormalities: value of MR phase imaging to distinguish thrombus from flowing blood, The interpretation of conventional spin-echo and gradient-echo MR images of intracranial vascular lesions can be complex and ambiguous owing to variable effects on image intensity caused by flowing blood or thrombus. MR phase images. obtained simultaneously with conventional-magnitude images. are useful for evaluating proton motion (i.e.. blood flow). and therefore can simplify the diagnosis of the presence or absence of thrombosis within a vascular structure or lesion. Fourteen patients with a variety of intracranial vascular abnormalities (aneurysms. superior sagittal sinus thrombosis. neoplasms adjacent to venous sinuses. and vascular malformations) were evaluated with conventional MR and phase imaging for the presence of blood flow. The phase images correlated with angiography in all cases. Phase imaging was not necessarily better than conventional spin-echo imaging in all cases. but it simplified the evaluation of thrombus vs blood flow in many. In three of five aneurysms. the phase images were diagnostic for evaluating lumen patency whereas the conventional images were ambiguous. Phase imaging was advantageous for detecting tumor invasion of the venous sinus when venous blood was enhanced by gadopentetate dimeglumine. A laminar flow phantom experiment determined the lower limits of sensitivity of phase imaging to be 0.5 cm/sec in the slice-select and 2.5 cm/sec in the read gradient directions. Phase imaging is a simple. reliable technique that can distinguish thrombosis from flowing blood within intracranial lesions. It is easily performed and adds no additional time to the MR examination.
Paranasal sinuses on MR images of the brain: significance of mucosal thickening, One hundred twenty-eight patients were examined prospectively to determine the significance of mucosal thickening seen in the paranasal sinuses during routine MR imaging of the brain. On the basis of responses to a questionnaire. each patient was categorized as symptomatic (n = 60) or asymptomatic (n = 68) for paranasal sinus disease. Patients were categorized further on the basis of the maximal mucosal thickening seen by MR in any paranasal sinus. A modified t test was used to compare the prevalence of various degrees of mucosal thickening between symptomatic and asymptomatic groups. Statistically significant differences between the groups were seen only in those patients with normal sinuses and in those with 4 mm or more of mucosal thickening. We conclude that mucosal thickening of up to 3 mm is common and lacks clinical significance in asymptomatic patients. An ancillary finding is that 1- to 2-mm areas of mucosal thickening in the ethmoidal sinuses occur in 63% of asymptomatic patients. This minimal mucosal thickening in the ethmoidal sinuses is thought to be a normal variant. possibly a function of the physiologic nasal cycle.
Angiography is useful in detecting the source of chronic gastrointestinal bleeding of obscure origin, The treatment of patients with chronic gastrointestinal bleeding can be a frustrating diagnostic challenge. In the past 10-15 years. a variety of new diagnostic procedures (e.g.. fiber-optic endoscopy. scintigraphy. and double-contrast barium studies) have become available to examine these patients. Despite these new procedures. a small number of patients continue to bleed without a defined cause. We sought to evaluate the role of visceral angiography in patients with chronic gastrointestinal bleeding in whom findings on an extensive noninvasive workup have been normal. Between 1983 and 1990. we obtained angiograms on 36 such patients. The cause of bleeding was established by angiography in 16 patients (44%). In 11 of these 16. angiography revealed only a structural abnormality without active bleeding. Twenty patients had normal angiographic findings. No angiograms were false-positive. but three were false-negative (8%). No complication occurred as a result of the angiographic procedures. Our experience shows that visceral angiography can provide a positive diagnosis in a significant number of patients with chronic gastrointestinal bleeding of obscure origin in whom all other diagnostic measures have been unrevealing. Despite improvements in noninvasive diagnostic techniques. angiography still remains an important tool for examining this group of patients.
Iliac artery stenosis or obstruction after unsuccessful balloon angioplasty: treatment with a self-expandable stent, Obstruction or stenosis of the iliac artery was treated by placement of a self-expandable stent in 91 patients. A total of 100 lesions was treated. All patients had had poor results of balloon angioplasty including residual stenosis. iliac occlusion. and dissection. The stent used in all cases was a self-expandable stainless steel endoprosthesis mounted on a 7- or 9-French catheter and covered by an invaginated tubular rolling membrane. The diameter of the expanded stent varied from 7 to 12 mm. A total of 129 stents was placed. Technical success was 97%. Thromboses occurred immediately after placement in two patients and within the first month in six; these were mainly due to residual obstruction. Eighty-two (93%) of 88 patients with a follow-up longer than 3 months had no recurrent symptoms. Restenosis caused by intimal hyperplasia inside the stent occurred in 10 patients; these required repeated intervention in only four cases. In the remaining six patients. no further complications occurred. Our results show that self-expanding endoprostheses are of value for improving the results of inadequate percutaneous transluminal angioplasty.
Effects of percutaneous transvenous mitral commissurotomy on levels of plasma atrial natriuretic peptide during exercise, To clarify the factors that influenced the secretion of human atrial natriuretic peptide (ANP) during exercise. we studied the relations between the changes in ANP. transmitral pressure gradient. heart rate and blood pressure at exercise in 16 patients with mitral stenosis before and after percutaneous transvenous mitral commissurotomy (PTMC). Before PTMC. ANP levels increased from 107 +/- 70 to 183 +/- 96 pg/ml during exercise testing (p less than 0.01). concomitant with the increment in mean transmitral pressure gradient. heart rate and systolic blood pressure. After PTMC. ANP levels also increased from 78 +/- 43 to 117 +/- 64 pg/ml. concomitant with the increment of those parameters. However. increments of ANP. mean transmitral pressure gradient and heart rate after PTMC were lower than those before PTMC. Because the most important factor influencing the secretion of ANP was unclear. the differences between these parameters were calculated at submaximal exercise before and after PTMC. There was a significant relation only between the change in ANP and mean transmitral pressure gradient (r = 0.70. p less than 0.01). These results suggest that the most important factor influencing the secretion of ANP during exercise is the change in transmitral pressure gradient in patients with mitral stenosis.
Pathogenesis of pulmonary fibrosis in interstitial lung disease. Alveolar macrophage PDGF(B) gene activation and up-regulation by interferon gamma, Alveolar macrophages are believed to be central in orchestrating the fibrotic response in interstitial lung disease (ILD). To test the hypothesis that macrophages from patients with ILD were dedicated to growth factor production and that this was independent of other indices of macrophage activation. we measured the mRNA of the B chain of PDGF and TGF-beta. as well as HLA-DR-alpha in alveolar macrophages from patients with ILD and from normal control subjects. When alveolar macrophages were examined immediately after lavage. cells from patients with ILD had increased PDGF(B) but similar TGF-beta and HLA-DR-alpha mRNA when compared with control subjects. Discoordinate regulation of these genes was observed when alveolar macrophage PDGF(B) mRNA increased while TGF-beta and HLA-DR-alpha mRNA decreased after culture for 24 h. This response was not disease-related as these changes were similar in cells from patients with ILD and from control subjects. Because a lymphocytic alveolitis is present in many cases of ILD. we asked whether interferon gamma (IFN-gamma) modulated the activation of these genes. In both the patients and the control subjects. PDGF(B) and HLA-DR-alpha. but not TGF-beta. mRNA were increased after incubation with IFN-gamma. These results indicate that PDGF(B) mRNA may be increased in alveolar macrophages in ILD and that PDGF(B). TGF-beta. and HLA-DR-alpha are independently regulated genes in alveolar macrophages. but that IFN-gamma increases both PDGF(B) and HLA-DR-alpha mRNA. We speculate that IFN-gamma induced PDGF(B) gene activation may be an important mechanism by which lymphocytes promote pulmonary fibrosis.
Early combination of selegiline and low-dose levodopa as initial symptomatic therapy in Parkinson's disease. Experience in 26 patients receiving combined therapy for 26 months, Thirty-eight patients newly diagnosed as having Parkinson's disease (mean age. 57.3 years; mean Parkinson's disease duration. 2.7 years) in the earlier phase of the disease (mean Hoehn/Yahr stage. 2; mean motor scores. 11.4) were given selegiline (Deprenyl). 10 mg daily. and maintained on this drug alone until significant clinical worsening warranted the addition of low-dose levodopa (Sinemet. 25/100 three to four doses per day). Five of these patients were not yet receiving additional levodopa despite some worsening of motor scores. Of the 33 patients now taking combined therapy. seven have been followed up for 6 months or less. Twenty-four (92%) of the 26 patients taking combined therapy for a mean of 26 months (8.5 to 99 months) who have had Parkinson's disease for 6 years showed a dramatic improvement in their parkinsonism shortly after the addition of levodopa. with significant decreases in their rated motor scores. such improvement being maintained at their latest neurologic evaluation. Eighteen (75%) of these 24 patients responded to the combined selegiline/levodopa therapy with degrees of improvement equal to or greater than 50%. compared with their motor status at the start of combined therapy just before the addition of levodopa. This degree of "reversal" of parkinsonism on addition of levodopa (mean carbidopa/levodopa dose. 98/389 mg) was not observed in any of these same patients receiving selegiline alone for an average of 13.8 months. Four patients taking combined therapy developed mild. transient. abnormal involuntary movements. and end-of-dose pattern of response after more than 2 years of combined therapy (24.75 and 33.5 months. respectively).
Different pathohistological presentations of acute renal involvement in Hantaan virus infection: report of two cases, We present two patients with Hantaan virus infection. admitted to the Department of Nephrology. Skopje. at the same time. with the same clinical presentation (chills. fever. abdominal pain. hemorrhages. nausea. headache. proteinuria. hematuria. oliguria. acute renal failure) but with different pathohistological findings and different disease courses. In the first case diffuse proliferative glomerulonephritis was found. with a complete recovery of renal function after a month. with a mild proteinuria and erythruria during the second and the third month. In the second case. glomeruli were normal in general. with slight mesangial proliferation found in two out of twenty. but interstitial edema. lymphocyte infiltrations and tubular changes were noted. Complete recovery was not noted after 3 months of follow-up. The patient is now without hemodialysis treatment. with polyuria. in the stable phase of chronic renal failure which is not improving.
Validation of the Glasgow Meningococcal Septicemia Prognostic Score: a 10-year retrospective survey, OBJECTIVE: To derive performance characteristics for the Glasgow Meningococcal Septicemia Prognostic Score (GMSPS). DESIGN: Retrospective case-note study. SETTING: Two children's hospitals with Regional Intensive Care Unit. PATIENTS: One hundred twenty-three children with proven meningococcal septicemia (some with concurrent meningitis) from January 1. 1977 to December 31. 1986. MEASUREMENTS AND MAIN RESULTS: All 14 children who died after arrival scored greater than or equal to 8 either on admission (n = 8) or afterward (n = 6). Of 109 survivors. five scored greater than or equal to 8 (two were postictal at the time of scoring). A GMSPS of greater than or equal to 10 at or after admission predicted death with sensitivity 100%. specificity 98%. and positive predictive value of 88%; for GMSPS of both greater than or equal to 8 or 9. the values were 100%. 95%. and 74%. respectively. CONCLUSIONS: The GMSPS is a rapid clinical score that performs well in identifying children with poor prognosis who might benefit from early intensive care. It should be studied prospectively and compared with other scoring systems.
Total parenteral nutrition increases mortality after hemorrhage, OBJECTIVES: To determine the effect of total parenteral nutrition (TPN) and different enteral feeding formulas on survival and liver function following hemorrhage in rats. DESIGN: Prospective randomized controlled study. SETTING: Laboratory of a large university-affiliated medical school. SUBJECTS: Sixty-seven male Sprague-Dawley rats weighing 350 to 450 g. INTERVENTIONS: Jugular and gastroduodenal feeding catheters were inserted in animals 1 day before hemorrhage. and animals were started on one of six different fluid or nutritional regimens: TPN. iv saline. an enteral amino acid-based formula (AA) (Vivonex-TEN). an enteral peptide-based formula (PEP) (Reabilan-HN). an enteral intact-protein based formula (PRO) (Osmolite-HN). or enteral saline. A catheter was inserted in the tail artery and animals were hemorrhaged 5 mL/kg at baseline and 1 hr later. Animals were returned to their cages and observed for survival. Liver function was determined by measuring circulating bile acid levels at baseline and 24 hr after hemorrhage. MEASUREMENTS AND MAIN RESULTS: Mortality was significantly increased in animals receiving TPN (63%) and AA (24%). Mortality was 13% in animals receiving PRO and 0% in animals receiving PEP and saline. Liver function deteriorated in all animals after hemorrhage except the PEP group. CONCLUSIONS: TPN and AA increased mortality in animals after hemorrhage. PEP was associated with zero mortality and protection of liver function after hemorrhage.
Early miscarriage and fetal malformations after induction of ovulation (by clomiphene citrate and/or human menotropins), in vitro fertilization, and gamete intrafallopian transfer, From the reviewed data. it appears that CC. hMG-hCG. or the association of these drugs with IVF-ET and GIFT programs do not carry an increased risk for congenital malformations as a whole. nor is there any specific malformation that has an increased incidence or is related in any way with the use of these drugs. Table 7 represents the specific malformation rate per 1.000 births in the general population and in newborns delivered after treatment with CC. hMG-hCG. or IVF-ET and GIFT. The malformation rate in the treated groups does not differ from that of the general population. However. as shown by McIntosh et al.. the incidence of congenital malformations often rises with a longer follow-up. Most of the reports about babies born after ovulation induction are based on the initial examination done shortly after birth. Thus. studies including examination of these infants up to at least 12 months of age will be undoubtedly of value. Also. data concerning the reproductive capability of women born after ovulation induction is lacking. With regard to the abortion rate in pregnancies achieved after such treatments and procedures. it can be concluded that it does not appear to be higher than that of the general population. particularly when early pregnancy loss. advanced maternal age. the infertility status. and the increased incidence of multiple pregnancies occurring in these patients are taken into consideration.
Decrease in luteal gonadotropin concentration in conception cycles after in vitro fertilization/gamete intrafallopian transfer, The concentrations of the gonadotropins. luteinizing hormone (LH). and follicle-stimulating hormone (FSH) were measured in the luteal phase of the cycle in patients undergoing ovarian hyperstimulation. In nonconception cycles. FSH and LH were increased in the late luteal phase compared with conception cycles in which both gonadotropins were suppressed. Estradiol (E2) and progesterone concentrations increased in pregnancy cycles and may be the sole cause for the decreased gonadotropin concentrations as shown by equivalent concentrations of LH and FSH in both pregnancy and nonpregnancy cycles after matching for E2 concentrations. Subjects who subsequently had twin pregnancy or a spontaneous abortion were compared with those with a successful ongoing singleton conception. There were no significant differences relative to LH and FSH between the three groups. although in twin pregnancy FSH tended to be lower at day 16 from oocyte recovery. It is concluded that suppression of LH and FSH in hyperstimulated pregnancy cycles occurs after the time of the rising human chorionic gonadotropin concentrations in plasma.
A comparative, randomized study of low-dose human menopausal gonadotropin and follicle-stimulating hormone in women with polycystic ovarian syndrome, Treatment with low-dose follicle-stimulating hormone (FSH) is associated with a high rate of ovulation in anovulatory women with polycystic ovarian syndrome (PCOS). but it is not clear whether the success of treatment is because of the use of pure FSH or the low dose of gonadotropin. We undertook a randomized controlled study to compare the effects of urinary FSH and human menopausal gonadotropin (hMG) using a low-dose regimen in 30 women with PCOS. Each subject received a maximum of three cycles of either FSH or hMG. Ovulation occurred in 75% of subjects and in 77% of cycles induced with FSH and in 94% of women. 85% of cycles of those treated with hMG. A single dominant follicle developed in 70% (FSH) and 65% (hMG) of cycles. respectively. Five singleton pregnancies occurred in each group. This study shows that low-dose FSH and hMG are equally successful in inducing ovulation. suggesting that the success of treatment depends on the low dose of gonadotropin used rather than the presence or absence of luteinizing hormone in the preparation.
Use of combined exogenous gonadotropins and pulsatile gonadotropin-releasing hormone in patients with polycystic ovarian disease [published erratum appears in Fertil Steril 1991 Jun;55(6):1213, We previously tested a combined regimen based on the administration of gonadotropin in the early follicular phase followed by pulsatile gonadotropin-releasing hormone (GnRH) until complete follicular maturation in patients suffering from polycystic ovarian disease. Despite good clinical results. a high rate of premature luteinization was observed with this approach. We therefore evaluated in this study whether starting pulsatile GnRH therapy before gonadotropin administration might reduce premature luteinization. Eight women underwent induction of ovulation with both combined therapy and pure exogenous follicle-stimulating hormone alone using a crossover scheme. No premature luteinization and a single follicular growth were recorded with the modified combined regimen. Clinical results (8/8 versus 3/7 ovulatory cycles; 3/8 versus 1/7 pregnancies) favor the combined approach over gonadotropin alone.
The luteal phase after oocyte recovery in a spontaneous cycle, There is disagreement as to whether follicular aspiration and oocyte recovery leads to a defective luteal phase. A group of 20 women with mild endometriosis was studied over two consecutive spontaneous cycles. Follicular aspiration and oocyte recovery was performed 32 hours after the onset of the endogenous luteinizing hormone surge during the second cycle. There was little disturbance of the luteal phase or in the pituitary gonadal relationship in the aspirated cycle. Although a significantly lower serum progesterone was noted on day 8 of post-oocyte recovery. all results were within the normal range seen in the control cycles.
Metabolic effects of isradipine versus hydrochlorothiazide in diabetes mellitus [published erratum appears in Hypertension 1991 May;17(5):722, Most antihypertensive drugs have negative effects on metabolic control in diabetic patients. Calcium antagonists have been widely used in antihypertensive treatment of diabetics. although a possible influence on glucose tolerance. insulin secretion. and insulin action is unknown. Therefore. the effect of the calcium antagonist isradipine on glucose tolerance and insulin secretion (75 g oral glucose tolerance test) and on peripheral and hepatic insulin action (euglycemic clamp) was evaluated in 11 type II diabetic patients. All patients were treated with placebo or isradipine for 8 weeks (double-blind. crossover design). A second group of six diabetic patients received a thiazide diuretic. hydrochlorothiazide. according to the same protocol. Systolic blood pressure was significantly lowered after isradipine and hydrochlorothiazide compared with placebo (127 +/- 3 versus 139 +/- 6 mm Hg and 129 +/- 4 versus 142 +/- 4. respectively; p less than 0.05). Fasting blood glucose (190 +/- 21 versus 152 +/- 15 mg/dl; p less than 0.01). glucose levels. basal and glucose-stimulated insulin levels were significantly higher after hydrochlorothiazide compared with placebo but remained unchanged after calcium antagonist treatment. Basal hepatic glucose production and peripheral insulin resistance were significantly elevated after hydrochlorothiazide compared with placebo or calcium antagonist therapy. These data indicate that the calcium antagonist isradipine has no effect on glucose tolerance. insulin secretion. and insulin action in type II diabetic patients and might therefore be a useful drug for antihypertensive treatment in diabetes mellitus. However. diuretic treatment can lead to impairment of metabolic control and reduction of insulin action in type II diabetes mellitus.
Reasons for the lack of benefit of immediate angioplasty during recombinant tissue plasminogen activator therapy for acute myocardial infarction: a regional wall motion analysis. European Cooperative Study Group, Regional ventricular wall motion analysis utilizing three different methods was performed on predischarge left ventriculograms from 291 of 367 patients enrolled in a randomized trial of single chain recombinant tissue-type plasminogen activator (rt-PA). aspirin and heparin with and without immediate angioplasty in patients with acute myocardial infarction. With univariate analysis. no difference in regional wall motion variables between the two treatment groups was observed. However. with individual baseline risk assessment by multivariate linear regression analysis using baseline characteristics known to be related to left ventricular function after thrombolytic therapy or outcome of coronary angioplasty. or both. an excess of high risk patients in the invasive treatment group was detected. To adjust for this unequal distribution of baseline risk. multivariate linear regression analysis was performed. No benefit of immediate coronary angioplasty was observed after adjustment. Reocclusion or reinfarction. or both. occurred more frequently in the invasive than in the noninvasive treatment group (18% versus 13%. respectively). Among patients with a patent infarct-related vessel on angiography between days 10 and 22 and without reinfarction before angiography. there was a trend toward benefit from the invasive strategy. indicating that reocclusion and reinfarction might be responsible for the lack of benefit of the invasive strategy. This implies that immediate coronary angioplasty may be beneficial in selected patients. provided that these complications can be prevented.
Cardiac tamponade early after thrombolysis for acute myocardial infarction: a rare but not reported hemorrhagic complication, Among 392 consecutive patients admitted for acute myocardial infarction and treated with thrombolytic drugs. 4 patients (1%) developed an early hemorrhagic pericardial effusion (without ventricular wall rupture) evolving within 24 h to cardiogenic shock consequent to cardiac tamponade. They all suffered from a large anterior myocardial infarction treated within 4 h after onset of symptoms with intravenous anisoylated plasminogen streptokinase activator complex (one case). recombinant tissue-type plasminogen activator (rt-PA) (two cases) or streptokinase (one case). anticoagulation with heparin (all cases) and aspirin (three cases). As soon as pericardial effusion was established by echocardiography. emergency percutaneous pericardiocentesis was performed at the bedside 20 +/- 6 h after thrombolytic therapy was started. This corrected immediately the clinical and hemodynamic status of each patient and a catheter was left in the pericardial space for 34 +/- 18 h. Thus. in the presence of unexplained clinical and hemodynamic deterioration occurring during the first 24 h after thrombolytic treatment of a large myocardial infarction. cardiac tamponade should be suspected. Immediate percutaneous pericardiocentesis followed by continuous drainage is a simple and definitive treatment for this complication.
Delayed plasma clearance of phenylalanine and tyrosine in elderly men, The plasma levels of 17 amino acids were measured in three groups of men: healthy young men. healthy elderly men. and demented tube-fed elderly men living in a nursing home. prior to. and again 2. 4. and 6 hours after the consumption of a standard protein-containing meal. The standard meal provided per kilogram of body weight 8.3 calories. 0.33 grams of protein. 0.90 grams of carbohydrate. and 0.37 grams of fat. The concentrations of all amino acids. except tryptophan. rose significantly at 2 hours and returned to baseline by 6 hours. Plasma phenylalanine and tyrosine were significantly (P less than 0.05) higher at 2 hours in the two groups of elderly men than in the young healthy men. In other respects the pre- and post-prandial amino acid profiles were not influenced by age. The ratio. tyrosine/other large neutral amino acids (tyr/LNAA). was significantly higher in both elderly groups than in the young men at nearly all time points before and after the test meal. It was generally higher in the demented older men than in the healthy older men. The data demonstrated a delayed plasma clearance of phenylalanine and tyrosine in old age. The elevated plasma tyr/LNAA ratio in the elderly men may have tended to augment an entry of tyrosine. the precursor of norepinephrine and dopamine. into their brains.
Genetic analysis of diabetes in the nonobese diabetic mouse. I. MHC and T cell receptor beta gene expression, Backcross nonobese diabetic (NOD) ((NOD x SWr)F1 x NOD) mice (108 females and 105 males) were typed for MHC. TCR V beta. and monitored for 350 days for the onset of diabetes. The presence of "antipolar" antibodies in the sera and the occurrence of insulitis was examined in a proportion of these backcross mice. There was no difference in the incidence of diabetes in mice heterozygous for TCR V beta b/a vs those homozygous for TCR V beta b/b. Among the 17 diabetics (all female) detected in this backcross. 14/17 were H-2nod/nod but 3/17 were H-2nod/q. This supports a previous observation suggesting that the MHC-linked diabetogenic gene originally thought to be recessive may rather be dominant but have a low penetrance in the heterozygous state. Antipolar autoantibodies were found in both female and male backcross mice. and were similarly distributed in diabetic and nondiabetic mice. There appeared to be no correlation between the level of these auto-antibodies and development of diabetes. The incidence and severity of insulitis was linked to MHC but no influence of TCR genes on insulitis nor an association between insulitis and antipolar antibodies could be demonstrated in this study. Further analyses of H-2nod/nod intercross mice homozygous for TCR V beta a or TCR V beta b are currently underway.
Molecular analysis of IgM rheumatoid factor binding to chimeric IgG, To localize regions on IgG bound by rheumatoid factors (RF). we studied IgM RF binding to chimeric IgG antibodies consisting of murine V regions fused to human constant regions. Using a modified RF ELISA. we showed that polyclonal RF from rheumatoid arthritis patients bound IgG1. 2. and 4 strongly; IgG3 was also bound. although less well. The majority of 18 monoclonal RF from patients with Waldenstrom's macroglobulinemia bound IgG1. 2. and 4 only. In contrast to RF from RA. 14 of 18 monoclonal RF did not react with IgG3. Only 3 of 18 monoclonal RF bound IgG3 well. By shuffling C region domains between IgG3 and IgG4. we showed that sequence variation in the CH3 domain is responsible for the differential binding of monoclonal RF to IgG3 and IgG4. Hybrid IgG3/IgG4 antibodies containing the CH3 domain of IgG4 were bound by monoclonal RF. whereas those containing the CH3 domain of IgG3 were not. To evaluate the contribution of the N-linked carbohydrate moiety at Asn-297 to RF binding sites on IgG. we measured RF binding to aglycosylated IgG antibodies produced by mutating Asn-297 to another amino acid. Glycosylated and aglycosylated IgG1. 2. and 4 were bound identically by monoclonal and polyclonal RF. Aglycosylated IgG3. however. was bound better than glycosylated IgG3 by polyclonal RF and by IgG3-reactive monoclonal RF.
The sequential generation of neutrophil chemoattractant proteins in acute inflammation in the rabbit in vivo. Relationship between C5a and proteins with the characteristics of IL-8/neutrophil-activating protein 1, An in vivo experimental peritonitis model was investigated in the rabbit using zymosan as the inflammatory stimulus. After an i.p. injection of zymosan. exudate was removed at intervals and tested in the back skin of assay rabbits. Assay rabbits received i.v. injections of 125I-albumin and 111In-neutrophils. and the local accumulation of each label was measured in response to intradermal injections of exudate samples mixed with a potentiating dose of PGE2. When peritoneal exudate samples were tested in the presence of a specific anti-C5a antibody. virtually all the edema-inducing and neutrophil chemoattractant activity was abolished in samples taken up to 2 h after the zymosan injection. Later samples. however. contained increasing levels of a non-C5a component. In C5a-depleted 6-h exudate two peaks of inflammatory activity were separated using cation exchange HPLC. Evidence is presented that C5a itself is unable to stimulate the production of these activities. Both peaks of activity appear related to IL-8/NAP-1 as they inhibited the binding of 125I-IL-8/NAP-1 to human neutrophils.
Modulation of monocyte chemotactic function in inflammatory lesions. Role of inflammatory mediators, Monocyte recruitment and accumulation in the synovial tissue is pivotal in the evolution of rheumatoid arthritis (RA). In the present study we examined the chemotactic potential of monocytes obtained from synovial fluid (SF) of patients with RA. Functionally. SF monocytes exhibited greatly diminished chemotactic activity to C5a compared with monocytes from the peripheral blood. In contrast. their chemotactic responsiveness to the synthetic peptide. FMLP. was nearly normal. To define a mechanism for this differential chemotactic dysfunction. cell-surface receptors for C5a (C5aR) and FMLP (FMLP-R) were evaluated. Whereas FMLP-R expression was similar on both blood and inflammatory monocytes. C5aR expression was markedly reduced on SF cells. Because decreased C5a binding in certain RA SF samples could not be attributed to free C5a. known or suspected components of inflammatory SF were evaluated for their ability to modulate chemotactic ligand receptors. Bacterial products including LPS and streptococcal cell walls. which are potent monocyte activators. down-regulated C5aR without affecting FMLP-R. Moreover. the cytokines IFN-gamma and granulocyte-macrophage-CSF selectively decreased C5aR in parallel with decreased in vitro chemotactic activity to C5a. Thus. these data indicate that 1) synovial effusions may contain C5a and/or inflammatory mediators that modulate phenotypic and functional changes in monocytes. 2) chemotactic ligand receptors are independently regulated in inflammatory lesions. and 3) decreased C5aR expression and chemotactic potential likely provide a mechanism whereby monocyte-macrophages persist within the inflamed synovium.
Characterization of a membrane antigen of Leishmania amazonensis that stimulates human immune responses, To investigate human immune responses to defined leishmania Ag we have begun to characterize biochemically and immunologically. an abundant 42-kDa surface Ag of Leishmania amazonensis. a causative agent of human leishmaniasis. We have shown that this Ag. La gp42. is expressed on the surface of L. amazonensis promastigotes. being anchored to the membrane by a glycosyl-phosphatidylinositol moiety. As demonstrated by lectin blotting studies. La gp42 is glycosylated. binding both Con A and wheat germ agglutinin. Immunologically. La gp42 is strongly recognized by sera from patients with different forms of leishmaniasis as well as by patients with Chagas' disease. In addition. we show that purified La gp42 stimulates the proliferation of human T lymphocytes obtained from several leishmaniasis patients. Finally. the N-terminal sequence of La gp42 was obtained and a serologically cross-reactive 42-kDa protein with a homologous sequence was identified in Leishmania major.
Variation of HIV infectibility of macrophages as a function of donor, stage of differentiation, and site of origin, Heterosexual transmission of HIV-1 is likely to involve transmission of virus present in seminal fluid to inflammatory cells. particularly macrophages. present in the endometrium and peritoneal cavity. We have investigated the susceptibility of peritoneal macrophages and the corresponding autologous blood monocytes from normal women to infection by the BA-L strain of HIV-1. In 10 of 18 examples. peritoneal macrophages showed signs of infection within 4-5 days. which was earlier than the autologous monocytes. In contrast to peritoneal macrophages. lung macrophages from 10 of 11 normal donors failed to show significant reverse transcriptase (RT) values 3 weeks post infection. Monolayer cultures of monocytes cultured for 5 days prior to infection developed RT values similar overall to those of freshly isolated cells although individual donors varied as to which culture condition was optimal. The ease of infection of peritoneal macrophages did not correlate with levels of CD4 antigen or degree of pelvic inflammatory development. nor were macrophages harvested from women early in the menstrual cycle significantly more susceptible to infection than those collected from midcycle on. This unexplained heightened infectibility of peritoneal macrophages in a proportion of normal women suggests that those individuals could be more at risk for heterosexual transmission of HIV-1 infection.
Trichinella spiralis infection--United States, 1990, Since 1947. when the Public Health Service began to record statistics on trichinosis. the number of cases reported by state health departments each year has declined: in the late 1940s. health departments reported an average of 400 cases and 10-15 deaths each year; from 1982 through 1986. the number declined to an average of 57 per year (Figure 1) and a total of three deaths (1.2). Although this trend reflects a decline in the number of cases related to commercially purchased pork. recent outbreaks of trichinosis in Iowa and Virginia emphasize the continuing need for education about the dangers of eating inadequately cooked pork.
Infant botulism: a review of 12 years' experience at the Children's Hospital of Philadelphia, Fifty-seven patients with infant botulism were cared for at The Children's Hospital of Philadelphia between 1976 and 1987. The ages of the children ranged from 18 days to slightly more than 7 months. The average duration of hospitalization was 44 +/- 34 days. with the average intensive care unit stay lasting 29 +/- 25 days (54 of 57 patients). The majority (77%) of the patients were ultimately intubated and mechanically ventilated (68%). The principal indication for intubation was loss of protective airway reflexes and not hypercarbia or hypoxemia. In those patients who required mechanical ventilation the average duration was 23 +/- 22 days. with the 10 most severely affected patients (greater than or equal to 28 days of mechanical ventilation) averaging 53 +/- 25 days. Excluding patients ventilated for more than a month. those who underwent tracheostomy were hospitalized nearly twice as long as those who were managed by nasotracheal intubation only (33.5 days vs 63.2 days). The use of continuous nasogastric feedings has supplied most infants with sufficient enteral feedings to avoid weight loss and the need for central intravenous alimentation.
Comparison between parental report and results of microbiologic agar assay for presence of antibiotic in urine of Argentinian children with acute lower respiratory tract infection, This study compares two sources of information on prior use of antibiotics in children with acute lower respiratory tract infection. The presence of antibiotics in respiratory specimens complicates recovery of bacterial pathogens and the selection of appropriate antibiotic treatment. The first source of information is the parents. who are asked about recent use of antibiotics by their child. The second source is an agar diffusion assay that detects antibiotics in urine specimens. In Argentina. where antibiotics are readily available without prescription. parental information about a child's recent antibiotic therapy was found to be relatively reliable only when their answer was affirmative.
Effects of atrial natriuretic peptide on ischemic brain edema in rats evaluated by proton magnetic resonance method, We examined the effect of atrial natriuretic peptide on cerebral edema in 96 rats. Forty-four rats were given 30 (n = 11). 120 (n = 26). or 150 (n = 7) micrograms/kg of the peptide intravenously over 24 hours after occlusion of the left middle cerebral artery to induce cerebral ischemia. We then measured the brain water content. the brain sodium and potassium contents. the in vitro proton nuclear magnetic resonance longitudinal (T1) and transverse (T2) relaxation times. and the area of the edematous regions. Compared with saline treatment (n = 39). peptide treatment decreased the brain water content in a dose-dependent manner and decreased the brain sodium content significantly (p less than 0.05). Peptide treatment also suppressed the lengthening of both T1 and T2 in edematous tissue (p less than 0.05 and p less than 0.01. respectively) and reduced the area of the edematous regions observed by magnetic resonance imaging (p less than 0.01). Atrial natriuretic peptide appears to have a pharmacological effect on ischemic brain edema. possibly by suppressing the elevation of water content through regulation of electrolyte transport in the brain.
Reversion of recent-onset atrial fibrillation to sinus rhythm by intravenous flecainide, Spontaneous reversion to sinus rhythm is a frequent occurrence in recent-onset atrial fibrillation (AF). In a randomized. double-blind. controlled study. intravenous flecainide (2 mg/kg. maximum dose 150 mg) was compared with placebo in the treatment of recent-onset AF (present for greater than or equal to 30 minutes and less than or equal to 72 hours' duration and a ventricular response greater than or equal to 120 beats/min). Intravenous digoxin (500 micrograms) was administered concurrently to all patients in both groups who had not previously taken digoxin. The trial medication was administered over 30 minutes. Exclusion criteria included hemodynamic instability. severe heart failure. recent antiarrhythmic therapy. hypokalemia and pacemaker dependence. One hundred two consecutive patients with recent-onset AF were enrolled in the study. All patients underwent continuous electrocardiographic monitoring in the intensive care or coronary care unit. Twenty-nine (57%) patients given flecainide and digoxin. but only 7 (14%) given placebo and digoxin. reverted to sinus rhythm in less than or equal to 1 hour after starting the trial medication infusion and remained in stable sinus rhythm (chi-square 18.9. p = 0.000013; odds ratio 8.3. 95% confidence interval 2.9 to 24.8). At the end of the 6-hour monitoring period. 34 patients (67%) in the flecainide-digoxin group were in stable sinus rhythm. whereas only 18 patients (35%) in the placebo-digoxin group had reverted (chi-square 8.83. p = 0.003; odds ratio 3.67. 95% confidence interval 1.5 to 9.1).
Interleukin-2 and interferon-gamma production in follicular lymphomas, In situ hybridization with specific RNA radiolabeled probes was used to analyze the production of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) by 21 low-grade follicular lymphomas (FLs). All of the 21 FLs tested contained lymphokine-synthesizing cells in the interfollicular and follicular areas. Enumeration of lymphokine synthesizing cells indicated heterogeneous IL-2 production among lymph nodes tested; 2 of the 21 had much higher densities of IL-2-producing cells (855 and 570/cm2) than did the remaining 19 (mean. 92 +/- 15/cm2). IFN-gamma-producing cells displayed no such variation (mean. 77 +/- 8 IFN-gamma-producing cells/cm2). The mean IL-2/IFN-gamma-producing cell ratio was 2.69 +/- 0.84. indicating preferential induction of IL-2. The detailed distribution of lymphokine-producing cells showed that IL-2 and IFN-gamma-producing cells were located mainly in the follicular areas. The mean follicular/interfollicular ratio was 1.82 +/- 0.16 for IL-2 and 1.92 +/- 0.19 for IFN-gamma-producing cells. The results show that T-cell activation. defined by lymphokine production. occurs in FL lymph nodes in direct contact with malignant B cells. Thus. lymphokine production may play an important role in the control of tumor growth. which is the result of interaction between tumor cells and host-derived immune reaction.
Localization of urokinase-type plasminogen activator in stromal cells in adenocarcinomas of the colon in humans, Human colon adenocarcinomas and adjacent normal colon tissues were stained immunohistochemically with three different monoclonal antibodies and one preparation of polyclonal antibodies against each of the two plasminogen activators. uPA (urokinase type) and tPA (tissue type). The staining patterns seen with the respective sets of antibodies were identical. In all of 10 cases. staining for uPA in the normal colon tissue was confined to scattered fibroblastlike cells in the lamina propria. Other cells. including epithelial and endothelial cells. were uPA negative. All the tumor infiltrates contained many more uPA-positive cells than the normal tissues. but the staining was confined to fibroblastlike cells and endothelial cells in the tumor stroma. while no staining of the malignant epithelial cells was detected. Analysis for uPA by enzyme-linked immunosorbent assay (ELISA) in four cases showed an average uPA content of 0.15 ng uPA/mg protein in the normal colon tissues and 1.6 ng uPA/mg protein in the tumors. Tissue-type plasminogen activator immunoreactivity was confined to endothelial cells in both the normal colon tissue and in the colon carcinomas. These findings may indicate that colon cancer cells recruit stromal cells to produce uPA involved in degradation of the extracellular matrix during invasive growth.
Clenbuterol plus acivicin decrease tumor growth and increase muscle mass in rats maintained on total parenteral nutrition, Two problems associated with supplemental nutrition of tumor-bearing organisms are control of tumor growth and reduction of cachexia. To investigate these problems. rats bearing methylcholanthrene-induced sarcomas were maintained on total parenteral nutrition (TPN) for 10 to 12 days beginning 23 days after tumor inoculation. Combined treatment of one group of these rats with the glutamine antimetabolite. acivicin. and the beta 2-adrenergic agonist. clenbuterol. arrested tumor growth. increased skeletal muscle mass and protein content. increased gut mass. and decreased total plasma lipid levels. Resting energy expenditure and cardiac mass were increased by TPN and were increased further by acivicin plus clenbuterol. These results demonstrate that tumor growth and muscle wasting can be controlled during TPN of tumor-bearing organisms. Therefore. cachectic depletion of lean body tissue may not be obligatory in neoplastic disease.
Long-term effect of cromolyn sodium on nonspecific bronchial hyperresponsiveness: a review, Long-term treatment with cromolyn sodium will reduce airway hyperresponsiveness in patients with bronchial asthma. Short-term use of cromolyn sodium (less than 6 weeks) is effective in preventing seasonal increases in allergen-induced hyperresponsiveness. Cromolyn sodium therapy for greater than 12 weeks appears to be beneficial in reducing baseline hyperresponsiveness. The effect of cromolyn sodium on bronchial hyperresponsiveness may result from its ability to stabilize mast cells. Other contributory properties of cromolyn sodium are reviewed.
Limitations of the electrocardiogram in estimating infarction size after acute reperfusion therapy for myocardial infarction, OBJECTIVE: To assess the ability of the 12-lead electrocardiogram to estimate infarction size after reperfusion therapy for acute myocardial infarction. DESIGN: The presence or absence of Q waves and the Selvester QRS score obtained before and after hospital discharge were compared with radionuclide estimates of infarction size and ejection fraction at discharge and 6 weeks later. regional wall motion at discharge and 6 weeks later. and myocardial perfusion defect size quantitated with Tc-99m-sestamibi at discharge. SETTING: A tertiary referral center. PATIENTS: A consecutive series of 43 patients with acute myocardial infarction who received acute reperfusion therapy and were assessed using 12-lead electrocardiography. radionuclide angiography. and Tc-99m-sestamibi tomographic imaging before discharge. INTERVENTIONS: All 43 patients received acute reperfusion therapy: 21 patients received intravenous tissue plasminogen activator. and 22 patients underwent primary percutaneous transluminal coronary angioplasty. MAIN OUTCOME MEASURE: The correlation of QRS score and Q waves with three radionuclide estimates of infarction size. RESULTS: A significant correlation was found between myocardial perfusion defect size at discharge and both left ventricular ejection fraction and regional wall motion at discharge and 6 weeks later (r = -0.71 to -0.81; all comparisons. P less than 0.001). Little correlation was found between electrocardiographic findings and radionuclide measurements of left ventricular function and perfusion. Presence or absence of Q waves at discharge was not associated with any difference in ejection fraction. regional wall motion. or perfusion defect at discharge. No correlation was found between QRS score and ejection fraction or myocardial perfusion defect size at discharge. The QRS score at discharge correlated only weakly with regional wall motion at discharge and 6 weeks later. This lack of correlation was unchanged when electrocardiograms obtained after hospital discharge were analyzed. CONCLUSION: Although inexpensive and readily available. the 12-lead electrocardiogram does not appear to provide a reliable estimate of infarction size after reperfusion therapy for acute myocardial infarction.
Increase in serum concentrations of IgG2 and IgG4 by selenium supplementation in children with Down's syndrome, In a previous study on children with Down's syndrome a reduced rate of infections was reported by their parents after the children had received six months' treatment with selenium supplements. In the present study the concentrations of the four IgG subclasses were measured in 29 of these children in samples of serum obtained before and immediately after the period of supplementation and one year after it had finished. Selenium had a significant augmentative effect on the serum concentrations of IgG2 and IgG4. but not of IgG1 and IgG3. This effect was not related to age. as among children over the age of 6 years the serum concentrations of IgG2 and IgG4 had decreased significantly one year after the treatment had been stopped. This study suggests that selenium has an immunoregulatory effect. which might be of importance in both basic research and clinical practice.
Effect of natriuretic agents, vasoactive agents and of the inhibition of metabolism on sodium handling in the isolated perfused kidney of the nephrotic rat, 1. The kidney taken from a rat rendered nephrotic by exposure to puromycin aminonucleoside retains sodium abnormally when perfused in isolation and has an abnormally low vascular resistance (J. D. Firth et al.. Clin. Sci. 1989; 76. 387-95). In this study the relation of oxygen consumption to sodium reabsorption has been examined in the isolated nephrotic organ. which has also been exposed to a variety of natriuretic agents and to the effect of inhibition of metabolism by cooling. in an attempt to discern the transport process. or processes. responsible for abnormal tubular handling of sodium. In addition. the effects of three endogenous vasoconstrictors. noradrenaline. angiotensin II and endothelin. on the function of the isolated nephrotic kidney have been examined. 2. The ratio of mol of sodium reabsorbed by the tubules of the isolated nephrotic kidney to mol of oxygen consumed was reduced in comparison with the control kidney (means +/- SEM): 9.22 +/- 0.97 versus 15.43 +/- 1.55 (P less than 0.002). 3. In the presence of ouabain (1 mmol/l). acetazolamide (1 mmol/l). frusemide (200 mumol/l). the combination of these three agents together. hydroflumethiazide (100 mumol/l). benzamil (100 nmol/l) or atrial natriuretic peptide (1000 pmol/l). a lesser increment in sodium excretion was induced in the isolated nephrotic kidney than in the control kidney and the nephrotic organ continued to excrete less sodium in both absolute and fractional terms. 4. This suggests that enhanced tubular sodium reabsorption in the isolated nephrotic kidney does not depend upon abnormally increased activity of the Na+/K(+)-adenosine triphosphatase. bicarbonate-dependent sodium transport. Na+/K+/2Cl- co-transport. electrically neutral proportionate reabsorption of sodium and chloride (distal tubule). epithelial sodium channel (distal tubule) or atrial natriuretic peptide-sensitive sodium transport processes. 5. When isolated nephrotic kidneys and normal kidneys were cooled to 8-10 degrees C the handling of sodium became virtually identical in the two groups. On re-warming to 37 degrees C. the original differences in sodium handling between nephrotic and control kidneys were restored. This implies that the mechanism responsible for the abnormal tendency to retain sodium is temperature-sensitive; as yet it remains otherwise undefined. 6. The sensitivity of the renal vessels to noradrenaline. angiotension II and endothelin. as judged by the percentage reduction in perfusate flow rate produced by a given concentration of any of these agents. was not substantially altered in the nephrotic kidney compared with the control kidney. Increase in vascular tone was not associated with amelioration of the tendency of the isolated nephrotic organ to retain sodium. Increasing concentrations of angiotensin II caused the filtration rate to increase in the nephrotic kidney. This effect was unexpected: in the control preparation. as anticipated. angiotensin II caused the filtration rate to decrease.
Aldose reductase messenger RNA in the lens epithelium in vivo: effects of diabetes mellitus and galactosaemia, 1. Quantitative in situ hybridization histochemistry was used to examine the regulation of aldose reductase messenger RNA in the rat lens after the induction of diabetes mellitus or after feeding a 50% (w/w) galactose diet. 2. Although increased staining for aldose reductase in the lens epithelium has previously been observed by immunohistochemistry after 3 weeks of diabetes or after 7 days of galactose feeding. we have not been able to detect any increase in the amount of aldose reductase messenger RNA in these cells as compared with controls (113 +/- 7%. 105 +/- 9%. 100 +/- 7%. respectively) at these time points (P greater than 0.05). 3. After 15 days of galactose feeding. however. there was a significant increase of 140% (+/- 12%) in the amount of aldose reductase messenger RNA in the lens epithelial cells as compared with controls (P = less than 0.001). 4. These results demonstrate that increased availability of galactose. a high-affinity substrate for the enzyme. leads to increased aldose reductase messenger RNA. which suggests a role for aldose reductase in sugar metabolism in the lens.
Hemodynamic study during transdermal application of nitroglycerin tape in patients with cirrhosis, We studied 14 patients with portal hypertension and cirrhosis using portal and hepatic vein catheterizations to determine the effects of transdermal application of nitroglycerin tape (containing 10 mg of nitroglycerin and capable of releasing 6 to 7 mg of nitroglycerin in 12 hr) on splanchnic hemodynamics. Patients randomly received nitroglycerin (n = 7) or a placebo (n = 7). No significant changes were observed after the administration of the placebo. In contrast. transdermal nitroglycerin caused a significant reduction in portal pressure. as evaluated by measurements of the portal venous pressure gradient (-22%. p less than 0.01). The reduction of portal pressure was due to a decrease in the portal venous pressure. with no changes in the free hepatic venous pressure. Despite the fall in portal pressure. the hepatic blood flow was maintained. These findings suggest that transdermal nitroglycerin could be potentially useful in the treatment of portal hypertension associated with cirrhosis.
Expression of specific UDP-glucuronosyltransferase isoforms in carcinogen-induced preneoplastic rat liver nodules, The expression of specific UDP-glucuronosyltransferase isoforms in 2-acetylaminofluorane-induced rat liver preneoplastic nodules was studied; livers from pair-fed littermates were used as controls. For comparison. liver and kidney from 3-methylcholanthrene-treated or untreated (control) rats were used. Steady-state UDP-glucuronosyltransferase mRNA levels were determined by Northern blot analysis or in situ hybridization of tissue sections using a 30-mer oligonucleotide specific for the 3-methylcholanthrene-inducible UDP-glucuronosyltransferase (which is active toward 4-nitrophenol) or a double-stranded cDNA probe specific for androsterone-UDP-glucuronosyltransferase. For 3-methylcholanthrene-inducible UDP-glucuronosyltransferase. the mRNA level was very low in control liver; there was a 15-fold increase after 3-methylcholanthrene treatment. This mRNA was present at relatively high concentration in the kidney and there was a threefold increase after 3-methylcholanthrene administration. In livers with preneoplastic nodules 1 mo after cessation of carcinogen administration. this mRNA concentration was approximately 15 times greater than in control liver. Similar changes in the level of the 3-methylcholanthrene-inducible UDP-glucuronosyltransferase were also observed by in situ hybridization of tissue sections. Immunocytochemical studies using an antiserum that recognizes the 3-methylcholanthrene-inducible UDP-glucuronosyltransferase showed a marked increase in the concentration of this isoform in preneoplastic nodules compared with the adjacent nonnodular liver.
Incidence of pulmonary aspiration in intubated patients receiving enteral nutrition through wide- and narrow-bore nasogastric feeding tubes, A descriptive study was performed to compare the incidence of pulmonary aspiration in 25 critically ill patients who had endotracheal tubes in place and were receiving enteral nutrition through a narrow-bore nasogastric tube (n = 10) or a wide-bore nasogastric tube (n = 15). Results of chi-square analysis of this comparison were not significant. p less than 0.05. Aspiration occurred in one subject. The amount and rate of tube feeding delivered was examined. The number of checks for residual feeding was found to be significantly greater in the wide-bore tube group. A comparison of the assessment of nasogastric tube placement on x-ray examination showed that tube placement was reported on x-ray results with more frequency in the wide-bore group. Questions are raised by these observations regarding the use of narrow-bore tubes in the critically ill population with endotracheal tubes in place.
Pulmonary vascular reactivity and permeability to alveolar hypoxia in the dog, Hemodynamics and vascular permeability were studied during acute alveolar hypoxia in isolated canine lung lobes perfused at constant flow with autogenous blood. Hypoxia was induced in the presence (COI + Hypox. n = 6) or absence (Hypox. n = 6) of cyclooxygenase inhibition (COI) with indomethacin or meclofenamate. Hypoxic ventilation reduced blood PO2 from 143 to 25-29 Torr without a change in PCO2. During hypoxia a capillary filtration coefficient (Kf) was obtained gravimetrically as an index of vascular permeability to water. In COI + Hypox. pulmonary arterial pressure (Pa) increased from 11.5 +/- 0.7. post-COI normoxia. to a peak of 22.1 +/- 2.3 during hypoxia (P less than 0.01) without a change in capillary pressure (Pc). In contrast. hypoxia changed neither Pa nor Pc in Hypox relative to an untreated normoxic control group (Normox. n = 6. P greater than 0.05). Kfs (means +/- SE in ml.min-1.Torr-1.100 g-1) for Normox (0.070 +/- 0.014). Hypox (0.082 +/- 0.024). and COI + Hypox (0.057 +/- 0.017) did not differ from one another (P greater than 0.05). Although COI markedly enhanced the pressor response to acute alveolar hypoxia. hypoxia increased neither Pc nor vascular permeability regardless of COI.
Reduction in the number of UCHL-1+ cells and IL-2 production in the peripheral blood of patients with visceral leishmaniasis, PBMC from patients with visceral leishmaniasis (VL). before and after successful antimony therapy. were analyzed for their phenotypes and for their ability to produce IL-2 and IFN-gamma and to proliferate against PHA and leishmanial Ag. In agreement with results of earlier studies. PBMC from active VL patients showed a markedly reduced proliferative response and IL-2 and IFN-gamma production. compared with those of healthy controls. The levels of CD4+ and CD8+ T cells were within the normal range. but there was a significant decrease in UCHL-1+ cells (helper-inducer). compared with healthy individuals. The inhibited cellular responses. and lymphokine secretion and decreased level of UCHL-1+ cells in the PBMC of the VL patients returned to the normal range after successful chemotherapy. PBMC from active VL patients were fractionated into adherent cells and nonadherent cells. and the non-adherent were further fractionated into UCHL-1+ and UCHL-1- subpopulations. Results from cell depletion and reconstitution experiments suggest that the IL-2 production by nonadherent cells stimulated with PHA was inhibited by adherent cells. but the IL-2 production by nonadherent cells in response to specific Ag was not. In contrast. UCHL-1- cells seem to mediate the inhibition of Ag-driven IL-2 production by nonadherent cells but not mitogen-stimulated IL-2 secretion by nonadherent cells. Ag-specific IL-2 production principally involves UCHL-1+ cells.
Regulation of MHC class II antigen expression. Opposing effects of tumor necrosis factor-alpha on IFN-gamma-induced HLA-DR and Ia expression depends on the maturation and differentiation stage of the cell, MHC class II induction by cytokines has been suggested to play a major role in the initiation and propagation of immune and autoimmune processes. TNF-alpha has been found both to enhance and also to inhibit IFN-gamma-induced MHC class II expression. In the present studies. the effect of TNF-alpha on IFN-gamma induced MHC class II expression was tested in various cell lines. On the basis of the data. we propose that. depending on the stage of differentiation and maturation of the cells. TNF-alpha might synergize or antagonize the affects of IFN-gamma on the regulation of MHC class II expression. Thus. in immature cells such as HL-60 or THP-1. TNF-alpha enhances IFN-gamma-induced class II expression. However. when differentiation was induced in these cells by TPA or IFN-gamma. the additive effect of TNF-alpha on the IFN-gamma induced DR expression was eliminated. Furthermore. TNF-alpha down-regulates the IFN-gamma-induced class II expression in differentiated cells such as human skin fibroblasts or activated macrophages. In bone marrow cells induced to differentiate in vitro. TNF-alpha decreased the IFN-gamma-induced MHC class II expression in a maturation-dependent fashion. These results provide a rational explanation for the conflicting reports regarding the effect of TNF-alpha on IFN-gamma-induced class II expression. But more importantly they may be relevant to the biologic function of TNF-alpha. Thus. we show that TNF-alpha-treated mice have reduced level of Ia expression on peritoneal macrophages and in vivo treatment with TNF-alpha antagonizes the ability of IFN-gamma to induce class II expression on these macrophages.
Differences in human immunodeficiency virus type 1 (HIV-1) anti-p24 reactivities in serum of HIV-1-infected and uninfected subjects: analysis of indeterminate western blot reactions, Anti-p24 reactions in sera from 42 human immunodeficiency virus type 1 (HIV-1)-infected and 36 uninfected people with indeterminate Western blot antibody tests for HIV-1 were studied. Anti-p24 reactivity in HIV-1-infected people was completely blocked by HIV-1 recombinant p24 antigen. whereas the reaction in uninfected individuals with indeterminate patterns was inhibited partly or not at all. In contrast to infected individuals. anti-p24 reactivity from uninfected individuals could not be detected by an inhibition ELISA for HIV-1 p24 antibody. These results suggest a practical way to distinguish anti-p24 reactivity in sera from patients with HIV-1 infection from that seen in uninfected patients with indeterminate Western blot reactions.
Myeloablative combination chemotherapy without total body irradiation for neuroblastoma, Myeloablative treatment intensification in 25 patients diagnosed when older than 12 months of age with stage IV neuroblastoma included sequential delivery of cisplatin 120 mg/m2 x 1. hyperfractionated radiation (2.100 cGy) to the primary site and adjacent lymph nodes. carmustine (BCNU) 200 mg/m2 x 1. melphalan 60 mg/m2/d x 3 (n = 13) or thiotepa 300 mg/m2/d x 3. (n = 12). and etoposide (VP 16) 300 mg/m2/d x 3. Seventy-two hours after the last dose of VP 16. histologically tumor-free and 4-hydroperoxycyclophosphamide (4-HC; 100 mumol/L)-purged autologous bone marrow (ABMT) was infused. Acute toxicities included grade 3 to 4 oral mucositis. grade 1 to 2 diarrhea. and fevers. No patient required infusion of unpurged reserve autografts. At ABMT. 16 patients (group I) were progression-free 6.5 months to 14 months (median. 9 months) from diagnosis: seven remain progression-free 20 months to 46 months (median. 39 months) off therapy. six relapsed 4 months to 17 months post-ABMT. and three died of toxicity (candidiasis. metabolic derangement. and venoocclusive disease [VOD]). The event-free survival of group I patients is 44% at 24 months post-ABMT. Nine patients (group II) were in second remission at ABMT. including three who had relapsed after other transplant procedures: two are progression-free 24 months and 41 months off therapy. four relapsed 3 months to 12 months post-ABMT. and three died of toxicity (aspergillosis. hemorrhagic cystitis. VOD). Only one of 10 relapses involved a primary site. suggesting a beneficial effect of local radiation. In terms of survival or toxicity. an advantage for melphalan or thiotepa was not evident. Regimens such as this may prolong the survival of selected patients with poor-risk neuroblastoma. but concerns over late relapses and toxicity mandate continuing efforts to devise alternative. less risky. and more clearly beneficial approaches for definitive ablation of neuroblastoma.
Selective 2-[18F]fluorodopa uptake for melanogenesis in murine metastatic melanomas, The relationship between 3.4-dihydroxy-2-[18F]fluoro-L-phenylalanine (2-[18F]FDOPA) uptake and melanogenesis was studied using mice bearing two B16 melanomas: B16-F1 has a higher melanin synthesis ability and a slower growing rate than the higher metastatic B16-F10. A significantly higher 2-[18F]FDOPA uptake by B16-F1 than by B16-F10 and a reverse relationship for the uptake of [14C] 2-deoxy-2-fluoro-D-glucose and [3H]thymidine were observed 1 hr postinjection. F1-to-F10 ratios of both the 2-[18F]FDOPA uptake and the acid-insoluble radioactivity increased to about 5 at 6 hr. which paralleled the melanin content. FM3A mammary carcinoma showed a 2-[18F]FDOPA uptake similar to the B16-F10 but without the acid-insoluble radioactivity. With D.L-DOPA loading. a 55% decreased uptake by FM3A 1 hr postinjection was significantly greater than the 20% reduction in both melanomas. O-Methylated 2-[18F]FDOPA was a predominant acid-soluble metabolite in all tumors. Whole-body autoradiography discriminated the two melanomas clearly. 2-[18F]FDOPA may be a promising tracer for the selective imaging of melanogenesis.
Quinidine inhibits prolactin secretion induced by thyrotropin-releasing hormone, high medium potassium or hyposmolarity in GH4C1 cells, In cultured GH4C1 cells quinidine inhibited basal prolactin (PRL) secretion and that induced by 0.1 to 10 nM thyrotropin-releasing hormone (TRH). 30 mM medium K+ or 30% medium hyposmolarity but did not inhibit secretion induced by 100 nM 12-O-tetradecanoylphorbol 13-acetate. Inhibition of basal PRL secretion was highly correlated with the drug concentration between 30 microM to 1 mM quinidine; 50% inhibition of basal secretion occurred at 300 microM and at this concentration quinidine completely blocked PRL secretion stimulated by TRH. K+ and hyposmolarity. Significant inhibition of TRH-induced PRL secretion was produced by 15 microM quinidine. a concentration equivalent to that in plasma during standard antiarrhythmic therapy with quinidine in humans. In rats in vivo. a single injection of 2 mg i.p. of quinidine gluconate/100 g b.wt. 1 hr before TRH injection significantly inhibited induced TSH secretion by 15%. Quinidine inhibition of secretion may be caused by blocking depolarization of the cell membrane. thus depressing voltage-gated Ca++ channels and preventing a rise in intracellular Ca++ release.
The effect of suramin, tumor necrosis factor and interferon gamma on human prostate carcinoma, Suramin. an antiparasitic agent which has been shown to block the stimulatory effect of growth factors on certain cancers. is currently being evaluated in clinical trials and as an antineoplastic agent in patients with advanced prostate carcinoma. Preliminary studies suggested that suramin inhibits the growth in vitro of human prostate carcinoma. The present study was performed in order to evaluate the effect of suramin. recombinant human tumor necrosis factor (TNF). interferon gamma and the combination of suramin plus TNF or interferon gamma on proliferation of PC-3. a human. hormone unresponsive prostate carcinoma cell line. In medium containing 2% fetal calf serum (FCS) suramin. at doses of 10 microM. 30 microM and 100 microM (levels readily achievable in humans) inhibited proliferation of PC-3. TNF. at a concentration of 500 units/ml.. induced an approximately 50% inhibition of growth of PC-3. The combination of suramin plus TNF induced a greater inhibition of growth than did either agent alone. even at the low dose of 10 microM suramin. Interferon gamma. 500 units/ml.. inhibited PC-3 growth. However. the combination of interferon gamma plus suramin (30 microM) induced less inhibition of proliferation than did interferon gamma alone. These results may serve as a rationale for clinical trials employing the combination of TNF plus suramin in patients with advanced prostate carcinoma.
Use of internal validity in the construct of an index of undernutrition, An index of undernutrition (IOU) has been developed from a crosssectional study of 200 general surgical patients. The IOU was constructed using a ranking method based upon the relative values of anthropometric measurements (weight loss. mid-arm muscle area. mid-arm fat area) and serum protein concentrations (albumin. transferrin). The IOU was derived without reference to the incidence of adverse clinical events and took the form of a boolean cluster. A subsequent prospective longitudinal study evaluated the IOU in 367 general surgical patients at the time of admission to hospital. The results of this study supported the validity of the IOU. There was no association between gender and IOU scores. However. patients with high scores were more likely to be elderly (p less than 0.02). have cancer (p less than 0.001). stay in hospital longer (p less than 0.001). or experience an adverse clinical event after surgery (p less than 0.001). In accord with other published indices of undernutrition. the association between the extent of undernutrition and the incidence of adverse clinical events was only of moderate diagnostic potential (overall accuracy 68%). This study demonstrates that it is possible to derive an index of protein-energy undernutrition that is independent of the incidence of adverse clinical events.
Central catheter-related infections: comparison of pulmonary artery catheters and triple lumen catheters for the delivery of hyperalimentation in a critical care setting, We prospectively studied the risk of catheter-related sepsis (CRS) in 75 critically ill patients who received total parenteral nutrition (TPN) through 158 pulmonary artery catheters (PACs) and 214 triple-lumen catheters (TLCs). We relied on semiquantitative cultures of the catheter tips. peripheral blood cultures in febrile patients and clinical response to catheter removal to diagnose catheter-related sepsis. The infection rate was 2.5% (4/158) of PACs and 6.5% (14/214) of TLCs (p = 0.124). Colonization rates were 29.1% for PACs and 32% for TLCs. PACs were left in place a significantly shorter length of time than TLCs. 3.1 vs 5.1 days (p less than 0.005). Guidewire exchanges and subclavian vein insertions were associated with a decreased rate of CRS when compared to new insertions and internal jugular vein insertions. respectively. We conclude that pulmonary artery catheters can be used safely for the delivery of hyperalimentation in critically ill patients with no increased risk for catheter-related sepsis compared to triple-lumen catheters. The use of the PAC in this manner allows for the use of a single central venous catheter for the delivery of hyperalimentation and hemodynamic monitoring.
Liver function tests abnormalities in patients with inflammatory bowel disease receiving artificial nutrition: a prospective randomized study of total enteral nutrition vs total parenteral nutrition, Liver and biliary abnormalities are well-known complications of inflammatory bowel disease (IBD). It has been suggested that using total parenteral nutrition (TPN) may further impair liver function in these patients; this seems not to be so with total enteral nutrition (TEN). However. prospective trials comparing the incidence of liver function test (LFT) abnormalities with either TPN or TEN have not been carried out. Twenty-nine IBD inpatients with normal LFT. randomized to receive either TEN with a polymeric diet or isocaloric. isonitrogenous "all-in-one" TPN because of protein-energy malnutrition and/or severe disease. were included in the study. Sixteen patients (five with ulcerative colitis and 11 with Crohn's disease) received TEN. and 13 patients (eight ulcerative colitis and five Crohn's disease) were on TPN. All patients were on systemic steroids. and nine of them were on oral metronidazole. Both groups were homogeneous regarding age. sex. diagnosis. disease activity. nutritional status. daily nutrient supply. and days on artificial nutrition. Serum albumin levels significantly increased with TEN (32 +/- 1 to 38.2 +/- 1.6 g/liter. p less than 0.01). but not with TPN (32.1 +/- 2.2 to 33.9 +/- 1.4 g/liter. NS). Clinical improvement occurred in both groups of patients as shown by the change in the disease activity indexes. In all cases. measurements of serum alkaline phosphatase. serum bilirubin. aspartate aminotransferase. alanine aminotransferase. and gamma-glutamyltransferase were performed weekly. There were no significant differences in the initial LFT between both groups.
Microorganisms and diarrhea in enterally fed intensive care unit patients, Thirty-six intensive care unit patients. receiving aseptic or manually (routine) reconstituted enteral feeding formulas. were evaluated prospectively for the relationship of microbial involvement. gastric pH. and antimicrobial therapy to diarrhea. The routine protocol group had a significantly higher incidence of bacterial contamination than the aseptic protocol group (Fisher's exact test. p less than 0.05). There were no significant direct associations between isolate category (Gram-negative bacilli. Gram-positive cocci. Gram-negative cocci. yeast). gastric pH. or antimicrobials and diarrhea. However. two organisms (Group D Enterococci and yeast) were indirectly implicated in some cases of diarrhea.
Internal biliary drainage, parenteral nutrition, and variation in the total parenteral nutrition feeding solutions: influence on the healing of colon anastomosis in jaundiced rats, The influence of preoperative internal biliary drainage and various types of total parenteral nutrition (TPN) on the healing of a colon anastomosis in 50 jaundiced rats was investigated. Jaundice was induced by division and ligation of the common bile duct. After 5 days a colon anastomosis was made. Ten days thereafter the bursting pressure of the anastomosis was measured as an assessment of wound healing. Bursting pressures were significantly lower in jaundiced rats compared with a sham-operated nonjaundiced group. Preoperative internal biliary drainage significantly improved bursting pressure (p less than 0.001) as did preoperative TPN (p less than 0.001). In the second part of the study the influence of four different feeding solutions on the healing of a colon anastomosis was tested. Solutions with and without 20% fat emulsion and a solution with branched-chain amino acids were tested as well as glucose only. No significant differences were observed among these four groups on the parameters tested.
Protective effect of intrauterine release of levonorgestrel on pelvic infection: three years' comparative experience of levonorgestrel- and copper-releasing intrauterine devices, A randomized. multicenter comparison of two intrauterine contraceptive devices (IUDs) was carried out. Nine hundred thirty-seven women were fitted with a copper-releasing IUD. the Nova-T. and 1821 women with an IUD that releases 20 micrograms of levonorgestrel daily. After 36 months. the cumulative gross rates of amenorrhea and hormonal side effects were significantly higher in the levonorgestrel-IUD users. The cumulative 36-month gross pregnancy rate was 3.7 for the Nova-T and 0.3 for the levonorgestrel IUD (P less than .001). demonstrating the levonorgestrel IUD's high contraceptive efficacy. For the first time. a protective effect of the levonorgestrel IUD against pelvic inflammatory disease as compared with the Nova-T was seen statistically. The cumulative 36-month gross rate of pelvic inflammatory disease was 2.0 in Nova-T- and 0.5 in levonorgestrel-IUD users (P less than .013). This significantly lowered incidence of pelvic inflammatory disease may help to solve one of the major concerns associated with intrauterine contraception.
Scrapie-associated prion protein accumulates in astrocytes during scrapie infection, In the course of scrapie. a transmissible spongiform encephalopathy caused by an unconventional agent. a normal cellular protein is converted to an abnormal form that copurifies with infectivity and aggregates to form deposits of amyloid. We have used immunocytochemistry and methods that enhance detection of amyloidogenic proteins to investigate the types of cells in the central nervous system which are involved in the formation of the abnormal scrapie-associated protein. We show that this protein accumulates in astrocytes prior to the cardinal neuropathological changes in scrapie--astrogliosis. vacuolation. neuron loss. and amyloid deposition. These findings implicate the astrocyte in the formation of the scrapie isoform of the prion protein and amyloid in scrapie and suggest that this cell type might also be involved in the replication of the scrapie agent.
The role of CD4+ and CD8+ T cells in the destruction of islet grafts by spontaneously diabetic mice, Spontaneous development of diabetes in the nonobese diabetic (NOD) mouse is mediated by an immunological process. In disease-transfer experiments. the activation of diabetes has been reported to require participation of both CD4+ and CD8+ T-cell subsets. These findings seem to indicate that the CD4+ cells are the helper cells for the activation of cytotoxic CD8+ cells that directly destroy islet beta cells in type I diabetes. In this report we challenge this interpretation because of two observations: (i) Destruction of syngeneic islet grafts by spontaneously diabetic NOD mice (disease recurrence) is CD4+ and not CD8+ T-cell dependent. (ii) Disease recurrence in islet tissue grafted to diabetic NOD mice is not restricted by islet major histocompatibility complex antigens. From these observations we propose that islet destruction depends on CD4+ effector T cells that are restricted by major histocompatibility complex antigens expressed on NOD antigen-presenting cells. Both of these findings argue against the CD8+ T cell as a mediator of direct islet damage. We postulate that islet damage in the NOD mouse results from a CD4+ T-cell-dependent inflammatory response.
The question of FK 506 nephrotoxicity after liver transplantation, Formal studies have not been published on the nephrotoxicity of FK 506 when the drug was used from the outset. This kind of information was sought in 101 recipients of primary livers. 24 hearts. and 3 double lungs or heart-lung. Perioperative renal dysfunction was commonly seen. which appeared to be related to FK 506 doses and plasma levels. particularly when the drug was given IV. This was reversible. Late renal function has been generally satisfactory in all three cohorts of patients. and the incidence of hypertension has been low. The therapeutic index of FK 506 is a good one. as revealed by these observations in patients whose most notable achievement was a low mortality.
Incidence and treatment of rejection episodes in primary orthotopic liver transplantation under FK 506, FK 506 therapy with low doses of steroids was adequate to control rejection in most liver recipients. Rejection episodes were readily reversed with single IV doses of methylprednisone or hydrocortisone. Short courses of OKT3 (3 to 5 days 5-10 mL) controlled severe rejections. The rate of retransplantation directly due to rejection was low (1.6%). There was a limited need for steroids either early or out to 6 to 12 months.
Interrelationship between protein-energy malnutrition and essential fatty acid deficiency in nursing infants, The influence of severe protein-calorie malnutrition on essential fatty acid (EFA) status was evaluated in nursing infants aged 2-5 mo. A control group of the same age and with normal weight-for-height was also selected for this study. The fatty acid pattern of total phospholipids from plasma and red blood cells (RBCs) was determined and then used as a biochemical variable for evaluating EFA status. A sharp fall in the relative percentage of n-6 (omega-6) fatty acids concomitant with an increase in the n-9 fatty acids in plasma and RBC phospholipids was observed. These results are consistent with the picture of EFA deficiency and showed that the deficiency state is well correlated with the severity of malnutrition. Calculation of the product-precursor ratio of polyunsaturated fatty acids derived from linoleic acid (18:2n-6) in RBC phospholipids provides evidence for an impairment in the elongation-desaturation pathway promoted by the protein-calorie malnutrition.
Clinical evaluation of closed-loop control of blood pressure in seriously ill patients, OBJECTIVE: To compare the effectiveness of a new method of closed-loop (automatic) control of BP with usual manual control. DESIGN: Within-subject crossover trial. SETTING: General and open heart ICUs in a university teaching hospital. PATIENTS: Convenience sample of 74 seriously ill patients aged 17 to 88 yr. Twenty had hypertension: postoperative (n = 7). neurologic damage (n = 6). miscellaneous (n = 7). and were prescribed nitroprusside (n = 11) or nitroglycerin (n = 9). Fifty-four had hypotension: septic (n = 33). other (n = 21). and were prescribed norepinephrine (n = 30). dopamine (n = 11). epinephrine (n = 8). or dobutamine (n = 5). An additional 21 trials were omitted from analysis because of technical (n = 7). clinical (n = 1). or drug-related problems (n = 13). INTERVENTION: Closed-loop and manual drug administrations 1-hr were studied during periods in each patient. The target and observed mean arterial pressure (MAP) and drug infusion rate were recorded electronically every 30 sec. MAIN OUTCOME MEASUREMENTS: Time taken to achieve initial control (min); fidelity of control (the integral of size and duration of error from target MAP +/- 10% in mm Hg.hr/hr); and average drug dose administered (microgram/min as % maximum possible per drug). RESULTS: Compared with manual control. closed-loop achieved faster initial control (log-rank chi 1 = 5.04. p less than .05) and greater fidelity (mean 1.37 vs. 2.36; F = 7.15. p less than .01). There was no difference in average drug dose administered. There was uniformity in the efficacy advantage of closed-loop drug administration across drugs and patient classifications. CONCLUSION: The new closed-loop system is more effective than the usual manual control in managing acute BP disturbances in the seriously ill patient.
Aortic root blood flow increases after pancuronium in neonates with hyaline membrane disease, OBJECTIVE: To determine the effects of muscle paralysis on aortic root blood flow in preterm infants with hyaline membrane disease. DESIGN: Each patient served as his/her own control in a prospectively controlled trial. SETTING: Neonatal ICU in a university hospital. PATIENTS: Ten ventilator-dependent preterm infants weighing 800 to 2820 g. 0 to 8 days of age. with hyaline membrane disease and seven control patients. INTERVENTIONS: Noninvasive measurement of aortic root blood flow by Doppler echocardiography 30 min before and 60 min after respiratory paralysis with 0.1 to 0.5 mg/kg of iv pancuronium. or following ventilator changes in control subjects. RESULTS: Mean aortic root blood flow increased significantly (p less than .001). from 212 to 276 mL/min.kg. accompanied by significant increases in stroke volume and heart rate. CONCLUSIONS: Pancuronium bromide may have a direct beneficial effect on the circulation of preterm infants with hyaline membrane disease.
Tissue oxygenation in hemorrhagic shock measured as transcutaneous oxygen tension, subcutaneous oxygen tension, and gastrointestinal intramucosal pH in pigs, BACKGROUND AND METHODS: Tissue oxygenation. measured in peripheral tissue as transcutaneous PO2 (PtCO2) and subcutaneous PO2. was compared with the oxygenation in GI mucosa. which was measured as intramucosal wall pH (pHi). during experimental hemorrhagic shock and resuscitation in pigs. The pigs were hemorrhaged stepwise to a BP of 80 and 45 mm Hg. followed by retransfusion. PtCO2 was measured in the groin and subcutaneous PO2 was measured in the hip region. Intraluminal PCO2 was measured in the stomach. in the small intestine. and the sigmoid colon using silicone catheters. A simultaneous determination of arterial blood HCO3 concentration allowed pHi to be calculated using Henderson-Hasselbalch equation. Cardiac output was determined by thermodilution. and oxygen delivery (DO2) was calculated. RESULTS: Early indications of shock were decreases in PtCO2 and intestinal pHi (p less than .01). All measured variables decreased at the second step of bleeding. PtCO2 and subcutaneous PO2 was correlated to DO2 through the entire experiment (r2 = .25 and .49. respectively). Also. the pHi of the small intestine and the sigmoid colon correlated with DO2 (r2 = .36 and .25. respectively). PtCO2 and subcutaneous PO2 correlated with pHi in the small intestine and sigmoid colon. CONCLUSIONS: PtCO2 and pHi in the small intestine and sigmoid colon were the variables that most rapidly indicated blood volume loss. Subcutaneous PO2 and PtCO2. and small intestine and sigmoid colon pHi were correlated to total body oxygen transport. Peripheral tissue perfusion followed intestinal perfusion to some extent.
Reversible impairment of myocardial contractility due to hypercarbic acidosis in the isolated perfused rat heart, BACKGROUND AND METHODS: Striking increases in PCO2 of the myocardium have recently been documented during cardiac arrest. The purpose of the present study was to investigate selective effects of hypercarbia as distinct from acidosis on left ventricular contractile function and oxygen utilization. An isolated. spontaneously beating rat heart preparation was utilized. The perfusate was equilibrated with gases containing 5%. 10%. 20%. and 30% CO2. In a subset of experiments. the [H+] was adjusted independently of PCO2 by decreasing the concentration of HCO3-. RESULTS: When the PCO2 of the perfusate was progressively increased from 36 to 146 torr (4.8 to 29.5 kPa). the left ventricular systolic pressure (LVSP) generated by the isolated heart and the maximum rate of pressure change in the left ventricle (dP/dt) were decreased to 20% of their control values. However. comparable acidosis in the absence of hypercarbia produced only minimal decreases in the LVSP or dP/dt such that contractility remained at greater than or equal to 88%. Increases in the perfusate PCO2 but not in the perfusate H+ were highly correlated with decreases in both myocardial contractility and oxygen consumption (r2 = .88). CONCLUSION: Hypercarbia rather than acidosis accounts for decreased contractility and oxygen utilization in the isolated perfused rat heart.
Influence of noninvasive positive pressure ventilation on inspiratory muscles, Intermittent positive pressure ventilation reduces inspiratory muscle electromyographic activity among patients with restrictive ventilatory failure. It has therefore been suggested that the reduction of energy expenditure at night could result in improved inspiratory muscle function during the day. Reported successes with nocturnal ventilation have not included measurements of inspiratory muscle endurance. We therefore electively ventilated six (five female. one male) patients (mean +/- SD) aged 36 +/- 13 years in whom respiratory failure (room air PaCO2. 60 +/- 13 mm Hg; PaO2. 44 +/- 11 mm Hg; SaO2. 75 +/- 12 percent) was consequent on restrictive ventilatory disease (vital capacity. 25 +/- 7 percent predicted; FEV1/FVC. 81 +/- 12 percent; total lung capacity. 40 +/- 5 percent predicted; MIPRV -42 +/- 10 cm H2O; MEP. 81 +/- 28 cm H2O). Positive pressure ventilation was administered with a customized closely fitting nasal mask attached to a volume-cycled pressure-limited ventilator. Full respiratory polysomnographic measurements as well as arterial blood gases. pulmonary function. distance walked in six minutes. and inspiratory muscle endurance were measured at baseline and after 3 and 14 months of ventilation. Ventilation improved saturation (baseline on O2; SWS 87 +/- 10. REM 79 +/- 14. ventilator on R/A; SWS 90 +/- 6. REM 89 +/- 5 percent) and transcutaneous Pco2 (baseline on O2; SWS 85 +/- 26. REM 94 +/- 39. ventilator on R/A; SWS 53 +/- 9. REM 58 +/- 9 mm Hg). During ventilation. the quantity and distribution of sleep was similar to that observed prior to ventilation. Daytime gas exchange improved as did the six-minute walking test (initial test = 429 +/- 120 m. three months after ventilation = 567 +/- 121 m). both of these improvements being sustained at 14 months. Inspiratory muscle endurance measured using a pressure threshold load (mean mouth pressure = 45 percent MIPRV) improved from 7.1 +/- 3.4 minutes at baseline to 14.8 +/- 7.6 minutes at 3 months. an improvement sustained at 14 months. There was no change in measured lung volumes or respiratory muscle strength. We conclude that the improvement in nocturnal gas exchange. daytime functioning. and arterial blood gases resulting from nocturnal positive pressure ventilation is associated with an increase in inspiratory muscle endurance sustained at 14 months.
Regulation of thyrotropin-releasing hormone receptors is cell type specific: comparison of endogenous pituitary receptors and receptors transfected into non-pituitary cells, TRH. which does not elevate cyclic AMP. and elevation of cellular cyclic AMP decrease the density (down-regulate) of TRH receptors (TRH-Rs) on pituitary (GH3) cells. In this study we measured the effects of TRH and elevation of cyclic AMP on TRH-Rs expressed in non-pituitary cells transfected with a recently cloned mouse pituitary TRH-R complementary DNA. In stably transfected rat glioma (C6-2) cells and transiently transfected COS-1 cells TRH caused TRH-R down-regulation while elevation of cyclic AMP caused increases in TRH-R density. Hence. the effects of cyclic AMP on TRH-Rs in transfected C6-2 and COS-1 cells are different from those in GH3 cells while the effects of TRH on TRH-R are similar in all three cell types. These data show that regulation of TRH-Rs is cell type specific.
Prevention of bacterial meningitis. Vaccines and chemoprophylaxis, The morbidity and mortality caused by bacterial meningitis remains significant despite advances in antimicrobial therapy and supportive care. Prevention of meningitis by routine immunization of infants. who are at greatest risk. offers the only practical way of reducing the incidence of this disease. Widespread use of the recently developed protein conjugate vaccines against Haemophilus influenzae type b by itself could reduce the incidence of bacterial meningitis in the U.S. by more than half. To prevent disease caused by the other pathogens. an effective vaccine against the group B meningococcus must be developed. and the immunogenicity of the pneumococcal and quadrivalent meningococcal vaccines should be improved. Until such time that universal immunization of infants with highly immunogenic vaccines is possible. continued efforts must focus on targeting immunization at high-risk individuals and using chemoprophylaxis to prevent secondary disease where indicated. Addendum: On October 4. 1990. the U.S. Food and Drug Administration licensed the praxis Haemophilus influenzae type b-protein conjugate vaccine (Hboc) for use in infants at 2. 4. and 6 months of age with a booster dose at 15-18 months. Physicians are directed to statements by the Immunizations Practices Advisory Committee and the American Academy of Pediatrics for official recommendations concerning its use.
Clinical applications of carbon dioxide/digital subtraction arteriography, During an 18-month period 33 patients in whom there were contraindications to the use of iodinated contrast arteriography underwent 40 carbon dioxide/digital subtraction arteriograms for lower extremity ischemia (19). severe hypertension and renal insufficiency (12). or arterial aneurysm (2). Contraindications to iodinated contrast agents included renal insufficiency. congestive heart failure. and contrast hypersensitivity. Sixteen aortic. 15 iliac-femoral-popliteal-tibial. five aorta-iliac-femoral and four aorta-iliac-femoral-popliteal-tibial carbon dioxide/digital subtraction arteriography studies were performed. In 11 studies. imaging of selected arterial segments required the addition of 10 to 60 ml of dilute nonionic contrast. Guided by carbon dioxide/digital subtraction arteriography studies four femoral-tibial bypasses. three aneurysmorrhaphies. two aortorenal bypasses. one aortofemoral bypass and one femoral-femoral bypass were successfully performed in 11 patients. In addition. carbon dioxide/digital subtraction arteriography directed angioplasties of the common iliac (4). superficial femoral (6). popliteal (3). or tibioperoneal trunk (1) were performed in 10 patients. Complications of carbon dioxide/digital subtraction arteriography included transient deterioration in renal function in three patients in whom 20 ml of nonionic contrast was used. a nonfatal myocardial infarction after a popliteal percutaneous transluminal angioplasty in one patient. and transient tachypnea and tachycardia during a carbon dioxide/digital subtraction arteriography study in one patient. Diagnostic arteriograms are obtainable using carbon dioxide as the contrast agent. Carbon dioxide/digital subtraction arteriography permits patients with symptomatic arterial disease at high risk for contrast related complications to safely undergo arteriography and subsequent arterial reconstruction or endovascular intervention.
Confirmation of hepatitis C virus infection by new four-antigen recombinant immunoblot assay, A new four-antigen recombinant immunoblot assay (4-RIBA) for confirmation of hepatitis C virus (HCV) C-100 enzyme-linked immunosorbent assay (ELISA) reactivity was tested in stored serum samples (1984-86) of blood donors and recipients and compared with results from polymerase chain reaction (PCR) analysis of fresh (1990) plasma samples in donors and recipients from the original study. Of 37 HCV C-100 ELISA-positive blood products. 8 were 4-RIBA positive. of which 7 were implicated in post-transfusion non-A. non-B hepatitis (PT-NANBH) and/or PCR confirmed recipient HCV infection. Of 9 recipients with PT-NANBH. 8 were reactive in 4-RIBA (6 positive and 2 indeterminate). With fresh plasma samples. 3 donors and 6 recipients who were 4-RIBA positive were also PCR positive. 4 4-RIBA indeterminate and 78 4-RIBA negative samples of donors and recipients were PCR negative. Of 6 4-RIBA positive recipients. 5 were PCR positive four to six years later. 1.6% of the 383 recipients became chronically infected with HCV. The new 4-RIBA represents a candidate confirmation test to discriminate between infective and non-infective HCV C-100 ELISA-positive blood donors.
Haemophilus b conjugate vaccines for prevention of Haemophilus influenzae type b disease among infants and children two months of age and older. Recommendations of the immunization practices advisory committee (ACIP), These recommendations include information on use of two vaccines recently licensed for use with infants: Haemophilus b Conjugate Vaccine (Diphtheria CRM197 Protein Conjugate) (HbOC). manufactured by Praxis Biologics. Inc.. and Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) (PRP-OMP). manufactured by Merck Sharp and Dohme. newly licensed for use with infants. This statement also updates recommendations for use of these and other Haemophilus b conjugate vaccines with older children and adults.
Etiologic diagnosis in neurotologic disease, The inner ear is a converter (transducer) of mechanical to electrical energy for both hearing and balance functions. This task is accomplished as a result of the presence of the chemicals within the perilymph and endolymph. Maintaining normal hearing and balance function is dependent upon the availability of the proper chemicals to perform this transduction task. The inner ear functions as an internal body organ and its efficiency in regard to performing its tasks related to hearing and balance function are chemically dependent upon many body systems.
Endolymph pressure in Meniere's disease, During the streptomycin perfusion/shunt of the lateral semicircular duct operation for Meniere's disease. the lateral semicircular duct is exposed by removal of the bone of the lateral semicircular canal. Before perfusion with streptomycin and creation of a shunt in the lateral semicircular duct. the pressure in the lateral semicircular duct is measured while electrocochleography is being recorded. In most ears with Meniere's disease. the pressure necessary to indent the lateral semicircular duct is 2 to 3 mm of water. The pressure is more in those ears with a large negative summating potential than in those with a normal negative summating potential. The pressure is less after the shunt in the lateral semicircular duct is created and the negative summating potential returns to normal. In some ears with the classic picture of Meniere's disease. the endolymph pressure is normal and there is a normal negative summating potential. Presumably. one should not create a shunt in the lateral semicircular duct in ears with normal pressure.
Fine-needle aspiration in the diagnosis of head and neck growths: is it necessary, The results of fine-needle aspiration cytology performed on 150 patients at the Geneva Clinic of Otolaryngology were analyzed. The accuracy rate was 80%. The study was nondiagnostic in 10% of the cases and falsely negative in another 10%. These results are similar to those in other centers. Nevertheless. several recent reports attest to the accuracy of fine-needle aspirations cytology. and in some clinics it is now part of the initial workup of every patient with a growth in the head and neck. On the basis of our own retrospective analysis. we believe fine-needle aspiration is a useful study only in patients with a previously treated malignancy and who have a new lump in the neck suspected to be a recurrence.
Patient-controlled analgesia (PCA) in head and neck surgery, Patients undergoing head and neck surgery often have significant pain because of the anatomic area involved. the nature of the surgery and trauma associated with the anesthesia and surgery. or the use of packing postoperatively. A patient-controlled analgesia (PCA) infuser is available that allows the patient to direct delivery of their own analgesia. The physician orders the narcotic analgesic dose to be given. the interval between doses. and the total amount of analgesic to be delivered over 4 hours. The patient simply presses a button connected to the analgesic infuser. which delivers a predetermined intravenous dose of the particular analgesic. The infuser is then "locked out" for an interval of 10 to 15 minutes before the patient can direct another dose of medicine. This system allows the patients to initiate intravenous delivery of their narcotic analgesic. and maintain control of pain. using small incremental doses of the analgesic agent. This PCA pump has been used successfully in a number of patients undergoing various general. head and neck. and facial aesthetic procedures. The general concept of the PCA pump. guidelines for use. and contraindications are presented.
Maxillary sinus hypoplasia: classification and description of associated uncinate process hypoplasia, Maxillary sinus hypoplasia is an anomaly of the paranasal sinuses occasionally encountered by otolaryngologists. Although this entity has been previously reported. an association between maxillary sinus hypoplasia and anomalies of other paranasal sinus structures. such as the uncinate process. has not yet been described. Additionally. the literature lacks a system by which the various types of maxillary sinus hypoplasia can be classified using computerized tomographic (CT) imaging. Two hundred and two consecutive coronal sinus computerized tomographic scans from patients undergoing evaluation at our institution were analyzed to determine the prevalence of MSH and associated paranasal sinus anomalies. The overall prevalence of maxillary sinus hypoplasia was 10.4%. Three distinct patterns of hypoplasia were evident. Type I. characterized by a normal uncinate process. a well-defined infundibular passage. and mild sinus hypoplasia. occurred in 14 patients (6.9%). Type II. characterized by absence or hypoplasia of the uncinate process. an ill-defined infundibular passage. and soft-tissue density opacification of a significantly hypoplastic sinus occurred in 6 patients (3.0%). Type III. characterized by absence of the uncinate process and a profoundly hypoplastic. cleft-like sinus. occurred in 1 patient (0.5%). Recognition of associated anomalies of the uncinate process in patients with maxillary sinus hypoplasia undergoing sinus surgery is of utmost clinical significance because the uncinate process serves as a key landmark during functional endoscopic sinus surgery. Failure to recognize hypoplasia or absence of the uncinate process could lead to inadvertent intraoperative damage to the adjacent medial orbital wall.
31P localized magnetic resonance spectroscopy of head and neck tumors--preliminary findings, Magnetic resonance imaging (MRI) is a powerful tool for accurate assessment of the anatomic extent of head and neck neoplasms. The development of methods for spatial localization by use of multiply tuned radio frequency coils that permit the measurement of multiple nuclear MR spectra (1H and 31P) from precisely defined volumes of interest has provided a basis for integrating spectroscopy into the clinical MRI examination. This offers a means for noninvasive monitoring of relative concentrations of mobile metabolites within a tumor. With the use of imaging to determine proper coil placement. a test-retest variance of about 17% is seen on MR spectroscopy. Data are presented from MRI/MRS studies for four head and neck lesions: (1) a squamous cell carcinoma of the lip; (2) a juvenile angiofibroma extending into the nasal cavity; (3) a massive chondrosarcoma of the nasal septum; and (4) a cervical nodal metastasis of a squamous cell carcinoma of the pharynx. Spectra are evaluated by comparison of relative concentrations of phosphorus compounds. The concentrations of phosphomonoesters and phosphodiesters are significantly higher in the neoplasms studied than in normal skeletal muscle. The developing role of integrated MRI/MRS to monitor the response of malignant neoplasm to radiation therapy is discussed.
Metronidazole in head and neck surgery--the effect of lengthened prophylaxis, Previous studies of antibiotic prophylaxis have shown that treatment for 24 hours has been beneficial for head and neck surgery and that longer periods of antibiotic therapy have not improved results. Metronidazole (Flagyl). unlike other antibiotics tested. has been shown to be effective in an experimental abscess. even if treatment is begun up to 120 hours after administration of inoculum. This article presents a prospective. randomized. multifactorial study comparing a brief vs. a prolonged duration of metronidazole and cefazolin prophylaxis in 50 consecutive patients with a head and neck cancer undergoing operation. Patients receiving 2 days vs. 7 or more days of antibiotic prophylaxis were compared. Statistical analysis of data demonstrated a striking reduction in severity of wound complications and a reduced incidence of wound infections in the group treated with 7 or more days of antibiotic prophylaxis.
Correlation between histology and nerve excitability after reinnervation of paralyzed strap muscles in the rabbit, We have recently shown that the mean muscle chronaxie for nerve pedicle implanted into denervated rabbit strap muscle is comparable to that of normal nerve. This study correlates excitability with histologic characteristics of muscles reinnervated via nerve-muscle pedicles (NMP) and direct nerve implants (DNI). Strength duration curves were measured in 13 rabbits 3.5 to 5 months after reinnervation by NMP (n = 6) and DNI (n = 7). Following this. control (n = 5) and reinnervated straps were harvested immediately before the animals were killed and frozen in liquid nitrogen. The material was submitted for hematoxylin-eosin stains as well as trichrome stains for general morphology. myofibrillar ATPase and NADH for fiber typing. and cholinesterase for determination of denervated fibers. In all animals with low chronaxie. expected type grouping from reinnervation was noted (n = 10). By contrast. the three animals in which chronaxie was abnormally elevated demonstrated fibrosis. inflammation. and absence of or poor type grouping. This suggests that type grouping is necessary for excitability after reinnervation of paralyzed striated muscles.
Thermochemotherapy in inoperable head and neck cancer, A combined hyperthermia and chemotherapy approach was used to treat five patients with locally advanced or recurrent squamous cell carcinoma of the head and neck whose tumors had failed to respond to chemotherapy. In two patients. tumor had recurred after initial combined modality therapy (surgery/radiation) and had failed to respond to one course of cisplatin/5-fluorouracil (cisplatin/5-FU) chemotherapy. The three remaining patients were enrolled onto a phase II evaluation of induction chemotherapy with cisplatin/fluorouracil for advanced head and neck carcinomas and had failed to achieve a partial remission after one treatment cycle. Palpable cervical tumors were heated to 40 degrees to 42 degrees C for 30 to 40 minutes. during which time cisplatin (100 mg/m2) was infused intravenously. A 5-day infusion of 5-fluorouracil (1000 mg/m2/d) followed. Despite less than a partial response to previous cisplatin/fluorouracil chemotherapy alone. two patients had complete clinical resolution of the heated tumor volume with two cycles of the combined thermochemotherapy approach. One patient achieved a partial remission with this approach. The remaining two patients died shortly after the initial thermochemotherapy treatment. as a result of progressive tumor growth. The two complete responders were subsequently treated with radiation (1 patient) and radical neck dissection (1 patient) and remained without evidence of disease 2 and 26 months after the completion of therapy. respectively. The toxicity of this combined modality approach was acceptable and appeared to be no greater than had been experienced during earlier treatment with chemotherapy alone. Further studies using a combination of these treatment modalities for locally advanced head and neck carcinomas are warranted.
Acute epiglottitis in children and adults: a large-scale incidence study, With the introduction of an anti-haemophilus type B vaccine. a standard incidence rate for acute epiglottitis is needed to judge its efficacy. Epiglottitis is thought to be more common in children than in adults. but this relation has never been clearly established. This article attempts to evaluate the incidence of this disease. A review of the literature regarding the incidence is correlated to new data from the 1981 Census of Canada and the Med-Echo System of the province of Quebec. It suggests that the incidence rate is approximately 60/million for children (1/17.000). whereas it is 10/million for adults (1/103.000). These rates are based on the analysis of 712 pediatric cases and 257 adult cases. After a review from various sources. my estimation is that a slightly lower than 3-to-1 ratio of cases is probable between the pediatric and adult cases of acute epiglottitis.
Inhibition of endogenous superoxide dismutase with diethyldithiocarbamate in acute island skin flaps, Oxygen free radicals have been implicated in postischemic tissue damage in a variety of experimental models including the island skin flap. Previous studies have demonstrated that supplementing animals with exogenous superoxide dismutase (SOD). a free radical scavenger. improves tissue survival in island flaps. No studies to our knowledge have attempted to inhibit endogenous SOD in a skin flap model. In this experiment 20 control rats demonstrated a 12.00% flap necrosis 7 days after a modified ventral island skin flap was raised. A second group of 20 rats were supplemented with exogenous SOD (50.000 U/kg 30 minutes preoperatively and 12 hours postoperatively) and demonstrated a statistically significant decreased flap necrosis of 5.28%. A third group of 20 rats received diethyldithiocarbamate (DDC. 0.5 gm/kg 12 hours preoperatively). an agent previously shown to inhibit SOD. and demonstrated a statistically significant increased flap necrosis of 19.77%. In a final group of 20 rats the effect of DDC was overcome by supplementation with exogenous SOD. obtaining a flap necrosis of 8.35%. Our results add further support to the importance of SOD and oxygen free radicals in postischemic tissue damage by demonstrating increased tissue necrosis with inhibition of endogenous SOD. This suggests that there is a baseline degree of SOD activity in ischemic areas working to preserve tissue. It appears that the copper-containing species of SOD found primarily in the cytoplasm plays a pivotal role in preservation of postischemic tissue.
Continuous intravenous infusion of morphine for severe dyspnea, We describe eight patients who had terminal lung cancer causing severe dyspnea unrelieved by oxygen. nonnarcotic drugs. or intermittent bolus narcotics. We treated these patients with continuous intravenous infusion of morphine. beginning with bolus IV injections of 1 or 2 mg of morphine every 5 to 10 minutes until the patient reported relief. A continuous morphine infusion was then started. with the hourly dose equal to 50% of the cumulative bolus dose. Vital signs. degree of sedation. and blood gases were serially followed. Six patients achieved good dyspnea relief. one had moderate relief. and one had a poor response. Variable changes were noted in the PaO2. whereas PaCO2 steadily increased in five of seven patients. and pH decreased in six. There was little change in systolic blood pressure or pulse. and only one individual had less than 10 respirations per minute. The major side effect of treatment was sedation. treated by temporarily discontinuing morphine until the patients' mental status improved and then restarting the infusion at a 50% lower hourly morphine dose. Mean time of study was 30 hours (range 16 to 87 hours). Seven of the eight study patients died during treatment. Whether morphine therapy shortened survival is uncertain. We conclude that continuous morphine infusion is effective therapy for severe dyspnea. The treatment is ethically justified. Relief of suffering is the primary goal of therapy. and less risky treatments are unavailable.
FK 506 prevents spontaneous diabetes in the BB rat, The BB rat is the experimental analogue of human juvenile diabetes mellitus. From 30 through 120 days after birth. 59 BB rats were treated with water (n = 20). or FK 506 in daily intragastric doses of 1 mg/kg (n = 19) or 2 mg/kg (n = 20). Diabetes developed in 75%. 15%. and 0% of the three groups. Animals protected from diabetes by FK 506. and killed in the nondiabetic state at 120 days had normal intraperitoneal glucose tolerance tests. virtual absence histopathologically of autoimmune insulitis. normal pancreatic insulin content. and immunocytochemical confirmation of islet insulin and glucagon content. Forty five to 75 days after stopping FK 506. about 3/4 of the animals who were diabetes free at 120 days have remained so. These results provide support for a clinical trial of FK 506 for recent onset diabetes.
The combined antiischemic effects of the thromboxane receptor antagonist SQ 30,741 and tissue-type plasminogen activator, The thromboxane-receptor antagonist. SQ 30.741. may be used as adjuvant therapy for thrombolysis and has also been shown to have antiischemic activity that is independent of its thrombolytic activity. Since tissue-type plasminogen activator (t-PA) and SQ 30.741 may be administered simultaneously. we determined whether the antiischemic effects of SQ 30.741 can be potentiated by t-PA. This was accomplished by combining doses of t-PA and SQ 30.741. which alone were not cardioprotective. Anesthetized dogs were subjected to left circumflex coronary artery occlusion for 90 minutes and reperfusion for 5 hours. The dogs were treated during reperfusion with a dose of t-PA that caused approximately a 30% reduction in plasma fibrinogen alone or in combination with 1.5 mg/kg + 0.4 mg/kg/hr SQ 30.741. which started 10 minutes after initiation of ischemia. At these doses. neither t-PA nor SQ 30.741 alone significantly reduced infarct size (57% +/- 6%. 50% +/- 10%. 57% +/- 6% of the left ventricular area at risk for vehicle controls. t-PA. and SQ 30.741 respectively); however. combination treatment resulted in a significant reduction in infarct size (37% +/- 5% of the left ventricular area at risk). Higher doses of t-PA and SQ 30.741 alone significantly reduced infarct size. The protective effects of t-PA and SQ 30.741 occurred without altering peripheral hemodynamic status. No differences in collateral or reperfusion blood flow were observed between groups. Thus although SQ 30.741 may act to improve the efficacy of thrombolysis. t-PA may in turn enhance the antiischemic activity of SQ 30.741 or at least reduce the threshold dose.
Recombinant tissue-type plasminogen activator: current concepts and guidelines for clinical use in acute myocardial infarction. Part II, The extraordinarily high prevalence of coronary heart disease. coupled with the alarming incidence of MI in Western society. has encouraged the investigation and development of pharmacologic agents that can be employed widely. quickly. effectively. and safely. Recombinant t-PA has played a vital role in the treatment of MI. restoring coronary arterial patency. limiting infarct size. preserving ventricular function. and improving patient survival. It has been shown to be safe when given to carefully selected patients and. although indications for clinical use have been relatively restricted. they appear to be expanding considerably. Future investigations must continue to focus on patient selection to allow treatment for all patients who would derive benefit and to establish dosing regimens and adjuvant therapies that will maximize coronary reperfusion while concomitantly limiting reocclusion and hemorrhagic complications.
Complete atrioventricular block complicating inferior wall acute myocardial infarction treated with reperfusion therapy. TAMI Study Group, Previous studies report larger myocardial infarcts and increased in-hospital mortality rates in patients with inferior wall acute myocardial infarction (AMI) and complete atrioventricular block (AV). but the clinical implications of these complications in patients treated with reperfusion therapy have not been addressed. The clinical course of 373 patients--50 (13%) of whom developed complete AV block--admitted with inferior wall AMI and given thrombolytic therapy within 6 hours of symptom onset was studied. Acute patency rates of the infarct artery after thrombolytic therapy were similar in patients with or without AV block. Ventricular function measured at baseline and before discharge in patients with complete AV block showed a decrement in median ejection fraction (-3.5 vs -0.4%. p = 0.03) and in median regional wall motion (-0.14 vs +0.24 standard deviations/chord. p = 0.05). The reocclusion rate was higher in patients with complete AV block (29 vs 16%. p = 0.03). Patients with complete AV block had more episodes of ventricular fibrillation or tachycardia (36 vs 14%. p less than 0.001). sustained hypotension (36 vs 10%. p less than 0.001). pulmonary edema (12 vs 4%. p = 0.02) and a higher in-hospital mortality rate (20 vs 4%. p less than 0.001). although the mortality rate after hospital discharge was identical (2%) in the 2 groups. Multivariable logistic regression analysis revealed that complete AV block was a strong independent predictor of in-hospital mortality (p = 0.0006). Thus. despite initial successful reperfusion. patients with inferior wall AMI and complete AV block have higher rates of in-hospital complications and mortality.
Rapid detection of the A----G(8344) mutation of mtDNA in Italian families with myoclonus epilepsy and ragged-red fibers (MERRF), We devised a rapid PCR-based method to screen for an A----G transition at nucleotide 8344 of the human mitochondrial tRNA(Lys) gene. which was recently reported. by Shoffner and co-workers. to be associated with myoclonus epilepsy and ragged-red fibers (MERRF). a maternally transmitted mitochondrial encephalomyopathy (Shoffner et al. 1990). We confirmed this association in five of seven Italian MERRF pedigrees. The mutation was specific for the MERRF trait. because it was never found in mtDNA of non-MERRF individuals. including 14 normal and 110 diseased controls. Our study corroborates the idea that the A----G(8344) mutation is the most frequent and widespread genetic cause of MERRF.
Homozygous tyrosinase gene mutation in an American black with tyrosinase-negative (type IA) oculocutaneous albinism, We have identified a tyrosinase gene mutation in an American black with classic. tyrosinase-negative oculocutaneous albinism. This mutation results in an amino acid substitution (Cys----Arg) at codon 89 of the tyrosinase polypeptide. The proband is homozygous for the substitution. suggesting that this mutation may be frequently associated with tyrosinase-negative oculocutaneous albinism in blacks.
Early changes in lung tissue hyaluronan (hyaluronic acid) and hyaluronidase in bleomycin-induced alveolitis in hamsters, Intratracheal instillation of bleomycin in hamsters initiates a series of events that mimic human interstitial pulmonary fibrosis. Because glycosaminoglycans and particularly hyaluronan (hyaluronic acid. HA). may play an important role in the extracellular matrix response to early injury and subsequent fibrosis. this study was undertaken to define the early time course of changes in HA and hyaluronidase. Hamsters were given either 1 unit bleomycin sulfate in 0.2 ml saline or 0.2 ml saline (control). and randomly selected animals from both groups were killed at Days 3. 5. 6. 7. 9. and 17. Glycosaminoglycan fractions prepared from lung tissue of individual animals were analyzed for HA. The maximal HA content was reached 6 days after instillation of bleomycin and was 14.6-fold the normal value. The weight of injured lungs was 2.3-fold the control value. Thus. the increase in HA content was 30-fold. By Day 7 the HA content had dropped sharply. It then declined gradually to approximately double control values at Day 17. The specific activity of lysosomal hyaluronidase was the same in bleomycin-treated lungs and control lungs. Total units of the enzyme were increased in injured lungs. even at the time of maximal HA content. indicating active turnover of HA. The maximal HA content occurs prior to the rise in collagen and elastin biosynthesis. This observation in addition to the magnitude of the increase and its abrupt decline suggest that HA may be an important initiating factor for pathologic changes in lung extracellular matrix components.
A lifelong bleeding disorder associated with a deficiency of plasminogen activator inhibitor type 1, A 36-year-old patient was investigated for a lifelong history of epistaxis and delayed bleeding after minor surgeries. Deficiencies or abnormalities of the coagulation system. of platelet function. or of factor XIII and alpha-2-antiplasmin were excluded. Consistently. however. over a period of 7 years. a high basal euglobulin fibrinolytic activity was observed that was characterized by a high tissue-type plasminogen activator (t-PA) activity. normal t-PA antigen. and undetectable plasminogen activator inhibitor type-1 (PAI-1) antigen and activity. The high specific activity of t-PA (640.000 IU/mg) and the minimal amounts of t-PA/PAI-1 complexes detected by fibrin zymography suggest that in this patient all t-PA was active. This is in striking contrast to normal plasma. where the majority of t-PA is complexed to PAI-1. Thus. in this patient. a severe deficiency of PAI-1 is associated with a delayed type bleeding tendency. Our observation underscores the importance of plasma PAI-1 for the stabilization of the hemostatic plug.
No effect of misoprostol on renal function of rheumatoid patients treated with diclofenac, Non-steroidal anti-inflammatory drugs can reversibly decrease renal function in patients with rheumatoid arthritis (RA). To test whether orally administered prostaglandins could mitigate this decrease. we studied the effect of misoprostol in 24 RA patients during treatment with diclofenac in a randomized. placebo-controlled crossover trial. At baseline. 21 patients had a creatinine clearance below 80 ml/min/1.73 m2. The two treatment phases (with either misoprostol. 600 micrograms daily. or matching placebo tablets) were separated by a washout phase in which diclofenac (150 mg daily) was continued. After treatment with misoprostol/diclofenac the glomerular filtration rate was 72 +/- 5 ml/min (mean +/- standard error). and the effective renal plasma flow was 295 +/- 21 ml/min. After treatment with placebo/diclofenac. the corresponding values were 71 +/- 5 ml/min and 296 +/- 21 ml/min. respectively. We concluded that misoprostol has no effect on the renal function of RA patients treated with diclofenac.
Mitomycin C-loaded microcapsules in the treatment of colorectal liver metastases. Pharmacokinetics of regionally administered particulate chemotherapy, Microencapsulated mitomycin C has been used for the treatment of intrahepatic tumors in Japan. but there have been no reports of its use in western countries. In this study. the pharmacokinetic profile of intrahepatic arterial mitomycin C microcapsules is reported. Regional mitomycin C was administered to six patients. both in the microencapsulated form and in solution. The clearance (140 +/- 31 1/hour. mean +/- SD) and half-life of drug in plasma (0.39 +/- 0.03 hours). and volume distribution (246 +/- 23 1) were significantly higher. and peak drug concentrations (80 +/- 75 ng/ml) significantly lower with the microencapsulated preparation than with the free drug (clearance. 46 +/- 8 1/hour; half-life. 0.11 +/- 0.02 hours; volume distribution. 33 +/- 4; peak drug concentration. 812 +/- 423 ng/ml). on Student's t testing (P less than 0.05). The results show that very little systemic exposure is associated with the microencapsulated form of mitomycin C. Dose escalation should be feasible without increasing systemic toxicity.
Screening mammography, Screening mammography can reduce mortality from breast cancer and is the only means of detecting nonpalpable cancers that are often more curable. Based on this. guidelines have evolved but compliance with them has been slow. Reservations are based on yield-cost-benefit-harm considerations. but uniformed and/or disadvantaged women and reluctance if not resistance to screening mammography by primary care physicians are major problems. The challenges are to overcome these obstacles and to obtain sufficient competent personnel and facilities to make reproducibly optimum screening mammography. which is accurately interpreted. widely available to all eligible women at the lowest possible cost.
Diagnostic imaging in cancer care. The role of cost/benefit analysis, As the cost of medical care rises. there is increasing need to analyze the costs and benefits of diagnostic imaging. A review of previous research shows reasonable success at defining costs and the ability to identify safety and risk. but limited data on defining benefits in economic terms. The technology to analyze costs and benefits is improving. and satisfactory research protocols and methods have recently become generally accepted. While research studies to determine costs and benefits or efficacy are themselves costly. time consuming. and difficult to perform in clinical practice. the wise allocation of medical resources in the US requires physicians in all specialties to evaluate the technology when we are responsible for its use.
Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study, In the Thrombolysis in Myocardial Infarction (TIMI) Phase II trial. patients received intravenous recombinant tissue-type plasminogen activator (rt-PA) and were randomized to either a conservative or an invasive strategy. Within this study. the effects of immediate versus deferred beta-blocker therapy were also assessed in patients eligible for beta-blocker therapy. a group of 1.434 patients of which 720 were randomized to the immediate intravenous group and 714 to the deferred group. In the immediate intravenous group. within 2 hours of initiating rt-PA metoprolol was given (5 mg intravenously at 2-minute intervals over 6 minutes. for a total intravenous dose of 15 mg. followed by 50 mg orally every 12 hours in the first 24 hours and 100 mg orally every 12 hours thereafter). The patients assigned to the deferred group received metoprolol. 50 mg orally twice on day 6. followed by 100 mg orally twice a day thereafter. The therapy was tolerated well in both groups and the primary end point. resting global ejection fraction at hospital discharge. averaged 50.5% and was virtually identical in the two groups. The regional ventricular function was also similar in the two groups. Overall. there was no difference in mortality between the immediate intravenous and deferred groups. but in the subgroup defined as low risk there were no deaths at 6 weeks among those receiving immediate beta-blocker therapy in contrast to seven deaths among those in whom beta-blocker therapy was deferred. These findings for a secondary end point in a subgroup were not considered sufficient to warrant a recommendation regarding clinical use. There was a lower incidence of reinfarction (2.7% versus 5.1%. p = 0.02) and recurrent chest pain (18.8% versus 24.1%. p less than 0.02) at 6 days in the immediate intravenous group. Thus. in appropriate postinfarction patients. beta-blockers are safe when given early after thrombolytic therapy and are associated with decreased myocardial ischemia and reinfarction in the first week but offer no benefit over late administration in improving ventricular function or reducing mortality.
Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris, To elucidate the pathogenic contribution of a potent vasoconstrictor. endothelin-1. to coronary artery spasm. we provoked spasm with intracoronary administration of acetylcholine or ergonovine and performed sensitive immunoassays of plasma levels of endothelin-1 and atrial natriuretic factor (ANF) in the peripheral vein and coronary sinus of patients with a tentative diagnosis of vasospastic angina (VSA. n = 19). The validity of coronary sinus blood sampling was verified by simultaneous measurement of the ANF level. The plasma endothelin-1 levels in venous and coronary sinus blood of the spasm-provoked patients (n = 12) were 1.71-fold and 2.16-fold higher. respectively. than those of nonprovoked cases (n = 5. p less than 0.01). During left coronary spasm. the endothelin-1 level in coronary sinus transiently decreased from 2.27 +/- 0.14 to 1.76 +/- 0.14 pg/ml (p less than 0.01) and returned to the control level (1.98 +/- 0.20 pg/ml) after the spasm resolved. whereas the change was equivocal during right coronary spasm. In contrast. the patients in whom spasm was not provoked showed no changes and maintained low endothelin-1 levels both before and after the maximal provocation (0.90 +/- 0.13 versus 0.90 +/- 0.13 pg/ml).
Noninvasive diagnostic assessment of peripheral vascular disease, Noninvasive techniques have assumed an increasingly important role in the management of patients with vascular disease. Both ultrasonic and plethysmographic instruments allow objective evaluation of vascular disorders by the measurement of segmental limb blood pressures. analysis of blood velocity disturbances. recording of digit or limb pulse waveforms. or imaging of vascular disease. with or without Doppler flow analysis or color-flow mapping. These techniques have been applied for screening asymptomatic individuals. diagnosis of symptomatic patients. monitoring of interventional or surgical procedures. and follow-up of the natural history or the efficacy of medical. interventional. or surgical therapy of vascular disease. This article reviews the clinical application of these modalities to patients with peripheral arterial disease and briefly discusses cost-effectiveness and potential abuses of noninvasive technology.
Effect of plasma from patients with essential hypertension on vascular resistance in the isolated perfused rat kidney, 1. Isolated perfused rat kidneys were used to study the effects of plasma fractions obtained by gel filtration from essential hypertensive patients (n = 40) and from normotensive subjects (n = 36) on resistance vessels. Perfusion pressure was recorded at a constant flow. 2. Plasma fractions were obtained by gel filtration and contained substances with a molecular mass in the range 1000-1500 Da. The plasma fractions from hypertensive patients used in this study had been shown to increase blood pressure after intravenous injection in rats. 3. In the isolated rat kidneys. the hypertensive fractions increased perfusion pressure by 20 +/- 17 mmHg (mean +/- SD. range 5-58 mmHg. n = 40). The analogous fractions from normotensive subjects did not change perfusion pressure significantly. 4. In Ca2(+)-free medium containing 2 mmol/l ethyleneglycol bis-(aminoethyl ether)tetra-acetate. the change in perfusion pressure induced by active plasma fractions was reduced by 95.2 +/- 6.3%. Addition of nifedipine to the perfusion medium reduced. but did not abolish. the pressure response of the kidneys. 5. In solutions containing phentolamine or saralasin. vasoconstriction was not reduced. 6. Thus in the active fractions from hypertensive plasma. a vasopressor agent with direct action on resistance vessels can be demonstrated. This substance probably acts by increasing Ca2+ influx in vascular smooth muscle cells.
Metabolic control in diabetic subjects in three Swedish areas with high, medium, and low sales of antidiabetic drugs, OBJECTIVE: The relationship between use of antidiabetic drugs and metabolic control was studied in Swedish diabetic populations in areas with high (Gotland). medium (Tierp). and low (Skelleftea) sales of antidiabetic drugs. RESEARCH DESIGN AND METHODS: The study population consisted of 405 drug-treated diabetic subjects aged 50-74 yr. In all three areas. glyburide comprised approximately 75% of the oral treatment. RESULTS: In accordance with sales. Gotland was found to be a heavy-use area. characterized by a high prevalence of insulin treatment (43%). combination therapy with sulfonylureas and biguanide (28%). and high prescribed daily doses (PDDs) of glyburide (15.5 +/- 0.8 mg) compared with other areas. In Skelleftea. 38% were on insulin. 4% were on combination therapy. and the PDD of glyburide was 7.1 +/- 0.6 mg. In Tierp. 27% were on insulin. 26% were on combination therapy. and the PDD of glyburide was 11.4 +/- 0.7 mg. In Gotland. both men and women had significantly lower HbA1c levels. regardless of treatment mode. and a tendency to be more overweight compared with the area with the least pharmacological intensity (Skelleftea). CONCLUSIONS: In the three diabetic populations. good metabolic control. defined as an HbA1c level of less than 7% and acceptable weight control (body mass index less than 27 for men and less than 25 for women). was achieved among only 16% in Gotland. 17% in Skelleftea. and 12% in Tierp.
A comparative analysis of the cycle fecundity rates associated with combined human menopausal gonadotropin (hMG) and intrauterine insemination (IUI) versus either hMG or IUI alone, Human menopausal gonadotropin (hMG) superovulation combined with washed intrauterine insemination (IUI) has been advocated for the treatment of various forms of infertility when more traditional therapy has failed. To assess the relative efficacy of combined treatment with hMG and IUI compared with either hMG or IUI alone. pregnancy outcomes of the three treatment groups were compared in couples having infertility because of male factor. cervical factor. endometriosis. or unexplained. A total of 751 cycles were analyzed from 322 couples. The mean cycle fecundity rate associated with hMG/IUI therapy was significantly higher than either hMG or IUI therapy alone for all patients (hMG/IUI = 19.6%. hMG = 6.3%. IUI = 3.4%). The improvement in cycle fecundity rates with hMG/IUI therapy was also observed when the couples were separated by infertility diagnostic groups: male factor (hMG/IUI = 15.3%. hMG = 4.4%. IUI = 3.0%). cervical factor (hMG/IUI = 26.3%. hMG = 7.9%. IUI = 5.1%). endometriosis (hMG/IUI = 12.85%. hMG = 6.6%). and unexplained infertility (hMG/IUI = 32.6%. hMG = 5.5%. IUI = 0%). Moreover. in patients who had failed to conceive with hMG or IUI alone. the cycle fecundity rate when they were switched to hMG/IUI therapy equaled that of patients who received combined therapy from the onset. We conclude that cycle fecundity rates and cumulative pregnancy rates are significantly greater using a combination of hMG and IUI compared with either modality alone in the treatment of male factor. cervical factor. endometriosis. or unexplained infertility. Indeed. in couples with nontubal related infertility. cycle fecundity rates with hMG/IUI approach the rates seen with in vitro fertilization and gamete intrafallopian tube transfer.
Evidence for altered receptor-binding activity of serum follicle-stimulating hormone in male infertility, It is generally assumed that the immunological activity of the follicle-stimulating hormone (FSH) molecule. as reported in the radioimmunoassay (RIA). is identical to the molecule's biological activity. To test the validity of this assumption. the receptor-binding and immunological activities of FSH in the serum of 35 infertile males and 11 fertile males were determined by radioreceptor assay (RRA) and by the standard RIA. The results were analyzed in terms of the ratio of binding (RRA) to immunological (RIA) activity x 100%. referred to as the B/I%. for each patient based on data from the RRA and RIA. respectively. The B/I% for fertile men ranged from 44% to 113% (mean of 80%). In the group of 11 infertile men with normal FSH levels by RIA (50 to 300 ng/mL). there was no significant difference in B/I% (range of 27% to 99%. mean of 59%) from the fertile controls. However. a statistically significant decrease in B/I% (range of 7% to 35%. mean of 18%) was noted in the 24 hypergonadotropic infertile men with RIA levels of serum FSH greater than 300 ng/mL. These significant discrepancies between receptor-binding and immunological activities of serum FSH raise the question of whether RIAs alone are valid parameters for the endocrine evaluation of infertile men with elevated serum FSH levels.
Comparison of the indirect immunobead, radiolabeled, and immunofluorescence assays for immunoglobulin G serum antibodies to human sperm, The relative sensitivities of the indirect immunobead test. the indirect flo cytometric immunofluorescence assay. and an indirect radiolabeled antiglobulin assay were compared. Eighteen immunobead test positive sera and 18 negative sera were used as the standard for the other two assays. Of the 18 positive sera. 14 (77%) and 5 (27%) were positive in the immunofluorescence assay and the radiolabeled antiglobulin assay. respectively. Four (22%) of the low titer immunobead test positive sera were negative by both the immunofluorescence assay and the radiolabeled antiglobulin assay. However. there was a significant positive correlation between the results of the immunofluorescence assay and the radiolabeled antiglobulin assay (r = 0.73) and between the results of the radiolabeled antiglobulin assay and the titer of the immunobead test (r = 0.82). The use of an unselected sperm population in the radiolabeled antiglobulin assay and the classical indirect immunofluorescence method using methanol-fixed sperm gave false-positive results in the radiolabeled antiglobulin assay and the immunofluorescence assay. These results suggested that immunoglobulin G antisperm antibody positive sera may be reactive both to sperm surface and internalized sperm antigens.
Effect of diabetes and aging on carboxymethyllysine levels in human urine, Carboxymethyllysine (CML) has been identified as a modified amino acid that accumulates with age in human lens proteins and collagen. CML may be formed by oxidation of fructoselysine (FL). the Amadori adduct formed on nonenzymatic glycosylation of lysine residues in protein. or by reaction of ascorbate with protein under autoxidizing conditions. We proposed that measurements of tissue and urinary CML may be useful as indices of oxidative stress or damage to proteins in vivo. To determine the extent to which oxidation of nonenzymatically glycosylated proteins contributes to urinary CML. we measured the urinary concentrations of FL and CML in diabetic (n = 26) and control (n = 28) patients. The urinary concentration of FL correlated strongly with HbA1 measurements and was significantly higher in diabetic compared with control samples (9.2 +/- 6.5 and 4.0 +/- 2.8 micrograms/mg creatinine. respectively; P less than 0.0001). There was also a strong correlation between the concentrations of CML and FL in both diabetic and control urine (r = 0.67. P less than 0.0001) but only a weakly significant increase in the CML concentration in diabetic compared with control urine (1.2 +/- 0.5 and 1.0 +/- 0.3 micrograms/mg creatinine. respectively; P = 0.05). The molar ratio of CML to FL was significantly lower in diabetic compared with control patients (0.25 +/- 0.12 and 0.43 +/- 0.16. respectively; P less than 0.0001).
Restoration of Na(+)-K+ pump activity and resting membrane potential by myo-inositol supplementation in neuroblastoma cells chronically exposed to glucose or galactose, myo-Inositol uptake by culture neuroblastoma cells at a concentration of myo-inositol less than 50 microM was largely Na+ dependent. Exposing neuroblastoma cells to media supplemented with increasing concentrations of myo-inositol resulted in an increase in myo-inositol accumulation and intracellular content. but myo-inositol incorporation into phospholipids was not increased. The data indicate that myo-inositol exists as separate pools in neuroblastoma cells. and one or more of these pools may contribute to phospholipid synthesis. Exposing neuroblastoma cells to an increased concentration of glucose caused a decrease in myo-inositol uptake by two separate mechanisms. Acute exposure of the cells to 30 mM glucose caused a myo-inositol concentration-dependent decrease in Na(+)-dependent myo-inositol uptake. We propose that the acute inhibition of myo-inositol uptake by glucose is likely due to a competitive type of inhibition. Chronic exposure of cells to media containing 30 mM glucose or 30 mM galactose also caused decreases in myo-inositol uptake and incorporation into inositol phospholipids and intracellular myo-inositol content. This decrease in myo-inositol metabolism persisted at a higher concentration of external myo-inositol than the acute inhibition. Supplementing media containing 30 mM glucose or 30 mM galactose with 250 microM myo-inositol restored myo-inositol metabolism and content. The inhibition of myo-inositol uptake by cells chronically exposed to increased concentrations of glucose or galactose was due to a noncompetitive type of inhibition that was blocked by the addition of sorbinil. Chronic exposure of neuroblastoma cells to media containing 30 mM glucose or 30 mM galactose caused a decrease in Na(+)-K(+)-ATPase transport activity and resting membrane potential.
Altered expression of diabetes in BB/Wor rats by exposure to viral pathogens, Autoimmune diabetes mellitus affects greater than 50% of diabetes-prone BB (DP BB) rats but less than 1% of diabetes-resistant BB (DR BB) rats. We report an outbreak of spontaneous diabetes among DR BB rats that coincided with serologic evidence of the onset of viral infection. This apparent link between a change in the environment and the expression of diabetes then led us to study the interaction of environmental exposure to viral pathogens in this disorder with virally seropositive and seronegative populations of BB rats and polyinosinic-polycytidylic acid (poly I:C). an interferon inducer known to accelerate diabetes onset in DP rats. We administered a cytotoxic anti-RT6 monoclonal antibody. poly I:C. or both to DR rats. Depletion of the RT6.1+T-lymphocyte population has previously been shown to induce diabetes and thyroiditis in DR rats. RT6 alone did not induce diabetes in seronegative DR rats. and poly I:C was only weakly effective. but nearly all animals given both reagents became diabetic. When given to seropositive DR rats. either reagent alone induced diabetes; when given to non-BB rats. neither agent was effective. Poly I:C also accelerated the onset of DP diabetes to a greater extent in seropositive than in seronegative rats. We conclude that expression of the genetic predisposition to diabetes present in all BB rats depends on cellular factors that include the presence or absence of regulatory (RT6+) T lymphocytes and modulatory environmental factors including exposure to viral pathogens.
Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats, Elimination of environmental viruses by cesarean derivation of the University of Massachusetts colony of BB/Wor rats increased the frequency and accelerated the tempo of spontaneous diabetes among diabetes-prone (DP) rats. In contrast. the viral-antibody-free (VAF) environment did not alter the resistance of pre-VAF diabetes-resistant (DR) rats to spontaneous and RT6+ T-lymphocyte-depletion-induced diabetes. Pre-VAF and VAF rats have essentially the same lymphocyte subsets. and VAF-DP rats are susceptible to the adoptive transfer of diabetes and to the diabetes-accelerating effects of polyinosinic-polycytidylic acid injections. These results suggest that the presence of environmental viral pathogens may act to inhibit effector cell function in lymphopenic DP rats while enhancing effector cell activity in nonlymphopenic DR rats.
Stimulatory effects of alpha-hANP on testosterone secretion in man, Several recent observations suggest that atrial natriuretic peptides (ANP) can modulate steroidogenesis in isolated rat Leydig cells. At present. it is unknown whether ANP influence human testicular steroidogenesis. We therefore evaluated the effects of alpha-human ANP (hANP) administration on testosterone plasma levels in peripheral and internal spermatic venous blood of young men (catheterized for contrast study of varicocele). Six subjects were injected with 100 micrograms alpha-hANP in the cubital vein. Six different patients similarly received 50 micrograms LHRH. Three controls received 2 ml saline. Plasma LH. FSH. and testosterone were then determined 15 min before. at time of injection. and 15. 30. 45. and 60 min thereafter in spermatic vein and peripheral venous blood. as well as at 120 min in peripheral blood. LHRH--induced LH increase was followed by a marked increase of spermatic vein testosterone concentrations. but the peripheral testosterone concentration did not increase. Similarly. alpha-hANP administration did not affect peripheral testosterone and LH concentrations. but significantly increased spermatic vein testosterone levels (P less than 0.01). Our findings demonstrate that alpha-hANP exerts its stimulatory effect on testicular steroidogenesis in man without modifying gonadotropin secretion. suggesting that alpha-hANP may directly influence Leydig cell function.
Contrasting effects of various potassium salts on renal citrate excretion, Mechanisms for the citraturic response to potassium citrate treatment were sought by assessing renal citrate clearance and acid-base status after oral administration of potassium citrate. potassium bicarbonate. and potassium chloride. After 2 weeks of treatment of eight patients with stones at a dose of 80 meq/day. urinary citrate rose significantly from 2.5 +/- 1.6 mmol/day (no drug) to 5.1 +/- 1.7 mmol/day with potassium citrate and to 4.5 +/- 1.5 mmol/day with potassium bicarbonate (P less than 0.05). but did not change significantly with potassium chloride. Citrate clearance increased from 8.0 to 27.4 mL/min with potassium citrate and 25.8 mL/min with potassium bicarbonate (P less than 0.05). but did not increase with potassium chloride. Both potassium citrate and potassium bicarbonate significantly raised urinary bicarbonate and decreased urinary ammonium. titratable acid. and net acid excretion. Potassium chloride was without effect. Effects of potassium citrate on urinary citrate. citrate clearance. and acid-base status tended to be more prominent than those of potassium bicarbonate. but these changes were not significant. Thus. the citraturic action of potassium citrate is largely accountable for by provision of an alkali load. Potassium itself had no effect in the absence of potassium deficiency.
High testosterone levels of ovarian origin affect adrenal steroidogenesis, Androgens of ovarian origin have been suggested to affect adrenal enzymatic activity. To investigate this possibility. the 17-hydroxyprogesterone (17-OH P) and cortisol (F) responses to an ACTH stimulation test (0.25 mg iv. bolus) were evaluated in 10 normal women and in 39 hyperandrogenic women with normal (14 subjects) or high (25 subjects) testosterone (T) levels. The 17-OH P release and the ratio between 17-OH P and F release in response to the ACTH stimulation test were significantly higher (P less than 0.05) in hyperandrogenic women with high T levels than in normal subjects. Eight hyperandrogenic women with high T received intranasal GnRH agonist (Buserelin. 1200 micrograms/day) for 4 weeks. and the 17-OH P and F release in response to the ACTH stimulation was reassessed after agonist treatment. At the end of GnRH agonist administration the mean circulating levels of T were significantly reduced (P less than 0.05). The F response to the ACTH test was not modified by pretreatment with the GnRH agonist. The 17-OH P response to the ACTH stimulation test after the GnRH agonist was unchanged in comparison with control tests. as well as the ratio between 17-OH P and F responses to the ACTH test. These data do not seem to confirm. as previously suggested. that high T levels of ovarian origin affect adrenal steroidogenesis.
Enhanced production of neutrophil-activating peptide-1/interleukin-8 in rheumatoid arthritis, Production of the neutrophil-activating peptide (NAP)-1/IL-8 by mononuclear phagocytes from patients with RA and from control subjects was studied under various conditions. Mononuclear cells from bone marrow (BMMC). PBMC. and synovial fluid (SFMC) were cultured for up to 48 h in the absence or presence of Escherichia coli LPS. different interleukins. interferon-gamma. zymosan. or immune complexes. and the neutrophil-stimulating activity released into the culture medium was determined. As shown by neutralization with an antiserum raised against human recombinant NAP-1/IL-8. over 90% of this activity could be attributed to NAP-1/IL-8. In unstimulated mononuclear cells from control individuals and BMMC from RA patients. the production of NAP-1/IL-8 was very low and was enhanced moderately by stimulation with LPS. By contrast. the spontaneous production of NAP-1/IL-8 was 3- to 10-fold higher in PBMC and even much higher in SFMC from RA patients. In all instances. the yield of NAP-1/IL-8 could be enhanced by stimulation in culture. In addition to LPS. rheumatoid factor-containing immune complexes. zymosan. and IL-1 were highly effective in inducing NAP-1/IL-8 production. while IL-3. GM-CSF. tumor necrosis factor (TNF). and IL-2 were somewhat less potent. An inhibitory effect was obtained with IFN-gamma. which significantly decreased the spontaneous NAP-1/IL-8 release from SFMC and the IL-1- and LPS-induced NAP-1/IL-8 from RA and control PBMC. Inhibition was also observed with glucocorticoids. The production of NAP-1/IL-8 was markedly reduced by dexamethasone in phagocytosis-stimulated PBMC. and almost totally inhibited in SFMC obtained from joints after intraarticular administration of betamethasone. By contrast. the cyclooxygenase inhibitor. indomethacin. tended to increase the NAP-1/IL-8 yield from PBMC in culture.
Platelet-activating factor (PAF) stimulates the production of PAF acetylhydrolase by the human hepatoma cell line, HepG2, The human hepatoma cell line. HepG2. secreted an activity that degrades platelet-activating factor (PAF) by the hydrolysis of the sn-2 acetyl group. This activity was Ca++ independent. inhibited by diisopropylfluorophosphate but not by p-bromophenacyl bromide. and resistant to treatment with trypsin or pronase. Separation of HepG2-conditioned medium by gel filtration disclosed that the activity was associated with lipoproteins. An antiserum against PAF acetylhydrolase immunoprecipitated this activity. It was not recognized by an antibody against lecithin:cholesterol acyltransferase (LCAT). which also is secreted by HepG2 cells. Therefore the phospholipase A2 activity of LCAT was excluded as a source of the observed activity. PAF added to the culture medium stimulated the secretion of the PAF-degrading activity by HepG2 cells. while lyso-PAF was inactive. Maximal stimulation was observed with 5 ng/ml PAF. which induced a fivefold increase. The presence of 5 ng/ml PAF. enhanced the secretion of [35S]methionine-labeled PAF acetylhydrolase and cycloheximide inhibited both the basal and PAF-stimulated secretion of the labeled enzyme. We conclude that HepG2 cells produce PAF acetylhydrolase. The liver may be a major source of plasma PAF acetylhydrolase. and PAF may induce the production of its inactivating enzyme by the liver.
Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus, To define the mechanisms of impaired muscle glycogen synthase and reduced glycogen formation in non-insulin dependent diabetes mellitus (NIDDM). glycogen synthase activity was kinetically analyzed during the basal state and three glucose clamp studies (insulin approximately equal to 300. 700. and 33.400 pmol/liter) in eight matched nonobese NIDDM and eight control subjects. Muscle glycogen content was measured in the basal state and following clamps at insulin levels of 33.400 pmol/liter. NIDDM subjects had glucose uptake matched to controls in each clamp by raising serum glucose to 15-20 mmol/liter. The insulin concentration required to half-maximally activate glycogen synthase (ED50) was approximately fourfold greater for NIDDM than control subjects (1.004 +/- 264 vs. 257 +/- 110 pmol/liter. P less than 0.02) but the maximal insulin effect was similar. Total glycogen synthase activity was reduced approximately 38% and glycogen content was approximately 30% lower in NIDDM. A positive correlation was present between glycogen content and glycogen synthase activity (r = 0.51. P less than 0.01). In summary. defects in muscle glycogen synthase activity and reduced glycogen content are present in NIDDM. NIDDM subjects also have less total glycogen synthase activity consistent with reduced functional mass of the enzyme. These findings and the correlation between glycogen synthase activity and glycogen content support the theory that multiple defects in glycogen synthase activity combine to cause reduced glycogen formation in NIDDM.
Increased apo A-I and apo A-II fractional catabolic rate in patients with low high density lipoprotein-cholesterol levels with or without hypertriglyceridemia, Low HDL-cholesterol (HDL-C) levels may elevate atherosclerosis risk. and often associate with hypertriglyceridemia (HTG); however. the metabolic causes of low HDL-C levels with or without HTG are poorly understood. We studied the turnover of radioiodinated HDL apolipoproteins. apo A-I and apo A-II. in 15 human subjects with low HDL-C. six with normal plasma TG levels (group 1) and nine with high TG (group 2). and compared them to 13 control subjects with normal HDL-C and TG levels (group 3). The fractional catabolic rate (FCR) was equally elevated in groups 1 and 2 vs. group 3 for both apo A-I (0.313 +/- 0.052 and 0.323 +/- 0.063 vs. 0.245 +/- 0.043 pools/d. P = 0.003) and apo A-II (0.213 +/- 0.036 and 0.239 +/- 0.037 vs. 0.185 +/- 0.031 pools/d. P = 0.006). Thus. high FCR characterized low HDL-C regardless of the presence or absence of HTG. In contrast. transport rate (TR) of apo A-I did not differ significantly among the groups and the apo A-II TR differed only between groups 2 and 3 (2.15 +/- 0.57. 2.50 +/- 0.39. and 1.83 +/- 0.48 mg/kg per d for groups 1 to 3. respectively. P = 0.016). Several HDL-related factors were similar in groups 1 and 2 but differed in group 3. as with FCR. including the ratio of lipoprotein lipase to hepatic lipase activity (LPL/HL) in post-heparin plasma. the ratio of the HDL-C to apo A-I plus apo A-II levels. and the percent of tracer in the d greater than 1.21 fraction. In linear regression analysis HDL-C levels correlated inversely with the FCR of apo A-I and apo A-II (r = -0.74. P less than 0.0001 for both). Major correlates of FCR were HDL-C/apo A-I + apo A-II. LPL/HL. and plasma TG levels. We hypothesize that lipase activity and plasma TG affect HDL composition which modulates FCR. which in turn regulates HDL-C. Thus. HTG is only one of several factors which may contribute to elevated FCR and low HDL-C. Given the relationship of altered HDL composition with high FCR and low HDL-C levels. factors affecting HDL composition may increase atherosclerosis susceptibility.
Late potentials on signal-averaged electrocardiograms and patency of the infarct-related artery in survivors of acute myocardial infarction, This study evaluated the relation between patency of the infarct-related artery and the presence of late potentials on the signal-averaged electrocardiogram (ECG) in 124 consecutive patients (98 men. 26 women; mean age 59 years) with acute myocardial infarction receiving thrombolytic therapy. acute percutaneous transluminal coronary angioplasty or standard care. All patients were studied by coronary angiography. measurement of ejection fraction and signal-averaged ECG. The infarct-related artery was closed in 51 patients and open in 73. Among patients with no prior myocardial infarction undergoing early attempted reperfusion therapy. a patent artery was associated with a decreased incidence of late potentials (20% versus 71%; no significant difference in ejection fraction). In the 48 patients receiving thrombolytic agents within 4 h of symptom onset. the incidence of late potentials was 24% and 83% among patients with an open or closed artery. respectively (p less than 0.04). The most powerful predictors of late potentials were the presence of a closed infarct-related artery. followed by prior infarction and patient age. Among patients receiving thrombolytic agents within 4 h of symptom onset. the only variable that was predictive of the presence of late potentials was a closed infarct-related artery. These data imply that reperfusion of an infarct-related artery has a beneficial effect on the electrophysiologic substrate for serious ventricular arrhythmias that is independent of change in left ventricular ejection fraction as an index of infarct size. These findings might explain. in part. the low late mortality rate in survivors of myocardial infarction with documented reperfusion of the infarct-related artery.
A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasminogen activator therapy in acute myocardial infarction, The adjunctive use of intravenous captopril with tissue plasminogen activator early during acute myocardial infarction offers theoretic advantages of diminishing left ventricular volume. preventing ventricular dilation and improving patient survival. To test the safety and efficacy of combined early administration of intravenous captopril and recombinant tissue-type plasminogen activator (rt-PA). 38 patients treated with rt-PA 3 +/- 0.3 h (mean +/- SE) after the onset of myocardial infarction were randomized to intravenous followed by oral captopril or placebo therapy. They underwent cardiac catheterization with measurement of hemodynamic variables and left ventricular function and determination of serum renin. angiotensin and aldosterone levels on days 1 and 7. Oral administration of the selected agent was continued for 3 months along with other antianginal medications. including nonangiotensin-converting enzyme inhibitor vasodilators. Repeat measurements of left ventricular function were obtained before hospital discharge and at 3 months. There were no significant differences in baseline clinical characteristics between groups. One patient in the captopril-treated group became hypotensive during intravenous therapy. requiring discontinuation of treatment. Compared with the placebo-treated group. the captopril-treated group had significant reductions at day 7 in left ventricular end-diastolic pressure (22.5 +/- 1.5 versus 16.3 +/- 1.6 mm Hg. p less than 0.01) and mean systemic arterial pressure (93.6 +/- 3.3 versus 86.2 +/- 2.7 mm Hg. p less than 0.05).
Comparison of indium-111 antimyosin antibody and technetium-99m pyrophosphate localization in reperfused and nonreperfused myocardial infarction, Recent imaging studies suggest that technetium-99m (Tc-99m) pyrophosphate yields a considerably larger estimate of myocardial infarct size than does indium-111 (In-111) monoclonal antimyosin antibody. To determine whether Tc-99m pyrophosphate may be taken up by reversibly injured myocytes. particularly in the setting of coronary reperfusion. the tissue localization of Tc-99m pyrophosphate and antimyosin antibody was compared in 11 dogs 24 to 68 h after anterior descending coronary artery occlusion (4 dogs with permanent occlusion. 7 with reperfusion). Technetium-99m pyrophosphate and In-111 antimyosin antibody content was determined in serial 2 to 3 mm wide endocardial and epicardial samples taken through the infarct zone in multiple short-axis left ventricular slices. The number of samples with increased In-111 antimyosin antibody (defined as greater than or equal to mean + 2 SD of normal) was not significantly different from that with increased Tc-99m pyrophosphate. This was true in both reperfused and nonreperfused infarcts. However. the intensity of uptake of Tc-99m pyrophosphate exceeded that of In-111 antimyosin antibody. particularly in the border zones of reperfused infarcts. and the area with moderate to marked increase in tracer uptake (greater than or equal to 2 times normal) was significantly larger with Tc-99m pyrophosphate than In-111 antimyosin antibody (p less than 0.001). A specific zone of abnormal Tc-99m pyrophosphate with normal In-111 antimyosin antibody content could not be identified. Histologic evidence of myocardial necrosis was found in virtually every sample with increased In-111 antimyosin antibody. Tc-99m pyrophosphate. or both.
Shifts in interleukin-4 and interferon-gamma production by T cells of patients with elevated serum IgE levels and the modulatory effects of these lymphokines on spontaneous IgE synthesis, Interleukin-4 (IL-4) has been demonstrated to induce IgE synthesis by peripheral blood mononuclear cells (PBMNCs) of healthy donors. In this study. we demonstrated that IL-4 also can enhance spontaneous IgE synthesis by PBMNCs of allergic/atopic patients and patients with Buckley's or hyper-IgE syndrome. Spontaneous IgE production by PBMNCs of these patients was suppressed by interferon (IFN)gamma or IFN-alpha in a dose-dependent fashion. Despite high serum IgE levels. no IL-4 could be detected in the serum of the patients. but indirect evidence was obtained indicating that enhanced IL-4 production in vivo may be associated with the high serum-IgE levels in these patients. Spontaneous IL-4 production was measured in PBMNC cultures of 4/21 patients tested. Furthermore. spontaneous IgE synthesis by PBMNCs of three other patients of seven tested in vitro was partly blocked by anti-IL-4 antiserum. In addition. levels of soluble CD23 (which is specifically induced by IL-4) were strongly elevated in sera of patients. Finally. activation of PBMNCs of the patients resulted in levels of IL-4 and of IFN-gamma synthesis that were higher and lower. respectively. than levels produced by PBMNCs of healthy control donors tested in parallel. Collectively. our data indicate that spontaneous IgE synthesis in vitro can be modulated by IL-4. IL-5. IFN-gamma. and IFN-alpha. In addition. our data suggest that enhanced IL-4 and reduced IFN-gamma production is associated with the elevated serum IgE levels observed in these patients.
Actual or ideal body weight: which should be used to predict energy expenditure, Assessing energy expenditure in obese people is problematic. Two questions arise: Can we predict energy expenditure accurately? Does actual or ideal body weight better predict energy expenditure? Two groups of obese subjects--65 hospitalized adults and 65 nonhospitalized adults--were studied. Both groups had actual body weights that were at least 30% above ideal body weights. For both groups. energy expenditure was measured by indirect calorimetry and calculated using the variables sex. actual and ideal body weight. age. and ventilatory status. All but three patients were receiving nutrition support by the enteral route (either orally or by tube) or by the parenteral route (with hypertonic dextrose. amino acid. and fat). The nonhospitalized subjects fasted during measurements of energy expenditure. Regression equations were derived to predict energy expenditure. Actual body weight better predicted energy expenditure than did ideal body weight. We conclude that actual weight should be used to predict energy expenditure in obese individuals.
Assessment and quality control of incontinence care in long-term nursing facilities, A statistical quality-control process was used to assess how well incontinence management procedures were being implemented by indigenous nursing staff in four nursing homes. Eighty-one incontinent patients were treated with the prompted-voiding toileting procedure. Thirty-six of these patients proved responsive to the toileting procedures. and nursing home staff was instructed to maintain the toileting program for these responsive patients. The first part of the quality-control model involved setting job standards specifying how dry the patients should be if toileted on a 2-hour schedule. Second. a job-monitoring control chart was used to continuously assess how well the job standards were being met. The remaining forty-five patients. who were unresponsive to the toileting protocol. were managed with a 2-hour changing schedule. Job standards specifying how wet (volume) the patient would be if changed on a two-hour basis were set. Control-chart monitoring of these patients urine output assessed how well the changing procedures were being implemented. Incontinence care in nursing homes is difficult to supervise because of problems in measuring how consistently nursing aides change or toilet patients. This paper describes a management system for effective incontinence care.
CD4+ suppressor cells inhibit the function of effector cells of experimental autoimmune encephalomyelitis through a mechanism involving transforming growth factor-beta, Nylon wool adherent. CD4+ T cells from the spleens of rats that have recovered from experimental autoimmune encephalomyelitis (EAE) inhibit the in vitro production of IFN-gamma. but not IL-2. by effector cells of EAE when cocultured in the presence of myelin basic protein Ag. When anti-transforming growth factor-beta (TGF-beta) antibodies are added to the co-cultures. IFN-gamma production is restored to normal levels. Irrelevant control antibodies have no effect. The same pattern of response was obtained with cells incubated in serum-free medium. In other experiments. purified TGF-beta was added to cultures of effector cells in the presence of antigen. TGF-beta inhibited the production of IFN-gamma by these cells in a dose-dependent manner. but had no apparent inhibitory effect on IL-2 production. Finally. supernatants from cultures containing effector cells and CD4+ suppressor cells plus Ag contained measurable amounts of TGF-beta. whereas supernatants from cultures of effector cells plus Ag contained no measurable amounts of TGF-beta. These results suggest that CD4+ Ts cells of EAE regulate effector cells of EAE through a mechanism that involves the secretion of TGF-beta and that the inhibitory function of this cytokine can be reversed with neutralizing antibodies directed against TGF-beta.
Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis, A total number of 132 T cell clones (TCC) were obtained by PHA-stimulation of single T cells from mononuclear cell suspensions of conjunctival flogistic infiltrates of three patients with vernal conjunctivitis (VC). The phenotype and functional properties of these TCC were compared with those of 122 TCC contemporarily established from PB mononuclear cell suspensions of the same patients. 120 TCC established from lymph nodes of three patients with nonspecific hyperplastic lymphoadenitis and 159 TCC established from thyroid lymphocyte infiltrates of three patients with Graves' disease. The great majority of conjunctival TCC displayed the CD4+ CD8- phenotype (CD4/CD8 ratios ranging from 6.1 to 7.0). whereas the mean CD4/CD8 ratios for control TCC ranged from 0.9 to 2.4. After stimulation with either PHA or PMA plus anti-CD3 mAb. conjunctival TCC differed from control TCC for their ability to produce cytokines. In particular. a large number of conjunctival TCC produced IL-4. but no. or limited amounts of. IFN-gamma. whereas no difference was observed between conjunctival and control TCC with regard to the production of IL-2. The failure of IFN-gamma production by conjunctival TCC was apparently not caused by delay or block in cytokine production. but actually reflected the lack of IFN-gamma transcription. Virtually all conjunctival TCC able to produce IL-4. but not IFN-gamma. as well as most of those producing both cytokines. provided helper function for IgE synthesis in allogeneic normal B cells. The accumulation in the conjunctiva of patients with vernal conjunctivitis of CD4+ T cells that. apart from the production of IL-2. resembles murine Th2 cells for their profile of cytokine production and helper function suggests a possible role for these cells in the pathogenesis of the disease.
Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni, To characterize Th cell populations induced by helminth infection. spleen cells from mice infected with Schistosoma mansoni were stimulated with parasite (worm or egg Ag) or mitogen (Con A) and the supernatants assayed for the Th1-specific cytokines IFN-gamma and IL-2 and the Th2-specific cytokines IL-4 and IL-5. Th2 cytokine production was not detected in substantial quantity until the 6 to 8th wk of infection and after reaching peak levels at 8 to 12 wk declined slowly thereafter. The time courses of IL-4 and IL-5 production. whereas differing from each other. closely resembled corresponding published data on IgE and peripheral blood eosinophil levels during murine schistosome infection. In contrast. Th1 cytokine responses occurred only during the first 6 wk of infection and were virtually absent during the peak period of Th2 production. To assess the role of egg deposition in the observed pattern of Th response. cytokine production was assayed in mice carrying unisexual schistosome infections in which parasite eggs are absent. Splenocytes from these animals displayed only marginal Th2 cytokine synthesis but greater Th1 cytokine responses than the corresponding cells from mice with bisexual infections. Moreover. cultures of liver tissue or isolated granulomas from infected mice constitutively produced high levels of IL-4 and IL-5 but failed to synthesize significant amounts of IL-2 and IFN-gamma even when stimulated with egg Ag or mitogen. Taken together the data indicate that egg deposition is the major stimulus of Th2 cytokine response in S. mansoni-infected mice and suggest that T cells belonging to this subset must play a major role in egg granuloma formation.
Resistance in murine schistosomiasis is contingent on activated IL-2 receptor-bearing L3T4+ lymphocytes, negatively regulated by Lyt-2+ cells, and uninfluenced by the presence of IL-4, These studies assess the roles of subpopulations of T lymphocytes in inducing and modulating resistance to Schistosoma mansoni. C57BL/6 mice were depleted in vivo of L3T4+. Lyt-1+. Lyt-2+. IL-2R+ cells. or IL-4 by administration of appropriate mAb. Resistance and various correlative parameters of the immune response were studied in normal. depleted. and congenitally athymic mice. Depletion of T lymphocytes by anti-L3T4 or anti-IL-2R mAb reduced the development and expression of resistance. IgG2a and IgE antibody formation. and delayed type hypersensitivity reactivity against schistosome Ag. Depletion with anti-IL-4 antibody led to profound suppression of IgE-eosinophil-mediated antibody-dependent cell-mediated cytotoxicity and passive cutaneous anaphylaxis responses against the parasite and no effect on IgG2a antibody. Ag-mediated blast transformation. or resistance. Depletion of Lyt-2+ cells produced augmented development and expression of resistance and an increase in the immunological parameters of anti-schistosome reactivity. These studies suggest that protective immunity to S. mansoni in mice. induced by irradiated cercariae. is dependent on L3T4+. IL-2R+ lymphocytes and negatively regulated by Lyt-2+ cells. IL-4 does not appear to be essential for the development of resistance but is essential for the IgE response to the parasite.
Ig repertoire of human polyspecific antibodies and B cell ontogeny, A total of 463 EBV Ig-secreting clones were derived from embryonic tissues. cord blood. and adult peripheral blood. Subcloning and analysis of the H and K loci (germline vs rearranged DNA status) of 44 primary clones insured clonality in at least 92% of cases. Whatever the cell origin. a somewhat constant proportion of clones (i.e.. 11 to 16%) expressed polyspecific antibodies when tested on a panel of nine Ag. including self-Ag. The VH and VK repertoires have been studied using VH1-VH6 and VK1-VK4 family-specific probes. For all EBV clones the VH and VK utilization was similar to that of the normal untransformed population. A correlation was observed between the level of expression and the gene number for VH. whereas a clear distortion appeared for VK. Moreover. the usage pattern of VH and VK families of the polyspecific clones did not significantly differ from that of clones of unknown specificity. suggesting that polyspecificity was not linked to a restricted repertoire.
Hydrogen peroxide as a mediator of dopac-induced effects on melanoma cells, Dopac increases tyrosinase activity and exerts cytotoxic effects in cultures of human melanoma cells. The possible role of hydrogen peroxide in these actions was examined. Catalase (100 micrograms/ml) completely reversed the cytotoxic action of 0.3 mM dopac and reduced its tyrosinase-stimulating effect by approximately one half. The results show that extracellular hydrogen peroxide is a mediator of both the tyrosinase-stimulating and cytotoxic actions of dopac. Analysis of the degradation products of melanin from dopac-treated melanoma cells after hydriodic acid (HI) hydrolysis revealed the presence of aminohydroxy-phenylacetic acid (AHPAc). This substance is obtained by HI hydrolysis of melanin formed by oxidation of cysteinyl-dopac. Thus. the presence of AHPAc indicates that dopac is transported into the melanocytes where it serves as a substrate for tyrosinase.
The role of tumour necrosis factor-alpha in acquired immunodeficiency syndrome, Tumour necrosis factor-alpha (TNF) is a primary mediator in the pathogenesis of infection. tissue injury and inflammation. It is synthesised by various activated. phagocytic and non-phagocytic cells. and a wide variety of infectious or inflammatory stimulae are capable of triggering TNF biosynthesis. Recent studies indicate that overproduction of TNF in septicaemia is a critical step in triggering septic shock and multiple organ damage. Intravenous administration of recombinant human TNF induced the same types of derangement in cardiovascular homatologic. inflammatory and metabolic homeostasis that are found with endotoxic or septic shock. Chronic TNF production causes a potentially lethal syndrome of cachexia. anaemia. and protein and lipid wasting. Several investigators have recently demonstrated elevated levels of serum TNF in patients with acquired immunodeficiency syndrome (AIDS). these levels being closely correlated with the severity of the disease. This review discusses the role of TNF in the pathophysiology of AIDS and of several disorders associated with the latter. In addition. it discusses the interactions between TNF and several agents used in AIDS therapy. and suggests the use of TNF-antagonists in combination as a therapeutic regimen for AIDS patients.
Ribose facilitates thallium-201 redistribution in patients with coronary artery disease, To investigate whether i.v. infusion of ribose. an adenine nucleotide precursor. postischemia facilitates thallium-201 (201Tl) redistribution and improves identification of ischemic myocardium in patients with coronary artery disease (CAD). 17 patients underwent two exercise 201Tl stress tests. performed 1-2 wk apart. After immediate postexercise planar imaging. patients received either i.v. ribose (3.3 mg/kg/min x 30 min) or saline as a control. Additional imaging was performed 1 and 4 hr postexercise. Reversible defects were identified by count-profile analysis. Significantly more (nearly twice as many) reversible 201Tl defects were identified on the post-ribose images compared to the post-saline (control) images at both 1 and 4 hr postexercise (p less than 0.001). Quantitative analyses of the coronary arteriogram was available in 13 patients and confirmed that the additional reversible defects were in myocardial regions supplied by stenosed arteries. We conclude that ribose appears to facilitate 201Tl redistribution in patients with CAD and enhances identification of ischemic myocardium.
HIV-1 propagates in human neuroblastoma cells, A major question in the pathogenesis of AIDS encephalopathy and dementia is whether HIV-1 directly infects cells of the central nervous system (CNS). The propagation of HIV was attempted in six cell lines: three related and three unrelated to the nervous system. HIV was able to propagate in two human neuroblastoma cell lines and a lymphocytic cell line control but did not result in infections of African green monkey kidney cells. human cervix carcinoma cells. and one human brain astrocytoma cell line. Neuroblastoma cell lines infected with HIV showed peaks of reverse transcriptase activity at 10-14 days postinfection. After prolonged growth in cell cultures. one of the neuroblastoma cell lines showed multiphasic virus production. additional high peaks of reverse transcriptase activity. 20-fold greater than the first. lasting from 36 to 74 days and 110 to 140 days postinfection. The presence of HIV was confirmed by p24 antigen capture. The neuroblastoma cell lines had weak but detectable levels of CD4 immunoreactivity by immunoperoxidase and flow immunocytometric analysis. Although no T4-specific RNA sequences were detected by hybridization of Northern blots of total and poly A-selected RNA extracted from the two neuroblastoma cell lines by using a T4 specific complimentary DNA probe. monoclonal antibodies to the CD4 receptor blocked HIV infection in both neuroblastoma cell lines. Thus. the infection of neuroblastoma cells by HIV occurs in part by a CD4-dependent mechanism. Passaging the neuroblastoma cell lines weekly and bimonthly resulted in similar cell cycle-DNA content patterns for the more permissive cell line and with significant numbers of cells in the S phase. HIV-infected neuroblastoma cell lines provide an in vitro model for the evaluation of virus-host cell interactions and may be useful in addressing the issue of the persistence of HIV in the human CNS.
Mortality and duration of hemodialysis treatment, Decrease in the average duration of hemodialysis treatment time is a continuing phenomenon. We investigated the relationship of 3-year mortality to duration of dialysis in a 1984-1985 national random sample of 600 hemodialysis patients from 36 dialysis units. Mortality was negatively associated with duration of dialysis treatments. as shown by the Cox model. adjusted for other patient and dialysis unit covariates. With adjustment for other covariates. patients receiving an average dialysis treatment duration of less than 3.5 hours had relative mortality risks of 1.17 to 2.18 compared with those with treatments longer than 3.5 hours (mortality risk of 1.0). Reverse causation (the possibility that more seriously ill patients received dialysis for a shorter time) appears unlikely. We conclude that duration of the dialysis procedure is an important element in determining patient mortality as one of the factors determining the adequacy of dialysis.
Aerosol alpha 1-antitrypsin treatment for cystic fibrosis, In cystic fibrosis neutrophil-dominated inflammation on the respiratory epithelial surface results in a chronic epithelial burden of the destructive enzyme. neutrophil elastase. alpha 1-antitrypsin (alpha 1AT). the main inhibitor of neutrophil elastase in lung. was given in aerosol form to 12 cystic fibrosis patients. It suppressed neutrophil elastase in the respiratory epithelial lining fluid (ELF) and restored the ELF anti-neutrophil elastase capacity when ELF alpha 1AT reached 8 mumol/l. This treatment also reversed the inhibitory effect of cystic fibrosis ELF on pseudomonas killing by neutrophils. which suggests that it may augment host defence in cystic fibrosis.
Tuberculosis among foreign-born persons entering the United States. Recommendations of the Advisory Committee for Elimination of Tuberculosis, In 1989. the Department of Health and Human Services Advisory Committee for Elimination of Tuberculosis published a plan for eliminating tuberculosis from the United States by the year 2010. This plan gives a top priority to implementing strategies to prevent tuberculosis in high-incidence groups. Foreign-born persons (as a group) residing in the United States have higher rates of tuberculosis than persons born in the United States. In 1989. the overall U.S. tuberculosis rate was 9.5 per 100.000 population; for foreign-born persons arriving in the United States. the estimated case rate was 124 per 100.000. In the period 1986-1989. 22% (20.316) of all reported cases of tuberculosis occurred in the foreign-born population. A majority of foreign-born persons who develop tuberculosis do so within the first 5 years after they enter the United States. The ACET recommends that all foreign-born persons applying for permanent entry into the United States continue to be screened for disease. Deficiencies in the current screening methods should be corrected. The policy requiring that persons found to have infectious tuberculosis (known or suspected) be prevented from entering the country until treatment has rendered them noninfectious should be continued; however. persons with noninfectious tuberculosis should be permitted to enter the United States. Tuberculin skin testing and preventive therapy programs for foreign-born persons must be expanded both overseas and domestically if the goal of eliminating tuberculosis from the United States by the year 2010 is to be met.
Mosquito-transmitted malaria--California and Florida, 1990, In 1990. two persons--one each in California and Florida--were diagnosed with malaria classified as cryptic; their infections may have been acquired in the United States through bites of mosquitoes that became infected after biting parasitemic migrant workers.
Birth defects among low birth weight infants--metropolitan Atlanta, 1978-1988, Approximately 3%-4% of newborn infants have a major birth defect diagnosed during their first year of life. Because many infants with birth defects are born prematurely and/or have intrauterine growth retardation. the rate of birth defects is expected to vary by birth weight. This report summarizes a population-based study of the relation between birth defect rates and the birth weight of infants born in metropolitan Atlanta from 1978 through 1988.
Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6, During intrathymic T-cell ontogenesis. functionally competent CD3+CD4+CD8- and CD3+CD4-CD8+ T lymphocytes develop from immature CD4-CD8- thymocytes after transiently acquiring a double-positive CD4+CD8+ phenotype. The partition between CD4+CD8- and CD4-CD8+ T cells is generally considered to be irreversible. although a small percentage of circulating CD3+ T lymphocytes coexpressing CD4 and CD8 molecules has been identified. It has been suggested that in CD8+ T cells the CD4 genes may be methylated and thus highly repressed. whereas in CD4+ T cells the CD8 genes are unmethylated and their transcription can be induced by physiological stimuli such as interleukin-4. Here. we demonstrate that infection with human herpesvirus 6 (HHV-6). a virus proposed as a potential cofactor in AIDS. dramatically upregulates the expression of CD4--the receptor for human immunodeficiency virus type-1 (HIV-1)--in a human neoplastic T-cell line. More importantly. HHV-6 induces de novo expression of CD4 messenger RNA and protein in normal mature CD8+ T lymphocytes. rendering them susceptible to infection with HIV-1. These findings demonstrate that human CD3+CD4-CD8+ T lymphocytes can reacquire CD4 in the post-thymic life and elucidate a novel mechanism--receptor regulation--through which HHV-6 may positively interact with HIV-1 in coinfected patients.
Differential diagnosis of fatal and benign cytochrome c oxidase-deficient myopathies of infancy: an immunohistochemical approach, To differentiate the 2 major myopathies of infancy due to cytochrome c oxidase (COX) deficiency. we studied muscle biopsies from 4 patients with fatal myopathy and 4 with benign myopathy using biochemical. histochemical. and immunohistochemical techniques. Immunohistochemistry with antibodies directed against individual subunits of COX differentiated the 2 phenotypes: the fatal infantile myopathy was characterized by absence of the nuclear DNA (nDNA)-encoded subunit VIIa.b of COX. while in the benign myopathy both VIIa.b and the mitochondrial DNA (mtDNA)-encoded subunit II were absent. Early differential diagnosis between fatal and benign COX-deficient myopathies is of critical importance for prognosis and management of these infants. because the benign form is initially life-threatening but ultimately reversible.
A prion protein missense variant is integrated in kuru plaque cores in patients with Gerstmann-Straussler syndrome, Kuru plaques are the pathologic hallmark in Gerstmann-Straussler syndrome (GSS). To demonstrate that prion protein (PrP) is a component of kuru plaque cores. we fractionated and sequenced kuru plaque core derived peptides. following digestion with Achromobacter lyticus protease I. We identified 3 PrP-derived peptides by reverse-phase high-performance liquid chromatography and found a fragment of digests derived from a missense variant of PrP. The variant PrP was also present in the prion rod fraction in patients with GSS. This substitution may play a major role in cerebral amyloidogenesis.
Bone mass in endometriosis patients treated with GnRH agonist implant or danazol, Before treatment. the trabecular bone mineral content of the lumbar spine and femoral neck was not significantly different between endometriosis patients and age-matched controls (N = 26). In 17 subjects treated with a monthly goserelin implant. serum estradiol (E2) levels were suppressed into the menopausal range. Mean decreases from pre-treatment values in the lumbar spine and femoral neck were -5.7 and -3.8% at 3 months and -8.2 and -7.7% at 6 months of treatment. respectively; lumbar spine values were significantly different (P less than .05) from those of the control group. whose values changed little during the same period. Significant increases over baseline values were also observed in urinary calcium-creatinine ratio and serum alkaline phosphatase. In nine danazol-treated subjects. serum E2 levels were generally within the early follicular-phase range. There were no significant changes in bone assessments. Normal menses returned within 2 months after cessation of either medication. Six months after goserelin treatment. the lumbar spine and femoral neck bone mineral content was still reduced but to values not significantly different from the pre-treatment and control values; urinary calcium-creatinine ratio was decreased. whereas serum alkaline phosphatase was still elevated. The rapid and deep suppression of ovarian steroidogenesis by a monthly goserelin implant induced significant bone loss compared with the control and danazol groups. This loss was not reversed completely 6 months after cessation of treatment. but bone densities at that time were not different from those of controls. Studies of larger numbers of patients followed for longer periods will be required to resolve the question of complete reversibility.
In vivo T-cell activation by staphylococcal enterotoxin B prevents outgrowth of a malignant tumor, Treatment of T cells with staphylococcal enterotoxins in vitro is known to activate T cells in a subset restricted manner based on beta-chain variable region (V beta) gene expression. In particular. staphylococcal enterotoxin B (SEB) activates T cells bearing V beta 7 or V beta 8. We examined the ability of SEB to activate T cells in vivo. Treatment of C3H mice with doses of SEB ranging from 5 to 250 micrograms resulted in a dose-dependent activation of V beta 8+ T cells as reflected by increased interleukin 2 receptor (IL-2R) expression. proliferation to exogenous IL-2 and allogeneic cells. and production of gamma interferon. SEB also caused proliferation of the CD8+ subset of V beta 8+ cells in vivo. Thus. T-cell activation by SEB in vivo appears to be specific since V beta 2+ cells (non-SEB reactive) did not show increases in IL-2R expression similar to those seen with V beta 8+ cells nor did they proliferate. We then studied the ability of these activated cells to potentiate the immune response to a malignant progressor tumor. Treatment of C3H mice with 50 micrograms of SEB at the time of inoculation with tumor fragments resulted in a statistically significant decrease in the frequency of tumor outgrowth. These data demonstrate that treatment of C3H mice with SEB results in specific activation of V beta 8+ cells in vivo and that these activated cells are capable of preventing the outgrowth of a malignant tumor.
Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: evidence supporting a physiologic role for EPI as a natural anticoagulant, Although in vitro experiments have established that extrinsic pathway inhibitor (EPI) is the only known plasma inhibitor of factor VIIa-tissue factor (TF) catalytic activity of potential physiologic significance. evidence of its function in vivo has been lacking. TF-induced intravascular coagulation may occur in patients despite normal plasma levels of EPI and. in our earlier studies. normal plasma EPI levels did not protect rabbits from intravascular coagulation induced by an infusion of purified TF (1 microgram/kg). Studies have now been carried out in which plasma EPI levels were reduced in rabbits to below 20% of the initial level by injection of anti-rabbit EPI IgG. Infusion into such animals of purified rabbit TF apoprotein (0.25 microgram/kg) reconstituted into phospholipid vesicles induced substantial disseminated intravascular coagulation. Infusion of control saline or phospholipid vesicles not containing TF was without significant effect as was infusion of TF (0.25 microgram/kg) into animals injected with nonimmune goat IgG. These data establish that EPI can dampen TF-induced intravascular coagulation in rabbits. They support the hypothesis that EPI plays a significant role in regulating coagulation resulting from the exposure of blood to trace concentrations of TF during the illnesses and minor injuries of normal existence.
Physiologic basis of endocrine therapy for prostatic cancer, Advances in our understanding of hypothalamic-pituitary gonadal regulation have led to the development of pharmaceutical agents that produce a medically castrate state with minimal morbidity. The selection of the method for androgen ablation in a given patient with stage D adenocarcinoma of the prostate should be based on patient preference and on cost. because the therapeutic outcomes of medical castration and orchiectomy are equivalent. The addition of androgen receptor antagonists to a given patient's regimen should be made with the knowledge that the impact on the mortality rate is modest and the cost significant. Further manipulation of androgen production or action in patients with hormonally resistant cancer is unlikely to improve either the disease progression or the mortality rate. Research efforts should be focused on the development of effective chemotherapy for such disease.
Total androgen ablation: American experience, In conclusion. the intergroup study in the US. as well as preliminary results of the Anandron and leuprolide study. would support the view that combined androgen blockade is better than monotherapy in achieving clinical responses. prolonging the time to progression. and improving the survival rate. This improvement in survival rate is not a huge advance but is a step in the right direction. Future clinical trials are needed to evaluate newer methods to improve survival rates. The results also open up the possibility of employing this combined androgen blockade in earlier stages of prostate cancer in order to delay progression of the cancer and perhaps improve patient survival. Only carefully constructed clinical trials will be able to answer these questions.
Cost-benefit analysis of pharmacologic erection program (PEP) versus penile prosthesis, We compared the current dollar inclusive costs of the two most commonly implanted penile prostheses with our pharmacologic erection program (PEP). The inclusive cost of implantation for the inflatable penile prosthesis (IPP) is $9.000 and for the malleable penile prosthesis (MPP) $3.150. The inclusive cost of PEP at maximal dose and maximal frequency of use over a five-year period is $3.450. Penile prosthesis was found to be more cost-effective for the long-term treatment of younger impotent men. whereas in the elderly group the use of PEP over a limited time span may be equally or more cost-effective.
Effect of LH-RH analogue in patients with benign prostatic hyperplasia, Twelve prostatic hyperplasia patients with total urine retention and. consequently. a permanent catheter. were treated for six months with luteinizing hormone-releasing hormone (LH-RH) analogue having long-term effect. Seven of the 12 patients no longer needed a permanent catheter after the six-month treatment period. Transurethral resection of the prostate was performed for 3 patients. The remaining 2 patients continued to have a catheter. The mean prostatic volume. which was 83 g at the start of the study. fell by 51 percent. to 41 g. Treatment with LH-RH proved to be safe even for patients in poor physical condition. and it also seemed to improve symptoms of prostatic hyperplasia.
Role of prostaglandins in pregnancy-induced hypertension, Enzymes involved in prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) synthesis were studied in maternal and fetal platelets and venous endothelium from normotensive pregnant controls (n = 70). women with mild preeclampsia (MP. n = 45). and severe preeclampsia (SP. n = 34). Activities of phospholipase A2 (PHA2). cyclooxygenase (PGHS). and PGI2 synthetase (PGIS) or TXA2 synthetase (TXAS) were determined in platelets and in endothelial cells. The PGHS enzyme was studied further by immunoblot methodology. In maternal platelets: Vmax (per 10(-10) mol/mg protein) and Michaelis-Menten constant (Km) (10(-7) mol. mean +/- SEM) of PHA2 were 3.0 +/- 0.8. 3.0 +/- 0.7. and 31.7 +/- 10.9* maximum velocity (Vmax) and 1.8 +/- 0.3. 2.0 +/- 0.8. and 0.8 +/- 0.2 (Km) in normal control (NC). mild preeclampsia (MP). and severe preeclampsia (SP). respectively (*P less than 0.05 against NC). The apparent overall PGHS plus TXAS activity was 10.2 +/- 1.8. 23.8 +/- 7.1. and 68.8 +/- 18.8* (Vmax) and 3.2 +/- 1.3. 5.4 +/- 1.4. and 6.9 +/- 1.2* (Km. *P less than 0.05 against NC). TXA synthesis in fetal platelets demonstrated PHA2 activity of 6.4 +/- 1.4. 12.0 +/- 1.3. and 17.2 +/- 3.2* (Vmax) and 3.5 +/- 0.9. 2.2 +/- 1.5. and 0.7 +/- 0.3* (Km. *P less than 0.05 against NC). respectively. whereas an apparent overall PGHS plus TXAS activity was 18.5 +/- 2.8. 87.5 +/- 12.5*. and 3.6 +/- 0.1* (Vmax) and 4.8 +/- 1.0. 8.8 +/- 1.2. and 0.8 +/- 0.3* (Km. *P less than 0.05 against NC).
Vascular reactivity in normal and abnormal gestation, Preeclampsia is characterized by enhanced pressor responsiveness to angiotensin II. This report summarizes studies by our laboratory to investigate possible roles for calcium. sodium. membrane pumps. and the vasoactive hormones. atrial natriuretic peptide (hANP) and endothelin. in modulating the change in vascular reactivity characteristic of preeclampsia. Urinary calcium excretion. 1 alpha-25(OH)2D3 levels. and serum free calcium levels were all decreased. whereas parathyroid hormone levels and intraplatelet calcium concentrations were increased in women with preeclampsia. Erythrocyte sodium content was elevated. while red blood cell membrane Na-K-ATPase activity was decreased in patients with severe disease. Preeclamptics also had elevated levels of hANP. which failed to increase further when saline was infused or when blood pressure was increased transiently with angiotensin II administration. Finally. endothelin levels that are reduced in normal gestation. were increased in preeclampsia. While the cause of increased vascular reactivity is still unclear. there appear to be changes in the intracellular cation environment. combined with loss of compensating mechanisms. both at the membrane and humoral level. as well as enhanced concentrations of a potent vasoconstrictor in blood; all which lead to increases in vasoreactivity and blood pressure in preeclampsia.
Tissue plasminogen activator treatment of experimental subretinal hemorrhage, To determine if tissue plasminogen activator. a clot-specific fibrinolytic agent. could eventually be used to assist in the clearance or removal of subretinal hemorrhage. we studied the effect of subretinal injections of tissue plasminogen activator. autologous blood. balanced salt solution. and the combination of either tissue plasminogen activator or balanced salt solution after subretinal injection of autologous blood on retinal morphologic characteristics and clearance of subretinal hemorrhage in the albino rabbit. No morphologic evidence of tissue plasminogen activator toxicity was found in the rabbit retina at a dose of 25 to 50 micrograms/0.1 ml. Subretinal hemorrhage cleared faster after subretinal injection of tissue plasminogen activator when compared to balanced salt solution (P = .0005) but did not completely prevent overlying retinal degeneration. Both tissue plasminogen activator and balanced salt solution were found to decrease the toxic effects of subretinal blood on the morphologic characteristics of the rabbit retina. and this effect can be explained at least partly by dilution of the subretinal blood.
Absence of bcl-2 major breakpoint region and JH gene rearrangement in lymphocyte predominance Hodgkin's disease. Results of Southern blot analysis and polymerase chain reaction, Recent evidence suggests that nodular lymphocyte predominance Hodgkin's disease (NLPHD) is a distinct entity that may be related to progressively transformed germinal centers. abnormal B-lymphoid hyperplasia. and low-grade B-cell lymphoma. bcl-2 is a marker for the translocation t(14;18)(q32;q21). which occurs in most follicular-derived B-cell lymphomas. Eleven cases of NLPHD and 19 cases of Hodgkin's disease of nodular sclerosis (NSHD) and mixed cellularity (MCHD) type were analyzed for immunoglobulin JH gene rearrangement. bcl-2 translocation was determined with Southern blot analysis and the polymerase chain reaction using biotin labeled probes to the major breakpoint region and the alkaline phosphatase reaction. All cases of NLPHD were negative for JH gene rearrangement and bcl-2 translocation. Cases of NSHD and MCHD were similarly negative for bcl-2. although three cases exhibited clonal JH gene rearrangements. These results confirm that a clonal B-cell population is not detected in NLPHD. Cases of NLPHD differ from most low-grade follicular B-cell lymphomas in that they lack bcl-2 gene rearrangement and t(14;18) translocation at the major breakpoint region.
Juvenile ceroid lipofuscinosis. Evidence for methylated lysine in neural storage body protein, Juvenile ceroid lipofuscinosis. or Batten disease. is a hereditary disorder characterized by progressive visual loss. seizures. cognitive and psychomotor deterioration. and early death. usually between 15 and 35 years of age. Individuals with this disease have massive deposits of autofluorescent inclusion bodies in cells of most tissues. The accumulation of these intracellular deposits suggests that juvenile ceroid-lipofuscinosis is a storage disease resulting from the inability of cells to metabolize some normal cellular constituent. It has been reported that the storage material is largely protein. much of which is a specific mitochondrial protein that apparently is not properly metabolized in subjects with Batten disease. The storage bodies were partially purified from the retinas of two siblings who died as a result of juvenile ceroid lipofuscinosis. as well as from the cerebral cortex of an unrelated individual with this disorder. Chromatographic analysis of storage body protein acid hydrolysates indicated that they contained a large amount of the modified amino acid epsilon-N-trimethyllysine. The abundance of this amino acid in the storage protein suggests that the disease may result from excessive methylation or from a failure to demethylate intermediate forms of the stored proteins. Acid hydrolysis also solubilized a fluorescent component from the retinal storage material. suggesting that the stored protein has a bound fluorescent adduct.
Streptokinase and recombinant tissue plasminogen activator (rt-PA) are equally effective in treating acute myocardial infarction, In recent trials. patients with myocardial infarction who received either recombinant tissue-type plasminogen activator (rt-PA) or streptokinase showed essentially no difference in the amount of myocardial salvage. in mortality reduction. or in the incidence of bleeding complications. These findings thus failed to fulfill the expectation that rt-PA would be twice as effective as streptokinase as a thrombolytic agent. The basis for this mistaken prediction was an unfortunate overemphasis on an inadequate surrogate endpoint. namely. the patency or reperfusion rate at 90 minutes after the start of therapy. Using the 90-minute patency or reperfusion rate as an endpoint has several serious limitations. First. it is an observation made at only one point in time during a dynamic process that may change even during the infusion proper. Second. a single view at 90 minutes completely disregards the possibility of subsequent reocclusion which often occurs within 1 hour after treatment. Third. an image at 90 minutes is more a reflection of the speed of thrombolysis than of whether lysis will eventually occur; the pace of clot lysis depends on both the agent used and the age of the thrombus. Fourth. lysis at 90 minutes is of minimal relevance for myocardial salvage unless observed within the time frame when infarction size can be limited significantly. which is generally less than 4 hours between symptom onset and the time that reperfusion is accomplished. Fifth. a stable state of vessel patency is meaningful for mortality reduction even if stabilization occurs after completion of the infarction. Such "late." but lasting. patency is a critical component of the "open vessel" principle and explains. at least in part. the survival benefit that accrues to patients treated even 24 hours after the onset of symptoms. There is currently no evidence that rt-PA has a more beneficial effect on survival or function than does streptokinase or any other plasminogen activator used in treating acute myocardial infarction; nor is there any evidence that patients who receive rt-PA therapy show a decreased incidence of bleeding complications compared with those who receive streptokinase. despite the relative fibrinogen-sparing attribute of rt-PA. Given the poor predictive value of the 90-minute angiogram for ultimate clinical advantage of one agent over another. studies that are limited to this endpoint are of marginal use in evaluating treatment regimens used in mortality studies. The best evidence to date indicates that streptokinase and rt-PA are of equivalent value for survival after acute myocardial infarction. a conclusion that can be justifiably challenged only with a valid mortality study.
Immediate enteral feeding in burn patients is safe and effective, Recent animal studies indicate that immediate enteral feeding may be beneficial in patients with major burns. Yet. largely because of the fear of complications. immediate enteral feeding is not commonly performed in patients with major burns until after the resuscitation period. The purpose of this study was to evaluate the safety and efficacy of immediate enteral tube feedings in patients with burns larger than 20% of their body surface area. The daily intake of enteral feedings begun immediately (less than 6 hours) after burn was measured during the first 7 days after burn in 106 consecutive patients with a mean +/- SD burn size of 40% +/- 21%. The incidence of complications related to enteral feeding was low; aspiration pneumonia did not occur. Vomiting was the major complication observed and occurred 21 times in 16 patients during the 745 study days (2.8% daily incidence). The mean number of calories absorbed enterally increased daily and met the patient's calculated resting energy expenditure (REE) on day 3 after burn (99% +/- 7% REE). The results of this study indicate that immediate enteral feeding is a safe and effective method of delivering nutritional support to burn victims with major burns.
Impaired macrophage function in severe protein-energy malnutrition, Protein-energy malnutrition induces immunosuppression that predisposes to sepsis. but the mechanisms are unclear. This study examines the role of the macrophage in host defense in the malnourished state. Swiss-Webster mice (N = 300) were randomly allocated to control (24% casein) or low-protein (2.5% casein) diets for 8 weeks. We studied the ability of two populations of macrophages. peritoneal macrophages. and Kupffer cells to produce superoxide anion after in vivo administration of endotoxin or mycobacterium (bacille Calmette-Guerin). Phorbol diester and Candida albicans were used as stimuli. In another group of mice. we evaluated the ability of interferon gamma to up-regulate superoxide anion release and Candida phagocytosis and killing. Mice under protein-energy malnutrition demonstrated decreased mean body weights. serum protein levels. and cell yields. Superoxide anion production in resident and activated (lipopolysaccharide. interferon gamma. bacille Calmette-Guerin infection) peritoneal macrophages was significantly reduced in the malnourished group. Candida phagocytosis and killing were also both depressed in malnourished mice. Kupffer cells failed to generate superoxide anion in all groups. We conclude that severe protein-energy malnutrition significantly impairs macrophage function. which could diminish response to acute and chronic septic challenges. Interferon gamma up regulated peritoneal macrophage and Kupffer cell microbicidal function. which suggests a therapeutic role for this lymphokine in the malnourished septic host.
Tumor necrosis factor alone does not explain the lethal effect of lipopolysaccharide, Lethality and tumor necrosis factor production induced by different types of lipopolysaccharide were studied in naive (non-primed) rats during the late phase of endotoxin tolerance. The correlation with antilipopolysaccharide antibodies was also analyzed. No correlation was found between tumor necrosis factor levels and lipopolysaccharide-induced mortality in naive animals. Low-toxicity lipopolysaccharide preparations induced levels of tumor necrosis factor similar to those induced with more toxic types of lipopolysaccharide. Late tolerance was associated with progressively lower levels of lipopolysaccharide-induced tumor necrosis factor and increasing titers of antilipopolysaccharide antibodies after repeated injections of homologous lipopolysaccharide. During late endotonxin tolerance. a direct correlation between the lipopolysaccharide dose and peak tumor necrosis factor serum levels was found. We conclude that since tumor necrosis factor serum levels do not correlate with mortality. tumor necrosis factor alone cannot explain the lethal effect of lipopolysaccharide.
Relative contributions of host and microbial factors in bacterial translocation, To study the relative contributions of host and microbial factors in bacterial translocation. germfree mice were mono-associated with either Proteus mirabilis. Escherichia coli. or Enterococcus faecalis. Germfree mice included T-cell-deficient nude mice and normal littermates. natural killer cell-deficient beige mice and normal littermates. and triply immunodeficient mice with beige. T-cell. and B-cell mutations and their littermates. Each bacterial species colonized the cecum in similarly high numbers. Bacteria were recovered from the mesenteric lymph node of every mouse in inconsistent numbers. eg. greater numbers of P mirabilis and E coli were recovered from T-cell-deficient nude mice than from their normal littermates. but the opposite was observed with E faecalis. Comparing the three bacterial species resulted in relatively consistent observations. eg. the incidence of E faecalis translocation to the liver was greater than that of E coli or P mirabilis translocation. Thus. the identity of the translocating microbe significantly affected the recovery of viable translocating bacteria.
Aggressive peripheral T-cell lymphomas containing Epstein-Barr viral DNA: a clinicopathologic and molecular analysis, The Epstein-Barr virus (EBV) has been shown to be associated with posttransplant lymphoma. Hodgkin's disease. and T-cell lymphoma. in addition to African Burkitt's lymphoma. In a retrospective study of 56 consecutive cases of T-cell lymphoma. EBV DNA was found by Southern blot and in situ DNA hybridization in 10 (20%) of 50 peripheral T-cell lymphomas. but in none of six cases of T-lymphoblastic lymphoma. Peripheral T-cell lymphomas containing EBV DNA could be subclassified into three categories according to histology and immunophenotypic studies: (1) T-cell lymphoma of the helper phenotype. five cases. Two cases had histologic features resembling angioimmunoblastic lymphadenopathy (AILD). (2) T-cell lymphoma of the cytotoxic/suppressor phenotype. four cases. AILD-like features could also be recognized in two cases. Reed-Sternberg-like giant cells were identified in three cases designated Hodgkin-like T-cell lymphoma. (3) Angiocentric T-cell lymphoma or lymphomatoid granulomatosis in one case. initially affecting the skin and nose; no T-cell subset could be defined. Six of the eight EBV DNA-positive patients tested for serum EBV antibodies had elevated titers of IgG antiviral capsid antigen (greater than 640) and/or early antigen (greater than 10). From combined studies of Southern blot hybridization by using EBV termini fragment probe and in situ DNA hybridization. the EBV genomes appeared to be clonotypically proliferated in the neoplastic T cells. The patients in all three groups usually had prolonged fever preceding the diagnosis. hepatosplenomegaly. an aggressive clinical course. and poor response to chemotherapy; nine died with a median survival of only 8 months. We propose that these EBV-associated aggressive T-cell lymphomas. like human T-cell leukemia/lymphoma virus-positive T-cell lymphoma. have characteristic clinicopathologic features and should be treated as a separate disease entity.
Cost of surfactant replacement treatment for severe neonatal respiratory distress syndrome: a randomised controlled trial [published erratum appears in BMJ 1991 Jan 5;302(6767):27, OBJECTIVE--To estimate the cost of treating babies with severe respiratory distress syndrome with natural porcine surfactant. DESIGN--Retrospective controlled survey. SETTING--Regional neonatal intensive care unit. Belfast. PATIENTS--33 Preterm babies with severe respiratory distress syndrome who were enrolled in a European multicentre trial during 1985-7. 19 Babies were treated with surfactant and 14 served as controls. INTERVENTIONS--Treatment with natural porcine surfactant. MAIN OUTCOME MEASURE--Cost associated with surfactant replacement treatment per extra survivor in the treatment group and cost per quality adjusted life year for each extra survivor. RESULTS--Fifteen (79%) of the 19 treated babies and five (36%) of the 14 control babies survived. On average. the control babies required 20 days in hospital compared with 61 days for the treated babies (or 95 [corrected] days per extra survivor in the treatment group). The cost per extra survivor in the treatment group was pounds 13.720. with the cost per quality adjusted life year estimated at pounds 710. CONCLUSION--These costs compare favourably with those of established forms of treatment in adults. Thus surfactant replacement treatment for severe respiratory distress syndrome is fairly inexpensive and cost effective.
Mobile extracorporeal shockwave lithotripsy, During the last 18 months. extracorporeal shockwave lithotripsy (ESWL) has been provided at Epsom District Hospital using a mobile unit containing a Dornier HM4 lithotriptor. Patients with upper ureteric and renal stones were selected for treatment. which was performed without anaesthesia or sedation as a day-case procedure; 83 patients were treated. 5 of them with bilateral stones. Seventy patients required 1 treatment session. 17 required 2 and 1 patient required 3. There were no serious complications but 3 patients needed ureteroscopy to remove obstructing stones. The overall success rate was 86%. The cost to treat each NHS patient was 253 pounds. Mobile lithotripsy as a day-case procedure is a safe and cost-effective means of treating urolithiasis and can be performed in a District General Hospital.
Induced bone development in transplants of fresh human pseudomalignant heterotopic ossification tissue in athymic nude mice, Biopsy specimens of mature trabecular bone from tumors of two typical cases of pseudomalignant heterotopic ossification (PHO; myositis ossificans circumscripta) were transplanted into athymic nude mice. Specimens of normal metaphyseal bone in adjacent areas were also transplanted in the contralateral hindquarter muscles for controls. By seven days. control bone transplants were necrotic and enveloped in granulation tissues whereas PHO transplants were surrounded by proliferating connective tissue derived from the host-bed muscle tissues. In the intervals from 14 and 21 days. the PHO transplants showed vascular and hypertrophied connective-tissue proliferation with appositional deposits of new bone. The microscopic features of the new bone suggested that it was of mouse host-bed origin because the new bone from Case 1. a female. showed nuclei without sex chromatin. The quantities of new bone were measured by correlated histomorphometric and computer image analysis of microradiographs. Little or no cartilage development was noted at any stage. The normal control trabecular bone tissue was slowly resorbed by macrophages and mononuclear phagocytes; multinucleated giant cells were few and relatively small. Except in one questionably small area of one transplant. nontumorous undemineralized normal human bone failed to induce bone formation within the 28-day period of observation. The quantity of new bone formed in athymic mice in response to implants of PHO. estimated from equivalent quantities of bone developed from implants of lyophilized matrix-free bone morphogenetic protein (BMP) was about 1 microgram/g of wet PHO tumor weight. Although circumstantial evidence implicates BMP in the pathogenesis of heterotopic ossification. more research should be directed toward regional and systemic factors inhibiting bone development in normal and abnormal conditions. including malignant bone tumors.
Efficacy of oral streptokinase-streptodornase in the treatment of ankle sprains, To evaluate the analgesic and antiinflammatory properties of oral streptokinase-streptodornase (SS) in cases of minor trauma. 190 patients with ankle sprains were studied. Subjects were randomly given an active drug or a placebo in doses of two tablets three times a day for eight days. A scoring system was used to rate the following symptoms: spontaneous pain. mobilization pain. wearing pain. articular disability. flaccidity. muscular spasm. edema. and hematoma. Each symptom was categorized as none (0). mild (1). moderate (3). or severe (4). Patients were evaluated at the beginning of the study and on the fourth and eighth days of treatment. At the end of the trial. the decrease in each symptom score was significantly greater in patients receiving SS than in patients receiving a placebo. Analgesic intake during the study was also noticeably lower in the SS group. The incidence of drug-induced side effects (mainly abdominal discomfort) was minimal. Oral SS ameliorates the inflammatory symptoms associated with ankle sprains and therefore may be used as an alternative to nonsteroidal antiinflammatory drugs.
Periarticular heterotopic ossification after total hip arthroplasty. Risk factors and consequences, The formation of periarticular heterotopic bone after total hip arthroplasty is a frequent complication. The reported occurrences concerning this complication vary considerably in different reports. ranging from 15% to 90% with significant amounts in 1%-27% of the cases. Heterotopic ossification (HO) starts with the surgical operation. and the extent is well delineated on roentgenograms after six to 12 weeks. The amount of bone varies from small islands in the soft tissue to widespread bridging ossification. The cause of HO seems to be mainly related to systemic factors and is chiefly dependent on gender. diagnosis. and concurrent antiinflammatory medication. Patients at risk seem to be those with HO after a previous surgical operation. patients suffering from certain types of ankylosing spondylitis. otherwise healthy men with osteoarthrosis. patients with hypertrophic osteoarthrosis. and patients operated upon for fresh fractures or other posttraumatic conditions. The surgical technique and the local tissue trauma probably moderate both the occurrence and amount of HO. HO does not seem to cause pain or to decrease hip muscle strength but does limit hip mobility in cases with significant amount of ossification.
Total hip arthroplasty. The role of antiinflammatory medications in the prevention of heterotopic ossification, Postoperative prophylaxis with antiinflammatory medications. primarily indomethacin. is extremely effective in preventing the severest degrees of heterotopic ossification (HO) after a total hip arthroplasty (THA) and the recurrence of excised HO developed after a previous hip surgery. Prophylaxis with indomethacin should be given in 25-mg doses three times daily for at least three weeks. starting on the first postoperative morning. However. a shorter treatment period may be equally effective in preventing the severest degrees of HO. and a postoperative delay of five days before the initiation of prophylaxis does not seem to be followed by the development of severe HO. As evaluated one year after surgery. treatment with antiinflammatory medications in the immediate postoperative weeks did not increase the incidence of implant-bone interface radiolucencies. aseptic loosening. or revisions in cemented or cementless THAs when compared with cases that did not have postoperative treatment. However. although no major complications have been reported regarding the use of antiinflammatory medications in the prevention of HO after THA. orthopedic surgeons prescribing such treatment should be aware of their contraindications as well as early and late side effects. Since several antiinflammatory agents are reported to be effective in preventing HO. future reports dealing with HO after THA should always include information about the postoperative antiinflammatory treatment used.
Prevention of heterotopic ossification in high-risk patients by radiation therapy, Heterotopic ossification (HO) is a frequent occurrence after cemented and cementless total hip arthroplasty (THA). Patients at risk for this complication include those with preexisting ipsilateral or contralateral HO. diffuse idiopathic skeletal hyperostosis. hypertrophic osteoarthrosis. posttraumatic arthritis. and ankylosing spondylitis. Low-dose radiation therapy effectively prevents HO in this high-risk group when treatment is begun early in the postoperative period. A prospective evaluation has established the efficacy of fractionated and single-dose radiation therapy protocols. Limited radiation portals are used in patients receiving cementless prostheses. A rectangular radiation portal obliquely oriented to the prosthesis enables radiation treatment of the periarticular soft tissues while avoiding exposure of the bone-prosthesis interface. Radiation therapy to this interface may inhibit or delay bony ingrowth. Radiation therapy is the only treatment used to prevent HO that is delivered locally and not systemically. Low-dose radiation therapy using a limited radiation portal is the treatment of choice to prevent HO in high-risk patients after cementless THA.
Heart rate variability in patients with ventricular arrhythmias: effect of antiarrhythmic drugs. Antiarrhythmic Drug Evaluation Group (ADEG), The purpose of this study was to investigate whether heart rate variability could be reliably assessed in patients with ventricular arrhythmias and to evaluate whether it is affected by antiarrhythmic drugs. The study was based on an analysis of 239 ambulatory electrocardiographic (ECG) recordings obtained from 67 patients with frequent and complex ventricular arrhythmias enrolled in the Antiarrhythmic Drug Evaluation Group (ADEG) study. In each recording. after exclusion of premature ventricular complexes. the number of times during a 24 h period in which two consecutive sinus RR intervals differed by more than 50 ms was calculated. The total 24 h count from each recording was then used as an index of heart rate variability. This method is a reliable marker of cardiac parasympathetic activity. Recordings were analyzed at baseline (n = 56). during long-term treatment with amiodarone (n = 17). flecainide (n = 22) or propafenone (n = 17) and after washout in selected patients (n = 5). Despite the presence of a different number of arrhythmias. total 24 h counts in the same patient appeared reproducible over time (r = 0.83 between two different recordings. n = 49. p less than 0.0001). Baseline counts (median 1.698. range 26 to 13.648) were not correlated (r = 0.15) with the number of arrhythmias. The three antiarrhythmic drugs had a disparate effect on total 24 h counts: no change was observed in patients treated with amiodarone (median percent change [delta %]-8. p = NS). whereas a significant (p less than 0.025) decrease occurred in patients treated with flecainide (median delta % -56%) or propafenone (median delta % -64%).
Catecholamine responses to histamine infusion in man, To evaluate the effects of histamine-induced hypotension on plasma catecholamine levels. eight normal men. aged 20 to 40 years. were infused with incremental doses of histamine starting at 0.2 microgram/kg/min at a 30 degree tilt position with monitoring of blood pressure (BP) and heart rate. Histamine dosage was increased every 5 minutes by 0.1 to 0.2 microgram/kg/min until mean BP fell greater than 15 mm Hg or a dosage of 1.6 micrograms/kg/min was reached. Plasma catecholamine samples were taken between the fourth and fifth minute of each histamine dosage. Identical measurements were made during nitroglycerin-induced hypotension in these subjects. Histamine produced threefold greater increases in heart rate and plasma norepinephrine (NE) levels than did nitroglycerin for comparable decreases in BP. Although NE levels increased twofold to fivefold from baseline with histamine infusion. epinephrine levels increased minimally at the highest doses or not at all. Our data demonstrate that histamine selectively releases NE from adrenergic nerve terminals without significant adrenal catecholamine release. We suggest that neural NE release plays an important role in the cardiac effects of histamine.
Specific destruction of host-reactive mature T cells of donor origin prevents graft-versus-host disease in cyclophosphamide-induced tolerant mice, In cyclophosphamide (CP)-induced tolerance. a long lasting skin allograft tolerance was established in many H-2-identical strain combinations without graft vs host disease. Destruction of donor-reactive T cells of host origin. followed by intrathymic clonal deletion of these cells. has been revealed to be the chief mechanisms of this system. Here. we studied the fate of host-reactive populations in donor-derived T cells of C3H/He (C3H) (H-2k. Mls-1b. Mls-2a) mice rendered CP-induced tolerant to AKR/J (AKR) (H-2k. Mls-1a. Mls-2b). by assessing AKR-derived Thy-1.1+ T cells bearing TCR V beta 3 that are specifically reactive with Mls-2a-encoded Ag of the recipient C3H mice. In the AKR-derived Thy-1.1+ lymph node cells of the C3H mice that had been treated with AKR spleen cells plus CP. CD4(+)-V beta 3+ T cells were obviously decreased by day 10 after the CP treatment. At this stage. the Thy-1.1+ T cells were not detected in the C3H thymus. suggesting that the obvious decrease of CD4(+)-V beta 3+ T cells of AKR origin was not due to intrathymic clonal deletion in the recipient C3H mice. Therefore. the destruction of the host-reactive mature T cells of donor origin. as well as that of the donor-reactive mature T cells of host origin. occurred by the CP treatment at the induction phase. Furthermore. after the establishment of intrathymic mixed chimerism in the recipient C3H mice. V beta 3+ T cells were not detected among the Thy-1.1+ T cells of AKR origin in the mixed chimeric thymus. suggesting that the host-reactive immature T cells repopulated from the injected donor hematopoietic cells were clonally deleted in the recipient thymus. These two mechanisms appear to prevent graft vs host disease in CP-induced tolerance.
T and B cell responses to myelin-oligodendrocyte glycoprotein in multiple sclerosis, The pathogenesis of multiple sclerosis (MS) is believed to involve an autoimmune component directed against the myelin sheath. One potential target Ag for such autoimmune attack is the myelin-oligodendrocyte glycoprotein (MOG) because an anti-MOG mAb has profound influence on the course of experimental autoimmune encephalomyelitis. which to some extent represents an experimental model of MS. Using single cell assays. we have evaluated T and B cell reactivities to MOG in MS patients and controls. T cell reactivity was estimated by counting the number of cells that secreted IFN-gamma in response to MOG. whereas B cell reactivity was estimated by enumerating cells secreting antibodies that bound to MOG. MOG reactive T cells were detected in the peripheral blood of the majority of the 16 MS patients examined (mean 1/7299 mononuclear cells). but infrequently and at lower numbers in samples from neurologic controls. MOG-reactive T cells were more frequent among MS patients' cerebrospinal fluid (CSF) mononuclear cells (mean 1/450 cells). The T cell response to MOG was evidently MHC class II restricted. because Fab fragments of a rabbit polyclonal anti HLA-DR antibodies abrogated the Ag-induced increase in number of cells that secreted IFN-gamma. as analyzed on CSF and PBMC from three patients with MS. Anti-MOG IgG antibody-secreting cells were detected in blood in 8 of 16 MS patients (mean 1/25.641 cells). but they were also strongly accumulated in CSF. being detected in 8 of 10 MS patients examined (mean 1/265 cells). while rarely found in controls. The findings imply that MOG may represent a pathogenetically important target Ag in MS.
Generation and cloning of stable human IgE-secreting cells that have rearranged the C epsilon gene, Although the secretion of Ig isotypes other than IgM is generally accompanied by a DNA rearrangement that deletes C mu (and the other IgCH genes located between VDJ and the expressed CH gene). a system has recently been described that generates a high frequency of IgE-secreting cells that have failed to delete IgCH genes or to rearrange their C epsilon genes. These cells. derived from EBV-transformed human PBMC. secrete IgM and IgD as well as IgE. To determine whether the absence of C epsilon rearrangement and CH gene deletion is a general phenomenon for human IgE-secreting cells. we have characterized IgE-secreting cells that are generated by culturing purified human B cells with EBV plus IL-4 in the presence of irradiated human PBMC. In contrast to the earlier observation. we have not been able to detect any cells that demonstrate cytoplasmic staining for IgE and concurrently stain for a second Ig isotype. Stable IgE-secreting cell lines and clones produced by this method have rearranged one of their C epsilon genes and have deleted both C mu genes. These observations demonstrate that the generation of human IgE-secreting cells can involve the same gene rearrangement and deletional mechanisms that lead to the generation of cells that secrete other isotypes.
Comparative efficacy and safety of intravenous and oral administration of a TRH analogue (RX77368) in motor neuron disease, Ten consecutive patients with motor neuron disease (MND) who had bulbar symptoms received one or two intravenous doses followed by increasing oral doses of a TRH analogue (RX77368). Similar improvements in speech. swallowing and in tongue and jaw movements were seen after iv and oral administration in nine. five and eight patients respectively. The initial time course of improvement correlated with increasing plasma levels of the drug. but most clinical effects persisted when the levels decreased and became undetectable after 24 hours. The oral solution was tasteless and had no. or minimal. side effects.
Acute regional cerebral blood flow changes caused by severe head injuries, To evaluate the changes in cerebral blood flow (CBF) that occur immediately after head injury and the effects of different posttraumatic lesions on CBF. 61 CBF studies were obtained using the xenon-computerized tomography method in 32 severely head-injured adults (Glasgow Coma Scale score (GCS) less than or equal to 7). The measurements were made within 7 days after injury. 43% in the first 24 hours. During the 1st day. patients with an initial GCS score of 3 or 4 and no surgical mass had significantly lower flows than did those with a higher GCS score or mass lesions (p less than 0.05): in the first 1 to 4 hours. those without surgical mass lesions had a mean CBF of 27 cc/100 gm/min. which rose to 44 cc/100 gm/min by 24 hours. Patients without surgical mass lesions who died tended to have a lower global CBF than did those with better outcomes. Mass lesions were associated with a high global CBF and bihemispheric contusions with the lowest flows. By 24 hours after injury. global blood flow increased in groups that originally had low flows and decreased in those with very high initial flows. such that by 36 to 48 hours. most patients had CBF values between 32 and 55 cc/100 gm/min. Lobar. basal ganglion. and brain-stem blood flow values frequently differed by 25% or more from global averages. Brain-stem CBF varied the most but did not correlate with clinical signs of brain-stem dysfunction. Double studies were performed at two different pCO2 values in 10 patients with various posttraumatic lesions. and the CO2 vasoresponsivity was calculated. Abnormal CO2 vasoresponsivity was found with acute subdural hematomas and defuse cerebral swelling but not with epidural hematomas. In patients without surgical mass lesions. the findings suggest that CBF in the first few hours after injury is often low. followed by a hyperemic phase that peaks at 24 hours. Global CBF values vary widely depending on the type of traumatic brain injury. and brain-stem flow is often not accurately reflected by global CBF values. These findings underscore the need to define regional CBF abnormalities in victims of severe head injury if treatment is intended to prevent regional ischemia.
Effect of chronic D-Ala,2 D-Leu5-enkephalin or pertussis toxin treatment on the high-affinity state of delta opioid receptor in neuroblastoma x glioma NG108-15 hybrid cells, Chronic treatment of neuroblastoma x glioma NG108-15 hybrid cells with the opioid agonist D-Ala.2 D-Leu5-enkephalin (DADLE) induces a homologous desensitization of the delta opioid receptors present in these cells. Since the Kd value of the delta opioid receptor's high-affinity state reflects the potency of the agonist. we examined the effect of receptor desensitization in NG108-15 cells on the percentage of receptor in the high-affinity state. When NG108-15 hybrid cells were treated with 10 or 100 nM DADLE for 4 hr at 24 degrees C. loss of DADLE's ability to inhibit adenylate cyclase was observed. However. when competition binding experiments were carried out with P2P3 membranes isolated from the delta opioid-desensitized hybrid cells. it was determined that 41.7 +/- 3.4% of the total binding sites remained in the high-affinity state. with no apparent alteration in the Kd value of either high- or low-affinity states. Similarly. when NG108-15 cells were treated with 100 ng/ml of pertussis toxin for 3 hr at 37 degrees C. 39.9 +/- 3.6% of the binding sites remained in the high-affinity state. This reduction in the percentage of receptor in high-affinity state was agonist specific. for chronic treatment of hybrid cells with levorphanol. a partial agonist. or the antagonist naloxone did not alter the percentage of opioid receptors in the high-affinity state. Furthermore. the delta opioid receptors remaining in the high-affinity state after chronic DADLE treatment were still sensitive to both Na+ and guanyldylimidodiphosphate. indicating that opioid ligand binding remained coupled to the G-proteins.
Trauma care reimbursement: comparison of DRGs to an injury severity-based payment system, Concern exists that per case payment using Diagnosis Related Groups (DRGs) inadequately pays trauma centers. In this study. 45 Trauma Resource Groups (TRGs). an alternative patient classification system based on the Injury Severity Score and patient age. is developed and compared to 172 Diagnosis Related Groups (DRGs) that include trauma diagnoses. TRGs were developed using 1983 Maryland trauma patient hospital discharge abstracts (n= 34.702). the same source used to assign a DRG. We compared estimated TRG and DRG payments to actual charges for 17.398 trauma cases treated during 1986 at five trauma centers and 18 community hospitals in the Central Maryland Metropolitan Statistical Area. The unexpected findings of this study are that an anatomic severity-based classification of hospital trauma discharges (TRGs) does not perform as well as DRGs in: 1) explaining variations in length of stay for trauma cases. or 2) assuring an appropriate distribution of revenues to regional trauma centers and community hospitals. Solutions discussed include segregating community hospital and trauma center costs in computation of average per case rate setting. and inclusion of physiologic and mechanism of injury parameters in prospective payment classification systems to increase explained variance of resource use.
Osteogenic sarcoma arising adjacent to a long-standing ameloblastoma. A case report, Ameloblastoma is an uncommon odontogenic tumor usually occurring in the mandible. Rarely do other primary tumors occur with or arise from ameloblastoma. We describe a patient with simultaneous osteogenic sarcoma of the maxilla and recurrent ameloblastoma.
Limited small cell lung cancer: prognostic significance of a complete response to the induction phase of chemotherapy followed by thoracic irradiation, Limited-stage small cell lung cancer is frequently treated with induction combination chemotherapy (ICC). followed by consolidation with thoracic irradiation. It has been suggested that patients who do not have a complete response to ICC are unlikely to have control of occult distant metastasis and consequently have such a poor prognosis that thoracic irradiation is unlikely to be of benefit. To examine this hypothesis. 48 patients treated on prospective protocols who achieved a complete response to ICC or subsequently to thoracic irradiation were analyzed. Twenty-four patients had a complete response to ICC (CR-ICC). and 24 subsequently converted to complete-response status after thoracic irradiation (CR-TI). The two groups had similar prognostic factors and treatment. Comparing CR-ICC and CR-TI patients. survival was 40% versus 26% at 2 years and 35% versus 4% at 5 years. respectively (P less than .05). Freedom from distant metastasis was 41% at 5 years for the CR-ICC patients and 8% for the CR-TI patients (P less than .05). A modest number of CR-TI patients were long-term survivors. suggesting a value for thoracic irradiation as consolidation therapy.
Breast sonography, Sonographic equipment for breast imaging has continued to improve. and the role of breast sonography has evolved to that of an indispensable adjunct to mammography. Breast sonography is not useful for screening for breast cancer in any age group. Its main use is for the differentiation of cystic vs solid palpable and mammographically visible masses. If strict sonographic criteria are used for a simple cyst. the diagnostic accuracy approaches 100%. Sonographic diagnosis of a simple cyst precludes the need for further workup. including aspiration. biopsy. or followup. This article emphasizes the technical aspects of breast sonography. especially those factors that alter the diagnostic information on the images. These factors can be especially problematic in differentiating cysts and solid masses. the most common diagnostic use of breast sonography. Selection of equipment depends largely on the requirements of a specific practice. Optimally. the sonographic equipment is located close to where mammography is performed. and the sonographic and mammographic findings are interpreted together.
Detection of bullous lung disease: conventional radiography vs digital storage phosphor radiography, The detection of fine linear contours and altered aeration are requirements for the radiologic diagnosis of bullous lung disease and are severe measures of the spatial and contrast resolution of chest imaging systems. We compared plain film radiography with five postprocessing algorithms of storage phosphor digital radiography (2144 x 1744 x 10 bit matrix with 0.2-mm pixel size) in the detection of CT-proved bullous lung disease (35 patients and 25 normal control subjects). Receiver-operating-characteristic analysis of 2160 observations by six interpreters was done to evaluate the observers' performance. By analysis of variance (p less than .05). we found that the default digital algorithm and the three edge-enhancing algorithms of high and medium frequencies performed less well than plain films did. but the differences fell short of statistical significance. Gray-scale reversal was the only digital algorithm that performed significantly less well than plain films did. We conclude that any differences between digital algorithms and plain films in the detection of bullous lung disease were too small to be detected in this study. Any difference between the two methods in providing clinically important. diagnostic information is likely to be insignificant.
Gallstone fragmentation during biliary lithotripsy: effect of stone composition and structure, In vitro lithotripsy with the Siemens Lithostar was conducted on 36 radiolucent or minimally calcified gallstones housed in an anthropomorphic phantom. The ease and pattern of fragmentation were correlated with global composition for the entire stone. regional or microcomposition (determined by Fourier-transform infrared spectroscopy). and microstructure (determined by scanning electron microscopy). Stones made up of more than 62% cholesterol required 50% more shock waves to pulverize all fragments to 0.3 cm or less than did stones of less than 62% cholesterol (p less than .01). An inverse relationship was found between the number of shock waves needed for fragmentation and the cholesterol content (r = .77). Although a broad range of fragmentation responses occurred. little variation was seen in the ease of fragmentation within stone families. The majority of stones fractured along radially oriented cholesterol plates. but one third of stones treated showed initial chipping or flaking at the periphery before radial fracture. This type of peripheral erosion most often occurred in stones with peripheral pigment rims. These stones required more shock waves and lagged in pulverization compared with more homogeneous cholesterol stones. The efficiency of fragmentation during biliary lithotripsy correlates with the stones' global cholesterol content. A stone's architecture. as reflected by its regional composition and microstructure. partially predicts the mechanism of fragmentation. These in vitro data may be useful in further refining criteria for selecting patients and understanding the fragmentation process.
Automated percutaneous lumbar diskectomy, The use of automated percutaneous lumbar diskectomy for the treatment of herniated lumbar disks is increasing. More than 3000 physicians have been trained to perform the procedure. and over 40.000 cases have been completed worldwide. This review describes the development of automated percutaneous lumbar diskectomy. the selection of appropriate patients. how the technique is performed. and its efficacy relative to other methods of treatment.
Sonography of the fetal heart: findings on the four-chamber view, The normal and pathologic sonographic appearances of the fetal heart on four-chamber views are reviewed. Performed correctly. the four-chamber view is the best method of examining the complex cardiac anatomy of the small fetal heart and of detecting major congenital heart disease.
MR anatomy and pathology of the hypothalamus, The hypothalamus. the ventral-most portion of the diencephalon. surrounds the anterior inferior portion of the third ventricle (Fig. 1). It functions primarily as an integrative mechanism for various autonomic and neuroendocrine activities including temperature regulation. water balance. behavior. and appetite. This pictorial essay illustrates the value of MR in depicting the normal anatomy and abnormalities of the hypothalamic region.
The importance of preoperative evaluation of the subclavian vein in dialysis access planning, Adequate venous outflow is critical to the proper function of a vascular-access graft (arteriovenous fistula) used for chronic hemodialysis. Stenosis of the subclavian vein can significantly compromise this venous outflow. The development of such subclavian vein stenoses has been associated with the prior placement of temporary subclavian vein dialysis catheters. We evaluated the importance of preoperative detection of these stenoses before placement of a permanent vascular-access graft in the upper extremity. Upper extremity venography was performed before placement of a permanent vascular-access graft in 43 patients. A total of 62 extremities were evaluated. A 40% prevalence of moderate or severe subclavian vein stenosis was found in patients with prior or existing temporary dialysis catheters in the subclavian vein. No stenoses were found in patients without a history of dialysis catheters in the subclavian vein. This difference in the prevalence of subclavian vein stenosis is statistically significant (p less than .001). In no case was the stenosis suspected clinically. Before placement of a permanent vascular-access graft. the subclavian vein should be evaluated in all patients with a history of a temporary dialysis catheter in the subclavian vein. The use of sites other than the subclavian vein for temporary dialysis is strongly encouraged.
Dynamic QRS-complex and ST-segment monitoring in acute myocardial infarction during recombinant tissue-type plasminogen activator therapy. The TEAHAT Study Group, Changes of the QRS complex are the electrocardiographic expression of irreversible injury of the myocardium. In humans. the process of infarction occurs over several hours. A more rapid development of QRS changes has been reported in patients treated with thrombolytic agents. Patients with strongly suspected acute myocardial infarction (AMI) included in a placebo-controlled trial of 100 mg of recombinant tissue-type plasminogen activator (rt-PA) were monitored for 24 hours with continuous. on-line vectorcardiography. The magnitude of the QRS vector changes correlated with infarct size estimated by the maximal value of lactate dehydrogenase-1 (r = 0.69. p less than 0.001) as well as with left ventricular ejection fraction 30 days after randomization (r = 0.49. p less than 0.001). Treatment with intravenous rt-PA limited total QRS vector change but the QRS vector changes observed occurred more rapidly and reached a plateau 131 minutes earlier in patients treated with rt-PA than in those receiving placebo (p less than 0.01). A certain pattern of highly variable ST vector magnitude was identified and was associated with higher maximal lactate dehydrogenase-1 values (23 +/- 13 vs 14 +/- 10 mu kat/liter. p less than 0.001) and a tendency to higher 1-year mortality (24 vs 9%. p = 0.08) than in patients without this pattern. In patients with this pattern. rt-PA did not affect maximal lactate dehydrogenase-1. time to maximal creatine kinase and final magnitude of QRS vector change.
Influence of dilated cardiomyopathy, myocarditis and cardiac transplantation on the relation between plasma atrial natriuretic factor and atrial pressures, To determine whether dilated cardiomyopathy. myocarditis or cardiac transplantation affect the relation between plasma immunoreactive atrial natriuretic factor (ANF) and cardiac filling pressures. right atrial plasma ANF concentration. pulmonary arterial wedge pressure and right atrial pressure were measured in patients with dilated cardiomyopathy (n = 48). dilated cardiomyopathy secondary to myocarditis (n = 20) and prior cardiac transplantation (n = 34). ANF level significantly correlated with both pulmonary arterial wedge and right atrial pressures in patients with dilated cardiomyopathy; however. the presence or absence of myocarditis did not significantly alter these relations (p = 0.88 and p = 0.33 for interaction terms. respectively). For the combined group the ANF-pulmonary arterial wedge pressure relation had a slope of 8.1 pg/ml/mm Hg (95% confidence interval (CI). 5.4 to 10.8; p = 0.0001) and the ANF-right atrial pressure relation a slope of 13.6 pg/ml/mm Hg (CI. 8.5 to 18.7; p = 0.0001). Receiver operator curve analysis identified an optimal dividing point of ANF 150 pg/ml with 100% (CI. 72 to 100%) of patients with right atrial pressure greater than or equal to 8 mm Hg having ANF greater than or equal to 150 pg/ml. but only 56% (CI. 42 to 69%) with pressure less than 8 mm Hg having ANF less than 150 pg/ml. Unlike the patients with cardiomyopathy (with or without myocarditis). cardiac transplant recipients displayed no correlation between ANF level and either pulmonary arterial wedge pressure (p = 0.50) or right atrial pressure (p = 0.29) despite similarly elevated ANF concentrations (mean +/- standard deviation 168 (83) pg/ml in transplant patients versus 185 (114) pg/ml in cardiomyopathy patients). It is concluded that left and right intracardiac pressures are important determinants of circulating ANF level unaffected by inflammation in patients with cardiomyopathy.
Experimental hyperthermia: protective effect of oxygen carrying fluorocarbon and crystalloids intraperitoneally, The treatment of hyperthermia produced by passive warming was studied in anesthetized rats weighing 250-300 grams. In the first set of seven experiments. the authors found that venous blood oxygen fell as core temperature rose. Intraperitoneal injection of 20 ml of the oxygen carrying fluorocarbon (perfluorotributylamine. FC-43) emulsion in three of the animals shifted the curve to the right improving venous oxygen content (p less than 0.1). In the second series of experiments. a catheter was placed in the carotid artery. This catheter was attached to a pressure transducer for continuous recording of blood pressure and heart rate. Periodic blood samples were removed for measurement of blood gases. pH. and lactate. Four of the animals received 20 ml of isotonic saline. three received 20 ml of FC-43 emulsion both given intraperitoneally. and four served as controls. In the control group. there was an increase in systolic blood pressure and heart rate which peaked at a colon temperature of 42 degrees C. followed by cardiovascular collapse and death around 43 degrees C. Arterial PO2 (corrected for temperature) remained relatively constant up to 42 degrees C. and then fell. The arterial PCO2 rose sharply when the core temperature exceeded 43 degrees C. Arterial lactate content began to increase at 42 degrees C and above 43 degrees C was 2.5 fold elevated. Isotonic saline provided circulatory support but did not change the hypoxia or mixed acidosis from CO2 and lactate above 43 degrees C. FC-43 emulsion decreased hypoxia and improved circulatory performance but was associated with a mild respiratory alkalosis as arterial PCO2 fell.
Injuries in the 1987 national amateur volleyball tournament, In a prospective study of injuries in the 1987 United States Volleyball Association's national tournament. we found 154 injuries in 1520 participants during 7812 hours of play. The injury rate in this study was 1.97/100 hours of play. Before the tournament. the participants' history was taken. and during the week of participation. records were kept of every player who presented with an injury. Players ranged in age from 17 to 60 and competed in five age/gender groups. Females had an injury rate of 2.3 and males had an injury rate of 1.7. The highest injury rate was seen in the men's open division. ages 17 to 35 (2.7). and the lowest rate was seen in the men's Golden Masters. ages 46 and up (1.5). Seventy-nine percent of the injuries occurred during the tournament and 21% were considered to be chronic injuries with an acute exacerbation. The upper extremities accounted for 20% of the injuries. The ankle (17.6%). low back (14.2%). and knee (11%) were the most common injury sites. Strains (36%) and sprains (28%) were the most frequent types of injury. Only eight (5.2%) injuries resulted in more than 5 days of time loss. Two of these injuries involved the knee and two others required surgery. It is likely that in studies relying upon retrospective methods. fewer of the less severe injuries are found. thereby leading to an overestimation of the percentages of knee and ankle injuries and the proportion of severe injuries. The clinician contemplating providing care for a high-level tournament should expect a preponderance of minor injuries occurring in a variety of anatomical locations.
A three-phase analysis of the prevention of recreational softball injuries, Recreational sports injuries are expensive to society. Prevention of such injuries must be a major public health goal. In a previous retrospective study. base sliding was found to be responsible for 71% of recreational softball injuries. Because most injuries occurred during rapid deceleration against stationary bases. quick-release (break-away) bases were evaluated as a means to modify this mechanism of injury. In a prospective study. 633 softball games were played on a break-away base fields and 627 games were played on stationary base fields. Forty-five sliding injuries occurred on the stationary base diamonds (1 injury for every 13.9 games) and only two sliding injuries occurred on the break-away fields (1 injury for every 316.5 games). The medical costs for injuries on the stationary base fields was 79 times greater than that on the break-away fields. In a 1035 game follow-up study performed on all fields equipped with break-away bases. two sliding injuries occurred (1 injury for every 517.5 games). Installing break-away bases in fields used by recreational leagues would achieve a significant reduction of serious softball injuries (98%) and. therefore. should be mandatory. Based on our findings. the Centers for Disease Control has estimated 1.7 million injuries would be prevented nationally per year. saving $2.0 billion per year nationally in acute medical care costs.
A simplified human whole blood assay for measurement of dust mite-specific gamma interferon production in vitro, A simplified microassay for the measurement of spontaneous and dust mite antigen-induced gamma interferon (IFN) production in vitro using unseparated human blood has been developed. Gamma IFN in 72-hour culture supernatants was measured using a solid phase radioimmunoassay. Maximum production in allergic patients occurred between 25 and 50 micrograms/mL of mite antigen. Both spontaneous and antigen-stimulated levels were highest in the group of mite-allergic patients compared with nonallergic patients or normal controls. Gamma IFN production was lower in a group of mite-allergic patients on immunotherapy compared with the nonimmunotherapy group. Treatment with even small doses of oral corticosteroids completely obliterated both spontaneous and stimulated gamma IFN production. These results indicate that this whole blood assay coupled with a lymphokine radioimmunoassay is a convenient. rapid. and sensitive method for measuring cell-mediated immunity to allergens and responses to IT or drug treatment that can be easily adapted to testing large number of patients.
Hormone-sensitive adenylate cyclase system in lymphocytes from asthmatic patients: possible defects at the postreceptor sites, To clarify the mechanism of beta adrenergic hyporesponsiveness. which is related to bronchial hypersensitivity in asthmatic patients. cAMP responsiveness in peripheral lymphocytes was examined. The cAMP response to isoproterenol significantly decreased in the lymphocytes from asthmatics compared with those from healthy subjects. In contrast. the responses to GTP. Gpp(NH)p (a GTP analogue). sodium fluoride. and forskolin (a direct stimulator of the catalytic unit) were similar between the two groups. These results suggest that impairment of the stimulatory GTP binding protein or the catalytic unit is not the major cause of beta adrenergic hyporesponsiveness in asthma. and that hyporesponsiveness may be due to other mechanisms in the hormone-sensitive adenylate cyclase system.
Striatal function in normal aging: implications for Parkinson's disease, Central to several current theories of the etiology of Parkinson's disease is the premise that the nigrostriatal dopaminergic system degenerates with normal aging. Much of the evidence for this assertion has come from postmortem neurochemical studies. We have used L-6-[18F] fluoro-Dopa and positron emission tomography in 26 healthy volunteers (age range. 27-76 years) to examine striatal and frontal cortical tracer uptake. Data have been analyzed by using a graphical approach to calculate an influx constant (Ki) for L-6-[18F]fluoro-Dopa uptake into the caudate. putamen. and medial frontal cortex of each subject. In the population studied. there was no decline in Ki with age for any of these structures. A series of physiological measurements made on the older subjects also showed few significant changes with age. The positron emission tomographic findings demonstrate preservation of nigrostriatal dopaminergic function in normal aging. The pathological process causing Parkinson's disease may operate closer to the time of presentation than has been suggested.
Effects of antiretroviral dideoxynucleosides on polymorphonuclear leukocyte function, Dideoxynucleosides (zidovudine[AZT]. dideoxycytidine[ddC]. and dideoxyinosine[ddI]) are promising new agents for the management of human immunodeficiency virus type 1 (HIV-1) infections. In light of recent data demonstrating defects in the polymorphonuclear leukocyte (PMN) bactericidal activity of HIV-1-infected patients and since many chemotherapeutic agents affect PMN function. we examined their effects on the function of PMNs from both healthy and HIV-1-infected individuals in vitro. AZT (0.1 to 25 microM). ddC (0.01 to 1 microM). and ddI (0.2 to 50 microM) had no effect on viability. chemotaxis to N-fromylmethionyl leucyl phenylalanine. phagocytosis of Candida albicans or Staphylococcus aureus. or superoxide production following stimulation by N-formylmethionyl leucyl phenylalanine. Killing of C. albicans was not affected by AZT but was enhanced by 0.1 and 1 microM ddc (a 1 microM. killing was 26.0 +/- 2.02% compared with 17.0 +/- 0.73% for controls: P = 0.006) and 0.2 to 50 microM ddI (at 10 microM. killing was 25.0 +/- 0.68% compared with 17.8 +/- 0.91% for controls; P = 0.002). Killing of S. aureus was unchanged by AZT and ddC but was significantly enhanced by ddI at 0.2 to 20 microM (at 2 microM. killing was 71.2 +/- 5.57% compared with 51.4 +/- 6.29% for controls; P = 0.0045). In addition. the preexisting defective bactericidal capacity of PMNs from HIV-1-infected patients was enhanced by ddI (P less than 0.025). Potential enhancement by these dideoxynucleosides of certain PMN functions of HIV-1-infected patients deserves further study.
Nasogastric feeding at home: acceptability and safety, A questionnaire was administered to 70 families with experience of home enteral nutrition. All but one patient received at least some of their feeding overnight. During 11.041 patient days of home enteral nutrition. no serious complications were seen. Sleep disturbance was common. however. and affected 59 parents and 35 children. A nocturnal cough or 'chestiness' were noted in 10 children suggesting occult gastro-oesophageal reflux. Enteral feeding disposables were not prescribable by general practitioners. and funding for the equipment was inadequate in the hospital and community. The mean time to arrange funding for equipment was eight months (range two weeks to two years). Parental views on home enteral nutrition were positive and none felt that its disadvantages outweighed the benefits. Altogether 35 children were described as being more happy and active. Given adequate preparation and continued support at home. parents can manage home enteral nutrition safely and effectively.
Inhibition of 5-lipoxygenase product formation and polymorphonuclear cell degranulation by tenidap sodium in patients with rheumatoid arthritis, We studied the effect of tenidap sodium. a new antiinflammatory/antirheumatic drug (120 mg/day for 7 days). on eicosanoid production and neutrophil degranulation in patients with rheumatoid arthritis. Endogenous prostaglandin E2 levels and ex vivo production of leukotriene B4 (LTB4) were measured in synovial fluid samples obtained at baseline and 1 week later. We measured peripheral blood polymorphonuclear cell (PMN) degranulation following surface-bound IgG stimulation. a possible 5-lipoxygenase product-mediated event. by determining lactoferrin and elastase release into the culture fluid. We found decreased levels of endogenous prostaglandin E2 as measured by radioimmunoassay. and decreased ex vivo production of LTB4 by PMN as measured by high performance liquid chromatography. in synovial fluid samples from patients who took tenidap. Release of the granule proteins lactoferrin and elastase was decreased in PMN obtained from patients receiving tenidap. as well as in the PMN incubated in vitro with tenidap. Improvement in clinical measures paralleled the biochemical changes. The unique 5-lipoxygenase inhibitory property of tenidap. as measured by LTB4 production and degranulation. suggests that it may have clinical activity which differentiates it from nonsteroidal antiinflammatory drugs.
Requirement of heparin for arterial and venous thrombolysis with recombinant tissue-type plasminogen activator, The effect of concomitant intravenous (IV) heparin (200 U/kg bolus. followed by 100 U/kg/h) on the efficacy of arterial and venous thrombolysis with IV recombinant tissue-type plasminogen activator (rt-PA; 0.5 mg/kg over 1 hour) was investigated in a combined femoral arterial and venous thrombosis model in the dog. The arterial model consisted of a high-grade stenosis. endothelial damage. and a thrombotic occlusion. and the venous model consisted of a 125I-fibrin-labeled blood clot. After a dose-finding pilot study in four dogs. a randomized. prospective. and blind study was performed in 20 animals pretreated with 2.8 mg/kg IV acetyl salicylic acid (ASA). The combination of rt-PA and heparin (group I. n = 10) induced early (less than 30 minutes) arterial reperfusion in seven dogs. late (greater than 30 minutes) reflow in two dogs. and persistent occlusion in one dog. rt-PA alone (group II. n = 10) was associated with early reperfusion in one dog. late reflow in three dogs. and persistent occlusion in six dogs (P = .018). Reocclusion occurred in five of nine reperfused dogs of group I and in one of four reperfused dogs of group II (P = not significant). Venous clot lysis amounted to 81% +/- 4% (mean +/- SEM) for group I and to 49% +/- 7% for group II (P less than .001). Template bleeding times increased moderately. but significantly. in group I (from 2.2 +/- 0.2 minutes at baseline to 7.0 +/- 1.4 minutes at 30 minutes. P = .006). but only marginally in group II (from 2.2 +/- 0.2 minutes to 3.6 +/- 0.7 minutes. P = .09). No systemic fibrinogen depletion was observed. Thus. the concommitant use of heparin with rt-PA accelerates arterial reperfusion and enhances venous thrombolysis in dogs pretreated with ASA. These results. obtained in a randomized prospective study design. add to a growing body of experimental and clinical evidence. indicating that thrombolytic therapy with rt-PA requires concomitant adjunctive IV heparin for optimal efficacy. even in the face of treatment with ASA.
Expression of the c-myc protein is down-regulated at the terminal stages during in vitro differentiation of B-type chronic lymphocytic leukemia cells, The translocated c-myc oncogene in Burkitt's lymphoma (BL) and murine plasmacytoma (MPC) has been proposed to be expressed at a stage of differentiation at which the gene is normally silent. resulting in a continuous proliferation and an inhibited terminal differentiation. To determine whether c-myc is differently expressed at the various stages of the differentiation pathway. we used B-type chronic lymphocytic leukemia (B-CLL) cells. representing resting B lymphocytes. inducible to proliferation and/or differentiation in vitro. The c-myc protein. and Ig lambda-light chain and PCA-1 antigen as markers of B-cell maturation. were analyzed in single. morphologically defined cells by immunocytochemical double-staining. The proliferation of individual cells was determined by 3H-thymidine incorporation and by analysis of Ki-67 antigen expression. The results show that the level of c-myc expression correlates to the stage of differentiation and to the proliferative activity. Uninduced resting cells did not express c-myc. The c-myc protein was observed in the highest amount at the proliferative B-lymphoblast stage of maturation and was reduced in plasmablasts and undetectable in plasma cells. The results suggest that maturation of B cells into nonproliferative. terminally differentiated plasma cells is associated with a downregulated c-myc expression and thus support the view that the deregulated c-myc gene in BL and MPC is expressed at an inappropriate stage of maturation and thereby inhibits terminal differentiation.
Monitoring of specific antibodies to human immunodeficiency virus structural proteins: clinical significance, Levels of antibodies to six major structural proteins of human immunodeficiency virus type 1 (gp120. gp41. p66. p31. p24. and p17) were assessed in serial samples from 22 persons with severe hemophilia (16 asymptomatic and 6 who developed acquired immunodeficiency syndrome [AIDS] or AIDS-related complex) with an automated dot blot assay using purified recombinant antigens. High and sustained levels of antibody to gp120. gp41. and p31 were found in all patients irrespective of their clinical condition for 4 to 6 years after seroconversion. In contrast. immune response to p66 and p17 was significantly lower in symptomatic patients. Over time. the levels of these two antibodies. as well as anti-p24. decreased and tended to become undetectable. Abnormal immune response and low levels of antibody to p66 and p17 are early indications of rapid clinical progression.
Variability of breathlessness measurement in patients with chronic obstructive pulmonary disease, The purpose of our study was to evaluate the reproducibility of a Borg rating of dyspnea in patients with COPD. We examined nine patients with COPD who performed a SST on four separate days within a ten-day period. The patients walked on a treadmill for 6 min. At the end of each minute. patients matched a Borg rating to the intensity of their breathlessness. We measured the HR. VE. VO2. VT and f at the end of each minute. While the mean VO2. VE. HR. VT and f stabilized after one or two attempts. the Borg ratings decreased with successive tests. We conclude that the Borg scale for measuring breathlessness shows progressive decreases with repetition whereas VO2. VE. HR. VT and f stabilize after one or two practice attempts. This suggests that desensitization to dyspnea may play a role in the improvement of patients after exercise.
Intermittent abdominal pressure ventilator in a regimen of noninvasive ventilatory support, The purpose of this work is to present 640 patient-years of experience using the intermittent abdominal pressure ventilator (IAPV) in a regimen of noninvasive ventilatory support for patients with paralytic/restrictive respiratory insufficiency. Fifty-two of the 54 patients who used the IAPV used 24-hour noninvasive ventilatory support. Thirty-eight of the 52 patients could tolerate less than 15 minutes of free time off their ventilators except by the successful use of glossopharyngeal breathing (GPB). No patient. however. retained an indwelling tracheostomy and none required or used supplemental oxygen therapy. Forty-eight of the 54 patients used the IAPV for daytime support for a mean of 12.9 +/- 11.5 years (3 months to 39 years) while using other forms of noninvasive support overnight. All 48 patients maintained normal minute ventilation and end-tidal PCO2 on the IAPV. One patient used the IAPV only for nocturnal ventilatory support for six months. Five patients relied on the IAPV as their sole method of ventilatory support 24 hours a day for a mean of 13.4 +/- 11.2 years (range. 2 to 31 years). Three of these five patients had no free time and were studied by nocturnal SaO2 monitoring that demonstrated a mean SaO2 of 95 percent or greater and a minimum SaO2 of 86 percent. The maximum end-tidal PCO2 was 49 mm Hg during sleep on the IAPV. The 48 patients receiving daytime IAPV support reported few difficulties. However. two of the five patients using the IAPV 24 hours a day had development of sacral decubiti. The IAPV became ineffective for 12 patients after 12.3 +/- 9.5 years of use. These patients then switched to daytime mouth IPPV. We conclude that the IAPV is a safe and effective method of long-term daytime ventilatory support for patients with paralytic/restrictive respiratory insufficiency. Its use is optimized when employed in combination with other noninvasive methods of ventilatory support. thus eliminating the need for tracheostomy. and optimizing the use of GPB. Regular follow-up is important because the IAPV can become less effective with time.
Intermittent volume cycled mechanical ventilation via nasal mask in patients with respiratory failure due to COPD, Intermittent mechanical ventilation via nasal CPAP mask was provided to 13 patients admitted to this institution for exacerbation of chronic respiratory failure. Ten suffered from COPD. two suffered from obesity hypoventilation syndrome (OHS). and one from severe hypothyroidism. All except one presented with dyspnea and hypercapnia due solely to progression of their underlying disease processes. Six of the patients with COPD and the patient with hypothyroidism responded to positive pressure ventilation by mask with improvements in blood gas values and clinical status. The remaining two patients with COPD and the two patients with OHS were unable to use the system. Four of the patients with COPD and chronic respiratory failure have been subsequently maintained on daily volume ventilation via nasal mask for about 20 months with persistent clinical and physiologic improvements. Application of volume ventilation through the nasal CPAP mask is a feasible strategy for providing long-term mechanical ventilation to selected patients with COPD and respiratory failure.
Effects of hydralazine and increased cardiac output on recombinant tissue plasminogen activator-induced thrombolysis in canine pulmonary embolism, We employed a canine model of pulmonary embolism. induced by injection of autologous radiolabelled blood clots. to investigate effects of hydralazine and an increase in cardiac output per se on recombinant tissue plasminogen activator-induced thrombolysis. Emboli increased pulmonary artery pressure (PAP) and decreased CO from 2.7 to 1.8 L/min-1. Following embolization. dogs were randomly divided into three groups. Group 1 received .5 mg/kg of rtPA over 30 minutes. Group 2 received the same dose of rtPA and were pretreated with hydralazine to increase CO approximately 50 percent. In the group 3 dogs. CO was increased by opening a systemic A-V fistula. Following embolization. CO remained low in group 1. the mean 2 h time-averaged CO was 1.9 L/min-1. The CO was 2.9 and 3.1 L/min-1 in groups 2 and 3. respectively. Corresponding to the increased flow in groups 2 and 3. rate and extent of pulmonary thrombolysis significantly increased. These results indicate that an increase in CO augments rtPA-induced pulmonary thrombolysis.
Cholestasis and changes of portal pressure caused by chlorpromazine in the perfused rat liver, Chlorpromazine (10 mumol/L) causes a marked increase in portal pressure in perfused rat liver. Simultaneously. oxygen consumption. hepatic clearance of taurocholate and bile flow are diminished. These effects are prevented by the cyclooxygenase inhibitors indomethacin (15 mumol/L). acetylsalicylate (3 mmol/L) or ibuprofen (200 mumol/L). On addition of chlorpromazine the liver releases increased amounts of prostaglandin D2; this increase does not occur in the presence of indomethacin. At higher concentrations of chlorpromazine (100 mumol/L) the inhibition of taurocholate clearance and bile flow is accompanied by only a moderate increase of portal pressure. and indomethacin is without effect. At this high concentration. substantial cell damage. as indicated by the release of lactate dehydrogenase. is present. We conclude that arachidonic acid-derived metabolites. notably prostanoids. are involved in the inhibition of bile flow and of taurocholate clearance observed at low concentrations of chlorpromazine. The data suggest that changes in the microcirculation are responsible for the impairment of the liver functions. At higher concentrations of chlorpromazine the cell toxicity of the drug becomes prominent.
Ultrastructural localization of interferon-producing cells in the livers of patients with chronic hepatitis B, Cells expressing alpha- and gamma-interferon were localized in the liver tissue of patients with chronic hepatitis B by means of light and electron microscopy using monoclonal antibodies. Interferon-positive cells were regularly seen in the infiltrating mononuclear cells. and the number showed a good correlation with the degree of the necroinflammatory activity of the disease. In chronic persistent hepatitis and in normal livers. they were infrequent or virtually absent. alpha-Interferon was shown to be positive in lymphocytes. polymorphonuclear leukocytes and fibroblasts. Kupffer cells and. weakly. in the cytoplasm of a few hepatocytes in cases of active hepatitis. whereas gamma-interferon was demonstrated only in lymphocytes. The expression of human leukocyte class I antigens on hepatocytes showed a close association with the number of interferon-producing cells. but not with the presence of virus particles and HBcAg in liver cells. when studied using electron microscopy and double-labeling. Interferon seems to be an important regulator of the local immune response in the liver in patients with chronic hepatitis B. Its functions may play a role in inducing the human leukocyte class I antigen expression on hepatocytes. thus enhancing the elimination of virus-containing hepatocytes by major histocompatibility complex-restricted cytotoxic lymphocytes.
Swedish Agency for Research Cooperation with Developing Countries. Prospects for public health benefits in developing countries from new vaccines against enteric infections, The symposium participants concluded that vaccines with even moderate efficacy can be highly useful to prevent large numbers of severe illness episodes and deaths and that the decision of whether to initiate a vaccine program should be based on measures or estimates of public health effectiveness rather than only on protective efficacy. Studies of protective efficacy are of course critical to establish the vaccine's biologic activity. but additional aspects of public health effectiveness are also crucial in making these decisions. First-generation vaccines are available against typhoid. cholera. and soon rotavirus diarrhea. and vaccines against enterotoxigenic E. coli diarrhea and shigellosis are under development. The problems related to enteric diseases are enormous; the vaccines may soon be produced at low cost and promise to be relatively more easy to distribute than most previous vaccines. The number of illnesses and deaths averted from vaccine programs are potentially great. Pilot programs using the new vaccines should urgently be considered in areas where the disease burden is high. and steps should be taken to monitor effectiveness of the intervention in these programs. Such studies of vaccine effectiveness and costs in a "real world" situation are an essential step of the research process and should be used to guide the organization of larger-scale programs. Finally. many of the necessary research and development activities relevant to public health vaccinology must address country-specific problems. Developing countries should consider the role of vaccine-related research among the priorities for their essential national health research and build the necessary capabilities in applied and basic medical sciences and in the social sciences.
Detection of Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid by inhibition ELISA and its diagnostic potential in tuberculous meningitis, Inhibition ELISA was used to quantitate Mycobacterium tuberculosis antigen 5 in cerebrospinal fluid (CSF) specimens of 40 patients with a clinical diagnosis of tuberculous meningitis. In all 10 culture-proven patients. the assay was positive; in 30 culture-negative patients. the assay yielded positive results for 21. CSF antigen 5 concentrations ranged from 9 to 82 ng/ml (mean +/- SD. 45.5 +/- 6.2). In 40 patients with nontuberculous neurologic diseases. mean concentration was 1.45 ng/ml. Thus. inhibition ELISA for the detection of M. tuberculosis antigen 5 in CSF has definite diagnostic potential during the active phase of the disease and should be a routine diagnostic test. particularly when bacteriologic cultures in CSF are negative for M. tuberculosis.
New serologic tests for early detection of coccidioidomycosis, Arizona college students suspected of having recently acquired coccidioidomycosis were tested for anticoccidioidal antibodies and circulating fungal antigens using conventional antibody detection methods and new ELISA procedures. Of 233 patients with compatible symptoms. 26 had anticoccidioidal antibodies detected by conventional tests. ELISA detected antibodies in sera from 20 of these patients and also from another 25 patients. Patients with antibodies detected by either conventional or ELISA procedures were significantly more likely to have abnormal chest radiographs. elevated erythrocyte sedimentation rates. or absent upper respiratory symptoms than were other patients. Circulating antigen was found in sera from 35 patients. 33 of whom had no detectable anticoccidioidal antibodies at that time. Detectable antigen was noted frequently in sera obtained within the first month after the onset of symptoms and was infrequently detected later when more patients exhibited antibodies. These results indicate the feasibility of developing ELISA procedures using spherule-derived antigens for earlier detection of coccidioidal infections.
Assessment of hypothalamic-pituitary function in patients with familial amyloidotic polyneuropathy, This study was performed to evaluate hypothalamic-pituitary hormone regulation in patients with familial amyloidotic polyneuropathy. Twenty-two patients without clinically overt endocrinological dysfunction were studied. A thyrotropin-releasing hormone test revealed abnormal growth hormone regulation in 9 of 17 (53%) patients. and abnormal prolactin regulation in 9 of 18 (50%) patients. Abnormalities in either growth hormone or prolactin regulation were found in 12 of 17 (71%) patients. Serum somatomedin C levels were normal in all 22 patients. In 3 of 18 (17%) patients the plasma arginine vasopressin levels were low relative to the serum osmolality levels. Thus abnormalities in hypothalamic-pituitary hormone regulation may be common in familial amyloidotic polyneuropathy.
Rhythmic bacterial susceptibility to antibiotics at a large hospital, The in vitro susceptibility response of Staphylococcus aureus. Klebsiella pneumoniae. Escherichia coli. Proteus mirabilis and Pseudomonas aeruginosa to a set of antibiotics was investigated in a survey comprising 19.380 positive cultures over a period of 5 years in a large hospital environment. Four out of the five species (P. aeruginosa being the exception) presented a species-specific. drug-independent. rhythmic variation of their level of susceptibility to several antibiotics over the time of the study. The species-specific rhythmic responses were further characterized by spectral analysis. autocorrelation and cross-correlation functions. Through this analysis it was possible to rank the species according to their main period of oscillation. The longest period of oscillation was detected for S. aureus (38 months). K. pneumoniae and E. coli presented intermediate values (25 and 23 months respectively). and P. mirabilis the shortest period of oscillation (11 months). Species displaying long periods of oscillation tended to present very low levels of susceptibility. while species displaying short periods of oscillation usually presented the highest levels of susceptibility observed. Although some hospital environmental factors. such as drug consumption. were also analyzed. no correlation was found between them and the in vitro bacterial cyclic responses to antibiotics.
The benefit to cost ratio of work-site blood pressure control programs, Reduction in the cost of health care claims among hypertensive employees was examined over a 4-year period after exposure to a 3-year blood pressure control program. to see whether work-site monitoring and counseling produced a subsequent benefit. Hypertensive employees at three experimental sites (N = 183 to 367 subjects) were compared with subjects at a control site (N = 169) who had received no postscreening follow-up or monitoring. and with matched normotensive employees. The cost of subsequent health care claims for hypertensive employees at the experimental sites was lower than claims for those at the control site. but there was no significant difference across the sites in claims for normotensive employees. After adjusting to a standard 1982 dollar. the data showed from $1.89 to $2.72 in reduced health care claims per dollar spent operating the hypertension control program.
Dengue epidemic--Peru, 1990, From March to July 1990. an epidemic of classical dengue caused by dengue types 1 and 4 (DEN-1 and DEN-4) occurred in Iquitos and the surrounding area of the department of Loreto in the Amazon region of Peru (Figure 1). A smaller outbreak was reported in Tarapoto in the neighboring department of San Martin. Although cases were reported in Peru during 1953-1955 and in 1958 (1). the epidemic in 1990 was the first laboratory confirmation of indigenous transmission of dengue in Peru. This report summarizes the preliminary findings of the epidemiologic investigation by the Peruvian Ministry of Health (MOH) and the U.S. Naval Medical Research Institute Detachment (NAMRID). Lima. Peru. which conducted special studies and laboratory confirmation of cases in persons seen at the Peruvian Naval Medical Center. Iquitos. Peru.
Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q, Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterized by an early age of onset. usually before 25 years of age. and an autosomal dominant mode of inheritance. The largest and best-studied MODY pedigree is the RW family. The majority of the diabetic subjects in this pedigree has a reduced and delayed insulin-secretory response to glucose. and it has been proposed that this abnormal response is the manifestation of the basic genetic defect that leads to diabetes. Using DNA from members of the RW family. we tested more than 75 DNA markers for linkage with MODY. A DNA polymorphism in the adenosine deaminase gene (ADA) on the long arm of chromosome 20 was found to cosegregate with MODY. The maximum logarithm of odds (lod score) for linkage between MODY and ADA was 5.25 at a recombination fraction of 0.00. These results indicate that the odds are greater than 178.000:1 that the gene responsible for MODY in this family is tightly linked to the ADA gene on chromosome 20q.
Report of an expert panel on the Public Health Laboratory role in early intervention and treatment of human immunodeficiency virus infections, A coordinated national effort to control the HIV epidemic based on an early intervention model must be initiated. This national strategy will provide for an effective distribution. application. and utilization of limited Federal. State. and local resources.
Consequences of the nuclear power plant accident at Chernobyl [published erratum appears in Public Health Rep 1991 May-Jun;106(3):352, The Chernobyl Nuclear Power Plant accident. in the Ukrainian Soviet Socialist Republic (SSR). on April 26. 1986. was the first major nuclear power plant accident that resulted in a large-scale fire and subsequent explosions. immediate and delayed deaths of plant operators and emergency service workers. and the radioactive contamination of a significant land area. The release of radioactive material. over a 10-day period. resulted in millions of Soviets. and other Europeans. being exposed to measurable levels of radioactive fallout. Because of the effects of wind and rain. the radioactive nuclide fallout distribution patterns are not well defined. though they appear to be focused in three contiguous Soviet Republics: the Ukrainian SSR. the Byelorussian SSR. and the Russian Soviet Federated Socialist Republic. Further. because of the many radioactive nuclides (krypton. xenon. cesium. iodine. strontium. plutonium) released by the prolonged fires at Chernobyl. the long-term medical. psychological. social. and economic effects will require careful and prolonged study. Specifically. studies on the medical (leukemia. cancers. thyroid disease) and psychological (reactive depressions. post-traumatic stress disorders. family disorganization) consequences of continued low dose radiation exposure in the affected villages and towns need to be conducted so that a coherent. comprehensive. community-oriented plan may evolve that will not cause those already affected any additional harm and confusion.
Cancer mortality in Cuba and among the Cuban-born in the United States: 1979-81, The Cuban-born population of the United States. enumerated at 608.000 in the 1980 census. has been little studied with regard to cancer mortality. Being older and rarely migrating back to Cuba. Cuban Americans present a good subject for comparative cancer mortality. Age-adjusted death rates for selected causes of cancer are compared in this paper for Cubans in Cuba. the Cuban-born in the United States. and all whites in the United States. Two forms of cancer have been of particular concern in Cuba. cancer of the lung and cancer of the prostate. because of their relatively high death rates. The age-adjusted death rates for both of these cancers are lower among the Cuban-born in the United States than they are among Cubans in Cuba and whites in the United States. Death rates for cancer of the cervix and cancer of the rectum among the Cuban-born in this country are also low relative to Cubans in Cuba and whites in the United States. Stomach cancer mortality among Cuban-born men in the United States is lower than for men in Cuba or for white men in the United States. but Cuban-born women in this country have rates that are slightly higher than those of U.S white women. Mortality rates from colon cancer in both sexes and breast cancer among women are intermediate between the lower rates in Cuba and the higher rates among U.S. whites. Finally. the Cuban-born in the United States have higher death rates from cancer of the liver than do Cubans in Cuba or whites in the United States.
Use of process evaluation to guide health education in Forsyth County's project to prevent cervical cancer, The Forsyth County. NC. Cervical Cancer Prevention Project is a 5-year public health education program designed to increase the proportion of black women in the county who are appropriately screened for cervical cancer. In this paper. the authors report on process evaluation--the procedures used to monitor the intervention and to insure that the target population was reached with a high quality. community-based health education program. A system that encompasses documentation of program activities. interviews with women in waiting rooms of primary care providers. semiannual interviews with a panel of approximately 100 women from the target population. and telephone followup with participants in direct education workshops was designed and implemented. Through October 1990. more than 2.100 interviews had been conducted. Data from these activities have facilitated continued development and refinement of educational materials. provided guidance for developing new strategies for reaching the target population. and provided continuous feedback to program managers to allow monitoring the impact of all program activities.
Home blood pressure monitoring for mild hypertensives, A clinical trial of 204 untreated patients with mild hypertension was conducted to assess the effect of home blood pressure monitoring on blood pressure level. pharmacologic treatment. reduction of risk factors. and use of health services. After 1 year. no statistically significant differences were found between the treatment and control groups. The findings indicate that. while home blood pressure monitoring may be useful. it has no measurable short-term impact on these aspects of blood pressure management for patients with mild hypertension.
The surveillance of communicable disease in Vermont: who reports, The Vermont Department of Health reviewed 2.035 reports of selected notifiable diseases received from January 1. 1986. through December 31. 1987. Laboratories provided 1.160. or 71 percent. of the initial reports on 1.636 confirmed cases. This demonstrates that laboratories. when required by law and when part of active surveillance. can make a significant contribution to surveillance of infectious disease. A survey of primary care physicians indicated that 18 percent always reported notifiable diseases. The most frequently mentioned reason for lack of reporting was an assumption that the laboratory would report the cases.
Ossification of the cervical ligamentum flavum, A case of a 61-year-old man with ossification of the cervical ligamentum flavum is reported. The ossification was located on the left side of C3-4. The symptoms improved with laminectomy and resection. Ossification of the ligamentum flavum usually occurs in the lower thoracic spine. and is rare in the cervical region. Including the present one. only eight cases have been reported to our knowledge. The clinical features and pathogenesis are discussed.
Reliable confirmation and quantitation of human immunodeficiency virus type 1 antibody using a recombinant-antigen immunoblot assay, The recombinant DNA-derived. human immunodeficiency virus (HIV) antigen-based immunoblot assay (RIBA-HIV216) is a new supplemental (confirmatory) test developed to detect antibodies to HIV-1. The assay employs four recombinant viral antigens. corresponding to HIV-1 p24. p31. p41 and gp120 proteins. in an immunoblot format. With this assay. HIV-1 antigen reactivity was detected in all 683 infected patient serum or plasma specimens evaluated; 665 (97.6%) of these sera met the criteria for a positive interpretation. and 18 (2.6%) were classified as indeterminate. All 683 samples reacted with the recombinant gp41-equivalent protein. The first sequential enzyme immunoassay (EIA)-reactive samples collected from 33 seroconverting homosexual men reacted on RIBA-HIV216. Eleven (1.1%) of 999 EIA-negative blood donor sera reacted weakly with a single recombinant antigen (p24 or p31). whereas 13 to 48 percent had indeterminate reactions on viral lysate Western blots. One (1.5%) of 66 EIA-positive. Western blot-negative blood donor samples and 19 (29%) of 66 EIA-positive. Western blot-indeterminate blood donor samples scored indeterminate on RIBA-HIV216. Nonspecific reactivity was seen with only 1 (0.8%) of 114 patient sera containing possible interfering antibodies. whereas 33 percent of these samples had indeterminate reactions on Western blot and 35 percent had equivocal reactions on immunofluorescence assay (IFA). We conclude that the RIBA-HIV216 is approximately as sensitive as and significantly more specific than virus-derived Western blot and IFA. The RIBA-HIV216 also allows for semiquantitation of specific antibodies that may be of value in clinical staging and therapeutic monitoring.
Genomic variability in field populations of Schistosoma mansoni in Brazil as detected with a ribosomal gene probe, A cloned fragment of the ribosomal gene of Schistosoma mansoni. pSM 389. which contains part of the small rRNA gene plus a portion of the nontranscribed intergenic spacer. was used in Southern hybridization analyses to investigate genomic variation in natural populations of S. mansoni in Brazil. Genomic DNAs were isolated from schistosomes from infected patients (some of whom did not respond to antischistosomal chemotherapy). and from snails from disparate geographic locations in Brazil. Restriction fragment length polymorphisms (RFLPs) were evident in Southern blot hybridizations of these schistosome DNAs. and the RFLPs indicated that the genomic profiles of a number of Brazilian strains were more similar to each other than they were to parasites from two laboratory reference strains of Puerto Rican origin. In addition. the Brazilian isolates could generally be separated from each other based on these RFLPs. Isolates from the southeastern state of Minas Gerais were more similar to each other than they were to parasites isolated in the northeastern states of Alagoas and Pernambuco. Variation was evident among individual worms from some of the isolates. and these individual variations contributed to the complex RFLP patterns that were characteristic for particular isolates. The variation within a natural population isolated directly from snails at Ressaca. Belo Horizonte. may be more marked than that exhibited by more established strains maintained in the laboratory for numerous generations.
Common T-cell receptor V beta usage in oligoclonal T lymphocytes derived from cerebrospinal fluid and blood of patients with multiple sclerosis, T-cell populations were investigated in the blood and cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. Individual T cells were directly cloned from the cerebrospinal fluid and blood before in vitro expansion. and their clonotypes were compared by Southern blot analysis of the rearrangement patterns of their T-cell receptor beta chain and gamma chain genes. This allowed the determination of whether two T cell clones shared the same T-cell receptor and thus arose from identical. clonally expanded (oligoclonal) progenitor T cells. As an extension of previous studies. oligoclonal T-cell clones were identified in both cerebrospinal fluid and blood populations in 5 of 9 patients with inflammatory demyelinating disease among a total of 486 blood and cerebrospinal fluid T-cell clones. In contrast. no clonally expanded T-cell populations were found among a total of 424 clones derived from either blood of 4 normal control subjects or blood and cerebrospinal fluid of 8 patients with other neurological diseases. Analysis of T-cell receptor V beta genes among 4 oligoclonal T-cell populations derived from 3 patients with multiple sclerosis demonstrated common usage of the V beta 12 gene segment. These data suggest that oligoclonal T cells share similar specificities and that clonal expansion may have resulted from specific stimulation by an antigen. Moreover. identical clones between blood and cerebrospinal fluid were observed in 3 of 9 patients with demyelinating disease. thus providing further evidence of an equilibrium between peripheral and central nervous system immune compartments.
Local cerebral glucose utilization in rats with petit mal-like seizures, The quantitative 2-[14C]deoxyglucose autoradiographic method was applied to the measurement of local cerebral metabolic rates for glucose in a model of genetic petit mal-like seizures in a strain of Wistar rats. During the experimental period. epileptic rats exhibited synchronous spike-and-wave discharges recorded from the cerebral cortex. whereas the electroencephalographic pattern of control animals was normal. An overall consistent increase in local cerebral metabolic rates for glucose was observed in epileptic rats as compared to nonepileptic control rats. This increase was statistically significant in 52 of the 59 cerebral structures studied and concerned all cerebral functional systems. These results are in accordance with positron emission tomography measurements in humans with typical childhood absence epilepsy. There is a lack of anatomical correlation between areas demonstrating hypermetabolism and areas where spike-and-wave discharges are recorded. Thus. the diffuse increase in cerebral energy metabolism in epileptic rats as compared to controls is not directly related to the occurrence of spike and wave discharges.
Atrial natriuretic factor and postnatal diuresis in respiratory distress syndrome, To find out if atrial natriuretic factor plays a part in the control of urine output during the initiation alone or throughout postnatal diuresis in neonates with respiratory distress syndrome. atrial natriuretic factor concentrations and clinical and renal variables were measured prospectively three times during the first three days of life in 13 premature infants. Atrial natriuretic factor concentrations rose significantly between the first and second sample times as did the urine output and output:input ratio. By the time that the third sample was taken. atrial natriuretic factor concentration had decreased significantly since the second sample had been taken. while urine flow was maintained. All subjects initiated a spontaneous diuresis that was related to the second concentration of atrial natriuretic factor. With partial correlation analysis a significant relationship was shown between the concentration of atrial natriuretic factor and the maintenance of urine output throughout the study period. Individual hormone concentrations did not. however. correlate with simultaneous renal variables. Changes in the concentrations of atrial natriuretic factor coincided with initiation of spontaneous diuresis in babies with respiratory distress syndrome. and may have a role in the complex mechanisms that maintain this diuresis.
Interhospital transfer of a patient undergoing extracorporeal carbon dioxide removal, Extracorporeal circulation techniques are being used increasingly in patients with acute cardiac or pulmonary failure. Some of these patients may subsequently require transportation. which has limited the use of these techniques in hospitals without on site transplantation facilities. We report a case of adult respiratory distress syndrome that demonstrates a solution to this problem.
The impact of breast cancer on sexuality, body image, and intimate relationships, For women. breast cancer remains a common and dreaded experience. It is normal for a diagnosis of breast cancer to evoke grief. anger. and intense fear. Most women. however. face this crisis and master it without developing major psychiatric disorders or severe sexual dysfunction. The options of breast conservation and reconstruction give women a new sense of control over their treatment and are quite successful in helping women feel comfortable with their bodies again. The effectiveness of breast conservation and reconstruction in preventing or ameliorating sexual problems after breast cancer diagnosis is less clear. however. Any impact these options have on sexuality is subtle and may relate more to a woman's feelings of being desirable than to how often she has sex. her lovemaking practices. or how much she enjoys sex. We need more information on how chemotherapy and hormonal therapy affect women's sex lives. As clinicians. we should pay more attention to our patients' complaints of vaginal pain. dryness. and overall loss of sexual desire during systemic treatment. Practical advice on lovemaking techniques and a clinician's open attitude towards discussing sexual issues can prevent a great deal of anxiety and sadness as women with breast cancer search for ways to keep their sex lives satisfying.
Effect of sinorphan, an enkephalinase inhibitor, on plasma atrial natriuretic factor and sodium urinary excretion in cirrhotic patients with ascites, We examined the acute effects of sinorphan. an inhibitor of enkephalinase. on plasma atrial natriuretic factor (ANF) and urinary sodium excretion in cirrhotic patients with ascites. A single oral dose of sinorphan (100 or 30 mg in 11 and 5 patients. respectively) was administered against placebo according to a double blind cross-over protocol. Basal plasma ANF levels varied over a large range between 2.6-79 pmol/L. Sinorphan. at a dose of 100 mg. inhibited 70% of plasma enkephalinase activity 60 min after ingestion and elicited simultaneously an increase in plasma ANF and cGMP levels 1.8 and 1.5 times basal values. respectively. There was a transient increase in sodium urinary output without a change in creatinine clearance over the initial 2-h period following drug administration. An increase in urinary cGMP was also observed on a longer period of 6 h. Plasma aldosterone decreased significantly. but the lowest concentration was reached 1 h later than the peak of plasma ANF. Mean blood pressure and PRA were unmodified. The effects of 30 mg sinorphan on plasma ANF. cGMP. and aldosterone were also significant. but less marked than those of the higher dose. Therefore. enkephalinase inhibition transiently increases sodium urinary excretion in cirrhotic patients with ascites via a mechanism that is likely to imply reduction of ANF catabolism. These results suggest that ANF could play a role in the control of sodium homeostasis in liver cirrhosis with ascites.
Evaluation of Clinitek 200 and Rapimat II/T for screening for urinary tract infection, Two machines. the Clinitek 200 and the Rapimat II/T. were evaluated for their ability to screen urine samples for significant bacteriuria and other elements indicative of urinary tract pathology. The automated screening procedures were compared with a conventional approach of microscopy and quantitative culture for 1020 urine specimens obtained from patients in a 700 bed general hospital. When compared with the bacterial culture method both machines gave identical results with a negative predictive value of 0.99. while when compared with microscopy alone the Clinitek 200 and Rapimat II/T gave negative predictive values of 0.92 and 0.87. respectively. It is concluded that both machines would provide cost effective screening of urine specimens.
Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors, Insulin resistance and hyperinsulinaemia may play an important role in both the development of hypertension and its accompanying metabolic aberrations. In order to investigate this possibility. nine non-obese. non-diabetic. non-smoking. middle-aged men with untreated hypertension were treated with metformin 850 mg b.i.d. for 6 weeks as a pilot study and within-patient comparison. Metformin decreased total and LDL-cholesterol (P less than 0.01). triglyceride (P less than 0.01). fasting plasma insulin (P less than 0.01) and C-peptide levels (P less than 0.02). Glucose disposal. an indicator of insulin action measured by means of the euglycaemic clamp technique. increased (P less than 0.001). Tissue plasminogen activator (t-PA) activity increased (P less than 0.02). and t-PA antigen decreased (P less than 0.01). whereas plasminogen activator inhibitor (PAI-1) and fibrinogen were unaffected by metformin treatment. Body weight remained unchanged. Withdrawal of metformin was associated with the return of both blood pressure and metabolism towards the initial levels. In conclusion. metformin treatment increased insulin action. lowered blood pressure. improved the metabolic risk factor profile and tended to increase the fibrinolytic activity in these mildly hypertensive subjects. These results support the view that insulin resistance plays a role in hypertension. and may open up a new field for the alleviation of abnormalities associated with cardiovascular disease.
Chronic pain and substance abuse: a pilot study of opioid maintenance, Recent reports suggest that opioid maintenance may be appropriate for treatment-resistant patients with chronic nonmalignant pain syndromes. However. a history of substance abuse is thought to be a contraindication for such treatment. We present a pilot study of a methadone maintenance-type treatment for patients with both chronic pain and substance abuse. evaluating the ability to attract and hold patients. the methodology for assessing change. and the potential problems and pitfalls. Weekly random urinalysis. weekly psychotherapy. and quarterly self-report tests of pain. mood. and function were used to evaluate change. Three out of 4 patients remained in treatment for 19-21 months. stopped needle use. and/or markedly decreased substance abuse. and appear to have improved functionally. Surprisingly. all 3 patients had significant psychopathology requiring treatment with psychotropic medication. This treatment may warrant further research.
Lead poisoning among bricklayers--Washington State, In May 1989. four members of an 11-man crew of bricklayers in western Washington state developed symptomatic lead poisoning while replacing the brick lining of an acid-accumulation tank at a paper mill. Peak blood lead levels (BLLs) for the four workers ranged from 88 to 123 micrograms/dL. An investigation indicated the source of the lead exposure was a special brick mortar that contained 71% lead oxide and was formulated to resist the normally acidic environment of the tank.
Control of excessive lead exposure in radiator repair workers, In 1988. 83 automotive repair workers with blood lead levels (BLLs) greater than 25 micrograms/dL were reported to state health departments in the seven states that collaborated with CDC's National Institute for Occupational Safety and Health (NIOSH) in maintaining registries of elevated BLLs in adults. In 18 (22%) of these 83 persons. BLLs were greater than 50 micrograms/dL. Among automotive repair workers for whom a job category was specified. radiator repair work was the principal source of lead exposure. The major sources of exposure for radiator repair workers are lead fumes generated during soldering and lead dust produced during radiator cleaning. This report summarizes current BLL surveillance data for radiator repair workers and describes three control technologies that are effective in reducing lead exposures in radiator repair shops.
Active HSV-1 immunization prevents the cocarcinogenic activity of HSV-1 in the oral cavity of hamsters, Previous investigations have demonstrated that herpes simplex virus (HSV) increased the oral carcinogenic activity of 7.12-dimethylbenz[a]anthracene (DMBA) probably by enhancing the DMBA-induced amplification and overexpression of c-erb-B-1 proto-oncogene in hamster buccal pouch epithelium. The present study investigated the effect of active type 1 HSV (HSV-1) immunization on the development of oral cancer induced by HSV-1 and DMBA. alone or in combination. in the hamster buccal pouch. The results were similar to our previous report in that HSV-1 significantly enhanced the oncogenic effect of DMBA. and the numbers of pouches harboring tumor nodules and the numbers and sizes of tumors developed by topical DMBA were significantly increased by HSV-1 inoculation to the site of the DMBA application. Although HSV-1 immunization did not alter the carcinogenic activity of DMBA in animals receiving topical DMBA in combination with mock inoculation. it prevented the cocarcinogenic effect of HSV-1 in animals receiving topical DMBA in conjunction with HSV-1 inoculation. These data indicate that active HSV-1 immunization completely obstructs the co-oncogenic effect of HSV-1 in the oral cavity of hamsters.
Pericardial effusion after intravenous recombinant tissue-type plasminogen activator for acute myocardial infarction, The effect of thrombolytic therapy on the frequency. time course and sequelae of pericardial effusion after myocardial infarction are unknown. A prospective. serial. 2-dimensional echocardiographic study of patients with myocardial infarction who received recombinant tissue-type plasminogen activator (rt-PA) was undertaken to address this issue. The study population comprised 52 of the 112 patients enrolled in the first Thrombolysis and Angioplasty in Myocardial Infarction trial at Duke University Medical Center. Enrollment in the serial echocardiography protocol was determined by equipment and support staff availability. Complete echocardiographic studies were performed within 90 minutes after initiation of thrombolytic therapy (day 0). and on days 1. 3 and 6. Patients undergoing serial echocardiography did not differ in demographic or clinical characteristics from those who did not. Pericardial effusion was present in 3 of 38 patients (8%) at day 0. in 2 of 44 (5%) at day 1. in 8 of 43 (19%) at day 3. and in 10 of 42 (24%) at day 6. By day 6. 3 of 10 pericardial effusions were moderate in size. 1 of 10 was large and the remainder were small. No patients developed echocardiographic or hemodynamic signs of cardiac tamponade. The prevalence and time course of pericardial effusion among patients with acute myocardial infarction who received rt-PA in this study are similar to observations reported in earlier studies in which patients did not receive thrombolytic therapy. Adverse sequelae of pericardial effusion after thrombolytic therapy are rare.
Lack of gastric acid rebound after stopping a successful short-term course of nizatidine in duodenal ulcer patients, To assess whether there is rebound of gastric acidity after a short-term course of H2-receptor antagonists. we performed a 24-h in situ pH monitoring on 17 duodenal ulcer patients before. during. and after completing 4 wks' treatment with nizatidine 300 mg at bedtime (2200 h). Three around-the-clock continuous intragastric pH-metries were carried out the day before beginning treatment. at the end of the nizatidine course. and 67 h after the last dose of the drug was given. Nizatidine produced mean pH values that were significantly higher (p less than 0.001) than those of the pretreatment profile during both the whole 24-h period and the nighttime (2400-0759). and this confirms that it effectively inhibited gastric acidity. Conversely. there was no significant difference between the acidity indexes of pH profiles obtained before dosing and after discontinuing treatment in any of the time intervals considered. Therefore. it appears that a short term course of nizatidine therapy does not cause rebound hyperacidity in duodenal ulcer patients.
IgA antigliadin antibodies, cellobiose/mannitol sugar test, and carotenemia in the diagnosis of and screening for celiac disease, Serum IgA antigliadin antibodies (IgAAGA) assay. cellobiose/mannitol sugar permeability test (ST). and carotenemia were evaluated prospectively as diagnostic tests in 60 consecutive adult patients with suspected celiac disease (CD). CD was confirmed histologically in 26 patients. IgAAGA. ST. and carotenemia had a sensitivity of 65.4%. 96.2%. and 76.9%. a specificity of 97.1%. 73.5%. and 70.6%. and positive likelihood ratio of 22.2. 3.6. and 2.6. respectively. Multivariate logistic regression showed that IgAAGA and ST had a sensitivity and specificity of 96.2% and 70.6% and a positive likelihood ratio of 47.3 if both were positive. Assuming a prevalence of CD of 1:2000 in the general population. for every 89 positive IgAAGA and 549 altered ST there would be one celiac patient. whereas. if both tests were positive. the patient was certain to have CD. We conclude that. of the tests studied. IgAAGA and ST are respectively the most specific and the most sensitive and that. used together. they can diagnose CD.
A case of gastric plasmacytoma: genetic analysis and immunofixation electrophoresis, A case of early gastric plasmacytoma in a 66-yr-old woman is reported. The demonstration of monotypic IgM lambda immunoglobulin in plasma cells infiltrating the gastric antrum contributed the histological diagnosis. Genetic analysis of the tumor cells confirmed the presence of a monoclonal neoplastic population of plasma cells in the tumor. Monoclonal immunoglobulin (IgM lambda) was demonstrated in serum. not by conventional immunoelectrophoresis. but by a highly sensitive immunofixation electrophoresis technique. Serum monoclonal immunoglobulin disappeared after subtotal gastrectomy. The value of immunofixation electrophoresis of serum protein and DNA analysis of tumor cells was emphasized for the diagnosis of gastric plasmacytoma.
Comparative in vitro activity of a new quinolone, fleroxacin, against respiratory pathogens from patients with cystic fibrosis, We evaluated fleroxacin. a newer fluoroquinolone. against isolates from sputum from patients with cystic fibrosis. These isolates included rough and mucoid Pseudomonas aeruginosa. Pseudomonas cepacia. Staphylococcus aureus. Haemophilus influenzae. and Escherichia coli. Selected isolates were tested by the broth microdilution method to examine the influence of various pHs. inoculum sizes. and biological fluids (serum or sputum from patients with cystic fibrosis). Fleroxacin MICs for 50 and 90% of isolates of P. aeruginosa were 2.0 and 4 micrograms/ml. those for P. cepacia were 2 and 16 micrograms/ml. those for S. aureus were 0.5 and 1 microgram/ml. those for H. influenzae were 0.06 and 0.06 micrograms/ml. and those for E. coli were 0.01 and 0.03 micrograms/ml. respectively. Fleroxacin activity against mucoid P. aeruginosa was similar to the activities of enoxacin and ofloxacin but eightfold lower than that of ciprofloxacin. It was twofold more active than norfloxacin and enoxacin but was twofold less active than ciprofloxacin. ofloxacin. and nafcillin against S. aureus. Fleroxacin inhibitory activity against P. cepacia was two- to fourfold lower than that of ciprofloxacin but eightfold greater than those of the other quinolones tested. Alterations in pH. diluent. and inoculum size did not significantly affect fleroxacin activity. These results. combined with available pharmacokinetic and tissue distribution data. support the need for clinical evaluation of fleroxacin in pulmonary infections in patients with cystic fibrosis.
Mitomycin C as an adjuvant treatment to resected gastric cancer. A 10-year follow-up, Seventy consecutive patients were entered in a two-arm randomized trial after surgical resection for locally advanced gastric cancer. In the first arm. 37 patients were included as a control group. receiving no further treatment after surgery. In the second arm. 33 patients were treated with adjuvant chemotherapy consisting of mitomycin C (MMC). 20 mg/m2 administered intravenously once every 6 weeks for four consecutive cycles. All patients in both arms were followed in the same way for 5 years. At 5 years 23 of 37 patients in the control arm and 7 of 33 patients in the treatment arm were dead because of relapse. Actuarial survival curve was statistically significant in favor of patients given adjuvant MMC (p less than 0.001). After 10 years follow-up. 31 of 37 patients in the control arm and 16 out of 33 patients in the treatment arm were dead because of relapse. the statistical differences continuing in the actuarial survival curve in favor of treated patients (p less than 0.01). The best advantages of adjuvant treatment were observed in the T3N0M0 stage. The most frequent relapse site was the peritoneal cavity and the relapse pattern shows special decrease in liver metastases in treated patients. Toxicity was acute and mild. No delayed toxicity or second malignancies were observed. These data suggest that adjuvant MMC after resected surgery of gastric cancer is a successful treatment and its effects are still evident after 10 years of follow-up.
Antiproliferative effects of cytokines on squamous cell carcinoma, A panel of 12 squamous cell carcinoma of the head and neck (SCCHN) cell lines has been used to determine sensitivity of tumor cells to cytokines. tumor necrosis factor alpha (TNF-alpha). interferon gamma (IFN-gamma). and interferon alfa (IFN-alpha) in vitro. Antiproliferative activity of these cytokines on squamous cell carcinoma of the head and neck monolayers was measured in a colorimetric MTT [3-(4.5-dimethylthiazol-2yl)-2.5-diphenyl tetrazolium bromide]-based assay. All 12 cell lines tested were sensitive to IFN-gamma. with the 50% inhibitory dose (ID50) ranging from 0.07 +/- 0.001 to 104 +/- 4.6 U/mL. The TNF-alpha showed antiproliferative activity on three cell lines at relatively high doses (ID50 from 55 +/- 4.1 to 847.10 +/- 10 U/mL). and IFN-alpha was growth inhibitory in only one line (ID50 = 1211 +/- 46.2 U/mL). The combination of IFN-gamma and TNF-alpha had a synergistic antiproliferative effect on eight cell lines and an additive effect on two cell lines. In two cell lines. the effect of the combination was equal to that of IFN-gamma alone. A combination of IFN-alpha and TNF-alpha resulted in cell growth inhibition in six of the seven lines tested. and this effect was synergistic. These in vitro studies indicate that combinations of IFN-gamma and TNF-alpha or IFN-alpha and TNF-alpha may be more growth inhibitory against squamous cell carcinoma of the head and neck and at lower doses than each of these cytokines used singly.
Predictors of chlamydial infection and gonorrhea among patients seen by private practitioners, OBJECTIVE: To identify the predictors of chlamydial infection and gonorrhea among patients tested by general practitioners. DESIGN: Prospective study. SETTING: General private practice. family planning and abortion clinic. adolescent clinic. sexually transmitted disease (STD) clinic and community health clinic in downtown Montreal. PATIENTS: The 2856 patients were included because of symptoms compatible with an STD. a history of sexual contact with a person known or suspected to have chlamydial infection. a history of a nonexclusive sexual relationship or presentation for an abortion. MEASURES: Patient information was obtained by the attending physician on a standard form. Enzyme immunoassay (EIA) for Chlamydia trachomatis and culture for Neisseria gonorrhoeae were performed on cervical (female) or urethral (male) samples. Stepwise logistic regression was used to identify the predictors of infection. RESULTS: The EIA results were positive in 11.1% of the cases and the culture results in 2.3%. Among the males chlamydial infection was independently associated with low age (odds ratio [OR] = 0.88 per year). heterosexuality (OR = 4.99). urethral discharge (OR = 3.74) and the absence of a history of gonorrhea (OR = 0.51). Gonorrhea was associated with urethral discharge (OR = 24.3) and homosexuality (OR = 3.68). Among the females chlamydial infection was associated with low age (OR = 0.79 per year). a history of sexual contact with a person known to have chlamydial infection (OR = 2.30). multiple sexual partners in the previous 12 months (OR = 1.60) and a reason for the test other than screening purposes (OR = 0.60). Gonorrhea was associated with a reason other than screening (OR = 0.24) and low age (OR = 0.74 per year). Among the patients tested for screening purposes age was the only significant predictor of chlamydial infection (OR = 0.79 per year). and the prevalence of gonorrhea was 0.4%. The actual rate of chlamydial infection was 11.8% among the patients younger than 25 years. 5.7% among those 25 to 34 years and 0.6% among those over 34. CONCLUSIONS: Age alone can be used as a criterion to screen for chlamydial infection among asymptomatic patients without a history of sexual contact with a person known or suspected to have such infection and with a history of a nonexclusive relationship. The prevalence in our population justifies screening people up to 34 years of age.
Influence of coronary collateral vessels on myocardial infarct size in humans. Results of phase I thrombolysis in myocardial infarction (TIMI) trial. The TIMI Investigators, BACKGROUND. The influence of coronary collateral vessels on infarct size in humans remains controversial. partly because no previous study has examined the impact of collaterals present at the onset of acute myocardial infarction on infarct size. METHODS AND RESULTS. The present study used the data base of the Thrombolysis in Myocardial Infarction (TIMI) Phase I trial to correlate the presence or absence of angiographically documented collaterals in the initial hours of myocardial infarct evolution with the size of the infarct as assessed by serial measurements of serum creatine kinase (CK). To avoid the confounding effects of reperfusion on enzymatic estimates of infarct size. this report is limited to those 125 patients who failed to recanalize at 90 minutes after administration of tissue plasminogen activator or streptokinase. Patients with angiographically documented collaterals (group A. n = 51) had significantly lower values of peak serum CK than patients without collaterals (group B. n = 74) (1.877 +/- 216 versus 2.661 +/- 212 IU/l. respectively [mean +/- SEM]. p = 0.004). Similarly. CK-derived infarct size estimates were significantly lower in group A than in group B (20.6 +/- 2.5 versus 31.4 +/- 2.8 CK gram equivalents. p = 0.001). The infarct size observed in patients with collaterals was less for anterior infarctions as well as for infarctions of other locations; thus. the beneficial effects of collaterals were independent of the site of the infarct. In 65 of the 125 patients who failed to reperfuse. left ventricular ejection fraction (LVEF) was assessed by contrast ventriculography both at initial cardiac catheterization (before thrombolytic therapy) and at hospital discharge. Among the patients who had both studies. global LVEF tended to increase from pretreatment to hospital discharge in group A (from 50.6 +/- 1.8% to 53.4 +/- 1.8%. p = 0.10) but decreased in group B patients (from 50.3 +/- 1.8% to 47.8 +/- 1.7%. p = 0.02). At hospital discharge. global LVEF was greater in patients with coronary collaterals (53.5 +/- 1.7% versus 49.6 +/- 1.7%. p = 0.01). CONCLUSIONS. The results demonstrate that. in patients in whom thrombolytic therapy fails to induce reperfusion. the presence of coronary collateral vessels at the onset of myocardial infarction is associated with limitation of infarct size as assessed enzymatically and with improved ventricular function on discharge as assessed by LVEF.
Noninvasive quantification of regional myocardial blood flow in coronary artery disease with oxygen-15-labeled carbon dioxide inhalation and positron emission tomography, BACKGROUND. Oxygen-15-labeled water is a diffusible. metabolically inert myocardial blood flow tracer with a short half-life (2 minutes) that can be used quantitatively with positron emission tomography (PET). The purpose of this study was to validate a new technique to quantify myocardial blood flow (MBF) in animals and to assess its application in patients. METHODS AND RESULTS. The technique involves the administration of 15O-labeled carbon dioxide (C15O2) and rapid dynamic scanning. Arterial and myocardial time activity curves were fitted to a single tissue compartment tracer kinetic model to estimate MBF in each myocardial region. Validation studies consisted of 52 simultaneous measurements of MBF with PET and gamma-labeled microspheres in nine closed-chest dogs over a flow range of 0.5-6.1 ml/g/min. A good correlation between the two methods was obtained (y = 0.36 + 1.0x. r = 0.91). Human studies consisted of 11 normal volunteers and eight patients with chronic stable angina and single-vessel disease. before and after intravenous dipyridamole infusion. In the normal group. MBF was homogeneous throughout the left ventricle both at rest and after administration of dipyridamole (0.88 +/- 0.08 ml/g/min and 3.52 +/- 1.12 ml/g/min. respectively; p less than or equal to 0.001). In patients. resting MBF was similar in the distribution of the normal and stenotic arteries (1.03 +/- 0.23 and 0.93 +/- 0.21 ml/g/min. respectively). After dipyridamole infusion. MBF in normally perfused areas increased to 2.86 +/- 0.83 ml/g/min. whereas in the regions supplied by stenotic arteries it increased to only 1.32 +/- 0.27 ml/g/min (p less than or equal to 0.001). CONCLUSIONS. PET with C15O2 inhalation provides an accurate noninvasive quantitative method for measuring regional myocardial blood flow in patients.
Increased thrombin levels during thrombolytic therapy in acute myocardial infarction. Relevance for the success of therapy, BACKGROUND. It has been suggested that thrombolysis in a feedback reaction may generate pro-coagulant activities. METHODS AND RESULTS. Fifty-five patients were treated with urokinase-preactivated prourokinase (n = 35) or tissue-type plasminogen activator (n = 20) for acute myocardial infarction and underwent coronary angiography at 90 minutes and at 24-36 hours into thrombolysis. and fibrinogen (Ratnoff-Menzie). D-dimer (ELISA) and thrombin-antithrombin III complex levels (ELISA) were measured. Primary patency was achieved in 39 patients (70.9%). 13 of whom (33.3%) suffered early reocclusion. Nonsignificant decreases in fibrinogen levels were observed while D-dimer levels increased +3.008 +/- 4.047 micrograms/l (p less than 0.01). differences not being significant in respect to the thrombolytic agents or to the clinical course. In contrast. while thrombin-antithrombin III complex levels decreased -4.4 +/- 13.0 micrograms/l in patients with persistent patency. they increased +7.5 +/- 13.6 micrograms/l in case of nonsuccessful thrombolysis (p less than 0.02) and +11.9 +/- 23.8 micrograms/l in case of early reocclusion (p less than 0.001). For patients with thrombin-antithrombin III complex levels greater than 6 ng/l 120 minutes into thrombolysis. the unfavorable clinical course was predicted with 96.2% sensitivity and 93.1% specificity. CONCLUSION. Generation of thrombin. occurring during thrombolysis. is a major determinant for the success of therapy and thrombin-antithrombin III levels may serve as predictors for the short-term prognosis.
Marked differences in immunocytological localization of [3H]estradiol-binding protein in rat pancreatic acinar tumor cells compared to normal acinar cells, [3H]Estradiol can bind to a specific protein in normal rat pancreatic acinar cells. Electron microscopic immunocytochemical analysis has shown this protein to be localized primarily in the rough endoplasmic reticulum and mitochondria. Rat exocrine pancreatic tumor cell lines. whether grown in tissue culture (AR42J) or as a tumor mass after sc injection into rats (DSL-2). lacked detectable amounts of this [3H]estradiol-binding protein (EBP). as determined by the dextran-coated charcoal assay. Furthermore. primary exocrine pancreatic neoplasms induced with the carcinogen azaserine contained little or no detectable [3H]estradiol-binding activity. However. electron immunocytochemical studies of transformed cells indicated the presence of material that cross-reacted with antibodies prepared against the [3H]EBP. The immunopositive reaction in transformed cells was localized almost exclusively in lipid granules. Such lipid organelles in normal acinar cells. although present less frequently than in transformed cells. have never been observed to contain EBP-like immunopositive material. Presumably. the aberrant localization of EBP in these acinar tumor cells results in loss of function of this protein. which in normal pancreatic acinar cells appears to exert a modulating influence on zymogen granule formation and the process of secretion.
Recombinant human alpha-interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France, We have conducted a multicenter randomized controlled trial comparing two doses of recombinant human alpha-interferon for efficacy in 60 patients with chronic non-A. non-B hepatitis. The source of infection appeared to be transfusion in 30 patients. intravenous drug abuse in 16 patients and was unknown in 14 patients. Patients were randomly assigned to no treatment or to treatment with either 1 or 3 MU of alpha-interferon given three times a week for 24 wk. Forty-five patients (75%) were positive for antibody to hepatitis C virus. During the 24-wk treatment period. mean serum ALT levels decreased in both treatment groups. but the decrease was statistically significant only in the 3 MU group. However. at 24 wk. the proportion of patients with normal ALT levels was similar in the 3 MU group (39%) and the 1 MU group (45%). and both were significantly higher than in controls (0%). Repeat liver biopsy specimens showed a significant decrease in the severity of histological changes in the 3 MU group but not in the 1 MU group or in controls. Responses to alpha-interferon did not correlate with patient's age. gender. source of infection. pretreatment serum ALT. presence of anti-hepatitis C virus or cirrhosis. After treatment. the mean ALT levels rose in both treated groups. The proportion of patients with normal ALT levels at wk 48 was 28% in the 3 MU group and 20% in the 1 MU group. In conclusion. a dose of 3 MU was superior to 1 MU of alpha-interferon given three times weekly for 24 wk in inducing improvements in serum ALT levels and liver histological examinations.
Altered density of glomerular binding sites for atrial natriuretic factor in bile duct-ligated rats with ascites, The renal response to atrial natriuretic factor is blunted in cirrhosis with ascites. This might be due to alterations of renal receptors for atrial natriuretic factor. Therefore density and affinity of glomerular atrial natriuretic factor binding sites of bile duct-ligated rats with ascites (n = 10) and of sham-operated controls (n = 10) were determined. Glomerular atrial natriuretic factor binding sites were identified to be of the B-("biologically active") and C-("clearance") receptor type. Discrimination and quantitative determination of B and C receptors for atrial natriuretic factor were achieved by displacement experiments with atrial natriuretic factor(99-126) or des(18-22)atrial natriuretic factor(4-23). an analogue binding to C receptors only. Density of total glomerular atrial natriuretic factor binding sites was significantly increased in bile duct-ligated rats (3.518 +/- 864 vs. 1.648 +/- 358 fmol/mg protein; p less than 0.05). This was due to a significant increase of C-receptor density (3.460 +/- 866 vs. 1.486 +/- 363 fmol/mg protein; p less than 0.05). whereas density of B receptors was not significantly different in bile duct-ligated rats (58 +/- 11 vs. 162 +/- 63 fmol/mg protein). Affinity of atrial natriuretic factor to its glomerular binding sites did not differ significantly between both groups. These data suggest that an altered glomerular atrial natriuretic factor receptor density could be involved in the renal resistance to atrial natriuretic factor in cirrhosis with ascites.
Chemical sympathectomy alters the development of hypertension in miniature swine, To determine if the neurotoxin 6-hydroxydopamine could be used to chemically sympathectomize neonatal miniature swine. eight newborn swine were treated with 6-hydroxydopamine beginning on the first day after birth and continuing at regular intervals for the next 6 months. Six littermates served as controls and received vehicle injections. A significant reduction in the pressor response to intravenous tyramine (95%) and in the tissue norepinephrine content of the kidneys. left ventricle. and gastrocnemius muscle (more than 93%) provided evidence for an effective long-term sympathectomy in the 6-hydroxydopamine-treated animals. In addition. the blood pressure response of these young. chemically sympathectomized swine to chronic deoxycorticosterone acetate treatment was evaluated. Mean arterial pressure before deoxycorticosterone was similar in the 6-hydroxydopamine-treated (116 +/- 2 mm Hg) and control (125 +/- 5 mm Hg) groups. One week after deoxycorticosterone. mean arterial pressure had risen significantly by 20-22 mm Hg in both groups. Blood pressure continued to increase in the control group. reaching a value of 163 +/- 6 mm Hg by the third week after treatment. In contrast. mean arterial pressure in the 6-hydroxydopamine group did not increase further during weeks 2 and 3 after deoxycorticosterone. In conclusion. chronic treatment of neonatal swine with 6-hydroxydopamine produced an animal model with an effective. general. peripheral sympathectomy. The significant attenuation of the hypertensive response in these sympathectomized animals lends further support to the hypothesis that an intact sympathetic nervous system is necessary for the full expression of deoxycorticosterone hypertension in miniature swine.
Temperature-sensitive tyrosinase associated with peripheral pigmentation in oculocutaneous albinism, Several types of autosomal recessive oculocutaneous albinism (OCA) are associated with abnormal tyrosinase function and a generalized reduction in or absence of cutaneous and eye melanin. Each is thought to result from a different mutant allele at the tyrosinase locus. with the mutation producing an enzyme with little or no activity in all involved tissues. In this paper. we report a new type of OCA that results from a tyrosinase allele producing a temperature-sensitive enzyme. The proband had white hair in the warmer areas (scalp and axilla) and progressively darker hair in the cooler areas (extremities) of her body. Melanocyte and melanosome architecture were normal. Quantitative hairbulb tyrosinase (dopa oxidase) assay demonstrated a loss of activity above 35-37 degrees C. Plasma pheomelanin and urine eumelanin intermediates were reduced and correlated with hair melanin content. This is the first temperature-sensitive tyrosinase mutation to be reported in humans and is analogous to the Siamese mutation in the cat and the Himalayan mutation in the mouse.
A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism. A human homologue to the Siamese cat and the Himalayan mouse, Type I oculocutaneous albinism (OCA) is an autosomal recessive disorder in which deficient synthesis of melanin pigment results from abnormal activity of melanocyte tyrosinase. A novel type I OCA phenotype in which hypopigmentation is related to local body temperature is associated with a missense substitution in tyrosinase. codon 422 CGG (Arg)----CAG (Gln). This substitution results in a tyrosinase polypeptide that is temperature-sensitive. This form of type I OCA thus is homologous to the temperature-related forms of albinism seen in the Siamese cat and the Himalayan mouse.
Effects of maternal diabetes on fetal rat lung ion transport. Contribution of alveolar and bronchiolar epithelial cells to Na+,K(+)-ATPase expression, Fetuses of streptozotocin-induced diabetic rats exhibited delayed lung maturation and a 40% reduction in the steady-state level of lung Na+.K(+)-ATPase alpha 1 subunit mRNA and Na+.K(+)-ATPase activity at 21 d of gestation. In in situ hybridization experiments the signal specific for Na(+)-pump alpha 1 subunit message was strongest above columnar epithelial cells of air-conducting structures. Strong labeling was also present above cuboidal cells lining the forming alveoli. but not above mesenchymal cells. Immunocytochemical localization of the protein paralleled the distribution of the mRNA. Mesenchymal cells were more abundant in fetal lungs of diabetic mothers. and thus the decreased overall levels of Na+.K(+)-ATPase may result from the observed morphological pulmonary immaturity. One day after birth there was no apparent difference in lung morphology at the light microscopic level. in the localization or the steady-state level of Na+.K(+)-ATPase alpha 1 isoform mRNA. or in enzyme activity. Na+.K(+)-ATPase has a likely role in the active phase of fluid absorption in the airways of newborns before the onset of breathing. Decreased fluid clearance and lack of thinning of the lung's connective tissue may contribute to the increased risk for respiratory distress in infants of diabetic mothers.
Increase in the expression of a family of small guanosine triphosphate-binding proteins, rab proteins, during induced phagocyte differentiation, Rab is a newly identified family of small G-proteins that share 35-70% homology with the yeast Sec4p and Ypt1p involved in the regulation of the secretory pathway. Mature phagocytes display functions requiring organized intracellular traffic and. for this reason. we questioned whether phagocyte differentiation could correlate with the increased expression of rab proteins. Rabbit antisera raised against the recombinant proteins rab1Ap. 2p. 4p. and 6p were able to detect the corresponding proteins in the human monoblast leukemic cell line U937. When these cells were induced to differentiate into monocyte/macrophage-like cells displaying functional characteristics of a normal phagocyte. rab1Ap. 2p. 4p. and 6p were increased and this correlated with an increase in the rab transcripts. Using a rab5 probe. we also observed an increased expression of the rab5 gene in differentiated cells. Similarly. differentiation of the human leukemic myeloblast HL60 cell line along either monocyte or granulocyte pathways induced an increased expression of the rab proteins. Rab proteins were also detected in human neutrophils and in guinea pig alveolar macrophages. As degranulation is one of the phagocyte functions acquired in the late stage of differentiation. we investigated whether rab proteins would be involved in this process. Although rab proteins were tightly membrane bound. none of them was detected in the specific or azurophil granules purified from human neutrophils. The increased expression of rab proteins in mature phagocytes suggests that they may promote functions highly developed in these cells.
Role of adenosine triphosphate (ATP) and NaK ATPase in the inhibition of proximal tubule transport with intracellular cystine loading, Cellular cystine loading with cystine dimethyl ester inhibits volume absorption. transepithelial potential difference. glucose transport. and bicarbonate transport in proximal convoluted tubules perfused in vitro. This study examined the roles of ATP and NaK ATPase in this in vitro model of the Fanconi syndrome of cystinosis. Intracellular ATP was measured using the luciferin-luciferase assay. Intracellular ATP was reduced by 60% in proximal convoluted tubules incubated with 0.5 mM cystine dimethyl ester for 15 min at 37 degrees C (P less than 0.001). Incubation of cystine loaded tubules with 1 mM exogenous ATP increased intracellular ATP to levels not significantly different than that of controls. On the other hand. Vmax NaK ATPase activity was unchanged even though the incubation times and the concentration of cystine dimethyl ester were doubled to 30 min and 1 mM. respectively. In proximal convoluted tubules perfused in vitro. 0.5 mM cystine dimethyl ester resulted in an 89% inhibition in volume absorption (0.81 +/- 0.14 to 0.09 +/- 0.09 nl/mm.min). while there was only a 45% inhibition in volume absorption (P less than 0.01) due to cellular cystine loading in the presence of 1 mM lumen and bath ATP (0.94 +/- 0.05 to 0.52 +/- 0.11 nl/mm.min). These data demonstrate that proximal tubule cellular cystine loading decreases cellular ATP concentration. but does not directly inhibit NaK ATPase activity. The inhibition in transport and decrease in intracellular ATP due to cellular cystine loading was ameliorated by exogenous ATP. These data are consistent with cellular ATP depletion playing a major role in the inhibition of proximal tubule transport due to intracellular cystine loading.
Long-lasting depression of the factor XII-dependent fibrinolytic system in patients with myocardial infarction undergoing thrombolytic therapy with recombinant tissue-type plasminogen activator: a randomized placebo-controlled study, In a randomized placebo-controlled study. seven patients with acute myocardial infarction allocated to intravenous treatment with 100 mg of recombinant tissue-type plasminogen activator (rt-PA) and seven patients allocated to placebo were studied during eight sampling periods before and after treatment. Seven patients with acute myocardial infarction treated intravenously with 1.5 million U of streptokinase were later studied during two sampling periods before and after treatment. The placebo group showed no significant deviations of endogenous factor XII-dependent fibrinolytic activity (p greater than 0.05). In the rt-PA group. this activity decreased significantly (p less than 0.001) after the infusion and remained depressed throughout the 1st 4 days. A significant decrease in activity (p less than 0.05) was also found in the streptokinase-treated patients. The depletion of factor XII-dependent fibrinolytic activity was not due to generation of inhibition or a depletion of factor XII. prekallikrein and plasminogen. but could be related to the proactivator of this system. It is concluded that rt-PA (and streptokinase) treatment in patients with acute myocardial infarction causes a prolonged depletion of factor XII-dependent fibrinolytic activity. This depression of endogenous fibrinolytic activity needs to be evaluated in relation to the enhanced risk of coronary reocclusion after thrombolytic therapy.
Long-term care needs of hospitalized persons with AIDS: a prospective cohort study, OBJECTIVE: As the treatment for HIV infection has improved. AIDS has become a chronic disease. and the demand for long-term care has increased. The authors studied a cohort of hospitalized persons with AIDS to determine the proportion and characteristics of AIDS patients who could appropriately be cared for in long-term care facilities with skilled nursing. DESIGN: Prospective cohort study. SETTING: Medical wards of five Seattle tertiary care hospitals. PARTICIPANTS: 120 consecutive hospitalized persons with AIDS and their primary care physicians. nurses. and social workers. MEASUREMENTS AND MAIN RESULTS: Appropriateness for long-term care was determined by the patients' physicians. nurses. and social workers. Persons with AIDS who were appropriate for long-term care constituted 32% of the cohort (38 of 120). accounting for 35% of hospital days (11 of these 38 were discharged to long-term care facilities). Four admission characteristics were independently related to appropriateness: impaired activities of daily living. diagnosis of central nervous system illness or poor cognition. living alone. and weight loss. A discriminant function correctly classified over 80% of patients for appropriateness and was developed into a predictive index for planning patient care (sensitivity = 0.74. specificity = 0.85). CONCLUSIONS: The authors conclude that one-third of hospitalized persons with AIDS may be appropriate for care in long-term care settings. accounting for one-third of the days AIDS patients currently spend in hospitals. These patients can be identified early in hospital stays using a simple predictive index at the bedside.
Detection of infection with human immunodeficiency virus (HIV) type 1 in infants by an anti-HIV immunoglobulin A assay using recombinant proteins, To diagnose infection with the human immunodeficiency virus (HIV) soon after birth in infants born to HIV type 1-infected women. we developed antiviral IgA Western blot and dot blot assays with recombinant HIV-1 proteins. Thirty-three infants born to HIV-1-seropositive mothers and nine infants born to HIV-1-seronegative intravenous drug-abusing mothers were followed prospectively. Infection was documented by positive virus culture. Results with the polymerase chain reaction were used for comparison. Twelve infants were found infected with HIV-1; the earliest age at which cultures became positive ranged from birth to 31 weeks of age. Of the 12 culture-positive infants. 10 had anti-HIV IgA antibodies detectable initially between birth (cord blood) and 27 weeks of age. Anti-HIV IgA was not present in the uninfected infants or in the control subjects. either by Western blot or dot blot assays. Testing for anti-HIV IgA antibodies with recombinant HIV-1 proteins is an effective method for detecting viral infection in newborn and young infants.
Point mutation in meningococcal por A gene associated with increased endemic disease, The por A gene. which encodes expression of meningococcal class 1 outer membrane protein. responsible for antigenic subtype specificity. has been cloned and sequenced in an isolate of Neisseria meningitidis (B:15:P1.7.16) from a patient in the Gloucester area with meningococcal meningitis. Comparison of the sequence with that of the equivalent gene from the P1.7.16 reference strain reveals a point mutation which generates a single aminoacid change in the epitope responsible for P1.16 specificity. Monoclonal antibodies with P1.16 specificity do not react with synthetic peptides that correspond to the altered epitope. and do not promote complement-mediated bactericidal killing of the isolate. Analysis of other strains shows widespread distribution of infections due to B:15:P1.7.16 meningococci with the altered epitope (P1.16b) in England and Wales.
Polymyositis mediated by T lymphocytes that express the gamma/delta receptor, BACKGROUND. The invasion and destruction of nonnecrotic muscle fibers by CD8+ cytotoxic T cells is considered a hallmark of polymyositis. In the cases of polymyositis reported so far. the autoinvasive CD8+ T cells expressed the common form of T-cell receptor for the recognition of antigen. the so-called alpha/beta T-cell receptor. We describe a 69-year-old man with polymyositis mediated by CD4-. CD8- T cells expressing the recently discovered. uncommon gamma/delta T-cell receptor. METHODS. We used immunofluorescence or immunoperoxidase techniques to study frozen sections of muscle from our patient. who had mild weakness of cervical and proximal limb muscles. and from control patients with polymyositis. inclusion-body myositis. dermatomyositis. or granulomatous myopathy with monoclonal antibodies against T-cell-related antigens (CD2. CD3. CD4. CD8. and gamma/delta T-cell receptor). B cells (CD22). major histocompatibility complex (MHC) and MHC-related antigens (MHC Class I. CD1a. CD1b. and CD1c). and the 65-kd heat-shock protein. The membrane contacts between the autoinvasive cells and the sarcolemma were investigated by electron microscopy. RESULTS. In the patient described here. but not in 28 others with inflammatory myopathies. myriad gamma/delta T cells surrounded and invaded nonnecrotic muscle fibers. All muscle fibers were highly reactive for MHC Class I antigen and the 65-kd heat-shock protein. Treatment with prednisone improved the clinical and histologic findings. CONCLUSIONS. Polymyositis can be mediated by gamma/delta T cells. This new form of polymyositis appears to be highly responsive to steroids.
Prolonged relief of neuralgia after regional anesthetic blocks. A call for further experimental and systematic clinical studies, Thirty-eight consecutive patients with neuralgia after peripheral nerve injury were treated with one or two series of peripheral local anesthetic blocks. All patients experienced an initial total relief of ongoing pain for 4-12 h. Evoked pain (hyperalgesia or allodynia). which occurred in 17 patients. was blocked simultaneously with the spontaneous pain. In 18 patients the analgesia outlasted the conduction block and there was a period of complete pain relief of 12-48 h in 13 patients and of 2-6 days in the other 5. In 8 patients there was a second phase of analgesia of 4 h to 6 days duration occurring within 12 h of pain recurrence. Thus. mono- or biphasic prolonged complete analgesia occurred in 25 out of 38 patients. A prolonged analgesia may be the result of a central action of the local anesthetic at the spinal level after intra-axonal incorporation and centripetal axoplasmic transport. To test this hypothesis. an experimental study with [3H]lidocaine was performed in 6 rats. The radioactive local anesthetic was injected into one hind limb foot with the other side serving as a control. Tissue samples from the peripheral nerve. nerve root and the lumbosacral spinal cord segment were analyzed for radioactivity using a scintillation counter technique at various time intervals after the [3H]lidocaine injection. There was a low grade of activity in all samples and no difference between the test side and the control side. Thus these experiments provided no evidence in support of this hypothesis. Various alternative peripheral and central mechanisms are discussed. Further studies specifically directed to these alternatives and with longitudinal controls are prompted.
Common ankle injuries in the athlete, The ankle is often a neglected joint by the athlete because of an inadequate understanding of the injury. Sprains and fractures are common injuries in the athlete because of the force of impact on the ankle during activity. Appropriate management of ankle injuries promotes healing and prompt return to sports activities.
Promoter region of the human platelet-derived growth factor A-chain gene, The platelet-derived growth factor (PDGF) A- and B-chain genes are widely expressed in mammalian tissues and their homodimeric gene products appear to regulate the autocrine growth of both normal and transformed cells. In this study. we analyzed the 5' flanking sequences of the human PDGF A-chain gene to seek elements important to regulating its transcription. The promoter region was exceptionally G + C-rich and contained a "TATA box" but no "CAAT box." The transcription start site was identified 845 base pairs 5' to the translation initiation site by S1 nuclease mapping and by primer extension. Both in vitro transcription and transient expression of the chloramphenicol acetyltransferase gene linked to the PDGF A-chain 5' flanking sequences established that the putative promoter region was active. and RNase H mapping established that the three characteristic mRNAs (1.9. 2.3. and 2.8 kilobases) used the same transcription start site. which was used in normal endothelial cells and in two human tumor cell lines that express high levels of A-chain transcripts. The results established an exceptionally G + C-rich promoter region and a single transcription start site active for each of the three mRNAs of the PDGF A-chain gene. DNA sites of potential importance in mediating the activation of the PDGF A-chain gene in normal cells and in transformed cell lines expressing high levels of PDGF A chain were identified.
Characterization of the terminal regions of hepatitis C viral RNA: identification of conserved sequences in the 5' untranslated region and poly(A) tails at the 3' end, We have determined the nucleotide sequence at the extreme 5' and 3' termini of the hepatitis C virus (HCV) genome. Our analyses of these sequences show (i) the nucleotide sequence in the 5' untranslated region is highly conserved among HCV isolates of widely varying geographical origin. (ii) within this region. there are blocks of nucleotide sequence homology with pestiviruses but not with other viruses. (iii) the relative position of short open reading frames present in the same region of the HCV genome is similar to that of the pestiviral genome. (iv) RNAs truncated at the 5' and 3' ends are found. but the origin and functions of these RNAs are unknown. and (v) poly(A) tails appear to be present on 3' subgenomic RNAs. These data differentiate HCV from the flaviviruses and indicate a closer evolutionary relationship of HCV with the pestiviruses. However. HCV also appears to be substantially different from other known pestiviruses. These data are consistent with the assignment of HCV to a separate viral genus.
An atrial natriuretic factor analogue at low doses attenuates forearm reflex vasoconstriction to cardiopulmonary receptor deactivation in patients with hypertension, Contrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings. particularly at low. biologically. significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47.663. anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (-10 mm Hg x 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 micrograms/kg/min x 60 min. which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 micrograms/kg/min x 60 min. each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell x 30 min). Forearm blood flow (venous plethysmography). intraarterial blood pressure. and heart rate were monitored continuously. and venous immunoreactive ANF. plasma renin activity. aldosterone level. and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values. an indirect index of sympathetic discharge. were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit. decreased aldosterone level and plasma renin activity. whereas resting norepinephrine levels. blood pressure. and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion. but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action. ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF.
The use of intraaortic balloon pumping as an adjunct to reperfusion therapy in acute myocardial infarction. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group, To assess the risk and possible benefits of use of the percutaneous IABP in patients given thrombolytic therapy as treatment for acute myocardial infarction. we prospectively evaluated 810 consecutive patients entered into the TAMI trials. During hospitalization the 85 patients treated with the IABP had more cardiac risk factors. were slightly older (58 vs 56 years). and more often had anterior infarction (62% vs 38%). At acute cardiac catheterization. patients treated with the IABP also had more multivessel coronary disease (67% vs 43%). more frequent TIMI grade 0 or 1 flow (44% vs 28%). lower global ejection fraction (40% vs 52%). and worse regional infarct (-3.2 vs -2.5 SD/chord) and noninfarct (-0.67 vs +0.36 SD/chord) zone function. Although mortality rates (32% vs 4%) and in-hospital complications were greater in patients treated with the IABP. a greater improvement in global (delta ejection fraction: +1.9% vs +0.7%) and noninfarct zone (delta SD/chord: +0.11 vs -0.09) left ventricular function was observed in patients treated with the IABP at 1-week follow-up angiography. In addition. no reinfarction or reocclusion of the infarct-related artery occurred while patients were being treated with the IABP. These results suggest that the IABP may have a specific role after thrombolytic therapy in treating patients at high risk for reocclusion or at high risk for hemodynamic deterioration because of large infarction or critical stenoses in coronary vessels supplying the noninfarct zone.
Protein-energy undernutrition and the risk of mortality within 1 y of hospital discharge in a select population of geriatric rehabilitation patients, To determine whether undernourished elderly patients are at increased risk for mortality. independent of nonnutritional factors affecting outcomes. 109 patients were evaluated at admission to a geriatric rehabilitation unit (GRU) and then followed prospectively for 1 y after hospital discharge. During the interval of observation. 33 (30%) patients died. 11 before hospital discharge and 22 within the year subsequent to discharge. Of the 81 nutritional and nonnutritional variables analyzed. the best predictor of mortality. as determined by stepwise-discriminant-function analysis. within 1 y of hospital discharge was the percent of usual body weight lost in the year previous to admission. followed by the subscapular skinfold thickness and the discharge Katz Index of Activities of Daily Living (ADL) score. Percent of weight lost was also the strongest predictor of 1-y post-GRU-admission mortality. These results provide compelling evidence for the importance of nutritional status in predicting both in-hospital and postdischarge mortality in a population of frail. male GRU patients.
Lowering of HDL2-cholesterol and lipoprotein A-I particle levels by increasing the ratio of polyunsaturated to saturated fatty acids, The protective role of high-density lipoproteins (HDLs) has been attributed to the subfractions HDL2 (according to the density) and lipoprotein A-I (LpA-I) (according to the composition in apolipoproteins). We investigated the effect of a high ratio of polyunsaturated to saturated fatty acids (P:S) on these subfractions in a homogeneous group of young adult males. Two prescribed diets were consumed successively at the subjects' homes for 3 wk each in a random order; one diet contained 70 g butter (P:S 0.2. diet B). the other contained 70 g sunflower margarine (P:S 1.1. diet M). Total calorie. fat. and cholesterol intakes were similar for the two diets. Cholesterol and apolipoprotein B in serum and in low-density lipoproteins (LDLs) were lower with diet M than with diet B. However. significant decreases in protective subfractions of HDL. HDL2. and LpA-I were observed. This undesirable effect of the diet with a high P:S could cancel the benefits of lowering the LDL-cholesterol concentrations.
Acute and sustained release of the atrial natriuretic factor prohormone N-terminus with acute myocardial infarction, This investigation was designed to determine if acute ischemic cardiac injury causes the release of the 98 amino acid (aa) N-terminus of the 126 aa atrial natriuretic factor prohormone (pro ANF). Seventeen patients with acute myocardial infarction. but without clinical evidence of congestive heart failure. had their circulating concentrations of the whole N-terminus (ie. pro ANF 1-98). the midportion of the N-terminus of the ANF prohormone (consisting of aa 31-67; pro ANF 31-67) and creatine phosphokinase (CPK) monitored daily for 14 days. All seventeen patients had elevated plasma pro ANF 1-98 and pro ANF 31-67 concentrations at the time of presentation. Maximal increase on day three post-infarction correlated with the size of infarction estimated by the maximal CPK (r = 0.675; p less than 0.05) but did not correlate with the amount of left ventricular dysfunction. Another three patients with acute myocardial infarction were treated with tissue plasminogen activator (tPA). The measured pro ANF 1-98 and pro ANF 31-67 levels in these patients were within our normal range and significantly lower (p less than 0.001) than seen in patients with acute myocardial infarction not given thrombolytic therapy. Six patients with unstable angina. likewise. had normal circulating pro ANFs 1-98 and 31-67 concentrations during prolonged episodes of chest pain. These data suggest that myocardial necrosis but not ischemia triggers the release of the entire 126 aa prohormone.
A practical approach to laparoscopic cholecystectomy, A prospective study of 500 consecutive cholecystectomies was initiated with the introduction of laparoscopic cholecystectomy. Laparoscopic cholecystectomy was attempted in 96% of patients presenting with primary gallbladder disease and was completed in 95%. There were no deaths or bile duct injuries. Two patients undergoing laparoscopic cholecystectomy were transfused for postoperative bleeding. and only one patient required reoperation for any reason. A prospective study showed reduced operating time (20 minutes) and patient charges ($546) using electrosurgical dissection compared with laser. Reusable trocars were used without any associated injury or morbidity. An effective strategy for selective cholangiography was developed based on patient history. liver enzymes. and common duct diameter. In conclusion. laparoscopic cholecystectomy appears to be a safe operation. The cost-effectiveness of laparoscopic cholecystectomy can be enhanced ($1.271) with no loss of patient benefit using the combination of electrosurgery. reusable trocars. and selective cholangiograms in low-risk patients.
The response of the canine cerebral circulation to hyperventilation during anesthesia with desflurane, Arterial CO2 tension (PaCO2) is an important factor controlling cerebral blood flow (CBF) and cerebral vascular resistance (CVR) in animals and humans. The normal responsiveness of the cerebral vasculature to PaCO2 is approximately 2 ml.min-1.100 g-1.mmHg-1. This study examined the effect of desflurane. a new volatile anesthetic. on the responsiveness of the cerebral vasculature to changes in PaCO2. Mean arterial pressure (MAP). CBF. CVR. intracranial pressure (ICP). and cerebral metabolic rate for O2 (CMRO2) were measured in five dogs anesthetized with desflurane (0.5-1.5 MAC) at normocapnia (PaCO2 = 40 mmHg) and at two levels of hypocapnia (PaCO2 = approximately 30 and approximately 20 mmHg). Under desflurane anesthesia. similar changes in CBF and CVR occurred with hyperventilation at all MAC levels of desflurane. At 0.5 MAC. CBF decreased significantly. from 81 +/- 6 to 40 +/- 3 ml.min-1.100 g-1 (P less than 0.05. mean +/- SE) when PaCO2 was decreased from 40 to 24 mmHg; i.e.. the CBF decreased approximately 2.6 ml.min-1.100 g-1.mmHg-1. At 1.0 MAC desflurane. CBF decreased significantly. from 79 +/- 10 to 43 +/- 5 ml.min-1.100 g-1 with hyperventilation (2.0 ml.min-1.100 g-1.mmHg-1); at 1.5 MAC desflurane. CBF decreased from 65 +/- 6 to 38 +/- 2 ml.min-1.100 g-1 with hyperventilation (1.6 ml.min-1.100 g-1.mmHg-1). Despite the significant decreases in CBF with hyperventilation. there was no significant change in ICP. Dose-dependent decreases in MAP were observed with increasing concentrations of desflurane but were not significantly affected by ventilation.
Desflurane is a trigger of malignant hyperthermia in susceptible swine, Desflurane (difluoromethyl 1-fluoro 2.2.2-trifluoroethyl ether: CF2-H-O-CFH-CF3) is a potent inhalation anesthetic agent being investigated for possible clinical use. The authors examined the effects of this agent on normal swine and those from a special breeding program that were considered purebred for susceptibility to malignant hyperthermia (MH). Animals were exposed to 1 or 2 MAC or both doses of desflurane and observed for changes in end-tidal CO2. arterial blood gases. lactate. catecholamines. core temperature. blood pressure. and heart rate. All normal swine tolerated exposure to desflurane without clinical signs of MH. but significant changes in heart rate and blood pressure were noted. In contrast. of six MH susceptible swine tested. two had unequivocal MH reactions to deflurane. defined by significant increases of end-tidal CO2 (greater than 50 mmHg). an increase in PaCO2 (greater than 70 mmHg). a decrease in blood pH (less than 7.30). an increase in blood lactate concentration. and an increase in core temperature. Two other susceptible swine showed equivocal signs of MH but not until desflurane had been administered for 40-60 min. Finally. two other susceptible swine showed no signs of MH after 60 min of exposure to 2 MAC desflurane. These latter four animals all developed episodes of MH immediately after intravenous succinylcholine (2 mg/kg). The increased PaCO2. blood lactate concentrations. and temperature. and the decrease in pH induced by desflurane. were successfully treated with dantrolene and supportive measures. All surviving animals were biopsied 1 to 2 weeks after the exposure to desflurane for in vitro contracture testing to confirm MH susceptibility.
Respiratory response to arm elevation in patients with chronic airflow obstruction, We have shown that patients with chronic airflow obstruction (CAO) complain of disabling dyspnea when performing seemingly trivial tasks with unsupported arms. Surprisingly little is known about the metabolic and ventilatory responses to unsupported upper extremity activity even though some of the muscles of the upper torso and shoulder girdle are used to perform simple and complex everyday tasks as well as partake in ventilation. To determine the effect of simple arm elevation in 20 patients with CAO we studied their lung function. VO2. VCO2. and VE. with arms down at the side (AD). during 2 min with arms extended forward up to shoulder level (AE). and during recovery. To determine the pattern of ventilatory muscle recruitment we also measured endoesophageal (Ppl). gastric (Pg). and transdiaphragmatic (Pdl) pressures. In five of the patients the electromyographic signal (EMG) of the sternocleidomastoid (Sm) muscle was recorded and analyzed in its time domain (amplitude) and power spectrum density (median frequency). Within 30 s of arm elevation VO2. VCO2. and VE rose and remained elevated for 1 min after the arms were lowered. The increase in VE resulted from increases in respiratory rate and minimal rise in tidal volume (VT). With AE. FEV1 decreased by 5% (p less than 0.02) but FRC increased by 2% (p less than 0.05). Peak inspiratory pressure (Pimax) dropped from 54 +/- 4 to 48 +/- 4 cm H2O (p less than 0.005); Pdimax remained unchanged. Immediately after raising the arms Pgi. inspiratory swing in Pdi (delta Pdi). end-expiratory Ppl. and end-expiratory Pg increased significantly.
Decreased oxyhemoglobin affinity in patients with sleep apnea syndrome, Oxyhemogloblin affinity (P50 at pH 7.4. PaCO2 = 40 mm Hg. temperature = 37 degrees C) and 2.3-DPG concentration were assessed in 15 nonsmokers (14 men and one woman 46 to 63 yr of age) with sleep apnea syndrome (SAS) and in 10 normal subjects (eight men and two women 22 to 48 yr of age). In patients with SAS. mean nocturnal apnea index was 46 +/- 20/h. and mean nocturnal SO2 was 86 +/- 6% versus 94.6 +/- 1.8% during the daytime. Daytime mean P50 of the patients was 28.5 +/- 1.2 mm Hg versus 27.1 +/- 0.3 mm Hg in the normal subjects (p less than 0.05). Daytime mean 2.3-DPG was 1.23 +/- 0.25 moles DPG/mole hemoglobin versus 0.80 +/- 0.15 (p less than 0.05). Significant correlations were found in patients between P50 and mean nocturnal SO2 (r = -0.62. p less than 0.01) and between P50 and 2.3-DPG (r = 0.68. p less than 0.01). The measurements were repeated in five patients after surgical or positive-pressure treatment. P50 and 2.3-DPG both decreased and returned to normal values. In conclusion. the oxyhemoglobin dissociation curve is shifted to the right in patients with SAS and there is an increase in 2.3-DPG. These could be protective mechanisms against the development of polycythemia. pulmonary hypertension. and cor pulmonale.
Inhibition of cyclooxygenase metabolite production attenuates ischemia-reperfusion lung injury, We investigated if cyclooxygenase metabolites of arachidonic acid were involved in ischemia-reperfusion lung injury by determining if inhibition of their production attenuated the injury. Isolated rat lungs were perfused with physiologic salt solution osmotically stabilized with Ficoll until circulating blood elements were not detected in lung effluent. Ischemia was induced by stopping ventilation and perfusion for 90 min. Lung ventilation and perfusion were then resumed. Ischemia-reperfusion resulted in the production of prostacyclin and thromboxane assessed by lung effluent and tissue measurements of their respective stable metabolites. 6-keto-PGF1 alpha thromboxane B2 (TxB2). In contrast. prostaglandin F2 alpha did not increase. Ischemia-reperfusion also caused lung injury as assessed by increased lung 125I-BSA accumulation compared with nonischemic control lungs. Addition of the cyclooxygenase inhibitors. indomethacin. or flubiprofen to the lung perfusate before and after ischemia inhibited lung injury as well as the production of 6-keto-PGF1 alpha and TxB2. Addition of a thromboxane synthetase inhibitor (U 63557A) reduced lung injury as well as TxB2 formation without affecting the production of 6-keto-PGF1 alpha. The attenuation of lung injury was not explained by direct H2O2 removal by indomethacin. flubiprofen. or U 63557A because the concentrations of the inhibitors used in the isolated lung experiments did not remove exogenously added H2O2 from buffer in vitro. We conclude that cyclooxygenase metabolites of arachidonic acid are involved in ischemia-reperfusion injury to isolated rat lungs.
NIH conference. Diagnosis and management of asymptomatic primary hyperparathyroidism: consensus development conference statement, Endocrinologists. surgeons. radiologists. epidemiologists. and primary health care providers convened to address both indications for surgery in asymptomatic patients with hyperparathyroidism as well as how patients who do not have surgery should be monitored and managed to minimize the risk for complications. The National Institutes of Health Consensus Development Conference Panel concluded that a diagnosis of hyperparathyroidism is established by showing persistent hypercalcemia and an elevated serum parathyroid hormone concentration; that the current and acceptable treatment for hyperparathyroidism is surgery; that the diagnosis of hyperparathyroidism in an asymptomatic patient does not in all cases mandate referral for surgery; that conscientious surveillance may be justified in patients whose calcium levels are only mildly elevated and whose renal and bone status are close to normal; and that preoperative localization in patients without previous neck operation is rarely indicated and has not proved to be cost effective.
Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States, A national surveillance study was conducted to determine trends in antimicrobial resistance patterns among three common causes of community-acquired respiratory tract infections. Fifteen participating U.S. medical centers submitted clinically significant isolates of Haemophilus influenzae. Moraxella (Branhamella) catarrhalis. and Streptococcus pneumoniae to two central laboratories for testing with a group of 12 antimicrobial agents. The majority of isolates were recovered from adult males greater than 50 years old. Overall. 84.1% of 378 M. catarrhalis and 16.5% of 564 H. influenzae (29.5% of type b strains; 15.0% of non-type b strains) produced beta-lactamase and were thus resistant to penicillin. ampicillin. and amoxicillin. Resistance in H. influenzae to other agents was 2.1% to tetracycline. 0.7% to trimethoprim-sulfamethoxazole. 1.1% to cefaclor. and 0.2% to cefuroxime and amoxicillin-clavulanate. while the M. catarrhalis isolates yielded very low MICs of these latter drugs. As demonstrated in prior studies. erythromycin showed little activity against H. influenzae. Of 487 S. pneumoniae isolates. 1 (0.2%) was penicillin resistant. while 3.8% were relatively resistant to penicillin. 4.5% were resistant to trimethoprim-sulfamethoxazole. 2.3% were resistant to tetracycline. 1.2% were resistant to chloramphenicol. and 0.2% were resistant to erythromycin. Overall. the lowest resistance rates for these common bacterial respiratory pathogens were noted with amoxicillin-clavulanate. cefuroxime. and cefaclor.
Sustained in vitro activity of human albumin microspheres containing chlorhexidine dihydrochloride against bacteria from cultures of organisms that cause urinary tract infections, The potential of chlorhexidine dihydrochloride (CH HCl) incorporated into human albumin microspheres to provide sustained activity in vitro against Escherichia coli. Staphylococcus aureus. and Pseudomonas aeruginosa from quality controls and from cultures of organisms that cause urinary tract infections was investigated. CH HCl was entrapped into five different formulations of human albumin microspheres. A technique was developed to evaluate the antibacterial activity of these microspheres and of controls (unloaded microspheres or gel). CH HCl microspheres exhibited antibacterial activity over a period of 16 days. Similar results were obtained with microspheres suspended in a methocel gel. and their antibacterial activity also continued for about 16 days. Empty microspheres or gel media alone were ineffective. The release rates of CH HCl from human albumin microspheres coated onto catheters by use of different gel formulations were also determined. The microsphere formulations were found to provide sustained antibacterial activity even at a low drug concentration.
Effect of serum on the in vitro activities of 11 broad-spectrum antibiotics, We evaluated the effect of serum on the in vitro activities of 11 antimicrobial agents against gram-negative isolates obtained from 100 patients with nosocomial bacteremia. The test organisms included 25 stains of Pseudomonas aeruginosa and 75 strains of the family Enterobacteriaceae. MICs were determined by broth microdilution with Mueller-Hinton broth alone or supplemented with 25 or 50% pooled. heat-inactivated human serum (25S or 50S. respectively). Among the antibiotics evaluated. the protein binding ranged from 9 to 95%. The antibiotics tested and their MICs for 90% of the strains tested in 50S included ciprofloxacin (0.12 micrograms/ml). ceftazidime (1 micrograms/ml). imipenem (1 micrograms/ml). aztreonam (4 micrograms/ml). cefpirome (4 micrograms/ml). cefotaxime (16 micrograms/ml). cefoperazone (16 micrograms/ml). desacetylcefotaxime plus cefotaxime (32 micrograms/ml). ceftriaxone (greater than 32 micrograms/ml). ticarcillin (128 micrograms/ml). and desacetylcefotaxime (greater than 128 micrograms/ml). MICs for 90% of the strains tested were calculated with 95% confidence intervals to show the precision of the MICs for these strains. With the exceptions of ceftriaxone (greater than 95% protein bound) and cefoperazone (90% protein bound). serum had no significant effect on the in vitro activities of various agents. A fourfold-or-greater increase in the MIC of ceftriaxone was observed in 45 of 100 isolates with 50S and in 30 of 100 isolates with 25S. With cefoperazone. 17 of 100 isolates demonstrated more than 2 twofold dilution increases in 50S. Testing of antibiotics which were less protein bound illustrated minor effects primarily with members of the Enterobacteriaceae. The presence of serum did not adversely affect the in vitro activities of broad-spectrum agents against these nosocomial isolates.
Comparative in vitro activities of sparfloxacin (CI-978; AT-4140) and other antimicrobial agents against staphylococci, enterococci, and respiratory tract pathogens [published erratum appears in Antimicrob Agents Chemother 1991 Mar;35(3):603, The in vitro activity of sparfloxacin (CI-978; AT-4140) was compared with those of other antimicrobial agents against isolates of staphylococci. enterococci. and various respiratory tract pathogens. Sparfloxacin was the most active drug tested against staphylococci (MIC for 90% of the strains tested [MIC90]. 0.125 micrograms/ml) and enterococci (MIC90. 1.0 microgram/ml). It was also active against Haemophilus influenzae (MIC90. less than or equal to 0.06 microgram/ml). Moraxella (Branhamella) catarrhalis (MIC90. 0.125 microgram/ml). Streptococcus pneumoniae (MIC90. 0.5 microgram/ml). and Streptococcus pyogenes (MIC90. 1.0 microgram/ml).
Antiendothelial cell antibodies detected by a cellular based ELISA in Kawasaki disease, Kawasaki disease is an acute vasculitic illness of childhood associated with significant morbidity and mortality. A cellular based enzyme linked immunosorbent assay (ELISA) was used to demonstrate the presence of antiendothelial cell antibodies in sera from children with Kawasaki disease. Twenty one of 32 patients with Kawasaki disease had raised IgM antibody titres and four had raised IgG antiendothelial antibody titres. There was a significant difference in the IgM antiendothelial cell antibody titres when comparing the patients with normals and febrile controls. The antibody titre paralleled the disease activity in patients studied serially. There was no relative increase in binding of antiendothelial cell antibodies after cytokine stimulation. These findings may be of importance in further research into the understanding of mechanisms involved in this and other forms of vasculitis in man.
Correlation of serum antigen and antibody concentration with clinical features in HIV infection, Serum antigen and antibody values were studied in 164 infants and children infected perinatally with HIV. HIV antigens p17. p24. gp41. and gp120 were determined in sera by immunoblot and antigen capture assays. Lymphocyte blast transformation. serum immunoglobulins. and circulating immune complexes were also evaluated. Altogether 50 patients had HIV antigens measured: 31 (62%) patients had p17 antigen in the serum and 29 (58%) had p24 antigen present. In 19 (38%) and nine (18%) patients. respectively. gp120 and gp41 were detected. All four HIV antigens were detected in seven (14%) patients. There was a positive correlation between the concentration of each HIV sequential specimens were outcome. When sequential specimens were analysed. 120 (73%) patients had p24 antigen present. Patients with stage P2B and P2D (Centers for Disease Control classification) had the highest concentrations of p24 antigen with a mean of approximately 200 pg/ml. Altogether 70% of patients with a p24 antigen concentration of greater than 30 pg/ml eventually died or had severe clinical disease within six to 24 months. Infants under 15 months of age with a p24 antigen concentration as low as 5 pg/ml also did poorly. Increased immunoglobulins and decreases in mitogenic responses and absolute CD4+ lymphocyte counts were more prevalent in patients with raised p24 antigen. Raised concentrations of circulating immune complexes were seen in the symptomatic phase of the disease whereas in the terminal stage of the disease raised serum antigen and a decrease in circulating immune complexes and absolute CD4+ lymphocyte count were evident. Loss of p24 and/or p17 antibody as well as a decreasing ELISA optical density for HIV antibody also signalled progression of the disease.
Clinical significance of low serum thyrotropin concentration by chemiluminometric assay in 85-year-old women and men, The prevalence and causes of low serum thyrotropin concentration were studied in 886 individuals at age 85 years (601 women and 285 men). All participants were subject to detailed clinical and biochemical evaluation. including determination of serum thyrotropin and free thyroxine concentrations by chemiluminometric assays. Samples with thyrotropin concentrations below 0.20 mU/L or above 6.0 mU/L and/or free thryoxine concentrations above 22.0 pmol/L were selected for further assays. These selected individuals were followed-up during 3 years. Of 18 individuals without thyroid hormone treatment who had thyrotropin concentrations less than 0.20 pmol/L (13 below 0.10 pmol/L). only two were proved to be hyperthyroid; in another three. hyperthyroidism could not be excluded. The results indicate that most elderly individuals with low serum thyrotropin concentrations are not hyperthyroid and that abnormal thyroxine-binding globulin (in conjunction with drug treatment or nonthyroidal illness) is not a common cause of low thyrotropin concentration.
Pneumothorax complicating small-bore feeding tube placement, Small-bore Silastic feeding tubes are being used with increasing frequency for short- and long-term enteral hyperalimentation. We present three cases where these flexible tubes were passed into the tracheobronchial tree and then out into the pleural space. The result in each case was a pneumothorax or hydropneumothorax. These cases were collected at one community hospital over a 6-month period. A review of the current literature reveals reports of 10 similar cases. We conclude that. although the exact incidence of pleural complications of small-bore feeding tubes is unknown. it is not insignificant. The traditional methods of assessing proper nasogastric tube placement are inadequate when applied to these small tubes. Only a chest roentgenogram can assure placement in the stomach. Education of hospital staff on methods to avoid malposition of feeding tubes has resulted in an absence of pulmonary complications over a subsequent 1-year period.
Successful treatment of pure myopathy, associated with complex I deficiency, with riboflavin and carnitine, We describe a 6-year-old boy who presented with progressive muscle weakness. Additional investigations revealed the existence of a myopathy and a pure motor neuropathy. Biochemical studies in muscle tissue showed a defect of NADH dehydrogenase (complex I). The patient dramatically improved on treatment with riboflavin and L-carnitine. Seven months after the start of the treatment. complex I activity was determined again and appeared to be normalized. Normalization of the enzymatic defect at this level has not been reported before. We provide a survey of nine patients with pure myopathy. associated with complex I deficiency and onset of symptoms in childhood.
The role of glycosylation in the biosynthesis and acquisition of ligand-binding activity of the folate-binding protein in cultured KB cells, The biosynthesis. processing. and ligand-binding function of the membrane-associated and soluble forms of the folate-binding protein (FBP) in KB cells. a cultured human cell line. were studied using pulse-chase labeling with [35S] methionine. The intermediary and mature forms of the protein were isolated by immunoprecipitation and affinity chromatography and analyzed by sodium dodecyl sulfate electrophoresis and autoradiography. The earliest species identified had an Mr of 32 Kd and disappeared over 5 hours concomitant with the appearance of a 38-Kd cellular FBP. As the 38-Kd species disappeared. a 40-Kd form appeared in the medium. When tunicamycin was added to the culture medium to inhibit core glycosylation. a 26-Kd aglycosylated species and minor 28-Kd and 30-Kd forms appeared. Endoglycosidase H. which cleaves high mannose but not complex oligosaccharides. reduced the 32-Kd species to 26-Kd but the enzyme had no effect on the 38-Kd form. indicating that this species is complex glycosylated. Monensin. which blocks complex glycosylation. also inhibited synthesis of the 38-Kd species. Although both the 32-Kd and 38-Kd forms had ligand-binding sites (as demonstrated by binding to a folate-Sepharose matrix). the 26-Kd aglycosylated species. labeled in the presence of tunicamycin. lacked similar binding sites because it did not bind to the affinity matrix. In contrast. the aglycosylated 26-Kd form. which was obtained by treatment of the 32-Kd species with endoglycosidase H. did bind to the folate affinity matrix. indicating that it retained ligand-binding function. Thus. the high mannose oligosaccharide moiety is not required for the folate-binding property of the FBP. but its addition to the polypeptide chain precedes a later step that is necessary for the mature protein to have ligand-binding function.
Accessory receptors regulate coupling of the T-cell receptor complex to tyrosine kinase activation and mobilization of cytoplasmic calcium in T-lineage acute lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL) cells have abundant cytoplasmic CD3/Ti but express low amounts on the cell surface and are deficient in CD3/Ti-mediated signal transduction. Nevertheless. plating T-ALL cells on dishes containing immobilized anti-CD3 monoclonal antibodies with a source of growth factors induced the expression of CD25 (interleukin-2 receptor alpha chain) and stimulated the formation of blast colonies in 12 of 14 cases studied. The proliferative response to CD3 ligation was modulated by the presence of antibodies to the CD2. CD4. or CD8 accessory T-cell receptors. The effect of these accessory receptors on signal transduction mediated by CD3/Ti was next investigated by monitoring cytoplasmic calcium concentration [( Ca2+]i) and by measuring tyrosine phosphorylation after stimulation. Crosslinking CD3. CD2. CD4. or CD8 alone did not induce cytoplasmic calcium mobilization in T-ALLs. but crosslinking the accessory receptors with CD3/Ti induced calcium responses in three of the T-ALLs and enhanced calcium responses in three of the T-ALL cell lines. including HPB-ALL. MOLT-4. and CEM. Crosslinking CD4 but not CD2 with CD3/Ti greatly enhanced tyrosine phosphorylation of multiple substrates in comparison with crosslinking either CD4 or CD3/Ti separately on both normal mature T cells and the CEM T-ALL cell line. Thus. CD4 regulates CD3/Ti signal transduction in T-ALL cells through the tyrosine phosphorylation of substrates whereas CD2 may regulate [Ca2+]i signal transduction through a separate mechanism.
Acute myeloblastic leukaemia--a model for assessing value for money for new treatment programmes, OBJECTIVE--To measure the effects of changes in treatment of acute myeloblastic leukaemia that may give better value for money. DESIGN--Retrospective analysis of patients' notes to identify items of management costing money; prospective costing of these items. The Medical Research Council acute myeloblastic leukaemia 9 trial was used to identify the amount and distribution of these costs when either one or two courses of induction treatment were required to obtain complete remission. These findings were then extrapolated to four published international controlled trials using similarly intense treatment and in which the number of courses of treatment required for complete remission was stated. to compare British costs for treatment with idarubicin and daunorubicin. both in combination with cytarabine. SETTING--Leukaemia unit. Royal Marsden Hospital. London. SUBJECTS--Data on 10 patients receiving intensive induction treatment for acute myeloblastic leukaemia were used to identify 160 items of cost in four broad groups: general (including accommodation). diagnostic. supportive treatment. and cytotoxic chemotherapy. One newly treated patient was prospectively assessed over one month. including a time and motion study. to cost these items; then costs for 268 patients from the MRC trial receiving moderate induction chemotherapy including daunorubicin were assessed. and costs for treatment of 522 patients in the four international studies comparing daunorubicin with idarubicin were analysed. MAIN OUTCOME MEASURES--Cost effectiveness was measured as the overall cost to obtain complete remission in untreated patients with acute myeloblastic leukaemia after treatment with idarubicin or daunorubicin. RESULTS--The 160 costed items were measured for their sensitivity in varying the total cost of treatment. this being assessed within Britain in other district general and private hospitals to measure the extremes of cost of these items. Overall. idarubicin. although more expensive. showed a substantial saving (1477 pounds per patient) in total hospital costs. more than offsetting the increased cost (607 pounds) of the new treatment. an overall savings of 870 pounds per patient (5%). CONCLUSION--Approaches modelling cost effectiveness may be an essential part of planning new programmes of treatment in the future. This method can be used to estimate the cost effectiveness of the treatments in different environments and countries where costs may vary widely.
Solid and cystic pancreatic tumors. Clinical, histochemical, and electron microscopic features in ten cases, Ten cases of the rare solid and cystic pancreatic tumors are presented. All except one occurred in young women (mean age. 25 +/- 9.2 years). The large neoplasms were evenly distributed across the pancreas; in one case. metastasis occurred; all other cases were free from disease after complete resection. Histologic hallmarks of solid and cystic neoplasms were papillary growth. large intracytoplasmic granules. and immunoreactivity with alpha 1-antitrypsin. alpha 1-antichymotrypsin. phospholipase A2. and neuroendocrine markers (neuron-specific enolase [NSE]. synaptophysin). This suggests both endocrine as well as exocrine differentiation.
Effect of theophylline and dipyridamole on the respiratory response to isocapnic hypoxia in normal human subjects, 1. Twelve healthy young men took part in this investigation of the effect of oral theophylline and dipyridamole (two drugs known to affect the pharmacological effects of the purine nucleoside adenosine) on the respiratory response to isocapnic hypoxia. 2. The subjects underwent hypoxic rebreathing manoeuvres after 3-day pretreatments with each of the drugs for 12 h and were at least 2 h postprandial. For each in-Minute ventilation. the maximum rate of isometric inspiratory pressure development at the mouth and the ratio of inspiratory duration to total breath duration were analysed breath-by-breath and regressions of these variables upon the haemoglobin oxygen saturation were performed. 3. The slopes and intercepts of the lines describing the relationships of minute ventilation and the maximum rate of isometric inspiratory pressure development at the mouth with haemoglobin oxygen saturation were unaffected by the study drugs. and no differences in the pattern of breathing were observed. 4. We conclude that oral administration of these drugs does not result in alteration of the response of the respiratory system to progressive isocapnic hypoxia. 5. This suggests that either adenosine has no physiological role in hypoxic respiratory control as measured. or that it has opposing peripheral chemoreceptor and central respiratory centre effects which could not be distinguished by the techniques used.
The role of superovulation with menotropins in ovulatory infertility: a review, The risks of menotropin therapy (ovarian hyperstimulation syndrome. multiple gestation. adnexal torsion) are well known and have been previously described. Superovulation should not be considered for the indications described herein until more traditional therapies for infertility have been tried and found unsuccessful and sufficient time has elapsed for conception to occur. The cost of superovulation is high: the medications are expensive. frequent E2 monitoring and US studies are costly. and pregnancy complications relating to the higher rate of pregnancy loss and multiple gestation may add substantially to the overall cost. Yet. compared with IVF and GIFT. superovulation cycles combined with IUI cost between one third to one sixth that of an IVF cycle. Protocols involving combined CC/hMG/hCG. which reduce the total number of ampules of Pergonal needed per cycle and still provide multiple follicular development. may further reduce costs. There is a growing consensus that superovulation-IUI protocols should be attempted before GIFT and IVF in couples with normal pelvic viscera. There is little doubt that IVF and GIFT cycles are more costly. stressful. and complex. No comparative data have clearly shown IVF and GIFT to be superior to superovulation protocols in ovulatory women with normal pelvic anatomy. In the only study examining this issue published to date. Kaplan et al. retrospectively analyzed all GIFT and superovulation/IUI cycles at a single university center and found GIFT to be three times more efficient. However. the inherent limitations of a nonrandomized. nonprospective study of this kind are obvious as these authors have suggested. Therefore. it may be wise to consider the use of superovulation before assisted reproductive technologies until this issue is settled. It would be interesting to determine if the high PRs reported for couples with unexplained infertility or mild endometriosis in IVF and GIFT cycles in some centers not incorporating superovulation/IUI protocols would hold up if such an approach was routinely followed. Despite the increasing acceptance of superovulation protocols. we must be aware that many of the studies suggesting a role of hMG in treating ovulatory infertile women with normal pelvic anatomy suffer from deficiencies in experimental design. In a payor-driven system. such as in the United States. the difficulties in designing and carrying out scientifically sound clinical studies examining infertility therapies are obvious. The lack of federal or outside funding for the study of infertility issues contributes to the problem. It is our hope that better designed studies examining the role of superovulation in the treatment of ovulatory infertile women with normal pelvic anatomy will be forthcoming.
Androgen responses to acutely increased endogenous insulin levels in hyperandrogenic and normal cycling women, We examined androgen responses in hyperandrogenic (polycystic ovarian disease [PCOD]) and normal women after an acute endogenous insulin elevation. Standard intravenous glucose tolerance tests (IVGTTs). modified to include a tolbutamide injection 20 minutes after IVGTTs. were performed. Polycystic ovarian disease patients were studied in the untreated state. after 6 weeks of ovarian androgen suppression with leuprolide acetate. after a 6-week rest period. and after 6 weeks of antiandrogen therapy with spironolactone. Normal menstruating women were studied during the early follicular. midcycle. and luteal phases of a single cycle. An acute rise in insulin did not alter serum testosterone or androstenedione levels in PCOD or normal women. A significant rise in dehydroepiandrosterone sulfate after modified IVGTTs was found in both hyperandrogenic and normal cycling women. Although these results are not supportive of the theory that insulin acts on the ovary to stimulate androgen production. they may be because of the short time course of insulin elevation that occurs during an IVGTT.
The role of endogenous opiates in athletic amenorrhea, We hypothesized that menstrual disturbances in female athletes arise from opioid-induced abnormalities in gonadotropin and/or prolactin (PRL) secretion. To investigate this hypothesis. we measured luteinizing hormone. follicle-stimulating hormone. and PRL levels in eumenorrheic and amenorrheic athletes during thyrotropin-releasing hormone and gonadotropin-releasing hormone tests at baseline. after naloxone infusions. after exercise to exhaustion. and after similar exercise during naloxone infusions. Contrary to our hypothesis. amenorrheic runners did not have significant alterations in basal. postexercise. or stimulated hormone levels compared with eumenorrheic runners. In addition. opioid blockade by naloxone did not enhance gonadotropin release by amenorrheic athletes.
Placebo-controlled trial of high-dose Mesterolone treatment of idiopathic male infertility, The possible effect of Mesterolone (Schering N.V.. Brussels. Belgium) (1 alpha-methyl-5-alpha-androstane-17 beta-ol-3-one) on semen quality and fertility of men with idiopathic oligoasthenospermia and/or teratozoospermia has been evaluated in a double-blind trial. The study included 52 patients who were treated during 12 months with either 150 mg/d of Mesterolone or placebo. The overall pregnancy rate was similar in the Mesterolone-treated cases (26%) and in the placebo control cases (48%). although a significant increase in motility and in the proportion of spermatozoa with normal morphology was recorded in the Mesterolone-treated cases. Because similar semen improvement also occurred in the placebo controls. our findings cast doubt on the possible usefulness of high-dose Mesterolone treatment of idiopathic male infertility.
Luteinizing hormone pulse frequency and in vitro bioactivity in male idiopathic infertility, We investigated 51 patients with idiopathic oligospermia and 10 control subjects. Blood samples were collected every 20 minutes from 10 P.M. to 10 A.M. and luteinizing hormone (LH) pulsatility was analyzed. A pool of all samples obtained from each subject was used to measure bioactive LH in an in vitro mouse Leydig cell bioassay and immunoactive LH in an immunoradiometric assay. Mean immunoactive LH pulse frequency was higher and mean bioactive to immunoactive LH ratio was lower in infertile men than in controls. There was a significant negative correlation between bioactive LH to immunoreactive LH ratio and LH pulse frequency. These data indicate that the defect in the gonadal axis in oligospermic men resides not in the hypothalamic-pituitary function but rather in the testis itself.
A pilot study of the use of gonadotropin-releasing hormone analog for triggering ovulation, Our study demonstrated the feasibility of using GnRH-a for triggering ovulation in women receiving hMG for ovulation induction: 11 of 13 patients had good pituitary LH and FSH surge followed by normal ovulatory P rise. and 4 became pregnant. In a selected group of patients. this method for triggering ovulation may be advantageous to using hCG.
Molecular diagnosis of cutaneous T-cell lymphoma: polymerase chain reaction amplification of T-cell antigen receptor beta-chain gene rearrangements, The goal of our study was to molecularly diagnose CTCL. by cloning the T-cell antigen receptor beta chain (TCR-beta) gene rearrangement from the malignant T cells of a patient with Sezary syndrome. in order to generate a specific oligonucleotide probe capable of detecting CTCL cells through polymerase chain reaction (PCR) amplification. Total RNA isolated from peripheral blood lymphocytes was reverse transcribed and resultant first strand cDNA was PCR amplified utilizing a concensus primer to the TCR-beta variable region (V beta) and a 3' primer to the TCR-beta constant region (C beta). PCR reaction products were subcloned into a plasmid vector and sequenced. Sequence analysis revealed that the patient's in-frame TCR-beta gene rearrangement utilized V beta 6.4. D beta 1.1. J beta 2.2. and C beta 2.1 gene segments. Oligo-primers to V beta 6.4 and J beta 2.2 were utilized to PCR amplify genomic DNA taken from the patient's blood and involved skin. Screening the amplified DNA with an oligo-probe specific for the patient's V-D-J junctional sequences resulted in the detection of the patient-specific sequences. No sequences were detected from DNA from other malignant or benign infiltrates. Thus. we have defined a "molecular fingerprint" specific for a patient's malignant T-cells and can molecularly diagnose CTCL through PCR amplification.
Altered polymorphonuclear leukocyte Fc gamma R expression contributes to decreased candicidal activity during intraabdominal sepsis, We investigated the effects of untreated intraabdominal sepsis on polymorphonuclear leukocyte (PMN) candicidal activity. Two groups of swine were studied. Group I (n = 6) underwent sham laparotomy. group II (n = 7) underwent cecal ligation and incision. Untreated intraabdominal sepsis resulted in a progressive decrease in PMN candicidal activity. Concomitant rosetting and phagocytosis assays demonstrated a decrease in both the attachment and phagocytosis of Candida albicans opsonized with both normal and septic swine serum by PMNs in group II. Iodine 125-labeled swine immunoglobulin G (IgG) and fluorescein isothioalanate (FITC)-labeled swine IgG were used to investigate Fc gamma receptor ligand interactions. Scatchard analyses demonstrated a progressive decline in both the binding affinity constant and number of IgG molecules bound per PMN. Stimulation of the oxidative burst markedly reduced 125I-labeled IgG binding in both group I and group II. with a greater decrement being seen in animals with intraabdominal sepsis. Further. in group II. PMN recycling of the Fc gamma receptor to the cell surface after generation of the oxidative burst was reduced by postoperative day 4. Binding of monoclonal antibodies to Fc gamma receptor II. but not Fc gamma receptor I/III markedly reduced intracellular candicidal activity. Immunofluorescence studies revealed a homogeneous pattern of FITC-IgG uptake by nearly all group I PMNs. whereas by postoperative day 8 a substantial number of PMNs from group II failed to internalize the FITC-IgG. These studies suggest that untreated intraabdominal sepsis reduces PMN candicidal activity and that this is due. in part. to altered PMN Fc gamma receptor ligand interactions.
Principles for effective surveys of hunger and malnutrition in the United States, To be effective. the information derived from a survey must be used to make decisions that affect policies and programs. This paper discusses why scientifically sound surveys may not be effective and vice versa. Effectiveness depends on the information being relevant to the decision-maker's understanding of the problem to be solved. To the extent that science contributes to both understanding the problem and providing the information for a decision. the survey will be scientific and effective. The measurement of malnutrition and barriers to communication are not at present the major obstacles to effective scientific surveys relative to hunger and malnutrition in the United States. Rather. the obstacles seem to be poor scientific conceptualization and measurement of hunger. on the one hand. and poor sampling techniques for malnutrition. on the other hand. These frontiers of knowledge have implications for science and policy beyond surveys. The challenge for the American Institute of Nutrition is to recruit the scientific skills need to understand hunger and identify pockets of malnutrition and their causes--scientific skills that go beyond those traditionally associated with nutrition research.
Elevated urinary C-peptide excretion in multiple trauma patients, A simple. indirect method of estimating integrated insulin secretion is the measurement of C-peptide. a byproduct of insulin biosynthesis. in plasma and in 24-hr urine samples. We determined. in 29 severely injured hypermetabolic and highly catabolic multiple trauma patients. the plasma level and daily excretion rate of C-peptide. 48-72 hrs postinjury. Data from a set of eight patients who underwent glucose-based total parenteral feeding for 6 days were analyzed for the course of changes in the excretory pattern of C-peptide and catecholamines. The molar ratio of plasma C-peptide to insulin in the trauma patients was similar to that in unstressed controls. indicating that the rate of hepatic insulin extraction is not appreciably altered due to trauma. This is also evident from a significant correlation (p = 0.001) between the plasma C-peptide and insulin levels. The excretion of C-peptide was elevated to three times the normal both in absolute terms and when normalized to creatinine excretion. This was also accompanied by a twofold increase in the plasma levels. indicating an enhanced secretion rate of C-peptide and hence of insulin in response to trauma. Injury-induced insulin resistance does not seem to be due to a decreased insulin secretion. An increase in insulin output would appear to be a significant and desirable response for a continued anabolic stimulus coexistent with the net catabolic phase. Parenteral feeding augmented the excretion of C-peptide and catecholamines and this effect peaked on the fourth day of nutritional therapy.
Ipsilateral fracture-dislocation of the hip, knee, and ankle: case report, A case of ipsilateral fracture-dislocation of the hip. knee. and ankle is presented. The patient had no neurovascular compromise or postoperative complications. A review of the literature produced no previous reports of this combination of injuries.
Reactive oxygen metabolites in endotoxin-induced acute renal failure in rats, Based on recent reports that reactive oxygen metabolites may play a role in endotoxin-induced injury in other tissues. we postulated that reactive oxygen metabolites may be important mediators of endotoxin-induced acute renal failure. Superoxide dismutase. a scavenger of superoxide. or catalase. which destroys hydrogen peroxide. did not protect against endotoxin-induced renal failure. Similarly. neither the hydroxyl radical scavenger dimethylthiourea nor the iron chelator deferoxamine (which presumably would act by preventing the generation of hydroxyl radical via the iron-catalyzed Haber-Weiss reaction) prevented the endotoxin-induced fall in renal function. In separate experiments. we found no increase in renal cortical lipid peroxidation (a marker of reactive oxygen metabolite-mediated tissue injury) in endotoxin-treated rats. providing further evidence against a role for reactive oxygen metabolites in endotoxin-induced renal injury. Finally. using the aminotriazole-induced inhibition of catalase (a measure of in vivo changes in the hydrogen peroxide generation) we found no evidence of enhanced hydrogen peroxide generation in the renal cortex in endotoxin-treated rats. Taken together. the data from these three separate experimental approaches suggest that reactive oxygen metabolites are not important mediators of endotoxin-induced acute renal failure.
Effect of intravenous infusion of atriopeptin 3 on immediate renal allograft function, Thirty-eight recipients of nineteen pairs of cadaveric kidneys were entered into a double-blind randomized study in which one recipient received a 12-hour intravenous infusion of Atriopeptin III (AP-3). a synthetic analogue of atrial natriuretic factor. commencing at release of the vascular clamps. and the other received a placebo infusion. In an initial dose ranging study. successive groups of six kidneys (3 pairs) were randomized to receive each of 0.0125. 0.025. 0.05 micrograms/kg/min AP-3 or placebo. Thereafter 20 kidneys (10 pairs) received 0.1 micrograms/kg/min or placebo. There was no discernable effect of AP-3 on allograft creatinine clearance or sodium excretion either when the highest dose of AP-3 was considered alone or when all doses were considered together. Averaged creatinine clearance over the period 0 to 24 hours after transplantation was 20.1 +/- 14.7 ml/min in patients receiving active treatment and 18.2 +/- 13.7 ml/min in those receiving placebo. Thus. despite the documentation of a protective effect of atrial natriuretic factor in animal models of renal ischemia. it is unlikely that intravenous infusion of AP-3 in this dose range will be of benefit in improving immediate renal allograft graft function.
Changes in the central ANF-system of renovascular hypertensive rats, The central atrial natriuretic peptides (ANF)-system was investigated in volume-dependent. one-kidney. one-clip (1K1C) and renin-dependent two-kidney. one-clip (2K1C) renovascular hypertensive rats by radioimmunological measurement of ANF concentration in 18 selected brain areas. Significant changes were found in nine brain areas of 1K1C and in eight brain areas of 2K1C hypertensive rats. Except undirectional changes in the organum vasculosum laminae terminalis and the supraoptic nucleus. ANF concentration was changed in the opposite direction in all other brain areas. with an activation of the central ANF system in 1K1C and an inhibition in 2K1C hypertension. The localization of the alterations (circumventricular organs. anteroventral third ventricle region. hypothalamo hypophyseal system. brain stem) implies major differences in the central regulation of blood pressure and electrolyte and fluid homeostasis between these two models. The activation of the central ANF system in 1K1C hypertension may be a compensatory mechanism to prevent further increments in blood pressure and plasma volume. In contrast. the depression of the central ANF system in 2K1C hypertension may promote the elevation of the blood pressure.
Enhanced insulin sensitivity in extrarenal potassium handling in uremic rats, Translocation of potassium to the intracellular compartment is impaired in advanced chronic renal failure. The purpose of this study was to evaluate the role of endogenous insulin in the disposal of an oral potassium load in uremia. Experiments were done on male Sprague-Dawley rats. Chronic renal failure (CRF) was induced by 3/4 nephrectomy. The results show that the addition of oral glucose to a potassium load was more effective in the translocation of potassium to the intracellular compartment in uremic animals. Further. suppression of endogenous insulin secretion with somatostatin caused a much higher increase in plasma potassium (K) of uremic rats (1.09 +/- 0.15 mEq/liter in CRF vs. 0.28 +/- 0.03 mEq/liter in control). Experiments to assess the activity of the Na pump were done in soleus muscles derived from these animals. Although a 50% reduction of the basal Na pump activity was found in the uremic muscles. the addition of insulin 100 mU/ml caused a relatively greater stimulation of ouabain-sensitive 86Rb uptake in the uremic muscle as compared to the control tissue (203% vs. 77% increment). These data suggest a greater sensitivity to insulin action on extrarenal potassium disposal in uremia.
Enhanced renal leukotriene production in murine lupus: role of lipoxygenase metabolites, To investigate the potential role of leukotrienes in murine lupus. we measured renal hemodynamics and renal leukotriene production in MRL-lpr/lpr mice at 12 and 20 weeks of age. Over this age range. these animals develop overt manifestations of autoimmune disease with nephritis similar to human SLE. In the current study. we demonstrated that glomerular filtration rate (GFR) and PAH clearance (CPAH) deteriorated with age in MRL-lpr/lpr mice. but not in MRL(-)+/+ controls. Impaired renal hemodynamic function in MRL-lpr/lpr mice was associated with enhanced ionophore-stimulated production of both leukotriene B4 (LTB4) and leukotriene C4 (LTC4) by preparations of renal cortex. There was a significant inverse correlation between GFR and in vitro production of both LTC4 and LTB4 in kidneys from MRL-lpr/lpr mice. but not in control animals. In addition. in vitro LTC4 production was correlated with the severity of renal histomorphologic abnormalities. Administration of the specific peptidoleukotriene receptor antagonist SKF104353 to 20 week old MRL-lpr/lpr mice significantly improved both GFR and CPAH. whereas this agent had no effect of renal hemodynamics in MRL(-)+/+ controls. These results suggest that renal production of LTC4 and LTB4 is increased in MRL-lpr/lpr mice with nephritis. and that enhanced production of peptidoleukotrienes causes reversible renal dysfunction. Increased leukotriene production within the kidney may therefore be important in the pathogenesis of lupus nephritis.
Interferon gamma-mediated renal MHC expression in mercuric chloride-induced glomerulonephritis, In rodents. mercuric chloride (HgCl2) causes an autoimmune disorder with glomerulonephritis (GN). and represents an animal model for the pathogenesis of GN. We have tested the hypothesis that HgCl2 induces major histocompatibility complex (MHC) expression in renal parenchymal cells. and studied the kinetics of this induction and its temporal relation to the development of immune complex deposition in the glomeruli. Mice treated with doses of HgCl2 between 2 and 3.2 mg/kg three times for one week had increased renal expression of MHC class I and class II (at the mRNA and the product levels). Class I induction was observed in proximal tubule cells. endothelial cells and glomerular cells. Class II induction was seen mainly in interstitial cells and. to a lesser extent. in tubule cells. Renal MHC expression was maximal at one week. decreased progressively after the second week of HgCl2 administration. and reached basal levels by 23 weeks. In contrast. the amount of lymphocyte infiltration in the kidney increased from the first to the fifth week and was followed by the appearance of glomerular immune deposits from the third week on. Glomerular immune complex deposits were maximal at five weeks and. by 23 weeks. immune deposits in HgCl2-treated mice were only slightly increased over those observed in the sham group. Renal MHC induction by HgCl2 was significantly reduced by treatment with monoclonal antibody against interferon gamma.
Update: surveillance of outbreaks--United States, 1990, Although disease outbreaks are often preventable public health problems. no uniform national system exists in the United States for surveillance of outbreaks. In 1988. CDC's Epidemiology Program Office participated with the epidemiology programs in four states (Maryland. New York. Oklahoma. and Washington) in a 5-month trial of an electronic system for the timely surveillance of outbreaks (1). This report updates the initial trial by summarizing a pilot project of surveillance of outbreaks in nine states--Maryland. Mississippi. Missouri. New York. Oklahoma. Rhode Island. South Dakota. Vermont. and Washington.
Update: Yersinia enterocolitica bacteremia and endotoxin shock associated with red blood cell transfusions--United States, 1991, From April 1987 through August 1988. four cases of Yersinia enterocolitica bacteremia associated with red blood cell (RBC) transfusions were reported to CDC. This report summarizes findings from the investigation of an additional six cases reported from six different states from January 1989 through February 1991.
Fatal pediatric poisoning from leaded paint--Wisconsin, 1990, Although fatal lead poisoning among children occurs rarely in the United States. it represents a medical and public health emergency. This report summarizes the investigation of a child who died from poisoning associated with ingestion of lead-based paint.
Tuberculosis outbreak on Standing Rock Sioux Reservation--North Dakota and South Dakota, 1987-1990, From 1987 through 1988. a cluster of cases of tuberculosis (TB) occurred among persons residing on the Standing Rock Sioux Reservation; recognition of this cluster prompted an epidemiologic investigation by the Indian Health Service (IHS). Standing Rock Sioux Tribal Health and Community Health Programs. South Dakota State Department of Health. North Dakota State Department of Health. and CDC. This report summarizes the findings of that investigation and follow-up public health interventions.
The effect of intrauterine intravascular blood transfusion on iron metabolism in fetuses with Rh alloimmunization, Fetal plasma ferritin concentrations were measured in 43 normal fetuses at 18-36 weeks and in 78 blood samples collected before transfusion from 23 fetuses with Rh alloimmunization. Among controls. there was a significant correlation between fetal serum ferritin and gestational age (r = 0.39. P = .009). consistent with an increase in fetal storage of iron during normal pregnancy. In Rh-alloimmunized fetuses. the ferritin concentration was above the reference range in 63% of the samples. Before the first transfusion. the fetal ferritin concentration was increased compared with controls (mean multiples of the mean = 2.6. range 1-26) and showed a negative correlation with fetal hematocrit (r = -0.43. P less than .05). suggesting that the worse the fetal anemia. the higher the iron store. Serial transfusions were associated with further increase in serum ferritin. which correlated primarily with the total volume of blood transfused. Three fetuses had plasma serum ferritin concentrations above 1 mg/L. a level compatible with a diagnosis of iron overload in children. These observations suggest that there is a potential risk of iron overload in Rh-alloimmunized fetuses undergoing intrauterine blood transfusion.
Vestibular autorotation test asymmetry analysis of acoustic neuromas, The vestibular autorotation test (VAT) measures the vestibulo-ocular reflex (VOR) response from 2 to 6 Hz. during 18 seconds of active head movements. while the patient attempts to fixate on a wall-mounted target. A new method of measuring eye velocity asymmetry from VAT data is presented. based on computer estimation of the 0th harmonics of discrete Fourier spectra over short segments of digital eye and head velocity records. Eye asymmetries greater than a 3% normal range are shown to be directionally correlated with the side of the lesions in patients with unilateral labyrinthectomies. Among patients with a diagnosis of acoustic neuroma. who were tested preoperatively with the VAT. nine of nine patients showed eye asymmetries greater than 3% toward the side of the neuroma. Those patients with acoustic neuromas who have sufficiently vigorous high-frequency head responses showed mean percentages of eye asymmetry that were linearly correlated with the size of the acoustic neuroma. These results suggest that VAT high-frequency asymmetry provides a useful method of diagnostic evaluation of the side and extent of unilateral peripheral lesions.
The "plateau effect" of cis-platinum-induced hearing loss, Cis-platinum-induced hearing loss has been reported to exhibit a "plateau effect" over the 2 to 8 kHz range. We examined serial audiometry data from 27 patients treated with cis-platinum. Although a plateau at 60 to 70 dB HL often occurred. this hearing loss was clearly exceeded in a number of patients. We identified 14 patients with sufficient cis-platinum-induced sensorineural hearing loss to evaluate a plateau limit to hearing loss over the 4 to 8 kHz range. Half of these 14 patients had hearing losses that exceeded the plateau level. More severe 4 to 8 kHz hearing losses did not correlate with number of treatments. cumulative dosages of cis-platinum. pre-existing hearing loss. radiation therapy. other chemotherapeutic agents. or even hearing losses below 4 kHz. Although cis-platinum therapy can induce a plateau of moderate hearing impairment for some patients over the 4 to 8 kHz range. a significant proportion of patients will experience more severe hearing impairment in this range. even after only one or two courses of cis-platinum.
Vestibular and postural findings in the motion sickness syndrome, The motion sickness syndrome constitutes varying degrees of subjective motion intolerance and three objective findings: hyperactive VOR (79%). hip sway strategy (60%). and positional nystagmus (42%). It is present in subjects who have a strong history of motion sickness. Vestibular rehabilitation appears to help control symptoms. The study also suggests an inheritance pattern. but a structured pedigree could not be constructed. Prospective studies are warranted to further establish the patterns of the motion sickness syndrome.
Vestibular compensation after labyrinthectomy and vestibular neurectomy in cats, Labyrinthectomy and vestibular neurectomy are two ablative procedures used for definitive control of disabling vertigo. It is not known if vestibular compensation after labyrinthectomy and vestibular neurectomy differs. We have addressed this question by examining the pattern of recovery of the vestibular ocular reflex in cats after either labyrinthectomy or vestibular neurectomy. Temporal bone histologic examination confirmed the surgical lesion. Our results demonstrate a reduction of the long time constant of the vestibular ocular reflex in both groups of animals. Although gain of the vestibular ocular reflex recovered substantially. it never returned to control levels in either group. In general. animals that had undergone vestibular neurectomy demonstrated greater vestibular ocular reflex asymmetries than did labyrinthectomized animals. The recovery pattern of the vestibular ocular reflex indicates vestibular compensation is more rapid after labyrinthectomy than after vestibular neurectomy. We believe this result is related to survival of the vestibular nerve after labyrinthectomy. but not after vestibular neurectomy. suggesting that the vestibular nerve can contribute to the adaptive response after labyrinthectomy.
Intrinsic vasculature of the labyrinthine segment of the facial nerve--implications for site of lesion in Bell's palsy, Recent studies of the intrinsic vasculature of the cat facial nerve have demonstrated relatively poor blood supply to the labyrinthine segment. In this study. the intrinsic vasculature of the human facial nerve was systematically evaluated in 25 temporal bones and three fresh cadaver nerves. Cross-sectional vessel counts were obtained for the labyrinthine. tympanic. and mastoid segments. Capillary densities for each segment were derived from these data. The labyrinthine segment of the human facial nerve. like that in the cat. contains fewer and smaller intrinsic blood vessels than do the mastoid and tympanic segments. This may indicate that the labyrinthine segment of the facial nerve may be more vulnerable to ischemic damage. In conjunction with the previously demonstrated narrowness of the labyrinthine fallopian canal. these findings support the contention that the labyrinthine segment is a likely site of lesion in Bell's palsy.
Glomus tumors of the temporal bone: electron microscopic and immunohistochemical evaluation, Glomus tumors arising in the temporal bone are now recognized as being part of the diffuse neuroendocrine system. Material from 12 glomus tumors was studied by means of electron microscopic and immunohistochemical techniques to determine whether there was an association between tumor size. patient age. and the neuroendocrine functions of these tumors. Electronmicroscopic evaluation (seven tumors) revealed a highly variable concentration of neurosecretory granules. Immunohistochemical staining (nine tumors) demonstrated that glomus tumors do arise from neural ectoderm and that they all contain serotonin. The concentration of serotonin seems to correlate with the concentration of neurosecretory granules seen on electronmicroscopy. In addition. higher levels of serotonin were found in two patients who were in their late sixties. It is possible that some of the neuroendocrine activity associated with glomus tumors could be the result of the release of serotonin.
Transcanal infracochlear approach to the petrous apex, Computerized tomography and magnetic resonance imaging have now made it possible to reliably differentiate cholesteatoma from cholesterol granuloma of the petrous apex. The treatment for cholesteatoma is complete surgical excision when possible. whereas cholesterol granuloma needs only adequate drainage for control. A new transcanal infracochlear approach for drainage of cholesterol granuloma involving the anterior petrous apex is described. Absolute measurements from 10 cadaveric temporal bones were obtained to determine the distances between the cochlea. jugular bulb. carotid artery. and facial nerve. In all specimens the petrous apex was entered without invading the cochlea. carotid. or jugular bulb. Advantages of this technique include a more direct route to the petrous apex. dependent drainage. and preservation of the normal hearing mechanism. including the tympanic membrane. Clinical indications for this technique include failure of other treatment approaches and a high jugular bulb obstructing an infralabyrinthine approach. Experience to date shows that patients experience little difficulty from the procedure.
The modified transcochlear approach to the cerebellopontine angle, We have modified the transcochlear approach to improve exposure of the anterior petrous apex. clivus. anterior cerebellopontine angle. and the prepontine region. These changes include resection of the external auditory canal. middle ear. glenoid fossa. and posterior zygomatic arch. This approach provides improved exposure of the petrous carotid artery. jugular bulb. and clivus. It offers the largest and most lateral access to the anterior cerebellopontine and prepontine region. The results of this approach in 11 patients are discussed.
Comparison of speech perception abilities in deaf children with hearing aids or cochlear implants, The speech perception abilities of deaf children with a single- or multi-channel cochlear implant are compared with those of deaf children who derive substantial benefit from conventional hearing aids. The children with hearing aids have unaided pure-tone thresholds ranging from 90- to 110-dB HL through at least 2000 Hz. and aided thresholds of 30- to 60-dB HL. The group data show that the speech perception scores of the subjects with hearing aids were significantly higher than those of the subjects with implants on a range of speech perception measures. Although a few subjects with implants achieved scores as high as those who used hearing aids. the majority did not. Even though the children with implants receive substantial benefit from their devices. they continue to have limited auditory perception abilities relative to their peers who derive benefit from conventional hearing aids. The data highlight the importance of establishing hearing aid benefit in potential candidates for implant.
MRI of the facial nerve during paralysis, Gadolinium-enhanced MRI was used to evaluate 10 patients with Bell's palsy and one patient with facial paralysis secondary to Lyme disease. Nine of the eleven patients showed increased signal intensity of their facial nerve with gadolinium-enhanced MRI. In all nine patients. the facial nerve was involved at the labyrinthine. geniculate ganglion and proximal tympanic portions of the facial nerve. while two of the nine patients also had involvement of the mastoid segment of the facial nerve. Patients whose facial nerve enhancement was limited to the labyrinthine. geniculate ganglion and proximal tympanic facial nerve ultimately had complete return of facial function. Patients whose facial nerve enhanced in the mastoid segment experienced incomplete return of facial function. Gadolinium is effective in localizing the site of inflammation during facial paralysis. Those patients with enhancement localized to the labyrinthine. geniculate ganglion and proximal tympanic segments were more likely to regain complete facial function. In contrast. patients who had enhancement of the mastoid segment of the facial nerve had poorer prognoses for complete return of facial function.
Cochlear nucleus cell size is regulated by auditory nerve electrical activity, Accumulating evidence suggests that sensorineural hearing loss in animals is rapidly followed by degenerative changes in central auditory neurons. For example. cochlear removal in birds and mammals results in a reduction in central auditory neuron cell size within 48 hours. A similar decrease in cell size after pharmacologic blockade of auditory nerve electrical activity with tetrodotoxin has been reported. In the present study. we evaluate the reversibility of central auditory changes after a profound sensorineural hearing loss caused by blockade of auditory nerve actions potentials. Tetrodotoxin. which blocks voltage-sensitive sodium channels. was embedded in a slow-release vehicle and placed next to the round window membrane of gerbils. Tetrodotoxin diffused into perilymph and unilaterally blocked electrical activity in auditory nerve axons. Electrical activity blockade was confirmed with recordings of auditory brainstem response. Animals were killed immediately after 24 hours of electrical blockade or 7 days after a transient 24- or 48-hour blockade. Large spherical cells of the anteroventral cochlear nucleus ipsilateral to manipulation were measured and compared to large spherical cells on the opposite. unmanipulated side of the brain. Animals killed immediately after a 24-hour blockade of electrical activity showed a mean decrease of 16% in cell size ipsilateral to the blockade (p less than 0.05). In animals allowed to recover for 7 days after blockade for 24 or 48 hours. cell size returned to previous levels. There was no longer a consistent difference in cell size between the two sides of the brain in these animals (p greater than 0.05).
Identification of a gene located at chromosome 5q21 that is mutated in colorectal cancers, Recent studies have suggested the existence of a tumor suppressor gene located at chromosome region 5q21. DNA probes from this region were used to study a panel of sporadic colorectal carcinomas. One of these probes. cosmid 5.71. detected a somatically rearranged restriction fragment in the DNA from a single tumor. Further analysis of the 5.71 cosmid revealed two regions that were highly conserved in rodent DNA. These sequences were used to identify a gene. MCC (mutated in colorectal cancer). which encodes an 829-amino acid protein with a short region of similarity to the G protein-coupled m3 muscarinic acetylcholine receptor. The rearrangement in the tumor disrupted the coding region of the MCC gene. Moreover. two colorectal tumors were found with somatically acquired point mutations in MCC that resulted in amino acid substitutions. MCC is thus a candidate for the putative colorectal tumor suppressor gene located at 5q21. Further studies will be required to determine whether the gene is mutated in other sporadic tumors or in the germ line of patients with an inherited predisposition to colonic tumorigenesis.
Effect of stable xenon on regional cerebral blood flow and the electroencephalogram in normal volunteers, We evaluated the effects of breathing 35% stable xenon in 65% oxygen on regional cerebral blood flow and the electroencephalogram in 20 normal volunteers. We measured blood flow in 32 brain regions over both hemispheres with the xenon-133 intravenous injection technique in two protocols. In the first protocol (n = 10). a baseline study was followed by a second study during 5 minutes of breathing stable xenon; in the other protocol (n = 8). the baseline study was followed by a second study after 5 minutes of breathing stable xenon. Two volunteers were excluded due to excessive movements during the inhalation of stable xenon. Some of the remaining 18 volunteers had varying alterations of consciousness accompanied by electroencephalogram changes. After stable xenon inhalation the electroencephalogram returned to normal within 2-3 minutes. During stable xenon inhalation mean +/- SD PECO2 dropped significantly from 39.4 +/- 4.4 to 33.3 +/- 5.4 mm Hg in the first protocol and from 39.4 +/- 2.6 to 34.8 +/- 4.1 mm Hg in the second protocol due to hyperventilation in 13 volunteers. Mean regional cerebral blood flow increased significantly by 13.5-25.4% without correction for PECO2. In the first protocol regional cerebral blood flow increased by greater than 12% in 11-14 (depending on the flow parameter) of the 20 hemispheres. In the second protocol regional cerebral blood flow increased by greater than 12% in 9-13 of the 16 hemispheres. We conclude that cautious interpretation is necessary in the assessment of regional cerebral blood flow with 35% xenon-enhanced computed tomography.
Effect of high-dose methylprednisolone and U74006F on eicosanoid synthesis after subarachnoid hemorrhage in rats, Free radicals and lipid peroxidation of membrane fatty acids are thought to play a role in the pathogenesis of arterial vasospasm and the physiopathologic patterns of neuronal damage after subarachnoid hemorrhage. We have evaluated the effects of treatment with either high-dose methylprednisolone every 8 hours or a single dose of U74006F on the temporal profile of ex vivo synthesis of four selected eicosanoids in brain slices after experimental induction of subarachnoid hemorrhage in rats. Prostaglandins D2 and E2. prostacyclin and leukotriene C4 levels were determined by radioimmunoassay after 1-hour incubation of the brain slices. The synthesis of prostaglandin D2 and 6-ketoprostaglandin F1 alpha at 48 hours after subarachnoid hemorrhage was significantly higher when compared to sham-operated animals (p = 0.01); prostaglandin E2 release was significantly enhanced at 6 hours after subarachnoid hemorrhage (p = 0.01). The release of the lipoxygenase metabolite was significantly enhanced at 1. 6. and 48 hours after subarachnoid hemorrhage induction. Both treatment regimens significantly reduced the ex vivo synthesis of prostaglandin D2. prostaglandin E2. and leukotriene C4 at 1. 6. and 48 hours after subarachnoid hemorrhage. whereas the effects on 6-ketoprostaglandin F1 alpha synthesis differed in the two treatment groups. U74006F enhanced the synthesis of prostacyclin metabolite in the early phase after subarachnoid hemorrhage. and high-dose methylprednisolone reduced the increasing synthesis at 48 hours. A strict comparison between the two treatments was not possible because of the different modalities of administration. However. these data suggest that the antioxidant effect of single-dose treatment with U74006F influenced the early and delayed effects on enzymatic lipid peroxidation. whereas the effects of methylprednisolone administration every 8 hours were more significant in the delayed phase.
Decreased levels of polyunsaturated fatty acids in preeclampsia, Plasma levels of polyunsaturated fatty acids in the n-3 and n-6 classes. which include linoleic. linolenic. arachidonic. eicosapentaenoic. and docosahexaenoic acids. were quantified with high-performance liquid chromatography in nonpregnant volunteers and in patients with normal pregnancies or preeclampsia at term. The total polyunsaturated fatty acid levels were not significantly different between nonpregnant and normal pregnant patients but was significantly lower in the preeclamptic patients compared with normal pregnant patients. This decreased level could represent altered fatty acid metabolism or altered storage and mobilization from lipid pools. Compared with nonpregnant patients. normal pregnant patients had significantly higher levels of eicosapentaenoic and docosahexaenoic acid. This may reflect normal physiologic changes in pregnancy. and the decreased level of eicosapentaenoic acid seen in preeclamptic patients may play a significant role in the pathophysiology of preeclampsia.
Meconium-stained amniotic fluid: a risk factor for microbial invasion of the amniotic cavity, The purpose of this study was to determine whether meconium-stained amniotic fluid is a marker for microbial invasion of the amniotic cavity. Amniocentesis was performed on 707 patients presenting with preterm labor and intact membranes. Meconium-stained amniotic fluid was present in 4.2% (30/707) of patients with preterm labor. The prevalence of positive amniotic fluid cultures was significantly higher in women with meconium-stained amniotic fluid than in women with clear fluid (33% [10/30] vs 11% [75/677]; p = 0.001; odds ratio = 4.01; 95% confidence interval = 1.6 to 9.4). Patients with meconium-stained amniotic fluid were also more likely to have failed tocolysis and delivered a preterm neonate more frequently than patients with clear fluid (83% [25/30] vs 38% (258/677); p = 0.0001; odds ratio = 8.1; 95% confidence interval = 2.9 to 24.4). We conclude that meconium-stained amniotic fluid is a risk factor for microbial invasion of the amniotic cavity and preterm delivery in women with preterm labor and intact membranes.
A comparison of flurbiprofen, tranexamic acid, and a levonorgestrel-releasing intrauterine contraceptive device in the treatment of idiopathic menorrhagia, Treatment with flurbiprofen (100 mg twice a day for 5 days). tranexamic acid (1.5 gm three times a day for 3 days and 1 gm twice a day for another 2 days). and an intrauterine contraceptive device releasing 20 micrograms levonorgestrel per day was compared in women with idiopathic menorrhagia. The menstrual blood loss during two control periods in 15 women subsequently treated with flurbiprofen and tranexamic acid was 295 +/- 52 ml and 203 +/- 25.2 ml in the 16 women later fitted with a levonorgestrel-releasing intrauterine contraceptive device. Menstrual blood loss was reduced by all three forms of treatment. The reduction in menstrual blood loss expressed as a percentage of the mean of two control cycles for each form of treatment was as follows: flurbiprofen. 20.7% +/- 9.9%; tranexamic acid. 44.4% +/- 8.3%; levonorgestrel-releasing intrauterine contraceptive device after 3 months. 81.6% +/- 4.5%; levonorgestrel-releasing intrauterine contraceptive device after 6 months. 88.0% +/- 3.1%; levonorgestrel-releasing intrauterine contraceptive device after 12 months. 95.8% +/- 1.2%. The reduction in menstrual blood loss achieved by the levonorgestrel-releasing intrauterine contraceptive device was greater than that recorded with flurbiprofen (p less than 0.001) and tranexamic acid (p less than 0.01). and was greater for tranexamic acid when compared with flurbiprofen (p less than 0.05). The levonorgestrel-releasing intrauterine contraceptive device was the only form of treatment to reduce mean menstrual blood loss below 80 ml per menstruation. the upper limit of normal menstrual blood loss.
Cost-effectiveness of alpha-1 antitrypsin replacement therapy in treatment of congenital chronic obstructive pulmonary disease, BACKGROUND: Alpha 1-antitrypsin (AAT) replacement therapy is an expensive intervention ($20.000-$30.000 per patient annually) which may slow or arrest the progression of chronic obstructive pulmonary disease (COPD) in AAT-deficient patients. While FDA-approved. therapy efficacy is unknown. The costs and benefits of AAT replacement therapy were evaluated for patients with congenital COPD. METHODS: Epidemiological and disease cost data were taken from published sources. A discrete-time model of disease stage probability transition was developed to calculate the present-value expected cost of disease treatment. under a range of possible therapy efficacy and other parameter values. RESULTS: At an efficacy of 70 percent. the cost per life year saved with AAT replacement therapy would be between $28.000 and $72.000 (1990 US dollars). depending on patient age. sex. and smoking status. At 30 percent efficacy. the cost per life year saved range would be between $50.000 and $128.000. A controlled efficacy study would cost $53 million or less. if the true efficacy were 50 percent or better. CONCLUSIONS: With efficacy of 30 percent or higher. therapy cost-effectiveness would be comparable to other widely used medical interventions. The economic assessment methodology was used to evaluate both the therapeutic innovation and the value of additional clinical research.
Mast cells and cell-to-cell interactions in airways, Dog mastocytomas (anatomic and biochemical features comparable to normal dog and human mast cells) were used to study actions of mast cell mediators on several airway effector systems. We showed mastocytoma cell adherence to both cultured tracheal epithelial cells and tracheal tissue sections for greater than 48 h that was abolished completely by pretreatment of mast cells with proteases. This mast cell-epithelial cell adhesion-interaction reaction is probably mediated by a mast cell plasma membrane protein. Mast cell mediators stimulate short circuit current and ion flux across dog tracheal epithelia mounted in Ussing chambers. Pretreatment of epithelia with indomethacin blocks this effect. probably by inhibiting LTC4-induced activation of epithelial cyclooxygenases. Mastocytoma cells also increase secretion from cultured serous submucosal gland cells. Blockade of cyclooxygenase and lipoxygenase pathways in mastocytoma cells activated by calcium ionophore does not alter secretion of the serous cells induced by mastocytoma supernatant. but secretion induced by mastocytoma supernatant or purified mast cell chymase is markedly reduced by an inhibitor of chymase. These results suggest that mast cells can alter airway secretions not only by actions on ion flux in epithelial cells but also by actions on submucosal gland secretion; this latter action appears to be mediated by mast cell chymase. Finally. supernatants from mastocytoma cells stimulated by calcium ionophore greatly increase the sensitivity and magnitude of the contractile response of dog bronchial smooth muscle to histamine. These effects are blocked by an inhibitor of mast cell tryptase.
Role of arachidonic acid metabolites in oleic acid induced pulmonary injury in a canine model. Effect of ketoconazole (thromboxane synthetase inhibitor), This study was designed to investigate the effects of ketoconazole. a thromboxane synthetase inhibitor. on pulmonary and systemic hemodynamics and pulmonary function in experimental respiratory distress syndrome. Pulmonary artery infusion of oleic acid (PAIOA). 0.1 ml/kg. was used to cause lung injury. Ten dogs were randomized into two groups (Gps): Gp I (n = 5) acted as control. whereas Gp II (n = 5) were treated with IV ketoconazole (2.5 mg/kg bolus then 10 mg/kg/hour for 2.5 hours). Hemodynamics. extravascular lung water (EVLW). serum levels of PGE2. and TxB2 were obtained at baseline (BL) and at 30-minute intervals for 2.5 hours (T30-T150). After 30 minutes of PAIOA the mean arterial pressure (MAP) decreased significantly in both Gps (131 +/- 17 vs. 88 +/- 9 mmHg Gp 1. 119 +/- 9 vs. 79 +/- 8 mmHg Gp II. P less than 0.05); however. while MAP returned to BL values in Gp II. it remained significantly lower throughout the experimental interval in Gp I. Mean pulmonary artery pressure (MAP) was not significantly affected by PAIOA in either Gp. while pulmonary vascular resistance increased significantly from BL at T120 in Gp II. Pulmonary function measured by partial pressure of arterial O2 (PaO2) and extravascular lung water (EVLW) were significantly affected by PAIOA. There was a significant decrease in PaO2 (66 +/- 6 vs. 96 +/- 8 mmHg. Gp I and 60 +/- 7 vs. 100 +/- 6 mmHg. Gp II) as well as an increase in EVLW (604 +/- 61 vs. 135 +/- 9 ml. Gp I and 641 +/- 110 vs. 117 +/- 18 ml. Gp II) in both Gps.
Rehabilitation in spinal cord disorders. 3. Comprehensive management of spinal cord injury, This self-directed learning module highlights advances in the management of the person with a spinal cord deficit. Traumatic spinal cord injury is being used as the model. but the principles apply to all patients with spinal cord deficits. This article is part of the chapter on rehabilitation of spinal cord disorders for the Self-Directed Medical Knowledge Program Study Guide for practitioners and trainees in physical medicine and rehabilitation. Specifically. this section contains information regarding prehospital care. acute assessment and management. primary rehabilitation by systems. sexuality and psychosocial issues. management of pain and spasticity. functional goals. the role of functional electrical stimulation. and long-term follow-up.
Cost-effectiveness analysis of mass screening for breast cancer in Japan, The official Japanese recommendation for breast cancer screening is physical examination by a physician. in contrast to US recommendations of mammography. In this analysis of breast cancer screening. the authors used Japanese data in a cost-effectiveness model to compare the following five strategies: (1) no screening (N); (2) physical examination alone (PE); (3) mammography (MG); (4) PE followed by MG if PE findings were abnormal (PE----MG); and (5) PE combined with MG for all screened women (PE + MG). None of these programs would save medical expenditures. The total discounted net costs per patient (in US dollars) were as follows: N. +54; PE. +412; MG. +517; PE----MG. +340; and PE + MG. +731. The number of years of life saved per cohort of 100.000 asymptomatic Japanese women would range from 708 (PE----MG) to 3724 (PG + MG). The additional cost of each strategy (compared with N) per additional year of life would be +49.700 for PE. +40.400 for PE----MG. +14.300 for MG. and +18.000 for PE + MG. The least costly screening option (PE----MG) does not have the lowest cost per additional year of life saved (MG does). MG would be preferable to the current Japanese recommendation of PE alone.
Activity of intrapleural recombinant gamma-interferon in malignant mesothelioma, Twenty-two consecutive patients with malignant diffuse pleural mesothelioma were treated with recombinant gamma-interferon by the intrapleural route. Diagnosis was made by thoracoscopic examination and all cases were confirmed by the French Mesothelioma Panel of Pathologist. Patients were staged based on thoracoscopic examination and computed tomography (CT) scan: 12 patients were classified as Stage I and 10 were Stage II. A solution of gamma-interferon (40 X 106 U) was infused twice a week over 2 months. Every patient experienced fever. One patient had a Grade 2 leukopenia and one patient suffered from pleural empyema. Response evaluation was based on the following: (1) CT scan performed 2 weeks after treatment ended. and (2) repeat thoracoscopic examination with histopathologic verification in nine patients who had demonstrated a stabilization or a regression of the disease on CT scan. From the original group. 19 patients could be evaluated. Four complete thoracoscopic histopathologic responses and one partial response were observed in Stage I patients (56%). One partial response was observed in Stage II patients.
Parkinson's disease: new treatment strategies, Recent interest has focused on two novel approaches to the treatment of Parkinson's disease-medications to slow or arrest disease progression. and cerebral transplantation. Two recent studies have demonstrated that selegiline can slow. although not halt. the progression of recent-onset Parkinson's disease. The data are sufficiently compelling to justify the use of this drug in most new patients. It also seems reasonable to extrapolate from the data and offer this medication to all patients but those with the most advanced Parkinson's disease. The current focus on excessive oxidative stress as a causative factor has led some investigators to recommended treating patients with the antioxidant tocopherol (vitamin E). There is no clinical evidence demonstrating its effectiveness. but a current multicenter study is being conducted. with the results expected within the next 2 years. High-dose vitamin E (such as 800 to 2000 U/d). taken for a number of months. is probably harmless. It is probably reasonable. therefore. to allow patients to take this over-the-counter compound until more definitive evidence is available. Another antioxidant. vitamin C. has also been advocated as a means of slowing the progression of Parkinson's disease. There are no studies that demonstrate any clinical effectiveness. and there are also no ongoing studies investigating this issue in patients with Parkinson's disease. The excitement surrounding the initially favorable results of adrenal-brain transplantation has waned with the failure of numerous institutions to replicate the original dramatic success. While mild or occasionally moderate improvement has been noted in subsequent patients undergoing adrenal-brain transplantation. the improvement has not been sufficient to justify the risk and expense of this surgery.
Intractable epilepsy and structural lesions of the brain: mapping, resection strategies, and seizure outcome, Forty-seven patients with structural brain lesions on neuroimaging studies and partial epilepsy intractable to medical therapy were studied. Prolonged noninvasive interictal and ictal EEG recording was performed. followed by more focused mapping using chronically implanted subdural electrode plates. Surgical procedures included lesion biopsy. maximal lesion excision. and/or resection of zones of epileptogenesis depending on accessibility and involvement of speech or other functional areas. The epileptogenic zone involved exclusively the region adjacent to the structural lesion in 11 patients. It extended beyond the lesion in 18 patients. Eighteen other patients had remote noncontiguous zones of epileptogenesis. Postoperative control of epilepsy was accomplished in 17 of 18 patients (94%) with complete lesion excision regardless of extent of seizure focus excision. Postoperative control of epilepsy was accomplished in 5 of 6 patients (83%) with incomplete lesion excision but complete seizure focus excision and in 12 of 23 patients (52%) with incomplete lesion excision and incomplete focus excision. The extent of lesion resection was strongly associated with surgical outcome either in itself (p less than 0.003). or in combination with focus excision. Focus resection was marginally associated with surgical outcome as a dichotomous variable (p = 0.048) and showed a trend toward significance (p = 0.07) only as a three-level outcome variable. We conclude that structural lesions are associated with zones of epileptogenesis in neighboring and remote areas of the brain. Maximum resection of the lesion offers the best chance at controlling intractable epilepsy; however. seizure control is achieved in many patients by carefully planned subtotal resection of lesions or foci.
Clinical effects of allopurinol on intractable epilepsy, We studied the clinical efficacy of allopurinol as add-on therapy in 31 patients with intractable epilepsy. When administered for a short time. allopurinol was effective in 17 patients (55%); 8 were seizure-free. 8 had 75% decrease in seizure frequency. and 1 had greater than 50% decrease. Allopurinol was most effective in patients with localization-related epilepsy. especially in secondarily generalized tonic-clonic seizures. Allopurinol was not as effective in patients with Lennox syndrome or West syndrome. or in severe myoclonic epilepsy in infants. When allopurinol was administered greater than 1 year. its initial effectiveness continued in 8 of 14 patients who exhibited initial improvement. In 2 of the remaining 6 patients. the initial improvement disappeared during the course of treatment but control was regained by increasing the dosage of allopurinol. Mild side effects were observed in 4 patients (13%): drowsiness in 3 and abdominal pain in 1. Allopurinol may be a useful antiepileptic drug (AED). and a double-blind placebo-controlled trial should be performed.
Effect of metoclopramide on angiotensins, aldosterone, and atrial peptide during hypoxia, The coupling of aldosterone with renin is altered during acute hypoxemia. We measured the various components of the renin-angiotensin system and the plasma levels of immunoreactive atrial natriuretic factor (iANF) during room air and hypoxic gas-mixture breathing before and after administration of metoclopramide. a competitive antagonist of dopamine. Seven resting volunteers were studied 1 wk apart under room air and hypoxic conditions (inspired O2 fraction 0.12). During hypoxemia. the release of aldosterone induced by metoclopramide was significantly smaller. This change was associated with a slight increase in iANF and with a decrease in plasma angiotensin II levels. without any change in immunoreactive blood angiotensin I concentrations. Plasma electrolytes and blood acid-base status did not show relevant changes. nor did blood pressure and heart rate. We conclude that the decreased aldosterone concentrations seen under hypoxemia are related to decreased angiotensin II levels. Other influences. such as elevated ANF. may also mediate this effect.
Effects of PEEP on pulmonary hemodynamics in intact dogs with oleic acid pulmonary edema, The effects of positive end-expiratory pressure (PEEP) on the pulmonary circulation were studied in 14 intact anesthetized dogs with oleic acid (OA) lung injury. Transmural (tm) mean pulmonary arterial pressure (Ppa)/cardiac index (Q) plots with transmural left atrial pressure (Pla) kept constant were constructed in seven dogs. and Ppa(tm)/PEEP plots with Q and Pla(tm) kept constant were constructed in seven other dogs. Q was manipulated by using a femoral arteriovenous bypass and a balloon catheter inserted in the inferior vena cava. Pla was manipulated using a balloon catheter placed by thoracotomy in the left atrium. Ppa(tm)/Q plots were essentially linear. Before OA. the linearly extrapolated pressure intercept of the Ppa(tm)/Q relationship approximated Pla(tm). OA (0.09 ml/kg into the right atrium) produced a parallel shift of the Ppa(tm)/Q relationship to higher pressures; i.e.. the extrapolated pressure intercept increased while the slope was not modified. After OA. 4 Torr PEEP (5.4 cmH2O) had no effect on the Ppa(tm)/Q relationship and 10 Torr PEEP (13.6 cmH2O) produced a slight. not significant. upward shift of this relationship. Changing PEEP from 0 to 12 Torr (16.3 cmH2O) at constant Q before OA led to an almost linear increase of Ppa(tm) from 14 +/- 1 to 19 +/- 1 mmHg. After OA. Ppa(tm) increased at 0 Torr PEEP but changing PEEP from 0 to 12 Torr did not significantly affect Ppa(tm). which increased from 19 +/- 1 to 20 +/- 1 mmHg. These data suggest that moderate levels of PEEP minimally aggravate the pulmonary hypertension secondary to OA lung injury.
Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1, We examined the effects of TGF-beta 1 on induction of several activated macrophage antimicrobial activities against the protozoan parasite Leishmania. and on induction of tumoricidal activity against the fibrosarcoma tumor target 1023. TGF-beta by itself did not affect the viability of either the intracellular or extracellular target in concentrations up to 200 ng/ml. As little as 1 ng/ml TGF-beta. however. suppressed more than 70% of the intracellular killing activity of macrophages treated with lymphokines. In contrast. more than 100 ng/ml TGF-beta was required to suppress intracellular killing by cells activated with an equivalent amount of recombinant IFN-gamma. Addition of TGF-beta for up to 30 min after exposure to activation factors significantly reduced macrophage killing of intracellular parasites. Pretreatment of macrophages with TGF-beta was even more effective: treatment of cells with TGF-beta for 4 h before addition of activation factors abolished all macrophage intracellular killing activity. Regardless of treatment sequence. however. TGF-beta had absolutely no effect. at any concentration tested. on activated macrophage resistance to infection induced by lymphokines or by the cooperative interaction of IFN-gamma and IL-4. Effects of TGF-beta on tumoricidal activity of activated macrophages was intermediate to that of its effects on intracellular killing or resistance to infection. Lymphokine-induced tumor cytotoxicity was marginally (25%) affected by TGF-beta; 200 ng/ml was able to suppress IFN-gamma-induced tumoricidal activity by 40%. Thus. TGF-beta dramatically suppressed certain activated macrophage cytotoxic effector reactions. but was only partially or not at all effective against others. even when the same activation agent (IFN-gamma) was used. The biochemical target for TGF-beta suppressive activity in these reactions may be the pathway for nitric oxide production from L-arginine. because TGF-beta also inhibited the generation of nitric oxide by cytokine-activated macrophages.
The role of CD4+ cells in sustaining lymphocyte proliferation during lymphocytic choriomeningitis virus infection, The murine immune response to lymphocytic choriomeningitis virus (LCMV) infection involves the activation of CD8+. class I MHC-restricted and virus-specific CTL. At times coinciding with CTL activation. high levels of IL-2 gene expression and production occur. the IL-2R is expressed. and T cell blastogenesis and proliferation are induced. We have previously found that. although both CD4+ and CD8+ T cell subsets transcribe IL-2. the CD4+ subset appears to be the major producer of IL-2 whereas the CD8+ subset appears to be the major proliferating population when the subsets are separated after activation in vivo. The studies presented here were undertaken to examine the contribution made by the CD4+ subset to lymphocyte proliferation in vivo. Responses to LCMV infection were examined in intact mice and in mice depleted of CD4+ or CD8+ subsets by antibody treatments in vivo. Protocols were such that in vivo treatments with anti-CD4 or anti-CD8 depleted the respective subset by greater than 90%. In situ hybridizations demonstrated that the IL-2 gene was expressed in non-B lymphocytes isolated from either CD4+ cell-depleted or CD8+ cell-depleted mice on day 7 post-infection with LCMV. When placed in culture. however. cells from CD8+ cell-depleted mice produced significantly higher levels of detectable IL-2 than did cells isolated from CD4+ cell-depleted mice on day 7 post-infection. IL-2 was apparently produced in vivo in mice depleted of either CD4+ or CD8+ cells. as expression of the gene for the p55 chain of the IL-2R. IL-2 responsiveness. and lymphocyte proliferation were observed with cells isolated from both sets of mice. Lymphocyte proliferation was shown to be sustained in mice depleted of CD4+ cells in vivo by three criteria: 1) non-B lymphocytes isolated from infected mice depleted of CD4+ cells underwent more DNA synthesis than did those isolated from uninfected mice or from infected mice depleted of CD8+ cells; 2) leukocyte yields were expanded during infection of CD4+ cell-depleted mice; and 3) CD8+ cell numbers were increased during infection of CD4+ cell-depleted mice. The majority of non-B lymphocytes having the characteristics of blast lymphocytes was recovered in the CD8+ populations isolated from infected CD4+ cell-depleted mice. These findings suggest that the requirement for the CD4+ subset to sustain CD8+ lymphocyte proliferation in vivo is limited. and that CD4+ and CD8+ cell types can function independently in many aspects of their responses to viral infections.
Antigenicity and immunogenicity of a multiple peptidic construction of the Schistosoma mansoni Sm-28 GST antigen in rat, mouse, and monkey. 1. Partial protection of Fischer rat after active immunization, Among the schistosome proteins characterized as vaccine candidates. an Ag of 28 kDa (Sm-28-GST) has received considerable attention. It was shown to be antigenic in humans and protective in mice. rats. hamsters. and baboons. Synthetic peptides derived from its sequence have been used to characterize the immune response to the molecule and one of these. comprising aminoacids 115-131 has been shown to incorporate both T and B cell recognition sites in a variety of experimental models. An octameric ("octopus") construction of the 115-131 peptide has been synthesized and its antigenicity and immunogenicity have been examined. The octopus construct is immunogenic in rats. mice and baboons in the presence of CFA (for rodents) and Bacille-Calmette-Guerin vaccine (for primates) as adjuvants. This clearly indicates that the construction allowed the conservation of the immune sites of the cognate protein. Moreover. anti-octopus sera from immunized Fischer rats were able to mediate platelet-. macrophage-. and eosinophil-dependent cytotoxicity toward schistosomula. Rats immunized with the 115-131 octopus were partially protected against a challenge infection with Schistosoma mansoni cercariae and this was paralleled by an increased level of IgG and more importantly. of IgE Sm-28-GST-specific antibodies.
Substance P acts directly upon cloned B lymphoma cells to enhance IgA and IgM production, The IgA producing murine B lymphoma. CH12.LX.C4.4F10 (4F10) and the IgM producing murine lymphoma. CH12.LX.C4.5F5 (5F5) were found to express substantial numbers of substance P (SP) receptors having dissociation constants equal to 0.69 nM. Binding of SP by these B lymphoma cells was via the tachykinin-specific C-terminus sequence. Phe-X-Gly-Leu-Met-NH2. because SP. SP antagonist (D-Pro2-D-Phe7-D-Trp9-SP). eledoisin. and substance K could effectively inhibit radiolabeled SP binding. whereas the SP N-terminus fragment. SP (1-4). could not. The functionality of these receptors could be demonstrated by the ability of subnanomolar concentrations of SP to induce Ig secretion in a dose-dependent fashion. However. the presence of a second stimulus in these cultures was required to obtain maximal increases. IgA secretion by 4F10 cells was elevated only 25 to 37%. and IgM secretion by 5F5 cells was not significantly increased in cultures in which nanomolar concentrations of SP were present. Conversely. coculturing 5F5 cells with a suboptimal concentration of LPS (50 ng/ml) and 10(-10)M SP resulted in an approximate threefold increase in supernatant IgM when compared to control cultures stimulated with LPS alone. While not as dramatic. 10(-10) M SP also enhanced IgA secretion of LPS-stimulated 4F10 cells by approximately 45%. This enhancement of Ig secretion was SP-specific. as evidenced by the ability of 1000-fold excess of SP antagonist to block SP-induced. but not LPS-induced. Ig production. Clearly. SP could act synergistically with LPS to enhance Ig secretion; therefore. we questioned whether this augmentation was also reflected at the level of H chain mRNA expression. 10(-9)M SP induced modest increases (50 to 60%) in mu-chain mRNA expression by LPS-stimulated 5F5 cells when compared with cells stimulated with LPS alone. The 4F10 cells did not display this magnitude of difference for alpha-chain mRNA expression. Thus. although SP-induced increases of mu-chain mRNA by 5F5 cells may contribute to the increased Ig secretion observed by these LPS-activated lymphocytes. it is unlikely that increased mRNA expression can totally account for the threefold increases in secretion that were observed.
Multiple patterns of alloantigen presenting/stimulating cell dysfunction in patients with AIDS, The APC/stimulating cell (APC/SC) potential of PBMC from Walter Reed stage 1 and 2 patients and patients with AIDS was tested by using these PBMC as stimulators in an allogeneic MLR. The responding cells were PBMC from unrelated. HIV- donors that were either unfractionated or depleted of APC by plastic and nylon wool adherence. Using this approach. we observed no defect in the APC/SC potential of PBMC from Walter Reed stage 1 and 2 patients. However. PBMC from AIDS patients used as allogeneic stimulators exhibited three different patterns of APC/SC function: 1) no defect in alloantigen (ALLO) APC/SC potential; 2) a defect in ALLO APC/SC function that was detected only if the responder cells were depleted of APC (presenting cell defect); and 3) a defect in ALLO APC/SC function. irrespective of whether the responder cells were depleted of APC (stimulating cell defect). These results indicate that in addition to Th cell defects associated with AIDS. the PBMC from AIDS patients can also exhibit a defect in APC/SC function. This study provides an approach that permits the testing of Ag-presenting function in all AIDS patients. and is therefore not limited to testing patients for whom HIV-. HLA-identical T cells and APC are available.
Infection of CD8+ T lymphocytes with HIV. Requirement for interaction with infected CD4+ cells and induction of infectious virus from chronically infected CD8+ cells, In this study. we have investigated the basic requirements for HIV-1 infection of CD8+ lymphocytes in vitro. Unfractionated PBL obtained from healthy HIV-1 seronegative donors were activated with PHA and infected in vitro with HIV-1LAV. Based on immunofluorescent labeling. the vast majority of cells (85 to 97%) surviving peak virus replication belonged to the CD8+ subset and only a small percentage (0.5 to 1.5%) were CD4+. Amplification of HIV-1 proviral sequences by polymerase chain reaction performed on the sorted surviving CD8+ cells demonstrated that CD8+ cells harbored HIV-1 proviral DNA. In addition. stimulation of these HIV-1-infected. CD8(+)-sorted cells either with PHA or anti-CD2 mAb resulted in induction of virus replication. as measured by reverse transcriptase activity. Electron microscopic analysis of CD8+ cells chronically infected with HIV-1 and stimulated with PHA showed typical virions budding from. and associated with. the surface of cells immunolabeled with gold beads directed toward the CD8 molecule. Infection of CD8+ cells with HIV-1 occurred only when CD4+ cells were present in the PHA-activated lymphocyte population exposed to HIV-1 at the beginning of the culture or when sorted CD8+CD4- lymphocytes were cocultured with autologous sorted CD8-CD4+ cells that had been previously infected with HIV-1. Coculture of these cells with PHA-blasts and incubation of their supernatants with a CD4+ cell line showed that these chronically infected CD8+ cells could spread HIV-1 infection to uninfected CD4+ cells after stimulation with PHA or anti-CD2 mAb. Therefore. these results suggest that the minimal requirement for in vitro infection of CD3+CD8+CD4- lymphocytes is the presence of infected CD4+ cells and that infected CD8+ T lymphocytes can further spread the infection to CD4+ cells.
T-dependent destruction of thyroid isografts exposed to IFN-gamma, Several autoimmune diseases are accompanied by tissue-specific expression of class II molecules of the MHC. and it has been suggested that this elicits a T cell response against tissue-specific Ag to which the individual is not tolerant. However. recent transgenic studies have indicated that non-lymphoid expression of class II genes in the pancreas. liver. and kidney is either innocuous or induces peripheral tolerance. To test this hypothesis in another organ-specific autoimmune disease. we attempted to induce autoimmune thyroiditis in normal mice with class II+ thyroid tissue. Normal thyroid lobes were cultured with and without IFN-gamma and then transplanted to adult isogeneic recipients. The thyroid that had been induced to express class II genes by IFN-gamma was destroyed in normal mice. whereas the control cultured thyroid and the native cervical gland survived. Both types of transplants remained intact and functional in congenic nu/nu recipients. indicating that neither exposure to IFN-gamma nor expression of class II genes compromised the thyroid. Thus. in some tissues. exposure to IFN-gamma and/or the induction of class II expression can lead to T-dependent autoimmune disease.
Myasthenia gravis. T epitopes on the delta subunit of human muscle acetylcholine receptor, Autoimmune T cell lines specific for muscle nicotinic acetylcholine receptor (AChR) were propagated from the blood of three myasthenia gravis patients by the use of a pool of synthetic peptides (delta-pool) corresponding to the complete sequence of the delta-subunit of human muscle AChR. Propagation of AChR-specific T cell lines was attempted unsuccessfully from four other myasthenia gravis patients and from four healthy controls. The lines had CD3+. CD4+. CD8- phenotype. strongly recognized the delta-pool. and cross-reacted vigorously with non-denatured AChR purified from mammalian muscle. They did not cross-react detectably with pools of similar overlapping synthetic peptides corresponding to the complete sequences of the alpha- and gamma-subunits of human muscle AChR. The sequence segments of the delta-subunit that contain T epitopes were identified by investigating the response of the three CD4+ T cell lines to the individual synthetic peptides forming the delta-pool. Each line had an individual pattern of peptide recognition. Although no immunodominant region. recognized in association with different DR haplotypes. could be identified. the sequence segments most strongly recognized by the CD4+ T cell lines were clustered within residues 121-290. One of the peptides more strongly recognized by the T cells corresponded to a sequence segment with high predicted propensity to form an amphipathic alpha-helix. a structural motif proposed to be typical of T epitopes.
Complement-mediated lysis of Trypanosoma cruzi trypomastigotes by human anti-alpha-galactosyl antibodies, Antibodies that lyse trypomastigotes in a complement-mediated reaction are believed to be the main participants in the protection against virulent Trypanosoma cruzi. Antibodies with a specificity for alpha-galactosyl-containing determinants--generally called antiGal--were studied to determine their role in the lysis of trypomastigote forms. The titers of antiGal markedly increase in Chagas's disease. In the present study we demonstrate binding of this antibody to T. cruzi and the complement-mediated lysis of trypomastigotes by antiGal. Lysis of metacyclic trypomastigotes by whole Chagasic (Ch) serum or isolated antiGal fractions was equally inhibited by alpha- but not by beta-galactosides. Most of the lytic power of the Ch antiGal as well as of the whole Ch serum was removed by absorption on Synsorb-linked Gal alpha 1. 3Gal beta 1. 4GlcNAc followed by rabbit erythrocyte absorption. The Ch antiGal had a lower affinity for melibiose bound to agarose than for the trisaccharide linked to Synsorb. and was several times more effective in the immunolysis of trypomastigotes than the corresponding antiGal from normal human serum. Lytic antibodies were partly absorbed by Serratia marcescens but not by Escherichia coli O111. A human volunteer immunized with an S. marcescens vaccine elicited a specific antiGal response that was lytic to trypomastigotes (70% lysis). We suggest that in vivo high-affinity antiGal antibody clones. as occur in Ch patients. may significantly contribute to the destruction of the parasite. whereas low-affinity antiGal clones are much less effective in the protection against T. cruzi infection.
Rapid localization of indium-111-labeled inhibited recombinant tissue plasminogen activator in a rabbit thrombosis model, The thrombus localizing properties of indium-111-recombinant tissue plasminogen activator (111In-rt-PA) have been investigated in an effort to achieve prompt and accurate detection of thrombi. Unlike previous studies with rt-PA. the active plasminogen catalytic site was permanently inhibited with peptides of chloromethyl ketone so that the radiotracer binds to fibrin without causing fibrinolysis. Thrombi were created in the external jugular vein of 14 male New Zealand white rabbits followed by injection of 111In-rt-PA. The agent cleared rapidly in vivo with a half-time of 4.6 min. The thrombus: blood ratio in nonheparinized rabbits (n = 7) was 6.39 +/- 0.86. The ratio in heparinized rabbits (n = 4) was 3.11 +/- 0.23. Thrombi were clearly visible in the planar images of both groups 1 hr postinjection. The combination of rapid thrombus localization and positive images. especially in the presence of anticoagulation. suggests that further work is warranted with rt-PA thrombus imaging.
Absent splenic uptake of indium-111-oxine-labeled autologous leukocytes in functional asplenia, An incidental finding of absent splenic uptake of autologous. indium-111-oxine-labeled leukocytes in an immunosuppressed renal transplant recipient was documented to be associated with functional asplenia based on absence of technetium-99m-sulfur colloid clearance by a morphologically normal spleen. The patient had recently suffered an episode of disseminated varicella infection that might have led to the development of functional asplenia.
Possible regulation of atrial natriuretic factor by neutral endopeptidase 24.11 and clearance receptors, The effects of a clearance receptor ligand Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Gly-Ala-Cys-NH2 with a disulfide bridge between the two cycteines [C-ANF(4-23)] and the potent neutral endopeptidase (NEP) inhibitor SQ 28.603 on mean arterial pressure (MAP). plasma atrial natriuretic factor (ANF) concentration and renal excretion of sodium and cyclic GMP were determined in conscious deoxycorticosterone acetate/salt hypertensive rats and normotensive rats. In the hypertensive rats. i.v. infusion of C-ANF(4-23) produced depressor responses of approximately 25 mm Hg. but did not significantly affect plasma ANF concentration or stimulate cyclic GMP excretion. In contrast. SQ 28.603 (300 mumol/kg i.v.) significantly reduced MAP and increased excretion of sodium and cyclic GMP. When C-ANF(4-23) was administered in combination with SQ 28.603. the depressor activity was additive and plasma ANF concentrations were significantly increased. The excretion of cyclic GMP was slightly enhanced. but. was not significantly different from the effects of SQ 28.603 alone. Neither SQ 28.603 nor C-ANF(4-23) affected MAP or plasma ANF in the normotensive rats. Finally. the in vitro hydrolysis of C-ANF(4-23) by NEP was prevented by SQ 28.603. indicating that inhibition of NEP may protect peptides recognized by the clearance receptors as well as the biological receptors for ANF. Therefore. the additive effects of C-ANF(4-23) and SQ 28.603 may be due to blockade of separate pathways which inactivate ANF or to the inhibition of C-ANF(4-23) degradation by NEP.
5-lipoxygenase inhibitory activity of zileuton, Zileuton [N-(1-benzo[b]thien-2-ylethyl)-N-hydroxyure] inhibited 5-hydroxyeicosatetraenoic acid synthesis by rat basophilic leukemia cell 20.000 x g supernatant and rat polymorphonuclear leukocytes (PMNL) (IC50 = 0.5 and 0.3 microM) respectively. It also inhibited leukotriene (LT)B4 biosynthesis by rat PMNL (IC50 = 0.4 microM). human PMNL (IC50 = 0.4 microM) and human whole blood (IC50 = 0.9 microM). Inhibition of human PMNL LTB4 biosynthesis was removed readily by a simple wash procedure. At concentrations up to 100 microM. the compound produced little or no inhibition of several related enzymes. such as platelet 12-lipoxygenase. soybean and rabbit reticulocyte 15-lipoxygenase and sheep seminal vesicle cyclooxygenase. At p.o. doses from 0.5 to 5 mg/kg in the dog. zileuton produced a rapid and sustained inhibition of ex vivo blood LTB4 biosynthesis which correlated with the pharmacokinetic behavior of the compound. In a similar ex vivo study in the rat. the compound displayed an p.o. ED50 of 2 mg/kg. Zileuton was highly effective in preventing 6-sulfidopeptide LT formation in the rat peritoneal cavity triggered by an antigen-antibody reaction with an ED50 of 3 mg/kg. In experimental models of inflammation. zileuton significantly reduced arachidonic-acid induced mouse ear edema (ED50 = 31 mg/kg) and also attenuated inflammatory cell accumulation in the rat pleural Arthus reaction. The effectiveness of this compound for preventing LT formation in vitro. ex vivo and in vivo suggests its utility for preventing the pathophysiological effects of the LTs and other 5-lipoxygenase products in animals and in humans.
Outbreak of pellagra among Mozambican refugees--Malawi, 1990, Micronutrient deficiency disorders. including pellagra. have emerged as major problems in refugee populations that depend on international relief assistance for food supplies. This report summarizes an investigation of pellagra that occurred among Mozambican refugees in Malawi during 1990.
Nutritional assessment of children in drought-affected areas--Haiti, 1990, From January through June 1990. a drought occurred in the Caribbean nation of Haiti. To determine whether the nutritional status of young children had been affected by drought-related reductions in food supply. in September 1990 a nutrition survey was conducted in the five departments most affected (Nord-Ouest. Nord. Nord-Est. Artibonite. and Centre) of Haiti's nine departments.
A second maternally expressed Drosophila gene encodes a putative RNA helicase of the "DEAD box" family, Recently. a family of proteins containing the conserved motif Asp-Glu-Ala-Asp. the "DEAD box" proteins. has been identified. This family is typified by the eukaryotic translation initiation factor eIF4A. and its members are believed to share the functional property of ATP-dependent RNA unwinding. One of the previously identified members of this family (vasa) is the product of a maternally expressed gene from Drosophila melanogaster that is known to play a role in the formation of the embryonic body plan. We report here the isolation of a Drosophila gene that has an mRNA expression pattern somewhat similar to that of vasa and also encodes a DEAD box protein. We have termed this gene ME31B to reflect its maternal (ovarian germ-line) expression and its location within the 31B chromosome region. Comparisons with the other members of this family reveal that although ME31B is most like the protein Tif1/Tif2. which probably represents the Saccharomyces cerevisiae version of eIF4A. it is unlikely that ME31B represents the Drosophila eIF4A protein per se. A search for mutations in the ME31B gene has established that the P element which causes the female-sterile mutation flipper lies in the 3' flank of the ME31B gene.
Regulation of luteinizing hormone-releasing hormone receptor binding by heterologous and autologous receptor-stimulated tyrosine phosphorylation, Pancreatic cancers overexpress tyrosine kinase and luteinizing hormone-releasing hormone (LH-RH) receptor (LH-RHR)-mediated tyrosine phosphatase. LH-RHR is a 60-kDa protein. One of the substrates of epidermal growth factor (EGF)-stimulated tyrosine kinase activity and LH-RH- and somatostatin-stimulated tyrosine phosphatase activity is also a 60-kDa protein. This suggests the possibility that LH-RHR regulation by tyrosine phosphatase and tyrosine kinase is mediated by (de)phosphorylation of existing LH-RHR. To test this hypothesis. membranes of MIA PaCa-2 cells. a human dedifferentiated pancreatic cancer cell line. were incubated without hormone (control) or with 0.1 microM EGF or somatostatin analogue RC-160 for 1 hr at 4 degrees C to phosphorylate the 60-kDa protein. Competition binding experiments with I125-labeled [D-Trp6]LH-RH by displacement with a nonradioactive ligand showed that the LH-RH binding in 69% of the points was increased by EGF and 85% was decreased by RC-160 compared with controls (n = 61; both significant. P less than 0.001). The specific binding was altered. increasing 50-150% after preincubation with EGF and decreasing 60-70% after RC-160. No change was seen in the binding affinity constant after pretreatment with EGF or RC-160. This shows that phosphorylation regulates binding of LH-RH and may explain the up-regulation by EGF and down-regulation by RC-160 and by LH-RH of the LH-RH response.
The pituitary gland is required for protection against lethal effects of Salmonella typhimurium, One-half of pituitary-intact or sham-operated rats survive infection with 10(9) colony-forming units of Salmonella typhimurium. whereas rats without a pituitary gland all die within a few days. When the dose of S. typhimurium is reduced 600-fold. 15-25% of the hypophysectomized rats survive. and the survival rate is significantly enhanced by administration of tetracycline. recombinant interferon gamma (IFN-gamma). or recombinant growth hormone (GH). The protective effect of GH is abolished by heat inactivation or with an antibody to GH. Spleens from normal and hypophysectomized rats treated with tetracycline. IFN-gamma. or GH have 59-99% fewer bacteria 5 days after infection as compared to control rats. Peritoneal macrophages from hypophysectomized rats that are infected in vitro with S. typhimurium kill half as many extracellular bacteria as compared to pituitary-intact rats. and this bactericidal capacity is significantly augmented 75-95% by either GH or IFN-gamma. These data establish that the pituitary gland is essential for homeostasis during an infectious episode and that GH plays an important role in host resistance by augmenting the ability of macrophages to kill S. typhimurium.
Restricted T-cell receptor V beta gene usage by myelin basic protein-specific T-cell clones in multiple sclerosis: predominant genes vary in individuals, Recent studies in experimental autoimmune encephalomyelitis as a model for multiple sclerosis (MS) have demonstrated limited heterogeneity in T-cell antigen receptors (TCR) specific for myelin basic protein (MBP). To investigate restricted beta-chain variable-region (V beta) gene usage in humans. we analyzed TCR gene rearrangements in two lines and 34 MBP-specific T-cell clones that were isolated from five MS patients and two healthy subjects. The T cells were characterized for their specificity to MBP epitopes and HLA-restricting molecules. We demonstrate here that MBP-specific T-cell clones from these different MS patients and healthy individuals. in contrast to T cells from rodents. display a more diverse V beta gene usage as evidenced by their TCR V beta gene rearrangements. However. the different MBP-specific T-cell clones isolated from each individual MS patient showed a common V beta gene usage. suggesting individual-specific TCR restriction. Out of 16 MBP-specific clones derived from a single MS patient. 12 clones (75%) utilized the V beta 15 gene for their TCR gene rearrangement. MBP-specific clones isolated from four other MS patients also showed a consistent tendency for a predominant. but different. TCR V beta gene rearrangement. These results suggest a TCR heterogeneity among MBP-specific T-cell clones from different individuals but a limited TCR V beta gene usage among MBP-specific T-cell clones of the same individual. The predominant V beta gene used by the MBP-specific T-cell clones studied here was not found to correlate with the epitope specificity of T cells or with their restricting HLA molecule. These findings may support the possibility of intervention with monoclonal antibodies to specific V beta gene products as an approach to immune therapy of MS but also imply the necessity for an individual-specific immunotherapeutic approach.
Immunological suppression by human CD8+ T cells is receptor dependent and HLA-DQ restricted, Mechanisms of specific immunologic unresponsiveness or tolerance and their regulation by the major histocompatibility complex remain central issues in immunology. Recent findings that potentially reactive anti-self T cells are not completely clonally deleted in the thymus and that specific immunological unresponsiveness can be acquired in certain infectious diseases. such as leprosy. suggest that peripheral unresponsiveness can be developed and maintained in adults. Human antigen-specific T suppressor cells represent one mechanism of peripheral tolerance. Clones of CD8+ T suppressor cells have been derived from blood or lesions of patients with lepromatous leprosy who are selectively unable to mount cellular immunity to Mycobacterium leprae. Using a panel of M. leprae-specific CD4+ and CD8+ T-cell clones of differing major histocompatibility complex class II haplotypes. suppression in vitro was found to be restricted by HLA-DQ and not by HLA-DR and inhibited by antibodies to HLA-DQ. In addition. antigen-induced suppression could be inhibited by antibodies specific to appropriate polymorphic T-cell receptor beta chains of the CD8+ clones. The results establish that activation of specific T suppressor cells is dependent on their polymorphic T-cell receptors and suggest that HLA-DQ serves as the preferred restricting element for suppression.
Comparison of celiprolol and propranolol in stable angina pectoris. Celiprolol International Angina Study Group, The comparative antianginal effects and safety of propranolol and celiprolol. a highly beta 1-selective adrenoceptor blocker with selective partial beta 2-adrenoceptor agonist activity. were assessed in an international multicenter. placebo run-in. active control. double-blind. randomized. titration-to-effect study of 140 patients with stable. exercise-induced angina pectoris. At baseline. all patients received placebo for 2 weeks. then titrated doses of once-daily celiprolol (200. 400. 600 mg) or twice-daily propranolol (total daily dose 80. 160. 320 mg) over 4 weeks. followed by a 2-week maintenance period. Heart rate and blood pressure. at rest and with exercise. weekly anginal attack frequency. nitroglycerin consumption and symptom-limited treadmill exercise times (modified Bruce protocol) were assessed. Compared with their respective baselines. both celiprolol and propranolol reduced anginal attack and nitroglycerin consumption rates to a comparable degree. while improving exercise tolerance (p less than 0.05). Treatment with propranolol compared with celiprolol. however. was associated with a significantly lower heart rate at rest (p less than 0.01). The double-product at the conclusion of exercise testing was significantly reduced by both drugs. Celiprolol and propranolol had similar effects on blood pressure. and were well tolerated. More symptomatic bradycardia occurred with propranolol. Despite the differences in their hemodynamic actions. once-daily celiprolol is as effective as twice-daily propranolol in the treatment of patients with stable angina pectoris.
Cardiovascular effects of bupropion in depressed patients with heart disease, OBJECTIVE: The cardiovascular effects of therapeutic plasma levels of tricyclic antidepressants in depressed patients with and without preexisting cardiac disease have been well characterized and include orthostatic hypotension and conduction delay. Bupropion. structurally unrelated to tricyclic antidepressants. is relatively free of cardiac side effects in depressed patients without cardiac disease. However. it is unknown whether bupropion is safe for depressed patients with preexisting heart disease. so the authors studied the cardiovascular effects of bupropion in such patients. METHOD: The subjects were 36 inpatients with DSM-III major depression and preexisting left ventricular impairment (N = 15). ventricular arrhythmias (N = 15). and/or conduction disease (N = 21). The patients continued their cardiac drug regimens and received bupropion for 3 weeks (mean +/- SD dose = 442 +/- 47 mg/day). Cardiovascular functioning was measured by pulse. blood pressure. high-speed ECG. 24-hour portable ECG. and radionuclide angiography. RESULTS: Although bupropion caused a rise in supine blood pressure. it did not cause significant conduction complications. did not exacerbate ventricular arrhythmias. had a low rate of orthostatic hypotension. and had no effect on pulse rate. However. bupropion treatment was discontinued for 14% of the patients because of adverse effects. including exacerbation of baseline hypertension in two patients. CONCLUSIONS: The cardiovascular profile of bupropion may make this drug a useful agent in the treatment of the depressed patient with preexisting cardiovascular disease. Further studies. with longer durations of bupropion treatment and more subjects. are needed to confirm these findings.
Acute ventilatory response to green coffee dust extract, The lung function response to inhalation of an extract of green coffee was studied in ten healthy subjects who were prescreened for airway hyperresponsiveness to an aerosol of green coffee extract. The effects of this provocation were evaluated at rest and following moderate exercise as well as with and without pretreatment with 80 mg of disodium cromoglycate (DSCG). There was a statistically significant decrement in lung function over time (P less than .001) following coffee provocation both at rest and following exercise. No significant protection against this response was observed with DSCG pretreatment. While the majority of these "healthy" coffee reactors exhibited baseline nonspecific airway hyperresponsiveness to methacholine (PC20 FEV1 less than 25 mg/mL in 7/10). there was no correlation in these ten subjects between baseline responsiveness to methacholine and the degree of lung function decrement following coffee (P greater than .05). Also. no correlation was observed between skin prick and lung function response to coffee extract. We conclude that inhalation of green coffee extract causes significant bronchoconstriction in selected healthy volunteers and that this response is not prevented by pretreatment with DSCG.
Comparison of intranasal cromolyn sodium, 4%, and oral terfenadine for allergic rhinitis: symptoms, nasal cytology, nasal ciliary clearance, and rhinomanometry, Topical intranasal cromolyn sodium. 4% solution. and oral terfenadine. 60 mg tablets. both relieve symptoms of allergic rhinitis with few or no adverse effects. but no comparison of their relative efficacy has been reported. In this double-blind. double-dummy study. 79 patients. ages 12-56 years with symptoms of allergic rhinitis. were randomized to receive either active cromolyn sodium. 1 spray in each nostril QID. or active terfenadine BID along with the appropriate placebo spray or tablet for 4 weeks following a 1-week baseline qualification period. Patients' daily symptom scores were reviewed weekly and constituted the primary efficacy measures. Changes in nasal cytology. nasal ciliary clearance. and rhinomanometry were also assessed. The presence of adverse effects and the overall score of medication efficacy at the end of each week was recorded. The cromolyn sodium and terfenadine groups had comparable baseline scores for severity of allergic rhinitis symptoms and both treatments resulted in significant improvement (P less than .0001) with no statistical difference between them for total symptom scores at the end of 4 weeks. Eosinophils in nasal samples were decreased significantly in the cromolyn treated group with no significant change in the terfenadine-treated group. There were no significant differences between treatment groups in ciliary clearance or rhinomanometry. Adverse effects were uncommon and mild. We conclude that cromolyn sodium and terfenadine are comparably effective and well-accepted treatments for allergic rhinitis.
Periodic acid-Schiff-positive organisms in primary cutaneous Bacillus cereus infection. Case report and an investigation of the periodic acid-Schiff staining properties of bacteria, Primary cutaneous Bacillus cereus infection frequently presents as a single necrotic bulla on the extremity of an immunocompromised patient. In lesional biopsy specimens and smears. the large gram-positive rods of B cereus may be mistaken for Clostridium species. This is a potentially serious error. as Bacillus species are resistant to penicillin and other beta-lactam antibiotics. We studied a case in which large periodic acid-Schiff-staining organisms were seen in the biopsy specimen from a necrotic bulla on the finger of a neutropenic patient with diffuse large cell lymphoma. The tissue biopsy specimen subsequently yielded a pure culture of B cereus. Staining with periodic acid-Schiff was then performed on a series of bacterial species in human tissue and from smears of culture colonies. The following bacterial species were found to be consistently periodic acid-Schiff positive after diastase digestion: B cereus. Corynebacterium diphtheriae. Propionibacterium acnes. Klebsiella pneumoniae. and Micrococcus luteus.
Pathophysiological role of augmented atrial natriuretic polypeptide gene expression in DOCA-salt hypertension. Effects of atrial natriuretic polypeptide monoclonal antibody, To elucidate the pathophysiological significance of endogenous atrial natriuretic polypeptide (ANP) in hypertension. we investigated the biosynthesis and secretion of ANP in deoxycorticosterone acetate (DOCA)-salt hypertensive rats and also examined the effect of passive immunization with monoclonal antibody raised against alpha-rat ANP on the development of hypertension in DOCA-salt rats. The plasma ANP level in DOCA-salt rats was significantly elevated in comparison to control rats. While the atrial ANP concentration in DOCA-salt rats was not significantly altered. the atrial level of ANPmRNA in DOCA-salt rats was two-fold higher than that in control rats. These results suggest the augmented biosynthesis of ANP in the atrium and the oversecretion of ANP from the heart in DOCA-salt rats. The levels of ANP and ANPmRNA in the ventricle of DOCA-salt rats exhibited significant increases. compared with those in control rats. suggesting the induction of ANP gene expression in the ventricle of DOCA-salt hypertensive rats under pre/after overload. Weekly intravenous administrations of monoclonal antibody with high affinity for alpha-rat ANP significantly augmented the rise in blood pressure of DOCA-salt rats. These results support the hypothesis that the augmented secretion of ANP is one of the defensive mechanisms to counteract high arterial pressure in this model of hypertension.
Plasma sodium-potassium ATPase inhibition activity in low- and normal-renin hypertension, Thirty-seven subjects with low- and normal-renin hypertension (plasma renin activity less than 0.45 ng/L/sec on a 100 mmol Na diet) were studied on a 10 and 100 mmol sodium diet (100 mmol K and 25 mmol Ca) to examine the effect of varied sodium intake on plasma Na.K-ATPase inhibitory activity (NKAIA) (% inhibition). On the 10 mmol Na diet. plasma NKAIA correlated with mean arterial pressure (MAP) (r = 0.384. P = .019). On the 100 mmol Na diet. plasma NKAIA correlated with daily urinary sodium excretion (r = 0.384. P = .019). With the increase in sodium intake. the mean change in MAP was 0.5 +/- 7.8 mm Hg (range -12.7 to 16.3) and the mean change in plasma NKAIA was -4.2 +/- 11.2% inhibition (range -37.5 to 16). The change in MAP was correlated to the change in plasma NKAIA (r = 0.384. P = .019). Plasma NKAIA is related to mean arterial pressure or urinary sodium excretion depending on the dietary sodium intake. and is related to sodium-induced changes in MAP in low and normal renin hypertensive patients.
Yeast-expressed p55 precursor core protein of human immunodeficiency virus type 1 does not elicit protective immunity in chimpanzees, Yeast-expressed p55 precursor core protein of human immunodeficiency virus type 1 (HIV-1) was used to immunize chimpanzees. The animals developed high titers of antibodies to p55 as well as to the p24 and p17 mature cleavage products of the core precursor. Virus-neutralizing antibodies were not elicited. The induced immune responses did not prevent establishment of HIV-1 infection following challenge of one immunized chimpanzee with live virus.
CD16+ NK cells decrease in all stages of HIV infection through a selective depletion of the CD16+CD8+CD3- subset, Natural killer (NK) cell-related phenotypes were analyzed in human immunodeficiency virus (HIV) infection. Our study involved 168 HIV-infected patients (72 CDC Stage II. 48 Stage III. and 46 Stage IV) and 60 healthy individuals. Analyses were conducted using flow cytometry and monoclonal antibodies. In comparison to the control group. all patient groups showed a significant decrease (p less than 0.001) of the CD16+ and CD16+CD3- phenotypes; furthermore. the comparison among patient groups showed no significant difference. It seems. therefore. that the decrease begins in the asymptomatic stage (CDC II) and remains constant during the infection. CD16+ NK cells were further divided into two subsets: CD16+CD8+ and CD16+CD8-. This subdivision shows a severe selective depletion of the CD16+CD8+ subset. but not in the CD16+CD8- subset. The depletion of the CD16+CD8+ subset also appears in the CDC asymptomatic stage and remains constant in CDC stages III and IV. Elsewhere. we observed that CD16+CD8+ lymphocytes are CD3-; complementary analysis of CD3-CD8+ cells showed a depletion comparable to that of the CD16+CD8+ phenotype. Depletion of the CD3-CD8+ subset. which belongs to the NK cell compartment. was observed although the total CD8 population showed a statistically significant increase. We conclude that. in HIV infection. there is a quantitative decrease of the NK CD16+ cell population. which appears to be due to a selective depletion of the CD16+CD8+CD3- compartment. This severe depletion appears to begin early in the infection.
Vagally mediated acid hypersecretion and lesion formation in anesthetized rat under hypothermic conditions, The pathophysiological changes associated with hypothermia were investigated in the rat stomach under anesthetized conditions. The animal was placed in a styrene foam box and the core body temperature was kept between 24 and 36 degrees C using a heat lamp and refrigerant pack. Lowering of body temperature (less than 30 degrees C) produced acid hypersecretion and induced hemorrhagic lesions in the gastric mucosa; these responses reached the maximum at 28 degrees C. and a significant relationship was found between acid output and lesion score. Hypothermia (28 degrees C) also caused a marked increase of gastric contractile activity and mucosal blood flow (MBF). but the ratio of acid output to MBF became greater when compared to that obtained under normothermic conditions. These changes induced by hypothermia (28 degrees C) were completely blocked by vagotomy and were significantly inhibited by atropine. hexamethonium. clonidine. or TRH antiserum. However. lowering body temperature did not significantly affect acid secretory. motility. and ulcerogenic responses induced by carbachol in the vagotomized rat. excluding local mechanisms (suppression of the inhibitory nerves) in the hypothermia-induced changes. We conclude that hypothermia alone stimulates vagally dependent acid secretion and motility. resulting in damage in the gastric mucosa. These changes may be centrally mediated by TRH. which is released in association with the thermogenic response to hypothermia.
Using ADLs to establish eligibility for long-term care among the cognitively impaired, Using a database from the Oregon Medicaid program. we examined the differences in the potential insurance coverage of demented persons by using different formulations of ADL (activities of daily living) dependencies in which the definition of dependency did or did not include the need for supervision. For those with clear dementia. 81-88% of the persons with significant behavioral problems were correctly identified when a cut score of three or more ADLs was used; this percentage was even higher for two or more ADLs. This approach was not as effective in correctly discriminating those who had no behavioral problems.
Comparison of the effects of streptokinase and tissue plasminogen activator on regional wall motion after first myocardial infarction: analysis by the centerline method with correction for area at risk, In a trial of streptokinase versus recombinant tissue-type plasminogen activator (rt-PA) for a first myocardial infarction. 270 patients were randomized. Regional left ventricular function was assessed in 214 patients at 3 weeks. The infarct-related artery was the left anterior descending artery in 78 patients. the right coronary artery in 122 and a dominant left circumflex artery in 14. Analysis was by the centerline method with a novel correction for the area of myocardium at risk. whereby the search region was determined by the anatomic distribution of the infarct-related artery. Infarct-artery patency at 3 weeks was 73% in the streptokinase group and 71% in the rt-PA group. Global left ventricular function did not differ between the two groups. Mean chord motion (+/- SD) in the most hypokinetic half of the defined search region was similar in the streptokinase and rt-PA groups (-2.4 +/- 1.5 versus -2.3 +/- 1.3. p = 0.63). There were no differences in hyperkinesia of the noninfarct zone. Compared with conventional centerline analysis. regional wall motion in the defined area at risk was significantly more abnormal. The two methods correlated strongly. however (r = 0.99. p less than 0.0001). and both methods produced similar overall results. Patients with a patent infarct-related artery and those with an occluded artery at the time of catheterization had similar levels of global function (ejection fraction 58 +/- 12% versus 57 +/- 12%. p = 0.58).
Noninvasive detection of reperfusion in acute myocardial infarction based on plasma activity of creatine kinase MB subforms, Successful thrombolytic therapy is associated with an accelerated release of creatine kinase (CK) MB from necrotic myocardium. With use of a previously validated assay. the plasma kinetics of the myocardial subform (MB2) and the plasma-modified subform (MB1) were determined in blood samples obtained from 56 patients with acute Q wave myocardial infarction: 33 patients who received thrombolytic therapy (group A) and 23 patients managed conservatively (group B). Plasma MB2 activity increased more rapidly in the group A patients. but there was substantial overlap with group B. Plasma MB1 activity did not differ significantly between the two groups. The MB2/MB1 ratio was significantly higher in group A patients than in group B patients between 2 and 10 h after the onset of infarction. Among group A patients. the ratio increased from 2.4 +/- 1.6 to 4.6 +/- 2.0 in the 1st h after therapy (p less than 0.001). The peak ratio was 6.3 +/- 2.5 in group A patients and 3.1 +/- 1.2 in group B patients. Twenty-seven of the 33 group A patients had a peak ratio greater than 3.8 versus 5 of the 23 group B patients (p less than 0.001). In seven group A patients. the ratio was greater than 3.8 before plasma CK MB activity was out of the normal range. Angiography was performed at 5.0 +/- 3.5 days in 39 patients. Eighteen (90%) of 20 patients with a patent infarct-related artery had a peak ratio greater than 3.8; 17 (89.5%) of 19 patients with an occluded infarct-related artery had a ratio less than 3.8 (p less than 0.001).
Bleeding time prolongation and bleeding during infusion of recombinant tissue-type plasminogen activator in dogs: potentiation by aspirin and reversal with aprotinin, Thrombolytic therapy is associated with a bleeding tendency that may be exacerbated by adjunctive antiplatelet agents. The effect of recombinant tissue-type plasminogen activator (rt-PA) alone or in combination with aspirin on serial measurements of template bleeding time. ex vivo platelet aggregation and coagulation factors and the frequency of bleeding was studied in dogs. During infusion of rt-PA (15. 30 or 60 micrograms/kg per min for 90 min). a dose-related increase in bleeding time was observed. In a randomized blinded study of 25 dogs. the baseline bleeding time (mean +/- SD) was 3.5 +/- 1 min in control animals and 4 +/- 2 min after oral aspirin (15 mg/kg body weight). Infusion of rt-PA (15 micrograms/kg per min for 90 min) prolonged the bleeding time to a maximum of 15 +/- 12 min. In contrast. combined aspirin and rt-PA therapy produced an increase to greater than 30 min during infusion. reverting to 13 +/- 10 min within 2 h after cessation of infusion. Recurrent continuous bleeding from incision sites occurred in one of six dogs given aspirin alone. two of seven given rt-PA alone and all six dogs given both aspirin and rt-PA (p = 0.02). Bleeding time greater than 9 min correlated significantly with bleeding frequency (p less than 0.0001). with a sensitivity of 100% and a specificity of 87%. Intravenous bolus injection of aprotinin (20.000 kallikrein inhibitor units/kg body weight) in six dogs given both rt-PA and aspirin produced a decrease in bleeding time from greater than 30 min to 9.5 +/- 9 min and resulted in cessation of bleeding. Thus. bleeding and bleeding time prolongation in this canine model are potentiated by a marked interactive effect of rt-PA and aspirin that is rapidly reversible. Template bleeding times may provide a useful quantitative index for monitoring the bleeding tendency associated with thrombolytic therapy.
Early thrombolytic treatment reduces analgesic requirement in patients with myocardial infarction, The duration and amount of analgesics required were investigated in 67 patients with myocardial infarction treated with intravenous recombinant tissue-type plasminogen activator (rtPA) or placebo in a randomized double-blind trial. Infusion of rtPA (100 mg)/placebo was started within 5 h after the onset of symptoms. and the requirement for analgesics during the following 48 h was recorded. Sixty-seven per cent of the 30 rtPA-treated patients required analgesic treatment for less than 6 h. compared to 38% of the 37 patients in the placebo group (P = 0.04). During the study period. patients in the rtPA group used the equivalent of 5.3 mg (median value) intravenous morphine. which was significantly less than the 11.2 mg used in the placebo group (P = 0.04). In conclusion. the present study suggests that early thrombolysis with intravenous rtPA reduces the amount and duration of analgesic treatment required by patients with myocardial infarction.
Effect on neutrophil kinetics and serum opsonic capacity of intravenous administration of immune globulin to neonates with clinical signs of early-onset sepsis, This study was designed to test the hypothesis that administration of immune globulin to human neonates with early-onset bacterial sepsis would (1) facilitate neutrophil egress from the marrow. (2) improve serum opsonic capacity. and (3) facilitate recovery from the infectious illness. Twenty-two newborn infants with clinical signs of early-onset sepsis were given an intravenous infusion of either 750 mg of immune globulin (IVIG) per kilogram of body weight or the same volume of a vehicle control (albumin). All 22 infants survived. but significant hematologic. immunologic. and respiratory differences were observed after the IVIG and not after the control infusion. Eleven of the patients had neutropenia; 24 hours after the infusions. the neutropenia had resolved in all six IVIG recipients but persisted in all five control recipients (p less than 0.001). Ten patients had I/T neutrophil ratios (a measure of immature neutrophils to total neutrophils on the leukocyte differential count) of less than 0.2. One hour after completion of the infusions. all five IVIG recipients had elevated I/T ratios (mean +/- SEM:0.10 +/- 0.05 before vs 0.43 +/- 0.03 after infusion; p less than 0.001). suggesting a prompt release of neutrophils from the marrow neutrophil storage pool into the circulation; no increase in the I/T ratio was observed in the control recipients. Six hours after the IVIG infusions. the ratio of arterial oxygen tension to fraction of inspired oxygen increased; no increase was observed after control infusions. Serum concentrations of IgG. IgG1. IgG2. IgG3. IgG4. and total hemolytic complement and the capacity of serum to support opsonophagocytosis of type II and type III group B streptococci increased markedly in the IVIG recipients but not in the control subjects. We conclude that administration of 750 mg IVIG per kilogram to neonates with clinical signs of early-onset sepsis was associated with immunologic. hematologic. and physiologic improvement.
Total parenteral nutrition-induced steatosis: reversal by parenteral lipid infusion, Prolonged use of total parenteral nutrition (TPN) may be associated with hepatic complications. primarily steatosis and cholestasis. A case is reported of an 18-year-old woman with chronic idiopathic intestinal pseudo-obstruction syndrome who was on prolonged home parenteral nutrition without lipid supplementation and developed steatosis. This finding was reversed by addition of lipid emulsion. at a dose of 0.5 g/kg/day. to the parenteral nutrition solution. The lack of lipid supplementation as a possible cause of steatosis. as well as other mechanisms of liver steatosis associated with TPN. are discussed.
Metabolic and immune effect of vitamin E supplementation after burn, The effect of dietary vitamin E supplementation was studied in burned guinea pigs. Forty-four guinea pigs bearing a catheter gastrostomy received a 30% total body surface area full thickness flame burn and were given identical enteral diets (175 kcal/kg/day) except for the amount of vitamin E. Groups 1. 2. 3. and 4 received 0. 4 mg/kg/day (approximately equivalent to guinea pig's RDA) 20 or 100 mg/kg/day of vitamin E respectively. After 14 days of enteral feeding. there were no significant differences between groups in the body weights and the weights of carcass. gastrocnemius muscle. liver. and spleen. Resting metabolic expenditure on PBD 3. 6. 9. and 12 was similar in all groups. No statistical differences were seen in ear-thickness response to 2.4-dinitrofluorobenzene and lymphocytic proliferative responses to phytohemagglutinin. However. mucosal weight and protein content in group 1 were significantly less compared to groups 2 and 4 (p less than 0.05). Anemia was also significantly greater in group 1. Histologic examination of the intestinal wall. however. did not yield any physical differences associated with the addition of vitamin E to the diet. This study suggests that vitamin E supplementation in diets of burned animals may have a beneficial effect on maintenance of intestinal mucosa and erythrocyte counts over a wide-dose range.
Liver function tests in patients receiving parenteral nutrition, A 5-year prospective study was performed to monitor liver function tests (LFTs) in patients receiving total parenteral nutrition (TPN). A gradual and progressive rise was seen in the plasma concentration of bilirubin. aspartate transaminase. and alkaline phosphatase. The rate of rise was not increased in patients with LFT abnormalities before the start of TPN. Half of the patients had an episode of sepsis during TPN. but overall abnormal LFTs did not appear more common in these patients than in those without obvious sepsis. Patients with malignant disease. those requiring long-term TPN. and those requiring a nonstandard TPN regimen were more likely to develop raised LFTs.
Short-bowel syndrome: a review of the role of nutrition support, Advances in long-term venous access devices and in parenteral nutrition solutions have made it possible for patients with severe short bowel syndrome to survive and to live in our society. The spectrum of this disease is such that some patients may be able to lessen their dependence or even become free from parenteral therapy. This review will discuss the role of nutrition support in the patient with short bowel syndrome.
Cost analysis of microsurgical reconstruction in the head and neck, In a cost-conscious environment. pressure exists to justify the use of expensive techniques such as reconstructive microsurgery in head and neck patients. Therefore. the costs and effectiveness of 39 consecutive free tissue transfers in patients with head and neck defects due to neoplasia (77%). trauma (13%). or congenital causes (10%) were assessed by reviewing clinical and billing records. The technical success rate was 95% with a 29% rate of complications. Most patients returned to preoperative levels of social activities. and none admitted dissatisfaction with their results. Average cost was $27.000 per case with 16 days of hospitalization. Average cost for aerodigestive tract tumors was $37.400 with 21 days of hospitalization. Costs were directly related to the etiology of the defect and incidence of complications. Applying cost-effectiveness principles we believe that these costs are justified by the high level of patient satisfaction and enhanced quality of life.
Immunohistochemical analysis of plasminogen activator expression in human colorectal carcinomas: correlation with CEA distribution and tumor cell kinetics, Fifty cases of colorectal adenocarcinoma were immunohistochemically examined for the relationship between distribution of plasminogen activators (PAs) and the degree of differentiation of cancer cells as reflected by carcinoembryonic antigen (CEA) expression as well as tumor cell kinetics. The A chain of urokinase-type PA (u-PA-A) was mainly observed in the apical portions of highly differentiated cancer cells. Increased expression and change in localization to the cytoplasm were found with progressive dedifferentiation. The numbers of DNA polymerase alpha (pol. alpha) positive cancer cells also increased in line with u-PA-A expression. The B chain of u-PA (u-PA-B). and the A and B chains of tissue-type PA (t-PA-A and -B) did not show similar alteration. The present findings suggest that the distribution of u-PA-A in colorectal carcinoma tissues. the degree of tumor differentiation. and the proliferation kinetics of cancer cells are closely related.
Economic cost of diabetes mellitus--Minnesota, 1988, For diabetes mellitus (DM) and other chronic diseases. important indicators of disease burden include morbidity. mortality. measures of disability and quality of life. and economic burden. Because of limited data. however. the economic burden of DM has been difficult to measure. Although national costs for DM have been estimated recently (1-5). state-specific estimates have. in general. not been possible. This report summarizes an analysis prepared by the Minnesota Diabetes Surveillance Project (MDSP). Minnesota Department of Health. that estimated the economic impact of DM in Minnesota for 1988.
Treatment of severe Plasmodium falciparum malaria with quinidine gluconate: discontinuation of parenteral quinine from CDC drug service, CDC has recently reviewed data on the reported incidence in the United States of Plasmodium falciparum malaria and has evaluated information on the effective management of severe life-threatening infections. As a result of this review. CDC has concluded that the drug of choice in the United States for treatment of complicated P. falciparum infections is parenteral quinidine gluconate. Therefore. effective immediately. parenteral quinine dihydrochloride will no longer be available from the CDC Drug Service.
A universal ossicular replacement prosthesis: clinical trials of 152 cases, An ossicular replacement prosthesis is described that advances implant design in several respects. The head is a flattened egg shape. which eliminates pressure points against the pars tensa and provided balance on the stapes. Dense hydroxylapatite ceramic provides maximal biocompatibility. The shaft. of either Teflon or Plastipore. is easily cut to size and is replaceable to minimize wastage. Interchangeable partial or total shaft variants are provided. Trials in more than 200 patients have produced optimal results. Among 152 mature patients in 85% of the good-risk cases. the air-bone gap closed to within 20 dB and in 65% to within 10 dB; in 69% of all cases the gap closed to within 20 dB. Extrusion rates were 5% in good-risk cases and 7% overall. Long-term extrusions have not occurred. Inasmuch as cartilage interpositioning is unnecessary. the prosthesis is rapidly prepared and implanted by an easily mastered technique.
The intracutaneous progressive dilution multi-food test, Data have been published supporting the view that skin response is more valid and reliable than symptom provocation for interpretation of the intracutaneous provocative food test (IPFT). As such. an intracutaneous progressive dilution food test technique interpreted by skin response is now the standard IPFT technique taught at American Academy of Otolaryngic Allergy-sponsored courses. While this test technique is less time-consuming than the 5-day oral challenge food test of Rinkel. the 15- to 90-minute per test demand still presents a significant deterrant to widespread use. Here we present a time-efficient. multi-test technique that allows testing of three to seven foods at one time. The technique is not recommended for use on patients with a history of severe allergic reactions. such as asthma or angioedema. or for testing any food that by history may produce an anaphylactic reaction.
Metastatic angiosarcoma of the brain, Two patients with metastatic angiosarcoma of the brain are described. In one. a 17-year-old man. the tumor was located at the pineal region and exhibited significant vascularity. It was sensitive to radiation therapy and disappeared after radiation of 50 Gy; however. it recurred after 1 year and a new lesion was found in the liver. The other patient is a 31-year-old woman who experienced sudden onset of headache. Computed tomography scan revealed three separate masses in the brain. One tumor was surgically removed. The other two were sensitive to radiation therapy and disappeared after radiation of 40 Gy. A new lesion was found in the femur 16 months after the operation. Brain metastasis from angiosarcoma is exceedingly rare. Both patients developed symptoms with intracranial hemorrhage. The diagnosis of the metastatic lesions preceded diagnosis of the primary lesion by 12 and 16 months. respectively. Ulex europaeus 1 lectin and factor VIII were very useful in establishing the diagnosis of angiosarcoma.
Primary malignant melanoma of the gasserian ganglion associated with neurofibromatosis, A case of primary intracranial malignant melanoma of the left gasserian ganglion associated with temporal lobe gliosis in a patient suffering from von Recklinghausen's disease is reported. The association of primary malignant melanoma of the trigeminal nerve and neurofibromatosis is discussed.
Xanthoma in Meckel's cave. A case report, A case of xanthoma located within Meckel's cave and the semilunar ganglion is described in a patient with a trigeminal nerve deficit. This is the first case of xanthoma in such a location. The distinctive morphological appearance is illustrated and the possible histogenesis is discussed.
Selegiline: initial or adjunctive therapy of Parkinson's disease, Parkinson's disease (PD) is a progressive neurologic motor disorder. Currently. levodopa/carbidopa is the standard mode of therapy for PD; however. it does not prevent progression of the disease. Selegiline (also known as deprenyl). is a selective irreversible monoamine oxidase type B inhibitor virtually devoid of the tyramine reaction at the recommended dosage of 10 mg/d. It is approved by the Food and Drug Administration for the adjunctive use in the management of patients with PD who are receiving levodopa/carbidopa and exhibit a "wearing off" effect of levodopa. Numerous clinical trials have been conducted evaluating selegiline's role in the treatment of PD. Preliminary evidence from the DATATOP trial suggests that selegiline may slow the progression of PD when used as initial therapy. However. final results of this trial and additional long-term controlled trials comparing selegiline to levodopa and placebo groups are necessary to further clarify selegiline's role in the treatment of PD.
Hepatitis C: prevention and treatment, Widespread screening of donor blood for hepatitis B led to the recognition that most cases of post-transfusion hepatitis were due to an agent or agents. collectively known as non-A. non-B. Until recently. the causative agent for non-A. non-B hepatitis was unknown. In 1988. a new agent. hepatitis C virus. was identified. It is estimated that 150.000 new cases of hepatitis C occur each year and that one-half of patients with hepatitis C develop chronic liver disease. Hepatitis C is responsible for 15.000 new cases of cirrhosis annually. In 1990. an antibody assay was approved for commercial use. Widespread screening of donor blood with this assay should reduce the risk of transfusion-associated hepatitis C. For those patients already infected. antiviral therapy with alpha interferon may offer the chance of cure or significant palliation.
Multivessel coronary artery disease: a key predictor of short-term prognosis after reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group, Results of recent studies have suggested that routine cardiac catheterization may be unnecessary after reperfusion therapy for acute myocardial infarction. Therefore to better define the short-term prognostic value of early coronary angiography. and specifically the prognostic significance of multivessel coronary artery disease. the angiographic findings of 855 patients consecutively enrolled in five phases of the TAMI study were correlated with their in-hospital outcome. All patients received intravenous thrombolytic therapy (tissue plasminogen activator. urokinase. or both agents) and underwent cardiac catheterization within 90 minutes of the initiation of therapy. Multivessel disease. defined as the presence of greater than or equal to 75% luminal diameter stenosis in two or more major epicardial arteries. was documented in 236 patients. When compared with the group of patients without multivessel disease. this group had a higher prevalence of coronary risk factors and more frequently had a history of antecedent ischemic chest pain. Although the severity of the infarct zone dysfunction was similar in the two groups (-2.77 +/- 1.00 vs -2.50 +/- 1.09 SD/chord. p = NS). global left ventricular ejection fraction was lower in the group with multivessel disease (48.6 +/- 12.4% vs 51.8 +/- 10.6%. p less than 0.01). This was associated with a significant difference in the function of the noninfarct zone. Whereas this region was hyperkinetic in the group with minimal or single-vessel disease. it was hypocontractile or dyskinetic in those with multivessel disease (+0.66 +/- 1.53 vs -0.52 +/- 1.73 SD/chord. p = 0.0001).
Obesity and weight loss alter serum polyunsaturated lipids in humans, Serum omega 6 (n-6) fatty acids were assessed in 12 obese women during an outpatient very-low-calorie diet (VLCD). Ten subjects (S10) achieved a mean weight loss of 17 kg over 3-5 mo (initial weight-for-height 157%). Serum was obtained before (baseline) and monthly during the VLCD and from five of them (S5) after 2-3 mo of weight stability (refed) at 21 kg of loss. At baseline for S10. the serum phospholipid (PL) 20:4 omega 6 was 9.16 wt% and differed from normal (12.81 wt%) by P less than 0.0001. but cholesterol ester (CE) 20:4 omega 6 did not differ from normal. During 3 mo of VLCD. the S10 serum PL and CE 18:2 omega 6 fell (P less than 0.005 and 0.0001. respectively). Serum PL 20:4 omega 6 rose to normal during VLCD months 1-3 (P less than 0.01) while the serum CE 20:4 omega 6 rose above normal (P less than 0.0002). During the VLCD. S5 results paralleled S10. However when refed. S5 PL and CE 18:2 omega 6 and 20:4 omega 6 all reverted to baseline (PL 20:4 omega 6 below normal. P less than 0.001). Serum PL 20:4 omega 6 is low in moderate obesity. corrects to normal during a VLCD. but regresses to the predict abnormality after weight loss.
The ventilatory and oxygen costs in the anesthetized rhesus monkey of inhaling drugs used in the therapy and diagnosis of asthma, We examined in male Rhesus monkeys the effects on oxygen consumption (VO2). carbon dioxide production (VCO2). minute ventilation (VE). heart and respiratory rates. and functional residual capacity (FRC) of breathing normal saline (NS). salbutamol (albuterol). methacholine (MCh). sodium cromoglycate (SCG). epinephrine (adrenaline). and terbutaline in doses commonly prescribed to human infants and children. We studied 10 anesthetized and intubated monkeys with a mean age and weight of 6.0 yr and 9.1 kg. respectively. VO2 increased over control. by 46.5% after salbutamol (p less than 0.0005). 25% after methacholine (p less than 0.001). 13.2% after epinephrine (p less than 0.01). and 16% after terbutaline (p less than 0.001). but it did not increase after either SCG or NS. VE increased by 82% after MCh and salbutamol (p less than 0.001). less dramatically after epinephrine and terbutaline at 50.5 and 31.5% (p less than 0.02 and p less than 0.001). respectively. and not at all after SCG and NS. Heart rate response was greatest after salbutamol. and nodal and ventricular arrhythmias were noted in four of 10 monkeys after MCh challenge. FRC did not change significantly except after salbutamol. where there was a small rise of 1.8 ml/kg (p less than 0.05).
Influence of elevated plasma levels of atrial natriuretic factor on bronchial reactivity in asthma, Recent studies have demonstrated that elevation of plasma atrial natriuretic factor (ANF) levels may produce significant bronchodilation in the constricted asthmatic airway. The current study was designed to examine the effect of both physiologic and pharmacologic plasma levels of ANF on bronchial reactivity to histamine in asthmatic subjects. A total of eight atopic men with well-controlled asthma were studied. mean (SD) FEV1 3.50 (0.73) L. equivalent to 87 (11)% of predicted; bronchial reactivity as measured by histamine PC20 was 0.77 mg/ml (geometric mean). On four separate study days infusions of 1. 3. or 10 pmol/kg/min of ANF or placebo were administered in a double-blind. randomized manner. Once steady-state plasma levels had been achieved. measurement of bronchial reactivity was repeated. Mean (SEM) basal ANF level was 18.5 (3.5) pg/ml and rose to 41 (4.3). 157 (15). and 500 (30) pg/ml with increasing doses of ANF. With placebo infusion geometric mean histamine PC20 was 0.77 mg/ml and rose to 1.15 mg/ml (p less than 0.05). 1.90 mg/ml (p less than 0.001). and 3.38 mg/ml (p less than 0.001). corresponding to a 1.5-. 2.5-. and 4.4-fold protection with respective ANF infusions. There was no significant change in plasma epinephrine. These results show that at both physiologic and pathophysiologic plasma levels ANF may significantly decrease bronchial reactivity to histamine in asthma.
Eugenol causes oxidant-mediated edema in isolated perfused rabbit lungs, Eugenol. an extract of cloves. has been associated with pulmonary edema when inhaled from commercially available clove cigarettes. We tested the hypothesis that eugenol directly causes lung edema through oxidant-mediated mechanisms by infusing eugenol (0.1 and 1.0 mM) into isolated rabbit lungs perfused with a cell-free albumin and physiologic salt solution. We observed lung edema (1.0 mM) as demonstrated by increased lung weight gain and wet-to-dry lung weight ratios without alterations in mean pulmonary artery pressure. The oxygen metabolite scavengers catalase (1.000 U/ml) and dimethylthiourea (30 mM) attenuated lung edema. Instillation of dimethylurea. superoxide dismutase. or heat-inactivated catalase did not prevent lung edema formation. We conclude that eugenol causes lung edema in isolated lungs through oxidant-mediated mechanisms in the absence of circulating formed blood elements. Eugenol may be a valuable compound in the laboratory investigation of edemogenic disorders.
Asbestos exposure and asbestos-related pleural and parenchymal disease. Associations with immune imbalance, The study hypothesis was that asbestos exposure and asbestos-related pleural plaques and interstitial disease are associated with (1) immune imbalances favoring helper-inducer T-cell subsets in blood and bronchoalveolar lavage (BAL) and (2) T-lymphocyte accumulation in BAL. One hundred twenty-two asbestos-exposed subsets (AES). including 27 nonsmokers (NS). were evaluated and compared with 10 unexposed normal subjects. Data were collected on medical. smoking. and occupational histories. physical examination. spirometry. lung volumes. single-breath DLCO. chest films read by a "B" reader. and T-lymphocyte characterization in blood and BAL using flow cytometry analysis of monoclonal-antibody-treated cells. On average. AES were 47 yr of age and had 23 yr of asbestos exposure. Fifty-eight (48%) had pleural thickening. and seven (6%) had profusion greater than or equal to 1/0. In blood. asbestos-exposed NS had lower total and percent CD8 and lower total CD3 than did normal subjects. In BAL. asbestos-exposed NS had higher total CD3 than did normal subjects. Among AES. increased asbestos exposure was associated with increased percent CD8 in BAL and decreases in both percent lymphocytes and total CD8 in blood. Increase in CD4/CD8 ratio in BAL were associated with pleural thickening. In those seven with profusion greater than or equal to 1/0. there was increased percent CD4 in blood and decreased percent CD8 in BAL. These results suggest immune imbalance favoring helper-inducer T-cell subsets in association with asbestos exposure systemically and with pleural plaques in BAL.
Methodologic issues in maintenance therapy clinical trials, In the early 1980s. the National Institute of Mental Health supported a multicenter. randomized. controlled. clinical trial on unipolar and bipolar disorder to evaluate the comparative efficacies of lithium carbonate. imipramine hydrochloride. a lithium-imipramine combination. and placebo in preventing the recurrence of affective disorders. The objective of this report is to present a reanalysis of the relative efficacies of these treatments in patients with unipolar disorder to focus attention on general issues related to the design and conduct of maintenance therapy trials. We show that the earlier conclusions of that study that imipramine and the combination therapy are more effective than lithium and placebo in preventing the recurrence of depression in unipolar patients can be accounted for by alternative explanations that are a consequence of the design of the study. Our findings have important implications for the design. conduct. and interpretation of results of maintenance therapy clinical trials in general.
A comparison of the roles of cefamandole and ceftriaxone in abdominal surgery, In a prospective. randomized study. we compared the ability of ceftriaxone sodium (serum half-life. 8.0 hours) and cefamandole naftate and sodium carbonate (serum half-life. 0.8 hours) to prevent wound infection in 1238 patients undergoing abdominal surgery. Prophylaxis consisted of single-dose therapy at the time of induction of anesthesia. and treatment regimens contained ceftriaxone sodium. 1 g/d intravenously. or cefamandole naftate and sodium carbonate. 1 g intravenously every 6 hours. Except for low-risk biliary procedures. cephalosporin therapy was accompanied by the administration of metronidazole. No significant difference was noted in the incidence of wound infection. ie. 5.6% for the ceftriaxone group (95% confidence interval. 3.8% to 7.4%) and 6.9% for the cefamandole group (95% confidence interval. 4.9% to 8.9%). Single-dose prophylaxis with 1 g of cefamandole naftate and sodium carbonate was relatively inexpensive and provided a cost savings of 64%. When treatment was required. a 23% cost savings was associated with the use of a once-daily dose of 1 g of ceftriaxone sodium.
Human interleukin-9: genomic sequence, chromosomal location, and sequences essential for its expression in human T-cell leukemia virus (HTLV)-I-transformed human T cells, We have isolated the genomic sequence of human interleukin-9 (IL-9) based on its sequence homology with a human IL-9 cDNA isolated from human T-cell leukemia virus (HTLV)-I-transformed T cells by expression cloning. The entire genomic sequence has been determined and the gene consists of five exons and four introns. The human IL-9 gene is mapped to the long arm of human chromosome 5 at band 5q31-32. a region found to be deleted in a number of patients with acquired 5q- abnormalities and hematologic disorders. Several blocks of transcriptional control sequences have been identified at the 5'-flanking region of the human IL-9 gene that may play an important role in the control of IL-9 gene expression. The 5'-regulatory region of the human IL-9 gene also contains sequences identified in the 5'-flanking regions of other cytokine genes mapped to the long arm of human chromosome 5. including IL-3. IL-4. IL-5. and granulocyte-macrophage colony-stimulating factor and other T-cell growth factor genes including IL-2 and IL-6. The IL-9 gene is constitutively expressed in the HTLV-I-transformed human T cells and the expression of IL-9 in these cells can be further induced by 12-O-tetradecanoyl phorbol 13-acetate. Transient transfection analysis using the plasmid containing the 5'-flanking region of IL-9 gene upstream from the firefly luciferase ciferase report gene indicated that the 0.9-kb Smal-Sacl fragment of the IL-9 gene contains sequences required for the constitutive and activated expression of IL-9 gene in HTLV-I-transformed cells. These results will now allow us to study the regulatory mechanism of IL-9 gene expression in normal and leukemic human T cells.
Retrovirus-induced feline pure red blood cell aplasia: pathogenesis and response to suramin, Feline leukemia virus. subgroup C/Sarma (FeLV-C/Sarma) induces pure red blood cell aplasia in cats. Although erythroid (BFU-E and CFU-E) and granulocyte/macrophage (CFU-GM) progenitors are infected with this virus. only erythropoiesis is impaired. Two to 3 weeks before the onset of anemia. CFU-E become undetectable in marrow cultures while earlier erythroid progenitors (BFU-E) persist. suggesting that FeLV-C/Sarma (presumably via its envelope glycoprotein gp70) inhibits the differentiation of BFU-E to CFU-E in vivo. To correlate in vitro observations with the progression of disease. prospective studies were performed in six cats. These studies showed that at the time that the frequencies of CFU-E decreased in marrow cultures. BFU-E no longer responded to hematopoietic growth factor(s). although the responses of CFU-GM were unchanged. In further studies. anemic cats received suramin. a reverse-transcriptase inhibitor with other diverse effects. Within 4 to 14 days. erythropoiesis improved and up to 1.616 CFU-E were detected per 10(5) marrow mononuclear cells. However. progenitor cells remained infected. suggesting that suramin modulated erythroid differentiation without inhibiting progenitor infection. These observations led to the hypothesis that the gp70 of FeLV-C/Sarma impairs BFU-E differentiation by interference with ligand/receptor interactions or signal transduction pathways unique to erythroid cells. Understanding this mechanism should provide insights into the interactions controlling early erythropoiesis.
Idiotypic cross-reactivity of immunoglobulins expressed in Waldenstrom's macroglobulinemia, chronic lymphocytic leukemia, and mantle zone lymphocytes of secondary B-cell follicles, Monoclonal antibodies (MoAbs) specific for autoantibody-associated cross-reactive idiotypes (CRIs) of Waldenstrom's IgM react frequently with the surface Ig (slg) expressed by leukemia cells of patients with chronic lymphocytic leukemia (CLL). Evaluation of the molecular basis for this cross-reactivity indicates that such CRIs are encoded by conserved antibody variable region genes (V genes) that have undergone little or no somatic hypermutation. We find that such anti-CRI MoAbs stain a subpopulation of cells within the mantle zones surrounding the germinal centers of normal human tonsil. In contrast. MoAbs specific for variable region subgroup determinants react with cells in both the mantle zones and germinal centers of secondary B-cell follicles. To test whether mantle zone B cells not reactive with existing anti-CRI MoAbs may express slg bearing as-yet-unrecognized CRIs present on Igs produced by neoplastic cells of some patients with Waldenstrom's macroglobulinemia or CLL. we immunized mice with purified Waldenstrom's IgM that have been characterized for their variable region subgroups using subgroup-specific antisera raised against synthetic peptides. The supernatants of hybridomas generated from the splenocytes of immunized mice were screened for their ability to stain a subpopulation of mantle zone lymphocytes in human tonsil. With this approach. two new anti-CRI MoAbs were identified. designated OAK1 and VOH3. OAK1 binds to a CRI present on a subset of kappa light chains of the VK1 subgroup. VOH3 recognizes a CRI determinant(s) present on a subset of antibody heavy chains of the VH3 subgroup. Flow cytometric analyses demonstrated that OAK1 specifically binds leukemia cells from 5 to 20 patients (25%) with kappa light chain expressing CLL. In addition. VOH3 reacted with the leukemia cells from 1 of 17 (6%) patients tested. The success of these methods demonstrates that the variable regions of the Igs produced by mantle zone B cells share idiotypic determinants with Igs expressed in B-cell CLL (B-CLL) and Waldenstrom's macroglobulinemia.
Vasospasm in a coronary artery aneurysm, Coronary artery aneurysms are not believed to have enough intact smooth muscle to generate significant vasoconstriction. A case is presented illustrating vasospasm of a large fusiform aneurysm of a right coronary artery during angioplasty. Pathophysiology of aneurysms is discussed.
Rheumatoid factors and complex formation. The role of light-chain framework sequences and glycosylation, New information regarding rheumatoid factors (RFs) indicates that the RFs synthesized in synovium and lymphoid tissues of patients with rheumatoid arthritis (RA) are different from monoclonal and nonspecific RFs associated with other inflammatory states. The characteristics of RF associated with RA are as follows. They are of all Ig isotypes (not just IgM). indicating T-cell participation in antibody maturation. They have higher avidity for human IgG than for rabbit IgG. They use the human germline heavy-chain variable region (VH) gene VHIII more frequently than other VH genes. and light chains from multiple families. (In contrast. monoclonal RFs use predominantly VH1 and very commonly the V kappa IIIb germline gene HUMkv325). RA IgG is somatically mutated. (In contrast. monoclonal RFs use unmutated germline Ig genes). This suggests they are matured by stimulation either with specific antigens or other activation signals such as cytokines. They are abnormally glycosylated. In general. during periods of disease activity in adult and juvenile RA. a galactose is missing from the Fc of the IgG molecule. leaving an empty "pocket" between the C gamma 2 domains of heavy chains. The IgG RFs self-associate. This may result at least in part when galactose on the F(ab')2 portion of one IgG molecule fills the empty pocket in the Fc of another Ig molecule. Self-association forms immune complexes capable of fixing complement and probably of causing joint damage and vasculitis.
Amoxicillin-clavulanic acid for treating drug-resistant Mycobacterium tuberculosis, This report describes two patients with multidrug resistant tuberculosis who were successfully treated with the addition of amoxicillin-clavulanic acid to second-line drugs. Mycobacterium tuberculosis possesses a beta-lactamase contributing to its resistance to beta-lactam antibiotics. The combination of clavulanic acid. a beta-lactamase inhibitor. and amoxicillin has been shown bactericidal for M tuberculosis in vitro. These data suggest that resistant tuberculosis may warrant a trial of treatment including amoxicillin-clavulanic acid.
Acute effects of alpha- and beta-adrenoceptor blockade on plasma atrial natriuretic peptides during exercise in elderly patients with mild hypertension, In a randomized study in 26 elderly patients with mild essential hypertension. acute effects of alpha- and beta-adrenoceptor blockade on plasma ANP levels were examined at rest and during ergometric exercise. Plasma ANP level and LVEF were measured before and after administration of prazosin (an alpha 1-adrenergic blocker). atenolol (a cardioselective beta-adrenergic blocker). or carteolol (a nonselective beta-adrenergic blocker). Plasma ANP level was increased by exercise. Carteolol and atenolol increased plasma ANP levels at rest and during exercise. but the effect of atenolol was not statistically significant. Prazosin significantly suppressed the ANP values at rest and during exercise. The LVEF was increased by prazosin and decreased by beta-blockers. especially by carteolol. Multivariate regression analysis showed that LVEF was the most significant predictor of the plasma ANP level at maximal exercise; the resting blood pressure and heart rate were not predictors of this value. The results showed that single administrations of an alpha-blocker and a nonselective beta-blocker had opposite effects on the plasma ANP level both at rest and during exercise in elderly patients with mild essential hypertension. The observed difference in the ANP response seems to be related to changes in left ventricular function rather than changes in blood pressure or heart rate.
Abnormal pattern of luteinizing hormone pulsatility in women with epilepsy, Dysfunction of the hypothalamic-pituitary-ovarian axis in epileptic females has been suggested in the latest years. To further elucidate this issue. we assessed reproductive endocrine function in 10 normally cycling. drug-free epileptic women and in 5 normal controls. evaluating the basal hormonal profile and luteinizing hormone (LH) pulsatility in the midfollicular phase. Luteinizing hormone pulse frequency was significantly higher in epileptic women with a consequent reduction of the LH interpulse interval. We suggest that epilepsy may interfere with the functional activity of the gonadotropin-releasing hormone pulse generator. The pathogenetic mechanisms for this phenomenon may be the spreading of paroxysmal activity within the hypothalamic areas or. alternatively. a neurotransmitter dysfunction giving rise both to the seizure disorder and to the abnormal LH pulsatile pattern.
Secretory changes in preovulatory endometrium during controlled ovarian hyperstimulation with buserelin acetate and human gonadotropins, Twenty-one patients with unexplained infertility underwent controlled ovarian hyperstimulation with buserelin acetate and human menopausal and chorionic gonadotropins. and follicular growth was monitored by ultrasonography and daily 17 beta-estradiol (E2) assays. Endometrial biopsy was performed when E2 levels were greater than or equal to 250 pg/mL per follicle and the follicular diameter was greater than or equal to 17 mm. As controls. we studied 20 preovulatory endometrial biopsies from patients with a male infertility factor. The biopsy material was examined at light. scanning. and transmission electron microscopes. and a morphometric analysis was performed. Preovulatory endometrial mucosa during controlled ovarian hyperstimulation showed accentuated proliferative aspects in both the glandular and stromal components and more frequent early secretory phenomena compared with the controls. The preovulatory progesterone (P) levels observed in our study seem to exclude the possibility that such early secretory aspects of the hyperstimulated endometrium are because of higher P concentrations in patients compared with controls.
Altered thymic and peripheral T-lymphocyte repertoire preceding onset of diabetes in NOD mice, Insulitis occurs by 5 wk of age in all NOD mice. However. diabetes is detectable only after 3-5 mo of age and only in approximately 50% of females and 10% of males in our colony. Therefore. it is predictable that changes in the T-lymphocyte repertoire of diabetes-prone mice occur and predispose them to disease. We demonstrate here that an altered (with respect to control BALB/cJ mice) thymic T-lymphocyte maturation reflected by a depletion (approximately 12%) of CD4+CD8+ T lymphocytes and a reciprocal increase in CD4-CD8- T lymphocytes precedes the onset of diabetes. This depletion was detected only approximately 3 mo after insulitis and is manifested by a specific loss (approximately 3%) of immature T lymphocytes bearing V beta 8lo (lo is a relative level of expression) T-lymphocyte receptor. By onset of diabetes. an even greater decrease (approximately 35%) of CD4+CD8+ and a reciprocal increase of CD4-CD8- T lymphocytes were apparent and accompanied by the same depletion (3%) of V beta 8 lo T lymphocytes. Administration of cyclophosphamide (CY). which accelerates the appearance of diabetes in NOD mice. caused similar depletions of CD4+CD8+ and V beta 8lo thymic T lymphocytes. The same alterations in the distribution of these thymic T-lymphocyte subsets were evident even earlier in insulitis- and diabetes-free NON mice. indicating that these changes in thymic T-lymphocyte development may be necessary but not sufficient to give rise to diabetes. Despite the common genetic origin of NOD and NON mice. differences at their MHC-linked and -unlinked loci may account for their differential susceptibility to diabetes.
Fucosyltransferases: differential plasma and tissue alterations in hepatocellular carcinoma and cirrhosis, To determine whether abnormal metabolism of L-fucose in hepatocellular carcinoma is accompanied by alterations in the activities of fucosyltransferases. the latter were determined in plasma and liver tissue of patients with this disease and in cirrhotic and normal subjects. Activities of alpha-2/alpha-3 and alpha-6-L-fucosyltransferases were all significantly greater in plasma from patients with hepatocellular carcinoma than in plasma from cirrhotic patients or normal subjects (p less than 0.025). The activity of each enzyme was dependent. to a similar extent. on Mn2+. Mg2+ and triton X-10. irrespective of the source. and all displayed pH optimums in the range of 7.5 to 8.0. In contrast. activities of alpha-2/alpha-3 fucosyltransferases were significantly lower (p less than 0.025) in homogenates prepared from tumorous liver tissue than in that prepared from nontumorous tissue from hepatocellular carcinoma and cirrhotic patients. whereas for the alpha-6 enzyme the situation was reversed (typically. tumor tissue levels were 5 pmol/hr/mg; in nontumor tissue they were 2 pmol/hr/mg). Activities of galactosyl and mannosyltransferase in tumor tissue were greater in all cases than in nontumor cirrhotic tissue. Plasma fucosyltransferases are specifically elevated in hepatocellular carcinoma but different mechanisms appear to underlie the changes seen for alpha-2/alpha-3 and alpha-6-L-fucosyltransferases.
Effect of acute hypoxia on respiration and brain stem blood flow in the piglet, Changes in local brain stem perfusion that alter extracellular fluid Pco2 and/or [H+] near central chemoreceptors may contribute to the decrease in respiration observed during hypoxia after peripheral chemoreceptor denervation and to the delayed decrease observed during hypoxia in the newborn. In this study. we measured the changes in respiration and brain stem blood flow (BBF) during 2-4 min of hypoxic hypoxia in both intact and denervated piglets and calculated the changes in brain stem Pco2 and [H+] that would be expected to occur as a result of the changes in BBF. All animals were anesthetized. spontaneously breathing. and between 2 and 7 days of age. Respiratory and other variables were measured before and during hypoxia in all animals. and BBF (microspheres) was measured in a subgroup of intact and denervated animals at 0. 30. and 260 s and at 0 and 80 s. respectively. During hypoxia. minute ventilation increased and then decreased (biphasic response) in the intact animals but decreased only in the denervated animals. BBF increased in a near linear fashion. and calculated brain stem extracellular fluid Pco2 and [H+] decreased over the first 80 s both before and after denervation. We speculate that a rapid increase in BBF during acute hypoxia decreases brain stem extracellular fluid Pco2 and [H+]. which. in turn. negatively modulate the increase in respiratory drive produced by peripheral chemoreceptor input to the central respiratory generator.
Serum amyloid A (SAA3) produced by rabbit synovial fibroblasts treated with phorbol esters or interleukin 1 induces synthesis of collagenase and is neutralized with specific antiserum, We report that nucleic acid sequence analysis of a full-length cDNA clone for a rabbit serum amyloid A (SAA)-like protein has identified this protein as more closely related to SAA3 than to SAA1. SAA3 induced collagenase synthesis in rabbit synovial fibroblasts. and immune IgG raised against this SAA protein abrogated the induction. Using antisera to immunoprecipitate biosynthetically labeled 3H-SAA and 3H-collagenase from culture medium. we compared the levels of SAA and collagenase synthesized by cultures of rabbit fibroblasts at early passage (passages 3-6) with those synthesized by late passage cells (passage 16). Comparatively high levels of both proteins were produced constitutively by fibroblasts at low passage. With increasing passage. levels of both proteins drop so that by passage 16. constitutive production of SAA and collagenase was only approximately 15-20% that of passage 3 cells. Cells at low passage could be readily stimulated with phorbol myristate acetate (PMA) or interleukin 1 (IL-1) to synthesize increased amounts of both SAA and collagenase. In passage 5 cells treated with PMA. we detected increased SAA mRNA by 1.5 h and collagenase mRNA by 5 h. However. older passage cells were more refractory to stimulation and required longer induction times. We suggest that SAA3 may be expressed by fibroblasts at sites of acute inflammation or injury. and that elevated levels of SAA3 may signify "activated" fibroblasts which are already producing increased amounts of collagenase constitutively and which are predisposed to further stimulation.
Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region, 15 immunoglobulin heavy chain constant (CH) and variable region (VH) polymorphisms were selected to span the entire length of the heavy chain cluster. These polymorphisms were examined in 34 sib pairs concordant for multiple sclerosis (MS) and in 23 sporadic MS patients. Allele frequencies were calculated for the 2 MS patient groups and compared with those found in a control population from the same geographical location and of similar ethnic background. No significant association was found between MS and the 7 CH region polymorphisms examined. However. a significant correlation between the MS phenotype and a VH2 family polymorphism was observed in both MS patient populations (familial MS patients chi 2 = 8.16. P less than 0.005; sporadic MS patients chi 2 = 8.90. P less than 0.005). One allele of the VH2-5 gene segment was found to be over-represented in both MS groups. VH2-5 has recently been physically mapped close to the CH region. between 180 and 360 kb away. These results indicate that a locus near or within the CH-proximal VH region is associated with increased susceptibility to MS.
Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus, We have studied the effects of oral administration of vanadate. an insulinometic agent and a potent inhibitor of phosphotyrosyl protein phosphatase (PTPase) in vitro. on blood glucose and PTPase action. in two hyperinsulinemic rodent models of non-insulin-dependent diabetes mellitus (NIDDM). Oral administration of vanadate (0.25 mg/ml in the drinking water) to ob/ob mice for 3 wk lowered blood glucose level from 236 +/- 4 to 143 +/- 2 mg/dl without effect on body weight. Administration of vanadate to db/db mice produced a similar effect. Electron microscopic examination revealed no signs of hepatotoxicity after 47 d of treatment. There was a slight reduction in insulin receptor autophosphorylation when tested by immunoblotting with antiphosphotyrosine antibody after in vivo stimulation. and the phosphorylation of the endogenous substrate of the insulin receptor. pp185. was markedly decreased in the ob/ob mice. Both cytosolic and particulate PTPase activities in liver of ob/ob mice measured by dephosphorylation of a 32P-labeled peptide corresponding to the major site of insulin receptor autophosphorylation were decreased by approximately 50% (P less than 0.01). In db/db diabetic mice. PTPase activity in the cytosolic fraction was decreased to 53% of control values (P less than 0.02) with no significant difference in the particulate PTPase activity. Treatment with vanadate did not alter hepatic PTPase activity as assayed in vitro. or receptor and substrate phosphorylation as assayed in vivo. in ob/ob mice despite its substantial effect on blood glucose. These data indicate that vanadate is an effective oral hypoglycemic treatment in NIDDM states and suggest that its major effects occurs distal to the insulin receptor tyrosine kinase.
Brain natriuretic peptide as a novel cardiac hormone in humans. Evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide, Using a specific radioimmunoassay for human brain natriuretic peptide (hBNP) with a monoclonal antibody. we have investigated its synthesis. secretion. and clearance in comparison with those of atrial natriuretic peptide (ANP) in normal subjects and patients with congestive heart failure (CHF). Mean BNP-like immunoreactivity (-LI) levels in normal atrium and ventricle were 250 and 18 pmol/g. respectively. The plasma BNP-LI level in normal subjects was 0.90 +/- 0.07 fmol/ml. which was 16% of the ANP-LI level. In contrast. the plasma BNP-LI level markedly increased in patients with CHF in proportion to its severity. and surpassed the ANP-LI level in severe cases. There was a significant step-up of the plasma BNP-LI level in the coronary sinus (CS) compared with that in the aortic root (Ao) and the difference between these BNP-LI levels. delta(CS-Ao)BNP. also increased with the severity of CHF. In addition. the step-up of the BNP-LI level in the anterior interventricular vein [delta(AIV-Ao)BNP] was comparable to delta(CS-Ao)BNP. indicating that BNP is secreted mainly from the ventricle. Predominant BNP synthesis in the ventricle was also confirmed by Northern blot analysis. Catheterization and pharmacokinetic studies revealed that hBNP is cleared from the circulation more slowly than alpha-hANP; this was in part attributed to lower (about 7%) binding affinity of hBNP to clearance receptors than that of alpha-hANP. A predominant molecular form of BNP-LI in the heart and plasma was a 3-kD form corresponding to hBNP. These results indicate that BNP is a novel cardiac hormone secreted predominantly from the ventricle. and that the synthesis. secretion and clearance of BNP differ from those of ANP. suggesting discrete physiological and pathophysiological roles of BNP in a dual natriuretic peptide system.
Evidence for clonal spread of a single strain of beta-lactamase-producing Enterococcus (Streptococcus) faecalis to six hospitals in five states, Beta-lactamase-producing (Bla+) enterococci have been reported in three state and two countries. Pulsed-field gel electrophoresis was used to compare 14 Bla+ Enterococcus (Streptococcus) faecalis isolated from hospitalized patients in seven states and three continents. The restriction endonuclease digestion patterns of isolates from Connecticut. Massachusetts. Lebanon. and Argentina were all markedly different. indicating that these were different strains. However. isolates from Delaware. Texas. Pennsylvania (Philadelphia and Pittsburgh). Florida. and Virginia were similar. indicating that these isolates were derivatives of a single strain. This conclusion was supported by hybridization using individual fragments as probes. Spread of Bla+ enterococci within the hospital setting was also demonstrated. These findings illustrate the value of pulsed-field gel electrophoresis for epidemiologic analyses and support the importance of identifying and containing organisms with new resistance properties in an effort to decrease their transmission to and from. as well as within. hospitals.
In vivo interferon-gamma therapy augments the in vitro ability of chronic granulomatous disease neutrophils to damage Aspergillus hyphae, During the recently completed double-blind. placebo-controlled. randomized trial of recombinant interferon-gamma (rIFN-gamma) therapy in chronic granulomatous disease (CGD). a metabolic assay of neutrophil damage to Aspergillus fumigatus hyphae was used to monitor neutrophil function before and during therapy. In this assay. 5 x 10(4) conidia that had germinated into hyphae were exposed to 5 x 10(5). 15 x 10(5). or 50 x 10(5) CGD neutrophils. By analysis of variance. neutrophils from patients on rIFN-gamma were found to produce significantly more damage to hyphae than those from the placebo group (P less than .01). In subgroup analysis. this effect was best seen in the hyphae exposed to 50 x 10(5) CGD neutrophils. where neutrophils from patients receiving rIFN-gamma produced significantly more damage to the hyphae than those from the placebo group (P less than .05). In vivo rIFN-gamma therapy improves the ability of CGD neutrophils to damage Aspergillus fumigatus hyphae in an in vitro assay.
Prevaccination serologic screening for measles in health care workers, A model was developed from which the cost-effectiveness of prevaccination serologic screening for measles could be estimated. for any combination of antibody screening costs and prevalence of antibody to measles. This model was tested using sera obtained prospectively from 222 health care workers. including 181 born in or after 1957 who had no history of measles. no measles vaccine after 1980. and no documentation of immunity to measles. In addition. 41 subjects born before 1957 who had no history of measles were studied. A rapid. reliable. and inexpensive ($5 per test) commercial ELISA was used to test for antibodies to measles; its seroprevalence in the subject population was 86%. From the model. it was estimated that prevaccination serologic testing would be cost-effective if antibody screening cost less than or equal to $12.75 per test. In this subject population. prevaccination serologic screening for measles was cost-effective.
Thrombin-induced leukopenia and thrombocytopenia are attenuated by PAF antagonist WEB 2086, Thrombin has been shown to increase pulmonary transvascular permeability in vivo. This permeability change appears to be dependent on polymorphonuclear leukocytes (PMNs). In vitro. thrombin has been demonstrated to increase PMN adherence to endothelial cells coincident with generation of platelet activating factor (PAF) by endothelial cells. These observations have led to the suggestion that PAF mediates. in part. the attachment of PMNs to endothelial cells. We examined this hypothesis in vivo and in vitro with a specific PAF receptor antagonist. WEB 2086. Prior infusion of WEB 2086 into conscious sheep significantly attenuated the drop in peripheral blood PMN counts observed during and after infusion of alpha-thrombin (30 NIH U/kg). These data suggest that WEB 2086 prevented PMN margination on endothelial cells. WEB 2086 also attenuated the thrombocytopenia seen after thrombin infusion and ameliorated the thrombin-induced hypoxemia and hemoconcentration. WEB 2086 did not affect the thrombin-induced hemodynamic response. the degree of intravascular coagulation as assessed by fibrin degradation product generation. or thromboxane B2 generation. In vitro. WEB 2086 prevented the augmented adherence of sheep PMNs to sheep endothelial cell monolayers after thrombin stimulation. The results of the present study are consistent with the hypothesis that PAF mediates. at least in part. thrombin-induced leukopenia and thrombocytopenia in vivo.
The nigrostriatal dopaminergic pathway in Wilson's disease studied with positron emission tomography, Movement disorders. including Parkinsonism. are prominent features of neurological Wilson's disease (WD). This suggests there may be dysfunction of the nigrostriatal dopaminergic pathway. To explore this possibility. five patients were studied using positron emission tomography (PET) with 18F-6-fluorodopa (6FD). and magnetic resonance imaging (MRI). We calculated striatal 6FD uptake rate constants by a graphical method and compared the results with those of 18 normal subjects. It was found that four patients with symptoms all had abnormally low 6FD uptake. and the one asymptomatic patient had normal uptake. PET evidence for nigrostriatal dopaminergic dysfunction was present even after many years of penicillamine treatment. It is concluded that the nigrostriatal dopaminergic pathway is involved in neurological WD.
Recombinant tissue plasminogen activator in two patients with basilar artery occlusion, Two patients with angiographically proved basilar artery occlusion were treated with systemic recombinant tissue plasminogen activator (rtPA) according to protocol. The first patient was in a locked-in state and gradually deteriorated. On repeat angiography the basilar artery remained occluded. He died and necropsy revealed a pontine haemorrhagic infarction. The second patient. who was comatose and with decerebrate posturing. made a remarkable recovery. Angiography showed reperfusion. Therapy was initiated in the first patient after six hours and in the second after two hours. Treatment with rtPA is promising but probably not feasible for every patient. Success may depend on duration of occlusion and composition of occluding thrombus.
A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene, Of the various classes of antibodies that B lymphocytes can produce. class M (IgM) is the first to be expressed on the membrane of the developing cells. Pre-B cells. the precursors of B-lymphocytes. produce the heavy chain of IgM (mu chain). but not light chains. Recent data suggest that pre-B cells express mu chains on the membrane together with the 'surrogate' light chains lambda 5 and V pre B (refs 2-7). This complex could control pre-B-cell differentiation. in particular the rearrangement of the light-chain genes. We have now assessed the importance of the membrane form of the mu chain in B-cell development by generating mice lacking this chain. We disrupted one of the membrane exons of the gene encoding the mu-chain constant region by gene targeting in mouse embryonic stem cells. From these cells we derived mice heterozygous or homozygous for the mutation. B-cell development in the heterozygous mice seemed to be normal. but in homozygous animals B cells were absent. their development already being arrested at the stage of pre-B-cell maturation.
Differential effect of recombinant tissue plasminogen activator-induced thrombolysis in the central nervous system and systemic arteries, Recombinant tissue plasminogen activator (rTPA) has been more effective in inducing thrombolysis in laboratory studies of intracranial thrombosis than clinical studies of systemic or coronary thrombosis would indicate. To evaluate this discrepancy. 21 rabbits were subjected to embolic occlusion of the right internal carotid artery (ICA) by retrograde injection of a tin-tagged. 2-hour-old autologous clot through the external carotid artery with angiographic monitoring in the same manner as in a previously reported model. The emboli lodged intracranially at the bifurcation of the ICA in 10 animals and in the cervical ICA in 11 animals. Digital subtraction angiography confirmed total occlusion of the ICA in all animals. Treatment started one-half hour after embolization and consisted of a bolus of 0.5 mg/kg of rTPA followed by an infusion of 1 mg/kg/h for 2 hours. All of the animals with intracranial emboli and 6 of the animals with cervical emboli were treated intravenously. The remaining 5 animals with cervical emboli were treated by intracarotid infusion of the same dose of rTPA. In the intravenously treated group. serial digital subtraction angiography documented thrombolysis in 9 of the 10 animals with intracranial emboli and only 1 of the 6 with cervical emboli. Thrombolysis occurred in 4 of the 5 rabbits with cervical emboli treated with intracarotid rTPA. Intravenous rTPA therapy produced a significantly (P less than 0.01) higher rate of thrombolysis in intracranial as compared to cervical thrombus.
Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing, Rous sarcoma virus was shown to induce in chicken embryo fibroblasts (CEF) a 4.1-kilobase mRNA (designated CEF-147) encoding a 603-amino acid protein. Analysis of the protein sequence showed that it shared 59% amino acid identity with sheep prostaglandin G/H synthase. the enzyme that catalyzes the rate-limiting steps in the production of prostaglandins. Significant differences. at both the protein and mRNA levels. existed between the src oncogene product-inducible prostaglandin synthase and the protein isolated and cloned from sheep seminal vesicle. suggesting that the src-inducible prostaglandin synthase may be a new form of the enzyme. A distinguishing feature of src-inducible prostaglandin synthase mRNA is its low abundance in nonproliferating chicken embryo fibroblasts and its relatively high abundance in src-transformed cells. Additionally. the majority of the src-inducible prostaglandin synthase RNA present in nonproliferating cells was found to be nonfunctional because of the presence of an unspliced intron that separated the signal peptide from the remainder of the protein. Upon mitogenic stimulation. this intron was removed. resulting in the induction of fully-spliced CEF-147 mRNA.
Effects of time required for reperfusion (thrombolysis or angioplasty, or both) and location of acute myocardial infarction on left ventricular functional reserve capacity several months later, The purpose of this study was to determine whether reperfusion of acute myocardial infarction (AMI) by recombinant tissue-type plasminogen activator (rt-PA) or percutaneous transluminal coronary angioplasty. or both. would improve left ventricular (LV) function when it is measured several months later at rest or maximal bicycle exercise. or both. Radionuclide angiography was performed in 44 patients 5 months (range 6 weeks to 9 months) after AMI to assess function. and tomographic myocardial thallium-201 imaging was performed at maximal exercise and delayed rest to determine whether there was any evidence of myocardial ischemia. As expected. no patient had chest pain or redistribution of a thallium defect during the exercise test. because patients had undergone angioplasty (n = 28) or coronary bypass graft surgery (n = 5) where clinically indicated for revascularization. The LV ejection fraction was plotted as a function of the time elapsed between the onset of chest pain and the time when coronary angiography confirmed patency of the infarct-related artery (achieved in 91% of 44 patients by rt-PA [n = 31] or percutaneous transluminal coronary angioplasty [n = 9] ). Functional responses differed markedly between patients with anterior (n = 20) versus inferior (n = 24) wall AMI. LV ejection fraction during exercise correlated with time to reperfusion in patients with an anterior wall AMI (r = -0.58; standard error of the estimate = 11.9%; p less than 0.02) but not in patients with an inferior AMI (r = 0.10; standard error of the estimate = 13.1%; difference not significant.
A comparison of tocopherol and tocotrienol for the chemoprevention of chemically induced rat mammary tumors, Two forms of vitamin E. tocopherol and tocotrienol. were tested for chemopreventive activity in two chemically induced rat mammary-tumor models. When mammary tumors were induced by 7.12-dimethylbenz(a)anthracene (DMBA. 50 mg/kg). only the tocotrienol group had a statistically significant increase in tumor latency. There was no effect of either compound on tumor multiplicity. When tumors were induced by N-nitrosomethylurea (NMU. 30 mg/kg). neither analogue of vitamin E modified latency. whereas tocotrienol increased tumor multiplicity. In summary. neither vitamin analog had a major impact on mammary-tumor development after tumor induction with either DMBA or NMU.
Effect of tocotrienols on hepatocarcinogenesis induced by 2-acetylaminofluorene in rats, The effects of tocotrienols on hepatocarcinogenesis in rats fed with 2-acetylaminofluorene (AAF) were followed morphologically and histologically for a period of 20 wk. No differences between treated and control rats in the morphology and histology of their livers was observed. Cell damage was extensive in the livers of AAF-treated rats but less extensive in the AAF-tocotrienols-treated rats when compared with normal and tocotrienols-treated rats. 2-Acetylaminofluorene significantly increases the activities of both plasma and liver microsomal gamma-glutamyltranspeptidase (GGT) and liver microsomal UDP-glucuronyltransferase (UDP-GT). Tocotrienols administered together with AAF significantly decrease the activities of plasma GGT after 12 and 20 wk (P less than 0.01. P less than 0.002. respectively) and liver microsomal UDP-GT after 20 wk (P less than 0.02) when compared with the controls and with rats treated only with tocotrienols. Liver microsomal GGT also showed a similar pattern to liver microsomal UDP-GT but the decrease was not significant. These results suggest that tocotrienols administered to AAF-treated rats reduce the severity of hepatocarcinogenesis.
Variable expression of albinism within a single kindred, We studied the albinotic characteristics in 13 members of a white family (age range. 2 to 73 years). which were graded according to severity and were correlated with visual acuity. Clinical. electrophysiologic. and biochemical characteristics of this family do not fit any known category of human albinism. The degree of heterogeneity in expression of albinotic features was unexpected. The correlation between visual acuity and nystagmus was particularly strong. The brown-haired propositus had severe skin involvement. iris transillumination. fundus hypopigmentation. and foveal hypoplasia. He had no manifest nystagmus. however. and his visual acuity was nearly normal. These observations suggest that nystagmus imposes a visual deficit beyond that related to foveal hypoplasia alone.
Herpes simplex dendritic keratitis after keratoplasty, We treated three patients with herpes simplex dendritic keratitis that occurred between three and 11 months after keratoplasty. The patients had no history of herpetic infection. The eyes of two of the patients were grafted for corneal scarring of undetermined origin. The eye of the third patient was grafted for pseudophakic bullous keratopathy. At the time of onset of dendritic keratitis. all three patients were receiving either maintenance or higher doses of topical corticosteroids. All infections responded to topical antiviral treatment. The findings in these patients illustrate the importance of considering herpes simplex keratitis in the differential diagnosis of all late-onset epithelial defects in the corneal graft. even in the absence of a history of herpes simplex keratitis.
Human-rodent contact and infection with lymphocytic choriomeningitis and Seoul viruses in an inner-city population, We collected 1180 sera and 1363 questionnaires with information on demography. rodent exposure. and history of travel from persons visiting a sexually transmitted disease (STD) clinic in Baltimore between 1986-1988. Serological tests for two rodent-borne viruses detected antibodies to lymphocytic choriomeningitis virus (LCMV) in 54 individuals (4.7%; n = 1149) and antibodies to Seoul virus (SEOV) in three persons (0.25%; n = 1180). Antibody prevalence to LCMV increased with age. but there were no racial or sexual differences. Neutralization tests and questionnaire responses implicated a domestic. rat-borne hantavirus as the source of SEOV antibody. Self-reported human-rodent contact indicated more exposure to house mice than rats within residences. although rats were more commonly sighted on streets. Infections with rodent-borne viruses were rare compared to the high rates of reported contact.
Cost effectiveness of low-dose zidovudine therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection, We did a cost-effectiveness analysis of zidovudine therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection. The incremental direct medical costs of zidovudine therapy were determined. and data on the effects of therapy were derived from the report of the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group Protocol 019. Zidovudine therapy has an annual incremental cost of $2653 per person. The cost per year of life saved ranges between $6553 and $70 526. depending on which epidemiologic model of potential long-term zidovudine effect is used (in sensitivity analyses. the cost per year of life saved ranges between $2649 and $250 546). Although expensive. zidovudine therapy has the potential to yield a substantial survival benefit to patients. The cost effectiveness of zidovudine therapy compares favorably with that of other common medical therapies.
Positron emission tomography in progressive supranuclear palsy, Positron emission tomography with 6-[18F]fluoro-L-dopa (6-FD) provides in vivo information on the function of nigrostriatal dopaminergic neurons. We used 6-FD and positron emission tomography to investigate the integrity of the nigrostriatal system in seven patients with progressive supranuclear palsy. All patients had axial hypertonia. vertical gaze palsy. and parkinsonian features. Dementia. pyramidal signs. and ataxia were seen in varying proportions. We analyzed the scans with a graphic method to calculate a steady-state 6-FD uptake rate constant for the whole striatum. Results were compared with those obtained in seven age-matched controls. As a group. the patients with progressive supranuclear palsy had reduced 6-FD uptake constants. The 6-FD uptake constant correlated inversely with the duration of the disease. Normal positron emission tographic findings in one patient with the shortest duration of symptoms suggests that in early progressive supranuclear palsy. parkinsonism may relate to dysfunction distal to the dopaminergic neurons.
Predictors of survival in systemic sclerosis (scleroderma), We conducted followup of 264 patients with definite systemic sclerosis (SSc) who were entered into the multicenter Scleroderma Criteria Cooperative Study (SCCS) during 1973-1977. At the end of the study (average 5.2 years of followup). 38% were known to be alive. 50% were dead (68% of these deaths definitely related to SSc). and 12% were lost to followup. Survival analyses of 484 demographic. clinical. and laboratory items recorded at entry into the SCCS (within 2 years of physician diagnosis of SSc) were performed. Survival declined linearly. and the cumulative survival rate was less than 80% at 2 years. 50% at 8.5 years. and 30% at 12 years after entry. Analysis using combinations of entry variables identifying organ system involvement confirmed that renal. cardiac. pulmonary. and gastrointestinal involvement in SSc predicted reduced survival; however. data on organ system involvement at study entry could not be used to consistently predict which organ system would ultimately be involved as the primary cause of death. By survival tree analysis. the individual entry variables best predicting reduced survival included older age (greater than 64 years). reduced renal function (blood urea nitrogen greater than 16 mg/dl). anemia (hemoglobin less than or equal to 11 gm/dl). reduced pulmonary diffusing capacity for carbon monoxide (less than or equal to 50% of predicted). reduced total serum protein level (less than or equal to 6 gm/dl). and reduced pulmonary reserve (forced vital capacity less than 80% with hemoglobin greater than 14 gm/dl or forced vital capacity less than 65% with hemoglobin less than or equal to 14 gm/dl). Cox proportional hazards model analysis confirmed these results. Different combinations of variables led to markedly different survival rates. The poorest prospects for survival were in patients with SSc who were less than or equal to 64 years old with a hemoglobin level less than or equal to 11 gm/dl. and in those greater than 64 years old with a blood urea nitrogen level greater than 16 mg/dl. These results may be useful in predicting individual patients at risk for shortened survival.
Activation of CD16+ effector cells by rheumatoid factor complex. Role of natural killer cells in rheumatoid arthritis, The role of natural killer (NK) cells in rheumatoid arthritis (RA) remains unclear. A pathogenetic function of rheumatoid factors (RF) also has not been defined. In the present studies. natural killer (NK) cells were examined as a model for FC gamma receptor type III-positive (FC gamma RIII+) cells. with regard to their interaction with RF. NK cell antigen CD16 (FC gamma RIII) and CD56 expression and functional NK and antibody-dependent cell-mediated cytotoxicity (ADCC) activity were compared in peripheral blood lymphocytes and autologous synovial fluid lymphocytes (SFL) of RA patients. Peripheral blood lymphocytes and SFL showed normal CD56 expression. In contrast. both the frequency and the density of CD16 antigen were decreased in SFL. Furthermore. diminished NK cytotoxicity and a significant decrease in ADCC were observed in SF NK cells. In subsequent in vitro studies with normal fresh NK cells. it was demonstrated that IgG-containing RF complexes from RA patients induced a modulation of FC gamma RIII structure from the NK cell surface. a decrease in NK activity. and a complete loss of ADCC. When purified RF was incubated with NK-enriched cell lines from RA patients. increased transcription and subsequent production of interferon-gamma and tumor necrosis factor alpha were observed. These data suggest a direct involvement of RF complexes in the pathogenetic process of chronic inflammation in RA.
Enhanced CD3-mediated T lymphocyte proliferation in patients with systemic lupus erythematosus, Nonfractionated peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE) showed enhanced proliferative responses when stimulated via the CD3 pathway. In contrast. proliferative responses induced by phytohemagglutinin were diminished in SLE patients. Levels of CD3-induced interleukin-2 production and interleukin-2 receptor expression were comparable with normal levels. Highly purified T cells also showed augmented CD3 responses. but only in the presence of phorbol myristate acetate or a combination of phorbol myristate acetate plus calcium ionophore A23187. and not with calcium ionophore alone. The data suggest integrity of the T cell receptor/CD3 pathway for T cell activation in patients with SLE. as examined in cultures stimulated with specific anti-CD3 monoclonal antibodies rather than with multivalent lectins. An increased response via the CD3 complex could contribute to the autoimmune activity in human SLE.
Effect of radiation on the expression of carcinoembryonic antigen of human gastric adenocarcinoma cells, The changes of antigenic expression of cultured human gastric adenocarcinoma MKN45 cells caused by irradiation were investigated to elucidate the immune responses to localized irradiation. The expression of carcinoembryonic antigen (CEA) showed remarkable increases in the culture supernatant and on the surface of the membrane of irradiated cells. The expression of major histocompatibility complex Class I antigen on the membrane also was enhanced by irradiation. In addition. the irradiated cell groups. when analyzed using a CEA-specific probe. showed remarkable increases in the CEA mRNA. These enhancements increased in the 10-Gy and 15-Gy irradiated populations compared with the 5-Gy irradiated population. These results suggest that the enhancement of expression of CEA by radiation takes place at the CEA gene expression (mRNA) level but not at the protein level.
Formation of neutralizing antibodies against natural interferon-beta, but not against recombinant interferon-gamma during adjuvant therapy for high-risk malignant melanoma patients, In an adjuvant clinical trial. 34 high-risk malignant melanoma patients were treated with natural interferon (IFN)-beta and recombinant IFN-gamma. Patients with tumor location on head. neck. and trunk received 3 million IU IFN-beta intravenously (IV) three times weekly for 24 weeks. Patients with tumor location on the extremities received subcutaneous (SC) injection of 2 million IU of IFN-beta distal the locoregional lymph nodes instead. All patients were given 50 micrograms IFN-gamma SC on 3 consecutive days every 4 weeks. Antibody formation was detected by coincubation of IFN and patients' serum and assessment of the inhibition of the cytopathic effect by a virus suspension. Soluble interleukin-2 receptors (sIL-2R) were determined by enzyme-linked immunosorbent assay (ELISA) technique. No antibodies against IFN-gamma were observed. The overall incidence of antibody formation to IFN-beta was 55.8% (19/34). Ninety-two percent of the SC-treated patients (13/14) and 30% (six of 20) of the IV-treated patients developed antibodies. Soluble interleukin-2 receptors were found to be significantly lower in antibody-positive patients than in antibody-negative patients. The authors conclude that IFN-beta antibody formation is frequent and might influence IFN induced sIL-2R elevation in vivo.
Relations between heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease, BACKGROUND. Previous studies have shown that little if any increase in heart rate occurs 1 minute before the onset of ischemia in ambulant patients with coronary artery disease. This study tested the hypothesis that there are characteristic relations between heart rate and ischemia in ambulant patients with coronary artery disease. METHODS AND RESULTS. Twenty-one patients with proven coronary disease demonstrated 212 episodes of ischemia during 504 hours of continuous monitoring of the electrocardiogram. An important increase in heart rate (from 74 +/- 11 to 90 +/- 14 beats/min. p less than 0.001) occurred between 5 and 30 minutes (not 1 minute) before the onset of ischemia. A significantly higher heart rate at onset of ischemia was seen during Bruce protocol exercise testing than during daily life (117 +/- 12 versus 95 +/- 15 beats/min. p less than 0.01). However. when a less-strenuous. but more prolonged. exercise protocol was used in a subgroup of patients (n = 12). ischemia occurred at a heart rate that was significantly lower than during the Bruce protocol (88 +/- 14 versus 103 +/- 15 beats/min. p less than 0.05) and was not significantly different from the threshold heart rate at onset of ischemia during daily life (88 +/- 14 versus 84 +/- 12 beats/min. p = NS). As part of two placebo-controlled trials. treatment with both propranolol and nitroglycerin altered the distribution of ischemic events by heart rate but in opposite directions. Although propranolol largely eliminated events occurring at high (greater than 100 beats/min) and moderate (80-100 beats/min) heart rates. the number of events at low (less than 80 beats/min) heart rates was increased. In contrast. nitroglycerin reduced episodes at low and moderate heart rates only. CONCLUSIONS. Important increases in heart rate occur before the onset of ischemia during daily life. but this increase occurs much earlier than has been reported. Duration of heart rate increase appears to influence the heart rate threshold for ischemia. and this may contribute to the occurrence of ischemia at lower heart rates during daily life than during standard exercise testing. Last. different classes of drugs appear to have characteristic effects on ischemia occurring at different heart rates that may be useful in planning therapy.
Significance of a negative exercise thallium test in the presence of a critical residual stenosis after thrombolysis for acute myocardial infarction, BACKGROUND. After thrombolytic therapy for acute myocardial infarction. increasing emphasis is placed on early submaximal exercise testing. with further intervention advocated only for demonstrable ischemia. Although significant residual coronary artery lesions after successful thrombolysis are common. many patients paradoxically have no corresponding provokable ischemia. METHODS AND RESULTS. The relation between significant postthrombolytic residual coronary artery disease and a negative early. submaximal exercise thallium-201 tomogram was studied among 101 consecutive patients with uncomplicated myocardial infarction and at least 70% residual stenosis of the infarct artery. A negative test occurred in 49 (48.5%) patients with a mean 88% residual infarct artery stenosis. Further characteristics of the group were as follows: mean time to treatment was 3.1 hours; mean age was 54 +/- 10 years; 80% were male; 47% had anterior infarction; 39% had multivessel disease; mean left ventricular ejection fraction was 53 +/- 14%; and mean peak creatine kinase level was 3.820 +/- 3.123 IU/ml. A similar group of 52 (51.5%) patients. treated within 3.3 hours from symptom onset. with a mean postthrombolysis stenosis of 90%. had a positive exercise test. Characteristics of this group were as follows: age was 58 +/- 10 years; 92% were male; 56% had anterior infarction; 40% had multivessel disease; and mean left ventricular ejection fraction was 54 +/- 15%. The peak creatine kinase level associated with the infarction. however. was lower: 2.605 +/- 1.805 IU/ml (p = 0.04). There was no difference in performance at exercise testing with respect to peak systolic pressure. peak heart rate. or time tolerated on the treadmill between the two groups. By multivariate logistic regression. only peak creatine kinase level predicted a negative stress result in the presence of a significant residual stenosis (odds ratio. 4.2; 95% confidence interval. 1.1-16.3). CONCLUSIONS. The explanation for the relatively frequent finding of a negative early stress 201Tl tomogram after apparently successful reperfusion appears to be more extensive myocardial necrosis and not delay in therapy or inadequate exercise performance.
A1-adenosine receptor inhibition of adenylate cyclase in failing and nonfailing human ventricular myocardium, BACKGROUND. Receptors that couple via the stimulatory G protein. Gs. to adenylate cyclase and to a positive inotropic response have been extensively investigated in falling human heart. In contrast. much less is known about receptors. such as the A1-adenosine receptor. that couple to adenylate cyclase via the inhibitory G protein. Gi. to give a negative inotropic response. Activation of such Gi-coupled receptors might worsen heart failure. Furthermore. alpha Gi is increased in failing human ventricular myocardium. which may enhance inhibitory receptor coupling to adenylate cyclase. METHODS AND RESULTS. A1-Adenosine receptor inhibition of adenylate cyclase was examined in crude particulate preparations derived from 12 nonfailing and 12 failing human left ventricles. Experimental conditions were designed for maximal inhibitory responses. Dose-response curves were performed with the selective A1-adenosine receptor agonist R-phenylisopropyl-adenosine (R-PIA). No differences in nonfailing versus failing heart were observed for basal adenylate cyclase activity (49.0 +/- 4.1 versus 45.7 +/- 2.6 pmol cyclic AMP/min/mg). maximal R-PIA-mediated inhibition (31.1 +/- 2.6 versus 30.2 +/- 1.6 pmol cyclic AMP/min/mg). ED50 (R-PIA x 10(-7) 1.28 +/- 0.10 versus 1.36 +/- 0.08). or slope (1.06 +/- 0.06 versus 1.03 +/- 0.10). respectively. Furthermore. fluoride. forskolin. and manganese adenylate cyclase activation were not different in failing heart. which is consistent with no change in the catalytic unit of adenylate cyclase. The inhibitory G protein alpha Gi. as quantitated by pertussis toxin-catalyzed ADP-ribosylation. was increased in failing heart (105.7 +/- 5.8 versus 132.7 +/- 3.4 optical density units. p less than 0.003). Basal adenylate cyclase activity was reduced in failing heart (7.8 +/- 0.8 versus 4.5 +/- 0.4 pmol cyclic AMP/min/mg. p less than 0.005) with assay conditions designed to assess G protein effects. CONCLUSIONS. The A1-adenosine receptor pathway exerts a major inhibitory effect on human myocardial adenylate cyclase activity. Although alpha Gi was increased in failing heart. A1-adenosine receptor inhibition of adenylate cyclase was not altered in preparations of failing versus nonfailing human ventricular myocardium.
Experience with a gastrointestinal marker (51CrCl3) in a combined study of ileal function using 75SeHCAT and 58CoB12 measured by whole body counting, Introduction of a radioactive gastrointestinal marker (51CrCl3) into a combined study (75SeHCAT + 58CoB12) of ileal function by whole body counting has been undertaken. The technique was assessed in 23 subjects (15 patients with inflammatory bowel disease. six on non-steroidal anti-inflammatory drugs for rheumatoid arthritis. and two normal subjects). Mean (SD) 51CrCl3 retention was only 4.1 (6.0)% on day 4. and was similar on day 7 in subjects given a second dose of 51CrCl3 on day 4. Only one subject had more than 20% of 51CrCl3 retention after four days. A 51CrCl3 correction method adequately corrected for colonic hold up of 58CoB12. when compared with final equilibrium values of 58CoB12 retention. Use of the non-absorbed 58CoB12 fraction as a gastrointestinal marker gave good agreement with the 51CrCl3 method in correcting 75SeHCAT values. In all subjects studied. corrections for colonic retention of 75SeHCAT on day 4. were small (less than 7% of dose) and did not affect the assessment of any subject. In conclusion. an additional gastrointestinal marker such as 51CrCl3 is unnecessary in our combined study since that role can be effected. when indicated by the non-absorbed 58CoB12 fraction.
A pilot study of fluticasone propionate in untreated coeliac disease, Although gluten withdrawal is likely to remain the mainstay of treatment for adult coeliac disease. many patients find the diet inconvenient and unpalatable and compliance among asymptomatic patients is often poor. Oral corticosteroids have been used for patients who seem to be resistant to gluten withdrawal but preparations with low systemic bioavailability might be preferable. We have given a new glucocorticoid (fluticasone propionate) to 12 adults with untreated coeliac disease for six weeks while they were on a normal diet. One patient defaulted and one suffered a relapse in a pre-existing neoplasm. Excluding these. there was an improvement of symptoms. a mean weight gain of 2 kg. and a rise in albumin of 5.4 g/l. There was a significant improvement in the lactulose/mannitol excretion ratio (p less than 0.05) and in all histological variables examined in paired biopsy specimens (surface and crypt intraepithelial lymphocyte/enterocyte and goblet cell/enterocyte ratios and enterocyte height. p less than 0.01 or better). In six paired specimens sucrase and alkaline phosphatase activity increased in all (p less than 0.05) and lactase in five of six. No appreciable side effects were observed. but two patients had suppressed cortisol values and synacthen responses at six weeks. A further three. with normal pretrial results. had a blunted tetracosactrin response at six weeks. Fluticasone propionate seems worthy of further assessment in the treatment of coeliac disease as an adjunct to gluten withdrawal.
Arachidonic acid and docosahexaenoic acid are increased in human colorectal cancer, Increased arachidonic acid concentrations in experimental rodent colonic cancer have been described recently. In humans. a reduced erythrocyte stearic acid to oleic acid ratio has been reported in patients with colorectal cancer and it has been proposed that similar changes exist in the cancer tissue. The long chain fatty acids in the cancers of 15 patients with colorectal cancer were measured and compared with values in the unaffected mucosa. The values were expressed as mean (SD) mg fatty acid/g tissue and compared by analysis of variance. In the cancer tissue arachidonic acid was increased (0.703 (0.109) mg/g v 0.603 (0.127) mg/g. p less than 0.05) as was docosahexaenoic acid (0.211 (0.066) mg/g v 0.148 (0.039) mg/g. p less than 0.001). In contrast. the stearic acid to oleic acid ratio in the cancer tissue was increased rather than decreased. as previously suggested (0.36 (0.05) v 0.29 (0.7). p less than 0.01). Increased arachidonic acid and docosahexaenoic acid concentrations may be related to reduced lipid peroxidation. which is a feature of rapidly growing cells. Alternatively. the increased arachidonic acid values could be due to enhanced desaturase activity upon linoleic and linolenic acid. leading perhaps to increased formation of prostaglandins and other lipoxygenase products.
Levocabastine nasal spray better than sodium cromoglycate and placebo in the topical treatment of seasonal allergic rhinitis, The efficacy and safety of the nasal administration (twice in each nostril. four times a day) of levocabastine (0.5 mg/ml) were compared with those of sodium cromoglycate (20 mg/ml) and placebo in a 2-week. parallel. double-blind trial in patients with seasonal allergic rhinitis. At the end of treatment. 89% of patients in the levocabastine-treated group rated their treatment as globally good or excellent as compared with 32% (p = 0.003) of sodium cromoglycate-treated and 35% (p = 0.002) of placebo-treated patients. According to the investigators' ratings. the severest nasal symptom and ocular complaints responded better to levocabastine than to cromoglycate (p = 0.05 and p = 0.03) or placebo treatment (p = 0.03 and p = 0.001). Visual analogue scale ratings in patients' diaries indicated that at the end of therapy. nasal symptoms were less severe in the levocabastine-treated group than in the sodium cromoglycate-treated (p = 0.03) or placebo-treated group (p = 0.001). Total symptom severity as a percentage of the theoretical maximum symptom severity during the treatment period was lower for levocabastine than for sodium cromoglycate (p = 0.06) or placebo (p = 0.004) for the severest nasal symptom (35% versus 47% and 76%). sneezing (the most frequent symptom) (27% versus 42% and 67%). and itchy nose (18% versus 37% and 67%). The percentage of days at which nasal symptoms were entirely absent was markedly higher in the levocabastine-treated (33%) than in the sodium cromoglycate-treated (9%; p = 0.006) or placebo-treated (3%; p = 0.001) group.
Lysis of intraventricular hematoma with tissue plasminogen activator. Case report, A 42-year-old woman suffered a severe intracerebral and intraventricular hemorrhage from a ruptured anterior cerebral artery aneurysm. Evacuation of the frontal hematoma and clipping of the aneurysm was performed but the intraventricular blood clot persisted. causing ventricular dilatation and high intracranial pressure (ICP) 24 hours after surgery despite external ventricular drainage. Over this period of time the patient's clinical condition improved from Grade V to Grade IVb (World Federation of Neurological Surgeons classification). The intraventricular hematoma was lysed with a total of 8 mg recombinant tissue plasminogen activator injected directly into the ventricles on the 1st and 2nd postoperative days. resulting in rapid normalization of ventricular size and ICP. The patient has since made a substantial recovery and has been able to return home.
Increasing breast cancer screening among the medically underserved--Dade County, Florida, September 1987-March 1991, Efforts to detect breast cancer at early stages are critical in reducing breast cancer-associated mortality. However. in the United States. different barriers (e.g.. lack of insurance. limited access to medical care. and limited awareness of the importance of early diagnosis and treatment) prevent certain groups from using early detection services. To promote early detection of breast cancer among an estimated 67.000 medically underserved women aged greater than or equal to 40 years. the Early Detection Program (EDP) was begun in Dade County. Florida. in the fall of 1987 (1). This report summarizes the progress of the program for September 1987 through March 1991.
Outbreaks of rubella among the Amish--United States, 1991, From January 1 through April 19. 1991. at least nine outbreaks of rubella. involving more than 400 cases. have been reported in Amish communities in the United States. These outbreaks have been reported from Mecosta and Montcalm counties. Michigan; Allegany. Cattaraugus. Chautauqua. and St. Lawrence counties. New York; Geauga. Knox. and Trumbull counties. Ohio; and Lawrence County. Tennessee. In addition. serologically confirmed cases of rubella have been reported from Amish communities in six Pennsylvania counties. suggesting widespread rubella activity among the Amish in Pennsylvania. In general. cases have occurred among unvaccinated children and young adults.
Thyroid function in small for gestational age fetuses, Thyroid function was studied in fetal blood samples obtained by funipuncture from 49 small for gestational age (SGA) fetuses at 21-38 weeks' gestation. Levels of TSH. thyroxine-binding globulin. thyroxine (T4). free T4. triiodothyronine (T3). and free T3 were compared with those from 62 appropriate for gestational age (AGA) fetuses. Levels of TSH were significantly higher and T4 and free T4 significantly lower in the SGA than in AGA fetuses. Furthermore. there were significant associations between the increase in TSH and decrease in free T4 and the degrees of fetal hypoxemia and acidemia. respectively.
An idiotypic network model of AIDS immunopathogenesis, Considerations from a network theory of the immune system suggest that human immunodeficiency virus and allogeneic stimuli may act synergistically to cause AIDS. The immune responses to these stimuli include two components that are directed against each other. In some AIDS risk groups other antigens that mimic major histocompatibility complex antigens may substitute for allogeneic stimuli. Implications for the prevention of AIDS are discussed.
Interleukin 4 promotes expression of mast cell ICAM-1 antigen, Cell recognition molecules play a crucial role in the regulation of immune cells. We recently found that mast cells (MCs) express leukocyte recognition molecules. including ICAM-1 antigen. a natural ligand of LFA-1. We here report that interleukin 4 (IL-4). a pleiotropic cytokine and mast cell differentiation factor. selectively promotes expression of surface ICAM-1 antigen and ICAM-1 mRNA in human MCs. IL-4 also up-regulates ICAM-1 antigen in cells of monocyte/macrophage lineage but has no effect on ICAM-1 antigen expressed on basophils. fibroblasts. or lymphocytes. The increase in expression of mast cell/macrophage ICAM-1 antigen induced by IL-4 may contribute to the accumulation of leukocytes and facilitate cell-contact-dependent regulation of immune cells in inflamed tissues.
Seizures in patients simultaneously receiving theophylline and imipenem or ciprofloxacin or metronidazole, Five patients had apparently drug-induced seizures while simultaneously receiving theophylline and either imipenem (three patients). ciprofloxacin (one patient). or ciprofloxacin and metronidazole (one patient). Seizures ceased upon reduction in dosage or discontinuation of the suspected offending agents. Imaging studies failed to reveal new structural lesions in the central nervous system in any patient. and only one had a history of neurologic disease. Although the exact mechanism for seizure induction cannot be determined from these cases. potential drug interactions exist. because theophylline. imipenem. and ciprofloxacin are all believed to increase excitation of the central nervous system by inhibition of gamma-aminobutyric acid binding to receptors. In addition. ciprofloxacin decreases the clearance of theophylline from the body. predisposing the patient to elevated theophylline levels. Physicians prescribing theophylline with imipenem. ciprofloxacin. or metronidazole should carefully monitor patients for indications for drug therapy. drug dosage. organ impairment affecting drug metabolism. and signs of toxicity. Seizures may accompany oral theophylline therapy. even at "therapeutic" serum theophylline concentrations.
Analysis of N-acetylgalactosamine-4-sulfatase protein and kinetics in mucopolysaccharidosis type VI patients, A sensitive and specific. monoclonal antibody-based immunoquantification assay has facilitated determination of the N-acetylgalactosamine-4-sulfatase (4-sulfatase) protein content in cultured fibroblasts from normal controls and mucopolysaccharidosis type VI (MPS VI) patients. The assay enabled the quantification of 4-sulfatase protein by using a panel of seven monoclonal antibodies and has shown that fibroblasts from 16 MPS VI patients contained less than or equal to 5% of the level determined for normal controls. Fibroblasts from the most severely affected patients contained the lowest levels of 4-sulfatase protein. usually with few epitopes detected. while fibroblasts from mildly affected patients had higher levels of 4-sulfatase protein. with all seven epitopes detected. The pattern of epitope expression is proposed to reflect the conformational changes in the 4-sulfatase protein that arise from different mutations in the 4-sulfatase gene. Immunoquantification in combination with a specific and highly sensitive 4-sulfated trisaccharide-based assay of enzyme activity in these MPS VI patient fibroblasts enabled the determination of residual 4-sulfatase catalytic efficiency (kcat/Km). The capacity of fibroblasts to degrade substrate (catalytic capacity) was calculated as the product of 4-sulfatase catalytic efficiency and the content of 4-sulfatase in fibroblasts. One patient. 2357. with no clinical signs of MPS VI but with reduced 4-sulfatase activity and protein (both 5% of normal) and dermatansulfaturia. had 5% of normal catalytic capacity. The other 15 MPS VI patient fibroblasts had 0%-1.4% of the catalytic capacity of fibroblasts from normal controls and were representative of the spectrum of MPS VI clinical phenotypes. from severe to mild.
Pulsed-field electrophoresis screening for immunoglobulin heavy-chain constant-region (IGHC) multigene deletions and duplications, Genome regions containing multiple copies of homologous genes. such as the immunoglobulin (Ig) heavy-chain constant-region (IGHC) locus. are often unstable and give rise to duplicated and deleted haplotypes. Analysis of such processes is fundamental to understanding the mechanisms of evolution of multigene families. In the IGHC region. a number of single and multiple gene deletions. derived from either unequal crossing-over or looping-out excision. have been described. To study these haplotypes at the population level. a simple and efficient method for preparing large numbers of DNA samples suitable for pulsed-field gel electrophoresis (PFGE) analysis was set up. and a sample of 110 blood donors was screened. Deletions were found to be frequent. as expected on the basis of previous serological surveys for homozygotes. Furthermore. a number of multigene duplications. never identified before. were detected. The total frequency of individuals bearing rearranged IGHC haplotypes was 10%. The genes involved in these deletions and duplications were assessed by densitometric analysis of standard Southern blots hybridized with several IGHC probes; two types of deletion and two types of duplication could thus be characterized. These data provide further evidence of the instability of the IGHC locus and demonstrate that unequal crossing-over is the most likely origin of rearranged IGHC haplotypes; they also suggest that such recombination events may be relatively frequent. Moreover. the simplicity and effectiveness of the large-scale PFGE screening approach will be of great help in the study of multigene families and of other loci involved in aberrant recombinations.
Analysis of the relationship of von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia and identification of a potential type IIA vWD mutation (IIe865 to Thr), Reports of families with members affected with both von Willebrand disease (vWD) and hereditary hemorrhagic telangiectasia (HHT) suggest a possible relationship between these two disorders. vWD. the most common inherited bleeding disorder in humans. is due to either a quantitative or qualitative defect in von Willebrand factor (vWF). The gene for vWF has been cloned and mapped to chromosome 12 (12p12----12pter). HHT. an uncommon inherited bleeding disorder. is characterized by malformed. dilated. fragile blood vessels. The chromosomal location of the gene for HHT is unknown. We studied two families by RFLP analysis to determine whether there is a molecular basis for the association of vWD and HHT. Family A is affected with both type IIA vWD and HHT; family B is affected with HHT alone. Linkage of HHT to the vWF gene was not detected. and vWF was ruled out as a candidate gene for HHT. The vWF gene was found to be tightly linked to type IIA vWD in family A (lod score 3.61 at recombination fraction .00). By PCR and DNA sequence analysis of vWF exon 28. a single T----C transition resulting in the substitution of Thr for Ile865 was identified. This substitution is located immediately adjacent to two previously identified type IIA vWD mutations.
Anaphylaxis and desensitization to the murine monoclonal antibody used for renal graft rejection, The murine monoclonal antibody muromonab CD3 is currently used to reverse acute renal graft rejection. We report a case of systemic anaphylaxis during a muromonab CD3 infusion despite pretreatment with systemic antihistamines and corticosteroids. Rapid intravenous desensitization was performed the following day without untoward reactions and daily muromonab CD3 infusions were successful in reversing renal graft rejection. A second rapid desensitization to CD3 was performed 1 month later without any complications. Serum muromonab CD3-specific IgG and IgE antibodies were detected in serum samples obtained after the anaphylactic reaction. The anaphylactic reaction to muromonoab CD3 monoclonal antibody could have been due to allergen-specific antibodies noted in postreaction serum or a cross-reactive antibody to mouse antigens or both. More importantly. this case illustrates that rapid desensitization can be performed successfully without serious complications; therefore. systemic anaphylaxis can develop in susceptible atopic individuals receiving muromonab CD3 monoclonal antibody for renal graft rejection.
Killing of intracellular Mycobacterium tuberculosis by receptor-mediated drug delivery, p-Aminosalicylic acid (PAS) conjugated to maleylated bovine serum albumin (MBSA) was taken up efficiently through high-affinity MBSA-binding sites on macrophages. Binding of the radiolabeled conjugate to cultured mouse peritoneal macrophages at 4 degrees C was competed for by MBSA but not by PAS. At 37 degrees C. the radiolabeled conjugate was rapidly degraded by the macrophages. leading to release of acid-soluble degradation products in the medium. The drug conjugate was nearly 100 times as effective as free PAS in killing the intracellular mycobacteria in mouse peritoneal macrophages infected in culture with Mycobacterium tuberculosis. The killing of intracellular mycobacteria mediated by the drug conjugate was effectively prevented by simultaneous addition of excess MBSA (100 micrograms/ml) or chloroquine (3 microM) to the medium. whereas these agents did not affect the microbicidal action of free PAS. These results suggest that (i) uptake of the PAS-MBSA conjugate was mediated by cell surface receptors on macrophages which recognize MBSA and (ii) lysosomal hydrolysis of the internalized conjugate resulted in intracellular release of a pharmacologically active form of the drug. which led to selective killing of the M. tuberculosis harbored by mouse macrophages infected in culture. This receptor-mediated modality of delivering drugs to macrophages could contribute to greater therapeutic efficacy and minimization of toxic side effects in the management of tuberculosis and other intracellular mycobacterial infections.
In vitro susceptibilities of ocular Bacillus cereus isolates to clindamycin, gentamicin, and vancomycin alone or in combination, A broth dilution assay was used to determine the in vitro susceptibilities of 10 ocular isolates of Bacillus cereus to clindamycin. gentamicin. and vancomycin both alone and in combination. The checkerboard technique was used to determine fractional inhibitory and bactericidal concentration indices for combinations of clindamycin-gentamicin and vancomycin-gentamicin.
In vitro and in vivo activities of LJC10,627, a new carbapenem with stability to dehydropeptidase I, The activity of LJC10.627 was compared with the activities of imipenem and other antibiotics. LJC10.627 was more active against most members of the family Enterobacteriaceae. Pseudomonas spp.. and Acinetobacter spp. but slightly less active than imipenem against staphylococci and streptococci. LJC10.627 showed stability to mouse dehydropeptidase I and was more effective in vivo than imipenem plus cilastatin against gram-negative bacterial infections and as effective against staphylococcal infections.
Inhibition of human immunodeficiency virus type 1 morphogenesis in T cells by alpha interferon, Some murine retroviruses exhibit altered release of virus when cells are treated with alpha interferon (IFN-alpha). resulting in the accumulation of intracellular virions in cytoplasmic vacuoles. In studies of the inhibitory effect of IFN-alpha (Wellferon) on acute human immunodeficiency virus type 1 infection of human T-cell lines. we found that in C3 cells. the 50% effective concentration was 9 U/ml and the 90% effective concentration was 310 U/ml. There was no apparent accumulation of intracellular particles detected by p24 antigen levels or by processing the cells for electron microscopy. Extracellular reverse transcriptase activity and p24 levels decreased in parallel with increasing IFN. whereas the intracellular viral proteins decreased only slightly. By electron microscopy. cells treated with higher concentrations of IFN (512 U/ml) disclosed very few particles budding into extracellular spaces; no intracellular particles could be seen. despite nearly normal levels of intracellular viral protein detected by the p24 antigen assay and correct processing detected by Western blot (immunoblot) analysis. Thus in human immunodeficiency virus-infected cells. the major block produced by IFN-alpha appeared to be late in the viral cycle at the morphogenesis stage of virion production. Chronically infected Jurkat cells treated with IFN appeared to be inhibited in growth rate. as virus production decreased proportionally with cell number.
In vitro susceptibilities of Coxiella burnetii, Rickettsia rickettsii, and Rickettsia conorii to the fluoroquinolone sparfloxacin, In vitro susceptibilities of Rickettsia rickettsii. Rickettsia conorii. and Coxiella burnetii to the new fluoroquinolone sparfloxacin (AT-4140; RP 64206) were determined. Plaque and dye uptake assays were used to measure the MICs against R. rickettsii and R. conorii. The susceptibilities of C. burnetii Nine Mile and Q 212 were determined in two acute-infection models and in two chronic-infection models. The MICs were 0.125 to 0.25 microgram/ml for R. rickettsii and 0.25 to 0.5 microgram/ml for R. conorii. Sparfloxacin (1 microgram/ml) cured cells recently infected with C. burnetii Nine Mile and Q 212 within 4 to 9 days and cured multiplying. persistently infected cells within 10 days. As previously described with other fluoroquinolones (D. Raoult. M. Drancourt. and G. Vestris. Antimicrob. Agents Chemother. 34:1512-1514. 1990). sparfloxacin failed to cure cells persistently infected with C. burnetii and blocked from dividing with cycloheximide. As determined by the dye uptake assay. no cellular toxicity was noted with sparfloxacin at up to 128 micrograms/ml. These results are consistent with those previously obtained with fluoroquinolones (D. Raoult. M. Yeaman. and O. Baca. Rev. Infect. Dis. 11[Suppl. 5]:S986. 1989). although sparfloxacin may be slightly more active.
Monoclonal antibodies to conserved regions of the major core protein (gag24) of HIV-1 and HIV-2, Five mouse monoclonal antibodies were raised against a recombinant protein comprising the complete sequence of gag24 protein from HTLV-IIIB. All monoclonal antibodies recognized the native protein in enzyme-linked immunosorbant assay (ELISA) and Western blots. All monoclonal antibodies also cross-reacted with an human immunodeficiency virus type 2 (HIV-2) strain in western blots. whereas only one antibody detected HIV-2 p25 in ELISA. By using synthetic peptides. cross-reacting epitopes were mapped and three regions were defined. The conserved immunogenic sites were located in the carboxyterminal region of the protein. Inhibition experiments with human sera showed that this region is also immunogenic in humans.
Clinical and neurophysiological studies of aldose reductase inhibitor ponalrestat in chronic symptomatic diabetic peripheral neuropathy, Increased flux through the polyol pathway mediated by the enzyme aldose reductase may be associated with the development of diabetic neuropathy. Fifty-four diabetic patients (median age 56 yr. range 25-65 yr) with chronic neuropathic symptoms were randomly allocated to placebo or aldose reductase inhibition (300 or 600 mg ponalrestat ICI 128436) groups for 24 wk. Patients with vibration perception thresholds (VPTs) greater than 35 V at the great toe or thermal difference thresholds (TTs) greater than 10 degrees C on the dorsum of the foot were excluded from the trial. No significant changes were observed in symptoms of pain. numbness. or paresthesia between ponalrestat and placebo groups. and there were no improvements in VPT or TT at several sites. Posterior tibial nerve conduction velocity changed from 35.3 +/- 4.9 m/s at baseline to 33.4 +/- 4.0 m/s at 24 wk (NS) with placebo compared with 37.6 +/- 5.6 vs. 37.2 +/- 8.7 m/s (NS) with 300 mg ponalrestat and 34.5 +/- 6.1 vs. 36.2 +/- 6.8 m/s (NS) with 600 mg ponalrestat. Further studies are indicated with intervention at an earlier stage in the evolution of neuropathy and for longer periods.
Evidence for impaired coupling of receptors to Gi protein in adipocytes from streptozocin-induced diabetic rats, Adenosine and prostaglandins of the E series inhibit lipolysis in adipocytes by binding to cell surface receptors. This inhibition is mediated via Gi. It has been reported that Gi is almost absent in livers from diabetic rats. Therefore. we have evaluated the sensitivity of adipocytes from diabetic rats to the adenosine analogue N6-phenylisopropyl adenosine (PIA) and to prostaglandin E1 (PGE1). Diabetes was induced with streptozocin (65 mg/kg i.v.). and after 7 days. adipocytes were isolated. Lipolysis (measured in the presence of adenosine deaminase) was inhibited by PIA and PGE1 in both control and diabetic cells. However. the dose-response curves were markedly shifted to the right in the cells from diabetic rats. The IC50 for PIA was 0.30 +/- 0.02 nM in controls and 0.83 +/- 0.08 in diabetic rats (P less than 0.001). and the IC50 for PGE1 was 3.16 +/- 0.18 nM in controls and 5.26 +/- 0.57 nM in diabetic rats (P less than 0.02). These findings indicate decreased sensitivity to both adenosine and PGE1. Adipocyte membranes were isolated from control and diabetic rats. Adenosine receptors (measured by binding of 125I-labeled hydroxy-PIA) were not altered in cells from diabetic rats. However. the ability of Gpp(NH)p (a nonhydrolyzable GTP analogue) to inhibit adenosine-receptor binding was markedly decreased in membranes from diabetic rats. suggesting a change at the level of Gi. The alpha-subunits of Gi1. Gi2. Gi3. and Gs were quantitated on Western blots with a series of recently characterized anti-peptide antisera. This revealed that the amounts of each of these G proteins were normal in membranes from the diabetic rats.
Specific triggering of gamma, delta T cells by K562 activates the gamma, delta T cell receptor and may regulate natural killer-like function, Freshly isolated and resting gamma/delta T cell lines. although capable of lysing a variety of MHC-unrestricted targets. fail to lyse K562. Yet. the killing of K562 can be specifically induced by antibodies to CD3 or delta-chains. Although this phenomenon may be caused by redirected lysis. it also raised the possibility that K562 may possess ligands capable of specifically interacting with the gamma/delta receptor. We found that K562 specifically induced both CD3 and delta modulation as well as IL-2R expression and IL-2 production by gamma/delta cells. supporting the idea that the TCR-gamma/delta is specifically triggered by K562 cells. Moreover. although the gamma/delta cell clones lysed other target cells (e.g.. Molt 4. U937. Jurkat etc.). these latter targets did not induce delta modulation or IL-2R expression. In addition. F(ab)2 anti-CD3 antibodies inhibited activated gamma/delta T cells from killing K562 but did not inhibit the lysis of the other targets. Taken together. these results suggest that gamma/delta cells lyse some targets by utilizing receptors (perhaps NK-like) distinct from the gamma/delta receptor. We also found that triggering of the gamma/delta receptor by K562 inhibited the capacity of resting gamma/delta to lyse Molt 4 cells under conditions in which the K562 cells were not lysed. These findings suggest that the gamma/delta receptor maybe directly involved in the lysis of certain targets (i.e.. K562) and. importantly. may potentially regulate the function of NK-like receptors that are involved in the lysis of other targets.
Staphylococcal enterotoxin-dependent lysis of MHC class II negative target cells by cytolytic T lymphocytes, The enterotoxins of Staphylococcus aureus (SE) are extremely potent activators of human and mouse T lymphocytes. In general. T cell responses to SE are MHC class II dependent (presumably reflecting the ability of SE to bind directly to MHC class II molecules) and restricted to responding cells expressing certain T cell receptor beta-chain variable (TCR V beta) domains. Recently we demonstrated that CD8+ CTL expressing appropriate TCR V beta could recognize SE presented on MHC class II-bearing target cells. We now show that MHC class II expression is not strictly required for T cell recognition of SE. Both human and mouse MHC class II negative target cells could be recognized (i.e.. lysed) in a SE-dependent fashion by CD8+ mouse CTL clones and polyclonal populations. provided that the CTL expressed appropriate TCR V beta elements. SE-dependent lysis of MHC class II negative targets by CTL was inhibited by mAb directed against CD3 or LFA-1. suggesting that SE recognition was TCR and cell contact dependent. Furthermore. different SE were recognized preferentially by CTL on MHC class II+ vs MHC class II- targets. Taken together. our data raise the possibility that SE binding structures distinct from MHC class II molecules may exist.
Early appearing gamma/delta-bearing T cells during infection with Calmette Guerin bacillus, To search for a potential role of TCR gamma/delta T cells in host-defense against mycobacterial infection. we analyzed the kinetics. repertoire. specificity. and cytokine production of gamma/delta T cells in the peritoneal exudate cells (PEC). lymph node (LN) cells and spleen cells during an i.p. infection with a sublethal dose (5 x 10(5) of viable Bacillus Calmette-Guerin (BCG) in mice. In the PEC on day 7 after infection. approximately 26% of the CD3+ cells were CD4-CD8-. most of which expressed TCR gamma/delta on their surface. However. the PEC on day 28 contained an increased number of alpha/beta T cells that were CD4+8- or CD4-8+ and the proportion of gamma/delta T cells in the PEC reciprocally decreased to 18% of the CD3+ cells. The kinetics of gamma/delta and alpha/beta T cells in the LN during BCG infection showed in much the same pattern as that seen in the PEC. When purified CD4-CD8- cells in the LN on day 7 after BCG infection were cultured with sonicated BCG lysate. PPD derived from Mycobacterium tuberculosis or recombinant 65 kDa heat shock protein derived from Mycobacterium bovis. the gamma/delta T cells on this stage significantly proliferated and secreted IL-2 in response to sonicated BCG lysate and PPD but not to 65 kDa heat shock protein. V gene segment usage analysis with PCR method revealed that purified protein derivative-reactive gamma/delta T cells preferentially used V gamma 1/2/V delta 6. whereas gamma/delta T cells polyclonally expanded in response to the BCG lysate. These results suggest that gamma/delta T cells specific for mycobacterial antigens preceding alpha/beta T cells in appearance during infection may serve as a first line of defense against mycobacterial infection.
Differential production of Th1- and Th2-derived cytokines does not determine the genetically controlled or vaccine-induced rate of cure in murine visceral leishmaniasis, Recent studies with models of cutaneous leishmaniasis have provoked much interest in the role of CD4+ T cell subsets in determining the outcome of infectious disease. In Leishmania major infections. cure vs progressive disease correlates with the expansion of Th1-like or Th2-like CD4+ populations. respectively. We have investigated whether similar responses are associated with the differential patterns of infection seen in models of visceral leishmaniasis. caused by L. donovani. Splenic lymphocytes from infected Lsh congenic C57BL/10 (Lshs;H-2b) and B10.L-Lshr (Lshr;H-2b) mice and MHC congenic non-curing B10.D2/n (Lshs;H-2d) mice were examined for the production of cytokines representative of these CD4+ populations (IL-2. IL-3. IL-4. IL-5. and IFN-gamma). In all three strains examined. there was no evidence for the production of Th2-restricted cytokines. In addition. levels of serum IgE were depressed during the early phase of infection. indicative of in vivo IFN-gamma production. In the non-curing B10.D2/n strain. late phase of infection was associated with the decreased ability to produce cytokines in response to Ag and not with the production of IL-4 or IL-5 in response to Ag or mitogen. Serum IgE levels were also not raised above levels seen in uninfected controls. C57BL/10 mice were vaccinated with SDS-PAGE fractionated amastigote Ag bound to nitrocellulose and cytokine levels determined at various times after infection. The protocol used for vaccination was able to induce significant modulation of the course of infection in this strain and it was clear that IFN-gamma production in vitro provided an excellent correlate of rate of cure. Occasional individuals produced low levels of IL-5 in culture in response to parasite Ag. but this did not correlate with disease progression. Together. these data suggest that over-expansion of Th2-type cells and production of their specific cytokines (IL-4 and IL-5) is not a contributing factor to the variable long term course of L. donovani infection in these strains of mice.
Mechanisms of host defense against Candida species. I. Phagocytosis by monocytes and monocyte-derived macrophages, We studied the biochemical basis of phagocytosis of Candida albicans. a serious pathogen. and Candida parapsilosis. which is rarely pathogenic. by human monocytes (Mo) and monocyte-derived macrophages (MDM). Optimal phagocytosis of both species by Mo required the presence of extracellular Ca2+ and opsonization through both the classic and alternative complement pathways. Serum-opsonized Candida were ingested equally by Mo and MDM; unopsonized Candida were phagocytosed only by macrophages. and uptake began slowly. This opsonin-independent phagocytosis required Ca2+ and could be blocked by yeast mannan or mannose-BSA conjugate. suggesting a role for the mannose receptor. Opsonized Candida elicited a vigorous increase in the concentration of [Ca2+]i in Mo and MDM. but no Ca2+ transient was detected in MDM stimulated with unopsonized Candida. Pretreatment of MDM with ionomycin to increase [Ca2+]i had no effect on phagocytosis of unopsonized Candida. Addition of 5 mM EGTA completely inhibited changes in [Ca2+]i in Mo and MDM. suggesting that the Ca2+ transient induced by opsonized Candida is due to an influx of extracellular Ca2+. Differences in pathogenicity between the two Candida species could not be explained by differences in any aspect of phagocytosis. Uptake mediated by the macrophage mannose receptor could play a role in clearance of Candida under opsonin-poor conditions.
Factors affecting the rearrangement efficiency of an Ig test gene, A rearrangement test gene. pHRD. containing the mouse IgH enhancer and the metallothionein promoter. has previously been shown to rearrange efficiently after transfection into a pre-B cell line. Experiments are now reported that assess the requirements of the DNA substrate as well as of the transfected cells for efficient rearrangement. It was found that deletion of the metallothionein promoter or substitution of the IgH enhancer by the kappa enhancer did not affect rearrangement. However. deletion of the Ig enhancer reduced the efficiency. Transfection of pHRD into stable hybrids of pre-B cells and myeloma cells resulted in a high frequency of rearrangement only if certain myeloma chromosomes were lost. Furthermore. pHRD introduced into rearrangement incompetent myeloma cells upon subsequent cell fusion with pre-B cells was rearranged only very rarely and then apparently only immediately after cell fusion. Stable pre-B cell x myeloma hybrids that retained the critical myeloma chromosomes were found to have lost VDJ recombinase activity and transcripts of the RAG-1. RAG-2 and TdT genes. It is concluded that transcription. i.e.. the copying of the DNA by polymerase. is probably not required for rearrangement. but that the rearrangement substrate must be in an "open" chromatin state. such as may be provided by transcriptional factors. Furthermore. the absence of rearrangement in myeloma cells is apparently due to the continued action of an inhibitor of rearrangement.
Characterization of syngeneic rat monoclonal antibodies to the HSN tumor using syngeneic monoclonal anti-idiotopic antibodies, Twelve syngeneic anti-idiotopic mAb (anti-idiotypic/idiotopic antibodies Ab2)) were prepared from CBH/Cbi rats immunized with one of three monoclonal anti-HSN antibodies (Ab1) (11/160. ALN/11/53. or ALN/16/53) specific for the HSN tumor. The sera of the rats used for hybridoma production and all of the monoclonal Ab2 specifically inhibited the binding to HSN of the immunizing Ab1 only. It is concluded that. in this completely syngeneic system. only the private idiotopes associated with the antibody-combining site were immunogenic. Analyses using Western blotting showed that the Ab2 bound to intact Ab1 and to isolated H chains where the intra-strand disulfide bonds remained intact. The Ab2 did not bind to L chains or to fully reduced H chains of the Ab1. It is concluded that the idiotopes expressed on the H chain were conformational. When a panel of 13 monoclonal Ab1 (including the three used for immunization) were tested for reactivity with the Ab2. three reacted specifically with their respective Ab2 and 8 gave no binding suggesting that each Ab1 had a distinct idiotypic specificity despite the fact that all the Ab1 competed with each other for binding to Ag. However. the two remaining Ab1 (ALN/9/94 and ALN/12/17) generated from different tumor-bearing rats. were found to possess the same idiotypic specificity as 11/160. A detailed analysis using seven Ab2 raised against 11/160 showed that while the idiotype of ALN/9/94 and 11/160 were very similar. that of ALN/12/17 showed some clear differences. These three Ab1 have been shown previously to bind a sequential epitope on the HSN Ag in Western blots and it is postulated that the common idiotype of these Ab1 reflects their recognition of a sequential epitope. This may also account for the relatively frequent occurrence in tumor bearer sera of antibodies with this Id.
Human peripheral blood lymphocytes targeted with bispecific antibodies release cytokines that are essential for inhibiting tumor growth, We have compared the mechanisms by which human PBL targeted with bispecific antibodies either lyse tumor cells or block their growth in culture or in mice. We found that resting PBL were unable to mediate lysis. but were able to block tumor growth. Moreover. targeted PBL were unable to lyse bystander cells. whereas targeted PBL did block the growth of bystander tumor cells in culture and in nude mice. Supernatants from cultures of targeted PBL. or from PBL grown on anti-CD3-coated flasks. blocked the growth of tumor cells in the absence of added effector cells. and antibodies against TNF-alpha and IFN-gamma reversed the inhibition of tumor growth. but had no effect upon cytolysis mediated by targeted by PBL. Our results show that targeted human PBL mediate two different antitumor activities: lysis. which occurs rapidly and requires the direct attachment of the target cell to the cytotoxic cell. and tumor growth inhibition. which is mediated by cytokines released into the medium as a result of receptor cross-linking. The inhibition of bystander tumor growth in mice by targeted PBL suggests that factor release is sufficient to block tumor growth in vivo. Targeted factor release therefore provides a mechanism by which targeted PBL could block the growth of tumor cells in vivo that were not bound by the effector cells. but which were located in the vicinity of tumor cells that were bound.
Combined gonadotropin releasing hormone agonist/human menopausal gonadotropin therapy (GnRH-a/hMG) in normal, high, and poor responders to hMG, Patients who failed to conceive after gonadotropin stimulation in in vitro fertilization treatment were classified into normal. high. or poor responders. They were routinely offered another cycle with a combination of a gonadotropin releasing hormone agonist and gonadotropin therapy (in order to evaluate whether this combined therapy could improve their response). The gonadotropin-induced cycle was compared with the combined therapy cycle. With the combination treatment. in the normal responders the phase of ovarian stimulation was significantly (P less than 0.001) prolonged. and the number of follicles and oocytes collected (5.7 +/- 0.7 vs 3.1 +/- 0.4) was increased. without any change in serum estradiol level compared to the control cycle. In high responders the number of oocytes was not modified by the combined treatment compared with the control cycle. However. serum estradiol level was significantly (P less than 0.005) decreased. The combined therapy did not modify any parameter of response in poor responders. We conclude that the response to combined agonist/gonadotropin therapy is dependent on the patient's own basal response. No improvement in response was expected in poor responders.
In vitro assays show a dissociation of reverse transcriptase activity and core antigen (p24) production in two HIV-1 isolates from a patient receiving long-term treatment with zidovudine (ZDV), Two HIV-1 isolates were obtained from a patient receiving long-term treatment with zidovudine (ZDV). The in vitro sensitivity to ZDV triphosphate of the reverse transcriptase (RT) from both isolates appeared to be unchanged compared to that of the LAV-Bru HIV-1 reference strain. When isolates were grown in CEM cells (a T-lymphoblastoid tumor cell line) and their RT activity and core antigen (p24) production were determined. the level of p24 production compared to RT activity was high; in infected CEM cells treated with ZDV. RT activity was at background level while the p24 production was still significant. thus indicating a dissociation of RT activity and core antigen production.
Exacerbation of dideoxycytidine-induced neuropathy with dideoxyinosine, Dideoxycytidine (ddC) and dideoxyinosine (ddI) are nucleoside derivatives that exhibit antiretroviral activity against the human immunodeficiency virus (HIV). Both of these agents are under active investigation as potential therapies for patients with HIV infection. In addition. both drugs may be obtained for HIV-infected individuals who cannot tolerate zidovudine. A major focus of the research effort involving these agents has been to define their toxicities. Both agents may cause peripheral neuropathy. We wish to report a patient who developed severe neuropathy following the administration of ddI that was given shortly after the patient was removed from a clinical trial of ddI. The rapid development of toxicity indicates that this side effect is additive or synergistic for these agents.
Prostate specific antigen levels after definitive irradiation for carcinoma of the prostate, Prostate specific antigen (PSA) levels were determined in 78 patients judged clinically to be free of disease at intervals of 36 or more months (range 38 to 186 months. median 87 months) after completion of irradiation therapy by 125iodine implantation or external beam radiation. Of this select group of patients 38% had undetectable serum PSA levels (0.5 ng./ml. or less) and 38% had PSA levels that were within normal limits (4.0 ng./ml. or less). All stages and grades were represented. Undetectable PSA levels were only rarely found (3%) in patients with carcinoma of the prostate before treatment. In 24 of these 78 patients a negative biopsy of the irradiated prostate had been obtained 18 to 42 months after treatment. When the PSA level was drawn. which ranged from 7 to 16 years after treatment. an equal percentage of these biopsied patients had either an undetectable. normal or elevated level. Irradiation is able to decrease PSA to undetectable levels in some patients with prostatic carcinoma. Whether this reflects suppression of marker production alone or. more importantly. ablation of prostate cancer producing that marker remains to be determined.
Effects of 30-h sleep loss on cardiorespiratory functions at rest and in exercise, The effects of 30-h sleep deprivation on cardiorespiratory function either at rest or in exercise were studied in 15 young healthy male volunteers. All subjects performed 1-min incremental exercise tests on a bicycle ergometer until exhaustion and endurance exercise tests at 3/4 of their maximal work rates. Arterialized venous blood samples were withdrawn at rest and during exercise tests to investigate the influence of sleep loss on blood gases. In addition. resting plasma catecholamine levels were also measured in ten subjects. The results showed that 1) resting heart rate. plasma catecholamine levels. and blood pH were decreased while minute ventilation (VI) and CO2 production (VCO2) were increased after 30 h of sleep loss (P less than 0.05). and 2) the maximal exercise performance was reduced by sleeplessness. as indicated by the decreases in the maximal heart rate. peak VI. peak VCO2. peak O2 consumption. and time to exhaustion (P less than 0.05). However. no significant changes in exercise endurance. arterialized venous pH. and PCO2 were found in exercise after sleep deprivation either. We therefore conclude that 30-h sleep loss alters cardiorespiratory function at rest and the ability to perform maximal exercise but not exercise endurance.
Recombinant virus vaccine-induced SIV-specific CD8+ cytotoxic T lymphocytes, Evidence indicates that cytotoxic T lymphocytes (CTLs) may be important in containing the spread of the human immunodeficiency virus (HIV) in the infected host. Although the use of recombinant viruses has been proposed as an approach to elicit protective immunity against HIV. the ability of recombinant viral constructs to elicit CD8+ CTL responses in higher primates has never been demonstrated. A live recombinant virus. vaccinia-simian immunodeficiency virus of macaques (SIVmac). was used to determine whether such a genetically restricted. T lymphocyte-mediated antiviral response could be generated in a primate. Vaccinia-SIVmac vaccination elicited an SIVmac Gag-specific. CD8+ CTL response in rhesus monkeys. These CTLs recognized a peptide fragment that spans residues 171 to 195 of the Gag protein. The rhesus monkey major histocompatibility complex (MHC) class I gene product restricting this CTL response was defined. Both the vaccinated and SIVmac-infected monkeys that shared this MHC class I gene product developed CTLs with the same Gag epitope specificity. These findings support the use of recombinant virus vaccines for the prevention of HIV infections in humans.
Quantitative estimation of infarct size by simultaneous dual radionuclide single photon emission computed tomography: comparison with peak serum creatine kinase activity, To test the hypothesis that simultaneous dual energy single photon emission computed tomography (SPECT) with technetium-99m (99mTc) pyrophosphate and thallium-201 (201TI) can provide an accurate estimate of the size of myocardial infarction and to assess the correlation between infarct size and peak serum creatine kinase activity. 165 patients with acute myocardial infarction underwent SPECT 3.2 +/- 1.3 (SD) days after the onset of acute myocardial infarction. In the present study. the difference in the intensity of 99mTc-pyrophosphate accumulation was assumed to be attributable to difference in the volume of infarcted myocardium. and the infarct volume was corrected by the ratio of the myocardial activity to the osseous activity to quantify the intensity of 99mTc-pyrophosphate accumulation. The correlation of measured infarct volume with peak serum creatine kinase activity was significant (r = 0.60. p less than 0.01). There was also a significant linear correlation between the corrected infarct volume and peak serum creatine kinase activity (r = 0.71. p less than 0.01). Subgroup analysis showed a high correlation between corrected volume and peak creatine kinase activity in patients with anterior infarctions (r = 0.75. p less than 0.01) but a poor correlation in patients with inferior or posterior infarctions (r = 0.50. p less than 0.01). In both the early reperfusion and the no reperfusion groups. a good correlation was found between corrected infarct volume and peak serum creatine kinase activity (r = 0.76 and r = 0.76. respectively; p less than 0.01).
Effect of nitroglycerin on coronary collateral function during exercise evaluated by quantitative analysis of thallium-201 single photon emission computed tomography, A noninfarcted. entirely collateral-dependent myocardial region provides an opportunity to assess the effect of nitroglycerin on coronary collateral function during exercise. Stress thallium-201 computed tomography was performed in seven patients with effort angina and no history of myocardial infarction. both before and after nitroglycerin (0.3 mg). All patients had single-vessel disease with total or subtotal (99% with delay) occlusion of proximal left anterior descending coronary artery and well-developed collaterals. The pressure-rate product. mean blood pressure. and heart rate at peak exercise did not differ before and after nitroglycerin. The size of the perfusion defect and the severity of ischemia during exercise estimated by quantitative analysis of thallium-201 single photon emission computed tomography were significantly less after nitroglycerin administration (extent score: 23 +/- 17 vs 7 +/- 9. p less than 0.01; severity score: 20 +/- 22 vs 3 +/- 4. p less than 0.05). The pressure-rate products at peak exercise did not differ before and after nitroglycerin. which suggested that the reduction in perfusion defect size was unlikely to be the result of decreased myocardial oxygen consumption. These results suggest that nitroglycerin improved coronary collateral function during exercise and thus prevented exercise-induced myocardial ischemia.
The effect of enteric-coated aspirin on the morning increase in platelet activity, In vitro platelet aggregability to adenosine diphosphate (ADP) and epinephrine increases in the morning. as does the frequency of myocardial infarction. A single-blind. randomized. cross-over study of 15 healthy males was conducted to determine: (1) if other measures of platelet activity show a morning increases and (2) if aspirin eliminates any increases in platelet activity detected. Subjects received 325 mg of enteric-coated aspirin (ECA) or placebo. During placebo therapy.platelet thromboxane A2 production (following collagen stimulation) increased significantly after the subjects got up. as did platelet aggregability to ADP. epinephrine. and collagen. ECA markedly reduced baseline platelet thromboxane A2 production and eliminated the increase after the subjects got up. It also abolished biphasic aggregation in response to epinephrine and ADP (thereby eliminating the morning increase in aggregability to these agents). lengthened collagen lag time. reduced synergistic aggregation to combined agonists. was effective on day 2. and did not alter increases of tissue plasminogen activator that occurred following the subjects' arising. If aspirin prevents myocardial infarction by its antiplatelet action. as seems likely. the preferential reduction of morning infarction observed in the Physicians' Health Study. and the demonstration that aspirin eliminates the morning increase in platelet activity. suggest that the morning increase in myocardial infarction is due in part to a concurrent relatively modest increase in platelet activity.
Antiarrhythmic actions of tocainide in canine models of previous myocardial infarction, The antiarrhythmic and antifibrillatory efficacies of the class IB antiarrhythmic agent tocainide were characterized in conscious dogs in the early subacute phase of anterior myocardial infarction (48 hours after infarction) and in anesthetized dogs with ventricular tachyarrhythmias that were inducible by programmed stimulation more chronically (10.8 +/- 1.0 days) after anterior myocardial infarction. The frequency of spontaneous premature ventricular complexes in the early subacute postinfarction phase was reduced significantly from 48.4% +/- 10.5% to 8.2% +/- 5.0% of total complexes (p less than 0.01) by the cumulative intravenous administration of 10 mg/kg tocainide. In the late postinfarction setting. the intravenous administration of tocainide (6 mg/kg intravenous loading dose + 100 micrograms/kg/min intravenous maintenance infusion) suppressed the initiation of ventricular tachyarrhythmias by programmed stimulation in 5 of 12 animals that were tested and slowed the rate of tachycardia in 3 additional animals. However. the incidence of ventricular fibrillation and of the total number of arrhythmia-related deaths that resulted from the occurrence of a secondary ischemic insult in the presence of previous infarction did not differ significantly between tocainide (75% [9 of 12] incidence of both ventricular fibrillation and of total number of arrhythmia-related deaths) and saline-vehicle control groups (80% [12 of 15] incidence of ventricular fibrillation; 93.3% [14 of 15] incidence of total number of arrhythmia-related deaths). These findings suggest that although class I agents such as tocainide may be efficacious in the suppression of spontaneous premature ventricular complexes and ventricular arrhythmias immediately after myocardial infarction. they may be of limited value in the prevention of malignant ischemic arrhythmias that occur later after myocardial infarction.
Treatment of AIDS with combinations of antiretroviral agents, Although 3'-azido-3'-deoxythymidine (zidovudine. AZT) has demonstrated efficacy in the treatment of human immunodeficiency virus (HIV) infection. there are limitations associated with its use. Consequently. other agents. such as 2'.3'-dideoxycytidine (ddC) and 2'.3'-dideoxyinosine (ddI). are being assessed for the treatment of patients with HIV infection. However. the most effective therapy for HIV infection may be combination therapy with zidovudine and any of a number of other therapies. To obtain maximum efficacy. combination regimens should include agents that do not share cross-resistance. have different mechanisms of action. and have different dose-limiting toxicities; the relative merits of a concurrent dosage schedule (limits drug failure) and a consecutive dosage schedule (limits toxicity) must also be considered. In addition. the shift between administering a starting regimen and a rescue regimen should be based on time on therapy. disease breakthrough. or drug complication. Eventually. the shift may be precipitated by the in vitro resistance patterns of individual viruses. as is now the case with antibiotics for infection. Several trials are currently in progress to assess combination therapy with zidovudine and ddC; initial results indicate that the combination may allow for improved efficacy and decreased side effects. compared with treatment with either drug alone. Trials of combination therapy with ddI. interferon alfa. and acyclovir are also in progress. It is hoped that these initial studies will pave the way for rational drug sequencing in the treatment of patients with acquired immunodeficiency syndrome.
The pulsatile secretion of gonadotropins and growth hormone, and the biological activity of luteinizing hormone in men acutely intoxicated with ethanol, The effects of acute alcohol ingestion were studied on pulsatile secretion of immunoreactive luteinizing hormone (LH). follicle-stimulating hormone (FSH). and growth hormone (GH). and on serum bioactive LH. testosterone. cortisol. and prolactin. A dose of 1.5 g ethanol per kg of body weight was administered by mouth to eight healthy male volunteers (aged 20 to 26 years) during 3 hr from 1800 to 2100 hr. Blood samples were collected every 20 min for 20 hr until 1400 hr of the following day. Each subject served as his own control in an identical experiment without ethanol. carried out at least 1 month later. Ethanol ingestion decreased serum testosterone concentration on average by 23% (p less than 0.05) between 10 and 16 hr after starting the drinking. The mean levels of LH and FSH and the mean number and amplitude of LH and FSH pulses remained unchanged. Ethanol ingestion did not affect the biological activity of LH. In each subject alcohol administration reduced the nightly peak of GH secretion. and in addition. changed the timing of this peak in most subjects. Only marginal changes were found in the prolactin levels but ethanol ingestion increased the cortisol levels on average by 36% (p less than 0.05) between 11 and 14 hr after the start of drinking. We conclude that the decrement in serum testosterone evoked by ethanol is not attributable to impaired pulsatile secretion of gonadotropins nor to reduced biological activity of LH. In contrast. ethanol profoundly suppressed the pulsatile secretion of growth hormone.
Eicosanoids and platelet-activating factor in allergic respiratory diseases, The nature of the lipid mediators released at an inflammatory site in the airways is dependent not only on the individual cells and inflammatory stimuli present but also on a complex interaction between neighboring cells and their lipid products. These lipid mediators share overlapping activities. and current research is directed toward determining the critical molecules involved in the pathogenesis of particular inflammatory states. How may the release of these lipid mediators play a role in the pathogenesis of asthma? Allergic persons after inhalation of specific allergen have a dual bronchospastic response. The early asthmatic response occurring shortly after allergen challenge is most likely secondary to the action of bronchoconstrictor molecules (e.g.. LTC4. PGD2. PAF) released by human lung mast cells as a consequence of IgE-mediated degranulation. An inflammatory process than occurs in the airways that is characterized by an influx of eosinophils and neutrophils into the airway epithelium and bronchial fluids. This inflammatory response corresponds to the late asthmatic phase occurring several hours after allergen challenge. Release of sulfidopeptide leukotrienes. PAF. and cyclooxygenase products by cells infiltrating the airways may be involved in the bronchial smooth muscle constriction. mucosal edema. and mucus hypersecretion observed during these late asthmatic responses. In the future. the therapeutic use of specific antagonists of the biosynthetic enzymes of the 5-lipoxygenase pathway and receptor antagonists of the eicosanoids and PAF holds great promise for the modulation of airway inflammation.
Importance of the aminoglycoside dosing regimen in the penicillin-netilmicin combination for treatment of Enterococcus faecalis-induced experimental endocarditis, The penicillin-aminoglycoside combination is recommended for the treatment of systemic enterococcal infections. However. the optimal dosing regimen of the aminoglycoside remains to be elucidated. We evaluated the efficacy of penicillin. alone or in combination with various dosing regimens of netilmicin. for the treatment of experimental left-sided Enterococcus faecalis endocarditis in rabbits. Animals were injected intramuscularly for 4 days with penicillin alone or in combination with netilmicin in one of the following regimens: netilmicin at a low dose (2 mg/kg of body weight every 8 h). netilmicin at a high dose (4 mg/kg every 8 h). or netilmicin at a single daily high dose (12 mg/kg every 24 h). MICs and MBCs were 3.1 and 6.2 micrograms/ml and 8 and 8 micrograms/ml for penicillin and netilmicin. respectively. A netilmicin concentration of 4 micrograms/ml was the lowest concentration that achieved synergism with penicillin. as shown by the kill-curve method. Mean peak levels of netilmicin in serum were 5.6 (netilmicin at 2 mg/kg). 9.8 (netilmicin at 4 mg/kg). and 20.6 (netilmicin at 12 mg/kg) micrograms/ml. Mean penicillin levels in serum were constantly above the MIC. Penicillin plus netilmicin at a high dose given three times daily was more effective (P less than 0.05) than any other regimen in reducing bacterial titers in vegetations and was the only treatment that induced a significant bactericidal activity in rabbit serum during the trough. We concluded that divided doses of aminoglycoside are more effective than the same total dose given once daily in combination with penicillin.
Genomic organization of IgH gene compared with the expression of Bcl-2 gene in t(14;18)-positive lymphoma, In three lymphoma cell lines carrying t(14;18). named FL-18. FL-218. and FL-318. the genomic organization of IgH gene was compared with the expression of bcl-2 gene; the t(14;18) of the FL-18 cells occurred downstream from the major breakpoint cluster region (mbr) of a bcl-2 gene. and that of the FL-218 and FL-318 cells within the mbr. The FL-318 expressed the normal-sized bcl-2 transcript of 8.5-kb mRNA having the noncoding region 3 to the mbr. which was found in the FL-18. and the FL-218 lacking the intact bcl-2 gene did not. This finding suggests that in t(14;18)-positive lymphoma having the breakpoint within the mbr. transcription of the nontranslocated bcl-2 allele is not necessarily silent. In addition. the FL-218 and FL-318 expressed aberrant bcl-2 transcripts and heterogenous IgH transcripts lacking the VH region. and the bcl-2 transcripts each comigrated with parts of the sterile IgH mRNAs. The FL-318. which did not exhibit switch recombination on either IgH allele. contained abundant amounts of l gamma mRNAs. a prerequisite for the recombination into the C gamma locus. One of the I-mRNA species comigrated with the aberrant bcl-2 transcript. The FL-18 and FL-218 lacking the I gamma mRNAs had completed switch recombination of both IgH alleles. This result raises a possibility that deregulated bcl-2 transcription caused by t(14;18) is capable of playing a role in class switch recombination of IgH gene.
Detection of T-cell receptor gamma chain V gene rearrangements using the polymerase chain reaction: application to the study of clonal disease cells in acute lymphoblastic leukemia, This report describes the development and characterization of a method for the amplification of rearranged V-J segments of the human T-cell receptor gamma chain (TCRG) locus using an adaptation of the polymerase chain reaction (PCR) technique. The technique uses a single pair of 'consensus' primers to amplify rearrangements involving the V gamma I subgroup genes. which are common in malignant cells from acute lymphoblastic leukemia (ALL) patients. Using this method we were able to detect rearrangements in the TCRG locus in disease cells from patients with T-cell ALL (12 of 12). common ALL (10 of 14). and Null cell ALL (2 of 2) at presentation. Monoallelic and biallelic rearrangements involving V gamma I subgroup genes were identified by restriction analysis of PCR products from DNA samples from a T-cell leukemic cell line. T-cell clones. and disease cells from patients with ALL of T-and B-cell lineage at presentation. These results confirmed the presence of cell clones within the presentation samples and. in one case. confirmed the persistence of the original malignant cell clone at relapse. This is a rapid and specific method for the detection and characterization of rearrangements of the TCRG locus without recourse to Southern blotting. Therefore. the PCR technique described herein can provide the basis for the study of clonal evolution and minimal residual disease on a high proportion of patients with ALL.
T-cell receptor tau delta +/CD3+4-8-T- cell acute lymphoblastic leukemias: a distinct subgroup of leukemias in children. A report of five cases, In a 10-year study of T-cell acute lymphoblastic leukemias (T-ALL) in children. we have identified five cases expressing the T-cell receptor tau delta (TCR tau delta). The incidence (26%) of TCR tau delta+T-cell leukemias in our material was high. Clinically. the TCR tau delta+ leukemias represented a distinct subgroup of T-cell leukemias. Mean age at onset of disease. 1.8 years. was remarkably low for mature T-cell leukemias. White blood cell counts were high. lymph node enlargements were discrete. and no mediastinal tumors were seen. Four of five TCR tau delta+ leukemias carried rearrangements of the C tau 2 gene. and transcribed the T-early alpha genetic element.
Unproven methods of cancer management. Livingston-Wheeler therapy, Livingston-Wheeler's cancer treatment is based on the belief that cancer is caused by a bacterium she has named Progenitor cryptocides. Careful research using modern techniques. however. has shown that there is no such organism and that Livingston-Wheeler has apparently mistaken several different types of bacteria. both rare and common. for a unique microbe. In spite of diligent research to isolate a cancer-causing microorganism. none has been found. Similarly. Livingston-Wheeler's autologous vaccine cannot be considered an effective treatment for cancer. While many oncologists have expressed the hope that someday a vaccine will be developed against cancer. the cause(s) of cancer must be determined before research can be directed toward developing a vaccine. The rationale for other facets of the Livingston-Wheeler cancer therapy is similarly faulty. No evidence supports her contention that cancer results from a defective immune system. that a whole-foods diet restores immune system deficiencies. that abscisic acid slows tumor growth. or that cancer is transmitted to humans by chickens.
The epidemiology of breast cancer, Table 5 presents risk factors for breast cancer generally regarded as established. together with their approximate relative risks. With the exception of age. country of birth. and a history of breast cancer in both a mother and a sister. all of the relative risks reported to date are of a relatively modest magnitude. Thus. new risk factors need to be identified and knowledge of existing risk factors refined. Factors for which the evidence of an etiologic role has mounted over the past several years. but which are not yet considered to be established. include the protective effects of parity and lactation in certain age groups and the increased risks associated with alcohol consumption and with DES exposure during pregnancy. In addition. physical activity has emerged as a factor worthy of further study. Some evidence suggests that use of oral contraceptives for several years at an early age modestly increases the risk for breast cancer diagnosed before age 35 and perhaps age 45. Use of estrogen-replacement therapy for 20 years or more has been found by a few studies to increase the risk for breast cancer in the postmenopausal years; further studies of very long-term users are needed. Also. other risks and benefits of these hormones need to be taken into account when women decide whether to use them. Surprisingly elusive has been the etiologic role of endogenous hormones. especially in view of the large number of studies that have been concerned with them. A better understanding of the role of endogenous hormones should help explain the mechanisms of action of known and suspected risk factors. Areas of high priority for further research thus include establishing with more certainty whether the risk for breast cancer is increased in any subgroups of women who use oral contraceptives and estrogen-replacement therapy and determining the etiologic roles of specific endogenous hormones. The possible risks associated with alcohol consumption and lack of physical activity need to be studied more thoroughly. and ideas about new potential risk factors are needed. Although epidemiologic studies will continue to be concerned with diet. enthusiasm for its etiologic role in women has been considerably dampened by the lack of association in many of the studies reported to date. The studies in women exposed to radiation. DES. and oral contraceptives suggest that the timing of some exposures may be critical. since the effects of these agents may mostly be limited to specific time periods of rapid breast development.(ABSTRACT TRUNCATED AT 400 WORDS).
Unproven methods of cancer management. Laetrile, "Laetrile" is used interchangeably with "amygdalin" to designate natural substances. derived primarily from apricots and almonds. that can release cyanide. which is lethal to living organisms. In the 1920s. Dr. Ernst T. Krebs. Sr.. formulated a theory that amygdalin could kill cancer cells. His theory was inconsistent with biochemical facts and has since been modified at least twice by his son. Ernst T. Krebs. Jr. Extensive work has been done by cancer scientists to test the claim that Laetrile fights cancer. Many animal experiments in the 1970s showed a complete lack of tumor killing by Laetrile. Reviews of the medical records of patients whose cancers were claimed to be reduced or cured after Laetrile treatment found insufficient medical evidence to judge Laetrile's efficacy. Finally. in a clinical trial in cancer patients reported in 1982. Laetrile neither caused shrinkage of tumors. nor increased survival time. nor alleviated cancer symptoms. nor enhanced well-being. Several reports in the medical literature document instances in which Laetrile has caused serious. life-threatening toxicity when taken in large doses in the manner prescribed by Laetrile advocates. In light of the lack of efficacy of Laetrile and its demonstrated ability to cause harm. Laetrile should not be used to treat cancer.
Amiloride delays the ischemia-induced rise in cytosolic free calcium, An increase in cytosolic free calcium (Cai) has been shown to occur early during ischemia in perfused rat. ferret. and rabbit hearts. It has been proposed that this increase in Cai may occur as a result of exchange of Nai for Cao. which occurs as a result of an increase in Nai arising from exchange of Nao for H+i. The latter exchange is stimulated by the intracellular acidification that occurs during ischemia. To test this hypothesis. we examined Cai. Nai. ATP. and pHi during ischemia in rats in the presence and absence of 1 mM amiloride. a Na-H exchange inhibitor. Cai was measured using 19F nuclear magnetic resonance (NMR) of 1.2-bis(2-amino-5-fluorophenoxy)ethane-N.N.N'.N'-tetra-acetic acid (5F-BAPTA)-loaded rat hearts. Nai was measured using 23Na NMR. and the shift reagent 1.4.7.10-tetraazacyclododecane-N.N'.N".N"'-tetramethylenephosph onate (Tm[DOTP]-5) was used to separate Nai and Nao. ATP and pH were determined from 31P NMR measurements. During 20 minutes of ischemia. amiloride did not significantly alter the ATP decline but did significantly attenuate the rise in Nai and Cai. After 20 minutes of ischemia. time-averaged Cai was 1.0 +/- 0.2 microM (mean +/- SEM) in amiloride-treated hearts compared with 2.3 +/- 0.9 microM in nontreated hearts. After 20 minutes of ischemia. Nai in the untreated heart was threefold greater than control. whereas in the amiloride-treated heart. Nai was not significantly different from control. These data are consistent with the involvement of Na-Ca exchange in the rise in Cai during ischemia.
Effects of quinapril, a new angiotensin converting enzyme inhibitor, on left ventricular failure and survival in the cardiomyopathic hamster. Hemodynamic, morphological, and biochemical correlates, The effect of chronic therapy with quinapril on the temporal progression of left ventricular failure and survival was assessed in the CHF 146 cardiomyopathic (CM) hamster. which is an idiopathic model of congestive heart failure. Age-matched Golden Syrian (GS) hamsters served as normal controls. Quinapril was administered in the drinking water at average daily doses of 10.2. 112.4. and 222.4 mg/kg/day. In untreated CM hamsters. in vitro left ventricular performance progressively deteriorated with increasing age beginning at roughly 180 days. This decline in left ventricular performance was accompanied by a decrease in coronary flow and an increase in left ventricular volume. Administration of quinapril from 180 to 300 days of age prevented the decline of in vitro left ventricular contractile performance and coronary flow and also reduced the age-dependent increases in left ventricular volume. The cardioprotective effects of quinapril were observed at doses of 112.4 and 222.4 mg/kg/day but not at 10.2 mg/kg/day. Lung angiotensin converting enzyme activity was significantly inhibited by quinapril in GS and CM hamsters at 240 and 300 days of age at all dose levels. In contrast. significant inhibition of ventricular angiotensin converting enzyme activity was observed consistently at doses of 112.4 and 222.4 mg/kg/day quinapril but not at 10.2 mg/kg/day. In the survival protocol. CM and GS hamsters were treated with vehicle or quinapril (100 mg/kg/day) from 180 to 522 days of age. During the initial 210 days of treatment (from 180 to 390 days of age) 78.3% of the vehicle-treated CM hamsters died compared with 27.7% of quinapril-treated CM hamsters. Quinapril increased the median survival time of CM hamsters by 32.9% (112 days). It is concluded that chronic quinapril therapy exerts a significant cardioprotective effect and also increases survival.
Differences in prostaglandin metabolism in cultured aortic and pulmonary arterial endothelial cells exposed to acute and chronic hypoxia, In vivo. a marked difference in blood oxygen tension exists between the pulmonary artery and the aorta. Responses of vascular endothelial cells from these vessels to changes in ambient oxygen might be influenced by the oxygen tension to which they are continuously exposed in vivo or by their anatomic site. To explore this hypothesis. we initially studied the production of the cyclooxygenase metabolites prostacyclin and thromboxane in bovine aortic and main pulmonary arterial endothelial cells grown in 21% O2 and exposed to different degrees of acute hypoxia over a wide range of times. We found that short-term hypoxia (3% or 0% O2) rapidly and transiently activates the cyclooxygenase pathway in both cell types. with a more rapid response in bovine aortic endothelial cells. To determine whether culture in an oxygen tension similar to that to which main pulmonary arterial endothelial cells are exposed in vivo alters this response. we evaluated these cyclooxygenase metabolites in bovine aortic and main pulmonary arterial endothelial cells cultured long-term in 3% O2. both at baseline and after exposure to acute anoxia (0% O2). In both cell types. we found a decrease in prostacyclin and thromboxane synthesis at baseline and evidence of an increase in the Vmax of thromboxane synthetase following stimulation with exogenous arachidonic acid. In chronically hypoxic cells exposed to acute anoxia. there were marked differences in enzyme activity compared with that in endothelial cells maintained in 21% O2 with differences depending on the origin of the endothelial cells. In bovine aortic endothelial cells. production of neither cyclooxygenase metabolite increased; in bovine main pulmonary arterial endothelial cells. only thromboxane production increased. suggesting isolated activation of the cyclooxygenase-thromboxane synthetase pathway. These studies demonstrate that acute and chronic hypoxia have profound effects on endothelial cell cyclooxygenase metabolism and that these effects depend on the duration and degree of the hypoxic exposure and the vascular bed from which the endothelial cells are derived.
The day-long antianginal effectiveness of nitroglycerin patches. A double-blind study using dose-titration, This study was designed to determine the day-long antianginal effectiveness of nitroglycerin patches in the nitrate-exposed patient. as well as the doses required. Eight men with chronic stable angina. a positive treadmill test. and demonstrated responsiveness to long-term oral isosorbide dinitrate were studied after they had been taking effective doses of isosorbide dinitrate three times a day for at least two weeks. Treadmill exercise bouts were performed every 1 to 2 hours over 1 day. after the 8 am application of active nitroglycerin patches in a previously titrated dose. and on another day after application of placebo patches. Mean necessary effective patch dose was 125 sq cm (60 to 220 sq cm). Mean exercise duration to angina rose from 271 to 480 s (p less than 0.001) 1 hour after active patches. while resting systolic blood pressure fell from 122 mm Hg to 100 mm Hg (p less than 0.001). (After placebo patches: +19 s and -2 mm Hg. respectively.) Active patches were superior to placebo throughout the day. but in declining degree (by 94 s at 7 pm. p less than 0.05). Thus. nitroglycerin patches can provide a significant day-long antianginal effect in the patient with long-term exposure to nitrate. However. the need for large doses and individual titration may make this therapy impractical.
Intestinal absorption of free oral hyperalimentation in the very short bowel syndrome, Ten adult ambulatory patients with the nonactive digestive disease short bowel syndrome were prospectively studied to quantitatively assess their free oral intake and their net digestive absorption of total calories. fat. protein. and carbohydrate during a 3-day period at least 6 months after a resection. The remaining portions of small bowel had a mean length of 75 cm (range. 0-200 cm); the remaining colon lengths had a mean of 67% of normal (range. 0%-100%). The experimental diets were formulated according to a home dietary inquiry. During the study period. pooled intakes and digestive losses were measured for total calories. fat. and protein using the bomb calorimetry. Van de Kamer. and Kjeldahl techniques. respectively. The ingested diet provided 58 +/- 14 kcal.kg-1.day-1 (mean +/- SD) and consisted of 46% carbohydrate. 31% fat. and 23% protein. Net digestive absorption was 67% +/- 12% for total calories. 79% +/- 15% for carbohydrate. 52% +/- 16% for fat. and 61% +/- 19% for protein. The larger net digestive absorption of carbohydrate (P less than or equal to 0.004) compared with fat and protein suggests salvage of colonic cholesterol in short bowel syndrome patients. It is concluded that these patients with the short bowel syndrome adapted to a hypercaloric. hyperprotein diet to compensate for increased fecal losses and that this hyperphagia does not seem to have impaired their net digestive absorption.
Non-A, non-B hepatitis and anti-HCV antibodies in dialysis patients, To define the prevalence of non-A. non-B hepatitis. antibodies to HCV were detected in 193 patients on renal replacement therapy (52 transplant and 141 hemodialysis patients) and in 50 staff members of a Nephrology Department. Unequivocal seroconversion was documented in 5 transplant (9.6%) and in 26 dialysis patients (18.4%). In the dialysis population. the prevalence of anti-HCV antibodies was evaluated in patients grouped according to the number of blood transfusions and to the different sections of dialytic treatment. The most striking findings were the marked differences in the prevalence of anti-HCV antibodies among patients treated in different sections (from 0% to 70%). and the presence of a significant increase in alanine-amino-transferase (ALT) concentrations in 14 anti-HCV negative patients. The results suggest that the diffusion of non-A. non-B hepatitis is mainly transfusion-related. with the possibility of significant environmental diffusion related to the violation of infection-control measures. The current immunoassay is probably unable to detect the actual frequency of the infection.
Study of parameters involved in specific immunoadsorption of apolipoprotein B, A therapeutic immunoadsorption system on immobilized and anti-apolipoprotein B as a plasma cholesterol lowering procedure was optimized. Several antibodies were compared and highest adsorption capacity was obtained with goat polyclonal antibodies. Optimum quantities of antibodies to be immobilized on the gel and quantities of apo-B to be applied to columns were determined. The amount of antibodies released from immunoadsorbents can be minimized by treatment with a 0.005% glutaraldehyde solution with an acceptable reduction rate of adsorption capacity. Each phase. adsorption and desorption respectively. were well-defined and synchronized so two columns could be used in parallel in an automated procedure. In these conditions. the immunoadsorption system can efficiently. specifically and safely remove cholesterol and has to be subjected to clinical trials.
Acute sternal opening after cardiac surgery in children: effect on plasma atrial natriuretic peptide, Plasma atrial natriuretic peptide (ANP) was measured immediately before and 15 minutes after re-opening of the sternotomy and delayed sternal closure were performed to alleviate possible myocardial compression in 3 children. As acute re-opening of the sternotomy is a rare occurrence our sample size was necessarily small. ANP increased following the procedure in all 3 patients. and this was significant (p less than 0.02) when compared to plasma levels obtained from 9 children who underwent sternotomy prior to elective cardiac surgery. Following acute re-opening of the sternotomy there was an increase in median urine output and a decrease in median central venous pressure. Our results illustrate that it is atrial wall stress rather than intra-atrial pressure that determines release of ANP. and in addition suggest ANP may be a factor in the rapid clinical improvement following delayed sternal closure for atypical tamponade in children.
Production and characterization of a human hyperimmune intravenous immunoglobulin against Pseudomonas aeruginosa and Klebsiella species, A hyperimmune globulin for intravenous use (H-IVIG) was prepared from the plasma of donors immunized with Pseudomonas aeruginosa and Klebsiella vaccines. H-IVIG preparations contained substantially higher IgG antibody levels to all nine P. aeruginosa vaccine antigens and to 22 of the 24 Klebsiella vaccine antigens than did commercial IVIG. The H-IVIG was more effective at promoting the opsonophagocytic killing of P. aeruginosa and Klebsiella vaccine serotype strains than normal IVIG. The H-IVIG neutralized greater than 20 times more toxin A than commercial IVIG. Only the H-IVIG offered significant protection against Klebsiella K2 sepsis. The H-IVIG provided significantly better protection against six of the eight P. aeruginosa vaccine serotypes than normal IVIG when compared in a murine burn wound sepsis model. The H-IVIG also protected mice against an Enterobacter aerogenes challenge. whereas normal IVIG was ineffective.
Immune cell activation in melioidosis: increased serum levels of interferon-gamma and soluble interleukin-2 receptors without change in soluble CD8 protein, To evaluate immune cell activation in patients with melioidosis. serum samples were assayed for interferon-gamma (IFN-gamma). soluble interleukin-2 receptors (sIL-2R). and soluble CD8 protein (sCD8). Forty patients with sepsis (23 fatal cases. 17 survivors) and 13 with localized disease were studied during acute illness; 12 additional patients were studied after discharge while on maintenance antimicrobial therapy. Serum concentrations of IFN-gamma and sIL-2R were greatly elevated. but sCD8 concentrations were not. These levels increased with disease severity and were associated with fatal outcomes. Macrophage activation by high concentrations of the cytokine IFN-gamma may contribute to pathophysiology and death in septicemic patients. Both IFN-gamma and sIL-2R seem to be predictive of outcome in patients with severe melioidosis and may prove useful in detection of relapse.
An outbreak of soft-tissue infections due to Mycobacterium fortuitum associated with electromyography, An outbreak of infections due to Mycobacterium fortuitum associated with electromyography (EMG) is described. During a 6-week period. six patients who received EMG at one facility developed soft-tissue infections manifested by slowly expanding suppurative nodules at sites of needle electrode insertion. M. fortuitum was isolated from five patients; four isolates that were evaluated further were M. fortuitum biovariant fortuitum. EMG procedures were done in one laboratory by one physician and assistant. Standard procedures included use of reusable needle electrodes disinfected with 2% glutaraldehyde and then rinsed with tap water. On recognition of the outbreak. the procedure was changed to include autoclaving of needle electrodes. Active surveillance for 1 year revealed no further cases. M. fortuitum could not be isolated from the laboratory. EMG equipment and reagents. or skin of the medical personnel. The outbreak demonstrates that nontuberculous mycobacterial infection may be associated with EMG.
Interferon-gamma enhances the effect of antimalarial chemotherapy in murine Plasmodium vinckei malaria, Most nonimmune patients with Plasmodium falciparum infection are no longer cured by such standard antimalarial drugs as chloroquine. Thus. alternative treatment regimens are necessary. A combination therapy was tested consisting of a subcurative dose of chloroquine and interferon-gamma (IFN-gamma) in BALB/c mice with lethal Plasmodium vinckei malaria. Treatment with either agent alone prolonged median survival by 1-2 days compared with placebo-treated mice. However. a combination of 80 micrograms of chloroquine given at the time of infection plus 1 x 10(4) units of IFN-gamma/day for 11 days (starting 3 days before infection) cured 83% of infected mice. Moreover. these mice showed solid immunity when challenged with the homologous strain of P. vinckei. However. when these mice were infected with the heterologous strain of Plasmodium berghei. the same degree of parasitemia developed as did in P. berghei-infected control mice. Thus. the combination of chemotherapy with the cytokine IFN-gamma leads to substantial improvement of antimalarial treatment and to a rapid development of strain-specific immunity in murine P. vinckei malaria.
Comparison of spinal fluid beta 2-microglobulin levels with CD4+ T cell count, in vitro T helper cell function, and spinal fluid IgG parameters in 163 neurologically normal adults infected with the human immunodeficiency virus type 1, Beta 2-microglobulin levels were measured in the cerebrospinal fluid (CSF) and serum of 163 human immunodeficiency virus-positive (HIV+) persons with normal neurologic physical examinations. None were on antiretroviral therapy. Only 3% had a positive CSF HIV p24 antigen test. The CSF beta 2-microglobulin levels increased as the CD4+ T cell count decreased. Intrathecal production of beta 2-microglobulin was suggested by finding CSF concentrations greater than serum concentrations in 15% of patients. The CSF beta 2-microglobulin levels rose as in vitro T helper cell function deteriorated. independent of CD4+ T cell count. CSF beta 2-microglobulin levels paralleled CSF IgG. IgG index. and IgG synthesis. Higher CSF beta 2-microglobulin levels were found in persons with positive CSF oligoclonal bands. CSF beta 2-microglobulin concentration may serve as a marker for subclinical neurologic damage due to HIV. If this is established. defining the effect of anti-HIV interventions on CSF beta 2-microglobulin would be warranted.
Depressed aerobic enzyme activity of skeletal muscle in severe chronic heart failure, A reduction in exercise capacity is a common feature of congestive heart failure. We hypothesized that depressed aerobic enzyme activity of skeletal muscle may contribute to this exercise intolerance. Biopsy samples of vastus lateralis muscle were obtained from seven patients with severe chronic heart failure and analyzed for aerobic enzyme activity. Compared with normal laboratory controls. the patients with heart failure had a moderate reduction (greater than 60%) in skeletal muscle citrate synthase and a marked reduction (greater than 90%) in succinate dehydrogenase and cytochrome oxidase (all p less than 0.001). Depression of aerobic enzyme activity of skeletal muscle is associated with severe chronic heart failure and is likely one of the contributory factors for impaired exercise capacity seen in the advanced stages of this condition.
A prostacyclin analog impairs the response to tissue-type plasminogen activator during coronary thrombolysis: evidence for a pharmacokinetic interaction, Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However. experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists. in addition to TXA2. As a consequence. greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However. a recent clinical trial. combining tissue plasminogen activator (t-PA) with the prostacyclin analog. iloprost. did not detect such a benefit. To address the mechanism of this response. we compared the effect of iloprost. a stable analog of prostacyclin. with GR32191. a TXA2/prostaglandin endoperoxide receptor antagonist. on the response to i.v. t-PA in a closed chest. canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6. P less than .05). consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast. iloprost increased the time to reperfusion by 50% (n = 5. P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments. steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8. P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect. as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.
PMCs--an alternative to DRGs for trauma care reimbursement, Payments made for inpatient trauma care were compared using two different patient classification systems--Patient Management Categories (PMCs) and Diagnosis Related Groups (DRGs). Two databases were used in this study: 1) estimated costs for all inpatient claims from one large payor for adult injured patients (n = 5.256) treated at 79 acute care facilities (trauma centers and non-trauma centers) in one geographic region; and 2) hospital charges from statewide. all-payor Maryland data. including 25.987 adult injured patients. The accuracy of PMCs and DRGs in predicting actual costs was examined by level of injury severity and by types of hospital. trauma center vs. non-trauma center. Level of injury (minor. single significant. multiple significant. and major) were defined and operationalized using PMCs. Overall. both DRG and PMC payment systems were nearly equal to the actual costs associated with all injured patients. This relationship can be designed into the weighting scale used for payment. The distribution of DRG payments by injury severity level. however. is not reflective of the differential resources required to manage each patient type. In particular. multiple injuries and major injuries that require the specialized services of a trauma center were inaccurately categorized by DRGs and systematically underpaid by 21.0% to 39.0% by DRG payment. By contrast. the Patient Management Category System classifies patients into more clinically specific and accurate categories and offers a more equitable method of distributing payments by injury severity. These same relationships were also found at the hospital level. demonstrating the potential for use of PMCs as an equitable and viable alternative.
Ribavirin treatment for chronic hepatitis C, We evaluated oral ribavirin as therapy for chronic hepatitis C infection in a pilot study including 10 patients. Patients (7 men. 3 women; mean age 40 years. range 23-54) all had biopsy-proven chronic non-A. non-B hepatitis and were repeatedly positive for antibodies to hepatitis C virus. Treatment was with oral ribavirin 1000-1200 mg per day in two divided doses for 12 weeks. The median serum alanine aminotransferase concentration for all patients at enrollment was 3.15 mu kat/l (range 1.22-7.79) and decreased significantly (p less than 0.005) to 1.25 mu kat/l (0.78-2.04) after 12 weeks of treatment. Within 6 weeks of the end of treatment the median serum alanine aminotransferase concentration was not significantly different from that before treatment. Side-effects were mild and fully reversible after cessation of therapy. We conclude that ribavirin is the first drug to offer a potentially effective oral treatment for chronic hepatitis C. It should be further evaluated in controlled trials. possibly in combination with interferon alpha.
Inappropriate use of transillumination for breast cancer screening--Wisconsin, 1990, The overall effectiveness of early breast cancer detection efforts requires the appropriate use and maintenance of dedicated radiographic mammography systems. However. the effectiveness of early detection efforts can be compromised if proven technology is improperly used and/or maintained or if ineffective technology is successfully marketed as an equivalent or superior alternative to mammography. This report summarizes state and federal responses to the inappropriate use of a nonradiographic imaging technique in a breast cancer screening service advertised and used in Wisconsin in 1990.
Measles outbreak--New York City, 1990-1991, In March 1990. a large measles outbreak began in New York City. Through December 1990. approximately 2500 cases and eight measles-associated deaths were reported. However. since January 1991. transmission has increased; through May 7. more than 2000 cases and nine deaths were reported to the New York City Department of Health (NYCDH) in 1991.
The second-generation antihistamines. What makes them different, Physicians often are faced with the decision of whether to prescribe a drug for its positive therapeutic effects or avoid prescribing it because of unacceptable side effects. This dilemma can sometimes be eased by keeping current on new therapeutic options as they become available. The authors provide a useful update on the state of the art in antihistamine therapy.
Current approaches to prevention of HIV infections, The HIV education and prevention strategy of the Centers for Disease Control has three principal components: (a) public information and education. (b) education for school-aged populations. and (c) risk reduction education and individual counseling and testing services for people at increased risk of HIV infection. The most visible components of the public information and education programs are the National Public Information Campaign ("America Responds to AIDS"). the National AIDS Hotline system. and the National AIDS Information Clearinghouse. Components of the youth education program consist of funding for national health and education organizations. funding for State and local education departments. training. surveillance of education efforts. and evaluation. Counseling and testing has entailed performance of approximately 2.500.000 HIV antibody tests with pre- and post-test counseling. notification and counseling of sexual and needle-sharing partners of those infected with HIV. and targeted risk reduction education through community-based organizations. Over time. these activities will continue to evolve and become more effective.
AIDS knowledge in low-income and minority populations, A convenience sample of 587 subjects was selected from the waiting areas of community health centers in Harris County. TX. They completed a structured interview that included questions on their knowledge of acquired immunodeficiency syndrome (AIDS) transmission and prevention. Hispanic patients were interviewed in their preferred language. They were given a cumulative correct score for 10 questions on AIDS. An ANOVA showed significant differences in knowledge between each radial group. Cumulative scores were whites. 78 percent correct; blacks. 68 percent correct; and Hispanics. 61 percent correct. Only 58 percent of Hispanics reported that using a condom during sexual intercourse lowered the risk of contracting AIDS. compared with 84 percent of whites and 83 percent of blacks. A regression analysis showed significant effects for both education and racial group. but not for age and sex. These findings show that knowledge of AIDS can be predicted according to the race and education of the population using these community health centers. Additional attention should be focused on educating low-income blacks and Hispanics about AIDS.
AIDS awareness in North Dakota--a knowledge and attitude study of the general population, The AIDS program of the North Dakota Department of Health and Consolidated Laboratories has provided a broad range of information concerning AIDS (acquired immunodeficiency syndrome) and HIV (human immunodeficiency virus) to State residents over the past few years. The ultimate intent of these intervention efforts was to decrease viral transmission. To assess residents' knowledge and attitudes regarding AIDS. a statewide. random telephone study was conducted by AIDS Program personnel in the fall of 1987. 1988. and 1989. with technical assistance from the Bureau of Governmental Affairs. University of North Dakota. Study results indicated a majority of the respondents considered themselves to have at least "some" knowledge about AIDS. Participants' comprehension of viral transmission routes and prevention methods increased over the 3 years. yet misconceptions still exist. Identified areas of misconception were accentuated in subsequent State educational programs. When the results were compared with national studies. knowledge levels in North Dakota were generally similar to but frequently superior to the nationwide levels.
Black-white differences in alcohol use by women: Baltimore survey findings, Although black women suffer disproportionately from alcohol-related illnesses and causes of death. little is known about the extent to which poorer outcomes are a function of differences in drinking. the use of health services. or some combination of these factors. This study. using interview data obtained in the Baltimore Epidemiologic Catchment Area household survey. compares racial differences in alcohol use and abuse among a sample of 2.100 women. After controlling for differences in sociodemographic characteristics. black women were found to be at no greater risk than whites for heavy drinking or for suffering from alcohol abuse or dependence. Racial differences. however. were observed in heavy drinking by years of education. A similar percentage of black women and white women who had not completed high school were heavy drinkers. but black women with 12 or more years of education were less likely to be heavy drinkers than whites with comparable education. These findings raise questions about the extent to which differences in drinking contribute to the poorer alcohol-related health outcomes of black women in Baltimore. Additionally. the finding that education was inversely related to heavy drinking among black women may be helpful in shaping early alcohol abuse intervention and treatment services that target black women.
Using linked program and birth records to evaluate coverage and targeting in Tennessee's WIC program, Public health nutrition programs are intended to serve low-income families who are at greater nutritional risk than the general population. Not all persons who are program-eligible are at equal risk. however. It would be desirable to evaluate a program's ability to enroll persons from higher risk backgrounds in the population (coverage) and. conversely. the extent to which those enrolled in this program are at higher risk (targeting). A method for the evaluation of coverage and targeting was developed using data from the Tennessee Women. Infants. and Children Special Supplemental Food Program (WIC) linked with birth certificates. The linked computer file was created by matching the name and date of birth in both record files. The birth records were the common source of information used to characterize the risk background for both the WIC and non-WIC participants. Maternal sociodemographic information on the birth records was used to define the health risk background of each child. The coverage and targeting of "at-risk" children were computed and compared for 50 counties or county-aggregates in Tennessee. Considerable variation in the coverage and targeting rates of at-risk children was observed among Tennessee counties. although the counties within each WIC administrative region tended to have similar coverage and targeting patterns. Using the existing data in linked program and vital records provides a direct evaluation of a program. Coverage and targeting evaluation can be used to detect underserved populations within small geographic areas.
A proposal for strengthening medical school training in STD prevention techniques, Despite increases in national rates of sexually transmitted disease (STD). surveys indicate that medical students generally lack programs to train them in STD prevention techniques and in counseling patients about STD. The authors of this proposal investigated STD education for medical students at the University of California at Los Angeles and propose a project to involve third-year medical students in STD prevention techniques during their STD-clinic rotation. The long-term goal is to decrease the incidence and prevalence of STD. The immediate aims are to increase medical students' knowledge of STD prevention and to help them develop the communication skills necessary to effectively counsel patients about STD. Interventions would consist of a series of lectures and workshops using audiovisual aids. small group discussions. and role playing. and would be conducted by health educators and guest lecturers. A quasi-experimental research design would be used in testing the effectiveness of the project in two experimental and two control groups involving a total of 80 third-year medical students. The first intervention would be a 1-week lecture series. Written tests would be given before and after the first intervention to measure the baseline of the students' knowledge of STD prevention methods. The second intervention would be a 1-week workshop series. Students' interviews with patients would be videotaped before and after the second intervention so that the interviewer's communication skills may be assessed and compared. Sets of interventions would be scheduled for the fall of 1990 and the spring of 1991. Six months after the completion of the project. a followup questionnaire would be given to evaluate the project's overall effectiveness.
Review of laboratory findings for patients with chronic fatigue syndrome, Various abnormalities revealed by laboratory studies have been reported in adults with chronic fatigue syndrome. Those most consistently reported include depressed natural killer cell function and reduced numbers of natural killer cells; low levels of circulating immune complexes; low levels of several autoantibodies. particularly antinuclear antibodies and antithyroid antibodies; altered levels of immunoglobulins; abnormalities in number and function of lymphocytes; and modestly elevated levels of two Epstein-Barr virus-related antibodies. immunoglobulin G to viral capsid antigen and to early antigen.
Regulation of Ras-GAP and the neurofibromatosis-1 gene product by eicosanoids, Ras-GAP (GTPase activating protein) is a regulatory protein that stimulates the intrinsic guanosine triphosphatase (GTPase) activity of the proto-oncogene product p21ras. A domain of the neurofibromatosis gene product (NF1) that has sequence similarity to the catalytic domain of Ras-GAP and to yeast IRA gene products also has a specific stimulatory activity toward p21ras GTPase. Arachidonic acid and phosphatidic acid inactivate GAP. but no agents have been identified that stimulate GAP and thereby switch p21ras off. With the use of recombinant Ha-c-Ras and Ras-GAP. NF1. and GAP catalytic domains. it was found that prostaglandins PGF2 alpha and PGA2 stimulated Ras-GAP and that prostacyclin PGI2 inhibited Ras-GAP. The stimulatory effect of PGF2 alpha was saturable and structure-specific and competed with the inhibitory effect of arachidonic acid. Arachidonic acid also inhibited the catalytic activity of NF1. but prostaglandins were not stimulatory. These results suggest a mechanism for the allosteric control of Ras function through the modulation of arachidonate metabolism.
Prospective evaluation of posttransfusion hepatitis, The incidence of posttransfusion hepatitis (PTH) was determined prospectively at our institution. An active surveillance program of transfused surgical patients was set up; alanine aminotransferase (ALT) levels were determined before transfusion and at monthly intervals for 6 months after transfusion. Patients with confirmed ALT values greater than 2.5 times the upper reference values were referred to the out-patient clinics for diagnosis. Of 4051 surgical patients who underwent transfusion between January 1986 and December 1989. 2459 (60.7%) were enrolled in the surveillance program. and 1018 (25.1%) completed the follow-up; 238 patients received autologous blood only and were used as controls. No PTH was observed in the control patients. and the incidence of the disease in patients receiving homologous blood was 10.97 percent in 1986. 6.58 percent in 1987. 5.55 percent in 1988. and 4.29 percent in 1989; the decreasing trend is significant (p = 0.018).
A cryoglobulin with cold agglutinin and erythroid stem cell suppressant properties, A 93-year-old woman presented with profound anemia (hematocrit 23% [0.23]); there was clumping of her red cells in test tubes and on peripheral blood smears. There was also a marked decrease in erythroid precursors in the bone marrow and reticulocytopenia in the peripheral blood. An IgM kappa monoclonal gammopathy was found in low concentration (approximately 1%) in her serum. and the cold agglutinins had a titer of 2560. However. the cold agglutinin titer of the supernatant after cryoglobulin precipitation was 40. Redissolving the cryoglobulin in the supernatant resulted in a cold agglutinin titer of 1280. Moreover. the addition of the patient's whole serum inhibited erythroid colony formation in culture. The inhibition was removed by cryoprecipitation of the cryoglobulin. The patient was given steroid therapy. to which she responded with reticulocytosis and an elevation of hematocrit. By 3 months. the cold agglutinin titer had fallen to 10. She remained well 4 years later. Whereas reports of cryoprecipitable cold agglutinins are rare. this case is unique because there have been no previous reports that these cold active proteins also have erythroid stem cell-suppressant properties.
Adrenergic receptor responsiveness and congestive heart failure, Our knowledge and understanding of the structure. mechanism of action and regulation of receptor-adenylate cyclase systems have increased dramatically in the last few years. A family of receptors (including the beta-adrenergic receptors) and guanine nucleotide regulatory proteins (G proteins) have been purified and cloned. Structure-function studies are beginning to provide insight into how the various components of the transmembrane signaling apparatus interact to promote alterations in the activity of the effector systems. Much effort has been devoted to understanding how various pathophysiologic conditions. such as ischemia or congestive heart failure. and the therapeutic methods used to treat such conditions perturb or regulate receptor systems. It has become abundantly clear that such regulation does occur but is not restricted to simple alterations in receptor number. and may well involve covalent modification (phosphorylation) of receptors or alteration in the ability of receptors to interact with G proteins. In addition. regulation of the quantity or functionality of the various G proteins and the catalytic unit of adenylate cyclase itself appear to occur. For example. recent evidence suggests that congestive heart failure in humans is associated with a decreased number of beta-adrenergic receptors as well as an increased quantity of the inhibitory G protein (Gi). These alterations may provide important insight into how to develop new therapeutic methods. Mechanisms generally responsible for transmembrane signaling. how the components are regulated by pathophysiologic conditions. and drugs used to treat disease states are discussed in detail.
Local cardiac responses--alternative methods of control, Much attention has been paid to the influence of the beta-adrenoceptor system on cardiac function in heart failure. Full agonists and partial agonists acting on cardiac beta 1 receptors have been widely investigated. as has the density of these receptors in the failing heart. However. other cardiac control mechanisms may play important roles in the normal heart as well as in heart failure. The Frank-Starling mechanism of enhanced cardiac contraction produced by mechanical stretching of the ventricular myofibrils is well known. When treating patients with heart failure with diuretics. vasodilators and other drugs that influence preload. it is important to consider their overall effects in relation to the Starling curves. Atrial stretching also produces compensatory responses which are currently being intensively studied. Reflex release of atrial natriuretic factor after stimulation of atrial receptors has important physiologic effects in heart failure. The atria. but not the ventricles. are innervated by the vagus; the influence of the parasympathetic nervous system on the heart and circulation is often overlooked. The initial increase in heart rate during exercise is primarily due to withdrawal of vagal influence. Besides acetylcholine. the parasympathetic transmitter. many other local hormones may affect cardiac function; these include prostaglandins. 5-hydroxytryptamine and histamine. Although the activity of the sympathetic nervous system is mediated primarily through beta 1 adrenoceptors. both beta 2 and alpha receptors are also found in the heart. Myocardial alpha 1 receptors. which mediate a positive inotropic effect. have been identified. and prejunctional alpha 2 receptors may mediate inhibition of norepinephrine release from sympathetic nerves.
Structured lipid made from fish oil and medium-chain triglycerides alters tumor and host metabolism in Yoshida-sarcoma-bearing rats, The effects of structured lipid composed of fish oil and medium-chain triglycerides (Fish/MCT) on tumor and the host metabolism was compared with conventional long-chain triglycerides (LCTs) in Yoshida-sarcoma-bearing rats receiving TPN for 3 d. The two parenterally fed groups were divided into two treatments. saline or tumor necrosis factor (TNF). given intravenously at 20 micrograms/kg body wt. Changes in tumor volume. body weight. urinary nitrogen. whole-body and tissue protein kinetics. and fatty acid composition were measured. The study revealed that Fish/MCT feeding inhibited tumor growth. which could be attributed to decreased tumor protein synthesis. Body weight and nitrogen were better maintained by Fish/MCT feeding. In addition. the effects of Fish/MCT on tumor growth were synergistic with TNF treatment. The results demonstrate that dietary fat composition can influence fatty acid compositions of tumor tissue as well as tumor protein kinetics after a short period of TPN feeding.
Dietary treatment for familial hypercholesterolemia--differential effects of dietary soy protein according to the apolipoprotein E phenotypes, Familial hypercholesterolemia. one form of type IIa hyperlipidemia. usually responds poorly to standard low-lipid diets. To define the responsiveness to a soy-protein diet in this disease. one homozygous and twenty heterozygous type IIa patients were submitted to a 4-wk traditional hypocholesterolemic diet followed by 4 wk in which animal protein was substituted with texturized soy protein. Soy was then withdrawn for a further 4 wk. No significant changes in plasma lipids were observed during low-lipid diets. The soy diet. however. caused a marked decrease in total (-20.8%) and low-density-lipoprotein (-25.8%) cholesterol and in apolipoprotein B (-14.1%). The plasma cholesterol reduction was higher in patients with apolipoprotein E3/E3 or E3/E4 vs an almost negligible effect on E3/E2. These results confirm that soy-protein diets can lower cholesterol in type IIa patients with familial disease. Data on the sensitivity of patients with different apo-E isoforms agree with recent hypotheses suggesting that soy proteins may activate B.E receptors.
Mild orotic aciduria and uricosuria in severe trauma victims, Hypermetabolic responses with respect to pyrimidine and purine kinetics in trauma victims were investigated during the catabolic phase before and after nutritional support. Orotic acid and uric acid excretions were measured in 32 adult. severely traumatized. hypermetabolic. and highly catabolic patients while they were receiving fluids with no calories or nitrogen. Patients were then fed intravenously amino acids and glucose or glucose alone or fed enterally for 5-6 d. Daily excretions of orotic acid. uric acid. urea. nitrogen. and creatinine were monitored. Mild orotic aciduria and uricosuria with hypouricemia were the basal-trauma responses. The significant (P = 0.001. r = 0.70) positive correlation between orotic and uric acid excretion demonstrates the parallelism between pyrimidine and purine metabolism. Feeding for 5-6 d could decrease but not readily abolish the injury-induced metabolic changes in nitrogen. pyrimidine. and purine metabolism. Glucose infusion alone may be sufficient to counteract the metabolic effects of trauma in the early flow phase of injury.
Depression of thymus-dependent immunity in wasting protein-energy malnutrition does not depend on an altered ratio of helper (CD4+) to suppressor (CD8+) T cells or on a disproportionately large atrophy of the T-cell relative to the B-cell pool, We report cell numbers within major subsets of lymphocytes in the spleen. mesenteric nodes. and recirculating pool of weanling mice subjected to protein-energy malnutrition (PEM). PEM and thymus (T)-dependent immunodepression were induced in male C57BL/6J mice by a low-protein (LP) diet fed ad libitum. Recirculating lymphocyte numbers were estimated by enumerating labeled and unlabeled cells after equilibration of a known number of fluorescein isothiocyanate-labeled C57BL/6J donor lymphocytes within well-nourished or LP recipients. Involution of the recirculating lymphocyte pool of the LP group was proportionately less than the lymphoid atrophy of the spleen and mesenteric nodes. The LP protocol exerted no influence on the ratio of helper (CD4+) to suppressor (CD8+) T cells and increased the ratio of T cells to B cells in the secondary lymphoid organs and recirculating pool. These results challenge two established concepts: that T-dependent immunodepression in PEM depends on a reduced CD4(+)-CD8+ ratio and that PEM induces greater involution within the T-cell system than within the B-cell system.
Direct vasodilator effect of hyperventilation-induced hypocarbia in autonomic failure patients, Hyperventilation produces small decreases in blood pressure in normal subjects and larger decreases in patients with autonomic failure. The authors studied the mechanism for this observation by measuring mean arterial pressure (MAP) and arterial blood gas (ABG) changes in eight patients with severe primary autonomic failure after various maneuvers designed to alter PaCO2. PaO2. and pH. Maneuvers included voluntary hyperventilation. breathing a 5% CO2/95% O2 mixture. breathing 12% O2. breathing through a 1 meter tube to increase dead space. breathing 100% O2. and infusion of 120 mEq NaHCO3 over 30 minutes. All maneuvers led to expected changes in ABGs. Voluntary hyperventilation lowered MAP by 23 +/- 4 (p less than 0.01) mmHg but MAP was raised 11 +/- 3 and 7 +/- 1 mmHg by hyperventilation resulting from increasing breathing dead space or from breathing 5% CO2. respectively. Breathing 100% O2 or 12% O2 had no significant effect on MAP. and NaHCO3 infusion raised MAP by 8 +/- 4 (p less than 0.05) mmHg. With all maneuvers. change in MAP correlated with change in PaCO2 (r = 0.72. p less than 0.001) and change in pH (r = -0.57. p less than 0.01) but not with PaO2. Multiple regression analysis showed that only changes in PaCO2 predicted the change in MAP for all maneuvers. The authors conclude that a decrease in PaCO2 causes the observed decreases in MAP with hyperventilation. This most likely represents a direct peripheral vasodilator effect of hypocarbia rather than a reflex or centrally-mediated mechanism since our patient population is characterized by inadequate or absent autonomic cardiovascular reflex responses.
Effect of saline infusion on urinary calcium excretion in essential hypertension, Urinary excretion of sodium and calcium was examined in hypertensive (n = 8) and normotensive (n = 7) subjects following infusion of 2% saline at a rate of 11 mL/min for 90 min. The urinary sodium excretion was 204 +/- 38 (mean +/- SEM) muEq/min in normotensives and 233 +/- 28 muEq/min in hypertensives before infusion of saline and increased maximally to 499 +/- 114 muEq/min (P less than .05) and to 928 +/- 68 muEq/min (P less than .01). respectively. after saline infusion. In normotensives. urinary calcium excretion did not change significantly; however. in hypertensives excretion increased markedly (P less than .01) from 6.1 +/- 0.7 muEq/min to 12.3 +/- 1.6 muEq/min. Plasma atrial natriuretic peptide (ANP) levels increased significantly (P less than .05) in both groups. Serum ionized calcium and plasma parathyroid hormone (PTH) levels did not change significantly. The increments of urinary sodium and calcium and of plasma ANP. as well as the preinfusion plasma PTH level. were significantly (P less than .05) higher in hypertensives than in normotensives. The present study showed that exaggerated natriuresis was accompanied by hypercalcinuria and an enhanced rise in plasma ANP in hypertensives. Basal levels of plasma PTH were elevated in hypertensives. The calcium deficiency may be attributable to a close relationship between urinary sodium and calcium. and causally related to the disturbance of sodium and volume homeostasis in hypertension. which results in exaggerated natriuresis.
Importance of the renin-angiotensin system in sodium regulation in essential hypertension, To elucidate the effect of natriuretic and antinatriuretic factors on the excretion of an intravenous sodium load. we observed the natriuretic responses of 12 patients with essential hypertension (EHT) and 7 age- and sex-matched normotensive (NT) subjects following the intravenous administration of 1500 mL of normal saline over a 3 h period. After saline infusion. both groups showed increases in urinary sodium excretion (UNaV). The increases in glomerular filtration rate (GFR). atrial natriuretic peptide (ANP) and urinary dopamine excretion (UDAV) and the suppression of plasma renin activity (PRA) were similar in both groups. However. no significant change in blood pressure (BP) was seen in either group. Since significant negative linear correlations between the basal level of PRA and percent change in UNaV or GFR were seen only in EHT. we observed the influence of suppressing the renin-angiotensin system with a converting enzyme inhibitor. After a 7 day treatment with enalapril. GFR and UNaV in EHT after saline infusion were comparable to data obtained in the absence of enalapril. despite a reduction in preexpansion BP. Furthermore. a significant positive correlation between the basal BP and the percent increase in UNaV was seen among EHT after enalapril treatment. These results suggest that the state of the renin-angiotensin system is important in renal sodium excretion in EHT.
Changes in blood pressure, plasma triglyceride and aldosterone concentration, and red cell cation concentration in patients with hyperinsulinemia, Blood pressure. plasma concentration of triglyceride. aldosterone. renin activity (PRA). and atrial naturietic peptide (ANP). and red blood cell. urine. and plasma sodium and potassium concentration were determined in 24 healthy individuals divided into two groups defined as being either hyperinsulinemic or normoinsulinemic. The results demonstrated that the hyperinsulinemic group had significantly higher values for both systolic (P less than .01) and diastolic (P less than .05) blood pressure. In addition. plasma concentrations of triglyceride (P less than .02). aldosterone (P less than .05) and potassium (P less than .05) were higher in hyperinsulinemic individuals as compared to those who were normoinsulinemic. Furthermore. red cell potassium was lower (P less than .01) and red cell sodium higher (P less than .01) in the hyperinsulinemic group. Finally. the magnitude of hyperinsulinemia correlated directly with systolic (r = 0.50. P less than .01) and diastolic (r = 0.44. P less than .05) blood pressure. concentration of plasma triglyceride (r = 0.55. P less than .01) and aldosterone (r = 0.46. p less than .05). and erythrocyte sodium concentration (r = 0.57. p less than .01). In contrast. plasma insulin response was negatively correlated with erythrocyte potassium concentration (r = 0.40. P less than 0.05). These observations provide further support for the view that hyperinsulinemia. presumably secondary to resistance to insulin-stimulated glucose uptake. is associated with a cluster of variables that may play important roles in the etiology and clinical course of hypertension.
Calcium antagonists in experimental atherosclerosis. Use-dependence of isradipine: a potential explanation for enhanced action in atherosclerotic animals and tissue selectivity, In the context of atherosclerosis. calcium antagonists should be evaluated from two points of view: their hemodynamic action on the atherosclerotic cardiovascular system. and their preventive action on atherosclerosis. Contraction of atherosclerotic vessels in response to vasoconstrictors. especially serotonin and acetylcholine. is enhanced mainly because of endothelial dysfunction. Due to their antivasoconstrictor effect. calcium antagonists partly compensate for this endothelial dysfunction. Agents which show a pronounced 'use-dependence'. such as isradipine. are of particular interest as their action increases with the intensity of contraction. Therefore. their action is most prominent where it is most needed. Nevertheless. experiments in atherosclerotic animals indicate that the dose has to be chosen more cautiously than for young animals. as the dose-response curve for several effects is bell-shaped. Calcium antagonists also interfere with the process of atherosclerosis. In cholesterol-fed rabbits. lesion development is reduced. and regression after reverting to a normal diet is modestly enhanced. Calcium antagonists do not lower blood lipid levels. However. they attenuate proliferative lesions following endothelial damage due to a balloon catheter or electrical stimulation. The mechanism of these effects is still not clear. Blockade of the potential-sensitive L-type calcium channel is probably the important mechanism. Many types of cells (macrophages. other leukocytes and platelets. smooth muscle cells. connective tissue cells. endothelium. etc.) are involved in the genesis of atherosclerotic plaques. but it is not known which of these are the important targets of calcium antagonists. Calcium antagonists are most effective when administered at the onset of atherosclerosis. as they probably inhibit events occurring during the initiation of the atherosclerotic process.
MIDAS, the Multicenter Isradipine/Diuretic Atherosclerosis Study. Design features and baseline data, The Multicenter Isradipine/Diuretic Atherosclerosis Study (MIDAS) is a randomized. double-blind. active-control trial to compare the effectiveness of two treatment regimens for the control of hypertension in reducing the rate of progression of early extracranial carotid artery atherosclerosis in hypertensive patients. The two double-blind treatment regimens are 2.5 or 5 mg isradipine twice daily and 12.5 mg or 25 mg hydrochlorothiazide twice daily. Patients whose blood pressure is not controlled with either of these regimens will receive. in addition to the highest tolerated dose of the blinded drug. 2.5 to 10 mg open-label enalapril twice daily. The MIDAS study has enrolled 883 patients to treatment with either isradipine or hydrochlorothiazide. Inclusion criteria included men and women over the age of 40 years. the presence of an atherosclerotic lesion in the extracranial carotid artery demonstrated on B-mode ultrasound scanning (maximum thickness between 1.3 and 3.5 mm). an average sitting diastolic blood pressure between 90 and 115 mm Hg. and low-density lipoprotein levels between 130 and 189 mg/dL. An assessment of each patient's blood pressure and any side effects is made every three months; a B-mode ultrasound examination of the carotid arteries was performed at baseline and every six months thereafter; an electrocardiogram was carried out at baseline and once a year thereafter; and a brief quality-of-life assessment was made at baseline and every year thereafter.
Multicenter evaluation of efficacy, tolerability and safety of a new first-line antihypertensive drug, isradipine, in a Latin-American population, Isradipine. a new antihypertensive dihydropyridine calcium antagonist. was evaluated for its efficacy. tolerability. and safety in 91 ambulatory patients who had mild-to-moderate hypertension. The design of the present study included a two-week wash-out period after confirmation of disease. followed by 12 weeks of active treatment with 2.5 mg isradipine twice daily. Patients were switched from other antihypertensive drugs. mainly diuretics and beta-blockers. The dose of isradipine remained virtually unchanged throughout the study and resulted in a mean decrease of 22 mm Hg in systolic blood pressure (SBP) (P less than .00001) and 19 mm Hg in diastolic blood pressure (DBP) (P less than .00001). Heart rate was unchanged (difference of -1 beats/min). as was the mean body weight of the study patients. Isradipine was generally well tolerated. Side effects were few and. when present. tended to diminish and eventually disappear during the treatment period. All of the clinical laboratory parameters tested and electrocardiograph intervals remained unchanged. In conclusion. these results indicate that isradipine is a novel drug which is highly effective and well tolerated in the treatment of mild to moderate hypertension in this group of patients.
Isradipine twice daily lowers blood pressure over 24 H, The objective of this study was to compare the effects of isradipine and placebo on blood pressure (BP) at the end of the dosing interval ('trough'). Following a three-week placebo period. 187 patients who had previously shown a response to treatment with isradipine (based on office BP measurements) were randomized to double-blind treatment with 2.5 mg isradipine twice daily or placebo for six weeks. Four of these patients withdrew from the study during the double-blind phase because of adverse events (one taking isradipine and three taking placebo). Blood pressure during the double-blind study was always measured 12 h after drug administration (trough values). The rate of normalization [defined as diastolic BP (DBP) less than or equal to 90 mm Hg] was 52/96 (54%) in the isradipine-treated group compared with 30/87 (33%) in the placebo group. A further 12/96 (12%) patients taking isradipine showed a fall in DBP of greater than or equal to 10 mm Hg. although their DBP was still not less than 90 mm Hg. compared with 5/87 (6%) patients receiving placebo. This difference was statistically significant (P = .003). Thus. isradipine in a dose of 2.5 mg twice daily lowers blood pressure over 24 h.
Isradipine: overall clinical experience in hypertension in the United States, Isradipine is a new dihydropyridine calcium antagonist shown to be efficacious. safe. and well tolerated in the treatment of hypertension. regardless of patient age or race. There has been no evidence of negative inotropism. atrioventricular conduction delay. nor clinically significant changes in laboratory parameters associated with isradipine treatment. A total of 934 patients have been treated with isradipine in double-blind hypertension trials (involving 297 patients treated with placebo and 414 treated with active controls. such as hydrochlorothiazide and enalapril). Both the mean changes from baseline in diastolic and systolic blood pressures and the percentage of patients responding to treatment (blood pressure decrease of at least 10 mm Hg) were greater with isradipine than with placebo or active controls. Blood pressure response increases with increases in isradipine dose up to 10 to 15 mg daily; higher doses do not. on average. result in greater blood pressure reduction. The incidence of adverse reactions with isradipine is similar to that for active controls and slightly more than for placebo. There were fewer discontinuations with isradipine and. in addition. a decrease in the incidence of new adverse reactions with increasing duration of treatment. down to 1% at 24 months.
Isradipine in the treatment of hypertension. Some additional effects observed during a one-year study, After a placebo run-in phase of four weeks' duration. 1.25 mg or 2.5 mg isradipine twice daily orally was administered for one year to 23 patients who had been diagnosed as hypertensive. Good control of blood pressure was recorded in the majority of patients until the third month of treatment. After five months. it was necessary to add a beta-blocker to the treatment regimens of some of the patients in order to maintain the target blood pressure of 140/90 mm Hg. Patients were exercise-tested using bicycle ergometry. After three months. diastolic blood pressure was significantly lower during exercise when comparing the treatment values with those taken at the end of the placebo run-in (baseline values). Values for systolic blood pressure did not differ between treatment and baseline. These results may be explained by the decrease in peripheral vascular resistance produced by isradipine. After one year. the results were modified by the administration of the beta-blocker bopindolol (Sandonorm. Sandoz Pharma Ltd.. Basle. Switzerland). Total cholesterol. high-density lipoprotein cholesterol. and apolipoprotein B levels did not change during treatment. Triglycerides were lower after three months. but slightly higher after one year. with an average value lying within the normal range. The influence of isradipine on plasma renin activity (PRA) and aldosterone levels was followed by measuring values at rest and during exercise. It was found that PRA was higher during the first three months. then inversely inhibited to lower levels. Aldosterone levels were also increased after three months. but without a subsequent decrease. The results are compared with those obtained with diltiazem in a similar treatment regimen.
Antihypertensive effect of isradipine on blood pressure at rest and during exercise, After three months of treatment with isradipine. 20 patients with mild hypertension had reduced their resting blood pressure (BP) from 157/103 to 132/85 mm Hg and their BP during isometric exercise from 192/124 to 166/105 mm Hg. The isradipine dose necessary to normalize BP (both at rest and post-exercise) was 1.25 mg twice daily (2 x 1/2 tablet) in 50% of patients and 2.5 mg twice daily (2 x 1 tablet) in 25%. In the remaining 25% of patients. isradipine was combined with 1 mg/day bopindolol. There were virtually no accompanying side effects; in particular. reflex tachycardia was negligible or absent. It is concluded that isradipine is a reliable antihypertensive treatment in mild-to-moderate hypertension.
Time course of the blood pressure response to oral isradipine in uncomplicated mild-to-moderate essential hypertension, Forty-five patients with supine diastolic blood pressures (DBPs) above 95 mm Hg at the end of a four-week placebo run-in period were randomized to receive either 1.25 mg. 2.5 mg. or 5 mg isradipine twice daily as monotherapy for 12 weeks. Blood pressures (BP) were measured every 14 days. always by the same observer and using standard techniques. The Montevideo Mathematical Model was used to determine the time course of the response to treatment in each dosage group. Of the 33 patients who completed the study. four of the 12 patients receiving 1.25 mg isradipine twice daily had their BP controlled by weeks 10 or 12 (supine DBP less than or equal to 90 mm Hg). seven of 11 by 2.5 mg twice daily. and five of 10 by 5 mg twice daily. Mean DBPs for each dosage group were significantly reduced by week 12 (P less than .015 in all groups). The Montevideo Model allows estimation of the time after onset of treatment by which BP is reduced by a given amount. This model indicated that. with 2.5 mg isradipine twice daily. a fall in mean arterial pressure of 10 mm Hg is to be expected within three weeks of initiating drug administration.
Antihypertensive effects of isradipine and captopril as monotherapy or in combination, The antihypertensive effects of isradipine and captopril were studied in 140 patients (70 men) with mild-to-moderate hypertension. aged 26 to 74 years. in a double-blind. randomized. between-patient comparative trial. Initial treatment started with 1.25 mg isradipine twice daily or 12.5 mg captopril twice daily. If normotension was not achieved after four weeks. doses were increased to 2.5 mg twice daily or 25 mg twice daily. respectively. If the maximum dose as monotherapy did not result in normotension. captopril (12.5 mg or. if necessary. 25 mg twice daily) was added to regimens of the isradipine-treated patients or isradipine (1.25 mg or. if necessary. 2.5 mg twice daily) was given in addition to the captopril-treated patients. After 24 weeks of active treatment. systolic blood pressure was significantly reduced (P less than .001) with isradipine (from 168 +/- 18 to 144 +/- 14 mm Hg) and with captopril (from 168 +/- 20 to 143 +/- 10 mm Hg). Diastolic blood pressure also fell significantly (P less than .001) in both groups (isradipine: from 105 +/- 5 to 84 +/- 5 mm Hg; captopril; from 105 +/- 4 to 85 +/- 4 mm Hg). With isradipine as monotherapy. diastolic blood pressure was normalized in 49% of patients compared with 56% with captopril as monotherapy (P = NS). Combining both drugs resulted in an increased rate of normalization (to 87%). The results indicate that combined treatment with a calcium antagonist and an angiotensin-converting enzyme inhibitor is effective in lowering blood pressure and is well tolerated during long-term therapy.
A multicenter comparison of the safety and efficacy of isradipine and enalapril in the treatment of hypertension, This multicenter trial compared the efficacy and safety of isradipine and enalapril in 160 patients with essential hypertension. Patients received isradipine or enalapril for 10 weeks after a placebo wash-out period of three to five weeks. Dosage was titrated for six weeks on the basis of blood pressure (BP) response and was then maintained for the remainder of the study. Isradipine reduced systolic and diastolic BP by 12 and 9 mm Hg. respectively. and enalapril by 10 and 7 mm Hg. respectively (between-treatment difference P less than .05 for diastolic BP). Overall. isradipine resulted in a higher responder rate. particularly among patients who had higher entry BPs. Fifteen enalapril-treated patients and four isradipine-treated patients discontinued treatment (four taking enalapril and none taking isradipine withdrew because of lack of efficacy). The most frequently reported adverse reactions were headache. dizziness. and edema in the isradipine group. and cough. headache. and chest pain in the enalapril group. Both drugs produced significant reductions in BP. but. in this study isradipine was more effective. The drugs were similarly well tolerated.
Effect of isradipine on 24-h blood pressure profile demonstrated by repeated monitoring, The antihypertensive effect of isradipine was assessed by repeated 24-h ambulatory blood pressure monitoring. Using an SPS device (Sandoz Pharma. Basel. Switzerland). monitoring was carried out in 10 male patients with mild essential hypertension (1) after a placebo period. (2) after six months. and (3) after 12 to 13 months of treatment with isradipine (average dose 2.5 mg twice daily). Mean 24-h blood pressure decreased significantly after both periods 2 and 3 (from 148/93 mm Hg to 137/87 and 130/85 mm Hg. respectively). The total number of hypertensive systolic and diastolic blood pressure values also decreased. The normal circadian blood pressure curve was preserved. showing the reduction throughout the 24-h period. and the early morning rise in blood pressure was markedly blunted. These results indicate that isradipine has a favorable effect on the 24-h blood pressure profile that persisted throughout six and 12 months of antihypertensive therapy.
Twenty-four-hour blood pressure control with isradipine in mild essential hypertension, The hypotensive effect of isradipine was assessed in 26 male patients. aged 40 to 64 years. with hypertension. After withdrawal of previous antihypertensive treatment and a four-week placebo period. patients were randomized into a double-blind active-treatment period of eight weeks to receive either placebo or 1.25 to 2.5 mg isradipine twice daily. Twenty-four-hour ambulatory blood pressure was measured by Accutracker (Suntech. Oxford. England) after the placebo period and at the end of the active-treatment period. In the isradipine group n = 13). both systolic and diastolic blood pressure and number of blood pressure spikes decreased significantly (P less than .0001). whereas there was a significant increase of these variables in the placebo control group (n = 13). The results of this study indicate that. in these subjects. blood pressure control was achieved throughout the 24-h period by monotherapy with isradipine.
Low-dose isradipine once daily effectively controls 24-h blood pressure in essential hypertension, In one study of 10 patients with mild-to-moderate hypertension. equivalent total daily doses (13 +/- 2 mg) of isradipine given twice daily and a modified-release formulation of isradipine (isradipine MR) given once daily were found to control adequately 24 h ambulatory blood pressure compared with placebo (P less than .001 for each v placebo). In another study of 22 patients with essential hypertension. 5 and 10 mg isradipine MR once daily has been shown to reduce the average 24 h blood pressure by 11 +/- 1/6 +/- 1 mm Hg (P less than .001) and 13 +/- 2/9 +/- 1 mm Hg (P less than .001). respectively. compared with placebo. There was no loss of efficacy with isradipine MR during the 24 h observation period with either dose. In conclusion. low-dose isradipine MR once daily is an effective first-line treatment in essential hypertension.
Decreased fibrinolytic activity and increased platelet function in hypertension. Possible influence of calcium antagonism, Twelve patients with mild hypertension were compared. after 14 days of placebo. with an age- and gender-matched group of 12 healthy volunteers for platelet aggregability and fibrinolytic activity. Following this. 10 of the 12 hypertensives were treated with the calcium antagonist isradipine for 12 months. Blood was drawn for determinations of platelet aggregation and fibrinolytic activity after two weeks and 12 months of treatment. Platelet aggregation tended to increase in the hypertensives compared with controls. indicated by a lowering of the adenosine diphosphate (ADP) threshold value for irreversible aggregation. Tissue-plasminogen activator (t-PA) activity was significantly decreased in hypertensives compared to controls (P less than .05). During therapy. platelet aggregation decreased and t-PA activity increased (P less than .05). The present data suggest that fibrinolytic activity is decreased and platelet aggregation increased in mild hypertension. Besides the blood pressure-lowering effect. isradipine may protect against thromboembolic diseases by modifying platelet function and fibrinolytic activity.
Effect of isradipine on factors affecting blood viscosity, The objective of the study was to investigate the effect of isradipine on red blood cell filtrability in 20 men with mild-to-moderate hypertension. In this prospective. double-blind study. parallel groups of hypertensive male patients were randomized to receive either isradipine (n = 11) or placebo (n = 9). An additional group of nine normotensive age-matched volunteers served as controls. Tests were performed before and after patients were treated with either isradipine or placebo. The hypertensive patients differed from the normotensive controls in having a higher level of fibrinogen (P less than .04). a higher hematocrit (P less than .001). a higher filtration rate (P less than .05; impaired red blood cell deformability). and a higher mean corpuscular volume (MCV; P less than .005). Treatment with isradipine lowered blood pressure and improved red blood cell filterability (P less than .05) compared with placebo.
Platelet-activating effect of low-density lipoprotein and its reversal by isradipine, The effect of the calcium antagonist isradipine on platelet aggregation (induced ex vivo by serotonin and low-density lipoprotein [LDL]) was studied in 17 nonsmoking patients with essential hypertension. Platelet aggregation was measured after a four-week placebo period. and after four and 12 weeks of treatment with isradipine. Both the serotonin-induced and the LDL plus serotonin-induced platelet aggregation were significantly decreased after four weeks of isradipine treatment compared with placebo. The amplifying effect of LDL on the serotonin-induced aggregation was significant both after placebo and after active treatment with isradipine. A further decrease in platelet aggregation induced by LDL plus serotonin was observed after 12 weeks of isradipine treatment so that no amplification of serotonin-induced aggregation by LDL could be detected. In conclusion. it appears that treatment with isradipine restores the impaired platelet response to serotonin and LDL in hypertensive patients. The inhibition of this response may represent a cellular mechanism of thrombovascular protection.
Effects of isradipine on platelet function in hypertension at rest and during exercise, The effects of eight weeks of treatment with isradipine (1.25 mg twice daily for four weeks. followed by 2.5 mg twice daily for four weeks) on ex vivo platelet function were investigated in ten male patients with hypertension. Systolic and diastolic blood pressures. platelet aggregation in response to adenosine diphosphate (ADP). serum thromboxane B2. and beta-thromboglobulin levels were significantly decreased (P less than .05) at rest before exercise ergometry. during exercise. and at rest after exercise. The platelet count and plasma levels of 6-oxo-prostaglandin F1 alpha (PGF1 alpha) were not affected by isradipine. It is concluded that treatment of hypertension with a compound that lowers blood pressure and inhibits platelet activation may be of clinical benefit when routinely applied in hypertensive patients.
Beneficial effects of the calcium antagonist isradipine on apolipoproteins in hypertensive patients, The objective of the study was to assess the effects of the calcium antagonist isradipine on plasma lipids. lipoproteins. and apolipoproteins in patients with essential hypertension. After a four-week placebo wash-out period. 73 patients (41 men. 32 women) were studied in a double-blind. randomized. crossover study comparing sustained-release isradipine (isradipine SR) with the standard isradipine formulation. Nineteen patients received 5 mg/day and 54 patients 10 mg/day. Lipids were evaluated at the end of the placebo period and after 12 weeks of treatment with isradipine. In both treatment groups. lipid and lipoproteins were not modified. However. apolipoprotein A-I levels increased significantly (P less than .001) and the ratio of apolipoprotein B to apolipoprotein A-I concentration decreased significantly (P less than .01) irrespective of gender. These data show that the levels of plasma apolipoprotein A-I. a strong predictor of coronary heart disease. are favorably affected by isradipine of either formulation. The mechanisms of this effect remain to be elucidated.
Negative inotropic activity of the calcium antagonists isradipine, nifedipine, diltiazem, and verapamil in diseased human myocardium, The use of calcium antagonists in the treatment of cardiac failure is limited by the negative inotropic effects they exert. The comparative inotropic activity of four calcium antagonists was therefore investigated. using electrically driven human papillary muscle strips and human atrial trabeculae. These inotropic effects were studied with cumulative concentration-response curves. The four calcium antagonists included in this study were all found to significantly (P less than or equal to .05) diminish the force of contraction above 0.01 mumol/L. but with different potencies. On the basis of the relationship between therapeutic vasoactive plasma concentrations and the negative inotropic effective concentrations in our system in vitro. the ranking order of potential negative inotropism in the treatment of cardiac failure with calcium antagonists was verapamil greater than nifedipine greater than diltiazem greater than isradipine. Thus. to minimize cardiodepressant risk. the use of calcium antagonists with weak negative inotropic effects at relevant concentrations should be preferred. especially in the case of patients with compromised cardiac function.
Regression of left ventricular hypertrophy in the short-term treatment of hypertension with isradipine, This was a study of the effectiveness of isradipine. a calcium antagonist of the dihydropyridine group. in reversing left ventricular hypertrophy (LVH) in patients with mild-to-moderate hypertension. Mean arterial pressure was effectively reduced at 90 days of treatment (from 129.5 +/- 2.0 to 111.5 +/- 2.8 mm Hg; P less than .001). The electrocardiographic Romhilt-Estes score for LVH showed early reduction at 45 days of treatment (from 7.1 +/- 0.6 to 5.1 +/- 0.4 points; P less than .001). and further diminutions were observed at 90 days of treatment (3.8 +/- 0.4 points; P less than .01). The echocardiographically determined left ventricular mass indices confirmed these findings (from 175.0 +/- 8.9 to 141.7 +/- 5.5 and to 124.8 +/- 4.2 g/m2; P less than .001) for 45 and 90 days. respectively. The results indicate that isradipine is effective in reducing left ventricular mass and that these reductions are observed early in the course of treatment.
Acute antihypertensive and renal effects of isradipine in hypertensive patients with normal and reduced renal function, The renal effects of a single oral dose of placebo v a new dihydropyridine calcium antagonist. isradipine. were investigated in 12 patients with mild-to-moderate essential hypertension. Six patients (group A) had normal creatinine concentrations greater than 1.6 mg/dL. Patients maintained a constant daily intake of approximately 120 mmol of sodium and 50 mmol of potassium. Measurements were taken at 30. 60. and 90 min after drug administration. Results indicated that isradipine at a dose of 5 mg once daily produced significant antihypertensive and renal responses. In conclusion. there is therapeutic benefit with isradipine independent of the status of renal function.
Effects of isradipine on peripheral hemodynamic reflex responses in mild-to-moderate essential hypertension, In a randomized double-blind. placebo-controlled. crossover study of isradipine (5 mg twice daily). effects on peripheral hemodynamic reflex responses were studied in nine patients (mean age 48 years) at baseline and after six weeks of active treatment. Assessments included vital signs. resting blood flow in the calf and finger (using an electrocardiograph-triggered venous occlusion plethysmograph). reflex responses during isometric exercise and cold pressor resistance. and venous capacitance in the forearm and calf. Isradipine lowered systolic and diastolic blood pressure as well as mean arterial pressure in patients with mild-to-moderate essential hypertension without reflex tachycardia or venoconstriction. All of the reflex responses studied were attenuated. It is concluded that vasodilatation of the peripheral circulation induced by isradipine contributes partially to the blood pressure-lowering effect.
Effect of isradipine and atenolol on lung function in patients with mild essential hypertension, Twenty-six hypertensive patients took part in an open. randomized. parallel-group pilot study of the effects of a nine-week treatment period with the calcium antagonist isradipine and the beta 1-blocking agent atenolol. The mean dosage in the isradipine group was 7.9 +/- 3.5 mg/day. and 69.2 +/- 43.5 mg/day in the atenolol group. A significant reduction of the arterial blood pressure was seen with both treatment regimens. Lung volumes and airways resistance remained unchanged. but. in the atenolol-treated group. the linear relationship between alveolar pressure and airways resistance at the lower lung volumes during forced expiration at 25% of forced vital capacity was affected by a shift to higher airways resistance. This change can be interpreted as an early sign of altered air-flow behavior in the small airways in subjects susceptible to beta-adrenoceptor blockade. The calcium antagonist isradipine did not produce changes in any parameters of lung function in this group of patients.
Management of perioperative hypertension using intravenous isradipine, The antihypertensive action of acute intravenous isradipine was investigated during fentanyl/pancuronium/nitrous oxide anesthesia for noncardiac surgery. An intravenous (iv) infusion of 0.5 mg isradipine (n = 10) or placebo (n = 11) was administered double-blind over 5 min if mean arterial pressure (MAP) was greater than 110 mm Hg. The number of patients with a favorable blood pressure reduction (delta MAP greater than or equal to 10% with MAP less than or equal to 110 mm Hg) was 80% with isradipine and 20% with placebo (P less than .05). and the mean MAP reduction from baseline was 26 +/- 12 and 2 +/- 16 mm Hg. respectively (P less than .001). Due to reflex activation of the sympathetic nervous system. the heart rate increased by 14 +/- 12 beats/min with acute iv isradipine. The antihypertensive effect was sustained for 45 min. Isradipine was also well tolerated. It is concluded that intravenous isradipine is an effective antihypertensive agent for the treatment of perioperative hypertension during noncardiac surgery.
Isradipine, a calcium antagonist, in the control of hypertension following coronary artery-bypass surgery, Arterial hypertension is common after coronary artery-bypass grafting (CABG) surgery and may lead to postoperative complications. Therefore. the effects of the calcium antagonist isradipine were studied in 10 postoperative CABG patients who had a mean arterial pressure (MAP) above 100 mm Hg. Isradipine. given as a continuous infusion. reduced MAP to the range of 85 +/- 5 mm Hg in all patients within 15 min. Systemic vascular resistance fell and cardiac output increased in all patients. A slight increase in heart rate was seen in some. but not all. patients. There were no adverse effects. In conclusion. isradipine appears to be a useful agent in the treatment of postoperative hypertension following CABG surgery.
The place of isradipine in the treatment of hypertension, Isradipine is a new dihydropyridine calcium antagonist with a high degree of selectivity for the coronary. cerebral. and skeletal muscle vasculature. The drug has minimal depressant activity on sinoatrial node automaticity and negligible negative chronotropic. dromotropic. and inotropic actions. Isradipine reduces blood pressure and systemic vascular resistance without changes in cardiac output and stroke volume. Renal blood flow is maintained while renal vascular resistance is reduced; this is accompanied by both short- and long-term diuretic and natriuretic effects. Doses of 1.25 to 5 mg twice daily lowers blood pressure effectively over 24 h. In open as well as placebo-controlled trials. 2.5 to 10 mg isradipine twice daily was safe and well tolerated. and reduced systolic and diastolic values in up to 85% of patients with mild-to-moderate hypertension. Efficacy is similar to those of nifedipine and nitrendipine. and potentially superior to those of propranolol. atenolol. prazosin. hydrochlorothiazide. and diltiazem. The drug can be safely combined with beta-blockers. angiotensin-converting enzyme (ACE) inhibitors. and diuretics. Adverse effects are dose-dependent and secondary to arterial vasodilatation. such as headache. flushing. ankle edema. dizziness. palpitations. and tachycardia. At the recommended dose of 2.5 mg twice daily. the total incidence of side effects does not differ from that with placebo. The antiatherosclerotic. antitrophic. and cerebroprotective effects seen in experimental animal models are promising for the drug in the treatment of human hypertension. Isradipine may not only reduce blood pressure. but may also reduce the risk for the consequences of this peril. namely. cerebral stroke and myocardial infarction.
Fetal liver dysfunction in Rh alloimmunization, The liver enzymes. aspartate transaminase (AST). alanine transaminase (ALT). gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP). were measured in the blood of 25 fetuses with severe Rh alloimmunization at the time of their first. second and third intravascular transfusions and in 17 comparison fetuses. In the comparison group. GGT increased with advancing gestation (r = 0.7; P = 0.002). whereas ALP. AST and ALT did not correlate with gestational age. Rh hydropic fetuses (n = 8) had higher blood ALT levels than the comparison fetuses (P = 0.008) had significantly increased transaminases when compared with non hydropic fetuses (n = 17). In hydropic fetuses. AST correlated with the nucleated red cell count before transfusion (r = 0.94; P = less than 0.0001). Fetal transaminases were no longer increased in hydropic fetuses by the second (AST) or third (ALT) transfusion. In both hydropic and non hydropic fetuses. GGT increased by the second transfusion (median percentage change +85%. range -83% to +596%; P = 0.003). The rise in fetal GGT was transitory and correlated with the increase in fetal haematocrit at the first transfusion (r = 0.58; P = 0.006). This study reports liver dysfunction secondary to extramedullary erythropoiesis in Rh alloimmunization and implicates portal hypertension for the rise in fetal GGT with transfusion.
Management of women referred to early pregnancy assessment unit: care and cost effectiveness, OBJECTIVE--To assess the efficiency of an early pregnancy assessment unit in the care of women with bleeding or pain in early pregnancy. DESIGN--Analysis of women attending in the first year of the unit's operation and in the six months immediately before its introduction. SETTING--Early pregnancy assessment unit in a district general hospital serving a population of 310.000. PATIENTS--1141 women referred with bleeding or pain in early pregnancy. MAIN OUTCOME MEASURES--Length of stay in hospital required for diagnosis and treatment. RESULTS--Before the unit was established the mean admission time was one and a half (range half to three) days for women who required no treatment and three (one and a half to five) days in women requiring evacuation of uterus. These times were reduced to two hours as an outpatient and one day respectively for most women after the unit was established. Between 318 and 505 women were estimated to have been saved from unnecessary admission. and 233 had their stay reduced; the associated saving was between pounds 95.000 and pounds 120.000 in one year. CONCLUSIONS--The early pregnancy assessment unit improved the quality of care and also produced considerable savings in financial and staff resources.
Concomitant pelvic irradiation, 5-fluorouracil and mitomycin C in the treatment of advanced cervical carcinoma, This was a Phase II study of 24 late (FIGO) Stage IIb and 39 Stage III patients. External beam radiotherapy was given daily. five days a week. using 15 x 15 cm parallel opposed pelvic fields. The first 20 patients had 45.00 Gy mid-plane dose in 20 fractions. Days 1-28. the last 43 patients had 50.40 Gy in 28 fractions. Days 1-43. This was followed by an intracavitary boost of 17.00 Gy to Point A in two fractions over seven days. The first seven patients had concomitant 5-fluorouracil (5FU) 1 g/m2/day (maximum 1.5 g/day) Days 2-5. 30-33 and 57-60. with mitomycin C 10 mg/m2 (maximum 15 mg) Days 2 and 57. Two patients had WHO Grade 4 cytopenia. and only two were able to have full dose intensity. The 5FU dose was reduced to 0.8 g/m2/day. for Days 2-5 and 30-33; mitomycin C was given on Day 2 only. Treatment morbidity with the reduced chemotherapy intensity was comparable with that of radiotherapy alone. Median follow-up was 16 months (range 6-44). Median survival was 35 months. The results were compared with historical controls treated using the same radiation method alone. Two-year survival for late Stage IIb patients was 67% with the combination and 72% with radiotherapy alone; for Stage III. 67% and 49% respectively. Two-year pelvic control for late Stage IIb was 87% (combination) and 84% (radiotherapy alone) and for Stage III. 61% and 55% respectively. In contrast to reports from other centres. these results do not show an overall significant improvement on radiotherapy alone. A Phase III study may not be practicable.
A randomized comparison of intravenous heparin with oral aspirin and dipyridamole 24 hours after recombinant tissue-type plasminogen activator for acute myocardial infarction. National Heart Foundation of Australia Coronary Thrombolysis Group, BACKGROUND. This study addressed the need for heparin administration to be continued for more than 24 hours after coronary thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). METHODS AND RESULTS. A total of 241 patients with acute myocardial infarction were treated with 100 mg rt-PA and a bolus of 5.000 units i.v. heparin followed by 1.000 units/hr i.v. heparin for 24 hours. At 24 hours. 202 patients were randomized to continue intravenous heparin therapy (n = 99) in full dosage or to discontinue heparin therapy and begin an oral antiplatelet regimen of aspirin (300 mg/day) and dipyridamole (300 mg/day) (n = 103). On prospective recording. there were no differences in the pattern of chest pain. reinfarction. or bleeding complications. Coronary angiography on cardiac catheterization at 7-10 days showed no differences in patency of the infarct-related artery. The proportion of patients with total occlusion (TIMI grade 0-1) of the infarct-related artery was 18.9% in the heparin group and 19.8% in the aspirin and dipyridamole group. In the patients with an incompletely occluded infarct-related artery. the lumen was reduced by 69 +/- 2% of normal in the heparin group and 67 +/- 2% in the aspirin and dipyridamole group. Left ventricular function assessed on cardiac catheterization and radionuclide study at day 2 and at 1 month showed no differences between the two groups. Left ventricular ejection fraction on radionuclide ventriculography at 1 month was 52.4 +/- 1.2% in the heparin group and 51.9 +/- 1.2% in the aspirin and dipyridamole group. CONCLUSIONS. We conclude that heparin therapy can be discontinued 24 hours after rt-PA therapy and replaced with an oral antiplatelet regimen without any adverse effects on chest pain. reinfarction. coronary patency. or left ventricular function.
Evidence for reduced fibrinolytic activity in unstable angina at rest. Clinical, biochemical, and angiographic correlates, BACKGROUND. The goal of this study was to evaluate the role of the fibrinolytic system in patients with unstable angina at rest associated with transient electrocardiographic changes. METHODS AND RESULTS. Tissue plasminogen activator activity in plasma was comparable among patients with unstable angina (n = 17). patients with stable exertional angina (n = 10). and control patients with normal coronary arteriograms (n = 8). In contrast. plasminogen activator inhibitor-1 (PAI-1) activity in plasma was elevated in the unstable angina group (21.67 +/- 9.52 AU/ml) as compared with either the stable angina group (12.01 +/- 7.06 AU/ml. p less than 0.02) or the controls (12.49 +/- 8.54 AU/ml. p less than 0.02). Coronary angiography performed within 24 hours after the last anginal episode showed a similar extent of coronary artery disease in the unstable and stable angina groups. However. intracoronary thrombi were observed in eight patients in the unstable angina group while no thrombus was noted in the stable angina group (chi 2 = 7.22. p less than 0.01). CONCLUSIONS. We conclude that patients with unstable angina at rest have a reduced fibrinolytic activity and an increased incidence of intracoronary thrombi. It is postulated that elevated PAI-1 activity in the presence of coronary arterial wall injury may be an important factor leading to the development of acute coronary syndromes.
Response of atrial natriuretic factor to acute and chronic increases of atrial pressures in experimental heart failure in dogs. Role of changes in heart rate, atrial dimension, and cardiac tissue concentration, BACKGROUND. This study evaluated the role of changes in heart rate. atrial pressure. volume. and cardiac tissue atrial natriuretic factor (ANF) concentration in the modulation of plasma ANF concentration in a model of pacing-induced heart failure. METHODS AND RESULTS. The effects of acute right ventricular pacing (250 beats/min). acute volume expansion (35 ml/min). and volume expansion after 1 week of right ventricular pacing on plasma ANF concentration were compared in eight dogs (group 1). As shown during right ventricular pacing previously. volume expansion produced significant increases in cardiac filling pressures and left atrial volume. Right ventricular pacing and volume expansion produced similar increments in plasma ANF concentration: from 32 +/- 12 to 168 +/- 153 pg/ml (p less than 0.05) and from 32 +/- 9 to 137 +/- 113 pg/ml (p less than 0.05). respectively. When pacing was initiated after volume expansion. plasma ANF concentration increased further to 462 +/- 295 pg/ml (p less than 0.05) despite little change in filling pressures and left atrial volume. With repeated volume expansion after 1 week of pacing. there were no significant further increases in left atrial volume and plasma ANF concentrations (from 332 +/- 121 to 407 +/- 113 pg/ml) despite significant increases in filling pressures. Atrial and ventricular tissue samples were also obtained from 21 dogs paced to severe heart failure (group 2) and from 14 normal dogs (controls). In all groups. atrial ANF was higher than ventricular ANF concentration. At 1 week (group 1). left atrial appendage ANF concentration (6.2 +/- 2.5 versus 16.1 +/- 10.3 ng/mg) was reduced. whereas left ventricular free wall ANF concentration (0.62 +/- 0.31 versus 0.24 +/- 0.16 pg/mg) was increased compared with that of controls (both p less than 0.001). At severe heart failure (group 2). atrial ANF remained low. whereas ventricular ANF concentration was similar to that of the controls. CONCLUSIONS. These data indicate that in pacing-induced heart failure. changes in heart rate. atrial pressure. and volume all contribute to the increased plasma ANF concentration. However. by 1 week (early heart failure). ANF release is attenuated. perhaps because of the inability of the atria to be stretched further and because of reduced atrial ANF concentration. In addition. the ventricle may be an additional source of ANF.
Inhibition of neutral endopeptidase (EC 3.4.24.11) leads to an atrial natriuretic factor-mediated natriuretic, diuretic and antihypertensive response in rodents, 1. Atrial natriuretic factor is metabolized by neutral endopeptidase (atriopeptidase; EC 3.4.24.11) in vitro. Inhibitors of this enzyme have been reported to prolong the half-life of atrial natriuretic factor in vivo and to potentiate the renal and haemodynamic effects of exogenous atrial natriuretic factor. 2. (+/-)-Candoxatrilat. a selective neutral endopeptidase inhibitor. potentiated the natriuretic and diuretic response to volume loading in anaesthetized rats. Part of the response to volume loading and the potentiation by (+/-)-candoxatrilat was prevented by a polyclonal atrial natriuretic factor antiserum. The diuretic and natriuretic responses evoked by hydrochlorothiazide were not altered by the antiserum. 3. (+/-)-Candoxatrilat reduced systolic blood pressure of one-kidney deoxycorticosterone acetate-salt hypertensive rats for over 5 h. This response was abolished by pretreatment with atrial natriuretic factor antiserum. 4. These data demonstrate that the neutral endopeptidase inhibitor (+/-)-candoxatrilat has natriuretic/diuretic and antihypertensive effects in rodents. and that these effects are mediated via endogenous atrial natriuretic factor.
Long-term treatment of hirsutism: desogestrel compared with cyproterone acetate in oral contraceptives, OBJECTIVE: Effectiveness of 2-year treatment of hirsutism with low estrogen oral contraceptives (OCs) containing nonandrogenic or antiandrogenic progestogen. Evaluation of changes in plasma lipids. DESIGN: Ten patients treated with desogestrel 150 micrograms + 30 micrograms ethinyl estradiol. 6 with desogestrel 150 micrograms + 50 micrograms ethinyl estradiol. 10 with cyproterone acetate 2 mg + 35 micrograms ethinyl estradiol. Random allocation. Paired comparisons. Control group: 19 normal women. not treated. SETTING: Academic tertiary care. PATIENTS: Women with hirsutism (idiopathic and/or polycystic ovary). 24 of 26 completed treatment. INTERVENTION: Two-year treatment. MAIN OUTCOME MEASURES: Hirsutism score. plasma testosterone. and lipids. RESULTS: Initial hirsutism scores (11.8 +/- 0.6 SE) declined with treatment (-7.2 +/- 0.4. P less than 0.01) to 4.7 +/- 0.6. almost reaching control (3.6 +/- 0.3). Initial plasma cholesterol (4.33 mmol/L +/- 0.30 SE). similar to control (4.78 +/- 0.24). increased slowly over 2 years (+2.04 +/- 0.34. P less than 0.01). High-density lipoproteins cholesterol (1.05 mmol/L +/- 0.04 SE). similar to control (1.12 +/- 0.07). did not change the 1st year and increased at 2 years (+0.57 +/- 0.11. P less than 0.01). No differences appeared among treatment groups. CONCLUSIONS: Treatment is very effective. 2 years for best results. The OCs tested are equally efficacious. Changes in plasma lipids are of some concern but of difficult interpretation.
The effect of danazol on pulsatile gonadotropin secretion in women with endometriosis, OBJECTIVE: To determine whether the effect of danazol on gonadotropin pulsatility was due to a direct effect of the drug or the suppression in the estradiol (E2) levels. DESIGN: Prospective analysis of serial blood samples at 10-minute intervals for 5 hours on days 3. 4. or 5 of the control cycle and 2 months after the start of danazol treatment. SETTING: Tertiary institutional outpatient care. PATIENTS. PARTICIPANTS: Six eugonadal women with minimal endometriosis. INTERVENTIONS: Oral administration of danazol. 200 mg three times daily. MAIN OUTCOME MEASURES: Gonadotropin mean levels. pulse frequency. and amplitude. RESULTS: The mean level of E2 was the same in the control cycle as that during danazol treatment (170 pmol/L). Danazol administration resulted in a 16% increase in the mean luteinizing hormone (LH) pulse amplitude (95% confidence interval [CI] 6% to 26%. P less than 0.01). associated with a 20% decrease in LH pulse frequency (95% CI -71% to +31%. P = 0.37). There was a nonsignificant increase in follicle-stimulating hormone (FSH) pulse amplitude (2%. 95% CI -9% to +14%. P = 0.68) and in FSH pulse frequency (27%. 95% CI -4% to +58%. P = 0.08). The 22% decrease in the mean LH level (95% CI -85% to +12%. P = 0.13) and the 20% decrease in the mean FSH level (95% CI -53% to +37%. P = 0.33) were also not significant. CONCLUSIONS: The increase in LH pulse amplitude represents a direct effect of danazol on the hypothalamic-pituitary axis.
Gonadotropin-releasing hormone agonist improves the efficiency of controlled ovarian hyperstimulation/intrauterine insemination, OBJECTIVE: Leuprolide acetate (LA) has improved the efficiency of human menopausal gonadotropins (hMG) in in vitro fertilization cycles. We hypothesized that the combination of LA/hMG/intrauterine insemination (IUI) would be more efficacious than hMG/IUI cycles. DESIGN: During an 18-month period. all patients completing either a hMG/IUI cycle (group I) or a LA/hMG/IUI cycle (group II) had the characteristics and outcomes of their stimulation cycles assessed. The groups were not prospectively randomized. SETTING: Referral center at a tertiary care hospital. PATIENTS: One hundred twenty three patients in group I completed 219 cycles. and 64 patients in group II completed 102 cycles. Twenty-eight of the patients who failed to conceive with hMG/IUI were advanced to group II. MAIN OUTCOME MEASURES: Pregnancy/IUI is compared between the two groups. RESULTS: Group II demonstrated significantly greater clinical pregnancy/IUI than group I (26.5% and 16.0%. respectively. P less than 0.05). as well as a higher live birth/IUI (21.6% and 12.8%. respectively. P less than 0.05). No difference was present in the rate of fetal wastage or multiple births. CONCLUSIONS: In our patients with recalcitrant infertility. the addition of a gonadotropin-releasing hormone agonist to hMG/IUI improved the pregnancy rate. without increasing the rate of multiple births or fetal wastage.
Normalization of Na(+)-K(+)-ATPase activity in isolated membrane fraction from sciatic nerves of streptozocin-induced diabetic rats by dietary myo-inositol supplementation in vivo or protein kinase C agonists in vitro, A myo-inositol-related defect in nerve Na(+)-K(+)-ATPase in experimental diabetes has been invoked in the pathogenesis of diabetic neuropathy. but the mechanism linking altered myo-inositol metabolism and Na(+)-K(+)-ATPase regulation in diabetic nerve is uncertain. Decreased Na(+)-K(+)-ATPase in diabetic rat nerve is normalized by aldose reductase inhibitors or dietary myo-inositol. which preserve normal nerve myo-inositol content in vivo. Decreased Na(+)-K(+)-ATPase in diabetic rabbit nerve is acutely reversed by exposure to protein kinase C agonists in vitro. This study explored the relationship between the myo-inositol-sensitive and protein kinase C-agonist-sensitive Na(+)-K(+)-ATPase defects in diabetic rat nerve. Ouabain-sensitive ATPase activity was measured in an enriched membrane fraction isolated from nondiabetic. streptozocin-induced diabetic. and myo-inositol-supplemented streptozocin-induced diabetic rats before and after the membranes were exposed to protein kinase C agonists in vitro. The decreased ouabain-sensitive ATPase activity in plasma membranes from untreated diabetic rats was increased after exposure to two structurally unrelated protein kinase C agonists; the normal ouabain-sensitive ATPase in plasma membranes from myo-inositol-supplemented diabetic rats was unaffected by protein kinase C agonists. The nonadditivity and implied equivalence of the Na(+)-K(+)-ATPase defect corrected by myo-inositol in vivo and by protein kinase C agonists in vitro are consistent with the postulated existence of a deficient myo-inositol-dependent phospholipid-derived protein kinase C agonist (presumably diacylglycerol) in diabetic nerve that regulates nerve Na(+)-K(+)-ATPase either directly or via a protein kinase C mechanism.
Exclusive expression of MHC class II proteins on CD45+ cells in pancreatic islets of NOD mice, The expression of MHC class II molecules on beta-cells of the pancreatic islet has been proposed to play a role in the genesis of insulin-dependent diabetes mellitus in the NOD mouse. We investigated this by immunofluorescent double labeling of islet cells with anti-MHC and anti-CD45 to identify cells of hematopoietic origin. MHC class I expression increased with age on CD45- islet cells. MHC class II expression was not observed on CD45- islet cells at any age; the only cells in the islet that were MHC class II positive were also CD45+. This indicates that all MHC class II-positive cells in the islet are lymphoid cells that infiltrate the islet. whereas the islet endocrine cells express no MHC class II molecules. However. an increase in MHC class I expression occurred on beta-cells. and this may play a role in immunopathogenesis.
Ventilatory dysfunction precedes pulmonary vascular changes in monocrotaline-treated rats, Rats with established monocrotaline (MCT)-induced pulmonary hypertension also exhibit a profound increase in lung resistance (RL) and a decrease in lung compliance. Because airway/lung dysfunction could precede and influence the evolution of MCT-induced pulmonary vascular disease. it is important to establish the temporal relationship between development of pulmonary hypertension and altered ventilatory function in MCT-treated rats. To resolve this issue. we segregated 47 young Sprague-Dawley rats into four groups: control (n = 13). MCT1 (n = 9). MCT2 (n = 11). and MCT3 (n = 14). Each MCT rat received a single subcutaneous injection of MCT (60 mg/kg) 1 MCT1). 2 (MCT2). or 3 (MCT3) wk before the functional study. At 1 wk after MCT. significant increases in RL and alveolar wall thickness were observed. as was a significant decrease in carbon monoxide diffusing capacity (DLCO). Medial thickness of pulmonary arteries (50-100 microns OD) and right ventricular hypertrophy were not observed until 2 and 3 wk post-MCT. respectively. Coincident with the right ventricular hypertrophy at 3 wk post-MCT were decreased DLCO and increased alveolar wall thickness and lung dry weight. Pressure-volume curves of air-filled and saline-filled lungs showed marked rightward shifts during the 1st and 2nd wk after MCT administration and then decreased at the 3rd wk. These data suggest that MCT-induced alterations in airway/lung function preceded those of pulmonary vasculature and. therefore. implicate airway/lung dysfunctions as potentially contributing to the later development of pulmonary vascular abnormalities.
Evidence for hypoxic depression of CO2-ventilation response in carotid body-resected humans, Steady-state CO2-ventilation response curves with hyperoxia (end-tidal PO2 greater than 200 Torr) and mild hypoxia (end-tidal PO2 approximately equal to 60 Torr) were compared in five carotid body-resected (BR) patients and five control patients. The data were analyzed by fitting a linear equation. V = S(PETCO2-B). where V is minute ventilation S is the response curve slope. PETCO2 is end-tidal PCO2. and B is the response curve threshold. S slightly increased from hyperoxia to hypoxia in both BR and control groups. On the other hand. B moderately increased with hypoxia in BR patients. whereas it slightly decreased in controls. These changes were all not significant. However. in accordance with the change in B. the response curve to hypoxia at V of 10 1/min was significantly shifted in opposite directions in the two groups. i.e.. rightward and leftward shift in BR and control groups. respectively. Thus the average magnitude of V calculated at PETCO2 of 40 Torr in hypoxia was significantly lower in BR patients than in controls (P less than 0.01). We conclude that this hypoxic depression of the CO2-ventilation response found in BR patients may have resulted. at least in part. from modulation of the brain stem neural mechanisms that were elicited by loss of afferent discharges from the carotid body.
Hyperoxia prevents hypoxia-induced bronchial hyperreactivity via a cyclooxygenase-independent mechanism, We tested the hypothesis that prior exposure to alveolar hyperoxia prevents the hypoxia-induced enhancement of bronchial reactivity. possibly via a cyclooxygenase-dependent mechanism. In 15 sheep. specific lung resistance (sRL) was measured before and after 30 min of exposure to either air or a hypoxic gas mixture (13% O2). The sheep then inhaled 50 breaths of aerosolized 5% histamine solution (n = 9) or 10 breaths of 2.5% carbachol solution (n = 9). and measurements of sRL were repeated. On subsequent days the above protocols were repeated after a 30-min exposure to hyperoxia (O2 greater than or equal to 95%). without or after pretreatment with indomethacin (2 mg/kg). After air-sham exposure. carbachol and histamine increased mean sRL to 370 +/- 40 (SE) and 309 +/- 65% of baseline. respectively. Exposure to the hypoxic gas mixture had no effect on baseline sRL but enhanced the airway responsiveness to carbachol and histamine; mean sRL increased to 740 +/- 104 and 544 +/- 76% of baseline. respectively (P less than 0.05). Prior 30-min exposure to hyperoxia prevented the hypoxia-induced enhancement of bronchial reactivity to carbachol (sRL = 416 +/- 66% of baseline) and histamine (sRL = 292 +/- 41% of baseline) without affecting the airway responsiveness to these agents after air. Pretreatment with indomethacin did not reverse the protective effects of hyperoxia or the hypoxia-induced enhancement of bronchial reactivity. We conclude that 1) prior exposure to alveolar hyperoxia prevents the hypoxia-induced enhancement of bronchial reactivity and 2) neither the protective effects of hyperoxia nor the hypoxia-induced enhancement of bronchial reactivity is mediated via a cyclooxygenase-dependent mechanism.
Localization and in vitro actions of atrial natriuretic peptide in the cat carotid body, Previous studies of atrial natriuretic peptide (ANP) have indicated that its release from the heart and from discrete areas of the central nervous system evokes coordinated physiological and behavioral adjustments that mitigate the adverse hypertensive effects of volume overload and/or acute increases in sodium intake. Because the reflex activity initiated by arterial chemoreceptors of the carotid body directly contributes to the integrated regulation of systemic blood pressure. we have investigated the possibility that ANP has a significant role in the chemosensory process as well. Our immunocytochemical studies show that ANP-like immunoreactivity is present in the preneural chemosensitive type I cells in the cat carotid body. Furthermore we found that the biologically active ANP fragment atriopeptin III is a potent inhibitor of carotid sinus nerve activity evoked by hypoxia. Our findings suggest that circulating and/or endogenous ANP may modulate carotid body function as part of a coordinated response to changes in systemic volume and solute balance.
Fungal translocation is associated with increased mortality after thermal injury in guinea pigs, Thermal injury increases the rate of translocation of Candida albicans in guinea pigs. but early enteral feeding can significantly decrease this rate. We studied the combined effects of C. albicans translocation and early feeding on outcome of thermal injury in guinea pigs. Eighty guinea pigs were subjected to a flame burn covering 50% total body surface area. One hour before burn injury. half of the animals underwent gavage with 3 x 10(10) viable C. albicans. a dosage that in previous studies was associated with greater than 90% incidence of yeast translocation to the mesenteric lymph nodes. The other half underwent gavage with an equal volume of saline. After injury. half of each group were randomly selected to receive guinea pig feed ad libitum and the other half were starved for 72 hours. All were allowed access to water ad libitum. Mortality rate was recorded at 3 3 days. The group that underwent gavage with C. albicans and subsequent starvation after burn injury had a significantly higher mortality rate than had any of the other groups. We conclude that induced translocation of C. albicans in guinea pigs increases mortality after burn injury. Moreover. early enteral feeding has a protective effect. presumably by decreasing translocation rates has been shown in previous studies.
Antacid, sucralfate, and prostaglandin E2 effects on the growth and potential for translocation of Pseudomonas aeruginosa, Escherichia coli, and Staphylococcus aureus in an in vitro gastric simulation, Viable bacteria in the gut of thermally injured patients may be translocated through the gut mucosa. causing widespread infection. Increased flora from optimization of bacterial growth by pH elevation. coupled with the decreased intestinal motility common among patients whose mucosal integrity has been compromised. may increase the incidence of translocation. Gastric pH in these patients is monitored and maintained around pH 6 by various agents to reduce susceptibility to stress ulceration. Whole milk. given as a nutrient source. also raises pH. An in vitro trial simulating gastric fluid under conditions found in patients with burns was conducted to evaluate the growth of commonly ingested bacteria. Bicarbonate buffer containing pepsin and adjusted to pH 2. 4. or 7 with HCl was dosed with magnesium and aluminum hydroxide antacid (Maalox) (10 ml). sucralfate (Carafate) (0.4 gm). or prostaglandin E2 (PGE2) (10 ng) before inoculation with Escherichia coli (3 x 10(2) organisms). Pseudomonas aeruginosa (3 x 10(2) organisms). or Staphylococcus aureus (2 x 10(1) organisms). Bacterial growth and pH were determined periodically over the 24-hour trial. Milk was added at intervals in half the samples to simulate patient feeding. Maalox increased pH in all samples containing milk (initially pH 2. 4. or 7) to over 7.0 in 2 hours. and increased pH more slowly without milk. Carafate had a moderating effect. increasing pH 2 and pH 4 and decreasing pH 7. with a narrower pH range found in the milk groups. PGE2 treatments combined with milk also increased pH 2 and pH 4. but slightly elevated pH 7 within 24 hours. Without milk. PGE2 did not alter pH from initial values.
Length of care in patients with severe burns with or without early enteral nutritional support. A retrospective study, The possible influence of early enteral nutritional support on the length of care was explored retrospectively in 25 patients with burns greater than 20% total body surface area (TBSA). Patients were divided into two groups according to the time of their admission: group 1. from July 1986 to February 1987 (n = 12) and group 2. from July 1987 to January 1988 (n = 13). The only difference in treatment between the two groups was the start of early enteral nutritional support in group 2. Age. percent TBSA burned. surfaces of skin grafts. associated respiratory injury. and medical condition were identical in both groups. The following parameters were compared: lag time between hospital admission and the beginning of nutritional support. energy intake. nitrogen intake during the 4-week postadmission period. and length of care. A regression analysis including all patients was also performed to identify the factors associated with length of care. Lag time was shorter in group 2 than in group 1: 3 +/- 2 days versus 7 +/- 2 days (p less than 0.01). Group 2 received more energy than group 1 during the first 2 weeks after admission: 120 +/- 54 kj/kg/day versus 73 +/- 34 kj/kg/day (p less than 0.05) and 175 +/- 36 kj/kg/day versus 137 +/- 41 kj/kg/day (p less than 0.05) for the first and the second week. respectively.
Sublingual administration of testosterone-hydroxypropyl-beta-cyclodextrin inclusion complex simulates episodic androgen release in hypogonadal men, In search of a more physiological testosterone (T) replacement therapy for hypogonadal states. we evaluated an inclusion complex of T with 2-hydroxypropyl-beta-cyclodextrin (HPBCD). HPBCD enhances T solubility and absorption. but HPBCD is not absorbed. Five hypogonadal men (mean age. 32.4 +/- 2.3 yr) with serum T levels below the normal range were treated in two separate experimental phases with either a 2.5- or 5.0-mg tablet of sublingual (SL) T-HPBCD three times daily for 7 days. Acute pharmacodynamic changes were monitored at baseline and 10. 20. and 40 min and 1. 1.5. 2. 3. 4. and 8 h after administration of the first dose. At the 5-mg dose. a maximal concentration (Cmax) of T (85.4 +/- 11.0 nmol/L) was achieved in 20 min (63 +/- 24-fold increase). followed by a rapid decline to below the normal range (less than 12 nmol/L) at 2 h. with an estimated half-life of decline of 1.87 +/- 0.19 h. The dihydrotestosterone (DHT) Cmax (4.1 +/- 0.5 nmol/L) occurred at 32 +/- 5 min (8.9 +/- 1.3-fold increase) and declined to below the normal range (less than 1.2 nmol/L) after 3 h. The integrated 8 h value for the ratio of T/DHT was 10.0 +/- 1.1. which fell within the normal range. The increment in androstenedione paralleled that in T. and the Cmax (6.8 +/- 0.9 nmol/L) was reached in 24 +/- 4 min (2.3 +/- 0.6-fold increase). Compared to baseline. the Cmax was significantly greater for T (P less than 0.005). DHT (P less than 0.0005). and androstenedione (P less than 0.005). Both estradiol (E2) and estrone (E1) remained in the normal range (less than 200 pmol/L). although the Cmax for E1 was significantly greater than baseline (P less than 0.05). Serum LH levels were suppressed (19.0 +/- 2.6%) at 2 h (P less than 0.05). without a significant change in FSH. During 7 days of treatment. there was no cumulative increase in basal T. DHT. and E2 levels or further decline in LH or FSH levels. There was no change in sex hormone-binding globulin levels. Similar results were observed with the 2.5-mg dose. suggesting that the capacity of SL absorption may be limited to a certain dose of T-HPBCD. The fluctuations in T after SL administration of T-HPBCD resemble endogenous episodic secretion. We conclude that T. complexed with HPBCD. is rapidly absorbed by the SL route and quickly metabolized without sustained elevations of DHT or E2.
The role of the cholinergic pathway in growth hormone feedback, Cholinergic pathways play an important role in the regulation of GH secretion. To assess their participation in GH feedback. we investigated the effect of pyridostigmine (an acetylcholinesterase inhibitor) on plasma GH responses to GH-releasing hormone (GHRH) plus TRH. insulin hypoglycemia. and arginine as well as on the inhibition of these responses by exogenous GH. The GH response to each stimulus was inhibited by an infusion of GH (0.55 micrograms/m2/min). started 4 h earlier. Pyridostigmine (120 mg. orally). administered 30 min before the stimulus. enhanced GH responses to GHRH and insulin during both saline and GH infusions. However. GH responses during combined administration of pyridostigmine and GH were less than those during pyridostigmine alone. GH responses to arginine. in contrast. were not affected by pyridostigmine in either the absence or presence of exogenous GH. TSH responses to TRH were unaltered by either GH or pyridostigmine. Pyridostigmine enhancement of GH responses to a maximally stimulatory dose of GHRH suggests that its effect is exerted by inhibition of somatostatin release. The lack of effect of pyridostigmine on plasma GH responses to arginine suggests that arginine and pyridostigmine increase GH secretion through a common pathway. The enhancement by pyridostigmine of GH responses in both the presence and absence of exogenous GH suggests that exogenous GH and pyridostigmine exert their discordant effects on GH secretion through independent mechanisms.
Thyrotropin receptor autoantibodies induce human thyroid cell growth and c-fos activation, Graves' disease encompasses hyperthyroidism and a diffuse goiter associated with autoantibodies to the TSH receptor (TRAb). Although the cause of the goiter formation has been attributed to TRAb. the limited growth pattern of human adult thyroid cells in vitro has caused such a conclusion to be based on studies of nonhuman thyroid cell growth. We have recently characterized a predictable and precise technique for the measurement of human thyroid cell proliferation and function using fetal thyroid cells and have used this system to examine the influence of TRAb on human thyroid cell growth. Highly purified human immunoglobulin G (hIgG) preparations from normal individuals (n = 5) had no significant influence on human thyroid cell growth. However. hIgG from patients with detectable TRAb (TRAb-hIgG) (n = 13) induced a dose-related increase in extracellular cAMP (maximum effect at 0.1 mg/ml) and a 3-fold increase in human thyroid cell growth over a 4-day period (maximum effect at 1.5 mg/ml). Under basal thyroid cell culture conditions there were detectable. but low. levels of mRNA specific for the protooncogene c-fos. and this was markedly. and rapidly. induced by the addition of TRAb-hIgG but not normal hIgG. These data demonstrate induction of cellular growth by TRAb-hIgG in an homologous human thyroid cell culture system. Such observations support the hypothesis that goiter formation in patients with Graves' disease is. at least in part. secondary to the growth stimulating activity of TRAb-hIgG.
Stimulation of glycosaminoglycan accumulation by interferon gamma in cultured human retroocular fibroblasts, Fully expressed Graves' disease involves an accumulation of glycosaminoglycan (GAG) in the retroocular connective tissue which contributes to the pathogenesis of ophthalmopathy. We treated cultured retroocular and dermal fibroblasts with recombinant interferon gamma (100 U/ml) for 16-24h and measured [3H]GAG accumulation. The cytokine stimulated [3H]GAG accumulation in retroocular fibroblast cultures obtained from eight different donors by 36-124% above control values. In contrast. interferon gamma had no consistent effect on macromolecular accumulation in dermal fibroblast cultures derived from the pretibium or from areas ordinarily uninvolved in Graves' dermopathy. These results suggest that retroocular fibroblasts may be uniquely targeted for one action of interferon gamma which involves the modulation of GAG metabolism.
Paradoxical response of growth hormone to peptide histidine methionine in acromegaly: comparison with the effects of thyrotropin-releasing hormone and vasoactive intestinal peptide, We examined whether peptide histidine methionine (PHM) induces a paradoxical rise in plasma GH in patients with acromegaly. PHM (100 micrograms) was given as an iv bolus to eight patients with active acromegaly. and plasma GH levels were measured before and at intervals up to 120 min after the injection. For comparison. the effects of TRH (500 micrograms) and vasoactive intestinal peptide (VIP. 100 micrograms). peptides known to paradoxically stimulate GH secretion in acromegalics. were assessed in all of the patients. A paradoxical rise (greater than 50% above the basal) in plasma GH was observed in five patients after both TRH and VIP administrations. although TRH responders were not always VIP responders. nor did VIP responders always respond to TRH. In two patients. the GH response to PHM fulfilled the criteria of a paradoxical increase. Both of these patients were also TRH and VIP responders. These results suggest that PHM may be another hypothalamic hormone capable of paradoxically stimulating GH secretion in at least some acromegalics. although PHM appears to be a less potent stimulator of GH release than TRH and VIP. The pathophysiological significance of this phenomenon is yet to be determined.
Molecular analysis of major histocompatibility complex alleles associated with the lupus anticoagulant, Autoantibodies to phospholipids (APA) occur frequently in systemic lupus erythematosus (SLE) and other autoimmune disorders and predispose to intravascular thromboses. Major histocompatibility complex (MHC) class II alleles (HLA-DR and DQ) were determined by restriction fragment length polymorphisms (RFLP) in 20 patients with APA (lupus anticoagulant). HLA-DQw7 (DQB1*0301). linked to HLA-DR5 and -DR4 haplotypes. occurred in 70% and was significantly increased compared to 139 race-matched normal controls (P = 0.002. P corrected [pc] = 0.05. odds ratio [OR] = 5.1). Moreover. the frequency of HLA-DQw7 was significantly higher in SLE patients with APA as compared with patients without APA but with other autoantibodies. including anti-Ro and La (P = 0.0001. pc = 0.002. OR = 10.7). anti-Ro alone (P = 0.001. pc = 0.02. OR = 11.2). anti-dsDNA (P = 0.001. pc = 0.02. OR = 7.1). and possibly anti-Sm (P = 0.04. pc = NS. OR = 6.8) and anti-nRNP (U1-RNP) (P = 0.01. pc = NS. OR = 7.8). The DQB1*0301 allele of DQw7 showed the strongest association. while the frequencies of the DQA1*0301 (45%) and DQA1*0501 (50%) alleles did not differ from the controls. Among the HLA-DQB1*0301 (DQw7) negative patients. all possessed HLA-DQw8 (DQB1*0302) and/or HLA-DQw6 (DQB1*0602 or DQB1*0603) alleles. The HLA-DQB1*0301 chain shares an identical seven amino acid sequence with DQB1*0302. *0602. and *0603 chains in the third hypervariable region of the HLA-DQ molecule. This candidate "epitope" may play a role in mediating an autoimmune response to APA.
Clonal analysis of CD4+/CD8+ T cells in a patient with aplastic anemia, T cell clones were established from peripheral blood of a patient with severe aplastic anemia. 8 of 18 individual clonal T cell populations stably coexpressed CD4 and CD8 molecules. a phenotype characteristic for thymocytes and a minor subpopulation of circulating T lymphocytes. Analysis of T cell receptor genes revealed identical rearrangements of T cell receptor beta chain genes. suggesting clonality of these T cells. CD4+/CD8+ T cells clones were found to be efficiently cytotoxic towards autologous lymphoblasts. Autocytotoxicity could be blocked by a CD3 MAb. a MAb specific for monomorphic MHC class II determinants. and particularly. by an MHC-DP-specific MAb. suggesting specificity for autologous DP molecules. Perhaps more important. CD4+/CD8+ T cell clones inhibited differentiation of autologous progenitor enriched bone marrow cells in vitro by a direct cell-mediated mechanism. These data suggest that circulating cytotoxic CD4+/CD8+ T cell clones specific for autologous MHC-DP determinants may be involved in hematopoietic failure in some cases of aplastic anemia.
Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema, Patients with hereditary angioneurotic edema (HANE) have serum levels of functionally active inhibitor of the first component of complement (C1 INH) between 5 and 30% of normal. instead of the 50% expected from the single normal allele. Increases in rates of catabolism have been documented in patients with HANE and certainly account for some of decrease in C1 INH level. A possible role for a decrease in synthesis of C1 INH in producing serum levels of C1 INH below the expected 50% of normal has not been well studied. We studied the synthesis of C1 INH in skin fibroblast lines. which produce easily detectable amounts of C1 INH. In type I HANE cells. C1 INH synthesis was 19.6 +/- 4.0% (mean +/- SD) of normal. much less than the 50% predicted. In type II HANE cells. the total amount of C1 INH synthesis (functional and dysfunctional) was 98.9 +/- 17% of normal; the functional protein comprised 43% of the total. Thus. type II HANE cells synthesized functional C1 INH at a much greater rate than for the type I cells. In both type I and II HANE cells. amounts of steady-state C1 INH mRNA levels paralleled rates of C1 INH synthesis. indicating that control of C1 INH synthesis occurred at pretranslational levels. Both type I and type II fibroblasts synthesized normal amounts of C1r and C1s. These data suggest that the lower than expected amounts of functionally active C1 INH in type I HANE may be due. in part. to a decrease in rate of synthesis of the protein. and that the expressions of the normal C1 INH allele in HANE is influenced by the type of abnormal allele present.
Primary cutaneous gamma/delta T-cell lymphoma presenting as disseminated pagetoid reticulosis, The first case of primary gamma/delta cutaneous T-cell lymphoma (CTCL) with a fatal outcome is reported. The patient had the clinical and histopathologic features of disseminated pagetoid reticulosis. a rare form of CTCL characterized by a strong epidermotropic lymphoid infiltrate. Extensive immuno-cytochemical studies showed that the neoplastic cells were almost exclusively localized in the epidermis. expressed the gamma/delta variant of the T-cell receptor (CD3+. TCR-delta-1+) and were CD5+. CD7+. CD27+. CD29+. CD43+. CD44+. CD45+. CD45RA+. CD54+. CD69+. but beta F1-. Ti gamma a-. BB3-. A13-. CD2-. CD4-. CD8-. CD11a-. CD49d-. CD25-. CD30-. and HLA-DR-. A comparison of our results with those of the literature. which have not included gamma/delta T-cell receptor analysis. suggests that some reported cases of pagetoid reticulosis may have phenotypes similar to our case. Electron microscopy studies demonstrated that the gamma/delta T lymphocytes were villous. containing dense and multivesicular bodies. and formed close contacts with the surrounding keratinocytes. suggesting that these cells should have a role in the skin-associated lymphoid tissue. The proliferating cells in our case might represent the neoplastic counterpart of the recently reported CD2- subset of normal human peripheral blood gamma/delta T lymphocytes.
A novel approach to analysis of transcriptional regulation in human cells: initial application to melanocytes and melanoma cells, An assay system for transcriptional profile analysis of cultured eukaryotic cells has been developed to simultaneously handle multiple samples in a rapid. sensitive. and internally controlled manner. The methodology incorporates a microtiter plate assay system. a rapid cell-harvest enzyme-assay technique. and the bacterial reporter genes beta-glucuronidase and beta-galactosidase. We demonstrate. using beta-actin and SV40 (late) transcription promoting sequences. that this technically refined microtiter-triton-lysate (MTL) assay methodology can readily differentiate between the transcriptional states of human melanocytes before and after pharmacologic stimulation and malignantly transformed versus normal cell environments. Differences in the transcriptional environments are revealed by the relative expression of transcription element probes. The transcriptional activity ratio of the beta-actin compared to the SV40 late transcription promoting sequences was approximately 1:2 in primary cultured melanocytes. 2:1 in 12-0-tetradecanoyl phorbol-13-acetate (TPA)-treated melanocytes and 1:4 in the Tang melanoma cell line. Because this MTL assay methodology can accommodate a panel of transcription element probes. we anticipate that the resultant transcriptional profiles will prove useful in deciphering the diverse transcriptional changes that occur within normally regulated and malignantly transformed cells.
Analysis of beta, gamma, and delta T-cell receptor genes in lymphomatoid papulosis: cellular basis of two distinct histologic subsets, To investigate the histogenesis of lymphomatoid papulosis (LYP). we have analyzed the configuration of the beta. gamma. and delta T-cell receptor (TCR) and Ig genes in DNA from 31 biopsies of 18 patients with this condition and also from peripheral blood mononuclear cells of eight of these patients. Immunoglobulin genes were in a germ-line configuration in all patients. and TCR genes were in a germ-line configuration in six patients. In nine patients. one or two rearranged bands (RB) were detected with both beta and gamma TCR probes and in one patient with beta. gamma. and delta TCR probes. Two patients. in whom beta and delta TCR genes were in a germline configuration. had evidence of multiple discrete rearrangements of gamma TCR genes. consistent with a polyclonal T-cell population. Analysis of multiple biopsies revealed that RB. when present. were identical in different lesions from individual patients. All but one of the peripheral blood samples showed a germ-line configuration. The exception had evidence of a rearrangement of gamma and delta in peripheral blood and a beta and gamma rearrangement within tissue. This study has established that only a proportion of patients with LYP have a monoclonal T-cell proliferation. Correlation with the clinicopathologic and immunophenotypic data revealed that a T-cell clone was limited to patients with Willemze type B LYP or "mixed type" LYP. whereas patients with type A LYP consistently showed a germline configuration of TCR genes. This study indicates that in LYP the atypical hyperchromatic cerebriform mononuclear cells of type B invariably constitute a monoclonal T-cell population whereas the atypical CD30 positive type A cells represent a proliferation of cells of non-B. non-T-cell lineage.
Intravenous nitroglycerine in the management of posttreatment hypertension during electroconvulsive therapy, Intravenous nitroglycerine is not described in the psychiatric literature for management of the inevitable and potentially dangerous pressor response encountered in electroconvulsive treatment. However. the anesthesia literature has documented the use of nitroglycerine for the management of similar catecholamine-based hypertension. Unlike other approaches. nitroglycerine creates a controlled. significant. brief vasodilatation after convulsive treatment accompanied by desirable coronary vasodilatation without increased cardiac stress. A review of a series of treatments in which this technique was used confirms the clinical efficacy and safety of this approach.
Radioimmunodetection of neuroblastoma with iodine-131-3F8: correlation with biopsy, iodine-131-metaiodobenzylguanidine and standard diagnostic modalities, Iodine-131-3F8. a murine IgG3 monoclonal antibody specific for ganglioside GD2 was evaluated by radioimmunoscintigraphy in 42 patients with neuroblastoma. Comparison was made with 131I-metaiodobenzylguanidine (MIBG). 99mTc-methylene diphosphonate (MDP) bone scans. as well as computed axial tomography (CT) or magnetic resonance imaging (MRI). Iodine-131-3F8 detected more abnormal sites (283) than [131I] MIBG (138) or 99mTc-MDP (69). especially in patients with extensive disease. In 20 patients with soft-tissue tumors demonstrated by CT/MRI. 131I-3F8 detected the disease in 18. Upon surgical resection. two tumors interpreted as negative with 131I-3F8 imaging revealed ganglioneuroma. one showing microscopic foci of neuroblastoma. In contrast. 131I-3F8 imaging identified tumors that were confirmed histologically as neuroblastomas. In 26 patients with evidence of marrow disease by antibody scans. 14/26 had confirmation by iliac crest marrow aspirate/biopsy examinations. We conclude that 131I-3F8 scintigraphy has clinical utility in the management of patients with neuroblastoma by improving the sensitivity of tumor detection.
Myocardial distribution of indium-111-antimyosin Fab in acute inferior and right ventricular infarction: comparison with technetium-99m-pyrophosphate imaging and histologic examination, In a postmortem study of a 69-yr-old female patient who had suffered 2 yr previously a non-Q-wave anterior infarction and who had sustained just seven days earlier a left inferior and right ventricular infarction. the distribution of 111In-antimyosin Fab was compared to the results of 99mTc-pyrophosphate imaging and histologic examination. Indium-111-antimyosin Fab imaging could not be performed because of cardiogenic shock. However. postmortem gamma scintillation counting revealed increased activities of antimyosin Fab in the inferoapical and right ventricular infarcted regions in which 99mTc-pyrophosphate positive imagings were observed; in contrast. a histologically confirmed old subendocardial anterior infarction had no definite activity. Thus. the myocardial distribution of 111In-antimyosin Fab corresponded well to the results of 99mTc scintigrams and histologic examinations in a human heart. suggesting that this technique could be useful in vivo for detecting several-day-old myocardial infarction of the right ventricle as well as the left ventricle. Tissue from the 2-yr-old infarction was not identified by this technique.
Hemarthrosis in patients with acquired factor VIII inhibitor, We describe 2 patients who presented with hemarthrosis and were found to have an underlying Factor VIII inhibitor. One case was associated with a renal cell carcinoma. Factor VIII inhibitor should be included in the differential diagnostic lists of causes of hemarthrosis.
Astemizole, an H1 antagonist, has no additional therapeutic effect in rheumatoid arthritis, Mast cells are found in increased numbers in the synovium of patients with rheumatoid arthritis (RA) and may play a role in synovitis. They produce proinflammatory substances including histamine. A double blind placebo controlled study was undertaken in 60 patients with active RA using the H1 receptor blocker. astemizole. as an adjuvant to usual therapies. After 3 months of treatment there were no significant differences in clinical and laboratory variables between the groups. We conclude that H1 antagonist treatment with astemizole has no additional therapeutic effect in RA.
Neurotrophic protein S100 beta stimulates glial cell proliferation, Nervous system development involves a coordinated series of events. including regulation of cell proliferation and differentiation by specific extracellular factors. S100 beta is a neurotrophic protein that has been implicated in regulation of cellular proliferation. but direct evidence was lacking. In this report. nanomolar concentrations of S100 beta are shown to stimulate proliferation of rat C6 glioma cells and primary astrocytes. An S100 mutant with a single amino acid change was inactive. S100 beta also stimulated increases in the steady-state levels of c-myc and c-fos protooncogene mRNAs and complemented the effects of platelet-derived growth factor. Two neuroblastoma cell lines did not proliferate in response to S100 beta. suggesting that the mitogenic activity of S100 beta is selective for astroglial cells. These results suggest that S100 beta may be involved in the coordinate development and maintenance of the central nervous system by synchronously stimulating the differentiation of neurons and the proliferation of astroglia.
Improved serodiagnosis of hepatitis C virus infection with synthetic peptide antigen from capsid protein, Cloning and expression of hepatitis C virus have allowed the development of immunoassays to detect hepatitis C virus infection. However. currently available recombinant fusion protein C100-3 assays. based on a nonstructural protein of the virus. are limited in sensitivity. particularly for detecting acute infection. In this report seroconversion panels showed that an assay based on synthetic peptides. derived from immunodominant regions of both capsid and nonstructural proteins. accelerated hepatitis C virus antibody detection by 4-10 weeks. In screening. this enzyme immunoassay increased detection from 47% to 64% in plasmapheresis donors with elevated alanine aminotransferase levels (greater than 100 international units per liter). from 15% to 24% in anti-hepatitis B core antigen-positive blood donors. and from 28% to 42% in renal dialysis patients when compared with nonstructural peptide-based assays. The screening assay was repeatedly reactive for 27 of 2902 volunteer blood donor samples (0.93%); four sera reacted only with the capsid antigen. The peptide test distinguished true from false positive results in agreement with recombinant immunoblot assay in 96% of blood donor samples repeatably reactive on a recombinant hepatitis C virus enzyme immunoassay.
Splicing of juvenile and adult tau mRNA variants is regulated by thyroid hormone, The effect of thyroid hormone on the expression of tau transcripts was studied during postnatal brain development. The level of tau mRNA was only slightly changed postnatally in the cerebral hemispheres of hypothyroid rats. whereas the level of tau mRNA in the cerebellum was maintained at a higher level than in the euthyroid controls. As shown by in situ hybridization studies. such an alteration in tau mRNA expression can be ascribed to an effect of thyroid hormone on the rate of migration of the granule cells in the cerebellum; that tau mRNAs remain high in the cerebellum as long as the granule cells are migrating correlates with the observation that hypothyroidism slows the rate of migration of granule cells. RNase protection assays also showed that thyroid hormone deficiency delays the transition between the immature and mature tau transcripts in both brain regions. Thus. one of the effects of thyroid hormone is to regulate the splicing mechanism that allows replacement of the juvenile tau variants by the adult entities during neuronal differentiation.
In vivo footprinting of MHC class II genes: bare promoters in the bare lymphocyte syndrome, Major histocompatibility complex (MHC) class II genes are coordinately regulated and show tissue-specific expression. With the use of in vivo footprinting. common promoter sites in these genes were found to be occupied only in cells that expressed the genes. in spite of the presence of the promoter binding proteins. In vivo analysis of mutant cell lines that exhibited coordinate loss of class II MHC expression. including several from individuals with bare lymphocyte syndrome. revealed two in vivo phenotypes. One suggests a defect in gene activation. whereas the other suggests a defect in promoter accessibility.
Blood-brain barrier disruption after cardiopulmonary resuscitation in immature swine, We investigated blood-brain barrier permeability in 2-3-week-old anesthetized pigs during and after cardiopulmonary resuscitation. We assessed permeability by tissue uptake of radiolabeled aminoisobutyric acid. after correcting for plasma counts in tissue with radiolabeled inulin. Among 14 regions examined. the transfer coefficient of aminoisobutyric acid in nonischemic control animals ranged from 0.0018 +/- 0.0001 ml/g/min in diencephalon to 0.0049 +/- 0.0003 ml/g/min in cervical spinal cord. After 8 minutes of cardiac arrest followed by either 10 or 40 minutes of continuous sternal compression. there was no increase in the transfer coefficient. Likewise. during the immediate period after ventricular defibrillation. there was no increase in transfer coefficient despite the brief. transient hypertension. However. after 8 minutes of arrest. 6 minutes of cardiopulmonary resuscitation. and 4 hours of spontaneous circulation. the transfer coefficient was significantly increased by 59-107% in 10 of 11 regions rostral to the pons. Plasma volume in tissue measured by inulin was not elevated. suggesting that the increased transfer coefficient was not due to increased surface area. Thus. after an 8-minute period of complete ischemia. the blood-brain barrier remains intact during and immediately after resuscitation despite large vascular pressure fluctuations. However. in contrast to previous work on adult dogs. immature pigs are prone to a delayed increase in permeability. thereby allowing circulating substances greater access to the brain.
Selective attenuation by perivascular blood of prostanoid-dependent cerebrovascular dilation in piglets, Cerebral hemorrhagic insults are common in neonates. However. the consequences of intracranial blood on cerebral hemodynamics are poorly understood. We examined the effects of perivascular blood on cerebrovascular dilator responses in 29 piglets. Fresh. autologous blood (n = 15) or cerebrospinal fluid (n = 14) was placed under the dura mater over the parietal cortex. and the piglets were allowed to recover from anesthesia. One to four days later. a closed cranial window was placed over the parietal cortex and pial arteriolar responses to arterial hypercapnia (PaCO2 greater than 55 mm Hg). hemorrhagic hypotension (mean arterial blood pressure less than 35 mm Hg). or topical application of 10(-6) and 10(-4) M isoproterenol were determined. Pial arterioles in the cerebrospinal fluid group dilated 27 +/- 4% (mean +/- SEM) (n = 11) in response to hypercapnia. 26 +/- 5% (n = 9) in response to hypotension. and 26 +/- 3% in response to 10(-6) M and 40 +/- 4% in response to 10(-4) M isoproterenol (n = 11). In the group in which blood was placed on the parietal cortex. pial arterioles did not dilate significantly in response to hypercapnia (8 +/- 3%. n = 11) or hypotension (2 +/- 5%. n = 13) but dilated normally in response to isoproterenol (25 +/- 5% in response to 10(-6) M and 36 +/- 7% in response to 10(-4) M. n = 13). We conclude that prolonged contact of pial arterioles with extravascular blood selectively attenuates cerebrovascular dilation in piglets.
Effects of insulin on blood, plasma, and brain glucose in hyperglycemic diabetic rats, This study. in biologically bred hyperglycemic diabetic rats. examined the effect of a intravenous insulin infusion (1.5 units.hr-1) on blood. plasma. and brain glucose concentrations to determine their relationship during decreasing blood and plasma glucose levels. The data were compared to saline-treated diabetic rats and saline-treated nondiabetic littermates. The volume and duration of the treatment infusion were similar in all groups. Insulin infusion in diabetic rats produced the expected reduction in blood and plasma glucose. and normoglycemia was produced within 78 +/- 37 minutes (mean +/- SD). However. once normoglycemia was achieved. brain glucose was still significantly greater by 44% than in nondiabetic rats (p = 0.015). Moreover. the ratio of brain to plasma glucose was more than 50% greater in diabetic than nondiabetic rats. irrespective of whether or not they received insulin (p less than 0.01). We conclude that measurement of blood or plasma glucose in diabetic subjects will tend to underestimate the amount of glucose in the brain and that this relationship is not influenced by acute insulin therapy.
Description of a closed window technique for in vivo study of the feline basilar artery, Recent interest in the regulatory functions of large cerebral arteries has led to many studies addressing the specific reactivity of these vessels. Current data originate mainly from in vitro experiments. as in vivo studies of larger intracranial cerebral arteries have been cumbersome so far due to the lack of a suitable animal model. We provide a detailed technical description of a closed transclival window method for in vivo study of the basilar artery in cats. We present our experience with this preparation in 29 animals. which shows that the technique is feasible and allows repeated. accurate. and reproducible measurements of the basilar artery. although possible depressive effects of the anesthesia on vascular reactivity have to be taken into account. With hyperventilation. the basilar artery constricted by 12.2 +/- 7.6% of the baseline diameter. The cerebral blood flow response to hypocapnia with this preparation was 2.0 +/- 0.4%/torr PaCO2. An exudative clouding of the window occurred in some cats but had no apparent effect on vascular reactivity. We also discuss possible pitfalls in the surgical preparation.
Prospective gene rearrangement studies and multiparameter analysis of acute myeloid leukemia, Twenty-six cases of acute myeloid leukemia (AML) with cytochemical and immunophenotypic data were studied prospectively for immunoglobulin and T-cell receptor gene rearrangement. Dysmyelopoiesis was seen in 100% and Auer rods in 18%. Sudan black B was positive in 83% of the cases. peroxidase in 76%. nonspecific esterase in 74% (fluoride-inhibited in 82%). chloroacetate in 70%. acid phosphatase and PAS in 100%. and immunoperoxidase stains for platelet glycoprotein IIIa and factor VIII in 0% of the cases studied. Flow cytometry revealed myeloid phenotype in 19 of 20 cases. In four cases 5-86% of cells were TdT positive. Heavy-chain gene rearrangement was demonstrated in three cases (12%) and kappa light chain gene rearrangement in one; clinically significant rearrangement of the T-cell receptor gene was not found. Rearrangements of immunoglobulin genes are found occasionally in AML; these may represent nonspecific findings or coexistent lymphoid differentiation in AML.
Alterations of polymorphonuclear leukocyte glycogen metabolism and glucose uptake in dialysis patients, Human polymorphonuclear leukocytes (PMNs) are activated during extracorporeal circulation. An indicator of PMN activation may be the glycogen-degrading enzyme phosphorylase. It is unknown whether dialysis therapy may influence PMN carbohydrate metabolism. Therefore. PMNs were isolated from healthy control subjects. patients undergoing continuous ambulatory peritoneal dialysis (CAPD). and patients undergoing regular hemodialysis therapy (RDT) before. during. and at the end of hemodialysis (HD) treatment using dialyzers made of polysulfone or polymethylmethacrylate (PMMA). Nifedipine (NIF) was continuously infused during HD with PMMA in 5 patients at a dose of 18 micrograms/kg body weight per hour. Glycogen. activity of glycogen synthetase and phosphorylase (active and inactive forms of both enzymes). and glucose uptake with and without stimulation with the chemotactic peptide FMLP were determined in these PMNs. During HD with PMMA. there was a significant increase of PMN phosphorylase "a" activity 15 and 30 minutes after the start of HD. HD with polysulfone did not stimulate the active "a" form of the glycogen-degrading enzyme in PMNs. HD with PMMA significantly inhibited the active I-form of glycogen synthetase. whereas polysulfone activated glycogen synthetase I. NIF inhibited phosphorylase "a" activation during HD with PMMA. PMN glycogen content and glucose uptake were improved during HD with polysulfone. but not with PMMA. PMN glycogen content. activity of glycogen synthetase. and glucose uptake were significantly lower also in CAPD patients compared with healthy controls. These data show that HD with PMMA activates PMN glycogenolysis. This effect can be inhibited by calcium channel blockers. PMN glycogen content of RDT and CAPD patients is significantly lower compared with healthy controls due to inhibition of glycogen synthesis. Elimination of dialyzable factor(s) improves. but does not restore. PMN glycogen synthesis and glucose uptake.
Urokinase-type plasminogen activator is expressed in stromal cells and its receptor in cancer cells at invasive foci in human colon adenocarcinomas, In this study in situ hybridization methods were used to examine biopsy samples from 13 adenocarcinomas of the colon for the presence of mRNA for the urokinase-type plasminogen activator (u-PA) and its specific cell-surface receptor (u-PAR). In all cases. u-PA mRNA was present in fibroblastlike cells in the stroma adjacent to the invasive tumor nodules. Urokinase-type plasminogen activator mRNA was not detected in the malignant cells. All specimens also contained u-PAR mRNA in cells located at the tumoral-stromal interface of invasive foci. but in contrast at least some of these cells were in all but one case identified as being of malignant origin. Stromal cells. probably tumor-infiltrating macrophages and neutrophils. also were positive in these areas. These results support the view that components of the plasminogen activation system may act to influence proteolytic events occurring at the interface between stroma and malignant cells in adenocarcinomas of the colon in humans.
Importance of viability and attachment to an ascites tumor in the release of plasminogen activator, Tumor plasminogen activator (PA) has been alleged to play a role in the growth and metastasis of tumors. Before such a role can be realized. PA first must be released from tumor cells. Having determined intra- and extracellular PA and PA-inhibitor activities in an experimental pancreatic ascites tumor grown in hamsters. the release of PA from these cells was investigated. No PA activity was detected in the suspension medium of freshly isolated tumor cells; inclusion of plasminogen. fibrinogen. or collagen in the medium yielded similar negative results. On the other hand. PA activity was demonstrated to be released in a time-dependent manner from these tumor cells embedded in fibrin clots. Plasminogen activator activity also was not found in the suspension medium of frozen-thawed tumor cells. despite the fact that most of them had breaks on their cell membrane. Unlike freshly isolated tumor cells. PA was not released from frozen-thawed cells embedded in fibrin clots. Full PA activity was demonstrated in frozen-thawed cells treated with Triton X-100. however. Frozen-thawed cells exhibited signs of severe damage. and more than 80% of them failed to exclude trypan blue. Obviously PA is released from viable tumor cells embedded in fibrin clots but not suspended in artificial medium. The PA-release mechanism. not PA itself. is destroyed in cells rendered nonviable by freeze thawing.
Lack of evidence for a percent saturation gap in cyanide poisoning, STUDY OBJECTIVES: To determine if toxic concentrations of cyanide in blood result in a difference between calculated and measured percent hemoglobin oxygen saturation (percent saturation gap). DESIGN: An in vitro laboratory study. SETTING: Hospital laboratory. TYPE OF PARTICIPANTS: Arterial blood from five stable patients residing in a tertiary hospital ICU. Venous blood samples obtained from five healthy volunteers. INTERVENTIONS: Two-mL aliquots from each blood sample were placed into four test tubes and mixed with phosphate buffer. Cyanide was added to three of the tubes so that the four tubes contained 0. 6. 12. and 25 mg/L cyanide. MEASUREMENTS AND MAIN RESULTS: The percent saturation gap was calculated by subtracting the percent oxyhemoglobin measured on an oximeter from the percent saturation calculated by a blood gas analyzer. Using two-tailed. paired t tests. we could not demonstrate a difference in mean percent saturation gaps between arterial samples or venous samples with and without cyanide. All blood samples had a normal percent saturation gap (P greater than .99 by Fisher's exact test). We had greater than a 95% chance of demonstrating a difference in mean percent saturation gaps of only 0.46% in arterial blood and of 3.3% in venous blood if such a difference existed. CONCLUSIONS: Our results. as well as a review of the literature. indicate that there are no data supporting the suggestion that a percent saturation gap should imply the diagnosis of poisoning by inorganic cyanide.
Acute misoprostol toxicity, Misoprostol (Cytotec) is a recently released prostaglandin E1 analog approved for use in prevention of nonsteroidal anti-inflammatory drug-induced gastropathy. We report one of the first known examples of toxicity in an acute ingestion since the drug was first released in international markets in 1984. After an accidental ingestion of 3 mg misoprostol (approximately 15 times the maximum recommended therapeutic dose). a 71-year-old woman exhibited fever. tremor. tachycardia. hypertension. nausea. and abdominal cramping. Recovery ensued with standard supportive care. The physiology of this unique drug and implications for management of acute toxicity are summarized.
Pharmacologic control of plasma exudation into tracheobronchial airways, We have employed anesthetized guinea pigs to examine effects of nonsteroidal antiasthma drugs on airway plasma exudation. which is a process of potential pathogenetic importance in asthma. This study focused on exudation of plasma into the airway luman (circumventing problems with a changing blood pool in tissue samples). Topical tracheal superfusions with a neurogenic agent (capsalcin). bradykinin. and histamine increased mucosal blood flow (Laser Doppler flowmetry) and produced significant exudation of macromolecular plasma tracers (fluorescein-labeled dextran 156000 D; 131I-albumin 70.000 D). Lidocaine 3 x 10(-5) M. applied topically. inhibited capsalcin- but not bradykinin-induced plasma exudation. Intravenously administered terbutaline. enprofylline. and theophylline and topical cromoglycate dose-dependently inhibited the inflammatory stimuli-induced mucosal exudation of plasma. Cromoglycate did not alter airway blood flow. and both terbutaline and enprofylline increased the blood flow. Hence. these three types of drugs did not inhibit exudation by stopping flow. Further. both neural and non-neural exudative responses were inhibited. suggesting that the drugs may have acted directly on the permeability-regulating microvascular endothelial cells. It is proposed that antiexudative actions may contribute to the antiasthma effects of beta 2-agonists. xanthines. and cromoglycates.
Defective candidacidal activity of alveolar macrophages and peripheral blood monocytes from patients with chronic obstructive pulmonary disease, We investigated the in vitro candidacidal activity of alveolar macrophages (AM) and peripheral blood monocytes (PBM) from normal subjects or from patients with chronic obstructive pulmonary disease (COPD) displaying defective skin test delayed-type hypersensitivity (DTH) reactivity to seven antigens including Candida albicans. The results showed that cells from patients with COPD were significantly less effective than cells from control subjects in the killing of C. albicans. To explore whether the observed functional impairment could be reversed. interferon-gamma (IFN-gamma) was added to AM and PBM from patients with COPD. alone or in the presence of lipopolysaccharide (LPS) as a suboptimal stimulus. The cells were cultured for 24 h and then assayed for anti-Candida activity. After IFN-gamma treatment. the fungicidal activity of cells from patients with COPD was comparable to that of unstimulated AM or PBM from healthy donors. Treatment with IFN-gamma plus LPS resulted in a further enhancement in the killing of C. albicans. To gain more insight into the mechanisms involved in the modulation of killing. we evaluated the possible stimulating activity of IFN-gamma plus LPS treatment on the secretion of tumor necrosis factor (TNF) and interleukin-1 (IL-1). two cytokines produced by activated macrophages and capable of stimulating natural effectors. The results showed that IFN-gamma plus LPS can indeed stimulate TNF and IL-1 secretion by AM and PBM from patients with COPD. Therefore. a precise role can reasonably be ascribed to these soluble factors in the observed augmentation of candidacidal activity as ascertained by treatment with IFN-gamma plus LPS.
Chromosomally mediated beta-lactamase production and gentamicin resistance in Enterococcus faecalis, We have analyzed four distinct strains of multiply resistant. beta-lactamase-producing enterococci isolated during an outbreak of colonization with these strains on an infant-toddler surgical ward at The Children's Hospital in Boston. Mass. All four strains were resistant to erythromycin. penicillin. and tetracycline and to high levels of gentamicin and streptomycin. One strain was also resistant to chloramphenicol. Plasmid profiles revealed four different plasmid patterns. with the number of identified plasmids ranging from zero to three. The gene coding for beta-lactamase production could be transferred at low frequency (less than 10(-8)) to an enterococcal recipient from one strain in conjunction with all of the other resistance determinants. Probes derived from the staphylococcal beta-lactamase gene and gentamicin resistance gene failed to hybridize with any of the detectable plasmids. but both genes were present on restriction fragments of genomic DNA in all strains. Our results indicate that the beta-lactamase genes and gentamicin resistance genes in these strains are integrated into the bacterial chromosome. The cotransmissibility of the resistance determinants raises the possibility of their incorporation into a multiresistance transposable genetic element.
Anti-human immunodeficiency virus synergism by zidovudine (3'-azidothymidine) and didanosine (dideoxyinosine) contrasts with their additive inhibition of normal human marrow progenitor cells, The anti-human immunodeficiency virus (HIV) activity and hemopoietic toxicity of zidovudine (AZT) and didanosine (dideoxyinosine;ddI). alone and in combination. were assessed in a variety of cell types. AZT was more potent than ddI as an inhibitor of HIV in vitro. Synergistic inhibition of HIV by the combination of these agents was observed in MT4 cells. peripheral blood lymphocytes. and macrophages. Toxicity assessment in vitro by using progenitor (erythroid and granulocyte-macrophage) colony-forming assays with normal human bone marrow showed ddI to be less toxic than AZT. Addition of inhibitory concentrations of ddI to AZT resulted in additive inhibition of progenitor CFUs. These in vitro findings suggest that combinations of ddI and AZT at appropriately modified doses may provide an enhanced degree of selectivity in anti-HIV chemotherapy.
Biochemical properties and purification of metallo-beta-lactamase from Bacteroides fragilis, The beta-lactamase from Bacteroides fragilis GAI-30144 hydrolyzed imipenem. oxyiminocephalosporins. cephamycins. and penicillins. Enzyme activity was inhibited by EDTA. Zinc completely reversed inactivation of the enzyme by EDTA. The molecular mass of purified enzyme was estimated to be 33.000 daltons.
Staff training: a key factor in reducing intravascular catheter sepsis, A children's hospital nutritional care team prospectively monitored the frequency of sepsis in central venous catheters used for administering parenteral nutrition. During an initial study period of 12 months. 26/58 (45%) of catheters were removed because of proved sepsis. The possible causes of this alarmingly high rate were examined. with catheter care techniques on the wards coming under particular scrutiny. As a result protocols were modified and an intensive staff training programme implemented throughout the hospital. led by the nutritional care sister. Subsequently. the catheter sepsis rate was significantly reduced with only 9/107 (8%) of consecutive catheters becoming infected. These findings emphasise the key role that education of staff plays in controlling central venous catheter sepsis and the importance and cost effectiveness of special nursing staff in implementing such measures.
Production of endothelium-derived contracting factor is enhanced after coronary reperfusion, To determine whether coronary reperfusion enhances the production of endothelium-derived contracting factor. we investigated dogs subjected to global cardiac ischemia (45 minutes) followed by reperfusion (60 minutes). Segments of reperfused and control coronary arteries were suspended in organ chambers to measure isometric force. Perfusate hypoxia caused endothelium-dependent contraction in the control and reperfused arteries. However. reperfused arteries exhibited hypoxic contraction that was significantly greater than control segments. The hypoxic contractions in both the control and reperfused arteries could be inhibited by NG-monomethyl-L-arginine (L-NMMA). the blocker of endothelial cell synthesis of nitric oxide from L-arginine. The action of L-NMMA could be reversed by L-arginine but not D-arginine. Thus. after reperfusion. augmented production of endothelium-derived contracting factor occurs by an L-arginine-dependent pathway. We hypothesize that nitric oxide produced by L-arginine metabolism combines with superoxide anion to produce the peroxynitrite anion (ONOO-). which is metabolized to endothelium-derived contracting factor or induces its synthesis. Augmented production of endothelium-derived contracting factor would favor vasospasm after reperfusion.
Retinal toxicity of human tissue plasminogen activator in vitrectomized rabbit eyes, The retinal toxicity of human tissue plasminogen activator in normal rabbit eyes has recently been reported. We now report the retinal toxicity of tissue plasminogen activator in three groups of vitrectomized rabbit eyes. Group 1 underwent gas compression of the vitreous followed by tissue plasminogen activator injection in doses of 25. 50. and 100 micrograms (all doses were administered in 100 microL of fluid). Group 2 underwent lensectomy and vitrectomy followed by tissue plasminogen activator injection of 100 micrograms. Group 3 underwent lensectomy. vitrectomy. and complete fluid/gas exchange prior to injections of 12.5 and 25 micrograms of tissue plasminogen activator. Control eyes received 100 microL of balanced salt solution. In group 1. no retinal toxic reactions were observed after administration of 25 or 50 micrograms of tissue plasminogen activator. but all eyes receiving 100 micrograms demonstrated retinal damage on ophthalmoscopy. electroretinography. and light microscopy. In group 2. no retinal toxic reactions were seen after administration of 100 micrograms of tissue plasminogen activator. In group 3. two of 11 eyes receiving 25 micrograms of tissue plasminogen activator demonstrated toxic retinal changes by ophthalmoscopy. electroretinography. and light microscopy. These results suggest that gas compression of the vitreous does not significantly alter the toxic changes seen caused by tissue plasminogen activator. While lensectomy and vitrectomy appears to widen the therapeutic window for tissue plasminogen activator. the margin of safety is reduced with the addition of a large gas bubble.
Synovial T lymphocyte-specific immune response to Chlamydia trachomatis in Reiter's disease, We studied the lymphocyte proliferative response to Chlamydia trachomatis in Reiter's syndrome (RS) compared with that in other rheumatic diseases. RS patients showed significantly increased C trachomatis-specific synovial fluid (SF) T cell proliferation. Proliferating cells were found in both CD4+ and CD8+ T cell subsets. The SF lymphocyte proliferative response to C trachomatis in RS was inhibited by anti-class I and class II major histocompatibility complex monoclonal antibodies. while the response to tuberculin purified protein derivative was inhibited only by anti-class II monoclonal antibodies. T cell receptor gamma/delta-bearing T cells were not consistently increased in RS SF compared with peripheral blood. nor did such cells consistently expand upon in vitro culture with C trachomatis. Finally. there was no correlation between the cellular immune response and levels of antibody to C trachomatis antigens. Our results indicate that a specific T cell response to C trachomatis within the joint plays a role in the pathogenesis of RS.
The effect of topical nitroglycerin on transcutaneous oxygen, The use of topical nitroglycerin has been reported to aid the healing of chronic skin ulcers. In this study. the effect of 2% nitroglycerin ointment on transcutaneous oxygen pressure (TcPO2) was investigated in skin adjacent to the area of ointment application. Topical nitroglycerin caused a two-fivefold decrease in TcPO2 in skin next to or up to 9 cm away from the site of application of the ointment.
Audit of ankle injuries in an accident and emergency department, OBJECTIVE--To determine whether the treatment of ankle injuries in an accident and emergency department could be improved by an audit of existing treatment and the creation and use of a protocol. DESIGN--The study consisted of three parts: a review of the current treatment and published reports on treatment. the formation of a protocol. and a study of treatment after introducing the protocol. SETTING--Accident and emergency department of a district general hospital. PATIENTS--550 patients attending the department with ankle injuries over four months. RESULTS--The review of treatment showed that patients with fractures were detected and treated adequately. but most had radiography. Patients with ligamentous injuries may have been undertreated. After introducing the protocol the number of patients undergoing radiography was reduced from 205 (80%) to 186 (70%) (0.0027 less than p less than 0.01). In 87% of the notes reviewed the protocol had been completed. Sixty six patients with ligamentous injuries were reviewed in the department or soft tissue clinic compared with 20 before the protocol was introduced. There was a 53% reduction in inappropriate referrals to the fracture clinic (13 before v nine after). CONCLUSIONS--Using a protocol can. at little expense. improve the treatment of ankle injuries and reduce the cost of radiology in an accident and emergency department. IMPLICATION--Treatment of other conditions may be improved by introducing a protocol.
Antiphospholipid antibodies and recurrent pregnancy loss, Women with antiphospholipid antibodies have a significant risk of reproductive failure and adverse pregnancy outcomes. The incidence of recurrent abortion. fetal death. and intrauterine fetal growth retardation is significant. Women with a history of recurrent abortion and unexplained fetal death or a history of recurrent thrombotic episodes should be screened for the presence of antiphospholipid antibodies. The benefit of routine screening of pregnant women for the presence of these antibodies has not been established. and the yield from such screening studies has been found to be low. No treatment regimen has eliminated fetal loss and adverse pregnancy events completely in women with the antiphospholipid antibody syndrome. Even when treatment is instituted. maternal and fetal status must be monitored closely. Management of such patients has not been standardized. and various treatment regimens have been found to be efficacious. Multicenter randomized treatment trials are currently underway. and standardization of therapy in these patients may be achieved.
Transcription, storage and release of atrial natriuretic factor in the failing human heart, 1. In this study the relationship between the synthesis of atrial natriuretic factor at the level of atrial natriuretic factor mRNA and the atrial storage and circulating plasma levels of atrial natriuretic factor were investigated in 15 patients with heart failure. The patients underwent right and left heart catheterization before cardiac surgery for valve replacement or coronary artery bypass grafting. 2. Plasma concentrations of atrial natriuretic factor were correlated to atrial levels of atrial natriuretic factor mRNA. Atrial levels of atrial natriuretic factor mRNA and plasma concentrations of atrial natriuretic factor exhibited a close correlation to both pulmonary artery pressure and left atrial pressure. No relationship. however. could be found between the right atrial content of atrial natriuretic factor and both the expression of atrial natriuretic factor mRNA in the atria and the plasma levels of atrial natriuretic factor. 3. From these data it may be concluded that increased plasma levels of atrial natriuretic factor in the pressure- and/or volume-overloaded heart are associated with an elevated level of atrial natriuretic factor mRNA. We suggest that not only plasma levels of atrial natriuretic factor but also the expression of atrial natriuretic factor in the atrial are related to left ventricular filling pressures in the failing human heart.
Spontaneous release of interferon gamma by intestinal lamina propria lymphocytes in Crohn's disease. Kinetics of in vitro response to interferon gamma inducers, The spontaneous induced release of interferon gamma (IFN gamma) by cultured intestinal lamina propria lymphocytes was investigated in patients with Crohn's disease. In contrast to normal lymphocytes. intestinal lymphocytes from these patients spontaneously released IFN gamma and seemed to contain IFN gamma in their cytoplasm. Autologous peripheral lymphocytes did not release IFN gamma. When stimulated with interferon inducers lamina propria lymphocytes from Crohn's disease tissue showed an increase in IFN gamma release 24 hours after induction with no appreciable further increase over the next two days of culture. while in control cells. either peripheral or intestinal. IFN gamma release progressively increased. peaking 72 hours after induction. These findings indicate that in Crohn's disease the intestinal lymphocytes are stimulated in vivo to produce IFN gamma and that the spontaneous IFN gamma production is compartmentalised to the gut lymphocytes. These data support the concept that locally released IFN gamma has a crucial role in cell interactions in the lamina propria and contribute to the locally occurring immune phenomena in Crohn's disease. including the increased epithelial expression of major histocompatibility complex class II antigens.
Patterns of pulsatile luteinizing hormone and follicle-stimulating hormone secretion in prepubertal (midchildhood) boys and girls and patients with idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome): a study using an ultrasensitive time-resolved immunofluorometric assay, To study the ontogeny of spontaneous pulsatile LH and FSH secretion before the onset of puberty. plasma LH and FSH were measured by an ultrasensitive time-resolved immunoflurometric assay in 16 boys and 6 girls. aged 6.5 +/- 0.2 yr (+/- SEM; range. 4.4-8.0) with short stature. Eight male patients with idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome). aged 24.1 +/- 3.4 yr. were also investigated. Blood samples were withdrawn at 10- to 20-min intervals for 12 h from 2000-0800 h. Pituitary responsiveness was assessed by a standard iv LHRH challenge test. LH and/or FSH pulses were detectable in all but two prepubertal subjects. In boys. low amplitude LH (0.16 +/- 0.06 U/L) and FSH (0.19 +/- 0.03 U/L) pulses were detectable at mean frequencies of 2.19 +/- 0.37 and 2.13 +/- 0.46 pulses/12 h. respectively. In girls. low amplitude LH (0.29 +/- 0.18 U/L) pulses. but higher (P less than 0.05 compared to boys) amplitude FSH (1.62 +/- 1.05 U/L) pulses were observed at frequencies of 1.71 +/- 0.56 and 1.67 +/- 0.53 pulses/12 h. respectively. Mean FSH in prepubertal girls (1.95 +/- 0.88 U/L) was significantly (P less than 0.05) higher than that in boys (0.46 +/- 0.07 U/L). but mean LH was not different at 0.17 +/- 0.07 and 0.10 +/- 0.03 U/L. respectively. Patients with Kallmann's syndrome had mean LH and FSH levels indistinguishable from those of prepubertal boys. Nocturnal augmentation of pulsatile LH or FSH secretion was observed in 74% of children (71% in girls and 75% in boys). but in none of the eight patients with Kallmann's syndrome. A close temporal association was observed between sleep onset and the appearance of nocturnal pulsatile gonadotropin secretion. The FSH response to exogenous LHRH in prepubertal girls was significantly greater than that in patients with Kallmann's syndrome and prepubertal boys. but LH responses were not different. Our results show that pulsatile LH and FSH secretion occurs in the majority of boys and girls in midchildhood. with a robust association with nocturnal sleep onset. Between the ages of 4-8 yr. these low amplitude and low frequency pulses are unable to activate gonadal function. The regulation of FSH secretion in prepubertal girls appears to be different from that in prepubertal boys.(ABSTRACT TRUNCATED AT 400 WORDS).
Reduction of gonadotropin-releasing hormone pulse frequency is associated with subsequent selective follicle-stimulating hormone secretion in women with polycystic ovarian disease, Polycystic ovarian disease (PCO) is characterized by hyperandrogenism. ovulatory dysfunction. and altered gonadotropin secretion. Mean plasma FSH concentrations are low. while LH is elevated in a majority of patients. LH pulsatile secretion has been shown to occur at rapid follicular phase frequencies (approximately one pulse per h) in PCO. suggesting persistent rapid frequency GnRH secretion in this disorder. Anovulatory women with PCO were given estradiol (E2; Estraderm skin patches) and progesterone (P; vaginal suppositories) to produce midluteal concentrations for 21 days. The aim was to determine if E2 and P would slow LH (GnRH) pulse frequency and if this would result in augmented FSH secretion and follicular development after withdrawal of E2 and P. Plasma LH was measured every 10 min for 8 h before. during (days 10 and 20). and 7 days after withdrawal of E2 and P (day 28). On each of these study days FSH was measured hourly. and E2 and P were measured every 2 h. After sampling. GnRH (25 and 250 ng/kg. iv) was given to assess pituitary responsiveness. Follicular development was monitored by vaginal ultrasound through day 34 of the study. Basal LH frequency was 8.5 +/- 0.5 pulses/8 h (mean +/- SEM). During E2 and P. LH pulse frequency fell to 3.3 +/- 1.0 (10 days) and 2.3 +/- 0.8 (20 days). 39% and 27% of the basal value. respectively. and subsequently increased to 5.6 +/- 0.7 (66% of basal) 7 days after withdrawal of E2 and P. LH pulse amplitude (basal. 7.2 +/- 1.5 IU/L) was not reduced until day 20. but remained suppressed (3.9 +/- 1.1 IU/L) on day 28. As a result. mean LH (basal. 21.0 +/- 3.5 IU/L) fell progressively during E2 and P. to 3.8 +/- 1.2 IU/L on day 20. and remained low (39% of basal) 7 days after steroid withdrawal. Mean plasma FSH (basal. 7.1 +/- 0.9 IU/L) also fell during steroid administration. but in contrast to LH. had risen to 93% of the basal value by 7 days after E2 and P. LH release in response to exogenous GnRH revealed marked initial responses which did not decrease until day 20. but remained suppressed (8% of basal) after withdrawal of E2 and P. FSH responses were also suppressed on day 20. but had increased to 75% of the basal value by day 28. Initiation of follicular development occurred in all patients. and the lead follicle measured 12.3 +/- 0.8 mm 13 days post-E2 and P. Ovulation occurred in one patient.(ABSTRACT TRUNCATED AT 400 WORDS).
Effects of recombinant human interleukin-2 and tumor necrosis factor-alpha with or without interferon-gamma on human thyroid tissues from patients with Graves' disease and from normal subjects xenografted into nude mice, We have compared the effects of interleukin-2 (IL-2) or tumor necrosis factor-alpha (TNF alpha) administration with or without interferon-gamma (IFN gamma) on Graves' and normal thyroid tissue xenografts in the nude mouse (in the absence of an intact immune system) in terms of possible functional. immunological. or histological changes. The dosages of recombinant human IL-2. TNF alpha. and IFN gamma given to each mouse were 250. 800. and 4000 U. respectively; they were injected ip daily for 6 consecutive weeks. The parameters measured included the free T4 index. thyroid autoantibodies. and mouse TSH during the course of the study. Thyroid epithelial cell (TEC) HLA-DR expression was measured in thyroid tissue before xenotransplantation and at death; in addition. light microscopic studies were carried out at those times. There were no significant differences in thyroid function between the results in unstimulated (control) animals and those obtained with cytokine administration in either group of tissues. with the exception of the group receiving TNF alpha together with IFN gamma; in this latter group. the free T4 index declined significantly 4-6 weeks after commencement of treatment in the animals with normal thyroid tissue xenografts. The reduction of thyroid function induced by the combination of IFN gamma and TNF alpha observed in normal thyroid tissue may be due to inhibition of thyroperoxidase and thyroglobulin gene transcription. However. there was no such effect on the Graves' thyroid tissue xenografts. perhaps because of down-regulation of this tissue in response to cytokines. after having been released from long term in vivo immune stimulation. On the other hand. TNF alpha plus IFN gamma induced TEC HLA-DR expression on both types of thyroid xenografts at death. although IL-2 alone did not induce HLA-DR expression. and IFN gamma induced TEC significantly only on normal thyroid xenografts (but not on Graves' xenografts). In light microscopic examination. Graves' thyroid xenografts treated with IL-2 alone or TNF alpha plus IFN gamma appeared normal at death. In addition. normal thyroid xenografts treated with the same cytokines did not show discernible differences compared to those at human surgery or when the xenografts were untreated at death. We conclude that Graves' TEC did not differ from normal TEC in any significant fashion at the time of death. aside from a reduced responsiveness to the stimuli applied.
Effect of H1-receptor blockade on late cutaneous reactions to antigen: a double-blind, controlled study, This study is of the effect of the blockade of histamine H1 receptors by a long-acting antihistamine on the immediate and late clinical response to antigen (Ag) and on the recruitment of eosinophils in the late-phase cutaneous reaction. Ten adult volunteers with late-phase reactions to the intradermal injection of either Dermatophagoides pteronyssinus or Phleum pratense (timothy) pollen performed a double-blind. crossover study. Each volunteer took astemizole. 10 mg. or identical placebo. daily for 2 weeks. Ag in the concentration that induced a late reaction in the screening visit was injected intradermally at the end of each drug period. The early reaction was measured serially for 30 minutes and the late reaction at 4 and 6 hours. Biopsies of the Ag and control sites were also performed at 6 hours. After a 6-week washout period. subjects then took the opposite medication for 2 weeks and returned for skin testing and biopsy. Skin testing demonstrated that astemizole inhibited the immediate response to both histamine and allergen but had no effect on the late response at 4 hours and at 6 hours. Biopsy specimens revealed no significant effect on eosinophil recruitment at 6 hours. We conclude that histamine H1-receptor blockade has no effect on the late cutaneous reaction to Ag.
The effect of inhaled ipratropium bromide alone and in combination with oral terfenadine on bronchoconstriction provoked by adenosine 5'-monophosphate and histamine in asthma, The aim of this study was to investigate the effect of terfenadine. an antihistamine. 180 mg orally. the anticholinergic drug. ipratropium bromide (IB). 0.5 mg nebulized aerosol. the combination of these two drugs. and placebo tablets and aerosol on histamine- and adenosine 5'-monophosphate (AMP)-induced bronchoconstriction in a randomized. double-blind fashion. Airway response was evaluated as FEV1. After placebo. the geometric mean (GM) provocative concentration causing a 20% in FEV1 from the postsaline baseline value (PC20) for histamine and AMP was 0.63 and 5 mg/ml. respectively. Terfenadine displaced the FEV1 concentration-response curves obtained with both histamine (GM PC20 values increasing to 26.92 mg/ml) and AMP (GM PC20 values increasing to 26.7 mg/ml) to the right. IB had a small. but significant. protective effect against the fall in FEV1 produced by histamine and AMP. the GM PC20 values increasing to 1.69 and to 12.6 mg/ml. respectively. Terfenadine and IB in combination produced protection against histamine and AMP that was more than the production produced by either drug alone. the GM PC20 values increasing to 54.76 and 47.7 mg/ml. respectively. There was no correlation between degree of bronchodilatation induced by active treatments and concentration ratios for AMP or histamine. These data suggest that histamine release and vagal reflexes both contribute to AMP-induced bronchoconstriction in clinical asthma in man.
Distinct subsets of accessory cells activate Thy-1+ triple negative (CD3-, CD4-, CD8-) cells and Th-1 delayed-type hypersensitivity effector T cells, The SJL strain of mice possess a unique developmental delay in the ability to exhibit delayed-type hypersensitivity (DTH) responses after immunization with a wide variety of Ag. Similar to other models of DTH. the adoptive transfer of syngeneic Ag-pulsed macrophages from DTH-responsive mice into these DTH-unresponsive mice results in the activation of Ag-specific. CD4+ DTH effector Th1 T cells. The absence of other defects in APC-dependent immune responses indicate that the macrophages is the sole APC required for the induction of DTH effector T cells in SJL mice. The defect occurs during the sensitization phase of the DTH response; however. it has not been determined whether a Th cell. which is required for the induction of CD4+ DTH effector T cells. was present in the DTH unresponsive SJL mice. In this study. we have determined that the Thy-1+ helper cell is induced upon Ag stimulation of nonresponder mice and present evidence for the existence of an accessory cell distinct from the macrophage that induces CD4+ DTH effector T cells. Our data indicate that CD4+ DTH effector T cells are induced in an Ag-specific and MHC-restricted manner by an adherent macrophage that expresses the Mac-1+. Mac-2-. Mac-3+. I-A+ phenotype. Adoptive transfer of as few as 100 of the Mac-1+. Mac-2-. or Mac-3+ subsets from DTH responsive donors to DTH unresponsive recipients is able to overcome the DTH deficit. The activation of CD4+ DTH effector T cells in the SJL mouse cells also requires a Thy-1+. Lyt-1+. CD3-. CD4-. CD8-. helper cell. In contrast to the Mac-1+. Mac-3+. I-A+ accessory cell. this helper cell requires an adherent. irradiation resistant. accessory cell that expresses the Mac-1+. Mac-2-. Mac-3-. I-A- surface phenotype for activation. Further. the interaction between this accessory cell and the Thy-1+ helper cell is neither Ag-specific nor MHC restricted. This is the first demonstration of an accessory cell requirement for the Thy-1+. Lyt-1+. B220-. CD4-. CD8-. CD3- DTH Th cell. These data indicate that the activation of the triple negative helper cells and subsequent activation of the CD4+ effector T cells are regulated by two distinct macrophage subpopulations.
Differential control of IFN-gamma and IL-2 production during Trypanosoma cruzi infection, In murine infection with Trypanosoma cruzi. immune responsiveness to parasite and non-parasite Ag becomes suppressed during the acute phase of infection. and this suppression is known to extend to the production of IL-2. To determine whether suppression of lymphokine production was specific for IL-2. or was a generalized phenomenon involving suppressed production of other lymphokines. we have begun an investigation of the ability of mice to produce of a number of lymphokines during infection. initially addressing this question by studying IFN-gamma production. Supernatants from Con A-stimulated spleen cells from infected resistant (C57B1/6) and susceptible (C3H) mice were assayed for IFN-gamma. Supernatants known to be suppressed with respect to IL-2 production from both mouse strains contained IFN-gamma at or above that of supernatants from normal spleen cells. Samples were assayed in an IFN bioassay to ensure that the IFN-gamma detected by ELISA was biologically active. Thus. suppression during T. cruzi infection does not extend to the production of all lymphokines. The stimulation of IFN-gamma production was confirmed by detection of IFN-gamma mRNA in unstimulated spleen cells from infected animals. and in Con A. Con A + PMA. and in some cases. parasite Ag-stimulated spleen cells from infected animals. IFN-gamma mRNA levels in mitogen-stimulated spleen cells equalled or exceeded those found in similarly stimulated normal cells. In contrast. stimulated spleen cells from infected animals had reduced levels of IL-2 mRNA relative to normal spleen cells. Thus at both the protein and mRNA level. IFN-gamma production is stimulated by T. cruzi infection. whereas IL-2 production is suppressed. Serum IFN-gamma in infected C57B1/6 and C3H mice was detected 8 days after infection. peaked on day 20 of infection. and subsequently fell. but remained detectable at low levels throughout the life of infected mice. Infected animals were depleted of cell populations known to be capable of producing IFN-gamma. and Thy-1+. CD4-. CD8-. NK- cells. and to a lesser degree. CD4+ and CD8+ cells were found to be responsible for the production of IFN-gamma during infection. We also report that IL-2 can induce IFN-gamma production in vitro and in vivo by spleen cells from infected animals. and that IL-2 can synergize with epimastigote or trypomastigote antigen to produce high levels of IFN-gamma comparable to those found in supernatants from mitogen-stimulated cells.
Role of listeriolysin-O (LLO) in the T lymphocyte response to infection with Listeria monocytogenes. Identification of T cell epitopes of LLO, Using a murine model. we investigated the role of the bacterial exotoxin listeriolysin O (LLO) in cellular immunity to Listeria monocytogenes. A correlation between LLO production by infecting bacteria and generation of protective immunity to virulent LLO-producing bacteria was noted. Using isogeneic hemolysin (Hly+ or Hly-) strains of L. monocytogenes. we demonstrated that LLO production by infecting bacteria is required to elicit T cells reactive both to bacteria-associated Ag and to the secreted LLO molecule as measured by IL-2 production in vitro. Distinct sets of T cells specific for largely nonoverlapping pools of antigenic determinants represented by LLO and cell-associated Ag (heat-killed L. monocytogenes) are generated after infection. We have used models for prediction of T cell epitopes based on primary structure of LLO. and synthetic amphipathic LLO peptides were evaluated as Ag in vitro or as immunogenes in vivo. Infection of several strains of mice (H-2k and H-2d) with LLO-producing L. monocytogenes resulted in the generation of T cells that could respond consistently to two peptides. LLO 215-234 and LLO 354-371. Mouse strains lacking expression of I-E molecules (e.g.. B10.A(4R) and C57BL/6) responded to LLO but not to the peptides tested. With C3HeB/FeJ mice. antibodies to I-Ek blocked the presentation of LLO 215-234. The importance of the N-terminal portion of LLO 215-234 was evidenced by the drastic reduction in antigenic activity of truncated peptides (e.g.. LLO 221-234 and LLO 224-234). LLO 215-234. the strongest and most consistent activator of T cells from L. monocytogenes-immune mice. fit well some models for antigenic peptides in several ways. It could be predicted to form an amphipathic alpha-helix. it contained multiple "Rothbard motifs" (charged residue or glycine. two or three hydrophobic amino acids and then a glycine or polar residue). it had a net charge of +2. and it contained the correct spacing of amino acids (five to six residues between a hydrophobic and basic amino acid) that is characteristic of I-Ek-binding peptides. Immunization with 8 of 10 synthetic LLO peptides generated T cells that recognized the immunizing peptide in vitro. but such T cells were only poorly reactive with LLO. Our results indicate that LLO is an important target Ag for stimulation of CD4+ L. monocytogenes-specific T cells. and that LLO 215-234 is antigenically dominant in C3HeB/FeJ mice.
Specific release of granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and IFN-gamma by human tumor-infiltrating lymphocytes after autologous tumor stimulation, Tumor-infiltrating lymphocytes (TIL) have been cultured from a variety of human tumors. and some melanoma TIL have demonstrated specific. MHC-restricted recognition of autologous tumor in short term lysis assays. The current study investigates cytokine release by TIL as an indicator of specific tumor recognition. We have identified two of four melanoma and one of seven breast carcinoma TIL cultures that specifically release granulocyte-macrophage-CSF. TNF-alpha. and IFN-gamma after autologous tumor stimulation. The other cultures either do not secrete cytokine or secrete cytokine in a nonspecific fashion. The amount of specific cytokine released is directly related to the number of TIL and stimulating tumor cells. Studies of TIL. from two melanoma patients. separated into CD4+ and CD8+ populations revealed that CD8+ cells were responsible for virtually all of the specific cytokine secretion. although both populations released cytokines when activated by immobilized anti-CD3 antibody. Specific cytokine release by CD8+ TIL was inhibited by anti-MHC class I mAb. Specific cytokine release was also detected from a CD4+ breast cancer TIL culture. and this was inhibited by anti-MHC class II mAb. The clinical significance of this specific mode of immune antitumor reactivity is currently under investigation.
Changing patterns of epiglottitis in children, With an increased awareness of appropriate management of childhood epiglottitis. overall morbidity and mortality has decreased. However. some trends have developed over the past several years that are variations on the classic picture. In a series of 42 patients seen from 1977 to 1986. epiglottitis has occurred in a progressively younger population. Thirty-six percent of our patients were found to be less than 2 years old. and 51% were less than 3 years old. Also. the causative organism. Haemophilus influenzae. has been found to be increasingly ampicillin-resistant. The incidence. presentation. management. and outcome of the patients are reviewed. and compared to similar data from other series in the literature.
Preservation of facial contour during parotidectomy, Parotid surgery often leaves a facial contour deformity. Free abdominal dermal-fat grafts were used to preserve the facial contour of nine patients undergoing parotid surgery. This procedure is simple to perform and provides an improved cosmetic result without significantly increasing operative time or lengthening hospitalization. No troublesome fat absorption occurred postoperatively. The dermal-fat graft also serves as a barrier to regenerating neurons. thereby preventing postoperative gustatory sweating.
Diagnostic efficacy of in vitro methods vs. skin testing in patients with inhalant allergies, The purpose of our study was to investigate the diagnostic efficacy of two selected methods of in vitro allergy testing. Specifically. the PRIST/modified RAST I125 isotope systems and the Quantizyme/modified EAST alkaline phosphatase method were compared. The time. expense. convenience. and diagnostic efficacy of the two procedures are discussed. Special attention is given to the practicality of each method for the practicing physician.
Protective effect of electrical stimulation in the deafened guinea pig cochlea, The effect of chronic intrascalar electrical stimulation on the spiral ganglion cell survival of the ototoxically deafened guinea pig was investigated. Immediately after ototoxic drug administration. unilateral sinusoidal (1 kHz) charge-balanced electrical stimulation on a 50% duty cycle was administered for 2 hours per day. 5 days per week. at intensities from 0 (control) to 400 microAmp via an implanted scala tympani electrode. The relationship of electrically evoked middle latency response (EMLR) to stimulation protocol and cell survival was studied. At 9 weeks post-drug treatment. the animals were killed and temporal bones were prepared for morphometric analysis of spiral ganglion cell density. The subjects showed essentially complete elimination of outer hair sensory cells. with minimal remaining inner hair cells confined to apical turns. Variable loss of spiral ganglion cell populations was observed. which related to electrical stimulation. In animals that received daily unilaterally electrical stimulation. statistically significant increases in survival of spiral ganglion cells were observed in the stimulated ear. compared to the nonstimulated ear-particularly in basal cochlear regions near the electrode. Spiral ganglion cell density was a function of stimulation current intensity level. Moreover. the slope of the amplitude input/output (I/O) function of the EMLR was found to be dependent on stimulating current level. The effect of stimulation on induced survival may be dependent on a number of mechanisms. including metabolic effects of direct activation of "deafferented" spiral ganglion cells. These data support the suggestion that implantation may provide optimal benefits when performed shortly after deafness.
Is melanoma changing, Nine hundred ninety-five cases of melanoma of the head and neck were divided into two groups so that certain comparisons could be made concerning the behavior of melanoma over a 55-year period. One hundred twelve melanomas of the ocular system were excluded from this review. The first group consisted of 660 melanomas seen during a period from 1932 to 1972. The second group consisted of 223 melanomas seen during a period from 1973 to 1987. Thirteen parameters. including sex. age. distribution. pre-existing mole. amelanotic melanoma. delay in diagnosis. classification. levels. local recurrence. regional metastasis. systemic metastasis. morbidity. and survival. were studied to assess the behavior and the variations. There is no question that the most important aspect of the favorable changes that have occurred are because of earlier diagnosis and better management by a larger group of well-trained specialists. There are some subtler changes that could possibly indicate biologic alterations. but this requires more time and study to substantiate.
Videoendoscopic evaluation of patients with dysphagia: an adjunct to the modified barium swallow, The modified barium swallow is currently the most comprehensive. widely available. and easily interpreted technique for the evaluation of patients with dysphagia by the head and neck surgeon. However. it requires the facilities. personnel. and use of a radiology suite. a trained speech pathologist. and exposure of the patient to radiation. It would therefore be helpful to have an adjunctive. physician based. nonradiographic method of examination that could provide information similar to and possibly even more complete than that supplied by the modified barium swallow. Such an adjunctive method could help otolaryngologist-head and neck surgeons confronted by a new patient with swallowing difficulties to orient themselves to the nature and severity of the problem while waiting for the modified barium swallow to be scheduled. performed. and reviewed. It could also be a helpful tool for management of patients with cancer of the head and neck. whose swallowing function may change rapidly in the early postoperative period. In such cases. intervals between modified barium swallow examinations (dictated by concern over radiation exposure) may be too far apart to allow up-to-the-minute decisions on case management. Finally. some patients who may be too ill to travel to the radiology suite might benefit from a bedside procedure that would yield information about swallowing function similar to that provided by the modified barium swallow. Videoendoscopic evaluation of dysphagia (VEED) is a protocol I developed and have used regularly since 1984. Experience with this method of dysphagia evaluation has shown that it answers the needs outlined above. Its usefulness also goes beyond that of the modified barium swallow by providing a more detailed understanding of the component anatomic and functional deficits that comprise a given patient's swallowing problem. information about upper aerodigestive tract sensory deficits. and a means for visual feedback training of pharyngeal and laryngeal musculature. The protocol is reviewed here. Case reports illustrating the clinical usefulness of VEED as an adjunct to the modified barium swallow are also presented. and the relative strengths and weaknesses of VEED and the modified barium swallow are compared.
Growth and histopathology of human head and neck squamous cell carcinoma implanted intraorally in nude mice, A human squamous cell carcinoma (SCC) from the floor of the mouth (FOM) was implanted by a needle aspiration technique in the FOM site of athymic nude mice. Mice were killed at 3-week intervals. and the oral cavity. mandible. and neck were sectioned and examined histologically. Tumor growth was observed in 65% of the animals. with histologic features consistent with the engrafted human invasive SCC. These features included invasion of connective tissue in 92%. invasion of muscle in 77%. invasion and destruction of bone in 54%. and vascular invasion in 15% of the mice. In contrast. FOM tumor implanted subcutaneously on back sites of nude mice was totally encapsulated by fibrous connective tissue with evidence of capsular invasion. SCC from other head and neck sites showed similar locally invasive growth after intraoral implantation in nude mice. The results demonstrate the invasive characteristics of human head and neck SCC grown in the homologous oral cavity site in nude mice and support the nude mouse as a biologically relevant in vivo model in the investigation of the biologic characteristics and therapy of head and neck carcinoma.
FTZ-F1, a steroid hormone receptor-like protein implicated in the activation of fushi tarazu, The Drosophila homeobox segmentation gene fushi tarazu (ftz) is expressed in a seven-stripe pattern during early embryogenesis. This characteristic pattern is largely specified by the zebra element located immediately upstream of the ftz transcriptional start site. The FTZ-F1 protein. one of multiple DNA binding factors that interacts with the zebra element. is implicated in the activation of ftz transcription. especially in stripes 1. 2. 3. and 6. An FTZ-F1 complementary DNA has been cloned by recognition site screening of a Drosophila expression library. The identity of the FTZ-F1 complementary DNA clone was confirmed by immunological cross-reaction with antibodies to FTZ-F1 and by sequence analysis of peptides from purified FTZ-F1 protein. The predicted amino acid sequence of FTZ-F1 revealed that the protein is a member of the nuclear hormone receptor superfamily. This finding raises the possibility that a hormonal ligand affects the expression of a homeobox segmentation gene early in embryonic development.
Overview of biochemical markers used for nutrition support, Altered metabolism has been shown to exist in the settings of surgical stress. cancer. cirrhosis. sepsis. and trauma. Each condition is characterized by varying degrees of alteration in metabolic processes. and within a given patient. these metabolic alterations will change as the patient's status changes. Nutrition support is an integral part of the metabolic management of critically ill patients. Metabolic changes impact nutritional substrate requirements and utilization. As the patient's clinical condition deteriorates. clinical signs and symptoms become less reliable in predicting or assessing the existing physiologic state. Objective measurements are needed to define the metabolic status during these physiologic changes. The purpose of this article is to review selected indices that have been used to identify abnormalities in nutritional substrate metabolism. Although some of these tests are readily available and inexpensive. many have not been used outside of the research setting and. therefore. their clinical utility has yet to be determined. However. their use as research tools for defining metabolism warrants their inclusion in order to assist the clinician in interpreting research studies. The biochemical markers discussed include glucose. lactate. pyruvate. triglycerides. beta-hydroxybutyrate. acetoacetate. urinary nitrogen. acute phase proteins. visceral proteins. 3-methylhistidine. plasma amino acids. oxygen consumption. and resting energy expenditure. Each marker is defined in terms of its biochemical significance. and the literature describing changes that occur in various stress states is cited.
Economic analyses in hypertension: applications for healthcare providers, Hypertension affects millions of Americans. With healthcare dollars becoming more closely scrutinized. economic studies are playing an important role in helping decision makers choose who should receive treatment and which treatments and methods of administration are most cost-effective. This article provides an overview of the different methods used in economic evaluation and demonstrates the utility of each method using studies from the hypertension literature.
Recurrent hepatocellular carcinoma after partial hepatectomy: value of treatment with transcatheter arterial chemoembolization, The usefulness of transcatheter arterial chemoembolization (TACE) of the hepatic artery was retrospectively evaluated in 66 patients who underwent the procedure for treatment of hepatocellular carcinoma that recurred after partial hepatectomy. The materials infused were Gelfoam sponge or Gelfoam sponge plus Lipiodol and an anticancer agent. A control group of 15 patients with recurrent tumor received oral anticancer agents alone. The cumulative survival rate for the TACE group was 88% for the first year. 57% for 2 years. 42% for 3 years. and 27% for 5 years. whereas that of the control group was 80% for the first year. 27% for 2 years. and 18% for 3 years. Thus. the prognosis of the TACE group was significantly better (p less than or equal to .01. log-rank test) than that of the control group. The survival rate was inversely correlated with the ratio of the volume of the recurrent tumor to the volume of the whole residual liver. These results suggest that TACE is more effective than oral chemotherapy for treatment of hepatocellular carcinoma that recurs after partial hepatectomy.
Double blind crossover comparison of the effects of dual chamber pacing (DDD) and ventricular rate adaptive (VVIR) pacing on neuroendocrine variables, exercise performance, and symptoms in complete heart block, OBJECTIVE--To compare the effects of dual chamber pacing (DDD) and ventricular rate adaptive pacing (activity sensing) (VVIR) in patients with complete heart block. DESIGN--Double blind crossover comparison with one month in each pacing mode. PATIENTS--10 consecutive patients aged 23-74 presenting with complete anterograde atrioventricular block at rest and on exercise and with an intact atrial rate response received Synergyst I (Medtronic) pacemakers. MAIN OUTCOME MEASURES--Symptom scores. maximal exercise performance on a treadmill. and the plasma concentrations of atrial natriuretic peptide. adrenaline. and noradrenaline. RESULTS--No significant differences were identified between pacing modes in symptom scores for dyspnoea. fatigue. and mood disturbance; exercise time; and maximal oxygen consumption. One patient with intact ventriculoatrial conduction developed pacemaker syndrome during VVIR pacing. Resting plasma concentrations of atrial natriuretic peptide were raised in complete heart block and were restored to normal by DDD pacing but not by VVIR pacing. Resting plasma catecholamine concentrations were normal in complete heart block and in both pacing modes. During exercise the increase in the concentrations of all three hormones was similar in both pacing modes. CONCLUSIONS--In patients with complete anterograde and retrograde atrioventricular block. symptoms and maximal exercise performance were no better during DDD than during VVIR pacing.
Kinetic modeling of in vivo--nuclear magnetic resonance spectroscopy data: 5-fluorouracil in liver and liver tumors, Kinetic modeling has been applied to the time course of the nuclear magnetic resonance signal intensities of 5-fluorouracil and the sum of its catabolites. alpha-fluoro-beta-ureido propanoic acid and alpha-fluoro-beta-alanine. as monitored in liver tumors of seven patients with cancer after brief intraarterial infusion of 5-fluorouracil. Because these data represent only relative tissue concentrations. only ratios of clearance and volume parameters can be estimated (e.g.. clearance/central volume of distribution or central volume of distribution/steady-state volume of distribution). On the other hand. parameters that do not refer to volumes. such as half-lives or maximal velocity of metabolic conversion of a nonlinear model. can be estimated in absolute terms. A nonlinear three-compartment model gave satisfactory fits with all of the individual data sets. Kinetics of 5-fluorouracil and catabolites were similar in five patients with metastases of colorectal adenocarcinomas but differed from those of two patients with cholangiocarcinoma and metastases of an anaplastic carcinoma of unknown origin. respectively.
A checklist for managing the dementia patient, Primary care physicians seeing a growing number of elderly demented patients must consider a number of problem areas when treating such patients. This article offers the mnemonic FICS'M (Family. Intellectual status. Continence. Sleep. and Mobility) to help physicians address treatable problems associated with dementing illnesses. Strategies are offered to minimize morbidity from the particular problem and from the treatment. such as trying "low toxicity" therapies and medications with few side effects. Other medical. ethical. and legal issues are discussed. including handling dangerous behaviors and abuse. nursing home placement and autopsy. and specific treatment of both the dementia itself and associated disorders--agitation. depression. and delirium.
Neuromyotonia in hereditary motor neuropathy, Two siblings with a distal motor neuropathy experienced cramping and difficulty in relaxing their muscles after voluntary contraction. Electromyographic recordings at rest revealed repetitive high voltage spontaneous electrical discharges that were accentuated after voluntary contraction and during ischaemia. Regional neuromuscular blockage with curare indicated hyperexcitability of peripheral nerve fibres and nerve block suggested that the ectopic activity originated in proximal segments of the nerve. Symptoms were improved with diphenylhydantoin. carbamazepine and tocainide.
Cerebrovascular CO2 reactivity in migraine: assessment by transcranial Doppler ultrasound, Cerebrovascular reactivity to CO2 inhalation was studied by transcranial Doppler sonography in 30 patients with classic or common migraine and 39 healthy controls without clinical or ultrasonic signs of arteriosclerosis. Systolic and diastolic Doppler frequencies of the middle cerebral artery were plotted against end-tidal CO2 partial pressure; the reactivity index (I x R) was defined as relative frequency change during a PCO2 increase of 5 mmHg. In the normal subjects. I x R was 20.0 +/- 6.3 for systolic velocities. and 26.0 +/- 8.2 for diastolic values. Migraineurs during their headache-free interval had significantly higher I x R values on the affected side (mean: 41.6 systolic. 61.2 diastolic). compared with either controls (P less than 0.01) or the contralateral side (mean: 28.3 systolic. 30.8 diastolic; P less than 0.01). During the headache attack. CO2 reactivity was significantly lower than normal only for systolic velocities (mean: 8.3; P less than 0.05). Increased CO2 reactivity is thought to be one phenomenon of migraine. Transcranial Doppler CO2 testing of cerebrovascular reactivity is a reliable method that may be of interest for the diagnostic evaluation and management of migraine patients.
Antiphospholipid antibodies and recurrent abortion, We examined the association between anticardiolipin antibodies. lupus anticoagulant. and the risk of recurrent spontaneous abortion in a case-control study conducted in a network of general and teaching hospitals in northern Italy. Subjects consisted of 220 women with two or more unexplained consecutive spontaneous abortions and 193 controls admitted for acute conditions other than immunologic. infective. gynecologic. or cardiovascular. Lupus anticoagulant was detected in 16 of 220 cases (7%. 95% confidence interval 4-11%) but in none of the 193 controls (Fisher exact test. P less than .001). Increased anticardiolipin antibody levels were demonstrated in 19 of 99 cases (19%. 95% confidence interval 12-31%) (seven immunoglobulin (Ig) G. eight IgM. and four IgG and IgM) and in four (all IgG) of 157 controls (3%) for whom data were available. These results offer quantitative evidence on the association between antiphospholipid antibodies and recurrent abortion.
Increased incidence of nosocomial pneumonia in mechanically ventilated patients with subclinical aspiration, Nosocomial pneumonia is frequent and is associated with high mortality in intubated mechanically ventilated patients. To determine whether there is a significant relationship between subclinical aspiration from nasogastric feeding and development of nosocomial pneumonia. we studied 24 ventilated patients who received nasogastric feeding. Endotracheal aspirates were tested twice daily for the presence of glucose using a glucose oxidase reagent strip. Subclinical aspiration was defined by the presence of glucose in nonbloody endotracheal aspirates. Nosocomial pneumonia was defined by the presence of all of the following conditions: (1) new or worsening infiltrate on chest roentgenogram consistent with pneumonia. (2) temperature greater than 38 degrees C and/or white blood cell count greater than 10.000/mm3 with 10% or more band forms. (3) culture of a new organism in the sputum. and (4) purulent tracheobronchial secretions. Twelve patients had no positive glucose tests of their endotracheal aspirates during their intensive care unit stay. one of whom developed nosocomial pneumonia. Twelve patients had endotracheal aspirates that were positive for glucose on 1 to 5 occasions. Of these patients. seven had bloody glucose-positive aspirates. four of whom developed clinical pneumonia. The remaining five patients had nonbloody glucose-positive endotracheal aspirates and all developed nosocomial pneumonia. There was a significantly greater incidence of pneumonia among patients who had nonbloody glucose-positive aspirates than among patients without glucose-positive aspirates (p less than 0.001. Fisher's exact test). We conclude that subclinical aspiration of nasogastric feeding. as detected by nonbloody glucose-positive endotracheal aspiration. is associated with the development of nosocomial pneumonia.
Gonadal function after allogenic bone marrow transplantation for thalassaemia, Thirty prepubertal patients with thalassaemia major (15 boys and 15 girls) aged from 9.3 to 17.2 years (mean 12.9) who had successfully undergone allogenic bone marrow transplantation were studied. Before the transplant all patients were given short courses of high doses of busulphan (total dose 14 mg/kg) followed by cyclophosphamide (total dose 200 mg/kg). Pituitary gonadal function was assessed between 0.7 and 5.1 years (mean 2.3) after bone marrow transplantation. Increased gonadotrophin concentrations indicating gonadal damage were found in 80% of the girls. probably as a result of the chemotherapy. In all the prepubertal boys the basal follicle stimulating hormone and luteinising hormone concentrations were normal. Most of the boys had reduced gonadotrophin and testosterone responses after gonadotrophin releasing hormone and human chorionic gonadotrophin tests. This could have been the result of iron overload but the effect of cytotoxic agents cannot be excluded. These findings emphasise the need for vigilant long term follow up of thalassaemic patients treated with cytotoxic chemotherapy for bone marrow transplantation so that those requiring hormone replacement can be identified and treated.
Racial heterogeneity of HIV antigenemia in people with HIV infection, We compared the prevalence of HIV p24 antigenemia in black and white US patients with HIV infection. The prevalence of HIV antigenemia increased with severity of HIV disease (P less than 0.001). In all clinical categories. whites were more likely to be HIV-antigenemic than blacks (overall prevalence 38 versus 18%; P less than 0.01). Anti-p24 antibodies were detected in a higher proportion of blacks (84%) than whites (65%; P = 0.02). Blacks had significantly higher total serum immunoglobulin levels than whites (median 3.8 versus 3.2 mg/dl; P less than 0.00001). Racial differences in HIV antigen expression may result from differences in humoral response to HIV infection. These differences should be considered when HIV antigen is used as a surrogate marker in clinical trials.
Selective uptake of glutamine in the gastrointestinal tract: confirmation in a human study, Recent animal data suggest that the gut plays a far more important metabolic role than previously thought. During critical illness. disruption in bowel barrier function may result in a chronic hypermetabolic state and contribute to multiorgan failure. Animal studies have demonstrated that enterocytes of the gastrointestinal tract use glutamine as a respiratory fuel and during critical illness the consumption of glutamine by the gut significantly increases. The selective uptake of glutamine by the gut. to date. has not been confirmed in humans. Seven patients who sustained multisystem trauma necessitating laparotomy underwent portal venous catheterization. This was done by carefully reopening the obliterated umbilical vein and facilitating access to the left branch of the portal vein using a standard central venous catheter. Portal venous and systemic blood samples were recorded for 5 days after operation. Amino acid levels in both circulations were recorded at 48 h and 5 days. Using Student's t test for related samples. the differences between individual amino acids in portal and systemic circulations were compared. At 48 h. mean(s.d.) portal venous glutamine was 85(5) per cent of the systemic levels (253(80) compared with 296(90) mumol/ml. P less than 0.002). At 5 days. portal glutamine was 87(3) per cent of the systemic levels (255(69) compared with 292(83) mumol/ml. P less than 0.003). Levels of citrulline. a breakdown product of glutamine metabolism. were elevated in the portal venous circulation at 48 h (20(4) compared with 16(3) mumol/ml. P less than 0.005) and at 5 days (21(5) compared with 14(3) mumol/ml. P less than 0.002). No significant differences between any of the other amino acids analysed were identified. This study confirms. for the first time in humans. that selective uptake of glutamine occurs in the gut. In stressed states. glutamine deficiency is associated with gut mucosal atrophy. This has significant implications as glutamine is not provided in most commercially available parenteral and enteral nutrition formulations.
Stimulation of protein synthesis in human tumours by parenteral nutrition: evidence for modulation of tumour growth, Eighteen patients with localized colorectal carcinoma were randomized to receive intravenous nutrition or to be fasted during the 24 h before surgery. Protein synthesis. an index of tumour growth. was then measured by the incorporation of [13C]leucine into tumour protein immediately before surgery. The mean (s.e.m.) rate of tumour protein synthesis in patients receiving nutrition (42.7(3.5) per cent per day) was 89 per cent higher than the rate in the fasted group (22.6(1.9) per cent per day) (P = 0.002). As tumours consist of a variety of different cell types. in vitro rates of protein synthesis were measured in malignant cells isolated from colorectal tumours and cultured with autologous serum obtained from the patient in either the fasted or the fed state. There was a mean increase of 81 per cent in protein synthesis when fed rather than fasted serum was used (P less than 0.02). indicating that the malignant cells themselves respond to nutrient supply. This increase in tumour protein synthesis provides the first evidence in vivo that the exogenous supply of nutrients can modulate the rate of growth of a human tumour.
Carbon dioxide laser ablation of cutaneous metastases from malignant melanoma, Multiple cutaneous and superficial subcutaneous metastases from malignant melanoma in 30 patients were treated palliatively by carbon dioxide laser ablation when lesions were to numerous. too large or recurring too rapidly for multiple local excisions. The number of lesions per patient ranged from three to 250 (median 30). Patients were treated under local or general anaesthetic and as day cases or inpatients. After a median follow-up interval of 8 months fewer than 1 per cent of lasered metastases have recurred locally. Sixteen patients have developed cutaneous metastases at other sites requiring further treatment. Approximately 2000 lesions have been treated on 64 occasions. Patients reported little or no pain after the operation and required only simple dry dressings. Wounds were completely healed in 2-6 weeks with good cosmetic results. This simple and effective treatment is becoming an alternative to isolated limb perfusion.
Trial of flecainide acetate in the management of tinnitus, A two-phase trial of flecainide acetate in the management of tinnitus has been carried out in 22 patients with severe long-term tinnitus resistant to other treatments. Although 5 (23%) patients reported some limited benefit the results are not conclusive but suggest that. for such patients. flecainide deserves a place as a drug worth considering as a last resort. with the prospect of it occasionally giving a worthwhile degree of relief.
Renal sensitivity to endothelium-derived-relaxing-factor-mediated vasodilatation in the spontaneously hypertensive rat, 1. The sensitivity of the kidney to endothelium-derived-relaxing-factor-mediated vasodilatation has been investigated in the spontaneously hypertensive rat and the Wistar-Kyoto normotensive rat using an isolated perfused rat kidney model. 2. No difference in the slope. ED50 or maximum of the concentration-response curves for the endothelial-dependent vasodilators A23187. a calcium ionophore. and acetylcholine could be demonstrated between kidneys obtained from the spontaneously hypertensive and the Wistar-Kyoto normotensive rats. 3. No difference in the slope or the ED50 of the concentration-response curve for the endothelial-independent vasodilators. atrial natriuretic factor and sodium nitroprusside. could be demonstrated between kidneys obtained from the spontaneously hypertensive and the Wistar-Kyoto normotensive rats. However. in the spontaneously hypertensive rats. the maximum vasodilator response to atrial natriuretic factor. but not to sodium nitroprusside. was increased. 4. The perfused kidney from the spontaneously hypertensive rat also showed an increase in the maximum but not in the slope or ED50 of the concentration-response curve for vasoconstriction induced by the alpha 1-adrenoceptor agonist methoxamine. 5. The involvement of endothelium-derived relaxing factor in mediating the renal vasodilator response to A23187 and acetylcholine was confirmed in experiments performed in perfused kidneys obtained from normotensive Wistar rats. 6. It is concluded that the sensitivity of the kidney to endothelium-derived-relaxing-factor-mediated vasodilatation is not modified in the spontaneously hypertensive rat. This does not. however. exclude a role for the synthesis of endothelium-derived relaxing factor in the maintenance of blood pressure in the spontaneously hypertensive rat.
In vitro perfused-superfused cat carotid body for physiological and pharmacological studies, An in vitro perfused carotid body preparation was developed to study its chemosensory responses to physiological and pharmacological stimuli. The carotid bifurcation with the carotid body was vascularly isolated and excised from pentobarbital sodium-anesthetized cats. The CB was perfused in a chamber by gravity (80 Torr) with modified Tyrode's solution (N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-NaOH at pH 7.40) equilibrated at a given Po2 and superfused with the same medium at (Po2 of 20 Torr). The temperature was maintained at 35.5 +/- 0.5 degrees C. The frequency of chemosensory discharges (CD) was recorded from the whole carotid sinus nerve (n = 24). and the responses were tested by repeated interruptions of perfusate flow (SF). perfusion with hypoxic medium. and injections of nicotine and cyanide (0.1 nmol to 1 mumol) and hypercapnic medium. During hyperoxic perfusion. SF resulted in a sigmoidal increase in CD. reaching a maximum that was 23.6 +/- 4.4-fold greater than the basal activity. Restoration of flow returned CD promptly to basal values. After normoxic perfusion. SF led to a similar maximal activity more rapidly. but the duration was shorter. Reduction of the perfusate PO2 (Po2 from 450 Torr to 150. 30. and less than 10 Torr) caused a nonlinear increase in CD. CO2 stimuli (PCo2 38-110 Torr) resulted in a linear increase in CD. Nicotine or cyanide increased CD in a dose-dependent manner. The preparation retained its initial responsiveness for 2-3 h. making extensive experimental studies feasible.
Coronary patency, infarct size and left ventricular function after thrombolytic therapy for acute myocardial infarction: results from the tissue plasminogen activator: Toronto (TPAT) placebo-controlled trial. TPAT Study Group, Infarct size. left ventricular function and infarct-related coronary artery patency were examined in 108 patients who took part in a previously reported placebo-controlled trial of recombinant tissue-type plasminogen activator (rt-PA) in acute myocardial infarction. Coronary angiography was performed 17 +/- 0.8 h after initiation of treatment in 47 patients (group A) or at 10 days in 61 patients (group B). Both groups underwent radionuclide ventriculography 3.8 +/- 0.8 h and again on day 9 after treatment and quantitative thallium scintigraphy on day 8. In group A. the infarct-related artery was patent in 53%; these patients had a smaller global (15.1 +/- 2.5% vs. 25.7 +/- 4.7%. p = 0.029) and regional (14.7 +/- 2.5% vs. 24.1 +/- 4.7%. p = 0.044) fixed thallium defect than did those with an occluded artery. Infarct regional ejection fraction improved by 10.1 +/- 2.1% between early and late studies when the infarct-related artery was patent and by 4.8 +/- 1.4% if it was occluded (p = 0.048); changes in global and noninfarct regional ejection fraction were similar irrespective of perfusion status. Infarct regional ejection fraction and fixed thallium defect were inversely related only when the infarct-related artery was occluded (r = -0.83. p less than 0.0001). In group B. 10 day patency of the infarct-related artery was 67%; there was no difference in patency by treatment assignment or in left ventricular function or infarct size between patients with and without infarct-related artery patency. There was no evidence of an effect of rt-PA therapy beyond that expressed through coronary patency alone in either group A or group B.
Doppler echocardiographic transmitral peak early velocity does not directly reflect hemodynamic changes in humans: importance of normalization to mitral stroke volume, Doppler echocardiographic transmitral peak early velocity normalized to the time-velocity integral during diastole is equivalent to volumetric peak filling rate normalized to stroke volume. To compare the pathophysiologic validity of normalized and nonnormalized peak early flow velocity. pulsed Doppler echocardiography with simultaneous high fidelity left ventricular pressure measurements was performed in 52 patients with coronary artery disease. Left ventricular loading conditions were changed by intravenous administration of norepinephrine in 15 patients and synthetic atrial natriuretic polypeptide in 15 others. Norepinephrine increased nonnormalized and normalized peak early flow velocities in association with significantly elevated end-diastolic. peak systolic and mitral valve opening pressures and decelerated the time constant of left ventricular isovolumetric pressure decline. Atrial natriuretic polypeptide did not change either nonnormalized or normalized peak early flow velocity. despite significant reductions in end-diastolic. peak systolic and mitral valve opening pressure and an accelerated time constant. Normalized peak early flow velocity showed the highest univariate correlation with long-term change in mitral valve opening pressure (n = 52. r = 0.67. p less than 0.0001). It provided a modest univariate correlation (n = 30. r = 0.74. p less than 0.0001) with immediate change in mitral valve opening pressure during norepinephrine infusion. whereas this correlation was lower (n = 30. r = 0.57. p less than 0.001) during polypeptide infusion. However. multivariate regression analysis relating normalized peak velocity with long- and short-term changes in end-diastolic. peak systolic and mitral valve opening pressures. time constant and constant of left ventricular chamber stiffness improved the correlation coefficients (r = 0.80 to 0.85. all p less than 0.0001). In contrast. neither univariate nor multivariate correlations of nonnormalized velocity with long- and short-term changes in these hemodynamic variables were satisfactory. Thus. nonnormalized peak early flow velocity does not directly reflect underlying hemodynamic changes in humans. Normalization to mitral stroke volume clarifies the dependence of peak early flow velocity on the determinants of early diastolic filling. When left ventricular early diastolic filling is evaluated by Doppler echocardiography. normalized peak early flow velocity should be taken into consideration.
Normalization of left ventricular mass and associated changes in neurohormones and atrial natriuretic peptide after 1 year of sustained nifedipine therapy for severe hypertension, Sixteen patients with severe hypertension were treated for 1 year with extended release nifedipine. during which time serial changes in left ventricular mass index and associated alterations in left ventricular systolic function. left ventricular filling. plasma renin activity. atrial natriuretic peptide and catecholamines were evaluated. Mean seated blood pressure (+/- SE) was significantly reduced from 200 +/- 8/122 +/- 3 to 144 +/- 5/89 +/- 2 mm Hg (p less than 0.0001) at 1 year. After 6 months. left ventricular mass index was significantly reduced by 19% from 121 +/- 8 to 96 +/- 7 g/m2 and this reduction was sustained at 1 year. Septal and posterior wall thickness were reduced from 13.4 +/- 0.1 to 11.2 +/- 0.04 mm and from 12.8 +/- 0.1 to 10.0 +/- 0.03 mm (p less than 0.001). respectively. The prevalence of left ventricular hypertrophy decreased from 63% to 25%. Left ventricular fractional shortening increased from 34 +/- 2% to 41 +/- 3% (p less than 0.05) and the relation between fractional shortening and end-systolic stress did not change. Over the year of sustained blood pressure reduction. the peak velocity of early filling increased from 57 +/- 3 to 63 +/- 4 cm/s (p = 0.07). peak velocity of late filling did not change and the ratio of late to early peak left ventricular filling velocity significantly decreased (p less than 0.05). Plasma atrial natriuretic peptide levels. markedly elevated at entry. decreased from 70 +/- 15 to 41 +/- 8 pg/ml at 1 year (p less than 0.05). Plasma renin activity and catecholamine levels were not altered.
Diarrhea associated with tube feeding: the importance of using objective criteria, Since the published incidence of tube feeding-associated diarrhea varies widely between 2.3 and 68%. and because commonly used definitions of diarrhea are subjective and imprecise. we determined the actual fecal output of malnourished patients during the first 6 days of tube feeding. Nine patients on the same isoosmolar formula were evaluated for diarrhea. Patients were interviewed daily as to whether they thought diarrhea was present or absent. Frequency of defecation was recorded. and stool was collected daily for weight. When assessed subjectively. the incidence of diarrhea rose from 11% on day 1. to 25% on day 4. and to 43% by day 6. The group (n = 4) complaining of diarrhea averaged 3.0 bowel movements per day. whereas those denying diarrhea (n = 5) averaged fewer than 0.2 bowel movements per day (p less than 0.01). Stool weight. however. plateaued for all patients by day 6 at 52.7 +/- 35.7 g of stool per day. No patient produced in excess of 250 g of stool per day. We suggest that traditional subjective measures for assessing diarrhea may be flawed and should not be relied upon when evaluating and treating tube feeding-associated diarrhea.
The effect of oral nitroglycerin on portal blood velocity as measured by ultrasonic Doppler. A double blind, placebo controlled study, We studied the effect of oral nitroglycerin on portal blood velocity (PBV) in 20 cirrhotic patients by a double blind. placebo controlled method using noninvasive Doppler sonography. After we obtained baseline Doppler in the fasting state. 0.6 mg nitroglycerin or placebo was given orally and the mean of 3 s averaged mean PBVs was repeated at 5 min intervals for 60 min. Ten patients each received nitroglycerin or placebo. Portal vein flows were antegrade in all. Of the 10 patients receiving nitroglycerin. seven (P = 0.002) showed a greater than 10% fall in the mean PBVs for at least 15 min. Of these seven "responders." five patients had a 10% decrease in mean systemic blood pressure for at least 15 min. None of the "nonresponders" had systemic hypotension. Our study suggests that the PBV-reducing effect of nitroglycerin in cirrhotics may be explained in part by systemic hypotension.
Decrease in the size of tetanic responses produced by nitrendipine or by extracellular calcium ion removal without blocking twitches or action potentials in skeletal muscle, The effects of removing extracellular Ca++ ions or of adding the organic calcium channel antagonist. nitrendipine. were tested on twitches and tetani (100 Hz for 2 sec) in frog toe muscles. Under conditions that did not reduce or that potentiated twitches. both procedures reduced the size of the tetanic responses. This depression was seen as an inability to maintain the maximum tetanic tension for more than 0.5 sec. Intracellular microelectrode recordings showed that the muscle fibers were depolarized (mean about 23 mV) during the stimulus train and the fiber only slowly repolarized after the train. The latter effect is the "late negative afterpotential" and it is produced by the accumulation of K+ ions in the t-tubules during the action potential train. Neither the depolarization nor the late negative afterpotentials were decreased in amplitude by nitrendipine. These results indicate that the voltage-sensitive. slow Ca++ channels are opened by the accumulation of K+ ions in the t-tubules during the tetanus and that the Ca++ ions entering via these channels are required to maintain the full strength of the tetanic contraction. It is suggested that this is a function of these Ca++ channels concentrated in the t-tubules of skeletal muscle fibers.
The inhibition of metabolic oxalate production by sulfhydryl compounds, A number of sulfhydryl compounds were shown to inhibit CO2 and oxalate formation from glyoxylate by rat liver homogenates and hepatocytes. The most significant inhibition occurred with cysteine and this inhibition was concentration-dependent. In rats made hyperoxaluric by administering ethylene glycol in their drinking water. daily intraperitoneal injections of cysteine caused a rapid and marked decrease in urinary oxalate excretion which was maintained over the duration of the treatment (28 days). Over this time period. the level of urinary oxalate excretion in these ethylene glycol-treated rats was reduced to that of the controls. It is postulated that the decrease is due to the formation of a cysteine-glyoxylate adduct. 2-carboxy-4-thiazolidine carboxylate. which prevents glyoxylate being further oxidized to oxalate. Cysteine or similar sulphydryl compounds may therefore have potential as therapeutic agents in the prevention of renal stones.
Localization of receptors for luteinizing hormone-releasing hormone in pancreatic and mammary cancer cells, Previous work showed that hamster and human pancreatic tumors but not normal pancreata exhibit low-affinity cell-membrane receptors for luteinizing hormone-releasing hormone (LHRH). Although the regression of experimental pancreatic cancers induced by treatment with LHRH agonists or antagonists could be explained in part by the creation of sex-steroid deficiency. direct effects mediated by LHRH receptors might also play a role. Here. we demonstrate that pancreatic tumor cells do exhibit high-affinity binding sites for LHRH. but only in their nuclei; low-affinity sites are associated with the cell membranes. These binding sites appear to be LHRH receptors since electron microscopic immunohistochemical studies show that an antibody to the LHRH receptor reacted with sites in the nucleus of pancreatic tumor cells. Immunoreactive sites in the nucleus also were found in a restricted set of normal hamster pituitary cells thought to be luteinizing hormone-secreting cells and in MXT mouse mammary tumor cells. Such nuclear receptors may be involved in the transmission of the direct action of LHRH analogues on the tumor cells. resulting in the enhancement of programmed cell death.
Linkage of recognition and replication functions by assembling combinatorial antibody Fab libraries along phage surfaces, We describe a method based on a phagemid vector with helper phage rescue for the construction and rapid analysis of combinatorial antibody Fab libraries. This approach should allow the generation and selection of many monoclonal antibodies. Antibody genes are expressed in concert with phage morphogenesis. thereby allowing incorporation of functional Fab molecules along the surface of filamentous phage. The power of the method depends upon the linkage of recognition and replication functions and is not limited to antibody molecules.
Human immunodeficiency virus infection of human lymph nodes in the SCID-hu mouse, The SCID-hu mouse is a small animal in which human hematolymphoid organs can be engrafted and maintained in vivo. In this study. parameters are described for reproducible infection of SCID-hu mice after i.v. inoculation. Infection was found to be dependent upon the time after inoculation. the virus isolate. the titer of virus. and the human target organ implanted into the mouse. Ten to 14 days after the i.v. administration of HIV isolates derived freshly from patients (e.g.. JR-CSF. JR-FL. SM). 100% of engrafted human lymph nodes in SCID-hu mice were infected; greater than 95% of these animals were also viremic. Implants of human thymus or connective tissue. as well as the endogenous murine hematolymphoid organs. were not infected. As demonstrated by a combination of in situ hybridization and immunohistochemistry. both T-lymphoid and myelomonocytic lineage cells were infected in this system. HIV isolates that have been adapted to growth in vitro (e.g.. HTLV-IIIb) were not infectious. When either 3'-azido-3'-deoxythymidine (AZT) or 2'.3'-dideoxyinosine (ddIno) was administered to SCID-hu mice before HIV infection. the animals were protected in dose ranges similar to those used in man. This animal model may now be used as an efficient intermediate step between the lab and the clinic to study the infectious process in vivo and to best select efficacious antiviral compounds against HIV.
Stress-induced elevations of gamma-aminobutyric acid type A receptor-active steroids in the rat brain, A 3 alpha-hydroxy A-ring-reduced metabolite of progesterone. 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone). and one of deoxycorticosterone (DOC). 3 alpha.21-dihydroxy-5 alpha-pregnan-20- one (allotetrahydroDOC). are among the most potent known ligands of gamma-aminobutyric acid (GABA) receptors designated GABAA in the central nervous system. With specific radioimmunoassays. rapid (less than 5 min) and robust (4- to 20-fold) increases of allopregnanolone and allotetrahydroDOC were detected in the brain (cerebral cortex and hypothalamus) and in plasma of rats after exposure to ambient temperature swin stress. Neither steroid was detectable in the plasma of adrenalectomized rats either before or after swim stress. However. allopregnanolone. but not allotetrahydroDOC. was still present in the cerebral cortex (greater than 3 ng/g) after adrenalectomy. These data demonstrate the presence of allopregnanolone and allotetrahydroDOC in brain and show that acute stress results in a rapid increase of these neuroactive steroids to levels known to modulate GABAA receptor function.
The acute effects of flecainide in the swine heart failing from incessant supraventricular tachycardia, The acute hemodynamic and electrophysiologic effects of flecainide in tachycardia-induced ventricular dysfunction were investigated using an animal model. Seven swine were initially (CON) evaluated by echocardiography and then by right heart catheterization and provocative electrical ventricular stimulation both before and after treatment with intravenous flecainide. Rapid atrial pacing at 210 to 240 beats/min (SVT) was then employed for 2 to 4 weeks until echocardiographic evidence of left ventricular dysfunction developed. Immediately upon termination of pacing. the above studies were repeated both before and after treatment with flecainide. Significant (p less than 0.0001) pacing-related hemodynamic effects on the cardiac output (CON:3.0 L/min versus SVT:1.6 L/min). right ventricular ejection fraction (CON:55% versus SVT:17%). and pulmonary wedge pressure (CON:8 mm Hg versus SVT:22 mm Hg) were observed. Pacing-related electrophysiologic effects included increases in the PR interval (CON:94 msec versus SVT:119 msec. p less than 0.001) and QTc interval (CON:418 msec versus SVT:450 msec. p = 0.016). With serum flecainide concentrations in the human therapeutic range. no significant effect on hemodynamic or electrophysiologic parameters in either the normal or failing heart were detected. Nonsustained ventricular tachycardia induced prior to pacing in one animal and after pacing in another animal was seen before but not following use of flecainide. No acute proarrhythmic effects were observed. In summary. intravenous flecainide had no significant acute adverse hemodynamic. electrophysiologic. or proarrhythmic effects in an animal model of tachycardia-induced ventricular dysfunction.
The use of intravenous milrinone in chronic symptomatic ischemic heart disease, To evaluate the antiischemic effects of intravenous milrinone. 20 patients with angiographically proved coronary artery disease and stable angina were studied at rest and during exercise under control conditions and after an intravenous loading injection of milrinone (50 micrograms/kg/10 min) followed by an infusion with 0.5 micrograms/kg/min. Hemodynamic parameters. epinephrine. norepinephrine. and atrial natriuretic factor were assessed. Control ergometry revealed ischemia; however. during exercise with intravenous milrinone. ischemia was eliminated. Because of unloading effects. there was also a significant decrease in ST segment depression (p less than 0.001). Heart rate increased significantly (p less than 0.001) at rest but increased significantly less after exercise testing (p less than 0.001). The changes in mean arterial pressure. cardiac output. and myocardial oxygen consumption during exercise were not significantly different between the milrinone and control phase. Intravenous milrinone delayed the onset of angina (p less than 0.001) and significantly shortened the duration of anginal attacks (p less than 0.05); exercise duration in the milrinone phase was longer than in the control phase (p = 0.051). Because of vasodilatation. a mild secondary increase in norepinephrine was observed during the milrinone phase. and there was a significantly smaller increase in atrial natriuretic factor during exercise while receiving milrinone as a result of preload reduction (p less than 0.05). Intravenous milrinone produced beneficial hemodynamic and antiischemic effects in patients with coronary artery disease. stable angina. and reproducible ST segment depression probably by enhancing myocardial contractility and reducing preload and afterload.
Lipoprotein (a) blood levels in unstable angina pectoris, acute myocardial infarction, and after thrombolytic therapy, Lipoprotein (a) [Lp(a)] appears to be involved in atherogenesis and in vitro studies have suggested that it may interfere with thrombolysis. In this study. Lp(a) serum levels were determined by radioimmunoassay in 124 patients with ischemic heart disease. Of these. 47 had acute myocardial infarction. 13 had unstable angina. and 64 were age-matched patients with stable angina. Of the 60 patients with acute coronary artery disease. 34 received thrombolysis and 26 did not. In addition to Lp(a). serum plasminogen. alpha 2 antiplasmin. fibrinogen. and D-dimer (cross-linked fibrin degradation products) levels were measured. These tests were repeated after 6 hours in patients with myocardial infarction and unstable angina. No significant difference was found for admission Lp(a) levels among patients with myocardial infarction (0.324 +/- 0.047 g/liter). unstable angina (0.435 +/- 0.123 g/liter) and stable angina (0.431 +/- 0.023 g/liter). between patients with myocardial infarction with or without thrombolytic treatment. nor between late and early measurements in patients with unstable angina and acute myocardial infarction. Plasminogen. alpha 2 antiplasmin and fibrinogen values decreased significantly after thrombolytic treatment. The size of this decrease correlated positively with higher Lp(a) blood levels (p less than 0.05). Patients with Lp(a) greater than 0.25 g/liter had a 66% decrease in fibrinogen and a 53% decrease in anti-plasmin. compared with 35 and 32%. respectively. in patients with Lp(a) level less than or equal to 0.25 g/liter (p less than 0.05). Plasminogen levels revealed a similar trend. with a 61% decrease for the higher values and a 45% decrease for the lower values.
Quantitation of energy expenditure by infrared thermography, The objective of this study was to adapt infrared thermography (IRT) to measure heat loss in human beings. IRT images were digitized and a mean body surface temperature was computed; heat losses caused by radiation. convection. and evaporation were calculated by using these data. Because subjects were standing during the procedure a small amount of heat was conducted through the feet; this heat was ignored. Total heat loss measured by IRT was not significantly different from values calculated from simultaneous indirect calorimetry (IC) determinations in fasting health subjects and in postsurgical patients receiving a constant infusion of energy. In healthy subjects. after eating the patterns of response to IRT and IC were as predicted from previous direct calorimetry data. Heat loss measured by IC increased first. 30 min postprandially. followed by an increase in heat loss at 60 min as measured by IRT. It was concluded that IRT as a noninvasive method can be used to quantitate heat loss in human beings.
Factors associated with umbilical catheter-related sepsis in neonates, To determine factors associated with risk for umbilical catheter-related sepsis. we studied neonates with one or more catheters in place for more than 3 days. Among 225 infants with 357 umbilical catheters. catheter-related sepsis occurred in 14 infants (6%). Catheter-related sepsis occurred in 5% of infants with umbilical arterial catheters and in 3% of infants with umbilical venous catheters. Staphylococcal species accounted for 71% of cases of catheter-related sepsis. Multiple logistic regression analysis revealed that very low birth weight and longer duration of antibiotic therapy were significantly associated with risk for umbilical arterial catheter-related sepsis. Increased risk for umbilical venous catheter-related sepsis was best predicted by the simultaneous occurrence of higher birth weight and infusion of hyperalimentation solution. Catheter duration correlated with duration of antibiotic therapy and with infusion of hyperalimentation solution for both types of catheters; however. in the multivariable analysis. duration of catheterization was not found to be a significant independent predictor of risk for catheter-related sepsis for either type of catheter.
Tyrosinase gene mutations associated with type IB ("yellow") oculocutaneous albinism [ublished erratum appears in Am J Hum Genet 1991 Sep;49(3):696, We have identified three different tyrosinase gene mutant alleles in four unrelated patients with type IB ("yellow") oculocutaneous albinism (OCA) and thus have demonstrated that type IB OCA is allelic to type IA (tyrosinase negative) OCA. In an inbred Amish kindred. type IB OCA results from homozygosity for a Pro----Leu substitution at codon 406. In the second family. type IB OCA results from compound heterozygosity for a type IA OCA allele (codon 81 Pro----Leu) and a novel type IB allele (codon 275 Val----Phe). In the third patient. type IB OCA results from compound heterozygosity for the same type IB allele (codon 275 Val----Phe) and a novel type IB OCA allele. In a fourth patient. type IB OCA results from compound heterozygosity for the codon 81 type IA OCA allele and a type IB allele that contains no identifiable abnormalities; dysfunction of this type IB allele apparently results from a mutation either well within one of the large introns or at some distance from the tyrosinase gene. In vitro expression of the Amish type IB allele in nonpigmented HeLa cells demonstrates that the Pro----Leu substitution at codon 406 greatly reduces but does not abolish tyrosinase enzymatic activity. a finding consistent with the clinical phenotype.
The N-terminal and C-terminal portions of the atrial natriuretic factor prohormone increase during preeclampsia, The influence of preeclampsia on the circulating concentrations of the 28-amino-acid carboxy terminus (C-terminus) (i.e.. atrial natriuretic factor) and the amino terminus (N-terminus) of the 126-amino-acid atrial natriuretic factor prohormone (pro ANF) was studied in the third trimester with the use of three specific radioimmunoassays that recognize: (1) atrial natriuretic factor (i.e.. amino acids 99 to 126). (2) the whole 98-amino-acid N-terminus. and (3) amino acids 31 to 67 from the midportion of the N-terminus of the prohormone. The C-terminus was significantly increased (p less than 0.001) in the third trimester in women with preeclampsia. the mean +/- SEM of 15 subjects was 150 +/- 7 pg/ml versus 89 +/- 7 pg/ml in the third trimester in 12 women during normal pregnancies and 65 +/- 2 pg/ml in 19 healthy nonpregnant women. The whole 98-amino-acid N-terminus. likewise. was significantly increased (p less than 0.001) in women with preeclampsia to 4706 +/- 629 pg/ml versus 2160 +/- 79 pg/ml in women in the third trimester of normal pregnancies and versus the circulating concentration of 1847 +/- 127 pg/ml in healthy nonpregnant women. ProANF 31 to 67 mean circulating concentration in preeclampsia was 4638 +/- 725 pg/ml. which was also significantly (p less than 0.001) increased compared with its mean circulating concentration in the third trimester of normal pregnancy of 1758 +/- 83 pg/ml or that in healthy nonpregnant women (1400 +/- 105 pg/ml). The circulating concentrations of both the N-terminus and C-terminus of the atrial natriuretic factor prohormone decreased within 24 hours after delivery in contrast to a normal pregnancy in which they both increase post partum. These results indicate a marked difference in the metabolism of both the N-terminus and the C-terminus of the atrial natriuretic factor prohormone in women with preeclampsia versus that in women with normal pregnancies or that in healthy nonpregnant women.
Umbilical arterial and venous acid-base and blood gas values and the effect of chorioamnionitis on those values in a cohort of preterm infants, Umbilical arterial and venous acid-base and blood gas values in uncomplicated premature births are similar to values that are reported in term infants and are unaffected by birth weight or gestational age. In this group of patients chorioamnionitis had no significant effects on umbilical arterial acid-base or blood gas values or on the percentage of patients that were born with acidemia. Apgar scores were significantly lower in the group with chorioamnionitis in spite of a virtual absence of acidemia. which again suggests that low Apgar scores alone do not confirm a diagnosis of birth asphyxia.
Cost-effectiveness of prenatal testing for Chlamydia trachomatis, We investigated the cost-effectiveness of strategies for screening pregnant women for Chlamydia trachomatis. Screening was not cost-effective unless certain conditions were met. Direct antigen testing of all pregnant women would be cost-effective if the test cost less than $6.30 or the prevalence of infection exceeded 6%. However. the positive predictive value of the test was only 51%. Culturing was not cost-effective until the prevalence of infection exceeded 14.8%. If a direct antigen test cost less than $3.90 or prevalence exceeded 8.7%. direct antigen testing of all women and using culture to confirm positive direct antigen tests would be cost-effective. If a direct antigen test cost $8.00 and culture cost $25.00. the excess cost of performing a direct antigen test in all women and confirming positive results with culture would be $2.09 per pregnant woman. Screening all pregnant women for chlamydia is not cost-effective. but the excess cost is modest when direct antigen tests are used.
Effects of altered PaO2 and PaCO2 on left ventricular function and coronary hemodynamics in sheep, The effects of acute changes in arterial carbon dioxide and oxygen tension. produced by altering the inspired gas mixtures while maintaining constant-volume intermittent positive pressure ventilation. on global function. regional left ventricular function. and coronary hemodynamics were studied in eight sheep during halothane anesthesia. Hypercapnia (Paco2. 73.5 +/- 2.3 mm Hg. mean +/- SD) increased heart rate. stroke volume. and cardiac output but decreased systolic shortening in the base of the left ventricle. Hypocapnia (PaO2. 24 +/- 1.5 mm Hg) decreased cardiac output and coronary flow below levels seen with hypercapnia but not below levels seen with normocapnia. Systolic shortening decreased in both apical and basal regions. and left ventricular relaxation was impaired as evidenced by a reduction of the nadir of LV dP/dt. Hypoxemia (PaO2. 39 +/- 1.5 mm Hg) elicited a hyperdynamic response of the circulation. increased coronary blood flow. and exhausted the coronary flow reserve. Neither changes in PaCO2 nor changes in PaO2 caused postsystolic shortening. although hypercapnia caused nonuniformity of contraction in the left ventricle. Thus. marked alterations in oxygen and carbon dioxide tensions do not cause left ventricular dysfunction. even though moderate hypoxia reduces the coronary flow reserve.
Double-blind trial of pentigetide ophthalmic solution, 0.5%, compared with cromolyn sodium, 4%, ophthalmic solution for allergic conjunctivitis, Fifty patients (25 per group) with the signs and symptoms of allergic conjunctivitis confirmed by positive skin test enrolled in this randomized. double-blind. parallel group. 2-week comparison of pentigetide. 0.5%. ophthalmic solution (Pentyde) and cromolyn sodium. 4%. USP ophthalmic solution (Opticrom). The physician and the patient rated the patient's overall ocular condition on days 3. 8. and 15. On day 15 both the physician and the patients rated the pentigetide group as significantly (Chi-square. P less than .05) more improved than the cromolyn sodium group. The physician rated independently conjunctival symptoms and ocular signs at days 1. 3. 8. and 15. Improvement in signs and symptoms favored pentigetide in the majority of comparisons to cromolyn sodium (14 of 18). The pentigetide group showed significantly (ANOVA. P less than .05) greater improvement in hyperemia. edema. lacrimation. and blurred vision/photophobia. Patients completed daily diaries for seven symptoms. At the end of the study. comparisons to baseline between groups favored the pentigetide group for six of the seven symptoms; for itching. improvement favored significantly (ANOVA. P less than .05) the pentigetide group. The mean severity of all symptoms decreased by 64% in the pentigetide group as compared with a decrease of 46% in the cromolyn sodium group. Adverse experiences were minor and comparable in both groups. No clinically abnormal changes were noted for visual acuity. intraocular pressure. or common laboratory tests. This double-blind. active-controlled trial demonstrates that pentigetide. 0.5%. ophthalmic solution is safe and effective in the treatment of allergic conjunctivitis.
Interleukin 1 alpha, tumor necrosis factor alpha, and interferon gamma in psoriasis, Although recent studies have suggested that a variety of cytokines released by keratinocytes and inflammatory leukocytes could contribute to induction or persistence of the inflammatory processes in psoriasis. it remains unclear how production of these cytokines is regulated in psoriatic patients. To elucidate the biologic relevance of these cytokines to the pathogenesis of psoriasis. we investigated serum levels of interleukin 1 alpha. tumor necrosis factor alpha. and interferon gamma in 21 patients with psoriasis vulgaris. together with 21 healthy controls. The mean serum levels of interleukin 1 alpha and tumor necrosis factor alpha were not significantly different from those in controls. while those of interferon gamma were significantly elevated in the patients with psoriasis. Serum levels of interleukin 1 alpha correlated negatively with clinical disease severity expressed as psoriasis area and severity index score and with duration of psoriasis. In contrast. interferon gamma levels were related. although not significantly. to disease severity. In addition. an inverse correlation was noted between the interleukin 1 alpha levels and interferon gamma levels. These results indicate that interleukin 1 alpha and interferon gamma may be relevant to the induction and perpetuation. respectively. of the inflammatory responses in psoriasis. and that these cytokines. which have similar biologic properties. may strictly regulate one another's production in vivo.
Allergy to penicillin: fable or fact, OBJECTIVE--To assess whether. on the basis of one blood test. penicillin allergy might be excluded sufficiently for general practitioners to give oral penicillin to patients claiming a history of penicillin allergy. DESIGN--Prospective study of patients referred by general practitioners. SETTING--Outpatient allergy clinic in a district general hospital. PATIENTS--175 referred patients who gave a history of immediate type reaction to penicillin. of whom 144 attended as requested and 132 completed the investigations. MAIN OUTCOME MEASURES--History and examination. serum radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin. and oral challenge with penicillin. RESULTS--Of 132 patients. four were confirmed to have penicillin allergy by the radioallergosorbent test and 128 had an oral penicillin challenge without ill effect. CONCLUSIONS--Most patients who gave a history of penicillin allergy are not so allergic. and their actual allergic state should be substantiated whenever feasible. For patients reporting minor or vague reactions negative findings with a radioallergosorbent test to phenoxymethylpenicillin and benzylpenicillin provide sufficient evidence to give oral penicillin safely.
Reduction of canine myocardial infarct size by a diffusible reactive oxygen metabolite scavenger. Efficacy of dimethylthiourea given at the onset of reperfusion, A number of scavengers of reactive oxygen metabolites reduce myocardial injury when given before ischemia and reperfusion. but few. if any. have proven to be effective when given near the onset of reperfusion. This is particularly true when infarct size is measured after at least 48 hours of reperfusion. when the full extent of myocardial damage has become apparent. Dimethylthiourea (DMTU) is an extremely diffusible. potent scavenger of hydroxyl radical. hydrogen peroxide. and hypochlorous acid. with a long half-life of 43 hours. Sixteen chloralose-anesthetized dogs underwent 90 minutes of left anterior descending coronary artery (LAD) occlusion followed by 48 hours of reperfusion. Collateral flow was measured by radioactive microspheres. Infarct size and risk area were measured by a postmortem dual-perfusion technique using triphenyl tetrazolium chloride and Evan's blue dye. In eight dogs. therapy with DMTU (500 mg/kg i.v.) was given during the last 15 minutes of ischemia and the first 15 minutes of reperfusion. In eight control dogs. the same volume of 0.9% saline was given during the last 15 minutes of ischemia through the first 15 minutes of reperfusion. Infarct size as a percent of risk area was reduced in the DMTU-treated group compared with the saline-treated controls (DMTU = 42 +/- 4% versus saline = 59 +/- 4%. p less than 0.01).
Depression of endothelium-dependent relaxation in aorta from rats with Brugia pahangi lymphatic filariasis, A role for altered endothelial cell function is emerging in the pathogenesis of disease. We have previously demonstrated that Dirofilaria immitis. the canine heartworm. depresses endothelium-dependent responses and alters the mechanism of relaxation in the in vivo femoral artery of infected dogs. Exposure of rat aorta to the parasite or parasite-conditioned medium selectively depresses endothelium-dependent relaxation. D. immitis is closely related to the major human filarial pathogens. This study was designed to examine the effect of chronic infection with the filarial nematode Brugia pahangi on endothelium-mediated responses of the rat aorta in vitro. We tested the hypothesis that endothelium-dependent responses are depressed in the aorta from rats infected with B. pahangi. Rings of thoracic and abdominal aorta were suspended in muscle baths for measurement of isometric tension. Dose-response relations to norepinephrine. endothelium-dependent dilators (acetylcholine. histamine. and A23187). and nitroglycerin were done. In some experiments. inhibitors of cyclooxygenase (indomethacin and aspirin). guanylate cyclase (methylene blue). and nitric oxide formation (N-nitro-L-arginine methyl ester; L-NOARG) were used. No differences in vascular reactivity were detected in the thoracic aorta. In contrast. endothelium-dependent responses in abdominal aorta of Brugia-infected rats were significantly depressed when compared with control aorta from noninfected rats. Acetylcholine relaxation was further depressed by indomethacin and aspirin. After L-NOARG. acetylcholine relaxation in control abdominal aorta was completely abolished; however. in abdominal aorta of Brugia-infected rats. acetylcholine still caused relaxation. Methylene blue inhibited acetylcholine relaxation in both control and Brugia-infected abdominal aorta; however. relaxation in Brugia-infected aorta was significantly greater than control. This study demonstrates that endothelium-dependent relaxation can be altered by chronic experimental filarial infection in the absence of direct contact between the blood vessel and the parasite. The mechanism of relaxation in the Brugia-infected abdominal aorta appears to be altered when compared with control. suggesting that parasites are capable of modulating vascular reactivity by inducing changes in endothelial cell behavior. The mechanism may involve parasite-induced local inflammation or alterations in endothelial cell metabolism. Understanding how chronic experimental filarial infection alters vascular reactivity may enhance our understanding of the pathogenesis of human filariasis.
Regulation of cytosolic calcium by parathyroid hormone and oscillations of cytosolic calcium in fibroblasts from normal and pseudohypoparathyroid patients, The second messengers for PTH action on fibroblasts have not been determined. The hypothesis that Ca2+ is a second messenger was examined by spectrofluorometric measurement of cytosolic calcium ([Ca2+]i). of fura-2-loaded human dermal skin fibroblasts. PTH induced: 1) transient elevations of [Ca2+]i due to both Ca2+ influx and intracellular release which were independent of CAMP generation. and 2) membrane depolarization. PTH treatment of fibroblasts depolarized by KCl induced oscillations of [Ca2+]i. but spontaneous oscillatory activity was not observed. Transient elevations of [Ca2+]i similar to that induced by PTH were observed with PTH-related peptide (PTHrp). PTH regulation of [Ca2+]i was normal in fibroblasts from patients with pseudohypoparathyroidism (PHP) type Ia (deficiency of the stimulatory GTP-binding protein. Gs). but PTH induced transient decreases in [Ca2+]i in fibroblasts from patients with PHP type Ib (defective PTH receptor). Both PHP Ia and Ib fibroblasts exhibited: 1) spontaneous [Ca2+]i oscillations. possibly due to voltage gated Ca2+ entry and Ca2+ induced Ca2+ release; and 2) greater sensitivity than normal fibroblasts for release of Ca2+ from intracellular stores when [Ca2+]i was decreased by lowering external Ca2+. Conclusions: 1) PTH-induced transient elevations in [Ca2+]i in normal fibroblasts result from Ca2+ entry and intracellular release which are independent of CAMP generation; 2) [Ca2+]i homeostasis is altered in PHP fibroblasts. resulting in Ca2+ oscillations; 3) PTH regulation of [Ca2+]i is altered in PHP Ib. but not in PHP Ia fibroblasts.
Protein kinase C is involved in PTH-induced homologous desensitization by directly affecting PTH receptor in the osteoblastic osteosarcoma cells, We have investigated mechanisms of PTH-induced homologous desensitization reflected in the refractoriness of cAMP response to the second exposure to PTH in the clonal rat osteosarcoma cell line. UMR-106. Preincubation with 10(-7) M rat (r) PTH-(1-34) for 6 h caused the desensitization. resulting in a 65% decrease in cAMP accumulation in response to further exposure to rPTH. This desensitization was apparent at 10(-10) M rPTH and maximal at 10(-7) M rPTH. UMR-106 cells treated with protein kinase C (PK-C) activating phorbol ester. phorbol 12-myristate 13-acetate (PMA. 10(-6) M) for 6 h also induced desensitization manifested by a loss of rPTH-stimulated cAMP accumulation to 50% of that in the control cells. On the other hand. 4 alpha-phorbol 12.13-didecanoate. incapable of activating PK-C. failed to induce desensitization. Fifty micromolar H-7 (PK-C inhibitor) significantly blocked both rPTH- and PMA-induced desensitization. Thus. PK-C seemed to play a major role in rPTH-induced desensitization. Pretreatment with neither rPTH nor PMA changed the cAMP responsiveness to 10 micrograms/ml cholera toxin or 100 microM forskolin. Islet activating protein failed to influence the desensitization in this cell line. PTH receptor binding. assessed by using 125I-labeled [Nle8.Nle18.Tyr34]PTH-(1-34) as a radioligand. was decreased along with PTH receptor numbers by pretreatment with rPTH or PMA. These data indicate that rPTH-induced homologous desensitization occurs at least in part through the activation of PK-C and that PK-C directly affects PTH receptor in UMR-106 cells.
The luteal phase during gonadotropin therapy: effects of two human chorionic gonadotropin regimens, OBJECTIVE: Luteal phase abnormalities are known to complicate ovulation induction with gonadotropins. This study was performed to test the effect of a modified human chorionic gonadotropin (hCG) regimen on the luteal phase during gonadotropin treatment. DESIGN: Fifteen women from a private practice setting volunteered to be studied during each of two nonconception. gonadotropin-stimulated cycles. After ovarian stimulation with human menopausal gonadotropins (hMG). hCG was administered either as a single dose of 10.000 IU (single dose) or in two divided doses of 5.000 IU given 1 week apart (split dose). MAIN OUTCOME MEASURES: Early. midluteal. and late luteal estradiol (E2) and progesterone (P) levels and luteal phase lengths were measured. and their median values and intraquartile ranges (IQR) compared using nonparametric analysis. RESULTS: Early and midluteal E2 and P levels were similar regardless of which hCG regimen was administered. The median late luteal E2 level was 1.146.0 pg/mL (the IQR ranged from 633 to 1.650. IQR = 1.017) with the split-dose regimen and 240.0 pg/mL (the IQR ranged from 150 to 460. IQR = 310) with the single-dose regimen. The median late luteal P level was 108.0 ng/mL (the IQR ranged from 58.5 to 129. IQR = 70.5) with the split-dose regimen and 4.2 ng/mL (the IQR ranged from 1.9 to 11.7. IQR = 9.8) with the single-dose regimen. Median luteal phase lengths were 16 days (the IQR ranged from 15 to 17. IQR = 2) for the split-dose regimen and 11 days (the IQR ranged from 10 to 12. IQR = 2) for the single-dose regimen. CONCLUSION: In hMG-stimulated cycles. a second dose of hCG given during the midluteal phase significantly increases late luteal E2 and P levels and consistently lengthens the luteal phase.
Possible role of pure human follicle-stimulating hormone in the treatment of severe male-factor infertility by assisted reproduction: preliminary report, OBJECTIVE: Experimental clinical trial assessing the potential of systemic follicle-stimulating hormone (FSH) to improve sperm fertilizing ability in in vitro fertilization (IVF). DESIGN: Retrospective clinical evaluation of severe male factor patients failing fertilization in IVF or showing severe sperm defects. SETTING: Academic tertiary clinical care unit. PATIENTS. PARTICIPANTS: Fourteen patients (41 cycles) who failed IVF. 22 patients (32 cycles) with severe quantitative and qualitative semen abnormalities indicating poor fertilization. INTERVENTIONS: Treatment: FSH 150 U IM three times a week for 3 months. MAIN OUTCOME MEASURE(s): Pretreatment and post-treatment evaluation of endocrine profile. basic semen analysis. and fertilization and pregnancy rates. Hypothesis: FSH treatment may improve spermatogenesis quality by its multiple actions on the Sertoli-gamete cell compartment without interfering with testicular hormonogenic function. RESULTS: No significant changes were observed in the endocrine profile or in semen parameters; individual cases showed improvements in sperm concentration and motility. Significant increase in fertilization rate of preovulatory oocytes was demonstrated; seven term pregnancies were achieved. CONCLUSIONS: A multicenter randomized. double-blind trial with crossover is needed to demonstrate the benefit of systemic FSH administration and if this effect is FSH exclusive.
Combined intrafallopian/intrauterine reduction of a quintuplet gestation, We describe the first successful outcome of a case of combined tubal and intrauterine quadruplet pregnancy in the literature. The patient's risk factors for combined pregnancy included a history of PID as well as the use of hMG therapy. A laparoscopic salpingectomy was performed. followed by a multifetal pregnancy reduction procedure. Two healthy infants were delivered at 37 weeks of gestation.
In vivo additive antiretroviral effect of combined zidovudine and foscarnet therapy for human immunodeficiency virus infection (ACTG Protocol 053), Zidovudine and foscarnet each have antiretroviral activity against human immunodeficiency virus (HIV) and. when combined in vitro. inhibit HIV replication in an additive or synergistic fashion. To determine if an in vivo additive or synergistic antiretroviral effect might result from combined therapy. six symptomatic HIV-infected patients were studied who had persistently quantifiable serum HIV p24 antigen despite 9-27 weeks of full-dose oral zidovudine therapy (1200 mg/day). These patients were given intravenous foscarnet (30 mg/kg every 8h) for 2 weeks with continued oral zidovudine for 14 days. followed by zidovudine alone for 6 months. Serum p24 antigen concentrations decreased in all six patients during the period of combined therapy by a mean 53% (P = .005). Subsequently. serum p24 antigen levels rose to the baseline value in four patients after 4-14 weeks. As predicted from in vitro studies. combined treatment with zidovudine and foscarnet resulted in an additive in vivo effect. but the effect was transient.
Antibodies to hepatitis C virus in prospectively followed patients with posttransfusion hepatitis, In an attempt to investigate the incidence and clinical course of type C viral hepatitis among patients with posttransfusion hepatitis. antibodies to hepatitis C virus (anti-HCV) in sera were measured from 42 prospectively followed cardiovascular surgery patients who developed hepatitis after blood transfusions. Of these. 35 (83.3%) had anti-HCV seroconversion during a 6- to 12-month follow-up period. The mean interval between blood transfusion and onset of active anti-HCV seroconversion was approximately 3 months after the first elevation of serum alanine aminotransferase levels (18.1 vs. 6.4 weeks). There was no correlation between fluctuations in serum alanine aminotransferase levels and anti-HCV titers. Of 26 patients with type C posttransfusion hepatitis who were followed greater than 1 year. 20 (76.9%) continued to have abnormal serum alanine aminotransferase levels. The results indicate that HCV is the major agent of posttransfusion hepatitis in Taiwan. Furthermore. it plays an important role in chronic hepatitis among transfused patients.
The interaction of vasodilating drugs and sympathetic blockade in normal and ischemic canine hindlimbs, The purpose of this study was to determine if intraarterial vasodilating drugs could augment the vasodilation produced by sympathetic blockade. such as occurs during epidural anesthesia. Papaverine (2 mg/min). nitroglycerin (1 microgram/kg/min). aand saline were infused into the femoral artery before and after lumbar sympathectomy in six arterially isolated canine hindlimbs. Femoral blood flow was controlled with a perfusion circuit at baseline (80 ml/min). half-baseline (40 ml/min). and low (5 ml/min) flow rates so that hindlimb mean arterial pressure served as an index of peripheral vasodilation. At low flow. hindlimb arteriovenous oxygen content difference increased from 1.4 (baseline) to 6.2 ml O2/dl. consistent with peripheral ischemia. At baseline flow before sympathectomy. papaverine and nitroglycerin caused a decrease in hindlimb mean arterial pressure of 30% and 18%. respectively (p less than 0.01 vs saline control). equivalent to the decreases of 31% and 16% after sympathectomy (p less than 0.01). At half-baseline. papaverine and nitroglycerin reduced hindlimb mean arterial pressure by 22% and 12%. respectively (p less than 0.01). and caused comparable vasodilation after sympathectomy. Neither drug significantly changed hindlimb mean arterial pressure at low flow. Sympathectomy itself reduced hindlimb mean arterial pressure by 23% at baseline flow (p less than 0.01). by 18% at half-baseline flow (p less than 0.01). but had no effect at low flow. We conclude that intraarterial papaverine and nitroglycerin cause peripheral vasodilation that is synergistic with sympathectomy-induced adrenergic blockade. but they cannot augment vasodilation caused by peripheral ischemia.
Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement, and renal function after cardiopulmonary bypass, The use of aprotinin to reduce blood loss after cardiopulmonary bypass is under debate. Concern has been raised about the renal effects of aprotinin. We administered a mean aprotinin dose of 4.2 x 10(6) kallikrein-inhibiting units to 13 patients with coronary disease undergoing cardiopulmonary bypass for 74 +/- 5 minutes (mean +/- standard error of the mean); 13 comparable patients having cardiopulmonary bypass served as control subjects. and all were studied postoperatively for 24 hours. Aprotinin reduced postoperative blood loss by 50% (p = 0.0082). Two of the 13 patients who received aprotinin needed one red cell unit each versus a total of 18 units in eight of 13 control patients (p = 0.0096). Blood pressure. hemoglobin value and serum protein concentration were higher after operation in the aprotinin group (p less than 0.05 to p less than 0.01). Platelet counts did not differ. but plasma thromboxane was lower in aprotinin recipients (p less than 0.001). In control patients fibrinogen degradation products (D dimer) doubled. and alpha 2-antiplasmin activity was halved during and after cardiopulmonary bypass (p less than 0.01 to p less than 0.001). whereas aprotinin patients showed no changes. The complement breakdown products C4a. C3a. and C3dg as well as C9 neoantigen increased from prebypass baseline in both groups (p less than 0.001); the increment of C3a and C3dg was greater in the aprotinin than in the control patients (p less than 0.001). Serum electrolytes. osmolality. and creatinine remained normal in both groups of patients. Creatinine clearance was normal or above normal and virtually identical in both groups. Osmolar clearance and fractional sodium excretion were higher in the aprotinin group than in the control group shortly after cardiopulmonary bypass (p less than 0.05 to p less than 0.01); renal function was unremarkable the next morning. No adverse clinical effects attributable to aprotinin were seen. In summary. aprotinin offers advantages for cardiopulmonary bypass.
Improving the cost-effectiveness of AIDS health care in San Juan, Puerto Rico, In an era of decreasing availability of funds and increasing demand. the AIDS epidemic threatens to overwhelm health-care services in some countries. We describe a comprehensive model for the treatment of AIDS in San Juan. Puerto Rico. and compare it with traditional hospital-based services. Given the existing allocation of funds. the comprehensive model emphasised prevention. education. surveillance. early detection. and outpatient care to reduce hospital care. In 1987. the last year of the traditional system. there were 95 admissions of AIDS patients to hospital. and in 1988. the first year of the comprehensive model. there were 100 admissions. The mean length of stay of AIDS inpatients was reduced from 22.3 days in 1987 to 11.3 days in 1988. a 46.8% reduction (p = 0.001). The annual mean (SE) cost of inpatient care per AIDS patient fell from $15.118 (1699) in 1987 to $3869 (659) in 1988. Savings were used to improve non-hospital services. including outreach. education. emergency and outpatient care. laboratory and epidemiological services. and research. and to introduce an employee incentive scheme. Management strategies that reduce the length of inpatient care and provide less costly treatment alternatives can improve AIDS health care in developing nations.
The efficacy in Navajo infants of a conjugate vaccine consisting of Haemophilus influenzae type b polysaccharide and Neisseria meningitidis outer-membrane protein complex, BACKGROUND AND METHODS. Several conjugate vaccines against Haemophilus influenzae type b have been developed in the search for one that induces protection even in young infants. We evaluated the safety and efficacy of a conjugate vaccine that links the H. influenzae type b capsular polysaccharide to the outer-membrane protein complex (OMPC) of Neisseria meningitidis serogroup B. We conducted a double-blind. placebo. controlled trial in Navajo infants. who are at high risk for systemic infections caused by H. influenzae type b. The infants were randomly assigned to receive the first dose of vaccine or placebo at 42 to 90 days of age and the second at 70 to 146 days of age. RESULTS. Of the infants in the trial. 2588 were assigned to receive the vaccine and 2602 to receive placebo. The mean follow-up was 269 days in the vaccine group and 267 days in the placebo group. Before the age of 18 months. there was 1 systemic H. influenzae type b infection in the vaccine group. as compared with 22 in the placebo group (P less than 0.001; point estimate of efficacy. 95 percent; 95 percent confidence interval. 72 to 99 percent). Of the 22 H. influenzae type b infections in the placebo group. 13 were meningitis. Among the children who received both doses. there was 1 H. influenzae type b infection in the vaccine group (n = 2056) and 14 in the placebo group (n = 2105) (P less than 0.001; point estimate of efficacy. 93 percent; 95 percent confidence interval. 53 to 98 percent). The single infection in the vaccine group occurred at 15 1/2 months of age in an infant with osteomyelitis. Between the first and second doses there were no H. influenzae type b infections in the vaccine group and eight in the placebo group (P less than 0.005; point estimate of efficacy. 100 percent; 95 percent confidence interval. 41 to 100 percent). CONCLUSIONS. The H. influenzae type b OMPC vaccine. administered at 2 and 4 months of age. is safe and induces a high rate of protection against invasive disease caused by H. influenzae type b in infants under the age of 18 months. Protection begins after the first dose.
Parotid sialography with a new Zonarc program, The use of panoramic zonography with the Zonarc-MLA and LAT-PA program for parotid sialography is presented. It provides curved layer tomograms. and shadows of the bony structures are therefore not disturbingly superimposed on the image of the sialogram. The visibility in the retromandibular region tended to be better. Radiation doses in plain film radiography are up to 60 times higher than in Zonarc radiography.
Primary spontaneous cerebrospinal fluid rhinorrhea, Spontaneous cerebrospinal fluid (CSF) rhinorrhea constitutes only 3% to 4% of CSF fistulas. Nontraumatic. normal pressure CSF fistulas with resultant rhinorrhea. in which no cause can be identified. or primary spontaneous CSF rhinorrhea. is considerably rarer. Presented here are two cases of CSF rhinorrhea of this nature. including the diagnostic workup and treatment. Reviews of literature support laboratory quantitative glucose determination as the most effective and least morbid method for confirming the presence of CSF. Iodine-contrast (metrizamide/lohexol) computerized tomographic cisternography has been shown to be the most effective and least morbid method for localizing the fistula. For inactive. intermittent. small. or questionable CSF leaks. radionuclide cisternography has been shown to be more effective in identifying the presence of these leaks. although not necessarily the location. Numerous reports provide evidence to support the use of an extracranial rhinologic approach for surgical repair of the leak. as a more successful yet less morbid procedure than a craniotomy when used appropriately.
The use of fine-needle aspiration in the diagnosis of metastatic pulmonary adenoid cystic carcinoma, Nine patients with a history of adenoid cystic carcinoma (ACC) arising in the head and neck and in whom transthoracic fine-needle aspiration (FNA) was performed to investigate pulmonary lesions are described. FNA yielded a definitive diagnosis of metastatic ACC in all cases. In six of the nine patients. the pulmonary metastases were asymptomatic. Lung lesions were discovered up to 19 years after primary tumor presentation. and in two. pulmonary spread was the only evidence of recurrent disease. On the basis of the FNA diagnosis. these two patients were treated surgically for their isolated pulmonary metastases. and are disease free at 107 and 139 months. Six of the nine patients received radiation or chemotherapy; one initially refused treatment. Thoracotomy was avoided in these patients on the basis of the FNA diagnosis. All are alive with disease at 25 to 246 months. The metastatic tumors were indistinguishable cytologically from two primary pulmonary ACCs that were available for comparison. Our experience suggests FNA is a useful tool in the diagnosis of ACC in pulmonary material--one which obviates the need for thoracotomy with its associated morbidity.
A functional evaluation of ansa cervicalis nerve transfer for unilateral vocal cord paralysis: future directions for laryngeal reinnervation, There are a variety of methods for treating unilateral vocal cord paralysis. but to date there are few objective studies that evaluate the functional results of nerve transfer from the ansa cervicalis. Six dogs underwent unilateral recurrent laryngeal nerve section with immediate reanastamosis to the sternothyroid branch of the ansa cervicalis. After 5 to 6 months. measurements of vocal efficiency and acoustic parameters. videolaryngoscopy. videostroboscopy. and evoked electromyography were performed. Identical measurements were made in eight control dogs during normal electrically induced phonation and a simulated unilateral recurrent laryngeal nerve paralysis. Histologic analysis of both vocalis muscles. recurrent laryngeal nerves. ansa cervicalis. and the ansa-recurrent laryngeal nerve anastamosis site was performed. Evidence of reinnervation was found in all of the animals that underwent nerve transfer. The vocal efficiency and acoustic quality after ansa cervicalis nerve transfer were dependent on the degree of electrical stimulation from the transferred nerve to the reinnervated cord during phonation. In the absence of electrical stimulation to the nerve transfer. physiologic vocal cord motion could not be elicited from the reinnervated cord.
Quest for the aberrant vessel, In most cases of posterior epistaxis. the terminal branches of the internal maxillary artery (IMA)--principally the sphenopalatine artery--are believed to be the source of hemorrhage. However. we recently treated three patients in which unexpected or aberrant vascular anatomy resulted in persistent posterior epistaxis.
Prediction of bithermal caloric response from monothermal stimulation, The use of either cold or warm caloric stimulation alone as a screening tool for unilateral weakness has been suggested as a means of both shortening testing time and reducing patient discomfort. The validity of the monothermal caloric test must be well established before it can be routinely used in clinical situations. The purpose of this investigation was to re-evaluate the monothermal caloric test by examining the correlations between unilateral weakness derived from bithermal caloric stimulation compared to monothermal caloric results using either warm or cool stimulation alone. A retrospective analysis of 200 patients indicated significant correlations between bithermal and monothermal unilateral weakness for patients with unilateral weakness of less than 15% and greater than 30% for both warm and cool water stimulation. For patients with 15% to 30% unilateral weakness. the bithermal and monothermal calorics were significantly correlated for only the cool condition. When predicting normal or greater than 20% unilateral weakness. either of the monothermal calorics have greater than 85% efficiency. with specificity greater than 94% and sensitivity greater than 64%. However. the false-negative rate is 29% for warm and 36% for cool calorics. The high rate of false-negative findings indicates that screening tests have no place in a diagnostic battery. especially in view of the implications for missing significant pathology.
Skin grafting of the larynx, Skin grafting as a method of restoring the lumen in cases of laryngeal stenosis has been promoted and practiced in the past. Lately. little has been heard of the method. I have personally used skin grafting in almost every case of repair of acute injury or chronic stenosis of the larynx in the last several years. The rationale for grafting is (1) to cover any areas of epithelial loss or dehiscence during the healing period. (2) to reduce the chance of prolonged granulation and subsequent contracture. and (3) to serve as a logical material to use as the interface between a stent and the lumen of the larynx. This report discusses the use of skin grafting in 20 cases of severe acute injury or chronic stenosis. Other procedures needed to enhance the stenotic lumen are also described. In this series. 17 patients are decannulated. one wears a plug continually. and two did not or could not complete the recommended therapy. Among those completing therapy. 100% are either decannulated or wear a plug.
Identification of perilymph proteins by two-dimensional gel electrophoresis, Perilymph has a total protein component that is quantitatively distinct from serum and cerebrospinal fluid (CSF). The goal of this research was to determine if perilymph contains any qualitatively unique protein constituents that will distinguish it from serum or CSF. To test this hypothesis. matched sets of perilymph. serum. and CSF were obtained from 18 guinea pigs and seven human subjects. The purity of each sample was assured by measurement of the protein concentration of each sample and comparison of this parameter to known normal values for perilymph. serum. and CSF. Each sample was then subjected to two-dimensional gel electrophoresis. separating proteins by isoelectric point in the horizontal dimension and by relative molecular weight in the vertical dimension. All gels were processed under precisely identical physical conditions by use of a diamine silver stain. A small number of perilymph proteins not found in plasma were identified in both the guinea pig and the human specimens. The finding of unique perilymph proteins may permit the development of a sensitive marker that will aid in the diagnosis of perilymph fistula.
Normocytic and macrocytic anemias, Differential diagnosis of normocytic and macrocytic anemias is guided by the patient history. physical examination results. reticulocyte count. and specific red blood cell abnormalities identified on the peripheral smear. In some cases this information is sufficient for diagnosis. When further tests are needed. a stepwise approach. as described by the author. ensures maximum cost-effectiveness without sacrificing diagnostic accuracy.
Antihypertensive effect of cicletanine is exaggerated in NaCl-sensitive hypertension, Cicletanine (CIC). a furopyridine derivative. lowers blood pressure in hypertensive animals and humans. We have previously identified an NaCl-sensitive substrain of spontaneously hypertensive rat (SHR-S) that displays enhanced sensitivity to the depressor effects of exogenous atrial natriuretic peptide (ANP) when fed a high NaCl diet. The current study tested the hypotheses that CIC has an exaggerated antihypertensive effect in NaCl-supplemented SHR-S and that this effect might be ANP dependent. CIC (40 mg/kg/day) or vehicle was administered by gavage in a single daily dose for three weeks beginning immediately prior to initiation of 1% or 8% NaCl diets in seven-week-old male SHR-S. CIC significantly decreased mean arterial pressure (MAP) and the ratio of left ventricular and septum weight to body weight (LV + S/BW) in both 8% NaCl- and 1% NaCl-fed SHR-S. The depressor effect of CIC was greater in the 8% NaCl group (-26 mmHg) than in the 1% NaCl group (-13 mmHg). CIC was associated with significant reduction in RAP in the 8% NaCl group but not in the 1% NaCl group. Neither CIC treatment nor 8% NaCl significantly altered plasma ANP or cyclic guanosine monophosphate (GMP) levels in plasma. aorta. or kidney. CIC was associated with significant decreases in plasma norepinephrine (NE) levels in the 1% NaCl group but not in the 8% NaCl group. The data demonstrate that the antihypertensive effect of CIC is exaggerated in NaCl-sensitive hypertension. The antihypertensive effect of CIC appears not to be related to ANP or cyclic GMP but may be related to a combination of a sympatholytic and natriuretic/diuretic effects in SHR-S.
Emergency department screening for syphilis in patients with other suspected sexually transmitted diseases, STUDY OBJECTIVE: To evaluate targeted screening for syphilis among a high-risk group of emergency department patients. STUDY DESIGN AND TYPE OF PARTICIPANTS: During a four-month period. 260 patients with suspected sexually transmitted diseases other than syphilis had rapid plasma reagins drawn to determine the incidence of otherwise unsuspected syphilis. RESULTS: Twenty-two patients (8%) had a reactive rapid plasma reagin. Of these. 16 (6%) also had a reactive FTA-ABS and were determined to have syphilis. The cost for screening was $104.90 for each patient with syphilis. Using Poisson regression to control for changing rates over time and for prior differences in rates of syphilis detection in the three hospitals involved in the study. it was determined that our intervention led to 2.4-fold as many cases identified as would have been expected considering prior rates and the increasing incidence of syphilis. CONCLUSION: Syphilis screening of this high-risk population in the ED is warranted.
Susceptibility of Neisseria gonorrhoeae to cefpodoxime: determination of MICs and disk diffusion zone diameters, We studied the susceptibilities of 77 strains of Neisseria gonorrhoeae to four antibiotics: cefpodoxime. ceftriaxone. penicillin. and tetracycline. All strains were susceptible to ceftriaxone. Cefpodoxime MICs (range. 0.001 to 0.125 micrograms/ml) were parallel to and approximately four times those of ceftriaxone. and all strains will probably be considered susceptible to cefpodoxime. Disk diffusion zone diameters for cefpodoxime ranged from 35 to 57 mm. Of the strains. 32% were penicillin resistant and 51% were tetracycline resistant (MIC. greater than or equal to 2 micrograms/ml). Susceptibility measurements were consistent for disk diffusion zone diameter and MIC. with an overall agreement of 215 of 225 (96%) for ceftriaxone. penicillin. and tetracycline combined. On the basis of these in vitro data. cefpodoxime should be evaluated in the treatment of gonorrhea.
Prevention of arrhythmias after noncardiac thoracic operations: flecainide versus digoxin, Cardiac arrhythmias are known complications of thoracic operations. The prophylactic value of flecainide administered as a constant-rate. intravenous infusion (0.15 mg.kg-1.h-1) after a loading dose (2 mg.kg-1) was compared with digoxin (10 micrograms.kg-1 for 12 hours. then 0.25 mg.24 h-1) in a randomized study in 30 patients using Holter monitoring during the first 72 hours after operation. Drug monitoring was performed every day to keep a serum level of flecainide of 200 to 600 ng.mL-1 and a digoxin level of 0.8 to 2 ng.mL-1. Failure. defined as the appearance of atrial fibrillation or flutter or the development of complex ventricular arrhythmias (Lown IVb and V). was observed in one patient in the flecainide group (7%) and in 7 patients in the digoxin group (47%) (p less than 0.05). It is concluded that flecainide is more efficient than digoxin in preventing and treating cardiac arrhythmias after thoracic operations. At the dosage used side effects related to flecainide or digoxin were not observed.
Neuroendocrine activity in untreated heart failure, Neuroendocrine activity was studied in 60 consecutive untreated patients with dyspnoea and a clinical suspicion of heart failure. On the basis of the so-called Boston clinical criteria the diagnosis of heart failure was regarded as unlikely in 26 patients. possible in 15 patients. and definite in 19 patients. These groups were studied before any drug treatment was started and were compared with a control group of 69 healthy individuals. Plasma atrial natriuretic peptide concentration was clearly raised in patients with definite heart failure and slightly raised in patients with possible heart failure. Plasma adrenaline concentration was somewhat raised in patients with definite or possible heart failure. whereas plasma noradrenaline concentration was raised only in patients with definite heart failure. Plasma renin activity was not increased in any of the patient groups and plasma aldosterone concentration was slightly increased only in patients with definite heart failure. In the total patient series there were significant correlations between plasma atrial natriuretic peptide concentration and markers of the severity of left ventricular dysfunction. There was some evidence of neuroendocrine activation in untreated heart failure: plasma concentrations of atrial natriuretic peptide and catecholamines were increased but the renin-angiotensin-aldosterone system showed little or no activation.
Assessment of tumour-infiltrating lymphocytes, regional lymph node lymphocytes and peripheral blood lymphocytes and their reaction to interferon-gamma in patients with renal carcinoma, The immunological distribution of tumour-infiltrating lymphocytes (TIL). regional lymph node lymphocytes (RLNL) and peripheral blood lymphocytes (PBL) was evaluated by means of immunohistochemical staining using monoclonal antibodies of each subset of lymphocytes (stored in frozen sections) in a series of 22 patients with renal carcinoma. The immunological effect of IFN (interferon)-gamma on these immunocompetent cells was also investigated. The effect of IFN-gamma on TIL was an increase in CD3 (pan-T cells). especially an increase in CD8 (cytotoxic/suppressor-T cells). When examining these cells according to stage and grade. a marked increase in CD3 was found in low stage and low grade patients. With regard to RLNL. there was a tendency towards a decrease in CD3 and an increase in CD20 (B-cells) following the administration of IFN-gamma. No specific effect on stage and grade was observed apart from a reduction in T cell subset ratios in high grade patients. With regard to PBL. no specific trend was noted except for an increase in CD16 (NK cells) when IFN-gamma was administered.
Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma, Between November 1983 and February 1986. 358 patients with previously untreated metastatic prostatic carcinoma entered a multicentre. randomised trial in the United Kingdom and the Republic of Ireland. in which the LHRH analogue Zoladex (ICI Pharmaceuticals PLC). administered subcutaneously every 28 days. was compared with orchiectomy. Both treatments were equally effective in lowering serum testosterone concentrations to within the surgically castrate range and this was accompanied by equivalent subjective and objective response rates and times to treatment failure. At a median follow-up of 2 years there was no difference in overall survival. confirming that Zoladex is an effective medical alternative to orchiectomy in patients with metastatic disease.
Coronary vasoconstriction induced by vasopressin. Production of myocardial ischemia in dogs by constriction of nondiseased small vessels, BACKGROUND. We studied the effect of intracoronary administration of arginine-8-vasopressin on blood flow in nondiseased coronary arteries and determined whether this vasoconstriction was severe enough to produce ischemia in 30 dogs. METHODS AND RESULTS. In group 1 (n = 6). after vasopressin administration coronary blood flow was decreased by 41% (p less than 0.002) without changes in heart rate or aortic pressure. and left ventricular ejection fraction measured by radionuclide angiocardiography was decreased by 18% (p less than 0.0005). In group 2 (n = 6). ischemia was confirmed by measurement of transmural pH changes. Administration of vasopressin decreased subendocardial pH of the infused zone from 7.40 +/- 0.03 to 7.31 +/- 0.07 (p less than 0.01). The subendocardial pH of the zone not infused with vasopressin did not change. To overcome the intrinsic regulation of blood flow. operating primarily in small coronary arteries. we hypothesized that vasopressin must increase resistance primarily in large rather than small coronary arteries. After intracoronary infusion in group 3 (n = 6). however. most (94%) of the increase in resistance during vasopressin administration was explained by an increase of resistance in small coronary arteries. In group 4 (n = 9). vasopressin decreased coronary blood flow by 50% and decreased local shortening by 90% at a time when systemic hemodynamics were unchanged. Coronary constriction induced by vasopressin. or the recovery from it. also was not altered by cyclooxygenase blockade. CONCLUSIONS. Thus. vasopressin produces myocardial ischemia by constricting small. nondiseased coronary arteries severely enough to overcome the competition from normal coronary regulation. and this ischemic event is not mediated by prostaglandin products.
Amelioration of nerve Na(+)-K(+)-ATPase activity independently of myo-inositol level by PGE1 analogue OP-1206.alpha-CD in streptozocin-induced diabetic rats, An oral prostaglandin E1 (PGE1) analogue. OP-1206.alpha-CD. was given to rats with streptozocin (STZ)-induced diabetes to examine the therapeutic effects of OP-1206 on short-term and long-term diabetic neuropathy and its action mechanism with special reference to nerve Na(+)-K(+)-ATPase activity. In the short-term experiment. OP-1206 was administered daily to diabetic rats in 3- and 30-mg/kg doses for 4 wk from the day of STZ injection. In the long-term study. 10 micrograms/kg OP-1206 was also given daily for 8 wk from 7 mo after induction of diabetes. The compound improved decreased sciatic motor nerve conduction velocity in both short-term and long-term diabetic rats. The nerve Na(+)-K(+)-ATPase activity of diabetic rats. reduced by 40% compared with controls. was reversed to the level of controls in both experiments. whereas weight loss and hyperglycemia were unchanged. and neither nerve sorbitol accumulation nor myo-inositol depletion was corrected. In a morphometric analysis of myelinated nerve fibers (MNFs) in long-term diabetes. the mean diameter of the largest 10% of MNFs was significantly reduced in untreated diabetic compared with control rats. but OP-1206 completely reversed this reduction. The results suggest that OP-1206 ameliorates a decrease in nerve Na(+)-K(+)-ATPase activity without any effect on nerve myo-inositol level and that the compound may be not only a potent therapeutic agent for the treatment of diabetic neuropathy but also a useful research tool to investigate the mechanism of nerve Na(+)-K(+)-ATPase activity regulation.
Uncoupling of attenuated myo-[3H]inositol uptake and dysfunction in Na(+)-K(+)-ATPase pumping activity in hypergalactosemic cultured bovine lens epithelial cells, Attenuation of both the active transport of myo-inositol and Na(+)-K(+)-ATPase pumping activity has been implicated in the onset of sugar cataract and other diabetic complications in cell culture and animal models of the disease. Cultured bovine lens epithelial cells (BLECs) maintained in galactose-free Eagle's minimal essential medium (MEM) or 40 mM galactose with and without sorbinil for up to 5 days were examined to determine the temporal effects of hypergalactosemia on Na(+)-K(+)-ATPase and myo-inositol uptake. The Na(+)-K(+)-ATPase pumping activity after 5 days of continuous exposure to galactose did not change. as demonstrated by 86Rb uptake. The uptake of myo-[3H]inositol was lowered after 20 h of incubation in galactose and remained significantly below that of the control throughout the 5-day exposure period. The coadministration of sorbinil to the galactose medium normalized the myo-[3H]inositol uptake. No significant difference in the rates of passive efflux of myo-[3H]inositol or 86Rb from preloaded galactose-treated and control cultures was observed. Culture-media reversal studies were also carried out to determine whether the galactose-induced dysfunction in myo-inositol uptake could be corrected. BLECs were incubated in galactose for 5 days. then changed to galactose-free physiological medium with and without sorbinil for a 1-day recovery period. myo-Inositol uptake was reduced to 34% of control after 6 days of continuous exposure to galactose. Within 24 h of media reversal. myo-inositol uptake returned to or exceeded control values in BLECs switched to either MEM or MEM with sorbinil.2+ reversible and occurred independently of changes in Na(+)-K(+)-ATPase pumping activity in cultured lens epithelium. indicating that the two parameters are not strictly associated and that the deficit in myo-inositol uptake occurs rapidly during hypergalactosemia.
Decrease in skin collagen glycation with improved glycemic control in patients with insulin-dependent diabetes mellitus, Glycation. oxidation. and nonenzymatic browning of protein have all been implicated in the development of diabetic complications. The initial product of glycation of protein. fructoselysine (FL). undergoes further reactions. yielding a complex mixture of browning products. including the fluorescent lysine-arginine cross-link. pentosidine. Alternatively. FL may be cleaved oxidatively to form N(epsilon)-(carboxymethyl)lysine (CML). while glycated hydroxylysine. an amino-acid unique to collagen. may yield N(epsilon)-(carboxymethyl)hydroxylysine (CMhL). We have measured FL. pentosidine. fluorescence (excitation = 328 nm. emission = 378 nm). CML. and CMhL in insoluble skin collagen from 14 insulin-dependent diabetic patients before and after a 4-mo period of intensive therapy to improve glycemic control. Mean home blood glucose fell from 8.7 +/- 2.5 (mean +/- 1 SD) to 6.8 +/- 1.4 mM (P less than 0.005). and mean glycated hemoglobin (HbA1) from 11.6 +/- 2.3% to 8.3 +/- 1.1% (P less than 0.001). These changes were accompanied by a significant decrease in glycation of skin collagen. from 13.2 +/- 4.3 to 10.6 +/- 2.3 mmol FL/mol lysine (P less than 0.002). However. levels of browning and oxidation products (pentosidine. CML. and CMhL) and fluorescence were unchanged. These results show that the glycation of long-lived proteins can be decreased by improved glycemic control. but suggest that once cumulative damage to collagen by browning and oxidation reactions has occurred. it may not be readily reversed. Thus. in diabetic patients. institution and maintenance of good glycemic control at any time could potentially limit the extent of subsequent long-term damage to proteins by glycation and oxidation reactions.
Differential adhesion of Pseudomonas aeruginosa to human respiratory epithelial cells in primary culture, Human nasal polyps in outgrowth culture were used to study the Pseudomonas aeruginosa adhesion to respiratory cells. By scanning electron microscopy. P. aeruginosa were seen associated with ciliated cells. but by transmission electron microscopy. bacteria were never seen at the interciliary spaces or attached along cilia. but were identified trapped at the extremities of cilia. usually as bacterial aggregates. A fibronectin-containing fibrillar material was seen associated with aggregated bacteria. By time-lapse video microscopy. bacteria were seen to aggregate in the culture medium following their addition to the culture wells. Progressively. these aggregates were trapped by cilia or attached to migrating cells of a lower cell layer that protruded beneath the upper layer cells. at the outgrowth periphery. P. aeruginosa adhesion to these lower cell layer migrating cells was significantly higher than to ciliated or nonciliated cells of the upper cell layer. Migrating cells were intensely labeled by the complexes Con A and arachis hypogea agglutinin (PNA)-FITC. in contrast to the other cells. The percentage of PNA-labeled cells with attached bacteria was significantly higher than that without bacteria. These results suggest that changes of cell surface glycoconjugates related with cell migration may favor P. aeruginosa adhesion to respiratory cells.
Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts, To test whether generation of oxygen radicals during postischemic reperfusion might promote peroxidation of cardiac membrane lipids. four groups of Langendorff-perfused rabbit hearts were processed at the end of (a) control perfusion. (b) 30 min of total global ischemia at 37 degrees C without reperfusion. (c) 30 min of ischemia followed by reperfusion with standard perfusate. (d) 30 min of ischemia followed by reperfusion with the oxygen radical scavenger human recombinant superoxide dismutase (h-SOD). The left ventricle was homogenized and tissue content of malonyldialdehyde (MDA). an end product of lipid peroxidation. was measured on the whole homogenate as well as on various subcellular fractions. Reperfusion was accompanied by a significant increase in MDA content of the whole homogenate and of the fraction enriched in mitochondria and lysosomes. This phenomenon was not observed in hearts subjected to ischemia but not reperfused. and was similarly absent in those hearts which received h-SOD at reflow. Reperfused hearts also had significantly greater levels of conjugated dienes (another marker of lipid peroxidation) in the mitochondrial-lysosomal fraction. Again. this phenomenon did not occur in ischemic hearts or in reperfused hearts treated with h-SOD. Unlike the effect on tissue MDA and conjugated dienes. reperfusion did not significantly stimulate release of MDA in the cardiac effluent. Treatment with h-SOD was also associated with significant improvement in the recovery of cardiac function. In conclusion. these data directly demonstrate that postischemic reperfusion results in enhanced lipid peroxidation of cardiac membranes. which can be blocked by h-SOD. and therefore is most likely secondary to oxygen radical generation at reflow.
Direct vasoconstriction as a possible cause for amphotericin B-induced nephrotoxicity in rats, In anesthetized rats we tested the hypothesis that amphotericin B (AmB) reduces glomerular filtration rate (GFR) by activating the tubuloglomerular feedback (TGF) mechanism. Infusion of 1 mg/kg AmB over 50 min was followed by a reduction in kidney GFR (from 0.47 +/- 0.03 to 0.39 +/- 0.02 ml/min per 100 g body wt during the second hour after infusion; P less than 0.05) and by an increase in urine flow and urinary chloride excretion. Single-nephron GFR (SNGFR) measured in proximal (TGF interrupted) or distal tubules (TGF intact) decreased to a similar degree from 33.4 +/- 1.8 and 30.6 +/- 1.2 nl/min in the control period to 19.7 +/- 1.9 and 21.2 +/- 1.6 nl/min during the second hour after AmB infusion (P less than 0.05). Distal chloride concentrations and TGF responses to changes in loop of Henle flow rate were not significantly altered by AmB. AmB at 10(-5) M reduced the diameter of isolated perfused afferent arterioles from rabbit kidneys. In isometrically contracting rings of rabbit aorta and renal artery in vitro AmB produced endothelium-independent constriction. with half-maximal contraction (EC50) being achieved by 1.8 x 10(-6) and 2.6 x 10(-6) M in intact vessels and 1.3 x 10(-6) and 1.7 x 10(-6) M in endothelium-denuded vessels respectively. Tension development did not occur in Ca-free media or in the presence of Ca channel blockers. Pretreatment with ouabain or Bay K 8644 potentiated the effect of AmB. The vasoconstrictive effect of AmB was counteracted by aminophylline and atrial natriuretic peptide. We conclude that the AmB-induced reduction in GFR is not caused by TGF activation and that AmB has a direct vasoconstrictor effect that is probably initiated by depolarization-induced opening of Ca channels. This effect may be an important component of the nephrotoxic actions of AmB.
L-type cardiac calcium channels in doxorubicin cardiomyopathy in rats morphological, biochemical, and functional correlations, Doxorubicin (DXR) is an effective antitumor agent in a wide spectrum of neoplasms. Chronic treatment is associated with cardiomyopathy and characteristic myocardial ultrastructural changes. which include swelling of the t tubules. Accordingly. we investigated excitation-contraction coupling in cardiomyopathic rat heart resulting from chronic DXR treatment. Using the whole-cell patch clamp technique. we studied the L-type calcium channel in single cells enzymatically isolated from normal (CTRL) and DXR rat hearts. Despite similar cell dimensions. the total membrane capacitance was significantly smaller in the DXR cells (138 +/- 9 pF) than in the CTRL cells (169 +/- 11 pF) (mean +/- SEM. n = 9. P less than 0.05). The mean current and the current density-voltage relationships of the CTRL and the DXR cells were significantly different (n = 9. P less than 0.001) with the maximal peak L-type calcium current (ICa) density increased from 6.4 +/- 0.9 in CTRL cells to 10.5 +/- 2.4 microA/cm2 in the DXR cells (P less than 0.05). There was no shift either in the current-voltage relationship or the steady-state inactivation curve in the two cell groups. However. the fast time constant of inactivation was increased at a membrane voltage of -10 to 10 mV. Calcium channel antagonist equilibrium binding assays using [3H]-PN200-110 revealed no difference in the maximal receptor binding capacity (CTRL. 194 +/- 27 and DXR 211 +/- 24 fmol/mg protein; P greater than 0.05. n = 6) and in receptor affinity (CTRL. 0.15 +/- 0.05 and DXR 0.13 +/- 0.03 nM; P less than 0.05). These data suggest that a decrease in effective capacitance might be associated with t-tubular damage. Despite this decrease. ICa was increased in the DXR cells. Such an increase may result from an alteration in the properties of the calcium channels and/or recruitment of "hibernating" channels in the remaining surface and t-tubular membranes.
Structure of a monoclonal kappa chain of the V kappa IV subgroup in the kidney and plasma cells in light chain deposition disease, That structural abnormalities may be responsible for nonamyloid immunoglobulin (Ig) light chain deposition disease (LCDD) is suggested by previous results of Ig biosynthesis studies. but this hypothesis was not documented at the molecular level. We report on the first complete primary sequence deduced from cDNA analysis of a kappa light chain responsible for LCDD associated with an apparently nonsecretory myeloma. Bone marrow myeloma cells contained intracellular kappa chains and no heavy chains by immunofluorescence. Kidney biopsy showed typical nonamyloid PAS-positive kappa chain deposits. SDS-PAGE analysis of material extracted from a kidney biopsy specimen and of Ig produced by the myeloma cells revealed kappa chains of abnormally high apparent molecular mass (30.000). Comparison of the NH2-terminal aminoacid sequence of the kappa chain deposited in the kidney and of the complete sequence of several identical kappa cDNA clones from bone marrow cells showed the identity of the tissue deposited and plasma cell kappa chain. The kappa mRNA had an overall normal structure and corresponded to the V kappa IV gene rearranged to J kappa 1 and followed by a normal constant exon of the Km(3) allotype. The variable sequence differed from the V kappa IV germline gene by nine point mutations. including an Asp----Asn substitution at position +70 resulting in a potential N-glycosylation site. In vitro biosynthesis experiments and treatment with N-glycosidase provided evidence for the intracellular glycosylation of the monoclonal kappa chain. The peculiar sequence and the glycosylation of a kappa chain of the rare V kappa IV subgroup might be responsible for structural abnormalities leading to tissue deposition.
Acetylcholine receptor-reactive T and B cells in myasthenia gravis and controls, Myasthenia gravis (MG) is strongly associated with antibodies to acetylcholine receptor (AChR). whereas the extent of T cell involvement is not settled. The number of cells secreting interferon-gamma (IFN-gamma) in response to AChR during 48 h culture of blood mononuclear cells (PBL) may reflect AChR-reactive T cells. Using an immunospot assay. we detected such cells in 23 of 30 patients with MG at a mean number of 1 per 33.333 PBL. AChR-reactive T cells were also found in patients with other neurological diseases (OND) and in healthy subjects but at lower frequencies and numbers. The T cell response to purified protein derivative and to PHA. and also to two major myelin proteins (basic protein and proteolipid protein) did not differ between MG and the two control groups. underlining the specificity of an augmented T cell reactivity to AChR in MG. Evaluation of the B cell response by enumerating anti-AChR IgG antibody secreting cells revealed such cells in 27 of 28 patients with MG at a mean value of 1 per 14.085 PBL. Cells secreting anti-AChR antibodies of the IgA and IgM isotypes were also detected in MG. but less frequently. at lower numbers. and only in conjunction with IgG antibody secreting cells. Anti-AChR antibody secreting cells were also found among patient with OND and in healthy controls. but at lower frequencies and numbers. These data confirm that AChR is a major target for autoimmune response in MG.
Cytokine secretion by C3H-lpr and -gld T cells. Hypersecretion of IFN-gamma and tumor necrosis factor-alpha by stimulated CD4+ T cells, Mice homozygous for lpr and gld develop profound lymphadenopathy characterized by the expansion of two unusual T cell subsets. a predominant Ly-5(B220)+ CD4- CD8- double negative (DN) population and a minor CD4 dull+ Ly-5(B220)+ population. The mechanisms promoting lymphoproliferation are unknown. but one possibility is a abnormality in the production of cytokines that regulate T cell growth. In the present report. unfractionated LN cells and sorted T cell subsets from C3H-lpr. -gld. and -+/+ mice were compared for spontaneous and induced secretion of a spectrum of lymphokines. In addition. CD4+. CD4 dull+ Ly-5(B220)+. and DN T cells were examined for expression of CD3 epsilon. TCR-alpha/beta heterodimers. Ly-6C. and CD44 and for proliferative responses to immobilized anti-TCR mAb and cofactors. These studies revealed that sorted DN T cells did not secrete IL-3. IL-4. IL-5. IL-6. GM-CSF. TNF-alpha. or IFN-gamma spontaneously or after TCR-alpha/beta cross-linking. In contrast. stimulated unfractionated lpr and gld LN cells proliferated strongly and secreted high levels of IFN-gamma and TNF-alpha and low levels of IL-3. IL-4. and IL-6. Despite a 5- to 10-fold deficit in the frequency of CD4+ and CD8+ T cells. cytokine secretion by lpr and gld LN generally exceeded that of +/+ LN. Comparisons of cytokine secretion by stimulated CD4+ T cells revealed that +/+. lpr. and gld CD4+ Ly-5(B220)- T cells proliferated strongly. but only lpr and gld cells produced significant levels of IFN-gamma. The lpr and gld CD4+ T cells also produced higher levels of TNF-alpha and IL-2 than +/+ cells. In contrast to normal CD4+ T cells. lpr and gld CD4+ Ly-5(B220)+ T cells proliferated weakly and did not secrete TNF-alpha. IL-2. or. in most experiments. IFN-gamma after stimulation. Phenotypic studies of T cell subsets revealed that unstimulated lpr and gld CD4+ Ly-5(B220)- T cells express significantly higher levels of CD44 than +/+ CD4+ T cells. In addition. CD4 dull+ Ly-5(B220)+ cells closely resembled DN T cells in size and expression of TCR-alpha/beta. CD3epsilon. CD44. and Ly-6C. Since elevated CD44 expression is generally associated with T cell activation and only previously activated normal CD4+ T cells produce high levels of IFN-gamma in vitro. our data suggest that lpr and gld CD4+ Ly-5(B220)- T cells contain a higher than normal proportion of primed or memory T cells and thus may be polyclonally activated in vivo.(ABSTRACT TRUNCATED AT 400 WORDS).
Analysis of the time course of IFN-gamma mRNA and protein production during primary murine listeriosis. The immune phase of bacterial elimination is not temporally linked to IFN production in vivo, IFN-gamma clearly plays an important role in the murine host response against Listeria monocytogenes. but the time course of its production and its precise role in immunity remain controversial. To address these issues. we sequentially monitored IFN production and bacterial accumulation in vivo in C57B1/6 mice during primary listeriosis. IFN-gamma mRNA levels (measured by Northern blot analysis of freshly isolated splenic RNA) and serum IFN (measured by ELISA) were both maximal on day 1 of infection. decreasing steadily after day 2 to barely detectable levels by days 4 to 6. Significantly. there was no direct relationship between IFN levels and listericidal activity in vivo. Between days 1 and 3. the period of maximal IFN production. host bacterial load (assessed by quantitating live L. monocytogenes/spleen) increased approximately 10- to 50-fold. On the other hand. during the immune phase of infection (between days 5 and 7). a period when both IFN mRNA and protein were barely detectable. the host bacterial load decreased 1.000- to 10.000-fold. The paucity of IFN production in vivo during the immune phase was unexpected in light of previous reports demonstrating abundant in vitro lymphokine release by splenocytes isolated during the same time period. By direct comparisons of IFN production in vivo and in vitro. however. we could show that the late (days 6-7) peak of IFN release observed in Ag-stimulated cultures was an in vitro artifact. By contrast the pattern of spontaneous IFN release (obtained when freshly isolated cells were incubated in the absence of Ag) conformed more closely to that observed in vivo. Because listerial Ag stimulated vigorous lymphokine release in vitro. we sought to determine whether an analogous effect could be observed in vivo. In fact. even the infusion of very large doses of live bacteria (5-20.000.000/mouse) did not stimulate endogenous IFN-gamma production in mice infected for 6 to 7 days. These studies suggest three major conclusions: 1) IFN production in vivo occurs primarily during the early phase of listeriosis; 2) the dramatic decrease in bacterial numbers observed late in infection cannot be directly attributed to increased IFN production by LM-immune T cells; 3) although Ag-driven cultures of freshly isolated cells can provide useful information about the potential lymphokine-producing capabilities of Ag-specific T cells. these results have limited relevance in understanding patterns of T cell lymphokine production in vivo.
Defective HLA DRA X box binding in the class II transactive transcription factor mutant 6.1.6 and in cell lines from class II immunodeficient patients, 6.1.6 is one of several immunoselected mutants from EBV-transformed human B cell lines that have undergone coordinate loss of expression of all their HLA class II genes. Similar defects have been found in cells from some patients with class II immunodeficiencies. Previous studies have suggested that the defects in 6.1.6 and in the other class II regulatory mutants are in transactive factors required for class II transcription. The defective factors. however. have not been identified. Here we present two lines of evidence that serve to localize the site of action of the factor that is defective in 6.1.6. First. transfected indicator genes linked to HLA DRA promoter fragments that include the conserved X box region are transiently expressed at greatly reduced levels in 6.1.6. compared with the progenitor cell line T5-1. Second. a DNA-protein complex. termed X-A. formed by nuclear extracts from T5-1 with DRA sequences containing the X box and a few bases 5' and 3' to it. is missing with extracts from 6.1.6. Extracts from some but not all patients with class II-negative immunodeficiency also fail to form X-A. whereas extracts from class II-negative mutants derived from the Burkitt's line Raji do form an apparently normal X-A complex. The X-A complex contains proteins of approximately 22. 32. 82. and 92 kDa that can be cross-linked to a 5-bromodeoxyuridine-substituted X box probe by UV light. A defect in an X box-binding protein. or in a factor required for its binding. is a likely cause for the loss of transcription of the class II genes in 6.1.6.
Bacteriology of inadequately treated active chronic otitis media in paediatric age group, Haphazardly treated active otitis media was investigated bacteriologically in 214 children. Analysis showed that Pseudomonas aeruginosa was more prevalent than other micro-organisms. Candida was also found in appreciable quantity. The author contends that this was due to inadequate self treatment before these children reported in his hospital. He advocates that decision regarding the chemotherapeutic agent to be used should be based on culture and in vitro sensitivity.
The effect of the calcium antagonist, isradipine, on working capacity, pulmonary function, morbidity and survival rate in patients with severe chronic obstructive pulmonary disease (COPD): a randomized, double-blind, placebo-controlled study, Beneficial effects of calcium antagonists on the pulmonary haemodynamics of patients with chronic obstructive pulmonary disease (COPD) have been observed in several studies. Such effects include a decrease in pulmonary vascular resistance. an increase in cardiac output. and an increase in oxygen delivery. The clinical implications of these effects are uncertain. The randomized. double-blind. placebo-controlled. long-term study described here is the first to investigate the clinical effects of a calcium antagonist on patients with COPD. The aim was to test the hypothesis that the calcium antagonist. isradipine. could increase working capacity and lung function. and decrease morbidity and mortality. Fifty-two patients with COPD were investigated. During a 22-month observation period no statistically significant differences between the isradipine group and the placebo group were found with regard to these parameters. It is concluded that the existing evidence does not justify the introduction of calcium antagonists as part of the routine treatment of COPD.
A controlled trial of insulin infusion and parenteral nutrition in extremely low birth weight infants with glucose intolerance, To determine whether a continuous insulin infusion improves glucose tolerance in extremely low birth weight infants. we conducted a prospective. randomized trial in 24 neonates 4 to 14 days old (mean birth weight 772.9 +/- 128 gm; mean gestational age 26.3 +/- 1.6 weeks). Infants who had glucose intolerance were randomly assigned to receive either intravenous glucose and total parenteral nutrition with insulin through a microliter-sensitive pump or standard intravenous therapy alone. One infant assigned to receive insulin never required it. The groups were similar in birth weight. gestational age. race. gender. medical condition. and energy intake before the study. The mean duration of therapy was 14.6 days (range 7 to 21 days). During the study. the 11 insulin-treated infants tolerated higher glucose infusion rates (20.1 +/- 2.5 vs 13.2 +/- 3.2 mg/kg/min (1.1 +/- 0.1 vs 0.7 +/- 0.2 mmol/L); p less than 0.01). had greater nonprotein energy intake (124.7 +/- 18 vs 86.0 +/- 6 kcal/kg/day; p less than 0.01). and had better weight gain (20.1 +/- 12.1 vs 7.8 +/- 5.1 gm/kg/day; p less than 0.01) than the 12 control infants. The incidence of hypoglycemia. electrolyte imbalance. chronic lung disease. and death did not differ between groups. We conclude that a controlled insulin infusion improves and sustains glucose tolerance. facilitates provision of calories. and enhances weight gain in glucose-intolerant premature infants.
Preclinical detection of Parkinson's disease: biochemical approaches, Dysfunction of NADH: ubiquinone oxidoreductase (complex I) of the mitochondrial electron transport chain has been linked to the pathogenesis of Parkinson's disease. While simple assays of complex I activity are unlikely to be useful in the preclinical detection of Parkinson's disease. other more sophisticated physical-chemical approaches including detection of free radical damage may have utility. Leber's hereditary optic neuropathy may provide a useful model system for development of such strategies.
Effects of lipoprotein (a) on success rate of thrombolytic therapy in acute myocardial infarction, Lipoprotein (a) [Lp(a)] and plasminogen share a high degree of homology as recently evidenced by amino acid and deoxyribonucleic acid analysis. As Lp(a) is enzymatically inactive. it has been suggested that high levels of Lp(a) may suppress the profibrinolytic activity at the cell surface and increase the risk for arteriosclerosis and thrombosis by competitive inhibition of plasminogen. The present study evaluated whether high levels of Lp(a) influence thrombolytic therapy in patients with acute myocardial infarction. Forty-one patients with acute myocardial infarction received a combination low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA) and human single-chain urokinase-type plasminogen activator (scu-PA). This regimen did not induce plasminemia or a lytic state as indicated by well-maintained levels of fibrinogen. Coronary patency was assessed angiographically 90 minutes after initiation of treatment. Thrombolysis was successful in 30 and unsuccessful in 11 patients. Patients with high Lp(a) levels (greater than or equal to 25 mg/dl) (n = 9) responded equally well to thrombolytic therapy (8 of 9. patency 89%) as did patients with normal or low levels of Lp(a) (22 of 32. patency 70%. difference greater than 0.1). Lp(a) levels did not differ significantly between patients with successful and unsuccessful thrombolysis. Our results demonstrate that high levels of Lp(a) do not affect thrombolysis in patients with acute myocardial infarction when low-dose pharmacologic concentrations of rt-PA and scu-PA are applied in combination.
Intracellular compartmentation of cardiac troponin T and its release kinetics in patients with reperfused and nonreperfused myocardial infarction, In a previous study on the diagnostic efficiency of troponin T measurements in patients with suspected acute myocardial infarction (AMI). the authors found a high variability of troponin T serum concentration changes on day 1 in patients with AMI who underwent thrombolytic treatment. Therefore. the aims of the present study were to investigate the intracellular compartmentation of troponin T and to analyze the effects of AMI reperfusion on the appearance kinetics of cardiac troponin T in serum. Cardiac troponin T was measured with a newly developed bideterminant sandwich assay using cardiospecific. affinity-purified polyclonal antibodies and peroxidase-labeled monoclonal antibody. An unbound cytosolic troponin T pool was found in ultracentrifuged homogenates of myocardial tissue of different species ranging from 0.013 to 0.036 mg/g wet weight. The soluble troponin T molecule had electrophoretic properties identical to troponin T compartmented in the myofibrils. The clinical study group comprised 57 patients with AMI undergoing thrombolytic treatment. Blood flow to the infarct zone and point of time of reperfusion were tested by immediate and late angiography. The appearance of troponin T in serum on day 1 after the onset of AMI depended strongly on reperfusion and on duration of ischemia before reperfusion. Thus. in patients with early reperfused AMI. a marked peak in troponin T serum concentrations was found at 14 hours after the onset of pain. This early troponin T peak was absent in patients with AMI reperfusion occurring greater than 5.5 hours after the onset of pain and in patients with nonreperfused AMI. By contrast. the kinetics of troponin T release after the first day after AMI were unaffected by reperfusion.
Rosette formation by Plasmodium coatneyi-infected red blood cells, Animal models are needed for the study of cytoadherence in falciparum malaria. Red blood cell (RBC) rosette formation is one type of cytoadherence and appears to be associated with knob formation. endothelial cell adhesion and sequestration of Plasmodium-infected RBCs. Since Plasmodium coatneyi-infected RBCs develop knobs and sequester. we hypothesized that they also form rosettes. RBCs from P. coatneyi-infected rhesus monkeys (Macaca-mulatta) were collected. allowed to mature overnight in vitro and found to form rosettes as hypothesized. This observation adds to the known falciparum-like characteristics of P. coatneyi. and suggests that the Macaca mulatta-P. coatneyi model may be appropriate for pathophysiologic studies of cytoadherence.
Heterogeneity of the T-cell receptor beta gene rearrangements generated in myelin basic protein-specific T-cell clones isolated from a patient with multiple sclerosis, Seventeen T-cell clones derived from the peripheral blood of a patient with multiple sclerosis and reactive with a synthetic peptide corresponding to residues 152-170 of the human myelin basic protein molecule were previously shown to be cytotoxic for myelin basic protein-coated target cells. Genetic restriction studies have now demonstrated that these clones recognize myelin basic protein in association with human leukocyte antigen DRw13. Studies of the T-cell receptor beta gene rearrangements generated by these clones demonstrated 12 different patterns. as evaluated by Southern blot analysis. Thus. the human T-cell response to myelin basic protein is exceedingly heterogeneous. even among T cells that recognize the same small fragment of the molecule in association with the same class II restriction element.
Relationship between plasma atrial natriuretic factor and urinary kallikrein excretion in essential hypertensives, In order to seek possible relationships between renal kallikrein and atrial natriuretic factor (ANF). we measured urinary kallikrein (UK) and ANF in 84 normal subjects (NS) and in 104 uncomplicated essential hypertensives (HP). Atrial natriuretic factor was significantly higher in HP than in NS (38.5 +/- 1.3 vs 29.0 +/- 1.3 pg/mL. P less than .01). whereas UK was significantly lower in HP than in NS (11.1 +/- 0.9 v 15.3 +/- 0.6 nkatal/24 h. P less than .01). Calculating the 95% of the percentile distribution of the single values of UK in the group of NS we were able to show that 24 out of 104 HP had a UK which fell below the lowest limit (4.5 nkat/24 h) of the normal range. We therefore divided our HP into two subgroups: patients with normal kallikrein excretion (NK) (n = 80; mean UK 13.8 +/- 0.8 nkat/24 h) and patients with low kallikrein excretion (LK) (n = 24; mean UK 2.3 +/- 0.3 nkat/24 h). Normal kallikrein patients had a mean plasma ANF value of 31.9 +/- 1.2 pg/mL which was almost superimposable to that found in NS; on the contrary. the mean plasma level of ANF in LK patients (50.7 +/- 2.2 pg/mL) was significantly higher than that measured in NK patients and in NS (P less than .01 v NK patients and NS. respectively). Since a low urinary kallikrein excretion may represent a marker of an impaired production of renal kallikrein. the high levels of ANF found in the LK subgroup could be the result of a compensatory response of the atrium attempting to maintain sodium and volume homeostasis.
Expression of c-jun during macrophage differentiation of HL-60 cells, Cellular transcription factors are important in the regulation of cellular genes. Recent studies have indicated that a class of cellular genes known as early response genes are important in the control of cellular growth properties. Two of these genes. c-jun and c-fos. play an important role in the control of cellular differentiation. Because the acute myelogenous leukemia cell line. HL-60. is capable of differentiating to either macrophages or granulocytes. it provides a good model to understand differential gene expression. To determine if the modulation of c-jun was important in the differentiation of HL-60 cells to either macrophages or granulocytes. expression of c-jun mRNA was determined by Northern analysis at various times following treatment with a variety of differentiating agents. including 12-tetradeconyl-phorbol 13-acetate (TPA). retinoic acid (RA). dimethyl sulfoxide (DMSO). or 1.25 dihydroxyvitamin D3 [1.25 (OH)2 D3]. Both TPA and 1.25(OH)2D3. which induce HL-60 cells to differentiate to macrophages. resulted in marked increases in c-jun mRNA; while RA and DMSO. which induce HL-60 cells to differentiate to granulocytes. did not greatly alter c-jun mRNA expression. HL-60 cell lines resistant to macrophage differentiation after exposure to either 1.25(OH)2D3 or TPA did not result in increases in c-jun mRNA. These results suggest that elevation of c-jun mRNA in HL-60 cells correlated temporally with differentiation to macrophages. Thus. c-jun may be a critical cellular transcription factor involved in macrophage differentiation.
Cytokine influence on killing of fresh chronic lymphocytic leukemia cells by human leukocytes, The feasibility of combining the Lym-1 monoclonal antibody (MoAb) with interferon-gamma (IFN-gamma) in the treatment of chronic lymphocytic leukemia (CLL) was evaluated. We used an in vitro tumor lysis model that incorporated fresh CLL cells from 21 different patients as targets for two distinct normal human leukocyte effector subsets. neutrophils. and peripheral blood mononuclear cells (PBMCs). Lym-1 antigen (Lym-1-Ag) expression varied greatly and did not correlate with the expression of other CLL-associated antigens such as CD5. CD19. or HLA-DR. CLL cells were not lysed by neutrophils alone or with IFN-gamma in the absence of Lym-1. Neutrophil Lym-1-dependent cytotoxicity (ADCC) in the absence of IFN-gamma was weak and inconsistent. IFN-gamma exposure induced MoAb-dependent lysis of 80% of 21 CLL targets and resulted in an eightfold augmentation of neutrophil ADCC against the remainder. Cytotoxicity correlated directly and positively with Lym-1-Ag expression. Confirmation of the need for interaction between neutrophil IgG Fc receptors (Fc gamma Rs) and the Fc portion of the Lym-1 MoAb was obtained by demonstrating that purified Staphylococcus aureus Protein A (SpA) inhibited ADCC. IFN-gamma exposure caused no consistent alternations in Lym-1-Ag expression on CLL cells so that target antigen upregulation was unlikely to account for augmentation of neutrophil ADCC. PBMCs alone. exposed to interkeukin-2 (IL-2) or IFN-gamma. or with Lym-1 in the presence or absence of IL-2 or IFN-gamma were unable to lyse CLL targets. PBMCs were able to kill Raji Burkitt lymphoma cells in conjunction with Lym-1. so their ability to interact with Lym-1-coated targets and their lytic functions appeared intact. These results emphasize the importance of examining fresh tumor cells with different leukocyte effector subsets before designing a clinical trial that combines a therapeutic MoAb with a cytokine.
Appraisal of a new scheme for prenatal screening for Down's syndrome, OBJECTIVE--To appraise a new method of prenatal screening for Down's syndrome based on maternal serum concentrations of alpha fetoprotein. unconjugated oestriol. and human chorionic gonadotrophin combined with maternal age--the "triple test." DESIGN--Examination of the cost effectiveness of the triple test relative to screening only by maternal age over a range of population detection rates. SETTING--Leicestershire Health Authority. MAIN OUTCOME MEASURES--Costs per affected fetus detected. RESULTS--The triple test is more cost effective than screening only by maternal age for risk cut off points for amniocentesis. resulting in a detection rate over 45%. The most efficient detection rate is around 60-65%. for which the cost per case detected is around 29.000 pounds. through screening with higher detection rates is still likely to be cost beneficial. CONCLUSIONS--Prenatal screening for Down's syndrome based on the triple test should replace screening based only on maternal age. Individual women's preferences should be elicited by the use of structured decision analysis in order to maximise utility and so increase the benefits of the screening programme.
Economic issues relating to access to medications, Millions of uninsured. low-income workers (a disproportionate number of them black) are financially unable to obtain prescription drugs for treatment of conditions such as hypertension. As a result. funds spent to diagnose their underlying illnesses may be wasted. and they are likely to suffer complications that require much more costly care. The tendency for income levels to be inversely correlated with blood pressure means that those least able to pay for antihypertensive medication are those most susceptible to complications. Since current programs are inadequate to help most of these patients. there is a need for a joint initiative by the federal government and the pharmaceutical industry to fund programs to make medications easily accessible for the medically indigent population.
Laser radiation at various wavelengths for decompression of intervertebral disk. Experimental observations on human autopsy specimens, The interaction of laser radiation with the nucleus pulposus from autopsy specimens of human intervertebral disks was evaluated at different wavelengths (193 nm. 488 nm & 514 nm. 1064 nm. 1318 nm. 2150 nm. 2940 nm. and 10600 nm). A significant correlation of linear least squares fit of the mass ablated as a function of incident energy was found for all lasers used except the Excimer at 193 nm. The 2940-nm Erbium:YAG laser was most efficient in terms of mass of disk ablated per joule in the limited lower range where this wavelength was observed. At higher energy levels. the CO2 laser in the pulsed mode was most efficient. However. the Nd:YAG 1064-nm and 1318-nm lasers are currently best suited for percutaneous laser disk decompression because of the availability of usable waveguides. Carbonization of tissue with the more penetrating Nd:YAG 1064-nm laser increases the efficiency of tissue ablation and makes it comparable to the Nd:YAG 1318-nm laser.
The use of aspirin to prevent heterotopic ossification after total hip arthroplasty. A preliminary report, The reported incidence of heterotopic ossification (HO) after total hip arthroplasty (THA) ranges up to 50%. HO causes pain and restricted range of motion (ROM) in a significant number of these THA patients. From 1983 to 1988. 177 primary cemented THAs were performed in 131 consecutive patients. Six hundred fifty milligrams of buffered aspirin administered twice daily for two weeks was used as a prophylaxis for thromboembolic disease. There was an unusually low incidence of HO in this group of patients. Aspirin treatment was instituted the night before surgery and continued for two weeks. except in 13 patients (7%) who had to stop treatment because of gastrointestinal symptoms. All patients had at least one year of roentgenographic study postoperatively. According to the Brooker Classification of HO. there were 169 (96%) Grade I and Grade 0 hips. six (3%) Grade II. two (1%) Grade III. and no Grade IV. None of the patients had symptomatic restriction of ROM attributable to heterotopic bone. Aspirin is a safe and inexpensive agent for prevention of HO after THA.
Magnetic resonance imaging and late-onset epilepsy, The value of magnetic resonance imaging (MRI) in investigation of patients with late-onset epilepsy has not been studied systematically. We evaluated prospectively the usefulness of MRI in 50 patients with late-onset epilepsy in whom a computed tomography (CT) scan was normal (32). did not allow a definitive diagnosis to be made (12). or showed irrelevant lesions (6). Patients were assessed clinically and had an EEG. and CT and MRI scans were reported by one neuroradiologist blinded to clinical and laboratory data. Of the 32 patients with a normal CT scan. MRI was normal in 20. showed irrelevant ischemic lesions in 8. and showed the cause of seizures in 4 patients. Of the 12 patients with nondiagnostic CT. MRI clarified the diagnosis in 5 and was normal in 2 patients. In 6 patients. both scans showed irrelevant ischemic lesions. and in 1 patient MRI showed a relevant additional lesion. The incidence of MRI-detected white matter ischemic lesions was no greater than in an age- and sex-matched group of subjects without seizures. MRI was diagnostic in 32% of the patients with partial seizures and/or focal EEG findings. as compared with 0% of patients without focal features (p less than 0.01). We conclude that MRI is useful in investigation of patients with late-onset epilepsy with focal features.
Discontinuation of phenytoin and carbamazepine in patients receiving felbamate, Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23-36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 +/- 0.93 (mean +/- SEM). decreasing to 0.87 +/- 0.71 with addition of FBM. and 0.82 +/- 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reductions of 33. 54. and 63%. Toxicity attributable to FBM was not observed. and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition. as PHT dosages were reduced. FBM clearance decreased 21%. As the CBZ dosages were reduced. FBM clearance decreased an additional 16.5%.
Cost-effectiveness of extracorporeal shock-wave lithotripsy versus cholecystectomy for symptomatic gallstones, To evaluate the cost-effectiveness of extracorporeal shock-wave lithotripsy vs. cholecystectomy for symptomatic gallstones. a model was constructed that projects charges and survival for both treatments. For a 45-year-old woman with one small stone. treatment with extracorporeal shock-wave lithotripsy rather than cholecystectomy is projected to result in an average gain of only 3 days of life and an average increase in direct medical charges of $1729 over 5 years of follow-up. The resulting marginal cost-effectiveness of extracorporeal shock-wave lithotripsy vs. cholecystectomy is $216.000 of extra charges per year of life gained with extracorporeal shock-wave lithotripsy. Extracorporeal shock-wave lithotripsy is projected to be much more cost-effective for elderly than for young patients (10-20-fold difference). but considerably less cost-effective for multiple stones than a single stone (2-4-fold difference). and less cost-effective for women than men (twofold difference). Adjusting for effects of morbidity on quality of life. extracorporeal shock-wave lithotripsy is projected to have slightly better quality-adjusted survival than cholecystectomy for the small subset of patients with one stone (by 8 to 43 days at 5 years) but not for young patients with multiple stones. It is concluded that decisions about appropriate use of extracorporeal shock-wave lithotripsy should consider the effects of patient characteristics on clinical and economic outcomes.
Ursodeoxycholic acid for the treatment of home parenteral nutrition-associated cholestasis. A case report, Severe cholestasis associated with long-term home parenteral nutrition is rare. and no treatment is known to be effective. This study shows a case of a patient who developed jaundice while receiving long-term home parenteral nutrition. Causes of jaundice. other than the patient's parenteral feedings. were excluded. The patient's jaundice did not respond to alterations in his parenteral feeding program or to metronidazole. Ursodeoxycholic acid (600 mg/day) led to a prompt and sustained improvement in his hyperbilirubinemia. When ursodeoxycholic acid was stopped. the patient again became jaundiced. but this resolved with reinstitution of ursodeoxycholic acid. This case suggests that ursodeoxycholic acid may be an effective treatment for home parenteral nutrition--associated cholestasis and should be evaluated further in patients with cholestasis associated with parenteral feeding.
Content and boundaries of medicine in long-term care: physicians talk about stroke, Twenty physicians were interviewed about roles. treatments. goals. and relationships with older patients. especially stroke patients. Findings from this descriptive. anthropological investigation address the problem of congruence between needs and existing services. and in doing so. recast the ongoing debate about the medicalization of long-term care. This study emphasized the nonmedical features of geriatric medicine in general and stroke care in particular. In many instances. these physicians attempt to bridge gaps between medical and emotional needs and clinical and social services with social and psychotherapeutic as well as biomedical interventions. Because we found physicians' activities with stroke patients to be so broadly construed. treatment and management of stroke may be seen as paradigmatic for the role of physicians in long-term care.
Dopaminergic abnormalities in borderline essential hypertensive patients, To explore whether an altered metabolic pathway of dihydroxyphenylalanine (DOPA) may be related to some previously observed dopamine abnormalities in borderline hypertension. we measured basal and DOPA-induced (500 mg orally) changes in blood pressure and pulse rate as well as in three hourly plasma and urine samples. We found that borderline hypertensive patients compared with controls 1) showed a higher baseline urinary excretion of methoxytyramine. a marker of exocytotic dopamine release. with a greater DOPA-induced decrease of systolic blood pressure without reflex tachycardia; 2) had in response to DOPA a blunted plasma DOPA and free dopamine increase but an accentuated plasma dopamine sulfate and urinary DOPAC excretion; and 3) eliminated comparable quantities of dopamine in urine despite a lower rise in the glomerular DOPA load. Furthermore. although DOPA elicited natriuresis in both groups. its effect was greater in borderline hypertensive patients. who lacked the urinary sodium correlation with urinary dopamine excretion seen in control subjects. These data are compatible with increased basal exocytotic dopamine release and accelerated neuronal and renal (extraneuronal) dopamine generation from administered DOPA in borderline hypertension. The DOPA-induced hypernatriuresis exceeding augmented dopamine in borderline hypertensive patients. contrasting with the urinary sodium and dopamine correlation in control subjects. suggests that DOPA induced an additional natriuresis in borderline hypertensive patients by a decrease in renal sympathetic tone because of its central inhibition of sympathetic outflow. which also may account for the absence of reflex tachycardia.
Depot leuprolide acetate dosage for sexual precocity, Twenty-one children with early puberty have been evaluated to determine adequate dosage of depot leuprolide acetate. The minimal dosage of depot leuprolide acetate required. using intervals of 1.5 mg or less when given every 28 days. was determined. This dosage. as determined by suppression of gonadotropin responses to GnRH stimulation. was 4.14 +/- 1.33 mg (mean +/- SD) and 0.15 +/- 0.07 mg/kg.28 days. The dosage correlates with bone age and pubertal stage and is larger among patients with more advanced puberty. Five patients required a larger dosage from 5-10 months after initial suppression. Therefore. to monitor suppression. GnRH testing should be repeated at least at 6-month intervals. Samples 20 and 40 min after GnRH stimulation are sufficient to indicate adequacy of treatment. so an abbreviated test could be used.
Identification of Neisseria gonorrhoeae using the Neisstrip rapid enzyme detection test, A rapid enzyme activity strip test (Neisstrip. Lab M Ltd. Bury) was compared retrospectively with Phadebact Monoclonal GC coagglutination (Pharmacia Diagnostics. Uppsala. Sweden). cystine trypticase agar sugar utilisation (CTA). and Gonochek II (J W Turner. Liverpool) enzyme methods for identification of 95 Neisseria spp and related species. These had been previously identified using standard methods and included 29 that had given aberrant results. Neisstrip identified correctly all but two. including nine incorrectly identified by Phadebact and 18 erroneously identified using CTA sugars. Results were similar to those obtained with Gonochek II. After this a prospective study was performed testing 400 oxidase positive isolates derived from clinical samples cultured on gonococcal selective medium. Two organisms. both Moraxella spp. were incorrectly identified as N gonorrhoeae by the Neisstrip. The superoxol test. when used with either the Phadebact or Neisstrip tests. maintained 100% sensitivity and specificity. The Neisstrip is a rapid. economic test that is accurate and easy to interpret. It may be used alone or in conjunction with a superoxol test or a coagglutination test. which is relatively accurate but more expensive. and found by some technical staff to be more difficult to interpret.
Red cell aplasia in myelodysplastic syndrome, Six cases of red cell aplasia occurring in patients with myelodysplastic syndromes (MDS) showed a diversity of clinical course and prognosis. In some patients red cell aplasia may have represented an evolution of MDS while in others autoimmune destruction of erythoblasts may have been the mechanism. A proliferative phase is seen in many of these patients. the clinical importance of which is uncertain.
Evidence suggesting involvement of interleukin-4 (IL-4) production in spontaneous in vitro IgE synthesis in patients with atopic dermatitis, To investigate the regulatory role of interleukin-4 (IL-4) and interferon-gamma (INF-gamma) and their involvement in the abnormality of IgE synthesis in patients with atopic dermatitis (AD). we studied the effect of recombinant human IL-4 and INF-gamma. as well as blocking antibodies (Abs) to these lymphokines on spontaneous IgE synthesis by peripheral blood lymphocytes (PBLs) from patients with AD and from healthy control subjects. PBLs from patients with AD demonstrated elevated spontaneous IgE production that was not stimulated further by the addition of recombinant IL-4. whereas for the healthy control subjects. recombinant IL-4 increased spontaneous IgE production by PBLs. INF-gamma that has been previously demonstrated to antagonize the effect of IL-4 on IgE synthesis. decreased IgE production of patients with AD. Addition of Abs to INF-gamma did not change spontaneous IgE production for patients with AD or for healthy control subjects. Together with our observation that IL-4 Abs lowered the high spontaneous IgE production by PBLs from patients with AD. these results suggest that in AD. IL-4 production by lymphocytes. together with a lack of INF-gamma production. is at least partially responsible for the increased spontaneous IgE production.
Cyclosporine A metabolism by cytochrome P-450III occurs in microsomes from rat liver but not from normal epidermis or psoriatic lesions, Cyclosporine A is efficacious in the treatment of psoriasis when taken orally or injected intralesionally but not topically. Lack of penetration to necessary locations or rapid metabolism during passage through the epidermis may account for the ineffectiveness. Cytochromes P-450III in the liver are known to be involved in cyclosporine metabolism and inactivation. This study was undertaken to determine if an epidermal cytochrome P-450III exists that can inactivate topical cyclosporine A. Rats were treated with the macrolide antibiotic erythromycin to induce the cytochrome P-450III family of enzymes. Microsomal fractions were prepared from liver and epidermis of rats and from lesional areas of psoriasis patients. NADPH cytochrome C reductase activity was determined as a positive control for microsomal enzymatic activity. Formation of metabolite 1. the predominant metabolite of cyclosporine A. by liver microsomes was increased 193% after 10 d erythromycin treatment. The cytochrome P-450 dependent activity in microsomes from the epidermis of control and erythromycin-treated rats and in microsomes from psoriatic tissue was at the detection limits of the assay system. Cytochrome P-450III gene family mRNA were detectable by polymerase chain reaction in liver but not in psoriatic or normal epidermis. The lack of detectable P-450III mRNA and the absence or minimal conversion of cyclosporine A to inactive metabolites by epidermal microsomes suggest that the ineffectiveness of topical cyclosporine A in psoriasis may not be due to inactivation of cyclosporine A by cytochrome P-450 in the skin.
Long-term follow-up and prognostic factor analysis in advanced ovarian carcinoma: the Gynecologic Oncology Group experience, Long-term follow-up was obtained on 726 women with advanced ovarian carcinoma (suboptimal stage III and stage IV) who had received primary chemotherapy on two Gynecologic Oncology Group (GOG) protocols between 1976 and 1982. The first study compared melphalan alone versus melphalan plus hexamethylmelamine versus cyclophosphamide plus doxorubicin (CA). The second study evaluated the same CA regimen with or without cisplatin. Eligibility for the two studies was the same. At last contact. 76 patients were alive. In a multivariate analysis. cell type other than clear cell or mucinous. cisplatin-based treatment. good performance status. younger age. lower stage. clinically nonmeasurable disease. smaller residual tumor volume. and absence of ascites were favorable characteristics for overall survival (P less than .05). Second-look laparotomy was negative significantly more often among those with endometrioid tumors; there were no negative second-look laparotomies among those with mucinous or clear cell tumors. There were 30 patients with suboptimal stage III disease who had a negative second-look laparotomy; 18 (60%) have experienced recurrence. and 13 (43%) have died. Although cisplatin treatment was beneficial. new treatments are clearly needed.
Effect of the ANF analog A68828 in cisplatin-induced acute renal failure, Experiments were conducted to determine the effects of the reduced-size atrial natriuretic factor (ANF) analog. A68828. on renal function in rats with cisplatin (CP)-induced acute renal failure. CP was given as a single intraperitoneal injection (7.5 mg/kg) 3 days before experiments. In separate groups of rats. the renal response to intravenous infusion of A68828 at 3. 10 or 30 micrograms/kg/min or ANF[1-28] at 0.03. 0.1 or 0.3 micrograms/kg/min for 2 hr was evaluated. Another group of CP-treated rats were infused with the vehicle (0.1% bovine serum albumin in 0.9% NaCl). CP treatment resulted in a marked decline in glomerular filtration rate (GFR). arterial pressure. heart rate and reabsorption of water and electrolytes compared to untreated control animals. Infusion of A68828 produced a dose-dependent improvement in the glomerular filtration rate. The highest dose of A68828 produced a nearly 3-fold increase in the glomerular filtration rate. whereas arterial pressure was decreased; heart rate was unchanged. Despite producing a significant diuresis and natriuresis. net tubular reabsorption of water and sodium was also increased. Similar dose-dependent effects were observed with the native peptide. ANF[1-28]. These data indicate that infusion of the reduced-sized analog of ANF. A68828. can significantly improve glomerular and tubular function in rats with acute renal failure induced by CP.
Epidemiology of Rh hemolytic disease of the newborn in the United States, Nationwide surveillance of Rh hemolytic disease of the newborn (RhHDN) indicates that. after a substantial decline in incidence. reported rates reached a plateau in the late 1970s. We conducted a study designed to validate RhHDN surveillance data. to obtain corrected incidence estimates. and to identify potential reasons for the reported plateau. We obtained data from the Birth Defects Monitoring Program. a national surveillance system that collects data from public and private hospitals participating voluntarily. We asked hospitals for copies of the medical records for all infants discharged with a code for RhHDN and for a sample of the medical records of infants discharged with a code for other and unspecified hemolytic disease during 1986. The estimated incidence rate of RhHDN was 10.6 per 10.000 total births. with some regional variations. Our findings indicate that. despite the availability of an effective preventive measure. RhHDN continues to contribute significantly to infant morbidity and mortality in the United States.
Dose-response studies with thyrotropin-releasing hormone (TRH) in abstinent male alcoholics: evidence for selective thyrotroph dysfunction, A reduced thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) has been reported in subjects with a history of alcoholism whereas prolactin (PRL) responses have generally been normal. One hypothesis proposed to explain the reduced TSH response is down-regulation of pituitary TRH receptors. If this is correct. PRL response should also be diminished. To account for the different dose-response characteristics of TSH/PRL we have given four dosages of TRH (25. 100. 500 and 800 micrograms) to eight noncirrhotic. male alcoholics abstinent from ethanol a minimum of 28 days and to seven male control subjects. Across the TRH dose range the alcoholic subjects exhibited reduced basal TSH (p = .01) and a reduced TSH response (p = .0023) but no differences in basal and stimulated PRL levels. Alcoholic subjects had higher basal T4. T3 and FT4I values than did control subjects but covarying for T4. T3 and FT4I did not change the significance of either TSH or PRL findings. No significant differences in estradiol. estrone. testosterone. cortisol or glucose were noted between groups. The present study confirms the observation of a lower TSH response to TRH in abstinent alcoholics and indicates that the lower response cannot be overcome by increasing TRH dosage. The similar PRL response between groups suggests normal lactotroph function in noncirrhotic abstinent alcoholics and argues against the pituitary TRH receptor down-regulation hypothesis.
A controlled trial of aerosolized ribavirin in infants receiving mechanical ventilation for severe respiratory syncytial virus infection, BACKGROUND. Although the antiviral agent ribavirin improves the course of lower respiratory tract disease in spontaneously breathing infants with respiratory syncytial virus infection. it is not known whether ribavirin can benefit infants with severe respiratory syncytial virus disease who require mechanical ventilation. METHODS. We conducted a randomized. double-blind. placebo-controlled evaluation of ribavirin (20 mg per milliliter) administered continuously in aerosolized form to infants receiving mechanical ventilation for respiratory failure that was caused by documented respiratory syncytial virus infection. RESULTS. Of the 28 infants (mean [+/- SD] age. 1.4 +/- 1.7 months) enrolled. 7 had underlying diseases predisposing them to severe infection (mean age. 3.0 +/- 2.6 months). and 21 were previously normal (mean age. 0.8 +/- 0.9 month). Among the 14 infants who received ribavirin. the mean duration of mechanical ventilation was 4.9 days (as compared with 9.9 days among the 14 who received placebo; P = 0.01). and the mean length of supplemental oxygen use was 8.7 days (as compared with 13.5 days; P = 0.01). The mean length of the hospital stay was 13.3 days after treatment with ribavirin and 15.0 with placebo (P = 0.04). When only the 21 previously normal infants were considered. the mean length of the hospital stay was 9.0 days for the ribavirin recipients and 15.3 days for those who received placebo (P = 0.005). CONCLUSIONS. In infants who require mechanical ventilation because of severe respiratory syncytial virus infection. treatment with aerosolized ribavirin decreases the duration of mechanical ventilation. oxygen treatment. and the hospital stay.
Differential regulation of rasGAP and neurofibromatosis gene product activities, The ras-encoded p21ras proteins bind GTP very tightly. but catalyse hydrolysis to GDP very slowly. In humans. two genes encode proteins that stimulate this GTPase activity (GAP. or GTPase-activating proteins). one of relative molecular mass 120.000. referred to as p120-GAP. and another NF1-GAP. which is encoded by the neurofibromatosis type-1 gene. Both GAPs are widely expressed in mammalian tissues. Here we show that although they will both bind oncogenic mutants of p21ras. neither will stimulate their GTPase activity. NF1-GAP binds to the p21ras proteins up to 300 times more efficiently than p120-GAP. The two GAPs are inhibited to different extents by certain lipids: micromolar concentrations of arachidonate. phosphatidate and phosphatidylinositol-4.5-bisphosphate affect only NF1-GAP. This inhibition does not compete with p21ras. and lipid-inactivated NF1-GAP can still bind p21ras. We used the detergent dodecyl maltoside. which inhibits only NF1-GAP. to distinguish between the two activities in cell extracts and found both types present together in several mammalian cell lines. In contrast. GAP activity in extracts of Xenopus oocytes was not affected by dodecyl maltoside. By these criteria. the mammalian cells contain both GAP activities and the oocytes have only p120-like GAP activity. These results indicate that more than one GAP regulates p21ras in the same cell.
Soluble CD8 levels in the CSF and serum of patients with multiple sclerosis, CD8 is a membrane glycoprotein of 34 kd on cytotoxic/suppressor T lymphocytes and is an endogenous ligand for MHC class I proteins on target cells. CD8 is released in a soluble form upon T-lymphocyte activation. In multiple sclerosis (MS). T lymphocytes exhibit decreased membrane expression of the CD8 molecule and defective suppressor function. We measured soluble CD8 (sCD8) levels in the CSF of patients with MS. other inflammatory neurologic diseases (INDs). and noninflammatory neurologic diseases (NINDs). sCD8 levels in the CSF of MS and IND patients were elevated compared with NIND patients. Patients with acute infections of the CNS showed the highest absolute values of sCD8. but the amount of sCD8 per CSF white blood cell was greatest in MS and NIND patients. We found no difference in serum sCD8 levels among the groups. In MS. the combination of increased CSF sCD8 levels and sCD8 per cell may reflect CD8 T-lymphocyte activation within the brain or immunodysregulation confined to the CNS.
Selegiline (deprenyl) treatment and death of nigral neurons in Parkinson's disease, We studied the effect of selegiline (deprenyl) treatment on the number of Lewy bodies and neuron counts in the substantia nigra in patients with Parkinson's disease (PD). The number of medial nigral neurons was greater and the number of Lewy bodies fewer in those PD patients who had been treated with selegiline in combination with levodopa as compared with patients who had received levodopa alone. This suggests that selegiline treatment may retard the death of nigral neurons. but alternative explanations. such as the reduction of levodopa dosage in selegiline-treated patients. are possible.
The hazards of hypercaloric nutritional support in respiratory disease, This case illustrates the dangers of hypercaloric feeding in a patient with limited respiratory reserve. in this instance secondary to heart-lung transplantation. The patient's postoperative course was complicated by repeated bouts of infection and/or rejection that resulted in intubation and ventilatory support. The excessive caloric and protein load given to the patient resulted in increased CO2 generation with subsequent inability to wean the patient off the ventilator. Recognition of the problem and appropriate decreases in substrate intake permitted extubation.
Effect of maternal carbon dioxide inhalation on human fetal breathing movements in term and preterm labor, Induced maternal hypercapnia is a potent stimulus to fetal breathing movements in nonlaboring pregnant women. To determine the effect of maternal CO2 administration on fetal breathing movements during spontaneous labor. 14 healthy pregnant volunteers at term and 34 in preterm labor were recruited. If fetal breathing movements were markedly decreased or absent. the subjects were administered a prepared gas mixture of 3% CO2 in air. In term labor and in true preterm labor. fetal breathing movements were markedly decreased and could not be induced by maternal hypercapnia. Among women with suspected preterm labor. initial absence of fetal breathing movements and failure to evoke this response by maternal hypercapnia predicted delivery within 48 hours with a sensitivity of 80% and specificity of 95.5%. Induced maternal hypercapnia fails to stimulate fetal breathing movements in true term and preterm labor and may assist in distinguishing between true and false preterm labor.
Advances in pediatric drug therapy of asthma, Most pediatric patients requiring medication to prevent or treat asthmatic symptoms require only the use of inhaled beta 2 agonists. Children younger than 6 years old usually require use of the nebulized or oral forms of beta 2 agonists. Theophylline or cromolyn is added as a second-line agent to the regimens of children who need an additional agent. Anticholinergic agents are added as third-line agents for resistant cases of asthma. Inhaled and oral steroids are reserved for resistant cases of childhood chronic asthma. even though adults frequently are given inhaled steroids as second-line agents. Parenteral steroids are used for the treatment of status asthmaticus.
Pharmacology of the nitrovasodilators. Antianginal, antihypertensive, and antiplatelet actions, The nitrovasodilators. nitroglycerin and sodium nitroprusside. cause both arterial and venous smooth muscle dilation by the intracellular release of nitric oxide. Nitric oxide activates guanylate cyclase. resulting in an accumulation of cyclic GMP. The endogenous formation of nitric oxide results in vasodilatory activity similar to the nitrovasodilators. Nitroglycerin is commonly used in the treatment of angina pectoris because of its ability to decrease myocardial oxygen consumption. Most likely. this response occurs as a result of a reduction in preload. which can decrease arterial wall tension and improve coronary blood flow. This pharmacologic effect warrants the use of nitroglycerin in the treatment of myocardial ischemia or infarction. congestive heart failure. and hypertension. Sodium nitroprusside is effective in reducing arterial blood pressure in hypertensive crisis as a result of systemic vasodilation leading to a reduction in preload and afterload. Sodium nitroprusside is not as effective in the treatment of angina pectoris or in diminishing of myocardial ischemia because it does not preferentially improve blood flow to ischemic myocardium over nonischemic myocardium. Inhibition of platelet aggregation has been demonstrated with these drugs. but the clinical applications need further investigation. Nursing interventions for the patient on nitrovasodilator therapy include careful hemodynamic monitoring and drug infusion. along with elimination of physical and emotional stimuli that can aggravate the patient's underlying pathology.
Utilization and clinical manifestations of human immunodeficiency virus type 1-infected children presenting to a pediatric emergency department, A retrospective review was conducted of 22 human immunodeficiency virus type 1 (HIV-1)-infected children under 13 years of age presenting to an inner city pediatric emergency department to determine their clinical manifestations of disease and utilization of emergency department services. When compared with a population of 78 normal children. the infected children were more likely to present with cough. difficulty in breathing. and lethargy. Pneumonia. diarrhea. and dehydration were more common diagnoses in the infected children. who were more likely to be admitted. had more invasive procedures. and required more professional staff to provide care. There was no significant difference in the frequency of visits (visits/month of age) when comparing the two groups. As expected. the infected children presented with problems associated with pediatric HIV-1 infection. Our results suggest that HIV-1-infected children require an increased level of care in the emergency department and subsequent admission to the hospital. These children did not visit the emergency department more frequently than the controls. This may be the result of an active outpatient HIV clinic in our hospital. which is available to both scheduled and unscheduled patients.
A one-year prospective ED cohort of pediatric burns: a proposal for standardizing scald burns, During a 12-month period ending on 11/30/88. data were collected on 143 pediatric patients visiting a pediatric emergency department with burns. Sixty-four percent were males. Common causes of the burns included hot water (17%). hot food (23%). hot appliances (18%). and charcoal and grills (9%). Sixty-six percent of the burns took place at home. The hospitalization rate was 8%. A suggestion for standardizing scalds based on fluidity and function is proposed. since there is ambiguity regarding definition of a scald.
Molecular biology of prion diseases, Prions cause transmissible and genetic neurodegenerative diseases. including scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt-Jakob and Gerstmann-Straussler-Scheinker diseases of humans. Infectious prion particles are composed largely. if not entirely. of an abnormal isoform of the prion protein. which is encoded by a chromosomal gene. A posttranslational process. as yet unidentified. converts the cellular prion protein into an abnormal isoform. Scrapie incubation times. neuropathology. and prion synthesis in transgenic mice are controlled by the prion protein gene. Point mutations in the prion protein genes of animals and humans are genetically linked to development of neuro-degeneration. Transgenic mice expressing mutant prion proteins spontaneously develop neurologic dysfunction and spongiform neuropathology. Understanding prion diseases may advance investigations of other neurodegenerative disorders and of the processes by which neurons differentiate. function for decades. and then grow senescent.
Selective elimination of HIV-1-infected cells with an interleukin-2 receptor-specific cytotoxin, Infection by human immunodeficiency virus type 1 (HIV-1) is associated with cellular activation and expression of the interleukin-2 (IL-2) receptor. A genetically engineered fusion toxin. DAB486 IL-2. that contains the enzymatic site and translocation domain of diphtheria toxin and the receptor binding domain of IL-2 specifically kills cells that express high-affinity IL-2 receptors. This toxin selectively eliminated the HIV-1-infected cells from mixed cultures of infected and uninfected cells and inhibited production of viral proteins and infectious virus. Thus. cellular activation antigens present a target for early antiviral intervention.
Past, present, and future of nutritional support, Early rudimentary attempts to provide adequate nutrition by mouth. intestinal tube. and vein in order to reduce morbidity and mortality have advanced to strategies designed to maintain the integrity of the body cell mass. Technology has progressed geometrically in recent years with the development of organ-specific enteral and parenteral substrate mixtures; sophisticated assessment. delivery. and monitoring systems; and improved safety and efficacy. Nutritional support is rapidly evolving into the practice of clinical biochemistry. in which nutrient substrates will be formulated to enhance or maximize cellular function. not only under normal conditions. but under a wide variety of pathophysiologic conditions.
Nutritional assessment and indications for nutritional support, The goal of nutritional assessment is to identify prospectively all those patients who would develop a nutrition-related complication. In practical terms. there is no single test capable of achieving this goal. At present. the best method of nutritional assessment is an organized step-by-step multifactorial approach. This involves assessment of the primary illness. the patient history. and the prognosis. A nutritional status examination is done. and the current intake is compared with the nutritional goals. A decision is then made whether to force feed. If forced feeding is initiated. the effectiveness of the therapy must be monitored frequently until the patient recovers and is able to be sustained by volitional oral intake.
Amino acids in surgical nutrition. Principles and practice, Amino acids will always be an integral part of nutritional support in all patients. The use of specific amino acids in pharmacologic doses may be beneficial to certain critically ill patients. indicating that such compounds are conditionally essential. As our knowledge of the altered regulation of amino acid metabolism in surgical patients improves. the design of more effective feeding regimens will follow. The goal should be to provide the best nutrition to all patients at all times.
Total parenteral nutrition in the pediatric patient, Over the past 50 years. tremendous advances have been made in the management of children who cannot receive enteral nutrition. Challenges for the future include devising techniques to decrease catheter sepsis. particularly in children with a short bowel. who have a disproportionate number of septic episodes. possibly related to bacterial translocation. The delineation of risk factors for cholestasis associated with total parenteral nutrition and refinement of administration of such nutrition in premature neonates to decrease the incidence of this complication. as well as the morbidity of osteopenia. will extend our ability to help these children.
Perioperative nutritional support, In selected malnourished patients. perioperative nutritional support can decrease the morbidity and mortality rates associated with major surgical procedures. Preoperative nutritional support should be delivered via the gastrointestinal tract whenever feasible. generally in the form of enteral diets. which can be given via a feeding tube or as a dietary supplement. Patients with a functional gut who cannot eat because of anorexia or upper gastrointestinal tract obstruction are candidates for preoperative tube feedings. Total parenteral nutrition should be the mainstay of nutritional support when the gastrointestinal tract cannot be used adequately. An improvement in nutritional indices (e.g.. serum transferrin. lymphocyte count) may be associated with decreased perioperative morbidity. although the strength of this relation is not clear. In the absence of improvement in such indices. the duration of nutritional support required to decrease operative morbidity is unknown. Postoperatively. enteral tube feedings (delivered via a nasojejunal tube or feeding jejunostomy) should be provided to all preoperatively malnourished patients with a functional gastrointestinal tract who are unable to consume adequate calories orally. Postoperative TPN should be reserved for malnourished patients with a nonfunctional gut or for patients who develop a postoperative complication that precludes enteral feeding. Current nutritional formulas have often neglected the metabolic and nutritional requirements of the intestinal tract. In the future. the combined use of specific nutrients and growth factors may improve nutritional rehabilitation in catabolic patients.
Management of the short-bowel syndrome, The patient with short-bowel syndrome after massive small-intestinal resection represents one of the greatest clinical challenges a general surgeon must face. Maintaining optimal nutritional and metabolic support until maximum bowel adaptation can occur is the top priority of therapy. Currently. no operative procedure for adjunctive management of the short-bowel syndrome is sufficiently safe and effective to recommend its routine use. Long-term parenteral nutrition remains the cornerstone of successful management.
End-tidal CO2 monitoring in mitral stenosis patients undergoing closed mitral commissurotomy, Arterial to end-tidal carbon dioxide difference (P(a-E')CO2) was recorded in 20 mitral stenosis patients (group A) for closed mitral commissurotomy and 20 healthy individuals (group B) for elective limb surgery. Mitral stenosis patients showed a greater difference than group B patients. Repeated measurements of P(a-E')CO2 in mitral stenosis patients at various stages of closed mitral commissurotomy not only showed a mean increase from before thoracotomy but there was also no correlation between P(a-E')CO2 before thoracotomy with that after thoracotomy. after commissurotomy or after chest closure. This indicated that end-tidal CO2 monitoring was unsuitable to measure adequacy of ventilation during closed mitral commissurotomy.
Urinary leukotriene E4 in patients with asthma. Effect of airways reactivity and sodium cromoglycate, A group of 17 patients with allergic asthma was challenged with aerosolized antigen. and the excretion of the peptidoleukotriene metabolite leukotriene (LT) E4 in the urine was determined as an index of leukotriene synthesis. The allergen challenge caused a drop in FEV1 of 25 to 59% within the first 2 h in all patients. This was associated with an increase in urine LTE4 excretion during the subsequent 12 h. The amount of urinary LTE4 excreted increased from a 12-h baseline level of 46 +/- 6.8 ng to a postallergen challenge level of 92 +/- 13 ng. In a similar experimental protocol methacholine challenge alone did not significantly increase urinary LTE4 excretion. In comparing all individuals as a group. there was no significant positive correlation between the magnitude of the drop in FEV1 during the immediate asthmatic response (IAR) and the increased amount of LTE4 excreted in the urine (p = 0.08). These parameters were still not significantly correlated when airways reactivity (log PC20) was also considered (p = 0.057). However. when each individual was compared to self in the presence and absence of cromoglycate. a significant correlation was found to exist between the drop in FEV1 during the IAR. the excretion of urinary LTE4. and the airways reactivity. No correlation was found between the increase in urine LTE4 excreted during the 12 h following allergen challenge and the severity of late (3 to 12 h) responses to allergen. but there was a significant prolonged (12 to 36 h) elevated urine LTE4 excretion in those patients with the most severe late asthmatic response.
Ig CH and D14S1 variants in rheumatoid arthritis--linkage and association studies, We have looked for an effect of 14th chromosomal genes linked to immunoglobulin heavy chain (IgCH) or D14S1 regions on susceptibility to rheumatoid arthritis (RA) by both linkage (sibling pair analysis) and association studies. There was no overall linkage between RA and either IgCH or D14S1. However. Gm haplotype similarity in affected siblings appeared greater in either DR4-positive as compared to DR4-negative sibships or in sibships without clinical or serological evidence of autoimmune thyroid disease when compared to sibships with such evidence. In association studies there were no associations at the D14S1 locus. Within the Ig CH region there were no overall associations. However. within the RA population G1m (z) and G3m (g) both appeared less frequent in DR4-negative RA versus both DR4-positive RA and versus control groups. Analysis of DNA variants at Ig CH loci showed differences at the gamma 4 locus with a 9.0 kb fragment appearing less frequently in DR4-positive RA versus DR4-negative RA and control groups. The results suggest a weak or HLA-DR dependent effect of genes linked to the Ig CH region on susceptibility to RA.
Improvement of estradiol 17 beta-D-glucuronide cholestasis by intravenous administration of dimethylethanolamine in the rat, The intravenous administration of dimethylethanolamine in the rat promotes a selective enrichment of liver membranes with polyunsaturated phosphatidylcholines. The effect of dimethylethanolamine pretreatment on cholestasis induced by estradiol 17 beta-D-glucuronide. a potent cholestatic agent. was assessed in this study. Dimethylethanolamine. dissolved in sodium-taurocholate was infused intravenously (0.3 mg/kg/min) for 15 hr. One group of control rats (estradiol 17 beta-D-glucuronide controls) received the bile salt only. An estradiol 17 beta-D-glucuronide bolus was then injected intravenously (10.4 mg/kg) into dimethylethanolamine-pretreated and estradiol 17 beta-D-control rats. and its effect on bile flow and biliary lipid secretion was compared for 3 hr. The estradiol 17 beta-D-glucuronide inhibitory effect on bile flow and biliary lipid secretion was significantly antagonized by dimethylethanolamine pretreatment. The maximum inhibition of bile flow was found 30 min after estradiol 17 beta-D-glucuronide administration. when it decreased from 3.5 +/- 0.4 microliters/min/100 gm (basal) to 0.9 +/- 0.3 microliters/min/100 gm in estradiol 17 beta-D-glucuronide controls. whereas in dimethylethanolamine-pretreated rats this decreased only from 3.2 +/- 0.4 (basal) to 2.3 +/- 0.4 microliters/min/100 gm. Bile flow and the biliary secretion of cholesterol. phosphatidylcholine and bile salts were significantly higher in the dimethylethanolamine-pretreated rats than in estradiol 17 beta-D-glucuronide controls (p less than 0.02) during the cholestatic phase. The inhibitory effect of estradiol 17 beta-D-glucuronide on bile flow was associated with a marked decrease of membrane fluidity (p less than 0.001) assessed by 1.6-diphenyl-1.3.5-hexatriene fluorescence anisotropy and with a cholesterol enrichment of microsomes. sinusoidal and canalicular liver plasma membranes and inhibition of sinusoidal Na+.K(+)-ATPase activity (p less than 0.05). These membrane alterations persisted 180 min after estradiol 17 beta-D-glucuronide administration despite complete normalization of bile flow. Dimethylethanolamine pretreatment significantly counteracted the reduction of membrane fluidity (p less than 0.001). the cholesterol enrichment and the inhibition of Na+.K(+)-ATPase (p less than 0.05) promoted by estradiol 17 beta-D-glucuronide administration in all membrane subfractions 30 and 180 min after administration. In addition. dimethylethanolamine-pretreated rats had more polyunsaturated fatty acids in membrane phosphatidylcholine with respect to the control groups. Dilatation of canaliculi and loss of microvilli were evident in estradiol 17 beta-D-glucuronide controls 180 min after estradiol 17 beta-D-glucuronide administration.(ABSTRACT TRUNCATED AT 400 WORDS).
Successful treatment of primary progressive follicular mucinosis with interferons, Follicular mucinosis is a primary idiopathic disease or a secondary. lymphoma-associated dermatosis. An effective standard therapy for the benign group is unknown. We describe a patient with primary benign disseminated progressive follicular mucinosis who was successfully treated with recombinant interferon alfa-2b and interferon-gamma. Interferons might act by down-regulation of activated inflammatory cells and/or by induction of enhanced elimination of extracellular mucin via increasing phagocytosis by macrophages.
Multiple miliary osteoma cutis, We describe the clinical. radiographic. histologic. and metabolic features of an unusual case of multiple miliary osteoma cutis in an otherwise healthy 57-year-old woman. Although the pathogenesis of this rarely reported entity is not fully understood. the novel application of a dynamic bone study revealed a high rate of internal bone remodeling within the lesion. This finding prompted a brief therapeutic trial of a diphosphonate. not previously reported in the treatment of this condition.
Cardiac surgery in the octogenarian: perioperative outcome and clinical follow-up, The perioperative and follow-up results of cardiac operations employing extracorporeal circulation and cold cardioplegic arrest were examined in 191 consecutive patients greater than or equal to 80 years of age having surgery over a 5 year period (1982 to 1986). Most patients had severe preoperative symptoms with functional class III (39.8%) or IV (57.1%) limitation. The overall 30 day postoperative cardiac mortality rate was 15.7%. The total in-hospital mortality rate was 18.8%; the mean postoperative hospital stay was 16.4 +/- 13.3 days. The perioperative mortality rate for elective operations was as follows: coronary artery bypass (5.6%). aortic valve replacement (9.6%). aortic valve replacement with coronary bypass (17.9%) and mitral valve surgery with or without coronary bypass (21.4%). Urgent operations were performed in 39 patients (20.4%) with a total perioperative mortality rate of 35.9%; urgent coronary artery bypass was performed in 26 patients (67%) with an in-hospital mortality rate of 23.1%. Clinical evidence of left ventricular failure. functional class IV symptoms. left ventricular ejection fraction less than 50%. mitral valve repair or replacement for severe mitral regurgitation and urgent operation were associated with an increased perioperative mortality rate. Follow-up study in all 155 patients surviving postoperative hospitalization at 22.6 +/- 14.8 months showed significant improvement in symptom status in all surgical subgroups. There were 18 follow-up deaths (11.6%); 10 were noncardiac. The actuarial survival rate of the entire study group was significantly better than that in age- and gender-matched control subjects (p = 0.037).
Rocky Mountain spotted fever, Rocky Mountain spotted fever. the most prevalent rickettsial disease in the United States. is one of the most severe of all infectious diseases. It remains an important infectious disease because of its prevalence. the difficulty of clinical diagnosis. potentially fatal outcome. and lack of a widely available sensitive and specific diagnostic test during the acute stage of the illness.
Effect of a new monoclonal antibody, TA-2, that inhibits lymphocyte adherence to cytokine stimulated endothelium in the rat, An important event in the migration of lymphocytes out of the blood is their adherence to endothelial cells (EC). In inflammatory sites cytokines activate EC and promote lymphocyte EC adherence and migration. Small peritoneal exudate lymphocytes (sPEL) preferentially migrate from the blood to cutaneous delayed-type hypersensitivity reactions and to sites injected with IFN-gamma. IFN-alpha/beta. and TNF-alpha. rather than to peripheral lymph nodes. The basis of this migration is sPEL adherence to cytokine-activated EC. To study this adhesion mAb to rat sPEL were screened for inhibition of sPEL adherence to IFN-gamma-stimulated EC. One mAb. TA-2. inhibited IFN-gamma-stimulated adherence to EC by 60%. This antibody had no effect on the baseline adherence of sPEL to unstimulated EC. Treatment of sPEL. but not EC. with TA-2-inhibited adhesion. TA-2 also inhibited adhesion to EC activated with mIL-1 alpha. TNF-alpha. and LPS. and the adhesion of spleen T cells to activated EC. The TA-2 Ag was expressed on virtually all lymph node. spleen. and sPEL lymphocytes but sPEL expressed two to three times higher levels than lymph node lymphocytes. and the highest levels were found on CD4+ and CD45R- memory T cells. TA-2 immunoprecipitated a group of four polypeptides with molecular mass of 150. 130. 83. and 66 kDa. Finally. TA-2 inhibited sPEL adhesion to TNF-alpha and IL-1 stimulated human umbilical vein EC to the same extent as an anti-human VCAM-1 mAb. and combinations of TA-2 and anti-VCAM-1 were not different from treatment with either antibody alone. Thus. TA-2 appears to recognize rat VLA-4 based on immunoprecipitation. immunofluorescence. and lymphocyte EC studies. VLA-4 mediates the adhesion of rat lymphocytes to rat microvascular EC stimulated with IFN-gamma. mIL-1 alpha. TNF-alpha. and LPS. VLA-4 is important in the increased adhesion of sPEL to EC and the enhanced sPEL migration to inflammation may in part be explained by increased expression of VLA-4 on these cells.
Soluble IL-2 receptor as an agent of serum-mediated suppression in human visceral leishmaniasis, In visceral leishmaniasis (VL). patient's lymphocytes are not activated by leishmania Ag stimulation. and their sera exhibit a potent nonspecific suppressive effect on the responses of normal lymphocytes. Sera were obtained from 33 VL patients. eight patients with subclinical VL. and from 27 normal volunteers. Only sera from VL patients markedly reduced Con A-induced lymphocyte proliferative responses. as well as IL-2 or IFN-gamma production by normal lymphocytes. Addition of exogenous human rIL-2 to cultures containing VL patient sera partially reversed the normal lymphocyte proliferative capacity and restored IFN-gamma production. This phenomenon was consistent with the presence of greatly elevated levels of soluble IL-2R (sIL-2R) in VL patients' sera (4299 +/- 2351 U/ml). well above those of normal sera (180 +/- 94 U/ml). or of sera from patients with subclinical leishmania infection without immunosuppression (1002 +/- 281 U/ml). Furthermore. the removal of sIL-2R reduced VL serum suppressive activity as evaluated by effects on IL-2 and on IFN-gamma production. These data suggest the participation of high levels of sIL-2R in the serum-mediated suppression in VL.
IFN-gamma- and IL-5-producing cells compartmentalize to different lymphoid organs in Trichinella spiralis-infected mice, The differential induction of cytokines associated with Th1 and Th2 subsets has recently been described during Trichinella spiralis infection. Increased levels of resistance appear to correlate with elevated levels of the Th1-associated cytokines. IFN-gamma and IL-2. In the present report. a filter immunoplaque assay is used to quantify the actual numbers of cells that secrete IFN-gamma and IL-5. It is demonstrated that. in T. spiralis-infected B10.Q mice. Th1- and Th2-associated responses are compartmentalized to different lymphoid organs. Thus. Ag-induced IFN-gamma-producing cells predominate in the spleen. whereas IL-5-producing cells prevail in the mesenteric lymph nodes (MLN). A corresponding compartmentalization of Ag-specific IgA and IgG1 antibody-secreting cells to the MLN is also noted. The virtual absence of Th1-associated responses in the MLN appears to be an Ag-associated phenomenon. MLN from either naive or T. spiralis-infected mice do have the capacity to secrete IFN-gamma if stimulated with Con A. The striking compartmentalization of Ag-driven cytokine responses seen in this parasite system may facilitate study of the mechanisms that regulate the induction of Th1 and Th2 subsets.
Immune response to Schistosoma mansoni infections in inbred rats. VII. Resistance is contingent on OX-8(+)-regulated high affinity IL-2 receptor-bearing W3/25+ lymphocytes but not on IL-4-dependent cells, These studies assess the roles of subpopulations of T lymphocytes in resistance to Schistosoma mansoni. CDF rats were depleted of the T cell subpopulation bearing the high affinity IL-2R by in vivo treatment with ART18+ mAb or of soluble IL-4 by treatment with 11B11 mAb. The development of parasites. the expression of resistance after sensitization. and the intensity of delayed type hypersensitivity (DTH). Ag-mediated blast transformation (AMBT). IgG2a. passive cutaneous anaphylaxis. and IgE-mediated antibody-dependent cell-mediated cytotoxicity responses against S. mansoni or control Ag were ascertained. Isolated T cell subpopulations were assessed in vivo and in vitro for effects upon the protective Ir. Depletion with ART18 mAb suppressed the development of W3/25+ helper-inducer cells and resulted in the initial survival of more worms. decreased resistance to challenge after initial sensitization. decreased IgG2a and IgE antibody. AMBT. and DTH reactivity against schistosome Ag. Depletion with ART18 did not prevent the development of OX8+ (T suppressor) cells. Depletion with 11B11 mAb led to insignificant changes in initial parasite survival and resistance to challenge; had no effect on IgG2a antibody. AMBT. or DTH; but profoundly suppressed the IgE responses against the parasite. Protective immunity to S. mansoni in rats is dependent upon IL-2R-bearing T lymphocytes and regulated by OX8+ cells but not absolutely contingent upon IL-4 or the IgE response.
The initial immune response to HIV and immune system activation determine the outcome of HIV disease, A study was conducted to assess the relative contribution of the HIV-1-specific immune response and -nonspecific immune activation to HIV disease progression. The titer of antibody to the p24 core protein and the concentration of serum neopterin were measured in 238 HIV-1-seropositive subjects in a prospective cohort study of homosexual men. Antibody titers were extremely variable among cohort participants but relatively stable over time. suggesting inherent differences in the initial immune response capacity. Neopterin concentrations were also variable at cohort entry but generally increased over time. These two markers. measured at cohort entry. had powerful and independent predictive value for the development of AIDS up to 54 months before diagnosis. Subjects with low antibody titers and high levels of neopterin. had the highest incidence of AIDS (60% over 54 months). Patients with low antibody or high neopterin alone had an intermediate risk (34% incidence) and less than 10% of those with high antibody and low neopterin developed AIDS. We propose that the initial immune response to HIV and virus-mediated immune system activation are independent and innately variable components of an individual's response to HIV infection that interact to determine the clinical outcome.
Safety and immunogenicity of multiple conventional immunizations administered during early HIV infection, Twenty-one asymptomatic adults who had recently received multiple polysaccharide. live viral. and protein-derived vaccines were identified as being infected with human immunodeficiency virus (HIV). The mean subject age was 24 years (range 18-33); 20 of 21 (95%) were male. The mean T4 count was 523/mm3 with a mean T4/T8 ratio of 0.6. Serologic responses to immunization with meningococcus group C. adenovirus types 4 and 7. tetanus. and diphtheria were evaluated for the HIV seropositive subjects and were compared with the responses of similarly vaccinated age-. sex-. and race-matched HIV-seronegative controls. Significantly fewer (p less than 0.03) HIV subjects responded to meningococcus C (bactericidal antibody) and adenovirus 4 (neutralizing antibody) vaccines than did normals; the HIV-infected subjects who did respond produced functional antibody comparable to that of normals. Booster responses of HIV subjects to tetanus and diphtheria were comparable to those of normals. HIV-infected vaccine nonresponders did not differ from HIV-infected responders in total white blood cell. T4. T4/T8. total serum IgG. or delayed-type hypersensitivity skin test reactivity. All HIV subjects had negative cultures for live vaccine viruses (rubella. measles. adenovirus. and poliovirus). Postimmunization. no clinically apparent adverse reactions to vaccination were detected.
Toward rational nutritional support of the human immunodeficiency virus-infected patient [editorial, The acquired immunodeficiency syndrome and (human immunodeficiency virus) infection loom as our major public health priorities for at least the next two decades. Despite the recent exciting early development of vaccines and newer drug therapies. we are all faced with a reservoir of almost one-quarter million cases in the United States and several times that worldwide. Since the vast majority of HIV-infected patients develop AIDS. which is a chronic progressive disease that produces gastrointestinal dysfunction and wasting. development of rational strategies for nutritional support of these patients should also be a high priority.
Effect of various lipid emulsions on total parenteral nutrition-induced hepatosteatosis in rats, The effect of various lipid emulsions on the development of fatty liver during total parenteral nutrition (TPN) was investigated in rats given TPN for 7 days. Medium-chain triglycerides (MCT). long-chain triglycerides (LCT). chemically defined triglycerides (CDT; structured lipid with a high purity of 94.3%). and a mixture of MCT and LCT (MIX) were prepared as the lipid emulsions. TPN provided 350 kcal/kg/day. with a nonprotein calorie/nitrogen ratio of 160. The TPN-1 group received 10% nonprotein calories and the TPN-2 group received 30% nonprotein calories. MCT TPN was found to have some disadvantages. especially with regard to nitrogen balance and plasma albumin levels. Total cholesterol and phospholipids tended to be high in the MCT TPN group. The hepatic lipid content was higher in the lipid-free TPN and the MCT TPN groups. and lower in the CDT and LCT TPN groups. Histologically. the livers of the MIX. CDT. and LCT TPN groups showed less fatty change than those of the FREE and MCT groups.
Alteration of whole-body protein kinetics according to severity of surgical trauma in patients receiving total parenteral nutrition, This study was conducted to clarify the mechanisms of body nitrogen losses according to the severity of surgical trauma. Thirteen male patients who underwent operation for esophageal cancer (group E). and 11 men (who underwent gastric or colorectal surgeries (group GC) were studied. The measurement of whole-body protein turnover. synthesis. and breakdown were made preoperatively on the 3rd and 10th postoperative day with constant infusion of [15N]glycine during isocaloric and isonitrogenous total parenteral nutrition. Significant increases in the rates of whole-body protein turnover (flux) and breakdown were seen in group E on the 3rd postoperative day (p less than 0.01. p less than 0.01. respectively). whereas the increases were not significant in group GC. The rates of whole-body protein flux and breakdown were significantly greater in group E than group GC (p less than 0.01. p less than 0.01. respectively). The rate of protein synthesis significantly increased in group E (p less than 0.05). but did not alter or slightly decreased in group GC. The rates of whole-body protein flux and breakdown in group E were still significantly greater on the 10th postoperative day than preoperatively. It was concluded that unchanged or slightly decreased rates of whole-body protein synthesis with slightly increased breakdown were seen in the group of patients who underwent gastric or colorectal surgery. whereas synthesis increased significantly with a greater increase of breakdown in patients receiving severe surgical procedures. esophagectomy for esophageal cancer.
Rapid diagnosis of meningococcal meningitis by polymerase chain reaction, Rapid diagnosis of meningococcal disease followed by early treatment is essential. However. culture of blood or cerebrospinal fluid (CSF) may be unsuccessful because antibiotic treatment is often started before adequate specimens are collected. and because bacteria may die during transportation to the laboratory. We have used the polymerase chain reaction (PCR) to detect meningococcal DNA in a culture-negative CSF of a 15-year-old girl with meningococcal disease. Two oligonucleotides flanking the dihydropteroate synthase gene (dhps) of Neisseria meningitidis were used as primers. The PCR reaction is a rapid technique for the early detection of meningococcal meningitis. and also when culture is negative.
Serodiagnosis of hepatitis C virus (HCV) infection with an HCV core protein molecularly expressed by a recombinant baculovirus, An enzyme-linked immunosorbent assay (ELISA) was developed for serological diagnosis of hepatitis C virus (HCV) infection. using HCV core protein (p22) synthesized by a recombinant baculovirus. Among 58 clinically well-defined chronic non-A. non-B hepatitis (NANBH) patients. 49 (84.5%) were positive for p22 antibody (anti-p22). whereas 42 (72.4%) were positive for C100-3 antibody (anti-C100-3). as measured by the present assay using the HCV nonstructural protein as antigen. Thirty-nine patients (67.2%) had both antibodies. No significant level of anti-p22 was detected in sera of chronic hepatitis B patients or normal blood donors. In typical post-transfusion NANBH patients. anti-p22 could be detected at. or even before. the first alanine aminotransferase peak. Anti-p22 was also detected in blood donors who were previously shown to be involved in transmitting HCV but in whose serum anti-C100-3 was not detectable. The ELISA detecting antibody to the HCV core protein expressed and properly processed in animal cells will be useful for mass screening of donor blood as well as for early diagnosis of hepatitis C.
Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes, We have evaluated the muscarinic acetylcholine family of G protein-coupled receptors (mAChRs) for their oncogenic potential. These receptors are preferentially expressed in postmitotic cells. transducing signals specified by their endogenous agonist. the neurotransmitter acetylcholine. Cells transfected with individual human mAChR genes were morphologically indistinguishable from parental NIH 3T3 cells in the absence of agonist. In contrast. when cultures were supplemented with carbachol. a stable analog of acetylcholine. foci of transformation readily appeared in m1. m3. or m5 but not in m2 or m4 mAChRs transfectants. Receptor expression was verified by ligand binding and was similar for each transfected culture. Transformation was dose-dependent and required only low levels of receptor expression. In transformation-competent cells. agonist induced phosphatidylinositol hydrolysis. whereas in m2 or m4 transfectants. receptors were coupled to the inhibition of adenylyl cyclase. These findings demonstrate that mAChRs linked to phosphatidylinositol hydrolysis can act as conditional oncogenes when expressed in cells capable of proliferation.
Immunogenicity of an engineered internal image antibody, We engineered an antibody expressing in the third complementarity-determining region of its heavy chain variable region a "foreign" epitope. the repetitive tetrapeptide Asn-Ala-Asn-Pro (NANP) of the circumsporozoite protein of Plasmodium falciparum parasite. one of the etiologic agents of malaria in humans. A monoclonal antibody to P. falciparum specific for the (NANP)n amino acid sequence bound to the engineered antibody. and a synthetic (NANP)3 peptide blocked this interaction. Immunization of rabbits and mice with the engineered antibody resulted in the elicitation of a humoral response to (NANP)3 synthetic peptide and P. falciparum parasite. In mice. in which immunity to the (NANP)n epitope is highly restricted by immune response genes. antibodies were induced in responder and nonresponder haplotypes of the major histocompatibility complex. Rabbit antibodies efficiently inhibited the in vitro invasion of cultured liver cells by P. falciparum parasite. Collectively. this study indicates that immunity to malaria in the absence of the parasite can be induced using antibody variable regions engineered to mimic the parasite's molecular structure. In general terms. the results suggest that antibody (idiotype) mimicry of an exogenous antigen is possible and may only require a discrete stretch of identity between the two molecules. The implication for the preparation of antibody-based vaccines and idiotype regulation of immunity are discussed.
Bispecific antibodies that mediate killing of cells infected with human immunodeficiency virus of any strain, Although AIDS patients lose human immunodeficiency virus (HIV)-specific cytotoxic T cells. their remaining CD8-positive T lymphocytes maintain cytotoxic function. To exploit this fact we have constructed bispecific antibodies that direct cytotoxic T lymphocytes of any specificity to cells that express gp120 of HIV. These bispecific antibodies comprise one heavy/light chain pair from an antibody to CD3. linked to a heavy chain whose variable region has been replaced with sequences from CD4 plus a second light chain. CD3 is part of the antigen receptor on T cells and is responsible for signal transduction. In the presence of these bispecific antibodies. T cells of irrelevant specificity effectively lyse HIV-infected cells in vitro.
Evidence for retrotransposition of the I factor, a LINE element of Drosophila melanogaster, LINEs are transposable elements found in various eukaryotes such as plants. protists. insects. and mammals. Their transposition is usually difficult to study. particularly in humans. where some diseases have been shown to result from LINE insertion mutations. This is due to the fact that most copies of any particular family of elements are defective and that their transposition frequency is low. By contrast. the I factor of Drosophila melanogaster transposes at high frequency during I-R hybrid dysgenesis and is a good model for studying the LINE element superfamily. LINEs encode putative polypeptides showing similarities with viral reverse transcriptases but. unlike viral retrotransposons. they do not have terminal repeats and their ability to transpose by reverse transcription has previously only been inferred from structural analysis. Here we present direct evidence for LINE retrotransposition. Transposition of an I factor marked by an intron resulted in accurate removal of the intron.
Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris, Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV). almost entirely as the common Jewish extended haplotype [HLA-B38. SC21. DR4. DQw8] or as the haplotype HLA-B35. SC31. DR4. DQw8. and that HLA-DR4. DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients. DR4. DQw8 was found in 12 of the patients and DRw6. DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4. DQw8 haplotypes was [HLA-B38. SC21. DR4. DQw8] and 2 were HLA-B35. SC31. DR4. DQw8; most were the presumed fragments (SC31. DR4. DQw8) or (SC21. DR4. DQw8) or DR4. DQw8 with some other complotype. Of the patients with DRw6. DQw5. all were DRw14. DQw5. and 6 had a rare Caucasian haplotype. HLA-Bw55. SB45. DRw14. DQw5. Four of 6 of these were found in patients of Italian extraction. as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews. HLA-B38(35). SC21(SC31). DR4. DQw8. and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55. SB45. DRw14. DQw5 and has also partially fragmented so that many patients carry only DRw14. DQw5. The available data do not permit the specific localization of either the DR4. DQw8- or the DRw14. DQw5-linked susceptibility genes.
A single base insertion in the putative transmembrane domain of the tyrosinase gene as a cause for tyrosinase-negative oculocutaneous albinism, We have determined a molecular defect to be the likely basis for inactivity of the tyrosinase (EC 1.14.18.1) from a patient with tyrosinase-negative oculocutaneous albinism. A single base (thymine) was inserted in exon 5 of the tyrosinase gene following codon 471 in the putative transmembrane coding region. This insertion caused a shift in the reading frame of 19 amino acids at the 3' end and introduced a premature termination signal that would be expected to truncate the protein by 21 amino acids at the carboxyl terminus. The albino tyrosinase was not recognized by antibodies directed to the carboxyl terminus of tyrosinase. Furthermore. as shown by gel electrophoresis of the immunoprecipitated protein. the tyrosinase was approximately 3 kDa smaller than normal. Similar immunoprecipitation data were obtained when cloned normal and mutant tyrosinases were expressed in COS-1 cells.
Building skills of recovering women drug users to reduce heterosexual AIDS transmission, Although most women infected with HIV are intravenous drug users. some contact the virus through sexual contact with IV drug users. To reach at-risk women. public health officials must develop a range of prevention strategies. One approach. skills training. holds promise as a means of altering risk-related sexual behavior. In this study. 91 women methadone patients were pretested and randomly assigned to an information-only control control group or a skills-building intervention group. Skills-building intervention consisted of five sessions of small groups in which participants identified their own high risk sexual behaviors. discussed their negative associations with condoms. and practiced skills which involved asking partners to use condoms. Compared with members of the control group. respondents in the intervention group reported that they initiated discussion of sexual issues with their partners more frequently. felt more comfortable talking with them about safer sex. and reported using and carrying condoms more frequently. The high rates of attendance and program retention by skills-building participants suggest that such groups may be supportive and useful in the design of risk reduction and drug abuse treatment programs. The modest outcomes of this study underscore the difficulty of altering risk behavior but also serve as a basis for future AIDS prevention studies.
Promoting heart health for Southeast Asians: a database for planning interventions, This paper is a report of baseline data that the authors collected on the prevalence of hypertension in a sample of 397 Southeast Asian immigrants residing in central Ohio and the implications of those data for the design of ethnically approved and scientifically valid interventions. The context for collection of these data over a 9-month period in 1989 is described. Baseline demographic characteristics including distributions by ethnicity. sex. age. and length of stay in the United States. as well as family heart health history. hypertension level. and heart health awareness of these subjects are presented. For example. 85 percent of the immigrants did not know what could be done to prevent heart disease. Implications for the design of ethnically approved and scientifically valid prevention strategies are discussed. Based on these data. the authors realized that multiple health education strategies tailored to what they were learning about Southeast Asians would be needed. Through Southeast Asian leaders. they were led to using wall calendars. with words specific to each Southeast Asian language. that had a monthly heart health slogan as one avenue to reach Southeast Asians. Another strategy was to develop videotapes featuring cultural content but including heart health "commercials." The authors concluded that. although scientific validity of risk reduction interventions are important. customizing these strategies to ethnically specific modes of interaction are equally important.
Shigellosis from swimming in a park pond in Michigan, In July 1989 an outbreak of shigellosis occurred among visitors to a recreational park in Oakland County. MI. An epidemiologic investigation discovered an association between illness and swimming in a pond at the park. especially for those who had put their head underwater. No other factors were epidemiologically incriminated. A total of 65 cases were identified; nine were culture confirmed. all Shigella sonnei. Several water samples evaluated for fecal coliform counts shortly after the outbreak were found satisfactory. Cultures of water samples were negative for Shigella species. Inspection of the park's sewage disposal and toilet facilities found all equipment in proper working condition and no evidence of a sewage contamination event from these potential sources. No other commercial or residential sources of potential sewage contamination existed near the pond. Investigators concluded that Shigella contamination of the pond by a swimmer or swimmers on one or more occasions was a strong possibility. Factors supporting this conclusion included elevated incidence of S. sonnei in the community during the 2 months prior to the outbreak. greater use of the pond. warm water and air temperatures. and inadequate water exchange in the pond. This report adds one of the few documented outbreaks of shigellosis implicating bather contamination to the literature on the growing number of incidents that have been associated with recreational use of water.
New York State's two-dose schedule for measles immunization, In April 1989. New York became the first State in the United States to adopt a two-dose schedule for routine measles immunization. Although a two-dose schedule had been under discussion for the previous 10 years. this policy change was finally prompted in New York State by widespread measles outbreaks in 1989 among college and high school students who had been appropriately vaccinated with a single dose of measles vaccine. These outbreaks affected 21 college and secondary school campuses with 91 cases of measles and led to the administration of 53.093 doses of vaccine at a cost in excess of $859.000 for vaccine alone. In addition. there were major disruptions of intercollegiate athletic and scholastic events and physician and public confusion over the different recommendations for "outbreak" versus "routine" measles immunization. In response. the New York State Department of Health adopted a policy of two doses of measles vaccine required for entrance into kindergarten and college beginning in the fall of 1990. This report describes the data and process that were used in reaching this policy decision.
Crossover comparison of maximum dose glyburide and glipizide, Patients with non-insulin-dependent diabetes mellitus (NIDDM) failing to respond to therapy with a maximum dose of glyburide (GB) or glipizide (GZ) are often given a trial of the alternate second-generation sulfonylurea (SGS) before insulin therapy is considered. The efficacy of this therapeutic maneuver has not been thoroughly tested. We studied 26 subjects with fasting serum glucose (FSG) levels greater than 8.3 mmol/L (150 mg/dL) despite maximum doses of either GB (20 mg/day) or GZ (40 mg/day). Group 1 consisted of 16 subjects taking GB (mean FSG = 12.7 mmol/L [228 mg/dL]) and group 2 included 10 subjects taking GZ (mean FSG = 13.0 mmol/L [234 mg/dL]). Subjects continued taking their original SGS for 8 weeks then switched to a maximum dose of the alternate agent for an additional 8 weeks. Values for FSG. hemoglobin A1c. and lipids were recorded before the study and after 8 weeks on each SGS trial. No significant changes were noted for any variable in either group. When maximum dose GB therapy was compared to maximum dose GZ therapy in the combined study group (n = 26). no advantage was noted for either agent. We conclude that metabolic control in NIDDM patients failing to respond to therapy with maximum dose GB or GZ is not improved by switching to the alternate SGS.
Platelet antiaggregate activity, Calcium ions act as a second messenger to platelet agonists. with increases in intracellular calcium bringing about changes in shape. aggregation. and release reactions. Changes in platelet function have been reported previously in migraine sufferers and there is evidence that hyperaggregability occurs during a migraine attack. It was decided to assess platelet aggregation with platelet-rich plasma (PRP) from nicardipine-treated migraine sufferers because dihydropyridine derivatives are known to inhibit adenosine diphosphate (ADP)- and epinephrine-induced aggregation. Aggregation induced by 1.4 mumol/L arachidonic acid was similar in PRP from control subjects and untreated migraine sufferers. whereas 1 or 2 mumol/L ADP-induced aggregation was lower in PRP from migraine sufferers. Treatment with 20 mg of nicardipine three times daily for 2 months significantly (p less than 0.05) increased 2 mumol/L ADP-induced aggregation. It is concluded that nicardipine was acting either on migraine pathogenic mechanisms or directly on the platelets.
Restricted V gene usage in T-cell lymphomas as detected by anti-T-cell receptor variable region reagents, Monoclonal antibodies reactive with variable regions of the human T-cell receptor (TCR) may be used to detect populations of T lymphocytes with restricted V gene usage. The authors have studied a series of 44 T-cell lymphomas with a panel of seven reagents reactive with four different TCR beta-chain variable region families. The authors found that. with this limited panel. restricted V gene usage of the neoplastic cells could be demonstrated in 29% of TCR-positive lymphomas. Whereas this is somewhat higher than expected. no preferential use of specific families could be demonstrated. An additional. unexpected finding was that most large cell T-cell lymphomas did not express TCR despite the presence of cytoplasmic CD3. The findings indicate that with a somewhat expanded panel it should be feasible to demonstrate restricted V gene usage as an indicator of clonality in a majority of T-cell lymphomas in a manner similar to the application of anti-immunoglobulin subclass antibodies in the diagnosis of clonal B cell proliferations.
Most CD8+ cells in skin lesions of CD3+ CD4+ mycosis fungoides are CD3+ T cells that lack CD11b, CD16, CD56, CD57, and human Hanukah factor mRNA, To define further the characteristics of CD8+ cells in skin lesions of CD3+ CD4+ mycosis fungoides (MF). the authors used single- and double-label immunohistologic techniques and in situ hybridization to detect antigens and transcripts associated with certain types of cytotoxic or suppressor function. The cytotoxic markers included CD16. CD56. CD57. and an anti-sense probe for human Hanukah factor (HuHf) mRNA. Analysis of 23 cases demonstrated that lesional CD8+ cells were CD3+ T cells that generally lacked expression of any of the cytotoxic markers studied. Analysis of another 10 cases confirmed the CD3+ T-cell lineage of lesional CD8+ cells and demonstrated that these cells also lacked expression of the suppressor-associated marker. CD11b. In aggregate. these results indicate that most CD8+ cells in CD3+ CD4+ MF skin lesions are of T-cell rather than NK-cell differentiation. Their overall phenotype suggests that they may be major histocompatibility complex (MHC)-restricted cytotoxic T cells lacking appreciable levels of HuHF serine protease. Because the induction of CD8+ suppressor T cells is mediated by CD4+ T cells expressing the CD45RA+ RO- phenotype. CD45 epitope expression was studied in 15 MF cases. The vast majority (13/15) contained CD3+ CD4+ tumor cells that were CD45+ RA- RB+ RO+ 2B11+. This phenotype is consistent with memory T cells rather than suppressor-inducer T cells. and correlates with the paucity of phenotypically defined suppressor T cells in CD3+ CD4+ MF skin lesions.
Hemostasis activation during esophageal variceal sclerotherapy with thrombin in cirrhotics, Sclerotherapy of bleeding esophageal varices in liver cirrhotics is a common procedure. but little is known about the possible entry of sclerosants into the systemic circulation. We injected a mixture of thrombin. sodium tetradecyl. and cefazolin and studied the effect of this sclerosant on selected hemostasis parameters. Twenty-four patients with liver cirrhosis (Child's Classification C) were studied 29 times. Blood samples were drawn before and immediately after the injection of the sclerosant. In seven patients we collected a sample 30 minutes and 24 hours after treatment. Before injection. almost all patients had elevated D-dimer. t-PA and PAI-1 levels. Fibrinogen. antithrombin. alpha-2 antiplasmin. and protein C were decreased. Only thrombin/antithrombin III complex (TAT) levels were within normal ranges. Immediately after the injection. TAT. D-dimer. and t-PA levels rose significantly (P less than 0.001. P less than 0.01. P less than 0.001). PAI-1 and PC levels decreased (P less than 0.01). while antithrombin. alpha-2 antiplasmin. and fibrinogen concentrations were unchanged. TAT and D-dimer levels were still elevated after 24 hours (P less than 0.05). These data indicate that thrombin entered the systemic circulation (elevated TAT) and that the hemostasis system was briefly systemically activated (elevated D-dimer). In spite of these changes in the hemostasis system. clinically there were no detectable thrombotic or hemorrhagic complications.
Percutaneous endoscopic jejunostomy in a patient with previous esophagectomy, Establishment of a percutaneous endoscopic jejunostomy via direct jejunal puncture was accomplished in a 45-year-old woman five years after a partial esophagectomy with cervical esophagogastrostomy for adenocarcinoma of the esophagus. The patient had recurrence of the cancer at the anastomotic site with subsequent inability to eat. necessitating a feeding tube for prolonged enteral nutrition. Although percutaneous puncture of the jejunum has been previously described. it has been limited to patients who had undergone partial or complete gastrectomies with Bilroth II anastomoses. This case report of direct endoscopic jejunal tube placement in a patient after esophagectomy further establishes this procedure as a viable alternative to surgically placed feeding tubes in patients with altered gastric anatomy.
T lymphocyte-synovial fibroblast interactions induced by mycobacterial proteins in rheumatoid arthritis, An in vitro system was established in which single-cell suspensions of lymphocytes and synovial cells from the joints of patients with rheumatoid arthritis were cultured and produced an outgrowth of an organized inflammatory tissue with an extracellular matrix and capsule. The tissue outgrowth. which had histologic features of pannus. required the addition of mycobacterial antigen and interleukin-2 to the tissue culture medium and was dependent upon the presence of T lymphocytes and their interaction with synovial fibroblasts.
Myocardial beta-adrenergic adenylate cyclase complex in a canine model of chagasic cardiomyopathy, Infection of beagles with an opossum-derived strain of Trypanosoma cruzi (Tc-O) results in features of early and chronic chagasic cardiomyopathy. that is. increases in PR interval. atrioventricular block. and frequent ventricular premature contractions. ventricular tachycardia. and decreased left ventricular ejection fraction. These signs are not observed in animals infected with a canine strain of T. cruzi (Tc-D). To understand the biochemical basis for these early cardiac effects. we examined the beta-adrenergic adenylate cyclase complex in myocardial membranes prepared from animals infected with either of the two strains. In animals infected with Tc-O (symptomatic). the maximum velocity (Vmax) decreased and concentration of agonist resulting in 50% of Vmax (Kact) increased for isoproterenol-dependent adenylate cyclase activity; in animals infected with Tc-D (asymptomatic). Vmax and Kact for isoproterenol were unchanged from control. uninfected animals. beta-Receptor density decreased by 20% in symptomatic animals with no change in affinity. whereas no differences were observed between uninfected and infected asymptomatic animals. A complex pattern of changes was apparent in the guanine nucleotide binding protein. Gs. in the setting of infection. Alterations in cholera toxin-dependent ADP-ribosylation patterns as well as immunochemical detection with anti-G alpha s antisera suggested a change in the biochemical nature of the Gs species and not necessarily a physical loss of this protein. Reconstitution of adenylate cyclase activity in cyc- membranes demonstrated a decrease in hormone-sensitive Gs activity in membranes prepared from symptomatic animals without a change in activity demonstrable in the presence of Gpp(NH)p. Collectively. the results suggest that the depression in beta-adrenergic adenylate cyclase activity associated with symptomatic infection of beagles with T. cruzi occurs primarily as a result of changes in the Gs protein complex. most likely resulting in an uncoupling of the beta-adrenergic receptor from the Gs protein.
Components of excess ventilation in patients initiated on mechanical ventilation, OBJECTIVE: To determine the causes of excess minute ventilation in patients initiated on mechanical ventilation. DESIGN: Prospective study of recently intubated. mechanically ventilated patients. SETTING: The medical ICU in a county hospital. PATIENTS: Fifty-two mechanically ventilated medical ICU patients were studied within 36 hrs of intubation. Patients were all supported with volume-cycled ventilation in the assist-control mode. INTERVENTIONS: Timed expired gas collection and an arterial blood gas. MEASUREMENTS AND MAIN RESULTS: Measurements of minute ventilation and CO2 production (VCO2) were made from a timed expired gas collection. PaCO2 was sampled during the gas collection and deadspace was determined. Minute ventilation. VCO2. deadspace. and PaCO2 values in the patients were compared with predicted normal values. and excess minute ventilation due specifically to each component was calculated. Patients were separated clinically into groups: adult respiratory distress syndrome (ARDS). sepsis. obstructive lung disease. pneumonia. and drug overdose. Comparisons were then made between groups. Excess minute ventilation for the entire study population was secondary to increased deadspace (39%). low PaCO2 (36%). increased VCO2 (15%). and the interactive effect of deadspace and VCO2 (10%). VCO2 contributed little to excess minute ventilation early in respiratory failure. even in the ARDS and sepsis groups. Deadspace contributed significantly to excess minute ventilation in all groups. especially in the ARDS group. where it accounted for 53% of the excess ventilation. Low PaCO2 set-point was the predominant cause of excess minute ventilation in the sepsis group. where it contributed to 57% of their total excess minute ventilation. CONCLUSIONS: Although all groups initiated on mechanical ventilation had an excess ventilatory requirement. the contribution of individual components varied considerably between clinical groups.
The function but not the expression of rat liver inhibitory guanine nucleotide binding protein is altered in streptozotocin-induced diabetes, Adenylate cyclase activity was examined as a measure of inhibitory guanine nucleotide binding protein (Gi) function in liver plasma membranes from rats made chemically diabetic by streptozotocin (STZ) treatment. Clonidine activation of the alpha 2 adrenergic receptor. which activates Gi. inhibited forskolin--stimulated adenylate cyclase activity in control membranes. However. there was no effect on adenylate cyclase activity in membranes from STZ diabetic animals. Also. a polyclonal antipeptide antibody was raised to a highly conserved segment of the Gi alpha 2 subunit. This antibody specifically recognizes a 41 kilodalton protein. is blocked by an excess of peptide. does not recognize the alpha-subunit of transducin. and immunoprecipitates a 41 kilodalton protein which was ADP-ribosylated by pertussis toxin. Immunoblots using this antibody detect no difference between normal and STZ diabetic animals in the level of liver plasma membrane Gi expression. Therefore. STZ-induced diabetes altered the function of Gi but had no effect on Gi expression.
Umbilical cord occlusion stimulates breathing independent of blood gases and pH, The role of umbilical cord occlusion in the initiation of breathing at birth was investigated by use of 16 unanesthetized fetal sheep near full term. Artificial ventilation with high-frequency oscillation was used to control fetal arterial blood gas tensions. At baseline. PCO2 was maintained at control fetal values and PO2 was elevated to between 25 and 50 Torr. In the first study on six intact and four vagotomized fetuses. arterial PCO2 and PO2 were maintained constant during two 30-min periods of umbilical cord occlusion. Nevertheless. the mean fetal breathing rate increased significantly when the umbilical cord was occluded. In the second study on six intact fetuses. hypercapnia (68 Torr) was imposed by adding CO2 to the ventilation gas. When the umbilical cord was occluded. there was a significantly greater stimulation of breathing (rate. incidence. and amplitude) in response to hypercapnia than in response to hypercapnia alone. During cord occlusion. plasma prostaglandin E2 concentration decreased significantly. Results indicate that cord occlusion stimulates breathing possibly by causing the removal of a placentally produced respiratory inhibitor such as prostaglandin E2 from the circulation.
PEEP inhibits hypoxic pulmonary vasoconstriction in dogs, The effects of an increase in alveolar pressure on hypoxic pulmonary vasoconstriction (HPV) have been reported variably. We therefore studied the effects of positive end-expiratory pressure (PEEP) on pulmonary hemodynamics in 13 pentobarbital-anesthetized dogs ventilated alternately in hyperoxia [inspired O2 fraction (FIO2) 0.4] and in hypoxia (FIO2 0.1). In this intact animal model. HPV was defined as the gradient between hypoxic and hyperoxic transmural (tm) mean pulmonary arterial pressure [Ppa(tm)] at any level of cardiac index (Q). Ppa(tm)/Q plots were constructed with mean transmural left atrial pressure [Pla(tm)] kept constant at approximately 6 mmHg (n = 5 dogs). and Ppa(tm)/PEEP plots were constructed with Q kept constant approximately 2.8 l.min-1.m-2 and Pla(tm) kept constant approximately 8 mmHg (n = 8 dogs). Q was manipulated using a femoral arteriovenous bypass and a balloon catheter in the inferior vena cava. Pla(tm) was held constant by a balloon catheter placed by left thoracotomy in the left atrium. Increasing PEEP. from 0 to 12 Torr by 2-Torr increments. at constant Q and Pla(tm). increased Ppa(tm) from 14 +/- 1 (SE) to 19 +/- 1 mmHg in hyperoxia but did not affect Ppa(tm) (from 22 +/- 2 to 23 +/- 1 mmHg) in hypoxia. Both hypoxia and PEEP. at constant Pla(tm). increased Ppa(tm) over the whole range of Q studied. from 1 to 5 l/min. but more at the highest than at the lowest Q and without change in extrapolated pressure intercepts. Adding PEEP to hypoxia did not affect Ppa(tm) at all levels of Q.
Reduction in susceptibility to natural killer cell-mediated lysis of human FO-1 melanoma cells after induction of HLA class I antigen expression by transfection with B2m gene, Induction of HLA class I antigens on cultured melanoma cells FO-1 after transfection with a human or a mouse B2m gene was associated with a statistically significant reduction in their susceptibility to natural killer (NK) cell-mediated lysis. These results indicate that the structural differences between human and mouse beta 2-mu do not abolish the ability of the HLA class I molecular complex to modulate NK cell-mediated lysis of melanoma cells FO-1. The role of HLA class I antigens in the phenomenon is corroborated by the ability of anti-HLA class I MAb to enhance. although to a different extent. the susceptibility of transfected FO-1 cells to NK cell-mediated lysis. Gamma interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) significantly reduced the susceptibility to NK cell-mediated lysis of transfected FO-1 cells. Surprisingly. TNF-alpha reduced the extent of lysis more than IFN-gamma. although the latter cytokine enhanced HLA class I antigen expression more than the former one. This finding. in conjunction with a reduction in the susceptibility to NK cell-mediated lysis of untransfected FO-1 cells incubated with IFN-gamma or TNF-alpha. suggests that the two cytokines reduce NK cell-mediated lysis of transfected cells by modulating not only the expression of HLA class I antigens. but also that of other structures. Induction of HLA class I antigens and their modulation with IFN-gamma did not affect the susceptibility to lymphokine-activated killer (LAK) cell-mediated lysis of transfected FO-1 cells. Characterization of the molecular mechanism(s) underlying abnormalities in HLA class I antigen expression by melanoma cells and of the role of these molecules in the interactions of melanoma cells with various types of effector cells may suggest novel immunotherapeutic approaches to melanoma.
Regulation of phospholipase D and primary granule secretion by P2-purinergic- and chemotactic peptide-receptor agonists is induced during granulocytic differentiation of HL-60 cells, We have compared the abilities of extracellular ATP (acting via P2-purinergic receptors) and formylated peptides (FMLP) to stimulate both phospholipase D (PLD)-based signal transduction and primary granule (azurophilic) secretion in HL-60 cells induced to differentiate along the granulocytic pathway. In undifferentiated HL-60 cells. neither ATP nor FMLP elicited significant PLD activation or increased secretion despite the previously documented ability of ATP to stimulate large increases in polyphosphoinositide hydrolysis and Ca2+ mobilization. Conversely. within 1 d after induction of granulocytic differentiation by dibutyryl cAMP. both ATP and FMLP induced large increases in azurophilic secretion and corresponding increases in PLD activity. ATP-activated PLD activity was near-maximal within 1 d after dibutyryl cAMP treatment. while the FMLP-induced activity increased continuously over 4 d. with a maximal level twice that stimulated by ATP. Additional experiments characterized the activation of PLD by receptor-independent pathways at different stages of differentiation; these included studies of phorbol ester action in intact cells and GTP gamma S action in electropermeabilized cells. An apparent role for guanine nucleotide-binding regulatory proteins in PLD regulation was also indicated by the significant reduction in FMLP- and ATP-stimulated PLD activity observed in cells pretreated with pertussis toxin. At all stages of differentiation. there was good correlation between the relative efficacies of ATP versus FMLP in stimulating both secretion and PLD activity. These data indicate: (a) that the receptor-regulated phospholipase D signaling pathway is induced during differentiation of myeloid progenitor cells; and (b) that differential activation of this signaling system by various Ca(2+)-mobilizing receptor agonists may underlie the differential regulation of secretion and other phagocyte functions by such agents.
Molecular analysis of an extended family with type IA (tyrosinase-negative) oculocutaneous albinism, We have analyzed the tyrosinase coding region of three individuals having Type IA OCA within an extended family using genomic DNA amplification and dideoxy sequencing. Two of the affected individuals are dizygotic twins. All three have a common missense mutation at codon 81 (Pro----Leu) within exon I. The twins have a second missense mutation at codon 371 (Asn----Thr) within exon III and the third individual has a second missense mutation at codon 47 (Gly----Asp) within exon I. For each of these three individuals. the loss of enzyme function is the result of two different mutations. showing that they are compound heterozygotes of two mutant tyrosinase alleles.
Human immunodeficiency virus type 1 (HIV-1) genomic sequences and distinct changes in CD8+ lymphocytes precede detectable levels of HIV-1 antibodies in high-risk homosexuals, Polymerase chain reaction (PCR) identified regions of the gag. LTR. and env genes of human immunodeficiency virus type 1 (HIV-1) in 5 (13%) of 38 high-risk homosexual men who were negative for HIV-1 antibodies by Western blot (WB). Significant increases in CD8+ cells. particularly those bearing activation CD8+CD38+ and CD8+Ia+ antigens. and marked reductions in CD4+ cells were detected in WB-PCR+ subjects compared with 33 WB-PCR- homosexuals. WB-PCR+ subjects had impaired B cell but not T cell functions. Immunologic characteristics of WB-PCR+ homosexuals were indistinguishable from those of 17 WB+PCR+ subjects. Subjects progressing from WB-PCR- to WB-PCR+ to WB+PCR+ showed sequential phenotypic and functional alterations in their B and T cell compartments. These changes and the presence of HIV-1 genomic sequences were the first indications of HIV-1 infection and together with p24 antigenemia signified an inevitable progression to AIDS.
Morphologic and staining characteristics of a cyanobacterium-like organism associated with diarrhea, A spherical organism 9-10 microns in diameter. seen in three outbreaks of diarrhea in Southeast Asia and the United States during the past 2 years. bore characteristics of a cyanobacterium when observed in formalin-preserved stool specimens and by electron microscopy. Organisms in freshly passed stool specimens showed an internal morula of lipid-containing globules. In fresh water. the morula divided into two sausage-shaped structures resembling the sporocysts of an isosporid coccidian. After 7 months. the organisms had not developed the crescentic sporozoites seen in the Coccidia but had begun to multiply slowly in culture. It was impossible to stain the internal structures of the organisms because the outer cyst wall ruptured during desiccation. releasing the contents of the cysts. The organisms were readily identified by their intense blue autofluorescence under UV light. but they were also recognizable by bright-field microscopy and by a modified acid-fast stain. Almost all infected persons suffered intermittent diarrhea for 2-3 weeks and many emphasized a feeling of intense fatigue during the course of their illness.
Scrapie-infected spleens: analysis of infectivity, scrapie-associated fibrils, and protease-resistant proteins, Scrapie-associated fibrils (SAF) and protease-resistant proteins (PrP) were isolated from spleens and brains of clinical animals (mice and hamsters) from three scrapie agent-host strain combinations. and their concentrations were compared with infectivity levels. The spleens of infected animals contained lower levels of infectivity. PrP. and SAF than did brains. Regardless of the route of infection. both SAF and infectivity were detected in spleen before brain. Infectivity increased in brains and spleens of 139A-infected mice before the detection and increase in SAF. suggesting that the synthesis of SAF and PrP may not be the limiting factor in agent replication. In contrast to those in ME7- and 263K-infected animals. the Western blot profiles for PrP from brain and spleen of 139A-infected mice exhibited distinct differences. Results indicate that SAF and PrP found in the spleens are both organ- and scrapie strain-specific.
The effect of intravenous flumazenil on interictal electroencephalographic epileptic activity: results of a placebo-controlled study, The effect on interictal electroencephalographic epileptic activity of intravenous flumazenil (Ro 15-1788). a benzodiazepine antagonist and potential antiepileptic drug. was studied in 10 patients. Comparison was made with intravenous diazepam (10 mg) and placebo using a single-blind. single-dose. cross-over design. A dose of 3 mg flumazenil was well tolerated and produced a significantly greater reduction in the number of epileptic transients during the first 40 minutes after injection than did placebo (p less than 0.05). This effect was similar to that of diazepam in magnitude and duration. When flumazenil (3 mg) was administered immediately after intravenous diazepam (10 mg). the reduction in interictal epileptic activity was not significantly different from that produced by diazepam alone. The results suggest that either flumazenil has intrinsic antiepileptic activity and in this respect acts as a partial agonist at the benzodiazepine receptor. or that it is antagonising an endogenous proconvulsant ligand in these patients.
Congenital muscular dystrophy: brain alterations in an unselected series of Western patients, The typical form of congenital muscular dystrophy (CMD) described in Western countries is generally considered different from its Japanese variant because of the absence of CNS involvement. Evaluations from both a clinical and a neuroradiological point of view were made of the CNS functions of 12 unselected Western children affected by CMD. In five patients. clinical observation and intelligence tests showed a mild to severe mental retardation. One of these patients suffered also from a severe form of epilepsy. In the same five patients. various degrees of white matter hypodensity. ventricular enlargement and cerebral atrophy were also detected. Similar neuroradiological abnormalities were also found in five of the seven children who did not have clinical symptoms or signs of CNS involvement. In one of these cases. necropsy neuropathological examination showed the gyral anomalies characteristic of the Japanese type of CMD. This study clearly indicates the high frequency of subclinical CNS alterations in typical Western CMD. suggesting that it should be considered a type of myoencephalopathy like its Japanese counterpart.
Minoxidil versus nitroglycerin: a prospective double-blind controlled trial in transcutaneous erection facilitation for organic impotence, A new type of topically applied drug (minoxidil) to facilitate erection is presented. Minoxidil acts directly on arterial smooth muscles via relaxation. This drug (1 ml. of a 2% solution) was studied under strict laboratory conditions in a double-blind controlled trial on 33 patients (4 with neurogenic plus arterial. 10 with neurogenic and 19 with arterial impotence) and compared to placebo and nitroglycerin (2.5 gm. of a 10% ointment). The application sites were the penile shaft (nitroglycerin) or glans penis (minoxidil and placebo). Increases in diameter and rigidity were measured with the RigiScan device and arterial flow was evaluated by conventional Doppler sonography. Side effects were considered as well. This drug proved to be more active than nitroglycerin and placebo in increasing diameter. rigidity and arterial flow of the penis. The highest activity proved to occur in neurogenically impotent patients. Fewer side effects also were found with minoxidil than with nitroglycerin. For these reasons minoxidil is proposed as a long-term therapeutic agent for organic impotence.
Effect of tissue plasminogen activator on intimal platelet accumulation in cerebral arteries after subarachnoid hemorrhage in cats, Recombinant tissue plasminogen activator may be effective in preventing cerebral vasospasm after subarachnoid hemorrhage by resolving subarachnoid clots. We previously demonstrated that blood placed on the adventitial surface of cerebral arteries enhances intimal platelet accumulation. positively correlating with endothelial damage and other pathologic changes in vessel walls. In this study. we investigated the ability of a single bolus injection of tissue plasminogen activator to prevent platelet accumulation in cerebral vessels after subarachnoid hemorrhage. Subarachnoid hemorrhage was produced in cats by the transorbital intracisternal injection of 2.5 ml autologous arterial blood around the proximal part of the right middle cerebral artery. In 10 animals. 25 micrograms tissue plasminogen activator was injected at intervals of 10 (five cats) and 60 minutes (five cats) after subarachnoid hemorrhage. Intracisternal physiological saline (0.5 ml) was injected in six cats 10 minutes after subarachnoid hemorrhage. Platelets labeled with indium-111 were injected intravenously just before subarachnoid hemorrhage. and their radioactivity was measured in cerebral arteries at death. The results indicated that. after subarachnoid hemorrhage. early injection of tissue plasminogen activator inhibited intimal platelet accumulation. but later injection did not. although the extent of subarachnoid clot was reduced at both plasminogen injection times.
Delirium in an elderly woman possibly associated with administration of misoprostol, Misoprostol has been associated with adverse reactions. including gastrointestinal symptoms. gynecologic problems. and headache. Changes in mental status. however. have not been reported. We present a case in which an 89-year-old woman in a long-term care facility became confused after the initiation of misoprostol therapy. The patient's change in mental status was first reported nine days after the initiation of therapy. Her delirium significantly improved after misoprostol was discontinued and her mental status returned to normal within a week. Because no other factors related to this patient changed significantly. the delirium experienced by this patient possibly resulted from misoprostol therapy.
Cost-effectiveness evaluation of measles immunization strategies on a college campus, Since live rubeola vaccine became available in 1963. routine immunization of children at age 15 months has been the recommended strategy for eliminating measles in the United States. However. due to increasing measles outbreaks. especially among previously immunized populations. the Immunization Practices Advisory Committee (ACIP) recently recommended modifying the one-dose measles vaccination policy to a two-dose schedule. one at 15 months and one at age 5 or 6 years. To address the present college population. ACIP recommended vaccinating all college students who lack proof of immunity. We used the methods of decision analysis to examine the cost effectiveness of implementing such a program in a specific college population. namely. students at the University of California at Los Angeles (UCLA). We developed a model to examine three possible vaccination strategies: "wait." "screen." and "vaccinate all." Estimates of probabilities and cost were derived from several outbreaks at UCLA as well as statewide data. In the baseline case. the least expensive strategy is to wait until an outbreak occurs before implementing a vaccination program. The additional cost incurred by screening per measles case avoided is $122.871. However. using sensitivity analysis. we found that the overall cost of elective vaccination strategies is driven by the cost of the vaccine itself. If vaccine could be provided at a nominal cost to the university. a strategy of vaccinating all students without proof of immunity (by either history of two vaccinations or positive titer) would provide the high level of immunity needed to prevent outbreaks and still be most cost effective ($16.644 per measles case avoided).
Cardiovascular effects of isradipine in essential hypertension, The immediate and short-term cardiovascular effects of oral isradipine therapy were evaluated in 11 patients with mild to moderate systemic hypertension. Isradipine. 5 mg administered orally. induced a significant reduction in arterial pressure from 165 +/- 6/88 +/- 3 mm Hg to 140 +/- 5/76 +/- 2 mm Hg (p less than 0.001) within 2.5 hours by a decrease in total peripheral resistance associated with an increase in heart rate and cardiac output. Contrary to the acute effect. oral therapy with isradipine for 3 months reduced arterial pressure through a decrease in total peripheral resistance but without causing an increase in heart rate or cardiac output or activation of the sympathetic nervous system. Isradipine slightly reduced left ventricular mass and improved cardiac systolic function and left ventricular filling. Renal blood flow increased. and renal vascular resistance (p less than 0.01) and total blood volume (p less than 0.002) decreased without a change in either sodium excretion or body weight. Thus. isradipine. when given for 3 months. decreased arterial pressure by reducing total peripheral resistance without activation of reflexive mechanisms. Its favorable effects on systemic hemodynamics. total blood volume. renal blood flow. and cardiac structure and function suggest isradipine to be an excellent choice for antihypertensive therapy.
Altered interleukin-2 secretion in patients with primary fibromyalgia syndrome, Interleukin-2 (IL-2) production was studied in T lymphocytes and isolated CD4+ T lymphocytes from 12 patients with primary fibromyalgia syndrome and 10 healthy volunteers. The dose and time kinetics of IL-2 production by concanavalin A-stimulated T cells and CD4+ T cells of fibromyalgia patients differed from findings in controls by 1) a need for a higher concentration of mitogen in order to achieve optimal IL-2 secretion. and 2) a delay in the peak time of optimal IL-2 secretion. Unlike normal IL-2 secretion. which was higher after removal of CD8+ T cells. the pattern and degree of IL-2 secretion by cells from fibromyalgia patients were not changed following removal of CD8+ T cells. Addition of calcium ionophore in assays using suboptimal concanavalin A concentrations did not correct the reduction in IL-2 secretion by fibromyalgia patient T cells. but addition of phorbol myristate acetate induced normal secretion of IL-2. These findings suggest that there is a defect in the IL-2 pathway. which is related to protein kinase C activation and does not involve impairment of Ca2+ elevation. in patients with fibromyalgia.
Epidemiology of absence epilepsy: EEG findings and their predictive value, This population-based study of absence epilepsy comprised 97 children. ranging in age from newborns to 15 years. All had regular bilaterally synchronous and symmetric 2-4 Hz spike-and-slow wave discharges and absences with or without generalized tonic-clonic seizures (GTCS). Patients without GTCS tended to have long episodes of 2-4 Hz spike-and-slow wave discharges (greater than or equal to 10 sec). and simultaneous clinical correlates more frequently than those with GTCS. Posterior delta rhythm was found only in patients without GTCS. Focal abnormalities. albeit transient. were more frequent among patients with GTCS. The initial electroencephalogram was of some early predictive value in patients with only absences at the time of the initial registration. Brief episodes of 2-4 Hz spike-and-slow wave (less than 10 sec) without clinical correlates were associated with a slightly increased risk of future GTCS.
Prognostic significance of acute epilepsia partialis continua, We present 3 patients in whom epilepsia partialis continua was the presenting sign of an acute. rapidly evolving and catastrophic neurologic illness. Initial seizures were partial simple (i.e.. eye deviation in one. finger twitching in one) which progressed to multifocal partial seizures. The course of the epilepsia partialis continua was 36-41 days. Prognosis was uniformly poor (i.e.. death in 2. vegetative state in 1); therefore. epilepsia partialis continua in the context of an acute neurologic illness may herald a grim outcome.
Increased expression of the CD45RO (memory) antigen on T cells in HIV-infected children, Expression of the CD45RO putative memory cell antigen on CD4 (helper) and CD8 (cytotoxic/suppressor) lymphocytes of children born to HIV-infected women was investigated using the UCHL1 antibody. Significantly raised numbers of CD45RO+ CD8 lymphocytes were found in all nine of the infected children compared with uninfected and control children. Expression of CD45RO on CD4 lymphocytes was variable; absolute numbers were not increased. although the percentage was increased in four out of nine infected children. All the infected children except two (who had comparatively low numbers of CD45RO+ CD8 cells) were clinically well. which suggests that an increase in CD45RO+ CD8 cells may be indicative of a functionally active immune response against HIV.
Lymphocytes from HIV-infected individuals show aberrant inositol polyphosphate metabolism which reverses after zidovudine therapy, Lymphocytes or lymphoblastoid cells that have been infected by HIV in vitro or exposed to its envelope glycoprotein (gp120) show abnormal inositol polyphosphate-mediated signal transduction and associated defects in calcium regulation. Such cells behave as though they were chronically activated and fail to respond to further activating signals. We now show that similar changes are seen in lymphocytes obtained from HIV-infected subjects at various stages of infection. despite the fact that only a minority of such cells are infected. Furthermore. the defect in the phosphatidylinositol hydrolysis pathway in lymphocytes obtained from AIDS patients reverses after treatment with zidovudine. in parallel with improvements in phytohaemagglutinin-induced proliferative response and interferon-gamma production.
Recognition of poliovirus/HIV chimaeras by antisera from individuals with HIV infection, The neutralization of five poliovirus/HIV chimaeras by serum from HIV-infected individuals was examined to evaluate the presentation of HIV envelope sequences. to assess the immune response of individuals to specific epitopes. and to relate it to the stage of disease. The sera were unable to differentiate between four of the chimaeras and the Sabin vaccine strain. With a fifth construct containing an immunodominant gp41 sequence. significant differential recognition was observed in approximately 67% of individuals with asymptomatic HIV infection [groups II and III of the Centers for Disease Control (CDC) classification of HIV infection] and 37% of patients with symptomatic disease (CDC group IV). Furthermore. among patients with CDC stage IV disease antibody levels against this construct and the titre achieved decreased with progression to further disease from approximately 40% in AIDS-related complex (ARC) patients (CDC group IVA and IVC-2 to 14% in those with AIDS (other group IV diseases). Loss of antibody to this construct did not result from a reduction in the anti-polio or anti-envelope response. but from a decline in antibody levels to the HIV sequence inserted in antigenic site 1.
Na+, K(+)-ATPase inhibition and intracellular electrolyte content in essential and secondary hypertension, A crucial role of humoral factors in the pathogenesis of primary hypertension is discussed. In 1982 Hamlyn et al demonstrated the presence of a Na+. K(+)-ATPase inhibitor in the plasma of essential hypertensives and showed a significant correlation of the Na+. K(+)-ATPase inhibition with the blood pressure. In this study we examined whether an Na+. K(+)-ATPase inhibitor could be found in the blood of essential hypertensives as compared to patients with secondary hypertension (renal hypertension. renal artery stenosis. pheochromocytoma). Second. the possible correlation between an inhibition of Na+. K(+)-ATPase and the intracellular electrolyte composition was examined. The results demonstrate a similar reduction of Na+. K(+)-ATPase inhibition in both essential hypertensives and secondary hypertensives as compared to normotensive controls. Further. the intracellular electrolyte composition (Na+. Na; K+. Ca) does not show a significant correlation to the degree of Na+. K(+)-ATPase inhibition. whereas a significant correlation between the degree of Na+. K(+)-ATPase inhibition and intracellular Cl- concentration could be demonstrated. The present study shows that an endogenous Na+. K(+)-ATPase inhibitor is also present in secondary forms of hypertension. thus implying that a specific role in the pathogenesis of primary hypertension for an Na+. K(+)-inhibitor is unlikely.
Cytochemically detectable glucose-6-phosphate dehydrogenase-stimulating/Na-K-ATPase-inhibiting activity of plasma and hypothalamus in reduced renal mass hypertension, Plasma from normal humans and rats on a high sodium intake. and from patients and rats suffering from hereditary hypertension has an increased cytochemically detectable glucose-6-phosphate dehydrogenase (G6PD)-stimulating/Na-K-ATPase inhibiting activity. The hypothalamic content of this activity is also increased by a high sodium intake and in the spontaneously hypertensive rat (SHR). Using cytochemical techniques. the ability of plasma and the hypothalamus of reduced renal mass hypertensive rats to stimulate G6PD activity and to inhibit Na-K-ATPase was measured. The mean G6PD-stimulating capacity of the plasma from the hypertensive and normotensive groups of rats was 351 +/- 67 and 11.42 +/- 1.98 G6PD-stimulating units/mL respectively (P less than .001). The time courses of the ability of plasma from a hypertensive and a normotensive rat to inhibit fresh tissue Na-K-ATPase after 2. 4. 6. and 8 min of exposure demonstrated that the hypertensive rat plasma had a greater capacity to inhibit Na-K-ATPase. The mean G6PD-stimulating capacity of the hypothalamus from the hypertensive and normotensive groups of rats was 252.263 +/- 147.958 X 10(3) and 6.38 +/- 2.35 X 10(3) G6PD-stimulating units per hypothalamus. respectively (P less than .01). It is proposed that the raised concentration of cytochemically detectable G6PD-stimulating/Na-K-ATPase-inhibiting substance in both genetic and nongenetic forms of hypertension may be a manifestation of a communal hypertensinogenic mechanism. Thus. the raised plasma concentration would have a direct peripheral vascular constricting effect and the high hypothalamic concentration would be responsible for a central nervous hypertensinogenic effect.
Effect of hypoxic exercise on atrial natriuretic factor and aldosterone regulation, To evaluate the possible physiologic role of atrial natriuretic factor (ANF) in the observed dissociation of aldosterone secretion from the renin-angiotensin system during hypoxic exercise. 12 untrained men. ages 18 to 24. were studied on two separate days for 30 min during hypoxic (16% O2) and normoxic (room air) exercise on a bicycle ergometer. Workloads were adjusted to produce individual heart rates that remained within 70 to 75% of their previously measured maximum. Hemoglobin saturation decreased during hypoxia from 98 +/- 0.1% to 90 +/- 0.4% (P less than .01). Plasma aldosterone levels increased significantly (P less than .01) under both breathing conditions. yet were on average 36% lower during hypoxia than during normoxia (P less than .001). Plasma ANF levels increased during exercise under both conditions (P less than .01). yet levels were 45% greater during hypoxia than during normoxia (P less than .001). Plasma renin activity. adrenocorticotropic hormone. cortisol. potassium. and systolic blood pressure increased during exercise on both study days (P less than .01. compared to basal level). and showed no difference between normoxic and hypoxic conditions. Plasma pH was slightly higher during hypoxic exercise (P less than .05. compared to normoxia). We conclude that acute hypoxemia is a potent enhancing stimulus for ANF release during dynamic exercise and that ANF is probably a contributing factor in the dissociation of aldosterone secretion from the renin-angiotensin system under these conditions.
Hepatitis C virus: evidence for sexual transmission, OBJECTIVE--To determined the prevalence of hepatitis C virus infection and associated risk factors in patients attending a genitourinary medicine clinic. as evidence for sexual transmission. DESIGN--Seroprevalence estimated by reactivity in an enzyme immunoassay for antibodies to C100 protein with supplementary testing with a recombinant immunoblot assay and an assay for hepatitis C virus RNA. SETTING--Outpatient genitourinary medicine clinic in central London. PATIENTS--The panel of 1046 serum samples was from 1074 consecutive patients attending the clinic during November and December 1987 and having blood taken for routine testing for syphilis. Before samples were anonymised demographic and risk factor information was extracted from the clinic notes. Samples had already been tested for antibody to HIV-I and antibody to hepatitis B core antigen. MAIN RESULTS--Significantly more homosexual subjects than heterosexual subjects were positive for hepatitis C antibody determined by enzyme immunoassay alone (19/275 (6.9%) v 8/771 (1.0%). odds ratio 7.14. p less than 0.0001) and also when reactive serum samples were also tested by recombinant immunoblot assay (6/270) (2.2%) v 3/770 (0.4%). odds ratio 5.88. p less than 0.02). There were also significant associations in patients positive for hepatitis C antibody with positivity for antibodies to HIV and to hepatitis B core antigen. lifetime number of sexually transmitted diseases (homosexual men only). and age (all groups combined). Most patients whose serum samples contained specific antibodies to hepatitis C virus were viraemic. CONCLUSIONS--The study provides strong evidence for the sexual transmission of hepatitis C virus. Assays derived from other gene products are desirable to investigate the specificity and sensitivity of the enzyme immunoassay for C100 antibody as a marker of hepatitis C virus infection.
A prospective comparison of class IA, B, and C antiarrhythmic agents in combination with amiodarone in patients with inducible, sustained ventricular tachycardia, BACKGROUND. Clinical experience suggests that combinations of antiarrhythmic agents provide more effective control of ventricular tachyarrhythmias than does therapy with single agents. METHODS AND RESULTS. Antiarrhythmic and electrophysiological effects of three class I antiarrhythmic agents. one from each subclass A. B. and C. were assessed in single use and in combination with amiodarone in patients with inducible. sustained ventricular tachycardia that was not suppressed by monotherapy with these agents. Thirty-one patients underwent an electrophysiology test on four occasions: at baseline; after 2-4 days of treatment with quinidine. mexiletine. or encainide; after 2 weeks of treatment with 1.200 mg/day amiodarone; and last. after 2-4 days of treatment with both amiodarone and the previously tested class I agent. The combination of a class I agent and amiodarone prevented the induction of sustained ventricular tachycardia in only one of 31 (3%) patients. Ventricular tachycardia became hemodynamically stable in 11 of 31 (34%) patients because of a marked prolongation in the tachycardia cycle length. It increased from 323 +/- 39 to 423 +/- 84 msec (n = 11. p less than 0.01) by adding encainide to amiodarone therapy. and it showed a tendency to lengthen when quinidine was added to amiodarone (from 373 +/- 77 to 425 +/- 58 msec; n = 10. NS). Each class I agent increased amiodarone-induced depression in myocardial conduction. but the extent of the additional depression seemed to differ among the three subclasses. Ventricular refractoriness was increased by all class I agents when used in combination with amiodarone. although not by mexiletine or encainide when used alone. CONCLUSIONS. Class I antiarrhythmic agents slow ventricular conduction and increase ventricular refractoriness when used in combination with amiodarone. When amiodarone and class I drugs by themselves do not suppress the induction of ventricular tachycardia. the combination of amiodarone and a class I agent seldom results in noninducibility; however. it often lengthens the ventricular tachycardia cycle length and may render the ventricular tachycardia hemodynamically stable.
Effect of diltiazem on symptomatic and asymptomatic episodes of ST segment depression occurring during daily life and during exercise, BACKGROUND. Silent myocardial ischemia is an adverse prognostic marker in patients with coronary disease; however. controlled data on the effect of treatment are sparse and contradictory. and the relations among the occurrence of ST segment depression. drug efficacy. and heart rate are unclear. METHODS AND RESULTS. Sixty patients with stable coronary artery disease. a positive treadmill exercise test and asymptomatic ST segment depression on ambulatory electrocardiographic recording were assessed in a multicenter. double-blind. placebo-controlled. cross-over trial. Treadmill exercise tests and 72-hour electrocardiographic recordings were obtained at the end of two 2-week treatment periods with sustained-release diltiazem 180 mg b.i.d. or equivalent placebo. Episodes of asymptomatic ST depression decreased by 50% or more in 70% of the patients from a median number of 4.5 (range. 0-19) to 1.5 (range. 0-13) (p = 0.0001); their cumulative duration also decreased from 78.5 (range. 0-60) to 24.5 (range. 0-411) minutes (p = 0.001). No circadian variation was found in the efficacy of diltiazem. The occurrence of ischemic type ST segment depression was modulated by changes in heart rate rather than by absolute heart rate. Diltiazem also improved exercise test end points but to a lesser extent. Time to ST segment depression increased to 341 +/- 148 from 296 +/- 154 seconds (p = 0.005). Although less frequent with diltiazem administration (45 versus 54 patients. p less than 0.03). exercise-induced ST depression was more often asymptomatic (98% versus 72% of patients. p less than 0.0001). CONCLUSIONS. Diltiazem reduces the frequency and severity of ischemic type ST depression in patients with stable coronary artery disease.
Effective thrombolysis without marked plasminemia after bolus intravenous administration of vampire bat salivary plasminogen activator in rabbits, BACKGROUND. The use of recombinant tissue-type plasminogen activator (t-PA) in thrombolytic therapy is frequently associated with significant fibrinogenolysis. In contrast. recombinant vampire bat salivary plasminogen activator (Bat-PA) displays strict fibrin specificity. an attribute that could be desirable in a fibrinolytic agent. METHODS AND RESULTS. The efficacy and fibrin selectivity of Bat-PA was evaluated and compared with that of t-PA using a rabbit model of femoral arterial thrombosis. Administration of 8.1. 14. and 42 nmol Bat-PA/kg by bolus intravenous injection restored flow in 50%. 75%. and 80% of the rabbits. respectively. The incidence of reperfusion after bolus intravenous injection of 14 and 42 nmol t-PA/kg was 15% and 78%. respectively. The maximal femoral artery reperfusion flows were equivalent after treatment with 42 nmol Bat-PA/kg or 42 nmol t-PA/kg. but the time to reach maximal flow for Bat-PA was approximately one half that of t-PA. Furthermore. the rapid restoration of flow by 42 nmol Bat-PA/kg. in contrast to equimolar t-PA. was accomplished without fibrinogenolysis and with only small decreases in the plasminogen and alpha 2-antiplasmin levels. Equipotent doses of Bat-PA and t-PA both resulted in approximate 2.5-fold increases in the template bleeding times of aspirin-pretreated rabbits. The clearance of Bat-PA from rabbits exhibited biexponential elimination kinetics; approximately 80% was cleared by the relatively slow beta phase (half-life of 17.1 minutes). Overall. Bat-PA was cleared approximately fourfold slower than t-PA. CONCLUSIONS. Bolus intravenous administration of Bat-PA would facilitate prompt initiation of thrombolytic therapy. and the avoidance of plasminemia could result in fewer and less severe bleeding complications.
Plasminogen activator inhibitor-1 suppresses endogenous fibrinolysis in a canine model of pulmonary embolism, BACKGROUND. Plasminogen activator inhibitor-1 (PAI-1). the specific. fast-acting inhibitor of tissue-type plasminogen activator (t-PA). binds to fibrin and has been found in high concentrations within arterial thrombi. These findings suggest that the localization of PAI-1 to a thrombus protects that same thrombus from fibrinolysis. In this study. clot-bound PAI-1 was assessed for its ability to suppress clot lysis in vivo. METHODS AND RESULTS. Autologous. canine whole blood clots were formed in the presence of increasing amounts of activated PAI-1 (0-30 micrograms/ml). Approximately 6-8% of the PAI-1 bound to the clots under the experimental conditions. Control and PAI-1-enriched clots containing iodine-125-labeled fibrin (ogen) were homogenized. washed to remove nonbound elements. and delivered to the lungs of anesthetized dogs where the homogenates subsequently underwent lysis by the endogeneous fibrinolytic system. 125I-labeled fibrin degradation products appeared in the blood of control animals within 10 minutes and were maximal by 90 minutes. PAI-1 reduced fibrin degradation product release in a dose-responsive manner at all times between 30 minutes and 5 hours (greater than or equal to 76% inhibition at 30 minutes. PAI-1 greater than or equal to 6 micrograms/ml). PAI-1 also suppressed D-dimer release from clots containing small amounts of human fibrin (ogen). t-PA administration attenuated the effects of PAI-1. whereas latent PAI-1 (20 micrograms/ml) had no effect on clot lysis. Blood levels of PA and PAI activity remained unaltered during these experiments. CONCLUSIONS. The results indicate that PAI-1 markedly inhibits endogenous fibrinolysis in vivo and. moreover. suggest that the localization of PAI-1 to a forming thrombus is an important physiological mechanism for subsequent thrombus stabilization.
Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure, BACKGROUND. Organic nitrates such as nitroglycerin and isosorbide dinitrate are useful in the treatment of congestive heart failure (CHF). but tolerance develops rapidly during continuous administration. Because combination therapy of nitrate and hydralazine has been shown to provide both short- and long-term benefit but nitrate alone produces hemodynamic tolerance. we questioned whether hydralazine can preserve the favorable preload effects of nitroglycerin. METHODS AND RESULTS. Using an in vivo model of nitroglycerin tolerance in the CHF rat. we examined the effects of hydralazine bolus dosing during continuous nitroglycerin infusion. Continuous infusion of nitroglycerin alone (10 micrograms/min) produced initial reductions in left ventricular end-diastolic pressure of 40-50%. which returned to baseline by 8 hours (tolerance development). Coadministration of hydralazine (2 x 0.1 mg) maintained the effects of nitroglycerin infusion on left ventricular end-diastolic pressure (45% reduction at 10 hours). This hydralazine dose alone reduced left ventricular peak systolic pressure by approximately 12 +/- 3% but had no effect on left ventricular end-diastolic pressure. Hydralazine dosing did not affect steady-state plasma concentrations of nitroglycerin or metabolites. and hydralazine was unable to prevent nitroglycerin tolerance induced in vitro. CONCLUSIONS. The beneficial interaction of hydralazine on the preload effects of nitroglycerin may explain the long-term clinical efficacy of hydralazine/nitrate combination in CHF. Our results also suggest that the mechanism of in vivo nitrate tolerance in CHF may be systemic rather than vascular in origin.
Energy expenditure and substrate metabolism measured by 24 h whole-body calorimetry in patients receiving cyclic and continuous total parenteral nutrition, 1. Twenty-four hour energy expenditure and its components. i.e. 'basal metabolic rate'. activity energy expenditure and diet-induced thermogenesis were measured. using continuous whole-body indirect calorimetry. in patients receiving total parenteral nutrition while in remission from Crohn's disease (weight 51.9 +/- 9.9 kg. body mass index 19.2 +/- 2.0 kg/m2). 2. Total parenteral nutrition was infused continuously over 24 h in four subjects and cyclically. between 22.00 and 10.00 hours. in eight subjects. Twenty-four hour energy expenditure (6.83 +/- 1.10 MJ/24 h) was lower than total energy intake (10.09 +/- 1.63 MJ/24 h). resulting in a positive energy balance (3.26 +/- 1.42 MJ) in all subjects. Repeated measurements of resting energy expenditure in the continuously fed subjects (5.82 +/- 1.11 MJ/24 h) did not change significantly at different times of day (coefficient of variation 2.2-6.6%). In contrast. in cyclically fed subjects. resting energy expenditure was 24.2 +/- 9.0% higher towards the end of the 12 h feeding period than the 'basal metabolic rate'. which was measured just before the start of the feeding period. 3. Diet-induced thermogenesis. calculated as the increment in resting energy expenditure above 'basal metabolic rate' over the 24 h period (adjusted for the reduction in energy expenditure during sleep). was found to be 0.60 +/- 0.29 MJ or 6.1 +/- 3.1% of the energy intake. 4. The energy cost of activity (activity energy expenditure) in the continuously fed patients. calculated as the difference between 24 h energy expenditure and the integrated 24 h measurements of resting energy expenditure. was 0.88 +/- 0.53 MJ. i.e. 12.9 +/- 5.9% of the 24 h energy expenditure. 5. The non-protein non-glycerol respiratory quotient exceeded 1.0 for varying periods of time (0.5-17 h) in 11 subjects. indicating net lipogenesis from carbohydrate. 6. The results demonstrate favourable rates of deposition. during intravenous feeding. of both energy and nitrogen over a 24 h period in patients recovering from an episode of Crohn's disease. The efficacy of these commonly used total parenteral nutrition regimens in these patients is related to three features that are absent in normal healthy individuals. namely a low basal metabolic rate. a low activity-related energy expenditure and prolonged periods of lipogenesis from carbohydrate.
Na+,K(+)-ATPase activity and hormones in single nephron segments from nephrotic rats, 1. In the nephrotic syndrome the kidneys retain salt and water. which leads to oedema formation. The site of this sodium retention has been localized in the cortical collecting tubule by micropuncture studies. Whether or not this phenomenon is an intrinsic renal problem or is the consequence of changes in hormonal activities is still a matter of discussion. 2. Using the model of puromycin aminonucleoside-induced nephrotic syndrome in the rat. we measured Na+.K(+)-ATPase activity in nephron segments from control and nephrotic rats and investigated the regulatory role of aldosterone and endogenous-ouabain-displacing factor. 3. Nephrotic animals had a twofold increase in Na+.K(+)-ATPase activity in the cortical collecting tubule only (control versus nephrotic: 1065 +/- 68 versus 2081 +/- 274 pmol h-1 mm-1. P = 0.036). which was not modified by adrenalectomy and was independent of the kidney content of endogenous ouabain-displacing factor. Na+.K(+)-ATPase activity in the cortical collecting tubule correlated with the sodium balance in both control and nephrotic rats. 4. The data are consistent with the view that sodium retention in this model of the nephrotic syndrome is a primary event. i.e. an increase in sodium transport throughout the cortical collecting tubule expressed as a twofold increase in Na+.K(+)-ATPase activity which is no longer under hormonal regulation (aldosterone and endogenous ouabain-displacing factor).
Coronary thrombolysis with recombinant tissue plasminogen activator. Intracoronary vs intravenous administration, We employed a canine model of coronary thrombosis. induced by injection of radioactive blood clot. via a catheter placed in the left anterior descending coronary artery. to compare effects of recombinant tissue plasminogen activator (rtPA) administered intravenously and administered directly into the coronary circulation. A control group did not receive rtPA. Compared with controls. both rtPA regimens induced coronary thrombolysis. However. compared with intravenous administration. rate and extent of coronary thrombolysis were increased with intracoronary administration. Most likely. the enhanced thrombolysis with intracoronary administration is explained by an increase in delivery of the drug to the thrombus.
Effect of antiallergic agents and bronchial hypersensitivity in short-term bronchial asthma, The effect of antiallergic agents with no antihistamine activity on bronchial hypersensitivity to histamine inhalation was studied in 37 asthmatic patients. Improvement in bronchial hypersensitivity to histamine was observed in 11 out of the 24 (46 percent) antiallergic agents-treated patients. but in none of the 13 (0 percent) untreated patients. The 11 patients whose bronchial hypersensitivity improved with antiallergic agents consisted of eight short-term cases of less than one year's duration and three long-term cases of more than one year's duration. Thus. improvement in bronchial hypersensitivity was observed in 8 of 11 (73 percent) short-term cases. and 3 of 13 (23 percent) long-term cases. A significant improvement in %FEV1 was observed only in the short-term cases treated with antiallergic agents. but the improvement of baseline FEV1 did not seem to explain entirely the improvement in bronchial hypersensitivity seen. The decrease in bronchial hypersensitivity was in parallel with that of other asthmatic symptoms. These results suggest that antiallergic agents might be most effective in the treatment of asthmatic patients with a short-term disease duration.
Direct mechanical ventricular actuation for cardiac arrest in humans. A clinical feasibility trial, Direct mechanical ventricular actuation (DMVA) is a non-blood-contacting method of biventricular cardiac massage which may be applied expediently for total circulatory support. The purpose of this study was to assess the feasibility of DMVA application for patients suffering refractory cardiac arrest. Following informed consent. DMVA was applied in 22 patients. Vascular access for hemodynamic monitoring was possible in only 12 patients. whose outcomes serve as the basis for this report. The mean age of the patients was 48.2 +/- 4.2 years (seven men; five women). The average time from witnessed cardiac arrest to DMVA application was 81 +/- 9 minutes. Application took less than two minutes from the time of skin incision and resulted in immediate hemodynamic improvement. Systolic and diastolic blood pressures averaged 78 +/- 4 and 41 +/- 4 mm Hg. respectively. with a mean cardiac output of 3.14 +/- 0.18 L/min during a mean of 228 +/- 84 minutes of circulatory support (range. 25 minutes to 18 hours). In selected cases the device was temporarily removed for 2 to 3 minutes and open-chest cardiac massage (OCCM) performed at similar compression rates. DMVA increased arterial pressures 65 percent and cardiac output 190 percent compared to OCCM. Initial arterial pH (7.12 +/- 0.04) improved by the time the device was removed (7.24 +/- 0.05). Serum lactate levels decreased from 18.0 +/- 2.3 mumol/L to 14.9 +/- 2.9 mumol/L. Four patients were successfully defibrillated: two had inadequate cardiac function and died within 1 h. and two were successfully resuscitated. but later died from cardiac failure and respiratory insufficiency. Another patient regained normal neurologic function during DMVA and was successfully bridged to cardiopulmonary bypass for emergent coronary artery bypass grafting. but died later from myocardial infarction. There were only two complications: (1) a cardiac laceration during pericardiotomy (1/22 patients); and (2) a ventricular rupture during OCCM (1/22). No complication resulted from the device. We found DMVA to be a feasible method for acute cardiovascular stabilization in victims suffering refractory cardiac arrest. Human clinical trials employing earlier DMVA application are required to determine its resuscitative potential.
NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse, NOD/Lt mice harboring a hybrid rat insulin-promoter/SV40 large T-antigen gene spontaneously develop beta-cell adenomas. NIT-1 is a pancreatic beta-cell line established from one of these transgenic mice. Immunocytochemical staining of passage 18 cells showed most contained insulin. with less than 5% containing glucagon. and none containing pancreatic polypeptide or somatostatin. Glucagon content radioimmunoassayed in cell extracts was only 0.27% of the insulin content. Two-hour insulin secretion at 16.5 mM glucose was 638 ng/10(6) cells (41% of intracellular content) compared to only 1.3 ng glucagon (32% of intracellular content). Stimulated insulin secretion was consistently observed in response to 11 and 16.5 mM glucose between passages 11 and 19. At passage 19. both theophylline and tolbutamide stimulated insulin secretion at 5.5 mM glucose. Northern-blot analysis confirmed high levels of insulin mRNA but only trace glucagon mRNA and undetectable somatostatin mRNA. Interferon-gamma (IFN-gamma)-induced MHC class I RNA expression was correlated with markedly increased antigen expression at the cell surface. Similarly. a MHC-linked "occult" class I-like antigen detected by Cr release assay only after exposure of standard NOD/Lt islet cells to IFN-gamma was strongly induced by IFN-gamma in NIT-1 cells. Cell surface MHC class II antigen was not constitutively expressed on NIT-1 cells and could not be detected after IFN-gamma incubation. despite demonstration of IFN-gamma-induced Aa. Ab. and Li invariant-chain RNA transcripts. Similarly IFN-gamma induction of intercellular adhesion molecule 1 (Icam-1) transcripts was not accompanied by demonstrable cell surface expression of ICAM-1 antigen.
Atrial natriuretic peptide and response to changing plasma volume in diabetic nephropathy, We evaluated the renal and hormonal responses to volume expansion induced by water immersion in subjects with diabetic nephropathy (n = 12) and in healthy control subjects (n = 9). Immersion induced similar average increments in sodium excretion (+/- 223 vs. 176 mumol/min) and comparable decrements in renovascular resistance (RVR; -15 vs. -16 U). However. whereas the control subjects responded uniformly. the response among diabetic subjects was highly variable. with a subset of patients exhibiting paradoxical antinatriuresis and vasoconstriction. Immersion was associated with marked elevation of atrial natriuretic peptide (ANP) in plasma of diabetic versus control subjects (61 +/- 9 vs. 19 +/- 2 pM. respectively; P less than 0.001). Yet for each picomolar increment in plasma ANP during immersion. the corresponding increases in urinary excretion of cyclic guanosine monophosphate (26 vs. 279 pmol/min) and sodium (9 vs. 47 mumol/min) and the reciprocal lowering of RVR (0.7 vs. 1.9 U) were blunted in the diabetic versus control group. Volume contraction in the postimmersion period was associated with disproportionate antinatriuresis and renal vasoconstriction in the diabetic group. despite a persistent elevation of ANP (29 +/- 2 vs. 16 +/- 2 pM. P less than 0.01). We propose that renal insensitivity to ANP in diabetic nephropathy could contribute to altered vasoreactivity and abnormal excretory responsiveness to changing plasma volume. Blunted natriuresis in response to ANP release and enhanced sodium retention during volume contraction could account for the expanded extracellular fluid volume that has consistently been reported to accompany the development of diabetic nephropathy.
Enteral feeding as sole treatment for Crohn's disease: controlled trial of whole protein v amino acid based feed and a case study of dietary challenge, A controlled trial was performed to compare enteral feeding with either an amino acid based feed or a whole protein feed as sole treatment for active Crohn's disease. Twenty four patients were studied (nine with ileal. 11 with ileocolonic. and four with colonic disease). Both feeds proved effective; nine of 13 patients randomised to receive the amino acid based feed were in clinical remission within three weeks as defined by a simple activity index compared with eight of 11 treated with the whole protein feed. Patients in clinical remission were then crossed over onto the other feed. None of the six patients who were changed to the whole protein feed relapsed over the subsequent three week period compared with three of seven patients who were changed to the amino acid based feed. In responders the median serum C reactive protein concentration fell from 21 mg/l (range 9-82) on entry to 6 mg/l (range 3-19) at six weeks. Seven patients relapsed within eight months of starting solid food (mean 3.7 months). while nine were still in remission (follow up period 3-9 months. median six months). Detailed studies of staged reintroduction of food and permitted food additives were carried out over a four year period in a patient with extensive stricturing small bowel Crohn's disease who had been brought into remission by open treatment with enteral feeding. Carrageenan. other permitted emulsifiers. bread. meat. potatoes. oranges. refined sugar. dairy produce. flour. and rice were all reintroduced without any objective ill effect. but green vegetables provoked a clinical and biochemical relapse within one week of introduction.
An in vitro technique to assess oxygenator potential for respiratory failure therapies, To assess microporous membrane oxygenators (MMO) for long-term respiratory support. an in vitro test of 4 days duration has been developed. The objective is to screen oxygenators before they undergo expensive animal trials. As a sensitive indicator of performance change. CO2 transfer rates (VCO2) are determined with fresh bovine blood at the start. after 48 hours and after 96 hours of perfusion. Blood is used only for gas exchange evaluation and is replaced with plasma in the intervening periods. Data are obtained at blood flow rates (QB) of 1.0. 1.5 and 2.0 l/min for gas: blood flow ratios (QG:QB) of 2:1 and 5:1. The test has been conducted on Bentley BOS-CM50 oxygenators (n = 10). With heated dry air ventilation there was no significant change in VCO2 with time for all QB and QG:QB combinations. Plasma leakage did not occur into the gas compartment of the MMO. Similar results were obtained with heated humidified air ventilation. The findings are in agreement with existing animal studies of 4-7 days duration.
Subrenal capsule assay using nude mice as a predictor of the response of the gastric cancer to chemotherapy, Feasibility of utilizing human gastric cancers as first transplant generation xenografts in nude mice for determining tumor sensitivity to chemotherapeutic agents was demonstrated by applying subrenal capsule (SRC) assay. A total of 55 human gastric tumors from patients were tested in this assay. Mitomycin-C (MMC) and hexycarbamyl-5-FU (HCFU. 5-FU derivative) were selected for the treatment of these patients after surgery and also for this assay as first transplant. Evaluable rate of MMC in this assay was 92.7% and that of HCFU was 90.9%. Sensitivity of tumors to MMC was 25% and to HCFU was 32%. Correlation between response to chemotherapy of human tumors in patients and in nude mice was 78.6%. These results indicate that this assay could predict effective drugs for patients with gastric cancer.
Acquired immunity and epidemiology of Schistosoma haematobium, Human immune responses to schistosome infection have been characterized in detail. But there has been controversy over the relative importance of ecological factors (variation in exposure to infection) and immunological factors (acquired immunity) in determining the relationships between levels of infection and age typically found in areas where infection is endemic. Independent effects of exposure and age on the rates of reinfection with Schistosoma haematobium after chemotherapy have been demonstrated in the Gambia and Zimbabwe. This age effect could be the result of acquired immunity to infection. Indeed. allowing for variation in exposure and age. low rates of reinfection in the Gambia are correlated with high amounts of specific IgE antibodies--human IgE can kill S. mansoni schistosomulae in vitro. Further. animals can acquire immunologically mediated resistance to S. mansoni infection. although nonimmunological factors could also be involved. Acquisition of this immunity seems to be related to the cumulative effects of repeated infection and provides only partial protection. These characteristics are consistent with immuno-epidemiological data for both S. mansoni and S. haematobium infections of humans. We have now analysed age-prevalence data for human infection with S. haematobium. and find patterns of variation that are indeed consistent with the epidemiological effects of acquired immunity predicted by mathematical models.
Antiretinal antibodies in serum of patients with age-related macular degeneration, Antibodies. immunoreactive with normal human retinal proteins. were detected by Western immunoblot analysis in the sera of 30 patients with age-related macular degeneration (AMD). Sera from 14 of these patients demonstrated positive binding predominantly to a doublet protein of molecular weight between 58 and 62 kD. The sera from the remaining 16 patients and from 12 control subjects reacted either weakly or not at all with the doublet protein. No correlation was found with any specific type of AMD. The serum antibodies also immunocrossreacted with the same proteins from isolated photoreceptor outer segments; this was confirmed by indirect immunofluorescence on intact retinas. The crossreactivity of the serum antibodies with a protein of Mr 58 to 62 kD. the lower band present in the bovine purified neurofilament-68 kD preparation. suggests strongly that this protein may be a component of the neuronal cytoskeleton. However. it is not clear whether these autoantibodies play a direct role in the etiology of AMD or represent a nonspecific response to retinal damage.
Carbon dioxide laser surgery of oral leukoplakia, Oral leukoplakia is a precancerous lesion of the oral mucosa. The risk of malignant transformation depends on the clinical and histologic classification and the location of the lesion. For a nonhomogeneous leukoplakia. this risk is 23.4% to 38.0%. In the presence of epithelial dysplasia. the possibility of malignant transformation is 36.3% to 43.0%. Leukoplakia is limited to the epithelium. so a selective removal of this part of the mucosa seems to be the best preventive treatment. Carbon dioxide laser surgery accomplishes a superficial removal by evaporation. A total of 70 patients with 103 oral leukoplakias were treated with carbon dioxide laser evaporation. This resulted in an excellent wound healing with virtually no scarring. The patients were followed up during a period of up to 12 years (mean 5.3 years). showing a cure rate of 90%.
Premenstrual syndrome. Tailoring treatment to symptoms, Despite the interest in premenstrual syndrome (PMS) taken by the media and the public in recent years. some women still do not recognize the cyclic nature of their symptoms. Thus. PMS continues to elude diagnosis. Dr Nader discusses the major categories of symptoms and when they occur. summarizes theories on the cause of PMS. and comments on how well these theories have been substantiated by testing. Choosing agents for treatment on the basis of symptoms to be controlled is also described.
Treating the progressive stages of Parkinson's disease, Parkinson's disease affects thousands of Americans. men and women equally and apparently with little regard to race. Its diagnosis depends largely on repeated clinical observations of representative signs. such as resting tremor. rigidity. bradykinesia. and gait disturbances. Patients progress through stages: Early disease involves only one limb or side and confers minimal disability. but advanced disease restricts patients to full care. Treatment is chosen on the basis of disease stage and patient response. Combination carbidopa-levodopa (Sinemet) is appropriate for any significant degree of disability. and other antiparkinsonian drugs and anticholinergic agents may be used as adjuncts. Electroconvulsive therapy. use of selegiline hydrochloride (Eldepryl). and surgery are still undergoing investigation but may hold promise.
Gamma globulin prophylaxis to reduce post-transfusion non-A, non-B hepatitis after cardiac surgery with cardiopulmonary bypass, A prospective. randomized study of immune serum globulin (ISG) for prevention of post-transfusion hepatitis was performed on 196 patients (100 controls without gammaglobulin or placebo and 96 who received ISG) undergoing valve replacement or coronary artery bypass with extracorporeal circulation. The dose of ISG was 2 ml i.m. at premedication and 2 ml i.m. on postoperative day 3. Probable non-A. non-B hepatitis developed postoperatively in ten of the 100 controls and two of the 96 in the ISG group. Two ISG patients and three controls with non-A. non-B hepatitis still have increased serum aminotransferase values after 3-5 years. but liver biopsy revealed hepatitis. which histologically was very mild. in only two control and two ISG patients. Low-dose gamma globulin thus reduced the incidence of acute. probable non-A. non-B hepatitis in cardiac surgery with cardiopulmonary bypass.
Regulation of B cell antigen receptor signal transduction and phosphorylation by CD45, CD45 is a member of a family of membrane proteins that possess phosphotyrosine phosphatase activity. and is the source of much of the tyrosine phosphatase activity in lymphocytes. In view of its enzymatic activity and high copy number. it seems likely that CD45 functions in transmembrane signal transduction by lymphocyte receptors that are coupled to activation of tyrosine kinases. The B cell antigen receptor was found to transduce a Ca(2+)-mobilizing signal only if cells expressed CD45. Also. both membrane immunoglobulin M (mIgM) and CD45 were lost from the surface of cells treated with antibody to CD45. suggesting a physical interaction between these proteins. Finally. CD45 dephosphorylated a complex of mIg-associated proteins that appears to function in signal transduction by the antigen receptor. These data indicate that CD45 occurs as a component of a complex of proteins associated with the antigen receptor. and that CD45 may regulate signal transduction by modulating the phosphorylation state of the antigen receptor subunits.
p53 mutations in human cancers, Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer. The p53 mutational spectrum differs among cancers of the colon. lung. esophagus. breast. liver. brain. reticuloendothelial tissues. and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon. brain. and lymphoid malignancies. whereas G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung and liver. Mutations at A:T base pairs are seen more frequently in esophageal carcinomas than in other solid tumors. Most transitions in colorectal carcinomas. brain tumors. leukemias. and lymphomas are at CpG dinucleotide mutational hot spots. G to T transversions in lung. breast. and esophageal carcinomas are dispersed among numerous codons. In liver tumors in persons from geographic areas in which both aflatoxin B1 and hepatitis B virus are cancer risk factors. most mutations are at one nucleotide pair of codon 249. These differences may reflect the etiological contributions of both exogenous and endogenous factors to human carcinogenesis.
Intracoronary recombinant tissue-type plasminogen activator in unstable angina: a pilot angiographic study, The effectiveness of intracoronary (IC) recombinant thromboplastin activator (rt-PA) was prospectively evaluated in seven patients with unstable angina and complex angiographic lesions or intracoronary filling defects (ICFD). There were four men and three women. with a mean age of 60 years. Three patients had multivessel disease and all patients had rest angina; none had evolving myocardial infarction. All patients were pretreated with aspirin and were given heparin. IC rt-PA was infused at the rate of 1 mg/min to a total of 50 mg. and angiographic changes were observed every 15 minutes. At 50 minutes. angiographic improvement was seen in two patients (28%). one of whom had complete and one of whom had partial resolution of ICFD. In two patients (28%) there was no change in the lesion. and three patients (42%) had worsening of the lesion appearance. In two of the latter. paradoxical closure was observed at the end of the infusion. and was treated successfully with ad hoc emergency angioplasty. This pilot study suggests that IC rt-PA at the dosage used may have variable effects on complex coronary lesions associated with unstable angina. and this may be of relevance in further trials evaluating IC thrombolysis in unstable coronary ischemic syndromes.
Comparison of tomographic and planar imaging for the evaluation of thrombolytic therapy in acute myocardial infarction using pre- and post-treatment myocardial scintigraphy with technetium-99m sestamibi, Pre- and post-treatment myocardial scintigraphy with technetium-99m hexakis 2-methoxy-isobutyl-isonitrile (Tc-99m sestamibi) was performed in patients who underwent thrombolytic therapy for acute myocardial infarction comparing planar imaging and single-photon emission computed tomography (SPECT). Twenty-one patients were injected with Tc-99m sestamibi before thrombolytic treatment. SPECT and planar imaging were acquired after completion of the treatment. The scintigraphy was repeated 5 days later in 20 subjects. Planar and SPECT studies were evaluated using an uptake score. Patients were divided according to the status of the infarct-related vessel (patent in 13 patients. group 1. and occluded in seven. group 2) and to the presence of functional recovery in serial echocardiographic controls (present in 10 patients. group A. and absent in 10. group B). The scintigraphic defect extent in the 5-day images correlated with the enzymatic infarct size: SPECT: r = 0.75. p less than 0.0002; planar: r = 0.68. p less than 0.002. The decrease of the uptake defects correlated with the reduction of the left ventricular wall asynergy (admission versus 1 month echocardiogram): SPECT: r = 0.92. p less than 0.000001; planar: r = 0.82. p less than 0.00001. The percent decrease of the uptake defects was significantly higher in patients in group 1 and group A compared with group 2 and. respectively. group B--SPECT: group 1: 51.4 +/- 27.7 versus group 2: 13.1 +/- 8.6. p less than 0.02; group A: 64.2 +/- 15.3 versus group B: 11.9 +/- 8.1. p less than 0.0002; planar group 1: 41 +/- 30.4 versus group 2: 7.7 +/- 6.2. p less than 0.05; group A: 52.5 +/- 24.3 versus group B: 6.1 +/- 6. p less than 0.0002. This study confirms the reliability of pre- and post-treatment myocardial scintigraphy with Tc-99m sestamibi for evaluating the outcome of thrombolytic treatment in myocardial infarction. The results seems slightly more accurate using SPECT. but a simple three-view planar study also gives useful data.
Rapid changes of atrial natriuretic peptide concentration during percutaneous transluminal coronary angioplasty, In 34 patients undergoing routine coronary angioplasty. concentrations of atrial natriuretic peptide (ANP). plasma renin (PR). and plasma aldosterone (PA) were estimated before. during. and after vessel occlusion and were correlated with hemodynamic changes. For the group as a whole. averaged right atrial pressure rose significantly (p less than 0.001) from 4.4 +/- 1.8 mm Hg at baseline to 6.7 +/- 3.0 mm Hg during vessel occlusion. and average right atrial ANP concentrations increased significantly (p less than 0.005) from 50.1 +/- 18.8 pg/ml to 59.7 +/- 21.4 pg/ml during balloon inflation. Data analysis of subgroups did not show any differences in right atrial pressure elevations between patients with left anterior descending artery (LAD) or right coronary artery (RCA) disease; ANP elevation was significant only in patients with LAD occlusion (p less than 0.001). In individual patients no statistically significant correlations were found to be present between changes in right atrial pressures and changes in atrial ANP concentrations. During vessel occlusion. PR dropped from 0.86 +/- 1.11 ng/ml/hr to 0.65 +/- 0.85 ng/ml/hr (p less than 0.001) in all patients. and PA decreased from 63.0 +/- 50.9 ng/ml to 52.2 +/- 43.4 ng/ml (p less than 0.01). Our data support the concept that. although an increase in right atrial pressure leads to ANP release in the majority of patients. atrial pressure and stretch are not the only regulatory factors of ANP release in humans.
Incidence of left ventricular thrombi formation after thrombolytic therapy with recombinant tissue plasminogen activator, heparin, and aspirin in patients with acute myocardial infarction, To evaluate the prevalence of left ventricular thrombi after thrombolytic therapy. 144 consecutive patients with acute myocardial infarction (AMI) were prospectively studied with two-dimensional echocardiography 1 and 8 days after admission. Patients were treated 2.1 +/- 0.8 hours after the onset of symptoms. Thrombolytic protocol included 120 mg of recombinant tissue plasminogen activator (rt-PA). 5000 IU of heparin. followed by a continuous infusion of 25.000 IU/24 hours for at least 5 days. and 250 mg of aspirin a day. Seventy-six patients had AMI of the anterior wall; of these. seven (9.2%) developed left ventricular thrombi. The remaining 68 patients had infarctions of the inferior wall; of these. two (2.9%) developed left ventricular thrombi. Since anterior wall infarction not treated with thrombolytic therapy is associated with a 25% to 40% rate of left ventricular thrombi. we conclude that early thrombolytic therapy with rt-PA. heparin. and aspirin reduces the formation of left ventricular thrombus in AMI of the anterior wall. Apical left ventricular thrombi developed more frequently in patients with previous infarctions compared with those without (4 of 17 versus 4 of 127. p = 0.01). During the 12-month follow-up period. no patient in the study had manifestations of peripheral emboli.
Coronary recanalization rate after intravenous bolus of alteplase in acute myocardial infarction, The demonstration in animals that recombinant tissue-type plasminogen activator produces prolonged thrombolysis after its clearance from the circulation has prompted a few pilot studies of bolus administration in patients. Alteplase (bolus dose of 70 mg) resulted in the highest recanalization rate in our previous pilot study comparing bolus doses of 50. 60 and 70 mg of alteplase in patients with acute myocardial infarction. The aim of the present trial was to assess the efficacy and safety of the same bolus dose in a larger number of patients. A further objective was to study the angiographic reocclusion rate at 12 to 24 hours in patients who had a recanalized infarct-related coronary artery at 90 minutes and were randomized at that time to a bolus dose or an infusion for 3 hours of 30 mg of alteplase. Sixty patients with acute myocardial infarction and angiographically documented total occlusion of the infarct-related coronary artery before thrombolysis were treated within 5 hours of onset of symptoms with an intravenous 70-mg bolus dose of alteplase (or 80 mg if body weight was greater than or equal to 90 kg). Each patient received 5.000 IU of heparin intraarterially and 100 mg of aspirin by mouth before administration of alteplase. Coronary angiography was repeated 60 and 90 minutes after alteplase administration. The recanalization rate of the infarct-related coronary artery was 55% (95% confidence interval. 43 to 66%) at 60 minutes and 48% (95% confidence interval. 37 to 60%) at 90 minutes. Pretreatment levels of lipoprotein (a) were not significantly related to recanalization.
Efficacy of alternating therapy with oxamniquine and praziquantel to treat Schistosoma mansoni in children following failure of first treatment, Two hundred children infected with Schistosoma mansoni were treated with either 20 mg/kg oxamniquine or 60 mg/kg praziquantel. Cure rates (about 85%) were similar as was the percentage reduction (80%) in egg counts in uncured children. Treatment with the alternative drug of children not cured with the first treatment resulted in negative stools in 11 of 12 cases examined one month after the second round of therapy. In order to minimize the risk of the development of drug resistance. our data suggest that infected patients be treated with one drug. and therapeutic failures with another. Evidence from experiments in mice with isolates obtained after failures of one treatment in children suggests that therapeutic failure does not necessarily indicate the presence of drug-resistant schistosomes. The value of using mice to assess drug resistance in schistosomes is questioned.
Influence of changes in arterial carbon dioxide tension on the electroencephalogram and posterior tibial nerve somatosensory cortical evoked potentials during alfentanil/nitrous oxide anesthesia, The effects of variation of arterial CO2 tension (PaCO2) on the electroencephalogram (EEG) and posterior tibial nerve somatosensory cortical evoked potentials (PTN-SCEP) during opioid/N2O anesthesia have not been well documented. We studied the effects of hypocapnia (PaCO2 approximately 23 mmHg) and hypercapnia (PaCO2 approximately 50 mmHg) during steady-state alfentanil/N2O anesthesia in 16 patients. EEG and PTN-SCEP were recorded continuously. while PaCO2 was altered in 15-min intervals by varying the inspired CO2 concentration. Hypocapnia caused significant increases in power in the delta. theta. and beta bands (P less than 0.01). with the greatest increase observed in the alpha band. Relative power increased in the alpha band but remained unchanged in the delta. theta. and beta bands. Median frequency and 95% spectral edge frequency were unaltered during hypocapnia. In contrast. hypercapnia caused a significant decrease of power in the alpha and beta bands. whereas delta and theta power remained unchanged. This was reflected in a significant decrease of the 95% spectral edge frequency. from 8.9 (6.7-11.6) to 7.0 (5.6-8.6) Hz. All EEG parameters returned to normal upon restoration of normocapnia. There was a significant negative correlation between power in the alpha band and end-tidal CO2 in all patients (r = 0.47 to -0.89). PTN-SCEP latencies and amplitudes were not significantly different from control values during hypocapnia and hypercapnia. It is concluded that variations in PaCO2 within the limits 20-50 mmHg produce substantial changes in the EEG power spectrum. especially in the alpha band (8-12 Hz). but do not alter PTN-SCEP.
Confirmation of endotracheal tube placement: a miniaturized infrared qualitative CO2 detector, STUDY OBJECTIVES: A miniaturized. infrared. solid-state. end-tidal CO2 detector was used to confirm emergency endotracheal tube (ETT) placement. DESIGN: This prospective. clinical study used a miniature. infrared. solid-state end-tidal CO2 detector to confirm ETT placement in an acute setting. SETTING: The ICU. emergency department. and hospital floor. TYPE OF PARTICIPANTS: There were 88 consecutive adult patients requiring 100 emergency intubations. MEASUREMENTS AND MAIN RESULTS: The indication for airway intervention was considered urgent in 79% and under arrest conditions in 21%. The mean number of intubation attempts was 1.83 (range. one to five) with difficulty of intubation of 6.48 and confirmation of 7.75. on a linear scale from 0 (lowest) to 10 (highest). Determination of ETT position revealed intratracheal intubation in 96% and esophageal intubation in 4%. Placement was confirmed by direct visualization or radiography in all cases. Sensitivity and specificity for ETT localization was 100% (P less than .0001). CONCLUSION: This hand-held infrared capnometer reliably confirms ETT placement under emergency conditions.
Hypercarbic ventilatory responses of human heart-lung transplant recipients, To evaluate the effects of chronic pulmonary denervation on ventilatory control. we compared the hypercarbic ventilatory responses (HCVR) of 12 human heart-lung transplant recipients (HL) and 24 normal control subjects (C). The six male HL were subsequently compared with eight male heart transplant recipients (H). as well as the 12 male C. All subjects had normal spirometry. but lung volumes of both transplant groups were somewhat less than those of C. The HCVR of HL and C were indistinguishable (2.68 +/- 0.28 versus 2.71 +/- 0.22 L/min/mm Hg. respectively). The increment of mouth occlusion pressure (delta Pm0.1/delta CO2). however. was markedly greater in HL (P much less than 0.01). The three male groups also had equivalent HCVR. and again. the HL had an increased delta Pm0.1/delta CO2. HL men exhibited larger increments of VT and decreased frequency responses during CO2 rebreathing than did male C and H. although these differences were statistically significant only in the comparison between the transplant groups. We conclude that HL with normal spirometry have appropriate HCVR. despite pulmonary denervation. Pm0.1 responses of these subjects are increased. however. reflecting either a compensatory response to greater respiratory impedances or an occult alteration of ventilatory mechanics. Moreover. compared with subjects with similar pulmonary function. e.g.. heart transplant recipients. the breathing pattern of HL during progressive hypercarbia is consistent with the absence of vagal-mediated inflation inhibition.
Airway blood flow modifies allergic airway smooth muscle contraction, We tested the hypothesis that airway perfusion modifies the contractile response of airway smooth muscle to allergen challenge by influencing the clearance of locally released spasmogens. In six intact. lightly sedated. sheep allergic to Ascaris suum. we measured tracheal mucosal blood flow (Qtr) with a soluble gas uptake method and tracheal dead space (Vtr). an index of airway smooth muscle tone. by helium dilution before and serially after local aerosol challenge with A. suum extract or ragweed extract (control). The former challenge was repeated during continuous intravenous infusion of either vasopressin or nitroglycerin. which by themselves had no effect on Vtr and decreased and increased Qtr. respectively. Ragweed had no effect on Qtr and Vtr. whereas A. suum increased mean (+/- SE) Qtr by 111 +/- 31% (p less than 0.05) and decreased mean Vtr by 15 +/- 2% (p less than 0.05) immediately after challenge. with Qtr returning to baseline by 40 min and Vtr by 80 min. Vasopressin infusion prevented the A. suum-induced increase in Qtr and prolonged the decrease in mean Vtr (p less than 0.05). During nitroglycerin infusion. A. suum failed to alter Qtr or Vtr. Vasopressin and nitroglycerin had no effect on the contractile responses of tracheal smooth muscle to A. suum in vitro. These results indicate that the effects of vasopressin and nitroglycerin on antigen-induced airway smooth muscle contraction in vivo were due to alterations in airway blood flow rather than to alterations in the release of or airway smooth muscle responsiveness to chemical mediators.
Arachidonic acid metabolites in middle ear effusions of children, Middle ear effusions (MEEs) from 78 children (98 ears) with otitis media were examined for products of arachidonic acid (AA) metabolism. including leukotrienes B4. C4. D4. and E4 and prostaglandins D2 and E2. by high-performance liquid chromatography. Leukotrienes B4 and D4 were recovered most frequently: 59% and 54%. respectively. Leukotriene B4 was found in highest concentration. 1.29 +/- 3.46 ng/0.1 mL. The concentrations of leukotrienes B4 (p less than .03). (4 (p less than .01). and E4 (p less than .02) were significantly higher in culture-positive than in culture-negative MEEs. Neither the concentration nor the type of AA metabolite correlated with bacterial species isolated. chronicity of effusion. age of subject. or consistency of MEE. These data suggest that the AA metabolites are synthesized relatively frequently during otitis media of childhood. Leukotriene B4 is the most frequently detected AA metabolite in MEEs and is highly associated with the presence of viable bacteria.
Formation of noninfectious HIV-1 virus particles lacking a full-length envelope protein, Deletions were constructed within a functional human immunodeficiency virus type 1 (HIV-1) proviral clone in order to assess the role of the envelope protein in virus particle formation. A graded exonuclease deletion technique was used to produce 12 clones with deletions of 175-308 nucleotides in the first conserved domain of envelope. This included 9 clones with frameshift deletions and 3 clones with in-frame deletions. Isogenic pairs of env deletion clones were produced with or without an additional deletion in the vif and vpr genes. Upon transfection. all clones produced virus particles. as determined by p24 antigen. reverse transcriptase. and sucrose gradient assays with conditioned media. Virus particles produced from clones with deletions in env or vif and vpr. or both regions. banded on sucrose gradients with a mobility similar to that of virus produced by the parental clone. The p24 gag capsid protein in the particles was resistant to trypsin. but the particles were disrupted by treatment with Triton X-100. suggesting the presence of a surrounding lipid bilayer. Furthermore. electron microscopic studies revealed both mature and immature virus particles derived from COS cells transfected with the env deletion clones. Cocultivation experiments with lymphoid cells and cells transfected with each of the env deletion clones demonstrated that the virus particles were noninfectious.
Determination of released CD4 and CD8 antigens in the suction-blister fluid and horny-tissue extract in patients with psoriasis, The amounts of soluble CD4 and CD8 antigens were measured in suction-blister fluid and extracts of horny tissue in patients with psoriasis. The levels of soluble CD4 and CD8 in the suction-blister fluid of lesional skin in psoriasis was significantly higher than from normal skin and the uninvolved skin in psoriasis. Levels of soluble CD4 and CD8 in the extracts of horny tissue in psoriasis were significantly higher than those from non-psoriatic skin.
Immunoglobulin D benign monoclonal gammopathy. A case report, The authors report a case. perhaps the first. of immunoglobulin D (IgD) benign monoclonal gammopathy. The patient. a 48-year-old black woman. initially had a 500 mg/dl IgD-lambda M-spike. hypercalcemia. and anemia. There was no bone pain. lytic bone lesions. or evidence of renal failure. The bone marrow showed 2.8% plasma cells with a diffuse (not nodular) IgD plasmacytosis and strong lambda predominance. Only trace amounts of free lambda light chains could be demonstrated by immunoelectrophoresis in serum and concentrated urine. The anemia responded quickly to iron therapy. Chemotherapy was not initiated. Over the 6+ years of follow-up. the patient has had no progression of clinical disease attributable to her IgD monoclonal gammopathy. The IgD M-spike has steadily decreased.
Expression of D-mannose binding sites on human spermatozoa: comparison of fertile donors and infertile patients, OBJECTIVE: The hypothesis that defective expression of D-mannose binding sites (presumptive elements of the sperm-zona pellucida binding mechanism) is related to male infertility was tested. DESIGN: Experiments were performed on sperm samples from two groups of men classified. respectively. as fertile and infertile. based on their reproductive history. SETTING: The study was carried out in an andrologic laboratory of a University Hospital. PATIENTS. PARTICIPANTS: Fertile men were healthy sperm donors; infertile men were patients with fertility problems. INTERVENTIONS: D-mannose binding sites were visualized by fluorescence microscopy using a mannosylated neoglycoprotein probe. MAIN OUTCOME MEASURES: The hypothesis as reported in the objective section was formulated before data collection and was not modified thereafter. RESULTS: Sperm from fertile men displayed a characteristic pattern of changes in the expression of D-mannose binding sites during in vitro capacitation. This pattern was altered in sperm from infertile men. CONCLUSIONS: If the relationship between defective expression of D-mannose binding sites and decreased sperm fertilizing ability is validated by parallel tests of sperm-zona binding. it may be used for development of chemical tests replacing the current ones using human zonae pellucidae.
Ovulatory dysfunction during continuous administration of low-dose levonorgestrel by subdermal implants, OBJECTIVE: To study the endocrinologic profile of regularly menstruating users of levonorgestrel subdermal implants. DESIGN: Observational. prospective. case-controlled comparative study. SETTING: The Family Planning Clinic of PROFAMILIA. in Santo Domingo. Dominican Republic. PATIENTS. PARTICIPANTS: Thirty one regularly cycling Norplant users and 12 nonhormonal contraceptors who volunteered to participate. INTERVENTIONS: Norplant contraceptive implants were inserted in 31 subjects between 13 and 77 months before this study. MAIN OUTCOME MEASURES: Follicle-stimulating hormone. luteinizing hormone. estradiol (E2). and progesterone (P) were serially assayed for one menstrual cycle. RESULTS: Almost half of the cycles among Norplant users were anovulatory; all the rest (55%) had some form of dysfunction: diminished gonadotropin surge. luteal phase insufficiency (low P levels and shortened luteal phase). and E2 profiles different from normal controls. CONCLUSIONS: Anovulation is clearly one of the main mechanisms of action of Norplant. but even in presumptive ovulatory cycles. the dysfunctions described possibly contribute to the high contraceptive effectiveness of Norplant.
Platelet-activating factor-acether is a component of human follicular fluid, OBJECTIVE: Platelet-activating factor-acether (PAF-acether) presence was investigated in 27 human follicular fluids (FFs). DESIGN: Aggregation of washed rabbit platelets was used to measure PAF-acether. Data were compared using Student's t-test. SETTING: Follicular fluids came from the in vitro fertilization program at Antoine Beclere Hospital. and PAF-acether was assayed at Institut National de la Sante et de la Recherche Medicale. Unites 187 and 200. Clamart. France. PATIENTS. PARTICIPANTS: The study concerned five infertile women 29 to 39 years of age. INTERVENTIONS: Ovaries were stimulated with human menopausal gonadotropin under gonadotropin-releasing hormone agonist (GnRH-a) action. MAIN OUTCOME MEASURES: The height of platelet aggregation was compared between FFs and synthetic PAF-acether. RESULTS: Mean FF concentration of PAF-acether was 1.367 to 3.467 pg/mL among women. Values were higher for patients in a long than in a short GnRH-a protocol (P less than 0.05). However. PAF-acether concentration was not related to fertilization rate. CONCLUSIONS: Platelet-activating factor-acether is possibly involved in oocyte release from the follicle. a process occulted by follicular puncture.
The Lupron screening test: tailoring the use of leuprolide acetate in ovarian stimulation for in vitro fertilization, STUDY OBJECTIVE: To evaluate the prognostic and therapeutic value of a Lupron (leuprolide acetate; Tap Pharmaceuticals. North Chicago. IL) screening test before ovarian stimulation for in vitro fertilization (IVF). DESIGN: Prospective. SETTING: Outpatient IVF program. PATIENTS: Eighty patients exhibited four early estradiol (E2) patterns. Patients with pattern A and B remained on a flare-up ovarian stimulation protocol. Patients with pattern C were randomized to three ovarian stimulation protocols. Patients with pattern D were treated with the flare-up protocol using a high pure follicle-stimulating hormone (FSH) dose. RESULTS: Patterns. A. B. C. and D occurred in 44%. 16%. 25%. and 15% of the patients. respectively. The E2 pattern recurred in 77% of subsequent IVF cycles. Pattern A and B patients achieved a 41% (23/56) and 22% (5/23) ongoing pregnancy rate (PR) per stimulated cycle. An early luteal phase Lupron protocol had the best ongoing PR per stimulated cycle (10/27. 37%) in patients with a pattern C response. Pattern D patients had a 20% (5/25) ongoing PR per stimulated cycle. CONCLUSION: The Lupron screening test allows prospective selection of stimulation protocols in ovulatory patients undergoing IVF. Early E2 patterns A and B should be treated with the flare-up protocol. Pattern C patients benefit from the luteal phase Lupron protocol and pattern D patients benefit from a high pure FSH flare-up protocol.
Relationship of follicle number, serum estradiol, and other factors to birth rate and multiparity in human menopausal gonadotropin-induced intrauterine insemination cycles, OBJECTIVE: To determine the characteristics associated with pregnancy and multiple gestation after human menopausal gonadotropin intrauterine insemination (hMG-IUI). DESIGN: Prospective study of all patients undergoing hMG-IUI between January 1. 1984 and December 31. 1989. SETTING: University affiliated private clinic. PATIENTS: Four hundred twenty-four infertility patients undergoing 779 cycles of hMG-IUI. MAIN OUTCOME MEASURES: The relationship between estradiol (E2). number and size of follicles. age. and initial semen quality on pregnancy and multiple gestations in hMG-IUI cycles. RESULTS: The number of follicles greater than or equal to 12 mm was correlated with births and predicted all multiple births (r = 0.140. P less than 0.001). The corrected birth rate was 25.8% for age less than 35 and 14.0% for age greater than or equal to 35 when four or more follicles were greater than or equal to 12 mm. The uncorrected clinical pregnancy rate (PR) and birth rate were 12.8% and 10.5%. respectively. Decreased births were associated with tubal adhesions alone (P less than 0.03) or with endometriosis (P less than 0.002). more than four cycles of treatment (P = 0.01). initial sperm count less than 5 x 10(6) per mL (P less than 0.01). initial sperm motility less than 30% (P less than 0.002). and age greater than or equal to 35 (P less than 0.01). Estradiol was correlated with birth rate (r = 0.160. P less than 0.001). which increased from 3.6% when E2 was less than 500 pg/mL to 19.6% when E2 was greater than or equal to 2.500 pg/mL. CONCLUSIONS: The outcome of hMG-IUI is related to the number of follicles greater than or equal to 12 mm. to E2. and to age. Optimal PRs from hMG-IUI require mild ovarian hyperstimulation.
The decision to suggest screening lower gastrointestinal endoscopy: the effect of training, Primary care residency directors in the Southeastern US were surveyed to obtain information on training in lower gastrointestinal endoscopy (LGIE). All residents in a sample of programs were asked to complete a similar questionnaire. Response was 77% for family practice residencies and 60% for internal medicine residencies. Significantly fewer (43%) internal medicine residents reported receiving training in either 35 cm or 60 cm LGIE than family practice residents (77%). When asked if they would suggest LGIE to screen an asymptomatic patient. 67% of family practice and 84% of internal medicine residents replied affirmatively. Those residents who had received training were significantly more likely to suggest screening LGIE. The screening decision was not influenced by the specialty of the physician who supervised the resident training. Out-of-pocket cost to the patient was expected to be a major consideration in the screening decision. but this was not supported statistically. Greater availability of residency training in LGIE will likely increase its use in screening.
Immunoturbidimetric assay for estimating free light chains of immunoglobulins in urine and serum, An immunoturbidimetric assay for the assessment of free kappa and lambda light chains of immunoglobulins was developed using a commercial polyclonal antiserum with reactivity towards epitopes on the light chains. which are not expressed when they are bound to heavy chains. The assay. on a centrifugal analyser. is simple and rapid. The limit of detection is 5 mg/l of free light chain. with an assay range of 5-120 mg/l. intrabatch precisions from 1.5-6.4%. and interbatch precisions from 6.5-8.9%. The assay was only slightly less sensitive than colloidal gold staining of cellulose acetate electrophoreses for the detection of Bence-Jones protein in urine. For the serial monitoring of response to chemotherapy in patients with myeloma. the assay correlated well with serum paraprotein estimates obtained by densitometric scanning of Ponceau stained cellulose acetate electrophoreses. but not with serum beta-2 microglobulin measurements. even after correction for the effects of creatinine. These assays may prove to be of use for the monitoring of tumour response in the treatment of Bence-Jones myeloma.
Short-term antibiotic treatment in Whipple's disease, We report the results of short-term antibiotic treatment in 19 patients with Whipple's disease (WD). The diagnosis was based on clinical features and on a characteristic small bowel biopsy. Patients received treatment for a mean of 7.9 weeks (range 4-20). Fourteen were treated with de-methyl-chlortetracycline (600 mg/day). and 1 also received chloramphenicol (1 g/day); 1 was treated with ampicillin (2 g/day). and 4 were treated with amoxicillin (1.5 g/day). In all patients. the clinical response was rapid and excellent. body weight increased significantly. diarrhea subsided. and fecal fat values returned to normal. Intestinal biopsies obtained after treatment was completed showed significant improvement based on a decrease in the number of macrophages staining positive with periodic acid-Schiff (PAS). normalization of villous structure. and decreased dilatation of lymphatic channels; free bacilli were absent. as shown both by light and electron microscopy. Seventeen patients have been followed for a mean of 99.4 months (range 6-300). Two died 30 and 72 months after diagnosis of Whipple's disease. 1 of laryngeal carcinoma and the other of colonic carcinoma. Fifteen patients are in excellent health. Three patients treated with tetracycline have had clinical and/or histologic relapses. In our experience. short-course antibiotic treatment with tetracycline or ampicillin and derivatives can be effective in WD. with few relapses and excellent outcome. No neurologic symptoms. either initially or during follow-up were observed.
Classification of amyloidosis by the detection of clonal excess of plasma cells in the bone marrow, In 28 cases of amyloidosis. bone marrow was examined to determine whether detection of clonal excess of plasma cells could be used to distinguish immunoglobulin-derived amyloidosis from other forms of amyloidosis. Patients were selected from a group of 315 cases of biopsy-proved amyloidosis in which bone marrow aspiration and biopsy had been done. There was no detectable monoclonal immunoglobulin in the serum or in the urine in 28 patients. Of 13 patients with immunoglobulin-derived amyloidosis. a clonal excess of plasma cells in the bone marrow could be detected in 11 (sensitivity. 85%). even though no immunoglobulin could be found circulating in the serum or urine after immunofixation with two light chain antisera of different sources. The 15 remaining patients had other forms of amyloidosis; 14 had polyclonal populations of plasma cells in the bone marrow (specificity. 93%). The positive predictive value of clonal excess was 92% and its negative predictive value was 88%. We conclude that. in the subset of patients with amyloidosis who do not have a circulating M component in the serum or urine detection of a clonal excess of plasma cells is useful in characterizing the type of amyloidosis. Correct classification is important for appropriate assessment of prognosis and therapy for the group of patients.
Abnormal tubular handling of sodium and water induced by atrial natriuretic peptide in essential hypertension, Atrial natriuretic peptide (ANP) was given as an intravenous bolus injection (2.0 micrograms kg-1) to 12 essential hypertensive patients (EH) and 13 normotensive control subjects (C) in order to study the effect of ANP on renal glomerular and tubular function using the lithium clearance technique. Urinary sodium excretion (EH. + 370% vs. C. + 120%; P less than 0.001) and urine volume (EH. + 137% vs. C. + 62%; P less than 0.01) increased significantly more in EH than in controls after ANP injection. Glomerular filtration rate. renal plasma flow. and plasma concentrations of angiotensin II. aldosterone and arginine vasopressin remained almost unchanged after ANP injection. whereas the filtration fraction increased to the same extent in both groups. Both proximal (EH. - 15% vs. C. - 5%; P less than 0.01) and distal fractional reabsorption (EH. - 12% vs. C. - 5%; P less than 0.01) of sodium decreased more markedly after ANP in EH than in controls. The increase in plasma cGMP and urinary excretion of cGMP was the same in the two groups. Mean blood pressure decreased and heart rate increased to the same extent in both groups. It is concluded that the increase in urinary sodium excretion and urine volume induced by ANP bolus injection is exaggerated in EH due to a more pronounced reduction in the reabsorption of sodium and water in both the proximal and the distal tubule.
Increased amino acid transport into brain tumors measured by PET of L-(2-18F)fluorotyrosine, The uptake of L-(2-18F)fluorotyrosine (F-Tyr). a newly synthetized amino acid tracer. was studied in 15 patients with various brain tumors by dynamic PET. The higher F-Tyr accumulation in tumors (mean 27% above contralateral tissue) was associated with two-fold transport rates into tumors. while the rate constants describing irreversible incorporation were decreased. The increased F-Tyr transport was not correlated to 68Ga-EDTA accumulation and cannot be explained by disruption of the blood-brain barrier. Kinetic analysis of 2-(18F)-fluoro-deoxy-glucose accumulation in the same patients demonstrated that increased metabolic rates in tumors are mainly caused by altered phosphorylation rates while transport of glucose is less affected. Since F-Tyr transport rates clearly separated tumors from normal tissue and since F-Tyr accumulation was related to tumor grade. PET studies of F-Tyr uptake are of clinical value for diagnosis and classification of brain tumors.
Multicenter controlled trial comparing high-frequency jet ventilation and conventional mechanical ventilation in newborn infants with pulmonary interstitial emphysema, One hundred forty-four newborn infants with pulmonary interstitial emphysema were stratified by weight and severity of illness. and randomly assigned to receive treatment with high-frequency jet ventilation (HFJV) or rapid-rate conventional mechanical ventilation (CV) with short inspiratory time. If criteria for treatment failure were met. crossover to the alternate ventilatory mode was permitted. Overall. 45 (61%) of 74 infants met treatment success criteria with HFJV compared with 26 (37%) of 70 treated with CV (p less than 0.01). Eighty-four percent of patients who crossed over from CV to HFJV initially responded to the new treatment. and 45% ultimately met success criteria on HFJV. In contrast. only 9% of those who crossed over from HFJV to CV responded well to CV (p less than 0.01). and the same 9% ultimately met success criteria (p less than 0.05). Therapy with HFJV resulted in improved ventilation at lower peak and mean airway pressures. as well as more rapid radiographic improvement of pulmonary interstitial emphysema. in comparison with rapid-rate CV. Survival by original assignment was identical. When survival resulting from rescue by the alternate therapy in crossover patients was excluded. the survival rate was 64.9% for HFJV. compared with 47.1% for CV (p less than 0.05). The incidence of chronic lung disease. intraventricular hemorrhage. patent ductus arteriosus. airway obstruction. and new air leak was similar in both groups. We conclude that HFJV. as used in this study. is safe and is more effective than rapid-rate CV in the treatment of newborn infants with pulmonary interstitial emphysema.
High-dose chemotherapy with reinfusion of purged autologous bone marrow following dose-intense induction as initial therapy for metastatic breast cancer, We assessed the toxicity and efficacy of high-dose chemotherapy consolidation with reinfusion of purged autologous bone marrow in women with metastatic breast cancer responding to a dose-intense outpatient regimen. Thirty women with hormone-unresponsive metastatic breast cancer. previously untreated with adjuvant doxorubicin or with any chemotherapy for metastatic disease. were treated with cyclophosphamide. methotrexate. doxorubicin. fluorouracil. vincristine. and leucovorin for 16 weeks. Twenty-four patients responded to therapy; 8 showed a complete response. and 16 showed a partial response. These patients proceeded to the next phase of the protocol. ie. marrow harvest and treatment with 6000 mg/m2 cyclophosphamide and 800 mg/m2 thiotepa given over 4 days. Harvested marrow was purged with 100 micrograms/mL 4-hydroperoxycyclophosphamide. and all patients engrafted satisfactorily. The predominant side effects were myelosuppressive and gastrointestinal. and there were no deaths from toxic effects. Three of the 16 patients who showed a partial response after the outpatient phase of treatment achieved a complete response after high-dose therapy. The partial response seen in two more patients converted to a complete response at all sites except bone. The median time to disease progression for all patients in this study was 13 months. and the median survival was 22 months. Four of the original 30 patients remained without disease progression a median of 27 months from entry into the study. This study indicates that this dose-intense regimen can be safely administered. even with the use of purged marrow. with an acceptable toxicity profile. This approach results in a high response rate in women with metastatic breast cancer and could form the basis for a regimen to be tested in the high-risk adjuvant setting.
Changes in lipid environment decrease Na, K-ATPase activity in obstructive nephropathy, Unilateral ureteral obstruction markedly alters sodium and water reabsorption by the affected kidney. These abnormalities may be due. at least in part. to decreased Na.K-ATPase activity in various segments of the nephron during obstruction. The reason for this decreased activity has. however. remained speculative. The present study examines the potential mechanisms underlying the decreased Na.K-ATPase activity in obstruction. The Na.K-ATPase activity was markedly reduced in basolateral membrane vesicles prepared from the cortex of the obstructed kidney of rats with unilateral ureteric obstruction of 24 hours duration when compared to basolateral membrane vesicles from contralateral kidneys of the same rats or to basolateral membrane vesicles from kidneys of sham operated animals. However. no such difference was present three days post-release of unilateral ureteric obstruction. When basolateral membrane vesicles were incubated with sodium dodecyl sulphate to permeabilize the vesicles. no difference in the proportion of enzyme latency was detected between the basolateral membrane vesicles from obstructed kidneys and those from sham operated rats. Immunoblotting with antibodies to the alpha subunit of Na.K-ATPase revealed equal amounts of enzyme in the basolateral membrane vesicles from contralateral kidneys. obstructed kidneys and sham operated rats. When incubated with liposomes under conditions conducive to fusion and lipid exchange the activity of Na.K-ATPase in basolateral membrane vesicles from obstructed kidneys was reconstituted almost to normal levels. This increase in enzyme activity did not occur in basolateral membranes from contralateral kidneys or in membranes from kidneys of sham operated rats incubated in the same manner.
Prevention of vasospasm by clot removal and intrathecal bolus injection of tissue-type plasminogen activator: preliminary report, In this study. we evaluated the efficacy of postoperative intrathecal injections of tissue-type plasminogen activator (tPA) in preventing cerebral vasospasm in cases with a diffuse severe subarachnoid hemorrhage. All 10 cases were graded Group 3 according to the classification of Fisher and associates. and the CT number (Hounsfield number) of the subarachnoid clot was over 75. After clipping the aneurysm and removing the clot. three cisternal drainage catheters were inserted into both sylvian cisterns and the prepontine cistern. and continuous ventricular drainage was performed routinely. Postoperatively. tPA (0.5 mg/2.5 ml) was infused as a bolus into both basal cisterns and the lateral ventricle twice daily for about 6 days. Angiography and cerebral blood flow studies using single photon emission computed tomography were performed on Day 4 or 5 and between Days 7 and 10 after onset of the hemorrhage. To date. there have been no cases that have shown angiographic vasospasm or delayed ischemic neurological deficits. This preliminary study indicates that the intrathecal bolus injection of tPA produces a marked effect on vasospasm.
An open trial of OKT3 in patients with multiple sclerosis, We report our experience with treatment with Muromonab-CD3 (Orthoclone OKT3) of 16 patients with multiple sclerosis (MS) who were in a progressive phase of their disease (n = 13) or in an acute severe attack lasting longer than 1 month without recovery (n = 3). We induced acute severe T-cytopenia with OKT3. Fifteen patients completed treatment for 10 days. Side effects were common and severe and included hypotension. nausea and vomiting. diarrhea. fever. and myalgia. In two of two patients tested. there was a transient though major rise in the levels of interferon gamma and tumor necrosis factor in the first 12 hours of treatment. Nonetheless. we did not detect new clinical or MRI activity of MS during the period of treatment. although many patients deteriorated transiently in disability scores. At the conclusion of follow-up. only four patients had deteriorated by 1.0 or more points on the Expanded Disability Status Scale of Kurtzke (EDSS) (73% stabilization rate). Of those patients who deteriorated. two died of complications of MS (EDSS 10). Only two patients had clinical improvement at 1 year follow-up. The attendant toxicity of OKT3 makes it unlikely that it will play a major role in the treatment of MS.
Adjunctive leuprolide therapy does not improve cycle fecundity in controlled ovarian hyperstimulation and intrauterine insemination of subfertile women, Problems arising from controlled ovarian hyperstimulation for intrauterine insemination. such as premature luteinization and asynchronous ovarian follicular development. are identical to those encountered with controlled ovarian hyperstimulation for in vitro fertilization (IVF) and gamete intrafallopian transfer (GIFT). It has been suggested that the adjunctive use of GnRH agonists for controlled ovarian hyperstimulation improves the efficiency of GIFT and IVF cycles. We hypothesized that adjunctive use of leuprolide acetate. a GnRH agonist. would have a similarly beneficial effect on cycle quality and cycle fecundity in subfertile women treated with controlled ovarian hyperstimulation and intrauterine insemination. We randomly assigned the first cycle of controlled ovarian hyperstimulation and intrauterine insemination for each of 97 subfertile women to include either human menopausal gonadotropins (hMGs) alone or hMGs following midluteal pre-treatment with leuprolide. If a pregnancy did not occur in the first cycle. the woman was given the other treatment in the second cycle. Although the cycles that included leuprolide required a larger amount of hMGs and more days of stimulation per cycle. the mean estradiol concentrations and numbers of follicles were not different. Despite prevention of premature luteinization with leuprolide. the cycle fecundity was not different between groups (0.11 with adjunctive leuprolide treatment and 0.22 with hMGs alone). We conclude that in unselected subfertile patients. the adjunctive use of leuprolide for controlled ovarian hyperstimulation and intrauterine insemination does not improve cycle fecundity compared with treatment cycles that do not include adjunctive leuprolide therapy.
Proteinase trapping: screening for viral proteinase mutants by alpha complementation, Many virally encoded proteinases cleave themselves out of a polyprotein. with cleavage occurring usually at their own N terminus. This property was used to develop an in vivo screening system using the lacZ gene fragment of M13mp18. When a fusion protein of the alpha fragment of beta-galactosidase and an active 2A proteinase of human rhinovirus 2 was expressed. alpha complementation was not affected. as the 2A proteinase cleaved itself off the alpha fragment. However. fusion of an inactive 2A prevented alpha complementation. as the 2A polypeptide remained fused to the alpha fragment. After random mutation of the 2A gene by PCR amplification. mutants were screened; M13 phage defective in alpha complementation were obtained at an efficiency of 5% and were shown to contain mutated 2A genes. Intermolecular cleavage was then examined by expressing an alpha fragment-inactive proteinase fusion protein as substrate for an active 2A proteinase expressed from an M13 vector. alpha complementation indicated intermolecular processing of the 2A cleavage site on the alpha fragment-inactive proteinase fusion protein. This versatile system thus allows the high-density screening of both active and inactive proteinase mutants. cleaving either intramolecularly or intermolecularly. and should be applicable to other proteinases of high specificity.
Molecular mimicry by Trypanosoma cruzi: the F1-160 epitope that mimics mammalian nerve can be mapped to a 12-amino acid peptide, Antigenic mimicry by Trypanosoma cruzi antigens that share epitopes with mammalian tissues may drive autoreactive B- or T-cell clones to expand and cause autoimmune pathogenesis. We have been studying one of these antigens. F1-160. a 160-kDa protein on the surface of T. cruzi that antigenically mimics a 48-kDa protein found in mammalian axonal and myenteric plexus cells. The F1-160 antigen has been characterized by cloning and expression of T. cruzi DNA encoding F1-160 in Escherichia coli. Recombinant peptides from various regions of the F1-160 gene were expressed and used to compete with affinity-purified polyclonal anti-F1-160 antibodies binding to nerve. Recombinant 48-amino acid peptide (48X) derived from expression of base pairs 611-761 of the DNA sequence completely inhibited anti-F1-160 binding to nerve. Recombinant peptides expressed from DNA lacking this region did not inhibit anti-F1-160 binding to nerve. Three peptides were synthesized to encompass the 48X peptide. a 12-amino acid peptide and two 18-amino acid peptides. The 12-amino acid peptide TPQRKTTEDRPQ (12X). corresponding to bases 615-651. completely inhibited the binding of anti-F1-160 antibodies to nerve at a concentration of 80 ng/ml (30 microM). The two 18-residue peptides did not inhibit. even at 10 micrograms/ml. Thus. the epitope of F1-160 crossreactive with nervous tissue can be mapped to a 12-amino acid peptide. Some humans with T. cruzi infection make antibodies to F1-160 and to the 48X and 12X peptides. Control sera from uninfected persons did not react with these antigens. Anti-48X antibodies. immunoselected from human serum with 48X peptide. bind to human nerve axons. This demonstrates that some individuals infected with T. cruzi make antibodies to the F1-160 epitope crossreactive with nervous tissues.
C terminus of the small GTP-binding protein smg p25A contains two geranylgeranylated cysteine residues and a methyl ester, smg p25A. also known as the rab3A protein. is a small GTP-binding protein that has been implicated in intracellular vesicle transport and the secretion of neurotransmitters. It has been shown to bind reversibly to membranes. though its cDNA-predicted sequence contains no obvious membrane-binding domains. However. smg p25A does contain a cDNA-predicted C-terminal Cys-Ala-Cys sequence at positions 218 through 220. which suggests that it may be posttranslationally modified. In the present study we used two different approaches to investigate this possibility. First. we incubated pheochromocytoma cells with [3H]mevalonolactone. examined the proteins that became labeled by two-dimensional gel electrophoresis. and demonstrated that two of these proteins exactly corresponded to smg p25A. Second. we purified smg p25A from bovine brain membranes and analyzed both the full-length protein and a proteolytically derived C-terminal peptide by a combination of high performance liquid chromatography and mass spectrometry. This approach revealed that the protein's C-terminal region is methyl-esterified and contains two geranylgeranyl groups linked via thioether bonds to Cys-218 and Cys-220. Since smg p25A is one of several small GTP-binding proteins that share a C-terminal Cys-Xaa-Cys consensus sequence (where Xaa is an unspecified amino acid). our results suggest that these proteins may be similarly geranylgeranylated and methyl-esterified.
Comparative rates of desensitization of beta-adrenergic receptors by the beta-adrenergic receptor kinase and the cyclic AMP-dependent protein kinase, Three separate processes may contribute to rapid beta-adrenergic receptor desensitization: functional uncoupling from the stimulatory guanine nucleotide-binding protein Gs. mediated by phosphorylation of the receptors by two distinct kinases. the specific beta-adrenergic receptor kinase (beta ARK) and the cyclic AMP-dependent protein kinase A (PKA). as well as a spatial uncoupling via sequestration of the receptors away from the cell surface. To evaluate the relative importance and potential role of the various processes in different physiological situations. a kinetic analysis of these three mechanisms was performed in permeabilized A431 epidermoid carcinoma cells. To allow a separate analysis of each mechanism. inhibitors of the various desensitization mechanisms were used: heparin to inhibit beta ARK. the PKA inhibitor peptide PKI to inhibit PKA. and concanavalin A treatment to prevent sequestration. Isoproterenol-induced phosphorylation of beta 2 receptors in these cells by beta ARK occurred with a t1/2 of less than 20 sec. whereas phosphorylation by PKA had a t1/2 of about 2 min. Similarly. beta ARK-mediated desensitization of the receptors proceeded with a t1/2 of less than 15 sec. and PKA-mediated desensitization with a t1/2 of about 3.5 min. Maximal desensitization mediated by the two kinases corresponded to a reduction of the signal-transduction capacity of the receptor/adenylyl cyclase system by about 60% in the case of beta ARK and by about 40% in the case of PKA. Receptor sequestration was much slower (t1/2 of about 10 min) and involved no more than 30% of the cell surface receptors. It is concluded that beta ARK-mediated phosphorylation is the most rapid and quantitatively most important factor contributing to the rapid desensitization. This rapidity of the beta ARK-mediated mechanism makes it particularly well suited to regulate beta-adrenergic receptor function in rapidly changing environments such as the synaptic cleft.
In vitro and in vivo evaluation of Ro 09-1428, a new parenteral cephalosporin with high antipseudomonal activity, Ro 09-1428. a new parenteral cephalosporin with a catechol moiety attached at position 7 of the cephalosporin ring. showed high in vitro activity against Escherichia coli. Klebsiella pneumoniae. Proteus mirabilis. Proteus vulgaris. and Streptococcus pyogenes. with MICs for 90% of strains tested (MIC90s) of less than or equal to 0.39 micrograms/ml. Morganella morganii. Providencia rettgeri. Citrobacter freundii. Haemophilus influenzae. Staphylococcus aureus. and Streptococcus pneumoniae were inhibited with MIC90s of less than or equal to 3.13 micrograms/ml. Serratia marcescens was less susceptible to Ro 09-1428. with a MIC90 of 25 micrograms/ml. The most distinctive feature of Ro 09-1428 was its potent activity against Pseudomonas aeruginosa and Acinetobacter calcoaceticus. with MIC90s of 0.39 and 6.25 micrograms/ml. respectively. Most of the ceftazidime-resistant strains of P. aeruginosa. E. cloacae. and C. freundii were inhibited by Ro 09-1428. while those of S. marcescens were resistant at a concentration of 12.5 micrograms/ml. Ro 09-1428 was more active than ceftazidime against staphylococci. PBP 3 was the most sensitive target in E. coli and P. aeruginosa. The response to ferric iron in growth medium suggests that Ro 09-1428 may be taken up by transport mechanisms similar to those of other catechol cephalosporins. In accordance with its in vitro activity. Ro 09-1428 activity was equal to or greater than ceftazidime activity in efficacy against experimental septicemias in mice. The results indicate that Ro 09-1428 is a broad-spectrum cephalosporin with advantages over ceftazidime in its activity against P. aeruginosa. staphylococci. and ceftazidime-resistant strains of C. freundii and E. cloacae.
Comparative activity of cefepime, alone and in combination, against clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients, The comparative in vitro activity and synergy of cefepime were evaluated with clinical isolates of Pseudomonas aeruginosa and Pseudomonas cepacia from cystic fibrosis patients. The activity of cefepime. both alone and in combination. was comparable to those of other antibiotics. The clinical efficacy of cefepime in cystic fibrosis patients merits investigation.
Altered stores of atrial natriuretic peptide in specific brain nuclei of NaCl-sensitive spontaneously hypertensive rats, Previous studies from our laboratories have demonstrated a selective increase in stores of atrial natriuretic peptide (ANP) in the anterior hypothalamus of NaCl-sensitive spontaneously hypertensive rats (SHR-S) compared to NaCl-resistant Wistar-Kyoto (WKY) controls and have suggested that anterior hypothalamic ANP contributes to the pathogenesis of NaCl-sensitive hypertension in SHR-S by local inhibition of norepinephrine release. We have also observed blunting of cardiopulmonary and arterial baroreflex function in SHR-S compared to WKY. In the current study. ANP stores in 12 brain nuclei thought to participate in the pathogenesis of hypertension. including locus coeruleus (LC). A1/C1 area (A1/C1). nucleus tractus solitarii (NTS). medial preoptic nucleus (MPON). suprachiasmatic nucleus (SCN). supraoptic nucleus (SON). anterior hypothalamic area (AHA). paraventricular hypothalamic nucleus (PVN). ventromedial hypothalamic nucleus (VMN). dorsomedial hypothalamic nucleus (DMN). lateral hypothalamic nucleus (LN). and posterior hypothalamic area (PHA). were compared in 10-week-old male SHR-S and WKY rats following 3 weeks of 1% v 8% NaCl feeding. Individual brain nuclei were obtained by the micropunch technique and ANP content of bilateral brain nuclei from individual rats was measured by radioimmunoassay. ANP content was significantly decreased in NTS and LC and elevated in AHA of SHR-S compared to WKY rats on either diet. Dietary NaCl supplementation was associated with increased ANP content in PVN of both strains. These alterations in ANP content in SHR-S may be related to the reduced release of norepinephrine from nerve terminals in AHA and to the presumed central defect in baroreceptor function.
Effects of atriopeptidase inhibitor UK 79300 on left ventricular hydraulic load in patients with congestive heart failure, We investigated effects of the first orally active atriopeptidase inhibitor UK 79300 (Pfizer Clinical Research. UK) on left ventricular hydraulic load in patients with congestive heart failure NYHA II and III. In our study. 6 patients received 200 mg and 4 patients received 400 mg of UK 79300. and 4 patients received placebo (controls). Before and 90 min after oral administration of UK 79300 or placebo aortic input impedance was assessed to characterize left ventricular hydraulic load. Plasma levels of atrial natriuretic peptide (ANP) significantly increased by 126% after 200 mg and by 141% after 400 mg of UK 79300. but remained unchanged in control patients. Mean arterial pressure and flow. resistive term. characteristic impedance and oscillatory aortic input pressure power showed minor changes without statistical significance on an intergroup comparison. We conclude that acute atriopeptidase inhibition by UK 79300 effectively increases endogenous ANP levels up to 2.5-fold. However. these changes were not accompanied by significant effects on left ventricular hydraulic load.
Curdlan sulfate and HIV-1. I. In vitro inhibitory effects of curdlan sulfate on HIV-1 infection, Action mechanisms of a newly synthesized polysaccharide. curdlan sulfate (CRDS). on human immunodeficiency virus type 1 (HIV-1) infection were investigated in vitro using syncytium formation microassay and p24 antigen capture enzyme-linked immunosorbent assay. These assays measured the titer of infectious virions and the amounts of HIV-1 core antigen p24 in soluble. intraviral. and intracellular forms. CRDS treatments were performed for 1 h at 37 degrees C. H9 cells pretreated with 0.1 to 100.0 micrograms/ml of CRDS appreciably inhibited HIV-1 infection. CRDS-treated HIV-1 virions were less able to infect H9 cells than untreated virions. The simultaneous treatment of H9 cells and HIV-1 virions with CRDS induced a significant inhibition of HIV-1 infection. resulting in the temporary disappearance of virions at the highest dose of CRDS. In contrast. CRDS treatment of newly HIV-1-infected H9 cells caused a significant decrease in the titer of infectious HIV-1 and the p24 amounts of all three forms. but no absolute elimination. Taken together. these results indicate that CRDS may block the binding of the HIV-1 envelope to the H9 cell surface. with emphasis on the high affinity of CRDS to the HIV-1 envelope.
Gene rearrangement in B- and T-lymphoproliferative disease detected by the polymerase chain reaction, Gene rearrangement and monoclonality have been detected in normal cells and in lymphoproliferative disease by using the polymerase chain reaction and primers for the V and J regions of the Ig heavy chain gene or T-cell receptor gamma-chain gene. Using the Ig primers monoclonality was detected in 20 of 20 normal B-lymphocyte clones and in 39 of 52 cases of various types of B-lymphoproliferative disease. but not in 11 cases of T-lymphoproliferative disease. Using the T-cell receptor primers. monoclonality was detected in 186 of 192 normal T-lymphocyte clones. in 11 of 11 cases of T-lymphoproliferative disease. in 9 of 12 cases of B-acute lymphocytic leukemia. and in 1 of 21 cases of B-non-Hodgkin's lymphoma. but not in nine cases of B-chronic lymphocytic leukemia nor in 10 cases of myeloma. Monoclonality was detected in material obtained by lymph node aspiration in four of six additional cases of non-Hodgkin's lymphoma. It was not detected in 10 cases of acute myeloid leukemia nor in four cases of reactive lymphadenopathy. Detection of gene rearrangement by the polymerase chain reaction has a number of advantages over Southern blotting and is likely to become the initial diagnostic technique of choice to detect monoclonality.
Regulation of jun-B expression by a cyclic AMP (cAMP)-dependent mechanism in human myeloid cells, The present studies have examined the regulation of the jun-B early response gene by cyclic AMP (cAMP)-dependent signaling pathways. The 2.0-kb jun-B transcript was at low but detectable levels in uninduced human HL-60 myeloid leukemia cells. In contrast. treatment with 1 mmol/L8-bromo-adenosine 3'.5'-cyclic monophosphate (8-Br-cAMP) in the presence of isobutylmethylxanthine. an inhibitor of cAMP-dependent phosphodiesterase. was associated with increases in jun-B transcripts that were maximal by 1 hour and then decreased to near pretreatment levels by 6 hours. Similar findings were obtained with 8-(4-chlorophenylthio)-adenosine 3'.5'-cyclic monophosphate (8-CPT-cAMP) and N6.2'-0-dibutyryladenosine 3'.5'-cyclic monophosphate (dBt-cAMP). jun-B transcripts were also increased with other agents that increase intracellular cAMP levels. such as prostaglandin E2 (PGE2) and forskolin. Moreover. inhibition of cAMP-dependent protein kinase by the isoquinolinesulfonamide H-8 blocked 8-Br-cAMP-induced increases in jun-B expression. The results of nuclear run-on assays demonstrate that treatment of HL-60 cells with PGE2. forskolin. 8-Br-cAMP. and dBt-cAMP is associated with increases in the rate of jun-B transcription. The present findings also demonstrate that the related jun-D gene is similarly regulated by a cAMP-dependent pathway. Taken together. these findings suggest that stimulation of cAMP-dependent protein kinase is involved in the induction of jun gene expression in myeloid leukemia cells.
Hepatitis C infection in children with hemophilia A and B, Antibodies to hepatitis C virus (anti-HCV) were quantitated in stored sera from selected groups of hemophilic children (less than or equal to 18 years of age). During the period 1987 to 1989. seropositivity rates were as follows: untransfused hemophiliacs 0% (0 of 11 cases). hemophiliacs treated exclusively with vapor-heated factor VIII or IX concentrates 0% (0 of 9 cases). hemophiliacs treated only with cryoprecipitate or single donor blood products 0% (0 of 9 cases). and hemophiliacs regularly treated with unheated or dry heat-treated factor VIII or IX concentrates 95% (21 of 22 cases). Corresponding alanine aminotransferase (ALT) results were similar: values were always below the upper limit of laboratory normal (40 U/L) in untransfused hemophiliacs. hemophiliacs treated with vapor-heated factor concentrates. or those who received only cryoprecipitate or single donor blood products. By contrast ALT values were greater than 40 U/L in 82% (18 of 22 cases) of hemophilic children regularly infused with unheated or dry heat-treated factor concentrates. Three conclusions are drawn from this data: (1) HCV is a major cause of chronic hepatitis in multitransfused hemophilic children. (2) unheated and dry heat-treated clotting factor concentrates carry a very high risk of transmitting HCV infection. and (3) clotting factor concentrates inactivated by vapor heating carry a very low and perhaps zero risk of transmitting HCV infection. These findings are of therapeutic significance for previously untransfused hemophiliacs susceptible to HCV infection.
The interaction of plasminogen activator inhibitor 1 with plasminogen activators (tissue-type and urokinase-type) and fibrin: localization of interaction sites and physiologic relevance, Plasminogen activator inhibitor 1 (PAI-1). an essential regulatory protein of the fibrinolytic system. harbors interaction sites for plasminogen activators (tissue-type [t-PA] and urokinase-type [u-PA]) and for fibrin. In this study. anti-PAI-1 monoclonal antibodies (MoAbs) were used to identify interaction sites of PAI-1 with these components. The binding sites of 18 different MoAbs were established and are located on five distinct "linear" areas of PAI-1. MoAbs. binding to two distinct areas of PAI-1. are able to prevent the inhibition of t-PA by PAI-1. In addition. two interaction sites for fibrin were identified on PAI-1. The area located between amino acids 110 and 145 of PAI-1 contains a binding site for both components and its significance is discussed in the context of the t-PA inhibition by fibrin-bound PAI-1. Subsequently. the MoAbs were used to assess the role of platelet-PAI-1 in clot-lysis. An in vitro clot-lysis system was used to demonstrate that clot-lysis resistance is dependent on the presence of activated platelets and that PAI-1 is a major determinant for lysis-resistance. We propose that. upon activation of platelets. PAI-1 is fixed within the clot by binding to fibrin and retains its full capacity to inhibit t-PA and u-PA.
Evidence of activation of the protein C pathway during acute vascular damage induced by Mediterranean spotted fever, Mediterranean spotted fever (MSF) is a rickettsiosis that induces widespread microvascular injury. To obtain quantitative information on the in vivo activation and inactivation of the protein C system during the acute phase of endothelial damage. several components of the protein C pathway were studied in 28 MSF patients. Upon admission (day 1). patients showed clear evidence of endothelial damage as reflected by the significant decrease in the ratio VIII:C/vWF:Ag (0.36 +/- 0.14. mean +/- SD) compared with normals (0.98 +/- 0.14). and clinical and laboratory signs of hemostatic alterations such as decreased platelet count. positive fibrinogen/fibrin degradation products. and increased thrombin:antithrombin-III complex levels. Antigenic protein C (72% +/- 18%) and protein C inhibitor (PCI) (41% +/- 20%) were significantly decreased (P less than .001). Complexes of activated protein C (APC) with PCI or with alpha 1-antitrypsin (alpha 1AT) and of plasma kallikrein with PCI (KK:PCI) were measured using sandwich enzyme-linked immunosorbent assays. APC:alpha 1AT complex levels were increased in patients at day 1 (27 +/- 13 ng/mL) compared with controls (7 +/- 2 ng/mL). and APC:PCI and KK:PCI complexes. which were not detectable in any of the controls. were present in 57% and 75% of the 28 MSF patients. with mean levels of 11 +/- 5 and 46 +/- 16 ng/mL. respectively. After remission of the disease (day 30). a trend toward normal values in the majority of the parameters studied was found. This study shows that. in the course of endothelial injury. MSF patients experience a generalized activation of the protein C pathway. resulting in consumption of protein C and PCI. and in the appearance of APC:inhibitor complexes. Moreover. these data provide the evidence that KK:PCI circulating complexes occur in vivo.
Effects of urokinase receptor occupancy on plasmin generation and proteolysis of basement membrane by human tumor cells, The goal of the present study was to assess the relative importance of receptor-bound and secreted plasminogen activator urokinase (u-PA) in generating cell-surface plasmin and fostering destruction of normal tissue by tumor cells. We first showed that active site-inhibited u-PA could displace endogenous u-PA from the surface of the human colon adenocarcinoma cell line HCT 116. We then prepared expression vectors for u-PA and for a mutant molecule in which the codon for the active site serine residue was changed to encode alanine. Expression of non-functional mutant u-PA decreased the level of cell-bound active u-PA by more than 95% via a mechanism that involved competition for receptor sites. Decreased cell-surface u-PA activity was associated with a decrease in cell-bound plasmin activity to undetectable levels. suggesting that receptor-bound u-PA plays an important role in the generation of plasmin on the cell surface. Transfectants that secreted eightfold to 20-fold elevated levels of active wild-type u-PA showed approximately 50% increases in cell-associated u-PA and only twofold to fourfold increases in cell-associated plasmin. suggesting that the role of secreted u-PA in generating cell-surface plasmin activity was relatively minor. In parent cells and both types of transfectants there was a good correlation between the amount of plasmin bound to the tumor cell surface and the extent to which a basement membrane substrate was degraded. These studies show that receptor-bound u-PA provides an efficient mechanism for plasmin generation on the surface of tumor cells. which. in turn. contributes significantly to their degradative potential.
Interferon-alpha overrides the deficient adhesion of chronic myeloid leukemia primitive progenitor cells to bone marrow stromal cells, Primitive blast colony-forming cells (BI-CFC) from chronic myeloid leukemia (CML) patients are defective in their attachment to bone marrow-derived stromal cells compared with normal BI-CFC. We investigated the effect of recombinant interferon-alpha 2a (IFN-alpha) on this interaction between hematopoietic progenitor cells and bone marrow-derived stromal cells by culturing normal stromal cells with IFN-alpha (50 to 5.000 U/mL). At 50 U/mL we found that: (1) the capacity of stromal cells to bind two types of CML primitive progenitor cells (BI-CFC and long-term culture-initiating cells) was increased; and (2) the amount of sulfated glycosaminoglycans (GAGs) in the stromal layer was increased. However. sulfated GAGs were not directly involved in binding CML BI-CFC. unlike binding by normal BI-CFC. which is sulfated GAG-dependent. Neuraminidase-treated control stromal cells bound an increased number of CML BI-CFC. reproducing the effect of IFN-alpha. whereas the binding to IFN-alpha-treated stromal cells was unaffected by neuraminidase treatment. Thus. the enhanced attachment by primitive CML progenitor cells to INF-alpha-treated stromal cells might be due to changes in the neuraminic acid composition in the stromal cell layer. Our in vitro evidence may provide insights into the mechanism of action of IFN-alpha in vivo. Prolonged administration may alter the marrow microenvironment in some patients such that it can restrain the aberrant proliferation of Philadelphia chromosome (Ph)-positive stem cells while permitting Ph-negative stem cells to function normally.
High-dose melphalan with 6-hydroxydopamine-purged autologous bone marrow transplantation for poor-risk neuroblastoma, Long-term results are presented of 28 patients who were diagnosed with neuroblastoma at more than 12 months of age and who received melphalan 180 mg/m2 (n = 6) or 240 mg/m2 (n = 22) to consolidate remissions of Stage IV disease or to control refractory disease. Twenty-four patients also received dianhydrogalactitol 180 to 240 mg/m2. and 11 received total body irradiation 450 to 600 cGy. Autologous bone marrow transplantation (ABMT) was performed with marrow that was unpurged (n = 2) or purged ex vivo (n = 26) with 6-hydroxydopamine (6-OHDA) 20 micrograms/ml plus ascorbate 200 micrograms/ml. The median time to an absolute neutrophil count of 500/microliters was 21 days and to self-sustaining platelet counts more than 20.000/microliters. 28 days. One patient required infusion of unpurged reserve marrow. Two groups of patients underwent ABMT: (1) 17 patients (Group I) who were in first remission a median of 7 months after diagnosis; and (2) 11 patients (Group II) who had refractory disease or were in second remission. For Group I. event-free survival was 29% at 12 months and 6% at 24 months post-ABMT. All Group II patients died of disease or ABMT-related toxicity. Overall. of the 28 patients. one is a long-term relapse-free survivor; five died of ABMT-related toxicity; ten patients with tumors present at ABMT had progressive disease within 6 months of ABMT; and 12 patients with no measurable disease at ABMT relapsed 4 to 32 months (median. 12) post-ABMT. Among the latter. six relapses involved the primary site. and six were restricted to distant sites. These results--in accord with the long-term outcome in other series--suggest that for neuroblastoma high-dose melphalan cannot be relied on to ablate residual disease or to salvage patients with refractory tumors. In addition. the pattern of relapse in several patients could be explained by infusion of incompletely purged autografts; this would support recent laboratory evidence that 6-OHDA/ascorbate is a suboptimal purging method.
Demonstration of transient bacterobilia by foreign body implantation in feline biliary tract, The biliary tract of cats is known to be free of autochthonous bacteria above the sphincter of Oddi. In this experiment we investigated whether transient bacterobilia occurs in the biliary system under normal conditions. Polyethylene tubes and human cholesterol stones were implanted surgically into the gallbladder of cats. Sham cholecystostomy was performed as control operation. These cats were euthanized at two. six. and 12 weeks. and the implants were removed. cultured. and studied by scanning electron microscopy (SEM). Cultures and SEM also were undertaken for material scraped from the mucosal surface of the biliary tract from these animals. Colonization of bacteria on the polyethylene tubes and the gallstones was found six and 12 weeks after implantation. Adherent bacterial biofilms were demonstrated on the surfaces of these implants. This experiment showed that transient bacterobilia exists in the feline biliary tract. The foreign body implants have facilitated the adhesion of planktonic bacteria in the bile onto their surfaces and have initiated the formation of adherent biofilms within which these bacteria persisted until the system was sampled.
Immaturity and aneuploidy in human oocytes after different stimulation protocols, OBJECTIVE: To study immaturity and aneuploidy in human oocytes after two different stimulation protocols. DESIGN: Retrospective. SETTING: Outpatient IVF clinic/laboratory. PATIENTS: One hundred forty-three patients of whom 65 were stimulated with clomiphene citrate (CC)/human menopausal gonadotropin (hMG) and 78 were stimulated with gonadotropin-releasing hormone agonist (GnRH-a)/hMG. Only patients with at least one oocyte unfertilized were included in this study. RESULTS: Stimulation with GnRH-a/hMG. as compared with CC/hMG stimulation. resulted in larger numbers of oocytes (P less than 0.00001). a higher fertilization rate (P less than 0.02). and oocyte retrieval at a later average cycle day (P less than 0.000005). Cytogenetic findings of immaturity were observed in 33.9% of unfertilized oocytes after CC/hMG stimulation. compared with only 17.8% after GnRH-a/hMG stimulation (P less than 0.0005). Aneuploidy findings were the same for both groups. CONCLUSION: In GnRH-a/hMG stimulation. oocytes approach the normal day of ovulation more closely. This may allow for better oocyte maturation and higher fertilization and pregnancy rates.
Subcutaneous gonadotropin therapy in male patients with hypogonadotropic hypogonadism, OBJECTIVE: The response to subcutaneous (SC) gonadotropin replacement therapy. using human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) or hCG alone. was evaluated in male hypothalamic hypogonadism. DESIGN: Sixteen patients with hypothalamic hypogonadism were treated with gonadotropins for induction of puberty and normalization of spermatogenesis. The results were analyzed retrospectively. SETTING: The study was carried out in a clinical endocrinology department providing tertiary care and in private practices of endocrinology. PATIENTS: Eight patients with idiopathic hypogonadotropic hypogonadism and eight patients with Kallmann's syndrome in prepubertal or early pubertal stages. INTERVENTIONS: Human chorionic gonadotropin and hMG were administered SC in individual dosages. MAIN OUTCOME MEASURES: Increase of serum testosterone (T). testicular volume. semen volume. and sperm count were evaluated. RESULTS: Normalization of serum T and complete sexual maturation was achieved in all patients. Spermatogenesis was induced in all but two patients. Seven patients showed normal findings in semen volume and sperm count. and two patients had semen quality close to normal. In five patients sperm count remained less than 10 x 10(6)/mL. CONCLUSIONS: The results obtained by SC gonadotropin replacement prove this mode of administration to be effective in stimulating steroidogenesis and spermatogenesis in hypogonadotropic males.
Flow characteristics of enteral feeding with psyllium hydrophilic mucilloid added, One therapy for managing diarrhea in patients in intensive care units who are receiving enteral nutrition is administration of psyllium hydrophilic mucilloid (PHM). This laboratory study was conducted to determine whether the addition of PHM (Metamucil) to enteral feeding formula (Entrition) adversely affected the flow characteristics of the feeding formula through a small-bore feeding tube. Descriptive data were obtained from 72 trials of feeding formula with varied infusion rates. formula osmolality and temperature. and PHM concentrations. Two thirds (n = 48) of the trials were successful (PHM did not clog the tubing and obstruct flow). The remaining one third of the trials (n = 24) were unsuccessful. Successful formula infusion was influenced by formula temperature and osmolality but not by infusion rate. PHM concentration. or flow interruption. If formula with PHM was followed by formula without PHM. the infusion was successful regardless of infusion rate or formula osmolality. Thus. the data from this laboratory study indicate that when therapeutic doses of PHM are prescribed. it is feasible for PHM to be mixed in room-temperature feeding formula and infused without clogging the feeding tube.
Rapid infusion of Sandoglobulin in patients with primary humoral immunodeficiency, We studied 16 patients with primary disorders of humoral immunity to determine the practicality of infusing intravenous gamma globulin at rates of infusion and concentrations higher than the 4 mg/kg/min and 6% currently recommended. In the first portion of the study. the concentration of Sandoglobulin was increased from 6% to 12%. In the second portion. the flow rate was increased to 5 mg/kg/min. and if no reactions occurred. the time of each successive infusion was decreased by 10 minutes until infusions were completed in 15 to 20 minutes or vasomotor reactions occurred. Thirteen of the 16 patients completed the study; six patients achieved reaction-free rates greater than 15 mg/kg/min. and the other patients achieved rates ranging from 7.1 to 12 mg/kg/min. Seven patients had infusion times less than 30 minutes. with four patients completing infusions in 15 minutes. In the 13 patients who completed the study. there were 14 reactions in 159 infusions. mostly fever and chills. and often at the end or after the infusion. Only one infusion could not be completed because of an adverse reaction. Three patients were not able to complete the study because of adverse reactions; there were seven reactions in 11 infusions in these three patients. although none of the reactions were considered serious. Overall. in this study. most immunodeficient patients (13/16) were able to tolerate infusion rates of Sandoglobulin two to 10 times higher than the standard rates now recommended. The maximal rate of infusion must be individualized. but for carefully selected patients. infusions of 400 mg/kg can be completed in 1 hour or less.
Abnormal thymocyte development and production of autoreactive T cells in T cell receptor transgenic autoimmune mice, Development of a C57BL/6-+/+ TCR transgenic mouse containing the rearranged TCR alpha- and beta-chain specific for the Db + HY male Ag results in production of a nearly monoclonal population of early thymocytes expressing the Db + HY reactive TCR. These thymocytes are autoreactive in H-2Db male mice and undergo clonal deletion and down-regulation of CD8. To study the effect of the lpr gene on development of autoreactive T cells. these transgenic mice were backcrossed with C57BL/6-lpr/lpr mice. T cell populations in the thymus and spleen were analyzed by three-color flow cytometry for expression of CD4. CD8. and TCR. The thymus of TCR transgenic H-2b/b lpr/lpr male mice had an increase in percent and absolute number of CD8dull thymocytes compared to TCR transgenic H-2b/b +/+ male mice. However. there was not a complete defect in clonal deletion. because clonal deletion and down-regulation of CD8 was apparent in both +/+ and lpr/lpr H-2Db HY+ male mice compared to H-2Db HY- female mice. The phenotype of splenic T cells was almost identical in TCR transgenic +/+ and lpr/lpr males with about 50% CD4-CD8- T cells and 50% CD8+ T cells. However. there was a dramatic increase in the SMLR proliferative response of splenic T cells from TCR transgenic lpr/lpr males compared to TCR transgenic +/+ males. To determine the specificity of this response. spleen cells from TCR transgenic lpr/lpr and +/+ mice were cultured with irradiated H-2b/b and H-2k/k male and female spleen cells. T cells from TCR transgenic C57BL/6-lpr/lpr male mice had an increased proliferative response to H-2b/b male spleen cells compared to T cells from TCR transgenic C57BL/6(-)+/+ male mice. but both lpr/lpr and +/+ mice had a minimal response to irradiated H-2b/b female or H-2k/k male or female stimulator cells. The splenic T cells from TCR transgenic lpr/lpr mice also had an increased specific cytotoxic activity against H-2b/b male target cells compared to TCR transgenic +/+ mice. These results demonstrate that there is a defect in negative selection of self-reactive T cells in the thymus of lpr/lpr mice and a defect in induction or maintenance of clonal anergy of self-reactive T cells in the periphery of lpr/lpr mice.
Hydrocortisone inhibits rat basophilic leukemia cell mediator release induced by neutrophil-derived histamine releasing activity as well as by anti-IgE, We determined the ability of hydrocortisone to inhibit rat basophilic leukemia cell mediator release induced by anti-IgE and by neutrophil-derived histamine-releasing activity (HRA-N). Serotonin release induced by HRA-N and anti-IgE was inhibited by 78 +/- 5 and 70 +/- 4%. respectively (IC50 7.5 x 10(-7)M) by hydrocortisone (10(-5)M). HRA-N does not cause arachidonic acid metabolism. however. anti-IgE induced the generation of PGD2 and leukotriene (LT)C4. and the generation of both mediators was inhibited by 10(-5)M hydrocortisone (IC50 = 4.8 x 10(-7)M. and 3.6 x 10(-9)M. respectively). Inhibition required at least 5 to 6 h of hydrocortisone exposure and was maximal after 22 h. The observed effects of hydrocortisone could be reproduced by human recombinant lipocortin-I (5 x 10(-7)M). Hydrocortisone. 10(-5)M. was a less potent inhibitor of calcium ionophore A23187-mediated serotonin release and PGD2 and LTC4 generation (inhibition of 20 +/- 2. 17 +/- 10. and 37 +/- 10%. respectively). Inasmuch as A23187-induced stimulation is not dependent on receptor coupling. the enhanced ability of hydrocortisone to inhibit IgE- and HRA-N-mediated events as compared with A23187 suggests that one possible site of action of hydrocortisone may be interruption of receptor-effector signals. In the presence of arachidonic acid. hydrocortisone-treated cells released as much LTB4 and PGD2 as control cells. however. serotonin release and LTC4 generation were inhibited 50 and 55%. respectively. Thus. these data suggest that hydrocortisone has three possible sites of action: 1) inhibition of phospholipase A2 activity. 2) inhibition of glutathione-s-transferase. and 3) inhibition of serotonin release by a third mechanism. possibly by interrupting the coupling of receptor and effector systems.
Chimeric gamma-delta signal joints. Implications for the mechanism and regulation of T cell receptor gene rearrangement, Rearrangement of Ag receptor genes requires recognition by the lymphocyte recombinase of heptamer-nonamer signal sequences followed by two endonucleolytic cleavages and two DNA ligations to form the coding and signal joints. The phenomenon of trans-rearrangement. in which Ag receptor gene segments located on different chromosomes recombine to yield chimeric products. provides an in vivo system in which to investigate the ability of the recombinase to carry out each of these functions in trans. Trans-rearrangements between TCRG and TCRD loci. similar in structure and frequency to those observed previously in human lymphoid tissues. were demonstrated in normal mouse thymus by PCR with crossed V gamma/J delta and V delta/J gamma primer pairs. A simple mechanistic model for trans-rearrangement was then tested. This model posits an ability of the recombinase to catalyze the formation of both coding and signal joints in trans and therefore predicts that trans-rearrangements will generate chimeric signal joints. In adult thymus. chimeric D delta 2-J gamma 1 and D delta 2-J gamma 2 signal joints. containing fused heptamer-nonamer sequences. could be detected by PCR and were each present at frequencies sufficient to account for a large proportion of the corresponding TCRG/TCRD trans-rearrangements. In agreement with the predictions of the model. chimeric signal joints were found as both linear chromosomal and circular episomal DNA. The results provide a framework for understanding the formation of chromosomal translocations in normal and neoplastic lymphoid cells and support the possibility of a looping mechanism for standard gene rearrangement. To test the form of regulation of TCRG rearrangement. the frequencies of specific signal joints from standard and trans-rearrangements were compared. Although J gamma 1 and J gamma 2 segments participated with equal frequency in trans-rearrangement with D delta 2. only the J gamma 1 segment participated in standard rearrangement with V gamma 5. The results suggest that V-J recombination in the TCRG locus is regulated directly at the DNA level by cis-acting constraints which do not affect the accessibility of individual TCRG gene segments to recombination in trans.
Expression of c-jun, jun-B, and c-fos proto-oncogenes in human primary melanocytes and metastatic melanomas, Analysis of the regulation of c-jun. jun-B. and c-fos RNA transcript expression was performed in human primary melanocytes and metastatic melanoma cell strains. The medium requirements for human melanocyte in vitro growth are phorbol esters. agents that elevate intracellular cAMP levels. hormones. and growth factors. Cellular jun. jun-B. and c-fos gene expression are known to be affected by growth promoting agents. In primary melanocytes. the expression of c-jun. jun-B. and c-fos RNA transcripts was dependent on the growth-promoting agents present in the medium. Uniformly high c-jun. jun-B. and c-fos RNA transcript levels were observed in melanocytes cultivated in complete medium. Higher levels of c-jun RNA transcripts and low levels of c-fos RNA transcripts were observed in melanocytes cultivated in plain medium. In contrast. a range of c-jun. jun-B. and c-fos RNA transcript levels was detected in metastatic melanoma cell strains cultivated in medium with or without serum. In general. an increase in jun-B and c-fos RNA transcript expression and a decrease in c-jun RNA transcript expression was observed in metastatic melanomas compared to neonatal melanocytes. These data suggest a potential role for c-jun. jun-B. and c-fos genes in the transformation of melanocytes to malignant melanoma.
Rh isoimmunization complicating a triplet gestation. A case report, A case occurred of Rh isoimmunization complicating a triplet gestation. Management of that extremely rare situation required careful attention to the problems inherent in both multiple pregnancy and isoimmunization. Amniocentesis and frequent antepartum fetal monitoring were the cornerstones of therapy.
Hemodynamic and metabolic effects of aortic unclamping following emergency surgery for traumatic thoracic aortic tear in shunted and unshunted patients, Nine cases of traumatic aortic tear treated during 1986-1987 were reviewed. Two patients had functioning Gott shunts. six patients had simple crossclamp. and one patient had a Gott shunt placed which was nonfunctional. Anesthetic management was similar in all patients. Clamp times ranged in unshunted patients from 25 to 38 minutes. and in shunted patients from 42 to 50 minutes. The crossclamp time of the patient with the nonfunctional shunt was 42 minutes. Declamping was accompanied in unshunted patients by decreases in core temperature of up to 1 degree C and acute decreases in PaO2. Marked respiratory and metabolic acidosis occurred with declamping. Respiratory acidosis resolved within 30 minutes with hyperventilation. but metabolic acidosis persisted despite bicarbonate therapy (mean = 1.2 mEq/kg) up to 6 hours after declamping. Associated elevations in serum potassium resolved as pH returned to baseline. Acid-base and electrolyte abnormalities were less marked in patients who were shunted.
A triazolodiazepine platelet activating factor receptor antagonist (WEB 2086) reduces pulmonary dysfunction during endotoxin shock in swine, We wanted to determine the effects of WEB 2086. a platelet activating factor (PAF) antagonist. in lipopolysaccharide (LPS) shock in anesthetized pigs. In a randomized study. LPS from S. abortus equi. 2 micrograms/kg/h was given IV for six hours. Thirteen animals received LPS and WEB 2086. 10 mg/kg/h IV for 6.5 hours. beginning 30 minutes before LPS. Eleven septic controls received saline and LPS. three nonseptic controls received saline and WEB 2086. and three nonseptic controls received saline only. In six animals we investigated the effect of synthetic PAF in doses between 50 and 10.000 ng on arterial (AP) and pulmonary arterial (PAP) pressure before and during infusion of WEB 2086. The LPS-induced rise in PAP was reduced by WEB 2086 (p = 0.01) but not the decrease in AP. The LPS-induced leukopenia. hypoxia. increase in airway pressure. and release of plasminogen activator inhibitor were reduced by WEB 2086. Platelet activating factor produced an increase in PAP and a biphasic response in AP. All PAF dose response curves were shifted to the right by WEB 2086. Platelet activating factor was a pulmonary hypertensive agent and contributed to the LPS-induced respiratory alterations.
Structural measures as predictors of injury basketball players, The purpose of this study was to investigate the relationship between structure and injury in basketball players. with the goal of developing equations to predict injury. We examined 45 subjects who were participating in a community center basketball league. Each subject was measured prior to the season for bilateral weight. quadricep girth. calf girth. Q-angle of the knee. dorsiflexion of the ankle. forefoot varus. rearfoot valgus. and true and apparent leg length. All lower extremity injuries causing a game to be missed were recorded during the 16-game season. Average values for bilateral weight. quadricep girth. Q-angle. rearfoot valgus. and leg length measures for the injured players were all larger than the average for the non-injured players by at least one standard deviation. A logistic regression equation using three of the variables correctly predicted the injury status of 91% of the players. The three-variable equation was then used prospectively to predict injury status for members of a small college basketball team. Only one player missed a game due to injury. and the equation identified that player as the most likely to be injured. This study demonstrates a strong relationship between structural measures and lower extremity injury in basketball players.
Infection control of parenteral nutrition solutions, Microbial contamination of parenteral nutrition solutions is a preventable cause of in patients receiving nutrition support. The components of the parenteral nutrition solutions have variable microbial growth potential. Crystalline amino acid and dextrose solutions are poor growth media for bacteria but may support fungal growth. Lipid emulsions provide an excellent medium for growth of bacteria and fungal species. Total nutrient admixtures will support microbial growth better than standard parenteral nutrition solutions will but less well than will lipid emulsion alone. Control of infection related to contaminated infusate depends on compounding procedure. quality control. appropriate storage. and procedures to prevent in-use contamination. Guidelines are presented for the preparation and administration of parenteral nutrition infusates that will minimize microbial contamination.
Catheter infection control in parenteral nutrition, Catheter sepsis rates related to total parenteral nutrition are variable and depend on several patient-specific factors. These factors include the presence of immunosuppression or critical illness. the use of multiple intravascular catheters. and bacterial translocation. Catheter-related sepsis may present in the patient as fever. chills. change in mental status. hypotension. and leukocytosis. In patients with suspected catheter-related infection whose peripheral blood cultures do not grow the same organism as a blood culture drawn from the catheter. a guidewire exchange of the catheter has been shown to be effective. This technique should be considered a surgical procedure. Complications that are associated with guidewire exchange of central venous catheters are catheter malposition. embolism of air or septic thrombi. and cardiac arrhythmias.
Cerebral hemorrhagic risk of aspirin or heparin therapy with thrombolytic treatment in rabbits, We studied the incidence of cerebral hemorrhage in an animal model of embolic stroke to determine the safety of aspirin. heparin. and tissue plasminogen activator therapies. We occluded the middle cerebral arteries of rabbits with labeled blood clots and administered either tissue plasminogen activator. heparin. aspirin. tissue plasminogen activator plus aspirin. tissue plasminogen activator plus heparin. or saline at various times after stroke. Compared to saline controls. both the aspirin-only and the tissue plasminogen activator-plus-aspirin groups had a significantly higher incidence of cerebral hemorrhage. whereas the heparin and tissue plasminogen activator combination groups did not. We conclude that aspirin antiplatelet therapy alone may increase the risk of hemorrhagic infarction. whereas heparin or tissue plasminogen activator therapy appears to be relatively safe.
Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats, Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle. low-dose (375 mg/kg) dimethylthiourea. high-dose (750 mg/kg) dimethylthiourea. low-dose (0.5 mg/kg) MK-801. high-dose (2.0 mg/kg) MK-801. or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia. brain water content was determined. In eight vehicle-treated controls. mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example. 50.2% (p less than 0.001) in the high-dose dimethylthiourea group. 53.7% (p less than 0.001) in the low-dose MK-801 group. and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.
Short-bowel syndrome in children. Quality of life in an era of improved survival, A number of disorders in childhood can result in short-bowel syndrome (small bowel length. less than 100 cm). Improved care has increased survival in patients with short-bowel syndrome. but the quality-of-life factors associated with such improved survival have not been examined. to our knowledge. Sixteen consecutive pediatric patients with short-bowel syndrome (bowel length range. 22 to 98 cm) were followed up for 2 to 10 years. The original diagnoses were as follows: necrotizing enterocolitis (n = 6). multiple intestinal atresias (n = 4). extensive aganglionosis (n = 2). meconium peritonitis (n = 2). and midgut volvulus (n = 2). The range of initial hospitalization was from 62 to 395 days. and 13 of 16 patients have required readmission (two to 14 times). All patients required multiple operations (range. two to 14 operations). including combinations of venous access. adhesiolysis. tapering enteroplasty. reversed intestinal segments. and pull-through procedure. Nine of 16 patients received home total parenteral nutrition. and 12 of 16 patients required home elemental diets. usually via pump feedings. Fifteen patients (94%) survived. Two survivors are deaf. and one of these has mild developmental delay. Seven survivors (age range. 6 to 10 years) attend a regular school. four while receiving total parenteral nutrition or an elemental diet. Ten of 15 survivors are off all nutritional support (including the child with a 22-cm small bowel). with four others weaning. The presence or absence of an ileocecal valve did not affect outcome. Modern nutritional support methods provide excellent survival and quality of life for children with short-bowel syndrome.
Serum sulfate concentration and the anion gap in hemodialysis patients, First-of-the-month predialysis serum sulfate (SO4) and other blood chemistry values were measured prospectively for 5 to 7 months in 14 patients undergoing single pass chronic tri-weekly maintenance hemodialysis with bicarbonate dialysate. Blood was also obtained predialysis and again immediately postdialysis from seven patients (five of whom also participated in the chronic study). As expected. the patients manifested a high anion gap (AG) metabolic acidosis. Serum SO4 was only moderately stable from month to month (the average coefficient of variation was 0.30; correlation between the serum SO4 value of month one and months two and five were r = 0.59. p = 0.026; and r = 0.38. p = 0.182. respectively). The ratio of mean serum SO4 to mean AG (5.0 +/- 0.4 [SE] mEq/L divided by 19.1 +/- 0.5 mEq/L) was 0.26. Although there was a statistically significant correlation between the serum SO4 and the blood urea nitrogen (BUN). there was no such correlation between SO4 and AG. A single hemodialysis reduced serum SO4 by 54% (from 3.5 +/- 0.5 mEq/L to 1.6 +/- 0.1 mEq/L). but there was no correlation between the change in SO4 and the change in AG. The authors concluded that SO4 contributes importantly to the elevated AG in patients receiving chronic hemodialysis. Single pass bicarbonate hemodialysis temporarily reduces. but does not normalize. both the serum SO4 and the AG of such patients.
Unusual presentation of extranodal peripheral T-cell lymphomas with multiple paraneoplastic features, Three patients with extranodal peripheral T-cell lymphoma and a distinctive clinical presentation are described. They had acute onset of fever. weight loss. progressive liver failure. bleeding diathesis. pancytopenia. and myelodysplastic changes in the bone marrow. Each patient had one or more paraneoplastic complications: severe rhabdomyolysis with myoglobinuria and secondary renal failure. cutaneous vasculitis. gluten-sensitive enteropathy. polyserositis. and increased macrophages with hemophagocytic activity. They did not have peripheral lymphadenopathy. The complex clinical presentations simulated collagen vascular disorders. systemic infections. or severe liver disease rather than a malignant lymphoma. Routine histologic studies revealed a small population of lymphoma cells in the bone marrow. spleen. and liver. Immunophenotyping studies demonstrated their T-cell phenotype. and cytogenetic analysis showed the clonality in Patients 1 and 2; clonal T-cell receptor gene rearrangement was found in Patients 2 and 3. These studies should be considered in the evaluation of patients with constitutional symptoms. liver failure. coagulopathy. and pancytopenia even in the absence of peripheral lymphadenopathy.
Vasoactive hormones in uremic patients on continuous ambulatory peritoneal dialysis, Plasma levels of atrial natriuretic peptide (ANP). renin activity (PRA). and endothelin (ET) are often elevated in uremic patients on hemodialysis treatment. The profile of these vasoactive hormones and their relationships with hemodynamic indices in patients on continuous ambulatory peritoneal dialysis (CAPD). however. are not clear. We therefore measured plasma concentrations of ANP. PRA. ET. together with parathyroid hormone (PTH) in 17 patients (mean age 38.5 years) on maintenance CAPD over a period of 12 weeks. Baseline ANP. PRA. and ET levels were significantly higher than those of healthy subjects. and no significant changes in these indices were observed over the 12 week period. There was a significant positive correlation between levels of plasma ANP and PRA [rank correlation coefficient. R(s) = 0.496. p less than 0.05] as has been reported in cardiac failure. Despite the absence of clinically overt heart failure. a significant proportion (approximately 50%) of our patients demonstrated evidence of myocardial dysfunction on echocardiography. Furthermore. a significant positive correlation was demonstrated between plasma ANP and left atrial size [R(s) = 0.61. p less than 0.01] and an inverse correlation existed between plasma ANP and the left ventricular ejection fraction [R(s) = 0.51. p less than 0.05]. Twelve patients (71%) had biochemical evidence of hyperparathyroidism with raised levels of serum PTH. Our study demonstrates increased levels of plasma ANP. PRA. and ET in uremic patients on long-term CAPD. A positive correlation exists between plasma ANP and PRA suggesting their myocardial function may be compromised and this was confirmed on echocardiography. The possibility that high circulating PTH concentrations contribute to impaired cardiac function in such patients. deserves further study.
Plasma levels of an endogenous Na(+)-K+ pump inhibitor in relation to haemodynamic data in cardiopathic patients, 1. Despite the fact that numerous studies provide evidence for the existence of an endogenous inhibitor of the cell membrane Na(+)-K+ pump in plasma. little is known about the relationships between this factor and the main haemodynamic parameters. 2. In order to shed some light on this. we attempted to correlate haemodynamic parameters. measured during heart catheterization in a group of 22 cardiopathic subjects. with plasma digitalis-like activity levels. determined by two different procedures. 3. The ability of plasma to inhibit a human renal Na(+)-K(+)-ATPase showed an inverse correlation with cardiac index and a direct correlation with peripheral resistance. Plasma cross-reactivity with digoxin antibodies correlated directly with left atrial pressure. 4. These results furnish confirmation of a number of theoretical assumptions which attribute to the digitalis-like factor the ability to modify the contractility of the cardiovascular system.
Cost-effectiveness of antihypertensive treatment. General considerations, Cost-effectiveness analysis. a set of methods for estimating the costs and health effects of medical interventions. helps decision makers to compare alternative treatments and to decide which interventions are appropriate in which situations. This article outlines some fundamental principles of cost-effectiveness analysis and discusses the characteristics necessary if alternative therapies are to be more cost-effective than traditional drug treatment for hypertension. The discussion focuses primarily on the newer drugs like angiotensin converting enzyme inhibitors. alpha-adrenergic receptor blockers. and calcium antagonists.
Cost and quality trade-offs in the treatment of hypertension, The cost-effectiveness of treatment for hypertension is positively related to the level of pretreatment blood pressure and to the level of success in achieving patient adherence to prescribed medical regimens. Opportunities to improve the cost-effectiveness of treatment include limiting treatment to patients with well-documented sustained increases in blood pressure. giving higher priority to the treatment of patients with diastolic blood pressures of 100 mm Hg and above. and relying on lower-cost medications if clinical responses to treatment permit. In patients with mild hypertension. a comparison of strategies for initiating pharmacological treatment that takes into account potential side effects as well as the costs of medications indicates a difference of $270/patient-yr between the least and most expensive alternatives. Whether the additional costs of more expensive treatment strategies are "worth it" depend on any additional health benefits actually conferred. Moreover. higher-cost strategies may have negative influences on patients' decisions to adhere to prescribed regimens or to continue in treatment. Cost is a particular problem for the treatment of chronic conditions like hypertension because of inadequate insurance coverage for medications. especially for the poor.
Nucleotide deletion resulting in frameshift as a possible cause of complete thyroxine-binding globulin deficiency in six Japanese families, Complete T4-binding globulin deficiency (TBG-CD) is inherited in an X-linked fashion. A nucleotide substitution has been shown to cause this hereditary condition in caucasians of French Canadian origin. Heterogeneity in molecular mechanisms for TBG-CD has also been reported. Genomic DNA from a Japanese male exhibiting TBG-CD was subjected to polymerase chain reaction. and the generated DNA fragments were sequenced. A single nucleotide deletion was found in the first base of the codon for amino acid 352 of the common-type TBG molecule. This mutation causes a frameshift in translation and premature termination. Compared with common-type TBG. the mutated polypeptide results in 1) 22 different amino acids on its carboxy-terminus. 2) a 22-amino acid truncation. and 3) the absence of a potential N-linked glycosylation site. These alterations may lead to profound changes in the secondary and tertiary structures of the molecule. To ascertain the presence of this nucleotide deletion in the genomic DNA of affected subjects. a mutated primer was designed which together with the nucleotide deletion produced a new endonuclease restriction site in the polymerase chain reaction fragment. Results revealed the presence of the mutation in genomic DNA of the subject. and his mother was shown to have both mutant and normal alleles. The same mutation was also detected in five other unrelated families carrying TBG-CD. This mutation may be frequent in Japanese subjects with TBG-CD.
Comparison of transdermal to oral estradiol administration on hormonal and hepatic parameters in women with premature ovarian failure, Five women with premature ovarian failure were studied in a randomized cross-over design to compare the biochemical effects of transdermal to oral estradiol administration when used in doses appropriate for endometrial preparation in a donor oocyte program. Patients randomly received increasing dosages of oral micronized or transdermal estradiol for 4 week. with progesterone added in the last 2 weeks. to mimic a normal hormonal cycle. Serum samples were assayed throughout treatment and compared to those from normally cycling premenopausal controls. In general. serum estradiol remained within the normal range in both treatment groups. whereas peak serum estrone levels were 10-fold higher in the orally treated group than those in the transdermally treated group. Serum levels of sex hormone-binding globulin. thyroid binding globulin. and renin substrate were all significantly elevated by day 14 in the orally treated patients and unchanged in the transdermal subjects. While plasminogen was unaltered by either route of administration. antithrombin-III levels fell with both treatments. Changes in gonadotropin levels were similar in both groups. with suppression of FSH by the end of the simulated cycles. but not into the normal premenopausal range. In conclusion. both estrogen replacement regimens provided near-normal serum estradiol profiles. However. despite the relatively high doses necessary to mimic a hormonally normal cycle. the transdermal route did not significantly alter the hepatic parameters studied. suggesting that this route of administration may have less adverse hepatic effects.
Increased induction of HLA-DR by interferon-gamma in cultured fibroblasts derived from patients with Graves' ophthalmopathy and pretibial dermopathy, We investigated the effects of several cytokines on HLA-DR expression in cultured fibroblasts derived from retroocular connective tissue and pretibial and abdominal skin of patients with Graves' ophthalmopathy (GO) and pretibial dermopathy (PTD). as well as from normal individuals. We hypothesized that differences in response to cytokines between fibroblasts from various anatomical areas might play a role in the site-selective involvement of the extrathyroidal manifestations of Graves' disease. HLA-DR expression in fibroblasts was quantitated by scanning densitometry of whole cell lysates subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting. Direct immunofluorescence of cell monolayers was also performed. We hypothesize that unique characteristics of these fibroblasts may play a role in GO and PTD. Cultured retroocular. pretibial. and abdominal fibroblasts from patients with Graves' disease as well as from normal individuals did not express HLA-DR spontaneously. Treatment in vitro with interferon-gamma (IFN gamma; 100 U/mL) for 5 days induced HLA-DR by 50- to 80-fold (P less than 0.0001) in fibroblasts from all sites and subjects studied. However. IFN gamma-induced HLA-DR expression was significantly greater in retroocular (P less than 0.005) and pretibial (P less than 0.0005) fibroblasts from patients with GO and PTD than in fibroblasts obtained from the same anatomical sites of normal individuals. Further. retroocular and pretibial fibroblasts from patients with GO and PTD responded to IFN gamma more vigorously than did abdominal fibroblasts from these same patients (P less than 0.0001). IFN gamma-induced HLA-DR expression was enhanced by concomitant treatment with tumor necrosis factor-alpha (100 U/mL). In contrast. treatment of retroocular fibroblasts with transforming growth factor-beta (10 ng/mL). epidermal growth factor (1 ng/mL). or interleukin-6 (IL-6; 100 U/mL) significantly attenuated IFN gamma-induced HLA-DR reactivity by 40-59% (P less than 0.05). Incubation of retroocular fibroblasts with tumor necrosis factor-alpha. IL-1 alpha (10 U/mL). IL-2 (10 U/mL). IL-6. granulocyte-macrophage colony-stimulating factor (100 U/mL). epidermal growth factor. and transforming growth factor-beta alone did not affect HLA-DR expression. These results indicate that several cytokines can influence HLA-DR expression in cultured fibroblasts. The enhanced induction of HLA-DR by IFN gamma in retroocular and pretibial fibroblasts compared with that in abdominal fibroblasts may partially explain the selective involvement of the retroocular connective tissue and pretibial skin in fully expressed Graves disease.
Alleviation of cocaine-induced coronary vasoconstriction by nitroglycerin, Cocaine induces vasoconstriction of epicardial coronary arteries in patients with and without coronary artery disease. and this vasoconstriction is particularly marked in segments narrowed by atherosclerosis. To assess the effect of nitroglycerin on cocaine-induced coronary vasoconstriction. computer-assisted quantitative analysis was performed on non-diseased and diseased coronary artery segments in 23 patients (18 men. 5 women. aged 43 to 65 years) 1) at baseline. 2) after administration of intranasal saline solution (in 8 patients) or 2 mg/kg of cocaine (in 15 patients). and then 3) after administration of sublingual placebo (in 6 patients) or 0.4 or 0.8 mg of nitroglycerin (in 9 patients) in the 15 patients given cocaine. In response to cocaine administration. coronary artery cross-sectional area decreased 22 +/- 7% (mean +/- SD) in non-diseased segments (p less than 0.05) and 45 +/- 18% in diseased segments (p less than 0.02). The magnitude of vasoconstriction was greater (p = 0.01) in the diseased segments. Sublingual nitroglycerin abolished the vasoconstriction in both non-diseased and diseased segments. Thus. nitroglycerin alleviates cocaine-induced vasoconstriction in patients with coronary artery disease.
Retrograde coronary venous administration of recombinant tissue-type plasminogen activator: a unique and effective approach to coronary artery thrombolysis, Recent studies of interventional therapy by way of the coronary venous system have demonstrated that it can protect acutely ischemic myocardium. To evaluate the efficacy of coronary venous retroinfusion compared with systemic intravenous administration of recombinant tissue-type plasminogen activator (rt-PA). 14 dogs were studied with a copper coil-induced thrombus in the left anterior descending coronary artery. The rt-PA (24.000 fluorescence units/kg) was administered continuously. either intravenously (n = 8) or retrogradely (n = 6). for 30 min beginning 60 min after coronary occlusion. Thrombolysis was determined by repetitive coronary angiography. All dogs were killed 3 h after termination of rt-PA infusion and infarct size was measured by the triphenyltetrazolium chloride staining technique. Complete thrombolysis occurred in five of the six dogs in the retroinfusion group and four of the eight dogs in the systemic intravenous infusion group. Partial lysis was achieved in two dogs treated by intravenous infusion. Lysis did not occur in one dog treated with retroinfusion and in two dogs treated with intravenous infusion. Time to thrombolysis was 13.4 +/- 2.3 min in the retroinfusion group versus 27.8 +/- 4.8 min in the intravenous group (p less than 0.001). Myocardial functional recovery in the ischemic zone measured by two-dimensional echocardiography 60 min after reperfusion was significant only in the retroinfusion group (p less than 0.05).
Meningococcal disease in the United States--1986. Meningococcal Disease Study Group, Active surveillance for invasive meningococcal disease was conducted during 1986 and 1987 in six areas of the United States with a total population of approximately 34 million persons. The incidence of meningococcal disease was 1.3:10(5). The highest incidence of disease among the surveillance areas was in Los Angeles County (1.65:10(5). Neisseria meningitidis serogroups B and C caused about equal amounts of disease. which reflects a recent increase in the incidence of group C disease. Group C caused more than half of the cases of meningococcal disease in Los Angeles and Tennessee but less than one-third of the cases in Missouri and Oklahoma. Multilocus enzyme electrophoresis demonstrated that a group of closely related isolates of N. meningitidis was prevalent in Los Angeles during the surveillance period and was associated with an increased incidence of meningococcal disease there.
Variation in class 5 protein expression by serogroup A meningococci during a meningitis epidemic, Serogroup A meningococci were isolated from patients and healthy carriers in The Gambia between 1982 and 1988. The class 5 proteins expressed by these bacteria were identified by electrophoretic migration and by serologic tests. Three protein serologic groupings (seroclasses) called A (protein 5a). B (proteins 5b. 5d. or 5e). and C (protein 5c or 5C) were found among 331 bacterial isolates. The number of class 5 proteins expressed per isolate varied from none to four. with a median of two. The class 5 protein composition differed for certain paired isolates obtained from the nasopharynx. blood. and cerebrospinal fluid of diseased patients and for certain pairs of sequential isolates from the nasopharynx of healthy carriers; the medical relevance of this variation remains unclear. although the 5C protein was preferentially isolated from the nasopharynx and the 5a protein from diseased patients. The data show that a large proportion of healthy carriers in The Gambia were exposed to bacteria expressing each of the three seroclasses and that many people were exposed to bacteria expressing each of the three seroclasses and that many people were exposed to two or all three seroclasses during the epidemic of 1982-1983.
Purine analogs as chemotherapeutic agents in leishmaniasis and American trypanosomiasis, The metabolic pathways for purines in parasitic protozoans differ significantly from the corresponding pathways in human beings. Leishmania and Trypanosoma cruzi have particular enzymatic reactions that have relevance for chemotherapy. Certain purine analogs are metabolized by the parasites to nucleotides and aminated to the analogs of adenine nucleotides. These halt protein synthesis and cause the break-down of RNA. The most important purine analogs with respect to chemotherapeutic potential are the pyrazolo [3.4-D]-pyrimidines. The prototype. allopurinol. is nontoxic to human beings and is aminated to adenine nucleotide analogs by the organism. Studies in vitro and in vivo have demonstrated its antiparasitic action and led to its development as a chemotherapeutic agent for diseases caused by these organisms. Clinical investigations now have demonstrated the therapeutic efficacy of allopurinol in cutaneous leishmaniasis caused by Leishmania braziliensis and in chronic Chagas' Disease.
Dichotic listening failure in dysphoric neuropsychiatric patients who endorse multiple seizure-like symptoms, In the present investigation. the dichotic word listening performance of a sample of 25 dysphoric neuropsychiatric patients who endorsed multiple partial seizure-like symptoms was compared with that of matched samples of normal controls and patients with mood disorders who did not endorse multiple seizure-like symptoms. Eighty percent of the patients who endorsed multiple episodic phenomena failed the dichotic listening task. compared with 8% of normal controls and 28% of patients with typical mood disorders. After treatment with carbamazepine. a subsample of polysymptomatic patients manifested significantly fewer seizure-like symptoms. This clinical improvement was typically associated with markedly improved dichotic listening performance in most cases. The results are consistent with our previous hypothesis that "subclinical" electrophysiological dysfunction may severely disrupt the normal transmission and processing of auditory information. Because it is sensitive to this type of presumed cerebral dysfunction and relatively specific. impaired dichotic listening performance is likely to be a useful clinical marker for this complex neuropsychiatric syndrome.
Stroke-like episodes in familial mitochondrial encephalomyopathy: clinical and biochemical aspects, Acute episodes of focal neurological dysfunction are a well-recognized complication of the mitochondrial encephalomyopathies. Because of rapid remission. biochemical tests and other diagnostic procedures are mostly performed after the acute phase. We report the case of a patient suffering from mitochondrial disease manifesting primarily with seizures. progressive deafness and dementia. who experienced multiple stroke-like episodes. Other members of the family with evidence of mitochondrial dysfunction are presented briefly. EEG and biochemical findings in the acute stage are correlated with clinical symptoms. showing characteristics distinct from the chronic illness. The possible involvement of dietary factors in the provocation of stroke-like episodes is discussed and regulation of glucose intake suggested as a strategy in the prevention of stroke-like episodes.
Modeling zidovudine therapy: a cost-effectiveness analysis, Zidovudine (ZDV). the first FDA-approved therapy for HIV/AIDS. poses a dilemma to the policymaker. On the one hand. ZDV extends the life of HIV-infected persons. producing a clear benefit. On the other hand. some fear that prolonging the lives of infected individuals may contribute to the increased spread of the virus and to a steep rise in the overall costs of AIDS to society. To address this issue. we present a simple model of ZDV therapy against a backdrop of HIV transmission in a population of sexually active. gay men. We find no basis for the fear of dramatic increases in the incidence of AIDS or its associated costs among gay men due to widespread ZDV distribution. On the contrary. our analysis suggests that ZDV therapy is cost-effective. particularly when it is accompanied by modest efforts to promote behavior change and prevention.
Therapeutic use of monoclonal anti-CD4 antibody in rheumatoid arthritis, Ten patients with severe rheumatoid arthritis were treated with a murine monoclonal anti-CD4 (B-F5) antibody in an open study (one with 10 mg/day. 2 with 15 mg/day. 7 with 20 mg/day) for 10 consecutive days. Tolerance was excellent. All patients improved during treatment clinically (Ritchie's index. morning stiffness. pain scale) (p = 0.005). as well as biologically C-reactive protein (p = 0.008) with an average 60% reduction of each of these variables at Day 15. and clinical benefit lasted over 6 months in some patients. No significative depletion was noted in total lymphocyte or CD3. CD4. CD8. CD20. positive cells after treatment. Evidence of murine immunization was found in only 2 patients.
Effect of interferon-gamma on B lymphocytes of patients with systemic lupus erythematosus, We studied the effect of interferon-gamma (IFN-gamma) on B cells in systemic lupus erythematosus (SLE). Low density B cells. which were fractionated on density gradients of Percoll. increased. and high density B cells decreased in number in SLE. Proliferative response of the high density B cells to interleukin 4 was reduced by IFN-gamma in normal controls. but not in SLE. IgG production of whole B cells induced by interleukin 2 or phytohemagglutinin induced T cell factors was enhanced by IFN-gamma in both normal controls and SLE in which activated B cells were thought to be increased in number. Therefore. IFN-gamma may be one of the factors which promote polyclonal B cell activation in SLE.
A novel autoantibody reactive with a 48 kDa tRNA associated protein in patients with scleroderma, We identify 4 patients with progressive systemic sclerosis (PSS) possessing a previously undescribed serum anti-tRNA Ab (anti-Wa antibody). These sera yielded identical precipitin lines under double immunodiffusion using calf thymus extract and supernatant of pig spleen homogenate as antigen sources. Furthermore. all 4 sera were found to react with a 48 kDa protein using immunoblotting. This protein was subsequently found to be associated with tRNA when immunoprecipitation was conducted. In a survey of autoimmune patients' sera. anti-Wa Ab was observed in 3% (4 of 130) of patients with PSS. but not in other systemic rheumatic diseases. None of the 4 patients with PSS with anti-Wa Ab had myositis except that one patient complained of mild myalgia.
Intestinal mucosal permeability in inflammatory rheumatic diseases. I. Role of antiinflammatory drugs, Using the 51Cr-EDTA resorption test. gut permeability was measured in 129 patients with inflammatory joint diseases and in 97 control patients (42 patients with no inflammatory rheumatic disorders taking antiinflammatory medication and 55 healthy controls). Thirty-two patients (30 arthritis and 2 control patients) taking nonsteroidal antiinflammatory drugs (NSAID) as well as corticosteroids were excluded from statistical analysis. The intake of NSAID significantly increased gut permeability in controls but not in the arthritis groups. The same applied to corticosteroid intake. This could be due to the restricted number of arthritis patients who had never taken antiinflammatory drugs or to a disease related increased permeability. There was no statistically significant difference in altered gut permeability between patients taking NSAID and patients taking corticosteroids. Our findings suggest that drug induced alteration of gut permeability may not only be accounted for by an inhibition of mucosal cyclooxygenase activity. but that other enzymatic pathways in the arachidonic cascade might be implicated.
Antigenicity and accessory cell function of human articular chondrocytes, It is postulated that chondrocytes may be actively involved in the pathogenesis of inflammatory joint diseases. presumably by providing tissue specific antigens that may initiate or sustain autoimmune reactions. To investigate whether chondrocytes may also function as accessory cells in ongoing immune processes. mixed leukocyte-chondrocyte cultures and antigen presentation assays were studied. Freshly isolated and short term cultured HLA class II antigen (Ia) negative as well as gamma-interferon treated Ia positive chondrocytes were weakly or not stimulatory to allogeneic or autologous resting lymphocytes derived from either normal donors or patients with rheumatoid arthritis. In an antigen presenting system using tetanus toxoid. the majority of chondrocyte preparations tested induced an antigen driven response in HLA matched allogeneic or autologous resting T cells which. however. was much less when compared to blood monocytes. In contrast. using activated T cells derived from tetanus toxoid specific T cell lines. an efficient antigen presenting capacity could be demonstrated in both Ia positive and initially Ia negative chondrocytes. Interestingly. the latter population had acquired Ia antigens upon incubation with the T cell line.
Perioperative total parenteral nutrition in surgical patients. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group, BACKGROUND. We undertook this study to test the hypothesis that perioperative total parenteral nutrition (TPN) decreases the incidence of serious complications after major abdominal or thoracic surgical procedures in malnourished patients. METHODS. We studied 395 malnourished patients (99 percent of them male) who required laparotomy or noncardiac thoracotomy. They were randomly assigned to receive either TPN for 7 to 15 days before surgery and 3 days afterward (the TPN group) or no perioperative TPN (the control group). The patients were monitored for complications for 90 days after surgery. RESULTS. The rates of major complications during the first 30 days after surgery in the two groups were similar (TPN group. 25.5 percent; control group. 24.6 percent). as were the overall 90-day mortality rates (13.4 percent and 10.5 percent. respectively). There were more infectious complications in the TPN group than in the controls (14.1 vs. 6.4 percent; P = 0.01; relative risk. 2.20; 95 percent confidence interval. 1.19 to 4.05). but slightly more noninfectious complications in the control group (16.7 vs. 22.2 percent; P = 0.20; relative risk. 0.75; 95 percent confidence interval. 0.50 to 1.13). The increased rate of infections was confined to patients categorized as either borderline or mildly malnourished. according to Subjective Global Assessment or an objective nutritional assessment. and these patients had no demonstrable benefit from TPN. In contrast. severely malnourished patients who received TPN had fewer noninfectious complications than controls (5 vs. 43 percent; P = 0.03; relative risk. 0.12; 95 percent confidence interval. 0.02 to 0.91). with no concomitant increase in infectious complications. CONCLUSIONS. The use of preoperative TPN should be limited to patients who are severely malnourished unless there are other specific indications.
Auditory screening of infants, Within the last 20 years. infant hearing screening has progressed from a laudable goal to a state-mandated reality in many areas of the United States. The high risk register provides a means by which history and neonatal physical examination can be used to identify the infant at risk for hearing loss. Two procedures (crib-O-gram and auditory brainstem-evoked response) have been the most common methods of screening for hearing loss in the newborn or in intensive care nurseries. Evoked cochlear emissions reportedly are identifiable in 90 to 100% of normal-hearing infants. This observation has lead to the use of evoked otoacoustic emissions as a hearing screening procedure with infants.
Maintenance of superior mesenteric arterial perfusion prevents increased intestinal mucosal permeability in endotoxic pigs, Lipopolysaccharide increases intestinal mucosal permeability to hydrophilic compounds such as chromium 51-labeled edetate (51Cr-EDTA). We sought to determine whether this phenomenon is partly mediated by lipopolysaccharide-induced mesenteric hypoperfusion. We assessed permeability in an isolated segment of ileum by measuring plasma-to-lumen clearances (C) for two probes. 51Cr-EDTA and urea. and expressing the results as a ratio (CEDTA/CUREA). In control pigs (n = 6) resuscitated with Ringer's lactate (RL). mucosal permeability was unchanged during the 210-minute period of observation. In pigs (n = 7) infused with lipopolysaccharide (50 micrograms/kg) and similarly resuscitated with RL. mesenteric perfusion (Qsma) decreased significantly and permeability increased progressively and significantly. When endotoxic pigs (n = 6) were resuscitated with a regimen (RL plus hetastarch plus dobutamine) that preserved normal Qsma. lipopolysaccharide-induced mucosal hyperpermeability was prevented. Resuscitation of endotoxic pigs (n = 6) with RL plus hetastarch provided intermediate protection against both mesenteric hypoperfusion and increased permeability. These data suggest that diminished Qsma contributes to impaired ileal mucosal barrier function in experimental endotoxicosis.
Oral-TPN-induced bacterial translocation and impaired immune defenses are reversed by refeeding, Although certain defined diets have been shown to promote bacterial translocation (BT). the ability to reverse diet-induced BT has not previously been investigated. Furthermore. little is known about the effects of defined diets on host immune defenses. To address these questions. we measured BT and immune reactivity in rats fed a normal diet or enteral elemental (ORAL-TPN) diet. After 7 days on the elemental or normal diet. the rats were killed. and BT and mitogen responsiveness to concanavalin A and phytohemagglutinin were measured. In separate experiments. the effects of these diets on in vivo host defenses was measured with a Staphylococcus aureus abscess model. Additional experiments were performed to determine the time required to reverse ORAL-TPN-induced BT and impairment of host immune defenses by reinstituting normal feedings. Administration of the ORAL-TPN diet for 7 days was associated with BT to the mesenteric lymph node complex of all animals. decreased blastogenic response of blood and splenic lymphocytes to mitogens. and decreased ability to control an in vivo infectious challenge with S. aureus. Each of the derangements was reversed by the reinstitution of normal feedings. In summary. the enteral administration of an elemental diet for 7 days is associated with disruption of the gut microflora. BT. and the development of an immunocompromised state. all of which can be reversed by refeeding the animals a normal diet.
Selective decontamination of the digestive tract: a stratified, randomized, prospective study in a mixed intensive care unit, To evaluate the use of selective decontamination of the digestive tract (SDD) (polymyxin. amphotericin. tobramycin. and intravenous cefotaxime) in a mixed intensive care unit. we performed a stratified. randomized. prospective study. The 331 patients were recruited over an 18-month period. with 256 patients remaining more than 48 hours. Stratification by acute physiology and chronic health evaluation (APACHE II) preceded randomization to control (standard antibiotic therapy) or treatment (SDD) groups. Nosocomial infection was significantly reduced in the SDD group (16.7%; 21 of 126 patients) compared with the control group (30.8%; 40 of 130 patients; p = 0.008). No difference was found in overall mortality rate or length of stay between the two groups. Those patients with admission APACHE II scores 10 to 19 demonstrated the most significant reduction in nosocomial infection (23 of 70 control vs 13 of 76 SDD; p = 0.03) and mortality (15 of 70 control vs 8 of 76 SDD; p = 0.07). Emergence of multiresistant microorganisms was not a clinical problem. but a definite change occurred in the ecology of environmental and colonizing bacteria. With the exception of cefotaxime. a reduction was noted in systemic antibiotic usage in the SDD group. We conclude that SDD is useful in selected patients in a mixed intensive care unit.
Immunosuppressive mechanisms in protein-calorie malnutrition, Protein-calorie malnutrition (PCM) induces immunosuppression leading to increased mortality rates. Impaired macrophage respiratory burst activity (superoxide anion [O2-] generation) occurs in PCM. but cellular mechanisms are unclear. The major pathway resulting in O2- production involves inositol lipid-dependent signal transduction. This study examined the effect of mild versus severe PCM on macrophage O2- generating signal transduction pathways specific for responses to Candida albicans. Mice (CFW/Swiss Webster: n = 300) were randomized to either control or low protein diets for 3 or 8 weeks. Peritoneal macrophages were harvested for O2- production. mannose-fucose receptor (MFR) expression. membrane phospholipid analysis. arachidonic acid (AA) content. prostaglandin E2 (PGE2) production. and protein kinase C levels. O2- release was impaired in both mild and severe PCM. MFR expression was also decreased at these time points. Inositol lipid content was significantly lower at the 8-week time point only. although PGE2 and AA were significantly higher in the low protein diet group at 3 weeks. Protein kinase C levels were unchanged by PCM. Thus. mild PCM significantly increases macrophage-PGE2 production secondary to increased AA phospholipid content. with subsequent inhibition of O2- and MFR expression. Severe PCM inhibits macrophage (O2-) through depletion of critical membrane phospholipid components with subsequent impairment in signal transduction.
Sepsis alters skeletal muscle energetics and membrane function, The effects of sepsis on skeletal muscle energetics and membrane function are poorly understood. and the time course of changes in energy metabolism are unclear. To clarify these relationships. high energy phosphate ratios. intracellular pH. and phosphocreatine breakdown rates were measured in vivo in the gastrocnemius muscle of adult male Wistar rats after cecal ligation and puncture or sham operation with 31P magnetic resonance spectroscopy. Adenosine triphosphate (ATP) concentration and Na(+)-K+ ATPase and creatine kinase activities were determined in vitro. Within 24 hours. Na(+)-K+ ATPase activity increased by 60% in rats with cecal ligation and puncture. all of which had positive bacterial cultures. as compared to none of the sham-operated controls. Phosphocreatine/ATP ratios decreased by 20% in association with a quantitatively similar increase in phosphocreatine breakdown (9.7 +/- 0.5 vs 11.9 +/- 0.5 mumoles/gm wet wt/sec; p = 0.01). ATP concentrations were maintained. and intracellular pH did not change significantly. In this model. changes in phosphocreatine breakdown were not related to total creatine kinase activity. which did not change significantly. or increases in adenosine 5'-diphosphate (ADP) concentration (62 +/- 8 vs 92 +/- 8 mumols/L; p = 0.02). Thus. in early sepsis before a measurable decrease in pH occurs. ATP is utilized at an increased rate to help maintain ionic balance and/or to support other metabolic processes. Phosphocreatine stores are used to buffer ATP concentrations.
Community acquired pneumonia: aetiology and prognostic index evaluation, A 10 month prospective study of all adults admitted to Waikato Hospital with community acquired pneumonia was performed to assess aetiology. mortality. hospital stay. and the value of a prognostic index based on that obtained from a British Thoracic Society study. The 92 patients in the survey had a mean age of 56 (range 13-97) years. A microbiological diagnosis was established in 72%; Streptococcus pneumoniae (33%). Mycoplasma pneumoniae (18%). and influenza A virus (8%) were the most common microorganisms. Other causative organisms were Legionella pneumophila (4 cases). Staphylococcus aureus (3). Klebsiella pneumoniae (2). Haemophilus influenzae (2). Nocardia brasiliensis (1). and Acinetobacter calcoaceticus (1). Chlamydia sp. influenza B virus and adenovirus were each found in one case; all were cultured on nasopharygeal aspirates. Aspiration was considered to be the underlying cause in five patients. two with epilepsy and one with pseudobulbar palsy. Five of the six deaths that occurred were in patients over 75 years of age and the other was 69. In four of the six the established causative organisms were Chlamydia sp (1). K pneumoniae (1). and S aureus (2). Patients had a 16 fold increased risk of death if they had two or more of the following on admission: a respiratory rate of 30/minute or more. diastolic blood pressure of 60 mm Hg or less. and either confusion or a plasma urea concentration greater than 7.0 mmol/l.
Indices of reperfusion in patients with acute myocardial infarction using characteristics of the CK-MB time-activity curve, The purpose of this study was to identify indices of coronary artery reperfusion in patients treated with thrombolytic therapy for acute myocardial infarction (AMI) by means of characteristics from the serum creatine kinase (CK) isoenzyme MB time-activity curve. Frequent blood sampling as performed in three groups with a first AMI: 29 patients treated with intravenous thrombolytic therapy who had a patent infarct-related artery with normal flow (TIMI-3) at acute catheterization (reperfusion group); four patients with a persistently closed infarct-related artery (no reperfusion group); and 44 patients who did not receive any therapy aimed at coronary reperfusion (no thrombolytic therapy group). In the latter group we prospectively estimated that 25% would have spontaneous reperfusion. A physiologically based computer-calculated multi-compartment method was used to determine the characteristics of the serum CK-MB time-activity curve. In addition to demonstrating an earlier increase. a shorter time to peak of serum CK-MB and a lower estimated infarct size in the reperfusion group (p = 0.025 to 0.00001). the appearance rate constant (k1) and time from estimated initial increase to peak of CK-MB in the blood stream (tRP) were significantly different from those values in the no thrombolytic therapy group (p less than 00001). A cutoff level indicating reperfusion if k1 was greater than 0.185 or tRP was less than 16.5 hours demonstrated overlapping values between these two groups in only four patients (k1). two patients (tRP). and six patients with a combination.
Effects of enoximone on exercise tolerance in patients with mild to moderate heart failure, To evaluate the efficacy of enoximone on exercise tolerance in patients with mild to moderate heart failure. 33 patients underwent cardiopulmonary exercise tests before and 3 hours after placebo or after receiving 25 or 100 mg of enoximone administered randomly in a double-blind manner. The electrocardiogram was monitored and blood pressure measured every minute throughout cycle ergometer exercise testing with a ramp protocol in which the work rate increased 1 W every 6 seconds after a 4-minute 20-W warm-up. Minute ventilation. oxygen uptake (VO2). and carbon dioxide output were measured every 10 seconds in order to determine anaerobic threshold (AT) and peak VO2. Five patients were excluded from evaluation before breaking the double-blind key because of insufficient data. Heart rate increased and systolic blood pressure decreased throughout the testing only in the group taking 100 mg (n = 10). Significant increases in AT (14.4 to 16.2 ml/min/kg) and peak VO2 (20.8 to 22.9 ml/min/kg) were observed in the group taking 100 mg. The increases in AT showed a dose response. namely +0.7% in the placebo (n = 9). +6.9% in the 25-mg (n = 9) and 12.5% in the 100-mg group. The work rates at the AT point increased in the 25- and 100-mg groups. These results indicate that a single oral administration of enoximone improves exercise tolerance in patients with mild to moderate heart failure.
Review of duodenal diverticula, Duodenal diverticula occur in 2-5% of patients undergoing barium studies of the upper intestinal tract. Duodenal diverticula are classified into two types: extraluminal or intraluminal. Usually of little clinical significance. they can cause obstruction. cholelithiasis. ascending cholangitis. ulcers. and hemorrhage. and may perforate. Associated intestinal tract malformations have been reported in 40% of patients with intraluminal duodenal diverticula. Diagnosis is made by endoscopy or upper gastrointestinal series. In symptomatic cases. extraluminal diverticula are amenable to surgery. whereas intraluminal diverticula may be either surgically or endoscopically resected. Imaging of the biliary tree should be performed prior to any intervention.
High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. The Swiss-Dutch J5 Immunoglobulin Study Group, PURPOSE AND PATIENTS: We measured the serum concentrations of interleukin-6 (IL-6) in 70 patients with established septic shock caused predominantly by gram-negative bacteria. The aims of the study were to determine whether and for how long IL-6 was detectable in the circulation of these patients. to assess whether IL-6 levels were associated with patients' outcomes. and. finally. to examine the interplay between IL-6. tumor necrosis factor (TNF). interleukin-1 beta (IL-1 beta). and interferon-gamma (IFN-gamma). RESULTS: IL-6 was detected in 64% of the patients at study entry but in only 18% on Day 1 and 2% on Day 10. Serum levels of IL-6 were higher (median: 3.5 ng/mL. range: less than 0.1 to 305 ng/mL) in patients dying of fulminant septic shock than in those surviving (median: 0.5 ng/mL. range: less than 0.1 to 135 ng/mL; p = 0.003) or in those with a transient reversal of shock but who ultimately died of a relapse of shock (median: less than 0.1 ng/mL. range: less than 0.1 to 12.5 ng/mL; p = 0.005). However. no cutoff values of IL-6 confidently predicted the outcome of an individual patient. The serum concentrations of IL-6 measured at study entry correlated with the duration of survival (r = -0.51. p = 0.004) and with the levels of TNF-alpha (r = 0.53; p less than 0.0001) but not with the levels of either IL-1 beta (r = 0.01. p = 0.90) or IFN-gamma (r = 0.06. p = 0.60). CONCLUSIONS: These results indicate that circulating levels of IL-6 are detectable in a majority of patients with gram-negative septic shock. Concentrations of IL-6 peaked near the onset of shock and rapidly decreased to undetectable levels within approximately 24 hours in most patients. Levels of IL-6 measured at study entry correlated with levels of TNF and with patients' outcomes. Yet. IL-6 does not appear to be a clinically useful laboratory test for predicting the outcome of an individual patient.
The relationship between the arterial to end-tidal PCO2 difference and hemoglobin saturation in patients with congenital heart disease, In right-to-left (RL) intracardiac shunting. the venous blood that is added to the oxygenated blood in the left heart is both poor in oxygen and rich in carbon dioxide. Thus. any given degree of arterial desaturation is associated with an obligatory arterial to end-tidal carbon dioxide tension difference (PaCO2--PETCO2). This paper presents a theoretical analysis of the relationship between PaCO2-PETCO2 and arterial hemoglobin saturation (SaO2) in cyanotic heart disease. Using the shunt equation as a starting point. a curvilinear. negative correlation between PaCO2-PETCO2 and SaO2 can be demonstrated. The slope of the regression of PaCO2--PETCO2 against SaO2 is shown to be positively correlated to Hb concentration. PaCO2. and the respiratory quotient R. The slope of the regression is also slightly increased at relatively high SaO2s and at high inspired oxygen fractions. although these latter factors are of lesser significance. However. in addition to the above primary effects of RL shunting. secondary effects may occur if pulmonary perfusion is reduced sufficiently to cause "alveolar hypoperfusion." which also creates an alveolar dead space. Primary and secondary effects are additive. This theoretical analysis is illustrated with a study of 27 children with congenital heart disease. Their lungs were ventilated with a Servoventilator 900 C. and carbon dioxide single-breath tests were obtained on-line with the use of a computerized system based on the Siemens-Elema carbon dioxide analyzer 930. Blood was sampled for PaCO2 measurement and arterial Hb saturation was measured by pulse oximetry (SpO2).
Nasal provocation test with lysine acetylsalicylate in aspirin-sensitive patients, The authors have studied nasal provocation testing (NPT) with aspirin in 45 aspirin-sensitive patients (40 affected by nasal polyposis) and in 38 aspirin-tolerant patients (27 affected by nasal polyposis). The test was positive in 37.7% of aspirin-intolerant subjects. but only in 7.9% of subjects in the control group (P less than .01).
Airborne infection. Theoretical limits of protection achievable by building ventilation, Of 67 office workers 27 (40%) had documented tuberculin skin test conversions after an estimated 4-wk exposure to a coworker with cavitary tuberculosis. Worker complaints for more than 2 yr before the tuberculosis exposure prompted investigations of air quality in the building before and after the tuberculosis exposure. Carbon dioxide concentrations in many parts of the building were found to be above recommended levels. indicating suboptimal ventilation with outdoor air. We applied a mathematical model of airborne transmission to the data to assess the role of building ventilation and other transmission factors. We estimated that ventilation with outside air averaged about 15 feet 3/min (cfm) per occupant. the low end of acceptable ventilation. corresponding to CO2 levels of about 1.000 ppm. The model predicted that at 25 cfm per person 18 workers would have been infected (a 33% reduction) and at 35 cfm. a level considered optimal for comfort. that 13 workers would have been infected (an additional 19% reduction). Further increases in outdoor air ventilation would be impractical and would have resulted in progressively smaller increments in protection. According to the model. the index case added approximately 13 infectious doses (quanta) per hour (qph) to the office air during the exposure period. 10 times the average infectiousness reported in a large series of tuberculosis cases. Further modeling predicted that as infectiousness rises. ventilation would offer progressively less protection. We conclude that outdoor air ventilation that is inadequate for comfort may contribute to airborne infection but that the protection afforded to building occupants by ventilation above comfort levels may be inherently limited. especially when the level of exposure to infection is high.
Fabry disease: detection of 13-bp deletion in alpha-galactosidase A gene and its application to gene diagnosis of heterozygotes, Polymerase chain reaction amplification of reverse-transcribed messenger RNA from a patient with Fabry disease revealed a 13-base pair deletion in the 5' region (exon 1) of alpha-galactosidase A complementary DNA. This gene rearrangement was not detected by Southern or Northern analysis. Short direct repeats were present around the breakpoints. and considered to be of pathogenetic significance. Gene diagnosis of the mother and a female cousin was successfully achieved by polymerase chain reaction amplification of genomic DNA; the former as a Fabry disease heterozygote and the latter as a normal homozygote.
Nitrous oxide sedation causes post-hyperventilation apnoea, We have studied. in six normal subjects. the effect of nitrous oxide sedation on the ventilatory pattern and oxygen saturation using pulse oximetry (SpO2) after hyperventilation to an end-tidal carbon dioxide partial pressure (PE'CO2) of 3 kPa. This value of PE'CO2 was shown to be less than the apnoeic threshold of all these subjects when their ventilation vs PE'CO2 response curves were plotted. All subjects became apnoeic when told to relax following hyperventilation while breathing 75% nitrous oxide for 90 s. Apnoea was defined as cessation of breathing for 20 s or more. The mean duration of apnoea was 78 s (range 29-130 s). All subjects demonstrated arterial desaturation (mean SpO2 75%. range 44-87%). In contrast. following hyperventilation with air. no apnoea was seen in any subject. although there was some evidence of desaturation (mean SpO2 92.5%. range 88-98%). It was concluded that subjects who are sedated with nitrous oxide behave similarly to those who are anaesthetized rather than to those who were fully conscious. in that they become apnoeic below the apnoeic threshold point. The reduction in SpO2 after hyperventilation was explained almost entirely by apnoea and may explain abnormalities of respiratory control and hypoxaemia in patients recovering from general anaesthesia or sedation accompanied by hypocapnia. This mechanism may be of importance in obstetric patients after breathing Entonox. when apnoea and hypoxaemia may reduce oxygen delivery to the fetus.
Dysfunction of the beta- and alpha-adrenergic systems in a model of congestive heart failure. The pacing-overdrive dog, The functional integrity of the beta- and alpha-adrenergic stimulatory pathways in a rapid ventricular pacing model of congestive heart failure in dogs was investigated; normal dogs served as controls. Total beta-adrenergic receptor density was 35% lower (p less than 0.01) in the pacing-overdrive dogs. and the beta-adrenergic receptor-mediated stimulation of adenylate cyclase (Vmax) was found to be 68% and 72% lower (p less than 0.01) in the left and right ventricles of the paced dogs. In addition. the basal adenylate cyclase activity was found to be 56% and 68% lower (p less than 0.01) in the left and right ventricles of the failing heart. Similarly. the Vmax of 5'-guanylylimidodiphosphate (GppNHp) and forskolin stimulation of adenylate cyclase activity was significantly lower. 70% and 55%. respectively (p less than 0.01). in both ventricles of the paced dogs. However. although the concentration yielding half-maximal velocity for beta-agonist and GppNHp stimulation of adenylate cyclase was similar in both groups. that for forskolin stimulation of the enzyme was significantly increased (p less than 0.01). Pertussis toxin-mediated ADP-ribosylation of membranes from control and failing hearts revealed a significant decrease in the inhibitory guanine nucleotide binding protein content (48 +/- 9%. p less than 0.01) in the hearts of the paced dogs. Moreover. although the pertussis toxin treatment increased the basal and the forskolin-stimulated adenylate cyclase activity in both normal and failing heart membranes. the adenylate cyclase activity remained significantly depressed in the failing heart after pertussis toxin treatment (p less than 0.01). Consistent with the depressed adenylate cyclase activity. mechanical studies on isolated papillary muscles and trabeculae revealed a decrease in baseline total tension (from 7.0 +/- 0.7 to 3.8 +/- 0.4 g/mm2. p less than 0.01) and dT/dt (from 26 +/- 8 to 13 +/- 1 g/mm2/sec. p less than 0.01) in the pacing-overdrive model. Tension generation and dT/dt observed in the paced dogs in response to increasing concentrations of forskolin demonstrated a rightward shift in the dose-response curve and a decrease in maximal forskolin stimulation (p less than 0.01). Similarly. maximal tension and dT/dt in the presence of isoproterenol was significantly lower than in the normal dogs (p less than 0.01). The decrease in beta-adrenergic responsiveness was accompanied by a decrease and rightward shift in alpha 1-adrenergic responsiveness (increase in tension was 1.1 +/- 0.1 g/mm2 in paced dogs versus 2.1 +/- 0.1 g/mm2 in controls. p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS).
Natriuretic peptides as cardiac hormones in normotensive and spontaneously hypertensive rats. The ventricle is a major site of synthesis and secretion of brain natriuretic peptide, To study synthesis. storage. and secretion of brain natriuretic peptide (BNP) in the heart. we have measured BNP mRNA and BNP concentrations in the hearts of Wistar-Kyoto rats and also have investigated its secretion from the isolated perfused heart. The atrium expressed the BNP gene at a high level. and a considerable amount of BNP mRNA also was present in the ventricle. which corresponded to approximately 40% of the atrial BNP mRNA concentration. When tissue weight was taken into account. the total content of BNP mRNA in the ventricle was approximately threefold larger than that in the atrium. although the atrial natriuretic peptide (ANP) mRNA content in the ventricle was only 7% of that in the atrium. By contrast. the BNP concentration in the ventricle was 4.07 +/- 0.97 pmol/g. which was less than 1% of that in the atrium (451 +/- 86 pmol/g). The basal secretory rate of BNP from the isolated perfused whole heart was 49.3 +/- 6.1 fmol/min. approximately 60% of which was maintained even after atrial removal. whereas the secretory rate of ANP was reduced to less than 5%. We also studied age-matched spontaneously hypertensive rats-stroke prone. The rank order of the BNP mRNA concentration in the hearts of these rats was left ventricle greater than right ventricle greater than right atrium = left atrium. and the total BNP mRNA content and BNP secretory rate in the ventricle were twice as large as in Wistar-Kyoto rats. These results demonstrate that BNP is a novel cardiac hormone in rats and is predominantly synthesized in and secreted from the ventricle. This is in striking contrast to ANP. which occurs mainly in the atrium. The results also suggest possible pathophysiological roles of BNP in certain cardiovascular disorders.
Inhibition of diabetes-associated complications by nucleophilic compounds, Mono- and diaminoguanidine inhibited ambient glucose-induced glycosylated end product formation of albumin and collagen 125I-labeled albumin covalent binding in vitro. Diaminoguanidine was a stronger inhibitor than monoaminoguanidine. These compounds also inhibited rat eye lens aldose reductase activity in vitro noncompetitively with respect to NADPH with Ki = 30.6 mM for monoaminoguanidine and Ki = 12.5 mM for diaminoguanidine. When administered daily for 98 days at a dose of 25 mg/kg body wt i.p.. both compounds lowered eye lens sorbitol and aldose reductase activity in normoglycemic and alloxan-induced diabetic rats. Again. diaminoguanidine was a better inhibitor. Daily long-term administration of mono- and diaminoguanidine (25 mg/kg body wt i.p.) inhibited and prevented experimental diabetes-induced lens opacity in rats. respectively. It appears that diaminoguanidine has a better therapeutic potential in controlling diabetic complications.
Detection and partial sequencing of hepatitis C virus RNA in the liver, To detect hepatitis C virus RNA. total RNA was extracted from liver tissue. reverse transcribed to complementary DNA. and amplified by polymerase chain reaction. The reaction products were analyzed by ethidium bromide staining in acrylamide gel and hybridization with a radiolabeled probe. Hepatitis C virus RNA was thereby detected in 17 of 27 (63%) liver tissue specimens obtained from patients with non-A. non-B chronic liver diseases. Of these 27 patients. viral RNA was detected in 12 of 17 (71%) liver tissues from anti-hepatitis C virus-positive patients and in 5 of 10 (50%) liver tissues from anti-hepatitis C virus-negative patients. Direct sequencing of amplified complementary DNA (35 nucleotides) of the 17 RNA-positive samples showed only 66% to 77% homology to the reported hepatitis C virus complementary DNA sequence. These results indicate that the majority of anti-hepatitis C virus-positive patients are currently infected with hepatitis C virus. and some of the anti-hepatitis C virus-negative patients with non-A. non-B hepatitis are harboring hepatitis C virus in the liver. Detection of hepatitis C virus RNA appears to provide a useful indicator in the study of hepatitis C virus infection.
Liver macrophage-mediated cytotoxicity toward mastocytoma cells involves phagocytosis of tumor targets, Macrophage-mediated cytotoxicity toward tumor cells usually involves extracellular lysis of the targets. In this study. we report that liver macrophages from rats treated with lipopolysaccharide (5 mg/kg. intravenous) also kill certain tumor cell targets by phagocytosis. Liver macrophages were coincubated with P815 mouse mastocytoma cells for 24 to 72 hr at an effector/target ratio of 10:1. Macrophage phagocytosis was characterized by flow cytometry and by light and electron microscopy. For flow-cytometric studies. P815 cells were prelabeled with the fluorescent dye 1.1'-dioctadecyl-3.3.3'.3'-tetramethyl-indocarbocyanine perchlorate. We found that coincubation of macrophages with labeled targets resulted in a time-dependent increase in macrophage-associated fluorescence. reaching a maximum at 72 hr. This correlated with light-microscopic observations of increased numbers of tumor cells in the macrophages and enhanced macrophage surface area and density. Electron microscopic studies revealed that the initial event in the phagocytic process involved the capture of P815 cells by the pseudopodia of the macrophages. Target cells were then surrounded by lamellipodia. internalized in phagosomes and destroyed. These data. together with previous studies. provide evidence for multiple mechanisms of cytotoxicity mediated by activated liver macrophages.
Cryptosporidium infection in an adult mouse model. Independent roles for IFN-gamma and CD4+ T lymphocytes in protective immunity, Cryptosporidium is a protozoan parasite that can cause chronic life-threatening diarrhea in immunocompromised persons. Host immune responses are poorly understood. an impediment to development of effective therapy. In mice. normal adult BALB/c animals resist infection whereas chronic symptomatic cryptosporidiosis develops in adult nude mice and in neonatally infected BALB/c mice treated with anti-CD4 mAb. To define further the immune defects that allow mice to be infected with Cryptosporidium. adult BALB/c mice were treated with cytolytic anti-CD4 or anti-CD8 or with neutralizing anti-IFN-gamma or anti-IL-2 mAb. Chronic infection. manifested by continuous shedding of sparse but statistically significant numbers of oocysts. occurred with anti-CD4 +/- anti-CD8 mAb treatment although anti-CD8 mAb treatment alone did not allow infection. Treatment with anti-IFN-gamma mAb greatly enhanced oocyst shedding but infection was self-limited. Treatment with a combination of anti-CD4 and anti-IFN-gamma mAb permitted both chronic infection and shedding of large numbers of oocysts. Furthermore mice treated initially with anti-CD4 mAb showed a substantial increase in oocyst shedding when later treated with anti-IFN-gamma mAb; and mice treated initially with both mAbs showed a decline in oocyst shedding when anti-IFN-gamma mAb was stopped. Anti-IFN-gamma mAb treatment of congenitally athymic adult BALB/c mice led to an approximately a 75-fold increase in oocyst shedding. Treatment of adult BALB/c mice with anti-IL-2 mAb did not permit Cryptosporidium infection. These results suggest that redundant immunologic mechanisms limit Cryptosporidium infection such that both CD4+ cells and IFN-gamma are required to prevent initiation of infection whereas either alone can limit the extent (IFN-gamma) or duration (CD4+ T cells) of infection. They also suggest that production of IFN-gamma by a non-T cell contributes to host immunity.
Autoantibody-encoding kappa L chain genes frequently rearranged in lambda L chain-expressing chronic lymphocytic leukemia, Patients with kappa L chain expressing chronic lymphocytic leukemia (CLL) frequently have leukemia cells reactive with a murine mAb. designated 17.109. Raised against a monoclonal IgM rheumatoid factor autoantibody. this mAb recognizes a major kappa-L chain-associated cross reactive Id. designated 17.109-CRI. Molecular studies reveal that the 17.109-CRI in CLL is a serologic marker for expression of a conserved kappa L chain V region gene (V Kappa gene) of the V Kappa 3 subgroup. designated Humkv325. We isolated an upstream gene fragment of Humkv325 to examine for Ig gene rearrangements of this and other closely related V Kappa 3 genes by Southern analyses. Consistent with Humkv325 encoding the 17.109-CRI. we find that the genomic DNA from all 17.109-reactive leukemia cell populations have gene rearrangements that are detected using this probe. In addition. we observe V Kappa 3 gene rearrangements frequently in the genomic DNA of lambda L chain-expressing leukemia cells. Of the genomic DNA from 33 lambda-L chain-expressing CLL samples. 8 (24%) had additional nongerm-line bands detected with the Humkv325 probe. Consistent with these bands representing Ig gene rearrangements. the additional band in each but one sample also hybridized with probes specific for the J Kappa region and/or the kappa-deleting element. Using the polymerase chain reaction (PCR). we examined the genomic DNA from all lambda L chain-expressing CLL for V Kappa 3 gene rearrangements to J Kappa and/or Kde. PCR on each DNA sample with V Kappa 3 gene rearrangements detected by Southern analysis generated gene fragments that hybridized specifically with oligonucleotides corresponding to framework or CDR of the Humkv325 gene. Nucleic acid sequence analyses of representative samples confirmed that these DNA contained abortive Humkv325 gene rearrangements. PCR for rearranged V Kappa 3 genes in the DNA of other lambda-L chain-expressing CLL either did not generate any PCR product or produced fragments that failed to hybridize with all Humkv325 oligonucleotide probes. Nucleic acid sequence analyses of the latter demonstrated that these represent abortive V Kappa gene rearrangements involving another conserved V Kappa 3 gene. designated Vg. These studies indicate that Humkv325 and Vg frequently may undergo Ig gene rearrangement independent of their expression. As such. the frequent use of Humkv325 in CLL may be secondary. in part. to an enhanced propensity of this V Kappa 3 gene to undergo genetic rearrangement during B cell ontogeny.
Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease, It has been difficult to demonstrate functionally distinct T cell populations in humans on the basis of cytokine secretion. As previous investigators have examined the T cell cytokine profile from immunized animals. we examined whether Th1 or Th2 type T cells could be identified in the peripheral blood or cerebrospinal fluid (CSF) immune compartments from subjects with or without inflammatory diseases. Using limiting dilution analysis and growth with PHA and IL-2/IL-4. we directly cloned a total of 177 T cells from the peripheral blood and CSF of seven subjects. four with inflammatory disease and three control subjects. and examined the cytokine message profile after stimulation with ionomycin and PMA. We found that most clones from both the peripheral blood and CSF express IL-1. IL-2. IL-4. IFN-gamma. or TNF-alpha cytokine mRNA after activation with ionomycin and PMA. All T cell clones tested produced TNF-alpha mRNA. and all but 14 produced IFN-gamma mRNA. As reported previously. Th0 cells. which produced IFN-gamma. IL-2. IL-4. and IL-5 mRNA. were found in most subjects. In striking contrast. Th1 cells. which expressed IL-2 and IFN-gamma but not IL-4 or IL-5 mRNA. were present in both peripheral blood and CSF of subjects with inflammatory disease but not found in peripheral blood or CSF of subjects without systemic inflammation. Th2 cells. expressing IL-4 and IL-5 but not IFN-gamma or IL-2 mRNA. were not found in any subject. These data present the first evidence for Th1 T cell clones in humans that may be associated with systemic inflammation.
Activation of AP-1 by IL-1 and phorbol esters in T cells. Role of protein kinase A and protein phosphatases, We have examined the regulation of the AP-1 transcription complex in the IL-1-responsive murine T cell thymoma cell line EL-4 6.1 C10. Our results demonstrate that AP-1-mediated gene expression in T cells may be regulated by several signaling pathways and factors. including IL-1. protein kinase C. protein kinase A (PKA). and one or more serine/threonine-specific protein phosphatases. The activation of protein kinase C results in an increase in nuclear AP-1 DNA binding activity. as well as enhanced gene expression. IL-1 and agents that elevate intracellular cAMP levels do not. by themselves. induce AP-1 activation. but they synergize with phorbol esters. IL-1 and forskolin may enhance AP-1 function by different mechanisms. because forskolin enhanced gene expression without producing an increase in nuclear AP-1 DNA binding. whereas IL-1 increased AP-1-binding activity and gene expression. These observations. in conjunction with the lack of a demonstrable effect of IL-1 on cAMP production in EL-4 cells. are consistent with the view that IL-1 enhances AP-1 activation by a pathway that does not directly involve cAMP and PKA. However. the induction of AP-1 activity by IL-1 and phorbol esters is dependent upon the presence of PKA. as evidenced by the loss of AP-1 inducibility in cells transfected with a cDNA encoding protein kinase inhibitor. a specific inhibitor of PKA. The effect of protein kinase inhibitor on AP-1 activation in response to IL-1 and tetradecanoyl-phorbol-13-acetate was reversed in the presence of the serine/threonine protein phosphatase inhibitor okadaic acid. Thus. the level of AP-1 activity in T cells may be determined by the balance between the activities of several serine/threonine protein kinases and phosphatases.
Magnesium deficiency affects plasma lipoprotein composition in rats, Weanling rats were pair-fed for 8 d with control and Mg-deficient diets containing 960 and 30 mg of Mg/kg. respectively. The marked reduction in plasma Mg levels indicated that the rats fed the Mg-deficient diet were indeed deficient. In the Mg-deficient rats the percent composition of triglycerides in VLDL. LDL and HDL was elevated and that of protein was reduced. Although the proportion of cholesterol was reduced in LDL and HDL. that of phospholipid was decreased only in HDL. Magnesium deficiency induced a decrease in the percent composition of apolipoprotein (apo) E and a relative increase in the apo C for VLDL. In HDL from Mg-deficient rats. the proportion of apo AI was higher than normal. apo AIV was lower than normal and apo E was virtually absent. The percent composition of oleic and linoleic acids was increased but that of stearic and arachidonic acids was depressed in both VLDL and HDL derived from Mg-deficient rats compared with pair-fed controls. Whether these alterations in lipoprotein profile contribute to hyperlipoproteinemia or are the results of the metabolic changes that produce hyperlipoproteinemia remain to be determined.
Deficient human immunodeficiency virus type 1-specific cytotoxic T cell responses in vertically infected children, Cytotoxic T lymphocyte (CTL) responses to human immunodeficiency virus type 1 (HIV-1) gag proteins were studied prospectively in 17 children (12 infected) born of mothers with HIV-1 seropositivity and in five pediatric patients with hemophilia infected by transfusion of HIV-1-contaminated factor VIII concentrate. B lymphoblastoid cells infected with vaccinia virus vectors expressing HIV-1 gag gene products were combined with autologous peripheral blood mononuclear cells to detect circulating CTLs. Effector cells were defined by monoclonal antibody-mediated. complement-dependent cytolysis. Circulating HIV-1 gag-specific cytotoxic responses were detectable in 4 of 5 HIV-1-infected pediatric hemophilic patients. and were similar in magnitude to those previously described in adults. In contrast. circulating HIV-1 gag-specific cytolysis was detectible in only 3 of 12 vertically infected children. Depletion data revealed that the majority of detectible gag-specific cytolysis was CD8 T cell-mediated. No apparent relationships between CD4 T cell counts. CD8 T cells counts. or serum p24 antigen levels and CTL responses were seen. Deficient CTL development may. in part. explain the more rapid onset of symptomatic disease following vertical HIV infection.
Need for the lead mobilization test in children with lead poisoning, We evaluated the recommendation of the Centers for Disease Control. that children with moderate lead poisoning undergo the lead mobilization test (LMT) to determine the need for a full course of chelation treatment. Current criteria for selection for this test include a blood Pb concentration (bPb) between 25 and 55 micrograms/dl and an erythrocyte protoporphyrin level greater than 35 micrograms/dl. To determine whether the eligibility criteria could be refined to a smaller group of patients. we compared bPb determinations obtained on the day of the LMT in 198 children with moderate Pb poisoning to the results of the LMT. We found that children with bPb less than 25 micrograms/dl were unlikely to respond to the test dose of calcium disodium ethylenediamine tetraacetate with a Pb diuresis (24/25 patients had low urinary Pb excretion on the LMT). In contrast. 88% of children with bPb greater than or equal to 40 micrograms/dl were likely to excrete sufficient Pb to indicate the need for a full course of chelation. We conclude that the LMT is indicated for children with bPbs between 25 and 40 micrograms/dl. Children with bPb between 40 and 55 micrograms/dl may receive chelation therapy without having an LMT. if the performance of the LMT is not practical. Patients with levels less than 25 micrograms/dl should be followed clinically and removed from further Pb exposure.
The effect of oxyphenonium bromide and oxybutynin hydrochloride on detrusor contractility and reflux in children with vesicoureteral reflux and detrusor instability, In a prospective study the effects of the anticholinergic drugs oxyphenonium bromide and oxybutynin hydrochloride on detrusor contractility and reflux were studied. Although anticholinergic properties are claimed of both drugs. only oxybutynin hydrochloride proved to decrease detrusor contractility and the degree of reflux. probably due to a direct spasmolytic effect on the detrusor. Therefore. in cases of reflux and detrusor instability treatment with oxybutynin hydrochloride is recommended.
Pharmacokinetics of low-molecular-weight heparin and unfractionated heparin during elective aortobifemoral bypass grafting, Perioperative monitoring has demonstrated that administration of heparin on an empirical basis is associated with a wide variation in patient response and elimination rate. This problem may be overcome by intervention on the basis of perioperative monitoring or by using forms of heparin with different pharmacokinetic properties. When compared with unfractionated heparin. low-molecular-weight heparin has a higher bioavailability after subcutaneous administration. a linear clearance mechanism with a prolonged half-life. and is at least as effective in preventing postoperative vein thrombosis. Theoretically these characteristics of low-molecular-weight heparin could lead to more predictable levels of heparin activity. In this study we compared the pharmacokinetics of low-molecular-weight heparin and unfractionated heparin after an intravenous injection in patients undergoing aortic graft surgery. Heparin activity was measured before heparin administration and at 5. 20. 35. 50. 65. 80. 95. and 110 minutes after administration. The anti-Xa activity in the low-molecular-weight heparin group showed less variation and was more sustained when compared to the unfractionated heparin group. Fibrin degradation products were moderately correlated with the anti-factor Xa levels of the low-molecular-weight heparin group. but no correlation was found in the unfractionated heparin group. The anti-factor Xa activity of low-molecular-weight heparin was. in contrast to that of unfractionated heparin. not completely reversible by protamine administration. The blood loss was comparable in both groups. In contrast to what was expected. the pharmacokinetic profiles of low-molecular-weight heparin and unfractionated heparin showed a similarity after intravenous injection in patients undergoing aortobifemoral bypass grafting. Factors that could have influenced the pharmacokinetic behavior of heparin are discussed.
A feasibility study of the SDI test for the evaluation of gastrointestinal cancer sensitivity to anticancer drugs, The succinic dehydrogenase inhibition (SDI) test has been widely used to evaluate the sensitivity of cancer cells to anticancer agents. Recently. the techniques for tissue culture have progressed; the ability to make formazan has improved with the use of methylthiazol tetrazolium bromide (MTT) instead of triphenyl tetrazolium chloride (TTC) in this assay. Therefore. we modified the SDI test in order to evaluate the drug response to gastrointestinal cancer and applied it in a clinical study. In this assay. the optimal concentration levels of mytomycin-C and Adriamycin for the clinical materials are 10 micrograms/ml. that is. 10 times higher than for the cancer cell line. and that of Cisplatin is 30 micrograms/ml. for Cisplatin is unstable in the culture medium. To evaluate its antitumor effect. it was found necessary to expose the cancer cells to 5-fluorouracil (5-FU) for 3 days. We applied this assay for the clinical materials; the evaluable rate of this assay is 83.3%. The peculiarity of this assay is its high evaluable rate. These results suggest that this test may be useful for clinical application.
Diagnosis of tuberculosis by DNA amplification in clinical practice evaluation, Various polymerase chain reaction (PCR) assays have been devised for the rapid identification of mycobacteria in clinical specimens. To assess the value of such assays in routine laboratory work the results obtained by PCR were compared with those obtained by standard microbiological methods for 514 specimens collected for investigation of mycobacterial infection. Specimens were tested for the presence of Mycobacterium tuberculosis complex and atypical mycobacteria in two assays. one based on amplification of the 65 kDa gene and the other on the IS6110 insertion sequence. For the 489 samples that did not contain inhibitors of the amplification reaction PCR findings correlated well with bacteriological and/or clinical data in 476 (97.4%). 6 PCR results turned out to be false negatives. 3 to be false positives and 4 to be mis-identification of strains. Pre-treatment of samples with guanidium thiocyanate reduced the proportion of false-negative results and of samples that contained inhibitors. This study confirms the potential of DNA amplification for early diagnosis of mycobacterial infections.
Prevention of HIV-1 IIIB infection in chimpanzees by CD4 immunoadhesin, The first step in infection by the human immunodeficiency virus (HIV) is the specific binding of gp120. the envelope glycoprotein of HIV. to its cellular receptor. CD4. To inhibit this interaction. soluble CD4 analogues that compete for gp120 binding and block HIV infection in vitro have been developed. To determine whether these analogues can protect an uninfected individual from challenge with HIV. we used the chimpanzee model system of cell-free HIV infection. Chimpanzees are readily infected with the IIIB strain of HIV-1. becoming viraemic within about 4-6 weeks of challenge. although they do not develop the profound CD4+ T-cell depletion and immunodeficiency characteristic of HIV infection in humans. CD4 immunoadhesin (CD4-IgG). a chimaeric molecule consisting of the N-terminal two immunoglobulin-like regions of CD4 joined to the Fc region of human IgG1. was selected as the CD4 analogue for testing because it has a longer half-life than CD4. contributed by the IgG Fc portion of the molecule. In humans. this difference results in a 25-fold increased concentration of CD4-IgG in the blood compared with recombinant CD4. Here we report that pretreatment with CD4-IgG can prevent the infection of chimpanzees with HIV-1. The need for a preventative agent is particularly acute in perinatal HIV transmission. As recombinant CD4-IgG. like the parent IgG molecule. efficiently crosses the primate placenta. it may be possible to set up an immune state in a fetus before HIV transfer occurs. thus preventing infection.
Avian osteoclasts as estrogen target cells, Although in vivo effects of 17 beta-estradiol (estrogen) on bone turnover have been shown to occur mainly through influences on osteoclast-mediated bone resorption. the mechanism by which estrogen reduces bone resorption is unclear. To approach this question. we have examined authentic osteoclasts for evidence of a direct osteoclast response to estrogen in vitro. Highly purified (greater than (90%) viable avian osteoclasts from birds maintained on a low calcium diet were obtained using an osteoclast-specific monoclonal antibody coupled to magnetic beads. Isolated cells were either analyzed directly for estrogen receptor (ER) levels or cultured to assess the biological effects of estrogen. Northern blot analysis revealed a 5.2-kilobase mRNA that hybridized with a cDNA to human ER mRNA in the osteoclasts. An anti-human ER antibody recognized proteins of 66 kDa and 140 kDa in osteoclast extracts by Western blot analysis. The 66-kDa size is in close agreement with the reported size of the human ER. Nuclear binding of estrogen to intact viable osteoclasts was steroid-specific and saturable. with 5662 +/- 1420 molecules bound per nucleus (mean +/- SEM). In vitro estrogen responses in osteoclasts included a dose-dependent decrease in resorption as well as an increase in nuclear protooncogene mRNA levels. These observations indicate that osteoclasts are capable of directly responding to estrogen in vivo.
Altered antigen receptor signaling in anergic T cells from self-tolerant T-cell receptor beta-chain transgenic mice, T-cell tolerance to the minor lymphocyte-stimulating antigen Mls-1a in a T-cell receptor (TcR) V beta 8.1 transgenic line of mice is maintained by both clonal deletion and clonal anergy. Approximately 20-50% of peripheral CD4+ (but not CD8+) T cells isolated from these mice are anergic and fail to proliferate following TcR ligation. We have examined key events in T-cell signaling in peripheral T cells isolated from these mice. In this report. we show that the anergic CD4+ T cells did not mobilize calcium or express receptors for interleukin 2 (IL-2) following TcR ligation. However. the cells retained viability and functional potential because stimulation with phorbol 12-myristate 13-acetate and ionomycin bypassed the block in receptor-mediated signaling and induced IL-2 receptor expression and proliferation of the anergic cells.
Analysis of the enhancer element that controls expression of sevenless in the developing Drosophila eye, The sevenless gene encodes a protein-tyrosine kinase receptor expressed in a complex pattern during the development of the Drosophila melanogaster eye. We have previously shown that this pattern is regulated transcriptionally by an enhancer located in the body of the sevenless gene. Here we extend our analysis of the sevenless enhancer. defining a 475-base-pair fragment that contains elements necessary for the correct qualitative and quantitative expression of the sevenless gene. Within this fragment are sequence elements conserved in the sevenless gene of a distantly related Drosophila species and protected from DNase I digestion by nuclear extracts isolated from adult heads and imaginal discs. Partial deletions of the 475-base-pair fragment result in preferential loss of expression in different subsets of cells. These results suggest that the normal pattern of expression is generated by the combined action of separate cell-specific regulatory elements.
Nutritional support in the critically ill surgical patient, Aggressive nutritional support in the critically ill surgical patient is essential if improved outcome is to be realized. An understanding of the metabolic alterations of trauma and sepsis provides the foundation for a nutritional prescription for the individual patient. Careful nutritional assessment; titration of fluid. electrolytes. and micronutrients; provision of adequate calories and nitrogen to meet metabolic needs; and the selective use of specialized formulations are important components of nutritional management in the ICU.
Beneficial effects of isovolemic hemodilution using a perfluorocarbon emulsion in a stroke model, In a clinically applicable cat stroke model. 16 purpose-bred adult animals were used to evaluate the beneficial effects of two treatment regimens: isovolemic hemodilution with either a perfluorocarbon emulsion or dextran 40 (a glucose polymer). Animals that received these treatment regimens were then compared with a control group of untreated animals. Focal cerebral infarctions were produced by transorbital ligation of the left middle cerebral artery. The randomly allocated treatment arms of the study were instituted 3 hours after ligation of the middle cerebral artery. thereby simulating a human clinical situation. In vivo mitochondrial metabolic activity of the peri-infarct cerebral tissue was continually assessed by means of a multiwavelength near-infrared spectrophotometer. This allowed measurement of cellular oxygenation at the cytochrome aa3 level. the terminal member of the cytochrome chain. Sequential proton-based magnetic resonance imaging was used to measure intracerebral water in vivo. Cardiac output. oxygen consumption/delivery. chemical. histologic. and rheologic parameters were also assessed. The data collected were analyzed by group means and standard statistical analyses. which revealed that the group treated with the perfluorocarbon emulsion had both less brain edema in the early post-infarct period (p less than 0.05). as well as a higher level of oxidation of cytochrome aa3 (p less than or equal to 0.025). This evidence supports the premise that isovolemic hemodilution with an oxygen-carrying hemodiluent may be beneficial in the treatment of ischemic strokes.
Arteriographic findings in EDTA chelation therapy on peripheral arteriosclerosis, In a randomized. double-blind. controlled study. 153 patients with claudication were each given either 20 infusions of Na2EDTA or 20 infusions of saline. Walking distances and ankle/brachial indices were measured before. during. and after treatment. In 30 patients. angiograms and transcutaneous oxygen tensions were obtained before. during. and after treatment. The patients' subjective evaluations of the effect of treatment were also recorded. It is concluded that EDTA chelation therapy has no effect in patients with intermittent claudication in the legs caused by arteriosclerosis.
Tissue plasminogen activator release and plasminogen activator inhibitor levels in coronary artery disease, Unstable angina and Q wave myocardial infarction are associated with intraluminal coronary thrombosis. a process to which impaired fibrinolysis may contribute. The authors examined the extrinsic fibrinolytic system. including tissue plasminogen activator antigen. plasminogen activator inhibitor activity and antigen. and euglobulin clot lysis time before and after venous occlusion in 56 patients undergoing coronary angiography for chest pain syndromes and in 16 healthy controls. Fibrinolysis variables were similar (with greater than 95% confidence) in the patients with thrombus-associated coronary syndromes as compared with those with chest pain syndromes not due to coronary thrombosis. These fibrinolytic variables were also similar to those in patients without coronary artery disease and in healthy controls. Their data suggest that defective fibrinolysis is not involved. at least systemically. in the pathogenesis of thrombus-associated coronary artery syndromes.
Immune activation markers and AIDS prognosis, Four assays for serum levels of cellular products of immune activation were examined as prognostic markers for AIDS in a prospective study of asymptomatic HIV-seropositive homosexual men. Baseline serum values of beta 2-microglobulin (beta 2M). neopterin. soluble CD8 (sCD8). and soluble interleukin-2 receptor (sIL-2R) for 185 men were examined univariately and multivariately as predictors of AIDS during 36 months of follow-up. Thirty-three cases of AIDS (18%) were diagnosed during the follow-up period. All four assays correlated highly with each other (r = 0.48-0.63). and all four were good univariate predictors of AIDS and comparable to CD4 lymphocyte count. beta 2M. neopterin. and sCD8 predicted AIDS independently of both CD4 count and HIV p24 antigen or p24 antibody in multivariate analysis. Within the range of CD4 count 200-499 x 10(6) cells/l. an immune activation marker used in combination with an assay for p24 antigen identifies those at 3-6% risk of AIDS over 36 months (low risk on both assays) and those at 63-86% risk (high risk on both assays). These results can be used to guide physicians and patients making decisions about treating asymptomatic HIV infection with zidovudine in individuals with CD4 lymphocyte count of 200-499 x 10(6) cells/l.
HIV-1 seropositivity and mortality at University Hospital, Kinshasa, Zaire, 1987, This study examines the impact of HIV-1 infection and AIDS on 500 of 563 consecutive deaths at University Hospital. Kinshasa. Zaire. in late 1987. HIV-1 seroprevalence was 31% for the entire population and 43% for the 247 adults. Forty-two (38%) of the 110 HIV-1-seropositive adult deaths occurred in those between the ages of 25 and 34 years. The mean age of death for seropositives was 36 years. 7.5 years less than seronegative deaths. AIDS and AIDS-associated diagnoses such as cryptococcal meningitis. chronic diarrhea and pneumonia accounted for 42% of all adult deaths and 74% of all HIV-1-seropositive adult deaths. Seventeen per cent of 50 sera initially negative by enzyme-linked immunosorbent assay (ELISA) were ultimately found to be HIV-1-seropositive by Western blot or p24 antigen testing. The data indicate that HIV-1 infection and AIDS contribute significantly to adult mortality in Kinshasa population and that sensitivity of ELISA tests decreases in terminal HIV-1 infection.
The ethics of nontreatment of patients with cancers of the head and neck, There are three levels at which nontreatment decisions for patients with cancers of the head and neck might be made: not doing further diagnostic procedures when the data gained would not make a significant difference to treatment decisions; not continuing aggressive therapy when its benefits are outweighed by the ensuing burdens and harms; and. at the policy level. not providing costly aggressive therapy at all because of the number of patients with unmet. more basic needs. These three levels of nontreatment decisions are discussed in light of ethical theory. briefly introduced. Arguments are made in favor of nontreatment decisions at the two clinical levels mentioned above. but against a policy decision to ration treatment for patients with cancers of the head and neck.
Hurler syndrome with special reference to histologic abnormalities of the growth plate, Hurler syndrome is a mucopolysaccharide disorder resulting from an heritable deficiency in alpha-L-iduronidase. an enzyme required in the catabolism of heparan sulfate and dermatan sulfate glycosaminoglycan (GAGs). The resultant intracellular accumulation of GAG leads to disruption of the intracellular and extracellular environment and dysfunction of multiple organ systems. Among the most noted manifestations of this disease is disproportionate short trunk dwarfism. which develops during the first years of life. Histochemical and electron-microscopic observations on a 30-month-old child with Hurler syndrome showed marked irregularities in chondrocyte orientation within the growth plate. along with disruption of the normal columnar architecture. Vacuolization with enlargement of the cellular border was the characteristic ultrastructural finding. An heritable abnormality in the enzymatic degradation of structural glycosaminoglycans leads to profound disruption of the normal mechanisms of growth and development.
Prediction of maximum exercise tolerance in patients with COPD, Exercise tolerance in patients with COPD is difficult to predict from measurements of lung function. We examined multiple physiologic and psychosocial variables in an attempt to predict exercise performance in a group of patients with COPD enrolled in a clinical trial of pulmonary rehabilitation. A total of 119 patients (FEV1 = 1.41 +/- 0.64 L) were divided randomly into either a study group (group A. n = 58) or validation group (group B. n = 61). Stepwise multiple regression in group A revealed that peak oxygen uptake (peak VO2) was predicted best by the following equation: Peak VO2 (L/min) = (0.0327 x DCO) + (0.0040 x MVV)-(0.0156 x peak-exercise VD/VT) + (0.0259 x resting VE) + 0.848; r = 0.90; SE = 0.233 L/min. This equation was then cross-validated in group B. It demonstrated excellent validity: measured peak VO2 (L/min) = (1.13 x predicted peak VO2)-0.0891; r = 0.90; SE = 0.239 L/min. We conclude that exercise tolerance was predicted reasonably well from measurements of lung function and gas exchange in this group of patients with COPD. However. the variability of the prediction would limit its usefulness in individual patients.
Persistence of respiratory abnormalities four years after the onset of toxic oil syndrome, We studied a random sample of 436 subjects with TOS aged 18 to 60 years. to assess the prevalence of respiratory involvement four years after onset of the syndrome. Clinical evaluation together with chest roentgenograms. electrocardiogram and functional respiratory tests were carried out. Respiratory involvement occurred in 390 (89.4 percent) individuals and was the most common abnormality detected. followed by neurological disorders in 289 (66.3 percent). osteoarticular symptoms in 171 (39.2 percent). psychiatric disorders in 96 (22 percent). hepatic involvement in 91 (20.9 percent). and sclerodermatous sequelae in 89 (20.4 percent). Among patients with respiratory involvement. dyspnea and cough were the most common complaints. Decreased VC was observed in 151 (34.6 percent) patients and reduced transfer factor of CO in 95 (21.8 percent) patients. Airway obstruction and alveolar hypoventilation were observed only in nine (2.1 percent) patients. Six (1.4 percent) patients suffered from pulmonary artery hypertension.
Effect of low-molecular-weight heparin on recombinant tissue plasminogen activator-induced thrombolysis in canine pulmonary embolism, We employed a canine model of pulmonary embolism induced by radioactive blood clots to determine if low-molecular-weight heparin augments recombinant tissue plasminogen activator (rtPA)-induced thrombolysis. Following embolization. dogs were randomized: group 1 dogs received heparin; group 2 dogs received low-molecular-weight heparin; group 3 dogs received 1.5 mg/kg of rtPA over 45 minutes; group 4 dogs received rtPA 3 mg/kg over 45 minutes; and group 5 dogs received 1.5 mg/kg of rtPA plus low-molecular-weight heparin. Over three hours. little thrombolysis occurred in groups 1 and 2. In contrast. significant thrombolysis occurred in groups 3 to 5. 46 percent. 49 percent. and 46 percent. respectively (all p less than 0.01 compared with groups 1 and 2). We conclude that there is an upper limit to the dose-thrombolytic rate relationship with rtPA. and that low-molecular-weight heparin does not augment rtPA-induced thrombolysis.
Inspiratory muscle relaxation rate after voluntary maximal isocapnic ventilation in humans, We have investigated whether the capacity of the inspiratory muscles to generate pressure and flow during a ventilatory load is related to changes in inspiratory muscle relaxation rate. Five highly motivated normal subjects performed voluntary maximal isocapnic ventilation (MIV) for 2 min. Minute ventilation and esophageal. gastric. and transdiaphragmatic pressures were measured breath by breath. We observed that ventilation. peak inspiratory and expiratory pressures. and inspiratory flow rate declined from the start of the run to reach a plateau at 60 s that was sustained for the remainder of the exercise. In a subsequent series of studies. MIV was performed for variable durations between 15 and 120 s. The normalized maximum relaxation rate of unoccluded inspiratory sniffs (sniff MRR. %pressure loss/10 ms) was determined immediately on stopping MIV. Sniff MRR slowed as the duration of MIV increased and paralleled the decline in inspiratory pressure and ventilation observed during the 2-min exercise. No further slowing in MRR occurred when ventilation became sustainable. We conclude that. during MIV. the progressive loss of ventilation and capacity to generate pressure is associated with the early onset and progression of a peripheral fatiguing process within the inspiratory muscles.
ATP-dependent K+ channels modulate vasoconstrictor responses to severe hypoxia in isolated ferret lungs, In normo- and hypoglycemic ferret lungs. the pulmonary vascular response to severe hypoxia (PiO2 less than or equal to 10 mmHg) is characterized by an initial intense vasoconstriction followed by marked vasodilation. whereas in hyperglycemic lungs. vasodilation is minimal. causing vasoconstriction to be sustained. In contrast. the response to moderate hypoxia is characterized by a slowly developing sustained vasoconstriction which is unaffected by glucose concentration. To determine the role of ATP-dependent K+ (KATP) channels in these responses. we examined the effects of cromakalim. which opens KATP channels. and glibenclamide. which closes them. During steady-state vasoconstriction induced in isolated ferret lungs by moderate hypoxia. cromakalim caused dose-dependent vasodilation (EC50 = 7 x 10(-7) M) which was reversed by glibenclamide (IC50 = 8 x 10(-7) M). indicating that KATP channels were present and capable of modulating vascular tone. During severe hypoxia in hypoglycemic lungs [( glucose] less than 1 mM). glibenclamide markedly inhibited the secondary vasodilation. Raising perfusate glucose concentration to 14 +/- 0.4 mM had the same effect. As a result. initial vasoconstrictor responses were well sustained. However. neither glibenclamide nor hyperglycemia affected vasoconstrictor responses to moderate hypoxia or KCl. indicating that effects during severe hypoxia were not due to nonspecific potentiation of vasoconstriction. These findings suggest that in the ferret lung (a) severe hypoxia decreased ATP concentration and thereby opened KATP channels. resulting in increased K+ efflux. hyperpolarization. vasodilation. and reversal of the initial vasoconstrictor response; and (b) hyperglycemia prevented this sequence of events.
Selective effects of acute and chronic ethanol exposure on neuropeptide and guanine nucleotide stimulated phospholipase C activity in intact N1E-115 neuroblastoma, The influence of acute and chronic ethanol exposures on the coupling of neurotensin and bradykinin receptors to phospholipase C was determined in intact N1E-115 cells. Phospholipase C was monitored by the formation of total [3H]inositol phosphates in the presence of lithium in cells prelabeled with [3H]inositol. Acute exposure to ethanol over a range of 50 to 200 mM inhibited the stimulation of [3H]inositol phosphate formation elicited by neurotensin and bradykinin. In cells chronically exposed to 100 mM ethanol for 7 days. neither basal- nor neurotensin-stimulated [3H]inositol phosphate formation differed significantly from those of control (untreated) cells. In contrast. the [3H]inositol response to bradykinin was significantly inhibited in cells chronically exposed to ethanol. Because chronic ethanol exposure had no parallel effects on either the specific binding of [3H]bradykinin or the stimulation of [3H]inositol phosphate formation by the stable GTP analog. guanine 5'-(y-thiotriphosphate). it is suggested that chronic ethanol impairs the ability of bradykinin receptors to activate the guanine nucleotide binding protein associated with phospholipase C. In addition. because chronic ethanol had no effect on the inositol phosphate response to neurotensin. it is proposed that certain types of receptor-guanine nucleotide binding protein interactions are more vulnerable than are others to disruption by chronic ethanol treatment.
Activation of phospholipase D by E-series prostaglandins in human erythroleukemia cells, Phospholipase D (PLD) can be activated by a variety of receptor agonists in different cell types. However. an effect of prostaglandins (PGs) on the activity of this enzyme has not been demonstrated previously. In this study. we found that PGE1 could stimulate PLD in human erythroleukemia cells. as measured by phosphatidylethanol formation. with an ED50 of 3.5 x 10(-7) M. PGE2 was also active. but other PGs including prostacyclin. PGD2 and PGF2. had no effect. PGE1 also elicited cyclic AMP production over the same concentration range that activated PLD. However. it is unlikely that cyclic AMP per se is responsible for PGE-induced PLD activation. because PLD could be substantially activated by PGE2 at concentrations (0.1-1 microM) which did not stimulate cyclic AMP production. Furthermore. no increase of phosphatidylethanol formation could be observed when cells were treated with other adenylyl cyclase-activating agents such as prostacyclin. forskolin and vasoactive intestinal peptide. In Ca+(+)-free medium. PLD activation by PGE1 and PGE2 was greatly reduced. indicating that their effect was through a Ca+(+)-dependent pathway. Pretreatment of cells with pertussis toxin abolished PGE1- and PGE2-stimulated PLD activity. implying the involvement of a G protein in the PGE-mediated signal transduction pathway. Our results not only indicate that E-series PGs may initiate some of their cellular effects through a novel pathway. activation of PLD. but also suggest that PGE-stimulated PLD activity in human erythroleukemia cells is Ca+(+)-dependent and is regulated via a pertussis toxin-sensitive G protein.
Studies of concanavalin A in nonobese diabetic mice. I. Prevention of insulin-dependent diabetes, Concanavalin A (Con A) administered in vivo inhibited the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic mice. By experimental day 310 only one of 10 Con A-treated animals had developed IDDM compared to six of 11 cohort controls receiving buffered saline and 65% of colony controls. Treatment consisted of an initial 70-day course of Con A at a dose of 10 micrograms/g b. wt.. i.p. in sterile saline every other day. After two deaths occurred in the Con A group. treatment was stopped at day 70. The remaining animals were given two 1-week booster doses beginning on experimental days 118 and 189. The single animal in the Con A group that eventually developed IDDM at day 293 had not received an injection for 107 days. Histological examination revealed peri-islet lymphocytosis but no islet infiltration in the Con A group. Surviving control animals showed both peri-islet and islet infiltrates. One-week Con A treatment significantly suppressed in vitro responses of spleen cells to Con A and allogeneic lymphocytes. The treatment increased the frequency of "blast-sized" cells in vivo and decreased the CD4+/CD8+ ratio among resting splenocytes. It is concluded that polyclonal T cell activation by Con A provides protection against autoimmune diabetes in nonobese diabetic mice concomitant with phenotypic and morphologic lymphocyte changes.
Comparison of patient-controlled analgesia and epidural morphine for postcesarean pain and recovery, A greater awareness of the advantages and limitations of new methods of administering postcesarean analgesia would help the obstetrician care for the recovering patient. Patient-controlled analgesia and epidural morphine are two new modalities for postoperative pain relief. The purpose of this prospective investigation was to compare their effectiveness. safety. side effects. patient satisfaction and cost. During an eight-month period. 161 women undergoing cesarean delivery were assigned to receive narcotics by either epidural morphine (76 patients) or patient-controlled analgesia (85 patients) using a combined continuous infusion and demand dosing of meperidine. The demographic characteristics of the two groups were similar. Mild or no pain was reported with similar frequencies in both groups. No reduced respiration or undesired sedation was seen in either group. The postoperative times before sitting at the bedside. ambulating. tolerating clear liquids and leaving the hospital were also comparable. No complications were encountered with patient-controlled analgesia. but pruritus and alarms from apnea monitors occurred commonly in the epidural morphine group. The costs to the patient were similar for the two groups. Patient-controlled analgesia using a combined continuous infusion and demand dosing is an acceptable alternative to epidural morphine after cesarean delivery.
Nutritional influence on the plasma and urine-free alkaline ribonuclease levels in severe trauma victims, The significance of free alkaline ribonuclease (RNase) activity as a criterion of protein metabolism and nutrition in traumatized man is evaluated in this report. Plasma and urinary levels of RNase were measured in severely injured. hypermetabolic patients and in normal controls. Significant increases in the plasma and urinary RNase levels were seen in these polytrauma victims and they were positively correlated. Plasma RNase levels were also significantly related to blood urea nitrogen and daily urinary nitrogen excretion. Urinary clearance of RNase was increased by 220% in trauma victims. although the creatinine clearance was not affected by trauma. In a subgroup of eight patients who were fed intravenously (1.4 times basal energy expenditure calories and 250-300 mg of N per kilogram per day) for 6 days. the daily excretions of urinary RNase. nitrogen. 3-methylhistidine. creatinine. and catecholamines were measured. There was a significant negative correlation between daily urine RNase and nitrogen balance. A general increase in all the metabolic parameters on the first day of feeding was seen. suggesting a nutritional stress superimposed on the trauma-induced metabolic stress. Excretion of RNase. 3-methylhistidine. and creatinine peaked on the first day of feeding and then decreased. The normal levels could not be reached even after 6 days of adequate nutrition. The results suggest that RNase levels could be used as a biomarker of protein metabolism.
Effect of taurine on total parenteral nutrition-associated cholestasis, A decrease in the formation/secretion of bile has been well documented in animals on total parenteral nutrition (TPN). Either an excess or an imbalance of amino acids (AA) has been most often implicated. In view of recent work showing that taurine promotes bile flow. bile acid secretion. and protects against hepatotoxic bile acids. the effect of adding taurine (15 mg/dL) to an AA solution was examined in guinea pigs on TPN for 3 days. The TPN-taurine group had a larger bile flow than the group without taurine and had bile acid secretory rates (BASR) similar to those of controls who were on saline by central catheter and had free access to food. Bile composition showed an increase in the secondary bile acid. 7-ketolithocholate and a concomitant decrease in chenodeoxycholate (CDC) in both experimental groups. Taurine led to a reversal of the usual predominance of glycine over taurine conjugated bile acids as well as to increases in HCO3 in cholesterol secretion. In response to a challenge with a large load of CDC. the TPN-taurine animals increased their BASR beyond those observed in the two other groups. These observations suggest that the addition of taurine to TPN solutions could play a role in the prevention of altered biliary function associated with AA solutions.
Liver dysfunction associated with long-term total parenteral nutrition in patients with massive bowel resection, Sixteen patients with massive bowel resection receiving long-term home total parenteral nutrition (HTPN) for 31 to 145 months were reviewed for evidence of liver disease. Patients were divided into three groups: group 1 with duodenocolostomy (n = 3). group 2 with an estimated 15-43 cm residual small bowel (n = 7). and group 3 with an estimated 55-120 cm residual small bowel (n = 6). Two patients in group 1 developed liver cirrhosis; one was diabetic and died of sepsis and liver failure at the 88th month on HTPN; the other died of lung cancer at the 46th month on HTPN. The third patient. followed for 33 months. had transient severe liver function abnormalities associated with a blood transfusion. In groups 2 and 3. only one patient (with a history of probable liver disease before HTPN) developed biopsy-proven cirrhosis at the 60th month of HTPN. All four patients with clinically apparent liver disease developed persistent elevation of serum aspartate aminotransferase (AST) early in HTPN. Four other patients (all in group 3) with abnormal AST values in the early phase of HTPN normalized them later; they did not develop clinical liver disease over a mean follow-up time of 110 months (range. 39-152). None of the remaining eight patients (seven in group 2 and one in group 3) had significant liver function test abnormalities and none developed clinical liver disease over a mean follow-up period of 72 months (range. 39-120).
Energy expenditure and substrate utilization in the course of renutrition of malnourished children, Energy expenditure (EE) and substrate utilization in the course of renutrition of malnourished children is not well understood in children receiving total parenteral nutrition (TPN). The aim of this study was to evaluate. during protein-glucose renutrition. EE and substrate utilization and the relationship between EE and growth and/or protein metabolism. Seven malnourished children were studied during the first 3 weeks of TPN. Weight-for-height = 81.4 +/- 8.0%. with an initial weight of 4.5 +/- 3.3 kg. Caloric support was progressively increased according to a preestablished protocol. Every 7 days the following were determined: (1) EE at 3 different 3-hour intervals per day using an open circuit indirect calorimetric system. (2) anthropometrically defined fat free mass (FFM). and (3) 24-hour urinary 3-methylhistidine (3-M-His) and protein balance. Compared to initial values. EE increased 13% at day 7 and 36% at day 14. A negative relationship was found between the amount of perfused glucose and lipid utilization (r = -0.82; p less than 0.0001). EE per kilogram of total body FFM changes during renutrition were more than EE changes per kilogram of total body weight. There was a relationship between EE and weight gain (r = 0.62; p less than 0.005) and a positive relationship between EE and protein gain (r = 0.48; p = 0.012) and 3-M-His excretion (r = 0.51; p less than 0.026).
Early enteral nutrition after brain injury by percutaneous endoscopic gastrojejunostomy, Twenty-seven patients in a series of 52 patients with severe brain injury (Glasgow Coma Scale score less than or equal to 8) underwent insertion of intestinal feeding tubes at the bedside. The technique required endoscopy with externalization of gastric and intestinal ports through the abdominal wall. Feedings were begun through the intestinal tube with Vital HN within 4 hours of its insertion with simultaneous gastric decompression via the gastric tube. Tubes were placed 2.3 (range 0-5) days after injury. Full caloric intake (3020 kcal/24 h) was achieved by 6.8 (range 2-8) days after injury to 4.2 (range 2-8) days after placement of the feeding tube. Only 1 patient failed to tolerate feedings immediately after tube insertion. Technical inability to insert the tubes occurred in 3 patients and the intestinal tube migrated into the stomach in 2 patients; diarrhea occurred in only 1 patient. With this technique. it was possible to deliver an average daily intake of 1.2 g/kg of protein in 8-day balance periods beginning at the time of tube insertion. These data included 3- to 4-day periods in which feedings were steadily increased. In 16 patients in whom nitrogen balance was measured for 8-day balance periods. average nitrogen balance was -5.7 (range -11.3 to +3.5) g/24 h. The reduction in nitrogen loss by this technique appears equal to or superior to either gastric feeding or TPN. This technique provides the ability to enterally feed a high proportion of brain-injured patients (except those in barbiturate coma) very early after injury using a bedside procedure.
Lack of predictive value of the APACHE II score in hypoalbuminemic patients, The APACHE II score predicts mortality in severely ill patients. This score does not account for the serum albumin level. Ninety-three patients (28 with serum albumin levels less than 2.5 g/dL [group I] and 65 with serum albumin levels greater than or equal to 2.5 [group II]) were retrospectively reviewed. Patients were comparable in age. APACHE II score. and compliance with required protein needs. Patients with severe hypoalbuminemia had nearly double the death rate of patients with mildly low or normal albumin concentrations (54% compared with 29%). The death rate in the severely hypoalbuminemic patients was 5.1-fold higher than would be predicted by their APACHE II score. The death rate in those patients with mildly low or normal albumin levels had only a 1.9-fold higher rate than would be predicted by their APACHE II score. It is concluded that severe hypoalbuminemia increases the risk of death significantly higher than would be predicted by the APACHE II score. APACHE II score is not as accurate in a severely hypoalbuminemic population.
Obligatory negative nitrogen balance following spinal cord injury, Obligatory nitrogen losses due to paralysis in the spinal cord-injured (SCI) patient prevent positive nitrogen balance (NB) regardless of the calorie and protein intakes. Ten patients with SCI and 20 controls with nonspinal cord injury (NSCI) matched for time. sex. age. and injury severity score (ISS) were admitted to our Level I trauma center. In both groups. total nutritional support was delivered within 72 hours of admission based on predicted energy expenditures (PEE = Harris-Benedict equation x 1.2 x 1.6) and 2 g of protein/kg of ideal body weight (IBW). Subsequent changes in nutrient delivery were based on NB. No SCI patient established positive NB during the 7-week period following injury despite an average delivery of 2.4 g of protein/kg IBW and 120% of the PEE at the time of peak negative NB (-10.5). In six SCI patients. an average increase of 25% in delivered protein and 12% in delivered calories over a 1-week period effected no change in average NB (-7.4 vs -6.8). Indirect calorimetry in five SCI patients showed that calorie intakes were 110% more than average measured energy expenditures. In contrast. 17 of 20 NCSI patients achieved positive NB within 3 weeks of admission. They required an average delivery of 2.3 g of protein/kg IBW and 110% of PEE to reach positive NB. These data demonstrate the phenomenon of obligatory negative NB acutely following SCI. Aggressive attempts to achieve positive NB in these patients will fail and result in overfeeding.
Biocompatibility of aldehyde-fixed bovine pericardium. An in vitro and in vivo approach toward improvement of bioprosthetic heart valves, Aldehyde-induced side effects limit the clinical usefulness of bioprosthetic heart valves. Treatment of aldehyde-fixed pericardium with L-glutamic acid at pH 3.5 and storage in a nontoxic. bacteriostatic solution resulted in a lower degree of calcification in 63-day subcutaneous implants in rats (13.3 +/- 2 mg calcium per gram dry weight of tissue). as compared with commercially available tissue (169 +/- 24 mg/gm. p less than 0.05). Endothelial cells died within 1 day after seeding on the commercial tissue; however. considerable endothelial cell proliferation was measured. even 14 days after seeding on L-glutamic acid-treated pericardium. Improved biocompatibility of this alternative treatment may be due to stable chemical binding of free. reactive aldehyde groups.
Plasma concentrations of calcitonin gene-related peptide in fluid overload, To investigate the hypothesis that calcitonin gene-related peptide (CGRP). a potent vasodilator. is an important physiological defence against fluid overload. plasma CGRP concentrations were measured in various degrees of fluid overload in 26 haemodialysis patients. for whom diuresis. mediated by atrial natriuretic peptide (ANP). is not a possible defence mechanism. Plasma CGRP concentrations were positively correlated with the degree of fluid excess (r = 0.815. p = 0.0001) and were significantly higher in 5 patients with severe fluid overload than in those less severely affected (143 [SE 14] vs 52 [11] pmol/l; p less than 0.001). CGRP may be an effective defence against complications of fluid overload since it can increase capitance by vasodilatation.
Transformation suppressor activity of a Jun transcription factor lacking its activation domain, The oncoprotein c-Jun is thought to be a mediator of ras transformation as both its synthesis and activity as a transcription factor are stimulated by ras expression. But c-Jun co-operates with ras in transformation assays. suggesting that they act along different pathways (reviewed in ref. 4). Here we show by means of a dominant-negative mutated transcription factor that c-Jun potentially in conjunction with other factors that interact with it is necessary for transformation by ras. The mutant Jun lacks an activation domain and blocks stimulation of transcription by several oncoproteins. including Ras. v-Src. polyoma middle T. c-Jun and c-Fos. as well as by the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibition is specific for motifs that bind Jun: activation of an NF-kappa B/Rel motif is not affected. This Jun mutant acts as an anti-oncogene in ras-transformed cells. generating non-transformed revertants that have acquired anchorage and density-dependent growth. as well as reduced tumorigenicity in vivo. Mutants of other transcription factors designed to inhibit transformation will enable us to study their role in signal transduction.
Epileptic palatal myoclonus, Palatal myoclonus (PM) is usually caused by lesions of the brainstem. We report a case of PM of focal cortical origin in a patient with epilepsia partialis continua. The PM sometimes occurred in isolation. and at other times was accompanied by unilateral face. neck. and arm twitching. This was documented by both EEG and SPECT.
A prospective trial comparing Biobrane, Duoderm and xeroform for skin graft donor sites, Many new dressings have been introduced for use on split-thickness skin graft donor sites in an effort to reduce pain at the donor site and decrease healing time. while maintaining a low infection rate and cost. To assess these factors in two such dressings. Biobrane (temporary wound dressing) (Winthrop) and Duoderm (hydrocolloid dressing) (Convatec). we compared them with a conventional fine mesh gauze dressing. xeroform. in a prospective. randomized study of 30 donor sites in the same number of patients. Wounds were considered healed when they were 100 per cent re-epithelialized and required no further dressings. Patient self-assessment of pain was quantified on a scale of zero to ten. with ten being the most severe pain. Donor sites dressed with xeroform had a healing time of 10.5 days. which was significantly better (p less than 0.05) than Duoderm (15.3 days) or Biobrane (19.0 days). although the protocol for Duoderm use (wound visualization at seven day intervals) extended the apparent healing times in this group. Duoderm was the most comfortable dressing (0.53 grade) when compared with Biobrane (1.44) and xeroform (2.41. p less than 0.05). No infections occurred in donor sites dressed with xeroform. but two developed in patients using Biobrane. One patient with a Duoderm dressing had a donor site infection during a drug-related neutropenic reaction. Xeroform was the least expensive dressing to use ($1.16 per patient). followed by Duoderm ($54.88 per patient) and Biobrane ($102.57 per patient). The results of our study confirm the usefulness of xeroform as a donor site dressing as it promotes relatively rapid healing. is easy to use and is inexpensive. We found Duoderm to be ideal for smaller donor sites when pain could be significantly reduced with minimal increase in cost. Biobrane is too costly and the infection rate too high for it to be used routinely as a skin graft donor site dressing.
Disturbance of basal and stimulated serum levels of intact parathyroid hormone in primary hyperparathyroidism, In patients with primary hyperparathyroidism. measurements were made of basal and stimulated levels of intact parathyroid hormone (PTH). The basal PTH values were elevated in all but six of 89 patients and provided clear separation towards normal individuals (n = 75) and patients with hypercalcemia of other origin (n = 34). The PTH value correlated with the serum calcium concentration in hyperparathyroidism and with the weight of excised parathyroid adenomas but not with that of chief cell hyperplasias. A constant ethylenediaminetetraacetic acid infusion during 60 minutes of induced essentially linear reductions of plasma-ionized calcium concentrations. averaging 0.02 mmol/L/10 minutes. which were associated with swift. curvilinear. elevations of PTH levels that reached a plateau after 10 to 20 minutes. The increment in serum PTH level correlated with the basal PTH value both in patients with hyperparathyroidism and controls. However. in proportion to the much greater glandular mass in the patients with hyperparathyroidism. the secretion of PTH was relatively reduced. The findings support the value of the intact PTH assay in the differential diagnosis of hypercalcemia and show that PTH secretion in vivo is extremely sensitive to hypocalcemic stimulation. that the pathological parathyroid tissue in hyperparathyroidism is characterized by a reduction of hormone release per unit weight. and that the hormone secretion in hyperparathyroidism operates closer to its maximal capacity than under normal circumstances.
Disruption of the blood-brain barrier in open and closed cranial window preparations in rats, The goal of this study was to determine whether the severity of disruption of the blood-brain barrier during acute hypertension is similar in open and closed cranial window preparations. Intravital fluorescent microscopy and fluorescein-labeled albumin were used to evaluate disruption of the blood-brain barrier under control conditions and during acute arterial hypertension in 10 rats equipped with an open cranial window and in six rats equipped with a closed cranial window. Permeability of the blood-brain barrier was quantified by calculating the clearance of fluorescein-labeled albumin and by counting the number of microvascular leaky sites under control conditions and during acute hypertension. Pressure in cerebral venules and intracranial pressure were measured in rats equipped with an open cranial window and a closed cranial window. respectively. under control conditions and during acute hypertension. In rats equipped with an open cranial window. arterial pressure increased from 118 +/- 6 to 189 +/- 3 mm Hg (mean +/- SEM) and pial venous pressure increased from 7 +/- 1 to 22 +/- 3 mm Hg during acute hypertension induced with 30 micrograms/kg/min phenylephrine for 5 minutes. In addition. the clearance of fluorescent albumin increased from 0.11 +/- 0.03 to 1.2 +/- 0.4 ml/sec x 10(-6) and the number of microvascular leaky sites increased from 0 to 25 +/- 1 during phenylephrine infusion. In rats equipped with a closed cranial window. arterial pressure increased from 122 +/- 5 to 187 +/- 7 mm Hg and intracranial pressure increased from 3 +/- 1 to 12 +/- 1 mm Hg during the intravenous infusion of 30 micrograms/kg/min phenylephrine for 5 minutes.
Lack of effect of PN 200-110 on neuronal injury and neurological outcome in middle cerebral artery-occluded rats, We evaluated the influence of a continuous intravenous infusion of 0.24 mg/kg PN 200-110 started 20 minutes before the induction of ischemia and continued for 2 hours on infarct size. histopathology. and neurological outcome in middle cerebral artery-occluded rats treated with PN 200-110 (n = 8). placebo (n = 7). or saline (n = 8). Neurological examination was performed 24 hours after occlusion. We quantified infarct size by 2.3.5-triphenyl-tetrazolium chloride. hematoxylin and eosin. and Nissl staining and by computerized analysis of tracings of the infarcted areas and evaluated neuronal injury at the infarct periphery. The different types of ischemic cell damage were quantified by direct visual counting. We found no differences among saline-. placebo-. and PN 200-110-treated rats regarding infarct size. amount of neuronal alteration. and neurological outcome. Our results indicate the lack of a significant protective effect of this drug in experimental focal ischemia.
Genomic structure of the human prion protein gene, Creutzfeld-Jacob disease and Gerstmann-Straussler syndrome are rare degenerative disorders of the nervous system which have been genetically linked to the prion protein (PrP) gene. The PrP gene encodes a host glycoprotein of unknown function and is located on the short arm of chromosome 20. a region with few known genes or anonymous markers. The complete structure of the PrP gene in man has not been determined despite considerable interest in its relationship to these unusual disorders. We have determined that the human PrP gene has the same simple genomic structure seen in the hamster gene and consists of two exons and a single intron. In contrast to the hamster PrP gene the human gene appears to have a single major transcriptional start site. The region immediately 5' of the transcriptional start site of the human PrP gene demonstrates the GC-rich features commonly seen in housekeeping genes. Curiously. the genomic clone we have isolated contains a 24-bp deletion that removes one of five octameric peptide repeats predicted to form a B-pleated sheet in this region of the PrP. We have also identified 5' of the PrP gene an RFLP which has a high degree of heterozygosity and which should serve as a useful marker for the pter-12 region of human chromosome 20.
Pyruvate dehydrogenase deficiency due to a 20-bp deletion in exon II of the pyruvate dehydrogenase (PDH) E1 alpha gene, A 20-bp deletion in the last exon of the pyruvate dehydrogenase (PDH) E1 alpha gene was found in a severely affected female patient diagnosed with PDH deficiency. PDH-complex activity in the patient's fibroblasts was 22% of that in normal controls. The mutation was characterized using PCR techniques with both patient cDNA and genomic DNA. followed by sequencing of the products. E1 beta cDNA sequence was found to be the same as that in controls. The deletion causes a frameshift and the occurrence of a premature stop codon. Western blot analysis revealed an extra band migrating just above the PDH E1 beta band. Northern blot analysis showed normal levels of both E1 alpha and E1 beta message when probed with the respective cDNAs. However. a larger intermediate-size transcript was observed for this patient in the E1 beta blot. The 20-bp deletion was not found in either parent's genomic DNA. and hence we conclude that the mutation must have occurred de novo. either in the germ-line cells or immediately following fertilization.
Utility of a transdermal delivery system for antihypertensive therapy. Part 1, A retrospective evaluation of patient-level Medicaid claims data from two states was undertaken to discern the fiscal utility of transdermally delivered clonidine versus both the oral formulation of clonidine and oral formulations of eight other antihypertensive agents. In the first phase of our two-part study. we compared paid claims data (n = 1.135) from Florida for transdermal and oral clonidine. Multivariate regression analysis was used to evaluate the incremental impact of six variables on health-care expenditures in the first year after patients were given a diagnosis of hypertension. These variables were: age. gender. prior utilization of medical services. regimen complexity. and dosage formulation. Patients prescribed transdermal clonidine experienced a significant (p less than or equal to 0.001) increase in prescription expenditures and significant reductions in the use of physician (p less than or equal to 0.05). laboratory (p less than or equal to 0.10). and hospital (p less than or equal to 0.05) services. Moreover. savings were maximized (p less than or equal to 0.001) where multi-drug regimens incorporated the transdermal delivery system. In the second phase of our study we compared paid claims data (n = 8.894) from South Carolina for transdermal clonidine and for nine oral antihypertensive agents: atenolol. captopril. clonidine. diltiazem. enalapril. metoprolol. prazosin. terazosin. and verapamil-SR. Once again. regression analysis was used. this time to evaluate the incremental impact of five variables on health-care expenditures in the first year post diagnosis: age. gender. prior utilization of medical services. regimen complexity. and Medication Possession Ratio (MPR). an index of compliance. The data from part 2 of our study revealed that patients assigned a b.i.d. oral antihypertensive agent experienced a significant reduction (p less than or equal to 0.05) in MPR and a significant (p less than 0.05) increase in health-care expenditures when compared to patients prescribed the transdermal delivery system and to patients prescribed once-daily oral medications. These data confirm previous findings concerning the impact of complicated dosing regimens on compliance in hypertensive patients. In this two-part paper we report the data from both phases of our study.
Small area analysis of hospital discharges for musculoskeletal diseases in Michigan: the influence of socioeconomic factors, PURPOSE: The rise in health care costs has occasioned a number of initiatives in an attempt to reduce the rate of increase. Despite the growth of health maintenance organizations and preferred provider organizations and the introduction of Medicare's prospective payment system. health care costs have continued to increase. Coincident with these efforts. a number of researchers have shown that there exists wide variation in age-adjusted hospital discharge rates. which translate into significant variation in per capita expenditures. Much of the focus on the reasons for hospital admission variability has been on physician practice variation. If most of the variation in hospital discharge rates is due to physician practice style. then payment systems can be developed (e.g.. capitation) that limit physician practice variation without harming patients. We examined socioeconomic factors in Michigan communities to assess their association with hospital discharge rates for patients with musculoskeletal diseases. PATIENTS AND METHODS: Data on hospital discharges from 1980 and 1987 were taken from the Michigan Inpatient Data Base. All admissions from the major diagnostic category 8. diagnosis-related group (DRG) 209-256 were included. Zip code-specific hospitalization data were grouped into small geographic areas or hospital market communities (HMCs). Discharge rates were calculated. and profiles of the socioeconomic characteristics of each of the HMCs were developed. A Poisson regression model with an extrasystematic component of variance was used to analyze the association of HMC socioeconomic characteristics with age-adjusted hospital use. RESULTS: We found that four socioeconomic variables. average annual income per capita. percent of the population with four years of college. percent of the population living in an urban area. and percent of families with incomes below the poverty line. explained 26.6% (R2) of the variation in overall hospital discharge rates (p less than 0.001). Moreover. we found that the ability of the model to explain variability was influenced by the type of disease. and that these socioeconomic variables had a consistent effect across the range of DRGs. Finally. we noted that. over the period of 1980 to 1987. socioeconomic factors remained important in explaining hospital use despite the dramatic changes in the delivery of care over this period. CONCLUSION: Socioeconomic factors play a significant role in explaining the observed variation in hospital discharge rates for musculoskeletal diseases. Models utilizing only physician practice variation to account for the population-based differences in discharge rates are overly simplistic. In order to ensure that vulnerable subsets of the population are not harmed by the introduction of cost-containment strategies based on simplistic models. more attention must be paid to the socioeconomic and epidemiologic factors related to hospital use.
Injuries among young soccer players, We registered all new injuries among 496 male youth soccer players. aged 12 to 18 years. during the course of one year. The incidence of injury was 3.7 injuries per 1000 hours of soccer per player. The incidence increased with age. and at the higher ages within the youth players. approached the incidence rate of senior players (age greater than or equal to 18 years). Seventy percent of the injuries were located in the lower extremities. particularly the knee (26%) and ankle (23%). Back pain occurred in 14% of players. Fractures. which accounted for 4% of injuries. were most often in the upper extremities. We conclude that youth soccer is a relatively low-risk sport with an injury pattern that differs slightly from that of senior players.
Syndesmotic ankle sprains, In this study we reviewed ankle sprains in a professional football team over a 6 year period. Fifteen players who sustained syndesmotic ankle sprains were compared with 28 players who sustained significant lateral ankle sprains. Players with syndesmotic sprains missed significantly more games and practices and they received substantially more treatments than players with lateral ankle sprains. Physical examination findings. results of radiographic evaluations. and etiologic factors are discussed. The external rotation stress test. a clinical method for diagnosis of this type of sprain at the time of injury. is described. Results of this study clearly demonstrate a prolonged recovery time for syndesmotic ankle sprains. Physicians and trainers who are aware of this injury can differentially diagnose these two types of sprains in the early postinjury period by the method described.
Schistosoma mansoni tropomyosin: production and purification of the recombinant protein and studies on its immunodiagnostic potential, A cDNA that encodes Schistosoma mansoni tropomyosin. except for 10 amino acids at the amino terminus. has been cloned into a pOTSNCO plasmid vector. Induced expression resulted in a constant level of recombinant protein production. The recombinant S. mansoni tropomyosin was purified from preparative SDS-PAGE gel and by a combination of 20% ammonium sulfate fractionation and fast protein liquid chromatography-ion-exchange chromatography. The purified recombinant S. mansoni tropomyosin was tested as an immunodiagnostic reagent in Western blot and enzyme-linked immunosorbent assays. Sera from individual patients with chronic S. mansoni infection. but not S. haematobium. S. japonicum. parasitic infections other than schistosomiasis. and without infection reacted with the recombinant tropomyosin. The species specificity of S. mansoni tropomyosin suggests that further study of its potential as an immunodiagnostic reagent is warranted.
Inhibitory activity against Plasmodium vivax sporozoites induced by plasma from Saimiri monkeys immunized with circumsporozoite recombinant proteins or irradiated sporozoites, Two Saimiri monkey vaccine trials have been conducted comparing four recombinant Plasmodium vivax circumsporozoite proteins and irradiated sporozoites. Only a small number of animals immunized with certain recombinants or irradiated sporozoites became fully protected against sporozoite challenge. Preimmunization and postimmunization plasma samples obtained from 30 monkeys on the day of challenge were tested in an in vitro assay based on sporozoite development into exoerythrocytic stages in primary cultures of Saimiri monkey hepatocytes. The percentage of inhibition was determined by comparison of the number of exoerythrocytic stages developing from sporozoites preincubated with a preimmunization and a postimmunization plasma sample of each animal. The plasma samples of the day of challenge of nearly all the immunized animals had a variable. but significant inhibitory effect. when compared with the corresponding preimmunization sample. We found no correlation between the degree of in vitro inhibition of liver stage development. and the in vivo protection against sporozoite challenge of individual animals. The variable results of the incubation of sporozoites with "normal" plasma of different animals indicates that the in vitro results were affected by plasma factors unrelated to anti-sporozoite antibodies.
Modifications by halothane of responses to acute hypoxia in systemic vascular capacitance, resistance, and sympathetic nerve activity in dogs, To examine the effects of halothane on segmental vascular responses to hypoxia. we used cardiopulmonary bypass with venous outflow divided into three compartments (splanchnic. coronary. and "other") in dogs anesthetized with pentobarbital sodium. The reservoir volume changes represented the inverted changes in systemic blood volume (SBV). In addition. sympathetic efferent nerve activity (SENA) was simultaneously recorded from the ventral ansa subclavian nerve. Experiments were done in two groups: severe hypoxia (PO2 of 19 mm Hg) and moderate hypoxia (PO2 of 50 mm Hg). Hypoxia provoked a significant decrease in SBV of 22.3 +/- 3.1 mL/kg and 10.5 +/- 1.6 mL/kg during severe and moderate hypoxia. respectively. Two percent end-tidal halothane attenuated the decrease in SBV to 10.3 +/- 1.3 mL/kg during severe hypoxia. and 1% halothane attenuated the decrease to 3.7 +/- 1.4 mL/kg during moderate hypoxia. Subsequent chemoreceptor denervation in the presence of 1% halothane completely abolished the moderate hypoxia-induced decrease in SBV. In the presence of halothane. vascular resistance during hypoxia was significantly less than that during control conditions. Sympathetic efferent nerve activity increased significantly during severe and moderate hypoxia by about 180% and 55%. respectively. During severe hypoxia. halothane did not cause any change in the response of SENA. whereas during moderate hypoxia. halothane tended to decrease SENA. but not significantly. and subsequent chemoreceptor denervation completely abolished the increase in SENA. Coronary resistance showed a hypoxia-induced reduction that was not influenced by halothane. These results suggest that acute hypoxia causes a decrease in SBV dependent on the severity of hypoxia.
Effect of chemical conjugation of recombinant single-chain urokinase-type plasminogen activator with monoclonal antiplatelet antibodies on platelet aggregation and on plasma clot lysis in vitro and in vivo, The murine monoclonal antiplatelet antibodies MA-TSPI-1 (directed against human thrombospondin) and MA-PMI-2. MA-PMI-1. and MA-LIBS-1 (directed against ligand-induced binding sites [LIBS] on human platelet glycoprotein IIb/IIIa) were conjugated with recombinant single-chain urokinase-type plasminogen activator (rscu-PA) using the cross-linking reagent N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). The conjugates (rscu-PA/MA-TSPI-1. rscu-PA/MA-PMI-2. rscu-PA/MA-PMI-1. and rscu-PA/MA-LIBS-1). purified by immunoadsorption and gel filtration. were obtained with recoveries of 34% to 45%. with an average stoichiometry of 1.6 to 1.8 IgG molecules per rscu-PA molecule. and with unaltered specific activities and affinities. Preincubation of human platelet-rich plasma with rscu-PA/MA-PMI-2. rscu-PA/MA-PMI-1. or unconjugated rscu-PA resulted in partial inhibition of ADP-induced aggregation; 25% inhibition was obtained with 63 micrograms/mL rscu-PA and with 6 micrograms u-PA/mL rscu-PA/MA-PMI-2 or 1.2 micrograms u-PA/mL rscu-PA/MA-PMI-1. In an in vitro system composed of a 125I-fibrin-labeled platelet-rich human plasma clot immersed in normal human plasma. the conjugates had threefold to greater than 15-fold less fibrinolytic potency than unconjugated rscu-PA. The thrombolytic potency of rscu-PA/MA-PMI-1 and rscu-PA/MA-LIBS-1 was compared with that of rscu-PA and that of a control conjugate rscu-PA/MA-1C8 in a pulmonary embolism model in the hamster. using clots prepared from platelet-poor or platelet-rich human plasma. Lysis was measured 30 minutes after the end of a 60-minute intravenous infusion of the thrombolytic agents. rscu-PA. rscu-PA/MA-PMI-1. rscu-PA/MA-LIBS-1. as well as rscu-PA/MA-1C8 had comparable thrombolytic potencies (percent lysis per dose administered) towards platelet-poor human plasma clots. In contrast. the thrombolytic potency of rscu-PA/MA-PMI-1 and of rscu-PA/MA-LIBS-1 towards platelet-rich clots was 2.3- to 3-fold higher than that of rscu-PA (P less than .005) and fivefold to sevenfold higher than that of the control conjugate (P less than .01).
Interferon-gamma enhances growth factor-dependent proliferation of clonogenic cells in acute myeloblastic leukemia, Interferon-gamma (IFN-gamma) has been reported to antagonize the stimulatory effect of various conditioned media on the growth of normal hematopoietic progenitor cells and clonogenic blasts from patients with chronic myelogenous leukemia (CML) and acute myeloblastic leukemia (AML). In the present study. using purified recombinant cytokines and homogenous cell populations. we provide evidence for a synergistic or additive effect of IFN-gamma with recombinant human (rhu) hematopoietic growth factors in the stimulation of clonogenic blasts from most AML patients examined. Under conditions of limiting cell concentration. rhuIFN-gamma alone showed little effect on blast proliferation. whereas in conjunction with recombinant human interleukin-3 (rhuIL-3). IFN-gamma significantly enhanced colony formation in 13 of 15 AML cases. Maximal stimulation was obtained at low concentrations of IFN-gamma (2 to 20 pmol/L) in four cases and at higher concentrations (700 to 7.000 pmol/L) in the remainder. IFN-gamma also synergized with recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) in 9 of 13 cases. Within 1 hour of exposure. IFN-gamma induced a twofold to fourfold accumulation of tumor necrosis factor alpha (TNF alpha)-specific transcripts in AML blasts and several AML cell lines that include HL-60 and OCI-AML 1. Further. the synergy between IFN-gamma and IL-3 on AML blasts was partially or completely abrogated by a TNF alpha neutralizing antibody. suggesting that growth enhancement by IFN-gamma may be mediated through TNF alpha production in AML blast culture. Exposure of normal precursors (burst-forming unit-erythroid [BFU-E] and colony-forming unit granulocyte-macrophage [CFU-GM]) to IFN-gamma also resulted in significant growth enhancement. suggesting that the proliferative response elicited by IFN-gamma was not limited to AML blasts. Finally. in M07-E. an IL-3-dependent human "megakaryoblastic" cell line. IFN-gamma also significantly enhanced IL-3-supported colony formation. much in the same way as in primary AML blasts. In contrast. IFN-gamma inhibited growth of all CSF-independent leukemic cell lines tested. This inhibition was partially alleviated by anti-TNF alpha antibody. In summary. our data indicate that IFN-gamma can enhance or antagonize cell proliferation. depending on the cell type. Further. TNF alpha appears to mediate the biologic effect of IFN-gamma either in growth stimulation or growth inhibition.
Intracranial, intraaxial, space-occupying lesions in patients with intractable partial seizures: an anatomoclinical, neuropsychological, and surgical correlation, Fifty of approximately 250 patients evaluated for intractable partial seizures were shown to have a space-occupying lesion detected with radiographs and/or neuroimaging. Twenty-eight males and 22 females had a mean age at seizure onset of 13 years and a mean duration of seizures of 11 years. All patients had closed-circuit television with EEG monitoring and complete neurologic and neuropsychological assessment. Findings were correlated with lesion location and surgical data. Twenty-seven lesions (54%) were located in the temporal lobe. Thirty-five lesions (70%) were neoplastic. All patients with temporal lobe lesions had complex partial seizures. as did 74% of patients with extratemporal lesions. A good correlation between clinical seizure characteristics and lesion localization was found with the temporal. occipital. and frontal lesions but not with the parietal lesions. Sixty-six percent of patients had focal interictal EEG findings. Lateralization corresponded to the side of the lesion in 64% and was localized to the region of the lesion in 30%. Lateralized ictal EEGs occurred in 58% of patients. corresponding with the side of the lesion in all but one patient. Abnormal findings on neuropsychological testing were congruent with lesion lateralization in 56% of patients and were localized to the region in 26%. Thirty-nine of 47 patients who underwent a subtotal lobectomy to include the lesion are seizure-free after greater than or equal to 1 year of follow-up. and five others are markedly improved.
Surgical versus medical treatment for epilepsy. II. Outcome related to social areas, We conducted a retrospective parallel cohort study comparing surgical and medical treatment for epilepsy. The surgical group contained all 201 patients treated with resective surgery for epilepsy in Norway since the first operation in 1949 until January 1988. The 185 patients in the control group. medically treated only. were closely matched for year of treatment. age at treatment. sex. seizure type. and neurologic deficit before treatment. Between 75 and 95% of the survivors (median 17 years after treatment) completed two questionnaires on their social situation. Although surgical treatment improved the seizure situation (about one-fourth had some neurologic deficit). a considerably smaller long-range influence on different social aspects was observed. There were no significant differences between the two groups in educational status. social pensions. social status. marital status. fertility. dependency in residential situation. the need for aid in daily activities of living (ADL). or the need for being looked after. when we controlled for pretreatment status. In all. 25.3% of the surgically treated patients and 8.5% of the controls were not receiving anti-epileptic drugs (AEDs) at the time of investigation (Mann-Whitney U test. two-tailed p = 0.0011). A considerably higher proportion of the surgically treated (53.2%) than control patients (24.2%) claimed that the treatment had improved their "working ability" (Mann-Whitney U test. two-tailed p less than 0.0001). but this resulted in significant improvements in the actual working situation only for those in regular education or work before treatment (chi 2 = 6.514. p = 0.038).
Double-blind study of Gabapentin in the treatment of partial seizures, Forty-three patients completed a double-blind. placebo-controlled study of Gabapentin (GBP) as add-on therapy in partial and secondarily generalized seizures. All patients were followed for an initial 3-month baseline period. after which they were randomly allocated to receive either a placebo or 900 or 1.200 mg/day GBP for 3 months. A statistically significant difference in seizure frequency from the baseline to the treatment phase was noted between patients receiving placebo and GBP 1.200 mg. in whom seizure frequency decreased 57%. The GBP dosage of 900 mg appeared to be ineffective. A close relationship was observed between the serum GBP concentrations and the GBP dosage based on the seizure frequency. Serum GBP concentrations greater than 2 micrograms/ml resulted in a lower frequency of seizures. The adverse effects were minor and consisted mainly of transient drowsiness. GBP appears to be effective in the treatment of partial epileptic seizures in a dosage-related manner.
Effects of magnesium sulfate on pentylenetetrazol-induced status epilepticus, The use of magnesium sulfate (MgSO4) as an anticonvulsant is controversial. Status epilepticus was induced in 0.5% halothane-anesthetized Wistar rats with a threshold (90 mg/kg) or suprathreshold (200 mg/kg) dose of intravenous (i.v.) pentylenetetrazol (PTZ) under stereotactic hippocampal depth electrode monitoring. Fifteen minutes after seizure induction. the maximum hemodynamically tolerated dose of MgSO4 (10 mg/kg/min in 22 min) was administered i.v. MgSO4 was ineffective in altering seizure discharge. A subgroup of nine animals received hypertonic mannitol before MgSO4 to open the blood-brain barrier (BBB) to facilitate Mg2+ CNS penetration. Again MgSO4 was ineffective in attenuating epileptic activity. These results support the contention that MgSO4 is not an effective treatment for status epilepticus. We hypothesize that because Mg2+ blocks Ca2+ influx into the neuron through the N-methyl-D-aspartate (NMDA) receptor-operated calcium channel in a voltage-dependent manner it would be ineffective in neurons that are continuously depolarizing as in status epilepticus.
Role of Mls-1 locus and clonal deletion of T cells in susceptibility to collagen-induced arthritis in mice, The role of T cell-mediated and humoral immunity to type II collagen has been well documented in collagen-induced arthritis (CIA). Previous work from our laboratory has indicated that genomic deletions of TCR V beta genes may play a role in CIA resistance in mice. This indicated a selectivity of TCR usage by autoreactive T cells in CIA in mice. Certain strains of mice. although having a normal genomic V beta TCR repertoire. can show clonal deletion of peripheral T cells that bear specific V beta gene products in their TCR. These clonally deleted T cells are reactive with self-Ag such as minor lymphocyte stimulation (Mls) Ag. An Mls-congenic strain. BALB.D2.Mlsa. which differs only at the Mls-1 a locus from BALB/c (Mls-1b). was used to examine the effect of clonal deletion of Mls-1a-reactive T cells in CIA. These two strains were crossed to three CIA-susceptible strains. B10.RIII (H-2r. Mls-1b). DBA/1 (H-2q. Mls-1a). and B10.Q (H-2q. Mls-1b). and the crosses were injected with type II collagen. A significantly decreased incidence of arthritis was observed in the (BALB.D2.Mlsa x B10.Q)F1 hybrids. compared with (BALB/c x B10.Q)F1 hybrids. upon immunization with chick type II collagen. The BALB.D2.Mlsa cross mice also had significantly lower levels of antimouse collagen antibodies. Flow cytometric analysis confirmed the clonal deletion of Mls-1a-reactive V beta 8.1. V beta 6. V beta 7. and V beta 9 subsets in the (BALB.D2.Mlsa x B10.Q)F1 hybrids. The study of H-2q/d mice in (BALB.D2.Mlsa x B10.Q) x B10.Q back-crosses demonstrated a significant correlation between CIA resistance and Mls-1a locus. On the other hand. B10.RIII crosses showed only a modest decrease in CIA incidence in the presence of Mls-1a. As expected. all the DBA/1 crosses had an equal incidence of CIA. which was somewhat less than that seen in DBA/1 mice themselves. These studies point out that the Mls-1a locus could play a role in decreasing CIA incidence by clonal deletion of T cells bearing specific V beta TCR. which may be involved in the pathogenesis of CIA. The influence of the clonal deletion of T cells on CIA. and hence the usage of specific V beta TCR by autoreactive anti-type II collagen T cells. however. depends not only on the source of the type II collagen and the MHC class II molecules involved but also on other background genes in mice.
Unusual alpha beta-T cells expanded in autoimmune lpr mice are probably a counterpart of normal T cells in the liver, Autoimmune MRL-lpr/lpr (lpr) mice develop severe lymphadenopathy. characterized by the accumulation of alpha beta-T cells with CD4-8- double negative (DN) phenotype. at the onset of disease. We previously demonstrated that the liver is a major site for the proliferation of such DN alpha beta-T cells. Herein. we further demonstrate that a large proportion of alpha beta-T cells in the liver and other organs. except the thymus. of lpr mice have unique properties. such as DN phenotype. relatively dull TCR intensity. a preponderance of V beta 8+ cells. and Pgp-1 expression. Interestingly. alpha beta-T cells in the liver of normal mice were found to consist of T cells with intermediate intensity of TCR (i.e.. brighter than thymic dull TCR and lower than thymic bright TCR) as well as with bright intensity of TCR in the immunofluorescence test. These hepatic alpha beta-T cells with intermediate TCR in normal mice were found to have properties similar to those of alpha beta-T cells in lpr mice. These results suggest that abnormal alpha beta-T cells in lpr mice are a counterpart of normal T cells in the liver. An abnormal expansion of such T cells in the liver might be fundamental to the pathogenesis involved in these autoimmune mice.
Abnormal regulation of IFN-gamma secretion in vitamin A deficiency, T lymphocytes from vitamin A-deficient (A-) mice show a decreased ability to stimulate B lymphocytes for Ag-specific secondary IgG1 responses in vivo and in vitro. Experiments reported here traced the molecular basis for this functional defect to an overproduction of IFN-gamma by A- CD4+ T cells compared with cells from A-sufficient (A+) mice. Secretion of IL-2 and IL-4 by cells from A- and A+ mice was equivalent. Retinoic acid supplementation in vitro decreased IFN-gamma secretion from A- T cells. indicating that IFN-gamma production is retinoid-responsive. Adding IFN-gamma neutralizing antibodies to cultures established with cells from immune A- mice substantially increased IgG1 production. whereas IL-4 addition moderately increased IgG1 production. Adding retinoic acid to the cultures either at initiation. or 48 h later. fully restored IgG1 production by A- cultures to the level of A+ control cultures. These results are consistent with a role for vitamin A in negatively regulating IFN-gamma secretion.
Control of T cell responses to staphylococcal enterotoxins by stimulator cell MHC class II polymorphism, The bacterial toxic mitogens or superantigens are a family of related proteins that elicit potent T cell proliferative responses. These responses require APC that express MHC class II proteins. but they are not MHC restricted and they do not depend on a processing step. presumably because these mitogens bind directly to MHC class II molecules. These mitogens stimulate T cells by interacting in an unknown way with the portion of the TCR encoded by certain V beta gene segments. In this paper. we explore the importance of MHC class II polymorphism in T cell responses to staphylococcal enterotoxins. We find that certain MHC molecules present SEB to V beta 8-bearing T cells far better than others. These data suggest that one route of host defence against bacterial toxic mitogens may be to alter MHC class II molecules so that stimulation is inhibited.
Defective presentation of endogenous antigens by a murine sarcoma. Implications for the failure of an anti-tumor immune response, MHC class I-restricted CTL play a central role in the immune response against methylcholanthrene (MCA)-induced sarcomas in mice. We. therefore. hypothesized that MCA-induced tumors may evade immune recognition by failing to present Ag to CD8+ CTL. Of a number of previously described MCA-induced sarcomas. one. MCA 101. fails to induce CTL. is nonimmunogenic. and grows rapidly and lethally in nonimmunosuppressed recipients. To better understand the nonimmunogenicity of MCA 101 we examined its ability to present foreign Ag to CTL. Unlike immunogenic sarcomas. MCA 101 failed to present endogenously synthesized influenza virus Ag to influenza virus-specific CTL. The deficiency in presentation of endogenous Ag by MCA 101 was attributed to a markedly reduced rate of synthesis of class I molecules because up-regulation of class I synthesis by IFN-gamma greatly increased the presentation of influenza A virus Ag. Despite low levels of cell surface class I expression. MCA 101 presented exogenous peptide Ag to anti-influenza CTL with efficiency similar to immunogenic MCA sarcoma cell lines. These findings could not be attributed to deficiencies in class I assembly or transport. as has been suggested by others who have studied mutant cells with defective Ag presentation. Furthermore. our studies suggest that some tumor cells can escape recognition by CTL and subsequent immune eradication by suppressing presentation of endogenous Ag.
Effect of polymyxin B on experimental shock from meningococcal and Escherichia coli endotoxins, Meningococcemia is the most frequent cause of septic shock in healthy children. To determine whether polymyxin B (PMB) might improve mortality from meningococcal shock. its protective activity was evaluated in rabbits challenged with an LD90 of meningococcal lipooligosaccharide (LOS) and compared with an LD80 of Escherichia coli O111:B4 lipopolysaccharide (LPS). PMB (5 mg/kg) administered intravenously 30 min before meningococcal LOS challenge had no significant effect on heart rate. mean arterial pressure. serum bicarbonate. serum tumor necrosis factor (TNF) levels. or survival relative to controls. However. PMB premixed with LOS in vitro increased serum bicarbonate levels (P less than .05) and improved 24-h survival (P less than .05). In contrast. PMB given before E. coli LPS challenge increased serum bicarbonate levels. decreased TNF levels. and improved 24-h survival (all. P less than .05). In vitro studies confirmed that PMB at 10 micrograms/ml neutralized E. coli LPS but not meningococcal LOS activity. Thus. pretreatment with PMB apparently protects rabbits against shock induced by E. coli LPS but not by meningococcal LOS.
PET studies of fluorodeoxyglucose metabolism in patients with recurrent colorectal tumors receiving radiotherapy, Forty-four patients with recurrent colorectal carcinoma were examined prior to a combination of conventional photon radiotherapy (40 Gy) and neutron therapy (10 Gy). Twenty-one of these underwent a PET examination after photon therapy and 12 also were studied after the end of combined therapy. CEA plasma levels were measured from blood samples taken immediately before the PET study. A significant decrease in FDG uptake despite good palliative results were observed in only 50% of the patients. This may be explained by inflammatory reactions caused by radiation injury. Inflammation and metabolically active residual tumor tissue cannot be distinguished. It is concluded that an observation interval longer than 6 mo may more effectively detect residual tumor activity. In 14 of 41 examinations. an increased FDG uptake was associated with a normal CEA value. and in only two cases were normal FDG uptake values and increased CEA levels found. suggesting that PET is more sensitive than the measurements of CEA plasma levels for tumor recurrence.
X-linked recessive nephrolithiasis with renal failure, BACKGROUND AND METHODS. Nephrolithiasis may occur as a consequence of a number of hereditary disorders. We describe a large kindred from northern New York with hereditary nephrolithiasis accompanied by urinary concentrating defects. nephrocalcinosis. renal insufficiency. and renal wasting of potassium. phosphate. calcium. and uric acid. The pattern of inheritance was established by examining the patients and their records and interviewing family members. Selected members of the family were evaluated in detail. with measurements of erythrocyte cation fluxes and carbonic anhydrase (carbonate dehydratase) activity. RESULTS. The kindred consisted of 162 family members from six generations. All nine affected persons were male and appeared to have inherited the disease from their mothers. No affected man transmitted the gene to a son. but the daughters of affected men were carriers. The patients presented in childhood with calcium nephrolithiasis and proteinuria. with progression to nephrocalcinosis. urinary concentrating defects. and renal insufficiency. Renal biopsies revealed tubular atrophy. interstitial fibrosis. and glomerulosclerosis; the characteristic features of other forms of hereditary nephritis were absent. Abnormalities in the renal excretion of calcium. phosphate. potassium. and uric acid were found only in the adult members of the kindred. although renal biopsies were abnormal even in younger members. In one patient who has had a renal transplant for seven years. the disease has not recurred. CONCLUSIONS. This kindred manifested an X-linked recessive nephrolithiasis with renal failure. a new form of hereditary renal disease. Most of the identifiable physiologic abnormalities occurred after the development of nephrolithiasis and renal insufficiency and may not be of pathogenetic importance.
Production of interferon gamma, interleukin 2, interleukin 4, and interleukin 10 by CD4+ lymphocytes in vivo during healing and progressive murine leishmaniasis, The expression of interleukin (IL) 2. IL-4. IL-10. and interferon gamma (IFN-gamma) by lymphocyte subsets was examined during infection of resistant C57BL/6 and susceptible BALB/c mice with the protozoan parasite Leishmania major. CD4+ and CD8+ T lymphocytes and B lymphocytes were isolated from the lymph nodes draining infectious lesions. and their RNA was examined for lymphokine transcripts. Distinct patterns of CD4+ cell cytokine expression were apparent: C57BL/6 CD4+ cells contained IFN-gamma and IL-2 mRNA. whereas BALB/c CD4+ cells expressed IL-4 and IL-10 message. CD8+ cells contributed little lymphokine expression during disease. but B cells were a major source of IL-2 mRNA in both strains of mice. BALB/c mice made resistant by treatment with anti-CD4 antibody at the time of infection repopulated lymph nodes with CD4+ cells that expressed IL-2 and IFN-gamma. Protective treatment with anti-IL-4 antibody in vivo also resulted in the appearance of CD4+ cells with increased IFN-gamma and diminished IL-4 and IL-10 expression. These data establish CD4+ cells as the primary source of IFN-gamma in healing mice and of IL-4 and IL-10 during progressive infection and confirm that the spectral extremes of this disease are characterized by the presence of CD4+ cells expressing Th1 or Th2 phenotypes in vivo.
Gamma-interferon promotes proliferation of adult human astrocytes in vitro and reactive gliosis in the adult mouse brain in vivo, Reactive gliosis is a characteristic response of astrocytes to inflammation and trauma of the central nervous system. To investigate whether soluble factors (cytokines) from inflammatory mononuclear cells that accumulate at lesion sites can provide the cellular signals to initiate gliosis and to identify such cytokines. we have tested and found that supernatants derived from subsets of activated human T lymphocytes (CD8+ or CD4+) are potent mitogens for cultured human adult astrocytes. This effect is blocked by a neutralizing antibody to gamma-interferon (IFN). Recombinant IFN alone can induce proliferation of human adult astrocytes in vitro and increase the extent of trauma-initiated gliosis in the adult mouse brain. The astrocyte proliferation-inducing activity of supernatants of glial cultures treated with IFN can be completely blocked with IFN-neutralizing antibody. suggesting that the proliferative effect does not require intermediary cytokines or cells. These results implicate IFN as an important mediator of the gliosis observed in pathologic conditions of the adult central nervous system associated with infiltrating lymphocytes.
Genetic analysis of microtubule motor proteins in Drosophila: a mutation at the ncd locus is a dominant enhancer of nod, The nod (no distributive disjunction) and the ncd (non-claret disjunctional) mutations are both female-specific. recessive meiotic mutations in Drosophila melanogaster. Mutations at either locus show high frequencies of nondisjunction at meiosis I and both have been shown to encode kinesin-like proteins. Unlike the ncd mutation. which affects all chromosome pairs. the nod mutation affects only the disjunction of nonexchange chromosomes. Although both the nod and ncd mutations are fully recessive. females doubly heterozygous for nod and ncd mutations show levels of X and fourth chromosome nondisjunction that are 6- to 35-fold above those observed in control females. Exchange between chromosomes can suppress this effect; thus. only nonexchange chromosomes segregating via the distributive system are sensitive in double heterozygotes. Since the phenotype of double heterozygotes mimics that of the nod mutation. we infer that ncd is a dominant enhancer of nod. Failure of ncd to fully complement nod reveals the chromosome segregation machinery to be dosage sensitive. The probability that the distributive system will fail is enhanced in females simultaneously haploinsufficient at the nod and ncd loci.
Effect of negative pressure ventilation on arterial blood gas pressures and inspiratory muscle strength during an exacerbation of chronic obstructive lung disease, The effects of intermittent negative pressure ventilation have been studied in 20 patients with chronic obstructive pulmonary disease during an exacerbation of their disease. Measurements of arterial blood gas tensions and maximal inspiratory pressure (MIP) were performed before and after six hours of negative pressure ventilation or standard treatment (control day) given in random order on two consecutive days. After negative pressure ventilation the mean (SD) value of MIP increased from 68.1 (21.5) to 74.8 (20) cm H2O;* arterial oxygen tension (PaCO2) fell from 60.6 (12.2) to 50.9 (8.9) mm Hg* but PaO2 changed little (from 48.4 (7.4) to 47.6 (8.2) mm Hg). There were no significant changes on the control day in arterial blood gas tensions (PaO2 47.8 (8.1) and 48.9 (9.4) and Paco2 59.8 (10.9) and 57.5 (8.06) mm Hg) or in MIP (69.4 (22.4) and 70.9 (22.9) cm H2O). Six patients tolerated negative pressure ventilation poorly and these patients showed less improvement after negative pressure ventilation. Our results suggest that intermittent negative pressure ventilation can increase alveolar ventilation in patients with an exacerbation of chronic obstructive lung disease. particularly in those who tolerate the procedure well. Most subjects showed a fall in PaCO2 and an increase in MIP. The fact that PaO2 was unchanged despite the fall in PaCO2 suggests that gas exchange may deteriorate with negative pressure ventilation in these patients.
Effects of sulfonylureas on adipocyte and skeletal muscle insulin action in patients with non-insulin-dependent diabetes mellitus, The effect of glibenclamide treatment on insulin action in isolated fat cells was studied in eight moderately obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Insulin receptor binding and the effect of insulin on glucose transport and lipogenesis were determined before and after 3 months of glibenclamide therapy. At the end of the treatment period. mean daytime plasma glucose concentrations were reduced (10.8 +/- 0.4 versus 7.0 +/- 0.3 mmol/L. p less than 0.001) whereas mean daytime plasma insulin level was increased (40 +/- 12 versus 71 +/- 9 mU/L. p less than 0.001). Adipocyte insulin receptor binding as well as basal glucose transport and metabolism were unaffected by drug treatment. In contrast. insulin-stimulated glucose transport and lipogenesis were both significantly enhanced (p less than 0.05). These findings are comparable to those of another study involving seven moderately obese subjects with NIDDM who had biopsies of the lateral vastus muscle taken for measurement of insulin receptor function and glycogen synthase activity before and during 2 months of gliclazide treatment. In that study insulin receptors purified with wheatgerm agglutinin showed unchanged insulin binding and receptor kinase activity. Moreover. gliclazide had no impact on maximal glycogen synthase activity. However. under physiologic hyperinsulinemic conditions gliclazide therapy was associated with an increased sensitivity of glycogen synthase for its allosteric activation by glucose-6-phosphatase (p less than 0.04). In conclusion. sulfonylurea treatment of NIDDM enhances insulin-stimulated peripheral glucose utilization in part through a potentiation of insulin action on adipose tissue glucose transport and lipogenesis and skeletal muscle glycogen synthase.
Increased fibrinolytic potential induced by gliclazide in types I and II diabetic patients, This study examined the effect of gliclazide on tissue-type plasminogen activator (t-PA)-related fibrinolysis in 23 Type I diabetic patients without residual beta-cell function and 17 Type II diabetic patients initially treated with tolbutamide. The Type I diabetic patients received gliclazide for a period of 6 months; the Type II diabetic patients were shifted from tolbutamide to gliclazide. In Type I diabetic patients. after 2-3 months of treatment with gliclazide. we observed a significant increase in plasma concentrations of total t-PA antigen that remained stable until discontinuation of the drug (p less than 0.0002). whereas the plasma concentrations of plasminogen activator inhibitor (PAI) did not change significantly during the study. Next. we investigated the possibility of gliclazide inducing t-PA-related fibrinolysis in a subset of Type II diabetics without detectable concentrations of t-PA during treatment with tolbutamide. The concentrations of active t-PA increased significantly 3 months after a change in treatment to gliclazide. and active t-PA again decreased in one patient to undetectable levels after 12 months with gliclazide. Moreover. the plasma concentrations of total t-PA antigen increased significantly (p less than 0.02) in this group of diabetic patients while PAI remained unchanged. The changes in t-PA-related fibrinolysis could not be related in either Type I or Type II diabetics to changes in metabolic state evaluated by blood glucose. HbA1c. cholesterol. triglycerides. or apolipoproteins A and B. We conclude that gliclazide has the potential to exert extrametabolic non-insulin-mediated effects on t-PA-related fibrinolysis in diabetic patients.
Hemorrhage-induced reductions in plasma atrial natriuretic factor in the ovine fetus, To investigate the effects of blood volume reduction on fetal plasma atrial natriuretic factor concentrations. chronically catheterized ovine fetuses at 109 to 138 days' gestation were subjected either to withdrawal of two consecutive blood samples or to a moderate hemorrhage. In fetuses from which two blood samples of 3.5 ml each (approximately 1% of fetal blood volume) were withdrawn under basal conditions at 15- to 30-minute intervals. plasma atrial natriuretic factor concentrations in the second sample decreased by 17 +/- 7 pg/ml from 178 +/- 8 pg/ml in the first sample (p less than 0.02). If the fetal blood removed during the first sample was replaced with an equal volume of maternal blood. plasma atrial natriuretic factor concentrations did not change significantly. In these same samples. plasma arginine vasopressin and angiotensin II concentrations were unchanged between the two samples regardless of whether volume was replaced. In fetuses subjected to hemorrhages of 21% +/- 2% over 10 minutes without blood replacement. plasma atrial natriuretic factor concentration at 1.5 hours after hemorrhage was suppressed by 42 +/- 10 pg/ml from basal level of 139 +/- 9 pg/ml (p less than 0.05). Plasma atrial natriuretic factor returned to control levels by 5.5 hours after hemorrhage as blood volume returned to normal. Thus in the ovine fetus a reduction in blood volume results in a decrease in plasma atrial natriuretic factor concentrations. Also. atrial natriuretic factor appears to be more sensitive to changes in blood volume than other vasoactive hormones studied.
Acupuncture and transcutaneous stimulation analgesia in comparison with moderate-dose fentanyl anaesthesia in major surgery. Clinical efficacy and influence on recovery and morbidity, The efficacy of acupuncture and transcutaneous stimulation analgesia. supplemented by small doses of fentanyl (mean 1.2 micrograms/kg. SD 1.7) was compared with moderate-dose fentanyl anaesthesia (mean 22.9 micrograms/kg. SD 2.8) in 29 patients who underwent surgery for retroperitoneal lymph node dissection. The present study describes the anaesthetic techniques and comparison of haemodynamics. demand for analgesics after surgery. recovery and blood gases. restoration of urinary and bowel functions. convalescence in terms of self-reliance and the postoperative course in respect of fatigue and morbidity. A more rapid return of consciousness. an absence of hypercapnia and a smaller decrease in pH were observed in patients who received acupuncture and transcutaneous stimulation (p less than 0.05). No clinically relevant disadvantages attributable to the method were demonstrated.
Lumbar epidural diamorphine following thoracic surgery. A comparison of infusion and bolus administration, Twenty-two patients received a single dose of diamorphine 5 mg through a lumbar epidural catheter before thoracic surgery. The patients were transferred after surgery to a high dependency unit where they were allocated randomly to receive either an infusion of epidural diamorphine at a rate of 1 mg/hour (group 1) or bolus doses of epidural diamorphine 5 mg on demand (group 2). There was no statistically significant difference between the groups in visual analogue pain scores in the first 18 postoperative hours. Arterial carbon dioxide tension was elevated in both groups and was consistently higher in group 1 than in group 2. with a statistically significant intergroup difference 12 hours after operation. Respiratory rate was not a useful index of respiratory depression. The commonest nonrespiratory side effect was urinary retention. but the incidences of this and other minor side effects were similar in the two groups.
Methicillin-resistant Staphylococcus aureus: colonization and infection in a long-term care facility, OBJECTIVE: To assess methicillin-resistant Staphylococcus aureus (MRSA) colonization. transmission. and infection over a 1-year period in a long-term care facility with endemic MRSA. DESIGN: Monthly surveillance for MRSA colonization of nares. perineum. rectum. and wounds. SETTING: Long-term care facility attached to an acute care Veterans Affairs medical center. PATIENTS: All 341 patients in the facility had monthly surveillance cultures for 1 year. OUTCOME MEASUREMENTS: Colonization and infection with MRSA. MAIN RESULTS: The monthly MRSA colonization rate was 23% +/- 1.0%; colonization occurred most commonly in the nares and wounds. Poor functional status was associated with MRSA colonization. Most patients (65%) never acquired MRSA; 25% of patients were already colonized at admission to the facility or at the start of the study. and only 10% of newly admitted patients acquired MRSA while in the facility. These latter patients acquired several different strains in a pattern of acquisition similar to that generally seen within the facility. In the course of 1 year. only nine patients who acquired MRSA had a roommate with the same phage type; no clustering was evident. and none of these patients developed infection. Nine other patients (3%) developed MRSA infection; five of these patients required hospitalization. but none died as a result of infection. CONCLUSIONS: In the long-term care facility in which our study took place. MRSA was endemic. and the infection rate was low. In such settings. the cost effectiveness of aggressive management of MRSA (widespread screening for MRSA and eradication with antimicrobial agents) needs to be assessed.
High rate of infectivity and liver disease in blood donors with antibodies to hepatitis C virus, OBJECTIVE: To determine the epidemiologic. clinical. serologic. and histologic importance of antibodies to hepatitis C virus (anti-HCV) in blood donors. DESIGN: Cross-sectional identification and prospective evaluation of seropositive donors; retrospective assessment of infectivity; and nested case-control study for risk factors. SETTING: Liver unit of a referral-based university hospital. SUBJECTS: Of 30.231 consecutive donors. 368 (1.2%) were found to be anti-HCV-reactive by enzyme-linked immunosorbent assay (ELISA). Two hundred and fifty-four of these 368 donors were evaluated for risk factors by comparison with 284 age- and sex-matched controls. Eighty-six spouses of seropositive donors were also evaluated. MEASUREMENTS AND MAIN RESULTS: Twenty-four percent of the seropositive donors had a history of percutaneous exposure to blood. This rate increased to 45% when only those donors confirmed to be anti-HCV positive by a second-generation recombinant immunoblot assay (RIBA-2) were considered. A family history of liver disease (odds ratio. 2.8; 95% Cl. 1.6 to 4.8). previous blood transfusion (odds ratio. 6.1; 95% Cl. 3 to 12.5). and a history of tattooing or intravenous drug abuse (odds ratio. 8.4; 95% Cl. 2.3 to 31) were associated with anti-HCV seropositivity. An elevated alanine aminotransferase (ALT) level was found in 58% of the seropositive donors. Of the 150 donors tested. 104 (69%; Cl. 62% to 77%) were confirmed by RIBA-2 to be anti-HCV positive. Of the 105 donors who had a biopsy. 16% had normal histologic findings. 11% had minimal changes. 21% had chronic persistent hepatitis. 45% had chronic active hepatitis. and 7% had active cirrhosis. All 77 donors with RIBA-2-confirmed seropositivity had histologic abnormalities. Of 43 donors evaluated in an infectivity study. 82% were implicated in previous HCV transmission. Only 2.3% of the spouses were anti-HCV positive. The ELISA. RIBA-2. and ALT results correlated with infectivity and abnormal histologic findings. CONCLUSIONS: In our geographic area. almost 70% of donors who are anti-HCV positive by ELISA are confirmed to be positive by RIBA-2; most of these donors appear to be chronic carriers of HCV and have substantial liver disease.
Contribution of prostaglandins to pressure natriuresis in Dahl salt-sensitive rats, To examine the role of prostaglandins on pressure natriuresis in Dahl salt-sensitive (DS) rat. the pressure-natriuresis relationships in DS and Dahl salt-resistant (DR) rats were characterized with or without indomethacin (2 mg/kg/h) by utilizing an in vivo renal perfusion study. When untreated. in the DS rat the pressure-natriuresis curve was blunted (P less than .05) and excretion of prostaglandin E2 (38 +/- 11 to 109 +/- 43 pg/min) was decreased in comparison to the DR rat. With indomethacin. the pressure-natriuresis curve in the DR rat was blunted. while no significant changes were observed in the DS rat. Plasma renin activity and concentration of atrial natriuretic peptide were not changed by the treatment of indomethacin in both strains. These results suggest that the decrease in renal prostaglandins. at least in prostaglandin E2. plays some role in blunting pressure natriuresis in DS rat.
Renal effects of ANF (95-126), a new atrial peptide analogue, in dogs with experimental heart failure, Atrial natriuretic factor 95-126 [ANF (95-126)] is a novel 32 amino acid peptide which is thought to originate from the kidney. The systemic hemodynamic and renal effects of equimolar doses of intravenous synthetic ANF (95-126) and synthetic alpha ANF (99-126) were examined in normal dogs (n = 6) and in dogs with an arteriovenous (AV) fistula and chronic compensated high-output heart failure (n = 5). ANF (95-126) and alpha ANF (99-126) were infused at 5 and 10 pmol/kg/min for 75-min periods each. In the normal and AV fistula dogs the two peptides similarly decreased mean arterial pressures and right atrial pressures (P less than .05). Creatinine clearance and urinary volume excretion increased (P less than .05) in the normal dogs with both peptides. but only ANF (95-126) produced significant elevations (P less than .05) of these two parameters in the AV fistula animals. With the highest infusion dose. ANF (95-126) increased urinary sodium excretion to at least twice the levels observed with alpha ANF (99-126) in both groups of dogs (P less than .05). The decreases in plasma renin and aldosterone were comparable for the two peptides in both groups of animals. These results indicate that ANF (95-126) is more potent than alpha ANF (99-126) for the promotion of a natriuresis. particularly in AV fistula dogs with compensated high-output heart failure. in which the sodium excretory actions of alpha ANF (99-126) were attenuated markedly.
Contractile response of aorta to alpha 1-adrenergic stimulation in Ca(2+)-free medium is reduced in spontaneous hypertension, Vascular responses of aortic rings to alpha 1-adrenergic stimulation by phenylephrine (Phe) from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were studied in Ca(2+)-containing medium and Ca(2+)-free medium plus 50 mumol/L EGTA. Although there was no difference in the sustained force development between SHR and WKY vessels in response to 100 mmol/L KCl or 10 mumol/L Phe in Ca(2+)-containing medium. the transient contractile response to 10 mumol/L Phe in Ca(2+)-free medium was substantially smaller in SHR compared to that in WKY. Subsequent addition of 2.5 mmol/L Ca2+ restored the sustained contractile response to a similar level in both SHR and WKY vessels. The transient contractile response to Phe in Ca(2+)-free medium containing EGTA. presumably due to the release of intracellular Ca2+. decreased progressively with preincubation time in Ca(2+)-free medium. indicating intracellular Ca2+ depletion. Such a temporal change of aortic response was more pronounced in SHR than in WKY. The subsequent response to Ca2+ repletion in the presence of Phe. on the other hand. increased progressively with Ca(2+)-depletion period and was higher in SHR than in WKY. The rate of relaxation after washout of Phe was slower in SHR aorta compared to WKY aorta. These results. together with our earlier findings. collectively suggest that the previous known deficiency in Ca2+ pumping mechanisms of vascular muscle microsomes leading to a reduced functional size of intracellular Ca2+ pool may account for the smaller contractile response of SHR aorta to alpha 1-adrenergic stimulation in Ca(2+)-free medium and the slower rate of relaxation.
Atrial natriuretic factor modulates the plasma levels of a Na+/K+ATPase inhibitor in volume expanded borderline hypertensives, To evaluate the existence of a relationship between atrial natriuretic factor (ANF) and plasma Na+/K+ATPase inhibitory activity in humans. we examined the hemodynamic and humoral response to volume expansion in 41 borderline hypertensive patients (BHT) with either normal (n = 33) or low plasma renin activity (n = 8). The study was carried out by measuring blood pressure. forearm circulation. plasma renin activity (PRA). ANF. and plasma levels of an endogenous Na+/K+ATPase inhibitor before and after 2 h of acute intravenous NaCl infusion (0.22 mL/min/kg bodyweight). The early (45 min) changes of ANF and those of Na+/K+ATPase inhibitory activity attained at the end of saline infusion were inversely related in BHT with normal PRA and directly related in the low-PRA population (r = 0.64). The time-course of ANF response to sodium loading was significantly delayed in BHT characterized by normal venous distensibility. They also showed a greater increase in plasma Na+/K+ATPase inhibitory activity occurring with an hypertensive. vasoconstrictive. and sodium retaining response as well. We conclude that in normal PRA borderline hypertensives. ANF may modulate the release of a plasma Na+/K+ATPase inhibitor in a setting where extracellular volume is acutely expanded. Our findings also suggest that dissimilarities in peripheral venous distensibility are able to influence the time-course of ANF response. The blunted ANF increase observed in response to NaCl loading in a subset of BHT could represent an early marker of the attitude of such patients to develop high blood pressure leading to the release of a Na(+)-pump inhibitor and influencing individual salt-sensitivity.
Endocrine therapy for desmoid tumors, Two female patients with desmoid tumors (aggressive fibromatosis) showed tumor regression after endocrine therapy. In one patient. tumor response to tamoxifen has been maintained over several years of treatment. In the second patient. who had inoperable mesenteric fibromatosis. the tumor progressed on tamoxifen but regressed after treatment with Zoladex (goserelin acetate. ICI. Melbourne. Australia) and medroxyprogesterone acetate (MPA). To the authors' knowledge this is the first report of the use of Zoladex in the treatment of desmoid tumors. This review of the literature reveals that the biology of this disease is related to the endogenous hormonal environment and that estrogen receptors have been documented in desmoid tumors. Thirty-five cases are identified where endocrine agents have been employed. with a response rate of 51%. Furthermore. tumors may respond to second-line hormonal therapy after failing to respond to initial endocrine treatment. Endocrine treatments have also been used in other disorders of fibroblastic origin. The authors recommend that endocrine treatment be employed in inoperable desmoid tumors or where there has been postsurgical recurrence. In addition. the role for endocrine therapy in other soft tissue neoplasms should be determined.
ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage, The role of ATP-regulated K+ channels in protecting the myocardium against ischemia/reperfusion damage was explored using glibenclamide and pinacidil to block and activate the channels. respectively. Electrical and mechanical activity of arterially perfused guinea pig right ventricular walls was recorded simultaneously via an intracellular microelectrode and a force transducer. The preparations were subjected to either 1) 20 minutes of no-flow ischemia with or without glibenclamide (1 and 10 microM) followed by reperfusion. or 2) 30 minutes of no-flow ischemia with or without pinacidil (1 and 10 microM) followed by reperfusion. No-flow ischemia for 20 minutes produced changes in electrical and mechanical activity that were completely reversed on reperfusion; resting membrane potential declined by 13 +/- 1.2 mV. action potential duration at 90% repolarization (APD90) decreased by 62%. and developed tension fell by greater than 95%. but resting tension did not change significantly. Glibenclamide (10 microM) had no effect on activity during normal perfusion. but during ischemia. resting membrane potential fell slightly further (17 +/- 1.8 mV) and APD90 declined by only 24%. Developed tension declined more slowly and to a lesser extent. but resting tension rose significantly between 10 and 20 minutes of ischemia. Reperfusion of glibenclamide-treated tissues elicited arrhythmias (extrasystoles and tachycardia). and the preparations failed to recover mechanical function. Glibenclamide at 1 microM produced qualitatively similar effects. albeit less severe. After 30 minutes of no-flow ischemia in untreated tissues. resting tension increased by approximately 130% during the no-flow period. Reperfusion caused arrhythmias (extrasystoles. tachyarrhythmias. and fibrillation) and failed to restore resting or developed tension to preischemic levels. Pinacidil at 1 microM did not affect electrical or contractile function. but at 10 microM it had a negative inotropic effect. decreasing APD90 and developed tension by 5% and 18%. respectively. Both concentrations of the drug caused a faster and greater decline in APD90 during the no-flow period. Resting tension did not change during 30 minutes of no-flow ischemia in the presence of pinacidil. and reperfusion led to 85% and complete recovery of electrical and mechanical activity at 1 and 10 microM. respectively. The data indicate that glibenclamide enhances whereas pinacidil reduces myocardial damage caused by ischemia/reperfusion. The results are consistent with the hypothesis that activation of ATP-regulated K+ channels during ischemia is an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.
Blockade of the ATP-sensitive potassium channel modulates reactive hyperemia in the canine coronary circulation, The mechanism of reactive hyperemia remains unknown. We hypothesized that reactive hyperemia was related to the opening of ATP-sensitive potassium channels during coronary occlusion. The resulting hyperpolarization of the smooth muscle cell plasma membrane might reduce calcium influx through voltage-dependent calcium channels and result in relaxation of smooth muscle tone and vasodilation. In eight open-chest. anesthetized dogs. 30-second coronary occlusions resulted in an average flow debt repayment of 200 +/- 41%. After low-dose (0.8 mumol/min) and high-dose (3.7 mumol/min) infusion of intracoronary glibenclamide. flow debt repayment fell to 76 +/- 14% and 50 +/- 8%. respectively (p less than 0.05 compared with control for both). The decline in flow debt repayment was due to a significant reduction both in maximum coronary conductance during reactive hyperemia and in its duration. In addition. there was a significant decline in the sensitivity of the coronary circulation to adenosine-induced vasodilation after glibenclamide. While more variable. there was no overall change in the sensitivity of the coronary vasculature to acetylcholine-induced vasodilation after glibenclamide. We conclude that reactive hyperemia is determined in a large part by the ATP-sensitive potassium channel. probably through its effect on membrane potential and voltage-sensitive calcium channels. Because reactive hyperemia was never fully abolished at the highest doses of glibenclamide tested. it is possible that additional mechanisms are involved in the genesis of this complex phenomenon.
Sulfonylureas, ATP-sensitive K+ channels, and cellular K+ loss during hypoxia, ischemia, and metabolic inhibition in mammalian ventricle, Sulfonylurea derivatives glibenclamide and tolbutamide are selective blockers of ATP-sensitive K+ (KATP) channels. However. their ability to prevent cellular K+ loss and shortening of action potential duration during ischemia or hypoxia in the intact heart is modest compared with their efficacy at blocking KATP channels in excised membrane patches. In the isolated arterially perfused rabbit interventricular septum. the increase in unidirectional K+ efflux and shortening of action potential duration during substrate-free hypoxia were effectively blocked by glibenclamide. but only by very high concentrations (100 microM); during hypoxia with glucose present. glibenclamide was only partially effective at reducing K+ loss. During total global ischemia (10 minutes). up to 100 microM glibenclamide or 1 mM tolbutamide attenuated shortening of action potential duration but only reduced [K+]0 accumulation by a maximum of 32 +/- 6%. In isolated patch-clamped guinea pig ventricular myocytes in which the whole-cell ATP-sensitive K+ current was activated by exposure to the metabolic inhibitors. glibenclamide (up to 100 microM) and tolbutamide (10 mM) were only partially effective at blocking the whole-cell ATP-sensitive K+ current (maximum block. 51 +/- 10% and 50 +/- 9%. respectively). especially when ADP was included in the patch electrode solution. In inside-out membrane patches excised from these myocytes. glibenclamide blocked unitary currents through KATP channels with a Kd of 0.5 microM and a Hill coefficient of 0.5 in the absence of ADP at the cytosolic membrane surface. but block was incomplete when 100 microM ADP (+2 mM free Mg2+) was present. ADP had a similar effect on block of KATP channels by tolbutamide. These findings suggest that free cytosolic [ADP]. which rises rapidly to the 100 microM range during early myocardial ischemia and hypoxia. may account for the limited efficacy of sulfonylureas at blocking ischemic and hypoxic cellular K+ loss under these conditions.
Regulation of rat hypothalamic preprogrowth hormone-releasing factor messenger ribonucleic acid by dietary protein, To further evaluate nutrient regulation of GRF synthesis. we measured hypothalamic preproGRF messenger (m) RNA in food-deprived rats refed diets varying in nutrient composition by nuclease protection analysis. Adult male Sprague-Dawley rats were allowed free access to food (Fed). food deprived for 72 h (72-h FD). or 72 h FD then refed for 72 h with either a normal (NF) diet or isocaloric diets containing no protein (PF). carbohydrate (CF). or fat (FF). Seventy-two-hour FD rats displayed the expected 80% reduction in hypothalamic preproGRF mRNA. Upon refeeding. levels were normalized in rats refed NF. CF. or FF diets. In contrast. preproGRF mRNA in rats refed a PF diet was similar to that in 72-h FD rats. Rats refed a PF diet failed to gain weight and consumed less food than animals refed NF. CF. or FF diets. However. the lack of the GRF response to the PF diet was due to protein deprivation rather than caloric restriction. since hypothalamic preproGRF mRNA returned to 66% of Fed values in rats refed an equivalent amount (grams per day) of a NF diet. In 72-h FD rats refed isocaloric diets containing 4%. 8%. or 12% protein. preproGRF mRNA was restored to Fed values in a protein concentration-dependent manner being completely restored by the 12% diet. A lack of dietary protein was sufficient to regulate hypothalamic preproGRF mRNA since feeding rats a PF diet without prior food deprivation resulted in 70% reduction in preproGRF mRNA. whereas CF and FF diets were without effect. These data indicate that decreased hypothalamic preproGRF mRNA expression in 72-h FD rats occurs as a result of dietary protein deprivation.
Light- and electron-microscopical study of a case of gold salt-induced hepatotoxicity, A 56-yr-old woman with long-standing rheumatoid arthritis exhibited jaundice. pruritus and abdominal discomfort after 8 yr of periodic gold sodium thiomalate injections amounting to a cumulative dose in excess of 2.5 gm. Histopathological examination of the liver biopsy specimen showed submassive loss of parenchyma. collapse of reticulin and mixed cellular inflammatory infiltrates. Macrophages contained dark granules. which displayed the characteristics of aurosomes when examined by transmission electron microscopy and electron microprobe analysis. It is likely that hepatocellular injury occurred when the lysosomal storage capacity for gold was exceeded.
High frequency of IL-4-producing CD4+ allergen-specific T lymphocytes in atopic dermatitis lesional skin, In atopic dermatitis (AD) hypersensitivity reactions to allergens are commonly observed and are assumed to make a major contribution in the pathomechanism of the disease. It may be expected that allergen-reactive Th cells play a central role in these reactions. In the present study the occurrence and function of allergen-specific T lymphocytes in dermal inflammatory lesions were studied. To this aim panels of randomly cloned CD4+ T cells from lesional skin biopsies of two housedust mite Dermatophagoides pteronyssinus (Dp)-allergic AD patients were screened for reactivity with Dp allergens. The results were compared with similar tests for Dp reactivity of T-lymphocyte clones (TLC) from the peripheral blood of these patients. In the panels of TLC generated from lesional skin (S-TLC). a considerable number of TLC appeared to be Dp-specific. 47% (n = 17) and 10% (n = 29). respectively. In the panels from the peripheral blood. the percentages of Dp-specific TLC were only 0% (n = 22) and 3% (n = 34). suggesting accumulation or expansion of these T cells in lesional skin. The function of these TLC was studied by assaying the secretion of IL-4 and IFN-gamma. which have been shown to be produced in aberrant ratios by Dp-specific TLC from the peripheral blood of AD patients (Wierenga et al: J Immunol 144:4651. 1990). All Dp-specific S-TLC produced IL-4 in combination with no or low levels of IFN-gamma. whereas many of the non-Dp-specific S-TLC and blood-derived TLC (B-TLC) were observed to produce high levels of IFN-gamma without significant amounts of IL-4. A functional consequence of these cytokine profiles was demonstrated by the finding that TLC producing substantial amounts of IL-4 enhanced expression of the low-affinity Fc receptor for IgE (CD23) on antigen-presenting cells to a greater extent than did IFN-gamma-producing TLC.
Role of hair follicles in the repigmentation of vitiligo, Vitiligo is a common pigment disease that is difficult to treat. The mechanism of repigmentation is not known. We combined Dopa-Toluidine Blue complex stain. hair follicle split-Dopa stain. and hair follicle split-scanning electron microscope (SEM) to observe the changes of melanocytes in 23 normal. 24 vitiliginous. and 36 repigmented skin specimens. We found that only active (Dopa-positive) melanocytes existed in the epidermis of normal skin. There were some inactive (Dopa-negative) melanocytes in the outer root sheaths of normal hair follicles. which form the melanocyte reservoir in human skin. In the patients with vitiligo the active melanocytes in the epidermis were totally missing. whereas the inactive melanocytes in the outer root sheaths of hair follicles were not affected. Treatment stimulated the inactive melanocytes in the middle and/or lower parts of the outer root sheaths of hair follicles to divide. proliferate. and migrate upward along the surface of the outer root sheath to the nearby epidermis. where the melanocytes continued to migrate radially to form the pigmented island visible clinically in repigmented vitiligo lesions. During the migration to the epidermis. the melanocytes matured gradually from an inactive phase to an active condition. In conclusion. the existence of these inactive melanocytes provided the melanocyte sources for repigmentation of vitiligo.
Inhibition of Langerhans cell ATPase and contact sensitization by lanthanides--role of T-suppressor cells, Lanthanides are rare earths. elements 55-71 in the periodic table. that are of interest in biologic systems as isomorphic competitors for calcium binding sites. Lanthanides were tested for their inhibitory influence on the Ca++/Mg(++)-dependent ATPase of epidermal langerhans cells in vitro. and on the immunologic function of Langerhans cells in vivo. The trivalent ions of lanthanides. lanthanum. and cerium completely inhibited the ATPase staining of Langerhans cells in vitro. When mice were sensitized with dinitrofluorobenzene on skin sites pretreated with topical lanthanum chloride. and challenged on untreated ear skin. a markedly reduced contact hypersensitivity response was observed. This hyporesponsiveness was found to be antigen specific. and could be passively transferred to naive syngeneic animals recipients by CD4-CD8+ spleen cells. These results suggest that inhibition of the epidermal Langerhans cell surface ATPase by application of topical lanthanum and the induction of antigen-specific immunologic tolerance may be related events.
Fibrinolytic parameters in spermatozoas and seminal plasma, Urokinase-type (u-PA) and tissue-type plasminogen activator antigen (t-PA) as well as plasminogen activator-inhibitor activity were determined in seminal plasma and lysates of the respective spermatozoas in 67 ejaculate of males in infertile marriage without genito urinary pathology. U-PA was determined by a competition RIA. t-PA by an ELISA and PAI by a spectrophotometric assay. 15 patients showed normozoospermia. 11 azoospermia and 41 oligoasthenoteratozoospermia (OAT-syndrome). In lysates of spermatozoas. significantly higher levels of both plasminogenactivators and PAI were found in patients with OAT syndrome as compared to those exhibiting normozoospermia. Whereas PAI was absent in the seminal plasma of normozoospermic ejaculate. patients with azoospermia (180 +/- 13 mU/ml.) and OAT-syndrome (60 +/- 5 mU/ml.) showed high PAI levels. The similarly high values of t-PA (190.8-227.8 ng./ml.) and u-PA (19.4-32 ng./ml.) in the same compartment confirm their predominantly prostatic origin and seem to have no influence on the quality of the ejaculate.
Trauma to elbows, knees, and ankles, In summary. the emergency department or office-based physician should distinguish first between inflammation and injury. A clinical diagnosis of fracture should be made before obtaining and reading films. Comparison views help to resolve doubt. A neurologic examination should be documented before undertaking reduction. Finally. if in doubt. a splint for 24 to 48 hours until an orthopedic opinion is available causes no harm.
Nutrition and health services needs among the homeless, This review discusses nutrition and related health problems among homeless Americans. summarizes recent information. and identifies needs for services and future research. The nature of homelessness today provides a context for the discussion. Many homeless persons eat fewer meals per day. lack food more often. and are more likely to have inadequate diets and poorer nutritional status than housed U.S. populations. Yet many homeless people eligible for food stamps do not receive them. While public and private agencies provide nutritious food and meals for homeless persons. availability of the services to homeless persons is limited. Many homeless people lack appropriate health care. and certain nutrition-related health problems are prevalent among them. Compared with housed populations. alcoholism. anemia. and growth problems are more common among homeless persons. and pregnancy rates are higher. The risks vary among homeless persons for malnutrition. nutrition-related health problems. drug and alcohol abuse. and mental illness. For example. among homeless persons. fewer heads of families than single adults are substance abusers. and mental illness varies in prevalence among single men. single women. and parents in homeless families. Homeless persons need improved access to food. nutrition. and health services. More nutrition education needs to be available to them and to service providers. Use of representative samples and validation of self-reported nutrition and health data will help future investigators to clarify the relationships between the characteristics of the homeless and their nutritional status.
The feasibility of collecting drug abuse data by telephone, An evaluation was made of the use of telephone survey methods to collect illicit drug use data. Using data from a national survey that collects data by personal interviews. marijuana and cocaine use prevalence rates among households with telephones and those without were compared in order to assess coverage errors in telephone surveys. Drug use rates were substantially higher among households without telephones. with 24.9 percent of those living in households without telephones reporting use of marijuana in the past year. compared with only 9.4 percent of persons living in households with telephones. Trends in drug use were divergent. with substantial decreases in use occurring between 1985 and 1988 in households with telephones. but not in those without. National prevalence patterns and trends among households with telephone appear to be consistent with national patterns and trends in the total household population. because about 93 percent of the population lives in households with telephones. However. surveys conducted by telephone were found to produce underestimates of illicit drug use prevalence. In a 1988 national telephone survey. estimated rates of past year use were 5.2 percent for marijuana and 1.4 percent for cocaine. Comparable data from a personal visit survey (including only households with telephones and reedited and reweighted to control for differences in data collection protocols) were 8.0 percent for marijuana and 3.1 percent for cocaine use. Comparisons with several other telephone surveys collecting illicit drug use data showed similar results. Based on these results. researchers are advised to use caution in using telephone surveys to produce drug use prevalence estimates.
Resting pulse rate of children and young adults associated with blood pressure and other cardiovascular risk factors, Few researchers have investigated the resting pulse rate of children and young adults as a risk factor or indicator for subsequent cardiovascular morbidity in a representative sample of the total population. Data from the first National Health and Nutrition Examination Survey for persons ages 6-24 years revealed mean resting pulse rates that declined with age until ages 12-16. were higher in females than males. and in whites than blacks. At ages 12-17 and 18-24. blood pressure and body temperature showed consistent. independent. positive associations with pulse rate in whites. However. relatively little of the overall variation in pulse rate was explained by measured variables in multivariate regression analyses. Mother-child. age-specific correlation coefficients for pulse and blood pressure were generally positive. Further research is needed on the associations of resting pulse rate with sex. race. and blood pressure and with subsequent cardiovascular morbidity.
A study guided by the Health Belief Model of the predictors of breast cancer screening of women ages 40 and older, In late 1987. a total of 852 Rhode Island women ages 40 and older were interviewed by telephone (78 percent response rate) to measure their use of breast cancer screening and to investigate potential predictors of use. Predictors included the women's socioeconomic status. use of medical care. a provider's reported recommendations for screening. and the women's health beliefs about breast cancer and mammography. The Health Belief Model guided the construction of the interview questions and data analysis. Logistic regression was used to identify leading independent predictors of breast cancer screening according to contemporary recommendations: reporting that a medical provider had ever recommended a screening mammogram (odds ratio [OR] = 18.77). having received gynecological care in the previous year (OR = 4.92). having a regular source of gynecological care (OR = 2.63). having ever had a diagnostic mammogram (OR = 2.32). and perceiving mammography as safe enough to have annually (OR = 1.93). The findings suggest that programs intended to increase the use of breast cancer screening should include "inreach" and "outreach" elements; inreach to patients with established patient-provider relationships. by assuring that physicians recommend screening to all eligible patients. and outreach to all eligible women. by helping them overcome barriers to effective primary care. and by promoting mammography. emphasizing its effectiveness and safety. The findings also suggest that socioeconomically disadvantaged women. who are less likely to be screened than other women. should become special targets of inreach and outreach interventions.
Interpretative views on Hispanics' perinatal problems of low birth weight and prenatal care, From a public health perspective. there is a need to recognize that Hispanics. and in particular Mexican Americans. are a very heterogeneous group. They represent all shades of acculturation. education. income. and citizenship status. As this minority group continues to increase in numbers. pertinent information about their perinatal health problems in the context of their sociocultural characteristics will be required. This review examines critically the recent literature related to low birth weight and prenatal care and suggests alternative ways to address these perinatal health issues. Low birth weight is examined in the context of the problem of intrauterine growth retardation and the potential mechanisms and consequences of different types of growth limitation in utero which have not been studied in this population. The use of prenatal care by Mexican American women and its association with birth weight is examined as an indication of maternal behavior or as a health care intervention. The implications for public health policy are discussed in relation to the identification. interpretation. and evaluation of these perinatal health issues in this minority population.
Childhood injury prevention in a suburban Massachusetts population, A controlled population-based study of a childhood injury prevention program in four suburban Massachusetts communities was able to demonstrate a 15.3 percent decrease in injury rates for children ages 0-5 years. A substantial improvement was seen in the relative risk for injury in the intervention as compared with control communities. The major intervention was a pediatric counseling program taking place within a context of various community education efforts. Process data on patient satisfaction and physician compliance. and educational and behavioral outcomes from previously reported studies. when combined with injury incidence data in this report. support the hypothesis that physician counseling may be an important factor in the favorable results observed in these suburban communities. These data also suggest that a decrease in injury incidence may be possible when interactive physician counseling takes place within the context of community education programs. A comprehensive strategy that includes technological. legislative. and educational activities is suggested as the optimal approach to childhood injury prevention.
Quantifying the disease impact of alcohol with ARDI software, Alcohol-Related Disease Impact (ARDI) Software has been developed for the Centers for Disease Control (CDC) to allow States to calculate mortality. years of potential life lost (YPLL). direct health-care costs. indirect morbidity and mortality costs. and nonhealth-sector costs associated with alcohol use and misuse. The mortality related measures--mortality. YPLL. and indirect mortality costs--are computed for 35 diagnoses related to alcohol use and misuse. A review of clinical research studies and injury surveillance studies was conducted to produce estimates of the alcohol-attributable fraction (AAF) for each diagnosis. For these measures. age-specific and age-adjusted rates are also calculated. Health care costs. morbidity costs. and nonhealth-sector costs are prorated from national studies to the State or locality. This multiple-measure approach to quantifying a health problem is termed "disease impact estimation." National estimates of the disease impact of alcohol use and misuse have been produced using ARDI software and State-specific estimates are in preparation. Designed to CDC specifications. ARDI is completely menu-driven and operates within Lotus 1-2-3 software as a set of linked spreadsheets. ARDI adapts national epidemiologic and health economics methods for use by State and local health agencies. ARDI produces data on the health consequences of alcohol use and misuse for use by locally based policymakers. public health professionals. and researchers. while permitting comparison and compilation of these data across jurisdictions.
Aetiology of community acquired pneumonia in Valencia, Spain: a multicentre prospective study, A year long multicentre prospective study was carried out in the Valencia region of Spain. to determine the cause of community acquired pneumonia. The study was based on 510 of 833 patients with pneumonia. Of these. 462 were admitted to hospital. where 31 patients died. A cause was established in only 281 cases--208 of bacterial. 60 of viral. and 13 of mixed infection. The most common microorganisms were Streptococcus pneumoniae (14.5%). Legionella sp (14%). Influenza virus (8%). and Mycoplasma pneumoniae (4%). There was a higher incidence of Legionella sp than in other studies.
Reduction of myocardial infarct size by poloxamer 188 and mannitol in a canine model, Poloxamer 188 has been reported to inhibit thrombosis. decrease whole blood viscosity. and improve perfusion of damaged tissue. Mannitol has free radical scavenging capabilities that might contribute to myocardial salvage after ischemia. Because these agents appear to work in different ways. we studied their cardioprotective properties when they were used separately and in combination. After 75 minutes of left anterior descending coronary artery (LAD) occlusion. dogs received poloxamer 188 (48 mg/kg). mannitol (0.5 gm/kg). or both intravenously during an additional 15 minutes of LAD occlusion and for 45 minutes of reperfusion. whereas control dogs received an equal volume of saline solution. After surgery the animals were maintained for 24 hours and then killed. Areas of myocardial infarction (MI) and risk of infarction (R) were calculated by means of planimetric analysis of slices of myocardium stained with 1.5% triphenyltetrazolium and 0.5% Evans blue dye. The ratio of MI/R (mean +/- standard error of the mean) were: control. 25.6 +/- 1.8% (n = 10); poloxamer 188. 12.7 +/- 2.0% (n = 10); mannitol. 10.6 +/- 2.5% (n = 11); and poloxamer 188 plus mannitol. 8.0 +/- 4.1% (n = 10). Measurement of microvascular blood flow indicated a similar 86% to 91% reduction of blood flow to the area at risk in all treatment groups. Consequently both poloxamer 188 and mannitol appear to increase salvage of ischemic myocardium and a combination of the two may be more effective than either agent alone.
Efficacy of slow-release nifedipine on myocardial ischemic episodes in variant angina pectoris, To evaluate the efficacy of slow-release nifedipine (a single dose of 20 mg given at 10 P.M. or 2 doses of 20 mg at 10 P.M. and 6 A.M.) on ischemic episodes in patients with variant angina. a single-blind crossover study with ambulatory electrocardiographic monitoring was performed in 15 patients (13 men and 2 women. mean age 63 years). In all. there were 646 ischemic episodes detected with ambulatory electrocardiographic monitoring during the study period. and 618 episodes of them occurred during placebo periods with a circadian variation. Sixty-nine percent of the episodes in placebo periods were asymptomatic. The number of anginal attacks. nitroglycerin tablets taken. ST-segment elevation and the total ischemic duration significantly decreased during nifedipine therapy compared with results after the placebo therapy period. respectively (p less than 0.01 or 0.05). Twenty-eight ischemic episodes occurred during nifedipine therapy when the plasma level of nifedipine was low. Thus. asymptomatic ischemic episodes more frequently occur than symptomatic episodes and the administration of slow-release nifedipine is highly effective in suppressing not only symptomatic but also asymptomatic myocardial ischemia in patients with variant angina. The timing of the administration of slow-release nifedipine is an important factor in suppressing ischemic episodes.
A variant form of thrombasthenia, We encountered two siblings with abnormal bruising since infancy. Studies revealed functional platelet defects characterized by a lack of platelet aggregation and adenosine triphosphate release on exposure to adenosine diphosphate and collagen as well as variable responses with ristocetin (at concentrations of less than or equal to 1.25 g/L) and arachidonic acid. In addition. little or no platelet aggregation was observed after exposure to hexadimethrine bromide (Polybrene). the calcium ionophore A23187. and the thromboxane/endoperoxide analogue U46619. The membrane proteins IIIa and Ib were present. as determined with monoclonal antibody testing. and no platelet-associated IgG was found. Platelet analysis with routine electron microscopy and ultrastructural cytochemistry revealed normal morphologic features and no deficiencies in the number of alpha granules dense bodies and other organelles. The platelet abnormality may represent a new variant of thrombasthenia.
The cost of medical care for injuries to children, STUDY OBJECTIVES: To estimate the mean cost of initial medical treatment for a variety of injury types and injury causes and project the national cost of initial medical care for injuries to children. DESIGN: We combined injury incidence data from the Massachusetts Statewide Childhood Injury Prevention Project (SCIPP) with a claims data set (1987 charges) from the Health Data Institute. Lexington. Massachusetts. SETTING AND STUDY POPULATION: SCIPP incidence data were obtained from hospital emergency department and inpatient facilities for a population of 87.000 Massachusetts children 0 to 19 years old between 1979 and 1982. Health Data Institute charge data for children were derived from insurance claims for 3% of all privately insured patients throughout the United States. RESULTS: The estimated mean cost of initial hospitalization for injury was $5.094. while ED care was $171. Projected annual cost for initial medical care of injury to children for the nation was $5.1 billion. which was about equally divided between cases seen in EDs and those requiring inpatient care. Although there was little difference in mean cost between the genders. mean cost increased with age. Because of both a higher injury incidence and a greater mean cost per injury. the projected initial cost of injuries to teenagers 15 to 19 years old was much higher than that of younger children. CONCLUSION: Expenditures for medical care of injured children. particularly adolescents. are great. The prevention of childhood injuries should become a higher priority in the United States. To improve the quality of national estimates of the incidence and cost of injury. a national surveillance system for nonfatal injuries should be developed. Such a system should include information on the major causes of injury and their costs.
Analysis at the clonal level of T-cell phenotype and functions in severe aplastic anemia patients, The aim of this study was to analyze at the clonal level the phenotype and functions of T cells from patients with severe aplastic anemia (SAA). For this purpose we studied 175 T-cell clones obtained from peripheral blood (PB) and bone marrow (BM) of four SAA patients and 97 clones from two healthy controls. The percentage of CD8+ T-cell clones obtained from the patients' PB and BM was higher. but not significantly (P = .07 and P = .14. respectively). than that obtained in controls. A higher proportion of T-cell clones from SAA patients exhibited lectin-dependent cytolytic activity and especially natural killer-like activity when compared with controls (PB: P less than .01. P less than .05; BM: P less than .05. P less than .01. respectively). Lymphokine release was tested before and after mitogen stimulation. A number of patients' clones were able to release interferons (IFNs) spontaneously (PB: 28.6% v 0%. P less than .05; BM: 28.6% v 0%. P less than .10). After mitogen stimulation. patients' BM T-cell clones produced IFNs in greater proportions (90.9% v 46.7%. P less than .01) and in greater quantities (PB: 25.5 arbitrary units [AU]/mL v 5.7 AU/mL. P less than .03; BM: 26 AU/mL v 9.1 AU/mL. P = .011) as compared with controls. Tumor necrosis factor (TNF) activity was not found in supernatants of unprimed T-cell clones. After mitogen stimulation. PB T-cell microcultures produced TNF alpha in greater proportions (97.9% v 72.2%. P less than .01) and. also in this case. in greater quantities (PB: 7.2 AU/mL v 1.5 AU/mL. P = .007; BM: 9.9 AU/mL v 1.5 AU/mL. P = .003) than controls. In conclusion. T-cell clones from SAA patients exhibit predominantly a CD8+ phenotype. a greater cytotoxic activity. and can be shown to produce greater quantities of suppressor lymphokines when compared with controls.
Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma, To test the possibility that interleukin-9 (IL-9). the human homologue of the mouse T-cell growth factor P40. may be involved in the pathogenesis of human lymphomas. we examined IL-9 expression in a variety of tumors both by Northern blot analysis and by in situ hybridization. Of 18 B-cell non-Hodgkin's lymphomas and 11 peripheral T-cell lymphomas. none expressed IL-9 message. By contrast. IL-9 message was found in two of six cases of large cell anaplastic lymphoma (LCAL) and in 6 of 13 cases of Hodgkin's disease (HD). In HD the strongest signals were observed in Hodgkin (H) and Sternberg-Reed (SR) cells. but IL-9 mRNA was also detected in small lymphocytic cells. A search for IL-9 message in a panel of 20 cell lines derived both from hematopoietic and nonhematopoietic tumors confirmed the unique association of IL-9 expression with HD and LCAL in as much as the only two cell lines with IL-9 message were derived from cases of HD and LCAL. These results suggest that IL-9 is not involved as an autocrine growth factor in the pathogenesis of most B- and T-cell lymphomas. but that it may play a role in HD and LCAL.
Sensitive detection of clonal antigen receptor gene rearrangements for the diagnosis and monitoring of lymphoid neoplasms by a polymerase chain reaction-mediated ribonuclease protection assay, This report describes a novel assay involving the polymerase chain reaction (PCR) and RNase protection for the rapid and sensitive detection of malignant lymphoid cells by nucleotide sequences within their individual rearranged gamma T-cell receptor (TCRG) genes. In this assay. clonal rearrangements are amplified from the DNA of diagnostic tumor specimens using a consensus V segment primer and a consensus J segment primer to which the promoter for T7 RNA polymerase has been appended. The PCR product from this amplification is transcribed into a radiolabeled RNA probe. Test RNA transcribed from the opposite DNA strand is synthesized by similar methods from TCRG genes of a subsequent biopsy specimen. The test RNA is hybridized with the probe. and mismatched nucleotide sequences in the RNA hybrids are digested by RNase A. Detection of fully protected probe by means of polyacrylamide gel electrophoresis and autoradiography indicates the presence of malignant cells in the test specimen. Dilution experiments with DNA of cell lines from acute lymphoblastic leukemias (ALLs) show that detection of one tumor cell among 10(5) normal bone marrow cells is usually possible. Residual disease was also successfully detected in several cases of ALL during clinical remission. including detection in one case at the 10(-5) level. The procedure described here may provide a simplified and rapid method for the sensitive diagnosis and monitoring of lymphoid malignancies. This procedure should be applicable to most antigen receptor genes. and unlike most comparable methods. requires neither analysis of nucleotide sequence nor synthesis of tumor-specific oligonucleotide probes or primers.
Immunoglobulin subclasses and prophylactic use of immunoglobulin in immunoglobulin G subclass deficiency, Persistent low serum levels of one or several immunoglobulin G (IgG) subclasses can be found in a high proportion of adult patients with increased susceptibility to infections. It is hard to envision that the low subclass level in itself is responsible for this susceptibility because healthy blood donors have been described who are completely devoid of certain subclasses in serum. This apparent discrepancy may be partly explained by the observation that most subclass-deficient patients have underlying aberrations in T-cell and B-cell interaction and function that may impair their capacity to compensate for even minor deficiencies. A prospective blind crossover study of the effect of prophylactic Ig substitution therapy was done in 43 adult patients with IgG subclass deficiency. The patients were randomized to receive 1 year of therapy with intramuscular Ig 25 mg/kg/wk or 1 year of saline injections. A significant protective effect of the prophylactic Ig therapy was seen with a great reduction in the number of days of infection. In addition. several immunologic parameters were altered after 1 year of Ig therapy. Nineteen of the patients later were included in an open study using 50 mg/kg/wk of Ig. After 6 months of treatment. significant protection against infection was observed. with a reduction of 6.2 days in the number of days per month with infection. This marked effect of prophylactic Ig suggests that the Ig aberrations seen in IgG subclass-deficient patients contributed to their susceptibility to infection. The effect of 25 mg/kg/wk was much less pronounced than that of 50 mg/kg/wk. and normal serum IgG subclass levels were not achieved even during the higher-dose therapy. However. it seems likely that subcutaneous or intravenous administration of larger doses of Ig would allow for more efficient therapy.
Cardiac rehabilitation services: what are they and are they worth it, The objectives of cardiac rehabilitation include lowering mortality but. more importantly. increasing functional capacity so reducing disability and potentially improving quality of life. The data suggest that cardiac rehabilitation services are worth the patient's costs and efforts and as such. they should be considered an integral component of comprehensive cardiovascular care by cardiologists and primary care physicians. While there is considerable agreement on the roles of exercise testing and training in the three position stands. there are also substantiated. and important. differences in their recommendations on other cardiac rehabilitation services. such as counseling and risk factor management. The challenge for the 1990's is not only to continue to better define the effectiveness of cardiac rehabilitation services. but more urgently. how to deliver effective services most efficiently. This will help physicians provide optimum care for their patients. will improve the patient's likelihood of regaining for themselves an active and productive life. and should generate a more equitable and accountable reimbursement system for quality health care.
Anti-interleukin-1 alpha autoantibodies in humans: characterization, isotype distribution, and receptor-binding inhibition--higher frequency in Schnitzler's syndrome (urticaria and macroglobulinemia), Since autoantibodies (Abs) to cytokines may modify their biologic activities. high-affinity binding factors for interleukin-1 alpha (IL-1 alpha BF) were characterized in human sera. IL-1 alpha BF was identified as IgG (1) by sucrose density-gradient centrifugation followed by immunodiffusion autoradiography. (2) by ligand-blotting method. (3) by ligand binding to affinity-immobilized serum IgG. and (4) by IgG affinity purification followed by sucrose density-gradient centrifugation. IL-1 alpha binding activity resided in the F(ab)2 fragment. The apparent equilibrium constant was in the range of IgG found after immunization with conventional antigens (i.e.. 10(-9) to 10(-10) mol/L). Anti-IL-1 alpha IgG auto-Abs represented only an extremely small fraction of total IgG (less than 1/10(-5)). Some sera with IL-1 alpha BF and purified IgG thereof were able to inhibit by 96% to 98% the binding of human recombinant IL-1 alpha to its receptor on murine thymoma EL4-6.1 cells. whereas other sera did not. When 125I-labeled anti-IL-1 alpha IgG complexes were injected into rats. they prolonged the plasma half-life of 125I-labeled IL-1 alpha several fold and altered its tissue distribution. The predominant class was IgG (12/19). mainly IgG4 (9/19). but in five of the sera. anti-IL-1 alpha IgA was also detected. In a screening of 271 sera. IL-1 alpha BF was detected in 17/98 normal subjects and was not more frequent in several control groups of patients. except in patients with Schnitzler's syndrome (fever. chronic urticaria. bone pain. and monoclonal IgM paraprotein) (6/9; p less than 0.005). The pathologic significance of these auto-Abs remains to be determined.
VH gene analysis of spontaneously activated B cells in adult MRL-lpr/lpr mice. J558 bias is not limited to classic lupus autoantibodies, To determine the genetic origins of lupus auto-antibodies. we analyzed the relationship between VH gene usage and auto-Ag-binding properties of 352 B cell hybridomas derived from MRL-lpr/lpr mice. The hybridomas were derived from neonatal. 1-month-old. 3-month-old. and 6-month-old mice. The experimental strategy provided that the hybridomas were monoclonal at initial evaluation. so the Ag binding and V gene frequencies of the entire population could be determined. Initially. 1032 Ig-producing hybridomas were evaluated for binding to six Ag; VH gene family use was determined in 119 anti-DNA and anti-rabbit thymus extract (RTE) antibodies (autoantibodies) and in 233 age-matched Ig that did not bind to any of the six Ag (nonbinders). Neonatal B cells. including cross-reactive IgM autoantibodies and nonbinder IgM. used relatively 3' VH genes. The majority of B cells in adult mice used VH genes of the J558 family. Although J558 use was significantly higher among the autoantibodies (anti-DNA and anti-RTE) than among the nonbinder Ig. this difference was due to a higher frequency of J558 use by 1-month-old mice. At 3 months. J558 use by the nonbinder Ig increased to the same frequency of J558 use as in the autoantibody population. J558 use in both groups of antibodies exceeded a previously reported estimation of J558 expression in the functional B cell repertoire of young adult MRL-lpr/lpr mice. Several subgroups of antibodies that share properties with pathogenic Ig. including IgG. cross-reactive Ig. and anti-dsDNA autoantibodies. demonstrated a marked preferential expression of the J558 family. These results suggest that there is an age-related bias in the activation of B cells using J558 VH genes in MRL-lpr/lpr mice that is under the influence of a selective force distinct from. or in addition to. an ssDNA or RTE auto-Ag-driven response.
Immune suppression induced by protoscoleces of Echinococcus multilocularis in mice. Evidence for the presence of CD8dull suppressor cells in spleens of mice intraperitoneally infected with E. multilocularis, Immunoregulatory states induced by i.p. inoculation with the metazoan parasite Echinococcus multilocularis in the murine system were investigated. Proliferative responses and IL-2 production induced by Con A in spleen cells from BALB/c mice were significantly depressed at an early stage after infection with E. multilocularis protoscoleces (PSC). Addition of plastic-adherent cells from normal syngeneic mice to the nonadherent spleen cells from infected mice did not restore the depressed Con A responsiveness. On the other hand. exogenous IL-2 reconstituted completely the proliferative responses to Con A. Flow cytometry analysis revealed that CD4- CD8+ cells with a low density of CD8 Ag (CD8dull cells) increased in spleens from infected mice 2 weeks after inoculation. Addition of the spleen cell subpopulation containing the CD8dull cells. but not that depleted of the CD8dull cells. to normal spleen cells resulted in marked suppression of the Con A responses. These findings suggest that the CD8dull cells detected in spleens of mice inoculated with E. multilocularis PSC may play a key role in the suppressive regulation of immune responses. The relevance of the immune suppression seen in the early stages of experimental infection with E. multilocularis PSC to the eventual establishment of a host-parasite relationship is discussed.
Reversible operculum syndrome caused by progressive epilepsia partialis continua in a child with left hemimegalencephaly, In a child with left hemimegalencephaly and seizures. a reversible operculum syndrome developed when continuous epileptic discharges spread from the left hemisphere to the contralateral central regions. The operculum syndrome lasted for three months until left hemispherectomy was performed. Soon after surgery the seizures and the operculum syndrome resolved. The operculum syndrome is a facio-pharyngo-glosso-masticatory diplegia usually due to structural lesions in both opercular regions. The reversibility of the syndrome in the reported case demonstrates that the operculum syndrome is sometimes functional rather than lesional.
Duration of etidronate effect demonstrated by serial bone scintigraphy, There have been several reports of etidronate disodium (EHDP) interference upon the biodistribution of 99mTc-methylene diphosphonate (MDP). With the increasing use of etidronate for the treatment of Paget's disease. hypercalcemia. and osteoporosis. nuclear physicians can expect to encounter increasing numbers of cases in which EHDP-induced artifacts impair the diagnostic utility of bone scans. The temporal duration of this effect is unknown yet obviously important. We report serial bone scintigraphy in a patient who received a single dose of EHDP for hypercalcemia. Normal biodistribution of 99mTc-MDP was noted at 15 days. suggesting that 2 wk are sufficient before performing a bone scan after a single intravenous dose of etidronate.
Malnutrition induces an increase in intermediate filament protein content of rat cerebral cortex, Wistar rats were fed a normal protein (25% casein) or an isoenergetic low protein (8% casein) diet from the day of giving birth until pups were weaned. Some litters were killed at weaning; others (both normal and malnourished animals) received the 25% protein diet until d 90 when they were killed. Intermediate filament (IF) preparations were obtained by extraction of the cerebral cortex with a high salt PBS solution containing 1% Triton X-100. The pellet contained the bulk of the cytoskeleton proteins from tissue. identified as the 150- and 68-kDa subunits of neurofilaments (NF-M and NF-L. respectively). the 66-kDa associated protein. the 57-kDa intermediate filament-like protein. and the 50-kDa glial fibrillary acidic protein. Intermediate filament-enriched fractions from control and malnourished rats at both d 21 and 90 were scanned following two-dimensional gel electrophoresis to determine the effects of postnatal malnutrition on the intermediate filament protein content. The results indicated that postnatal malnutrition imposed during the brain growth spurt period did not alter the expression of IF proteins of the cerebral cortex in 21-d-old rats. but increased the expression of NF-L and NF-M proteins in adult rats.
Enhancement of primary systemic acquired immunity by exogenous triiodothyronine in wasted, protein-energy malnourished weanling mice, The objectives of this investigation were to expand information regarding the types of acquired immune responses that can be stimulated by triiodothyronine (T3) supplements in wasting protein-energy malnutrition (PEM) and to determine whether T3 can exert its enhancing influence on acquired immunity in PEM against diverse genetic backgrounds. Two experiments were conducted with weanling C57BL/6J mice. Animals were allowed ad libitum access for 14 d to a nutritionally complete purified diet (C). an isoenergetic low protein (0.6%) formulation (LP) or the low protein diet containing 0.2 microgram T3/g (LPT3). The LP diet produced wasting as judged by weight loss and carcass composition. This diet also depressed both the antibody response to sheep red blood cells (Experiment 1) and the complete major histocompatibility complex-disparate skin graft rejection response (Experiment 2). The LPT3-fed mice experienced wasting at least equivalent in magnitude to that of animals fed LP. but they exhibited significantly more vigorous responses than LP-fed animals in both immune reactions examined. In conjunction with previous results obtained using the CBA/J strain of mouse. the results show that not only humoral (antibody) responses but also at least some cell-mediated responses can be improved by T3 supplements in wasting PEM. Moreover. this influence on acquired immunity is apparent in at least two genetically unrelated mouse strains. thus increasing confidence in its basic biological significance.
Effects of intravenous nutrition on lipoprotein metabolism, body composition, weight gain and uremic state in experimental uremia in rats, The effect on serum lipids. lipoprotein fractions. body composition. weight gain and uremic state of including fat in intravenous nutrition was evaluated in rats with chronic uremia. Uremic rats were given high energy (1385 kJ.kg body weight-1.day-1). low nitrogen (0.6 g N.kg body weight-1.day-1) total parenteral nutrition (TPN) for 12 d with either glucose or glucose plus 30% lipids (Intralipid) as the energy source. Additional uremic and nonuremic groups were fed a standard diet orally. During TPN. serum triglyceride and cholesterol levels were slightly higher in rats fed lipid-based TPN compared to those administered glucose-based TPN or fed the oral diet; but there were no differences 8 h after feeding. The serum lipoprotein fractions showed accumulation of lipids in LDL resulting from the lipid-based TPN but no differences in VLDL. In orally fed uremic rats. more lipids were found in HDL than in the TPN-treated rats. The fractional clearance of the fat emulsion was normal and independent of the nutrition composition. Uremic rats administered lipid-based TPN for 21 d had the same weight gain as orally fed. nonuremic control rats (23 +/- 3 vs. 22 +/- 2%); glucose-based TPN did not support normal growth (10 +/- 1%). Uremic rats fed orally did not grow and retained significantly more body water than TPN-fed uremic rats. In uremic animals. lipid-based TPN also was associated with normal body composition despite significantly lower levels of carnitine in plasma. skeletal muscle and heart tissue.
Hypoglossal-facial nerve interpositional-jump graft for facial reanimation without tongue atrophy, The hemitongue paralysis that occurs as a result of a classic hypoglossal-facial nerve crossover procedure can result in profound functional deficits in speech. mastication. and swallowing. The procedure is not an option in patients with bilateral facial paralysis or those at risk for combined cranial nerve deficits. To address some of the drawbacks and limitations of this classic procedure. we developed the hypoglossal-facial nerve interpositional jump graft (12-7 jump graft) procedure. This procedure involves interposing a nerve graft between a partially severed but functionally intact twelfth cranial nerve and the degenerated seventh cranial nerve. and is often combined with other reanimation procedures. To date. we have performed 33 12-7 jump graft procedures in 30 patients (three were treated for bilateral facial paralysis); this report describes the procedure and its indications. and details the results of 23 procedures performed in 20 patients for whom 24-month follow-up data are available. Twelfth nerve deficits occurred in only three patients in this report. Recovery of facial function began between 3 and 24 months postoperatively. Facial tone and symmetry were achieved in every patient. no patient had significant mass movement. and 13 patients (two of whom were treated for bilateral facial paralysis) had excellent and three had superb restoration of facial movement. These results show the 12-7 jump graft to be a valuable adjunct for facial reanimation in selected patients.
Facial nerve stimulation with cochlear implantation. VA Cooperative Study Group on Cochlear Implantation, The course of the facial nerve may place it within the current field generated by an activated cochlear implant to produce incidental facial movement. We investigated the presence of facial nerve stimulation associated with cochlear implants in the VA Cooperative Study of Advanced Cochlear implants. Twelve of 82 patients enrolled in this study demonstrated facial nerve stimulation within 2 years of implant activation. Facial nerve stimulation in six patients with multiple channel implants (Nucleus or ineraid devices) either resolved spontaneously (n = 2). or was eliminated by deactivating basal (n = 2) or apical (n = 2) electrodes. Two of six patients with single-channel electrodes (3-M/Vienna devices) demonstrated facial nerve stimulation that resolved spontaneously (n = 2). resolved with lowering current output (n = 2). or was refractory to processor adjustment (n = 2). Intraoperative assessment in one of the refractory cases indicated that facial nerve stimulation resulted from current spread through the modiolus to activate the facial nerve. A variety of factors. including implant design. stimulus parameters. and local tissue impedances. may interact to produce incidental facial stimulation. Low-impedance pathways between the scala tympani and the modiolus may deserve increased recognition as an interactive factor in cochlear implant performance.
Microsubglottoscopy: an expansion of operative microlaryngoscopy, The development of the adult subglottiscope has facilitated expansion of the indications for operative microlaryngoscopy to include surgery in the subglottic region of the larynx. as well as in the upper cervical trachea. A set of microlaryngeal instruments with an elongated shaft has been developed to support the use of the subglottiscope in the adult patient population. During the 18-month period from January 1. 1988. through June 30. 1989. sixteen adult patients with subglottic or upper cervical tracheal pathology were operated on a total of twenty-three times. using the adult subglottiscope to facilitate exposure and treatment. The patients' pathologic conditions included subglottic stenosis. subglottic granuloma. subglottic extension of laryngeal hemangioma and papilloma. and suprastomal granuloma. Two selected cases are presented to highlight indications for the use of this instrument. We have found the exposure of these subglottic and upper cervical tracheal lesions. using the binocular. microlaryngeal approach facilitated by the adult subglottiscope. to be improved over that obtained with existing microlaryngoscopes or conventional tracheoscopes.
Successful treatment of selected cases of abductor spasmodic dysphonia using botulinum toxin injection, Ten patients with abductor spasmodic dysphonia. who exhibited spasmodic bursts and heightened activity of the cricothyroid muscle during speech. were selected for participation. Between 5 and 20 U of botulinum toxin type A were injected into both right and left cricothyroid muscles. Six patients benefited substantially. whereas four did not. Acoustic analyses of voice patterns showed similar changes to the clinical impressions. Significant group improvements were found in sentence duration while selected patients improved in the proportion of their speech that was voiced and the duration of their voiceless consonants. Those patients with abductor spasmodic dysphonia and other muscle abnormalities in addition to the cricothyroid and with constant breathiness did not benefit.
Immunomodulation of the induction phase of lymphokine-activated killer activity by acute phase proteins, Effective treatment of head and neck cancer with biologic response modifiers may be benefitted by an understanding of in vivo factors capable of modulating the lymphokine-activated killer (LAK) cell phenomenon. Eighteen patients with squamous cell carcinoma of the head and neck were studied. Killer cells from each patient. activated by recombinant interleukin-2 (10 U/ml). were induced in either complete medium alone or complete medium plus 10% autologous serum solution and analyzed. Cytotoxicity against both K562 and squamous cell carcinoma (MDA686-Ln) cell lines was determined by use of standard chromium-release assays. The immunomodulatory capacity of serum was correlated with levels of various acute phase proteins. Autologous serum significantly inhibited the induction phase of the LAK phenomenon in 61% of patients and stimulated it in 22%. No patients with early stage I or II disease had significant inhibition of induction. No direct correlation between inhibition and serum acute phase protein levels were seen. An inverse relationship was seen between the C3 component of complement and induction inhibition (r = -0.6). These findings suggest that advances of in vivo immunomodulatory therapy will require elucidation of mechanisms of serologic inhibition of the induction phase of the LAK phenomenon. Such studies may lead to serologic modification to enhance treatment efficacy of biologic response modifiers.
Determining side of vestibular dysfunction with rotatory chair testing, Determining side of vestibular lesion remains a challenging task during neurotologic investigations. particularly if auditory lateralizing signs are absent. Traditionally. absent or decreased caloric response has been regarded as evidence of unilateral vestibular deficit. But. the inability of the chair test to detect side of lesion has been generally accepted because rotation stimulates both end organs. A retrospective study postulated and tested a hypothesis that low-frequency asymmetry of sinusoidal harmonic acceleration (SHA) testing can determine side of lesion when phase is abnormal. The present prospective. double-blind study was designed to further test the retrospective study hypothesis. Results showed that SHA asymmetry detects side of unilateral vestibular deficit when phase is abnormal in 97% of cases.
Fourth branchial pouch sinus: diagnosis and treatment, The fourth branchial pouch sinus (FBPS) is a rare translaryngeal anomaly with diverse manifestations. including neonatal stridor and recurrent deep neck infection. Review of the world literature reveals 23 reports of sinuses consistent with fourth pouch origin. We present two additional cases. including the only example of a right-sided FBPS. Retrograde excision. beginning at the piriform apex. ensures complete removal of the tract and protection of the recurrent nerve. The posterior border of the thyroid ala must be resected or retracted for adequate exposure. Failure to remove the translaryngeal portion of the tract almost guarantees recurrence.
The role of preoperative CT scans in staging external auditory meatus carcinoma: radiologic-pathologic correlation study, Survival is related to the pathologic extent of tumor in external auditory meatus (EAM) carcinoma. This study assesses the validity of preoperative CT scans in staging EAM carcinoma. The accuracy of staging EAM carcinoma with preoperative CT scans was evaluated by comparing radiography and histopathology. Patients who received preoperative CT scan were selected from a retrospective series of 35 temporal bone resections for EAM squamous cell carcinoma. The CT scans were systematically reviewed for tumor involvement in 12 anatomic areas. The histopathology slides for the corresponding patients were reviewed according to the same criteria. CT scan findings accurately diagnosed the extent of tumor involvement identified during histopathologic examination. These tumors demonstrated the capacity to spread along existing anatomic pathways as well as direct bone erosion. We conclude that preoperative CT scans accurately stage EAM squamous cell carcinoma.
Prognostic factors in advanced head and neck cancer patients undergoing multimodality therapy, A retrospective analysis was performed to investigate potential prognostic factors for complete remission to neoadjuvant chemotherapy and overall survival in patients with previously untreated stage III and stage IV head and neck cancer. Eighty consecutive patients were treated in one of two studies investigating three or four courses of neoadjuvant chemotherapy. Before local therapy and surgery and/or radiotherapy. 29% attained a complete remission. No strong significant and independent predictor of complete remission was identified. Only nodal stage (N) was found moderately associated with complete remission (p = 0.06). Node-negative patients had higher remission rates. Less important predictors were tumor stage (T) and site of disease; nasopharyngeal patients had superior remission rates (56%). With a median followup of 45 months and estimated 3-year survival rate of 38% (median 23.7 months). individual factors predictive of survival included pretherapy weight loss. performance status. alcohol use. pretherapy serum albumin level. site of disease. and N stage. In multivariate testing weight loss was identified as the strongest independent predictor of survival (p less than 0.0001) and surpassed other health status measures. such as performance status and serum albumin level. In addition. N stage (p = 0.019) and alcohol use (p = 0.017) were found to be predictive. A cross-classification by N stage and weight loss revealed risk groups with distinctly different prognoses. which may be useful for design and analysis in future trials.
Myringoplasty in children, This series examines the results of myringoplasty in children using the overlay technique. Controversy still surrounds the issue of proper timing of surgery on the basis of preoperative assessment of tubal function. Results of this technique in children. using contralateral ear status as the primary predictor of success. found an overall success rate of 78%. Age appears to be a significant factor because children 10 years old and younger were found to have a higher incidence of surgical failures.
Vagal body tumors, Six cases of vagal body tumor are reviewed. All first presented as painless neck masses with normal cranial nerve function. Otologic symptoms were infrequent. occurring only with temporal bone involvement. In true vagal paragangliomas. cranial nerve and auditory function is usually preserved until there is extensive disease of the skull base. Tumor progression after radiotherapy was documented in four patients. three of whom were treated with 4500 cGy or more. One patient was found to have regional lymph node metastases. The six patients had a total of 10 head and neck paragangliomas. illustrating the high incidence of synchronous and metachronous lesions. Because of the high incidence of multiple lesions. these tumors threaten lower cranial nerves bilaterally in many instances. Because cranial nerve function is preserved until late. and because vagal and accessory nerve paralysis is usually unavoidable with resection. we advocate conservative treatment in selected cases. It may be reasonable to postpone surgery until cranial nerve impairment becomes evident or other vital structures are threatened.
Oncocytic metaplasia of the pharynx, Oncocytic metaplasia of the pharynx has been infrequently described. with only two previous cases in the literature. With the advent of panendoscopy during the last decade. however. a better understanding of this histopathologic diagnosis is desirable. Thirty-three cases are reviewed. with thirty occurring in the nasopharynx. This was most commonly discovered as an unrelated finding during endoscopic evaluation of a head and neck mass or malignancy in twenty-two patients. either histologically after random biopsy or after biopsy of small but visible lesions. An additional eight cases manifested otitis media or eustachian tube dysfunction. The histology. terminology. and benign clinical nature of these lesions are discussed.
Retropharyngeal space infection: changing trends, Retropharyngeal space infection. now a rare entity since the introduction of modern antibiotic chemotherapy. has traditionally been described to occur in children less than 4 years of age with suppurative disorders of the ear. nose. and throat. Recent reports suggest a changing trend in the epidemiology. bacteriology. diagnostic imaging. treatment. and clinical course of this entity. However. the medical literature concerning this topic over the last two decades has consisted mainly of case reports. We reviewed eight cases of retropharyngeal space infection at our institutions over a 15-year period. representing one of the largest clinical series of its kind in the last 20 years. Patient ages ranged from 3 months to 41 years. Findings of these cases and 13 cases from similar reports obtained by a MEDLINE computer search of the recent literature were analyzed. Results show a trend toward occurrence in older age groups. polymicrobial infections. successful use of CT scan as a diagnostic modality. and fewer patients requiring incision and drainage. These findings will be discussed and contrasted to conventional wisdom.
Overlapping loss of heterozygosity by mitotic recombination on mouse chromosome 7F1-ter in skin carcinogenesis, A significant role for mouse chromosome 7 abnormalities during chemically induced skin carcinogenesis has been advanced based on previous cytogenetic and molecular studies. To determine the frequency of allelic losses at different loci of chromosome 7 in skin tumors induced in the outbred SENCAR mouse stock by a two-stage initiation-promotion protocol. we compared the constitutional and tumor genotypes of premalignant papillomas and squamous cell carcinomas for loss of heterozygosity at different informative loci. In a previous study. these tumors had been analyzed for their allelic composition at the Harvey ras-1 (Ha-ras-1) locus and it was found that 39% of squamous cell carcinomas had lost the normal Ha-ras-1 allele exhibiting 3 or 2 copies of the mutated counterpart or gene amplification. In the present study. by combining Southern blot and polymerase chain reaction fragment length polymorphism analyses. we detected complete loss of heterozygosity at the beta-globin (Hbb) locus. distal to Ha-ras-1. in 15 of 20 (75%) skin carcinomas. In addition. 5 of 5 informative cases attained homozygosity at the int-2 locus. 27 centimorgans distal to Hbb. Polymerase chain reaction analysis of DNA extracted from papillomas devoid of stromal contamination by fluorescence-activated sorting of single cell dispersions immunolabeled with anti-keratin 13 antibody revealed loss of heterozygosity at the Hbb locus. demonstrating that this event occurs during premalignant stages of tumor development. Interestingly. loss of heterozygosity was only detected in late-stage lesions exhibiting a high degree of dysplasia and areas of microinvasion. Analysis of allelic ratios by densitometric scanning of tumors that had become homozygous at Hbb but retained heterozygosis at Ha-ras-1 indicated mitotic recombination as the mechanism underlying loss of heterozygosity on mouse chromosome 7 during chemically induced skin carcinogenesis. These findings are consistent with the presence of a putative tumor suppressor gene linked to the Hbb locus in the 7F1-ter region of mouse chromosome 7. the functional inactivation of which may constitute a critical event in skin tumor progression. possibly during the malignant conversion stage.
Protein-tyrosine-phosphatase CD45 is phosphorylated transiently on tyrosine upon activation of Jurkat T cells, The leukocyte common antigen (CD45) is an abundant lymphocyte surface antigen that has been reported to be involved in signaling through the T-cell antigen receptor. CD45 is a transmembrane protein-tyrosine-phosphatase. An internal segment comprises two domains each of which is homologous to other protein-tyrosine-phosphatases; the extracellular segment has the hallmarks of a ligand-binding motif. Since tyrosine phosphorylation is an early signal resulting from stimulation of the T-cell antigen receptor and CD45 is required for proper activation through the receptor. we explored whether CD45 might be regulated by tyrosine phosphorylation. Treatment of a T-cell leukemia line (Jurkat) with either phytohemagglutinin or anti-CD3 antibodies induced phosphorylation of tyrosine residues in CD45; treatment with phorbol 12-myristate 13-acetate did not. Phosphorylation of CD45 was transient. disappearing within 40 min after phytohemagglutinin treatment. The requirement for stringent conditions of phosphatase inhibition suggests that CD45 is capable of autodephosphorylation in vivo. These observations support recent reports indicating CD45 is involved in an early step in the T-cell activation cascade. They also suggest that phosphorylation/dephosphorylation of tyrosine residues in CD45 should be explored further as a possible regulatory mechanism.
Cloning of a cellular factor, interleukin binding factor, that binds to NFAT-like motifs in the human immunodeficiency virus long terminal repeat, Human immunodeficiency virus (HIV) gene expression is regulated by both general transcription factors and factors induced by activation of T lymphocytes such as NF-kappa B and the nuclear factor of activated T cells (NFAT). Within the HIV long terminal repeat (LTR). two purine-rich domains between nucleotides -283 and -195 have homology to a regulatory region found in the interleukin 2 promoter. which binds NFAT and other cellular factors. In the HIV LTR. this region has been demonstrated to have both positive and negative regulatory effects on HIV gene expression. In an attempt to clone genes encoding cellular factors that bind to these NFAT-like elements in the HIV LTR. we used lambda gt11 expression cloning with oligonucleotides corresponding to these binding motifs. A ubiquitously expressed cDNA encoding a 60-kDa protein. which we termed interleukin binding factor (ILF). binds specifically to these purine-rich motifs in the HIV LTR. This factor also binds to similar purine-rich motifs in the interleukin 2 promoter. through with lower affinity than to HIV LTR sequences. Sequence analysis reveals that the DNA binding domain of ILF has strong homology to the recently described fork head DNA binding domain found in the Drosophila homeotic protein fork head and a family of hepatocyte nuclear factors. HNF-3. Other domains found in ILF include a nucleotide binding site. an N-glycosylation motif. a signal for ubiquitin-mediated degradation. and a potential nuclear localization signal. These results describe a DNA binding protein that may be involved in both positive and negative regulation of important viral and cellular promoter elements.
Transformation-dependent activation of urokinase-type plasminogen activator by a plasmin-independent mechanism: involvement of cell surface membranes, Transformed cells produce elevated levels of the urokinase-type plasminogen activator (u-PA). which has been linked with the invasive or migratory phenotype of these cells. The u-PA is secreted and normally maintained in the inactive. single-chain form (scu-PA) and it has been assumed that natural activation occurs via a plasmin-mediated cleavage converting scu-PA to the active. two-chain form (tcu-PA). We now demonstrate that secreted scu-PA in Rous sarcoma virus-transformed chicken embryo fibroblast (RSVCEF) cultures is activated by an endogenous. plasmin-independent mechanism. Normal CEFs and CEFs infected with a temperature-sensitive RSV mutant and incubated at the nonpermissive temperature do not activate scu-PA. Conditioned medium harvested from plasmin-free cultures of RSVCEFs contains active tcu-PA as determined by two independent methods. The scu-PA is progressively converted with time in culture and requires the presence of intact cells or a plasma membrane-enriched fraction. When added to RSVCEF cultures. a synthetic peptide corresponding to residues 20-41 of the growth factor domain of chicken u-PA blocks the conversion to tcu-PA. and scu-PA accumulates in the cultures. These results suggest that scu-PA is secreted by cells. becomes bound to a u-PA receptor. and is proteolytically converted to active tcu-PA by a catalytic mechanism on the surface of RSV-transformed fibroblasts.
A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function, The present studies were designed to provide careful measures of effects of oxandrolone. an anabolic steroid. intravenous nutritional supplementation. and the combination of these two treatments on liver functions. metabolic balances. nitrogen metabolism. and nutritional status in patients with moderate to severe alcoholic hepatitis. Of 43 patients originally recruited. 39 (19 men. 20 women) with typical clinical and laboratory features of alcoholic hepatitis (11 Child's-Pugh class B; 28 class C) were admitted to a metabolic unit and completed a 35-day three-phase protocol. Phase I was a 10-day baseline period of observation. during which routine and special quantitative tests of liver function (galactose and antipyrine metabolism). a 7-day elemental balance study. and a 15N. 13C-leucine metabolism study were done. Phase II was a 21-day treatment period during which patients were randomly assigned to receive one of four regimens: 1) standard therapy. consisting of abstinence. a balanced. nutritionally adequate diet. and multivitamins; 2) oxandrolone (20 mg orally four times a day) plus standard therapy; 3) nutritional supplementation. consisting of 2 L daily of 3.5% crystalline amino acids (in 5% dextrose). given by peripheral vein; or 4) a combination of oxandrolone and nutritional supplementation. along with standard therapy. Metabolic balances were repeated during phase II. Phase III was 2 or 3 days posttreatment. during which special studies of liver functions and volumes and leucine metabolism were repeated. All patients who completed phase I of study and were randomly allocated to one of the four treatment groups completed the subsequent two phases. Overall. with time. patients showed highly significant improvements in most clinical and laboratory features. For most standard laboratory tests (e.g.. serum albumin. transferrin. prothrombin time) improvements were more marked in patients treated with nutritional supplementation and/or oxandrolone than in those given standard therapy alone. Liver volumes fell in all treatment groups. with greater improvement in those treated with nutritional supplementation. Improvements in galactose and antipyrine metabolism rates were significant only in those treated with nutritional supplementation or oxandrolone. Effects of treatments on metabolic balances. nitrogen metabolism. and measures of nutrition are described in this issue in a companion paper. We conclude that the addition of nutritional supplementation and oxandrolone to standard therapy of moderately severe or severe alcoholic hepatitis is well tolerated. and leads to more rapid improvement in the laboratory parameters measured.
A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. II. Short-term effects on nitrogen metabolism, metabolic balance, and nutrition, Patients with moderately severe or severe alcoholic hepatitis. described in a companion paper in this issue. had serial studies of energy and protein metabolism and elemental balances before and during treatment for 21 days with one of four randomly assigned regimens: 1) standard therapy. consisting of abstinence. a balanced. nutritionally adequate diet. and multivitamins; 2) oxandrolone (20 mg orally four times a day) plus standard therapy; 3) nutritional supplementation. consisting of 2 liters of 3.5% crystalline amino acids in 5% dextrose given by peripheral vein (PPN) plus standard therapy; and 4) a combination of the other three treatments. Dietary and intravenous intakes and weights were recorded daily. and weekly averages were calculated. Anthropometric measurements and blood studies were done weekly; blood studies included white blood cell counts and differentials. serum prealbumin. transferrin. and total protein and plasma aminograms. Four-days complete balance studies and measures of 15N.1-13C-leucine metabolism also were performed at baseline and after the treatment period. Major findings were as follows: a) Intakes of total calories and protein were significantly higher in PPN-treated than in other groups. b) All patients had positive elemental balances. both at baseline and at the end of the treatment period. However. those treated with PPN (with or without oxandrolone) had higher positive balances of nitrogen. potassium. phosphorus. and magnesium. indicating improvement in lean body mass. c) Anthropometric measurements showed no significant changes. but measures of the visceral protein compartment (serum prealbumin. transferrin. total protein. total lymphocyte count) improved significantly with time. For most of these variables. increases were significantly greater in those treated with PPN with or without oxandrolone than in the other groups. However. for prealbumin. the increase was greatest in the oxandrolone-treated group d) PPN treatment produced dramatic increases in levels of branched-chain amino acids and improvement in the ratio of plasma branched chain to aromatic amino acids. Other treatments had no effect on plasma aminograms. e) Metabolism of 15N.1-13C-leucine was normal and was not affected significantly by treatment. Therapy with PPN and/or oxandrolone was tolerated well. We conclude that PPN has favorable effects on energy and protein metabolism in florid alcoholic hepatitis; oxandrolone has lesser effects. although it may exert some additional action and particularly increases serum prealbumin levels. The results support the use of nutritional supplementation in therapy of moderately severe or severe alcoholic hepatitis.
APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease, The amyloid precursor protein (APP) gene codes for the precursor to the beta-protein found in the amyloid deposits of Alzheimer disease (AD). Recently Goate et al. identified in codon 717 of this gene a missense mutation which segregates with AD in a familial AD (FAD) kindred. The same mutation was also found in affected subjects from a second FAD family but not in other FAD families or in normal controls. The following work was undertaken to determine the frequency of the codon 717 mutation in FAD and nonfamilial AD cases and in normal controls. We tested 76 FAD families. 127 "sporadic" AD subjects. 16 Down syndrome cases. and 256 normal controls for this mutation. and none were positive. We also tested for the APP codon 693 mutation associated with hereditary cerebral hemorrhage with amyloidosis-Dutch type. for PRIP gene missense mutations at codons 102. 117. and 200. and for the PRIP insertion mutations which are associated with Creutzfeld-Jakob disease and Gerstmann-Straussler Scheinker syndrome. No examples of these mutations were found in our population. Thus these APP and PRIP mutations are rare in both FAD and nonfamilial AD.
GM1-gangliosidosis (genetic beta-galactosidase deficiency): identification of four mutations in different clinical phenotypes among Japanese patients, GM1-gangliosidosis is a genetic neurological disorder caused by mutations in the lysosomal acid beta-galactosidase gene. While its phenotypic expression is complex. it is usually classified as being of infantile. juvenile. or adult form. on the basis of age at onset. the rate of symptomatic progression. and severity of central nervous system involvement. We have analyzed the acid beta-galactosidase gene in 12 Japanese patients from nine families. The aim was to identify mutations in individual patients and then to examine possible correlation between the mutations and the clinical phenotypes. Northern blotting studies with a full-length human beta-galactosidase cDNA showed that the mRNA ranged from undetectable to substantially decreased in the infantile patients but was normal in quantity and size in all juvenile and adult patients. Four distinct missense mutations have been identified. each limited to the respective clinical forms within our small-size samples. In the infantile patient with decreased but detectable mRNA. a point mutation was found resulting in Arg49----Cys. In the infantile patient with nearly undetectable mRNA. mutation Arg457----Ter was identified. The mutation Arg201----Cys was found in all four of the juvenile patients. while all six adult patients were homozygous for the point mutation Ile51----Thr. The mutations found in the juvenile and adult patients alter restriction sites in the normal gene and thus are amendable to quick screening. The prediction that these mutations are responsible for the clinical disease was confirmed by no expression of the catalytic activity of the mutant proteins in the COS-I cell expression system.
Identification of a missense mutation in one allele of a patient with Pompe disease, and use of endonuclease digestion of PCR-amplified RNA to demonstrate lack of mRNA expression from the second allele, Infantile-onset glycogen storage disease type II. or Pompe disease. results from a genetic deficiency of the lysosomal enzyme acid alpha glucosidase (GAA). Sequencing of the cDNA from a cell line (GM 244) derived from a patient with Pompe disease demonstrated a T953-to-C transition that predicted a methionine-to-threonine substitution at codon 318. The basepair substitution resulted in loss of restriction-endonuclease sites for NcoI and StyI. Analysis of genomic DNA revealed both a normal and an abnormal NcoI fragment. indicating that the patient was a genetic compound. NcoI and StyI digestion of cDNA. amplified by PCR from reverse-transcribed RNA. demonstrated that greater than 95% of the GAA mRNA in GM 244 was derived from the allele carrying the missense mutation. The missense mutation was uncommon. since it was not detected in 37 additional GAA-deficient chromosomes. as determined by digestion of genomic DNA with NcoI and hybridization. The amino acid substitution predicts a new potential site for N-linked glycosylation. as well as major changes in secondary structure of the protein. We could confirm that the mutation was responsible for the enzyme deficiency by demonstrating that a hybrid minigene containing the mutation did not express GAA enzyme activity after transient gene expression. We have therefore now provided the first identification of a single-basepair missense mutation in a patient with Pompe disease and furthermore have demonstrated that the patient is a genetic compound with the second allele barely expressing mRNA.
Gaucher disease: heterologous expression of two alleles associated with neuronopathic phenotypes, To investigate the molecular basis for the distinct neuronopathic phenotypes of Gaucher disease. acid beta-glucosidases expressed from mutant DNAs in Gaucher disease type 2 (acute) and type 3 (subacute) patients were characterized in fibroblasts and with the baculovirus expression system in insect cells. Expression of the mutant DNA encoding a proline-for-leucine substitution at amino acid 444 (L444P) resulted in a catalytically defective. unstable acid beta-glucosidase in either fibroblasts from L444P/L444P homozygotes or in insect cells. This mutation was found to be homoallelic in subacute neuronopathic (type 3) Gaucher disease. In comparison. expression of the mutant cDNA encoding an arginine-for-proline substitution at amino acid 415 (P415R) resulted in an inactive and unstable protein in insect cells. This allele was found only in a type 2 patient with the L444P/P415R genotype. The substantial variation in the type 3 phenotype (L444P homozygotes) suggests the complex nature of the molecular basis of phenotypic variation in Gaucher disease. Yet. the association of neuronopathic phenotypes with alleles producing severely compromised (L444P) or functionally null (P415R) enzymes indicates that the effective level of residual activity at the lysosome is likely to be a major determinant of the severity of Gaucher disease.
The Health of the Public Program at the University of Washington: a new role for academic medical centers, The University of Washington Health of the Public Program has convened a consortium composed of the region's academic medical center. the two largest managed care plans in Washington. and representatives of the state's major private and public purchasers of health care. The consortium's purpose is to test the feasibility of collaboratively collecting cross-system data. assessing variations in practice. and implementing site-specific interventions to improve the management of common illnesses and encourage preventive care. Changes under way in the ambulatory training environment and in the undergraduate curriculum as a result of the consortium's initial efforts are described. In today's climate of cost consciousness and concerns about quality. academic medical centers can play an important role in helping to improve community-wide outcomes of care.
Quantitative assessment of HIV-1 DNA load by coamplification of HIV-1 gag and HLA-DQ-alpha genes, We developed an assay for simultaneous amplification. detection and quantitation of HIV-1 gag gene and the DQ-alpha locus of the histocompatibility (HLA) region of the human genome by polymerase chain reaction (PCR). Crude cell lysates from control cell lines and peripheral blood mononuclear cells (PBMC) from HIV-1-infected and control individuals were coamplified using optimized concentrations of primers directed at both loci. followed by simultaneous hybridization with radioactively labeled HIV-1-gag and HLA-DQ-alpha probes. Simultaneous quantitation of the 242-base-pair HLA and 115-base-pair HIV products was accomplished by both end-point dilution analysis and image analysis of autoradiographs relative to standard curves derived from infected cell lines. We observed good agreement between input cell counts on fresh samples and the HLA-DQ-alpha target copy number values determined by both end-point dilution analysis and comparison of band intensities with standard curves. HIV-1 proviral load in symptomatic patients ranged from 200 to 4000 HIV-PCR-units per 1 x 10(6) PBMC (mean of 1245 copies). whereas asymptomatic patients had levels ranging from two to 1000 HIV-PCR-units per 1 x 10(6) PBMC (mean of 213 copies). This HIV/HLA coamplification approach should be particularly useful for analysis of frozen repository samples from natural history studies. and may facilitate wider application of quantitative PCR analysis.
A pilot study of the efficacy and safety of bolus administration of alteplase in acute myocardial infarction, OBJECTIVE--To examine the efficacy. safety. and the pharmacokinetic profile of a bolus dose administration regimen of alteplase in the treatment of acute myocardial infarction. DESIGN--An open pilot study. SETTING--District general hospital. PATIENTS--33 suitable consecutive patients presenting within six hours of the onset of symptoms who satisfied the electrocardiographic criteria for acute myocardial infarction. INTERVENTIONS--Two intravenous boluses of 35 mg alteplase. 30 minutes apart. MAIN OUTCOME MEASURES--Angiographic coronary patency at 90 minutes and 24 hours. Plasma alteplase concentration-time profile and pharmacokinetic analysis. RESULTS--Coronary patency at 90 minutes: 26 of 30 arteries (87%. 95% confidence interval (CI) 74-99%). Coronary patency at 24 hours: 24 of 29 arteries (83%. CI 69-97%). Mean (SD) plasma tissue plasminogen activator (t-PA) concentration reached 4434.8 (2117.8) and 4233.3 (2217.5) ng/ml within 10 minutes of each bolus and fell to 425.8 (288.3) ng/ml between boluses. The estimated peak concentrations at two minutes after boluses were 12.389 (8580) ng/ml and 10.811 (6802) ng/ml. The derived pharmacokinetic variables were volume of distribution 3.11 (1.89) 1. clearance 21.3 (9.3) 1/h. half life 5.9 (1.7) minutes. CONCLUSIONS--This simple administration regimen achieved brief. high concentrations of plasma t-PA that were well tolerated. The regimen was associated with a high coronary patency rate at 90 minutes that was well maintained at 24 hours.
Ig VH gene expression among human follicular lymphomas, Thirty-six randomly selected cases of low grade follicular lymphoma (FL) were analyzed for Ig heavy chain variable region (VH) gene expression. Assignment to one of the six human VH gene families (VH1 to VH6) was made with a polymerase chain reaction-based technique using family-specific leader primers. The frequency of VH family use in FL was found to be similar to that reported for normal peripheral blood lymphocytes and is therefore also roughly proportional to VH family size. To evaluate expression within an individual family. all of the lymphoma VH genes from the middle size VH4 family were sequenced and compared with previously published sequences. Of these eight lymphoma VH sequences. six were most closely related to just two of the 10 known functional VH4 germline genes. Nonrandom usage by FL of the JH3. JH4. and JH5 joining segments was also observed. Nucleotide sequences were also determined for 10 randomly selected lymphoma VH genes from the large VH3 family. With one possible exception. none of these lymphoma VH sequences appear to represent any of the VH3 genes that may be preferentially used in the fetal repertoire.
Differences in beta-adrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy, BACKGROUND. We measured the content and activities of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex and adrenergic neurotransmitter levels in left and right ventricular myocardial preparations derived from 77 end-stage failing human hearts from patients with idiopathic dilated cardiomyopathy (IDC) or ischemic dilated cardiomyopathy (ISCDC). METHODS AND RESULTS. The results were compared with data obtained in 21 nonfailing hearts removed from organ donors. Compared with ISCDC ventricles. IDC left and right ventricles exhibited a greater degree of total beta- or beta 1-receptor downregulation. In contrast. compared with IDC right ventricles. isolated tissue preparations of ISCDC right ventricles exhibited a greater degree of subsensitivity to the inotropic effect of isoproterenol. indicating a relatively greater degree of functional uncoupling of right ventricular ISCDC beta-receptors from mechanical response. In addition. relative to IDC left ventricles. preparations of ISCDC left ventricle exhibited greater subsensitivity to beta-agonist-mediated adenylate cyclase stimulation. indicating functional uncoupling of left ventricular ISCDC beta-receptors from cyclic AMP generation. The uncoupling of beta-receptors in ISCDC left and right ventricles may have been a result of abnormalities in G protein activation of adenylate cyclase; compared with age- and cardiac function-matched respective left or right IDC ventricles. ISCDC left ventricles exhibited less stimulation of adenylate cyclase by NaF or forskolin but no change in Mn2+ stimulation. whereas ISCDC right ventricles exhibited less stimulation by the nonhydrolyzable guanine nucleotide Gpp (NH)p. Also. IDC right ventricles exhibited a "selective" (not present in IDC left ventricles or ISCDC ventricles) decrease in stimulation of adenylate cyclase by Mn2+. Tissue neurotransmitter levels and pertussis toxin-catalyzed ADP ribosylation were altered to similar extents in IDC and ISCDC. CONCLUSIONS. These data indicate that potentially important differences exist in the regulatory behavior of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex in IDC versus ISCDC. differences that presumably relate to the distinct pathophysiologies of these two types of heart muscle disease.
Comparative effects of APSAC and rt-PA on infarct size and left ventricular function in acute myocardial infarction. A multicenter randomized study, BACKGROUND. Recombinant tissue-type plasminogen activator (rt-PA or alteplase) and anisoylated plasminogen streptokinase activator complex (APSAC or anistreplase) have been demonstrated to limit infarct size significantly and to preserve left ventricular function when injected soon after acute myocardial infarction. However. as yet. the efficacy and safety of these two thrombolytic agents have not been directly compared in one trial; this was the aim of this study. METHODS AND RESULTS. One hundred eighty-three patients suffering from a first acute myocardial infarction were randomly allocated to either APSAC (30 units over 5 minutes) or single-chain rt-PA (100 mg over a 3-hour period) within 4 hours of the onset of symptoms. Global and regional left ventricular function were assessed from contrast angiography an average of 5.3 +/- 2.3 days after initial therapy. Radionuclide angiography and thallium-201 single-photon emission computerized tomography were performed before hospital discharge. Infarct size was assessed by single-photon emission computerized tomography and expressed in percentage of the total myocardial volume. Ninety patients received APSAC and 93 received rt-PA within a mean period of 172 +/- 52 minutes after the onset of symptoms. The two groups were similar in age. location of the acute myocardial infarction. Killip class. and time of randomization. The patency rate of the infarct-related artery was 72% in the APSAC group and 76% in the rt-PA group (NS). Initial and predischarge left ventricular ejection fraction as well as infarct size were similar in both therapeutic groups (0.50 +/- 0.14 versus 0.52 +/- 0.12 for initial and 0.48 +/- 0.10 versus 0.47 +/- 0.10 for predischarge ejection fraction. 11 +/- 7% versus 9 +/- 7% for infarct size. respectively. for APSAC- and rt-PA-treated patients). Bleeding complications requiring blood transfusion occurred in one APSAC patient and in two rt-PA patients. One patient in the rt-PA group died of a massive intracranial hemorrhage. At the end of the 3-week follow-up period. five APSAC patients (5.5%) and seven rt-PA patients (7.5%) had died. CONCLUSIONS. The early infusion of APSAC or rt-PA in acute myocardial infarction produced a similar patency rate. limitation of infarct size. and preservation of left ventricular systolic function with an equivalent rate of bleeding complications.
Abnormal vasomotor changes early after coronary angioplasty. A quantitative arteriographic study of their time course, BACKGROUND. To study the impact of percutaneous transluminal coronary angioplasty (PTCA) on coronary vasomotion. we prospectively analyzed spontaneous changes in coronary diameter and the response to the cold pressor test and intracoronary nitroglycerin in 11 patients subjected to successful single-vessel PTCA. METHODS AND RESULTS. All antianginal medications were stopped 48 hours before each study. The minimum diameter of the PTCA segment and the diameter of a distal segment in the angioplastied vessel and of a segment in a control vessel not manipulated by the balloon catheter or guide wire were measured by computerized edge detection immediately before PTCA and 5 minutes after. 4 hours after. and 8 days after PTCA. At 4 hours. PTCA and distal segments were constricted by 38 +/- 9% and 16 +/- 5%. respectively. compared with the values at 5 minutes (p less than 0.01). Before angioplasty. the cold pressor test caused vasoconstriction of PTCA and distal segments by 23 +/- 6% (p less than 0.0001) and 15 +/- 4% (p less than 0.008). respectively. but no constrictor response was elicited at 5 minutes or 4 hours after angioplasty. Eight days after PTCA. the basal coronary diameters were similar to those observed 5 minutes after PTCA and the response to the cold pressor test was similar to that observed before PTCA. All segments dilated significantly with nitroglycerin at all times. and no vasoconstriction changes were found in the control segments. CONCLUSIONS. Four hours after PTCA. transient spontaneous vasoconstriction of the PTCA and distal segments occurs. which is so intense that the cold pressor test does not cause any further constriction. These abnormalities resolve within 8 days of PTCA.
Cyclooxygenase pathway mediates lung injury induced by phorbol and platelets, The role of platelets in lung injury has not been well defined. In the present study of isolated perfused rat lungs. phorbol myristate acetate (PMA; 0.15 microgram/ml) or platelets (6.7 X 10(4)/ml) alone did not discernibly change the pulmonary arterial pressure (PAP) or lung weight (LW). However. the combination of platelets and PMA drastically increased the PAP and LW (delta PAP 26.2 +/- 1.0 mmHg. delta LW 2.7 +/- 0.4 g). delta PAP was positively correlated with the increase in thromboxane B2 produced by infusion of platelets and PMA (thromboxane B2 = 35.6 + 0.97 delta PAP. r = 0.67. P less than 0.01). The hypertension and edema formation induced by PMA and platelets were strongly attenuated by indomethacin. an inhibitor of platelet cyclooxygenase (delta PAP 5.6 +/- 2.0 mmHg. P less than 0.001; delta LW 0.0 +/- 0.1 g. P less than 0.001). and by imidazole. an inhibitor of thromboxane A2 synthase (PAP 8.0 +/- 2.5 mmHg. P less than 0.001; LW 0.0 +/- 0.3 g. P less than 0.01). Inactivation of platelet lipoxygenase with nordihydroguaiaretic acid mildly depressed pulmonary pressure but did not affect delta LW (delta PAP 18.9 +/- 1.6 mmHg. P less than 0.05; delta LW 3.1 +/- 0.3 g. P greater than 0.05). In vitro experiments showed that the capacity of platelets to release oxygen radicals was only 2.6% of that found for granulocytes. These results suggest that platelets may be activated by PMA to increase PAP and vascular permeability.
Effects of CO2 rebreathing on pulmonary mechanics in premature infants, The effects of hypercapnia produced by CO2 rebreathing on total pulmonary. supraglottic. and lower airway (larynx and lungs) resistance were determined in eight premature infants [gestational age at birth 32 +/- 3 (SE) wk. weight at study 1.950 +/- 150 g]. Nasal airflow was measured with a mask pneumotachograph. and pressures in the esophagus and oropharynx were measured with a fluid-filled or 5-Fr Millar pressure catheter. Trials of hyperoxic (40% inspired O2 fraction) CO2 rebreathing were performed during quiet sleep. Total pulmonary resistance decreased progressively as end-tidal PCO2 (PETCO2) increased from 63 +/- 23 to 23 +/- 15 cmH2O.l-1.s in inspiration and from 115 +/- 82 to 42 +/- 27 cmH2O.l-1.s in expiration between room air (PETCO2 37 Torr) and PETCO2 of 55 Torr (P less than 0.05). Lower airway resistance (larynx and lungs) also decreased from 52 +/- 22 to 18 +/- 14 cmH2O.l-1.s in inspiration and from 88 +/- 45 to 30 +/- 22 cmH2O.l-1.s in expiration between PETCO2 of 37 and 55 Torr. respectively (P less than 0.05). Resistance of the supraglottic airway also decreased during inspiration from 7.2 +/- 2.5 to 3.6 +/- 2.5 cmH2O.l-1.s and in expiration from 7.6 +/- 3.3 to 5.3 +/- 4.7 cmH2O.l-1.s at PETCO2 of 37 and 55 Torr (P less than 0.05). The decrease in resistance that occurs within the airway in response to inhaled CO2 may permit greater airflow at any level of respiratory drive. thereby improving the infant's response to CO2.
Effect of hyperventilation on oxygenation of the brain cortex of newborn piglets, A new phosphorescence imaging method (Rumsey et al. Science Wash. DC 241: 1649-1651. 1988) has been used to continuously monitor the PO2 in the blood of the cerebral cortex of newborn pigs. A window was prepared in the skull and the brain superfused with artificial cerebrospinal fluid. The phosphorescent probe for PO2. Pd-meso-tetra(4-carboxyphenyl)porphine. was injected directly into the systemic blood. The phosphorescence of the probe was imaged. and the lifetimes were measured using flash illumination and a gated video camera. The PO2 in the blood of the veins and capillary beds of the cortex was calculated from the lifetimes. Systemic blood pressure was continuously monitored while the systemic arterial PCO2. PO2. and blood pH were measured periodically. The PO2 in the blood was quantitated for 60- to 200 microns2 regions within the image (from a total field of approximately 3 mm diam). The PO2 in the microvasculature was not uniform across the viewing field but increased or decreased in each region independently of the other regions. Thus at any point in time the PO2 in a region could be substantially above or below the average value. During hyperventilation. which lowered arterial PCO2 and increased pH of the blood. the average PO2 decreased in proportion to the decrease in arterial PCO2. For example. hyperventilation. which decreased arterial PCO2 from its normal value of 40 Torr to 10 Torr. caused a rapid (within 5 min) decrease in PO2 in the blood of capillaries and veins to approximately one-third of normal.
Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice, The role of CD4+ and CD8+ T lymphocytes in terminating respiratory syncytial virus (RSV) replication. causing disease. and protecting from reinfection was investigated using a BALB/c mouse model in which CD4+ or CD8+ lymphocytes or both were depleted by injections of Mab directed against the respective mouse lymphocyte determinants. Kinetics of RSV replication. illness. and pathology were assessed after primary infection and rechallenge. Both CD4+ and CD8+ lymphocyte subsets were involved in terminating RSV replication after primary infection. When both T lymphocyte subsets were depleted RSV replication was markedly prolonged. yet no illness was evident. suggesting that host immune response rather than viral cytocidal effect was the primary determinant of disease in mice. Both CD4+ and CD8+ lymphocytes contributed to illness. although CD8+ lymphocytes appeared to play the dominant role in this particular system. Analysis of histological responses suggested that CD4+ lymphocytes were required for the appearance of peribronchovascular lymphocytic aggregates seen in normal mice after rechallenge. and that the presence of alveolar lymphocytes was correlated with illness. It is postulated that antibody is an illness-sparing mechanism for protecting mice from RSV infection. and that T lymphocytes are an important determinant of illness. Further delineation of RSV-induced immunopathogenesis in primary infection and reinfection will provide important information for the development of vaccine strategies.
Detection of replicative intermediates of hepatitis C viral RNA in liver and serum of patients with chronic hepatitis C, The hepatitis C virus is a positive stranded hepatotropic RNA virus. We describe a method of detecting positive and negative strands of hepatitis C viral RNA using the polymerase chain reaction. We tested serum and liver tissue from nine patients with chronic hepatitis C. The positive RNA strand of HCV was detected in the sera and livers of all nine. the negative strand was detected in the livers of eight (89%). and in the sera of five (55%). Titers of both strands of HCV RNA were determined by serial endpoint dilutions. The amount of the negative strand in the serum and liver was usually 10-100 times less than the positive strand. Predigestion of serum with ribonucleases did not alter the detection of the negative strand. This suggests that the negative strand found in the serum may be protected from digestion by being associated with virions.
Differential effects of insulin deficiency on albumin and fibrinogen synthesis in humans, Insulin deficiency decreases tissue protein synthesis. albumin mRNA concentration. and albumin synthesis in rats. In contrast. insulin deficiency does not change. or. paradoxically. increases estimates of whole body protein synthesis in humans. To determine if such estimates of whole body protein synthesis could obscure potential differential effects of insulin on the synthetic rates of individual proteins. we determined whole body protein synthesis and albumin and fibrinogen fractional synthetic rates using 5-h simultaneous infusions of [14C]leucine and [13C]bicarbonate. in six type 1 diabetics during a continuous i.v. insulin infusion (to maintain euglycemia) and after short-term insulin withdrawal (12 +/- 2 h). Insulin withdrawal increased (P less than 0.03) whole body proteolysis by approximately 35% and leucine oxidation by approximately 100%. but did not change 13CO2 recovery from NaH13CO3 or estimates of whole body protein synthesis (P = 0.21). Insulin deficiency was associated with a 29% decrease (P less than 0.03) in the albumin fractional synthetic rate but a 50% increase (P less than 0.03) in that of fibrinogen. These data provide strong evidence that albumin synthesis in humans is an insulin-sensitive process. a conclusion consistent with observations in rats. The increase in fibrinogen synthesis during insulin deficiency most likely reflects an acute phase protein response due to metabolic stress. These data suggest that the absence of changes in whole body protein synthesis after insulin withdrawal is the result of the summation of differential effects of insulin deficiency on the synthesis of specific body proteins.
Anti-HIV and anti-anti-MHC antibodies in alloimmune and autoimmune mice, Alloimmune mice (mice that have been exposed to cells from another murine strain) were shown to make antibodies against gp120 and p24 of human immunodeficiency virus (HIV). and mice of the autoimmune strains MRL-lpr/lpr and MRL-(+)/+ made antibodies against gp120. This is surprising because the mice were not exposed to HIV. Furthermore. anti-anti-MHC antibodies (molecules that have shapes similar to those of major histocompatibility complex molecules) were detected in both alloimmune sera and MRL mice. These results are discussed in the context of a possible role for allogeneic stimuli in the pathogenesis of acquired immunodeficiency syndrome. as suggested by an idiotypic network model.
Mannitol-induced diuretic renal ultrasonography: a new technique, We herein describe a new technique to improve the ultrasonic imaging of nonobstructed stone-bearing kidneys. Mannitol-induced diuresis opens up the collapsed renal collecting system and yields better ultrasonographic imaging by increasing the amount of fluid surrounding the calculi. The potential usages of this technique include ultrasound localization for percutaneous stone extraction and during ultrasonographic monitoring of stones treated by extracorporeal shock-wave lithotripsy (ESWL).
A comparative immunohistochemical study of Kuru and senile plaques with a special reference to glial reactions at various stages of amyloid plaque formation, The authors examined 10 patients with Gerstmann-Straussler syndrome or Creutzfeldt-Jakob disease and 10 with Alzheimer's disease (AD). Immunohistochemistry using anti-prion protein (PrP) and anti-beta/A4 protein (beta/A4) coupled with formic acid pretreatment could detect Congophilic and non-Congophilic deposits. Prion protein deposits were classified into five types and compared with types of beta/A4 deposits. Kuru plaques with multicentric cores and fine granular deposits were a characteristic feature of PrP deposits. Some types of PrP or beta/A4 deposits depend on the anatomic sites. To clarify the relationship of microglia and astrocytes to PrP or beta/A4 deposits. double-immunostaining method was performed. In both kuru and senile plaques. microglia were closely linked to the Congophilic plaques. Astrocytes. however. extended their processes toward the plaques even in the non-Congophilic plaques. These observations strongly suggest that similar glial association with plaque formation may be involved in both kuru and senile plaques. although the amyloid core proteins differ.
Recurrent hypoglycemia secondary to drug-dispensing error, We present three patients who developed hypoglycemia due to inadvertent dispensing of sulfonylurea drugs. Each patient had a similar clinical course characterized by hypoglycemia that remitted during hospitalization and recurred after discharge. The cause of the hypoglycemia was determined only after close inspection of the patients' medications. not the label on the container. Our experience suggests that hypoglycemia due to drug-dispensing error may be more common than is generally recognized.
Coronary occlusion following diagnostic angiography: salvage by intracoronary stenting, Catheter-induced coronary artery dissection and occlusion is a rare but serious complication of diagnostic cardiac angiography. This report describes the successful management of this complication with an intracoronary stent after prolonged balloon inflations and intracoronary thrombolytic therapy were unsuccessful.
Atrial natriuretic peptide-induced relaxation of pre-constricted isolated rat perfused lungs: a comparison in control and hypoxia-adapted animals, 1. To further understand the vasodilator actions of atrial natriuretic peptide and its role in hypoxic pulmonary hypertension. we studied the effects of atrial natriuretic peptide in the isolated perfused rat lung during normoxic ventilation and after elevation of pulmonary artery pressure by either hypoxic ventilation or infusion of prostaglandin F2 alpha. Control animals were compared with littermates that had become adapted to a 10% O2 environment for 3 weeks. Atrial natriuretic peptide was compared with atriopeptin I and atriopeptin III in order to study its structure-activity relationship. 2. Five experiments. each involving six control and six chronically hypoxic rats. were performed. During normoxic ventilation. atrial natriuretic peptide (30 ng-3 micrograms) produced a dose-dependent reduction in pulmonary artery pressure in chronically hypoxic rats. but had no action in the control animals. 3. Atrial natriuretic peptide dose-dependently abolished hypoxic pulmonary vasoconstriction to a greater extent in chronically hypoxic rats (EC50 98 ng) than in control rats (EC50 298 ng; P less than 0.001). Bolus atrial natriuretic peptide (100 ng) produced a plasma concentration of 22.6 pmol/l at 1 min. which is within the pathophysiological range. Initial plasma atrial natriuretic peptide levels were 9.4 pmol/l in control animals and 27.4 pmol/l in chronically hypoxic rats. 4. Chronically hypoxic rats were more sensitive to atriopeptin I. atriopeptin III and atrial natriuretic peptide than were the control rats (P less than 0.05). Atrial natriuretic peptide and atriopeptin III were equipotent and were 10 times more potent than atriopeptide I in both groups (P less than 0.001).
Effect of glutamine-enriched total parenteral nutrition on septic rats, 1. The effect of total parenteral nutrition with or without glutamine enrichment was studied in septic rats after 4 days of treatment. 2. Septic rats treated with glutamine-enriched total parenteral nutrition survived sepsis significantly better than other TPN-treated septic rats: the cumulative percentage of deaths over 4 days in septic rats treated with glutamine-enriched total parenteral nutrition was 25% compared with 55% in septic rats given total parenteral nutrition without glutamine and 70% in septic rats given glucose. 3. Glutamine-enriched total parenteral nutrition resulted in improved nitrogen balance in septic rats: the cumulative nitrogen balance over the 4 days of treatment was the least negative as compared with other groups of septic rats. 4. The rate of loss of intracellular glutamine in skeletal muscle was markedly decreased (P less than 0.001) in response to glutamine-enriched total parenteral nutrition in septic rats. 5. The rate of protein synthesis was increased (21.2%) and the rate of protein degradation was decreased (35.5%) in response to glutamine-enriched total parenteral nutrition in septic rats. 6. It is concluded that the administration of glutamine-enriched total parenteral nutrition is beneficial to septic rats and possibly to septic patients.
The value of flexible bronchoscopy in childhood pulmonary tuberculosis, The value of 121 flexible bronchoscopy (FB) procedures was evaluated in 54 children. aged three months to 14 years. suspected of having pulmonary tuberculosis. Specimens from FB were culture-positive for Mycobacterium tuberculosis in seven of the 13 bacteriologically confirmed cases. Bronchial abnormalities consistent with the diagnosis were found in 31 of 54 cases. Separate or coexistent findings at initial FB included airway compression (20 cases). granulation tissue (ten cases). and obstructive caseum (four cases). Chest roentgenograms underestimated bronchial involvement in 14 children. Further FB monitoring documented disease evolution. The FB was important in the management of patients. as it (1) guided the use of prednisone therapy. especially in the children with a chest roentgenogram not suggestive of bronchial involvement; (2) indicated a need for resection of granulation tissue by rigid bronchoscopy (three cases); and (3) guided the surgical decision (two children with persistent bronchial obstruction). Thus. FB is a safe and valuable procedure in the management of childhood pulmonary tuberculosis.
Comparison of enteral nutrition and drug treatment in active Crohn's disease. Results of the European Cooperative Crohn's Disease Study. IV, This study compared the effect of enteral nutrition as the sole therapy of active Crohn's disease with drug treatment. Patients with active Crohn's disease (Crohn's Disease Activity Index greater than 200) were randomized to receive either enteral nutrition with a liquid oligopeptide diet (n = 55) or a combination of 6-methylprednisolone. 48 mg daily. subsequently tapered. and sulfasalazine. 3 g daily (n = 52). The two groups were not different with respect to age. sex. body weight. location of disease. or treatment before the study. The severity of disease was similar at the beginning of the study in both groups [Crohn's Disease Activity Index (mean +/- SEM). 323 +/- 12 vs. 316 +/- 11]. Remission was defined as a decrease of the initial Crohn's Disease Activity Index by 40% or at least 100 points. Twenty-nine patients in the diet group and 41 patients in the drug group reached remission within 6 weeks of therapy (chi 2 test. P less than 0.01). The median elapsed time to remission was 30.7 days in the diet group compared with 8.2 days in the drug group (Mantel Cox. P less than 0.01). To determine whether one of these treatments was more beneficial for a subgroup of patients. the effectiveness of both treatments was analyzed separately in patients with very severe disease (initial Crohn's Disease Activity Index greater than 300) and less severe disease (initial Crohn's Disease Activity Index less than 300). and in patients with different disease location. However. no influence of initial disease activity or disease location on the effect of either treatment could be shown. These data show that enteral nutrition is less effective than a combination of 6-methylprednisolone and sulfasalazine in treating active Crohn's disease.
Effects of atrial natriuretic factor in chronic hypoxic spontaneously hypertensive rats, The present study was designed first to investigate the pulmonary hypertensive effects of chronic hypoxia in spontaneously hypertensive rats and second to compare the cardiovascular effects of atrial natriuretic factor on rats exposed to hypoxia and on control rats kept at sea level. Catheters were placed in the femoral and pulmonary arteries for measurement of mean systemic arterial pressure and mean pulmonary arterial pressure. The cardiac output was measured by thermodilution method. It was found that 4 weeks of simulated 18.000-foot hypoxia led to polycythemia. right ventricular hypertrophy. and pulmonary hypertension. which resulted from an increased pulmonary vascular resistance. However. systemic arterial pressure was not significantly different between the two groups of rats. Atrial natriuretic factor administration decreased systemic arterial pressure and pulmonary arterial pressure to a lesser extent in the hypoxic group compared with the sea level control group. It is concluded that these animals showed an impaired response to atrial natriuretic factor after long-term exposure to hypoxia.
Opportunities to improve the cost-effectiveness of treatment for hypertension, The cost-effectiveness of treatment for hypertension depends on the pretreatment level of blood pressure. age and sex of the patient. presence of other cardiovascular risk factors. long-term control of blood pressure. and the annual costs of treatment. Treatment of very mild hypertension (diastolic blood pressure. 90-94 mm Hg). even if the benefits do exceed the risks. does not appear to be particularly cost-effective. Opportunities to improve the cost-effectiveness of hypertension management lie in 1) avoidance of patient mislabeling by careful documentation of blood pressures on multiple occasions in the office and during usual activities outside the office before the diagnosis is made and treatment is begun; 2) efforts to increase adherence to scheduled visits and medication regimens; 3) attempts to step-down dosages or discontinue medications after periods of good blood pressure control; 4) explicit consideration of costs. as well as benefits. in decisions on the needed frequency of office visits. choice of medications. and use of laboratory tests; and 5) efforts to improve practice efficiency. Future practice guidelines for hypertension management should take these factors into account and should make trade-offs between benefits. risks. and costs explicit for specific types of patients.
Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion, To assess further the relationship between gonadal sex steroids and PRL. GH. and insulin-like growth factor-I (IGF-I) secretion and to help clarify the mechanism underlying the pubertal growth spurt. we studied 11 children (10 girls) with central precocious puberty before and during gonadal suppression with the GnRH agonist (GnRH-a) leuprolide acetate. Nocturnal sampling for plasma levels of GH and PRL. GH response to GH-releasing factor-(1-44). and plasma IGF-I levels were determined before and 3-6 months after pituitary-gonadal suppression. Treatment caused a significant decrease in the LH and FSH responses to GnRH (P less than 0.01) and the plasma concentration of estradiol (P less than 0.05). The patients' mean height velocity SD score for chronological age. initially 3.8 +/- 1.9. decreased significantly to 0.9 +/- 0.9 with treatment (P less than 0.005). Nocturnal GH secretion (mean GH concentration. sum of GH pulse areas. sum of GH pulse amplitudes. and GH pulse frequency) and mean IGF-I levels (1.38 +/- 0.6 vs. 1.72 +/- 0.34 U/mL) were not significantly altered by treatment. However. the mean peak GH response to GH-releasing factor-(1-44) was 29.2 +/- 6.8 micrograms/L before treatment and declined significantly to 17.7 +/- 3.4 micrograms/L after gonadal suppression (P less than 0.05). PRL secretion was similar before and after GnRH-a-induced suppression. These results indicate that the decrease in height velocity noted during GnRH-a treatment occurred independently of changes in nocturnal GH secretion and IGF-I levels. These data are consistent with the premise that sex steroids can modulate growth by a direct action on skeletal growth.
Serum melatonin in central precocious puberty is lower than in age-matched prepubertal children, In children a progressive decrease in nocturnal serum melatonin (MT) has been shown with advancing age. suggesting a reduction in the amplitude of the circadian MT curve with maturation. Whether this alteration of MT levels is related to human sexual maturation or occurs independently remains to be elucidated. Also. the impact of gonadal steroids on the MT rhythm remains an open question. We examined 56 patients (51 females and 5 males) with central precocious puberty (52 idiopathic and 4 neurogenic). Patients were studied before and 3. 6. and 12 months after initiation of GnRH analog treatment. Three hundred and thirty-seven endocrinologically normal subjects (190 males and 147 females) served as controls. In all subjects nocturnal serum MT (blood collection between 2300 and 0100 h) was measured with a highly specific RIA. In young patients. aged 1-5 yr. we found significantly lower MT levels than in age-matched controls. Pubertal patients. aged 5-9 yr. displayed nocturnal MT levels in the same range as control subjects approaching normal pubertal age. In contrast to endocrinologically normal children. there was no age-dependent decrease in nocturnal MT in untreated precocious puberty; rather. it appeared that serum MT had already declined in association with the onset of sexual maturation. Although there was a significant difference in weight between patients and age-matched controls. the low MT values in patients 1-5 yr old were only partly explained by the weight difference (P less than 0.0009); their pubertal status also contributed significantly (P less than 0.006). Pituitary-gonadal suppression induced by long term GnRH analog treatment did not result in a return to prepubertal MT levels; rather. nocturnal MT decreased during therapy. The collected data indicate that nocturnal serum MT levels are related to sexual maturation. since serum MT is similar in precocious puberty and normal pubertal children. Since suppression of the pituitary-gonadal axis did not result in increases in nocturnal MT levels in young patients with precocity (i.e. return to age-appropriate levels). the reduction of nocturnal MT with normal puberty is not likely to be dependent on pubertal gonadotropin or sex steroid milieu.
Serum bioactive and immunoreactive luteinizing hormone and follicle-stimulating hormone levels in women with cycle abnormalities, with or without polycystic ovarian disease, Serum steroid. gonadotropin. and alpha-subunit levels were assessed in 35 women with cycle abnormalities [11 with and 24 without polycystic ovarian disease (PCOD) according to strict clinical and biochemical criteria] and 8 regularly cycling women in the early (cycle day 3 or 4) and mid (cycle day 7 or 8) follicular phase. LH and FSH levels were estimated using two immunological techniques [RIA and immunoradiometric assay (IRMA)] and in vitro bioassays (BIO). using mouse Leydig cells and rat granulosa cells. respectively. In PCOD patients mean alpha-subunit. free androgen index [FAI; testosterone x 100/sex hormone-binding globulin (SHBG)]. androstenedione. estrone. and estradiol (E2) were significantly elevated compared to levels in the early follicular phase of control cycles and non-PCOD patients. In addition. in PCOD patients mean IRMA-LH and RIA-LH levels were distinctly increased (2.8- to 3.6 fold. respectively; both comparisons. P less than 0.001) compared to control values. but in the same order of magnitude (1.3- to 1.4-fold increments) as that in non-PCOD patients. However. the median BIO-LH level in PCOD patients was 5.9-fold higher than that in non-PCOD patients and 4.0-fold higher than the BIO-LH in the early follicular phase of control women. Consequently. the median BIO/IRMA-LH ratio was 4.8-fold higher in PCOD patients compared to non-PCOD patients. In women with cycle abnormalities. individual BIO/IRMA-LH ratios correlated with BIO-LH (rs = 0.48). FAI (rs = 0.39). free estrogens (E2/SHBG ratios; rs = 0 0.47). and dehydroepiandrosterone sulfate (rs = 0.60) concentrations. Mean IRMA-. RIA-. and BIO-FSH levels and BIO/IRMA-FSH ratios were not significantly different when various groups were compared. Although RIA- and IRMA-LH levels showed good correlation (rs = 0.88). RIA-LH levels were consistently higher. resulting in distinctly higher RIA-LH/FSH ratios (mean. 4.5) compared to IRMA-LH/FSH ratios (median. 1.8) in PCOD patients.(ABSTRACT TRUNCATED AT 400 WORDS).
The effect of long-acting analog of luteinizing hormone-releasing hormone on growth hormone secretory dynamics in children with precocious puberty, Long-acting preparations of LHRH (LHRHa). such as leuprolide acetate. have been shown to selectively and reversibly suppress the clinical and biochemical features of central precocious puberty (CPP). The withdrawal of gonadal sex steroids results in a decline of growth velocity and a decrease in the rate of bone age maturation. with resultant improvement in predicted adult stature. The purpose of this study was to define GH secretory dynamics in children treated with leuprolide acetate. Twelve-hour nocturnal GH studies were performed in five children (four girls and one boy) with CPP before and after 6 months of treatment with leuprolide acetate. Mean GH levels. GH secretory rate. and number of GH secretory episodes were determined. Secretory profiles were analyzed using the Cluster program. Growth velocity. somatomedin-C. and dehydroepiandrosterone sulfate were measured before and after 6 months of therapy. By 6 months of therapy. there was a significant decrease in mean growth velocity from 10.5 +/- 3.3 to 6.7 +/- 1.6 cm/yr. Somatomedin-C levels remained the same at 46.90 +/- 9.51 and 52.5 +/- 12.40 nmol/L. Levels of dehydroepiandrosterone sulfate remained unchanged at 118.6 +/- 71.4 and 139.0 +/- 61.3 mumol/L at 0 and 6 months of the study. By 6 months. there was a significant decrease in mean GH levels from 13.6 +/- 5.3 to 6.4 +/- 3.4 micrograms/L (P less than 0.05). Total GH levels decreased from 1367.9 +/- 687.3 to 447.0 +/- 186.5 ng/12 h. The number of GH secretory episodes remained the same at 5.4 +/- 1.5 and 4.8 +/- 1.0/12 h at 0 and 6 months of study. Therefore. the decrease in GH that occurs during the withdrawal of gonadal sex steroids with LHRHa in children with CPP is an amplitude-modulated phenomenon. as the number of secretory peaks remains unchanged.
In vitro characterization of a murine recipient anti-donor effector cell responsible for the development of chronic graft-versus-host disease, Injection of parental spleen cells into unirradiated F1 hybrid recipients is frequently used for the induction of murine graft-vs-host disease (GVHD). Injection of C57BL/6 spleen cells into B6D2F1 recipients results in the acute form of GVHD whereas injection of DBA/2J cells into the same recipients results in a chronic form of GVHD. In vivo studies have suggested that injection of DBA/2J cells into B6D2F1 recipients results in the chronic form of GVHD instead of acute GVHD because of recipient B6D2F1 effector cells that inhibit DBA/2J CD8+ T cell function. The present report describes the development of an in vitro assay that measures the activity of these B6D2F1 effector cells. The results obtained using this assay indicate that these B6D2F1 effector cells are found primarily in the LN. need to be activated in order to function. are inhibited by anti-CD8 antibodies. and mediate their function as a result of DBA/2J cells binding to Ag expressed on their cell surface.
A summary index for the assessment of quality of life in angina pectoris, When exploring the effects of anti-anginal therapy on quality of life (QL). it is essential to use concise. reliable. outcome measures which focus on those aspects of the disease which are affected by the anginal pain. and which are expected to be responsive to medical intervention. Analysis based on a single comprehensive index is preferable to the use of several indexes as it avoids the potential for conflicting inferences from multiple comparisons. In this paper. we describe the development of a QL index which summarizes the three questionnaires used in the North Karelian Quality of Life (KarQuol) study. The summary index (SI) will be used to compare transdermal and oral nitrate therapy in patients with angina pectoris. and represents the first stage in the construction of a disease-specific evaluative index for future trials.
Anti-anginal therapy and quality of life. A comparison of the effects of transdermal nitroglycerin and long-acting oral nitrates, A total of 112 male patients with severe effort-induced angina pectoris (New York Heart Association functional classes II and III) participated in a randomized open trial consisting of a 6 month phase with 3 month treatment cross-overs. The aim of the study was to compare the effect of transdermal nitroglycerin (TN) patches and long-acting oral nitrates (LAON) on quality of life (QL). During the cross-over period 30 patients (20 on TN and 10 on LAON) withdrew from the study. over half of them within the first month. Although the results should be interpreted with some caution. they showed that improvement in QL was present for both treatments but greater during the transdermal therapy (unadjusted p = 0.07. adjusted p = 0.03). Anginal attacks were associated with improved QL scores. and fewer attacks occurred on TN (p = 0.06). Improvement in QL was most pronounced in patients whose recorded duration of angina was less than 8 years.
Pertussis toxin inhibits hormonal stimulation of bone resorption in fetal rat limb bones, The cellular basis for hormonal control of bone resorption is poorly understood. As the identifiable receptors for bone resorbing agents such as parathyroid hormone (PTH) and 1.25-dihydroxyvitamin D3 [1.25(OH)2D3] are located on osteoblasts rather than osteoclasts. the nature of cellular signaling is obscure. Here it is reported that exposure of fetal rat limb bones to pertussis toxin. a bacterial protein that inhibits certain GTP binding proteins (G-proteins) involved in signal transduction. markedly inhibits bone resorption elicited by PTH. 1.25(OH)2D3 and prostaglandin E2. Pertussis toxin does not block the inhibition of alkaline phosphatase activity by PTH or 1.25(OH)2D3. and it potentiates the cyclic AMP response to PTH. These data support the existence of a pertussis toxin-sensitive G-protein that participates in regulation of bone resorption. The putative G-protein is apparently not involved in the initial transduction of hormonal signals. but it may be part of a final common pathway through which the osteoclast is activated by agents with widely divergent initial actions.
Lupus anticoagulants, anticardiolipin antibodies, and fetal loss. A case-control study, BACKGROUND. Lupus anticoagulants and anticardiolipin antibodies are antiphospholipid antibodies that have been associated with fetal loss. but they have not been shown unequivocally to be a risk factor for this event. METHODS. To estimate the risk of fetal loss in association with these antibodies. we conducted a hospital-based case-control study of 331 women with spontaneous abortion or fetal death (case patients) and 993 controls. The subjects were included in the study only if they reported that they had had no previous spontaneous fetal loss. Each control was a pregnant woman who. in the same period of pregnancy as a case patient. had not had a fetal loss. Lupus anticoagulants were identified in blood samples through a series of coagulation tests. and IgG anticardiolipins by an enzyme-linked immunosorbent assay. Each subject was interviewed in person to obtain information on potential confounding variables. such as sociodemographic characteristics and medical conditions. RESULTS. Lupus anticoagulants were found in blood from 17 case patients (5.1 percent) and 38 controls (3.8 percent). The crude odds ratio for the association between lupus anticoagulants and fetal loss was 1.36 (95 percent confidence interval. 0.75 to 2.43); the odds ratio adjusted for confounders was 1.42 (95 percent confidence interval. 0.72 to 2.80). An IgG anticardiolipin level of 5 units or more was found in 4 case patients (1.2 percent) and 15 controls (1.5 percent). The crude and adjusted odds ratios for fetal loss were 0.80 (95 percent confidence interval. 0.26 to 2.41) and 1.28 (95 percent confidence interval. 0.38 to 4.21). respectively. CONCLUSIONS. There is not apparent justification for considering lupus anticoagulants or IgG anticardiolipins to be risk factors for fetal loss among women who present with spontaneous abortion or fetal death and have had no previous spontaneous fetal loss.
Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases, Mitogen activated protein (MAP) kinases (MAPKs) are a family of protein-serine/threonine kinases activated as an early intracellular response to a variety of hormones and growth factors. They are unique in requiring both serine/threonine and tyrosine phosphorylation to become active and are the only examples of protein-serine/threonine kinases activated by tyrosine phosphorylation. Nerve growth factor (NGF) promotes differentiation of phaeochromocytoma (PC12) cells. which respond by conversion within hours from a chromaffin-like to a sympathetic neuron-like phenotype. NGF stimulation of PC12 cells increases the activity of two protein kinases by greater than 20-fold within minutes. both strikingly similar to MAPKs. They are inactivated by either protein-tyrosine phosphatases or the protein-serine/threonine phosphatase termed protein phosphatase 2A (ref. 8). they activate protein S6 kinase-II (refs 9. 10). and they phosphorylate identical threonine residues on myelin basic protein (our unpublished results) to those phosphorylated by other MAPKs. Immunological data indicate that these protein kinases. termed peak-I and peak-II (Fig. 1a) are probably ERK2 and ERK1. respectively. two widely expressed MAPK isoforms. Here we identify the 'MAP kinase kinases' (MAPKKs) in PC12 cells which are activated by NGF and report that MAPKKs are dependent on serine/threonine phosphorylation for activity and promote phosphorylation of serine/threonine and tyrosine residues on MAPKs.
Complement activation by artificial blood substitute Fluosol: in vitro and in vivo studies, A perfluorocarbon blood substitute. Fluosol. is undergoing clinical trials as an adjunct to chemotherapy. The adverse effects associated with its administration have been postulated to result from complement activation. When gel electrophoresis and Western blotting of Fluosol are used after its incubation with serum. activated C3 and factors Bb and H are bound to the Fluosol particles in a time-dependent fashion. which suggests that complement activation with Fluosol. as does that with zymosan. occurs on the surface of the particles. Paradoxically. it is found. both by the measurement of Fluosol-bound C3d and by fluid-phase C5a. that lower concentrations of Fluosol cause greater amounts of complement activation. which suggests a complex interaction of activators and inhibitors that changes as the available surface area is decreased. Studies performed with bystander red cell-bound C3d demonstrated in vivo complement activation occurring in six patients receiving Fluosol as an adjunct to chemotherapy for colon cancer. In two patients. there was a marked increase in red cell-bound C3d after Fluosol infusion; these two patients also developed adverse reactions during Fluosol infusion. These studies suggest that the Fluosol surface plays a major role in the initiation and regulation of complement activation that is seen during Fluosol infusion.
Indications for radiography in patients with acute ankle injuries: role of the physical examination, A prospective study was performed to test the hypothesis that a thorough physical examination can eliminate the need for a large number of radiographs obtained in patients with acute ankle trauma. Two hundred one patients were seen in the emergency department for acute ankle trauma and referred to the department of radiology for ankle radiographs. Radiology residents performed a brief but thorough physical examination of the ankle in all 201 patients. Solely on the basis of a strict set of physical examination criteria (examination for gross deformity. instability. crepitation. focal bony tenderness. severe soft-tissue tenderness. moderate or severe soft-tissue swelling. and ecchymosis). the radiologists determined whether or not the radiographs were indicated. All patients. irrespective of the physical examination. underwent ankle radiography. and the results were correlated with those of the physical examination. On the basis of the results of the physical examinations. 101 (50%) of the radiologic studies were not indicated. In only one of these patients was a fracture seen on radiographs. The radiograph in this case showed a small avulsion fracture of the dorsal aspect of the talus that was clinically insignificant (no cast or surgery was required). Our results suggest that a brief but thorough physical examination can eliminate the need for a large percentage of radiographs ordered in patients with acute ankle trauma.
Thrombosis and thrombolysis in unstable angina, Pathophysiology of unstable angina involves spasm. plaque rupture. activation of platelets. and coagulation. The incidence and frequency of intracoronary thrombus formation are presently under active assessment in order to establish the potential benefit of thrombolytic therapy. A preliminary study was conducted in patients admitted in our coronary care unit for unstable angina with typical clinical and electrocardiographic criteria and with early coronary angiogram. After exclusion of 4 patients with left main coronary stenosis or contraindications for thrombolysis. 16 patients received thrombolytic infusion and 14 underwent a second coronary angiogram. Seven patients had an intracoronary thrombus (6 nonocclusive. 1 occlusive) and at the second angiogram only 3 nonocclusive thrombi were modified (1 disappeared. 2 were reduced). Moreover. the quantitative Coronary Angiography Analysis System (CAAS) in the 11 cases suitable for analysis did not show any significant changes. especially in the Ambrose type IIB lesions. In-hospital clinical outcome was not influenced by thrombolytic therapy (5 ischemic recurrences. 1 fatal myocardial infarction. 4 emergency and 4 elective revascularization procedures). This short series is in agreement with the literature data. Only one third of patients with active unstable angina remains refractory to conventional therapy. The transient benefit of thrombolysis is limited to patients with demonstrated intracoronary thrombi. Clinical or angiographic improvement are not always in correlation and until now do not seem able to prevent short-term recurrences or the need for revascularization procedures.
Impaired response of atrial natriuretic factor to blood volume expansion in acute right ventricular infarction, To assess the role of atrial natriuretic factor (ANF) in right ventricular (RV) infarction. 30 patients with inferior wall acute myocardial infarction (15 with RV involvement) and normal left heart filling pressures were studied 39 +/- 12 hours after the onset of symptoms. Serial measurements of cardiac output. right atrial. pulmonary artery and pulmonary wedge pressures. as well as plasma ANF. plasma renin activity. plasma aldosterone and vasopressin were obtained before and 30 minutes after acute volume expansion to raise wedge pressure greater than or equal to 20 mm Hg. Baseline mean right atrial pressure and plasma ANF levels were greater in patients with than without RV infarction (8 +/- 3 vs 5 +/- 2 mm Hg; p less than 0.0001. and 4.6 +/- 2.9 vs 2.7 +/- 1.5 fmol/ml; p less than 0.05. respectively). There were no differences in other baseline hemodynamic or humoral parameters between both groups. After volume expansion. pulmonary wedge pressure was similar in both groups. but right atrial pressure increased to higher levels in patients with RV infarction (19 +/- 2 vs 14 +/- 2 mm Hg; p less than 0.0001). Despite this greater stimulus for ANF secretion. the increase in plasma ANF was less pronounced in patients with RV infarction (63 +/- 81 vs 455 +/- 417%; p less than 0.002). especially among those with paroxysmal supraventricular tachyarrhythmias. Thus. despite higher baseline plasma levels of ANF. response to volume loading is markedly attenuated in patients with RV infarction complicating an inferior wall acute myocardial infarction.
Positive direct antiglobulin tests in myeloma patients. Occurrence, characterization, and significance, Review of direct antiglobulin testing (DAT) in 88 patients with multiple myeloma (MM) and five with Waldenstrom's macroglobulinemia revealed 26 cases with a positive DAT. Twenty-two of these had immunoglobulin G-M protein. three had light chain MM. and one had immunoglobulin A-MM protein. None of the immunoglobulin GD-MM (n = 2). nonsecretory MM (n = 5). or Waldenstrom's macroglobulinemia patients (n = 5) were positive. None of the patients had hemolysis attributable to the adsorption of the M protein. The serum concentration of M protein was higher in DAT-positive patients (57.6 +/- 3.8 g/L. mean +/- SEM) than in the negative ones (35.7 +/- 6.4 g/L; probability value of the difference was less than 0.01). The erythrocyte eluates from DAT-positive patients contained a single immunoglobulin. of the same class as the M protein. and did not react with a panel of ABO-compatible erythrocytes. Addition of melphalan during incubation did not affect the results. The M protein of DAT-positive patients was of immunoglobulin G-3 subclass in 7 of 10 patients. A positive direct antiglobulin test frequently is seen in patients with multiple myeloma. the reaction is due to passive adsorption of the M protein onto the erythrocytes. is most frequently observed with immunoglobulin G3-MM. and usually does not produce hemolysis.
Acute and sustained changes in sodium balance during nifedipine treatment in essential hypertension, PURPOSE: To assess the changes in sodium excretion and sodium balance after initiation of nifedipine treatment and after withdrawal of nifedipine. PATIENTS: Eight patients with uncomplicated mild to moderate essential hypertension were entered in a single-blind. placebo-controlled study of 39 days' duration. METHODS: Two 7-day periods while on a fixed sodium intake of 150 mmol/day approximately 3 weeks apart. After 4 days of a placebo and fixed sodium intake. patients were given nifedipine GITS (gastrointestinal therapeutic system) once a day and carefully studied for the following 4 days. Thereafter. patients continued to receive nifedipine GITS. and approximately 3 weeks later they were studied again for a week while on a fixed sodium intake. Nifedipine administration was stopped and changes occurring after withdrawal were studied. RESULTS: Nifedipine caused a significant increase in sodium excretion with a cumulative loss of sodium of 38 mmol per subject within the first 4 days of treatment. The withdrawal of nifedipine treatment caused a significant decrease in sodium excretion and a cumulative retention of sodium of 42 mmol per subject within the first 4 days of withdrawal. CONCLUSION: Nifedipine causes an acute and a sustained reduction in sodium balance in patients with essential hypertension. This prolonged effect may contribute to the mechanism whereby nifedipine lowers blood pressure.
Screening recommendations for gestational diabetes mellitus, As a result of extensive experiences in multiple centers and a review of the current literature. we conclude that a plasma glucose level obtained 1 hour after a 50 gm oral glucose challenge is the "best" gestational diabetes mellitus screening test. This universal screening is performed at least once during pregnancy. The screening threshold should be no higher than 140 mg/dl. or an unacceptable loss in sensitivity occurs. Universal screening for gestational diabetes mellitus is justified by morbidity reduction. cost. and protocol simplicity and ease.
Adrenal and ovarian steroid hormone responses to gonadotropin-releasing hormone agonist treatment in polycystic ovary syndrome, It has been postulated that in polycystic ovary syndrome ovarian steroids can influence adrenal steroidogenesis. To test this hypothesis. basal and dexamethasone-suppressed-corticotropin-stimulated steroid hormone responses were compared among three groups of women before. during. and after gonadotropin-releasing hormone agonist treatment for 3 months. The groups were characterized as follows: (1) women with polycystic ovary syndrome with high dehydroepiandrosterone sulfate levels (greater than 400 micrograms/dl). (2) women with polycystic ovary syndrome with normal dehydroepiandrosterone sulfate levels (less than 300 micrograms/dl). and (3) normal ovulatory women. In response to gonadotropin-releasing hormone agonist. basal serum luteinizing hormone. follicle-stimulating hormone. estradiol. estrone. 17-hydroxyprogesterone. androstenedione. and testosterone in all three groups were suppressed to similar levels. Basal serum dehydroepiandrosterone sulfate levels in the group with high levels declined. but they did not reach the normal. unaltered concentrations in the other two groups. Two subjects with polycystic ovary syndrome in this group with high levels. who showed the greatest declines in basal serum dehydroepiandrosterone sulfate levels (34%. 40%). also had evidence of 3 beta-hydroxysteroid dehydrogenase deficiency before treatment. which was resolved by the end of treatment. In both groups with polycystic ovary syndrome. the increase in maximum incremental rise of dehydroepiandrosterone and dehydroepiandrosterone sulfate levels in response to a pharmacologic dose of corticotropin from a dexamethasone-suppressed baseline (adrenal androgen capacity) remained unaltered during gonadotropin-releasing hormone agonist administration. We conclude that ovarian steroids may promote excessive adrenal androgen secretion in women with polycystic ovary syndrome. may induce 3 beta-hydroxysteroid dehydrogenase deficiency as a mechanism for adrenal involvement in some women with polycystic ovary syndrome. and do not influence adrenal androgen capacity.
Hexamethylmelamine chemotherapy for persistent or recurrent epithelial ovarian cancer, The purpose of this study was to determine the activity and toxicity of hexamethylmelamine chemotherapy in patients with persistent or recurrent epithelial ovarian cancer. Forty-nine women received hexamethylmelamine 100 to 150 mg/day for 14 days. repeated at 4-week intervals. All patients had previously received at least one chemotherapy regimen. and 46 (94%) had received cisplatin. Among 25 patients with clinically measurable disease there were three complete and two partial responses. for an objective response rate of 20%. The mean progression-free interval for responders was 38.6 months versus 9.6 months for nonresponders or patients with nonmeasurable disease (p less than 0.001). Thirteen patients are alive. eight with no clinical evidence for disease. Only four patients discontinued therapy because of toxic reactions. Hexamethylmelamine appears to be a well-tolerated drug with activity against ovarian cancer previously treated with cisplatin.
Genetic identification of pregnancies responsible for choriocarcinomas after multiple pregnancies by restriction fragment length polymorphism analysis, The pregnancies responsible for two cases of choriocarcinomas were determined by the restriction fragment length polymorphism of human leukocyte antigen-DQ genes in the tumors and leukocytes from the patients. their husbands. and their children. The first case was preceded by three normal pregnancies. and the second case was preceded by two normal pregnancies and a complete hydatidiform mole. Comparison of the restriction fragment length polymorphism patterns revealed that the first case of choriocarcinoma carried the parental genome and originated from the third normal pregnancy. whereas the second case was of androgenetic origin from the complete mole. By choosing an appropriate probe (or probes). restriction fragment length polymorphism analysis is shown to be a useful method for identification of the pregnancy responsible for choriocarcinoma.
Relationship between fetal biophysical activities and umbilical cord blood gas values, In a prospective study of 62 patients undergoing cesarean section before the onset of labor a fetal biophysical profile assessment was performed within 3 hours before the cesarean section. The presence or absence of the individual fetal biophysical activities (fetal heart rate reactivity. fetal breathing movements. fetal body movements. and fetal tone) were correlated with umbilical cord blood gas and acid-base measurements (artery and vein). Fetuses with nonreactive nonstress test results or the absence of breathing had significantly lower cord artery pH. PO2 bicarbonate. and base excess measurements but not a significantly different PCO2 level as compared with fetuses that had these activities present. Fetuses with the absence of movements or tone had lower pH. PO2 bicarbonate. and base excess levels and higher PCO2 levels as compared with fetuses with the presence of movements or tone. respectively. These blood gas and acid-base differences were observed in both umbilical cord artery and vein. Subsequent analysis of the blood gas and acid-base measurements of the fetuses with compromised biophysical activities revealed that there are different levels of acidemia. hypoxemia. and hypercapnia at which the individual biophysical activities are compromised. These data suggest that the first manifestations of fetal hypoxemia and acidemia are nonreactive nonstress test results and loss of fetal breathing; in advanced acidemia. hypoxemia. and hypercapnia fetal movements and fetal tone are compromised.
Effects of nitroglycerin and diltiazem on well-developed coronary collateral circulation in conscious dogs, The purpose of the present study was to compare the effects of nitroglycerin and diltiazem on coronary collateral circulation. Studies were conducted in 8 conscious dogs instrumented for the measurement of left circumflex coronary artery (LCCA) flow. subendocardial segment lengths in areas perfused by the LCCA. and left anterior descending coronary artery (LAD). Brief. repeated LCCA occlusions sufficiently developed collateral vessels for the resting metabolic requirement in the LCCA region. One week following the cessation of repeated LCCA occlusions. two-minute coronary occlusions with and without drug pretreatment were performed on separate days. The ischemic responses to coronary occlusions were not altered by diltiazem (50 micrograms/kg. IV). but nitroglycerin (5 micrograms/kg. IV) attenuated myocardial ischemia definitely. The authors conclude that nitroglycerin produces greater effects than diltiazem in attenuating myocardial ischemia in the collateral dependent zone when effects of each drug on systemic and coronary circulation were minimized by pretreatment with small doses.
Incidence of non-A, non-B hepatitis after screening blood donors for antibodies to hepatitis C virus and surrogate markers, OBJECTIVE: To compare the effect of screening blood donors for antibodies to hepatitis C virus (anti-HCV) on the incidence of non-A. non-B hepatitis in recipients with that of screening blood donors for antibodies to hepatitis B core antigen (anti-HBc) and elevated alanine aminotransferase levels. DESIGN: Cohort analysis of serum samples from donors and recipients. Recipients were followed for 12 months to determine the occurrence of non-A. non-B hepatitis. SETTING: The blood-transmitted viruses unit and the liver unit of a university teaching hospital. SUBJECTS: A total of 250 patients who had open heart surgery and their 3142 blood donors. MEASUREMENTS: Donor sera were tested for anti-HCV by enzyme-linked immunosorbent assay (ELISA) and. in the event of a positive result. by recombinant immunoblot assay (RIBA). Antibodies to anti-HBc and serum alanine aminotransferase (ALT) levels were also measured. Measurements of anti-HCV and ALT activity in recipients were done before transfusion and at regular intervals during follow-up. MAIN RESULTS: Of the 250 transfusion recipients. 40 developed non-A. non-B hepatitis. Of the 3142 donors. 70 were positive for anti-HCV by ELISA. 440 were positive for anti-HBc. and 177 had alanine aminotransferase levels between 0.67 and 1.33 mukat/L. The sensitivity (87%). specificity (89%). positive predictive value (59%). and negative predictive value (97%) of blood-donor screening were higher for anti-HCV than for anti-HBc (82%. 36%. 21%. and 91%. respectively) and 70%. 29%. and 91%. respectively). The expected number of donors excluded because of the presence of anti-HCV was considerably smaller than that of donors with positive results for surrogate markers of hepatitis. CONCLUSION: Screening blood donors for the presence of anti-HCV is more accurate than screening for surrogate markers (anti-HBc and ALT) and protects more effectively against post-transfusion non-A. non-B hepatitis.
Descartes before the horse: I clone, therefore I am: the hepatitis C virus in current perspective, In an unprecedented approach to viral discovery. the hepatitis C virus (HCV) was cloned before it was established by conventional methods of viral detection or by genomic characterization. Hepatitis C virus is a small (10-kb). single-stranded RNA virus with a genomic organization that places it in the family Flaviviridae. The virus is global in distribution. with a prevalence between 0.3% and 1.5%. The same agent causes parenterally acquired and sporadic non-A. non-B hepatitis. Nonparenteral modes of spread are poorly defined. but low-level sexual transmission is probable. There is a strong association between the presence of antibody to HCV (anti-HCV) and hepatocellular carcinoma; a causal role for HCV is suspected but has not been proved. Hepatitis C virus accounts for at least 85% of the cases of transfusion-associated hepatitis; an anti-HCV-reactive donor was retrospectively identified in nearly 90% of cases. Among donors confirmed by recombinant immunoblot assay (RIBA) to be anti-HCV positive. 80% to 90% are infectious. Hepatitis C virus RNA can be detected within 1 to 2 weeks of exposure and persists throughout the course of infection. Generally. the presence of anti-HCV cannot be confirmed until 9 to 20 weeks after exposure. creating a window period of seronegativity and potential infectivity. It is anticipated that the anti-HCV assay will reduce the number of cases of transfusion-associated hepatitis by 50% in the United States; a 70% reduction has been documented in Spain.
Shedding of the soluble form of the CD8 complex by CD8+/HLA-DR+ cells in HIV-1-infected patients, High levels of the soluble form of the CD8 molecule (sCD8) are detectable in the serum of HIV-1-infected patients. To investigate the mechanisms accountable for the release of this molecule we evaluated the presence of sCD8 in the supernatants obtained from in vitro cultures of highly purified CD8 cells isolated from 20 HIV-1-infected patients. At resting conditions cultured CD8 cells from HIV-1-infected patients released low amounts of sCD8; no statistically significant differences were observed between unstimulated cultures from HIV-1-seropositive patients and from HIV-1-seronegative subjects at risk for HIV-1 infection or normal healthy controls. Following in vitro activation of highly purified CD8 cells with a series of stimulatory agents. including phorbol myristate acetate. phytohemagglutinin (PHA) and recombinant interleukin-2. CD8 cells of HIV-1-infected patients significantly increased the shedding of sCD8. By expressing the results of activation-related release index (ARRI = sCD8 levels detected in the cultures with stimulatory agent/sCD8 levels detected in the unstimulated cultures). significantly higher values were observed upon PHA stimulation in HIV-1-infected patients than in control subjects. In order to identify the cell subset responsible for the enhanced release of sCD8 by PHA-stimulated cultures. we correlated the amounts of sCD8 detected in the supernatants with the phenotypic profile of CD8+ cells recovered from the cultures. A significant relationship was demonstrated between the percentage of CD8+/HLA-DR+ lymphocytes and sCD8 levels.
B-cell activation during HIV-1 infection. III. Down-regulating effect of mitogens, Spontaneous in vitro production of HIV-1-specific antibodies. a hallmark of infected subjects. is often down-regulated by the addition of pokeweed mitogen. We observed that a decrease in such ongoing anti-HIV-1 antibody synthesis could also be induced in cultures from most patients by addition of phytohemagglutinin and Concanavalin A. but not by Epstein-Barr virus. a selective B-cell mitogen. In most cases. this down-regulatory effect of mitogens was evident within the first 24 h of culture. The observed mitogen-associated decrease in spontaneous antibody synthesis was prevented by treating peripheral blood mononuclear cells with agents inhibiting non-major histocompatibility complex-restricted cytotoxic activity or by adding third-party cells to the cultures. In most cases. the mitogen-induced effect was also counteracted by removal of T lymphocytes or CD8+ T-cell sub-population. These findings recall a similar phenomenon observed in normal subjects following intentional immunization. and indicate that mitogen-induced down-regulation of spontaneous in vitro anti-HIV-1-antibody production most probably occurs through a lectin-dependent cytotoxic effect on activated B cells.
Occupational allergic contact dermatitis caused by nitroglycerin, Irritant contact dermatitis caused by occupational contact with nitroglycerin has been known since the end of the last century. Nitroglycerin is an allergen. and the transdermal drug delivery systems for nitroglycerin recently used to treat angina pectoris have sensitized. 4 patients with allergic contact dermatitis caused by nitroglycerin from explosives are described. and 1 patient who was sensitized by transdermal nitroplaster. On patch testing. dynamite and/or the explosive components nitroglycerin. ethylene glycol dinitrate and dinitrotoluene gave allergic reactions. The following concentrations and vehicles are suggested for patch testing: nitroglycerin 0.5-2% pet.. dinitrotoluene and ethylene glycol dinitrate 0.1-0.5% pet. Persons exposed to nitroglycerin at work should try to avoid skin contact by using protective gloves. It is advisable that those who have become allergic to nitroglycerin should wear disposable protective gloves when handling explosives.
Low serum levels of alpha-interferon, gamma-interferon, and interleukin-2 in alcoholic cirrhosis, The existence of cellular immune deficit in alcoholic cirrhosis. together with the role of alpha- and gamma-interferon and interleukin-2 in the immune system. led us to compare serum levels of these immune system mediators in a group of 40 patients with alcoholic cirrhosis classified according to Child-Pugh's grade of severity of liver disease and 23 healthy volunteers. Serum levels of alpha-IFN. gamma-IFN. and IL-2 were significantly depressed in alcoholic cirrhotics. with no significant differences between the different degrees of hepatic damage. The results suggest a profound alteration in the immune system of alcoholic cirrhotics. which may contribute to the development of the disease and the accompanying immune system deficit.
Randomized, double-blind, placebo-controlled trial of eight-week course of recombinant alpha-interferon for chronic non-A, non-B hepatitis, Forty-nine Japanese patients were enrolled in a randomized. placebo-controlled. double-blind trial of alpha-interferon for chronic non-A. non-B hepatitis: 24 patients received 3 million units of recombinant human alpha alpha-interferon (alpha-2a) thrice weekly for eight weeks. and 25 patients received placebo in a similar schedule. The mean serum alanine aminotransferase (ALT) dropped from 155 +/- 91 (SD) to 69 +/- 72 during interferon treatment. but remained unchanged (158 +/- 140 to 147 +/- 130) during placebo treatment (P less than 0.001). Serum ALT level fell to the normal range in 29% of interferon-treated patients. but in only 4% of placebo-treated patients. Pre- and posttreatment liver biopsies were obtained in all but one case. Average histological activity indices (HAI) were markedly improved in the interferon-treated group (9.5 +/- 3.7 to 7.0 +/- 4.3). but were unchanged in the placebo group (8.5 +/- 4.3 to 8.5 +/- 4.9). In addition. we compared the efficacy of interferon treatment between anti-hepatitis C virus (HCV) antibody positive and negative groups. Biochemical and histological improvements were similar and statistically significant in patients with and without antibody to hepatitis C virus. These data indicate that a eight-week course of alpha-interferon induces biochemical and histological improvement in more than half the patients with chronic non-A. non-B hepatitis.
Pituitary hormone response to thyrotropin-releasing hormone in secondary amenorrheic women associated with simple weight loss, OBJECTIVE: To investigate endocrine dysfunction in simple weight loss amenorrhea. DESIGN: We studied pituitary hormone responses to thyrotropin-releasing hormone (TRH) in 10 women with simple weight loss amenorrhea. SETTING: Department of Obstetrics and Gynecology. University Hospital. University of Tokushima at Tokushima. Japan. PATIENTS. PARTICIPANTS: Secondary amenorrheic women associated with simple weight loss who did not have anorexia nervosa. INTERVENTIONS: Intravenous injection of 500 micrograms of synthetic TRH. MAIN OUTCOME MEASURE: Serum levels of luteinizing hormone (LH). follicle-stimulating hormone (FSH). thyrotropin. and prolactin were measured before and 15. 30. and 60 minutes after TRH injection. RESULTS: In normally menstruating women on day 7 of the cycle TRH did not affect serum LH and FSH levels. In women with simple weight loss amenorrhea. however. TRH raised serum LH and FSH levels significantly (P less than 0.01. respectively). Prolactin response to TRH was significantly (P less than 0.05) lower in women with simple weight loss amenorrhea than in normally menstruating women. CONCLUSIONS: These results indicate that TRH causes a significant rise in serum LH and FSH and the impaired prolactin response in women with simple weight loss amenorrhea.
Thrombolytic therapy: then and now, Although thrombolytic agents were discovered nearly 60 years ago. it is only within the past decade that the clinical use of these agents has revolutionized the treatment of acute myocardial infarction. There are four currently available agents approved for use in treatment of myocardial infarction: streptokinase. urokinase. tissue plasminogen activator. and anistreplase. Although each of these agents works in a unique fashion. the common end point of therapy is the dissolution of a fibrin clot by the conversion of plasminogen to plasmin. A number of clinically measurable end points have been used to determine the effectiveness of these agents in the treatment of acute myocardial infarction. including mortality. reperfusion. patency. left ventricular function. left ventricular volumes. and quantitative creatine kinase isoenzyme analysis. Secondary end points have included bleeding and stroke. as well as recurrent ischemic events. Numerous clinical studies have demonstrated the effectiveness of all of these agents in achieving the desired end points and comparative studies. including several large-scale trials. have failed to differentiate among these agents with regard to efficacy. Newer dosing regimens for currently available thrombolytic agents. as well as new thrombolytic agents. are currently under active investigation and will be the subject of intense research over the next few years. Despite the lack of consensus as to which agent is superior. it is clear that thrombolytic therapy for acute myocardial infarction is the treatment of choice.
Effects of antiarrhythmic drugs on canine atrial flutter due to reentry: role of prolongation of refractory period and depression of conduction to excitable gap, Antiarrhythmic drugs prolong the effective refractory period and depress conduction. To determine the exact role played by these two electrophysiologic effects in the termination of reentry. the effects of disopyramide. flecainide. propafenone and E-4031. a new class III drug. were examined in a canine model of atrial flutter (cycle length 120 +/- 4 to 131 +/- 3 ms) caused by reentry. Atrial flutter was induced in 32 anesthetized open chest dogs after placement of an intercaval crush. The excitable gap ranged from 9 +/- 2% to 11 +/- 4% of the basic flutter cycle length. The effective refractory period in the reentrant circuit during atrial flutter was estimated by subtracting the excitable gap from the basic flutter cycle length. Prolongation of flutter cycle length by the test drugs was proportional to the interatrial conduction time (r = 0.87. p less than 0.001). Atrial flutter was terminated by each test drug in all dogs except for flecainide and propafenone in one dog each. E-4031 prolonged the refractory period during atrial flutter to 129 +/- 6 ms. which did not differ significantly from the flutter cycle length immediately before termination (134 +/- 4 ms). The refractory period during atrial flutter after injection of the other drugs was shorter than the flutter cycle length before termination of atrial flutter (for example. flecainide 126 +/- 5 vs. 179 +/- 11 ms. p less than 0.01).
Augmentation of cellular immune function during the early phase of zidovudine treatment of AIDS patients, Twenty-five patients with AIDS in AIDS Clinical Trials Group Protocol 002 were treated with either low or high dosages of zidovudine. This resulted in moderate. transient increases by 10 and 20 weeks in lymphocyte blastogenesis and interferon-gamma (IFN-gamma) production in vitro in response to phytohemagglutinin with and without recombinant interleukin-2. Immune responses to cytomegalovirus and herpes simplex virus type 1 antigens were augmented less frequently during therapy. Natural killer (NK) cell lysis of uninfected and human immunodeficiency virus-infected cells was also transiently increased by 10 and 20 weeks. IFN-gamma production. the only immune parameter directly associated with increases in numbers of CD4+ T cells. peaked at 10 weeks of treatment. The limited efficacy of zidovudine treatment in AIDS patients is associated with moderate. temporary increases in nonspecific and herpesvirus-specific T lymphocyte responses and NK cell function.
Testicular function in active ankylosing spondylitis. Therapeutic response to human chorionic gonadotrophin, Testicular function was studied in 22 patients with ankylosing spondylitis (AS) with serum measurements of hormone levels. seminal fluid analysis and testicular reserve test. Results were correlated with disease activity. The abnormal findings were elevated luteinizing hormone (LH). inversion of estradiol/testosterone ratio (E2:T) and diminished testicular reserve for testosterone (T) and slightly increased for estradiol (E2). Nine patients with severe active AS received biweekly 2.500 IU of human chorionic gonadotrophin injections with a resulting increase in E2 serum levels. When the values of E2 reached 40 pg/ml or higher. there was a decrease of the sedimentation rate (p less than 0.05) and a reversal to normal of the E2:T ratio. This was accompanied by an improvement in AS at the 10th week that lasted up to 9 weeks after discontinuation of treatment. Our findings suggest a possible role of sex hormones in the physiopathogenesis of AS and offers a possible therapeutic alternative.
Stimulation of protein, RNA, and nucleotide synthesis in lymphocytes after abdominal surgery is not affected by postoperative amino acid supply, The effects of abdominal surgery on protein. RNA. and de novo purine nucleotide synthesis in lymphocytes. and modification of these changes by postoperative amino acid supply. were investigated in 24 patients undergoing cholecystectomy (n = 12) or removal of gastric cancer (n = 12). Mono-nuclear cells were isolated from the peripheral venous blood and incubated with radioactive tracers in vitro. Protein and RNA synthesis. as measured using [14C] glycine and [3H]uridine. respectively. increased postoperatively. Nucleotide synthesis determined by the incorporation of radioactivity from [14C] glycine into nucleotides increased simultaneously. The concentration of 5-phosphoribosyl 1-pyrophosphate (PRPP) estimated by the incorporation of [14C]adenine into nucleotides also increased. These changes were greater and of longer duration in patients with cancer operation than in those with cholecystectomy. In neither case were they affected by the amount of amino acid intake. or increases in energy intake. These results suggest that abdominal surgery stimulates protein and ribonucleic acid (RNA) synthesis in lymphocytes. Increased RNA synthesis may be ensured by increased synthesis of nucleotides. and increased PRPP concentrations appear to regulate the rate of nucleotide synthesis. The responses are apparently dependent upon the severity of surgery. but unrelated to the amount of amino acid supplied postoperatively.
Effects of immediate postoperative enteral nutrition on body composition, muscle function, and wound healing, Thirty-two patients undergoing bowel resection were randomized to receive either immediate postoperative nasojejunal feeding with full strength Osmolite solution for 56 hours (n = 16) or routine postoperative hypocaloric fluids and gradual reintroduction of diet (n = 16). Body composition changes were measured at 14 days after operation with in vivo neutron activation analysis. the wound healing response by subcutaneous implantation of Gortex tubes. and muscle function by grip strength. maximum ventilatory volume. and stimulation of the ulnar nerve at the wrist. Postoperative fatigue up to 3 months after operation was assessed using a 10-point analogue. Successful immediate enteral nutrition was established in 12 of the 16 patients. Enterally fed patients had a mean daily caloric intake of 1179 +/- 388 kcal/d (mean +/- SD) over the first 4 postoperative days compared with 382 +/- 71 kcal/d for the controls (p less than 0.0001). The amount of hydroxyproline accumulating in the Gortex tubes was also significantly greater (2.5 +/- 1.1 nmol/g tube vs 1.5 +/- 0.8 nmol/g tube; p less than 0.02). However. the amount and composition of the weight lost was not significantly different. Muscle function was not preserved. and postoperative fatigue occurred to an equal extent in both groups. Complications were similar in both groups. except for a preponderance of bowel obstructions in the controls. The time to passage of first flatus and first bowel motion. although shorter in the fed group. did not reach significance (p = 0.07). We conclude that immediate enteral nutrition is feasible and results in an improved wound healing response.
Prospective randomized evaluation of two regimens for converting from continuous to intermittent feedings in patients with feeding gastrostomies, Forty enterally fed male patients were randomized to one of two regimens designed to determine the better means of converting them from continuous to intermittent enteral feedings. All patients received a nutritionally complete iso-osmolal 1 kcal/cc formula containing 6 g of nitrogen/L beginning on the second postgastrostomy day. Half of the patients (20) were randomized to a discontinuous regimen abruptly changing from continuous to gradually increasing intermittent feedings until reaching their nutritional goals. Intravenous fluids were given to maintain normal fluid balance. The other 20 patients were randomized to an overlapping regimen. receiving continuous feedings at a decreasing rate while intermittent feedings were progressively increased. Intravenous fluids were used during the first three stages only. There were no significant differences (p less than 0.05) in major diagnosis. type of gastrostomy. age. weight. height. admission or discharge serum albumin concentration. calculated basal energy expenditure (BEE). or nutrient goals (1.5 X BEE. 1.5 g of protein/kg per day).
Effects of enteral fat emulsion on fat absorption in obstructive jaundiced rats, The effects of fat emulsion given enterally on fat absorption were studied with obstructive jaundiced rats (J group) as compared with jaundice-free rats (C group). The J and C groups were subdivided into JE and CE groups using emulsified fat for the fat absorption test. and JU and CU groups using unemulsified fat. Rats in all groups were fed for 7 days with regular rat chow. After fasting for 12 hours. 14C-labeled fat emulsion was infused to the JE and CE. and 14C-labeled unemulsified fat to the JU and CU groups through a gastrostomy for the absorption test. The hourly and cumulative output of 14CO2 by respiration. absorption rate of 14C-labeled fat in the intestine. and metabolic oxidation rate of the absorbed fat were determined during an 8-hour period after the gastroenteral administration of emulsified or unemulsified fat. The peak of hourly output was seen after the first 2 hours in the CE. JE. and CU groups. following which a remarkable decline was seen in the CE and CU groups. However. a more gentle descent in the JE. and fluctuation at a low level in the JU group were observed. The cumulative output in the JE was 61% of that in the CE. while the output in the JU was 16% of that in the CU group. The absorption rate in the JE was 81% of that in the CE group. while the rate in the JU was 22% of that in the Cu group.
Survival in septic guinea pigs is influenced by vitamin E, but not by vitamin C in enteral diets, Oxygen-free radicals are produced during sepsis. and may contribute to cell injury and dysfunction. We studied the effect of different levels of vitamins E and C in the diet fed enterally to septic guinea pigs. Sixty-four female guinea pigs were provided with gastrostomies and allowed to recover. Intraperitoneal osmotic pumps were then implanted that provided effusion of Escherichia coli and Staphylococcus aureus for the next 7 days. Three days after pump implantations. the animals were started on one of nine diets. The diets were isocaloric and isonitrogenous. and differed only in the amounts of vitamins E and C. Three levels of each vitamin were used. based on the Recommended Daily Allowance (RDA). The feedings were continued for 2 weeks. during which time mortality was observed. The amount of vitamin C had no effect on outcome. with mortality rates of 68% (15/22) in the 1 x RDA group. 73% (16/22) in the 5 x RDA group. and 65% (13/20) in the 25 x RDA group. However. vitamin E altered outcome significantly. with mortality rates of 86% (18/21) in the 1 x RDA group. 45% (10/22) in the 3 x RDA group. and 76% (16/21) in the 9 x RDA group. Mortality in the 3 x RDA group was significantly lower than that in the 1 x RDA group and in the 9 x RDA group.
Effect of total parenteral nutrition with xylitol on protein and energy metabolism in thermally injured rats, The use of xylitol as an alternative carbohydrate calorie source in total parenteral nutrition may offer unique pharmacologic and nutritional properties in the therapy of the thermally injured. Male Sprague-Dawley rats (250 g) received a 15-second dorsal scald injury (25-30% BSA) and were parenterally fed isovolemic diets (60 ml/day) that provided 200 kcal/kg/d. 9.68 g of amino acids/kg/d. and 23.5% nonprotein calories (NPC) as fat for 3 days. The balance of NPC were provided as dextrose (Dex) or 50% xylitol:50% dextrose (Xyl/Dex). Rectus muscle and liver fractional protein synthetic rates (FSR. %/day). whole body leucine appearance (Flux). oxidation (OX). protein breakdown (PB). and synthesis (PS) were estimated using a 4-hour iv infusion of [1-14C]leucine on day 3. Mean values (+/- SE) for leucine kinetics (mumol leucine/hr/100 g). cumulative nitrogen balance (mg N) and plasma insulin concentration (Table I). (microU/mL). The partial replacement of dextrose calories with xylitol did not significantly alter whole body and tissue leucine kinetics. daily and cumulative nitrogen balance. insulin concentration. and energy expenditure (indirect calorimetry). These data indicate that xylitol may be useful as an alternative carbohydrate calorie source in parenteral nutrition to avoid possible deleterious side effects of glucose overfeeding in the critically ill but did not improve protein metabolism under the conditions of this study.
Septicemia caused by contaminated parenteral nutrition pouches: the refrigerator as an unusual cause, Eleven patients in a hospital presented with septicemia caused by Enterobacter cloacae. The origin was the contamination of parenteral nutrition admixture from a resting place in the refrigerator of the parenteral mixture preparation room.
Differential gene expression in the recovery from ischemic renal injury, Recovery from renal ischemia requires regeneration of damaged tubular epithelium. Previous studies have examined the expression of proto-oncogenes and growth factors after ischemia. but the response of genes coding for structural and functional genes has not been scrutinized. Rats were subjected to 40 minutes of renal artery occlusion and 60 minutes to 96 hours of reperfusion. Total RNA was isolated and mRNA for the structural protein actin. the enzymes superoxide dismutase and renin. the proto-oncogene c-fos. the nuclear protein histone H2b. and the putative marker for cell injury TRPM-2 was quantitated by Northern hybridization. Expression of the proto-oncogene c-fos was seen early but for only short duration. Histone gene expression was not markedly increased until 24 hours after ischemia. but remained increased for several days. Renin mRNA was undetectable one hour after ischemia. but was present in normal amounts at 24 and 48 hours. In contrast. superoxide dismutase mRNA was present in decreased amounts 24. 48. and 96 hours after ischemia. TRPM-2 gene expression was greatly increased 24 to 72 hours after ischemia and began decreasing at 96 hours. This selective sequence of gene expression or repression after renal ischemia might maximize the proliferative repair process. This information will be useful for designing therapies to further enhance recovery from acute renal injury.
Urinary procoagulant and fibrinolytic activity in human glomerulonephritis. Relationship with renal function, Fibrin deposition in kidney is a common event in some forms of human and experimental glomerulonephritis. and is thought to result from local activation of blood coagulation and/or impaired removal by the fibrinolytic system. We studied the urinary procoagulant and fibrinolytic activities in 46 patients with renal disease (26 with IgA nephritis. 13 with other forms of glomerulonephritis and 7 with non-inflammatory kidney disease) and in 15 matched healthy subjects. as possible indicators of the coagulation-fibrinolysis balance in kidney. Procoagulant activity was slightly but not significantly increased in patients with serum creatinine levels higher than 1.5 mg/dl (group II) as compared with patients with normal creatinine (group I) and controls. It was identified as tissue factor by biological criteria (dependence on factor VII). Fibrinolysis studies showed that both plasminogen activator activity and urokinase antigen were significantly lower in group II than in group I patients and controls (P less than 0.0005). Reduced fibrinolytic activity in patients' urine was due to decreased excretion of urokinase since no inhibitor was detected by both fibrin autography and functional assay. No differences were found between patients and controls in plasma fibrinolytic activity. plasminogen activator inhibitor. and procoagulant activity of blood monocytes. The urinary changes in severe renal disease may reflect an unbalance of the coagulation-fibrinolysis equilibrium in kidney and might be of pathogenetic and clinical relevance.
Comparison of four laser types for experimental pain stimulation on oral mucosa and hairy skin, The use of different lasers for stimulation in human experimental pain research has provided a sensitive method for evaluation of thin nerve fiber functions. In this study. sensory and pain thresholds were compared to argon-. copper vapour-. Nd:YAG-. and CO2 laser stimulation on hairy skin and on oral mucosa. The influence on thresholds with respect to laser type. stimulation site. surface colour. and stimulus parameters (laser beam diameter and pulse duration) was investigated. Significant differences in thresholds between the four lasers were found on both surfaces; however. no significant differences existed between thresholds on the skin and on the tongue when the same laser was used. The observations imply that wavelength-dependent optical properties of the stimulated tissue influence on threshold determinations. Furthermore. the results indicate that temporal and spatial summation mechanisms may exist for laser induced warmth and pain perceptions. Laser stimulation may be a new tool for the investigation of origin and genesis of various orofacial pain syndromes.
Nd:YAG laser hyperthermia treatment of rat mammary adenocarcinoma in conjunction with surface cooling, Electromagnetic radiation ranging from radiofrequency to microwave has classically been used to induce hyperthermia for treatment of cancer. This paper presents a new technique using near infrared radiation from an Nd:YAG laser in conjunction with surface cooling to induce hyperthermia in a rat tumor model. A CW Nd:YAG laser hyperthermia system was used to induce hyperthermic temperatures in chemically (DMBA) induced rat mammary adenocarcinomas. The laser was interfaced to a computer and a thermometry unit that provided feedback to control the tumor temperature between 43.2-43.5 degrees C. A thermocouple was placed at the base of the tumor and its temperature was used to control laser exposure. All tumors were 10 to 20 mm in diameter. Surface cooling methods investigated included forced air flow from a fan. forced oxygen flow plus an IV drip. and forced moist oxygen flow from a nebulizer. Twelve rat mammary adenocarcinomas have been treated with Nd:YAG laser hyperthermia. In 4 treatments. no surface cooling was employed. In one treatment the surface was cooled using oxygen flow plus IV drip. In 7 treatments the skin was cooled using the nebulizer technique. The nebulization provided the most effective and reproducible surface cooling. Nd:YAG laser hyperthermia delivered in conjunction with nebulizer surface cooling produced efficient heating of rat mammary adenocarcinomas. A mean temperature of 42.1 degrees C was obtained at the base of the tumors while the mean surface temperature was 37.0 degrees C.
Nosocomial infection and pseudoinfection from contaminated endoscopes and bronchoscopes--Wisconsin and Missouri, Flexible fiber-optic endoscopes are widely used in the United States for diagnostic and therapeutic procedures. Between uses. endoscopes should be cleaned and disinfected either manually or by using automated machines. However. outbreaks have occurred among patients exposed to contaminated endoscopes or to inadequately disinfected bronchoscopes (1-4). This report summarizes one outbreak of nosocomially acquired infection (Wisconsin) and one of pseudoinfection (Missouri) linked to endoscopes contaminated during cleaning and disinfection by automated reprocessing machines.
Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI, Epidemiological surveys have identified a strong inverse relationship between the amount in the plasma of high density lipoproteins (HDL). apolipoprotein AI (ApoA-I). the major protein component of HDL. and the risk for atherosclerosis in humans. It is not known if this relationship arises from a direct antiatherogenic effect of these plasma components or if it is the result of other factors also associated with increases in ApoA-I and HDL levels. Because some strains of mice are susceptible to diet-induced formation of preatherosclerotic fatty streak lesions. and because of available techniques for the genetic manipulation of this organism. the murine system offers a unique setting in which to investigate the process of early atherogenesis. To test the hypothesis that induction of a high plasma concentration of ApoA-I and HDL would inhibit this process. we studied the effects of atherogenic diets on transgenic mice expressing high amounts of human ApoA-I. We report that transgenic mice with high plasma ApoA-I and HDL levels were significantly protected from the development of fatty streak lesions.
In vitro activity of CD4+ and CD8+ T lymphocytes from mice immunized with a synthetic malaria peptide, In previous work. a T-helper epitope was mapped within the circumsporozoite protein of the murine malaria parasite Plasmodium yoelii. A 21-mer synthetic peptide corresponding to this epitope (amino acid positions 59-79; referred to as Py1) induced a specific T-cell proliferation in BALB/c and C57BL/6 mice and provided help for the production of antibodies to peptides from the repetitive region. (Gln-Gly-Pro-Gly-Ala-Pro)n. of the P. yoelii circumsporozoite protein when mice were immunized with the Py1 peptide conjugated to the repetitive peptide. Experiments were then designed to study the in vitro antiparasite efficacy of T cells elicited in vivo by peptide immunization. T-cell activity was evaluated on cultured hepatic stages of P. yoelii. Peptide immunizations led to the preferential activation of CD8+ T cells in BALB/c mice and of both CD4+ and CD8+ T cells in C57BL/6 mice. Parasite elimination was mediated directly by these cells and did not seem to be dependent on lymphokine secretion. These data suggest that peptide-primed CD4+ T cells as well as CD8+ T cells could be cytolytic for the hepatic phase of malaria parasites. The fact that the same peptide could activate different lymphocyte populations. depending on the strain of mouse. highlights the importance of a better understanding of the fine mechanisms behind the immune responses to synthetic peptides being tested for malaria vaccine development.
Binding of thymic factors to the conserved decanucleotide promoter element of the T-cell receptor V beta gene is developmentally regulated and is absent in SCID mice, The gene segments encoding the beta chain of the T-cell antigen receptor undergo rearrangement in a precise developmental order: a D beta gene segment joins to a J beta gene segment prior to the rearrangement of a V beta gene segment to join the D/J beta fusion. Current evidence suggests that the rearrangement of V beta is restricted to T cells. whereas D-to-J beta rearrangements may occur in both B and T cells. Thus. the T-cell specificity seems to be regulated by the V beta coding region or its 5' flanking sequence. In support of this hypothesis. evidence is provided for thymus-specific factors that bind a highly conserved 10-base-pair (decamer) sequence that is an essential promoter element in mouse and human V beta genes. The presence of decamer-binding activities was assayed by gel mobility-shift analysis using protein extracts from thymus. spleen. and nonlymphoid organs of adult mice. Two shifted complexes. designated T2 and T3. were seen only when the decamer was incubated with extracts from thymus. When extracts from mice of various gestational ages were tested for decamer-binding activity. one of the thymus-specific complexes. T2. was first detected at day 16; this coincides with the time of initial activation of the V beta locus. No decamer-binding activity was detected in extracts prepared from the thymuses of SCID (severe combined immunodeficiency) mice. which characteristically fail to rearrange these genes. Moreover. neither T2 nor T3 was detectable with extracts from spleen or from two T-cell lines that express the beta chain; this suggests that the presence of these two complexes is not absolutely required for transcription of the T-cell receptor beta locus. We conclude that there are tissue-specific and developmentally regulated factors that form complexes with the decamer sequence 5' of V beta; these may represent initiation factors that control the activation of germ-line T-cell receptor V beta genes for transcription and/or rearrangement.
Requiring formal training in preventive health practices for child day care providers, The study was a test of the feasibility of mandating training in preventive health practices for child day care providers in California. Three approaches were taken to determining the feasibility of mandatory training. They were (a) to identify persons and groups with the capability to provide training. (b) to identify systems and networks for communication and collaboration on health issues related to day care at the local level. and (c) to determine the child day care providers' concerns. needs. and future interests regarding child health. Information was collected on relevant courses offered by universities. colleges. and adult education programs; on training offered by child health authorities; and on formal curriculums offered by local and national sources. Day care center and family day care home providers were surveyed to determine their knowledge of child health issues. their concerns. and their future needs. The providers surveyed cared for a total of 14.340 children. Information on local networks was obtained from the surveys. from interviews. and from a special task force that had been set up to advise the State legislature. Study results supported the conclusion that a coordinated system of State-wide training was feasible. given the existing networks of training and educational resources. the number of day care providers who had already been motivated to seek some training in child health practices. and the almost unanimous interest among day care providers in obtaining training. Mandating training in child health for day care providers will require a commitment in the form of new legislation outlining basic requirements and allocating funding. The implementation and costs of such a mandate at the State and local level are discussed.
Evaluating South Carolina's community cardiovascular disease prevention project, A community cardiovascular disease prevention program was undertaken as a cooperative effort of the South Carolina Department of Health and Environmental Control and the Centers for Disease Control of the Public Health Service. As part of the evaluation of the project. a large scale community health survey was conducted by the State and Federal agencies. The successful design and implementation of the survey. which included telephone and in-home interviews as well as clinical assessments of participants. is described. Interview response rates were adequate. although physical assessments were completed on only 61 percent of those interviewed. Households without telephones were difficult and costly to identify. and young adults were difficult to locate for survey participation. The survey produced baseline data for program planning and for measuring the success of ongoing intervention efforts. Survey data also have been used to estimate the prevalence of selected cardiovascular disease risk factors.
Association between exercise and other preventive health behaviors among diabetics, Two hundred and seventy patients were studied to investigate the cross sectional association between exercise and other preventive health behaviors in a diabetic population. Patients included both insulin and noninsulin dependent diabetics and were recruited from the Family Practice and Pediatrics Clinics at Bowman Gray School of Medicine. During screening. patients underwent a physical examination as well as completing a survey to assess exercise and health behavior habits. Three exercise groups were compared: (a) patients who expended more than 600 kilocalories per week during exercise. (b) patients who expended 600 kilocalories or less. and (c) patients who did not exercise. The mean body weights of both exercise groups were found to be less than the nonexercise group. and the heavy exercise group also had a lower mean body mass index. Heavy exercisers reported greater caloric intakes than both moderate and nonexercisers. There were no differences found concerning the composition of their diets among groups. The heavy exercise group reported wearing their seatbelts a greater percentage of the time and visited the dentist more often compared with the sedentary group. There were no significant differences found among exercise groups concerning blood sugar monitoring. alcohol consumption. smoking. or in obtaining periodic health examinations. It was concluded that exercise was associated with several. but not a majority. of other healthful behaviors in a population of diabetics.
Minerals in hair, serum, and urine of healthy and anemic black children, Hair mineral analysis can be used as a reliable screening test for heavy metals. but it is not an established method for defining nutritional and disease states. Wide variation in test results is a major problem in utilizing the technique for clinical purposes. Better reference values are needed. especially for children. as well as information about how hair mineral values correlate with body fluid values. A total of 48 black children were studied. Of these. 20 were normal children. ages 1 to 17; 12 were normal infants. ages 5 weeks to 12 months; 3 were children with iron overload; 7 had iron deficiency anemia; and 6 had thalassemia trait. There were in all 17 boys and 31 girls. The distribution of 15 minerals in hair. serum. and urine samples was determined by energy dispersive X-ray fluorescence. Mineral concentrations from the normal children were compared with concentrations obtained from the children with iron overload. iron deficiency anemia. and thalassemia trait. Statistical analysis revealed no significant differences among any of the groups. Mineral concentrations from the normal infants and children may be useful as reference values. The analysis of hair iron as a valid screening test for body iron status in children is not supported by our data.
Reporting of communicable diseases by university physicians, Billing records from the outpatient clinics of the University of Arizona were compared to case reports of communicable diseases received by the local health department. Of 286 cases of reportable diseases found. 183 (64 percent) were reported to the local health department. Sexually transmitted diseases were more likely to be reported than other diseases [risk ratio (RR) = 1.97; 95 percent confidence interval (CI). 1.62-2.39]. Diseases of residents of Pima County were more likely to be reported than those of residents of other Arizona counties (RR = 1.40; 95 percent CI. 1.11-1.77). and diseases in Arizona residents were more likely to be reported than those of residents of other States (RR = 2.37; 95 percent CI. 1.35-4.15). Diseases of citizens of other countries were never reported. The only significant difference found among the specialty clinics of the medical center was that pediatricians reported less frequently than others (RR = 0.75; 95 percent CI. 0.58-0.98).
Drug use and sexual behavior of indigent African American men, A total of 108 African American men in a free lunch program with histories of drug abuse were surveyed to determine the relationships among drug use. sexual activity. AIDS prevention practices. and perceived risk of AIDS. Of the 108. 69.5 percent were homeless and only 12 percent were currently receiving drug abuse treatment. More than half of the participants had injected drugs. and 38 percent had shared needles. Among the 80 percent who were sexually active. 40 percent reported using condoms every time they had sex. Respondents in monogamous relationships tended to use condoms less frequently. Those who shared needles were more likely to have sex with IV drug users and had more sexual partners. Respondents who used crack used condoms less frequently. Those with multiple partners were more likely to engage in anal intercourse. Three-quarters perceived themselves at risk of AIDS.
Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice, The maturation of T cells in the thymus is dependent on the expression of major histocompatibility complex (MHC) molecules. By disruption of the MHC class II Ab beta gene in embryonic stem cells. mice were generated that lack cell surface expression of class II molecules. These MHC class II-deficient mice were depleted of mature CD4+ T cells and were deficient in cell-mediated immune responses. These results provide genetic evidence that class II molecules are required for the maturation and function of mature CD4+ T cells.
Resistance to ddI and sensitivity to AZT induced by a mutation in HIV-1 reverse transcriptase, Serial human immunodeficiency virus type-1 (HIV-1) isolates were obtained from five individuals with acquired immunodeficiency syndrome (AIDS) who changed therapy to 2'.3'-dideoxyinosine (ddI) after at least 12 months of treatment with 3'-azido-3'-deoxythymidine (zidovudine. AZT). The in vitro sensitivity to ddI decreased during the 12 months following ddI initiation. whereas AZT sensitivity increased. Analysis of the reverse transcriptase coding region revealed a mutation associated with reduced sensitivity to ddI. When this mutation was present in the same genome as a mutation known to confer AZT resistance. the isolates showed increased sensitivity to AZT. Analysis of HIV-1 variants confirmed that the ddI resistance mutation alone conferred ddI and 2'.3'-dideoxycytidine resistance. and suppressed the effect of the AZT resistance mutation. The use of combination therapy for HIV-1 disease may prevent drug-resistant isolates from emerging.
Lipid-lowering diets in patients taking pravastatin, a new HMG-CoA reductase inhibitor: compliance and adequacy, We examined seven 1-d diet records kept during 1 y by 272 men and women instructed to follow a lipid-lowering diet while participating in a clinical trial of pravastatin. a new 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The mean percentage of calories from total fat and saturated. unsaturated. and monounsaturated fatty acids was similar throughout the year even though the patients knew they were taking an effective lipid-lowering agent. However. the diets of greater than 40% of women included less than two-thirds of the recommended dietary allowance (RDA) of folic acid. vitamins B-6 and D. and calcium and zinc; in men. folic acid and zinc intakes were low. We conclude that patients comply with lipid-lowering diets even when they know that they are receiving an effective serum lipid-lowering agent. However. for both men and women special attention should be given to the intake of several nutrients.
Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators, We have cloned a member of the steroid hormone receptor superfamily of ligand-activated transcription factors. The receptor homologue is activated by a diverse class of rodent hepatocarcinogens that causes proliferation of peroxisomes. Identification of a peroxisome proliferator-activated receptor should help elucidate the mechanism of the hypolipidaemic effect of these hepatocarcinogens and aid evaluation of their potential carcinogenic risk to man.